PMID- 23916056 TI - Proteomic characterization of novel histone post-translational modifications. AB - Histone post-translational modifications (PTMs) have been linked to a variety of biological processes and disease states, thus making their characterization a critical field of study. In the last 5 years, a number of novel sites and types of modifications have been discovered, greatly expanding the histone code. Mass spectrometric methods are essential for finding and validating histone PTMs. Additionally, novel proteomic, genomic and chemical biology tools have been developed to probe PTM function. In this snapshot review, proteomic tools for PTM identification and characterization will be discussed and an overview of PTMs found in the last 5 years will be provided. PMID- 23916057 TI - Preoperative left ventricular internal dimension in end-diastole as earlier identification of early patent ductus arteriosus operation and postoperative intensive care in very low birth weight infants. AB - Patent ductus arteriosus (PDA) is common in premature infants. In very low birth weight infants (VLBWI), PDA requires surgical therapy in many cases. It is unclear to know at-risk infants showing cardio-dysfunction after PDA surgery. The purpose of this study was to identify at-risk infants showing cardio-dysfunction after surgery for patent ductus arteriosus (PDA). We examined the relationship between left ventricular (LV) performance before and after PDA ligation in a retrospective observational cohort study. We studied 64 preterm neonates with symptomatic PDA before and after surgical ligation. Echocardiographic examinations were performed pre- and postoperatively. M-mode measurements included left ventricular internal dimension in end-diastole (LVIDd) and LV fractional shortening (FS). All cases showed decreased LVFS after PDA closure. Most cases (49/64, 77%) showed postoperative FS decreased to below normal (<28%). Preoperative relative LVIDd was significantly larger in abnormal FS infants (137 +/- 18%) than in normal FS infants (118 +/- 11%; p<0.01). A cut-off value of preoperative relative LVIDd (absolute LVIDd/normal value) for predicting postoperative cardio-dysfunction was 127.4% (sensitivity, 0.735; specificity, 0.933; area under curve, 0.817). Determination of preoperative LVIDd might facilitate earlier identification of infants needing early PDA surgery and postoperative intensive care. PMID- 23916058 TI - Do spiritual patients want spiritual interventions?: A qualitative exploration of underserved cancer patients' perspectives on religion and spirituality. AB - OBJECTIVE: This study examines religion and spirituality among advanced cancer patients from an underserved, ethnically-diverse population by exploring patient conceptualizations of religion and spirituality, the role of religion and spirituality in coping with cancer, and patient interest in spiritual support. METHOD: Qualitative semi-structured interviews were conducted with patients who had participated in a study of a "mind-body" support group for patients with all cancer types. Analysis based on grounded theory was utilized to identify themes and theoretical constructs. RESULTS: With regard to patient conceptualizations of religion and spirituality, three categories emerged: (1) Spirituality is intertwined with organized religion; (2) Religion is one manifestation of the broader construct of spirituality; (3) Religion and spirituality are completely independent, with spirituality being desirable and religion not. Religion and spirituality played a central role in patients' coping with cancer, providing comfort, hope, and meaning. Patients diverged when it came to spiritual support, with some enthusiastic about interventions incorporating their spiritual values and others stating that they already get this support through religious communities. SIGNIFICANCE OF RESULTS: Spirituality plays a central role in the cancer experience of this underserved ethnically-diverse population. While spirituality seems to be a universal concern in advanced cancer patients, the meaning of spirituality differs across individuals, with some equating it with organized religion and others taking a more individualized approach. It is important that psychosocial interventions are developed to address this concern. Future research is needed to further explore the different ways that patients conceptualize spirituality and to develop spiritually-based treatments that are not "one size fits all." PMID- 23916059 TI - Resistance of beef cattle of two genetic groups to ectoparasites and gastrointestinal nematodes in the state of Sao Paulo, Brazil. AB - The resistance to infestations by ectoparasites and infections by gastrointestinal nematodes was studied in 45 animals (males and females) of two genetic groups: purebred Nelore (NI, n=28) and Three-Cross (1/2 Angus+1/4 Canchim+1/4 Nelore - TC, n=17). The animals were monitored for 24 months, during which they were left to graze in tropical pastures without receiving treatment for parasites. Each month the animals were examined for infestations by external parasites, to count the numbers of cattle ticks Rhipicephalus microplus with diameter greater than 4.5mm present on the left side, horn flies (Haematobia irritans) present in the lumbar region and botfly larvae (Dermatobia hominis) present on the entire body. The H. irritans counts were performed with the aid of digital photographs. At the time of examination, fecal samples were collected to count the eggs per gram (EPG) and to perform coprocultures, and peripheral blood samples were drawn to determine the packed cell volume (PCV) and to count the eosinophils. For statistical analysis, the count data were transformed into log10 (n+1), where n is the number of parasites. For PCV, significant effects (P<0.05) were found for collection month (CO), genetic group (GG) and gender (SX), with means and respective standard errors of 41.5 +/- 0.65% for the NI animals, 39.3 +/- 0.83% for the TC, 41.5 +/- 0.72% for the females and 39.3 +/- 0.77% for the males. Regarding the eosinophil counts, only the effect of sex was significant (P<0.01), with means and respective standard errors of 926.0 +/- 46.2/MUL, for males and 1088.0 +/- 43.8/MUL of blood, for females. The NI animals presented lower mean counts for all the external parasites compared to the TC animals (P<0.01). For ticks, the transformed means followed by standard errors for the NI and TC animals were 0.06 +/- 0.01 and 0.34 +/- 0.02, while for horn flies these were 0.92 +/- 0.05 and 1.36 +/- 0.06 and for botfly larvae they were 0.05 +/- 0.03 and 0.45 +/- 0.05, respectively. The average EPG values were only influenced by CO (P<0.01). The coprocultures revealed the presence of the following endoparasites: Haemonchus spp., Cooperia spp., Oesophagostomum spp. and Trichostrongylus spp., the last in smaller proportion. There were no significant differences between the genetic groups for the endoparasite loads, except for Cooperia spp., which were present in greater number (P<0.05) in the NI group. The results obtained in this experiment confirm previous findings of greater susceptibility of the Nelore breed to Cooperia spp. and high resistance to ectoparasites. PMID- 23916060 TI - Cryptosporidium suis and Cryptosporidium scrofarum in Eurasian wild boars (Sus scrofa) in Central Europe. AB - From 2011 to 2012, to identify Cryptosporidium spp. occurrence in Eurasian wild boars (Sus scrofa) 29 randomly selected localities (both forest areas and enclosures) across the Central European countries of Austria, the Czech Republic, Poland, and the Slovak Republic were investigated. Cryptosporidium oocysts were microscopicaly detected in 11 out of 460 faecal samples examined using aniline carbol-methyl violet staining. Sixty-one Cryptosporidium infections, including the 11 infections that were detected by microscopy, were detected using genus- or species-specific nested PCR amplification of SSU rDNA. This represents a 5.5 fold greater sensitivity for PCR relative to microscopy. Combining genus- and species specific PCR tools significantly changes the perspective on the occurrence of Cryptosporidium spp. in wild boars. While RFLP and direct sequencing of genus specific PCR-amplified products revealed 56 C. suis (20) and C. scrofarum (36) monoinfections and only 5 mixed infections of these species, species-specific molecular tools showed 44 monoinfections and 17 mixed infections with these species. PCR analysis of the gp60 gene did not reveal any other Cryptosporidium infections. Similar to domestic pigs, C. scrofarum was detected as a dominant species infecting adult Eurasian wild boars (Sus scrofa). Cryptosporidium infected wild boars did not show signs of clinical disease. This report is perhaps the most comprehensive survey of cryptosporidial infection in wild boars. PMID- 23916061 TI - Relationship of cognitive reserve and cerebrospinal fluid biomarkers to the emergence of clinical symptoms in preclinical Alzheimer's disease. AB - The levels of beta-amyloid (Abeta) and phosphorylated tau (p-tau), as measured in cerebrospinal fluid, have been associated with the risk of progressing from normal cognition to onset of clinical symptoms during preclinical Alzheimer's disease. We examined whether cognitive reserve (CR) modifies this association. Cerebrospinal fluid was obtained at baseline from 239 participants (mean age, 57.2 years) who had been followed for up to 17 years with clinical and cognitive assessments (mean follow-up, 8 years). A composite score based on the National Adult Reading Test, vocabulary, and years of education at baseline was used as an index of CR. Cox regression models showed that the increased risk of progressing from normal cognition to symptom onset was associated with lower CR, lower baseline Abeta, and higher baseline p-tau. There was no interaction between CR and Abeta, suggesting that the protective effects of higher CR are equivalent across the observed range of amyloid levels. In contrast, both tau and p-tau interacted with CR, indicating that CR was more protective at lower levels of tau and p-tau. PMID- 23916062 TI - Structural brain plasticity in Parkinson's disease induced by balance training. AB - We investigated morphometric brain changes in patients with Parkinson's disease (PD) that are associated with balance training. A total of 20 patients and 16 healthy matched controls learned a balance task over a period of 6 weeks. Balance testing and structural magnetic resonance imaging were performed before and after 2, 4, and 6 training weeks. Balance performance was re-evaluated after ~20 months. Balance training resulted in performance improvements in both groups. Voxel-based morphometry revealed learning-dependent gray matter changes in the left hippocampus in healthy controls. In PD patients, performance improvements were correlated with gray matter changes in the right anterior precuneus, left inferior parietal cortex, left ventral premotor cortex, bilateral anterior cingulate cortex, and left middle temporal gyrus. Furthermore, a TIME * GROUP interaction analysis revealed time-dependent gray matter changes in the right cerebellum. Our results highlight training-induced balance improvements in PD patients that may be associated with specific patterns of structural brain plasticity. In summary, we provide novel evidence for the capacity of the human brain to undergo learning-related structural plasticity even in a pathophysiological disease state such as in PD. PMID- 23916064 TI - Outbreak of Salmonella enterica serotype I 4,5,12:i:- infections: the challenges of hypothesis generation and microwave cooking. AB - We investigated an outbreak of 396 Salmonella enterica serotype I 4,5,12:i:- infections to determine the source. After 7 weeks of extensive hypothesis generation interviews, no refined hypothesis was formed. Nevertheless, a case control study was initiated. Subsequently, an iterative hypothesis-generation approach used by a single interviewing team identified brand A not-ready-to-eat frozen pot pies as a likely vehicle. The case-control study, modified to assess this new hypothesis, along with product testing indicated that the turkey variety of pot pies was responsible. Review of product labels identified inconsistent language regarding preparation, and the cooking instructions included undefined microwave wattage categories. Surveys found that most patients did not follow the product's cooking instructions and did not know their oven's wattage. The manufacturer voluntarily recalled pot pies and improved the product's cooking instructions. This investigation highlights the value of careful hypothesis generation and the risks posed by frozen not-ready-to-eat microwavable foods. PMID- 23916065 TI - Understanding communication among health care professionals regarding death and dying in pediatrics. AB - OBJECTIVE: Effective communication regarding death and dying in pediatrics is a vital component of any quality palliative care service. The goal of the current study is to understand communication among health care professionals regarding death and dying in children. The three hypotheses tested were: (1) hospital staff (physicians of all disciplines, nurses, and psychosocial clinicians) that utilize consultation services are more comfortable communicating about death and dying than those who do not use such services, (2) different disciplines of health care providers demonstrate varying levels of comfort communicating about a range of areas pertaining to death and dying, and (3) health care staff that have had some type of formal training in death and dying are more comfortable communicating about these issues. METHODS: A primary analysis of a survey conducted in a tertiary care teaching children's hospital. RESULTS: Health care professionals who felt comfortable discussing options for end of life care with colleagues also felt more comfortable: initiating a discussion regarding a child's impending death with his/her family (r = 0.42), discussing options for terminal care with a family (r = 0.58), discussing death with families from a variety of ethnic/cultural backgrounds (r = 0.51), guiding parents in developmentally age appropriate discussions of death with their children (r = 0.43), identifying and seeking advice from a professional role model regarding management concerns (r = 0.40), or interacting with a family following the death of a child (r = 0.51). Among all three disciplines, physicians were more likely to initiate discussions with regards to a child's impending death (F = 13.07; p = 0.007). Health care professionals that received formal grief and bereavement training were more comfortable discussing death. Significance of the results: The results demonstrated that consultation practices are associated with a higher level of comfort in discussing death and dying in pediatrics. PMID- 23916063 TI - Null association between abdominal muscle and calcified atherosclerosis in community-living persons without clinical cardiovascular disease: the multi ethnic study of atherosclerosis. AB - OBJECTIVE: Lean muscle loss has been hypothesized to explain J-shaped relationships of body mass index (BMI) with cardiovascular disease (CVD), yet associations of muscle mass with CVD are largely unknown. We hypothesized that low abdominal lean muscle area would be associated with greater calcified atherosclerosis, independent of other CVD risk factors. MATERIALS/METHODS: We investigated 1020 participants from the Multi-Ethnic Study of Atherosclerosis who were free of clinical CVD. Computed tomography (CT) scans at the 4th and 5th lumbar disk space were used to estimate abdominal lean muscle area. Chest and abdominal CT scans were used to assess coronary artery calcification(CAC), thoracic aortic calcification (TAC), and abdominal aortic calcification (AAC). RESULTS: The mean age was 64+/-10 years, 48% were female, and mean BMI was 28+/-5 kg/m2. In models adjusted for demographics, physical activity, caloric intake, and traditional CVD risk factors, there was no inverse association of abdominal muscle mass with CAC (prevalence ratio [PR] 1.02 [95% CI 0.95,1.10]), TAC (PR 1.13 [95% CI 0.92, 1.39]) or AAC (PR 0.99 [95% CI 0.94, 1.04]) prevalence. Similarly, there was no significant inverse relationship between abdominal lean muscle area and CAC, TAC, and AAC severity. CONCLUSION: In community-living individuals without clinical CVD, greater abdominal lean muscle area is not associated with less calcified atherosclerosis. PMID- 23916066 TI - Detection of neovascularization in retinal images using multivariate m-Mediods based classifier. AB - Diabetic retinopathy is a progressive eye disease and one of the leading causes of blindness all over the world. New blood vessels (neovascularization) start growing at advance stage of diabetic retinopathy known as proliferative diabetic retinopathy. Early and accurate detection of proliferative diabetic retinopathy is very important and crucial for protection of patient's vision. Automated systems for detection of proliferative diabetic retinopathy should identify between normal and abnormal vessels present in digital retinal image. In this paper, we proposed a new method for detection of abnormal blood vessels and grading of proliferative diabetic retinopathy using multivariate m-Mediods based classifier. The system extracts the vascular pattern and optic disc using a multilayered thresholding technique and Hough transform respectively. It grades the fundus image in different categories of proliferative diabetic retinopathy using classification and optic disc coordinates. The proposed method is evaluated using publicly available retinal image databases and results show that the proposed system detects and grades proliferative diabetic retinopathy with high accuracy. PMID- 23916067 TI - DNA methylation and differentiation: HOX genes in muscle cells. AB - BACKGROUND: Tight regulation of homeobox genes is essential for vertebrate development. In a study of genome-wide differential methylation, we recently found that homeobox genes, including those in the HOX gene clusters, were highly overrepresented among the genes with hypermethylation in the skeletal muscle lineage. Methylation was analyzed by reduced representation bisulfite sequencing (RRBS) of postnatal myoblasts, myotubes and adult skeletal muscle tissue and 30 types of non-muscle-cell cultures or tissues. RESULTS: In this study, we found that myogenic hypermethylation was present in specific subregions of all four HOX gene clusters and was associated with various chromatin epigenetic features. Although the 3' half of the HOXD cluster was silenced and enriched in polycomb repression-associated H3 lysine 27 trimethylation in most examined cell types, including myoblasts and myotubes, myogenic samples were unusual in also displaying much DNA methylation in this region. In contrast, both HOXA and HOXC clusters displayed myogenic hypermethylation bordering a central region containing many genes preferentially expressed in myogenic progenitor cells and consisting largely of chromatin with modifications typical of promoters and enhancers in these cells. A particularly interesting example of myogenic hypermethylation was HOTAIR, a HOXC noncoding RNA gene, which can silence HOXD genes in trans via recruitment of polycomb proteins. In myogenic progenitor cells, the preferential expression of HOTAIR was associated with hypermethylation immediately downstream of the gene. Other HOX gene regions also displayed myogenic DNA hypermethylation despite being moderately expressed in myogenic cells. Analysis of representative myogenic hypermethylated sites for 5 hydroxymethylcytosine revealed little or none of this base, except for an intragenic site in HOXB5 which was specifically enriched in this base in skeletal muscle tissue, whereas myoblasts had predominantly 5-methylcytosine at the same CpG site. CONCLUSIONS: Our results suggest that myogenic hypermethylation of HOX genes helps fine-tune HOX sense and antisense gene expression through effects on 5' promoters, intragenic and intergenic enhancers and internal promoters. Myogenic hypermethylation might also affect the relative abundance of different RNA isoforms, facilitate transcription termination, help stop the spread of activation-associated chromatin domains and stabilize repressive chromatin structures. PMID- 23916068 TI - ERAP1 structure, function and pathogenetic role in ankylosing spondylitis and other MHC-associated diseases. AB - The endoplasmic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme involved in the final processing of Major Histocompatibility Complex class I (MHC I) ligands and with a significant influence in the stability and immunological properties of MHC-I proteins. ERAP1 polymorphism is associated with ankylosing spondylitis among HLA-B27-positive individuals and the altered enzymatic activity of natural variants has significant effects on the HLA-B27 peptidome, suggesting a critical pathogenetic role of peptides in this disease. Likewise, the association of ERAP1 with other MHC-I associated disorders and its epistasis with their susceptibility MHC alleles point out to a general role of the MHC-I peptidome in these diseases. The functional interaction between ERAP1 and HLA-B27 or other MHC-I molecules may be related to the processing of specific epitopes, or to a more general peptide-dependent influence on other biological features of the MHC-I proteins. In addition, from a consideration of the reported functions of ERAP1, including its involvement in angiogenesis and macrophage activation, a more complex and multi-level influence in the inflammatory and immune pathways operating in these diseases cannot be ruled out. PMID- 23916069 TI - HLA-B27 and antigen presentation: at the crossroads between immune defense and autoimmunity. AB - The HLA-B27 is historically studied as a susceptibility factor in spondyloarthropathies and, primarily, in ankylosing spondylitis (AS). Over the recent years however, it has been rediscovered as protective factor against some severe viral infections. This is due to the high capacity of virus-specific, HLA B27-restricted CD8+ T cells for both intrinsic (i.e. polyfunctionality, high avidity, low sensitivity to Treg cell-mediated suppression) and extrinsic (i.e. rapid and efficient antigen processing and presentation) factors. It is tempting to speculate that these two aspects are not independent and that the association of B27 molecules to autoimmunity is the downside of this superior functional efficacy which, in given genetic backgrounds and environmental conditions, can support a chronic inflammation leading to spondyloarthropathies. Still, the pathogenic role of HLA-B27 molecules in AS is elusive. Here, we focus on the biology of HLA-B27 from the genetics to the biochemistry and to the structural/dynamical properties of B27:peptide complexes as obtained from atomistic molecular dynamics simulation. Overall, the results point at the antigen presentation as the key event in the disease pathogenesis. In particular, an extensive comparison of HLA-B*2705 and B*2709 molecules, that differ in a single amino acid (Asp116 to His116) and are differentially associated with AS, indicates that position 116 is crucial for shaping the entire peptide-presenting groove. PMID- 23916071 TI - Editorial. PMID- 23916072 TI - The clinical biomechanics award paper 1993 Posture and the compressive strength of the lumbar spine. AB - The effect of posture on spinal compressive strength was examined in a series of three experiments on cadaveric material. Lumbar 'motion segments', consisting of two vertebrae and the intervening disc and ligaments, were compressed while positioned in various angles of flexion and extension. In the first experiment load sharing between the disc, the apophyseal joint surfaces, and the intervertebral ligaments was inferred from measurements of intradiscal pressure (IDP). Results showed that extension caused the apophyseal joints to become load bearing, and damage could occur at compressive loads as low as 500 N. Flexion angles greater than about 75% of the full range of flexion (as defined by the posterior ligaments) generated high tensile forces in these ligaments, and caused substantial increases in IDP. The optimum range for resisting compression therefore appeared to be 0-75% flexion. The second experiment compared the distribution of compressive stress within the disc at the endpoints of this range, and showed that at 0% flexion high stress concentrations occur in the posterior annulus of many discs, whereas an even distribution of stress was usually found at 75% flexion. However, the third experiment showed that there was no significant difference in the compressive strength of motion segments positioned in 0% and 75% flexion. A comparison of the range of flexion/ extension movements in vivo and in vitro led us to conclude that in life a position of moderate flexion is to be preferred when the lumbar spine is subjected to high compressive forces. PMID- 23916070 TI - Genetics of ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a chronic inflammatory arthritis that affects the spine and sacroiliac joints. It causes significant disability and is associated with a number of other features including peripheral arthritis, anterior uveitis, psoriasis and inflammatory bowel disease (IBD). Significant progress has been made in the genetics of AS have in the last five years, leading to new treatments in trial, and major leaps in understanding of the aetiopathogenesis of the disease. PMID- 23916073 TI - Investigation of low-force high-frequency activities on the development of carpal tunnel syndrome. AB - The objective of this study was to determine the effects of repetitive motion on the flexor tendons and synovium in the carpal tunnel. One possible mechanism of tendon damage is fraying of the tendons as they slide past each other in the carpal tunnel. Increases in tendon friction were measured in human cadaver arms. The flexor tendons were loaded using pneumatic cylinders while load cells were used to measure tendon force both distal and proximal to the carpal tunnel. Results showed that tendon force distal to the carpal tunnel decreased by over 10% after 6 h, while tendon force proximal to the carpal tunnel remained constant. Two rhesus monkeys were used to further study the effects of repetitive motion. One arm of each animal was subjected to 729000 repetitive cycles over a 3 week period. Results of the animal study showed that highly repetitive motions encountered over a relatively short period of time had little effect on the tissue in and around the carpal tunnel. PMID- 23916074 TI - Spectral signature of forces to discriminate perturbations in standing posture. AB - This study proposes a methodology for the collection and analysis of the spectral characteristics of human movement patterns. Specifically, the purpose of this study was to determine the reliability of the spectral signature obtained from postural forces and the usefulness of the technique in identifying perturbations in standing posture. Data collected included trials of the experimental protocol under normal standing conditions and under three experimental conditions designed to perturb stability. Results of this investigation indicated that spectral signatures created from ground forces using the methodology proposed in this study were highly reliable within individuals and across different testing sessions. These data further indicate that spectral signatures obtained from ground reaction forces during standing provide a sensitive indicator of an individual's postural stability. PMID- 23916075 TI - Back shape measurement using video rasterstereography and three-dimensional reconstruction of spinal shape. AB - Video rasterstereography is a method for back surface measurement comprising automatic back surface reconstruction and shape analysis. It is particularly appropriate for the examination of scoliosis. In this application shape analysis includes model-based calculations of vertebral rotation (determined from surface rotation) and of the spinal midline in three dimensions. The results are delivered in quasi-real time (computing time < 5 min). The aim of the present study was to validate the method by comparison of rasterstereographic and radiographic data. Anteroposterior radiographs and rasterstereographs (478) of 113 scoliosis patients were analysed, each pair taken on the same day. Matching the radiographic midline of the spine to its rasterstereographic equivalent, the deviations between the two curves are properly expressed by their root mean square (r.m.s.) deviation. A r.m.s. deviation in the order of 4 mm was found. Similarly, the r.m.s. deviation of vertebral rotation from surface rotation was about 3 degrees . No systematic difference of vertebral and surface rotation, as reported by other authors, could be found. This may be attributed to our method of data evaluation, consisting of a sophisticated analysis of surface curvature and shape asymmetry. These mathematical procedures are made possible by the high sampling density and resolution of video rasterstereography. Conventional scoliosis parameters (e.g. Cobb angle, apical rotation, apex height, etc.) can be estimated with limited accuracy from the reconstructed midline. The relevant standard deviations are given. PMID- 23916076 TI - Effects of meniscectomy and anterior cruciate ligament transection on rabbit knee joint in-vitro mechanics and cartilage gross morphology. AB - The effects of meniscectomy and anterior cruciate ligament transection on knee joint compression compliance, capacity of energy storage and cartilage gross morphology were studied in rabbits six and 12 weeks postoperatively. Joints with meniscectomy and intact ligaments at 12 weeks had a similar joint compression compliance as sham-operated joints with intact menisci, but had moderate unicompartmental osteoarthritis. Further, the capacity of energy storage of such a joint was reduced. Knees with anterior cruciate ligament transection had a higher joint compression compliance than knees with intact joint structures. Anterior cruciate ligament transection caused severe cartilage degeneration of both knee compartments at 6 weeks, but in knees with intact menisci the tibial cartilage was better preserved than in knees with meniscectomy. Synovitis was pronounced in anterior cruciate ligament transected knees. In conclusion, meniscectomy reduced the capacity of energy storage of the joint and was followed by moderate unicompartmental cartilage degeneration at 12 weeks. Anterior cruciate ligament transection especially when combined with meniscectomy led during a similar observation period to more dramatic effects on joint compression compliance and morphology. PMID- 23916077 TI - Anatomy and actions of the trapezius muscle. AB - Dissection studies revealed the fascicular anatomy of the trapezius. Its occipital and nuchal fibres passed downwards but mainly transversely to insert into the clavicle. Fibres from C7 and T1 passed transversely to reach the acromion and spine of the scapula. Its thoracic fibres converged to the deltoid tubercle of the scapula. Volumetric studies demonstrated that the fibres from C7, T1, and the lower half of ligamentum nuchae were the largest. The essentially transverse orientation of the upper and middle fibres of trapezius precludes any action as elevators of the scapula as commonly depicted. Rather the action of these fibres is to draw the scapula and clavicle backwards or to raise the scapula by rotating the clavicle about the sternoclavicular joint. By balancing moments the trapezius relieves the cervical spine of compression loads. PMID- 23916078 TI - Three-dimensional movement at externally fixated tibial fractures and osteotomies during normal patient function. AB - Three-dimensional movements at four externally fixated tibial fractures and four leg-lengthening osteotomies were measured using the Oxford micromovement transducer. By measuring movements in 6 degrees of freedom during normal patient activity, both shear and angulatory displacements have been found to be of the same order as axial displacements, and are often more dominant. The magnitude of such movements may be as high as 2 mm and 2 degrees in early healing to a small fraction of this in later stages, regardless of whether the fractures are initially reduced and whether they are oblique or transverse. Also, the main bars of certain fixators have torsional 'backlash' looseness, causing significant torsional movement at the fracture and shear perpendicular to the plane of the bone screws. Further interesting findings concern the movement of fractures during walking, 'dynamization' (telescopic movement of the fixator bar) and muscle activity. Axial, angular, and shear movements reverse direction in phase with the 'heel-strike' and 'toe-off' sequence of walking. During dynamization (where the fixator bar is 'loose'), fracture movements at a given load are often less than when not dynamizing (where the fixator bar is 'locked'). Active muscle response can cause movements of 5-6 times greater than movements arising from the transfer of force through the tibia during weight bearing. Also, the tensile stiffness during the above activities has been shown to be more than an order of magnitude lower than the apparent compressive stiffness. PMID- 23916079 TI - Viscoelasticity of the individual spine. AB - Three subjects held barbells of 10.5 and 20.5 kg on the shoulders for 45 min. At regular intervals both stature and trunk height were measured using a stadiometer. Experiments were performed in the morning and afternoon and each condition was repeated three times. The three repeated measurements were averaged, yielding eight creep curves per subject. These curves were fitted with the equation describing a Kelvin unit. The ratio of the elastic modulus and the coefficient of viscosity was used to characterize the viscoelastic response. All inter-subject differences were significant. No differences were found between the creep rates concerning stature and trunk height, 10.5 and 20.5 kg load, and morning and afternoon. Characterization of the viscoelastic properties of the individual spine based on these relatively simple measurements appears to be possible. PMID- 23916080 TI - Bone metabolism regulators and arterial stiffness in postmenopausal women. AB - BACKGROUND: Osteoprotegerin (OPG), osteopontin (OPN) and matrix Gla protein (MGP) are markers of bone metabolism but they are also involved in vascular calcification. However, their precise role is not completely understood. Arterial stiffness is considered an independent predictor of cardiovascular events and it may be one of the causes of the increased cardiovascular risk associated with postmenopausal status. Medial and intimal calcification may increase arterial stiffness. The aim of our study was to assess the relationship of OPG, OPN and MGP with aortic pulse wave velocity (aPWV) as a marker of arterial stiffness in postmenopausal women. MATERIALS AND METHODS: Circulating OPG, OPN and serum total MGP were measured in 144 postmenopausal women using the enzyme-linked immunosorbent assay method. Aortic PWV was determined by an oscillometric method. RESULTS: Osteoprotegerin correlated with age (p<0.001, r=0.27), aPWV (p<0.001, r=0.32) and hypersensitive C reactive protein (hsCRP) (p<0.001, r=0.37), OPN correlated directly with hsCRP (p<0.001, r=0.39) and inversely with high density lipoprotein cholesterol (p=0.02, r=-0.02). No significant association was found between total MGP and clinical, biochemical and vascular parameters. The correlation between OPG and aPWV persisted even after the adjustment for various potential confounders (p=0.02, r=0.19). In multiple regression analysis in the whole study population the most important predictors of aPWV were OPG (beta=0.230, p=0.006), hsCRP (beta=0.212, p=0.01) and systolic blood pressure (beta=0.163, p=0.04). After exclusion of patients treated with statins the independent predictors were hsCRP (beta=0.275, p=0.005) and OPG (beta=0.199, p=0.04). CONCLUSION: Circulating OPG, but not OPN and total MGP, is associated with aPWV and may be a marker of the increased arterial stiffness and cardiovascular risk in postmenopausal women. PMID- 23916081 TI - Assessment of menopause-related symptoms in mid-aged women with the 10-item Cervantes Scale. AB - OBJECTIVE: To develop a short 10 item version of the original menopause Cervantes Scale (CS) in order to assess menopausal symptoms in a large cohort of mid-aged Colombian women. METHODS: Reliability of the new short tool was assessed through internal consistency determination (Cronbach's alpha values) and intra-class correlation coefficient (ICC) analysis. Ten items out of the 31 composing the original CS were selected according to their clinical relation with menopausal symptoms. Subsequently the short tool was used to assess menopausal symptoms and related factors among 1739 mid-aged women. RESULTS: The CS-10 displayed a mean (+/-SD) ICC value of 0.45 (+/-0.06) and a Cronbach's alpha of 0.778 suggesting good internal reliability. For the entire sample median [interquartile range] CS 10 global scores were 10.0 [12.0], and for pre-, peri- and postmenopausal women: 8.0 [9.2], 9.0 [9.0] and 14.0 [14.0], respectively. Median global CS-10 scores significantly increased with menopausal status, marital status and ethnicity. Multiple linear regression analysis determined that higher global CS-10 scores (worse quality of life) correlated with age, parity, years since menopause, body mass index, ethnics (black) and smoking habit. CONCLUSION: The CS-10 seems to be a simple instrument that may aid everyday clinical consultation and help at performing an accurate diagnosis of menopause-related symptoms. Further studies are needed to confirm our preliminary findings. PMID- 23916082 TI - Faster is better. PMID- 23916083 TI - MRI brain scans in two patients with the argus II retinal prosthesis. PMID- 23916084 TI - Dominant optic atrophy: novel OPA1 mutations and revised prevalence estimates. PMID- 23916085 TI - Treatment of CIN with retinoic acid and topical interferon alfa-2b. PMID- 23916086 TI - Author reply: To PMID 22704834. PMID- 23916087 TI - Subclinical keratoconus: the need for an objective classification system. PMID- 23916088 TI - Endoscope an adjunct rather than alternative. PMID- 23916089 TI - Author reply: To PMID 22892148. PMID- 23916090 TI - Author reply: To PMID 23084125. PMID- 23916091 TI - Alexithymia and non-treatment: an Internet based study of 312 people with chronic anxiety. AB - BACKGROUND: Despite the availability of highly efficacious treatments, many individuals with anxiety disorders never receive adequate treatment. Alexithymic deficits, such as difficulties in recognizing feelings and focusing on emotional experiences, may contribute to low rates of help seeking. METHODS: Multiple Internet-based strategies (announcements of anxiety disorder websites, postings in online self-help forums, notices in anxiety chat rooms) were used to recruit a sample of 312 participants with chronic and clinically relevant anxiety symptoms. Those who had never received professional treatment (n = 49) were compared to those with current or previous treatment (n=263) with regard to alexithymia, anxiety, depression and health-related quality of life. RESULTS: Logistic regression analysis revealed that the strongest predictor for belonging to the never treated group was the externally oriented thinking facet of alexithymia. In addition, substantially more participants in the never treated group (49%) were considered high-alexithymic (20-item Toronto Alexithymia Scale total score >= 61) compared to the treated group (35%). CONCLUSIONS: The main finding was a strong relationship between the externally oriented thinking facet of alexithymia and the non-use of professional help for anxiety. Internet-based programs could be a promising first step in supporting this group of people to overcome their anxiety. PMID- 23916092 TI - Bovine herpes virus-1 (BoHV-1) in cattle-a review with emphasis on reproductive impacts and the emergence of infection in Ireland and the United Kingdom. AB - Bovine reproductive disease attributable to bovine herpes virus-1 (BoHV-1) was first described in Germany in the 19th century, being recognised primarily as the cause of infectious vulvovaginitis and balanoposthitis until the mid-1950s when a more virulent strain of the virus (BoHV-1.1) associated with respiratory disease (infectious bovine rhinotracheitis; IBR) emerged in the western United States. Subsequently, IBR emerged as a clinical condition in Europe, from the 1970s onward. While the ability of BoHV-1 to produce respiratory disease is now well recognised, the potential negative outcomes of infection on fertility and reproduction are less frequently considered. This review was conducted against the background of the prioritization of disease caused by BoHV-1 as one of several diseases to be addressed by Animal Health Ireland, with the twin goals of summarizing the published literature on the potential outcomes of infection at different stages of breeding and pregnancy, and of describing the emergence of BoHV-1 as a significant pathogen in Ireland and the UK. PMID- 23916093 TI - Morphological evaluation of spermatogenesis in Lake Magadi tilapia (Alcolapia grahami): a fish living on the edge. AB - Spermatogenesis in Lake Magadi tilapia (Alcolapia grahami), a cichlid fish endemic to the highly alkaline and saline Lake Magadi in Kenya, was evaluated using light and transmission electron microscopy. Spermatogenesis, typified by its three major phases (spermatocytogenesis, meiosis and spermiogenesis), was demonstrated by the presence of maturational spermatogenic cells namely spermatogonia, spermatocytes, spermatids and spermatozoa. Primary spermatogonia, the largest of all the germ cells, underwent a series of mitotic divisions producing primary spermatocytes, which then entered two consecutive meiotic divisions to produce secondary spermatocytes and spermatids. Spermatids, in turn, passed through three structurally distinct developmental stages typical of type-I spermiogenesis to yield typical primitive anacrosomal spermatozoa of the externally fertilizing type (aquasperm). The spermatozoon of this fish exhibited a spheroidal head with the nucleus containing highly electron-dense chromatin globules, a midpiece containing ten ovoid mitochondria arranged in two rows and a flagellum formed by the typical 9 + 2 microtubule axoneme. In addition, the midpiece, with no cytoplasmic sheath, appeared to end blindly distally in a lobe like pattern around the flagellum; a feature that was unique and considered adaptive for the spermatozoon of this species to the harsh external environment. These observations show that the testis of A. grahami often undergoes active spermatogenesis despite the harsh environmental conditions to which it is exposed on a daily basis within the lake. Further, the spermiogenic features and spermatozoal ultrastructure appear to be characteristic of Cichlidae and, therefore, may be of phylogenetic significance. PMID- 23916094 TI - Prevalence of Trypanosoma cruzi infection in Latin American pregnant women and level of compliance of the Valencian Health Programme in the city of Alicante. PMID- 23916095 TI - The voice of radiology. PMID- 23916096 TI - Radiation. PMID- 23916097 TI - When the government comes knocking: government audits of radiology practices. PMID- 23916098 TI - Utilizing the 5S methodology for radiology workstation design: applying lean process improvement methods. PMID- 23916099 TI - Authors' reply. PMID- 23916100 TI - The chromatin remodeller ATRX: a repeat offender in human disease. AB - The regulation of chromatin structure is of paramount importance for a variety of fundamental nuclear processes, including gene expression, DNA repair, replication, and recombination. The ATP-dependent chromatin-remodelling factor ATRX (alpha thalassaemia/mental retardation X-linked) has emerged as a key player in each of these processes. Exciting recent developments suggest that ATRX plays a variety of key roles at tandem repeat sequences within the genome, including the deposition of a histone variant, prevention of replication fork stalling, and the suppression of a homologous recombination-based pathway of telomere maintenance. Here, we provide a mechanistic overview of the role of ATRX in each of these processes, and propose how they may be connected to give rise to seemingly disparate human diseases. PMID- 23916101 TI - Effects of ankle arthrodesis on walking: kinematic and kinetic studies. AB - We have studied the effects of ankle arthrodesis on the gait of three subjects with special attention to the time and sagittal plane kinematic and kinetic characteristics. Each subject had a painless arthrodesis and no other gait limitation. To compensate for this disability they showed an increased range of movement at the ipsilateral mid-tarsal, knee and hip joints, and required greater than normal resuftan joint moments to be generated at the ipsilateral knee and hip joints. The subjects exhibited stride-to-stride kinetic compensation at the knee and hip joints, with associated variability in resultant joint moments and power patterns. However, they achieved a symmetric gait by mimicking ipsilateral movements with the opposite limb. PMID- 23916102 TI - Lumbar muscle size and locations from CT scans of 96 women of age 40 to 63 years. AB - Computed tomography scans of 96 women aged between 40 and 63 years were systematically measured to determine torso muscle moment arms and cross-sectional areas at L 2L 3, L 3L 4 and L 4L 5 disc levels. The major findings were as follows: (1) the mean muscle moment arm and area data were not different bilaterally; (2) psoas, quadratus lumborum, and latissimus dorsi muscle moment arms consistently changed at the three disc levels, while erector spinae, rectus abdominis, transverse abdominis and the oblique muscles remained about the same distance from the three disc centroids; (3) psoas and quadratus lumborum muscles increased in mean size at the lower levels and (4 gross torso anthropometry and body weight had a significant (P < 0.01) but varied correlation (r(2) from 0.12 to 0.65) with the size of the erector spinae and psoas muscles, and with the moment arms of the rectus abdominis, transverse abdominis, latissimus dorsi, and oblique muscles. PMID- 23916103 TI - Electrically evoked knee flexion torque increases with increased pelvifemoral angles. AB - This study was designed to determine the extent to which knee flexion torques would differ when submaximal hamstring muscle contractions were evoked by constant levels of electrical stimulation and when the pelvifemoral angle was increased. Nineteen healthy subjects (ten women and nine men) underwent electrical stimulation of the hamstring muscles while randomly positioned either supine, sitting upright, or sitting leaning forward. The pelvifemoral angle for each position was measured from lateral photographs: the knee flexion torque was calculated from the knee flexion force, and lever arms measured directly at a constant knee angle. A repeated measures ANOVA demonstrated significant differences for pelvifemoral angles (F = 485.00, P < 0.001) and knee flexion torques (F = 21.97, P < 0.001) among the positions. The mean torques in the upright and leaning forward positions were 2.2 and 3.7 times greater, respectively, than mean torques in the supine position. The increase between the supine and leaning forward positions exceeded the increase previously reported in the literature for subjects performing maximal voluntary knee flexion efforts. PMID- 23916104 TI - Passive compliance and length of the hamstring muscles of healthy men anc women. AB - This study examined the passive compliance and length of the hamstring muscles of 15 healthy men and 15 healthy women (ages 21-37) with passive straight-leg raising between 65 degrees and 80 degrees . Subjects were positioned on their left sides with the pelvis stabilized and the right thigh fixed at 90 degrees on a horizontal platform. After three practice trials of maximal passive knee extension, subjects received three trials for data collection. Muscle activity was monitored with surface EMG and passive resistance to knee extension was measured with a dynamometer as the limb was photographed at six force-dependent positions. The passive compliance was computed as the ratio of the change in the knee angle (DeltaAngle) to the change in passive torque (DeltaTorque), (DeltaAngle/DeltaTorque). Hamstring muscle lengths were measured simultaneously. An ANovA revealed a difference (P = 0.001) between the passive compliance ratios of the men (1.4 +/- 0.-03) and women (2.2 +/- 0.08) but not between their initial knee angles or their maximal knee angles. Independent t-tests showed a difference (P < 0.001) between the maximal passive torque of the men (41.4 +/- 5.7 Nm) and women (27.4 +/- 7.7 Nm). The torques were not different when standardized to body mass. Although ANOVAS showed that the absolute hamstring muscle lengths differed between genders, they were not different when standardized as a percentage of the femur length. PMID- 23916105 TI - Thorecolumlbar fascia can increase the efficiency of the erector spinae muscles. AB - A model is developed which demonstrates that the thoracolumbar fascia can increase the axial stress generated by active contraction of the erector spinae muscles by restricting their radial expansion (bulging). The radial stress in the muscles was calculated from their radii, the radius of the abdominal cavity, and the intra-abdominal pressure generated during lifting. Radii were measured from magnetic resonance images and values of intra-abdominal pressure obtained from the literature. The resulting radial stress was used to calculate the increase in axial stress developed as a result of restricting radial expansion. Values for the axial stress generated by contraction of an unrestricted muscle, which are also required for this calculation, were obtained from the literature. The results indicate that restriction of radial expansion of the erector spinae muscles by the thoracolumbar fascia may increase the stress generated during their contraction by up to about 30%. This would lead to a proportional increase in the extensor moment exerted by these muscles. PMID- 23916106 TI - Determination of stresses in below-knee walking casts. AB - Glass fibre bandages are now commonly used for definitive below-knee walking casts, in preference to plaster of Paris, since they are better able to withstand the stresses imposed upon them. This paper describes a technique for recording the cast strains in glass fibre bandages and shows typical stress levels in patient and volunteer casts. A typical map of the stress variations in walking casts during gait in a volunteer has been produced. The study shows that the high stresses recorded along the medial and lateral borders of the foot by the strain gauge technique are confirmed by clinical experience, since this is where failure is most commonly seen in below-knee walking casts. It is concluded that the current generation of polyurethane impregnated glass fibre splinting bandages are too brittle in many cases for below-knee walking casts and that a more flexible fabric would reduce the incidence of cast breakdown. PMID- 23916107 TI - Kinematic analysis of one-leg long hopping in patients with an old rupture of the anterior cruciate ligament. AB - Sixteen males (mean age 30 +/- 8 years), all possessing an old rupture of the anterior cruciate ligament which had not been repaired surgically, underwent a biomechanical evaluation of a one-leg long hop using opto-electronic motion analysis and ground reaction force analysis. In concordance with previous findings, the length of a one-leg long hop on the injured leg was shorter than on the non-injured leg. Furthermore, performance of the non-injured leg was impaired compared to a reference group. There was no significant difference in knee flexion angles at impact, but there was a lower eccentric knee angular velocity in the injured leg, 597 degrees /s (SD 101), as compared with 701 degrees /s (SD 130) for the non-injured leg (P < 0.01). No statistically significant differences were found for the reaction force components. The level of evaluation, mechanisms for the provocation of knee joint instability and possible adaptations are discussed. PMID- 23916108 TI - Measurement of shock acceleration during walking and running using the Shock Meter. AB - The Shock Meter was developed to measure shock acceleration of the lower leg during running or walking and is suitable for use in the clinical or sports environment. This instrument measures the shock factor, previously defined by the author, on a 0 to 10 scale to allow for the comparison of different footwear and gait. A study was carried out to determine the repeatability and accuracy of the Shock Meter during both walking and treadmill running. It was shown that this instrument can discriminate changes in shock factor of 10% (P < 0.05). As might be expected, shoes with hard heels were found to cause the greatest shock acceleration. In a study of three runners, there appeared to be trend for the shock factor to increase with speed only up to some transition speed. It is suggested that this transition is associated with the change from heel strike to mid or forefoot contact. Further studies are required to understand this more fully. PMID- 23916109 TI - A method to study the lumbar back muscle activity to be used in back pain prevention: Thesis summary. PMID- 23916110 TI - Year book of podiatric medicine and surgery 1988 Richard M. Jay, Ed Year Book Medical Publishers, 1988, 328 pp, L32.50 (Distributed by Wolfe Medical, London). PMID- 23916111 TI - Magnetic resonance imaging of the spine M T Modic, T J Masaryk, S Ross Year Book Medical Publishers, 1989, 280 pp, L64.00 (Distributed by Wolfe Medical, London). PMID- 23916113 TI - Erratum. PMID- 23916114 TI - Non-contact laser-scanning confocal microscopy of the human cornea in vivo. AB - PURPOSE: To investigate the utility of using non-contact laser-scanning confocal microscopy (NC-LSCM), compared with the more conventional contact laser-scanning confocal microscopy (C-LSCM), for examining corneal substructures in vivo. METHODS: An attempt was made to capture representative images from the tear film and all layers of the cornea of a healthy, 35 year old female, using both NC-LSCM and C-LSCM, on separate days. RESULTS: Using NC-LSCM, good quality images were obtained of the tear film, stroma, and a section of endothelium, but the corneal depth of the images of these various substructures could not be ascertained. Using C-LSCM, good quality, full-field images were obtained of the epithelium, subbasal nerve plexus, stroma, and endothelium, and the corneal depth of each of the captured images could be ascertained. CONCLUSIONS: NC-LSCM may find general use for clinical examination of the tear film, stroma and endothelium, with the caveat that the depth of stromal images cannot be determined when using this technique. This technique also facilitates image capture of oblique sections of multiple corneal layers. The inability to clearly and consistently image thin corneal substructures - such as the tear film, subbasal nerve plexus and endothelium - is a key limitation of NC-LSCM. PMID- 23916115 TI - Corneal swelling caused by conventional and new-design low-Dk soft contact lenses following a 10-day daily wear trial regime. AB - PURPOSE: To investigate the efficacy and safety of a fenestrated and channelled soft contact lens (F-SCL) compared to a standard and non-fenestrated soft contact lens (S-SCL) in experienced soft contact lens (SCL) wearers. METHODS: This was a randomised, crossover, single-blinded (subject), and multicentre clinical trial. Sixteen experienced SCL wearers were randomly divided into two groups (FS and SF). The FS group first wore F-SCLs followed by S-SCLs, each for 10 days, separated by a 1-week washout period, whereas the SF group wore the S-SCLs first and crossed over to F-SCLs in the same manner. The F-SCLs were designed with three equally spaced, symmetrical fenestrations and a partial-thickness, connecting, circumferential channel on the back surface of the mid-periphery of the lens. Measurement of central corneal thickness using ultrasonic pachymetry was performed on the day of screening, after the 1-week washout period, and after 10 days of wearing each kind of lens, based on which central corneal swelling was calculated and compared. One eye in each subject was chosen at random for analysis. RESULTS: Central corneal swelling was 1.92+/-1.73% vs. 5.26+/-2.14% in F-SCLs vs. S-SCLs wearers, which was statistically significant (P<0.001). There was no significant difference between the groups in terms of SCL-corrected visual acuity or SCL-related adverse events. CONCLUSION: The use of F-SCLs led to reduced corneal swelling compared to S-SCLs. The newly incorporated features appear to improve tear mixing and thereby the oxygen supply to the cornea, which results in reduced corneal oedema. PMID- 23916116 TI - Microbial contamination of contact lens care accessories and compliance with care regimens in Nepal. AB - PURPOSE: To determine the rates of microbial contamination and identify contaminants associated with contact lens (CL) care accessories. To investigate self-reported compliance levels with care of CL accessories and its association with contamination level. METHODS: A total of 46 CL cases and care solutions from asymptomatic soft contact lens wearers were collected. Samples from the CL cases and care solutions were cultured for microbiological identification and enumeration. A questionnaire regarding compliance to care and hygiene procedures were administered to each subject on their visit. RESULTS: The percentage of microbial contamination for CL cases and care solutions was 50% and 10.9%, respectively. All the contaminants were bacterial. Staphylococcus aureus (37.0%, 17 of 46 cases) and Escherichia coli (8.7%, 4 of 46 cases) were the most common microorganisms detected in CL cases. In care solutions, S. aureus (8.7%, 4 of 46 samples), Pseudomonas aeruginosa (2.2%, 1 of 46 samples) were common contaminants. CL cases and care solutions that were used for <3 months were significantly less contaminated than those used for >3 months (10.9% versus 39.1%, p<0.05). Polyquad and Aldox based MPS solution showed no contamination. Subjects with medium or low compliance had highly significant rates of contaminations both in CL cases and solutions than for subjects with high compliance (p<0.05). CONCLUSIONS: Nepalese Soft CL wearers are at high risk of developing ocular complications due to high CL case and solution contamination. Frequent replacement of CL cases and solutions, as well as good compliance is recommended to reduce risk of contamination. PMID- 23916117 TI - Aluminium, carbonyls and cytokines in human nipple aspirate fluids: Possible relationship between inflammation, oxidative stress and breast cancer microenvironment. AB - The human breast is likely exposed to Al (aluminium) from many sources including diet and personal care products. Underarm applications of aluminium salt-based antiperspirant provide a possible long-term source of exposure, especially after underarm applications to shaved and abraded skin. Al research in breast fluids likely reflects the intraductal microenvironment. We found increased levels of aluminium in noninvasively collected nipple aspirate fluids (NAF) from 19 breast cancer patients compared with 16 healthy control subjects (268 vs 131 MUg/l, respectively; p < 0.0001). In the same NAF samples we found significantly increased levels of protein oxidative carbonyls in cancer patients compared to healthy women (2.35 vs 0.41 nmol/mg prot, respectively; p < 0.0001). Aluminium content and carbonyl levels showed a significant positive linear correlation (r(2) 0.6628, p < 0.0001). In cancer NAF samples (containing higher amounts of aluminium salts) we also found a significantly increased levels of pro inflammatory cytokines (IL-1beta, IL-6, IL-12 p70, and TNF-alpha) and chemoattractant CC and CXC chemokines (IL-8, MIP-1alpha and MCP-1). In 12 invasive cancer NAF samples we found a significant positive linear correlation among aluminium, carbonyls and pro-inflammatory IL-6 cytokine (Y = 64.79x-39.63, r(2) 0.8192, p < 0.0005), as well as pro-inflammatory monocyte chemoattractant MCP-1 cytokine (Y = 2026x-866, r(2) 0.9495, p < 0.0001). In addition to emerging evidence, our results support the possible involvement of aluminium ions in oxidative and inflammatory status perturbations of breast cancer microenvironment, suggesting aluminium accumulation in breast microenvironment as a possible risk factor for oxidative/inflammatory phenotype of breast cells. PMID- 23916118 TI - Structure and function of heme proteins in non-native states: a mini-review. AB - Heme proteins perform various biological functions ranging from electron transfer, oxygen binding and transport, catalysis, to signaling. Although adopting proper native states is very important for these functions, progresses in representative heme proteins, including cytochrome c (cyt c), cytochrome b5 (cyt b5), myoglobin (Mb), neuroglobin (Ngb), cytochrome P450 (CYP) and heme-based sensor proteins such as CO sensor CooA, showed that various native functions, or new functions evolved, are also closely associated with non-native states. The structure and function relationship of heme proteins in non-native states is thus as important as that in native states for elucidating the precise roles of heme proteins in biological systems. PMID- 23916119 TI - The role of preoperative oxidative stress and mandibular third molar postoperative outcome--reply. PMID- 23916120 TI - Intensification of insulin therapy in patients with type 2 diabetes: a retrospective, non- interventional cohort study of patients treated with insulin glargine or biphasic human insulin in daily clinical practice. AB - BACKGROUND: The aim of this study is to compare the efficacy of intensification of insulin treatment with insulin glargine and biphasic human insulin in patients with type 2 diabetes on concomitant therapy with oral antidiabetic drugs (OAD) in daily clinical practice. METHODS: A retrospective multicentre parallel two-arm study included 301 patients with type 2 diabetes already on treatment with biphasic human insulin twice daily (bd) in combination with OAD. Data were collected retrospectively from 142 patients who had been switched from biphasic human insulin to insulin glargine in a period of 6-12 months prior to their inclusion (active group) and compared to data collected retrospectively from 159 patients who continued treatment with biphasic human insulin bd for the same time period (control group). Our primary objective was to examine the efficacy of the two treatments, assessed as change in HbA1c. Secondary objectives were to examine for changes in fasting blood glucose (FBG), body weight, treatment with OAD or fast-acting insulin and safety, by assessing the frequency and severity of hypoglycaemic episodes. RESULTS: At the end of the study there was a significant reduction in HbA1c in both arms. The least squares (LS) mean [(95% confidence intervals (CI)] reduction in HbA1c was -1.13 (-0.96 to -1.30)% in the active and 0.59 (-0.41to -0.77)% in the control group [LS mean treatment difference 0.53 (0.31-0.76)%, p < 0.001]. Similarly, fasting blood glucose declined significantly in both arms. The LS mean decline in FBG was -47.02 (-37.89 to -56.14) mg/dl in the active and -19.73 (-11.57 to -27.89) mg/dl in the control group [LS mean treatment difference 27.85 (15.74-39.95) mg/dl, p < 0.001]. No significant difference in hypoglycaemic episodes and in body weight was found. In the active group, more patients received rapid-acting pre-meal insulin and used insulin secretagogues drugs. CONCLUSIONS: Glargine alone or in combination with fast acting insulin is more effective in reducing glycaemia than biphasic human insulin alone or in combination with fast acting insulin in patients with type 2 diabetes without increase in hypoglycaemic episodes or body weight. PMID- 23916121 TI - "How I kept track of it of course was my business": cancer patient self monitoring as self-stylized work. AB - OBJECTIVES: Self-monitoring behaviors of cancer patients benefit patients, caregivers, and providers, and yet the phenomenon of self-monitoring from the cancer-patient perspective has not been studied. We examined cancer patients' self-monitoring preferences and practices, focusing on the meaning of self monitoring within the cancer experience. METHODS: Semi-structured interviews were conducted among adult cancer patients who had been seen at least once at a rural United States cancer center. Questions sought out the meaning of self-monitoring and its practical aspects. Qualitative data were analyzed by adapting the four stepped method by Giorgi for empirical phenomenological analysis. RESULTS: Twenty participants were interviewed (11 women and 9 men). Transcribed interviews revealed that cancer patient self-monitoring is self-stylized work that ranges from simple to complex, while being both idiosyncratic and routine. Participants reported using tools with systems for use that fit their distinctive lives for the purpose of understanding and using information they deemed to be important in their cancer care. Three conceptual categories were discerned from the data that help to elucidate this self-stylized work as fitting their individual priorities and preferences, reflecting their identities, and being born of their work lives. SIGNIFICANCE OF RESULTS: Findings highlight patients' unique self-monitoring preferences and practices, calling into question the assumption that the sole use of standardized tools are the most effective approach to engaging patients in this practice. Self-monitoring efforts can be validated when providers welcome or adapt to patients' self-stylized tools and systems. Doing so may present opportunity for improved communications and patient-centered care. PMID- 23916122 TI - Examination of several techniques for predicting trabecular elastic modulus and ultimate strength in the human lumbar spine. AB - Parameters quantifying architecture changes are needed to characterize trabecular bone strength. Trabecular elastic modulus and ultimate strength in the human lumbar spine were predicted by using several techniques. Elastic modulus was best predicted with apparent density, ash density, ultrasonic velocity, computed tomography number, and histomorphological parameters. The ultimate strength was best predicted with apparent density, ultrasonic velocity, or histomorphological parameters. Based on the clinical acceptance of dual-photon absorptiometry as a measure of bone mass of the axial skeleton, the relatively poor predictive value of bone mineral content by dual-photon absorptiometry was not expected. However, since dual-photon absorptiometry integrates the attenuation through the entire cross-section of the vertebra, this technique would not be capable of predicting mechanical properties of trabecular bone alone. The measurement of computed tomography number at the position at which the specimen was cut to measure the mecchanical properties was understandably a better predictor. As expected, little predictive power is obtained by measuring the Ca, P, or Ca/P ratio, since the range of chemical composition of bone is very narrow. PMID- 23916123 TI - Influence of cutting technology on initial fixation strength and thread quality of different bone pins. AB - A comparison of the fixation strength was made for the Steinmann, Denham, and the Apex commercial bone pins, which have different drilling end geometry and self tapping thread design. Additional tests were made to assess the effects of pre drilling with an orthopaedic twist drill bit prior to pin insertion. Peak pull out force and pin displacement were measured for these pins inserted into the distal metaphysis of human cadaveric tibiae. The quality of thread reproduction in the bone resulting from the cutting process was assessed from thread profiles of negative moulds cast into the threaded holes. The Apex pins had similar pull out forces to the Denham pins, despite their smaller diameter. Values for both pins were significantly greater than those for the Steinmann pin. The thread profiles showed that the Denham pin caused substantial damage to the cortical bone and formed poor quality threads in the cancellous bone. The Apex pin formed a better thread, which was improved further by the use of a pre-drilled pilot hole. PMID- 23916124 TI - Gait analysis in patients with anterior knee pain. AB - The purpose of this study was to examine the kinematic and kinetic parameters of the gait of patients with anterior knee pain. Fifteen symptomatic patients and 15 female control subjects were asked to perform 10 barefoot walks along a 10-m walkway. Ground reaction force data were collected using a force platform. Rearfoot motion data were collected using a video kinematic analysis system. The results showed that the controls exerted a significantly higher lateral force compared to patients. There was also a significant difference between controls and patients in the amount of time taken to maximum lateral force and in the time taken to achieve maximum angle between the axis of the calcaneus and axis of the tendo achilles. These results indicate that extended time to maximum lateral force rather than excessive lateral force is a discriminating factor in the gait of female patients with anterior knee pain who have a low recreational status. This contradicts previous studies using running analysis on athletes with this condition and suggests that in terms of diagnosis and treatment, care must be taken when comparing results from groups of different recreational status. PMID- 23916125 TI - Transfer strategies used to rise from a chair in normal and low back pain subjects. AB - The mechanics of rising from a chair are analysed in two groups of male subjects including five normal subjects and five chronic non-specific, low back pain subjects. Chair height, foot placement and arm position were controlled while force plate, video and electromyographic data were collected. The task was broken into three phases: initiation, chair unloading, and ascending. Moment and power analyses of the ascending phase showed two different strategies were used among the normal subjects. A 'knee strategy', comprising higher knee muscle moments, propelled the body into the standing posture while keeping the trunk relatively vertical; a 'hip-trunk strategy' flexed the trunk farther forward, decreasing the knee moments, but at the same time increasing the moments at the hip and low back. The low back pain subjects used a modified strategy that distributed the moments and power more evenly throughout the lower limb and low back. PMID- 23916126 TI - Patellofemoral pain syndrome: the possible role of an inadequate neuromuscular mechanism. AB - The patellofemoral pain syndrome is described by a great number of papers as a pathology related mainly to the knee extensor mechanism. However, this knee problem may have an influence on the other joints of the lower extremity. To explain the interdependence between joints of the lower extremity, the support moment concept was used as a framework for the present study. Based on this concept we hypothesized that patellofemoral pain syndrome subjects reduce the stress on their painful patellofemoral joint by decreasing the use of the knee extensor muscles during functional activities. In order to achieve the same support moment, a smaller contraction of the knee extensors could be compensated by an overuse of the hip extensors and ankle plantarflexors. The aim of this study was to verify these compensations in a strenuous functional activity for the knee by comparing 11 subjects having a patellofemoral pain syndrome with 11 normal subjects. Three squat tests were performed:NATURAL, IMPOSED, and TIP TOES. The results obtained in the tip toes test indicated that patellofemoral pain subjects have: (a) a significantly greater knee extensor moment, and (b) a significantly lower hip extensor moment as compared to the normal. A greater straightening of the trunk was observed on patellofemoral pain syndrome patients during the tip toes test as compared to the other tests. Contrary to the expected hypothesis, the patellofemoral pain subjects did not show a strategy tending to decrease the knee extensor moments. In fact in the squat test on tip toes, the subjects affected by a patellofemoral pain syndrome overused the knee extensor muscles. PMID- 23916127 TI - Dynamic shoulder flexion strength: for use in occupational risk analysis and clinical assessment. AB - Given the likelihood of increased risk of musculoskeletal injury when joint torque strength demands approach the maximum isometric torque, this study determined the flexion torque strength capabilities of the shoulder in young men and women. To our knowledge this is the first study to report dynamic shoulder flexion torques. Peak static flexion torque values were collected at shoulder angles of 0 degrees (anatomical position) and 45 degrees of flexion in 25 female and 26 male subjects seated in an upright position. Dynamic concentric and eccentric shoulder flexion torques were collected at 50 degrees s(-1) angular velocity from 0 degrees to each subject's comfortable flexion limit on a KIN-COM dynamometer. Results indicated that for both static and dynamic strength measures, female subjects produced, on average, half of the torque output of males. Mean male flexion torques were: static at 0 degrees = 89.9 N m; static at 45 degrees = 68.6 N m; dynamic at 45 degrees = 46.9 N m (concentric); dynamic at 45 degrees = 75.3 N m (eccentric). PMID- 23916128 TI - Effect of various head and neck positions on vertebral artery blood flow. AB - The purpose of this study was to assess blood flow velocity in the vertebral arteries with duplex Doppler ultrasound during various positions of the head and neck. Vertebral artery morphology and blood flow velocity were assessed in a control group and in a group of subjects who displayed clinical signs and symptoms of vertebrobasilar insufficiency. The two groups did not differ in vertebral artery gross morphology as assessed by ultrasound. The arteries were examined for vascular impedance by calculating the ratio of peak systolic velocity to end diastolic velocity (systolic/diastolic ratio). In the context of this study, a lower velocity ratio implied less resistance to vascular flow. These velocity ratios were established during several positions of the head and neck, including a widely used provocational test manoeuvre for vertebrobasilar insufficiency. No meaningful significant differences in mean velocity ratios were found between the two groups. None of the subjects had abnormal spectral flow patterns during the different testing positions. PMID- 23916129 TI - Toward early detection of the tendency to stress fractures. AB - Certain characteristics of the foot structure represented by the contact pressure display method provide a clear indication of the tendency to experience stress fractures. The main results of the research project are (i) the static foot ground pressure diagram may supply basic information about the foot structure, needed to understand its behaviour, (ii) a new concept of stress intensity parameters was introduced and appeared to be basic for the foot structure evaluation, (iii) a set of criteria was established to classify the foot structure and its tendency to stress fractures, (iv) a simple computerized screening technique can calculate and classify the values of above parameters and relate them to the established criteria. The results may enable a scientific and practical approach in characterizing foot orthopaedic problems and might help to rate the stress fracture risk. PMID- 23916130 TI - Relationship between foot placement and mediolateral ground reaction forces during running. AB - This study investigated the relationship between foot placement relative to midline and mediolateral ground reaction forces during running. Data from 40 runners seen over a period of 2 years in a running injury clinic were analysed. A linear regression analysis revealed no significant relationship between foot placement and peak mediolateral values. Significance was found between foot placement and impulse, indicating that as the foot became more crossed over the lateral contribution to the total impulse increased (and vice versa). However, only 15% of the total variance in this model was accounted for. Despite these weak findings, subjects in the extreme range of foot placement (both wide-base and cross-over) appeared to exhibit stronger influences on mediolateral impulses. Therefore in the second phase of this study a symptom-free runner was tested while running with a 5-cm cross-over and wide-base gait, along with a neutral gait pattern. In the cross-over gait the contribution of the lateral impulse to the total impulse was 97%. Similar findings were noted with the medial contribution in the wide-based gait. Finally, the cross-over gait resembled the mediolateral force pattern observed during a 45-degree cut to the right (but exhibited lesser magnitudes), while the wide-base gait was similar to a cut to the left. PMID- 23916131 TI - Ground reaction force and its moment with respect to the knee joint centre in a total condylar arthroplasty series. AB - In a group of patients with rheumatoid arthritis (n = 5)and osteoarthrosis (n =3) who had had had 12 total condylar knee arthroplasties a new technique for assessment of ground reaction forces was used. This technique graphically displays force vectors superimposed in real time on a video recording of the subject walking. We found that this new technique could assess reliably moments of the ground reaction force vectors with respect to the centre of the knee joint. Four patients had bilateral total condylar knee arthroplasty. All patients were subjectively satisfied with their operations and had neither radiographic nor clinical signs of loosening. Considerable moments were found in the dorsal part of the medial tibiofemoral compartment. These moments increased with extension deficits and varus angles. The size of these moments were consistent with earlier findings of increased bone strengths in the same compartment as the biological answer to stress demands and earlier studies of moment after total condylar knee arthroplasty. PMID- 23916132 TI - Influence of activity on plantar force distribution. AB - The purpose of the study was to quantify the influence of physical activity on force distribution on the plantar surface of the foot. Eleven healthy subjects each performed 10 walking trials over a force distribution platform: five trials before and five trials after a 30-min run. For the analysis the foot was divided into three different regions (rearfoot, midfoot, forefoot), and maximal and average forces were determined for each region. The only statistically significant difference was found in the maximal force in the forefoot, but the difference was relatively small (<3%). The results suggested that the half-hour run did not have a large effect on the plantar force distribution. Differences between subjects were significant for all variables, indicating that relevant information on individual foot structure and/or gait may be obtained from the plantar force distribution. PMID- 23916133 TI - Fatigue failure at the disc-vertebra interface during cyclic axial compression of cadaveric specimens. AB - Seven specimens of adjacent lumbar vertebrae, with the disc between them, were obtained from five cadavers (age 40-80 years). The vertebrae were bisected in the transverse plane, posterior elements were removed and the specimens subjected to cyclic compression, with a peak load of 1.9 kN at a frequency of 0.5 Hz. During loading, the bulging of the end-plate into the more caudal of the two vertebrae was monitored using a displacement transducer. Application of the load was continued for 7000 cycles, or until the end-plate displacement reached 1.5 mm, whichever happened first. One specimen did not fail; another failed within only five loading cycles, i.e. not by fatigue. The remaining five specimens showed signs of fatigue failure but the end-plate remained intact. PMID- 23916134 TI - Nelfinavir and bortezomib inhibit mTOR activity via ATF4-mediated sestrin-2 regulation. AB - Endoplasmic reticulum (ER) stress and autophagy are two basic cell survival mechanisms often occurring in concert. Extensive ER stress in cancer cells deliberately induced by chemotherapeutic drugs may lead to growth arrest and cell death. However, the link between ER stress and autophagy is not well understood. In this study, the treatment of cancer cells with ER stress-inducing drug nelfinavir resulted in the expression of endogenous mTOR inhibitor sestrin-2 (SESN2). Upregulation of SESN2 expression was associated with expression of ER stress markers ATF4, ATF3, and CHOP. SESN2 upregulation also occurred in cells treated with the proteasome inhibitor bortezomib. Ectopic expression of ATF4, but not of ATF3 or CHOP, caused transcriptional upregulation of SESN2 expression, indicating expressional regulation of SESN2 by ATF4. Transient overexpression of ectopic SESN2 resulted in mTOR inhibition and autophagy, confirming a link between ER stress, SESN2 upregulation, and mTOR inhibition. Accordingly, cancer cells treated with the ER stress-inducing agent nelfinavir showed reduced mTOR activity and associated increases in the expression levels of ATF4 and SESN2. These results show that ATF4-regulated SESN2 expression presents a new link between ER stress and mTOR inhibition and autophagy. mTOR inhibition by nelfinavir, which is currently in clinical trials for cancer patients, may also explain its observed ability to induce autophagy, growth arrest, and radiosensitization in cancer cells. PMID- 23916136 TI - Laparoscopic ureteral replacement by Boari flap: multi-institutional experience in 30 cases. AB - INTRODUCTION: The Boari flap is an excellent technique for replacement of distal ureteral injuries. There are few reports with the use of laparoscopic surgery, especially with long term results. Our goal is to present the results of a multi institutional study of 30 cases. MATERIAL AND METHODS: We analyzed 30 patients treated between December 2001 and January 2009 who underwent a laparoscopic intracorporeal Boari flap, in three Latin American centers. In all cases the same surgical technique was employed. The database was recorded prospectively and analyzed retrospectively. RESULTS: The mean age was 43.2 years (range 9 to 71 years). Most were women (22 of 30) with a slight predominance of left-side lesions (17 of 30). The most common cause of ureteral injury was hysterectomy in 14 patients (46.6%) and endoscopic ureterolithotomy in 9 patients (30%). The mean length of ureteral resection was 7 cm. (5 to 20 cm). The average operative time was 161.16 min (90 to 280 min). The average estimated blood loss was 123 mL. (0 to 500 mL), and hospital stay was 4.86 days (2 to 10 days). There were no intraoperative complications or conversion to open surgery. Postoperative complications occurred in 5 patients (16.6%), Clavien 1 in 2 patients (6.6%) and Clavien 3 in three patients (10%). The success rate was 96.6% (29 patients) with a mean follow up of 32 months (5 to 60 months). CONCLUSIONS: Laparoscopic Boari flap in our hands had good short and long term results. PMID- 23916135 TI - SPARCL1 suppresses metastasis in prostate cancer. AB - PURPOSE: Metastasis, the main cause of death from cancer, remains poorly understood at the molecular level. EXPERIMENTAL DESIGN: Based on a pattern of reduced expression in human prostate cancer tissues and tumor cell lines, a candidate suppressor gene (SPARCL1) was identified. We used in vitro approaches to determine whether overexpression of SPARCL1 affects cell growth, migration, and invasiveness. We then employed xenograft mouse models to analyze the impact of SPARCL1 on prostate cancer cell growth and metastasis in vivo. RESULTS: SPARCL1 expression did not inhibit tumor cell proliferation in vitro. By contrast, SPARCL1 did suppress tumor cell migration and invasiveness in vitro and tumor metastatic growth in vivo, conferring improved survival in xenograft mouse models. CONCLUSIONS: We present the first in vivo data suggesting that SPARCL1 suppresses metastasis of prostate cancer. PMID- 23916137 TI - The role of matrix metalloproteinase MMP-9 and TIMP-2 tissue inhibitor of metalloproteinases as serum markers of bladder cancer. AB - INTRODUCTION: The diagnosis and molecular staging of bladder cancer based on the detection of gelatinases mRNA (MMP-2 and MMP-9) in peripheral blood circulating and mononuclear cells have shown promising results. We analyze if the determination of the corresponding protein synthesis products makes it possible to diagnose and characterize patients with bladder cancer. MATERIAL AND METHOD: Quantification of the serum levels of MMP-2, MMP-9 and TIMP-2 in a series of 42 individuals (31 patients with bladder cancer in different stages and 11 healthy controls) using the ELISA technique was carried out. The determinations were compared between cases and controls (Mann-Whitney U) and between different groups of tumors (Mann-Whitney U or Kruskal-Wallis), according to the clinical pathological characteristics (age, gender, T category, M category or grade). Diagnostic yield of these markers was evaluated by analysis of the ROC curves. RESULTS: There is a correlation between the determinations of MMP-2 and TIMP-2 (R=.699; P>.0001) and MMP-9 and TIMP-2 (R=.305; P=.049). Patients with bladder cancer have higher levels of MMP-9 (p<0.0001) and TIMP-2 (P=.047) than the controls. Furthermore, the MMP-9/TIMP-2 ratio is also superior in cancer patients (P<.001). Differences were not detected between cancer and controls regarding age (P=.64) or gender (P=.64). Differences were also not detected regarding MMP-2 (P=.35) or MMP-2/TIMP-2 rate (P=.45). Within the cancer patient population, the MMP-2 and MMP-9 values differ according to T category (P=.022 and P=.038, respectively) and those of the TIMP-2 according to M category (P=.036). ROC curve analysis showed that both MMP-9 and the MMP-9/TIMP-2 ratio discriminate patients with cancer and controls, with equivalent diagnostic accuracy (ABC 0.953) and cut offs of 3.93 ng/mL (S 90%; Sp 81%) and 0.053 ng/mL (S 96%; Sp 84%), respectively. CONCLUSIONS: The results obtained suggest that both serum MMP-9 and TIMP-2 would have an application in the prediction of the development and progression of bladder cancer, and a potential utility as clinical markers of the disease. Multicenter, prospective studies that confirm their preliminary results are necessary. PMID- 23916138 TI - Laparoscopic surgery of vesicoureteral reflux: an experience in 42 patients with the Lich-Gregoir extravesical technique. AB - INTRODUCTION: Vesico-ureteral reflux (VUR) is a common congenital anomaly of the urinary tract in the pediatric population, existing controversy regarding its management. Patients selected for treatment options are offered, from endoscopic injection of substances sub-ureteral to ureteral reimplantation surgery. OBJECTIVE: To evaluate the use of the laparoscopic surgical technique for the treatment of vesico-ureteral reflux, with an analysis of the procedure, results and complications. MATERIAL AND METHODS: We evaluated a series of 50 ureteral units in 42 patients, who undergoing laparoscopic transperitoneal ureteral reimplant, using the classic technique of Lich-Gregoir detrusorrafia. RESULTS: The mean operative time was 74 min. There were no intraoperative nor immediate postoperative. At longer follow-up VUR was cured in all cases. CONCLUSIONS: Laparoscopic surgery is an effective alternative in the surgical treatment of vesico-ureteral reflux, with results comparable to open surgery techniques and over sub-ureteral injection techniques. PMID- 23916139 TI - Prevalence of Trypanosoma cruzi infection in Latin American pregnant women and level of compliance of the Valencian Health Programme in the city of Alicante: a reply. PMID- 23916140 TI - Patients with obstructive sleep apnea after laparoscopic bariatric surgery: oxygen and continuous positive pressure could always be enough? PMID- 23916142 TI - EEG characterization of audiogenic seizures in the hamster strain GASH:Sal. AB - The study was performed to characterize GASH:SAL audiogenic seizures as true epileptic activity based on electroencephalographic markers acquired with a wireless implanted radiotelemetry system. We analyzed cortical EEG patterns synchronized with video recordings of convulsive behavior of the GASH:Sal hamster following an acoustic stimulus. All GASH:Sal presented archetypal motor symptoms comparable to current animal models of generalized tonic-clonic epilepsy. Seizures consisted of an initial bout of wild running, followed by opisthotonus, tonic-clonic convulsions, tonic limb extension, and terminated in postictal depression. EEG patterns correlated with behavior and displayed phase appropriate spike-wave complexes, low-amplitude desynchronized activity, and high frequency large-amplitude peaks. Our results confirm that electroencephalographic profiles of the audiogenic seizures of the hamster GASH:Sal are parallel to EEG patterns of other animal models of generalized tonic-clonic seizures. Therefore, this animal may serve as an appropriate model for epilepsy research. PMID- 23916143 TI - Low incidence of SCN1A genetic mutation in patients with hemiconvulsion hemiplegia-epilepsy syndrome. AB - Genetic mutations in SCN1A account for more than two-thirds of patients with classic Dravet syndrome. A role for SCN1A genetic mutations in the development of hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome was recently suggested based on the observation that HHE syndrome and classic Dravet syndrome share many clinical features. We previously identified a 2 bp-deletion mutation in SCN1A in a Dravet patient, and we found out the patient also had HHE syndrome upon clinical re evaluation. We subsequently screened 10 additional HHE patients for SCN1A. Among the 11 patients who were diagnosed with HHE syndrome, six patients had no other etiology with the exception of prolonged febrile illness, therefore classified as idiopathic HHE syndrome, whereas five patients were classified as symptomatic HHE syndrome. Direct sequencing of all coding exons and flanking intronic sequences of the SCN1A gene was performed, but we failed to identify additional mutations in 10 patients. The patient with SCN1A mutation had the earliest onset of febrile convulsion and hemiparesis. Our study suggests that SCN1A genetic mutation is only a rare predisposing cause of HHE syndrome. PMID- 23916144 TI - Early detection of bone metabolism changes under different antiepileptic drugs (ED-BoM-AED)--a prospective multicenter study. AB - PURPOSE: To determine early changes in bone turnover markers induced by treatment with oxcarbazepine or valproate. METHODS: In this prospective study, 31 adults with newly diagnosed epilepsy were included who were started on therapy with either oxcarbazepine (OXC, n=16, mean age 45.6 years, 37.5% female) or valproate (VPA, n=15, mean age 42.2 years, 33.3% female). Clinical characteristics were obtained at baseline, after 2 weeks and 3 months. In addition, blood samples were drawn at each visit. Calcium, phosphate, alkaline phosphatase (AP), receptor activator of NF-kappaB ligand (RANKL), osteoprotegerin (OPG), osteocalcin (OC) and cathepsin K were determined. RESULTS: In OXC treated patients, OPG increased by 0.06 pmol/L (p=0.0004) after 2 weeks and remained elevated by 0.05 pmol/L (p=0.02) after 3 months. Between 2 weeks and 3 months of OXC treatment, OC increased by 1.98 ng/mL (p=0.02). During the first 3 months of OXC treatment, total serum AP increased by 11%+/-9% (p=0.02). Compared to baseline, serum calcium raised by 0.06 mmol/L (p=0.04) after 2 weeks and by 0.07 mmol/L (p=0.004) after 3 months of OXC treatment. In VPA treated patients, a late OPG increase by 0.07 pmol/L (p=0.007) occurred after 3 months. During the first 3 months of OXC treatment, total serum AP decreased by by 7%+/-15% (p=0.03). No changes in OC or calcium were seen. RANKL was below detection limit in 16 out of 31 patients (52%) and did not change significantly during treatment. Cathepsin K was below detection limit at baseline in 27 out of 31 patients (87%) and was therefore not further evaluated. Phosphate did not change during treatment. CONCLUSION: Increased bone turnover can be measured within few weeks of newly started treatment with OXC, while significant changes under VPA treatment occurred only after 3 months. Our data suggest distinct mechanisms of increased bone turnover in different anticonvulsants. These variable mechanisms may require individual prevention and treatment strategies. PMID- 23916146 TI - Development of a pharmacophore model for the catecholamine release-inhibitory peptide catestatin: virtual screening and functional testing identify novel small molecule therapeutics of hypertension. AB - The endogenous catecholamine release-inhibitory peptide catestatin (CST) regulates events leading to hypertension and cardiovascular disease. Earlier we studied the structure of CST by NMR, molecular modeling, and amino acid scanning mutagenesis. That structure has now been exploited for elucidation of interface pharmacophores that mediate binding of CST to its target, with consequent secretory inhibition. Designed pharmacophore models allowed screening of 3D structural domains. Selected compounds were tested on both cultured catecholaminergic cells and an in vivo model of hypertension; in each case, the candidates showed substantial mimicry of native CST actions, with preserved or enhanced potency and specificity. The approach and compounds have thus enabled rational design of novel drug candidates for treatment of hypertension or autonomic dysfunction. PMID- 23916145 TI - Molecular basis of HHQ biosynthesis: molecular dynamics simulations, enzyme kinetic and surface plasmon resonance studies. AB - BACKGROUND: PQS (PseudomonasQuinolone Signal) and its precursor HHQ are signal molecules of the P. aeruginosa quorum sensing system. They explicate their role in mammalian pathogenicity by binding to the receptor PqsR that induces virulence factor production and biofilm formation. The enzyme PqsD catalyses the biosynthesis of HHQ. RESULTS: Enzyme kinetic analysis and surface plasmon resonance (SPR) biosensor experiments were used to determine mechanism and substrate order of the biosynthesis. Comparative analysis led to the identification of domains involved in functionality of PqsD. A kinetic cycle was set up and molecular dynamics (MD) simulations were used to study the molecular bases of the kinetics of PqsD. Trajectory analysis, pocket volume measurements, binding energy estimations and decompositions ensured insights into the binding mode of the substrates anthraniloyl-CoA and beta-ketodecanoic acid. CONCLUSIONS: Enzyme kinetics and SPR experiments hint at a ping-pong mechanism for PqsD with ACoA as first substrate. Trajectory analysis of different PqsD complexes evidenced ligand-dependent induced-fit motions affecting the modified ACoA funnel access to the exposure of a secondary channel. A tunnel-network is formed in which Ser317 plays an important role by binding to both substrates. Mutagenesis experiments resulting in the inactive S317F mutant confirmed the importance of this residue. Two binding modes for beta-ketodecanoic acid were identified with distinct catalytic mechanism preferences. PMID- 23916147 TI - Biotransformation of ent-pimaradienoic acid by cell cultures of Aspergillus niger. AB - Microbial transformation stands out among the many possible semi-synthetic strategies employed to increase the variety of chemical structures that can be applied in the search for novel bioactive compounds. In this paper we obtained ent-pimaradienoic acid (1, PA, ent-pimara-8(14),15-dien-19-oic acid) derivatives by fungal biotransformation using Aspergillus niger strains. To assess the ability of such compounds to inhibit vascular smooth muscle contraction, we also investigated their spasmolytic effect, along with another five PA derivatives previously obtained in our laboratory, on aortic rings isolated from male Wistar rats. The microbial transformation experiments were conducted at 30 degrees C using submerged shaken liquid culture (120 rpm) for 10 days. One known compound, 7alpha-hydroxy ent-pimara-8(14),15-dien-19-oic acid (2), and three new derivatives, 1beta-hydroxy ent-pimara-6,8(14),15-trien-19-oic acid (3), 1alpha,6beta,14beta-trihydroxy ent-pimara-7,15-dien-19-oic acid (4), and 1alpha,6beta,7alpha,11alpha-tetrahydroxy ent-pimara-8(14),15-dien-19-oic acid (5), were isolated and identified on the basis of spectroscopic analyses and computational studies. The compounds obtained through biotransformation (2-5) did not display a significant antispasmodic activity (values ranging from 0% to 16.8% of inhibition); however the previously obtained diterpene, methyl 7alpha-hydroxy ent-pimara-8(14),15-dien-19-oate (8), showed to be very effective (82.5% of inhibition). In addition, our biological results highlight the importance to study the antispasmodic potential of a large number of novel diterpenes, to conduct further structure-activity relationship investigations. PMID- 23916148 TI - Synthesis and evaluation of novel 3-(3,5-dimethylbenzyl)uracil analogs as potential anti-HIV-1 agents. AB - A novel series of uracil derivatives with a 3,5-dimethylbenzyl group at the N(3) position were synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors. Some of these compounds showed good-to-moderate activity with EC50 values in the submicromolar range. Among them, compound 10c showed significant potency against HIV-1 activity with an EC50 value of 0.03 MUM and a high selectivity index of 2863. Preliminary structure-activity relationships and molecular modeling analyses were used to explore the major interactions between HIV-1 reverse transcriptase and the potent inhibitor 10c, which may serve as an important lead for further optimization. PMID- 23916150 TI - NMR determination of Electrophorus electricus acetylcholinesterase inhibition and reactivation by neutral oximes. AB - Neurotoxic organophosphorus compounds (OPs), which are used as pesticides and chemical warfare agents lead to more than 700,000 intoxications worldwide every year. The main target of OPs is the inhibition of acetylcholinesterase (AChE), an enzyme necessary for the control of the neurotransmitter acetylcholine (ACh). The control of ACh function is performed by its hydrolysis with AChE, a process that can be completely interrupted by inhibition of the enzyme by phosphylation with OPs. Compounds used for reactivation of the phosphylated AChE are cationic oximes, which usually possess low membrane and hematoencephalic barrier permeation. Neutral oximes possess a better capacity for hematoencephalic barrier permeation. NMR spectroscopy is a very confident method for monitoring the inhibition and reactivation of enzymes, different from the Ellman test, which is the common method for evaluation of inhibition and reactivation of AChE. In this work (1)H NMR was used to test the effect of neutral oximes on inhibition of AChE and reactivation of AChE inhibited with ethyl-paraoxon. The results confirmed that NMR is a very efficient method for monitoring the action of AChE, showing that neutral oximes, which display a significant AChE inhibition activity, are potential drugs for Alzheimer disease. The NMR method showed that a neutral oxime, previously indicated by the Ellman test as better in vitro reactivator of AChE inhibited with paraoxon than pralidoxime (2-PAM), was much less efficient than 2-PAM, confirming that NMR is a better method than the Ellman test. PMID- 23916149 TI - Investigation of acyclic uridine amide and 5'-amido nucleoside analogues as potential inhibitors of the Plasmodium falciparum dUTPase. AB - Previously we have shown that trityl and diphenyl deoxyuridine derivatives and their acyclic analogues can inhibit Plasmodium falciparum dUTPase (PfdUTPase). We report the synthesis of conformationally restrained amide derivatives as inhibitors PfdUTPase, including both acyclic and cyclic examples. Activity was dependent on the orientation and location of the amide constraining group. In the case of the acyclic series, we were able to obtain amide-constrained analogues which showed similar or greater potency than the unconstrained analogues. Unfortunately these compounds showed lower selectivity in cellular assays. PMID- 23916151 TI - Synthesis and biological evaluation of 1,7,8,8a-tetrahydro-3H-oxazolo[3,4 a]pyrazin-6(5H)-ones as antitumoral agents. AB - A series of 1,7,8,8a-tetrahydro-3H-oxazolo[3,4-a]pyrazin-6(5H)-ones has been synthesized by an intramolecular, palladium(II) catalyzed, aminooxygenation of alkenyl ureas, readily available from glycine allylamides as starting materials. Biological tests showed that the obtained compounds are endowed with an interesting antitumoral activity against two human thyroid cancer cell lines, namely FTC-133 and 8305C, by promoting the apoptotic pathway and DNA fragmentation. PMID- 23916153 TI - Neonatal health of infants born to mothers with asthma. AB - BACKGROUND: Maternal asthma is associated with serious pregnancy complications, but newborn morbidity is understudied. OBJECTIVE: We wanted to determine whether infants of asthmatic mothers have more neonatal complications. METHODS: The Consortium on Safe Labor (2002-2008), a retrospective cohort, included 223,512 singleton deliveries at >= 23 weeks' gestation. Newborns of mothers with asthma (n = 17,044) were compared with newborns of women without asthma by using logistic regression models with generalized estimating equations to calculate adjusted odds ratios (ORs) and 95% CIs. Electronic medical record data included gestational week at delivery, birth weight, resuscitation, neonatal intensive care unit (NICU) admission, NICU length of stay, hyperbilirubinemia, respiratory distress syndrome, apnea, sepsis, anemia, transient tachypnea of the newborn, infective pneumonia, asphyxia, intracerebral hemorrhage, seizure, cardiomyopathy, periventricular or intraventricular hemorrhage, necrotizing enterocolitis, aspiration, retinopathy of prematurity, and perinatal mortality. RESULTS: Preterm delivery was associated with maternal asthma for each week after 33 completed weeks of gestation and not earlier. Maternal asthma also increased the adjusted odds of small for gestational age (OR = 1.10; 95% CI, 1.05-1.16), NICU admission (OR = 1.12; 95% CI, 1.07-1.17), hyperbilirubinemia (OR = 1.09; 95% CI, 1.04 1.14), respiratory distress syndrome (OR = 1.09; 95% CI, 1.01-1.19), transient tachypnea of the newborn (OR = 1.10; 95% CI, 1.02-1.19), and asphyxia (OR = 1.34; 95% CI, 1.03-1.75). Findings persisted for term infants (>= 37 weeks) who had additional increased odds of intracerebral hemorrhage (OR = 1.84; 95% CI, 1.11 3.03) and anemia (OR = 1.30; 95% CI, 1.04-1.62). CONCLUSIONS: Maternal asthma was associated with prematurity and small for gestational age. Adverse neonatal outcomes, including respiratory complications, hyperbilirubinemia, and NICU admission, were increased in association with maternal asthma even among term deliveries. PMID- 23916152 TI - New potent and selective polyfluoroalkyl ketone inhibitors of GVIA calcium independent phospholipase A2. AB - Group VIA calcium-independent phospholipase A2 (GVIA iPLA2) has recently emerged as an important pharmaceutical target. Selective and potent GVIA iPLA2 inhibitors can be used to study its role in various neurological disorders. In the current work, we explore the significance of the introduction of a substituent in previously reported potent GVIA iPLA2 inhibitors. 1,1,1,2,2-Pentafluoro-7-(4 methoxyphenyl)heptan-3-one (GK187) is the most potent and selective GVIA iPLA2 inhibitor ever reported with a XI(50) value of 0.0001, and with no significant inhibition against GIVA cPLA2 or GV sPLA2. We also compare the inhibition of two difluoromethyl ketones on GVIA iPLA2, GIVA cPLA2, and GV sPLA2. PMID- 23916154 TI - Quantification and characterization of dissolved organic nitrogen in wastewater effluents by electrodialysis treatment followed by size-exclusion chromatography with nitrogen detection. AB - Dissolved organic nitrogen (DON) can act as a precursor of nitrogenous disinfection byproducts during oxidative water treatment. Quantification and characterization of DON are still challenging for waters with high concentrations of dissolved inorganic nitrogen (DIN, including ammonia, nitrate and nitrite) relative to total dissolved nitrogen (TDN) due to the cumulative analytical errors of independently measured nitrogen species (i.e., DON = TDN - NO2(-) - NO3(-) - NH4(+)/NH3) and interference of DIN species to TDN quantification. In this study, a novel electrodialysis (ED)-based treatment for selective DIN removal was developed and optimized with respect to type of ion-exchange membrane, sample pH, and ED duration. The optimized ED method was then coupled with size-exclusion chromatography with organic carbon, UV, and nitrogen detection (SEC-OCD-ND) for advanced DON analysis in wastewater effluents. Among the tested ion-exchange membranes, the PC-AR anion- and CMT cation-exchange membranes showed the lowest DOC loss (1-7%) during ED treatment of a wastewater effluent at ambient pH (8.0). A good correlation was found between the decrease of the DIN/TDN ratio and conductivity. Therefore, conductivity has been adopted as a convenient way to determine the optimal duration of the ED treatment. In the pH range of 7.0-8.3, ED treatment of various wastewater effluents with the PC AR/CMT membranes showed that the relative residual conductivity could be reduced to less than 0.50 (DIN removal >90%; DIN/TDN ratio <= 0.60) with lower DOC losses (6%) than the previous dialysis and nanofiltration methods (DOC loss >10%). In addition, the ED method is shorter (0.5 h) than the previous methods (>1-24 h). The relative residual conductivity was further reduced to ~ 0.20 (DIN removal >95%; DIN/TDN ratio <= 0.35) by increasing the ED duration to 0.7 h (DOC loss = 8%) for analysis by SEC-OCD-ND, which provided new information on distribution and ratio of organic carbon and nitrogen in different molecular weight fractions of effluent organic matter. PMID- 23916155 TI - Mobility of nanosized cerium dioxide and polymeric capsules in quartz and loamy sands saturated with model and natural groundwaters. AB - The environmental and health risks posed by emerging engineered nanoparticles (ENPs) released into aquatic environments are largely dependent on their aggregation, transport, and deposition behavior. Herein, laboratory-scale columns were used to examine the mobility of polyacrylic acid (PAA)-coated cerium dioxide nanoparticles (nCeO2) and an analogous nanosized polymeric capsule (nCAP) in water saturated quartz sand or loamy sand. The influence of solution ionic strength (IS) and cation type (Na(+), Ca(2+), or Mg(2+)) on the transport potential of these ENPs was examined in both granular matrices and results were also compared to measurements obtained using a natural groundwater. ENP suspensions were characterized using dynamic light scattering and nanoparticle tracking analysis to establish aggregate size, and laser Doppler electrophoresis to determine ENP electrophoretic mobility. Regardless of IS, virtually all nCeO2 particles suspended in NaNO3 eluted from the quartz sand-packed columns. In contrast, heightened nCeO2 and nCAP particle retention and dynamic (time dependent) transport behavior was observed with increasing concentrations of the divalent salts and in the presence of natural groundwater. Enhanced particle retention was also observed in loamy sand in comparison to the quartz sand, emphasizing the need to consider the nature of the aqueous matrix and granular medium in evaluating contamination risks associated with the release of ENPs in natural and engineered aquatic environments. PMID- 23916156 TI - Assessing the effects of bacterial predation on membrane biofouling. AB - Membrane biofouling is one of the major obstacles limiting membrane applications in water treatment. In this study, Bdellovibrio bacteriovorus HD 100, a Gram negative predatory bacterium, was evaluated as a novel way to mitigate membrane biofouling and its subsequent performance decline. Dead-end microfiltration (MF) tests were carried out on Escherichia coli DH5alpha and B. bacteriovorus HD 100 co-culture feed solutions. Predation of E. coli was performed at either a low or high multiplicity of infection (MOI), which is defined as the predator to prey cell ratio. The MOIs tested were 2 and 200, and the viability of both the E. coli prey and the predator was monitored over 48 h. The higher MOI (high predator, HP) culture showed a nearly 6-log loss in E. coli number after 24 h when compared to both the control and low MOI (low predator, LP) cultures, whereas the E. coli population within both predated cultures (HP and LP) became nearly identical at 48 h and 4-log lower than that of the control. The unpredated cultures led to significant loss in water flux at 12, 24, and 48 h of culture, but the HP and LP membranes showed less loss of flux by comparison. Analysis of the total membrane resistance showed a similar trend as the flux decline pattern; however, irreversible resistance of the membrane was much higher for the 48 h LP culture compared to the unpredated and HP cultures at 48 h. This increase in irreversible resistance was attributed mainly to E. coli debris, which accumulated in the medium after the predator lysed the prey cells. These results show that pretreatment of wastewater using a suitable concentration of predatory bacteria such as B. bacteriovorus can enhance membrane performance. PMID- 23916158 TI - Supramolecular organization of protonated aminosilicones in water. AB - This study deals with the ionically-driven self-assembly of oligomeric aminosilicones, judiciously protonated with a variety of organic acids. Depending on the length of the silicone and the strength of the associated acids, (inverse) water-in-silicone emulsions, small nanoparticles, or catanionic vesicles were prepared and characterized by conventional (TEM) or original (DIC optical microscopy, DOSY NMR) techniques. For chains longer than about 40 units, a specific PEG-based sulfonic acid was synthesized and used to generate a supramolecular block-like copolymer and ensure fast and efficient emulsification. In all instances, a simple impulse such as pH increase triggered phase separation of the colloidal objects. PMID- 23916159 TI - Variety is the spice of life: the enormous diversity of plant biotic interactions. PMID- 23916157 TI - Multi-laboratory evaluations of the performance of Catellicoccus marimammalium PCR assays developed to target gull fecal sources. AB - Here we report results from a multi-laboratory (n = 11) evaluation of four different PCR methods targeting the 16S rRNA gene of Catellicoccus marimammalium originally developed to detect gull fecal contamination in coastal environments. The methods included a conventional end-point PCR method, a SYBR((r)) Green qPCR method, and two TaqMan((r)) qPCR methods. Different techniques for data normalization and analysis were tested. Data analysis methods had a pronounced impact on assay sensitivity and specificity calculations. Across-laboratory standardization of metrics including the lower limit of quantification (LLOQ), target detected but not quantifiable (DNQ), and target not detected (ND) significantly improved results compared to results submitted by individual laboratories prior to definition standardization. The unit of measure used for data normalization also had a pronounced effect on measured assay performance. Data normalization to DNA mass improved quantitative method performance as compared to enterococcus normalization. The MST methods tested here were originally designed for gulls but were found in this study to also detect feces from other birds, particularly feces composited from pigeons. Sequencing efforts showed that some pigeon feces from California contained sequences similar to C. marimammalium found in gull feces. These data suggest that the prevalence, geographic scope, and ecology of C. marimammalium in host birds other than gulls require further investigation. This study represents an important first step in the multi-laboratory assessment of these methods and highlights the need to broaden and standardize additional evaluations, including environmentally relevant target concentrations in ambient waters from diverse geographic regions. PMID- 23916160 TI - Sleep in family caregivers of patients admitted to hospice: A pilot study. AB - OBJECTIVES: Caring for a dying family member is known to interfere with sleep, yet little is known about caregiver sleep once the patient is admitted to hospice. The aim of this pilot study was to describe the sleep of partners and other family caregivers of patients in hospice. METHODS: The pilot study used a cross-sectional, descriptive, and comparative design. Participants included the primary family caregivers of patients recently admitted to a hospice in Norway. Caregiver sleep during the prior month was measured with the Pittsburgh Sleep Quality Index (PSQI). During the patient's hospice stay, caregiver sleep was measured using wrist actigraphy for four nights and three days. RESULTS: Twenty family caregivers (12 partners and 8 other relatives) completed the study protocol without difficulty. On the PSQI, most caregivers (n = 13) reported clinically significant sleep problems during the prior month. Once the patient was admitted to hospice, actigraphy indicated that 10 caregivers had clinically significant sleep disruption (>=15% wake after sleep onset) and six averaged <7 hours of sleep per night. Partner caregivers reported more trouble falling asleep, and less sleep medication use, in the prior month than other types of family caregivers. However, once the patient was admitted to hospice, and after adjusting for caregiver age, partner caregivers experienced less sleep disruption than other caregivers. SIGNIFICANCE OF RESULTS: Findings demonstrate feasibility of the study protocol and indicate that sleep problems are common for caregivers of dying patients, even after the patient is admitted to hospice. The caregiver's relationship to the patient may be an important factor to consider in future studies. PMID- 23916161 TI - Assessment of xylitol serum levels during the course of parenteral nutrition including xylitol in intensive care patients: a case control study. AB - BACKGROUND & AIMS: Xylitol has been approved for parenteral nutrition and may be beneficial in catabolic situations. The aim was to establish an easy method to monitor xylitol serum levels in patients receiving xylitol and to determine whether xylitol is safe. METHODS: A commercially available xylitol test was validated and used to measure serum levels in 55 patients admitted to our intensive care unit with an indication for parenteral nutrition with xylitol for at least 24 h. Controls consisted of the most recent 56 patients admitted to the intensive care unit who received parenteral nutrition without xylitol for at least 2 days. Xylitol serum levels were determined using the test. Adverse events, liver enzymes, lactate, bilirubin, gamma-glutamyl transpeptidase, and insulin requirement were secondary endpoints. RESULTS: Patients receiving xylitol received 32.6% less insulin than controls. The amount of energy they received was comparable (xylitol: 810.1; controls: 789.8 kcal). Mean liver enzymes and lactate levels were similar in both groups. Adverse events considered attributable to xylitol did not occur. Xylitol did not accumulate in patients' blood and returned to near baseline values one day after parenteral nutrition was stopped. CONCLUSIONS: Parenteral nutrition with xylitol appears to be safe for critical care patients. There were no signs of hepatoxicity. TRIAL REGISTRATION DRKS: DRKS00004238. PMID- 23916162 TI - Relationship between intra-abdominal pressure and trunk EMG. AB - Intra-abdominal pressure (IAP) has been proposed as an important mechanism in manual lifting and breathing mechanics. Direct (invasive) measures of IAP have required the swallowing of a radio transducer or insertion of a pressure sensor into the rectum or down the oesophagus to the stomach. The purpose of this study was to investigate the relationship between a non-invasive method (EMG) and IAP. Several tasks involving abdominal muscle activation were performed to assess whether or not IAP played a common role in these tasks. IAP and EMG from rectus abdominis, the abdominal obliques, intercostals and erector spinae were measured. Peak IAP reached 340 mmHg (valsalva) for one subject but most values were less than 100 mmHg for tasks other than valsalva. The IAP and EMG data provide some insight into the role of IAP during the performance of specific tasks. Peak IAP within 60 ms of the onset of vigorous abdominal activation indicated the importance of a very rapid pressure response to abdominal muscle activation. The correlations between various muscle EMG time histories and IAP exceeded 0.80 for only two activities (i.e. r(2) = 0.82 between the intercostals and IAP during valsalva manoeuvres). These data suggest that no unifying hypothesis exists to explain the role of IAP for a wide variety of movement tasks; rather, the role of IAP is task specific. PMID- 23916163 TI - Concentric and eccentric torque variations of the quadriceps femoris in patellofemoral pain syndrome. AB - The purpose of this study was to investigate the extent of torque reduction in the quadriceps femoris in subjects complaining of patellofemoral pain syndrome compared to subjects with sound knees. Fifty-five patients (21 women and 34 men) and 30 healthy subjects (15 women and 15 men) took part in this study. Using the KINCOM isokinetic dynamometer, quadriceps torque was assessed at 30 degrees /s, 60 degrees /s, and 120 degrees /s, both in the concentric and eccentric modes. Findings demonstrated a significant (P < 0.01) reduction of between 30% and 40% in the patients when compared with the control group. This reduction was not speed or mode-specific. Men were stronger than women by a margin of 22% and 14% for the concentric and eccentric modes in the control group. Parallel figures for the patellofemoral pain syndrome group were 25% and 17%. Good to high correlations were found between peak and average torque in both groups. There were no significant differences between the muscles referring to the dominant versus the non-dominant legs of the control group. PMID- 23916164 TI - Biomechanical assessment of upright stance in parkinson's disease: a single subject study. AB - In order to evaluate the usefulness of biomechanical measures in the clinical assessment of Parkinson's disease, we studied the kinematics of upright stance in a patient with evident fluctuations in clinical state (ON-OFF), which allowed us to optimize experimental control. We determined the total amount of movement and the variability of whole body and body segment kinematics in the vertical, anterior-posterior (A-P), and medial-lateral planes. The total excursion parameter (TEX) represented the co-ordinate path over a 20 s period, and the movement variability parameter (VAR) was calculated based on the standard deviation about the quadratic fit to this path. Discriminant analysis was employed to assess the ability of these parameters to discriminate the patient's clinical state, and statistical reduction of the number of measures was accomplished with a stepwise selection procedure. Measures of shoulder A-P movement and the vertical motion of the centre of gravity (COG) were selected for inclusion in both discriminant functions. The VAR function included only four measures (vertical COG and A-P head, shoulder, and hip), while the TEX function required six measures to discriminate the clinical state. Results obtained with the VAR function were superior to those obtained with TEX, and VAR discriminated the OFF state, a common characteristic of Parkinson's disease, especially well. The results are promising, as the measures appear sensitive to the patient's clinical state even though fluctuation of symptoms was reduced in the latter part of the study by various treatments. PMID- 23916165 TI - Shoulder-arm muscular activity and reproducibility in carpenters' work. AB - The purpose of the present study was to analyse the levels of muscle activity that experienced carpenters reach in some arm-shoulder muscles when performing familiar tasks, and to find whether there are intra- and inter-individual similarities in muscle activity. Ten healthy carpenters performed twice on the same day: their tasks were, manual screwdriving at eye level, manual sawing on a saw horse, and nailing upward into the ceiling. Two weeks later the experiment was repeated. Normalized electromyography was used. The median activity levels during the period analysed did not exceed 15% of maximum electromyographic activity for any of the muscle groups studied. For some muscles and activities there were wide ranges of median activity levels. The most activated muscles in all three tasks were the trapezius pars descendens, infraspinatus and anterior deltoid. There was an intra-individual similarity between the median values from each trial. PMID- 23916166 TI - Prosthetic alignment effects on gait symmetry: a case study. AB - The loss of a significant portion of a lower extremity causes changes in the usual pattern of human ambulation. These changes have been documented kinematically, kinetically and metabolically, giving insight into the costs of limb amputation relative to ambulatory efforts. The role of the prosthetist is to provide a limb substitute to achieve the best gait performance, while assuring maximum comfort for the patient. This case study examined the effects of antero posterior alignment of a below-knee prosthesis on sagittal plane gait kinematics by comparing the anatomical side with the prosthetic side. The greatest changes due to variations of alignment were found during the prosthetic stance phase; knee angles showed the greatest asymmetry between anatomical and prosthetic sides. The stance phase on the prosthetic side was reduced with anterior socket displacement due to early knee flexion and toe-off. Posterior socket displacement caused a greater maximum centre of gravity height, but anterior socket displacement caused greater knee flexion which decreased the maximum centre of gravity height. Asymmetries in temporal and other kinematic parameters were not always minimal at the optimal alignment subjectively selected by a certified prosthetist. Comparisons of asymmetry ratios with prosthetic side data revealed the subclinical sensitivity of this amputee to antero-posterior alignment discrepancies. PMID- 23916167 TI - Biomechanical comparison of two paraplegic gait patterns. AB - A study is presented comparing the kinetic and kinematic characteristics of two gait patterns in common use by paraplegics. Data were collected using a combined kinetic and kinematic process from a total of 14 subjects with lesion of the spinal cord. Significant differences were derived for gait velocity and for the axial load transmission by the walking aids in both gaits. The cumulative effect of load transmission on the upper limb joints did not display clear differences between gaits. Load and moment impulse values over a given test distance were consistently greater using a swing-to gait than a swing-through gait, although the differences were not always statistically significant. It is suggested that closer consideration of the biomechanical demands of aided gait should be undertaken prior to the selection and training of paraplegic gait patterns. PMID- 23916168 TI - Implementation of a two-dimensional biomechanical model i n an opto-electronic motion analysis system. AB - The objective of this study was to implement a dynamic, two-dimensional biomechanical model, a force plate, and electromyography in a three-dimensional, opto-electronic motion analysis system. Further objectives were to present kinematic and kinetic data for basic movements used in rehabilitation and athletic testing, and to make the system rapid and adaptable for clinical use. Kinematic data, including joint movements and muscle length changes, as well as kinetic data, including net torque and net power output, are presented for the ankle, knee and hip joints when performing two-legged vertical counter-movement jumps, walking, and one-leg long hops. Coefficients of variation for net torque and the net power output were between 1.6% and 18.1% when analysing the countermovement jumps, and there were similar results for walking. When performing the hop, the coefficients of variation for net torques were all less than 16%, but power output values were unequivocally non-satisfactory (30% maximum). In conclusion, reliability was acceptable for the counter-movement jumps and for the analysis of walking, but power output reliability for the hops at touch-down was found to be poor, probably due to soft tissue and marker movement relative to the underlying bone. The moderate amount of time needed for testing makes the system useful for clinical practice. PMID- 23916169 TI - Flexibility in structurally normal young females and in young females with idiopathic scoliosis. AB - The bending stiffness of the trunk as related to ventral flexion was calculated in 10 young females with untreated idiopathic scoliosis and in 10 young females with structurally normal spines. Seven clinical measurements of joint flexibilities were also made. The ages of the subjects ranged from 10 to 16 years. The girls with scoliosis had similar or lower flexibility compared with the normal controls. The study provided no evidence that untreated scoliosis occurs or progresses because of increased flexibility. This report supports previous findings. PMID- 23916171 TI - [Overall child development: beyond pharmacological iodine supplementation]. AB - Iodine deficiency is a factor that may compromise child development, but is not the only one. Other health determinants, some of them outside the healthcare system, are able to influence development. Fighting iodine deficiency may be a pragmatic and useful strategy if it is found to be not maleficent, beneficial to health, and cost-effective, and does not make us lose the notion that child development goes beyond psychomotor or cognitive performance. This article analyzes such constraints from a critical point of view. PMID- 23916170 TI - Radiation therapy in primary mediastinal B-cell lymphoma with positron emission tomography positivity after rituximab chemotherapy. AB - PURPOSE: To investigate the role of radiation therapy (RT) in patients affected with primary mediastinal B-cell lymphoma (PMBCL) with residual (18)fluorodeoxyglucose positron emission tomography ((18)FDG-PET)-positive disease after rituximab chemotherapy (R-CT). METHODS AND MATERIALS: Thirty-seven patients treated with R-CT and RT, all with (18)FDG-PET scan at diagnosis and before RT, were included. All (18)FDG-PET scans were reviewed, and responses were classified according to the Deauville 5-point scoring system. Outcomes measures were overall survival (OS) and progression-free survival (PFS), estimated for the whole cohort and for subgroups according to (18)FDG-PET score after R-CT. RESULTS: The median follow-up time was 40.9 months. Three patients were assigned to Deauville score 1 (8.1%), 9 to score 2 (24.3%), 7 to score 3 (19%), 14 to score 4 (37.8%), and 4 to score 5 (10.8%). After RT, all patients with score 3-4 experienced a complete response (CR). Among patients with score 5, 1 was in CR (25%), 2 had persistent positivity (50%), and 1 showed progressive disease (25%). A total of 4 patients experienced progression or relapse: 1 of 33 (3%) with scores 1-4, and 3 of 4 (75%) with score 5. The 3-year OS and PFS of the whole cohort were 89.8% and 88.7%, respectively. OS was significantly different between scores 1-3 and scores 4-5 (100% vs 77% at 3 years, P<.05). Patients with a score of 5 had a significantly worse outcome than did all other patients (OS at 2 years, 33.3% vs 100%). CONCLUSIONS: Approximately 50% of PMBCL patients show residual disease at (18)FDG-PET scan after R-CT. RT is able to convert to CR approximately 85% of these patients, but those with a Deauville score of 5 (10%) appear at high risk of progression and death, and they might be candidates for intensified programs. PMID- 23916172 TI - Position statement: hypoglycemia management in patients with diabetes mellitus. Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition. AB - OBJECTIVE: To provide practical recommendations for evaluation and management of hypoglycemia in patients with diabetes mellitus. PARTICIPANTS: Members of the Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition. METHODS: Recommendations were formulated according to the Grading of Recommendations, Assessment, Development, and Evaluation system to describe both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (PubMed). Papers in English and Spanish with publication date before 15 February 2013 were included. For recommendations about drugs only those approved by the European Medicines Agency were included. After formulation of recommendations, they were discussed by the Working Group. CONCLUSIONS: The document provides evidence-based practical recommendations for evaluation and management of hypoglycemia in patients with diabetes mellitus. PMID- 23916173 TI - Loading of shoulder girdle muscles in consequence of a glenohumeral arthrodesis. AB - Sometimes a glenohumeral arthrodesis operation is performed at patients with a brachial plexus lesion. In the glenohumeral arthrodesis the humerus is fused to the scapula. The fusion angles between scapula and humerus determine the restoration of function after the operation. In this study the effect of fusion angles on the hand position and maximal force exertion has been simulated using a musculoskeletal model of the shoulder girdle. Mean scapular and clavicular positions (10 subjects) are used as input variables. Mean fusion angles (18 patients with a glenohumeral arthrodesis) are used as reference position. Output variables are the maximal force which can be exerted with the hand and muscle forces of the thoracoscapular muscles. In order to achieve a mobility area in the mid-sagittal plane, the humerus should be internally rotated 60 degrees with a little abduction and forward flexion. Maximal force can be exerted when the scapula is laterally rotated and protracted beside the thorax. In that position m. serratus anterior has good moment arm to counterbalance the external moment. It is recommended to use an external fixator for the glenohumeral arthrodesis in order to be able to adjust the fusion angles outside the operation theatre. PMID- 23916174 TI - Complex nature of stress inside loaded articular cartilage. AB - We show that in the early stages of loading of the cartilage matrix extensive water exudation and related physicochemical and structural changes give rise to a distinctly consolidatable system. By enzymatically modifying the pre-existing osmotic condition of the normal matrix and measuring its hydrostatic excess pore pressure, we have studied the exact influence of physicochemistry on the consolidation of cartilage. We argue that the attainment of a certain minimum level of swelling stiffness of the solid skeleton, which is developed at the maximum hydrostatic excess pore pressure of the fluid, controls the effective consolidation of articular cartilage. Three related but distinct stresses are developed during cartilage deformation, namely (1) the swelling stress in the coupled proteoglycan/collagen skeleton in the early stages of deformation, (2) the hydrostatic excess pore pressure carried by the fluid component, and (3) the effective stress generated on top of the minimum value of the swelling stress in the consolidation stages following the attainment of the fluid's maximum pore pressure. The minimum value of the swelling pressure is in turn generated over and above the intrinsic osmotic pressure in the unloaded matrix. The response of the hyaluronidase-digested matrix relative to its intact state again highlights the important influence of the osmotic pressure and the coefficient of permeability, both of which are related to the volume fraction of proteoglycans on cartilage deformation, and therefore its ability to function as an effective stress-redistributing layer above the subchondral bone. PMID- 23916175 TI - Control of positioning the cervical spine and its application to measuring extensor strength. AB - The great variability of the flexion of the cervical spine renders an exact description of the control of various positions difficult. A method was developed enabling a precise control of positioning the cervical spine and head in the sagittal plane. In three repeated measurements the mean values of the position of external anatomical landmarks and distances between them exhibited a good reproducibility. Any variable effect of gravity on the activity of the neck muscles at different positions of the cervical spine was eliminated by the passive compensation of gravity. The significance of methodical details is illustrated by the results of an applied study. The maximum strength of neck extensors was examined in 12 male subjects in a supine position at four different flexion angles from 0 to 30 degrees of the cervical spine. The vertical force component was measured. The maximum voluntary moments of forces about the bilateral motion axis of the C7?T1 motion segment exhibited a tendency to decrease with increasing flexion. PMID- 23916176 TI - A comparison of gait symmetry and hip movements in the assessment of patients with monarticular hip arthritis. AB - Three parameters of hip function have been studied and compared in patients with osteoarthritis of the hip. Clinical indices such as the Harris hip score are cheap and easy to perform but can be misleading. Ground reaction force asymmetries are useful in the assessment of disease severity and treatment outcome and are easy to perform and interpret. The loading rate asymmetries are the most sensitive indicators of this gait dysfunction. Measurement of joint movements using flexible electrogoniometers provides useful functional data but is of limited value if flat walking alone is measured. Whilst none of these tests is entirely reliable each provides valuable information to help with patient assessment. PMID- 23916177 TI - Interfragmentary lag screws and external fixation for severe open tibial fractures: a biomechanical and clinical study. AB - The stability offered by the interfragmentary lag screw with a unilateral external fixator frame was studied in both experimental and prospective clinical studies. The in-vitro stability of the fixation with and without the interfragmentary lag screw was tested by a universal testing machine in compression, four-point bending, and torsion in 18 human tibiae. The in-vivo study was conducted prospectively in 18 patients with 19 severe open tibial fractures. All patients were treated with one definite surgical procedure on admission. The interfragmentary lag screw increased the sytem stiffness 47.4 times in compression, 9.9 times in bending, and 3.2 times in torsion. The immediate one-stage care of severe open fractures with a simple external fixation system in combination with the interfragmentary lag screw shortens hospitalization and may enhance healing. PMID- 23916178 TI - Formalin fixation effects on vertebral bone density and failure mechanics: an in vitro study of human and sheep vertebrae. AB - Vertebral bone density of two human vertebral specimens was evaluated using dual anergy X-ray absorptiometry and single-energy quantitative computed tomography immediately before and after 4 weeks of fixation. The repeated QCT assessment of these segments produced a mean rate of change of 1.17 HU/month, while for DXA the mean rate of change was -0.002 g/month for BMC and -0.0004 g/cm(2)/month for BMD. Ten fresh and 10 fixed sheep lumbar spines underwent absorptiometry before being sectioned into units comprising a central vertebra and adjacent intervertebral discs, plus 1 cm of the flanking vertebral end-plate for embedding into bone cement. The fixed sheep spines underwent a repeat scan after 4 weeks in 10% formalin. Mechanical testing produced a significantly lower average failure load for unfixed specimens (9.3 kN) than for the fixed material (10.8 kN). Failure strain was not significantly different between groups. Linear regression showed a high correlation of BMC values before and after 4 weeks of formalin fixation, while the slopes of the regression for BMD and failure load of both fresh and fixed groups were not significantly different. While formalin fixation may result in a slight increase in compressive strength this does not appear to be associated with a systematic change in mineral density. PMID- 23916179 TI - In-vitro relationships between vertebral body density, size, and compressive strength the elderly thoracolumbar spine. AB - The bone density of thoracolumbar vertebral columns (T1-L2) from 12 individuals having a mean age of 73 years was examined using quantitative computed tomography and dual energy X-ray absorptiometry. Spinal units, comprising three vertebrae, from different regions were then tested for compressive strength in a materials test device. Results showed segmental variations in trabecular and integral bone density of the vertebral bodies and their capacity for load bearing. Failure strength increased craniocaudally, whereas failure stress (load/cross-sectional area) decreased. Vertebral compressive strength was moderately correlated with bone mineral density as assessed with dual energy X-ray absorptiometry. In contrast, trabecular bone density determined from quantitative computed tomography was a poor predictor of compressive strength, as was bone mineral content. Use of an integral measure of bone density may provide a more practical guide to bone fragility. PMID- 23916180 TI - Chair rise strategies in the elderly. AB - The elderly often have difficulty with rising from a chair. The purpose of this study was to characterize their rising strategies. A group of 22 elderly adults with a range of functional impairments was asked to rise from chairs of varying heights. Videotape motion analysis was used to identify strategies, estimate centre of mass, and measure time to rise. Three movement strategies were identified, "momentum transfer", "stabilization", and "combined" based on the velocity of trunk movement and base of support rearrangement. "Momentum transfer" uses horizontal momentum developed in the trunk to rise; "stabilization" uses centre of mass and base of support repositioning but very little momentum; "combined" uses elements of both momentum transfer and stabilization. Differences in the time to rise and the centre of mass to base of support separation between the momentum transfer and stabilization strategies were significant at each chair height. The momentum transfer, combined, and stabilization may form a continuum of chair rise strategies. PMID- 23916181 TI - Passive stiffness of the human neck in flexion, extension, and lateral bending. AB - The passive bending stiffness, tolerable bending moment levels, and elastic energy storage capabilities of the cervical spine were evaluated in 40 male and 19 female volunteer subjects from a university student population, about the flexion, extension, and lateral bending axes. Bending moments were applied to the neck while subjects lay on a frictionless jig and simultaneous angular displacements of the skull relative to the rib cage were recorded. Myoelectric signals from the sternocleidomastoid and splenius capitis muscles were amplified over audio speakers to train subjects to relax their musculature. Tolerable levels of bending moments were quite low (less than 10 N m on average for all conditions) given the very large magnitude of bending moment applied to the neck estimated from impact models. Subjects tolerated greater moment and elastic energy storage in the cervical passive tissues during flexion than in both extension and in lateral bending. In addition males were able to tolerate larger applied moments, were stiffer, and stored more energy than females in all loading conditions. The data derived from this study of loading at very slow rates provide a lower limit for bending moments and for cervical spine stiffness, and yield a first approximation to dynamic bending stiffness values that may be included in models of the cervical spine. PMID- 23916182 TI - Axial rotation of the prosthetically replaced knee. AB - Meniscal total knee replacement differs from total condylar designs in that it allows free axial rotation. This reduces torque forces on the tibial component and may help to prevent aseptic loosening. The amount of rotation occurring in patients with meniscal total knee replacement was an average range of 6 degrees. The average movement of the polyethylene 'menisci' is 3 mm. PMID- 23916183 TI - Knee angle as a determinant of lower leg tremor. AB - The effects of knee joint angle (muscle length) and spring load stiffness on some mechanical parameters of lower leg tremor were studied among twelve male subjects during isometric knee extensions against three springs differing in stiffness at knee angles of 90, 110, and 130 degrees. The power spectral density function was estimated for the acceleration (tremor) signal. The results showed knee angular position to have a significant influence on the lower leg tremor parameters so that higher peak frequencies and lower tremor amplitude values were typical for the shorter knee extensor lengths. Frequency changes with knee angle were explained by the effect of changes in stiffness of a spring-mass system (knee extensor musculature) as a function of muscle length. It was suggested that tremor amplitude is influenced by motor unit recruitment and firing characteristics. PMID- 23916184 TI - Effect of glycosaminoglycan polysulphate on the human intervertebral discs based on stature measurements. AB - Glycosaminoglycan polysulphate has been shown to protect against loss of glycosaminoglycans in experimental osteoarthritis and has been used in humans to achieve the same result. It was assumed that if glycosaminoglycan polysulphate generally affects human connective tissues its use would increase or maintain intervertebral disc height by preventing water loss. Stature was measured during a resting-loading-resting period of 1.5 h. Four baseline measurements were taken of six subjects during a 4-week period. Thereafter each subject was given glycosaminoglycan polysulphate for 3 weeks and stature was measured once a week until a stable condition was reached; no less than three measurements were obtained. No effect of glycosaminoglycan polysulphate on the stature could, however, be seen in the mean values for all six subjects. PMID- 23916185 TI - [Ventilation monitoring by impedance tomography]. PMID- 23916186 TI - The Maillard reaction and pet food processing: effects on nutritive value and pet health. AB - The Maillard reaction, which can occur during heat processing of pet foods or ingredients, is known to reduce the bioavailability of essential amino acids such as lysine due to the formation of early and advanced Maillard reaction products (MRP) that are unavailable for utilisation by the body. Determination of the difference between total and reactive lysine by chemical methods provides an indication of the amount of early MRP present in foods, feeds and ingredients. Previous research reported that the difference between total and reactive lysine in pet foods can be up to 61.8%, and foods for growing dogs may be at risk of supplying less lysine than the animal may require. The endogenous analogues of advanced MRP, advanced glycation endproducts, have been associated with age related diseases in humans, such as diabetes and impaired renal function. It is unknown to what extent advanced MRP are present in pet foods, and if dietary MRP can be associated with the development of diseases such as diabetes and impaired renal function in pet animals. Avoidance of ingredients with high levels of MRP and processing conditions known to favour the Maillard reaction may be useful strategies to prevent the formation of MRP in manufactured pet food. Future work should further focus on understanding the effects of ingredient choice and processing conditions on the formation of early and advanced MRP, and possible effects on animal health. PMID- 23916187 TI - Dysfunctional role of parietal lobe during self-face recognition in schizophrenia. AB - BACKGROUND: Anomalous sense of self is central to schizophrenia yet difficult to demonstrate empirically. The present study examined the effective neural network connectivity underlying self-face recognition in patients with schizophrenia (SZ) using [15O]H2O Positron Emission Tomography (PET) and Structural Equation Modeling. METHODS: Eight SZ and eight age-matched healthy controls (CO) underwent six consecutive [15O]H2O PET scans during self-face (SF) and famous face (FF) recognition blocks, each of which was repeated three times. RESULTS: There were no behavioral performance differences between the SF and FF blocks in SZ. Moreover, voxel-based analyses of data from SZ revealed no significant differences in the regional cerebral blood flow (rCBF) levels between the SF and FF recognition conditions. Further effective connectivity analyses for SZ also showed a similar pattern of effective connectivity network across the SF and FF recognition. On the other hand, comparison of SF recognition effective connectivity network between SZ and CO demonstrated significantly attenuated effective connectivity strength not only between the right supramarginal gyrus and left inferior temporal gyrus, but also between the cuneus and right medial prefrontal cortex in SZ. CONCLUSION: These findings support a conceptual model that posits a causal relationship between disrupted self-other discrimination and attenuated effective connectivity among the right supramarginal gyrus, cuneus, and prefronto-temporal brain areas involved in the SF recognition network of SZ. PMID- 23916189 TI - Brain correlates of auditory hallucinations: stimulus detection is a potential confounder. PMID- 23916188 TI - Racial patterns of cardiovascular disease risk factors in serious mental illness and the overall U.S. population. AB - BACKGROUND: Serious mental illness (SMI) and minority race are each associated with elevated cardiovascular disease (CVD) mortality. However, little is known about racial variation in CVD risk factors in individuals with SMI. This study aimed to determine racial patterns of CVD risk factors in individuals with SMI and to compare these patterns to those of the general population. METHODS: Overweight/obese adults with SMI (163 whites; 111 African Americans) examined from 2008 to 2011 during a weight loss trial were compared at study baseline to overweight/obese adults (1103 whites; 550 African Americans) of similar age, sex, and race in the 2007 to 2010 National Health and Nutrition Examination Survey. RESULTS: All CVD risk factors except cholesterol were higher in SMI than the overall U.S. population. After adjusting for age and sex, both racial groups with SMI had similarly high risks of smoking, obesity, diabetes, and hypertension, while African Americans with SMI had lower risks of high cholesterol (RR 0.73; 95% CI 0.57-0.94) and metabolic syndrome (RR 0.75; 95% CI 0.63-0.91) than whites with SMI. In the U.S. population sample, African Americans compared to whites had higher risks of obesity (RR 1.23; 95% CI 1.14-1.34), diabetes (RR 1.68; 95% CI 1.21-2.34), and hypertension (RR 1.44; 95% CI 1.31-1.60) but no significant difference in smoking, high cholesterol, and metabolic syndrome. CONCLUSIONS: Compared to the general population, the greater burden and dissimilar racial pattern of CVD risk factors in SMI underscore the need for CVD prevention programs targeting the SMI population. PMID- 23916190 TI - Adsorptive removal of fluoride from aqueous medium using a fixed bed column packed with Zr(IV) loaded dried orange juice residue. AB - The potential of the adsorbent prepared from DOJR marketed as cattle food in Japan was identified as an efficient and low cost adsorbent for fluoride using fixed bed column. DOJR was loaded with Zr(IV) ions to develop active adsorption sites for fluoride. Fluoride adsorption performance of column packed with Zr(IV) loaded DOJR was assessed under variable operating conditions such as Zr(IV) loading temperature, initial fluoride concentration, bed depth, initial pH, and flow rate. Breakthrough curve modeling showed that Thomas and bed depth service time (BDST) models were in good agreement with the experimental data. Application of adsorbent investigated in this study to the treatment of actual waste plating solution containing fluoride ion showed successful removal below acceptable standard in Japan using a fixed bed column, hence, Zr(IV)-DOJR can be expected to be a promising candidate for the treatment waste water containing trace amount of fluoride ion in fixed bed column. PMID- 23916191 TI - Improving motor functions in children with Down syndrome. PMID- 23916192 TI - Delirium: a disturbance of circadian integrity? AB - Delirium is a serious neuropsychiatric syndrome of acute onset that occurs in approximately one in five general hospital patients and is associated with serious adverse outcomes that include loss of adaptive function, persistent cognitive problems and increased mortality. Recent studies indicate a three domain model for delirium that includes generalised cognitive impairment, disturbed executive cognition, and disruption of behaviours that are under circadian control such as sleep-wake cycle and motor activity levels. As a consequence, attention has focused upon the possible role of the circadian timing system (CTS) in the pathophysiology of delirium. We explored this possibility by reviewing evidence that (1) many symptoms that occur in delirium are influenced by circadian rhythms, (2) many features of recognised circadian rhythm disorders are similar to characteristic features of delirium, (3) common risk factors for delirium are known to disrupt circadian systems, (4) physiological disturbances of circadian systems have been noted in delirious patients, and (5) positive effects in the treatment of delirium have been demonstrated for melatonin and related agents that influence the circadian timing system. A programme of future studies that can help to clarify the relevance of circadian integrity to delirium is described. Such work can provide a better understanding of the pathophysiology of delirium while also identifying opportunities for more targeted therapeutic efforts. PMID- 23916193 TI - Prospective evaluation of pronator quadratus repair following volar plate fixation of distal radius fractures. AB - PURPOSE: To evaluate the efficacy of pronator quadratus (PQ) repair after volar plating of distal radius fractures. METHODS: All consecutive distal radius fractures treated operatively with a volar plate during a 1-year period were assigned to receive a repair of the PQ versus no repair. Surgical exposure, reduction, and postoperative rehabilitation were equivalent in both groups. Clinical outcomes with a minimum follow-up of 12 months were assessed via range of motion; grip strength; Disabilities of the Arm, Shoulder, and Hand (DASH) scores; and visual analog scale (VAS) scores. RESULTS: A total of 60 consecutive distal radius fractures were treated operatively with a locking volar plate. Full follow-up data were available for 33 patients in the PQ repair group and 24 patients in the control group. At 12 months, the mean DASH score was 8 for the repair group and 5 for the control group. Range of motion at the wrist, grip strength, and VAS scores were also not significantly different between groups. In addition, we found no significant differences in any of the parameters at the 2-, 6-, or 12-week intervals, although we observed greater grip strength and wrist flexion in the repair group at 6 weeks. Reoperation was required for 4 patients in the repair group and 1 in the control group. CONCLUSIONS: Pronator quadratus repair after volar plating of a distal radius fractures did not significantly improve postoperative range of motion, grip strength, or DASH and VAS scores at 1 year. The rates of reoperation between groups were not significantly different. PMID- 23916194 TI - Nonsurgical treatment of elbow stiffness. PMID- 23916195 TI - Experience of anxiety among patients with severe COPD: A qualitative, in-depth interview study. AB - OBJECTIVES: Anxiety often arises in conjunction with dyspnoea in patients with severe COPD. Considering the provoking symptomatology and the high mortality rate for COPD, it is reasonable to believe that these conditions trigger death-related and existential anxiety. Although anxiety causes considerable distress and reduces quality of life, people's experience of anxiety has been studied relatively little. The aim of this study was to explore severely ill COPD patients' experience of anxiety and their strategies to alleviate anxiety. METHODS: This qualitative, in-depth interview study explored perceptions of anxiety and the alleviation strategies that are adopted. Interviews were analyzed using a thematic content analysis approach, involving interpretive coding and identification of themes. People suffering from COPD (stage III or IV) were recruited from a pulmonary outpatient clinic in the west of Sweden. Purposive sampling was used, and thirty-one (31) patients were included. RESULTS: Most of the patients had experienced anxiety associated with COPD. Analyses revealed three major themes, death anxiety, life anxiety, and counterweights to anxiety. Death anxiety included fear of suffocation, awareness of death, fear of dying and separation anxiety. Life anxiety included fear of living and fear of the future. Counterweights to anxiety concerned coping with suffocation, avoiding strategy, and a sense of joy that defied their vulnerable situation. SIGNIFICANCE OF RESULTS: The majority of patients experienced anxiety, which limited their lives. Although the patients experienced both life anxiety and death anxiety, they were able to cope with the situation and find a defiant joy to some extent. PMID- 23916196 TI - [Foreword]. PMID- 23916197 TI - [Use of the self-organizing map (SOM) for the characterization of macrobenthic populations]. AB - Macrobenthic organisms are much used nowadays as bio-indicators for their ability to reflect different disturbances of aquatic ecosystems. However, they have never been used to assess the ecological status of the lagoons of Benin. The current study aims at revealing the ecological state of the lagoon of Porto-Novo through the study of changes in the settlement of benthic organisms collected in this lagoon. The sampling was carried out from July 2007 to June 2009 on a frequency of four seasons of collection per year. The self-organizing map (SOM) of Kohonen has been used for various patterns of distribution of collected organisms. A discriminant analysis (AFD) has allowed the identification of the parameters that govern the patterns observed in this environment. Four groups of macrobenthic communities emerged that were well predicted (75%). The distribution of benthic macro invertebrates of this lagoon is therefore zonal, seasonal and discriminated by variables of mineralization and sediment grain size. The difference in taxonomic richness corresponds to environmental conditions of stations appearing more or less stable and highlighting a gradient of the stress on organisms. Places with unstable conditions are affected by human activities due to their proximity to homes that are enriched in organic matter. These places are full of polluted-tolerant species such as the Gastropods Potamididae, Cirratulidae Polychaetes, Diptera Chironomidae and Oligochaeta. The macrobenthic fauna, which is well differentiated in the groups, is then subjected to human disturbance. PMID- 23916198 TI - [Diabetes of rich, diabetes of poor. Diabetes as an evidence for health inequalities in Senegal]. AB - This paper's objective is to show how diabetes is the place of polarization of new uncertainties in Senegal and also to highlight how this "disease of modernity" is the source of pronounced health inequalities in urban and rural Senegalese areas. PMID- 23916199 TI - Climate and health: observation and modeling of malaria in the Ferlo (Senegal). AB - The aim of this work, undertaken in the framework of QWeCI (Quantifying Weather and Climate Impacts on health in the developing countries) project, is to study how climate variability could influence malaria seasonal incidence. It will also assess the evolution of vector-borne diseases such as malaria by simulation analysis of climate models according to various climate scenarios for the next years. Climate variability seems to be determinant for the risk of malaria development (Freeman and Bradley, 1996 [1], Lindsay and Birley, 1996 [2], Kuhn et al., 2005 [3]). Climate can impact on the epidemiology of malaria by several mechanisms, directly, via the development rates and survival of both pathogens and vectors, and indirectly, through changes in vegetation and land surface characteristics such as the variability of breeding sites like ponds. PMID- 23916200 TI - [Presence of lead in leaves of Solanum macrocarpon cultivated in Cotonou (Benin): role of poorly composted poultry manure]. AB - This work assesses the impact of the use of chicken manure and irrigation water on the toxicological quality of Solanum macrocarpon, a highly appreciated vegetable. A control site in Glo-Djigbe, gardeners' sites at Houeyiho, Fidjrosse, and Agongbomey were included in the study. Lead has been sought in the environment of S. macrocarpon culture by Atomic Absorption Spectrophotometry (AAS). Regarding the content of lead in the droppings, the averages in mg/kg varied between 0.696 and 3.618. The soil of Houeyiho (46.320+/-0.651mg/kg) was more contaminated with lead than that of the other sites. The irrigation water used in the study sites was slightly contaminated with lead with values ranging between 0.038 and 0.017mg/L. Leaves taken from the control site, Glo-Djigbe were contaminated with lead with a value of 0.936+/-0.070mg/kg compared to those of Agongbomey, Houeyiho and Fidjrosse. The leaves of S. macrocarpon were contaminated with lead at significantly values higher than those imposed by the FAO (0.1mg/kg). Consumption without precautions could expose people to diseases related to the accumulation of this metal. PMID- 23916201 TI - [Native plant resources to optimize the performances of forest rehabilitation in Mediterranean and tropical environment: some examples of nursing plant species that improve the soil mycorrhizal potential]. AB - The overexploitation of natural resources, resulting in an increased need for arable lands by local populations, causes a serious dysfunction in the soil's biological functioning (mineral deficiency, salt stress, etc.). This dysfunction, worsened by the climatic conditions (drought), requires the implementation of ecological engineering strategies allowing the rehabilitation of degraded areas through the restoration of essential ecological services. The first symptoms of weathering processes of soil quality in tropical and Mediterranean environments result in an alteration of the plant cover structure with, in particular, the pauperization of plant species diversity and abundance. This degradation is accompanied by a weakening of soils and an increase of the impact of erosion on the surface layer resulting in reduced fertility of soils in terms of their physicochemical characteristics as well as their biological ones (e.g., soil microbes). Among the microbial components particularly sensitive to erosion, symbiotic microorganisms (rhizobia, Frankia, mycorrhizal fungi) are known to be key components in the main terrestrial biogeochemical cycles (C, N and P). Many studies have shown the importance of the management of these symbiotic microorganisms in rehabilitation and revegetation strategies of degraded environments, but also in improving the productivity of agrosystems. In particular, the selection of symbionts and their inoculation into the soil were strongly encouraged in recent decades. These inoculants were selected not only for their impact on the plant, but also for their ability to persist in the soil at the expense of the residual native microflora. The performance of this technique was thus evaluated on the plant cover, but its impact on soil microbial characteristics was totally ignored. The role of microbial diversity on productivity and stability (resistance, resilience, etc.) of eco- and agrosystems has been identified relatively recently and has led to a questioning of the conceptual bases of controlled inoculation in sustainable land management. It has been suggested that the environmental characteristics of the area to rehabilitate should be taken into account, and more particularly its degradation level in relation to the threshold of ecological resilience. This consideration should lead to the optimization of the cultural practices to either (i) restore the original properties of an ecosystem in case of slightly degraded environments or (ii) transform an ecosystem in case of highly degraded soils (e.g., mine soils). In this chapter, we discuss, through various examples of experiments conducted in tropical and Mediterranean areas, the performance of different strategies to manage the microbial potential in soils (inoculation of exotic vs. native species, inoculation or controlled management potential microbial stratum via aboveground vegetation, etc.) based on the level of environmental degradation. PMID- 23916202 TI - [The international man-media Tessekere (OHMi) Observatory: a research tool to study the complexity of arid ecosystems in Sahel]. AB - In the Sahelian zone, the drought phenomenon, combined with anthropic factors (monoculture, bush fires, defect or deficit of manure, overgrazing, etc.), has seriously affected ecological great balances, involving a degradation of the natural resources as well as a fall in agricultural productions, pointing to a process of desertification. To face these challenges, in the course of the 8th ordinary session of the conference of the Heads of States of the African Union held in January 2007 in Addis Ababa (Ethiopia), 11 countries adopted the Panafrican project called the Green Great Wall (GGW). The total objective of the GGW is to contribute i) to the fight against the desert's advance, ii) to the development of the Saharan-Sahelian zones toward a durable management of the natural resources, and iii) to the fight against poverty. It deals with the construction of a set of zones of afforestation crossing the whole African continent in the long term (7000km of which are in the west). Even if some decisions in the launching phase the GGW must be taken quickly, one cannot do without investment in interdisciplinary research. In particular, associating fundamental research and applied research will allow us to ensure the success in the medium and long term of such a large-scale reforestation project. Research segmented in compartmentalized knowledge fields needed to get adequate tools, among which OHMi Tessekere, initiated by INNEE (Centre national de la recherche scientifique [CNRS]), in partnership with UCAD, constitutes an example. This suitable scientific tool, capable of action flexibility, of self-financing capacity, anchored in civil society, ready to implement a pragmatic and local interdisciplinarity founded currently on the concept of socio-ecological system (SES), is the one we chose to conduct our studies on the Ferlo arid ecosystems. PMID- 23916203 TI - Health-risk market garden production linked to heavy metals in irrigation water in Benin. AB - Heavy metals in the Benin market garden products: is irrigation water the first factor in question, and what is the level of health risk linked to the consumption of these vegetables? Such are the essential problems that this survey attempts to solve. Comparison of the level of lead (Pb), cadmium (Cd) and arsenic (As) pollution shows that all the vegetables taken from three market sites are differently contaminated, as well as their irrigation water and the soil. But establishing that water is the first factor responsible for the presence of heavy metals in market garden products is not so obvious. Otherwise, the health risk assessment revealed that the total daily exposure dose (DED) of Cd, namely 8.05MUg/kg/day, is high compared to the daily dose defined by the WHO, which is 1MUg/kg/day. Also, the ensuing quotient of danger (QD) is 8.05; such a value poses public health risks for the consumer. PMID- 23916204 TI - [Schistosomiasis caused by Schistosoma mansoni in the Kou valley: Characterization of the transmission system and socioeconomic impact]. AB - Schistosomiasis is one of the waterborne diseases which benefit from environmental and behavioral changes induced by the mobilization of surface water resources in Sahelian countries, such as Burkina Faso. Studies have established the existence of human schistosomiasis in the Kou valley, one of the oldest hydro agricultural zones in the country. However, the role of population behavior in the transmission pattern of this disease and its socioeconomic impact in this valley are poorly understood. It is in response to these questions that this study was undertaken. The objectives of this study were to identify activities that exposed most of the Valley's population to infection by schistosomiasis, and to contribute knowledge on the consequences of this disease. The study was conducted in the cold dry season at the Kou Valley, located in the South Sudanese area of Burkina Faso. It has adopted the strategy of direct observation to examine host-parasites interactions. The study of the socioeconomic consequences of the infection has been first to identify subjects that actually carry the parasite by screening the population by the Kato-Katz method. These were then subjected to a questionnaire. Data were analyzed using Epi Info 6.4. This work has revealed six activities at risk of infection for the residents of the Valley with an increased risk of factor for rice farming, household activities and swimming. In view of these activities, women and young people seem to be most vulnerable to infection. This disease causes significant economic losses as a function of socio-professional categories of infected persons. PMID- 23916205 TI - [African agriculture faced with global changes: researches and innovations based on ecological sciences]. AB - In the context of environmental and socio-economic changes, the agriculture of Sub-Saharan African countries will have to ensure food security of the population, while reducing its environmental footprint. The biophysical and social systems of agricultural production are complex. Innovative agricultural practices will be based on an intensification of ecological processes that determine the functioning of the soil-plant system, farmers' fields and agro ecosystems. This ecological engineering approach is useful to take up the challenge of Sub-Saharan agricultures in the future, as shown in researches conducted by IESOL International Joint Lab "Intensification of agricultural soils in West Africa" (ISRA, UCAD, TU, OU, INERA, IRD). PMID- 23916206 TI - Selection of antimalarial drug resistance after intermittent preventive treatment of infants and children (IPTi/c) in Senegal. AB - Senegal has since 2003 used sulphadoxine-pyrimethamine (SP) for Intermittent Preventive Treatment (IPT) of malaria in risk groups. However, the large-scale IPT strategy may result in increasing drug resistance. Our study investigated the possible impact of SP-IPT given to infants and children on the prevalence of SP resistant haplotypes in the Plasmodium falciparum genes Pfdhfr and Pfdhps, comparing sites with and without IPTi/c. P. falciparum positives samples (n=352) were collected from children under 5years of age during two cross-sectional surveys in 2010 and 2011 in three health districts (two on IPTi/c and one without IPTi/c intervention) located in the southern part of Senegal. The prevalence of SP-resistance-related haplotypes in Pfdhfr and Pfdhps was determined by nested PCR followed by sequence-specific oligonucleotide probe (SSOP)-ELISA. The prevalence of the Pfdhfr double mutant haplotypes (CNRN and CICN) was stable between years at<10% in the control group (P=0.69), while it rose significantly in the IPTi/c group from 2% in 2010 to 20% in 2011 (P=0.008). The prevalence of the Pfdhfr triple mutant haplotype (CIRN) increased in both groups, but only significantly in the IPTi/c group from 41% to 65% in 2011 (P=0.005). Conversely, the Pfdhps 437G mutation decreased in both groups from 44.6% to 28.6% (P=0.07) and from 66.7% to 47.5% (P=0.02) between 2010 and 2011 in the control and the IPTi/c groups, respectively. Combined with Pfdhfr, there was a weak trend for decreasing prevalence of quadruple mutants (triple Pfdhfr+Pfdhps 437G) in both groups (P=0.15 and P=0.34). During the two cross-sectional surveys, some significant changes were observed in the SP-resistance-related genes. However, since these changes were observed in the two groups, the IPTi/c strategy does only seem to have limited impact on resistance development and other factors as well. However, continuous monitoring will be needed, due to the up-scaling of the IPTi/c strategy in Senegal according to WHO recommendations. PMID- 23916207 TI - [Dystocia risk score: a decision making tool to combat maternal mortality]. AB - As a way to prevent maternal mortality and stillbirth, the dystocia risk score includes three components: a left column provides a list of eight characteristics to check for in the woman; an upper horizontal section provides a checklist of possible outcomes of the pregnancy itself: and a rectangular grid indicates the prognosis in three zones: a large red (dangerous), a medium-sized grey (doubtful) and a small blue (hopeful). The DRS is positive if there is at least one cross in the dangerous zone and/or two crosses in the doubtful zone (it indicates that the woman should be referred to a center specialized in obstetric emergency care); elsewhere, the DRS is negative. The validation test gives good results (sensitivity=83.61%, specificity=90.05%, positive predictive value=72.34%, and negative predictive value=94.04%). Its large-scale use would accelerate the identification of pregnant women with a high risk of dystocia. Their timely referral to specialized emergency obstetrics centers would increase the efficacy of care and reduce the levels of maternal mortality and stillbirth. PMID- 23916208 TI - Access to drinking water and health of populations in Sub-Saharan Africa. AB - Water is at the center of the plant and animal life, the foundation upon which the health of human settlement and development of civilizations rely on. In tropical regions, 80% of diseases are transmitted either by germs in the water, or by vectors staying in it. In Sub-Saharan Africa, statistics show particularly high levels of unmet needs of populations in access to drinking water in a context of socioeconomic development. For this purpose, this study aims to determine the influence of access to drinking water on the health of populations in Sub-Saharan Africa. Using data from Demographic and Health Surveys (DHS) from Cameroon, Senegal and Chad, it is clear from the descriptive analysis that 60% (Cameroon), and 59% (Chad) of the cases of childhood diarrhea in these two countries are due to the consumption of dirty water. In terms of explanatory analysis, we note that when a household in Cameroon, Senegal or Chad does not have access to drinking water, children under 5 years old residing there are respectively 1.29, 1.27 and 1.03 times more likely to have diarrhea than those residing in households with easy access to drinking water. In view of these results, it is recommended to increase access to drinking water in particular by reducing disparities between the rich and poor people. PMID- 23916209 TI - [Water pollution and health risks at Yaounde, Cameroon]. AB - The aim of this article consists of developing an ecosystemic approach to collect information about groundwater pollution in order to determine its origin and infer the health risks in Mingoa's watershed through the study of 12 spontaneous settlements. From an environmental point of view, family interviews and direct observations allowed us to inventory springs, wells and latrines, and to collect information. So, we have selected, on the basis of predefined criteria, 21 wells and springs for physico-chemical and bacteriological laboratory analyses. Two hundred children aged less than 5 years were subjected to KOAP examination. A number of 1224 latrines were inventoried, for an average use of 15 people per latrine, producing 913.3 kg/year of excreta. Most of 91% of people use these latrines. The superficial aquifers, connected to the wells and springs, present high values of nitrogen, phosphorous pollutant and fecal contamination indicators (coliforms and fecal streptococcus), which make water inappropriate to human consumption. PCA analysis establishes that water pollution comes mainly from traditional pit latrines. The overall prevalence of diarrhea and parasite infestation was important (=40%). The presence of cysts of Entamoeba histolytica, Ascaris limbricoides, and Entamoeba coli confirms this high prevalence and testify to very approximate hygiene and environment conditions. PMID- 23916210 TI - [Parasitological profile of two forms of schistosomiasis (urinary and intestinal forms) at ten sites in Burkina Faso (Sub-Saharan Africa country)]. AB - In spite of great progress in schistosomiasis control during the last decade in Burkina Faso, this disease remains a public health concern in the country. Indeed, our study consisted of the analysis of parasitological data related to Schistosoma haematobium and Schistosoma mansoni and in malacological investigations. The prevalence rate of Schistosoma haematobium varies from 3.3% to 50.4% and from 3.3% to 39.1% for Schistosoma mansoni, but only in the western part of Burkina Faso. Schoolboys are more infested than girls, but the phenomenon is reversed in adults. Biomphalaria pfeifferi, Bulinus truncatus, Bulinus senegalensis and Bulinus globosus were collected during this study. Thus, the behavioral factors as well as the dynamics and the distribution of the intermediate mollusks play a major role in the persistence of the disease. PMID- 23916211 TI - Converging hazard assessment of gold nanoparticles to aquatic organisms. AB - The gold nanoparticles (Au-NPs) are being increasingly used because of their huge diversity of applications, and consequently, elevated levels in the environment are expected. However, due to their physico-chemical properties and functionalization a high variety of Au-NPs can be found, and complete toxicological information for each type of Au-NPs still lacks, and even, the toxicological information for the same species is sometimes contradictory. Therefore, hazard assessment should be done case by case. Hence, the objective of this study was to obtain ecotoxicological information of the same Au-NPs in aquatic organisms and to find a rationale for Au-NPs toxicity. For such a purpose, bare and hyaluronic acid capped Au-NPs (12.5 nm) along with Au-NPs bulk material were tested on freshwater algae, Daphnia and zebrafish. Results showed that while gold nanoparticles were found to be harmless to the tested organisms, the soluble gold showed to be toxic to algae and Daphnia, with an LC50 between 1 and 2 mg L(-1). Comparing our results with those gathered in the literature, it appears that a common hazard assessment of Au-NPs on the studied organisms can be elucidated. PMID- 23916212 TI - Characteristics of lead geochemistry and the mobility of Pb isotopes in the system of pedogenic rock-pedosphere-irrigated riverwater-cereal-atmosphere from the Yangtze River delta region, China. AB - Knowledge of the characteristics of Pb and its isotopic transfer in different compartments is scant, especially for the mobility of Pb isotopes in the geochemical cycle. The present study characterizes differential Pb transport mechanism and the mobility of Pb isotopes in the pedogenic parent rock-pedosphere irrigated riverwater-cereal-atmosphere system in the Yangtze River delta region, by determining Pb concentration and Pb isotopic ratios of pedogenic parent rocks, fluvial suspended particle matter, tillage soils, soil profiles, irrigated riverwater, fertilizer, Pb ore, cereal roots and grains. The results show that Pb isotopes in the geochemical cycle generally follow the equation of (208)Pb/(206)Pb=-1.157*(206)Pb/(207)Pb+3.46 (r(2)=0.941). However, Pb isotopes have different mobility in different environmental matrixes. Whereas in the pedosphere, the heavier Pb ((208)Pb) usually shows stronger mobility relative to the lighter Pb, and is more likely to transfer into soil exchangeable Pb fraction and carbonates phase. The lighter Pb shows stronger transfer ability from soil to cereal grain via root compared to the heavier Pb. However, the cereal grains have lower (206)Pb/(207)Pb and higher (208)Pb/(206)Pb ratios than root and tillage soil, similar to the airborne Pb and anthropogenic Pb, implying that a considerable amount of Pb in cereal grains comes from the atmosphere. The estimate model shows that 16.7-52.6% (average: 33.5%) of Pb in rice grain is the airborne Pb. PMID- 23916213 TI - A GIS-based evaluation of the effect of decontamination on effective doses due to long-term external exposures in Fukushima. AB - Despite the enormous cost of radiation decontamination, there has been almost no quantitative discussion on how much it would reduce the long-term external radiation exposure in the Evacuation Zone and Planned Evacuation Zone (restricted zone) in Fukushima. The aim of this study is to assess the effectiveness of decontamination and return options and to identify important parameters for estimating the long-term cumulated effective dose (CED) during 15, 30 and 70 year period using data on land-use, population and decontamination in the restricted zone (about 1100 km(2)) in Fukushima. Decontamination of the land is assumed to have a certain efficacy in terms of the reduction of CED. The EeCC (external exposure conversion coefficient) is the parameter having the greatest effect on the percentage of area having CED during the 30 years above 100 m Sv after decontamination, ranging from 13% (EeCC=0.2) to 55% (EeCC=0.6). Therefore, we recommend a detailed investigation of the EeCC in Japan. PMID- 23916214 TI - Biomechanics of the patello-femoral joint. AB - This paper presents a review of the biomechanics of the patello-femoral joint. The evolution of sagittal plane models of the joint from that of a simple pulley is explained. The importance of other biomechanical factors, such as the Q-angle and the cartilage structure, and their relationship to chondromalacia are also discussed. A hypothesis relating to collagen fibre orientation in cartilage is presented. PMID- 23916215 TI - Measurement of three-dimensional shoulder movement by an electromagnetic sensor. AB - As a consequence of the difficulty in the measurement of three-dimensional motion in the clinical setting, the assessment of the shoulder joint is performed using movements about a single axis, for example, abduction, flexion and humeral rotation. The development of the Isotrak, an electromagnetic movement sensor, has made the measurement of spatial motion possible; this instrurhent has been used to measure movement at the shoulder joint. In addition to the difficulty of measurement, there is the problem of representing three-dimensional movements graphically. This paper demonstrates the inadequacy of the traditional system of clinical angles and shows that a system of spherical polar coordinates is better suited to display complex movement. Isotrak is therefore thought to be suitable for the clinical assessment of shoulder movement and this system allows for the graphical description of complex movements which have previously been difficult to define, despite the fact that it may be less easy, initially, to interpret than the traditional system. PMID- 23916216 TI - Measurement of time-dependent height-loss during sitting. AB - The application of a static load causes the spine to deform with time, that is to say the spine 'creeps'. This phenomenon has been measured in vivo as a change in body height. Fifteen females within three different age groups were exposed to repeated five minute sessions of sitting, during which the shrinkage of the spine was measured continuously. All the subjects demonstrated shrinkage during these exposures. A trend towards increased shrinkage in the oldest group was observed and statistical differences on initial shrinkage were also noted. These findings were contrary to those observed in some other studies, but were, however, in agreement with recent in vitro studies. Apart from the aim of studying differences in 'creep' behaviour between subjects of different ages, the endeavour was to improve the technique so as to measure the continuous change in height due to a certain static load. PMID- 23916217 TI - Three-dimensional model for studying the dynamic loads on the spine during lifting. AB - To compute the dynamic loads on the spine during lifting, a kinematical description of the motor act is required. This was obtained by means of an automatic system that allows the detection of small retro-reflective markers in a television field. Geometrical relations between the markers and the anatomical landmarks have been determined to define the location of each body segment in space. The dynamic equilibrium equations have been used to calculate the loads on the L3/L4 intervertebral disc and a sensitivity analysis was carried out. The movements analysed were lifting and lowering a load to and from a table. The results show that in the experimental conditions tested (spontaneous speed of execution of the tasks) the inertial factors are extremely important in the determination of compression on the intervertebral disc. PMID- 23916218 TI - Pressure distribution at the ankle joint. AB - Biomechanical factors such as trauma or overweight are discussed in relation to the aetiology of osteochondral lesions. As a consequence of the possible influence of these factors on joint loading patterns the pressure distribution on the load-bearing ankle joint has been investigated in a cadaveric biostatic model. By creating different joint positions with and without either lateral or medial ligament dissection, mimicking a ligamentous supination or pronation trauma, the pressure distribution under these various loading conditions was determined using pressure-sensitive film. The location of transduced contact area, the size and the amount of pressure was evaluated during the study. The results show that the location of the contact area was dependent on the joint position. Even without ligament dissection there was a minimum of contact area in the varus and the supination position with a pressure maximum lying on the medial border of the talus. Ligament dissection of the lateral ligaments resulted in an increased contact area in all the joint positions except for the varus and the supination position. In addition, the pressure increased significantly in the dorsal extension, varus and supination positions following lateral ligament dissection. Medial ligament dissection yielded results opposite to those observed with the lateral ligament dissection. The pressure maximum was observed to be, in the valgus and pronation position, on the lateral talar border with a significant increase of the pressure maxima following ligament dissection. PMID- 23916219 TI - High fat-sucrose diet effects on femoral neck geometry and biomechanics. AB - Diets high in fat and sucrose may affect calcium metabolism, by decreasing calcium absorption in the gastrointestinal tract and decreasing calcium reabsorption in distal renal tubules, but information about the effects of high fat-sucrose diet on immature-bone material and structural properties is lacking. The present study examined the effects of a high fat-sucrose diet on the geometrical and biomechanical properties of the femoral neck in rapidly-growing rats. Sprague-Dawley female rats were assigned randomly to a high fat-sucrose diet group or a control-diet group for 10 weeks. Cantilever-bending tests to failure were conducted, and geometrical and material properties were calculated from fracture-surface cross-sections and were correlated with mechanical data. Geometrically, the high fat-sucrose diet decreased the relative size of the femoral neck cortical shell and increased the trabecular core. The femoral necks of rats fed the high fat-sucrose diet had signiflcanctly lower structural rigidity, load at proportional limit, maximum load, energy at proportional limit, total energy, normal stress at proportional limit and maximum normal stress than the controls. PMID- 23916220 TI - Postural changes associated with pregnancy and their relationship with low-back pain. AB - This longitudinal study examined the postural changes that occur during pregnancy and their association with low-back pain. The lordotic curvature, kyphotic curvature and position of the line of gravity were measured. The degree of low back pain was assessed using a daily pain diary. Each measurement was recorded in 30 healthy pregnant women on a monthly basis until term and once post partum. The results reveal many different postural behaviours, but the majority of women experienced a flattening of the lumbar spine during pregnancy. The changes in kyphotic curvature were not so well defined. In the majority of women the position of the line of gravity was unaffected during pregnancy. Most women experienced some degree of low-back pain but in most cases it was mild. Although Pearson product-moment correlations revealed few significant correlations, the most interesting finding was that in the early stages of pregnancy, the changes in lordosis and lowback pain were inversely related. PMID- 23916221 TI - Three-dimensional force model of the low-back for simple computer programming. AB - A three-dimensional static model is described to evaluate the forces on low-back muscles and on the spine during manual handling tasks and other forceful activities. It is simple to use either with a calculator or programmed onto a micro-computer, whilst being more accurate than existing simple models. Comparisons are made with a more sophisticated model that requires mathematical libraries and programming skills. As predictions are similar, so is the area of validity: the proposed model's accuracy is good for light tasks but poorer for strenuous ones. PMID- 23916222 TI - Weight-lifting in a postural restraining device: a reliable method to generate paraspinal constant force contractions. AB - Epidemiological studies have shown correlations between muscular deficiencies (low endurance capacity) and low back pain. With the emergence of new electromyographic surface recording methodologies (power spectrum investigations), a renewed interest in the electromyographic signal during sustained muscular contractions can be observed. A technique is described which is acceptable to chronic low back pain patients and which creates comparable constant force contractions in normal controls and pain patients. This method has advantages over those procedures requiring maximum voluntary contractions by the patients. PMID- 23916223 TI - Teichoic acid biosynthesis as an antibiotic target. AB - The relentless spread of antibiotic-resistant pathogens makes it imperative to develop new chemotherapeutic strategies to overcome infection. The bacterial cell wall has served as a rich source for both validated and unexploited pathways that are essential for virulence and survival. Lipoteichoic acids (LTAs) and wall teichoic acids (WTAs) are cell wall polymers that play fundamental roles in Gram positive bacterial physiology and pathogenesis, and both have been proposed as novel antibacterial targets. Here we describe recent progress toward the discovery of teichoic acid biosynthesis inhibitors and their potential as antibiotics to combat Staphylococcus aureus infections. PMID- 23916224 TI - Problem behavior of individuals with Down syndrome in a nationwide cohort assessed in late adolescence. AB - OBJECTIVE: To assess problem behavior in adolescents with Down syndrome and examine the association with sex and severity of intellectual disability. STUDY DESIGN: Cross-sectional data of a Dutch nationwide cohort of Down syndrome children aged 16-19 years were collected using a written parental questionnaire. Problem behavior was measured using the Child Behavior Checklist and compared with normative data. The degree of intellectual disability was determined using the Dutch Social competence rating scale. RESULTS: The response rate was 62.8% (322/513), and the mean age 18.3 years (SD +/- 0.8). The total score for problem behavior was higher in adolescents with Down syndrome than in adolescents without Down syndrome (26.8 vs 16.5; P < .001). Overall, 51% of adolescents with Down syndrome had problem scores in the clinical or borderline range on 1 or more Child Behavior Checklist subscales; this is more than twice as high as adolescents without Down syndrome. Adolescents with Down syndrome had more internalizing problems than their counterparts without Down syndrome (14% and 9%, respectively, in the clinical range); the percentages for externalizing problems were almost equal (7% and 9%, respectively, in the clinical range). The highest problem scores in adolescents with Down syndrome were observed on the social problems and thought problems subscales (large to very large standardized differences). Male sex and/or more severe mental disabilities were associated with more behavioral problems. CONCLUSIONS: Serious problem behavior is more prevalent in adolescents with Down syndrome. This demonstrates the need for a focus on general behavior improvement and on the detection and treatment of specific psychopathology in individuals with Down syndrome. PMID- 23916225 TI - Long-term linear growth and puberty in pediatric liver transplant recipients. AB - OBJECTIVE: To explore linear growth, puberty, and predictors of linear growth impairment among pubertal liver transplant recipients. STUDY DESIGN: Review of data collected prospectively through the Studies of Pediatric Liver Transplantation registry. Thirty-one variables were tested as risk factors for linear growth impairment, and factors significant at P < .1 were included in a logistic regression model. Risk factor analysis was limited to 512 patients who had complete demographic and medical data. RESULTS: A total of 892 patients surviving their first liver transplant by >1 year, with >= 1 height recorded, who were between 8 and 18 years old between the years 2005 and 2009 were included. Median follow-up was 70.2 +/- 38.6 months, mean age was 12.9 +/- 3.3 years, and mean height z-score (zH) was -0.5 +/- 1.4 SD. Twenty percent had linear growth impairment at last follow-up. Of 353 subjects with Tanner stage data, 39% of girls and 42% of boys ages 16-18 years were not yet Tanner 5. Growth impairment rates were higher among boys than girls (30% vs 7%, P < .05) at Tanner stage 4, and occurred in 8/72 (11%) of Tanner 5 subjects. Among patients with parental height data, zH were lower than calculated mid-parental zH (P < .005). Independent predictors of growth impairment included linear growth impairment at transplant (OR 11.53, P <= .0001), re-transplantation (OR 4.37, P = .001), non white race (P = .0026), and primary diagnosis other than biliary atresia (P = .0105). CONCLUSIONS: Linear growth impairment and delayed puberty are common in pubertal liver transplant recipients, with pre-transplant growth impairment identified as a potentially modifiable risk factor. Catch-up growth by the end of puberty may be incomplete. PMID- 23916226 TI - Perinatal transmission of dengue: a report of 7 cases. AB - Perinatal transmission of dengue virus was confirmed by the evidence of virus in fetal tissue, newborn serum, and placenta of pregnant women. Abortion, several different clinical findings, and placental inflammatory findings were documented. No association was seen between severity of maternal dengue and disease of the newborn. PMID- 23916227 TI - Participation and performance trends in 'Ultraman Hawaii' from 1983 to 2012. AB - BACKGROUND: Participation and performance trends have been investigated in a single stage Ironman triathlon such as the 'Ironman Hawaii,' but not for a multi stage ultra-triathlon such as the 'Ultraman Hawaii' covering a total distance of 515 km. The aims of this study were to analyze (1) changes in participation and performance, (2) sex-related differences in overall and split time performances, and (3) the age of peak performance in Ultraman Hawaii. METHODS: Age and race times including split times for 98 women and 570 men who successfully finished Ultraman Hawaii (day 1 with 10-km swimming and 145-km cycling, day 2 with 276-km cycling, and day 3 with 84-km running) between 1983 and 2012 were analyzed. Changes in variables over time of annual winners and annual top three women and men were investigated using simple linear regression analyses. RESULTS: The number of female finishers increased (r2 = 0.26, p < 0.01), while the number of male finishers remained stable (r2 = 0.03, p > 0.05). Overall race times decreased for both female (r2 = 0.28, p < 0.01) and male (r2 = 0.14, p < 0.05) winners and for both the annual top three women (r2 = 0.36, p < 0.01) and men (r2 = 0.14, p = 0.02). The sex difference in performance decreased over time from 24.3% to 11.5% (r2 = 0.39, p < 0.01). For the split disciplines, the time performance in cycling on day 1 (r2 = 0.20, p < 0.01) and day 2 decreased significantly for men (r2 = 0.41, p < 0.01) but for women only on day 2 (r2 = 0.45, p < 0.01). Split times showed no changes in swimming and running. The age of the annual winners increased from 28 to 47 years for men (r2 = 0.35, p < 0.01) while it remained stable at 32 +/- 6 years for women (r2 < 0.01, p > 0.05). The age of the annual top three finishers increased from 33 +/- 6 years to 48 +/- 3 years for men (p < 0.01) and from 29 +/- 7 years to 49 +/- 2 years for women (p < 0.01). CONCLUSIONS: Both the annual top three women and men improved performance in Ultraman Hawaii during the 1983-2012 period although the age of the annual top three women and men increased. The sex-related difference in performance decreased over time to reach approximately 12% similar to the reports of other endurance and ultra-endurance events. Further investigations are required to better understand the limiting factors of the multi-activities ultra-endurance events taking place over several days. PMID- 23916228 TI - Areca nut extracts increased the expression of cyclooxygenase-2, prostaglandin E2 and interleukin-1alpha in human immune cells via oxidative stress. AB - BACKGROUND AND OBJECTIVES: Areca nut has been identified as a carcinogen. Inflammation reveals a strong link with tumourigenesis. The aim of this study was to investigate the effects of areca nut on the expression of the key pro inflammatory mediators involved in malignancy, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), interleukin (IL)-1alpha and nuclear factor-kappaB (NF kappaB), by human immune cells. The role of oxidative stress was also examined. MATERIALS AND METHODS: Human peripheral blood mononuclear cells (PBMCs) were treated with extracts of ripe areca nut (rANE) or tender areca nut (tANE). Expression of pro-inflammatory mediators was assayed using Western blotting, reverse transcription-polymerase chain reaction, competitive enzyme immunoassay or enzyme-linked immunosorbent assay (ELISA). Activity of NF-kappaB was evaluated using an ELISA-based method. RESULTS: Both rANE and tANE enhanced the expression of COX-2, PGE2 and IL-1alpha by PBMCs. The secretion of PGE2 was induced by rANE (<=20-40MUgml(-1)) and tANE (<=160MUgml(-1)) significantly in a dose- and time dependent manner. However, the above enhancing effects of ANEs could be attenuated by antioxidants. ANEs also increased the nuclear expression of the redox-sensitive factor NF-kappaB. CONCLUSIONS: The results demonstrate that ANEs induced the expression of pro-inflammatory mediators mainly through the induction of oxidative stress and implicate the possibility of using antioxidants for disease prevention. PMID- 23916229 TI - Comparison [(3)H]-flumazenil binding parameters in rat cortical membrane using different separation methods, filtration and centrifugation. AB - Radioligand receptor binding assays are a common method to evaluate the affinity of newly synthesized benzodiazepine ligands for the receptor. [(3)H]-flumazenil is an antagonist of benzodiazepine receptors and is generally used as a radioligand. In this study, the binding parameters of [(3)H]-flumazenil to rat cortical membranes were evaluated using two separation methods: filtration with GF/C filters and centrifugation. Additionally, the effects of vacuum pressure, exposure time to the cocktail, and geometry on the filtration method were studied. The binding parameters of [(3)H]-flumazenil (Kd and Bmax) were determined through saturation studies using two methods. The results from this study showed that the filtration method is time consuming and requires more steps to be completed. Because filtration causes partial elution of bound [(3)H] flumazenil into the liquid scintillation cocktail, the results are not reproducible, which result in inaccurate estimation of the binding parameters. The centrifugation method in contrast to filtration is straightforward and produces reproducible as well as reliable results, all of the steps are performed in a single polypropylene tube, which eliminates the loss of tissue and avoids other systematic errors associated with transfer and handling. PMID- 23916230 TI - Mechanical consequences of annular tears and subsequent intervertebral disc degeneration. AB - The relationship between degeneration of the intervertebral disc and changes to its mechanics is unclear. The aim of this study was to examine, in a sheep model, the effect of creating a lesion in the outer, anterior annulus on the mechanics of the intervertebral joint complex and the disc. Forty-one 2-year-old Merino wethers were allocated randomly into a control group or an annular lesion group and additionally to non-survivors which were sacrificed immediately or survivors sacrificed 6 months later. The annular lesion group had incisions made in two non adjacent intervertebral discs and a plate was secured across the vertebrae at one level. Mechanical tests were performed on specimens consisting of the two vertebrae, the intervening disc and associated ligaments. Stiffness of the specimens was measured in flexion, extension, and in pure torsion. The tests were conducted first on the intact intervertebral joints and then after removal of the zygapophyseal joints and the interspinous and supraspinous ligaments. The results showed that the creation of an annular lesion caused immediate changes to the mechanics of the disc. In torsion, where no axis of rotation was imposed on the joints, there was a clear reduction in stiffness compared with controls. After 6 months the discs in the lesion groups approached the stiffness of the controls. The plates had a marked effect on the stiffness of the joints in flexion and extension, but after 6 months this difference was not apparent. The mechanics of the intact joints were not affected immediately by the lesion but after 6 months they were less stiff than the controls. There was clear evidence of a progressive degenerative response in the nucleus in all discs with a lesion. The addition of a plate to limit movement did not markedly affect this biological response to the injury but there was some evidence that after 6 months there were fewer degenerative changes to the zygapophyseal joints in the plated specimens. Recovery of the mechanical integrity of the disc was more marked in the joints that were plated, supporting the concept that limiting motion of an injured intervertebral disc facilitates a healing response in the annulus. PMID- 23916231 TI - Gait following lateral collateral ligament repair. AB - Kinetic parameters of gait were examined in two groups of individuals who had sustained trauma of the lateral collateral ligament of the ankle. One group were diagnosed as having second-degree sprains and were immobilized in a plaster cast for 2 weeks (conservative treatment), while the other group had third-degree sprains and underwent surgical repair prior to being immobilized for 6 weeks in a plaster cast. Following removal of the cast subjects received similar programmes of physical therapy which were designed to mobilize the joint, strengthen the muscles, and improve proprioception. Six months after the initial ankle trauma gait patterns were recorded and analyzed. Few differences were observed between the two groups of subjects in either the pattern or the magnitude of the three orthogonal ground reaction forces. Furthermore, within each group no differences were observed between the sound and injured legs; however, there were differences between the corresponding legs of the two treatment groups. PMID- 23916232 TI - Evaluation of ischial weight-bearing orthoses, based on in-vivo hip joint force measurements. AB - The reduction of hip joint forces by ischial weight-bearing orthoses, used for the treatment of Legg-Perthes and other joint diseases, was measured in vivo in a patient with two instrumented endoprostheses. Three different types of orthoses reduced hip joint loading by about 30%, independent of their cuff design and the position in which the femur was held. The direction of the joint forces was changed in such a way that the size of the load-carrying joint areas decreased by up to 3.4% with two conventional orthoses. With the third model with improved containment of the femoral head this area increased by up to 8.2%. All the orthoses studied support the pelvis too close to the affected joint, leading to insufficient load reduction. A design concept is proposed which prevents tilting of the pelvis in the frontal plane and may improve the force reduction at the hip joint. PMID- 23916233 TI - Biomechanics and muscular activity during sit-to-stand transfer. AB - In the present study 10 healthy subjects were measured, performing sit-to-stand transfers in a natural way. Starting position and speed of movement were standardized. Sagittal kinematics, the ground reaction force, and muscle activity of nine leg muscles were recorded. During sit-to-stand transfer the mass centre of the body was moved forward and upward. Based on the velocity of the mass centre of the body three phases were distinguished. In horizontal direction forward rotation of the upper body contributed to the velocity of the mass centre of the body, whereas extension of the legs contributed considerably in vertical direction. After seat-off most muscles were concentrically active, whereas the shortening velocity of the rectus femoris was very low. Thus hip and knee joints were extended and a relatively high knee moment was delivered to control the ground reaction force in a slightly backward direction. Co-contraction of hamstrings and rectus femoris in sit-to-stand transfer was judged to be efficient. PMID- 23916235 TI - Relationships between alignment, kinematic and kinetic measures of the knee of normal elderly subjects in level walking. AB - Twelve normal elderly subjects were tested to analyse the relationships between static radiographic alignment and dynamic kinematic and kinetic measures at the knee in gait. A standard precision radiograph was used to measure the static lower limb alignment and a 3D optoelectric system was used to measure the biomechanical performance of the knee in level walking. Relationships were calculated between static radiographic angular measures and dynamic knee angular measures, dynamic knee joint forces, and dynamic knee joint moments during gait in corresponding motion planes; and between dynamic knee angular measures and dynamic knee joint forces and dynamic knee moments during gait and in corresponding motion planes. The results showed that the static lower-limb alignment measures did not closely correlate with the kinetic measures of the knee in gait although about half of the static angular alignment measures were significantly related to some of the dynamic knee angular measures. Instead, six of nine dynamic angular measures of the knee were significantly related to the dynamic forces and moments of force in the corresponding motion planes. These results suggest that static alignment measures alone at the present time are not sufficient to predict the dynamic knee joint forces in intact knees. PMID- 23916236 TI - EMG mean power frequency: Obtaining a reference value. AB - Normalization of the electromyographic mean power frequency is generally performed on the basis of single estimates. Random variation of reference values based on such single estimates can seriously impair data reported in normalized form. In the present study we have examined five procedures for calculation of an initial reference value: calibration contractions at 0-kg (repeated) and 2-kg hand load, and regression routines at 0-kg and 2-kg hand load. There was a large between-subject variation if all different routines were considered, a moderate between-routine variation, and a quite small within-subject variation. The correlation between the different routines was high. At the same load level calibration and regression routines gave equivalent results, but the variability was less at the higher load level. The variations found are of such a magnitude that it is necessary to reduce the influence of random variation. Procedure proposed for reduction of this variability is repeated calibration measurements. A preferred test position for the trapezius muscle is straight arm, 90 degrees of abduction in the scapular plane, 2-kg hand load. PMID- 23916237 TI - Influence of prosthesis alignment on the standing balance of below-knee amputees. AB - The effect of alignment of the prosthesis on the standing balance of below knee amputees was investigated in this work. Alignment variations consisted of varus and valgus tilt and plantar- and dorsiflexions. The foot-ground reaction forces measured in the anteroposterior, mediolateral, and vertical directions as well as global parameters describing the total sway activity, asymmetry, and weight bearing imbalance were used to compare the various alignment positions studied. The results indicate the presence of a common standing pattern in below-knee amputees, where activity of the foot-ground reaction forces in the anteroposterior direction is significantly higher in the contralateral limb compared with the amputated limb. It was also found that the varus and valgus alignments were the least stable of all alignments. PMID- 23916239 TI - Gender variation of spinal structures. PMID- 23916238 TI - Estimation of disc compression during transient whole-body vibration. AB - This study was performed to examine health effects of transient whole-body vibrations on the lumbar spine. The aim was to detect extremes in the time course of compressive load acting on the disc L3-4 in order to estimate the health risk which depends on the amplitude of peak values of compression. Five healthy males were repeatedly exposed to various transient displacements with nearly sinusoidal or half-sinusoidal waveforms, different durations, and peak accelerations between about 1.4 and 4.1 ms(-2). Accelerations in the z direction were measured on the skin over the spinous processes of L3-4 in five subjects and averaged individually. Complete time series of dynamic compressive forces were calculated by means of a biomechanical model using the calculated effective mass of the human body above the disc L3-4 and relative accelerations between the vertebrae L3-4 for the first time. The amplitudes of the absolute peak values of the compressive forces were influenced only by the interaction between the initial direction and the duration of the waveform. Direct comparisons with the results of other authors are impossible due to methodical differences and missing data in the time domain. The nearly constant peak compressive forces with a shorter duration of transients connected with a higher-frequency content support the proposal to put more weight on vibrations above 8 Hz in a revised International Standard ISO 2631. The comparison of the calculated internal forces with results of in-vitro studies indicates a possible health risk for persons with a low vertebral strength during repetitive exposures to moderate transient whole-body vibrations. PMID- 23916240 TI - Author's reply. PMID- 23916241 TI - Endoscopic ultrasound-guided fine needle aspiration and biopsy using a 22-gauge needle with side fenestration in pancreatic cystic lesions. AB - BACKGROUND: Cytologic diagnosis by endoscopic ultrasound-guided fine needle aspiration is associated with low sensitivity and adequacy. A newly designed endoscopic ultrasound-guided fine needle biopsy device, endowed with a side fenestration, is now available. AIMS: We carried out a study with the aim of evaluating the feasibility, safety, and diagnostic yield of the 22-gauge needle with side fenestration for endoscopic ultrasound fine needle aspiration and biopsy of pancreatic cystic lesions. METHODS: 58 patients with 60 pancreatic cystic lesions consecutively referred for endoscopic ultrasound guided-fine needle aspiration were enrolled in a prospective, dual centre study, and underwent fine needle aspiration and biopsy with the 22-gauge needle with side fenestration. RESULTS: Fine needle aspiration and biopsy was technically feasible in all cases. In 39/60 (65%) pancreatic cystic lesions, the specimens were adequate for cyto-histologic assessment. In lesions with solid components, and in malignant lesions, adequacy was 94.4% (p = 0.0149) and 100% (p = 0.0069), respectively. Samples were adequate for histologic evaluation in 18/39 (46.1%) cases. There were only 2 (3.3%) mild complications. CONCLUSIONS: Fine needle aspiration and biopsy with the 22-gauge needle with side fenestration is feasible, and superior to conventional endoscopic ultrasound-guided fine needle aspiration cytology from cystic fluid, particularly in pancreatic cystic lesions with solid component or malignancy, with a higher diagnostic yield and with no increase in complication rate. PMID- 23916242 TI - Transoral closure of pharyngeal perforation caused by gastrointestinal endoscopy. AB - OBJECTIVE: We present a case of pharyngeal perforation caused by gastrointestinal endoscopy that was successfully repaired with transoral mucosal sutures. This is the first report of a transoral surgical closure of a perforation caused by an endoscope. We describe the repair procedure, the necessary equipment, and the effectiveness of suturing pharyngeal perforations. PATIENT: An 87-year-old woman brought to our emergency department by ambulance because of hematemesis and endoscopic hemostasis was successfully performed. But after hemostasis, CT scan showed emphysema extending from the right lower jaw to the superior mediastinum and pharyngeal perforation was observed by laryngeal fiberscope. INTERVENTION: Even though she had received conservative treatment, exacerbation of inflammation was observed and therefore we performed transoral surgery for closing the pharyngeal perforation. MAIN OUTCOME MEASURE: We followed up with CT scans, blood test and vital signs. RESULTS: The pharyngeal perforation smoothly closed and exacerbation of inflammation was not observed, even after oral ingestion began. CONCLUSION: Transoral closure of a pharyngeal perforation is less invasive and performing this procedure at an early stage can lead to a favorable outcome. PMID- 23916243 TI - Re: MR differentiation of low-grade chondrosarcoma from enchondroma. PMID- 23916244 TI - Raw-data-based iterative reconstruction versus filtered back projection: image quality of low-dose chest computed tomography examinations in 87 patients. AB - OBJECTIVE: The objective was to compare standard-dose chest computed tomography (CT) reconstructed with filtered back projection (FBP) versus low-dose images with FBP and raw-data-based iterative reconstruction. METHODS: Eighty-seven consecutive patients (46 male; mean age, 54.54 +/- 16.12; mean body mass index, 24.58 +/- 4.07) referred for initial chest CT with full-dose examinations [mean dose-length product (DLP), 183.37 +/- 44.13 mGy . cm] and follow-up chest CT with half-dose examinations (mean DLP, 91.08 +/- 23.81 mGy . cm) were included. The full-dose protocol was reconstructed with FBP; the half-dose protocol was reconstructed with FBP and sinogram-affirmed iterative reconstruction (SAFIRE). Noise and signal-to-noise ratio were compared using a paired Student's t test; subjective image quality and lesion conspicuity were compared using Wilcoxon signed ranks test. RESULTS: Actual radiation dose of follow-up CT was about 50% (49.26% +/- 2.62%) of standard-dose protocol. Compared to full-dose images with FBP, there was no significant difference in half-dose images with SAFIRE in the objective noise (ascending aorta: P=.38, descending aorta: P=.70, trachea on mediastinal images: P=.37) and SNR (ascending aorta: P=.14, descending aorta: P=.72, trachea on mediastinal images: P=.06) on mediastinal images. Noise was significantly lower (P<.001) and SNR was significantly higher (P<.001) in half dose images with SAFIRE on lung images. Noise was significantly higher (P<.001) and SNR was significantly lower (P<.001) in half-dose images with FBP. Subjective image quality was similar on both mediastinal images (P=.317) and lung images (P=.614) of half-dose SAFIRE images versus full-dose FBP images. Lesion conspicuity was also similar. Subjective image quality was significantly lower on both mediastinal images (P<.001) and lung images (P<.001) of half-dose FBP images versus full-dose FBP images. The conspicuity of some lesions was significantly lower (ground-glass opacity, P<.0001; ill-defined micronodule, P<.0001; lung cyst, P<.0001; emphysematous lesion, P=.003) on half-dose FBP versus full-dose FBP images. CONCLUSION: Compared to full-dose CT images reconstructed with the conventional FBP algorithm, SAFIRE with three iterations could provide similar or better image quality at 50% less dose. PMID- 23916245 TI - Conservative management of iatrogenic superior vena cava (SVC) perforation after attempted dialysis catheter placement: case report and literature review. AB - A 68-year-old male with end-stage renal disease, congestive heart failure, and facial and bilateral arm swelling was referred for placement of a tunneled dialysis catheter. Distal left subclavian vein access was obtained. The procedure was complicated by iatrogenic perforation of the superior vena cava (SVC). This resulted in rapid development of a right-sided hemothorax and hemodynamic instability. A right-sided thoracostomy tube was placed to drain the pleural cavity. Extrapericardial perforation of the SVC can be managed conservatively in select cases without endovascular balloon dilatation and/stent graft deployment or surgical repair provided the antegrade blood flow is maintained via patent collateral circulation. PMID- 23916246 TI - Potential role for phosphatidylinositol transfer protein (PITP) family in lipid transfer during phospholipase C signalling. AB - The hallmark of mammalian phosphatidylinositol transfer proteins (PITPs) is to transfer phosphatidylinositol between membrane compartments. In the mammalian genome, there are three genes that code for soluble PITP proteins, PITPalpha, PITPbeta and RdgBbeta and two genes that code for membrane-associated multi domain proteins (RdgBalphaI and II) containing a PITP domain. PITPalpha and PITPbeta constitute Class I PITPs whilst the RdgB proteins constitute Class II proteins based on sequence analysis. The PITP domain of both Class I and II can sequester one molecule of phosphatidylinositol (PI) in its hydrophobic cavity. Therefore, in principle, PITPs are therefore ideally poised to couple phosphatidylinositol delivery to the PI kinases for substrate provision for phospholipases C during cell activation. Since phosphatidylinositol (4,5)bisphosphate plays critical roles in cells, particularly at the plasma membrane, where it is a substrate for both phospholipase C and phosphoinositide-3 kinases as well as required as an intact lipid to regulate ion channels and the actin cytoskeleton, homeostatic mechanisms to maintain phosphatidylinositol(4,5)bisphosphate levels are vital. To maintain phosphatidylinositol levels, phospholipase C activation inevitably leads to the resynthesis of PI at the endoplasmic reticulum where the enzymes are located. Phosphatidic acid generated at the plasma membrane during phospholipase C activation needs to move to the ER for conversion to PI and here we provide evidence that Class II PITPs are also able to bind and transport phosphatidic acid. Thus RdgB proteins could couple PA and PI transport bidirectionally during phospholipase C signalling. PMID- 23916248 TI - Frequency domains of resting state default mode network activity in schizophrenia. AB - Probabilistic independent component analysis was applied to identify the default mode network (DMN) in resting state data obtained with functional magnetic resonance imaging from 25 DSM-IV schizophrenia and 25 matched healthy subjects. Power spectrum analysis showed a significant diagnosis * frequency interaction and higher power in one frequency band, indicating an alteration of DMN frequency spectrum in schizophrenia. PMID- 23916250 TI - Precision and the rules of prioritization. PMID- 23916247 TI - Regulation of transient receptor potential channels by the phospholipase C pathway. AB - Transient Receptor Potential (TRP) channels were discovered while analyzing visual mutants in Drosophila. The protein encoded by the transient receptor potential (trp) gene is a Ca(2+) permeable cation channel activated downstream of the phospholipase C (PLC) pathway. While searching for homologs in other organisms, a surprisingly large number of mammalian TRP channels was cloned. The regulation of TRP channels is quite diverse, but many of them are either activated downstream of PLC, or modulated by it. This review will summarize the current knowledge on regulation of TRP channels by PLC, with special focus on TRPC-s, which can be considered as effectors of PLC and the heat- and capsaicin sensitive TRPV1, which is modulated by the PLC pathway in a complex manner. PMID- 23916249 TI - Brain mechanisms for prepulse inhibition in adults with Tourette syndrome: initial findings. AB - Prepulse inhibition (PPI) of the startle reflex is disrupted in a number of developmental neuropsychiatric disorders, including Tourette syndrome (TS). This disruption is hypothesized to reflect abnormalities in sensorimotor gating. We applied whole-brain functional magnetic resonance imaging (fMRI) to elucidate the neural correlates of PPI in adult TS subjects using airpuff stimuli to the throat to elicit a tactile startle response. We used a cross-sectional, case-control study design and a blocked-design fMRI paradigm. There were 33 participants: 17 with TS and 16 healthy individuals. As a measure of PPI-related brain activity, we looked for differential cerebral activation to prepulse-plus-pulse stimuli versus activation to pulse-alone stimuli. In healthy subjects, PPI was associated with increased activity in multiple brain regions, of which activation in the left middle frontal gyrus in the healthy controls showed a significant linear correlation with the degree of PPI measured outside of the magnet. Group comparisons identified nine regions where brain activity during PPI differed significantly between TS and healthy subjects. Among the TS subjects, activation in the left caudate was significantly correlated with current tic severity as measured by the total score on the Yale Global Tic Severity Scale. Differential activation of the caudate nucleus associated with current tic severity is consistent with neuropathological data and suggests that portions of cortical striatal circuits may modulate the severity of tic symptoms in adulthood. PMID- 23916251 TI - Fusarium mycotoxins: effects on reproductive function in domestic animals--a review. AB - On a global scale, cereal grains and animal feed may be contaminated with trichothecenes, such as deoxynivalenol and T-2 toxin, zearalenone (ZEA), and fumonisins, the major mycotoxins of Fusarium fungi. Of these mycotoxins, ZEA is unequivocally implicated in reproductive disorders of swine and other domestic animals. Experiments in vivo and in vitro indicate that ZEA and its metabolites exert estrogenic effects resulting in functional and morphological alterations in reproductive organs. Recently, the potential of trichothecenes and fumonisins to cause reproductive disorders in domestic animals has been investigated. The present review summarizes the toxicological data on the effects of Fusarium mycotoxins on ovarian function, testicular function, placenta and fetus, and puberty/sexual maturity of domestic animals. The results of in vivo animal studies and in vitro tests are reported and discussed. PMID- 23916252 TI - The influence of reduced glutathione in fertilization medium on the fertility of in vitro-matured C57BL/6 mouse oocytes. AB - It is well known that IVM oocytes show a decreased potential for fertility and development compared with in vivo-matured oocytes. In this study, we added reduced glutathione (GSH) to the fertilization medium during IVF to investigate its effect on the fertility and early embryo development of IVM oocytes. The fertilization rate for IVM oocytes and fresh sperm increased with the addition of GSH (0, 1.0, and 2.0 mM: 51%, 76%, and 70%). Moreover, the addition of GSH to the fertilization medium also improved the developmental potential compared with the control sample (0 mM). In addition, we performed IVF using IVM oocytes and frozen/thawed sperm that had been cryopreserved in a mouse bank. Results indicated a marked increase in the fertilization rate when 1.0 mM GSH was added to the fertilization medium compared with when no GSM was used (0.0 mM GSH: 2% (3/195); 1.0 mM GSH: 33% (156/468)). Furthermore, the fertilization rate improved dramatically via zona drilling using laser equipment (52%: 267/516), whereas normal offspring were obtainsed after transferring embryos created via IVF using IVM oocytes and frozen/thawed sperm. This is the first report in which offspring have been obtained via IVF using IVM oocytes and frozen/thawed sperm. PMID- 23916253 TI - Novel selective inhibitors of aminopeptidases that generate antigenic peptides. AB - Endoplasmic reticulum aminopeptidases, ERAP1 and ERAP2, as well as Insulin regulated aminopeptidase (IRAP) play key roles in antigen processing, and have recently emerged as biologically important targets for manipulation of antigen presentation. Taking advantage of the available structural and substrate selectivity data for these enzymes, we have rationally designed a new series of inhibitors that display low micromolar activity. The selectivity profile for these three highly homologous aminopeptidases provides a promising avenue for modulating intracellular antigen processing. PMID- 23916254 TI - The discovery of inhibitors of Fas-mediated cell death pathway using the combined computational method. AB - In this study, pharmacophore and 3D-QSAR models were developed for analogues of 3 substituted-benzofuran-2-carboxylate as inhibitors of Fas-mediated cell death pathways. Our pharmacophore model has good correspondence with experimental results and can explain the variance in biological activities coherently with respect to the structure of the data set compounds. The predictive power for our synthesized compounds were 0.96 for the pharmacophore model, 0.58 for the comparative molecular field analysis (CoMFA) model, and 0.57 for the comparative molecular similarity analysis (CoMSIA) model. PMID- 23916255 TI - Design, synthesis, and mechanism of action of 2-(3-hydroxy-5-methoxyphenyl)-6 pyrrolidinylquinolin-4-one as a potent anticancer lead. AB - New 6- (or 6,7-) substituted 2-(hydroxyl substituted phenyl)quinolin-4-one derivatives were synthesized and screened for antiproliferative effects against cancer cell lines. Structure-activity relationship correlations were established and the most promising compound 2-(3-hydroxy-5-methoxyphenyl)-6-pyrrolidin-1 ylquinolin-4-one (6h) exhibited strong inhibitory activity against various human cancer cell lines, particularly non-small cell lung cancer NCI-H522. Additional studies suggested a mechanism of action resembling that of the antimitotic drug vincristine. The presence of a C-ring OH group in 6h will allow this compound to be converted readily to a water soluble and physicochemically stable hydrophilic prodrug. Compound 6h is proposed as a new anticancer lead compound. PMID- 23916256 TI - Modulation of NMDA receptor function as a treatment for schizophrenia. AB - Schizophrenia is a devastating mental illness that afflicts nearly 1% of the world's population. Currently available antipsychotics treat positive symptoms, but are largely ineffective at addressing negative symptoms and cognitive dysfunction. Thus, improved pharmacotherapies that treat all aspects of the disease remain a critical unmet need. There is mounting evidence that links NMDA receptor hypofunction and the expression of schizophrenia, and numerous drug discovery programs have developed agents that directly or indirectly potentiate NMDA receptor-mediated neurotransmission. Several compounds have emerged that show promise for treating all symptom sub-domains in both preclinical models and clinical studies, and we will review recent developments in many of these areas. PMID- 23916257 TI - Discovery and SAR of 5-aminooctahydrocyclopentapyrrole-3a-carboxamides as potent CCR2 antagonists. AB - SAR study of 5-aminooctahydrocyclopentapyrrole-3a-carboxamide scaffold led to identification of several CCR2 antagonists with potent activity in both binding and functional assays. Their cardiovascular safety and pharmacokinetic properties were also evaluated. PMID- 23916258 TI - Discovery and SAR of a novel series of GIRK1/2 and GIRK1/4 activators. AB - This Letter describes a novel series of GIRK activators identified through an HTS campaign. The HTS lead was a potent and efficacious dual GIRK1/2 and GIRK1/4 activator. Further chemical optimization through both iterative parallel synthesis and fragment library efforts identified dual GIRK1/2 and GIRK1/4 activators as well as the first examples of selective GIRK1/4 activators. Importantly, these compounds were inactive on GIRK2 and other non-GIRK1 containing GIRK channels, and SAR proved shallow. PMID- 23916259 TI - Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4 amine derived JNK1 inhibitors. AB - As the result of a rhJNK1 HTS, the imidazo[1,2-a]quinoxaline 1 was identified as a 1.6 MUM rhJNK1 inhibitor. Optimization of this compound lead to AX13587 (rhJNK1 IC50=160 nM) which was co-crystallized with JNK1 to identify key molecular interactions. Kinase profiling against 125+ kinases revealed AX13587 was an inhibitor of JNK, MAST3, and MAST4 whereas its methylene homolog AX14373 (native JNK1 IC50=47 nM) was a highly specific JNK inhibitor. PMID- 23916260 TI - Evaluation of steroidal amines as lipid raft modulators and potential anti influenza agents. AB - The influenza A virus (IFV) possesses a highly ordered cholesterol-rich lipid envelope. A specific composition and structure of this membrane raft envelope are essential for viral entry into cells and virus budding. Several steroidal amines were investigated for antiviral activity against IFV. Both, a positively charged amino function and the highly hydrophobic (ClogP>=5.9) ring system are required for IC50 values in the low MUM range. An amino substituent is preferential to an azacyclic A-ring. We showed that these compounds either disrupt or augment membrane rafts and in some cases inactivate the free virus. Some of the compounds also interfere with virus budding. The antiviral selectivity improved in the series 3-amino, 3-aminomethyl, 3-aminoethyl, or by introducing an OH function in the A-ring. Steroidal amines show a new mode of antiviral action in directly targeting the virus envelope and its biological functions. PMID- 23916261 TI - [Severe neonatal acidosis: comparison and analysis of obstetrical practices in two French perinatal centers]. AB - OBJECTIVES: To identify and compare risk factors for severe neonatal acidosis, defined by an umbilical artery pH inferior to 7.00, and clinical practices in two different perinatal centers. PATIENTS AND METHODS: In a retrospective study, from 2003 to 2008, in two university perinatal centers (Poitiers and Saint-Antoine in Paris) on all term pregnancies complicated by severe neonatal acidosis (umbilical artery pH<7.00), we elected to compare the following risk factors: maternal characteristics, medical and obstetrical histories, progress of pregnancy, labour and delivery as well as the neonatal status. RESULTS: Among 23,508 births, 177 term newborns had severe neonatal acidosis. The rate was similar for both perinatal centers of Poitiers and Saint-Antoine (0.92% and 0.77% respectively). Factors associated with severe neonatal acidosis were similar in both centers: maternal age, thick meconium, prior cesarean section. There were differences in obstetrical practices between the two centers: there were more caesarean sections and assisted vaginal deliveries in Paris and more inductions of labour in Poitiers. CONCLUSION: Severe neonatal acidosis is associated with the geographical origin, the progress of labour and the mode of delivery. It seems that severe neonatal acidosis is unrelated to cesarean delivery. PMID- 23916262 TI - [Anthropometric measures of central abdominal fat and discriminant capacity for metabolic syndrome in a Spanish population]. AB - INTRODUCTION: The metabolic syndrome (MS) carries an increased risk of cardiovascular disease and diabetes mellitus. Insulin resistance is probably the mechanism underlying the changes detected in lipid and carbohydrate metabolism in these patients, who have, as a common anthropometric feature, a predominantly increased abdominal fat distribution. PATIENTS AND METHODS: A total of 3316 patients were studied, of whom 63.40% were female and 36.60 male, with a mean age of 42.36+/-14.63 years, and a body mass index (BMI) of 32.76+/-6.81kg/m(2). Weight, height and waist circumference (CC) were measured using standard techniques. The waist/height (ICA) was calculated using two indicators, expressed as waist in cm divided by height in m(2), and as waist divided by height, both in cm. The prevalence of metabolic syndrome in the sample was 33.70%. In order to assess the predictive ability of BMI, ICA and CC to detect the existence of MS, receiver operating curves (ROC) were constructed and the areas under the curve (AUC) calculated for each anthropometric parameter. RESULTS: An AUC of 0.724 (95%CI: 0.706 to 0.742), P<.001, was obtained for CC, 0.709 (95%CI: 0.691 to 0.728), P<.001 for ICA with height in m(2), and 0.729 (95%CI: 0.711 to 0.747), P<.001 for ICA with height in cm, and for the BMI it was 0.680 (95%CI 0.661 0.699), P<.001. CONCLUSIONS: Anthropometric indices that assess abdominal fat distribution have a better predictive capacity for detecting MS, compared to total adiposity indicators such as BMI. PMID- 23916263 TI - Health and social welfare of expatriates in Southeast Asia. AB - Since the end of the Vietnam War and increasing tourism to Asia, there has been ongoing reverse migration of Westerners to Southeast Asia. Some, but not all, have pensions and modest assets. Some acquire a locals spouse and raise a second family. Many of those who arrived early are now aging rapidly and are depleting their financial resources. Health problems become socio/economic threats. None of the Asian target countries that attract reverse migrants have adequate health care and social safety nets that are available to them. The usual health care safety nets expected in western countries do not cover their nationals in a foreign country. This essay discusses these problems as seen from the perspective of two practicing physicians in Southeast Asia. PMID- 23916264 TI - [Back to the roots!]. PMID- 23916265 TI - [The assessment of pain intensity using one-dimensional scales]. AB - BACKGROUND: The assessment of pain intensity is mandatory in many medical disciplines. However, several pitfalls are associated with this task, as, for example, the selection of an instrument which is suitable for different groups of patients; the reliable and valid interpretation of the results, etc. Thus, the aim of the present review is to summarise the recent literature on this topic and to provide a selection of suitable instruments to assess pain intensity in different groups of patients. METHODS: The recent literature was screened and summarised. RESULTS: Assessment of pain has to be performed in consideration of the target population (e. g., age, health condition, cognitive function). CONCLUSIONS: The selection of appropriate pain measurement scales is mandatory for achieving valid results. PMID- 23916266 TI - [Temporomandibular disorders: Evaluation of the usefulness of a self-test questionnaire]. AB - BACKGROUND: A self-test questionnaire has been provided in the internet and in some dental offices for some time now. By using this questionnaire, interested individuals may assess whether they have a temporomandibular disorder (TMD) which might require therapy. It is the aim of this article to examine whether the 11 questions are apt to reliably identify patients with suspected TMDs within a given population. METHODS: Each question has been examined for its relevance by resorting to the current literature. Accordingly, the inclusion of each question into the self-test questionnaire has been rated as suitable or unsuitable. RESULTS: Only 21/2 of the 11 questions are useful to detect individuals with as yet undiagnosed TMDs. CONCLUSIONS: Due to its missing content validity, the questionnaire cannot be recommended. PMID- 23916267 TI - [Quantitative Sensory Testing in the facial area: a review]. AB - Quantitative Sensory Testing is an established method to evaluate somatosensory function. In the facial area, the procedures depend on the localisation of disorders and the modalities of interest. The test stimuli are of thermal or mechanical nature (touch, pain, vibration, or pressure stimuli). According to the protocol of the German Neuropathic Pain Network, comprehensive information on the function of afferent nerves can be generated in the facial area as well. Standard values have been obtained for the cheek and intraoral mucosa. For various orofacial pain conditions, studies concerning the somatosensory function are available. Changed functional patterns are not limited to neuropathic pain, but also occur in other orofacial pain conditions, indicating, for example, central sensitisation. The standardised collection of QST parameters may improve the understanding of the pathophysiology of orofacial pain and effect therapeutic approaches. Comprehensive studies may lead to the development of specific screenings that are feasible in a clinical setting. PMID- 23916268 TI - [The therapy of masticatory muscle pain with oral splints]. AB - Myofascial masticatory muscle pain is the second most frequent pain-related complaint in the orofacial region. Like unspecific musculoskeletal pain in other body segments, masticatory muscle pain is characterised by a multifactorial aetiology. The aim of this article is to document the current knowledge about the therapy with oral splints. It is shown that in both the short and long term, oral appliances can achieve sufficient pain relief in the majority of patients. In chronic myofascial jaw pain associated with psychosocial impairment in patients, effectiveness of splint therapy is limited, though. Within an interdisciplinary pain management programme, additional involvement of a psychotherapist is essential. PMID- 23916269 TI - [Pharmacological therapy of temporomandibular joint pain]. AB - Pharmacological interventions in temporomandibular joint (TMJ) pain differ from corresponding therapeutic interventions of jaw muscle (myofascial) pain. An actual systematic literature search lists and evaluates available articles on randomised controlled trials for treatment of arthralgia of the TMJ. On the basis of the few available trial reports, non-steroidal anti-inflammatory drugs (NSAIDs) seem to be effective, but side effects and drug interactions need to be considered. In relation to other therapeutic modalities, the rapidity of the onset of action of NSAIDs seems to be different, and the extension of side effects can be varied or reduced by changing the application route (oral versus topical). Palmitoylethanolamide (PEA) as dietary supplement for special medical purposes can apparently evoke positive therapeutic effects in TMJ arthralgia which need to be analysed in further studies. PMID- 23916270 TI - [Persistent idiopathic facial pain and atypical odontalgia]. AB - The terms 'persistent idiopathic facial pain' (PIFP) and 'atypical odontalgia' (AO) are currently used as exclusion diagnoses for chronic toothache and chronic facial pain. Knowledge about these pain conditions in medical and dental practices is of crucial importance for the prevention of iatrogenic tissue damage by not-indicated invasive interventions, such as endodontic treatment and tooth extraction. In the present paper, etiology and pathogenesis, differential diagnostic criteria, and diagnostic approaches will be explained and relevant therapeutic principles will be outlined. PMID- 23916271 TI - [Self-help meets science: Patient participation in guideline development]. AB - This article describes the development and current state of collective self-help in Germany, which is unique in Europe. It has received high recognition from both our society and the state, e. g., in the form of mandatory funding of self-help through the statutory health insurance funds. Since 2004, patient participation in the decision-making bodies of the self-governed German health care system has also been statutorily regulated, first of all in the so called "Joint Federal Committee". The relationship between doctors' organisations, such as the German Medical Association (Bundesarztekammer), the National Association of Statutory Health In-surance Physicians together with the Regional Associations of Statutory Health In-surance Physicians (Kassenarztliche Bundesvereinigung), and the scientific medical societies, has also shifted towards more cooperation, and specific bodies have been set up to this end. Finally, the Agency for Quality in Medicine (AQuMed, AZQ) and the Association of Scientific Medical Societies (AWMF) have contributed enormously to the involvement of patient representatives in guideline development groups. The author shares his personal experience in the closing section. PMID- 23916272 TI - [Iron substitution in outpatients in Switzerland: Increase of costs associated with intravenous administration]. AB - Iron anaemia and iron-deficient erythropoiesis are treated with oral iron supplements. For chronic haemodialysis or in the case of therapy failure or intolerance to oral iron therapy, intravenous supplements are administered. The costs of iron supplements borne by statutory health care insurance had strongly increased during the observation period from 2006 to 2010. Based on the invoice data of a large health insurance company with a market share of around 18 %, prescription data of iron preparations and laboratory tests were analysed and extrapolated to the Swiss population. During the 5-year observation period, costs of intravenous iron substitution increased by 16.5 m EUR (340.3 %) and the number of individuals treated by 243.5 %. A sharp rise was observed in women of menstruating age, which was mainly due to prescriptions issued by primary care physicians. More than 8 % of intravenous iron substitutions were administered without prior laboratory analysis,and must therefore be regarded as off-label use. A cost-benefit analysis is needed to demonstrate the additional value of intravenous over oral iron supplementation, and intravenous iron supplementation should be administered only to patients with proven iron deficiency. PMID- 23916273 TI - [Continuing Medical Education in Germany - mandatory and voluntary obligations]. AB - After 1945 the common medical training infrastructure was broken up into two different political systems. While in the Federal Republic of Germany the structure was based on physicians' self-governance, in the German Democratic Republic medical professional structures were organised by the government. After the unification of the two German states, which took place on October 3, 1990, the centralistic structure was replaced by the system of physician self governance. Before January 1, 2004, continuing medical education (CME) in West Germany relied on a system of voluntary obligations. In East Germany, though, professional CMEs were compulsory; they were called "obligatorische periphere Fortbildung." Based on 15 expert interviews on the topic of "CME in Germany", the different circumstances and conditions were analysed taking account of the historical background. Only selected professionals with experience in both German states (one with a federal, the other with a centralistic system), were chosen for the survey. PMID- 23916274 TI - [Learning curve in laser treatment of benign prostatic syndrome: a systematic review]. AB - The aim of the present systematic review was to evaluate the evidence of a potential learning curve for laser treatment of benign prostatic hyperplasia. A systematic literature search was conducted in November 2011 using The Cochrane Library, EMBASE and MEDLINE. Overall, 18 sources (mostly case series) were included for further assessment. The majority of publications assume that a general learning curve exists. It is estimated that a range of 20 to 50 cases is needed to achieve a stable outcome level. For the most part, these findings are based on the HoLEP (Holmium laser enucleation of prostate) technique and intraoperative measures, such as enucleation efficiency. Valid conclusions regarding patient-related end-points are difficult to make, although some studies report a decreasing trend for complication rates with increasing experience of the surgeon. No statistically significant differences were found for postoperative outcomes such as IPSS (International Prostate Symptom Score), Qmax (peak flow rate) or Quality of Life. Overall, the present results are highly limited by the low evidence level and methodological problems of the publications available. Several publications suggest that adequate training during the implementation phase is relevant. PMID- 23916275 TI - [Something we need to talk about: nocebo]. PMID- 23916276 TI - A feasibility study of a brief psycho-educational intervention for psychogenic nonepileptic seizures. AB - PURPOSE: We have previously reported that one in six patients stops experiencing psychogenic nonepileptic seizures (PNES) following our communication protocol. This prospective multicentre study describes a psycho-educational intervention for PNES building on the initial communication of the diagnosis and examines the feasibility of its delivery by healthcare professionals with minimal experience in psychological therapies. METHOD: Three healthcare professionals with minimal training in psychological therapies took part in a one-day training course. 20 participants attended for a four-session manualised psycho-educational intervention delivered at three different clinical neuroscience centres. Participants completed self-report measures prior to the intervention at baseline (n=29) and seven months after diagnosis (n=13) measures included seizure frequency, health related quality of life, healthcare utilisation, activity levels, symptom attributions and levels of functioning. Therapy sessions were audiorecorded and manual adherence assessed. RESULTS: Of 29 patients enrolled into the study, 20 started and 13 completed the intervention and provided follow up information. At follow-up, 4/13 of patients had achieved complete seizure control and a further 3/13 reported a greater than 50% improvement in seizure frequency. After training, epilepsy nurses and assistant psychologists demonstrated sufficient adherence to the manualised psycho-educational intervention in 80% of sessions. CONCLUSION: The delivery of our brief manualised psycho-educational intervention for PNES by health professionals with minimal training in psychological treatment was feasible. The intervention was associated with higher rates of PNES cessation than those observed in our previous studies describing the short-term outcome of the communication of the diagnosis alone. An RCT of the intervention is justified but a significant proportion of drop-outs will have to be anticipated. PMID- 23916277 TI - A grass-based diet favours muscle n-3 long-chain PUFA deposition without modifying gene expression of proteins involved in their synthesis or uptake in Charolais steers. AB - N-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are subject of growing interest as they are of particular relevance for meat quality and human health. However, their content in the muscles of cattle is generally low probably as the complex result of their biosynthesis from dietary n-3 PUFA in the muscle and/or in other tissues/organs and of their subsequent uptake by the muscle. In view of this, this study aimed at understanding whether the changes in the muscle n-3 LCPUFA content, depending on the diet (maize silage v. grass) or the muscle type (Rectus abdominis, RA v. Semitendinosus, ST) in 12 Charolais steers, were related to variations in the gene expression of proteins involved in n-3 LCPUFA biosynthesis or cellular uptake. Tissue fatty acid composition was analysed by gas-liquid chromatography and mRNA abundance of proteins by quantitative real time PCR. The grass-based diet resulted in a 2.3-fold (P < 0.0002) increase in both RA and ST n-3 LCPUFA content compared with the maize silage-based diet, whereas no difference in the expression of genes involved in n-3 LCPUFA biosynthesis and uptake was observed between diets. ST exhibited a 1.5-fold higher n-3 LCPUFA content than RA (P < 0.003), whereas the gene expression of proteins involved in n-3 LCPUFA biosynthesis and uptake was 1.3- to 18-fold higher in RA than in ST (P < 0.05). In conclusion, diet- or muscle type-dependent changes in the muscle n-3 LCPUFA content of Charolais steers did not seem to be mediated by the gene expression regulation of proteins involved in the biosynthesis or uptake of these fatty acids. PMID- 23916278 TI - Quantitative assessment of ankle joint dynamics during recovery from injury. AB - Our laboratory has developed efficient procedures which utilize system identification methods to determine the dynamic characteristics of the normal ankle. The objective of the present work was to assess the feasibility, validity, and sensitivity of using quantitative measures of joint dynamics to monitor the mechanical consequences of soft tissue injury and immobilization. Three patients recovering from fractures of the lower leg were examined repeatedly throughout their post-immobilization periods. Patients had no difficulty with the experimental procedures and measures of their ankle dynamics were qualitatively similar to those of normals. Stiffness was low in a region near the mid-range and increased sharply near the limits of movement. Repeated measures of joint dynamics showed progressive changes throughout the post-immobilization period which were consistent with the return of function. Consequently, the mid-range stiffness decreased while the width of the low-stiffness region increased. These results indicate that system identification methods should be considered for use in the clinical assessment of joint function. PMID- 23916279 TI - Computed tomography-osteoaboorptiometry: a method of assessing the mechanical condition of the major joints in a living subject. AB - A method of making a visual display of subchondral mineralization in the major synovial joints is described. Unlike existing procedures, it can be used on the living subject. A modified application of computed tomography-densitometry, computed tomography-osteoabsorptiometry makes it possible to explore the mechanical adaptability to the prevailing mechanical force. This claim is based upon the comparison of information obtained from 20 anatomical specimens with CT osteoabsorptiometry and x-ray densitometry of sections; both methods yielding virtually identical results. The distribution of the subchondral density was then expressed as a map of the articular surface with the aid of an image analyser. This method can make a useful contribution to basic clinical research, as well as providing a diagnostic technique which can also be used for observing progress after a corrective osteotomy or any other procedure causing a change in mechanical function. Examples of its use on living patients are given. PMID- 23916280 TI - Ground reaction force comparison of canine cemented and cementless total hip replacement. AB - Ground reaction forces were studied in the hindlimbs of ten dogs after cemented and cementless total hip replacement. The femoral components in five dogs were surgically press fitted into the medullary canal for porous ingrowth fixation (cementless) while the remaining five dogs had their femoral component cemented in place. Gait analysis was performed monthly for four postoperative months. Reductions in vertical ground reaction forces were observed in both cemented and cementless implanted hindlimbs one and two months after surgery. By three months postoperative, both groups had effectively returned to their preoperative vertical ground reaction force levels on the implanted hindlimb. At three and four months post implantation, the cemented group demonstrated equal load distribution between the operated and unoperated hindlimbs, whereas the cementless group showed a disparity in load distribution between the operated and unoperated hindlimbs which persisted for the four-month test period. We believe that the paired comparisons between operated and unoperated limbs are more descriptive of antalgic gait than comparisons with preoperative control values. PMID- 23916281 TI - System identification of human ankle dynamics: intersubject variability and intrasubject reliability. AB - Intersubject variability and intrasubject reliability of quantitative measures of normal human ankle mechanics were examined in fifteen young adults. Each subject was examined on two occasions to characterize passive joint dynamics, in terms of the position-stiffness relation, and active joint dynamics, in terms of the torque-stiffness relation. Quantitative, objective measures of joint properties corresponding to those in clinical use were also made for comparison purposes. Results demonstrated that measures of passive and active joint dynamics generally had an intrasubject reliability which was as good as or better than most clinical measures. Intersubject variability was somewhat larger as is the case for the clinical measures. PMID- 23916282 TI - Three-dimensional kinematics of the human back. AB - This study examined the use of a new device, the 3space isotrak, to measure the kinematic behaviour of the backs of normal subjects and of patients from two orthopaedic practices. The device was shown to measure angles with a root mean square error of less than 0.2 degrees and individuals showed a maximum standard deviation from the mean of movements repeated five times of less than 4 degrees . Eighty normal subjects both male and female in four age ranges 20-29, 30-39, 40 49 and 50 years and over were measured. The three-dimensional kinematic patterns were similar for all groups, showing normals to have clearly identified patterns of movement. A general trend for decreasing mobility with age and some sex differences were also demonstrated. The clinical series showed widespread disruption to the primary and coupled movements of all the patients. When grouped together by clinical diagnosis the patient groups showed evidence of discrete and identifiable alterations from the normal kinematic patterns. However, further studies of homogeneous patient groups are required in order to demonstrate whether the measurements are of actual clinical use. The clinical studies also demonstrated that clinical subjective assessment of back mobility bore little relation to the true movements and therefore the clinical measurement of back movements should be reassessed. This study has shown the 3space isotrak to be an effective tool in the clinic for the three-dimensional kinematic measurement of low back mobility. PMID- 23916283 TI - Changes in plantar surface shape induced by corrective forefoot eversion. AB - An investigation is presented of the change in shape of the plantar surface of the foot when the forefoot is everted (prohated) from its natural unloaded orientation into a corrected position frequently used during shoe insert fabrication. Both free and corrected casts were made of 13 asymptomatic feet using established casting techniques. Digital scans capture each plantar surface shape into a computer where an analysis of the transverse slope of the plane is made at various longitudinal locations between midheel and metatarsal head regions. The profile of the slopes show results which are consistent with pronation about the midtarsal joint. These results may be useful as a first stage in establishing the appropriate shape corrections to be used in a computer-aided design system for shoe insert design. PMID- 23916284 TI - Strength of cerclage fixation systems: a biomechanical study. AB - This study examined the load to failure ratio and stiffness of eight different cerclage techniques commonly used in the clinical management of fractures. For a single-loop cerclage, titanium cable was the strongest, while stainless steel wire secured with a commercial tightener was the weakest (P < 0.05). When a single-loop configuration is necessary (i.e. trochanteric attachment) a cable system is superior to cerclage wiring. A double-wrap of either cable or wire was considerably stronger than any single-wrap cerclage technique and stronger than two cerclage wires (P < 0.05). PMID- 23916285 TI - Effects of supplementary exercise intervention programmes on posture of adolescent boys: Thesis Summary. PMID- 23916286 TI - Thoracolumbar fascia. PMID- 23916287 TI - Authors' response. PMID- 23916288 TI - Comment on paper by Hukins et al. PMID- 23916289 TI - Notice of meetings. PMID- 23916290 TI - Prognostic implications of histologic grade and intensity of Bcl-2 expression in follicular lymphomas undergoing rituximab-containing therapy. AB - This study aimed to determine the correlations of 7 histopathologic prognostic indicators of follicular lymphoma (follicular lymphoma grade, CD10 expression, Bcl-2 expression, IGH/BCL2 fusion, diffuse area, fibrosis, and marginal zone differentiation) with progression-free survival, overall survival, and follicular lymphoma histologic grade in 255 follicular lymphoma patients who were treated with rituximab-containing therapy. The complete response, overall response, 6 year progression-free survival, and 6-year overall survival rates were 83%, 96%, 56%, and 97%, respectively. Patients with follicular lymphoma grades 3a and 3b showed 100% 6-year and 10-year overall survival, and progression-free survival did not significantly differ between patients with follicular lymphoma grade 3 and those with follicular lymphoma grades 1 and 2. The absence or presence of Bcl 2 expression and intensity of Bcl-2 expression were not significant prognostic indicators of progression-free survival and overall survival. Likewise, the presence of IGH/BCL2 fusion, diffuse area, fibrosis, and marginal zone differentiation were not significantly correlated with progression-free survival and overall survival. Follicular lymphoma grade 3 was correlated with nodal disease and negative or lower intensity of Bcl-2 expression, but not with age, stage, or IGH/BCL2 status. In the prerituximab era, grade 3 disease was reported to be associated with a poor prognosis; however, the opposite was true for patients treated with rituximab-containing therapy, regardless of their age or disease stage. Bcl-2 expression and marginal zone differentiation were not prognostic indicators in follicular lymphoma patients treated with rituximab containing therapy. PMID- 23916291 TI - A subset of malignant phyllodes tumors harbors alterations in the Rb/p16 pathway. AB - Breast phyllodes tumors are fibroepithelial neoplasms with variable risk of aggressive local recurrence and distant metastasis, and the molecular pathogenesis is unclear. Here, we systematically study p16 and Rb expression in 34 phyllodes tumors in relation to proliferation. Tissue microarrays were constructed from 10 benign, 10 borderline, and 14 malignant phyllodes (5 cores/tumor) and from 10 fibroadenomas (2 cores/tumor). Tissue microarrays were labeled by immunohistochemistry for p16, Rb, and Ki-67 and by in situ hybridization for high-risk human papillomavirus. Cytoplasmic and nuclear p16 were scored by percentage labeling (0%-100%, diffuse >95%) and intensity. Nuclear Rb was scored by percentage labeling (0%-100%, diffuse >75%) and intensity. p16 and Rb labeling were repeated on whole sections of cases with Rb loss on the tissue microarray. Twenty-nine percent (4/14) malignant phyllodes showed diffuse strong p16 labeling with Rb loss in malignant cells (diffuse p16+/Rb-), whereas 21% (3/14) malignant phyllodes showed the reverse pattern of p16 loss with diffuse strong Rb (p16-/diffuse Rb+). Results were consistent between tissue microarrays and whole sections. No borderline phyllodes, benign phyllodes, or fibroadenoma showed diffuse p16+/Rb- or p16-/diffuse Rb+ phenotypes. No cases contained high-risk human papillomavirus. Average Ki-67 proliferation indices were 15% in malignant phyllodes, 1.7% in borderline phyllodes, 0.5% in benign phyllodes, and 0% in fibroadenoma. Ki-67 was highest in malignant phyllodes with diffuse p16+/Rb- labeling. In summary, 50% malignant phyllodes display evidence of Rb/p16 pathway alterations, likely reflecting p16 or Rb inactivation. These and other mechanisms may contribute to the increased proliferation in malignant phyllodes relative to other fibroepithelial neoplasms. PMID- 23916292 TI - Effects of creep feeding and supplemental glutamine or glutamine plus glutamate (Aminogut) on pre- and post-weaning growth performance and intestinal health of piglets. AB - BACKGROUND: Creep feeding is used to stimulate piglet post-weaning feed consumption. L-Glutamine (GLN) is an important source of fuel for intestinal epithelial cells. The objective of this study was to determine the impact of creep feeding and adding GLN or AminoGut (AG; containing glutamine + glutamate) to pre- and post-weaning diets on pig performance and intestinal health. Litters (N = 120) were allotted to four treatments during 14-21 d of lactation: 1) No creep feed (NC, n = 45); 2) creep fed control diet (CFCD, n = 45); 3) creep fed 1% GLN (CFGLN, n = 15); 4) creep fed .88% AG (CFAG, n = 15). After weaning, the NC and CFCD groups were sub-divided into three groups (n = 15 each), receiving either a control nursery diet (NC-CD, CFCD-CD) or a diet supplemented with either GLN (NC-GLN, CFCD-GLN) or with AG (NC-AG, CFCD-AG). Litters that were creep fed with diets containing GLN or AG also were supplemented with those amino acids in the nursery diets (CFGLN-GLN, CFAG-AG). Glutamine was added at 1% in all three post-weaning diet phases and AG was added at .88% in phase 1 and 2 and at .66% in phase 3. RESULTS: Feed conversion (feed/gain) showed means among treatment means close to significance (P = 0.056) and Tukey's test for pairwise mean comparisons showed that Pigs in the CFGLN-GLN group had the best feed conversion (feed/gain) in the first three-week period post-weaning, exceeding (P = 0.044) controls (CFCD CD) by 34%. The NC-AG group had (P = 0.02) the greatest feed intake in the last three week of the study, exceeding controls (CFCD-CD) by 12%. CFGLN-GLN, CFCD-GLN and sow reared (SR) pigs had the greatest (P = 0.049) villi height exceeding the CFCD-AG group by 18%, 20% and 19% respectively. The CFAG-AG group had the deepest (P = 0.001) crypts among all treatments. CFGLN-GLN, CFCD-GLN and SR groups had the greatest (P = 0.001) number of cells proliferating (PCNA) exceeding those in the NC-CD group by 43%, 54% and 63% respectively. Sow reared pigs showed the greatest (P = 0.001) intestinal absorption capacity for xylose and mannitol. CONCLUSION: Supplementation of creep feed and nursery diets with GLN and/or AminoGut in the first three week improved feed conversion possibly due to improved intestinal health. PMID- 23916295 TI - Relative motion at the bone-prosthesis interface. AB - Bone ingrowth in porous surfaces of human joint implants is a desired condition for long-term fixation in patients who are physically active (such as in sport or work). It is generally recognized that little actual bone ingrowth occurs. The best clinical results report between 10 and 20% of the total prosthetic surface in contact with bone will feature good bone ingrowth. One inhibiting factor is the relative motion of the bone with respect to the implant during load-bearing. This study investigated mathematically the interface micromotion (transverse reversible relative motion) between a flat metal tibial prosthetic surface of a prototype implant, and the bone at the resection site. The aim was to assess the effect of perimeter fixation versus midcondylar pin fixation and the effect of plate thickness and plate stiffness. Results showed that in the prototype design the largest reversible relative bone motion occurred at the tibial eminence. By design, the skirt fixation at the perimeter would prevent bone motion. A PCA (Howmedica Inc.) prosthesis has been widely used clinically and was chosen for a control because its fixation by two pegs beneath the condyles is a common variation on the general design of a relatively thick and stiff metal tibial support tray with pegs in each condylar area. The PCA tibial prosthesis showed the largest bone motion at the perimeter along the midcondylar mediolateral line, while being zero at the pegs. Maximum relative bone motion for the prototype was 37 MUm and for the control was 101 MUm. Averaged values showed the prototype to have 38% of the relative reversible bone motion of the control (PCA). PMID- 23916293 TI - Expression of substance P, neurokinin-1 receptor and immune markers in the brains of individuals with HIV-associated neuropathology. AB - The tachykinin neuropeptide substance P (SP) has an important signaling role in both the nervous and the immune systems. Two naturally occurring variants of the neurokinin-1 receptor (NK1R) mediate the effects of SP, full-length receptor (NK1R-F) and a truncated form (NK1R-T) that lacks 96 amino acid residues at the C terminus. We previously reported decreased expression of the NK1R-F in the CNS of HIV-positive individuals in comparison to HIV-negative control subjects. There were no differences in the expression of the NK1R-T in the same groups. In the current study, we quantified the expressions of SP precursor mRNA preprotachykinin (TAC1), NK1R (full and truncated forms), viral load (HIV-gag) and several proinflammatory and immune markers (CD4, CCR5, CXCR4, fractalkine, IL 6, IL-10, CCL2, CCL20 and CD163) in the frontal cortex of autopsied brains from HIV-1-positive individuals with or without HIV-associated neuropathology. The expressions of SP and, to lesser extent, NK1R-F were decreased while the expressions of CXCR4, CCR5 and CCL2 were increased in CNS of individuals with HIV associated neuropathology. There was no change in HIV loads associated with neuropathology; however, we found a positive correlation between viral loads and the expression of haptoglobin-hemoglobin scavenger receptor CD163. An analysis of CSF from corresponding samples demonstrated an increase in proinflammatory markers (CCL2 MIP-1alpha and MIP-1beta) associated with neuropathology. Although our data confirm the overall inflammatory nature of HIV-associated neuropathology, we observed a decrease in the expression of SP and NK1R-F, which is also associated with other forms of neuroinflammation. PMID- 23916296 TI - Biomechanical comparison between high tibial osteotomy (HTO) and combined HTO and fibular osteotomy. AB - The ojectives of this study were to determine the changes in the lateral ligamentous stability of knee joint that occur after performing high tibial osteotomy with and without fibular osteotomy. Utilizing cadaveric specimens, lateral ligamentous stability was assessed by calculating the length of the lateral collateral ligament, and the lateral opening at different flexion angles when varus stress was applied to the tibia. The Polhemus 3-SPACE system was used to collect motion data describing the six-degrees-of-freedom three-dimensional tibiofemoral motions. It was found that the separation distance between the two attachment points of the lateral collateral ligament decreased by an average of 5 mm at all flexion angles after performing a 5-degree valgus high tibial osteotomy. Performing an additional 5-degrees of osteotomy caused this distance to further decrease. It was further found that performing a fibular osteotomy following a 5-degree valgus high tibial osteotomy produced no changes in the length of the lateral collateral ligament. It was also found that the lateral opening increased an average of 5 mm at all flexion angles after performing a 5 degree valgus high tibial osteotomy. Performing a 10-degree osteotomy caused a further increase in the lateral opening. It was further found that performing a fibular osteotomy following a 5-degree valgus high tibial osteotomy caused the lateral opening to return to its original value. That is to say, the fibular osteotomy negated the lateral opening caused by the tibial osteotomy and produced a pattern of lateral opening similar to the one found in the intact knee. PMID- 23916294 TI - Immunogenicity of single versus mixed allele vaccines of Plasmodium vivax Duffy binding protein region II. AB - The Duffy binding protein (DBP) of Plasmodium vivax is vital for host erythrocyte invasion. DBP region II (DBPII) contains critical residues for receptor recognition and anti-DBPII antibodies have been shown to inhibit erythrocyte binding and invasion, thereby making the molecule an attractive vaccine candidate against P. vivax blood stages. Similar to other blood-stage antigens, allelic variation within the DBPII and associated strain-specific immunity is a major challenge for development of a broadly effective vaccine against P. vivax malaria. We hypothesized that immunization with a vaccine composed of multiple DBP alleles or a modified epitope DBP (DEKnull) will be more effective in producing a broadly reactive and inhibitory antibody response to diverse DBPII alleles than a single allele vaccine. In this study, we compared single, naturally occurring DBPII allele immunizations (Sal1, 7.18, P) and DEKnull with a combination of (Sal1, 7.18, P) alleles. Quantitative analysis by ELISA demonstrated that the multiple allele vaccine tend to be more immunogenic than any of the single allele vaccines when tested for reactivity against a panel of DBPII allelic variants whereas DEKnull was less immunogenic than the mixed-allele vaccine but similar in reactivity to the single allele vaccines. Further analysis for functional efficacy by in vitro erythrocyte-binding inhibition assays demonstrated that the multiple allele immunization produced a stronger strain neutralizing response than the other vaccination strategies even though inhibition remained biased toward some alleles. Overall, there was no correlation between antibody titer and functional inhibition. These data suggest that a multiple allele vaccine may enhance immunogenicity of a DBPII vaccine but further investigation is required to optimize this vaccine strategy to achieve broader coverage against global P. vivax strains. PMID- 23916297 TI - Radiographic study of skin displacement errors in the foot and ankle during standing. AB - The accuracy of skin markers for the prediction of skeletal locations in the foot and ankle was assessed using radiographs. The relationship between skin and skeletal markers was examined for three weight-bearing positions of the right lower limb: a 10 degrees calcaneal inversion position, a neutral alignment, and a 5 degrees calcaneal eversion position. Significant discrepanices in the respective locations of skin and skeletal markers were observed; however, it was not possible from the results of this study to recommend the use of particular landmarks in preference to the other locations employed. PMID- 23916298 TI - Cushioning effect of heel cups. AB - Three types of heel cups, two rubber and one plastic, were evaluated in this study. The vertical forces under the heel were monitored using the Computer Dyno Graphy system in 16 normal subjects. Peak force reduction in walking and running after heel cup use was found for all three types of heel cups. The shock absorbency (peak force reduction as a ratio) of heel cups was better in walking (3.5 km h(-1)) than in running (10 km h(-1)). Pressure-sensitive film under the heel revealed that the pressure concentration at the location of calcaneal tuberosity could be smoothed out by the use of heel cups. When plastic heel cups were used, pedobarography showed that the contact area of the heel while standing decreased to 61% of that when barefoot. Roentgenographic study in six patients with heel pain syndrome showed that the thickness of the heel pad increased from 14.4 mm (SD 1.4 mm) to 17.0 mm (SD 1.2 mm) when plastic heel cups were used. PMID- 23916299 TI - Spine configuration and range of motion in normals and scoliotics. AB - The purposes of this study were twofold: to observe the effects of various seated postures on normal and scoliotic spines, and to investigate thoracolumbar range of motion in both normal and scoliotic spines. Eleven adolescent females with mild adolescent idiopathic scoliosis involving the thoracolumbar spine, and 20 healthy female subjects participated in the study. The Iowa Anatomical Position System was used to analyse the lumbar spine curvature. The five upright postures examined were standing, side-bending left, side-bending right, trunk extension, and trunk flexion. The seated postures consisted of erect sitting, slouched sitting, and each leg crossed two different ways in both erect and slouched positions. All seated postures were found to lie well within the extreme passive ranges of motion established by side-bending left, side-bending right, extension, and flexion. The thoracolumbar ranges of motion for scoliotics and normals were similar. Seated postures decreased the lumbar lordosis exhibited in standing for both scoliotics and normals. In general, the variety of seated postures had similar effects in normals and scoliotics, and individual seated postures varied little from each other in their effects on the thoracolumbar spine. All seated postures increased the lateral curvature in scoliotics. PMID- 23916300 TI - Failure sites and peak tensile forces of the composite triceps surae muscle by passive extension in the rabbit. AB - The triceps surae muscle-tendon unit of rabbit was tested by a passive extension technique. The effects of different stretch rates were evaluated. Functioning as a composite muscle-tendon unit, the triceps surae responded viscoelastically to the tensile loads. The sites of failure were consistent at the muscular portion near the musculotendinous junction. Failure occurred within 0.1-1.0 mm of the distal musculotendinous junction for the soleus muscle and within 5-10 mm proximal to the distal musculotendinous junction in the lateral head of gastrocnemius muscle. In the medial head of gastrocnemius muscle failure occurred within 15-30 mm proximal to the distal musculotendinous junction. There was a greater peak tensile force requirement and a greater energy absorption when tested with faster stretch rates. These results furnish evidence that the biomechanical property of composite musculotendinous unit is strain-rate dependent and behaves viscoelastically. PMID- 23916301 TI - Aramid-epoxy composite internal fixation plates: a pilot study. AB - Mechanical tests were conducted on an aramid-epoxy composite laminate in vitro and in vivo to determine its suitability for internal fixation plates. This material, fashioned into blank test coupons the size of the standard 4-hole AO ASIF plates, had a tensile modulus of elasticity significantly lower than bone. In three-point bending, blank test coupons exhibited a low yield strength that would limit utility in significant load-bearing situations, but changes in the layer configuration of the composite could be expected to improve this characteristic. Under destructive loads, these specimens appeared to be less subject to catastrophic failure than carbon fibre composites. Using 4-hole test coupons fastened to a plastic tube simulating bone, four-point bending tests showed that strain-shielding was significantly reduced by aramid composite relative to carbon fibre composite or metal plates. Finally, in-vivo tests on canine femora demonstrated that aramid composite plates were well tolerated and caused less strain shielding during weightbearing, but significant differences in cortical atrophy and porosity beneath steel versus aramid plates were not apparent. Although the plates were relatively flexible, they could not be preformed during surgery like a metal plate. PMID- 23916303 TI - On the validity of mathematical modelling of the spine. PMID- 23916302 TI - Sitting posture in a waiting-room environment. AB - Information on sitting posture in a leisure environment is lacking. The purpose of this study was to determine the prevalence of various sitting postures by observing adults in straight-backed chairs in the waiting areas of several airport terminals. A total of 374 subjects (231 men, 143 women) were studied. The majority of the subjects used the backrest (87%). Men more frequently sat in the slouched position than did women. Most of the group (87%) used a crossed-leg position; women predominantly used the knee-over-knee crossed-leg position while the men slightly favoured the ankle-over-knee crossed-leg position. No preference for laterality was found with respect to the crossed-leg sitting postures. PMID- 23916304 TI - Author's reply. PMID- 23916305 TI - The parental overprotection scale: associations with child and parental anxiety. AB - BACKGROUND: Parental overprotection has commonly been implicated in the development and maintenance of childhood anxiety disorders. Overprotection has been assessed using questionnaire and observational methods interchangeably; however, the extent to which these methods access the same construct has received little attention. Edwards et al. (2008, 2010) developed a promising parent-report measure of overprotection (OP) and reported that, with parents of pre-school children, the measure correlated with observational assessments and predicted changes in child anxiety symptoms. We aimed to validate the use of the OP measure with mothers of children in middle childhood, and examine its association with child and parental anxiety. METHODS: Mothers of 90 children (60 clinically anxious, 30 non-anxious) aged 7-12 years completed the measure and engaged in a series of mildly stressful tasks with their child. RESULTS: The internal reliability of the measure was good and scores correlated significantly with observations of maternal overprotection in a challenging puzzle task. Contrary to expectations, OP was not significantly associated with child anxiety status or symptoms, but was significantly associated with maternal anxiety symptoms. LIMITATIONS: Participants were predominantly from affluent social groups and of non-minority status. Overprotection is a broad construct, the use of specific sub dimensions of behavioural constructs may be preferable. CONCLUSIONS: The findings support the use of the OP measure to assess parental overprotection among 7-12 year-old children; however, they suggest that parental responses may be more closely related to the degree of parental rather than child anxiety. PMID- 23916306 TI - Picture sequencing task performance indicates theory of mind deficit in bipolar disorder. AB - BACKGROUND: This paper reports the performance of DSM-IV-TR diagnosed bipolar disorder (BD) patients on a well-recognised measure of theory of mind (ToM) that commonly elicits group-related differences in schizophrenia research. METHODS: Forty-nine BD patients and 49 age and gender matched controls completed Langdon and Coltheart (1999)Picture Sequencing Task. RESULTS: Relative to controls, patients with BD performed significantly worse on the ToM relevant false-belief stories of the picture sequencing task, but not on the control stories requiring social script knowledge, executive control or an understanding of causal connexions. There were no differences in the ToM performance of symptomatic versus euthymic patients or those categorised as having BD I or BD II. LIMITATIONS: As sub group sizes were small, data suggesting a trait-like deficit in ToM should be interpreted with caution. CONCLUSIONS: The results support previous evidence of ToM impairment in BD and indicate a potential endophenotypic overlap in the phenomenology of both schizophrenia and BD. PMID- 23916307 TI - A clinical predictive score for mood disorder risk in low-income primary care settings. AB - BACKGROUND: Despite availability of validated screening tests for mood disorders, busy general practitioners (GPs) often lack the time to use them routinely. This study aimed to develop a simplified clinical predictive score to help screen for presence of current mood disorder in low-income primary care settings. METHODS: In a cross-sectional study, 197 patients seen at 10 primary care centers in Santiago, Chile completed self-administered screening tools for mood disorders: the Patient Health questionnaire (PHQ-9) and the Mood Disorder Questionnaire (MDQ). To determine participants' current-point mood disorder status, trained clinicians applied a gold-standard diagnostic interview (SCID-I). A simplified clinical predictive model (CM) was developed based on clinical features and selected questions from the screening tools. Using CM, a clinical predictive score (PS) was developed. Full PHQ-9 and GP assessment were compared with PS. RESULTS: Using multivariate logistic regression, clinical and demographic variables predictive of current mood disorder were identified for a simplified 8 point predictive score (PS). PS had better discrimination than GP assessment (auROC-statistic=0.80 [95% CI 0.72, 0.85] vs. 0.58 [95% CI 0.52, 0.62] p-value <0.0001), but not as good as the full PHQ-9 (0.89 [95% CI 0.85, 0.93], p value=0.03). Compared with GP assessment, PS increased sensitivity by 50% at a fixed specificity of 90%. Administered in a typical primary care clinical population, it correctly predicted almost 80% of cases. LIMITATIONS: Further research must verify external validity of the PS. CONCLUSION: An easily administered clinical predictive score determined, with reasonable accuracy, the current risk of mood disorders in low-income primary care settings. PMID- 23916308 TI - Management of mycetomas in France. AB - OBJECTIVE OF THE STUDY: Mycetomas are chronic sub-cutaneous tropical infections in which exogenous causative agents, fungal (eumycetes) or bacterial (actinomycetes), generate grains. The typical presentation is multi-fistulized pseudotumors. This disease, particularly eumycetoma, is difficult to treat. It is a major health problem in tropical and subtropical countries. In France, the disease is rare, but patients have access to a broader range of treatments. The authors had for objective to present the cases of mycetomas diagnosed in developed country and their management. PATIENTS AND METHODS: A retrospective study was made on the clinical presentation and management of mycetomas from 1995 to 2011, in the Bobigny Avicenne teaching hospital. RESULTS: Six patient files were studied. The patients were men with a median age of 31 years (16-70). Five patients were from Sub Saharan Africa, one from Sri Lanka. The etiologies were one actinomycetoma and five eumycetomas. There was bone involvement in five cases. There was one atypical presentation: a primary intra-osseous mycetoma. Three patients were cured including two by surgical management and one by medical treatment (actinomycetoma). Antifungal therapy failed (four patients) in every case (voriconazole, itraconazole, ketoconazole, terbinafine, caspofungin). CONCLUSION: The results of this study made in a non-epidemic zone revealed that despite a typical clinical presentation, the diagnosis and management were delayed because this imported disease is rare in France. The patients received new broad-spectrum triazole and caspofungin, but none were cured with antifungal therapy alone. PMID- 23916309 TI - [Erythema multiforme: what is your diagnosis? Measles]. PMID- 23916310 TI - How does an error in positioning the template affect the accuracy of implants inserted using a single fixed mucosa-supported stereolithographic surgical guide? AB - Computer-aided implantology using a single fixed stereolithographic surgical guide involves a sequence of diagnostic and therapeutic events, and errors can creep in at different stages. Taken together, these can be termed the 'total error'. A positioning of the surgical guide on the support surface different to that of the diagnostic template may generate an error that reoccurs with all the implants inserted, and this error can be termed the 'guide positioning error'. The aim of the present study was to measure the deviation between the planned and inserted implants due to this guide positioning error, to evaluate if this error was statistically significant, and concurrently, to assess the influence of the type of arch (upper vs lower jaw) and mucosal thickness on the guide positioning error. Twenty-four subjects were treated and 172 implants inserted. Preoperative and postoperative computed tomography images were compared using Mimics software to determine the total error and guide positioning error. Quantitative data were described; the t-test and Pearson correlation coefficient were used. The guide positioning error was found to affect the accuracy, but was statistically significant only for global coronal deviation (P = 0.038). Arch of support and mucosa thickness did not affect the guide positioning error. PMID- 23916311 TI - [Computer-aided implantology: Contribution of the Robodent(r) passive robotic system.] AB - The use of the Robodent(r) passive robotic system improves the accuracy of implant placement and thus allows extending the field of indications for flapless surgical technique. Surgery can be performed with a greater operative safety and peroperative modification of the surgical protocol is possible. PMID- 23916312 TI - [Computer-assisted temporomandibular joint reconstruction.] AB - Prosthetic replacement of TMJ is gradually becoming a common procedure because of good functional and aesthetic results and low morbidity. Prosthetic models available can be standard or custom-made. Custom-made prosthesis are usually reserved for complex cases, but we think that computer assistance for custom-made prosthesis should be indicated for each case because it gives a greater implant stability and fewer complications. Computer assistance will further enlarge TMJ prosthesis replacement indications. PMID- 23916313 TI - Childhood invasive pneumococcal disease caused by non-7-valent pneumococcal vaccine (PCV7) serotypes under partial immunization in Taiwan. AB - BACKGROUND/PURPOSE: Emerging non-7-valent pneumococcal conjugate vaccine (PCV7) serotypes have replaced PCV7 serotypes in childhood invasive pneumococcal disease (IPD). This study was designed to describe the IPD caused by non-PCV7 serotypes under partial PCV7 immunization in Taiwan. METHODS: All children <18 years of age diagnosed with IPD at National Cheng Kung University Hospital from 1998 to 2010 were enrolled. Clinical and laboratory information was collected. Pneumococcal isolates were tested for antimicrobial susceptibility and interpreted using Clinical Laboratory Standard Institute guidelines (2008). Serotypes were determined using the capsular swelling method. RESULTS: One hundred and five patients with IPD were identified, including 75 PCV7 and 30 non-PCV7 isolates. Pneumonia (63.3%) was the leading clinical manifestation of non-PCV7 IPDs and 78.9% of pneumonia cases were associated with necrotizing pneumonia or empyema. Children with non-PCV7 IPDs had longer febrile days, required longer intensive care unit stays, and had a higher C-reactive protein level than those with PCV7 IPDs (p < 0.05). Serotype 3 is the most common non-PCV7 serotype (46.7%) and possesses the highest potential for pulmonary complications (p < 0.05, odds ratio: 0.114; 95% confidence interval, 0.013 - 0.973). CONCLUSION: The changing epidemiology of IPDs following the introduction of PCV7 has been noted. Expanded serotype coverage of the vaccine is warranted. PMID- 23916314 TI - Accuracy of the spanish emotional labour scale. PMID- 23916315 TI - LAR-RPTPs: synaptic adhesion molecules that shape synapse development. AB - The synapse is the most elementary operating unit in neurons, creating neural circuits that underlie all brain functions. Synaptic adhesion molecules initiate neuronal synapse connections, promote their stabilization and refinement, and control long-term synaptic plasticity. Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) have previously been implicated as essential elements in central nervous system (CNS) development. Recent studies have demonstrated that LAR-RPTP family members are also involved in diverse synaptic functions, playing a role in synaptic adhesion pathways together with a host of distinct transmembrane proteins and serving as major synaptic adhesion molecules in governing pre- and postsynaptic development, dysfunctions of which may underlie various disorders. This review highlights the emerging role of LAR RPTPs as synapse organizers in orchestrating synapse development. PMID- 23916316 TI - What motivates hospital CEOs to commit to ethical integration in their organizations. PMID- 23916317 TI - Factors associated with the concentration of immunoglobulin G in the colostrum of dairy cows. AB - Transfer of sufficient immunoglobulin G (IgG) to the neonatal calf via colostrum is vital to provide the calf with immunological protection and resistance against disease. The objective of the present study was to determine the factors associated with both colostral IgG concentration and colostral weight in Irish dairy cows. Fresh colostrum samples were collected from 704 dairy cows of varying breed and parity from four Irish research farms between January and December 2011; colostral weight was recorded and the IgG concentration was determined using an ELISA method. The mean IgG concentration in the colostrum was 112 g/l (s.d. = 51 g/l) and ranged from 13 to 256 g/l. In total, 96% of the samples in this study contained >50 g/l IgG, which is considered to be indicative of high quality colostrum. Mean colostral weight was 6.7 kg (s.d. = 3.6 kg) with a range of 0.1 to 24 kg. Factors associated with both colostral IgG concentration and colostral weight were determined using a fixed effects multiple regression model. Parity, time interval from calving to next milking, month of calving, colostral weight and herd were all independently associated with IgG concentration. IgG concentration decreased (P < 0.01) by 1.7 (s.e. = 0.6) g/l per kg increase in the colostral weight. Older parity cows, cows that had a shorter time interval from calving to milking, and cows that calved earlier in spring or in the autumn produced colostrum with higher IgG concentration. Parity (P < 0.001), time interval from calving to milking (P < 0.01), weight of the calf at birth (P < 0.05), colostral IgG concentration (P < 0.01) and herd were all independently associated with colostral weight at the first milking. Younger parity cows, cows milked earlier post-calving, and cows with lighter calves produced less colostrum. In general, colostrum quality of cows in this study was higher than in many previous studies; possible reasons include use of a relatively low-yielding cow type that produces low weight of colostrum, short calving to colostrum collection interval and grass-based nutritional management. The results of this study indicate that colostral IgG concentration can be maximised by reducing the time interval between calving and collection of colostrum. PMID- 23916318 TI - Effect of carbodiimide (EDC) on the bond stability of etch-and-rinse adhesive systems. AB - OBJECTIVE: Recent studies supported the use of protein cross-linking agents during bonding procedures to inactivate endogenous dentin proteases, preventing dentin collagen degradation thus improving bond durability. The aim of this study was to evaluate the effect of a 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-containing conditioner on the stability of the adhesive interface created by two etch-and-rinse adhesives. METHODS: Human dentin was etched with 35% phosphoric acid, treated with 0.3M EDC-containing conditioner followed by a three step or a two-step etch-and-rinse adhesive. Adhesives were applied to control specimens without EDC pre-treatment. Specimens were subjected to microtensile bond strength test and pulled to failure after 24h or 1 year of storage and interfacial nanoleakage expression was evaluated and quantified by light microscopy. Additionally, to investigate endogenous dentin matrix metalloproteinase activity a zymographic assay was performed on protein extracts obtained from phosphoric-acid-etched dentin powder with or without EDC treatment. RESULTS: The use of the EDC-containing conditioner did not affect immediate bond strength to dentin but contributed to preserve the bond strength after 1 year (p<0.05) for both tested adhesives. No difference was found in the interfacial nanoleakage expression that increased after aging irrespective from the treatment. EDC pre-treatment inhibited dentin endogenous MMPs as assayed with the zymography. SIGNIFICANCE: In conclusion, the results of the study provide proof that EDC can produce long-term inactivation of MMPs in acid-etched dentin matrices contributing to bond strength preservation over time. Future studies are needed to support the use of EDC in vivo. PMID- 23916319 TI - Access to HIV counseling and testing among people who inject drugs in Central Asia: strategies for improving access and linkages to treatment and care. AB - INTRODUCTION: As a population profoundly affected by the HIV epidemic and in critical need of linkages to HIV treatment and care, PWID in Central Asia remain largely underserved. This paper provides an overview of the current state of HIV testing and counseling in Central Asia for PWID, identifies main barriers leading to gaps in service delivery, and discusses implications for improving strategies that promote HIV testing for PWID. METHODS: We reviewed a number of sources for this paper including unpublished government reports, published papers, and Ministries of Health of Kazakhstan, Kyrgyzstan, Tajikistan, and Uzbekistan country progress reports to the UN General Assembly Special Session on HIV/AIDS (UNGASS) for 2012. RESULTS: Between 29 and 65% of PLWH in some Central Asian countries have been tested for HIV in the last 12 months. The rates have been increasing in the recent years but still are relatively low. Stigma, discrimination, human rights violations, and repressive legislation are barriers to HTC for people who inject drugs (PWID). CONCLUSION: The use of innovative evidence-based HTC models, such as community mobile-vans, self-testing at home, and rapid HIV testing among PWID in Central Asia are discussed and recommendations given regarding amendments in legislation and scaling up of existing community-based pilot projects to support HIV testing among PWID in CA. PMID- 23916320 TI - Clinical and pharmacological aspects of bath salt use: a review of the literature and case reports. AB - Bath salts are designer drugs with stimulant properties that are a growing medical and psychiatric concern due to their widespread availability and use. Although the chemical compounds in the mixtures referred to as "bath salts" vary, many are derivatives of cathinone, a monoamine alkaloid. Cathinones have an affinity for dopamine, serotonin, and norepinephrine synapses in the brain. Because of the strong selection for these neurotransmitters, these drugs induce stimulating effects similar to those of methamphetamines, cocaine, and 3,4 methylenedioxy-N-methylamphetamine (MDMA). Much of the emerging information about bath salts is from emergency department evaluation and treatment of severe medical and neuropsychiatric adverse outcomes. This review consists of a compilation of case reports and describes the emergent literature that illustrates the chemical composition of bath salts, patterns of use, administration methods, medical and neuropsychiatric effects, and treatments of patients with bath salt toxicity. PMID- 23916322 TI - Factors associated with variability and stability of cannabis use in young adulthood. AB - BACKGROUND: This study investigated the factors associated with initiating cannabis use, reverting to cannabis use and remaining a cannabis user in young adulthood. This is an important area of research as the risk for cannabis initiation is extending beyond adolescence and opportunities to influence cannabis use pathways can emerge throughout the life-course. METHODS: A large, community-based sample was followed prospectively. Data from two successive waves (mean age 23 years and 27 years respectively) of the Path Through Life Study (PATH) were analysed (n=2045). The longitudinal design enabled change in cannabis use in young adulthood to be predicted based on factors assessed approximately four years prior. RESULTS: An environment of licit drug use was strongly associated with initiating cannabis use (tobacco: OR=4.98, 95%CI: 2.31-10.76) and reverting to cannabis use in young adulthood (alcohol: OR=2.13, 95%CI: 1.42 3.19). Greater fun seeking was found to orientate people towards initiating cannabis use in young adulthood (OR=1.17, 95%CI: 1.04-1.30). Higher psychoticism increased the odds of remaining a cannabis user (OR=1.19, 95%CI: 1.07-1.33). Religious involvement was protective of cannabis initiation (OR=0.89, 95%CI: 0.83 0.95). Early childhood factors did not influence the pattern of cannabis use in young adulthood. CONCLUSIONS: The findings make an important contribution to the development of prevention and intervention strategies for young adults by drawing attention to specific areas of risk and protection. PMID- 23916321 TI - Methadone and buprenorphine-naloxone are effective in reducing illicit buprenorphine and other opioid use, and reducing HIV risk behavior--outcomes of a randomized trial. AB - AIMS: Determine the extent to which buprenorphine injectors continue treatment with buprenorphine-naloxone or methadone, and the impact of these treatments on substance use and HIV risk in the Republic of Georgia. METHODS: Randomized controlled 12-week trial of daily-observed methadone or buprenorphine-naloxone followed by a dose taper, referral to ongoing treatment, and follow-up at week 20 at the Uranti Clinic in Tbilisi, Republic of Georgia. Eighty consenting treatment seeking individuals (40/group) aged 25 and above who met ICD-10 criteria for opioid dependence with physiologic features and reported injecting buprenorphine 10 or more times in the past 30 days. Opioid use according to urine tests and self-reports, treatment retention, and HIV risk behavior as determined by the Risk Assessment Battery. RESULTS: Mean age of participants was 33.7 (SD5.7), 4 were female, mean history of opioid injection use was 5.8 years (SD4.6), none were HIV+ at intake or at the 12-week assessment and 73.4% were HCV+. Sixty-eight participants (85%) completed the 12-week medication phase (33 from methadone and 35 from buprenorphine/naloxone group); 37 (46%) were in treatment at the 20-week follow-up (21 from methadone and 16 from the buprenorphine/naloxone group). In both study arms, treatment resulted in a marked reduction in unprescribed buprenorphine, other opioid use, and HIV injecting risk behavior with no clinically significant differences between the two treatment arms. CONCLUSIONS: Daily observed methadone or buprenorphine-naloxone are effective treatments for non-medical buprenorphine and other opioid use in the Republic of Georgia and likely to be useful for preventing HIV infection. PMID- 23916323 TI - Vitamin D deficiency in alcohol-use disorders and its relationship to comorbid major depression: a cross-sectional study of inpatients in Nepal. AB - BACKGROUND: Mounting evidence suggests that deficiency of vitamin D may be associated with major health problems, including alcohol-use disorders (AUD) and major depression (MD). This study aimed to identify the vitamin D status of Nepalese inpatients with an AUD. We explored socio-demographic and alcohol-use related correlates and the relationship between vitamin D deficiency and comorbid MD. METHODS: A cross-sectional study was conducted on AUD inpatients (N=174) at eight alcohol/drug treatment centres around Kathmandu. Structured questionnaires were administered to assess the socio-demographic and alcohol-use parameters and to establish DSM-IV diagnoses of AUD and MD. Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D (25(OH)D) concentration of <50 nmol/L. RESULTS: The prevalence of vitamin D deficiency was 64%. Higher age, having a stable job or business, shorter time since last alcohol intake and winter serum samples were related to having lower 25(OH)D levels. Several features of AUD severity were associated with low vitamin D levels: guilt about drinking, using alcohol as eye opener, and history of relapse after alcohol treatment (p <= 0.03). Patients with a comorbid major depression, in particular secondarily depressed cases, were less likely to have vitamin D deficiency (X(2)=6.8; p=0.01). CONCLUSIONS: This study confirms high rates of vitamin D deficiency in alcohol treatment sample and shows a positive association between vitamin D deficiency and severity of alcohol-use disorders. Competing risk and other confounders may help explain the vitamin D status among patients with alcohol-use disorders and comorbid major depression. PMID- 23916324 TI - Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence. AB - BACKGROUND: Alcohol use, abuse and dependence remain a pressing public health problem. Based on its mechanism of action, varenicline seemed to be a likely candidate for treating alcohol dependence. METHODS: Alcohol dependent subjects (n=40) were enrolled in a 13-week double-blind placebo controlled clinical trial. Subject visits were once per week. At each visit, subjects were tested for breath alcohol levels, provided self-report data on alcohol and nicotine use, and on mood and craving. In addition, subjects received once a week medical management (MM). RESULTS: There was no difference between varenicline and placebo treated groups on any of the drinking outcomes. Compared to placebo-treated subjects, varenicline treated subjects had decreased rates of alcohol craving and cigarette smoking, as well as greater mood improvements during the later part of the study (weeks 6-13). In addition, among subjects who were cigarette smokers, those treated with varenicline were significantly less likely to report heavy drinking during the trial. CONCLUSIONS: Although varenicline was not significantly more effective than placebo at reducing drinking during the trial, its effects on alcohol craving and mood suggest that future investigation of the mechanism of action of varenicline, as well as additional clinical studies may be warranted. In particular, the findings regarding the influence of smoking status on heavy drinking among varenicline-treated subjects should be investigated in future studies. PMID- 23916325 TI - Usefulness of ICF-CY to define functioning and disability in very low birth weight children: a retrospective study. AB - BACKGROUND: Preterm birth is associated with variable degrees of brain injury, adverse neurodevelopmental outcomes and continuing special health care needs. STUDY AND AIMS: This observational, retrospective and cross-sectional study aims to describe the functional features of VLBW infants using the ICF-CY classification and to identify the association between gender, twinship, birth weight, gestational age, adjusted age and functioning as defined by the ICF biopsychosocial model. SAMPLE: 56 VLBW infants (corrected age of 12-24 months) were consecutively enrolled. INSTRUMENTS: Three assessment tools were used: a neuro-functional assessment (NFA); the Griffiths Mental Development Scales Revised: Birth to 2 years (Griffiths 0-2) to evaluate psychomotor development and the ICF-CY questionnaire for ages 0-3. RESULTS: A two-step cluster component analysis with the Bayesian information criterion was conducted based on NFA and Griffiths 0-2 scores and four groups of infant's functioning (very low, low, intermediate, high) emerged. Study findings demonstrate that the traditional assessment tools tend to poorly evaluate the interaction between the person's functioning and environment factors (EF), even thought EF results to be relevant for VLBW infants. The higher number of symptoms, more difficulties in activities and participations and the higher number of environmental facilitators maximize the difference between infants with very low and those with intermediate or higher functioning. The distribution of gender or the presence of siblings is not significantly associated to any group. CONCLUSION: This study shows that a more complete evaluation of functioning of VLBW children, based on the biopsychosocial approach, is needed and can be successfully implemented in the follow-up routine through ICF-CY questionnaire. PMID- 23916327 TI - It's a microscopic world after all: prebiotics, probiotics, and synbiotics. PMID- 23916328 TI - Five treatments nurses can better direct. PMID- 23916329 TI - Adapting the Acute Care for Elders (ACE) model to your hospital. PMID- 23916330 TI - Infection control strategy by killing drug-resistant bacteria. PMID- 23916331 TI - Global alert to avian influenza virus infection: from H5N1 to H7N9. AB - Outbreak of a novel influenza virus is usually triggered by mutational change due to the process known as 'antigenic shift' or re-assortment process that allows animal-to-human or avian-to-human transmission. Birds are a natural reservoir for the influenza virus, and subtypes H5, H7, and H9 have all caused outbreaks of avian influenza in human populations. An especially notorious strain is the HPAI influenza virus H5N1, which has a mortality rate of approximately 60% and which has resulted in numerous hospitalizations, deaths, and significant economic loss. In March 2013, in Eastern China, there was an outbreak of the novel H7N9 influenza virus, which although less pathogenic in avian species, resulted in 131 confirmed cases and 36 deaths in humans over a two-month span. The rapid outbreak of this virus caused global concern but resulted in international cooperation to control the outbreak. Furthermore, cooperation led to valuable research-sharing including genome sequencing of the virus, the development of rapid and specific diagnosis, specimen sharing for future studies, and vaccine development. Although a H7N9 pandemic in the human population is possible due to its rapid transmissibility and extensive surveillance, the closure of the live-bird market will help mitigate the possibility of another H7N9 outbreak. In addition, further research into the source of the outbreak, pathogenicity of the virus, and the development of specific and sensitive detection assays will be essential for controlling and preparing for future H7N9 outbreaks. PMID- 23916332 TI - The role of environmental variables on Aedes albopictus biology and chikungunya epidemiology. AB - Aedes albopictus is a vector of dengue and chikungunya viruses in the field, along with around 24 additional arboviruses under laboratory conditions. As an invasive mosquito species, Ae. albopictus has been expanding in geographical range over the past 20 years, although the poleward extent of mosquito populations is limited by winter temperatures. Nonetheless, population densities depend on environmental conditions and since global climate change projections indicate increasing temperatures and altered patterns of rainfall, geographic distributions of previously tropical mosquito species may change. Although mathematical models can provide explanatory insight into observed patterns of disease prevalence in terms of epidemiological and entomological processes, understanding how environmental variables affect transmission is possible only with reliable model parameterisation, which, in turn, is obtained only through a thorough understanding of the relationship between mosquito biology and environmental variables. Thus, in order to assess the impact of climate change on mosquito population distribution and regions threatened by vector-borne disease, a detailed understanding (through a synthesis of current knowledge) of the relationship between climate, mosquito biology, and disease transmission is required, but this process has not yet been undertaken for Ae. albopictus. In this review, the impact of temperature, rainfall, and relative humidity on Ae. albopictus development and survival are considered. Existing Ae. albopictus populations across Europe are mapped with current climatic conditions, considering whether estimates of climatic cutoffs for Ae. albopictus are accurate, and suggesting that environmental thresholds must be calibrated according to the scale and resolution of climate model outputs and mosquito presence data. PMID- 23916333 TI - A current analysis of chemotherapy strategies for the treatment of human African trypanosomiasis. AB - Despite the recent advances in drug research, finding a safe, effective, and easy to use chemotherapy for human African trypanosomiasis (HAT) remains a challenging task. The four current anti-trypanosomiasis drugs have major disadvantages that limit more widespread use of these drugs in the endemic regions of sub-Saharan Africa. Pentamidine and suramin are limited by their effectiveness against the only first stage of Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, respectively. In addition, melarsoprol and eflornithine (two second stage drugs) each have disadvantages of their own. The former is toxic and has increasing treatment failures while the latter is expensive, laborious to administer, and lacks efficacy against T. b. rhodesiense. Furthermore, melarsoprol's toxicity and decreasing efficacy are glaring problems and phasing out the drug as a frontline treatment against T. b. gambiense is now possible with the emergence of competent, safe combination chemotherapies such as nifurtimox-eflornithine combination treatment (NECT). The future of eflornithine, on the other hand, is more promising. The drug is useful in the context of combination chemotherapy and potential orally administered analogues. Due to the limits of monotherapies, greater emphasis should be placed on the research and development of combination chemotherapies, based on the successful clinical tests with NECT and its current use as a frontline anti-trypanosomiasis treatment. This review discussed the current and future chemotherapy strategies for the treatment of HAT. PMID- 23916334 TI - Development of a polymerase chain reaction applicable to rapid and sensitive detection of Clonorchis sinensis eggs in human stool samples. AB - Microscopic examination of eggs of parasitic helminths in stool samples has been the most widely used classical diagnostic method for infections, but tiny and low numbers of eggs in stool samples often hamper diagnosis of helminthic infections with classical microscopic examination. Moreover, it is also difficult to differentiate parasite eggs by the classical method, if they have similar morphological characteristics. In this study, we developed a rapid and sensitive polymerase chain reaction (PCR)-based molecular diagnostic method for detection of Clonorchis sinensis eggs in stool samples. Nine primers were designed based on the long-terminal repeat (LTR) of C. sinensis retrotransposon1 (CsRn1) gene, and seven PCR primer sets were paired. Polymerase chain reaction with each primer pair produced specific amplicons for C. sinensis, but not for other trematodes including Metagonimus yokogawai and Paragonimus westermani. Particularly, three primer sets were able to detect 10 C. sinensis eggs and were applicable to amplify specific amplicons from DNA samples purified from stool of C. sinensis infected patients. This PCR method could be useful for diagnosis of C. sinensis infections in human stool samples with a high level of specificity and sensitivity. PMID- 23916335 TI - Clinical features, diagnostic tools, and treatment regimens for visceral leishmaniasis in Bulgaria. AB - PURPOSE: Visceral leishmaniasis (VL), caused by the parasite Leishmania infantum, which was once largely confined to Southern Europe is now being diagnosed throughout Northern Europe, including Great Britain. In an effort to help EU clinicians improve their diagnosis and management of VL, this paper defines clinical features typical of the disease as it presents in Bulgaria, where VL is endemic. METHODS: The list of clinical symptoms presented here was gleaned from the medical records (patient histories, epidemiological survey cards, laboratory data) of 59 Bulgarian patients with VL. This study also includes microscopic, serological, and molecular laboratory techniques. RESULTS: Described and analyzed are the clinical features, diagnostic techniques, and therapeutic regimens of 59 cases--part of the total number of VL case histories (P = 120, 116 Bulgarian and 4 not Bulgarian) collected in Bulgaria over the past 24 years (1988-2011). Although all of the studied 59 cases presented with classical symptoms of VL, only in three occasions, the initial diagnosis was correct. CONCLUSIONS: Left untreated, zooanthroponotic VL leads to debilitating chronic disease and even death. Yet, because VL is hard to recognize and relatively new to Northern Europe, misdiagnosis is common and treatment too often inappropriate and delayed. PMID- 23916336 TI - Three Leishmania/L. species--L. infantum, L. major, L. tropica--as causative agents of mucosal leishmaniasis in Iran. AB - Cases of human oro-mucosal leishmaniasis are mainly reported in areas where Leishmania (Viannia) braziliensis perpetuates and the damages are mainly located at the cartilaginous nasal septum and frontal portions of the nasal fossa. In Iran, an area free of any L.(V) braziliensis, three Leishmania species are known to perpetuate through distinct (i) blood-feeding sand flies and (ii) rodents or (iii) canidae. Thus while establishing the diagnosis of any human oro-mucosal lesions, three Leishmania species - L. infantum, L. major, and L. tropica - must be considered as potential etiological agents of these damages. With these objectives in mind, features such as localization, extent, severity of oro mucosal lesions, and duration of symptoms at the time of diagnosis were recorded from 11 patients with respect to the presence or absence of cutaneous lesions in other body parts. The biopsy samples were collected from the oro-mucosal and cutaneous lesions and were processed for further identification of the Leishmania species. The lesions ranged from mucosal nodules without ulceration, nodules with erosion, and shallow to deep ulcerations. Leishmania major was isolated from six (55%) cases showing lesions or scars. The scars were restricted to upper and lower extremities. For the other five patients who did not display any signs of former or active cutaneous leishmaniasis, L. major, L. tropica, and L. infantum were isolated from their lesions. In conclusion L. major, L. infantum, and L. tropica, regardless of common tropism, can be seen in mucosal tissues. However, L. major was the predominant species detected from the lesions in the nasal, gingival, and hard and soft palates, and L. tropica was isolated from the gingival and lower lip lesions. Leishmania infantum was isolated from two severe cases of deep mucosal damage displayed by the epiglottis, cricoarytenoid muscle, and laryngeal mucosa. One important finding was the association of L. major with active or scarred skin lesions. PMID- 23916338 TI - Theoretical considerations and practical results on the influence of the representation of the foot for the estimation of internal forces with models. AB - With a hypothetical experiment the differences in internal force estimates due to different mechanical representations of the foot are demonstrated. It is shown that the magnitude of the internal force estimates is dependent on the formulation of the model. A comparative approach (the systematic change of one condition while all other parameters are kept as constant as possible) is suggested to eliminate the influence of systematic errors. The implications of the hypothetical experiment are applied to a practical situation using four different specifications of a generalized three-dimensional six-segment model of the foot. The four specifications vary with respect to the degrees of freedom at the six joints, the distribution algorithm, and the maximum muscle force criterion. The bone-to-bone contact force at the tibio-talar joint during a lateral side shuffle movement executed with two different shoes is used to investigate the influence of the model specifications. The four models estimate distinctly different force magnitudes; however, the result of the comparison between the two shoe conditions is similar for all four models. This is an indication that models should primarily be used for the investigation of the influence of systematically changed external conditions on internal force estimates. PMID- 23916337 TI - Accuracy of HRP2 RDT (Malaria Antigen P.f(r)) compared to microscopy and PCR for malaria diagnosis in Senegal. AB - Rapid diagnosis tests (RDTs) allow for the confirmation of malaria diagnosis. In Senegal, RDTs detecting HRP2 have been adopted in 2008 for malaria diagnosis. However, the sustainability of this strategy requires adequate and regular quality control. PCR on DNA extracted in nitrocellulose band of RDTs enable quality control. A RDT (Malaria Antigen P.f(r)) and a thick smear were performed on patients with suspected malaria. DNA was extracted from the nitrocellulose band of RDTs to which a non-specific PCR and a specific PCR were applied. The results of the RDT were compared with those obtained from the thick smear and the PCR to measure sensitivity, specificity as well as positive and negative predictive values. For 81.6% of the 273 patients involved, the thick smear was positive. Rapid diagnosis tests were positive for 85.7% of the patients. Non specific PCR was positive on 87.9% of RDTs. Plasmodium falciparum was found in 99.5% of patients and Plasmodium ovale appeared in only 0.4% of patients. Sensitivity of the Malaria Antigen Pf(r) RDT in relation to thick smear and to PCR was 98.2% and 97.1% respectively. Quality control with PCR on the nitrocellulose band performed several months after it was used confirms its adequate level of sensitivity. The collection and screening of DNA present in already used RDT is a good means of quality control for this tool. It is also a relevant alternative to the molecular approach in the context of a reduction in the transmission of malaria. PMID- 23916339 TI - Reliability of pressure measurements: the EM ED F system. AB - The reliability of foot pressure measurement using the EMED F system has been tested by recording 25 walks with 10 volunteer subjects at three different speeds. Coefficients of reliability calculated for 1-25 walks showed that a good level of reliability was achieved using one measurement for most force/pressure variables but when the mean result of three or more walks was used reliability was excellent. Measurements related to time were more variable than the total force, the peak pressure and the area. The total force and peak pressure were also shown to increase with increasing speed but this was not true for all sites on the foot. PMID- 23916340 TI - Thickness of the human ligamentum flavum as a function of load: an in vitro experimental study. AB - Human cadaver spine specimens, consisting of the third and fourth lumbar vertebral laminae and the intervening ligamentum flavum, were studied. The specimens were loaded in axial traction with 1, 2, 4, and 8 kg respectively. To avoid contact deformation the thinning of the yellow ligament was recorded through an opto-electronic laser system. An average elongation of 6 mm was found at 8 kg of traction with a corresponding average thinning of 2 mm. The results indicated that the thickness changes of the ligamentum flavum might affect the dimensions of the lumbar spinal canal during, for example, normal changes in body posture. PMID- 23916341 TI - Interface pressures in below elbow casts. AB - Intra-cast pressures were measured in casts worn by patients with Colles' fractures and by volunteers. This study has shown that the loading as determined by the interface pressures in conventional backslab-below elbow casts is low and generally nonspecific. However, moulding the backslab increases the intra-cast pressures and these higher pressures are maintained throughout the period of immobilization as compared with non-moulded casts. There is no evidence of three point loading in the casts; as a method of applying forces to the fracture site conventional casting does not appear to be particularly effective. PMID- 23916342 TI - Instantaneous axes of rotation of the typical cervical motion segments: I. an empirical study of technical errors. AB - The reliability of the conventional technique for determining the instantaneous axes of rotation of the cervical motion segments was evaluated by comparing the determinations made by two observers and the same observer on two separate occasions. Different observers found the same mean location for the instantaneous axis at each segment in a test population of 17 normal subjects, but for any given subject the interobserver and intraobserver differences were large, with a relative variation of up to 35%. Thus, while reliable for determining the mean location of the instantaneous axis of rotation in a population, the technique was not reliable for determining the axis in a given subject. Qualitative analysis suggested that the identification of the radiographic images of the vertebrae and their tracing is the greatest source of error for this technique. PMID- 23916343 TI - Instantaneous axes of rotation of the typical cervical motion segments: II. optimization of technical errors. AB - The reliability of a modified protocol for plotting the instantaneous axes of sagittal rotation for the cervical spine was evaluated by measuring the observer differences when the process was performed separately by two observers, and by a single observer, on two separate occasions. Small observer differences were found both for individual steps in the process and for the process as a whole. These differences were substantially less than those found using the conventional technique for plotting the instantaneous axes of rotation. The improvement in the technique was resultant from the use of stricter criteria for recognizing and tracing vertebral landmarks. PMID- 23916344 TI - Pathological gaits: inefficiency is not a rule. AB - Theenergy expenditure per unit distance, or cost of gait, depends on the efficiency of the locomotory mechanism, which is a function of speed. We compared the cost of gait at corresponding speeds between pathologic (hemiplegic, above knee amputee, paraplegic) and normal subjects respectively, using a polynomial regression on data available from the literature. In all pathologies the cost speed function showed a minimum at a speed which may be defined as optimum, as in normal gait. Within the speed range possible for the patients, the cost-speed functions were significantly different from the normal one in the above-knee amputee and in the paraplegic, but not in the hemiplegic. In the amputee, the minimum cost was increased by 38% with respect to that of the normal at a corresponding speed. In contrast, the minimum cost was increased by only 11 % in the paraplegic, despite the much more severe impairment. PMID- 23916345 TI - Effects of arthrodeses on walking: kinemati and kinetic studies of subtalar and knee arthrodesis. AB - We studied the effects of subtalar (n=2) or knee (n=2) arthrodesis on the gait of four subjects with particular attention to the temporal and sagittal plane kinematic and kinetic characteristics. Each subject had a painless arthrodesis and no other gait limitation. To compensate for their disability the subtalar arthrodesis subjects showed altered angular displacement patterns at the ipsilateral ankle, knee and hip joints, and greater than normal resultant joint moments at the knee and hip in late stance. A symmetric gait was achieved by mimicking ipsilateral movements with the opposite limb. Compensations for subtalar joint arthrodesis were shown to differ from those for a unilateral arthrodesed ankle joint. To compensate for knee arthrodesis, subjects showed an increased range of movement at both the ankle and hip joints, and excessive resultant joint moments generated at the hip joint. Little variability was seen in the kinematics of the hip joint, suggesting that its role in locomotion (maintenance of progression) was rigidly defined. Variation from normal patterns were also seen in the kinematics of the contralateral limb, primarily in a 'vaulting' response. The results of this study indicate that contrary to the effects of unilateral ankle or subtalar arthrodesis, the locomotor system is unable to compensate effectively for the complete loss of movement at one knee joint, and an inefficient asymmetric gait is produced. The magnitude of the resultant joint moments at the ipsilateral hip joint, combined with the lack of kinematic flexibility may predispose this joint to subsequent degeneration. PMID- 23916347 TI - Erratum. PMID- 23916346 TI - Fascial deformation in the lateral elbow region: a conceptual approach. AB - In embalmed preparations, the antebrachial fascia in the lateral elbow region is shown to be deformed by load application to the triceps muscle. From this fascia, muscles arise which are primarily concerned with the extension of wrist and fingers. In the case of lateral epicondylitis (tennis elbow), the superficial site of attachment of these extensors at the lateral epicondyle is extremely painful. Triceps training may help to diminish (or prevent) this pain by altering the forces acting at the lateral epicondyle. PMID- 23916348 TI - Sex- and age-specific incidence of autoimmune rheumatic diseases in the Chinese population: a Taiwan population-based study. AB - OBJECTIVES: The purpose of this study was to estimate the sex- and age-specific incidence rates of major autoimmune rheumatic diseases (ARDs) in Taiwan using a population longitudinal database. METHODS: A health insurance database containing the records of 1,000,000 beneficiaries of Taiwan National Health Insurance from 2005 to 2009 was used. RESULTS: Between 2005 and 2009, the overall incidence rate of the major ARDs was 29.8 (95% CI = 28.3-31.3) per 100,000 person-years. Among the ARDs studied, the incidence of rheumatoid arthritis (RA; per 100,000 person years) was highest (17.2, 95% CI = 16.1-18.4) and was followed by Sjogren's syndrome (11.8, 95% CI = 10.8-12.7), systemic lupus erythematosus (SLE; 7.2, 95% CI = 6.5-8.0), systemic sclerosis (SS; 1.1, 95% CI = 0.8-1.4), vasculitis (1.0, 95% CI = 0.7-1.3), Behcet disease (0.9, 95% CI = 0.6-1.1), dermatomyositis (DM; 0.7, 95% CI = 0.5-1.0), and polymyositis (PM; 0.6, 95% CI = 0.4-0.8). Females had a higher incidence ratio than did males, but a significant female/male incidence ratio was only observed for SLE (8.5, 95% CI = 6.1-12.0), Sjogren's syndrome (6.0, 95% CI = 4.8-7.6), RA (3.0, 95% CI = 2.6-3.5), and SS (2.6, 95% CI = 1.4 4.6). CONCLUSIONS: ARDs are three to four times more common among women than among men in the Chinese population of Taiwan. The incidence of RA was the highest, followed by Sjogren's syndrome and SLE, while the incidence of Behcet disease was the lowest in this study. This nationwide, population-based, longitudinal epidemiological study of ARDs in Taiwan provides data for future global comparisons and may provide clues as to the etiology of these diseases. PMID- 23916349 TI - Haplotype phasing after joint estimation of recombination and linkage disequilibrium in breeding populations. AB - A novel method for haplotype phasing in families after joint estimation of recombination fraction and linkage disequilibrium is developed. Results from Monte Carlo computer simulations show that the newly developed E.M. algorithm is accurate if true recombination fraction is 0 even for single families of relatively small sizes. Estimates of recombination fraction and linkage disequilibrium were 0.00 (SD 0.00) and 0.19 (SD 0.03) for simulated recombination fraction and linkage disequilibrium of 0.00 and 0.20, respectively. A genome fragmentation phasing strategy was developed and used for phasing haplotypes in a sire and 36 progeny using the 50 k Illumina BeadChip by: a) estimation of the recombination fraction and LD in consecutive SNPs using family information, b) linkage analyses between fragments, c) phasing of haplotypes in parents and progeny and in following generations. Homozygous SNPs in progeny allowed determination of paternal fragment inheritance, and deduction of SNP sequence information of haplotypes from dams. The strategy also allowed detection of genotyping errors. A total of 613 recombination events were detected after linkage analysis was carried out between fragments. Hot and cold spots were identified at the individual (sire level). SNPs for which the sire and calf were heterozygotes became informative (over 90%) after the phasing of haplotypes. Average of regions of identity between half-sibs when comparing its maternal inherited haplotypes (with at least 20 SNP) in common was 0.11 with a maximum of 0.29 and a minimum of 0.05. A Monte-Carlo simulation of BTA1 with the same linkage disequilibrium structure and genetic linkage as the cattle family yielded a 99.98 and 99.94% of correct phases for informative SNPs in sire and calves, respectively. PMID- 23916350 TI - Knee effusion and quadriceps muscle strength. AB - Ten healthy subjects with no musculoskeletal problems were tested using a computerized exercise dynamometer. Quadriceps femoris concentric performance was examined during maximal effort isokinetic knee extension at joint angular velocities of 2.09 and 4.18 rad s(-1). A saline and dextrose solution was injected into the knee joint cavity in 30-ml increments, and peak torque and power tests were undertaken with knee effusions of 0, 30, 60, and 90 ml. A protocol which included and excluded a local skin anaesthetic and submaximal exercise prior to the maximal effort test was also undertaken. The results showed that quadriceps peak torque and power were not significantly affected by the amount of knee effusion at either joint angular velocity when submaximal exercise was performed prior to the maximal effort test. However, peak torques were significantly decreased during isokinetic muscle action without prior submaximal muscle work. It was suggested that these findings may be related to fluid movement in the knee joint compartments, the compliance of the joint capsule, and the location that fluid was injected into the joint cavity. Joint swelling is a common symptom of individuals with osteoarthritis and rheumatoid arthritis, as well as those suffering acute joint trauma. This study has extended previous work on joint swelling by examining quadriceps function during joint movement, thus moreeffectivelysimulating joint and muscle activity which occursduring functional activities. Patients with knee joint swelling are thought to experience greater difficulty undertaking quadriceps exercises, and will not perform these exercises effectively until swelling in the joint is reduced. The current study provides some evidence to suggest that a moderate amount of swelling does not impair performance. Assuming that patients do not have other symptoms that contraindicate exercise, they can be encouraged to do more active muscle work. PMID- 23916351 TI - Relationship between plantar pressure distribution under the foot and insole comfort. AB - In this paper, four pairs of insoles with different comfort characteristics were used to investigate the relationship between the pressure distribution under the foot and running shoe comfort. Fourteen male subjects were tested in four insole conditions by walking and running on a treadmill. The pressure at the plantar surface of the foot was measured by using an EMED pressure-measuring insole. For walking there were significantly higher pressures and forces in the midfoot area and significantly lower pressures in the medial forefoot and hallux area by wearing the most comfortable insole compared with wearing the least comfortable insole. The shift of the pressure from forefoot to midfoot for the most comfortable insole provided an even distribution of the pressure at the plantar surface of the foot. The results also demonstrated that the path of centre of force at the plantar surface of the foot moved to the lateral aspect of the foot for the most comfortable insole. For running, only the pressure in the medial forefoot area was found significantly lower for the most comfortable insole than for the least comfortable insole. The results of this study indicated that the pressure distribution between the plantar surface of the foot and the shoe could detect the change of shoe comfort. Thus it is a suggestion that pressure measurement may be related to understand factors important for shoe comfort. Comfort of sport shoes is important for the appropriate execution of sport activities. Additionally, comfort may influence fatigue and possibly the development of injuries. The quantification of comfort of sport shoes and the understanding of mechanical and/or biological functions related to it may be enhanced with the use of pressure measurements between the plantar surface of the foot and the shoe sole. PMID- 23916352 TI - Cervical zygapophyseal joints: geometrical parameters and relationship to cervical kinematics. AB - The relationship was examined between the height and slope of the cervical zygapophyseal joints and the patterns of motion of the cervical vertebrae. The height and orientation of the C3?C7 superior articular processes were measured in lateral radiographs of 40 normal subjects. The C4-C6 facets were oriented at approximately 40 degrees to the vertical, while the C3 and C7 facets were more steeply oriented. The heights of the superior articular processes were found to increase at progressively lower vertebral levels. Contrary to published views, the slope of the superior articular facets has no bearing on the pattern of motion of the cervical vertebrae. No relationship was found between slope of the facets and the location of the instantaneous axes of rotation of the cervical vertebrae. In contrast the height of the articular processes was perfectly related to the location of the axes of rotation. Articular height, but not slope, is a major determinant of the patterns of motions of the cervical vertebrae. This study provides data necessary to confirm or deny the putative roles of the cervical zygapophyseal joints in determining motion of the cervical spine in the sagittal plane. PMID- 23916353 TI - Transfer of movement between calcaneus and tibia in vitro. AB - Excessive foot eversion and/or abnormal tibial rotation have been associated with knee injuries. The mechanical coupling of leg and foot, which may be related to the aetiology of knee injuries, is still not well understood. The goal of this study was to determine in vitro, as a function of loading and flexion position of the foot, the movement transfer from calcaneal eversion-inversion to tibial rotation and vice versa occurring in the ankle-joint complex. A lower leg holding and loading device with 6 degrees of freedom was used in the investigation. Fourteen fresh-frozen, foot-leg specimens were tested. The movement transfer from calcaneus to tibia and vice versa differed significantly between the specimens. The transferred movement was not the same for all input modes. Specifically, calcaneal eversion resulted in significant internal tibial rotation; however, internal tibial rotation did not induce any calcaneal eversion. Vertical loading of the tibia and foot flexion position had a major influence on this movement transfer. The amount of calcaneal eversion transferred to internal tibial rotation depends on the individual mechanical coupling at the ankle-joint complex. Therefore excessive pronation, in running for instance, is only critical for high knee loading when coupled with a high movement transfer in the ankle joint complex. The interindividual differences may also signal difficulties for prosthesis design in total ankle-joint replacement and for the design of shoe orthotics. PMID- 23916354 TI - Influence of selective arthrodesis on the movement transfer between calcaneus and tibia in vitro. AB - Arthrodeses of foot and ankle are well established, accepted, and practical methods for treatment of painful joint degeneration, foot deformity, and instability. Consecutive changes in gait and over-use injuries have been explained by the created lever arms and the overall compensatory motion in the neighbouring joints, rather than by changes in the mechanical coupling of foot and tibia. Thus the purpose of this study was to quantify the change of movement transferred from calcaneus to tibia, and vice versa, for selective joint fusions (ankle, subtalar, and talonavicular joints) under different flexion and loading conditions. In six fresh cadaveric foot-leg specimens, transfer of rotational movement between calcaneus and tibia occurred in all arthrodesis conditions. Fusion of the subtalar joint, which is commonly believed to be crucial in the transfer of rotational movement in the ankle joint complex, decreased the movement transfer from calcaneal inversion to external tibial rotation about 71.8% and, vice versa, from external tibial rotation to calcaneal inversion about 35.8%. However, the movement transfer did not change when calcaneal eversion and internal tibial rotation were the input movements. The ankle (talocrural) joint must have more than 1 degree of freedom, since significant movement transfer still occurred when the subtalar joint was fused. It could be that other structures such as ligaments also play an important role in transferring movement. Consequently it may be difficult to predict the effect of a planned arthrodesis since the resulting restriction of motion and movement transfer may be substantially determined by the integrity of the surrounding soft tissue, especially the ligaments. PMID- 23916355 TI - Effects of torsions in the wrist joint on carpal-bone behaviour and the radiotriquetral ligaments: an experimental study. AB - The orientations of the radiotriquetral ligaments in the wrist joint suggest the role of counteracting torsions in the radiocarpal joint. This is tested in a series of kinematic experiments with three specimens, the joints being forced to rotate about the longitudinal axis of the third metacarpal. The reorientations of the marked insertion sites of the dorsal and palmar radiotriquetral ligaments are assessed and related to the individual carpal-bone movements. The three specimens react similarly to the imposed torsions: a hyperpronation is related to a dorsal flexion and a hypersupination to a palmar flexion. The dorsal radiotriquetral ligaments are highly addressed during hypersupination, but the palmar ligaments show no significant elongations during hyperpronations. The mechanism of wrist joint injuries due to trauma like a fall on the outstretched hand is poorly documented. The torsions occurring during these trauma are simulated in cadaver experiments. Large effects upon the dorsal ligaments are found in comparison to the palmar ligaments. This indicates that the palmar radiotriquetral ligaments protect the joint against hyperpronations. Planning of the restoration of hand function in the injured hand should include the different roles of these two ligaments. PMID- 23916356 TI - Repetitive lifting and spinal shrinkage, effects of age and lifting technique. AB - The assumed advantages of the so-called leg-lifting technique over the back lifting technique are still the subject of much debate. The present study was aimed at studying the consequences of performing both lifting techniques on net lumbar moments and spinal shrinkage. Furthermore, the relation between age and spinal shrinkage was studied. Five subjects approximately 40 years old and six subjects 20 years old performed six 5-min bouts of repetitive lifting using each technique on a separate day. Net lumbar moments were calculated using a two dimensional dynamic linked segment model. Spinal shrinkage was measured at T12 and at the head after each bout of lifting and every 5 min during 1 h preceding the lifting bouts. The peak moments were marginally but significantly higher in the leg-lift. No differences in mean moments and shrinkage between lifting techniques were found. The shrinkage after the back-lift was more pronounced in the older subjects and a similar tendency was found after the leg-lift. The creep rate, i.e. the rate at which the shrinkage approaches its equilibrium was higher in the older subjects. No clear relations of anthropometrical variables and net moments with shrinkage was found. The common advice of using a leg-lift rather than a back-lift was not supported by the present study. Both the mechanical load on the low back (net moments) and the resulting shrinkage show considerable interindividual variation, the causes of which need further elucidation. The leg lifting technique is still widely advocated, thought its merits from a biomechanical point of view have been questioned. In this study spinal shrinkage and lumbar moments calculated by means of a dynamic linked segment model are used to compare the leg-lift to the more commonly used back-lift. PMID- 23916357 TI - Design and testing of a flexible hip prosthesis. AB - A prosthesis with flexibility and optimal proximal fit was constructed in titanium alloy. The aim was to create the same elasticity as in the femoral shaft. Distally it was cylindrical with slots in the stem and a spacer made of polymer was placed in the slots. The proximal part of the prosthesis was wedge shaped in both planes and a collar with a conical contact surface to bone was used. Pure titanium was plasma sprayed on the upper part as well as underneath the collar allowing bony ingrowth. A test jig was constructed and 10 million cycles with 4000 N loading was planned. The prosthesis broke after 600 000 cycles and it was a typical fatigue failure. A commercially available flexible prosthesis was tested as a reference and broke after 29 000 cycles. It is concluded that construction of a flexible hip prosthesis using metal with reasonable security against fatigue failure breakage is difficult, and we are somewhat doubtful if it is possible. PMID- 23916358 TI - Passive insufficiency of two-joint shoulder muscles. AB - This preliminary study examined the effects of full elbow flexion and full elbow extension on the end-point of active range of motion of shoulder flexion and shoulder extension respectively. The end-points were measured from lateral photographs of the right upper limbs of 30 men after they flexed and extended their shoulders with their elbows held in full flexion and full extension. Angular measurements showed that full elbow flexion limited shoulder flexion range of motion and that full elbow extension limited shoulder extension range of motion. The results indicated that passive muscle insufficiency of active shoulder flexion and extension was probably brought about by lengthening the triceps brachii and the biceps brachii muscles respectively. Clinicians are encouraged to considerthis passive insufficiency when measuring range of motion of shoulderflexion and extension and when implementing therapeutic interventions. PMID- 23916359 TI - Ribcage compressibility in living subjects. AB - The purpose of this study was to examine the responses of normal living subjects to the application of anteroposterior forces to the ribcage. Seventeen subjects aged between 25 and 37 years were tested during slow oscillatory loading while breath-holding at the end of a normal expiration. The mean stiffness coefficient was found to be 9.4 N mm(-1) (SD 2.9) and the mean gradient of the force-strain relation was 1888 N (SD 646). Comparison with previously published cadaver data indicates that the embalmed cadaver ribcage stiffness is in the order of three times stiffer than living subjects, while fresh cadavers showed comparable stiffness to living subjects. A number of studies have used models to predict and understand the behaviour of the thoracic spine. Validation of the behaviour of models which include the thoracic spine and ribcage depends on comparison of model response predictions with observed responses of human subjects. The present study provides data on the anteroposterior compressibility of the ribcage of living subjects which may be suitable for use in model validation studies. PMID- 23916360 TI - [Anales de Pediatria: the past, the present and the future]. PMID- 23916361 TI - A snapshot of cognitive functioning: deriving a tool for the efficient assessment of cognition in schizophrenia and other chronic psychiatric disorders in a real world inpatient setting. AB - Previous research has led to the development of short batteries of tests that efficiently measure the cognitive functioning of individuals with schizophrenia. To attempt to replicate previous findings, we applied an empirical test selection strategy to archival cognitive test data of two non-overlapping inpatient samples of individuals with schizophrenia or schizoaffective disorder (total N=110). We then extended previous findings by applying the empirical test selection strategy to the archival data of two non-overlapping inpatient samples of individuals with various psychiatric disorders (total N=149). For each sample, tests were selected by examining the relationships between individual test scores and averaged test scores representing global cognitive functioning while taking into account test administration times. Across patient samples, digit symbol coding tasks, verbal fluency tasks, and tests with a processing speed component (Trail Making Test Part A and Stroop) emerged as efficient and effective indicators of overall cognitive functioning. A brief cognitive assessment tool incorporating coding, fluency, and processing speed tasks would provide a valid and clinically useful snapshot of a patient's level of cognitive functioning if more comprehensive testing cannot be completed. PMID- 23916362 TI - Effect of diagnostic labeling and causal explanations on medical students' views about treatments for psychosis and the need to share information with service users. AB - This study examines whether medical students' views of treatments for 'schizophrenia' and of patients' rights to be informed about their condition and their medication were influenced by diagnostic labeling and causal explanations and whether they differed over medical training. Three hundred and eighty-one Italian students attending their first or fifth/sixth year of medical studies read a vignette portraying someone who met diagnostic criteria for 'schizophrenia' and completed a self-report questionnaire. The study found that labeling the case as 'schizophrenia' and naming heredity among its causes were associated with confidence in psychiatrists and psychiatric drugs. Naming psychological traumas among the causes was associated with confidence in psychologists and greater acknowledgment of users' right to be informed about drugs. Compared to first year students, those at their fifth/sixth-year of studies more strongly endorsed drugs, had less confidence in psychologists and family support, and were less keen to share information on drugs with patients. These findings highlight that students' beliefs vary during training and are significantly related to diagnostic labeling and belief in a biogenetic causal model. Psychiatric curricula for medical students should include greater integration of psychological and medical aspects in clinical management of 'schizophrenia'; more information on the psychosocial causes of mental health problems. PMID- 23916363 TI - Evaluating hippocampal internal architecture on MRI: inter-rater reliability of a proposed scoring system. AB - BACKGROUND: Asymmetry of hippocampal internal architecture (HIA) has been reported to be a frequent imaging finding in epilepsy patients with temporal lobe epilepsy (TLE) who exhibit other signs of hippocampal sclerosis. HIA asymmetry may also be an independent predictor of the side of seizure onset in patients with otherwise normal MRI scans. The study of HIA asymmetry and its relationship to the laterality of TLE would benefit from a reliable method of assessing the clarity of HIA in MRI scans. We propose a visual scoring system that rates HIA clarity from 1 (imperceptible) to 4 (excellent) and report the inter-rater reliability (IRR) of this system. METHODS: In the initial preliminary phase of this study we examined IRR using a kappa statistic (kappa) among a mixed group of expert and non-expert reviewers using only a brief description of the scoring system to score single images from a series of patients. In the second phase we explored the effect of training on the use of our HIA scoring system by assessing IRR among neuroimaging experts before and after a brief interactive training session. In this phase, multiple slices from each patient were scored. Separate kappa values and intraclass correlation coefficients (ICC) were calculated from the scores given to each hippocampal image and from the asymmetry of scores between left and right for each slice. In the third phase the effect of training on non-expert reviewers was explored using a similar approach as with the expert reviewers. RESULTS: In the preliminary phase of the study, HIA scoring of single images showed substantial agreement among expert reviewers (kappaHIA=0.65), fair agreement among non-expert reviewers (kappaHIA=0.27), and a fair to moderate degree of agreement among all the reviewers as a whole (kappaHIA=0.40). In the second phase, prior to training there was substantial agreement among expert reviewers in regard to the individual HIA scores (kappaHIA=0.62; ICCHIA=0.81) but only moderate agreement on the degree of asymmetry (kappaAsym=0.47; ICCAsym=0.71). Training improved agreement on the individual HIA scores (kappaHIA=0.58-0.72; ICCHIA=0.76-0.84) and on the degree of asymmetry (kappaAsym=0.61-0.67; ICCAsym=0.81-0.85). Among non-expert reviewers, scores improved from only a fair degree of agreement pre-training (kappaHIA=0.25, kappaAsym=0.25; ICCHIA=0.68, ICCAsym=0.66) to a moderate level of agreement after training (kappaHIA=0.54, kappaAsym=0.52; ICCHIA=0.78, ICCAsym=0.81). CONCLUSIONS: The proposed HIA scoring system has a substantial degree of inter-rater reliability among experienced neuroimaging reviewers. Training improves the detection of asymmetries in HIA score in particular. Non-expert reviewers can employ the system with a moderate degree of reliability, and training has an even greater impact on the improvement of scoring reliability. PMID- 23916364 TI - Eugene Braunwald, MD. PMID- 23916365 TI - The prognostic significance of the biomarker p16 in oropharyngeal squamous cell carcinoma. AB - AIMS: There is an increasing incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell cancers (OPSCC) mostly associated with favourable outcomes. p16 immunohistochemistry is a surrogate marker for HPV positivity in OPSCC. The prognostic strength of p16 over traditional prognostic factors is not fully characterised. In this study, we evaluated the clinical and demographic differences between p16-positive and -negative OPSCC and characterised its prognostic strength versus traditional prognostic factors. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded blocks and clinical information from 217 OPSCC patients, treated with radiotherapy (alone or in combination with other therapies) between 2000 and 2010 were collected retrospectively. Immunohistochemistry for p16 protein was carried out; cancer-specific survival (CSS), recurrence-free survival (RFS) and locoregional control (LRC) were calculated for both univariate and multivariate analyses. RESULTS: Ninety-two per cent of the OPSCC originated from tonsil and tongue base sites, 61% were p16 positive. Patients with p16-positive OPSCC were younger (P < 0.0001), with lower alcohol (P = 0.0002) and tobacco (P = 0.0001) exposure. The tumours were less differentiated (P = 0.0069), had a lower T stage (P = 0.0027), higher nodal status (P = 0.014) and higher American Joint Committee on Cancer (AJCC) prognostic group (P = 0.0036). AJCC prognostic group was significant for RFS (P = 0.0096) and CSS (P = 0.018) in patients with p16-negative OPSCC, but not those with p16-positive tumours (P = 0.30 and 0.54). Other significant factors for CSS and RFS in univariate analysis were: pretreatment haemoglobin (P < 0.0001 and <0.0001), chemoradiotherapy (P = 0.005 and 0.03) and P16 status (P < 0.0001 and 0.0001). In multivariate analysis, p16 positivity was the strongest independent prognostic variable for both CSS, RFS and LRC (P < 0.0001, hazard ratio 4.15; 95% confidence interval 2.43-7.08), (P < 0.0001, hazard ratio 6.15; 95% confidence interval 3.57-10.61) and (P = 0.001, hazard ratio 3.74; confidence interval 1.76 7.95). CONCLUSION: This study shows that p16 is the single most important prognostic variable in OPSCC, surpassing traditional prognostic factors for both CSS and RFS. Furthermore, disease stage has no prognostic significance in p16 positive patients, highlighting the need for routine p16 assessment in OPSCC. PMID- 23916366 TI - Predictive factors of malignancy in patients with cytologically suspicious for Hurthle cell neoplasm of thyroid nodules. AB - BACKGROUND: Our aim was to evaluate predictive factors of malignancy in patients with cytologically suspicious for Hurthle cell neoplasm (HCN) of thyroid nodules. MATERIALS AND METHODS: We searched cases with cytologically suspicious for HCN from 11,569 ultrasound-guided fine-needle aspirations (US-FNA) performed at our institution. Nodules that were confirmed surgically or followed-up for at least 2 years were compared with respect to age, gender, tumor size, US diagnosis, and US findings to predict malignancy. RESULTS: The incidence of cases with cytologically suspicious for HCN was 1.2% (143 of 11,569). Of 75 nodules that underwent sufficient follow-up or surgery, malignancies were found in 11 (14.7%). Malignant histological examination revealed oncocytic variants of papillary thyroid carcinoma (PTC) in 3 cases, classic PTC in 1, Hurthle cell carcinoma in 3, follicular carcinoma in 3 and an unclassified carcinoma in 1. In univariate analysis, tumor size was significantly larger in malignant nodules compared to benign nodules (p = 0.026). The best cut-off value of tumor size in predicting malignancy was 2.5 cm. (p = 0.006, sensitivity: 63.6%, specificity: 79.7%). The incidences of hypoechogenicity and malignant US diagnoses were higher in malignant nodules than in benign nodules (p < 0.001). In multivariate analysis, tumor size was an independent factor in predicting malignancies. (p = 0.037, odd ratio: 2.09, confidence interval: 1.046-4.161). CONCLUSION: Preoperative US provides predictive factors of malignancy in thyroid nodules with cytologically suspicious for HCN. Predictive factors include tumor size of 2.5 cm or greater, hypoechoic nodule and malignant US diagnosis. PMID- 23916367 TI - Vitamin A status and factors associated in healthy school-age children. AB - BACKGROUND & AIMS: Vitamin A deficiency (VAD) is one of the most widespread vitamin deficiencies. Vitamin A is essential for children in order to ensure a healthy life span and sustain the normal growth and development. Aim of this study is to examine vitamin A status, and factors associated with it, in healthy school-age children. METHODS: The study was carried out in schools in Altindag, the district of Ankara, from April to May 2009. 585 girls and 478 boys, a total of 1063 healthy children aged 5-16 years were taken into the study. Serum retinol, ferritin and hs-CRP levels and complete blood count of each case were measured. A questionnaire was developed to collect socio-economic and demographic information of the participants. RESULTS: Any subclinical VAD (SRL <0.7 MUmol/L) was not detected in the children attending the study. However, SRLs were suboptimal in 2.2% of cases and these children were under a high risk of developing subclinical, and subsequently clinical VAD. There were significant positive correlations between serum retinol and hemoglobin values, and statistically significant negative correlation between serum retinol level and ferritin and hsCRP. CONCLUSIONS: Vitamin A deficiency does not constitute an important public health problem for Altindag, Ankara, Turkey. Frequency of such vitamin deficiencies should be revealed before launching nationwide public health programs to fight with these deficiencies. PMID- 23916368 TI - Ethics of data sequestration in electronic health records. PMID- 23916369 TI - Feasibility and toleration criteria in the withdrawal of sedation and mechanical ventilation in trauma patients. AB - Figueroa-Ramosa et al. (2013) concluded that the combination of sedation withdrawal and mechanical ventilation withdrawal trial was feasible and well tolerated. The conclusion is not well supported because of the absence of a comparison to the uncombined protocol and due to evidence that the patients did not tolerate them particularly well. PMID- 23916370 TI - Establishing a clinic for young people in a rural setting: a community initiative to meet the needs of rural adolescents. AB - This paper describes the establishment and evaluation of a rural clinic for young people. A conceptual approach to community development was used to establish the clinic in a small north Victorian rural health service, with qualitative methods used to evaluate services. Study participants were members of an operational committee and advisory committee for the establishment of the rural clinic for young people. The clinic was evaluated against the World Health Organization framework for the development of youth-friendly services. With robust community support, the clinic was established and is operational. Most consultations have been for sexual and mental health. Qualitative evaluation identifies that not all the World Health Organization benchmarks have been met, but this is hampered predominantly by financial constraints. In conclusion, establishing clinic for young people in a small rural setting can be achieved with community support and the development of referral pathways. PMID- 23916371 TI - Ephyra jellyfish as a new model for ecotoxicological bioassays. AB - The aim of this study was a preliminary investigation on the possibility of using the ephyra of Scyphozoan jellyfish Aurelia aurita (Linnaeus, 1758), the common moon jellyfish, as an innovative model organism in marine ecotoxicology. A series of sequential experiments have been carried out in laboratory in order to investigate the influence of different culturing and methodological parameters (temperature, photoperiod, ephyrae density and age) on behavioural end-points (% of Frequency of Pulsations) and standardize a testing protocol. After that, the organisms have been exposed to two well known reference toxic compounds (Cadmium Nitrate and SDS) in order to analyse the acute and behavioural responses during static exposure. Results of this work indicate that the proposed behavioural end point, frequency of pulsations (Fp), is an easily measurable one and can be used coupled with an acute one (immobilization) and that ephyrae of jellyfish are very promising model organisms for ecotoxicological investigation. PMID- 23916373 TI - Effects of the observation method (direct v. from video) and of the presence of an observer on behavioural results in veal calves. AB - This study aimed at assessing the effect of the observation method (direct or from video) and the effect of the presence of an observer on the behavioural results in veal calves kept on a commercial farm. To evaluate the effect of the observation method, 20 pens (four to five calves per pen) were observed by an observer for 60 min (two observation sessions of 30 min) and video-recorded at the same time. To evaluate the effect of the presence of the observer in front of the pen, 24 pens were video-recorded on 4 consecutive days and an observer was present in front of each pen for 60 min (two observation sessions of 30 min) on the third day. Behaviour was recorded using instantaneous scan sampling. For the study of the observer's effect, the analysis was limited to the posture, abnormal oral behaviour and manipulation of substrates. The two observation methods gave similar results for the time spent standing, but different results for all other behaviours. The presence of an observer did not affect the behaviour of calves at day level; however, their behaviour was affected when the observer was actually present in front of the pens. A higher percentage of calves were standing and were manipulating substrate in the presence of the observer, but there was no effect on abnormal oral behaviour. In conclusion, direct observations are a more suitable observation method than observations from video recordings for detailed behaviours in veal calves. The presence of an observer has a short-term effect on certain behaviours of calves that will have to be taken into consideration when monitoring these behaviours. PMID- 23916372 TI - Assaying hematopoiesis using zebrafish. AB - The zebrafish has become a commonly used model for studying hematopoiesis as a result of its unique attributes. Zebrafish are highly suitable for large-scale genetic and chemical screens compared to other vertebrate systems. It is now possible to analyze hematopoietic lineages in zebrafish and validate cell function via transplantation assays. Here, we review advancements over the past decade in forward genetic screens, chemical screens, fluorescence-activated cell sorting analysis, and transplantation assays. Integrating these approaches enables new chemical and genetic screens that assay cell function within the hematopoietic system. Studies in zebrafish will continue to contribute and expand our knowledge about hematopoiesis, and develop novel treatments for clinical applications. PMID- 23916374 TI - Factors associated with seasonal influenza vaccination in Chinese nursing home older adults. PMID- 23916375 TI - JAMDA impact factor. PMID- 23916376 TI - Soy food consumption and breast cancer. AB - Breast cancer is the most frequently diagnosed cancer in female worldwide and occurs as an interaction of genes and diet. As regards diet numerous studies all over the world have associated the disease with many foods and nutrients including soy and its compounds. Soy food and soy products are rich in phytoestrogens, naturally occurring hormone-like compounds with weak estrogenic effects. Despite inconsistencies in the available data, an inverse association between soy food consumption and breast cancer is likely. However, it seems that this correlation is more obvious in Asian rather than Western populations, where the consumption of soy is already higher. Moreover, the vast majority of studies that demonstrate this inverse association are case-control studies, a fact that should be taken into account. In this review, the current scientific evidence relating breast cancer and soy consumption is reported through a systematic way. PMID- 23916377 TI - Low-level DNAemia of parvovirus B19 (genotypes 1-3) in adult transplant recipients is not associated with anaemia. AB - BACKGROUND: After acute parvovirus B19 (B19V) infection of immunocompetent individuals, viral genomes persist lifelong in various tissues. In immunocompromized patients, acute B19V infection may be associated with severe anaemia. It is unclear whether reactivation of latent B19V DNA may contribute to persistent viraemia and anaemia in transplant recipients. OBJECTIVE AND STUDY DESIGN: We retrospectively analysed the impact of B19V infection in 371 adult transplant recipients (kidney, liver, heart, bone marrow). The patients' pre transplantation serostatus was determined. 1431 sera or plasmas obtained in monthly intervals during six months following transplantation were analysed for the presence of B19V DNA by quantitative PCR which allows discrimination between B19V genotypes 1-3. RESULTS: Overall, 82% of the patients were seropositive. B19V DNA (<600-1100 geq/ml) was detected in 4.0% of patients and classified as genotype 1 in 12, genotype 2 in one and genotype 3 in two patients. Whereas 5.5%, 6.7% and 5.7% of liver, heart and bone marrow recipients displayed DNAemia, viral genomes were detected only in 1.4% of kidney recipients. Haemoglobin levels and reticulocyte counts showed no differences between DNAemic and non-DNAemic patients. In a control group of 120 healthy subjects, 78% were seropositive and 2.5% displayed DNAemia. CONCLUSIONS: Prevalence and level of B19V DNAemia in adult transplant recipients was comparable to that observed in healthy individuals, but with a distinct accumulation within the first weeks post transplantation. The presence of low-level DNAemia in transplant recipients was not associated with anaemia. PMID- 23916378 TI - Viral diseases affecting the pleura. AB - BACKGROUND: Viruses affect the human body in multiple ways producing various disease states. The infections of the pulmonary parenchyma have been well described. However, there has been no current review of the literature pertaining to the pleura. AIM: To review the available literature pertaining to diseases of the pleura that are caused by viral infections. METHODS: A Medline search was performed and available research and review articles relating to viral infections that resulted in pleural effusions, pleural masses, pleural thickening, and pleural nodularity were reviewed. CONCLUSION: There are numerous viruses that cause diseases of the pleura. Pleural effusions and lesions within the pleura are the most common presentation of the disease state. Polymerase chain reaction has the potential to further diagnose viral infections and expand our knowledge base in this field. PMID- 23916379 TI - Cytomegalovirus (CMV) glycoprotein H-based serological analysis in Japanese healthy pregnant women, and in neonates with congenital CMV infection and their mothers. AB - BACKGROUND: Congenital cytomegalovirus (CMV) infection is caused by maternal primary infection as well as CMV reinfection or reactivation during pregnancy, although differences in the clinical impact between these modes of infection remain to be clarified. OBJECTIVES: To investigate the latest prevalence and risk of multiple CMV infection in healthy pregnant women, as well as the types of maternal CMV infection associated with congenital CMV infection. STUDY DESIGN: Seroprevalence against CMV and IgG subclasses were determined in 344 serum samples from healthy pregnant women in Japan. CMV genotype and serotype were also determined in 18 pairs of mothers and neonates with congenital CMV infection identified in our CMV screening program. RESULTS: Thirty-two percent of the pregnant women were seronegative, while 66% of CMV seropositive women had IgG3 antibodies against one epitope on glycoprotein H (gH) as the major subclass, and 52% had IgG1 antibodies against one epitope on glycoprotein B (gB). Only a single genotype determined by CMV gH neutralizing epitope was found in the urine from the 18 neonates with congenital CMV infection, even though one case possessed antibodies against multiple CMV strains. In that case, the antibodies against the strain not detected in the urine from the infant disappeared within one month after birth, whereas the antibodies against the infecting CMV strain continued to be detected at 12 months after birth. CONCLUSIONS: Two (11%) of 18 cases of congenital CMV infection occurred via maternal CMV reinfection. Maternal humoral immunity did not prevent congenital CMV infection with another gH subtype. PMID- 23916380 TI - Outcome of patients with splanchnic venous thrombosis presenting without overt MPN: a role for the JAK2 V617F mutation re-evaluation. AB - INTRODUCTION: Although investigation for JAK2 V617F mutation is recommended in patients presenting with splanchnic venous thrombosis (SVT), no specific clinical advice is given to SVT patients presenting without myeloproliferative neoplasms (MPN) and JAK2 V617F mutation. In MPN-free SVT patients, to investigate the clinical outcome, the clinical impact of re-evaluation for the JAK2 V617F mutation, and relationships with the occurrence and time to diagnosis of MPN. MATERIALS AND METHODS: A cohort of non-cirrhotic SVT patients, enrolled at a single centre and prospectively analyzed. RESULTS: In 121 SVT patients prospectively followed from 1994 to 2012, a MPN was present in 28 (23.1%). Additional 13 patients (10.7%) showed only the JAK2 V617F mutation. During the follow-up, the JAK2 V617F mutation and/or MPN were identified in 8 patients (median time of development: 21 months, range 6-120), whereas 72 remained (MPN and JAK2 V617F)-free until the end of the observation. The mortality rate was higher among patients presenting with MPN and/or the JAK2 V617F mutation than in patients who developed later or remained disease-free (p=0.032). The thrombosis free survival was lower in patients with (p=0.04) or developing later MPN and the JAK2 V617F mutation (p=0.005) than in patients (MPN and JAK2 V617F)-free. The incidence of bleeding was similar among groups. CONCLUSIONS: MPN with or without circulating positive clones for JAK2 V617F mutation can occur long after a SVT, identifying at risk patients for new thrombotic events. If confirmed in other studies, re-evaluation for JAK2 V617F mutation may be of help in early MPN detection and clinical management of SVT patients. PMID- 23916381 TI - Management of bleeding associated with dabigatran and rivaroxaban: a survey of current practices. PMID- 23916382 TI - Why does pandemic influenza virus kill? PMID- 23916383 TI - Human papillomavirus types 16 and 18 in esophagus squamous cell carcinoma: a meta analysis. AB - PURPOSE: A possible carcinogenic role of human papillomavirus (HPV) has been investigated in esophageal squamous cell carcinoma (ESCC) for nearly 30 years with mixed results. We performed a meta-analysis to assess the prevalence of "high-risk" HPV, HPV-16/18, in this disease. We also evaluated the association between infection with HPV-16/18 and ESCC risk by meta-analysis of case-control studies. METHODS: Eligible studies published up to September 30, 2012 were retrieved via both computer searches of MEDLINE and EMBASE and manual review of references. A random-effects model was used to calculate summary prevalence and odds ratios (ORs) and corresponding 95% confidence intervals (CIs). RESULTS: A total of 5755 cases of ESCC from 68 studies were included in this meta-analysis. Overall, 11.67% (95% CI, 7.74%-16.21%) of ESCC cases harbored HPV-16 and 1.82% (95% CI, 0.90%-2.95%) harbored HPV-18. In addition, meta-analysis of 10 case control studies showed a significant increase in ESCC risk with HPV-16 infection (summary ORs = 3.55; 95% CIs, 2.05%-6.14%). However, this increased risk in ESCC was not made for HPV-18 infection (summary ORs = 1.25; 95% CIs, 0.46%-3.43%). CONCLUSIONS: This meta-analysis indicated that HPV-16 and -18 can be detected in ESCC. HPV-16, but not HPV-18, is significantly associated with the risk of ESCC. However, it is early to conclude that both types of HPV are involved in esophageal carcinogenesis. PMID- 23916384 TI - The application of publication guidelines should extend to cover their designing stage and protocol writing. PMID- 23916385 TI - Electrochemotherapy for the treatment of ocular basal cell carcinoma; a novel adjunct in the disease management. AB - Basal Cell Carcinoma (BCC) affecting the ocular region is potentially problematic due to its ability to infiltrate aesthetic and functional structures. Due to the paucity of local tissue, resection frequently requires reconstruction with skin grafts or local flaps. Surgical treatment may not be suitable for patients with multiple co-morbidities. Electrochemotherapy (ECT) is a technique where cells are temporarily permeabilized after exposure to a brief electrical field and when combined with normally impermeant chemotherapy drugs can resolve cutaneous cancers - even those previously recalcitrant to chemotherapy or radiotherapy. Its particular advantage is its speed of application and the minimal damage to the surrounding healthy tissue structures. We present a series of 3 patients with BCCs in the peri-ocular region and significant co-morbidities deemed unsuitable for surgical resection, who underwent ECT. The lesions were all primary BCC ranging in size from 0.5 cm(2) to 1 cm(2). Two lesions were on the upper eyelid and one on the lower eyelid. ECT was performed using an 8-needle electrode and a CE approved electroporation generator with intra-lesional Bleomycin. All lesions responded to treatment. All BCC's completely resolved, with acceptable scarring. No side effects were reported from the Bleomycin or the electric pulses. ECT for peri-ocular BCC is an adjunct to surgical excision in the management of surgically problematic lesions. This technique could provide a useful initial treatment option for patients who are medically unfit or where resection and would be associated with significant morbidity. PMID- 23916386 TI - Secondary reconstruction of a mobile eye socket 30 years after enucleation of the eyeball for retinoblastoma: a case report. AB - A mobile eye socket is generally reconstructed by inserting an implant into the scleral pocket immediately after bulbar exenteration, or by attaching the extra ocular muscles to the implanted artificial eyeball immediately after enucleation. However, exposure of the implanted material and other problems can occur. We achieved satisfactory reconstruction of a mobile eye socket by using an autogenous cartilage graft and a pericranial flap in a patient with long-standing anophthalmia due to enucleation. This case is presented with a review of the relevant literature. PMID- 23916387 TI - IntegraTM permits early durable coverage of improvised explosive device (IED) amputation stumps. AB - INTRODUCTION: Improvised explosive device (IED) blasts cause serious injury. Survivors are left with multiple amputations, considerable soft tissue loss and open fractures with gross contamination. We present our early experience of IntegraTM in the acute management of military wounds. METHOD: The clinical records of all patients with IED injuries who underwent early reconstruction with IntegraTM during the six month period between August and December 2009 in our unit were reviewed and data gathered prospectively. RESULTS: There were 7 male soldiers, aged 21-31 years (mean=26). All sustained trunk and limb injuries, including multiple amputations. Number of procedures prior to application of IntegraTM was 4-10 (mean=5). Application of IntegraTM took place 6-24 days post injury (mean=13). Size of wounds covered with IntegraTM was 1-11.5% TBSA (mean=5%). Anatomical sites reconstructed included amputation stumps, and both upper and lower limbs. There was partial take of Integra in 3 wounds in 2 patients. All wounds were eventually treated with delayed split skin grafting and healed satisfactorily. CONCLUSION: IEDs produce a large zone of injury with massive soft tissue damage, multiple discontinuous wounds which are significantly contaminated. The physiological insult is equivalent to a large cutaneous burn and there is a paucity of available donor sites. Multiple amputees also have a greater energy and power requirement(1-4) and cannot spare remaining functional muscles as donors. The literature suggests that microvascular flaps have a high failure rate in military patients.(5) Reconstruction began as soon as wounds were considered sufficiently clean. IntegraTM was applied with the aim of providing higher quality coverage than that provided by split skin grafting alone (particularly for amputation stumps) whilst minimising operative time and morbidity. IntegraTM allows timely closure of battlefield wounds with minimal operative time and morbidity. The procedure can begin whilst still in the acute phase and certainly before one would consider lengthy complex operations such as free flaps. Our experience suggests that IntegraTM can allow early closure with robust tissue, promoting early rehabilitation and return to duties. PMID- 23916388 TI - Medicinal plant extracts variously modulate susceptibility of Escherichia coli to different antibiotics. AB - Antioxidant activity of green and black tea and extracts of medicinal plants and their ability to modulate antibiotic susceptibility in Escherichia coli were studied. Among a number of extracts tested the maximal capacity to scavenge DPPH radicals and chelate iron in chemical tests was found in green and black tea, Arctostaphylos uva-ursi and Vaccinium vitis-idaea. These extracts contained high level of polyphenols and in aerobic conditions exhibited prooxidant features, producing H2O2 and inducing expression of the katG gene encoding catalase HPI in E. coli cells. A good correlation between the polyphenol content and the ability of extracts to protect bacteria against peroxide stress was observed (r = 0.88). Polyphenol-rich extracts and iron chelators demonstrated the highest modulating effect on the antibiotic susceptibility by changing the time period before lysis started and by influencing the colony-forming ability of bacteria. The direction of the modulating effect was dependent on nature of antibiotic applied: under treatment with ciprofloxacin and ampicillin the extracts predominantly provided protective effects, while under treatment with kanamycin a bactericidal action was enhanced. Mechanism of modulating action of extracts on bacterial antibiotic susceptibility probably involves antioxidant, preferentially iron-chelating, or prooxidant properties of polyphenols. PMID- 23916389 TI - Reply to: medial forebrain bundle stimulation-speed access to an old or entry into a new depression neurocircuit? PMID- 23916390 TI - Medial forebrain bundle stimulation-speed access to an old or entry into a new depression neurocircuit? PMID- 23916391 TI - Functional and white matter abnormalities in the language network in patients with schizophrenia: a combined study with diffusion tensor imaging and functional magnetic resonance imaging. AB - BACKGROUND: Schizophrenia is a mental disorder characterized by functional abnormalities in the language network. Anatomical white matter (WM) abnormalities (volume and integrity) have also been reported for this pathology. Nevertheless, few studies have investigated anatomo-functional relationships in schizophrenia, and none has focused on the language comprehension network in relation to various diffusion parameters. We hypothesized that the WM abnormalities that are reflected by several diffusion parameters underlie functional deficits in the language network. METHODS: Eighteen DSM-IV patients with schizophrenia and 18 healthy controls without any significant differences in sex, age, or level of education were included. First, functional brain activation within the language network was estimated. Then, using diffusion tensor imaging, fractional anisotropy (FA), radial diffusivity (RD), and mean diffusivity (MD) values were extracted within WM regions adjacent to this network and their anatomo-functional relationships were investigated. RESULTS: Compared with healthy participants, both functional and diffusion deficits were observed in patients with schizophrenia. Primarily, an altered diffusion-functional relationship was observed in patients in the left middle temporal region: functional activations were positively correlated with FA, but were negatively correlated with RD. CONCLUSIONS: Our findings indicate a close relationship between diffusion and functional deficits in patients with schizophrenia, suggesting that WM integrity disturbance might be one cause of functional alterations in the language network in patients with schizophrenia. Thus, the present multimodal study improves our understanding of the pathophysiology of schizophrenia. PMID- 23916392 TI - Determination of kappaFLC and kappa Index in cerebrospinal fluid: a valid alternative to assess intrathecal immunoglobulin synthesis. AB - Intrathecal immunoglobulin synthesis is observed in several disorders of the central nervous system, but its detection by current laboratory tests is relatively insensitive and operator depending. We assessed the diagnostic accuracy of a nephelometric assay for k free light chain determination in cerebrospinal fluid and serum. The patients were grouped according to clinical and laboratory criteria. ROC curves for all methods were performed to find the best cut-off value. kFLC Index seems to be more accurate than other parameters. Our data indicate that nephelometric assay for kFLCs in CSF reliably detect intrathecal immunoglobulin synthesis and discriminate multiple sclerosis patients. PMID- 23916393 TI - Anomalous origins of coronary arteries: frequency and association with coronary disease. PMID- 23916394 TI - Engineering medical decisions: computer algorithms and the manipulation of choice. PMID- 23916395 TI - In vitro development of preimplantation porcine embryos using alginate hydrogels as a three-dimensional extracellular matrix. AB - Between Days 10 and 12 of gestation, porcine embryos undergo a dramatic morphological change, known as elongation, with a corresponding increase in oestrogen production that triggers maternal recognition of pregnancy. Elongation deficiencies contribute to embryonic loss, but exact mechanisms of elongation are poorly understood due to the lack of an effective in vitro culture system. Our objective was to use alginate hydrogels as three-dimensional scaffolds that can mechanically support the in vitro development of preimplantation porcine embryos. White cross-bred gilts were bred at oestrus (Day 0) to Duroc boars and embryos were recovered on Days 9, 10 or 11 of gestation. Spherical embryos were randomly assigned to be encapsulated within double-layered 0.7% alginate beads or remain as non-encapsulated controls (ENC and CONT treatment groups, respectively) and were cultured for 96h. Every 24h, half the medium was replaced with fresh medium and an image of each embryo was recorded. At the termination of culture, embryo images were used to assess morphological changes and cell survival. 17beta Oestradiol levels were measured in the removed media by radioimmunoassay. Real time polymerase chain reaction was used to analyse steroidogenic transcript expression at 96h in ENC and CONT embryos, as well as in vivo-developed control embryos (i.e. spherical, ovoid and tubular). Although no differences in cell survival were observed, 32% (P<0.001) of the surviving ENC embryos underwent morphological changes characterised by tubal formation with subsequent flattening, whereas none of the CONT embryos exhibited morphological changes. Expression of steroidogenic transcripts STAR, CYP11A1 and CYP19A1 was greater (P<0.07) in ENC embryos with morphological changes (ENC+) compared with CONT embryos and ENC embryos with no morphological changes (ENC-), and was more similar to expression of later-stage in vivo-developed controls. Furthermore, a time-dependent increase (P<0.001) in 17beta-oestradiol was observed in culture media from ENC+ compared with ENC- and CONT embryos. These results illustrate that preimplantation pig embryos encapsulated in alginate hydrogels can undergo morphological changes with increased expression of steroidogenic transcripts and oestrogen production, consistent with in vivo-developed embryos. This alginate culture system can serve as a tool for evaluating specific mechanisms of embryo elongation that could be targeted to improve pregnancy outcomes. PMID- 23916396 TI - Recombinant spider silk with cell binding motifs for specific adherence of cells. AB - Silk matrices have previously been shown to possess general properties governing cell viability. However, many cell types also require specific adhesion sites for successful in vitro culture. Herein, we have shown that cell binding motifs can be genetically fused to a partial spider silk protein, 4RepCT, without affecting its ability to self-assemble into stable matrices directly in a physiological like buffer. The incorporated motifs were exposed in the formed matrices, and available for binding of integrins. Four different human primary cell types; fibroblasts, keratinocytes, endothelial cells and Schwann cells, were applied to the matrices and investigated under serum-free culture conditions. Silk matrices with cell binding motifs, especially RGD, were shown to promote early adherence of cells, which formed stress fibers and distinct focal adhesion points. Schwann cells acquired most spread-out morphology on silk matrices with IKVAV, where significantly more viable cells were found, also when compared to wells coated with laminin. This strategy is thus suitable for development of matrices that allow screening of various cell binding motifs and their effect on different cell types. PMID- 23916397 TI - Histological adequacy of EUS-guided liver biopsy when using a 19-gauge non-Tru Cut FNA needle. PMID- 23916398 TI - Outcomes of repeat colonoscopy in patients with polyps referred for surgery without biopsy-proven cancer. AB - BACKGROUND: Despite advances in endoscopic treatment, many colonic adenomas are still referred for surgical resection. There is a paucity of data on the suitability of these lesions for endoscopic treatment. OBJECTIVE: To analyze the results of routine repeat colonoscopy in patients referred for surgical resection of colon polyps without biopsy-proven cancer. DESIGN: Retrospective review. SETTING: University hospital. PATIENTS: Patients referred to a colorectal surgeon for surgical resection of a polyp without biopsy-proven cancer. INTERVENTIONS: Repeat colonoscopy. MAIN OUTCOME MEASUREMENTS: The rate of successful endoscopic treatment. RESULTS: There were 38 lesions in 36 patients; 71% of the lesions were noncancerous and were successfully treated endoscopically. In 26% of the lesions, previous removal was attempted by the referring physician but was unsuccessful. The adenoma recurrence rate was 50%, but all recurrences were treated endoscopically and none were cancerous. Two patients were admitted for overnight observation. There were no major adverse events. LIMITATIONS: Single center, retrospective. CONCLUSIONS: In the absence of biopsy-proven invasive cancer, it is appropriate to reevaluate patients referred for surgical resection by repeat colonoscopy at an expert center. PMID- 23916399 TI - Endoscopic view of malignant melanoma of the rectum. PMID- 23916400 TI - Clinical outcomes of early gastric cancer with lateral margin positivity after endoscopic submucosal dissection. PMID- 23916401 TI - Limitations of asthma control questionnaires in the management and follow up of childhood asthma. AB - It is important to achieve asthma control whenever possible in clinical practice. Asthma control questionnaires undoubtedly provide a useful measure of asthma control in research studies but their place in routine clinical practice has yet to be secured. There is considerable variation in the results yielded from different validated asthma control tools. It remains to be seen whether they improve the reliability of reporting of symptoms to health care professionals when compared to verbal reporting. In the presence of sensible care from compassionate and well informed doctors and nurses asthma control questionnaires will not improve outcomes for children. A patient-focused clinical encounter supplemented with lung function measurements and occasional eNO testing has more to offer families and children than control questionnaires and their routine use in the clinic cannot be recommended on the basis of current evidence. PMID- 23916402 TI - 'Midwives are the backbone of our health system': lessons from Afghanistan to guide expansion of midwifery in challenging settings. AB - BACKGROUND: over the last decade Afghanistan has made large investments in scaling up the number of midwives to address access to skilled care and the high burden of maternal and newborn mortality. OBJECTIVE: at the request of the Ministry of Public Health (MOPH) an evaluation was undertaken to improve the pre service midwifery education programme through identification of its strengths and weaknesses. The qualitative component of the evaluation specifically examined: (1) programme strengths; (2) programme weaknesses; (3) perceptions of the programme's community impact; (4) barriers to provision of care and challenges to impact; (5) perceptions of the recently graduated midwife's field experience, and (6) recommendations for programme improvement. DESIGN: the evaluation used a mixed methods approach that included qualitative and quantitative components. This paper focuses on the qualitative components which included in-depth interviews with 138 graduated midwives and 20 key informants as well as 24 focus group discussions with women. SETTING: eight provinces in Afghanistan with functioning and accredited midwifery schools between June 2008 and November 2010. PARTICIPANTS: midwives graduated from one of the two national midwifery programmes: Institute of Health Sciences and Community Midwifery Education. Key informants comprised of stakeholders and female residents of the midwives catchment areas. FINDINGS: midwives described overall satisfaction with the quality of their education. Midwives and stakeholders perceived that women were more likely to use maternal and child health services in communities where midwives had been deployed. Strengths included evidence-based content, standardised materials, clinical training, and supportive learning environment. Self-reported aspects of the quality education in respect to midwives empowerment included feeling competent and confident as demonstrated by respect shown by co workers. Weaknesses of the programme included perceived low educational requirement to enter the programme and readiness of programmes to commence education. Insecurity and geographical remoteness are perceived as challenges with clients' access to care and the ability of midwives to make home visits. KEY CONCLUSIONS: the depth of midwives' contribution in Afghanistan - from increased maternal health care service utilisation to changing community's perceptions of women's education and professional independence - is overwhelmingly positive. Lessons learned can serve as a model to other low resource, post-conflict settings that are striving to increase the workforce of skilled providers. PMID- 23916403 TI - Young women's recent experience of labour and birth care in Queensland. AB - BACKGROUND: young parenthood continues to be an issue of concern in terms of clinical and psychosocial outcomes for mothers and their babies, with higher rates of medical complications such as preterm labour and hypertensive disease and a higher risk of depression. The aim of this study was to investigate how young age impacts on women's experience of intrapartum care. METHODS: secondary analysis of data collected in a population based survey of women who had recently given birth in Queensland, comparing clinical and interpersonal aspects of the intrapartum maternity care experience for 237 eligible women aged 15-20 years and 6534 aged more than 20 years. Descriptive and multivariate analyses were undertaken. RESULTS: in the univariate analysis a number of variables were significantly associated with clinical aspects of labour and birth and perceptions of care: young women were more likely to birth in a public facility, to travel for birth and to live in less economically advantaged areas, to have a normal vaginal birth and to have one carer through labour. They were also less likely to report being treated with respect and kindness and talked to in a way they could understand. In logistic regression models, after adjustment for parity, other socio-demographic factors and mode of birth, younger mothers were still more likely to birth in a public facility, to travel for birth, to be more critical about interpersonal and aspects of care and the hospital or birth centre environment. CONCLUSION: this study shows how experience of care during labour and birth is different for young women. Young women reported poorer quality interpersonal care which may well reflect an inferior care experience and stereotyping by health professionals, indicating a need for more effective staff engagement with young women at this time. PMID- 23916404 TI - What does it take to have a strong and independent profession of midwifery? Lessons from the Netherlands. AB - In the 1970s, advocates of demedicalising pregnancy and birth 'discovered' Dutch maternity care. The Netherlands presented an attractive model because its maternity care system was characterised by a strong and independent profession of midwifery, close co-operation between obstetricians and midwives, a very high rate of births at home, little use of caesarean section, and morbidity and mortality statistics that were among the best in the developed world. Over the course of the following 40 years much has changed in the Netherlands. Although the home birth rate remains quite high when compared to other modern countries, it is half of what it was in the 1970s. Midwifery is still an independent medical profession, but a move toward 'integrated care' threatens to bring midwives into hospitals under the direction of medical specialists, more women are interested in medical pain relief, and there is a growing concern that current, albeit slight, increases in rates of intervention in physiological births foreshadow the end of the unique approach to birth in the Netherlands. The story of Dutch maternity care thus offers an ideal opportunity to examine the social, organisational, and cultural factors that work to support, and to diminish, the independent practice of midwifery in high-resource countries. We may wish to believe that providing ample and convincing evidence of the value of midwifery care will be enough to promote more and better use of midwifery, but the lessons from the Netherlands make clear that an array of social forces play a critical role determining the place of midwives in the health care system and how the care they provide is deployed. PMID- 23916406 TI - Locomotor adaptation and locomotor adaptive learning in Parkinson's disease and normal aging. AB - OBJECTIVE: Locomotor adaptation enables safe, efficient navigation among changing environments. We investigated how healthy young (HYA) and older (HOA) adults and persons with Parkinson's disease (PD) adapt to walking on a split-belt treadmill, retain adapted gait parameters during re-adaptation, and store aftereffects to conventional treadmill walking. METHODS: Thirteen PD, fifteen HYA, and fifteen HOA walked on a split-belt treadmill for ten minutes with one leg twice as fast as the other. Participants later re-adapted to the same conditions to assess retention of the split-belt gait pattern. After re-adaptation, we assessed aftereffects of this pattern during conventional treadmill walking. RESULTS: Persons with PD exhibited step length asymmetry throughout many adaptation and adaptive learning conditions. Early adaptation was similar across groups, though HYA and HOA continued to adapt into late adaptation while PD did not. Despite pervasive step length asymmetry among conditions which were symmetric in HYA and HOA, persons with PD demonstrated significant step length aftereffects during conventional treadmill walking after split-belt walking. CONCLUSIONS: Though they may exhibit a default asymmetry under various walking conditions, persons with PD can adapt and store new walking patterns. SIGNIFICANCE: Locomotor adaptation therapy may be effective in ameliorating asymmetric gait deficits in persons with PD. PMID- 23916407 TI - A semi-physiologically-based pharmacokinetic model characterizing mechanism-based auto-inhibition to predict stereoselective pharmacokinetics of verapamil and its metabolite norverapamil in human. AB - Verapamil and its major metabolite norverapamil were identified to be both mechanism-based inhibitors and substrates of CYP3A and reported to have non linear pharmacokinetics in clinic. Metabolic clearances of verapamil and norverapmil as well as their effects on CYP3A activity were firstly measured in pooled human liver microsomes. The results showed that S-isomers were more preferential to be metabolized than R-isomers for both verapamil and norverapamil, and their inhibitory effects on CYP3A activity were also stereoselective with S-isomers more potent than R-isomers. A semi-physiologically based pharmacokinetic model (semi-PBPK) characterizing mechanism-based auto inhibition was developed to predict the stereoselective pharmacokinetic profiles of verapamil and norverapamil following single or multiple oral doses. Good simulation was obtained, which indicated that the developed semi-PBPK model can simultaneously predict pharmacokinetic profiles of S-verapamil, R-verapamil, S norverapamil and R-norverapamil. Contributions of auto-inhibition to verapamil and norverapamil accumulation were also investigated following the 38th oral dose of verapamil sustained-release tablet (240mg once daily). The predicted accumulation ratio was about 1.3-1.5 fold, which was close to the observed data of 1.4-2.1-fold. Finally, the developed semi-PBPK model was further applied to predict drug-drug interactions (DDI) between verapamil and other three CYP3A substrates including midazolam, simvastatin, and cyclosporine A. Successful prediction was also obtained, which indicated that the developed semi-PBPK model incorporating auto-inhibition also showed great advantage on DDI prediction with CYP3A substrates. PMID- 23916405 TI - Storing maternal memories: hypothesizing an interaction of experience and estrogen on sensory cortical plasticity to learn infant cues. AB - Much of the literature on maternal behavior has focused on the role of infant experience and hormones in a canonical subcortical circuit for maternal motivation and maternal memory. Although early studies demonstrated that the cerebral cortex also plays a significant role in maternal behaviors, little has been done to explore what that role may be. Recent work though has provided evidence that the cortex, particularly sensory cortices, contains correlates of sensory memories of infant cues, consistent with classical studies of experience dependent sensory cortical plasticity in non-maternal paradigms. By reviewing the literature from both the maternal behavior and sensory cortical plasticity fields, focusing on the auditory modality, we hypothesize that maternal hormones (predominantly estrogen) may act to prime auditory cortical neurons for a longer lasting neural trace of infant vocal cues, thereby facilitating recognition and discrimination. This couldthen more efficiently activate the subcortical circuit to elicit and sustain maternal behavior. PMID- 23916408 TI - Characterizing the micro-scale elastic modulus of hydrogels for use in regenerative medicine. AB - Our objective was to characterize the elasticity of hydrogel formulations intended to mimic physical properties that cells and tissues experience in vivo. Using atomic force microscopy (AFM), we tested a variety of concentrations in a variety of biomaterials, including agarose, alginate, the collagens, fibrin, hyaluronic acid, kerateine, laminin, Matrigel, polyacrylamide, polyethylene glycol diacrylate (PEGDA) and silicone elastomer (polydimethylsiloxane). Manipulations of the concentration of biomaterials were detectable in AFM measurements of elasticity (Young's modulus, E), and E tended to increase with increased concentration. Depending on the biomaterials chosen, and their concentrations, generation of tunable biocompatible hydrogels in the physiologic range is possible. PMID- 23916409 TI - Cannabis abuse in adolescence and the risk of psychosis: a brief review of the preclinical evidence. AB - Epidemiological studies suggest that Cannabis use during adolescence confers an increased risk for developing psychotic symptoms later in life. However, despite their interest, the epidemiological data are not conclusive, due to their heterogeneity; thus modeling the adolescent phase in animals is useful for investigating the impact of Cannabis use on deviations of adolescent brain development that might confer a vulnerability to later psychotic disorders. Although scant, preclinical data seem to support the presence of impaired social behaviors, cognitive and sensorimotor gating deficits as well as psychotic-like signs in adult rodents after adolescent cannabinoid exposure, clearly suggesting that this exposure may trigger a complex behavioral phenotype closely resembling a schizophrenia-like disorder. Similar treatments performed at adulthood were not able to produce such phenotype, thus pointing to a vulnerability of the adolescent brain towards cannabinoid exposure. The neurobiological substrate of the adolescent vulnerability is still largely unknown and experimental studies need to elucidate the cellular and molecular mechanism underlying these effects. However, the few data available seem to suggest that heavy adolescent exposure to cannabinoids is able to modify neuronal connectivity in specific brain areas long after the end of the treatment. This is likely due to disruption of maturational events within the endocannabinoid system during adolescence that in turn impact on the correct neuronal refinement peculiar of the adolescent brain, thus leading to altered adult brain functionality and behavior. PMID- 23916410 TI - DNA methylation of dermal MSCs in psoriasis: identification of epigenetically dysregulated genes. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are likely involved in pathological processes of immune-related diseases, including psoriasis, because of their immunoregulatory and pro-angiogenic effects. DNA methylation plays an essential role in regulating gene expression and maintaining cell function. OBJECTIVE: This study aimed to investigate the gene methylation profile of dermal MSCs from patients with psoriasis. METHODS: We isolated and expanded dermal MSCs from psoriatic patients and normal controls using the attachment assay and conducted genome-wide DNA methylation profile and gene ontology analyses using microarray. RESULTS: The cultured cells were indentified as MSCs by surface marker and differentiation assays. The genome-wide promoter methylation profile of MSCs from psoriatic derma was markedly different from the normal derma derived MSCs. Genes involved in cell communication, surface receptor signaling pathway, cellular response to stimulus, and cell migration were differently methylated. Several aberrantly methylated genes related epidermal proliferation, angiogenesis, and inflammation were found differently expressed in psoriatic patients. CONCLUSIONS: These results indicated that the MSCs from dermal of psoriasis are probably participant in the pathogenesis and development of psoriasis through an extraordinarily complex mechanism. PMID- 23916411 TI - Spatial variability in selenium and mercury interactions in a key recreational fish species: implications for human health and environmental monitoring. AB - Selenium's (Se) protective effects against mercury (Hg) toxicity have been demonstrated; however, this is seldom considered in health assessments, where dietary exposure is still evaluated by Hg concentration alone. Se:Hg ratios and selenium health benefit values (Se HBVs) offer a more comprehensive seafood safety model. Here we describe total mercury (THg), methylmercury (MeHg) and Se concentrations in fish from a Hg-polluted estuary. Spatial variation in THg, MeHg and Se was evident, though all regions maintained Se:Hg ratio values >1. Se HBV varied between regions and in one region mean negative values (-5.17) were evident. This study provides the first evidence that quoting a single all encompassing Se HBV is not appropriate when species demonstrate strong site fidelity. It highlights the need for research into Se-Hg relationships in environments with established Hg pollution and reinforces the assertion that Se concentration be considered in assessments of human health risk to Hg exposure. PMID- 23916412 TI - Proteomic identification of Reticulocalbin 1 as potential tumor marker in renal cell carcinoma. AB - Renal cell carcinoma (RCC) biomarkers are necessary for diagnosis and prognosis. They serve to monitor therapy response and follow-up, as drug targets, and therapy predictors in personalized treatments. Proteomics is a suitable method for biomarker discovery. Here we investigate differential protein expression in RCC, and we evaluate Reticulocalbin 1 (RCN1) use as a new potential marker. Neoplastic and healthy tissue samples were collected from 24 RCC patients during radical nephrectomy. Seven specimens were firstly processed by proteomic analysis (2-DE and MALDI-TOF) and 18 differentially expressed proteins from neoplastic and healthy renal tissues were identified. Among them, RCN1 was over-expressed in all cancer specimens analyzed by proteomics. Consequently RCN1 use as a potential marker was further evaluated in all 24 donors. RCN1 expression was verified by Western blotting (WB) and immunohistochemistry (IHC). WB analysis confirmed RCN1 over-expression in 21 out of 24 tumor specimens, whereas IHC displayed focal or diffuse expression of RCN1 in all 24 RCC tissues. Thus RCN1 appears as a potential marker for clinical approaches. A larger histopathological trial will clarify the prognostic value of RCN1 in RCC. BIOLOGICAL SIGNIFICANCE: The present work aimed at finding new biomarkers for RCC - a life-threatening disease characterized by high incidence in Western countries - by performing differential proteomic analysis of neoplastic and normal renal tissues obtained from a small cohort of RCC patients. Some of the identified proteins have been previously associated to renal cancer however data confirming the possible use of these proteins in clinical practice are not available to date. By IHC we demonstrated that RCN1 could be easily employed in clinical practice, confirming RCN1 over expression in RCC tissues of all examined patients, and weak protein expression in healthy renal tissues only in correspondence to the renal tubule section. These data indicate a promising role of RCN1 as a possible marker in RCC and indicate the proximal convoluted renal tubule as a putative origin point for RCC. Since IHC staining displayed different grades of intensity in tested tissues, we hypothesized that RCN1 could also be employed as a prognostic marker or as a response predictor for RCC-targeted therapy. To test such a hypothesis, a larger retrospective trial on paraffin-embedded tissues obtained from radical or partial nephrectomy of RCC patients is planned to be performed by our group. PMID- 23916413 TI - A new method to assess temporal features of gait initiation with a single force plate. AB - The aim of this study was to investigate whether time of toe-off and heel-contact during gait initiation could be assessed with a single force plate. Twenty subjects performed ten self-paced gait initiations and seven other subjects performed ten gait initiations in four new conditions (slow, fast, obstacle and splint). Several force-plate parameters were measured with a single force plate, and actual toe-off and heel-contact were assessed with a motion analysis system. Results showed strong temporal correlations and closeness (r=.86-.99, mean error=3-86 ms) between two force-plate parameters and the kinematics events (toe off and heel-contact). These new parameters may be of interest to easily measure duration of anticipatory postural adjustments and swing phase during clinical assessments. PMID- 23916414 TI - Obstacle crossing following stroke improves over one month when the unaffected limb leads, but not when the affected limb leads. AB - While it is well established that obstacle crossing is impaired following stroke, it is not known whether obstacle crossing improves as gait improves following stroke. The purpose of this study was to determine whether obstacle crossing changed over a one month time period in people with a recent stroke. Twenty participants receiving rehabilitation following a recent stroke were tested on two occasions one month apart. Participants received usual care rehabilitation, including physiotherapy, between the tests. The main outcome measure was obstacle crossing speed as participants stepped over a 4-cm high obstacle. Secondary measures were spatiotemporal variables. Data were collected via a three dimensional motion analysis system. When leading with the affected limb no changes in obstacle crossing speed or spatiotemporal variables were observed over the one month period. When leading with the unaffected limb, crossing speed significantly increased (p=.002), and affected trail limb swing time (p=.03) and crossing step double support time reduced (p=.016). While not significant, the lead and trail limb pre-obstacle distance increased (p=.08), and lead swing time (p=.052) reduced. Change in obstacle crossing speed did not correlate with change in level gait speed. Obstacle crossing does not necessarily improve over a one month time period in people receiving rehabilitation following stroke. These findings suggest that there may be a need for more targeted training of obstacle crossing, particularly when leading with the affected limb. PMID- 23916415 TI - Pathways towards designing effective medical communication curricula. PMID- 23916416 TI - Communicating global cardiovascular risk: are icon arrays better than numerical estimates in improving understanding, recall and perception of risk? AB - OBJECTIVE: Experts recommend that adults have their global cardiovascular risk assessed. We investigated whether icon arrays increase understanding, recall, perception of CVR, and behavioral intent as compared with numerical information. METHODS: Male outpatient veterans, at an intermediate to high cardiovascular risk participated in a randomized controlled trial of a computer tutorial presenting individualized risk. Message format was presented in 3 formats: percentages, frequencies, and frequencies with icon arrays. We assessed understanding immediately (T1) and recall at 20 min (T2) and 2 weeks (T3) after the intervention. We assessed perceptions of importance/seriousness, intent to adhere, and self-efficacy at T1. Self-reported adherence was assessed at T3. RESULTS: One-hundred and twenty male veterans participated. Age, education, race, health literacy and numeracy were comparable at baseline. There were no differences in understanding at T1 [p = .31] and recall at T3 [p = .10]. Accuracy was inferior with frequencies with icon arrays than percentages or frequencies at T2 [p <= .001]. There were no differences in perception of seriousness and importance for heart disease, behavioral intent, self-efficacy, actual adherence and satisfaction. CONCLUSION: Icon arrays may impair short-term recall of CVR. PRACTICE IMPLICATIONS: Icon arrays will not necessarily result in better understanding and recall of medical risk in all patients. PMID- 23916417 TI - The regulation of maturation promoting factor during prophase I arrest and meiotic entry in mammalian oocytes. AB - Mammalian oocytes arrest at prophase of meiosis I at around birth and they remain arrested at this stage until puberty when the preovulatory surge of luteinizing hormone (LH) causes ovulation. Prophase I arrest in the immature oocyte results from the maintenance of low activity of maturation promoting factor (MPF), which consists of a catalytic subunit (CDK1) and regulatory subunit (cyclin B1). Phosphorylation-mediated inactivation of CDK1 and constant degradation of cyclin B1 keep MPF activity low during prophase I arrest. LH-mediated signaling manipulates a vast array of molecules to activate CDK1. Active CDK1 not only phosphorylates different meiotic phosphoproteins during the resumption of meiosis but also inhibits their rapid dephosphorylation by inhibiting the activities of CDK1 antagonizing protein phosphatases (PPs). In this way, CDK1 both phosphorylates its substrates and protects them from being dephosphorylated. Accumulating evidence suggests that the net MPF activity that drives the resumption of meiosis in oocytes depends on the activation status of CDK1 antagonizing PPs. This review aims to provide a summary of the current understanding of the signaling pathways involved in regulating MPF activity during prophase I arrest and reentry into meiosis of mammalian oocytes. PMID- 23916418 TI - Confounders of mutation-rate estimators: selection and phenotypic lag in Thermus thermophilus. AB - In a recent description of the rate and character of spontaneous mutation in the hyperthermophilic bacterium Thermus thermophilus, the mutation rate was observed to be substantially lower than seen in several mesophiles. Subsequently, a report appeared indicating that this bacterium maintains an average of about 4.5 genomes per cell. This number of genomes might result in a segregation lag for the expression of a recessive mutation and might therefore lead to an underestimate of the rate of mutation. Here we describe some kinds of problems that may arise when estimating mutation rates and outline ways to adjust the rates accordingly. The emphasis is mainly on differential rates of growth of mutants versus their parents and on various kinds of phenotypic lag. We then apply these methods to the T. thermophilus data and conclude that there is as yet no reliable impact on a previously described rate. PMID- 23916420 TI - Late-onset Pompe disease (LOPD): correlations between respiratory muscles CT and MRI features and pulmonary function. AB - Late onset Pompe disease (LOPD) is a rare muscle disorder often characterized, along the disease course, by severe respiratory failure. We describe herein respiratory muscles and lung abnormalities in LOPD patients using MR imaging and CT examinations correlated to pulmonary function tests. Ten LOPD patients were studied: 6 with a limb-girdle muscle weakness, 1 with myalgias, 2 with exertional dyspnoea and 1 with isolated hyperckemia. Respiratory function was measured using forced vital capacity (FVC) in both upright and supine positions, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP) and peak cough flow (PCF) tests. The involvement (atrophy) of diaphragms, abdominal respiratory muscles and intercostal muscles was ranked by CT and MRI examinations using appropriate scales. Height of lungs and band-like atelectasis presence were also recorded. Seven out of 10 patients showed a functional diaphragmatic weakness (FVC drop percentage >25%). In 8 out of 10 patients, involvement of both diaphragms and of other respiratory muscles was seen. The mean height of lungs in patients was significantly reduced when compared to a control group. Marked elevation of the diaphragms (lung height < 15 cm) was also seen in 6 patients. Multiple unilateral or bilateral band-like atelectasis were found in 4 patients. Statistically significant correlations were found between diaphragm atrophy grading, evaluated by MRI and CT, and FVC in supine position, FVC drop percentage passing from upright to supine position, PCF and MIP. Our data showed that diaphragm atrophy, often associated to reduced lung height and band-like atelectasis, can be considered the CT-MRI hallmark of respiratory insufficiency in LOPD patients. Early recognition of respiratory muscles involvement, using imaging data, could allow an early start of enzyme replacement therapy (ERT) in LOPD. PMID- 23916419 TI - Imaging-genetics in dyslexia: connecting risk genetic variants to brain neuroimaging and ultimately to reading impairments. AB - Dyslexia is a common pediatric disorder that affects 5-17% of schoolchildren in the United States. It is marked by unexpected difficulties in fluent reading despite adequate intelligence, opportunity, and instruction. Classically, neuropsychologists have studied dyslexia using a variety of neurocognitive batteries to gain insight into the specific deficits and impairments in affected children. Since dyslexia is a complex genetic trait with high heritability, analyses conditioned on performance on these neurocognitive batteries have been used to try to identify associated genes. This has led to some successes in identifying contributing genes, although much of the heritability remains unexplained. Additionally, the lack of relevant human brain tissue for analysis and the challenges of modeling a uniquely human trait in animals are barriers to advancing our knowledge of the underlying pathophysiology. In vivo imaging technologies, however, present new opportunities to examine dyslexia and reading skills in a clearly relevant context in human subjects. Recent investigations have started to integrate these imaging data with genetic data in attempts to gain a more complete and complex understanding of reading processes. In addition to bridging the gap from genetic risk variant to a discernible neuroimaging phenotype and ultimately to the clinical impairments in reading performance, the use of neuroimaging phenotypes will reveal novel risk genes and variants. In this article, we briefly discuss the genetic and imaging investigations and take an in depth look at the recent imaging-genetics investigations of dyslexia. PMID- 23916421 TI - Selective newborn screening of inborn errors of amino acids, organic acids and fatty acids metabolism in the Kingdom of Bahrain. AB - Mandatory newborn screening for metabolic disorders has not been implemented in most Middle Eastern countries. Early detection and treatment of inborn errors of metabolism can reduce mortality and minimize morbidity. Preliminary studies conducted in some parts of Middle East suggest that the incidences of inborn errors of metabolism are reported to be higher in the region than anywhere else in the world due to the consanguinity. In this study the incidence of inborn errors of amino acids, organic acids and fatty acids oxidation disorders was investigated from the results of blood spot analysis of 1986 symptomatic children from 1st January 2008 to 31st of December 2011. Out of 1986 newborns screened 25 infants were diagnosed and confirmed with amino acids (n=11), organic acids (n=9) and fatty acids oxidation (n=5) disorders. Overall incidences based on number of live birth between 2008 and 2011 inclusive were 1:6000, 1:8000 and 1:14,000 for amino acids, organic acids and fatty acids oxidation disorders; respectively. Out of 25 infants diagnosed, 21 were the children of first cousin marriages. Results from this study suggest high incidence of inborn errors of amino acids, organic acids and fatty acids oxidation metabolism in Bahrain and significant contribution of consanguinity in inherited metabolic disorders. Mandatory screening for inborn errors of metabolism in Bahrain is highly recommended. PMID- 23916422 TI - Placental programming of chronic diseases, cancer and lifespan: a review. AB - Particular paths of fetal growth are now known to predict a range of disorders in adult life. This is thought to reflect fetal programming, the phenomenon whereby nutrition and other influences during development set the body's organs and systems for life. The thesis of this review is that normal variations in the processes of placental development lead to variations in the supply of nutrients to the fetus and programme a small number of key systems that are linked to later disease. A baby's growth and nutrition depend both on the function of the placenta, reflected in its gross morphology at birth, and on the mother's lifetime nutrition, reflected in her height and weight. In many studies, the effects of placental size and shape on later disease have been examined within different categories of mother's body size. The review shows that variations in gross placental morphology at birth predict a wide range of disorders in later life. Any particular placental phenotype seems to predict a limited number of diseases. Further research into the links between the processes of placentation and the morphology of the placenta at birth is now required. We need to know more about the relative importance of nutrient flow, nutrient balance and the timing of nutritional events in determining disorders in later life. We also need to understand why, compared to other placental mammals, the human placenta is so variable in its morphology and functional capacity. PMID- 23916423 TI - Why social attachment and oxytocin protect against addiction and stress: Insights from the dynamics between ventral and dorsal corticostriatal systems. AB - The present article advances a neurobiological model of the reciprocal associations between social attachment and drug abuse, and social attachment and chronic stress, as overlapping systems are involved in stress coping and social attachment. In terms of coping, responding to a novel stressor or challenge involves initial novelty processing and activation of learning mechanisms that allow habituation to the stressor through familiarization. Similarly, social attachments are initially formed by being attracted by rewarding properties of an as-yet novel individual, and subsequently developing feelings of attachment towards the familiarized individual. Attachment and familiarization increase the availability of "internal working models" for the control of behavior and emotion, which may explain why secure attachments are associated with increased resilience in the face of stress, accompanied by less reactive reward responding (i.e., increased resilience against drug addiction). The present article seeks to illuminate the role of the neuropeptide oxytocin, which may be involved in the overlapping mechanisms of stable attachment formation and stress coping by shifting processing from novelty and reward seeking to appreciation of familiarity. Oxytocin may accomplish this by facilitating a ventral-to-dorsal shift in activation in corticostriatal loops, which produces a shift from a reactive reward drive (wanting) to stable appreciation of familiar social aspects ("liking" or "loving"). The authors suggest that through dopaminergic, serotonergic and endogenous opioid mechanisms, oxytocin is involved in shifting the balance between wanting and liking in corticostriatal loops by facilitating consolidation of social information from ventral reactive reward systems to dorsal internal working models that aid in prospectively selecting optimal actions in the future, increasing resilience in the face of stress and addiction. PMID- 23916424 TI - Pre-exposure to ethanol, but not to caffeine and nicotine, induced place preference and self-administration of the NMDA receptor antagonist-benzodiazepine combination, Zoletil(r). AB - Zoletil(r) is an equal amount combination of the NMDA receptor antagonist, tiletamine, and the benzodiazepine, zolazepam, usually used as a veterinary anesthetic. Previous studies have shown that pre-exposure to Zoletil(r) and other psychoactive drugs (e.g. ketamine, diazepam) plays a significant role in the abuse liability of the compound. However, these studies were only focused on illicit psychoactive drugs and not on the more widely used licit psychoactive substances. Thus, the goal of the present work is to investigate whether pre exposure to the three most commonly used licit psychoactive substances (caffeine, nicotine, and ethanol) affects the rewarding and reinforcing effects of Zoletil(r). Rats were pretreated with caffeine (1.25 or 2.5 mg/kg), nicotine (125 or 250 MUg/kg), ethanol (0.5, 2, or 4 g/kg), or saline (1 ml/kg) for 14 days, and evaluated for subsequent Zoletil(r) place preference (2.5 mg/kg) and self administration (250 MUg/kg). Zoletil(r) produced neither place preference nor self-administration in saline-pretreated rats. Pre-exposure to caffeine or nicotine does not have significant effects on Zoletil(r)'s abuse potential. However, pretreatment of ethanol significantly produced Zoletil(r) place preference and self-administration. These results suggest that individuals who are exposed to ethanol may have a high propensity to use/abuse Zoletil(r). More importantly, the present result advocates the careful monitoring on the use and dispensation of Zoletil(r) or related substances. PMID- 23916426 TI - The clinician and the scientific evidence. PMID- 23916427 TI - Effects of medications and laser on induced tooth movement and associated root resorption: four key points. AB - The following four fundamental points on the use of experimental models will be described to ensure an accurate evaluation of the effects of medication and laser therapy on induced tooth movement and associated root resorption: (1) If the objective is to check the effect on root resorption, the forces experimentally applied must produce a lesion on the cementoblast layer in all specimens; (2) If the objective is to optimize induced tooth movement and reduce treatment time without side effects, the forces experimentally applied should not produce a lesion in the cementoblast layer in any specimen; (3) The laser therapy operator, the person administering medication and the person that places appliances should not know which animals will effectively receive the test treatment, and the control groups should receive placebo treatments; (4) CT and microscopic analysis of the specimens should be random, and the group to which the specimen belongs should not be identified, to ensure that the person reading images and the pathologists are not influenced in their evaluation of phenomena. These measures will ensure that results are more reliable and easier to extrapolate to orthodontic clinical practice. PMID- 23916428 TI - Class II malocclusion treatment using Jasper Jumper appliance associated to intermaxillary elastics: a case report. AB - INTRODUCTION: Skeletal, dental and profile discrepancies can be amended by using functional orthodontic appliances. OBJECTIVE: This study is a report of the treatment of a patient, 11 years and 4 months old, with Class II, division 1, malocclusion, convex profile, protrusion of upper incisors, pronounced overjet and overbite, and mild crowding. METHODS: The patient was treated with a Jasper Jumper associated to fixed appliances for 6 months and Class II intermaxillary elastics (3/16-in) during the last 4 months. After debonding, a Hawley retainer was used during daytime and a modified Bionator for night use during one year. In the lower dental arch a bonded lingual retainer was used. This treatment combination improved the profile, as well as the overjet, overbite and molar relation. RESULTS: There was clockwise mandibular rotation and increase of lower anterior facial height. The lower incisors were protruded and extruded and the lower molars were extruded. The centric occlusal relation was checked and it was coincident to the maximum usual intercuspation. CONCLUSIONS: It was demonstrated that the Jasper Jumper is an efficient alternative to Class II malocclusion treatment, providing improvement in the facial profile, although the changes are more dentoalveolar than skeletal. PMID- 23916425 TI - Investigating cockroach allergens: aiming to improve diagnosis and treatment of cockroach allergic patients. AB - Cockroach allergy is an important health problem associated with the development of asthma, as a consequence of chronic exposure to low levels of allergens in susceptible individuals. In the last 20 years, progress in understanding the disease has been possible, thanks to the identification and molecular cloning of cockroach allergens and their expression as recombinant proteins. Assays for assessment of environmental allergen exposure have been developed and used to measure Bla g 1 and Bla g 2, as markers of cockroach exposure. IgE antibodies to cockroach extracts and to specific purified allergens have been measured to assess sensitization and analyze association with exposure and disease. With the development of the field of structural biology and the expression of recombinant cockroach allergens, insights into allergen structure, function, epitope mapping and allergen-antibody interactions have provided further understanding of mechanisms of cockroach allergic disease at the molecular level. This information will contribute to develop new approaches to allergen avoidance and to improve diagnosis and therapy of cockroach allergy. PMID- 23916429 TI - Sagittal and vertical aspects of Class II division 1 subjects according to the respiratory pattern. AB - INTRODUCTION: The teeth position, specially maxillary and mandibular incisors, in relation to basal bone and surrounding soft tissues must be considered in the elaboration of diagnosis, treatment planning and execution to obtain alignment, leveling, intercuspation, facial balance and harmony with stability of results. OBJECTIVE: To evaluate the modifications in the positioning of incisors in individuals with Angle Class II, division 1 malocclusion in two distinct moments of dentocraniofacial development, with mean interval of 2 years and 5 months. METHODS: The measures were obtained by means of lateral cephalograms of 40 individuals, being 23 nasal breathers (NB) and 17 mouth breathers (MB). The analyzed measures were overjet, overbite, UCI-NA, LCI-NB, UCI.NA, LCI.NB, UCI.SN, LCI.GoGn, UCI.LCI, ANB, GoGn.SN, and OccPl.SN. Statistical analysis (2-way repeated-measures ANOVA) was applied to verify intergroups differences. RESULTS: Overjet, UCI-NA, LCI-NB, ANB, GoGn.SN, and OccPl.SN demonstrated statistically significant difference (p < 0.05) when observed the moment or the respiratory method. CONCLUSIONS: There is alteration in the positioning of incisors during growth with interference of the respiratory pattern. PMID- 23916430 TI - Morphological evaluation of the active tip of six types of orthodontic mini implants. AB - OBJECTIVE: To morphologically evaluate the active tip of six different types of self-drilling mini-implants for orthodontic anchorage. METHODS: Images of the active tips of the mini-implants were obtained with a Zeiss optical microscope Stemi 200-C, with magnification of 1.6X. The images of the surface were viewed with the Axio Vision program (Zeiss, Jena, Germany) to calculate linear and angular measures. Mini-implant morphology and the details of tips and threads were also evaluated through Scanning Electronic Microscopy (SEM) (JEOL, model JSM5800 LV - JEOL, Tokyo, Japan) with magnifications of 90X and 70X, respectively. The evaluation of the mini-implant taper shape was assessed using the formula: (b - a) / (2 x D). RESULTS: The following variables were measured: (1) active tip width, (2) major diameter of external thread, (3) minor diameter of internal thread and taper of the mini-implant, (4) number of threads and lead of the screw, (5) angle of thread, (6) flank width and (7) pitch width. CONCLUSIONS: Mini-implants from different manufacturers presented active tips with different characteristics. Mechanical testing is necessary to correlate the analyzed characteristics aiming to determine the best performance. PMID- 23916431 TI - Stability of molar relationship after non-extraction Class II malocclusion treatment. AB - OBJECTIVE: This study aimed to evaluate the stability of molar relationship after non-extraction treatment of Class II malocclusion. METHODS: The sample comprised 39 subjects (16 females, 23 males) with initial Class II malocclusion treated with no extractions, using fixed appliances. Mean age at the beginning of treatment was 12.94 years, at the end of treatment was 15.14 years and at post retention stage was 21.18 years. Mean treatment time was 2.19 years and mean time of post-treatment evaluation was 6.12 years. To verify the influence of the severity of initial Class II molar relationship in stability of molar relationship, the sample was divided into two groups, one presenting a 1/2-cusp or 3/4-cusp Class II molar relationship, and the other with full-cusp Class II molar relationship. In dental casts from initial, final and post-retention stages, molar, first and second premolars and canine relationships were measured. Data obtained were analyzed by dependent ANOVA, Tukey and Pearson's correlation tests, as well as independent t test between the two groups divided by severity of initial molar relationship. RESULTS: There was a non-statistically significant 0.12-mm relapse of molar relationship. The initial severity of Class II molar relationship was not correlated to relapse in the post-retention period. When compared, the two groups showed no difference in relapse of molar relationship. CONCLUSIONS: It was concluded that correction of Class II molar relationship is stable and initial severity does not influence relapse of molar relationship. PMID- 23916432 TI - A comparative clinical study of the failure rate of orthodontic brackets bonded with two adhesive systems: conventional and self-etching primer (SEP). AB - OBJECTIVE: This study compared the clinical performance of orthodontic brackets bonded with Transbond adhesive paste after two primer systems: a two-stage conventional system (acid etching + Transbond XT adhesive primer) and a single stage self-etching primer (SEP) (Transbond Plus). METHODS: The sample comprised 480 metal brackets bonded to the teeth of 24 consecutive patients treated for 36 to 48 months. A split-mouth design was used for bonding, and both systems were used in each patient. Bracket failure rates for each system were analyzed; and failure causes as reported by the patients and the quadrant of teeth for which brackets failed were recorded. RESULTS: The conventional system group had a failure rate of 5.41%, whereas the rate for SEP was 4.58%. In this group, there were 5 failures (38.4%) in the right maxillary quadrant, 2 (15.4%) in the left maxillary quadrant, 4 (30.8%) in the right mandibular quadrant, and 2 (15.4%) in the left mandibular quadrant. In the SEP group, there were 4 (36.4%) failures in the right maxillary quadrant, 1 (9%) in the left maxillary quadrant, 3 (27.3%) in the right mandibular quadrant, and 3 (27.3%) in the left mandibular quadrant. Results of descriptive statistical analysis and odds ratio did not show any significant differences between rates (p = 0.67). CONCLUSIONS: The clinical efficiency of SEP was similar to that of the conventional system. PMID- 23916433 TI - Effect of dental bleaching after bracket bonding and debonding using three different adhesive systems. AB - OBJECTIVE: To evaluate the influence of bonding and debonding of orthodontic brackets on dental in-home bleaching, taking into account three different adhesive systems. METHODS: Forty-four bovine incisors were divided into four groups according to the primer system used for orthodontic bracket bonding. Following the debonding of orthodontic brackets, the teeth were stored in staining solution for 96 hours. Then, teeth were whitened using 10% carbamide peroxide for two weeks at a 6-hour-a-day regime. Standardized digital photographs were taken at the following intervals: T0 (initial); T1 (after debonding); T2 (after pigmentation); T3, T4 and T5 representing 1, 7, and 14 days of bleaching. Repeatability and stability tests were carried out to check the method accuracy. Images were analyzed using Adobe Photoshop 7.0 software considering (L*a*b*) color coordinate values and a modified color difference total (DeltaE'). RESULTS: The results of this study (ANOVA and Tukey; p < 0.01) demonstrated that after 7 days of bleaching, experimental groups showed significantly less teeth whitening compared to the control group. However, there were no significant color differences between the groups after 14 days, according to values of lightness (L*). CONCLUSIONS: Regardless of the adhesive primer system applied, bonding and debonding of orthodontic brackets alters the outcome of tooth whitening in the first 7 days of bleaching, however it has no influence on the whitening of the dental structure after 14 days of in-home dental bleaching with 10% carbamide peroxide. PMID- 23916434 TI - Assessment of the dimensions and surface characteristics of orthodontic wires and bracket slots. AB - OBJECTIVE: The purpose of this study was to evaluate the dimensions and surface characteristics of orthodontic wires and bracket slots of different commercial brands. METHODS: Thirty metallic brackets (0.022 x 0.028-in and 0.022 x 0.030-in) were divided into three groups: DYN/3M group = Dyna-Lock, 3M/Unitek (stainless steel, or SS); STD/MO group = Slim Morelli (SS); and Ni-Free/MO group = Slim Morelli (Ni-Free). The stainless steel wires (0.019 x 0.025-in) were divided into two groups: MO group = Morelli; and 3M group = 3M/Unitek. The bracket and wire measurements were done by two methods: (a) Surface Electron Microscopy (SEM), and (b) Profile Projection. The surface analysis was done qualitatively, based on SEM images and/or by a rugosimeter. The quantitative results were analyzed by ANOVA with Tukey's test (p < 0.05) and Student's t test. RESULTS: A significant difference in the dimensions of slots was observed, and the NiFree/MO group showed the greatest changes when compared to the other groups. The analysis of surface topography of the brackets indicated greater homogeneity of the metallic matrix for DYN/3M and STD/MO groups. As for the dimensions of the wires, groups showed statistically different mean heights. CONCLUSIONS: It was concluded that wires and brackets slots can present altered dimensions, which might directly and unintentionally affect the planned tooth movement. PMID- 23916435 TI - Shear bond strength of metallic and ceramic brackets using color change adhesives. AB - OBJECTIVE: To determine the shear bond strength of orthodontic brackets using color change adhesives that are supposed to aid in removing excess of bonding material and compare them to a traditional adhesive. METHODS: Ninety metallic and ninety ceramic brackets were bonded to bovine incisors using two color change adhesives and a regular one. A tensile stress was applied by a universal testing machine. The teeth were observed in a microscope after debonding in order to determine the Adhesive Remnant Index (ARI). RESULTS: The statistical analysis (ANOVA, Tukey, and Kruskall-Wallis tests) demonstrated that the mean bond strength presented no difference when metallic and ceramic brackets were compared, but the bond resistance values were significantly different for the three adhesives used. The most common ARI outcome was the entire adhesive remaining on the enamel. CONCLUSIONS: The bond strength was similar for metallic and ceramic brackets when the same adhesive system was used. ARI scores demonstrated that bonding with these adhesives is safe even when ceramic brackets were used. On the other hand, bond strength was too low for orthodontic purposes when Ortho Lite Cure was used. PMID- 23916436 TI - Assessment of motivation, expectations and satisfaction of adult patients submitted to orthodontic treatment. AB - OBJECTIVE: The purpose of this study was to analyze the psychological aspects of adult patients who sought and underwent orthodontic treatment, evaluating their expectations and discomfort during treatment, as well as their satisfaction after completion of dental movement. RESULTS AND CONCLUSIONS: Data obtained from previous published papers, and also from questionnaires answered by 54 patients, showed that adult patients stood out for their attention to details and high interest in the esthetic improvements provided by treatment, and also for a greater perception of their initial malocclusion. On the other hand, the same data showed that adult patients, once informed about the limitations of their treatment and having confidence on the orthodontist, presented a high level of satisfaction with treatment results, revealing themselves as good patients for indication and execution of orthodontic procedures. PMID- 23916437 TI - Expectations of orthodontic treatment in adults: the conduct in orthodontist/patient relationship. AB - INTRODUCTION: The high demand for orthodontic treatment, evidenced over the last few decades, has been justified mainly by the greater importance given to facial esthetics, influencing individual's self esteem. However, the professional frequently does not meet all the patient's expectations, for not establishing good communication and not knowing about the critical points during orthodontic treatment. OBJECTIVE: The aim of this study was to elucidate patients' desires and doubts regarding orthodontic treatment, by means of a survey applied to 60 adult patients. RESULTS: The analysis of results revealed that most individuals (38.3%) noticed treatment success after its conclusion. Occlusion deviation was pointed out by 66.7% as the main reason for seeking treatment, and esthetics ranked as second (with 48.3%). Treatment time was considered within the prediction by 46.7% of the interviewees and the results were judged as very good by 43.3%. The social relations of most participants were not affected by treatment (73.3%). Also, 58.3% of the interviewees reported pain as the main complaint and 53.3% found it difficult to use dental floss. Most participants saw the orthodontist as a professional who was concerned about their health (76.7%), and believed that he/she was more able to treat them (96.6%) when compared with the general practitioner. CONCLUSIONS: The orthodontist/patient relationship enables an understanding of the expectations regarding orthodontic treatment, resulting in greater motivation and cooperation, leading to a successful outcome. PMID- 23916438 TI - Evaluation of the influence of dental bleaching with 35% hydrogen peroxide in orthodontic bracket shear bond strength. AB - OBJECTIVE: The purpose of this study was to evaluate, in vitro, the bond strength of brackets bonded to premolars previously subjected to bleaching with a 35% hydrogen peroxide. METHODS: Twenty one healthy premolars were selected and randomly divided into three groups (n = 7). Group I (G1) included teeth that were not submitted to bleaching. The enamel surfaces of Groups II (G2) and III (G3) were submitted to a bleaching process with 35% hydrogen peroxide (Whiteness HP Maxx). On Group II (G2), after bleaching, the teeth were stored for 24 hours in distilled water at 98.6 degrees F, and then, premolar metallic brackets were bonded using Transbond XT (3M) resin. Group III (G3) was submitted to the same procedure seven days after bleaching. After bonding, all teeth were stored in distilled water at 98.6 degrees F for 24 hours. All groups were submitted to a traction test using an EMIC DL2000 universal testing machine at a speed of 0.5 mm/min. RESULTS AND CONCLUSION: The bracket resistance to debonding was compared between the groups by the Kruskal-Wallis nonparametric test (p < 0.05) and it was verified that the bleaching agent significantly reduced bracket adhesion when bonded 24 hours after bleaching. However, seven days after bleaching, there was no significant difference on the resistance to debonding among groups G1 (19,52 kgf) and G3 (18,44 kgf), meaning that it is necessary to wait longer after bleaching to bond brackets. PMID- 23916439 TI - Maxillary incisor retraction: evaluation of different mechanisms. AB - OBJECTIVE: To mechanically evaluate different systems used for incisors retraction. METHODS: Three different methods for incisors retraction using 0.019 x 0.025-in stainless steel wire were evaluated. The samples were divided into three groups: Group A (retraction arch with 7-mm high vertical hooks); Group G3 (elastic chain attached to the mini-implant and to the 3-mm stainless steel hook welded to the retraction arch); Group G6 (elastic chain attached to the mini implant and to the 6-mm stainless steel hook welded to the retraction arch). A dental mannequin was used for evaluation in order to simulate the desired movements when the device was exposed to a heat source. The analysis of variance (ANOVA) and the Tukey test were used (p < 0.05). RESULTS: The results demonstrated that Groups G3 and G6 exhibited less extrusion and less incisor inclination during the retraction phase (p < 0.05). With regard to incisor extrusion, statistically significant differences were observed between Groups A and G3, and between Groups A and G6 (p < 0.05). Regarding incisor inclination, statistically significant differences were observed between the three evaluated systems (p < 0.05). CONCLUSIONS: Arches with 6-mm vertical hooks allow the force to be applied on the center of resistance of the incisors, thus improving mechanical control, when compared with the other two systems. PMID- 23916440 TI - Changes on facial profile in the mixed dentition, from natural growth and induced by Balters' bionator appliance. AB - OBJECTIVE: The purpose of this study was to evaluate the facial profile changes induced by Balters' bionator appliance in Class II division 1 patients, at mixed dentition stage. METHODS: The sample consisted of 28 pre-pubertal individuals at stages 1 and 2 of skeletal maturation (CVM), which were divided into two groups. The experimental group consisted of 14 individuals (7 boys and 7 girls, initial mean age of 8y12m) which were treated with Balters' bionator appliance for 14.7 months. The effects of treatment were compared to a control group of 14 subjects (7 boys and 7 girls, initial mean age of 8y5m) with Class II malocclusion, division 1, not orthodontically treated, which were followed up for 15.4 months. The statistical analysis was performed using Student's t test, at a significance level of 5%. RESULTS: The results showed that the Balters' bionator appliance promoted a significant increase on the mentolabial angle, in addition to demonstrating a tendency to reduce the facial skeletal convexity, to restrict the maxillary growth and to increase the nasolabial angle and the lower anterior facial height. CONCLUSIONS: It can be concluded that the Balters' bionator appliance improved the facial profile of children treated at mixed dentition stage. PMID- 23916441 TI - Comparative study of the soft tissue of young Japanese-Brazilian, Caucasian and Mongoloid patients. AB - OBJECTIVE: To determine the normality mean values in the soft tissue cephalometric measurements of young Japanese-Brazilian, with normal occlusion and to compare the results of the variables with compatible samples of young Caucasians and Mongoloids. METHODS: Forty radiographs of young Caucasians, 32 of Japanese-Brazilians and 33 of Mongoloids were used. The three samples presented individuals with normal occlusion and well-balanced face. The samples were divided by gender due to the soft tissue characteristics and to facilitate comparison. The following statistical tests were performed: Analysis of variance (ANOVA) and analysis of covariance (ANCOVA) with p < 0.05. RESULTS: The Japanese Brazilian sample of females showed thinner soft tissues in the nasion region and smaller nose when compared to the Caucasians. The Mongoloid sample showed thinner tissues in the supramentonian and pogonion regions. In males, the Japanese Brazilians had thinner tissues in the nasion region; thicker lower lip and supramentonian region in comparison to the Caucasian sample. For the Mongoloid, soft tissue was thicker in the glabella and ANS-Sn regions. CONCLUSIONS: It is necessary to use specific soft tissue standards for this mixed race. PMID- 23916442 TI - Assessing the predictability of ANB, 1-NB, P-NB and 1-NA measurements on Steiner cephalometric analysis. AB - OBJECTIVE: To evaluate, in the initial and final stages of corrective orthodontic treatment, the predictability of the ANB, 1-NB, PNB and 1-NA during case individualization, which considers the characteristics of the patient, professional experience and the mechanics to be used. METHODS: Ninety patients were selected at the State University of Londrina (UEL, Brazil), presenting Angle Class I and II malocclusions, treated with and without extraction of four premolars and divided into three groups: Horizontal, balanced and vertical. The cephalometric variables were evaluated in the initial, prognosis and final stages of treatment in order to observe the behavior of the estimates, or how they were higher or lower than the values obtained. RESULTS: It was noticed the influence of the facial pattern on the behavior of the measures examined, the values proposed for the ANB were statistically different from values obtained at the end of the treatment; in the vertical group the final value was the one that most approached the proposed value; regarding 1-NB the values proposed with the Steiner analysis for the balanced and vertical groups were not achieved. For P NB, there was no difference between genders. For 1-NA it was observed that the values obtained at the end of treatment differ from estimates in the three groups. CONCLUSIONS: The limitations of the estimates of the measures do not invalidate its clinical or teaching use, if aware of its deficiencies, the analysis can be used with restrictions. PMID- 23916443 TI - Angle Class I malocclusion with anterior open bite treated with extraction of permanent teeth. AB - This clinical case reports the orthodontic treatment of a Class I malocclusion with anterior open bite and bimaxillary dentoalveolar protrusion in a 28-year-old female patient. The treatment of choice was to perform tooth extractions followed by retraction of the anterior teeth, with consequent closure of the anterior open bite and better accommodation of the teeth on their bony bases. This case was presented to the Brazilian Board of Orthodontics and Facial Orthopedics (BBO), representing the Category 2 -- i.e., an Angle Class I malocclusion, with anterior open bite, treated with extraction of permanent teeth --, as part of the requisites to become a BBO diplomate. PMID- 23916444 TI - Vertical control in the Class III compensatory treatment. AB - INTRODUCTION: Compensatory orthodontic treatment, or simply orthodontic camouflage, consists in an important alternative to orthognathic surgery in the resolution of skeletal discrepancies in adult patients. It is important to point that, to be successfully performed, diagnosis must be detailed, to evaluate, specifically, dental and facial features, as well as the limitations imposed by the magnitude of the discrepancy. The main complaint, patient's treatment expectation, periodontal limits, facial pattern and vertical control are some of the items to be explored in the determination of the viability of a compensatory treatment. Hyperdivergent patients who present with a Class III skeletal discrepancy, associated with a vertical facial pattern, with the presence or tendency to anterior open bite, deserve special attention. In these cases, an efficient strategy of vertical control must be planned and executed. OBJECTIVE: The present article aims at illustrating the evolution of efficient alternatives of vertical control in hiperdivergent patients, from the use, in the recent past, of extraoral appliances on the lower dental arch (J-hook), until nowadays, with the advent of skeletal anchorage. But for patients with a more balanced facial pattern, the conventional mechanics with Class III intermaxillary elastics, associated to an accentuated curve of Spee in the upper arch and a reverse curve of Spee in the lower arch, and vertical elastics in the anterior region, continues to be an excellent alternative, if there is extreme collaboration in using the elastics. PMID- 23916445 TI - Evaluation of radiographic magnification in lateral cephalograms obtained with different X-ray devices: experimental study in human dry skull. AB - OBJECTIVE: The purpose of this study was to evaluate the influence of the magnification factor of the radiographic image in angular, linear and proportional measurements. METHODS: From a dried human skull where metallic spheres with predetermined size were fixed (1.0 mm), 14 radiographs were obtained in devices from three different manufacturers: Panoura, Instrumentarium and Tomeceph. The Pearson correlation test was used to investigate the relationship between the rate of radiographic magnification and the cephalometric measurements assessed. RESULTS: According to the results, the linear measurements showed a high positive correlation, pointing out great influence of the magnification factor, while the angular and proportional measurements did not correlate. CONCLUSIONS: Comparisons between linear cephalometric measurements obtained with different devices from the same manufacturer showed maximum rates of expansion of 0.6%, 1.25% and 2.3%, respectively, for the devices from Instrumentarium (OP-100, Instrumentarium, Finland), Panoura (10CSU, Yoshida, Japan) and Satelec/Tomeceph (XMind, Satelec/Tomeceph Orion Corporation, Finland). PMID- 23916446 TI - Distal movement of upper permanent molars using midpalatal mini-implant. AB - OBJECTIVE: To assess whether palatal mini-implants are effective as direct anchorage for distal movement of the upper molars. METHODS: It was used an acrylic model of the upper dental arch. After making a groove in the region corresponding to dental alveolus, acrylic teeth were fixed in this groove with #7 wax, with the roots being previously immersed in adhesive wax. The orthodontic appliance was placed according to the Edgewise technique and then a mini-implant (SIN, Sao Paulo, Brazil) was inserted at the site corresponding to the palatal raphe. A 0.019 x 0.025-in stainless steel archwire was made and attached to the upper arch with elastics. A transpalatal bar (0.019 x 0.025-in) was mounted and two hooks were welded to it in order to retain chain elastics (Unitek, Brazil) to be connected to the mini-implant under a force of 1.5 N on each side. The maxillary model was immersed in water 40 times and photographed after each immersion, for observing dental movements. Analysis of variance (ANOVA) and Tukey's test were used for analyzing the obtained data. RESULTS: Molars displaced distally 3.1 mm, in average, with distal inclination ranging from 3 to 5 mm. CONCLUSIONS: Molar movements occurred due to distal inclination, with a slight rotation and no extrusive effect. PMID- 23916447 TI - Determination of the force systems produced by different configurations of tear drop orthodontic loops. AB - OBJECTIVE: To determine the mechanical characteristics of teardrop loop with and without helix fabricated using different metal alloy compositions (stainless steel and beta-titanium), submitted to different intensities of bends preactivation (0 degrees and 40 degrees ), and with different cross-sectional dimension of the wire used to build these loops (0.017 x 0.025-in and 0.019 x 0.025-in). METHODS: Eighty loops used to close spaces were submitted to mechanical tests. The magnitudes of horizontal force, the moment/force ratio, and the load/deflection ratio produced by the specimens were quantified. Loops were submitted to a total activation of 5.0 mm and the values were registered for each 1.0 mm of activation. For statistic data analysis, a analysis of variance was performed and a Tukey's Multiple Comparison test was used as supplement, considering a 5% level of significance. RESULTS: In general, teardrop loops with helix produced lower magnitudes of horizontal force and load/deflection ratio, and higher moment/force ratio than teardrop loops without helix. Among all analyzed variables, metal alloy composition presented greater influence in the horizontal force and in the load/deflection ratio. The moment/force ratio showed to be more influenced by the preactivation of loops for space closure. PMID- 23916448 TI - Evaluation of the susceptibility to pigmentation of orthodontic esthetic elastomeric ligatures. AB - OBJECTIVE: The purpose of this laboratory study was to evaluate changes in the pigmentation of esthetic elastomeric ligatures after immersion in a staining solution. METHODS: Sixty ligatures were selected and divided into 12 groups according to their brand and also considering their condition, i.e., unstretched or stretched. The groups were divided into: Morelli (clear), TP Orthodontics (clear), American Orthodontics (clear), 3M/Unitek (clear), American Orthodontics (pearl color) and 3M/Unitek (pearl color), separated in groups of 5 unstretched and 5 stretched ligatures. Assessment of their color changes was performed by means of digital photograph and computer analysis using Adobe Photoshop. Standardized digital photographs were taken at T0 (before the staining process, with unstretched ligatures) and at T1 (following the 5-days staining process). The staining solution was composed of artificial saliva and foods with staining potential. At T1 the ligatures were either stretched or unstretched. RESULTS: The results of this study showed that esthetic elastomeric ligatures are prone to staining. Among the evaluated brands, TP Orthodontics and American Orthodontics clear ligatures were the most stable. Moreover, 3M/Unitek pearl ligatures demonstrated statistically significant changes in all variables. CONCLUSIONS: Esthetic elastomeric ligatures are susceptible to staining and no statistically significant difference was found between unstretched or stretched ligatures, with the sole exception of the TP Orthodontics brand. The 3M/Unitek's pearl color ligatures displayed the greatest staining potential. PMID- 23916449 TI - Class II malocclusion treatment using high-pull headgear with a splint: a systematic review. AB - OBJECTIVE: To systematically review the scientific evidence regarding the effectiveness of high-pull headgear in growing Class II subjects. METHODS: A literature survey was performed by electronic database search. The survey covered the period from January 1966 to December 2008 and used Medical Subject Headings (MeSH). Articles were initially selected based on their titles and abstracts; the full articles were then retrieved. The inclusion criteria included growing subjects with 8 to 15 years of age, Class II malocclusion treatment with high pull headgear, and a control group with Class II malocclusion. References from selected articles were hand-searched for additional publications. Selected studies were evaluated methodologically. RESULTS: Four articles were selected; none were randomized controlled trials. All of the articles clearly formulated their objectives and used appropriate measures. The studies showed that high-pull headgear treatment improves skeletal and dental relationship, distal displacement of the maxilla, vertical eruption control and upper molars distalization. One of the studies showed a slight clockwise rotation of the palatal plane; the others showed no significant treatment effect. The mandible was not affected by the treatment. CONCLUSIONS: While there is still a lack of strong evidence demonstrating the effects of high-pull headgear with a splint, other studies indicate that the anteroposterior relations improve due to distalization of the maxilla and upper molars, with little or no treatment effects in the mandible. Greater attention to the design should be given to improve the quality of such trials. PMID- 23916450 TI - Compassionate containment? Balancing technical safety and therapy in the design of psychiatric wards. AB - This paper contributes to the international literature examining design of inpatient settings for mental health care. Theoretically, it elaborates the connections between conceptual frameworks from different strands of literature relating to therapeutic landscapes, social control and the social construction of risk. It does so through a discussion of the substantive example of research to evaluate the design of a purpose built inpatient psychiatric health care facility, opened in 2010 as part of the National Health Service (NHS) in England. Findings are reported from interviews or discussion groups with staff, patients and their family and friends. This paper demonstrates a strong, and often critical awareness among members of staff and other participants about how responsibilities for risk governance of 'persons' are exercised through 'technical safety' measures and the implications for therapeutic settings. Our participants often emphasised how responsibility for technical safety was being invested in the physical infrastructure of certain 'places' within the hospital where risks are seen to be 'located'. This illuminates how the spatial dimensions of social constructions of risk are incorporated into understandings about therapeutic landscapes. There were also more subtle implications, partly relating to 'Panopticist' theories about how the institution uses technical safety to supervise its own mechanisms, through the observation of staff behaviour as well as patients and visitors. Furthermore, staff seemed to feel that in relying on technical safety measures they were, to a degree, divesting themselves of human responsibility for risks they are required to manage. However, their critical assessment showed their concerns about how this might conflict with a more therapeutic approach and they contemplated ways that they might be able to engage more effectively with patients without the imposition of technical safety measures. These findings advance our thinking about the construction of therapeutic landscapes in theory and in practice. PMID- 23916451 TI - Epidemiological and molecular characterization of community and hospital acquired Staphylococcus aureus strains prevailing in Shenyang, Northeastern China. AB - In order to obtain adequate information for the treatment of methicillin resistant Staphylococcus aureus (MRSA) infections, it is crucial to identify trends in epidemiological and antimicrobial resistance patterns of local S. aureus strains. Community and hospital acquired S. aureus isolates (n=202) were characterized using staphylococcal cassette chromosome mec (SCCmec) typing, pulse field gel electrophoresis (PFGE) analysis, spa typing and minimal inhibitory concentration (MIC) determination. The prevalence of the Panton-Valentine leukocidine (pvl) and several antibiotic resistance genes among the isolates were also detected by PCR. All of the S. aureus isolates were susceptible to vancomycin, daptomycin and linezolid. Three hospital isolates were resistant to teicoplanin while 14 showed intermediate resistance to teicoplanin. The resistance patterns of community-acquired MRSA (CA-MRSA) isolates to other antimicrobials were similar to those of hospital-acquired MRSA (HA-MRSA) isolates except for clindamycin and gentamicin. There was excellent correlation between phenotypes and genotypes in the determination of S. aureus resistance to erythromycin, gentamicin, and tetracycline. The SCCmec type II and SCCmec type IV were the predominant types detected in hospital and community isolates, respectively. The most frequently encountered spa types were t002 and t030 both in HA- and CA-MRSA isolates. Pulsotype A was the most predominant pulsotype identified among the isolates tested, followed by pulsotype B. Seventy-two hospital isolates (19 HA-MRSA and 53 HA-MSSA) and 10 CA-MRSA were positive for the pvl gene. This study shows that the combination of susceptibility testing and various molecular methods has provided useful information on the antibiotic resistance and molecular diversity of S. aureus in a specific region of China. The high proportion of pvl positive MSSA and MRSA isolates observed in this study indicates that adequate measures are needed to curtail the spread of those MRSA and MSSA clones prevailing both in hospital and the community. PMID- 23916452 TI - Trichomonas vaginalis and associated factors among women living with HIV/AIDS in Amazonas, Brazil. AB - OBJECTIVES: Our goal was to determine the prevalence of Trichomonas vaginalis and its associated factors among women living with HIV attending an AIDS clinic in Manaus, Amazonas, Brazil. METHODS: Cross-sectional study among women attending an AIDS clinic in Manaus between March and December 2010 for gynecological examination were invited to participate. Enrolled patients answered a face-to face interview including demographic, behavioral and clinical data. They also underwent a gynecological evaluation and cervical scrape samples were collected for wet mount, Gram stain, culture and cytological analysis. A blood sample was obtained to determine TCD4+ lymphocytes and viral load. RESULTS: A total of 341 (91.2%) women participated in the study. The prevalence of T. vaginalis was 4.1% (95% CI: 2.0-6.2%). Median age was 32 (interquartile range 27-38) years and median years of schooling was 9.0 (interquartile range 4-11). A total of 165 (53.2%) HIV women were classified as patients with AIDS. In multivariate analyses, squamous intraepithelial lesions in cytology [OR=2.46 (95% CI: 1.31 4.63, p=0.005)] and anal sex practice [OR=3.62 (95% CI: 1.08-12.19, p=0.037)] were associated with T. vaginalis. CONCLUSIONS: These results highlight that HIV infected women should be screened for T. vaginalis. The control of this infection may have an impact on preventing reproductive complications among these women. PMID- 23916453 TI - Spectrum and potency of ceftaroline against leading pathogens causing community acquired respiratory tract and skin and soft tissue infections in Latin America, 2010. AB - Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with in vitro bactericidal activity against Gram-positive organisms, including methicillin-susceptible and -resistant Staphylococcus aureus, beta-haemolytic and viridans group streptococci, and Streptococcus pneumoniae, as well as common Gram-negative organisms. In this study a total of 986 isolates collected in 2010 from patients in 15 medical centers in five Latin American countries from the Assessing Worldwide Antimicrobial Resistance Evaluation Program were identified as community-acquired respiratory tract or skin and soft tissue infection pathogens. Ceftaroline was the most potent agent tested against S. pneumoniae with a MIC90 value (0.12MUg/mL) that was eight-fold lower than ceftriaxone, levofloxacin, and linezolid. Its spectrum of coverage (100.0% susceptible) was similar to tigecycline, linezolid, levofloxacin and vancomycin. Against Haemophilus influenzae and Moraxella catarrhalis, ceftaroline was the most active agent tested. The activity of ceftaroline against S. aureus (including MRSA) was similar to that of vancomycin and tetracycline (MIC90, 1MUg/mL) and linezolid (MIC90, 2MUg/mL). The beta-haemolytic streptococci exhibited 100.0% susceptibility to ceftaroline. Ceftaroline activity against Escherichia coli, Klebsiella spp., and Enterobacter spp. was similar to that of ceftriaxone and ceftazidime. These parenteral cephalosporin agents have potent activity against non-extended-spectrum beta-lactamase-phenotype strains, but are not active against extended-spectrum beta-lactamase-phenotype strains. These results confirm the in vitro activity of ceftaroline against pathogens common in community-acquired respiratory tract and skin and soft tissue infection in Latin America, and suggest that ceftaroline fosamil could be an important therapeutic option for these infections. PMID- 23916454 TI - Virologic and immunologic effectiveness of darunavir-based salvage therapy in HIV 1-infected adults in a Brazilian clinical practice setting: results of a multicenter and retrospective cohort study. AB - BACKGROUND: Darunavir has been proven efficacious for antiretroviral-experienced HIV-1-infected patients in randomized trials. However, effectiveness of darunavir based salvage therapy is understudied in routine care in Brazil. METHODS: Retrospective cohort study of HIV-1-infected patients from three public referral centers in Belo Horizonte, who received a darunavir-based therapy between 2008 and 2010, after virologic failure. Primary endpoint was the proportion of patients with viral load<50 copies/mL at week 48. Change in CD4 cell count was also evaluated. Outcome measures were analyzed on an intent-to-treat basis applied to observational studies. Sensitivity analysis was conducted to evaluate the impact of missing data at week 48. Predictors of virologic failure were examined using rare-event, finite sample, bias-corrected logistic regression. RESULTS: Among 108 patients, the median age was 44.2 years, and 72.2% were male. They had long-standing HIV-1 infection (median 11.6 years) and advanced disease (76.9% had an AIDS-defining event). All patients had previously received protease inhibitors and nucleoside reverse transcriptase inhibitors, 75% nonnucleoside reverse transcriptase inhibitors, and 4.6% enfuvirtide. The median length of protease inhibitor use was 8.9 years, and 90.8% of patients had prior exposure to unboosted protease inhibitor. Genotypic resistance profile showed a median of three primary protease inhibitor mutations and 10.2% had three or more darunavir resistance-associated mutations. Virologic success at week 48 was achieved by 78.7% (95% CI=69.7-86%) of patients and mean CD4 cell count increase from baseline was 131.5 cells/MUL (95% CI=103.4-159.6). In multiple logistic regression analysis, higher baseline viral load (RR=1.04 per 10,000 copies/mL increase; 95% CI=1.01-1.09) and higher number of darunavir resistance-associated mutations (RR=1.23 per each; 95% CI=0.95-1.48) were independently associated with virologic failure. CONCLUSION: Virologic suppression is a realistic endpoint for most treatment-experienced patients who begin a darunavir-based therapy outside the controlled conditions of a randomized trial, at routine care settings. PMID- 23916455 TI - Brazilian experience in EU-CORE: daptomycin registry and treatment of serious Gram-positive infections. AB - OBJECTIVES: To collect data about non-controlled prescribing use of daptomycin and its impact among Brazilian patients with serious Gram positive bacterial infection, as well as the efficacy and safety outcomes. MATERIALS AND METHODS: This is a multi-center, retrospective, non-interventional registry (August 01, 2009 to June 30, 2011) to collect data on 120 patients (44 patients in the first year and 76 patients in the second year) who had received at least one dose of commercial daptomycin in Brazil for the treatment of serious Gram-positive bacterial infection. RESULTS: Right-sided endocarditis (15.8%), complicated skin and soft tissue infections (cSSTI)-wound (15.0%) and bacteremia-catheter-related (14.2%) were the most frequent primary infections; lung (21.7%) was the most common site for infection. Daptomycin was used empirically in 76 (63.3%) patients, and methicillin-resistant Staphylococcus aureus (MRSA) was the most common suspected pathogen (86.1%). 82.5% of the cultures were obtained prior to or shortly after initiation of daptomycin therapy. Staphylococcus spp. - coagulase negative, MRSA, and methicillin-susceptible S. aureus were the most frequently identified pathogens (23.8%, 23.8% and 12.5%, respectively). The most common daptomycin dose administered for bacteremia and cSSTI was 6mg/kg (30.6%) and 4mg/kg (51.7%), respectively. The median duration of inpatient daptomycin therapy was 14 days. Most patients (57.1%) did not receive daptomycin while in intensive care unit. Carbapenem (22.5%) was the most commonly used antibiotic concomitantly. The patients showed clinical improvement after two days (median) following the start of daptomycin therapy. The clinical success rate was 80.8% and the overall rate of treatment failure was 10.8%. The main reasons for daptomycin discontinuation were successful end of therapy (75.8%), switched therapy (11.7%), and treatment failure (4.2%). Daptomycin demonstrated a favorable safety and tolerability profile regardless of treatment duration. CONCLUSIONS: Daptomycin had a relevant role in the treatment of Gram-positive infections in the clinical practice setting in Brazil. PMID- 23916456 TI - Health related quality of life among patients with chronic hepatitis C: a cross sectional study of sociodemographic, psychopathological and psychiatric determinants. AB - INTRODUCTION: Chronic hepatitis C virus infection patients have higher rates of psychiatric disorders than the general population. Chronic hepatitis C virus infection is known to be associated with impaired health related quality of life. To our knowledge, there is no previous research of health related quality of life in chronic hepatitis C patients that combined structured psychiatric interview and careful psychopathological evaluation, including depression, anxiety and fatigue instruments. The aim of this study was to evaluate health related quality of life of chronic hepatitis C patients and to investigate the association with sociodemographic, psychopathological and psychiatric factors. MATERIALS AND METHODS: Eighty-one individuals with chronic hepatitis C virus infection receiving care at a Brazilian public university-based outpatient service for infectious diseases were enrolled in the study. The World Health Organization Quality of Life Scale Brief Version was used to assess health related quality of life. Standard psychiatric interview (Mini International Neuropsychiatric Interview-Plus) was conducted to establish Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I psychiatric diagnosis. Further instruments completed psychopathological investigation: Beck Depression Inventory, Hospital Anxiety and Depression Scale, Brief Fatigue Inventory, Hamilton Depression Scale and Hamilton Anxiety Scale. Pearson Chi-Square and Kruskal-Wallis were performed for categorical and continuous univariate analysis, respectively. Correlation between psychopathological and health related quality of life scores was performed according to Spearman's correlation. Multivariate analysis was performed according to stepwise forward ordinal logistic regression. The significance threshold was fixed at alpha=0.05. RESULTS: Depressive disorders were associated with worse scores in overall health related quality of life and in all domains. Fatigue was associated with lower scores in physical and psychological domains, and married status with higher scores in psychological health related quality of life. We found strong correlation among scores of depression, fatigue and health related quality of life. CONCLUSION: Depression and fatigue must be properly investigated and managed in HCV patients in order to improve HRQL. WHOQOL-BREF proved to be a useful instrument to assess HRQL in HCV patients. PMID- 23916457 TI - Categorization of dengue fever according to phase of illness--a suggestion for clinical studies using single diagnostic sample. PMID- 23916458 TI - Epidemiological evolution of vertical HIV transmission in Rondonia, Brazil. PMID- 23916459 TI - A literature review on cardiovascular risk in human immunodeficiency virus infected patients: implications for clinical management. AB - INTRODUCTION: In recent years, there has been growing concern about an increasing rate of cardiovascular diseases in human immunodeficiency virus-infected patients, which could be associated with side effects of highly active antiretroviral therapy. It is likely that the metabolic disorders related to anti human immunodeficiency virus treatment will eventually translate into a increased cardiovascular risk in patients submitted to such regimens. OBJECTIVE: To evaluate if human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy are at higher risk of cardiovascular diseases than human immunodeficiency virus infected patients not receiving highly active antiretroviral therapy, or the general population. RESEARCH DESIGN AND METHODS: We conducted a computer-based search in representative databases, and also performed manual tracking of citations in selected articles. RESULT: The available evidence suggests an excess risk of cardiovascular events in human immunodeficiency virus-infected persons compared to non-human immunodeficiency virus infected individuals. The use of highly active antiretroviral therapy is associated with increased levels of total cholesterol, triglycerides, low-density lipoprotein and morphological signs of cardiovascular diseases. Some evidence suggested that human immunodeficiency virus-infected individuals on highly active antiretroviral therapy regimens are at increased risk of dyslipidemia, ischemic heart disease, and myocardial infarction, particularly if the highly active antiretroviral therapy regimen contains a protease inhibitor. CONCLUSION: Physicians must weigh the cardiovascular risk against potential benefits when prescribing highly active antiretroviral therapy. Careful cardiac screening is warranted for patients who are being evaluated for, or who are receiving highly active antiretroviral therapy regimens, particularly for those with known underlying cardiovascular risk factors. A better understanding of the molecular mechanisms responsible for increased risk of cardiovascular diseases in human immunodeficiency virus-infected patients will lead to the discovery of new drugs that will reduce cardiovascular risk in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy. PMID- 23916460 TI - Spray granulation: importance of process parameters on in vitro and in vivo behavior of dried nanosuspensions. AB - The use of fluid bed granulation for drying of pharmaceutical nanoparticulates on micron-sized granule substrates is a relatively new technique, with limited understanding in the current literature of the effects of process parameters on the physical properties of the dried nanoparticle powders. This work evaluated the effects of spray mode, spray rate and atomizing pressure for spray granulation of drug nanosuspensions through a systematic study. Naproxen and a proprietary Novartis compound were converted into nanosuspensions through wet media milling and dried onto a mannitol based substrate using spray granulation. For naproxen, various physical properties of the granules, as well as the in vitro re-dispersion and dissolution characteristics of the nano-crystals, were measured. It was found that the spray mode had the most drastic effect, where top spray yielded smaller re-dispersed particle sizes and faster release rates of drug from granules than bottom spray. This was attributed to the co-current spraying in bottom spray resulting in denser, homogenous films on the substrate. Similar in vitro results were obtained for the proprietary molecule, Compound A. In vivo studies in beagle dogs with Compound A showed no significant difference between the liquid and the dried forms of the nanosuspension in terms of overall AUC, differences were observed in the tmax which correlated with the rank ordering observed from the in vitro dissolution profiles. These findings make spray granulation amenable to the production of powders with desired processing and handling properties, without compromising the overall exposure of the compound under investigation. PMID- 23916461 TI - Comparative evaluation of novel biodegradable nanoparticles for the drug targeting to breast cancer cells. AB - Nanomedicine formulations such as biodegradable nanoparticles (nps) and liposomes offer several advantages over traditional routes of administration: due to their small size, nanocarriers are able to selectively accumulate inside tumours or inflammatory tissues, resulting in improved drug efficacy and reduced side effects. To further augment targeting ability of nanoparticles towards tumour cells, specific ligands or antibodies that selectively recognise biomarkers over expressed on cancer cells, can be attached to the surface either by chemical bond or by hydrophilic/hydrophobic interactions. In the present work, Herceptin (HER), a monoclonal antibody (mAb) able to selectively recognise HER-2 over-expressing tumour cells (such as breast and ovarian cancer cells), was absorbed on the surface of nanoparticles through hydrophilic/hydrophobic interactions. Nps were prepared by a modified single emulsion solvent evaporation method with five different polymers: three commercial polyesters (poly(epsilon-caprolactone) (PCL), poly (D,L-lactide) (PLA) and poly (D,L-lactide-co-.glycolide) (PLGA)) and two novel biodegradable polyesterurethanes (PURs) based on Poly(epsilon caprolactone) blocks, synthesised with different chain extenders (1,4-cyclohexane dimethanol (CDM) and N-Boc-serinol). Polyurethanes were introduced as matrix forming materials for nanoparticles due to their high chemical versatility, which allows tailoring of the materials final properties by properly selecting the reagents. All nps exhibited a small size and negative surface charge, suitable for surface functionalisation with mAb through hydrophilic/hydrophobic interactions. The extent of cellular internalisation was tested on two different cell lines: MCF-7 and SK-BR-3 breast cancer cells showing a normal and a high expression of the HER-2 receptor, respectively. Paclitaxel, a model anti neoplastic drug, was encapsulated inside all nps, and release profiles and cytotoxicity on SK-BR-3 cells were also assessed. Interestingly, PUR nps were superior to commercial polyester-based nps in terms of higher cellular internalisation and cytotoxic activity on the tested cell lines. Results obtained warrants further investigation on the application of these PUR nps for controlled drug delivery and targeting. PMID- 23916462 TI - Dissection of the elements of osmotic stress response transcription factor Hot1 involved in the interaction with MAPK Hog1 and in the activation of transcription. AB - The response to hyperosmotic stress is mediated by the HOG pathway. The MAP kinase Hog1 activates several transcription factors, regulates chromatin modifying enzymes and, through its interaction with RNA polymerase II, it directs this enzyme to osmotic stress-controlled genes. For such targeting, this kinase requires the interaction with transcription factors Hot1 and Sko1. However, phosphorylation of these proteins by Hog1 is not required for their functionality. In this study, we aim to identify the Hot1 elements involved in Hog1-binding and in the activation of transcription. Two-hybrid experiments demonstrated that the Hot1 sequence between amino acids 340 and 534 and the CD element of Hog1 are required for the interaction between the two proteins and the Hot1-dependent transcription regulation. Inside this Hot1 region, short sequence KRRRR (KR4, amino acids 381-385) is essential for the kinase binding. Our data show that another element, sequence EDDDDD (ED5, amino acids 541-546), is essential for Hot1 binding to chromatin. Under osmotic stress conditions, both Hot1 elements, Hog1-interaction KR4 and DNA-binding ED5, are involved in the appropriate recruitment of Hog1 and RNA polymerase II to genes controlled by this transcription factor. Moreover, both sequences are required for osmotolerance and KR4 is necessary for the functionality of the HOG pathway. According to several experiments described in this study, the Hot1 protein is capable of forming homodimers. PMID- 23916463 TI - Drosophila nuclear factor DREF regulates the expression of the mitochondrial DNA helicase and mitochondrial transcription factor B2 but not the mitochondrial translation factor B1. AB - DREF [DRE (DNA replication-related element)-binding factor] controls the transcription of numerous genes in Drosophila, many involved in nuclear DNA (nDNA) replication and cell proliferation, three in mitochondrial DNA (mtDNA) replication and two in mtDNA transcription termination. In this work, we have analysed the involvement of DREF in the expression of the known remaining genes engaged in the minimal mtDNA replication (d-mtDNA helicase) and transcription (the activator d-mtTFB2) machineries and of a gene involved in mitochondrial mRNA translation (d-mtTFB1). We have identified their transcriptional initiation sites and DRE sequences in their promoter regions. Gel-shift and chromatin immunoprecipitation assays demonstrate that DREF interacts in vitro and in vivo with the d-mtDNA helicase and d-mtTFB2, but not with the d-mtTFB1 promoters. Transient transfection assays in Drosophila S2 cells with mutated DRE motifs and truncated promoter regions show that DREF controls the transcription of d-mtDNA helicase and d-mtTFB2, but not that of d-mtTFB1. RNA interference of DREF in S2 cells reinforces these results showing a decrease in the mRNA levels of d-mtDNA helicase and d-mtTFB2 and no changes in those of the d-mtTFB1. These results link the genetic regulation of nuclear DNA replication with the genetic control of mtDNA replication and transcriptional activation in Drosophila. PMID- 23916465 TI - Comparative study of enamel adhesion between RelyXTM Unicem(r) (3M), a self adhesive bonding agent, and the combination of MIP(r) (3M), a hydrophilic adhesive, and Transbond Supreme Low Viscosity(r) (3M), a traditional hydrophobic adhesive. AB - Although the bond strength of self-adhesive bonding agents is inferior to that of other families of adhesives, it is still adequate for orthodontic purposes provided prior enamel etching is performed. AIM: To determine the efficacy of RelyXTM Unicem((r)) (3M) self-adhesive cement both in vitro and in vivo and to compare it with the combination of MIP((r)) (3M), a moisture-insensitive primer, with a traditional hydrophobic adhesive, Transbond Supreme Low Viscosity((r)) (3M). IN VITRO: Comparison of bonding results on 23 trial dentures using RelyXTM Unicem((r)) (3M) with bonding results on 29 trial dentures using a combination of MIP((r)) and Transbond Supreme Low Viscosity((r)) (3M), by means of a multipurpose Instron((r)) 4444 testing machine. RESULTS: the breaking force of MIP((r))/Transbond Supreme Low Viscosity((r)) (3M) (mean: 144+/-37.5 Newtons) was significantly higher than that of RelyXTM Unicem((r)) (3M) (mean=110+/-26 Newtons) (P=0.001). IN VIVO: A 12-month prospective, randomized, monocentric, single-blind clinical study in order to investigate the failure rate of orthodontic attachments according to the type of adhesive used, and the precise site of the debonding. Bracket bonding was performed on 16 patients with randomized allocation of the two adhesives to each of the semi-arches. RESULTS: The failure rates were: 15.3% for the MIP((r))/Transbond Supreme Low Viscosity((r)) (3M) combination and 8.2% for the RelyXTM Unicem((r)) (3M), with a significant difference (P=0.039). The more posterior the bonded teeth, the greater the superiority of RelyXTM Unicem((r)) (3M). The in vivo results did not concord with those obtained in vitro. RelyXTM Unicem((r)) (3M) exhibited lower adhesion values in vitro and yet it presented a debonding rate almost half that of the MIP((r))/Transbond Supreme Low Viscosity((r)) (3M). The viscosity of RelyXTM Unicem((r)) (3M) and its moisture tolerance would appear to account for these results. CONCLUSION: With prior etching, RelyXTM Unicem((r)) (3M), a self adhesive, self-etching bonding agent is compatible with use in the orthodontic indirect bonding technique. The MIP((r))/Transbond Supreme Low Viscosity((r)) (3M) combination, though very effective, still remains sensitive and requires special care during usage. PMID- 23916467 TI - Rheumatoid Arthritis (RA) associated interstitial lung disease (ILD). AB - Rheumatoid Arthritis (RA) is the most common Connective Tissue Disease (CTD) and represents an increasing burden on global health resources. Interstitial lung disease (ILD) has been recognised as a complication of RA but its potential for mortality and morbidity has arguably been under appreciated for decades. New studies have underscored a significant lifetime risk of ILD development in RA. Contemporary work has identified an increased risk of mortality associated with the Usual Interstitial Pneumonia (UIP) pattern which shares similarity with the most devastating of the interstitial pulmonary diseases, namely Idiopathic Pulmonary Fibrosis (IPF). In this paper, we discuss recent studies highlighting the associated increase in mortality in RA-UIP. We explore associations between radiological and histopathological features of RA-ILD and the prognostic implications of same. We emphasise the need for translational research in this area given the growing burden of RA-ILD. We highlight the importance of the respiratory physician as a key stakeholder in the multidisciplinary management of this disorder. RA-ILD focused research offers the opportunity to identify early asymptomatic disease and define the natural history of this extra articular manifestation. This may provide a unique opportunity to define key regulatory fibrotic events driving progressive disease. We also discuss some of the more challenging and novel aspects of therapy for RA-ILD. PMID- 23916466 TI - Axis I psychiatric diagnoses in adolescents and young adults with 22q11 deletion syndrome. AB - BACKGROUND: 22q11.2 deletion syndrome (22q11DS) associates with schizophrenia spectrum disorders (SSDs), autism spectrum disorders (ASDs), and other psychiatric disorders, but co-occurrence of diagnoses are not well described. METHODS: We evaluated the co-occurrence of SSDs, ASDs and other axis I psychiatric diagnoses in 31 adolescents and adults with 22q11DS, assessing ASDs using either stringent Collaborative Program for Excellence in Autism (ASD-CPEA) criteria, or less stringent DSM-IV criteria alone (ASD-DSM-IV). RESULTS: Ten (32%) individuals met criteria for an SSD, five (16%) for ASD-CPEA, and five others (16%) for ASD-DSM-IV. Of those with ASD-CPEA, one (20%) met SSD criteria. Of those with ASD-DSM-IV, four (80%) met SSD criteria. Depressive disorders (8 individuals; 26%) and anxiety disorders (7; 23%) sometimes co-occurred with SSDs and ASDs. SSDs, ASDs, and anxiety occurred predominantly among males and depression predominantly among females. CONCLUSIONS: Individuals with 22q11DS can manifest SSDs in the presence or absence of ASDs and other axis I diagnoses. The results suggest that standard clinical care should include childhood screening for ASDs, and later periodic screening for all axis I diagnoses. PMID- 23916468 TI - Silibinin meglumine, a water-soluble form of milk thistle silymarin, is an orally active anti-cancer agent that impedes the epithelial-to-mesenchymal transition (EMT) in EGFR-mutant non-small-cell lung carcinoma cells. AB - Silibinin is the primary active constituent of a crude extract (silymarin) from milk thistle plant (Silybum marianum) seeds. We explored the ability of an oral milk thistle extract formulation that was enriched with a water-soluble form of silibinin complexed with the amino-sugar meglumine to inhibit the growth of non small-cell lung carcinoma (NSCLC) mouse xenografts. As a single agent, oral silibinin meglumine notably decreased the overall volumes of NSCLC tumors as efficiently as did the EGFR tyrosine kinase inhibitor (TKI) gefitinib. Concurrent treatment with silibinin meglumine impeded the regrowth of gefitinib-unresponsive tumors, resulting in drastic tumor growth prevention. Because the epithelial-to mesenchymal transition (EMT) is required by a multiplicity of mechanisms of resistance to EGFR TKIs, we evaluated the ability of silibinin meglumine to impede the EMT in vitro and in vivo. Silibinin-meglumine efficiently prevented the loss of markers associated with a polarized epithelial phenotype as well as the de novo synthesis of proteins associated with the mesenchymal morphology of transitioning cells. Our current findings with this non-toxic, orally active, and water-soluble silibinin formulation might facilitate the design of clinical trials to test the administration of silibinin meglumine-containing injections, granules, or beverages in combination with EGFR TKIs in patients with EGFR mutated NSCLC. PMID- 23916469 TI - The atypical lipopolysaccharide of Francisella. AB - Bacterial lipopolysaccharides (LPSs) are ubiquitous molecules that are prominent components of the outer membranes of most gram-negative bacteria. Genetic and structural characterizations of Francisella LPS have revealed substantial differences when compared to more commonly studied LPSs of the Enterobacteriaceae. This review discusses both the general characteristics and the unusual features of Francisella LPS. PMID- 23916471 TI - Neuromyelitis optica: concept, immunology and treatment. AB - Neuromyelitis optica (NMO) is an inflammatory disorder of the central nervous system (CNS) that predominantly affects the optic nerves and spinal cord. Previously, it has been considered to be a severe variant of multiple sclerosis (MS), especially common in Asia. However, the finding that most NMO patients have autoantibodies against aquaporin-4 (AQP4) has improved our knowledge of its pathogenesis and led to the concept that NMO is a disease distinct from MS. Although the 2006 NMO revised criteria are useful for diagnosing NMO, their usefulness in the diagnosis of early-stage NMO is limited. Hence, there is an urgent need for new and more precise diagnostic methods. Interleukin-6 may play important roles in NMO pathogenesis, as it is involved in the survival of plasmablasts that produce anti-AQP4 antibody in the peripheral circulation and in the enhancement of inflammation in the CNS. Severe blood-brain barrier disruption in NMO allows the anti-AQP4 antibody to access the astrocytic endfeet. The anti AQP4 antibody causes astrocytic damage through complement activation. Thus, NMO is an astrocytopathic, rather than a demyelinating, disease. Some brain lesions specific to NMO have recently been reported. Significant advances in the understanding of NMO pathogenesis are beginning to improve existing treatment strategies and will help develop new treatments. This review focuses on the current advances in NMO research and its clinical characteristics, immunological findings, neuroimaging and pathophysiology. PMID- 23916470 TI - Galectin-3 modulates Th17 responses by regulating dendritic cell cytokines. AB - Galectin-3 is a beta-galactoside-binding animal lectin with diverse functions, including regulation of T helper (Th) 1 and Th2 responses. Current data indicate that galectin-3 expressed in dendritic cells (DCs) may be contributory. Th17 cells have emerged as critical inducers of tissue inflammation in autoimmune disease and important mediators of host defense against fungal pathogens, although little is known about galectin-3 involvement in Th17 development. We investigated the role of galectin-3 in the induction of Th17 immunity in galectin 3-deficient (gal3(-/-)) and gal3(+/+) mouse bone marrow-derived DCs. We demonstrate that intracellular galectin-3 negatively regulates Th17 polarization in response to the dectin-1 agonist curdlan (a beta-glucan present on the cell wall of fungal species) and lipopolysaccharide, agents that prime DCs for Th17 differentiation. On activation of dectin-1, gal3(-/-) DCs secreted higher levels of the Th17-axis cytokine IL-23 compared with gal3(+/+) DCs and contained higher levels of activated c-Rel, an NF-kappaB subunit that promotes IL-23 expression. Levels of active Raf-1, a kinase that participates in downstream inhibition of c Rel binding to the IL23A promoter, were impaired in gal3(-/-) DCs. Modulation of Th17 by galectin-3 in DCs also occurred in vivo because adoptive transfer of gal3(-/-) DCs exposed to Candida albicans conferred higher Th17 responses and protection against fungal infection. We conclude that galectin-3 suppresses Th17 responses by regulating DC cytokine production. PMID- 23916472 TI - HIG2 promotes colorectal cancer progression via hypoxia-dependent and independent pathways. AB - HIG2 (hypoxia-inducible gene 2) is a biomarker of hypoxia and elevated in several cancers. Here, we show that HIG2 also upregulated HIF-1alpha expression under hypoxic conditions and enhanced AP-1 expression under normoxic conditions, which affects colorectal cancer cell survival. Importantly, over-expression of HIG2 promoted tumor growth by suppressing apoptosis in a mouse orthotopic model. These results are likely relevant to human disease since we found that the expression of HIG2 is gradually elevated as tumors progress. Collectively, these findings suggest that HIG2 plays an important role in promoting colorectal cancer growth in hypoxia-dependent and independent manners. PMID- 23916473 TI - High preoparative levels of serum periostin are associated with poor prognosis in patients with hepatocellular carcinoma after hepatectomy. AB - AIMS: Periostin (POSTN) is implicated in cancer development and progression. The aim of this study was to evaluate the diagnostic and prognostic significance of serum POSTN in patients with hepatocellular carcinoma (HCC) receiving curative surgery. METHODS: Enzyme-linked immunosorbent assay was performed to determine serum POSTN levels in 69 healthy volunteers, 30 patients with hepatolithiasis, 27 patients with cirrhosis, and 56 HCC patients. The relationships between serum POSTN and clinicopathologic features were analyzed. Receiver operating characteristics analysis was used to calculate diagnostic accuracy of serum POSTN, serum alpha-fetoprotein (AFP), and their combination. The prognostic impact of serum POSTN on overall survival (OS) and relapse-free survival (RFS) was also investigated. RESULTS: The median serum POSTN level was significantly (P < 0.05) increased in HCC patients, compared to healthy controls, patients with hepatolithiasis, and patients with liver cirrhosis. Elevated serum POSTN was only significantly associated with Edmondson grade (P = 0.007). The combination of serum POSTN and AFP had a markedly higher area under the curve (0.805 (95% confidence interval [CI]: 0.677-0.932)) than POSTN (0.582 (95% CI: 0.427-0.736)) or AFP (0.655 (95% CI: 0.504-0.806)) alone. Kaplan-Meier analysis indicated that elevated serum POSTN was associated with OS (P = 0.031) and RFS (P = 0.027). Moreover, multivariate analysis revealed elevated serum POSTN as an independent poor prognostic marker for OS and RFS. CONCLUSIONS: Preoperative serum POSTN has limited diagnostic value in distinguishing HCC from non-malignant liver diseases, but serves as independent prognostic biomarker in HCC patients. PMID- 23916474 TI - An isolation technique to prevent the spread of tumor cells during radical gastrectomy for gastric carcinoma located on the anterior wall of the gastric antrum. AB - OBJECTIVE: To report an isolation technique for reducing the spread of tumor cells during radical gastrectomy for lesions located on the anterior wall of the gastric antrum. METHODS: The isolation technique involves using linear cutting staplers and a waterproof membrane to completely "block" and isolate the area to be resected. Blood samples from the portal vein and peritoneal wash samples were obtained immediately after laparotomy and during surgical resection. RT-PCR was used to determine levels of carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20). Carbon nanoparticles were injected into the subserosa of the blocked region before resection to determine lymph flow out of the region. RESULTS: A total of 76 patients (median age, 59 years; range, 22-73 years), with tumors on the anterior wall of the gastric antrum were included (blocking group, n = 40; non-blocking group, n = 36). In the blocking group, the carbon nanoparticles did not flow beyond the blocking line. There were no significant differences between the groups in CEA or CK20 mRNA levels in portal vein blood or peritoneal wash fluid immediately after laparotomy. CEA and CK20 levels were significantly lower in portal vein blood in the blocking group during tumor resection. During a median follow-up of 30 months, the incidence of metastasis or recurrence in the blocking group was lower than the non-blocking group, although it did not reach statistical significance (17.9% vs. 25.0%, respectively). CONCLUSION: The blocking technique can reduce hematogenous and lymphatic spread of tumor cells into the systemic circulation, and may prevent metastasis or recurrence after radical gastrectomy for gastric carcinoma. PMID- 23916475 TI - The activation of P2Y6 receptor in cultured spinal microglia induces the production of CCL2 through the MAP kinases-NF-kappaB pathway. AB - Rat primary cultures of spinal microglia were stimulated by UTP, a known P2Y2/4 receptor agonist, which resulted in the production and release of the C-C chemokine CCL2 (monocyte chemoattractant protein-1; MCP-1) measured by real-time PCR and ELISA, respectively. In an in vitro preparation of rat spinal microglia, with regard to the P2Y subtypes, the expression of P2Y1, 2, 6, 12, 13 and P2Y14, but not P2Y4, were detected by RT-PCR. The subtype of microglial P2Y receptor which could be involved in the production of CCL2 was also determined. The UTP induced production of CCL2 was significantly blocked by pretreatment with reactive blue 2 and suramin, nonselective P2Y receptor antagonists, and MRS2578, a selective P2Y6 receptor antagonist. By contrast, knockdown of the P2Y2 receptor by RNA interference had no effect. The stimulatory effect of UTP was inhibited by phospholipase C (PLC) inhibitor U73122 and Src tyrosine kinase inhibitor PP2. A potential role of mitogen activated protein kinases was suggested since UTP induced CCL2 production was significantly blocked by both U0126 and SB 202190, which are potent inhibitors of extracellular signal-regulated kinase (ERK) and p38, respectively. Moreover, UTP-stimulated phosphorylation of these kinases involved the activation of the P2Y6 receptor. Lastly, activation of nuclear factor-kappaB (NF-kappaB) by UTP is likely to be essential in the expression of CCL2. Together, these findings suggest that stimulation of spinal microglia P2Y6 receptors induce the production of CCL2 through either PLC-mediated ERK or p38 phosphorylation and the subsequent activation of NF-kappaB. PMID- 23916476 TI - 2-Guanidine-4-methylquinazoline acts as a novel competitive antagonist of A type gamma-aminobutyric acid receptors. AB - The pentameric A type gamma-aminobutyric acid receptors (GABAARs) are the major inhibitory neurotransmitter receptors in the nervous system and have long been considered as important pharmaceutical targets for the treatment of multiple neurological or psychological disorders. Here, we show that 2-guanidine-4 methylquinazoline (GMQ), a recently identified acid-sensing ion channel (ASIC) modulator, strongly and preferentially inhibits GABAAR among the major neurotransmitter-gated ion channels in cultured rat hippocampal neurons. GMQ inhibited GABA (1 MUM)-induced currents in a competitive manner, with an IC50 (0.39+/-0.05 MUM) comparable to that of bicuculline. Schild analysis revealed a slope of 1.04+/-0.06 for GMQ on alpha1beta2 GABAARs expressed in HEK293T cells. Single-channel analysis showed that GMQ decreased open probability of GABAARs without affecting conductance. Moreover, GMQ inhibited GABAergic neurotransmission in hippocampal neurons, while having no significant effect on the basal field excitatory postsynaptic potentials (fEPSPs) and the intrinsic excitability of neurons. Using site-directed mutagenesis, we further demonstrated that mutations at Glu155 of beta2 subunit and Phe64 of alpha1 subunit, both located inside the GABA binding pocket, profoundly decreased the sensitivity of the receptor to both GABA and GMQ. Interestingly, these mutations did not significantly affect the inhibition by amiloride, a diuretic structurally similar to GMQ and a known GABAAR inhibitor. We conclude that GMQ represents a novel chemical structure that acts, possibly, by competing with GABA binding to GABAARs. It is anticipated that GMQ and its analogs will facilitate the development of new chemical probes for GABAARs. PMID- 23916477 TI - Inhibition of Src tyrosine kinase activity by squamosamide derivative FLZ attenuates neuroinflammation in both in vivo and in vitro Parkinson's disease models. AB - The participation of neuroinflammation in the pathogenesis of Parkinson's disease (PD) has long been validated. Excessive activated microglia release a large number of pro-inflammatory factors, damage surrounding neurons and eventually induce neurodegeneration. Inhibition of microglial over-activation might be a promising strategy for PD treatment. FLZ (formulated as: N-(2-(4-hydroxy-phenyl) ethyl)-2-(2, 5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide, the code name: FLZ), a natural squamosamide derivative from a Chinese herb, has been shown to inhibit over-activated microglia and protect dopaminergic neurons in previous studies, but the mechanism remains unclear. In the present study, we further investigated the mechanism in lipopolysaccharide (LPS)-induced in vivo and in vitro PD models. FLZ treatment significantly improved the motor dysfunction of PD model rats induced by intra-nigral injection of LPS and this beneficial effect of FLZ attributed to the inhibition of microglial over activation and the protection on dopaminergic neurons in the substantia nigra (SN). In vitro mechanistic study revealed that the inhibitive effect of FLZ on microglia was mediated by suppressing Src kinase related inflammatory signaling pathway activation and subsequent NF-kappaBp65 nuclear translocation, inhibiting nitric oxide (NO) and reactive oxygen species (ROS) production, decreasing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. In conclusion, the present study supports that FLZ exerts neuroprotection against LPS-induced dopaminergic neurodegeneration through its anti-inflammatory effect, which is mediated by suppressing Src tyrosine kinase and the downstream inflammatory signaling pathway. Furthermore, this study defines a critical role of Src tyrosine kinase in neuroinflammation, and suggests that particular tyrosine kinase inhibition may be a potential anti-inflammatory approach for PD treatment. PMID- 23916478 TI - Psychobiology of cocaine addiction: Contribution of a multi-symptomatic animal model of loss of control. AB - Transition to addiction is the shift from controlled to uncontrolled drug use that occurs after prolonged drug intake in a limited number of drug users. A major challenge of addiction research in recent years has been to develop models for studying this pathological transition. Toward this goal, a DSM-IV/5-based multi-symptomatic model of cocaine addiction has been developed in the rat. It is based on an operational translation of the main features of the disease. 1. Addiction is not just taking drug; it is a non-adaptive drug use: The procedure models addiction in relation to its clinical definition. 2. All drug users do not face the same individual risk of developing addiction: The model includes an individual-based approach. 3. Addiction develops after protracted periods of controlled drug use: This procedure allows for the study of the long-term shift from controlled drug use to addiction. We describe this model in detail and show how it can contribute to our understanding of the pathophysiology of cocaine addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23916479 TI - Iptakalim attenuates self-administration and acquired goal-tracking behavior controlled by nicotine. AB - Iptakalim is an ATP-sensitive potassium channel opener, as well as an alpha4beta2 containing nicotinic acetylcholine receptor (nAChR) antagonist. Pretreatment with iptakalim diminishes nicotine-induced dopamine (DA) and glutamate release in the nucleus accumbens. This neuropharmacological profile suggests that iptakalim may be useful for treatment of nicotine dependence. Thus, we examined the effects of iptakalim in two preclinical models. First, the impact of iptakalim on the interoceptive stimulus effect of nicotine was evaluated by training rats in a discriminated goal-tracking task that included intermixed nicotine (0.4 mg/kg, SC) and saline sessions. Sucrose was intermittently presented in a response independent manner only on nicotine sessions. On intervening test days, rats were pretreated with iptakalim (10, 30, 60 mg/kg, IP). Results revealed that iptakalim attenuated nicotine-evoked responding controlled by the nicotine stimulus in a dose-dependent manner. In a separate study, the impact of iptakalim on the reinforcing effects of nicotine was investigated by training rats to lever-press to self-administer nicotine (0.01 mg/kg/infusion) [Dosage error corrected]. Results revealed that pretreatment with iptakalim (1, 3, 6 mg/kg, IV) decreased nicotine intake (i.e., less active lever responding). Neither behavioral effect was due to a non-specific motor effect of iptakalim, nor to an ability of iptakalim to inhibit DA transporter (DAT) or serotonin transporter (SERT) function. Together, these finding support the notion that iptakalim may be an effective pharmacotherapy for increasing smoking cessation and a better understanding of its action could contribute to medication development. PMID- 23916480 TI - CB1 cannabinoid receptor-mediated aggressive behavior. AB - This study examined the role of cannabinoid CB1 receptors (CB1r) in aggressive behavior. Social encounters took place in grouped and isolated mice lacking CB1r (CB1KO) and in wild-type (WT) littermates. Cognitive impulsivity was evaluated in the delayed reinforcement task (DRT). Gene expression analyses of monoaminooxidase-A (MAO-A), catechol-o-methyl-transferase (COMT), 5 hydroxytriptamine transporter (5-HTT) and 5-HT1B serotonergic receptor (5HT1Br) in the median and dorsal raphe nuclei (MnR and DR, respectively) and in the amygdala (AMY) were performed by real time-PCR. Double immunohistochemistry studies evaluated COMT and CB1r co-localization in the raphe nuclei and in the cortical (ACo), basomedian (BMA) and basolateral (BLA) amygdaloid nuclei. The behavioral effects of the CB1r agonist ACEA (1 and 2 mg/kg) on aggression were also evaluated in isolated OF1 mice. CB1KO mice housed in groups showed higher levels of offensive aggression. Isolation increased aggressive behavior only in WT. In grouped CB1KO mice COMT gene expression was significantly higher in the MnR and DR, while MAO-A gene expression was lower in the MnR. Gene expression of 5HT1Br, COMT and MAO-A was higher in the amygdala of CB1KO mice. CB1r double immunohistochemistry revealed cytoplasmic-labeled COMT-ir cells in the raphe nuclei and in the ACo, BMA and BLA. CB1r immunolabeling was observed only in ACo, BMA and BLA, where it was localized in axons and buttons. The density of labeled processes increased in BLA. Acute administration of the CB1 agonist ACEA (2 mg/kg) significantly decreased the aggression levels of OF1 mice. These results suggest that CB1r plays an important role in social interaction and aggressive behavior. PMID- 23916482 TI - Differential regulation of Bdnf expression in cortical neurons by class-selective histone deacetylase inhibitors. AB - Histone deactylase (HDAC) inhibitors show promise as therapeutics for neurodegenerative and psychiatric diseases. Increased expression of brain-derived neurotrophic factor (BDNF) has been associated with memory-enhancing and neuroprotective properties of these drugs, but the mechanism of BDNF induction is not well understood. Here, we compared the effects of a class I/IIb selective HDAC inhibitor SAHA, a class I selective inhibitor MS-275, a class II selective inhibitor MC1568 and a HDAC6 selective inhibitor tubacin on Bdnf mRNA expression in rat primary neurons. We show that inhibition of class II HDACs resulted in rapid upregulation of Bdnf mRNA levels, whereas class I HDAC inhibition produced a markedly delayed Bdnf induction. In contrast to relatively slow upregulation of Bdnf transcripts, histone acetylation at BDNF promoters I and IV was rapidly induced by SAHA. Bdnf induction by SAHA and MS-275 at 24 h was sensitive to protein synthesis inhibition, suggesting that delayed Bdnf induction by HDAC inhibitors is secondary to changed expression of its regulators. HDAC4 and HDAC5 repressed Bdnf promoter IV activity, supporting the role of class II HDACs in regulation of Bdnf expression. In addition, we show a critical role for the cAMP/Ca2+ response element (CRE) in induction of Bdnf promoter IV by MS-275, MC1568, SAHA and sodium valproate. In contrast, MEF2-binding CaRE1 element was not necessary for promoter IV induction by HDAC inhibition. Finally, we show that similarly to Bdnf, the studied HDAC inhibitors differentially induced expression of neuronal activity-regulated genes c-fos and Arc. Together, our findings implicate class II HDACs in transcriptional regulation of Bdnf and indicate that class II selective HDAC inhibitors may have potential as therapeutics for nervous system disorders. PMID- 23916481 TI - Neurobiological mechanisms that contribute to stress-related cocaine use. AB - The ability of stressful life events to trigger drug use is particularly problematic for the management of cocaine addiction due to the unpredictable and often uncontrollable nature of stress. For this reason, understanding the neurobiological processes that contribute to stress-related drug use is important for the development of new and more effective treatment strategies aimed at minimizing the role of stress in the addiction cycle. In this review we discuss the neurocircuitry that has been implicated in stress-induced drug use with an emphasis on corticotropin releasing factor actions in the ventral tegmental area (VTA) and an important pathway from the bed nucleus of the stria terminalis to the VTA that is regulated by norepinephrine via actions at beta adrenergic receptors. In addition to the neurobiological mechanisms that underlie stress induced cocaine seeking, we review findings suggesting that the ability of stressful stimuli to trigger cocaine use emerges and intensifies in an intake dependent manner with repeated cocaine self-administration. Further, we discuss evidence that the drug-induced neuroadaptations that are necessary for heightened susceptibility to stress-induced drug use are reliant on elevated levels of glucocorticoid hormones at the time of cocaine use. Finally, the potential ability of stress to function as a "stage setter" for drug use - increasing sensitivity to cocaine and drug-associated cues - under conditions where it does not directly trigger cocaine seeking is discussed. As our understanding of the mechanisms through which stress promotes drug use advances, the hope is that so too will the available tools for effectively managing addiction, particularly in cocaine addicts whose drug use is stress-driven. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23916484 TI - Ciliary body and choroidal pseudomelanoma from ultrasonographic imaging of hypermature cataract in 20 cases. AB - PURPOSE: To describe a series of 20 patients with opaque media, referred with uveal melanoma, but subsequently found to have pseudomelanoma from oblique imaging of hypermature cataract on ultrasonography. DESIGN: Case series. PARTICIPANTS: Twenty patients. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Ultrasound imaging. RESULTS: All eyes had opaque media from hypermature cataract with no view of the fundus. All were referred because of suspected uveal melanoma, based on ultrasonographic imaging. The echogenic mass appeared to be in the ciliary body (n = 17) or choroid (n = 3). The median patient age was 54 years (range, 17-86 years). Most patients were white (n = 13) or black (n = 4). There was a history of eye trauma (n = 3) and ocular surgery (n = 1). Visual acuity was light perception to hand movements (n = 18) and 20/50 to 20/100 (n = 2). The cataract was in an anatomic position (n = 18) or subluxated (n = 2). On B-scan ultrasonography, the mass was dome-shaped (n = 10) or elliptical (n = 10), displayed an acoustically hollow center with a dense rim (n = 20), and was located in the ciliary body (n = 17) or choroid (n = 3). The mean thickness was 7.2 mm and the mean base was 9.3 mm. Features suggestive of cataract rather than melanoma included a lack of contiguity with the uvea (n = 20) on videoimaging using standard ultrasonography and ultrasound biomicroscopy, a lack of a transillumination shadow, and a lack of a sentinel vessel. For those in the ciliary body region, an additional feature was the ultrasonographic presence of mass in all 4 quadrants (n = 17), representing oblique imaging of the lens equator. For those in the choroid region, the pseudomelanoma shifted when the patient was imaged in a reclined compared with an upright position. After cataract surgery, the lack of melanoma was confirmed. CONCLUSIONS: Dense cataract can preclude a fundus view, necessitating ultrasonography for imaging the posterior segment of the eye. Ultrasonographic confusion with a ciliary body and choroidal melanoma can occur because the dome-shaped cataract can simulate a dome shaped melanoma. PMID- 23916483 TI - Cannabinoids in disguise: Delta9-tetrahydrocannabinol-like effects of tetramethylcyclopropyl ketone indoles. AB - Synthetic indole-derived cannabinoids have become commonly used recreational drugs and continue to be abused despite their adverse consequences. As compounds that were identified early in the epidemic (e.g., naphthoylindoles) have become legally banned, new compounds have appeared on the drug market. Two tetramethylcyclopropyl ketone indoles, UR-144 [(1-pentyl-1H-indol-3-yl)-(2,2,3,3 tetramethylcyclopropyl)methanone] and XLR-11 [(1-(5-fluoropentyl)-1H-indol-3-yl) (2,2,3,3-tetramethylcyclopropyl)methanone], recently have been identified in confiscated products. These compounds are structurally related to a series of CB2 selective compounds explored by Abbott Labs. The purpose of the present study was to evaluate the extent to which UR-144 and XLR-11 shared cannabinoid effects with Delta9-tetrahydrocannabinol (Delta9-THC). Indices of in vitro and in vivo activity at cannabinoid receptors were assessed. Similar to other psychoactive cannabinoid agonists, XLR-11 and UR-144 showed low nanomolar (<30) affinity for CB1 and CB2 receptors, activated these receptors as full agonists, and produced dose-dependent effects that were blocked by rimonabant in mice, including antinociception, hypothermia, catalepsy and suppression of locomotor activity. The potency of both compounds was several-fold greater than Delta9-THC. XLR-11 and UR-144 also substituted for Delta9-THC in a Delta9-THC discrimination procedure in mice, effects that were attenuated by rimonabant. Analysis of urine from mice treated with the compounds revealed that both were extensively metabolized, with predominant urinary excretion as glucuronide conjugates. Together, these results demonstrate that UR-144 and XLR-11 share a pharmacological profile of in vitro and in vivo effects with Delta9-THC and other abused indole-derived cannabinoids and would be predicted to produce Delta9-THC like subjective effects in humans. PMID- 23916485 TI - Bupivacaine injection remodels extraocular muscles and corrects comitant strabismus. AB - PURPOSE: To evaluate the clinical effectiveness and anatomic changes resulting from bupivacaine injection into extraocular muscles to treat comitant horizontal strabismus. DESIGN: Prospective, observational clinical series. PARTICIPANTS: Thirty-one comitant horizontal strabismus patients. METHODS: Nineteen patients with esotropia received bupivacaine injections in the lateral rectus muscle, and 12 patients with exotropia received bupivacaine injections in the medial rectus. Sixteen of these, with large strabismus angles, also received botulinum type A toxin injections in the antagonist muscle at the same treatment session. A second treatment was given to 13 patients who had residual strabismus after the first treatment. MAIN OUTCOME MEASURES: Clinical alignment measures and muscle volume, maximum cross-sectional area, and shape derived from magnetic resonance imaging, with follow-up examinations for up to 3 years. RESULTS: At an average of 15.3 months after the final treatment, original misalignment was reduced by 10.5 prism diopters (Delta; 6.0 degrees ) with residual deviations of 10Delta or less in 53% of patients. A single treatment with bupivacaine alone reduced misalignment at 11.3 months by 4.7Delta (2.7 degrees ) with residual deviations of 10Delta or less in 50% of patients. Alignment corrections were remarkably stable over follow ups for as long as 3 years. Six months after bupivacaine injection, muscle volume had increased by 6.6%, and maximum cross-sectional area had increased by 8.5%, gradually relaxing toward pretreatment values thereafter. Computer modeling with Orbit 1.8 (Eidactics, San Francisco, CA) suggested that changes in agonist and antagonist muscle lengths were responsible for the enduring changes in eye alignment. CONCLUSIONS: Bupivacaine injection alone or together with botulinum toxin injection in the antagonist muscle improves eye alignment in comitant horizontal strabismus by inducing changes in rectus muscle structure and length. PMID- 23916486 TI - Subgrouping of primary angle-closure suspects based on anterior segment optical coherence tomography parameters. AB - PURPOSE: To identify subgroups of primary angle-closure suspects (PACS) based on anterior segment optical coherence tomography (AS-OCT) and biometric parameters. DESIGN: Cross-sectional study. PARTICIPANTS: We evaluated 243 PACS subjects in the primary group and 165 subjects in the validation group. METHODS: Participants underwent gonioscopy and AS-OCT (Carl Zeiss Meditec, Dublin, CA). Customized software (Zhongshan Angle Assessment Program, Guangzhou, China) was used to measure AS-OCT parameters. An agglomerative hierarchical clustering method was first used to determine the optimum number of parameters to be included in the determination of subgroups. The best number of subgroups was then determined using Akaike Information Criterion (AIC) and Gaussian Mixture Model (GMM) methods. MAIN OUTCOME MEASURES: Subgroups of PACS. RESULTS: The mean age of the subjects was 64.8 years, and 65.02% were female. After hierarchical clustering, 1 or 2 parameters from each cluster were chosen to ensure representativeness of the parameters and yet keep a minimum of redundancy. The parameters included were iris area, anterior chamber depth (ACD), anterior chamber width (ACW), and lens vault (LV). With the use of GMM, the optimal number of subgroups as given by AIC was 3. Subgroup 1 was characterized by a large iris area, subgroup 2 was characterized by a large LV and a shallow ACD, and subgroup 3 was characterized by elements of both subgroups 1 and 2. The results were replicated in a second independent group of 165 PACS subjects. CONCLUSIONS: Clustering analysis identified 3 distinct subgroups of PACS subjects based on AS-OCT and biometric parameters. These findings may be relevant for understanding angle-closure pathogenesis and management. PMID- 23916487 TI - Resident compliance with the american academy of ophthalmology preferred practice pattern guidelines for primary open-angle glaucoma. AB - PURPOSE: To examine resident adherence to preferred practice pattern (PPP) guidelines set up by the American Academy of Ophthalmology for follow-up care of primary open-angle glaucoma (POAG) patients. DESIGN: Retrospective chart review. PARTICIPANTS: One hundred three charts were selected for analysis from all patients with an International Classification of Diseases, Ninth Revision, code of open-angle glaucoma or its related entities who underwent a follow-up evaluation between July 2, 2003, and December 15, 2004, at the resident ophthalmology clinic in the Durham Veteran Affairs Medical Center. METHODS: Follow-up visits of POAG patients were evaluated for documentation of 19 elements in accordance to PPP guidelines. MAIN OUTCOME MEASURES: Compliance rates for the 19 elements of PPP guidelines first were averaged in all charts, and then were averaged per resident and were compared among 8 residents between their first and second years of residency. RESULTS: The overall mean compliance rate for all 19 elements was 82.6% for all charts (n = 103), 78.8% for first-year residents, and 81.7% for second-year residents. The increase from first to second year of residency was not significant (P>0.05). Documentation rates were high (>90%) for 14 elements, including all components of the physical examination and follow-up as well as most components of the examination history and management plan. Residents documented adjusting target intraocular pressure downward, local or systemic problems with medications, and impact of visual function on daily living approximately 50% to 80% of the time. Documentation rates for components of patient education were the lowest, between 5% and 16% in all charts. CONCLUSIONS: Residents' compliance with PPP guidelines for a POAG follow-up visit was very high for most elements, but documentation rates for components of patient education were poor. Adherence rates to PPP guidelines can be used as a tool to evaluate and improve resident performance during training. However, further studies are needed to establish the advantages of using PPP guidelines for resident education and to determine if such assessments can lead to improved patient care. PMID- 23916488 TI - Ranibizumab versus Bevacizumab for Neovascular Age-related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial. AB - OBJECTIVE: To evaluate the relative efficacy and safety profile of bevacizumab versus ranibizumab intravitreal injections for the treatment of neovascular age related macular degeneration (AMD). DESIGN: Multicenter, prospective, noninferiority, double-masked, randomized clinical trial performed in 38 French ophthalmology centers. The noninferiority limit was 5 letters. PARTICIPANTS: Patients aged >=50 years were eligible if they presented with subfoveal neovascular AMD, with best-corrected visual acuity (BVCA) in the study eye of between 20/32 and 20/320 measured on the Early Treatment of Diabetic Retinopathy Study chart and a lesion area of less than 12 optic disc areas (DA). METHODS: Patients were randomly assigned to intravitreal administration of bevacizumab (1.25 mg) or ranibizumab (0.50 mg). Hospital pharmacies were responsible for preparing, blinding, and dispensing treatments. Patients were followed for 1 year, with a loading dose of 3 monthly intravitreal injections, followed by an as needed regimen (1 injection in case of active disease) for the remaining 9 months with monthly follow-up. MAIN OUTCOME MEASURES: Mean change in visual acuity at 1 year. RESULTS: Between June 2009 and November 2011, 501 patients were randomized. In the per protocol analysis, bevacizumab was noninferior to ranibizumab (bevacizumab minus ranibizumab +1.89 letters; 95% confidence interval [CI], -1.16 to +4.93, P < 0.0001). The intention-to-treat analysis was concordant. The mean number of injections was 6.8 in the bevacizumab group and 6.5 in the ranibizumab group (P = 0.39). Both drugs reduced the central subfield macular thickness, with a mean decrease of 95 MUm for bevacizumab and 107 MUm for ranibizumab (P = 0.27). There were no significant differences in the presence of subretinal or intraretinal fluid at final evaluation, dye leakage on angiogram, or change in choroidal neovascular area. The proportion of patients with serious adverse events was 12.6% in the bevacizumab group and 12.1% in the ranibizumab group (P = 0.88). The proportion of patients with serious systemic or ocular adverse events was similar in both groups. CONCLUSIONS: Bevacizumab was noninferior to ranibizumab for visual acuity at 1 year with similar safety profiles. Ranibizumab tended to have a better anatomic outcome. The results are similar to those of previous head-to-head studies. PMID- 23916489 TI - Purification of eukaryotic tetherin/Vpu proteins and detection of their interaction by ELISA. AB - Tetherin/BST-2/CD317 inhibits HIV-1 release from infected cells, while HIV-1 Vpu efficiently antagonizes tetherin based on intermolecular interactions between the transmembrane domains of each protein. In this study, we successfully partially purified His-tagged tetherin with a glycophosphatidylinositol deletion (delGPI) and His-tagged full-length Vpu from transiently transfected 293T cells using affinity chromatography. The in vitro interaction between these purified proteins was observed by a pull-down assay and ELISA. Detection of the Vpu/tetherin interaction by ELISA is a novel approach that would be advantageous for inhibitor screening in vitro. Successful co-purification of the tetherin/Vpu complex also provides a basis for further structural studies. PMID- 23916490 TI - Expression regulation of zebrafish interferon regulatory factor 9 by promoter analysis. AB - We previously showed that a fish interferon (IFN) regulatory factor 9 (IRF9) homologue, crucian carp Carassius auratus IRF9, displays constitutively nuclear localization and involvement in fish IFN-dependent JAK-STAT signaling; however, little is known about the expression regulation of fish IRF9. Here, we characterized the expression of zebrafish IRF9 by promoter analysis. Zebrafish IRF9 gene promoter contained several putative transcription factor binding sites, including one ISRE (IFN-stimulated response element), one GAS (IFN gamma activation sequence) and three GATEs (IFNgamma activated transcriptional element, GATE1/2/3). Further sequence analyses revealed that GAS and GATE motifs existed in all promoters of IRF9 from mammals and fishes. Luciferase assays confirmed that zebrafish IRF9 promoter could be activated by zebrafish IFNphis and zebrafish IFNgamma2, as well as transcription factors IRF3, IRF7, and combination of IRF9 and STAT2. Treatment of recombinant crucian carp IFN protein or overexpression of zebrafish IFNgamma2 both led to significant increase in crucian carp IRF9 mRNA and protein in cultured fish cells. Comparison of IFN-stimulated promoter activity revealed much more significant induction of zebrafish IRF9 by zebrafish IFNgamma2 than by zebrafish IFNphis. Mutation analyses showed that the putative GAS and GATE3 contributed to zebrafish IFNgamma2-triggered IRF9 expression, whereas the putative ISRE and the other two GATEs were not functional for induction of zebrafish IRF9. These results together indicated that the expression property of IRF9 might be conserved from fish to mammals and that some not yet identified mechanisms could exist in IRF9 gene transcription regulation in response to IFNs. PMID- 23916491 TI - Involvement of Ran in the regulation of phagocytosis against virus infection in S2 cells. AB - Phagocytosis plays important roles in innate and adaptive immunity in animals. Some small G proteins are found to be related to phagocytosis. However, the Ran GTPase has not been intensively characterized in immunity. In this paper, the sequence analysis showed that the Ran was highly conserved in animals, suggesting that its function was preserved during animal evolution. The results showed that Ran was upregulated in S2 cells in response to DCV infection. It was further revealed that the antiviral phagocytosis could be mediated by Ran in S2 cells. By comparison with the early marker and late marker of phagosomes, the results showed that the Ran protein played an essential role at the early stage of phagocytosis or throughout the entire phagocytic process. Therefore our findings enlarged our limited knowledge about the phagocytosis regulation by small G proteins concerning to the nucleus. PMID- 23916492 TI - 21-hydroxylase deficiency in the neonate - trends in steroid anabolism and catabolism during the first weeks of life. AB - Deficiency of 21-hydroxylase provides an in vivo model of intrauterine induction of enzymes participating in steroid anabolism and catabolism. Quantitative data for 93 steroid metabolites in urine from 111 patients and 7 controls (25 samples) were compared over the first six weeks of life. Net flux through the key anabolic enzymes was examined by comparison of the totals of steroids derived from the intermediates prior to and following each enzymatic step. Metabolic relationships were established on structural grounds and by Pearson correlation. The relative importance of each catabolic route was evaluated after summing metabolites classified according to their structure as fetal, neonatal, and classical (adult) type. Hierarchical cluster analysis identified the structure at C3-C5 as a key distinguishing feature of the major catabolic streams and demonstrated a split point in metabolic pattern in patients at 7 days. Changes with time in steroid metabolism, larger in patients than in controls, could be interpreted as reflecting increased cortisol demand post partum, the clinical onset of salt wasting and a transition in catabolism from fetal to postnatal life. Faster involution of the fetal zone and pronounced enhancement of steroid production in zona fasciculata and zona glomerulosa were indicated in patients. Predominant at birth were 'planar' fetal-type 5alpha-reduced metabolites, adapted to placental excretion, which gave way to additionally hydroxylated neonatal-type metabolites, facilitating renal excretion. Classical metabolism made gains over the study period. Overproduction of steroids in utero in 21-hydroxylase deficiency would have induced fetal catabolic pathways dependent on 5alpha-reduction. A progressive increase of steroids likely to arise from 5alpha-reductase type 2 activity, again more distinct in disease, was observed. We demonstrate that the key intermediates in the hypothetical 'backdoor' pathway of androgen synthesis are part of a broader catabolic network and should not be examined in isolation. PMID- 23916493 TI - From Incan time to today, the unresolved problem of cranioplasty. PMID- 23916494 TI - Perspectives on the evolution of endovascular treatment of carotid cavernous fistulas. PMID- 23916495 TI - The effect of surgical level on self-reported clinical outcomes after minimally invasive transforaminal lumbar interbody fusion: L4-L5 versus L5-S1. AB - OBJECTIVE: The anatomic and biomechanical aspects of the L5-S1 level present unique operative challenges compared with the L4-L5 level. However, it has not been determined if self-reported outcomes and complications are different between patients treated with a minimally invasive transforaminal lumbar interbody fusion at these specific levels. METHODS: There were 36 consecutive patients identified who were treated with a minimally invasive transforaminal lumbar interbody fusion procedure. Surgical indications included spondylolisthesis (grade 1 or 2) and degenerative disk disease with associated clinical symptoms. Patients completed a visual analog scale (VAS) for their back and leg and Oswestry Disability Index preoperatively and postoperatively. Outcomes were compared between patients with L4-L5 involvement and patients with L5-S1 involvement. In all patients, fusion was evaluated by dynamic view flexion and extension views at 1 year. In all patients with indeterminate results or incomplete imaging, computed tomography was performed to evaluate for bridging bone and stable hardware positioning. RESULTS: The surgical indications between the 2 groups were similar (chi(2) = 0.089, df = 2, P = 0.956). There was no significant difference in mean operating time, intraoperative blood loss, and hospital stay (P = 0.937, 0.627, and 0.587). There was no significant difference in the long-term postoperative questionnaire results (P = 0.819 for VAS [back], 0.626 for VAS [leg], and 0.962 for Oswestry Disability Index) or the mean preoperative to postoperative change in Cobb angle (P = 0.626) between the 2 groups. Two complications, one in each group, were a rash from an antibiotic and postoperative nausea. CONCLUSIONS: Despite differences in biomechanics and unique anatomic challenges at the L5-S1 interspace, there is no difference in self-reported outcomes for patients treated with minimally invasive transforaminal lumbar interbody fusion at the L4-L5 level compared with the L5-S1 level. PMID- 23916496 TI - Surgery of the mind, mood, and conscious state: an idea in evolution. AB - Since the beginning of recorded history, humans have sought a physical means of altering disordered behavior and consciousness. This quest has spawned numerous innovations in neurosurgery and the neurosciences, from the earliest prehistoric attempts at trepanation to the electrocortical and anatomic localization of cerebral function that emerged in the 19th century. At the start of the 20th century, the overwhelming social impact of psychiatric illness intersected with the novel but imperfect understanding of frontal lobe function, establishing a decades-long venture into the modern origin of psychosurgery, the prefrontal lobotomy. The subsequent social and ethical ramifications of the widespread overuse of transorbital lobotomies drove psychosurgery to near extinction. However, as the pharmacologic treatment of psychiatric illness was established, numerous concomitant technical and neuroscientific innovations permitted the incremental development of a new paradigm of treating the disordered mind. In this article, we retrospectively examine these early origins of psychosurgery and then look to the recent past, present, and future for emerging trends in surgery of the psyche. Recent decades have seen a revolution in minimalism, noninvasive imaging, and functional manipulation of the human cerebrum that have created new opportunities and treatment modalities for disorders of the human mind and mood. Early contemporary efforts were directed at focal lesioning of abnormal pathways, but deep-brain stimulation now aims to reversibly alter and modulate those neurologic activities responsible for not only psychiatric disorders, but also to modulate and even to augment consciousness, memory, and other elements of cerebral function. As new tools become available, the social and medical impact of psychosurgery promises to revolutionize not only neurosurgery, but also humans' capability for positively impacting life and society. PMID- 23916497 TI - Infected intracranial meningiomas. AB - OBJECTIVE: Infection associated with an intracranial meningioma is an extremely rare condition. Only six cases have been described in the literature. Because of its dual pathologies, initial radiologic diagnosis can be difficult. We present the first reported case of multiple infected intracranial meningiomas and correlate the radiologic and histologic findings. METHODS: A 70-year-old woman presented with sepsis and a left hemiparesis following ureteroscopy and lithotripsy. A large right parietal lesion and a smaller left frontal lesion were diagnosed on magnetic resonance imaging. Diffusion-weighted imaging and an apparent diffusion coefficient map demonstrated features of cerebral metastases. RESULTS: A 2-stage excision confirmed atypical meningiomas containing an intratumoral abscess secondary to Escherichia coli. The patient made a full neurologic recovery. Despite the additional techniques, the radiologic diagnosis was initially challenging because of the dual pathologies. Nonetheless, the radiologic appearance was consistent with the complex histologic findings. CONCLUSIONS: In the appropriate clinical context, diffusion-weighted imaging and apparent diffusion coefficient map aid the diagnosis of infected intracranial meningiomas. PMID- 23916498 TI - Clinical applications of diffusion tensor imaging. AB - Advancements in diffusion-weighted imaging during the past decade have led to the use of diffusion tensor imaging to further characterize the structural integrity of neural tissue and to noninvasively trace neuronal tracts in the brain and spine. This has led to many clinical applications that have aided in surgical planning for brain and spinal cord tumors and has increased the diagnostic potential of magnetic resonance imaging in disorders such as multiple sclerosis, Alzheimer disease, and traumatic brain injury. PMID- 23916499 TI - Olfactory colloid cyst: case report and review of extraventricular colloid cyst literature. AB - OBJECTIVE: A rare case of an extraventricular colloid cyst located in the olfactory groove extending downward into the ethmoid sinus is presented. This is the second reported case in the world literature. METHODS: A 56-year-old-woman presented with a lesion that was causing hyposmia and cerebrospinal fluid rhinorrhea. The lesion was an extraventricular colloid cyst displacing the left olfactory nerve downward and eroding into the left ethmoid sinus. RESULTS: The lesion was excised, and the anterior skull base was reconstructed successfully via a unilateral subfrontal approach. CONCLUSIONS: There were no complications, and the patient made a full recovery, with resolution of the cerebrospinal fluid rhinorrhea. PMID- 23916500 TI - Seasonal variability of glycated hemoglobin in a diabetic population from southern Europe. AB - AIMS: To analyze the seasonal variations in A1c levels among a southern European diabetic population. METHODS: We examined all monthly-grouped A1c determinations from diabetic patients during the period 2006-2011, in a region of southern Spain. RESULTS: There were 61,329 records available. The mean A1c value was 56mmol/mol (7.2%+/-1.7%) (95% CI, 55-56mmol/mol (7.2%-7.3%), with a range of 0.2%. The highest value was in February and the lowest in July (56mmol/mol (7.3%) and 54mmol/mol (7.1%), respectively) (P<0.01). However, spectral analysis and correlation coefficients did not reach significance, and the series presented no seasonal pattern. CONCLUSIONS: In our area, although the A1C levels have some monthly fluctuation they show no significant seasonal pattern. Thus, the seasonal fluctuation of HbA1c is not a limitation for decision making in clinical practice. PMID- 23916501 TI - What is sarcoidosis? PMID- 23916502 TI - Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD. AB - BACKGROUND: Aclidinium is a novel, long-acting muscarinic antagonist indicated for maintenance treatment of COPD. METHODS: In this 52-week, parallel-group, double-blind study, patients with moderate-to-severe COPD were randomized (1:1) to receive aclidinium twice-daily (BID) 200 MUg or 400 MUg via a novel, dry powder inhaler (Genuair((r))/Pressair((r))) [Registered trademarks of Almirall, SA, Barcelona, Spain for use within the European Union, Iceland, Norway, and Switzerland as Genuair((r)) and within the United States as Pressair((r))]. Safety, the primary objective, was assessed via adverse events (AEs), clinical laboratory tests, vital signs, and 12-lead electrocardiograms. Efficacy was evaluated using spirometry, SGRQ, and rescue medication use. RESULTS: A total of 605 patients were randomized in the study. The percentage of patients reporting any treatment-emergent AE (TEAE) was comparable between groups; most TEAEs were mild or moderate. Anticholinergic TEAEs were reported by low percentages of patients in either treatment group (dry mouth: 200 MUg, 1.3%; 400 MUg, 2.7%; constipation: 200 MUg, 2.9%; 400 MUg, 1.7%). Cardiac TEAEs were also reported by a low percentage of patients (<2% for any event in any group) and did not appear to be dose dependent. There were no clinically relevant abnormalities in other safety outcomes. Both aclidinium 200 MUg and 400 MUg resulted in improvements from baseline to Week 52 in FEV1, with numerically greater increases observed with the higher dose. Clinically important improvements in SGRQ scores and a reduction in rescue medication use were observed throughout the study for both doses. CONCLUSIONS: Long-term treatment with aclidinium 200 MUg or 400 MUg BID was well tolerated, with sustained benefits in lung function and health status in patients with COPD throughout the 1-year study. PMID- 23916503 TI - Bivalirudin in acute coronary syndromes and percutaneous coronary intervention: should we use it? AB - Major bleeding remains a major risk factor for percutaneous coronary intervention of acute coronary syndromes and is associated with higher morbidity, mortality, prolonged hospital stay and costs. With the recognition that bleeding is an important factor in patient outcomes, the prevention of bleeding has become as important a goal as the prevention of ischaemia. The direct thrombin inhibitor bivalirudin has been shown to reduce ischaemia and importantly, is associated with less bleeding. In this article we review the evidence base that supports the use of bivalirudin across all spectrums of coronary syndromes and percutaneous coronary intervention. An algorithm for the use of bivalirudin in high risk subgroups and coronary syndromes is suggested. PMID- 23916504 TI - Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism. AB - We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) <=0.1mg/kg (~80% 5-HT3 receptor occupancy; OR) and <=3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ~15%, 60%, 95%) in SA. Ondansetron exhibited a MED <=3.0MUg/kg (~25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED <=1.0mg/kg (~25% 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism. PMID- 23916505 TI - Alterations to the circuitry of the frontal cortex following exposure to the polybrominated diphenyl ether mixture, DE-71. AB - Recent studies have identified exposure to polybrominated diphenyl ethers (PBDEs) as a risk factor for deficits in cognitive functioning seen in children as well as adults. Additionally, similar alterations in learning and memory have also been observed in animal models of PBDE exposure. However, given these findings, the molecular alterations that may underlie these neurobehavioral endpoints have not been identified. As the frontal cortex is involved in modulating several cognitive functions, the purpose of our study was to investigate the possible changes to the GABAergic and glutamatergic neurotransmitter systems located in the frontal cortex following exposure to the PBDE mixture, DE-71. Primary cultured neurons isolated from the frontal cortex showed a dose-dependent reduction in neurons as well as neurite outgrowth. Furthermore, evaluation of DE 71 neurotoxicity in the frontal cortex using an in vivo model showed alterations to specific proteins involved in mediating GABA and glutamate neurotransmission, including GAD67, vGAT, vGlut, and GABA(A) 2alpha receptor subunit. Interestingly, these alterations appeared to be preferential for the GABA and glutamate systems located in the frontal cortex. These findings identify specific targets of PBDE neurotoxicity and provide a possible molecular mechanism for PBDE-mediated neurobehavioral deficits that arise from the frontal cortex. PMID- 23916506 TI - Induction of protection against leishmaniasis in susceptible BALB/c mice using simple DOTAP cationic nanoliposomes containing soluble Leishmania antigen (SLA). AB - A suitable adjuvant and delivery system are needed to develop an effective vaccine against leishmaniasis. To induce a Th1 type of response and protection in BALB/c mice against Leishmania major infection, 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) nanoliposomes bearing an intrinsic adjuvanticity, were used as an antigen delivery system and immunoadjuvant for soluble Leishmania antigens (SLA). DOTAP liposomes containing different concentrations of SLA were prepared by using lipid film method followed by sonication. The prepared vesicles showed a diameter of about 100nm, a positive zeta potential and approximately 70% encapsulation efficiency of SLA. BALB/c mice were immunized subcutaneously (SC), three times in a 3-week interval with different concentrations of liposomal SLA (12.5, 25, and 50MUg of SLA/50MUl/mice), free SLA and as well as free liposome. The group of mice received 50MUg of SLA in DOTAP-nanoliposomes showed a significantly (p<0.001) smaller footpad swelling and the lowest spleen and footpad parasite burden after the challenge. This group also showed the highest IFN-gamma production compared to the other groups, lower IL-4 level and higher IgG2a antibody titer. Taken together, the results indicated that simple DOTAP nanoliposome containing 1MUg/MUl SLA are appropriate delivery systems to induce a Th1 type of immune response and protection against L. major infection in BALB/c mice. PMID- 23916507 TI - Evaluating the developmental toxicity of trypanocidal nitroaromatic compounds on zebrafish. AB - Current therapies against African and American trypanosomiasis are problematic and with no immediate prospect of a vaccine there is an urgent need for cheap, more effective treatments. To aid the drug discovery pipeline, we report a novel in vivo screening approach using zebrafish (Danio rerio) embryos as a means of rapidly assessing a compounds developmental toxicity. This technique, amenable to high-throughput screening, was validated using several trypanocidal nitroaromatic prodrugs including nifurtimox and benznidazole. PMID- 23916508 TI - Detection and chronology of parasitic kinetoplast DNA presence in hair of experimental Leishmania major infected BALB/c mice by Real Time PCR. AB - Hair can accumulate foreign chemical or biological substances. Recently, it has been reported that parasite DNA can also be detected in the hair of Leishmania infantum infected dogs. The aim of this work has been to find out whether parasite DNA incorporates in the hair of Leishmania major experimentally infected animals. For this purpose, a group of 4 BALB/c mice, intradermally inoculated in both ears with 1000 L. major V1 strain promastigote forms, was monitored for parameters associated to the infection during 35 days. Weekly, ear swelling was measured, and hair samples from ears and leg were collected. Blood samples were obtained before challenge and at day 35 post infection, when parasite load was measured in ear, lymph node and spleen by limit dilution. Ear swelling and other parameters observed in the infected mice were consistent with those described for this model. The presence of parasite kinetoplast DNA (kDNA) was detected by Real Time PCR in all ear and leg hair samples at the final timepoint. These data suggests that hair is a specialized tissue in the sequestration and removal of foreign DNA. Detection of DNA in hair could be, therefore, a useful tool to chronologically record the infection process during experimental mice assays. PMID- 23916509 TI - Functional expression of TRPV1 and TRPA1 in rat vestibular ganglia. AB - Both TRPV1 and TRPA1 are non-selective cation channels. They are co-expressed, and interact in sensory neurons such as dorsal root ganglia (DRG) and trigeminal ganglia (TG), and are involved in nociception, being activated by nociceptive stimuli. Immunohistological localization of TRPV1 in vestibular ganglion (VG) neurons has been reported. Although TRPA1 is co-expressed with TRPV1 in DRG and TG neurons, it is unclear whether TRPA1 channels are expressed in VG neurons. Moreover, it is unknown whether TRPV1 and TRPA1 channels are functional in VG neurons. We investigated the expression of TRPV1 and TRPA1 in rat VG neurons by RT-PCR, in situ hybridization, immunohistochemistry, and Ca(2+) imaging experiments. Both TRPV1 and TRPA1 RT-PCR products were amplified from the mRNA of rat VG neurons. In situ hybridization experiments showed TRPV1 and TRPA1 mRNA expression in the majority of VG neurons. Immunohistochemistry experiments confirmed TRPV1 protein expression. In Ca(2+) imaging experiments, capsaicin, a TRPV1 agonist, induced a significant increase in intracellular calcium ion concentration ([Ca(2+)]i) in rat primary cultured VG neurons, which was almost completely blocked by capsazepine, a TRPV1-specific antagonist. Cinnamaldehyde, a TRPA1 agonist, also caused an increase in [Ca(2+)]i, which was completely inhibited by HC030031, a TRPA1-specific antagonist. Moreover, in some VG neurons, a [Ca(2+)]i increase was evoked by both capsaicin and cinnamaldehyde in the same neuron. In summary, our histological and physiological studies reveal that TRPV1 and TRPA1 are expressed in VG neurons. It is suggested that TRPV1 and TRPA1 in VG neurons might participate in vestibular function and/or dysfunction such as vertigo. PMID- 23916510 TI - Patella fracture after medial patellofemoral ligament reconstruction using suture anchors. AB - The medial patellofemoral ligament (MPFL) acts as a soft tissue restraint to lateral subluxation of the patella, and is frequently damaged following patellar dislocation. A number of techniques for repair or reconstructions of the MPFL have been reported. We report two cases of patellar fracture following MPFL reconstruction utilizing suture anchors and bone tunnels that do not completely traverse the patella. The first case occurred seven months after surgery and the second case was at six weeks following surgery. There have been previous reports of patellar fracture following MPFL reconstruction, particularly when patellar tunnels completely traverse the patella. The authors decided to use suture anchors to reduce the risk of patellar fracture, and they feel that the fractures reported in this paper resulted from surgical error rather than system error. We feel that this is an important learning point when initially using this technique, and should be disseminated to other surgeons who undertake this surgery. PMID- 23916511 TI - Is it over-respectful or disrespectful? Differential patterns of brain activity in perceiving pragmatic violation of social status information during utterance comprehension. AB - A critical issue in the study of language communication is how extra-linguistic information, such as the social status of the communicators, is taken into account by the online comprehension system. In Mandarin Chinese, the second person pronoun (you/your) can be in a respectful form (nin/nin-de) when the addressee is of higher status than the speaker or in a less respectful form (ni/ni-de) when the addressee is of equal or lower status. We conducted an event related potential (ERP) study to investigate how social status information affects pronoun resolution during utterance comprehension. Participants read simple conversational scenarios for comprehension, with each scenario including a context describing a speaker and an addressee and a directly-quoted utterance beginning with the second-person pronoun. The relative status between the speaker and the addressee was varied, creating conditions in which the second-person pronoun was either consistent or inconsistent with the relationship between conversants, or in which the two conversants were of equal status. ERP results showed that, compared with the status-consistent and status-equal conditions, the status-inconsistent condition elicited an anterior N400-like effect on nin-de (over-respectful) and a broadly distributed N400 on ni-de (disrespectful). In a later time window, both the status-reversed and the status-equal conditions elicited a sustained positivity effect on nin-de and a sustained negativity effect on ni-de. These findings suggest that the comprehender builds up expectance towards the upcoming pronoun based on the perceived social status of conversants. While the inconsistent pronoun causes semantic integration difficulty in an earlier stage of processing, the strategy to resolve the inconsistency and the corresponding brain activity vary according to the pragmatic implications of the pronoun. PMID- 23916512 TI - Experience of action depends on intention, not body movement: an experiment on memory for mens rea. AB - How do we know whether our own actions were voluntary or involuntary? Intentional theories of sense of agency suggest that we consciously perceive the intentions that accompany our actions, but reconstructive theories suggest that we perceive our actions only through the body movements and other effects that they produce. Intentions would then be mere confabulations, and not bona fide experiences. Previous work on voluntary action has focused on immediate experiences of authorship, and few studies have considered memory for voluntary actions. We devised an experiment in which both voluntary action and involuntary movement always occurred at the same time, but could either involve the same hand (congruent condition), or different hands (incongruent condition). When signals from the voluntary and involuntary movements involved different hands, they could therefore potentially interfere in memory. We found that recall of a voluntary action was unaffected by an incongruent involuntary movement. In contrast, recall of an involuntary movement was strongly influenced by an incongruent voluntary action. Our results demonstrate an "intentional capture" of body movement by voluntary actions, in support of intentional theories of agency, but contrary to reconstructive theories. When asked to recall both actions and movements, people's responses are shaped by memory of what they intended to do, rather than by how their body moved. PMID- 23916513 TI - Modular peptide binding: from a comparison of natural binders to designed armadillo repeat proteins. AB - Several binding scaffolds that are not based on immunoglobulins have been designed as alternatives to traditional monoclonal antibodies. Many of them have been developed to bind to folded proteins, yet cellular networks for signaling and protein trafficking often depend on binding to unfolded regions of proteins. This type of binding can thus be well described as a peptide-protein interaction. In this review, we compare different peptide-binding scaffolds, highlighting that armadillo repeat proteins (ArmRP) offer an attractive modular system, as they bind a stretch of extended peptide in a repeat-wise manner. Instead of generating each new binding molecule by an independent selection, preselected repeats - each complementary to a piece of the target peptide - could be designed and assembled on demand into a new protein, which then binds the prescribed complete peptide. Stacked armadillo repeats (ArmR), each typically consisting of 42 amino acids arranged in three alpha-helices, build an elongated superhelical structure which enables binding of peptides in extended conformation. A consensus-based design approach, complemented with molecular dynamics simulations and rational engineering, resulted in well-expressed monomeric proteins with high stability. Peptide binders were selected and several structures were determined, forming the basis for the future development of modular peptide-binding scaffolds. PMID- 23916514 TI - Operative care and surveillance in severe trauma patients. Interference between resuscitation treatments and anaesthesiology, and consequence on immunity. AB - Major trauma remains a worldwide cause of morbi-mortality. Early mortality is the consequence of hemorrhagic shock and traumatic brain injury. During early resuscitation, anaesthesia is often mandatory to perform surgery. It is mandatory to master the hemodynamic effects of hypnotic drugs in order to anticipate their potential deleterious effects in the setting of hemorrhagic shock. After early resuscitation, trauma patients present a high prevalence of nosocomial pneumonia, which sustains major morbidity. Nosocomial pneumonia are the consequence of an overwhelming systemic inflammatory response syndrome (SIRS) as well as a trauma related immunosuppression. The administration of hemisuccinate of hydrocortisone modulates the SIRS and reduces the risk of nosocomial pneumonia as well as the length of mechanical ventilation. Finally in the operating theatre, fighting against hypothermia and un-anatomical positions, which can aggravate rhabdomyolysis, are both mandatory. PMID- 23916515 TI - Trauma-induced coagulopathy. AB - Hemorrhage is the leading cause of death in trauma patients who arrive alive at hospital. This type of hemorrhage has a "coagulopathic" component, specific to major trauma and associated with poor outcomes. Over the last decade, a better understanding of this trauma-induced coagulopathy lead to a new therapeutic approach requiring earlier and more aggressive management. This hemostatic resuscitation includes early activation of massive transfusion protocols with: 1) immediate delivery of blood packs with high ratios for RBC units: fresh frozen plasma: platelet-concentrates; 2) antifibrinolytics; 3) substitution of coagulation factors. However, early identification of coagulopathic patients requiring aggressive hemostatic resuscitation remains challenging, with an increasing role of point of care devices for hemostatic diagnosis and monitoring. Efforts have to be focused on the early diagnosis of coagulopathy for immediate delivery of blood products and coagulation factors to the right, accurately screened patients through pre-established protocols within the golden hour. PMID- 23916516 TI - Case scenario - thoracic trauma. AB - Among trauma patients, blunt chest trauma remains a major cause of morbidity and mortality. We report the case of an 85-year old patient under new oral anticoagulant implicated in a multiple-vehicle accident. The patient presented a complex thoracic trauma involving multiple rib fractures, flail chest, hemothorax and lung contusions. All the thoracic lesions were situated at the left side. Despite the absence of neurological lesion and hemodynamic instability, the patient required the admission in our intensive care unit related to the worsening of a respiratory distress. This respiratory distress resulted from the association of the thoracic injuries with related hypoxemia and a high level of pain. The management of this case included the reversal of the anticoagulant therapy, use of non-invasive ventilation, the placement of a paravertebral block and the surgical fixation of the flail chest. We provide a discussion of the risk/benefit balance for all the medical and surgical strategies used in this case as the interest of chest ultrasonography in thoracic trauma situations. PMID- 23916517 TI - Update on prehospital emergency care of severe trauma patients. AB - The prognosis of severe trauma patients is determined by the ability of a healthcare system to provide high intensity therapeutic treatment on the field and to transport patients as quickly as possible to the structure best suited to their condition. Direct admission to a specialized center ("trauma center") reduces the mortality of the most severe trauma at 30 days and one year. Triage in a non-specialized hospital is a major risk of loss of chance and should be avoided whenever possible. Medical dispatching plays a major role in determining patient care. The establishment of a hospital care network is an important issue that is not formalized enough in France. The initial triage of severe trauma patients must be improved to avoid taking patients to hospitals that are not equipped to take care of them. For this purpose, the MGAP score can predict severity and help decide where to transport the patient. However, it does not help predict the need for urgent resuscitation procedures. Hemodynamic management is central to the care of hemorrhagic shock and severe head trauma. Transport helicopter with a physician on board has an important role to allow direct admission to a specialized center in geographical areas that are difficult to access. PMID- 23916518 TI - In Trauma we care! PMID- 23916519 TI - The concept of damage control: extending the paradigm in the prehospital setting. AB - OBJECTIVE: The purpose of this review is to present the progressive extension of the concept of damage control resuscitation, focusing on the prehospital phase. ARTICLE TYPE: Review of the literature in Medline database over the past 10 years. DATA SOURCE: Medline database looking for articles published in English or in French between April 2002 and March 2013. Keywords used were: damage control resuscitation, trauma damage control, prehospital trauma, damage control surgery. Original articles were firstly selected. Editorials and reviews were secondly studied. DATA SYNTHESIS: The importance of early management of life-threatening injuries and rapid transport to trauma centers has been widely promulgated. Technical progress appears for external methods of hemostasis, with the development of handy tourniquets and hemostatic dressings, making the crucial control of external bleeding more simple, rapid and effective. Hypothermia is independently associated with increased risk of mortality, and appeared accessible to improvement of prehospital care. The impact of excessive fluid resuscitation appears negative. The interest of hypertonic saline is denied. The place of vasopressor such as norepinephrine in the early resuscitation is still under debate. The early use of tranexamic acid is promoted. Specific transfusion strategies are developed in the prehospital setting. CONCLUSION: It is critical that both civilian and military practitioners involved in trauma continue to share experiences and constructive feedback. And it is mandatory now to perform well-designed prospective clinical trials in order to advance the topic. PMID- 23916520 TI - The initial management of trauma patients is an especially relevant setting to evaluate professional practice patterns. AB - The initial management of trauma patients in a dedicated location is a crucial step in the treatment of these patients. The characteristics of this phase are such that they meet all the criteria for a professional practice patterns evaluation (PPPE or PPE): formalized protocols, clear-cut timeframes, specific roles of different stakeholders, and multidisciplinary medical and paramedical team. In addition, the expected result of the PPE approach, improved care, will have a direct impact on patient outcomes. This PPE modeled on an audit aims at evaluating the care process based on representative criteria. These criteria should include: the planned structure and organization; the protocols; the strategy and time frames for procedure implementation; the relationships between stakeholders; the results. For each criterion, differences between the expected characteristics and the observed reality are analyzed. The prospective (independent observer or video) and/or retrospective (records, register) collection of data during 20 consecutive encounters should be sufficient to identify dysfunctions and provide guidance on the changes that need to be implemented. The proposed data collection form includes 15 items representative of the five defined criteria. These items often describe departmental choice. The pursuit of quality is defined first in terms of medical and paramedical results, but also in administrative and financial terms. Following the analysis produced by a representative group of actors, a multidisciplinary discussion of the results should be followed by proposals for simple changes approved by everyone. After a few months of implementation, the impact of the proposed improvement measures will be assessed by a new survey. This approach, in addition to improving the quality of care, allows better team stress management and greater work enjoyment. PMID- 23916521 TI - Accumulation, elimination, and effects of parenteral exposure to aluminum in newborn and adult rats. AB - Aluminum (Al) delivered to preterm infants via parenteral nutrition may exceed the limit of 5 MUg/kg/day set by the US Food and Drug Administration. This study evaluated the effect of the administration of an equivalent amount of Al (0.12 mg/kg/day) to newborn rats. The study included the administration of a higher amount of Al (24.8 mg/kg/day) not only to newborn rats but also to adult (2- and 4-month-old) rats. Aluminum was intraperitoneally administered for a period of 10 days. Newborn animals were evaluated for developmental changes every day starting from the second day after birth. Twenty days after the last administration, 10 animals were killed and their organs were removed; the remainders were killed on day 40. A dosage of 24.8 mg/kg/day was administered to the two groups of adult rats, which were killed following the same protocol after 20 and 40 days. The results of physical parameters and developmental and behavioral tests were not conclusive and no significant differences were observed between the lower and higher Al dose and control groups. The group that received 0.12 mg/kg/day showed significant differences in Al accumulation only in the liver and muscle. The groups that received a higher dose of Al showed an accumulation in all tissues among all age groups studied, but the newborn group showed the greatest accumulation (results for day 20). After 40 days, Al content in all tissues decreased more than 50% in this group, whereas among the adults, the Al content increased or remained constant. An increase in age correlated with a lower elimination rate. Considering the ongoing human Al exposure, along with its age related elimination rate, Al accumulation in the body may be long-lasting. PMID- 23916522 TI - Concentric and eccentric: muscle contraction or exercise? PMID- 23916523 TI - [Nursing care management in dermatological patient on phototherapy narrow band UVB]. AB - Phototherapy with narrow band ultraviolet B is a treatment used in some dermatology units, and is the first choice in some dermatological diseases due to being comfortable and cheap. The aim of this paper is to describe the management and nursing care by grouping more specific diagnoses, following NANDA-NIC/NOC taxonomy, such as the methodology from application, technique, material, and personnel to space-related aspects, with the aim of avoiding the clinical variability and the possible associated risks for the patients, and for the nurses who administer the treatment. The continuity of the same nurse in the follow-up sessions stimulates the relationship between medical personnel and patients, key points for loyalty and therapeutic adherence. This paper examines a consensus procedure with the Dermatology Unit Team and accredited by the Hospital Quality Unit. PMID- 23916524 TI - [Hand hygiene, an important role for the patient]. PMID- 23916525 TI - Efficacy and tolerability of lamotrigine in juvenile myoclonic epilepsy in adults: a prospective, unblinded randomized controlled trial. AB - PURPOSE: Controlled randomized studies recommending the clinical use of lamotrigine in adult populations with the diagnosis of Juvenile Myoclonic Epilepsy are still lacking. To compare the efficacy and tolerability of lamotrigine versus valproate in adult patients with JME. METHODS: This was a prospective, randomized, controlled, pragmatic, long-term and open-label treatment trial. Patients were randomized to use valproate or lamotrigine. The primary end points of the study were: (1) time from randomization to treatment failure (withdrawal); (2) time from randomization to seizures remission. Secondary ending points were: (1) frequency of clinically important adverse events and (2) change in the QOLIE-31 after randomization. The definition of seizure remission was based on disappearance of all seizure types and EEG discharges. RESULTS: We found that the time to withdraw treatment after randomization was not significantly different in lamotrigine and valproate groups. Long-term seizures freedom was equal in the both groups of the trial; only 8 (19.1%) patients randomized to lamotrigine and 6 (19.4%) randomized to valproate were not seizure free after 4 months of treatment. Between 17.03% (lamotrigine) and 35.3% (valproate) of patients reported adverse reactions at some point in the intention-to treat study (p = 0.07). All subscales of the QOLIE 31 questionnaire, except that related to side effects of medication, improved more than 5 points with respect to baseline period in both groups CONCLUSION: Lamotrigine is effective in adult patients with Juvenile Myoclonic Epilepsy and better tolerated than valproate, although the incidence of idiosyncratic reactions could be a cause of concern. PMID- 23916526 TI - Progression of low-grade dysplasia to advanced neoplasia based on the location and morphology of dysplasia in ulcerative colitis patients with extensive colitis under colonoscopic surveillance. AB - BACKGROUND: The management of low-grade dysplasia (LGD) in ulcerative colitis (UC) patients remains unclear. AIM: The aim of our study was to study the risk of progression of LGD to advanced neoplasia (AN), defined as high-grade dysplasia (HGD) or colorectal cancer (CRC) for UC patients undergoing surveillance based on location and morphology of LGD. METHODS: 997 UC patients underwent 3152 surveillance colonoscopies from 1998 to 2011. Kaplan-Meier estimates and incidence rates calculated. RESULTS: Of the 102 patients with LGD (65 raised and 37 flat), 5 (4.9%) patients progressed to AN (3 HGD and 2 CRC) after a median follow-up of 36 months (interquartile range 18-71 months). Initial location of dysplasia was in the proximal colon in 47, distal colon in 55 patients. Four of the 5 (80%) patients with AN had initial dysplasia in the distal colon. Distal colonic LGD had an incidence rate for AN of 2.1 cases per 100 person years at risk, while proximal LGD had an incidence of 0.5 cases per 100 person years. Flat LGD in the distal colon was more likely to progress to AN [hazard ratio=3.6; 95% confidence interval, CI (1.3-10.6)]. Twenty of the 102 patients (15 flat and 5 raised) underwent colectomy: 2 (10%) had evidence of AN in colectomy (1 HGD and 1 CRC), 9 had LGD and remaining 9 did not have dysplasia. CONCLUSIONS: The frequency of progression of LGD to AN is low. Flat dysplasia located in the distal colon is associated with a greater risk of progression to AN. PMID- 23916527 TI - Effects of non-invasive neurostimulation on craving: a meta-analysis. AB - This meta-analysis was conducted to evaluate the available evidence regarding the effects of non-invasive neurostimulation of the dorsolateral prefrontal cortex (DLPFC), on craving in substance dependence and craving for high palatable food. Non-invasive neurostimulation techniques were restricted to repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS). A total of 17 eligible studies were identified. Random effects analysis revealed a pooled standardized effect size (Hedge's g) of 0.476 (CI: 0.316-0.636), indicating a medium effect size favouring active non-invasive neurostimulation over sham stimulation in the reduction of craving (z=5.832, p<0.001). No significant differences were found between rTMS and tDCS, between the various substances of abuse and between substances of abuse and food, or between left and right DLPFC stimulation. In conclusion, this meta-analysis provides the first clear evidence that non-invasive neurostimulation of the DLPFC decreases craving levels in substance dependence. PMID- 23916530 TI - Stressing the cell cycle in senescence and aging. AB - Senescence represents a permanent exit from the cell cycle and its role in curtailing the proliferation of damaged and potentially oncogenic cells has relevance both as a front-line defense against cancer and as an underlying cause of aging. The retinoblastoma protein (RB) and p53 tumor suppressors are central to the process and the growth arrest is primarily implemented by the cyclin dependent kinase (CDK) inhibitors, p16INK4a and p21CIP1. In contrast to terminal differentiation, senescence is a general response to a diverse range of cellular stresses and is typically accompanied by a characteristic set of phenotypic changes. Of particular note is a secretory program whose autocrine and paracrine effects can advertize the presence of senescent cells within a tissue and promote their clearance by the immune system. In this short review, we will highlight recent advances in understanding the relationship between senescence and aging and the distinction between senescence and terminal differentiation, from a cell cycle perspective. PMID- 23916532 TI - Epidural injection of hydroxyethyl starch in the management of postdural puncture headache. PMID- 23916531 TI - Preparation of uniformly isotope labeled KcsA for solid state NMR: expression, purification, reconstitution into liposomes and functional assay. AB - We report the expression, purification, liposome reconstitution and functional validation of uniformly (13)C and (15)N isotope labeled KcsA, a bacterial potassium channel that has high homology with mammalian channels, for solid-state NMR studies. The expression and purification is optimized for an average yield of ~35-40mg/L of M9 media in a time-efficient way. The protein purity is confirmed by gel electrophoresis and the protein concentration is quantified by UV-vis absorption spectroscopy. Protocols to efficiently reconstitute KcsA into liposomes are also presented. The presence of liposomes is confirmed by cryo electron microscopy images and the effect of magic angle spinning on liposome packing is shown. High-resolution solid-state NMR spectra of uniformly isotope labeled KcsA in these liposomes reveal that our protocol yields to a very homogenous KcsA sample with high signal to noise and several well-resolved residues in NMR spectra. Electrophysiology of our samples before and after solid state NMR show that channel function and selectivity remain intact after the solid-state NMR. PMID- 23916533 TI - The influence of timing on the effectiveness of epidural blood patches in parturients. AB - BACKGROUND: Postdural puncture headache is common in parturients following lumbar puncture. If headache is severe and persistent, an epidural blood patch is recommended. In this paper we reviewed the efficacy of epidural blood patches over a 13-year period at two hospitals in Finland with a particular emphasis on its timing. METHODS: The hospitals' databases were searched to identify parturients who underwent an epidural blood patch from March 1998 to June 2011. Parturients' records were reviewed to establish the characteristics and associated symptoms of headache and the effectiveness of the epidural blood patch. RESULTS: A total of 129 parturients received 151 epidural blood patches. These followed spinal (n = 49), epidural (n = 47) or combined spinal-epidural blocks (n = 33). The success rate of the first procedure was 89%, with permanent relief in 76%. The first procedure provided permanent relief of postdural puncture headache for 86% of 78 patients having the procedure after 48 h, compared to 65% of 37 patients when it was performed between 24 and 48 h, and 50% of 14 patients with the procedure within the first 24 h after dural puncture (P = 0.003). A second procedure was performed for 22 parturients due to incomplete relief (n = 5) or recurrent symptoms (n = 17); all had complete resolution of symptoms. CONCLUSIONS: Epidural blood patch performed later than 48 h following lumbar puncture or accidental dural puncture is effective in parturients with postdural puncture symptoms. The recurrence rate of symptoms after an initially successful epidural blood patch is high, and therefore patients should be provided with counselling and contact information. PMID- 23916534 TI - Tone burst stimulus for auditory brainstem responses: prediction of hearing threshold at 1kHz. AB - OBJECTIVE: To assess differences in hearing threshold estimation of four different ABR tone-bursts at 1kHz. METHODS: Twenty-one (21) ears from 11 subjects were tested with pure-tone audiometry (PTA): 5 ears (24%) were normal hearing, 5 (24%) affected by mild hearing loss, 7 (33%) showed moderate hearing loss and 4 (19%) severe hearing loss. After PTA each subject underwent tone-burst ABR test at 1kHz using a linear gated (L_ABR) or Blackman windowed (B_ABR) stimuli with (nn_ABR) and without ipsilateral notched noise. Stimulation rate and filters settings were unchanged. RESULTS: Overall correlation between PTA and all ABRs thresholds was high, ranging from 0.84 to 0.94. In normal hearing ears none of the differences was significant, except for those measured with B_nn_ABR, which showed a mean 16dB overestimation of the pure-tone threshold (p<0.05). In mild hearing loss group none of the differences between thresholds were significant. In moderate and severe hearing loss groups significant differences were measured with L_nn_ABR (p<0.05) with a mean 7.5dB underestimation of PTA. CONCLUSIONS: Although very similar, some significant differences were found when considering specific group of patients with different degrees of hearing loss. PMID- 23916535 TI - Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. PMID- 23916536 TI - Cortical and subcortical volumes in adolescents with alcohol dependence but without substance or psychiatric comorbidities. AB - Most prior studies of the effects of excessive alcohol intake on the adolescent brain examined alcohol-use-dependent samples with comorbid psychiatric and substance use disorders. In the Cape Town region, we identified a sizeable cohort of adolescents with alcohol use disorders (AUD) without externalizing or other psychiatric disorders. We examined brain morphology in 64 such adolescents compared to age- and gender-matched healthy controls. Magnetic resonance imaging data were analyzed using FSL's FIRST software for subcortical volumes, and cortical gray matter (GM) was analyzed using voxel-based morphometry (VBM) and regions of interest (ROI) analysis. AUD boys had smaller thalamic and putamen volumes compared to non-drinking boys, while AUD girls had larger thalamic and putamen volumes compared to non-drinking girls. VBM revealed a large region of decreased GM density in AUDs compared to controls located in the left lateral frontal, temporal, and parietal lobes, extending medially deep into the parietal lobe. Smaller GM volume in this region was also present when examined using ROI analysis. Our lack of findings in other brain regions, particularly the hippocampus, suggests that reports of smaller brain volumes in adolescent AUDs in the literature are a consequence of psychiatric and substance abuse comorbidities. PMID- 23916537 TI - Neural responses during emotional processing before and after cognitive trauma therapy for battered women. AB - Therapy for combat and accident-related posttraumatic stress disorder (PTSD) has been reported to influence amygdala and anterior cingulate cortex (ACC) response during emotional processing. It is not yet understood how therapy influences different phases of emotional processing, and whether previous findings generalize to other PTSD populations. We hypothesized that cognitive trauma therapy for battered women (CTT-BW) would alter insula, amygdala, and cingulate responses during anticipation and presentation of emotional images. Fourteen female patients with PTSD related to domestic violence completed the Clinician Administered PTSD Scale (CAPS) and functional magnetic resonance imaging (fMRI) before and after CTT-BW. The fMRI task involved cued anticipation followed by presentation of positive versus negative affective images. CTT-BW was associated with decreases in CAPS score, enhanced ACC and decreased anterior insula activation during anticipation, and decreased dorsolateral prefrontal cortex and amygdala response during image presentation (negative-positive). Pre-treatment ACC activation during anticipation and image presentation exhibited positive and negative relationships to treatment response, respectively. Results suggest that CTT-BW enhanced efficiency of neural responses during preparation for upcoming emotional events in a way that reduced the need to recruit prefrontal-amygdala responses during the occurrence of the event. Results also suggest that enhancing ACC function during anticipation may be beneficial for PTSD treatment. PMID- 23916538 TI - Executive dysfunction correlates with caudate nucleus atrophy in patients with white matter changes on MRI: a subset of LADIS. AB - White matter changes (WMC) are common magnetic resonance imaging (MRI) findings, particularly in the elderly. Recent studies such as the Leukoaraiosis and Disability Study (LADIS) have found that WMC relate to adverse outcomes including cognitive impairment, depression, disability, unsteadiness and falls in cross sectional and follow-up studies. Frontostriatal (or frontosubcortical) brain circuits may serve many of these functions, with the caudate nuclei playing a role in convergence of cognitive functions. This study aimed to determine whether reduced caudate volume relates to cognitive functions (executive functions, memory functions and speed of processing) and WMC. We determined caudate nuclei volumes, through manual tracing, on a subgroup of the LADIS study (n=66) from four centres with baseline and 3-year follow-up MRI scans. Regression analysis was used to assess relationships between caudate volume, cognitive function and WMC. Severity of WMC did not relate to caudate volume. Smaller caudate volumes were significantly associated with poorer executive functioning at baseline and at 3 years, but were not associated with scores of memory or speed of processing. Thus, in patients with WMC, a surrogate of small vessel disease, caudate atrophy relates to the dysexecutive syndrome, supporting the role of caudate as an important part of the frontostriatal circuit. PMID- 23916539 TI - Identification and characterization of a novel IkappaB-epsilon-like gene from lamprey (Lampetra japonica) with a role in immune response. AB - Nuclear factor of kappa B (NF-kappaB) is a stimuli-activated transcription factor, regulates the expression of a diverse array of genes. Inhibitor of kappa B-epsilon (IkappaB-epsilon) is an inhibitor of NF-kappaB, which retains NF-kappaB in an inactive state in the cytoplasm. Lampreys (Lampetra japonica) belong to the lowest class of vertebrates with little information about its IkappaBs. We have identified a cDNA sequence IkappaB-epsilon-like in the lamprey and the deduced amino acid sequence of IkappaB-epsilon-like. It contains a conserved DSGxxS motif and six consecutive ankyrin repeats, which are necessary for signal-induced degradation of the molecule. Phylogenetic analysis indicated it had high sequence homology with IkappaB-epsilons from other vertebrates. FACS analysis showed that IkappaB-epsilon-like located in cytoplasm of leukocytes. The degradation of IkappaB-epsilon-like could be observed in leukocytes of L. japonica stimulated with lipopolysaccharide. These results indicate that IkappaB-epsilon proteins are conserved across vertebrates and the NF-kappaB-like signaling pathway may exist in the oldest agnatha. PMID- 23916541 TI - Blood transfusion in Bangladesh with particular emphasis on the treatment of Thalassemia patients. PMID- 23916540 TI - Genomic structural characterization and transcriptional expression analysis of proteasome activator PA28alpha and PA28beta subunits from Oplegnathus fasciatus. AB - Proteasomes are multicatalytic subunit complexes involved in the degradation of cytosolic proteins and antigen presentation. In this study, we have characterized the alpha and beta subunits of proteasome activator complex from rock bream at the molecular level. RbPA28alpha and RbPA28beta possessed the characteristic features of the subunits identified from mammals and teleosts. The RbPA28alpha and RbPA28beta proteasome subunits contained a proline-rich motif (Region A), subunit-specific insert in the region corresponding to the KEKE motif of the known PA28alpha (Region B), conserved activation loop (Region C), a potential protein kinase C recognition site (Region D) and a highly homologous C-terminal region (Region E) among all three PA28 subunits. Multiple sequence alignment and pairwise alignment revealed that RbPA28alpha and RbPA28beta proteins shared high homology with the teleosts and mammals. RbPA28alpha and RbPA28beta genome possessed 11 exons interrupted by 10 introns. In silico promoter analysis of RbPA28alpha and RbPA28beta revealed various transcription factor-binding sites displaying their regulation under various stress conditions. Tissue distribution profiling showed a higher expression in blood and gills. Transcriptional expression analysis of RbPA28alpha and RbPA28beta showed up-regulation in the immune tissues following LPS and poly I:C challenges, providing further evidence for the immunological role of RbPA28alpha and RbPA28beta. PMID- 23916542 TI - Synthesis of 24-phenyl-24-oxo steroids derived from bile acids by palladium catalyzed cross coupling with phenylboronic acid. NMR characterization and X-ray structures. AB - Palladium-catalyzed cross coupling of phenyboronic acid with acetylated bile acids in which the carboxyl functions have been activated by formation of a mixed anhydride with pivalic anhydride afforded moderate to good yield of 24-phenyl-24 oxo-steroids. Unambiguous assignments of the NMR signals were made with the aid of combined 1D and 2D NMR techniques. X-ray diffraction studies confirmed the obtained structures. PMID- 23916543 TI - Reduced expression of steroid sulfatase in primary colorectal cancer. AB - Colorectal cancer (CRC) is considered an estrogen-dependent malignancy, and intratissue estrogen concentration can be controlled by steroid sulfatase (STS). Little is known about changes in the expression of STS during the development of CRC. Therefore, we analysed the STS mRNA levels in primary colonic adenocarcinoma tissues and adjacent histopathologically unchanged colonic mucosa from patients who underwent radical colon resection (n=90). We found a statistically significant decrease in STS transcript levels in CRC (P=0.0453). Moreover, we found that sodium butyrate (NaBu) significantly upregulated STS transcript levels in DLD-1 and HCT116 CRC cells. Our results suggest that STS expression can be decreased in the process of large intestinal carcinogenesis. Moreover, we observed that NaBu might increase STS expression in CRC cells. PMID- 23916544 TI - Expression of 17beta-hydroxysteroid dehydrogenase type 1 in gastric cancer. AB - There are several findings suggesting the protective role of estrogens in gastric carcinogenesis. Extragonadal 17beta-estradiol (E2) may be formed during estrone (E1) reduction to E2 by 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1). Therefore, we studied the HSD17B1 transcript and protein levels in primary nontumoral and tumoral gastric tissue from the same 21 patients with gastric cancer (GC). We also assessed the effect of 5-Aza-2'-deoxycytidine (5-dAzaC), on the methylation status of HSD17B1 and its expression and conversion of E1 to E2 in HGC-27 and EPG 85-257 GC cells. We identified the presence of HSD17B1 transcript and protein in HGC-27 and EPG 85-257 GC cells as well as in primary nontumoral and tumoral tissues from patients with GC. Moreover, we found that 5 dAzaC significantly up-regulated the HSD17B1 transcript and protein levels, which is associated with increased conversion of E1 to E2 in HGC-27 and EPG 85-257 GC cells. The changes in HSD17B1 expression in both HGC-27 and EPG 85-257 cells were accompanied by 5-dAzaC induced DNA demethylation in the 5' flanking region. Our results demonstrated that HSD17B1 expression and its ability to convert the weak estrogen E1 to the more potent E2 can be associated with DNA methylation in the 5' flanking region in GC cells. PMID- 23916545 TI - Proteomics-based identification of tumor relevant proteins in lung adenocarcinoma. AB - BACKGROUND: Lung cancer has the highest mortality rate among malignant tumors. Proteomics is a powerful tool to identify protein biomarkers. The identification of protein biomarkers associated with lung adenocarcinoma would have significance for making prognoses and designing targeted therapies. METHODS: In our study, we applied a two-dimensional difference gel electrophoresis approach coupled to a matrix-assisted laser desorption/ionization time-of-flight mass spectrometric analysis for the identification of proteins differentially expressed between lung adenocarcinoma and the paired normal bronchial epithelial tissues derived from seven patients (four of them developed distant metastasis after operation). In addition, we chose two candidate proteins and examine their expression levels in lung adenocarcinoma and adjacent normal tissues using immunohistochemistry methods, and their expression levels in serum of patients and healthy donors by ELISA. RESULT: In this study, 173 proteins were found to be differentially expressed (ratio>1.5 or<-1.5, P<=0.05), and 22 of them were identified by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. Thirteen proteins were at lower levels in the lung adenocarcinoma group, while nine proteins were at higher abundance. Immunohistochemistry analysis confirmed the expression levels of the two candidate proteins. The differential expression of the candidate secreted protein in serum from lung adenocarcinoma samples and healthy controls was showed by ELISA. CONCLUSION: Our results demonstrated a differential protein expression pattern for lung adenocarcinoma compared with the paired normal bronchial epithelial tissues. Further functional validation of candidate proteins is ongoing and might provide new insights in lung adenocarcinoma. PMID- 23916547 TI - Risk factors for multidrug resistance among previously treated patients with tuberculosis in eastern China: a case-control study. AB - BACKGROUND: Previous treatment has been documented as a major risk factor for multidrug-resistant tuberculosis (MDR-TB). However, risk factors for MDR-TB among previously treated patients in China are unclear. This study aimed to ascertain the risk factors for MDR-TB in this particular population in China. METHODS: A case-control study was conducted from July through August 2011 in five cities of Zhejiang Province. Cases were previously treated TB patients who had disease resistant to at least isoniazid and rifampin, whereas controls were previously treated TB patients who had disease sensitive to isoniazid and rifampin. RESULTS: Ninety-eight cases and 83 controls were identified. Multivariate analysis showed that a duration of first treatment of more than 8 months (odds ratio (OR) 2.18, 95% confidence interval (CI) 1.05-4.52), more than three prior episodes of anti TB treatment (more than 2 months of continuous treatment as one episode) (OR 5.57, 95% CI 2.38-13.00), adverse effects of anti-TB medication (OR 3.63, 95% CI 1.79-7.36), and more than three TB foci in the lung (OR 2.17, 95% CI 1.08-4.37) were associated with MDR-TB in previously treated TB patients. Low family income (p=0.056) was marginally significant in the univariate analysis. CONCLUSIONS: Particular clinical diagnostic results, such as more than three TB foci in the lung, non-standard or irregular therapy, and adverse effects of anti-TB medication, were found to be associated with MDR-TB in previously treated TB patients. High quality directly observed treatment should be strengthened to ensure that the previously treated patients can receive standard and regular regimens. PMID- 23916548 TI - A family cluster of Middle East Respiratory Syndrome Coronavirus infections related to a likely unrecognized asymptomatic or mild case. AB - BACKGROUND: Ninety confirmed cases of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) have been reported to the World Health Organization. We report the details of a second family cluster of MERS-CoV infections from Riyadh, Saudi Arabia. METHODS: We present the clinical, laboratory and epidemiological details of 3 patients from a family cluster of MERS-CoV infections. RESULTS: The first patient developed respiratory symptoms and fever 14 days after admission to hospital for an unrelated reason. He died 11 days later with multi-organ failure. Two of his brothers presented later to another hospital with respiratory symptoms and fever. MERS-CoV infection in the latter 2 patients was confirmed by reverse transcriptase polymerase chain reaction testing. All 3 patients had fever, cough, shortness of breath, bilateral infiltrates on chest x-ray, thrombocytopenia, lymphopenia and rises in serum creatinine kinase and alanine transaminase. No hospital or other social contacts are known to have acquired the infection. It appears that the index patient in this cluster acquired MERS-CoV infection whilst in hospital from an unrecognized mild or asymptomatic case. CONCLUSION: MERS-CoV acquisition from unrecognized mild or asymptomatic cases may be a more important contributor to ongoing transmission than previously appreciated. PMID- 23916546 TI - Shape abnormalities of the caudate nucleus correlate with poorer gait and balance: results from a subset of the LADIS study. AB - OBJECTIVE: Functional deficits seen in several neurodegenerative disorders have been linked with dysfunction in frontostriatal circuits and with associated shape alterations in striatal structures. The severity of visible white matter hyperintensities (WMHs) on magnetic resonance imaging has been found to correlate with poorer performance on measures of gait and balance. This study aimed to determine whether striatal volume and shape changes were correlated with gait dysfunction. METHODS: Magnetic resonance imaging scans and clinical gait/balance data (scores from the Short Physical Performance Battery [SPPB]) were sourced from 66 subjects in the previously published LADIS trial, performed in nondisabled individuals older than age 65 years with WMHs at study entry. Data were obtained at study entry and at 3-year follow-up. Caudate nuclei and putamina were manually traced using a previously published method and volumes calculated. The relationships between volume and physical performance on the SPPB were investigated with shape analysis using the spherical harmonic shape description toolkit. RESULTS: There was no correlation between the severity of WMHs and striatal volumes. Caudate nuclei volume correlated with performance on the SPPB at baseline but not at follow-up, with subsequent shape analysis showing left caudate changes occurred in areas corresponding to inputs of the dorsolateral prefrontal, premotor, and motor cortex. There was no correlation between putamen volumes and performance on the SPPB. CONCLUSION: Disruption in frontostriatal circuits may play a role in mediating poorer physical performance in individuals with WMHs. Striatal volume and shape changes may be suitable biomarkers for functional changes in this population. PMID- 23916549 TI - Three-dimensional renal CT angiography for guiding segmental renal artery clamping during laparoscopic partial nephrectomy. AB - AIM: To evaluate the effectiveness of three-dimensional (3D) renal computed tomography angiography (CTA) in guiding segmental renal artery clamping during laparoscopic partial nephrectomy (LPN). MATERIALS AND METHODS: Forty-three patients with renal tumours undergoing renal CTA before LPN were retrospectively enrolled in this study. 3D arteriogram reconstructed images were created to identify the renal tumour-supplying arteries. The number and location of these targeted vessels were annotated on 3D images preoperatively and compared with the clamped vessels during LPN. The consistency between target vessels annotated at CTA and clamped arteries at LPN was compared both using a patient-based analysis and vessel-based analysis. The chi(2) test was applied to analyse the influence of tumour size, location, and growth pattern on the number of clamped segmental renal branches. RESULTS: On patient-based analysis, the number of targeted vessels was consistent with the clamped vessels during LPN in 33 of 43 patients. On vessel-based analysis, 56 of 65 target vessels annotated at CTA were clamped during LPN. More segmental renal branches (p = 0.04) were clamped in patients with tumours of larger size. Tumour location and growth pattern had no association with the number of clamped segmental branches during LPN. CONCLUSION: High-quality CTA images and 3D reconstruction images can detect detailed information of tumour-supplying arteries to renal tumours. 3D renal CTA is an effective way to guide segmental renal artery clamping during LPN. PMID- 23916550 TI - Breast MRI artefacts: evaluation and solutions in 630 consecutive patients. AB - AIM: To evaluate the problems that may arise in breast magnetic resonance imaging (MRI) related to the presence of artefacts and pitfalls, in order to improve its accuracy, sensitivity, and specificity. MATERIALS AND METHODS: Six hundred and thirty breast MRI examinations performed using a 1.5 T magnet were analysed retrospectively. Each type of artefact that may have affected the correct interpretation of the acquired images was considered and analysed. In particular, the presence of technical artefacts, which are related to patient-dependent factors or to the examination itself, and non-technical artefacts, which are the result of inadequate and incorrect image interpretation occurring in absence of technical issues, were examined. In every case of suspicious findings, doubtful lesions were subjected to histological characterization for appropriate therapeutic planning. In the remainder of cases, patients underwent follow-up for at least 18 months. RESULTS: Artefacts were found in 33% of all examinations, among those 48.6% were caused by movement, 33.6% were due to non-homogeneous or failed fat saturation, 8.7% to incorrect positioning of the patient, 7.2% to metallic artefacts, 1.4% to aliasing, and 0.5% were "zebra artefacts". When the artefact was identified in a sequence, the sequence was performed a second time after corrective measures. No artefacts affected diagnostic interpretation of the obtained images. CONCLUSION: The present study provides a specific and precise review of the most frequent artefacts with a discussion of possible and practical solutions. A highly qualified team is required to perform accurate diagnostic tests and to limit or remove the possibility of misinterpretation. PMID- 23916551 TI - Image quality and radiation exposure in CT of the pancreas: 320-MDCT with and without adaptive iterative dose reduction versus 64-MDCT. AB - AIM: To compare the image quality and radiation exposure in computed tomography (CT) of the pancreas acquired using 320-multidetector (MD)CT versus 64-MDCT and to demonstrate the effects of adaptive iterative dose reduction (AIDR) on 320 MDCT. MATERIALS AND METHODS: One hundred and fifty patients were randomized into three groups including 320-section volume imaging using AIDR (group A), 320-slice volume scan without AIDR (group B), and 64-section helical imaging without AIDR (group C). Transaxial arterial, pancreatic phase, and volume-rendered CT angiographic images were reconstructed. CT radiodensity of the abdominal aorta, pancreas, signal-to-noise ratios (SNR), dose-length products (DLPs; mGy cm), and image quality were measured. RESULTS: No significant difference in CT radiodensity of the abdominal aorta or pancreas was noted between groups. Mean DLPs were 600.9 +/- 145.8, 681.6 +/- 97.5, and 1231.5 +/- 271.4 in groups A, B, and C, respectively. The DLP was reduced by 51% in group A and 45% in group B compared to group C (p < 0.001). SNRs of the pancreas during the pancreatic phase were comparable between groups A and C, but were significantly lower in group B (p < 0.001). Image quality, including the depiction of some small arterial branches on the arterial and CT angiographic images and the main pancreatic duct on the pancreatic-phase images, were significantly lower in group B than in groups A and C (p = 0.008-0.038). CONCLUSION: Radiation dose can be markedly reduced for contrast-enhanced CT imaging of the pancreas without compromising image quality using a 320-MDCT with AIDR, compared with 64-section helical CT. PMID- 23916552 TI - An observational study of patient selection criteria for post-cardiac arrest therapeutic hypothermia. AB - BACKGROUND: To date, there is no comprehensive assessment of how therapeutic hypothermia and post-arrest care are being implemented clinically. At this stage in the translation of post-arrest science to clinical practice, this analysis is overdue. This study examines the first step of post-arrest care--the selection of patients for TH and post-arrest care. METHODS: We conducted a systematic review to search for all publicly available TH and post-arrest protocols. Observational data was reported and no statistical inferences were made. RESULTS: Notable variation was observed in the following selection criteria: total ischemic time and hemodynamic requirements. Additionally, only some of the criteria were evidence based. CONCLUSION: This study demonstrates the wide range and variety of patient selection criteria that are being used for implementation of post-cardiac arrest care. The consequences of this selection criteria variability are currently unmeasured and likely underestimated. Variability is likely to breed inefficiency. Some patients who could benefit do not get treated. Other patients get cooled, yet will never regain consciousness. This variability may be important when considering inter-hospital variation in post-arrest care and outcomes. PMID- 23916553 TI - The impact of severe acidemia on neurologic outcome of cardiac arrest survivors undergoing therapeutic hypothermia. AB - INTRODUCTION: Therapeutic Hypothermia (TH) has become a standard of care in improving neurological outcomes in cardiac arrest (CA) survivors. Previous studies have defined severe acidemia as plasma pH<7.20. We investigated the influence of severe acidemia at the time of initiation of TH on neurological outcome in CA survivors. METHODS: A retrospective analysis was performed on 196 consecutive CA survivors (out-of-hospital CA and in-hospital CA) who underwent TH with endovascular cooling between January 2007 and October 2012. Arterial blood gas drawn prior to initiation of TH was utilized to measure pH in all patients. Shockable and non-shockable CA patients were divided into two sub-groups based on pH (pH<7.2 and pH>=7.2). The primary end-point was measured using the Pittsburgh Cerebral Performance Category (CPC) scale prior to discharge from the hospital: good (CPC 1 and 2) and poor (CPC 3 to 5) neurologic outcome. RESULTS: Sixty-two percent of shockable CA patients with pH>=7.20 had good neurological outcome as compared to 34% patients with pH<7.20. Shockable CA patients with pH>=7.20 were 3.3 times more likely to have better neurological outcome when compared to those with pH <7.20 [p=0.013, OR 3.3, 95% CI (1.28-8.45)]. In comparison, non-shockable CA patients with p>=7.20 did not have a significantly different neurological outcome as compared to those with pH<7.20 [p=0.97, OR 1.02, 95% CI (0.31-3.3)]. CONCLUSION: Presence of severe acidemia at initiation of TH in shockable CA survivors is significantly associated with poor neurological outcomes. This effect was not observed in the non-shockable CA survivors. PMID- 23916554 TI - Time to awakening and neurologic outcome in therapeutic hypothermia-treated cardiac arrest patients. AB - INTRODUCTION: Therapeutic hypothermia (TH) has been shown to improve outcomes in comatose Post-Cardiac Arrest Syndrome (PCAS) patients. It is unclear how long it takes these patients to regain neurologic responsiveness post-arrest. We sought to determine the duration to post-arrest awakening and factors associated with times to such responsiveness. METHODS: We performed a retrospective chart review of consecutive TH-treated PCAS patients at three hospitals participating in a US cardiac arrest registry from 2005 to 2011. We measured the time from arrest until first documentation of "awakening", defined as following commands purposefully. RESULTS: We included 194 consecutive TH-treated PCAS patients; mean age was 57+/ 16 years; 59% were male; 40% had an initial shockable rhythm. Mean cooling duration was 24+/-8h and mean rewarming time was 14+/-13h. Survival to discharge was 44%, with 78% of these discharged with a good neurologic outcome. Of the 85 patients who awakened, median time to awakening was 3.2 days (IQR 2.2, 4.5) post cardiac arrest. Median time to awakening for a patient discharged in good neurological condition was 2.8 days (IQR 2.0, 4.5) vs. 4.0 days (IQR 3.5, 7.6) for those who survived to discharge without a good neurological outcome (p=0.035). There was no significant association between initial rhythm, renal insufficiency, paralytic use, post-arrest seizure, or location of arrest and time to awakening. CONCLUSION: In TH-treated PCAS patients, time to awakening after resuscitation was highly variable and often longer than three days. Earlier awakening was associated with better neurologic status at hospital discharge. PMID- 23916555 TI - PXR-ALAS1: a key regulatory pathway in liver toxicity induced by isoniazid rifampicin antituberculosis treatment. PMID- 23916556 TI - Gut microbiota and bile acids: an old story revisited (again). PMID- 23916557 TI - Bacteria and vampirism in cinema. AB - A vampire is a non-dead and non-alive chimerical creature, which, according to various folklores and popular superstitions, feeds on blood of the living to draw vital force. Vampires do not reproduce by copulation, but by bite. Vampirism is thus similar to a contagious disease contracted by intravascular inoculation with a suspected microbial origin. In several vampire films, two real bacteria were staged, better integrated than others in popular imagination: Yersinia pestis and Treponema pallidum. Bacillus vampiris was created for science-fiction. These films are attempts to better define humans through one of their greatest fears: infectious disease. PMID- 23916558 TI - The role of HIF in cobalt-induced ischemic tolerance. AB - Understanding the endogenous survival pathways induced by ischemic tolerance may yield targets for neuroprotection from stroke. One well-studied pathway reported to be evoked by preconditioning stimuli is the transcription factor HIF (hypoxia inducible factor). However, whether HIF induction by ischemic insults is neuroprotective or toxic is still unclear. We examined the ability of three prolyl-hydroxylase inhibitors, which induce HIF, to protect hippocampal cultures from oxygen-glucose deprivation. Hippocampal cultures were exposed to ischemic preconditioning or various concentrations of cobalt chloride, deferoxamine (DFO) or dimethyloxylalyglycine (DMOG), prior to lethal oxygen-glucose deprivation (OGD). Cell survival of neurons and astrocytes was determined with dual-label immunocytochemistry. The induction of HIF targets was assessed in mixed as well as astrocyte-enriched cultures. Ischemic preconditioning, as well as low concentrations of cobalt and DFO, enhanced the survival of neurons following OGD. However, DMOG exacerbates OGD-induced neuronal death. At low concentrations, all three prolyl-hydroxylase (PHD) inhibitors increased the survival of astrocytes. Neuroprotective concentrations of cobalt induced the transcription of the cytokine erythropoietin (EPO) in astrocyte cultures. In addition, pretreatment with recombinant human erythropoietin (rH-EPO) also protected neurons from OGD. Our data suggest that HIF-induced EPO, released from astrocytes, protects neurons from OGD. However, the three PHD inhibitors each exhibited different neuroprotective profiles at low concentrations, suggesting that not all PHD inhibitors are created equal. The protective effects at low doses is reminiscent of HIF involvement in ischemic tolerance, in which sub-lethal insults induce HIF pathways resulting in neuroprotection, whereas the high-dose toxicity suggests that over-activation of HIF is not always protective. Therefore, the choice of inhibitor and dose may determine the clinical utility of these compounds. Deferoxamine exhibited little toxicity even at higher doses, and therefore appears a promising candidate for clinical use. PMID- 23916559 TI - Characterization of the defects in the ATP lid of E. coli MutL that cause transient hypermutability. AB - Mutator strains spontaneously arise in bacterial populations under stress in an attempt to increase evolutionary adaptation. Inactivation of the ubiquitous DNA mismatch repair pathway, whose normal function is to correct replication errors and hence increase replication fidelity, is often the cause of the mutator phenotype. One of the essential genes in this pathway, mutL, includes a short tandem repeat that is prone to polymerase slippage during replication. While extensive work has established that this repetitive sequence is a genuine genetic switch, the mechanism of MutL inactivation remains unclear. This short tandem repeat is translated into a LALALA motif that resides near the ATPase active site of MutL. Therefore, changes in the length of this motif are presumed to alter the ATPase activity of MutL. We have engineered variants of Escherichia coli MutL with shorter/longer LALALA motifs and characterized their ATPase and DNA binding functions. We have found that the deletion or insertion of a single LA repeat did not compromise the structural integrity of the protein, nor did it affect MutS- or DNA-binding activity. However, it severely compromised ATP binding and, consequently, engagement of the N-terminal domains; both essential activities for proper DNA mismatch repair. These results are discussed in the context of the structure of MutL. PMID- 23916560 TI - Isolation of polyketides from Prymnesium parvum (Haptophyta) and their detection by liquid chromatography/mass spectrometry metabolic fingerprint analysis. AB - Prymnesium parvum is a microalga that forms blooms coupled with the presence of potent exotoxins; however, no chemical standards are currently available for the toxins. Streamlined methods are presented for the separation and enrichment of polyketide toxins, prymnesin-1 (prym1) and prymnesin-2 (prym2). Prymnesins were separated by reversed-phase chromatography and detected by positive-mode electrospray ionization MS to generate a unique metabolic fingerprint. More than 10 ions were detected and mass assignments were in agreement with predicted isotopic distributions for the intact compounds and related fragments; ions occurred as multiply protonated species and with common salt adducts. The most prevalent ion was observed at 919.88 m/z, which represents the aglycone [prymagly+2H](2+) backbone structure common to both molecules. Expanded mass spectra for this and related ions were in excellent agreement (<0.5ppm) with empirically derived spectra based on elemental composition and naturally occurring isotopes. These investigations have confirmed the isolation of polyketide prymnesins from whole cells, which heretofore has not been reproduced since their original characterization. Moreover, this study represents the first time these compounds have been verified in aqueous materials. These tools should allow the direct identification and analysis of polyketide prymnesins, which will greatly improve our understanding of these toxins in P. parvum. PMID- 23916561 TI - Selection and orientation of different particles in single particle imaging. AB - The short pulses of X-ray free electron lasers can produce diffraction patterns with structural information before radiation damage destroys the particle. The particles are injected into the beam in random orientations and they should be identical. However, in real experimental conditions it is not always possible to have identical particles. In this paper we show that the correlation maximization method, developed earlier, is able to select identical particles from a mixture and find their orientations simultaneously. PMID- 23916562 TI - Detection of soluble co-factor dependent protein expression in vivo: application to the 4'-phosphopantetheinyl transferase PptT from Mycobacterium tuberculosis. AB - The need for early-on diagnostic tools to assess the folding and solubility of expressed protein constructs in vivo is of great interest when dealing with recalcitrant proteins. In this paper, we took advantage of the picomolar sensitivity of the bipartite GFP1-10/GFP11 system to investigate the solubility of the Mycobacterium tuberculosis 4'-phosphopantetheinyl transferase PptT, an enzyme essential for the viability of the tubercle bacillus. In vivo and in vitro complementation assays clearly showed the improved solubility of the full-length PptT compared to its N- and C-terminally truncated counterparts. However, initial attempts to purify the full-length enzyme overexpressed in Escherichia coli cells were hampered by aggregation issues overtime that caused the protein to precipitate within hours. The fact that the naturally occurring Coenzyme A and Mg(2+), essentials for PptT to carry out its function, could play a role in stabilizing the enzyme was confirmed using DSF experiments. In vitro activity assays were performed using the ACP substrate from the type I polyketide synthase PpsC from M. tuberculosis, a 2188 amino-acid enzyme that plays a major role in the virulence and pathogenicity of this microbial pathogen. We selected the most soluble and compact ACP fragment (2042-2188), identified by genetic selection of in-frame fragments from random library experiments, to monitor the transfer of the P-pant moiety from Coenzyme A onto a conserved serine residue of this ACP domain. PMID- 23916563 TI - Clinical characteristics and therapeutic outcomes of hematogenous vertebral osteomyelitis caused by methicillin-resistant Staphylococcus aureus. AB - OBJECTIVE: To evaluate the clinical characteristics and therapeutic outcomes of patients with hematogenous vertebral osteomyelitis (HVO) caused by methicillin resistant Staphylococcus aureus (MRSA). METHODS: We performed a cohort study of adult patients diagnosed with S. aureus HVO at a tertiary-care hospital over a 7 year period. RESULTS: Of the 139 patients with S. aureus HVO, MRSA caused 62 (44.6%) cases. In multivariate analysis, compared with methicillin-susceptible S. aureus (MSSA), MRSA was associated with a higher risk of persistent bacteremia (>=7 days) (8.40 fold; P < 0.001) and relapse (4.83 fold; P = 0.03), and increased hospital stay (1.69 fold; P = 0.001). Among the MRSA cases, relapse rates differed according to duration of antibiotics: 41.7% (4-6 weeks), 25.0% (6 8 weeks), and 5.6% (>=8 weeks) (P = 0.007). Bacteremia was more likely to persist for >=7 days in patients with an initial vancomycin trough <15 mg/L than in those with an initial trough >=15 mg/L (79.3% vs. 20.0%; P = 0.001). CONCLUSIONS: MRSA HVO was associated with more frequent persistent bacteremia (>=7 days) and relapse, and longer hospital stay compared to MSSA HVO. Antibiotic therapy for >=8 weeks and targeting a vancomycin trough of >=15 mg/L may be benefit patients with MRSA HVO. PMID- 23916564 TI - A possible role for the chloroplast pyruvate dehydrogenase complex in plant glycolate and glyoxylate metabolism. AB - Glyoxylate is a peroxisomal intermediate of photorespiration, the recycling pathway for 2-phosphoglycolate (2-PG) produced by the oxygenase activity of Rubisco. Under hot and dry growth conditions, photorespiratory intermediates can accumulate and must be detoxified by alternative pathways, including plastidal reactions. Moreover, there is evidence that chloroplasts are capable of actively producing glyoxylate from glycolate. Further metabolic steps are unknown, but probably include a CO2 release step. Here, we report that CO2 production from glycolate and glyoxylate in isolated tobacco chloroplasts can be inhibited by pyruvate, but not related compounds. We isolated a protein fraction that was enriched for the chloroplast pyruvate dehydrogenase complex (PDC). The fraction contained a protein complex of several MDa in size that included all predicted subunits of the chloroplast PDC and a so far unidentified HSP93-V/ClpC1 heat shock protein. Glyoxylate competitively inhibited NADH formation from pyruvate in this fraction. The Km for pyruvate and the Ki for glyoxylate were 330 and 270 MUM, respectively. Glyoxylate decarboxylation was also enriched in this fraction and could be in turn inhibited by pyruvate. Based on these data, we suggest that the chloroplast PDC might be part of a pathway for glycolate and/or glyoxylate oxidation in chloroplasts. PMID- 23916565 TI - Clinical characteristics of central diabetes insipidus in Taiwanese children. AB - BACKGROUND/PURPOSE: Data on the clinical features of children with central diabetes insipidus (CDI) are lacking in Taiwan. This study investigated the clinical manifestations and etiology of CDI in Taiwanese children. METHODS: From 1983 to 2012, 62 children with permanent diabetes insipidus were enrolled in the study. They were diagnosed at the Department of Pediatrics of National Taiwan University Hospital. Their medical records were thoroughly reviewed and their clinical symptoms and signs, laboratory data, and etiologies were analyzed. RESULTS: The patients' median age at diagnosis was 10 years and the median interval between initial manifestations and diagnosis was 0.5 years. The most common symptoms and signs were polyuria, polydipsia, nocturia, and growth retardation. Most patients had low urine osmolality and elevated plasma osmolality on diagnosis. Absence of a posterior pituitary hyperintense signal and thickening of the pituitary stalk were common findings on magnetic resonance imaging. Approximately 80% of the patients had anterior pituitary hormone deficiency and all patients had growth hormone deficiency. Approximately 60% of patients had intracranial lesions, the most common causes of which were germ cell tumor and Langerhans cell histiocytosis. Two patients were initially believed to have idiopathic CDI but intracranial lesions were detected during the follow-up period. CONCLUSION: Because a delayed diagnosis of CDI is common in Taiwanese children, a high index of suspicion is important. The underlying etiology of CDI in children may not initially be obvious. Long-term surveillance is therefore necessary, especially for the early detection of evolving treatable intracranial lesions. PMID- 23916566 TI - Phylogenetic relationships of the enigmatic longtailed rattlesnakes (Crotalus ericsmithi, C. lannomi, and C. stejnegeri). AB - The longtailed rattlesnakes of western Mexico represent an enigmatic group of poorly known venomous snake species: Crotalus ericsmithi, C. lannomi, and C. stejnegeri. In the 120 years since their discovery, fewer than twenty individuals have been deposited in natural history collections worldwide. These three species share similar morphological traits, including a particularly long tail that has been interpreted as either an ancestral condition among rattlesnakes or as derived within the longtailed group. An understanding of the phylogenetic distinctiveness and relationships among the longtailed rattlesnakes, and their relationships to other rattlesnake groups, has previously been hampered by a dearth of comparative material and tissues for collection of DNA sequence data. Facilitated by the recent availability of tissue samples from multiple individuals of each species, we estimate the phylogenetic relationships among the longtailed rattlesnakes and their placement among other rattlesnake groups, using DNA sequence data from three mitochondrial and three nuclear gene fragments. We explore phylogenetic signal in our data using Bayesian and maximum likelihood methods, species tree analyses and hypothesis testing. Our results strongly support the monophyly of longtailed rattlesnakes and suggest the three species diverged from each other during the mid to late Pliocene or early Pleistocene (~1.5-5.6 mya). Contrary to prevailing hypotheses, we find no evidence for an early or basal divergence of the longtailed clade within the rattlesnake tree, and instead estimate that it diverged relatively recently (~6.8 mya) from its sister lineage, composed of the diamondback rattlesnakes (C. atrox group) and the prairie rattlesnakes (C. viridis group). With our added sampling of lineages and identification of previously used problematic sequences, we provide a revised hypothesis for relationships among Crotalus species, yet underscore the need for future studies and new data to deliver a well-supported robust estimate of rattlesnake relationships. PMID- 23916567 TI - Protective effect of soybeans as protein source in the diet against cadmium-aorta redox and morphological alteration. AB - We investigated the effects of cadmium exposition on thoracic aorta redox status and morphology, and the putative protective effect of soybeans in the diet. Male Wistar rats were separated into 6 groups: 3 fed with a diet containing casein and 3 containing soybeans, as protein source. Within each protein group, one was given tap water (control) and the other two tap water containing 15 and 100 ppm of Cd(2+), respectively, for two months. In rats fed with casein diet, 15 ppm of Cd induced an increase of thiobarbituric acid-reactive substances (TBARS), and of the catalase (CAT) and glutathione peroxidase (GPx) activities, which were even higher with 100 ppm of Cd(2+), in aorta. Also, 100 ppm Cd(2+) exposure increased superoxide dismutase (CuZnSOD) activity; CAT, GPX, SOD, Nrf2 and metallothioneine II mRNA expressions and CAT, GPx and NOX-2 protein levels, compared with control. Aorta endothelial and cytoplasmic alterations were observed. However, with the soybeans diet, 15 and 100 ppm of Cd(2+) did not modify TBARS levels; CAT, GPX and Nrf2 mRNA expressions; CAT, GPx and NOX-2 protein; and the aorta morphology, compared with control. The soybean diet attenuates the redox changes and protects against morphological alterations induced, in a dose-dependent way, by Cd in aorta. PMID- 23916568 TI - Spontaneous self-assembly of DNA fragments into nucleus-like structures from yolk granules of fertilized chicken eggs: Antoine Bechamp meets Bong Han Kim via Olga Lepeshinskaya. AB - We found evidence that spontaneous self-assembly of DNA molecules from yolk granules occurred during the very early stage of egg fertilization. In order to find solid evidence for self-assembly of DNA molecules, we collected many available data in different stages of fertilized eggs, making a data table. At first by using acridine orange vital staining to demonstrate DNA, we noticed that some yolk granules emitted DNA signals that gradually increased with increasing incubation time from very small sizes to much larger nucleus-like structures. For convincing evidence, we also used another vital dye, Hoechst 33258 DNA-specific dye, to trace the changes in the yolk granules. The patterns of the DNA signals from yolk granules stained with Hoechst 33258 were the same as those from the yolk granules stained with acridine orange. A partial phase contrast microscopic image of the changes in the yolk granules showed some liquid-like material around the granules before the formation of the nucleus-like structures. Concomitant use of fluorescence and partial phase contrast microscopy suggested that these liquid like materials may have been released from yolk granules in which spontaneous self-assembly of DNA molecules had occurred. Finally, in order to verify whether the DNA signals came from real DNA molecules or not, by using deoxyribonuclease I (DNAse), we confirmed that the nucleus-like structures were really assembled DNA molecules. Thus, in this article, we report evidence for the self-assembly of DNA molecules toward cell-like structures and discuss our findings, comparing them with those in the works of other pioneers, especially Antoine Bechamp, Olga Lepeshinskaya and Bong Han Kim, who insisted on the existence of a mitosis-free alternative pathway for generating new cells. PMID- 23916569 TI - [New oral anticoagulants in primary care: The general practitioner's point of view]. AB - The assessment of new anticoagulants benefits is based on the assessment of thromboembolism and bleeding risks, referring when possible to CHA2DS2-VASc and HAS-BLED scores. The management of patients treated with new anticoagulants includes a clinical assessment and the annual measure of the creatinine clearance (three times per year in some particular cases). New anticoagulants make hemostasis tests not reliable. The general practitioner has a role in preventing interactions and reporting potential adverse drug reactions. The context of uncertainty about the risk/benefit ratio of new anticoagulants emphasizes the need to integrate the values of the patient in treatment decisions. PMID- 23916570 TI - [Supportive care in the management of treatment-resistant and chronic anorexia nervosa]. AB - Although many patients face a long and severe evolution, there is no consensus regarding the definition of chronic and/or refractory anorexia nervosa. The multiplication of treatments and therapies lead to what could be called a total resistance to treatment in these patients. Cognitive impairment in anorexia nervosa, known to be worsened by deep denutrition, is a striking issue as it could limit the ability of the patients to consent to needed care. Constrained admission ruled by French July 5th 2011 psychiatric law could be decided given the aforementioned consent issues. When care given to patients involuntarily admitted are unsuccessful, supportive and palliative care could be an alternative in chronic and refractory anorexia nervosa. The goals of care would be shifted at this point to active comfort measures and better quality of life. PMID- 23916571 TI - The lower cranial nerves: IX, X, XI, XII. AB - The lower cranial nerves innervate the pharynx and larynx by the glossopharyngeal (CN IX) and vagus (CN X) (mixed) nerves, and provide motor innervation of the muscles of the neck by the accessory nerve (CN XI) and the tongue by the hypoglossal nerve (CN XII). The symptomatology provoked by an anomaly is often discrete and rarely in the forefront. As with all cranial nerves, the context and clinical examinations, in case of suspicion of impairment of the lower cranial nerves, are determinant in guiding the imaging. In fact, the impairment may be located in the brain stem, in the peribulbar cisterns, in the foramens or even in the deep spaces of the face. The clinical localization of the probable seat of the lesion helps in choosing the adapted protocol in MRI and eventually completes it with a CT-scan. In the bulb, the intra-axial pathology is dominated by brain ischemia (in particular, with Wallenberg syndrome) and multiple sclerosis. Cisternal pathology is tumoral with two tumors, schwannoma and meningioma. The occurrence is much lower than in the cochleovestibular nerves as well as the leptomeningeal nerves (infectious, inflammatory or tumoral). Finally, foramen pathology is tumoral with, outside of the usual schwannomas and meningiomas, paragangliomas. For radiologists, fairly hesitant to explore these lower cranial pairs, it is necessary to be familiar with (or relearn) the anatomy, master the exploratory technique and be aware of the diagnostic possibilities. PMID- 23916572 TI - [Ethics and blood transfusion]. AB - Blood donation is an act of solidarity. Most often, this act is done on a volunteer basis and, depending on countries and circumstances, is not remunerated. The increase in need, the always-greater number of deferral criteria, the safety issues and the changes in the structures of our societies are among the many subjects for ethical debates. Taking these into account, the actors of the transfusion must analyze certain parameters: the value of a donation, the meaning of volunteering, the appropriateness of remunerating the act of giving a part of one's self, no longer as a donation or an expression of altruism and solidarity, but as a commercial act regimented by economic laws. PMID- 23916573 TI - Biosimilar G-CSF (filgrastim) is effective for peripheral blood stem cell mobilization and non-cryopreserved autologous transplantation. PMID- 23916574 TI - [Sickle cell anemia and transfusion safety in Bamako, Mali. Seroprevalence of HIV, HBV and HCV infections and alloimmunization belonged to Rh and Kell systems in sickle cell anemia patients]. AB - Red cell transfusion is one of the main treatments in sickle cell disease. However there are potential risks of blood transfusions. In order to propose strategies to improve blood safety in sickle cell disease in Mali, we conducted a prospective study of 133 patients with sickle cell anemia recruited at the sickle cell disease research and control center of Bamako, November 2010 to October 2011. The study aimed to determine the prevalence of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections by serum screening and the frequency of red cell alloimmunization before and after blood transfusion. The diagnosis of sickle cell syndrome was made by HPLC, the detection of markers of viral infection was performed by ELISA, and the diagnosis of alloimmunization was conducted by the Indirect Coombs test. Prevalence of viral infections observed at the time of enrolment of patients in the study was 1%, 3% and 1% respectively for HIV, HBV and HCV. Three cases of seroconversion after blood transfusion were detected, including one for HIV, one for HBV and one another for HCV in sickle cell anemia patients. All these patients had received blood from occasional donors. The red cell alloimmunization was observed in 4.4% of patients. All antibodies belonged to Rh system only. Blood transfusion safety in sickle cell anemia patients in Mali should be improved by the introduction of at least the technique for detecting the viral genome in the panel of screening tests and a policy of transfusions of blood units only from regular blood donors. PMID- 23916575 TI - Hypothalamic AMPK activation blocks lipopolysaccharide inhibition of glucose production in mice liver. AB - Endotoxic hypoglycaemia has an important role in the survival rates of septic patients. Previous studies have demonstrated that hypothalamic AMP-activated protein kinase (hyp-AMPK) activity is sufficient to modulate glucose homeostasis. However, the role of hyp-AMPK in hypoglycaemia associated with endotoxemia is unknown. The aims of this study were to examine hyp-AMPK dephosphorylation in lipopolysaccharide (LPS)-treated mice and to determine whether pharmacological hyp-AMPK activation could reduce the effects of endotoxemia on blood glucose levels. LPS-treated mice showed reduced food intake, diminished basal glycemia, increased serum TNF-alpha and IL-1beta levels and increased hypothalamic p-TAK and TLR4/MyD88 association. These effects were accompanied by hyp-AMPK/ACC dephosphorylation. LPS-treated mice also showed diminished liver expression of PEPCK/G6Pase, reduction in p-FOXO1, p-AMPK, p-STAT3 and p-JNK level and glucose production. Pharmacological hyp-AMPK activation blocked the effects of LPS on the hyp-AMPK phosphorylation, liver PEPCK expression and glucose production. Furthermore, the effects of LPS were TLR4-dependent because hyp-AMPK phosphorylation, liver PEPCK expression and fasting glycemia were not affected in TLR4-mutant mice. These results suggest that hyp-AMPK activity may be an important pharmacological target to control glucose homeostasis during endotoxemia. PMID- 23916576 TI - Benefits of primary surgical resection for symptomatic urethral prolapse in children. AB - OBJECTIVE: Urethral prolapse (UP) is a complete eversion of the distal urethral mucosa through the external meatus. UP must be distinguished by examination from trauma, prolapsed ureterocele, tumors or sexual abuse. Its management remains controversial. The aim of the study was to promote the benefits of primary surgical management for UP. METHODS: A retrospective multicenter review of children who received surgery for UP between 1991 and 2011 was carried out. Non complicated UP was primarily treated conservatively. A total of 19 patients were referred for complicated UP and underwent resection of the prolapsed urethral mucosa. RESULTS: The mean delay in diagnosis was 2.2 days (range 1-6) and the most common symptoms were vaginal spotting and bleeding. No predisposing factor was found, but most patients had a mean weight, height and BMI greater than the 50th percentile. All patients underwent surgery successfully. One patient experienced a complication, i.e., dysuria. There was no case of recurrence after a mean 28 months of follow-up. CONCLUSION: Early detection is based on bedside examination. The first-line treatment strategy for uncomplicated UP should be conservative management. Surgical resection is safe and effective for patients with significant symptoms. PMID- 23916577 TI - Flow confirmation study for central venous port in oncologic outpatient undergoing chemotherapy: evaluation of suspected system-related mechanical complications. AB - PURPOSE: To evaluate the efficacy and outcome of a flow confirmation study (FCS) in oncologic outpatients undergoing chemotherapy suspected of a central venous port (CVP) system-related mechanical complication. MATERIALS AND METHODS: A total of 66 patients (27 men, 39 women; mean age, 60 years) received FCS for the following reasons: prolonged infusion time during chemotherapy (n=32), inability to inject saline fluid (n=15), lateral neck and/or back pain (n=6), subcutaneous extravasation of anticancer drug (n=5), arm swelling (n=4), and inability to puncture the port (n=4). FCS consisted of examining the position of CVP, potential secondary shifts or fractures, and integrity of the system using contrast material through the port. RESULTS: Of the 66 patients, 43 had an abnormal finding uncovered by FCS. The most frequent abnormal findings was catheter kinking (n=22). Explantation and reimplantation of the CVP system was required in 21 of the 66 patients. Remaining 45 patients were able continue using the CVP system after the FCS without any system malfunction. CONCLUSION: FCS was effective for evaluating CVP system-related mechanical complications and was useful for deciding whether CVP system explantation and reimplantation was required. PMID- 23916578 TI - The value and limitations of contrast-enhanced transrectal ultrasonography for the detection of prostate cancer. AB - OBJECTIVES: To evaluate the role of contrast-enhanced transrectal ultrasonography (CE-TRUS) for detecting prostate carcinoma. METHODS: Sixty-five patients with elevated serum prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE) were assessed using transrectal ultrasound (TRUS) and CE-TRUS. In all the patients, CE-TRUS was performed with intravenous injection of contrast agent (SonoVue, 2.4 ml) before biopsy. The cancer detection rates of the two techniques were compared. False-positive and false-negative findings related to CE-TRUS were analyzed in comparison to the pathological results of biopsy or radical prostatectomy. The targeted biopsy to abnormal CE-TRUS areas was also compared to systematic biopsy. RESULTS: Prostate cancer was detected in 29 of the 65 patients. CE-TRUS showed rapid focal enhancement or asymmetric vessels of peripheral zones in 28 patients; 23 of them had prostate cancer. CE-TRUS had 79.3% sensitivity, compared to 65.5% of TRUS (P<0.05). There were five false positive and six false-negative findings from CE-TRUS. Benign prostate hyperplasia, and acute and chronic prostatitis were important causes related to the false-positive results of CE-TRUS. Prostate cancer originating from the transition zone or peripheral zone with lower PSA levels, small-size foci, and moderately or well-differentiated tumor was missed by CE-TRUS. The cancer detection rate of targeted biopsy (75%, 33/44 cores) was significantly higher than one of systematic biopsy (48.2%, 162/336) in those 28 cases (P<0.05). In addition, no significant correlation was found between the cancer detection rate with CE-TRUS and serum PSA levels. CONCLUSION: CE-TRUS may improve the detection rate of prostate cancer through targeted biopsy of contrast-enhanced abnormalities. Our findings indicate that systematic biopsies should not be eliminated on the basis of false-positive and false-negative findings related to CE-TRUS. PMID- 23916579 TI - New cytotoxic triterpenoid saponins from the whole plant of Clematis lasiandra Maxim. AB - Four new oleanane type triterpenoid saponins (1-4) and three known saponins (5-7) were isolated from the whole plant of Clematis lasiandra Maxim. The structures of the four new compounds were elucidated as 3-O-beta-D-ribopyranosyl-(1 -> 3)-alpha L-rhamnopyranosyl-(1 -> 2)-[beta-D-glucopyranosyl-(1 -> 4)]-beta-D-xylopyranosyl hederagenin (1), 3-O-beta-D-ribopyranosyl-(1 -> 3)-alpha-L-rhamnopyranosyl-(1->2) beta-D-xylopyranosyl oleanolic acid 28-O-beta-D-glucopyranosyl ester (2), 3-O beta-D-ribopyranosyl-(1 -> 3)-alpha-L-rhamnopyranosyl-(1 -> 2)-beta-D xylopyranosyl hederagenin (3) and 3-O-beta-D-ribopyranosyl-(1 -> 3)-alpha-L rhamnopyranosyl-(1 -> 2)-[beta-D-glucopyranosyl-(1->4)]-alpha-L-arabinopyranosyl hederagenin (4) on the basis of extensive spectroscopic analysis and chemical evidence. Compounds 1-7 were evaluated for their cytotoxicity against human tumor cell lines HL-60, Hep-G2 and SGC-7901, and all of the evaluated saponins showed significant cytotoxicity to those three tumor cell lines with IC50 in the range from 1.40 to 19.50 MUmol/L except for compounds 2 and 6. PMID- 23916581 TI - Novel NGF-potentiating limonoids from the fruits of Melia toosendan. AB - Four new limonoids (1-4), together with five known limonoids (5-9), were isolated from the fruits of Melia toosendan. Their structures were elucidated based on extensive spectroscopic analyses (1D- and 2D-NMR, HRESIMS, IR, [alpha](D)). The isolated compounds were evaluated for their neurite outgrowth-promoting activities. Compounds 2 and 6 significantly enhanced NGF-mediated neurite outgrowth in PC12 cells at concentrations ranging from 0.1 to 50.0 MUM. PMID- 23916580 TI - Isolation of xanthone and benzophenone derivatives from Cyclopia genistoides (L.) Vent. (honeybush) and their pro-apoptotic activity on synoviocytes from patients with rheumatoid arthritis. AB - A fast and efficient method for the isolation of the C-glucosidated xanthones mangiferin and isomangiferin from the South-African plant Cyclopia genistoides was developed for the first time. The procedure involved extraction, liquid liquid partitioning with ethyl acetate and subsequent precipitation of mangiferin and isomangiferin from methanol and acetonitrile-water fractions, respectively. Additionally, two benzophenone derivatives: 3-C-beta-glucosides of maclurin and iriflophenone, were isolated from C. genistoides extracts using semi-preparative HPLC. Apart from the above, the isolation procedure also yielded hesperidin and small amounts of luteolin. The structures of the compounds were determined by 1D and 2D NMR experiments and/or LC-DAD-ESI-MS. The selected Cyclopia constituents were screened for pro-apoptotic activity on TNF-alpha-stimulated synovial cells isolated from rheumatoid arthritis patients. The strongest effect, measured as percent of apoptotic cells, was recorded for isomangiferin (75%), followed by iriflophenone 3-C-beta-glucoside (71%), hesperidin (67%) and mangiferin (65%). The results are encouraging for further studies on the use of the above compounds in the treatment of rheumatoid arthritis. PMID- 23916582 TI - Prenatal diagnosis of scrotal-inguinal hernia: two case reports and review of the English literature. AB - We present two cases of a prenatal diagnosis of inguinal hernia and the fetal outcome. Initial differential diagnosis included sacrococcygeal teratoma and testicular termatoma, while the final diagnosis was scrotal-inguinal hernia based on sonographic visualization of bowel loop movement in the scrotal mass. PMID- 23916583 TI - Effects of the levonorgestrel-releasing intrauterine system on urinary symptoms in patients with adenomyosis. AB - OBJECTIVES: We hypothesized that treatment of adenomyosis with the levonorgestrel releasing intrauterine system (LNG-IUS) can concurrently improve urinary incontinence along with irritative and obstructive symptoms and thus positively affect the patients' quality of life. STUDY DESIGN: Sixty-five patients suffering from heavy prolonged menstrual bleeding (menorrhagia) with dysmenorrhea diagnosed with uterine adenomyosis by ultrasound were enrolled in this study. LNG-IUS was inserted in the outpatient department for the treatment of the uterine adenomyosis. The patients filled out two validated questionnaires, the Urogenital Distress Inventory (UDI-6) and the Incontinence Impact Questionnaire (IIQ-7), before and 6 months after the insertion of the LNG-IUS. The before and after scores were compared using the non-parametric Mann-Whitney U test. RESULTS: The mean (+/- SD) age of the patients was 44.5 +/- 6.5 years. Both UDI and IIQ scores were significantly lower at 6 months after treatment with the LNG-IUS (P<0.0001). UDI scores revealed improvement rates of 14.3%, 35.7%, and 22.7% for urinary incontinence, irritative symptoms, and obstructive symptoms, respectively. Moreover, improvements in irritative and obstructive symptoms were significantly correlated with improvements in menorrhagia and dysmenorrhea (P<0.04). IIQ scores demonstrated improvement rates of 18.9%, 14.6%, 19.7%, and 18.5% for physical activity, travel, social relations, and emotional health, respectively. CONCLUSIONS: LNG-IUS used for treating menorrhagia and dysmenorrhea improved urinary incontinence along with irritative and obstructive symptoms in patients with adenomyosis. PMID- 23916584 TI - Anatomical and functional assessment of anterior colporrhaphy versus polypropylene mesh surgery in cystocele treatment. AB - OBJECTIVE: To compare the anatomical and functional results of traditional anterior colporrhaphy and polypropylene mesh surgery in cystocele treatment. STUDY DESIGN: Prospective study conducted in the Urogynecology Clinic of Etlik Zubeyde Hanim Maternity and Women's Health Teaching and Research Hospital between June 2006 and February 2007. Forty patients with stage II and III cystocele according to the Pelvic Organ Prolapse Quantification system were allocated by a computer programme to conventional or mesh surgery. Twenty patients each underwent anterior colporrhaphy (group I) or polypropylene mesh (Sofradim((r)), Parieten) surgery (group II). Both groups were followed for 12 months. RESULTS: At the end of the 12th month, anatomical cure rates were 15/20 (75%) and 19/20 (95%) in groups I and II, respectively, and the difference between the two groups was statistically significant (p<0.05). De novo stress urinary incontinence developed in one patient in group I. Mesh erosion developed postoperatively in three cases (15%). CONCLUSION: In terms of anatomical cure rates, polypropylene mesh surgery was the more successful treatment option when compared with anterior colporrhaphy at the end of 1 year follow-up. PMID- 23916585 TI - Use of thiamine pyrophosphate to prevent infertility developing in rats undergoing unilateral ovariectomy and with ischemia reperfusion induced in the contralateral ovary. AB - OBJECTIVE: To investigate whether thiamine pyrophosphate can prevent infertility developing in rats undergoing unilateral ovariectomy and with ischemia reperfusion induced in the contralateral ovary. Biochemical examinations of the ovaries were also performed. STUDY DESIGN: Rats were divided into two main groups of three subgroups each. An ischemia reperfusion model was established in the first main group, while surgical unilateral ovariectomy was performed in the second. Thiamine pyrophosphate and melatonin were administered to the subgroups. No additional procedure was performed in the control groups. The rats were then left in laboratory environments and their fertility levels were determined. Malondialdehyde, total glutathione and DNA damage products were measured in those rats from which ovarian tissue was collected. RESULTS: The results showed that thiamine pyrophosphate prevented ischemia/reperfusion injury-related infertility, but melatonin did not provide adequate prevention. However, reproduction in healthy animals receiving melatonin began earlier compared to those receiving thiamine pyrophosphate. Melatonin suppressed oxidative stress caused by ischemia/reperfusion in ovarian tissue significantly better than did thiamine pyrophosphate. CONCLUSIONS: We think that different mechanisms, in addition to antioxidant activity, are involved in the prevention of reperfusion-associated infertility after ischemia. PMID- 23916586 TI - Cytotoxicity of bovine alpha-lactalbumin: oleic acid complexes correlates with the disruption of lipid membranes. AB - HAMLET/BAMLET (Human/Bovine alpha-Lactalbumin Made Lethal to Tumors) is a tumoricidal substance composed of partially unfolded human/bovine alpha lactalbumin (HLA/BLA) and several oleic acid (OA) molecules. The HAMLET mechanism of interaction involves an insufficiently understood effect on the membrane or its embedded components. We examined the effect of BLAOA (bovine alpha lactalbumin complexed with oleic acid, a HAMLET-like substance) and its individual components on cells and artificial lipid membranes using viability staining and metabolic dyes, fluorescence spectroscopy, leakage integrity assays and microscopy. Our results show a dose-dependency of OA used to prepare BLAOA on its ability to induce tumor cell death, and a correlation between leakage and cell death. BLAOA incorporates into the membrane, tightens the lipid packing and lowers their solvent accessibility. Fluorescence imaging reveals that giant unilamellar vesicles (GUVs) develop blebs and eventually collapse upon exposure to BLAOA, indicating that the lipid packing reorganization can translate into observable morphological effects. These effects are observed to be local in GUVs, and a tightly packed and solvent-shielded lipid environment is associated with leakage and GUV disruption. Furthermore, the effects of BLAOA on membrane are pH dependent, with an optimum of activity on artificial membranes near neutral pHs. While BLA alone is effective at membrane disruption at acidic pHs, OA is ineffective in a pH range of 4.5 to 9.1. Taken together, this supports a model where the lipid, fatty acid and protein components enhance each other's ability to affect the overall integrity of the membrane. PMID- 23916587 TI - Rehabilitation of faulty kinetic determinations and misassigned glycoside hydrolase family of retaining mechanism beta-xylosidases. AB - We obtained Cx1 from a commercial supplier, whose catalog listed it as a beta xylosidase of glycoside hydrolase family 43. NMR experiments indicate retention of anomeric configuration in its reaction stereochemistry, opposing the assignment of GH43, which follows an inverting mechanism. Partial protein sequencing indicates Cx1 is similar to but not identical to beta-xylosidases of GH52, including Q09LZ0, that have retaining mechanisms. Q09LZ0 beta-xylosidase had been characterized biochemically in kinetic reactions that contained Tris. We overproduced Q09LZ0 and demonstrated that Tris is a competitive inhibitor of the beta-xylosidase. Also, the previous work used grossly incorrect extinction coefficients for product 4-nitrophenol. We redetermined kinetic parameters using reactions that omitted Tris and using correct extinction coefficients for 4 nitrophenol. Cx1 and Q09LZ0 beta-xylosidases were thus shown to possess similar kinetic properties when acting on 4-nitrophenyl-beta-d-xylopyranoside and xylobiose. kcat pH profiles of Cx1 and Q09LZ0 acting on 4-nitrophenyl-beta-d xylopyranoside and xylobiose have patterns containing two rate increases with increasing acidity, not reported before for glycoside hydrolases. The dexylosylation step of 4-nitrophenyl-beta-d-xylopyranoside hydrolysis mediated by Q09LZ0 is not rate determining for kcat(4NPX). PMID- 23916589 TI - Biochemical and structural characterisation of dehydroquinate synthase from the New Zealand kiwifruit Actinidia chinensis. AB - One of the novel aspects of kiwifruit is the presence of a high level of quinic acid which contributes to the flavour of the fruit. Quinic acid metabolism intersects with the shikimate pathway, which is responsible for the de novo biosynthesis of primary and secondary aromatic metabolites. The gene encoding the enzyme which catalyses the second step of the shikimate pathway, dehydroquinate synthase (DHQS), from the New Zealand kiwifruit Actinidia chinensis was identified, cloned and expressed. A. chinensis DHQS was activated by divalent metal ions, and was found to require NAD(+) for catalysis. The protein was crystallised and the structure was solved, revealing a homodimeric protein. Each monomer has a NAD(+) binding site nestled between the distinct N- and C-terminal domains. In contrast to other microbial DHQSs, which show an open conformation in the absence of active site ligands, A. chinensis DHQS adopts a closed conformation. This is the first report of the structure of a DHQS from a plant source. PMID- 23916590 TI - Diet supplementation of Pediococcus pentosaceus in cobia (Rachycentron canadum) enhances growth rate, respiratory burst and resistance against photobacteriosis. AB - Cobia (Rachycentron canadum) is an economically important fish species for aquaculture in tropical and sub-tropical areas. Cobia aquaculture industry has severely damaged due to photobacteriosis caused by Photobacterium damselae subsp. piscicida (Pdp), especially in Taiwan. Antibiotics and vaccines have been applied to control Pdp infection, but the efficacy has been inconsistent. One species of lactic acid bacteria, Pediococcus pentosaceus strain 4012 (LAB 4012), was isolated from the intestine of adult cobia, and its culture supernatant can effectively inhibit Pdp growth in vitro. The acidic pH derived from metabolic acids in LAB culture supernatant was demonstrated to be an important factor for the suppression. After a 2-week feeding of LAB 4012, the growth rate of the fed cobia was 12% higher than that of the non-fed group, and the relative percentage of survival (RPS) of the fed cobia was found to be 74.4 in Pdp immersion challenge. In addition, the respiratory burst (RB) of peripheral blood leukocytes (PBL) in the LAB 4012-fed group was significantly higher than that of the non-fed group. Although feeding LAB 4012 did not improve specific antibody response in cobia after immunization with Pdp vaccine, it still significantly raised the survival rate by 22% over that of the non-fed group after Pdp immersion challenge. Judging by the quick induction of high protection against Pdp infection and promotion of growth in larvae, LAB 4012 was considered to be a viable probiotic for cobia aquaculture. PMID- 23916588 TI - PtdIns5P: news and views of its appearance, disappearance and deeds. AB - Accumulated evidence indicates that PtdIns5P, one of the seven phosphoinositides, found now to be constitutively present in yeast, plants and metazoa, serves as a signaling molecule to modulate pleiotropic cellular functions in both the nucleus and the cytoplasm. The enzymatic routes in biogenesis of basal PtdIns5P have remained incompletely understood. The role for candidate kinase PIKfyve that is principally involved in PtdIns(3,5)P2 production, has been questioned. In this review article we scrutinize the past obstacles that prevented the definitive implication of PIKfyve in PtdIns5P biosynthesis from PtdIns and focus on the recent pharmacological and genetic advancements that now make this conclusion well supported. We further summarize our current knowledge of the diverse stimuli modulating PtdIns5P levels, binding partners and regulated cellular process, with particular reference to the available mechanistic insights for the relevant signaling pathways. PMID- 23916591 TI - Short communication: quantitative comparison of iodothyronine deiodinase I and II mRNA expression in ovine tissues. AB - Iodothyronine deiodinases I and II (DIO1 and DIO2) remove iodine from T4 to convert it to a more biologically active T3. The relative contribution of different tissue deiodinases to the establishment of a euthyroid state in sheep is not known. The objective of this study was to quantitate the amounts of transcription of DIO1 and DIO2 deiodinases in different ovine tissues. Using RT qPCR, we found that DIO1 deiodinase is transcribed in skeletal muscle, kidney, and heart, more than thyroid, in diaphragm in quantities very similar to thyroid, and in liver, spleen, lung, and mammary gland lower than thyroid. We also found that the level of DIO2 transcription in all other tissues was lower than that in thyroid. In clinical settings, measurement of DIO1 and DIO2 expression in a given tissue may provide important clues on the intensity of selenium deficiency and its effects on the metabolism of thyroid hormones. PMID- 23916592 TI - Molecular typing of haemorrhagic septicaemia-associated Pasteurella multocida isolates from Pakistan and Thailand using multilocus sequence typing and pulsed field gel electrophoresis. AB - A comparative genetic study of 23 field isolates and vaccine strains of Pasteurella multocida associated with haemorrhagic septicaemia cases from Pakistan and Thailand was done using pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). The MLST sequence type (ST) for all 20 of the 23 isolates tested was 122. The PFGE results showed one band difference between the Pakistani and the Thai isolates. Sequence type 122 is the dominant associated profile with haemorrhagic septicaemia (HS) cases in South Asia. The study supports the concept of using PFGE for short-term epidemiology and MLST for long term epidemiology. PMID- 23916594 TI - Synthesis and structure-activity relationships of novel indazolyl glucocorticoid receptor partial agonists. AB - SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. PMID- 23916595 TI - Accelerated Caco-2 cell permeability model for drug discovery. AB - INTRODUCTION: By culturing Caco-2 cells according to a new and optimized protocol, it has been possible to accelerate the cell culture process in such a way that the cells can be used for experiments after only 6 days. The accelerated Caco-2 model has been compared to the traditional model (requiring 21-25 days of culture) in terms of tightness of the junctions, ability to rank chemical compounds for apparent permeability, active efflux and to discriminate P-gp substrates. METHODS AND RESULTS: In the new protocol, Caco-2 cells were cultured with the classical Caco-2 medium supplemented with puromycin. The initial cell seeding density was increased two times compared to the traditional procedure and the presence of a low concentration of puromycin in the culture medium reduced the Caco-2 permeability of mannitol. Bi-directional studies were performed with known P-gp substrates (rhodamine 123, digoxin and saquinavir) and with a total of 20 marketed drugs covering a wide range of physicochemical characteristics and therapeutic indications. Strong correlations were obtained between the apparent permeability in absorptive (Papp A->B) or secretory (Papp B->A) of the drugs in the accelerated model and in the traditional models and comparable efflux ratios were observed in the two studied models. DISCUSSION: The new protocol reduces costs for screening and leads to higher throughput compared to traditional Caco-2 cell models. This accelerated model provides short time-feedback to the drug design during the early stage of drug discovery. PMID- 23916596 TI - Taxonomic study of a salt tolerant Streptomyces sp. strain C-2012 and the effect of salt and ectoine on lon expression level. AB - Streptomyces strain C-2012 is a salt tolerant biocontrol PGPR that has been isolated from Iranian soil. The main aim of current study was finding strain C 2012 taxonomic position and to find the genes which are potentially involved in salt tolerance phenotype. Strain C-2012 chemotaxonomic, morphological and molecular characteristics indicate that this strain is a member of the genus Streptomyces. Phylogenetic analyses based on an almost complete 16S rRNA gene sequence revealed that this strain is closely related to Streptomyces rimosus JCM 4667(T). Also, DNA-DNA hybridization test estimated 74% relatedness between two strains and confirmed that C-2012 is a strain of S. rimosus. In order to find novel genes that are differentially expressed in response to the salt treatment, cDNA-AFLP was carried out. One of the selected expressed sequence tags (TDF-1) was found to be homologous to lon gene which produces a bacterial ATP-dependent proteases (proteases LA). Lon gene expression was induced following 450 mM salt (NaCl) treatment and its expression level was further (5.2-fold) increased in response to salt when ectoine was added to the medium. These results suggest that two protein protection systems including ectoine and ATP-dependent proteases synergistically are related. NaCl stress also caused an enhancement in the activity of extracellular protease. PMID- 23916597 TI - Oxidative stress and antioxidant status response of handball athletes: implications for sport training monitoring. AB - The chronic exposure to regular exercise training seems to improve antioxidant defense systems. However, the intense physical training imposed on elite athletes may lead to overtraining associated with oxidative stress. The purpose of the present study was to investigate the effect of different training loads and competition on oxidative stress, biochemical parameters and antioxidant enzymatic defense in handball athletes during 6-months of monitoring. Ten male elite handball athletes were recruited to the study. Blood samples were collected four times every six weeks throughout the season. During most intense periods of training and competitions there were significant changes in plasma indices of oxidative stress (increased TBARS and decreased thiols). Conversely, chronic adaptations to exercise training demonstrated a significant protective effect against oxidative stress in erythrocyte (decrease in TBARs and carbonyl group levels). Erythrocyte antioxidant enzyme activities were significantly increased, suggesting a training-induced antioxidant adaptation. Biomarkers of skeletal muscle damage were significantly increased during high-intensity training period (creatine kinase, lactate dehydrogenase and aspartate aminotransferase). No significant changes were observed in plasma IL-6, TNF-alpha and uric acid, whereas a significant reduction was found in the IL-1beta concentration and gamma glutamyl transferase activity. Oxidative stress and antioxidant biomarkers can change throughout the season in competitive athletes, reflecting the physical stress and muscle damage that occurs as the result of competitive handball training. In addition, these biochemical measurements can be applied in the physiological follow-up of athletes. PMID- 23916598 TI - Photoacoustic analysis of the ultrasonic irradiation effect in the photosynthetic activity in aquatic lirium plants. AB - We report, the application of the photoacoustic technique for monitoring the photosynthesis evolution in aquatic lirium (Eichhornia Crassipes), before and after it was exposed to ultrasonic irradiations. We obtained the disappearance of the phototobaric contribution in the PA signal measured for the irradiated samples with ultrasound of 17 kHz, and therefore of a possible damage in the centers producing the photosynthesis, due to the irradiation. These results show the utility of the ultrasonic irradiation, as well as, of the photosynthesis monitoring by means of the photoacoustic technique, for the elaboration and establishment of methodologies in the control of this aquatic plant, whose propagation causes many consequences extremely unfavorable for the environment, as well as for the diverse human activities that are developed in the bodies of water in the tropical and sub-tropical regions of the world. PMID- 23916593 TI - Glycogen synthase kinase-3 inhibitors: Rescuers of cognitive impairments. AB - Impairment of cognitive processes is a devastating outcome of many diseases, injuries, and drugs affecting the central nervous system (CNS). Most often, very little can be done by available therapeutic interventions to improve cognitive functions. Here we review evidence that inhibition of glycogen synthase kinase-3 (GSK3) ameliorates cognitive deficits in a wide variety of animal models of CNS diseases, including Alzheimer's disease, Fragile X syndrome, Down syndrome, Parkinson's disease, spinocerebellar ataxia type 1, traumatic brain injury, and others. GSK3 inhibitors also improve cognition following impairments caused by therapeutic interventions, such as cranial irradiation for brain tumors. These findings demonstrate that GSK3 inhibitors are able to ameliorate cognitive impairments caused by a diverse array of diseases, injury, and treatments. The improvements in impaired cognition instilled by administration of GSK3 inhibitors appear to involve a variety of different mechanisms, such as supporting long-term potentiation and diminishing long-term depression, promotion of neurogenesis, reduction of inflammation, and increasing a number of neuroprotective mechanisms. The potential for GSK3 inhibitors to repair cognitive deficits associated with many conditions warrants further investigation of their potential for therapeutic interventions, particularly considering the current dearth of treatments available to reduce loss of cognitive functions. PMID- 23916599 TI - Antinociceptive activity of crotoxin in the central nervous system: a functional Magnetic Resonance Imaging study. AB - Crotoxin, the main neurotoxic component of the venom of South American rattlesnake (Crotalus durissus terrificus), is reported to have potent antinociceptive activity. Several authors have shown mainly in behavioral pain models that crotoxin induces antinociceptive effects, supposed to be mediated by actions on the central nervous system. The antinociceptive effects of crotoxin (45 MUg/kg ip) in rats were verified in this study by increased response latencies in a Hargreaves test and tail flick test. In addition, it was demonstrated that crotoxin does not lead to motor impairments during a rotarod test and open field test. The main objective, carried out by blood oxygen level dependent functional Magnetic Resonance Imaging (BOLD fMRI) in anesthetized rats, was to determine which specific brain structures are involved in these antinociceptive effects. Moreover, potential antihyperalgesic effects were investigated by inducing a local hyperalgesia on the left hind paw. Therefore, antinociceptive effects (right paw) and antihyperalgesic effects (left paw) of crotoxin were able to be differentiated. As a result, crotoxin exhibited dominant antihyperalgesic but also antinociceptive effects during pain stimulation. Reductions of BOLD signal already occurred in brain input structures but were most prominent in primary and secondary somatosensory cortices. In conclusion, BOLD fMRI in anesthetized rats proved to be a helpful tool in toxinology, particularly in unraveled mechanisms of modulating nociception in the central nervous system by (potential) analgesics like crotoxin. PMID- 23916600 TI - Mitochondrial dysfunction contributes to the cytotoxicity induced by tentacle extract from the jellyfish Cyanea capillata in rat renal tubular epithelial NRK 52E cells. AB - Our previous studies have shown that tentacle extract (TE) from the jellyfish Cyanea capillata could induce a delayed jellyfish envenomation syndrome with severe multiple organ dysfunctions, among which renal injury with tubular necrosis seemed to be most serious. So, in this study, we aimed to explore the toxic effect of TE on rat renal tubular epithelial NRK-52E cells. Based on the previous findings that TE could cause oxidative damage in erythrocytes, the effects of TE on cell oxidative stress conditions, including ROS production and lipid peroxidation, and mitochondrial dysfunction associated with cell death were investigated in NRK-52E cells. The results showed that TE caused cell morphological change and decreased cell viability through induction of apoptosis and necrosis in NRK-52E cells. Meanwhile, ROS overproduction and mitochondrial membrane potential decrease were found before the cell death occurred. It was concluded that TE could induce cytotoxicity, especially apoptosis and necrosis, in NRK-52E cells, and mitochondrial dysfunction and ROS overproduction might play important roles in the process of cell injury and death. PMID- 23916601 TI - Interaction of characteristic structural elements of persimmon tannin with Chinese cobra PLA2. AB - To more fully understand the mechanism by which persimmon tannin (PT) inhibited phospholipase A2 (PLA2) and the structural requirements of PT for the inhibition, the interactions between PLA2 and seven characteristic structural elements of PT including epigallocatechin-3-gallate (EGCG), myricetin, epicatechin-3-gallate (ECG), epicatechin-3-gallate-(4beta -> 8, 2beta -> O -> 7)-epicatechin-3-gallate (A-type ECG dimer), epigallocatechin-3-gallate-(4beta -> 8, 2beta -> O -> 7) epigallocatechin-3-gallate (A-type EGCG dimer), epicatechin-(4beta -> 8, 2beta -> O -> 7)-epicatechin (A-type EC dimer) and epicatechin-(4beta -> 8)-epicatechin (B type EC dimer) were studied by enzymatic and spectroscopic methods. Molecular docking was also used to explore the possible residues involved in the interactions. The results revealed that A-type EGCG dimer and A-type ECG dimer showed higher inhibitory effects on the catalytic activity of PLA2 than monomers and B-type dimer. They induced greater conformational changes in PLA2 than other structural elements. In addition, molecular docking studies revealed that expect for lysine residues, other residues such as Trp18, Try27, Gly29, His47 and Tyr63 were involved in the interactions. We propose that A-type EGCG and ECG dimer units may be structural requirements for the interaction between PT and PLA2. Our data provide an additional structural basis for anti-PLA2 activity of persimmon tannin. PMID- 23916602 TI - Safety of intravenous equine F(ab')2: insights following clinical trials involving 1534 recipients of scorpion antivenom. AB - INTRODUCTION: The technology of antivenom production has gradually changed since the earliest production of antisera around the turn of the 20th century. Use of early antisera was associated with frequent acute adverse reactions and serum sickness. New F(ab')2 products, manufactured using pepsin degradation of immunoglobulin together with precipitation of unwanted protein and albumin serum fractions, should in concept cause fewer immune reactions in clinical use. METHODS: A linked set of five prospective clinical trials of an equine F(ab')2 antivenom, together with one historical control study, were completed during development of the product for a Biological License Application through the US FDA. Adverse events were recorded and categorized, with particular attention to the frequency of immune reactions. RESULTS: A total of 1534 patients ages 0.1 90.5 years received antivenom, in Arizona and in Mexico, for treatment of scorpion envenomation. Total dosing ranged from 1 to 5 vials except for one outlier who received 10 vials. Estimated protein exposure was 12-275 mg per patient (outlier, up to 550 mg). Three patients (0.2%) had acute reactions to antivenom infusion (one urticaria, one urticaria and dyspnea, and one panic attack). Eight (0.5%) had rashes suggestive of Type 3 immune reactions, although none had the full syndrome of serum sickness. Two women were treated for envenomation during the first trimester of pregnancy, one of whom subsequently experienced a spontaneous abortion. CONCLUSIONS: Rates of immune reaction to this product were two orders of magnitude lower than the range (up to 75% for early and 81% for late reactions) historically reported with use of minimally refined whole immunoglobulin products against a variety of infections and envenomations. Lower protein dose, greater purity of the active component, lack of the immunogenic Fc portion of the immunoglobulin molecule, and slow intravenous infusion are likely to be the reason for this. Clinical implications of a safer product include that it can be employed in settings where antivenom was once considered too dangerous to use, such as primary care clinics and remote rural areas. PMID- 23916603 TI - Development of a non-lethal biopsy technique for estimating total tetrodotoxin concentrations in the grey side-gilled sea slug Pleurobranchaea maculata. AB - High concentrations of tetrodotoxin (TTX) have been detected in some New Zealand populations of Pleurobranchaea maculata (grey side-gilled sea slug). Within toxic populations there is significant variability in TTX concentrations among individuals, with up to 60-fold differences measured. This variability has led to challenges when conducting controlled laboratory experiments. The current method for assessing TTX concentrations within P. maculata is lethal, thus multiple individuals must be harvested at each sampling point to produce statistically meaningful data. In this study a method was developed for taking approximately 200 mg tissue biopsies using a TemnoEvolution((r)) 18G * 11 cm Biopsy Needle inserted transversely into the foot. Correlation between the TTX concentrations in the biopsy sample and total TTX levels and in individual tissues were assessed. Six P. maculata were biopsied twice (nine days apart) and each individual was frozen immediately following the second sampling. Tetrodotoxin concentrations in biopsy samples and in the gonad, stomach, mantle and the remaining combined tissues and fluids were measured using liquid chromatography mass spectrometry. Based on the proportional weight of the organs/tissues a total TTX concentration for each individual was calculated. There were strong correlations between biopsy TTX concentrations and the total (r(2) = 0.88), stomach (r(2) = 0.92) and gonad (r(2) = 0.83) TTX concentrations. This technique will enable more robust laboratory studies to be undertaken, thereby assisting in understanding TTX kinetics, ecological function and origin within P. maculata. PMID- 23916604 TI - Role of phospholipase C-beta in RNA interference. AB - Phospholipase C-beta (PLCbeta) enzymes are activated by G proteins in response to agents such as hormones and neurotransmitters, and have been implicated in leukemias and neurological disorders. PLCbeta activity causes an increase in intracellular calcium which ultimately leads to profound changes in the cell. PLCbeta localizes to three cellular compartments: the plasma membrane, the cytosol and the nucleus. Under most cell conditions, the majority of PLCbeta localizes to the plasma membrane where it interacts with G proteins. In trying to determine the factors that localize PLCbeta to the cytosol and nucleus, we have recently identified the binding partner, TRAX. TRAX is a nuclease and part of the machinery involved in RNA interference. This review discusses the interaction between PLCbeta and TRAX, and its repercussions in G protein signaling and RNA silencing. PMID- 23916605 TI - Phospholipase C zeta (PLCzeta): oocyte activation and clinical links to male factor infertility. AB - Mounting scientific and clinical evidence supports the key role played by phospholipase C zeta (PLCzeta), a sperm-specific protein, in the activation of oocytes following fertilisation. Lacking a pleckstrin homology domain, PLCzeta remains the smallest known mammalian PLC and was first identified in 2002. Since then, PLCzeta has been the target for a multitude of studies in both mammalian and non-mammalian species focused upon its fundamental biochemical activity and crucial role as the mediator of oocyte activation. The earliest event subsequent to gamete fusion is the onset of a series of intracellular calcium oscillations within the oocyte, which are known to modulate cortical granule exocytosis, release meiotic arrest, regulate gene expression, recruit maternal mRNA, and initiate embryogenesis. Collectively these processes are known as 'oocyte activation' and together, represent a fundamental mechanism for early embryonic development. Evidence suggests that these processes are initiated and controlled by calcium release from ooplasmic sources in response to PLCzeta activity via the inositol-1,4,5-triphosphate (IP3) pathway. While the biochemical action of PLCzeta has been extensively studied, especially in relation to the EF-hands, X-Y linker, and C2 domain, all of which play critical roles for in vivo activity, there are still key gaps in our knowledge, particularly in terms of regulation and interaction with other proteins within the oocyte. Moreover, increasing clinical evidence has revealed a strong correlation between certain types of male infertility and the aberrant expression, localisation, structure and function of PLCzeta in human sperm, particularly in cases of recurrent intracytoplasmic sperm injection (ICSI) failure, globozoospermia, and oocyte activation deficiency (OAD). In addition, two heterozygous substitution mutations have been identified in the coding sequence of PLCzeta in one particular patient causing disruption to the catalytic X and Y domains and resulting in infertility. Although, such cases can be treated via the use of artificial oocyte activators (AOAs) such as calcium ionophores, significant concern remains over the use of such chemical agents, largely due to the fact that calcium release manifests as a single transient, rather than a series of oscillations as observed during normal fertilisation. Current interest in PLCzeta is thus to develop a series of prognostic, diagnostic and therapeutic approaches which could first identify male patients that are deficient in PLCzeta and then rescue oocyte activation ability via assisted reproductive technology (ART) and a pure, functionally-active, recombinant human PLCzeta protein. While significant progress has been made in such areas over recent years, there is a clear need to translate scientific findings to clinical settings in order to maximise successful outcome for patients. PMID- 23916606 TI - Pitfalls in post-mortem CT-angiography--intravascular contrast induces post mortem pericardial effusion. AB - We present a case where multi-phase post-mortem computed tomography angiography (PMCTA) induced a hemorrhagic pericardial effusion during the venous phase of angiography. Post-mortem non-contrast CT (PMCT) suggested the presence of a ruptured aortic dissection. This diagnosis was confirmed by PMCTA after pressure controlled arterial injection of contrast. During the second phase of multi-phase PMCTA the presence of contrast leakage from the inferior cava vein into the pericardial sac was noted. Autopsy confirmed the post-mortem nature of this vascular tear. This case teaches us an important lesson: it underlines the necessity to critically analyze PMCT and PMCTA images in order to distinguish between artifacts, true pathologies and iatrogenic findings. In cases with ambiguous findings such as the case reported here, correlation of imaging findings with autopsy is elementary. PMID- 23916607 TI - Current practice of liquid chromatography-mass spectrometry in metabolomics and metabonomics. AB - Based on publication and citation numbers liquid chromatography (LC-MS) has become the major analytical technology in the field of global metabolite profiling. This dominance reflects significant investments from both the research community and instrument manufacturers. Here an overview of the approaches taken for LC-MS-based metabolomics research is given, describing critical steps in the realisation of such studies: study design and its needs, specific technological problems to be addressed and major obstacles in data treatment and biomarker identification. The current state of the art for LC-MS-based analysis in metabonomics/metabolomics is described including recent developments in liquid chromatography, mass spectrometry and data treatment as these are applied in metabolomics underlining the challenges, limitations and prospects for metabolomics research. Examples of the application of metabolite profiling in the life sciences focusing on disease biomarker discovery are highlighted. In addition, new developments and future prospects are described. PMID- 23916608 TI - Lamin A/C cleavage by caspase-6 activation is crucial for apoptotic induction by photodynamic therapy with hexaminolevulinate in human B-cell lymphoma cells. AB - Photodynamic therapy (PDT) with a light-activated drug is an approved modality for cancer treatment. Hexaminolevulinate (HAL), a hexylester of 5-aminolevulinic acid as the photosensitising protoporphyrin IX (PpIX) precursor, is clinically used for both PDT and photodetection. Our previous studies have shown that HAL PDT can effectively induce apoptosis in several human blood malignant cell lines. However, the mechanisms involved in the apoptotic induction are still not fully elucidated. In this study we have focused on the role of cellular lamin A/C in the apoptotic induction. HAL-PDT-mediated apoptosis was confirmed by various techniques including fluorescence microscopy and electron microscopy in both human B-cell lymphoma Ramos and Daudi cell lines. The lamin A/C, together with caspases-6 and -3, was cleaved during the apoptosis. Western blots, immunocytochemistry, fluorescence microscopy and electron microscopy demonstrated that the specific caspase-6 inhibitor abrogated the HAL-PDT-mediated cleavages of both caspase-6 and lamin A/C and subsequent apoptosis in these two cell lines, suggesting that the cleavage of lamin A/C by the caspase-6 activation is crucial for such apoptotic induction. PMID- 23916609 TI - Transcription factor Sox4 is required for PUMA-mediated apoptosis induced by histone deacetylase inhibitor, TSA. AB - PUMA is a crucial regulator of apoptotic cell death mediated by p53-dependent and p53-independent mechanisms. In many cancer cells, PUMA expression is induced in response to DNA-damaging reagent in a p53-dependent manner. However, few studies have investigated transcription factors that lead to the induction of PUMA expression via p53-independent apoptotic signaling. In this study, we found that the transcription factor Sox4 increased PUMA expression in response to trichostatin A (TSA), a histone deacetylase inhibitor in the p53-null human lung cancer cell line H1299. Ectopic expression of Sox4 led to the induction of PUMA expression at the mRNA and protein levels, and TSA-mediated up-regulation of PUMA transcription was repressed by the knockdown of Sox4. Using luciferase assays and chromatin immunoprecipitation, we also determined that Sox4 recruits p300 on the PUMA promoter region and increases PUMA gene expression in response to TSA treatment. Taken together, these results suggest that Sox4 is required for p53 independent apoptotic cell death mediated by PUMA induction via TSA treatment. PMID- 23916610 TI - MicroRNA-187, down-regulated in clear cell renal cell carcinoma and associated with lower survival, inhibits cell growth and migration though targeting B7-H3. AB - Aberrantly expressed microRNAs (miRNAs) are frequently associated with the aggressive malignant behavior of human cancers, including clear cell renal cell carcinoma (ccRCC). Based on the preliminary deep sequencing data, we hypothesized that miR-187 may play an important role in ccRCC development. In this study, we found that miR-187 was down-regulated in both tumor tissue and plasma of ccRCC patients. Lower miR-187 expression levels were associated with higher tumor grade and stage. All patients with high miR-187 expression survived 5years, while with low miR-187 expression, only 42% survived. Suppressed in vitro proliferation, inhibited in vivo tumor growth, and decreased motility were observed in cells treated with the miR-187 expression vector. Further studies showed that B7 homolog 3 (B7-H3) is a direct target of miR-187. Over-expression of miR-187 decreased B7-H3 mRNA level and repressed B7-H3-3'-UTR reporter activity. Knockdown of B7-H3 using siRNA resulted in similar phenotype changes as that observed for overexpression of miR-187. Our data suggest that miR-187 is emerging as a novel player in the disease state of ccRCC. miR-187 plays a tumor suppressor role in ccRCC. PMID- 23916611 TI - Crystal structures of 26kDa Clonorchis sinensis glutathione S-transferase reveal zinc binding and putative metal binding. AB - The crystal structures of CsGST in two different space groups revealed that Asp26 and His79 coordinate a zinc ion. In one space group, His46 of an adjacent molecule participates in the coordination within 2.0A. In the other space group, Asp26, His79 and a water molecule coordinate a zinc ion. The CsGST-D26H structure showed that four histidine residues - His26 and His79 from one molecule and the same residues from a symmetry-related neighboring molecule - coordinate a zinc ion. The coordinated zinc ions are located between two molecules and mediate molecular contacts within the crystal. PMID- 23916612 TI - Characterization of bud emergence 46 (BEM46) protein: sequence, structural, phylogenetic and subcellular localization analyses. AB - The bud emergence 46 (BEM46) protein from Neurospora crassa belongs to the alpha/beta-hydrolase superfamily. Recently, we have reported that the BEM46 protein is localized in the perinuclear ER and also forms spots close by the plasma membrane. The protein appears to be required for cell type-specific polarity formation in N. crassa. Furthermore, initial studies suggested that the BEM46 amino acid sequence is conserved in eukaryotes and is considered to be one of the widespread conserved "known unknown" eukaryotic genes. This warrants for a comprehensive phylogenetic analysis of this superfamily to unravel origin and molecular evolution of these genes in different eukaryotes. Herein, we observe that all eukaryotes have at least a single copy of a bem46 ortholog. Upon scanning of these proteins in various genomes, we find that there are expansions leading into several paralogs in vertebrates. Usingcomparative genomic analyses, we identified insertion/deletions (indels) in the conserved domain of BEM46 protein, which allow to differentiate fungal classes such as ascomycetes from basidiomycetes. We also find that exonic indels are able to differentiate BEM46 homologs of different eukaryotic lineage. Furthermore, we unravel that BEM46 protein from N. crassa possess a novel endoplasmic-retention signal (PEKK) using GFP-fusion tagging experiments. We propose that three residues namely a serine 188S, a histidine 292H and an aspartic acid 262D are most critical residues, forming a catalytic triad in BEM46 protein from N. crassa. We carried out a comprehensive study on bem46 genes from a molecular evolution perspective with combination of functional analyses. The evolutionary history of BEM46 proteins is characterized by exonic indels in lineage specific manner. PMID- 23916613 TI - Epigallocatechin-gallate (EGCG) regulates autophagy in human retinal pigment epithelial cells: a potential role for reducing UVB light-induced retinal damage. AB - Autophagy is an intracellular catabolic process involved in protein and organelle degradation via the lysosomal pathway that has been linked in the pathogenesis of age-related macular degeneration (AMD). UVB irradiation-mediated degeneration of the macular retinal pigment epithelial (RPE) cells is an important hallmark of AMD, which is along with the change in RPE autophagy. Thus, pharmacological manipulation of RPE autophagy may offer an alternative therapeutic target in AMD. Here, we found that epigallocatechin-3-gallate (EGCG), a polyphenolic compound from green tea, plays a regulatory role in UVB irradiation-induced autophagy in RPE cells. UVB irradiation results in a marked increase in the amount of LC3-II protein in a dose-dependent manner. EGCG administration leads to a significant reduction in the formation of LC3-II and autophagosomes. mTOR signaling activation is required for EGCG-induced LC3-II formation, as evidenced by the fact that EGCG-induced LC3-II formation is significantly impaired by rapamycin administration. Moreover, EGCG significantly alleviates the toxic effects of UVB irradiation on RPE cells in an autophagy-dependent manner. Collectively, our study reveals a novel role of EGCG in RPE autophagy. EGCG may be exploited as a potential therapeutic reagent for the treatment of pathological conditions associated with abnormal autophagy. PMID- 23916614 TI - MAPK and PI3K pathways regulate hypoxia-induced atrial natriuretic peptide secretion by controlling HIF-1 alpha expression in beating rabbit atria. AB - Mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways are pivotal and intensively studied signaling pathways in hypoxic conditions. However, the roles of MAPK and PI3K in the regulation of hypoxia-induced atrial natriuretic peptide (ANP) secretion are not well understood. The purpose of the present study was to investigate the mechanism by which the MAPK/ERK (extracellular signal-regulated kinase) and PI3K signaling pathways regulate the acute hypoxia-induced ANP secretion in isolated beating rabbit atria. An acute hypoxic perfused beating rabbit atrial model was used. The ANP levels in the atrial perfusates were measured by radioimmunoassay, and the hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA and protein levels in the atrial tissue were determined by RT-PCR and Western blot. Acute hypoxia significantly increased ANP secretion and HIF-1alpha mRNA and protein levels. Hypoxia-induced ANP secretion was markedly attenuated by the HIF-1alpha inhibitors, rotenone (0.5MUmol/L) and CAY10585 (10MUmol/L), concomitantly with downregulation of the hypoxia-induced HIF-1alpha mRNA and protein levels. PD098059 (30MUmol/L) and LY294002 (30MUmol/L), inhibitors of MAPK and PI3K, markedly abolished the hypoxia-induced ANP secretion and atrial HIF-1alpha mRNA and protein levels. The hypoxia-suppressed atrial dynamics were significantly attenuated by PD098059 and LY294002. Acute hypoxia in isolated perfused beating rabbit atria, markedly increased ANP secretion through HIF-1alpha upregulation, which was regulated by the MAPK/ERK and PI3K pathways. ANP appears to be part of the protective program regulated by HIF-1alpha in the response to acute hypoxic conditions. PMID- 23916616 TI - Relationship between sweat chloride, sodium, and age in clinically obtained samples. AB - BACKGROUND: The relationship between sweat electrolytes and age is uncertain, as is the value of measuring sodium or the chloride:sodium ratio. METHODS: 13,785 sweat tests performed over 23 years at one center through the Macroduct collection in clinically obtained samples were analyzed. RESULTS: Sweat chloride tended to decrease over the first year of life, slowly increase until the fourth decade, then either level off or slightly decrease. In children, sweat sodium overlapped between those with positive and negative sweat tests, but not in adults. If the sweat test was positive, there was a higher likelihood of having a chloride:sodium ratio >1, but most subjects with a ratio >1 did not have CF. CONCLUSIONS: Sweat chloride and sodium vary with age. Measurement of sweat sodium did not add discriminatory value. The proportion of subjects with a chloride:sodium ratio >1, with or without CF, varied greatly between age ranges. PMID- 23916615 TI - A peroxisome biogenesis deficiency prevents the binding of alpha-synuclein to lipid droplets in lipid-loaded yeast. AB - Using a yeast model of Parkinson's disease, we found that alpha-synuclein (alphaS) binds to lipid droplets in lipid-loaded, wild-type yeast cells but not to lipid droplets in lipid-loaded, peroxisome-deficient cells (pex3Delta). Our analysis revealed that pex3Delta cells have both fewer lipid droplets and smaller lipid droplets than wild-type cells, and that the acyl chains of the phospholipids on the surface of the lipid droplets from pex3Delta cells are on average shorter (C16) than those (C18) on the surface of lipid droplets from wild type cells. We propose that the shift to shorter (C18->C16) acyl chains contributes to the reduced binding of alphaS to lipid droplets in pex3Delta cells. PMID- 23916617 TI - Tick-borne encephalitis: a disease neglected by travel medicine. AB - Tick-borne encephalitis (TBE) is a vector-borne disease that is primarily transmitted to humans by infected ticks and causes infection of the central nervous system. Clinical presentations range from meningitis to encephalitis with or without myelitis, and infection may result in death or long-term neurological sequelae. TBE is endemic in regions of at least 27 European as well as in some Asian countries. Infection and disease, however, can be averted successfully by tick-bite prevention and active vaccination. The risk of infection has shifted from daily life and occupational exposure to leisure-time activities, including travelling. Outdoor activities during the tick season with contact with nature increase the risk of tick bites. Although the number of travel-associated cases is unknown, it is certainly under-estimated because there is hardly any awareness of TBE in non-endemic countries. Therefore, the majority of cases remain undiagnosed, also because of the lack of diagnostic serology, as there is no routine screening for TBE in non-endemic regions. Because of the increasing number of travellers from TBE non-endemic to endemic regions, and in view of the fact that TBE was included in the list of notifiable diseases in the European Union in September 2012, this disease needs to become an important issue in travel medicine. PMID- 23916618 TI - Walking in an unstable environment: strategies used by transtibial amputees to prevent falling during gait. AB - OBJECTIVE: To investigate which strategies transtibial amputees use to cope with challenges of gait stability and gait adaptability, and how these strategies differ from strategies used by able-bodied controls. DESIGN: Cross-sectional study. SETTING: An instrumented treadmill mounted onto a 6 degrees -of-freedom motion platform in combination with a virtual environment. PARTICIPANTS: Transtibial amputees (n=10) and able-bodied controls (n=9). INTERVENTIONS: Mediolateral (ML) translations of the walking surface were imposed to manipulate gait stability. To provoke an adaptive gait pattern, a gait adaptability task was used in which subjects had to hit virtual targets with markers guided by their knees. MAIN OUTCOME MEASURES: Walking speed, step length, step frequency, step width, and selected measures of gait stability (short-term Lyapunov exponents and backward and ML margins of stability [MoS]). RESULTS: Amputees walked slower than able-bodied people, with a lower step frequency and wider steps. This resulted in a larger ML MoS but a smaller backward MoS for amputees. In response to the balance perturbation, both groups decreased step length and increased step frequency and step width. Walking speed did not change significantly in response to the perturbation. These adaptations induced an increase in ML and backward MoS. To perform the gait adaptability task, both groups decreased step length and increased step width, but did not change step frequency and walking speed. ML and backward MoS were maintained in both groups. CONCLUSIONS: Transtibial amputees have the capacity to use the same strategies to deal with challenges of gait stability and adaptability, to the same extent as able-bodied people. PMID- 23916619 TI - Foot pressure pattern and its correlation with knee range of motion limitations for individuals with medial knee osteoarthritis. AB - OBJECTIVE: To determine the foot pressure pattern of individuals with medial knee osteoarthritis (OA) and to analyze its relation with knee flexion/extension range of motion. DESIGN: Descriptive. SETTING: Rehabilitation center. PARTICIPANTS: Individuals with unilateral, painful medial knee OA (n=50; mean age, 75y; OA group) were enrolled as subjects, and young, healthy persons (n=50; mean age, 28y; young group) and elderly persons (n=44; mean age, 74y; elderly group) without any pain, deformity, or apparent OA changes in either knee were enrolled as controls. INTERVENTION: Walking 10m at a comfortable speed. MAIN OUTCOME MEASURES: Partial foot pressures as percentages of body weight (%PFP), anteroposterior length of the center of pressure (COP) path as a percentage of foot length (%Long), transverse width of the COP path as a percentage of foot width (%Trans), knee flexion/extension range of motion (in the OA group). RESULTS: The %PFP values for the heel and hallux, %Long, and %Trans were all significantly lower in the OA group than in controls (P<.001, all). Within the OA group, a limited range of knee extension was significantly associated with a short %Long (P<.001) but not with %Trans. CONCLUSIONS: Individuals with medial knee OA exhibited low pressure on the heel and hallux and short %Long of the COP path, and limitation of knee extension was associated with shortness of %Long. The shortness of %Long in the OA group likely resulted from insufficient knee extension during the heel-contact phase associated with low pressure on the heel. %Long is a useful parameter in gait analysis by using a foot pressure measurement system. PMID- 23916620 TI - Optical coherence tomography: imaging of the choroid and beyond. AB - Seventy percent of the blood flow to the eye goes to the choroid, a structure that is vitally important to the function of the retina. The in vivo structure of the choroid in health and disease is incompletely visualized with traditional imaging modalities, including indocyanine green angiography, ultrasonography, and spectral domain optical coherence tomography (OCT). Use of new OCT modalities, including enhanced depth imaging OCT, image averaging, and swept-source OCT, have led to increased visualization of the choroidal anatomy. The correlation of these new anatomical findings with other imaging modalities results increases understanding of many eye diseases and recognises of new ones. The status of the choroid appears to be a crucial determinant in the pathogenesis of diseases such as age-related choroidal atrophy, myopic chorioretinal atrophy, central serous chorioretinopathy, chorioretinal inflammatory diseases, and tumors. Extension of these imaging techniques has provided insights into abnormalities of the sclera and optic nerve. Future developments will include blood flow information, 3D rendering of various ocular structures, and the ability to evaluate changes in 3D structural information over time (4D imaging). PMID- 23916621 TI - Molecular phylogeny of tribe Stachydeae (Lamiaceae subfamily Lamioideae). AB - Although tribe Stachydeae (Lamiaceae) is considered monophyletic, relationships within the tribe are still poorly understood. The complexity of Stachydeae includes paraphyletic genera, considerable morphological plasticity, a range of ploidy levels, and presumably frequent natural hybridization. We performed parsimony and Bayesian phylogenetic analyses of nuclear (ribosomal ITS) and plastid (trnL intron, trnL-trnF spacer, rps16 intron) DNA sequence data from a taxonomically and geographically broad sampling of the tribe to identify major evolutionary lineages and to test taxonomic hypotheses within this largest of all lamioid tribes. We included 143 accessions corresponding to 121 species, representing both Old and New World species, and all 12 recognized genera of tribe Stachydeae. Both nuclear and plastid data corroborate monophyly of the tribe, with Melittis as sister to all remaining Stachydeae. For the latter well supported clade, we suggest the phylogenetic name Eurystachys. Within Eurystachys, although monophyly is supported by both nuclear and plastid data for several named and unnamed groups, the majority of recognized taxa appear to be para- or polyphyletic. The taxon compositions of most subclades are congruent between the plastid and nuclear tree topologies, whereas their relative phylogenetic placements are often not. This level of plastid-nuclear incongruence suggests considerable impact of hybridization in the evolution of Stachydeae. PMID- 23916622 TI - Meta-analysis supports association of a functional SNP (rs1801133) in the MTHFR gene with Parkinson's disease. AB - The MTHFR is a candidate risk gene for Parkinson's disease (PD), and a functional SNP (rs1801133) in the coding region of this gene has been investigated for the associations with the illness extensively among worldwide populations, but overall the results were inconsistent. Here, to assess the relationship between rs1801133 and risk of PD in general populations, we conducted a systematic meta analysis by combining all available case-control samples in European and Asian populations, with a total of 1820 PD cases and 7530 healthy controls, and the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for rs1801133 and PD were calculated using the Mantel-Haenszel method with a fixed-effect model. Overall, rs1801133 was significantly associated with the risk of PD (allelic model, pooled OR=1.212 for T allele, 95% CI=1.097-1.340, p-value=0.0002). When stratifying for ethnicity, significant association was also observed in European (allelic model, pooled OR=1.187 for T allele, 95% CI=1.058-1.332, p-value=0.004) and Asian samples (allelic model, pooled OR=1.293 for T allele, 95% CI=1.058 1.580, p-value=0.012) respectively. In addition, rs1801133 was also significantly associated with MTHFR mRNA expression in both CEU (European, p-value=0.0149) and CHB (Chinese, p-value=0.0178) HapMap populations. Collectively, our meta-analysis suggests that rs1801133 is significantly associated with susceptibility to PD in European and Asian populations, and MTHFR is likely an authentic risk gene for PD. PMID- 23916623 TI - A brief history of excitable map-based neurons and neural networks. AB - This review gives a short historical account of the excitable maps approach for modeling neurons and neuronal networks. Some early models, due to Pasemann (1993), Chialvo (1995) and Kinouchi and Tragtenberg (1996), are compared with more recent proposals by Rulkov (2002) and Izhikevich (2003). We also review map based schemes for electrical and chemical synapses and some recent findings as critical avalanches in map-based neural networks. We conclude with suggestions for further work in this area like more efficient maps, compartmental modeling and close dynamical comparison with conductance-based models. PMID- 23916624 TI - Right fronto-parietal dysfunction underlying spatial attention in bipolar disorder. AB - Although the neural underpinning of bipolar disorder (BD) is still unknown, recent research suggests that the right fronto-parietal cortex is particularly affected in BD patients. If this were true, we would expect atypical functional cerebral asymmetries in allocation of visuospatial attention. To test this hypothesis, euthymic BD patients and age- and gender-matched healthy controls were compared on the visual line-bisection task, a reliable measure of visuospatial attention, associated with right parietal function. Line bisection performance (i.e. absolute and directional bias) was compared between groups as a function of response hand and line position. The results showed a typical hand use effect in healthy controls involving a larger leftward bias (i.e. pseudoneglect) with the left hand than with the right hand. Although euthymic BD patients did not differ from healthy controls in the overall accuracy (i.e. absolute bias), they differed significantly in the directional line bisection bias. In contrast to healthy controls, BD patients did not significantly deviate from the veridical center, regardless of which hand was used to bisect horizontal lines. This finding indicates an atypical functional cerebral asymmetry in visuospatial attention in euthymic BD patients, supporting the idea of a dysfunction especially in the right fronto-parietal cortex. PMID- 23916626 TI - Concealing cellular defects in pluripotent stem cells. AB - Inherent and acquired defects in gene expression, protein homeostasis, metabolic pathways, and organelle function are linked to aging and a wide range of human diseases. Although concealed or dormant in the embryonic stage, they often manifest later in life. We review and discuss recent observations on how somatic cells bearing specific phenotypic defects can be reprogrammed into a pluripotent state where most phenotypic abnormalities can be reset or tolerated. Gaining insights into the tolerance of cellular defects in pluripotent stem cells will facilitate our understanding of the properties of reprogrammed cells and may provide theoretical guidance for induced pluripotent stem cell based disease modeling and clinical therapies. PMID- 23916625 TI - Molecular architecture of the mammalian circadian clock. AB - Circadian clocks coordinate physiology and behavior with the 24h solar day to provide temporal homeostasis with the external environment. The molecular clocks that drive these intrinsic rhythmic changes are based on interlocked transcription/translation feedback loops that integrate with diverse environmental and metabolic stimuli to generate internal 24h timing. In this review we highlight recent advances in our understanding of the core molecular clock and how it utilizes diverse transcriptional and post-transcriptional mechanisms to impart temporal control onto mammalian physiology. Understanding the way in which biological rhythms are generated throughout the body may provide avenues for temporally directed therapeutics to improve health and prevent disease. PMID- 23916627 TI - Spatio-temporal variation of biogenic volatile organic compounds emissions in China. AB - Aiming to reduce the large uncertainties of biogenic volatile organic compounds (BVOCs) emissions estimation, the emission inventory of BVOCs in China at a high spatial and temporal resolution of 36 km * 36 km and 1 h was established using MEGANv2.1 with MM5 providing high-resolution meteorological data, based on the most detailed and latest vegetation investigations. BVOC emissions from 82 plant functional types in China were computed firstly. More local species-specific emission rates were developed combining statistical analysis and category classification, and the leaf biomass was estimated based on vegetation volume and production with biomass-apportion models. The total annual BVOC emissions in 2003 were 42.5 Tg, including isoprene 23.4 Tg, monoterpene 5.6 Tg, sesquiterpene 1.0 Tg, and other VOCs (OVOCs) 12.5 Tg. Subtropical and tropical evergreen and deciduous broadleaf shrubs, Quercus, and bamboo contributed more than 45% to the total BVOC emissions. The highest biogenic emissions were found over northeastern, southeastern, and southwestern China. Strong seasonal pattern was observed with the highest BVOC emissions in July and the lowest in January and December, with daily emission peaked at approximately 13:00 or 14:00 local time. PMID- 23916628 TI - Adsorption of carbamazepine by carbon nanotubes: effects of DOM introduction and competition with phenanthrene and bisphenol A. AB - Carbon nanotubes, organic contaminants and dissolved organic matter (DOM) are co introduced into the environment. Thus, the interactions between these components have to be evaluated to better understand their environmental behavior. In this study, single-walled carbon nanotubes (SWCNTs) were used as sorbent, carbamazepine was the primary adsorbate, and bisphenol A and phenanthrene were used as competitors. Strong competition with bisphenol A and no effect of phenanthrene on adsorption of carbamazepine was obtained. The hydrophobic neutral fraction of the DOM exhibited the strongest reductive effect on carbamazepine adsorption, most probably due to interactions in solution. In contrast, the hydrophobic acid fraction decreased carbamazepine adsorption mainly via direct competition. When DOM and bisphenol A were co-introduced, the adsorption of carbamazepine was significantly reduced. This study suggests that the chemical nature of DOM can significantly affect the sorptive behavior of polar organic pollutants with carbon nanotubes when all are introduced to the aquatic system. PMID- 23916629 TI - A randomized pilot study of anger treatment for Iraq and Afghanistan veterans. AB - OBJECTIVE: Anger and aggression are serious problems for a significant proportion of veterans who have served in combat. While prior research has suggested that cognitive behavioral treatments may be effective for anger problems, there are few controlled studies of anger treatment in veterans and no studies of anger treatment focusing exclusively on veterans from the Iraq and Afghanistan wars. This randomized pilot study compared an adapted cognitive behavioral intervention (CBI) to a supportive intervention (SI) control condition for the treatment of anger problems in veterans returning from deployment in Iraq or Afghanistan. METHODS: 25 veterans with warzone trauma, problems with anger, and one or more additional hyperarousal symptoms were randomized and 23 started treatment (CBI, n = 12; SI, n = 11). Outcome measures were administered at pre- and post- treatment and at 3 months post-treatment. RESULTS: CBI was associated with significantly more improvement than SI on measures of anger and interpersonal functioning. Gains were maintained at follow-up. CONCLUSIONS: Findings suggest that CBI may be more effective than an active control providing psychoeducation, relaxation, and supportive therapy for treating anger problems in returning veterans. The findings need to be replicated in an adequately powered and more diverse sample. PMID- 23916630 TI - Cognitive bias modification of interpretations: a viable treatment for child and adolescent anxiety? AB - Anxiety disorders in children and adolescents are common and impairing. As many patients do not benefit from - or have difficulties accessing - frontline treatments, novel, effective and easy-to-deliver interventions are needed. Cognitive Bias Modification of Interpretations (CBM-I) training has been used to treat adult anxiety disorders. CBM-I methods train individuals to endorse benign rather than negative resolutions of ambiguous cues. Developmental extensions of CBM-I are important for several reasons. First, implementing CBM-I in symptomatic children and adolescents may facilitate early preventative gains. Second, as training uses simple learning mechanisms, CBM-I may reflect a developmentally suitable strategy for shaping adaptive processing styles. Third, as this age range involves protracted neurocognitive maturation and associated plasticity, administering CBM-I early could drive powerful, long-lasting benefits for emotional development. Finally, data from CBM-I studies could inform the cognitive mechanisms involved in the genesis of early-emerging anxiety. This paper provides the first organised review of CBM-I studies conducted in children and adolescents, and contains suggestions for future research that may help realise the therapeutic potential of early CBM-I interventions. PMID- 23916632 TI - Eye movements during recall of aversive memory decreases conditioned fear. AB - Cognitive-behavioral therapy for anxiety disorders typically involves exposure to the conditioned stimulus (CS). Despite its status as an effective and primary treatment, many patients do not show clinical improvement or relapse. Contemporary learning theory suggests that treatment may be optimized by adding techniques that aim at revaluating the aversive consequence (US) of the feared stimulus. This study tested whether US devaluation via a dual task--imagining the US while making eye movements--decreases conditioned fear. Following fear acquisition one group recalled the US while making eye movements (EM) and one group merely recalled the US (RO). Next, during a test phase, all participants were re-presented the CSs. Dual tasking, relative to the control condition, decreased memory vividness and emotionality. Moreover, only in the dual task condition reductions were observed in self-reported fear, US expectancy, and CS unpleasantness, but not in skin conductance responses. Findings provide the first evidence that the dual task decreases conditioned fear and suggest it may be a valuable addition to exposure therapy. PMID- 23916633 TI - Treating PTSD in refugees and asylum seekers within the general health care system. A randomized controlled multicenter study. AB - OBJECTIVE: There has been uncertainty about whether refugees and asylum seekers with PTSD can be treated effectively in standard psychiatric settings in industrialized countries. In this study, Narrative Exposure Therapy (NET) was compared to Treatment As Usual (TAU) in 11 general psychiatric health care units in Norway. The focus was on changes in symptom severity and in the diagnostic status for PTSD and depression. METHOD: Refugees and asylum seekers fulfilling the DSM-IV criteria for PTSD (N = 81) were randomized with an a-priori probability of 2:1 to either NET (N = 51) or TAU (N = 30). The patients were assessed with Clinician Administered PTSD Scale, Hamilton rating scale for depression and the MINI Neuropsychiatric Interview before treatment, and again at one and six months after the completion. RESULTS: Both NET and TAU gave clinically relevant symptom reduction both in PTSD and in depression. NET gave significantly more symptom reduction compared to TAU as well as significantly more reduction in participants with PTSD diagnoses. No difference in treatment efficacy was found between refugees and asylum seekers. CONCLUSIONS: The study indicated that refugees and asylum seekers can be treated successfully for PTSD and depression in the general psychiatric health care system; NET appeared to be a promising treatment for both groups. PMID- 23916631 TI - A randomized clinical trial of Behavioral Activation (BA) therapy for improving psychological and physical health in dementia caregivers: results of the Pleasant Events Program (PEP). AB - Dementia caregiving is associated with elevations in depressive symptoms and increased risk for cardiovascular diseases (CVD). This study evaluated the efficacy of the Pleasant Events Program (PEP), a 6-week Behavioral Activation intervention designed to reduce CVD risk and depressive symptoms in caregivers. One hundred dementia family caregivers were randomized to either the 6-week PEP intervention (N = 49) or a time-equivalent Information-Support (IS) control condition (N = 51). Assessments were completed pre- and post-intervention and at 1-year follow-up. Biological assessments included CVD risk markers Interleukin-6 (IL-6) and D-dimer. Psychosocial outcomes included depressive symptoms, positive affect, and negative affect. Participants receiving the PEP intervention had significantly greater reductions in IL-6 (p = .040), depressive symptoms (p = .039), and negative affect (p = .021) from pre- to post-treatment. For IL-6, clinically significant improvement was observed in 20.0% of PEP participants and 6.5% of IS participants. For depressive symptoms, clinically significant improvement was found for 32.7% of PEP vs 11.8% of IS participants. Group differences in change from baseline to 1-year follow-up were non-significant for all outcomes. The PEP program decreased depression and improved a measure of physiological health in older dementia caregivers. Future research should examine the efficacy of PEP for improving other CVD biomarkers and seek to sustain the intervention's effects. PMID- 23916634 TI - Cognitive behaviour therapy for common mental disorders in people with Multiple Sclerosis: A bench marking study. AB - BACKGROUND: Mental health problems such as depression and anxiety are common in Multiple Sclerosis (MS) and are often under treated. AIMS: This paper reports on the clinical effectiveness of a cognitive behaviour therapy service for common mental disorders in people with MS and compares it to previous randomised controlled trials (RCTs) of cognitive behaviour therapy (CBT) in this population. METHODS: 49 patients were deemed appropriate for CBT and 29 accepted treatment. Assessments were completed at baseline and end of treatment and included the Hospital Anxiety & Depression Scale. Results in the form of a standardized effect of treatment were compared with five previous RCTs. RESULTS: The results from this clinical service indicated statistically significant outcomes with reductions in depression and anxiety. The uncontrolled effect size was large but inferior to those found in published RCTs. CONCLUSIONS: Cognitive behaviour therapy is effective for people with MS in routine clinical practice. Possible limits on effectiveness include more liberal patient selection, lack of specificity in rating scales and heterogeneity of target problems. Given the high rates of distress in this population, routine psychological interventions within neurology services are justifiable. Future research should aim to maximise CBT in such settings. PMID- 23916635 TI - Failure to capitalize on sharing good news with romantic partners: Exploring positivity deficits of socially anxious people with self-reports, partner reports, and behavioral observations. AB - Extending prior work on social anxiety and positivity deficits, we examined whether individual differences in social anxiety alter the ability to share and respond to the good news of romantic partners (i.e., capitalization support) and how this influences romantic relationship satisfaction and commitment. In this study of 174 heterosexual couples (average age of 21.5 with 58.3% identifying as Caucasian), greater social anxiety was associated with the provision and receipt of less supportive responses to shared positive events as measured by trait questionnaires, partner reports, and behavioral observations in the laboratory. In longitudinal analyses, individuals in romantic relationships with socially anxious partners who experienced inadequate capitalization support were more likely to terminate their relationship and report a decline in relationship quality six months later. As evidence of construct specificity, social anxiety effects were independent of depressive symptoms. Taken together, social anxiety influenced a person's ability to receive and provide support for shared positive events; these deficits had adverse romantic consequences. Researchers and clinicians may better understand social anxiety by exploring a wider range of interpersonal contexts and positive constructs. The addition of capitalization support to the social anxiety literature offers new insights into interpersonal approaches and treatments. PMID- 23916636 TI - Quantitative analysis of initial adhesion of bacterial vaginosis-associated anaerobes to ME-180 cells. AB - Bacterial vaginosis is the leading vaginal disorder but the transition from health to this dysbiotic condition remains poorly characterized. Our goal was to quantify the ability of BV-associated anaerobes to adhere to epithelial cells in the presence of lactobacilli. Gardnerella vaginalis outcompeted Lactobacillus crispatus and Lactobacillus iners actually enhanced its adherence. PMID- 23916638 TI - 2012 annual meeting of the American Association of Hip and Knee Surgeons (AAHKS). PMID- 23916637 TI - Pesticide exposure and self-reported incident depression among wives in the Agricultural Health Study. AB - BACKGROUND: Depression in women is a public health problem. Studies have reported positive associations between pesticides and depression, but few studies were prospective or presented results for women separately. OBJECTIVES: We evaluated associations between pesticide exposure and incident depression among farmers' wives in the Agricultural Health Study, a prospective cohort study in Iowa and North Carolina. METHODS: We used data on 16,893 wives who did not report physician-diagnosed depression at enrollment (1993-1997) and who completed a follow-up telephone interview (2005-2010). Among these wives, 1054 reported physician diagnoses of depression at follow-up. We collected information on potential confounders and on ever use of any pesticide, 11 functional and chemical classes of pesticides, and 50 specific pesticides by wives and their husbands via self-administered questionnaires at enrollment. We used inverse probability weighting to adjust for potential confounders and to account for possible selection bias induced by the death or loss of 10,639 wives during follow-up. We used log-binomial regression models to estimate risk ratios and 95% confidence intervals. RESULTS: After weighting for age at enrollment, state of residence, education level, diabetes diagnosis, and drop out, wives' incident depression was positively associated with diagnosed pesticide poisoning, but was not associated with ever using any pesticide. Use of individual pesticides or functional or chemical classes of pesticides was generally not associated with wives' depression. Among wives who never used pesticides, husbands' ever use of individual pesticides or functional or chemical classes of pesticides was generally not associated with wives' incident depression. CONCLUSIONS: Our study adds further evidence that high level pesticide exposure, such as pesticide poisoning, is associated with increased risk of depression and sets a lower bound on the level of exposure related to depression, thereby providing reassurance that the moderate levels of pesticide exposure experienced by farmers' wives likely do not increase risk. PMID- 23916639 TI - Trends in hip arthroscopy utilization in the United States. AB - INTRODUCTION: The purpose of this study was to evaluate the changing incidence of hip arthroscopy procedures among newly trained surgeons in the United States, the indications for hip arthroscopy, and the reported rate of post-operative complications. METHODS: The ABOS database was used to evaluate the annual incidence of hip arthroscopy procedures between 2006-2010. Procedures were categorized by indication and type of procedure. The rate of surgical complications was calculated and compared between the published literature and hip arthroscopy procedures performed for femoroacetabular impingement (FAI)/osteoarthritis (OA) and for labral tears among the newly trained surgeon cohort taking the ABOS Part II Board exam. RESULTS: The overall incidence of hip arthroscopy procedures performed by ABOS Part II examinees increased by over 600% during the 5-year period under study from approximately 83 in 2006 to 636 in 2010. The incidence of hip arthroscopy for FAI/OA increased steadily over the time period under study, while the incidence of hip arthroscopy for labral tears was variable over time. The rate of surgical complications was 5.9% for hip arthroscopy procedures for a diagnosis of FAI/OA vs. 4.4% for a diagnosis of labral tear (P=0.36). CONCLUSIONS: The incidence of hip arthroscopy has increased dramatically over the past 5 years, particularly for the indication of FAI/OA. Reported surgical complication rates are relatively low, but appear higher than those rates reported in previously published series. Appropriate indications for hip arthroscopy remain unclear. PMID- 23916640 TI - The functional assessment test: a method of evaluating improvement in function after knee arthroplasty. AB - Questionnaires are marginally useful for objectively measuring function after knee arthroplasty. The Functional Assessment (FA) test is an easily administered, timed test of a person's ability to stand, walk and ascend/descend stairs that would be useful for quantifying a patient's function after knee arthroplasty. Four hundred forty-five individuals were included in the study: 313 without lower extremity arthritis or neurologic disease and 132 with advanced degenerative arthritis prior to knee arthroplasty. As expected, the test times were longer for individuals afflicted with knee arthritis. Arthroplasty patients were tested pre- and postoperatively to determine if their FA test time improved. The FA test takes less than a minute and is practical for use in the clinical setting as a simple means of quantifying function before and after knee arthroplasty. PMID- 23916641 TI - Characterization of sperm surface protein patterns of ejaculated and capacitated boar sperm, with the detection of ZP binding candidates. AB - Complementary molecules on the surface of both gametes are responsible for the interaction of sperm protein receptors with zona pellucida (ZP) saccharide structures, and many primary sperm receptors for ZP glycoproteins have been disclosed in various mammals. For our study, proteins were obtained from the surface of ejaculated and in vitro capacitated boar sperm. The isolated proteins were characterized by 1D- and 2D-electrophoretic protein profiles, and by glycoprotein staining. Our results show quantitative and qualitative differences in protein and glycoprotein patterns between ejaculated and capacitated sperm. Far-western blotting with ZP glycoproteins identified 17 interactions in the subproteome of the ejaculated sperm and 14 interactions in the subproteome of the capacitated sperm. High-molecular-mass proteins, coincident with binding to ZP, were sequence-identified. Angiotensin-converting enzyme (ACE), polycystic kidney disease receptor and egg jelly receptor (PKDREJ), and acrosin precursor were successfully identified. This is the first time PKDREJ has been identified on the surface of boar spermatozoa. PMID- 23916642 TI - Preparation and characterization of macromolecule cross-linked collagen hydrogels for chondrocyte delivery. AB - Collagen hydrogels are widely used in cartilage tissue engineering for their mimicked chondrogenic environment. Due to the rapid degradation nature and weak mechanical property, collagen hydrogels are often cross-linked in application. In this work, collagen hydrogels were soaked into oxidized alginate solution which used as macromolecular cross-linker to prepare the cross-linked hydrogels. Soaking method could retain the self-assemble property of collagen and also bring in a cross-linking network. The compressive modulus and degradation properties of collagen hydrogels were ameliorated after cross-linked, and chondrocytes encapsulated in the cross-linked hydrogels proliferated well and maintained the cell phenotype. This study implied that collagen hydrogels cross-linked by oxidized alginate may have a great potential for application in cartilage tissue engineering. PMID- 23916643 TI - Thermal stability of matrix protein from Newcastle disease virus. AB - The thermal stability of the matrix protein (M protein) of Newcastle disease virus (NDV) has been investigated using high-sensitivity differential scanning calorimetry (DSC) at pH 7.4. The thermal folding/unfolding of M protein at this pH value is a reversible process involving a highly cooperative transition between folded and unfolded monomers with a transition temperature (Tm) of 63 degrees C, an unfolding enthalpy, DeltaH(Tm), of 340 kcal mol(-1), and the difference in heat capacity between the native and denatured states of the protein, DeltaCp, of 5.1 kcal K(-1) mol(-1). The heat capacity of the native state of the protein is in good agreement with the values calculated using a structure-based parameterization, whereas the calculated values for the hypothetical fully-unfolded state of the protein is higher than those determined experimentally. This difference between the heat capacity of denatured M protein and the heat capacity expected for an unstructured polypeptide of the same sequence, together with the data derived from the heat-induced changes in the steady-state fluorescence of the protein, indicates that the polypeptide chain maintains a significant amount of residual structure after thermal denaturation. PMID- 23916644 TI - Evaluation of Albizia procera gum as compression coating material for colonic delivery of budesonide. AB - The purpose of this research was to develop and evaluate Albizia procera gum as compression-coating polymer for colonic delivery of budesonide. Tablets were prepared by direct compression method using spray-dried lactose and microcrystalline cellulose as filler binders. The compatibility between the drug and the polymer was studied through TGA and FTIR spectroscopy. In vitro drug release were studied in dissolution media with or without 2% rat cecal contents while in vivo X-ray study was conducted on rabbits. The results indicate that procera gum and the drug were compatible with each other and tablet coated with procera gum was suitable for colonic delivery of drugs. PMID- 23916645 TI - Anti-diabetic activity of Vaccinium bracteatum Thunb. leaves' polysaccharide in STZ-induced diabetic mice. AB - Vaccinium bracteatum Thunb. (VBT) is a traditional Chinese herbal medicine. The anti-diabetic activity of VBT leaves' polysaccharide (VBTLP) is studied in this paper. The results indicated VBTLP had a dose-dependent decrease on the blood glucose (BG) level, and the time effect of VBTLP on BG level was also significant. The insulin level of high dose group (HDG) was significantly higher (p<0.05) than that of model control (MC) group. Compared to MC, HDG and lose dose group (LDG) had significantly lower (p<0.05) TC and LDL-C levels, however, TG and HDL-C levels are similar. Compared to non-diabetic control (NC), HDG and LDG had similar plasma lipid levels except for higher LDL-C level. Although body weights of LDG and HDG were significant lower (p<0.05) than that of NC from week 2 to week 6, they were similar to that of PC. The results indicate VBTLP possesses a potential hypoglycemic effect in streptozotocin-induced diabetic mice. PMID- 23916646 TI - Modified bamboo rayon-copper nanoparticle composites as antibacterial textiles. AB - In the current study the bamboo rayon fabric grafted with acrylamide was utilized as a backbone to immobilize copper nanoprticles. The grafted bamboo rayon was first treated with CuSO4 followed by chemical reduction. The modified product was characterized using FTIR, TGA and SEM. The characteristic color developed after reduction was measured spectrophotometrically. The grafted bamboo rayon with Cu nanoparticles was then evaluated for antibacterial activity against both gram positive and gram negative bacteria and the durability of their antibacterial activity after washing. The product showed antibacterial activity against both types of bacterias which was found to be durable till 50 washes. The material can be claimed as suitable candidate for medical textile applications to prevent cross-infections. PMID- 23916647 TI - Effect of chitosan film incorporated with tea polyphenol on quality and shelf life of pork meat patties. AB - The objective of this study was to investigate the effect of chitosan (CH) film incorporated with tea polyphenol (TP) on quality and shelf life of pork meat patties stored at 4+/-1 degrees C for 12 days. The microbiological, physicochemical (pH, thiobarbituric acid-reactive substances (TBARS) values, and metmyoglobin (MetMb)), and sensory qualities were measured on all the samples. A microbiological shelf-life extension of 6 days was achieved for CH and CH-TP treatment groups when compared to the control group. Wrapping with CH-TP composite film tended to retard the increases in TBARS values and MetMb content. CH-TP composite film maintained acceptable sensory quality of pork meat patties throughout the storage. The results indicated that CH-TP composite film could be a promising material as a packaging film for extending the shelf life of pork meat patties. PMID- 23916648 TI - Interaction between amylose and 1-butanol during 1-butanol-hydrochloric acid hydrolysis of normal rice starch. AB - The aim of this study was to examine the interaction between amylose and 1 butanol during the 1-butanol-hydrochloric acid (1-butanol-HCl) hydrolysis of normal rice starch. The interaction model between amylose and 1-butanol was proposed using gas chromatography-mass spectrometry (GC-MS), (13)C cross polarization and magic angle spinning NMR analysis ((13)C CP/MAS NMR), differential scanning calorimetry (DSC), and thermalgravimetric analysis (TGA). GC-MS data showed that another form of 1-butanol existed in 1-butanol-HCl hydrolyzed normal rice starch, except in the form of free molecules absorbed on the starch granules. The signal of 1-butanol-HCl-hydrolyzed starch at 100.1 ppm appeared in the (13)C CP/MAS NMR spectrum, indicating that the amylose-1-butanol complex was formed. DSC and TGA data also demonstrated the formation of the complex, which significantly affected the thermal properties of normal rice starch. These findings revealed that less dextrin with low molecular weight formed might be attributed to resistance of this complex to acid during 1-butanol HCl hydrolysis. PMID- 23916649 TI - Astragalus polysaccharide reduces inflammatory response by decreasing permeability of LPS-infected Caco2 cells. AB - As the major constituent of Radix Astragali, Astragalus polysaccharide (APS) is known for its anti-inflammation and immunomodulatory functions. The objective of this study was to investigate the effect of APS on inflammatory response and structural changes in lipopolysaccharide (LPS)-infected Caco2 cells. Caco2 cells were co-cultured with APS and LPS, with APS added after the addition of LPS (post addition), before the addition of LPS (pre-addition), or simultaneously with the addition of LPS (simultaneous addition). The mRNA expression of inflammatory indicators and tight junctions was measured by RT-qPCR. Short circuit current (Isc) was recorded by an Ussing chamber system. Addition of APS significantly down-regulated the expression of TNF-alpha, IL-1beta and IL-8 (P<0.05) and the Isc levels (P<0.05) of LPS-infected Caco2 cells for all three administration treatments. The minimum anti-inflammatory concentration of APS was 50, 100, and 100 MUg/mL for pre-, post-, and simultaneous additions of APS, respectively. The mRNA expression of zonula occludens-1 (ZO-1) and occludin was significantly up regulated for post- and pre-additions of APS, respectively (P<0.05). Results suggested that APS had anti-inflammatory and structure protective properties for LPS-infected Caco2 cells, and may be used as a preventative treatment for intestine cells. PMID- 23916650 TI - Antioxidant capacities of mannans and glucans are related to their susceptibility of free radical degradation. AB - Microbial and plant polysaccharides in nature are frequently exposed to oxidative burst. They may act as antioxidants buffering the radical attack. This paper presents antioxidant properties of prepared yeast mannans, commercial beta glucans as well as the chemically prepared carboxymethylated beta-glucan (CM glucan). The hydroxyl radical antioxidant assay and the DPPH radical-scavenging assay were used. Yeast mannans and beta-glucans (1.6 mg mL(-1)) showed antioxidant capacities against OH(.) up to 14.1%, while CM-glucan was significantly higher antioxidant (65.4%). In the DPPH(.) assay, the antioxidant capacities of yeast mannans and beta-glucans (1.0 mg mL(-1)) were lower and reached up to ~6.5%. All polysaccharides tested were effectively degraded by OH(.) and the presence of salicylate considerably inhibited their degradation. Measure of Fe(2+) chelation revealed less than 13.1% effectivity for all polysaccharides. In all antioxidant and degradation experiments the yeast mannans showed very similar results to commercial beta-glucans. The antioxidant capacities of polysaccharides may be assessed by simple HPLC monitoring. PMID- 23916651 TI - Novel A18T and pA29S substitutions in alpha-synuclein may be associated with sporadic Parkinson's disease. AB - OBJECTIVE: Mutations in the alpha-synuclein-encoding gene SNCA are considered as a rare cause of Parkinson's disease (PD). Our objective was to examine the frequency of the SNCA point mutations among PD patients of Polish origin. METHODS: Detection of the known SNCA point mutations A30P (c.88G>C), E46K (c.136G>A) and A53T (c.157A>T) was performed either using the Sequenom MassArray iPLEX platform or by direct sequencing of the SNCA exons 2 and 3. As the two novel substitutions A18T (c.52G>A) and A29S (c.85G>T) were identified, their frequency in a control population of Polish origin was assessed and in silico analysis performed to investigate the potential impact on protein structure and function. RESULTS: We did not observe the previously reported point mutations in the SNCA gene in our 629 PD patients; however, two novel potentially pathogenic substitutions A18T and A29S were identified. Each variant was observed in a single patient presenting with a typical late-onset sporadic PD phenotype. Although neither variant was observed in control subjects and in silico protein analysis predicts a damaging effect for A18T and pA29S substitutions, the lack of family history brings into question the true pathogenicity of these rare variants. CONCLUSIONS: Larger population based studies are needed to determine the pathogenicity of the A18T and A29S substitutions. Our findings highlight the possible role of rare variants contributing to disease risk and may support further screening of the SNCA gene in sporadic PD patients from different populations. PMID- 23916652 TI - Early clinical features of patients with progressive supranuclear palsy with predominant cerebellar ataxia. AB - BACKGROUND: Patients who develop progressive supranuclear palsy with predominant cerebellar ataxia (PSP-C) develop cerebellar ataxia as the initial and principal symptom, may be misdiagnosed as having multiple system atrophy with predominant cerebellar features (MSA-C). Therefore, we investigated the clinical signs and symptoms between PSP-C and MSA-C early in their disease course. METHODS: We reviewed the medical records of 15 consecutive patients with pathologically proven PSP-C (4) and MSA-C (11). We recorded the presence or absence of clinical features that developed within 2 years of disease onset. RESULTS: The age at onset of PSP-C patients was older than that of MSA-C patients (p = 0.009). The frequencies of falls were higher in PSP-C patients than in MSA-C patients (p = 0.026). Additionally, the development of supranuclear vertical gaze palsy was higher in PSP-C patients than in MSA-C patients (p = 0.011), whereas the frequency of dysautonomia was lower in PSP-C patients than in MSA-C patients (p = 0.035). CONCLUSIONS: Older onset, early falls, and supranuclear vertical gaze palsy without dysautonomia may predict the diagnosis of PSP-C in patients with late-onset sporadic cerebellar ataxia. PMID- 23916653 TI - Orthostatic myoclonus: an underrecognized cause of unsteadiness? AB - BACKGROUND AND PURPOSE: Recently, orthostatic myoclonus (OM) has been suggested as a cause of gait impairment and unsteadiness in neurodegenerative diseases. The aim of this study was to investigate the frequency of orthostatic myoclonus, its clinical characteristics and the underlying associated neurological disorders. METHODS: A retrospective analysis of clinical data and electromyogram surface recordings from subjects with unexplained unsteadiness/gait impairment was performed. Diagnosis of OM was made when a pattern of non-rhythmic bursts was observed (duration range 20-100 ms; bursts per second <=16). RESULTS: Among 93 subjects studied, OM was the most frequent disorder (n = 16; 17.2%), followed by orthostatic tremor (13.9%) and low frequency tremors during orthostatism (12.9%). All patients with OM complained about unsteadiness during orthostatism and/or during gait. Leg jerking was only observed by visual inspection during orthostatism in four subjects and two also presented falls. Eleven out of 16 patients (68.7%) with OM had an associated neurodegenerative disease, such as multiple system atrophy (n = 3) Parkinson's disease (n = 2), Alzheimer's disease (n = 2), mild cognitive impairment (n = 2) and normal pressure hydrocephalus (n = 2). Although four subjects showed improvement of orthostatic myoclonus with antimyoclonic treatment, the follow-up was not systematic enough to evaluate their therapeutic effect on OM. CONCLUSIONS: Orthostatic myoclonus is often underdiagnosed and can be considered a possible cause of unsteadiness in subjects with neurodegenerative diseases. Electromyography surface recording is thereby an aid for investigating unsteadiness of unknown origin. PMID- 23916655 TI - The Candrive/Ozcandrive prospective older driver study: Methodology and early study findings. AB - Although the vast majority of active, older drivers are safe drivers, health conditions and related functional declines associated with increasing age can affect driving ability. This is a concern for older drivers, their families, and the public, as well as government agencies. To address these issues, the Canadian Institutes of Health Research (CIHR) Team in Driving in Older Persons (Candrive II) Research Program was funded in 2008 to create a prospective cohort of older active drivers to be followed for several years. In 2009 an Australian collaboration (Ozcandrive) joined the project funded by an Australian Research Council (ARC) Linkage Grant. This special issue describes the preliminary findings of the Candrive/Ozcandrive prospective study of 1300 older drivers in Canada, Australia and New Zealand. The methodology for the study, description of the cohort and findings related to older driver health and effects on driving, as well as the utility of some existing older driver assessment tools used on this population, are described. Future findings from this ongoing study will lead to insights into older driver safety and tools that will ideally help keep older drivers safely on the road. PMID- 23916654 TI - Importance of motor vs. non-motor symptoms for health-related quality of life in early Parkinson's disease. AB - BACKGROUND: The relative impact of motor- and non-motor symptoms on health related quality of life in early Parkinson's disease is poorly documented. METHODS: 188 patients with incident Parkinson's disease from a population-based study were examined at the time of diagnosis, before initiation of dopaminergic treatment, with follow-up of 166 patients three years later. Health-related quality of life was assessed by the 36-item Short-form Health Survey (SF-36). Motor and non-motor variables were derived from the Unified Parkinson's disease rating scale and other established scales. RESULTS: Multiple regression analyses showed that the non-motor symptoms strongest associated with reduced SF-36 scores at diagnosis and three years later were depression, fatigue and sensory complaints. The motor symptoms most related to impaired SF-36 scores were problems with gait and activities of daily living that cover personal needs. The variance of SF-36 mental summary scores was much better explained by non-motor vs. motor symptoms, both at baseline (R(2) = 0.384 vs. 0.095) and 3 years later (R(2) = 0.441 vs. 0.195). Also SF-36 physical summary scores were better explained by non-motor vs. motor symptoms with R(2) = 0.372 vs. 0.322 at baseline and R(2) = 0.468 vs. 0.315 after 3 years. CONCLUSION: In early PD, including the phase before dopaminergic treatment is initiated, non-motor symptoms are more important for reduced health-related quality of life than motor symptoms. Fatigue, depression, sensory complaints and gait disturbances emerge as the most relevant symptoms and should be given corresponding attention in the management of patients with early PD. PMID- 23916656 TI - Systemic diphenidol reduces neuropathic allodynia and TNF-alpha overexpression in rats after chronic constriction injury. AB - Diphenidol has been shown to block voltage-gated Na(+) channels, which are associated with specific types of pain. Here, we evaluated the effects of diphenidol on chronic constriction injury (CCI)-evoked allodynia and expression of tumor necrosis factor-alpha (TNF-alpha). A peripheral nerve injury was elicited in rats by placing four loosely constrictive ligatures around the sciatic nerve. After intraperitoneal injection of diphenidol, rats were tested for evidence of mechanical allodynia prior to surgery, and on postoperative days 3, 6, 7, 11, 13 and 14. We showed that CCI rats received diphenidol caused dose dependent increases in mechanical withdrawal threshold. Both diphenidol 2 and 10 MUmol/kg groups, but not 0.4 MUmol/kg diphenidol, displayed lower TNF-alpha level in the sciatic nerve than the CCI group (P<0.05) on day 7 after CCI. Our results support the conclusion that systemic diphenidol produced a dose-related inhibition of mechanical allodynia following chronic constriction injury of the sciatic nerve. This antiallodynic effect is related to the decrease of TNF-alpha expression in the sciatic nerve of CCI rats. PMID- 23916657 TI - Repeated valproate treatment facilitates fear extinction under specific stimulus conditions. AB - Single dose treatment with histone deacetylase inhibitor (HDACi) agents has been shown to enhance extinction learning in rodent models under certain conditions. The present novel studies were designed to examine the effects of repeated HDACi treatment, with valproate or sodium butyrate, on the extinction of conditioned fear. In Experiments 1 and 2, short duration CS exposure (30s) in combination with vehicle administration progressively attenuated conditioned fear responses over 40 or more sessions. This effective extinction training was not augmented by HDACi treatments. In Experiment 3, we used a long duration CS exposure (120 s) to weaken extinction training. With these extinction parameters, repeated valproate treatment substantially facilitated the acquisition and retention of fear extinction. Results of this study extend previous work suggesting that HDACi's have utility in augmenting the efficiency of fear extinction, although their apparent benefits are critically dependent upon specific parameters of extinction training. PMID- 23916658 TI - VEGF activates NR2B phosphorylation through Dab1 pathway. AB - Vascular endothelial growth factor (VEGF) and reelin are two major signaling pathways involved in many neuronal functions including neurogenesis and neuronal migration. Both VEGF and reelin have been shown to regulate NMDA type glutamate receptor (NMDAR) activity via independent mechanisms. However, it is not known whether the above signaling pathways influence each other on NMDAR regulation. We demonstrate that Disabled 1 (Dab1), a downstream signaling molecule of reelin pathway mediates VEGF-induced regulation of NMDAR subunit NR2B. Furthermore, VEGF treatment led to the association of VEGF receptor-2 (Flk1) and reelin receptor (apolipoprotein E receptor 2, ApoER2), and Dab1 as well as NR2B activation were Flk1-dependent. Moreover, VEGF treatment could significantly rescue the deficits in phospho-Dab1 levels in reeler (Reln-/-) neurons. Our results suggest a major role of VEGF in the regulation of reelin signaling, and Dab1 as a key molecule in the cross talk between reelin and VEGF signaling pathways. PMID- 23916659 TI - G-CSF attenuates noise-induced hearing loss. AB - In this study, we investigated the effects of granulocyte colony-stimulating factor (G-CSF) for the treatment of noise-induced hearing loss (NIHL) in a guinea pig model. Forty guinea pigs were randomly divided into four groups: control, noise (white noise, 3 h/d for 2 days at 115 dB), noise+G-CSF (350 MUg/kg/d for 5 days), and noise+saline. Auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) were used to determine the hearing threshold and outer hair cell function, respectively, in each group. Cochlear morphology was examined to evaluate hair cell injury induced by intense noise exposure. Fourteen days after noise exposure, the noise+G-CSF group had a lower ABR value than the noise group (P<0.05) or the noise+saline group (P<0.01). At most frequencies, the DPOAE value of the noise+G-CSF group showed a significant rise (P<0.05) compared to the noise group or the noise+saline group. Neither the ABR value nor the DPOAE value differed between the noise group and the noise+saline group. The morphology of the phalloidin-stained organ of Corti was consistent with the functional measurements. In conclusion, G-CSF can preserve hearing in an experimental model of NIHL in guinea pigs, by preserving hair cells after intense noise exposure. PMID- 23916660 TI - Anxiety behavior is reduced, and physical growth is improved in the progeny of rat dams that consumed lipids from goat milk: an elevated plus maze analysis. AB - The goat milk contains conjugated linoleic acid (CLA), which can influence physical growth and brain development. This study investigated the impact of a diet containing goat milk fat (GMF) on physical parameters of gestating (G) and/or lactating (L) rat dams, and their progeny's physical growth, and anxiety behavior. In the dams, body weight was evaluated during gestation and lactation. Maternal physical parameters, thoracic and abdominal circumference and liver weight were measured at weaning. In the progeny, indicators of somatic development, and consolidation of reflex responses (palm grasp, righting, free fall righting, vibrissa placing, auditory startle response, negative geotaxis and cliff avoidance) were determined. Anxiety behavior was tested on the elevated plus maze (EPM). Compared to the controls, GMF-pups presented higher body weight and tail length at days 18 and 21 (groups G+L and L). In the L-group, cliff avoidance and free-fall righting responses were respectively delayed, and accelerated. Fur appearance was anticipated in G+L pups. On postnatal day 35, the EPM responses of the G group indicated less anxiety than in the controls. Data show developmental and behavioral modifications in the progeny of dams fed the GMF-rich diet consumed during gestation and lactation, suggesting the involvement of CLA in such effects. PMID- 23916661 TI - Marginal association between SNP rs2046571 of the HAS2 gene and Parkinson's disease in the Chinese female population. AB - Recent GWASs have implicated many novel SNPs in the development of Parkinson's disease (PD). Single nucleotide polymorphism (SNP) rs2046571 of the HSA2 (encoding hyaluronan synthase 2) was reported to have marginal association with PD. Herein, we conducted a case-control study to evaluate the possible association between SNP rs2046571 and PD in Chinese. All subjects (1043 PD patient and 1044 normal control) were successfully genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No statistically significant difference in genotype frequency between cases and controls was observed (P=0.074), no statistically significant difference in genotype frequency between early-onset and late-onset was observed (P=0.264 and P=0.120, respectively). No statistically significant difference in genotype frequency between male cases and controls (P=0.108). But surprisingly, there was statistically marginal significant difference in genotype frequency between female cases and controls (P=0.042). Our findings suggested that rs2046571 of the HSA2 has marginal association with PD in Chinese population. PMID- 23916662 TI - Effect of Urtica dioica on memory dysfunction and hypoalgesia in an experimental model of diabetic neuropathy. AB - Diabetic neuropathy is considered as a disease of the peripheral nervous system, but recent evidences suggest the involvement of central nervous system as well. In this study we evaluated the effect of Urtica dioica (UD) extract against memory dysfunction and hypoalgesia on a mouse model of streptozotocin (STZ) induced diabetic neuropathy. STZ (50 mg/kg, i.p. consecutively for 5 days) was used to induce diabetes, followed by treatment with the UD extract (50 mg/kg, oral) and rosiglitazone (5 mg/kg, oral) for 8 weeks. Cognitive functions were evaluated using Morris water maze and passive avoidance step through task. Pain thresholds were measured using thermal, mechanical and chemical induced hyperalgesia. We observed that chronic diabetes resulted in a decline in circulating insulin level, elevated blood glucose, reduced body weight, increased water intake, cognitive impairment and hypoalgesia. UD significantly reduced the blood glucose and polydypsia, as well as improved the body weight, insulin level, cognition and insensate neuropathy. In conclusion, UD showed results comparable to rosiglitazone in reversing the long standing diabetes induced complications such as central and peripheral neuronal dysfunction. PMID- 23916663 TI - Implications of Read-Write genomics for cancer biology: comment on "How life changes itself: the Read-Write (RW) genome" by James A. Shapiro. PMID- 23916664 TI - Does concentration of surgical expertise improve outcomes for laparoscopic cholecystectomy? 9 year audit cycle. AB - BACKGROUND: Evidence from surgery shows that high volume is often associated with better outcomes. The aim of this study was to investigate this principle related to elective laparoscopic cholecystectomy practice. METHODS: A retrospective analysis of all conversions and complications for patients undergoing elective laparoscopic cholecystectomy was performed. Data was collected and then repeated after restrictions were implemented to concentrate practice. Hospital databases and patient notes were used to collect data. RESULTS: Between January 1999 and March 2004, 1605 laparoscopic cholecystectomies were performed by 8 surgeons. Case load varied from an average of <1 to 104 procedures per annum. Only 1 surgeon was an upper gastrointestinal specialist. Overall rates for conversion to open surgery were 4.9%, common bile duct injury was 0.31%, bile leak 0.75%, bowel injury 0.25%, haemorrhage 0.44% and death 0.06%, which met guidelines. Significant correlation between conversion and procedure number was identified (p=0.033) Between April 2006 and March 2010, 1820 laparoscopic cholecystectomies were performed by 4 surgeons. Case load varied from 23 to 268 procedures per annum, 2 surgeons were upper gastrointestinal specialists. Overall rates for conversion to open surgery were 3.5%, common bile duct injury 0.1%, bile leak 0.9%, bowel injury 0.21%, haemorrhage 0.16% and death 0.1%. Conversion rates were significantly lower in re-audit data (p=0.027), but remained lowest for the highest volume sub-specialist surgeons (p=0.016). CONCLUSIONS: Concentrating expertise to those surgeons with interest and commitment to laparoscopic cholecystectomy service led to standardisation and reduction in conversion rates. There is correlation between volume of surgery and outcomes. PMID- 23916665 TI - Evaluation of snake envenomation-induced renal dysfunction in dogs using early urinary biomarkers of nephrotoxicity. AB - Renal dysfunction in dogs envenomed by poisonous snakes is currently detected using traditional serum and urinary biomarkers such as creatinine and proteinuria. However, these markers lack sensitivity at the early stages of renal dysfunction and their diagnostic accuracy is affected by pre-analytical factors commonly occurring in these dogs, such as haemolysis and haemoglobinuria. Early detection of renal dysfunction would allow for the identification of dogs requiring intensive treatment and monitoring and may help inform prognosis. The aim of this study was to evaluate the performance of several novel urinary biomarkers of glomerular dysfunction, namely, urinary albumin (uAlb), immunoglobulin G (uIgG) and C-reactive protein (uCRP) and of proximal tubular dysfunction (urinary retinol binding protein (uRBP)) compared to traditional end points in dogs with renal damage caused by snake envenomation. Biomarker results were compared between 19 dogs bitten by snakes producing either neurotoxins or cytotoxins and 10 clinically healthy controls. uAlb, uIgG, and uRBP were significantly increased in snake-envenomed dogs at presentation compared to controls, whereas only uIgG and uCRP were significantly elevated 24h post envenomation. The urinary protein:creatinine ratio was also increased in envenomed dogs compared to controls, but because of the presence of haematuria and haemoglobinuria, differentiation between pre-renal and renal proteinuria was not possible. The results showed that these novel urinary biomarkers may assist in better detecting renal dysfunction in dogs envenomed by poisonous snakes at the acute disease stage compared to traditional laboratory endpoints. PMID- 23916666 TI - Transmission analysis of ultrasonic Lamb mode conversion in a plate with partial thickness notch. AB - Mode conversions of Lamb waves can occur upon encountering damage or defect such as a notch, leading to newly-converted modes apart from wave reflection and transmission. In this paper, the transmission of the fundamental Lamb modes symmetrical S0 and anti-symmetrical A0 with anti-symmetrical notches were investigated in steel plates within the relatively short propagation distance. The group velocity and modal energy of the converted modes were analyzed using simulations and experiments. Two-dimensional finite difference time domain (2D FDTD) method was employed to calculate the scattering field and extract numerical trends for simulation study and experimental confirmation. Both simulations and experiments revealed that the apparent group velocities of the converted modes in the transmitted signals subject to the notch positions. To describe the mode conversion degree and evaluate the notch severity, wave packets of the originally transmitted modes and newly-converted modes were separated and corresponding mode energy percentages were analyzed at different notch severities. Frequency sweeping measurements illustrated that the modal energy percentages varied monotonically over the notch-depth increase with a statistically consistency (R=1.00, P<0.0004). PMID- 23916667 TI - Analysis of the modulated acoustic radiation-force profile for a dual-beam confocal geometry. AB - A localized modulated radiation force can be produced when two confocal ultrasound beams of nearly equal frequencies interfere in an attenuating medium such as tissue. It is well-established that this force generates both shear and longitudinal waves. By scanning the focal point over a plane and observing the propagation of these waves, the mechanical properties of the medium can be imaged. In this paper, the modulated radiation force is analytically derived in the case of attenuating media, by expanding on the theory of ultrasound stimulated-vibro-acoustography (USVA) for lossless media. Furthermore, weak nonlinearities are considered in the formulation, since higher source pressures may prove to be necessary to improve the radiation-force profile - only the fundamental component is, however, studied in this paper. An analysis of the generated radiation force is performed and the effects of various parameters are investigated on its amplitude and spatial distribution. It will be shown that by carefully selecting the confocal geometry of the beams, as well as, the source pressure and center frequency, the spatial profile of the radiation force can be optimized. This, subsequently, could improve not only the resolution of the point spread-function in USVA, but also, the profile of the shear waves in elastography applications. PMID- 23916668 TI - Activin A regulation under global hypoxia in developing mouse brain. AB - Activin A is a multifunctional growth and differentiation factor with pronounced neuroprotective properties that is strongly up-regulated in various forms of acute brain disorders and injuries including epilepsy, stroke and trauma. In a pediatric context, activin A has been advanced as a potential marker for the severity of perinatal hypoxic-ischemic brain injury. Here we investigated the regulation of activin A under global hypoxia without ischemia in primary cultures of cortical neurons and in neonatal and adult mice of two strains (C57BL/6 and CD 1). From birth to adulthood, activin betaA subunit, activin receptors, and functional activin antagonists were all expressed at roughly similar mRNA levels in the brain of C57BL/6 mice. Independent of mouse line and age, we found both moderate (11% O2, 2h) and severe hypoxia (8%, 6h) to be consistently associated with normal or even reduced levels of activin betaA (Inhba) mRNA. The surprising unresponsiveness of Inhba expression to hypoxia was confirmed at the protein level. In situ hybridization did not indicate regional, hypoxia-related differences in Inhba expression. Pharmacologic stabilization of hypoxia inducible factors with the prolyl hydroxylase inhibitor FG-4497 did not influence Inhba mRNA levels in neonatal mice. Our data indicate that pure hypoxia differs from other, more complex types of brain damage in that it appears not to recruit activin A as an endogenous neuroprotective agent. PMID- 23916669 TI - Regular treadmill running improves spatial learning and memory performance in young mice through increased hippocampal neurogenesis and decreased stress. AB - A substantial amount of evidence has shown that treadmill running enhances neurogenesis, improves cognitive function, and protects the brain against neurodegenerative disorders. However, treadmill running is a type of forced exercise that could increase the level of corticosterone, which subsequently down regulates neurogenesis and impairs cognitive function. The purpose of this study was to investigate if regular treadmill running provides a balance between the positive and negative effects of treadmill running. The mice were divided into four groups: controls (CON), regular runners (RR), irregular duration runners (IDR) and irregular time-of-day runners (ITR). The RR mice ran daily on the treadmill at the same time-of-day, speed and duration. The IDR mice ran at the same time-of-day and speed, but for a different duration. The ITR mice ran at the same speed and duration, but at different time-of-day. The results showed that regular treadmill running could increase neurogenesis and improve spatial learning and memory performance, as well as decrease the level of corticosterone. The present finding emphasizes the importance of regular physical exercise on cognition. PMID- 23916670 TI - Effects of short-term portacaval anastomosis on the peripheral and brain disposition of the blood-brain barrier permeability marker sodium fluorescein in rats. AB - Contradictory results have been reported with regard to the effects of various models of hepatic encephalopathy on the blood-brain barrier (BBB) permeability, which may be due partly to the use of brain concentrations of BBB markers without attention to their peripheral pharmacokinetics. The purpose of the current study was to investigate the effects of short-term portacaval anastomosis (PCA), a type B model of hepatic encephalopathy, on the peripheral pharmacokinetics and brain distribution of sodium fluorescein (FL), which is a small molecule marker of BBB passive permeability. A single 25mg/kg dose of FL was administered intravenously to 10-day PCA and sham-operated rats, and serial blood and bile (0-30min) and terminal (30min) brain samples were collected, and the concentrations of FL and its glucuronidated metabolite (FL-Glu) were measured by HPLC. Additionally, the free fractions of FL (fu) in all the plasma samples were determined, and the effects of bile salts on fu were investigated in vitro. Passive permeability of BBB to FL was estimated by brain uptake clearance (Kin) based on both the brain concentrations of FL and plasma concentrations of free (unbound) FL. PCA caused a 26% increase in the fu of FL in plasma, which was due to competition of bile acids with FL for binding to plasma proteins. Additionally, PCA reduced the biliary excretion of FL-Glu by 55%. However, free Kin values (ul/min/g brain) for the sham (0.265+/-0.034) and PCA (0.228+/-0.038) rats were not significantly different. It is concluded that whereas 10-day PCA alters the peripheral pharmacokinetics of FL, it does not significantly affect the BBB permeability to the marker. PMID- 23916671 TI - Bone cancer pain: causes, consequences, and therapeutic opportunities. AB - Common cancers, including cancers of the breast, lung, and prostate, frequently metastasize to multiple bones where they can cause significant and life-altering pain. Similar to cancer itself, the factors that drive bone cancer pain evolve and change with disease progression. Once cancer cells have metastasized to bone, both the cancer cells and their associated stromal cells generate pain by releasing algogenic substances including protons, bradykinin, endothelins, prostaglandins, proteases, and tyrosine kinase activators. The release of these factors by cancer/stromal cells can induce sensitization and activation of nerve fibers that innervate the bone. Additionally, these factors can drive a remarkable increase in the number, size, and activity of bone-destroying osteoclasts, which can ultimately result in fracture of the tumor-bearing bone. Tumor growth in bone can also generate a neuropathic pain by directly injuring nerve fibers as well as inducing an active and highly pathological sprouting of both sensory and sympathetic nerve fibers that normally innervate the bone. This structural reorganization of sensory and sympathetic nerve fibers in the bone, combined with the cellular and neurochemical reorganization that occurs in the spinal cord and brain, appears to contribute to the peripheral and central sensitization that is common in advanced bone cancer pain. These mechanistic insights have begun to lead to advances in both how we understand and treat bone cancer pain. PMID- 23916672 TI - Delayed marrow infusion in mice enhances hematopoietic and osteopoietic engraftment by facilitating transient expansion of the osteoblastic niche. AB - Transplantation of bone marrow cells leads to engraftment of osteopoietic and hematopoietic progenitors. We sought to determine whether the recently described transient expansion of the host osteoblastic niche after marrow radioablation promotes engraftment of both osteopoietic and hematopoietic progenitor cells. Mice infused with marrow cells 24 hours after total body irradiation (TBI) demonstrated significantly greater osteopoietic and hematopoietic progenitor chimerism than did mice infused at 30 minutes or 6 hours. Irradiated mice with a lead shield over 1 hind limb showed greater hematopoietic chimerism in the irradiated limb than in the shielded limb at both the 6- and 24-hour intervals. By contrast, the osteopoietic chimerism was essentially equal in the 2 limbs at each of these intervals, although it significantly increased when cells were infused 24 hours compared with 6 hours after TBI. Similarly, the number of donor phenotypic long-term hematopoietic stem cells was equivalent in the irradiated and shielded limbs after each irradiation-to-infusion interval but was significantly increased at the 24-hour interval. Our findings indicate that a 24 hour delay in marrow cell infusion after TBI facilitates expansion of the endosteal osteoblastic niche, leading to enhanced osteopoietic and hematopoietic engraftment. PMID- 23916673 TI - Tender points. PMID- 23916674 TI - Peer-assessment of medical communication skills: the impact of students' personality, academic and social reputation on behavioural assessment. AB - OBJECTIVE: Peer-assessment of communication skills may contribute to mastery of assessment criteria. When students develop the capacity to judge their peers' performance, they might improve their capacity to examine their own clinical performance. In this study peer-assessment ratings are compared to teacher assessment ratings. The aim of this paper is to explore the impact of personality and social reputation as source of bias in assessment of communication skills. METHODS: Second year students were trained and assessed history taking communication skills. Peers rated the students' personality and academic and social reputation. RESULTS: Peer-assessment ratings were significantly correlated with teacher-ratings in a summative assessment of medical communication. Peers did not provide negative ratings on final scales but did provide negative ratings on subcategories. Peer- and teacher-assessments were both related to the students' personality and academic reputation. CONCLUSION: Peer-assessment cannot replace teacher-assessment if the assessment should result in high-stake decisions about students. Our data do not confirm the hypothesis that peers are overly biased by personality and reputation characteristics in peer-assessment of performance. PRACTICE IMPLICATIONS: Early introduction of peer-assessment in medical education would facilitate early acceptance of this mode of evaluation and would promote early on the habit of critical evaluation of professional clinical performance and acceptance of being evaluated critically by peers. PMID- 23916676 TI - Attitudes of Jewish and Bedouin responders toward family physicians' use of electronic medical records during the medical encounter. AB - OBJECTIVE: Culture is known to impact expectations from medical treatments. The effects of cultural differences on attitudes toward Electronic Medical Records (EMR) have not been investigated. We compared the attitudes of Jewish and Bedouin responders toward EMR's use by family physicians during the medical encounter, and examined the contribution of background variables to these attitudes. METHODS: 86 Jewish and 89 Bedouin visitors of patients in a regional Israeli University Medical Center responded to a self-reporting questionnaire with Hebrew and Arabic versions. RESULTS: T-tests and a linear regression analysis found that culture did not predict attitudes. Respondents' self-reported health status, Internet and e-mail use, and estimates of their physician's typing speed explained a total of 18.6% of the variance in attitudes (p<0.001). CONCLUSION: Bedouins respondents' attitudes toward EMR use were better than expected and similar to those of their Jewish counterparts. The most significant factor influencing respondents' attitudes was the physician's typing speed. PRACTICE IMPLICATIONS: (1) Further studies should consider the possible impact of cultural differences between the family physician and the healthcare client on attitudes. (2) Interventions to improve physicians' skill in operating EMRs and typing will potentially have a positive impact on patients' satisfaction with physicians' EMR use. PMID- 23916675 TI - Determinants of adherence to screening by colonoscopy in individuals with a family history of colorectal cancer. AB - OBJECTIVE: Although first-degree relatives (FDRs) of colorectal cancer (CRC) patients, as a high-risk population, have the most to gain from colonoscopy screening, their adherence is suboptimal. Thus, an assessment of the determinants of adherence to screening is of potential importance. METHODS: A cross-sectional study was conducted among 318 FDRs of 164 CRC patients treated at Tel-Aviv Sourasky Medical Center. Interviews were conducted with a questionnaire using I Change Model. RESULTS: Adherence to interval colonoscopy was low with only 73 FDRs (23.0%). Greater adherence was associated with socio-demographic variables (older age, siblings, having spouse, higher level of education and income) and behavioral variables (healthier lifestyle, utilization of preventive health services). Family physicians and kin were identified as the most influential figures on uptake. Intention, affective barriers, positive attitudes, social support, cues to action, age, and health maintenance were the strongest determinants of participation in CRC screening. CONCLUSION: Adherence to colonoscopy is determined by multiple variables. Medical staff can play a key role in increasing adherence to colonoscopy. PRACTICE IMPLICATIONS: Future interventions should focus on fostering positive attitudes, overcoming barriers, enhancing social support and providing a medical recommendation. Special efforts should be invested in young FDRs, those of low socio-economic status and those who underutilize preventive medicine. PMID- 23916677 TI - "I'm not abusing or anything": patient-physician communication about opioid treatment in chronic pain. AB - OBJECTIVE: To characterize clinical communication about opioids through direct analysis of clinic visits and in-depth interviews with patients. METHODS: This was a pilot study of 30 patients with chronic pain, who were audio-recorded in their primary care visits and interviewed after the visit about their pain care and relationship with their physicians. Emergent thematic analysis guided data interpretation. RESULTS: Uncertainties about opioid treatment for chronic pain, particularly addiction and misuse, play an important role in communicating about pain treatment. Three patterns of responding to uncertainty emerged in conversations between patients and physicians: reassurance, avoiding opioids, and gathering additional information. Results are interpreted within the framework of Problematic Integration theory. CONCLUSION: Although it is well-established that opioid treatment for chronic pain poses numerous uncertainties, little is known about how patients and their physicians navigate these uncertainties. This study illuminates ways in which patients and physicians face uncertainty communicatively and collaboratively. PRACTICE IMPLICATIONS: Acknowledging and confronting the uncertainties inherent in chronic opioid treatment are critical communication skills for patients taking opioids and their physicians. Many of the communication behaviors documented in this study may serve as a model for training patients and physicians to communicate effectively about opioids. PMID- 23916678 TI - Quantitation of influenza virus using field flow fractionation and multi-angle light scattering for quantifying influenza A particles. AB - Recent advances in instrumentation and data analysis in field flow fractionation and multi-angle light scattering (FFF-MALS) have enabled greater use of this technique to characterize and quantitate viruses. In this study, the FFF-MALS technique was applied to the characterization and quantitation of type A influenza virus particles to assess its usefulness for vaccine preparation. The use of FFF-MALS for quantitation and measurement of control particles provided data accurate to within 5% of known values, reproducible with a coefficient of variation of 1.9%. The methods, sensitivity and limit of detection were established by analyzing different volumes of purified virus, which produced a linear regression with fitting value R2 of 0.99. FFF-MALS was further applied to detect and quantitate influenza virus in the supernatant of infected MDCK cells and allantoic fluids of infected eggs. FFF fractograms of the virus present in these different fluids revealed similar distribution of monomeric and oligomeric virions. However, the monomer fraction of cell grown virus had greater size variety. Notably, beta-propialactone (BPL) inactivation of influenza viruses did not influence any of the FFF-MALS measurements. Quantitation analysis by FFF-MALS was compared to infectivity assays and real-time RT-PCR (qRT-PCR) and the limitations of each assay were discussed. PMID- 23916679 TI - Use and perceived benefits of complementary therapies by cancer patients receiving conventional treatment in Italy. AB - CONTEXT: In Italy, data regarding the use of complementary therapies (CTs) among patients with cancer are sparse and discordant. OBJECTIVES: The present study aimed to investigate the demographic and psychological characteristics of Italian cancer patients who use CTs and the perceived benefit of users. METHODS: Eight hundred three patients from six Italian oncology departments were interviewed about CT use and completed two questionnaires to explore psychological distress and the resilience trait called sense of coherence (SOC). Patients included in the study had different primary tumor sites and were in different phases of the disease and care process. RESULTS: At the time of measurement, 37.9% of patients were using one or more types of CTs. The most commonly used CTs were diets and dietary supplements (27.5%), herbs (10.8%), homeopathy (6.4%), and mind-body therapies (5.5%). The Italian context is characterized by a high percentage of patients who informed their physicians about CT use (66.3%) and who experienced benefits (89.6%); 75.2% of the patients had used CTs in the past. Multivariate analysis revealed that young, female patients, who previously used complementary and alternative medicine in the past, appear more likely to use at least one type of CT in the present. Predictors of the use of CTs varied according to the type of CT. Among psychological factors, SOC was positively associated with both past and present CT use. CONCLUSION: Overall prevalence of CTs among Italian cancer patients is high and is in accordance with the European average. In addition to clinical and sociodemographic factors, the resilience trait SOC also was associated with CT use. PMID- 23916680 TI - Dying with dementia: symptoms, treatment, and quality of life in the last week of life. AB - CONTEXT: Burdensome symptoms present frequently in dementia at the end of life, but we know little about the symptom control provided, such as type and dosage of medication. OBJECTIVES: To investigate symptom prevalence and prescribed treatment, explore associations with quality of life (QOL) in the last week of life, and examine symptom prevalence by cause of death of nursing home residents with dementia. METHODS: Within two weeks after death, physicians completed questionnaires about symptoms and treatment in the last week for 330 nursing home residents with dementia in the Dutch End of Life in Dementia study (2007-2011). We used linear regression to assess associations with QOL, measured by the Quality of Life in Late-Stage Dementia scale. Causes of death were abstracted from death certificates. RESULTS: Pain was the most common symptom (52%), followed by agitation (35%) and shortness of breath (35%). Pain and shortness of breath were mostly treated with opioids and agitation mainly with anxiolytics. At the day of death, 77% received opioids, with a median of 90 mg/24 hours (oral equivalents), and 21% received palliative sedation. Pain and agitation were associated with a lower QOL. Death from respiratory infection was associated with the largest symptom burden. CONCLUSION: Symptoms are common in dementia at the end of life, despite the large majority of residents receiving opioids. Dosages may be suboptimal with regard to weighing of effects and side effects. Future research may employ observation on a day-to-day basis to better assess effectiveness of symptom control and possible side effects. PMID- 23916681 TI - Differences in the symptom experience of older oncology outpatients. AB - CONTEXT: The relatively low number of older patients in cancer trials limits knowledge of how older adults experience symptoms associated with cancer and its treatment. OBJECTIVES: This study evaluated for differences in the symptom experience across four older age groups (60-64, 65-69, 70-74, >=75 years). METHODS: Demographic, clinical, and symptom data from 330 patients aged >60 years who participated in one Australian and two U.S. studies were evaluated. The Memorial Symptom Assessment Scale was used to evaluate the occurrence, severity, frequency, and distress of 32 symptoms commonly associated with cancer and its treatment. RESULTS: On average, regardless of the age group, patients reported 10 concurrent symptoms. The most prevalent symptoms were physical in nature. Worrying was the most common psychological symptom. For 28 (87.5%) of the 32 Memorial Symptom Assessment Scale symptoms, no age-related differences were found in symptom occurrence rates. For symptom severity ratings, an age-related trend was found for difficulty swallowing. As age increased, severity of difficulty swallowing decreased. For symptom frequency, age-related trends were found for feeling irritable and diarrhea, with both decreasing in frequency as age increased. For symptom distress, age-related trends were found for lack of energy, shortness of breath, feeling bloated, and difficulty swallowing. As age increased, these symptoms received lower average distress ratings. CONCLUSION: Additional research is warranted to examine how age differences in symptom experience are influenced by treatment differences, aging-related changes in biological or psychological processes, or age-related response shift. PMID- 23916682 TI - Proteomic serum profile of fatigued men receiving localized external beam radiation therapy for non-metastatic prostate cancer. AB - CONTEXT: Fatigue is the most distressing side effect of radiation therapy, and its progression etiology is unknown. OBJECTIVES: This study describes proteome changes from sera of fatigued men with non-metastatic prostate cancer receiving external beam radiation therapy (EBRT). METHODS: Fatigue scores, measured by the Functional Assessment of Chronic Illness Therapy-Fatigue, and serum were collected from 12 subjects at baseline (before EBRT) and at midpoint (Day 21) of EBRT. Depleted sera from both time points were analyzed using two-dimensional difference gel electrophoresis, and up/down regulated proteins were identified using liquid chromatography-tandem mass spectrometry. Western blot analyses confirmed the protein changes observed. RESULTS: Results showed that apolipoprotein (Apo)A1, ApoE, and transthyretin (TTR) consistently changed from baseline (Day 0) to midpoint (Day 21). The mean ApoE level of subjects with high change in fatigue (HF: n = 9) increased significantly from baseline to midpoint and were higher than in subjects with no change in fatigue. The mean ApoA1 level was higher in HF subjects at baseline and at midpoint than in no fatigue subjects at both time points. The mean TTR level of no fatigue subjects was higher at baseline and midpoint than in HF subjects. CONCLUSION: These ApoE, ApoA1, and TTR results may assist in understanding pathways that can explain fatigue progression etiology in this clinical population. PMID- 23916683 TI - Subsets of human type 2 macrophages show differential capacity to produce reactive oxygen species. AB - Reactive oxygen species (ROS) produced by macrophages have recently been shown to have immunosuppressive properties and induce regulatory T cells. Here we investigated the ROS producing capacity of well-defined human Mph2 subsets and studied the contribution of ROS in the Mph-T cell interaction. Mph were generated from monocytes using M-CSF (Mph2), IL-4 (Mph2a), or IL-10 (Mph2c). Upon PMA stimulation, Mph2 and Mph2c showed a high ROS producing capacity, whereas this was low for Mph2a. Mph2 and Mph2c displayed a reduced T cell stimulatory capacity compared to Mph2a. Addition of the ROS inhibitor DPI decreased the T cell proliferation and IFN-gamma production. When testing directly on Mph, DPI dose dependently decreased the IL-10 and IL-12p40 production of CD40L-stimulated Mph2 subsets. In conclusion, the ROS producing capacity is different among human Mph type-2 subsets. In all cases, DPI suppressed T cell proliferation and cytokine production, indicating a ROS-dependent mechanism of T cell activation. PMID- 23916684 TI - Environmental factors that impact the eating behaviors of low-income African American adolescents in Baltimore City. AB - OBJECTIVE: To understand environmental factors influencing the food-related habits of low-income urban African American adolescents. DESIGN: Qualitative research was conducted between February and April, 2010, using in-depth interviews, focus groups, and direct observation. SETTING: The study was conducted in low-income, predominantly African American neighborhoods of Baltimore City. PARTICIPANTS: A total of 20 adolescents were interviewed in 18 in depth interviews (n = 13) and 2 focus groups (n = 7). Participants were recruited from Baltimore City recreation centers and were eligible if they were African American and aged 10-16 years. PHENOMENON OF INTEREST: The food-related habits of low-income, African American, urban adolescents and reported perceptions of their food environments. ANALYSIS: Interviews were audio recorded, transcribed, coded, and analyzed for emerging themes. RESULTS: Six thematic categories emerged and were organized into 4 environmental contexts: the neighborhood context (accessibility of food and safety of neighborhood), the school context (school food environment), the family context (family health history, role modeling, and monitoring) and the peer context (peer behaviors). CONCLUSIONS AND IMPLICATIONS: Future efforts to reduce the obesity epidemic among low-income African American adolescents should address the social environment of the family; however, positive behavior change may not be sustainable without neighborhood or school food environment modifications. PMID- 23916685 TI - Pressure and inflammatory stimulation induced increase of cadherin-11 is mediated by PI3K/Akt pathway in synovial fibroblasts from temporomandibular joint. AB - OBJECTIVE: The goal of the study was to investigate the expression of cadherin-11 in synovial fibroblasts (SFs) under mechanical or inflammatory stimuli, and its potential relationship with PI3K/Akt signaling pathway. METHODS: SFs separated from rat temporomandibular joint (TMJ) were treated with hydrostatic pressures (HP) of 30, 60, 90, and 120 kPa, as well as tumor necrosis factor-alpha (TNF alpha) for 12, 24, 48, and 72 h. The location of cadherin-11 was observed by immunofluorescence microscopy, and its expression was detected by real-time PCR and Western blot. We also studied the activation of PI3K/Akt signaling pathway in SFs with HP or TNF-alpha stimulation. RESULTS: The results showed that increased expression of cadherin-11 could be found in the cell-cell contact site of SFs in response to HP and inflammatory stimulation. The mRNA and protein expression of cadherin-11 was positively correlated with the intensity of HP and the duration time of TNF-alpha treatment. Increased expression of vascular endothelial growth factor-D (VEGF-D) and activation of Akt were also found. Treatment with PI3K inhibitor LY294002 attenuated the pressure or inflammatory cytokine induction increases of cadherin-11, VEGF-D, and FGF-2 both in mRNA and protein levels. CONCLUSIONS: These findings suggest that cadherin-11 may play important roles in SFs following exposure to mechanical loading and inflammatory stimulation. In addition, PI3K/Akt pathway was associated with pressure or inflammation-induced cadherin-11 expression, which may involve in the pathogenesis of temporomandibular diseases. PMID- 23916686 TI - Gut microbiota limits heavy metals burden caused by chronic oral exposure. AB - Environmental exposure to pollutants such as heavy metal(s) is responsible for various altered physiological functions which are detrimental for health. The gut microbiota is critical for intestinal homeostasis but its role on xenobiotic handling is not fully understood, especially when continuous sub-chronic exposure is addressed. We first confirmed the essential role of the intestinal microbiome to limit heavy metal body burden by using germ-free mice following 6-weeks oral exposure. Significant increases of cadmium and lead absorption and dissemination in blood and target organs were measured in germ-free mice when compared with conventional specific pathogen free (SPF) mice. Besides the "barrier" function of the luminal microbiota, this may involve specific host-genes such as metallothioneins, which are differentially expressed in the gastrointestinal tract of each group of mice. Considering genes relevant for divalent metal transporters and oxidative pathways, significant differences in basal gene expression were measured between control and germ-free mice. Moreover, the magnitude of induction of these genes upon stimulation by heavy metals varied greatly depending on the dose and type of metal as well as the microbial status of the animal. Collectively, these data illustrate the complex host-microbes interplay occurring with environmental pollutants inside the gut. PMID- 23916687 TI - Salinomycin induces apoptosis in cisplatin-resistant colorectal cancer cells by accumulation of reactive oxygen species. AB - Postoperative chemotherapy for Colorectal cancer (CRC) patients is not all effective and the main reason might lie in cancer stem cells (CSCs). Emerging studies showed that CSCs overexpress some drug-resistance related proteins, which efficiently transport the chemotherapeutics out of cancer cells. Salinomycin, which considered as a novel and an effective anticancer drug, is found to have the ability to kill both CSCs and therapy-resistant cancer cells. To explore the potential mechanisms that salinomycin could specifically target on therapy resistant cancer cells in colorectal cancers, we firstly obtained cisplatin resistant (Cisp-resistant) SW620 cells by repeated exposure to 5 MUmol/l of cisplatin from an original colorectal cancer cell line. These Cisp-resistant SW620 cells, which maintained a relative quiescent state (G0/G1 arrest) and displayed stem-like signatures (up-regulations of Sox2, Oct4, Nanog, Klf4, Hes1, CD24, CD26, CD44, CD133, CD166, Lgr5, ALDH1A1 and ALDH1A3 mRNA expressions) (p < 0.05), were sensitive to salinomycin (p < 0.05). Salinomycin did not show the influence on the cell cycle of Cisp-resistant SW620 cells (p > 0.05), but could induce cell death process (p < 0.05), with increased levels of LDH release and MDA contents as well as down-regulations of SOD and GSH-PX activities (p < 0.05). Our data also showed that the pro-apoptotic genes (Caspase-3, Caspase-8, Caspase 9 and Bax) were up-regulated and the anti-apoptotic gene Bcl-2 were down regulated in Cisp-resistant SW620 cells (p < 0.05). Accumulated reactive oxygen species and dysregulation of some apoptosis-related genes might ultimately lead to apoptosis in Cisp-resistant SW620 cells. These findings will provide new clues for novel and selective chemotherapy on cisplatin-resistant colorectal cancer cells. PMID- 23916688 TI - Reconstitution of the interplay between cytochrome P450 and human glutathione S transferases in clozapine metabolism in yeast. AB - Clozapine, an often-prescribed antipsychotic drug, is implicated in severe adverse drug reactions (ADRs). Formation of reactive intermediates by cytochrome P450s (CYPs) has been proposed as a possible explanation for these ADRs. Moreover, a protective role for human glutathione S-transferases (hGSTs) was recently shown using purified enzymes. We investigated the interplay between CYP bioactivation and GST detoxification in a reconstituted cellular context using recombinant yeast expressing a bacterial CYP BM3 mutant (M11), mimicking the drug metabolizing potential of human CYPs, combined with hGSTA1-1, M1-1 or P1-1. Clozapine and the N-desmethylclozapine metabolite caused comparable growth inhibition and reactive oxygen species (ROS) formation, whereas the clozapine-N oxide metabolite was clearly less toxic. Clozapine metabolism by BM3 M11 and the hGSTs in yeast was confirmed by identification of stable clozapine metabolites and hGST isoform-specific glutathione-conjugates. Oxidative metabolism of clozapine by BM3 M11 increased ROS formation and growth inhibition. Co-expression of hGSTP1-1 protected yeast from BM3 M11 induced growth inhibition in presence of clozapine, whereas similar expression levels of hGSTA1-1 and hGSTM1-1 did not. ROS formation was not lowered by hGSTP1-1 co-expression and was unrelated to mitochondrial electron transport chain (mETC) activity. We present a novel cellular model to study the effect of CYP and GST interplay in drug toxicity. PMID- 23916689 TI - Molecular characterization, expression patterns, and subcellular localization of RIG-I in the Jinding duck (Anas platyrhynchos domesticus). AB - Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) have recently been identified as cytoplasmic sensors for RNA virus. Recent research has shown that RIG-I, a member of this family, play an important role in innate immunity. In this study, we cloned the RIG-I gene from Jinding duck by reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). We determined that the cDNA of duRIG-I contains a 14-bp 5' UTR, a 2802-bp open reading frame, and alternative 3' UTRs (295-bp and 927-bp) and encodes a polypeptide of 933 amino acids. Based on this sequence, the duRIG-I protein is predicted to have conserved domains typical of RLRs. In addition, duRIG-I was found to be distributed throughout DF1 cells by indirect immunofluorescence, as predicted. duRIG-I mRNA was scarcely detected in healthy tissues by semi quantitative RT-PCR (sqRT-PCR). To study the role of RIG-I in innate immunity, we used synthetic double-stranded RNA to mimic viral infection in vivo and detected duRIG-I transcripts in spleen and liver by quantitative real-time PCR (qRT-PCR). The expression of duRIG-I mRNA was significantly elevated at 8h post-injection (P < 0.05) and was indistinguishable from control levels at other time points (P > 0.05). These results suggest that duRIG-I plays an important role in innate immune responses to double-stranded RNA viruses and warrant further studies to reveal the possible mechanism. PMID- 23916690 TI - Immunity to betanodavirus infections of marine fish. AB - Betanodaviruses cause viral nervous necrosis in numerous fish species, but some species are resistant to infection by these viruses. It is essential to fully characterize the immune responses that underlie this protective response. Complete characterization of the immune responses against nodaviruses may allow the development of methods that stimulate fish immunity and of an effective betanodavirus vaccine. Such strategies could include stimulation of specific immune system responses or blockage of factors that decrease the immune response. The innate immune system clearly provides a front-line defense, and this includes the production of interferons and other cytokines. Interferons that are released inside infected cells and that suppress viral replication may be the most ancient form of innate immunity. This review focuses on the immune responses of fish to betanodavirus infection. PMID- 23916691 TI - Dual-tasking postural control in patients with right brain damage. AB - The control of dual-tasking effects is a daily challenge in stroke neurorehabilitation. It maybe one of the reasons why there is poor functional prognosis after a stroke in the right hemisphere, which plays a dominant role in posture control. The purpose of this study was to explore cognitive motor interference in right brain-lesioned and healthy subjects maintaining a standing position while performing three different tasks: a control task, a simple attentional task and a complex attentional task. We measured the sway area of the subjects on a force platform, including the center of pressure and its displacements. Results showed that stroke patients presented a reduced postural sway compared to healthy subjects, who were able to maintain their posture while performing a concomitant attentional task in the same dual-tasking conditions. Moreover, in both groups, the postural sway decreased with the increase in attentional load from cognitive tasks. We also noticed that the stability of stroke patients in dual-tasking conditions increased together with the weight bearing rightward deviation, especially when the attentional load of the cognitive tasks and lower limb motor impairments were high. These results suggest that stroke patients and healthy subjects adopt a similar postural regulation pattern aimed at maintaining stability in dual-tasking conditions involving a static standing position and different attention-related cognitive tasks. Our results indicate that attention processes might facilitate static postural control. PMID- 23916692 TI - Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging facilitates detection of metastases in normal-sized pelvic lymph nodes of patients with bladder and prostate cancer. AB - BACKGROUND: Conventional cross-sectional imaging with computed tomography and magnetic resonance imaging (MRI) has limited accuracy for lymph node (LN) staging in bladder and prostate cancer patients. OBJECTIVE: To prospectively assess the diagnostic accuracy of combined ultrasmall superparamagnetic particles of iron oxide (USPIO) MRI and diffusion-weighted (DW) MRI in staging of normal-sized pelvic LNs in bladder and/or prostate cancer patients. DESIGN, SETTING, AND PARTICIPANTS: Examinations with 3-Tesla MRI 24-36 h after administration of USPIO using conventional MRI sequences combined with DW-MRI (USPIO-DW-MRI) were performed in 75 patients with clinically localised bladder and/or prostate cancer staged previously as N0 by conventional cross-sectional imaging. Combined USPIO DW-MRI findings were analysed by three independent readers and correlated with histopathologic LN findings after extended pelvic LN dissection (PLND) and resection of primary tumours. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Sensitivity and specificity for LN status of combined USPIO-DW-MRI versus histopathologic findings were evaluated per patient (primary end point) and per pelvic side (secondary end point). Time required for combined USPIO-DW-MRI reading was assessed. RESULTS AND LIMITATIONS: At histopathologic analysis, 2993 LNs (median: 39 LNs; range: 17-68 LNs per patient) with 54 LN metastases (1.8%) were found in 20 of 75 (27%) patients. Per-patient sensitivity and specificity for detection of LN metastases by the three readers ranged from 65% to 75% and 93% to 96%, respectively; sensitivity and specificity per pelvic side ranged from 58% to 67% and 94% to 97%, respectively. Median reading time for the combined USPIO-DW-MRI images was 9 min (range: 3-26 min). A potential limitation is the absence of a node-to-node correlation of combined USPIO-DW-MRI and histopathologic analysis. CONCLUSIONS: Combined USPIO-DW-MRI improves detection of metastases in normal-sized pelvic LNs of bladder and/or prostate cancer patients in a short reading time. PMID- 23916694 TI - Methods and priorities of robotic surgery training program. PMID- 23916693 TI - Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy. AB - BACKGROUND: A subset of primarily localized renal cell carcinoma (RCC) patients will experience disease recurrence >=5 yr after initial nephrectomy. OBJECTIVE: To characterize the clinical outcome of patients with late recurrence beyond 5 yr. DESIGN, SETTING, AND PARTICIPANTS: Patients with metastatic RCC (mRCC) treated with targeted therapy were retrospectively characterized according to time to relapse. Relapse was defined as the diagnosis of recurrent metastatic disease >3 mo after initial curative-intent nephrectomy. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as early relapsers (ERs) if they recurred within 5 yr; late relapsers (LRs) recurred after 5 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Demographics were compared with the Student t test, the chi-square test, or the Fisher exact test. The survival time was estimated with the Kaplan-Meier method, and associations with survival outcome were assessed with univariable and multivariable Cox regression analyses. RESULTS AND LIMITATIONS: Among 1210 mRCC patients treated with targeted therapy after surgery for localized disease, 897 (74%) relapsed within the first 5 yr and 313 (26%) (range: 5-35 yr) after 5 yr. LRs presented with younger age (p<0.0001), fewer with sarcomatoid features (p<0.0001), more clear cell histology (p=0.001), and lower Fuhrman grade (p<0.0001). Overall objective response rates to targeted therapy were better in LRs versus ERs (31.8% vs 26.5%; p=0.004). LRs had significantly longer progression-free survival (10.7 mo vs 8.5 mo; p=0.005) and overall survival (OS; 34.0 mo vs 27.4 mo; p=0.004). The study is limited by its retrospective design, noncentralized imaging and pathology review, missing information on metastatectomy, and nonstandardized follow-up protocols. CONCLUSIONS: A quarter of patients who eventually developed metastatic disease and were treated with targeted therapy relapsed over 5 yr from initial nephrectomy. LRs have more favorable prognostic features and consequently better treatment response and OS. PMID- 23916695 TI - Interactions of serum cholesterol with anti-herpesvirus responses affect disease progression in clinically isolated syndromes. AB - OBJECTIVES: To investigate whether anti-herpesvirus antibodies are associated with serum cholesterol profiles in clinically isolated syndromes (CIS). METHODS: Pre-treatment serum samples from 118 high-risk CIS patients were analyzed for IgG antibodies against cytomegalovirus (anti-CMV), Epstein Barr virus (EBV) viral capsid antigen (VCA) and EBV nuclear antigen-1 (EBNA-1). A lipid profile consisting of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) was obtained. Clinical and MRI assessments were obtained at baseline, 6, 12, and 24 months after start of interferon-beta treatment. RESULTS: The study included 118 CIS patients (77 females, 41 males, 65.3% female; mean age: 28.1+/-SD 8.1 years). Anti-EBV EBNA-1 antibody levels were associated with LDL-C (p=0.009) and TC (p=0.008) levels. Anti-CMV positivity status was associated with reduced time to relapse (p=0.006) and the greater number of relapses (p=0.009) in patients with high HDL-C. Anti EBV VCA antibody levels were associated with greater number of new T2 lesions (p=0.002) and with increased brain atrophy (p<0.001) in patients with high LDL-C. CONCLUSIONS: Our results indicate that higher levels of anti-EBV EBNA-1 antibodies are associated with higher LDL-C and TC levels. Anti-CMV positive individuals have greater disease progression in the presence of higher HDL-C levels. Individuals with higher levels of anti-EBV VCA antibodies have greater progression on MRI measures in the presence of higher LDL-C. PMID- 23916696 TI - Dimethyl fumarate regulates histone deacetylase expression in astrocytes. AB - We previously showed that dimethyl fumarate (DMF) reduces inflammatory activation in astrocytes, involving activation of transcription factor Nrf2. However, the pathways causing Nrf2 activation were not examined. We now show that DMF modifies expression of histone deacetylases (HDACs) in primary rat astrocytes. After 4h incubation, levels of HDAC1, 2, and 4 mRNAs were increased by DMF; however, after 24h, levels returned to or were below control values. At that time, HDAC protein levels and overall activity were also reduced by DMF. Stimulation of astrocytes with pro-inflammatory cytokines significantly increased HDAC mRNA levels after 24h, although protein levels were not increased at that time point. In the presence of cytokines, DMF reduced HDAC mRNAs, proteins, and activity. Proteomic analysis of DMF-treated astrocytes identified 8 proteins in which lysine acetylation was increased by DMF, including histones H2a.1 and H3.3. A role for HDACs in mediating DMF actions is suggested by findings that the selective HDAC inhibitor SAHA increased nuclear Nrf2:DNA binding activity, reduced inflammatory activation of astrocytes which was reversed by a selective inhibitor of the Nrf2 target gene heme-oxygenase 1. These data show that DMF regulates astrocyte HDAC expression, which could contribute to Nrf2 activation, suppression of inflammatory responses and cause long-lasting changes in gene expression. PMID- 23916697 TI - To cognitively err is human. PMID- 23916698 TI - Myelolipoma associated with adrenocortical adenoma: an unusual cause of Cushing's syndrome. PMID- 23916699 TI - [Psycho-medical care of transsexuals in Spain in the era of depathologization of transsexualism as a mental disorder. An overall review]. AB - OBJECTIVE: To identify the strengths and weaknesses of Spanish healthcare protocols for transsexual persons and to compare them to current international protocols. To review the current status as regards transsexuality etiology and prevalence. To suggest measures to optimize care to achieve a significant improvement, including options for saving financial resources. METHODS: A comparison of the contents of texts related to transsexualism in the ICD-10, DSM IV, and guidelines of the Spanish gender units with international standards of care for transgender persons and the last draft version of the DSM-5. Systematic revision of the literature related to the etiology and prevalence of transsexualism. RESULTS: Significant discrepancies have been found as regards the minimum time period for diagnosis, access to hormone replacement therapy and to genital surgery, and the requirement of the so-called real-life experience. Impact of sex hormones on the etiology of transsexualism and underestimation of its prevalence was confirmed. CONCLUSIONS: The access to hormonal and surgical treatment requires a profound review, and decentralization of transsexual care is recommended, because all university hospitals haves psychiatrists, clinical psychologists, and endocrinologists available. Although gender reassignment surgery also requires plastic surgery specialists, plastic surgeons currently receive training in this field. PMID- 23916701 TI - miR-18b inhibits TGF-beta1-induced differentiation of hair follicle stem cells into smooth muscle cells by targeting SMAD2. AB - Human hair follicle mesenchymal stem cells (hHF-MSCs) are capable of differentiating into smooth muscle cells (SMCs) in response to transforming growth factor-beta (TGF-beta), and thus can be used for cardiovascular tissue engineering and regenerative medicine. However, the precise molecular mechanisms underlying SMC conversion of hHF-MSCs are still undefined. MicroRNAs (miRNAs) are small noncoding RNAs that modulate gene expression post-transcriptionally by binding to the complementary sequences of targeted mRNAs. Accumulating evidence indicates that miRNAs are associated with SMC differentiation in vitro andin vivo. In this study, we revealed that miR-18b was significantly downregulated during TGF-beta1-induced hHF-MSCs differentiation into SMC using miRNA array profiling and quantitative RT- PCR (qRT-PCR). Over-expression of miR-18b in hHF MSCs led to remarkable downregulation of SMC-specific markers such as SMA and calponin proteins. On the contrary, inhibition of endogenous miR-18b by its antisense oligonucleotide antagomir-18b reversed the changes of SMA and calponin proteins. We also showed that SMAD2, a key transcription regulator in TGF-beta signaling which was involved in SMC differentiation, is regulated by miR-18b. miR 18b could suppress the expression of SMAD2 protein by targeting the 3'UTR of SMAD2 gene without affecting its mRNA level in hHF-MSCs. Moreover, knockdown of SMAD2 by RNA interference could block the effect of inhibition of miR-18b on SMC differentiation, indicating that SMAD2 contributed to miR-18b mediated regulation of TGF-beta-induced SMC differentiation. In conclusion, this study demonstrated that miR-18b regulated the TGF-beta1-induced differentiation of hHF-MSCs into SMCs by targeting SMAD2 gene, and provided novel insights into the regulatory mechanisms of TGF-beta-induced SMC differentiation. PMID- 23916702 TI - Expression and proliferation profiles of PKC, JNK and p38MAPK in physiologically stretched human bladder smooth muscle cells. AB - OBJECTIVE: To determine protein kinase C (PKC), c-Jun NH2-Terminal Kinase (JNK) and P38 mitogen-activated protein kinases (p38MAPK) expression levels and effects of their respective inhibitors on proliferation of human bladder smooth muscle cells (HBSMCs) when physiologically stretched in vitro. MATERIALS AND METHODS: HBSMCs were grown on silicone membrane and stretch was applied under varying conditions; (equibiaxial elongation: 2.5%, 5%, 10%, 15%, 20%, 25%), (frequency: 0.05, 0.1, 0.2, 0.5, 1Hz). Optimal physiological stretch was established by assessing proliferation with 5-Bromo-2-deoxyuridine (BrdU) assay and flow cytometry. PKC, JNK and p38 expression levels were analyzed by Western blot. Specificity was maintained by employing specific inhibitors; (GF109203X for PKC, SP600125 for JNK and SB203580 for p38MAPK), in some experiments. RESULTS: Optimum proliferation was observed at 5% equibiaxial stretch (BrdU: 0.837+/-0.026 (control) to 1.462+/-0.023)%, (P<0.05) and apoptotic cell death rate decreased from 16.4+/-0.21% (control) to 4.5+/-0.13% (P<0.05) applied at 0.1Hz. Expression of PKC was upregulated with slight increase in JNK and no change in p38MAPK after application of stretch. Inhibition had effects on proliferation (1.075+/-0.024, P<0.05 GF109203X); (1.418+/-0.021, P>0.05 SP600125) and (1.461+/-0.01, P>0.05 SB203580). These findings show that mechanical stretch can promote magnitude dependent proliferative modulation through PKC and possibly JNK but not via p38MAPK in hBSMCs. PMID- 23916703 TI - Proteomic analysis in peritoneal dialysis patients with different peritoneal transport characteristics. AB - Peritoneal membranes can be categorized as high, high average, low average, and low transporters, based on the removal or transport rate of solutes. In this study, we used proteomic analysis to determine the differences in proteins removed by different types of peritoneal membranes. Peritoneal transport characteristics in patients who received peritoneal dialysis therapy were assessed by a peritoneal equilibration test. Two-dimensional differential gel electrophoresis technology followed by quantitative analysis was performed to study the variation in protein expression from peritoneal dialysis effluents (PDE) among different groups. Proteins were identified by MALDI-TOF-MS/MS analyses. Further validation in PDE or serum was performed utilizing ELISA analysis. Proteomics analysis revealed ten protein spots with significant differences in intensity levels among different groups, including vitamin D binding protein, complement C3, apolipoprotein-A1, complement factor C4A, haptoglobin, alpha-1 antitrypsin, immunoglobulin kappa light chain, alpha-2 microglobulin, retinol-binding protein 4 and transthyretin. The levels of vitamin D-binding protein, complement C3, and apolipoprotein-A1 in PDE derived from different groups were greatly varied (P<0.05). However, no significant difference was found in the serum levels of these proteins among different groups (P>0.05 for all groups). This study provides a novel overview of the differences in PDE proteomes of four types of peritoneal membranes. Vitamin D-binding protein, complement C3, and apolipoprotein-A1 showed enhanced expression in PDE of patients with high transporter. PMID- 23916704 TI - Characterization and comparative analysis of psychrophilic and mesophilic alpha amylases from Euplotes species: a contribution to the understanding of enzyme thermal adaptation. AB - The eukaryotic alpha-amylase isolated from the psychrophilic ciliated protozoon Euplotes focardii (EfAmy) was expressed in Escherichia coli and biochemically characterized. Its enzymatic activity was compared to that of the homologous protein from the mesophilic congeneric species Euplotes crassus (EcAmy). The comparison of the amino acid composition and the surface residue composition of the two enzymes indicated a preference for tiny residues and the avoidance of charged, aromatic and hydrophobic residues in EfAmy. Our comparative homology modeling study reveals a lack of surface salt bridges, a decreased number of the surface charged residues, decreased hydrogen bonds and bound ions, and a reduction of aromatic-sulfur interactions, cationic-pi interactions and disulfide interactions in EfAmy. In contrast, sequence alignment and homology modeling showed five unconserved prolines located on the surface loops of EcAmy. By analyzing amylolytic activity towards soluble starch as the substrate, we determined the temperature and pH dependence, thermostability and kinetic parameters of these two enzymes. We demonstrated that EfAmy shows the characteristics of a psychrophilic alpha-amylase, such as the highest hydrolytic activity at low temperatures and high thermolability. In contrast, the EcAmy showed mesophilic characteristics with the highest activity at moderate temperatures and a more than 2-fold increased half-life at 50 degrees C compared to EfAmy. The kcat and KM values of EfAmy were higher than those of the mesophilic EcAmy at all tested temperatures. Furthermore, both EfAmy and EcAmy showed maximum activities at pH 9 and maintained high activities in the presence of surfactants. These results suggest the potential applications of EfAmy and EcAmy as ingredients in detergents for industrial applications. PMID- 23916705 TI - Canonical Wnts, specifically Wnt-10b, show ability to maintain dermal papilla cells. AB - Although Wnts are expressed in hair follicles (HFs) and considered to be crucial for maintaining dermal papilla (DP) cells, the functional differences among them remain largely unknown. In the present study, we investigated the effects of Wnts (Wnt-3a, 5a, 10b, 11) on the proliferation of mouse-derived primary DP cells in vitro as well as their trichogenesis-promoting ability using an in vivo skin reconstitution protocol. Wnt-10b promoted cell proliferation and trichogenesis, while Wnt-3a showed those abilities to a limited extent, and Wnt-5a and 11 had no effects. Furthermore, we investigated the effects of these Wnts on cultured DP cells obtained from versican-GFP transgenic mice and found that Wnt-10b had a potent ability to sustain their GFP-positivity. These results suggest that canonical Wnts, specifically Wnt-10b, play important roles in the maintenance of DP cells and trichogenesis. PMID- 23916706 TI - Imaging and measuring the biophysical properties of Fc gamma receptors on single macrophages using atomic force microscopy. AB - Fc gamma receptors (FcgammaR), widely expressed on effector cells (e.g., NK cells, macrophages), play an important role in clinical cancer immunotherapy. The binding of FcgammaRs to the Fc portions of antibodies that are attached to the target cells can activate the antibody-dependent cell-mediated cytotoxicity (ADCC) killing mechanism which leads to the lysis of target cells. In this work, we used atomic force microscopy (AFM) to observe the cellular ultra-structures and measure the biophysical properties (affinity and distribution) of FcgammaRs on single macrophages in aqueous environments. AFM imaging was used to obtain the topographies of macrophages, revealing the nanoscale cellular fine structures. For molecular interaction recognition, antibody molecules were attached onto AFM tips via a heterobifunctional polyethylene glycol (PEG) crosslinker. With AFM single-molecule force spectroscopy, the binding affinities of FcgammaRs were quantitatively measured on single macrophages. Adhesion force mapping method was used to localize the FcgammaRs, revealing the nanoscale distribution of FcgammaRs on local areas of macrophages. The experimental results can improve our understanding of FcgammaRs on macrophages; the established approach will facilitate further research on physiological activities involved in antibody based immunotherapy. PMID- 23916707 TI - Pro-apoptotic signaling induced by photo-oxidative ER stress is amplified by Noxa, not Bim. AB - Pro-apoptotic signaling instigated by endoplasmic reticulum (ER) stress is tightly governed by the BH3-only proteins like Noxa and Bim, which help trigger apoptosis, in part by inactivating mitochondria protecting proteins like Mcl-1. Bim/Noxa-based pro-apoptotic signaling has been implicated for various ER stressors but not yet for those causing "ER-focused" production of severe oxidative stress. In the present study we found that photo-oxidative (phox)-ER stress induced by hypericin-based photodynamic therapy is associated with activation of PERK (an ER sessile, stress sensor), robust induction of CHOP (a pro-apoptotic transcription factor) and induction of Bim and Noxa (accompanied by an eventual drop in Mcl-1 levels). Interestingly Noxa, but not Bim, contributed toward phox-ER stress induced apoptosis, regulated by PERK in a CHOP-independent, temporally-defined manner. These observations shed further light on complex signaling pathways elicited byphox-ER stress and vouch for directing more investigation toward the role of PERK in cell death governance. PMID- 23916708 TI - Sugar-induced conformational change found in the HA-33/HA-17 trimer of the botulinum toxin complex. AB - Large-sized botulinum toxin complex (L-TC) is formed by conjugation of neurotoxin, nontoxic nonhemagglutinin and hemagglutinin (HA) complex. The HA complex is formed by association of three HA-70 molecules and three HA-33/HA-17 trimers, comprised of a single HA-17 and two HA-33 proteins. The HA-33/HA-17 trimer isolated from serotype D L-TC has the ability to bind to and penetrate through the intestinal epithelial cell monolayer in a sialic acid-dependent manner, and thus it plays an important role in toxin delivery through the intestinal cell wall. In this study, we determined the solution structure of the HA-33/HA-17 trimer by using small-angle X-ray scattering (SAXS). The SAXS image of HA-33/HA-17 exhibited broadly similar appearance to the crystal image of the complex. On the other hand, in the presence of N-acetylneuraminic acid, glucose and galactose, the solution structure of the HA-33/HA-17 trimer was drastically altered compared to the structure in the absence of the sugars. Sugar-induced structural change of the HA-33/HA-17 trimer may contribute to cell binding and subsequent transport across the intestinal cell layer. PMID- 23916709 TI - Early diagnosis of pyridoxine-dependent epilepsy: video-EEG monitoring and biochemical and genetic investigation. AB - Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive metabolic disease. A delay of treatment may affect outcome and early initiation of pyridoxine based on effective diagnosis is crucial to ensure good cognitive outcome in neonates. A consensus for the diagnosis of PDE is based on refractive seizures and responsiveness to pyridoxine, however, a growing body of evidence suggests that additional elements should be considered which include biochemical data, genetic screening, and EEG monitoring. We present a case study of a neonate with PDE, who presented with misleading clinical presentation and a novel mutation in the antiquitin (ALDH7A1) gene (A294V), and highlight important aspects in order to consider the definition of diagnosis and management of PDE in the light of more recent data. PMID- 23916710 TI - Efficient degradation of atrazine by magnetic porous copper ferrite catalyzed peroxymonosulfate oxidation via the formation of hydroxyl and sulfate radicals. AB - Magnetic porous copper ferrite (CuFe2O4) showed a notable catalytic activity to peroxymonosulfate (PMS). More than 98% of atrazine was degraded within 15 min at 1 mM PMS and 0.1 g/L CuFe2O4. In contrast, CuFe2O4 exhibited no obvious catalytic activity to peroxodisulfate or H2O2. Several factors affecting the catalytic performance of PMS/CuFe2O4 were investigated. Results showed that the catalytic degradation efficiency of atrazine increased with PMS and CuFe2O4 doses, but decreased with the increase of natural organic matters concentration. The catalytic oxidation also showed a dependence on initial pH. The presence of bicarbonate stimulated atrazine degradation by PMS/CuFe2O4 at low concentrations but inhibited the degradation at high concentrations. Furthermore, the reactive species for atrazine degradation in PMS/CuFe2O4 system were identified as hydroxyl radical (HO) and sulfate radical (SO4(.-)) through competition reactions of atrazine and nitrobenzene, instead of commonly used alcohol scavenging, which was not a reliable method in metal oxide catalyzed oxidation. Surface hydroxyl groups of CuFe2O4 were a critical part in radical generation and the copper on CuFe2O4 surface was an active site to catalyze PMS. The catalytic degradation of atrazine by PMS/CuFe2O4 was also effective under the background of actual waters. PMID- 23916711 TI - Performance evaluation of canine-associated Bacteroidales assays in a multi laboratory comparison study. AB - The contribution of fecal pollution from dogs in urbanized areas can be significant and is an often underestimated problem. Microbial source tracking methods (MST) utilizing quantitative PCR of dog-associated gene sequences encoding 16S rRNA of Bacteroidales are a useful tool to estimate these contributions. However, data about the performance of available assays are scarce. The results of a multi-laboratory study testing two assays for the determination of dog-associated Bacteroidales (DogBact and BacCan-UCD) on 64 single and mixed fecal source samples created from pooled fecal samples collected in California are presented here. Standardization of qPCR data treatment lowered inter-laboratory variability of sensitivity and specificity results. Both assays exhibited 100% sensitivity. Normalization methods are presented that eliminated random and confirmed non-target responses. The combination of standardized qPCR data treatment, use of normalization via a non-target specific Bacteroidales assay (GenBac3), and application of threshold criteria improved the calculated specificity significantly for both assays. Such measures would reasonably improve MST data interpretation not only for canine-associated assays, but for all qPCR assays used in identifying and monitoring fecal pollution in the environment. PMID- 23916712 TI - Admission plasma visfatin level strongly correlates with hematoma growth and early neurologic deterioration in patients with acute spontaneous basal ganglia hemorrhage. AB - BACKGROUND: Visfatin, a proinflammatory mediator, has been associated with poor clinical outcomes after acute brain injury. The present study is designed to investigate the potential association between plasma visfatin levels and the risk of hematoma growth (HG) and early neurologic deterioration (END) after intracerebral hemorrhage. METHODS: There were 85 patients as cases who presented with first-time hemorrhagic stroke that were assessed within 6h after the incident. The control group consisted of 85 healthy volunteers. HG was defined as hematoma enlargement >33% at 24h. END was defined as an increase of >= 4 points in National Institute of Health Stroke Scale score at 24h from symptoms onset. Plasma visfatin levels were determined using enzyme immunoassay. RESULTS: Plasma visfatin levels were significantly higher in patients compared to controls. Plasma visfatin level emerged as an independent predictor of HG [odds ratio (OR), 1.154; 95% confidence interval (CI), 1.046-3.108; P=0.009] and END (OR, 1.195; 95% CI, 1.073-3.516; P=0.005). For predicting HG, area under curve (AUC) of plasma visfatin level (0.814; 95% CI: 0.715-0.890) was similar to that of hematoma volume (0.839; 95% CI, 0.743-0.909) (P=0.703). For predicting END, AUC of plasma visfatin level (0.828; 95% CI: 0.730-0.901) was similar to that of hematoma volume (0.863; 95% CI, 0.771-0.928) (P=0.605). Visfatin did not improve AUC of hematoma volume for predicting HG and END (both P>0.05). CONCLUSION: Plasma visfatin level represents a novel biomarker for predicting HG and END. PMID- 23916713 TI - Enhanced visual responses in the superior colliculus and subthalamic nucleus in an animal model of Parkinson's disease. AB - Striatal dopaminergic denervation leads to a change in afferent activity within the basal ganglia. Coupled with the effect of local dopaminergic denervation in the subthalamic nucleus, this is likely to affect the responsiveness of subthalamic neurons to their hyperdirect inputs in Parkinson's disease. Therefore, in this report, we investigated subthalamic nucleus responses to visual stimuli relayed by one such input - the superior colliculus - in 6 hydroxydopamine (6-OHDA)-lesioned rats. We used a protocol where the superior colliculus was selectively unlocked from the inhibitory effect of anesthesia with an injection of bicuculline, attenuating GABAergic inhibition in the colliculus, which arises predominantly from the substantia nigra pars reticulata. We found that visual responses in the superior colliculus were facilitated by partial or total lesions of dopaminergic neurons in the substantia nigra pars compacta, once the colliculus was disinhibited by bicuculline. Responses were faster, larger in amplitude and lasted longer compared to those in control rats. In the subthalamic nucleus, visual responses were also increased in amplitude and magnitude in partial or total lesioned groups. A classic hypothesis in Parkinson's disease suggests that following dopaminergic denervation, the discharge of cells in the substantia nigra pars reticulata increases, thereby intensifying the inhibitory influence that this structure exerts on its targets in the thalamus and brainstem. Our results suggest that neuroadaptations may have taken place within the superior colliculus in order to maintain normal function in the face of increased inhibitory tone coming from the substantia nigra pars reticulata, which once reduced, gave rise to facilitated responding. This facilitated responding in the superior colliculus then appears to lead to facilitated responding in the subthalamic nucleus. PMID- 23916714 TI - Arthroscopic repair of large subscapularis tendon tears: 2- to 4-year clinical and radiographic outcomes. AB - PURPOSE: The purpose of this study was to evaluate outcome and structural integrity after arthroscopic repair of large subscapularis tendon (SSC) tears at 2 to 4 years' follow-up. METHODS: Between January 2006 and October 2008, 52 consecutive patients underwent arthroscopic repair of Lafosse type III and IV SSC ruptures. A total of 46 patients (38 men and 8 women) with a mean age of 62 years (range, 45 to 81 years) were available for final follow-up. Clinical findings were assessed for all patients preoperatively and postoperatively, including range of motion, the lift-off test, the belly-press test, the Constant score, and the modified University of California, Los Angeles score. Subscapularis muscle strength by use of the bear-hug test and external rotation were compared in both shoulders postoperatively. Patients were evaluated with plain radiographs and magnetic resonance imaging or computed tomographic arthrography before surgery. Postoperatively, radiographic examination was completed by use of magnetic resonance imaging or computed tomographic arthrography in 39 patients (85%). Patients completed the subjective shoulder value and rated their satisfaction at final follow-up. RESULTS: The mean follow-up period was 35.3 +/- 9.6 months (range, 23 to 57 months). An isolated lesion was detected in 13% of patients; a lesion of the SSC and supraspinatus tendon was found in 37%; and a lesion of the SSC, supraspinatus tendon, and infraspinatus tendon was detected in 50%. At latest follow-up, the mean Constant score significantly improved from 46.4 points to 79.9 points and the modified University of California, Los Angeles score improved from 15.1 points to 31.5 points (P < .001). Subscapularis strength was 92% and external rotation was 96% of the nonoperative shoulder. All outcome scores were similar between Lafosse type III and IV SSC ruptures. Radiographic evaluation showed a rerupture rate of 11%. The coracohumeral distance increased from 9.7 mm to 10.1 mm postoperatively (P = .086). The subjective shoulder value improved from 51% to 88% (P < .001), and 98% of patients were satisfied or very satisfied. CONCLUSIONS: Arthroscopic treatment of large to massive SSC ruptures results in significant clinical improvements, excellent maintenance of muscle strength, and durable tendon integrity at 2 to 4 years' follow-up. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23916715 TI - Attentional bias in older adults: effects of generalized anxiety disorder and cognitive behavior therapy. AB - Attentional biases are known to play a contributing, and perhaps even causal role in the etiology of anxiety and other negative affective states. The prevalence of anxiety disorders in the older cohort is growing, and there are both theoretical and empirical reasons to suspect that age-related factors could moderate attentional bias effects in the context of late-life anxiety. The current study included one of the most widely-used measures of attentional bias, the dot-probe task (Mathews & MacLeod, 1985). Participants were older adults who were either nonanxious or diagnosed with generalized anxiety disorder. The patient subsample also completed cognitive behavior therapy (CBT) or an equivalent wait list condition, after which the dot probe was administered a second time. Results showed that clinical anxiety had no particular importance for the deployment of attention, casting doubt on the universality of biased attention in older anxiety patients. Although there were no maladaptive biases detected toward either threat or depression words at pretreatment, there was nevertheless a marginally significant differential reduction in bias toward threat words following CBT. This reduction did not occur among those in the wait list condition. Implications are discussed. PMID- 23916716 TI - Physical examination during chemoradiation predicts outcome of locally advanced head and neck cancer. Secondary results of a randomized phase III trial (SAKK 10/94). AB - OBJECTIVES: To analyze the prognostic value of clinical tumor response during chemoradiation for locally advanced head and neck cancer. PATIENTS AND METHODS: The locoregional response at 50.4Gy was assessed by physical examination (PE) in patients treated within the randomized trial SAKK 10/94 using hyperfractionated radiotherapy (RT), median total dose 74.4Gy with or without cisplatin 20mg/m(2) chemotherapy on 5 consecutive days during weeks 1 and 5 or 6 of RT. Response was classified as a complete response (CR), complete response with uncertainty (Cru), partial response (PR), stable disease (SD), or progressive disease (PD). The primary endpoint was time to treatment failure (TTF) due to any cause. Secondary endpoints included locoregional-recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS). Univariate and multivariate Cox proportional hazards (PH) models were applied to analyze the associations between survival endpoints and clinical tumor response. RESULTS: A total of 136, 131 and 97 patients were evaluable for response at the primary tumor, lymph nodes and both sites combined, respectively. At 50.4Gy 57/136 (42%), 46/131 (35%) and 21/97 (22%) patients had a good response (CR/Cru vs. PR/SD) at the primary tumor, the lymph nodes, and both sites combined, respectively. The median follow-up times were 11.4, 9.6 and 11.4years for the three groups. Good responses were all significantly associated with improved TTF, LRRFS, DMFS and OS in univariate analysis whereas good response at the primary tumor and lymph nodes remained significantly associated with TTF and OS after multivariate Cox PH models. CONCLUSIONS: Locoregional response at 50.4Gy was identified as predictor of oncologic outcome. PE during treatment should not be underestimated in clinical practice. PMID- 23916717 TI - Driving pluripotency and reprogramming: nuclear receptors at the helm. AB - The identity of a cell is determined by the concerted interplay of multiple molecular modulators such as transcription factors, chromatin modifiers and signalling mediators. Among these, the transcriptional circuitry holds great influence on the specification and maintenance of a cellular state, and its perturbation can trigger a transition to another cell state. This is particularly striking in the field of pluripotency, where tempering the expression levels of one or few transcription factors is sufficient to induce the loss or acquisition of the pluripotent state. Recently, nuclear receptors, a class of transcription factors, have emerged as major players in the molecular network governing pluripotency. In this review, we discuss the importance of nuclear receptors in embryonic stem cell self-renewal, differentiation and cellular reprogramming, highlighting recent discoveries as well as providing an outlook in stem cell and nuclear receptor research. PMID- 23916718 TI - Genome-wide studies of nuclear receptors in cell fate decisions. AB - Nuclear receptors (NRs) are important mediators of the information encoded in the chemical structure of its corresponding ligand, as they interpret such information in the context of the cell identity and physiological status and convert it into sequential transcription regulatory events. At the cell level this can result in temporally coordinated processes such as cell fate transitions, which comprise the regulation of a plethora of gene programs including among others regulation of cell proliferation, metabolism and specific functionalities that are acquired by the differentiated cell. While both the early steps of nuclear receptor function and their impact on animal/organ physiology is rather well understood, little is known about the dynamic gene networks that ultimately cause a particular (cell) physiological phenomenon induced by the cognate NR ligand/hormone. Thanks to advances in massive parallel sequencing and bioinformatics analyses of genome-wide data sets, time has come for the development of NR systems biology. Indeed it is now possible to integrate global transcription factor binding, epigenetic chromatin histone and DNA modification patterns with transcriptomes and 3-dimensional chromatin structures, extract decision points in temporal studies and decipher the temporal control of gene networks that are the ultimate genetic readouts of NR ligand-induced physiological phenomena. In this review we will summarize the chronology of the development of increasingly larger data sets for NR action, with a particular focus on studies performed with the RAR/RXR nuclear receptor family, and discuss the present attempts to integrate a multitude of genome-wide data sets in the ultimate context of the temporal 3-dimensional chromatin structure. PMID- 23916720 TI - A representative of the dominant human colonic Firmicutes, Roseburia faecis M72/1, forms a novel bacteriocin-like substance. AB - During screening of human gut isolates in search of novel antimicrobials, the butyrate-producing strain Roseburia faecis M72/1 was found to produce an inhibitory substance active against Bacillus subtilis. Partial purification of the antimicrobial was achieved and activity found to be heat labile. Our findings suggest that R. faecis M72/1 produces a proteinaceous inhibitor whose production may be triggered by trypsin in the gastrointestinal tract. PMID- 23916721 TI - Using a simplex centroid to study the effects of pH, temperature and lactulose on the viability of Bifidobacterium animalis subsp. lactis in a model system. AB - This paper reports on the effects of lactulose (0-10 g/l) on Bifidobacterium animalis subsp. lactis, along with the influence of pH (4.5-8.5) and temperature (15-45 degrees C); the three factors were combined through a simplex centroid. The experiments were performed in a laboratory medium and the data of cells counts were modeled through the Weibull equation for the evaluation of the first reduction time, the shape parameter and the death time. These fitting parameters were used as input values to build a desirability profile and a second-order model through the DoE approach (Design of Experiments). The medium containing glucose was used as control. The prebiotic enhanced the viability of the microbial target, by prolonging the first reduction time and inducing a shoulder phase in the death kinetic; moreover, in some combinations the statistical analysis highlighted a kind of interaction with the pH. PMID- 23916722 TI - Fecal microbial metabolism of polyphenols and its effects on human gut microbiota. AB - We investigated the biotransformation of four common dietary polyphenols, rutin, quercetin, chlorogenic acid and caffeic acid, in an in vitro mixed culture model of human intestinal microbiota, to determine effects on human gut bacteria. All four compounds were biotransformed rapidly, disappearing from the medium within 0.5 h and later replaced by known phenolic acid breakdown products, at concentrations up to hundreds of micromolar, much higher than in no-polyphenol control experiments. Quantitative PCR was used to measure effects of the polyphenols on the balance between the major groups of intestinal bacteria that are known to influence gut health, i.e., Bifidobacterium spp., Bacteroidetes, and Firmicutes. Fermentation of polyphenols stimulated proliferation of bifidobacteria and decreased the ratio of Firmicutes to Bacteroidetes, relative to controls. Polyphenols also stimulated short chain fatty acid production by the bacteria. Pure bifidobacterial cultures were treated separately with either fermented media isolated from the incubations, the pure test polyphenols, or the biotransformation products detected in the fermentations. Growth stimulation was observed only with fermented polyphenol media and the pure biotransformation products. It appears that dietary polyphenols may have the ability to modify the gut microbial balance, but this effect is indirect, i.e., it is mediated by biotransformation products, rather than the original plant compounds. PMID- 23916719 TI - Quantitative fluorescence microscopy provides high resolution imaging of passive diffusion and P-gp mediated efflux at the in vivo blood-brain barrier. AB - Quantitative fluorescent microscopy is an emerging technology that has provided significant insight into cellular dye accumulation, organelle function, and tissue physiology. However, historically dyes have only been used to qualitatively or semi-quantitatively (fold change) determine changes in blood brain barrier (BBB) integrity. Herein, we present a novel method to calculate the blood to brain transfer rates of the dyes rhodamine 123 and Texas red across the in situ BBB. We observed that rhodamine 123 is subject to p-glycoprotein mediated efflux at the rat BBB and can be increased nearly 20-fold with p-glycoprotein inhibition. However, Texas Red appears to not be subject to MRP2 mediated efflux at the rat BBB, agreeing with literature reports suggesting MRP2 may lack functionality at the normal rat BBB. Lastly, we present data demonstrating that once dyes have crossed the BBB, diffusion of the dye molecule is not as instantaneous as has been previously suggested. We propose that future work can now be completed to (1) match BBB transfer coefficients to interstitial diffusion constants and (2) use dyes with specific affinities to cellular organelles or that have specific properties (e.g., subject to efflux transporters) to more fully understand BBB physiology. PMID- 23916723 TI - Structure and rheology of colloidal particle gels: insight from computer simulation. AB - A particle gel is a network of aggregated colloidal particles with soft solid like mechanical properties. Its structural and rheological properties, and the kinetics of its formation, are dependent on the sizes and shapes of the constituent particles, the volume fraction of the particles, and the nature of the interactions between the particles before, during and after gelation. Particle gels may be permanent or transient depending on whether the colloidal forces between the aggregating particles lead to irreversible bonding or weak reversible interactions. With short-range reversible interactions, network formation is typically associated with phase separation or kinetic arrest due to particle crowding. Much existing knowledge has been derived from computer simulations of idealized model systems containing spherical particles interacting with well-defined pair potentials. The status of current progress is reviewed here by summarizing the underlying methodology and key findings from a range of simulation approaches: Monte Carlo, molecular dynamics, Brownian dynamics, Stokesian dynamics, dissipative particle dynamics, multiparticle collision dynamics, and fluid particle dynamics. Then it is described how the technique of Brownian dynamics simulation, in particular, has provided detailed insight into how different kinds of bonding and weak reversible interactions can affect the aggregate fractal structure, the percolation behaviour, and the small-deformation rheological properties of network-forming colloidal systems. A significant ongoing development has been the establishment and testing of efficient algorithms that are able to capture the subtle dynamic structuring effects that arise from effects of interparticle hydrodynamic interactions. This has led to an appreciation recently of the potentially important role of these particle particle hydrodynamic effects in controlling the evolving morphology of simulated colloidal aggregates and in defining the location of the sol-gel phase boundary. PMID- 23916724 TI - Long-term outcome of young onset Parkinson's disease after subthalamic stimulation--a cross-sectional study. AB - OBJECTIVE: Age of onset is considered a poor prognostic factor for subthalamic deep brain stimulation (STN-DBS) outcome in the case of Parkinson's disease (PD). The goal of current study is to identify the long-term impact of STN-DBS for young onset PD (YOPD) patients. METHODS: 17 YOPD patients with a mean disease onset at 32.3 years were prospectively followed up at 1, 2, 5 and 7 years after STN-DBS. Unified Parkinson's disease rating scale (UPDRS) was evaluated in 4 combinations of Med/DBS on/off. RESULTS: UPDRS part II-IV improved significantly 7 years after operation. While a slowly progressive worsening of levodopa response on part III, synergistic effect of medication and stimulation consistently improves motor disabilities. STN-DBS could remarkably reduce levodopa equivalent daily dose at 7 years. The morbidity rates were low. However, these patients seem to have more transient stimulation dyskinesia (47.1%) and dopamine dysregulation syndrome (11.8%) after surgery. CONCLUSIONS: STN-DBS remains effective to improve motor disabilities over 7 years for YOPD and is a safe procedure concerning cognitive outcome and morbidity. However, stimulation dyskinesia and dopamine dysregulation syndrome deserve attention for the causal relationship between DBS surgery and behavioral outcomes. PMID- 23916725 TI - Which risk factors are more associated with ischemic rather than hemorrhagic stroke in black Africans? AB - OBJECTIVE: To comprehensively examine the relationship of vascular risk factors to stroke type in native black Africans. METHODS: We explored 34 candidate demographic, clinical, and laboratory variables in 282 consecutive adult stroke patients with brain imaging. RESULTS: Ischemic stroke (IS) was found in 61.7% (174). Gender, alcohol, cigarette, homocysteine, C-reactive peptide, anthropometry, and carotid parameters were not significantly associated with stroke type (p>0.05). Patients with IS had relatively lower BP, were significantly older, and more frequently had diabetes mellitus, cardiac disease, or previous transient ischemic attack than patients with hemorrhagic stroke (HS). However, in multivariate regression model predicting 69% of stroke type correctly, age>=62 years (OR: 4.0, 95% CI: 2.0-7.9), previous TIA (OR: 4.3, 95% CI: 1.2-15.7) and systolic BP>=140 mmHg (OR: 0.4, 95% CI: 0.2-0.9) were the only independent significant predictors of IS. CONCLUSIONS: With increasing proportion of the population over 61 years and better BP control, the proportion of IS is expected to rise in black African countries currently undergoing epidemiological transition (changing lifestyle/disease pattern). Therefore, relevant components of the stroke intervention quadrangle (stroke surveillance, acute care, preventive and rehabilitation services) should be tailored toward this need. PMID- 23916726 TI - Meeting commentary--"medicines for older adults: learning from practice to develop patient centric drug products". AB - A meeting jointly organised by the Academy of Pharmaceutical Sciences (APSGB), the Geriatric Medicine Society and the UCL School of Pharmacy took place on the 13th of March 2013, in Stevenage, UK. The meeting was attended by a number of experts involved with the treatment and development of drugs for the older adult, including clinicians, pharmacists, academics, regulators and representatives from industry. The event created the platform to discuss the provision of medicines for older adults from a pharmaceutical sciences perspective. PMID- 23916727 TI - Activation of the AMP-activated protein kinase reduces inflammatory nociception. AB - The activation of the adenosine monophosphate (AMP)-activated kinase (AMPK) has been associated with beneficial effects such as improvement of hyperglycemic states in diabetes as well as reduction of obesity and inflammatory processes. Recent studies provide evidence for a further role of AMPK in models of acute and neuropathic pain. In this study, we investigated the impact of AMPK on inflammatory nociception. Using 5-amino-1-beta-d-ribofuranosyl-imidazole-4 carboxamide (AICAR) and metformin as AMPK activators, we observed anti inflammatory and antinociceptive effects in 2 models of inflammatory nociception. The effects were similar to those observed with the standard analgesic ibuprofen. The mechanism appears to be based on regulation of the AMPKalpha2 subunit of the kinase because AMPKalpha2 knockout mice showed increased nociceptive responses that could not be reversed by the AMPK activators. On the molecular level, antinociceptive effects are at least partially mediated by reduced activation of different MAP-kinases in the spinal cord and a subsequent decrease in pain relevant induction of c-fos, which constitutes a reliable marker of elevated activity in spinal cord neurons following peripheral noxious stimulation. In summary, our results indicate that activation of AMPKalpha2 might represent a novel therapeutic option for the treatment of inflammation-associated pain, providing analgesia with fewer unwanted side effects. PERSPECTIVE: AMPK activation is associated with beneficial effects on diabetes and obesity. In addition, we have shown analgesic properties of pharmacologic AMPK activation in inflammatory nociception, indicating that AMPK might serve as a novel therapeutic target in pain with fewer unwanted side effects. PMID- 23916728 TI - Quercetin antagonism of GABAArho1 receptors is prevented by ascorbic acid through a redox-independent mechanism. AB - Quercetin is a natural flavonoid widely distributed in plants that acts as a neuroprotective agent and modulates the activity of different synaptic receptors and ion channels, including the ionotropic GABA receptors. GABA(Arho1) receptors were shown to be antagonized by quercetin, but the mechanisms underlying these antagonistic actions are still unknown. We have analyzed here if the antagonistic action produced by quercetin on GABA(Arho1) receptors was related to its redox activity or due to alternative mechanism/s. Homomeric GABA(Arho1) receptors were expressed in frog oocytes and GABA-evoked responses electrophysiologically recorded. Quercetin effects on GABA(Arho1) receptors were examined in the absence or presence of ascorbic acid. Chemical protection of cysteines by selective sulfhydryl reagents and site directed mutagenesis experiments were also used to determine rho1 subunit residues involved in quercetin actions. Quercetin antagonized GABA(Arho1) receptor responses in a dose-dependent, fast and reversible manner. Quercetin inhibition was prevented in the presence of ascorbic acid, but not by thiol reagents that modify the extracellular Cys-loop of these receptors. H141, an aminoacidic residue located near to the rho1 subunit GABA binding site, was involved in the allosteric modulation of GABA(Arho1) receptors by several agents including ascorbic acid. Quercetin similarly antagonized GABA evoked responses mediated by mutant (H141D)GABA(Arho1) and wild-type receptors, but prevention exerted by ascorbic acid on quercetin effects was impaired in mutant receptors. Taken together the present results suggest that quercetin antagonistic actions on GABA(Arho1) receptors are mediated through a redox independent allosteric mechanism. PMID- 23916729 TI - Cutthroat trout virus as a surrogate in vitro infection model for testing inhibitors of hepatitis E virus replication. AB - Hepatitis E virus (HEV) is one of the most important causes of acute hepatitis worldwide. Although most infections are self-limiting, mortality is particularly high in pregnant women. Chronic infections can occur in transplant and other immune-compromised patients. Successful treatment of chronic hepatitis E has been reported with ribavirin and pegylated interferon-alpha, however severe side effects were observed. We employed the cutthroat trout virus (CTV), a non pathogenic fish virus with remarkable similarities to HEV, as a potential surrogate for HEV and established an antiviral assay against this virus using the Chinook salmon embryo (CHSE-214) cell line. Ribavirin and the respective trout interferon were found to efficiently inhibit CTV replication. Other known broad spectrum inhibitors of RNA virus replication such as the nucleoside analog 2'-C methylcytidine resulted only in a moderate antiviral activity. In its natural fish host, CTV levels largely fluctuate during the reproductive cycle with the virus detected mainly during spawning. We wondered whether this aspect of CTV infection may serve as a surrogate model for the peculiar pathogenesis of HEV in pregnant women. To that end the effect of three sex steroids on in vitro CTV replication was evaluated. Whereas progesterone resulted in marked inhibition of virus replication, testosterone and 17beta-estradiol stimulated viral growth. Our data thus indicate that CTV may serve as a surrogate model for HEV, both for antiviral experiments and studies on the replication biology of the Hepeviridae. PMID- 23916730 TI - Shedding new light on viruses: super-resolution microscopy for studying human immunodeficiency virus. AB - For more than 70 years electron microscopy (EM) techniques have played an important role in investigating structures of enveloped viruses. By contrast, use of fluorescence microscopy (FM) methods for this purpose was limited by the fact that the size of virus particles is generally around or below the diffraction limit of light microscopy. Various super-resolution (SR) fluorescence imaging techniques developed over the past two decades bypass the diffraction limit of light microscopy, allowing visualization of subviral details and bridging the gap between conventional FM and EM methods. We summarize here findings on human immunodeficiency virus (HIV-1) obtained using SR-FM techniques. Although the number of published studies is currently limited and some of the pioneering analyses also covered methodological or descriptive aspects, recent publications clearly indicate the potential to approach open questions in HIV-1 replication from a new angle. PMID- 23916731 TI - Study of audiovestibular dysfunction in children with systemic lupus erythematosus. AB - OBJECTIVE: Inner ear dysfunction in systemic lupus erythematosis patients has been reported but audiovestibular involvement is not well documented especially in pediatrics. This study was designed to evaluate silent audiovestibular dysfunction among SLE children. METHODS: Case control study examined in allergy and immunology clinic; pediatrics hospital and audiovestibular clinic; Ain Shams University from January 2009 to December 2010. Thirty-five systemic lupus erythematosus children (diagnosed according to American College of Rheumatology); age group 8-16 years, were randomly selected. Five of them were excluded due to one or more exclusion criteria (previous otitis media, stroke, lupus cerebritis, meningitis or encephalitis, audiovestibular symptom). Ten of them refused enrollment or could not complete full battery. Seventeen females and three males, mean age 12.9 +/- 2.6 years, completed the study. Control group included 20 normal subjects, age and sex matched. Full clinical assessment, basic audiological evaluation and vestibular testing (videonystagmography VNG and computerized dynamic posturography CDP) were conducted for children included in the study. RESULTS: Five systemic lupus erythematosus patients had sensorineural hearing loss strongly associated with +ve antiphospholipid antibody and two had conductive hearing loss. Two children in control group had conductive hearing loss (p=0.05). Abnormal VNG findings was significantly higher among systemic lupus erythematosus children (40%) compared to controls (0%) and associated with +ve antiphospholipid antibodies (chi(2)=10, p=0.002, Fisher exact test=0.003). Twenty-five percentage of systemic lupus erythematosus children had abnormal CDP findings reflecting impaired balance function associated with positive antiphospholipid antibodies showing significant statistical difference compared to controls (0% affection) (chi(2)=5.7, p=0.017, Fisher exact test=0.047). CONCLUSION: Silent audiovestibular dysfunction is prevalent among systemic lupus erythematosus children especially those positive for antiphospholipid antibodies necessitating routine regular evaluation. PMID- 23916732 TI - Transoral surgery for an infant thyroglossal duct cyst. AB - A 2-month-old female infant with respiratory distress, cyanosis and swallowing difficulties following birth was referred to our hospital by the pediatric clinic. Flexible fiber optic laryngoscopic examination of the patient revealed a red-purple smooth-surfaced mass inside the tongue base and vallecula. No additional features were identified by otorhinolaryngological examination. A 2-cm cystic mass located at the tongue base was identified by neck computed tomography (CT) imaging. The cystic mass was marsupialized transorally with the assistance of the da Vinci robotic surgery system (TORS) and histopathologically diagnosed as a thyroglossal duct cyst. Surgery was completed with TORS without complications and prolonged intubation was extubated carefully. No respiratory distress or other complications were observed. All symptoms were completely resolved with surgery and the patient was discharged on the third postoperative day. The patient is still undergoing follow-up and no recurrence has been observed up to the eighth post-operative month. PMID- 23916733 TI - Neural correlates of reward-driven attentional capture in visual search. AB - Event-related potentials (ERPs) were used to investigate whether a physically non salient and task-irrelevant stimulus feature previously associated with reward can capture attention. In the training phase, participants implicitly associated a certain color with reward. In the subsequent test phase, participants searched for a uniquely shaped singleton among non-target shapes, with color completely irrelevant to the current task demand. Response time was delayed on trials wherein the target was simultaneously presented with an associated distracter, compared with trials without one. In ERPs, a lateralized reward-associated distracter elicited an N2pc component when a concurrent target was presented on the vertical meridian. The control experiment discounted the possibility that this N2pc was caused by familiarity of the reward-associated distracter. Presenting both the target and reward-associated distracter on the opposite side elicited N2pc, with the reward-associated distracter-elicited N2pc preceding the target-elicited N2pc, albeit only in trials with slow responses. These results show that the participants shifted their attention to the target only after noticing the task-irrelevant reward-associated distracter in slow trials. Therefore, task-irrelevant reward-driven salience can capture attention. Distracter positivity was observed in fast distracter-present trials presenting both a lateral distracter and a midline target. Thus, the reward-associated distracter should be actively suppressed to efficiently select the task-relevant target. Lastly, the distracter-elicited N2pc was negatively correlated with individual differences in reward drive score. This correlation may provide insight into reward sensitivity problems. PMID- 23916735 TI - The cell adhesion molecule L1 regulates the expression of FGF21 and enhances neurite outgrowth. AB - L1 plays a role in neural development. However, it remains unclear how L1 plays this role. In the present study, we have shown extensive outgrowth of long neurites in cerebellar neurons after treatment with either L1 or L1 antibody. Notably, the mRNA level of FGF21 was significantly increased in both L1 and L1 antibody treated neurons compared to control group. Consistently, the neurite outgrowth promoted by L1 was strongly inhibited by siRNA against FGF21 gene or a treatment of cells with FGFR inhibitor. These results demonstrate that FGF21/FGFR signaling promotes the neurite outgrowth in a L1-dependent manner. PMID- 23916734 TI - Sleep allostasis in chronic sleep restriction: the role of the norepinephrine system. AB - Sleep responses to chronic sleep restriction may be very different from those observed after acute total sleep deprivation. Specifically, when sleep restriction is repeated for several consecutive days, animals express attenuated compensatory increases in sleep time and intensity during daily sleep opportunities. The neurobiological mechanisms underlying these adaptive, or more specifically, allostatic, changes in sleep homeostasis are unknown. Several lines of evidence indicate that norepinephrine may play a key role in modulating arousal states and NREM EEG delta power, which is widely recognized as a marker for sleep intensity. Therefore, we investigated time course changes in brain adrenergic receptor mRNA levels in response to chronic sleep restriction using a rat model. Here, we observed that significantly altered mRNA levels of the alpha1 adrenergic receptor in the basal forebrain as well as alpha2- and beta1 adrenergic receptor in the anterior cingulate cortex only on the first sleep restriction day. On the other hand, the frontal cortex alpha1-, alpha2-, and beta1-adrenergic receptor mRNA levels were reduced throughout the period of sleep restriction. Combined with our earlier findings on EEG that sleep time and intensity significantly increased only on the first sleep restriction days, these results suggest that alterations in the brain norepinephrine system in the basal forebrain and cingulate cortex may mediate allostatic changes in sleep time and intensity observed during chronic sleep restriction. PMID- 23916736 TI - Usefulness of neutrophil-to-lymphocyte ratio to predict in-hospital outcomes in infective endocarditis. AB - BACKGROUND: The neutrophil-to-lymphocyte ratio is an independent predictor of worse prognosis in both infectious and cardiovascular disease. We hypothesized that an increased neutrophil-to-lymphocyte ratio at admission would predict in hospital unfavourable outcomes in patients with infective endocarditis (IE). METHODS: We retrospectively analyzed clinical, laboratory, and echocardiographic data in a total of 121 consecutive adult patients (64 men; mean age, 54.7 +/- 14.2 years) with definite IE. RESULTS: Among all patients, the prespecified clinical outcomes were experienced in 46 patients (38%). In-hospital mortality and central nervous system (CNS) events occurred in 29 (24%) and 21 patients (17%), respectively. The neutrophil-to-lymphocyte ratio at admission was found to be significantly higher for either composite end point. On using multiple Cox regression analysis, vegetation size >= 10 mm, end-stage renal disease, Staphylococcus aureus infection, low hemoglobin level, increased C-reactive protein (CRP) level, and high neutrophil-to-lymphocyte ratio at admission emerged as independent predictors of in-hospital unfavourable outcomes. In the receiver operating characteristics (ROC) curve analysis, a neutrophil-to-lymphocyte ratio > 7.1 had 80% sensitivity and 83% specificity in predicting adverse outcomes. CONCLUSION: High neutrophil-to-lymphocyte ratio at admission is an independent predictor of in-hospital mortality and CNS events in patients with IE. However, prospective validation of these findings is required. PMID- 23916737 TI - Ventricular fibrillation associated with J-wave manifestation following pericarditis after catheter ablation for paroxysmal atrial fibrillation. AB - We present a patient with ventricular fibrillation (VF) associated with J-wave manifestation following pericarditis after catheter ablation of paroxysmal atrial fibrillation (AF). The premature ventricular contraction induced VF with J-waves in the inferior leads 2 days after the procedure. The patient's juvenile onset of AF and a family history of sudden cardiac death strongly suggested an underlying hereditable channelopathy. The late gadolinium enhancement in the posterior wall, viewed by cardiac magnetic resonance imaging, matched the leads of the J-waves. VF might develop in juvenile onset of AF especially in individuals with a family history of sudden cardiac death. PMID- 23916738 TI - Hospitalization for uncomplicated hypertension: an ambulatory care sensitive condition. AB - BACKGROUND: Hospitalizations for ambulatory care sensitive conditions (ACSC) represent an indirect measure of access and quality of community care. This study explored hospitalization rates for 1 ACSC, uncomplicated hypertension, and the factors associated with hospitalization. METHODS: A cohort of patients with incident hypertension, and their covariates, was defined using validated case definitions applied to International Classification of Disease administrative health data in 4 Canadian provinces between fiscal years 1997 and 2004. We applied the Canadian Institute for Health Information's case definition to detect all patients who had an ACSC hospitalization for uncomplicated hypertension. We employed logistic regression to assess factors associated with an ACSC hospitalization for uncomplicated hypertension. RESULTS: The overall rate of hospitalizations for uncomplicated hypertension in the 4 provinces was 3.7 per 1000 hypertensive patients. The risk-adjusted rate was lowest among those in an urban setting (2.6 per 1000; 95% confidence interval [CI], 2.3-2.7), the highest income quintile (3.4 per 1000; 95% CI, 2.8-4.2), and those with no comorbidities (3.6 per 1000; 95% CI, 3.2-3.9). Overall, Newfoundland had the highest adjusted rate (5.7 per 1000; 95% CI, 4.9-6.7), and British Columbia had the lowest (3.7 per 1000; 95% CI, 3.4-4.2). The adjusted rate declined from 5.9 per 1000 in 1997 to 3.7 per 1000 in 2004. CONCLUSIONS: We found that the rate of hospitalizations for uncomplicated hypertension has decreased over time, which might reflect improvements in community care. Geographic variations in the rate of hospitalizations indicate disparity among the provinces and those residing in rural regions. PMID- 23916739 TI - Atrioventricular heart block and syncope coincident with diagnosis of systemic lupus erythematosus. AB - We describe a 59-year-old woman with cardiac conduction abnormalities caused by lupus-induced myocardial damage. She had a history of arthralgias and antinuclear antibodies but no clinical history of systemic lupus erythematosus. She presented with syncope and Mobitz type II second-degree atrioventricular block. Anti-double stranded DNA antibodies developed coincident with the identification of heart block. Cardiac magnetic resonance imaging showed late enhancing foci of gadolinium uptake that anatomically correlated with her conduction abnormalities. We conclude that her conduction disease represents an early and structural cardiac manifestation of systemic lupus erythematosus that is unusual in its presentation at the time of initial diagnosis. PMID- 23916740 TI - Stepping down from high dose fluticasone/salmeterol to extrafine BDP/F in asthma is cost-effective. AB - BACKGROUND: GINA guideline recommends stepping down treatment of asthma patients where control is achieved. The aim of this analysis was to estimate the costs and health outcomes associated with step down of controlled patients on high dose fluticasone/salmeterol (FP/S 1000/100 MUg daily) to either medium dose FP/S (500/100 MUg) dry powder or extrafine beclometasone/formoterol (BDP/F 400/24 MUg) pMDI in three European countries. METHODS: A patient-level simulation Markov model was constructed to enable the simulation of three comparative arms (FP/S 1000/100, FP/S 500/100, BDP/F 400/24). Transition probabilities and healthcare resources consumption were derived from a multinational clinical trial comparing BDP/F 400/24 MUg vs. FP/S 500/100 MUg as step down therapy in asthma. Direct costs and health state utilities were sourced from public source and published literature. The analysis was conducted from a health system perspective, based on six months horizon. Probabilistic sensitivity analyses were conducted. RESULTS: The ICER (Incremental Cost-Effectiveness Ratio) associated with high dose dry powder FP/S 1000/100 MUg vs. extrafine BDP/F 400/24 MUg was above 70,000 GBP and 200,000 ?/QALY (Quality Adjusted Life Years). An ICER of 29,000 GBP/QALY and above 30,000 ?/QALY was associated with medium dose dry powder FP/S 500/100 MUg vs. BDP/F 400/24 MUg. CONCLUSIONS: It was found that maintaining controlled patients on high dose FP/S is not cost-effective. Extrafine BDP/F 400/24 MUg daily can be considered to be a cost-effective option in the countries analyzed to maintain control of asthmatic patients stepped down from high dose FP/S 1000/100 MUg daily dry powder or suspension formulations. PMID- 23916742 TI - Tetramethylpyrazine protects against scopolamine-induced memory impairments in rats by reversing the cAMP/PKA/CREB pathway. AB - Tetramethylpyrazine is used in the treatment of many neurological diseases because of its neuroprotective effect. Here, we demonstrate that administration of tetramethylpyrazine effectively reverses memory deficits induced by scopolamine. Moreover, tetramethylpyrazine preserves postsynaptic protein synthesis and restores cAMP/PKA/CREB pathway signaling deficits. Our study not only explores the actions of tetramethylpyrazine on synapses, but also provides novel evidence for the possible therapeutic use of tetramethylpyrazine in dementia. PMID- 23916741 TI - Clostridium difficile infection after adult autologous stem cell transplantation: a multicenter study of epidemiology and risk factors. AB - We sought to describe the epidemiology of Clostridium difficile infection (CDI) among adult recipients of autologous hematopoietic stem cell transplantation (auto-HSCT) within the first year after HSCT in centers with variable epidemiology of hypertoxigenic strains. A multicenter, retrospective nested case control study was conducted among 873 auto-HSCT recipients at Johns Hopkins Hospital (JHH) and Hopital Maisonneuve-Rosemont (HMR) between January 2003 and December 2008. Despite center differences in the prevalence of NAP-1 strains during the study period (21% to 43% at JHH versus 80% to 84% in HMR), the 1-year incidence of CDI was similar in the 2 hospitals (6.2% at JHH versus 5.7% at HMR). The median time to infection was 11 days (interquartile range, 1 to 27 days). In case-control analyses, grade >=2 mucositis (odds ratio [OR], 3.00; P = .02) and receipt of a fourth-generation cephalosporin (OR, 2.76; P = .04) were identified as predictors for CDI. Mucositis was the strongest predictor of risk for CDI in multivariate analysis (adjusted OR, 2.77; P = .03). CDI is a common and early complication of auto-HSCT. Treatment-related gastrointestinal mucosal damage, along with the potentially modifiable risk of antimicrobial exposure, influence the risk for CDI early after auto-HSCT. PMID- 23916743 TI - Donor age dependent graft development and recovery in a rat model of Huntington's disease: histological and behavioral analysis. AB - Neural cell replacement therapy using fetal striatal cells has provided evidence of disease modification in clinical trials in Huntington's disease (HD) patients, although the results have been inconsistent. One of the contributing factors to the variable outcome could be the different capacity of transplanted cells derived from the primordial striatum to proliferate and maturate into striatal projection neurons. Based on the rodent lesion model of HD, the current study investigated how intrastriatal-striatal grafts from variable aged donors develop in vivo and how they influence functional recovery. Young adult female Sprague Dawley rats were lesioned unilaterally in the dorso-striatum with quinolinic acid (0.12 M) and transplanted 14 days later with single cell suspension grafts equivalent of one whole ganglionic eminence (WGE) from donors of embryonic developmental age E13, E14, or E15; animals with or without striatal lesion served as controls. All animals were tested on the Cylinder and the Corridor tests, as well as on apomorphine-induced rotation at baseline, post-lesion/pre grafting, and at 6 and 10 weeks post-grafting. A week prior to perfusion, a sub group in each grafted group received fluorogold injections into the ipsilateral globus pallidus to study graft efferent projections. In summary, the data demonstrates that the age of the embryonic donor tissue has an impact on both the graft mediated functional recovery, and on the in vivo cellular composition of the striatal transplant. E13 tissue grafts gave the best overall outcome indicating that WGE from different donor ages have different potential to promote functional recovery. Understanding the stages and process in rodent striatal development could improve tissue selection in clinical trials of cell therapy in HD. PMID- 23916744 TI - Effects of mPGES-1 deletion on eicosanoid and fatty acid profiles in mice. AB - mPGES-1 is considered an alternative target for anti-inflammatory treatment with improved selectivity and safety compared to NSAIDs. mPGES-1 depletion not only suppresses inflammation via absence of inducible PGE2 but might also cause an activation of anti-inflammatory pathways. We studied effects of mPGES-1 deletion on the eicosanoid and fatty acid (FA) profiles in mice. In LPS-induced peritoneal macrophages from mPGES-1 knock-out (mPGES-1-/-, KO) mice PGE2 production was markedly attenuated, whereas levels of PGD2 metabolites (15-deoxy-Delta(12,14) PGJ2 and 15-deoxy-Delta(12,14) PGD2) were increased compared to wild type mice. The levels of oxidized fatty acid 13-HODE were also significantly up-regulated in KO macrophages. Significant differences in the total lipid FA composition (decrease in monounsaturated FA and increase in eicosadienoic acid) were detected in spleen of KO and WT mice. These effects of mPGES-1 deletion on eicosanoid and fatty acid metabolism have important implications for future mPGES-1 inhibitors and deserve further investigation. PMID- 23916745 TI - Comparative analysis of gene expression profiles of acute hepatic failure and that of liver regeneration in rat. AB - To explore the relevance of rat liver regeneration (LR) to acute hepatic failure (AHF), Rat Genome 230 2.0 Array was used to detect their gene expression profiles in this study, and the reliability of the detection results was confirmed by real time-PCR. 1012 genes were found to be significantly changed in AHF occurrence and 948 genes in LR. Hierarchical clustering analysis showed that physiological activities of AHF and those of LR had no time correlation. Hierarchical clustering analysis (which is performed to group genes based on the similarity of expression patterns) showed that physiological activities of AHF and those of LR had no time correlation. K-means clustering analysis (which is used to check the difference in the relevant predictor variables between different groups is significant or not) demonstrated that gene expression trend of C1 group (genes relate to categories of stimulus-response and cell apoptosis, etc.) in AHF and in LR was extremely similar, that those of their C2 group (categories of regulation of homeostasis and hormone stimulation, etc.) were contrary, and that those of their C3 (material and energy metabolism and oxidation reduction, etc.), C4 (Cell cycle-related genes) and C5 (cell proliferation-related genes) groups were also similar with the gene expression changes of LR more abundant. GO classifications and functional clustering analysis (which was used to statistics the numbers or composition of proteins or genes at a function level) revealed that cellular processes including immune response, inflammatory reaction, cell migration and adhesion, etc. were increased both in AHF and in LR, whereas material and energy metabolism were decreased. Of them, stimulus response, inflammatory reaction and regulation of apoptosis, etc. were stronger in AHF occurrence than in LR, but ion homeostasis, hormonal response, regulation of cell division and proliferation, etc. were weaker in AHF occurrence. Gene expression changes and physiological activities of AHF and those of LR not only have similarities but also differences. PMID- 23916746 TI - Supercritical water oxidation of tannery sludge: stabilization of chromium and destruction of organics. AB - The supercritical water oxidation (SCWO) of industrial tannery sludge was investigated to understand the simultaneous destruction of organic pollutants and recovery of high content chromium. Experiments were performed in a batch reactor at temperatures of 350-500 degrees C, reaction time of 150-300 s and different oxygen ratios, to exhibit the effect of operation conditions. Results showed that removal efficiency of chemical oxygen demand (COD) increased with higher temperature, larger oxidant amount and reaction time; a maximum value of 96% was obtained. Meanwhile, destruction yield was much higher under supercritical conditions than that in subcritical water. In addition, removal efficiency of Cr from sludge reached more than 98% under all conditions; higher temperature played a positive role. Further, leaching toxicity tests of heavy metals in solid products were conducted based on toxicity characteristic leaching procedure. All heavy metals except nickel showed a greatly reduced leaching toxicity through their stabilization. The chromium oxide recovered in ash was amorphous below 550 degrees C, so that the structure of Cr could not be identified by X-ray diffraction pattern. Special attention should be paid on nickel as its leaching toxicity increased due to the corrosion of reactor surface under severe reaction conditions. PMID- 23916747 TI - Toxicity of manganese metallodrugs toward Danio rerio. AB - Manganese is an essential metal which can be neurotoxic in some instances. As Mn based metallodrugs are ever more prevalent in clinical practice, concern regarding the toxic effects of Mn discharges to water bodies on the biota prompted us to study the physicochemical parameters of these complexes and to assess their acute toxicity toward adult Danio rerio individuals, particularly in terms of brain tissue damage. Our results show that the Mn(III)-salen acetate complex EUK108 is toxic, which can be rationalized in terms of its lipophilicity, stability and redox activity. PMID- 23916748 TI - Evaluation of the efficiency of monopolar and bipolar BDD electrodes for electrochemical oxidation of anthraquinone textile synthetic effluent for reuse. AB - The efficiency of the electrochemical degradation of synthetic wastewater containing an anthraquinone dye has been comparatively studied in two electrolytic cells with a synthetic boron-doped diamond (Si/BDD) as an anode. The first is an individual cell (Cell 1) with monopolar electrode BDD and the second (Cell 2) has two bipolar electrodes BDD self-polarized. The bulk electrolysis was performed at the same initial operating conditions in order to quantify the influence of the initial pH and current density on dye discoloration and global mineralization removal. The current efficiency and the consumption energy were also evaluated. When the same solutions have been comparatively treated with the two cells, a quite good mineralization is found in Cell 2. This result supposed more fraction of the applied current is used for the electrocombustion reaction on Cell 2 if compared to Cell 1 and small amount rest for the side reaction of oxygen evolution. The HPLC analyses confirmed this hypothesis and showed that the concentration trend of intermediates (sulfanilic acid, phthalate acid and salicylic acid) with electrolysis time was different on two cells. Phototoxicity tests show that the electrochemical oxidation with BDD electrodes could be useful as a pretreatment technique for reducing hazardous wastewater toxicity. PMID- 23916749 TI - Insights into the dissolution and the three-dimensional structure of insensitive munitions formulations. AB - Two compounds, 2,4-dinitroanisole (DNAN) and 3-nitro-1,2,4-triazol-5-one (NTO) are the main ingredients in a suite of explosive formulations that are being, or soon will be, fielded at military training ranges. We aim to understand the dissolution characteristics of DNAN and NTO and three insensitive muntions (IM) formulations that contain them. This information is needed to accurately predict the environmental fate of IM constituents, some of which may be toxic to people and the environment. We used Raman spectroscopy to identify the different constituents in the IM formulations and micro computed tomography to image their three-dimensional structure. These are the first three-dimensional images of detonated explosive particles. For multi-component explosives the solubility of the individual constituents and the fraction of each constituent wetted by water controls the dissolution. We found that the order of magnitude differences in solubility amongst the constituents of these IM formulations quickly produced hole-riddled particles when these were exposed to water. Micro-computed tomography showed that particles resulting from field detonations were fractured, producing conduits by which water could access the interior of the particle. We think that micro-computed tomography can also be used to determine the initial composition of IM particles and to track how their compositions change as the particles dissolve. This information is critical to quantifying dissolution and developing physically based dissolution models. PMID- 23916750 TI - Iron uptake and regulation in Schizosaccharomyces pombe. AB - Schizosaccharomyces pombe is a useful model system for understanding many aspects of eukaryotic cell growth. Studies of S. pombe have identified novel genes that function in the regulation of iron homeostasis. In response to high levels of iron, Fep1 represses the expression of several genes involved in the acquisition of iron. When iron levels are limited, optimization of cellular iron utilization is coordinated by Php4, which represses genes encoding iron-using proteins. Results from studies in yeast have shed new light on the role of monothiol glutaredoxins (Grxs) in iron homeostasis. In S. pombe, the Grx4 protein serves as an inhibitory partner for Fep1 in response to iron deficiency, whereas it is required for the inhibition of Php4 under iron-replete conditions. PMID- 23916751 TI - Role of liquid culture media in the laboratory diagnosis of microbial keratitis. AB - PURPOSE: To determine whether liquid culture media are helpful in the diagnosis of infectious keratitis. DESIGN: Retrospective noncomparative case series. SUBJECTS AND METHODS: This is a retrospective review of microbiology records of 114 corneal scraping samples from infectious keratitis patients. Samples were processed by corneal smear microscopy (potassium hydroxide with calcofluor white and Gram stains) and culture examination (5% sheep blood agar, sheep blood chocolate agar, Sabouraud dextrose agar, brain heart infusion, thioglycolate broth, and Robertson's cooked meat broth. Cases where at least 1 liquid medium was taken were included in the study and all cases were required to have significant growth in culture as per the institutional criteria. Results of smear examination and culture growth were analyzed. RESULTS: Out of 114 cases, 44 (38.59%) were bacterial, 62 (54.38%) fungal, and 8 (7.01%) were mixed (bacteria + fungus) infection. Thirty-eight out of 44 cases of bacterial keratitis (86.36%) were diagnosed by solid media alone (criterion 1) and 6 of 44 (13.63%) required liquid media for diagnosis (P < .001). In fungal keratitis, 61 of 62 cases (98.38%) were diagnosed using solid media alone (criterion 1) while 1 case required liquid media for diagnosis. In mixed infection, none of the cases required liquid media for diagnosis of fungal component; however, all 8 cases required liquid media for establishing bacterial component. CONCLUSIONS: Liquid culture media increase the chance of isolation of bacteria in pure bacterial and/or mixed infection; however, their role in isolating fungus is limited. Owing to overlap in clinical diagnosis of bacterial and fungal keratitis, we recommend inclusion of both solid and liquid culture media in the laboratory diagnosis of nonviral keratitis. PMID- 23916753 TI - Tonotopic mapping of human auditory cortex. AB - Since the early days of functional magnetic resonance imaging (fMRI), retinotopic mapping emerged as a powerful and widely-accepted tool, allowing the identification of individual visual cortical fields and furthering the study of visual processing. In contrast, tonotopic mapping in auditory cortex proved more challenging primarily because of the smaller size of auditory cortical fields. The spatial resolution capabilities of fMRI have since advanced, and recent reports from our labs and several others demonstrate the reliability of tonotopic mapping in human auditory cortex. Here we review the wide range of stimulus procedures and analysis methods that have been used to successfully map tonotopy in human auditory cortex. We point out that recent studies provide a remarkably consistent view of human tonotopic organisation, although the interpretation of the maps continues to vary. In particular, there remains controversy over the exact orientation of the primary gradients with respect to Heschl's gyrus, which leads to different predictions about the location of human A1, R, and surrounding fields. We discuss the development of this debate and argue that literature is converging towards an interpretation that core fields A1 and R fold across the rostral and caudal banks of Heschl's gyrus, with tonotopic gradients laid out in a distinctive V-shaped manner. This suggests an organisation that is largely homologous with non-human primates. This article is part of a Special Issue entitled Human Auditory Neuroimaging. PMID- 23916752 TI - Assessment of rhythmic entrainment at multiple timescales in dyslexia: evidence for disruption to syllable timing. AB - Developmental dyslexia is associated with rhythmic difficulties, including impaired perception of beat patterns in music and prosodic stress patterns in speech. Spoken prosodic rhythm is cued by slow (<10 Hz) fluctuations in speech signal amplitude. Impaired neural oscillatory tracking of these slow amplitude modulation (AM) patterns is one plausible source of impaired rhythm tracking in dyslexia. Here, we characterise the temporal profile of the dyslexic rhythm deficit by examining rhythmic entrainment at multiple speech timescales. Adult dyslexic participants completed two experiments aimed at testing the perception and production of speech rhythm. In the perception task, participants tapped along to the beat of 4 metrically-regular nursery rhyme sentences. In the production task, participants produced the same 4 sentences in time to a metronome beat. Rhythmic entrainment was assessed using both traditional rhythmic indices and a novel AM-based measure, which utilised 3 dominant AM timescales in the speech signal each associated with a different phonological grain-sized unit (0.9-2.5 Hz, prosodic stress; 2.5-12 Hz, syllables; 12-40 Hz, phonemes). The AM based measure revealed atypical rhythmic entrainment by dyslexic participants to syllable patterns in speech, in perception and production. In the perception task, both groups showed equally strong phase-locking to Syllable AM patterns, but dyslexic responses were entrained to a significantly earlier oscillatory phase angle than controls. In the production task, dyslexic utterances showed shorter syllable intervals, and differences in Syllable:Phoneme AM cross frequency synchronisation. Our data support the view that rhythmic entrainment at slow (~5 Hz, Syllable) rates is atypical in dyslexia, suggesting that neural mechanisms for syllable perception and production may also be atypical. These syllable timing deficits could contribute to the atypical development of phonological representations for spoken words, the central cognitive characteristic of developmental dyslexia across languages. PMID- 23916754 TI - Explaining the high voice superiority effect in polyphonic music: evidence from cortical evoked potentials and peripheral auditory models. AB - Natural auditory environments contain multiple simultaneously-sounding objects and the auditory system must parse the incoming complex sound wave they collectively create into parts that represent each of these individual objects. Music often similarly requires processing of more than one voice or stream at the same time, and behavioral studies demonstrate that human listeners show a systematic perceptual bias in processing the highest voice in multi-voiced music. Here, we review studies utilizing event-related brain potentials (ERPs), which support the notions that (1) separate memory traces are formed for two simultaneous voices (even without conscious awareness) in auditory cortex and (2) adults show more robust encoding (i.e., larger ERP responses) to deviant pitches in the higher than in the lower voice, indicating better encoding of the former. Furthermore, infants also show this high-voice superiority effect, suggesting that the perceptual dominance observed across studies might result from neurophysiological characteristics of the peripheral auditory system. Although musically untrained adults show smaller responses in general than musically trained adults, both groups similarly show a more robust cortical representation of the higher than of the lower voice. Finally, years of experience playing a bass-range instrument reduces but does not reverse the high voice superiority effect, indicating that although it can be modified, it is not highly neuroplastic. Results of new modeling experiments examined the possibility that characteristics of middle-ear filtering and cochlear dynamics (e.g., suppression) reflected in auditory nerve firing patterns might account for the higher-voice superiority effect. Simulations show that both place and temporal AN coding schemes well-predict a high-voice superiority across a wide range of interval spacings and registers. Collectively, we infer an innate, peripheral origin for the higher-voice superiority observed in human ERP and psychophysical music listening studies. PMID- 23916755 TI - Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer. AB - The epithelial-to-mesenchymal transition (EMT), a process involving the breakdown of cell-cell junctions and loss of epithelial polarity, is closely related to cancer development and metastatic progression. While the cystic fibrosis transmembrane conductance regulator (CFTR), a Cl(-) and HCO3(-) conducting anion channel expressed in a wide variety of epithelial cells, has been implicated in the regulation of epithelial polarity, the exact role of CFTR in the pathogenesis of cancer and its possible involvement in EMT process have not been elucidated. Here we report that interfering with CFTR function either by its specific inhibitor or lentiviral miRNA-mediated knockdown mimics TGF-beta1-induced EMT and enhances cell migration and invasion in MCF-7. Ectopic overexpression of CFTR in a highly metastatic MDA-231 breast cancer cell line downregulates EMT markers and suppresses cell invasion and migration in vitro, as well as metastasis in vivo. The EMT-suppressing effect of CFTR is found to be associated with its ability to inhibit NFkappaB targeting urokinase-type plasminogen activator (uPA), known to be involved in the regulation of EMT. More importantly, CFTR expression is found significantly downregulated in primary human breast cancer samples, and is closely associated with poor prognosis in different cohorts of breast cancer patients. Taken together, the present study has demonstrated a previously undefined role of CFTR as an EMT suppressor and its potential as a prognostic indicator in breast cancer. PMID- 23916756 TI - Consensus of official position of IOF/ISCD FRAX initiatives in Asia-Pacific region. AB - The fracture risk assessment tool (FRAX((r))) has been developed for the identification of individuals with high risk of fracture in whom treatment to prevent fractures would be appropriate. FRAX models are not yet available for all countries or ethnicities, but surrogate models can be used within regions with similar fracture risk. The International Society for Clinical Densitometry (ISCD) and International Osteoporosis Foundation (IOF) are nonprofit multidisciplinary international professional organizations. Their visions are to advance the awareness, education, prevention, and treatment of osteoporosis. In November 2010, the IOF/ISCD FRAX initiative was held in Bucharest, bringing together international experts to review and create evidence-based official positions guiding clinicians for the practical use of FRAX. A consensus meeting of the Asia Pacific (AP) Panel of the ISCD recently reviewed the most current Official Positions of the Joint Official Positions of ISCD and IOF on FRAX in view of the different population characteristics and health standards in the AP regions. The reviewed position statements included not only the key spectrum of positions but also unique concerns in AP regions. PMID- 23916757 TI - Paternal treadmill exercise enhances spatial learning and memory related to hippocampus among male offspring. AB - Both epidemiologic and laboratory studies suggest that parents can shape their offspring's development. Recently, it has been shown that maternal exercise during pregnancy benefits the progeny's brain function. However, little is known regarding the influence of paternal exercise on their offspring's phenotype. In this study we attempt to determine the effects of 6 weeks paternal treadmill exercise on spatial learning and memory and the expression of brain-derived neurotrophic factor (BDNF) and reelin in their male offspring. Sibling males were divided into two groups: the control (C) and the exercise group (E). The mice in the E group were exercised on a motor-driven rodent treadmill for 5 days per week for 6 weeks. After 6 weeks of exercise, the male mouse was mated with its sibling female. After weaning, male pups underwent behavioral assessment (Open field and Morris water maze tests). Immunohistochemistry staining, real time-PCR and western blot were performed to determine hippocampal BDNF and reelin expression of the male pups after behavior tasks. Our results showed that paternal treadmill exercise improved the spatial learning and memory capability of male pups, which was accompanied by significantly increased expression of BDNF and reelin, as compared to those of C group. Our results provide novel evidence that paternal treadmill exercise can enhance the brain functions of their F1 male offspring. PMID- 23916758 TI - Changes in the brain expression of alpha-2 subunits of the GABA-A receptor after chronic restraint stress in low- and high-anxiety rats. AB - This study assessed the mechanisms underlying the behavioral differences between high- (HR) and low-anxiety (LR) rats selected for their behavior in the contextual fear test (i.e., the duration of the freezing response was used as a discriminating variable). Rats were subjected to chronic restraint stress (21 days, 3h daily). We found that in the HR group, chronic restraint stress decreased rat activity in the Porsolt test and reduced the concentration of corticosterone in the prefrontal cortex. The behavioral changes were accompanied by a lower expression of alpha-2 GABA-A receptor subunits in the secondary motor cortex (M2 area) and in the dentate gyrus of the hippocampus (DG) compared to LR restraint animals. Moreover, restraint stress increased the density of alpha-2 GABA-A subunits in the basolateral amygdala (BLA) in HR rats and decreased the expression of these subunits in the DG and M2 areas compared to the HR control group. The present results suggest that, in HR rats exposed to chronic restraint stress, the function of hippocampal and cortical GABAergic neurotransmission is attenuated and that this effect could have important influences on the functioning of the hypothalamic-pituitary-adrenal axis and on depressive symptoms. PMID- 23916759 TI - Short-term memory acquisition in female Huntington's disease mice is vulnerable to acute stress. AB - Huntington's disease (HD) is a neurodegenerative disorder marked by cognitive, psychiatric and motor decline, and is modifiable by unidentified environmental factors. We examined the effects of stress on cognitive function in R6/1 HD transgenic mice. Utilizing the Y-maze to assess short-term memory, we report that only female HD mice displayed vulnerability to 1h of confinement stress reflected by impaired memory acquisition. This could not be attributed to a different corticosterone response or exploratory behaviour in the task. This is the first demonstration of increased stress susceptibility in an animal model of HD involving a direct negative impact on cognitive function. PMID- 23916760 TI - Histopathological features of the outer membrane of chronic subdural hematoma and correlation with clinical and radiological features. AB - We compared the histopathological features of the outer membrane of a chronic subdural hematoma (CSH) with its clinico-radiological presentation in patients. One hundred and fifty-six patients undergoing surgery for CSH were prospectively included in this study. Histopathological specimens of the outer neomembrane obtained intraoperatively were studied. Histological features were classified into four types and analyzed in relation to the Glasgow Coma Scale (GCS) score at presentation and radiological features. On histopathological examination, there were no cases of type I, 42.3% cases of type II and 34.6% cases of type III and 23.1% cases of types IV CSH neomembranes. Patients presenting with a GCS <13 exclusively had type II neomembranes. Increased radiodensity and thickness of the hematoma correlated with type IV neomembranes. This study may serve as an incentive to investigate the histopathology of CSH membranes in predicting outcomes and the recurrence of subdural hemorrhage after drainage surgery. PMID- 23916761 TI - Agraphia caused by an infarction in Exner's area. AB - Sigmund Exner postulated in 1881 that lesions of the base of the medial frontal gyrus could specifically produce writing impairments and attributed the writing centre to this area. We report two patients who suffered from strokes in this area. These patients suffered from writing disturbances comprising both omitted words within a sentence or badly written words, as well as aphasia. These patients, in line with prior reports, illustrate the crucial role of the Exner area at the base of the medial frontal gyrus for the cerebral writing network; we suggest that this region plays an important role for phoneme-grapheme conversions. PMID- 23916762 TI - Guillain-Barre syndrome-like-onset neurosarcoidosis positive for immunoglobulin G anti-N-acetylgalactosaminyl-GD1a antibody. AB - Anti-ganglioside antibodies have been reported in various peripheral neuropathies, including Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, Fisher syndrome, monoclonal gammopathy-associated neuropathy, and other idiopathic neuropathies. To our knowledge, there has been no report of anti-ganglioside-positive sarcoidosis. We report a 62-year-old man with acute weakness of the limbs and sensory disturbance of the right arm and trunk resembling GBS. Soluble interleukin-2 receptor and angiotensin-converting enzyme levels were elevated. Anti-ganglioside antibodies (immunoglobulin G anti-N-acetylgalactosaminyl-GD1a antibody [IgG anti-GalNAc-GD1a antibody]) were detected. Neurophysiological examination demonstrated axonal neuropathy. Bilateral hilar lymphadenopathy was demonstrated on a chest CT scan, and abnormal uptake of 67 Gallium was detected by scintigraphy. The ratio of CD4 to CD8 was elevated in bronchoalveolar lavage fluid. Noncaseating epithelioid cell granulomas were detected in a specimen obtained via transbronchial lung biopsy. Because intravenous immunoglobulin did not improve the symptoms, we commenced steroid pulse therapy followed by oral prednisolone therapy. After steroid therapy, he recovered fully. Because the findings in our patient fulfilled the criteria for neurosarcoidosis, we diagnosed his illness as probable neurosarcoidosis. To the best of our knowledge, this is the first patient with GBS-like-onset neurosarcoidosis positive for anti-IgG anti GalNAc-GD1a antibody. PMID- 23916763 TI - Chronic inflammatory demyelinating polyneuropathy associated with primary biliary cirrhosis. AB - We report a patient with chronic inflammatory demyelinating polyneuropathy associated with primary biliary cirrhosis (PBC). Except for minimal biochemical abnormalities, clinical symptoms of PBC were not observed, and we diagnosed our patient with asymptomatic PBC from the results of a liver biopsy. Although the patient noticed little muscle weakness, an electrophysiological study demonstrated slow conduction velocities and prolonged distal latencies, with definite conduction blocks in the median, ulnar, and tibial nerves. The disturbed sensory pattern was asymmetrical, and sensory nerve action potentials were not evoked. From these observations, we diagnosed this patient with chronic inflammatory demyelinating polyneuropathy. Neuropathy associated with PBC is very rare. We must differentiate demyelinating neuropathy with PBC in patients with asymmetrical sensory dominant neuropathy with high immunoglobulin M titers, and investigate for the presence of anti-mitochondrial antibodies to rule out a complication of asymptomatic PBC. PMID- 23916764 TI - A 66-year-old man with multiple cerebral and cerebellar infarcts due to idiopathic hypereosinophilic syndrome. AB - A 66-year-old male, who was previously functionally independent, presented with cerebellar ataxia and cognitive impairment following hypereosinophilic syndrome (HES) complicated by multiple strokes. This patient highlights the importance of prompt diagnosis and treatment, and of referring patients with multiple HES related strokes for multidisciplinary neurological rehabilitation. PMID- 23916765 TI - Effects of dietary selenium supplementation on parasitemia, anemia and serum proteins of Trypanosoma brucei brucei infected rats. AB - Trypanosomosis has been associated with immunosuppression, anemia and oxidative damage while selenium possesses both immunostimulatory and antioxidative effects. This study was designed to assess the effect of dietary selenium supplementation on parasitemia, anemia, survival pattern and serum protein profiles of trypanosome-infected rats. Twenty five rats, divided into five groups (A-E) of 5 each, were treated as follows: 4, 8 and 16 ppm (ppm) of selenium in their feed, respectively throughout the experimental period and were infected with Trypanosoma brucei brucei on day 14 post supplementation, infected not supplemented and the negative control. Supplementation at 4 and 8 ppm increased the packed cell volume (PCV) and hemoglobin (Hb) concentration on day 7 of supplementation (PS) when compared with the unsupplemented groups. Following infection on day 14 PS, the PCV, Hb of 16 ppm and infected not supplemented groups were significantly (P < 0.05) lower than other groups on days 28 and 35 PS. Supplementation did not lead to significant (P > 0.05) changes on the total protein, albumin and globulin by day 14 PS. Infection, however, caused significant (P > 0.05) decrease in the total protein and albumin from day 28. The supplementation did not significantly (P > 0.05) increase the pre-patent period but caused a significant reduction in the parasitemia levels and increased survival intervals. Dietary selenium supplementation, from the results, may show promise in the management of African trypanosomosis as the supplementation was able to: reduce anemia and parasitemia and increase survival intervals of trypanosome infected rats. PMID- 23916766 TI - Echinococcus multilocularis: Single hepatic lesion experimentally established without metastasis in rats. AB - We herein describe the establishment of single hepatic lesions of Echinococcus multilocularis in rats. A 3mm incision was made on the liver with a surgical knife, and one small round vesicle of E. multilocularis (between 1 * 1 mm and <2 * 2 mm in diameter) was transplanted into the incision and covered with absorbable hemostat gauze. The presence and growth of the transplanted vesicle was monitored for 12 weeks using magnetic resonance imaging (MRI). Hepatic lesions, the metacestode of this parasite were confirmed in 12 of 17 infected rats (70.6%) by MRI and macroscopic examinations. The average size of the metacestodes with brood capsules at 12 weeks after the experimental transplantation of a single vesicle was 6.1 +/- 2.5 mm * 4.4 +/- 1.5mm. The smallest size of the metacestodes detected by MRI was approximately 3 * 3 mm. This new approach of establishing single hepatic metacestodes of E. multilocularis in experimental animals is expected to be useful for analyzing the immune-pathological mechanisms of hepatic AE. PMID- 23916767 TI - Single step spray drying method to develop proliposomes for inhalation: a systematic study based on quality by design approach. AB - Quality by Design (QbD) is a systematic approach to develop drug products which includes evaluation of formulation parameters to achieve defined final product quality. In the present study principles of QbD were extended to the preparation, in-vitro and in-vivo performance of rifapentine-loaded proliposomes for pulmonary inhalation where final product needs to comply with specific properties. The rifapentine-loaded proliposomes for the treatment of tuberculosis were prepared in single step by spray drying method and independent variables were optimized using factorial design approach. Contour plots and multiple regression analysis were used to study the effect of selected independent variables on dependent variables. The effect of presence of drug: hydrogenated soya phosphatidylcholine (HSPC) and type of charged lipid in the formulation at three levels were studied on mass median diameter (MMD), liposomal vesicle size, % encapsulation efficiency (% EE), mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF) as critical quality attributes. Optimized formulation (R-LDPI-7) with drug: HSPC ratio of 1:2 and stearyl amine as charged lipid were found to give respirable proliposomes with MMAD of 1.56 +/- 0.16 MUm and FPF of 92.5 +/- 1.5%. Sustained drug release with Higuchi diffusion kinetics was achieved from liposomally encapsulated rifapentine. Pulmonary pharmacokinetics of optimized batch R-LDPI-7 revealed longer retention of drug in lungs with 7 fold increase in both, the mean residence time and t1/2 as compared to R-DPI-0. The study results demonstrated the application of QbD principles and design of experiment (DOE) approach to develop drug encapsulated proliposomes for inhalation by spray drying in single step. PMID- 23916768 TI - Meiosis I: when chromosomes undergo extreme makeover. AB - The ultimate success of cell division relies on the accurate partitioning of the genetic material. Errors in this process occur in nearly all tumors and are the leading cause of miscarriages and congenital birth defects in humans. Two cell divisions, mitosis and meiosis, use common as well as unique mechanisms to ensure faithful chromosome segregation. In mitosis, alternating rounds of DNA replication and chromosome segregation preserve the chromosome complement of the progenitor cell. In contrast, during meiosis two consecutive rounds of nuclear division, meiosis I and meiosis II, follow a single round of DNA replication to reduce the chromosome complement by half. Meiosis likely evolved through changes to the mitotic cell division program. This review will focus on the recent findings describing the modifications that transform mitosis into meiosis. PMID- 23916769 TI - The multiple connections between pRB and cell metabolism. AB - The pRB tumor suppressor is traditionally seen as an important regulator of the cell cycle. pRB represses the transcriptional activation of a diverse set of genes by the E2F transcription factors and prevents inappropriate S-phase entry. Advances in our understanding of pRB have documented roles that extend beyond the cell cycle and this review summarizes recent studies that link pRB to the control of cell metabolism. pRB has been shown to regulate glucose tolerance, mitogenesis, glutathione synthesis, and the expression of genes involved in central carbon metabolism. Several studies have demonstrated that pRB directly targets a set of genes that are crucial for nucleotide metabolism, and this seems likely to represent one of the ways by which pRB influences the G1/S-phase transition and S-phase progression. PMID- 23916771 TI - Conduction abnormalities in arrhythmogenic right ventricular cardiomyopathy. PMID- 23916770 TI - Start and the restriction point. AB - Commitment to division requires that cells sense, interpret, and respond appropriately to multiple signals. In most eukaryotes, cells commit to division in G1 before DNA replication. Beyond a point, known as Start in yeast and the restriction point in mammals, cells will proceed through the cell cycle despite changes in upstream signals. In metazoans, misregulated G1 control can lead to developmental problems or disease, so it is important to understand how cells decipher the myriad external and internal signals that contribute to the fundamental all-or-none decision to divide. Extensive study of G1 control in the budding yeast Saccharomyces cerevisiae and mammalian culture systems has revealed highly similar networks regulating commitment. However, protein sequences of functional orthologs often indicate a total lack of conservation suggesting significant evolution of G1 control. Here, we review recent studies defining the conserved and diverged features of G1 control and highlight systems-level aspects that may be common to other biological regulatory networks. PMID- 23916772 TI - The serious adjustment bias and competing outcomes in hypertriglyceridemic waist phenotype. PMID- 23916773 TI - Can we predict which patients with ST-elevation myocardial infarction benefit most from radial access? Evidence from frequentist and Bayesian meta-regressions of randomized trials. PMID- 23916774 TI - Can aortic root rotation be quantified by three-dimensional speckle-tracking echocardiography? (from the MAGYAR-Healthy Study). PMID- 23916775 TI - Flying with giant coronary aneurysms caused by Kawasaki disease. PMID- 23916776 TI - D-dimer: a novel predictive marker for cardiovascular disease. PMID- 23916777 TI - Response to letter "associations of inflammatory biomarkers to body mass index among patients with acute coronary syndrome". PMID- 23916778 TI - A rare adult case of corrected transposition of the great vessels with situs inversus with a single coronary artery and an atrial septal defect. PMID- 23916779 TI - Comparison of pre-hospital 600 mg or 900 mg vs. peri-interventional 300 mg clopidogrel in patients with ST-elevation myocardial infarction undergoing primary coronary angioplasty. The Load&Go randomized trial. PMID- 23916780 TI - Recurrent acute myocardial infarction and CPAP effect in mild-severe OSA: is an independent risk factor? PMID- 23916781 TI - The feasibility of optical coherence tomography guided thrombus aspiration in patients with non-ST-elevation myocardial infarction after initial conservative therapy--a pilot study. PMID- 23916782 TI - Effectiveness of skeletal scintigraphy in transthyretin-related amyloidosis. PMID- 23916783 TI - The anatomical basis for anterior interosseous nerve palsy secondary to supracondylar humerus fractures in children. AB - INTRODUCTION: Various studies have found that 6.6 to 31% of supracondylar elbow fractures in children have nerve-related complications. One-third of these are cases of anterior interosseous nerve (AIN) palsy that usually result in a deficit of active thumb and index flexion. The goal of this cadaver study was to describe the course of the AIN to achieve a better understanding of how it may get injured. MATERIALS AND METHODS: On 35 cadaver specimens, the median nerve and its collateral branches destined to muscles were dissected at the elbow and forearm levels. The distance at which the various branches arose was measured relative to the humeral intercondylar line. Interfascicular dissection of the AIN was used to map its distribution within the median nerve. RESULTS: The AIN arises at an average of 45 mm from the humeral intercondylar line. Before emerging from the median nerve, the AIN fascicles were always found in the dorsal part of the median nerve. After emerging, the AIN was divided into two zones. Zone 1 was the transitional portion from its exit point until its entrance into the interosseous space, where it changes direction. Zone 2 was the interosseous portion between the radius and ulna that comes into contact with the anterior interosseous membrane to which it is attached over its entire length until it ends in the pronator quadratus (PQ) muscle. The muscle branches of the AIN destined for the flexor pollicis longus (FPL) and flexor digitorum profundus (FDP) muscles mostly originated in Zone 1, which is the transitional portion between the median nerve and the fixed Zone 2. The branches destined to the pronator teres (PT) and flexor carpi radialis (FCR) originating from the median nerve are more proximal and superficial. DISCUSSION: The injury mechanisms leading to selective AIN palsy secondary to supracondylar elbow fracture in children are probably the result of two factors: direct contusion of the posterior aspect of the median nerve, and thereby the AIN fascicles, by the proximal fragment; stretching of AIN in Zone 1, which has less ability to withstand stretching than the median nerve and its other branches because the AIN is fixed in Zone 2. CONCLUSION: Details about the origin and course of the AIN can explain the high percentage of AIN palsy in supracondylar elbow fractures in children. LEVEL OF EVIDENCE: Level IV. Anatomic study. PMID- 23916784 TI - Regulation of Akt-mTOR, ubiquitin-proteasome and autophagy-lysosome pathways in response to formoterol administration in rat skeletal muscle. AB - Administration of beta2-agonists triggers skeletal muscle anabolism and hypertrophy. We investigated the time course of the molecular events responsible for rat skeletal muscle hypertrophy in response to 1, 3 and 10 days of formoterol administration (i.p. 2000MUg/kg/day). A marked hypertrophy of rat tibialis anterior muscle culminated at day 10. Phosphorylation of Akt, ribosomal protein S6, 4E-BP1 and ERK1/2 was increased at day 3, but returned to control level at day 10. This could lead to a transient increase in protein translation and could explain previous studies that reported increase in protein synthesis following beta2-agonist administration. Formoterol administration was also associated with a significant reduction in MAFbx/atrogin-1 mRNA level (day 3), suggesting that formoterol can also affect protein degradation of MAFbx/atrogin1 targeted substrates, including MyoD and eukaryotic initiation factor-3f (eIF3-f). Surprisingly, mRNA level of autophagy-related genes, light chain 3 beta (LC3b) and gamma-aminobutyric acid receptor-associated protein-like 1 (Gabarapl1), as well as lysosomal hydrolases, cathepsin B and cathepsin L, was significantly and transiently increased after 1 and/or 3 days, suggesting that autophagosome formation would be increased in response to formoterol administration. However, this has to be relativized since the mRNA level of Unc-51-like kinase1 (Ulk1), BCL2/adenovirus E1B interacting protein3 (Bnip3), and transcription factor EB (TFEB), as well as the protein content of Ulk1, Atg13, Atg5-Atg12 complex and p62/Sqstm1 remained unchanged or was even decreased in response to formoterol administration. These results demonstrate that the effects of formoterol are mediated, in part, through the activation of Akt-mTOR pathway and that other signaling pathways become more important in the regulation of skeletal muscle mass with chronic administration of beta2-agonists. PMID- 23916786 TI - [Comparison between European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association (ACC/AHA) guidelines for initial management of ST-elevation myocardial infarction (STEMI)]. AB - The European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association (ACC/AHA) have recently updated guidelines for management of ST-elevation myocardial infarction (STEMI). The aim of this study is to compare the both recommendations. PMID- 23916785 TI - Arg kinase signaling in dendrite and synapse stabilization pathways: memory, cocaine sensitivity, and stress. AB - The Abl2/Arg nonreceptor tyrosine kinase is enriched in dendritic spines where it is essential for maintaining dendrite and synapse stability in the postnatal mouse brain. Arg is activated downstream of integrin alpha3beta1 receptors and it regulates the neuronal actin cytoskeleton by directly binding F-actin and via phosphorylation of substrates including p190RhoGAP and cortactin. Neurons in mice lacking Arg or integrin alpha3beta1 develop normally through postnatal day 21 (P21), however by P42 mice exhibit major reductions in dendrite arbor size and complexity, and lose dendritic spines and synapses. As a result, mice with loss of Arg and Arg-dependent signaling pathways have impairments in memory tasks, heightened sensitivity to cocaine, and vulnerability to corticosteroid-induced neuronal remodeling. Therefore, understanding the molecular mechanisms of Arg regulation may lead to therapeutic approaches to treat human psychiatric and neurodegenerative diseases in which neuronal structure is destabilized. PMID- 23916787 TI - Circulating plasma DNA and DNA integrity in breast cancer patients undergoing neoadjuvant chemotherapy. AB - BACKGROUND: In breast cancer patients undergoing neoadjuvant chemotherapy before surgery, biomarkers for predicting response to therapy are urgently required. PATIENTS AND METHODS: In 65 patients with locally confined breast cancer who had completed the course of chemotherapy until surgery, plasma DNA biomarkers obtained before and during therapy were evaluated concerning (early) estimation of therapy response. Levels of repetitive ALU 115 and ALU 247 elements as well as DNA integrity calculated according the formulas of Umetani (1) and Wang (2) were correlated with changes in histopathological staging at surgery and compared with conventional tumor markers CEA and CA 15-3. RESULTS: At surgery, 13 patients presented complete remission (CR), 32 partial remission (PR) and 20 no change of disease (NC). Pretherapeutic Her2/neu status was positively correlated with therapy response (p=0.019). DNA biomarkers before onset of therapy cycles 1, 2 and 6 did not indicate outcome after therapy. However, kinetics of ALU 115 from cycle 1 to 6 showed decreases in CR patients, while in NC patients, an increase was observed (p=0.033). Similar tendencies were found for ALU 247 fragments. DNA integrity index as well as CEA and CA 15-3 were not informative for therapy outcome. CONCLUSION: Kinetics of plasma DNA (ALU 115) is associated with response to neoadjuvant chemotherapy in patients with locally confined breast cancer. PMID- 23916788 TI - A 10-year human hepatitis B virus nucleic test external quality assessment in China: continual improvement. AB - BACKGROUND: Remarkable progress has been made in the quality assurance of Hepatitis B virus (HBV) DNA nucleic amplification techniques (NAT) during the past decade. And this report presents a 10-year external quality assessment (EQA) program performed by National Center for Clinical Laboratories in China since 2003. METHOD: EQA panels were produced using freeze-dried HBV plasma or negative controls and then calibrated against the first International Standard for HBV DNA. RESULTS: By 2012, total 35,570 qualitative EQA reports and 56,826 quantitative reports have been collected. The overall correct recognition rate in qualitative test increased from 95.15% in 2003 to 97.99% in 2012. The proportion of participants with acceptable quantitative results also rose to 87.99% in 2012 compared with that of 27.53% in 2003. Besides, we observed a satisfactory reproducibility of <5% in all parallel samples. However, some laboratories still had difficulties in exact quantification of some low viral loads, which near to the limits of the dynamic range of the assays. CONCLUSION: Taking together, current EQA program showed an encouraging improvement of HBV DNA NAT in China. Distributing more challenging samples and increasing the subtypes are still needed in the future. PMID- 23916789 TI - Scientifically unfounded precaution drives European Commission's recommendations on EDC regulation, while defying common sense, well-established science and risk assessment principles. PMID- 23916790 TI - Position statement on transcatheter aortic valve implantation in Portugal. AB - OBJECTIVE: To evaluate the clinical indications and guidelines for transcatheter aortic valve implantation (TAVI) and to propose adaptations for its use in Portugal. METHODS AND RESULTS: The working group analyzed the epidemiology of aortic stenosis and current clinical recommendations in the light of current evidence, taking into consideration their own experience in Portugal. The evidence shows that TAVI significantly reduces mortality in patients with severe aortic stenosis considered unsuitable for surgery. This technique has a comparable safety profile, efficacy and quality of life improvement to conventional surgery in patients with high surgical risk, when carefully selected by multidisciplinary teams. TAVI procedures should be performed within multidisciplinary programs in centers with on-site cardiac surgery by experienced teams treating no fewer than 50 cases per year in order to maintain proficiency. The technique is little used in Portugal, with seven implantations/year per million population, a seventh of the European average and the lowest rate in Europe. From a societal standpoint, it is important to evaluate clinical outcomes and analyze the incremental cost involved in order to define the situations in which the technique is appropriate and should be used. CONCLUSION: TAVI is the only treatment for severe aortic stenosis in patients unsuitable for surgery, and can also be applied in selected cases with high surgical risk. Patients who are considered for this treatment should be evaluated in centers of excellence performing the technique and with a formal program of multidisciplinary team work. The first cases should be supervised until the team has established its routine. The program should perform the recommended minimum number of procedures per year in order to maintain proficiency and must keep a prospective clinical registry for monitoring purposes. PMID- 23916791 TI - First record of the genus Microchoerus (Omomyidae, Primates) in the western Iberian Peninsula and its palaeobiogeographic implications. AB - In this paper we describe new material of Microchoerus (Microchoerinae, Omomyidae, Primates) from Zambrana (Miranda-Trebino Basin, northern Iberian Peninsula, Spain), a locality assigned to Reference Level MP18 (middle Headonian, Late Eocene). The specimens studied consist of two mandibular fragments, bearing p3-m3 and p4-m3. The teeth resemble in size and morphology those of Microchoerus erinaceus from Hordle Cliff, England, although some differences prevent us from making a definitive ascription to this species. We therefore refer the material from Zambrana to Microchoerus aff. erinaceus. Some traits, such as the development of the mesoconid and hypoconulid in the m1 and m2, and the shape of the hypoconulid lobe in the m3, are intermediate between those of M. erinaceus and Microchoerus edwardsi. Thus, the material from Zambrana is very similar to other species of Microchoerus present in Europe, representing a transitional form between M. erinaceus and M. edwardsi. The described material represents the first discovery of a primate from the Miranda-Trebino Basin, and also the westernmost record of the genus Microchoerus in the Iberian Peninsula. Moreover, the identification of this microchoerine, with clear similarities to the representatives of this genus described from other European sites, reinforces the idea of the existence of connections between western Iberia and the rest of Europe in the Late Eocene, previously hypothesized after the discovery of typical European artiodactyls in the site of Zambrana. PMID- 23916792 TI - Comparisons on enhancing the immunity of fresh and dry Cordyceps militaris in vivo and in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The immunomodulatory capacities of fresh Cordyceps militaris (FCM) and dry Cordyceps militaris (DCM) were compared. MATERIALS AND METHODS: In vivo immunomodulatory assay, different doses of FCM and DCM were orally administrated over a period of 15 days in a cyclophosphamide (CY) induced immunosuppression mice; in vitro testing, the spleen cells were extracted from healthy mice and treaded with CY, then cultured with different dose of FCM or DCM; the contents of Cordyceps militaris polysaccharide (CMP), cordycepin, adenosine, total polyphenol (TP) and total flavonoids (TF) in FCM and DCM were measured. RESULTS: Our studys indicated that, FCM was significantly stronger than DCM on increasing the spleen and thymus indexes, spleen lymphocyte activity, macrophage function, and promoting the levels of IL-2, IFN-gamma in vivo and in vitro. The contents of immunomodulatory CMP and TF in FCM were markedly higher than in DCM. CONCLUSION: All these results suggested that FCM was superior to DCM on enhancing immunity. PMID- 23916793 TI - Inhibition of venom serine proteinase and metalloproteinase activities by Renealmia alpinia (Zingiberaceae) extracts: comparison of wild and in vitro propagated plants. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The plant Renealmia alpinia has been used in folk medicine to treat snakebites in the northwest region of Colombia. In addition, it has been shown to neutralize edema-forming, hemorrhagic, lethal, and defibrin(ogen)ating activities of Bothrops asper venom. In this work, extracts of Renealmia alpinia obtained by micropropagation (in vitro) and from specimens collected in the wild were tested and compared in their capacity to inhibit enzymatic and toxic activities of a snake venom metalloproteinase isolated from Bothrops atrox (Batx-I) venom and a serine proteinase (Cdc SII) from Crotalus durissus cumanensis venom. MATERIALS AND METHODS: We have investigated the inhibition capacity of Renealmia alpinia extracts on enzymatic and toxic actions of isolated toxins, a metalloproteinase and a serine proteinase. The protocols investigated included inhibition of proteolytic activity on azocasein, inhibition of proteolytic activity on fibrinogen, inhibition of pro-coagulant activity, inhibition of hemorrhagic activity and inhibition of edema-forming activity. RESULTS: Colorimetric assays detected the presence of terpenoids, flavonoids, tannins and coumarins in Renealmia alpinia extracts. Renealmia alpinia extracts inhibited the enzymatic, hemorrhagic and fibrinogenolytic activities of Batx-I. Extracts also inhibited coagulant, defibrin(ogen)ating and edema-forming activities of Cdc SII. Results highlight that Renealmia alpinia in vitro extract displayed comparable inhibitory capacity on venom proteinases that Renealmia alpinia wild extract. No alteration was observed in the electrophoretic pattern of venom proteinases after incubation with Renealmia alpinia extracts, thus excluding proteolytic degradation or protein denaturation/precipitation as a mechanism of inhibition. CONCLUSIONS: Our results showed that Renealmia alpinia wild and in vitro extracts contain compounds that neutralize metallo- and serine proteinases present in snake venoms. The mechanism of inhibition is not related to proteolytic degradation of the enzymes nor protein aggregation, but is likely to depend on molecular interactions of secondary metabolites in the plant with these venom proteinases. PMID- 23916794 TI - Introduction: Preimplantation genetic screening is alive and very well. AB - Aneuploidy screening of all chromosomes (preimplantation genetic screening) at each stage of embryo development, the techniques available, and the advantages and disadvantages of each technique are reviewed. PMID- 23916795 TI - Methylation changes in mature sperm deoxyribonucleic acid from oligozoospermic men: assessment of genetic variants and assisted reproductive technology outcome. AB - OBJECTIVE: To characterize a potential genetic cause for methylation errors described in oligozoospermia. DESIGN: Analysis of PEG1/MEST-DMR and H19-DMR methylation level in sperm, in parallel with the study of several genes on the Y chromosome, DNMT3A, and DNMT3L. Clinical outcome was also looked at regarding PEG1/MEST-DMR and H19-DMR methylation level in sperm. SETTING: Research and diagnostic laboratories. PATIENT(S): One hundred nineteen normospermic and 175 oligozoospermic men consulting for couple infertility. INTERVENTION(S): We studied PEG1/MEST-DMR and H19-DMR methylation profiles in 294 men. We searched for Y chromosome gene aberrations and for mutations in both DNMT3A and DNMT3L genes in men showing epimutations. Assisted reproductive technology (ART) outcomes were also investigated. MAIN OUTCOME MEASURE(S): Sperm samples were collected from 294 volunteers for genomic DNA isolation that was used to study methylation profiles in imprinted loci and Y chromosome SMCY, DNMT3A, and DNMT3L genes. Pregnancy rate was also studied after ART treatment using sperm showing epimutations. RESULT(S): Epimutations in H19-DMR and PEG1/MEST-DMR were found in 20% and 3% of oligozoospermic men, respectively. We identified an amino acid change in DNMT3A in one case and in DNMT3L in eight men with altered methylation profiles. No mutations were detected in SMCY or in selected Y chromsome genes. No correlation between ART outcome and epimutations was found. CONCLUSION(S): We observed epimethylations in spermatozoa of oligozoospermic individuals, but no association was found with genetic variants or in the ART outcome. PMID- 23916796 TI - Pregnancies and deliveries per fresh cycle are no longer adequate indicators of in vitro fertilization program quality: how should registries adapt? PMID- 23916797 TI - Does culture medium influence offspring birth weight? AB - OBJECTIVE: To determine whether the type of medium used to culture human embryos in vitro influences neonatal birth weight after IVF/intracytoplasmic sperm injection (ICSI). DESIGN: A prospective study and a retrospective study. SETTING: Private assisted reproduction center. PATIENT(S): The prospective study included 449 IVF/ICSI cycles from August to December 2008. The retrospective analysis was performed for 2,518 IVF/ICSI cycles from October 2006 to December 2010. INTERVENTION(S): In the prospective study, patients were randomized for embryo culture in Cook or Vitrolife medium. The retrospective study was performed with three different culture media (MediCult, Cook, and Vitrolife). MAIN OUTCOME MEASURE(S): Mean birth weight, adjusted for gestational age and gender (z score) of newborns. RESULT(S): In the prospective study, the average z score was -0.19 +/- 0.85 in Cook and 0.08 +/- 1.40 in Vitrolife. In the retrospective study, the z scores obtained in each group were as follows: Cook, -0.14 +/- 0.96; MediCult, 0.06 +/- 1.13; and Vitrolife, 0.03 +/- 1.05. No significant differences were observed regarding the birth weight of children born in the different groups in both studies. CONCLUSION(S): The results do not show any relationship between the medium used for in vitro culture and mean birth weight adjusted for gestational age and gender of singletons born after IVF/ICSI. PMID- 23916798 TI - Ribosomal proteins as biomarkers for bacterial identification by mass spectrometry in the clinical microbiology laboratory. AB - Whole-cell matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is a rapid method for identification of microorganisms that is increasingly used in microbiology laboratories. This identification is based on the comparison of the tested isolate mass spectrum with reference databases. Using Neisseria meningitidis as a model organism, we showed that in one of the available databases, the Andromas database, 10 of the 13 species-specific biomarkers correspond to ribosomal proteins. Remarkably, one biomarker, ribosomal protein L32, was subject to inter-strain variability. The analysis of the ribosomal protein patterns of 100 isolates for which whole genome sequences were available, confirmed the presence of inter-strain variability in the molecular weight of 29 ribosomal proteins, thus establishing a correlation between the sequence type (ST) and/or clonal complex (CC) of each strain and its ribosomal protein pattern. Since the molecular weight of three of the variable ribosomal proteins (L30, L31 and L32) was included in the spectral window observed by MALDI-TOF MS in clinical microbiology, i.e., 3640-12000 m/z, we were able by analyzing the molecular weight of these three ribosomal proteins to classify each strain in one of six subgroups, each of these subgroups corresponding to specific STs and/or CCs. Their detection by MALDI-TOF allows therefore a quick typing of N. meningitidis isolates. PMID- 23916799 TI - The Medical Imaging & Technology Alliance conference on research endpoints appropriate for medicare coverage of new PET radiopharmaceuticals. AB - The outcomes of a 2011 Medical Imaging & Technology Alliance (MITA) conference helped shape considerations about what might be the most appropriate pathways for the regulatory and payment considerations of new PET radiopharmaceuticals. As follow-up to that conference, MITA convened a second conference of stakeholders to advise payers on what might be acceptable endpoints for clinical trials to support the coverage of novel PET agents. The conference involved experts on imaging and clinical research, providers of PET services, as well as representatives of interested medical societies, the PET industry, and the regulatory and payer communities. The principal outcome of their deliberations was that it was unrealistic to expect trials of new PET radiopharmaceuticals to directly demonstrate a health benefit. Rather, intermediate outcomes, such as a positive change in patient management, would be more efficient and appropriate. PMID- 23916800 TI - Characterization of the phytochelatin synthase from the human parasitic nematode Ancylostoma ceylanicum. AB - Hookworm disease is a debilitating worm infection that affects hundreds of millions of people. Despite the existence of anthelmintic drugs, reports have testified of a decrease in efficacy of these drugs. Therefore, it is imperative to find new drugs and drug targets for hookworm disease treatment. In this study we identify the gene encoding the phytochelatin synthase in the human hookworm, Ancylostoma ceylanicum (AcePCS). Phytochelatin synthase catalyzes the production of metal chelating peptides, the phytochelatins, from glutathione (GSH). In plants, algae, and fungi phytochelatin production is important for metal tolerance and detoxification. Phytochelatin synthase proteins also function in the elimination of xenobiotics by processing GSH S-conjugates. We found that in vitro AcePCS could both synthesize phytochelatins and hydrolyze a GSH S conjugate. Interestingly, the enzyme works through a thiol-dependent and, notably, metal-independent mechanism for both transpeptidase (phytochelatin synthesis) and peptidase (hydrolysis of GSH S-conjugates) activities. AcePCS mRNAs are expressed in vivo throughout the life cycle of A. ceylanicum. Mature adult male hookworms isolated from the small intestines of their hosts displayed significantly enhanced expression of AcePCS with transcript levels 5-fold greater than other developmental forms. Although the role of AcePCS in A. ceylanicum biology has yet to be fully investigated the results reported here provide encouraging evidence of the potential that this enzyme holds as a target for new chemotherapeutic intervention. PMID- 23916801 TI - Syringe access, syringe sharing, and police encounters among people who inject drugs in New York City: a community-level perspective. AB - BACKGROUND: Injection drug user (IDU) experience and perceptions of police practices may alter syringe exchange program (SEP) use or influence risky behaviour. Previously, no community-level data had been collected to identify the prevalence or correlates of police encounters reported by IDUs in the United States. METHODS: New York City IDUs recruited through respondent-driven sampling were asked about past-year police encounters and risk behaviours, as part of the National HIV Behavioural Surveillance study. Data were analysed using multiple logistic regression. RESULTS: A majority (52%) of respondents (n=514) reported being stopped by police officers; 10% reported syringe confiscation. In multivariate modelling, IDUs reporting police stops were less likely to use SEPs consistently (adjusted odds ratio [AOR]=0.59; 95% confidence interval [CI]=0.40 0.89), and IDUs who had syringes confiscated may have been more likely to share syringes (AOR=1.76; 95% CI=0.90-3.44), though the finding did not reach statistical significance. CONCLUSIONS: Findings suggest that police encounters may influence consistent SEP use. The frequency of IDU-police encounters highlights the importance of including contextual and structural measures in infectious disease risk surveillance, and the need to develop approaches harmonizing structural policing and public health. PMID- 23916802 TI - Police sexual coercion and its association with risky sex work and substance use behaviors among female sex workers in St. Petersburg and Orenburg, Russia. AB - BACKGROUND: Extensive research documents that female sex workers (FSWs) in Russia are very vulnerable to abuses from police, including police sexual coercion. However, despite qualitative data suggesting abusive policing practices are more likely for FSWs contending with substance abuse issues and risky sex work contexts, there is a paucity of quantitative study evaluating these associations specifically in terms of police sexual coercion. Such research is needed to guide structural interventions to improve health and safety for FSWs in Russia and globally. OBJECTIVE: The purpose of this study is to assess the prevalence of police sexual coercion among FSWs from two Russian cities, St. Petersburg and Orenburg, and to determine whether riskier sex work behaviors and contexts and substance use behaviors, including both IDU and risky alcohol use, are associated with increased risk for sexual coercion from police. METHOD: FSWs in St. Petersburg and Orenburg were recruited via time-location and convenience sampling and completed structured surveys on demographics (age, education), sex work risks (e.g., violence during sex work) and substance use. Logistic regression analyses assessed associations of substance use and risky sex work with police sexual coercion, adjusting for demographics. RESULTS: Participants (N=896) were aged 15 and older (94% were 20+ years). Most (69%) reported past year binge alcohol use, and 48% reported IDU the day before. Half (56%) reported 4+ clients per day. Rape during sex work ever was reported by 64%. Police sexual coercion in the past 12 months was reported by 38%. In the multivariate model, both current IDU (AOR=2.09, CI=1.45-3.02) and past year binge alcohol use (AOR=1.46, CI=1.03-2.07) were associated with police sexual coercion, as was selling sex on the street (not in venues) (AOR=7.81, CI=4.53-13.48) and rape during sex work (AOR=2.04, CI=1.43-2.92). CONCLUSION: Current findings document the substantial role police sexual violence plays in the lives of FSWs in Russia. These findings also highlight heightened vulnerability to such violence among self-managed and substance abusing FSWs in this context. Structural interventions addressing police violence against FSWs may be useful to improve the health and safety of this population. PMID- 23916803 TI - Prognosis of unexpected and expected pathologic N1 non-small cell lung cancer. AB - BACKGROUND: This study was undertaken to compare clinicopathologic features and survival between patients with unexpected N1 (clinical N0-pathologic N1) and expected N1 disease (clinical N1-pathologic N1) after operation for non-small cell lung cancer. METHODS: From 2003 to 2009, 305 patients who were found to have pathologic N1 disease after complete resection were retrospectively analyzed. Among these, 177 patients had negative findings for both computed tomography (CT) and positron emission tomography (PET)/CT (group cN0). Sixty-eight patients had negative CT and positive PET/CT or positive CT and negative PET/CT findings (group cN0-1). Sixty patients had positive findings for both CT and PET/CT (group cN1). RESULTS: Patients in the cN1 group had larger tumors (p<0.001), greater pathologic T stage (p=0.018), and greater percentage of squamous cell carcinoma (p<0.001) than did those in the other groups. Patients in the cN1 group had a greater number of positive N1 lymph nodes (p=0.004) and more frequent extracapsular nodal invasion (p<0.001). The 5-year overall survival was 66%, 63%, and 58% in groups cN0, cN0-1, and cN1, respectively (cN0 vs cN0-1, p=0.958; cN0 vs cN1, p=0.038). The 5-year disease-free survival was 54%, 52%, and 39% in groups cN0, cN0-1, and cN1, respectively (cN0 vs cN0-1, p=0.862; cN0 vs cN1, p=0.01). CONCLUSIONS: Patients with unexpected N1 disease showed better survival than did those with expected N1 disease, which seemed to be related to the pathologically minimal extent of the primary tumor and nodal involvement. PMID- 23916804 TI - Octogenarians with uncomplicated acute type a aortic dissection benefit from emergency operation. AB - BACKGROUND: The management of acute type A aortic dissection (aTAAD) in octogenarian patients is controversial. This study analyzed the surgical outcomes to identify patients who should undergo operations. METHODS: Beginning in January 2000, we established a registry including all octogenarian patients operated on for type A acute aortic dissection. We evaluated 79 consecutive patients enrolled up to December 2010. Their median age was 81.6 years (range, 80 to 89 years). Sixteen patients (20%) presented a complicated type because of a neurologic deficit, mesenteric ischemia, a requirement for cardiopulmonary resuscitation, or some combination of those features. Operations followed the standard procedure recommended for younger patients. Follow-up was 95% complete (mean, 4.6+/-2.8 years). RESULTS: The overall in-hospital mortality was 44.3%. The in-hospital mortality among patients with uncomplicated aTAAD was 33.3%. Multivariate analysis identified complicated aTAAD as the only risk factors for in-hospital mortality (p<0.0001). Postoperative complications occurred in 50 patients (68.5%) and were associated with a higher mortality (p<0.0001). The overall survival was 53% at 1 year and 32% at 5 years. In uncomplicated aTAAD, the overall survival was 63% at 1 year and 38% at 5 years. CONCLUSIONS: Octogenarians with uncomplicated aTAAD benefit from emergency surgical repair. In those patients, early and midterm outcomes are good and are similar to those in published series of younger patients. Complicated aTAAD should be medically managed. PMID- 23916805 TI - On-pump versus off-pump coronary artery bypass surgery: cost-effectiveness analysis alongside a multisite trial. AB - BACKGROUND: Questions have been raised about the costs and outcomes for patients receiving on-pump and off-pump coronary artery bypass graft surgery. As part of the Department of Veterans Affairs Randomized On/Off Bypass (ROOBY) multisite trial, a cost-effectiveness analysis was performed to compare on-pump versus off pump patients' quality-adjusted life-years and costs at 1 year. METHODS: One-year outcomes and costs (standardized to 2010 dollars) were estimated in multivariate regression models, controlling for site and baseline patient factors. The 1-year incremental cost-effectiveness analysis ratio with 95% confidence intervals was calculated using bootstrapping. RESULTS: Eighteen centers randomly assigned 2,203 participants to on-pump (n=1,099) versus off-pump (n=1,104) coronary artery bypass graft surgery. Both groups' quality of life improved significantly after surgery (p<0.01) compared with baseline, but no differences were found between treatment groups. Adjusted cost of the index coronary artery bypass graft surgery hospitalization was $36,046 on-pump and $36,536 off-pump (p=0.16). At 1 year, on pump adjusted cost was $56,023 versus $59,623 off-pump (p=0.046). Off-pump-to-on pump conversions after first distal anastomosis (4.8%) had significantly higher 1 year costs. Excluding conversions, there were no significant differences between treatments for index hospitalization or 1-year total costs. CONCLUSIONS: At 1 year, off-pump coronary artery bypass graft surgery was more expensive than on pump when late off-pump-to-on-pump conversions were included. Excluding late conversions, there was no difference in quality-adjusted life-years or costs. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00032630; http://clinicaltrials.gov/ct2/show/NCT00032630. PMID- 23916806 TI - The impact of previous catheter-based ablation on the efficacy of the Cox-maze IV procedure. AB - BACKGROUND: Failed catheter-based ablation for the treatment of atrial fibrillation is an indication for the Cox-maze procedure. Many patients are referred for the Cox-maze IV procedure with recurrent atrial fibrillation after a previous catheter-based ablation, but the efficacy and safety of surgical management in these patients remains unclear. METHODS: Data were collected prospectively on 129 consecutive patients who underwent a stand-alone Cox-maze IV procedure. Patients were grouped by the presence (n=61; 47%) or absence (n=68; 53%) of previous catheter ablation history. Follow-up was conducted at 3, 6, and 12 months (94% complete, mean 15.1+/-15.6 months) with electrocardiograms and 24 hour Holter monitoring. RESULTS: In patients with no ablation history compared with those with, freedom from atrial tachyarrhythmias and antiarrhythmic drugs were similar at 3 months (73% versus 67%), 6 months (85% versus 83%), and 12 months (81% versus 87%; p<0.05 for all). Those who had failed previous catheter ablation had significantly smaller left atria and longer durations of atrial fibrillation, and were more likely to have persistent atrial fibrillation compared with the group without prior ablation history. All analyzed baseline patient characteristics and comorbidities were similar between the groups. No differences were found in complication rates or surrogate measures of operative difficulty. CONCLUSIONS: The Cox-maze IV procedure is safe and effective in treating recurrent atrial fibrillation regardless of previous catheter ablation history. Surgical management should be considered in patients who have failed catheter ablation for the treatment of their atrial fibrillation. PMID- 23916807 TI - Thoracic endovascular aortic repair for aortobronchial fistula. AB - The objective was to provide a systematic review of outcomes of thoracic endovascular aortic repair for aortobronchial fistula. A literature search identified 134 patients. The technical success rate was 93.2%. The overall 30-day mortality was 5.9%. After a mean follow-up of 17.4 months, the aortic-related mortality was 14.3%. Recurrence of the aortobronchial fistula was observed in 11.1% of the patients. Thoracic endovascular aortic repair of aortobronchial fistulas appears to be a viable alternative with excellent short-term results. Strict follow-up and aggressive adjunctive measures are needed to treat ongoing infection to prevent late related mortality. PMID- 23916808 TI - Bilateral pulmonary artery banding as rescue intervention in high-risk neonates. AB - BACKGROUND: Presentation in shock and preoperative infection remain risk factors for neonatal cardiac surgery. This report describes bilateral pulmonary artery banding (bPAB) in ductal-dependent lesions with systemic outflow obstruction as rescue intervention before surgery with cardiopulmonary bypass in these high-risk neonates. METHODS: A retrospective chart review was conducted for 10 patients who underwent bPAB before conventional surgery with cardiopulmonary bypass. Patient characteristics including birth weight, gestational age, cardiac and noncardiac diagnoses, preoperative and postoperative markers of organ function, and outcome measures were examined. RESULTS: The majority of patients (8 of 10) were considered high-risk owing to multiorgan dysfunction syndrome. The median age at bPAB was 12 days (range, 5 to 26 days), and the median interval between bPAB and second surgery was 10.5 days (range, 5 to 79 days). Organ function improved after admission and continued to improve after bPAB in 9 of 10 patients. No patient experienced new complications between bPAB and subsequent operation. Of 8 patients who had stage I palliation, 5 have undergone or are awaiting completion Fontan, 1 underwent Kawashima procedure, 1 underwent orthotopic heart transplant, and 1 with hypoplastic left heart syndrome and intact atrial septum died at 44 days old. Both patients who underwent biventricular repair are alive and well. Median follow-up for survivors was 2.9 years (range, 0.25 to 6.25 years). CONCLUSIONS: Bilateral pulmonary artery banding is safe in ductal-dependent lesions with systemic outflow obstruction. High-risk patients with preoperative organ dysfunction or infection can recover within a short period and become lower risk candidates for complex congenital heart surgery using cardiopulmonary bypass. PMID- 23916809 TI - Atherosclerosis and interferon-gamma: new insights and therapeutic targets. AB - Atherosclerosis is considered to be a chronic inflammatory disease of the arterial wall. Atherogenesis is accompanied by local production and release of inflammatory mediators, for which the macrophage is a major source. The proinflammatory cytokine, interferon (IFN)-gamma derived from T cells, is expressed at high levels in atherosclerotic lesions. IFN-gamma is the classic macrophage-activating factor, vital for both innate and adaptive immunity. It primes macrophages to produce chemokines and cytotoxic molecules and induces expression of genes that regulate lipid uptake. IFN-gamma is a key trigger for the formation and release of reactive oxygen species. IFN-gamma has important effects on endothelial cells, promoting expression of adhesion molecules. Atherogenic effects of IFN-gamma have been shown in murine models where exogenous administration enhances atherosclerotic lesion formation while knockout of IFN gamma or its receptor reduces lesion size. IFN-gamma signaling is largely mediated by a Janus kinase (JAK) to signal transduction and activator of transcription (STAT)1 cytosolic factor pathway. A clear understanding of IFN gamma effects on atherogenesis should enable development of novel targeted interventions for clinical use in the prevention and treatment of atherosclerosis. This review will discuss the actions of the cytokine IFN-gamma and its complex effects on cells involved in atherosclerosis. PMID- 23916810 TI - Phosphodiesterase 5 inhibitor acts as a potent agent sensitizing acute myeloid leukemia cells to 67-kDa laminin receptor-dependent apoptosis. AB - (-)-Epigallocatechin-3-O-gallate (EGCG), a polyphenol in green tea, induces apoptosis in acute myeloid leukemia (AML) cells without affecting normal cells. In this study, we observed that cGMP acts as a cell death mediator of the EGCG induced anti-AML effect through acid sphingomyelinase activation. EGCG activated the Akt/eNOS axis, a well-known mechanism in vascular cGMP upregulation. We also observed that a major cGMP negative regulator, phosphodiesterase 5, was overexpressed in AML cells, and PDE5 inhibitor, an anti-erectile dysfunction drug, synergistically enhanced the anti-AML effect of EGCG. This combination regimen killed AML cells via overexpressed 67-kDa laminin receptors. PMID- 23916811 TI - Soluble urokinase plasminogen activator receptor levels reflect organ damage in systemic lupus erythematosus. AB - Assessments of disease activity and organ damage in systemic lupus erythematosus (SLE) remain challenging because of the lack of reliable biomarkers and disease heterogeneity. Ongoing inflammation can be difficult to distinguish from permanent organ damage caused by previous flare-ups or medication side effects. Circulating soluble urokinase plasminogen activator receptor (suPAR) has emerged as a potential marker of inflammation and disease severity, and an outcome predictor in several disparate conditions. This study was done to evaluate suPAR as a marker of disease activity and organ damage in SLE. Sera from 100 healthy donors and 198 patients with SLE fulfilling the 1982 American College of Rheumatology classification criteria and/or the Fries criteria were analyzed for suPAR by enzyme immunoassay. Eighteen patients with varying degree of disease activity were monitored longitudinally. Disease activity was assessed by the SLE disease activity index 2000 and the physician's global assessment. Organ damage was evaluated by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). Compared with healthy control subjects, serum suPAR levels were elevated significantly in patients with SLE. No association was recorded regarding suPAR levels and SLE disease activity in cross sectional or consecutive samples. However, a strong association was observed between suPAR and SDI (P < 0.0005). Considering distinct SDI domains, renal, neuropsychiatric, ocular, skin, and peripheral vascular damage had a significant effect on suPAR levels. This study is the first to demonstrate an association between serum suPAR and irreversible organ damage in SLE. Further studies are warranted to evaluate suPAR and other biomarkers as predictors of evolving organ damage. PMID- 23916812 TI - [Cultural adaptation and content validation of the "Pain level" outcome of the Nursing Outcomes Classification]. AB - AIMS: To translate and culturally adapt the Pain Level outcome to the Spanish context to validate the contents of the Spanish version of the "Pain level" outcome. METHOD: The original English version of the "Pain level" outcome was translated into Spanish (twice); then back-translated into English, and all the discrepancies were resolved after consulting with NOC authors. A panel consisting of 21 experts in pain care assessed this culturally adapted Spanish version, in order to score the content validity. In the first step, the experts scored the adequacy of each indicator to the concept "Pain level". In the second round, three new indicators were scored. The Statistical analysis included content validity index (CVI), probability of agreement by chance, and modified kappa statistic. RESULTS: A Spanish version was developed including label, definition, two groups of indicators, and two measurement scales. This version is fully adapted to the Spanish context and language. A set of 21 indicators (19 translated and two new) was selected, and 4 were deleted (three translated and one new). The CVI-average score was 0.83 and the CVI-universal agreement was 0.05. CONCLUSION: The Spanish-version of the outcome "Pain level" is semantically and culturally to adapted to a Spanish context and preserves equivalency with the original. Content validation has identified indicators useful for practice. The clinimetric properties (validity and reliability) of the adapted version could be tested in a clinical study with people suffering from acute pain. PMID- 23916813 TI - [Preference for etanercept pen versus syringe in patients with chronic arthritis. Nurse education workshop]. AB - OBJECTIVES: The aims of this study are to evaluate the level of fear of post injection pain prior to the administration, the difficulty in handling the device, and the level of satisfaction of patients using a pre-filled syringe versus an etanercept pen, as well as to evaluate the usefulness of the training given by nursing staff prior to starting with the pen, and the preferences of patients after using both devices. METHOD: A prospective study was designed to follow-up a cohort of patients during a 6 months period. The data was collected using questionnaires and analyzed with SPSS 18.00. Rank and McNemar tests were performed. Statistical significance was pre-set at an alpha level of 0.05. RESULTS: A total of 29 patients were included, of whom 69% female, and with a mean age 52.5+/-10.9 years. Of these, 48% had rheumatoid arthritis, 28% psoriatic arthritis, 21% ankylosing spondylitis, and 3% undifferentiated spondyloarthropathy. There were no statistically significant differences either with the fear or pain or handling of the device between the syringe and the pen (P=.469; P=.812; P=.169 respectively). At 6 months, 59% of patients referred to being satisfied or very satisfied with the pen. Almost all (93%) found useful or very useful the training given by nursing staff prior to using the pen, and 55% preferred the pen over the pre-filled syringe. CONCLUSIONS: The etanercept pen is another subcutaneous device option for patients with chronic arthritis. According to the present study, nursing educational workshops before starting this therapy are recommended. PMID- 23916814 TI - Allosteric inhibitor specificity of Thermotoga maritima 3-deoxy-D-arabino heptulosonate 7-phosphate synthase. AB - 3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS) catalyses the first step of the shikimate pathway for the biosynthesis of aromatic amino acids. Allosteric regulation of Thermotoga maritima DAH7PS is mediated by L-Tyr binding to a discrete ACT regulatory domain appended to a core catalytic (beta/alpha)8 barrel. Variants of T. maritima DAH7PS (TmaDAH7PS) were created to probe the role of key residues in inhibitor selection. Substitution Ser31Gly severely reduced inhibition by L-Tyr. In contrast both L-Tyr and L-Phe inhibited the TmaHis29Ala variant, while the variant where Ser31 and His29 were interchanged (His29Ser/Ser31His), was inhibited to a greater extent by L-Phe than L-Tyr. These studies highlight the role and importance of His29 and Ser31 for determining both inhibitory ligand selectivity and the potency of allosteric response by TmaDAH7PS. PMID- 23916815 TI - The V1/V2 loop of HIV-1 gp120 is necessary for Tat binding and consequent modulation of virus entry. AB - Preventing cell entry of human immunodeficiency virus 1 (HIV-1) is of interest for the development of innovative therapies. We previously reported a specific interaction between HIV-1 envelope glycoprotein 120 (gp120) and Tat at the cell surface, which enhances virus attachment and entry. We also identified a gp120 mimicking peptide, CT319, that competes with gp120 for Tat binding, thus inhibiting HIV-1 infection. Here we report a molecular dissection of gp120 regions involved in this mechanism. Our findings identify the V1/V2 loop of gp120 as involved in Tat binding, and define this interaction as functionally relevant for HIV-1 entry into host cells. PMID- 23916816 TI - Interest of rehabilitation in healing and preventing recurrence of ankle sprains. AB - To assess the impact of rehabilitation on healing and recurrence rate of ankle sprain, 1year apart, 111 patients, who suffered an ankle sprain (67 men and 44 women; 17 mild sprains, 67 medium and 27 severe), were included by emergency physicians of four emergency rooms (ER) of Finistere. The physician was free to prescribe, or not, further investigations. He prescribed systematically to patients RICE (rest, ice, compression, elevation) protocol, put an ankle brace, and gave a prescription of standardized rehabilitation. The prescription was the same for the four ER. All patients were recalled to 1year. Of the 111 patients initially included, 21 patients were excluded for lack of response after three phone calls. In the end, 90 patients were assessable (56 men and 34 women), mean age 31.4+/-12.6years (range 15-55) at the time of initial trauma. Emergency physicians had diagnosed, initially, 16 mild sprains (17.8%), 56 medium sprains (62.2%) and 18 severe sprains (20%). Of the 90 patients, 73 patients have been rehabilitated (81.1%). Of the 44 accidents of everyday life, 31 were rehabilitated (70.5%). Of the 27 sports accidents, 25 were rehabilitated (92.6%). Of the 19 work-related injuries, 17 were rehabilitated (89.5%). There is no significant relationship between rehabilitation and no recurrence (P=0.45) nor between rehabilitation and full recovery of the ankle (P=0.59). CONCLUSION: We find no association between rehabilitation and prevention of recurrence, nor between rehabilitation and healing of patients. However, our study is limited by the small size of the non-rehabilitated group. PMID- 23916817 TI - Species-specific effects of near-future CO(2) on the respiratory performance of two tropical prey fish and their predator. AB - Ocean surface CO2 levels are increasing in line with rising atmospheric CO2 and could exceed 900MUatm by year 2100, with extremes above 2000MUatm in some coastal habitats. The imminent increase in ocean pCO2 is predicted to have negative consequences for marine fishes, including reduced aerobic performance, but variability among species could be expected. Understanding interspecific responses to ocean acidification is important for predicting the consequences of ocean acidification on communities and ecosystems. In the present study, the effects of exposure to near-future seawater CO2 (860MUatm) on resting (M O2rest) and maximum (MO2max) oxygen consumption rates were determined for three tropical coral reef fish species interlinked through predator-prey relationships: juvenile Pomacentrus moluccensis and Pomacentrus amboinensis, and one of their predators: adult Pseudochromis fuscus. Contrary to predictions, one of the prey species, P. amboinensis, displayed a 28-39% increase in MO2max after both an acute and four day exposure to near-future CO2 seawater, while maintaining MO2rest. By contrast, the same treatment had no significant effects on MO2rest or MO2max of the other two species. However, acute exposure of P. amboinensis to 1400 and 2400MUatm CO2 resulted in MO2max returning to control values. Overall, the findings suggest that: (1) the metabolic costs of living in a near-future CO2 seawater environment were insignificant for the species examined at rest; (2) the MO2max response of tropical reef species to near-future CO2 seawater can be dependent on the severity of external hypercapnia; and (3) near-future ocean pCO2 may not be detrimental to aerobic scope of all fish species and it may even augment aerobic scope of some species. The present results also highlight that close phylogenetic relatedness and living in the same environment, does not necessarily imply similar physiological responses to near-future CO2. PMID- 23916818 TI - Effect of meal size and body size on specific dynamic action and gastric processing in decapod crustaceans. AB - Meal size and animal size are important factors affecting the characteristics of the specific dynamic action (SDA) response across a variety of taxa. The effects of these two variables on the SDA of decapod crustaceans are based on just a couple of articles, and are not wholly consistent with the responses reported for other aquatic ectotherms. Therefore, the effects of meal size and animal size on the characteristics of SDA response were investigated in a variety of decapod crustaceans from different families. A 6 fold increase in meal size (0.5%-3% body mass) resulted a pronounced increase in the duration of increased oxygen consumption, resulting in an increase in the SDA of Callinectes sapidus, Cancer gracilis, Hemigrapsus nudus, Homarus americanus, Pugettia producta and Procambarus clarkii. Unlike many other aquatic ectotherms a substantial increase between meal sizes was required, with meal size close to their upper feeding limit (3% body mass), before changes were evident. In many organisms increases in both duration and scope contribute to the overall SDA, here changes in scope as a function of meal size were weak, suggesting that a similar amount of energy is required to upregulate gastric processes, regardless of meal size. The SDA characteristics were less likely to be influenced by the size of the animal, and there was no difference in the SDA (kJ) as a function of size in H. americanus or Cancer irroratus when analysed as mass specific values. In several fish species characteristics of the SDA response are more closely related to the transit times of food, rather than the size of a meal. To determine if a similar trend occurred in crustaceans, the transit rates of different sized meals were followed through the digestive system using a fluoroscope. Although there was a trend towards larger meals taking longer to pass through the gut, this was only statistically significant for P. clarkii. There were some changes in transit times as a function of animal size. The foregut clearance times for Cancer magister increased with increasing body size, while smaller Carcinus maenas cleared the hindgut region at a faster rate than larger individuals. Unlike fish there was no clear relationship between transit rates and any of the SDA characteristics. While the fluoroscopy method is useful for assessing foregut activity and food passage, it is limited when inferring connections between nutrient assimilation and post-absorptive processes in crustaceans. Therefore, at least with respect to meal size, transit rates do not make a good proxy for determining the SDA characteristics in crustaceans. PMID- 23916819 TI - Genetic polymorphisms in Cytochrome P 4501B1 and susceptibility to idiopathic preterm labor in North Indian population. AB - OBJECTIVE: The etiology of preterm labor (PTL) is still unknown, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We investigated the relation between PTL and polymorphisms in Cytochrome P4501B1 (CYP1B1) gene, which is involved in the metabolism of a wide range of environmental toxins and hormones. DESIGN AND METHODS: Three hundred (n=300) cases of PTL and equal number of subjects of full term labor (FTL), after excluding all the known risk factors for PTL were included in the study. A two step allele specific PCR was performed for polymorphic analysis of CYP1B1 gene. RESULTS: The homozygous variant genotype of CYP1B1*2 (OR=2.97, 95%CI=1.08-8.08, p=0.033) and heterozygous variant of CYP1B1*3 (OR=2.57, 95%CI=1.88-3.63, p=0.001), and CYP1B1*7 (OR=2.59, 95%CI=1.85-3.62, p=0.001) were found to be significantly higher in PTL cases as compared to FTL. CONCLUSIONS: The present study demonstrates the possible association of homozygous variant of CYP1B1*2 and heterozygous variant of CYP1B1*3 and CYP1B1*7 genes with the increased risk of PTL. PMID- 23916820 TI - The anti-thrombotic effect of hydrogen sulfide is partly mediated by an upregulation of nitric oxide synthases. AB - INTRODUCTION: Hydrogen sulfide (H2S) known as a gasotransmitter is increasingly recognized for its anti-adhesive, anti-inflammatory and vasoactive properties. Due to these properties, we analysed anti-thrombotic effects of H2S and the participation of the nitric oxide synthase (NOS)-pathway. MATERIALS AND METHODS: In individual venules of the ear of hairless SKH1-hr mice, thrombus formation was induced using a phototoxic light/dye-injury model and intravital fluorescence microscopy. Animals were treated intravenously with the H2S donor Na2S or NaCl as control. In a second setting, the NOS inhibitor L-NAME was applied intraperitoneally as a bolus 12h prior to Na2S treatment and thrombus induction. Blood and ear tissue were sampled after microscopy for assessment of plasma concentrations of soluble (s)P-selectin, sE-selectin, sVCAM-1 and sICAM-1 and expression of endothelial (e)NOS and inducible (i)NOS, respectively. RESULTS: When mice were treated with Na2S, venular thrombus formation was significantly delayed versus that in animals of the NaCl-treated control group. While plasma levels of pro-thrombotic adhesion molecules were not affected by Na2S, immunohistochemistry of the vessel walls showed a significant up-regulation of eNOS and iNOS expression within the Na2S-treated group. The delay of thrombus formation in the Na2S-group was partly but significantly reverted by application of L-NAME. CONCLUSIONS: The anti-thrombotic efficacy of H2S involves the NOS pathway and may be of preventive and therapeutic value for clinical disorders with increased risk of thrombotic events. PMID- 23916821 TI - Injectable alginate hydrogel loaded with GDNF promotes functional recovery in a hemisection model of spinal cord injury. AB - We hypothesized that local delivery of GDNF in spinal cord lesion via an injectable alginate hydrogel gelifying in situ would support spinal cord plasticity and functional recovery. The GDNF release from the hydrogel was slowed by GDNF encapsulation in microspheres compared to non-formulated GDNF (free GDNF). When injected in a rat spinal cord hemisection model, more neurofilaments were observed in the lesion when the rats were treated with free GDNF-loaded hydrogels. More growing neurites were detected in the tissues surrounding the lesion when the animals were treated with GDNF microsphere-loaded hydrogels. Intense GFAP (astrocytes), low betaIII tubulin (neural cells) and RECA-1 (endothelial cells) stainings were observed for non-treated lesions while GDNF treated spinal cords presented less GFAP staining and more endothelial and nerve fiber infiltration in the lesion site. The animals treated with free GDNF-loaded hydrogel presented superior functional recovery compared with the animals treated with the GDNF microsphere-loaded hydrogels and non-treated animals. PMID- 23916822 TI - A potential carrier based on liquid crystal nanoparticles for ophthalmic delivery of pilocarpine nitrate. AB - Poor corneal penetration and short preocular retention of a clinical hydrophilic drug, pilocarpine nitrate (PN), for the treatment of open-angle glaucoma and acute angle-closure glaucoma, limit its ocular application. The purpose of this study was to investigate the potential of liquid crystal nanoparticles (LCNPs) for ocular delivery of PN. LCNPs were developed by a top-down method using glyceryl monoolein (GMO) and water in the presence of stabilizer Poloxamer 407. They were characterized by transmission electron microscopy (TEM) and small angle X-ray diffraction (SAXS). The size of LCNP is 202.28+/-19.32 nm and the encapsulation efficiency reached 61.03%. The in vitro release profiles indicated that PN could keep sustained release from PN-loaded LCNPs for 8h. An ex vivo corneal permeation study revealed that the apparent permeability coefficient of PN-loaded LCNPs was 2.05-fold higher than that of commercial eye drops. In addition, the topical administration test showed that PN-loaded LCNPs had a prolonged effect on decreasing intraocular pressure (IOP) of rabbits compared with commercial drug and physiological saline. In conclusion, LCNPs had been demonstrated to be potential for controlled-release ocular drug delivery. PMID- 23916823 TI - Risk based approach for design and optimization of stomach specific delivery of rifampicin. AB - The research envisaged focuses on risk management approach for better recognizing the risks, ways to mitigate them and propose a control strategy for the development of rifampicin gastroretentive tablets. Risk assessment using failure mode and effects analysis (FMEA) was done to depict the effects of specific failure modes related to respective formulation/process variable. A Box-Behnken design was used to investigate the effect of amount of sodium bicarbonate (X1), pore former HPMC (X2) and glyceryl behenate (X3) on percent drug release at 1st hour (Q1), 4th hour (Q4), 8th hour (Q8) and floating lag time (min). Main effects and interaction plots were generated to study effects of variables. Selection of the optimized formulation was done using desirability function and overlay contour plots. The optimized formulation exhibited Q1 of 20.9%, Q4 of 59.1%, Q8 of 94.8% and floating lag time of 4.0 min. Akaike information criteria and Model selection criteria revealed that the model was best described by Korsmeyer-Peppas power law. The residual plots demonstrated no existence of non-normality, skewness or outliers. The composite desirability for optimized formulation computed using equations and software were 0.84 and 0.86 respectively. FTIR, DSC and PXRD studies ruled out drug polymer interaction due to thermal treatment. PMID- 23916824 TI - Effect of type and ratio of solubilising polymer on characteristics of hot-melt extruded orodispersible films. AB - In formulating an orodispersible film (ODF), it is important for polymer choice to strike a balance between mechanical properties and release rates. Studies have been done to study polymer combinations. However, there is a lack of a systematic study to determine key factors affecting these properties. We studied the effect of varying the ratios of a solubilising polymer (Kollidon((r)) VA 64 or Soluplus((r))) to a film forming polymer, hydroxypropyl cellulose (HPC), on mechanical properties and release rates of hot-melt extruded ODFs using a 2(3) factorial design. The two drugs evaluated were chlorpheniramine and indomethacin. The main effects impacting mechanical properties were the drug and two-way interaction between drug and solubilising polymer. For dissolution, the main effects were the solubilising polymer; the drug; and the two-way interaction between solubilising polymer and ratio of solubilising to film forming polymer. Both drugs exhibited plasticising effects on the polymer matrix and had higher film ductility and lower film stiffness. Kollidon((r)) VA 64-containing films performed better in terms of drug release whereas Soluplus((r))-containing films had better mechanical properties. The dissolution rate can be improved by decreasing film thickness. The findings of our study will be crucial to forming a robust ODF formulation. PMID- 23916825 TI - Needle free parenteral drug delivery: leveraging active transdermal technologies for pediatric use. AB - Administration of medications via the parenteral route directly to the systemic circulation is an effective way of overcoming the first pass effect, obtaining quicker onset of action, and achieving higher bioavailability. However, needle phobia and the pain perceived during the injection process often make this a less preferred route than oral in terms of patient acceptance and compliance, particularly for pediatrics. Needleless injection technologies that deliver medications via the transdermal interface have been an active area of pharmaceutical research for many years. This review summarizes the various emerging technologies in the area of active transdermal delivery that can be potentially extended to pediatric applications. PMID- 23916826 TI - Dependence of the kinetic and thermodynamic parameters on hydrophilic-lipophilic character of alprazolam, clonazepam, diazepam, doxepin and haloperidol in alkaline environment. AB - Examination of the stability of clonazepam, diazepam, alprazolam, haloperidol, and doxepin in basic solutions was performed, together with an assessment of the kinetic (k, t0.1i t0.5) and thermodynamic (Ea, DeltaH(++)i DeltaS(++)) stability indicating parameters, which were compared with the lipophilicity (logP) of the studied drugs. It was observed that the calculated values of Ea, DeltaH(++) and DeltaS(++) for the studied drugs increased from 41.04 kJ/mol to 125.50 kJ/mol, from 37.82 kJ/mol to 122.24 kJ/mol and from -167.09 J/Kmol to 53.02 J/Kmol, respectively, along with an increase of lipophilicity (logP) from 2.12 to 4.30 for the most hydrophilic alprazolam to the most lipophilic haloperidol. The degradation products were identified using UPLC/MS/MS method. PMID- 23916827 TI - Symptom burden clusters: a challenge for targeted symptom management. A longitudinal study examining symptom burden clusters in breast cancer. AB - CONTEXT: Although there has been a growing interest in cancer symptom clusters, less is known about symptom burden clusters. OBJECTIVES: To explore clusters of burdensome symptoms over time, the impact on health status and quality of life, and coping capacity in patients with breast cancer. METHODS: In this longitudinal study, a sample of 206 patients completed the Memorial Symptom Assessment Scale, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, and the Sense of Coherence scale, at diagnosis of primary or recurrent breast cancer, and at one-, three-, and six-month follow-ups. RESULTS: Three clusters of burdensome symptoms were identified: emotional symptom burden, gastrointestinal symptom burden, and unwellness symptom burden. Most burdensome were emotional symptoms, with worrying, feeling sad, and feeling nervous as the core or defining symptoms. Over time, additional symptoms escalated the emotional symptom burden. The gastrointestinal symptom burden, with "change in the way food tastes" as a core symptom, was more often associated with chemotherapy. Less stable over time, the unwellness symptom burden could be interpreted as short- and long-term side effects of hormonal therapy. Of these clusters, only the emotional symptom burden cluster significantly diminished health status and quality of life. Patients reporting lower coping capacity experienced higher levels of symptom burden. CONCLUSION: This study provides insights into symptom burden clusters over time. A challenging approach toward symptom management in clinical oncology is to target the burden of a symptom cluster and to recognize the need for individually designed interventions to ameliorate symptom burden in cancer patients. PMID- 23916829 TI - Valence electron energy-loss spectroscopy study of ZrSiO4 and ZrO2. AB - ZrSiO4 (zircon) and m-ZrO2 (zirconia) are fundamental and industrially important materials. This work reports the detailed valence electron energy-loss spectroscopy (VEELS) studies of these compounds. The dielectric response functions, as well as single-electron interband transition spectra, are derived from VEELS data for both ZrSiO4 and m-ZrO2, in the range 5-50 eV using the Kramers-Kronig analysis method. Our interpretation of the interband transitions is given with the aid of ab initio calculations of density of states. The bandgap energies for both materials are also measured using VEELS. The surface and bulk plasmons are identified: the surface plasmon peaks locate at around 12 eV, and two bulk plasmon peaks are ~15-16 eV and ~25-27 eV, respectively. Although similarities in the VEELS exist between ZrSiO4 and m-ZrO2, two major differences are also noticed and explained in terms of composition and structure differences. PMID- 23916830 TI - Saliency-guided neural prosthesis for visual attention: design and simulation. AB - Recently the authors showed that a computational model of visual saliency could account for changes in gaze behavior of monkeys with damage in the primary visual cortex. Here we propose a neural prosthesis to restore eye gaze behavior by electrically stimulating the superior colliculus to drive visual attention. The saliency computational model is used to calculate the stimulation parameters from a real-time camera stream. Our simulations demonstrate that electrodes implanted in the superior colliculus at 1.0mm spacing are, in principle, able to recover specifically those visual attention behaviors which are lost when the primary visual cortex is damaged. PMID- 23916831 TI - Mitochondrial ferritin in neurodegenerative diseases. AB - Mitochondrial ferritin (FtMt) is a novel protein encoded by an intronless gene mapped to chromosome 5q23.1. Ferritin is ubiquitously expressed; however, FtMt expression is restricted to specific tissues such as the testis and the brain. The distribution pattern of FtMt suggests a functional role for this protein in the brain; however, data concerning the roles of FtMt in neurodegenerative diseases remain scarce. In the human cerebral cortex, FtMt expression was increased in Alzheimer's disease patients compared to control cases. Cultured neuroblastoma cells showed low-level expression of FtMt, which was increased by H2O2 treatment. FtMt overexpression showed a neuroprotective effect against H2O2 induced oxidative stress and Abeta-induced neurotoxicity in neuroblastoma cells. FtMt expression was also detected in dopaminergic neurons in the substantia nigra and was increased in patients with restless legs syndrome, while FtMt had a protective effect against cell death in a neuroblastoma cell line model of Parkinson's disease. FtMt is involved in other neurodegenerative diseases such as age-related macular degeneration (AMD), with an FtMt gene mutation identified in AMD patients, and Friedreich's ataxia, which is caused by a deficiency in frataxin. FtMt overexpression in frataxin-deficient cells increased cell resistance to H2O2 damage. These results implicate a neuroprotective role of FtMt in neurodegenerative diseases. PMID- 23916828 TI - Analysis of residual perinatal transmission of hepatitis B virus (HBV) and of genetic variants in human immunodeficiency virus and HBV co-infected women and their offspring. AB - BACKGROUND: Despite implementation of universal infant hepatitis B (HB) vaccination, mother-to-child transmission (MTCT) of hepatitis B virus (HBV) still occurs. Limited data are available on the residual MTCT of HBV in human immunodeficiency virus (HIV)-HBV co-infected women. OBJECTIVES: We assessed the prevalence of HBV infection among HIV-infected pregnant women and the rate of residual MTCT of HBV from HIV-HBV co-infected women and analyzed the viral determinants in mothers and their HBV-infected children. STUDY DESIGN: HIV-1 infected pregnant women enrolled in two nationwide perinatal HIV prevention trials in Thailand were screened for HB surface antigen (HBsAg) and tested for HBeAg and HBV DNA load. Infants born to HBsAg-positive women had HBsAg and HBV DNA tested at 4-6 months. HBV diversity within each HBV-infected mother-infant pair was analyzed by direct sequencing of amplified HBsAg-encoding gene and cloning of amplified products. RESULTS: Among 3312 HIV-1 infected pregnant women, 245 (7.4%) were HBsAg-positive, of whom 125 were HBeAg-positive. Of 230 evaluable infants born to HBsAg-positive women, 11 (4.8%) were found HBsAg and HBV DNA positive at 4-6 months; 8 were born to HBeAg-positive mothers. HBV genetic analysis was performed in 9 mother-infant pairs and showed that 5 infants were infected with maternal HBV variants harboring mutations within the HBsAg "a" determinant, and four were infected with wild-type HBV present in highly viremic mothers. CONCLUSIONS: HBV-MTCT still occurs when women have high HBV DNA load and/or are infected with HBV variants. Additional interventions targeting highly viremic women are thus needed to reduce further HBV-MTCT. PMID- 23916832 TI - Expression variations of chromogranin A and alpha1,2,4 GABA(A)Rs in discrete limbic and brainstem areas rescue cardiovascular alterations. AB - Recent interferences of hemodynamic functions via modified brain neuronal mechanisms have proven to be major causes of dementia and sleeping disorders. In this work, cerebral expression differences of the neuroactive vesicular chromogranin A (CgA) and distinct alpha GABA(A)R subunits were detected in the facultative hibernating hamster. In particular, damaged neuronal fields of hypotensive torpor (TORP) state were correlated to elevated CgA and GABA(A)R alpha1, alpha4 mRNA levels in the paraventricular hypothalamic nucleus (PVN), central amygdalar nucleus (CeA) plus solitary tractus nucleus (NTS). Conversely, few neurodegeneration signals of hypertensive arousal (AROU) state, accounted for mostly lower CgA levels in the same areas. This state also provided increased alpha2-containing sites in amygdala, hippocampal and NTS neurons together with elevated alpha4-containing receptors in the periventricular hypothalamic nucleus (Pe). Interestingly in our hibernating model, CgA appeared to preferentially feature inhibitory neurosignals as indicated by preliminary perfusion of amygdalar sites with its highly specific antihypertensive derived peptide (catestatin) promoting GABA-dependent sIPSCs. Overall, evident neuronal damages plus altered expression capacities of CgA and alpha1-, alpha2-, alpha4-GABA(A)Rs in CeA, Pe, PVN as well as NTS during both hibernating states corroborate for the first time key molecular switching events guaranteeing useful cardiovascular rescuing abilities of neurodegenerative disorders. PMID- 23916834 TI - Investigations into the skills of modern and traditional train driving. AB - Rail operations are housed inside a complex and extremely dynamic system where work is distributed in time and space. The train driver has traditionally relied on their own decisions, plans, and actions to navigate the rail environment, but the use of modern driver systems that force how these activities are regulated has altered this dynamic. This paper reports the findings of a study that set out to investigate the skills of modern (enhanced display-based) and traditional (real world) train driving. Data were collected from a variety of UK domain experts (n = 45) using an innovative methodology that converged multiple techniques for knowledge elicitation and analysis. The findings are represented in a model of dynamic train control and discussed according to the specific features and nature of tracking skill in the rail domain. The utility of the model is demonstrated through work of its application to the design of a train simulator and research tool for systematic study of rail human factor issues. PMID- 23916833 TI - Inhibition of LRRK2 kinase activity stimulates macroautophagy. AB - Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most important genetic contributors to Parkinson's disease. LRRK2 has been implicated in a number of cellular processes, including macroautophagy. To test whether LRRK2 has a role in regulating autophagy, a specific inhibitor of the kinase activity of LRRK2 was applied to human neuroglioma cells and downstream readouts of autophagy examined. The resulting data demonstrate that inhibition of LRRK2 kinase activity stimulates macroautophagy in the absence of any alteration in the translational targets of mTORC1, suggesting that LRRK2 regulates autophagic vesicle formation independent of canonical mTORC1 signaling. This study represents the first pharmacological dissection of the role LRRK2 plays in the autophagy/lysosomal pathway, emphasizing the importance of this pathway as a marker for LRRK2 physiological function. Moreover it highlights the need to dissect autophagy and lysosomal activities in the context of LRRK2 related pathologies with the final aim of understanding their aetiology and identifying specific targets for disease modifying therapies in patients. PMID- 23916835 TI - Neural network and Monte Carlo simulation approach to investigate variability of copper concentration in phytoremediated contaminated soils. AB - The statistical variation of soil properties and their stochastic combinations may affect the extent of soil contamination by metals. This paper describes a method for the stochastic analysis of the effects of the variation in some selected soil factors (pH, DOC and EC) on the concentration of copper in dwarf bean leaves (phytoavailability) grown in the laboratory on contaminated soils treated with different amendments. The method is based on a hybrid modeling technique that combines an artificial neural network (ANN) and Monte Carlo Simulations (MCS). Because the repeated analyses required by MCS are time consuming, the ANN is employed to predict the copper concentration in dwarf bean leaves in response to stochastic (random) combinations of soil inputs. The input data for the ANN are a set of selected soil parameters generated randomly according to a Gaussian distribution to represent the parameter variabilities. The output is the copper concentration in bean leaves. The results obtained by the stochastic (hybrid) ANN-MCS method show that the proposed approach may be applied (i) to perform a sensitivity analysis of soil factors in order to quantify the most important soil parameters including soil properties and amendments on a given metal concentration, (ii) to contribute toward the development of decision-making processes at a large field scale such as the delineation of contaminated sites. PMID- 23916836 TI - Impact of environmental policies on the adoption of manure management practices in the Chesapeake Bay watershed. AB - Pollution in the Chesapeake Bay is a problem and has been a focus of federal and state initiatives to reduce nutrient pollution from agriculture and other sources since 1983. In 2010 EPA established a TMDL for the watershed. Producers may voluntarily respond to intense and focused policy scrutiny by adopting best management practices. A detailed analysis of water quality best management practices by animal feeding operations inside and outside the watershed yield insight into this relationship. Our findings support the hypothesis that farmers will adopt water quality measures if links are made clear and there is an expectation of future regulations. PMID- 23916837 TI - Augmenter of liver regeneration, a protective factor against ROS-induced oxidative damage in muscle tissue of mitochondrial myopathy affected patients. AB - Mitochondria-related myopathies (MM) are a group of different diseases defined by a varying degree of dysfunctions of the mitochondrial respiratory chain which leads to reactive oxygen species (ROS) generation followed by oxidative stress and cellular damage. In mitochondrial myopathy muscle tissue an overexpression of antioxidant enzymes has been documented probably as an attempt to counteract the free radical generation. We previously documented, in human non-pathological muscle fibres, the expression of the augmenter of liver regeneration (ALR), a sulfhydryl oxidase enzyme, whose presence is related to the mitochondria; indeed it has been demonstrated that ALR mainly localizes in the mitochondrial inter membrane space. Furthermore we reported, in different experimental models, in vivo and in vitro, the anti-apoptotic and anti-oxidative capacities of ALR, achieved by up-regulating Bcl-2 anti-apoptotic family factors and the anti apoptotic/anti-oxidative secretory isoform of clusterin (sClu). With the present study we aimed to determine ALR, Bcl-2 protein, clusterin and ROS expression in muscle tissue biopsies from MM-affected patients. Non-pathological muscle tissue was used as control. Enzymatic, histochemical, immunohistochemical and immune electron microscopy techniques were performed. The data obtained revealed in MM derived muscle tissue, compared to non-pathological tissue, the over-expression of ROS, ALR and Bcl-2 and the induction of the nuclear, pro-apoptotic, isoform of clusterin (nCLU). PMID- 23916838 TI - Epitope-based DNA vaccine for Alzheimer's disease: translational study in macaques. AB - BACKGROUND: Clinical trials with passive and active Alzheimer's disease (AD) vaccines suggest that early interventions are needed for improvement of cognitive and/or functional performance in patients, providing impetus for the development of safe and immunologically potent active vaccines targeting amyloid beta (Abeta). The AN-1792 trial has indicated that Abeta-specific T cells may be unsafe for humans; therefore, other vaccines based on small Abeta epitopes are undergoing preclinical and clinical testing. METHODS: Humoral and cellular immune responses elicited in response to a novel DNA epitope-based vaccine (AV-1955) delivered to rhesus macaques using the TriGrid electroporation device were evaluated. Functional activities of anti-Abeta antibodies generated in response to vaccination were assessed in vitro. RESULTS: AV-1955 generates long-term, potent anti-Abeta antibodies and cellular immune responses specific to foreign T helper epitopes but not to self-Abeta. CONCLUSIONS: This translational study demonstrates that a DNA-based epitope vaccine for AD could be appropriate for human clinical testing. PMID- 23916839 TI - Dramatic fertility decline in aging C. elegans males is associated with mating execution deficits rather than diminished sperm quality. AB - Although much is known about female reproductive aging, fairly little is known about the causes of male reproductive senescence. We developed a method that facilitates culture maintenance of Caenorhabditis elegans adult males, which enabled us to measure male fertility as populations age, without profound loss of males from the growth plate. We find that the ability of males to sire progeny declines rapidly in the first half of adult lifespan and we examined potential factors that contribute towards reproductive success, including physical vigor, sperm quality, mating apparatus morphology, and mating ability. Of these, we find little evidence of general physical decline in males or changes in sperm number, morphology, or capacity for activation, at time points when reproductive senescence is markedly evident. Rather, it is the loss of efficient mating ability that correlates most strongly with reproductive senescence. Low insulin signaling can extend male ability to sire progeny later in life, although insulin impact on individual facets of mating behavior is complex. Overall, we suggest that combined modest deficits, predominantly affecting the complex mating behavior rather than sperm quality, sum up to block effective C. elegans male reproduction in middle adult life. PMID- 23916841 TI - Laboratory selection for increased longevity in Drosophila melanogaster reduces field performance. AB - Drosophila melanogaster is frequently used in ageing studies to elucidate which mechanisms determine the onset and progress of senescence. Lines selected for increased longevity have often been shown to perform as well as or superior to control lines in life history, stress resistance and behavioural traits when tested in the laboratory. Functional senescence in longevity selected lines has also been shown to occur at a slower rate. However, it is known that performance in a controlled laboratory setting is not necessarily representative of performance in nature. In this study the effect of ageing, environmental temperature and longevity selection on performance in the field was tested. Flies from longevity selected and control lines of different ages (2, 5, 10 and 15 days) were released in an environment free of natural food sources. Control flies were tested at low, intermediate and high temperatures, while longevity selected flies were tested at the intermediate temperature only. The ability of flies to locate and reach a food source was tested. Flies of intermediate age were generally better at locating resources than both younger and older flies, where hot and cold environments accelerate the senescent decline in performance. Control lines were better able to locate a resource compared to longevity selected lines of the same age, suggesting that longevity comes at a cost in early life field fitness, supporting the antagonistic pleiotropy theory of ageing. PMID- 23916840 TI - Role of PGC-1alpha in exercise training- and resveratrol-induced prevention of age-associated inflammation. AB - BACKGROUND/AIM: Age-related metabolic diseases are often associated with low grade inflammation. The aim of the present study was to investigate the role of the transcriptional co-activator PGC-1alpha in the potential beneficial effects of exercise training and/or resveratrol in the prevention of age-associated low grade inflammation. To address this, a long-term voluntary exercise training and resveratrol supplementation study was conducted. EXPERIMENTAL SETUP: Three month old whole body PGC-1alpha KO and WT mice were randomly assigned to four groups: untrained chow-fed, untrained chow-fed supplemented with resveratrol, chow-fed voluntarily exercise trained and chow-fed supplemented with resveratrol and voluntarily exercise trained. The intervention lasted 12 months and three month old untrained chow-fed mice served as young controls. RESULTS: Voluntary exercise training prevented an age-associated increase (p<0.05) in systemic IL-6 and adiposity in WT mice. PGC-1alpha expression was required for a training-induced prevention of an age-associated increase (p<0.05) in skeletal muscle TNFalpha protein. Independently of PGC-1alpha, both exercise training and resveratrol prevented an age-associated increase (p<0.05) in skeletal muscle protein carbonylation. CONCLUSION: The present findings highlight that exercise training is a more effective intervention than resveratrol supplementation in reducing age associated inflammation and that PGC-1alpha in part is required for the exercise training-induced anti-inflammatory effects. PMID- 23916842 TI - Effects of exercise on circadian rhythms and mobility in aging Drosophila melanogaster. AB - Daily life functions such as sleep and feeding oscillate with circa 24 h period due to endogenous circadian rhythms generated by circadian clocks. Genetic or environmental disruption of circadian rhythms is associated with various aging related phenotypes. Circadian rhythms decay during normal aging, and there is a need to explore strategies that could avert age-related changes in the circadian system. Exercise was reported to delay aging in mammals. Here, we investigated whether daily exercise via stimulation of upward climbing movement could improve circadian rest/activity rhythms in aging Drosophila melanogaster. We found that repeated exercise regimen did not strengthen circadian locomotor activity rhythms in aging flies and had no effect on their lifespan. We also tested the effects of exercise on mobility and determined that regular exercise lowered age-specific climbing ability in both wild type and clock mutant flies. Interestingly, the climbing ability was most significantly reduced in flies carrying a null mutation in the core clock gene period, while rescue of this gene significantly improved climbing to wild type levels. Our work highlights the importance of period in sustaining endurance in aging flies exposed to physical challenge. PMID- 23916843 TI - Use of co-combustion bottom ash to design an acoustic absorbing material for highway noise barriers. AB - The present study aims to determine and evaluate the applicability of a new product consisting of coal bottom ash mixed with Portland cement in the application of highway noise barriers. In order to effectively recycle the bottom ash, the influence of the grain particle size of bottom ash, the thickness of the panel and the combination of different layers with various particle sizes have been studied, as well as some environmental properties including leachability (EN 12457-4, NEN-7345) and radioactivity tests. Based on the obtained results, the acoustic properties of the final composite material were similar or even better than those found in porous concrete used for the same application. According to this study, the material produced presented no environmental risk. PMID- 23916844 TI - Analysis of the relation between the cellulose, hemicellulose and lignin content and the thermal behavior of residual biomass from olive trees. AB - The heterogeneity of biomass makes it difficult if not impossible to make sweeping generalizations concerning thermochemical treatment systems and the optimal equipment to be used in them. Chemical differences in the structural components of the biomass (cellulose, hemicellulose, and lignin) have a direct impact on its chemical reactivity. The aim of this research was to study the influence of the organic components of the raw material from olive trees (leaves, pruning residues, and wood) in the combustion behavior of this biomass, as well as to find the component responsible for the higher ash content of olive leaves. Accordingly, the study used a thermogravimetric analyzer to monitor the different states and complex transitions that occurred in the biomass as the temperature varied. The decomposition rates of the different samples were analyzed in order to establish a link between each combustion phase and the composition of the raw materials. Two methods were used to determine the hemicellulose and cellulose contents of biomass from olive trees. Significant differences among the results obtained by the different methods were observed, as well as important variations regarding the chemical composition and consequently the thermal behavior of the raw materials tested. PMID- 23916845 TI - Pyrolysis and gasification of meat-and-bone-meal: energy balance and GHG accounting. AB - Meat-and-bone-meal (MBM) produced from animal waste has become an increasingly important residual fraction needing management. As biodegradable waste is routed away from landfills, thermo-chemical treatments of MBM are considered promising solution for the future. Pyrolysis and gasification of MBM were assessed based on data from three experimental lab and pilot-scale plants. Energy balances were established for the three technologies, providing different outcomes for energy recovery: bio-oil was the main product for the pyrolysis system, while syngas and a solid fraction of biochar were the main products in the gasification system. These products can be used - eventually after upgrading - for energy production, thereby offsetting energy production elsewhere in the system. Greenhouse gases (GHG) accounting of the technologies showed that all three options provided overall GHG savings in the order of 600-1000kg CO2-eq. per Mg of MBM treated, mainly as a consequence of avoided fossil fuel consumption in the energy sector. Local conditions influencing the environmental performance of the three systems were identified, together with critical factors to be considered during decision making regarding MBM management. PMID- 23916846 TI - The hepatitis B vaccine protects re-exposed health care workers, but does not provide sterilizing immunity. AB - BACKGROUND & AIMS: Infection with hepatitis B virus (HBV) can be prevented by vaccination with HB surface (HBs) antigen, which induces HBs-specific antibodies and T cells. However, the duration of vaccine-induced protective immunity is poorly defined for health care workers who were vaccinated as adults. METHODS: We investigated the immune mechanisms (antibody and T-cell responses) of long-term protection by the HBV vaccine in 90 health care workers with or without occupational exposure to HBV, 10-28 years after vaccination. RESULTS: Fifty-nine of 90 health care workers (65%) had levels of antibodies to HBs antigen above the cut-off (>12 mIU/mL) and 30 of 90 (33%) had HBs-specific T cells that produced interferon-gamma. Titers of antibodies to HBs antigen correlated with numbers of HBs-specific interferon-gamma-producing T cells, but not with time after vaccination. Although occupational exposure to HBV after vaccination did not induce antibodies to the HBV core protein (HBcore), the standard biomarker for HBV infection, CD4(+) and CD8(+) T cells against HBcore and polymerase antigens were detected. Similar numbers of HBcore- and polymerase-specific CD4(+) and CD8(+) T cells were detected in health care workers with occupational exposure to HBV and in patients who acquired immunity via HBV infection. Most of the HBcore- and polymerase-specific T cells were CD45RO(+)CCR7(-)CD127(-) effector memory cells in exposed health care workers and in patients with acquired immunity. In contrast, most of the vaccine-induced HBs-specific T cells were CD45RO(-)CCR7( )CD127(-) terminally differentiated cells. CONCLUSIONS: HBs antigen vaccine induced immunity protects against future infection but does not provide sterilizing immunity, as evidenced by HBcore- and polymerase-specific CD8(+) T cells in vaccinated health care workers with occupational exposure to HBV. The presence of HBcore- and HBV polymerase-specific T-cell responses is a more sensitive indicator of HBV exposure than detection of HBcore-specific antibodies. PMID- 23916848 TI - Prophylactic cholecystectomy during abdominal surgery. AB - The presence of asymptomatic gallstones is no longer an indication for elective prophylactic cholecystectomy (PC) according to the recommendations of the 1991 French Consensus Conference on cholelithiasis. However, there may be potential benefits of performing prophylactic cholecystectomy during certain abdominal procedures for non-biliary disease; this remains a subject of debate. This debate has become livelier with the recent increase in bariatric surgery. Gastrectomy for cancer, small bowel resection, colonic resection, and splenectomy for hereditary spherocytosis as well as all bariatric surgical interventions can all alter the physiology of gallstone disease raising the question of the value of PC, but the specific morbidity of cholecystectomy must be kept in mind. The purpose of this study was to report epidemiological and pathophysiological data and the results from literature reports in order to assess the value of concomitant prophylactic cholecystectomy during various common surgical situations. PMID- 23916847 TI - Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. AB - BACKGROUND & AIMS: Cirrhosis and liver cancer are potential outcomes of advanced nonalcoholic fatty liver disease (NAFLD). It is not clear what factors determine whether patients will develop advanced or mild NAFLD, limiting noninvasive diagnosis and treatment before clinical sequelae emerge. We investigated whether DNA methylation profiles can distinguish patients with mild disease from those with advanced NAFLD, and how these patterns are functionally related to hepatic gene expression. METHODS: We collected frozen liver biopsies and clinical data from patients with biopsy-proven NAFLD (56 in the discovery cohort and 34 in the replication cohort). Samples were divided into groups based on histologic severity of fibrosis: F0-1 (mild) and F3-4 (advanced). DNA methylation profiles were determined and coupled with gene expression data from the same biopsies; differential methylation was validated in subsets of the discovery and replication cohorts. We then analyzed interactions between the methylome and transcriptome. RESULTS: Clinical features did not differ between patients known to have mild or advanced fibrosis based on biopsy analysis. There were 69,247 differentially methylated CpG sites (76% hypomethylated, 24% hypermethylated) in patients with advanced vs mild NAFLD (P < .05). Methylation at fibroblast growth factor receptor 2, methionine adenosyl methyltransferase 1A, and caspase 1 was validated by bisulfite pyrosequencing and the findings were reproduced in the replication cohort. Methylation correlated with gene transcript levels for 7% of differentially methylated CpG sites, indicating that differential methylation contributes to differences in expression. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, and genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and underexpressed. CONCLUSIONS: Functionally relevant differences in methylation can distinguish patients with advanced vs mild NAFLD. Altered methylation of genes that regulate processes such as steatohepatitis, fibrosis, and carcinogenesis indicate the role of DNA methylation in progression of NAFLD. PMID- 23916849 TI - Blastocoel-spanning filopodia in cleavage-stage Xenopus laevis: Potential roles in morphogen distribution and detection. AB - In the frog Xenopus laevis, dorsal-ventral axis specification involves cytoskeleton-dependent transport of localized transcripts and proteins during the first cell cycle, and activation of the canonical Wnt pathway to locally stabilize translated beta-catenin which, by as early as the 32-cell stage, commits nuclei in prospective dorsal lineages to the subsequent expression of dorsal target genes. Maternal ligands important for activating this dorsal specific signaling pathway are thought to interact with secreted glypicans and coreceptors in the blastocoel. While diffusion between cells is generally thought of as sufficient to accomplish the distribution of secreted maternal ligands to their appropriate targets, signaling may also involve other potential mechanisms, including direct transfer of morphogens via membrane-bounded entities, such as argosomes, exosomes, or even filopodia. In Xenopus, the blastocoel-facing, basolateral surfaces where signaling interactions ostensibly take place have not been previously examined in detail. Here, we report that the cleavage-stage blastocoel is traversed by hundreds of extremely long cellular protrusions that maintain long-term contacts between nonadjacent blastomeres during expansion of the interstitial space in early embryogenesis. The involvement of these protrusions in early embryonic patterning is suggested by the discoveries that (a) they fragment into microvesicles, whose resorption facilitates considerable exchange of cytoplasm and membrane between blastomeres; and (b) they are active in caveolar endocytosis, a prerequisite for ligand-receptor signaling. PMID- 23916850 TI - Multiple Shh signaling centers participate in fungiform papilla and taste bud formation and maintenance. AB - The adult fungiform taste papilla is a complex of specialized cell types residing in the stratified squamous tongue epithelium. This unique sensory organ includes taste buds, papilla epithelium and lateral walls that extend into underlying connective tissue to surround a core of lamina propria cells. Fungiform papillae must contain long-lived, sustaining or stem cells and short-lived, maintaining or transit amplifying cells that support the papilla and specialized taste buds. Shh signaling has established roles in supporting fungiform induction, development and patterning. However, for a full understanding of how Shh transduced signals act in tongue, papilla and taste bud formation and maintenance, it is necessary to know where and when the Shh ligand and pathway components are positioned. We used immunostaining, in situ hybridization and mouse reporter strains for Shh, Ptch1, Gli1 and Gli2-expression and proliferation markers to identify cells that participate in hedgehog signaling. Whereas there is a progressive restriction in location of Shh ligand-expressing cells, from placode and apical papilla cells to taste bud cells only, a surrounding population of Ptch1 and Gli1 responding cells is maintained in signaling centers throughout papilla and taste bud development and differentiation. The Shh signaling targets are in regions of active cell proliferation. Using genetic-inducible lineage tracing for Gli1-expression, we found that Shh-responding cells contribute not only to maintenance of filiform and fungiform papillae, but also to taste buds. A requirement for normal Shh signaling in fungiform papilla, taste bud and filiform papilla maintenance was shown by Gli2 constitutive activation. We identified proliferation niches where Shh signaling is active and suggest that epithelial and mesenchymal compartments harbor potential stem and/or progenitor cell zones. In all, we report a set of hedgehog signaling centers that regulate development and maintenance of taste organs, the fungiform papilla and taste bud, and surrounding lingual cells. Shh signaling has roles in forming and maintaining fungiform papillae and taste buds, most likely via stage-specific autocrine and/or paracrine mechanisms, and by engaging epithelial/mesenchymal interactions. PMID- 23916851 TI - SDF-1alpha/CXCR4 signaling mediates digit tip regeneration promoted by BMP-2. AB - Previously we demonstrated that BMP signaling is required for endogenous digit tip regeneration, and that treatment with BMP-2 or -7 induces a regenerative response following amputation at regeneration-incompetent levels (Yu et al., 2010, 2012). Both endogenous regeneration and BMP-induced regeneration are associated with the transient formation of a blastema, however the formation of a regeneration blastema in mammals is poorly understood. In this study, we focus on how blastema cells respond to BMP signaling during neonatal digit regeneration in mice. First, we show that blastema cells retain regenerative properties after expansion in vitro, and when re-introduced into the amputated digit, these cells display directed migration in response to BMP-2. However, in vitro studies demonstrate that BMP-2 alone does not influence blastema cell migration, suggesting a requirement of another pivotal downstream factor for cell recruitment. We show that blastema cell migration is stimulated by the cytokine, SDF-1alpha, and that SDF-1alpha is expressed by the wound epidermis as well as endothelial cells of the blastema. Blastema cells express both SDF-1alpha receptors, CXCR4 and CXCR7, although the migration response is inhibited by the CXCR4-specific antagonist, AMD3100. Mice treated with AMD3100 display a partial inhibition of skeletal regrowth associated with the regeneration response. We provide evidence that BMP-2 regulates Sdf-1alpha expression in endothelial cells but not cells of the wound epidermis. Finally, we show that SDF-1alpha-expressing COS1 cells engrafted into a regeneration-incompetent digit amputation wound resulted in a locally enhanced population of CXCR4 positive cells, and induced a partial regenerative response. Taken together, this study provides evidence that one downstream mechanism of BMP signaling during mammalian digit regeneration involves activation of SDF-1alpha/CXCR4 signaling by endothelial cells to recruit blastema cells. PMID- 23916852 TI - Monocatenary, branched, double-headed, and bolaform surface active carbohydrate esters via photochemical thiol-ene/-yne reactions. AB - An original and versatile method for the synthesis of a range of novel mannose based surfactants was developed via metal-free photo-induced thiol-ene/-yne 'click' reactions. This light-mediated hydrothiolation reaction involving a thiolated mannose was successfully applied to terminal and internal alkenes, dienes, and alkynes, leading to monocatenary, branched, double-headed, and bolaform amphiphilic carbohydrate esters, respectively. A surface activity study showed that these new compounds possess valuable properties and display specific behavior at the air-water interface. It also demonstrated the greater flexibility of the thioether moiety in the spacer of the surfactants produced via a thiol-ene reaction in comparison with the triazole heterocyclic rings in similar glucose based surfactants synthesized elsewhere by the alkyne-azide 1,3-dipolar addition. PMID- 23916853 TI - Synthesis and X-ray crystallographic investigation of N-(beta-D glycosyl)butanamides derived from GlcNAc and chitobiose as analogs of the conserved chitobiosylasparagine linkage of N-glycoproteins. AB - The linkage region, GlcNAcbetaAsn, is conserved in all eukaryotic N glycoproteins. As a logical extension of a research endeavor aimed at understanding the structural significance of GlcNAc and Asn as the linkage region constituents, the newer analogs GlcNAcbetaNHBu and (GlcNAcbeta(1 4)GlcNAc)alkanamides have been synthesized to assess the influence of aglycon as well as additional GlcNAc on the linkage region. X-ray crystallographic analysis of the GlcNAcbetaNHBu and (GlcNAcbeta(1-4)GlcNAc)betaNHBu is described. Comparative analysis of these structures with those of reported models and analogs shows that the deviation in N-glycosidic torsion, phiN among the GlcNAc alkanamides is negligible (<2 degrees ) whereas (GlcNAcbeta(1-4)GlcNAc)betaNHBu deviates by ~15 degrees as compared to GlcNAcbetaNHBu. Under the influence of the molecular packing, the conformation around the C1'-C2' bond deviates from anti to gauche in (GlcNAcbeta(1-4)GlcNAcbetaNHBu. Interestingly, C2-acetamido group in (GlcNAcbeta(1-4)GlcNAc)NHBu orients differently as compared to GlcNAc alkanamides and this orientation was found to be almost similar to beta-N,N' diacetylchitobiose trihydrate. The bifurcated anti-parallel pattern involving N H?O and C-H?O hydrogen bonds, a hallmark feature of the N-glycoprotein models, GlcNAcbetaNHAc and GlcNAcbetaAsn, is absent in both the title alkanamides. This is the first report on the crystal structure analysis of chitobiosyl alkanamide as analog of the N-glycoprotein linkage region, (GlcNAcbeta(1-4)GlcNAc)betaAsn. PMID- 23916854 TI - [White paper on radiation oncology in France. Twelve proposals to improve a major cancer treatment. Societe francaise de radiotherapie oncologique]. PMID- 23916855 TI - Chemical mutagenesis of Gluconobacter frateurii to construct methanol-resistant mutants showing glyceric acid production from methanol-containing glycerol. AB - To produce glyceric acid (GA) from methanol-containing glycerol, resistance to methanol of Gluconobacter frateurii NBRC103465 was improved by chemical mutagenesis using N-methyl-N'-nitro-N-nitrosoguanidine. The obtained mutant Gf398 produced 6.3 g/L GA in 5% (v/v) methanol-containing 17% (w/v) glycerol medium, in which the wild-type strain neither grew nor produced GA. PMID- 23916856 TI - Co-expression of TAL1 and ADH1 in recombinant xylose-fermenting Saccharomyces cerevisiae improves ethanol production from lignocellulosic hydrolysates in the presence of furfural. AB - Lignocellulosic biomass dedicated to bioethanol production usually contains pentoses and inhibitory compounds such as furfural that are not well tolerated by Saccharomyces cerevisiae. Thus, S. cerevisiae strains with the capability of utilizing both glucose and xylose in the presence of inhibitors such as furfural are very important in industrial ethanol production. Under the synergistic conditions of transaldolase (TAL) and alcohol dehydrogenase (ADH) overexpression, S. cerevisiae MT8-1X/TAL-ADH was able to produce 1.3-fold and 2.3-fold more ethanol in the presence of 70 mM furfural than a TAL-expressing strain and a control strain, respectively. We also tested the strains' ability by mimicking industrial ethanol production from hemicellulosic hydrolysate containing fermentation inhibitors, and ethanol production was further improved by 16% when using MT8-1X/TAL-ADH compared to the control strain. Transcript analysis further revealed that besides the pentose phosphate pathway genes TKL1 and TAL1, ADH7 was also upregulated in response to furfural stress, which resulted in higher ethanol production compared to the TAL-expressing strain. The improved capability of our modified strain was based on its capacity to more quickly reduce furfural in situ resulting in higher ethanol production. The co-expression of TAL/ADH genes is one crucial strategy to fully utilize undetoxified lignocellulosic hydrolysate, leading to cost-competitive ethanol production. PMID- 23916857 TI - Does age influence the symptom experience of lung cancer patients prior to surgery? AB - OBJECTIVES: Older patients with lung cancer are less likely to be offered surgery then younger patients. Although higher preoperative symptom burden is associated with poorer postoperative outcomes, few studies have examined age-related differences in symptom experience of lung cancer patients prior to surgery. This study evaluated for differences in symptom occurrence, severity, and distress between older (>=65 years) and younger (<65 years) patients prior to surgery. MATERIALS AND METHODS: Data were collected through chart review and a symptom assessment scale (i.e., Memorial Symptom Assessment Scale (MSAS)) that evaluated multiple dimensions of 32 symptoms. Descriptive statistics were used to present demographic and clinical characteristics of the sample. Logistic regression analyses were used to evaluate for age-related differences in each dimension of the symptom experience. RESULTS: A total of 270 patients completed the MSAS prior to surgery (113 younger and 157 older patients). Few age-related differences were found. When age differences were identified, older patients reported lower occurrence rates and lower severity and distress ratings. Cough, lack of energy, feeling drowsy and worrying was the four most common symptoms in both age groups. In the younger patients, feeling nervous was ranked fourth. Shortness of breath was ranked third by the older patients. The study confirmed the high occurrence rates for cough, pain, fatigue, shortness of breath, and sleep disturbance found in previous studies. However, "new" symptoms were identified including feeling nervous, worrying, sweats, feeling bloated, and problems with sexual interest. These "new" symptoms were reported by over 40% of the patients. CONCLUSIONS: Measurement of symptoms in lung cancer patients before surgery is important, because patients reported an average of 10 symptoms. Few age-related differences in the patients' symptom experience were identified. Psychological symptoms were common and warrant consideration. PMID- 23916858 TI - Chinese herbal medicine-derived compounds for cancer therapy: a focus on hepatocellular carcinoma. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hepatocellular carcinoma (HCC) as the major histological subtype of primary liver cancer remains one of the most common malignancies worldwide. Due to the complicated molecular pathogenesis of HCC, the option for effective systemic treatment is quite limited. There exists a critical need to explore and evaluate possible alternative strategies for effective control of HCC. With a long history of clinical use, Chinese herbal medicine (CHM) is emerging as a noticeable choice for its multi-level, multi-target and coordinated intervention effects against HCC. With the aids of phytochemistry and molecular biological approaches, in the past decades many CHM-derived compounds have been carefully studied through both preclinical and clinical researches and have shown great potential in novel anti-HCC natural product development. The present review aimed at providing the most recent developments on anti-HCC compounds derived from CHM, especially their underlying pharmacological mechanisms. MATERIALS AND METHODS: A systematic search of anti-HCC compounds from CHM was carried out focusing on literatures published both in English (PubMed, Scopus, Web of Science and Medline) and in Chinese academic databases (Wanfang and CNKI database). RESULTS: In this review, we tried to give a timely and comprehensive update about the anti-HCC effects and targets of several representative CHM-derived compounds, namely curcumin, resveratrol, silibinin, berberine, quercetin, tanshinone II-A and celastrol. Their mechanisms of anti-HCC behaviors, potential side effects or toxicity and future research directions were discussed. CONCLUSION: Herbal compounds derived from CHM are of much significance in devising new drugs and providing unique ideas for the war against HCC. We propose that these breakthrough findings may have important implications for targeted-HCC therapy and modernization of CHM. PMID- 23916859 TI - Refractory infantile spasms associated with mosaic variegated aneuploidy syndrome. AB - BACKGROUND: Mosaic variegated aneuploidy syndrome (Online Mendelian Inheritance in Man 257300), or premature chromatid separation syndrome, is a rare cancer prone disorder associated with an autosomal recessive trait related to BUB1B gene mutations. The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumor, and leukemia reported in several cases. Clinical features also include prenatal onset growth retardation, microcephaly, mild dysmorphism, feeding difficulty, hypotonia, seizures, and developmental delay. PATIENT: A boy patient exhibited severe developmental delay, microcephaly, hypotonia, intractable seizures including infantile spasms with hypsarrhythmia at 6 months old, and Dandy-Walker malformation on magnetic resonance imaging. Seizures were refractory to conventional antiepileptics and treatment with adrenocorticotropic hormone. Wilms tumor and an unidentified intraorbital tumor also developed at 22 months old. RESULTS: Chromosomal analysis showed multiple aneuploid cells, and premature chromatid separation was found in all chromosomes in 59.5% of 119 cells, indicating mosaic variegated aneuploidy syndrome. CONCLUSIONS: The present case report demonstrates that mosaic variegated aneuploidy syndrome can be associated with developmental brain anomalies that lead to early-onset epileptic encephalopathy. Awareness of this disorder is important not only for proper diagnosis but also for genetic counseling of the family. PMID- 23916860 TI - Ring chromosome 20: a pediatric potassium channelopathy responsive to treatment with ezogabine. AB - BACKGROUND: Ring chromosome 20 is a genetic disorder characterized by intractable epilepsy, behavioral problems, and cognitive deficit. The potassium channel coding gene KCNQ2 is localized at the locus q13.3 on the chromosome 20, the most common site where the ring occurs. Ezogabine is the first potassium channel opener marketed in the United States. PATIENTS: We describe an 8-year-old girl with mosaic ring chromosome 20 and refractory epilepsy who had a remarkable improvement in seizure control with ezogabine. CONCLUSIONS: This is the first report using the new antiepileptic drug ezogabine to treat pediatric epilepsy. We hypothesize that ring chromosome 20 patients have epilepsy related to abnormalities in the potassium channels, making it susceptible for treatment with potassium channel openers. PMID- 23916861 TI - Posterior reversible encephalopathy syndrome: incidence and associated factors in a pediatric critical care population. AB - BACKGROUND: Posterior reversible encephalopathy syndrome may occur frequently and be underrecognized in children and young adults admitted to a pediatric critical care unit. METHODS: Patients <21 years of age with the diagnosis of posterior reversible encephalopathy syndrome were reviewed in this retrospective cohort study conducted over a 30-month period. RESULTS: There were 2588 admissions to pediatric critical care unit, 226 neurology service consultations, and 10 patients diagnosed with posterior reversible encephalopathy syndrome (incidence of 1 in 259 pediatric critical care unit admissions, 0.4%). The majority of posterior reversible encephalopathy syndrome patients (9/10) presented with generalized tonic and or clonic seizures. Apart from hypertension and cytotoxic medication use, anemia, a previously unreported risk factor, was found in all 10 (100%) patients with posterior reversible encephalopathy syndrome. One-year follow up available in eight patients showed no residual neurological deficits attributable to posterior reversible encephalopathy syndrome with significant resolution of white matter signal abnormalities on neuroimaging. CONCLUSION: Our case cohort includes an estimation of incidence of posterior reversible encephalopathy syndrome in children and young adults with 1-year follow-up and anemia as a potential previously unreported risk factor. PMID- 23916862 TI - Feasibility of pedometer use to assess physical activity and its relationship with quality of life in children with epilepsy: a pilot study. AB - BACKGROUND: Children and youth with epilepsy have lower rates of self-reported and parent-reported physical activity as well as quality of life when compared with their peers. Increased physical activity may be associated with improved health and quality of life in children and youth with epilepsy through biopsychosocial mechanisms; however, supportive evidence is lacking. METHODS: This pilot study aims to determine the feasibility of pedometer use-an objective method-to assess daily steps and ability to complete quality of life-related questionnaires in children and youth with epilepsy. Feasibility was determined by percentage of study completion and participant enjoyment of physical activity in the form of walking as determined by the Childhood Self Adequacy and Predilection in Physical Activity. Secondary measures included the KidScreen 27 Quality of Life questionnaire, Childhood Depression Index, Body Mass Index, Harter's Self Perception Scale, and Parental Stress Index. CONCLUSIONS: Eight of 12 eligible participants completed the study. Step counts ranged from 266 to 17,220 steps per day. Seven participants found physical activity enjoyable regardless of step count, suggesting they would be amenable to participate in a future physical activity program. PMID- 23916864 TI - The distribution of ephrin-B1 and PNA-positive glycoconjugates is correlated with atypical melanoblast migration in Japanese Silky fowl embryos. AB - Melanoblasts are positively stimulated to migrate in the dorsolateral pathway of the avian embryo by ephrins, but are inhibited by PNA-binding glycoconjugates. We analyzed the potential role of these molecules in the Japanese Silky fowl, which displays intense internal pigmentation. The distribution of ephrin ligands was analyzed using Eph receptor-human Fc fusion proteins. Glycoconjugates were labeled using PNA-FITC. In Japanese Silky embryos, ventral areas, including the anterior- and posterior-half somites, expressed ephrin-B1 in a pattern that correlates with the atypical migratory pathways taken by Japanese Silky melanoblasts. White Leghorn embryos displayed little to no ephrin-Bs in the ventral paths. Conversely, PNA-binding barrier tissues, proposed to prevent melanoblasts from migrating ventrally in White Leghorn, are missing or have significant gaps in Japanese Silky embryos. Thus, studies of a naturally occurring pigmentation mutant confirm that a combination of cues regulates melanoblast migration in the chick embryo. PMID- 23916863 TI - eTACTS: a method for dynamically filtering clinical trial search results. AB - OBJECTIVE: Information overload is a significant problem facing online clinical trial searchers. We present eTACTS, a novel interactive retrieval framework using common eligibility tags to dynamically filter clinical trial search results. MATERIALS AND METHODS: eTACTS mines frequent eligibility tags from free-text clinical trial eligibility criteria and uses these tags for trial indexing. After an initial search, eTACTS presents to the user a tag cloud representing the current results. When the user selects a tag, eTACTS retains only those trials containing that tag in their eligibility criteria and generates a new cloud based on tag frequency and co-occurrences in the remaining trials. The user can then select a new tag or unselect a previous tag. The process iterates until a manageable number of trials is returned. We evaluated eTACTS in terms of filtering efficiency, diversity of the search results, and user eligibility to the filtered trials using both qualitative and quantitative methods. RESULTS: eTACTS (1) rapidly reduced search results from over a thousand trials to ten; (2) highlighted trials that are generally not top-ranked by conventional search engines; and (3) retrieved a greater number of suitable trials than existing search engines. DISCUSSION: eTACTS enables intuitive clinical trial searches by indexing eligibility criteria with effective tags. User evaluation was limited to one case study and a small group of evaluators due to the long duration of the experiment. Although a larger-scale evaluation could be conducted, this feasibility study demonstrated significant advantages of eTACTS over existing clinical trial search engines. CONCLUSION: A dynamic eligibility tag cloud can potentially enhance state-of-the-art clinical trial search engines by allowing intuitive and efficient filtering of the search result space. PMID- 23916865 TI - Vaccination of domestic ducks against H5N1 HPAI: a review. AB - Domestic ducks play an important role in the epidemiology of H5N1 highly pathogenic avian influenza (HPAI) viruses. Consequently, successful control of H5N1 HPAI in ducks is important for the eradication of the disease in poultry and in preventing infections in humans. Domestic ducks, however, include different species and breeds, and the susceptibility to infection, disease and response to vaccination can vary depending on the species and age of the bird. Most domestic duck species are descendants of mallard ducks (Anas platyrhynchos), but in Asian countries Muscovy ducks (Cairina moschata) are also commonly farmed. Current vaccines and vaccination practices are insufficient for the control of H5N1 HPAI virus infections in domestic waterfowl and new vaccination strategies are needed. Although vaccination has proven effective in protecting ducks against disease, shedding of the virus still occurs in clinically healthy vaccinated populations. To improve protection of ducks against H5N1 HPAI, vaccination programs must take into account the susceptibility of ducks to circulating viruses and the particular production systems and husbandry practices of the country. Vaccination needs to be implemented as part of a comprehensive control strategy that also includes biosecurity, surveillance, education and elimination of infected poultry. PMID- 23916866 TI - A simple method for quantifying biomass cell and polymer distribution in biofilms. AB - Biofilms are ubiquitous and play an essential role in both environmental processes and hospital infections. Standard methods are not capable of quantifying biomass concentration in dilute suspensions. Furthermore, standard techniques cannot differentiate biomass composition. In this study, a user friendly technique was developed for measuring biomass cell and polymer content in detached biofilms using a standard coulter counter. The method was demonstrated for an environmentally relevant strain of Pseudomonas aeruginosa (Schroeter) Migula grown in a bioreactor and also for a medically relevant strain of P. aeruginosa (PAO1) grown on standard growth pegs. Results were compared and validated by standard assays, including EPA method 1684 for measuring biomass, microscopic direct counts, and a crystal violet staining assay. The minimum detection limit for the coulter counter method (0.07 mg-biomass L(-1)) was significantly lower than the EPA method 1684 (1.9 +/- 0.4 mg/L) and the crystal violet assay (1.1 +/- 0.2 mg L(-1)). However, the coulter counter method is limited to dilute biomass samples (below 204 +/- 16 mg L(-1)) due to clogging of the aperture tube. While biomass measurements are useful, the major advantage of the coulter counter method is the ability to directly determine EPS, cell, and aggregate fractions after mild chemical treatment. The rapid technique (4-5 min per sample) was used to measure biomass fractions in dispersed P. aeruginosa (Schroeter) and PAO1 biofilms. This technique will be critical for understanding biofilm formation/dispersal. PMID- 23916867 TI - Mechanical factors in embryonic tendon development: potential cues for stem cell tenogenesis. AB - Tendons are connective tissues required for motion and are frequently injured. Poor healing and inadequate return to normal tissue structure and mechanical function make tendon a prime candidate for tissue engineering; however functional tendons have yet to be engineered. The physical environment, from substrate stiffness to dynamic mechanical loading, may regulate tenogenic stem cell differentiation. Tissue stiffness and loading parameters derived from embryonic development may enhance tenogenic stem cell differentiation and tendon tissue formation. We highlight the current understanding of the mechanical environment experienced by embryonic tendons and how progenitor cells may sense and respond to physical inputs. We further discuss how mechanical factors have only recently been used to induce tenogenic fate in stem cells. PMID- 23916869 TI - An improved fault-tolerant control scheme for PWM inverter-fed induction motor based EVs. AB - This paper proposes an improved fault-tolerant control scheme for PWM inverter fed induction motor-based electric vehicles. The proposed strategy deals with power switch (IGBTs) failures mitigation within a reconfigurable induction motor control. To increase the vehicle powertrain reliability regarding IGBT open circuit failures, 4-wire and 4-leg PWM inverter topologies are investigated and their performances discussed in a vehicle context. The proposed fault-tolerant topologies require only minimum hardware modifications to the conventional off the-shelf six-switch three-phase drive, mitigating the IGBTs failures by specific inverter control. Indeed, the two topologies exploit the induction motor neutral accessibility for fault-tolerant purposes. The 4-wire topology uses then classical hysteresis controllers to account for the IGBT failures. The 4-leg topology, meanwhile, uses a specific 3D space vector PWM to handle vehicle requirements in terms of size (DC bus capacitors) and cost (IGBTs number). Experiments on an induction motor drive and simulations on an electric vehicle are carried-out using a European urban driving cycle to show that the proposed fault-tolerant control approach is effective and provides a simple configuration with high performance in terms of speed and torque responses. PMID- 23916868 TI - The evolutionary transition to sideways-walking gaits in brachyurans was accompanied by a reduction in the number of motor neurons innervating proximal leg musculature. AB - The forwards-walking portly crab, Libinia emarginata is an ancient brachyuran. Its phylogenetic position and behavioral repertoire make it an excellent candidate to reveal the adaptations, which were required for brachyuran crabs to complete their transition to sideways-walking from their forwards-walking ancestors. Previously we showed that in common with other forwards-walking (but distantly related) crustaceans, L. emarginata relies more heavily on its more numerous proximal musculature to propel itself forward than its sideways-walking closer relatives. We investigated if the proximal musculature of L. emarginata is innervated by a greater number of motor neurons than that of sideways-walking brachyurans. We found the distal musculature of spider crabs is innervated by a highly conserved number of motor neurons. However, innervation of its proximal musculature is more numerous than in closely-related (sideways-walking) species, resembling in number and morphology those described for forwards-walking crustaceans. We propose that transition from forward- to sideways-walking in crustaceans involved a decreased role for the proximal leg in favor of the more distal merus-carpus joint. PMID- 23916870 TI - Construction of an scFv library by enzymatic assembly of V(L) and V(H) genes. AB - The single-chain Fv fragment (scFv) is the most frequently used form of recombinant antibody. It is possible to establish clones specific to a certain target by displaying the scFv library on phages followed by biopanning against the target. For the construction of superior scFv libraries, the light-chain variable region (VL) and the heavy-chain variable region (VH) fragments should be assembled into the scFv without loss of diversity. We have provided an efficient method for constructing scFvs by enzymatic assembly of the VL and VH domains using the concerted action of lambda-exonuclease and Bst DNA polymerase. First, we amplified the chicken VL and VH fragments using a phosphorylated primer with a 21-nucleotide overlap in the linker region. Then we recessed the overlapping parts of the VL and VH fragments with lambda-exonuclease, which yielded single stranded overhangs that specifically annealed between the VL and VH fragments; the complete double-stranded scFv was formed using Bst DNA polymerase. Complete scFvs were obtained using this method, whereby a library of scFvs was constructed from the immune library of chicken IgG. The diversity of this scFv library was analyzed by DNA fingerprinting method. The scFvs specific to the antigen could be isolated from this library after 5 rounds of panning. PMID- 23916871 TI - Physiological responses to emotional excitement in healthy subjects and patients with coronary artery disease. AB - Emotional excitement may trigger cardiovascular (CV) events, particularly in patients with coronary artery disease (CAD). Our aim was to compare changes in various biomarkers in CAD patients and age-matched healthy male subjects during "real-life" emotional excitement. Enthusiastic male ice hockey spectators (CAD n = 18, healthy subjects n = 16) attended Finnish national ice hockey play-off matches. Heart rate variability, plasma catecholamines, endothelin-1 (ET-1) and interleukin-6 (IL-6) were determined at the baseline and during the match. A significantly more marked increase in both ET-1 and IL-6 was observed in CAD patients compared with healthy subjects during the match (time * group interaction p = 0.009 and p = 0.018 for ET-1 and IL-6, respectively). The high frequency power of R-R intervals decreased in CAD patients (p<0.001) but did not change in healthy subjects (p = ns, time * group interaction p<0.001). Changes in adrenaline and noradrenaline did not differ between the groups. Emotional excitement causes more marked increases of markers of vasoconstriction and acute inflammation and withdrawal of cardiac vagal regulation in patients with CAD. PMID- 23916873 TI - Six-transmembrane epithelial antigen of the prostate-1 plays a role for in vivo tumor growth via intercellular communication. AB - Six-transmembrane epithelial antigen of the prostate-1 (STEAP-1) is a novel cell surface protein overexpressed only in the prostate among normal tissues and various types of cancer including prostate, bladder, lung, and ovarian cancer. Although its function in prostate and tumor cells has been remained unclear, due to its unique and restricted expression, STEAP-1 is expected to be an attractive target for cancer therapy. Here, we show that knockdown of STEAP-1 in human cancer cells caused the retardation of tumor growth compared with wild type in vivo. In contrast, STEAP-1 introduced tumor cells augmented the tumor growth compared with STEAP-1-negative wild type cells. Using dye transfer assay, we demonstrate that the STEAP-1 is involved in intercellular communication between tumor cells and adjacent tumor stromal cells and therefore may play a key role for the tumor growth in vivo. These data indicate the inhibition of the STEAP-1 function or expression can be a new strategy for cancer therapy. PMID- 23916874 TI - Does polyvinyl alcohol particle size change the outcome of prostatic arterial embolization for benign prostatic hyperplasia? Results from a single-center randomized prospective study. AB - PURPOSE: To evaluate whether different polyvinyl alcohol (PVA) particle sizes change the outcome of prostatic arterial embolization (PAE) for benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A randomized prospective study was undertaken in 80 patients (mean age, 63.9 y; range, 48-81 y) with symptomatic BPH undergoing PAE between May and December 2011. Forty patients underwent PAE with 100-um (group A) and 200-um PVA particles (group B). Visual analog scales were used to measure pain, and rates of adverse events were recorded. PAE outcomes were evaluated based on International Prostate Symptom Score (IPSS) and quality of-life (QoL) questionnaires, prostate volume (PV), prostate-specific antigen (PSA) levels, and peak flow rate measurements at baseline and 6 months. RESULTS: No differences between groups regarding baseline data, procedural details, or adverse events were noted. Mean pain scores were as follows: during embolization, 3.2 +/- 2.97 (group A) versus 2.93 +/- 3.28 (group B); after embolization, 0.10 +/- 0.50 (group A) versus 0 (group B; P = .20); and the week after PAE, 0.85 +/- 1.65 (group A) versus 0.87 +/- 1.35 (group B; P = .96). Patients in group B had greater decreases in IPSS (3.64 points; P = .052) and QoL (0.57 points; P = .07). Patients in group A had a greater decrease in PV (8.75 cm(3); P = .13) and PSA level (2.09 ng/mL; P < .001). CONCLUSIONS: No significant differences were found in pain scores and adverse events between groups. Whereas PSA level and PV showed greater reductions after PAE with 100-um PVA particles, clinical outcome was better with 200-um particles. PMID- 23916872 TI - CHO microRNA engineering is growing up: recent successes and future challenges. AB - microRNAs with their ability to regulate complex pathways that control cellular behavior and phenotype have been proposed as potential targets for cell engineering in the context of optimization of biopharmaceutical production cell lines, specifically of Chinese Hamster Ovary cells. However, until recently, research was limited by a lack of genomic sequence information on this industrially important cell line. With the publication of the genomic sequence and other relevant data sets for CHO cells since 2011, the doors have been opened for an improved understanding of CHO cell physiology and for the development of the necessary tools for novel engineering strategies. In the present review we discuss both knowledge on the regulatory mechanisms of microRNAs obtained from other biological models and proof of concepts already performed on CHO cells, thus providing an outlook of potential applications of microRNA engineering in production cell lines. PMID- 23916875 TI - A deficient translocation of CD3zeta, ZAP-70 and Grb2 to lipid raft, as a hallmark of defective adaptive immune response during chronic hepatitis B infection. AB - Hepatitis B is considered to be a worldwide public health problem. An immunosuppressor microenvironment has been proposed to contribute to viral persistence during chronic disease. Understanding the intracellular signaling cascade in T-cells from HBV-infected patients, will contribute to unravel the mechanisms that control the development of immune response during hepatitis B. We analyze lipid rafts formation and early activation signals in chronic HBV infected patients, compared to naturally immune subjects (NIS). Patients show: (1) diminished GM1 clustering, (2) A deficient lipid rafts recruitment of CD3zeta/ZAP-70/Grb2, and (3) these proteins do not merge with GM1 within the lipid rafts. Finally, immunoprecipitation assays proved that ZAP-70 does not associate to CD3zeta. These results show for the first time, defects regarding early key events in T-cell activation, in chronically infected HBV patients, which may contribute not only to understand HBV immune tolerance, but to reveal new potential therapeutic targets to control the infection. PMID- 23916876 TI - Prolonged ingestion of ovalbumin diet by Ova sensitized mice suppresses mBSA induced arthritis. AB - Concomitant chronic diseases are a common finding in clinics and may consist in a major issue in therapeutics. Here, we investigated whether prolonged ingestion of ovalbumin (Ova) by sensitized mice would reduce the severity of an associated concurrent immunomediated condition such as antigen-induced arthritis (AIA). AIA was induced by administration of methylated bovine albumin (mBSA) into the knee joints of previously immunized mice, and evaluated by articular leukocyte trafficking and levels of cytokines (TNF-alpha, IL-1beta) and chemokine (CXCL-1) in the periarticular tissue. Continuous Ova feeding by Ova sensitized mice decreased serum levels of anti-Ova IgE, and led to a significant suppression of leukocyte adhesion and infiltration into synovial tissue and cavity. Also, a marked cytokine reduction was observed, suggesting that prolonged ingestion of ovalbumin by sensitized mice suppresses specific IgE production with concomitant reduction in peripheral T cells, which may impact in the pathogenesis of AIA, a non-related condition. PMID- 23916877 TI - Allergenicity potential of red kidney bean (Phaseolus vulgaris L.) proteins in orally treated BALB/c mice and passively sensitized RBL-2H3 cells. AB - Red kidney bean (Phaseolus vulgaris L.) is one the most commonly consumed legumes that requires an in depth understanding of its allergenicity. Therefore, the aim of this study was to explore the allergenicity of red kidney bean proteins following oral exposure in BALB/c mice and elucidate the levels of Th1/Th2 transcription factors induced by red kidney bean proteins in rat basophilic leukemia cells (RBL-2H3 cells) passively sensitized with the sera of red kidney bean sensitized mice. Red kidney bean proteins showed enhanced levels of total and specific IgE, anaphylactic symptoms, thymic stromal lymphopoietin (TSLP) and peritoneal albumin over control. Enhanced release of beta-hexosaminidase along with up regulated expressions of GATA-3, STAT-6, T-bet, c-MAF and NFAT were observed in the RBL-2H3 cells exposed with red kidney bean proteins when compared to that of the controls. Taken together, exposure of red kidney bean proteins may cause allergic symptoms in mice and the ambivalent effect on Th2/Th1 transcription factors in RBL-2H3 cells. PMID- 23916879 TI - Modelling of thrombus growth in flow with a DPD-PDE method. AB - Hemostatic plug covering the injury site (or a thrombus in the pathological case) is formed due to the complex interaction of aggregating platelets with biochemical reactions in plasma that participate in blood coagulation. The mechanisms that control clot growth and which lead to growth arrest are not yet completely understood. We model them with numerical simulations based on a hybrid DPD-PDE model. Dissipative particle dynamics (DPD) is used to model plasma flow with platelets while fibrin concentration is described by a simplified reaction diffusion-advection equation. The model takes into account consecutive stages of clot growth. First, a platelet is weakly connected to the clot and after some time this connection becomes stronger due to other surface receptors involved in platelet adhesion. At the same time, the fibrin mesh is formed inside the clot. This becomes possible because flow does not penetrate the clot and cannot wash out the reactants participating in blood coagulation. Platelets covered by the fibrin mesh cannot attach new platelets. Modelling shows that the growth of a hemostatic plug can stop as a result of its exterior part being removed by the flow thus exposing its non-adhesive core to the flow. PMID- 23916878 TI - The invasive mosquito species Aedes albopictus: current knowledge and future perspectives. AB - One of the most dynamic events in public health is being mediated by the global spread of the invasive mosquito Aedes albopictus. Its rapid expansion and vectorial capacity for various arboviruses affect an increasingly larger proportion of the world population. Responses to the challenges of controlling this vector are expected to be enhanced by an increased knowledge of its biology, ecology, and vector competence. Details of population genetics and structure will allow following, and possibly predicting, the geographical and temporal dynamics of its expansion, and will inform the practical operations of control programs. Experts are now coming together to describe the history, characterize the present circumstances, and collaborate on future efforts to understand and mitigate this emerging public health threat. PMID- 23916880 TI - Mathematical modelling of the uptake and transport of salt in plant roots. AB - In this paper, we present and discuss a mathematical model of ion uptake and transport in roots of plants. The underlying physical model of transport is based on the mechanisms of forced diffusion and convection. The model can take account of local variations in effective ion and water permeabilities across the major tissue regions of plant roots, represented through a discretized coupled system of governing equations including mass balance, forced diffusion, convection and electric potential. We present simulation results of an exploration of the consequent enormous parameter space. Among our findings we identify the electric potential as a major factor affecting ion transport across, and accumulation in, root tissues. We also find that under conditions of a constant but realistic level of bulk soil salt concentration and plant-soil hydraulic pressure, diffusion plays a significant role even when convection by the water transpiration stream is operating. PMID- 23916881 TI - Surgery-induced behavioral changes in aged rats. AB - Elderly patients may experience impairments in cognition or mood following surgery. To study the development and underlying mechanisms of these postoperative behavioral changes, young (3 months) and aged (18-20 months) male rats were subjected to abdominal surgery followed by behavioral testing during a period of 6 weeks. Microglia activation (IBA-1) and neurogenesis (DCX) were immunohistochemically determined. In separate experiments, the effects of anesthesia and the cytokine response (IL-6) following surgery were evaluated. Increased age was associated with changes in affective behavior, decreased cognitive flexibility and increased microglia activation as well as increased weight loss and plasma IL-6 following surgery. No effects of surgery on cognition were observed at either age. However, aged rats displayed long-term changes in affective behavior and had increased microgliosis in the CA1 hippocampal region following surgery. Microglia activation following surgery was positively correlated to parameters of behavior and spatial learning. These findings support the hypothesis that elderly patients have an increased behavioral and (neuro)inflammatory response to surgery and these factors may be related. PMID- 23916882 TI - Acute exposure to offshore produced water has an effect on stress- and secondary stress responses in three-spined stickleback Gasterosteus aculeatus. AB - Pollution is one of today's greatest problems, and the release of contaminants into the environment can cause adverse changes in vitally important biological pathways. In this study, we exposed three-spined stickleback Gasterosteus aculeatus to produced water (PW), i.e. wastewater from offshore petroleum production. PW contains substances such as alkylphenols (APs) and aromatic hydrocarbons (PAHs) known to induce toxicant stress and endocrine disruption in a variety of organisms. Following exposure to PW, a standardized confinement treatment was applied as a second stressor (PW-stress), testing how fish already under stress from the pollutant would respond to an additional stressor. The endpoint for analysis was a combination of blood levels of cortisol and glucose, in addition to transcribed levels of a set of genes related to toxicant stress, endocrine disruption and general stress. The findings of this study indicate that low doses of PW do not induce vitellogenin in immature female stickleback, but do cause an upregulation of cytochrome (CYP1A) and UDP-glucuronsyltransferase (UDP GT), two biomarkers related to toxicant stress. However, when the second stressor was applied, both genes were downregulated, indicating that the confinement exposure had a suppressive effect on the expression of toxicant biomarkers (CYP1A and UDP-GT). Further, two of the stress related genes, heat shock protein 90 (HSP90) and stress-induced phosphoprotein (STIP), were upregulated in both PW- and PW-stress-treatment, but not in the water control confinement treatment, indicating that PW posed as a larger stress-factor than confinement for these genes. The confinement stressor caused an increased level of glucose in both control and PW-treated fish, indicating hyperglycemia, a commonly reported stress response in fish. PMID- 23916883 TI - Polyethylene glycol-drug ester conjugates for prolonged retention of small inhaled drugs in the lung. AB - Typically, inhaled drugs are rapidly absorbed into the bloodstream, which results in systemic side effects and a brief residence time in the lungs. PEGylation was evaluated as a novel strategy for prolonging the retention of small inhaled molecules in the pulmonary tissue. Hydrolysable ester conjugates of PEG1000, PEG2000, 2000, PEG3400 and prednisolone, a model drug cleared from the lungs within a few minutes, were synthesised and thoroughly characterised. The conjugates were stable in buffers with hydrolysis half-lives ranging from 1h to 70 h, depending on the pH and level of substitution. With the exception of PEG3400-prednisolone, conjugates did not induce a significant lactate dehydrogenase (LDH) release from Calu-3 cells after a 20 h exposure. Following nebulisation to isolated perfused rat lungs (IPRL), the PEG2000 and mPEG2000 conjugates reduced the maximum prednisolone concentration in the perfusate (Cmax) by 3.0 and 2.2 fold, respectively. Moreover, while prednisolone was undetectable in the perfusion solution beyond 20 min when the free drug was administered, prednisolone concentrations were still quantifiable after 40 min following delivery of the conjugates. This study is the first to demonstrate hydrolysable PEG drug ester conjugates are a promising approach for optimising the pharmacokinetic profile of small drugs delivered by inhalation. PMID- 23916884 TI - Spot-scanning beam proton therapy vs intensity-modulated radiation therapy for ipsilateral head and neck malignancies: a treatment planning comparison. AB - Radiation therapy for head and neck malignancies can have side effects that impede quality of life. Theoretically, proton therapy can reduce treatment related morbidity by minimizing the dose to critical normal tissues. We evaluated the feasibility of spot-scanning proton therapy for head and neck malignancies and compared dosimetry between those plans and intensity-modulated radiation therapy (IMRT) plans. Plans from 5 patients who had undergone IMRT for primary tumors of the head and neck were used for planning proton therapy. Both sets of plans were prepared using computed tomography (CT) scans with the goals of achieving 100% of the prescribed dose to the clinical target volume (CTV) and 95% to the planning TV (PTV) while maximizing conformity to the PTV. Dose-volume histograms were generated and compared, as were conformity indexes (CIs) to the PTVs and mean doses to the organs at risk (OARs). Both modalities in all cases achieved 100% of the dose to the CTV and 95% to the PTV. Mean PTV CIs were comparable (0.371 IMRT, 0.374 protons, p = 0.953). Mean doses were significantly lower in the proton plans to the contralateral submandibular (638.7 cGy IMRT, 4.3 cGy protons, p = 0.002) and parotid (533.3 cGy IMRT, 48.5 cGy protons, p = 0.003) glands; oral cavity (1760.4 cGy IMRT, 458.9 cGy protons, p = 0.003); spinal cord (2112.4 cGy IMRT, 249.2 cGy protons, p = 0.002); and brainstem (1553.52 cGy IMRT, 166.2 cGy protons, p = 0.005). Proton plans also produced lower maximum doses to the spinal cord (3692.1 cGy IMRT, 2014.8 cGy protons, p = 0.034) and brainstem (3412.1 cGy IMRT, 1387.6 cGy protons, p = 0.005). Normal tissue V10, V30, and V50 values were also significantly lower in the proton plans. We conclude that spot scanning proton therapy can significantly reduce the integral dose to head and neck critical structures. Prospective studies are underway to determine if this reduced dose translates to improved quality of life. PMID- 23916885 TI - Administration of IL-1Ra chitosan nanoparticles enhances the therapeutic efficacy of mesenchymal stem cell transplantation in acute liver failure. AB - BACKGROUND AND AIMS: To investigate the synergistic effect of IL-1Ra administration and stem cell transplantation in swine suffering from acute liver failure (ALF), to elucidate the mechanism of IL-1Ra activity and to demonstrate mesenchymal stem cell (MSC) transplantation as a potential treatment for ALF. METHODS: Thirty-five Chinese experimental mini-swine were divided into five groups randomly. Group A (n = 7) is the control group and all swine were injected with saline via portal veins. Group B (n = 7) received IL-1Ra via ear veins 6 h before receiving saline. Group C (n = 7) received MSC transplantation and all swine were injected with 8 * 107 MSCs via portal veins. Group D (n = 7) swine were treated with a combination of IL-1Ra and MSC transplantation E (n = 7) also received a combined treatment of both IL-1Ra and bone marrow (BM-MSC) transplantation, except that the IL-1Ra was in the form of chitosan nanoparticles. Liver function, level of cytokines and liver pathological changes were measured in the following 4 weeks. RESULTS: IL-1Ra chitosan nanoparticles exhibited controlled-release ability in PBS. Swine in Group E showed a significant improvement in inflammation environment, liver function and hepatocyte proliferation. Levels of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) in Group E were elevated compared to other groups. CONCLUSIONS: IL-1Ra chitosan nanoparticles showed significant liver targeting ability and controlled-release characteristics. Combined therapy with IL-1Ra chitosan nanoparticles and MCS transplantation exhibits great synergistic effects through paracrine function and suppression of inflammation. PMID- 23916886 TI - Differential cell responses to nanoparticle docetaxel and small molecule docetaxel at a sub-therapeutic dose range. AB - Current preclinical evaluations of nanoparticle taxanes have focused on the effect of nanoparticle size and shape on the efficacy and toxicity. It is generally assumed that nanoparticle therapeutics have the same cellular response on tumor and normal cells as their small molecule counterparts. Here, we show that nanoparticle taxanes can mediate cellular effects distinct from that of small molecule taxanes at the sub-therapeutic dose range. Cells that are exposed to two polymeric nanoparticle formulations of docetaxel were found to undergo a different cell cycle and cell fate than those of cells that were exposed to small molecule docetaxel. Our results suggest that nanoparticle formulation of therapeutics can affect the therapeutic effect of its cargo. FROM THE CLINICAL EDITOR: This study investigates the differences between subtherapeutic doses of docetaxel applied as small molecules vs. nanoparticle formulations, demonstrating differential effects on the cell cycle and overall cell fate. The study suggests that the carrier may change the therapeutic effects of its cargo, which has important implications on future research. PMID- 23916887 TI - Controlled release of 5-fluorouracil from microporous zeolites. AB - Zeolite particles with different pore diameter and particle size were loaded with the model anticancer drug 5-fluorouracil. The loaded zeolites were characterized by means of SEM, XRD, DSC, XPS, N2 physisorption and FT-IR. Higher loading of 5 FU was observed for NaX-FAU than BEA. Release studies were carried out in HCl 0.1N. Release of 5-FU from NaX-FAU showed exponential-type behaviour with the drug fully released within 10 min. In the case of BEA, the kinetics of 5-FU shows a multi-step profile with prolonged release over time. Molecular dynamics simulations showed that diffusion of the drug molecule through the BEA framework is lower than for NaX-FAU due to increased van der Waals interaction between the drug and the framework. The effect of zeolitic particles on the viability of Caco 2 monolayers showed that the NaX-FAU particles cause a reduction of cell viability in a more pronounced way compared with the BEA particles. FROM THE CLINICAL EDITOR: This article describes zeolite-based nanoparticles in generating time-controlled release of 5-FU from zeolite preparations for anti-cancer therapy. PMID- 23916888 TI - Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment. AB - This study examined a novel drug delivery system for treatment of malignant brain gliomas: DOX complexed with nanodiamonds (ND-Dox), and administered via convection-enhanced delivery (CED). Drug retention and toxicity were examined in glioma cell lines, and distribution, retention and toxicity were examined in normal rat parenchyma. Efficacy was assessed in a bioluminescence rodent tumor model. NDs markedly enhanced DOX uptake and retention in glioma cells. ND-Dox delivered via CED extended DOX retention and localized DOX toxicity in normal rodent parenchyma, and was significantly more efficient at killing tumor cells than uncomplexed DOX. Outcomes from this work suggest that CED of ND-Dox is a promising approach for brain tumor treatment. FROM THE CLINICAL EDITOR: In this paper, nanodiamonds were utilized to enhance delivery of DOX in a preclinical glioma model using a convection-enhanced delivery method, demonstrating remarkably enhanced efficacy. PMID- 23916889 TI - Synthesis of nanodiamond-daunorubicin conjugates to overcome multidrug chemoresistance in leukemia. AB - Nanodiamonds (NDs) are promising candidates in nanomedicine, demonstrating significant potential as gene/drug delivery platforms for cancer therapy. We have synthesized ND vectors capable of chemotherapeutic loading and delivery with applications towards chemoresistant leukemia. The loading of Daunorubicin (DNR) onto NDs was optimized by adjusting reaction parameters such as acidity and concentration. The resulting conjugate, a novel therapeutic payload for NDs, was characterized extensively for size, surface charge, and loading efficiency. A K562 human myelogenous leukemia cell line, with multidrug resistance conferred by incremental DNR exposure, was used to demonstrate the efficacy enhancement resulting from ND-based delivery. While resistant K562 cells were able to overcome treatment from DNR alone, as compared with non-resistant K562 cells, NDs were able to improve DNR delivery into resistant K562 cells. By overcoming efflux mechanisms present in this resistant leukemia line, ND-enabled therapeutics have demonstrated the potential to improve cancer treatment efficacy, especially towards resistant strains. FROM THE CLINICAL EDITOR: The authors of this study demonstrate superior treatment properties of resistant leukemia cell lines by utilizing nanodiamond vectors loaded with daunorubicin, paving the way to clinical studies in the hopefully not too distant future. PMID- 23916890 TI - Evaluation of a commercial real-time polymerase chain reaction assay for detection of environmental contamination with Clostridium difficile. AB - Contaminated environmental surfaces are an important source for transmission of Clostridium difficile. However, there are no efficient and easy methods to assess contamination. The performance of a commercial real-time polymerase chain reaction (PCR) assay was evaluated for detection of environmental toxigenic C. difficile in comparison with anaerobic culture followed by toxin testing of isolates. For 66 sites sampled, PCR had a sensitivity of 17.39%, specificity 100%, positive predictive value 100% and negative predictive value 69.35%. Increasing the PCR cycle threshold (CT) value to 45 increased sensitivity to 52% without decreasing specificity. The commercial PCR assay is not sufficiently sensitive for environmental monitoring, but improved sensitivity might be possible through CT value modification. PMID- 23916891 TI - Continuous exposure to Kaposi sarcoma-associated herpesvirus (KSHV) in healthcare workers does not result in KSHV infection. AB - Kaposi sarcoma (KS)-associated herpesvirus (KSHV or HHV-8) infection routes and risk of occupational exposure are still ill-defined. We analysed the risk for occupational acquisition of KSHV infection in healthcare workers (HCWs) with prolonged professional exposure to patients with classic KS, comparing the results to those obtained in healthy relatives of KS patients. Serum and/or saliva KSHV-specific antibodies and DNA were detected in five out of 35 healthy relatives of KS patients but in none of the eight HCWs, suggesting that, outside strict family contacts, horizontal transmission of KSHV is highly inefficient even for HCWs with prolonged contact with KS patients. PMID- 23916892 TI - Point-of-care tests for infection control: should rapid testing be in the laboratory or at the front line? AB - BACKGROUND: A point-of-care test (POCT) offers a rapid result to manage a patient immediately. The presumed simplicity of such tests belies observed variation between personnel in performing and interpreting results when not appropriately trained. The number of point-of-care devices being developed for the diagnosis of infectious diseases is increasing; by understanding the limitations associated with their use, such tests for infection control purposes may be possible. AIM: To review the expanding repertoire of POCTs for the diagnosis of infectious diseases and to assess their utility as tools to aid in the reduction of hospital acquired infection and outbreak management. METHODS: A systematic review using PubMed and Scopus of published literature on the subject of POCTs for the diagnosis of infectious diseases. FINDINGS: Although the number of publications describing POCTs is increasing, there remains a paucity of literature describing their use in a clinical setting. Of the literature reviewed, POCTs for the diagnosis of respiratory syncytial virus and norovirus have the greatest utility in an infection control setting, although the data suggest that sensitivity and training issues might be a problem. The future generation of POCT devices is likely to be molecular-based, improving sensitivity but at a significant cost to the user. CONCLUSIONS: POCTs have a role in infection control but currently the lack of good, consistent clinical data surrounding their use outside of the laboratory is a limiting factor in their implementation. PMID- 23916893 TI - Classical activation of microglia in CD200-deficient mice is a consequence of blood brain barrier permeability and infiltration of peripheral cells. AB - The interaction between CD200, expressed on several cell types, and its receptor CD200R, expressed on cells of the myeloid lineage, has been shown to be an important factor in modulating inflammation in macrophage function in several conditions including colitis and arthritis. More recently its modulatory effect on microglial activation has been identified and CD200-deficiency has been associated with increased microglial activation accompanied by increased production of inflammatory cytokines. The response of glia prepared from CD200 deficient mice to stimuli like lipopolysaccharide (LPS) is markedly greater than the response of cells prepared from wildtype mice and, consistent with this, is the recent observation that expression of Toll-like receptor (TLR)4 and signalling through NFkappaB are increased in microglia prepared from CD200 deficient mice. Here we show that glia from CD200-deficient mice are also more responsive to interferon-gamma (IFNgamma) which triggers classical activation of microglia. We investigated the effects of CD200-deficiency in vivo and report that there is an increase in expression of several markers of microglial activation including tumor necrosis factor (TNF)-alpha, which is a hallmark of classically-activated microglia. These changes are accompanied by increased IFNgamma, and the evidence suggests that this is produced by infiltrating cells including T cells and macrophages. We propose that these cells enter the brain as a consequence of increased blood brain barrier (BBB) permeability in CD200 deficient mice and that infiltration is assisted by increased expression of the chemokines, monocyte chemotactic protein-1 (MCP-1), IFNgamma-induced protein-10 (IP-10) and RANTES. This may have implications in neurodegenerative diseases where BBB permeability is compromised. PMID- 23916894 TI - Loss of astrocytic leptin signaling worsens experimental autoimmune encephalomyelitis. AB - Leptin is commonly thought to play a detrimental role in exacerbating experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Paradoxically, we show here that astrocytic leptin signaling has beneficial effects in reducing disease severity. In the astrocyte specific leptin receptor knockout (ALKO) mouse in which leptin signaling is absent in astrocytes, there were higher EAE scores (more locomotor deficits) than in the wildtype counterparts. The difference mainly occurred at a late stage of EAE when wildtype mice showed signs of recovery whereas ALKO mice continued to deteriorate. The more severe symptoms in ALKO mice coincided with more infiltrating cells in the spinal cord and perivascular brain parenchyma, more demyelination, more infiltrating CD4 cells, and a lower percent of neutrophils in the spinal cord 28 days after EAE induction. Cultured astrocytes from wildtype mice showed increased adenosine release in response to interleukin-6 and the hippocampus of wildtype mice had increased adenosine production 28 days after EAE induction, but the ALKO mutation abolished the increase in both conditions. This indicates a role of astrocytic leptin in normal gliotransmitter release and astrocyte functions. The worsening of EAE in the ALKO mice in the late stage suggests that astrocytic leptin signaling helps to clear infiltrating leukocytes and reduce autoimmune destruction of the CNS. PMID- 23916895 TI - Dysregulation in myelination mediated by persistent neuroinflammation: possible mechanisms in chemotherapy-related cognitive impairment. AB - Cognitive impairment is commonly reported as a consequence of chemotherapy and can have considerable impact on everyday life on cancer patients. Thus, it is imperative to have a clear understanding of this phenomenon and the underlying mechanism involved. In the present study we examined the role of neuroinflammation and myelination in chemotherapy-related cognitive impairment. Female Sprague-Dawley rats (12-months old) were used in the study (total n=52, 13rats/group). Rats were randomly assigned to either the chemotherapy or saline control group. The drug combination of cyclophosphamide, methotrexate, and 5 fluorouracil (CMF) was given i.p. once a week for 4weeks. Rats in the control group received normal saline of equal volume. Animals from each group were further randomized to receive either: cyclooxygenase (COX-2) inhibitor, NS-393, to block the inflammatory response or vehicle. NS-398 was given at 10mg/kg i.p. and equal volume of saline (vehicle) was injected i.p. as vehicle. Both NS-398 and vehicle were injected 1h after the first CMF dose and then given daily for 28days then rats were tested in the Y maze. Our data showed that: (1) CMF led to the increase in the levels of inflammatory mediators IL-1beta, TNF-alpha, and COX 2 while levels of the anti-inflammatory cytokine IL-10 decreased; (2) cognitive impairment and neuroinflammation resulting from CMF persisted 4weeks after the treatment ended; and (3) administration of NS-398 attenuated CMF-induced neuroinflammation and effects on myelin and cognitive impairment. These findings suggest the involvement of neuroinflammation in CMF-induced changes in myelin and myelination, and cognitive impairment. PMID- 23916897 TI - Smoking is bad for lungs, right? PMID- 23916896 TI - An exploratory panel of biomarkers for risk prediction in pulmonary hypertension: emerging role of CT-proET-1. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare, deadly condition. Although risk stratification is extremely important for assessment of prognosis and to guide therapy, there is lack of evidence concerning the role of novel biomarkers. In a pivotal study, we sought to comparatively investigate the predictive power of several new biomarkers in PAH. METHODS: Patients with prevalent PAH were enrolled in the study protocol, which included clinical, functional and echocardiographic assessment. Blood samples were collected at baseline for determination of NT-proBNP, CT-proET-1, MR-proANP, MR-proADM, copeptin and troponin I. Patients were clinically followed-up up to 12 months for first occurrence of hospital admission due to PAH-related clinical worsening, heart/lung transplantation or all-cause mortality. RESULTS: Among the 28 included patients the pre-specified end-point occurred in 8 (29% event rate). There were higher baseline levels of CT-proET-1, copeptin, MR-proANP, NT-proBNP and troponin I in patients who reached the composite end-point. They also had larger right atria. In multivariate Cox regression, CT-proET-1 was the only biomarker associated with increased hazard of reaching the primary composite end-point (hazard ratio per tertile increase = 10.1; 95% CI 2.0 to 50.6). CONCLUSIONS: CT proET-1 provided prognostic information independent of other biomarkers. Importantly, we have provided the first evidence that CT-proET-1 may be superior to commonly used biomarkers. PMID- 23916898 TI - Computed tomography urography for diagnosis of calyceal diverticulum complicated by urolithiasis: the accuracy and the effect of abdominal compression and prolongation of acquisition delay. AB - OBJECTIVE: To evaluate the accuracy of computed tomography urography (CTU) in the detection of caliceal diverticulum (CD) complicated with urolithiasis and the effect of compression and prolongation of acquisition delay. MATERIALS AND METHODS: All data were collected from a previous research between 2002 and 2011 at 3 hospitals. A total of 182 patients with evidence of renal parenchymal cystic lesion with calcific density were evaluated by CTU. Excretory phase imaging was acquired at 10 minutes and 60 minutes for each patient. Eighty-three patients received abdominal compression intervention during 10-minutes delay. RESULTS: CDs with stones were finally diagnosed in 41 patients (22.5%). Opacification within an apparent cyst was found in 31 patients (75.6%) when excretory phase images were acquired at 10 minutes and 38 patients (92.7%) at 60 minutes. The sensitivity and accuracy were significantly better with 60-minutes delay than with 10-minutes delay (92.7% vs 75.6%, P = .016 and 97.8% vs 94.0%, P = .016, respectively). The diagnostic results of compression group had significantly higher sensitivity and accuracy than that of the noncompression group (94.4% vs 60.9%, P = .025 and 98.8% vs 90.9%, P = .023, respectively). CONCLUSION: It is important to distinguish CD from other diseases such as complex cyst when diagnosing a renal parenchymal cystic lesion with wall calcification. CTU has high sensitivity and accuracy in the detection of CD. Abdominal compression and longer imaging delay can significantly improve the diagnostic effect of CTU. PMID- 23916899 TI - Reduction of osteoarticular acetabular dome impaction through an independent iliac cortical window. PMID- 23916900 TI - Incidence and risk factors of lower leg fractures in Belgian soccer players. AB - INTRODUCTION: Soccer is the world's most popular sport and one that is physically demanding and highly competitive. Consequently, the rate of injuries resulting from this sport is only increasing. It is estimated that 2-20% of all such injuries are fractures, one-third of which are located in the lower extremities. The aim of this epidemiological study was to investigate the incidence of lower leg fractures (LLFs) in Belgian soccer players and determine the possible risk factors that lead to them. METHODS: All injuries of players associated with the Royal Belgium Football Association (RBFA) were reported and collected in a nationwide registry. We retrospectively compared the incidence rate of and risk factors for LLFs in Belgian soccer players during two seasons, 1999-2000 and 2009 2010. RESULTS: In total, 1600 fractures (3%) were located in the lower leg. After a decade, the number of LLFs remained unchanged. Ankle fractures were the most common (37%), followed by foot and tibia fractures (33% and 22%, respectively). The least common were fibula fractures, which accounted for just 9%. A higher incidence of every type of LLF was observed in older and amateur-level soccer players, when compared with their younger and professional counterparts. Male players experienced more tibia and foot fractures, whereas the incidences of ankle and fibula fractures were comparable with those in female soccer players. The vast majority of fractures occurred during soccer games. CONCLUSION: Ankle fractures and foot fractures represented two-thirds of all fractures noted in this analysis. Male gender, recreational level and adult age were important risk factors for LLFs. After 10 years, the incidence of LLFs did not decrease. Given the socioeconomic impact of these injuries, improved prevention techniques are required to reduce their incidence, particularly with regard to the frequently occurring ankle and foot fractures in this population. PMID- 23916901 TI - Primary closure versus non-closure of dog bite wounds. a randomised controlled trial. AB - INTRODUCTION: Dog bite wounds represent a major health problem. Despite their importance, their management and especially the role of primary closure remain controversial. In this randomised controlled trial, the outcome between primary suturing and non-closure was compared. METHODS: 168 consecutive patients with dog bite injuries were included in this study. The wounds were allocated randomly in two treatment approaches: Group 1, consisting of eighty-two patients, had their wound sutured, whilst Group 2, consisting of eighty-six patients, did not have their wounds sutured. All wounds were cleansed using high-pressure irrigation and povidone iodine. All patients received the same type of antibiotic treatment. Our measured outcomes included presence of infection and cosmetic appearance. Cosmetic outcome was evaluated using the Vancouver Scar Scale (VSS). Wound and patient characteristics, such as time of management, wound location and size, and patient age, were recorded and analysed for their potential role in the resulting outcome. RESULTS: The overall infection rate was 8.3%. No difference in the infection rate between primary suturing and non-suturing group was detected in the present study. The cosmetic appearance of the sutured wounds was significantly better (mean score 1.74) compared to the wounds that were left open (mean score 3.05) (p=0.0001). The infection rate was comparable among all age groups. Wounds treated within 8h of injury demonstrated an infection rate of 4.5%, which is lower compared to the 22.2% rate observed in wounds treated later than 8h. The wounds located at the head and neck exhibited better results in both infection rate and cosmetic outcome. Additionally, wounds >3 cm negatively affected the cosmetic appearance of the outcome. CONCLUSIONS: Primary suturing of wounds caused by dog bites resulted in similar infection rate compared to non suturing. However, primary suturing exhibited improved cosmetic appearance. Time of management appeared to be critical, as early treatment resulted in lower infection rate and improved cosmetic appearance regardless suturing or not. Furthermore, wounds located at the head and face demonstrated better results. PMID- 23916902 TI - A systematic review of predictors of posttraumatic stress disorder (PTSD) for adult road traffic crash survivors. AB - Posttraumatic stress disorder (PTSD) is one of the most common psychological consequences for adult road traffic crash (RTC) survivors and can have serious and long-lasting consequences for recovery if left untreated. Prevalence rates of PTSD following a RTC vary from 6% to 45% (based on 51 prevalence estimates across 35 studies). Explanations for this wide variance are explored. A systematic review of published studies found 49 papers (44 unique studies) investigating predictors of later PTSD in RTC survivors. Consistent predictors of PTSD include rumination about the trauma, perceived threat to life, a lack of social support, higher Acute Stress Disorder symptom severity, persistent physical problems, previous emotional problems, previous anxiety disorder and involvement in litigation/compensation. Moderate predictors of PTSD are discussed, as well as factors, which consistently do not predict PTSD in RTC survivors. The results inform future models of post-RTC traumatic stress aetiology. PMID- 23916903 TI - Emergency stabilization of the pelvic ring: Clinical comparison between three different techniques. AB - BACKGROUND: Emergency devices for pelvic ring stabilization include circumferential sheets, pelvic binders, and c-clamps. Our knowledge of the outcome of these techniques is currently based on limited information. METHODS: Using the dataset of the German Pelvic Trauma Registry, demographic and injury associated characteristics as well as the outcome of pelvic fracture patients after sheet, binder, and c-clamp treatment was compared. Outcome parameters included transfusion requirement of packed red blood cells, length of hospital stay, mortality, and incidence of lethal pelvic bleeding. RESULTS: Two hundred seven of 6137 (3.4%) patients documented in the German Pelvic Trauma Registry between April 30th 2004 and January 19th 2012 were treated by sheets, binders, or c-clamps. In most cases, c-clamps (69%) were used, followed by sheets (16%), and binders (15%). The median age was significantly lower in patients treated with binders than in patients treated with sheets or c-clamps (26 vs. 47 vs. 42 years, p=0.01). Sheet wrapping was associated with a significantly higher incidence of lethal pelvic bleeding compared to binder or c-clamp stabilization (23% vs. 4% vs. 8%). No significant differences between the study groups were found in sex, fracture type, blood haemoglobin concentration, arterial blood pressure, Injury Severity Score, the incidence of additional pelvic packing and arterial embolization, need of red blood cell transfusion, length of hospitalisation, and mortality. CONCLUSIONS: The data suggest that emergency stabilization of the pelvic ring by binders and c-clamps is associated with a lower incidence of lethal pelvic bleeding compared to sheet wrapping. LEVEL OF EVIDENCE: Level III. PMID- 23916904 TI - The oral iron chelator deferasirox might improve survival in allogeneic hematopoietic cell transplant (alloHSCT) recipients with transfusional iron overload. AB - INTRODUCTION: Iron overload (IO) has been shown to be an important cause of mortality and morbidity in patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). This study aimed to evaluate the possible effect of oral iron-chelation treatment (deferasirox) on survival in alloHSCT recipients in the posttransplant period. MATERIALS AND METHODS: A total of 80 alloHSCT recipients with IO were analyzed, retrospectively. Pretransplant and posttransplant data were obtained from the patients' files. Patients were divided into two groups. Group 1; patients who did not receive any chelator treatment due to side effects or compliance problems. These patients were treated by phlebotomy. Group 2 consisted of patients who received deferasirox treatment. RESULTS: The median treatment duration with deferasirox was 122 days (min-max:91 225). The iron chelating treatment significantly reduced serum ferritin levels administered at a dosage of 20-30 mg/kg/day (p<0.001). The median OS in Group 1 was found 16.0 (min-max:1.0-63.0) months and 25.0 (min-max:3.0-72.0) months in Group 2. In univariate and multivariate analysis, patients in Group 1 showed poorer OS compared to those in Group 2 with an increase in risk of death (HR:3.22, min-max:1.67-6.23, p=0.001 and HR:3.51,, min-max:1.75-6.99, p<0.001; respectively). The median DFS in Group 1 was found 11.0 (min-max:3.0-24.0) months and 22.0 (min-max:8.0-43.0) months in Group 2. The difference was found statistically significant (p=0.023). The other factors that we found significant difference in multivariate analysis between groups were; presence of acute GVHD (patients with aGVHD had increased risk of death compared to patients without aGVHD (HR:2.49, min-max: 1.32-4.69, p=0.005), chronic GVHD (HR:2.57, min-max:1.23 5.41, p=0.013), median interval to tx (HR: 2.23, min-max:1.17-4.26, p=0.015) and HLA match (HR:3.01, min-max:1.35-6.73, p=0.007) CONCLUSION: Oral deferasirox (Exjade) treatment may improve survival in patients with iron overload who underwent alloHSCT. PMID- 23916905 TI - [The way of self-defence of the organism: inflammation]. AB - The acute and chronic constitutional reactions of the organism elicited by sterile causes and pathogenic structures threatening the soundness of the organism are surveyed by the author. It is emphasized that depending on causes which can be very different, there are various syndromes occurring in the clinical practice. On the basis of multitudiness of pathogenic factors and individual differences, the infammatory reactions are clinically, pathologically and pathobiochemically can be hugely variable. The acute inflammatory response may be sterile. It is often difficult to recognize in these processes whether the inflammation is harmful or beneficial for the organism as a whole. It is possible that the inflammatory response itself is the defending resource of the individual. The non-sterile acute inflammation is evoked by pathogenic microorganisms. The variety of clinical syndromes are explained by the high diversity of pathogenic microbes, the individualities of the defending organisms, and the natural and adaptive immunity of the organism which may be intact or possibly defective. In the latter case the inflammation itself is the disease, as a consequence of a pathological process conducted by the cortico-hypothalamo adernal axis. The acute inflammation is a defending, preventing and repairing process, constituting an important part of the natural innate immune response. It is inseparable from the natural innate immune response, which is in close cooperation with the adaptive, specific immune response with mutual effects on each of the other. The conductor and the response reactions of the two immune responses are also the same. There are alterations in serum proteins/glycoproteins synthesized mostly by the hepatocytes. Because the concentration of almost all proteins/glycoproteins may change, the use of the discriminative term "acute phase reactant" is hardly relevant. For example, the HDL molecule is a negative "acute phase reactant". On the gound of clinical, pathological and biochemical caracteristics, the chronic sterile inflammation is a very different entity. It has been established that atherosclerosis is one of the ab origine chronic inflammatory syndrome. It is a long-lasting pathological entity progressing, rather than resolving with different celerity, namely a unique vasculitis syndrome. We are speaking about risk factors instead of causes, which constitute larger or smaller groups to elicite the preventing reaction of the host. The propagations and final outcomes are quite different from that of the acute process. The disadvantages or benefits for the organism are scarcely predictable, albeit the chronic process may have roles in its prolonged nature. PMID- 23916906 TI - [New perspectives on childhood obesity]. AB - From preventional point of view, childhood obesity is very important, since proliferation of extra fatty tissue in childhood contribute metabolic processes favoring the development of type 2 diabetes, as well as it can accelerate cardiovascular complications. Anyone who is overweight in his or her life is likely to be confronted by such social stigma that could ultimately have a negative impact on self-esteem. The cornerstone of prevention is a healthy diet and age-adjusted physical training which may result in a physiological energy balance. PMID- 23916907 TI - [IL28B CC genotype: a protective factor and predictor of the response to interferon treatment in chronic hepatitis C virus infection]. AB - INTRODUCTION: In chronic hepatitis C-virus infection the possible role of gene variants encoding cytokines has become the focus of interest. AIM: The aim of the study was to investigate the effect of IL28B polymorphisms on the outcome of chronic hepatitis C-virus genotype 1 infection in the Hungarian population. In addition, the association between IL28B genotypes and the Th1/Th2 cytokine production of activated peripheral blood monocytes and lymphocytes was evaluated. METHOD: Total of 748 chronic hepatitis C-virus genotype 1 positive patients (365 males and 383 females, aged between 18 and 82 years; mean age, 54+/-10 years) were enrolled, of which 420 patients were treated with pegylated interferon plus ribavirin for 24-72 weeks. Of the 420 patients, 195 patients (46.4%) achieved sustained virological response. The IL28B rs12979860 polymorphism was determined using Custom Taqman SNP Genotyping Assays (Applied Biosystems, Life Technologies, Foster, CA, USA). For cytokine studies, tumour necrosis factor-alpha, interleukin 2, interferon-gamma, interleukin-2 and interleukin-4 production by LPS-stimulated monocytes and PMA-ionomycine activated lymphocytes were measured from the supernatant of the cells obtained from 40 hepatitis C-virus infected patients, using FACS-CBA Becton Dickinson test. The cytokine levels were compared in patients with different (CC, CT, TT) IL28B genotypes. RESULTS: The IL28B rs12979860 CC genotype occurred in lower frequency in hepatitis C-virus infected patients than in healthy controls (26.1% vs 51.4%, OR 0.333, p<0.001). Patients carried the T allele with higher frequency than controls (73.9%, vs 48.6%, OR 3.003, p<0.001). Pegylated interferon plus ribavirin treated patients with the IL28B CC genotype achieved higher sustained virological response rate than those with the CT genotype (58.6% vs 40.8%, OR 2.057, p = 0.002), and those who carried the T allele (41.8%, OR1.976, p = 0.002). LPS-induced TLR-4 activation of monocytes resulted in higher tumour necrosis factor-alpha production in patients with the IL28B CC genotype compared to non-CC individuals (p<0.01). Similarly, increased tumour necrosis factor-alpha, interleukin-2 and interferon-gamma production by lymphocytes was found in the IL28B CC carriers (p<0.01) CONCLUSIONS: The IL28B CC genotype exerts protective effect against chronic hepatitis C-virus infection and may be a pretreatment predictor of sustained virological response during interferon-based antiviral therapy. The IL28B CC polymorphism is associated with increased Th1 cytokine production of activated peripheral blood monocytes and lymphocytes, which may play a role in interferon induced rapid immune control and sustained virological response of pegylated interferon plus ribavirin treated patients. PMID- 23916908 TI - [Knowledge transfer in the instruction of healthcare informatics: quality, efficiency and measurability]. AB - INTRODUCTION: Electronic exams have been used at Semmelweis University within Health Care Informatics courses since 2006. The statistical analysis of the electronic exam sheets enabled the authors to assess the reliability of examinations, as well as recommend important measures to increase the quality and efficiency of knowledge transfer. AIM: The main objective of the study was to propose an optimal teaching methodology with a special focus on electronic exams, based on the statistical analysis of databases of electronic exams recorded at Health Care Informatics courses of Semmelweis University. METHOD: All data were analysed with statistical methods at the level of individual questions as well as exam results of each student (2801 medical students have undertaken 4933 electronic exams since 2006). Results were evaluated based on teaching methodology criteria. RESULTS: There was a significantly increased tendency in grades obtained at individual exams. The authors identified exam questions that are needed to be modified or even ignored, because they failed to correlate with the knowledge measurement of the students. CONCLUSIONS: Statistical analysis of exam results proved to be a useful tool to assess methodology of teaching, knowledge transfer, and their practical implications. It is essential to monitor continuously exam results, this may exert a significant impact on the improvement of the quality and efficiency of knowledge transfer processes. PMID- 23916909 TI - [First qualified physician in Hungary: Gaspar Szegedi Koros (1500?-1563). Contribution to the history of gynaecology in Hungary]. PMID- 23916911 TI - Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta analysis. AB - The hypothalamic-pituitary-adrenal (HPA) axis is a psychoneuroendocrine regulator of the stress response and immune system, and dysfunctions have been associated with outcomes in several physical health conditions. Its end product, cortisol, is relevant to fatigue due to its role in energy metabolism. The systematic review examined the relationship between different markers of unstimulated salivary cortisol activity in everyday life in chronic fatigue syndrome (CFS) and fatigue assessed in other clinical and general populations. Search terms for the review related to salivary cortisol assessments, everyday life contexts, and fatigue. All eligible studies (n=19) were reviewed narratively in terms of associations between fatigue and assessed cortisol markers, including the cortisol awakening response (CAR), circadian profile (CP) output, and diurnal cortisol slope (DCS). Subset meta-analyses were conducted of case-control CFS studies examining group differences in three cortisol outcomes: CAR output; CAR increase; and CP output. Meta-analyses revealed an attenuation of the CAR increase within CFS compared to controls (d=-.34) but no statistically significant differences between groups for other markers. In the narrative review, total cortisol output (CAR or CP) was rarely associated with fatigue in any population; CAR increase and DCS were most relevant. Outcomes reflecting within-day change in cortisol levels (CAR increase; DCS) may be the most relevant to fatigue experience, and future research in this area should report at least one such marker. Results should be considered with caution due to heterogeneity in one meta-analysis and the small number of studies. PMID- 23916912 TI - Orexigenic effects of endomorphin-2 (EM-2) related to decreased CRH gene expression and increased dopamine and norepinephrine activity in the hypothalamus. AB - Endomorphin-1 (EM-1) and endomorphin-2 (EM-2) are opioid peptides which are selective partial agonists of MU-opioid receptor. We studied the effects of EM-2 injected into the arcuate nucleus (ARC) of the hypothalamus on feeding behavior and gene expression of orexigenic [agouti-related peptide (AgRP), neuropeptide Y (NPY) and orexin-A] and anorexigenic [cocaine and amphetamine-regulated transcript (CART), corticotrophin releasing hormone (CRH) and proopiomelanocortin (POMC)] peptides in male Wistar rats fed a standard laboratory diet. Furthermore, we evaluated the effects of EM-2 on dopamine (DA), norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) steady state concentrations, in the hypothalamus. 64 rats (16 for each group of treatment) were injected into the ARC, at 9.00 am, with either vehicle or EM-2 (0.50-0.75 MUmol/kg) or EM-2 (0.50 MUmol/kg) plus beta-funaltrexamine (0.20 MUmol/kg). Food intake was recorded through 24h following injection, and hypothalamic DA, NE, 5-HT levels and neuropeptide gene expression were evaluated 24h after EM-2 administration. Compared to vehicle, EM-2 significantly increased food intake, throughout 24h post-injection. Furthermore, EM-2 treatment led to a significant increase of DA and NE concentrations and a decrease of CRH mRNA levels. On the other hand, beta funaltrexamine administration reverted both feeding stimulatory and neuromodulatory effects induced by EM-2. We can conclude that the orexigenic effect of MU-opioid receptor activation by EM-2 could be related to both inhibition of CRH and stimulation of dopamine and norepinephrine levels, in the hypothalamus. PMID- 23916913 TI - Notch-1 contributes to epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance in non-small cell lung cancer in vitro and in vivo. AB - Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) occurs in non-small cell lung cancer (NSCLC) patients who initially respond to TKI treatment but whose cancer then progresses. Recent studies have shown that Notch signal is associated with drug resistance. However, the exact mechanism of Notch during acquisition of resistance to EGFR-TKI in human lung cancer remains unclear. In the present study, we showed that the expression of Notch-1 was highly upregulated in EGFR-TKI acquired resistant lung cancer cells. More importantly, Notch-1 contributed to the acquisition of the epithelial-mesenchymal transition (EMT) phenotype, which was critically associated with acquired resistance to EGFR-TKI. Silencing of Notch-1 using siRNA resulted in mesenchymal-epithelial transition (MET), which was associated with impaired invasion and anchorage-independent growth of lung cancer and resensitisation to gefitinib in acquired resistant NSCLC cells. Finally, gefitinib treatment of Balb/c nu/nu with acquired resistant lung cancer xenografts in combination with Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L alanyl]-(S)-phenylglycine t-butyl ester (DAPT) resulted in effective tumour growth retardation, with decreased proliferative activity and increased apoptotic activity. Collectively, these data suggest that Notch-1 might play a novel role in acquired resistance to gefitinib, which could be reversed by inhibiting Notch 1. PMID- 23916914 TI - Acute, short-term hypercapnia improves microvascular oxygenation of the colon in an animal model of sepsis. AB - INTRODUCTION: The deterioration of microcirculatory oxygenation of the gut plays a vital role in the development of sepsis. Acute hypercapnia enhances the microcirculatory oxygenation of the splanchnic region under physiological conditions, while the effect of hypercapnia under sepsis is unknown. The aim of this study was to investigate the effects of acute hypercapnia and hypercapnic acidosis on the colonic microcirculation and early cytokine response in polymicrobial sepsis. METHODS: Experiments were performed on 103 male Wistar rats. Colon ascendens stent peritonitis (CASP) surgery with varying stent diameters was conducted to establish a moderate polymicrobial sepsis model. In a second series, 24h of sepsis development induced by CASP surgery was followed by 120min of volume-controlled and pressure-limited ventilation with either normocapnic (pCO2 45+/-5mmHg) or moderate hypercapnic ventilation targets (pCO2 75+/-5mmHg) via exogenous carbon dioxide application. The effect of acidosis was investigated by metabolically buffering the hypercapnic acidosis with tromethamine. Microcirculatory oxygenation of the colon wall (tissue reflectance spectrophotometry) and hemodynamic variables were recorded continuously and arterial blood gas and cytokine (TNF-alpha, IL-6, IL-10) levels were analyzed intermittently. RESULTS: In septic animals the microcirculatory oxygenation of the colon deteriorated under normocapnia (-7.0+/-7.6% at 90min) but was maintained under hypercapnic acidosis (+3.6+/-7.6%) and buffered hypercapnia (+1.5+/-4.4%). Cytokine levels were significantly higher in septic animals as opposed to sham animals but did not differ between normocapnic and hypercapnic groups. CONCLUSIONS: Acute hypercapnic acidosis and buffered hypercapnia both improve splanchnic microcirculatory oxygenation in a septic animal model, thereby counteracting the adverse effect induced by sepsis. The circulating pro- and anti inflammatory cytokine levels are not modulated after 120min of hypercapnia. PMID- 23916915 TI - Tailored Case Management for Diabetes and Hypertension (TEACH-DM) in a community population: study design and baseline sample characteristics. AB - BACKGROUND: Despite recognition of the benefits associated with well-controlled diabetes and hypertension, control remains suboptimal. Effective interventions for these conditions have been studied within academic settings, but interventions targeting both conditions have rarely been tested in community settings. We describe the design and baseline results of a trial evaluating a behavioral intervention among community patients with poorly-controlled diabetes and comorbid hypertension. METHODS: Tailored Case Management for Diabetes and Hypertension (TEACH-DM) is a 24-month randomized, controlled trial evaluating a telephone-delivered behavioral intervention for diabetes and hypertension versus attention control. The study recruited from nine community practices. The nurse administered intervention targets 3 areas: 1) cultivation of healthful behaviors for diabetes and hypertension control; 2) provision of fundamentals to support attainment of healthful behaviors; and 3) identification and correction of patient-specific barriers to adopting healthful behaviors. Hemoglobin A1c and blood pressure measured at 6, 12, and 24 months are co-primary outcomes. Secondary outcomes include self-efficacy, self-reported medication adherence, exercise, and cost-effectiveness. RESULTS: Of 377 randomized patients, 193 were allocated to the intervention and 184 to attention control. The cohort is balanced in terms of gender, race, education level, and income. The cohort's mean baseline hemoglobin A1c and blood pressure are above goal, and mean baseline body mass index falls in the obese range. Baseline self-reported non-adherence is high for diabetes and hypertension medications. Trial results are pending. CONCLUSIONS: If effective, the TEACH-DM intervention's telephone-based delivery strategy and nurse administration make it well-suited for rapid implementation and broad dissemination in community settings. PMID- 23916916 TI - A telephone intervention for dementia caregivers: background, design, and baseline characteristics. AB - Family caregivers of individuals with dementia are at heightened risk for emotional and mental health problems. Many caregivers do not seek assistance or become isolated in their caregiving role. Multi-component interventions have demonstrated efficacy for reducing emotional distress and burden, although these approaches are potentially costly and are not widely accessible. In response to these issues, we developed the Family Intervention: Telephone Tracking - Caregiver (FITT-C), which is an entirely telephone-based psychosocial intervention. The purpose of this paper is to describe the study design, methodology, and baseline data for the trial. This study uses a randomized controlled trial design to examine the efficacy of the FITT-C to reduce depressive symptoms and burden in distressed dementia caregivers. All participants (n=250) received a packet of educational materials and were randomly assigned to receive 6 months of the FITT-C intervention or non-directive telephone support. The FITT-C intervention was designed to reduce distress in caregivers and is based on the McMaster Model of Family Functioning, transition theory, and Lazarus and Folkman's Stress and Coping Models. The primary dependent variables were depressive symptoms (Centers for Epidemiological Studies - Depression) and burden (Zarit Burden Interview, Revised Memory and Behavior Problems Checklist - Reaction). Secondary outcome measures included family functioning, self-efficacy, and health-related quality of life. Results of the study will provide important data about the efficacy of a telephone-based approach to reduce distress in dementia caregivers. PMID- 23916917 TI - Comparison of different parametric proportional hazards models for interval censored data: a simulation study. AB - Interval censoring occurs frequently in clinical trials, but is often simplified to a right censoring problem because statistical methods in this area are under developed. It is recognized that analyzing interval censored data as right censored data can lead to biased results. Although statistical methods have been developed to estimate survival function and to test hypothesis, estimating hazard ratio (HR) in a proportional hazards (PH) model for interval censored data remains as a challenge. Semi-parametric PH model was developed but difficult to implement, and thus rarely used in practice. Parametric PH method can be easily implemented but received little attention in practice because the impact of mis specifying baseline hazard function on HR estimate was not well understood. We examined the performance of parametric PH models, using 3 baseline hazard functions: exponential, Weibull, and a 10-piece exponential function, under different underlying data distributions and censoring schema, through an extensive simulation study. Data were generated from 6 different models representing a range of possible scenarios in clinical trials. The simulation study revealed that mis-specifying baseline hazard function had little impact on the HR estimates. Robust estimate of HR with little bias and small mean square errors (MSE) were obtained using a PH model with a Weibull or 10-piece exponential function approximating baseline hazard function. Bigger bias and MSE were observed when using an exponential function to approximate a complex baseline hazard function. Examples are included. Based on these findings, we advocate the use of parametric PH models for the analysis of interval censored data. PMID- 23916918 TI - Recruitment and retention rates in behavioral trials involving patients and a support person: a systematic review. AB - BACKGROUND: Recruitment and retention challenges impede the study of behavioral interventions among patient-support person dyads. PURPOSE: The aim of the study was to characterize recruitment and retention rates of behavioral interventions involving dyads. METHODS: Using PRISMA guidelines and with the guidance of a medical librarian, we searched Medline, EMBASE, Cochrane Controlled Trials, PsycInfo, and CINAHL from inception until July 2011. Eligible articles involved RCTs of behavioral interventions targeting adult patients with a non-psychiatric illness and a support person. Sample and study characteristics, recruitment and retention strategies, and recruitment and retention rates were abstracted in duplicate. Quality of reporting was determined on a 5-point scale. Due to the heterogeneity in data reporting and missing data, a narrative synthesis was undertaken. RESULTS: 53 unique studies involving 8081 dyads were included. 9 studies were ascertained to have a "high quality" of reporting. A majority of the studies did not report target sample size, time to complete recruitment, and sample sizes at each follow-up time point. Strategies employed to recruit support persons were rarely reported. 16 studies did not report the number of dyads screened. The mean recruitment rate was 51.2% (range: 4.3%-95.4%), and mean retention rate was 77.5% (range: 36%-100%). CONCLUSIONS: Details regarding recruitment and retention methodology were sparse in these interventions. Where available, data suggests that resources need to be devoted towards recruitment of sample but that retention rates are generally adequate. PMID- 23916920 TI - Acetylcholine-induced AMP-activated protein kinase activation attenuates vasoconstriction through an LKB1-dependent mechanism in rat aorta. AB - Numerous studies of acetylcholine (ACh)-induced endothelium-dependent relaxation in arteries have been reported since the original description by Furchgott and Zawadzki (1980). ACh also produces endothelium-independent relaxation. However, it is still unknown whether ACh-induced AMP-activated protein kinase (AMPK) activation can attenuate vasoconstriction in endothelium-denuded rat aorta. Here, we investigated whether ACh may exert a regulatory effect for vascular tone via AMPK activation and its underlying mechanism in vascular smooth muscle cells (VSMCs). Western blotting showed that ACh dose- and time-dependently increased LKB1 and AMPK phosphorylation in VSMCs. The ACh-induced activation of AMPK required muscarinic receptors in VSMCs. LKB1 and AMPK activation by ACh inhibited myosin light-chain kinase (MLCK) and phosphorylated myosin light chain (p-MLC) expression in VSMCs. In addition, a tension study showed the inhibitory effect of ACh-induced AMPK activation on phenylephrine-mediated contraction in endothelium denuded rat aorta. These data suggest that the ACh-induced activation of AMPK may attenuate vasoconstriction via LKB1-AMPK-dependent mechanism in endothelium denuded rat aorta. PMID- 23916921 TI - Carotid revascularization before open heart surgery: the data-driven treatment strategy. PMID- 23916919 TI - Designing and implementing a comparative effectiveness study of two strategies for delivering high quality CHD prevention: methods and participant characteristics for the Heart to Health study. AB - BACKGROUND: Although lifestyle and medications are effective for coronary heart disease (CHD) risk reduction, few studies have examined the comparative effectiveness of various strategies for delivering high quality CHD risk reduction. In this paper, we report on the design and baseline characteristics of participants for just such a trial. METHODS: We conducted a randomized trial of the same lifestyle and medication intervention delivered in two alternate formats: counselor-delivered or web-based. The trial was conducted at 5 diverse practices in a family medicine research network and included men and women age 35 79 who were at high risk of CHD events based on 10-year predicted Framingham risk of >=10% or a known history of cardiovascular disease. After individual-level randomization, participants in both arms received a decision aid plus four intensive intervention visits and 3 maintenance visits over 12 months. The primary outcome was change in 10-year predicted CHD risk among patients without prior cardiovascular disease. Secondary outcomes, measured among all participants, included changes in CHD risk factors, cost-effectiveness, and acceptability at 4 and 12-month follow-up. RESULTS: We randomized 489 eligible patients: 389 without and 100 with a known history of cardiovascular disease. Mean age was 62.3. 75% were white, 25% African-American. 45% had a college education. 88% had health insurance. Mean 10-year predicted CHD risk was 16.9%. CONCLUSION: We have successfully recruited a diverse sample of practices and patients that will provide a rich sample in which to test the comparative effectiveness of two strategies to implement high quality CHD prevention. PMID- 23916922 TI - Relationship between testosterone level and early repolarization on 12-lead electrocardiograms in men. PMID- 23916923 TI - Matchmaking for the optimization of clinical trials of heart failure with preserved ejection fraction: no laughing matter. PMID- 23916924 TI - Long-term cardiovascular risk in women prescribed fertility therapy. AB - OBJECTIVES: The purpose of the study was to investigate whether fertility therapy might contribute to subsequent cardiovascular disease. BACKGROUND: Fertility medications are used for 1% of births yet may also lead to endothelial injury with long-term adverse consequences for the mother. METHODS: A population-based cohort analysis was performed of women who gave birth in Ontario, Canada, between July 1, 1993, and March 31, 2010, distinguishing those who did and did not receive fertility therapy in the 2 years before delivery. Cox proportional models were derived to estimate hazard ratios with and without adjustment for baseline characteristics. The primary outcome was a composite cardiovascular endpoint of death, nonfatal coronary ischemia, stroke, transient ischemic attack, thromboembolism, or heart failure. RESULTS: Among 1,186,753 women who delivered during the study period, 6,979 gave birth after fertility therapy. After 9.7 years of median follow-up, women who delivered after fertility therapy had fewer cardiovascular events than controls (103 vs. 117 events per 100,000 person years), equivalent to an unadjusted hazard ratio of 0.96 (95% confidence interval: 0.72 to 1.29, p = 0.79) and an adjusted hazard ratio of 0.55 (95% confidence interval: 0.41 to 0.74, p < 0.0001). An apparent relative lower risk was observed across all age and income groups. Women who received fertility therapy also had lower risk-adjusted all-cause mortality, thromboembolic events, subsequent depression, alcoholism, and self-harm (p < 0.01 for each). CONCLUSIONS: Successful fertility therapy was not associated with an increased risk of cardiovascular disease later in life. PMID- 23916925 TI - Effect of If-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial. AB - OBJECTIVES: The aim of this study was to test the effects of treatment with ivabradine on exercise capacity and left ventricular filling in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Because symptoms of HFpEF are typically exertional, optimization of diastolic filling time by controlling heart rate may delay the onset of symptoms. METHODS: Sixty one patients with HFpEF were randomly assigned to ivabradine 5 mg twice daily (n = 30) or placebo (n = 31) for 7 days in this double-blind trial. Cardiopulmonary exercise testing with echocardiographic assessment of myocardial function and left ventricular filling were undertaken at rest and after exercise. RESULTS: The ivabradine group demonstrated significant improvement between baseline and follow up exercise capacity (4.2 +/- 1.8 METs vs. 5.7 +/- 1.9 METs, p = 0.001) and peak oxygen uptake (14.0 +/- 6.1 ml/min/kg vs. 17.0 +/- 3.3 ml/min/kg, p = 0.001), with simultaneous reduction in exercise-induced increase in the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity (3.1 +/- 2.7 vs. 1.3 +/- 2.0, p = 0.004). Work load-corrected chronotropic response (the difference in heart rate at the same exercise time at the baseline and follow-up tests) showed a slower increase in heart rate during exercise than in the placebo-treated group. Therapy with ivabradine (beta = 0.34, p = 0.04) and change with treatment in exertional increase in the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity (beta = -0.30, p = 0.02) were independent correlates of increase in exercise capacity, and therapy with ivabradine (beta = 0.32, p = 0.007) was independently correlated with increase in peak oxygen uptake. CONCLUSIONS: In patients with HFpEF, short-term treatment with ivabradine increased exercise capacity, with a contribution from improved left ventricular filling pressure response to exercise as reflected by the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity. Because this patient population is symptomatic on exertion, therapeutic treatments targeting abnormal exercise hemodynamic status may prove useful. (Use of Exercise and Medical Therapies to Improve Cardiac Function Among Patients With Exertional Shortness of Breath Due to Lung Congestion; ACTRN12610001087044). PMID- 23916926 TI - Noninvasive detection of lipids in atherosclerotic plaque using ultrasound thermal strain imaging: in vivo animal study. AB - OBJECTIVES: This study sought to examine the feasibility of in vivo detection of lipids in atherosclerotic plaque (AP) by ultrasound (US) thermal (or temporal) strain imaging (TSI). BACKGROUND: Intraplaque lipid content is thought to contribute to plaque stability. Lipid exhibits a distinctive physical characteristic of temperature-dependent US speed compared with water-bearing tissues. As tissue temperature changes, US radiofrequency (RF) echoes shift in time of flight, which produces an apparent strain (thermal or temporal strain [TS]). METHODS: US heating-imaging pulse sequences and transducers were designed and integrated into commercial US scanners for US-TSI of arterial segments. US-RF data were collected while gradually increasing tissue temperature. Phase sensitive speckle tracking was applied to reconstruct TS maps coregistered to B scans. Segments from injured atherosclerotic and uninjured nonatherosclerotic common femoral arteries (CFA) in cholesterol-fed New Zealand rabbits, and segments from control normal diet-fed rabbits (N =14) were scanned in vivo at different time points up to 12 weeks. RESULTS: Lipid-rich atherosclerotic lesions exhibited distinct positive TS (+0.19 +/- 0.08%) compared with that in nonatherosclerotic (-0.10 +/- 0.13%) and control (-0.09 +/- 0.09%) segments (p < 0.001). US-TSI enabled serial monitoring of lipids during atherosclerosis development. The coregistered set of morphological and compositional information of US-TSI showed good agreement with histology. CONCLUSIONS: US-TSI successfully detected and longitudinally monitored lipid progression in atherosclerotic CFA. US-TSI of relatively superficial arteries may be a modality that could be integrated into a commercial US system for noninvasive lipid detection in AP. PMID- 23916928 TI - A randomized controlled trial to prevent post-operative atrial fibrillation by antioxidant reinforcement. AB - OBJECTIVES: This study was designed to assess whether the reinforcement of the antioxidant system, through n-3 fatty acids plus antioxidant vitamin supplementation, could reduce the incidence of post-operative atrial fibrillation. BACKGROUND: Therapy to prevent post-operative atrial fibrillation remains suboptimal. Although oxidative stress plays a key role in the pathogenesis of this arrhythmia, antioxidant reinforcement has produced controversial results. METHODS: A total of 203 patients scheduled for on-pump cardiac surgery were randomized to placebo or supplementation with n-3 polyunsaturated fatty acids (2 g/day) (eicosapentaenoic acid:docosahexaenoic acid ratio 1:2), vitamin C (1 g/day), and vitamin E (400 IU/day). The primary outcome was the occurrence of post-operative atrial fibrillation. Secondary outcomes were the biomarkers related to oxidative stress and inflammation. RESULTS: Post operative atrial fibrillation occurred in 10 of 103 patients (9.7%) in the supplemented group versus 32 of 100 patients (32%) in the placebo group (p < 0.001). Early after surgery, placebo patients presented with increased levels of biomarkers of inflammation and oxidative stress, which were markedly attenuated by antioxidant supplementation. The activity of catalase, superoxide dismutase, and glutathione peroxidase in atrial tissue of the supplemented patients was 24.0%, 17.1%, and 19.7% higher than the respective placebo values (p < 0.05). The atrial tissue of patients who developed atrial fibrillation showed NADPH oxidase p47-phox subunit protein and mRNA expression 38.4% and 35.7% higher, respectively, than patients in sinus rhythm (p < 0.05). CONCLUSIONS: This safe, well-tolerated, and low-cost regimen, consisting of n-3 polyunsaturated fatty acids plus vitamins C and E supplementation, favorably affected post-operative atrial fibrillation, increased antioxidant potential, and attenuated oxidative stress and inflammation. (Prevention of Post-Operative Atrial Fibrillation: Pathophysiological Characterization of a Pharmacological Intervention Based on a Novel Model of Nonhypoxic Pre-Conditioning; ISRCTN45347268). PMID- 23916929 TI - Cardiac epithelioid leiomyosarcoma as both intracardiac and pericardial mass with massive pericardial effusion: a rare presentation. PMID- 23916930 TI - Wearable cardioverter-defibrillator use in patients perceived to be at high risk early post-myocardial infarction. AB - OBJECTIVES: The aim of this study was to describe usage of the wearable cardioverter-defibrillator (WCD) during mandated waiting periods following myocardial infarction (MI) for patients perceived to be at high risk for sudden cardiac arrest (SCA). BACKGROUND: Current device guidelines and insurance coverage require waiting periods of either 40 days or 3 months before implanting a cardioverter-defibrillator post-myocardial infarction (MI), depending on whether or not acute revascularization was undertaken. METHODS: We assessed characteristics of and outcomes for patients who had a WCD prescribed in the first 3 months post-MI. The WCD medical order registry was searched for patients who were coded as having had a "recent MI with ejection fraction <=35%" or given an International Classification of Diseases, Ninth Revision 410.xx diagnostic code (acute MI), and then matched to device-recorded data. RESULTS: Between September 2005 and July 2011, 8,453 unique patients (age 62.7 +/- 12.7 years, 73% male) matched study criteria. A total of 133 patients (1.6%) received 309 appropriate shocks. Of these patients, 91% were resuscitated from a ventricular arrhythmia. For shocked patients, the left ventricular ejection fraction (LVEF) was <=30% in 106, 30% to 35% in 17, >36% in 8, and not reported in 2 patients. Of the 38% of patients not revascularized, 84% had a LVEF <=30%; of the 62% of patients revascularized, 77% had a LVEF <=30%. The median time from the index MI to WCD therapy was 16 days. Of the treated patients, 75% received treatment in the first month, and 96% within the first 3 months of use. Shock success resulting in survival was 84% in nonrevascularized and 95% in revascularized patients. CONCLUSIONS: During the 40-day and 3-month waiting periods in patients post-MI, the WCD successfully treated SCA in 1.4%, and the risk was highest in the first month of WCD use. The WCD may benefit individual patients selected for high risk of SCA early post-MI. PMID- 23916931 TI - Is the wearable cardioverter-defibrillator the answer for early post-myocardial infarction patients at risk for sudden death?: mind the gap. PMID- 23916927 TI - Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study. AB - OBJECTIVES: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. BACKGROUND: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. METHODS: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. RESULTS: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. CONCLUSIONS: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events. PMID- 23916932 TI - Fat, cachexia, and the right ventricle in heart failure: a web of complicity. PMID- 23916933 TI - Relationships between right ventricular function, body composition, and prognosis in advanced heart failure. AB - OBJECTIVES: This study sought to examine the relationships between right ventricular (RV) function, body composition, and prognosis in patients with advanced heart failure (HF). BACKGROUND: Previous studies investigating HF related cachexia have not examined the impact of RV function on body composition. We hypothesized that RV dysfunction is linked to weight loss, abnormal body composition, and worsened prognosis in advanced HF. METHODS: Subjects with advanced HF (n = 408) underwent prospective assessment of body composition (skinfold thickness, dual-energy X-ray absorptiometry), comprehensive echocardiography, and blood testing. Subjects were followed up for adverse events (defined as death, transplantation, or circulatory assist device). RESULTS: Subjects with RV dysfunction (51%) had lower body mass index, lower fat mass index, and were more likely to display cachexia (19%). The extent of RV dysfunction correlated with greater antecedent weight loss and a lower fat/lean body mass ratio. Over a median follow-up of 541 days, there were 150 events (37%). Risk of event was greater in subjects with RV dysfunction (hazard ratio: 3.09 [95% confidence interval (CI): 2.18 to 4.45]) and cachexia (hazard ratio: 2.90 [95% CI: 2.00 to 4.12]) in univariate and multivariate analyses. Increased body mass index was associated with a lower event rate (HR per kg/m(2): 0.92 [95% CI: 0.88 to 0.96]), and this protection was mediated by a higher fat mass (0.91 [95% CI: 0.87 to 0.96]) but not a fat-free mass index (0.97 [95% CI: 0.92 to 1.03]). CONCLUSIONS: RV dysfunction and cardiac cachexia often coexist, have additive adverse impact, and might be mechanistically interrelated. Wasting of fat but not of lean mass was predictive of adverse outcome, suggesting that fat loss is either a surrogate of enhanced catabolism or adipose tissue is cardioprotective in the context of HF. PMID- 23916934 TI - The disconnect between the guidelines, the appropriate use criteria, and reimbursement coverage decisions: the ultimate dilemma. AB - Recently, the American College of Cardiology Foundation in collaboration with the Heart Rhythm Society published appropriate use criteria (AUC) for implantable cardioverter-defibrillators and cardiac resynchronization therapy. These criteria were developed to critically review clinical situations that may warrant implantation of an implantable cardioverter-defibrillator or cardiac resynchronization therapy device, and were based on a synthesis of practice guidelines and practical experience from a diverse group of clinicians. When the AUC was drafted, the writing committee recognized that some of the scenarios that were deemed "appropriate" or "may be appropriate" were discordant with the clinical requirements of many payers, including the Medicare National Coverage Determination (NCD). To charge Medicare for a procedure that is not covered by the NCD may be construed as fraud. Discordance between the guidelines, the AUC, and the NCD places clinicians in the difficult dilemma of trying to do the "right thing" for their patients, while recognizing that the "right thing" may not be covered by the payer or insurer. This commentary addresses these issues. Options for reconciling this disconnect are discussed, and recommendations to help clinicians provide the best care for their patients are offered. PMID- 23916936 TI - Persistence of atrial septal defect after cryoballoon ablation of atrial fibrillation. PMID- 23916935 TI - Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). AB - OBJECTIVES: This study sought to examine the relationship between niacin treatment, lipoproteins, and cardiovascular (CV) outcomes in this secondary analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial. BACKGROUND: During a 3-year follow-up in 3,414 patients with established CV disease and low high-density lipoprotein cholesterol (HDL-C) levels, combined niacin + low-density lipoprotein cholesterol (LDL-C)-lowering therapy did not reduce CV events compared with LDL-C-lowering therapy alone. METHODS: Subjects taking simvastatin and/or ezetimibe were randomized to receive extended-release (ER) niacin 1,500 to 2,000 mg or minimal immediate-release niacin (<= 150 mg) as placebo at bedtime. LDL-C levels in both groups were maintained from 40 to 80 mg/dl. Hazard ratios were estimated by using Cox proportional hazards models for relationships between lipoproteins and the composite endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom driven revascularization. RESULTS: CV outcomes were not associated with ER niacin in any baseline lipoprotein tertile. In a subset of patients in both the highest triglyceride (>= 198 mg/dl) and lowest HDL-C (<33 mg/dl) tertiles, ER niacin showed a trend toward benefit (hazard ratio: 0.74, p = 0.073). In-trial LDL-C levels, non-HDL-C levels, and the total cholesterol/HDL-C ratio were positively associated with CV events in the control group, but these relationships were absent in the ER niacin group. CONCLUSIONS: Baseline lipoprotein tertiles did not predict differential benefit or harm with ER niacin added to LDL-C-lowering therapy, but a small dyslipidemic subgroup may benefit. ER niacin attenuated expected relationships of lipoprotein risk factors with CV events, raising the possibility that nonlipoprotein actions of niacin could affect risk. (Niacin Plus Statin to Prevent Vascular Events [AIM-HIGH]; NCT00120289). PMID- 23916937 TI - N-terminal pro-B-type natriuretic peptide and its relationship with cardiac function in adults with congenital heart disease. AB - OBJECTIVES: The aim of this study was to determine the value of N-terminal pro-B type natriuretic peptide (NT-proBNP) in adults with congenital heart disease (CHD) and investigate its relationship with ventricular function and exercise capacity. BACKGROUND: NT-proBNP may detect early deterioration in cardiac function. METHODS: In this cross-sectional study, extensive echocardiography, exercise testing, and NT-proBNP measurements were performed on the same day in consecutive adult patients with CHD. RESULTS: In total, 475 patients were included in this study (mean age of 34 +/- 12 years, 57% male, 90% New York Heart Association class I). The median NT-proBNP level was 15.1 pmol/l (interquartile range [IQR]: 7.1 to 31.3 pmol/l), and the NT-proBNP level was >14 pmol/l in 53% of patients. The highest NT-proBNP levels were observed in patients with Fontan circulation (36.1 pmol/l [IQR: 14.4 to 103.8 pmol/l]) and a systemic right ventricle (RV) (31.1 pmol/l [IQR: 21.8 to 56.0 pmol/l]), and the lowest values were seen in patients with aortic coarctation (7.3 pmol/l [IQR: 2.8 to 19.5 pmol/l]). NT-proBNP levels correlated with age (r = 0.39, p < 0.001) and were higher in women (median of 21.7 vs. 10.4 pmol/l; p < 0.001). In patients with aortic stenosis or aortic coarctation, NT-proBNP levels correlated with diastolic function parameters of E/E' ratio (r = 0.40, p < 0.001) and left atrial dimension (r = 0.36, p < 0.001). In patients with a systemic RV, NT-proBNP levels correlated with RV annulus diameter (r = 0.31, p = 0.024). In patients with tetralogy of Fallot, the strongest correlations were observed with left atrial dimension (r = 0.46, p < 0.001) and left ventricular ejection fraction (r = 0.37, p < 0.001). NT-proBNP levels were associated with exercise capacity (n = 198) (maximum workload: beta = -0.08, p = 0.021) and peak oxygen uptake (beta = 0.012, p = 0.011) in a multivariable regression model adjusted for age and sex. CONCLUSIONS: NT-proBNP levels in adults with CHD clearly differ by diagnosis and are related to echocardiographic parameters and exercise capacity. Disease specific correlations contribute to the understanding of the main hemodynamic problems per diagnosis. Follow-up data are needed to elucidate the additional prognostic value. PMID- 23916939 TI - The year in atherothrombosis. PMID- 23916938 TI - Prognostic stratification of patients with vasospastic angina: a comprehensive clinical risk score developed by the Japanese Coronary Spasm Association. AB - OBJECTIVES: The present study aimed to develop a comprehensive clinical risk score for vasospastic angina (VSA) patients. BACKGROUND: Previous studies demonstrated various prognostic factors of future adverse events in VSA patients. However, to apply these prognostic factors in clinical practice, the assessment of their accumulation in individual patients is important. METHODS: The patient database of the multicenter registry study by the Japanese Coronary Spasm Association (JCSA) (n = 1,429; median 66 years; median follow-up 32 months) was utilized for score derivation. RESULTS: Multivariable Cox proportional hazard model selected 7 predictors of major adverse cardiac events (MACE). The integer score was assigned to each predictors proportional to their respective adjusted hazard ratio; history of out-of-hospital cardiac arrest (4 points), smoking, angina at rest alone, organic coronary stenosis, multivessel spasm (2 points each), ST-segment elevation during angina, and beta-blocker use (1 point each). According to the total score in individual patients, 3 risk strata were defined; low (score 0 to 2, n = 598), intermediate (score 3 to 5, n = 639) and high (score 6 or more, n = 192). The incidences of MACE in the low-, intermediate-, and high risk patients were 2.5%, 7.0%, and 13.0%, respectively (p < 0.001). The Cox model for MACE between the 3 risk strata also showed prognostic utility of the scoring system in various clinical subgroups. The average prediction rate of the scoring system in the internal training and validation sets were 86.6% and 86.5%, respectively. CONCLUSIONS: We developed a novel scoring system, the JCSA risk score, which may provide the comprehensive risk assessment and prognostic stratification for VSA patients. PMID- 23916940 TI - Efficacy, safety, and outcomes of catheter ablation of atrial fibrillation in patients with heart failure with preserved ejection fraction. AB - OBJECTIVES: This study sought to investigate the efficacy and safety of catheter ablation for atrial fibrillation (AF) in patients with heart failure with preserved ejection fraction (HFPEF). BACKGROUND: AF is a precipitating factor for clinical deterioration of HFPEF. METHODS: Catheter ablation for AF was performed in a consecutive 74 patients with compensated HFPEF (left ventricular [LV] ejection fraction >50%). AF-free probability after catheter ablation and factors relating to maintenance of sinus rhythm were investigated. LV strain and strain rate were assessed by echocardiography at baseline and over 12 months after ablation. RESULTS: During a 34 +/- 16-month follow-up period, single- and multiple-procedure drug-free success rates were 27% (n = 20) and 45% (n = 33), respectively. Multiple procedures and pharmaceutically assisted success rate was 73% (n = 54). No major complications occurred during follow-up. Multivariate Cox regression analyses revealed that AF type (other than long-standing persistent AF) and lack of hypertension were independently associated with maintenance of sinus rhythm (hazard ratio [HR]: 1.81, 95% confidence interval [CI]: 1.03 to 3.17, p = 0.04; HR: 0.49, 95% CI: 0.24 to 0.96, p = 0.04, respectively). LV systolic indices (LV ejection fraction, LV strain/strain rate at systole) and diastolic indices (E/E', ratio of LV strain rate at diastole with early transmitral flow) were improved only in patients maintaining sinus rhythm at follow-up. CONCLUSIONS: Our results suggest that AF can be effectively and safely treated with a composite of repeat procedures and pharmaceuticals in patients with HFPEF. However, the current study was a single-arm analysis; therefore, larger randomized control studies are needed to verify the benefit of AF ablation in this cohort. PMID- 23916941 TI - Warfarin ridge: an unusual location of benign papillary fibroelastoma. PMID- 23916942 TI - Does fertility therapy hamper cardiovascular outcome? PMID- 23916944 TI - MicroRNA 23b regulates autophagy associated with radioresistance of pancreatic cancer cells. AB - BACKGROUND & AIMS: Tumor resistance to radiation is a challenge in the treatment of patients with pancreatic cancer. Improving our understanding of the mechanisms of radioresistance could lead to strategies to increase patients' response to therapy. We investigated the roles of microRNAs (miRNAs) involved in radioresistance of pancreatic cancer cells. METHODS: We established radioresistant pancreatic cancer cell lines and used array analysis to compare levels of different miRNAs between radioresistant cell lines and the parental cell lines from which they were derived. We transfected pancreatic cancer cells with miRNA mimics or inhibitors and evaluated their effects on cell radiosensitivity using a clonogenic survival assay. The effects of miRNA on autophagy were determined by transmission electron microscopy and immunoblot analysis. We used a luciferase reporter assay to identify messenger RNA targets of specific miRNAs. RESULTS: Radioresistant pancreatic cancer cells had reduced levels of the miRNA miR-23b and increased autophagy compared with cells that were not radioresistant. Overexpression of miR-23b inhibited radiation-induced autophagy, whereas an inhibitor of miR-23b promoted autophagy in pancreatic cancer cells. Overexpression of miR-23b sensitized pancreatic cancer cells to radiation. The target of miR-23b, ATG12, was overexpressed in radioresistant cells; levels of ATG12 protein correlated with the occurrence of autophagy. Expression of miR-23b blocked radiation-induced autophagy and sensitized pancreatic cancer cells to radiation. We observed an inverse correlation between the level of miR-23b and autophagy in human pancreatic cancer tissue samples. CONCLUSIONS: In pancreatic cancer cells, reduced levels of the miRNA miR-23b increase levels of ATG12 and autophagy to promote radioresistance. miR-23b might be used to increase the sensitivity of pancreatic cancer cells to radiation therapy. PMID- 23916943 TI - Associations between prenatal cigarette smoke exposure and externalized behaviors at school age among Inuit children exposed to environmental contaminants. AB - BACKGROUND: Smoking during pregnancy is common among Inuit women from the Canadian Arctic. Yet prenatal cigarette smoke exposure (PCSE) is seen as a major risk factor for childhood behavior problems. Recent data also suggest that co exposure to neurotoxic environmental contaminants can exacerbate the effects of PCSE on behavior. This study examined the association between PCSE and behavior at school age in a sample of Inuit children from Nunavik, Quebec, where co exposure to environmental contaminants is also an important issue. Interactions with lead (Pb) and mercury (Hg), two contaminants associated with behavioral problems, were also explored. METHODS: Participants were 271 children (mean age=11.3years) involved in a prospective birth-cohort study. PCSE was assessed through maternal recall. Assessment of child behavior was obtained from the child's classroom teacher on the Teacher Report Form (TRF) and the Disruptive Behavior Disorders Rating Scale (DBD). Exposure to contaminants was assessed from umbilical cord and child blood samples. Other confounders were documented by maternal interview. RESULTS: After control for contaminants and confounders, PCSE was associated with increased externalizing behaviors and attention problems on the TRF and higher prevalence of attention deficit hyperactivity disorder (ADHD) assessed on the DBD. No interactions were found with contaminants. INTERPRETATION: This study extends the existing empirical evidence linking PCSE to behavioral problems in school-aged children by reporting these effects in a population where tobacco use is normative rather than marginal. Co-exposure to Pb and Hg do not appear to exacerbate tobacco effects, suggesting that these substances act independently. PMID- 23916945 TI - Characterization of the swine U6 promoter for short hairpin RNA expression and its application to inhibition of virus replication. AB - Expression of short hairpin RNAs (shRNAs) by the RNA polymerase type III U6 promoter is an effective and widely used strategy for RNA interference (RNAi) which is a sequence-specific gene silencing mechanism. The U6 promoters from human, mouse, and swine were cloned, respectively for constructing various shRNA expression vectors. The transcription efficiency of each U6 promoter was analyzed for its activity to drive expression of shRNA targeting enhanced green fluorescent protein (EGFP) mRNA in different mammalian cells. All three U6 promoters were functional and the swine U6 promoter demonstrated the most efficient knockdown of EGFP synthesis in all these three species of cell lines including porcine kidney (PK-15), human embryonic kidney (HEK293T), and mouse fibroblast (LM) cells. Furthermore, the antiviral effect of shRNA targeting the classical swine fever virus (CSFV) NS5B driven by the swine U6 promoter was confirmed by the significant reduction of virus replication. PMID- 23916946 TI - Computational design of short-chain dehydrogenase Gox2181 for altered coenzyme specificity. AB - Short-chain dehydrogenase Gox2181 from Gluconobacter oxydans catalyzes the reduction of 2,3-pentanedione by using NADH as the physiological electron donor. To realize its synthetic biological application for coenzyme recycling use, computational design and site-directed mutagenesis have been used to engineer Gox2181 to utilize not only NADH but also NADPH as the electron donor. Single and double mutations at residues Q20 and D43 were made in a recombinant expression system that corresponded to Gox2181-D43Q and Gox2181-Q20R&D43Q, respectively. The design of mutant Q20R not only resolved the hydrogen bond interaction and electrostatic interaction between R and 2'-phosphate of NADPH, but also could enhance the binding with 2'-phophated of NADPH by combining with D43Q. Molecular dynamics simulation has been carried out to testify the hydrogen bond interactions between mutation sites and 2'-phosphate of NADPH. Steady-state turnover measurement results indicated that Gox2181-D43Q could use both NADH and NADPH as its coenzyme, and so could Gox2181-Q20R&D43Q. Meanwhile, compared to the wild-type enzyme, Gox2181-D43Q exhibited dramatically reduced enzymatic activity while Gox2181-Q20R&D43Q successfully retained the majority of enzymatic activity. PMID- 23916947 TI - Size unlimited markerless deletions by a transconjugative plasmid-system in Bacillus licheniformis. AB - Conjugative shuttle vectors of the pKVM series, based on an IncP transfer origin and the pMAD vector with a temperature sensitive replication were constructed to establish a markerless gene deletion protocol for Bacilli without natural competence such as the exoenzyme producer Bacillus licheniformis. The pKVM plasmids can be conjugated to strains of B. licheniformis and B. subtilis. For chromosomal gene deletion, regions flanking the target gene are fused and cloned in a pKVM vector prior to conjugative transfer from Escherichia coli to B. licheniformis. Appropriate markers on the vector backbone allow for the identification of the integration at the target locus and thereafter the vector excision, both events taking place via homologous recombination. The functionality of the deletion system was demonstrated with B. licheniformis by a markerless 939 bp in-frame deletion of the yqfD gene and the deletion of a 31 kbp genomic segment carrying a PBSX-like prophage. PMID- 23916948 TI - Multivariate modular metabolic engineering of Escherichia coli to produce resveratrol from L-tyrosine. AB - Microbial fermentations and bioconversion promise to revolutionize the conventional extraction of resveratrol from natural plant sources. However, the development of efficient and feasible microbial processes remains challenging. Current fermentation strategies often require supplementation of expensive phenylpropanoic precursors and two separate fermentation protocols, which are significantly more difficult and expensive to undertake when migrating to large scale fermentation processes. In this study, an Escherichia coli fermentation system, consisting of tyrosine ammonia lyase (TAL), 4-coumarate:CoA ligase (4CL), stilbene synthase (STS), malonate synthetase, and malonate carrier protein, was developed to produce resveratrol from L-tyrosine. Multivariate modular metabolic engineering, which redefined the overall pathway as a collection of distinct modules, was employed to assess and alleviate pathway bottlenecks. Using this strategy, the optimum strain was capable of producing 35.02 mg/L of resveratrol from L-tyrosine in a single medium. The strategy described here paves the way to the development of a simple and economical process for microbial production of resveratrol and other similar stilbene chemicals. PMID- 23916949 TI - A novel non-hydrolytic protein from Pseudomonas oryzihabitans enhances the enzymatic hydrolysis of cellulose. AB - Several kinds of protein such as the expansin, expansin-like proteins and LPMOs (lytic polysaccharide monooxygenases) are known to exert enhancement effects on cellulase activity. In this study, a novel cellulase synergistic protein named POEP1 was purified from the culture filtrate of Pseudomonas oryzihabitans CGMCC 6169, and was homogeneous on SDS-PAGE with a molecular weight of 60kDa. Mass spectrometry analysis indicated that it was an unknown protein without sequence similarity to the expansin and expansin-like proteins. Evaluation of the enzymatic hydrolysis of filter paper revealed that POEP1 had no cellulase activity but displayed high synergistic activity of 364% at a cellulase concentration of 0.1FPU/g of filter paper. When a mixture containing 0.6FPU cellulase and 700MUg POEP1 per g of cellulose was evaluated, the maximal sugar yield was achieved, which was 2.2-fold greater than that with the cellulase alone. POEP1 was found to have functional similarity to the expansin and expansin like proteins, which could decrease both the hydrogen-bond intensity and crystallinity, and cause the filter paper disruption. This study provided evidence for the existence of novel bacterial proteins in nature serving the same function as expansin and expansin-like proteins. PMID- 23916950 TI - Herpes virus in Alzheimer's disease: relation to progression of the disease. AB - Studies regarding different viruses of the herpes family, such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), or human herpes virus 6 (HHV-6) in Alzheimer's disease (AD) are scarce. DNA from peripheral blood leukocytes (PBL) and brain samples were analyzed for the presence of CMV, EBV, or HHV-6. All samples were negative for CMV. EBV positivity was 6% in AD brains, whereas 45% of PBL samples from AD patients and 31% from controls were positive for EBV (p = 0.05). HHV-6 showed a 23% positivity in PBL samples from AD and 4% from controls (p = 0.002). 17% of AD brains were HHV-6 positive. Within a group of elderly individuals, followed up for 5 years, EBV-positive or HHV-6-positive PBL increased in those who developed clinical AD. Virus serological positivity was also investigated, and IgG levels for CMV and EBV antigens were also increased in those subjects who developed AD during the follow-up. Our findings suggest that EBV and HHV-6 may be environmental risk factors for cognitive deterioration and progression to AD in elderly persons. PMID- 23916952 TI - Immobilized humic substances and immobilized aggregates of humic substances as sorbent for solid phase extraction. AB - In this work, humic substances (HS) immobilized, as a thin layer or as aggregates, on silica gel were tested as material for solid phase extraction. Some triazines (simazine, atrazine, therbutylazine, atrazine-desethyl desisopropyl-2-hydroxy, ametryn and terbutryn), have been selected as test analytes due to their environmental importance and to span a large range of solubility and octanol/water partition coefficient (logP). The sorbent was obtained immobilizing a thin layer of HS via physisorption on a pre-coated silica gel with a cationic polymer (polybrene). While the sorbent could be used as it is, it was demonstrated that additional HS could be immobilized, via weak interactions, to form stable humic aggregates. However, while a higher quantity of HS could be immobilized, no significant differences were observed in the sorption parameters. This sorbent have been tested for solid phase extraction to concentrate triazines from aqueous matrixes. The sorbent demonstrated performances equivalent to commercial alternatives as a concentration factor between 50 and 200, depending on the type of triazines, was obtained. Moreover the low cost and the high flow rate of sample through the column allowed using high quantity of sorbent. The analytical procedure was tested with different matrixes including tap water, river water and estuarine water. PMID- 23916951 TI - The Dynamic Multiprocess Framework: evidence from prospective memory with contextual variability. AB - The ability to remember to execute delayed intentions is referred to as prospective memory. Previous theoretical and empirical work has focused on isolating whether a particular prospective memory task is supported either by effortful monitoring processes or by cue-driven spontaneous processes. In the present work, we advance the Dynamic Multiprocess Framework, which contends that both monitoring and spontaneous retrieval may be utilized dynamically to support prospective remembering. To capture the dynamic interplay between monitoring and spontaneous retrieval, we had participants perform many ongoing tasks and told them that their prospective memory cue may occur in any context. Following either a 20-min or a 12-h retention interval, the prospective memory cues were presented infrequently across three separate ongoing tasks. The monitoring patterns (measured as ongoing task cost relative to a between-subjects control condition) were consistent and robust across the three contexts. There was no evidence for monitoring prior to the initial prospective memory cue; however, individuals who successfully spontaneously retrieved the prospective memory intention, thereby realizing that prospective memory cues could be expected within that context, subsequently monitored. These data support the Dynamic Multiprocess Framework, which contends that individuals will engage monitoring when prospective memory cues are expected, disengage monitoring when cues are not expected, and that when monitoring is disengaged, a probabilistic spontaneous retrieval mechanism can support prospective remembering. PMID- 23916954 TI - Development of novel amphiphilic magnetic molecularly imprinted polymers compatible with biological fluids for solid phase extraction and physicochemical behavior study. AB - In the present work, a novel amphiphilic magnetic molecularly imprinted polymer (M-MIP) has been synthesized by a simple non covalent method for the loading of gatifloxacin (GTFX) in polar solvent. This nanomaterial used as sorbent has been applied to the solid phase extraction of GTFX in different spiked biological fluids. For the first time, studies of dispersibility and solubility behaviors with different solvents and water were performed to demonstrate amphiphilicity and also to find the better nanomaterial obtained. Fourier transform infrared (FT IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X-ray (XRD) were used to characterize the nanomaterials, and Scatchard plot analysis to demonstrate the binding kinetic. Results suggest that the dispersibility, solubility and the adsorption in water have relationships with the structure of nanomaterials prepared. The oleic acid coated on the M-MIP combined with the washing process has enhanced the amphiphilicity of the nanomaterials. The M-MIP2 showed better selectivity and adsorption behavior with imprinted efficiency higher than (2) in water, as well as in biological fluids. Moreover, no interference with constituents of blank urine and blank serum samples for solid phase extraction (SPE) was observed. Moreover, loading recovery was found higher than 95% with low RSD. The novel amphiphilic magnetic nanomaterial prepared here as sorbent is suitable for SPE of GTFX in biological fluids for therapeutic monitoring control. It could be also used as carrier in drug delivery system for experimental and clinical studies. PMID- 23916953 TI - Dynamic binding capacity and specificity of 3,8-diamino-6-phenylphenanthridine Sepharose support for purification of supercoiled plasmid deoxyribonucleic acid. AB - Affinity chromatography represents a sole technique in purification of different biomolecules. The specific recognition between affinity ligands and target biomolecules has a major role in the specificity of the process. Therefore, choosing the right ligand is a crucial step for the development of a successful purification system. This work describes the application of the DNA intercalator 3,8-diamino-6-phenylphenanthridine (DAPP) as a chromatographic affinity ligand for the specific separation and purification of supercoiled plasmid DNA (pDNA). The support was prepared by coupling DAPP onto an epoxy-activated Sepharose matrix, using mild conditions and resulting in a ligand density of 0.15mmolDAPP/g derivatized Sepharose. The characterization of DAPP-Sepharose support in terms of dynamic binding capacity was achieved by studying the effect of plasmid DNA concentration and flow rate on pDNA adsorption. The maximum capacity value of 336.75MUgpDNA/mL gel was obtained at 1mL/min with a pDNA concentration of 150MUg/mL. Moreover, the values did not vary significantly with the variation of flow rate. In addition, the DAPP-Sepharose showed a high affinity towards pDNA as quantified by the respective dissociation constant (Kd=2.29+/-0.195*10(-7)M). The support was also tested for the purification of two plasmid molecules with different sizes (pVAX1-LacZ and pCAMBIA-1303, with 6.05kbp and 12.361kbp, respectively) from clarified Escherichia coli lysate solutions. Total retention of all lysate components was achieved without any added salt to the eluent buffer. The selective elution of impurities and supercoiled pDNA was accomplished simply by the addition of small amounts of salt to the buffer solution. The yield for pCAMBIA-1303 was 65% and for pVAX1-LacZ was 94%, with all host impurity levels in accordance with the requirements established by the regulatory agencies. PMID- 23916955 TI - Full thickness endoscopic resection of a colonic cancer: a case report. AB - We present a case of a 40-year-old woman, diagnosed with a flat lesion (type 0 IIa+IIc) of the colon. There was a strong suspicion for submucosal invasion, however the patient initially refused surgical intervention. Therefore, the lesion was treated with full-thickness endoscopic resection. An over-the-scope clip device was applied to seal the resulting colonic wall defect. Histological examination demonstrated a T2 adenocarcinoma, therefore the patient agreed to a left hemicolectomy. Examination of the surgical specimen demonstrated no residual neoplasia or involvement of adjacent lymph nodes. We discuss the potential advantages and limitations of this new approach, which may be indicated for patients who are not surgical candidates. PMID- 23916956 TI - Expression and/or activity of the SVCT2 ascorbate transporter may be decreased in many aggressive cancers, suggesting potential utility for sodium bicarbonate and dehydroascorbic acid in cancer therapy. AB - Hypoxia-inducible factor-1 (HIF-1) is a heterodimer transcription factor whose elevated activity in many cancers helps them to survive under hypoxic conditions and enhances their capacity to grow invasively, establish metastases, and survive chemo- or radiotherapy. Optimal intracellular levels of ascorbate suppress the level and transcriptional activity of HIF-1under normoxic or mildly hypoxic conditions by supporting the activity of proly and asparagyl hydroxylases that target HIF-1alpha. High intracellular ascorbate can also work in various ways to down-regulate activation of NF-kappaB which, like HIF-1 is constitutively active in many cancers and promotes aggressive behavior - in part by promoting transcription of HIF-1alpha. Yet recent evidence suggests that, even in the context of adequate ascorbate nutrition, the intracellular ascorbate content of many aggressive cancers may be supoptimal for effective HIF-1 control. This likely reflects low expression or activity of the SVCT2 ascorbate transporter. The expression of SVCT2 in cancers has so far received little study; but the extracellular acidity characteristic of many tumors would be expected to reduce the activity of this transporter, which has a mildly alkaline pH optimum. Unfortunately, since SVCT2 has a high affinity for ascorbate, and its activity is nearly saturated at normal healthy serum levels of this vitamin, increased oral administration of ascorbate would be unlikely to have much impact on the intracellular ascorbate content of tumors. However, cancers in which HIF-1 is active express high levels of glucose transporters such as GLUT-1, and these transporters can promote influx of dehydroascorbic acid (DHA) via facilitated diffusion; once inside the cell, DHA is rapidly reduced to ascorbate, which effectively is "trapped" within the cell. Hence, episodic intravenous infusions of modest doses of DHA may have potential for optimizing the intracellular ascorbate content of cancers, potentially rendering them less aggressive. Indeed, several published studies have concluded that parenteral DHA--sometimes in quite modest doses--can retard the growth of transplanted tumors in rodents. As an alternative or adjunctive strategy, oral administration of sodium bicarbonate, by normalizing the extracellular pH of tumors, has the potential to boost the activity of SCTV2 in tumor cells, thereby promoting increased ascorbate uptake. Indeed, the utility of oral sodium bicarbonate for suppressing metastasis formation in nude mice xenografted with a human breast cancer has been reported. Hence, oral sodium bicarbonate and intravenous DHA may have the potential to blunt the aggressiveness of certain cancers in which suboptimal intracellular ascorbate levels contribute to elevated HIF-1 activity. PMID- 23916957 TI - Effects of different lairage times after long distance transportation on carcass and meat quality characteristics of Hungarian Simmental bulls. AB - The objective of this study was to determine the effects of three lairage times (24 h, 48 h and 72 h) on the meat quality of tame trained to lead Hungarian Simmental bulls subjected to long commercial transportation of approximately 1800 km. A total of 30 bulls, with an average age of 24 months, were used. During the lairage, bulls received 0.5 kg concentrate feed per animal per day and ad libitum access to the hay and water. As the lairage duration increased, the pH(ult) decreased (P<0.05). Bulls lairaged for 24 h had lower L*, b* and H* values than those lairaged for 48 h and 72 h (P<0.05). The effect of lairage time on WHC, cooking loss and Warner-Bratzler shear force values was not significant. The b* value was considered the best predictor of muscle pH(ult). In conclusion, 72 h quiet lairage time is recommended after transportation in order to prevent the adverse effects of transportation on meat quality. PMID- 23916958 TI - Amino acid and nucleotide contents and sensory traits of dry-cured products from pigs with different genotypes. AB - The free amino acid and nucleotide contents of dry-cured ham, shoulder and loin from two genetic lines selected from pigs according to the paternal allele (homozygous AA and heterozygous AG) of the insulin-like growth factor-II gene were studied by HPLC. Their influence on the flavor and taste characteristics was also studied. The increase of lean content caused by the IGF-II mutation could affect proteolysis during the ripening process and therefore the sensory characteristics. The lower intramuscular fat content in the AA ham batch had a positive effect on the free amino acid content. However, similar flavor traits between ham batches were found, but the AG loin batch showed greater value. The enhancing effect of the IMP on the overall flavor intensity was limited by the amino acid and the IMF contents in dry-cured ham and loin, while in dry-cured shoulder, the IMP could be the reason for the significant differences in after taste and cured flavor scores. PMID- 23916959 TI - Effects of hot boning and moisture enhancement on the eating quality of cull cow beef. AB - The effects of chilling method and moisture enhancement were examined for improving eating quality of semimembranosus (SM) and longissimus lumborum (LL) from 62 cull beef cows. Chilling method included hot boning muscles after 45 to 60 min postmortem or conventional chilling for 24 h. Moisture enhancement included 1) a non-injected control (CONT) or injection processing (10% of product weight) using 2) Sodium Tripolyphosphate/salt (Na/STP), 3) Sodium Citrate (NaCIT), 4) Calcium Ascorbate (CaASC), or 5) Citrus Juices (CITRUS). Chilling method by moisture enhancement treatment interactions (P<0.09) were due to decreased hue, chroma and sarcomere length values in hot boned vs. conventionally chilled product (SM and LL) for CaASC vs. other moisture enhancement treatments. Chilling method by moisture enhancement treatment interactions (P<0.05) were due to decreased shear force and increased tenderness in conventionally chilled vs. hot boned LL using CaASC vs. Na/STP. Moisture enhancement can improve tenderness of cull cow beef depending on combinations of chilling method and moisture enhancement treatments used. PMID- 23916960 TI - Changes on physico-chemical, textural, lipolysis and volatile compounds during the manufacture of dry-cured foal "cecina". AB - The changes in the physico-chemical and textural properties, lipolysis and volatile compounds during the manufacture of dry-cured foal "cecina" were studied. The pH increased during the last stages of processing but gradually declined over the curing period. TBARS values, hardness and chewiness increased with processing time from 0.14, 2.74 and 0.83 to 3.49 mg malonaldehyde/kg, 20.33 kg and 5.05 kg*mm, respectively. Ripening time also affected the colour parameters: lightness (L*), redness (a*) and yellowness (b*) (P<0.001). The total average content of free fatty acid (FFA) increased significantly from 433.7 mg/100 g of fat in the raw pieces to 2655.5 mg/100 g of fat at the end of the drying-ripening stage. The main FFA at the end of the manufacturing process was palmitic acid (C16:0), followed by oleic (C18:1cis9), stearic (C18:0) and linoleic (C18:2n-6). A total of fifty five volatile compounds were identified during the manufacture of dry-cured foal "cecina", including esters, aldehydes, aliphatic hydrocarbons, branched hydrocarbons, alcohols, aromatic hydrocarbons, furans, ketones. Aldehydes reached their maximum level at the end of the post salting stage. In the final product, esters became the dominant chemical compounds. PMID- 23916961 TI - Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo. AB - OBJECTIVE: Bile acids are important regulators of intestinal physiology, and the nuclear bile acid receptor, farnesoid X receptor (FXR), is emerging as a promising therapeutic target for several intestinal disorders. Here, we investigated a role for FXR in regulating intestinal fluid and electrolyte transport and the potential for FXR agonists in treating diarrhoeal diseases. DESIGN: Electrogenic ion transport was measured as changes in short-circuit current across voltage-clamped T84 cell monolayers or mouse tissues in Ussing chambers. NHE3 activity was measured as BCECF fluorescence in Caco-2 cells. Protein expression was measured by immunoblotting and cell surface biotinylation. Antidiarrhoeal efficacy of GW4064 was assessed using two in vivo mouse models: the ovalbumin-induced diarrhoea model and cholera toxin (CTX)-induced intestinal fluid accumulation. RESULTS: GW4064 (5 MUmol/L; 24 h), a specific FXR agonist, induced nuclear translocation of the receptor in T84 cells and attenuated Cl(-) secretory responses to both Ca(2+) and cAMP-dependent agonists. GW4064 also prevented agonist-induced inhibition of NHE3 in Caco-2 cells. In mice, intraperitoneal administration of GW4064 (50 mg/mL) also inhibited Ca(2+) and cAMP-dependent secretory responses across ex vivo colonic tissues and prevented ovalbumin-induced diarrhoea and CTX-induced intestinal fluid accumulation in vivo. At the molecular level, FXR activation attenuated apical Cl(-) currents by inhibiting expression of cystic fibrosis transmembrane conductance regulator channels and inhibited basolateral Na(+)/K(+)-ATPase activity without altering expression of the protein. CONCLUSIONS: These data reveal a novel antisecretory role for the FXR in colonic epithelial cells and suggest that FXR agonists have excellent potential for development as a new class of antidiarrheal drugs. PMID- 23916962 TI - Evaluation of antiplasmodial activity of green synthesized silver nanoparticles. AB - In the present study silver nanoparticles (silver(np)) were synthesized from AgNO3 through simple green routes using either purified Alpha Amylase or aqueous leaf extracts of Ashoka and Neem respectively. The use of plant extract/enzyme for synthesis of nanoparticles is a single-step, cost effective and eco-friendly process. The silver(np) obtained by these three different ways were characterized using UV-visible spectroscopy, DLS, TEM, XRD and FTIR. These nanoparticles were found to be antiplasmodial with IC50 (MUg/ml) 3.75 (Amylase(np)), 8 (Ashoka(np)) and 30 (Neem(np)) whereas plant extracts or amylase alone did not show any activity up to 40 MUg/ml. Although AgNO3 was also found to have intrinsic antiplasmodial activity (IC50 0.5 MUg/ml), the hemolytic tendencies appeared to be higher for AgNO3 (MHC10: 10 MUg/ml) against the nanoparticulate preparations (MHC10: >40 MUg/ml). PMID- 23916963 TI - Oligoamines grafted hyperbranched polyether as high efficient and serum-tolerant gene vectors. AB - To develop low toxic, high efficient, and excellent serum-tolerant polycation gene delivery systems, a series of oligoamines grafted hyperbranched polyether (oligoamines-g-HBP) were synthesized by conjugating different oligoamines, including triethylenetetramine (TETA) and tetraethylenepentamine (TEPA), onto COOH-functionalized hyperbranched poly(3-ethyl-3-oxetanemethanol). It was found that oligoamines-g-HBP exhibited good buffering capacity, strong DNA binding and high resistance against protein adsorption. In vitro cytotoxicity measurement indicated that oligoamines-g-HBP had much lower cytotoxicity as compared with 25 kDa PEI. The transfection efficiency of TEPA-g-HBP/DNA complexes at a certain N/P ratio was significantly higher than that of 25 kDa PEI/DNA complexes. Interestingly, it was found that TEPA-g-HBP had much improved serum-tolerant capability as compared with 25 kDa PEI even when serum concentration was increased to 30%. Confocal laser images further showed that the amount of YOYO-1 labeled DNA in nuclei got increased with increasing the number of secondary amino ethylene groups in oligoamines-g-HBP. The oligoamines-g-HBP presented great potential as gene delivery vectors for further clinical applications. PMID- 23916964 TI - New insights into the bactericidal activity of chitosan-Ag bionanocomposite: the role of the electrical conductivity. AB - The relationship between electrical conductivity, structure and antibacterial properties of chitosan-silver nanoparticles (CS/AgnP) biocomposites has been analyzed. To test the film's antimicrobial activity, Gram-positive and Gram negative bacteria were studied. The interactions between silver nanoparticles with chitosan suggest the formation of silver ions which plays a major role in nanocomposite's bactericidal potency. In CS/AgnP biocomposites, the bactericide effectiveness increases by increasing AgnP concentrations up to 3 wt%, which is close to the electrical percolation threshold of ca. 3 wt%. As the AgnP concentration increases above this threshold, the bactericidal potency is greatly diminished. The elucidated correlation between electrical conductivity and antibacterial activity could be useful in the design of other nanocomposites that involve polymeric-based matrices. PMID- 23916966 TI - A new method combining sequential immunoaffinity depletion and differential in gel electrophoresis to identify autoantibodies as cancer biomarkers. AB - Easily measurable biomarkers are urgently required to detect early stages of cancer progression. Autoantibodies (aAbs), as a component of the humoral immune response against tumor cells, have such potential of diagnostic markers since they are circulating and stable proteins, produced rapidly and easily amenable to in vitro dosage. The identification of aAbs is based on the characterization of tumor-associated antigens (TAA) against which they are directed. Here, we propose a new method for an unbiased identification of TAA and thereby of aAbs as cancer biomarkers. This method that we called sequential immunoaffinity depletion differential in gel electrophoresis (SID-DIGE) is based on the immunodepletion of tumor cell lysates with IgG from control and tumor-bearing mice and direct matching of the flow throughs of these immunoaffinity separations on the same 2D format. This strategy reduces the complexity of the samples to be analyzed and maximizes the interest of assessing hundreds of proteins simultaneously. SID-DIGE has also the potential, contrary to existing serological proteome analysis (SERPA) techniques, to detect immunogenic proteins with conformational epitopes, including those resulting from post-translational modifications. Using a model of human colorectal tumors in mice for the proof of principle, we showed that SID DIGE outperforms the conventional SERPA technique, with the identification of 7 common TAA (validating our approach) and 18 additional aAbs proving the potential of this new method. In particular, the identification of aAbs directed against key enzymes supporting glycolysis gives credential to the role of hypoxia as a major determinant of the tumor proteome and thus as a source of immunogenicity. Overall, the developed methodology allowed efficient screening of sera for the identification of aAbs as potential biomarkers. PMID- 23916965 TI - The clinical effectiveness of web-based cognitive behavioral therapy with face-to face therapist support for depressed primary care patients: randomized controlled trial. AB - BACKGROUND: Most patients with mild to moderate depression receive treatment in primary care, but despite guideline recommendations, structured psychological interventions are infrequently delivered. Research supports the effectiveness of Internet-based treatment for depression; however, few trials have studied the effect of the MoodGYM program plus therapist support. The use of such interventions could improve the delivery of treatment in primary care. OBJECTIVE: To evaluate the effectiveness and acceptability of a guided Web-based intervention for mild to moderate depression, which could be suitable for implementation in general practice. METHODS: Participants (N=106) aged between 18 and 65 years were recruited from primary care and randomly allocated to a treatment condition comprising 6 weeks of therapist-assisted Web-based cognitive behavioral therapy (CBT), or to a 6-week delayed treatment condition. The intervention included the Norwegian version of the MoodGYM program, brief face-to face support from a psychologist, and reminder emails. The primary outcome measure, depression symptoms, was measured by the Beck Depression Inventory-II (BDI-II). Secondary outcome measures included the Beck Anxiety Inventory (BAI), the Hospital Anxiety and Depression Scale (HADS), the Satisfaction with Life Scale (SWLS), and the EuroQol Group 5-Dimension Self-Report Questionnaire (EQ 5D). All outcomes were based on self-report and were assessed at baseline, postintervention, and at 6-month follow-up. RESULTS: Postintervention measures were completed by 37 (71%) and 47 (87%) of the 52 participants in the intervention and 54 participants in the delayed treatment group, respectively. Linear mixed-models analyses revealed a significant difference in time trends between the groups for the BDI-II, (P=.002), for HADS depression and anxiety subscales (P<.001 and P=.001, respectively), and for the SWLS (P<.001). No differential group effects were found for the BAI and the EQ-5D. In comparison to the control group, significantly more participants in the intervention group experienced recovery from depression as measured by the BDI-II. Of the 52 participants in the treatment program, 31 (60%) adhered to the program, and overall treatment satisfaction was high. The reduction of depression and anxiety symptoms was largely maintained at 6-month follow-up, and positive gains in life satisfaction were partly maintained. CONCLUSIONS: The intervention combining MoodGYM and brief therapist support can be an effective treatment of depression in a sample of primary care patients. The intervention alleviates depressive symptoms and has a significant positive effect on anxiety symptoms and satisfaction with life. Moderate rates of nonadherence and predominately positive evaluations of the treatment also indicate the acceptability of the intervention. The intervention could potentially be used in a stepped-care approach, but remains to be tested in regular primary health care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12610000257066; http://apps.who.int/trialsearch/trial.aspx?trialid=ACTRN12610000257066 (Archived by WebCite at http://www.webcitation.org/6Ie3YhIZa). PMID- 23916967 TI - Overcoming matrix matching problems in multiplex cytokine assays. AB - Failure to match assay matrices with samples in immunoassays can result in incorrect sample values being reported. For multiplex assays this presents particular problems, due to the need to find a matrix suitable for all the analytes. Here, we describe strategies adopted to overcome matrix problems identified in establishing a cytokine multiplex assay in human plasma. Standard analytes were diluted in plasma samples to identify representative plasma for assay development. Horse sera were screened to evaluate potential interference before using to adjust a matrix to match plasma samples. Suitability of the matrix match was confirmed by evaluating recovery of known concentrations of analytes from plasma. Individual plasmas modified the assay signal for some analytes to a variable extent, particularly for IL-1alpha and IL-1beta. Addition of horse serum to assay buffer improved matching to plasma samples, although endogenous MCP-1 activity was apparent in one sample. Matching of plasma and assay matrices allowed recoveries within 10% to 20% of the expected values, unless the samples contained atypical interfering activity. Attention to choice of samples and diluent used for assay development is particularly important for measurement of sample analytes in cytokine multiplex assays. PMID- 23916968 TI - Fusion of mApple and Venus fluorescent proteins to the Sindbis virus E2 protein leads to different cell-binding properties. AB - Fluorescent proteins (FPs) are widely used in real-time single virus particle studies to visualize, track and quantify the spatial and temporal parameters of viral pathways. However, potential functional differences between the wild type and the FP-tagged virus may specifically affect particular stages in the virus life-cycle. In this work, we genetically modified the E2 spike protein of Sindbis virus (SINV) with two FPs. We inserted mApple, a red FP, or Venus, a yellow FP, at the N-terminus of the E2 protein of SINV to make SINV-Apple and SINV-Venus. Our results indicate that SINV-Apple and SINV-Venus have similar levels of infectivity and are morphologically similar to SINV-wild-type by negative stain transmission electron microscopy. Both mutants are highly fluorescent and have excellent single-particle tracking properties. However, despite these similarities, when measuring cell entry at the single-particle level, we found that SINV-Apple and SINV-Venus are different in their interaction with the cell surface and FPs are not always interchangeable. We went on to determine that the FP changes the net surface charge on the virus particles, the folding of the spike proteins, and the conformation of the spikes on the virus particle surface, ultimately leading to different cell-binding properties between SINV-Apple and SINV-Venus. Our results are consistent with recent findings that FPs may alter the biological and cellular localization properties of bacterial proteins to which they are fused. PMID- 23916970 TI - Future challenges and present ethical considerations in the use of personalized nutrition based on genetic advice. PMID- 23916971 TI - Associations of vitamin D intake with 25-hydroxyvitamin D in overweight and racially/ethnically diverse US children. AB - Overweight children and minorities are at risk of vitamin D deficiency. Little information exists on whether overweight children and minorities who do not meet dietary vitamin D recommendations are at risk for low 25-hydroxyvitamin D (25OHD) status. Vitamin D intake from foods and dietary supplements was estimated in 3,310 children/adolescents who were examined as part of the 2005-2006 National Health and Nutrition Examination Survey. Weight status was dichotomized into healthy weight or overweight/obese. Parent-reported race/ethnicity was categorized as non-Hispanic white, non-Hispanic black, Mexican American, or other. Adjusted logistic regression was used to determine whether children who did not achieve the Estimated Average Requirement (EAR) were at increased risk for inadequate 25OHD. Nearly 75% of children failed to meet the EAR. Overall, not meeting the EAR was associated with inadequate 25OHD (odds ratio=2.5; 95% CI 1.4 to 4.5). However, this association differed by weight status (P=0.02) and race/ethnicity (P=0.02). Overweight/obese children who failed to meet the EAR were five times more likely to be at risk for inadequate 25OHD than overweight/obese children who met it (95% CI 2.0 to 12.7; P<0.001). Non-Hispanic blacks with intakes below the EAR were nearly four times more likely to be at risk for inadequate 25OHD than those who met the EAR (95% CI 1.5 to 9.7; P<0.01). The majority of US children failed to meet current vitamin D recommendations. Overweight/obese and non-Hispanic black children were especially likely to be at risk for inadequate 25OHD when not consuming the EAR. PMID- 23916969 TI - Double strand break repair functions of histone H2AX. AB - Chromosomal double strand breaks provoke an extensive reaction in neighboring chromatin, characterized by phosphorylation of histone H2AX on serine 139 of its C-terminal tail (to form "gammaH2AX"). The gammaH2AX response contributes to the repair of double strand breaks encountered in a variety of different contexts, including those induced by ionizing radiation, physiologically programmed breaks that characterize normal immune cell development and the pathological exposure of DNA ends triggered by telomere dysfunction. gammaH2AX also participates in the evolutionarily conserved process of sister chromatid recombination, a homologous recombination pathway involved in the suppression of genomic instability during DNA replication and directly implicated in tumor suppression. At a biochemical level, the gammaH2AX response provides a compelling example of how the "histone code" is adapted to the regulation of double strand break repair. Here, we review progress in research aimed at understanding how gammaH2AX contributes to double strand break repair in mammalian cells. PMID- 23916972 TI - Trends in food and beverage sources among US children and adolescents: 1989-2010. AB - Despite the historical rise and recent plateau of child overweight and obesity, levels remain exceedingly high. To understand these trends and identify targets for intervention it is important to examine concomitant trends in children's diets. The objective of our analysis was to describe 21-year trends in total energy intake and the major food and beverage sources of energy among 2- to 18 year-olds in the United States. Six nationally representative surveys were examined in 2012, the Continuing Survey of Food Intakes by Individuals (1989-1991 and 1994-1996, 1998) and the National Health and Nutrition Examination Survey (2003-2004, 2005-2006, 2007-2008, and 2009-2010). Total energy intake among US children and adolescents rose considerably from 1989 to 2004, and subsequently declined through 2010. Seven sources were consistently major contributors across all time points: sugar-sweetened beverages, pizza, full-fat milk, grain-based desserts, breads, pasta dishes, and savory snacks. Intakes of full-fat milk, meats and processed meat products, ready-to-eat cereals, burgers, fried potatoes, fruit juice, and vegetables decreased from 1989-2010 whereas intakes of nonfat milk, poultry, sweet snacks and candies, and tortilla- and corn-based dishes increased linearly over the 21-year period. Significant nonlinear time trends were observed with recent decreases in intakes of sugar-sweetened beverages, pizza, pasta dishes, breads and rolls, and savory snacks and recent increases in intake of fruit. Energy intakes of US children began to decline in 2003-2004 and continued to decline through 2009-2010. However, among preschool children (aged 2 to 5 years) and children from low-income families, total energy intakes in 2009 2010 still remained significantly higher than in 1989-1991. PMID- 23916973 TI - Academy of Nutrition and Dietetics benchmarks for nutrition in child care 2011: are child-care providers across contexts meeting recommendations? AB - The Academy of Nutrition and Dietetics (Academy) recommends feeding practices for child-care providers to establish nutrition habits in early childhood to prevent obesity. With >12 million US children in child care, little is known about child care providers' feeding practices. The purpose of this study was to examine child care providers' feeding practices to assess whether providers met the Academy's benchmarks and whether attainment of benchmarks varied across child-care contexts (Head Start, Child and Adult Care Food Program [CACFP], and non-CACFP). Cross sectional data was collected in 2011 and 2012 from 118 child-care providers who completed self-administered surveys regarding their feeding practices for 2- to 5 year-old children. chi(2) tests and analysis of variance were used to determine variation across contexts. Head Start providers sat more frequently with children during meals (P=0.01), ate the same foods as children (P=0.001), and served meals family style (P<0.0001) more often compared with CACFP and non-CACFP providers. Head Start providers (P=0.002), parents (P=0.001), and children (P=0.01) received more nutrition-education opportunities compared with CACFP and non-CACFP. Head Start providers encouraged more balance and variety of foods (P<0.05), offered healthier foods (P<0.05), modeled healthy eating (P<0.001), and taught children about nutrition (P<0.001) compared with CACFP and non-CACFP providers. Providers across all three contexts used significantly more non-internal than internal mealtime verbal comments (P<0.0001). Head Start providers had greater compliance with the Academy's benchmarks compared with CACFP and non-CACFP providers. Possible reasons for this compliance might be attributed to Head Start nutrition performance standards and increased nutrition-training opportunities for Head Start staff. Head Start programs can serve as a model in implementing the Academy's benchmarks. PMID- 23916974 TI - Positive attitude toward healthy eating predicts higher diet quality at all cost levels of supermarkets. AB - Shopping at low-cost supermarkets has been associated with higher obesity rates. This study examined whether attitudes toward healthy eating are independently associated with diet quality among shoppers at low-cost, medium-cost, and high cost supermarkets. Data on socioeconomic status (SES), attitudes toward healthy eating, and supermarket choice were collected using a telephone survey of a representative sample of adult residents of King County, WA. Dietary intake data were based on a food frequency questionnaire. Thirteen supermarket chains were stratified into three categories: low, medium, and high cost, based on a market basket of 100 commonly eaten foods. Diet-quality measures were energy density, mean adequacy ratio, and total servings of fruits and vegetables. The analytical sample consisted of 963 adults. Multivariable regressions with robust standard error examined relations between diet quality, supermarket type, attitudes, and SES. Shopping at higher-cost supermarkets was associated with higher-quality diets. These associations persisted after adjusting for SES, but were eliminated after taking attitudinal measures into account. Supermarket shoppers with positive attitudes toward healthy eating had equally higher-quality diets, even if they shopped at low-, medium-, or high-cost supermarkets, independent of SES and other covariates. These findings imply that shopping at low-cost supermarkets does not prevent consumers from having high-quality diets, as long as they attach importance to good nutrition. Promoting nutrition-education strategies among supermarkets, particularly those catering to low-income groups, can help to improve diet quality. PMID- 23916975 TI - Induction of cytochrome P450 enzymes in primary equine hepatocyte culture. AB - In this study, we established cell culture conditions for primary equine hepatocytes allowing cytochrome P450 enzyme (CYP) induction experiments. Hepatocytes were isolated after a modified method of Bakala et al. (2003) and cultivated on collagen I coated plates. Three different media were compared for their influence on morphology, viability and CYP activity of the hepatocytes. CYP activity was evaluated with the fluorescent substrate 7-benzyloxy-4 trifluoromethylcoumarin. Induction experiments were carried out with rifampicin, dexamethasone or phenobarbital. Concentration-response curves for induction with rifampicin were created. Williams' medium E showed the best results on morphology and viability of the hepatocytes and was therefore used for the following induction experiments. Cells cultured in Dulbecco's Modified Eagle Medium were not inducible. Incubation with rifampicin increased the CYP activity in two different hepatocyte preparations in a dose dependent manner (EC50=1.20 MUM and 6.06 MUM; Emax=4.1- and 3.4-fold induction). No increase in CYP activity was detected after incubation with dexamethasone or phenobarbital. The hepatocyte culture conditions established in this study proved to be valuable for investigation of the induction of equine CYPs. In further studies, other equine drugs can be evaluated for CYP induction with this in vitro system. PMID- 23916976 TI - Human leukocyte antigen alleles and susceptibility to psoriatic arthritis. AB - OBJECTIVE: Our purpose was to determine associations between HLA alleles and psoriatic arthritis (PsA). METHODS: 678 PsA cases and 688 healthy controls were analyzed in a case-control design. The difference in the proportion of cases and controls with at least 1 copy of HLA alleles were tested for significance using chi(2) test and Fisher's exact test. Association analyses of haplotypes inferred by the Expectation-Maximization algorithm were performed. In the family-based association study, data from 283 families were analyzed. RESULTS: Univariate analysis revealed that cases were more likely to be carriers of HLA-C*01, -C*02, C*06, -C*12, -B*27, -B*38 and -B*57, whereas controls were more likely to be carriers of HLA-C*03, -C*07, -B*07, -B*51, -DRB1*15 and -DQB1*0602. In haplotype analyses, PsA cases were more likely to be carriers of the HLA haplotypes -C*01/ B*27, -C*02/-B*27, -C*12/-B*38, and -C*06/-B*57, while controls were more likely to be carriers of the haplotypes -C*07/-B*07 and -C*15/-B*51. In the family-based association analysis, the HLA alleles -A*02, -B*27 and -DRB1*07 were preferentially transmitted to cases, whereas the alleles -A*03, -A*28, -B*51, DRB1*11 and -DQB1*0301 were under transmitted. CONCLUSION: This large case control and family based association study shows that HLA-C*12/B*38, HLA-B*27 and HLA-C*06/B*57 are haplotypes (alleles) robustly associated with PsA. However, since patients with PsA also have psoriasis it is difficult to determine whether the primary association is with arthritis or psoriasis. PMID- 23916977 TI - Reply:. PMID- 23916978 TI - Production and flocculating performance of sludge bioflocculant from biological sludge. AB - Excess biological sludge was utilized to prepared bioflocculant with hydrochloric acid. The prepared crude bioflocculant was purified and fractionally precipitated to attain four purified sludge bioflocculant defined as PSB1-4. The PSB-2 has higher flocculating rate for kaolin suspension than others. When the pH of the flocculation system ranged from 4.0 to 11.0 the flocculating rates of PSB-2 were over 96.0%. X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectra showed that amino and hydroxyl groups were present in the bioflocculant molecules. More amine group existed in the bioflocculant PSB-2 relatively. The amino group was believed to play an important role in flocculation. The experiment of zeta potential measuring indicated that the charge neutralization contributed to flocculation process. Flocculating mechanism investigation reveals that the sludge bioflocculant caused kaolin suspension instability by means of charge neutralization firstly and then promoted the aggregation of suspension particles by adsorption and bridge. PMID- 23916979 TI - Bioaugmentation with an acetate-oxidising consortium as a tool to tackle ammonia inhibition of anaerobic digestion. AB - Ammonia is the major inhibitor of anaerobic digestion (AD) process in biogas plants. In the current study, the bioaugmentation of the ammonia tolerant SAO co culture (i.e. Clostridium ultunense spp. nov. in association with Methanoculleus spp. strain MAB1) in a mesophilic up-flow anaerobic sludge blanket (UASB) reactor subjected to high ammonia loads was tested. The co-cultivation in fed-batch reactors of a fast-growing hydrogenotrophic methanogen (i.e. Methanoculleus bourgensis MS2(T)) with the SAO co-culture was also investigated. Results demonstrated that bioaugmentation of SAO co-culture in a UASB reactor was not possible most likely due to the slow maximum growth rate (MUmax=0.007 h(-1)) of the culture caused by the methanogenic partner. The addition of M. bourgensis to SAO led to 42% higher growth rate (MUmax=0.01 h(-1)) in fed-batch reactors. This indicates that methanogens were the slowest partners of the SAO co-culture and therefore were the limiting factor during bioaugmentation in the UASB reactor. PMID- 23916980 TI - Preparation, characterization and optimization of nanocellulose whiskers by simultaneously ultrasonic wave and microwave assisted. AB - Simultaneously ultrasonic wave and microwave assisted technique (SUMAT), as a method of process intensification, was first applied to the preparation of nanocellulose whiskers (NCWs) from filter paper by sulfuric acid hydrolysis. The effects of temperature, sulfuric acid concentration, and mass of raw material and time on the yield of NCWs were investigated by single-factor experiments, and the preparation conditions were optimized with response surface methodology. The obtained NCWs were characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction and thermal gravimetry. The results showed NCWs were facilely prepared by using SUMAT. However, some harsh reaction conditions such as high temperature, strong acidity and long time treatment easily induced the reduction of the yield of NCWs. Under the optimal conditions, the yield and the crystallinity of NCWs with the crystal form of cellulose Ialpha is 85.75% and 80%, respectively. PMID- 23916981 TI - Effects of inoculum to substrate ratio, substrate mix ratio and inoculum source on batch co-digestion of grass and pig manure. AB - Biochemical methane potential (BMP) assay was conducted at 35 degrees C to evaluate the effects of inoculum to substrate ratio (ISR) and substrate mix ratio between para-grass and pig manure co-digesting using different inocula. Rubber latex digester (RLD) inoculum showed higher methanogenic activity (41.4 mL CH4/gVS) than pig farm digester (PFD) inoculum (37.3 mL CH4/gVS). However, the maximum methane yields, occurred at the highest para-grass mix ratio (G), were 369.6, 437.6, 465.9 and 442.6 mL CH4/gTSadded for RLD inoculum, versus 332.4, 475.0, 519.5 and 521.9 mL/gTSadded for PFD inoculum at ISR 1, 2, 3, and 4, respectively. HPr, HBu and HVa appeared at higher G, corresponding to substrate's higher biodegradability. Response surface indicated that higher ISR and G had a significantly positive impact on methane yield. It suggested the use of higher ISR, i.e. 3 or 4, for BMP assay of these co-substrates. Dominant species of fermentative bacteria in each inoculum was tested by DGGE. PMID- 23916982 TI - [Strategies to promote testosterone deficiency syndrome: a paradigm of disease mongering]. AB - The so-called "testosterone deficiency syndrome" is a blend of nonspecific symptoms typical of the physiological process of aging. This syndrome has been the subject of intense promotional activity that has presented the phenomenon as highly prevalent and with a major public health impact. This strategy has been accompanied by the emergence of new and easy to administer testosterone devices into the pharmaceutical market and has generated significant sales for drug companies. The commercial promotion of testosterone deficiency syndrome and its remedies has exploited cultural stereotypes of aging and sexuality through awareness campaigns promoted by the laboratories involved and has been disseminated by media with the participation of numerous experts and with the support of scientific associations, representing a paradigmatic case of disease mongering. This example might be of use in the response to disease mongering activities from the clinical and public health fields. PMID- 23916983 TI - [Coverage of cervical cancer screening in Catalonia, Spain (2008-2011)]. AB - OBJECTIVE: To estimate cervical cytology coverage for the period 2008-2011 by age groups and health regions from data recorded in the medical records of women attending centers within the Catalan national health system. METHODS: The data used to estimate coverage were obtained from the primary care information system. This information was anonymous and included age, center, date, and the results of cytological smears for a total of 2,292,564 women aged 15 years or more. RESULTS: A total of 758,690 smears were performed in 595,868 women. Among women aged 25-65 years, the estimated coverage was 32.4% of the assigned population and was 40.8% in the population attended. Geographical variation was observed, with higher coverage among health regions closer to Barcelona. Abnormal Pap smears increased slightly from 2008 to 2011 (from 3% to 3.5%, respectively, p <0.001). In women with a negative first smear, the mean interval until the second smear was 2.4 years, but only 50% of women with a negative first smear in 2008 attended a second round during the study period. CONCLUSIONS: Cervical screening coverage in the National Health Service of Catalonia includes one in three women. Second round participation was poor. Existing computer systems in primary care centers can ensure monitoring of population-based screening programs for cervical cancer. These systems could be used to plan an organized screening program to ensure wider coverage and better follow-up. PMID- 23916984 TI - A conceptual framework for understanding and reducing overuse by primary care providers. AB - Primary care providers frequently recommend, administer, or prescribe health care services that are unlikely to benefit their patients. Yet little is known about how to reduce provider overuse behavior. In the absence of a theoretically grounded causal framework, it is difficult to predict the contexts under which different types of interventions to reduce provider overuse will succeed and under which they will fail. In this article, we present a framework based on the theory of planned behavior that is designed to guide overuse research and intervention development. We describe categories of primary care provider beliefs that lead to the formation of intentions to assess the appropriateness of services, and propose factors that may affect whether the presence of assessment intentions results in an appropriate recommendation. Interventions that have been commonly used to address provider overuse behavior are reviewed within the context of the framework. PMID- 23916985 TI - In vivo activating transcription factor 3 silencing ameliorates the AMPK compensatory effects for ER stress-mediated beta-cell dysfunction during the progression of type-2 diabetes. AB - In obese Zucker diabetic fatty (ZDF) rats, ER stress is associated with insulin resistance and pancreatic beta-cell dysfunction; however the exact mechanisms by which ER stress drives type-2 diabetes remain uncertain. Here, we investigated the role of ATF3 on the preventive regulation of AMPK against ER stress-mediated beta-cell dysfunction during the end-stage progression of hyperglycemia in ZDF rats. The impaired glucose metabolism and beta-cell dysfunction were significantly increased in late-diabetic phase 19-week-old ZDF rats. Although AMPK phosphorylation reduced in 6- and 12-week-old ZDF rats was remarkably increased at 19weeks, the increases of lipogenice genes, ATF3, and ER stress or ROS-mediated beta-cell dysfunction were still remained, which were attenuated by in vivo-injection of chemical chaperon tauroursodeoxycholate (TUDCA), chronic AICAR, or antioxidants. ATF3 did not directly affect AMPK phosphorylation, but counteracts the preventive effects of AMPK for high glucose-induced beta-cell dysfunction. Moreover, knockdown of ATF3 by delivery of in vivo-jetPEI ATF3 siRNA attenuated ER stress-mediated beta-cell dysfunction and enhanced the beneficial effect of AICAR. Our data suggest that ATF3 may play as a counteracting regulator of AMPK and thus promote beta-cell dysfunction and the development of type-2 diabetes and could be a potential therapeutic target in treating type-2 diabetes. PMID- 23916986 TI - Human papillomavirus vaccine communication: perspectives of 11-12 year-old girls, mothers, and clinicians. AB - OBJECTIVES: Because little is known about the content of human papillomavirus (HPV) vaccine-related discussions with young adolescent girls in clinical settings, we explored communication between 11- and 12 year-old girls, mothers, and clinicians regarding HPV vaccines and concordance in reports of maternal and clinician communication. METHODS: We conducted individual interviews with 33 girls who had received the quadrivalent HPV vaccine in urban and suburban clinical settings, their mothers, and their clinicians. Data were analyzed using qualitative methods. RESULTS: From the perspectives of both girls and mothers, clinicians and parents were the preferred sources of HPV vaccine information for girls. Vaccine efficacy and risks/benefits of vaccination were the most commonly reported desired and actual topics of discussion by mothers, girls, and clinicians. Clinician recommendation of vaccination was reported by nearly one fifth of girls and nearly half of mothers. The most common concordant messages were related to efficacy of the vaccine, with concordance in 70% of triads. The most common discordant messages were related to sexual health. Approximately half of clinicians (16) reported discussing sexual health, but only 5 mothers (15%) and 4 girls (12%) reported this. Triads recruited from suburban (vs. urban) practices had higher degrees of concordance in reported vaccination communication. CONCLUSIONS: HPV vaccine efficacy and safety are important topics for clinicians to discuss with both girls and mothers; educating mothers is important because parents are a preferred source of vaccine-related information for girls. Because girls may be missing important vaccine-related messages, they should be encouraged to actively engage in vaccine discussions. PMID- 23916989 TI - Monitoring accelerations with GPS in football: time to slow down? AB - The aims of the current study were to examine the magnitude of between-GPS-models differences in commonly reported running-based measures in football, examine between-units variability, and assess the effect of software updates on these measures. Fifty identical-brand GPS units (15 SPI-proX and 35 SPIproX2, 15 Hz, GPSports, Canberra, Australia) were attached to a custom-made plastic sled towed by a player performing simulated match running activities. GPS data collected during training sessions over 4 wk from 4 professional football players (N = 53 files) were also analyzed before and after 2 manufacturer-supplied software updates. There were substantial differences between the different models (eg, standardized difference for the number of acceleration >4 m/s2 = 2.1; 90% confidence limits [1.4, 2.7], with 100% chance of a true difference). Between units variations ranged from 1% (maximal speed) to 56% (number of deceleration >4 m/s2). Some GPS units measured 2-6 times more acceleration/deceleration occurrences than others. Software updates did not substantially affect the distance covered at different speeds or peak speed reached, but 1 of the updates led to large and small decreases in the occurrence of accelerations (-1.24; 1.32, -1.15) and decelerations (-0.45; -0.48, -0.41), respectively. Practitioners are advised to apply care when comparing data collected with different models or units or when updating their software. The metrics of accelerations and decelerations show the most variability in GPS monitoring and must be interpreted cautiously. PMID- 23916988 TI - Current status and prospects for development of a vaccine against Trichomonas vaginalis infections. AB - Trichomonas vaginalis is a sexually transmitted pathogen with an annual worldwide incidence of over 276 million infections, the highest of all curable and non viral STI. A large proportion of cases are asymptomatic and under-diagnosed with conventional diagnostic tools. Infection has important maternal and fetal health consequences and can lead to a higher probability of HIV transmission and susceptibility. Lack of affordable accurate diagnostic tests globally and metronidazole resistance hinder T. vaginalis control efforts. Based on data from current vaccination studies in animal models, a human vaccine is achievable to intervene on the substantial incidence of infection. PMID- 23916987 TI - A Phase I, dose-escalation trial in adults of three recombinant attenuated Salmonella Typhi vaccine vectors producing Streptococcus pneumoniae surface protein antigen PspA. AB - BACKGROUND: Live, attenuated, orally-administered Salmonella strains are excellent vectors for vaccine antigens and are attractive as vaccines based on previous use of S. Typhimurium in animals. A Phase I dose escalation trial was conducted to evaluate the safety and immunogenicity of three newly constructed recombinant attenuated Salmonella enterica serovar Typhi vaccine (RASV) vectors synthesizing Streptococcus pneumoniae surface protein A (PspA). METHODS: The 3 S. Typhi strains used as vectors to deliver PspA were S. Typhi ISP1820; S. Typhi Ty2 RpoS(-); and S. Typhi Ty2 RpoS(+). Sixty healthy adults (median age 25.2 years) were enrolled into 4 Arms (total 15 subjects per Arm); within each Arm, subjects were randomized 1:1:1 into 3 Groups of 5. All subjects in the same Group received the same vaccine vector, and all subjects in the same Arm received the same titer of vaccine (10(7), 10(8), 10(9) or 10(10)CFU). Adverse events, safety, shedding, and IgG and IgA titers against Salmonella outer membrane proteins (OMPs), lipopolysaccharide (LPS) and PspA were evaluated. RESULTS: In the highest dose group, no subject experienced severe reactions or serious adverse events. Most adverse events were mild; one subject had a positive blood culture. No subject shed vaccine in stool. No statistically significant differences for post vaccination ELISA or ELISPOT results between Groups were detected. However, a limited number of >= 4 fold increases from baseline for IgA anti-OMPs, IgA and IgG anti-LPS, and IgA anti-PspA occurred for a few individuals as measured by ELISA, and IgA anti-OMPs as measured by ELISPOT assay. CONCLUSIONS: All three S. Typhi vectored pneumococcal vaccines were safe and well-tolerated. Immunogenicity was limited possibly due to pre-existing high antibody titers prior to vaccination. Increases in IgA were most often observed. PMID- 23916990 TI - Hybrid-SPRITE MRI. AB - In a FID based frequency encoding MRI experiment the central part of k-space is not generally accessible due to the probe dead time. This portion of k-space is however crucial for image reconstruction. SPRITE (Single Point Ramped Imaging with T1 Enhancement), SPI with a linearly ramped phase encode gradient, has been employed to image short relaxation time systems for many years with great success. It is a robust imaging method in significant measure because it provides acquisition of high quality k-space origin data. We propose a new sampling scheme, termed hybrid-SPRITE, combining phase and frequency encoding to ensure high quality images with reduced acquisition times, reduced gradient duty cycle and increased sensitivity. In hybrid-SPRITE, numerous time domain points are collected to assist image reconstruction. An Inverse Non-uniform Discrete Fourier Transform (INDFT) is employed in 1D applications. A pseudo-polar grid is exploited in 2D hybrid-SPRITE for rapid and accurate image reconstruction. PMID- 23916991 TI - Experimental issues in the measurement of multi-component relaxation times in articular cartilage by microscopic MRI. AB - A number of experimental issues in the measurement of multi-component T2 and T1rho relaxations in native and enzymatically digested articular cartilage were investigated by microscopic MRI (MUMRI). The issues included the bath solutions (physiological saline and phosphate buffered saline (PBS)), the imaging resolution (35-140 MUm), the specimen orientations (0 degrees and 55 degrees ), and the strength of spin-lock frequencies (0.5-2 kHz) in the T1rho experiments. In addition to cartilage, the samples of agar gel and doped water solution were also used in the investigation. Two imaging sequences were used: CPMG-SE and MSME. All raw data were analyzed by the non-negative least square (NNLS) method. The MSME sequence was shown to result in the observation of multi-component T2, even in the gel and liquid samples, demonstrating the artificial uncleanness of this sequence in the multi-component measurements. The soaking of cartilage in PBS reduced the observable T2 components to one at both 0 degrees and 55 degrees , suggesting the effect of phosphate ions on proton exchange between different pools of water molecules. The cartilage orientation with respect to the external magnetic field and the spin-lock strengths in the T1rho experiment both affected the quantification of the multi-component relaxation. The transitions between a mono-component and multi-components in cartilage under various experimental conditions call for the extra caution in interpreting the relaxation results. PMID- 23916992 TI - Encapsulated islets for diabetes therapy: history, current progress, and critical issues requiring solution. AB - Insulin therapy became a reality in 1921 dramatically saving lives of people with diabetes, but not protecting them from long-term complications. Clinically successful free islet implants began in 1989 but require life long immunosuppression. Several encapsulated islet approaches have been ongoing for over 30 years without defining a clinically relevant product. Macro-devices encapsulating islet mass in a single device have shown long-term success in large animals but human trials have been limited by critical challenges. Micro-capsules using alginate or similar hydrogels encapsulate individual islets with many hundreds of promising rodent results published, but a low incidence of successful translation to large animal and human results. Reduction of encapsulated islet mass for clinical transplantation is in progress. This review covers the status of both early and current studies including the presentation of corporate efforts involved. It concludes by defining the critical items requiring solution to enable a successful clinical diabetes therapy. PMID- 23916993 TI - The expression of aldehyde dehydrogenase 1 in invasive primary breast tumors and axillary lymph node metastases is associated with poor clinical prognosis. AB - The enzyme aldehyde dehydrogenase 1 (ALDH1) has been reported as a biomarker for identifying cancer stem cells. Previous studies have shown that ALDH1 expression in primary breast cancers was associated with poor clinical prognosis. In this study, we aimed to determine whether ALDH1 expression in axillary lymph node metastases (ALNM) of breast cancer patients was also associated with poor prognosis. Expression of ALDH1, ER, PgR, HER2 and KI-67 was examined in primary tumors and ALNM of 161 patients with invasive breast cancer. Survival analysis and multivariate analysis were used to determine the relationship between ALDH1 expression and clinical prognosis. Patients with positive ALDH1 expression in primary tumors and in ALNM had significantly shorter relapse-free survival (RFS) times and overall survival (OS) times compared to those whose tissues were ALDH1 negative. ALDH1-positivity in primary tumors was significant both in univariate and multivariate analyses of RFS and OS. ALDH1 expression in ALNM was significant in a univariate analysis of RFS and OS but not in a multivariate analysis of RFS and OS. We conclude that the expression of ALDH1 in primary breast tumors or ALNM may be one potential risk factor for poor, long-term outcomes. PMID- 23916994 TI - Pharmacological blockade of gap junctions induces repetitive surging of extracellular potassium within the locust CNS. AB - The maintenance of cellular ion homeostasis is crucial for optimal neural function and thus it is of great importance to understand its regulation. Glial cells are extensively coupled by gap junctions forming a network that is suggested to serve as a spatial buffer for potassium (K(+)) ions. We have investigated the role of glial spatial buffering in the regulation of extracellular K(+) concentration ([K(+)]o) within the locust metathoracic ganglion by pharmacologically inhibiting gap junctions. Using K(+)-sensitive microelectrodes, we measured [K(+)]o near the ventilatory neuropile while simultaneously recording the ventilatory rhythm as a model of neural circuit function. We found that blockade of gap junctions with either carbenoxolone (CBX), 18beta-glycyrrhetinic acid (18beta-GA) or meclofenamic acid (MFA) reliably induced repetitive [K(+)]o surges and caused a progressive impairment in the ability to maintain baseline [K(+)]o levels throughout the treatment period. We also show that a low dose of CBX that did not induce surging activity increased the vulnerability of locust neural tissue to spreading depression (SD) induced by Na(+)/K(+)-ATPase inhibition with ouabain. CBX pre-treatment increased the number of SD events induced by ouabain and hindered the recovery of [K(+)]o back to baseline levels between events. Our results suggest that glial spatial buffering through gap junctions plays an essential role in the regulation of [K(+)]o under normal conditions and also contributes to a component of [K(+)]o clearance following physiologically elevated levels of [K(+)]o. PMID- 23916995 TI - Multiple excitation of Fuchs-Kliewer phonons by Ne+ ions back-scattered by the LiF(100) surface at grazing incidence. AB - An analytic model is developed to describe the inelastic processes occurring when keV Ne(+) ions are scattered at grazing incidence by the (100) surface of LiF. The large energy losses (up to 30 eV) of the reflected Ne(+) particles reported by Borisov et al (1999 Phys. Rev. Lett. 83 5378) are shown to arise specifically from the long-range coupling between the projectiles and the so-called Fuchs Kliewer (FK) optical phonons of LiF whose fields extend far outside the surface. The strength of the coupling is estimated, allowing one to compute the average number of excited FK phonon quanta (homegaS = 0.071 eV) and hence the mean energy losses. For emerging, neutralized Ne(0), a distinct energy loss mechanism is shown to occur, namely the excitation of FK phonons and other types of surface collective modes associated with the screening of the F(0) 'hole' left behind by the neutralization process. This mechanism contributes a large fraction of the loss, additional to that suffered by the incident Ne(+) ion. The model explains the experimental observations quantitatively (1999 Phys. Rev. Lett. 83 5378). The paper ends with a discussion of the large energy broadening of the observed loss peaks. PMID- 23916996 TI - Evaluation of the sensitivity after reduction mammoplasty. Our experience and review of the literature. AB - AIM: The preservation of the sensitivity of the nipple-areola complex after reduction mammoplasty is an important goal of the modern surgery. The aim of this paper is to evaluate the differences in the recovery of sensitivity after reduction mammoplasty using different techniques. MATERIAL OF STUDY: Using the Semmes-Weinstein monofilament the sensitivity was evaluated in 64 patients undergone to a bilateral reduction mammoplasty: 36 were treated with inferior pedicle technique and 28 with a superior pedicle techniques. The evaluation of the sensitivity was performed in nine points: the nipple, the four quadrants of the areola and the 4 quadrants of the skin around the areola both in the preoperative and at 3 weeks, 3, 6 and 12 months postoperatively. RESULTS: The major alterations were found in the sensitivity of the nipple: the major deficiencies were seen in women treated with a superior pedicle techniques. Minor differences were found about the sensitivity of the areola and periareolar skin. CONCLUSION: The techniques which provide the preparation of a glandular flap with superior pedicle have an increased risk of altering the innervation of the nipple areola complex. The preparation of a glandular flap with inferior pedicle allows the restoration of the pre-operative sensitivity in 6-12 months. KEY WORDS: Breast sensitivity, Reduction mammoplasty, Sensitivity alteration. PMID- 23916997 TI - Reduced proceptivity and sex-motivated behaviors in the female rat after repeated copulation in paced and non-paced mating: effect of changing the male. AB - The mating inhibition after repeated copulation (sexual satiety) and its re commencement after changing the sexually active partner (Coolidge effect) are well recognized phenomena in males, but their occurrence in females is little explored. These two phenomena were compared in conditions when the female regulates copulation timing (pacing) and under non-paced mating. Female rats selected in proestrus copulated incessantly for 3 h with two different partners (for 90 min each), both of them sexually active and unknown for the female. During the entire test we recorded the hop/dart and ear wiggling frequencies and the lordosis quotient. In the pacing test we also registered the percentage of exits and the return latencies after mounts, intromissions and ejaculation within each copulatory series, the mean time the female spent in the neutral chamber and the number of crossings. In the non-paced mating situation there was a reduction in ear wiggling and hop/darting frequencies after 3 h of constant copulation. In the paced mating condition, also by the end of the test, the female spent more time in the neutral compartment and showed fewer crossings to the male's zone. Only when the female regulated mating, the change of the male provoked an increased hop/darting frequency accompanied by a reduced percentage of exits from the male's chamber after an intromission and in the time in the neutral compartment. These changes were not associated with alterations in receptivity, which was maximal along the test. Data are discussed by comparing the mating conditions and the sex differences in the effect of repeated copulation and partner replacement. PMID- 23916998 TI - Sleep restriction and serving accuracy in performance tennis players, and effects of caffeine. AB - Athletes often lose sleep on the night before a competition. Whilst it is unlikely that sleep loss will impair sports mostly relying on strength and endurance, little is known about potential effects on sports involving psychomotor performance necessitating judgement and accuracy, rather than speed, as in tennis for example, and where caffeine is 'permitted'. Two studies were undertaken, on 5h sleep (33%) restriction versus normal sleep, on serving accuracy in semi-professional tennis players. Testing (14:00 h-16:00 h) comprised 40 serves into a (1.8 m*1.1 m) 'service box' diagonally, over the net. Study 1 (8 m; 8 f) was within-Ss, counterbalanced (normal versus sleep restriction). Study 2 (6m;6f -different Ss) comprised three conditions (Latin square), identical to Study 1, except for an extra sleep restriction condition with 80 mg caffeine vs placebo in a sugar-free drink, given (double blind), 30 min before testing. Both studies showed significant impairments to serving accuracy after sleep restriction. Caffeine at this dose had no beneficial effect. Study 1 also assessed gender differences, with women significantly poorer under all conditions, and non-significant indications that women were more impaired by sleep restriction (also seen in Study 2). We conclude that adequate sleep is essential for best performance of this type of skill in tennis players and that caffeine is no substitute for 'lost sleep'. 210. PMID- 23916999 TI - Concerns regarding "Whole exome sequencing reveals minimal differences between cell line and whole blood derived DNA". PMID- 23917000 TI - [Turkish Adult Risk Factor Study survey 2012: overall and coronary mortality and trends in the prevalence of metabolic syndrome]. AB - OBJECTIVES: We aimed to analyze 1) overall and coronary mortality findings in the Turkish Adult Risk Factor (TARF) study survey 2012 and 2) the temporal trends in prevalence of metabolic syndrome (MetS) and its distribution across seven geographic regions. STUDY DESIGN: Information on the mode of death was obtained from first-degree relatives and/or health personnel of a local health office. Information collected in survivors was based on history, physical examination of the cardiovascular system and Minnesota coding of resting electrocardiograms. RESULTS: Of 1527 participants to be surveyed, 796 were examined; information was obtained on the health status in 502 subjects, and death was ascertained in 56 participants. Thirty deaths were attributed to coronary and cerebrovascular disease. Cumulative 22-year evaluation of participants in the age bracket 45-74 years revealed coronary mortality to be high, with 7.6 per 1000 person-years in men and 3.8 in women. Data used from 1754 identical subjects (median age 46 years initially), and examined in two periods 12 years apart, indicated an increase in the prevalence of MetS by 1.3% per aging of 1 year. Analysis across geographic regions showed a rise in the prevalence in the Mediterranean region, already having highest prevalence along with Southeast Anatolia, while the prevalence declined in the Marmara region and persisted to be lowest in the Aegean region. CONCLUSION: The prevalence of MetS in Turkish adults aged 40 years or over, currently standing at 53%, shows significant differences across geographic regions, being highest in the two southern regions and lowest in the Aegean region. PMID- 23917001 TI - [Relationship between human platelet antigen-1 gene polymorphism and clopidogrel resistance in patients with coronary artery disease]. AB - OBJECTIVES: It has been proposed that human platelet antigen-1 (HPA-1) gene polymorphism is associated with coronary artery disease (CAD) and affects platelet function. We aimed to investigate the distribution of HPA gene polymorphism between angiographic CAD and a control group and the relation between HPA gene polymorphism and platelet aggregation. STUDY DESIGN: The study population consisted of 94 patients with angiographic CAD and 115 patients without angiographic CAD. Platelet aggregation was measured with impedance aggregometry on the fifth day of percutaneous coronary intervention (PCI). Platelet aggregation >480 AU*min was defined as the clopidogrel resistance group. Blood samples were obtained from all participants at discharge for investigating HPA-1 gene polymorphism. RESULTS: There was no significant difference in the distribution of HPA-1 gene polymorphism between the control and CAD groups (78.7% vs. 78.1% for A allele and 21.3% vs. 21.9% for B allele, p=NS). The analysis between groups with and without clopidogrel resistance revealed no significant difference in the distribution of HPA-1A and HPA-1B alleles between the groups (A allele 78.7% vs. 78.9% and B allele 21.3% vs. 21.1%, p=NS). In the CAD group, there were no significant differences in platelet aggregation between HPA-1A and HPA-1B alleles (294+/-240 vs. 259+/-261 AU*min, p=NS). CONCLUSION: The distribution of HPA-1 gene polymorphism was not different in CAD patients compared to the control group. HPA-1 gene polymorphism was not associated with platelet aggregation or clopidogrel resistance assessed by impedance aggregometry in the CAD group. PMID- 23917002 TI - [Clopidogrel resistance and genetic factors]. PMID- 23917003 TI - Relationship between HbA1c levels and coronary artery severity in nondiabetic acute coronary syndrome patients. AB - OBJECTIVES: In this study, we aimed to investigate the relationship between HbA1c levels and the severity of coronary artery stenosis in patients with acute coronary syndrome (ACS) without diabetes mellitus. STUDY DESIGN: In this study, we included 65 patients (11 females, mean age: 57+/-11.42 years; 54 males, mean age: 54.56+/-8.51 years) who were diagnosed as acute myocardial infarction without diabetes mellitus. During hospitalization, fasting blood glucose, postprandial blood glucose and HbA1C were measured in each patient. Gensini score was used to assess the severity of coronary artery disease. RESULTS: Twenty patients (30.8%) had hypertension, 15 (23.1%) had impaired fasting glucose, 10 (15.3%) had combined impaired fasting and postprandial glucose, 28 had a low HDL cholesterol (45%), and 30 (46%) had abdominal obesity. Coronary angiography revealed one-vessel disease in 13 patients (20%), and two- and three-vessel disease in 52 patients (80%). There were no significant differences in terms of high-sensitive C-reactive protein (hs-CRP), total cholesterol, fasting glucose, and postprandial glucose (0.068, 0.974, 0.178, 0.677, respectively). There was no significant relation between the Gensini score and HbA1c levels (p=0.299), but there was a significant relation between the Gensini score and obesity (p=0.024). CONCLUSION: In our study, no significant relationship could be determined between the Gensini score and HbA1C, fasting and postprandial blood glucose levels, lipid profile, and hs-CRP levels in patients with nondiabetic ACSs. PMID- 23917004 TI - [Relationship between HbA1c levels and coronary artery severity in nondiabetic acute coronary syndrome patients]. PMID- 23917005 TI - Increased red cell distribution width level is associated with absence of coronary collateral vessels in patients with acute coronary syndromes. AB - OBJECTIVES: Several studies have evaluated a relationship between increased red cell distribution width (RDW) and morbidity and mortality of acute coronary syndrome (ACS). In this study, we aimed to investigate the association of serum RDW levels and development of coronary collateral vessel (CCV) in patients with ACS. STUDY DESIGN: We evaluated 226 patients with ACS in this prospective and cross-sectional study. Traditional laboratory and clinical parameters and serum RDW levels were measured on admission. All patients underwent coronary angiography on the first day after admission and patients with >80% stenosis were included in the study. The CCV was graded according to the Rentrop scoring system, and a Rentrop grade 0 was accepted as no CCV development (Group 1), while Rentrop grades 1-2-3 were accepted as presence of CCV development (Group 2). RESULTS: Only levels of RDW were significantly higher in Group 1 than in Group 2 (Group 1 RDW 14.6+/-1.9, Group 2 RDW 14.1+/-1.4, p=0.02). The predictive value of serum RDW level for absence of collaterals (sensitivity of 58% and specificity of 54%, area under the receiver operating characteristic (ROC) curve = 0.573) was 13.90. CONCLUSION: We found that high levels of RDW were associated with absence of CCV in patients with ACS. PMID- 23917006 TI - Efficacy and safety of valsartan and amlodipine single-pill combination in hypertensive patients (PEAK study). AB - OBJECTIVES: This study was designed to assess the safety, compliance and efficacy of amlodipine (Aml) and valsartan (Val) single-pill combination (SPC) in a large hypertensive patient population. STUDY DESIGN: This is a non-interventional, observational, open label study conducted in 166 centers in Turkey with a 24-week follow-up period. RESULTS: Of the 1184 enrolled patients, two-thirds were female (62.2%). The mean age was 57.7+/-11.3 years, and 26.1% of the patients were older than 65 years. The majority of patients (82.3%) were overweight or obese. During the course of the study, 150 (12.7%) patients experienced a total of 174 adverse events (AEs). The overall mean (SD) compliance rate was determined to be 96.9 (0.2)%. The most commonly reported AE was edema, with a new-onset edema incidence of 6.7%. In the entire group, Aml/Val SPC significantly reduced both systolic and diastolic blood pressure (BP), with a reduction of 29.6+/-0.9 / 14.7+/-0.6 mmHg (for each, p<0.001). CONCLUSION: As a result of the low incidences of AEs and new onset edema, the safety profile of Aml/Val SPC proved to be optimal. Aml/Val SPC reduced BP efficiently and met the needs of most patients to achieve the targets. Aml/Val SPC seems to be a beneficial option for effective BP control, which is a key factor influencing cardiovascular outcome. PMID- 23917007 TI - Treatment with enhanced external counterpulsation improves cognitive functions in chronic heart failure patients. AB - OBJECTIVES: Chronic heart failure (CHF) has been associated with an increased risk of poorer cognitive performance in older adults. Reversibility of cognitive impairment after medical treatment has been reported, although the restorative effects of enhanced external counterpulsation (EECP) on cognitive performance have not been studied. We investigated the effect of EECP on cognitive functions in CHF patients. STUDY DESIGN: Thirty-six individuals (mean age: 66+/-8 years) who were diagnosed with CHF and were New York Heart Association (NYHA) Class II III and Canadian Cardiovascular Society (CCS) Class II-III participated in this study. Neuropsychological assessment was performed in these patients. RESULTS: Patients in the EECP treatment group showed a statistically significant improvement in spontaneous naming (p=0.011) and forward row score of the attention subset among domains of cognition (p=0.020) and interference time of executive function (p=0.012). CONCLUSION: Enhanced external counter pulsation resulted in improvement in all domains of cognitive functions except verbal and visual memory tests. PMID- 23917008 TI - [A case of idiopathic ventricular tachycardia in a 14-year-old obese patient due to golden berry fruit extract pills for weight loss]. AB - Several studies have determined an association between obesity and increased risk of cardiac arrhythmia. Currently, due to the increased frequency of obesity, food , plant-, and drug-based therapies for weight loss have gained great attention. A 14-year-old female patient presented with complaints of palpitation of one-hour onset. Blood pressure was 110/70 mmHg and peripheral pulses were present. She had been using golden berry extract pill three times a day for 10 days. The electrocardiogram showed nonsustained monomorphic ventricular tachycardia (VT). Echocardiographic examination and cardiac magnetic resonance imaging (MRI) were normal. She returned to sinus rhythm following amiodarone infusion. She refused the electrophysiologic study, which plays a vital role in the diagnosis and establishment of the appropriate therapy. Although there was no decrease in body mass index (BMI) of the patient during the two-year follow-up, she had no complaint or evidence of VT on intermittent rhythm Holter studies. This case suggests the primary role of golden berry extract use in the development of VT, rather than obesity. PMID- 23917009 TI - Percutaneous right ventricle outflow tract stenting in a patient with trisomy 18 associated with double outlet right ventricle. AB - Trisomy 18, or Edwards syndrome, is the second most common chromosome anomaly after trisomy 21. Various types of congenital heart diseases are seen in the majority of trisomy 18 patients. Palliative treatment of right ventricular outflow tract (RVOT) stenosis includes options like balloon dilatation, stenting and surgery. Herein, we present a case with trisomy 18 and double outlet right ventricle, pulmonary stenosis, and ventricular septal defect. During the follow up, at the age of three months, his saturation dropped to 70% and an interventional procedure was planned. The patient was considered high risk, and after discussing treatment options with the family, RVOT stenting was chosen. The patient was lost on the 8th day of the follow-up. PMID- 23917010 TI - Catecholaminergic polymorphic ventricular tachycardia detected by an implantable loop recorder in a child. AB - We present a six-year-old boy with a history of recurrent syncope whose physical examination and family history were inconclusive. Laboratory findings, 12-lead ECG, chest radiography, Holter monitoring, event recorder monitoring, echocardiography, coronary computed tomography (CT) angiography, Brugada challenge test (ajmaline), cranial magnetic resonance imaging, and awake/sleep electroencephalogram were all unremarkable. Since syncope was exercise-induced, an electrophysiology study was also performed, but revealed no inducible ventricular arrhythmias. Implantable loop recorder (ILR) was implanted. Three weeks later, bidirectional ventricular tachycardia was found in ILR record during presyncope that was related to exercise. The patient, with the diagnosis of catecholaminergic polymorphic ventricular tachycardia, was started on high-dose beta-blocker therapy. Due to the recurrence of syncopes despite the presence of beta-blockers, an implantable cardioverter defibrillator was implanted. PMID- 23917011 TI - [Retrieval of embolized coronary stent: combination of various approaches]. AB - Device embolization is a potentially serious complication of percutaneous vascular interventions. Various devices and techniques can be used for the retrieval procedure. Herein, we report the retrieval of a stent that slipped off the balloon in the left main coronary artery and then embolized to the right femoral artery in a 77-year-old male. The stent could not be retrieved by snare, but was removed from the coronary tree via a balloon advanced inside it. The stent then embolized into the right femoral artery. Using a balloon catheter advanced through the stent and then via a biopsy forceps advanced over a femoro femoral wire loop, we were able to remove the stent from the patient. In conclusion, there is no proven standard method for the retrieval of embolized material. Different techniques and devices can be used depending on the creativity of the operator as well as the individual situation of the case. PMID- 23917012 TI - [A second percutaneous closure due to residual mitral paravalvular leak and successful treatment of device embolization]. AB - Paravalvular leak (PVL) is a common complication after surgical valve replacement. Most PVLs remain clinically silent; however, some may require reoperation due to symptomatic PVL. Surgical closure of PVL remains the most common therapy for these defects; however, redo surgery has some disadvantages, including a high recurrence rate as well as high morbidity and mortality rates. Percutaneous closure of PVLs has emerged as an alternative to surgical closure. A 42-year-old male patient underwent a second percutaneous closure due to residual mitral paravalvular leak. During the procedure, the closure device embolized in the descending aorta. The device was captured with a snare and successfully retrieved, and then PVL was successfully occluded with another device. PMID- 23917013 TI - Anomalous origin of the left coronary artery from the pulmonary artery presenting as dilated cardiomyopathy. AB - Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly and one of the causes of myocardial ischemia. It often presents with atypical signs and symptoms, especially in childhood. In this case report, an 11-year-old girl presented with dilated cardiomyopathy in our clinic and was followed for five years. Echocardiography showed multiple left-to right shunts on the interventricular septum, the confirmation of which was done by multi-slice computed tomography and coronary angiography. Therefore, we suggest that ALCAPA should be suspected in young patients diagnosed with dilated cardiomyopathy. PMID- 23917014 TI - [How to diagnose noncompaction cardiomyopathy?]. PMID- 23917015 TI - Statement on matching language to the type of evidence used in describing outcomes data. PMID- 23917016 TI - Clinical and hemodynamic improvement after stent implantation for pulmonary stenosis in failing Fontan circulation. PMID- 23917017 TI - [Dysphagia due compression of right pulmonary artery aneurysm to the esophagus]. PMID- 23917018 TI - Concomitant diagnosis of a large apical right ventricular thrombus in a newly diagnosed case of arrhythmogenic right ventricular dysplasia. PMID- 23917019 TI - Quadricuspid aortic valve associated with persistent left superior vena cava and right ventricular noncompaction cardiomyopathy. PMID- 23917020 TI - The importance of Lewis leads in a patient with wide QRS complex tachycardia. PMID- 23917021 TI - Ursolic acid and it is emerging anti-neoplastic effects in systemic malignancies. PMID- 23917022 TI - Two mammalian MAGOH genes contribute to exon junction complex composition and nonsense-mediated decay. AB - The exon junction complex (EJC) participates in the regulation of many post transcriptional steps of gene expression. EJCs are deposited on messenger RNAs (mRNAs) during splicing and their core consists of eIF4A3, MLN51, Y14, and MAGOH. Here, we show that two genes encoding MAGOH paralogs (referred to as MAGOH and MAGOHB) are expressed in mammals. In macrophages, the expression of MAGOHB, but not MAGOH mRNA, increases rapidly after LPS stimulation. Both MAGOH proteins interact with other EJC components, incorporate into mRNA-bound EJCs, and activate nonsense-mediated decay. Furthermore, the simultaneous depletion of MAGOH and MAGOHB, but not individual depletions, impair nonsense-mediated decay in human cells. Hence, our results establish that the core composition of mammalian EJCs is more complex than previously recognized. PMID- 23917023 TI - Isolation, molecular characterization, and phylogenetic analysis of encephalomyocarditis virus from South China tigers in China. AB - Although encephalomyocarditis virus (EMCV) can infect many host species and cause myocarditis and sudden death in many species, little is known about EMCV infection in tigers. A virus was isolated from organs of dead South China tigers with sudden death in southern China. The production of cytopathic effect on BHK cells, and the results of PCR, electron microscopy (EM), and whole genome sequencing indicated that the pathogen was EMCV, the strain was named FJ13. Other pathogenic agents were excluded as possible pathogenic agents. Phylogenetic analyses of the whole genome, ORF (open reading frame) and CCR (capsid coding region) using the neighbour-joining method revealed that EMCV isolates cluster into two groups (group 1 and 2) with two sub-clusters within group 1 (group 1a and 1b), and FJ13 belongs to group 1a. Animal experiment showed that the isolated strain FJ13 could cause clinical symptoms and pathological changes. The results of this study indicated that FJ13 caused myocarditis of tigers and provided new epidemiologic data on EMCV in China. PMID- 23917024 TI - Partial genetic characterization of Sedlec virus (Orthobunyavirus, Bunyaviridae). AB - Sedlec virus (SEDV) was isolated from the blood of a reed warbler (Acrocephalus scirpaceus) in July 1984 in South Moravia, Czech Republic. In this study first genetic data of SEDV are presented which allow an estimate on its phylogenetic and taxonomic positioning within the genus Orthobunyavirus. The phylogenetic analysis of a 369 nt long stretch within the S segment (nucleocapsid protein gene and non-structural S protein gene) indicates genetic relatedness of SEDV to Leanyer virus and Simbu group viruses, while the phylogenetic tree based on 1796nt long sequences of the L segment (RNA-dependent RNA polymerase gene) demonstrates genetic relationship of SEDV to two yet unclassified orthobunyaviruses: I612045 virus (isolated in India in 1961) and Oyo virus (isolated in Nigeria in 1964). Considering the genetic distances and the phylogenetic analyses, SEDV might represent a novel serogroup of the Orthobunyavirus genus. PMID- 23917025 TI - Variability in minimal genomes: analysis of tandem repeats in the microsporidia Encephalitozoon intestinalis. AB - Microsporidia are ubiquitous fungi with genomes that have undergone a strong reduction to the extreme cases of Encephalitozoon cuniculi and Encephalitozoon intestinalis. Genetic variability within species of the Encephalitozoon genus has been reported, with most of the studies based on the internal transcribed spacer (ITS) of the rDNA. However, in contrast to the picture of E. cuniculi and Encephalitozoon hellem, where different strains have been identified, no genetic variability has yet been observed in E. intestinalis. We have analysed tandem repeats included in putative coding sequences which could be used as polymorphic markers in E. intestinalis. Eight candidate loci (M2, M2A, M3, M5, M7, M7A, M8 and PTP1) were established and 9 E. intestinalis cultured strains from North America, South America and Europe were analysed. M2, M7 and PTP1 nucleotide sequences were identical among the different strains and the GenBank sequence. In contrast, we observed variants in 4 markers (M2A, M3, M7A and M8) which did not correspond to their respective reference sequences. The most noticeable finding was that with the M5 marker two genotypes were defined among the different strains studied, demonstrating genotypic variability of E. intestinalis. Although the diversity described is certainly not high, which can be explained by a lower chance of genetic variability in its minimal genome, we have demonstrated that polymorphisms actually exist in E. intestinalis. Epidemiological studies using this genetic marker should now be conducted to elucidate the genetic variability in E. intestinalis and improve our knowledge of the epidemiology of this microsporidia. PMID- 23917026 TI - Evidence of circulation of an epidemic strain of Pasteurella multocida in Jiangsu, China by multi-locus sequence typing (MLST). AB - Pasteurella multocida, the causative agent of fowl cholera, is a serious threat to poultry farming. In this study, we isolated and identified 40 P. multocida strains in fowl cholera outbreaks in Jiangsu province, China. The identified P. multocida was further characterized using multi-locus sequence typing (MLST). All of the 40 P. multocida strains studied are genetically identical and belong to the ST129 sequence type based on seven MLST loci. Our study provides evidence of a circulating epidemic strain of P. multocida in Jiangsu, China. PMID- 23917027 TI - Blood oxygen level-dependent (BOLD) MRI analysis in atherosclerotic renal artery stenosis. AB - PURPOSE OF REVIEW: Blood oxygen level-dependent MRI (BOLD MRI) is a noninvasive technique for evaluating kidney tissue oxygenation that requires no contrast exposure, with the potential to allow functional assessment in patients with atherosclerotic renal artery stenosis. Normal cortical-to-medulla oxygenation gradients are preserved in many patients treated for several years with medical antihypertensive therapy without restoring renal blood flow. The current review is of particular interest as new methods have been applied to the analyses of BOLD MRI, opening the perspective of its wider utilization in clinical practice. RECENT FINDINGS: Recent findings show that more severe vascular compromise ultimately overwhelms renal adaptive changes, leading to overt cortical hypoxia and expansion of medullary hypoxic zones. 'Fractional kidney hypoxia' method of analysis, developed as an alternative method of BOLD MRI analysis, avoids the assumption of discrete cortical and medullary values and decreases the bias related to operator selection of regions of interests. SUMMARY: We believe that thoughtful application and analysis of BOLD MRI can provide critical insights into changes in renal function prior to the onset of irreversible renal injury and may identify patients most likely to gain from measures to reverse or repair disorders of tissue oxygenation. PMID- 23917028 TI - Renovascular hypertension: is there still a role for stent revascularization? AB - PURPOSE OF REVIEW: Management of renovascular hypertension remains controversial and problematic, in part, due to failure of prospective trials to demonstrate added benefit to revascularization. RECENT FINDINGS: Effective drug therapy often can achieve satisfactory blood pressure control, although concerns persist of the potential for progressive, delayed loss of kidney function beyond a stenotic lesion. Recent studies highlight benefits of renal artery stenting in subsets of patients including those with recurrent pulmonary edema and those intolerant to blockade of the renin-angiotensin system. Occasional patients with recent deterioration in renal function recover sufficient glomerular filtration rate after stenting to avoid requirements for renal replacement therapy. Emerging paradigms from both clinical and experimental studies suggest that hypoxic injury within the kidney activates inflammatory injury pathways and microvascular rarification that may not recover after technically successful revascularization alone. Initial data suggest that additional measures to repair the kidney, including the use of cell-based therapy, may offer the potential to recover kidney function in advanced renovascular disease. SUMMARY: Specific patient groups benefit from renal revascularization. Nephrologists will increasingly be asked to manage complex renovascular patients, different from those in randomized trials, that require intensely individualized management. PMID- 23917029 TI - Calcium-sensing in the kidney. AB - PURPOSE OF REVIEW: Changes in extracellular calcium concentration affect several functions of the renal tubule. The calcium-sensing receptor (CaSR), initially identified in the parathyroid gland cells, is also expressed in the kidney and was assumed to mediate all effects of extracellular calcium on the renal tubule. The purpose of this review is to critically review the evidence supporting this assumption. RECENT FINDINGS: Recent results confirm that, in the kidney, the CaSR is mainly expressed in the thick ascending limb of the loop of Henle. There, it is involved in the control of calcium reabsorption, independently of its action on parathyroid hormone secretion, through an effect on the paracellular pathway permeability. Although extracellular calcium affects transports other than that of calcium, the direct evidence that CaSR is involved in these effects is still lacking in many instances. SUMMARY: As the CaSR in the kidney controls calcium reabsorption and excretion and subsequently affects blood calcium concentration, agonists and antagonists of the CaSR could be used to control blood calcium concentration in patients who have lost their ability to regulate parathyroid hormone secretion. In addition, more work is needed to further decipher the molecular mechanisms through which CaSR determines calcium transport in the loop of Henle. PMID- 23917031 TI - Current world literature. Pharmacology and therapeutics. PMID- 23917033 TI - Heterogeneous catalysis on the phage surface: Display of active human enteropeptidase. AB - Enteropeptidase (EC 3.4.21.9) plays a key role in mammalian digestion as the enzyme that physiologically activates trypsinogen by highly specific cleavage of the trypsinogen activation peptide following the recognition sequence D4K. The high specificity of enteropeptidase makes it a powerful tool in modern biotechnology. Here we describe the application of phage display technology to express active human enteropeptidase catalytic subunits (L-HEP) on M13 filamentous bacteriophage. The L-HEP/C122S gene was cloned in the g3p-based phagemid vector pHEN2m upstream of the sequence encoding the phage g3p protein and downstream of the signal peptide-encoding sequence. Heterogeneous catalysis of the synthetic peptide substrate (GDDDDK-beta-naphthylamide) cleavage by phage bound L-HEP was shown to have kinetic parameters similar to those of soluble enzyme, with the respective Km values of 19 MUM and 20 MUM and kcat of 115 and 92 s(-1). Fusion proteins containing a D4K cleavage site were cleaved with phage bound L-HEP/C122S as well as by soluble L-HEP/C122S, and proteolysis was inhibited by soybean trypsin inhibitor. Rapid large-scale phage production, one step purification of phage-bound L-HEP, and easy removal of enzyme activity from reaction samples by PEG precipitation make our approach suitable for the efficient removal of various tag sequences fused to the target proteins. The functional phage display technology developed in this study can be instrumental in constructing libraries of mutants to analyze the effect of structural changes on the activity and specificity of the enzyme or generate its desired variants for biotechnological applications. PMID- 23917030 TI - Structure, function, and regulation of the SLC4 NBCe1 transporter and its role in causing proximal renal tubular acidosis. AB - PURPOSE OF REVIEW: There has been significant progress in our understanding of the structural and functional properties and regulation of the electrogenic sodium bicarbonate cotansporter NBCe1, a membrane transporter that plays a key role in renal acid-base physiology. The NBCe1 variant NBCe1-A mediates basolateral electrogenic sodium-base transport in the proximal tubule and is critically required for transepithelial bicarbonate absorption. Mutations in NBCe1 cause autosomal recessive proximal renal tubular acidosis (pRTA). The review summarizes recent advances in this area. RECENT FINDINGS: A topological model of NBCe1 has been established that provides a foundation for future structure-functional studies of the transporter. Critical residues and regions have been identified in NBCe1 that play key roles in its structure, function (substrate transport, electrogenicity) and regulation. The mechanisms of how NBCe1 mutations cause pRTA have also recently been elucidated. SUMMARY: Given the important role of proximal tubule transepithelial bicarbonate absorption in systemic acid-base balance, a clear understanding of the structure-functional properties of NBCe1 is a prerequisite for elucidating the mechanisms of defective transepithelial bicarbonate transport in pRTA. PMID- 23917034 TI - Mediators of inflammation after cardiac ischemia: the role of invariant natural killer T (iNKT) cells. PMID- 23917035 TI - Oncoplastic reshaping in breast-conserving surgery in a peripheral hospital. The Novi Ligure "San Giacomo" hospital experience. AB - AIM: To confirm that oncoplastic approach to cancer is a fundamental part of modern breast conserving surgery also in a suburban hospital. MATERIAL OF STUDY: The Authors used oncoplastic techniques in 60 cases including 45 first level and 15 second level procedures: they show some cases of conservative surgery and breast reshaping with upper, medial and lower pedicle. DISCUSSION: Screening programs are able to identify early breast cancer; the breast conserving surgery with oncoplastic glandular reshaping should be an established custom to ensure oncological safety with the best cosmetic result. CONCLUSIONS: The oncoplastic approach to breast cancer should be the theoretical and practical knowledge of the breast surgeon. Today in fact the breast surgeon must be a "vertical surgeon" in order to treat cancer completely, interfaced with a multidisciplinary team to ensure a personalized treatment for each patient. In this presentation the Authors want to focus on oncoplastic surgery in a medium flow suburban hospital. PMID- 23917036 TI - Quantitative capillary zone electrophoresis method for the precise determination of charge differences arising from the manufacture of heparan-N-sulfatase. AB - A rapid and reproducible high-resolution capillary zone electrophoresis (CZE) method capable of resolving the charge isoforms of intact heparan-N-sulfatase (HNS) has been developed to monitor the charge consistency across different batches of HNS. Separation was carried out using a bare fused silica capillary with a buffer system composed of 25 mM Tris, pH 8.0. This CZE method allowed the separation and integration of 14 peaks, each arising from differences in the amount of sialic-acid and mannose-6-phosphate bearing glycoforms, which were confirmed using enzymatically modified samples. Standard conditioning and rinsing conditions of the capillary were used to achieve optimal repeatability. Excellent day-to-day precision was obtained for migration times of each peak relative to the electroosmotic flow marker with relative standard deviation (RSD)<= 0.5%. The precision of the relative peak areas (peak area percentages) ranged from 0.6% to 2.8% RSD for the major isoforms (peaks 3-12), from 4.0% to 5.0% RSD for peaks 1 and 2, and from 7.4% to 23.2% RSD for peaks 13 and 14. The method was able to discriminate charge variation across different batches of HNS, including those with both significant and minor process changes. PMID- 23917037 TI - Characterization of currently marketed heparin products: key tests for LMWH quality assurance. AB - During the 2007-2008 heparin crisis it was found that the United States Pharmacopeia (USP) testing monograph for heparin sodium or low molecular weight heparins did not detect the presence of the contaminant, oversulfated chondroitin sulfate (OSCS). In response to this concern, new tests and specifications were developed by the Food and Drug Administration (FDA) and USP and put in place to detect not only the contaminant OSCS, but also to improve assurance of quality and purity of these drug products. The USP monographs for the low molecular weight heparins (LMWHs) approved for use in the United States (dalteparin, tinzaparin and enoxaparin) are also undergoing revision to include many of the same tests used for heparin sodium, including; one-dimensional (1D) 500 MHz (1)H NMR, SAX-HPLC, percent galactosamine in total hexosamine and anticoagulation time assays with purified Factor IIa or Factor Xa. These tests represent orthogonal approaches for heparin identification, measurement of bioactivity and for detection of process impurities or contaminants in these drug products. Here we describe results from a survey of multiple lots from three types of LMWHs in the US market which were collected after the 2009 heparin sodium monograph revision. In addition, innovator and generic versions of formulated enoxaparin products purchased in 2011 are compared using these tests and found to be highly similar within the discriminating power of the assays applied. PMID- 23917038 TI - Analyses of marketplace tacrolimus drug product quality: bioactivity, NMR and LC MS. AB - Tacrolimus (FK506) is a potent, narrow therapeutic index, immunosuppressive drug used to avoid organ rejection in patients that have undergone organ transplantation. Recent clinical reports suggested a significant reduction in the tacrolimus concentration/dose ratio in the plasma of liver and kidney recipients when the reference listed drug was substituted with a generic drug. In response to these concerns about switching between tacrolimus from different approved manufacturers during treatment, the FDA initiated purity, potency and quality studies of the innovator and generic tacrolimus products available in the US marketplace. A combination of analytical methods, including mass spectrometry (LC MS), nuclear magnetic resonance (NMR) and bioactivity assay were developed and validated to assess the quality of tacrolimus. These tests measured the identity, impurities and activity of tacrolimus from active pharmaceutical ingredient (API) sources and with formulated drug product from five different approved manufactures. In addition, some testing was performed on tacrolimus capsules obtained from a non US approved Indian source. The data obtained showed no discernible difference in the impurity profiles and potency between the generic and innovator tacrolimus products. PMID- 23917039 TI - Cost-effectiveness on a local level: whether and when to adopt a new technology. AB - Cost-effectiveness analysis has become a widely accepted tool for decision making in health care. The standard textbook cost-effectiveness analysis focuses on whether to make the switch from an old or common practice technology to an innovative technology, and in doing so, it takes a global perspective. In this article, we are interested in a local perspective, and we look at the questions of whether and when the switch from old to new should be made. A new approach to cost-effectiveness from a local (e.g., a hospital) perspective, by means of a mathematical model for cost-effectiveness that explicitly incorporates time, is proposed. A decision rule is derived for establishing whether a new technology should be adopted, as well as a general rule for establishing when it pays to postpone adoption by 1 more period, and a set of decision rules that can be used to determine the optimal timing of adoption. Finally, a simple example is presented to illustrate our model and how it leads to optimal decision making in a number of cases. PMID- 23917040 TI - New devices for measuring forces on the kayak foot bar and on the seat during flat-water kayak paddling: a technical report. AB - The purpose was to develop and validate portable force-measurement devices for recording push and pull forces applied by each foot to the foot bar of a kayak and the horizontal force at the seat. A foot plate on a single-point force transducer mounted on the kayak foot bar underneath each foot allowed the push and pull forces to be recorded. Two metal frames interconnected with 4 linear ball bearings, and a force transducer allowed recording of horizontal seat force. The foot-bar-force device was calibrated by loading each foot plate with weights in the push-pull direction perpendicular to the foot plate surface, while the seat-force device was calibrated to horizontal forces with and without weights on the seat. A strong linearity (r2 = .99-1.0) was found between transducer output signal and load force in the push and pull directions for both foot-bar transducers perpendicular to the foot plate and the seat-force-measuring device. Reliability of both devices was tested by means of a test-retest design. The coefficient of variation (CV) for foot-bar push and pull forces ranged from 0.1% to 1.1%, and the CV for the seat forces varied from 0.6% to 2.2%. The current study opens up a field for new investigations of the forces generated in the kayak and ways to optimize kayak-paddling performance. PMID- 23917041 TI - Hydration and radiation effects on the residual stress state of cortical bone. AB - The change in the biaxial residual stress state of hydroxyapatite crystals and collagen fibrillar structure in sections of bovine cortical bone has been investigated as a function of dehydration and radiation dose using combined small and wide-angle X-ray scattering. It is shown that dehydration of the bone has a pronounced effect on the residual stress state of the crystalline phase, while the impact of radiation damage alone is less dramatic. In the initial hydrated state, a biaxial compressive stress of approximately -150 MPa along the bone axis exists in the hydroxyapatite crystals. As water evaporates from the bone material, the stress state moves to a tensile state of approximately 100 MPa. The collagen fibrillar structure is initially in a tensile residual stress state when the bone is hydrated and the state increases in magnitude slightly with dehydration. Radiation dose in continually hydrated samples also reduces the initial biaxial compressive stress magnitude in the hydroxyapatite phase; however, the stress remains compressive. Radiation exposure alone does not appear to affect the stress state of the collagen fibrillar structure. PMID- 23917042 TI - A novel strontium(II)-modified calcium phosphate bone cement stimulates human bone-marrow-derived mesenchymal stem cell proliferation and osteogenic differentiation in vitro. AB - In the present study, the in vitro effects of novel strontium-modified calcium phosphate bone cements (SrCPCs), prepared using two different approaches on human bone-marrow-derived mesenchymal stem cells (hMSCs), were evaluated. Strontium ions, known to stimulate bone formation and therefore already used in systemic osteoporosis therapy, were incorporated into a hydroxyapatite-forming calcium phosphate bone cement via two simple approaches: incorporation of strontium carbonate crystals and substitution of Ca(2+) by Sr(2+) ions during cement setting. All modified cements released 0.03-0.07 mM Sr(2+) under in vitro conditions, concentrations that were shown not to impair the proliferation or osteogenic differentiation of hMSCs. Furthermore, strontium modification led to a reduced medium acidification and Ca(2+) depletion in comparison to the standard calcium phosphate cement. In indirect and direct cell culture experiments with the novel SrCPCs significantly enhanced cell proliferation and differentiation were observed. In conclusion, the SrCPCs described here could be beneficial for the local treatment of defects, especially in the osteoporotic bone. PMID- 23917043 TI - Influence of polymer molecular weight in osteoinductive composites for bone tissue regeneration. AB - In bone tissue regeneration, certain polymer and calcium-phosphate-based composites have been reported to enhance some biological surface phenomena, facilitating osteoinduction. Although the crucial role of inorganic fillers in heterotopic bone formation by such materials has been shown, no reports have been published on the potential effects the polymer phase may have. The present work starts from the assumption that the polymer molecular weight regulates the fluid uptake, which determines the hydrolysis rate and the occurrence of biological surface processes. Here, two composites were prepared by extruding two different molecular weight L/D,L-lactide copolymers with calcium phosphate apatite. The lower molecular weight copolymer allowed larger fluid uptake in the composite thereof, which was correlated with a higher capacity to adsorb proteins in vitro. Further, the large fluid absorption led to a quicker composite degradation that generated rougher surfaces and enhanced ion release. Following intramuscular implantation in sheep, only the composite with the lower molecular weight polymer could induce heterotopic bone formation. Besides influencing the biological potential of composites, the molecular weight also regulated their viscoelastic behaviour under cyclic stresses. The results lead to the conclusion that designing biomaterials with appropriate physico-chemical characteristics is crucial for bone tissue regeneration in mechanical load-bearing sites. PMID- 23917045 TI - [Obesity is a risk factor of young onset of acute aortic dissection and postoperative hypoxemia]. AB - We reviewed the effect of obesity in the repair of type A acute aortic dissection (AAD). Between January, 2009 and June, 2010, repair of type A AAD was performed in 51 patients. We divided these patients into 2 groups according to body mass index( BMI). Twenty-two patients whose BMI was>=25 were classified as group O, and 29 patients whose BMI was<25 were classified as group N. The mean age of group O was younger than that in group N(60.2+/-11.9 versus 68.3+/-10.2 years, p=0.01). The incidence of postoperative hypoxemia was greater in group O than that in group N(81.8% versus 53.6 %, p=0.036). The intubation period was longer in group O than that in group N(8.0+/-7.1 days versus 3.7+/-3.1 days, p=0.014), and the intensive care unit (ICU) stay was longer in group O than that in group N(13.7+/-8.8 days versus 9.3+/-5.9 days, p=0.04). Obesity is thought to be a risk of young-onset of AAD and postoperative hypoxemia, as well as a prolonged intubation period and ICU stay. PMID- 23917044 TI - NOX4 mediates cytoprotective autophagy induced by the EGFR inhibitor erlotinib in head and neck cancer cells. AB - Most head and neck squamous cell carcinomas (HNSCCs) overexpress epidermal growth factor receptor (EGFR) and EGFR inhibitors are routinely used in the treatment of HNSCC. However, many HNSCC tumors do not respond or become refractory to EGFR inhibitors. Autophagy, which is a stress-induced cellular self-degradation process, has been reported to reduce the efficacy of chemotherapy in various disease models. The purpose of this study is to determine if the efficacy of the EGFR inhibitor erlotinib is reduced by activation of autophagy via NOX4-mediated oxidative stress in HNSCC cells. Erlotinib induced the expression of the autophagy marker LC3B-II and autophagosome formation in FaDu and Cal-27 cells. Inhibition of autophagy by chloroquine and knockdown of autophagy pathway genes Beclin-1 and Atg5 sensitized both cell lines to erlotinib-induced cytotoxicity, suggesting that autophagy may serve as a protective mechanism. Treatment with catalase (CAT) and diphenylene iodonium (DPI) in the presence of erlotinib suppressed the increase in LC3B-II expression in FaDu and Cal-27 cells. Erlotinib increased NOX4 mRNA and protein expression by increasing its promoter activity and mRNA stability in FaDu cells. Knockdown of NOX4 using adenoviral siNOX4 partially suppressed erlotinib-induced LC3B-II expression, while overexpression of NOX4 increased expression of LC3B-II. These studies suggest that erlotinib may activate autophagy in HNSCC cells as a pro-survival mechanism, and NOX4 may play a role in mediating this effect. PMID- 23917046 TI - [Patient with massive hemothorax due to blunt trauma saved by transcatheter arterial embolization (TAE)]. AB - A 78-year-old man who fell from a step ladder was transported to our hospital by ambulance under the diagnosis of multiple rib fractures and right hemothorax. Since he was in shock on arrival, endotracheal intubation and tube thoracotomy were immediately performed. Though 2 liters of blood was evacuated, persistent hemorrhage was observed, requiring continuous rapid infusion and blood transfusion. Emergency thoracic arteriography revealed active bleeding from a branch of the right internal thoracic artery. Transcatheter arterial embolization (TAE) was performed using vascular embolization coils and porous gelatin particles. These procedures successfully controlled active hemorrhage from the chest. Intrathoracic hematoma was evacuated through the 2nd large chest tube. Chest tubes were removed on the 7th day. He was discharged on the 17th day without any complications. PMID- 23917047 TI - [Usefulness of the axillary artery perfusion in open heart surgery in a patient with severe ascending aortic calcification]. AB - Because of high-aging Japanese society, high-risk patients with multiple co morbidities have been increasing in regular open-heart surgery. Especially, extensive aortic atherosclerosis with severe calcification that involves the ascending aorta can complicate the choice of sites of cannulations and aortic cross-clamping for cardiopulmonary bypass. To date, the standard peripheral arterial cannulation site in such cases has been the common femoral artery;however, this approach carries the risk of atheroembolism due to retrograde aortic perfusion, or it is undesirable in case of severe iliofemoral disease. Recently, it has been reported that arterial perfusion through the axillary artery provides sufficient antegrade aortic flow associated with fewer atheroembolic complications. In this paper, we report 3 successful cases of valvular surgeries in which axillary artery cannulation was used to avoid complications of brain. In cases of extensive aortic atherosclerosis with severe calcification, arterial perfusion through the axillary artery is a safe and effective method to provide sufficient arterial inflow during cardiopulmonary bypass, and is an excellent alternative to femoral artery cannulation. PMID- 23917048 TI - [Reexpansion pulmonary edema following thoracentesis]. AB - A 44-year-old female was presented to our department with a 4-day history of shortness of breath and chest pain. The chest X-ray showed pneumothorax with completely collapsed left lung. Thoracentesis was performed. She complained of dyspnea and the oxygen saturation decreased to 74% after thoracentesis. The 2nd chest X-ray and computed tomography demonstrated a left-sided pulmonary edema. A 67-year-old man came to our department complaining of persistent cough. The chest X-ray showed pneumothorax with collapsed right middle and lower lobes. Thoracentesis was performed. He complained of dyspnea and the oxygen saturation decreased to 87% after thoracentesis. The 2nd chest X-ray and computed tomography demonstrated an expanded right upper lobe, but also pulmonary edema in the right middle and lower lobes. Those patients were treated with supplemental oxygen without endotracheal intubation. Their oxygen saturation stabilized within 12 hours. They were successfully treated with the sole administration of oxygen. PMID- 23917049 TI - [Prolonged iatrogenic pneumothorax with refractory hepatic hydrothorax treated successfully with local anesthetic thoracoscopic talc poudrage]. AB - A 64-year-old woman with liver cirrhosis caused by hepatitis C was presented with aggravated dyspnea. She had refractory hepatic hydrothorax, requiring pleural puncture and drainage of approximately 3,000 ml per week. Four days after the last puncture, she consulted the emergency department and chest films revealed right tension pneumothorax. A drainage tube was inserted to her right pleural cavity, but middle and lower lobes were not expanded, and air leaks persisted. We thought that she was in high-risk of infections, like empyema, and needed surgical treatment to close the pulmonary fistula promptly. Considering her poor general condition, we performed local anesthetic thoracoscopic talc poudrage, and air leaks were controlled successfully. Perioperative period was uneventful. PMID- 23917050 TI - [Vacuum-assisted closure in a patient with methicillin-resistant Staphylococcus aureus (MRSA) mediastinitis after thoracic aortic surgery]. AB - Mediastinitis caused by methicillin-resistant Staphylococcus aureus (MRSA) is a serious complication in cardio-thoracic surgery. In mediastinitis cases, acute thoracic aortic graft infection is a lethal status. We described a successful treatment of MRSA thoracic graft infection by V.A.C. ATS therapy. Ascending aortic graft replacement was performed in a 55-year-old man, and deep mediastinitis by MRSA occurred on postoperative day 6. On postoperative day 8, negative pressure wound therapy (NPWT) using a home-made system, was carried out after re-sternotomy, debridement of inflammatory tissues and irrigation. Following the 1st NPWT, V.A.C. ATS therapy was introduced. MRSA vanished from the mediastinum after V.A.C. ATS therapy, and the mediastinum was closed with the omentum. He was discharged 43 days after the 1st operation. We consider that the advantage of V.A.C. ATS therapy is "making a bed-side free status" in even mediastinitis patients, which enables active walking and reinforcement of physical strength. V.A.C. ATS therapy might be useful for the treatment of MRSA mediastinitis. PMID- 23917052 TI - [Left apical tumor extirpation via left ventriculotomy with the aid of epicardial echocardiography]. AB - We reported a rare case of cardiac lipoma in the left ventricular apex. A 67-year old woman who was diagnosed with cardiac tumor in the left ventricular apex was underwent the extirpation of the tumor via left ventriculotomy with the aid of intraoperative epicardiac ultra-sound. An intraoperative epicardiac ultra-sound is a very useful tool to document a location of the tumor, and a left ventriculotomy approach for the extirpation of the tumor provides a good operative field. PMID- 23917051 TI - [Adult coarctation of aorta repaired under partial selective cerebral perfusion]. AB - We report a case of an adult coarctation of aorta in a 46-year-old woman repaired with partial selective cerebral perfusion. Preoperative cardiac catheterization revealed that pressure gradient between the upper and lower limb was more than 60 mmHg. Under general anesthesia, we entered the left thoracic cavity through standard thoracomy, and removed the coarctation of aorta under partial selective cerebral circulation. The left common carotid artery and the descending aorta were cannulated and perfused, and the main pulmonary artery was cannulated for venous drainage. The aortic arch was cross-clamped just proximal to the left common carotid artery. Reconstruction was carried out by graft replacement using a side armed 16 mm Dacron graft between the aortic arch and the descending aorta, and the left subclavian artery was connected to the side arm of the graft. Postoperatively, there is no pressure difference between the upper and lower extremities. PMID- 23917053 TI - [Pulmonary mucosal associated lymphoid tissue( MALT) lymphoma with 7-year natural history; computed tomography( CT) scan findings and pathological correlations]. AB - A 58-year-old man was found to have an abnormal shadow on chest computed tomography (CT). The size and density of the nodule increased gradually over 7 years. Partial lung resection was performed by a thoracoscopic procedure. The pathological examination and gene analysis revealed that the tumor was primary pulmonary B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma). The CT findings showed that the level of substantial shadow with air bronchograms gradually increased in the center of the mass shadow, while a radial filamentous and ground glass shadow increased in the periphery. The pathological findings showed a cellular lymphocytic infiltrate that had expanded without destroying the existing blood vessels and bronchi in the center area of the tumor, while had expanded in the interstitial area along with vessel bundles in the border area. The CT findings were consistent with the pathological findings. PMID- 23917054 TI - [Lung resection for lung cancer in patient with situs inversus totalis]. AB - Situs inversus, which occurs in 1-2 of every 10,000 births, is a congenital malformation in which the thoracic and abdominal viscera are arranged in partial on complete mirror image of the normal anatomy. In the case of situs inversus, special attention must be taken in performing surgery. We present a surgical case of primary lung cancer in an 81-year-old patient with situs inversus totalis. During surgery, we used the Univent bronchial tube for one-lung ventilation. The appearance of the right lung and the arrangement of the pulmonary vessels and the bronchi corresponded to those normally found on the right side was noted at left thoracotomy. Left middle lobectomy and partial resection of left upper lung were successfully performed. In lung resection for situs inversus, it is important to be aware the mirrorimage anatomy. The three dimensional computed tomography (3D CT) images were useful for preoperative evaluation of vessel variation. PMID- 23917055 TI - [Total quality management of clinical database]. AB - Data entry system should be constructed considering utility, accuracy, propriety, and feasibility. The methods for developing useful and accurate clinical databases are 1)system development based on the concept of "error proofing", 2)system test by real users, 3)guidances for participants, and 4)incentive for accurate data entry. In terms of propriety, to gain patient's consent on data collection and to publicly announce objectives and methods of clinical database are necessary. Confidentiality and anonymization of data are also important. Balancing efficacy and propriety for maximization of patients' and societal benefit is one of the important responsibilities of database management organizations. In addition, assessment of data quality such as audit and feedback is useful for enhancing accuracy and reliability of clinical databases. PMID- 23917056 TI - [Off-pump surgery for coronary-pulmonary artery fistula with giant coronary aneurysm; report of a case]. AB - A 60-year-old male was referred to our hospital due to suspected chronic heart failure. He also had a symptom of ischemic heart disease. The multi-detector row computed tomography (MDCT) demonstrated the coronary-pulmonary artery fistula with a giant coronary aneurysm, which was partly thrombosed. Two abnormal arteries to the aneurysm and the outflow to the pulmonary artery were clearly detected. Intraoperative epicardial echocardiography revealed the complete interruption of blood flow and the thrombus formation in the coronary aneurysm, that was achieved just by ligation of 2 arteries under off-pump surgery. Generally, congenital coronary-pulmonary artery fistula has complex morphological variations. In this case, MDCT and epicardial echocardiography were useful for the surgical decision-making to avoid the residual and/or the recurrent fistula. PMID- 23917057 TI - [Full root replacement with a Freestyle bioprosthesis for prosthetic valve endocarditis complicated by aortic-root pseudoaneurysm after subcoronary technique; report of a case]. AB - We report a surgical case of prosthetic valve endocarditis( PVE) after aortic valve replacement with a Freestyle stentless bioprosthesis, which was successfully treated with full root replacement using a Freestyle valve. A 80 year-old man underwent aortic valve replacement with a Freestyle stentless bioprosthesis, using subcoronary technique for aortic stenosis in 2004. Three years later he had late PVE, and we found the aortic-root pseudoaneurysm. Although homografts are the optimal for cases of severe aortic annular destruction, availability of these are limited in Japan. We chose a Freestyle valve with full root technique, which fitted well to the destroyed annulus. The postoperative course was uneventful. Freestyle stentless bioprosthesis can be useful option for PVE, meanwhile care should be taken to dead cavity between prosthesis and aortic wall in the subcoronary technique. PMID- 23917058 TI - [Mitral valve repair for papillary muscle rupture; report of a case]. AB - Papillary muscle rupture associated with acute myocardial infarction (AMI) is well known, but it's incidence is rare. We report a case of mitral valve repair with artificial chordae for partial papillary muscle rupture after AMI. A 75-year old man underwent percutaneous coronary intervention(PCI) for right coronary artery because of AMI about 2 months ago at another hospital, and suffered from dyspnea 1 week after PCI. He had emergency admission to our hospital for cardiac failure. Echo-cardiogram revealed severe mitral regurgitation due to posterior papillary muscle rupture. We performed mitral valve repair with neochorda implantation to left ventricular wall of papillary muscle rupture site and ring annuloplasty. Mitral regurgitation was well controlled on postoperative echo cardiogram. He was discharged at 25th postoperative day with no morbidity. PMID- 23917059 TI - [Acute aortic dissection induced by autonomic dysreflexia; report of a case]. AB - Autonomic dysreflexia can occur in patients with spinal cord injury and lead to excessive hypertension. A 61-year-old man who had been treated for spinal cord injury 28 years before in an accidental fall, was admitted with an acute aortic dissection and underwent replacement of ascending aorta. He had been injured the 6th cervical neurologic level and he had not been given regular medical care. His incident of aortic dissection during defecation might related to the elevation of blood pressure due to autonomic dysreflexia. PMID- 23917060 TI - [Mediastinal lymph node carcinoma of unknown primary site; report of a case]. AB - We experienced a rare case of a 38-year-old man with mediastinal lymph node carcinoma of unknown primary site. He had an abnormal shadow of upper mediastinal mass in a health check, and he was referred to our hospital. Chest computed tomography( CT) showed only one swollen mediastinal lymph node, and positron emission tomography(PET) revealed an accumulation of fluorodeoxyglucose in the nodule. Serum levels of neuron specific enolase (NSE) were found to be elevated. Preoperative examination did not detect the primary lesion. She underwent a mediastinal lymphadenectomy. The pathological diagnosis of the lesion was large cell neuroendocrine carcinoma. He was given platinum-based combined chemotherapy and radiotherapy as adjuvant therapy. He has been well without any sign of recurrence for 1 year after surgery. Surgical resection of mediastinal lymph node carcinoma of unknown primary site has the possibility of a good prognosis. PMID- 23917061 TI - [Benign clear cell tumor of the lung; report of a case]. AB - A 59-year-old woman was found to have an abnormal shadow on chest X-ray film during a general medical examination. A nodule with homogenous density and clear margin was seen in the lingular segment of the left lung. Since this shadow gradually enlarged during a 1.8 year follow up period, she was admitted to our hospital. A wedge resection was carried out by video-assisted thoracotomy. The resected tumor was histologically diagnosed as a benign clear cell tumor of the lung. Immunohistochemically, the tumor cells showed strong anti-melanoma monoclonal antibody (HMB-45) expression. This disease is extremely rare and only 31 cases including the present case have been reported in Japan. PMID- 23917062 TI - [Thymic sarcomatoid carcinoma; report of a case]. AB - The case was a 35-year-old male patient. Upon visiting a local doctor with complaints of cough and pain in the left chest, he was diagnosed as having an anterior mediastinal tumor. A large tumor of 15 cm in size was found by computed tomography( CT) scanning at the anterior mediastinum extending to the left thoracic cavity. Surgical resection was considered to be feasible, and the tumor was removed combined with the left brachiocephalic vein. Partial resection of the pericardium and the left upper lobe was also necessary. The diagnosis was a sarcoma-like thymic cancer by pathology. Although adjuvant chemotherapy was planned, the patient died of cancer recurrence at the 3rd postoperative month. PMID- 23917063 TI - The future is now: comparing the effect of episodic future thinking on impulsivity in lean and obese individuals. AB - The choice of small immediate rewards as opposed to larger delayed rewards, or delay discounting, is an important dimension of impulsive decision making. The inability to delay gratification is related to obesity, as well as other maladaptive behaviors such as substance abuse, problem drinking, smoking, pathological gambling, and risky HIV behaviors. One way to reduce delay discounting (DD) may be to use prospective imagery in the form of episodic future thinking (EFT) during inter-temporal decision making. We have recently shown that EFT reduces DD and ad libitum energy intake in obese individuals. However, no studies have examined whether the magnitude of the EFT effect differs between lean and overweight/obese individuals. We conducted a within-subject design experiment to compare the efficacy of EFT versus a control task in reducing DD between lean (N=24) and overweight/obese (N=24) women. Participants attended two sessions in which they engaged in either EFT or control episodic thinking during a DD task. We also examined whether individual differences such as trait time perspective, behavioral inhibition or behavioral activation moderated the EFT effect on DD. Results showed EFT reduced DD similarly for lean and overweight/obese individuals. The EFT effect was moderated by behavioral activation. This suggests EFT is just as effective in reducing impulsive decision making in obese individuals as it is in lean individuals and may be useful in reducing other impulsive obesity related behaviors. PMID- 23917064 TI - Food-related advertisements and food intake among adult men and women. AB - Television viewing may contribute to obesity via promotion of sedentary behavior and exposure to food-related commercials. However, the mechanisms by which food related commercials promote food intake are not well understood. Therefore, the purpose of the present study was to examine the impact of television advertisements on food intake according to sex and transportability, or the tendency to become engrossed in what one is viewing. Eighty-three undergraduate students, free of disordered eating symptoms, were stratified by sex and randomly assigned to one of three conditions (food-related advertisements, neutral advertisements, or no advertisements). They were then identified as high or low in transportability according to a median split. A significant interaction was found between advertisement condition and transportability such that those high in transportability ate more in the food than other advertisement conditions. A second interaction was found between sex and transportability with women high in transportability eating more food than women low in transportability irrespective of advertisement condition. No significant main effects of advertisement condition, sex, or transportability were found. Results suggest the importance of studying the impact of individual difference variables on the relationship between food-related advertising and food intake. PMID- 23917065 TI - Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities. AB - Poly-ADP-ribosylation is a post-translational modification that regulates processes involved in genome stability. Breakdown of the poly(ADP-ribose) (PAR) polymer is catalysed by poly(ADP-ribose) glycohydrolase (PARG), whose endo glycohydrolase activity generates PAR fragments. Here we present the crystal structure of PARG incorporating the PAR substrate. The two terminal ADP-ribose units of the polymeric substrate are bound in exo-mode. Biochemical and modelling studies reveal that PARG acts predominantly as an exo-glycohydrolase. This preference is linked to Phe902 (human numbering), which is responsible for low affinity binding of the substrate in endo-mode. Our data reveal the mechanism of poly-ADP-ribosylation reversal, with ADP-ribose as the dominant product, and suggest that the release of apoptotic PAR fragments occurs at unusual PAR/PARG ratios. PMID- 23917066 TI - Diversity and biosynthetic potential of culturable microbes associated with toxic marine animals. AB - Tetrodotoxin (TTX) is a neurotoxin that has been reported from taxonomically diverse organisms across 14 different phyla. The biogenic origin of tetrodotoxin is still disputed, however, TTX biosynthesis by host-associated bacteria has been reported. An investigation into the culturable microbial populations from the TTX associated blue-ringed octopus Hapalochlaena sp. and sea slug Pleurobranchaea maculata revealed a surprisingly high microbial diversity. Although TTX was not detected among the cultured isolates, PCR screening identifiedsome natural product biosynthesis genes putatively involved in its assembly. This study is the first to report on the microbial diversity of culturable communities from H. maculosa and P. maculata and common natural product biosynthesis genes from their microbiota. We also reassess the production of TTX reported from three bacterial strains isolated from the TTX-containing gastropod Nassarius semiplicatus. PMID- 23917067 TI - Two novel tyrosinase inhibitory sesquiterpenes induced by CuCl2 from a marine derived fungus Pestalotiopsis sp. Z233. AB - Two new sesquiterpenes, 1beta,5alpha,6alpha,14-tetraacetoxy-9alpha-benzoyloxy 7beta H-eudesman-2beta,11-diol (1) and 4alpha,5alpha-diacetoxy-9alpha-benzoyloxy 7betaH-eudesman-1beta,2beta,11, 14-tetraol (2), were produced as stress metabolites in the cultured mycelia of Pestalotiopsis sp. Z233 isolated from the algae Sargassum horneri in response to abiotic stress elicitation by CuCl2. Their structures were established by spectroscopic means. New compounds 1 and 2 showed tyrosinase inhibitory activities with IC50 value of 14.8 uM and 22.3 uM. PMID- 23917068 TI - Evaluation of anti-nociceptive and anti-inflammatory activities of a heterofucan from Dictyota menstrualis. AB - Fucan is a term that defines a family of homo- and hetero-polysaccharides containing sulfated l-fucose in its structure. In this work, a heterofucan (F2.0v) from the seaweed, Dictyota menstrualis, was evaluated as an antinociceptive and anti-inflammatory agent. F2.0v (20.0 mg/kg) inhibits 100% of leukocyte migration into the peritoneal cavity after chemical stimulation. However, F2.0v does not alter the expression of interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6), as well as tumor necrosis factor alpha (TNF-alpha). F2.0v (20.0 mg/kg) has peripheral antinociceptive activity with potency similar to dipyrone. On the other hand, it had no effect on pain response on the hot plate test. Confocal microscopy analysis and flow cytometry showed that F2.0v binds to the surface of leucocytes, which leads us to suggest that the mechanism of action of anti-inflammatory and antinociceptive F2.0v is related to its ability to inhibit the migration of leukocytes to the site of tissue injury. In summary, the data show that F2.0v compound has great potential as an antinociceptive and anti inflammatory, and future studies will be performed to further characterize the mechanism of action of F2.0v. PMID- 23917069 TI - Krempfielins J-M, new eunicellin-based diterpenoids from the soft coral Cladiella krempfi. AB - New four eunicellin-based diterpenoids, krempfielins J-M (1-4) were isolated from the organic extract of a Taiwanese soft coral Cladiella krempfi. The structures of the new metabolites were elucidated on the basis of extensive spectroscopic analysis. The structure of compound 2 is rare due to the presence of the highly oxygenated pattern. Anti-inflammatory activity of 1-6 to inhibit the superoxide anion generation and elastase release in FMLP/CB-induced human neutrophils was also evaluated, and 2 and 4 were shown to possess the ability to inhibit the elastase release. PMID- 23917070 TI - Leukocyte telomere length in mastocytosis: correlations with depression and perceived stress. AB - BACKGROUND: Mastocytosisis a rare disease associated with chronic symptoms related to mast cell mediator release. Patients with mastocytosis display high level of negative emotionality such as depression and stress sensibility. Brain mast cells are mainly localized in the diencephalon, which is linked to emotion regulatory systems. Negative emotionality has been shown to be associated with telomere shortening. Taken together these observations led us to hypothesize that mast cells activity could be involved in both negative emotionality and telomere shortening in mastocytosis. OBJECTIVE: To demonstrate a possible relationship between negative emotionality in mastocytosis and leukocytes telomere length. METHODS: Leukocyte telomere length and telomerase activity were measured among mastocytosis patients and were correlated with perceived stress and depression assessed by the Beck Depression Inventory revised and the Perceived Stress Scale. RESULTS: Mild-severe depression scores were frequent (78.9%) as well as high perceived stress (42.11%). Telomere length was correlated to perceived stress (r=0.77; p=0.0001) but not to depression in our population. Patients displaying Wild-type KIT significantly presented higher perceived stress levels. Patients with the D816VC KIT mutation who had high perceived stress scores displayed significantly shorter telomere but not if they had high depression scores. CONCLUSION: These findings suggest that high perceived stress in mastocytosis could accelerate the rate of leukocytes telomere shortening. Since mastocytosis is, by definition, a mast cell mediated disease; these cells could be involved in this phenomenon. Mechanistic causal relationships between these parameters need to be investigated. PMID- 23917071 TI - Density and structural effects in the radiation tolerance of TiO2 polymorphs. AB - The radiation response of TiO2 has been studied using molecular dynamics. The simulations are motivated by experimental observations that the three low pressure polymorphs, rutile, brookite and anatase, exhibit vastly different tolerances to amorphization under ion-beam irradiation. To understand the role of structure we perform large numbers of simulations using the small thermal spike method. We quantify to high statistical accuracy the number of defects created as a function of temperature and structure type, and reproduce all the main trends observed experimentally. To evaluate a hypothesis that volumetric strain relative to the amorphous phase is an important driving force for defect recovery, we perform spike simulations in which the crystalline density is varied over a wide range. Remarkably, the large differences between the polymorphs disappear once the density difference is taken into account. This finding demonstrates that density is an important factor which controls radiation tolerance in TiO2. PMID- 23917072 TI - Biochemical and anatomical responses related to the in vitro survival of the tropical bromeliad Nidularium minutum to low temperatures. AB - Nidularium minutum is a tropical bromeliad that grows in natural environment with temperatures ranging from 2 to 30 degrees C. In the present work we cultivated this species in vitro at 5, 10, 15, and 25 degrees C for 3 and 6 months aiming at assessing biochemical and morphological responses that allow its survival under low temperatures. No survival was observed for plants cultured constantly at 5 degrees C and the lowest biometric parameters were found for those grown at 10 degrees C. A thick aquiferous parenchyma, accumulation of reducing sugars, and increased pectin content in the cell walls were observed in plants grown at 10 and 15 degrees C when compared to those maintained at 25 degrees C. In plants cultured at 10 degrees C, leaf bleaching correlated with low chlorophyll content and lower survival rate after 6 months when compared to those grown at 15 degrees C. The best in vitro culture condition for slow growth and plant acclimatization was found to be at 15 degrees C. This probably correlated with the immediate availability of carbon to restore growth during acclimatization and also with higher root initiation under this condition. This study brings information about the responses related to functional adaptation to low temperatures in N. minutum cultured in vitro that can also be implicated in its survival under natural conditions. Additionally, it suggests the best temperature to form a minimal growth collection to be used in restocking and conservation programs for endangered tropical bromeliads. PMID- 23917073 TI - Nitric oxide alleviates arsenic-induced toxic effects in ridged Luffa seedlings. AB - Hydroponic experiments were conducted to investigate whether exogenous addition of nitric oxide (NO) as sodium nitroprusside (SNP) alleviates arsenic (As) toxicity in Luffa acutangula (L.) Roxb. seedlings. Arsenic (5 and 50 MUM) declined growth of Luffa seedlings which was accompanied by significant accumulation of As. SNP (100 MUM) protected Luffa seedlings against As toxicity as it declined As accumulation significantly. The photosynthetic pigments and chlorophyll fluorescence parameters such as Fv/Fm, Fv/F0, Fm/F0 and qP were decreased while NPQ was raised by As. However, the toxic effects of As on photosynthesis were significantly ameliorated by SNP. The oxidative stress markers such as superoxide radical, hydrogen peroxide and malondialdehyde (lipid peroxidation) contents were enhanced by As, however, these oxidative indices were diminished significantly in the presence of SNP. As treatment stimulated the activities of SOD and CAT while the activities of APX and GST, and AsA content and AsA/DHA ratio were decreased. Upon SNP addition, along with further rise in SOD and CAT activity, APX and GST activity, and levels of AsA and AsA/DHA ratio were restored considerably. Overall results revealed that significant accumulation of As suppressed growth, photosynthesis, APX and GST activities and decreased AsA content, hence led to the oxidative stress. However, the addition of SNP protected seedlings against As stress by regulating As accumulation, oxidative stress and antioxidant defense system. PMID- 23917074 TI - In silico proteome-wide amino aCid and elemental composition (PACE) analysis of expression proteomics data provides a fingerprint of dominant metabolic processes. AB - Proteome-wide Amino aCid and Elemental composition (PACE) analysis is a novel and informative way of interrogating the proteome. The PACE approach consists of in silico decomposition of proteins detected and quantified in a proteomics experiment into 20 amino acids and five elements (C, H, N, O and S), with protein abundances converted to relative abundances of amino acids and elements. The method is robust and very sensitive; it provides statistically reliable differentiation between very similar proteomes. In addition, PACE provides novel insights into proteome-wide metabolic processes, occurring, e.g., during cell starvation. For instance, both Escherichia coli and Synechocystis down-regulate sulfur-rich proteins upon sulfur deprivation, but E. coli preferentially down regulates cysteine-rich proteins while Synechocystis mainly down-regulates methionine-rich proteins. Due to its relative simplicity, flexibility, generality and wide applicability, PACE analysis has the potential of becoming a standard analytical tool in proteomics. PMID- 23917075 TI - Role of CYP2A13 in the bioactivation and lung tumorigenicity of the tobacco specific lung procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: in vivo studies using a CYP2A13-humanized mouse model. AB - The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is abundant in tobacco smoke, is a potent lung procarcinogen. The present study was aimed to prove that transgenic expression of human cytochrome P450 2A13 (CYP2A13), known to be selectively expressed in the respiratory tract and be the most efficient enzyme for NNK bioactivation in vitro, will enhance NNK bioactivation and NNK-induced tumorigenesis in the mouse lung. Kinetic parameters of NNK bioactivation in vitro and incidence of NNK-induced lung tumors in vivo were determined for wild-type, Cyp2a5-null and CYP2A13-humanized (CYP2A13 transgenic/Cyp2a5-null) mice. As expected, in both liver and lung microsomes, the loss of CYP2A5 resulted in significant increases in Michaelis constant (K m) values for the formation of 4-oxo-4-(3-pyridyl)-butanal, representing the reactive intermediate that can lead to the formation of O(6)-methylguanine (O(6) mG) DNA adducts; however, the gain of CYP2A13 at a fraction of the level of mouse lung CYP2A5 led to recovery of the activity in the lung, but not in the liver. The levels of O(6)-mG, the DNA adduct highly correlated with lung tumorigenesis, were significantly higher in the lungs of CYP2A13-humanized mice than in Cyp2a5 null mice. Moreover, incidences of lung tumorigenesis were significantly greater in CYP2A13-humanized mice than in Cyp2a5-null mice, and the magnitude of the differences in incidence was greater at low (30mg/kg) than at high (200mg/kg) NNK doses. These results indicate that CYP2A13 is a low K m enzyme in catalyzing NNK bioactivation in vivo and support the notion that genetic polymorphisms of CYP2A13 can influence the risks of tobacco-induced lung tumorigenesis in humans. PMID- 23917076 TI - Hepatitis B surface antigen inhibits MICA and MICB expression via induction of cellular miRNAs in hepatocellular carcinoma cells. AB - Hepatitis B surface antigen (HBsAg) seropositivity is an important risk factor for hepatocellular carcinoma (HCC), and HBsAg-transgenic mice have been reported to spontaneously develop HCC. The major histocompatibility complex class I related molecules A and B (MICA and MICB) are NKG2D ligands that play important roles in tumor immune surveillance. In the present study, we found that HBsAg overexpression in HepG2 cells led to upregulation of 133 and downregulation of 9 microRNAs (miRNAs). Interestingly, several HBsAg-induced miRNAs repressed the expression of MICA and MICB via targeting their 3'-untranslated regions. In addition, the expression of MICA and MICB was significantly reduced upon HBsAg overexpression, which was partially restored by inhibiting the activities of HBsAg-induced miRNAs. Moreover, HBsAg-overexpressing HCC cells exhibited reduced sensitivity to natural killer cell-mediated cytolysis. Taken together, our data suggest that HBsAg supresses the expression of MICA and MICB via induction of cellular miRNAs, thereby preventing NKG2D-mediated elimination of HCC cells. PMID- 23917077 TI - Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production. AB - Like many other human cancers, the development of malignant mesothelioma is closely associated with a chronic inflammatory condition. Both macrophages and mesothelial cells play crucial roles in the inflammatory response caused by asbestos exposure. Here, we show that adipocytes can also contribute to asbestos induced inflammation through dysregulated adipocytokine production. 3T3-L1 preadipocytes were differentiated into mature adipocytes prior to use. These cells took up asbestos fibers (chrysotile, crocidolite and amosite) but were more resistant to asbestos-induced injury than macrophages and mesothelial cells. Expression microarray analysis followed by reverse transcription-PCR revealed that adipocytes respond directly to asbestos exposure with an increased production of proinflammatory adipocytokines [e.g. monocyte chemoattractant protein-1 (MCP-1)], whereas the production of anti-inflammatory adipocytokines (e.g. adiponectin) is suppressed. This was confirmed in epididymal fat pad of mice after intraperitoneal injection of asbestos fibers. Such dysregulated adipocytokine production favors the establishment of a proinflammatory environment. Furthermore, MCP-1 marginally promoted the growth of MeT-5A mesothelial cells and significantly enhanced the wound healing of Y-MESO-8A and Y MESO-8D human mesothelioma cells. Our results suggest that increased levels of adipocytokines, such as MCP-1, can potentially contribute to the promotion of mesothelial carcinogenesis through the enhanced recruitment of inflammatory cells as well as a direct growth and migration stimulatory effect on mesothelial and mesothelioma cells. Taken together, our findings support a potential cancer promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis. PMID- 23917079 TI - Post-hypothermia fever is associated with increased mortality after out-of hospital cardiac arrest. AB - OBJECTIVE: Post-cardiac arrest fever has been associated with adverse outcome before implementation of therapeutic hypothermia (TH), however the prognostic implications of post-hypothermia fever (PHF) in the era of modern post resuscitation care including TH has not been thoroughly investigated. The aim of the study was to assess the prognostic implication of PHF in a large consecutive cohort of comatose survivors after out-of-hospital cardiac arrest (OHCA) treated with TH. METHODS: In the period 2004-2010, a total of 270 patients resuscitated after OHCA and surviving a 24-h protocol of TH with a target temperature of 32-34 degrees C were included. The population was stratified in two groups by median peak temperature (>=38.5 degrees C) within 36h after rewarming: PHF and no-PHF. Primary endpoint was 30-days mortality and secondary endpoint was neurological outcome assessed by Cerebral Performance Category (CPC) at hospital discharge. RESULTS: PHF (>=38.5 degrees C) was associated with a 36% 30-days mortality rate compared to 22% in patients without PHF, plog-rank=0.02, corresponding to an adjusted hazard rate (HR) of 1.8 (95% CI: 1.1-2.7), p=0.02). The maximum temperature (HR=2.0 per degrees C above 36.5 degrees C (95% CI: 1.4-3.0), p=0.0005) and the duration of PHF (HR=1.6 per 8h (95% CI: 1.3-2.0), p<0.0001) were also independent predictors of 30-days mortality in multivariable models. Good neurological outcome (CPC1-2) versus unfavourable outcome (CPC3-5) at hospital discharge was found in 61% vs. 39% in the PHF group compared to 75% vs. 25% in the No PHF group, p=0.02. CONCLUSIONS: Post-hypothermia fever >=38.5 degrees C is associated with increased 30-days mortality, even after controlling for potential confounding factors. Avoidance of PHF as a therapeutic target should be evaluated in prospective randomized trials. PMID- 23917078 TI - The formula for survival in resuscitation. AB - The International Liaison Committee on Resuscitation (ILCOR) Advisory Statement on Education and Resuscitation in 2003 included a hypothetical formula--'the formula for survival' (FfS)--whereby three interactive factors, guideline quality (science), efficient education of patient caregivers (education) and a well functioning chain of survival at a local level (local implementation), form multiplicands in determining survival from resuscitation. In May 2006, a symposium was held to discuss the validity of the formula for survival hypothesis and to investigate the influence of each of the multiplicands on survival. This commentary combines the output from this symposium with an updated illustration of the three multiplicands in the FfS using rapid response systems (RRS) for medical science, therapeutic hypothermia (TH) for local implementation, and bystander cardiopulmonary resuscitation (CPR) for educational efficiency. International differences between hospital systems made it difficult to assign a precise value for the multiplicand medical science using RRS as an example. Using bystander CPR as an example for the multiplicand educational efficiency, it was also difficult to provide a precise value, mainly because of differences between compression-only and standard CPR. The local implementation multiplicand (exemplified by therapeutic hypothermia) is probably the easiest to improve, and is likely to have the most immediate improvement in observed survival outcome in most systems of care. Despite the noted weaknesses, we believe that the FfS will be useful as a mental framework when trying to improve resuscitation outcome in communities worldwide. PMID- 23917081 TI - Endometrial echo complex thickness in postmenopausal endometrial cancer. AB - OBJECTIVE: To determine the preoperative pelvic ultrasonographic characteristics of postmenopausal women diagnosed with endometrial cancer (EC) at our institution. METHODS: Postmenopausal women with EC who underwent preoperative transvaginal pelvic ultrasound from 1999-2009 were identified from our institutional database. The histologic diagnosis was based on pathologic findings in the hysterectomy specimen. Endometrial echo complex (EEC) thickness was abstracted from ultrasound reports. In all instances, ultrasound preceded the biopsy by a maximum of 3 months. Means with standard deviations were calculated for all categorical data. Differences between type 1 and type 2 ECs were determined using Mann-Whitney U tests and Chi squared/Fisher's exact tests, as appropriate. A p-value of <0.05 was considered statistically significant. RESULTS: Among 250 patients with postmenopausal EC, 156 had type 1 EC while 94 had type 2 EC. Thirty-six percent of the cohort had an EEC <= 4 mm, including 37% of patients with type 1 EC and 34% of patients with type 2 EC (p=0.63). There were no significant differences between type 1 and type 2 ECs in any demographic characteristic, other than likelihood of postmenopausal bleeding. CONCLUSIONS: Current expert opinion recommends no further diagnostic procedure in a woman with postmenopausal bleeding and an EEC <= 4 mm. These results indicate that a sizable proportion of women with EC have EECs <= 4 mm during their initial evaluation. An EEC <= 4 mm does not completely rule out endometrial cancer and cannot supplant histologic evaluation. PMID- 23917082 TI - Interferon-gamma in ascites could be a predictive biomarker of outcome in ovarian carcinoma. AB - OBJECTIVE: The ovarian cancer-associated ascites is an ideal material for evaluating the interaction between the host immune system and cancer cells in the tumor micro-environment. The aim of this study was to investigate whether the selected target cytokine expression levels in ascites could serve as an immune biomarker for predicting outcomes in ovarian cancer. METHODS: Eighty-eight specimens of ovarian cancer-associated ascites were evaluated to select the target cytokine by a cytokine profiling kit. The 144 total samples were subsequently analyzed for this target cytokine. The correlation between the target cytokine and clinical characteristics was analyzed. RESULTS: Interferon gamma (IFN-gamma) was identified as the target cytokine. Higher levels of IFN gamma in the ascites of the tumor micro-environment were associated with advanced disease (p=0.012), higher tumor histological grading (p=0.004), and sub-optimal surgical status (p=0.040). By multivariate analysis, the adjusted hazard ratios (HRs) were 2.74 (95% confidence interval (CI) 1.85-4.05, p<0.001) for disease free survival (DFS) and 1.72 (95% CI 1.01-2.93, p=0.048) for overall survival (OS) for a 10-fold increase in IFN-gamma concentration in the ascites. An inverse dose-response relationship between IFN-gamma level and survival was also noted (Ptrend<0.001 for DFS and Ptrend<0.042 for OS). CONCLUSIONS: Patients with ovarian cancer and higher IFN-gamma expression levels in cancer-associated ascites will have shorter DFS and OS. IFN-gamma levels in the ascites may be a prognostic marker and a potential reference for immunotherapy targeting IFN gamma. PMID- 23917080 TI - ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: a comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. AB - OBJECTIVE: ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC). METHODS: The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel carboplatin chemotherapy (n=1158) or any first-line chemotherapy regimen (n=2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients. RESULT: Fine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p=0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours. CONCLUSION: Our study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival. PMID- 23917083 TI - Obstetric outcomes of patients undergoing total laparoscopic radical trachelectomy for early stage cervical cancer. AB - OBJECTIVE: To assess the obstetric outcomes of our total laparoscopic radical trachelectomy (TLRT) cases for early stage cervical cancer. MATERIALS AND METHODS: A total of 56 patients who underwent TLRT between December 2001 and August 2012 were reviewed retrospectively using clinicopathological, surgical, and follow-up data from patients' medical records. RESULTS: We performed this operation on 56 patients during the study period. The mean age of these 56 patients was 31.9 years (range 22-42 years). Fifty-three patients' fertility was preserved without requiring post-operative adjuvant treatment. Twenty-five women attempted to conceive, of whom 13 succeeded for a total of 21 pregnancies (52% pregnancy rate). Ten of these 21 pregnancies were the result of assisted reproductive technologies. Of those, 5 resulted in first trimester miscarriages, 2 in second trimester miscarriages, and 13 in live births. Ten pregnancies reached the third trimester. Preterm premature rupture of membranes (8/13, 61.5%) was the most common complication during pregnancy. The rate of preterm delivery was 47.6%. Three patients delivered at 22-28 weeks of gestational age. Two of these babies showed permanent damage: one has cerebral palsy; the other has developmental retardation. One pregnancy is ongoing. CONCLUSION: TLRT is a useful technique associated with an excellent pregnancy rate in fertility-preserving surgery to treat early stage cervical cancer. PMID- 23917084 TI - Validation of the human activity profile questionnaire as a measure of physical activity levels in older community-dwelling women. AB - The purpose of this study was to assess the validity of the Human Activity Profile (HAP) by comparing scores with accelerometer data and by objectively testing its cutoff points. This study included 120 older women (age 60-90 years). Average daily time spent in sedentary, moderate, and hard activity; counts; number of steps; and energy expenditure were measured using an accelerometer. Spearman rank order correlations were used to evaluate the correlation between the HAP scores and accelerometer variables. Significant relationships were detected (rho = .47-.75, p < .001), indicating that the HAP estimates physical activity at a group level well; however, scatterplots showed individual errors. Receiver operating characteristic curves were constructed to determine HAP cutoff points on the basis of physical activity level recommendations, and the cutoff points found were similar to the original HAP cutoff points. The HAP is a useful indicator of physical activity levels in older women. PMID- 23917085 TI - Opportunistic internal mammary lymph node biopsy during microvascular free flap breast reconstruction: a useful technique? PMID- 23917086 TI - (-)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites. AB - The interaction of (-)-reboxetine, a non-tricyclic norepinephrine selective reuptake inhibitor, with muscle-type nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that (-)-reboxetine: (a) inhibits (+/-) epibatidine-induced Ca(2+) influx in human (h) muscle embryonic (halpha1beta1gammadelta) and adult (halpha1beta1epsilondelta) AChRs in a non competitive manner and with potencies IC50=3.86+/-0.49 and 1.92+/-0.48 MUM, respectively, (b) binds to the [(3)H]TCP site with ~13-fold higher affinity when the Torpedo AChR is in the desensitized state compared to the resting state, (c) enhances [(3)H]cytisine binding to the resting but activatableTorpedo AChR but not to the desensitized AChR, suggesting desensitizing properties, (d) overlaps the PCP luminal site located between rings 6' and 13' in the Torpedo but not human muscle AChRs. In silico mutation results indicate that ring 9' is the minimum structural component for (-)-reboxetine binding, and (e) interacts to non luminal sites located within the transmembrane segments from the Torpedo AChR gamma subunit, and at the alpha1/epsilon transmembrane interface from the adult muscle AChR. In conclusion, (-)-reboxetine non-competitively inhibits muscle AChRs by binding to the TCP luminal site and by inducing receptor desensitization (maybe by interacting with non-luminal sites), a mechanism that is shared by tricyclic antidepressants. PMID- 23917087 TI - Inhibitors of switch kinase 'spleen tyrosine kinase' in inflammation and immune mediated disorders: a review. AB - Spleen tyrosine kinase (Syk), a member of Syk family of non-receptor protein tyrosine kinases plays a significant role in the immune cell signaling in B cells, mast cells, macrophages and neutrophils. Anomalous regulation of this kinase can lead to different allergic disorders and antibody-mediated autoimmune diseases such as rheumatoid arthritis, asthma, psoriasis and allergic rhinitis. Being involved in the growth and survive mechanism of B cells, its inhibition can be beneficial in B-cell lymphoma. Thus, Syk can be sited as a therapeutically relevant target for various allergic and autoimmune disorders. This review article describes the structure of Syk and its role in B-cell signaling. In addition to this, data regarding small molecule inhibitors of Syk has also been reviewed from different papers and patents published. PMID- 23917088 TI - Disorders of the cutaneous basement membrane zone--the paradigm of epidermolysis bullosa. AB - The cutaneous basement membrane zone (BMZ) is a highly specialized functional complex that provides the skin with structural adhesion and resistance to shearing forces. Its regulatory functions include control of epithelial mesenchymal interactions under physiological and pathological conditions. Mutations in genes encoding components of the BMZ are associated with inherited skin disorders of the epidermolysis bullosa (EB) group, characterized by skin fragility, mechanically induced blisters and erosions of the skin and mucous membranes. Although most disease-associated genes are known, the genetic basis of new EB subtypes linked to mutations in genes for focal adhesion proteins was uncovered only recently. The molecular mechanisms leading to blistering, abnormal wound healing, predisposition to skin cancer, and other complications in EB have been elucidated using animal models and disease proteomics. The rapid progress in understanding the molecular basis of EB has enabled the development of strategies for biologically valid causal therapies. PMID- 23917092 TI - CONTINUUM Multiple Sclerosis: Teaching us about more than MS and its ABCs. PMID- 23917094 TI - Diagnosis and differential diagnosis of multiple sclerosis. AB - PURPOSE OF REVIEW: When a patient presents with symptoms or imaging suggestive of multiple sclerosis (MS), making the correct diagnosis may at times be straightforward but in many cases is quite challenging. Symptoms may be difficult for patients to characterize and for clinicians to interpret; findings on examination may be subtle; imaging is not always specific; and the differential diagnosis of possible demyelinating disease is quite broad. Making a correct diagnosis of MS early in the disease course is likely to become even more important over time as new disease-modifying therapies, particularly those with potential neuroprotective benefits, are introduced. This article reviews the current diagnostic criteria for MS and illustrates their application as well as reviews the differential diagnosis for patients presenting with symptoms or imaging suggestive of demyelinating disease. RECENT FINDINGS: The diagnostic criteria for MS were revised by the International Panel on Diagnosis of Multiple Sclerosis in 2010. SUMMARY: The diagnostic criteria for MS have been revised several times over the years, most recently giving rise to the McDonald 2010 criteria. The diagnosis of MS begins with a patient who presents with symptoms typical for the disease, termed the "clinically isolated syndrome," which most commonly affects the optic nerves, brainstem, or spinal cord. If the patient's symptoms and imaging are typical for MS, the clinician can then apply the appropriate diagnostic criteria. If atypical clinical or imaging findings are present, alternative etiologies must be pursued as appropriate. PMID- 23917093 TI - Pathology of multiple sclerosis: where do we stand? AB - PURPOSE OF REVIEW: This article summarizes the pathologic features of multiple sclerosis (MS) and other inflammatory demyelinating diseases and discusses neuropathologic studies that have yielded novel insights into potential mechanisms of demyelination. RECENT FINDINGS: The pathologic hallmark of MS consists of focal demyelinated plaques within the CNS, with variable degrees of inflammation, gliosis, and neurodegeneration. Active MS lesions show a profound pathologic heterogeneity with four major patterns of immunopathology, suggesting that the targets of injury and mechanisms of demyelination in MS may be different in different disease subgroups. Recent pathologic studies have suggested that the subarachnoid space and cortex may be initial sites and targets of the MS disease process, that inflammatory cortical demyelination is present early in MS, and that meningeal inflammation may drive cortical and white matter injury in some MS patients. SUMMARY: MS is heterogeneous with respect to clinical, genetic, radiographic, and pathologic features; surrogate MRI, clinical, genetic, serologic, and/or CSF markers for each of the four immunopatterns need to be developed in order to recognize them in the general nonbiopsied MS population. Inflammatory cortical demyelination is an important early event in the pathogenesis of MS and may be driven by meningeal inflammation. These observations stress the importance of developing imaging techniques able to capture early inflammatory cortical demyelination in order to better understand the disease pathogenesis and to determine the impact of potential disease modifying therapies on the cortex. PMID- 23917095 TI - Acute disseminated encephalomyelitis, transverse myelitis, and neuromyelitis optica. AB - PURPOSE OF REVIEW: This review defines current clinical criteria for diagnosis, differential diagnosis, and clinical evaluation of acute disseminated encephalomyelitis, transverse myelitis, and neuromyelitis optica, and summarizes principles of treatment. RECENT FINDINGS: Consensus criteria for transverse myelitis and acute disseminated encephalomyelitis have been proposed. A specific biomarker, aquaporin-4 autoantibody, has been discovered for neuromyelitis optica that allows for early and accurate diagnosis even in the absence of cardinal findings of optic neuritis and myelitis. The antibody is pathogenic and is facilitating an understanding of the pathophysiology of neuromyelitis optica and development of antigen-specific treatments. SUMMARY: Clinical and radiologic findings combined with serologic findings may permit classification of syndromes of transverse myelitis and acute disseminated encephalomyelitis in ways that may predict risk of relapse, type of relapse, and prognosis. Treatment, especially to prevent relapse, is dependent on the specific disease context in which syndromes such as transverse myelitis occur. PMID- 23917096 TI - Present and emerging therapies for multiple sclerosis. AB - PURPOSE OF REVIEW: The treatment of multiple sclerosis (MS) is evolving beyond the current parenteral immunomodulators and early oral alternatives, offering physicians considerable choice of therapies. Although all agents are tested in similarly designed clinical studies, comparison of their outcomes is not possible except in carefully controlled head-to-head comparator studies. In this review, the current, recent, and most imminent therapies are discussed and an overall summary is presented along with a discussion of how they are perceived relative to the older or other recent agents. RECENT FINDINGS: The list of potentially effective agents for the treatment of MS may be exhaustive, but several have now completed their phase 3 trials and have received or imminently expect government approval. This review discusses these new agents in terms of their perceived mechanisms of action and their respective results, and attempts to position them among the currently approved and utilized agents for MS. SUMMARY: Although it is not yet possible to predict which treatment is best suited to a given patient, it is nevertheless important to have a perspective of the possible agents and their efficacy and safety, and a plan regarding how to use them in order to maximize benefit and minimize harm in controlling relapsing MS. PMID- 23917097 TI - Unusual symptoms and syndromes in multiple sclerosis. AB - PURPOSE OF REVIEW: In multiple sclerosis (MS), symptoms vary widely from patient to patient. Certain events in MS are well recognized (eg, optic neuritis, brainstem and spinal cord relapses) and do not lead to much clinical confusion. However, other events that occur in MS may be less expected and may be underrecognized by some clinicians and may lead to an extensive and potentially unnecessary investigation for what is a known problem in MS. RECENT FINDINGS: This article reviews Lhermitte sign, Pulfrich phenomenon, Uhthoff phenomenon, and the useless hand of Oppenheim, along with the underrecognized phenomena of transient neurologic events (including tonic spasms). Disorders of temperature regulation in MS (likely based on hypothalamic involvement) which can present with bizarre behavioral change and evade diagnosis, are also discussed. The article concludes with a review of epilepsy and sleep disorders in MS, both of which appear to occur at an increased frequency in the MS population and may have implications for therapy. SUMMARY: This article is meant to help clinicians recognize and treat this fascinating set of underrecognized phenomena in MS and perhaps save patients trips to the emergency department, extraneous testing, and ineffective intervention. PMID- 23917098 TI - Gait disorders in multiple sclerosis. AB - PURPOSE OF REVIEW: Ambulation, and more broadly mobility, is frequently affected by multiple sclerosis (MS). The purpose of this review is to present recent developments regarding the impact, outcome measures, and management of gait disorders in MS. RECENT FINDINGS: Recently published surveys have confirmed the high prevalence of walking limitations in MS and their impact on the functional status and quality of life of MS patients and their families. Validated clinical outcome measures include the Timed 25-Foot Walk, 6-Minute Walk, and Multiple Sclerosis Walking Scale-12. Further characterization of gait disorders is allowed by gait analysis systems, as well as pedometers and oscillometers that measure walking in the patient's daily life. A growing body of evidence demonstrates the benefits of various rehabilitation interventions on walking performance. Dalfampridine, an extended-release formulation of 4-aminopyridine, is the first symptomatic medication indicated to improve walking in patients with MS. Newer assistive devices, such as the hip flexion assist device and functional electrical stimulation devices, show promising results in preliminary studies. Various treatments for spasticity can be used without compromising ambulation, but their ability to enhance gait needs to be further assessed. SUMMARY: Gait disorders need to be identified and managed early in the course of MS, using a multimodal approach that needs to be adjusted over time based on the results of periodic assessments. PMID- 23917099 TI - Pediatric demyelinating diseases. AB - PURPOSE OF REVIEW: In the past decade, the number of studies related to demyelinating diseases in children has exponentially increased. Demyelinating disease in children may be monophasic or chronic. Typical monophasic disorders in children are acute disseminated encephalomyelitis and clinically isolated syndromes, including optic neuritis and transverse myelitis. However, some cases of acute disseminated encephalomyelitis or clinically isolated syndrome progress to become chronic disorders, including multiple sclerosis and neuromyelitis optica. This review summarizes the current knowledge on monophasic and chronic demyelinating disorders in children, focusing on an approach to diagnosis and management. RECENT FINDINGS: Improved diagnostic definitions for pediatric demyelinating diseases have led to enhanced recognition of these disorders. Additionally, increased awareness and focused national and international efforts continue to inform about the clinical course, response to treatment, and disease pathogenesis. SUMMARY: Significant advances have been made in the recognition, diagnosis, and management of pediatric demyelinating disorders over the past 10 years. This review summarizes these advances and provides an updated approach to the diagnosis and management of pediatric demyelinating disorders. PMID- 23917100 TI - General health issues in multiple sclerosis: comorbidities, secondary conditions, and health behaviors. AB - PURPOSE OF REVIEW: Comorbid conditions, secondary conditions, and health behaviors are increasingly recognized to be important factors influencing a range of outcomes in multiple sclerosis (MS). This review discusses the most common comorbidities experienced in MS, their impact on clinical outcomes, and the impact of health behaviors. Osteoporosis is a common secondary condition in MS that will be discussed along with vitamin D insufficiency. RECENT FINDINGS: Mental comorbidity is common in MS; depression has a lifetime prevalence of 50%, while anxiety has a lifetime prevalence of 36%. Physical comorbidity is also common, with the most frequently reported conditions including hyperlipidemia, hypertension, arthritis, irritable bowel syndrome, and chronic lung disease. Fracture risk is increased among patients with MS because of an increased risk of osteoporosis and propensity for falls. Vitamin D insufficiency is common and may contribute to increased fracture risk and increased disease activity. Comorbidities and smoking are associated with diagnostic delays, increased disability progression, lower health-related quality of life, and lower adherence to treatment. SUMMARY: Physical and mental comorbidity and adverse health behaviors are common in patients with MS. Comorbidities and health behaviors are associated with adverse outcomes in MS and should be considered in the assessment and management of patients with MS. PMID- 23917101 TI - Current and new directions in MRI in multiple sclerosis. AB - PURPOSE OF REVIEW: This article summarizes the use of MRI in the diagnosis and treatment of multiple sclerosis (MS). Current and emerging imaging techniques are reviewed pertaining to their utility in MS. RECENT FINDINGS: Conventional T1 weighted and T2-weighted sequences are used to identify and characterize disease pathology in MS. T2 lesion burden, postcontrast enhancement, T1 hypointensities, and regional and global atrophy are all informative and correlate to clinical measures, such as disease disability, to a variable extent. Newer techniques such as diffusion tensor imaging, magnetization transfer imaging, and MR spectroscopy are increasingly being incorporated into clinical trials and may provide improved specificity to the underlying pathology. Double inversion recovery and ultrahigh field-strength MRI have direct application in MS for evaluating cortical pathology. Newer functional MRI techniques such as resting-state functional connectivity are increasingly being applied in MS. SUMMARY: Conventional and emerging imaging techniques greatly inform our understanding of MS. These techniques are integral in diagnosis, in evaluating new treatments for MS, and for following patients in the clinical setting. PMID- 23917102 TI - Optic neuritis and the evaluation of visual impairment in multiple sclerosis. AB - PURPOSE OF REVIEW: This review covers causes of visual impairment in multiple sclerosis (MS), differential diagnosis, and treatment. Emerging technologies are sometimes used in assessing the visual system and may require a neurologist's familiarity. The most common causes are emphasized and discussed in detail, including illustrative cases. RECENT FINDINGS: The use of optical coherence tomography as both a clinical and research tool has advanced our understanding of how the afferent visual system is affected by MS. SUMMARY: Optic neuritis remains one of the most common initial manifestations of MS, although a number of other causes of visual impairment are possible even in the patient with known MS. Some causes of visual impairment are consequences or complications of MS treatment and are particularly important to recognize. Low-contrast letter acuity and optical coherence tomography are techniques or tests emerging from the research arena that may inform care of the patient with MS and are important for the neurologist to be aware of. PMID- 23917103 TI - Disclosing a misdiagnosis of multiple sclerosis: do no harm? AB - The difficulty of diagnosing multiple sclerosis (MS) has been well documented. However, recent data also suggests that neurologists frequently encounter the clinical challenge of having to undo a misdiagnosis of MS. Undiagnosing MS has important clinical, psychosocial, and economic consequences for the patient, the treating neurologist, and the healthcare system at large. This article presents a case of misdiagnosed MS and discusses ethical challenges and obligations for the neurologist. PMID- 23917104 TI - Multiple sclerosis treatment: risk mitigation. AB - The growing number of disease-modifying medications approved for multiple sclerosis (MS) treatment is a significant step forward and provides new options for our patients. These medications, however, have differing efficacy and risk profiles. Although accurate predictors of efficacy are not available, treatment choices can be guided by patient-specific risk stratification. The use of risk mitigation strategies can help clinicians tailor MS treatment recommendations for individual patients. PMID- 23917105 TI - Special considerations when coding for patients with multiple sclerosis. PMID- 23917112 TI - Amazonian plant natural products: perspectives for discovery of new antimalarial drug leads. AB - Plasmodium falciparum and P. vivax malaria parasites are now resistant, or showing signs of resistance, to most drugs used in therapy. Novel chemical entities that exhibit new mechanisms of antiplasmodial action are needed. New antimalarials that block transmission of Plasmodium spp. from humans to Anopheles mosquito vectors are key to malaria eradication efforts. Although P. vivax causes a considerable number of malaria cases, its importance has for long been neglected. Vivax malaria can cause severe manifestations and death; hence there is a need for P. vivax-directed research. Plants used in traditional medicine, namely Artemisia annua and Cinchona spp. are the sources of the antimalarial natural products artemisinin and quinine, respectively. Based on these compounds, semi-synthetic artemisinin-derivatives and synthetic quinoline antimalarials have been developed and are the most important drugs in the current therapeutic arsenal for combating malaria. In the Amazon region, where P. vivax predominates, there is a local tradition of using plant-derived preparations to treat malaria. Here, we review the current P. falciparum and P. vivax drug-sensitivity assays, focusing on challenges and perspectives of drug discovery for P. vivax, including tests against hypnozoites. We also present the latest findings of our group and others on the antiplasmodial and antimalarial chemical components from Amazonian plants that may be potential drug leads against malaria. PMID- 23917113 TI - Anti-obesity effect of Artemisia capillaris extracts in high-fat diet-induced obese rats. AB - This study evaluated the anti-obesity effects of Artemisia capillaris extracts in high-fat diet (HFD)-induced obese rats. After six weeks feeding with HFD, Wistar male rats (12-weeks-old) were divided into three groups: HFD-control group and HFD mixed with 0.4% and 0.8% Artemisia capillaris extracts treated groups. After seven weeks of treatments, the body weight gain of the 0.4% and 0.8% A. capillaris extracts treated groups were significantly less than that of the HFD control group by 11.8% and 15.4%, respectively. Also, A. capillaris extracts treated groups showed significantly lower serum TG, TC and LDL-c levels in a dose related manner, while causing the reverse effect in serum HDL-c, and exhibited a hepatoprotective effects in vivo, indicated by reduced hepatic lipid contents, and serum ALT and AST levels. These results show that A. capillaris extracts may prevent body weight increases and improve dyslipidemia in HFD-induced obese rats by enhancing their lipid metabolism. PMID- 23917114 TI - Contributions of NMR to the understanding of the coordination chemistry and DNA interactions of metallo-bleomycins. AB - Bleomycins are a family of glycopeptide antibiotics that have the ability to bind and degrade DNA when bound to key metal ions, which is believed to be responsible for their antitumor activity. Knowledge of the structures of metallo-bleomycins is vital to further characterize their mechanism of action. To this end, numerous structural studies on metallo-bleomycins have been conducted. NMR spectroscopy has had a key role in most of these studies, and has led to very important findings involving the coordination chemistry of metallo-bleomycins, and the details of many metallo-bleomycin-DNA spatial correlations for this important drug. This paper reviews the most important contributions of NMR to the bleomycin field. PMID- 23917115 TI - Advances in kinetic isotope effect measurement techniques for enzyme mechanism study. AB - Kinetic isotope effects (KIEs) are a very powerful tool for investigating enzyme mechanisms. Precision of measurement is the most important factor for KIE determinations, especially for small heavy atom KIEs. Internal competition is commonly used to measure small KIEs on V/K. Several methods, including such as liquid scintillation counting, mass spectrometry, nuclear magnetic resonance spectroscopy and polarimetry have been used to determine KIEs. In this paper, which does not aspire to be an exhaustive review, we briefly review different experimental approaches for the measurement of KIEs on enzymatic reaction with an emphasis on newer techniques employing mass spectrometry and nuclear magnetic resonance spectrometry as well as some corresponding examples. PMID- 23917116 TI - Anti-oxidant and anti-inflammatory activities of Inonotus obliquus and germinated brown rice extracts. AB - Inonotus obliquus (IO) is parasitic mushroom that grows on birch and other trees in Russia, Korea, Europe and United States. However, IO is not readily available for consumption due to its high cost and difficult growth. In this regard, IO was inoculated on germinated brown rice (GBR) in the present study and the antioxidant and anti-inflammatory activities of the IO grown on germinated brown rice (IOGBR) extracts were evaluated extensively and compared with those for IO and GBR. IOGBR showed highest antioxidant activities with scavenging total intracellular ROS and MDA levels as well as increasing the antioxidant enzymes activity in the H2O2-stimulated mice liver. It also exhibited best inflammatory activities by suppressing the proinflammatory mediators such as NO, PGE2, iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6 in an LPS-stimulated RAW 264.7 cell line. This study provides a comparative approach to find out an excellent natural source of antioxidants and anti-inflammatory agent as a dietary supplement. PMID- 23917117 TI - Genetics: DSTYK gene linked to urinary tract defects. PMID- 23917118 TI - Prostate cancer: ADT use associated with acute kidney injury. PMID- 23917120 TI - Bladder cancer: is contrast-enhanced CT necessary for following up NMIBC? PMID- 23917121 TI - Prostate cancer: AUA-ASTRO guidelines for post-RP radiation fail to go nuclear. PMID- 23917119 TI - Failed hypospadias in paediatric patients. AB - Failed hypospadias refers to any hypospadias repair that leads to complications or causes patient dissatisfaction. The complication rate after hypospadias repairs ranges from 5-70%, but the actual incidence of failed hypospadias is unknown as complications can become apparent many years after surgery and series with lifelong follow-up data do not exist. Moreover, little is known about uncomplicated repairs that fail in terms of patient satisfaction. Risk factors for complications include factors related to the hypospadias (severity of the condition and characteristics of the urethral plate), the patient (age at surgery, endocrine environment, and wound healing impairment), the surgeon (technique selection and surgeon expertise), and the procedure (technical details and postoperative management). The most important factors for preventing complications are surgeon expertise (number of cases treated per year), interposition of a barrier layer between the urethroplasty and the skin, and postoperative urinary drainage. Major complications associated with failed hypospadias include residual curvature, healing complications (preputial dehiscence, glans dehiscence, fistula formation, and urethral breakdown), urethral obstruction (meatal stenosis, urethral stricture, and functional obstruction), urethral diverticula, hairy urethra, and penile skin deficiency. PMID- 23917123 TI - Informal and involuntary mental patients in England and Wales: a comparison in the light of Rabone. AB - Informal and involuntary (compulsorily detained) patients are the two broad categories of patients in psychiatric hospitals today. In Rabone v Pennine Care NHS Trust the Supreme Court made, among other things, a distinction between the two types of patients. This article contributes to the literature by adding to that distinction. It looks at the evolution of the term, 'informal patient', gives an account of Rabone case and then deals with the comparison between the two types of patients. PMID- 23917122 TI - Dissection of androgen receptor-promoter interactions: steroid receptors partition their interaction energetics in parallel with their phylogenetic divergence. AB - Steroid receptors comprise a homologous family of ligand-activated transcription factors. The members include androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and progesterone receptor (PR). Phylogenetic studies demonstrate that AR, GR, MR, and PR are most closely related, falling into subgroup 3C. ER is more distantly related, falling into subgroup 3A. To determine the quantitative basis by which receptors generate their unique transcriptional responses, we are systematically dissecting the promoter-binding energetics of all receptors under a single "standard state" condition. Here, we examine the self-assembly and promoter-binding energetics of full-length AR and a mutant associated with prostate cancer, T877A. We first demonstrate that both proteins exist only as monomers, showing no evidence of dimerization. Although this result contradicts the traditional understanding that steroid receptors dimerize in the absence of DNA, it is fully consistent with our previous work demonstrating that GR and two PR isoforms either do not dimerize or dimerize only weakly. Moreover, both AR proteins exhibit substantial cooperativity between binding sites, again as seen for GR and PR. In sharp contrast, the more distantly related ER-alpha dimerizes so strongly that energetics can only be measured indirectly, yet cooperativity is negligible. Thus, homologous receptors partition their promoter-binding energetics quite differently. Moreover, since receptors most closely related by phylogeny partition their energetics similarly, such partitioning appears to be evolutionarily conserved. We speculate that such differences in energetics, coupled with different promoter architectures, serve as the basis for generating receptor-specific promoter occupancy and thus function. PMID- 23917124 TI - System-dependent regulations of colour-pattern development: a mutagenesis study of the pale grass blue butterfly. AB - Developmental studies on wing colour patterns have been performed in nymphalid butterflies, but efficient genetic manipulations, including mutagenesis, have not been well established. Here, we have performed mutagenesis experiments in a lycaenid butterfly, the pale grass blue Zizeeria maha, to produce colour-pattern mutants. We fed the P-generation larvae an artificial diet containing the mutagen ethyl methane sulfonate (EMS), and the F1- and F2-generation adults showed various aberrant colour patterns: dorsoventral transformation, anterioposterior background colouration gap, weak contrast, disarrangement of spots, reduction of the size of spots, loss of spots, fusion of spots, and ectopic spots. Among them, the disarrangement, reduction, and loss of spots were likely produced by the coordinated changes of many spots of a single wing around the discal spot in a system-dependent manner, demonstrating the existence of the central symmetry system. The present study revealed multiple genetic regulations for system dependent and wing-wide colour-pattern determination in lycaenid butterflies. PMID- 23917126 TI - PTSD symptoms, disclosure, and relationship distress: explorations of mediation and associations over time. AB - Emotional numbing symptoms of posttraumatic stress disorder (PTSD) are negatively associated with relationship satisfaction in combat veterans and their romantic partners. Many speculate that one mechanism of this association may be decreased disclosure by veterans, but previous studies lacked appropriate data to test this hypothesis. In a sample of 224 OIF/OEF-era National Guard service members (SMs) and 214 of their romantic partners, we measured SMs' PTSD symptoms. Four to six months later, we assessed both partners' reports of SMs' emotional disclosure and both partners' relationship satisfaction (83 SMs and 91 partners completed Time 2). In a path analysis, SMs' emotional numbing was negatively associated with their later relationship satisfaction. Furthermore, SMs' emotional numbing was negatively associated with both partners' reports of SMs' emotional disclosure. Finally, SMs' emotional numbing exerted significant or nearly significant indirect effects on both partners' relationship satisfaction via decreased emotional disclosure. The findings demonstrated the importance of accounting for both partners' perceptions when studying couple functioning in the context of PTSD or treating PTSD via conjoint intervention. PMID- 23917127 TI - [Ascending aorta replacement late after aortic valve replacement]. AB - Replacement of the asceding aorta is indicated in patients undergoing aortic valve replacement( AVR), if the diameter of the ascending aorta is greater than 5.0 cm. If the diameter of the asceding aorta is from 4.0 to 5.0 cm, it was arguable whether replacement of the ascending aorta should be performed. Nine patients who underwent reoperative ascending aorta replacement after AVR were reviewed retrospectively. Reoperation on the asending aorta replacement was performed 11.8+/-7.2 years (range 1y5m~23y3m) after AVR. Mean patient age was 69.9+/-6.3 (range 60~81). In 2 cases, reoperations were performed early year after AVR. Although ascending aorta was dilated at the 1st operation, replacement wasn't performed for the age and minimally invasive cardiac surgery (MICS). In 3 cases, reoperations were performed more than 10 years later. On these cases, ascending aorta aneurysm and dissection occurred with no pain and were pointed out by computed tomography(CT) or ultrasonic cardiogram(UCG). We think that patients with dilatation of the ascending aorta should undergo AVR and aorta replacement at the 1st operation regardness of age. It is important that patients who underwent AVR should undergo a regular checkup on the ascending aorta. PMID- 23917125 TI - A systematic analysis of the PARP protein family identifies new functions critical for cell physiology. AB - The poly(ADP-ribose) polymerase (PARP) family of proteins use NAD(+) as their substrate to modify acceptor proteins with ADP-ribose modifications. The function of most PARPs under physiological conditions is unknown. Here, to better understand this protein family, we systematically analyse the cell cycle localization of each PARP and of poly(ADP-ribose), a product of PARP activity, then identify the knockdown phenotype of each protein and perform secondary assays to elucidate function. We show that most PARPs are cytoplasmic, identify cell cycle differences in the ratio of nuclear to cytoplasmic poly(ADP-ribose) and identify four phenotypic classes of PARP function. These include the regulation of membrane structures, cell viability, cell division and the actin cytoskeleton. Further analysis of PARP14 shows that it is a component of focal adhesion complexes required for proper cell motility and focal adhesion function. In total, we show that PARP proteins are critical regulators of eukaryotic physiology. PMID- 23917128 TI - [Aortopulmonary fistula caused by aortic arch aneurysm rupture presenting severe left to right shunt and congestive heart failure]. AB - A 74-year-old female was admitted to our hospital due to hyperkinetic congestive heart failure. Noninvasive positive pressure ventilation, continuous hemodialysis and inotropic support were needed preoperatively. Computed tomography revealed saccular aortic arch aneurysm with aortopulmonary fistula toward the left pulmonary artery. Cardiac catheterization revealed severe left to right shunt with the pulmonary flow/systemic flow (Qp/Qs) ratio of 6.2.Emergency operation was performed under hypothermic circulatory arrest followed by selective cerebral perfusion and lower body perfusion. The aortopulmonary fistula was directly closed, reinforced with the aneurysmal wall, and total arch replacement was performed. Although the patient temporarily recovered by endoscopic suction of the blood from the lungs and continuous hemodialysis filtration, she died because of multiple organ failure due to mesenteric ischemia on postoperative day 34. PMID- 23917129 TI - [Surgical treatment of traumatic aortic rupture]. AB - This report focuses on 3 cases of traumatic aortic dissection or rupture at the isthmus. We selected 3 different methods of treatment. In the 1st case, we performed an emergency operation with graft replacement of the proximal descending aorta. In the 2nd case, we performed elective graft replacement 5 months after the rupture under careful blood pressure control. Thirdly, we performed emergency stent grafting at the isthmus, the rupture site. All cases were successfully treated, but it remains difficult to select the method of treatment for multisystem disorder. Our current strategy for traumatic rupture at the isthmus is immediate stent grafting. It will also be a very useful procedure for multisystem trauma. PMID- 23917130 TI - [Mixed squamous and glandular papilloma]. AB - The patient was a 64-year-old man. He had a smoking history for 43 years (20 cigarettes per day). Being pointed out a mass shadow in the left lower lung field on chest X-ray in a regular checkup, he was referred to our hospital. The chest computed tomography (CT) revealed a tumor shadow of 30 mm diameter in the left S8. Blood tests showed that carcinoembryonic antigen (CEA) and squamous cell carcinoma-related antigen (SCC) were elevated. Accumulation of standardized uptake value (SUV) max 9.78/15.17 match the tumor shadow in fluorodeoxyglucose positron emission tomography (FDGPET),suspected of malignancy. As a result of bronchoscopy, squamous cell carcinoma was suspected by cytology, and he was introduced to us for surgery. Video-assisted thoracic surgery (VATS)-left lower lobectomy and lymph node dissection was performed. By pathology, the tumor showed papillary growth in peripheral bronchus, with squamous cell and high columnar epithelial cell components. The tumor was diagnosed as mixed squamous and glandulas papilloma. In addition, a part of the squamous cells was considered to be atypical, indicating squamous cell carcinoma in situ in a mixed epithelial and glandular papilloma. PMID- 23917131 TI - [Pulmonary artery sling and single ventricle treated with a simultaneous operation of slide tracheoplasty, left pulmonary artery reimplantation, and bidirectional cavo-pulmonary shunt]. AB - Pulmonary artery sling is frequently combined with tracheal stenosis, and occasionally combined with congenital heart defects. However, there are few reports of successfully treated cases that were combined with single ventricle. In this article, we report a successfully treated case of pulmonary artery sling combined with tracheal stenosis, single ventricle, pulmonary atresia, vascular ring, and bilateral superior vena cava. A male infant was referred to our hospital for central cyanosis, and was diagnosed with single ventricle (tricuspid stenosis, multiple ventricular septal defect, and hypoplastic right ventricle)with pulmonary atresia by echocardiogram. Tracheal stenosis was shown at cardiac catheterization. Pulmonary artery sling and tracheal diverticulum were diagnosed by computed tomography (CT) and magnetic resonance imaging(MRI)examination. Furthermore, the patient was complicated by vascular ring, which consisted of right aortic arch, an aberrant left subclavian artery, and patent ductus arteriosus, and this ductus arteriosus was connected to the left subclavian artery and pulmonary arterial trunk. After 6 months of medical treatment, including continuous infusion of prostaglandin, re-evaluation was performed by cardiac catheterization. We considered that bidirectional cavo pulmonary shunt was appropriate for the patient since his pulmonary vasculature had matured well. An operation was performed under the use of cardio-pulmonary bypass. Release of vascular ring by division of the ductus, bilateral bidirectional cavo-pulmonary shunt, and a slide tracheoplasty for tracheal stenosis were performed simultaneously. His recovery was uneventful, and he is currently waiting to receive a Fontan-type operation. PMID- 23917132 TI - [Thoraco-abdominal aortic replacement in chronic phase in a patient with temporary paraplegia after Stanford B acute dissection]. AB - A 42-year-old man underwent was performed with thoraco-abdominal aneurysm replacement accompaniedy with reconstruction of abdominal branches and intercostal arteries. Eighteen months before, he had suffered from Stanford already been cured with paraplegia on being type B acute aortic dissection combined with paraplegia. When paraplegia had been occurred, cerebrospinal fluid drainage was had been performed promptly, and 4 days later, neurologic deficit was disappeared in 1 day. During the thoraco-abdominal aortic operation, cerebrospinal fluid drainage was performed done again. After the operation, paraplegia did was not occurred and he did not feel somewhat wrong with his legs. He was discharged from hospital on foot by himself. This case showed the efficacy of cerebral spinal fluid drainage for not only both with the prevention but also and treatment of paraplegia. PMID- 23917133 TI - [Penetrating injury of the coronary artery by a stump of suture for closure of esophageal musle layer]. AB - We report a case of a 57-year-old woman who presented with cardiac tamponade 13 days after thoracoscopic excision of the diverticulum of the esophagus. Computed tomography and electrocardiogram revealed neither evidence of aortic dissection nor acute myocardial ischemia. Unstable hemodynamic condition continued even after 400 ml blood drainage through pericardiocentesis, and emergency open surgery was performed. Active arterial bleeding was seen at the marginal branch of the left circumflex coronary artery. The stump of the suture [4-0 polydioxanone (PDS) II], which had been used for closure of the overlying esophageal muscle layer, penetrated the pericardium and injured the coronary artery. Vessel injury caused by a stump of a suture seems to be extremely rare. Careful selection of the suture around the pericardium and management of its stump are necessary. PMID- 23917134 TI - [Giant hemangioma of the rib]. AB - We experienced a rare case of a 73-year-old woman with giant hemangioma of the left 8th rib. She had an abnormal shadow of left lower lung field in a health check and was referred to our hospital. Preoperative examination suggested malignant rib tumor because of tumor growth beyond the disrupted bony cortex. She underwent resection of the left 8th rib with the 7th rib and the 7th intercostal muscles and reconstruction of the chest wall defect. The pathological diagnosis of the lesion was cavernous hemangioma. She was discharged after an uneventful postoperative course. She has been well without any sign of recurrence for 3 year after surgery. PMID- 23917135 TI - [Secondary spontaneous pneumothorax due to a ruptured bulla at a left-sided azygoesophageal recess in a patient with right aortic arch]. AB - Significant frequency of ruptured bullae at the azygoesophageal recess (AER) in secondary pneumothorax patients was reported recently. In normal anatomy, the AER usually exists only in the right thorax. We herein report a case of secondary spontaneous pneumothorax due to a ruptured bulla at a leftsided AER-like structure in a patient with right aortic arch. The case was a 70-year-old man who developed left spontaneous pneumothorax secondary to pulmonary emphysema. He was initially treated by thoracic drainage, but in vain, and finally referred to our department because of prolonged air leakage. Preoperative computed tomography demonstrated a bulla formation at a recess between the rightsided descending aorta and thoracic vertebrae. In thoracoscopic surgery, we confirmed air leakage from the bulla at the recess and the bulla was subsequently ligated. To the best of our knowledge bulla formation at a left-sided AER-like structure has never been reported. Local overinflation of the lung parenchyma may have been a cause of bulla formation in this case. PMID- 23917136 TI - [Acute pain at tumor recurrence site induced by vinorelbine infusion]. AB - We present a case of vinorelbine (VNR)-induced acute tumor pain. Oral control release oxycodone was administered for cancer pain by iliac bone metastasis. In chemotherapy by combined use of VNR and gemcitabine, severe pain in groin, thigh and hip occurred immediately after infusion of VNR. Oral rapid-release oxycodone was administered but the pain lasted half an hour and then resolved spontaneously. In the following course of chemotherapy by same regimen, pre medication of rapid-release oxycodone did not prevent the pain. PMID- 23917137 TI - [Quality management and participation into clinical database]. AB - Quality management is necessary for establishing useful clinical database in cooperation with healthcare professionals and facilities. The ways of management are 1) progress management of data entry, 2) liaison with database participants (healthcare professionals), and 3) modification of data collection form. In addition, healthcare facilities are supposed to consider ethical issues and information security for joining clinical databases. Database participants should check ethical review boards and consultation service for patients. PMID- 23917138 TI - [Aortic valve replacement and ventricular septal defect closure after previous bilateral internal thoracic artery bypass grafting; report of a case]. AB - The patient was a 74-year-old man with a history of ventricular-septal defect (VSD). He underwent coronary artery bypass grafting (CABG), which was performed using the bilateral internal thoracic artery (ITA) 9 years ago. Since 2009, he experienced heart failure, and in 2011, he started administration of tolvaptan, vasopressin V2 receptor antagonist. In 2011, he developed fever, and follow-up echocardiography revealed moderate aortic regurgitation and vegetation around the VSD and the aortic valve. Therefore, we performed redo-aortic valve replacement (AVR) and VSD closure. Both ITAs were carefully dissected and were clamped during cardiac arrest. The patient was discharged on the 36th postoperative day, without tolvaptan. AVR and VSD closure after bilateral ITA bypass grafting is a challenging procedure if the patent ITA crosses the midline. Patent ITA should be occluded to avoid cardioplegia washout during aortic cross-clamping. Multi detector-row computed tomography (MDCT) enables excellent imaging for dissecting ITA grafts. PMID- 23917139 TI - [Bilateral pulmonary artery banding for complex congenital heart disease in a patient with trisomy 13; report of a case]. AB - We described a case of a neonate of 13 trisomy with hypoplastic aortic arch and multiple ventricular septal defect (VSD). The patient presented symptoms of congestive heart failure due to pulmonary high flow. Because of ductal patency without prostaglandin infusion, bilateral pulmonary artery banding was performed for regulation of pulmonary high flow. Surgical intervention improved the clinical symptoms of the patient and permitted the patient to be discharged. We concluded that palliative surgery for the patient contributes to improve the quality of life both the patient and the family. This is the 1st report of bilateral pulmonary artery banding for a patient with 13 trisomy. PMID- 23917140 TI - [Annuloaortic ectasia associated with antithrombin III deficiency; report of a case]. AB - A 33-year-old male with hereditary deficiency of antithrombin III (AT III) was diagnosed with annuloaortic ectasia and scheduled for the aortic root replacement. As perioperative anticoagulation, AT III was administered to have its activity>=70% in addition to heparin. During the operation with cardiopulmonary bypass, 3,000 IU of AT III concentrate was infused, and there was no hemorrhagic complication. After the operation low-molecular-weight heparin was used instead of unfractionated heparin to avoid bleeding. However, renal infarction occurred on postoperative day 11. Heparin was continuously given in combination with 1,500 IU/day of AT III concentrate until oral warfarin reached within therapeutic range. The patient recovered without further sequelae. Cardiac surgery might be safely performed in patients with AT III deficiency by replenishing AT III concentrate to keep its activity higher than 80%. PMID- 23917141 TI - [Aspergillus prosthetic aortic valve endocarditis; report of a case]. AB - A 76-year-old woman, who had underwent aortic valve replacement (AVR) 2 months previously, was admitted to our hospital for persistent pyrexia. Her blood culture results were negative. A new heart murmur was noted on day 19 after admission. Esophageal echocardiography indicated the usual prosthetic valve endocarditis (PVE) findings, including a hyperechoic area in the prosthetic valve and deterioration of regurgitation. Medication was unable to prevent heart failure on day 39 after admission. Subsequently, we performed redo AVR and annulus debridement, but she died due to complicated sepsis in the postoperative period. As reports of Aspergillus PVE are scarce, its precise prognosis remains unknown. However, given that the prognoses of infective endocarditis related to Aspergillus species are poor, we believe that Aspergillus PVE can be fatal. Therefore, we suggest that Aspergillus PVE should be diagnosed as soon as possible, and that prompt surgery should be performed to improve the patient prognosis. PMID- 23917142 TI - [Diaphragmatic eventration with shock and respiratory distress requiring emergency plication; report of a case]. AB - A 80-year-old female with an eventration of the left diaphragm, which had been noticed with routine chest roentgenogram in 2006, presented with severe dyspnea and shock vital in 2012. The chest X-ray on admission disclosed elevation of the left hemidiaphragm, dislocation of the heart to the right. The diagnosis of eventration of the diaphragm was confirmed with a computed tomographic scan. She underwent diaphragmatic plication with endostaplers by thoracoscopic surgery. The postoperative course was uneventful except for transient reexpansion pulmonary edema. The patient was extubated on the 5th postoperative day. Dyspnea has disappeared after the operation. She was in a good condition without requiring any additional oxygen. PMID- 23917143 TI - [Mediastinal involvement of thyroid cancer with mediastinal lymph node metastasis; report of a case]. AB - We report a surgical case of mediastinal involvement of papillary adenocacinoma of thyroid with mediastinal lymph node metastasis. A 58-year-old male was admitted to our hospital with laryngeal discomfort. The laryngeal fiber scopy showed left recurrent nerve palsy, although he hadn't noticed hoarseness before admission. An enhanced computed tomography(CT)scan revealed a heterogeneous 3*3 cm mass in the upper mediastinum. The 18F-fluorodeoxyglucose-positron emission tomography( FDG-PET)showed an accumulation of FDG in the mass and also in a mediastinal lymph node. The incisional biopsy on mediastinoscopy revealed a papillary adenocarcinoma of thyroid and a total thyroidectomy with resection of mediastinal lymph node through cervical and reverse-T upper mini-sternotomy approach was performed. PMID- 23917145 TI - Comparative study of metallic silicide-germanide orthorhombic MnP systems. AB - We present a comparative study of the structural, energetic, electronic and elastic properties of MX type MnP systems (where X=Si or Ge, and M=Pt, Pd or Ni) using first-principles calculations. The optimized ground state properties of these systems are in excellent agreement with the experimental values. A detailed comparative study of the elastic properties of polycrystalline structures is also presented. We analyze the relationship between the composition and the properties of the systems. Finally, we present the properties of NiSi1-xGex alloys. We show that these properties depend linearly on the Ge content of the alloy. This work has important consequences for semiconductor devices in which silicides, germanides and alloys thereof are used as contact materials. PMID- 23917144 TI - Inflammation-related DNA damage and expression of CD133 and Oct3/4 in cholangiocarcinoma patients with poor prognosis. AB - Nitrative and oxidative DNA damage plays an important role in inflammation related carcinogenesis. Chronic inflammation such as parasite infection and primary sclerosing cholangitis can be an etiological factor of cholangiocarcinoma. Using a proteomic approach and double-fluorescent staining, we identified high expression and colocalization of albumin and cytokeratin-19 in liver fluke-associated cholangiocarcinoma tissues, compared with normal livers from cholangiocarcinoma patients and cadaveric donors, respectively. Albumin was detected not only in cells of hyperplastic bile ducts and cholangiocarcinoma, but also in liver stem/progenitor cell origin, such as canal of Hering, ductules, and ductular reactions, suggesting the involvement of stem/progenitor cells in cholangiocarcinoma development. To clarify the involvement of liver stem/progenitor cells in cholangiocarcinoma, we examined several stem/progenitor cell markers (CD133, CD44, OV6, and Oct3/4) in cholangiocarcinoma tissues analyzed by immunohistochemical staining, and measured 8-oxodG levels by using HPLC-ECD as an inflammation-related DNA lesion. In addition, a stem/progenitor cell factor Bmi1, 8-nitroguanine (formed during nitrative DNA damage), DNA damage response (DDR) proteins (phosphorylated ATM and gamma-H2AX), and manganese-SOD (Mn-SOD) were analyzed by immunohistochemistry. Stem/progenitor cell markers (CD133, OV6, CD44, and Oct3/4) were positively stained in 56, 38, 47, and 56% of 34 cholangiocarcinoma cases, respectively. Quantitative analysis of 8-oxodG revealed significantly increased levels in CD133- and/or Oct3/4-positive tumor tissues compared to negative tumor tissues, as well as 8-nitroguanine formation detected by immunohistochemistry. In the cases of CD44- and/or OV6-positive tissue, no significant difference was observed. Cholangiocarcinoma patients with CD133- and/or Oct3/4-positive tumor tissues showed significantly lower expression of Mn-SOD and higher DDR protein, gamma-H2AX. Moreover, CD133- and/or Oct3/4 positive cholangiocarcinoma patients had significant associations with tumor histology types, tumor stage, and poor prognoses. Our results suggest that CD133 and Oct3/4 in cholangiocarcinoma are associated with increased formation of DNA lesions and the DDR protein, which may be involved in genetic instability and lead to cholangiocarcinoma development with aggressive clinical features. PMID- 23917146 TI - Different activity levels of Dehalococcoides mccartyi revealed by FISH and CARD FISH under non-steady and pseudo-steady state conditions. AB - A mixed culture capable of dechlorinating perchloroethylene (PCE) to ethene was analyzed under non steady and pseudo-steady state conditions. Dehalococcoides mccartyi, considered to be the primary dechlorinating bacterium able to completely degrade chlorinated hydrocarbons to non toxic ethene, could be detected by CAtalyzed Reporter Deposition Fluorescence In Situ Hybridization (CARD-FISH) since the beginning of culture operation but highlighted by conventional FISH only during active PCE dechlorination to ethene and vinyl chloride (VC). Data generated from FISH and CARD-FISH analyses were compared to those generated from applying PCR-based techniques directed at defining cell abundances (Real Time PCR, qPCR) and assessing cell activities (Reverse Transcription qPCR, RT-qPCR) of Dehalococcoides strains involved in the PCE reductive dechlorination (RD) process. qPCR targeting reductive dehalogenase genes coding for enzymes involved in the individual steps of the RD process, showed that Dehalococcoides strains carrying the tceA gene dominated the community. This observation was consistent with PCE conversion products detected under pseudo-steady state (ethene and VC production), since this tceA gene is known to be associated to strains capable of reducing chlorinated solvents beyond 1,2-cis-dichloroethene (cis-DCE). In line with the FISH data, Dehalococcoides 16S rRNA and tceA genes were expressed only during pseudo-steady state conditions when PCE was converted completely to the final metabolic product ethene. Furthermore, Dehalococcoides cell abundances estimated by CARD-FISH correlated positively with their 16SrRNA gene copy numbers quantified by qPCR. This is consistent with the ability of both these methods to estimate total Dehalococcoides cell numbers including those with low metabolic activities. Thus, this study shows that application potential of FISH analysis to quantify rapidly and efficiently only active dechlorinators in complex communities. PMID- 23917147 TI - Application of a molecular based approach for the early detection of short term 3 chloroaniline shock loads on activated sludge bacterial community and functionality. AB - Microbial processes are central elements in wastewater treatment plants (WWTPs) to mineralize the organic matter, to degrade pollutants and to decrease the amount of suspended solids. This activity can be disrupted by organic and inorganic pollutants present in wastewater streams. Hence, it is of primary importance to investigate and monitor the structure and functionality of the sludge-resident microbial communities. We simulated a 3-chloroaniline (3-CA) shock load in 3-CA adapted and non-adapted semi-continuous activated-sludge (SCAS) reactors to selectively stress the Ammonia Oxidizing Bacteria (AOB). Recently developed setting-independent theoretical interpretation of molecular DNA and RNA fingerprinting patterns were used to evaluate the responses of the microbial populations. Ammonium accumulation in treated reactors upon 3-CA addition confirmed the disruption of the functionality under stress conditions. Molecular analyses coupled to their interpretation highlighted that shock loaded reactors clustered separately from non-treated ones, especially when AOBs community was specifically targeted. Furthermore, the interpretation of RNA-based analyses, as compared to DNA-based ones, allowed to more promptly depicting shifts in a stressed community. We showed that the use of RNA-based molecular tools in combination with a new set of parameters is a powerful tool to link functional failures with microbial structure modifications in WWTPs, providing a potential tool for a rational optimization of the processes (Microbial Resource Management - MRM). PMID- 23917149 TI - Primordium of an artificial Bruch's membrane made of nanofibers for engineering of retinal pigment epithelium cell monolayers. AB - Transplanted retinal pigment epithelium (RPE) cells hold promise for treatment of age-related macular degeneration (AMD) and Stargardt disease (SD), but it is conceivable that the degenerated host Bruch's membrane (BM) as a natural substrate for RPE might not optimally support transplanted cell survival with correct cellular organization. We fabricated novel ultrathin three-dimensional (3 D) nanofibrous membranes from collagen type I and poly(lactic-co-glycolic acid) (PLGA) by an advanced clinical-grade needle-free electrospinning process. The nanofibrillar 3-D networks closely mimicked the fibrillar architecture of the native inner collagenous layer of human BM. Human RPE cells grown on our nanofibrous membranes bore a striking resemblance to native human RPE. They exhibited a correctly orientated monolayer with a polygonal cell shape and abundant sheet-like microvilli on their apical surfaces. RPE cells built tight junctions and expressed RPE65 protein. Flat 2-D PLGA film and cover glass as controls delivered inferior RPE layers. Our nanofibrous membranes may imitate the natural BM to such extent that they allow for the engineering of an in vivo-like human RPE monolayer that maintains the natural biofunctional characteristics. Such ultrathin membranes may provide a promising vehicle for a functional RPE cell monolayer implantation in the subretinal space in patients with AMD or SD. PMID- 23917148 TI - Dual growth factor releasing multi-functional nanofibers for wound healing. AB - The objective of this research is to develop a dual growth factor-releasing nanoparticle-in-nanofiber system for wound healing applications. In order to mimic and promote the natural healing procedure, chitosan and poly(ethylene oxide) were electrospun into nanofibrous meshes as mimics of extracellular matrix. Vascular endothelial growth factor (VEGF) was loaded within nanofibers to promote angiogenesis in the short term. In addition, platelet-derived growth factor-BB (PDGF-BB) encapsulated poly(lactic-co-glycolic acid) nanoparticles were embedded inside nanofibers to generate a sustained release of PDGF-BB for accelerated tissue regeneration and remodeling. In vitro studies revealed that our nanofibrous composites delivered VEGF quickly and PDGF-BB in a relayed manner, supported fibroblast growth and exhibited anti-bacterial activities. A preliminary in vivo study performed on normal full thickness rat skin wound models demonstrated that nanofiber/nanoparticle scaffolds significantly accelerated the wound healing process by promoting angiogenesis, increasing re epithelialization and controlling granulation tissue formation. For later stages of healing, evidence also showed quicker collagen deposition and earlier remodeling of the injured site to achieve a faster full regeneration of skin compared to the commercial Hydrofera Blue(r) wound dressing. These results suggest that our nanoparticle-in-nanofiber system could provide a promising treatment for normal and chronic wound healing. PMID- 23917151 TI - Common bile duct lithiasis: therapeutic approach. AB - INTRODUCTION: Treatment of cholecysto-choledocholithiasis has been revisited from the standpoint of either endoscopic or laparoscopic mini invasive approach. A standard diagnostic-therapeutic procedure has not been unanimously defined. PATIENTS AND METHODS: Since 1997 to 2011 we have treated 924 patients: 555 gallbladder lithiasis, 276 acute biliary pancreatitis and 93 choledocholithiasis (without pancreatitis). We have compared, by the review of the literature, our results of two stage endoscopic stones removal followed by laparoscopic cholecystectomy versus one stage laparo-endoscopic rendezvous technique/VLC and laparoscopic approach alone. RESULTS: In our experience endoscopic removal of stones have been performed in 82 patients (88.17%); 11 patients (11.82%),not eligible for endoscopic approach, have been submitted to laparotomic therapy. In sum preoperative ERCP/ES with CBD cleaning followed by VLC, not with standing the valid results of laparoscopic approach alone remains the strategy more frequently applied in clinical practice, because the good results. CONCLUSIONS: The results of the treatment of CBD lithiasis of sequential laparo-endoscopic approach (two or one stage) and of laparoscopic approach alone are roughly overlappable. Therefore the first has remained the treatment of reference and comparison in all the clinical evaluation of different procedure. PMID- 23917152 TI - Misinterpretation of categorical rate ratios and inappropriate exposure-response model fitting can lead to biased estimates of risk: ethylene oxide case study. AB - There are pitfalls associated with exposure-response modeling of human epidemiological data based on rate ratios (RRs). Exposure-response modeling is best based on individual data, when available, rather than being based on summary results of that data such as categorical RRs. Because the data for the controls (or the lowest exposure interval if there are not enough controls) are random and not known with certainty a priori, any exposure-response model fit to RRs should estimate the intercept rather than fixing it equal to one. Evaluation of a model's goodness-of-fit to the individual data should not be based on the assumption that summary RRs describe the true underlying exposure-response relationship. These pitfalls are illustrated by Monte Carlo simulation examples with known underlying models. That these pitfalls are a practical concern is illustrated by the need for U.S. EPA to reconsider its most recent evaluation of ethylene oxide. If they had avoided these pitfalls, their exposure-response modeling would have been in better agreement with the log-linear model fit to the individual data. PMID- 23917150 TI - Nanoparticles for localized delivery of hyaluronan oligomers towards regenerative repair of elastic matrix. AB - Abdominal aortic aneurysms (AAAs) are rupture-prone progressive dilations of the infrarenal aorta due to a loss of elastic matrix that lead to weakening of the aortic wall. Therapies to coax biomimetic regenerative repair of the elastic matrix by resident, diseased vascular cells may thus be useful to slow, arrest or regress AAA growth. Hyaluronan oligomers (HA-o) have been shown to induce elastic matrix synthesis by healthy and aneurysmal rat aortic smooth muscle cells (SMCs) in vitro but only via exogenous dosing, which potentially has side-effects and limitations to in vivo delivery towards therapy. In this paper, we describe the development of HA-o loaded poly(lactide-co-glycolide) nanoparticles (NPs) for targeted, controlled and sustained delivery of HA-o towards the elastogenic induction of aneurysmal rat aortic SMCs. These NPs were able to deliver HA-o over an extended period (>30 days) at previously determined elastogenic doses (0.2-20 MUg ml(-1)). HA-o released from the NPs led to dose-dependent increases in elastic matrix synthesis, and the recruitment and activity of lysyl oxidase, the enzyme which cross-links elastin precursor molecules into mature fibers/matrix. Therefore, we were able to successfully develop a nanoparticle-based system for controlled and sustained HA-o delivery for the in vitro elastogenic induction of aneurysmal rat aortic smooth muscle cells. PMID- 23917153 TI - Functional balance in older adults with chronic obstructive pulmonary disease. AB - This study assessed functional balance among older adults at all grades of chronic obstructive pulmonary disease (COPD) and explored balance impairment predictors. A cross-sectional study with outpatients with COPD (N = 160; M = 72.2 years, SD = 7.9; mean forced expiratory volume in 1 s = 63.8% predicted, SD = 23.7) was conducted. The Timed Up and Go (TUG) test was used to assess functional balance. Functional balance impairment was defined as a TUG score exceeding the upper limit of the confidence intervals of normative values for healthy older adults. Participants performed the TUG test in 11.0 s (SD = 4.8 s). Functional balance impairment was present in 44.4% of the participants and was significantly more frequent in severe to very severe COPD (62.5%). Body mass index (odds ratio [OR] = 1.12), number of medications (OR = 1.20), restriction in recreational activities (OR = 1.66), and depression score (OR = 1.14) were multivariate predictors of functional balance impairment. Functional balance impairment is present in early COPD, although more evident at advanced grades. These findings highlight the importance of balance assessment in older patients at all COPD grades. PMID- 23917154 TI - Reproducibility of ultrasonography for assessing abdominal fat distribution in a population at high risk of diabetes. AB - BACKGROUND: Visceral fat plays an important role in the development of metabolic disease independently of the effect of overall abdominal fat. Ultrasonography is an accessible method of accurately assessing abdominal fat distribution in epidemiological studies, but few details about the reproducibility of this method have been published. OBJECTIVE: The aim of this study was to investigate the reproducibility of ultrasonography in the assessment of abdominal fat distribution in a population at high risk of type 2 diabetes. DESIGN AND METHODS: Ultrasonography was used to estimate visceral and subcutaneous abdominal fat. Intra- and interobserver variation, short-term variation and variation between estimates in the fasting and non-fasting state were examined in three samples of 30, 33 and 23 participants from the ADDITION-PRO study. A variance components model was used to calculate intra- and interobserver variation, and Bland-Altman plots were drawn for all three substudies. RESULTS: Coefficients of variation for intra- and interobserver variation were in the range 3.4-6.1%, except for interobserver variation for subcutaneous fat (9.5%). Short-term variation over a median of 35 days had a coefficient of variation of 15%. The effect of a meal was primarily on the visceral estimates and did not extend beyond the first postprandial hour. Non-fasting visceral estimates were larger than fasting estimates. CONCLUSION: Both visceral and subcutaneous fat can be estimated with ultrasonography with adequate intra- and interobserver reproducibility by clinical researchers with limited training, making it a feasible method of assessing abdominal fat distribution in epidemiological studies. PMID- 23917155 TI - Atmospheric transport modelling of time resolved 133Xe emissions from the isotope production facility ANSTO, Australia. AB - The verification of the Comprehensive Nuclear-Test Ban Treaty (CTBT) relies amongst other things on the continuous and worldwide monitoring of radioxenon. The characterization of the existing and legitimate background, which is produced mainly by nuclear power plants and isotope production facilities, is of high interest to improve the capabilities of the monitoring network. However, the emissions from legitimate sources can usually only be estimated. For this paper historic source terms of (133)Xe emissions from the isotope production facility at ANSTO, Sydney, Australia, have been made available in a daily resolution. Based on these high resolution data, different source term sets with weekly, monthly and yearly time resolution have been compiled. These different sets are then applied together with atmospheric transport modelling (ATM) to predict the concentration time series at two radioxenon monitoring stations. The results are compared with each other in order to examine the improvement of the prediction capability depending on the used time resolution of the most dominant source term in the region. PMID- 23917156 TI - Advances in lupus genetics. AB - PURPOSE OF REVIEW: The purpose of this review is to highlight recent progress in defining the effects of variation in the germline DNA sequence on the susceptibility to systemic lupus erythematosus. RECENT FINDINGS: The genetic contributions to lupus susceptibility have been increasingly defined in recent years, although a large proportion of the genetic heritability of this disease remains undiscovered. Various approaches have been taken to determine this 'missing heritability' and to further characterize the known genetic effects in order to more fully elucidate the cause and pathogenesis of this complex and heterogenous disease. SUMMARY: Characterizing the genetic contributions to lupus and their functional effects will advance our understanding of the biology of this disease and aid in the development of new therapeutics. PMID- 23917157 TI - Pathogenesis of pregnancy complications in systemic lupus erythematosus. AB - PURPOSE OF REVIEW: In spite of the advances made in the management of pregnancies in women with systemic lupus erythematosus (SLE), maternal complications and adverse fetal outcomes still exceed the rate of pregnancy complications in the general population. An intriguing question relates to the observation that pregnancy loss, intrauterine growth restriction (IUGR), preterm birth, and preeclampsia remain major complications in SLE pregnancies, not substantially altered by improved therapy and monitoring. RECENT FINDINGS: From the review of the recent literature on the pathogenesis of pregnancy loss, IUGR, preeclampsia, and prematurity, it appears that clinical or subclinical inflammation, presence of autoantibodies, hormonal dysfunction, and immune alterations of lupus contribute to pregnancy complications. Impairment of early placenta development leads to poor vascularization, resulting in placental ischemia and subsequent endothelial damage. Depending on the extent of the pathological process, pregnancy loss, IUGR, and preeclampsia can develop. SUMMARY: Early recognition of pregnancy complications is desirable in order to prevent their development or to prompt intervention that improves the outcomes. Several biomarkers have been investigated for their ability to predict complications at an early stage of pregnancy. However, up to date only lupus anticoagulant has emerged as a consistent predictor for adverse pregnancy outcomes. PMID- 23917158 TI - Challenges and opportunities in SLE clinical trials. AB - PURPOSE OF REVIEW: To provide an update on the field of clinical trials in systemic lupus erythematosus (SLE). This review will examine failed and successful clinical trials in SLE in order to draw lessons and determine the optimal ways forward. RECENT FINDINGS: Over the past decade, many clinical trials in SLE met with limited success, but in the past 2 years several SLE clinical trials have been successful. The two large phase III randomized controlled trials (RCTs) of belimumab achieved their primary endpoints and resulted in food and drug administration and European medicines agency approval of the drug. Characteristics of these trials were, among other things, a very large number of patients (>800 each), compound clinical endpoints, and a flexible design with regards to concomitant medication use. Likewise, large randomized controlled trials with mycophenolate mofetil, although nominally unsuccessful, clearly demonstrated the clinical benefit of this drug in lupus nephritis. Posthoc analyses of several failed trials involving abatacept and rituximab revealed design elements and/or outcomes that might have changed the outcomes of these studies. Many smaller trials have also been reported, in some instances with surprisingly positive results. SUMMARY: An improved understanding of specific design features in SLE clinical trials combined with robust outcomes will make it possible more effectively to design and conduct clinical trials in SLE. PMID- 23917161 TI - Five-year-olds understand fair as equal in a mini-ultimatum game. AB - In studies of children's resource distribution, it is almost always the case that "fair" means an equal amount for all. In the mini-ultimatum game, players are confronted with situations in which fair does not always mean equal, and so the recipient of an offer needs to take into account the alternatives the proposer had available to her or him. Because of its forced-choice design, the mini ultimatum game measures sensitivity to unfair intentions in addition to unfair outcomes. In the current study, we gave a mini-ultimatum game to 5-year-old children, allowing us to determine the nature of fairness sensitivity at a period after false belief awareness is typically passed and before formal schooling begins. The only situation in which responders rejected offers was when the proposer could have made an equal offer. But unlike adults, they did not employ more sophisticated notions of fairness that take into account the choices facing the proposer. Proposers, in their turn, were also not adult-like in that they had a very poor understanding that responders would reject unequal offers when an equal one was available. Thus, preschool children seem to understand "fair=equal" in this task, but not much more, and they are not yet skillful at anticipating what others will find fair beyond 50/50 splits. PMID- 23917159 TI - Childhood Sjogren syndrome: insights from adults and animal models. AB - PURPOSE OF REVIEW: Sjogren syndrome is a chronic autoimmune disease affecting lacrimal and salivary glands that often is accompanied by extraglandular disease manifestations. Although common in adults, the prevalence and prognosis of childhood Sjogren syndrome are unknown, in part due to lack of child-specific diagnostic and classification criteria. This review discusses difficulties in diagnosing childhood Sjogren syndrome and highlights recent findings in Sjogren syndrome treatment and pathogenesis from studies in adults and animal models over the past 18 months. RECENT FINDINGS: Studies of rituximab show some therapeutic potential in adult Sjogren syndrome, whereas newer modalities including gene therapy and mesenchymal stem cell transfer are promising. The pathogenesis of Sjogren syndrome is emerging, including roles of T and B lymphocytes, autoantibodies, interferons, and glandular epithelial cells. Specific recent notable findings in Sjogren syndrome pathogenesis include identification of a type II interferon signature in salivary glands of Sjogren syndrome patients, characterization of salivary gland-infiltrating T-cell subsets, and characterization of antimuscarinic acetylcholine receptor type 3 autoantibodies. SUMMARY: Childhood Sjogren syndrome is a poorly defined and underdiagnosed autoimmune disease that requires child-specific criteria in order to study disease burden and prognosis. Studies in adults and animal models continue to elucidate new potential diagnostic and therapeutic targets, which may be relevant for childhood Sjogren syndrome. VIDEO ABSTRACT: http://links.lww.com/COR/A3. PMID- 23917162 TI - The emergence of contingent reciprocity in young children. AB - Contingent reciprocity is important in theories of the evolution of human cooperation, but it has been very little studied in ontogeny. We gave 2- and 3 year-old children the opportunity to either help or share with a partner after that partner either had or had not previously helped or shared with the children. Previous helping did not influence children's helping. In contrast, previous sharing by the partner led to greater sharing in 3-year-olds but not in 2-year olds. These results do not support theories claiming either that reciprocity is fundamental to the origins of children's prosocial behavior or that it is irrelevant. Instead, they support an account in which children's prosocial behavior emerges spontaneously but is later mediated by reciprocity. PMID- 23917160 TI - Autoinflammatory bone disorders: update on immunologic abnormalities and clues about possible triggers. AB - PURPOSE OF REVIEW: To provide an update on the genetics and immunologic basis of autoinflammatory bone disorders including chronic recurrent multifocal osteomyelitis including the monogenic forms of the disease. RECENT FINDINGS: Ongoing research in murine, canine and human models of sterile bone inflammation has solidified the hypothesis that sterile bone inflammation can be genetically driven. Mutations in Pstpip2, LPIN2 and IL1RN have been identified in monogenic autoinflammatory bone disorders that have allowed more detailed dissection of the immunologic defects that can produce sterile osteomyelitis. Recent studies in murine chronic multifocal osteomyelitis, deficiency of the interleukin-1 receptor antagonist (DIRA), Majeed syndrome and SAPHO syndrome reveal abnormalities in innate immune system function. IL-1 pathway dysregulation is present in several of these disorders and blocking IL-1 therapeutically has resulted in control of disease in DIRA, Majeed syndrome and in some cases of SAPHO and CRMO. Basic research demonstrates the importance of the innate immune system in disease pathogenesis and offers clues about potential disease triggers. SUMMARY: Research and clinical data produced over the last several years support the important role of innate immunity in sterile osteomyelitis. Based on what has been learned in the monogenic autoinflammatory bone disorders, IL-1 is emerging as an important pathway in the development of sterile bone inflammation. PMID- 23917163 TI - Deciphering the synergism of endogenous glycoside hydrolase families 1 and 9 from Coptotermes gestroi. AB - Termites can degrade up to 90% of the lignocellulose they ingest using a repertoire of endogenous and symbiotic degrading enzymes. Termites have been shown to secrete two main glycoside hydrolases, which are GH1 (EC 3.2.1.21) and GH9 (EC 3.2.1.4) members. However, the molecular mechanism for lignocellulose degradation by these enzymes remains poorly understood. The present study was conducted to understand the synergistic relationship between GH9 (CgEG1) and GH1 (CgBG1) from Coptotermes gestroi, which is considered the major urban pest of Sao Paulo State in Brazil. The goal of this work was to decipher the mode of operation of CgEG1 and CgBG1 through a comprehensive biochemical analysis and molecular docking studies. There was outstanding degree of synergy in degrading glucose polymers for the production of glucose as a result of the endo-beta-1,4 glucosidase and exo-beta-1,4-glucosidase degradation capability of CgEG1 in concert with the high catalytic performance of CgBG1, which rapidly converts the oligomers into glucose. Our data not only provide an increased comprehension regarding the synergistic mechanism of these two enzymes for cellulose saccharification but also give insight about the role of these two enzymes in termite biology, which can provide the foundation for the development of a number of important applied research topics, such as the control of termites as pests as well as the development of technologies for lignocellulose-to-bioproduct applications. PMID- 23917164 TI - Cytotoxicity and the induction of the stress protein Hsp 70 in Chang liver cells in response to zearalenone-induced oxidative stress. AB - Zearalenone (ZEN) has been implicated in several cases of mycotoxicosis in farm animals and humans. The toxic effects of ZEN have been well characterized, but little is known regarding the mechanisms of ZEN toxicity, including the involvement of the oxidative stress pathway. Using Chang liver cells as a model, the aim of this study was to determine if ZEN could elevate the expression of the heat shock protein Hsp 70, induce cytotoxicity and modulate the levels of glutathione (GSH) and thiobarbituric acid reactive substance (TBARS). In addition, the cytoprotective effects of N-acetylcysteine amide (NACA) pre treatment were assessed. Finally, the involvement of oxidative stress in ZEN induced toxicity was confirmed. The results of this study demonstrated that ZEN induced Hsp 70 expression in a dose- and time-dependent manners. This effect occurred at low-ZEN concentrations, and could therefore be considered a biomarker of ZEN-induced toxicity. The cytotoxicity was reduced when Chang liver cells were exposed to sub-lethal heat shock prior to ZEN treatment, demonstrating a cytoprotective effect of Hsp 70. This cytoprotective effect suggested that Hsp 70 might play a key role in the cellular defense mechanism. When cells were pre treated with NACA prior to ZEN treatment, the cells were also protected from toxicity. This NACA cytoprotective effect suggested the involvement of oxidative stress in ZEN-induced toxicity, and this mechanism was supported by reduced Hsp 70 expression, inhibited cytolethality, increased GSH levels and decreased TBARS formation when cells were pre-treated with NACA prior to ZEN exposure. Our data clearly demonstrated that ZEN induced cytotoxicity in Chang liver cells by inhibiting cell proliferation, decreasing GSH levels and increasing TBARS formation in a dose-dependent manner. ZEN also, induced Hsp 70 expression, and the side effects of ZEN were significantly alleviated by pre-treatment with NACA. Oxidative stress is likely to be one of the primary pathways of ZEN toxicity. This oxidative stress may contribute, at least in part, to the mechanism of ZEN induced cytotoxicity. PMID- 23917166 TI - Contemporary management of regional nodes in penile cancer-improvement of survival? AB - PURPOSE: The management of regional nodes of penile squamous cell carcinoma has changed with time due to improved knowledge about diagnosis and treatment. To determine whether changes in the treatment of regional nodes have improved survival, we compared contemporary 5-year cancer specific survival of patients with squamous cell carcinoma of the penis with that of patients in previous cohorts. MATERIALS AND METHODS: In an observational cohort study of 1,000 patients treated during 56 years 944 were eligible for analysis. Tumors were staged according to the 2009 TNM classification, and patients were divided into 4 cohorts of 1956 to 1987, 1988 to 1993, 1994 to 2000 and 2001 to 2012, reflecting changes in clinical practice regarding regional nodes. Kaplan-Meier survival curves with the log rank test and Cox proportional hazards modeling were used to examine trends in 5-year cancer specific survival. RESULTS: The 5-year cancer specific survival of patients with cN0 disease treated between 2001 and 2012 was 92% compared to 89% (1994 to 2000), 78% (1988 to 1993) and 85% (1956 to 1987). The 5-year cancer specific survival improved significantly since 1994, the year dynamic sentinel node biopsy was introduced, at 91% (1994 to 2012) vs 82% (1956 to 1993) (p = 0.021). This conclusion still holds after adjustment for pathological T stage and grade of differentiation (HR 2.46, p = 0.01). Extranodal extension, number of tumor positive nodes and pelvic involvement in node positive (pN+) cases were associated with worse 5-year cancer specific survival. CONCLUSIONS: Despite less surgery being performed on regional nodes, 5-year cancer specific survival has improved in patients with cN0 disease. The number of tumor positive nodes, extranodal extension and pelvic involvement were highly associated with worse cancer specific survival in patients with pN+ disease. In this group other treatment strategies are needed as no improvement was observed. PMID- 23917165 TI - Comparison of tissue injury from focused ultrasonic propulsion of kidney stones versus extracorporeal shock wave lithotripsy. AB - PURPOSE: Focused ultrasonic propulsion is a new noninvasive technique designed to move kidney stones and stone fragments out of the urinary collecting system. However, to our knowledge the extent of tissue injury associated with this technique is not known. We quantitated the amount of tissue injury produced by focused ultrasonic propulsion under simulated clinical treatment conditions and under conditions of higher power or continuous duty cycles. We compared those results to extracorporeal shock wave lithotripsy injury. MATERIALS AND METHODS: A human calcium oxalate monohydrate stone and/or nickel beads were implanted by ureteroscopy in 3 kidneys of live pigs weighing 45 to 55 kg and repositioned using focused ultrasonic propulsion. Additional pig kidneys were exposed to extracorporeal shock wave lithotripsy level pulse intensity or continuous ultrasound exposure 10 minutes in duration using an ultrasound probe transcutaneously or on the kidney. These kidneys were compared to 6 treated with an unmodified Dornier HM3 lithotripter (Dornier Medical Systems, Kennesaw, Georgia) using 2,400 shocks at 120 shock waves per minute and 24 kV. Histological analysis was performed to assess the volume of hemorrhagic tissue injury created by each technique according to the percent of functional renal volume. RESULTS: Extracorporeal shock wave lithotripsy produced a mean +/- SEM lesion of 1.56% +/- 0.45% of functional renal volume. Ultrasonic propulsion produced no detectable lesion with simulated clinical treatment. A lesion of 0.46% +/- 0.37% or 1.15% +/ 0.49% of functional renal volume was produced when excessive treatment parameters were used with the ultrasound probe placed on the kidney. CONCLUSIONS: Focused ultrasonic propulsion produced no detectable morphological injury to the renal parenchyma when using clinical treatment parameters but produced injury comparable in size to that of extracorporeal shock wave lithotripsy when using excessive treatment parameters. PMID- 23917167 TI - Impact of the 2012 American Urological Association vasectomy guidelines on post vasectomy outcomes. AB - PURPOSE: The 2012 American Urological Association (AUA) vasectomy guidelines recommend the finding of rare nonmotile sperm, representing 100,000 or fewer nonmotile sperm per ml, as a metric of post-vasectomy success. At our institution success was previously defined as 2 sequential azoospermic centrifuged semen pellets. The criteria change of including rare nonmotile sperm as a success end point may simplify post-vasectomy followup and decrease the number of post vasectomy semen analyses required to assure occlusive success. MATERIALS AND METHODS: In the context of the new 2012 guidelines we retrospectively reviewed and analyzed the records of 972 of the 1,740 vasectomies (55.9%) performed between January 2000 and June 2012 after which at least 1 post-vasectomy semen analysis was done. RESULTS: A total of 1,919 post-vasectomy semen analyses were obtained from 972 patients with a mean +/- SE age of 39.7 +/- 0.2 years. Occlusive success was evident in 337 azoospermic men (36.4%), while 514 (52.9%) underwent 2 or more post-vasectomy semen analyses and 458 (47.1%) returned for a single post-vasectomy semen analysis but were lost to followup. Of these noncompliant patients 76.0% were azoospermic, 19.7% had rare nonmotile sperm, 1.5% had greater than 100,000 nonmotile sperm per ml and 2.8% had motile sperm. Three patients underwent repeat vasectomy for persistent rare nonmotile sperm. If the criteria defined by the 2012 guidelines had been used to monitor these men, the occlusive success rate would have improved to 97.6% (949 patients) (p <0.05). Repeat vasectomies as well as 896 subsequent post-vasectomy semen analyses would have been avoided. CONCLUSIONS: The AUA vasectomy guidelines provide clear, evidence-based criteria for vasectomy success. The guidelines simplify followup protocols, improve patient compliance and help avoid unnecessary post-vasectomy semen analyses and repeat vasectomies. PMID- 23917169 TI - Non-viable Lactobacillus reuteri DSMZ 17648 (PylopassTM) as a new approach to Helicobacter pylori control in humans. AB - Prevalence of infections by Helicobacter pylori, a pathogen involved in a number of gastrointestinal diseases, remains high in developing countries. Management of infections by eradication is not always an option. Lactobacillus reuteri (L. reuteri) DSMZ17648 (PylopassTM/Lonza) specifically co-aggregates H. pylori in vitro and was shown to reduce 13C urea breath test in vivo. In this pilot study, we tried to replicate previous findings in an independent sample and to evaluate effects of spray-drying vs. freeze-drying of cultures. A single-blinded, placebo controlled study was done in 22 H. pylori positive, asymptomatic adults. H. pylori levels were determined by 13C-urea-breath method after 14 days of supplementation, as well as after 6, 12, and 24 weeks follow-up. In the test group, but not in the placebo group, a significant reduction of H. pylori was observed. For the first time, spray-dried cells of L. reuteri DSMZ17648 have been used in a human study and results are in line with the first study results, supplementing with freeze-dried material. This is of special interest as spray drying results in dead cell material, meaning that the effect of L. reuteri must be independent of its probiotic activity. These results confirm the potential of PylopassTM as a novel way to reduce the load of H. pylori. PMID- 23917171 TI - Nanocarrier-Cell Surface Adhesive and Hydrodynamic Interactions: Ligand-Receptor Bond Sensitivity Study. AB - A hybrid approach combining fluctuating hydrodynamics with generalized Langevin dynamics is employed to study the motion of a neutrally buoyant nanocarrier in an incompressible Newtonian stationary fluid medium. Both hydrodynamic interactions and adhesive interactions are included, as are different receptor-ligand bond constants relevant to medical applications. A direct numerical simulation adopting an arbitrary Lagrangian-Eulerian based finite element method is employed for the simulation. The flow around the particle and its motion are fully resolved. The temperatures of the particle associated with the various degrees of freedom satisfy the equipartition theorem. The potential of mean force (or free energy density) along a specified reaction coordinate for the harmonic (spring) interactions between the antibody and antigen is evaluated for two different bond constants. The numerical evaluations show excellent comparison with analytical results. This temporal multiscale modeling of hydrodynamic and microscopic interactions mediating nanocarrier motion and adhesion has important implications for designing nanocarriers for vascular targeted drug delivery. PMID- 23917168 TI - Out of balance--systemic iron homeostasis in iron-related disorders. AB - Iron is an essential element in our daily diet. Most iron is required for the de novo synthesis of red blood cells, where it plays a critical role in oxygen binding to hemoglobin. Thus, iron deficiency causes anemia, a major public health burden worldwide. On the other extreme, iron accumulation in critical organs such as liver, heart, and pancreas causes organ dysfunction due to the generation of oxidative stress. Therefore, systemic iron levels must be tightly balanced. Here we focus on the regulatory role of the hepcidin/ferroportin circuitry as the major regulator of systemic iron homeostasis. We discuss how regulatory cues (e.g., iron, inflammation, or hypoxia) affect the hepcidin response and how impairment of the hepcidin/ferroportin regulatory system causes disorders of iron metabolism. PMID- 23917170 TI - Potential of phytase-mediated iron release from cereal-based foods: a quantitative view. AB - The major part of iron present in plant foods such as cereals is largely unavailable for direct absorption in humans due to complexation with the negatively charged phosphate groups of phytate (myo-inositol (1,2,3,4,5,6) hexakisphosphate). Human biology has not evolved an efficient mechanism to naturally release iron from iron phytate complexes. This narrative review will evaluate the quantitative significance of phytase-catalysed iron release from cereal foods. In vivo studies have shown how addition of microbially derived phytases to cereal-based foods has produced increased iron absorption via enzyme catalysed dephosphorylation of phytate, indicating the potential of this strategy for preventing and treating iron deficiency anaemia. Despite the immense promise of this strategy and the prevalence of iron deficiency worldwide, the number of human studies elucidating the significance of phytase-mediated improvements in iron absorption and ultimately in iron status in particularly vulnerable groups is still low. A more detailed understanding of (1) the uptake mechanism for iron released from partially dephosphorylated phytate chelates, (2) the affinity of microbially derived phytases towards insoluble iron phytate complexes, and (3) the extent of phytate dephosphorylation required for iron release from inositol phosphates is warranted. Phytase-mediated iron release can improve iron absorption from plant foods. There is a need for development of innovative strategies to obtain better effects. PMID- 23917172 TI - Counting motifs in the human interactome. AB - Small over-represented motifs in biological networks often form essential functional units of biological processes. A natural question is to gauge whether a motif occurs abundantly or rarely in a biological network. Here we develop an accurate method to estimate the occurrences of a motif in the entire network from noisy and incomplete data, and apply it to eukaryotic interactomes and cell specific transcription factor regulatory networks. The number of triangles in the human interactome is about 194 times that in the Saccharomyces cerevisiae interactome. A strong positive linear correlation exists between the numbers of occurrences of triad and quadriad motifs in human cell-specific transcription factor regulatory networks. Our findings show that the proposed method is general and powerful for counting motifs and can be applied to any network regardless of its topological structure. PMID- 23917173 TI - [Re-do coronary artery bypass grafting]. AB - Redo-coronary artery bypass grafting( redo-CABG) still remains a challenging operation and is associated with a significantly higher risk of morbidity and mortality when compared with primary CABG. The higher risk of redo-CABG is largely attributable to the increased technical difficulty and the greater incremental risk in redo-CABG patients. Annual reports by the Japanese Association for Thoracic Surgery in recent years reveled that the absolute and relative number of redo-CABG gradually decreased, and in-hospital mortality did not change significantly over this periods and was much higher than primary CABG. The increasing use of percutaneous coronary intervention (PCI) for previous CABG patients could be a reason for the decrease of redo-CABG, and therefore surgery of redo-CABG is becoming more limited. This paper presents the current indications, safe surgical technique, and perioperative management of redo-CABG patients, as well as the contemporary results of redo-CABG in our institution. PMID- 23917174 TI - [Coronary artery bypass grafting in patients with prior valvular surgery]. AB - Coronary artery bypass grafting (CABG) in patients with prior valvular surgery is not common, but carries increased risks of mortality and morbidity. In this article, we review and summarize our approach for such patients including preoperative evaluation, operative techniques, and postoperative care. Also, tips and pitfalls are described in detail by presenting our cases. PMID- 23917175 TI - [Reoperative aortic valve replacement; recent update]. AB - Historically, redo cardiac surgery for aortic valve replacement (AVR) is technically challenging and carries a high incidence of peri-operative complications. However, experience in the field continues to evolve generating reproducible, and increasingly safer results. Recent low initial operative mortalitysuggests that surgery is safe and reproducible. However, older age and multiple co-morbidities in this patient population may significantly influence late outcomes. The published data support open surgical technique as a safe, reliable approach for redo AVR. Minimum invasive approach for redo AVR and transcatheter aortic valve implantation (TAVI) technology are evolving rapidly and promises an exciting future. Careful observation for these new alternative options for redo AVR is mandatory and paramount. PMID- 23917176 TI - [Valve surgery in patients with prior coronary artery bypass grafting]. AB - Valve surgery in patients with prior coronary artery bypass grafting (CABG) is challenging procedure. If the patent graft was injured during resternotomy or dissection of the graft, operative mortality and morbidity was significantly increased. To avoid the injury, left internal mammary artery( LIMA)should be passed through under the left lung and right internal mammary artery (RIMA) should be avoided if valve surgery is anticipated in the future. We invented "internal mammary artery (IMA)-non-touch procedure" which included systemic hyperkalemia and mild hypothermia during cardiopulmonary bypass without touching IMA. With this technique, cardiac arrest can be achieved without myocardial injury avoiding IMA injury. Available transcatheter aortic valve replacement (TAVR) is awaited in Japan. Patent graft is no longer a risk for TAVR, although long term results have not been obtained. Therefore, once TAVR becomes available, TAVR can be the standard therapy for aortic valve replacement( AVR) in patients with prior CABG. PMID- 23917177 TI - [Re-do mitral valve repair]. AB - We describe proper indication and results of re-do mitral valve (MV) repair for recurrence of mitral regurgitation( MR) after MV repair. Among 1,163 patients who received MV repair for MV prolapsed between October 1991 and December 2010, 70 patients (6.0%) underwent redo MV operation. Only 14 patients (20%) among them received re-do MV repair and other 56 patients( 80%) underwent MV replacement. One patients of the 7 patients( 50%) who received re-do MV repair in 3 months after the operation received mitral valve replacement( MVR) for recurrence of MR 2 months after re-repair. However, in other 6 patients, postoperative echodoppler study performed after discharge revealed none or only trivial MR. In 6 of 7 patients, the cause of recurrence was detachment of the sutureline and hemolysis was present in 5 patients. Re-do repair was considered good indication for those patients who showed recurrence MR due to localize detachment of the sutureline. On the other hand, predictability of the results of re-do repair for chronic recurrent MR was low. Our newly developed stentless MV (Normo) would be a good solution for those patients who showed recurrence of MR after MV repair having low fesibility of re-do MV repair. PMID- 23917178 TI - [Mitral valve surgery after aortic valve replacement]. AB - The causes of mitral valve operation for patients who underwent aortic valve replacements (AVR)are rheumatic heart diseases, nonrheumatic insufficiency, infective endocarditis, prosthetic valve dysfunction and so on. No specific recommendation for surgical strategy of mitral valve surgery for those patients has been described and surgical strategy should be selected to each patient. The patients with rheumatic heart disease had higher risk for reoperation as compared with those with nonrheumatic heart disease and majority of patients with AVR who need reoperation because of mitral valve diseases had history of open or closed mitral commissurotomy. Therefore, mitral valve repair should be limited to lesions in which excellent durability of the repair can be expected to prevent re operation. PMID- 23917179 TI - [Reoperative aortic root replacement]. AB - Our experiences of secondary aortic root replacement after proximal aortic operation and their technical details are presented. Between November 1999 and February 2013, 50 patients underwent reoperative aortic root replacement(34 male, mean age 59.6+/-13.1 years). The mode of previous operation was ascending and arch replacement in 21, aortic valve replacement (AVR) in 19, and aortic root replacement in 10. Indications for reoperation included root dilation( n=13), aortic root abscess( n=13), residual proximal dissection (n=12), formation of pseudoaneurysm (n=5)and graft infection (n=3), and non-structural valve dysfunction (n=4). Mean interval from 1st operation was 84.3+/-85.2 months (range, 0.8 month~11.8 years). At reoperation, 29(58.0%)patients had Bentall operation, 11(22.0%)had valve sparing root replacement, 5(10.0%)had prosthetic valve preserved root replacement and 5(10.0%)had partial replacement of Valsalva sinus without reimplantation of coronaries. In-hospital mortality was 8.0%(4 of 50). The cause of mortality was sepsis in 2, low-output syndrome in 1 and hemorrhagic stroke in 1. During follow-up, 2 patients had a 3rd-time root replacement for pseudoaneurysm formation and infective endocarditis. Other 2 patients needed coronary artery bypass grafting(CABG) and AVR for structural valve deterioration. Freedom from 3rd-time aortic root related operation was 90.2+/-4.7% at 10 years. Actuarial survival after reoperation was 84.6+/-6.3% at 10 years. In conclusion, reoperative aortic root replacement can be performed with acceptable outcomes even in patients with complicated aortic pathologies. PMID- 23917180 TI - [Redo arch replacement after ascending aortic surgery]. AB - Redo aortic arch replacement is mainly performed in the patients who underwent the ascending aortic surgery for the acute type A aortic dissection previously, and still carries relatively high mortality up to 13.8% according to the 2010 annual report by The Japanese Association for Thoracic Surgery. It has been reported that the incidence of late reoperations after the initial proximal aortic surgery for aortic dissection is between 4 and 28%, and preoperative renal failure and impaired cardiac function are the predictors of increased in-hospital mortality after redo aortic surgery. As preoperative examinations,the electrocardiogram (ECG)-gated computed tomography is useful for precise assessment of proximal aorta and coronary arteries. In the case with retrosternal pseudoaneurysm of proximal aorta, the cerebral perfusion establishment via selective direct cannulation into common carotid arteries prior to performing a sternotomy is one of the strategies to prevent neurological complications. For the distal anastomosis during a redo arch replacement, it is also important to consider the potential staged operations to the residual lesions of the descending thoracic aorta, i.e., insertion of an elephant trunk. Based on the well considered surgical plan, redo aortic arch surgery could be safely performed with acceptable morbidity and mortality. PMID- 23917181 TI - [Redo surgery for residual distal dissection after the limited proximal aortic replacement for Stanford type A acute aortic dissection]. AB - Redo surgery for residual distal dissection after the limited proximal aortic repair for Stanford type A acute aortic dissection remains challenging with some difficulties. In essence, redo aortic repair predominantly depends on the significantly dilated parts of the residual dissection. According to that, the strategy including median or lateral approach and 1 or 2 staged repair would be determined with careful consideration for patients' age and function of the vital organs such as brain, heart, lung, liver, and kidney. Generally, for relatively young and low-risk patients, an aggressive 1 stage repair of the entire arch to descending aorta through a left thoracotomy is feasible. Meanwhile, 2 stage repair is beneficial for elderly high-risk patients, which consists of the 1st total arch replacement with elephant trunk through a median sternotomy followed secondly by the open descending aortic repair through a lateral thoracotomy or recently-advanced less-invasive endovascular aortic repair. In the initial repair, more aggressive total arch replacement with elephant trunk or frozen elephant trunk might be another useful option to potentially prevent such troublesome behaviors of the residual dissecting aorta requiring redo surgery in the late stage. PMID- 23917182 TI - [Operation for aortic regurgitation after ascending aortic replacement]. AB - In the clinical setting, surgery for aortic regurgitation after ascending aortic replacement is performed in a patient that underwent ascending aortic replacement due to acute aortic dissection (Stanford A). The 1st step is to determine preoperatively whether only surgery for aortic regurgitation should be performed or whether surgery should be performed for both aortic regurgitation and residual aortic dilatation. This decision should be based on the patient's general condition. Also, the possibility of preservation of the native aortic valve should be considered. Staged re-sternotomy using an inferior T-shaped mini sternotomy is useful for a retrosternal giant aneurysm of the thoracic aorta in combined surgery on both the aortic valve and aortic aneurysm. Steady cardiac and cerebral protection is important for obtaining good results. Postoperative intensive critical care and careful follow-up in the outpatient clinic are also important. In conclusion, it is important for surgeons to become proficient in surgery for aortic valve regurgitation after ascending aortic replacement, because more of these patients will be encountered in the future. PMID- 23917183 TI - [Re-right ventricular outflow reconstruction]. AB - The timing and indication of re-right ventricular outflow tract reconstruction (reRVOTR) remains controversial. The main cause for reRVOTR is pulmonary stenosis and pulmonary regurgitation. A pressure gradient of more than 50 mmHg between right ventricle and pulmonary artery or a right ventricular systolic pressure/left ventricular systolic pressure ratio higher than 0.7~0.8 is the threshold for recommending reoperation. Pulmonary regurgitation is difficult to quantify and is not an indication for reoperation until there was evidence of increasing right ventricular dilatation. That is, reoperation is recommended when there are mild to moderate pulmonary regurgitation with mild to moderate right ventricular dilatation and severe pulmonary regurgitation with or without right ventricular dilatation. ReRVOTR should be undertaken in maintaining normal right ventricular function, that is,under remaining free of symptoms. Therefore the right ventricular function needs to be assessed over time. PMID- 23917184 TI - [Fontan procedure in patients with hypoplastic left heart syndrome]. AB - In the recent years, the Fontan completion rate for hypoplastic left heart syndrome (HLHS) is improved because of the outcome of stage-1 palliation improved. However, there are still problems to be solved to achieve better hemodynamics after Fontan operation in patients with HLHS. The 2 major commandments other than classic 10 commandments are A:"good ventricular function" and B:"low pulmonary vascular resistance". To obtain these 2, the following problems should be rectified. They include residual arch obstruction, impaired right ventricule (RV) function, tricuspid regurgitation, elevated pulmonary vascular resistance, development of aorto-pulmonary collaterals and etc. The modern strategy for the treatment to achieve "good" Fontan circulation in HLHS patients, are 1)Norwood procedure with RV-pulmonary artery( PA) conduit, 2)staged palliation strategy, 3)repair co-existent and residual abnormality before stage 3(preferably at stage-2 palliation), 4)coil embolization of aorto-pulmonary collateral arteries before Fontan procedure, 5)the type of Fontan operation is extracardiac total cavopulmonary connection (TCPC) type, 6)fenestration if necessary, 7)careful and continuous follow-up is mandatory for early detection of arrhythmia, protein losing enteropathy (PLE), liver dysfunction and other fatal complications of long term after Fontan type procedure. PMID- 23917185 TI - [Reoperation after correction of common atrioventricular valve regurgitation]. AB - Surgery for common atrioventricular valve is classified into cases of groups at the univentricle repair with asplenic syndrome or cases of groups at the biventricular repair with atrial ventricular septal defect. The technique of the reoperation referred to a wide variety of surgical techniques such as commisuroplasty, valvuloplasty, annuloplasty, chordal repair, papillary muscle repair and valve replacement. This report examines the leaflet augmentation technique and supra-annular valve replacement for left atrioventricular valve after complete atrioventricular septal defect (AVSD) repair and semicircular annuloplasty with autologous pericardial strip for common atrioventricular valve after common atrioventricular valve repair. However, it is possible that numerous cases may require reoperation of valve plasty or valve replacement in the future. It is very important to follow up the subsequent history of the patients and to evaluate valve regurgitation and ventricular function while repeating cardiac catheterization, cardiac echo testing in addition to the clinical symptoms in a short period of time. PMID- 23917186 TI - [Re-aortic valve operations in children]. AB - We have performed aortic valve replacement (AVR) with mechanical valve, with/without annular enlargement in pediatric patients with left ventricular outflow tract obstruction (LVOT). Twenty-two patients underwent mechanical AVR between May 1993 and December 2012. The cumulative survival rates by the Kaplan Meier method were 95% in 5 year, and 95% in 10 year. Long-term result of mechanical AVR with/without annular enlargement in children is excellent. Therefore, it should be the 1st choice of surgical treatment at our institute. In this strategy, we had total 10 re-operation cases. Two cases:Konno operation after performing surgical aortic valvotomy, 6 cases:Konno operation after resection of subaortic stenosis, 1 case:re-valve replacement because of thrombus formation at mechanical valve, and 1 case:re-operation with somatic growth. At the age of operation, 2 years old and over cases had postoperative estimated effective orifice area index (EOAI)>0.85 cm2/m2 in the time of 20 years old. Since some issues concerning anticoagulation-related complications remain, careful observation is mandatory. PMID- 23917187 TI - [Bridge to bridge surgery;conversion from extracorporeal left ventricular assist device to implantable left ventricular assist device]. AB - Implantable left ventricular assist devices(I-LVADs)are approved only for bridge to transplantation (BTT) in the Japanese health insurance system, and paracorporeal Nipro-LVAD is the only one therapeutic choice for bridge to decision( BTD) and bridge to candidacy(BTC).Destination therapy(DT)with an I-LVAD is also not approved in Japan yet. Because average waiting period for heart transplantation is over 2 years, bridge to bridge( BTB) surgery, conversion from Nipro-LVAD to an I-LVAD, is often considered after the patient with Nipro-LVAD is approved by the committee as a heart transplantation recipient. Infection at the exit sites of Nipro-LVAD is a strong risk factor for pump pocket infection after BTB, and therefore BTB is not recommended for patients with Nipro-LVAD who have some infection at the exit sites. To achieve successful BTB, some attention should be made in Nipro-LVAD surgery. For instance, the heart and the outflow vascular graft should be covered with expanded polytetrafluoroethylene (ePTFE) sheet for next safe redo-sternotomy, and the inflow and outflow conduits should be placed appropriately to prevent infection at exit sites. In addition, several examinations and consultation for approval as a heart transplantation recipient should be scheduled as soon as possible after Nipro-LVAD implantation. PMID- 23917188 TI - [Surgical resection for postoperative local recurrent lung cancer]. AB - Reported recurrence rates after complete surgical resection range from 30 to 70%, depending on the final pathologic stage. Of these, 30 to 40% were local recurrent cancers. Chemotherapy and radiation therapy are commonly accepted treatment options for recurrent lung cancer, whereas surgical resection is limited to a relatively few patients. In this paper, we reviewed the current status of surgical resection for local recurrent lung cancer. Sites of local recurrences are defined as tumor in the ipsilateral lung, staple line, bronchial stump, and regional lymph nodes, which are potentially amenable to surgery. Surgical treatment of lung recurrence including ipsilateal lung or staple line, or sites of chest other than lung suggested a survival benefit in the recent retrospective studies. However, completion pneumonectomy or lobectomy has to be performed in almost of these cases, it is mandatory to evaluate an indication for re-operation by some general rules. During operation, surgeons considered a severe adhesion surrounding the bronchial stump and pulmonary artery because the manipulation of initial surgery occurred in the fibrosis of hilum and mediastinum. Surgeons should not hesitate to undergo standard thoracotomy through poster-lateral or median incision. It is secure to dissect main pulmonary artery in the pericardium for preparing the emergent bleeding or reconstruction. Handling suture for bronchial stump is necessary because it allows only a short margin to sew up. The perioperative management is based upon the post-pneumonectomy. PMID- 23917189 TI - [Re-operations for 2nd primary lung cancer detected during follow-up after lung cancer surgery]. AB - Re-operations for 2nd primary lung cancers are one of the most challenging modality for thoracic surgeons. Surgeons should have knowledge of indication of re-operations as well as surgical techniques and perioperative management of patients with 2nd primary lung cancers. When performing repeated pulmonary resection on the same side of the 1st surgery, following points are important for accomplishment of a safe re-operation:1.Wide thoracotomy with muscle dissections is recommended. 2.Throughout adhesion lysis between lung parenchyma and surrounding structures are required before manipulating pulmonary vessels. 3.The main pulmonary artery is encircled before dissection of the pulmonary artery. 4.Surgeons should be familiar with intrapericardial exposure of the main pulmonary artery. The techniques consist of division of the ligament of arteriosum, incision of the pericardium, and encircle of the origin of the mail pulmonary. Re-operations for metachronous lung cancers provided favorable survival in patients with adequate physiologic pulmonary reserve. PMID- 23917190 TI - [Completion pneumonectomy]. AB - Completion pneumonectomy (CP)is the complete removal of lung tissue remaining after an initial ipsilateral partial pulmonary resection and is one of the most invasive operations in the field of general thoracic surgery. Mortality and morbidity rates are higher after CP than standard pneumonectomy. CP is a highly demanding procedure, usually due to major pleural and sometimes pericardial dense adhesions from previous surgery or infection. Intra-pericardial control of the pulmonary artery and veins is recommended to avoid vessel injury. This operative intervention should, therefore, be performed only by experienced thoracic surgeons on carefully selected patients in order to improve ostoperative outcomes. Preoperative pulmonary and cardiac functions are decreased by the previous procedure. In addition, the rate of complications, such as residual respiratory and cardiac failure, is high because of excessive operative invasiveness and added transfusion load. Therefore, preoperative assessment, surgical indication, low invasive surgical technique, and good postoperative management are very important elements when CP is performed. This article reviews these operative strategies. PMID- 23917191 TI - [Polysurgery for intractable pneumothorax]. AB - Intractable secondary spontaneous pneumothorax (SSP) is occasionally lethal. Therefore, conservative treatments such as chemical pleurodesis are frequently performed for inoperable patients with intractable SSP. And then the operation for SSP is more serious and intractable than primary spontaneous pneumothoraces because of decreased pulmonary function and underlying lung diseases in these patients. Therefore, the indication of polysurgery for intractable pneumothorax is controversial. We had proposed the techniques of surgical approaches for polysurgery of intractable SSP. PMID- 23917192 TI - [Redo operation for recurrent, disseminated and metastaic thymoma]. AB - In this article, redo operation for recurrent thymoma was reviewed. Several cohort studies according the issues of the role of surgery for recurrent thymoma have been reported. Although these studies are of relatively small of seize and have selection biases, most of authors recommend surgical treatment for recurrent thymoma. Best results are expected in case of complete resection of the recurrence. Usually local recurrences are approached by a resternotomy, a clamshell incision or a hemi clamshell incision. Resternotomy associates with the risks of injury of brachiocepharic vein, heart and lungs and catastrophic hemorrhage. The degree of retrosternal adhesions and tumor invasion caused by recurrence are diverse. An oscillating saw is recommended for dividing the sternum. Video-assisted thoracic surgery(VATS)may help to dissect retrosternal adhesions. The most frequent pattern of recurrence is pleural implants after the initial operation with complete resection. In those cases, thoracotomy or VATS are often used. Redo operations for distant metastasis of thymoma are rare. Pleuropneumonectomy for pleural implantation is associated high morbidity and mortality rates, therefore this option is suitable for highly selected patients. Preoperative radiological evaluation of recurrent thymoma is important on planning of approach procedures. PMID- 23917193 TI - [Lung retransplantation; cadaveric lung retransplantation]. AB - Lung retransplantation accounts for only 2.6% of all lung transplantations performed worldwide. Overall survival after lung retransplantation is known to be worse than that of initial lung transplantation, but in cautiously selected lung recipients survival has been shown to be equally good. Decision about types of procedure is critical and meticulous patient care is also essential for success. PMID- 23917194 TI - [Lung re-transplantation using lobes from living-donors]. AB - Although the demand of organ re-transplantation has increased, the organ shortage from brain-dead donor raises an ethical controversy about the fairness of organ allocation for re-transplantation. Living donor lobar lung transplantation has become an alternative therapeutic option to brain-dead donor lung transplantation for not only pediatric but also adult patients. Lung re-transplantation using lobes from living donors have the potential to alleviate the ethical problems. This review focused on indications, surgical techniques, perioperative care and postoperative follow-up of living donor lobar lung re-transplantation. PMID- 23917195 TI - [Surgical intervention for residual space empyema and bronchopleural fistula after major pulmonary resection]. AB - Residual space empyema, that is a life threatening complication after major pulmonary resection, is based on postresectional hematoma, wound suppuration, and/or bronchopleurl fistula, demanding different strategies from parapneumonic empyema. Optimal managements should be occasionally completed in relation to the patient's physical conditions, serological findings, pathogens, and bronchopleural fistula. Bronchoscopic intervention can be a useful tool for a bronchopleural fistula when small. Thoracoscopic intervention can overcome the intractable residual space empyema. These interventions can save such invasive procedure as open window thoracotomy or thoracoplasty leading to damage pulmonary function as well as cosmetics, and prolong hospitalization. Vacuum-assisted closure system other than conventional thoracoplasty or thoracomyoplasty can be of help to obliterate the residual space empyema cavity after open window thoracotomy. PMID- 23917196 TI - [Surgical management of chylothorax after pulmonary resection]. AB - Chylothorax is a rare severe complication after general thoracic surgery. Recent advances of energy devices and limited pulmonary resection for early stage lung cancer decrease postoperative chylothorax. At an early stage, conservative treatment, such as chest tube drainage and reducing chyle flow by total elimination of oral or enteral fat intake should be initiated. When chyle flow continues 500~1,000 ml/day for 5 days or cardiopulmonary complications, immunodeficiency or malnutrition due to prolonged chylothorax are expected, surgical ligation of thoracic duct becomes the treatment option. After identification of wound localization by preoperative lymphangiography, direct wound ligature or en masse supradiaphragmatic ligature are recommended. Pre- or intraoperative ingestion of fatty substances via a nasogastric tube can facilitate wound localization by increasing the flow. Thoracoscopy is useful for searching the leaking point of chyle in detail. Due to the problems encountered with localizing wounds of thoracic duct, techniques have been developed to ligature the duct upstream, at its entry into the thorax. This wide ligature guarantees full ligature with close to 95% success rate. A chest tube can be removed immediately after reduction of pleural effusion less than 200 ml/day. PMID- 23917197 TI - [Re-thoracotomy for the management of postoperative complications after bronchoplastic and angioplastic reconstruction]. AB - Bronchoplastic and angioplastic reconstructions have become a common procedure as an alternative to pneumonectomy and provide an improved quality of life, which maximize residual lung tissue. Anastomotic complications in these procedures, such as anastomotic stricture, dehiscence, and vascular thrombosis, remain a matter of concern and are often fatal. Several different therapeutic approaches for these complications have been reported. In this paper, the management with re thoracotomy for postoperative complications after bronchoplastic and angioplastic reconstructions are described. PMID- 23917198 TI - [Reoperation for multidrug-resistant pulmonary tuberculosis]. AB - We have performed pulmonary resection combined with chemotherapy for multidrug resistant tuberculosis (MDR-TB). Postoperative complications of pulmonary resection for MDR-TB include space problem, prolonged air leak, bronchopleural fistula with or without empyema, chylothorax, and relapse. Indication, surgical technique, postoperative management, and follow-up of reoperation (thoracoplasty and muscle plombage, clousure of bronchopleural fistula, resuture of bronchial stump, open window thoracostomy, and 2nd pulmonary resection) for these complications are described. PMID- 23917199 TI - [Re-operation for recurrent pulmonary metastases]. AB - Fifty two patients with metastatic lung tumors were treated surgically in our hospital. Second pulmonary resections were performed in 6 patients. They consist of 1 male and 5 females, their age ranged from 59 to 80 years old( average 66 years old). Tumors originate from laryngeal cancer, colorectal cancer in 2 cases respectively, lung cancer and hepatic cancer in 1 case respectively. Three-year and 5-year survival was seen in 75% and 75% of patients, respectively. PMID- 23917200 TI - [Reoperation for the local recurrence of esophageal cancer]. AB - Survivals of the esophageal cancer patients underwent esophagectomy is becoming well. However, the 5-year survival rate after esophagectomy in Japan is 50.2% according to the examination by Japan Esophageal Society. The most reason of cancer death is disease recurrence. Most of recurrent lesions can't be removed by surgical procedures because of the various degrees of the disease progressions, whereas there must be a few cases that the curability is acquired by surgery. There are few evidences about the efficacy of reoperations for recurrent lesions after esophagectomy. Therefore, the indication of the surgical therapies for the recurrent lesions after radical esophagectomy should be carefully decided after due consideration about the status of the recurrent lesion and the patient's general condition. Now in this article, we will give an outline of the surgeries for the recurrent lesions, especially about lymph node recurrence. PMID- 23917201 TI - [Re-thoracotomy for intrathoracic complications after esophagectomy for esophageal cancer]. AB - We reviewed the indications for re-thoracotomy after esophagectomy for esophageal cancer. Hemothorax, chylothorax, tracheobronchial injury (fistula), pneumothorax, and pyothorax were the main causes of re-thoracotomy. Indications for emergency thoracotomy were as follows. 1)Hemothorax:bleeding through the chest drain continuing at >100 ml/hour for >=5 hour, or in cases when normal blood pressure cannot be maintained without blood transfusion. 2)Chylothorax:in cases with >=1.5 l/day of chyle drainage for >5 days under conservative treatment. Healing is not seen for 14 days after conservative treatment. Nutritional status of the patient has worsened. 3)Tracheobronchial injury:at 1st respiration state should be understood. After we maintain the patient's airway, fistula is treated by closure and plombage with omentum or muscle flap. Appropriate diagnosis and timing are important for re-thoracotomy for complications after esophagectomy. PMID- 23917202 TI - [Reoperation for the reconstruction organ necrosis after esophagectomy]. AB - Although the surgical technique and perioperative management have been improving, the mortality and morbidity rates for transthoracic esophagectomy followed by reconstruction are still comparatively high among the surgery for gastrointestinal cancers. Necrosis of reconstructed organ is a rare but fatal complication associated with high mortality rate. It is quite important to promptly and accurately diagnose the disturbance of blood circulation of reconstructed organs and appropriately treat those diseases. Otherwise, the patients could easily fall into endotoxic shock, disseminated intravascular coagulation(DIC) and multiple organ failure( MOF). Here, we will summarize the way of diagnosis and treatment for the necrosis of reconstructed organs and present 2 cases of reconstruction organ necrosis (gastric tube and ascending colon) after esophagectomy in our institute. PMID- 23917203 TI - SIPAR negatively regulates STAT3 signaling and inhibits progression of melanoma. AB - Persistently activated STAT3 is important for tumorigenesis in a variety of cancers, including melanoma. Although many co-factors in the regulation of STAT3 activity have been identified, it remains unclear how STAT3 phosphorylation is negatively regulated. Here, we report that SIPAR (STAT3-Interacting Protein As a Repressor) inhibits STAT3 activity by accelerating its dephosphorylation. We observed that SIPAR directly interacted with STAT3 upon IL-6 stimulation. Moreover, over-expression of SIPAR reduced, whereas depletion enhanced, the level of phosphorylated STAT3. We further demonstrated that SIPAR inhibited the growth of melanoma cells by decreasing the level of phosphorylated STAT3 and the expression of its target genes. These results suggest that SIPAR, functioning as a new negative regulator, inhibits STAT3 activity by enhancing its dephosphorylation and represses melanoma progression. PMID- 23917204 TI - TIS21(/BTG2/PC3) inhibits interleukin-6 expression via downregulation of STAT3 pathway. AB - Cancer cell growth was increased when co-cultured with fibroblasts, however, no effect was observed when co-cultured with TIS21-overexpressed fibroblast. Therefore, the role of TIS21 played in cancer microenvironment was investigated. TIS21 decreased interleukin-6 (IL-6) expression in human dermal fibroblast (HDF). Adenoviral transduction of TIS21 gene to HDF decreased the secretion of IL-6, whereas knockdown of the gene increased IL-6 expression. Furthermore, TIS21 overexpression inhibited STAT3 binding to IL-6 promoter region as well as JAK2 STAT3 signaling by inhibiting reactive oxygen species (ROS) generation by being localized in mitochondria. Mitochondria-target TIS21 (MT-TIS21) also inhibited IL 6 expression by downregulating STAT3 phosphorylation, whereas NF-kappaB pathway was not influenced by TIS21 expression. These results indicate that TIS21 negatively regulated cancer cell growth by inhibiting IL-6 expression through downregulation of STAT3 activation. PMID- 23917205 TI - Chronic nitric oxide deprivation induces an adaptive antioxidant status in human endothelial cells. AB - In a previous work, we showed an increased cell motility due to the accumulation and transcriptional activation of the Hypoxia Inducible Factor-1alpha (HIF 1alpha) and a reduced mitochondrial energy production in an in vitro model of endothelial dysfunction (ED) represented by human endothelial cells (ECs) chronically deprived of nitric oxide (NO) by L-NAME treatment. In the present study, in the attempt to unravel the pathway(s) linking NO deficiency to HIF 1alpha accumulation and activation, we focused our attention on Reactive Oxygen Species (ROS). We found that ROS were partially involved in HIF-1alpha stabilization, but not in the pro-migratory phenotype. Regarding mitochondrial dysfunction, it did not require neither ROS generation nor HIF-1alpha activity, and was not due to autophagy. Very interestingly, while acute treatment with L NAME induced a transient increase in ROS formation, chronic NO deprivation by long term L-NAME exposure drastically reduced cellular ROS content giving rise to an antioxidant environment characterized by an increase in superoxide dismutase-2 (SOD-2) expression and activity, and by nuclear accumulation of the transcription factor NF-E2-related factor-2 (Nrf2). These results might have important implications for our understanding of the consequences of NO deprivation in endothelium behavior and in the onset of cardiovascular diseases. PMID- 23917206 TI - IL-17 family cytokines mediated signaling in the pathogenesis of inflammatory diseases. AB - Inflammation is the immediate protective response of the body to pathogen invasions, allergen challenges, chemical exposures or physical injuries. Acute inflammation usually accompanies with transient infiltration of leukocytes, removal of danger signals and eventually tissue repair, while persistent and uncontrolled inflammation becomes a major stimulator in the progression of many chronic diseases in human, including autoimmune diseases, metabolic disorders and cancer. Interleukin (IL)-17 family is a recent classified subset of cytokines, playing critical roles in both acute and chronic inflammatory responses. In this review, we will summarize recent progresses on the signalings of this family cytokines and their impacts on the inflammatory responses or disorders. PMID- 23917207 TI - Regulation of inflammation by extracellular acidification and proton-sensing GPCRs. AB - Under ischemic and inflammatory circumstances, such as allergic airway asthma, rheumatoid arthritis, atherosclerosis, and tumors, extracellular acidification occurs due to the stimulation of anaerobic glycolysis. An acidic microenvironment has been shown to modulate pro-inflammatory or anti-inflammatory responses, including cyclooxygenase-2 (COX-2) expression, prostaglandin synthesis, and cytokine expression, in a variety of cell types, and thereby to exacerbate or ameliorate inflammation. However, molecular mechanisms underlying extracellular acidic pH-induced actions have not been fully understood. Recent studies have shown that ovarian cancer G protein-coupled receptor 1 (OGR1)-family G protein coupled receptors (GPCRs) can sense extracellular pH or protons, which in turn stimulates intracellular signaling pathways and subsequent diverse cellular responses. In the present review, I discuss extracellular acidic pH-induced inflammatory responses and related responses in inflammatory cells, such as macrophages and neutrophils, and non-inflammatory cells, such as smooth muscle cells and endothelial cells, focusing especially on proton-sensing GPCRs. PMID- 23917208 TI - Orexin receptors: multi-functional therapeutic targets for sleeping disorders, eating disorders, drug addiction, cancers and other physiological disorders. AB - The orexin peptides (orexin A, orexin B) and their receptors (orexin receptor type 1, orexin receptor type 2) are involved in multiple physiological processes such as the regulation of sleep/wakefulness state, energy homeostasis and reward seeking. A result of this has been the development of small-molecule orexin receptor antagonists as novel therapies for the treatment of insomnia and drug addiction. Increased levels of signaling via the orexin peptide/receptor system may protect against obesity, while somewhat unexpectedly, orexins acting at orexin receptors induce dramatic apoptosis resulting in the significant reduction of cell growth in various cancer cell lines. Meanwhile, the orexin peptide/receptor system is also involved in cardiovascular modulation, neuroendocrine and reproduction regulation. This review summarizes the latest developments in deciphering the biology of orexin signaling as well as efforts to manipulate orexin signaling pharmacologically. PMID- 23917209 TI - The potential role of small heat shock proteins in mitochondria. AB - Mitochondria play a central role in cellular metabolism, calcium homeostasis, redox signaling and cell fates. Mitochondrial homeostasis is tightly regulated, and mitochondrial dysfunction is frequently associated with severe human pathologies. Small heat shock proteins are molecular chaperones that play major roles in development, stress responses, and diseases, and have been envisioned as targets for therapy. The mechanisms that lie behind the cytoprotection of small heat shock proteins are related to the regulation of mitochondrial functions. This review recapitulates the current knowledge of the expression of various small heat shock proteins in mitochondria and discusses their implication in the role of mitochondria and their regulation. Based on their involvement in mitochondrial normal physiology and pathology, a better understanding of their roles and regulation will pave the way for innovative approaches for the successful treatment of a range of stress-related syndromes whose etiology is based upon dysfunction of mitochondria. PMID- 23917210 TI - Arthroscopic reconstruction of shoulder's labrum with extensive tears. AB - BACKGROUND: With the continuous development of arthroscopic techniques, the majority of superior labrum anterior-posterior (SLAP) lesions can be treated with minimally invasive endoscopic repair. The aim of this study was to determine the efficacy of arthroscopic capsulolabral reconstruction of SLAP lesions with extensive tears. METHODS: Eighteen patients with SLAP lesions with extensive tears (median age, 27.50 years) were included in this study. Twelve patients had type-V SLAP lesions, 4 patients had type-VIII SLAP lesions, and 2 patients had deeply located SLAP lesions. The average duration of follow-up was 15.83 months (range, 11-22 months). Outcome measures included shoulder range of motion (ROM), American Shoulder and Elbow Surgeons (ASES) and Constant-Murley scores, and visual analogue scale (VAS) pain score. RESULTS: After arthroscopic surgery, shoulder forward flexion, shoulder external rotation, and external rotation in 90 degrees of abduction were significantly greater than before surgery (169.5 degrees vs. 165.5 degrees , P = 0.001), (90 degrees vs. 63.5 degrees , P < 0.001), and (90 degrees vs. 81.5 degrees , P = 0.004), respectively. Median ASES and Constant-Murley scores after surgery were both 94 as compared to 77.0 and 77.5, respectively, before surgery (both, P < 0.001). The median VAS score decreased to 1.5 after surgery as compared to 6 before surgery (P < 0.001). CONCLUSIONS: Arthroscopic repair of SLAP lesions with extensive tears can achieve good outcomes. PMID- 23917211 TI - Assessing the impact of an ageing population on complication rates and in-patient length of stay. AB - BACKGROUND: Ireland has an ageing population; with the proportion of people aged over 80 years estimated to increase over the next 20 years from 1.1% to 2.1%. AIMS: The aim of this study was to examine the demographics of the population served by the surgical department in a tertiary referral centre in the west of Ireland and to examine whether increasing age had an influence on morbidity, mortality and length of stay. METHODS: Data pertaining to all surgical admissions over a 6-month period between was collected prospectively using an ACS-NSQIP based proforma. Data collected included patient age, gender, operative intervention, in-patient length of stay, mode of admission and complications related to their admission. RESULTS: A total of 2209 patients were admitted under the care of the general, vascular and breast services in our centre over a 6 month period between August and January. Two thousand and nineteen patients had complete data collected. The average age was 50.37 years (+/- 23.62), with 24.12% (n = 533) older than 70 years. Only 12.31% of patients aged younger than 70 years experienced morbidity, compared to 25.10% of older patients. It was shown that there was a stepwise increase with complication rates and hospital in-patient stay across each decade of increasing age. Multivariate analysis showed those factors most predictive of a complication to include emergency admission, major or complex major surgical intervention, female gender and age. Length of stay was also found to have a positive correlation with increasing age (Spearman's Rho, p < 0.001). CONCLUSION: Increasing age is associated with increased complication rates and increased hospital length of stay. PMID- 23917212 TI - Implications of charge ordering in high Tc cuprate superconductors in far infrared spectroscopy. AB - We addressed the issue of the absence of far-infrared signatures pertaining to charge ordering in the published far-infrared reflectivity data of La2-xSrxCuO4 single crystals while other experimental probes reveal that charge ordering is a hallmark of superconducting cuprates. Through direct comparison of the far infrared data reported by various groups side by side and also with the Raman scattering data, we found that the inconsistencies stem from the failure in capturing delicate spectral features embedded in the close-to-perfect ab-plane far-infrared reflectivity of La2-xSrxCuO4 single crystals by misidentifying the reflectivity as the Drude-like metallic reflectivity. The analysis of the close to-true reflectivity data reveals that only a small fraction (<3%) of the total doping-induced charge carriers (electrons) are itinerant on the electron lattice made up with the rest of the electrons (>97%) at all doping levels up to 16%. We conclude that the far-infrared reflectivity study is far from being ready to construct a coherent picture of the ubiquitous charge ordering phenomenon and its relationship with the high Tc superconductivity. PMID- 23917214 TI - Circadian rhythms, skeletal muscle molecular clocks, and exercise. AB - Skeletal muscle comprises approximately 40% of total body mass and, as such, contributes to maintenance of human health. In this review, we discuss the current state of knowledge regarding the role of molecular clocks in skeletal muscle. In addition, we discuss a new function for exercise as a time-setting cue for muscle and other peripheral tissues. PMID- 23917215 TI - Laparoscopic transperitoneal anterior adrenalectomy. AB - AIM: Aim of this study was to report the authors' experience with the anterior transperitoneal approach, and with an anterior submesocolic approach in case of left sided lesions. MATERIAL AND METHODS: From January 1994 to January 2011, 122 males and 170 females with a mean age of 50.7 years (range: 19-84) underwent laparoscopic adrenalectomy (LA) at 2 centers in Ancona and Rome (Italy) (that follow the same protocol). Fifteen patients underwent bilateral LA, the anterior transperitoneal approach was used in 233 cases (79.8%) and the anterior submesocolic in 59 (20.2%). One hundred and two patients had Conn's syndrome, 51 miscellaneous lesions, 55 Cushing's syndrome, 47 incidentalomas, 46 pheochromocytoma, 2 metastatic masses, 2 myelolipomas and 2 adrenogenital syndromes. The lesions had a mean diameter of 3.24 cm (range: 0.5-10). RESULTS: Mean operating time was 120 minutes (range: 30-390). Conversion to open surgery was required in 13 cases (4,45%). Blood pressure and heart rate were stable during the operation. There were 5 major complications. Mobilization and resumption of diet occurred on the first postoperative day. Mean hospital stay was 4.32 days (range: 2-30). DISCUSSION: Early identification and ligature of the adrenal vein, with minimal gland manipulation, are the major advantages, especially in case of pheochromocytoma. CONCLUSIONS: Adrenal masses can be successfully treated using a laparoscopic transperitoneal anterior approach, in presence of a suitable anesthesiological and surgical team's experience. KEY WORDS: Adrenal tumors, Laparoscopic adrenalectomy, Pheochromocytoma. PMID- 23917216 TI - Biomaterials and bioengineering tomorrow's healthcare. PMID- 23917217 TI - N-Palmitoylethanolamide protects the kidney from hypertensive injury in spontaneously hypertensive rats via inhibition of oxidative stress. AB - Hypertension is an important risk factor for kidney failure and renal events in the general population. Palmitoylethanolamide (PEA) is a member of the fatty acid ethanolamine family with profound analgesic and anti-inflammatory effects, resulting from its ability to activate peroxisome proliferator activated receptor (PPAR)alpha. A role for this nuclear receptor has been addressed in cardiovascular system and PPARalpha ligands have been shown to protect against inflammatory damage especially resulting from angiotensin II hypertension. In this study, we demonstrated that PEA significantly reduced blood pressure in spontaneously hypertensive rats (SHR) and limited kidney damage secondary to high perfusion pressure. To investigate the mechanisms involved in PEA effect, we found that PEA reduced cytochrome P450 (CYP) hydroxylase CYP4A, epoxygenase CYP2C23 and soluble epoxide hydrolase enzyme expression in the kidney, accompanied by a reduction of 20-hydroxyeicosatetraenoic acid excretion in the urine. Moreover, it markedly reduced kidney oxidative and nitrosative stress accompanied by decreased expression of renal NAD(P)H oxidase and inducible nitric oxide synthase and increased expression of Cu/Zn superoxide dismutase, in the kidney of SHR. Moreover, angiotensin II receptor (AT) evaluation revealed a decrease in AT1 receptor expression and a restoration of AT2 receptor level in the kidney from PEA-treated SHR. Consistently, angiotensin converting enzyme expression was reduced, implying a decrease in angiotensin II synthesis. These results indicate that PEA treatment lowers blood pressure and can protect against hypertensive renal injury by increasing the antioxidant defense and anti inflammatory response and modulating renin-angiotensin system. PMID- 23917218 TI - Melatonin improves short and long-term neurobehavioral deficits and attenuates hippocampal impairments after hypoxia in neonatal mice. AB - Hypoxic encephalopathy is a common cause of neonatal seizures and long-term neurobehavioral abnormalities. The purpose of this study was to determine whether administration of melatonin, starting at 1h before hypoxia and then every 24 h for 3 days, influences short and long-term neurobehavioral development and hippocampal impairments in postnatal day 1 mice subjected to hypoxia (5% oxygen and 95% nitrogen for 120 min). Melatonin significantly attenuated hypoxia-induced neurobehavioral deficits, including sensorimotor performance, locomotor functions, and hyperactivity up to two weeks after hypoxia insult. The above mentioned functional benefits of melatonin were associated with attenuation of cell death in the hippocampus. Importantly, melatonin improved learning and memory performance in the Morris water test, as associated with significantly increased proliferating cells (BrdU-positive cells) and differentiating neuroblasts (doublecortin-positive neuroblasts) in the hippocampus of hypoxic animals at 30 days after hypoxia. In addition, melatonin significantly decreased microglial activation and overproduction of pro-inflammatory mediators (tumor necrosis factor-alpha, interleukin-1beta and nitric oxide) from 3 to 30 days after hypoxia, possibly by inhibiting NF-kappaB activation in the hippocampus. The present results show that melatonin has short- and long-term protective effects against hypoxia-induced neurobehavioral deficits in the neonatal mouse. These beneficial effects are associated with increasing neurogenesis and attenuation of cell death and inflammatory responses in the hippocampus. PMID- 23917219 TI - Microparticles mediate MRP1 intercellular transfer and the re-templating of intrinsic resistance pathways. AB - Multidrug resistance (MDR) is a major impediment to the overall success of chemotherapy in clinical oncology. MDR has been primarily attributed by the ATP dependent transmembrane proteins, P-glycoprotein (P-gp, ABCB1) and Multidrug Resistance-Associated Protein 1 (MRP1, ABCC1). These proteins maintain sublethal concentrations of intracellular chemotherapeutics by virtue of their drug efflux capacity. In this study, we report the acquisition and dissemination of functional MRP1 via microparticle (MP) mediated intercellular transfer. After we showed the transfer and functionality of P-gp in drug sensitive recipient cells, we report the transfer and time-dependent functionality of MRP1 in drug sensitive leukaemia cells following exposure to MPs shed by MRP1-overexpressing MDR cells. We also demonstrate a remarkable capacity for MPs shed from cells with a P-gp dominant resistance profile to re-template a pre-existing MRP1 dominant profile in recipient cells. These findings have significance in understanding the molecular basis for tumour dominant phenotypes and introduce potential new strategies and targets for the acquisition of MDR and other deleterious traits. PMID- 23917220 TI - Abiotic degradation of antibiotic ionophores. AB - Hydrolytic and photolytic degradation were investigated for the ionophore antibiotics lasalocid, monensin, salinomycin, and narasin. The hydrolysis study was carried out by dissolving the ionophores in solutions of pH 4, 7, and 9, followed by incubation at three temperatures of 6, 22, and 28 degrees C for maximum 34 days. Using LC-MS/MS for chemical analysis, lasalocid was not found to hydrolyse in any of the tested environments. Monensin, salinomycin, and narasin were all stable in neutral or alkaline solution but hydrolysed in the solution with a pH of 4. Half-lives at 25 degrees C were calculated to be 13, 0.6, and 0.7 days for monensin, salinomycin, and narasin, respectively. Absorbance spectra from each compound indicated that only lasalocid is degraded by photolysis (half life below 1 h) due to an absorbance maximum around 303 nm, and monensin, salinomycin, and narasin are resistant to direct photolysis because they absorb light of environmentally irrelevant wavelengths. PMID- 23917221 TI - Periostin cooperates with mutant p53 to mediate invasion through the induction of STAT1 signaling in the esophageal tumor microenvironment. AB - Periostin (POSTN), a matricellular protein, has been reported to be important in supporting tumor cell dissemination. However, the molecular mechanisms underlying POSTN function within the tumor microenvironment are poorly understood. In this study, we observe that the inducible knockdown of POSTN decreases esophageal squamous cell carcinoma (ESCC) tumor growth in vivo and demonstrate that POSTN cooperates with a conformational missense p53 mutation to enhance invasion. Pathway analyses reveal that invasive esophageal cells expressing POSTN and p53(R175H) mutation display activation of signal transducer and activator of transcription 1 (STAT1) target genes, suggesting that the induction of STAT1 and STAT1-related genes could foster a permissive microenvironment that facilitates invasion of esophageal epithelial cells into the extracellular matrix. Genetic knockdown of STAT1 in transformed esophageal epithelial cells underscores the importance of STAT1 in promoting invasion. Furthermore, we find that STAT1 is activated in ESCC xenograft tumors, but this activation is attenuated with inducible knockdown of POSTN in ESCC tumors. Overall, these results highlight the novel molecular mechanisms supporting the capacity of POSTN in mediating tumor invasion during ESCC development and have implications of therapeutic strategies targeting the tumor microenvironment. PMID- 23917222 TI - Crosstalk between PKCalpha and Notch-4 in endocrine-resistant breast cancer cells. AB - The Notch pathway is functionally important in breast cancer. Notch-1 has been reported to maintain an estrogen-independent phenotype in estrogen receptor alpha (ERalpha)+ breast cancer cells. Notch-4 expression correlates with Ki67. Notch-4 also plays a key role in breast cancer stem-like cells. Estrogen-independent breast cancer cell lines have higher Notch activity than estrogen-dependent lines. Protein kinase Calpha (PKCalpha) overexpression is common in endocrine resistant breast cancers and promotes tamoxifen (TAM)-resistant growth in breast cancer cell lines. We tested whether PKCalpha overexpression affects Notch activity and whether Notch signaling contributes to endocrine resistance in PKCalpha-overexpressing breast cancer cells.Analysis of published microarray data from ERalpha+ breast carcinomas shows that PKCalpha expression correlates strongly with Notch-4. Real-time reverse transcription PCR and immunohistochemistry on archival specimens confirmed this finding. In a PKCalpha overexpressing, TAM-resistant T47D model, PKCalpha selectively increases Notch-4, but not Notch-1, expression in vitro and in vivo. This effect is mediated by activator protein-1 (AP-1) occupancy of the Notch-4 promoter. Notch-4 knockdown inhibits estrogen-independent growth of PKCalpha-overexpressing T47D cells, whereas Notch-4IC expression stimulates it. Gene expression profiling shows that multiple genes and pathways associated with endocrine resistance are induced in Notch-4IC- and PKCalpha-expressing T47D cells. In PKCalpha-overexpressing T47D xenografts, an orally active gamma-secretase inhibitor at clinically relevant doses significantly decreased estrogen-independent tumor growth, alone and in combination with TAM. In conclusion, PKCalpha overexpression induces Notch-4 through AP-1. Notch-4 promotes estrogen-independent, TAM-resistant growth and activates multiple pathways connected with endocrine resistance and chemoresistance. Notch inhibitors should be clinically evaluated in PKCalpha- and Notch-4-overexpressing, endocrine-resistant breast cancers. PMID- 23917224 TI - Dual detection of cancer biomarker CA125 using absorbance and electrochemical methods. AB - An enzyme-linked immunoassay based on dual signal transduction mechanisms has been developed for detection of ovarian cancer biomarker CA125. The immunoassay uses a nanoelectrode array (NEA) chip and absorbance methods for the dual detection. The NEA is used to confirm the optical detection of CA125 that is carried out in a high-binding 96-well plate. An alkaline phosphatase (AP) enzyme was used to label the detection antibody to allow for both the optical and electrochemical detection of CA125. Two kinds of substrates were catalyzed by the AP enzyme. para-Nitrophenylphosphate (PNPP) produces chromogenic para-nitrophenol (PNP), which can be optically detected at 405 nm. para-Aminophenylphosphate (PAPP) produces electroactive para-aminophenol (PAP), which can be detected amperometrically between -0.1 and 0.3 V. The linear ranges have been determined to be 5-1000 U mL(-1) and 5-1000 U mL(-1) for the optical and electrochemical immunoassays, respectively. The limit of detection of the optical immunoassay is 1.3 U mL(-1) and 40 U mL(-1) for the optical and electrochemical methods, respectively. PMID- 23917223 TI - SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cells. AB - SOX2 (Sex-determining region Y (SRY)-Box2) has important functions during embryonic development and is involved in cancer stem cell (CSC) maintenance, in which it impairs cell growth and tumorigenicity. However, the function of SOX2 in pancreatic cancer cells is unclear. The objective of this study was to analyze SOX2 expression in human pancreatic tumors and determine the role of SOX2 in pancreatic cancer cells regulating CSC properties. In this report, we show that SOX2 is not expressed in normal pancreatic acinar or ductal cells. However, ectopic expression of SOX2 is observed in 19.3% of human pancreatic tumors. SOX2 knockdown in pancreatic cancer cells results in cell growth inhibition via cell cycle arrest associated with p21(Cip1) and p27(Kip1) induction, whereas SOX2 overexpression promotes S-phase entry and cell proliferation associated with cyclin D3 induction. SOX2 expression is associated with increased levels of the pancreatic CSC markers ALDH1, ESA and CD44. Importantly, we show that SOX2 is enriched in the ESA(+)/CD44(+) CSC population from two different patient samples. Moreover, we show that SOX2 directly binds to the Snail, Slug and Twist promoters, leading to a loss of E-Cadherin and ZO-1 expression. Taken together, our findings show that SOX2 is aberrantly expressed in pancreatic cancer and contributes to cell proliferation and stemness/dedifferentiation through the regulation of a set of genes controlling G1/S transition and epithelial-to mesenchymal transition (EMT) phenotype, suggesting that targeting SOX2-positive cancer cells could be a promising therapeutic strategy. PMID- 23917225 TI - Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion. AB - Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A-accumulating) and Zmpste24-proficient (mature lamin A-containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target. PMID- 23917226 TI - Synthesis and evaluation of phosphorodithioate-based hydrogen sulfide donors. AB - A series of O-aryl- and alkyl-substituted phosphorodithioates were designed and synthesized as hydrogen sulfide (H2S) donors. H2S releasing capability of these compounds was evaluated using fluorescence methods. O-aryl substituted donors showed slow and sustained H2S release while O-alkylated compounds showed very weak H2S releasing capability. We also evaluated donors' protective effects against hydrogen peroxide (H2O2)-induced oxidative damage in myocytes and donors' toxicity toward B16BL6 mouse melanoma cells. PMID- 23917227 TI - [Clinical evaluation of intraoperative cardiac output measurement by a new arterial pressure waveform analysis method( FloTrac/Vigileo) in open heart surgery]. AB - We retrospectively evaluated the initial clinical experience of intraoperative cardiac output measurement by a new arterial pressure-based cardiac output (APCO:FloTrac/Vigileo) analysis in patients undergoing open heart surgery. Thirty two patients (mean age 76.4, range 59 to 90)who underwent cardiac surgery under cardiopulmonary bypass( CPB) from July 2008 to September 2009 in our institute were enrolled in this study. There were 14 women and 18 men. The cardiac operations included 28 valve surgeries and 4 coronary artery bypass grafting. The APCO was introduced initially, then a continuous cardiac output (CCO:Swan-Ganz catheter) analysis system was established following the induction of anesthesia. The correlation of both cardiac output measurements was evaluated at 5 time points, T1:induction of anesthesia, T2:sternotomy, T3:after weaning from CPB, T4:closure of the chest, and T5:arrival at intensive care unit. There were no serious complications related to APCO and CCO. The correlation between APCO and CCO was evaluated by Bland-Altman plot analysis. The percentages of correlation between both groups were T1:81.2%, T2:78.1%, T3:59.4%, T4:62.5%, and T5:65.6%. A good correlation was shown in all 6 patients with atrial fibrillation at T1 and T2. No correlation was shown in the 3 patients with left ventricular( LV) dysfunction below LVEF 40%, 1 case at T3, all 3 cases at T4, and 2 cases at T5. Before the institution of CPB, 3 of the 6 at T1 and 3 of the 7 at T2 in whom no correlation was shown, had severe aortic valve insufficiency (AVI).From these results, APCO appears to be an acceptable device to evaluate the intraoperative cardiac output measurement compared with CCO, except in patients with LV dysfunction or AVI at some time points. Further studies will be necessary to elucidate the precise clinical evidence to assess the efficacy of this new analysis device. PMID- 23917228 TI - [Treament using a free omental flap for pulmonary Aspergillosis with chronic methicillin-resistant Staphylococcus aureus( MRSA) empyema after fenestration]. AB - A case is 48-year-old man who had a history of Blalock-Taussig shunt and the radical operation for Fallot's tetralogy, had been performed cavernostomy and fenestration operation for aspergilloma of left upper lobe in the previous hospital due to control blood spitting. Although the contents of the abscess cavity were removed, the opened cavity was again infected by methicillin resistant Staphylococcus aureus (MRSA) and he was referred to our hospital. The plombage of free omental flap with vascular anastomosis was performed. He has been well without any symptoms or recurrence of empyema for 6 years after surgery. PMID- 23917229 TI - [Lower body ischemia due to bending of the stent after hybrid treatment for chronic stanford type B aortic dissection]. AB - Lower body ischemia due to bending of a stented graft at the thoracic aorta was rare, particularly when it occurred in several days after surgery. We experienced this complication and performed the 3rd-time thoracic endovascular repair( TEVAR).A 49-year-old man with a chronic aortic dissection of Stanford type B underwent TEVER;however we failed to close the entry because of the tortuously bended distal arch of the aorta. Then it was decided the patient undergo a hybrid treatment with arch replacement and frozen elephant trunk. Seventeen days after the surgery, the blood pressure of the patient's lower limb was reduced rapidly and his renal function deteriorated. Bending of the stent was revealed by computed tomography( CT). The patient underwent the 3rd-time emergency TEVAR, and his symptoms improved. PMID- 23917230 TI - [Pulmonary mycobacterium intracellulare infection complicated with pneumothorax and chronic empyema]. AB - A 75-year-old woman who had been treated for pulmonary Mycobacterium intracellulare infection was admitted to a nearby hospital because of hemoptysis, right pneumothorax, and empyema. She had been treated by thoracic drainage and pleural lavage, but was reffered to our hospital because of refractory empyema. Her chest radiograph and chest computed tomography( CT) showed right chronic empyema of which pleural aspirate was smear positive for acid-fast bacilli and positive for the polymerase chain reaction method(PCR)-Mycobacterium intracellulare. Serum levels of white blood cell and C-reactive protein(CRP) were found to be slightly elevated. She was treated with combined use of ethambutol, rifampicin, clarithromycin, and kanamycin and with pleural curettage by thoracoscopic surgery. After surgery additional treatment was done using urokinase which was administered into the thoracic cavity via an thoracic tube. Chronic empyema gradually improved with the treatment and the pleural effusion became bacterial free, enabling the patient to discharge from hospital without thoracic drainage. PMID- 23917231 TI - [Aortic valve-sparing operation for chronic dissecting aneurysm of the sinus of valsalva associated with redissection in a young woman who experienced out-of hospital cardiac arrest]. AB - A 38-year-old woman was admitted to our hospital because she experienced cardiopulmonary arrest at her wedding;her cardiac beats were resumed 20 min after cardiopulmonary resuscitation performed by her relatives and hotel staffs. Enhanced computed tomography revealed acute aortic redissection in chronic dissecting aneurysm in the right sinus of Valsalva, which was believed to have occurred in the 4th month of pregnancy 2 years before. Echocardiography showed moderate aortic regurgitation. We performed aortic valve-sparing operation and ascending aortic replacement with partial remodeling of the right sinus of Valsalva. She returned to work 2 months later without high-order dysfunction. PMID- 23917232 TI - [On pump beating heart mitral and tricuspid valve annuloplasty via right mini thoracotomy approach in a patient who had undergone cardiac surgery 3 times]. AB - The patient was an 84-year-old man. He had a history of 3-time median sternotomy with a functioning coronary bypass graft. Because of his dependence on inotropic agents caused by a progressing mitral and tricuspid valve insufficiency, we decided to perform surgery. To avoid heart damage and injury to the bypass graft by adhesiotomy, we performed on-pump beating heart mitral and tricuspid valve annuloplasty via right mini-thoracotomy approach. He was discharged 16 days after surgery. The on-pump beating heart valve repair via right mini-thoracotomy approach was useful in a selected case with multiple surgeries. PMID- 23917233 TI - [Multiple mitral valve aneurysms, mycotic arterial embolism and aneurysms with infective endocarditis]. AB - A 30-year-old woman with a more than 6-month history of fever, weight loss, general fatigue and dysesthesia of lower extremities was admitted to our hospital with a diagnosis of infective endocarditis. Blood cultures revealed Staphylococcus oralis. Echocardiography revealed severe mitral and moderate tricuspid regurgitation, as well as massive vegetations and aneurysms on the mitral valve. Computed tomography revealed an abdominal aortic aneurysm, left common and external iliac arterial aneurysms, and occlusion of the left common iliac, the deep femoral arteries and the bilateral tibioperoneal trunk. The ankle brachial pressure indices (ABI) were 0.94 (right) and 0.61 (left). She initially underwent mitral valve replacement and tricuspid annuloplasty. On postoperative day 24, the affected segments of the arteries were replaced with a woven Dacron bifurcated graft after resection of the mycotic abdominal and the iliac arterial aneurysms. We could not obtain a sufficient amount of omental pedicle to wrap the prosthesis. Her postoperative course was uneventful and mycotic arterial embolism and aneurysm did not recur. PMID- 23917234 TI - [Ventricular septal rupture and right ventricular free wall rupture after acute myocardial infarction]. AB - Cardiac rupture is a catastrophic complication of acute myocardial infarction with highly mortality rate. Three types of rupture are ventricular free wall rupture( VFR), ventricular septal rupture( VSR), and papillary muscle rupture( PMR). A combination of any 2 types of rupture is called ventricular double rupture (VDR), and very rare. We report a case of VDR (VSR and VFR) after acute myocardial infarction. A 76-year-old female with heart failure was admitted to our hospital. Echocardiography showed an apical VSR and pericardial effusion. She was diagnosed with VDR and emergent operation was performed. During operation, the site of VFR was right ventricle, which was the same infarction area of VSR. VSR was closed by infarction exclusion technique, concurrently excluding the site of VFR. VFR was successfully repaired by mattress sutures. Post-operative course was good without heart failure, though residual shunt was remained. The patient survived and was discharged from our hospital. PMID- 23917235 TI - [Mediastinal bronchogenic cyst causing severe tracheal stenosis]. AB - An 86-year-old female patient was transported to our hospital because of progressive dyspnea. Computed tomography revealed a 7-cm-diameter low-density mass located in the upper mediastinum behind the trachea. The mass compressed the trachea and caused severe tracheal stenosis. We diagnosed the tumor as a paratracheal type of bronchogenic cyst. The patient was immediately intubated, and a semiemergent operation was performed. Because of her advanced age, minimally invasive surgery was considered. The cyst was partially resected for fenestration. Just after the operation, the patient was extubated and became asymptomatic. The postoperative course was uneventful, and the patient was discharged from the hospital on the 14th postoperative day. The tumor was histologically diagnosed as a bronchogenic cyst. Six months after the operation, she was still asymptomatic. PMID- 23917236 TI - [Long survival case of resected lung cancer after chemotherapy with gefitinib]. AB - In another hospital, a 71-year-old man had been pointed out to have an abnormal shadow in the left lung field on chest radiograph at a medical checkup. Computed tomography( CT) scan revealed a mass both in the S1+2 and in the S10 of the left lung. The mass in the S1+2 was diagnosed as squamous cell carcinoma by bronchoscopy. CT scan revealed a swelling lymph node at the opposite side. He was diagnosed as having lung cancer (cT2N3M1:stage IV) and was given chemotherapy. The S1+2-mass showed a partial response and the S10-nodule was stable disease. He was then changed to gefitinib administration due to severe side effect of the chemotherapy. The side of S10-nodule once reduced, however, it grew up again after 16 months treatment with gefitinib. He was then referred to our hospital for surgery, and bisegmentectomy with mediastinal dissection was performed. He had no complications after the operation, and is well without recurrence for 8 years after the operation. PMID- 23917237 TI - [Work flow of registry in participating facilities and data audit in clinical database]. AB - Clinical database needs quality control and quality assurance of data. Medical staffs of facilities in clinical database need to confirm definitions of data submitted to clinical database and criteria of registered cases, and decide how to entry data before data entry. Especially good communication between surgeons and data managers becomes an important factor of data quality in facilities. Also, we need quality improvement initiatives based on high quality data. Clinical database has to assurance data quality. The indicators of data quality are, for examples, completeness of registration and accuracy of data entry and data quality is evaluated on data verification between data of clinical database and medical records in facilities. From these viewpoints, this article described about work flow of registry for participating facilities and medical staffs. PMID- 23917238 TI - [Early calcification of bioprosthetic valve in a hemodialysis patient with secondary hyperparathyroidism;report of a case]. AB - Aortic valve replacement using CEP Magna 21 mm bioprosthetic valve was performed because of aortic valve stenosis in a 75-year-old man with maintenance dialysis. In the 39th postoperative month, the bioprosthetic valve malfunction due to calcification was noted, and it was replaced. Judging from the previously reported cases, malfunction of an artificial valve in the 39th month is thought to be relatively early. Early-stage calcification of a bioprosthetic valve is considered to be caused by secondary hyperparathyroidism due to artificial dialysis. Therefore, careful consideration is necessary in selecting an artificial valve in a dialysis patient. To prevent early-stage calcification of a bioprosthetic valve in a dialysis patient, strict control of parathyroid hormones, blood phosphorus and calcium levels is necessary. In addition, due to the attendant risk of calcification of bioprosthetic valves, mechanical valves are recommended to dialysis patients, who are expected to survive for more than 3 years and who are not expected to develop hemorrhagic complications. PMID- 23917239 TI - [Total anomalous pulmonary venous connection with an unusual drainage vein from the right lung to the innominate vein;report of a case]. AB - We encountered a case of total anomalous pulmonary venous connection with a drainage vein following an unusual course. The drainage vein, after emerging from the right lung, crossed the midline and drained into the innominate vein. Along the course of this vein, severe stenosis was present in the region wedged between the aortic arch and pulmonary artery, leading to severe pulmonary congestion. The common pulmonary vein was well developed. There was no other intracardiac malformation except atrial septal defect. No heterotaxy syndrome associated. Because echocardiography was unable to provide a complete picture of the pulmonary veins and drainage veins, multidetector-row computed tomography was performed to ascertain the anatomy. Emergency surgical intervention was carried out and anastomosis of the common pulmonary vein to the left atrium was performed. The postoperative course was favorable. PMID- 23917240 TI - [Succesful case of open heart surgery in a dialysis patient with infectious endocarditis and severe bone marrow suppression: report of a case]. AB - We report a case of infectious endocarditis due to Corynebacterium species. The patient was 71-yearold man, who was on dialysis and had tracheostomy preoperatively. He went to the hospital complaining of dyspnea. He was diagnosed with congestive heart failure and treated after admission. His respiratory condition was exacerbated and he was intubated. Respiratory management prolonged over 2 weeks. Tracheostomy was performed. One month after admission, cardiac echo showed massive aortic valve regurgitation and vegetation of aortic valve. The patient was transferred to our hospital to undergo operation for aortic valve regurgitation and infectious endocarditis. In our hospital, labo data showed severe bone marrow suppresssion with white blood cell(WBC)1,700/ul, red blood cell(RBC)259*104/ul, platelet(PLT) 5.0*104/ul. Aortic valve replacement was performed. Because the patient had tracheostomy, we incised sternal bone in a T shape to avoid mediastinitis. After operation, patient recovered well and left hospital 48th day after the operation. PMID- 23917241 TI - [Vascular Behcet disease presenting large right coronary artery pseudoaneurysm after percutaneous coronary intervention( PCI): report of a case]. AB - A 37-year-old man was diagnosed with angina pectoris and underwent percutaneous coronary intervention(PCI) procedure for right coronary artery in other hospital. Five months after PCI procedure, he was admitted to the hospital because of fever, chest pain and respiratory discomfort. He was diagnosed as having a large right coronary artery pseudoaneurysm which was about 40 mm in diameter. He was transfered to our hospital. We did coronary artery bypass grafting(CABG)[ saphenous vein graft (SVG)-#3] and pseudoaneurysm closure, and he left our hospital on 37 post-operative day. After discharge from our hospital, he developed iliocecal ulcer, oral aphtha, folliculitis and arthralgia and was diagnosed with Behcet disease. Seven months after the 1st surgery, proximal anastomosis site of SVG was ruptured and presented huge ascending aorta pseudoaneurysm. We performed autologous pericardial patch plasty on ascending aorta, and covered there with omentum flap. He uneventfully left our hospital on 19 post-operative day. PMID- 23917242 TI - [Giant pseudoaneurysm of the ascending aorta following the aortic valve replacement;report of a case]. AB - 56-year-old male, who had undergone re-aortic valve replacement (AVR) 33 years ago, received preoperative study for pancreatic surgery. Computed tomography (CT) revealed a giant pseudoaneurysm (7 cm diameter) of the ascending aorta. The ascending aorta was not dilated. A midline skin incision was performed, followed by full sternotomy. A tight pericardial adhesion was carefully dissected. Cardiopulmonary bypass was established by femoral arterial and bicaval venous cannulation. The pseudoaneurysm was incised under the retrograde cardioplegic protection. A communication between ascending aorta and aneurysm was found 1 cm distal to the previous aortic suture line. This communication coincided with the cardioplegic root cannulation site. The aortic prosthetic valve was intact. The ascending aorta was replaced with 26 mm prosthetic graft. Postoperative course was uneventful. In this case, CT was useful to select the approach to the complicated postoperative surgical site. PMID- 23917243 TI - [Refractory methicillin-resistant Staphylococcus aureus empyema invasion from a cervical abscess: report of a case]. AB - The patient was a 68-year-old male. At the previous hospital, continuous hemodiafiltration (CHDF)was performed through internal jugular vein for diabetic nephropathy. Long term catheterisation caused the abscess of the sternoclavicular joint, which induced methicillin-resistant Staphylococcus aureus( MRSA) empyema. Endoscopic thoracic debridement was performed for the empyema, however inadequate drainage for the abscess. Thereafter, the patient transferred to our hospital. We performed adequate drainage for the abscess under general anesthesia at 5 days after hospitalization, and then open decortication for empyema at 26 days. The patient recovered well after operation and was discharged from the hospital at 46 days. This was a successful case of surgical treatment for refractory MRSA empyema, which controls all focus of infection. PMID- 23917244 TI - [Pulmonary thromboembolism that developed 16 days after surgery for lung cancer]. AB - An 79-year-old man underwent right upper lobectomy with mediastinal lymph node dissection for lung cancer. He was discharged without complications on postoperative day( POD) 8. However, on POD 16 he become dyspneic at home and was transported to a hospital by ambulance. Pulmonary thromboembolism (PTE) was detected by contrast-enhanced computed tomography. Anticoagulant therapy was initiated and inferior vena cava filter placement was performed.Due to its many possible clinical manifestations, early detection of postoperative PTE is difficult. Therefore prevention of PTE is thought to be more important. Intermittent application of pneumatic compression stockings and preventive anticoagulant therapy may help prevent PTE after surgery. PMID- 23917245 TI - Impact of flow on ligand-mediated bacterial flocculation. AB - To understand the adhesion-fragmentation dynamics of bacterial aggregates (i.e., flocs), we model the aggregates as two ligand-covered rigid spheres. We develop and investigate a model for the attachment/detachment dynamics in a fluid subject to a homogeneous planar shear-flow. The binding ligands on the surface of the flocs experience attractive and repulsive surface forces in an ionic medium and exhibit finite resistance to rotation (via bond tilting). For certain range of material and fluid parameters, our results predict a nonlinear or hysteretic relationship between the binding/unbinding of the floc surface and the net floc velocity (translational plus rotational velocity). We show that the surface adhesion is promoted by increased fluid flow until a critical value, beyond which the bonds starts to yield. Moreover, adhesion is not promoted in a medium with low ionic strength, or flocs with bigger size or higher binder stiffness. The numerical simulations of floc-aggregate number density studies support these findings. PMID- 23917246 TI - Magnetic ordering of nickel hydroxide layers 30 A apart obtained by intercalating dodecyl sulfate. AB - The nature of magnetic ordering in quasi-2D layered hydroxide of Ni (LH-Ni-DS) with hexagonal structure and synthesized by intercalating dodecyl sulfate (DS) ligand, (C12H25OSO3)(-), between the layers using a hydrothermal technique is investigated. The observation of (00l) peaks up to l = 8 in x-ray diffraction on the sample yields an interlayer spacing c ? 30.5 A and a crystallite size ? 16 nm. Assignment of the lines observed in the FTIR spectra to the various groups of the DS ligand confirms the intercalation. From the analysis of detailed investigations of the temperature dependence of the magnetization M at different magnetic fields, ac susceptibilities at frequencies from 0.1 to 1 kHz, and electron magnetic resonance spectra at 9.28 GHz, it is concluded that LH-Ni-DS orders ferromagnetically at TC ? 23 K. This TC is about 45% higher than TC ? 16 K reported for LH-Ni-Ac with c ? 8.6 A obtained by intercalating an acetate ligand between the layers. The roles of the interlayer dipolar interaction, magnetic anisotropy and exchange interactions in determining TC in LH-Ni-L systems for several ligands L yielding different c-axes are discussed. PMID- 23917248 TI - Impact of allele copy number of polymorphisms in FCGR3A and FCGR3B genes on susceptibility to ulcerative colitis. AB - BACKGROUND: Polymorphisms in the Fcgamma receptor genes have been implicated in several autoimmune diseases, including ulcerative colitis (UC). However, most of these reports had not taken into account the effect of copy number variation at this region. METHODS: We investigated the combined effect of allele and gene copy number of FCGR3A-158F/V and FCGR3B-NA1/NA2 on susceptibility to UC. Study subjects were composed of a total of 752 Japanese patients with UC and 2062 Japanese control subjects. To estimate allele copy number of the 2 polymorphisms, we integrated the results of PCR-based real-time Invader assay (PCR-RETINA) that measures the allelic ratio and Taqman assay that detects the total copy number. We analyzed the associations of allele copy number with UC using logistic regression model. RESULTS: Gene and allele copy numbers of FCGR3A and FCGR3B were successfully determined in more than 99.5% of the study subjects. Allele copy number of FCGR3A-158F/V demonstrated significant association with susceptibility to UC (P = 0.02), although each single-nucleotide polymorphism and copy number variation alone did not show significant association. Although allele copy number of FCGR3B-NA1/NA2 (P = 0.002) also showed significant association with UC susceptibility, this association seemed to reflect the effect of FCGR3B gene copy number. Subsequent haplotype analyses revealed a strong association of a haplotype FCGR2A-131H/R and copy number of FCGR3B gene (P = 6.5 * 10). CONCLUSIONS: Allele copy number of FCGR3A-158F/V and FCGR3B gene copy number were associated with UC susceptibility. Our results suggest that organizing handling of immune complex by FCGR3A, FCGR3B, and FCGR2A may play a crucial role in the pathogenesis of UC. PMID- 23917247 TI - Purinergic autocrine regulation of mechanosensitivity and serotonin release in a human EC model: ATP-gated P2X3 channels in EC are downregulated in ulcerative colitis. AB - BACKGROUND: Alterations in 5-hydroxytryptamine (HT) signaling in inflamed gut may contribute to pathogenesis of inflammatory bowel diseases. Adenosine 5' triphosphate (ATP) regulates mucosal-mechanosensory reflexes and ATP receptors are sensitive to mucosal inflammation. Yet, it remains unknown whether ATP can modulate 5-HT signaling in enterochromaffin cells (EC). We tested the novel purinergic hypothesis that ATP is a critical autocrine regulator of EC mechanosensitivity and whether EC expression of ATP-gated P2X3-ion channels is altered in inflammatory bowel diseases. METHODS: Laser confocal (fluo-4) Ca imaging was performed in 1947 BON cells. Chemical stimulation or mechanical stimulation (MS) was used to study 5-HT or ATP release in human BON or surgical mucosal specimens, and purine receptors by reverse transcription-polymerase chain reaction, Western Blot, or P2X3-immunoreactivity in BON or 5-HT human EC (hEC) in 11 control and 10 severely inflamed ulcerative colitis (UC) cases. RESULTS: ATP or MS triggered Ca-transients or 5-HT release in BON. ATP or adenosine diphosphate increased 5-HT release 5-fold. MS caused ATP release, detected after 5'ecto-ATPase inhibition by ARL67156. ARL67156 augmented and apyrase blocked Ca/5 HT mechanosensitive responses. 2-Methyl-thio-adenosine diphosphate 5' monophosphate-evoked (P2Y1,12) or mechanically-evoked responses were blocked or augmented by a P2Y1,12 antagonist, MRS2179, in different cells or inhibited by U73122. A P2Y12 antagonist, 2MeSAMP, augmented responses. A P2X1,3 agonist, alpha,beta-MeATP, triggered Ca responses, whereas a P2X1,2/3,3 antagonist, 2',3' O-(2,4,6-trinitrophenyl)-ATP, blocked mechanical responses or cell-surface 5'ATP- labeling. In hEC, alpha,beta-MeATP stimulated 5-HT release. In UC, P2X3 immunoreactivity decreased from 15% to 0.2% of 5-HThECs. Human mucosa and BON expressed P2X1, P2X3, P2X4, P2X5, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, and P2Y12R messenger RNA transcripts. CONCLUSIONS: ATP is a critical determinant of mechanosensation and 5-HT release via autocrine activation of slow P2Y1 phospholipase C/inositol-1,4,5-triphosphate-Ca or inhibitory P2Y12-purinergic pathways, and fast ATP-gated P2X3-channels. UC downregulation of P2X3-channels (or A2B) is postulated to mediate abnormal 5-HT signaling. PMID- 23917249 TI - Are inflammatory bowel disease patients undergoing surveillance colonoscopies at the recommended time? PMID- 23917250 TI - Gastroenterologists inconsistently advise against tobacco use in inflammatory bowel disease patients. PMID- 23917251 TI - Crohn's disease-like reaction predicts favorable prognosis in colitis-associated colorectal cancer. AB - BACKGROUND: Idiopathic inflammatory bowel disease is associated with an increased risk of developing colorectal cancer. Colitis-associated colorectal cancer (CAC) has unique histomorphology features; however, whether histomorphology is predictive of survival in CAC, independent of overall clinical tumor stage, remains unknown. The aim of this study is to determine if clinicodemographics and tumor histomorphologic features are prognostic in patients with CAC. METHODS: A cohort of CAC patients were identified from the Pathology Database at Cleveland Clinic; slides were reviewed and other relevant data were collected by retrospective review of medical records. RESULTS: Univariate analysis demonstrated that poor differentiation, N stage (N1/N2 versus N0), M stage (M1 versus M0), Tumor, Node, Metastasis (TNM) stage (III/IV versus I/II), positive margin, and Crohn's-like reaction were significantly associated with both overall survival (OS) and progression-free survival (PFS) in CAC. Additionally, the presence of >2 tumor-infiltrating lymphocytes/high-power field was found to be significantly associated with longer PFS. Multivariate analysis confirmed that high TNM stage (III/IV versus I/II) was associated with shorter OS and PFS (hazard ratio 2.7, 95% confidence interval [CI]: 1.1-6.7, P = 0.04; 4.84 [95% CI: 2.0-11.5], P < 0.001, respectively), and positive margin status was associated with shorter OS (hazard ratio 4.0 [95% CI: 1.0-15.7], P = 0.05), whereas the presence of Crohn's-like reaction was associated with longer OS and PFS (hazard ratio 0.3 [95% CI: 0.12-0.79], P = 0.02; 0.25 [95% CI: 0.11-0.58], P = 0.001, respectively). CONCLUSIONS: In CAC, high tumor clinical stage and positive margin predict worse survival but Crohn's disease-like reaction is associated with longer OS and PFS. PMID- 23917252 TI - Reply: To PMID 23399739. PMID- 23917253 TI - Combined enrichment of neuromelanin granules and synaptosomes from human substantia nigra pars compacta tissue for proteomic analysis. AB - This article gives a detailed description of a protocol using density gradient centrifugation for the enrichment of neuromelanin granules and synaptosomes from low amounts (>=0.15g) of human substantia nigra pars compacta tissue. This has a great advantage compared to already existing methods as it allows for the first time (i) a combined enrichment of neuromelanin granules and synaptosomes and (ii) just minimal amounts of tissue necessary to enable donor specific analysis. Individual specimens were classified as control or diseased according to clinical evaluation and neuropathological examination. For the enrichment of synaptosomes and neuromelanin granules from the same tissue sample density gradient centrifugations using Percoll(r) and Iodixanol were performed. The purity of resulting fractions was checked by transmission electron microscopy. We were able to establish a reproducible and easy to handle protocol combining two different density gradient centrifugations: using an Iodixanol gradient neuromelanin granules were enriched and in parallel, from the same sample, a fraction of synaptosomes with high purity using a Percoll(r) gradient was obtained. Our subfractionation strategy will enable a subsequent in depth proteomic characterization of neurodegenerative processes in the substantia nigra pars compacta in patients with Parkinson's disease and dementia with Lewy bodies compared to appropriate controls. BIOLOGICAL SIGNIFICANCE: Key features of Parkinson's disease are the degeneration of dopaminergic neurons in the substantia nigra pars compacta, an associated loss of the brain pigment neuromelanin and a resulting impairment of the neuronal network. The accumulation of iron binding neuromelanin granules is age- and disease-dependent and disease specific alterations could affect the neuronal iron homeostasis leading to oxidative stress induced cell death. The focus of the described method is the analysis of neuromelanin granules as well as axonal cell-endings of nerve cells (synaptosomes) of individual donors (control and diseased). It is the basis for the identification of disease-relevant changes in the iron homeostasis and the generation of new insight into altered protein compositions or regulations which might lead to disturbed communications between nerve cells resulting in pathogenic processes. PMID- 23917254 TI - Finding the same needles in the haystack? A comparison of phosphotyrosine peptides enriched by immuno-affinity precipitation and metal-based affinity chromatography. AB - Analysis of tyrosine (Tyr) phosphorylation by mass spectrometry (MS)-based proteomics remains challenging, due to the low occurrence of this post translational modification compared to serine and threonine phosphorylation events in mammalian systems. Conventional metal-based affinity chromatography methods used to enrich phosphopeptides can nowadays isolate over 10,000 phosphopeptides. However, these approaches are not particularly suitable for the selective enrichment of low abundant Tyr phosphorylated peptides as the higher abundant co-enriched serine (Ser) and threonine (Thr) phosphorylated peptides typically obscure their detection. Therefore, a more targeted approach based on immuno-affinity precipitation at the peptide level has been introduced for the specific analysis of Tyr phosphorylated species. This method typically leads to the detection of a few hundreds of phosphopeptides, albeit typically over 70% of those are Tyr phosphorylated. Here, we evaluated and compared phosphotyrosine peptides enriched by a phospho-Tyr immuno-affinity enrichment (employing pY99 antibodies) and a multidimensional approach consisting of metal-affinity based enrichment (Ti(4+)-IMAC) followed by hydrophilic interaction liquid chromatography (HILIC) fractionation. Our aim was to assess differences and similarities in the set of Tyr phosphorylated peptides detected by each approach. Our data suggest that both strategies are not redundant but complementary and should ideally be combined for a more comprehensive view at phosphotyrosine signaling. BIOLOGICAL SIGNIFICANCE: Here we evaluated enabling tools for the global analysis of phosphotyrosine phosphorylation. Phosphotyrosine phosphorylation is a key protein modification driving cellular response also involved in disease/cancer molecular pathways. PMID- 23917255 TI - Interplay among viral antigens, cellular pathways and tumor microenvironment in the pathogenesis of EBV-driven lymphomas. AB - Epstein-Barr virus (EBV) is a ubiquitous human gamma-herpes virus that has established an elegant strategy to persist as a life-long asymptomatic infection in memory B lymphocytes. EBV has potent transforming properties for B lymphocytes and it is pathogenically associated with a variety of lymphomas of B or NK/T cell origin. The viral latency programs expressed can hijack or deregulate cellular pathways critical for cell proliferation and survival, while impairing anti-viral immune responses. Similar effects may also be induced by EBV-encoded micro-RNAs, which may have a pathogenic role particularly in lymphomas showing a restricted expression of viral proteins. Of note, recent data have challenged the view that only the EBV latency is relevant for lymphomagenesis, suggesting that lytic EBV replication may also contribute to the development of EBV-associated lymphoproliferations. The recent advances in the elucidation of the mechanisms underlying EBV-induced cell transformation and immune evasion are providing the rationale for innovative and tailored treatment approaches for EBV-driven lymphomas. PMID- 23917256 TI - Willingness to receive a hypothetical avian influenza vaccine among US military personnel in mid-deployment. AB - Though no avian influenza vaccine currently exists, development efforts have increased. Given recent reports of suboptimal vaccination rates among US military personnel, we sought to assess factors associated with a willingness to receive a hypothetical avian influenza vaccine. A self-administered questionnaire was completed by US military personnel during mid-deployment to Iraq, Afghanistan, and surrounding regions. Respondents were predominately male (86.2%), Army (72.1%), and enlisted (86.3%) with a mean age of 29.6 y. The majority (77.1%) agreed to receive an avian influenza vaccine if available. Exploratory factor analysis (EFA) identified two factors, vaccine importance and disease risk, that best described the individual perceptions and both were associated with an increased willingness to receive the hypothetical vaccine (OR: 8.2 and 1.6, respectively). Importantly, after controlling for these factors differences in the willingness to receive this hypothetical vaccine were observed across gender and branch of service. These results indicated that targeted education on vaccine safety and efficacy as well as disease risk may modify vaccination patterns in this population. PMID- 23917257 TI - Determination of external forces in alpine skiing using a differential global navigation satellite system. AB - In alpine ski racing the relationships between skier kinetics and kinematics and their effect on performance and injury-related aspects are not well understood. There is currently no validated system to determine all external forces simultaneously acting on skiers, particularly under race conditions and throughout entire races. To address the problem, this study proposes and assesses a method for determining skier kinetics with a single lightweight differential global navigation satellite system (dGNSS). The dGNSS kinetic method was compared to a reference system for six skiers and two turns each. The pattern differences obtained between the measurement systems (offset +/- SD) were -26 +/- 152 N for the ground reaction force, 1 +/- 96 N for ski friction and -6 +/- 6 N for the air drag force. The differences between turn means were small. The error pattern within the dGNSS kinetic method was highly repeatable and precision was therefore good (SD within system: 63 N ground reaction force, 42 N friction force and 7 N air drag force) allowing instantaneous relative comparisons and identification of discriminative meaningful changes. The method is therefore highly valid in assessing relative differences between skiers in the same turn, as well as turn means between different turns. The system is suitable to measure large capture volumes under race conditions. PMID- 23917258 TI - Enhancing indoor inertial pedestrian navigation using a shoe-worn marker. AB - We propose a novel hybrid inertial sensors-based indoor pedestrian dead reckoning system, aided by computer vision-derived position measurements. In contrast to prior vision-based or vision-aided solutions, where environmental markers were used-either deployed in known positions or extracted directly from it-we use a shoe-fixed marker, which serves as positional reference to an opposite shoe mounted camera during foot swing, making our system self-contained. Position measurements can be therefore more reliably fed to a complementary unscented Kalman filter, enhancing the accuracy of the estimated travelled path for 78%, compared to using solely zero velocities as pseudo-measurements. PMID- 23917259 TI - A survey on temperature-aware routing protocols in wireless body sensor networks. AB - The rapid growth of the elderly population in the world and the rising cost of healthcare impose big issues for healthcare and medical monitoring. A Wireless Body Sensor Network (WBSN) is comprised of small sensor nodes attached inside, on or around a human body, the main purpose of which is to monitor the functions and surroundings of the human body. However, the heat generated by the node's circuitry and antenna could cause damage to the human tissue. Therefore, in designing a routing protocol for WBSNs, it is important to reduce the heat by incorporating temperature into the routing metric. The main contribution of this paper is to survey existing temperature-aware routing protocols that have been proposed for WBSNs. In this paper, we present a brief overview of WBSNs, review the existing routing protocols comparatively and discuss challenging open issues in the design of routing protocols. PMID- 23917260 TI - Single-chip fully integrated direct-modulation CMOS RF transmitters for short range wireless applications. AB - Ultra-low power radio frequency (RF) transceivers used in short-range application such as wireless sensor networks (WSNs) require efficient, reliable and fully integrated transmitter architectures with minimal building blocks. This paper presents the design, implementation and performance evaluation of single-chip, fully integrated 2.4 GHz and 433 MHz RF transmitters using direct-modulation power voltage-controlled oscillators (PVCOs) in addition to a 2.0 GHz phase locked loop (PLL) based transmitter. All three RF transmitters have been fabricated in a standard mixed-signal CMOS 0.18 um technology. Measurement results of the 2.4 GHz transmitter show an improvement in drain efficiency from 27% to 36%. The 2.4 GHz and 433 MHz transmitters deliver an output power of 8 dBm with a phase noise of -122 dBc/Hz at 1 MHz offset, while drawing 15.4 mA of current and an output power of 6.5 dBm with a phase noise of -120 dBc/Hz at 1 MHz offset, while drawing 20.8 mA of current from 1.5 V power supplies, respectively. The PLL transmitter delivers an output power of 9 mW with a locking range of 128 MHz and consumes 26 mA from 1.8 V power supply. The experimental results demonstrate that the RF transmitters can be efficiently used in low power WSN applications. PMID- 23917261 TI - A wireless passive pressure microsensor fabricated in HTCC MEMS technology for harsh environments. AB - A wireless passive high-temperature pressure sensor without evacuation channel fabricated in high-temperature co-fired ceramics (HTCC) technology is proposed. The properties of the HTCC material ensure the sensor can be applied in harsh environments. The sensor without evacuation channel can be completely gastight. The wireless data is obtained with a reader antenna by mutual inductance coupling. Experimental systems are designed to obtain the frequency-pressure characteristic, frequency-temperature characteristic and coupling distance. Experimental results show that the sensor can be coupled with an antenna at 600 degrees C and max distance of 2.8 cm at room temperature. The senor sensitivity is about 860 Hz/bar and hysteresis error and repeatability error are quite low. PMID- 23917262 TI - Helium separation via porous silicene based ultimate membrane. AB - Helium purification has become more important for increasing demands in scientific and industrial applications. In this work, we demonstrated that the porous silicene can be used as an effective ultimate membrane for helium purification on the basis of first-principles calculations. Prinstine silicene monolayer is impermeable to helium gas with a high penetration energy barrier (1.66 eV). However, porous silicene with either Stone-Wales (SW) or divacancy (555,777 or 585) defect presents a surmountable barrier for helium (0.33 to 0.78 eV) but formidable for Ne, Ar, and other gas molecules. In particular, the porous silicene with divacancy defects shows high selectivity for He/Ne and He/Ar, superior to graphene, polyphenylene, and traditional membranes. PMID- 23917263 TI - Effect of cross sectional geometry on PDMS micro peristaltic pump performance: comparison of SU-8 replica molding vs. micro injection molding. AB - Two different fabrication methods were employed to fabricate micropumps with different cross-sectional channel geometries. The first was to fabricate rectangular cross-sectional microchannel geometries using the well known fabrication method of replica molding (REM). The second, and far less utilized fabrication technique, was to create microchannel molds using an in-house fabricated handheld micro injection molding apparatus. The injection mold apparatus was designed for use with elastomeric room temperature vulcanization (RTV) polymers, as opposed to most other injection molding machines, which are designed for use with thermoplastic polymers. The injection mold's bottom plate was used as a microchannel molding template. The molding template was created by threading a small-diameter wire (150 MUm or less) through the injection mold's bottom plate, with subsequent adhesion and smoothing of a thin piece of aluminum foil over the wire-raised injection mold template. When molded against, the template produced a rounded/Gaussian-shaped PDMS microchannel. The design of the injection mold will be presented, along with a direct comparison for micropump performance metrics such as flow rate, valving characteristics, and maximum backpressures attainable for each of the respective micropump channel geometries. PMID- 23917267 TI - Mosquito nets: John Singer Sargent. PMID- 23917268 TI - Supreme Court rules against gene patents. PMID- 23917264 TI - Genome sequence of the date palm Phoenix dactylifera L. AB - Date palm (Phoenix dactylifera L.) is a cultivated woody plant species with agricultural and economic importance. Here we report a genome assembly for an elite variety (Khalas), which is 605.4 Mb in size and covers >90% of the genome (~671 Mb) and >96% of its genes (~41,660 genes). Genomic sequence analysis demonstrates that P. dactylifera experienced a clear genome-wide duplication after either ancient whole genome duplications or massive segmental duplications. Genetic diversity analysis indicates that its stress resistance and sugar metabolism-related genes tend to be enriched in the chromosomal regions where the density of single-nucleotide polymorphisms is relatively low. Using transcriptomic data, we also illustrate the date palm's unique sugar metabolism that underlies fruit development and ripening. Our large-scale genomic and transcriptomic data pave the way for further genomic studies not only on P. dactylifera but also other Arecaceae plants. PMID- 23917269 TI - Open access to data closes the book on efficacy of popular bone-graft device. PMID- 23917270 TI - Lithium may decrease suicide risk. PMID- 23917280 TI - Reporting genomic sequencing results to ordering clinicians: incidental, but not exceptional. PMID- 23917281 TI - Mandatory extended searches in all genome sequencing: "incidental findings," patient autonomy, and shared decision making. PMID- 23917282 TI - Return of secondary genomic findings vs patient autonomy: implications for medical care. PMID- 23917283 TI - Reenvisioning specialty care and payment under global payment systems. PMID- 23917284 TI - Piece of my mind. Fishing for yeti. PMID- 23917285 TI - Will physicians lead on controlling health care costs? PMID- 23917286 TI - Black-white differences in breast cancer outcomes among older Medicare beneficiaries: does systemic treatment matter? PMID- 23917287 TI - Donor-derived infections with central nervous system pathogens after solid organ transplantation. PMID- 23917288 TI - Views of US physicians about controlling health care costs. AB - IMPORTANCE: Physicians' views about health care costs are germane to pending policy reforms. OBJECTIVE: To assess physicians' attitudes toward and perceived role in addressing health care costs. DESIGN, SETTING, AND PARTICIPANTS: A cross sectional survey mailed in 2012 to 3897 US physicians randomly selected from the AMA Masterfile. MAIN OUTCOMES AND MEASURES: Enthusiasm for 17 cost-containment strategies and agreement with an 11-measure cost-consciousness scale. RESULTS: A total of 2556 physicians responded (response rate = 65%). Most believed that trial lawyers (60%), health insurance companies (59%), hospitals and health systems (56%), pharmaceutical and device manufacturers (56%), and patients (52%) have a "major responsibility" for reducing health care costs, whereas only 36% reported that practicing physicians have "major responsibility." Most were "very enthusiastic" for "promoting continuity of care" (75%), "expanding access to quality and safety data" (51%), and "limiting access to expensive treatments with little net benefit" (51%) as a means of reducing health care costs. Few expressed enthusiasm for "eliminating fee-for-service payment models" (7%). Most physicians reported being "aware of the costs of the tests/treatments [they] recommend" (76%), agreed they should adhere to clinical guidelines that discourage the use of marginally beneficial care (79%), and agreed that they "should be solely devoted to individual patients' best interests, even if that is expensive" (78%) and that "doctors need to take a more prominent role in limiting use of unnecessary tests" (89%). Most (85%) disagreed that they "should sometimes deny beneficial but costly services to certain patients because resources should go to other patients that need them more." In multivariable logistic regression models testing associations with enthusiasm for key cost-containment strategies, having a salary plus bonus or salary-only compensation type was independently associated with enthusiasm for "eliminating fee for service" (salary plus bonus: odds ratio [OR], 3.3, 99% CI, 1.8-6.1; salary only: OR, 4.3, 99% CI, 2.2-8.5). In multivariable linear regression models, group or government practice setting (beta = 0.87, 95% CI, 0.29 to 1.45, P = .004; and beta = 0.99, 95% CI, 0.20 to 1.79, P = .01, respectively) and having a salary plus bonus compensation type (beta = 0.82; 95% CI, 0.32 to 1.33; P = .002) were positively associated with cost-consciousness. Finding the "uncertainty involved in patient care disconcerting" was negatively associated with cost-consciousness (beta = -1.95; 95% CI, -2.71 to -1.18; P < .001). CONCLUSION AND RELEVANCE: In this survey about health care cost containment, US physicians reported having some responsibility to address health care costs in their practice and expressed general agreement about several quality initiatives to reduce cost but reported less enthusiasm for cost containment involving changes in payment models. PMID- 23917289 TI - Characteristics associated with differences in survival among black and white women with breast cancer. AB - IMPORTANCE: Difference in breast cancer survival by race is a recognized problem among Medicare beneficiaries. OBJECTIVE: To determine if racial disparity in breast cancer survival is primarily attributable to differences in presentation characteristics at diagnosis or subsequent treatment. DESIGN, SETTING, AND PATIENTS: Comparison of 7375 black women 65 years and older diagnosed between 1991 to 2005 and 3 sets of 7375 matched white control patients selected from 99,898 white potential controls, using data for 16 US Surveillance, Epidemiology and End Results (SEER) sites in the SEER-Medicare database. All patients received follow-up through December 31, 2009, and the black case patients were matched to 3 white control populations on demographics (age, year of diagnosis, and SEER site), presentation (demographics variables plus patient comorbid conditions and tumor characteristics such as stage, size, grade, and estrogen receptor status), and treatment (presentation variables plus details of surgery, radiation therapy, and chemotherapy). MAIN OUTCOMES AND MEASURES: 5-Year survival. RESULTS: The absolute difference in 5-year survival (blacks, 55.9%; whites, 68.8%) was 12.9% (95% CI, 11.5%-14.5%; P < .001) in the demographics match. This difference remained unchanged between 1991 and 2005. After matching on presentation characteristics, the absolute difference in 5-year survival was 4.4% (95% CI, 2.8%-5.8%; P < .001) and was 3.6% (95% CI, 2.3%-4.9%; P < .001) lower for blacks than for whites matched also on treatment. In the presentation match, fewer blacks received treatment (87.4% vs 91.8%; P < .001), time from diagnosis to treatment was longer (29.2 vs 22.8 days; P < .001), use of anthracyclines and taxols was lower (3.7% vs 5.0%; P < .001), and breast-conserving surgery without other treatment was more frequent (8.2% vs 7.3%; P = .04). Nevertheless, differences in survival associated with treatment differences accounted for only 0.81% of the 12.9% survival difference. CONCLUSIONS AND RELEVANCE: In the SEER Medicare database, differences in breast cancer survival between black and white women did not substantially change among women diagnosed between 1991 and 2005. These differences in survival appear primarily related to presentation characteristics at diagnosis rather than treatment differences. PMID- 23917290 TI - Raccoon rabies virus variant transmission through solid organ transplantation. AB - IMPORTANCE: The rabies virus causes a fatal encephalitis and can be transmitted through tissue or organ transplantation. In February 2013, a kidney recipient with no reported exposures to potentially rabid animals died from rabies 18 months after transplantation. OBJECTIVES: To investigate whether organ transplantation was the source of rabies virus exposure in the kidney recipient, and to evaluate for and prevent rabies in other transplant recipients from the same donor. DESIGN: Organ donor and all transplant recipient medical records were reviewed. Laboratory tests to detect rabies virus-specific binding antibodies, rabies virus neutralizing antibodies, and rabies virus antigens were conducted on available specimens, including serum, cerebrospinal fluid, and tissues from the donor and the recipients. Viral ribonucleic acid was extracted from tissues and amplified for nucleoprotein gene sequencing for phylogenetic comparisons. MAIN OUTCOMES AND MEASURES: Determination of whether the donor died from undiagnosed rabies and whether other organ recipients developed rabies. RESULTS: In retrospect, the donor's clinical presentation (which began with vomiting and upper extremity paresthesias and progressed to fever, seizures, dysphagia, autonomic dysfunction, and brain death) was consistent with rabies. Rabies virus antigen was detected in archived autopsy brain tissue collected from the donor. The rabies viruses infecting the donor and the deceased kidney recipient were consistent with the raccoon rabies virus variant and were more than 99.9% identical across the entire N gene (1349/1350 nucleotides), thus confirming organ transplantation as the route of transmission. The 3 other organ recipients remained asymptomatic, with rabies virus neutralizing antibodies detected in their serum after completion of postexposure prophylaxis (range, 0.3-40.8 IU/mL). CONCLUSIONS AND RELEVANCE: Unlike the 2 previous clusters of rabies virus transmission through solid organ transplantation, there was a long incubation period in the recipient who developed rabies, and survival of 3 other recipients without pretransplant rabies vaccination. Rabies should be considered in patients with acute progressive encephalitis of unexplained etiology, especially for potential organ donors. A standard evaluation of potential donors who meet screening criteria for infectious encephalitis should be considered, and risks and benefits for recipients of organs from these donors should be evaluated. PMID- 23917291 TI - History of kidney stones and the risk of coronary heart disease. AB - IMPORTANCE: Kidney stone disease is common and may be associated with an increased risk of coronary heart disease (CHD). Previous studies of the association between kidney stones and CHD have often not controlled for important risk factors, and the results have been inconsistent. OBJECTIVE: To examine the association between a history of kidney stones and the risk of CHD in 3 large prospective cohorts. DESIGN, SETTING, AND PARTICIPANTS: A prospective study of 45,748 men and 196,357 women in the United States without a history of CHD at baseline who were participants in the Health Professionals Follow-up Study (HPFS) (45,748 men aged 40-75 years; follow-up from 1986 to 2010), Nurses' Health Study I (NHS I) (90,235 women aged 30-55 years; follow-up from 1992 to 2010), and Nurses' Health Study II (NHS II) (106,122 women aged 25-42 years; follow-up from 1991 to 2009). The diagnoses of kidney stones and CHD were updated biennially during follow-up. MAIN OUTCOMES AND MEASURES: Coronary heart disease was defined as fatal or nonfatal myocardial infarction (MI) or coronary revascularization. The outcome was identified by biennial questionnaires and confirmed through review of medical records. RESULTS Of a total of 242,105 participants, 19,678 reported a history of kidney stones. After up to 24 years of follow-up in men and 18 years in women, 16,838 incident cases of CHD occurred. After adjusting for potential confounders, among women, those with a reported history of kidney stones had an increased risk of CHD than those without a history of kidney stones in NHS I (incidence rate [IR], 754 vs 514 per 100,000 person-years; multivariable hazard ratio [HR], 1.18 [95% CI, 1.08-1.28]) and NHS II (IR, 144 vs 55 per 100,000 person-years; multivariable HR, 1.48 [95% CI, 1.23-1.78]). There was no significant association in men (IR, 1355 vs 1022 per 100,000 person-years; multivariable HR, 1.06 [95% CI, 0.99-1.13]). Similar results were found when analyzing the individual end points (fatal and nonfatal MI and revascularization). CONCLUSIONS AND RELEVANCE: Among the 2 cohorts of women, a history of kidney stones was associated with a modest but statistically significantly increased risk of CHD; there was no significant association in a separate cohort of men. Further research is needed to determine whether the association is sex-specific. PMID- 23917293 TI - Severe intractable postprandial chest pain. PMID- 23917292 TI - Treating complicated grief. AB - IMPORTANCE: The death of a loved one is one of life's greatest, universal stressors to which most bereaved individuals successfully adapt without clinical intervention. For a minority of bereaved individuals, grief is complicated by superimposed problems and healing does not occur. The resulting syndrome of complicated grief causes substantial distress and functional impairment even years after a loss, yet knowing when and how to intervene can be a challenge. OBJECTIVE: To discuss the differential diagnosis, risk factors for and management of complicated grief based on available evidence and clinical observations. EVIDENCE REVIEW: MEDLINE was searched from January 1990 to October 2012. Additional citations were procured from references of select research and review articles. Available treatment studies targeting complicated grief were included. RESULTS: A strong research literature led to inclusion of complicated grief in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (termed persistent complex bereavement disorder as a subtype of other specified trauma and stressor-related disorders), although it is a condition for which more research is formally recommended, and there is still ongoing discussion about the optimal name and diagnostic criteria for the disorder. Reliable screening instruments are available, and the estimated prevalence rate is 7% of bereaved people. Randomized controlled data support the efficacy of a targeted psychotherapy including elements that foster resolution of complicating problems and facilitate the natural healing process. Preliminary studies suggest antidepressant medications may be helpful. CONCLUSION AND RELEVANCE: Individuals with complicated grief have greater risk of adverse health outcomes, should be diagnosed and assessed for suicide risk and comorbid conditions such as depression and posttraumatic stress disorder, and should be considered for treatment. PMID- 23917294 TI - Incidence of type 1 diabetes in Finland. PMID- 23917295 TI - Mortality trends in critical access hospitals. PMID- 23917296 TI - Mortality trends in critical access hospitals. PMID- 23917297 TI - Chelation therapy and cardiovascular outcomes. PMID- 23917298 TI - Mortality trends in critical access hospitals--in reply. PMID- 23917299 TI - Chelation therapy and cardiovascular outcomes. PMID- 23917300 TI - Chelation therapy and cardiovascular outcomes--in reply. PMID- 23917301 TI - Sildenafil and exercise capacity in heart failure. PMID- 23917302 TI - Sildenafil and exercise capacity in heart failure--in reply. PMID- 23917304 TI - The blood phenomena of altitude. PMID- 23917305 TI - JAMA patient page. Food allergies. PMID- 23917306 TI - SOX4 is associated with poor prognosis in prostate cancer and promotes epithelial mesenchymal transition in vitro. AB - BACKGROUND: The SOX4 transcription factor is involved in the development and cell fate decision. Although upregulation of SOX4 has been described in human prostate cancer (PCa), the prognostic value of SOX4 and its exact role in PCa progression remain unclear. METHODS: Three tissue microarrays were constructed from 241 Chinese PCa patients who underwent TURP. Immunohistochemistry (IHC) was used to detect the expression of SOX4. Genetic aberrations of epidermal growth factor receptor and HER2 were detected by fluorescence in situ hybridization. The effect of SOX4 on proliferation was evaluated by MTT (methyl thiazolyl tetrazelium), and cell migration and invasion were evaluated by transwell and wound-healing assays. The distribution of cell-cycle phase was analyzed by flow cytometry. Real-time PCR and western blot were used to study transcript and protein levels. RESULTS: Using tissue microarray, we found that SOX4 was overexpressed in 33.0% (76/230) Chinese PCa patients by IHC. SOX4 overexpression was significantly associated with high Gleason scores (P=0.009) and the presence of distant metastasis (P=0.023). Additionally, SOX4 overexpression was significantly correlated with high Ki67 labeling index (P=0.005) and tended to associate with amplification of HER2 (P=0.052) in our cohort. Notably, SOX4 was correlated with cancer-specific mortality of PCa patients by Kaplan-Meier analysis (P=0.001). Multivariate Cox regression analysis indicated that SOX4 was an unfavorable independent prognostic factor in Chinese PCas (P=0.017). SOX4 overexpression enhanced proliferation of Vcap cells and siRNA knockdown of SOX4 significantly decreased Vcap cell migration and invasion, suggesting a role of SOX4 in cancer metastasis. Additionally, flow cytometry DNA analysis revealed that siRNA SOX4 leads to significant accumulation of cells in the S phase and marked decrease of cells in the G2/M phase. Further in vitro study revealed that SOX4 silencing could inhibit TGF-beta (transforming growth factor-beta)-induced epithelial-mesenchymal transition (EMT) in Vcap cells. Overexpression of SOX4 could promote the EMT phenotype in Vcap cells. CONCLUSIONS: Our results define an important role for SOX4 in the progression of PCa by orchestrating EMT and may serve as a prognostic marker for PCa patients. PMID- 23917307 TI - Factors related to patient-perceived satisfaction after robot-assisted radical prostatectomy based on the expanded prostate cancer index composite survey. AB - BACKGROUND: Few studies have analyzed factors that influence longitudinal changes in patient-perceived satisfaction during the recovery period following robot assisted radical prostatectomy (RARP) for prostate cancer. We investigated variables that were associated with patient-perceived satisfaction after RARP using the expanded prostate cancer index composite (EPIC) survey. METHODS: Of 175 men who underwent RARP between 2010 and 2011, 140 men completed the EPIC questionnaire preoperatively and 3, 6 and 12 months postoperatively. On the basis of the EPIC question no. 32 (item number 80), patients were divided into four groups according to the pattern of satisfaction change at postoperative 3 and 12 months: satisfied to satisfied (group 1); satisfied to dissatisfied (group 2); dissatisfied to satisfied (group 3); and dissatisfied to dissatisfied (group 4). Longitudinal changes in EPIC scores over time in each group and differences in EPIC scores of each domain subscale between groups at each follow-up were analyzed. A linear mixed model with generalized estimating equation approach was used to identify independent factors that influence overall satisfaction among repeated measures from same patients. RESULTS: On the basis of the pattern of satisfaction change, groups 1, 2, 3 and 4 had 103 (74.3%), 21 (15.0%), 11 (7.9%) and 5 (2.9%) patients, respectively. The factor that was associated with overall satisfaction was urinary bother (UB) (beta=0.283, 95% confidence interval (0.024, 0.543 ); P=0.033) adjusted for other factors under consideration. CONCLUSIONS: UB was the independent factor influencing patient-perceived satisfaction after RARP. During post-RARP follow-up, physician should have the optimal management for the patient's UB. PMID- 23917308 TI - Safety and efficacy of resistance exercise in prostate cancer patients with bone metastases. AB - BACKGROUND: Due to concerns of fragility fracture, exercise is a perceived contraindication for prostate cancer patients with bone metastases. These patients experience significant functional impairment and muscle atrophy, which may lead to an increased likelihood of skeletal complicaTIOns (i.e., pathological fracture, bone pain) and/or falls. Safe resistance exercise prescription may counteract this effect. The aim of this feasibility trial was to determine the safety and efficacy of resistance exercise by prostate cancer survivors with bone metastatic disease. METHODS: Twenty men with established bone metastases secondary to prostate cancer were randomly assigned to a 12-week resistance exercise program in which exercise prescription was based on the location of bone lesions (n=10) or usual care (n=10). Outcomes included safety and tolerance of the exercise program, physical function, physical activity level, body composition, fatigue, quality of life and psychological distress. Outcomes were compared between groups using analysis of covariance adjusted for baseline values. RESULTS: Participants had significant disease load with 65% of participants presenting with two or more regions affected by bone metastases and an average Gleason score of 8.2+/-0.9. Five participants (exercise=2; usual care=3) did not complete the intervention, three of which were due to advancing disease (exercise=2; usual care=1). No adverse events or skeletal complications occurred during the supervised exercise sessions. The exercise program was well tolerated as evidenced by high attendance (83%) and compliance rates (93%), and the ability of the participants to exercise at an intensity within the target range for cancer survivors (rating of perceived exertion =13.8+/-1.5). The change in physical function (muscle strength ~11%; submaximal aerobic exercise capacity ~5% and ambulation ~12%), physical activity level (~24%) and lean mass (~3%) differed significantly between groups following the intervention, with favorable changes in the exercise group compared with the usual care group. No significant between-group differences were observed for fatigue, quality of life or psychological distress. CONCLUSIONS: This initial evidence involving a small sample size suggests that appropriately designed and supervised resistance exercise may be safe and well tolerated by prostate cancer patients with bone metastatic disease and can lead to improvements in physical function, physical activity levels and lean mass. Future trials involving larger sample sizes are required to expand these preliminary findings. PMID- 23917309 TI - Unraveling long range residual dipolar coupling networks in strongly aligned proteins. AB - Long-range residual dipolar couplings (lrRDCs) have the potential to serve as powerful structural restraints in protein NMR spectroscopy as they can provide both distance and orientation information about nuclei separate in sequence but close in space. Current nonselective methods for their measurement are limited to moderate alignment strengths due to the sheer abundance of active couplings at stronger alignment. This limits the overall magnitude and therefore distance across which couplings can be measured. We have developed a double resonance technique for the inversion of individual coupled spin pairs, called Selective Inversion by Single Transition Cross Polarization (SIST-CP). This technique enables the selective recoupling of lrRDCs, thus allowing the complex multiplets occurring in strongly aligned systems to be disentangled. This technique is demonstrated in the context of an application to the measurement of (13)C' (1)H(N) lrRDCs in strongly aligned proteins. PMID- 23917310 TI - R-thanatin inhibits growth and biofilm formation of methicillin-resistant Staphylococcus epidermidis in vivo and in vitro. AB - Staphylococcus epidermidis is one of the most frequent causes of device associated infections, because it is known to cause biofilms that grow on catheters or other surgical implants. The persistent increasing resistance of S. epidermidis and other coagulase-negative staphylococci (CoNS) has driven the need for newer antibacterial agents with innovative therapeutic strategies. Thanatin is reported to display potent antibiotic activities, especially against extended spectrum-beta-lactamase-producing Escherichia coli. The present study aimed to investigate whether a shorter derivative peptide (R-thanatin) could be used as a novel antibacterial agent. We found that R-thanatin was highly potent in vitro against coagulase-negative staphylococci, such as S. epidermidis, S. haemolyticus, and S. hominis, and inhibited biofilm formation at subinhibitory concentrations. Properties of little toxicity to human red blood cells (hRBCs) and human umbilical vein endothelial cells, a low incidence of resistance, and relatively high stability in plasma were confirmed. Excellent in vivo protective effects were also observed using a methicillin-resistant S. epidermidis (MRSE) induced urinary tract infection rat model. Electron microscopy and confocal laser scanning microscopy analyses suggested that R-thanatin disturbed cell division of MRSE severely, which might be the reason for inhibition of MRSE growth. These findings indicate that R-thanatin is active against the growth and biofilm formation of MRSE in vitro and in vivo. R-thanatin might be considered as a specific drug candidate for treating CoNS infections. PMID- 23917311 TI - Bioluminescence-based neuraminidase inhibition assay for monitoring influenza virus drug susceptibility in clinical specimens. AB - The QFlu prototype bioluminescence-based neuraminidase (NA) inhibition (NI) assay kit was designed to detect NA inhibitor (NAI)-resistant influenza viruses at point of care. Here, we evaluated its suitability for drug susceptibility assessment at a surveillance laboratory. A comprehensive panel of reference viruses (n = 14) and a set of 90 seasonal influenza virus A and B isolates were included for testing with oseltamivir and/or zanamivir in the QFlu assay using the manufacturer-recommended protocol and a modified version attuned to surveillance requirements. The 50% inhibitory concentrations (IC50s) generated were compared with those of NI assays currently used for monitoring influenza drug susceptibility, the fluorescent (FL) and chemiluminescent (CL) assays. To provide proof of principle, clinical specimens (n = 235) confirmed by real-time reverse transcription (RT)-PCR to contain influenza virus A(H1N1)pdm09 and prescreened for the oseltamivir resistance marker H275Y using pyrosequencing were subsequently tested in the QFlu assay. All three NI assays were able to discriminate the reference NA variants and their matching wild-type viruses based on the difference in their IC50s. Unless the antigenic types were first identified, certain NA variants (e.g., H3N2 with E119V) could be detected among seasonal viruses using the FL assays only. Notably, the QFlu assay identified oseltamivir-resistant A(H1N1)pdm09 viruses carrying the H275Y marker directly in clinical specimens, which is not feasible with the other two phenotypic assays, which required prior virus culturing in cells. Furthermore, The QFlu assay allows detection of the influenza virus A and B isolates carrying established and potential NA inhibitor resistance markers and may become a useful tool for monitoring drug resistance in clinical specimens. PMID- 23917312 TI - Interaction of Ethambutol with human organic cation transporters of the SLC22 family indicates potential for drug-drug interactions during antituberculosis therapy. AB - According to the 2012 WHO global tuberculosis (TB) report (http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf), the death rate for tuberculosis was over 1.4 million patients in 2011, with ~9 million new cases diagnosed. Moreover, the frequency of comorbidity with human immunodeficiency virus (HIV) and with diabetes is on the rise, increasing the risk of these patients for experiencing drug-drug interactions (DDIs) due to polypharmacy. Ethambutol is considered a first-line antituberculosis drug. Ethambutol is an organic cation at physiological pH, and its major metabolite, 2,2'-(ethylenediimino)dibutyric acid (EDA), is zwitterionic. Therefore, we assessed the effects of ethambutol and EDA on the function of human organic cation transporter 1 (hOCT1), hOCT2, and hOCT3 and that of EDA on organic anion transporter 1 (hOAT1) and hOAT3. Potent inhibition of hOCT1- and hOCT2-mediated transport by ethambutol (50% inhibitory concentration [IC50] = 92.6 +/- 10.9 and 253.8 +/- 90.8 MUM, respectively) was observed. Ethambutol exhibited much weaker inhibition of hOCT3 (IC50 = 4.1 +/- 1.6 mM); however, significant inhibition (>80%) was observed at physiologically relevant concentrations in the gastrointestinal (GI) tract after oral dosing. EDA failed to exhibit any inhibitory effects that warranted further investigation. DDI analysis indicated a strong potential for ethambutol interaction on hOCT1 expressed in enterocytes and hepatocytes and on hOCT3 in enterocytes, which would alter absorption, distribution, and excretion of coadministered cationic drugs, suggesting that in vivo pharmacokinetic studies are necessary to confirm drug safety and efficacy. In particular, TB patients with coexisting HIV or diabetes might experience significant DDIs in situations of coadministration of ethambutol and clinical therapeutics known to be hOCT1/hOCT3 substrates (e.g., lamivudine or metformin). PMID- 23917313 TI - Characterization of fecal extended-spectrum-beta-lactamase-producing Escherichia coli in a remote community during a long time period. AB - Carriage of extended-spectrum beta-lactamase-producing enterobacteria (ESBL-E) has increased in community settings. Little is known about their long-term evolution. French Guiana Amerindians living in a very remote village, already sampled in 2001 and 2006 for ESBL-E fecal carriage, were screened again in October 2010. Sociodemographic data and antibiotic intake data were collected during the previous year. ESBL-E strains collected in 2010 and their plasmid contents were typed. The results were compared to those of the previous campaigns. The prevalence of ESBL-E carriage in 2010 was 5.3%, whereas it was 8.0% and 3.2% in 2006 and 2001, respectively. As previously determined, no individual factor was associated with carriage, including personal antibiotic exposure. However, overall antibiotic use had decreased to a 0.67 treatments/subject/year in 2010 versus 1.09 in 2006 (P < 0.001), which supports the idea that population exposure to antibiotics impacts on ESBL-E community carriage rates. A wide diversity of ESBL Escherichia coli strains belonging to the A0, A1, B1, and D2 phylogroups and producing the CTX-M-1, CTX-M-2, and CTX-M 8 enzymes were isolated. Despite the overall genetic diversity of the strains evaluated by repetitive extragenic palindromic PCR (rep-PCR) and multilocus sequence typing, two CTX-M-1-producing clones were found to have spread. In contrast, similar ESBL-bearing I1/Igamma plasmids were present in various strains both within and between carriers, suggesting high rates of plasmid transfer. Our results suggest that overall antibiotic exposure affects ESBL-E fecal carriage in the community. ESBL-E spread may be the result of both strain dissemination and the transfer of plasmids in intestinal microbiota. PMID- 23917314 TI - Rapid emergence of resistance to linezolid and mutator phenotypes in Staphylococcus aureus isolates from an adult cystic fibrosis patient. AB - Linezolid has emerged as an important therapeutic option for the treatment of Staphylococcus aureus in patients with cystic fibrosis. We report the rapid emergence, upon treatment with linezolid, of linezolid-resistant S. aureus clinical isolates through the accumulation of resistance-associated 23S rRNA mutations, together with acquisition of an altered mutator phenotype. PMID- 23917315 TI - N-cinnamoylated aminoquinolines as promising antileishmanial agents. AB - A series of cinnamic acid conjugates of primaquine and chloroquine were evaluated for their in vitro antileishmanial activities. Although primaquine derivatives had modest activity, chloroquine conjugates exhibited potent activity against both promastigotes (50% inhibitory concentration [IC50] = 2.6 to 21.8 MUM) and intramacrophagic amastigotes (IC50 = 1.2 to 9.3 MUM) of Leishmania infantum. Both the high activity of these chloroquine analogues and their mild-to-low toxicity toward host cells make them promising leads for the discovery of new antileishmanial agents. PMID- 23917316 TI - SbcCD-mediated processing of covalent gyrase-DNA complex in Escherichia coli. AB - Quinolones trap the covalent gyrase-DNA complex in Escherichia coli, leading to cell death. Processing activities for trapped covalent complex have not been characterized. A mutant strain lacking SbcCD nuclease activity was examined for both accumulation of gyrase-DNA complex and viability after quinolone treatment. Higher complex levels were found in DeltasbcCD cells than in wild-type cells after incubation with nalidixic acid and ciprofloxacin. However, SbcCD activity protected cells against the bactericidal action of nalidixic acid but not ciprofloxacin. PMID- 23917317 TI - Vancomycin-rifampin combination therapy has enhanced efficacy against an experimental Staphylococcus aureus prosthetic joint infection. AB - Treatment of prosthetic joint infections often involves a two-stage exchange, with implant removal and antibiotic spacer placement followed by systemic antibiotic therapy and delayed reimplantation. However, if antibiotic therapy can be improved, one-stage exchange or implant retention may be more feasible, thereby decreasing morbidity and preserving function. In this study, a mouse model of prosthetic joint infection was used in which Staphylococcus aureus was inoculated into a knee joint containing a surgically placed metallic implant extending from the femur. This model was used to evaluate whether combination therapy of vancomycin plus rifampin has increased efficacy compared with vancomycin alone against these infections. On postoperative day 7, vancomycin with or without rifampin was administered for 6 weeks with implant retention. In vivo bioluminescence imaging, ex vivo CFU enumeration, X-ray imaging, and histologic analysis were carried out. We found that there was a marked therapeutic benefit when vancomycin was combined with rifampin compared with vancomycin alone. Taken together, our results suggest that the mouse model used could serve as a valuable in vivo preclinical model system to evaluate and compare efficacies of antibiotics and combinatory therapy for prosthetic joint infections before more extensive studies are carried out in human subjects. PMID- 23917318 TI - Mechanism of action of T-705 ribosyl triphosphate against influenza virus RNA polymerase. AB - T-705 (favipiravir; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) selectively and strongly inhibits replication of the influenza virus in vitro and in vivo. T-705 has been shown to be converted to T-705-4-ribofuranosyl-5-triphosphate (T-705RTP) by intracellular enzymes and then functions as a nucleotide analog to selectively inhibit RNA-dependent RNA polymerase (RdRp) of the influenza virus. To elucidate these inhibitory mechanisms, we analyzed the enzyme kinetics of inhibition using Lineweaver-Burk plots of four natural nucleoside triphosphates and conducted polyacrylamide gel electrophoresis of the primer extension products initiated from (32)P-radiolabeled 5'Cap1 RNA. Enzyme kinetic analysis demonstrated that T 705RTP inhibited the incorporation of ATP and GTP in a competitive manner, which suggests that T-705RTP is recognized as a purine nucleotide by influenza virus RdRp and inhibited the incorporation of UTP and CTP in noncompetitive and mixed type manners, respectively. Primer extension analysis demonstrated that a single molecule of T-705RTP was incorporated into the nascent RNA strand of the influenza virus and inhibited the subsequent incorporation of nucleotides. These results suggest that a single molecule of T-705RTP is incorporated into the nascent RNA strand as a purine nucleotide analog and inhibits strand extension, even though the natural ribose of T-705RTP has a 3'-OH group, which is essential for forming a covalent bond with the phosphate group. PMID- 23917319 TI - Human biotransformation of the nonnucleoside reverse transcriptase inhibitor rilpivirine and a cross-species metabolism comparison. AB - Rilpivirine is a nonnucleoside reverse transcriptase inhibitor used to treat HIV 1. In the present study, the pathways responsible for the biotransformation of rilpivirine were defined. Using human liver microsomes, the formation of two mono and two dioxygenated metabolites were detected via ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Mass spectral analysis of the products suggested that these metabolites resulted from oxygenation of the 2,6-dimethylphenyl ring and methyl groups of rilpivirine. Chemical inhibition studies and cDNA-expressed cytochrome P450 (CYP) assays indicated that oxygenations were catalyzed primarily by CYP3A4 and CYP3A5. Glucuronide conjugates of rilpivirine and a monomethylhydroxylated metabolite of rilpivirine were also detected and were found to be formed by UDP-glucuronosyltransferases (UGTs) UGT1A4 and UGT1A1, respectively. All metabolites that were identified in vitro were detectable in vivo. Further, targeted UHPLC-MS/MS-based in vivo metabolomics screening revealed that rilpivirine treatment versus efavirenz treatment may result in differential levels of endogenous metabolites, including tyrosine, homocysteine, and adenosine. Rilpivirine biotransformation was also assessed across species using liver microsomes isolated from a range of mammals, and the metabolite profile identified using human liver microsomes was largely conserved for both oxidative and glucuronide metabolite formation. These studies provide novel insight into the metabolism of rilpivirine and the potential differential effects of rilpivirine- and efavirenz-containing antiretroviral regimens on the endogenous metabolome. PMID- 23917320 TI - Pharmacokinetic properties of artemether, dihydroartemisinin, lumefantrine, and quinine in pregnant women with uncomplicated plasmodium falciparum malaria in Uganda. AB - Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens. PMID- 23917321 TI - Antimicrobial peptide GL13K is effective in reducing biofilms of Pseudomonas aeruginosa. AB - Human parotid secretory protein (PSP; BPIF2A) is predicted to be structurally similar to bactericidal/permeability-increasing protein and lipopolysaccharide (LPS)-binding protein. Based on the locations of known antimicrobial peptides in the latter two proteins, potential active peptides in the PSP sequence were identified. One such peptide, GL13NH2 (PSP residues 141 to 153) was shown previously to interfere with LPS binding and agglutinate bacteria without bactericidal activity. By introducing three additional positively charged lysine residues, the peptide was converted to the novel bactericidal cationic peptide GL13K (MIC for Pseudomonas aeruginosa, 8 MUg/ml [5.6 MUM]). We investigated the antibiofilm activity of GL13K against static, monospecies biofilms of P. aeruginosa PAO1. Two-hour exposure of a 24-h biofilm to 64 MUg/ml (44.8 MUM) GL13K reduced biofilm bacteria by 10(2), and 100 MUg/ml (70 MUM) GL13K reduced bacteria by 10(3). Similar results could be achieved on 48-h-old biofilms. Lower concentrations of GL13K (32 MUg/ml [22.4 MUM]) were successful in reducing biofilm cell numbers in combination with tobramycin. This combination treatment also achieved total eradication of the biofilm in a majority (67.5%) of tested samples. An alanine scan of GL13K revealed the importance of the leucine residue in position six of the peptide sequence, where replacement led to a loss of antibiofilm activity, whereas the impact of replacing charged residues was less pronounced. Bacterial metalloproteases were found to partially inactivate GL13K but not a d amino acid version of the peptide. PMID- 23917322 TI - Systematic review and meta-analysis of in vitro synergy of polymyxins and carbapenems. AB - Our objective was to examine the evidence of in vitro synergy of polymyxin carbapenem combination therapy against Gram-negative bacteria (GNB). A systematic review and meta-analysis were performed. All studies examining in vitro interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB were used. A broad search was conducted with no language, date, or publication status restrictions. Synergy rates, defined as a fractional inhibitory concentration index of <=0.5 or a >2-log reduction in CFU, were pooled separately for time-kill, checkerboard, and Etest methods in a mixed-effect meta-analysis of rates. We examined whether the synergy rate depended on the testing method, type of antibiotic, bacteria, and resistance to carbapenems. Pooled rates with 95% confidence intervals (CI) are shown. Thirty nine published studies and 15 conference proceeding were included, reporting on 246 different tests on 1,054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI, 64 to 87%) for Acinetobacter baumannii, 44% (95% CI, 30 to 59%) for Klebsiella pneumoniae, and 50% (95% CI, 30 to 69%) for Pseudomonas aeruginosa, with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. For A. baumannii, meropenem was more synergistic than imipenem, whereas for P. aeruginosa the opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill studies. The use of combination therapy led to less resistance development in vitro. The combination of a carbapenem with a polymyxin against GNB, especially A. baumannii, is supported in vitro by high synergy rates, with low antagonism and less resistance development. These findings should be examined in clinical studies. PMID- 23917323 TI - Population pharmacokinetics of colistin methanesulfonate in rats: achieving sustained lung concentrations of colistin for targeting respiratory infections. AB - Colistin methanesulfonate (CMS), the inactive prodrug of colistin, is administered by inhalation for the management of respiratory infections. However, limited pharmacokinetic data are available for CMS and colistin following pulmonary delivery. This study investigates the pharmacokinetics of CMS and colistin following intravenous (i.v.) and intratracheal (i.t.) administration in rats and determines the targeting advantage after direct delivery into the lungs. In addition to plasma, bronchoalveolar lavage (BAL) fluid was collected to quantify drug concentrations in lung epithelial lining fluid (ELF). The resulting data were analyzed using a population modeling approach in S-ADAPT. A three compartment model described the disposition of both compounds in plasma following i.v. administration. The estimated mean clearance from the central compartment was 0.122 liters/h for CMS and 0.0657 liters/h for colistin. Conversion of CMS to colistin from all three compartments was required to fit the plasma data. The fraction of the i.v. dose converted to colistin in the systemic circulation was 0.0255. Two BAL fluid compartments were required to reflect drug kinetics in the ELF after i.t. dosing. A slow conversion of CMS (mean conversion time [MCTCMS] = 3.48 h) in the lungs contributed to high and sustained concentrations of colistin in ELF. The fraction of the CMS dose converted to colistin in ELF (fm,ELF = 0.226) was higher than the corresponding fractional conversion in plasma after i.v. administration. In conclusion, pulmonary administration of CMS achieves high and sustained exposures of colistin in lungs for targeting respiratory infections. PMID- 23917326 TI - Neutron scattering and MUSR investigations of the low temperature state of LuCuGaO4. AB - LuCuGaO4 has magnetic Cu(2+) and diamagnetic Ga(3+) ions distributed on a triangular bilayer and is suggested to undergo a spin glass transition at Tg ~ 0.4 K. Using MUSR (muon spin rotation) and neutron scattering measurements, we show that at low temperature the spins form a short range correlated state with spin fluctuations detectable over a wide range of timescales: at 0.05 K magnetic fluctuations can be detected in both the MUSR time window and also extending beyond 7 meV in the inelastic neutron scattering response, indicating magnetic fluctuations spanning timescales between ~10(-5) and ~10(-10) s. The dynamical susceptibility scales according to the form chi"(omega)T(alpha), with alpha = 1, throughout the measured temperature range (0.05-50 K). These effects are associated with quantum fluctuations and some degree of structural disorder in ostensibly quite different materials, including certain heavy fermion alloys, kagome spin liquids, quantum spin glasses, and valence bond glasses. We therefore suggest that LuCuGaO4 is an interesting model compound for the further examination of disorder and quantum magnetism. PMID- 23917325 TI - The nature and discriminatory value of urinary neutrophil gelatinase-associated lipocalin in critically ill patients at risk of acute kidney injury. AB - BACKGROUND: Different molecular forms of urinary neutrophil gelatinase-associated lipocalin (NGAL) have recently been discovered. We aimed to explore the nature, source and discriminatory value of urinary NGAL in intensive care unit (ICU) patients. METHODS: We simultaneously measured plasma NGAL (pNGAL), urinary NGAL (uNGAL), and estimated monomeric and homodimeric uNGAL contribution using Western blotting-validated enzyme-linked immunosorbent assays [uNGAL(E1) and uNGAL(E2)] and their calculated ratio in 102 patients with the systemic inflammatory response syndrome and oliguria, and/or a creatinine rise of >25 MUmol/L. MEASUREMENTS AND MAIN RESULTS: Bland-Altman analysis demonstrated that, despite correlating well (r = 0.988), uNGAL and uNGAL(E1) were clinically distinct, lacking both accuracy and precision (bias: 266.23; 95% CI 82.03-450.44 ng/mg creatinine; limits of agreement: -1,573.86 to 2,106.32 ng/mg creatinine). At best, urinary forms of NGAL are fair (area under the receiver operating characteristic [AUROC] <=0.799) predictors of renal or patient outcome; most perform significantly worse. The 44 patients with a primarily monomeric source of uNGAL had higher pNGAL (118.5 ng/ml vs. 72.5 ng/ml; p < 0.001), remaining significant following Bonferroni correction. CONCLUSIONS: uNGAL is not a useful predictor of outcome in this ICU population. uNGAL patterns may predict distinct clinical phenotypes. The nature and source of uNGAL are complex and challenge the utility of NGAL as a uniform biomarker. PMID- 23917328 TI - Determining the radiation dose reduction potential for coronary calcium scanning with computed tomography: an anthropomorphic phantom study comparing filtered backprojection and the adaptive iterative dose reduction algorithm for image reconstruction. AB - PURPOSE: This study describes a method to determine the lowest possible thresholds for volume computed tomographic dose index (CTDI(min)) and maximum tolerable pixel noise (SD(max)) values for coronary calcium scanning while maintaining accurate Agatston score values. The method was applied to a comparison between the iterative reconstruction (IR) and filtered backprojection (FBP) image reconstruction algorithms in a phantom study. MATERIALS AND METHODS: An anthropomorphic thoracic phantom with a calibration insert for the quantification of coronary calcium, containing 200, 400, and 800 mg HA/cm of calcium mass spheres of 1, 3, and 5 mm diameter (QRM GmbH, Moehrendorf, Germany), was scanned without (G1) and with (G2) an additional 2 cm-thick wrap of muscle equivalent material. Electrocardiographically simulated volume scans were performed on a 320-row computed tomographic scanner (Aquilion ONE, Toshiba Medical Systems, Otawara, Japan) set to 120 kilovolt peak [kVp] and 10 to 580 mA variations in 21 steps. For the IR, the Adaptive Iterative Dose Reduction 3 dimensional algorithm (AIDR 3D) was used. Agatston scores were calculated semiautomatically on the computed tomographic console. Inclusion tests to assess the accuracy of the Agatston scores were performed to determine the CTDI(min) thresholds and the associated maximum pixel noise SD(max) for FBP and IR from identical raw data. The inclusion tests were as follows: (1) the semiautomatic identification of the 1 mm sphere with 800 mg HA/cm, (2) the exclusion of false positive lesions, and (3) a statistical outlier test. Statistical differences between the Agatston score means from both image reconstruction algorithms were evaluated using the paired t test. RESULTS: All Agatston scores using both reconstruction methods were normally distributed (P > 0.49). For FBP and IR, the mean +/- 1sigma of Agatston score, CTDI(min), and SD(max), respectively, were determined as follows: 697.8 +/- 7.7, 7.5 mGy, and 24.4 Hounsfield unit (HU) (G1 FBP); 678.8 +/- 14.3, 1.5 mGy, and 20.1 HU (G1-IR); 677.0 +/- 11.6, 14.5 mGy, and 27.3 HU (G2-FBP); and 643.9 +/- 13.4, 2.6 mGy, and 20.0 HU (G2-IR). The mean Agatston scores obtained using IR (both with and without the additional 2 cm muscle shell) were slightly (approximately 5%) but significantly lower (P <= 0.001) than those obtained using FBP reconstruction. CONCLUSIONS: The Adaptive Iterative Dose Reduction algorithm AIDR 3D shows potential to reduce dose exposure by approximately 80% in comparison with the dose currently applied with FBP image processing. On the basis of phantom evaluation, a target noise of 20 HU for the application of this method in coronary calcium scanning is recommended to avoid loss in accuracy. PMID- 23917327 TI - Immunization with recombinant leucine aminopeptidase showed protection against Fasciola gigantica in mice. AB - Leucine aminopeptidase (LAP) is expressed in all stages of Fasciola gigantica and, hence, is considered as a potential vaccine candidate. In this study, we have tested a vaccine potential of LAP and the types of immune responses it elicited in vaccinated mice. Recombinant F. gigantica leucine aminopeptidase (rFgLAP) was expressed in Escherichia coli, BL21 (DE3). The imprinting control region mice subcutaneously immunized with 50 MUg of rFgLAP combined with Freund's adjuvant (n = 10) exhibited a significant reduction in worm recoveries when compared with non-immunized and Freund's adjuvant controls at 60.8 and 64.3%, respectively, and both T helper (Th)1 and Th2 humoral immune responses were elicited in the hosts as reflected by the levels of IgG1 and IgG2a, with Th2 predominating. The levels of IgG1- and IgG2a-specific antibodies to rFgLAP were inversely and significantly correlated with the numbers of worm recoveries. The rFgLAP-vaccinated mice showed significantly reduced levels of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase and liver damage. These indicated that rFgLAP has a potential as a vaccine candidate against F. gigantica, whose efficacy will be studied further in economic animals including cattle, sheep, and goat. PMID- 23917329 TI - Genome-wide deserts for copy number variation in vertebrates. AB - Most copy number variations are neutral, but some are deleterious and associated with various human diseases. Copy number variations are distributed non-randomly in vertebrate genomes, and it was recently reported that ohnologs, which are duplicated genes derived from whole genome duplication, are refractory to copy number variations. However, it is unclear what genomic factors affect the deleterious effects of copy number variations and the biological significance of the biased genomic distribution of copy number variations remains poorly understood. Here we show that non-ohnologs neighbouring ohnologs are unlikely to have copy number variations, resulting in ohnolog-rich regions in vertebrate genomes being copy number variation deserts. Our results suggest that the genomic location of ohnologs is a determining factor in the retention of copy number variations and that the dosage-balanced ohnologs are likely to cause the deleterious effects of copy number variations in these regions. We propose that investigating copy number variation of genes in regions that are typically copy number variation deserts is an efficient means to find disease-related copy number variations. PMID- 23917330 TI - Gastroschisis associated with an omphalocele and intestinal atresia. PMID- 23917332 TI - Preconcentration determination of arsenic species by sorption of As(V) on Amberlite IRA-410 coupled with fluorescence quenching of L-cysteine capped CdS nanoparticles. AB - A simple and accurate method for arsenic speciation analysis in natural and drinking water samples is described in which preconcentration of arsenic as As(V) was coupled with spectrofluorometric determination. The extracted As(V) species with a column containing Amberlite IRA-410 were subjected to L-cysteine capped CdS quantum dots (QDs) and the fluorescence quenching of the QDs due to reduction of As(V) by L-cysteine was considered as a signal relevant to As(V) concentration. The As(III) species were also determined after oxidation of As(III) ions to As(V) with H2O2 and measurement of the total arsenic content. In treatment with 400 mL portions of water samples containing 30 MUg L(-1) As(V), the relative standard deviation was 2.8%. The detection limit of arsenic was also found to be 0.75 MUg L(-1) (1 * 10(-8) M). The reliability of proposed method was confirmed using certified reference materials. The trace amounts of arsenic species were then determined in different water samples, satisfactorily. PMID- 23917331 TI - Interstitial cells of Cajal in the normal human gut and in Hirschsprung disease. AB - Hirschsprung disease (HD) is the most prevalent congenital gastrointestinal motility disorder. The pathogenesis of HD is defined as a functional intestinal obstruction resulting from a defect in the intrinsic innervation of the distal bowel. In addition to the enteric nervous system, the interstitial cells of Cajal (ICC) play an important role in the generation of coordinated gastrointestinal peristalsis. The major function of the ICCs is the generation of slow waves that allow these cells to act as specialised pacemaker cells within various tissues. ICCs have additional functions in the gastrointestinal tract as regulators of mechanical activity and neurotransmission. Due to the central role of ICCs in gastrointestinal peristalsis, it has been suggested that defects or impairments of the ICCs may contribute to motility dysfunction in several gastrointestinal motility disorders. This review describes the distribution and functions of ICCs in the normal gut and in Hirschsprung disease. PMID- 23917333 TI - Clinical marine toxicology: a European perspective for clinical toxicologists and poison centers. AB - Clinical marine toxicology is a rapidly changing area. Many of the new discoveries reported every year in Europe involve ecological disturbances- including global warming--that have induced modifications in the chorology, behavior, and toxicity of many species of venomous or poisonous aquatic life including algae, ascidians, fish and shellfish. These changes have raised a number of public issues associated, e.g., poisoning after ingestion of contaminated seafood, envenomation by fish stings, and exposure to harmful microorganism blooms. The purpose of this review of medical and scientific literature in marine toxicology is to highlight the growing challenges induced by ecological disturbances that confront clinical toxicologists during the everyday job in the European Poison Centers. PMID- 23917334 TI - Occurrence of deoxynivalenol in wheat in Slovakia during 2010 and 2011. AB - In this study, a total of 299 grain samples of wheat were collected from four production regions: the maize, sugar beet, potato and feed sectors of Slovakia. The samples were analyzed for deoxynivalenol (DON) content by using an enzyme linked immunosorbent assay Ridascreen(r) Fast DON. Analysis of variance revealed a significant difference between years in DON contents (p < 0.027). The occurrence of samples with DON was 82.2% in 2010, with maximum DON content of 7.88 mg kg-1, and 70.7% in 2011, with maximum DON content of 2.12 mg.kg-1. The total mean DON content was 0.62 mg.kg-1; in the feed region 0.22 mg.kg-1; 0.63 mg.kg-1 in the maize region; 0.78 mg.kg-1 in the sugar beet region; 0.45 mg.kg-1 the potato region. The limit of 1.25 mg.kg-1 imposed by the European Union (EU) for DON content was exceeded in 13.7% of the studied samples. The average monthly rainfall for May to June played a critical role in DON content of wheat grains for maize and sugar beet producing regions. The present results indicate that DON content was at a high level in grains from wheat grown during 2010. PMID- 23917335 TI - Preoperative oral rehydration therapy with 2.5 % carbohydrate beverage alleviates insulin action in volunteers. AB - Preoperative carbohydrate loading enhances insulin action by approximately 50 %. In some Japanese hospitals, preoperative oral rehydration therapy is performed for preventing dehydration during surgery. We hypothesized that preoperative oral rehydration therapy with a 2.5 % carbohydrate beverage that is widely used in Japan can enhance insulin action. Therefore, we investigated the effect of this 2.5 % carbohydrate beverage on insulin action in volunteers. Six healthy volunteers participated in this crossover randomized study. The participants were segregated into 2 groups: an oral rehydration therapy with 2.5 % carbohydrate beverage group (group A) and a control group (group B). Subjects in group B were allowed to drink only water from 9 pm the day before the test; conversely, group A fasted from 9 pm onward and drank 500 ml of the beverage containing 2.5 % carbohydrate (OS-1; Otsuka Pharmaceutical Factory, Tokushima, Japan) between 9 and 12 pm and again at 6.30 am. At 8.30 am, a hyperinsulinemic normoglycemic clamp was initiated using an artificial pancreas STG-22 (Nikkiso, Tokyo, Japan). Insulin action was evaluated in both groups using the glucose infusion rate. Blood glucose levels at the initiation of the clamp procedure were similar. However, the glucose infusion rate for group A was significantly higher than that of group B (8.6 +/- 1.5 vs. 6.8 +/- 2.0 mg/kg/min, p = 0.009). In conclusion, the hyperinsulinemic normoglycemic clamp using an artificial pancreas showed that the administration of a 2.5 % carbohydrate oral rehydration solution for preoperative oral rehydration therapy improves insulin action in volunteers. PMID- 23917336 TI - Dispersed conductive polymer nanoparticles on graphitic carbon nitride for enhanced solar-driven hydrogen evolution from pure water. AB - Developing new methods to improve the photocatalytic activity of graphitic carbon nitride (g-C3N4) for hydrogen (H2) evolution has attracted intensive research interests. Here, we report that the g-C3N4 exhibits photocatalytic activity for H2 evolution from pure water. And, the activity is dramatically improved by loading highly dispersed conductive polymer nanoparticles. The H2 evolution rate increases up to 50 times for g-C3N4 with 1.5 wt% polypyrrole (PPy) nanoparticles on the surface. The reaction proceeding in a pure water system excludes the need for sacrificial agents. The role of the highly conductive PPy in enhancing H2 evolution is as a surface junction to increase the number of photoinduced electrons, and to facilitate electron transfer to the interface. PMID- 23917337 TI - Cellular Uptake and Intracellular Cargo Release From Dextran Based Nanogel Drug Carriers. AB - Nanogels (NG) hold great promise as a drug delivery platform. In this work, we examine the potential of lysozyme-dextran nanogels (LDNG) as drug carriers in vitro using two cell lines: a model target tissue, human umbilical cord vein endothelial cells (HUVEC) and a model of the mononuclear phagocyte system (phorbol 12-myristate 13-acetate (PMA)-stimulated THP-1 cells). The LDNG (~100 nm) were prepared with rhodamine-label dextran (LRDNG) via Maillard reaction followed by heat-gelation reaction and were loaded with a fluorescent probe, 5 hexadecanoylaminofluorescein (HAF), as a mock drug. Epifluorescence microscopy confirmed rapid uptake of LRDNG by HUVEC. Although LysoTracker Green staining indicated a lysosomal fate for LRDNG, the mock drug cargo (HAF) diffused extensively inside the cell within 15 min. Flow cytometry and confocal microscopy indicated slow uptake of LRDNG in PMA-stimulated THP-1 cells, with only 41% of cells containing LRDNG after 24 h exposure. Finally, 24 h exposure to LRDNG did not affect the viability of either cell type at the dose studied (20 MUg/ml). At a higher dose (200 MUg/ml), LRDNG resulted in a marked loss of viability of HUVEC and THP-1, measuring 30% and 38%, respectively. Collectively, our results demonstrate the great potential of LRDNG as a drug delivery platform, combining simple production, rapid uptake and cargo release in target cells with "stealth" properties and low cytotoxicity. PMID- 23917341 TI - Fever and rash in a 7-month-old infant. PMID- 23917342 TI - School readiness. PMID- 23917343 TI - Laparostomy with topical negative pressure for treating severe peritonitis. Preliminary experience with 16 cases and review of the literature. AB - INTRODUCTION: The aim of this study was to assess the authors' initial experience with laparostomy and intraperitoneal topical negative pressure (TNP) in patients with severe peritonitis. The authors also reviewed the recent literature on the effectiveness and safety of abdominal TNP. PATIENTS AND METHODS: Sixteen patients (10 male, 6 female, mean age 55 years), suffering from severe peritonitis, underwent emergency laparotomy and laparostomy with TNP. Abdominal sepsis originated from the small intestine (n = 7), large intestine (n = 6), biliary tract (n = 2), and pancreas (n = 1). In 2 patients abdominal wall mesh infection and soft tissue gangrene were observed. RESULTS: The mortality rate was 31.2%. The main complications probably related to TNP were enteric fistulae (25%), bleeding (25%), abdominal abscesses (12.5%), bowel ischemia (6.2%). Delayed primary closure was performed in 8 patients (57.1%) whereas in 6 cases a parietal graft was necessary, and one patient underwent an autologous skin graft. CONCLUSIONS: Laparostomy with intraperitoneal TNP is a safe and effective method for managing patients with severe peritonitis. Morbidity can be reduced through individualized application of the laparostomy dressing and pressure gradient. The abdominal wall should be managed in such a way as to make possible delayed primary closure. PMID- 23917344 TI - Oligomers matrix-assisted dispersion of high content of carbon nanotubes into monolithic column for online separation and enrichment of proteins from complex biological samples. AB - In this work, a new oligomer matrix-assisted dispersion (OMAD) method for the preparation of homogeneous dispersion of multi-walled carbon nanotubes (MWNTs) incorporated monolithic column was developed. Oligomers matrix as a scaffold could allow MWNTs to entangle with it instead of self-aggregation, so the MWNTs remain in the polymer network followed by in situ self-solidification. The OMAD method not only greatly enlarged the BET surface area of MWNTs incorporated monolithic column from 13.8 m(2) g(-1) to 85.5 m(2) g(-1) without a significant effect on the surface chemistry of the MWNTs, but also improved the dispersion of MWNTs making its content up to 5 wt% (with respect to monomers). The synthesized materials combine the favorable attributes of both high permeability and large surface area, making them excellent candidates for on-line separation and enrichment of proteins. The oligomer matrix-assisted dispersion MWNTs incorporated monolithic columns (OMAD-MMC) exhibited higher enrichment factors and the adsorption capacity is about 5-fold for basic proteins compared with MWNTs incorporated monolithic columns (MMC) prepared by the conventional in situ polymerization. The practical application of OMAD-MMC was proven by selective extraction of hemoglobin in human whole blood samples with SDS-PAGE. On the basis of the results, OMAD as a simple and effective method for dispersion high content MWNTs into monolithic columns shows great promise. PMID- 23917345 TI - MK-2206, an Akt inhibitor, enhances carboplatinum/paclitaxel efficacy in gastric cancer cell lines. AB - BACKGROUND: Several molecularly-targeted agents are being evaluated in gastric cancer cell lines. In this study we evaluated the synergistic potential of MK 2206, an oral potent allosteric Akt inhibitor, in combination with chemotherapeutic agents in human gastric cancer cell lines. MATERIALS AND METHODS: We evaluated effects of MK-2206 on cell growth and cell signaling using a panel of gastric cancer cell lines AGS, SNU-1 and SNU 16. The analysis of drug combinations was conducted by using CellTiter-BlueTM Cell Viability Assay which yielded the combination index (CI). MK-2206 and representative chemotherapy agent were further evaluated regarding their effects on Akt inhibition and downstream targets using western blots probed with the appropriate antibodies. We assessed the combination of MK-2206 and chemotherapy in three different treatment sequences. RESULTS: We demonstrated in vitro synergistic efficacy of MK-2206 when combined with carboplatinum and paclitaxel in the three cell lines examined. Efficacy was dose dependent. We assessed the combination of MK-2206 and carboplatinum/paclitaxel in three different treatment sequences; 24 h of exposure to combination chemotherapy followed by a 48 h exposure to MK-2206 resulted in the highest synergistic antiproliferative effect in all cell lines. On the other hand, the reverse sequence (MK-2206 followed by chemotherapy) and the concurrent treatment schedule were slightly synergistic or additive as well. The effects of MK-2206 on p-Akt and other downstream targets was reported. CONCLUSIONS: Our findings suggest that Akt inhibition augments the efficacy of existing gastric cancer therapeutics (carboplatinum and paclitaxel); thus, MK-2206 is a promising agent to treat gastric cancer patients who receive these cytotoxic agents. The magnitude of synergy depended on the treatment sequence; a schedule of MK-2206 dosed before or concurrently with chemotherapy was not as effective as being dosed after chemotherapy. Further experiments addressing MK-2206's mechanism of action in combination with chemotherapy are needed. PMID- 23917348 TI - Mouldable all-carbon integrated circuits. AB - A variety of plastic products, ranging from those for daily necessities to electronics products and medical devices, are produced by moulding techniques. The incorporation of electronic circuits into various plastic products is limited by the brittle nature of silicon wafers. Here we report mouldable integrated circuits for the first time. The devices are composed entirely of carbon-based materials, that is, their active channels and passive elements are all fabricated from stretchable and thermostable assemblies of carbon nanotubes, with plastic polymer dielectric layers and substrates. The all-carbon thin-film transistors exhibit a mobility of 1,027 cm(2) V(-1) s(-1) and an ON/OFF ratio of 10(5). The devices also exhibit extreme biaxial stretchability of up to 18% when subjected to thermopressure forming. We demonstrate functional integrated circuits that can be moulded into a three-dimensional dome. Such mouldable electronics open new possibilities by allowing for the addition of electronic/plastic-like functionalities to plastic/electronic products, improving their designability. PMID- 23917347 TI - Practice effects reveal visuomotor vulnerability in school and university rugby players. AB - This article reports on three pre- versus post-season prospective studies in which male university and high school contact sport players predominantly of Rugby Union (hereafter rugby) were compared with age, education, and IQ equivalent non-contact sport controls on the ImPACT (Immediate Postconcussion Assessment and Cognitive Testing) test. All analyses revealed a relative absence of practice effects on the Visual Motor Speed (VMS) composite for contact sport groups compared with controls. The VMS data for rugby players from each study were pooled and subjected to additional analysis (Rugby, n = 145; Controls, n = 106). Controls revealed significant improvement over the season (p < .001), whereas no learning effect was in evidence for rugby players whose performance remained the same (interaction effect, p = .028). It is apparent that practice effects have diagnostic potential in this context, implicating vulnerability on speeded visuomotor processing in association with participation in rugby. Pointers for further research and concussion management in the individual case are explored. PMID- 23917346 TI - Analysis of verbal fluency ability in amnestic and non-amnestic mild cognitive impairment. AB - The purpose of this study was to investigate the pattern of performance on letter and category fluency tests of individuals with mild cognitive impairment (MCI). Previous research has suggested that organization strategies, including "clustering" (i.e., groups of related words) and "switching" (i.e., shift from one cluster to another), are important for efficient verbal fluency performance. Participants were 25 individuals with single-domain amnestic MCI (aMCI), 49 with multidomain aMCI, 16 with non-amnestic MCI (naMCI), and 90 cognitively healthy older adults. Fluency performances were analyzed across two 30-s intervals for total words produced, cluster size, and switching. Analyses of variance (ANOVAs) with follow-up tests revealed that the single-domain aMCI group performed comparably with healthy controls on each dependent measure across both fluency tasks. In contrast, the multidomain aMCI group showed performance decrements in total words and switching production compared with healthy controls on both fluency tasks, whereas the naMCI group produced fewer words and switches on letter fluency. Each group generated more words and switches during the first 30 s on both fluency tasks, with the exception of the naMCI group, whose switching on letter fluency did not decrease as the task progressed. As indicated by the single-domain aMCI group's unimpaired performance, our findings demonstrate that verbal fluency performance decreases as domains beyond memory become impaired in MCI. Reduced switching ability, which has been linked to prefrontal executive functioning, contributed the most to the poorer performance of individuals with multidomain MCI and naMCI. PMID- 23917351 TI - Determination of the entropy via measurement of the magnetization: application to the spin ice Dy2Ti2O7. AB - The residual entropy of spin ice and other frustrated magnets is a property of considerable interest, yet the usual way of determining it, by integrating the heat capacity, is generally ambiguous. Here we note that a straightforward alternative method based on Maxwell's thermodynamic relations can yield the residual entropy on an absolute scale. The method utilizes magnetization measurements only and hence is a useful alternative to calorimetry. We confirm that it works for the spin ice Dy2Ti2O7, which recommends its application to other systems. The analysis described here also gives an insight into the dependence of entropy on magnetic moment, which plays an important role in the theory of magnetic monopoles in spin ice. Finally, we present evidence of a field induced crossover from correlated spin ice behaviour to ordinary paramagnetic behaviour with increasing applied field, as signalled by a change in the effective Curie constant. PMID- 23917353 TI - A BINOL-based ratiometric fluorescent sensor for Zn2+ and in situ generated ensemble for selective recognition of histidine in aqueous solution. AB - A novel BINOL-based ratiometric fluorescent sensor (R2) is presented, which can selectively respond to Zn(2+) over Cd(2+) and other metal ions with fluorescence enhancement in aqueous solution. The R2 was successfully applied in the imaging of Zn(2+) in living cells. Additionally, the in situ generated R2-Zn(II) ensemble could further serve as a probe to distinguish histidine from other amino acids via a displacement mode. PMID- 23917352 TI - Immunization against small ruminant lentiviruses. AB - Multisystemic disease caused by Small Ruminant Lentiviruses (SRLV) in sheep and goats leads to production losses, to the detriment of animal health and welfare. This, together with the lack of treatments, has triggered interest in exploring different strategies of immunization to control the widely spread SRLV infection and, also, to provide a useful model for HIV vaccines. These strategies involve inactivated whole virus, subunit vaccines, DNA encoding viral proteins in the presence or absence of plasmids encoding immunological adjuvants and naturally or artificially attenuated viruses. In this review, we revisit, comprehensively, the immunization strategies against SRLV and analyze this double edged tool individually, as it may contribute to either controlling or enhancing virus replication and/or disease. PMID- 23917355 TI - Cancer upregulated gene 2, a novel oncogene, enhances migration and drug resistance of colon cancer cells via STAT1 activation. AB - Cancer upregulated gene (CUG) 2, as a novel oncogene, has been predominantly detected in various cancer tissues, such as ovary, liver, lung and colon. We recently showed that CUG2 elevates STAT1 activity, leading to resistance to infection by oncolytic vesicular stomatitis virus. To investigate a possible role for CUG2-induced activation of STAT1 in oncogenesis, we first established a colon cancer cell line stably expressing CUG2 (Colon26L5-CUG2). Colon26L5-CUG2 exhibited higher levels not only in phosphorylation of STAT1, but also phosphorylation of Jak1/Tyk2 compared to that of the control (Colon26L5-Vec) cell line. Inhibition of Akt or ERK activity reduced phosphorylation of STAT1 in Colon26L5-CUG2 cells whereas inhibition of p38 MAPK did not significantly decrease levels of STAT1 phosphorylation, indicating that cell proliferation signals may be involved in CUG2-mediated activation of STAT1. Suppression of STAT1 expression diminished cell migration and wound healing compared to the control cells. In addition, since CUG2 expression conferred resistance to DNA damage caused by doxorubicin treatment, we investigated whether STAT1 is involved in resistance to doxorubicin-induced cell death. We found that STAT1 was not activated in Colon26L5-Vec cells while phosphorylated STAT1 was maintained in Colon26L5-CUG2 cells during doxorubicin treatment. Furthermore, suppression of STAT1 expression sensitized Colon26L5-CUG2 cells to doxorubicin-induced apoptosis whereas the control cells exhibited resistance to doxorubicin. Taken together, our results suggest that CUG2 enhances metastasis and drug resistance through STAT1 activation, which eventually contributes to tumor progression. PMID- 23917356 TI - Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart. AB - Cumulative evidence indicates that mitochondrial dysfunction has a role in heart failure progression, but whether mitochondrial quality control mechanisms are involved in the development of cardiac dysfunction remains unclear. Here we show that cytosolic p53 impairs autophagic degradation of damaged mitochondria and facilitates mitochondrial dysfunction and heart failure in mice. Prevalence and induction of mitochondrial autophagy is attenuated by senescence or doxorubicin treatment in vitro and in vivo. We show that cytosolic p53 binds to Parkin and disturbs its translocation to damaged mitochondria and their subsequent clearance by mitophagy. p53-deficient mice show less decline of mitochondrial integrity and cardiac functional reserve with increasing age or after treatment with doxorubicin. Furthermore, overexpression of Parkin ameliorates the functional decline in aged hearts, and is accompanied by decreased senescence-associated beta-galactosidase activity and proinflammatory phenotypes. Thus, p53-mediated inhibition of mitophagy modulates cardiac dysfunction, raising the possibility that therapeutic activation of mitophagy by inhibiting cytosolic p53 may ameliorate heart failure and symptoms of cardiac ageing. PMID- 23917357 TI - Detection and differential diagnosis of suspected malignant transformation of an endometrioma during pregnancy. AB - Asymptomatic female in her early 30s presented for her singleton nuchal translucency ultrasound at 12.4 weeks of gestational age. No fetal abnormalities were seen. A large maternal left adnexal mass was identified, prompting a transvaginal ultrasound. The findings were felt to be consistent with an endometrioma, albeit with a 1 cm solid nodule. At this point, the diagnosis was considered to likely represent a decidualised endometrioma; however, warranting careful follow-up. The 20-week anatomy scan demonstrated an enlarging solid nodule that now contained vascularity within the left adnexal mass prompting an MRI. These features were more suggestive of malignancy, although a decidualised endometrioma, which can demonstrate intrapartum growth and vascularity, remained in the differential. Intrapartum sonographic surveillance documented progressive growth. The lesion was uneventfully removed at the time of delivery. Pathology showed clear cell carcinoma within an endometrioma. PMID- 23917358 TI - Non-surgical management of superior mesenteric artery thrombosis using spinal cord stimulation. AB - We report the use of a spinal cord stimulator (SCS) for non-surgical management of superior mesenteric artery thrombosis. A 59-year-old woman with polycythaemia rubra vera presented with extensive superior mesenteric artery thrombosis not amenable to surgical or endovascular revascularisation. A SCS was implanted for analgesia thereby allowing enteral feeding to be tolerated during the acute period. Four months later the patient developed a focal ischaemic jejunal stricture and underwent resection of a short segment of small bowel with primary anastomosis that healed without complication. Spinal cord stimulation can facilitate non-surgical management of mesenteric ischaemia. PMID- 23917359 TI - A rare presentation of cerebral venous sinus thrombosis associated with tubercular meningitis. AB - Central nervous system (CNS) tuberculosis may manifest as meningitis, meningoencephalitis, tuberculoma, tubercular abscess, stroke due to tuberculous vasculitis and tuberculous encephalopathy. Occasionally, tubercular meningitis (TBM) can predispose to cerebral venous sinus thrombosis (CVST). We report a young man, who developed CVST as a complication of TBM. Worsening of pre-existing headache, impairment of consciousness and seizures should raise suspicion of CVST in any patient with CNS infection. Early diagnosis and appropriate clinical management are important for good outcome. PMID- 23917360 TI - First evidence of asymptomatic infection related to the Araucaria (Juquitiba like) hantavirus. AB - Hantavirus pulmonary syndrome (HPS) is a severe disease, transmitted to humans by inhalation of virus-contaminated aerosols from rodent excreta. Epidemiological, clinical and laboratory data confirmed a fatal HPS case and an asymptomatic infection in a household contact, both caused by Araucaria hantavirus, which has previously been found only in patients with HPS. This is the first report of asymptomatic infection related to a pathogenic hantavirus genotype, highlighting the need for additional studies on characterisation of viral and genetic mechanisms associated with this disease. PMID- 23917361 TI - Paraganglioma of urinary bladder. AB - Paraganglioma of the urinary bladder is extremely rare. In this report of a young man, hypertensive crisis and ventricular arrhythmia was provoked during cystoscopic evaluation of a bladder mass. A diagnosis of pheochromocytoma was considered following detection of high serum and urinary catecholamine levels. A preoperative meta-iodobenzylguanidine scan was, however, negative. The bladder mass was surgically removed following initiation of antihypertensive therapy. Pathological confirmation of extraadrenal pheochromocytoma was established. During a serial follow-up, serum and urine catecholamine levels were persistently elevated. This was explained by abnormalities on fluorodeoxyglucose positron emission tomography scan, which were considered to represent a metastatic malignant neuroendocrine tumour. The patient is on palliative chemotherapy for malignant paraganglioma. This case highlights variable presentation of pheochromocytoma, importance of having a high index of clinical suspicion for early recognition and prompt management and serious adverse consequence of a delayed diagnosis. PMID- 23917362 TI - Congenital adrenal hyperplasia and pregnancy. AB - A 32-year-old woman with classical congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency presented with infertility. She was treated with different steroid replacement regimens together with fludrocortisone. The aim of this case report is to discuss fertility barriers in women with classical CAH, and emphasise the risks and benefits of available steroid treatment options. Clinical considerations covered include preconception health and fertility planning, optimising fertility through suppression of excess hormone production, reducing fetal androgen exposure in utero and limiting maternal and fetal side effects of therapy and limiting chances of CAH in the baby. In this case suppression of androgen and progesterone levels was challenging but eventually was achieved and resulted in a spontaneous pregnancy. However, she miscarried in the first trimester, and fetal biopsy revealed a complete hydatiform mole. She is advised not to conceive while she is under investigation to determine the extent of the disease. PMID- 23917363 TI - Malignancy knows no boundaries. AB - A 47-year-old woman presented with ascites. There was history of large volume paracentesis and the drained ascitic fluid was found to be positive for malignant cells. Clinical examination revealed a soft tissue nodule over the skin of right iliac fossa and a small umbilical nodule besides presence of ascites. In addition, the patient had a breast lump of 2*2 cm in upper quadrant of right breast. Biopsy from the abdominal wall nodule revealed a malignant tumour with dense desmoplastic response. The tumour cells were pancytokeratin, CA125, WT1 positive and CDX2, CD10, villin, calretinin negative; thus immunohistochemically suggesting a primary tumor arising from ovary. Biopsy from breast lump showed malignant epithelial cells present in sheets with stromal dysplasia. Immunohistochemically tumour cells were positive for CK7. CA125, WT1, thus favouring a metastatic carcinoma to breast with possible primary arising from ovary. PMID- 23917364 TI - Human parvovirus B19 associated dilated cardiomyopathy. AB - We describe two children presenting with acute left ventricular dysfunction. Both cases had evidence of dilated cardiomyopathy, requiring inotropic support and were tested for cardiotropic viruses by conventional or real-time polymerase chain reaction using specific primers for enteroviruses, human parvovirus B19, Adenoviruses, Epstein-Barr virus (EBV), herpes simplex viruses 1 and 2 (HSV), human herpes virus-6 (HHV-6) and cytomegalovirus (CMV). IgG and IgM antibodies against parvovirus B19, EBV, HSV and CMV were also tested by ELISA. One case tested positive for parvovirus B19 infection and recovered completely within 6 months in absence of any specific therapy. The other case tested positive for parvovirus B19 infection in association with hypocalcaemia and was cured following standard heart failure therapy along with calcium and vitamin D supplementation. Sequence analysis of DNA products from both patients revealed genotype 3. To best of our knowledge this is first report of circulating genotype 3 from India. PMID- 23917365 TI - A 'benign' condition masquerading as arthritis. AB - A 9 year-old boy presented with a 3-week history of low-grade fever, on and off, and additive arthritis of the lower limb joints with no overt antecedent trauma. Investigations for juvenile idiopathic arthritis (JIA), reactive and tuberculous arthritis were normal. He was started on anti-inflammatory drugs as for seronegative oligoarticular JIA. Since arthritis persisted despite treatment, MRI of the left knee joint was planned prior to an aspiration/synovial biopsy. MRI revealed a partial tear of the anterior cruciate ligament with a significant effusion. On careful re-examination, at this point, he was found to have generalised hypermobility with a Beighton score of 9/9. This had been missed initially, leading to a delay in diagnosis and management. He was managed with careful physiotherapy and lifestyle modification. The left knee effusion resolved within a month. This case is being reported in order to highlight the fact that joint hypermobility syndrome can be misdiagnosed as arthritis. PMID- 23917366 TI - Anomalous left main coronary artery origin, silent ischaemia, risk of sudden death: a triad detected by combining coronary CT and dipyridamole SPECT. PMID- 23917367 TI - Immunodeficiency, centromeric region instability and facial anomalies (ICF) syndrome diagnosed in an adult who is now a long-term survivor. AB - We describe a 42-year-old British man of Indo-Caribbean origin with immunodeficiency, centromeric region instability and facial anomalies (ICF) syndrome. Most patients with ICF syndrome die of infection at a young age, usually in the first or second decade of life. The patient was born 3.5 weeks premature to non-consanguineous parents. He had a mild bird-like face abnormality, but had no other congenital malformations, cognitive impairment or developmental delays. He had recurrent ear and chest infections during childhood and developed bronchiectasis. Investigations revealed IgG, IgA and IgM deficiencies with a normal lymphocyte count and normal T cell proliferation to in vitro mitogenic stimulation. Following several unsuccessful attempts to make a diagnosis during childhood, a recent chromosomal analysis showed centromeric region instability of chromosomes 1 and 16, diagnosing ICF syndrome. The patient receives immunoglobulin replacement for hypogammaglobulinameia and has chest physiotherapy and antibiotics for bronchiectasis. Recently, he developed liver cirrhosis of unknown cause. PMID- 23917368 TI - Late relapse of progressive multifocal leucoencephalopathy postallogenic transplant in a young patient with CLL. AB - We describe a case of progressive multifocal leucoencephalopathy (PML) in a 39 year-old patient diagnosed with chronic lymphocytic leukaemia (CLL) who underwent two allogenic matched-sibling stem cell transplantations. PML was confirmed just after the first transplantation with cerebral MRI and by PCR in the cerebrospinal fluid. After immunosuppression withdrawal and cidofovir treatment, he achieved a reversal of clinical symptoms, John Cunningham (JC) virus positivity and MRI lesions regression. He remained asymptomatic for 5 years with no signs of infection activity, even though he received three new chemotherapy regimens due to a CLL relapse. However, after the second stem cell transplantation, new neurological symptoms began and a reactivation of the JC virus infection was detected. This time, treatment with mefloquine was started, but he experienced a progressive neurological deterioration and died 1 month after the symptoms began. PMID- 23917369 TI - Intestinal complications of Behcet's disease. AB - We report a case of a young female patient with long-standing oral and genital Behcet's disease (BD), who presented with progressive severe colonic inflammation and perforation, requiring multiple laparotomies. The case had ultimately a favourable outcome despite posing a number of diagnostic and therapeutic challenges. Intestinal complications, although rare, should be considered as important differential diagnoses in patients with BD presenting with abdominal pain, and is a difficult-to-prove differential diagnosis to Crohn's disease. PMID- 23917370 TI - Endovascular management of ruptured common iliac mycotic aneurysm in an HIV positive patient. AB - Isolated iliac artery aneurysms are a rare entity. The majority of cases are asymptomatic and often escape detection. Mortality rates after sudden rupture and emergent surgery for iliac artery aneurysm are very high. We report a case of a 56-year-old man who presented with right hip pain masquerading as septic arthritis or psoas abscess. CT showed ruptured right common iliac artery aneurysm with extensive active extravasation into psoas with a retroperitoneal haematoma. Aneurysm was repaired using an endovascular technique. Postoperative recovery was eventful with the patient experiencing severe back pain radiating down the leg accompanied with fever. CT showed persistent, right iliopsoas haematoma and pelvic haematoma with secondary hydronephrosis. Viral screen for hepatitis B, C and HIV returned positive. The patient was started on intravenous meropenem. Fever and pain settled. Repeated CT scan showed decrease in retroperitoneal pelvic haematoma. PMID- 23917371 TI - Recurrent confusional episodes associated with hypomagnesaemia due to esomeprazol. AB - In February 2011, the Food and Drug Administration informed that prescription of proton pump inhibitor (PPI) drugs may cause low serum magnesium levels if taken for prolonged periods of time. We present an ex-smoker, 76-year-old man, with high blood pressure, diabetes mellitus and Barrett's oesophagus (treated with esomeprazole since 2003) admitted due to fluctuating aphasia. Neurovascular and neuroimaging studies were normal. Dyslipidemia and atrial arrhythmia were discovered. The patient was discharged with the diagnosis of left middle cerebral artery transient ischaemic attack and anticoagulation treatment was recommended. The patient returned to the emergency department on further two occasions (confusional episodes) and was admitted in order to complete the neurological study that was normal. The patient was discharged with the diagnosis of probable epileptic seizures. After a week, he was admitted due to generalised temblor and unsteadiness. A complete blood test was performed and showed a severe hypomagnesaemia (not previously performed). PMID- 23917372 TI - Asymptomatic anomalous left anterior descending artery arising from the right coronary artery with a rare anterior course. AB - The presence of a malignant course on the coronary circulation is the second leading cause of sudden cardiac death in young adults. One type of malignant conformation is an anomalous left anterior descending artery (LAD) arising from the right coronary artery (RCA). In a study examining 70,850 patients undergoing coronary angiography, the prevalence of this anomaly was noted in 0.006% of total patients and in 2.3% of congenital coronary anomaly cases. Of the four patients presenting with this anomaly, only one was noted to have an interarterial course of the LAD between the aorta and pulmonary artery. We describe the case of a patient who was incidentally found to have a malignant anomalous LAD arising from the RCA when he presented with a non-ST elevation myocardial infarction due to a ruptured plaque in an obtuse marginal branch. This patient survived for 57 years with no symptoms. PMID- 23917373 TI - Cognitive behavioral therapy for children with autism: review and considerations for future research. AB - OBJECTIVE: Cognitive behavioral therapy (CBT) is now commonly used for high functioning children with an autism spectrum disorder. The objective of this article was to describe the methods and results of cognitive behavioral interventions for children with autism. METHOD: This article reviews CBT programs targeting anxiety, disruptive behavior, and core autism symptoms for children with autism. RESULTS: There is emerging evidence suggesting that CBT is possibly efficacious for anxiety and autism symptoms, but methodological weaknesses must be addressed before clear conclusions can be drawn. CONCLUSION: More research needs to be conducted to examine the effectiveness of CBT for children with autism. Specifically, future research should use more stringent methodology and assess the effectiveness of specific cognitive strategies and autism-related adaptations. PMID- 23917374 TI - Large-area aligned growth of single-crystalline organic nanowire arrays for high performance photodetectors. AB - Due to their extraordinary properties, single-crystalline organic nanowires (NWs) are important building blocks for future low-cost and efficient nano optoelectronic devices. However, it remains a critical challenge to assemble organic NWs rationally in an orientation-, dimensionality- and location controlled manner. Herein, we demonstrate a feasible method for aligned growth of single-crystalline copper phthalocyanine (CuPc) NW arrays with high density, large-area uniformity and perfect crossed alignment by using Au film as a template. The growth process was investigated in detail. The Au film was found to have a critical function in the aligned growth of NWs, but may only serve as the active site for NW nucleation because of the large surface energy, as well as direct the subsequent aligned growth. The as-prepared NWs were then transferred to construct single NW-based photoconductive devices, which demonstrated excellent photoresponse properties with robust stability and reproducibility; the device showed a high switching ratio of ~180, a fast response speed of ~100 ms and could stand continuous operation up to 2 h. Importantly, this strategy can be extended to other organic molecules for their synthesis of NW arrays, revealing great potential for use in the construction of large-scale high-performance functional nano-optoelectronic devices. PMID- 23917375 TI - A new strategy for synthesizing yolk-shell V2O5 powders with low melting temperature for high performance Li-ion batteries. AB - This paper presents the fabrication of yolk-shell V2O5 powders with a low melting temperature of 690 degrees C by using a simplified two-step process. The spherical V2O3-C composite obtained by spray pyrolysis transforms into yolk-shell V2O5 powder by a simple combustion process at 400 degrees C. The yolk-shell V2O5 powders are composed of nanoplate crystals several tens of nanometers in size, and have a BET surface area of 15 m(2) g(-1). The powders exhibit initial discharge and charge capacities of 271 and 264 mA h g(-1) at a current density of 1000 mA g(-1), respectively, and a corresponding Coulombic efficiency of 97.4%. After 100 cycles, the discharge capacity of the yolk-shell V2O5 powders is 201 mA h g(-1). In contrast, spherical V2O5 powders with a dense structure exhibit low initial discharge and charge capacities of 160 and 145 mA h g(-1), respectively. The structural stability of the yolk-shell during Li-ion insertion and extraction improves the electrochemical properties of the V2O5 powders, even at high current densities. PMID- 23917376 TI - Uncovering the genetic landscape driving castration-resistant prostate cancer. AB - Identification of the mechanisms that drive progression of metastatic castration resistant prostate cancer (CRPC) has fostered interest since early androgen studies in the 1940s. Little knowledge has surfaced about the role mutations play in prostate cancer development. A group at the Michigan Center for Translation Pathology studied exomes of lethal, metastatic CRPC and documented the overall mutation rates. In classifying these mutations, the monoclonal cause of CRPC was recognized. Nine identified genes showed significant mutations. Six of these genes had previously been reported as mutated in prostate cancer. The analysis also found significantly mutated androgen receptor (AR) cofactors and linked proteins, including FOXA1 and MLL2. Another finding concerned an aberration in CHD1. Prostate cancers with deletions or mutations in CHD1 showed a strong correlation with ETS gene family fusion negative prostate cancers (96%). In profiling these exomes, this group provides an original method to identify deletions and mutations that drive CRPC progression. PMID- 23917377 TI - ZC88, a novel 4-amino piperidine analog, inhibits the growth of neuroblastoma cells through blocking hERG potassium channel. AB - Many studies have provided convincing evidence for hERG as an important diagnostic and prognostic factor in human cancers, as well as a useful target for antineoplastic therapy. Our previous study also revealed that knockdown of herg gene expression by shRNA interference inhibited the growth of neuroblastoma cells in vitro and in vivo. In the experiment, a novel 4-amino piperidine analog, ZC88, was examined for its effect on hERG potassium channels and its antitumor potency was observed in vitro and in vivo. The results showed that ZC88 could block hERG1 and hERG1b channels expressed in Xenopus oocytes in a concentration-dependent manner. ZC88 displayed significant antiproliferative activity in several tumor cell lines and the tumor cells with higher expression of hERG presented higher sensitivity to ZC88. The mitotic progression of tumor cells was markedly suppressed in the presence of ZC88 through arresting cells in G0/G1 phase. ZC88 significantly inhibited the tumor growth in nude mice at a dosage with slight influence on the cardiac QT interval. The antitumor effect of ZC88 was correlated at least partly with its blockage of hERG channels, which implicated a positive role of hERG potassium channel in tumor cell proliferation. PMID- 23917379 TI - Novel antioxidants are not toxic to normal tissues but effectively kill cancer cells. AB - Free radicals are formed as a result of cellular processes and play a key role in predisposition to and development of numerous diseases and of premature aging. Recently, we reported the syntheses of a number of novel phenolic antioxidants for possible application in food industry. In the present study, analyses of the cellular processes and molecular gene expression effects of some of the novel antioxidants in normal human tissues and in cancer cells were undertaken. Results indicated that whereas the examined antioxidants showed no effects on morphology and gene expression of normal human oral and gingival epithelial tissues, they exerted a profound cell killing effect on breast cancer cells, including on chemotherapy-resistant breast cancer cells and on oral squamous carcinoma cells. Among the tested antioxidants, N-decyl-N-(3-methoxy-4-hydroxybenzyl)-3-(3,4 dihydroxyphenyl) propanamide and N-decyl-N-(3,5-dimethoxy-4-hydroxybenzyl)-3-(3,4 dihydroxyphenyl) propanamide were the most promising, with excellent potential for cancer treatment. Moreover, our gene expression databases can be used as a roadmap for future analysis of mechanisms of antioxidant action. PMID- 23917378 TI - PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells. AB - The present studies examined viability and DNA damage levels in mammary carcinoma cells following PARP1 and CHK1 inhibitor drug combination exposure. PARP1 inhibitors [AZD2281 ; ABT888 ; NU1025 ; AG014699] interacted with CHK1 inhibitors [UCN-01 ; AZD7762 ; LY2603618] to kill mammary carcinoma cells. PARP1 and CHK1 inhibitors interacted to increase both single strand and double strand DNA breaks that correlated with increased gammaH2AX phosphorylation. Treatment of cells with CHK1 inhibitors increased the phosphorylation of CHK1 and ERK1/2. Knock down of ATM suppressed the drug-induced increases in CHK1 and ERK1/2 phosphorylation and enhanced tumor cell killing by PARP1 and CHK1 inhibitors. Expression of dominant negative MEK1 enhanced drug-induced DNA damage whereas expression of activated MEK1 suppressed both the DNA damage response and tumor cell killing. Collectively our data demonstrate that PARP1 and CHK1 inhibitors interact to kill mammary carcinoma cells and that increased DNA damage is a surrogate marker for the response of cells to this drug combination. PMID- 23917380 TI - Life cycle and human health risk assessments as tools for decision making in the design and implementation of nanofiltration in drinking water treatment plants. AB - A combined methodology using life cycle assessment (LCA) and human health risk assessment (HHR) is proposed in order to select the percentage of water in drinking water treatment plants (DWTP) that should be nanofiltered (NF). The methodological approach presented here takes into account environmental and social benefit criteria evaluating the implementation of new processes into conventional ones. The inclusion of NF process improves drinking water quality, reduces HHR but, in turn, increases environmental impacts as a result of energy and material demand. Results from this study lead to balance the increase of the impact in various environmental categories with the reduction in human health risk as a consequence of the respective drinking water production and consumption. From an environmental point of view, the inclusion of NF and recommended pretreatments to produce 43% of the final drinking water means that the environmental impact is nearly doubled in comparison with conventional plant in impact categories severely related with electricity production, like climate change. On the other hand, the carcinogenic risk (HHR) associated to trihalomethane formation potential (THMFP) decreases with the increase in NF percentage use. Results show a reduction of one order of magnitude for the carcinogenic risk index when 100% of drinking water is produced by NF. PMID- 23917381 TI - A ground-like surface facilitates visual search in chimpanzees (Pan troglodytes). AB - Ground surfaces play an important role in terrestrial species' locomotion and ability to manipulate objects. In humans, ground surfaces have been found to offer significant advantages in distance perception and visual-search tasks ("ground dominance"). The present study used a comparative perspective to investigate the ground-dominance effect in chimpanzees, a species that spends time both on the ground and in trees. During the experiments chimpanzees and humans engaged in a search for a cube on a computer screen; the target cube was darker than other cubes. The search items were arranged on a ground-like or ceiling-like surface, which was defined by texture gradients and shading. The findings indicate that a ground-like, but not a ceiling-like, surface facilitated the search for a difference in luminance among both chimpanzees and humans. Our findings suggest the operation of a ground-dominance effect on visual search in both species. PMID- 23917382 TI - Layered crystal structure, conformational and vibrational properties of 2,2,2 trichloroethoxysulfonamide: an experimental and theoretical study. AB - The molecular structure of 2,2,2-trichloroethoxysulfonamide, CCl3CH2OSO2NH2, has been determined in the solid state by X-ray diffraction data and in the gas phase by ab initio (MP2) and DFT calculations. The substance crystallizes in the monoclinic P21/c space group with a = 9.969(3)A, b = 22.914(6)A, c = 7.349(2)A, beta = 91.06(3) degrees , and Z = 8 molecules per unit cell. There are two independent, but closely related molecular conformers in the crystal asymmetric unit. They only differ in the angular orientation of the sulfonamide (SO2NH2) group. The conformers are arranged in the lattice as center-symmetric NH . . . O(sulf)-bonded dimers. Neighboring dimers are linked through further NH . . . O(sulf) bonds giving rise to a crystal layered structure. The solid state infrared and Raman spectra have been recorded and the observed bands assigned to the molecular vibration modes. Also, the thermal behavior of the substance was investigated by TG-DT analysis. The stability of the molecule arising from hyper conjugative interactions and charge delocalization has been analyzed using natural bond (NBO) analysis. PMID- 23917384 TI - Diclegis for nausea and vomiting of pregnancy. PMID- 23917385 TI - Dabrafenib (Tafinlar) and trametinib (Mekinist) metastatic melanoma. PMID- 23917386 TI - Ocriplasmin (Jetrea) for vitreomacular adhesion. PMID- 23917383 TI - Nanocarrier Hydrodynamics and Binding in Targeted Drug Delivery: Challenges in Numerical Modeling and Experimental Validation. AB - This review discusses current progress and future challenges in the numerical modeling of targeted drug delivery using functionalized nanocarriers (NC). Antibody coated nanocarriers of various size and shapes, also called functionalized nanocarriers, are designed to be injected in the vasculature, whereby they undergo translational and rotational motion governed by hydrodynamic interaction with blood particulates as well as adhesive interactions mediated by the surface antibody binding to target antigens/receptors on cell surfaces. We review current multiscale modeling approaches rooted in computational fluid dynamics and nonequilibrium statistical mechanics to accurately resolve fluid, thermal, as well as adhesive interactions governing nanocarrier motion and their binding to endothelial cells lining the vasculature. We also outline current challenges and unresolved issues surrounding the modeling methods. Experimental approaches in pharmacology and bioengineering are discussed briefly from the perspective of model validation. PMID- 23917388 TI - Gliogenesis in the embryonic brain of the grasshopper Schistocerca gregaria with particular focus on the protocerebrum prior to mid-embryogenesis. AB - I investigate the pattern of gliogenesis in the brain of the grasshopper Schistocerca gregaria prior to mid-embryogenesis, with particular focus on the protocerebrum. Using the glia-specific marker Repo and the neuron-specific marker HRP, I identify three types of glia with respect to their respective positions in the brain: surface glia form the outmost cell layer ensheathing the brain; cortex glia are intermingled with neuronal somata forming the brain cortex; and neuropil glia are associated with brain neuropils. The ontogeny of each glial type has also been studied. At 24% of embryogenesis, a few glia are observed in each hemisphere of the proto-, deuto- and tritocerebrum. In each protocerebral hemisphere, such glia form a cluster that expands rapidly during later development. Closer examination reveals proliferative glia in such clusters at ages spanning from 24 to 36% of embryogenesis, indicating that glial proliferation may account for the expansion of the clusters. Data derived from 33 39% of embryogenesis suggest that, in the protocerebrum, each type of glia is likely to be generated by its respective progenitor-forming clusters. Moreover, the glial cluster located at the anterior end of the brain can give rise to both surface glia and cortex glia that populate the protocerebrum via subsequent migration. Proliferation is observed for all three glial types, indicating a possible source for the glia. PMID- 23917389 TI - Electric-field effects on the [FeFe]-hydrogenase active site. AB - The effect of a homogeneous electric field--as exerted by the protein environment and by an electrode potential--on the reactivity of the active site of [FeFe] hydrogenases is unravelled by density functional theory calculations. PMID- 23917390 TI - High-dose methylprednisolone pulse therapy upregulated FcgammaRIIb expression on B cells in primary Sjogren's syndrome patients with thrombocytopenia. AB - Abnormalities in B cell are characteristic feature of primary Sjogren's syndrome (pSS). As FcgammaRIIb is a key regulator of B cells, the objective of this study is to investigate the role of the inhibitory receptor FcgammaRIIb in B cells from pSS patients, and whether glucocorticoid can affect B cell subpopulations or FcgammaRIIb expression. Thirty pSS patients and 15 healthy controls were enrolled in this study. The results showed that the percentage of memory CD19(+)CD27(+) B cells was significantly lower in pSS patients compared to in healthy controls. FcgammaRIIb expression on memory CD19(+)CD27(+) B cells from active pSS patients was significantly reduced compared with those from inactive or healthy controls. The level of FcgammaRIIb on memory CD19(+)CD27(+) B cells from active pSS patients was negatively correlated with anti-SSA antibody titers and Sjogren's syndrome disease activity index. After a high-dose methylprednisolone pulse therapy for 3 days, FcgammaRIIb expression on memory B cells was upregulated, with the raised level of platelets. In vitro, dexamethasone could elevate FcgammaRIIb expression on B cells of pSS patients in a dose-dependent manner. Taken together, our data suggest that the upregulation of FcgammaRIIb may be expected to be a new therapeutic strategy in pSS patients. PMID- 23917391 TI - Association of biomarkers of inflammation, cartilage and bone turnover with gender, disease activity, radiological damage and sacroiliitis by magnetic resonance imaging in patients with early spondyloarthritis. AB - To assess the association between biomarkers of inflammation, cartilage and bone turnover with gender, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Spondylitis Disease Activity Score (ASDAS) and bone marrow oedema in resonance magnetic imaging (MRI) of sacroiliac joints (SIJs) and radiological damage in early spondyloarthritis (SpA). Cross-sectional study of 60 patients (56.7 % females; mean age, 32.4 years) with early SpA. Sociodemographic data, clinical features, serum matrix metalloproteinase 3 (MMP-3), high sensitivity C reactive protein (hsCRP), C-terminal cross-linking telopeptides of type I collagen (CTX-I) and urinary deoxypyridinoline, ASDAS, BASDAI, BASFI, BASRI and MRI of the SIJs were collected. The mean (SD) disease duration was 12.4 (6.8 months). Twenty-two (68.7 %) of the 32 patients had active sacroiliitis by MRI. MMP-3 and CTX I correlated with swollen joint (r = 0.515, r = 0.386, p = 0.01). hsCRP correlated with ESR (r = 0.303, p = 0.05), with CRP (r = 0.455, p = 0.01) and with total BASRI (r = 0.95, p = 0.05). Biomarkers were unrelated with the rest of variables. Levels of MMP-3 (44.3 +/- 52.4 vs 24.7 +/- 33.4, p < 0.05) and CTX-I (0.53 +/- 0.45 vs 0.24 +/- 0.38; p < 0.05) were higher in men. Our study shows that CTX-I and MMP-3 are a marker of peripheral disease activity in early SpA. Male gender had higher levels of CTX-I and MMP-3, which may indicate higher disease activity. Higher hsCRP levels trended towards correlation with more baseline radiographic damage. Therefore, these biomarkers may help identify a subgroup of patients who will need closer monitoring and more intensive treatment. PMID- 23917392 TI - Intestinal permeability, systemic endotoxemia, and bacterial translocation after open or laparoscopic resection for colon cancer: a prospective randomized study. AB - PURPOSE: In this prospective randomized study, we investigated the effect of surgery on intestinal permeability (IP), endotoxemia, and bacterial translocation (BT) in patients undergoing elective colectomy for colon cancer by comparing the laparoscopic with the open approach. METHODS: Seventy-two consecutive patients underwent colectomy for colon cancer: 35 cases open resection and 37 cases laparoscopic resection. IP was measured preoperatively and at days 1 and 3 after surgery. Serial venous blood sample were taken at 0, 30, 60, 90, 120, and 180 min and at 12, 24, and 48 h after surgery for endotoxin measurement. Tissue sample were taken from the liver, spleen, and mesenteric lymph nodes and were weighed under sterile conditions. RESULTS: IP was significantly increased in the open and closed group at day 1 compared with the preoperative level (p < 0.05), but no difference was found between laparoscopic and open surgery group. The concentration endotoxin systemic increased significantly in the both group during the course of surgery but returned to baseline levels at the second day 2. No difference was found between laparoscopic and open surgery. A significant correlation was observed between the maximum systemic endotoxin concentration and IP measured at D1 in the open group and in the laparoscopic group. The incidence of BT increased in laparoscopic and open group after bowel mobilization, compared with the before mobilization (p < 0.05). There was not a statistically significant difference in BT value between the two groups. CONCLUSION: An increase in IP, systemic endotoxemia, and BT were observed during the open and laparoscopic resection for colon cancer, without significant statistically difference between the two groups. PMID- 23917393 TI - Gefitinib enhances the effects of combined radiotherapy and 5-fluorouracil in a colorectal cancer cell line. AB - PURPOSE: In a phase I/II trial, patients with locally advanced rectal cancer received preoperative radiotherapy (RT) and concurrent with 5-fluorouracil (5-FU) and gefitinib. Results were promising. To elucidate the molecular and biological effects, we replicated the schedule in the LoVo human colorectal adenocarcinoma cell line. METHODS: RT (2 Gy daily for 3 days), 5-FU (0.3, 0.6, 1.25, 2.5, 5, 10 MUM) and gefitinib (0.2, 0.4, 0.8 MUM) were administered alone, in double combinations and all together. We assessed viable cells, cell cycle, cyclin, p53 and p21 expression, signalling pathways by means of phosphorylated epidermal growth factor receptor (p-EGFR), p-AKT and p-ERK 1-2 and clonogenic capacity. RESULTS: RT and 5-FU were cytotoxic. Gefitinib was cytostatic. RT reduced clonogenic capacity more than 5-FU. 5-FU induced more cell death than RT, but surviving cells were proliferative (cyclins and p-EGFR increased). 5-FU + RT had a synergistic effect. Gefitinib, enhancing G1 accumulation, reduced proliferation of cells surviving 5-FU and 5-FU + RT. It slightly increased the cytotoxicity of RT and 5-FU. CONCLUSIONS: As gefitinib limited the proliferation rate of cells surviving 5-FU and 5-FU + RT in the LoVo cell line, it may be a useful addition to chemotherapy and RT in rectal cancer patients. PMID- 23917394 TI - A case of electroacupuncture therapy for pressure ulcer. PMID- 23917395 TI - An exploratory review of the electroacupuncture literature: clinical applications and endorphin mechanisms. AB - Electroacupuncture (EA) is widely used in clinical practice and research, as well as in experimental investigations into the mechanisms of acupuncture. This study explores publication trends in clinical and experimental studies of EA (1975 2011) for pain and non-pain research; EA use for different clinical conditions (1974-2012); and the relation of EA research, including stimulation frequency, to opioid peptide mechanisms. Appropriate PubMed 'all fields' searches were conducted, identified studies were classified using PubMed filters and manually, and data extracted into tables. A total of 2916 clinical studies were located, of which 19% involved EA. Additionally, 3344 animal studies were located, of which 48% involved EA. The publication rate of EA studies per year has risen over time, but the percentage of studies of pain has fallen from 60% to 25%. The conditions most commonly treated with EA are musculoskeletal, neurological, obstetric and gastrointestinal, along with intraoperative and postoperative analgesia. EA studies, particularly with low frequency stimulation, are more likely to support the role of endogenous opioid mechanisms than manual acupuncture studies, and opioid release is more likely in the central nervous system than the circulation. EA is increasingly used in clinical and especially experimental research, particularly for non-pain conditions. Acupuncture does release endogenous opioids, but this probably depends on 'dosage', with the evidence more consistent and convincing for EA than for manual acupuncture. Different frequencies of EA appear to activate different endogenous opioid mechanisms. PMID- 23917396 TI - Curcumin-loaded nanoparticles induce apoptotic cell death through regulation of the function of MDR1 and reactive oxygen species in cisplatin-resistant CAR human oral cancer cells. AB - Curcumin is a polyphenolic compound which possesses anticancer potential. It has been shown to induce cell death in a variety of cancer cells, however, its effect on CAL27-cisplatin-resistant human oral cancer cells (CAR cells) has not been elucidated to date. The low water solubility of curcumin which leads to poor bioavailability, however, has been highlighted as a major limiting factor. In this study, we utilized water-soluble PLGA curcumin nanoparticles (Cur-NPs), and investigated the effects of Cur-NPs on CAR cells. The results showed Cur-NPs induced apoptosis in CAR cells but exhibited low cytotoxicity to normal human gingival fibroblasts (HGFs) and normal human oral keratinocytes (OKs). Cur-NPs triggered DNA concentration, fragmentation and subsequent apoptosis. Compared to untreated CAR cells, a more detectable amount of Calcein-AM accumulation was found inside the treated CAR cells. Cur-NPs suppressed the protein and mRNA expression levels of MDR1. Both the activity and the expression levels of caspase 3 and caspase-9 were elevated in the treated CAR cells. The Cur-NP-triggered apoptosis was blocked by specific inhibitors of pan-caspase (z-VAD-fmk), caspase 3 (z-DEVD-fmk), caspase-9 (z-LEHD-fmk) and antioxidant agent (N-acetylcysteine; NAC). Cur-NPs increased reactive oxygen species (ROS) production, upregulated the protein expression levels of cleaved caspase-3/caspase-9, cytochrome c, Apaf-1, AIF, Bax and downregulated the protein levels of Bcl-2. Our results suggest that Cur-NPs triggered the intrinsic apoptotic pathway through regulating the function of multiple drug resistance protein 1 (MDR1) and the production of reactive oxygen species (ROS) in CAR cells. Cur-NPs could be potentially efficacious in the treatment of cisplatin-resistant human oral cancer. PMID- 23917397 TI - Human Ntera2 cells as a predictive in vitro test system for developmental neurotoxicity. AB - Developmental neurotoxicity (DNT) of environmental chemicals is a serious threat to human health. Current DNT testing guidelines propose investigations in rodents, which require large numbers of animals. With regard to the "3Rs" (reduction, replacement, and refinement) of animal testing, alternative testing strategies are needed in order to refine and reduce animal experiments and allow faster and less expensive screening. The goal of this study was to establish components for a human cell-based test system to assess DNT potential of chemicals at an early stage of brain development. A human neural precursor cell line should be tested for suitability for semi-automated high-throughput DNT screening. We established assays suitable for detecting disturbances in two basic processes of brain development in 96-well scale: neuronal differentiation and migration using the human Ntera2 (NT2) cell line. We assessed the effects of four test compounds with well-established DNT potential in comparison with three compounds without specific DNT potential. We found that human NT2 cell cultures treated with the morphogen, retinoic acid, imitate neuronal differentiation, and migration in vitro. The developmental neurotoxicants methylmercury chloride, sodium arsenite, sodium valproate, and methylazoxymethanol significantly reduced the expression of the neuronal marker beta-tubulin type III and decreased the migration distance in developing NT2 cells. Both endpoints, differentiation and migration, can be read out directly in a standard fluorescence plate reader, enabling high-throughput screening. We conclude that NT2 cell tests are likely to become valuable components of a human cell-based modular in vitro DNT test systems. PMID- 23917398 TI - A classical but new kinetic equation for hydride transfer reactions. AB - A classical but new kinetic equation to estimate activation energies of various hydride transfer reactions was developed according to transition state theory using the Morse-type free energy curves of hydride donors to release a hydride anion and hydride acceptors to capture a hydride anion and by which the activation energies of 187 typical hydride self-exchange reactions and more than thirty thousand hydride cross transfer reactions in acetonitrile were safely estimated in this work. Since the development of the kinetic equation is only on the basis of the related chemical bond changes of the hydride transfer reactants, the kinetic equation should be also suitable for proton transfer reactions, hydrogen atom transfer reactions and all the other chemical reactions involved with breaking and formation of chemical bonds. One of the most important contributions of this work is to have achieved the perfect unity of the kinetic equation and thermodynamic equation for hydride transfer reactions. PMID- 23917400 TI - Graphene interconnects fully encapsulated in layered insulator hexagonal boron nitride. AB - We demonstrate improvements in the electrical performance of graphene interconnects with full encapsulation by lattice-matching layered insulator, hexagonal boron nitride (h-BN). A novel layer-based transfer method is developed to assemble the top passivating layer of h-BN on the graphene surface to construct the h-BN/graphene/h-BN heterostructures. The encapsulated graphene interconnects (EGIs) are characterized and compared with graphene interconnects on either SiO2 or h-BN substrates with no top passivating h-BN layer. We observe significant improvements in both the maximum current density and breakdown voltage in EGIs. Compared with the uncovered structures, EGIs also show an appreciable increase (~67%) in power density at breakdown. These improvements are achieved without degrading the carrier transport characteristics in graphene wires. In addition, EGIs exhibit a minimal environment impact, showing electrical behavior insensitive to ambient conditions. PMID- 23917399 TI - Endoglin is necessary for angiogenesis in human ovarian carcinoma-derived primary endothelial cells. AB - Endoglin (CD105, END) is upregulated in proliferating endothelial cells, suggesting potential therapeutic properties. However, it is not clear whether endoglin mediates an enhanced proliferative rate or may be upregulated as part of a negative feedback loop. To gain insights into context-dependent and cell type dependent regulatory effects of endoglin, we studied its role properties in human ovarian carcinoma-derived endothelial cells (ODMECs). We isolated and cultured primary ODMECs from epithelial ovarian carcinoma tissue. ODMECs had higher expression of endoglin and VEGFR-2, and also exhibited enhanced spontaneous formation of vessel-like structures in vitro. Transfection of siRNA targeting endoglin in ODMECs cells resulted in the reduction of the proliferation and tube formation. These results indicate that a subset of ODMECs display abnormal angiogenic properties and this phenotype was blocked by decreasing endoglin levels, suggesting endoglin is essential for stimulating angiogenesis, and targeting it may be an attractive approach to anti-angiogenesis therapy for ovarian carcinoma. PMID- 23917401 TI - The integrated landscape of driver genomic alterations in glioblastoma. AB - Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention. PMID- 23917402 TI - Role of microRNA-mediated MMP regulation in the treatment and diagnosis of malignant tumors. AB - Matrix metalloproteinases (MMPs) play important roles in tumor cell proliferation and apoptosis and contribute to tumor growth, angiogenesis, migration, and invasion primarily via extracellular matrix (ECM) degradation and/or the activation of pre-pro-growth factors. Recently, there has been considerable interest in the posttranscriptional regulation of MMPs via microRNAs (miRs). In this review, we highlight the complicated interactive network comprised of different MMPs and their regulating microRNAs, as well as the ways in which these interactions influence cancer development, including tumor angiogenesis, growth, invasion, and metastasis. Based on the conclusive roles that microRNAs play in the regulation of MMPs during cancer progression, we discuss the potential use of microRNA-mediated MMP regulation in the diagnosis and treatment of tumors from the clinical perspective. In particular, microRNA-mediated MMP regulation may lead to the development of promising new MMP inhibitors that target MMPs more selectively, and this approach may also target multiple molecules in a network, leading to the efficient regulation of distinct biological processes relevant to malignant tumors. A thorough understanding of the mechanisms underlying microRNA mediated MMP regulation during tumor progression will help to provide new insights into the diagnosis and treatment of malignant tumors. PMID- 23917404 TI - Hydrogen-bond mediated regio- and enantioselectivity in a C-H amination reaction catalysed by a supramolecular Rh(II) complex. AB - Enantioselective (up to 74% ee) and regioselective C-H amination reactions of 3 benzylquinolones were achieved with a chiral C2-symmetric Rh(II) complex exhibiting two lactam binding sites for substrate coordination via hydrogen bonds. PMID- 23917403 TI - The effect of acute administration of vitamin D on micro vascular endothelial function in Caucasians and South Asian Indians. AB - BACKGROUND: Vitamin D is a modulator of the immune system. There is some limited evidence that it also increases local blood flow in response to stress. MATERIAL AND METHODS: In the present study, we examined 20 age matched subjects; 10 whom were from India and 10 Caucasians from the United States. Subjects were administered 4000 IU of Vitamin D3 for 3 weeks at breakfast. The function of the endothelial cells was evaluated in 2 ways; first, the response to 4 minutes of vascular occlusion was measured with a laser Doppler flow meter and second, the blood flow response to local heat at 42 degrees C for 6 minutes. RESULTS: The results of the experiments showed that, as reported previously, the endothelial function in people from India was less than their Caucasian counterparts. The blood flow response to heat was reduced after 3 weeks administration of vitamin D in both groups and the response to vascular occlusion in the Caucasian group. But there was only a 20% reduction in the blood flow response to heat in the Caucasian group and a 50% reduction in the group from India. CONCLUSIONS: Thus acute doses of vitamin D may increase vascular tone and reduce blood flow to tissue during stressors. Dosages administered for a longer duration may have beneficial effects on endothelial function but this was not examined here. PMID- 23917405 TI - STAT6 promotes bi-directional modulation of PKM2 in liver and adipose inflammatory cells in rosiglitazone-treated mice. AB - STAT6 interacts with PPARgamma to elicit macrophage polarization towards an anti inflammatory, insulin-sensitizing phenotype. Mice deficient in STAT6 display liver lipid accumulation (hepatosteatosis). Rosiglitazone (RSG), a PPARgamma agonist, ameliorates hepatosteatosis and enhances insulin sensitivity. To elucidate the role of STAT6 in PPARgamma action on hepatosteatosis we compared liver proteomes of RSG-treated wild type and STAT6-deficient mice and we identified pyruvate kinase M2 (PKM2), a glycolysis and proliferation-regulating enzyme that displayed STAT6-dependent expression. RSG induced PKM2 within inflammatory cells in liver but suppressed its expression in adipose tissue. RSG diminished hepatosteatosis and oxidative stress, enhanced fat accumulation and improved insulin sensitivity in STAT6-deficient mice. Our data reveal a complex interaction between STAT6 and PPARgamma in the regulation of liver and adipose tissue lipid depot distribution and design STAT6 as a novel link between inflammatory cell metabolism and adipocyte and hepatocyte function. PMID- 23917406 TI - Detection and tentative identification of urinary phase I metabolites of phenylacetylindole cannabimimetics JWH-203 and JWH-251, by GC-MS and LC-MS/MS. AB - The synthetic phenylacetylindole cannabimimetics, JWH-203 and JWH-251, have been identified in 'herbal' smoking mixtures following the widespread legislative control of 'first generation' compounds such as JWH-018 and CP47, 497(C8). N Alkylindole cannabimimetics (including phenylacetylindoles) undergo extensive metabolism and little or none of the parent compounds are found in urine. Utilizing GC-MS and LC-MS/MS, a series of JWH-203 and JWH-251 urinary metabolites have been tentatively identified. These are products of mono- and dihydroxylation, monohydroxylation combined with formation of carbonyl group on the N-pentyl chain, carboxylation of N-pentyl chain and N-dealkylation combined with monohydroxylation. Additionally, trihydroxylated metabolites were detected for JWH-203. No parent compounds were detected. The monohydroxylated metabolites with the hydroxyl group positioned on the N-pentyl chain were the most abundant and were found to be suitable for establishing ingestion of JWH-203 or JWH-250. Maximum urinary concentrations of chain-monohydroxylated metabolites were observed at 2.5-3h (JWH-203) and 6-10h (JWH-251) following ingestion. These metabolites were observed (GC-MS) for to 10 and 8 days (JWH-203 and JWH-251, respectively). PMID- 23917407 TI - Comparison of two-concentration with multi-concentration linear regressions: Retrospective data analysis of multiple regulated LC-MS bioanalytical projects. AB - Linear calibration is usually performed using eight to ten calibration concentration levels in regulated LC-MS bioanalysis because a minimum of six are specified in regulatory guidelines. However, we have previously reported that two concentration linear calibration is as reliable as or even better than using multiple concentrations. The purpose of this research is to compare two concentration with multiple-concentration linear calibration through retrospective data analysis of multiple bioanalytical projects that were conducted in an independent regulated bioanalytical laboratory. A total of 12 bioanalytical projects were randomly selected: two validations and two studies for each of the three most commonly used types of sample extraction methods (protein precipitation, liquid-liquid extraction, solid-phase extraction). When the existing data were retrospectively linearly regressed using only the lowest and the highest concentration levels, no extra batch failure/QC rejection was observed and the differences in accuracy and precision between the original multi concentration regression and the new two-concentration linear regression are negligible. Specifically, the differences in overall mean apparent bias (square root of mean individual bias squares) are within the ranges of -0.3% to 0.7% and 0.1-0.7% for the validations and studies, respectively. The differences in mean QC concentrations are within the ranges of -0.6% to 1.8% and -0.8% to 2.5% for the validations and studies, respectively. The differences in %CV are within the ranges of -0.7% to 0.9% and -0.3% to 0.6% for the validations and studies, respectively. The average differences in study sample concentrations are within the range of -0.8% to 2.3%. With two-concentration linear regression, an average of 13% of time and cost could have been saved for each batch together with 53% of saving in the lead-in for each project (the preparation of working standard solutions, spiking, and aliquoting). Furthermore, examples are given as how to evaluate the linearity over the entire concentration range when only two concentration levels are used for linear regression. To conclude, two concentration linear regression is accurate and robust enough for routine use in regulated LC-MS bioanalysis and it significantly saves time and cost as well. PMID- 23917408 TI - Effects of instrument settings on radiofrequency ultrasound local estimator images: a preliminary study in a gallbladder model. AB - The aim of the present study was to evaluate the changes in radiofrequency ultrasound local estimator (RULES) images with different instrument settings. An Esaote Technos MPX Color Doppler Ultrasound Machine and RULES were used to capture images of a gallbladder model. The percentages of various colored areas (color filling rates) within the area of interest were calculated using different instrument gains, transducer frequencies and scan depths. Blue was predominant in the lumen of the model gallbladder, while red and green were primarily located near the inner edge of the lumen. When the depth was set at 62 mm and the gain at 105, the total color filling rates did not vary with different transducer frequencies. The blue color filling rate was greatest with a transducer frequency of 8.0 MHz, and the red and green color filling rates were greatest with a frequency of 12.5 MHz. Color variety was greatest when the transducer frequency was 12.5 MHz. When the transducer frequency was 12.5 MHz and the depth was 62 mm, the blue color filling rate was greatest with gains of 105 and 110, the red color filling rate was greatest with gains of 95 and 100 and the green color filling rate was greatest when the gain was 100. The total color filling rate was greatest at gains of 100 and 105. In conclusion, images obtained using RULES may be affected by the instrument gain and, to a certain extent, by transducer frequency. PMID- 23917409 TI - Treatment of coronary artery disease via MIDCAB in a patient with severe thalidomide phocomelia. PMID- 23917410 TI - Optimization and production of pyrrolidone antimicrobial agent from marine sponge associated Streptomyces sp. MAPS15. AB - Twenty-nine actinobacterial strains were isolated from marine sponge Spongia officinalis and screened for antagonistic activity against various bacterial and fungal pathogens. The active antibiotic producer MAPS15 was identified as Streptomyces sp. using 16S rRNA phylogenetic analysis. The critical control factors were selected from Plackett-Burman (PB) factorial design and the bioprocess medium was optimized by central composite design (CCD) for the production of bioactive metabolite from Streptomyces sp. MAPS15. The maximum biomass and active compound production obtained with optimized medium was 6.13 g/L and 62.41 mg/L, respectively. The economical carbon source, paddy straw was applied for the enhanced production of bioactive compound. The purified active fraction was characterized and predicted as pyrrolidone derivative which showed broad spectrum of bioactivity towards indicator organisms. The predicted antimicrobial spectra suggested that the Streptomyces sp. MAPS15 can produce a suite of novel antimicrobial drugs. PMID- 23917411 TI - Bench-scale bioethanol production from eucalyptus by high solid saccharification and glucose/xylose fermentation method. AB - In the bioethanol production process, high solid saccharification and glucose/xylose co-fermentation are important technologies for obtaining increased ethanol concentrations; however, bench-scale studies using combinations of these methods are limited. In this study, we hydrolyzed high solid concentration of milled eucalyptus using commercial enzymes and obtained 138.4 g/L total monomeric sugar concentration. These sugars were fermented to 53.5 g/L of ethanol by a xylose-utilizing recombinant Saccharomyces cerevisiae strain, MA-R4. These experiments were performed in bench scale (using 50 L scale solid mixer and 70 L scale fermenter). The results obtained in this study were comparable to our previous results in laboratory scale, indicating that we successfully achieved an efficient high solid saccharification and glucose/xylose co-fermentation system in bench scale. PMID- 23917412 TI - A scientific paradigm for targeted nanophotothermolysis; the potential for nanosurgery of cancer. AB - The application of gold nanoparticles (AuNPs) in nanophotothermolysis as a great photosensitizer is expanding, and this subject is a challenging area for cancer therapy. Recent technological advances in nanoscale manufacturing and synthesis promise the development of highly beneficial and innovative methods for the targeting of cancer. However, there is an obstacle to conducting effective laser based nanosurgery because AuNPs are activated by visible or near infrared wavelengths, and the penetration of a laser beam inside the body is limited by some absorbents, such as melanin, water, and blood molecules. Considering everything stated above, we have suggested the application of a folate-conjugated AuNP as an effective agent for targeted nanophotothermolysis and the application of an optical fiber to transport the laser light from the source to the target tissue inside the body. Thus, a new method of nanosurgery in which a surgeon is able to perform surgery at the cellular or even at the subcellular level may be possible. PMID- 23917413 TI - The effects of diode laser (660 nm) on the rate of tooth movements: an animal study. AB - Low-level laser has been indicated to have the capability to facilitate the differentiation of the osteoclastic and osteoblastic cells which are responsible for the bone remodeling process. The aim of this study was to evaluate the effects of InGaAlP laser with a wavelength of 660 nm on the rate of tooth movement and histological status. Thirty male Wistar rats of 7 weeks old were selected for this study. The rats were randomly divided into two groups of 15 each to form the experimental (laser-irradiated) and control (non-irradiated) groups. The control group received unilateral orthodontic appliance design (one quadrant), but the laser-irradiated group received split-mouth design, with orthodontic appliance on both sides and laser irradiation on one side only (group b) and on the contralateral side (group c). The orthodontic appliance consisted of a NiTi closed coil spring with a length of 5 mm which was ligated to maxillary molar and incisor. A total of 60 g of force was applied to the rat molar. The diode laser (660 nm) was irradiated with an output power of 25 mW in continuous mode for a total time of 5 min in the laser-irradiated group. After 14 days of orthodontic tooth movement, the amount of tooth movements was measured. In the laser-irradiated group, the amount of tooth movement was significantly greater than that of the non-irradiated group (2.3-fold), but there was no significant difference between the non-irradiated and indirectly irradiated groups. Histopathological studies revealed that the number of osteoclasts in the laser irradiated group was significantly greater than that of the non-irradiated group (1.5-fold) while this number was almost the same in the non-irradiated and indirectly irradiated groups. The results suggested that low-level laser can accelerate the rate of bone remodeling. However, in order to utilize the low level laser as an adjunct in orthodontic practice on patients, further research studies are needed for finding the appropriate dosage for the human tissues. PMID- 23917414 TI - Effectiveness of a new method of disinfecting the root canal, using Er, Cr:YSGG laser to kill Enterococcus faecalis in an infected tooth model. AB - Some lasers have demonstrated to provide effective disinfection when used as adjunctive device to the conventional treatment. The aim of this in vitro study was to determine the effectiveness of the erbium, chromium:yttrium scandium gallium garnet (Er, Cr:YSGG) laser by measuring its bactericidal effect inside the root canal experimentally colonized with Enterococcus faecalis. The laser was tested at different irradiation times (30 and 60 s) and energy of impulses (75 and 25 mJ). A total of 52 single-rooted extracted human teeth were endodontically prepared with rotary instrumentation. All were sterilized and inoculated with a suspension of E. faecalis (105 bacteria/ml). The teeth were randomized into three treatment (group 1, group 2, and group 3) and one control groups. In all groups, teeth were chemically irrigated with 5.25% sodium hypochlorite and 17% ethylenediaminetetraacetic acid. Groups 1 and 2 were also irradiated at 30 and 60 s, respectively, with an Er, Cr:YSGG laser at 75 mJ. Teeth of group 3 were treated with laser for 60 s at 25 mJ. Samples were processed to detect the presence of E. faecalis. For all groups, a bactericidal effect was observed. The use of laser at 75 mJ with an irradiation time of 30 and 60 s eliminated a percentage of 92.3 and 100% of E. faecalis, respectively. In the control group, a reduction of 92.3% was observed. Lower percentage of reduction (46.1%) was obtained in teeth treated with laser at 25 mJ for 60 s. No statistical differences were observed between the groups (P = 0.543, Fisher's exact test). The results indicated a bactericidal effect of Er, Cr:YSGG laser irradiation at the settings used in this study. The highest bactericidal effect of this laser was observed at 60 s of irradiation time, using an energy pulse of 75 mJ. PMID- 23917415 TI - Tissue laser biostimulation promotes post-extraction neoangiogenesis in HIV infected patients. AB - The aim of the study was to assess the rate of neoangiogenesis in extraction wound healing following exposure to biostimulating laser therapy and to analyze the correlation between parameters of neoangiogenesis as reflected by the number and surface area of newly formed blood vessels and clinical parameters such as gender, position of a tooth in the oral cavity, and CD4 lymphocyte count. Twenty seven patients with confirmed HIV infection were enrolled in the study (6 women, 21 men). Eighty-nine teeth were extracted; 45 sockets were exposed to 6 J laser radiation (laser parameters were set as follows: wavelength, 820 nm; output, 200 mW; dose, 6 J/cm(2); spot size, 38 mm(2); continuous radiation) for five consecutive days following tooth extraction, and the remaining extraction wounds were left to heal spontaneously without laser irradiation. Antigen CD34 was assessed by immunohistochemistry as a marker of angiogenesis, and its expression was examined by computer-assisted histomorphometric image analysis. As a result, we report that biostimulating laser therapy in HIV-infected patients of varying degrees of immunodeficiency greatly accelerated post-extraction neoangiogenesis, regardless of the patient's gender, tooth position, number of roots, or number of CD4 lymphocytes in the blood. Application of low-level laser therapy for the treatment of tooth extraction wounds in HIV(+) patients greatly enhanced the formation of new blood vessels, which in turn promoted wound healing. PMID- 23917422 TI - Asymmetrical flow field-flow fractionation as a novel technique for the analysis of PS-b-PI copolymers. AB - Asymmetrical flow field-flow fractionation (AF4) was used as a fractionation technique to investigate the molecular heterogeneity of poly(styrene-b-isoprene) diblock copolymers synthesized by either sequential living anionic polymerization or coupling of living precursor blocks. AF4 coupled to multi-angle laser light scattering (MALLS), refractive index (RI), and ultraviolet (UV) detectors was used to separate the diblock copolymers from the homopolymers and coupling products, and the molar masses of the different components were analyzed. In order to get more information about the separated block copolymers, homopolymers, and coupling products, fractions were collected directly after the AF4 channel. The collected fractions were analyzed offline by (1)H NMR to provide identification of the different species and additional information on the true chemical composition, and the microstructure of the diblock copolymer was obtained. PMID- 23917423 TI - Amino acid analysis: current topics and trends. PMID- 23917424 TI - Colorimetric sensors using nano-patch surface plasmon resonators. AB - A two-dimensional array of gold nano-patches on a highly reflective mirror is proposed for refractive index sensing based on changes in the reflected colors. The grating on the mirror creates localized surface plasmon resonances resulting in a minimum in the visible reflectance spectra. The wavelength of the resonance can be tuned by changing the width of the nano-patches and is also dependent on the refractive index of the surrounding medium. The color variation due to change in the refractive index is measured and used to realize a simple low-cost sensor with a refractive index resolution better than 10-5 just using image processing. The efficacy of the proposed sensor is also demonstrated for surface sensing by depositing thin layers of silicon dioxide. The color difference due to the addition of a 3 nm thick layer of silicon dioxide is detectable by the naked eye and deposition thickness of 2 A can be resolved using image processing. PMID- 23917425 TI - The IL28B effect on hepatitis C virus kinetics among HIV patients after the first weeks of pegylated-interferon/ribavirin treatment varies according to hepatitis C virus-1 subtype. AB - OBJECTIVE: To evaluate the IL28B effect on hepatitis C virus (HCV) decline during first weeks of treatment according to HCV-1 subtypes. METHODS: Patients coinfected with HIV/HCV genotype 1 and naive to peginterferon-alpha-2a and ribavirin (Peg-IFN-alpha-2a/RBV) were included. Plasma HCV-RNA was measured at baseline, and then at weeks 1, 2, and 4. HCV-1 subtype (1a or 1b) was determined. HCV viral decline was analyzed according to HCV-1 subtype between baseline and week 1, week 2 and week 4 of treatment. Additionally, we analyzed the effect of the IL28B (rs12979860) genotype on HCV viral decline with HCV-1a and HCV-1b genotype patients (CC versus non-CC). RESULTS: Two hundred and six patients were included in the study, of whom 113 (54.8%) and 93 (45.2%) were infected by HCV-1a and 1b genotypes, respectively. No differences were found between HCV-1 subtypes in terms of HCV viral decline or rapid virological response rate. The effect of the IL28B-CC genotype on HCV viral decline was observed only among patients infected with HCV-1b at all time points analyzed (week 1: CC 1.53 +/- 0.33, non CC 0.27 +/- 0.24, P <0.001; week 2: CC 1.81 +/- 0.39, non-CC 0.74 +/- 0.39, P = 0.002; week 4: CC 2.97 +/- 0.53, non-CC 1.2 +/- 0.61, P < 0.001). CONCLUSION: Our study suggests that the effect associated with the impact of the IL28B-CC genotype on HCV decline during the first weeks of treatment with Peg-IFN-alpha 2a/RBV differs according to HCV-1 subtype and may be limited to HCV-1b patients. PMID- 23917426 TI - Multicondition Optimization and Experimental Measurements of a Double-Blade Centrifugal Pump Impeller. AB - In order to improve internal unsteady flow in a double-blade centrifugal pump (DBCP), this study used major geometric parameters of the original design as the initial values, heads at three conditions (i.e., 80% design flow rate, 100% design flow rate, and 120% design flow rate) as the constraints conditions, and the maximum of weighted average efficiency at the three conditions as the objective function. An adaptive simulated annealing algorithm was selected to solve the energy performance calculation model and the supertransitive approximation method was applied to fix optimal weight factors of individual objectives. On the basis of hydraulic performance optimization, three-condition automatic computational fluid dynamics (CFD) optimization of impeller meridional plane for the DBCP was realized by means of Isight software integrated Pro/E, Gambit, and Fluent software. The shroud arc radii R0 and R1, shroud angle T1, hub arc radius R2, and hub angle T2 on the meridional plane were selected as the design variables and the maximum of weighted average hydraulic efficiency at the three conditions was chosen as the objective function. Performance characteristic test and particle image velocimetry (PIV) measurements of internal flow in the DBCP were conducted. Performance characteristic test results show that the weighted average efficiency of the impeller after the three-condition optimization has increased by 1.46% than that of original design. PIV measurements results show that vortex or recirculation phenomena in the impeller are distinctly improved under the three conditions. PMID- 23917427 TI - Synthesis and biological evaluation of flexible and conformationally constrained LpxC inhibitors. AB - Inhibitors of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represent promising candidates for the development of antibiotics possessing a so far unexploited mechanism of action. In a chiral pool synthesis, starting from the D-mannose derived mannonolactone 4, conformationally constrained C-glycosidic as well as open chained hydroxamic acids with a defined stereochemistry were prepared. Diversity was introduced by performing C-C coupling reactions like the Sonogashira and Suzuki cross-coupling reactions. The biological evaluation of the synthesized compounds revealed that in the case of the C-glycosides a long, linear and rigid hydrophobic side chain is required for antibiotic activity against E. coli. The open chain derivatives show higher biological activity than the conformationally constrained C-glycosides. The morpholinomethyl substituted open chain derivative 43, being the most potent compound presented in this paper, inhibits LpxC with a Ki value of 0.35 MUM and represents a promising lead structure. PMID- 23917428 TI - Damage Control Strategy and aggressive resuscitation in polytraumatized patient with severe hypothermia. Importance of multidisciplinary management from the territory to the operating room. Case report. AB - AIM: Our objective is to describe a case of hypothermic politrauma management in our country. MATERIAL OF STUDY: We report the case of a 29-year-old male who was a beating victim and fell off from 4 meters, and was afterwards found after an unknown time interval. The patient came to our DEA in cardiac arrest and underwent to a aggressive and prolonged resuscitation which included sternotomy and extracorporeal circulation. RESULTS: The patient was discharged in 40th postoperative day without neurologic complications and complete recovery. DISCUSSION: Even without a dedicated protocol for the hypothermic politrauma the correct multidisciplinary approach lead to the complete recovery of the patient. In literature many papers describe the aggressive resuscitation of hypothermic patients underlining that the politrauma management must be multidisciplinar. CONCLUSION: We want to underline the importance of the "Damage control strategy" in a politrauma team in the major hospitals in our country. KEY WORDS: Cardiopulmonary resuscitation, Extracorporeal circulation, Hypothermia, Polytrauma, Trauma team. PMID- 23917429 TI - N-Glycosylation of GABAA receptor subunits is altered in Schizophrenia. AB - The molecular mechanisms of schizophrenia have been under investigation for decades; however, the exact causes of this debilitating neuropsychiatric disorder are still unknown. Previous studies have identified multiple affected neurotransmitter systems, brain regions, and cell types, each making a unique contribution to symptom presentation and pathophysiology. Numerous studies have identified gene and protein expression changes in schizophrenia, but the role of post-translational modifications, specifically N-glycosylation, has only recently become a target of investigation. N-glycosylation of molecules associated with glutamatergic neurotransmission is disrupted in schizophrenia, but it was unknown if these alterations are exclusive to the glutamatergic system or due to a more generalized deficit.In normal human cortex, we found evidence for N-glycosylation of the alpha1, beta1, and beta2 gamma-aminobutyric type A receptor (GABAAR) subunits using deglycosylation protein shift assays. This was confirmed with lectin affinity assays that revealed glycan attachment on the alpha1, alpha4, and beta1-3 GABAAR subunits. Examining GABAAR subunit N-glycosylation in matched pairs of schizophrenia (N=14) and comparison (N=14) of superior temporal gyrus revealed a smaller molecular mass of immature N-glycans on the alpha1 subunit, more immature N-glycosylation of the 49-kDa beta1 subunit isoform, and altered total N-glycosylation of the beta2 GABAAR subunit in schizophrenia. Measures of altered N-glycosylation of the beta1 and beta2 subunits were confounded by an increased apparent molecular mass of all beta1 and beta2 subunit isoforms in schizophrenia. Although N-glycosylation of alpha1, beta1, and beta2 were all changed in schizophrenia, the concentrations of GABAAR subunits themselves were unchanged. These findings suggest that disruptions of N-glycosylation in schizophrenia are not exclusive to glutamate and may indicate a potential disruption of a central cell signaling process in this disorder. PMID- 23917431 TI - Use of serial ultrasound measures in the study of growth- and breed-related changes of ultrasonic measurements and relationship with carcass measurements in lean cattle breeds. AB - The growth and breed-related changes of rib and rump characteristics in lean beef cattle and the ability of ultrasound to predict carcass traits were investigated. Three hundred bulls from three breeds were scanned monthly (6-7 times) using real time ultrasound with final scans taken <7 days prior to harvest. The rib and rump ultrasound measurements, except intramuscular fat content, increased (P<0.05) with live weight. Breed affected most of traits. The 12th rib ultrasound measurements showed a weak to high positive correlation (0.131 to 0.976, P>0.05 to P<0.001) with 12th rib measurements in the carcass. Regression equations developed with the ultrasound measurements, explained 97% of the variation in longissimus muscle area, 88% of the variation in fat thickness and 57% of the variation in intramuscular fat content. When last ultrasound scan measurements were excluded from prediction equations, the R(2) significantly decreased. Ultrasound measures "in vivo" are viable options for assessing carcass attributes of lean cattle. PMID- 23917430 TI - Neural correlates of reward-based spatial learning in persons with cocaine dependence. AB - Dysfunctional learning systems are thought to be central to the pathogenesis of and impair recovery from addictions. The functioning of the brain circuits for episodic memory or learning that support goal-directed behavior has not been studied previously in persons with cocaine dependence (CD). Thirteen abstinent CD and 13 healthy participants underwent MRI scanning while performing a task that requires the use of spatial cues to navigate a virtual-reality environment and find monetary rewards, allowing the functional assessment of the brain systems for spatial learning, a form of episodic memory. Whereas both groups performed similarly on the reward-based spatial learning task, we identified disturbances in brain regions involved in learning and reward in CD participants. In particular, CD was associated with impaired functioning of medial temporal lobe (MTL), a brain region that is crucial for spatial learning (and episodic memory) with concomitant recruitment of striatum (which normally participates in stimulus response, or habit, learning), and prefrontal cortex. CD was also associated with enhanced sensitivity of the ventral striatum to unexpected rewards but not to expected rewards earned during spatial learning. We provide evidence that spatial learning in CD is characterized by disturbances in functioning of an MTL-based system for episodic memory and a striatum-based system for stimulus-response learning and reward. We have found additional abnormalities in distributed cortical regions. Consistent with findings from animal studies, we provide the first evidence in humans describing the disruptive effects of cocaine on the coordinated functioning of multiple neural systems for learning and memory. PMID- 23917436 TI - Autophagy at sea. AB - The 3rd EMBO Conference on, "Autophagy: Molecular mechanism, physiology and pathology" organized by Anne Simonsen and Sharon Tooze, was held in May 2013 on a sea cruise along the Norwegian coastline from Bergen to Tromso. Researchers from all corners of the world presented work covering autophagosome biogenesis, physiological regulation of autophagy, selective autophagy and disease. PMID- 23917437 TI - Pediatric nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the pediatric population. Increased recognition of this form of liver disease parallels the dramatic rise in childhood and adolescent obesity over the past 2 decades. Like adults, most children with NAFLD are obese, and comorbidities include insulin resistance, hypertension, and dyslipidemia. Unfortunately, pediatric NAFLD is not always a benign condition, with some children progressing to hepatic fibrosis and even cirrhosis in severe cases. The etiology of nonalcoholic steatohepatitis is not yet fully understood; however, hepatic steatosis in the context of insulin resistance and increased oxidative stress may lead to progressive disease. Although physical examination, laboratory evaluation, and radiographic findings provide clues to the potential presence of fatty liver disease, liver biopsy remains the gold standard for diagnosis. Lifestyle modification, including slow and steady weight loss, improved dietary habits, and increased daily, aerobic physical activity, remains the first-line approach in treating pediatric fatty liver disease. Antioxidant pharmacologic therapy such as use of vitamin E has shown some benefit in patients with biopsy proven steatohepatitis. Nutrition plays an essential role not only in the development of fatty liver disease but also potentially in the treatment and prevention of progression to more severe disease. PMID- 23917438 TI - Soluble receptor of transferrin (sTfR) as a marker of iron deficiency in inflammatory conditions. PMID- 23917439 TI - Parenteral nutrition amino acids product shortage considerations. PMID- 23917440 TI - Parenteral nutrition intravenous fat emulsions product shortage considerations. PMID- 23917441 TI - Risks associated with the transfer of toxic organo-metallic mercury from soils into the terrestrial feed chain. AB - Although the transfer of organo-metallic mercury (OrgHg) in aquatic food webs has long been studied, it has only been recently recognized that there is also accumulation in terrestrial systems. There is still however little information about the exposure of grazing animals to OrgHg from soils and feed as well as on risks of exposure to animal and humans. In this study we collected 78 soil samples and 40 plant samples (Lolium perenne and Brassica juncea) from agricultural fields near a contaminated industrial area and evaluated the soil-to plant transfer of Hg as well as subsequent trophic transfer. Inorganic Hg (IHg) concentrations ranged from 0.080 to 210mgkg(-1) d.w. in soils, from 0.010 to 84mgkg(-1) d.w. in roots and from 0.020 to 6.9mgkg(-1) d.w. in shoots. OrgHg concentrations in soils varied between 0.20 and 130MUgkg(-1) d.w. representing on average 0.13% of the total Hg (THg). In root and shoot samples OrgHg comprised on average 0.58% (roots) and 0.66% (shoots) of THg. Average bioaccumulation factors (BAFs) for OrgHg in relation to soil concentrations were 3.3 (for roots) and 1.5 (for shoots). The daily intake (DI) of THg in 33 sampling sites exceeded the acceptable daily intake (ADI) of THg of both cows (ADI=1.4mgd(-1)) and sheep (ADI=0.28mgd(-1)), in view of food safety associated with THg in animal kidneys. Estimated DI of OrgHg for grazing animals were up to 220MUgd(-1) (for cows) and up to 33MUgd(-1) (for sheep). This study suggested that solely monitoring the levels of THg in soils and feed may not allow to adequately taking into account accumulation of OrgHg in feed crops and properly address risks associated with OrgHg exposure for animals and humans. Hence, the inclusion of limits for OrgHg in feed quality and food safety legislation is advised. PMID- 23917443 TI - The retinal nerve fiber layer of patients with neuromyelitis optica and chronic relapsing optic neuritis is more severely damaged than patients with multiple sclerosis. AB - BACKGROUND: To compare the retinal nerve fiber layer (RNFL) in eyes of patients with relapsing remitting multiple sclerosis (RRMS), neuromyelitis optica (NMO) and chronic relapsing inflammatory optic neuritis (CRION). METHODS: Evaluation of 62 patients with RRMS, NMO, and CRION in a cross-sectional study with spectral domain optical coherence tomography. RESULTS: A total of 124 eyes were evaluated (96 RRMS, 18 NMO, and 10 CRION). Frequency of optic neuritis for each disease was: 34% for RRMS, 84% for NMO, and 100% for CRION. Visual acuity and RNFL thickness were significantly worse in NMO and CRION eyes than in RRMS, but there were no differences between NMO and CRION eyes. A RNFL of 41 MUm was 100% specific for optic neuritis associated with NMO and CRION when compared to RRMS. CONCLUSION: This study established RNFL values to differentiate optic neuritis of RRMS from NMO and CRION. Although similarities observed between NMO and CRION eyes might suggest that they are within the same disease spectrum, it is still recommended that these 2 conditions be differentiated on clinical grounds. Optical coherence tomography serves as an additional diagnostic tool and can be used to monitor disease progression. PMID- 23917442 TI - Influence of ambient air pollution on global DNA methylation in healthy adults: a seasonal follow-up. AB - BACKGROUND: DNA methylation changes are potential pathways of environmentally induced health effects. We investigated whether exposure to ambient concentrations of NO2, PM10, PM2.5 and O3 and traffic parameters were associated with global DNA methylation in blood of healthy adults. METHODS: 48 non-smoking adults (25 males) with a median age of 39years were sampled in winter and summer. Global DNA methylation in whole blood (% 5-methyl-2'-deoxycytidine, %5mdC) was analyzed with HPLC. Exposure to air pollutants at the home address was assessed using interpolated NO2, PM10, PM2.5 and O3 concentrations for various exposure windows (60- to 1-day moving average exposures and yearly averages) and GIS-based traffic parameters. Associations between pollutants and %5mdC were tested with multiple mixed effects regression models. RESULTS: Average %5mdC (SD) was 4.30 (0.08) in winter and 4.29 (0.08) in summer. Men had higher %5mdC compared to women both in winter (4.32 vs. 4.26) and summer (4.31 vs. 4.27). When winter and summer data were analyzed together, various NO2, PM10 and PM2.5 moving average exposures were associated with changes in %5mdC (95% CI) ranging from -0.04 ( 0.09 to 0.00) to -0.14 (-0.28 to 0.00) per IQR increase in pollutant. NO2, PM10, PM2.5 and O3 moving average exposures were associated with decreased %5mdC (95% CI) varying between -0.01 (-0.03 to 0.00) and -0.17 (-0.27 to -0.06) per IQR increase in pollutant in summer but not in winter. CONCLUSION: Decreased global DNA methylation in whole blood was associated with exposure to NO2, PM10, PM2.5 and O3 at the home addresses of non- adults. Most effects were observed for the 5 to 30-day moving average exposures. PMID- 23917444 TI - Bloating and distention in irritable bowel syndrome: the role of gas production and visceral sensation after lactose ingestion in a population with lactase deficiency. AB - OBJECTIVES: Bloating and distention are often attributed to dietary factors by patients with irritable bowel syndrome (IBS). This study examined the effects of gas production and visceral hypersensitivity on digestive symptoms after lactose ingestion in a population with lactase deficiency. METHODS: IBS patients (n=277) and healthy controls (HCs, n=64) underwent a 20-g lactose hydrogen breath test (LHBT) with evaluation of hydrogen gas production and lactose intolerance (LI) symptoms. Abdominal distention (199 IBS, 40 HCs) was measured during LHBT. Rectal sensitivity (74 IBS, 64 HCs) was assessed by barostat studies. RESULTS: Hydrogen production and distention were similar in IBS patients and HCs during LHBT; however, LI was more frequent in IBS (53.8 vs. 28.1%, P<0.001), especially bloating (39.0% vs. 14.1%, P<0.001) and borborygmi (39.0 vs. 21.9%, P=0.010). Only 59.0% of patients with bloating had distention. No correlation was observed between girth increment and bloating (P=0.585). IBS patients had lower rectal sensory thresholds (P=0.001). Multivariate analysis indicated that hydrogen production increased bloating (odds ratio (OR) 2.19, 95% confidence interval (CI) 1.09-4.39, P=0.028) and borborygmi (OR 12.37, 95% CI 3.34-45.83, P<0.001) but not distention (P=0.673). Visceral hypersensitivity was associated with bloating (OR 6.61, 95% CI 1.75-25.00, P=0.005) and total symptom score (OR 3.78, 95% CI 1.30 10.99, P=0.014). CONCLUSIONS: Gas production and visceral hypersensitivity both contribute to digestive symptoms, especially bloating and borborygmi, in IBS patients after lactose ingestion. Objective abdominal distention is not correlated with subjective bloating. PMID- 23917447 TI - Anti-obesity effect of Lactobacillus gasseri SBT2055 accompanied by inhibition of pro-inflammatory gene expression in the visceral adipose tissue in diet-induced obese mice. AB - PURPOSE: Probiotic Lactobacillus gasseri SBT2055 (LG2055) has an anti-obesity effect although it is unknown whether the effect influences inflammatory responses in adipose tissue and lipid metabolism in the liver, which are considered substantially relevant to adiposity. METHODS: C57BL/6 mice were fed a 10%-fat diet containing LG2055 cells for 24 weeks. We then studied body weight, fat tissue mass, liver fat content and inflammatory genes in the adipose tissue, and lipogenic and lipolytic genes in the liver. RESULTS: Consumption of LG2055 resulted in a significant reduction in body weight and fat tissue mass (epididymal and perirenal/retroperitoneal), with a lowered level of triglyceride content in the liver. DNA microarray analysis showed that LG2055 generally inhibited the up-regulation of pro-inflammatory genes, including CCL2 and CCR2, in the epididymal adipose tissue. In the liver, LG2055 tended to inhibit lipogenic gene up-regulation, including ACC1, FAS and SREBP1, but LG2055 did not markedly alter lipolytic genes. Real-time PCR analysis confirmed the DNA microarray results in part, showing a significant reduction in the mRNA expression of CCL2 in the epididymal adipose tissue, and a downward tendency in FAS mRNA expression in the liver, in the LG2055-fed group. CONCLUSIONS: LG2055 significantly prevented body weight gain, fat accumulation and pro-inflammatory gene expression in the adipose tissue. Relatively lower triglyceride levels and reduced expression of lipogenic genes were also observed in the liver. It is suggested that improvement in the inflammatory state of the adipose tissue might be a possible mechanism underlying the anti-obesity effect of LG2055. PMID- 23917448 TI - Comparison of blood pressure levels among children and adolescents with different body mass index and waist circumference: study in a large sample in Shandong, China. AB - PURPOSE: Several anthropometric indicators [such as body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR)] have been used to investigate the association between adiposity and high blood pressure (BP) in both adults and children. The present study compared the BP levels among children and adolescents with different BMI and WC in a large population in Shandong, China. METHODS: A total of 38,822 students (19,456 boys and 19,366 girls) aged 7 17 years participated in this study. Height, weight, WC, and BP of all subjects were measured, and BMI was calculated. The prevalence of overweight and obesity was obtained according to the International Obesity Task Force (IOTF) cutoffs; central obesity was defined as WC >= 90th percentile (P 90); relatively high BP status was defined as systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) >= 95th percentile for age and gender. RESULTS: Within each BMI categories (normal weight, overweight, and obesity), children and adolescents with WC >= P 90 had higher BP levels than those with WC < P 90 (p < 0.01). When BMI and WC were combined, the highest and lowest prevalences of relatively high BP were noted in obese with WC >= P 90 group (54.52% for boys and 48.71% for girls) and normal weight with WC < P 90 group (17.00% for boys and 14.13% for girls). CONCLUSION: Children and adolescents with high BMI and high WC might have an increased risk of elevated BP. Our results suggest that the additional measurement of WC is better than BMI alone to help identify high BP risks. PMID- 23917449 TI - Estimated dietary intakes and sources of flavanols in the German population (German National Nutrition Survey II). AB - BACKGROUND/OBJECTIVES: Data from intervention studies suggest a beneficial effect of flavanols on vascular health. However, insufficient data on their intake have delayed the assessment of their health benefits. The aim of this study was to estimate intake of flavanols and their main sources among people living in Germany. SUBJECTS/METHODS: Data from diet history interviews of the German National Nutrition Survey II for 15,371 people across Germany aged 14-80 years were analyzed. The FLAVIOLA Flavanol Food Composition Database was compiled using the latest US Department of Agriculture and Phenol-Explorer Databases and expanded to include recipes and retention factors. RESULTS: Mean intake of total flavanols, flavan-3-ol monomers, proanthocyanidins (PA), and theaflavins in Germany was 386, 120, 196, and 70 mg/day, respectively. Women had higher intakes of total flavanols (399 mg/day) than men (372 mg/day) in all age groups, with the exception of the elderly. Similar results were observed for monomers (108 mg/day for men, 131 mg/day for women) and PA (190 mg/day; 203 mg/day), although intake of theaflavins was higher in men (74 mg/day; 66 mg/day). There was an age gradient with an increase in total flavanols, monomers, and theaflavins across the age groups. The major contributor of total flavanols in all subjects was pome fruits (27%) followed by black tea (25%). CONCLUSIONS: This study demonstrated age- and sex-related variations in the intake and sources of dietary flavanols in Germany. The current analysis will provide a valuable tool in clarifying and confirming the potential health benefits of flavanols. PMID- 23917450 TI - Substantial practice variation exists in the management of childhood nephrotic syndrome. AB - BACKGROUND: Practice variation is common for nephrotic syndrome (NS) treatment. METHODS: A cross-sectional, web-based survey on NS treatment was administered to 58 Canadian pediatric nephrologists with the aim to document existing practice variation and compare practice with the recommendations of the Kidney Disease Improving Global Outcomes Clinical Practice Guideline for NS. RESULTS: Of the 58 nephrologists asked to participate in the survey, 40 (69 %) responded. Among these, 62 % prescribed initial daily glucocorticoid (GC) therapy for 6 weeks, 26 % for 4 weeks by 26 %, and 10 % prescribed 'other'. Alternate-day GC was continued for 6 weeks by 63 % of respondents and for >6 and <6 weeks by 32 and 6 %, respectively. For biopsy-confirmed minimal change disease, 65 and 46 % of respondents chose oral cyclophosphamide for frequently relapsing and steroid dependent phenotypes, respectively; calcineurin inhibitors or mycophenolate were the second most popular choices. Kidney biopsy was 'always' performed by 16, 39, and 97 % of respondents for frequently relapsing, steroid-dependent, and steroid resistant patients, respectively. Rituximab had been administered by 60 % of respondents; 22, 56, and 72 % reported that they would consider rituximab for frequently relapsing, steroid-dependent, and steroid-resistant patients, respectively. Most notable differences between practice and Guideline recommendations were first presentation GC duration, GC-sparing agent choices in frequently relapsing and steroid-dependent patients, and biopsy practices. CONCLUSIONS: There is substantial Canadian practice variation in NS treatment. Assessment of factors driving variation and strategies to implement Guideline recommendations are needed. PMID- 23917451 TI - Recovery of native erythropoietin in a patient with erythropoietin-associated pure red cell aplasia. PMID- 23917452 TI - Quantum transport enhancement by time-reversal symmetry breaking. AB - Quantum mechanics still provides new unexpected effects when considering the transport of energy and information. Models of continuous time quantum walks, which implicitly use time-reversal symmetric Hamiltonians, have been intensely used to investigate the effectiveness of transport. Here we show how breaking time-reversal symmetry of the unitary dynamics in this model can enable directional control, enhancement, and suppression of quantum transport. Examples ranging from exciton transport to complex networks are presented. This opens new prospects for more efficient methods to transport energy and information. PMID- 23917453 TI - Age at diagnosis may trump family history in driving BRCA testing in a population of breast cancer patients. AB - BACKGROUND: Standard BRCA genetic testing criteria include young age of diagnosis, family history, and Jewish ancestry. The purpose of this study was to assess the effect of these criteria on BRCA test utilization in breast cancer patients. METHODS: Breast cancer patients aged 18 to 64 years living in Pennsylvania in 2007 completed a survey on family history of breast and ovarian cancer and BRCA testing (N = 2,213). Multivariate logistic regression was used to estimate odds of BRCA testing by patient characteristics, and predicted probabilities of testing were calculated for several clinical scenarios. RESULTS: Young age at diagnosis (<50 years) was strongly associated with BRCA testing, with women diagnosed before age 50 years having nearly five times the odds of receiving BRCA testing compared to women diagnosed at age 50 or older (OR = 4.81; 95% CI, 3.85-6.00; P < 0.001). Despite a similar BRCA mutation prevalence estimate (8-10%), a young Jewish patient <50 years with no family history had markedly higher predicted probability of testing (63%) compared with an older, non-Jewish breast cancer patient with more than one first-degree relative (43%). CONCLUSION: Age at diagnosis, Jewish ancestry, and both maternal and paternal family history are strongly predictive of BRCA testing. However, among women diagnosed at age 50 or older, family history may be an underused criterion that may benefit from targeted intervention. IMPACT: Robust methods specific to ascertaining detailed family history, such as through electronic medical records, are needed to accurately identify patients for BRCA testing. PMID- 23917454 TI - Molecular signatures of epithelial ovarian cancer: analysis of associations with tumor characteristics and epidemiologic risk factors. AB - BACKGROUND: Six gene expression subtypes of invasive epithelial ovarian cancer were recently defined using microarrays by Tothill and colleagues. The Cancer Genome Atlas (TCGA) project subsequently replicated these subtypes and identified a signature predictive of survival in high-grade serous (HGS) cancers. We previously validated these signatures for use in formalin-fixed paraffin-embedded tissues. The aim of the present study was to determine whether these signatures are associated with specific ovarian cancer risk factors, which would add to the evidence that they reflect the heterogeneous etiology of this disease. METHODS: We modeled signature-specific tumor characteristics and epidemiologic risk factor relationships using multiple regression and multivariate response multiple regression models in 193 patients from a case-control study of epithelial ovarian cancer. RESULTS: We observed associations between the Tothill gene expression subtype signatures and both age at diagnosis (P = 0.0008) and race (P = 0.008). Although most established epidemiologic risk factors were not associated with molecular signatures, there was an association between breast feeding (P = 0.024) and first-degree family history of breast or ovarian cancer (P = 0.034) among the 106 HGS cases. Some of the above associations were validated using gene expression microarray data from the TCGA project. Weak associations were seen with age at menarche and duration of oral contraceptive use and the TCGA survival signature. CONCLUSIONS: These data support the potential for genomic characterization to elucidate the etiologic heterogeneity of epithelial ovarian cancer. IMPACT: This study suggests that molecular signatures may augment the ability to define etiologic subtypes of epithelial ovarian cancer. PMID- 23917456 TI - P2Y12 platelet receptors: importance in percutaneous coronary intervention. AB - Apart from their role in hemostasis and thrombosis, platelets are involved in many other biological processes such as wound healing and angiogenesis. Percutaneous coronary intervention is a highly thrombogenic procedure inducing platelets and monocytes activation through endothelial trauma and contact activation by intravascular devices. Platelet P2Y12 receptor activation by adenosine diphosphate facilitates non-ADP agonist-mediated platelet aggregation, dense granule secretion, procoagulant activity, and the phosphorylation of several intraplatelet proteins, making it an ideal drug target. However, not all compounds that target the P2Y12 receptor have similar efficacy and safety profiles. Despite targeting the same receptor, the unique pharmacologic properties of each of these P2Y12 receptor-directed compounds can lead to very different clinical effects. PMID- 23917455 TI - Specialty supplement use and biologic measures of oxidative stress and DNA damage. AB - BACKGROUND: Oxidative stress and resulting cellular damage have been suggested to play a role in the etiology of several chronic diseases, including cancer and cardiovascular disease. Identifying factors associated with reduced oxidative stress and resulting damage may guide future disease-prevention strategies. METHODS: In the VITamins And Lifestyle (VITAL) biomarker study of 209 persons living in the Seattle area, we examined the association between current use of several specialty supplements and oxidative stress, DNA damage, and DNA repair capacity. Use of glucosamine, chondroitin, fish oil, methylsulfonylmethane (MSM), coenzyme Q10 (CoQ10), ginseng, ginkgo, and saw palmetto was ascertained by a supplement inventory/interview, whereas the use of fiber supplements was ascertained by questionnaire. Supplements used by more than 30 persons (glucosamine and chondroitin) were evaluated as the trend across number of pills/week (non-use, <14 pills/week, 14+ pills/week), whereas less commonly used supplements were evaluated as use/non-use. Oxidative stress was measured by urinary 8-isoprostane and PGF2alpha concentrations using enzyme immunoassays (EIA), whereas lymphocyte DNA damage and DNA repair capacity were measured using the Comet assay. Multivariate-adjusted linear regression was used to model the associations between supplement use and oxidative stress/DNA damage. RESULTS: Use of glucosamine (Ptrend: 0.01), chondroitin (Ptrend: 0.003), and fiber supplements (P: 0.01) was associated with reduced PGF2alpha concentrations, whereas CoQ10 supplementation was associated with reduced baseline DNA damage (P: 0.003). CONCLUSIONS: Use of certain specialty supplements may be associated with reduced oxidative stress and DNA damage. IMPACT: Further research is needed to evaluate the association between specialty supplement use and markers of oxidative stress and DNA damage. PMID- 23917458 TI - The effect of tranexamic acid on hemoglobin levels during total knee arthroplasty. AB - The aim of this study was to evaluate the efficacy of perioperative administration of 1,4-amino-carboxylic acid (tranexamic acid) in reducing the intraoperative and postoperative blood loss in patients undergoing total knee replacement (TKR). Tranexamic acid is an antifibrinolytic agent that is 7-10 times as potent as epsilon aminocaproic acid. We had investigated the effect of tranexamic acid on blood loss intraoperatively and postoperatively during and after TKR thereby significantly preventing a decrease in postop Hb in these patients. This study was a randomized, prospective, observational, double-blinded study on 99 patients, after obtaining ethical committee approval and valid informed consent from patients to be part of the study. In the study group, the drug was administered in 2 doses 1 hour preoperatively and 6 hours postoperatively. The use of tranexamic acid injection in TKR surgeries can be considered as an effective method to control and minimize the blood loss during total knee arthroplasty surgeries. PMID- 23917457 TI - Effect of beta-carotene on oxidative stress and expression of cardiac connexin 43. AB - BACKGROUND: Intervention studies have shown an increased mortality in patients who received beta-carotene. However, the mechanisms involved in this phenomenon are still unknown. OBJECTIVE: Evaluate the influence of beta-carotene on oxidative stress and the expression of connexin 43 in rat hearts. METHODS: Wistar rats, weighing approximately 100 g, were allocated in two groups: CONTROL GROUP (n=30), that received the diet routinely used in our laboratory, and Beta Carotene Group (n = 28), which received beta-carotene (in crystal form, added and mixed to the diet) at a dose of 500 mg of beta-carotene/kg of diet. The animals received the treatment until they reached 200-250 g, when they were sacrificed. Samples of blood, liver and heart were collected to perform Western blotting and immunohistochemistry for connexin 43; morphometric studies, dosages of beta carotene by high-performance liquid chromatography as well as reduced glutathione, oxidized glutathione and lipids hydroperoxides were performed by biochemical analysis. RESULTS: Beta-carotene was detected only in the liver of Beta-Carotene Group animals (288 +/- 94.7 ug/kg). Levels of reduced/oxidized glutathione were higher in the liver and heart of Beta-Carotene Group animals (liver - CONTROL GROUP: 42.60 +/- 1.62; liver - Beta-Carotene Group: 57.40 +/- 5.90; p = 0.04; heart: - CONTROL GROUP: 117.40 +/- 1.01; heart - Beta-Carotene Group: 121.81 +/- 1.32 nmol/mg protein; p = 0.03). The content of total connexin 43 was larger in Beta-Carotene Group. CONCLUSION: Beta-carotene demonstrated a positive effect, characterized by the increase of intercellular communication and improvement of anti-oxidizing defense system. In this model, mechanism does not explain the increased mortality rate observed with the beta-carotene supplementation in clinical studies. PMID- 23917459 TI - Effectiveness of probiotic Phaeobacter bacteria grown in biofilters against Vibrio anguillarum infections in the rearing of Turbot (Psetta maxima) larvae. AB - The rearing environment of first-feeding turbot larvae, usually with high larvae densities and organic matter concentrations, may promote the growth of opportunistic pathogenic Vibrionaceae bacteria, compromising the survival of the larvae. The aim of this study was to assess the effectiveness of the biofilm forming probiotic Phaeobacter 27-4 strain grown on a ceramic biofilter (probiofilter) in preventing Vibrio anguillarum infections in turbot larvae. In seawater with added microalgae and maintained under turbot larvae rearing conditions, the probiofilter reduced the total Vibrionaceae count and the concentration of V. anguillarum, which was undetectable after 144 h by real-time PCR. The probiofilter also improved the survival of larvae challenged with V. anguillarum, showing an accumulated mortality similar to that of uninfected larvae (35-40 %) and significantly (p < 0.05) lower than that of infected larvae with no probiofilter (76 %) due to a decrease in the pathogen concentration and in total Vibrionaceae. Furthermore, the probiofilter improved seawater quality by decreasing turbidity. Phaeobacter 27-4 released from the probiofilters was able to survive in the seawater for at least 11 days. The bacterial diversity in the larvae, analysed by denaturing gradient gel electrophoresis, was low, as in the live prey (rotifers), and remained unchanged in the presence of V. anguillarum or the probiofilter; however, the probiofilter reduced the bacterial carrying capacity of the seawater in the tanks. Phaeobacter-grown biofilters can constantly inoculate probiotics into rearing tanks and are therefore potentially useful for bacterial control in both open and recirculating industrial units. PMID- 23917460 TI - A cytochrome P450 phenotyping cocktail causing unexpected adverse reactions in female volunteers. AB - BACKGROUND: A four-drug cytochrome P450 (CYP) phenotyping cocktail was developed to rapidly and safely determine CYP2D6, CYP2C19, CYP2C9 and CYP1A2 enzyme activity and phenotype. METHODS: The cocktail consisted of the single CYP phenotyping probes of 50 mg tramadol (CYP2D6), 20 mg omeprazole (CYP2C19), 25 mg losartan (CYP2C9) and 200 mg caffeine (CYP1A2) and was administered as a single oral dose. For enzyme activity measurements, urine was collected as 8 h post administration and blood was sampled at 4 h. The enzyme activity was determined by metabolic ratios of molar concentrations of the drugs and their enzyme catalyzed metabolites and was correlated to the relevant genotypes. RESULTS: In a pilot study in 12 healthy male volunteers the CYP genotype-phenotype correlation and robustness of the cocktail was successfully determined without detection of any adverse drug reactions. In the subsequent population study, four female volunteers experienced unexpected and unacceptable moderate and severe adverse reactions (ARs) of headache, dizziness, nausea, vomiting, blue fingers, nails and lips and difficulties in urinating, which led to the study being prematurely terminated after inclusion of only 22 subjects (15 males, 7 females) [corrected]. CONCLUSION: Attention must be paid to adverse reactions when designing new combinations of phenotype cocktails regardless of the doses and drugs involved. We specifically warn against the combination of tramadol, omeprazole, losartan and caffeine. PMID- 23917461 TI - NSAIDs and nephrocalcinosis. PMID- 23917462 TI - Scalable graphene field-effect sensors for specific protein detection. AB - We demonstrate that micron-scale graphene field-effect transistor biosensors can be fabricated in a scalable fashion from large-area chemical vapor deposition derived graphene. We electrically detect the real-time binding and unbinding of a protein biomarker, thrombin, to and from aptamer-coated graphene surfaces. Our sensors have low background noise and high transconductance, comparable to exfoliated graphene devices. The devices are reusable and have a shelf-life greater than one week. PMID- 23917464 TI - Heart failure: Heart failure clinical trials: how do we define success? PMID- 23917463 TI - Ultrastructural pathological changes in the cochlear cells of connexin 26 conditional knockout mice. AB - Mutations in the gene of connexin 26 (Cx26) are the most common cause of human non-syndromic hereditary deafness. The pathogenesis of deafness caused by Cx26 remains uncertain. To explore the basic mechanism underlying Cx26 null mutations, ultrastructural changes and a number of marker proteins in the cochlear sensory epithelium of Cx26 conditional knockout mice were observed in the current study. Cochlear specimens were obtained from Cx26 conditional knockout mice (cCx26ko), while wild-type mice served as controls. Antibodies against the pillar cell marker P75, the supporting cell marker prox1 and hair cell markers myosin 6 and phalloidin were labeled in different cells of the cochlear sensory epithelium of cochlear cryosections. The ultrastructural morphology of cochlear sensory epithelium was observed using transmission electron microscopy. Following the observation of cochlear sensory epithelium cell markers for hair cells and supporting cells, no significant changes were observed at the early stage, while the tunnel of the organ of Corti and Nuel's space was not developed prior to hearing onset in cCx26 knockout mice. Cell death was observed from postnatal day 10 (P10). The only region of surviving cells observed in the cochlea was the Hensen cell region, where microglia-like cells appeared following P180. Overall, the present study showed an abnormal ultrastructural morphology in the cochlear sensory epithelium in cCx26ko mice. Microglia-like cells may be involved in the process of cell degeneration in cCx26ko mice. PMID- 23917465 TI - Arrhythmias: AF pacing in sick sinus syndrome. PMID- 23917466 TI - Coronary artery disease: Variation in ischaemic heart disease between EU countries. PMID- 23917467 TI - Cardiac resuscitation: A new gold-standard medical therapy for CPR in patients with in-hospital cardiac arrest? PMID- 23917468 TI - Atherosclerosis: Addition of niacin to optimal statin therapy does not affect plaque regression. PMID- 23917469 TI - Are endosomal trafficking parameters better targets for improving mAb pharmacokinetics than FcRn binding affinity? AB - F.W.R. Brambell deduced the existence of a protective receptor for IgG, the neonatal Fc receptor (FcRn), long before its discovery in the early to mid-1990s. With the coincident, explosive development of IgG-based drugs, FcRn became a popular target for tuning the pharmacokinetics of monoclonal antibodies (mAbs). One aspect of Brambell's initial observation, however, that is seldom discussed since the discovery of the receptor, is the compliance in the mechanism that Brambell observed (saturating at 10s-100s of MUM concentration), vs. the comparative stiffness of the receptor kinetics (saturating in the nM range for most species). Although some studies reported that increasing the already very high Fc-FcRn affinity at pH 6.0 further improved mAb half-life, in fact the results were mixed, with later studies increasingly implicating non-FcRn dependent mechanisms as determinants of mAb pharmacokinetics. Mathematical modelling of the FcRn system has also indicated that the processes determining the pharmacokinetics of mAbs have more nuances than had at first been hypothesised. We propose, in keeping with the latest modelling and experimental evidence reviewed here, that the dynamics of endosomal sorting and trafficking have important roles in the compliant salvage mechanism that Brambell first observed nearly 50 years ago, and therefore also in the pharmacokinetics of mAbs. These ideas lead to many open questions regarding the endosomal trafficking of both FcRn and mAbs and also to what properties of a mAb can be altered to achieve an improvement in pharmacokinetics. PMID- 23917470 TI - Increasing running step rate reduces patellofemoral joint forces. AB - PURPOSE: Increasing step rate has been shown to elicit changes in joint kinematics and kinetics during running, and it has been suggested as a possible rehabilitation strategy for runners with patellofemoral pain. The purpose of this study was to determine how altering step rate affects internal muscle forces and patellofemoral joint loads, and then to determine what kinematic and kinetic factors best predict changes in joint loading. METHODS: We recorded whole body kinematics of 30 healthy adults running on an instrumented treadmill at three step rate conditions (90%, 100%, and 110% of preferred step rate). We then used a 3-D lower extremity musculoskeletal model to estimate muscle, patellar tendon, and patellofemoral joint forces throughout the running gait cycles. In addition, linear regression analysis allowed us to ascertain the relative influence of limb posture and external loads on patellofemoral joint force. RESULTS: Increasing step rate to 110% of the preferred reduced peak patellofemoral joint force by 14%. Peak muscle forces were also altered as a result of the increased step rate with hip, knee, and ankle extensor forces, and hip abductor forces all reduced in midstance. Compared with the 90% step rate condition, there was a concomitant increase in peak rectus femoris and hamstring loads during early and late swing, respectively, at higher step rates. Peak stance phase knee flexion decreased with increasing step rate and was found to be the most important predictor of the reduction in patellofemoral joint loading. CONCLUSION: Increasing step rate is an effective strategy to reduce patellofemoral joint forces and could be effective in modulating biomechanical factors that can contribute to patellofemoral pain. PMID- 23917471 TI - Hemodynamic response to upright resistance exercise: effect of load and repetition. AB - INTRODUCTION/PURPOSE: Upright resistance exercise causes large transient fluctuations in blood pressure during and immediately after the performance. We examined the effect of resistance load and the number of repetitions on the middle cerebral artery blood flow velocity (MCAv) response during and after upright squatting exercise. METHODS: Healthy males (n = 12; mean +/- SD: 26 +/- 5 yr) completed 30%, 60%, and 90% of their six-repetition maximum load, completing two and six repetitions of these loads during two visits (order randomized). Beat to-beat MCAv, blood pressure, and continuous end-tidal PCO2 during exercise, at nadir, and during recovery are reported as the change from preexercise standing baseline. RESULTS: During exercise, MCAvmean increased 31% +/- 16% (P < 0.001) across all loads (P = 0.74) and repetitions (P = 0.89), whereas mean arterial pressure (MAP) increased (all P < 0.05) as load and repetitions increased (e.g., 122 +/- 9 (two repetitions) vs 135 +/- 11 mm Hg (six repetitions) and 128 +/- 13 vs 143 +/- 14 mm Hg, at 30% and 60%, respectively). Within the six-repetition sets, peak MCAvmean remained unchanged across the set (P = 0.61), whereas MAP increased (P = 0.003). The 90% load produced the lowest MCAvmean nadir (pooled means, -18 +/- 6 vs -10 +/- 7 cm.s, P < 0.001 vs 30%) and MAP nadir (-34 +/- 7 and -43 +/- 5 mm Hg, for two and six repetitions, respectively; P < 0.001) after exercise. Postexercise MCAvmean reductions occurred via a selective, load dependent (P < 0.001) decrease in diastolic MCAv. MCAvmean remained below baseline for the longest period after the 90% six-repetition set (10 s postexercise, P < 0.01) and took the longest to recover (14.8 +/- 6.9 s, P = 0.002). CONCLUSION: These data indicate that higher relative loads produce a greater postexercise hypotension and result in a proportionate reduction in MCAvmean. PMID- 23917472 TI - Altered stride length in response to increasing exertion among baseball pitchers. AB - BACKGROUND: Overexertion caused by increased pitch counts can evoke protective biomechanical responses signified by decreased ball velocity, such as reduced throwing arm kinematics and kinetics. Among skilled pitchers, overexertion may not always present ball velocity decrements, because compensatory throwing biomechanics aid in maintaining peak ball velocity although lowering physiologic stress. METHODS: Nineteen pitchers (collegiate and elite high school), randomly crossed over to pitch two simulated games at +/- 25% of their desired stride length, were recorded by an eight-camera motion capture system (240 Hz) integrated with two piezoelectric force plates (960 Hz) and a professional model radar gun. HR, self-reported exertion scores, blood glucose and lactate, salivary biomarkers, peak linear hand and fastball velocities were examined. Repeated measures ANOVA as well as independent and pairwise t-tests examined significant differences (P <= 0.05). RESULTS: Shortened strides reduced mean pitching HR by 11.1 bpm (P < 0.001), improved recovery capacity by 5.76% (P = 0.012), and lowered salivary cortisol from baseline (P = 0.001). Physiologic stress elevated with greater strides, because salivary alpha amylase was significantly elevated from baseline (P = 0.011) with no improvements evidenced in pitching HR or recovery capacity. Linear hand and ball velocities remained equivalent between stride conditions. CONCLUSION: Stride length can affect physical exertion without disrupting ball velocity, where shortening strides can plausibly respond to competitive exertion in baseball pitchers. Current pitch count standards and radar velocity accounts have not been proven efficacious in predicting exertion in professional and collegiate baseball, where biomechanical compensations arise to maintain ball velocity. In some instances, compensatory adaptations may be pathomechanic where future research identifying injurious movement patterns can advance injury prevention in professional baseball. PMID- 23917473 TI - Prospects for rapid advances in the development of new medicines for special medical needs. AB - Broadly speaking, the goals of the US Food and Drug Administration (FDA) special designation programs--orphan, priority review, accelerated approval, and fast track--have been to expedite and sustain development and facilitate authorization of new medicines for unmet medical needs through so-called "push-pull" incentives. Although generally successful over time, their success has been confined to certain therapeutic areas and, within those areas, certain diseases. Times have changed. The research and development (R&D) burdens and public health urgency that acted as an impetus for the FDA to intervene more actively for certain disease areas are now broadly experienced across many disease areas. This betokens the need for the FDA to make designation and implementation decisions with a view that reaches beyond the immediate horizons of political expediency and patient advocacy to encompass the broader expanse of factors that now influence R&D decisions--global competitiveness, the needs of investors, emerging sponsors, and patient-focused drug development. PMID- 23917474 TI - Journal impact factor: the debate continues. PMID- 23917475 TI - Comparison study of two commercially available methods for the determination of infliximab, adalimumab, etanercept and anti-drug antibody levels. PMID- 23917476 TI - Monthly use of a real-time continuous glucose monitoring system as an educational and motivational tool for poorly controlled type 1 diabetes adolescents. AB - PURPOSE: Experience with the use of real-time continuous glucose monitoring systems (RT-CGMS) in teenagers with type 1 diabetes mellitus (T1DM) is limited. We aimed to assess the possibility of glycaemic control improvement and to characterize the group of adolescents, who may gain long-term benefits from the use of the RT-CGMS. METHODS: Forty T1DM patients, aged 14.6 +/- 2.1 years, with diabetes duration 7.4 +/- 3.6 years and initial HbA1c 9.3 +/- 1.5% were recruited. The analysis was based on one-month glucose sensors use, combined with the thorough family support. Patients were analysed in groups according to baseline HbA1c: below and above 7.5%, and 10.0%. Comparison between patients with or without improvement in HbA1c after 3-month follow-up was also performed. Patients' satisfaction based on the questionnaire was assessed. RESULTS: HbA1c level in entire study group decreased after three months, from 9.3 +/- 1.0% to 8.8 +/- 1.6% (P<0.001). In the group with HbA1c improvement, reduction was the highest: 9.0 +/- 1.3% vs. 8.0 +/- 1.2% (P<0.001). Only the group with initial HbA1c>10% did not achieve significant improvement: 11.2 +/- 0.5% vs. 10.9 +/- 1.1 (P=0.06). In satisfaction questionnaire the lowest scores (negative opinion) were reported by group of patients with initial HbA1c above 10%, while the highest scores (positive opinion) were found in the group with improvement of HbA1c after 3 month follow-up. CONCLUSION: Short-term use of CGMS RT, united with satisfaction questionnaire, performed in poorly controlled teenagers with T1DM, can be useful in defining the group of young patients, who can benefit from long term CGMS RT use in metabolic control improvement. PMID- 23917477 TI - Latent conditional individual-level models for infectious disease modeling. AB - Individual-level models (ILMs) have previously been used to model the spatiotemporal spread of infectious diseases. These models can incorporate individual-level covariate information, to account for population heterogeneity. However, incomplete or unreliable data are a common problem in infectious disease modeling, and models that are explicitly dependent on such information may not be robust to these inherent uncertainties. In this investigation, we assess an adaptation to a spatial ILM that incorporates a latent grouping structure based on some trait heterogeneous in the population. The resulting latent conditional ILM is then only dependent upon a discrete latent grouping variable, rather than precise covariate information. The posterior predictive ability of this proposed model is tested through a simulation study, in which the model is fitted to epidemic data simulated from a true model that utilizes explicit covariate information. In addition, the posterior predictive ability of the proposed ILM is also compared to that of an ILM that assumes population homogeneity. The application of these models to data from the 2001 UK foot-and-mouth disease epidemic is also explored. This study demonstrates that the use of a discrete latent grouping variable can be an effective alternative to utilizing covariate information, particularly when such information may be unreliable. PMID- 23917481 TI - Generation of organized anterior foregut epithelia from pluripotent stem cells using small molecules. AB - Anterior foregut endoderm (AFE) gives rise to therapeutically relevant cell types in tissues such as the esophagus, salivary glands, lung, thymus, parathyroid and thyroid. Despite its importance, reports describing the generation of AFE from pluripotent stem cells (PSCs) by directed differentiation have mainly focused on the Nkx2.1(+) lung and thyroid lineages. Here, we describe a novel protocol to derive a subdomain of AFE, identified by expression of Pax9, from PSCs using small molecules and defined media conditions. We generated a reporter PSC line for isolation and characterization of Pax9(+) AFE cells, which when transplanted in vivo, can form several distinct complex AFE-derived epithelia, including mucosal glands and stratified squamous epithelium. Finally, we show that the directed differentiation protocol can be used to generate AFE from human PSCs. Thus, this work both broadens the range of PSC-derived AFE tissues and creates a platform enabling the study of AFE disorders. PMID- 23917482 TI - Inoperable isolated cardiac hydatid cyst controlled with albendazole in an older adult with dementia. AB - Hydatid cyst, a human parasitic disease, remains a clinical problem in undeveloped and developing countries. Although liver and lungs are regular sites of infection, rarely other organs such as the heart can be involved. Herein, we report an isolated cardiac hydatid cyst in an 87-year-old man. He had a history of dementia for 5 years and no history for cardiac or pulmonary disease. He presented with exertional dyspnoea which continued up to 6 months. The diagnosis was made by echocardiography and computed tomography (CT). The patient was inoperable and was treated with albendazole 10 mg/kg for 6 months. After a 6 month follow-up, echocardiography revealed reduction in the size of the cyst. We believe this is the first documented case of cardiac hydatid cyst which regressed with only medical treatment in an older adult with dementia. PMID- 23917483 TI - Cross-national disparities in sex differences in life expectancy with and without frailty. AB - BACKGROUND: with continued ageing, levels of frailty are an increasing concern. Women live longer than men, but how life expectancies (LE) with frailty differ between men and women and whether sex differences are the same for all European countries is unknown. OBJECTIVE: to compare sex differences in LE in phenotypic frailty categories and disability at age >=50 between European countries. DESIGN: the Survey of Health, Ageing and Retirement in Europe (SHARE). SUBJECTS: a total of 50,351 people aged >=50 from SHARE wave 4 (included countries: Austria, Belgium, Czech Republic, Denmark, Estonia, France, Germany, Hungary, Italy, the Netherlands, Poland, Portugal, Slovenia, Spain, Sweden). METHODS: the SHARE Frailty Instrument for Primary Care and the Global Activity Limitation Indicator were combined to define four phenotypic frailty and disability categories: robust, pre-frail, frail and severely limited. LEs with each state by sex and country were calculated using Sullivan's method. RESULTS: at age 70, the LE robust ranged from 4.1 to 10.4 years (men) and 3.0 to 8.9 years (women), LE pre frail from 0.8-3.1 years (men) and 2.2-5.5 years (women), LE frail from 0.1-1.8 years (men) and 0.4-5.5 years (women) and LE with severe activity limitation from 1.9 to 4.4 years (men) and 2.9 to 7.5 years (women). At all ages and both sexes the fewest years were spent frail. CONCLUSIONS: this study is the first to compare differences in LE in frailty categories across European countries. In most European countries, years spent robust (free of frailty or limitation) are significantly less for women than men, perhaps due to socio-economic as well as biological factors. PMID- 23917484 TI - Would you be a geriatrician? Student career preferences and attitudes to a career in geriatric medicine. AB - BACKGROUND: career intentions of medical students may impact on education and workforce planning. We sought to determine (i) career choices of senior medical students; (ii) interest in geriatric medicine; (iii) factors influencing such choices; and (iv) the impact of a 6-week Medicine in the Community module. METHODS: cross-sectional survey of all senior UCD medical students, before and after completion of a 'Medicine in the Community' module, 2009-11. RESULTS: eighty-two per cent (274/336) completed the survey at module's end. Two-thirds (174) had chosen a future speciality, most frequently general practice (32.1%) and internal medicine (17%). Half (49.8%) believed career selection is made during medical school. Thirty-one per cent would consider a career in geriatric medicine; reasons cited were interesting field (34.5%), clinical variety (25%) and perception as emotionally rewarding (20.2%). Commonest deterrents were perceived slowness-of-pace and not wanting to work with older patients. Female students (adjusted OR: 1.89, P = 0.05) and those prioritising travel opportunities (adjusted OR: 2.77, P = 0.01) were more likely to consider geriatric medicine. Half (51.5%) reported that the community medicine module increased their interest in geriatric medicine; 91.3% that it would positively influence how they treated older patients. Students reporting a positive influence of the module were more likely to consider a career in geriatric medicine (OR: 1.62, P = 0.02). CONCLUSION: two-thirds of students had already chosen a future speciality. One-third would consider geriatric medicine. This may have important implications for workforce planning and development of geriatric medicine. Undergraduate exposure to the discipline may increase interest in geriatric medicine as a career, and positively influence management of older patients. PMID- 23917485 TI - Case study of skin temperature and thermal perception in a hot outdoor environment. AB - Focusing on the understanding and the estimation of the biometeorological conditions during summer in outdoor places, a field study was conducted in July 2010 in Athens, Greece over 6 days at three different sites: Syntagma Square, Ermou Street and Flisvos coast. Thermo-physiological measurements of five subjects were carried out from morning to evening for each site, simultaneously with meteorological measurements and subjective assessments of thermal sensation reported by questionnaires. The thermo-physiological variables measured were skin temperature, heat flux and metabolic heat production, while meteorological measurements included air temperature, relative humidity, wind speed, globe temperature, ground surface temperature and global radiation. The possible relation of skin temperature with the meteorological parameters was examined. Theoretical values of mean skin temperature and mean radiant temperature were estimated applying the MENEX model and were compared with the measured values. Two biometeorological indices, thermal sensation (TS) and heat load (HL)-were calculated in order to compare the predicted thermal sensation with the actual thermal vote. The theoretically estimated values of skin temperature were underestimated in relation to the measured values, while the theoretical model of mean radiant temperature was more sensitive to variations of solar radiation compared to the experimental values. TS index underestimated the thermal sensation of the five subjects when their thermal vote was 'hot' or 'very hot' and overestimated thermal sensation in the case of 'neutral'. The HL index predicted with greater accuracy thermal sensation tending to overestimate the thermal sensation of the subjects. PMID- 23917489 TI - Mechanochemistry. PMID- 23917486 TI - Cervical cancer screening service utilisation in UK. AB - This study investigates empirically how past screening behaviour, individual and household characteristics affect the current uptake of cervical cancer screening in UK. For the conceptual framework, we use a modified Grossman model which is extended for non-economic factors. A dynamic version of a random effects panel probit model with initial conditions is estimated on the balanced sub-sample of the data. The analysis sample is restricted to women of age 16 and older and grouped into different age categories with respect to the NHS Cervical Screening Programme (NHSCSP). As dataset a balanced panel data of 857 women with 11,998 observations from the British Household Panel Study (BHPS) for the period from 1992 to 2008 is used for the analysis. Results suggest show that previous screening uptake, age, partner status, employment status and a previous GP visit have a significant influence on the likelihood of the uptake of cervical cancer screening. PMID- 23917487 TI - Identification of a KRAS mutation in a patient with non-small cell lung cancer treated with chemoradiotherapy and panitumumab. AB - RTOG 0839 is a Phase II study of pre-operative chemoradiotherapy with or without panitumumab in potentially operable locally advanced non-small cell lung cancer (NSCLC). The investigational agent, panitumumab, is an anti-epithelial growth factor receptor (EGFR) antibody that improves progression-free survival in chemorefractory metastatic colorectal cancer (mCRC). Recently, both KRAS mutational status (i.e., mutated or not) and subtype (i.e., activating or inactivating) have been shown to be predictive of response to anti-EGFR therapy in mCRC. However, in NSCLC, it is unknown if KRAS mutational status or subtype predict benefit to anti-EGFR therapies because of unique genetic and epigenetic factors unique to each cancer. We present a patient with stage III NSCLC containing a KRAS G12D activating mutation who had a partial pathologic response, with disappearance of a minor KRAS mutant clone. This case suggests possible eradication of the G12D KRAS lung cancer clones by concurrent chemoradiation with panitumumab. PMID- 23917490 TI - Screening and identification of significant genes related to tumor metastasis and PSMA in prostate cancer using microarray analysis. AB - Tumor metastasis is one of the causes for the high mortality rate of prostate cancer (PCa) patients, yet the molecular mechanisms of PCa metastasis are not fully understood. In our previous studies, we found that PSMA suppresses the metastasis of PCa, yet the underlying mechanism remains unknown. To identify the genes related to tumor metastasis possibly regulated by PSMA, we performed tumor metastasis PCR array assay to analyze the differentially expressed tumor metastasis-related genes. Eighty-four tumor metastasis related genes were screened in si-PSMA LNCap cells (PSMA silenced by siRNA)/LNCap cells and in PC 3/LNcap cells, respectively. Expression levels of possible related genes were verified by real-time PCR in 4 prostate cancer cell lines (LNCap, 22RV1, PC-3 and DU145) and in 85 clinical samples (12 normal, 26 benign prostatic hypertrophy and 47 prostate cancer tissues). The results showed that 10 genes (including CDH6 and CXCL12) were upregulated and 4 genes (CCL7, ITGB3, MDM2 and MMP2) were downregulated in the si-PSMA LNCap cells. There were 41 genes significantly upregulated and 15 genes downregulated in PC-3 cells when compared with LNCap cells. Eight common genes were found in both the si-PSMA and PSMA(-) groups. CDH6, MMP3, MTSS1 were further identified as PSMA-related genes in the prostate cancer cell lines and clinical samples, and their expression showed a negative correlation with the stage of prostate cancer (P<0.0001) and PSMA level (P<0.05) in clinical samples, indicating their possible involvement in PSMA-related PCa metastasis regulation. These findings may provide insights into the mechanism involved in the suppression of PCa metastasis by PSMA and its possible interacting proteins, and may provide clues for further exploration of the molecular mechanism of PCa metastasis. PMID- 23917491 TI - Surgical approach to intramyocardial administration of bone marrow stem cells in an animal model. AB - AIM: The aim of the study was to evaluate the surgical approach to intramyocardial (i.m.) injection of Bone Marrow Stem Cells (BMSCs) in a pre clinical model and its complications. MATERIAL OF STUDY: In New Zealand rabbits an ischemia reperfusion injury lasting 20 min was induced by temporary ligation of anterior descending coronary artery during cardiac surgical procedure. Homologous BMSCs were isolated from the posterior iliac crest, cultured and re suspended for injection. BMSC were injected at the peri-infarcted area and side effects were evaluated. A control group with myocardial infarction was treated with i.m. injections of saline, to evaluate possible side effects of injection. Comparison of ventricular premature contractions (VPC), ventricular tachycardia and ventricular fibrillation were recorded during surgery and after 7 and 21 days. RESULTS: Seven rabbits developed intractable ventricular fibrillation during the experimental protocol, three during coronary ligation but before cell injections and four following i.m. injections. At day 7, hourly PVC were more frequent in the groups of animals that received i.m. injections of BMSCs (132 +/- 19 beats) compared to saline injections. (54 +/- 14). CONCLUSIONS: Intramyocardial injections of BMSCs induced an electrical instability as shown by a high number of PVC as compared with intramyocardial injections of saline. PMID- 23917492 TI - Adult congenital heart disease patients undergoing noncardiac surgery and the role of anesthesiologists as perioperative physicians. PMID- 23917493 TI - [The science of the mental present: implications of temporal illusions]. AB - Mental time consists of the mental present, past, and future. In this review, we aimed to elucidate how the brain constructs the mental present, by assessing several temporal illusions that occur within a time frame smaller than one second. We first reviewed the color phi phenomenon and the cutaneous rabbit phenomenon, followed by the flash-lag effect, and finally, reversal of the subjective temporal order due to arm-crossing and saccadic eye movements. After examining the hypotheses that explain each illusion, we proposed that the mental present is constructed in a postdictive manner by combining different aspects of information, such as motion and spatial positions, which are represented over multiple areas in the cerebral cortex. On the basis of the classic time quantum theory and recent findings in neurophysiology and psychology, we further suggest that the mental present is constructed by combining information from one to several periods of -100 ms, each consisting a period of the alpha rhythm in the brain. PMID- 23917494 TI - [The present in the brain]. AB - How is the present represented in the brain? This review introduces several theoretical and experimental issues regarding time perception, with special focus on the human visual system. Specifically, it addresses possible ways through which visual information can be processed to allow for the conscious experience of spatio-temporal local relations, object-based temporal localization, object duration, and mental time. We begin with a brief mention of isomorphism and its limitations, and from there we proceed to discuss low-level mechanisms for timing outer events. The concept of spatiotemporal receptive fields with biphasic temporal impulse response functions is introduced. Neurons with such receptive fields are believed to extract elementary information about spatial and temporal inclinations of light intensity. These visual primitives are later reconstructed in biologically meaningful ways to create each perceptual timeline in the brain. The precise mechanism by which each perceptual timeline is created remains unknown; however, for the purpose of this paper, we refer to it as "context", relative to which novel objects are to be spatiotemporally localized by using various cues. Localization involves estimation, including prediction and "postdiction" from currently available cues. As such, many aspects of the subjective present, such as "perceived timing", "subjective duration", and "mental clock" result from estimation and are thus prone to errors, leading often to time illusion. More than one perceptual timeline can exist and serve as an inner clock for multiple objects, multiple attributes, and even for multiple sensory modalities. Calibration across timelines is also a major issue; our ability to exercise flexible recalibration with short-term training or adaptation using salient time markers is briefly argued before ending the review. PMID- 23917495 TI - [Mechanisms of memory bridging past and present]. AB - The human mind develops through history within the passing of time. Thus, what determines the passing of time in the human mind? For example, when you are asked about yourself 10 years before now, you are able to answer by tracing back through your own experiences. You will be confident of your answer as far as you rely on your memory. Therefore, your personal memory is critical for the passage of time; however, how memory that allows for mental time travel is formed or maintained in the brain is largely unknown. This type of memory may exist only in humans. In this article, we review past studies on memories that emerge from time information in human and experimental animals. PMID- 23917496 TI - [Neural representation of time]. AB - Temporal information is essential for perception and behavior. Although the neural substrates for temporal processing have been elucidated in many different conditions, how individual neurons in each network represent time remains largely unknown. Here we review previous models of time representation in the brain, and propose that these models can be classified into four different groups based on two viewpoints. The first viewpoint is that temporal information is either prospective or retrospective. For example, the online control of movement timing requires prospective or predictive information, whereas the duration discrimination of previously presented stimuli depends on retrospective temporal information. The other viewpoint is whether neuronal coding is based on modulation of the firing rate in each neuron (rate coding) or the occurrence of synchronous activity across multiple neurons (temporal coding). The accumulator model and state-dependence model both represent time by modulating the rate of neuronal firing depending on the elapsed time, thereby providing the prospective and retrospective information, respectively. In contrast, temporal coding is used by the coincidence detection and entrainment/synchronization models acquired through learning. This classification might be helpful for comprehensive understanding of the neuronal mechanisms of temporal processing, each of which is implemented by the intrinsic property of each sensory system and/or by a dedicated network specialized for timing. We also propose a model incorporating serial stages of temporal processing to reproduce a fixed time interval, and suggest that future physiological and pharmacological experiments might prove our hypothesis. PMID- 23917497 TI - [Mental time: a novel approach in neuropsychology]. AB - Abstract Mental time is the cognitive conscious perception of past, present, and future. In this review we examine the novel research field of the neuropsychology of mental time in five ways. First, we review the mental time of amnesic patients. Second, we review reports of "Chronognosia". Third, we review confabulation associated with disturbance of mental time. Fourth, we present a new syndrome of mental time associated with "age awareness". Finally, we review concepts of prospective memory. PMID- 23917498 TI - [The contribution of patient H.M. to modern neuroscience]. AB - In 1953, 27-year-old H.M. underwent bilateral medial temporal lobes resection to control his seizures; however, he suffered from severe amnesia as a result. For the next five decades until his death in December 2008 at the age 82, he was the subject of numerous studies performed by over 100 investigators. The reason why research on H.M. continued for so long is mostly attributed to the efficient organization of excellent researchers. The principal findings of H.M. study encouraged the concept of medial temporal lobe memory system and multiple memory systems, and suggested the slow acquisition of semantic knowledge without medial temporal lobe memory system through repeated experience. By the grace of H.M.'s lifelong contribution, the neuroscience of memory is in full flourish. PMID- 23917499 TI - [Risk taking and the insular cortex]. AB - Risk taking can lead to ruin, but sometimes, it can also provide great success. How does our brain make a decision on whether to take a risk or to play it safe? Recent studies have revealed the neural basis of risky decision making. In this review, we focus on the role of the anterior insular cortex (AIC) in risky decision making. Although human imaging studies have shown activations of the AIC in various gambling tasks, the causal involvement of the AIC in risky decision making was still unclear. Recently, we demonstrated a causality of the AIC in risky decision making by using a pharmacological approach in behaving rats temporary inactivation of the AIC decreased the risk preference in gambling tasks, whereas temporary inactivation of the adjacent orbitofrontal cortex (OFC) increased the risk preference. The latter finding is consistent with a previous finding that patients with damage to the OFC take abnormally risky decisions in the Iowa gambling task. On the basis of these observations, we hypothesize that the intact AIC promotes risk-seeking behavior, and that the AIC and OFC are crucial for balancing the opposing motives of whether to take a risk or avoid it. However, the functional relationship between the AIC and OFC remains unclear. Future combinations of inactivation and electrophysiological studies may promote further understanding of risky decision making. PMID- 23917500 TI - [Social decision-making and theoretical neuroscience: prospects for human sciences and computational psychiatry]. AB - Learning to predict others' minds is critical for social cognition, but the underlying computation and neural mechanisms remains largely unknown. According to theories in social cognition, a simple conception is that humans simulate others' mental processes by directly recruiting one's own process to model others' minds. In this review, we first describe our recent finding and discuss its possible implications. Using human fMRI with model-based analysis on frameworks of reinforcement learning and value-based decision making, we found that simulation involves two hierarchical learning signals: a reward prediction error, generated by simulation of direct recruitment to model others' valuation, and an action prediction error, based on simulation and observation of the other's choices to track others' variability. These findings show that humans can learn to predict others' minds from simulation, using a scaffold of mentalizing signals. Then, we discuss prospects that theoretical neuroscience and computational approaches will play significant roles in understanding human behavior and neural mechanisms, leading to the so-called computational psychiatry as well as synthesis over different disciplines to study human. PMID- 23917501 TI - [Efficacy of intravenous phenobarbital treatment for status epilepticus]. AB - PURPOSE: Intravenous phenobarbital (IV-PB) therapy was launched in Japan in October 2008. We retrospectively investigated its efficacy and tolerability in patients with status epilepticus. METHODS: Forty-three consecutive patients received IV-PB for status epilepticus between June 2009 and April 2011. Among them, 39 patients had underlying diseases, which included acute diseases in 19 patients and chronic conditions in 20 patients. Although 18 patients had been taking antiepileptic drugs (AEDs) before the occurrence of status epilepticus, the blood AED concentrations in 8 patients was below the therapeutic levels. Before the administration of IV-PB, 39 patients were treated with intravenous benzodiazepine, 17 patients were treated with intravenous phenytoin, and 15 patients with intravenous infusion of lidocaine. RESULTS: The initial doses of IV PB ranged from 125 to 1,250 mg (1.9-20.0 mg/kg). Additional doses of IV-PB were required in 12 patients. Seizures were controlled in 35 patients (81%) after IV PB administration. Cessation of status epilepticus was attained in 24 patients after the initial dose and in 11 patients after additional doses. There were no serious adverse effects, although respiratory suppression was observed in 3 patients and drug eruption was observed in 1 patient. CONCLUSION: IV-PB is relatively safe and effective for controlling status epilepticus. If the first dose is not effective, additional doses are required up to the recommended maximum dose. PMID- 23917502 TI - [Radiculopathy in patients with Heerfordt's syndrome: two case presentations and review of the literature]. AB - As a subtype of the clinical presentations associated with sarcoidosis, the combination of uveitis, parotid gland swelling, and facial nerve palsy is known as Heerfordt's syndrome. This syndrome is an extremely rare disorder that has been estimated to affect only 4.1-5.6% of patients with sarcoidosis. We present 2 cases of Heerfordt's syndrome associated with radiculopathy in the trunk. The 2 patients experienced unilateral or bilateral radiculopathy in the trunk and in the trigeminal nerve area associated with Heerfordt's syndrome. Radiculopathy is also a rare manifestation in patients with neurosarcoidosis. A literature review revealed that only 51 cases of radiculopathy associated with sarcoidosis have been documented. A diagnosis of Heerfordt's syndrome was observed in 7 out of these 51 cases. Together with our 2 cases, 9 out of 53 patients with radiculopathy associated with sarcoidosis have been diagnosed as having Heerfordt's syndrome (estimated frequency, 16.9%). In conclusion, radiculopathy is a common neurological manifestation in patients with Heerfordt's syndrome. On the basis of our experience, we suggest that physicians consider the possibility of Heerfordt's syndrome in cases of radiculopathy with unknown cause. PMID- 23917503 TI - Implementing family-based childhood obesity interventions. AB - Family-based interventions have been effective in managing childhood obesity, and pediatric nurse practitioners (PNPs) are positioned to provide obesity interventions in both patient and family primary care settings. The purpose of this article is to guide the PNP in implementing family-based childhood obesity interventions, including identification, diagnostic evaluation, and management. PMID- 23917504 TI - Screening for cystic fibrosis: what every NP should know. AB - In a chronic childhood disease such as cystic fibrosis, it is important for nurse practitioners to be knowledgeable about the disease process, methods of mutation identification, and diagnostic criteria. Multiple studies have shown improved prognosis for patients diagnosed early. PMID- 23917505 TI - Detection of subclinical trastuzumab-induced cardiotoxicity in patients with breast cancer. PMID- 23917506 TI - Cardiac I123-MIBG correlates better than ejection fraction with symptoms severity in systolic heart failure. AB - BACKGROUND: The association of autonomic activation, left ventricular ejection fraction (LVEF) and heart failure functional class is poorly understood. OBJECTIVE: Our aim was to correlate symptom severity with cardiac sympathetic activity, through iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy and with LVEF in systolic heart failure (HF) patients without previous beta-blocker treatment. METHODS: Thirty-one patients with systolic HF, class I to IV of the New York Heart Association (NYHA), without previous beta-blocker treatment, were enrolled and submitted to 123I-MIBG scintigraphy and to radionuclide ventriculography for LVEF determination. The early and delayed heart/mediastinum (H/M) ratio and the washout rate (WR) were performed. RESULTS: According with symptom severity, patients were divided into group A, 13 patients in NYHA class I/II, and group B, 18 patients in NYHA class III/IV. Compared with group B patients, group A had a significantly higher LVEF (25% +/- 12% in group B vs. 32% +/- 7% in group A, p = 0.04). Group B early and delayed H/M ratios were lower than group A ratios (early H/M 1.49 +/- 0.15 vs. 1.64 +/- 0.14, p = 0.02; delayed H/M 1.39 +/- 0.13 vs. 1.58 +/- 0.16, p = 0.001, respectively). WR was significantly higher in group B (36% +/- 17% vs. 30% +/- 12%, p= 0.04). The variable that showed the best correlation with NYHA class was the delayed H/M ratio (r= -0.585; p=0.001), adjusted for age and sex. CONCLUSION: This study showed that cardiac 123I-MIBG correlates better than ejection fraction with symptom severity in systolic heart failure patients without previous beta-blocker treatment. PMID- 23917507 TI - Myocardial infarction area quantification using high-resolution SPECT images in rats. AB - BACKGROUND: Imaging techniques enable in vivo sequential assessment of the morphology and function of animal organs in experimental models. We developed a device for high-resolution single photon emission computed tomography (SPECT) imaging based on an adapted pinhole collimator. OBJECTIVE: To determine the accuracy of this system for quantification of myocardial infarct area in rats. METHODS: Thirteen male Wistar rats (250 g) underwent experimental myocardial infarction by occlusion of the left coronary artery. After 4 weeks, SPECT images were acquired 1.5 hours after intravenous injection of 555 MBq o f 99mTc Sestamibi. The tomographic reconstruction was performed by using specially developed software based on the Maximum Likelihood algorithm. The analysis of the data included the correlation between the area of perfusion defects detected by scintigraphy and extent of myocardial fibrosis assessed by histology. RESULTS: The images showed a high target organ/background ratio with adequate visualization of the left ventricular walls and cavity. All animals presenting infarction areas were correctly identified by the perfusion images. There was no difference of the infarct area as measured by SPECT (21.1 +/- 21.2%) and by histology (21.7 +/- 22.0%; p=0.45). There was a strong correlation between individual values of the area of infarction measured by these two methods. CONCLUSION: The developed system presented adequate spatial resolution and high accuracy for the detection and quantification of myocardial infarction areas, consisting in a low cost and versatile option for high-resolution SPECT imaging of small rodents. PMID- 23917509 TI - Right ventricular diastolic function in patients with thalassemia major. PMID- 23917508 TI - Anemia, heart failure and evidence-based clinical management. AB - Anemia is a prevalent comorbidity and marker of a poorer prognosis in patients with heart failure (HF). Its clinical relevance, as well as its pathophysiology and the clinical management of these patients are important subjects in the specialized literature. In the present review, we describe the current concepts on the pathophysiology of anemia in HF, its diagnostic criteria, and the recommendations for iron supplementation. Also, we make a critical analysis of the major studies showing evidences on the benefits of this supplementation. The four main components of anemia are addressed: chronic disease, dilutional, "renal" and malabsorption. In patients with HF, the diagnostic criteria are the same as those used in the general population: serum ferritin levels lower than 30 mcg/L in patients without kidney diseases and lower than 100 mcg/L or serum ferritin levels between 100-299 mcg/L with transferring saturation lower than 20% in patients with chronic kidney diseases. Finally, the therapeutic possibilities for anemia in this specific patient population are discussed. PMID- 23917510 TI - Poll: Jehovah's Witness patient among baixada santista and ABC paulista cardiologists. PMID- 23917511 TI - Case 3: - congestive heart failure in male with systemic sclerosis. PMID- 23917512 TI - Transseptal coronary angioplasty in patients with severe peripheral vascular disease. PMID- 23917513 TI - Risk of excessive sodium intake in the use of a thickener for dysphagia. PMID- 23917515 TI - 3D transesophageal echo in percutaneous correction of paraprosthetic regurgitation. PMID- 23917516 TI - Ultra preconcentration of polycyclic aromatic hydrocarbons in smoked bacon by a combination of SPE and DLLME. AB - A sample pretreatment method, solid-phase extraction combined with dispersive liquid-liquid microextraction (SPE-DLLME), was established for the sensitive determination of polycyclic aromatic hydrocarbons (PAHs) in smoked bacon samples. In the SPE-DLLME process, three PAHs including naphthalene (Naph), phenanthrene (Phen) and pyrene (Pyr) were extracted from samples and transferred into C18 SPE cartridge. The target analytes were subsequently eluted with 1.2 ml of acetonitrile-dichloromethane (5:1, v/v) mixture solution. The eluent was injected directly into the 5.0 ml ultrapure water in the subsequent DLLME procedure. The sedimented phase was concentrated under a gentle nitrogen flow to 120.0 ul. Finally, the analytes in the extraction solvent were determined by high performance liquid chromatography with a ultra-violet detector. Some important extraction parameters affecting the performance, such as the sample solution flow rate, breakthrough volume, salt addition as well as the type and volume of the elution solvent were optimized. The developed method provided an ultra enrichment factors for PAHs ranged from 3478 to 3824. The method was applied for the selective extraction and sensitive determination of PAHs in smoked bacon samples. The limits of detection (S/N = 3) were 0.05, 0.01, 0.02 MUg kg(-1) for Naph, Phen, Pyr, respectively. PMID- 23917514 TI - Epicardial fat: definition, measurements and systematic review of main outcomes. AB - Epicardial fat (EF) is a visceral fat deposit, located between the heart and the pericardium, which shares many of the pathophysiological properties of other visceral fat deposits, It also potentially causes local inflammation and likely has direct effects on coronary atherosclerosis. Echocardiography, computed tomography and magnetic resonance imaging have been used to evaluate EF, but variations between methodologies limit the comparability between these modalities. We performed a systematic review of the literature finding associations of EF with metabolic syndrome and coronary artery disease. The summarization of these associations is limited by the heterogeneity of the methods used and the populations studied, where most of the subjects were at high cardiovascular disease risk. EF is also associated with other known factors, such as obesity, diabetes mellitus, age and hypertension, which makes the interpretation of its role as an independent risk marker intricate. Based on these data, we conclude that EF is a visceral fat deposit with potential implications in coronary artery disease. We describe the reference values of EF for the different imaging modalities, even though these have not yet been validated for clinical use. It is still necessary to better define normal reference values and the risk associated with EF to further evaluate its role in cardiovascular and metabolic risk assessment in relation to other criteria currently used. PMID- 23917517 TI - Analysis of S Characteristics and Pressure Pulsations in a Pump-Turbine With Misaligned Guide Vanes. AB - Growing environmental concerns and the need for better power balancing and frequency control have increased attention in renewable energy sources such as the reversible pump-turbine which can provide both power generation and energy storage. Pump-turbine operation along the S-shaped curve can lead to difficulties in loading the rejection process with unusual increases in water pressure, which lead to machine vibrations. Pressure fluctuations are the primary reason for unstable operation of pump-turbines. Misaligned guide vanes (MGVs) are widely used to control the stability in the S region. There have been experimental investigations and computational fluid dynamics (CFD) simulations of scale models with aligned guide vanes and MGVs with spectral analyses of the S curve characteristics and the pressure pulsations in the frequency and time-frequency domains at runaway conditions. The course of the S characteristic is related to the centrifugal force and the large incident angle at low flow conditions with large vortices forming between the guide vanes and the blade inlets and strong flow recirculation inside the vaneless space as the main factors that lead to the S-shaped characteristics. Preopening some of the guide vanes enables the pump turbine to avoid the influence of the S characteristic. However, the increase of the flow during runaway destroys the flow symmetry in the runner leading to all asymmetry forces on the runner that leads to hydraulic system oscillations. The MGV technique also increases the pressure fluctuations in the draft tube and has a negative impact on stable operation of the unit. PMID- 23917518 TI - The BOLD signal and neurovascular coupling in autism. AB - BOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging) is commonly used to study differences in neuronal activity between human populations. As the BOLD response is an indirect measure of neuronal activity, meaningful interpretation of differences in BOLD responses between groups relies upon a stable relationship existing between neuronal activity and the BOLD response across these groups. However, this relationship can be altered by changes in neurovascular coupling or energy consumption, which would lead to problems in identifying differences in neuronal activity. In this review, we focus on fMRI studies of people with autism, and comparisons that are made of their BOLD responses with those of control groups. We examine neurophysiological differences in autism that may alter neurovascular coupling or energy use, discuss recent studies that have used fMRI to identify differences between participants with autism and control participants, and explore experimental approaches that could help attribute between-group differences in BOLD signals to either neuronal or neurovascular factors. PMID- 23917519 TI - Deficiency of cartilage oligomeric matrix protein causes dilated cardiomyopathy. AB - Alterations in cardiac extracellular matrix are involved in dilated cardiomyopathy (DCM) and its progression to heart failure. The matricellular protein cartilage oligomeric matrix protein (COMP) has been indicated localized in the heart. However, the role of COMP in cardiac homeostasis and disease remains elusive. COMP (-/-) mice, both male and female, developed DCM spontaneously at young age (3-5 months), with impaired cardiac function. Assessment of postnatal COMP (-/-) heart at 1 month, although functionally normal, revealed severe cardiac ultrastructure defect, in parallel with cardiomyocyte apoptosis, myofilament loss, connexin-43 deficiency and matrix metalloproteinase activation. Decreased COMP expression was observed in the heart sample of DCM patients compared with donor heart. Mechanistically, COMP (-/-) heart exhibited reduced integrin beta1 expression and signaling. Ectopic expression of COMP or integrin beta1 rescued COMP-deficiency-induced cardiomyocyte apoptosis, myofilament dissolution, and connexin-43 aberrance. Additionally, COMP directly bonded to the extracellular beta-tail domain of integrin beta1, prevented integrin beta1 ubiquitination/degradation, and maintained the cardiac homeostasis. COMP-integrin beta1 axis is a potential target of DCM. PMID- 23917520 TI - Remote ischaemic preconditioning involves signalling through the SDF-1alpha/CXCR4 signalling axis. AB - Ischaemic preconditioning is one of the most potent experimental modalities known to decrease infarct size after ischaemia and reperfusion. Much interest has been stimulated by the phenomenon of remote ischaemic conditioning (RIC), in which the preconditioning stimulus is applied to a limb remote from the heart to stimulate cardioprotection via an unidentified humoral factor, believed to be a protein between 3.5 and 15 kDa. Stromal cell-derived factor-1 (SDF-1alpha or CXCL12) is a chemokine of 10 kDa that is induced by hypoxia and recruits stem cells, but also exerts direct, acute, cardioprotection via its receptor, CXCR4. The serum dipeptidase DPPIV cleaves and inactivates SDF-1alpha. We measured SDF-1alpha in rat plasma and found it was significantly increased by RIC. DPPIV activity was unchanged after RIC, suggesting that increased synthesis or release or SDF-1alpha caused the increase in plasma levels. AMD3100, a highly specific inhibitor of CXCR4, was used to investigate the hypothesis that SDF-1alpha is involved in RIC. RIC in rats, which decreased infarct size from 53 +/- 3 % to 27 +/- 3 % (n = 6, P < 0.05), was blocked in rats treated with AMD3100 (40 +/- 4 %). RIC also improved functional recovery of cardiac papillary muscle, and this, too, was blocked by AMD3100. Direct application of SDF-1alpha was confirmed to be protective in this model and was blocked by AMD3100. RIC stimulates SDF-1alpha release, and this 10 kDa peptide appears to be required for the mechanism of RIC. PMID- 23917521 TI - High yield formation of lipid bilayer shells around silicon nanowires in aqueous solution. AB - The combination of nanoscaled materials and biological self-assembly is a key step for the development of novel approaches for biotechnology and bionanoelectronic devices. Here we propose a route to merge these two subsystems and report on the formation of highly concentrated aqueous solutions of silanized silicon nanowires wrapped in a lipid bilayer shell. We developed protocols and investigated the dynamics of lipid films on both planar surfaces and silicon nanowires using fluorescence recovery after photobleaching, demonstrating fully intact and fluid bilayers without the presence of a lipid molecule reservoir. Finally, the experimental setup allowed for in situ observation of spontaneous bilayer formation around the nanowire by lipid diffusion from a vesicle to the nanowire. Such aqueous solutions of lipid coated nanowires are a versatile tool for characterization purposes and are relevant for newly emerging bioinspired electronics and nanosensorics. PMID- 23917522 TI - Severity of mitral regurgitation predicts risk of death or cardiac transplantation in children with idiopathic dilated cardiomyopathy. AB - Clinical outcomes among children with idiopathic dilated cardiomyopathy (IDC) are diverse, which makes the decision as to when a patient should be listed for a cardiac transplantation challenging. This study aimed to determine echocardiographic and clinical variables that can help clinicians identify those at highest risk for death or cardiac transplantation. The study was a single center, retrospective chart review of children with IDC. Patients younger than 18 years with a diagnosis of IDC, as defined by a left ventricular end-diastolic dimension (LVEDD) z-score higher than 2, and fractional shortening of less than 28 % on the initial echocardiogram, were included in the study. Echocardiographic parameters including mitral regurgitation (MR) grade and certain clinical parameters at the time of presentation were assessed. A follow-up echocardiogram was similarly studied. The study included 49 children with IDC. Those who died or underwent cardiac transplantation were grouped as "nonsurvivors" (n = 26). The remaining children who either completely recovered or experienced chronic dilated cardiomyopathy were grouped as "survivors" (n = 23). The median age overall was 1.25 years (range 0.1-17 years). The follow-up echocardiograms of the survivors showed significant improvement in left ventricle size, systolic function, left atrial volume, and MR grade, whereas these parameters did not change in the nonsurvivor group. The use of inotropic medications at initial presentation was an independent predictor of death or cardiac transplantation (p < 0.05). The presence of moderate to severe MR at diagnosis also was predictive of a worse outcome. PMID- 23917523 TI - Intense THz pulses down-regulate genes associated with skin cancer and psoriasis: a new therapeutic avenue? AB - Terahertz (THz) radiation lies between the infrared and microwave regions of the electromagnetic spectrum and is non-ionizing. We show that exposure of artificial human skin tissue to intense, picosecond-duration THz pulses affects expression levels of numerous genes associated with non-melanoma skin cancers, psoriasis and atopic dermatitis. Genes affected by intense THz pulses include nearly half of the epidermal differentiation complex (EDC) members. EDC genes, which are mapped to the chromosomal human region 1q21, encode for proteins that partake in epidermal differentiation and are often overexpressed in conditions such as psoriasis and skin cancer. In nearly all the genes differentially expressed by exposure to intense THz pulses, the induced changes in transcription levels are opposite to disease-related changes. The ability of intense THz pulses to cause concerted favorable changes in the expression of multiple genes implicated in inflammatory skin diseases and skin cancers suggests potential therapeutic applications of intense THz pulses. PMID- 23917524 TI - Expert beliefs regarding novel lipid-based approaches to pediatric intestinal failure-associated liver disease. AB - OBJECTIVE: To determine expert beliefs regarding the probability of intestinal failure-associated liver disease (IFALD) with novel lipid-based approaches (lipid minimization/omega-3 lipids) in managing IFALD to facilitate Bayesian analyses of clinical trials of these therapies. STUDY DESIGN: Structured interviews were conducted using a validated approach to belief elicitation with 60 intestinal failure (IF) experts from across North America. Participants were asked to estimate, in an average population of infants referred for management of IF with early IFALD, the probability of advanced IFALD at 3 months following referral in each of 3 scenarios: (1) conventional lipid, (2) omega-3 lipids, and (3) lipid minimization. Probability distributions of the risk of advanced IFALD with each strategy were developed. Distributions of the elicited treatment effect for the novel approaches, relative to conventional lipid, were calculated. RESULTS: Median duration of experience of participants managing patients with IF was 8.5 (range, 2-35) years. The median probability of advanced IFALD using conventional lipid was 32.5%; omega-3 lipids, 17.5%; and lipid minimization, 13%. The median of the elicited treatment effects relative to conventional lipid was a relative risk of 0.53 for the omega-3 lipid and 0.45 for lipid minimization. CONCLUSIONS: There was consistent expert opinion that the novel lipid-based approaches are superior to conventional therapy, with similar estimates of treatment efficacy for the 2 approaches. The distributions of the elicited treatment effects can be used as prior distributions in Bayesian analyses of clinical trials of these novel strategies. PMID- 23917525 TI - Attenuation of sepsis-induced organ injury in mice by vitamin C. AB - BACKGROUND: Multiple organ dysfunction syndrome (MODS) is the principal cause of death in patients with sepsis. Recent work supports the notion that parenteral vitamin C (VitC) is protective in sepsis through pleiotropic mechanisms. Whether suboptimal levels of circulating VitC increase susceptibility to sepsis-induced MODS is unknown. MATERIALS AND METHODS: Unlike mice, humans lack the ability to synthesize VitC because of loss of L-gulono-gamma-lactone oxidase (Gulo), the final enzyme in the biosynthesis of VitC. To examine whether physiological levels of VitC are required for defense against a catastrophic infection, we induced sepsis in VitC sufficient and VitC deficient Gulo(-/-) mice by intraperitoneal infusion of a fecal stem solution (FIP). Some VitC deficient Gulo(-/-) mice received a parenteral infusion of ascorbic acid (AscA, 200 mg/kg) 30 minutes after induction of FIP. We used molecular, histological, and biochemical analyses to assess for MODS as well as abnormalities in the coagulation system and circulating blood cells. RESULTS: FIP produced injury to lungs, kidneys and liver (MODS) in VitC deficient Gulo(-/-) mice. MODS was not evident in FIP-exposed VitC sufficient Gulo(-/-) mice and attenuated in VitC deficient Gulo(-/-) mice infused with AscA. Septic VitC deficient Gulo(-/-) mice developed significant abnormalities in the coagulation system and circulating blood cells. These were attenuated by VitC sufficiency/infusion in septic Gulo(-/-) mice. CONCLUSIONS: VitC deficient Gulo(-/-) mice were more susceptible to sepsis-induced MODS. VitC sufficiency or parenteral infusion of VitC, following induction of sepsis, normalized physiological functions that attenuated the development of MODS in sepsis. PMID- 23917526 TI - Targeted therapies: HERA update-1 year is standard. PMID- 23917527 TI - Establishing brain functional laterality in adult mice through unilateral gene manipulation in the embryonic cortex. PMID- 23917528 TI - Pills of PTEN? In and out for tumor suppression. AB - The tumor-suppressive activity of PTEN has always been attributed to its endogenous intracellular function. Recently two different groups have demonstrated that PTEN is secreted/exported into the extracellular environment for uptake by recipient cells, and functions as a tumor suppressor in a cell non autonomous manner. PMID- 23917529 TI - Exo-endo trans splicing: a new way to link. AB - In addition to canonical cis splicing, which joins exons from a single pre-mRNA, various forms of trans splicing have been described, whereby two separate precursor transcripts are linked with each other. A new study by Hu et al. in Cell Research characterizes a novel and unusual splicing variation, called exo endo trans splicing. PMID- 23917530 TI - Crystal structures of isoorotate decarboxylases reveal a novel catalytic mechanism of 5-carboxyl-uracil decarboxylation and shed light on the search for DNA decarboxylase. AB - DNA methylation and demethylation regulate many crucial biological processes in mammals and are linked to many diseases. Active DNA demethylation is believed to be catalyzed by TET proteins and a putative DNA decarboxylase that may share some similarities in sequence, structure and catalytic mechanism with isoorotate decarboxylase (IDCase) that catalyzes decarboxylation of 5caU to U in fungi. We report here the structures of wild-type and mutant IDCases from Cordyceps militaris and Metarhizium anisopliae in apo form or in complexes with 5caU, U, and an inhibitor 5-nitro-uracil. IDCases adopt a typical (beta/alpha)8 barrel fold of the amidohydrolase superfamily and function as dimers. A Zn(2+) is bound at the active site and coordinated by four strictly conserved residues, one Asp and three His. The substrate is recognized by several strictly conserved residues. The functional roles of the key residues at the active site are validated by mutagenesis and biochemical studies. Based on the structural and biochemical data, we present for the first time a novel catalytic mechanism of decarboxylation for IDCases, which might also apply to other members of the amidohydrolase superfamily. In addition, our biochemical data show that IDCases can catalyze decarboxylation of 5caC to C albeit with weak activity, which is the first in vitro evidence for direct decarboxylation of 5caC to C by an enzyme. These findings are valuable in the identification of potential DNA decarboxylase in mammals. PMID- 23917531 TI - Genome analysis and signature discovery for diving and sensory properties of the endangered Chinese alligator. AB - Crocodilians are diving reptiles that can hold their breath under water for long periods of time and are crepuscular animals with excellent sensory abilities. They comprise a sister lineage of birds and have no sex chromosome. Here we report the genome sequence of the endangered Chinese alligator (Alligator sinensis) and describe its unique features. The next-generation sequencing generated 314 Gb of raw sequence, yielding a genome size of 2.3 Gb. A total of 22 200 genes were predicted in Alligator sinensis using a de novo, homology- and RNA based combined model. The genetic basis of long-diving behavior includes duplication of the bicarbonate-binding hemoglobin gene, co-functioning of routine phosphate-binding and special bicarbonate-binding oxygen transport, and positively selected energy metabolism, ammonium bicarbonate excretion and cardiac muscle contraction. Further, we elucidated the robust Alligator sinensis sensory system, including a significantly expanded olfactory receptor repertoire, rapidly evolving nerve-related cellular components and visual perception, and positive selection of the night vision-related opsin and sound detection-associated otopetrin. We also discovered a well-developed immune system with a considerable number of lineage-specific antigen-presentation genes for adaptive immunity as well as expansion of the tripartite motif-containing C-type lectin and butyrophilin genes for innate immunity and expression of antibacterial peptides. Multifluorescence in situ hybridization showed that alligator chromosome 3, which encodes DMRT1, exhibits significant synteny with chicken chromosome Z. Finally, population history analysis indicated population admixture 0.60-1.05 million years ago, when the Qinghai-Tibetan Plateau was uplifted. PMID- 23917533 TI - Living donor and recipient screening for latent tuberculosis infection by tuberculin skin test and interferon-gamma releasing assay in a country with an intermediate burden of tuberculosis. AB - There are few data on donor screening for latent tuberculosis infection (LTBI) using the tuberculin skin test (TST) and interferon-gamma releasing assay (IGRA). In South Korea, most renal allografts involve living donors (average, 80%). Hence, we have an opportunity to evaluate donor and recipient screening for LTBI by TST and IGRA. All donors and recipients admitted for kidney transplantation during a 20-month period were evaluated prospectively by using TST and Mycobacterium tuberculosis-specific enzyme-linked immunosorbent spot (ELISPOT) assay. The study population consisted of 205 living donor-recipient pairs (>=16 years) including 15 (7%) who yielded indeterminate donor or recipient ELISPOT results. Of the 205 donors, 63 (31%) gave a positive TST >=5 mm, 33 (16%) a positive TST >=10 mm, and 96 (47%) a positive ELISPOT. Of the 205 recipients, 9 (5%) gave a positive TST >=5 mm, 3 (2%) a positive TST >=10 mm, and 79 (39%) had a positive ELISPOT. Of the 205 donor-recipient pairs, only 59 (29%) gave negative donor and recipient ELISPOT results and 139 (68%) negative donor and recipient TSTs (<5 mm) (P < 0.001). One third of donor-recipient pairs tends to be positive in the TST, and two thirds of the donor-recipient pairs tends to be positive in the ELISPOT. Given the high positive rate of LTBI obtained by screening donors, further studies on the clinical value of solid organ transplant donors with positive TST or ELISPOT and health economics analysis in countries with intermediate burden of TB are needed for policy decisions on isoniazid (INH) prophylaxis. PMID- 23917534 TI - Diagnosis of false lumen perfusion at the initiation of cardiopulmonary bypass using right axillary arterial perfusion during total arch replacement. PMID- 23917532 TI - The endothelium abridges insulin resistance to premature aging. PMID- 23917537 TI - Update from EIC 2013. PMID- 23917535 TI - Contribution of membrane progesterone receptor alpha to the induction of progesterone-mediated apoptosis associated with mitochondrial membrane disruption and caspase cascade activation in Jurkat cell lines. AB - In the present study, we investigated the effects of progesterone (Pg) on the growth of A3 and its caspase-8-deficient mutant cell line, I9.2, both of which are subclones of a T-cell-derived leukemic Jurkat cell line that lacks the classic cytoplasmic/nuclear Pg receptor. Pg inhibited the cell growth of both cell lines in a dose- and time-dependent manner to a similar extent, regardless of the status of caspase-8 expression. The activation of caspase-9 and -3 was observed in both cell lines following treatment with 50 uM Pg for 24 h. In addition, the activation of caspase-8 was observed in A3 cells. The addition of the pan-caspase inhibitor Boc-D-FMK, significantly suppressed Pg-triggered cytocidal effects in both types of cells. Moreover, exposure to 50 uM Pg for 48 and 72 h resulted in lactate dehydrogenase leakage characteristic of the disruption of cellular membrane integrity. The function of membrane progesterone receptor alpha coupled directly with the Gi protein was revealed based on the restoration of Pg-triggered loss of mitochondrial membrane potential in the presence of pertussis toxin, an inhibitor specific for Gi protein. These results suggest that growth suppression accompanied with induction of apoptosis by Pg in both Jurkat clone cells was mediated through mitochondrial membrane disruption followed by the activation of the caspase cascade, as a result of the activation of non-genomic effects. The results of the present study provide novel insight into Pg actions toward its use for clinical application in patients with lymphocytic T cell leukemia. PMID- 23917540 TI - Lutein: a new dye for chromovitrectomy. AB - PURPOSE: To evaluate the feasibility, advantages, and safety of a novel lutein based dye for improving identification and removal of the vitreous, internal limiting membrane, and epiretinal membrane during chromovitrectomy in humans. METHODS: We prospectively evaluated 12 eyes that underwent pars plana vitrectomy using the dye in patients with macular hole, epiretinal membrane, or proliferative diabetic retinopathy/tractional diabetic macular edema. One surgeon performed standard chromovitrectomy and completed a postoperative questionnaire to compare the staining with that of the available dyes. The peeled membranes were evaluated histologically. Follow-up examinations were performed on postoperative Days 1, 7, 30, 90 and 180; best-corrected visual acuity, optical coherence tomography, fluorescein angiography, autofluorescence, and visual fields were performed. RESULTS: The green dye was deposited on the posterior pole because of its higher density than balanced saline solution; vigorous dye flushing into the vitreous cavity was unnecessary. The dye stained the posterior hyaloid/vitreous base by deposition onto the vitreous; brilliant blue stained the internal limiting membrane. The epiretinal membrane was poorly stained. The best corrected visual acuity improved in all eyes without clinical toxicity or toxicity on images/visual fields. Histology showed effective removal of the internal limiting membrane and epiretinal membrane in all eyes. CONCLUSION: The new dye improved intraoperative identification of the internal limiting membrane and the posterior hyaloid/vitreous base during chromovitrectomy. PMID- 23917541 TI - Vitrectomy for myopic foveoschisis with internal limiting membrane peeling and no gas tamponade. AB - PURPOSE: To evaluate the outcome of vitrectomy with internal limiting membrane peeling and no gas tamponade in the treatment of eyes with myopic foveoschisis. METHODS: Medical records of 10 eyes of 9 consecutive patients with myopic foveoschisis without macular hole treated by vitrectomy were reviewed. RESULTS: The patients' refractive error was -4.00 diopters to -34.00 diopters, and axial length was 28.38 mm to 35.90 mm. Six eyes had foveal retinal detachment with retinoschisis. All cases were treated by vitrectomy with internal limiting membrane removal without gas tamponade. The mean preoperative best-corrected visual acuity was 0.61 +/- 0.42 in logarithm of the minimum angle of resolution units (Snellen equivalent of 20/82). Myopic foveoschisis was reduced in 8 eyes (80%) with a single surgery. Two eyes without improvement developed a postoperative macular hole and were treated by additional vitreoretinal surgery. All 10 eyes showed anatomical repair, and 5 eyes showed improvement in best corrected visual acuity to 0.47 +/- 0.48 (Snellen equivalent of 20/60), by 17 months after the initial surgery. CONCLUSION: Vitrectomy with internal limiting membrane peeling and no gas tamponade can effectively treat some cases of myopic foveoschisis, suggesting that tractional forces at the vitreoretinal interface may contribute to the pathogenesis of myopic foveoschisis, thereby avoiding gas tamponade. PMID- 23917544 TI - Flow-through divided latissimus dorsi musculocutaneous flap for large extremity defects. AB - Reconstructing large defects of the extremities is a challenging problem for reconstructive microsurgeons. The latissimus dorsi musculocutaneous flap (LDMCF) is widely used for this purpose, but a skin graft is needed when the defect is wider than available flaps. We used flow-through divided LDMCFs to reconstruct large defects of the extremities in 5 consecutive patients from 2010 through 2012. The semicircular skin island was split longitudinally, and 1 skin island was advanced over the other to close a round or oval defect without a skin graft. Postoperatively, all flaps survived completely, and the mean Enneking score was 90.0%. The flow-through divided LDMCF is a reliable and versatile option for reconstructing large defects of the extremities. PMID- 23917545 TI - Comparison of nerve, vessel, and cartilage grafts in promoting peripheral nerve regeneration. AB - Peripheral nerve injury primarily occurs due to trauma as well as factors such as tumors, inflammatory diseases, congenital deformities, infections, and surgical interventions. The surgical procedure to be performed as treatment depends on the etiology, type of injury, and the anatomic region. The goal of treatment is to minimize loss of function due to motor and sensory nerve loss at the distal part of the injury. Regardless of the cause of the injury, the abnormal nerve regeneration due to incomplete nerve regeneration, optimal treatment of peripheral nerve injuries should provide adequate coaptation of proximal and distal sides without tension, preserving the neurotrophic factors within the repair line. The gold standard for the treatment of nerve defects is the autograft; however, due to denervation of the donor site, scarring, and neuroma formation, many studies have aimed to develop simpler methods, better functional results, and less morbidity. In this study, a defect 1 cm in length was created on the sciatic nerve of rats. The rats were treated with the following procedures: group 1, autograft; group 2, allogeneic aorta graft; group 3, diced cartilage graft in allogeneic aorta graft; and group 4, tubularized cartilage graft in allogeneic aorta graft. Group 5 was the control group. The effects of cartilage tissue in nerve regeneration were evaluated by functional and histomorphological methods.Group 1, for which the repair was performed with an autograft, was evaluated to be the most similar to the control group. There was not a statistically significant difference in myelination and Schwann cell rates between group 2, in which an allogeneic aorta graft was used, and group 3, in which diced cartilage in an allogeneic aorta graft was used. In group 4, myelination and Schwann cell formation were observed; however, they were scattered and irregular, likely due to increased fibrosis.In all of the groups, nerve regeneration at various rates was observed both functionally and histomorphologically. This study demonstrates that cartilage tissue has promoting effects in nerve regeneration. PMID- 23917542 TI - Antagonism of adenosine A2A receptor expressed by lung adenocarcinoma tumor cells and cancer associated fibroblasts inhibits their growth. AB - Recently it has become clear that the cost associated with the Warburg effect, which is inefficient production of ATP, is offset by selective advantages that are produced by resultant intracellular metabolic alterations. In fact tumors may be addicted to the Warburg effect. In addition these alterations result in changes in the extracellular tumor microenvironment that can also produce selective advantages for tumor cell growth and survival. One such extracellular alteration is increased adenosine concentrations that have been shown to impair T cell mediated rejection and support angiogenesis. The expression of the A2A receptor in non-small cell cancer (NSCLC) tissues, cell lines and cancer associated fibroblasts (CAF) was determined by performing immunohistrochemistry and immunoblot analysis. The efficacy of the A2A receptor antagonists in vivo was evaluated in a PC9 xenograft model. To determine the mode of cell death induced by A2A receptor antagonists flow cytometry, immunoblot, and cytotoxic analysis were performed. We found that a significant number of lung adenocarcinomas express adenosine A2A receptors. Antagonism of these receptors impaired CAF and tumor cell growth in vitro and inhibited human tumor xenograft growth in mice. These observations add to the rationale for testing adenosine A2A receptor antagonists as anticancer therapeutics. Not only could there be prevention of negative signaling in T cells within the tumor microenvironment and inhibition of angiogenesis, but also an inhibitory effect on tumor-promoting, immunosuppressive CAFs and a direct inhibitory effect on the tumor cells themselves. PMID- 23917546 TI - [Management of psychiatric inpatients with advanced cancer: a pilot study]. AB - The prevalence of cancer is not well established and probably underestimated in long-stay psychiatric inpatients. Psychiatric patients do not have the same access for cancer screening and care. Therapeutic decision-making is a real ethical problem. In this context, access to medical care should be provided by the establishment of guidelines and/or recommendations for this specific population. The aim of our study was to assess how cancer was managed among long term psychiatric inpatients. For this pilot study, we used a mixed methodology: a quantitative part with a retrospective chart review of cancer patients in a psychiatric institution and a qualitative part based on semi-structured interviews with psychiatrists with discourse analysis. Delay in cancer diagnosis can be explained by communication and behavior disorders, inadequate screening, and additional tests often refused by patients. Compliance and ethical issues (i.e. obtaining informed consent) are many pitfalls to optimal cancer care that should be explored in further research. PMID- 23917547 TI - Vesicles and reverse vesicles of an ionic liquid in ionic liquids. AB - First evidence and the mechanism of formation of closed bilayer structures by a single chain amino acid ionic liquid (IL), L-proline isopropylester laurylsulfate in both hydrophilic and hydrophobic ILs, is reported. Such ionic self-assemblies are shown to be guided by fine balance of solvophobic effects and ionic arrangements via hydrogen bonding and electrostatic interactions. PMID- 23917548 TI - Effect of particle size on ferroelectric and magnetic properties of BiFeO3 nanopowders. AB - The ferroelectric and magnetic behaviour of multiferroic BiFeO3 nanoparticles has been studied using piezoresponse force microscopy (PFM), Mossbauer spectroscopy and SQUID magnetometry. The results of the PFM studies indicate a decay of the spontaneous polarization with decreasing particle size. Nevertheless, particles with diameter ~50 nm still manifest ferroelectric behaviour. At the same time these particles are weakly ferromagnetic. The Mossbauer spectroscopy studies prove that the weak ferromagnetic state is due to non-compensated surface spins rather than distortions of the cycloidal spin structure characteristic for bulk BiFeO3. PMID- 23917549 TI - The influence of connectivity in forest patches, and riparian vegetation width on stream macroinvertebrate fauna. AB - We assessed two dimensions of stream connectivity: longitudinal (between forest patches along the stream) and lateral (riparian vegetation), using macroinvertebrate assemblages as bioindicators. Sites representing different land uses were sampled in a lowland basin that holds a mosaic of protected areas. Land use analysis, forest successional stages and riparian zone widths were calculated by the GIS analysis. Macroinvertebrate fauna was strongly affected by land-use. We observed a continuous decrease in the number of sensitive species, %Shredders and IBE-IOC biotic index from the upstream protected area to highly deforested sites, increasing again where the stream crosses a Biological Reserve. When analysing buffer strips, we found aquatic fauna responding to land-use alterations beyond the 30 m riparian corridor (60 m and 100 m wide). We discussed the longitudinal connectivity between forest patches and the riparian vegetation buffer strips necessary to hold high macroinvertebrate diversity. We recommend actions for the increase/maintenance of biodiversity in this and other lowland basins. PMID- 23917550 TI - Ecological characterisation of the Colombian entomopathogenic nematode Heterorhabditis sp. SL0708. AB - The entomopathogenic nematode Heterorhabditis sp. SL0708 (Rhabditida: Heterorhabditidae) isolated from soil in Alcala, Valle del Cauca (Colombia) was characterised ecologically using Galleria mellonella larvae (L) (Pyralidae: Galleriinae) as hosts. The effect of temperature on the viability, infectivity and reproduction, and of moisture on infectivity and storage in liquid were evaluated in infective juveniles (IJs). Significant differences were found in the viability, infectivity and reproduction of the IJs at different temperatures. No nematodes were recovered at 5 degrees C and 10 degrees C, and at 35 degrees C no infectivity was observed. Average daily nematode recovery was best at 25 degrees C, and survival of the IJs was low in substrates presenting 13% moisture. The optimal storage temperature for Heterorhabditis sp. SL0708 was between 20 degrees C and 30 degrees C, keeping its infectivity for up to 8 weeks. PMID- 23917551 TI - Foraging activity of the snail kite, Rostrhamus sociabilis (Aves: Accipitridae) in wetlands of southern Brazil. AB - The snail kite (Rostrhamus sociabilis) is widely distributed in the American continent. Its specialised diet consists mostly of the gastropod mollusk Pomacea sp and its foraging strategy probably varies depending on the season, prey availability, and climate factors, which can be reflected in its semi-nomad behaviour. This study was aimed at examining the hunting strategy of the snail kite, and its association with climate factors and habitat heterogeneity. Direct observations of birds between January 2010 and March 2011 in southernmost Brazil revealed that hunting was still the predominant foraging strategy (79% of records) to capture mollusks. Despite morphological specialisations to extract mollusks from the shells, the handling time (average = 92.4 s) was twice as much the time between prey search and capture (average = 55 s). The increase in the number of mollusks ingested apparently occurs when the resting time on perches or any other substrates near the hunting sites decreases between successive unsuccessful attempts. The correlation between the number of consumed preys and the climatic variables examined was low. Regarding habitat heterogeneity, our findings suggest that birds forage preferentially in marshes with low vegetation, which may increase the access to mollusks. The hunting efficiency of the snail kite was high (76 % successful attempts) compared to those of other birds of prey. PMID- 23917552 TI - Effects of recurrent disturbances on the periphyton community downstream of a dammed watercourse. AB - We evaluate experimentally the effect of a sequential disturbance-desiccation-on the structure and dynamics of a periphytic algal community in a semilotic environment of the Upper Parana River floodplain. We tested the hypothesis that the presence of recurrent disturbances have a direct negative effect on the attributes of the periphyton community. The sequential effect of desiccation on the periphytic community promoted its significant decrease in density, while the same was not observed in species richness. When desiccation was induced in a mature community, there was no difference in the community compared to control. The sequential disturbances on the community of periphytic algae in a mature stage, was characterised by greater stability. It is believed that the effects of variation in water levels caused by upstream reservoirs can likewise also modify the structure and stability of periphytic algae in the Upper Parana River floodplain. PMID- 23917553 TI - Fish assemblage structure of the Ipanema River, a small lotic environment partially protected by a Conservation Unit in southeastern Brazil. AB - A study on the fish assemblage of the Ipanema River, a small affluent of the Tiete River basin in southeastern Brazil, was performed aiming to look for structural patterns of species diversity in small lowland lotic environments. Fish samplings were performed every two months from June 2003 to April 2004 at four sample sites located on the lower stretch of the river. Local assemblage showed to be species rich, with fifty-two species belonging to Characiformes (25 spp.), Siluriformes (19 spp.), Cyprinodontiformes (3 spp.), Gymnotiformes (2 spp.), Perciformes (2 spp.), and Synbranchiformes (1 sp.). Fish fauna was composed of small-sized species (<200 mm SL) and by individuals of medium (up to 400 mm SL) to large (more than 400 mm SL) sized species. The Ipanema River, such as other small lotic transitional environments in the upper Parana River drainage, is considered important for conservation of fish fauna because they cover available habitats for persistent populations of small-sized species and for non-persistent individuals or shoals of medium and large-sized fish species, which occupy other habitats along their life-history (e. g. floodplains, oxbow lakes, main channel of great rivers). The importance of the Ipanema River basin for fish fauna conservation is also reinforced by the fact that it is located in a highly impacted region of southeastern Brazil, near the Sao Paulo metropolitan area. PMID- 23917554 TI - Does plant architectural complexity increase with increasing habitat complexity? A test with a pioneer shrub in the Brazilian Cerrado. AB - Understanding variation in plant traits in heterogeneous habitats is important to predict responses to changing environments, but trait-environment associations are poorly known along ecological gradients. We tested the hypothesis that plant architectural complexity increases with habitat complexity along a soil fertility gradient in a Cerrado (Neotropical savanna) area in southeastern Brazil. Plant architecture and productivity (estimated as the total number of healthy infructescences) of Miconia albicans (SW.) Triana were examined in three types of vegetation which together form a natural gradient of increasing soil fertility, tree density and canopy cover: grasslands (campo sujo, CS), shrublands (cerrado sensu strico, CE) and woodlands (cerradao, CD). As expected, plants growing at the CS were shorter and had a lower branching pattern, whereas plants at the CD were the tallest. Unexpectedly, however, CD plants did not show higher architectural complexity compared to CE plants. Higher architectural similarity between CE and CD plants compared to similarity between CS and CE plants suggests reduced expression of functional architectural traits under shade. Plants growing at the CE produced more quaternary shoots, leading to a larger number of infructescences. This higher plant productivity in CE indicates that trait variation in ecological gradients is more complex than previously thought. Nematode-induced galls accounted for fruit destruction in 76.5% infructescences across physiognomies, but percentage of attack was poorly related to architectural variables. Our data suggest shade-induced limitation in M. albicans architecture, and point to complex phenotypic variation in heterogeneous habitats in Neotropical savannas. PMID- 23917555 TI - Spatial and temporal variation of the phytoplankton community in a section of the Iguacu River, Parana, Brazil. AB - The work aimed to show variations in the composition and structure of the phytoplankton community at high water and low water in Iguacu Falls, Iguacu River and to examine the influence of these waterfalls and environmental variables on the community. Phytoplankton samples were taken monthly during a year from two sampling stations in the Iguacu River. A total of 408 taxa were identified, with Bacillariophyceae being the most strongly represented group. A large differentiation in the composition of the phytoplankton was observed between the sampling stations. The total richness and density of the phytoplankton groups was very low in both sample locations, as well as the Shannon diversity index, but the evenness value was generally high. No significant seasonal and spatial difference in the studied features of the phytoplankton community was seen. But, significant seasonal differences were observed when the density and richness of the algae classes were assessed separately. The heterogeneity of the Iguacu River's characteristics between the sampling sites caused no significant spatial differentiation in the features of the phytoplankton community. However, the seasonal variation of the climatic conditions has significantly influenced the composition and structure of the community in the Iguacu River. PMID- 23917556 TI - The role of a cascade of reservoirs and seasonal variation in the phytoplankton structure in a tropical river. AB - This study aims to analyse the influence of a cascade of reservoirs on the density, richness and functional groups of phytoplankton in the Contas River, a tropical river of Brazil. This river has two dams along its course, forming the Pedra and Funil reservoirs. Samples were collected over three consecutive years (Dec., 2007 to Dec., 2010) at 28 sampling stations along the river. We identified 198 species and the stretches downstream from the reservoirs showed greater richness. Chlorophyceae, followed by Bacillariophyceae and Cyanophyceae were the dominant groups and highest density was recorded during the rainy season. Overall, a longitudinal pattern in algal densities was found for both seasons, with the lowest values recorded in sections of the Pedra and Funil reservoirs and the highest densities in the downstream sections. Nine functional groups were identified (C, F, J, MP, S1, Sn, Td, Y, Ws); of these, F and J grouped the species with the highest relative abundance during the dry season, while the S1 group, represented by the cyanobacterium Planktothrix agardhii, was dominant in the rainy season. The present study showed a high longitudinal variation in the phytoplankton richness and density, attributed to the hydrological change between the lotic and lentic stretches. Furthermore, the effects of the cascade of reservoirs on phytoplankton, such as reduced density, increased richness and changes in algal associations, were strongly influenced by habitat heterogeneity found in this environment, as well as the rainfall in the region. PMID- 23917557 TI - Anaerobic decomposition of a native and an exotic submersed macrophyte in two tropical reservoirs. AB - Some aquatic plants have fast metabolism and growth, even at sub-optimal conditions, and become dominant in lentic environments such as large reservoirs, altering the nutrient cycle and impairing their environmental quality. There is great need in the knowledge impact processes of invasive species in aquatic environments, among the major, those related to the decomposition. This study evaluated the anaerobic decomposition of invasive submerged macrophytes Egeria densa Planch, native, and Hydrilla verticillata (L.f.) Royle, exotic in Porto Primavera and Jupia reservoirs, Parana basin. We evaluated the decay of organic matter, humification degree of the leached material, electrical conductivity and pH of the decomposition process. Mathematical models were utilised to describe the decomposition patterns over time. Both species showed the same heterogeneous pattern of decay of organic matter and carbon mineralisation. The models of carbon mineralisation, compared with the experimentally obtained data presented were adequate. Both species show no significant differences in the decomposition processes. Incubations of both species presented rapid t 1/2 for POC mineralisation and low DOC mineralisation. PMID- 23917558 TI - Bat assemblages in conservation areas of a metropolitan region in Southeastern Brazil, including an important karst habitat. AB - Species richness and abundance of bats were studied in four nature reserves, including a karst area which has many potential rocky shelters for bats, such as caves and rock crevices. The reserves were located in the greater Belo Horizonte metropolitan area, one of the most populated regions of Brazil, within the Atlantic Forest, and Cerrado (Brazilian savanna) ecological domains. Bats were sampled using mist-nets and, in the karst area, also by active searches in shelters. A total of 1,599 bats were captured representing 30 species belonging to four families. There was little similarity among the four chiropteran faunas. The greatest species richness was found in the karst area with 22 species recorded whereas richness estimates in the other areas indicated the need for further studies. Two hundred and sixty-five individuals of 14 species were captured from 56 shelters. Most of the shelters were frequently used for diurnal roosts, and all the bats found belonged to the Phyllostomidae, with the exception of Myotis nigricans (Vespertilionidae), Nyctinomops laticaudatus (Molossidae) and Peropteryx macrotis (Emballonuridae). The sanguinivorous Desmodus rotundus was the most common species in the shelters. The results of this study demonstrate the importance of maintaining multiple protected areas to ensure a representative fauna of bats in a region characterized by a vegetation transition zone and with intense economic activity and high environmental impact. This study also demonstrates the importance of rock shelters for maintaining local bat richness and the importance of active searches for bats in their diurnal roosts for a more thorough sampling of the bat fauna at a given locality. PMID- 23917559 TI - Seasonal variation of the protozooplanktonic community in a tropical oligotrophic environment (Ilha Solteira reservoir, Brazil). AB - The seasonal variation of the protozooplanktonic community (ciliates and testate amoebae) was studied in a tropical oligotrophic reservoir in Brazil, which was under the influence of two contrasting climatic seasons (rainy/warm and dry/cold). The aim of this study was to evaluate the effect of these climatic changes on physical, chemical and biological variables in the dynamic of this community. The highest mean density of total protozoans occurred in the rainy/warm season (5683.2 ind L-1), while the lowest was in the dry/cold (2016.0 ind L-1). Considering the seasonal variations, the protozoan groups that are truly planktonic, such as the oligotrichs (Spirotrichea), predominated in the dry season, whereas during the rainy season, due to the material input and resuspension of sediment, sessile protozoans of the Peritrichia group were the most important ones. The dominant protozoans were Urotricha globosa, Cothurnia annulata, Pseudodifflugia sp. and Halteria grandinella. The highest densities of H. grandinella were associated with more oxygenated and transparent water conditions, while the highest densities of C. annulata occurred in sites with high turbidity, pH and trophic state index (TSI). The study demonstrated that density and composition of protozooplanktonic species and groups of the reservoir suffered seasonal variation due to the environmental variables (mainly temperature, turbidity, water transparency, dissolved oxygen and TSI) and the biological variables (e.g. morphological characteristics, eating habits and escape strategies from predation of the species). PMID- 23917560 TI - Distribution of periphytic algae in wetlands (Palm swamps, Cerrado), Brazil. AB - The distribution of periphytic algae communities depends on various factors such as type of substrate, level of disturbance, nutrient availability and light. According to the prediction that impacts of anthropogenic activity provide changes in environmental characteristics, making impacted Palm swamps related to environmental changes such as deforestation and higher loads of nutrients via allochthonous, the hypothesis tested was: impacted Palm swamps have higher richness, density, biomass and biovolume of epiphytic algae. We evaluated the distribution and structure of epiphytic algae communities in 23 Palm swamps of Goias State under different environmental impacts. The community structure attributes here analyzed were composition, richness, density, biomass and biovolume. This study revealed the importance of the environment on the distribution and structuration of algal communities, relating the higher values of richness, biomass and biovolume with impacted environments. Acidic waters and high concentration of silica were important factors in this study. Altogether 200 taxa were identified, and the zygnemaphycea was the group most representative in richness and biovolume, whereas the diatoms, in density of studied epiphyton. Impacted Palm swamps in agricultural area presented two indicator species, Gomphonema lagenula Kutzing and Oedogonium sp, both related to mesotrophic to eutrophic conditions for total nitrogen concentrations of these environments. PMID- 23917561 TI - The orchid-bee fauna (Hymenoptera: Apidae) of 'Reserva Biologica de Una', a hotspot in the Atlantic Forest of southern Bahia, eastern Brazil. AB - The orchid-bee fauna of 'Reserva Biologica de Una' (REBIO Una), one of the largest Atlantic Forest remnants in southern Bahia, eastern Brazil, was surveyed for the first time. Baits with sixteen different scents were used to attract males of orchid bees. Eight hundred and fifty-nine males belonging to 26 species were actively collected with insect nets during 60 hours in January and February, 2009, and January, 2010. Euglossa avicula Dressler, 1982 and Euglossa milenae Bembe, 2007 have been recorded for the first time in the state of Bahia. It was found that REBIO Una has one of the most diverse and rich orchid-bee faunas of the entire Atlantic Forest domain and holds some rare species, such as Euglossa cyanochlora Moure, 1996. PMID- 23917562 TI - Adult male coatis play with a band of juveniles. AB - This study examined the play behaviour in one group of coatis (Nasua narica) at La Selva Biological Station in Costa Rica. We incidentally found adult males playing with juvenile coatis, and conducted post-hoc analyses to investigate this interaction. Coati groups consist of adult females and juveniles of both sexes until male juveniles reach two years of age and leave the band to become solitary. Adult males only tolerate juveniles for a brief period during breeding season when the males court females to mate. Outside of the breeding season, adult males are known to prey on juveniles. In this study, when adult males were present with the band, play occurred more than was expected by chance, and adult males engaged in many of these play bouts. Because the mechanisms driving infanticidal behaviour are not well understood, and adult male coatis show a range of behaviours from infanticide to highly affiliative interactions with juveniles, using coatis as a model system may elucidate mechanisms underlying infanticide. PMID- 23917563 TI - Benthic insects of the El Tala River (Catamarca, Argentina): longitudinal variation of their structure and the use of insects to assess water quality. AB - The aim of this work was to determine the structure of the benthic entomofauna and its variation along the El Tala River (Catamarca, Argentina). Five sampling stations were established, considering the location of nearby housing with respect to the watercourse. The following variables were determined in situ: altitude, latitude and longitude, bedstream width, river depth, river-current speed, water and air temperatures. Benthic insects were collected with a square parcel sampler of 0.09-m2 area and 300-um net opening and identified to the family level. Faunal density, richness, and diversity exhibited a longitudinal variation. From sampling Stations 1 (reference site) to 3, the number of orders and families decreased, whereas in sampling Station 4 those values increased and continued to do so through to Station 5 (downstream station). Station 5 showed the highest family richness (17) and the highest value for the Shannon-Wiener index (2.74) and the lowest value in Simpson's Dominance index (D = 0.22). These values could be explained because of the self-cleansing capabilities of the river downstream. The water quality of El Tala River is Class I (very clean and non impacted), according to the results obtained from the application of the biotic Biological-Monitoring-Working-Party and Average-Store-per-Taxon indices. PMID- 23917564 TI - Are orchid bees at risk? First comparative survey suggests declining populations of forest-dependent species. AB - The two largest Atlantic Forest remnants in the state of Espirito Santo, eastern Brazil, namely 'Reserva Biologica de Sooretama' (REBIO Sooretama) and 'Reserva Natural Vale' (RNV), were surveyed for their orchid-bee faunas. Seventeen scent baits were used to attract orchid-bee males. Three-thousand, two hundred and twenty-five males belonging to 24 species were actively collected with insect nets during 100 hours in March, April and December, 2009. In comparison with a previous study in the same area twelve years before, it is evident that the abundance of all forest-dependent orchid bees analysed declined around 50%, and it was statistically significant (P = 0.022) for Euglossa marianae Nemesio, 2011, the most sensitive to anthropogenic disturbances of all Atlantic Forest orchid bees. On the other hand, the abundance of populations of species tolerant to open or disturbed areas rose. Possible explanations are discussed. PMID- 23917565 TI - The orchid-bee faunas (Hymenoptera: Apidae) of two Atlantic Forest remnants in southern Bahia, eastern Brazil. AB - The orchid-bee faunas of the 'Parque Nacional do Pau Brasil' (8,500 ha) and 'RPPN Estacao Veracel' (6,000 ha), two Atlantic Forest remnants in the southern state of Bahia, northeastern Brazil, were surveyed. Seventeen chemical compounds were used as scent baits to attract orchid-bee males. Seven hundred and twelve males belonging to 20 species were actively collected with insect nets during 80 hours in February and April, 2009. Euglossa marianae Nemesio, 2011, the most sensitive orchid-bee species of the Atlantic Forest, was recorded at both preserves, though in low abundance. 'RPPN Estacao Veracel' is the smallest forest patch where Euglossa marianae has ever been recorded. PMID- 23917566 TI - Gonad maturation of Haemulon plumieri (Teleostei: Haemulidae) in Ceara state, Northeastern Brazil. AB - To elucidate the reproductive cycle of any animal, it is first necessary to understand the development of the germ cells and how this process occurs throughout the reproductive tract. Thus, the aim of the present study was to understand the oogenesis and spermatogenesis, as well as the ovarian and testis maturation and type of spawning, of Haemulon plumieri. A total of 119 females and 136 males were analysed. Based on micro and macroscopic characteristics of gonads, the following stages of maturation for females were determined: immature, maturing, ripe, partially spawning, spawning and resting. For males, only the stages immature, maturing, ripe and spent were observed. We can conclude that the ovarian development occurs cyclically, in which the female can spawn more than two times during the reproductive season with the spawning "synchronous in more than two groups". Since males do not present the "rest" stage after copulation, the maturation process is continuous. PMID- 23917567 TI - Reproductive biology of Haemulon plumieri (Teleostei: Haemulidae) in Ceara state, Northeastern Brazil. AB - The Haemulon plumieri is a typical reef-associated and tropical species found in warm and temperate waters of the Western Atlantic. Due to the large fishing effort directed to H. plumieri, the knowledge about its reproductive biology is essential for correct stock management and conservation. The aim of this study was to characterise reproductive biology with a focus on its seasonal variation of gonadal maturation stages, first maturation size and fecundity. Specimens were monthly collected and a total of 119 females and 136 males were analysed. The reproductive cycle of Haemulon plumieri is seasonal, with higher activity between March and May. Size at first maturity (L50) was estimated at 16.86 and 18.55 cm for females and males, respectively. The total fecundity ranged between 17,816 and 120,333 mature oocytes per female and relative fecundity was 235 +/- 63 oocyte.g-1 whereas batch fecundity varied between 20 and 25% from total fecundity. Since the species is widely caught, we suggest a closed season from March to May and to establish a minimum catch size of 18.5 cm for both sexes, since there is no evident sexual dimorphism. PMID- 23917568 TI - Modelling the growth of tambaqui, Colossoma macropomum (Cuvier, 1816) in floodplain lakes: model selection and multimodel inference. AB - The tambaqui, Colossoma macropomum, is one of the most commercially valuable Amazonian fish species, and in the floodplains of the region, they are caught in both rivers and lakes. Most growth studies on this species to date have adjusted only one growth model, the von Bertalanffy, without considering its possible uncertainties. In this study, four different models (von Bertalanffy, Logistic, Gompertz and the general model of Schnute-Richards) were adjusted to a data set of fish caught within lakes from the middle Solimoes River. These models were adjusted by non-linear equations, using the sample size of each age class as its weight. The adjustment evaluation of each model was based on the Akaike Information Criterion (AIC), the variation of AIC between the models (Deltai) and the evidence weights (wi). Both the Logistic (Deltai = 0.0) and Gompertz (Deltai = 1.12) models were supported by the data, but neither of them was clearly superior (wi, respectively 52.44 and 29.95%). Thus, we propose the use of an averaged-model to estimate the asymptotic length (Linfinity). The averaged-model, based on Logistic and Gompertz models, resulted in an estimate of Linfinity=90.36, indicating that the tambaqui would take approximately 25 years to reach average size. PMID- 23917569 TI - A new Tanaostigmodes Ashmead (Hymenoptera, Tanaostigmatidae) from Brazil. AB - Tanaostigmodes horacioi sp. nov. Perioto & Lara (Hymenoptera, Tanaostigmatidae) from Brazil is described and illustrated. T. horacioi is the second included species in the insculptus species group of Tanaostigmodes Ashmead, 1896. A key to species of the insculptus group is provided. PMID- 23917570 TI - New species of the genus Dentigaster Zettel (Hymenoptera, Braconidae, Cheloninae) from Brazil. AB - A new species of the genus Dentigaster Zettel, 1990 (Braconidae, Cheloninae) is described from savannah areas of Mato Grosso, Sao Paulo and Minas Gerais states, Brazil. This is the fourth species of the genus known for brazilian fauna. PMID- 23917571 TI - First report of Maconellicoccus hirsutus (Green, 1908) (Hemiptera: Coccoidea: Pseudococcidae) and the associated parasitoid Anagyrus kamali Moursi, 1948 (Hymenoptera: Encyrtidae), in Brazil. AB - The pink hibiscus mealybug (PHM), Maconellicoccus hirsutus (Green) (Hemiptera: Pseudococcidae) and the associated hymenopterous parasitoid, Anagyrus kamali Moursi, 1948 (Hymenoptera: Encyrtidae), are reported for the first time in Brazil. Specimens of the PHM were collected on nine hosts plants, Annona muricata L. (Anonnaceae), Glycine max (L.) Merr. (Fabaceae), Centrolobium paraensis Tul. (Fabaceae), Inga edulis Mart. (Fabaceae), Hibiscus rosa-sinensis L. (Malvaceae), Psidium guajava L. (Myrtaceae), Averrhoa carambola L. (Oxalidaceae), Citrus sinensis (L.) Osbeck (Rutaceae) and Solanum lycopersicum L. (Solanaceae), in four municipalities in the north-northeast of the state of Roraima. The plants C. paraensis, I. edulis and C. sinensis are recorded for the first time as a hosts for PHM. Characteristic injuries observed on the host plants infested by PHM and suggestions for its management are presented. PMID- 23917572 TI - Biological aspects of Eriopis connexa (Germar) (Coleoptera: Coccinellidae) fed on different insect pests of maize (Zea mays L.) and sorghum [Sorghum bicolor L. (Moench.)]. AB - Eriopis connexa (Germar) (Coleoptera: Coccinellidae) occurs in several countries of South America and its mass rearing is important for biological control programmes. This work evaluated biological aspects of E. connexa larva fed on eggs of Anagasta kuehniella (Zeller) (Lepidoptera: Pyralidae) and Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae) frozen for one day, fresh eggs of Diatraea saccharalis (Fabricius) (Lepidoptera: Pyralidae), S. frugiperda newly hatched caterpillars, nymphs of Rhopalosiphum maidis (Fitch) and Schizaphis graminum (Rondani) (Hemiptera: Aphididae). Duration of larva, pupa and larva to adult stages differed among prey offered, whereas the prepupa stage was similar. Larva, pupa, prepupa and larva to adult viabilities were equal or major of 87.5% in all prey, except for larva fed on newly-hatched larvae of S. frugiperda. Eriopis connexa has good adaptation to different prey corroborating its polyphagous feeding habit, which evidences the potential of this natural enemy for controlling corn and sorghum pests. PMID- 23917573 TI - Leukocytes respiratory burst activity as indicator of innate immunity of pacu Piaractus mesopotamicus. AB - The present study evaluated the assay to quantify the respiratory burst activity of blood leukocytes of pacu as an indicator of the innate immune system, using the reduction of nitroblue tetrazolium (NBT) to formazan as a measure of the production of reactive oxygen species (ROS). In order to assess the accuracy of the assay, fish were challenged by Aeromonas hydrophila and sampled one week after challenge. The A. hydrophila infection increased the leukocyte respiratory burst activity. The protocol showed a reliable and easy assay, appropriate to determine the respiratory burst activity of blood leukocytes of pacu, a neotropical fish, in the present experimental conditions. PMID- 23917574 TI - Diadema ascensionis (Echinodermata: Echinoidea) is not restricted to Oceanic Islands: evidence from morphological data. AB - The genus Diadema presently consists of seven species, two of which are known from the Brazilian coast: D. antillarum and D. ascensionis. The first is usually known for shallow coastal areas, while the second was apparently restricted to oceanic islands. In February 2011, a dense population of D. ascensionis was observed on the coastal reefs of Praia do Frances (Alagoas State, northeastern Brazil). Five specimens were collected and transported to the laboratory where morphological studies of the test and pedicellariae were conducted. Subsequently, visits were made to scientific collections in order to compare and confirm species identifications. Our observations confirm the presence of tridentate pedicellariae with narrow and strongly curved valves. The axial cavity in the tips of the spines is filled with dense nonreticular tissue. This taxonomic data confirms the occurrence of D. ascensionis in coastal areas. On the coastal reefs of Praia do Frances, animals were observed from the beach to the reef formations about 200 m offshore in areas with a sandy substrate and in reef cavities, usually in clear and well illuminated waters. Solitary individuals or groups of up to 15 individuals formed dense populations in the area. We stress the importance of pedicellariae for the specific identification of the Diadematidae, considering that they are quite constant and reliable at this taxonomic level. Our results demonstrate that D. ascensionis is not restricted to insular environments and that this species may be common in shallow coastal habitats. PMID- 23917575 TI - The orchid-bee faunas (Hymenoptera: Apidae) of 'Parque Nacional do Monte Pascoal', 'Parque Nacional do Descobrimento' and three other Atlantic Forest remnants in southern Bahia, eastern Brazil. AB - The orchid-bee faunas of 'Parque Nacional do Monte Pascoal', 'Parque Nacional do Descobrimento' and three other Atlantic Forest remnants ranging from 1 to 300 ha in southern Bahia, eastern Brazil, were surveyed. Baits with seventeen different scents were used to attract orchid-bee males. Four thousand seven hundred and sixty-four males belonging to 36 species were actively collected with insect nets during 300 hours from November, 2008 to November, 2009. Richness and diversity of orchid bees found in this study are the highest ever recorded in the Atlantic Forest domain. Eufriesea dentilabris (Mocsary, 1897) and Eufriesea violacea (Blanchard, 1840) were collected at the 'Parque Nacional do Monte Pascoal', the first record of these species for the state of Bahia and the northernmost record for both species. Females Exaerete dentata (Linnaeus, 1758) were also collected at 'Parque Nacional do Monte Pascoal' and old records of Eufriesea aeneiventris (Mocsary, 1896) in this area makes this site the richest and most diverse concerning its orchid-bee fauna in the entire Atlantic Forest and similar to areas in the Amazon Basin. PMID- 23917576 TI - Remarks about biology of Canthon rutilans Laporte, 1840 (Coleoptera: Scarabaeidae) with the first report of perching in a Brazilian Tropical Dry Forest. PMID- 23917577 TI - Revealing highly conserved regions in the E6 protein among distinct human papillomavirus types using comparative analysis of multiple sequence alignments. PMID- 23917578 TI - First record of Brevimulticaecum larvae (Nematoda, Heterocheilidae) in amphibians from northern Argentina. PMID- 23917579 TI - A facultative association between Plebeia droryana (Friese, 1900) (Hymenoptera: Apidae: Meliponini) and a wax scale insect, Ceroplastes janeirensis (Hemiptera: Coccoidea: Coccidae). PMID- 23917580 TI - Addressing key ecological questions to support policy-making in Brazil. PMID- 23917582 TI - Obesity: Cold exposure increases brown adipose tissue in humans. PMID- 23917583 TI - Metabolism: FTO-associated obesity risk is linked to brain food responses via modulation of ghrelin levels. PMID- 23917584 TI - Metabolic profiling of Alzheimer's disease brains. AB - Alzheimer's disease (AD) is an irreversible, progressive brain disease and can be definitively diagnosed after death through an examination of senile plaques and neurofibrillary tangles in several brain regions. It is to be expected that changes in the concentration and/or localization of low-molecular-weight molecules are linked to the pathological changes that occur in AD, and determining their identity would provide valuable information regarding AD processes. Here, we propose definitive brain metabolic profiling using ultra performance liquid chromatography coupled with electrospray time-of-flight mass spectrometry analysis. The acquired data were subjected to principal components analysis to differentiate the frontal and parietal lobes of the AD/Control groups. Significant differences in the levels of spermine and spermidine were identified using S-plot, mass spectra, databases and standards. Based on the investigation of the polyamine metabolite pathway, these data establish that the downstream metabolites of ornithine are increased, potentially implicating ornithine decarboxylase activity in AD pathology. PMID- 23917586 TI - Perisurgical induction of eculizumab in a patient with paroxysmal nocturnal hemoglobinuria: its inhibition of surgery-triggered hemolysis and the consequence of subsequent discontinuation. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement (C') induced lysis of PNH red blood cells (RBCs), which are deficient in the expression of CD55 and CD59. Surgery is one of the major clinical situations that trigger hemolytic attack and thrombosis in PNH. We describe here a case of 64 year-old man with classic PNH complicated by early-stage gastric cancer requiring distal gastrectomy under general anesthesia. We administered humanized monoclonal anti-C5 antibody (eculizumab; Soliris) for a limited period (600 mg, once a week * four times) perisurgically. Eculizumab effectively inhibited the C' system and the patient underwent a curative distal gastrectomy without significant surgery triggered hemolytic attack. Although discontinuation of eculizumab induced mild hemolysis 2 weeks after the last administration, it was treated conservatively without thrombotic complication. Limited-term induction of eculizumab could be an option for PNH patients with transient and anticipated high risks, with careful preparation for the discontinuation-related risks afterwards. PMID- 23917585 TI - Correlation between D-dimer levels and coronary artery reperfusion in acute myocardial infarction patients after thrombolytic treatment. AB - The correlation between plasma D-dimer level and reperfusion has not been clarified yet in thrombolytic therapy applied for acute myocardial infarction patients. The aim of this study was to investigate whether there is a relationship between reperfusion and fibrinolytic activity in acute myocardial infarction patients treated with thrombolytic therapy. Fibrinolytic activity was reflected by plasma D-dimer levels. During the study period, 186 patients were initially analyzed. But 18 of these patients were excluded from the study because they were not suitable for study criteria. Blood was collected from 168 acute myocardial infarction patients within first 6 h. Intravenous tissue plasminogen activator (100 mg) or streptokinase (1,500,000 U) was applied to patients. Mean age of the patients was 58 (28-86) years and majority was men (86%). The number of anterior, inferior, and lateral myocardial infarction patients were 76 (45.2%), 85 (50.6%), and seven (4.2%), respectively. The mean time from symptom onset to thrombolytic application was 134 (95-212) min. Reperfusion occurred in 115 (68.5%) patients. D-dimer levels were markedly high after thrombolytic therapy versus before (155 mg/dl, 362 mg/dl, P<0.005). We compared the D-dimer values before and after thrombolytic therapy between reperfused group and the nonreperfused group (189-409 mg/l in reperfused group, P=0.086; 82-258 mg/l in the nonreperfused group, P=0.173). In conclusion, in this study, D-dimer levels were elevated markedly in patients with ST elevation myocardial infarction after thrombolytic therapy, but no significant difference was seen in D-dimer levels between the reperfused and nonreperfused groups. PMID- 23917587 TI - Reference ranges for sonographic renal dimensions in preterm infants. AB - BACKGROUND: Ultrasonographic measurement of kidney dimensions is important in evaluation of renal disease in preterm infants who have multiple comorbidities that affect renal function. OBJECTIVE: The purpose of this study was to determine the reference ranges of kidney dimensions in preterm newborns and to provide a chart to use easily in daily practice. MATERIALS AND METHODS: We evaluated renal dimensions in 498 preterm infants with a gestational age of <37 weeks using sonography within the first week of life. We statistically analyzed the relationships between all dimensions and gender, gestational age (based on the last menstrual period), height and weight. Minimum and maximum values of dimensions were defined. RESULTS: All dimensions of the kidneys were statistically different in boys and girls (P < 0.05). Both longitudinal and anteroposterior dimensions of the right and left kidneys showed high correlation with gestational age, weight and height in girls and boys. Weight correlated best with dimensions. CONCLUSION: Nomograms from these data can be used to determine an abnormality in kidneys of preterm newborns. PMID- 23917588 TI - Pediatric neuroimaging using magnetic resonance imaging during non-sedated sleep. AB - BACKGROUND: Etiological studies of many neurological and psychiatric disorders are increasingly turning toward longitudinal investigations of infant brain development in order to discern predisposing structural and/or functional differences prior to the onset of overt clinical symptoms. While MRI provides a noninvasive window into the developing brain, MRI of infants and toddlers is challenging due to the modality's extreme motion sensitivity and children's difficulty in remaining still during image acquisition. OBJECTIVE: Here, we outline a broad research protocol for successful MRI of children under 4 years of age during natural, non-sedated sleep. MATERIALS AND METHODS: All children were imaged during natural, non-sedated sleep. Active and passive measures to reduce acoustic noise were implemented to reduce the likelihood of the children waking up during acquisition. Foam cushions and vacuum immobilizers were used to limit intra-scan motion artifacts. RESULTS: More than 380 MRI datasets have been successfully acquired from 220 children younger than 4 years of age within the past 39 months. Implemented measures permitted children to remain asleep for the duration of the scan and allowed the data to be acquired with an overall 97% success rate. CONCLUSION: The proposed method greatly advances current pediatric imaging techniques and may be readily implemented in other research and clinical settings to facilitate and further improve pediatric neuroimaging. PMID- 23917589 TI - Gonadal shielding for neonates. PMID- 23917590 TI - Neuroimaging findings in children with Keutel syndrome. AB - BACKGROUND: Keutel syndrome is a rare autosomal-recessive condition characterized by abnormal cartilage calcification. Neuroimaging findings associated with this condition have been randomly described in the literature. OBJECTIVE: To systematically evaluate the neuroimaging findings in a series of children with Keutel syndrome to broaden our base of knowledge. MATERIALS AND METHODS: Four children with confirmed Keutel syndrome were reviewed for the brain, head and neck imaging findings. RESULTS: Three of the four children, all siblings, showed evidence of moyamoya syndrome. All four siblings had pinna cartilage calcification. CONCLUSION: We propose that Keutel syndrome be considered and included among the secondary causes of moyamoya syndrome. In children with petrified auricle and neurological symptoms, Keutel syndrome should be considered and brain MRI with MRA is required. PMID- 23917591 TI - [Lead survival and complications (except infections). Are we doing better nowadays?]. AB - In the last decade manufacturers of cardiac rhythm management devices focused mainly on the reduction of both device and lead size. Furthermore the implementation of additional functions like cardiac monitoring and new algorithms as well as increasing defibrillation safety through higher energy delivery became of greater interest. The FDA recall (class I) of some of the commonly used ICD leads led to a change in thinking in ICD therapy, more attention to device and lead function control in addition to the increased awareness of lead complications. These issues changed our daily behaviour in ICD implantation and follow up effectively. The following article gives an overview of ICD lead performance, suitable recalls, complications as well as available control functions. The need for improved market supervision of lead function in the medical community and proven alternative device therapies for selected patients is being discussed. PMID- 23917592 TI - Laparoscopic versus open gastrectomy for early gastric cancer in Asia: a meta analysis. AB - OBJECTIVE: To perform a meta-analysis comparing laparoscopic versus open gastrectomy (LG vs. OG) for early gastric cancer (EGC) in Asia. METHODS: PubMed, Embase, CINAHL, AMED, the Cochrane database of Systematic Reviews, the Cochrane Controlled Trials Register, and the China National Knowledge Infrastructure electronic databases were systematically searched for studies published between January 1, 1992 and July 1, 2012. A series of clinical indices, including operative time, incision length, blood loss, harvested lymph nodes, time to flatus postoperatively, time to first oral intake postoperatively, use of analgesics, complications, duration of hospital stay, recurrence, and mortality were compared using weighted mean differences (WMDs) and odds ratios (ORs). RESULTS: Five randomized controlled trials and 11 case controls were included, including 1665 patients with EGC (919 LG, 746 OG). LG was associated with less trauma (incision length: WMD -12.91 cm; P<0.00001), less blood loss (WMD -121.04 mL, P<0.00001), less postoperative pain (number of times to use analgesics: WMD 1.64; P=0.001), faster bowel recovery (time to flatus: WMD -0.62 d; P=0.0001), fewer serious complications (OR 0.57; P=0.01), and shorter postoperative hospital stay (WMD -3.73 d; P=0.0007). However, LG had longer operative times (WMD 44.09 min; P<0.00001). LG also had fewer harvested lymph nodes, although this difference was not statistically significant (WMD -3.43 lymph nodes; P=0.04). There was no difference in recurrence rates (OR 0.58; P=0.33) and mortality between LG and OG. CONCLUSIONS: For the treatment of EGC in Asia, LG has several advantages, including safety, less trauma, and faster recovery. Our results should be validated in western studies. PMID- 23917593 TI - Laparoscopic versus open gastric resections for gastric gastrointestinal stromal tumors: a meta-analysis. AB - PURPOSE: We conducted a meta-analysis to compare surgical and oncologic outcomes of patients with gastric gastrointestinal stromal tumors (GISTs) undergoing laparoscopic resection surgery (LAP) and open resection surgery (OPEN). METHODS: PubMed, Ovid, Web of Science, Cochrane, CNKI, and Chinese Biomedical Database were searched. Statistical analysis was carried out by RevMan 5.0 software. The quality of evidence was assessed by the Newcastle-Ottawa scale. A decision tree analysis model was constructed to evaluate the treatment strategy. RESULTS: Seventeen studies involving 776 participants were included for the meta-analysis. The meta-analysis results showed that, compared with OPEN, LAP indicates potentially favorable outcomes in terms of intraoperative blood loss [weighted mean difference (WMD), -60.67; 95% confidence interval (95% CI), -116.66 to 4.69], time to first flatus (WMD, -1.19; 95% CI, -1.65 to -0.73), time to oral intake (WMD, -1.26; 95% CI, -1.89 to -0.63), and hospital stay (WMD, -2.62; 95% CI, -3.25 to -1.99). There were no differences in terms of the operative time, overall complication, and recurrence. Decision analysis showed that LAP was the strategy with a higher overall success (93%) compared with OPEN (88%). CONCLUSIONS: This meta-analysis showed that LAP for gastric GISTs was associated with less blood loss, earlier return of bowel function, earlier resumption of diet, and shorter length of hospital stay when compared with OPEN; however, LAP and OPEN had similar operative time, overall complication, and recurrence. The LAP might be superior to OPEN for the patients with GIST <5 cm. Methodologically, high-quality comparative studies are needed for further evaluation. PMID- 23917594 TI - Effects of the ischemic preconditioning on anastomotic healing in laparoscopic colon operations. AB - BACKGROUND: Previous experimental studies have repeatedly demonstrated the potential protective effect of remote ischemic preconditioning (IPC) on colon anastomosis. The purpose of this experimental study was to investigate the possible positive effects of IPC by interval insufflations in laparoscopic colon operations. METHODS: Thirty Wistar-albino rats were randomized into 3 groups. Colonic transsection and anastomosis were performed in the control group. In the laparoscopic colon operation without IPC group, the intra-abdominal pressure was raised to 14 mm Hg for 60 minutes, and then laparotomy and colonic anastomosis were performed. In the IPC group, the intra-abdominal pressure was raised to 14 mm Hg for 5 minutes, followed by desufflation. Laparotomy and colonic anastomosis were performed exactly as in the non-IPC group. On the seventh postoperative day, all animals were killed, and blood and tissue samples were obtained. Anastomotic healing and inflammatory responses were determined by histopathologic examination and by measuring the anastomotic bursting pressure, tissue hydroxyproline level, and tissue and serum nitric oxide, malondialdehyde (MDA), and catalase activity levels. Differences with P-values of <0.05 were considered to be statistically significant. RESULTS: Although the best anastomotic healing was detected in the control group, anastomotic healing was better in the IPC group than that in the non-IPC group. In terms of anastomotic bursting pressure, plasma MDA, serum catalase activity, and tissue nitric oxide levels, the IPC group was superior to the non-IPC group. No significant differences were found between the control and IPC groups, except in the plasma MDA levels. CONCLUSIONS: Use of IPC with colon anastomosis had positive effects on wound healing and may serve as a safe method to reduce the adverse effects of ischemia and wound healing in laparoscopic colon operations. PMID- 23917595 TI - Effect of computer game playing on baseline laparoscopic simulator skills. AB - BACKGROUND: Studies examining the possible association between computer game playing and laparoscopic performance in general have yielded conflicting results and neither has a relationship between computer game playing and baseline performance on laparoscopic simulators been established. OBJECTIVE: The aim of this study was to examine the possible association between previous and present computer game playing and baseline performance on a virtual reality laparoscopic performance in a sample of potential future medical students. DESIGN: The participating students completed a questionnaire covering the weekly amount and type of computer game playing activity during the previous year and 3 years ago. They then performed 2 repetitions of 2 tasks ("gallbladder dissection" and "traverse tube") on a virtual reality laparoscopic simulator. Performance on the simulator were then analyzed for association to their computer game experience. SETTING: Local high school, Norway. PARTICIPANTS: Forty-eight students from 2 high school classes volunteered to participate in the study. RESULTS: No association between prior and present computer game playing and baseline performance was found. The results were similar both for prior and present action game playing and prior and present computer game playing in general. CONCLUSION: Our results indicate that prior and present computer game playing may not affect baseline performance in a virtual reality simulator. PMID- 23917596 TI - Single-port versus standard laparoscopic resection for a gastric benign tumor in gastroscopic-laparoscopic rendezvous procedures using a laser-supported diaphanoscopy. AB - In this study, the standard laparoscopic technique versus the single-port approach was evaluated for the excision of benign gastric tumors using tissue sparing laser-supported diaphanoscopy for localization. The first group consisted of 10 patients suffering from benign gastric tumors treated by standard laparoscopic resection. The second group included 10 patients treated using the single-port technique. All procedures were successfully completed. Histopathologic examination confirmed 15 cases of gastrointestinal stromal tumor, 3 cases of lipoma, 1 case of leiomyoma, and 1 case of high-grade dysplasia. There was no statistically significant difference for the operation times between both groups. Comparison of the largest and smallest resection margins achieved using the standard laparoscopic technique and single-port techniques showed no statistically significant differences between the groups. During follow-up, all patients were evaluated using the total body image and cosmesis questionnaire. Although scores of all body-image functions were similar, independent of laparoscopic technique, scores of all cosmetic functions in patients operated using the single-port technique showed a statistically significant higher degree of satisfaction with the scar (P<0185). The postoperative pain scores evaluated by the visual analog scale score were not significantly different between 2 groups. The single-port technique was found to be a feasible option for the resection of submucosal or mucosal tumors. However, this method is not intended to replace standard laparoscopic resections. PMID- 23917597 TI - Laparoscopic-assisted minithoracotomy for repair of diaphragmatic penetrating trauma. AB - BACKGROUND: Stable patients with thoracoabdominal penetrating or blunt trauma resulting in diaphragmatic injuries represent a challenging dilemma. Laparoscopy has emerged as the most reliable and efficient diagnostic and treatment modality for such patients. OBJECTIVE: The aim of this study was to analyze our novel surgical technique for the management of penetrating diaphragmatic injuries in stable patients. MATERIALS AND METHODS: In this retrospective study, we analyzed data that had been prospectively collected on a new surgical repair technique established at our institution. We reviewed the records of 7 hemodynamically stable trauma patients with thoracoabdominal penetrating trauma resulting in diaphragmatic injuries. RESULTS: The 7 patients (5 with stab wounds, 2 with gunshot wounds) underwent laparoscopic exploration and laparoscopic-assisted minithoracotomy for the repair of diaphragmatic injuries. The mean length of stay was 4.4 days (range, 1 to 8 d). There were no tension pneumothoraces, missed injuries, or other procedure-related complications. CONCLUSIONS: If complete laparoscopic repair is not possible, laparoscopic-assisted repair of diaphragmatic injuries using minithoracotomy is a viable option. In our 7 patients, the results were good, with no morbidity. PMID- 23917598 TI - Drainage placement through the extraperitoneal tunnel can prevent its postoperative dislodgement effectively in laparoscopic rectal surgery. AB - BACKGROUND: Drainage placement is frequently used in laparoscopic rectal surgery, and dislodgement is common in conventional transperitoneal drainage placement. We proposed that extraperitoneal tunnel for drainage placement is useful to prevent the dislodgement. METHODS: We conducted an observational case-matched control study. In study group, a total of 40 patients undergoing laparoscopic rectal surgery with drainage through the extraperitoneal tunnel were enrolled. In control group, a total of 35 matched patients with drainage through the transperitoneal route were enrolled. Clinical data, tumor features, and intraoperative and postoperative characteristics were analyzed. RESULTS: Ten patients had drainage dislodgement in the transperitoneal group (28%) and 4 patients in the extraperitoneal group (10%). The P value was 0.039. Postoperative recovery was faster in the extraperitoneal group than in the transperitoneal group, as reflected by a shorter time to diet (P=0.049) and postoperative length of stay (P=0.032). In a multivariate analysis, drain dislodgement had a significant impact on the time to diet (P=0.023) and the postoperative length of stay (P=0.037). Drain placement influenced the time to diet (P=0.055) and the postoperative length of stay (P=0.079). CONCLUSIONS: In laparoscopic rectal surgery, drainage placement through the extraperitoneal tunnel can prevent its postoperative dislodgement effectively and is associated with better postoperative recovery. PMID- 23917599 TI - Thoracoscopic local ablation with diaphragmatic incision method for liver surface tumor in the hepatic dome. AB - PURPOSE: To assess the feasibility and effectiveness of thoracoscopic local ablation therapy with diaphragmatic incision method. BACKGROUND: Liver tumor in the hepatic dome limits the approach method of ablation. These lesions are accessible through a transdiaphragm, and incision of diaphragm by thoracoscopic surgery might be a valuable option. PATIENTS AND METHODS: Between July 1995 and December 2011, 59 patients with a tumor in the hepatic dome were indicated for thoracoscopic local ablation therapy. The diaphragm above tumor was incised and tumors were ablated thoracoscopically. RESULTS: The mean operating time and blood loss was 222 minutes and 33.8 g, respectively. There was no postoperative mortality, and 7 patients with complications recovered successfully. The 5-year overall survival (OS) rate for hepatocellular carcinoma was 51.0%. Local recurrence was suspected in 2 cases. CONCLUSIONS: Thoracoscopic ablation by incision of the diaphragm represents a feasible approach for the tumor in the hepatic dome with acceptable long-term outcomes. PMID- 23917600 TI - Incisional hernia: laparoscopic or open repair? AB - PURPOSE: To compare laparoscopic and open repair of incisional hernia in terms of complications and failure rates. METHODS: Between June 2005 and April 2012, 252 patients underwent incisional hernia repair. Of these, 126 underwent laparoscopic and 126 open repair. The median follow-up was 38.7 months. RESULTS: Baseline characteristics [age, body mass index, American Society of Anesthesiologists (ASA) score, comorbidities, hernia size, and follow-up] did not differ significantly. Mean operative time was similar (72 vs. 83 min). Laparoscopic repair was associated with less postoperative pain, less postoperative complications (3.9% vs. 13.4%, P=0.012), and shorter hospital stay (3.5 vs. 4.3, P=0.002). Recurrence occurred in 6 patients of group 1 and in 7 patients of group 2 (4.7% vs. 5.5%, P=not significant). CONCLUSIONS: In this study, the trend in favor of laparoscopic treatment for incisional hernias is remarkable. Fewer postoperative complications and shorter hospital stay with similar operative time may balance the higher costs associated with the technique. PMID- 23917601 TI - Safe and simple gastric conduit pull-through procedure through the posterior mediastinal route using echo probe cover in thoracoscopic subtotal esophagectomy. AB - A gastric conduit is commonly used to reconstruct the alimentary tract after esophagectomy. When the posterior mediastinum is applied to a reconstruction route, the gastric conduit created has been protected by an echo probe cover and, then blindly elevated to the neck. However, using this elevation method, the gastric conduit has the potential to catch on the vessels and nerves, posing a risk of major bleeding. We report a safe method of gastric conduit pull-through procedure to avoid unexpected technical complications. Two approximately 60-cm long polyester tapes are prepared and ligated at both ends forming a loop. A 50 cm-long echo probe cover of 10 cm in diameter is prepared, and the closed end of the echo probe cover is cut to make an open-ended echo probe cover. A line parallel to the long axis of the echo probe cover is drawn across the echo probe cover with a sterile surgical marking pen. The looped polyester tape is inserted into the echo probe cover. The looped polyester tape and echo probe cover are ligated with 2-0 silk, approximately 5 cm in front of the knots on both sides. After dissection is carried out according to practice, the previously crafted polyester tape is inserted into the chest cavity. The echo probe cover is placed to connect the distal and proximal ends of the esophagus, and its torsion is corrected using the line marked with the pen and a crease, both of which are parallel to the long axis of the echo probe cover. One end of polyester tape is fixed to the distal esophageal stump by using the clips, with the opposite end fixed to the proximal esophageal stump. Either one of the 2 lengths of polyester tape is connected to the gastric conduit. By pulling up this length of polyester tape from the neck, the gastric conduit can pass through the echo probe cover and be elevated to the neck. PMID- 23917602 TI - Laparoscopic repair of perforated peptic ulcer-technical tip. AB - Increasing number of gastrointestinal emergencies are managed laparoscopically. Laparoscopic repair of a perforated peptic ulcer remains contentious. Fashioning an omental patch is a crucial and an essential part of this repair, whether it is performed open or laparoscopically. This article describes a technique to fashion an adequate omental patch over the perforated peptic ulcer. PMID- 23917603 TI - Single-incision endoscopy-assisted ileocecal resection. AB - BACKGROUND: Minimally invasive laparoscopic surgery was widely performed for colectomies. In recent years, as a new approach, the sigmoid colon or rectum is removed through the anus, minimizing the need for skin incisions. However, the resected ileocecal portion or the right side of the colon may be difficult to remove from the anus. Therefore, it usually needs to be removed using a skin incision, which typically restricts the size of the tissue. In these cases, we applied a less-invasive single-incision endoscopy-assisted colectomy to avoid forceps interference and reduce the port size required for the energy device. In this study, we introduce an ideal single-incision technique. METHODS: We performed surgeries on 3 patients with cecal or proximal ascending colon cancer (1 early and 2 advanced cases). Under general anesthesia, we initially made a right pararectal incision (3 to 5 cm), which was dependent on the tumor size and fixed a GelPort (Applied Medical, Orange County, CA) and inserted 12- and 5-mm trocars. Through the 12-mm trocar, we inserted a gastrointestinal scope for dissecting the ileocecal area from the retroperitoneum using a hook knife, similar to the endoscopic submucosal dissection technique. After mobilization, all other maneuvers were performed by an open method. RESULTS: The mean surgery time was 185 minutes. There were no major complications among the patients. DISCUSSION: This single-incision endoscopy-assisted dissection needs no additional suction, irrigation, or electrocoagulator and is a realistic and idealistic technique at present. Transvaginal and transanal retrieval methods are still controversial. CONCLUSION: We believe that this endoscopic technique may be essential for advancement to minimally invasive laparoscopic surgery toward natural orifice transluminal endoscopic surgery. PMID- 23917604 TI - Tacks-free transabdominal preperitoneal (TAPP) inguinal hernioplasty, using an anatomic 3-dimensional lightweight mesh with peritoneal suturing: pain and recurrence outcomes-initial experience. AB - BACKGROUND: The emphasis for research in inguinal hernia repair has shifted from hernia recurrence to groin pain, which is considered the most important factor for poor quality of life. AIM: : To evaluate hernia recurrences and pain at trocar site and at inguinal hernia site, in patients who underwent tacks-free transabdominal preperitoneal inguinal hernia repair, using a lightweight nonfixed 3-dimensional mesh with peritoneal suturing. MATERIALS AND METHODS: Between 2009 and 2011, 32 patients (2 female) with mean age 51 years underwent hernia repair. The mean follow-up period was 12.4 months. RESULTS: The mean operative time was 84 minutes. There was minimal blood loss. No bowel or urinary bladder injury had occurred. Mean hospital stay was 1 day. One patient developed seroma 4 months postoperatively. There were no conversions to open repair, no hernia recurrence, and no deaths. The mean value of pain at trocar site and inguinal hernia site 12 hours postoperatively was 1.469 and 0.875, respectively. The pain was more intense bearing a peak at 12 hours postoperatively at the trocar site, compared with the inguinal site. CONCLUSIONS: It is demonstrated with this technique that there are no recurrences and the chronic pain is negligible. These findings call for confirmatory randomized trials in larger series with longer follow-up. PMID- 23917605 TI - Hypertonic saline-epinephrine local injection therapy for post-endoscopic sphincterotomy bleeding: removal of blood clots using pure ethanol local injection. AB - PURPOSE: Bleeding following endoscopic sphincterotomy (EST) is a rare but unavoidable complication of the procedure. We routinely perform local injection of hypertonic saline-epinephrine (HSE) for the treatment of post-EST bleeding. Any blood clot is removed only by irrigation with water after local injection of pure ethanol into the blood clot to cause crusting. We evaluated the usefulness of this treatment method. METHODS: Subjects were 8 patients (1.2%) with post-EST bleeding requiring hemostatic intervention among 682 patients undergoing EST. After determination of the bleeding point, local injection of HSE was performed. When an adherent blood clot was present, pure ethanol was injected into the blood clot and then irrigation with water was performed to remove the blood clot. RESULTS: Endoscopic hemostasis was successfully achieved in all the 8 patients (100%). In 4 patients (50%), the adherent blood clots were successfully removed only with pure ethanol local injection into the blood clot followed by irrigation with water. No complications of the hemostatic procedure occurred in any patients. CONCLUSIONS: This study indicated that hemostasis with HSE local injection can be safe and useful for the treatment of post-EST bleeding, and also that blood clot removal with pure ethanol local injection can be useful. PMID- 23917606 TI - Surgical glove-port single-incision laparoscopic gastric wedge resection of gastrointestinal stromal tumors: initial experience with 2 cases. AB - Gastrointestinal stromal tumors are localized mainly in the stomach, and the therapeutic approach is surgical resection. Laparoscopy can be performed for tumors located in the greater curvature of the stomach. Among the treatment alternatives, a single-incision laparoscopic technique is used more frequently than standard laparoscopy due to the successful results of laparoscopic surgery. Here, we report the use of single-incision surgical glove-port laparoscopy for the resection of 2 gastrointestinal stromal tumors localized in the greater curvature of stomach. PMID- 23917607 TI - Superior mesenteric vein thrombosis after laparoscopic sleeve gastrectomy. AB - Laparoscopic procedures for morbid obesity are becoming standard of care which, in experienced hands, has a very low mortality and morbidity. Superior mesenteric vein thrombosis has been reported in the literature after different bariatric and nonbariatric laparoscopic procedures. Laparoscopic sleeve gastrectomy is a relatively new procedure in the treatment of morbid obesity; its complications being well-known including staple line leak, bleeding, and stricture among others. We present a case of superior mesenteric vein thrombosis after laparoscopic sleeve gastrectomy successfully managed conservatively with therapeutic anticoagulation, and propose a different hypothesis for the development of such a complication. PMID- 23917608 TI - Single-incision laparoscopic surgery using a homemade transumbilical port for synchronous colon and hepatic lesions: a case report. AB - Single-incision laparoscopic surgery (SILS) is an emerging technique and has been utilized in various abdominal surgeries. Herein, we reported a case of synchronous colon and hepatic lesions that underwent right hemicolectomy and wedge resection of the liver by SILS. To the best of our knowledge, this is the first case report of synchronous colon and liver resection with SILS using homemade transumbilical port. PMID- 23917609 TI - Subvesical bile duct injury: an often missed cause of postcholecystectomy bile leak. AB - We report a case of postoperative bile leak originating from subvesical bile ducts. This anatomic variant of the bile duct is widely prevalent, often undiagnosed, and usually uncovered in the setting of iatrogenic biliary injury. Injury to these ducts during gallbladder surgery can be potentially averted by minimizing dissection into the hepatic parenchyma. Because of their small size, leaks originating from these ducts have good prognosis and almost never require surgical intervention. Preoperative knowledge of this uncommon variant may improve surgical technique aimed at avoiding biliary injury during cholecystectomy. PMID- 23917610 TI - Subdiaphragmatic bronchogenic cyst at the gastroesophageal junction presenting with Dysphagia: a case report. AB - BACKGROUND: Bronchogenic cysts are benign lesions derived from the primitive foregut. They frequently occur in the mediastinum, most commonly at the subcarinal level. Subdiaphragmatic location for bronchogenic cysts is extremely rare. METHODS: A 40-year-old woman presented with worsening dysphagia and was diagnosed as a bronchogenic cyst arising from infradiaphragmatic esophagus by computed tomographic scan and endoscopic ultrasound-guided aspiration. Total laparoscopic enucleation of the cystic mass was performed. RESULTS: The postoperative esophagogram revealed no leak or reflux and the patient was discharged on day 2. The histopathologic examination revealed a bronchogenic cyst. No recurrence of the cyst or symptoms was noted at 6 months. CONCLUSIONS: Infradiaphragmatic bronchogenic cysts are uncommon and may become symptomatic secondary to compression of surrounding structures. A complete resection by laparoscopy is feasible and represents a safe and minimally invasive alternative to traditional resection through laparotomy or thoracotomy. PMID- 23917611 TI - Influence of arbuscular mycorrhiza on growth and reproductive response of plants under water deficit: a meta-analysis. AB - Despite a large body of literature that describes the effects of arbuscular mycorrhizal colonization on plant response to water deficit, reviews of these works have been mainly in narrative form, and it is therefore difficult to quantify the magnitude of the effect. We performed a meta-analysis to examine the effect of mycorrhizal colonization on growth and yield of plants exposed to water deficit stress. Data were compared in the context of annual vs. perennial plants, herbaceous vs. woody plants, field vs. greenhouse conditions, degree of stress, functional group, regions of plant growth, and mycorrhizal and host species. We found that, in terms of biomass measurements, mycorrhizal plants have better growth and reproductive response under water stress compared to non-mycorrhizal plants. When variables such as habit, life cycle, or water stress level are considered, differences in mycorrhizal effect on plant growth between variables are observed. While growth of both annual and perennial plants is improved by symbiosis, perennials respond more favorably to colonization than annuals. Overall, our meta-analysis reveals a quantifiable corroboration of the commonly held view that, under water-deficit conditions, plants colonized by mycorrhizal fungi have better growth and reproductive response than those that are not. PMID- 23917612 TI - An efficient phosphorescence energy transfer between quantum dots and carbon nanotubes for ultrasensitive turn-on detection of DNA. AB - We have demonstrated an efficient phosphorescence energy transfer (PET) system for ultrasensitive detection of DNA. PMID- 23917613 TI - Dihydroartemisinin inhibits tumor growth of human osteosarcoma cells by suppressing Wnt/beta-catenin signaling. AB - Osteosarcoma (OS) is the most common type of bone cancer. Even with early diagnosis and aggressive treatment, the prognosis for OS is poor. In the present study, we investigated the proliferation and invasion inhibitory effect of dihydroartemisinin (DHA) on human OS cells and the possible molecular mechanisms involved. We demonstrated that DHA can inhibit proliferation, decrease migration, reduce invasion and induce apoptosis in human OS cells. Using an in vivo tumor animal model, we confirmed that DHA can prevent OS formation and maintain intact bone structure in athymic mice. In addition, we examined the possible molecular mechanisms mediating the function of DHA. We found that the total protein levels and transcriptional activity of beta-catenin in OS cells are reduced by DHA treatment, and this may result from the increased catalytic activity of glycogen synthase kinase 3beta (GSK3beta). Moreover, the inhibitory effect of DHA on OS cells is reversed by overexpression of beta-catenin, but is further enhanced by knockdown of beta-catenin, respectively. Collectively, our results reveal that DHA can inhibit tumor growth of OS cells by inactivating Wnt/beta-catenin signaling. Therefore, DHA is a promising chemotherapy agent in the treatment of human OS. PMID- 23917614 TI - RNA sensing: the more RIG-I the merrier? PMID- 23917615 TI - Messenger RNA is a functional component of a chromatin insulator complex. AB - Chromatin insulators are DNA protein complexes situated throughout the genome capable of demarcating independent transcriptional domains. Previous studies point to an important role for RNA in gypsy chromatin insulator function in Drosophila; however, the identity of these putative insulator-associated RNAs is not currently known. Here we utilize RNA-immunoprecipitation and high throughput sequencing (RIP-seq) to isolate RNAs stably associated with gypsy insulator complexes. Strikingly, these RNAs correspond to specific sense-strand, spliced and polyadenylated mRNAs, including two insulator protein transcripts. In order to assess the functional significance of these associated mRNAs independent of their coding function, we expressed untranslatable versions of these transcripts in developing flies and observed both alteration of insulator complex nuclear localization as well as improvement of enhancer-blocking activity. Together, these data suggest a novel, noncoding mechanism by which certain mRNAs contribute to chromatin insulator function. PMID- 23917616 TI - The myotubularin-amphiphysin 2 complex in membrane tubulation and centronuclear myopathies. AB - Myotubularin (MTM1) and amphiphysin 2 (BIN1) are two proteins mutated in different forms of centronuclear myopathy, but the functional and pathological relationship between these two proteins was unknown. Here, we identified MTM1 as a novel binding partner of BIN1, both in vitro and endogenously in skeletal muscle. Moreover, MTM1 enhances BIN1-mediated membrane tubulation, depending on binding and phosphoinositide phosphatase activity. BIN1 patient mutations induce a conformational change in BIN1 and alter its binding and regulation by MTM1. In conclusion, we identified the first molecular and functional link between MTM1 and BIN1, supporting a common pathological mechanism in different forms of centronuclear myopathy. PMID- 23917620 TI - Voltage-induced chromatic phase transition in ferrocene substituted polydiacetylene thin films. AB - A novel ferrocene substituted PDA (FEPDA) material was synthesized and its chromatic phase transition behavior was studied under the application of a negative bias voltage. By the combination with CMS techniques, FEPDA materials could be used as a probe for mapping the topographic carrier density distribution in organic devices. PMID- 23917618 TI - Age- and sex-based reference limits and clinical correlates of myocardial strain and synchrony: the Framingham Heart Study. AB - BACKGROUND: There is rapidly growing interest in applying measures of myocardial strain and synchrony in clinical investigations and in practice; data are limited regarding their reference ranges in healthy individuals. METHODS AND RESULTS: We performed speckle-tracking-based echocardiographic measures of left ventricular myocardial strain and synchrony in healthy adults (n=739, mean age 63 years, 64% women) without cardiovascular disease. Reference values were estimated using quantile regression. Age- and sex-based upper (97.5th quantile) limits were: 14.4% to -17.1% (women) and -14.4 to -15.2% (men) for longitudinal strain; -22.3% to -24.7% (women) and -17.9% to -23.7% (men) for circumferential strain; 121 to 165 ms (women) and 143 to 230 ms (men) for longitudinal segmental synchrony (SD of regional time-to-peak strains); and 200 to 222 ms (women) and 216 to 303 ms (men) for transverse segmental synchrony. In multivariable analyses, women had ~1.7% greater longitudinal strain, ~2.2% greater transverse strain, and ~3.2% greater circumferential strain (P<0.0001 for all) compared with men. Older age and higher diastolic blood pressure, even within the normal range, were associated with worse transverse segmental synchrony (P<0.001). Overall, covariates contributed to <=12% of the variation in myocardial strain or synchrony in this healthy sample. CONCLUSIONS: We estimated age- and sex-specific reference limits for measures of left ventricular strain and synchrony in a healthy community-based sample, wherein clinical covariates contributed to only a modest proportion of the variation. These data may facilitate the interpretation of left ventricular strain-based measures obtained in future clinical research and practice. PMID- 23917621 TI - Inflammatory effect of green propolis on dental pulp in rats. AB - Pulpotomy in deciduous teeth is a controversial issue, especially with regard to alternative materials used for the direct pulp capping of the root canal pulp tissue. The aim of the present study was to perform a histological analysis of the initial reaction of the root canal pulp tissue in rats, following pulpotomy and pulp capping with (1) green propolis extract, (2) iodoform paste, (3) green propolis extract + iodoform and (4) calcium hydroxide paste with saline solution. Analyses were performed after 24 hours, 72 hours and 7 days. The substances containing green propolis extract and iodoform led to the production of an intense inflammatory infiltrate and necrosis in the root canal pulp tissue throughout the analyses. In the calcium hydroxide group, inflammatory infiltrate only prevailed at the 72-hour evaluation. Among the substances tested, calcium hydroxide paste induced the lowest intensity of inflammatory response in the root canal pulp tissue. Longer studies should be carried out to analyze the pulp repair process following pulpotomy and pulp capping with the compounds analyzed. PMID- 23917622 TI - Experimental Techniques for Bubble Dynamics Analysis in Microchannels: A Review. AB - Experimental studies employing advanced measurement techniques have played an important role in the advancement of two-phase microfluidic systems. In particular, flow visualization is very helpful in understanding the physics of two-phase phenomenon in microdevices. The objective of this article is to provide a brief but inclusive review of the available methods for studying bubble dynamics in microchannels and to introduce prior studies, which developed these techniques or utilized them for a particular microchannel application. The majority of experimental techniques used for characterizing two-phase flow in microchannels employs high-speed imaging and requires direct optical access to the flow. Such methods include conventional brightfield microscopy, fluorescent microscopy, confocal scanning laser microscopy, and micro particle image velocimetry (micro-PIV). The application of these methods, as well as magnetic resonance imaging (MRI) and some novel techniques employing nonintrusive sensors, to multiphase microfluidic systems is presented in this review. PMID- 23917623 TI - Insertion torque and orthodontic mini-implants: a systematic review of the artificial bone literature. AB - This article systematically reviewed the literature to (1) identify variables that were associated with maximum insertion torque values during the insertion of orthodontic mini-implants into artificial bone, (2) quantify such associations and (3) assess adverse effects of this procedure. Computerized and manual searches were conducted up to 24 February 2012. Selection criteria included studies that (1) recorded maximum insertion torque during the insertion of orthodontic mini-implants into artificial bone, (2) used sample sizes of five screws or more, (3) assessed maximum insertion torque with electronic torque sensors, and (4) used orthodontic mini-implants with a diameter smaller than 2.5 mm. ASTM Standards F543-07(epsilon1) and F1839-08(epsilon1) and the Cochrane Handbook for Systematic Reviews were used as guidelines for this systematic review. Quality assessments were rated according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. A total of 23 studies were selected, many of which were multiple publications of the same study. Many domains in the risk of bias assessments were scored as "high" or "unclear" risk of bias. A wide variety of implant, test block, and insertion procedure-related associations with maximum insertion torque were recorded. The quality of most outcomes was classified as "moderate." Outcomes could not be combined in a meta-analysis because of high risk of bias, poor standardization, high heterogeneity, or inconsistency in direction of outcomes within or between studies. Adverse effects were only assessed in one study. Future studies should control publication bias, consult existing standards for conducting torque tests, and focus on transparent reporting. PMID- 23917624 TI - [Results and lessons of an innovating chemotherapy-induced nauseas and vomiting management strategy]. AB - Current chemotherapy-induced nausea and vomiting management guidelines recommend taking into account the emetogenic potential of the chemotherapy employed as well as individual risk factors to such effects. We performed an interventional prospective study to assess the impact of an innovating therapeutic optimization strategy. The latter combines current guidelines application to a specific consultation in order to individualize the treatment. This study included 170 patients and covered a total of 1,746 days of various chemotherapies. Among these patients, 86.5% never vomited and 53.8% never had any nausea or vomiting. These results seem generally better than the ones found in the literature with all kinds of chemotherapies. Regarding them, we have attempted to highlight the determining criteria for a successful antiemetic treatment. PMID- 23917626 TI - Genomic imprinting and parent-of-origin effects on complex traits. AB - Parent-of-origin effects occur when the phenotypic effect of an allele depends on whether it is inherited from the mother or the father. Several phenomena can cause parent-of-origin effects, but the best characterized is parent-of-origin dependent gene expression associated with genomic imprinting. The development of new mapping approaches applied to the growing abundance of genomic data has demonstrated that imprinted genes can be important contributors to complex trait variation. Therefore, to understand the genetic architecture and evolution of complex traits, including complex diseases and traits of agricultural importance, it is crucial to account for these parent-of-origin effects. Here, we discuss patterns of phenotypic variation associated with imprinting, evidence supporting its role in complex trait variation and approaches for identifying its molecular signatures. PMID- 23917630 TI - Non-coding RNA: Structure and function for lncRNAs. PMID- 23917628 TI - Genetic insights into common pathways and complex relationships among immune mediated diseases. AB - Shared aetiopathogenic factors among immune-mediated diseases have long been suggested by their co-familiality and co-occurrence, and molecular support has been provided by analysis of human leukocyte antigen (HLA) haplotypes and genome wide association studies. The interrelationships can now be better appreciated following the genotyping of large immune disease sample sets on a shared SNP array: the 'Immunochip'. Here, we systematically analyse loci shared among major immune-mediated diseases. This reveals that several diseases share multiple susceptibility loci, but there are many nuances. The most associated variant at a given locus frequently differs and, even when shared, the same allele often has opposite associations. Interestingly, risk alleles conferring the largest effect sizes are usually disease-specific. These factors help to explain why early evidence of extensive 'sharing' is not always reflected in epidemiological overlap. PMID- 23917632 TI - Involvement of autophagy in recombinant human arginase-induced cell apoptosis and growth inhibition of malignant melanoma cells. AB - Recombinant human arginase (rhArg) has been developed for arginine derivation therapy of cancer and is currently in clinical trials for a variety of malignant solid tumors. In this study, we reported for the first time that rhArg could induce obvious autophagy in human melanoma cells; inhibition of autophagy by chloroquine (CQ) significantly increased rhArg-induced cell apoptosis and growth inhibition of A375 cells. A significant increase in mitochondrial membrane potential loss and elevated intracellular reactive oxygen species (ROS) levels were detected in A375 cells after rhArg treatment when compared with control. Membrane transition inhibitor cyclosporine A blocked autophagy and accelerated cell death induced by rhArg, indicating that rhArg induced autophagy via mitochondria pathway. Furthermore, antioxidant N-acetyl-L-cysteine suppressed rhArg-induced autophagy and rescued cells from cell growth inhibition, suggesting that ROS played an important role in rhArg-induced A375 cell growth inhibition and autophagy. Akt/mTOR signaling pathway was involved in autophagy induced by rhArg in a time-dependent manner. Moreover, rhArg could induce ERK1/2 activation in a dose- and time-dependent manner and rhArg-induced autophagy was attenuated when p-ERK1/2 was inhibited by MEK 1/2 inhibitor, U0126. Taken together, this study provides new insight into the molecular mechanism of autophagy involved in rhArg-induced cell apoptosis and growth inhibition, which facilitates the development of rhArg in combination with CQ as a potential therapy for malignant melanoma. PMID- 23917633 TI - The pH signaling transcription factor PacC is required for full virulence in Penicillium digitatum. AB - Penicillium digitatum is the most important postharvest pathogen of citrus fruits. Along disease progression, the infected citrus peel tissue is acidified due to the accumulation of organic acids. So far, relatively little is known about the environmental factors that regulate pathogenicity in this fungus. In this study, the role of the pH signaling transcription factor PacC in the pathogenesis of P. digitatum was investigated. We identified the pacC ortholog (PdpacC) in P. digitatum and found that its transcript levels were elevated under alkaline conditions (pH >= 7) in vitro, as well as during the infection of citrus fruits in spite of the low pH (about 3.0 to 3.5) of the macerated tissue. Na(+) and pectin also induced the expression of PdpacC. Disruption of PdpacC resulted in impaired mycelial growth under neutral or alkaline pH conditions and on synthetic medium supplemented with pectin as the sole carbon source, and attenuated virulence towards citrus fruits. Introducing the full length of PdpacC into the DeltaPdpacC mutant restored all these phenotypes. The expression of the polygalacturonase gene Pdpg2 and pectin lyase gene Pdpnl1 in P. digitatum was upregulated in the wild type strain but not or weakly upregulated in the DeltaPdpacC mutant during infection. Disruption of Pdpg2 also resulted in attenuated virulence of P. digitatum towards citrus fruits. Collectively, we conclude that PdPacC plays an important role in pathogenesis of P. digitatum via regulation of the expression of cell wall degradation enzyme genes, such as Pdpg2 and Pdpnl1. PMID- 23917634 TI - Characterizations and functions of regulator of G protein signaling (RGS) in fungi. AB - Proteins that serve as regulator of G protein signaling (RGS) primarily function as GTPase accelerators that promote GTP hydrolysis by the Galpha subunits, thereby inactivating the G protein and rapidly switching off G protein-coupled signaling pathways. Since the first RGS protein was identified from the budding yeast Saccharomyces cerevisiae, more than 30 RGS and RGS-like proteins have been characterized from several model fungi, such as Aspergillus nidulans, Beauveria bassiana, Candida albicans, Fusarium verticillioides, Magnaporthe oryzae, and Metarhizium anisopliae. In this review, the partial biochemical properties and functional domains of RGS and RGS-like proteins were predicted and compared, and the roles of RGS and RGS-like proteins in different fungi were summarized. Moreover, the phylogenetic relationship among RGS and RGS-like proteins from various fungi was analyzed and discussed. PMID- 23917635 TI - Engineering of Thermomyces lanuginosus lipase Lip: creation of novel biocatalyst for efficient biosynthesis of chiral intermediate of Pregabalin. AB - Efficient and highly enantioselective hydrolysis of 2-carboxyethyl-3-cyano-5 methylhexanoic acid ethyl ester (CNDE) is the most crucial step in chemoenzymatic synthesis of Pregabalin. By using site-saturation mutagenesis and high-throughput screening techniques, lipase Lip from Thermomyces lanuginosus DSM 10635 was engineered to improve its activity towards CNDE. The triple mutant, S88T/A99N/V116D exhibited a 60-fold improvement in specific activity for CNDE (2.35 U/mg) over the wild-type Lip (0.039 U/mg). Modeling and docking studies demonstrated that the mutant could more effectively stabilize oxygen anions in transition states and the lid of Lip in the open conformation. Additionally, the kinetic resolution of CNDE catalyzed by Escherichia coli cell overexpressing S88T/A99N/V116D mutant afforded (3S)-2-carboxyethyl-3-cyano-5-methylhexanoic acid in 42.4 % conversion and 98 % ee within 20 h with a substrate loading of 1 M (255 g/l). These results demonstrated that a novel and promising biocatalyst was created for efficient chemoenzymatic manufacturing of Pregabalin. PMID- 23917636 TI - Effects of Lys and His supplementations on the regulation of nitrogen metabolism in lager yeast. AB - Significant positive correlations between wort fermentability and the assimilation of Lys and His under normal-gravity and high-gravity conditions indicated that Lys and His were the key amino acids for lager yeast during beer brewing. In order to obtain insight into the roles of Lys and His in nitrogen regulation, the influences of Lys, His and their mixture supplementations on the fermentation performance and nitrogen metabolism in lager yeast during high gravity fermentation were further investigated in the present study. Results showed that Lys and His supplementations improved yeast growth, wort fermentability, ethanol yield and the formation of flavor volatiles. Lys supplementation up-regulated Ssy1p-Ptr3p-Ssy5p (SPS)-regulated genes (LYP1, HIP1, BAP2 and AGP1) dramatically compared to nitrogen catabolite repression (NCR) sensitive genes (GAP1 and MEP2), whereas His supplementation activated SPS regulated genes slightly in exponential phase, and repressed NCR-sensitive genes significantly throughout the fermentation. Lys and His supplementations increased the consumption of Glu and Phe, and decreased the consumption of Ser, Trp and Arg. Moreover, Lys and His supplementations exhibited similar effects on the fermentation performance, and were more effective than their mixture supplementation when the same dose was kept. These results demonstrate that both Lys and His are important amino acids for yeast nitrogen metabolism and fermentation performance. PMID- 23917637 TI - Using a grass substrate to compare decay among two clades of brown rot fungi. AB - Interest in the mechanisms of wood-degrading fungi has grown in tandem with lignocellulose bioconversion efforts, yet many potential biomass feedstocks are non-woody. Using corn stover (Zea mays) as a substrate, we tracked degradative capacities among brown rot fungi from the Antrodia clade, including Postia placenta, the first brown rot fungus to have its genome sequenced. Decay dynamics were compared against Gloeophyllum trabeum from the Gloeophyllum clade. Weight loss induced by P. placenta (6.2 %) and five other Antrodia clade isolates (average 7.4 %) on corn stalk after 12 weeks demonstrated inefficiency among these fungi, relative to decay induced by G. trabeum (44.4 %). Using aspen (Populus sp.) as a woody substrate resulted in, on average, a fourfold increase in weight loss induced by Antrodia clade fungi, while G. trabeum results matched those on stover. The sequence and trajectories of chemical constituent losses differed as a function of substrate but not fungal clade. Instead, chemical data suggest that characters unique to stover limit decay by the Antrodia clade, rather than disparities in growth rate or extractives toxicity. High p-coumaryl lignin content, lacking the methoxy groups characteristically cleaved during brown rot, is among potential rate-distinguishing characters in grasses. This ineptitude among Antrodia clade fungi on grasses was supported by meta-analysis of other unrelated studies using grass substrates. Concerning application, results expose a problem if adopting the strategy of the model decay fungus P. placenta to treat corn stover, a widely available plant feedstock. Overall, the results insinuate phylogenetically distinct modes of brown rot and demonstrate the benefit of using non-woody substrates to probe wood degradation mechanisms. PMID- 23917638 TI - Rapid (<5 min) identification of pathogen in human blood by electrokinetic concentration and surface-enhanced Raman spectroscopy. AB - This study reports a novel microfluidic platform for rapid and long-ranged concentration of rare-pathogen from human blood for subsequent on-chip surface enhanced Raman spectroscopy (SERS) identification/discrimination of bacteria based on their detected fingerprints. Using a hybrid electrokinetic mechanism, bacteria can be concentrated at the stagnation area on the SERS-active roughened electrode, while blood cells were excluded away from this region at the center of concentric circular electrodes. This electrokinetic approach performs isolation and concentration of bacteria in about three minutes; the density factor is increased approximately a thousand fold in a local area of ~5000 MUm(2) from a low bacteria concentration of 5 * 10(3) CFU/ml. Besides, three genera of bacteria, S. aureus, E. coli, and P. aeruginosa that are found in most of the isolated infections in bacteremia were successfully identified in less than one minute on-chip without the use of any antibody/chemical immobilization and reaction processes. PMID- 23917639 TI - New insights into the effects of the herbicide imazethapyr on Cu(II) ecotoxicity to the aquatic unicellular alga Scenedesmus obliquus. AB - Interactions between heavy metals and organic contaminants can result in speciation changes of heavy metals. Therefore, it is unknown whether organic contaminants in aquatic environments act as selective agents to mediate the toxicity of heavy metals. To elucidate these interactions, the effects of the herbicide imazethapyr (IM) on Cu(II) ecotoxicity to the aquatic unicellular alga Scenedesmus obliquus were investigated. It was found that the toxicity of Cu could be mediated by IM. To explore the mechanisms involved, complex formation, the catalytic activity of the complex, the Cu species and the distribution of Cu and Fe in the algal cell were characterized. The results showed that Cu(II) and IM formed an octahedral complex with an IM:Cu molar ratio of 2:1. These complexes also catalyzed the disproportionation of hydrogen peroxide. Analysis of the K edge of Cu using XAFS spectroscopy indicated that when treated with Cu, the Cu was bound to polygalacturonic acid (on the cell wall), and once inside the cell, Cu may complex with the reduced glutathione (GSH) (in the cell). When the cell is treated with IM and Cu simultaneously, IM-Cu may be the primary complex formed. Once Cu combines with IM, it is difficult for it to interact with the cell wall. In addition, using scanning transmission soft X-ray microscopy, it was found that Cu could induce changes in the distribution of the essential trace element Fe, whereas IM-Cu cannot. This finding demonstrates the importance of interactions between heavy metals and organic contaminants, which are able to mediate the toxicity of heavy metals and should be considered in future risk assessments. PMID- 23917640 TI - A novel bioassay using root re-growth in Lemna. AB - A new phytotoxicity test method based on root elongation of three Lemna species (Lemna gibba, L. minor, and L. paucicostata) has been developed. Tests with aquatic plants have, typically, favored measurements on fronds (e.g. frond number, area, biomass) rather than on roots, due, in part, to issues associated with handling fragile roots and the time-consuming procedures of selecting roots with identical root lengths. The present method differs in that roots were excised prior to exposure with subsequent measurements on newly developed roots. Results show that there were species-specific difference in sensitivity to the five metals tested (Ag, Cd, Cr, Cu and Hg), with Ag being the most toxic (EC50=5.3-37.6 MUgL(-1)) to all three species, and Cr the least toxic for L. gibba and L. minor (1148.3 and 341.8 MUgL(-1), respectively) and Cu for L. paucicostata (470.4 MUgL(-1)). Direct comparisons were made with measurements of frond area, which were found to be less sensitive. More generally, root re-growth was shown to reflect the toxic responses of all three Lemna species to these five important metals. The root growth bioassay differs from three internationally standardized methods (ISO, OCED and US EPA) in that it is completed in 48 h, the required volume of test solutions is only 3 ml and non-axenic plants are used. Our results show that the Lemna root method is a simple, rapid, cost-effective, sensitive and precise bioassay to assess the toxic risks of metals and has practical application for monitoring municipal and industrial waste waters where metals are common constituents. PMID- 23917641 TI - An investigation of the inter-clonal variation of the interactive effects of cadmium and Microcystis aeruginosa on the reproductive performance of Daphnia magna. AB - Interactive effects between chemical and natural stressors as well as genetically determined variation in stress tolerance among individuals may complicate risk assessment and management of chemical pollutants in natural ecosystems. Although genetic variation in tolerance to single stressors has been described extensively, genetic variation in interactive effects between two stressors has only rarely been investigated. Here, we examined the interactive effects between a chemical stressor (Cd) and a natural stressor (the cyanobacteria Microcystis aeruginosa) on the reproduction of Daphnia magna in 20 genetically different clones using a full-factorial experimental design and with the independent action model of joint stressor action as the reference theoretical framework. Across all clones, the reduction of 21-day reproduction compared to the control treatment (no Cd, no M. aeruginosa) ranged from -10% to 98% following Cd exposure alone, from 44% to 89% for Microcystis exposure alone, and from 61% to 98% after exposure to Cd+Microcystis combined. Three-way ANOVA on log-transformed reproduction data of all clones together did not detect a statistically significant Cd*Microcystis interaction term (F-test, p=0.11), meaning that on average both stressors do not interact in inhibiting reproductive performance of D. magna. This finding contrasted expectations based on some known shared mechanisms of toxicity of Cd and Microcystis and therefore cautions against making predictions of interactive chemical+natural stressor effects from incomplete knowledge on affected biological processes and pathways. Further, still based on three-way ANOVA, we did not find statistically significant clone*Cd*Microcystis interaction when data for all clones were analyzed together (F-test, p=0.07), suggesting no inter-clonal variation of the interactive effect between Cd and Microcystis. However, when the same data were quantitatively analyzed on a clone-by-clone scale, we found a relatively wide range of deviations between observed and IA-model-predicted reproduction in combined Cd+Microcystis treatments (both in direction and magnitude), suggesting some biological significance of inter-clonal variation of interactive effects. In one of the twenty clones this deviation was statistically significant (two-way ANOVA, F-test, p=0.005), indicating an interactive Cd*Microcystis effect in this clone. Together, these two observations caution against the extrapolation of conclusions about mixed stressor data obtained with single clones to the level of the entire species and to the level of natural, genetically diverse populations. PMID- 23917642 TI - Comment on "Serum methylglyoxal level and its association with oxidative stress and disease severity in patients with psoriasis". PMID- 23917643 TI - Magnetic resonance imaging morphology and morphometry of the coccyx in coccydynia. AB - STUDY DESIGN: Retrospective case-control study. OBJECTIVE: To determine if differences exists between the bony anatomy of the coccyx in patients with coccydynia and that in subjects with no known coccygeal pathology. SUMMARY OF BACKGROUND DATA: Numerous bony characteristics of the coccyx have been described in patients with coccydynia but their significance is uncertain. This study aimed to evaluate these in patients with coccydynia and compare them with normal coccyges. METHODS: Magnetic resonance scans of the coccyx from 107 adults (mean age, 43 +/- 12 yr; 84 females) with clinically diagnosed coccydynia were retrospectively analyzed and compared with 112 computed tomographic scans from sex-matched adults with normal coccyges. The following were assessed: coccygeal segmentation; sacrococcygeal and intercoccygeal joint fusion, angles, and curvature; bony spicule formation; and subluxation. RESULTS: Compared with normal, females with coccydynia had a more ventrally curved coccyx (curvature index, 85 +/- 7 vs. 90 +/- 5; P< 0.01), a lower prevalence of sacrococcygeal joint fusion (27% vs. 58%, P< 0.01), and a higher frequency of bony spicule formation (44% vs. 19%, P< 0.01). Males with coccydynia showed a trend toward a more ventrally curved coccyx (curvature index: 86 +/- 6 vs. 89 +/- 5, P< 0.08), and a lower prevalence of sacrococcygeal (27% vs. 60%, P< 0.02) and intercoccygeal (0% vs. 22%, P< 0.02) joint fusion. Combining statistically significant coccygeal parameters in a logistic regression model yielded sensitivity, specificity, and positive predictive values of 72%, 71%, and 73%, respectively in females and 52%, 92%, and 73%, respectively in males. CONCLUSION: This is the most detailed comparison of coccygeal morphology and morphometry in adults with and without coccydynia investigated using cross-sectional imaging. Anatomical differences in joint fusion and coccygeal curvature may either predispose to the development of coccydynia or arise as a result of this condition. PMID- 23917644 TI - Contralateral motor deficits after lateral lumbar interbody fusion. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To report on the rare finding of motor deficits contralateral to the transpsoas approach in patients who underwent lateral lumbar interbody fusion (LLIF). SUMMARY OF BACKGROUND DATA: Although sensorimotor deficits occurring ipsilaterally to a transpsoas approach have more fully been elucidated, there seems to be a paucity of data on motor deficits contralateral to an LLIF approach. METHODS: The electronic medical records and radiographical studies of 244 patients who underwent LLIF at a single institution between 2006 and 2009 were retrospectively reviewed for reports on motor deficits contralateral to the surgical approach. RESULTS: Of the patients reviewed, 2.9% (7/244) presented with a postoperative contralateral motor deficit, the most severe of which was a 1/5 weakness of the quadriceps muscle. An average of 3 levels (range: 2-4) was fused in 7 patients who developed a contralateral motor deficit, and in 3 of the 7 patients, an anterior lumbar interbody fusion (ALIF) was performed in addition to the LLIF. At 1 year follow up, 3 patients presented with complete resolution of their muscle weakness, 1 patient still had mild weakness, 1 patient had decreased range of motion in the affected joint, and 1 patient had a 2/5 foot drop. One patient was lost to follow up. CONCLUSION: These data are among the largest reports of contralateral motor deficits after LLIF. Among possible underlying mechanisms are entrapment of the contralateral nerve root through translational correction of spondylolisthesis, front-to-back misalignment of the cage resulting in contralateral nerve root impingement, pressure on the contralateral peroneal nerve during positioning, and overdistraction neurapraxia when using ALIF at L5-S1 concomitantly. Awareness of the possibility of this rare complication can play an important role in surgical consideration and preoperative patient counseling. LEVEL OF EVIDENCE: 4. PMID- 23917645 TI - Optimal schedule of preoperative embolization for spinal metastasis surgery. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To investigate the relationship between intraoperative blood loss during spinal metastasis surgery and the surgical delay after preoperative embolization. SUMMARY OF BACKGROUND DATA: Delaying surgery after embolization is thought to diminish its effectiveness because of revascularization, but there has been no scientific study that supports this hypothesis. METHODS: We reviewed data from 66 consecutive posterior palliative decompression surgical procedures for spinal metastasis from thyroid and renal cell carcinoma (39 thyroid and 27 renal) in 58 patients between 2004 and 2012. All patients underwent preoperative angiography. The timing of preoperative embolization was determined on the basis of the operating room and interventional radiologist schedules. Excluding one case who did not receive embolization due to lack of hypervascularity, we analyzed 65 cases to compare intraoperative blood loss according to the completeness of embolization and the time lapse between embolization and surgery. RESULTS: Surgical procedures were performed on the same day of embolization in 21 cases (same day-group), and on the next day after embolization in 39 cases (next-day group). Five surgical procedures were performed 2 days later. The intraoperative blood loss was significantly lesser with complete embolization than with partial embolization (mean +/- standard deviation: 809 +/- 835 vs. 1210 +/- 904 mL, P = 0.03). Among those with complete embolization, the intraoperative blood loss as well as the perioperative transfusion requirement was significantly lesser in the same-day group than in the next-day group (mean +/- standard deviation: blood loss: 433 +/ 376 vs. 1012 +/- 974 mL, P = 0.01; transfusion requirement: 1.5 +/- 1.7 vs. 4.2 +/- 4.1 units, P = 0.04). CONCLUSION: Preoperative embolization showed greater effectiveness in reducing intraoperative blood loss when surgery for spinal metastasis was performed on the same day than when surgery was delayed. Surgery should be performed on the same day of embolization if possible. LEVEL OF EVIDENCE: 4. PMID- 23917646 TI - The influence of goal setting and SmartRoom patient education videos on readmission rate, length of stay, and patient satisfaction in the orthopedic spine population. AB - The SmartRoom technology, a system now owned by TeleTracking Technologies, aims to transform the delivery of patient care in the inpatient environment. The purpose of this project was to use goal setting and SmartRoom patient education videos to examine whether the videos more effectively engaged patients and their families in their discharge plan and encouraged them to take a more active role in their care while hospitalized. This study used a descriptive design to analyze the effect of goal setting and patient education videos on patient satisfaction at discharge, hospital average length of stay, and 30-day readmission rate in the orthopedic spine surgical care setting. Comparisons were made among three patient groups. No statistically significant difference was found for average length of stay and 30-day readmission across these three groups. However, patient satisfaction with discharge, as measured by the Hospital Consumer Assessment of Health Providers and Systems, revealed an increase in five items regarding discharge with statistically significant differences on two of the five items. PMID- 23917647 TI - Advances in MR imaging for cervical spondylotic myelopathy. AB - PURPOSE: To outline the pathogenesis of cervical spondylotic myelopathy (CSM), the correlative abnormalities observed on standard magnetic resonance imaging (MRI), the biological implications and current status of diffusion tensor imaging (DTI), and MR spectroscopy (MRS) as clinical tools, and future directions of MR technology in the management of CSM patients. METHODS: A systematic review of the pathogenesis and current state-of-the-art in MR imaging technology for CSM was performed. RESULTS: CSM is caused by progressive, degenerative, vertebral column abnormalities that result in spinal cord damage related to both primary mechanical and secondary biological injuries. The T2 signal change on conventional MRI is most commonly associated with neurological deficits, but tends not to be a sensitive predictor of recovery of function. DTI and MRS show altered microstructure and biochemistry that reflect patient-specific pathogenesis. CONCLUSION: Advanced imaging techniques, including DTI and MRS, show higher sensitivity to microstructural and biochemical changes within the cord, and may aid in management of CSM patients. PMID- 23917649 TI - Profile of neurologists in Brazil: a glimpse into the future of epilepsy and sudden unexpected death in epilepsy. PMID- 23917648 TI - The concept of peripheral modulation of bladder sensation. AB - It is recognized that, as the bladder fills, there is a corresponding increase in sensation. This awareness of the volume in the bladder is then used in a complex decision making process to determine if there is a need to void. It is also part of everyday experience that, when the bladder is full and sensations strong, these sensations can be suppressed and the desire to void postponed. The obvious explanation for such altered perceptions is that they occur centrally. However, this may not be the only mechanism. There are data to suggest that descending neural influences and local factors might regulate the sensitivity of the systems within the bladder wall generating afferent activity. Specifically, evidence is accumulating to suggest that the motor-sensory system within the bladder wall is influenced in this way. The motor-sensory system, first described over 100 years ago, appears to be a key component in the afferent outflow, the afferent "noise," generated within the bladder wall. However, the presence and possible importance of this complex system in the generation of bladder sensation has been overlooked in recent years. As the bladder fills the motor activity increases, driven by cholinergic inputs and modulated, possibly, by sympathetic inputs. In this way information on bladder volume can be transmitted to the CNS. It can be argued that the ability to alter the sensitivity of the mechanisms generating the motor component of this motor-sensory system represents a possible indirect way to influence afferent activity and so the perception of bladder volume centrally. Furthermore, it is emerging that the apparent modulation of sensation by drugs to alleviate the symptoms of overactive bladder (OAB), the anti-cholinergics and the new generation of drugs the beta 3 sympathomimetics, may be the result of their ability to modulate the motor component of the motor sensory system. The possibility of controlling sensation, physiologically and pharmacologically, by influencing afferent firing at its point of origin is a "new" concept in bladder physiology. It is one that deserves careful consideration as it might have wider implications for our understanding of bladder pathology and in the development of new therapeutic drugs. In this overview, evidence for the concept peripheral modulation of bladder afferent outflow is explored. PMID- 23917650 TI - Acute iris depigmentation following systemic moxifloxacin. PMID- 23917651 TI - Evaluation of sensitivity, motor and pain thresholds across the menstrual cycle through medium-frequency transcutaneous electrical nerve stimulation. AB - OBJECTIVES: The aim of this study was to identify variations in nervous thresholds in different phases of the menstrual cycle in eumenorrheic women and users of oral contraceptives. METHOD: An observational study was performed including 56 volunteers, consisting of 30 eumenorrheic women who were non-users of oral contraceptives and 26 users of oral contraceptives. An electrical stimulator was employed to assess their nervous thresholds, with pulses applied at a fixed frequency of 2,500 Hz, modulated at 50 Hz, with phase variances of 20 MUs, 50 MUs and 100 MUs. Sensitivity, motor and pain thresholds were evaluated during five menstrual cycle phases: phase 1 - menstrual, phase 2 - follicular, phase 3 - ovulatory, phase 4 - luteal and phase 5 - premenstrual. RESULTS: The results indicated low sensitivity thresholds of 100 MUs for non-users of oral contraceptives and 50 MUs for oral contraceptive users in phase 5. Low motor thresholds of 20 MUs, 50 MUs and 100 MUs were observed for non-users of oral contraceptives in phase 5, while that of oral contraceptive users was 100 MUs. Finally, a low pain threshold of 100 MUs was observed in phase 5, but only in the oral contraceptive group. CONCLUSION: Nervous thresholds vary systematically across the phases of the menstrual cycle, with or without the use of oral contraceptives. These variations should be taken into account during research performed in women. PMID- 23917652 TI - Myositis-specific and myositis-associated autoantibody profiles and their clinical associations in a large series of patients with polymyositis and dermatomyositis. AB - OBJECTIVE: To analyze the prevalence of myositis-specific and myositis-associated autoantibodies and their clinical correlations in a large series of patients with dermatomyositis/polymyositis. METHOD: This cross-sectional study enrolled 127 dermatomyositis cases and 95 polymyositis cases. The disease-related autoantibody profiles were determined using a commercially available blood testing kit. RESULTS: The prevalence of myositis-specific autoantibodies in all 222 patients was 34.4%, whereas myositis-associated autoantibodies were found in 41.4% of the patients. The most frequently found autoantibody was anti-Ro-52 (36.9%), followed by anti-Jo-1 (18.9%), anti-Mi-2 (8.1%), anti-Ku (4.1%), anti-SRP (3.2%), anti-PL 7 (3.2%), anti-PL-12 (2.7%), anti-PM/Scl75 (2.7%), and anti-PM/Scl100 (2.7%). The distributions of these autoantibodies were comparable between polymyositis and dermatomyositis, except for a higher prevalence of anti-Jo-1 in polymyositis. Anti-Mi-2 was more prevalent in dermatomyositis. Notably, in the multivariate analysis, anti-Mi-2 and anti-Ro-52 were associated with photosensitivity and pulmonary disorders, respectively, in dermatomyositis. Anti-Jo-1 was significantly correlated with pulmonary disorders in polymyositis. Moreover, anti Ro-52 was associated with anti-Jo-1 in both diseases. No significant correlation was observed between the remaining autoantibodies and the clinical and/or laboratory findings. CONCLUSIONS: Our data are consistent with those from other published studies involving other populations, although certain findings warrant consideration. Anti-Ro-52 and anti-Jo-1 were strongly associated with one another. Anti-Ro-52 was correlated with pulmonary disorders in dermatomyositis, whereas anti-Jo-1 was correlated with pulmonary alterations in polymyositis. PMID- 23917653 TI - Cognition, behavior and social competence of preterm low birth weight children at school age. AB - OBJECTIVE: The aim of this study was to assess the cognitive and behavioral development of preterm and low birth weight newborns living in a disadvantageous socioeconomic environment at school age. METHODS: This cross-sectional study included children aged 6-7 from a historical birth cohort of preterm (gestational age <37 weeks) and low birth weight (<2,500 g) infants. The Wechsler Intelligence Scale for Children III (WISC-III) was administered by a psychologist while the parents completed the Child Behavior Checklist. The results were compared to the test's reference. The perinatal information and follow-up data were collected from the hospital files. The demographic data were collected from the parents. The current performance was compared with the results from the Denver II and Bayley II tests, which were administered during the first years of life. RESULTS: The total intelligence quotient varied from 70 to 140 (mean 98.7+/-15.8). The borderline intelligence quotient was observed in 9.3% of the children. The Child Behavior Checklist indicated a predominance of social competence problems (27.8%, CI 19.2 to 37.9) compared with behavioral problems (15.5%, CI 8.9 to 24.2). Both the Child Behavior Checklist domains, such as schooling, social and attention problems, and the cognitive scores were significantly associated with maternal education and family income. The results of the Denver and Bayley tests were associated with the cognitive performance (p<0.001) and the Child Behavior Checklist social profile, including aggressive and externalizing behavior (p<0.001). CONCLUSIONS: Our data suggest that even low-risk preterm newborns are at risk for developing disturbances in early school age, such as mild cognitive deficits and behavioral disorders. This risk might increase under unfavorable socioeconomic conditions. PMID- 23917654 TI - Maternal morbidity and near miss associated with maternal age: the innovative approach of the 2006 Brazilian demographic health survey. AB - OBJECTIVE: To study the prevalence of potentially life-threatening maternal conditions and near miss in Brazil according to maternal age. METHODS: A secondary analysis of the 2006 Brazilian demographic health survey database using a validated questionnaire to evaluate maternal morbidity with a focus on age extremes. The study included 5,025 women with at least 1 live birth in the 5-year reference period preceding their interviews. Three age range periods were used: 15-19 years (younger age), 20-34 years (control), and 35-49 years (advanced maternal age). According to a pragmatic definition, any woman reporting eclampsia, hysterectomy, blood transfusion, or admission to the intensive care unit during her pregnancy/childbirth was considered a near-miss case. The associations between age and severe maternal morbidity were further assessed. RESULTS: For the 6,833 reported pregnancies, 73.7% of the women were 20-34 years old, 17.9% were of advanced maternal age, and only 8.4% were of younger age. More than 22% of the women had at least one of the complications appraised, and blood transfusion, which was more prevalent among the controls, was the only variable with a significant difference among the age groups. The overall rate of maternal near miss was 21.1 per 1000 live births. There was a trend of higher maternal near miss with increasing age. The only significant risk factor identified for maternal near miss was a lower literacy level among older women. CONCLUSIONS: There is a trend towards worse results with increasing age. The investigation of the determinants of maternal near miss at the community level using an innovative approach through a demographic health survey is an example suggested for under resourced settings. PMID- 23917655 TI - Humeral internal rotation osteotomy for the treatment of Erb-Duchenne-type obstetric palsy: clinical and radiographic results. AB - OBJECTIVE: To evaluate the functional and radiographic results in patients undergoing shoulder anterior soft tissue stretching in association with open reduction and internal rotation osteotomy to centralize the humeral head as a treatment for Erb-Duchenne obstetric palsy sequelae. METHOD: A total of 35 patients underwent this surgical treatment, and the mean follow-up was 4.6 years. The Mallet scale was applied before and after the surgical procedure. A total of 20 patients underwent computed tomography to assess the glenoid version and humeral head subluxation. RESULTS: Functional improvement was achieved, as evidenced by an increase in the Mallet scale score from 12.14 to 16.46 (p<0.001). The correction of retroversion was achieved once the glenoid version ranged from 21.4 to -12 degrees (p<0.001). The humeral head subluxation improved from 6.5 to 35.2% (p<0.001). Patients older than 6 years of age did not achieve glenohumeral joint improvement with respect to dysplastic abnormalities. CONCLUSION: Internal rotation osteotomy in association with the stretching of anterior soft tissues of the shoulder in patients under the age of 7 years provided improvements in the function, retroversion, and subluxation of the glenohumeral joint. PMID- 23917656 TI - Parental smoking patterns and their association with wheezing in children. AB - OBJECTIVE: To investigate parental smoking patterns and their association with wheezing in children. METHODS: We performed a case-control study that included 105 children between 6 and 23 months of age who were divided into two groups: cases (children with 3 previous episodes of wheezing) and controls (healthy children without wheezing). The children's exposure to cigarette smoking was estimated using a questionnaire completed by the mothers and by the children's urinary cotinine levels. RESULTS: Based on both the questionnaire results and cotinine levels, exposure to cigarette smoking was higher in the households of cases in which the incidence of maternal smoking was significantly higher than that of paternal smoking. Children in this group were more affected by maternal smoking and by the total number of cigarettes smoked inside the house. Additionally, the questionnaire results indicated that the risk of wheezing was dose dependent. The presence of allergic components, such as atopic dermatitis and siblings with allergic rhinitis and asthma, greatly increased the odds ratio when wheezing was associated with cotinine levels. CONCLUSION: Children exposed to tobacco smoke have an increased risk of developing wheezing syndrome. This risk increases in association with the number of cigarettes smoked inside the house and the presence of other allergic components in the family. PMID- 23917657 TI - Serum albumin level as a risk factor for mortality in burn patients. AB - OBJECTIVE: Hypoalbuminemia is a common clinical deficiency in burn patients and is associated with complications related to increased extravascular fluid, including edema, abnormal healing, and susceptibility to sepsis. Some prognostic scales do not include biochemical parameters, whereas others consider them together with comorbidities. The purpose of this study was to determine whether serum albumin can predict mortality in burn patients. METHODS: We studied burn patients >=16 years of age who had complete clinical documentation, including the Abbreviated Burn Severity Index, serum albumin, globulin, and lipids. Sensitivity and specificity analyses were performed to determine the cut-off level of albumin that predicts mortality. RESULTS: In our analysis of 486 patients, we found that mortality was higher for burns caused by flame (p=0.000), full-thickness burns (p=0.004), inhalation injuries (p=0.000), burns affecting >30% of the body surface area (p=0.001), and burns associated with infection (p=0.008). Protein and lipid levels were lower in the patients who died (p<0.05). Albumin levels showed the highest sensitivity and specificity (84% and 83%, respectively), and the area under the receiver-operating characteristic curve (0.869) had a cut-off of 1.95 g/dL for mortality. CONCLUSION: Patients with albumin levels <2 g/dL had a mortality risk of >80%, with 84% sensitivity and 83% specificity. At admission, the albumin level could be used as a sensitive and specific marker of burn severity and an indicator of mortality. PMID- 23917658 TI - The occurrence of dental caries is associated with atherosclerosis. AB - OBJECTIVE: Previous studies have suggested that marginal periodontitis is a risk factor for developing atherosclerosis. The objective of this study was to determine whether caries may also be associated with atherosclerosis. METHODS: The computed tomography data sets of 292 consecutive patients, 137 women and 155 men with a mean age of 54.1+/-17.3 years, were analyzed. Caries were quantified based on the number of decayed surfaces of all the teeth, and periodontitis was quantified on the basis of the horizontal bone loss in the jaw. The presence of chronic apical periodontitis (CAP) was assessed, and the aortic atherosclerotic burden was quantified using a calcium scoring method. RESULTS: The patients with <1 caries surfaces/tooth had a lower atherosclerotic burden (0.13+/-0.61 mL) than patients with >=1 caries surfaces/tooth. The atherosclerotic burden was greater in patients with a higher number of lesions with pulpal involvement and more teeth with chronic apical periodontitis. In the logistical regression models, age (Wald 49.3), number of caries per tooth (Wald 26.4), periodontitis (Wald 8.6), and male gender (Wald 11) were found to be independent risk factors for atherosclerosis. In the linear regression analyses, age and the number of decayed surfaces per tooth were identified as influencing factors associated with a higher atherosclerotic burden, and the number of restorations per tooth was associated with a lower atherosclerotic burden. CONCLUSION: Dental caries, pulpal caries, and chronic apical periodontitis are associated positively, while restorations are associated inversely, with aortic atherosclerotic burden. Prospective studies are required to confirm these observations and answer the question of possible causality. PMID- 23917659 TI - (Central) auditory processing: the impact of otitis media. AB - OBJECTIVE: To analyze auditory processing test results in children suffering from otitis media in their first five years of age, considering their age. Furthermore, to classify central auditory processing test findings regarding the hearing skills evaluated. METHODS: A total of 109 students between 8 and 12 years old were divided into three groups. The control group consisted of 40 students from public school without a history of otitis media. Experimental group I consisted of 39 students from public schools and experimental group II consisted of 30 students from private schools; students in both groups suffered from secretory otitis media in their first five years of age and underwent surgery for placement of bilateral ventilation tubes. The individuals underwent complete audiological evaluation and assessment by Auditory Processing tests. RESULTS: The left ear showed significantly worse performance when compared to the right ear in the dichotic digits test and pitch pattern sequence test. The students from the experimental groups showed worse performance when compared to the control group in the dichotic digits test and gaps-in-noise. Children from experimental group I had significantly lower results on the dichotic digits and gaps-in-noise tests compared with experimental group II. The hearing skills that were altered were temporal resolution and figure-ground perception. CONCLUSION: Children who suffered from secretory otitis media in their first five years and who underwent surgery for placement of bilateral ventilation tubes showed worse performance in auditory abilities, and children from public schools had worse results on auditory processing tests compared with students from private schools. PMID- 23917660 TI - The effects of auditory stimulation with music on heart rate variability in healthy women. AB - OBJECTIVES: There are no data in the literature with regard to the acute effects of different styles of music on the geometric indices of heart rate variability. In this study, we evaluated the acute effects of relaxant baroque and excitatory heavy metal music on the geometric indices of heart rate variability in women. METHODS: We conducted this study in 21 healthy women ranging in age from 18 to 35 years. We excluded persons with previous experience with musical instruments and persons who had an affinity for the song styles. We evaluated two groups: Group 1 (n = 21), who were exposed to relaxant classical baroque musical and excitatory heavy metal auditory stimulation; and Group 2 (n = 19), who were exposed to both styles of music and white noise auditory stimulation. Using earphones, the volunteers were exposed to baroque or heavy metal music for five minutes. After the first music exposure to baroque or heavy metal music, they remained at rest for five minutes; subsequently, they were re-exposed to the opposite music (70-80 dB). A different group of women were exposed to the same music styles plus white noise auditory stimulation (90 dB). The sequence of the songs was randomized for each individual. We analyzed the following indices: triangular index, triangular interpolation of RR intervals and Poincare plot (standard deviation of instantaneous beat-by-beat variability, standard deviation of the long-term RR interval, standard deviation of instantaneous beat-by-beat variability and standard deviation of the long-term RR interval ratio), low frequency, high frequency, low frequency/high frequency ratio, standard deviation of all the normal RR intervals, root-mean square of differences between the adjacent normal RR intervals and the percentage of adjacent RR intervals with a difference of duration greater than 50 ms. Heart rate variability was recorded at rest for 10 minutes. RESULTS: The triangular index and the standard deviation of the long term RR interval indices were reduced during exposure to both music styles in the first group and tended to decrease in the second group whereas the white noise exposure decreased the high frequency index. We observed no changes regarding the triangular interpolation of RR intervals, standard deviation of instantaneous beat-by-beat variability and standard deviation of instantaneous beat-by-beat variability/standard deviation in the long-term RR interval ratio. CONCLUSION: We suggest that relaxant baroque and excitatory heavy metal music slightly decrease global heart rate variability because of the equivalent sound level. PMID- 23917661 TI - Influence of obstructive sleep apnea on serum butyrylcholinesterase activity and ischemia-modified albumin levels. AB - OBJECTIVE: To investigate the effect of obstructive sleep apnea and continuous positive airway pressure treatment on serum butyrylcholinesterase activity and ischemia-modified albumin levels. METHODS: Thirty-two patients with obstructive sleep apnea and 30 age- and sex-matched controls were enrolled and underwent a diagnostic polysomnogram. The serum butyrylcholinesterase activity, ischemia modified albumin levels, metabolic parameters, and polysomnography scores were detected and evaluated. Nine patients were studied before and after treatment with continuous positive airway pressure. RESULTS: The serum ischemia-modified albumin levels were significantly higher and the butyrylcholinesterase activity was significantly lower in patients with obstructive sleep apnea than in the controls (p<0.001). The continuous positive airway pressure treatment decreased the modified albumin levels and elevated the buthrylcholinesterase activity (p=0.019 and p=0.023, respectively). The modified albumin levels were positively correlated with the apnea-hypopnea index (r=0.462, p=0.008) at baseline. Elevated ischemia-modified albumin levels can be more accurate than butyrylcholinesterase activity at reflecting the presence of obstructive sleep apnea. Receiver operating characteristic curves revealed a significant difference between the areas under the curve 0.916 for ischemia-modified albumin and 0.777 for butyrylcholinesterase (z=2.154, p=0.031). CONCLUSION: The elevated ischemia modified albumin level was significantly associated with obstructive sleep apnea and was more sensitive than butyrylcholinesterase activity in reflecting obstructive sleep apnea. The continuous positive airway pressure treatment helped to ameliorate the imbalance. PMID- 23917662 TI - Exercise prescription using the heart of claudication pain onset in patients with intermittent claudication. AB - OBJECTIVE: To assess the acute metabolic and cardiovascular responses to walking exercise at an intensity corresponding to the heart rate of claudication pain onset and to investigate the effects of a 12-week walking training program at this intensity on walking capacity. METHODS: Twenty-nine patients with intermittent claudication were randomly allocated to the walking training (n=17) or control (CO, n=12) group. The walking training group performed an acute exercise session comprising 15*2-min bouts of walking at the heart rate of claudication pain onset, with 2-min interpolated rest intervals. The claudication symptoms and cardiovascular and metabolic responses were evaluated. Walking training was then performed at the same intensity twice each week for 12 weeks, while the control group engaged in twice weekly stretching classes. The claudication onset distance and total walking distance were evaluated before and after the interventions. Brazilian Registry Clinical Trials: RBR-7M3D8W. RESULTS: During the acute exercise session, the heart rate was maintained within tight limits. The exercise intensity was above the anaerobic threshold and >80% of the heart rate peak and VO2peak. After the exercise training period, the walking exercise group (n=13) showed increased claudication onset distance (309+/-153 vs. 413+/-201m) and total walking distance (784+/-182 vs. 1,100+/-236m) compared to the control group (n=12) (p<0.05). CONCLUSION: Walking exercise prescribed at the heart rate of claudication pain onset enables patients with intermittent claudication to exercise with tolerable levels of pain and improves walking performance. PMID- 23917663 TI - Prevalence and factors associated with frailty in an older population from the city of Rio de Janeiro, Brazil: the FIBRA-RJ Study. AB - OBJECTIVE: Frailty syndrome can be defined as a state of vulnerability to stressors resulting from a decrease in functional reserve across multiple systems and compromising an individual's capacity to maintain homeostasis. The purpose of this study was to determine the prevalence of frailty and its association with social and demographic factors, functional capacity, cognitive status and self reported comorbidities in a sample of community-dwelling older individuals who are clients of a healthcare plan. METHODS: We evaluated 847 individuals aged 65 years or older who lived in the northern area of the city of Rio de Janeiro, Brazil. The subjects were selected by inverse random sampling and stratified by gender and age. To diagnose frailty, we used the scale proposed by the Cardiovascular Health Study, which consisted of the following items: low gait speed, grip strength reduction, feeling of exhaustion, low physical activity and weight loss. The data were collected between 2009 and 2010, and the frailty prevalence was calculated as the proportion of individuals who scored positive for three or more of the five items listed above. To verify the association between frailty and risk factors, we applied a logistic regression analysis. RESULTS: The prevalence of frailty syndrome was 9.1% (95% confidence interval [CI], 7.3-11.3); 43.6% (95% CI, 40.3-47) of the individuals were considered robust, and 47.3% (95% CI 43.8-50.8) were considered pre-frail (p<0.001). The frail individuals tended to be older (odds ratio [OR] 13.2, 95% CI, 8.7-20) and have lower education levels (OR 2.1, 95% CI, 1-4.6), lower cognitive performance (OR 0.76, 95% CI, 0.73-0.79) and reduced health perception (OR 65.8, 95% CI, 39.1 110.8). Frail individuals also had a greater number of comorbidities (OR 6.6, 95% CI, 4.4-9.9) and worse functional capacity (OR 3.8, 95% CI, 2.9-5). CONCLUSION: The prevalence of frailty was similar to that seen in other international studies and was significantly associated with educational level, cognition, comorbidities, functional capacity, perception of health and old age. PMID- 23917664 TI - Improved relationship between left and right ventricular electrical activation after cardiac resynchronization therapy in heart failure patients can be quantified by body surface potential mapping. AB - OBJECTIVES: Few studies have evaluated cardiac electrical activation dynamics after cardiac resynchronization therapy. Although this procedure reduces morbidity and mortality in heart failure patients, many approaches attempting to identify the responders have shown that 30% of patients do not attain clinical or functional improvement. This study sought to quantify and characterize the effect of resynchronization therapy on the ventricular electrical activation of patients using body surface potential mapping, a noninvasive tool. METHODS: This retrospective study included 91 resynchronization patients with a mean age of 61 years, left ventricle ejection fraction of 28%, mean QRS duration of 182 ms, and functional class III/IV (78%/22%); the patients underwent 87-lead body surface mapping with the resynchronization device on and off. Thirty-six patients were excluded. Body surface isochronal maps produced 87 maximal/mean global ventricular activation times with three regions identified. The regional activation times for right and left ventricles and their inter-regional right-to left ventricle gradients were calculated from these results and analyzed. The Mann-Whitney U-test and Kruskall-Wallis test were used for comparisons, with the level of significance set at p<=0.05. RESULTS: During intrinsic rhythms, regional ventricular activation times were significantly different (54.5 ms vs. 95.9 ms in the right and left ventricle regions, respectively). Regarding cardiac resynchronization, the maximal global value was significantly reduced (138 ms to 131 ms), and a downward variation of 19.4% in regional-left and an upward variation of 44.8% in regional-right ventricular activation times resulted in a significantly reduced inter-regional gradient (43.8 ms to 17 ms). CONCLUSIONS: Body surface potential mapping in resynchronization patients yielded electrical ventricular activation times for two cardiac regions with significantly decreased global and regional-left values but significantly increased regional-right values, thus showing an attenuated inter-regional gradient after the cardiac resynchronization therapy. PMID- 23917665 TI - Lack of reliable clinical predictors to identify obstructive sleep apnea in patients with hypertrophic cardiomyopathy. AB - OBJECTIVE: Obstructive sleep apnea is common among patients with hypertrophic cardiomyopathy and may contribute to poor cardiovascular outcomes. However, obstructive sleep apnea is largely unrecognized in this population. We sought to identify the clinical predictors of obstructive sleep apnea among patients with hypertrophic cardiomyopathy. METHODS: Consecutive patients with hypertrophic cardiomyopathy were recruited from a tertiary University Hospital and were evaluated using validated sleep questionnaires (Berlin and Epworth) and overnight portable monitoring. Ninety patients (males, 51%; age, 46+/-15 years; body mass index, 26.6+/-4.9 kg/m2) were included, and obstructive sleep apnea (respiratory disturbance index >=15 events/h) was present in 37 patients (41%). RESULTS: Compared with the patients without obstructive sleep apnea, patients with obstructive sleep apnea were older and had higher body mass index, larger waist circumference, larger neck circumference, and higher prevalence of atrial fibrillation. Excessive daytime sleepiness (Epworth scale) was low and similar in the patients with and without obstructive sleep apnea, respectively. The only predictors of obstructive sleep apnea (using a logistic regression analysis) were age >=45 years (odds ratio [OR], 4.46; 95% confidence interval [CI 95%], 1.47 13.54; p = 0.008) and the presence of atrial fibrillation [OR, 5.37; CI 95%, 1.43 20.12; p = 0.013]. CONCLUSION: Consistent clinical predictors of obstructive sleep apnea are lacking for patients with hypertrophic cardiomyopathy, which suggests that objective sleep evaluations should be considered in this population, particularly among elderly patients with atrial fibrillation. PMID- 23917666 TI - Assessment of the left atrial volume index and plasma NT-proANP level in patients with acute ST-elevation myocardial infarction. AB - OBJECTIVES: Acute ST-elevation myocardial infarction is associated with ventricular dysfunction due to ischemia-induced progressive myocardial damage. The decrease in ventricular compliance causes left atrial dilatation and stretching of the atrial myocardium, which are the main stimuli for the secretion of atrial natriuretic peptide. The aim of this study was to evaluate left atrial dimensions and atrial natriuretic peptide levels in patients early after their first acute ST-elevation myocardial infarction and assess the probable interaction between coronary lesions and these measurements. METHODS: A total of 110 patients with acute myocardial infarction and 50 controls were studied. Plasma atrial natriuretic peptide was measured at admission. Left ventricular function, diameter, and volume index were evaluated using transthoracic echocardiography. Gensini and vessel scores of the patients who underwent coronary angiography were calculated. RESULTS: Plasma atrial natriuretic peptide in the patients with myocardial infarction was increased compared with that in controls (3.90+/-3.75 vs. 1.35+/-0.72 nmol/L, p<0.001). Although the left atrial diameter was comparable in patients and controls, the left atrial volume index was increased in patients with acute myocardial infarction (26.5+/-7.1 vs. 21.3+/ 4.9 mL/m2, p<0.01). Multivariate regression analysis showed a strong independent correlation between the left atrial volume index and the plasma atrial natriuretic peptide level (beta=0.23, p=0.03). CONCLUSIONS: The left atrial volume index and plasma atrial natriuretic peptide level were correlated in patients with acute myocardial infarction. PMID- 23917667 TI - Interleukin 10 (IL10) and transforming growth factor beta1 (TGFbeta1) gene polymorphisms in persistent IgE-mediated cow's milk allergy. AB - OBJECTIVES: The aim of this cross-sectional study was to evaluate whether interleukin 10 (IL10) and transforming growth factor beta1 (TGFbeta1) gene polymorphisms were associated with persistent IgE-mediated cow's milk allergy in 50 Brazilian children. The diagnostic criteria were anaphylaxis triggered by cow's milk or a positive double-blind, placebo-controlled food challenge. Tolerance was defined as the absence of a clinical response to a double-blind, placebo-controlled food challenge or cow's milk exposure. METHOD: The genomic DNA of the 50 patients and 224 healthy controls (HCs) was used to investigate five IL10 gene polymorphisms (-3575A/T, -2849A/G, -2763A/C, -1082G/A, -592C/A) and one TGFbeta1 polymorphism (-509C/T). RESULTS: Among the five IL10 polymorphisms analyzed, homozygosis for the G allele at the -1082 position was significantly higher in the patients compared with the healthy controls (p=0.027) and in the persistent cow's milk allergy group compared with the healthy controls (p=0.001). CONCLUSIONS: Homozygosis for the G allele at the IL10 -1082G/A polymorphism is associated with the persistent form of cow's milk allergy. PMID- 23917668 TI - Aerobic exercise training induces metabolic benefits in rats with metabolic syndrome independent of dietary changes. AB - OBJECTIVES: We evaluated the effects of aerobic exercise training without dietary changes on cardiovascular and metabolic variables and on the expression of glucose transporter Type 4 in rats with metabolic syndrome. METHODS: Twenty male spontaneously hypertensive rats received monosodium glutamate during the neonatal period. The animals were allocated to the following groups: MS (sedentary metabolic syndrome), MS-T (trained on a treadmill for 1 hour/day, 5 days/week for 10 weeks), H (sedentary spontaneously hypertensive rats) and H-T (trained spontaneously hypertensive rats). The Lee index, blood pressure (tail-cuff system), insulin sensitivity (insulin tolerance test) and functional capacity were evaluated before and after 10 weeks of training. Glucose transporter Type 4 expression was analyzed using Western blotting. The data were compared using analysis of variance (ANOVA) (p<0.05). RESULTS: At baseline, the MS rats exhibited lower insulin sensitivity and increased Lee index compared with the H rats. Training decreased the body weight and Lee index of the MS rats (MS-T vs. MS), but not of the H rats (H-T vs. H). There were no differences in food intake between the groups. At the end of the experiments, the systolic blood pressure was lower in the two trained groups than in their sedentary controls. Whole-body insulin sensitivity increased in the trained groups. Glucose transporter Type 4 content increased in the heart, white adipose tissue and gastrocnemius muscle of the trained groups relative to their respective untrained groups. CONCLUSION: In conclusion, the present study shows that an isolated aerobic exercise training intervention is an efficient means of improving several components of metabolic syndrome, that is, training reduces obesity and hypertension and increases insulin sensitivity. PMID- 23917669 TI - FTY720 induces apoptosis in B16F10-NEX2 murine melanoma cells, limits metastatic development in vivo, and modulates the immune system. AB - OBJECTIVE: Available chemotherapy presents poor control over the development of metastatic melanoma. FTY720 is a compound already approved by the Food and Drug Administration for the treatment of patients with multiple sclerosis. It has also been observed that FTY720 inhibits tumor growth in vivo (experimental models) and in vitro (animal and human tumor cells). The aim of this study was to evaluate the effects of FTY720 on a metastatic melanoma model and in tumor cell lines. METHODS: We analyzed FTY720 efficacy in vivo in a syngeneic murine metastatic melanoma model, in which we injected tumor cells intravenously into C57BL/6 mice and then treated the mice orally with the compound for 7 days. We also treated mice and human tumor cell lines with FTY720 in vitro, and cell viability and death pathways were analyzed. RESULTS: FTY720 treatment limited metastatic melanoma growth in vivo and promoted a dose-dependent decrease in the viability of murine and human tumor cells in vitro. Melanoma cells treated with FTY720 exhibited characteristics of programmed cell death, reactive oxygen species generation, and increased beta-catenin expression. In addition, FTY720 treatment resulted in an immunomodulatory effect in vivo by decreasing the percentage of Foxp3+ cells, without interfering with CD8+ T cells or lymphocyte-producing interferon-gamma. CONCLUSION: Further studies are needed using FTY720 as a monotherapy or in combined therapy, as different types of cancer cells would require a variety of signaling pathways to be extinguished. PMID- 23917670 TI - Biomechanical analysis of the acetabular buttress-plate: are complex acetabular fractures in the quadrilateral area stable after treatment with anterior construct plate-1/3 tube buttress plate fixation? AB - OBJECTIVE: The acetabular buttress-plate has been widely used in treating difficult cases with satisfying clinical results. However, the biomechanical properties of a postoperative acetabular fracture fixed by the buttress-plate are not clear. The purpose of this study was to evaluate the biomechanical properties of stability after the anterior tube buttress-plate fixation of complex acetabular fractures in the quadrilateral area. METHODS: A construct was proposed based on anterior construct plate - 1/3 tube buttress plate fixation for acetabular both-column fractures. Two groups of six formalin-preserved cadaveric pelvises were analyzed: (1) group A, the normal pelvis and (2) group B, anterior construct plate-1/3 tube buttress plate with quadrilateral area fixation. The displacements were measured, and cyclical loads were applied in both standing and sitting simulations. RESULTS: As the load was added, the displacements were A= 1) regularization term. By placing the wide variety of existing fully corrective boosting-based classifiers on a common footing, and considering the primal and dual problems together, the framework allows a direct comparison between apparently disparate methods. By solving the primal rather than the dual the framework is capable of generating efficient fully-corrective boosting algorithms without recourse to sophisticated convex optimization processes. We show that a range of additional boosting-based algorithms can be incorporated into the framework despite not being fully corrective. Finally, we provide an empirical analysis of the performance of a variety of the most significant boosting-based classifiers on a few machine learning benchmark datasets. PMID- 23917695 TI - An analysis of the acoustic input impedance of the ear. AB - Ear canal acoustics was examined using a one-dimensional lossy transmission line with a distributed load impedance to model the ear. The acoustic input impedance of the ear was derived from sound pressure measurements in the ear canal of healthy human ears. A nonlinear least squares fit of the model to data generated estimates for ear canal radius, ear canal length, and quantified the resistance that would produce transmission losses. Derivation of ear canal radius has application to quantifying the impedance mismatch at the eardrum between the ear canal and the middle ear. The length of the ear canal was found, in general, to be longer than the length derived from the one-quarter wavelength standing wave frequency, consistent with the middle ear being mass-controlled at the standing wave frequency. Viscothermal losses in the ear canal, in some cases, may exceed that attributable to a smooth rigid wall. Resistance in the middle ear was found to contribute significantly to the total resistance. In effect, this analysis "reverse engineers" physical parameters of the ear from sound pressure measurements in the ear canal. PMID- 23917696 TI - Comparative study between 2 protocols for management of severe pain in patients with unresectable pancreatic cancer: one-year follow-up. AB - BACKGROUND: The efficacy of a celiac plexus block for the treatment of upper abdominal cancer-related pain has been documented. However, the effect of preprocedural pharmacological control of pain on its efficacy remains unknown. The researchers investigated the effect of first controlling severe pain with medications and then performing the celiac plexus block and compared the results with those obtained when the celiac block was performed first followed by pharmacotherapy for controlling severe pain; the impact on and duration of pain relief, effect on the quality of life, and analgesic requirements were analyzed. PATIENTS AND METHODS: Sixty patients with nonresectable pancreatic cancer reporting visual analog scale (VAS) >= 70 (visceral pain, continuous or intermittent) were randomized into 2 equal groups. Group I comprised patients in whom the celiac block was performed early after the first meeting and then analgesic requirements were managed according to the severity of pain and the World Health Organization analgesic ladder. Group II comprised patients in whom analgesics were first given to control pain and the celiac plexus block was performed only when the patients reported a VAS score < 40. VAS and total daily analgesic consumption were recorded before the block, followed by weekly for 1 month, monthly for 6 months, and finally in the 9th and 12th months. Patient satisfaction was assessed using a quality of life questionnaire (QLQ-C30). Patients were asked to report any side effects particularly related to the procedure and intake of opioids. RESULTS: Pain scores were comparable in both groups at initial assessment. However, in group II, VAS was reduced to 29.2 +/- 4.48 in 8 +/- 3 days through medical treatment before performing the block. At all time periods examined, pain scores were significantly lower in both groups compared with pretreatment scores (P < 0.0001). There was a significant decrease in VAS in group II when compared with group I at 2 months after the procedure and thereafter (P < 0.0001). Morphine sulfate consumption and frequency of opioid adverse effects were significantly lower in group II from the second month onward (P < 0.0001). The number of patients who showed good response to tramadol was significantly higher in group II in the second month until the 6th month (P < 0.05). QLQ-C30 was significantly lower in group II compared with group I from the 2nd month onward (P < 0.0001). CONCLUSIONS: Controlling severe pain with medication and then performing the celiac block seems to be more effective in controlling pain, reducing opioid consumption, and improving the quality of life of patients with pancreatic cancer compared with performing the celiac block at the beginning followed by pharmacotherapy for pain relief. PMID- 23917697 TI - Advances in the treatment of coeliac disease: an immunopathogenic perspective. AB - Coeliac disease is a common and fairly well-characterized systemic disorder that mainly affects the small intestine, but also has extraintestinal manifestations. The environmental trigger (gluten derived from wheat, rye and barley), the genetic predisposition conferred by the HLA-DQ2 and HLA-DQ8 haplotypes and many steps in the disease pathogenesis are known. This knowledge has enabled researchers to suggest novel alternative treatments or adjunctive therapies to the gluten-free diet, which is currently the only available and effective treatment for the condition. This Review focuses on emerging and potential treatment strategies that are based on the current concept of the disease pathophysiology. The search for novel future treatment modes, including nonpharmacological and pharmacological approaches, is also outlined. The potential pitfalls associated with the various research avenues are also discussed. PMID- 23917698 TI - Hepatitis: New route of HCV transmission. PMID- 23917699 TI - Liver: Carbamazepine accelerates liver regeneration in mice after acute injury. PMID- 23917700 TI - Competitors who choose to be red have higher testosterone levels. PMID- 23917702 TI - Is wound drainage necessary in hip arthroplasty? A meta-analysis of randomized controlled trials. AB - PURPOSE: The use of closed suction drainage systems for hip arthroplasty (HA) is a common practice. However, the effectiveness and safety are still questionable. Thus, the aim of this meta-analysis was to review the advantages and adverse effects of closed suction drainage systems in hip arthroplasty. METHODS: All randomized or quasi-randomized trials comparing the use of closed suction drainage systems with no drainage systems for hip arthroplasty were searched in PubMed, Medicine, EMBASE and other internet databases. We assessed the methodological quality of the studies and abstracted the relevant data independently. RESULTS: Sixteen studies involving 1,663 participants with surgical wounds comparing HA with and without the use of drainage were included in our analysis. Our results demonstrated blood transfusion was required more frequently the same as the persistent discharge in those who received drains. No significant differences in the incidence of wound hematoma, dehiscence or deep vein thrombosis were found between those allocated to drains and the non-drained wounds. Wound infection and the range of movement of the joint after surgery were similar between the two groups. CONCLUSIONS: Based on the current evidence, there is insufficient evidence to support the routine use of closed suction drainage in hip arthroplasty. At the same time, our meta-analysis study suggested that using of closed suction drainage in HA increased requirement for postoperative blood transfusion. However, there is a moderate possibility of selection bias and publication bias in this review. Because of the limited number of studies which may weaken the strength of the evidence of our results, more samples, high quality randomized trials are needed to increase the reliability of evidences. LEVEL OF EVIDENCE: II. PMID- 23917703 TI - [Immunotherapy for colorectal cancer]. AB - Recent studies have underlined the close link between immune response and prognosis of patients with colorectal cancer (CRC). Immune response understanding combined with biotechnology progress of the last years has allowed development of immunotherapy strategies in CRC. Immunotherapy strategies are divided in "active" or "passive" strategies (patients immune system stimulation or not) and considering the activation of antigen specific immune response or not. These immunotherapy strategies are well tolerated and induced cellular and humoral response correlated with clinical response. Many monoclonal antibodies targeting signalisation pathways or angiogenic growth factors have demonstrated their efficacy in CRC. Multiple vaccine strategies, using different tumour associated antigens, have demonstrated a biological efficacy but with poor clinical results. Results are more promising in adjuvant setting but need to be confirmed by randomized trials. Adoptive immunotherapy with transfer of tumour associated antigen specific T cell is probably the most promising strategy. Actually, except monoclonal antibodies, immunotherapy is not used in clinical practice in CRC due to the lack of results and absence of standardisation. PMID- 23917704 TI - Improving abdomen tumor low-dose CT images using a fast dictionary learning based processing. AB - In abdomen computed tomography (CT), repeated radiation exposures are often inevitable for cancer patients who receive surgery or radiotherapy guided by CT images. Low-dose scans should thus be considered in order to avoid the harm of accumulative x-ray radiation. This work is aimed at improving abdomen tumor CT images from low-dose scans by using a fast dictionary learning (DL) based processing. Stemming from sparse representation theory, the proposed patch-based DL approach allows effective suppression of both mottled noise and streak artifacts. The experiments carried out on clinical data show that the proposed method brings encouraging improvements in abdomen low-dose CT images with tumors. PMID- 23917705 TI - Biodegradability engineering of biodegradable Mg alloys: tailoring the electrochemical properties and microstructure of constituent phases. AB - Crystalline Mg-based alloys with a distinct reduction in hydrogen evolution were prepared through both electrochemical and microstructural engineering of the constituent phases. The addition of Zn to Mg-Ca alloy modified the corrosion potentials of two constituent phases (Mg + Mg2Ca), which prevented the formation of a galvanic circuit and achieved a comparable corrosion rate to high purity Mg. Furthermore, effective grain refinement induced by the extrusion allowed the achievement of much lower corrosion rate than high purity Mg. Animal studies confirmed the large reduction in hydrogen evolution and revealed good tissue compatibility with increased bone deposition around the newly developed Mg alloy implants. Thus, high strength Mg-Ca-Zn alloys with medically acceptable corrosion rate were developed and showed great potential for use in a new generation of biodegradable implants. PMID- 23917707 TI - Immunoinflammatory prognostic markers of early-onset neonatal sepsis in critically ill preterm newborns. PMID- 23917706 TI - Prevention of delirium in critically ill patients: a new beginning? PMID- 23917708 TI - Physical therapy in critically ill adult patients: recommendations from the Brazilian Association of Intensive Care Medicine Department of Physical Therapy. AB - Complications from immobility in intensive care unit patients contribute to functional decline, increased healthcare costs, reduced quality of life and higher post-discharge mortality. Physical therapy focuses on promoting recovery and preserving function, and it may minimize the impact of these complications. A group of Brazilian Association of Intensive Care Medicine physical therapy experts developed this document that contains minimal physical therapy recommendations appropriate to the Brazilian real-world clinical situation. Prevention and treatment of atelectasis, procedures related to the removal of secretions and treatment of conditions related to physical deconditioning and functional decline are discussed. Equally important is the consideration that prescribing and executing activities, mobilizations and exercises are roles of the physical therapist, whose diagnosis should precede any intervention. PMID- 23917709 TI - The effects of mechanical ventilation on oxidative stress. AB - OBJECTIVE: Mechanical ventilation is a mainstay of therapy in intensive care units; however, its deleterious effects need to be assessed. Therefore, we aimed to assess oxidative stress in patients admitted to an intensive care unit undergoing invasive mechanical ventilation. METHODS: This cross-sectional study included 12 invasive mechanical ventilation patients. Blood samples (3 mL) were collected on the first and last days on invasive mechanical ventilation. Thiobarbituric acid-reacting substances (TBARS) were assessed in plasma, and superoxide dismutase (SOD) and catalase (CAT) were assessed in erythrocytes. RESULTS: The mean age was 64.8 +/- 17.6 years, the tidal volume (VT) 382 +/- 44.5 mL, and the APACHE II score 15 +/- 7. When initial and final TBARS were compared, a significant difference was identified (3.54 +/- 0.74 vs. 4.96 +/- 1.47, p = 0.04). Antioxidant enzymes showed no significant differences. Correlations between PaO2/FiO2 and TBARS (r = 0.4), SOD and PaO2/FiO2 (r = 0.51) and APACHE II and SOD (r = 0.56) were identified. Six patients died. CONCLUSION: Patients undergoing invasive mechanical ventilation can develop redox state changes, showing increased TBARS and reduced antioxidant enzymes. PMID- 23917710 TI - Inflammatory and oxidative cord blood parameters as predictors of neonatal sepsis severity. AB - OBJECTIVES: Neonatal sepsis is a complex syndrome involving an uncontrolled systemic inflammatory response associated with an infection. It may result in the dysfunction or failure of one or more organs or even death. Given its high incidence in premature neonates, the identification of prognostic factors to optimize the early diagnosis and therapeutic interventions are highly desirable. This objective study determine the relationship between inflammatory markers and oxidative parameters as prognostic factors in early neonatal sepsis. METHODS: We conducted a prospective observational study by collecting data from 120 patients in the maternity unit of a university hospital. Preterm (<37 weeks of pregnancy) infants with at least one additional risk factor for neonatal sepsis were included. The levels of interleukin (IL)-6, IL-10, thiobarbituric acid reactive species (TBARS) and protein carbonyls and their association with sepsis severity were determined in the cord blood. RESULTS: Levels of IL-6 and TBARS, but not IL 10 and protein carbonyls, demonstrated a mild to moderate correlation with the SNAPPE-II severity score (r=0.435, p=0.02 and r = 0.385, p = 0.017, respectively). No correlations were found between these markers and mortality. CONCLUSION: TBARS and IL-6 have a mild to moderate correlation with SNAPPE-II, but none of the studied markers were able to predict mortality in our sample. PMID- 23917711 TI - Thrombocitopenia in sepsis: an important prognosis factor. AB - OBJECTIVE: To demonstrate an association between thrombocytopenia and platelet behavior in predicting mortality in septic patients. METHODS: Patients with criteria for sepsis at admission or at any time during hospitalization were selected; patients hospitalized for less than 24 hours were excluded. Thrombocytopenia was defined as a platelet count lower than 150.000/mm3, and recovery was defined as returning to levels above 150.000/mm3 after showing thrombocytopenia. We assessed the admission prognosis variables (APACHE II), platelet counts during the hospitalization and outcomes. RESULTS: Of the 56 patients included, 34 developed thrombocytopenia during sepsis (Group 1) and had a 76.4% mortality rate. The mortality rate among patients not showing thrombocytopenia (Group 2) was 40.9% (RR 1.87; 95% CI 1.12 - 3.12; p = 0.0163). In 44.1% of Group 1 patients, the platelet counts drops by >50% compared with the admission counts; 93.3% of these patients eventually died (RR 1.48; 95% CI 0.93 - 2.36; p = 0.0528). Among the Group 1 patients showing recovered platelet counts, 53.3% survived; 100% of the patients with unrecovered thrombocytopenia died (RR 2.14; 95% CI 1.35 - 3.39; p = 0.0003). Among the patients with APACHE II scores > 22, the thrombocytopenic patients had an 81.8% mortality rate (p = 0.25), while no deaths occurred among the non-thrombocytopenic patients. For the patients with APACHE II scores <= 22, the mortality rate of the thrombocytopenic patients was 74% (p = 0.0741), versus 42.8% for the non-thrombocytopenic patients. CONCLUSION: For this sample of septic patients, thrombocytopenia and its progression, defined as a >50% drop or failure to recover platelet count, were shown to be markers of poor prognosis. PMID- 23917712 TI - Positive end-expiratory pressure increases strain in patients with ALI/ARDS. AB - OBJECTIVE: The objective of this study was to assess the effects of positive end expiratory pressure on recruitment, cyclic recruitment and derecruitment and strain in patients with acute lung injury and acute respiratory distress syndrome using lung computed tomography. METHODS: This is an open, controlled, non randomized interventional study of ten patients with acute lung injury and acute respiratory distress syndrome. Using computed tomography, single, basal slices of the lung were obtained during inspiratory and expiratory pauses at a tidal volume of 6 ml/kg and a positive end-expiratory pressure of 5, 10, 15 and 20 cmH2O. The densities of the lung parenchyma were measured in Hounsfield units. The values for positive end-expiratory pressure-induced recruitment, cyclic recruitment and derecruitment and strain were then calculated. RESULTS: Increasing levels of positive end-expiratory pressure were correlated with increased recruitment and global strain (p < 0.01), which was significantly correlated with plateau pressure (r2 = 0.97, p < 0.01). In addition, increasing levels of positive end expiratory pressure systematically increased strain along the sternovertebral axis. CONCLUSION: While strain is an adverse effect of positive end-expiratory pressure, the decision use positive end-expiratory pressure with any patient should be balanced against the potential benefits of recruitment. Due to the small number of patients in this study, the present data should be treated as hypothesis generating and is not intended to limit the clinical application of a high level of positive end-expiratory pressure in patients with severe hypoxemia. PMID- 23917713 TI - The incidence of delirium in patients pretreated with statins who remain in an intensive care unit after cardiac surgery. AB - OBJECTIVE: To determine the association between the preoperative administration of statins and postoperative delirium in a prospective cohort of patients undergoing cardiac surgery. METHODS: All adult patients who were admitted to the intensive care unit following cardiac surgery between January and June 2011 were included. Delirium was screened during the postoperative period using the Confusion Assessment Method for Intensive Care Unit (CAM-ICU) and Intensive Care Delirium Screening Checklist (ICDSC). RESULTS: A total of 169 patients underwent elective cardiac surgery, and 40.2% of the patients were treated preoperatively with statins. Delirium was identified using the CAM-ICU in 14.9% of patients not taking preoperative statins in comparison with 11.8% of the patients taking statins (p = 0.817). Using the ICDSC, delirium was identified in 18.8% of patients not taking statins in comparison with 10.3% of the patients taking statins (p = 0.191). CONCLUSION: The use of preoperative statins is not correlated with postoperative delirium in patients undergoing cardiac surgery. PMID- 23917714 TI - Expiratory peak flow and respiratory system resistance in mechanically ventilated patients undergoing two different forms of manually assisted cough. AB - OBJECTIVE: Mechanical ventilation is associated with retained airway secretions. Manually assisted cough contributes to the displacement of bronchial mucus, whereas positive end-expiratory pressure increases collateral ventilation and maintains airway patency. This study aimed to assess the effects of manually assisted cough, either alone or added to increased positive end-expiratory pressure and inspiratory time (optimized manually assisted cough), on the expiratory peak flow and respiratory system mechanics in mechanically ventilated patients. METHODS: In this controlled and randomized clinical trial, respiratory mechanics and expiratory peak flow were assessed in male and female patients undergoing either tracheal suctioning alone, manually assisted cough followed by tracheal suctioning or optimized manually assisted cough followed by tracheal suctioning. RESULTS: Thirty-five patients completed the trial. Respiratory system resistance was significantly reduced after optimized manually assisted cough (16.0 +/- 3.6 versus 12.4 +/- 3.1 cmH2O/L/s; p = 0.04). The expiratory peak flow during optimized manually assisted cough was significantly higher in comparison with the values observed during manually assisted cough (112.3 +/- 15.6 versus 95.8 +/- 18.3 Lpm; p < 0.05). Both values were significantly higher than the values observed in the group undergoing tracheal suctioning alone (52.0 +/- 7.6 Lpm; p < 0.001). CONCLUSION: Optimized manually assisted cough increases the expiratory peak flow in comparison with manually assisted cough; in addition, this procedure reduces respiratory system resistance. PMID- 23917715 TI - The effects of orthostatism in adult intensive care unit patients. AB - OBJECTIVE: To assess the consciousness level, pulmonary and hemodynamic effects of orthostatic position in intensive care patients. METHODS: This study was conducted from April 2008 to July 2009 in the Adult Intensive Care Unit, Hospital das Clinicas, Universidade Estadual de Campinas, Sao Paulo, Brazil. Fifteen patients were included who were mechanically ventilated for more than seven days and had the following characteristics: tracheotomized; receiving intermittent nebulization; maximal inspiratory pressure of less than -25 cm H2O; Tobin score less than 105; preserved respiratory drive; not sedated; partial arterial oxygen pressure greater than 70 mm Hg; oxygen saturation greater than 90%; and hemodynamically stable. With inclinations of 0o, 30o and 50o, the following parameters were recorded: consciousness level; blinking reflex; thoracoabdominal cirtometry; vital capacity; tidal volume; minute volume; respiratory muscle strength; and vital signs. RESULTS: No neurological level changes were observed. Respiratory rate and minute volume (V E) decreased at 30% and later increased at 50%; however, these changes were not statistically significant. Abdominal cirtometry and maximal expiratory pressure increased, but again, the changes were not statistically significant. Regarding maximal inspiratory pressure and vital capacity, statistically significant increases were seen in the comparison between the 50o and 0o inclinations. However, tidal volume increased with time in the comparisons between 30o and 0o and between 50o and 0o. Mean blood pressure increased only for the comparison of 50o versus 0o. Heart rate increased with time for the comparisons between 30o and 0o, between 50o and 0o and between 50o and 30o. CONCLUSION: Passive orthostatism resulted in improved tidal volume and vital capacity, maximal inspiratory pressure and increased heart rate and mean blood pressure in critically ill patients. PMID- 23917716 TI - Effects of passive mobilization on acute hemodynamic responses in mechanically ventilated patients. AB - OBJECTIVE: To assess the effects of passive mobilization on acute hemodynamic responses in mechanically ventilated patients. METHODS: This cross-sectional, quantitative, observational study enrolled patients who were admitted to the intensive care unit, sedated and mechanically ventilated. The infusion of sedative and analgesic drugs aimed to maintain a Ramsay scale sedation level of 4 to 6. Passive mobilization consisted of hip and knee flexion-extension movements for five minutes. After 10 minutes of rest, an additional five minutes of flexion extension passive movements was performed for the shoulders. Hemodynamic assessments (heart rate and systolic, diastolic and mean blood pressure) were performed one minute before the mobilization protocol and one minute after each phase. The double product and myocardial oxygen consumption were calculated using appropriate formulas. RESULTS: A total of 13 patients (69.2% male, with a mean age of 69.1 +/- 15.8 years) were admitted from June to December, 2011. Passive mobilization led to statistically significant increases in heart rate, double product and myocardial oxygen consumption. However, mean blood pressure was not significantly altered. CONCLUSIONS: Our results suggest that passive mobilization of mechanically ventilated and sedated patients is safe and provides beneficial effects on acute hemodynamic parameters, particularly heart rate, although mean blood pressure is not significantly altered. PMID- 23917717 TI - Late-onset sepsis in preterm children in a neonatal intensive care unit: a three year analysis. AB - OBJECTIVE: To evaluate the prevalence factors and etiologies associated with late neonatal sepsis in preterm neonates in a neonatal intensive care unit. METHODS: This was a cross-sectional study of secondary data pertaining to preterm neonates admitted to the neonatal intensive care unit between 2008 and 2010 and was gathered from medical charts. The outcome variable, late neonatal sepsis, was characterized using the Brazilian national health surveillance agency criteria. Pearson's Chi-squared test, Fisher's exact test and the linear trend Chi-squared test were used to assess the qualitative variables for linear trends. The statistical significance level was set at p < 0.05. Bivariate and multivariate analyses of the independent and dependent variables were conducted to obtain a measure of the effect and prevalence ratios, considering a p-value of less than 0.20 to indicate statistical significance. RESULTS: This study included 267 preterm neonates. Of the participants, 28.5% were characterized as having late onset sepsis. Positive blood cultures were recorded for 17.1% of the neonates. Death occurred in 8.2% of the total cases, and of these deaths, 68.2% occurred within the sepsis group. Three deaths were associated with positive blood cultures, all of which grew Gram-negative bacteria. The bivariate analysis demonstrated that as the gestational age and birth weight decreased, the prevalence of late-onset sepsis trended upward. Ten or more days on mechanical ventilation was associated with late-onset neonatal sepsis in 80.8% of cases. Peripherally inserted central catheters left in place for 11 or more days were associated with late-onset neonatal sepsis in 76.2% of cases. The multivariate analysis demonstrated that a peripherally inserted catheter left in place for less than 11 days was associated with late-onset neonatal sepsis. Gram-negative bacteria, including Klebsiella pneumoniae and Escherichia coli, were the most frequent causative agents. CONCLUSIONS: Late sepsis remains a concern because of its prevalence in intensive care units and because it increases the number of invasive procedures that preterm children usually undergo in these units. The authors emphasize the expanding role of Gram-negative bacteria in late-onset neonatal sepsis and the need for more efficient methods to identify confirmed sepsis. PMID- 23917718 TI - Use of intravenous magnesium sulfate for the treatment of severe acute asthma in children in emergency department. AB - Severe acute asthma is a medical emergency that must be quickly diagnosed and treated. Initial treatment includes a bronchodilator agent and systemic corticosteroids. In severe cases with poor response to the standard treatment, intravenous magnesium sulfate is a therapeutic option. This article aimed a literature review on the use of intravenous magnesium sulfate in the emergency room treatment of children with acute asthma. The treatment parameters of effectiveness, indication, dosage, adverse effects and contraindications were assessed. A narrative review of the literature based on a search of the Medline and Lilacs databases and the Cochrane Database of Systematic Reviews for articles published between 2000 and 2010 was conducted. The keywords used included the following: asthma, children, emergency and magnesium sulfate. Eight controlled clinical trials, three meta-analyses, one retrospective study, eight review articles and one cross-sectional study were included. A total of 21 articles were analyzed. Several authors reported that intravenous magnesium was effective in the treatment of acute asthma in children. Adverse effects were rare. The use of intravenous magnesium sulfate was indicated for patients with moderate to severe acute asthma not responding to initial treatment with a bronchodilator agent and systemic corticosteroids. Few contraindications were reported but included kidney failure and atrioventricular block. Reports of adverse drug interactions with magnesium were rare. Although reported as safe, intravenous magnesium is infrequently used in children with acute asthma. Most often it is used in severe, progressed cases to prevent respiratory failure and/or admission to the intensive care unit. Intravenous magnesium was concluded to be effective and safe in children with severe acute asthma, although its use in the emergency room is still limited. PMID- 23917719 TI - Neurogenic pulmonary edema: a current literature review. AB - Neurogenic pulmonary edema in the setting of critically ill neurologic patients is a condition that is not fully understood, and it is a relatively rare condition. Severe brain damage, such as cerebral and subarachnoid hemorrhage, head injuries and seizures, represents a risk factor for developing neurogenic pulmonary edema. Misdiagnosis and inappropriate management may worsen cerebral damage because of secondary brain injury from hypoxemia or reduced cerebral perfusion pressure. These factors may increase morbidity and mortality. This study aimed to review the current concepts on pathophysiologic mechanisms involved in the development of neurogenic pulmonary edema and discuss the associated clinical and therapeutic aspects. PMID- 23917720 TI - Nutrition therapy in severe head trauma patients. AB - This article reviews the literature, organizes the major findings, and generates the best evidence-based recommendations on nutrition therapy for head trauma patients. Despite recent advances in head trauma diagnosis and therapy, the mortality associated with this condition remains high. Few therapeutic interventions have been proven to effectively improve this condition. Head trauma causes multiple metabolic and electrolytic disorders; it is characterized by a hypermetabolic state that is associated with intensive catabolism, leading to specific nutritional needs. The current literature lacks specific guidelines for nutrition therapy in severe head trauma patients, although a substantial amount of data has been reported and relevant issues are currently being studied; these data may allow better nutrition therapy guidelines for these patients. In addition to a well-trained multi-disciplinary team, the following recommendations appear to improve outcomes: introducing nutrition therapy early; preferred enteral administration; appropriate energy intake; formulations that are tailored to specific patients, including appropriate nutrients; and strict electrolytic and metabolic monitoring. Understanding the pathophysiology and the consequences of therapy is fundamental. PMID- 23917721 TI - Multidisciplinary care in the intensive care unit for a patient with Prader-Willi syndrome: a dental approach. AB - Prader-Willi syndrome is a genetic neurobehavioral disease affecting children's development and resulting in obesity, reduced height, hypotonia, endocrine disorders and cognitive deficits, which may impair oral integrity. This study aims to report on a case involving a white male 15-year-old patient with Prader Willi syndrome whose oral examination revealed bacterial plaque, gingivitis, poor occlusion, viscous salivation and multiple lip, jugal mucosa, inserted gum and tongue ulcerations. An excision biopsy revealed oral ulcerations typical of herpes, which were considered to be likely to correlate with herpes encephalitis. This result demonstrates that a large portion of the deleterious effects of Prader-Willi syndrome can be attenuated by appropriate diagnosis and early therapeutic intervention, highlighting the role of an integrated multidisciplinary team in the development of therapeutic protocols for Prader Willi syndrome patients. PMID- 23917722 TI - Highlights of the 25th Anniversary EANM Congress Milan 2012: nuclear medicine and molecular imaging at its best. AB - The European Association of Nuclear Medicine (EANM) celebrated its 25th Anniversary Congress in Milan under the chairmanship of Professor Emilio Bombardieri and the auspices of the Italian Society of Nuclear Medicine. As always, the Congress was a great success: more than 5,530 participants from 88 countries came from Europe and beyond. In spite of limited budgets, industry again made an important contribution: New innovative equipment and tracers demonstrating the latest technology and innovations were presented by 122 companies. This review is a brief summary of the major scientific contributions made in the fields of oncology, multimodality imaging, cardiovascular science, neurology and psychiatry, technological innovation and novel tracers, and in other clinical sciences as well as in radionuclide therapy, which all show promising and great innovations. PMID- 23917724 TI - Independent risk factors for urinary tract infection and for subsequent bacteremia or acute cellular rejection: a single-center report of 1166 kidney allograft recipients. AB - BACKGROUND: Urinary tract infection (UTI) is a frequent, serious complication in kidney allograft recipients. METHODS: We reviewed the records of 1166 kidney allograft recipients who received their allografts at our institution between January 2005 and December 2010 and determined the incidence of UTI during the first 3 months after transplantation (early UTI). We used Cox proportional hazards models to determine the risk factors for early UTI and whether early UTI was an independent risk factor for subsequent bacteremia or acute cellular rejection (ACR). RESULTS: UTI, defined as 10 or more bacterial colony-forming units/mL urine, developed in 247 (21%) of the 1166 recipients. Independent risk factors for the first episode of UTI were female gender (hazard ratio [HR], 2.9; 95% confidence intervals [CI], 2.2-3.7; P<0.001), prolonged use of Foley catheter (HR, 3.9; 95% CI, 2.8-5.4; P <0.001), ureteral stent (HR, 1.4; 95% CI, 1.1-1.8; P=0.01), age (HR, 1.1; 95% CI, 1.0-1.2; P=0.03), and delayed graft function (HR, 1.4; 95% CI, 1.0-1.9; P=0.06). Trimethoprim/sulfamethoxazole prophylaxis was associated with a reduced risk of UTI (HR, 0.6; 95% CI, 0.3-0.9; P=0.02). UTI was an independent risk factor for subsequent bacteremia (HR, 2.4; 95% CI, 1.2-4.8; P=0.01). Untreated UTI, but not treated UTI, was associated with an increased risk of ACR (HR, 2.8; 95% CI, 1.3-6.2; P=0.01). CONCLUSIONS: Female gender, prolonged use of Foley catheter, ureteral stent, age, and delayed graft function are independent risk factors for early UTI. UTI is independently associated with the development of bacteremia, and untreated UTI is associated with subsequent ACR. PMID- 23917723 TI - Transcriptional regulation of guidance at the midline and in motor circuits. AB - Axon navigation through the developing body of an embryo is a challenging and exquisitely precise process. Axonal processes within the nervous system harbor extremely complicated internal regulatory mechanisms that enable each of them to respond to environmental cues in a unique way, so that every single neuron has an exact stereotypical localization and axonal projection pattern. Receptors and adhesion molecules expressed on axonal membranes will determine their guidance properties. Axon guidance is thought to be controlled to a large extent through transcription factor codes. These codes would be responsible for the deployment of specific guidance receptors and adhesion molecules on axonal membranes to allow them to reach their targets. Although families of transcriptional regulators as well as families of guidance molecules have been conserved across evolution, their relationships seem to have developed independently. This review focuses on the midline and the neuromuscular system in both vertebrates and Drosophila in which such relationships have been particularly well studied. PMID- 23917725 TI - Ex vivo expanded human regulatory T cells can prolong survival of a human islet allograft in a humanized mouse model. AB - BACKGROUND: Human regulatory T cells (Treg) offer an attractive adjunctive therapy to reduce current reliance on lifelong, nonspecific immunosuppression after transplantation. Here, we evaluated the ability of ex vivo expanded human Treg to prevent the rejection of islets of Langerhans in a humanized mouse model and examined the mechanisms involved. METHODS: We engrafted human pancreatic islets of Langerhans into the renal subcapsular space of immunodeficient BALB/c.rag2(-/-).cgamma(-/-) mice, previously rendered diabetic via injection of the beta-cell toxin streptozocin. After the establishment of stable euglycemia, mice were reconstituted with allogeneic human peripheral blood mononuclear cells (PBMC) and the resultant alloreactive response studied. Ex vivo expanded CD25high CD4+ human Treg, which expressed FoxP3, CTLA-4, and CD62L and remained CD127low, were then cotransferred together with human PBMC and islet allografts and monitored for evidence of rejection. RESULTS: Human islets transplanted into diabetic immunodeficient mice reversed diabetes but were rejected rapidly after the mice were reconstituted with allogeneic human PBMC. Cotransfer of purified, ex vivo expanded human Treg prolonged islet allograft survival resulting in the accumulation of Treg in the peripheral lymphoid tissue and suppression of proliferation and interferon-gamma production by T cells. In vitro, Treg suppressed activation of signal transducers and activators of transcription and inhibited the effector differentiation of responder T cells. CONCLUSIONS: Ex vivo expanded Treg retain regulatory activity in vivo, can protect a human islet allograft from rejection by suppressing signal transducers and activators of transcription activation and inhibiting T-cell differentiation, and have clinical potential as an adjunctive cellular therapy. PMID- 23917726 TI - Galectin-3 inhibition sensitizes human renal cell carcinoma cells to arsenic trioxide treatment. AB - The anti-tumor effects of arsenic trioxide (ATO) were well established in acute promyelocytic leukemia, but not in renal cell carcinoma (RCC). Recent evidences indicate that galectin-3 (Gal-3) plays an anti-apoptotic role in chemotherapy induced tumor cell death. This study was intended to clarify the exact roles of Gal-3 performed in ATO-induced apoptosis in RCC cells. Weak apoptosis was observed in Gal-3-positive RCC cells (Caki-1, Caki-2, 786-0, and ACHN) following ATO treatment. However, ATO treatment upregulated Gal-3 expression concurrently caused a Synexin-cooperated translocation of Gal-3 from the nucleus to the cytoplasm. Gal-3-knockdown cells were more sensitive to ATO treatment as indicated by a strong mitochondria-dependent apoptosis following ATO treatment. Meanwhile, Gal-3 was found to inhibit ATO-induced apoptosis through enhancing Bcl 2 expression and stabilizing mitochondria. To confirm the results obtained from genetic method, we employed a Gal-3 inhibitor, modified citrus prectin (MCP), and co-treated the RCC cells with ATO. The cells showed an increased apoptosis in the syngeneic application of Gal-3 inhibition and ATO compared with ATO application alone. Based on these results, we conclude that Gal-3 inhibition sensitizes human renal cell carcinoma cells to ATO treatment through increasing mitochondria dependent apoptosis. Our studies implicate synergetic application of ATO and Gal 3 inhibition as a potential strategy for RCC treatment. PMID- 23917727 TI - Metal stoichiometry of isolated and arsenic substituted metallothionein: PIXE and ESI-MS study. AB - The stoichiometric analysis of the metal induced Metallothionein (MT) is pertinent for understanding the metal-MT interactions. Despite innumerable publications on MT, the literature addressing these aspects is limited. To bridge this gap, PIXE and ESI-MS analysis of the commercial rabbit liver MT1 (an isoform of MT), zinc induced isolated rat liver MT1, apo and Arsenic substituted rabbit liver MT1 have been carried out. These techniques in combination provide information about number and the signature of all the metal ions bound to MT. By using ESI-MS in the rabbit MT1, ions of Zn n MT1 (n = 0, 1, 4, 5, 6, 7) whereas, in rat MT1, the Zn1MT1 and Zn5MT1 ions are observed. PIXE analysis shows that some copper along with zinc is also present in the rabbit as well as rat MT1 which could not be assessed with ESI-MS. During As metallation reaction with rabbit MT1, with increase in arsenic concentration, the amount of arsenic bound to MT1 also increases, though not proportionally. The presence of both Zn and Cu in MT1 on Zn supplementation can be related to the role of MT in Zn and Cu homeostasis. Further, the presence of partially metallated MT1 suggests that MT1 may donate fractional amount of metal from it's fully metallated form to other proteins where Zn acts as a cofactor. PMID- 23917729 TI - A Methodology for Protective Vibration Monitoring of Hydropower Units Based on the Mechanical Properties. AB - It is important to monitor the radial loads in hydropower units in order to protect the machine from harmful radial loads. Existing recommendations in the standards regarding the radial movements of the shaft and bearing housing in hydropower units, ISO-7919-5 (International Organization for Standardization, 2005, "ISO 7919-5: Mechanical Vibration-Evaluation of Machine Vibration by Measurements on Rotating Shafts-Part 5: Machine Sets in Hydraulic Power Generating and Pumping Plants," Geneva, Switzerland) and ISO-10816-5 (International Organization for Standardization, 2000, "ISO 10816-5: Mechanical Vibration-Evaluation of Machine Vibration by Measurements on Non-Rotating Parts Part 5: Machine Sets in Hydraulic Power Generating and Pumping Plants," Geneva, Switzerland), have alarm levels based on statistical data and do not consider the mechanical properties of the machine. The synchronous speed of the unit determines the maximum recommended shaft displacement and housing acceleration, according to these standards. This paper presents a methodology for the alarm and trip levels based on the design criteria of the hydropower unit and the measured radial loads in the machine during operation. When a hydropower unit is designed, one of its design criteria is to withstand certain loads spectra without the occurrence of fatigue in the mechanical components. These calculated limits for fatigue are used to set limits for the maximum radial loads allowed in the machine before it shuts down in order to protect itself from damage due to high radial loads. Radial loads in hydropower units are caused by unbalance, shape deviations, dynamic flow properties in the turbine, etc. Standards exist for balancing and manufacturers (and power plant owners) have recommendations for maximum allowed shape deviations in generators. These standards and recommendations determine which loads, at a maximum, should be allowed before an alarm is sent that the machine needs maintenance. The radial bearing load can be determined using load cells, bearing properties multiplied by shaft displacement, or bearing bracket stiffness multiplied by housing compression or movement. Different load measurement methods should be used depending on the design of the machine and accuracy demands in the load measurement. The methodology presented in the paper is applied to a 40 MW hydropower unit; suggestions are presented for the alarm and trip levels for the machine based on the mechanical properties and radial loads. PMID- 23917728 TI - Rotatory instability of the knee after ACL tear and reconstruction. AB - Although ACL reconstructions provide satisfactory clinical results nowadays, regardless of the type of graft or the surgical technique used (out-in vs in-out or single- vs double-bundle), the residual rotatory instability which is often detected at clinical follow-ups is still a matter of concern among surgeons. In this paper we try to analyze all the aspects which might contribute to this phenomenon by summarizing the biomechanical functions of the two bundles of the ACL, and by evaluating all the other factors strictly related to the rotatory instability of a reconstructed knee, such as the anatomical positioning of the single- or double-bundle new ACL, or the importance of a valid lateral compartment (LCL, ALTFL). Clinical, biomechanical and cadaver studies are discussed in order to contribute to better understanding of the origin of post operative residual rotatory instability. PMID- 23917731 TI - Exuberant inflammatory reaction as a side effect of platelet-rich plasma injection in treating one case of tendinopathy. AB - Platelet-rich plasma (PRP) contains a large number of growth factors, which may enhance tendon healing processes. Local injection of PRP represents a relatively new treatment for tendinopathies. To date, no side effects have been reported after injection of PRP to treat tendinopathy. We report a case of exuberant inflammatory reaction after 1 injection of PRP to treat jumper's knee in a 35 year-old male type 1 diabetic patient. Injections of PRP should be proposed only after careful consideration in cases of patients with morbidity risks linked to insulin-dependent diabetes. PMID- 23917732 TI - The effects of sleep quality and sleep quantity on concussion baseline assessment. AB - OBJECTIVE: Proper concussion assessment is imperative for properly caring for athletes who sustain traumatic brain injuries. Decreased sleep quality and sleep quantity affect cognition and may threaten the validity of clinical measures often used as a part of the concussion assessment. The purpose of this study was to determine if sleep quality or sleep quantity affects performance on clinical measures of concussion. DESIGN: Prospective cohort design. SETTING: Clinical research center. PARTICIPANTS: One hundred fifty-five college student-athletes (57 females, 98 males; age = 18.8 +/- 0.8 years; mass = 78.4 +/- 19.6 kg; height = 177.4 +/- 12.3 cm). INTERVENTIONS: We performed preseason baseline testing by using a well-accepted and multifaceted protocol inclusive of neurocognition, balance performance, and symptom reporting. Information related to sleep quality and sleep quantity was also collected during preseason baseline testing. MAIN OUTCOME MEASURES: The CNS Vital Signs battery (computerized neurocognitive test), Sensory Organization Test (computerized dynamic posturography), and a Graded Symptom Checklist (symptom evaluation) were used. RESULTS: Subjects with a low sleep quantity the night before baseline reported both a greater number of symptoms and higher total symptom severity score. No clinically significant effects for sleep quality were observed. CONCLUSIONS: Sleep-deprived athletes reporting for baseline testing should be rescheduled for testing after a normal night's sleep. PMID- 23917733 TI - Motor vehicle accidents: the leading cause of death in collegiate athletes. AB - OBJECTIVE: To report the leading cause of death in National Collegiate Athletic Association (NCAA) athletes. DESIGN: Retrospective analysis from January 2004 to December 2008. SETTING: NCAA institutions. PARTICIPANTS: Collegiate athletes. ASSESSMENT OF RISK FACTORS: NCAA divisions, sport, gender, and race. MAIN OUTCOME MEASURES: Mortality. RESULTS: During the 5-year period, there were 273 deaths and a total of 1 969 663 athlete participation-years. Of these 273 deaths, 145 (53%) were due to accidents or unintentional injury, 45 (16%) from cardiac arrest, 25 (9%) suicides, and 18 (6%) homicides. The rate of death due to accidents was 7.36/100 000 participants per year. Motor vehicle accidents accounted for 100 accidents (69%). There was no significant difference in accident rates between NCAA divisions. Accidents were twice as likely in men compared with women (P < 0.0001). There was no significant difference in the accident rates in white versus black athletes. Although accidents usually occurred more frequently in the general population (5-fold) compared with NCAA athletes, certain athlete subgroups (Division I wrestling, Divisions I and II basketball, and Divisions I and II football) seem to be high-risk populations with death rates that were no different than the general population. This suggests that these athletes may engage in higher risk behaviors compared with other sporting subgroups. CONCLUSIONS: Motor vehicle accidents are the most common cause of sudden death in athletes across NCAA divisions, gender, race, and sport. Medical teams and institutions should design (1) effective safety prevention programs, and (2) catastrophic incident plans that can be implemented in the event of such tragedies. PMID- 23917734 TI - Increased frequency of ankle sprain does not lead to an increase in ligament laxity. AB - OBJECTIVE: Ankle sprains are the most common injury in the active population. With high reinjury rates and complaints of the ankle "giving way," it has been suggested that laxity of ankle ligaments increases with repeated sprains. The objective of this study was to determine if a relationship exists between ligament laxity and the number of ankle sprains. DESIGN: Cross-sectional study. SETTING: Biomechanics laboratory. PARTICIPANTS: A total of 203 Division I collegiate athletes (84 women; 119 men; age, 18.5 +/- 1.1 years; height, 178.5 +/ 10.8 cm; mass, 79.8 +/- 18.7 kg) participated in the study. INTERVENTION: Each participant reported the number of previous sprains on each ankle. Ligament laxity was measured using an instrumented ankle arthrometer. MAIN OUTCOME MEASURES: Measurements for anterior displacement (AD), inversion (IV), and eversion (EV) rotation of the ankle were obtained using an instrumented ankle arthrometer. RESULTS: There was no relationship between ligament laxity and the number of ankle sprains in either direction (AD, P = 0.86; IV, P = 0.64; EV, P = 0.81). In addition, comparing ligament laxity between previously sprained ankles and ankles that have never been sprained resulted in no differences in the direction of movement (AD, P = 0.98; IV, P = 0.96; EV, P = 0.67). CONCLUSIONS: Despite anecdotal evidence suggesting repeated ankle sprains increase ligament laxity, this report involving a large data set and a reliable measurement analysis found no relationship between the two. The results of this study make it necessary to rethink the causes of ligament laxity. Therefore, further research is necessary to understand the causes of "giving way" of the ankle and their role in repeated ankle sprains. PMID- 23917735 TI - Memantine's action against aminoglycoside-induced ototoxicity. AB - The objectives of this study were (1) to assess the protective role of NMDA antagonists against the ototoxic effects of aminoglycosides, (2) to provide any possible evidence between ototoxicity due to aminoglycosides and excitotoxicity. An animal experiment was conducted. Twenty-eight, 3-month-old female New Zealand rabbits, weighing 1,000-1,500 g, were studied prospectively for 28 days after intramuscular administration of amikacin (15 mg/kg/day divided into two equal doses) for 14 days. Twenty-one rabbits were categorized into three equal treatment groups and seven animals received no medication and served as the control group. The animals of A, B and C groups were injected, intramuscularly, with amikacin 15 mg/kg/day, divided into two equal doses every day for 14 days. Animals of group A received in parallel memantine (per os) and those of group B received p.o. the same volume of placebo solution. The rabbits of the third group (group C) received on the 15th day and every 2 days for the next 2 weeks, until the day 28, memantine of the same quantity as the members of group A. Differences in DPOAE amplitudes, and therefore in cochlear activity, between group A and group B were revealed. DPOAE amplitudes of group B were further reduced compared to the respective amplitudes in rabbits of group A. No improvement was observed in DPOAE measurements performed after the discontinuation of injections. The findings in group C should be examined separately. The measurements showed apparent reversal ototoxic effects in four of the animals. The development of aminoglycoside otoprotective strategies is a primary goal in ototoxicity research. The administration of NMDA antagonists has been shown to prevent, at least to some extent, toxic damage to hair cells in guinea pigs, treated with aminoglycoside antibiotics. PMID- 23917736 TI - Postnatal risk factors associated with hearing loss among high-risk preterm infants: tertiary center results from Turkey. AB - The aim of this study was to determine the postnatal risk factors associated with hearing loss as well as the prevalence of hearing loss among high-risk preterm infants in newborn hearing screening (NHS). We performed a retrospective study of high-risk preterm infants born with a gestational age <=32 weeks and/or a birth weight <=1,500 g. A NHS procedure was performed by automated auditory brainstem response (AABR) and automated evoked otoacoustic emission (TEOAE). Infants who failed TEOAE or AABR or both tests were referred to a tertiary audiology center for diagnosis confirmation and management. Postnatal risk factors associated with hearing loss were evaluated and compared for preterm infants with and without hearing loss. 1,360 high-risk preterm infants were assessed. Permanent hearing loss was found in 19 (1.4%) infants. Multivariate analysis revealed that proven sepsis (p = 0.019), mechanical ventilation >=5 days (p = 0.024), loop diuretics (p = 0.001), patent ductus arteriosus ligation (p = 0.018) and operation for retinopathy of prematurity (ROP) (p = 0.034) were significant related factors for the hearing loss. This study showed a low prevalence of hearing loss and an association between operation for ROP and hearing loss in preterm infants, which has not been defined previously. Our results suggest that every neonatal intensive care unit should determine their own risk factors and take precautions to prevent hearing loss for these high-risk preterm infants. PMID- 23917737 TI - Detection of feral GT73 transgenic oilseed rape (Brassica napus) along railway lines on entry routes to oilseed factories in Switzerland. AB - To obtain a reference status prior to cultivation of genetically modified oilseed rape (OSR, Brassica napus L.) in Switzerland, the occurrence of feral OSR was monitored along transportation routes and at processing sites. The focus was set on the detection of (transgenic) OSR along railway lines from the Swiss borders with Italy and France to the respective oilseed processing factories in Southern and Northern Switzerland (Ticino and region of Basel). A monitoring concept was developed to identify sites of largest risk of escape of genetically modified plants into the environment in Switzerland. Transport spillage of OSR seeds from railway goods cars particularly at risk hot spots such as switch yards and (un)loading points but also incidental and continuous spillage were considered. All OSR plants, including their hybridization partners which were collected at the respective monitoring sites were analyzed for the presence of transgenes by real-time PCR. On sampling lengths each of 4.2 and 5.7 km, respectively, 461 and 1,574 plants were sampled in Ticino and the region of Basel. OSR plants were found most frequently along the routes to the oilseed facilities, and in larger amounts on risk hot spots compared to sites of random sampling. At three locations in both monitored regions, transgenic B. napus line GT73 carrying the glyphosate resistance transgenes gox and CP4 epsps were detected (Ticino, 22 plants; in the region of Basel, 159). PMID- 23917739 TI - Effect of cadmium on cytogenetic toxicity in hairy roots of Wedelia trilobata L. and their alleviation by exogenous CaCl2. AB - Effects of cadmium (Cd) alone and in combination with calcium on mitosis and chromosomal aberration in the hairy root tips of Wedelia trilobata were investigated. The results showed that Cd concentrations below 50 MUmol/L had a lesser or even a promoting effect on the mitotic index (MI) and the rate of chromosomal aberration in hairy root tips, while those higher than 100 MUmol/L significantly decreased the MI and gradually stimulated the rate of chromosomal aberrations with prolonged time and increasing concentrations of Cd. Concentrations of 50 MUmol/L Cd mainly induced C-mitosis, while more than 100 MUmol/L Cd mainly caused chromosome breakage and chromosome adhesion in hairy root tip cells. When cultured with 300 MUmol/L Cd, micronuclei were only observed in the interphase, middle, and late phase of hairy root tip cells. Compared with untreated controls, exogenous calcium had an alleviating effect on Cd-induced cytotoxicity by effectively enhancing the MI and reducing the rate of chromosomal aberration in root tip cells. The results presented here provide evidence that W. trilobata hairy roots with rapid autonomous growth could be used as a sensitive tool for monitoring and evaluation of Cd pollution in the environment. PMID- 23917738 TI - Meta-analysis of environmental contamination by phthalates. AB - Phthalate acid esters (PAE), commonly named phthalates, are toxics classified as endocrine-disrupting compounds; they are primarily used as additives to improve the flexibility in polyvinyl chloride. Many studies have reported the occurrence of phthalates in different environmental matrices; however, none of these studies has yet established a complete overview for those compounds in the water cycle within an urban environment. This review summarizes PAE concentrations for all environmental media throughout the water cycle, from atmosphere to receiving waters. Once the occurrences of compounds have been evaluated for each environmental compartment (urban wastewater, wastewater treatment plants, atmosphere, and the natural environment), we reviewed data in order to identify the fate of PAE in the environment and establish whether geographical and historical trends exist. Indeed, geographical and historical trends appear between Europe and other countries such as USA/Canada and China, however they remain location dependent. This study aimed at identifying both the correlations existing between environmental compartments and the processes influencing the fate and transport of these contaminants into the environment. In Europe, the concentrations measured in waterways today represent the background level of contamination, which provides evidence of a past diffuse pollution. In contrast, an increasing trend has actually been observed for developing countries, especially for China. PMID- 23917740 TI - The fate and risk of selected pharmaceutical and personal care products in wastewater treatment plants and a pilot-scale multistage constructed wetland system. AB - The removal of 12 pharmaceuticals and personal care products (PPCPs) in two full scale wastewater treatment plants (WWTPs) and a tertiary treatment system was studied. The ecological risks of effluents from both secondary and tertiary treatment systems as well as excess sludge were evaluated. Primary treatment and ultraviolet light disinfection showed limited ability to remove most selected PPCPs. The combination of an anaerobic process and triple-oxidation ditches can eliminate DEET better than the anaerobic/anoxic/oxic process. Adsorption to sludge played a key role in the removal of triclocarban. Multistage constructed wetlands as a tertiary treatment efficiently removed caffeine and ibuprofen from wastewater and could decrease the risk of partial selected PPCPs. Selected PPCPs residues in excess sludge generally produced higher risks to the ecological environment than effluents from WWTPs. PMID- 23917741 TI - Effective photodegradation of methomyl pesticide in concentrated solutions by novel enhancement of the photocatalytic activity of TiO2 using CdSO4 nanoparticles. AB - Annihilation of electrons-holes recombination process is the main remedy to enhance the photocatalytic activity of the semiconductors photocatalysts. Doping of this class of photocatalysts by foreign nanoparticles is usually utilized to create high Schottky barrier that facilitates electron capture. In the literature, because nonpolar nanoparticles (usually pristine metals, e.g., Ag, Pt, Au, etc.) were utilized in the doping process, the corresponding improvement was relatively low. In this study, CdSO4-doped TiO2 nanoparticles are introduced as a powerful and reusable photocatalyst for the photocatalytic degradation of methomyl pesticide in concentrated aqueous solutions. The utilized CdSO4 nanoparticles form polar grains in the TiO2 matrix due to the electrons leaving characteristic of the sulfate anion. The introduced nanoparticles could successfully eliminate the harmful pesticide under the sunlight radiation within a very short time (less than 1 h), with a removal capacity reaching 1,000 mg pesticide per gram of the introduced photocatalyst. Moreover, increase in the initial concentration of the methomyl did not affect the photocatalytic performance; typically 300, 500, 1,000, and 2,000 mg/l solutions were completely treated within 30, 30, 40, and 60 min, respectively, using 100 mg catalyst. Interestingly, the photocatalytic efficiency was not affected upon multiple use of the photocatalyst. Moreover, negative activation energy was obtained which reveals super activity of the introduced photocatalyst. The distinct photocatalytic activity indicates the complete annihilation of the electrons holes recombination process and abundant existence of electrons on the catalyst surfaces due to strong electrons capturing the operation of the utilized polar CdSO4 nanoparticles. The introduced photocatalyst has been prepared using the sol gel technique. Overall, the simplicity of the synthesizing procedure and the obtained featured photocatalytic activity strongly recommend the introduced nanoparticles to treat the methomyl-containing polluted water. PMID- 23917742 TI - Toxic effects of hexaflumuron on the development of Coccinella septempunctata. AB - Studying the toxic risk of pesticide exposure to ladybird beetles is important from an agronomical and ecological perspective since larval and adult ladybirds are dominant predators of herbivorous pest insects (e.g., aphids) in various crops in China. This article mainly deals with the long-term effects of a single application of the insect growth regulator hexaflumuron on Coccinella septempunctata. A 72-h and a 33-day toxicity test with hexaflumuron (single application) were performed, starting with the second instar larvae of C. septempunctata. Exposure doses in the long-term experiment were based on the estimated 72-h acute LR50 (application rate causing 50% mortality) value of 304 g active ingredient (a.i.) ha(-1) for second instar larvae of C. septempunctata. The long-term test used five hexaflumuron doses as treatment levels (1/50, 1/100, 1/200, 1/400, and 1/800 of the 72-h acute LR50), as well as a solvent control and blank control treatment. The measurement endpoints used to calculate no observed effect application rates (NOERs) included development time, hatching, pupation, adult emergence, survival, and number of eggs produced. Analyzing the experimental data with one-way analysis of variance showed that the single hexaflumuron application had significant effects on C. septempunctata endpoints in the 33-day test, including effects on development duration (NOER 1.52 g a.i. ha(-1)), hatching (NOER 3.04 g a.i. ha(-1)), pupation (NOER 3.04 g a.i. ha(-1)), and survival (NOER 1.52 g a.i. ha(-1)). These NOERs are lower than the reported maximum field application rate of hexaflumuron (135 g a.i. ha(-1)) in cotton cultivation, suggesting potential risks to beneficial arthropods. PMID- 23917743 TI - Kinetics of phenol biodegradation at high concentration by a metabolically versatile isolated yeast Candida tropicalis PHB5. AB - A highly tolerant phenol-degrading yeast strain PHB5 was isolated from wastewater effluent of a coke oven plant and identified as Candida tropicalis based on phylogenetic analysis. Biodegradation experiments with C. tropicalis PHB5 showed that the strain was able to utilize 99.4% of 2,400 mg l(-1) phenol as sole source of carbon and energy within 48 h. Strain PHB5 was also observed to grow on 18 various aromatic hydrocarbons. Haldane model was used to fit the exponential growth data and the following kinetic parameters were obtained: MU max = 0.3407 h(-1), K S = 15.81 mg l(-1), K i = 169.0 mg l(-1) (R (2) = 0.9886). The true specific growth rate, calculated from MU max, was 0.2113. A volumetric phenol degradation rate (V max) was calculated by fitting the phenol consumption data with Gompertz model and specific degradation rate (q) was calculated from V max. The q values were fitted with Haldane model, yielding following parameters: q max = 0.2766 g g(-1) h(-1), K S ' = 2.819 mg l(-1), K i ' = 2,093 (R (2) = 0.8176). The yield factor (Y X/S ) varied between 0.185 to 0.96 g g(-1) for different initial phenol concentrations. Phenol degradation by the strain proceeded through a pathway involving production of intermediates such as catechol and cis,cis muconic acid which were identified by enzymatic assays and HPLC analysis. PMID- 23917744 TI - Mucopolysaccharidosis type I and craniosynostosis. AB - Mucopolysaccharidosis type-I is caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase, resulting in gradual deposition of glycosaminoglycans in multiple body organs, affecting physical appearance and system functioning. We present the first reported case associating MPS-I (Hurler-Scheie subtype) with craniosynostosis. A 2.5-year-old girl presented initially with macrocrania. On clinical and radiological examinations we noted a scaphocephaly with dysmorphic facial features of MPS confirmed later on. Intracranial hypertension was documented at fundoscopy (papilloedema) and ICP monitoring, and then surgically treated. This association of scaphocephaly and MPS-I highlights the importance of a meticulous physical examination performed by craniofacial, metabolic and ophthalmologic teams. PMID- 23917745 TI - Risk factors of surgical site infections after supratentorial elective surgery: a focus on the efficacy of the wound-drain-tip culture. AB - BACKGROUND: Surgical site infection (SSI) is one of the most dangerous complications after neurological surgery and is related to additional postoperative hospital days and an increased risk of death. One method for the early detection of SSI, the wound-drain-tip culture (WDC), has been widely used. However, no investigations on the relation between SSIs and wound drains after neurological surgery have been conducted. We performed this study to identify the risk factors for SSIs and to assess the relationship between SSIs and the results of WDC after elective supratentorial craniotomy. METHODS: A total of 535 patients underwent elective primary supratentorial craniotomy, and the results of their WDC were analyzed. The mean follow-up period was 14.1 +/- 12.2 months. In 347 (64.9 %) patients, the wound drain was removed within 2 days after operation. RESULTS: Until follow-up, 14 (2.62 %) patients suffered from SSIs. Among the 21 patients with positive WDCs, 8 (38.1 %) patients experienced SSIs. The organisms cultured from the SSIs were matched with the WDC results in 7 (87.5 %) patients. In the multivariate analysis, underweight group (OR = 15.41, p = 0.002), maintenance wound drain over 3 days (OR = 4.202, p = 0.043), and positive WDC (OR = 36.67, p < 0.001) were significantly associated with postoperative SSIs. In 6 (85.7 %) of 7 patients with a positive WDC for Serratia marcescens, SSIs ultimately developed. CONCLUSIONS: The prognostic value of the positive WDC still falls short of our expectations in the field of neurological surgery. And, the positive WDC results should be cautiously interpreted, considering the virulence of the cultured micro-organisms. PMID- 23917746 TI - Interdigitated silver-polymer-based antibacterial surface system activated by oligodynamic iontophoresis - an empirical characterization study. AB - There is a pressing need to control the occurrences of nosocomial infections due to their detrimental effects on patient well-being and the rising treatment costs. To prevent the contact transmission of such infections via health-critical surfaces, a prophylactic surface system that consists of an interdigitated array of oppositely charged silver electrodes with polymer separations and utilizes oligodynamic iontophoresis has been recently developed. This paper presents a systematic study that empirically characterizes the effects of the surface system parameters on its antibacterial efficacy, and validates the system's effectiveness. In the first part of the study, a fractional factorial design of experiments (DOE) was conducted to identify the statistically significant system parameters. The data were used to develop a first-order response surface model to predict the system's antibacterial efficacy based on the input parameters. In the second part of the study, the effectiveness of the surface system was validated by evaluating it against four bacterial species responsible for several nosocomial infections - Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Enterococcus faecalis - alongside non-antibacterial polymer (acrylic) control surfaces. The system demonstrated statistically significant efficacy against all four bacteria. The results indicate that given a constant total effective surface area, the system designed with micro-scale features (minimum feature width: 20 MUm) and activated by 15 MUA direct current will provide the most effective antibacterial prophylaxis. PMID- 23917747 TI - Psychiatric brain collection in Macedonia: general lessons for scientific collaboration among countries of differing wealth. AB - Macedonia is a small country, and the current state has been independent for only 22 years. Medical research, which requires an extensive infrastructure, has been limited. We describe our experience in developing Macedonian research through a mutually beneficial collaboration between institutions in Macedonia and the United States. PMID- 23917748 TI - Ozone exaggerates nasal allergic inflammation. AB - A double-blind randomised trail design was used to address the effect of ambient ozone on the nasal airways and to evaluate the effects of ozone on allergic mucosa. Ten grass pollen allergic rhinitics were exposed for 2 hours at rest on 2 separate occasions to 400 ppb ozone and filtered air respectively. The exposure to 400 ppb ozone and filtered air was performed prior to the grass pollen season and again during the season. Baseline nasal lavage in which histamine, eosinophil cationic protein (ECP), myeloperoxidase (MPO), total proteins, and albumin were measured and neutrophils, eosinophils and epithelial cells were counted, was made immediately prior to exposure (-120 min). After 2 h of exposure to ozone/filtered air repeated measurements were performed at 0, 30, 60, 120, 240, 360 minutes post exposure. Significant increases were observed when exposed to ozone versus filtered air during the pollen season for histamine (AUC1; p=0.05), MPO (AUC2; p=0.05), ECP (AUC2; p=0.008), total proteins (AUC, p=0.02; AUC1, p=0.007; AUC2, p=0.05), and albumin (AUC, p=0.007; AUC1, p=0.02; AUC2, p=0.005). There was also a significant increase in the total protein level (AUC, p=0.05; AUC1, p=0.02; AUC2 p=0.05) and albumin (AUC, p=0.03; AUC1, p=0.03; AUC2, p=0.04) after ozone exposure versus air out of season. Significant increase of the neutrophils (p=0.01 and p=0.007) in the nasal lavage fluid (NLF) at time points 0 min and 360 min respectively were observed, while eosinophils and epithelial cells significantly increased only at time point 360 min (p=0.02 and p=0.02 respectively) all of them after ozone exposure versus filtered air during the season. Neutrophils also significantly increased in the NLF at time point 0 min and 360 min (p=0.03 and p=0.01) while epithelial cells increased only at time point 360 min (p=0.01) after ozone exposure versus filtered air out of season. We can conclude that ozone induces neutrophil and eosinophil recruitment into the nose and this is accompanied by activation, as evidenced by release of MPO and ECP in NAL. Pre-existing allergic mucosal inflammation during the pollen season, exaggerates the response to ozone, particularly in relationship to the recruitment of eosinophils and neutrophils 6h following exposure. PMID- 23917749 TI - Predicting difficult airway in apparently normal adult and pediatric patients. AB - The aim of the study was to determine the predicting tests for difficult airway and difficult intubation in apparently normal patients. METHODS: We were using the literature about the specific tests for predicting difficult airway and single parameters that could be a significant test for prediction of difficult or impossible intubation. Clinical risk factors for difficult intubation in pediatric patients are related to the anatomic differences between pediatric patients and adults. Quantitative evaluation of difficult intubations could be realized using Cormack-Lehane (CL) scale and Mallampati score (without speaking- Mallampati test--and modified Mallampati test during speech). The Cormack-Lehane (CL) scale is a grading system commonly used to describe the view of the larynx during direct laryngoscopy. Grades 3 and 4, in which the glottis is not visualized, are considered difficult intubations. The Mallampati score, estimates the size of the tongue relative to the oral cavity and the ability to open the mouth. This system graded the patient (grades 1 to 4) based on the structures visible in the oropharynx with maximal mouth opening. Grade 3 or 4 suggests a significant chance that the patient will be difficult to intubate. RESULTS: Our results showed that 24 patients (20 adult patients and 4 pediatric patients), 3.2% from total of 750 involved in the study had difficult intubation (Mallampati grades 3 and 4). 35% of the patients had impaired glottis exposure (grades 3 and 4 of the Cormack-Lehane scale). CONCLUSION: We used only two criteria for describing both the visibility of the oropharyngeal structures and the quality of the laryngeal view. The effective and reliable prediction requires a combination of several parameters (BMI, head and neck movement, dentition status, upper lip bite test, interincisor gap and thyromental distance). PMID- 23917750 TI - Rhegmatogenous retinal detachment and conventional surgical treatment. AB - AIM: The aim of the paper was to present the efficacy and indications for application of conventional surgical treatment of retinal detachment by using external implants, that is,application of encircling band and buckle. MATERIAL AND METHOD: This study comprised patients from the University Eye Clinic in Skopje. A total of 33 patients were diagnosed and surgically treated in the period between May 2010 and August 2011. Conventional surgery was applied in smaller number of patients whose changes of the vitreous body were manifested by detachment of posterior hyaloid membrane, syneresis, with appearance of a small number of pigment cells in the vitreous body and synchysis, and the very retina was with fresh detachment without folds or epiretinal changes (that is, PVR A grade). There were a larger number of patients with more distinct proliferative changes of the vitreous body and of the retina, grades PVR B to C1-C2, and who also underwent the same surgical approach. Routine ophthalmologic examinations were performed, including: determination of visual acuity by Snellen's optotypes, determination of eye pressure with Schiotz's tonometer, examination of anterior segment on biomicroscopy, indirect biomicroscopy of posterior eye segment (vitreous body and retina) and examination on biomicroscopy with Goldmann prism, B scan echography of the eyes before and after surgical treatment. Conventional treatment was used by external application of buckle or application of buckle and encircling band. In case of one break, radial buckle was applied and in case of multiple breaks in one quadrant limbus parallel buckle was applied. Besides buckle, encircling band was applied in patients with total or subtotal retinal detachment with already present distinct changes in the vitreous body (PVR B or C1-C2) and degenerative changes in the vitreous body. Breaks were closed with cryopexy. RESULTS: The results obtained have shown that male gender was predominant and that the disease was manifested in younger male adults. According to the present risk factor, high myopia was found in 5 patients, which has been emphasized to be a significant risk factor for onset of retinal detachment. Lattice degeneration was the most common peripheral degenerative change. The most frequently found was horseshoe retinal hole with vitreous traction and the break location was most common in the upper retinal quadrants. The most commonly applied type was limbus radial buckle with encircling band, depending on the pathological process in the eye. The retina was postoperatively attached in 31 eyes. In two cases, the retina was not attached; in one eye due to the inadequately inserted implant and in the other case due to the larger number of breaks (3) with more distinct PVR (C2), and postoperative inflammation and proliferative components were more intensified. In one patient who did not have a total detachment, but had a larger break placed posterior to the equator and PVR C1, redetachment appeared one month later due to a manifested fibroproliferative reaction, although the break was closed. Regarding visual acuity, the day following the surgery there was no improvement; moreover, there was a small decline of visual acuity due to exudates in the vitreous body and vitreous hemorrhage. After 3 months, there was a significant improvement in the largest number of eyes. Intraoperative complications included intravitreous hemorrhage, and postoperative more distinct proliferative component in the vitreous body was found in two patients. CONCLUSION: Timely diagnosis and intervention in retinal detachment by application of an adequate method and less invasive technique gives excellent results in postoperative morbidity rate and rehabilitation of the vision. The results of the conventional treatment of retinal detachment justify its application in the treatment of this disease. PMID- 23917751 TI - Digital quantitative immunofluorescent detection of p53 protein in urinary bladder cancer tissue samples. AB - Bladder cancer is a significant health problem and is the fourth most common malignancy in the Western world. Histologically, transitional cell carcinoma (TCC) is the most common subtype and represents nearly 90% of all bladder cancers. Mutations of the tumour suppressor gene p53 are the most frequent genetic alteration found in human cancers, including urinary bladder carcinoma. Numerous studies have attempted to define p53 as a molecular marker with clinicopathological and predictive values. In this study we have investigated tissue samples of histopathologically confirmed TCC of the urinary bladder from 70 patients. Normal urinary bladder mucosa obtained from 40 patients with nonmalignant diseases were used as a negative control group. Immunofluorescence detection was performed using double-sandwich antibody technique, the microscope images were captured by digital camera and analyzed by ImageJ software. Corrected fluorescent intensity values corresponding to average malignant cells' nuclear p53 staining were calculated from each patient sample. We found that the mean corrected fluorescence intensity values of TCC samples grade I and II did not differ statistically significantly. On the contrary, those values were significant between the TCC grades II and III, as well as between grade I and III. In addition, a high correlation of p53 fluorescence intensity values from superficial TCC samples with the invasive TCC samples was found. However, the data showed no predictive value of p53 nuclear accumulation in TCC samples in terms of recidive, metastasis or cancer-related death, at least within the 2 years follow-up period. Given the relatively small size and heterogeneity of our patient groups, however, further studies are needed to demonstrate the clinicopathological value of digital quantitative immunofluorescent detection of nuclear p53 in TCC samples. PMID- 23917752 TI - Small bowel diverticulosis as a cause of ileus: a case report. AB - Small bowel diverticulosis (SBD) is a rare condition. In most cases it is asymptomatic, but sometimes it can be manifested with chronic non-specific or acute symptoms. Because of the absence of pathognomonic signs and symptoms and truly reliable diagnostic tests, SBD is hard to diagnose and this is usually done incidentally by radiographic examination or during laparatomy. For uncomplicated patients, those with chronic abdominal pain, syndromes of malabsorption related to jejunoileal diverticulosis, bacterial overgrowth or an episode of intestinal obstruction, as in our case, conservative management is the initial option for treatment. A case of a patient with obstructive symptoms of the gastrointestinal tract due to SBD that was conservatively treated and had a positive outcome is presented. PMID- 23917754 TI - Five hundred twelve years of history together... and many more years to come. PMID- 23917753 TI - Presentation, diagnosis and treatment of bilateral Rasmussen's encephalitis in a 12-year-old female. AB - AIM: To describe the clinical course and pathological diagnosis of a 12-year-old female who presented with an acute syndrome of right hemispheric epilepsy and cortical dysfunction and brain MRI demonstrating atrophy of the left cerebral and right cerebellar hemispheres. RESULTS: The patient presented with occasional partial seizures consisting of a left calf sensation followed by left leg clonic jerking. Initial brain MRI showed left cerebral and right cerebellar atrophy with T2 hyperintensity in the left parietal region. After six months, the seizure frequency increased and semiology evolved to include frequent clonic movements of the left side of the face, arm and leg and epilepsia partialis continua (EPC) of the left arm and leg. There was progressive weakness of the left leg and, to a lesser extent, her left arm. MRI at this time demonstrated an additional T2 hyperintensity in the right frontal lobe. An extensive evaluation for paraneoplastic, mitochondrial, and genetic epilepsy syndromes was unrevealing. On biopsy evaluation, chronic T-cell mediated encephalitis was demonstrated within bilateral frontal lobes. Treatment with immunomodulatory therapy resulted in some improvement in her seizure frequency and motor function. CONCLUSION: Rasmussen's encephalitis can be a challenging diagnosis. The patient's clinical history, including EPC, with bilateral frontal lobe biopsies confirming a T-cell mediated encephalitis supports a diagnosis of bilateral Rasmussen encephalitis. This case highlights the diagnostic challenges and treatment dilemmas that arise in an adolescent presenting with bilateral inflammatory lesions of Rasmussen's encephalitis. [Published with video sequences]. PMID- 23917755 TI - In ink and paper. PMID- 23917756 TI - Infection prevalence and outcomes in Brazilians ICUs: another brick in the wall... PMID- 23917757 TI - Searching for the Holy Grail: where do we go with the current biomarkers for sepsis? PMID- 23917758 TI - I Brazilian guidelines for respiratory physiotherapy in pediatric and neonatal intensive care units. AB - Developing guidelines for the role of the physiotherapist in neonatal and pediatric intensive care units is essential because these professionals are responsible for the rehabilitation of critically ill patients. Rehabilitation includes the evaluation and prevention of functional kinetic alterations, application of treatment interventions (respiratory and/or motor physiotherapy), control and application of medical gases, care of mechanical ventilation, weaning and extubation, tracheal gas insufflation, inflation/deflation of the endotracheal cuff protocol, and surfactant application, aiming to allow patients to have a full recovery and return to their functional activities. In this article, we present guidelines that are intended to guide the physiotherapist in some of the prevention/treatment interventions in respiratory therapy (airway clearance, lung expansion, position in bed, airway suction, drug inhalation, and cough assist), which help in the rehabilitation process of newborns and children in intensive care units during mechanical ventilation and up to 12 hours following extubation. PMID- 23917759 TI - Interleukin-12 in children with sepsis and septic shock. AB - OBJECTIVE: To examine the behavior of interleukin-12 and verify whether it can be used to differentiate septic conditions in children. METHODS: Septic children aged between 28 days and 14 years, prospectively enrolled from 01/2004 to 12/2005, were divided into sepsis (SG; n=47) and septic shock (SSG; n=43) groups. Interleukin-12 levels were measured at admission (T0) and 12 hours later (T12). Disease severity was assessed by the PRISM score. RESULTS: Interleukin-12 levels did not differentiate children with sepsis from those with septic shock at admission [SSG: 0.24 (0-226.4)=SG: 1.23 (0-511.6); p=0.135)] and T12 [SG: 6.11 (0 230.5)=SSG: 1.32 (0-61.0); p=0.1239)]. Comparing time points, no significant difference was observed in the SG [SG, T0: 1.23 (0-511.6)=T12: 6.11 (0-230.5); p=0.075]. In SSG however, interleukin-12 increased from T0 to T12 (SSG, T0: 0.24 (0-226.4)0.05). There was no correlation between onterleukin-12 levels at admission and the PRISM score for either group. CONCLUSION: Interleukin-12 levels cannot differentiate between septic conditions and are not related to disease severity at admission. In septic shock patients, interleukin-12 increases with time. PMID- 23917760 TI - Acute hemodynamic, respiratory and metabolic alterations after blood contact with a volume priming and extracorporeal life support circuit: an experimental study. AB - OBJECTIVE: To investigate the hemodynamic, respiratory and metabolic impact of blood contact with a priming volume and extracorporeal membrane oxygenation circuit, before the initiation of oxygenation and ventilation METHODS: Five animals were instrumented and submitted to extracorporeal membrane oxygenation. Data were collected at the baseline and 30 minutes after starting extracorporeal circulation, without membrane ventilatory (sweeper) flow. RESULTS: After starting extracorporeal membrane oxygenation, there was a non-significant elevation in pulmonary vascular resistance from 235 (178,303) to 379 (353,508) dyn.seg.(cm5)-1 (P=0.065), associated with an elevation in the alveolar arterial oxygen gradient from 235 (178,303) to 379 (353,508) mmHg (P=0.063). We also observed a reduction in the left ventricle stroke work from 102 (94,105) to 78 (71,87) (mL.mmHg)/beat (P=0.064), in addition to a reduction in cardiac output from 7.2 (6.8,7.6) to 5.9 (5.8,6.3) L/min (P=0.188). The right ventricle stroke work was counterbalanced between the pulmonary vascular resistance increment and the cardiac output reduction, maintaining a similar value. CONCLUSIONS: We presented an experimental model that is feasible and safe. Blood contact with the priming volume and extracorporeal membrane oxygenation circuit resulted in non-significant systemic or metabolic changes. PMID- 23917761 TI - Prevalence and outcomes of infections in Brazilian ICUs: a subanalysis of EPIC II study. AB - OBJECTIVE: To determine the prevalence of infections in Brazilian intensive care units and the associated mortality by analyzing the data obtained in the Extended Prevalence of Infection in Intensive Care (EPIC II) study. METHODS: EPIC II was a multicenter, international, cross-sectional prospective study of infection prevalence. It described the demographic, physiological, bacteriological, and therapeutic characteristics, outcome up to the 60th day, prevalence of infection, and mortality of all the patients admitted to the participating ICUs between zero hour and midnight on May 8, 2007. A total of 14,414 patients were included in the original study. Of these 14,414 patients, 1,235 were Brazilian and were hospitalized in 90 Brazilian ICUs. They represent the focus of this study. RESULTS: Among these 1,235 Brazilian patients, 61,6% had an infection on the day of the trial, and the lungs were the main site of infection (71.2%). Half of the patients had positive cultures, predominantly gram-negative bacilli (72%). On the day of the study, the median SOFA score was 5 (3-8) and the median SAPS II score was 36 (26-47). The infected patients had SOFA scores significantly higher than those of the non-infected patients 6 (4-9) and 3 (2-6), respectively). The overall ICU mortality rate was 28.4%: 37.6% in the infected patients, and 13.2% in the non-infected patients (p<0.001). Similarly, the in-hospital mortality rate was 34.2%, with a higher rate in the infected than in the non-infected patients (44.2% vs. 17.7%) (p<0.001). In the multivariate analysis, the main factors associated with infection incidence were emergency surgery (OR 2.89, 95%CI [1.72 4.86], p<0.001), mechanical ventilation (OR 2.06, 95% CI [1.5-2.82], p<0.001), and the SAPS II score (OR 1.04, 95% CI [1.03-1.06], p<0.001). The main factors related to mortality were ICC functional class III/ IV (OR 3.0, 95% CI [1.51 5.98], p<0.01), diabetes mellitus (OR 0.48, 95% CI [0.25-0.95], p<0.03), cirrhosis (OR 4.62, 95% CI [1.47-14,5], p<0.01), male gender (OR 0.68, 95% CI [0.46-1.0], p<0.05), mechanical ventilation (OR 1.87, 95% CI [1.19-2.95], p<0.01), hemodialysis (OR 1.98, 95% CI [1.05-3.75], p<0.03), and the SAPS II score (OR 1.08, 95% CI [1.06-1.10], p<0.001). CONCLUSION: The present study revealed a higher prevalence of infections in Brazilian ICUs than has been previously reported. There was a clear association between infection and mortality. PMID- 23917762 TI - Characterization of drug prescriptions in an adult intensive care unit. AB - OBJECTIVE: To characterize drug prescriptions in a university hospital adult intensive care unit. METHODS: Single-center, observational, descriptive, cross sectional study conducted at an adult general intensive care unit. The study population included all of the unit's inpatients from January to March 2011. The following characteristics for all prescriptions recorded during this period were examined: drug name (generic, brand name or abbreviation), dosage strength, pharmaceutical form, dose, route of administration, patient name, patient registration in the institution, clinic and hospital bed as well as the name, board license number, signature of the prescriber and date of the prescription. It was quantified the percentage of prescribed drugs included in the National List of Essential Drugs, the World Health Organization Model List of Essential Medicines and the University Hospital Center Pharmacotherapy Guide. The prescribed drugs were classified based on the Anatomical Therapeutic Chemical classification system (levels 1 and 2). RESULTS: Eight hundred forty-four prescriptions were reviewed from 72 patients (mean age: 59.04 +/- 21.80), 54.92% of whom were female. The mean number of prescriptions per patient was 11.72 +/- 11.68. The total number of drugs prescribed was 12,052 and 9,571 (79.41%) of the drugs were prescribed using the generic name. The most frequent absent information in the drug description was the pharmaceutical form of the drug (8,829/73.26%). The dosage strength was indicated in 7,231 (60%) of the prescriptions, and the prescriber and patient information were indicated in over 96% of the prescriptions. The prescribed drugs were classified in 13 therapeutic groups and 55 subgroups. Systemic antibacterials represented one of the most frequently prescribed subgroups. CONCLUSION: Most of the reviewed information was present in the prescriptions. However, the dosage strength and pharmaceutical form were absent in many prescriptions. The characterization of prescriptions at different hospital units is essential for the development of strategies that reduce drug utilization problems. PMID- 23917763 TI - Nutritional status, hyperglycemia, early nutrition, and mortality of patients hospitalized in an intensive care unit. AB - OBJECTIVE: Because patients hospitalized in intensive care units are at risk for poor nutrition, and nutritional therapy is not always started at an appropriate time, the present study aimed to correlate nutritional status, early nutrition, and hyperglycemia with patient mortality in an intensive care unit. METHODS: This archival cohort study used the secondary database of 453 patients who stayed at least 48 hours in an intensive care unit and were assessed for 8 days of hospitalization. Patient nutritional status was defined according to the body mass index. Early nutrition was defined as an feeding energy within the first 48 hours of hospitalization, regardless of the administration route. Blood glucose levels were monitored using a glucometer. RESULTS: A majority of patients were male (54.2%), and approximately half of patients were overweight (48.4%). At the end of the first 48 hours, 69.4% of patients had received nutrition, and only 13.5% of patients still exhibited hyperglycemia. The patients who received early nutritional therapy exhibited lower a mortality risk (p = 0.002), regardless of the presence of other factors associated with mortality. CONCLUSIONS: The significant correlation between early nutritional therapy and survival emphasizes the importance of nutrition in severely ill patients. The low frequency of hyperglycemia found in this study might indicate that the prescription of nutritional therapy and the application of an insulin protocol are appropriate at institutional intensive care units. PMID- 23917764 TI - Arterial blood gas analysis in two different intra-hospital transport methods for postoperative cardiac surgery patients. AB - OBJECTIVE: To evaluate the effects on blood gases by two methods of ventilation (with transport ventilation or self-inflating manual resuscitator) during intra hospital transport of patients after cardiac surgery. METHODS: Observational, longitudinal, prospective, randomized study. Two samples of arterial blood were collected at the end of the surgery and another at the end of patient transport. RESULTS: We included 23 patients: 13 in the Group with transport ventilation and 10 in the Group with self-inflating manual resuscitator. Baseline characteristics were similar between both groups, except for higher acute severity of illness in the Group with transport ventilation. We observed significant differences in comparisons of percentage variations of gasometric data: pH (transport ventilation + 4% x MR -5%, p=0.007), PaCO2 (-8% x +13%, p=0.006), PaO2 (+47% x 34%, p=0.01) and SatO2 (+0.6% x -1.7%, p=0.001). CONCLUSION: The use of mechanical ventilation results in fewer repercussions for blood gas analysis in the intra-hospital transport of cardiac surgery patients. PMID- 23917765 TI - Use of a noninvasive ventilation device following tracheotomy: an alternative to facilitate ICU discharge? AB - OBJECTIVE: We aimed to assess the use of noninvasive ventilation devices in patients with prolonged weaning following tracheotomy. METHODS: We performed a retrospective observational study using data collected from the clinical records of tracheotomized patients diagnosed with prolonged weaning. The participants were hospitalized in the adult intensive care unit of Moinhos de Vento Hospital, Porto Alegre (RS) between December 2007 and December 2008. RESULTS: In the data collection period, 1,482 patients were admitted to the intensive care unit. In total, 126 patients underwent tracheotomies, and 26 of these patients met the inclusion criteria for participating in the study. The average age of the patients in our sample was 73 +/- 12 years. In our sample, 57.7% of the participants were female, and 80.8% were admitted as a result of acute hypoxemic respiratory failure. After the tracheotomy, the patients remained under mechanical ventilation for an average of 29.8 days. After the initiation of the experimental protocol, the tracheotomized patients remained under ventilation for an average of 53.5 days on a portable noninvasive device connected to the tracheotomy. There were three possible outcomes for the patients. They were discharged, were weaned from the noninvasive ventilation, or died in the intensive care unit or hospital ward. In total, 76.9% (20/26) of the patients were discharged from the intensive care unit, and 53.8% (14/26) of the patients were discharged from the hospital. CONCLUSION: The use of noninvasive portable ventilators connected to the tracheotomy may represent an alternative for discontinuing ventilationand discharging tracheotomized patients with prolonged ventilatory weaning from intensive care unit. PMID- 23917766 TI - Influence of early mobilization on respiratory and peripheral muscle strength in critically ill patients. AB - OBJECTIVE: To evaluate the effects of an early mobilization protocol on respiratory and peripheral muscles in critically ill patients. METHODS: A randomized controlled clinical trial was conducted with 59 male and female patients on mechanical ventilation. The patients were divided into a conventional physical therapy group (control group, n=14) that received the sector's standard physical therapy program and an early mobilization group (n=14) that received a systematic early mobilization protocol. Peripheral muscle strength was assessed with the Medical Research Council score, and respiratory muscle strength (determined by the maximal inspiratory and expiratory pressures) was measured using a vacuum manometer with a unidirectional valve. Systematic early mobilization was performed on five levels. RESULTS: Significant increases were observed for values for maximal inspiratory pressure and the Medical Research Council score in the early mobilization group. However, no statistically significant improvement was observed for maximal expiratory pressure or MV duration (days), length of stay in the intensive care unit (days), and length of hospital stay (days). CONCLUSION: The early mobilization group showed gains in inspiratory and peripheral muscle strength. PMID- 23917767 TI - Prevalence and factors associated with bronchopulmonary dysplasia in a referral hospital in Minas Gerais, Brazil. AB - OBJECTIVE: The aim of the present study was to evaluate the prevalence and factors associated with bronchopulmonary dysplasia at a neonatal intensive care unit. METHODS: The study was a cross-sectional study that used secondary data from premature infants who were born with less than 32 weeks of gestational age and were admitted to a neonatal intensive care unit. Chi-square, Mann-Whitney and multivariate tests were used. Significance was set at p<0.05. RESULTS: A total of 88 premature infants were included in the study. Bronchopulmonary dysplasia occurred in 27.3% of the infants and was related to having a gestational age below 28 weeks (OR: 4.80; 95% CI: 1.50-15.34; p=0.008) and a patent ductus arteriosus (OR: 3.44; 95% CI: 1.10-10.76; p=0.034). The group with bronchopulmonary dysplasia used mechanical ventilation for a longer duration, with a median of 24.5 days (p<0.0001). At discharge, the corrected and chronological ages were higher in the group with bronchopulmonary dysplasia (p<0.0001), with respective medians of 38.4 weeks and 70.5 days. CONCLUSIONS: In this study, the prevalence of bronchopulmonary dysplasia was high; the high prevalence was related to extreme prematurity, patent ductus arteriosus, a longer period under mechanical ventilation and prolonged hospitalization. The increased survival of infants with low gestational age makes this disorder a public health issue. PMID- 23917768 TI - The correlation between plasma lactate concentrations and early neonatal mortality. AB - OBJECTIVE: To assess the correlation between plasma lactate concentrations in the first 6 hours of life and early neonatal mortality. METHODS: The patients were divided in 2 groups based on the cutoff point, obtained from a receiver operating characteristic (ROC) curve, of the plasma lactate concentration that best predicted neonatal mortality during the first 3 days of life. The differences between groups and the correlations between the investigated variables and the plasma lactate concentrations measured in the first 6 hours of life were analyzed using the Chi-square, Student's t, or Mann-Whitney tests and logistic regression. RESULTS: The best cutoff point of the plasma lactate concentration as determined by the ROC curve for death during the first 3 days of life was 4.2 mmol/L. The investigated groups differed with regards to the average birth weight, which was lower in the group with serum lactate levels > 4.2 mmol/L, and the match between birth weight and gestational age, where the group with serum lactate levels > 4.2 mmol/L exhibited a higher number of newborns small for their gestational age. Seizures, intracranial hemorrhage, and death during the first 3 days of life occurred more frequently in the group with serum lactate levels > 4.2 mmol/L. CONCLUSION: In the investigated samples, the presence of plasma lactate concentrations > 4.2 mmol/L in the first 6 hours of life correlated with neonatal death during the first 3 days of life, a higher frequency of neurologic morbidity, and newborns that were small for their gestational age. PMID- 23917769 TI - Motor physical therapy in hospitalized patients in an intensive care unit: a systematic review. AB - OBJECTIVE: To analyze the outcomes achieved by motor physical therapy in critically ill patients admitted to intensive care units. METHODS: A systematic literature review was performed, and clinical trials published between 2002 and 2011 were included in the study. The search involved the LILACS, SciELO, MedLine, EMBASE and Cochrane databases, using the keywords "intensive care unit", "physiotherapy", "physical therapy", "mobility", "mobilization" and "randomized controlled trials." Two researchers screened the articles independently and included works that addressed the effect of physical therapy on critically ill patients. RESULTS: From an initial analysis of 67 potentially relevant articles, only 8 met the selection criteria and addressed the outcomes of electrostimulation, cycle ergometry and kinesiotherapy techniques. The sample sizes ranged from 8 to 101 subjects, with mean ages between 52 and 79 years. All patients were undergoing invasive mechanical ventilation. Among the analyzed articles, 6 reported significant benefits of motor physical therapy, such as improvement in peripheral muscle strength, respiratory capacity and functionality, in critically ill patients. CONCLUSION: With this systematic review, it is possible to conclude that motor physical therapy is a feasible and safe therapy for critically ill patients and can minimize the deleterious effects of prolonged immobilization. Approaches involving electrostimulation, cycle ergometry and kinesiotherapy showed positive responses in patients under intensive care. Available evidence regarding the impact of motor physical therapy on length of stay in intensive care units and on mortality is still scarce, and further study in this area is warranted. PMID- 23917770 TI - Palliative care of elderly patients in intensive care units: a systematic review. AB - OBJECTIVE: The use of interventionist medical technology in terminal elderly patients must be associated with palliative care as a measure of clinical support in intensive care units. Palliative care is an important component of end-of-life care, and the assistance provided by the healthcare team should be guided by decisions made by patients and their family members. Prolongation of life not accompanied by therapies aimed at relieving symptoms, such as pain and dyspnea, contributes to patient and family member stress suffering. The aim of the present study was to survey advances made in the application of palliative care in intensive care units. METHODS: Medline and Bireme were used to perform a systematic literature review of intensive care units-based palliative care for elderly patients. RESULTS: A total of 29 articles describing palliative care in intensive care units were analyzed according to the variables "satisfaction of relatives when they participate in the discussions on palliative care" and "difficulties to implement such type of care due to lack of technical skills of the health caregivers." CONCLUSION: Palliative care for elderly patients in intensive care units must be more thoroughly investigated to improve the relationships and communication among patients, their relatives, and the healthcare team. As greater numbers of elderly patients are admitted to intensive care units, the skills of health caregivers must improve to meet the challenges posed by the end-of-life care. PMID- 23917771 TI - ProSealTM laryngeal mask airway for surfactant administration in the treatment of respiratory distress syndrome in a premature infant. AB - The administration of surfactant via tracheal cannula with mechanical ventilation is the conventional treatment for infant respiratory distress syndrome. Hemodynamic and respiratory changes due to tracheal intubation and the need for premedication justify the search for less invasive alternatives of surfactant administration. The objective of this study was to describe the use of the ProSealTM laryngeal mask airway as an option for the treatment of respiratory distress syndrome in a premature infant born at 31 weeks of gestation, at 1335 g, with respiratory difficulty after the first hour of life and exhibiting the clinical and radiologic features of respiratory distress syndrome. The surfactant was administered with the use of the ProSealTM laryngeal mask airway at 3.5 hours of life. It was well tolerated, with no need for tracheal intubation. Normal gasometry and radiologic improvement were observed after three and six hours of administration. Oxygen administration was suspended after eight days, with no comorbidities at discharge. The laryngeal mask airway seems to be a painless and less invasive alternative to treat respiratory distress syndrome and may reduce the need for tracheal intubation and mechanical ventilation. The efficacy and advantages of this route of treatment should be confirmed in a study of an adequate sample. PMID- 23917775 TI - Empty liposomes induce antitumoral effects associated with macrophage responses distinct from those of the TLR1/2 agonist Pam3CSK 4 (BLP). AB - Liposomes are frequently used in cancer therapy to encapsulate and apply anticancer drugs. Here, we show that a systemic treatment of mice bearing skin tumors with empty phosphatidylcholine liposomes (PCL) resulted in inhibition of tumor growth, which was similar to that observed with the synthetic bacterial lipoprotein and TLR1/2 agonist Pam(3)CSK(4) (BLP). Both compounds led to a substantial decrease of macrophages in spleen and in the tumor-bearing skin. Furthermore, both treatments induced the expression of typical macrophage markers in the tumor-bearing tissue. As expected, BLP induced the expression of the M1 marker genes Cxcl10 and iNOS, whereas PCL, besides inducing iNOS, also increased the M2 marker genes Arg1 and Trem2. In vitro experiments demonstrated that neither PCL nor BLP influenced proliferation or survival of tumor cells, whereas both compounds inhibited proliferation and survival and increased the migratory capacity of bone marrow-derived macrophages (BMDM). However, in contrast to BLP, PCL did not activate cytokine secretion and induced a different BMDM phenotype. Together, the data suggest that similar to BLP, PCL induce an antitumor response by influencing the tumor microenvironment, in particular by functional alterations of macrophages, however, in a distinct manner from those induced by BLP. PMID- 23917776 TI - Accessible gold clusters using calix[4]arene N-heterocyclic carbene and phosphine ligands. AB - We investigate the synthesis of accessible calix[4]arene-bound gold clusters consisting of open "coordinatively unsaturated" active sites, using a comparative approach that relies on calix[4]arene ligands with various upper- and lower-rim substituents. In contrast with a reported Au(I)-tert-butyl-calixarene phosphine complex, which exhibits a single cone conformer in solution, the H upper-rim analog exhibits multiple conformers in solution. This contrasts with observations of the tert-butyl upper-rim analog, which exhibits a single cone conformer in solution under similar conditions. In the solid state, as determined by single crystal X-ray diffraction, both H and tert-butyl upper-rim analogs exhibit exclusively cone conformer. A detailed structural analysis of these two solid state structures highlights a CH-pi interaction involving a methoxy lower-rim substituent and phenyl substituent on P as the key feature that enforces a tight configuration of Au(I) atoms on the same side of the calix[4]arene lower-rim plane. We hypothesize that such a configuration promotes chelation of the ligand to a gold surface and facilitates the synthesis of small Au11-sized clusters after reduction of both complexes. The new cluster, like the one reported with the tert-butyl analog, has an extraordinary 25% of surface atoms that are open and accessible to a 2-NT (2-naphthalenethiol) probe in solution. We also investigated the effect of calix[4]arene lower-rim substituents that coordinate to the metal, by using N-heterocyclic carbene (NHC) functional groups rather than phosphines. Four small (<1.6 nm diameter) calix[4]arene NHC-bound gold clusters were synthesized, including three using novel calix[4]arene NHC ligands. The smallest calix[4]arene NHC-bound Au cluster consisted of a 1.2 nm gold core, and its number density of accessible and open surface sites was measured. This required development of a new titration method for open sites on gold clusters, using a SAMSA fluorescein dye molecule, which excites and emits at lower energy relative to the previously used 2-NT probe. The number density of open sites on the new calix[4]arene NHC-bound gold cluster measured by the SAMSA fluorescein probe strongly supports the generality of a mechanical model of accessibility, which does not depend on the functional group involved in binding to the gold surface and rather depends on the relative radii of curvature of bound ligands and the gold cluster core. PMID- 23917777 TI - Colovesical fistula in sigmoid diverticulitis. A case report. AB - Colonic diverticulosis has continuously increased, noticeably left-sided disease. Colovesical fistula is an uncommon complication of diverticulitis, and its most common cause is diverticular disease. Pneumaturia and fecaluria are commonly related symptoms. We present the case of a 79-year-old woman complaining pneumaturia and fecaluria. Abdominal CT showed a colovesical fistula due to sigmoid diverticulitis. After surgical adhesiolysis between the sigmoid colon and the bladder, the defect of the bladder wall was repaired by simple closure. The colonic defect was treated by segmental resection including the rectosigmoid junction. Following the operation the patient continuously improved at months 6, 12 and 18 without evidence of recurrences. PMID- 23917779 TI - Electrochemical aptasensors for microbial and viral pathogens. AB - Aptamers are DNA and RNA oligonucleotides that can bind to a variety of nonnucleic acid targets with high affinity and specificity. Pathogen detection is a promising area in aptamer research. One of its major advantages is the ability of the aptamers to target and specifically differentiate microbial and viral strains without previous knowledge of the membrane-associated antigenic determinants or molecular biomarkers present in that particular microorganism. Electrochemical sensors emerged as a promising field in the area of aptamer research and pathogen detection. An electrochemical sensor is a device that combines a recognition element and an electrochemical transduction unit, where aptamers represent the latest addition to the large catalog of recognition elements. This chapter summarizes and evaluates recent developments of electrochemical aptamer-based sensors for microbial and viral pathogen detection, viability assessment of microorganisms, bacterial typing, identification of epitope-specific aptamers, affinity measurement between aptamers and their respective targets, and estimation of the degree of aptamer protection of oncolytic viruses for therapeutic purposes. PMID- 23917780 TI - 99mTc-DISIDA uptake in liver lesion and pulmonary metastases shown on SPECT/CT in a patient with hepatocellular carcinoma. AB - A 43-year-old man, previously submitted to right hepatectomy, right hepatic artery chemoembolization, and surgical resection of liver lesions, with well differentiated and moderately differentiated hepatocellular carcinoma (HCC) confirmed by histopathology, underwent cholescintigraphy with Tc diisopropyliminodiacetic acid (Tc-DISIDA) due to recurrent cholangitis. The scintigraphic images and the coregistered CT images showed radiotracer uptake in an area of biliary ectasia near the hepatic surface (which may be associated with recurrent cholangitis), in a hepatic nodule, and in multiple pulmonary metastases. PMID- 23917781 TI - Synovial hemangioma of Hoffa fat pad demonstrated by RBC SPECT/CT. AB - Synovial hemangioma of Hoffa fat pad is an extremely rare disease, which occurs in the knee joints. Because synovial hemangioma often shows nonspecific symptoms, such as pain, swelling, limping, or limitation of motion, diagnosis could be delayed in many cases. We present a 7-year-old boy referred to our department for Tc red blood cell (RBC) scan for the confirmation of hemangioma suggested by the MRI. RBC scan demonstrated intense radioactivity accumulation in Hoffa pad of right knee joint, and subsequent excision biopsy revealed the mass as venous hemangioma. PMID- 23917782 TI - Widespread hypermetabolic lesions due to multicentric form of Castleman disease as the cause of fever of unknown origin revealed by FDG PET/CT. AB - A 46-year-old male patient presented with fever for over 5 months. An FDG PET/CT was acquired to evaluate the source of the fever. The images showed many hypermetabolic foci throughout the imaged regions, which mainly corresponded to enlarged lymph nodes. Pathological examination demonstrated that the patient suffered from a multicentric form of Castleman disease. PMID- 23917783 TI - Impact of concurrent diagnostic level CT with PET/CT on the utilization of stand alone CT and MRI in the management of head and neck cancer patients. AB - PURPOSE OF THE REPORT: This study aims to determine if the expansion of a PET/CT service to include simultaneous contrast-enhanced CT with PET (PET/DCT) leads to a reduction of supplemental diagnostic CT (sCT) performed within a 6-month period centered around PET/CT for initial treatment planning of patients with head and neck cancers. PATIENTS AND METHODS: There were 91 patients with head and neck cancers who had a non-contrast-enhanced PET/CT with CT (PET/aCT), and 153 patients had a PET/DCT. We compared the utilization of sCT before and after PET/aCT or PET/DCT. Logistic regression analysis, unpaired t test, and analysis of variance were performed. RESULTS: Among the 75 patients who had sCT scans in the 3 months before their PET/CT, 44 (58.7%) scans were performed in patients who had a PET/aCT and 31 (41.3%) scans were performed in patients who had a PET/DCT (P < 0.001). Among the 36 patients who had a CT in the 3 months after their baseline PET/CT, 23 (63.9%) were performed in patients who had a baseline PET/aCT and 13 (36.1%) were performed in patients who had a baseline PET/DCT (P < 0.001). The adjusted odds ratio for performing an sCT within 3 months before and after baseline PET/DCT scan as opposed to a PET/aCT scan was 0.24 (P < 0.001) and 0.31 (P < 0.01), respectively. CONCLUSIONS: The opportunity to order simultaneous diagnostic CT imaging with PET/CT (PET/DCT) reduced the referrals for stand-alone CT neck imaging in the initial treatment plan of head and neck cancer patients when compared to a service that only offered the PET/CT scan with CT for attenuation correction (PET/aCT). PMID- 23917784 TI - Long-term follow-up of patients with differentiated thyroid cancer who had negative 131I whole-body scan at first evaluation after treatment. AB - PURPOSE OF THE REPORT: The evaluation of patients with differentiated thyroid cancer is commonly based on serum thyroglobulin (Tg) measurement and 131I whole body scan (WBS). The first follow-up (6-12 months after initial treatment) shows the response to therapy, a prognostic factor.The aims of the study were to describe the clinical outcome during a long-term follow-up of patients with negative 131I WBS in the first evaluation, and to assess clinical and histological characteristics related to the outcome in this patient population. PATIENTS AND METHODS: This retrospective study reviewed data from 209 patients followed at 2 Brazilian hospitals. A minimum of 10 years of follow-up was required. RESULTS: During mean follow-up of 13.7 +/- 4.2 years, 20% of patients developed recurrence. At the end of follow-up, 21% of patients had persistent disease. The clinical and histological characteristics related to adverse outcomes (recurrence or persistent disease) were lymph node metastases at diagnosis, high risk according to American Thyroid Association (ATA) classification, and incomplete response to treatment. Stimulated Tg levels (under thyroid hormone withdrawal) and basal Tg levels (with thyroid hormone) greater than 10 ng/mL at first evaluation were associated with an adverse outcome. CONCLUSION: Negative WBS at first evaluation should not be used as an isolated prognostic factor. This must be considered together with histopathological (ATA classification, lymph node metastases) and clinical/laboratory characteristics (stimulated and basal Tg; response to therapy). PMID- 23917785 TI - Antitumor effect of 89Sr for multiple bone metastases of breast cancer: diagnosis by 18F-FDG PET/CT. AB - 89Sr is useful for the palliation of painful bone metastasis, but its antitumor activity as a monotherapy has not been shown by 18F-FDG PET. Here, we report a case of a 75-year-old woman with multiple bone metastases of breast cancer in which 18F-FDG PET demonstrated a significant reduction in uptake of 18F-FDG after administration of 89Sr. PMID- 23917786 TI - Unsuspected uterine metastasis of breast carcinoma diagnosed by 18F-FDG PET/CT. AB - A 50-year-old woman with a history of bilateral lobular carcinoma of the breast in 1995 and 2001 was treated with mastectomy, axillary lymphadenectomy, chemotherapy, and hormone therapy which achieved a complete response. In 2009, the patient developed a progressive elevation of tumor markers. A CT scan was performed showing no suspicious malignant lesions. She was referred for (18)F-FDG PET/CT and the images revealed highly increased tracer uptake in the uterus suggestive of malignancy. The patient underwent hysterectomy with bilateral double adnexectomy and a histopathological diagnosis of massive carcinomatous infiltration of breast lobular carcinoma was done. PMID- 23917787 TI - FDG PET/CT in malignant eccrine porocarcinoma arising in a pre-existing poroma. AB - In a 61-year-old man with known poroma of right lower abdomen, malignant transformation to porocarcinoma was suspected and confirmed by biopsy. PET/CT was requested for tumor staging, which revealed high FDG uptake in the known skin nodules located in the right side of abdominal and chest wall and identified further some adenopathy in the right axillary. All nodules and axillary lymph nodes were removed, and diagnosis of eccrine porocarcinoma was confirmed. The primary tumor and secondary lesions of porocarcinoma show a high glucose metabolism; thus, PET/CT could be useful for staging, follow-up, and detection of recurrence of patients with eccrine porocarcinoma. PMID- 23917788 TI - Pharmacokinetics and biodistribution of 99mTc N-MPO in healthy human volunteers. AB - PURPOSE: Tc N-MPO ([Tc N(MPO)(PNP5)]: HMPO = 2-mercaptopyridine N-oxide, and PNP5 = N-ethoxyethyl-N,N-bis[2-(bis(3-methoxypropyl)phosphino)ethyl]amine) is a new Tc radiotracer useful for myocardial perfusion imaging. This study was designed to determine its pharmacokinetics and biodistribution in healthy volunteers. PATIENTS AND METHODS: Ten healthy volunteers were involved in this study. Each subject was administered approximately 925 MBq of Tc N-MPO under rest or stress conditions (n = 5 per group). Whole-body planar images were obtained at 10, 30, 60, 240, and 1440 minutes after injection. Organ uptake was quantified by region of-interest analysis. The blood clearance and urine excretion kinetics were determined by collecting blood and urine samples at different time points. RESULTS: Tc N-MPO showed significant accumulation in myocardium with prolonged retention. At rest, its percentage of injected dose (%ID) uptake in the heart, lungs, and liver at 10 minutes after injection was 2.47% (0.64%), 1.84% (0.64%), and 20.88% (5.23%), respectively. The liver uptake decreased to 6.79%ID (1.60%ID) at 60 minutes after injection and 4.50%ID (1.86%ID) at 240 minutes after injection. Under stress conditions, the heart uptake was slightly increased (2.57%ID [0.21%ID]). The rapid liver clearance led to favorable heart-to-liver ratios, reaching values of 0.27%ID (0.07%ID) under rest condition and 0.28%ID (0.05%ID) under stress condition at 60 minutes after injection. CONCLUSIONS: Tc N MPO demonstrates a highly favorable biodistribution in humans. The high heart uptake and the fast liver washout of Tc N-MPO will allow SPECT images of the left ventricle to be acquired as early as 10 minutes after injection. PMID- 23917789 TI - Adolescents' religious discordance with mothers: is there a connection to sexual risk behavior during emerging adulthood? AB - This study longitudinally investigates the relationship between adolescent/mother religious discordance and emerging adult sexual risk-taking 6-7 years later. We used Social Control Theory to examine the level and direction of concordance using data from Wave I and Wave III of the Add Health Study, focusing on constructs of religious importance, frequency of prayer, and attendance at religious services. We found that higher levels of adolescent/mother discordance in religious importance were related to increased emerging adult sexual risk taking compared to those with similar levels adolescent/mother religiosity, but this occurred only when mothers reported higher levels of religious importance than their children. In contrast, adolescents reporting higher frequency of prayer than their mothers reported lower levels of sexual risk-taking than those with similar frequency of adolescent/mother prayer. These findings suggest that the protective effects of family religious socialization can be interrupted. However, this influence of religious difference on sexual risk-behavior operates differently depending on the direction and level of religious difference. Even in emerging adulthood, a period marked by distance from childhood values and institutions, religious difference with a parent remains a meaningful influence. PMID- 23917790 TI - Arbitrary multicolor photodetection by hetero-integrated semiconductor nanostructures. AB - The typical photodetectors can only detect one specific optical spectral band, such as InGaAs and graphene-PbS quantum dots for near-infrared (NIR) light detection, CdS and Si for visible light detection, and ZnO and III-nitrides for UV light detection. So far, none of the developed photodetector can achieve the multicolor detection with arbitrary spectral selectivity, high sensitivity, high speed, high signal-to-noise ratio, high stability, and simplicity (called 6S requirements). Here, we propose a universal strategy to develop multicolor photodetectors with arbitrary spectral selectivity by integrating various semiconductor nanostructures on a wide-bandgap semiconductor or an insulator substrate. Because the photoresponse of each spectral band is determined by each semiconductor nanostructure or the semiconductor substrate, multicolor detection satisfying 6S requirements can be readily satisfied by selecting the right semiconductors. PMID- 23917791 TI - Quantitative DNA methylation analysis improves epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome. AB - Beckwith-Wiedemann syndrome (BWS) is a rare disorder characterized by overgrowth and predisposition to embryonal tumors. BWS is caused by various epigenetic and/or genetic alterations that dysregulate the imprinted genes on chromosome region 11p15.5. Molecular analysis is required to reinforce the clinical diagnosis of BWS and to identify BWS patients with cancer susceptibility. This is particularly crucial prenatally because most signs of BWS cannot be recognized in utero. We established a reliable molecular assay by pyrosequencing to quantitatively evaluate the methylation profiles of ICR1 and ICR2. We explored epigenotype-phenotype correlations in 19 patients that fulfilled the clinical diagnostic criteria for BWS, 22 patients with suspected BWS, and three fetuses with omphalocele. Abnormal methylation was observed in one prenatal case and 19 postnatal cases, including seven suspected BWS. Seven cases showed ICR1 hypermethylation, five cases showed ICR2 hypomethylation, and eight cases showed abnormal methylation of ICR1 and ICR2 indicating paternal uniparental disomy (UPD). More cases of ICR1 alterations and UPD were found than expected. This is likely due to the sensitivity of this approach, which can detect slight deviations in methylation from normal levels. There was a significant correlation (p<0.001) between the percentage of ICR1 methylation and BWS features: severe hypermethylation (range: 75-86%) was associated with macroglossia, macrosomia, and visceromegaly, whereas mild hypermethylation (range: 55-59%) was associated with umbilical hernia and diastasis recti. Evaluation of ICR1 and ICR2 methylation by pyrosequencing in BWS can improve epigenotype-phenotype correlations, detection of methylation alterations in suspected cases, and identification of UPD. PMID- 23917792 TI - Pollination and floral ecology of Arundina graminifolia (Orchidaceae) at the northern border of the species' natural distribution. AB - Arundina graminifolia is an early successional plant on Iriomote Island, the Ryukyus, Japan, where it is endangered. Populations flower for more than half a year, and many inflorescences bloom for one to several months. The nectarless gullet flowers, which open for up to six days, are self-compatible but cannot self-pollinate spontaneously; thus they rely on pollinating agents for capsule production. Field observations at two habitats identified at least six species of bees and wasps, primarily mate-seeking males of Megachile yaeyamaensis and Thyreus takaonis, as legitimate pollinators. Thus, this orchid is a pollinator generalist, probably owing to its long blooming period and simple flower morphology. Carpenter bees, which were previously reported to pollinate this orchid, frequently visited flowers but were too large to crawl into the labellum chamber and never pollinated the flowers. Extrafloral nectaries on inflorescences attracted approximately 40 insect taxa but were not involved with pollination. Fruit-set ratios at the population level varied spatiotemporally but were generally low (5.2-12.4 %), presumably owing to infrequent flower visits by mate seeking pollinators and the lack of food rewards to pollinators. PMID- 23917793 TI - Thrombotic microangiopathy: eculizumab for atypical haemolytic uraemic syndrome: what next? PMID- 23917795 TI - Chronic kidney disease: calcium-based versus non-calcium-based phosphate binders: effect on mortality in patients with CKD. PMID- 23917800 TI - Haemodialysis: prediction of brachial artery blood flow for fistula creation. PMID- 23917801 TI - Ambivalence and its influence on participation in screening for colorectal cancer. AB - Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, and an ideal target for early detection and prevention through cancer screening. Unfortunately, rates of participation in screening are less than adequate. In this article we explore why people who were offered a fecal immunochemical test for CRC decided to participate or not, and for those who did participate, what influenced them to take action and complete the test. We conducted four focus groups and 30 telephone interviews with 63 people. The main reason people decided to screen was "wanting to know" their CRC status, which operated on a continuum ranging from wanting to know, through varying degrees of ambivalence, to not wanting to know. The majority of participants expressed ambivalence about CRC screening, and the main cue to action was the opportunity to screen without being too inconvenienced. PMID- 23917797 TI - Obesity-related cardiorenal disease: the benefits of bariatric surgery. AB - The inexorable increase in the prevalence of obesity is a global health concern, which will result in a concomitant escalation in health-care costs. Obesity related metabolic syndrome affects approximately 25% of adults and is associated with cardiovascular and renal disease. The heart and kidneys are physiologically interdependent, and the pathological effects of obesity can lead to cardiorenal syndrome and, ultimately, kidney and heart failure. Weight loss can prevent or ameliorate obesity-related cardiorenal syndrome, but long-term maintenance of a healthy weight has been difficult to achieve through lifestyle changes or pharmacotherapy. Bariatric surgery offers both sustained weight loss and favourable metabolic changes, including dramatic improvements in glycaemic control and symptoms of type 2 diabetes mellitus. Procedures such as Roux-en-Y gastric bypass offer immediate multisystemic benefits, including bile flow alteration, reduced gastric size, anatomical gut rearrangement and altered flow of nutrients, vagal manipulation and enteric hormone modulation. In patients with cardiorenal syndrome, bariatric surgery also offers renoprotection and cardioprotection, and attenuates both kidney and heart failure by improving organ perfusion and reversing metabolic dysfunction. However, further research is required to understand how bariatric surgery acts on the cardiorenal axis, and its pioneering role in novel treatments and interventions for cardiorenal disease. PMID- 23917802 TI - Urine proteomes of healthy aging humans reveal extracellular matrix (ECM) alterations and immune system dysfunction. AB - Aging is a complex physiological process that poses considerable conundrums to rapidly aging societies. For example, the risk of dying from cardiovascular diseases and/or cancer steadily declines for people after their 60s, and other causes of death predominate for seniors older than 80 years of age. Thus, physiological aging presents numerous unanswered questions, particularly with regard to changing metabolic patterns. Urine proteomics analysis is becoming a non-invasive and reproducible diagnostic method. We investigated the urine proteomes in healthy elderly people to determine which metabolic processes were weakened or strengthened in aging humans. Urine samples from 37 healthy volunteers aged 19-90 years (19 men, 18 women) were analyzed for protein expression by liquid chromatography-tandem mass spectrometry. This generated a list of 19 proteins that were differentially expressed in different age groups (young, intermediate, and old age). In particular, the oldest group showed protein changes reflective of altered extracellular matrix turnover and declining immune function, in which changes corresponded to reported changes in cardiovascular tissue remodeling and immune disorders in the elderly. Thus, urinary proteome changes in the elderly appear to reflect the physiological processes of aging and are particularly clearly represented in the circulatory and immune systems. Detailed identification of "protein trails" creates a more global picture of metabolic changes that occur in the elderly. PMID- 23917803 TI - Systematic review of the diagnostic utility of SPECT imaging in dementia. AB - Single-photon emission-computed tomography (SPECT) may potentially contribute to the diagnostic work up of patients with neurodegenerative dementia. This systematic review aims to establish the diagnostic utility of 99mTc hexamethylpropyleneamine (99mTc-HMPAO) and 99mTc-ethylcysteine dimer SPECT in distinguishing between Alzheimer's disease (AD) and frontotemporal dementia (FTD), AD and vascular dementia (VD), AD and dementia with Lewy bodies (DLB), and AD and normal controls (NC). We searched MEDLINE and Embase databases via OVID for articles from January 1985 to May 2012 and identified additional studies from reviews and references. Of 755 studies, 49 studies met the inclusion and exclusion criteria for this systematic review; AD versus FTD (n=13), AD versus VD (n=18), AD versus DLB (n=5), and AD versus NC (n=18). We compiled relevant data and graded the studies with an internal and external validity criteria checklist. We pooled the studies with a clinical diagnosis and those using 99mTc-HMPAO SPECT in a meta-analysis, calculating the pooled weighted sensitivity, specificity, likelihood ratios, and diagnostic odds ratios using DerSimonian-Laird random effects model. The pooled weighted sensitivity and specificity of 99mTc-HMPAO SPECT in distinguishing clinically diagnosed AD from FTD are 79.7 and 79.9%, respectively, AD from VD are 74.5 and 72.4%, AD from DLB are 70.2 and 76.2%, and AD from NC are 76.1 and 85.4%. SPECT does have diagnostic value, particularly in differentiating Alzheimer's disease from frontotemporal dementia and normal controls; however, it should not be used in isolation, rather as an adjunct, and interpreted in the context of clinical information and paraclinical test results. PMID- 23917804 TI - Reduction in muscular motility by selective focused cold therapy: a preclinical study. AB - Application of freezing temperatures to the temporal branch of the facial nerve can temporarily inhibit motor nerve conduction, resulting in inhibition of voluntary contraction of the frontalis and glabella muscle groups. This feasibility study demonstrates the reduction in motility of muscle groups through application of low temperatures to nerves in a rat model. Twenty-seven adult female Sprague-Dawley rats received cryotreatment to the tibial nerve of the hind limb, and the contralateral limb was left untreated as a negative control. The use of a cold temperature application (-59 +/- 8 degrees C for 60 s) onto the rat tibial nerve resulted in temporary reduction of physiological function of the hind limb. Histological observations of the nerve revealed demyelination and axonal degeneration by 2 weeks post-treatment followed by complete axonal regeneration and remyelination at 16 weeks. Application of low temperatures to peripheral motor nerves resulted in temporary denervation and loss of function of the treated hind limb. Low temperature treatment on motor nerves did not result in any permanent or long-term changes to function and structure of the nerves. PMID- 23917805 TI - Odors: appetizing or satiating? Development of appetite during odor exposure over time. AB - BACKGROUND: Exposure to palatable food odors influences appetite responses, either promoting or inhibiting food intake. Possibly, food odors are appetizing after a short exposure (of circa 1-3 min), but become satiating over time (circa 10-20 min). OBJECTIVE: To investigate the effect of odor exposure on general appetite and sensory-specific appetite (SSA) over time. DESIGN: In a cross-over study, 21 unrestrained women (age: 18-45 years; BMI: 18.5-25 kg m(-2)) were exposed for 20 min to eight different odor types: five food odors, two nonfood odors and no-odor. All odors were distributed in a test room at suprathreshold levels. General appetite, SSA and salivation were measured over time. RESULTS: All food odors significantly increased general appetite and SSA, compared with the no-odor condition. The nonfood odors decreased general appetite. All effects did not change over time during odor exposure. Savory odors increased the appetite for savory foods, but decreased appetite for sweet foods, and vice versa after exposure to sweet odors. Neither food odors nor nonfood odors affected salivation. CONCLUSIONS: Palatable food odors were appetizing during and after odor exposure and did not become satiating over a 20-min period. Food odors had a large impact on SSA and a small impact on general appetite. Moreover, exposure to food odors increased the appetite for congruent foods, but decreased the appetite for incongruent foods. It may be hypothesized that, once the body is prepared for intake of a certain food with a particular macronutrient composition, it is unfavorable to consume foods that are very different from the cued food. PMID- 23917806 TI - Lack of association between DRD2 and OPRM1 genotypes and adiposity. AB - BACKGROUND: Dopaminergic and opioid systems are both involved in food intake and appetite control. The dopamine D2 receptor gene (DRD2) and the MU-opioid receptor gene (OPRM1) therefore represent plausible candidates for association with obesity. OBJECTIVE: Previous studies of these variants have yielded inconsistent findings, which are likely due to insufficient statistical power. The aim of the current study was to determine whether, in a large population-based sample, there are associations between adiposity and (i) the A1 (T) allele of the Taq1A polymorphism (rs1800497) in DRD2 and (ii) the G allele of the A118G polymorphism (rs1799971) in OPRM1. STUDY POPULATION: Annual clinic-based measures of body mass index (BMI) and waist circumference were taken from children (N=3720) at 5 measurement time points from ages 7 through to 11 years. BMI was also recorded in their mothers (N=2460) at comparable time points and at pre-pregnancy. All participants were genotyped. Our study was powered (at 80%) to detect per-allele effects on BMI of 0.21 kg m(-2). RESULTS: Our results indicate a lack of association between DRD2 and OPRM1 genotypes and adiposity. Combining the data across mothers and children found per-allele effects on BMI of 0.02 kg m(-2) (95% confidence interval (CI): -0.17, 0.20), P=0.9 for rs1800497 and -0.08 kg m(-2) (95% CI: -0.29, 0.22), P=0.4 for rs1799971. As a positive control, we also examined the effect of FTO genotype over the same time period and confirmed the expected relationship between variability at this locus and higher adiposity. CONCLUSION: Our findings question existing evidence suggesting associations at DRD2 and OPRM1 loci and adiposity. They also highlight the caution required when employing candidate gene approaches to further our understanding of the neurobiology of eating and obesity. PMID- 23917808 TI - Determinants of neonatal blood pressure. AB - Blood pressure (BP) measurements have been increasingly used across neonatal intensive care units to determine and monitor hemodynamic status in neonates. A number of studies have attempted to derive normative blood pressure data in both preterm and term infants. However, this still remains a complex process, as several maternal and neonatal factors influence neonatal blood pressure. Maternal conditions, including hypertension and preeclampsia, seem to have some impact on neonatal BP, while maternal drugs, in particular antenatal steroids, seem to have a strong influence. Among the neonatal factors, gestational age, post-conceptual age and weight seem to have the strongest influence. The paucity of data on the short and long term effects of maternal conditions and medication on neonatal BP requires further research. PMID- 23917809 TI - Effectiveness and safety of phosphodiesterase 5 inhibitors in patients with cardiovascular disease and hypertension. AB - Phosphodiesterase 5 (PDE 5) inhibitors are selective inhibitors of the enzyme PDE 5, which catalyzes the hydrolysis of cyclic guanosine monophosphate (cGMP), a potent vasodilator and nitric oxide (NO) donor, to its corresponding metabolites (monophosphates). The enzyme PDE 5 is widely distributed in the body, including the heart and blood vessels. Because of its distribution, it was hypothesized that its inhibition could lead to significant coronary vasodilation, which would benefit patients with coronary artery disease (CAD). This hypothesis led to the development of PDE 5 inhibitors with the first being sildenafil citrate. Subsequent studies with sildenafil in patients with CAD demonstrated a modest cardiovascular effect, but a potent action on penile erection in men, resulting in sildenafil becoming a first-line therapy of erectile dysfunction (ED). Subsequently, two more PDE 5 inhibitors (vardenafil and tadalafil) were developed and approved by the Food and Drug Administration (FDA) for the treatment of ED. Recent studies have shown several pleiotropic beneficial effects of PDE 5 inhibitors in patients with CAD, hypertension, heart failure, pulmonary arterial hypertension, diabetes mellitus and Raynaud's phenomenon. Side effects and interactions of PDE 5 inhibitors with other drugs have been minimal, with the exception of their coadministration with nitrates, which could lead to severe vasodilation and hypotension and therefore, their coadministration is prohibited. All these pleiotropic cardiovascular effects of PDE 5 inhibitors and their drug interactions will be discussed in this concise review in the context of the American College of Cardiology / American Heart Association guidelines and the recent developments in this field. PMID- 23917810 TI - Aldosterone synthase inhibition in hypertension. AB - Hypertension is an established risk factor for stroke, premature coronary artery disease and heart failure. Control of elevated blood pressure has been shown to result in significant reduction of cardiovascular risk. Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), not only causes salt and water reabsorbtion in the kidneys through its effect on the mineralocorticoid hormone receptor (MR), but also an MR-independent effect, not regulated by conventional MR blockade. Although many pharmacological agents target different levels of the RAAS cascade, these generally result in elevated renin concentration and plasma renin activity. This upstream feedback response subsequently results in elevated levels of angiotensin II, a potent vasoconstrictor and stimulus to aldosterone release. This aldosterone breakthrough counteracts the long-term blood pressure-lowering effect of these agents. Therefore the development of a new class of pharmacologic agents that directly inhibit the production of aldosterone may prove clinically useful in reducing aldosterone and thereby controlling elevated blood pressure. PMID- 23917812 TI - A seamless ubiquitous telehealthcare tunnel. AB - Mobile handheld devices are rapidly using to implement healthcare services around the World. Fundamentally, these services utilize telemedicine technologies. A disconnection of a mobile telemedicine system usually results in an interruption, which is embarrassing, and reconnection is necessary during the communication session. In this study, the Stream Control Transmission Protocol (SCTP) is adopted to build a stable session tunnel to guarantee seamless switching among heterogeneous wireless communication standards, such as Wi-Fi and 3G. This arrangement means that the telemedicine devices will not be limited by a fixed wireless connection and can switch to a better wireless channel if necessary. The tunnel can transmit plain text, binary data, and video streams. According to the evaluation of the proposed software-based SCTP-Tunnel middleware shown, the performance is lower than anticipated and is slightly slower than a fixed connection. However, the transmission throughput is still acceptable for healthcare professionals in a healthcare enterprise or home care site. It is necessary to build more heterogeneous wireless protocols into the proposed tunnel switching scheme to support all possible communication protocols. In addition, SCTP is another good choice for promoting communication in telemedicine and healthcare fields. PMID- 23917811 TI - Hypothyroxinemia induced by mild iodine deficiency deregulats thyroid proteins during gestation and lactation in dams. AB - The main object of the present study was to explore the effect on thyroidal proteins following mild iodine deficiency (ID)-induced maternal hypothyroxinemia during pregnancy and lactation. In the present study, we established a maternal hypothyroxinemia model in female Wistar rats by using a mild ID diet. Maternal thyroid iodine content and thyroid weight were measured. Expressions of thyroid associated proteins were analyzed. The results showed that the mild ID diet increased thyroid weight, decreased thyroid iodine content and increased expressions of thyroid transcription factor 1, paired box gene 8 and Na+/I- symporter on gestational day (GD) 19 and postpartum days (PN) 21 in the maternal thyroid. Moreover, the up-regulated expressions of type 1 iodothyronine deiodinase (DIO1) and type 2 iodothyronine deiodinase (DIO2) were detected in the mild ID group on GD19 and PN21. Taken together, our data indicates that during pregnancy and lactation, a maternal mild ID could induce hypothyroxinemia and increase the thyroidal DIO1 and DIO2 levels. PMID- 23917813 TI - Risk of spina bifida and maternal cigarette, alcohol, and coffee use during the first month of pregnancy. AB - This study was conducted to assess the association between the risks of spina bifida (SB) in relation to cigarette, alcohol, and caffeine consumption by women during the first month of pregnancy. Between 1988-2012, this multi-center case control study interviewed mothers of 776 SB cases and 8,756 controls about pregnancy events and exposures. We evaluated cigarette smoking, frequency of alcohol drinking, and caffeine intake during the first lunar month of pregnancy in relation to SB risk. Logistic regression models were used to calculate adjusted odds ratios and 95% confidence intervals. Levels of cigarette smoking (1 9 and >=10/day), alcohol intake (average >=4 drinks/day) and caffeine intake (<1, 1, and >=2 cups/day) were not likely to be associated with increased risk of SB. Further, results were similar among women who ingested less than the recommended amount of folic acid (400 MUg/day). PMID- 23917814 TI - Antimicrobial activity of a neem cake extract in a broth model meat system. AB - This work reports on the antimicrobial activity of an ethyl acetate extract of neem (Azadirachta indica) cake (NCE) against bacteria affecting the quality of retail fresh meat in a broth model meat system. NCE (100 ug) was also tested by the agar disc diffusion method. It inhibited the growth of all tested microorganisms. The NCE growth inhibition zone (IZ) ranged 11.33-22.67 mm while the ciprofloxacin (10 ug) IZ ranged from 23.41-32.67 mm. There was no significant difference (p <= 0.05) between the antimicrobial activity of NCE and ciprofloxacin vs. C. jejuni and Leuconostoc spp. The NCE antibacterial activity was moreover determined at lower concentrations (1:10-1:100,000) in micro-assays. The percent growth reduction ranged from 61 +/- 2.08-92 +/- 3.21. The higher bacterial growth reduction was obtained at 10 ug concentration of NCE. Species specific PCR and multiplex PCR with the DNA dye propidium monoazide were used to directly detect viable bacterial cells from experimentally contaminated meat samples. The numbers of bacterial cells never significantly (p <= 0.05) exceeded the inocula concentration used to experimentally contaminate the NCE treated meat. This report represents a screening methodology to evaluate the antimicrobial capability of a herbal extract to preserve meat. PMID- 23917815 TI - An assessment of food safety needs of restaurants in Owerri, Imo State, Nigeria. AB - One hundred and forty five head chefs and catering managers of restaurants in Owerri, Nigeria were surveyed to establish their knowledge of food safety hazards and control measures. Face-to-face interviews were conducted and data collected on their knowledge of risk perception, food handling practices, temperature control, foodborne pathogens, and personal hygiene. Ninety-two percent reported that they cleaned and sanitized food equipment and contact surfaces while 37% engaged in cross-contamination practices. Forty-nine percent reported that they would allow a sick person to handle food. Only 70% reported that they always washed their hands while 6% said that they continued cooking after cracking raw eggs. All respondents said that they washed their hands after handling raw meat, chicken or fish. About 35% lacked knowledge of ideal refrigeration temperature while 6% could not adjust refrigerator temperature. Only 40%, 28%, and 21% had knowledge of Salmonella, E. coli, and Hepatitis A, respectively while 8% and 3% had knowledge of Listeria and Vibrio respectively, as pathogens. Open markets and private bore holes supplied most of their foods and water, respectively. Pearson's Correlation Coefficient analysis revealed almost perfect linear relationship between education and knowledge of pathogens (r = 0.999), cooking school attendance and food safety knowledge (r = 0.992), and class of restaurant and food safety knowledge (r = 0.878). The lack of current knowledge of food safety among restaurant staff highlights increased risk associated with fast foods and restaurants in Owerri. PMID- 23917816 TI - Case-control study of arsenic in drinking water and lung cancer in California and Nevada. AB - Millions of people are exposed to arsenic in drinking water, which at high concentrations is known to cause lung cancer in humans. At lower concentrations, the risks are unknown. We enrolled 196 lung cancer cases and 359 controls matched on age and gender from western Nevada and Kings County, California in 2002-2005. After adjusting for age, sex, education, smoking and occupational exposures, odds ratios for arsenic concentrations >=85 ug/L (median = 110 ug/L, mean = 173 ug/L, maximum = 1,460 ug/L) more than 40 years before enrollment were 1.39 (95% CI = 0.55-3.53) in all subjects and 1.61 (95% CI = 0.59-4.38) in smokers. Although odds ratios were greater than 1.0, these increases may have been due to chance given the small number of subjects exposed more than 40 years before enrollment. This study, designed before research in Chile suggested arsenic-related cancer latencies of 40 years or more, illustrates the enormous sample sizes needed to identify arsenic-related health effects in low-exposure countries with mobile populations like the U.S. Nonetheless, our findings suggest that concentrations near 100 ug/L are not associated with markedly high relative risks. PMID- 23917817 TI - Tuning copper(II) ion selectivity: the role of basicity, size of the chelating ring and orientation of coordinating atoms. AB - Incorporation of the triazolyl moiety modulates the basicity and effective size of the chelating ring, changes the stoichiometry in complex formation and thereby imparts Cu(2+) ion selectivity. PMID- 23917819 TI - The new frontiers of acute kidney injury. PMID- 23917820 TI - Why is it important to assess indications for red blood cell transfusion in premature infants? PMID- 23917821 TI - N-acetylcysteine and deferrioxamine protects against acute renal failure induced by ischemia/reperfusion in rats. AB - OBJECTIVE: Antioxidants are widely used in animal models to prevent renal injury after ischemia/reperfusion, but it is unknown if the benefits of antioxidants are additive. In this study, we aimed to investigate the protective effects of N acetylcysteine plus deferoxamine in an animal model of kidney ischemia/reperfusion injury. METHODS: Bilateral kidney ischemia was mastintained for 45 minutes. N-acetylcysteine, deferoxamine or both were administered into the aorta above the renal arteries immediately prior to induction of ischemia. Five rats from each group were sacrificed 1, 6 or 12 hours after reperfusion for the determination of blood creatinine, kidney oxidative damage parameters and myeloperoxidase activity. RESULTS: The combination of N-acetylcysteine and deferoxamine, but not their isolated use, prevented the increase in creatinine after ischemia/reperfusion. This prevention was followed by a consistent decrease in myeloperoxidase activity and oxidative damage parameters both in the kidney cortex and medulla. CONCLUSION: Treatment with N-acetylcysteine and deferoxamine was superior to the isolated use of either compound in an animal model of kidney ischemia/reperfusion. PMID- 23917818 TI - Association of maternal and nutrient supply line factors with DNA methylation at the imprinted IGF2/H19 locus in multiple tissues of newborn twins. AB - Epigenetic events are crucial for early development, but can be influenced by environmental factors, potentially programming the genome for later adverse health outcomes. The insulin-like growth factor 2 (IGF2)/H19 locus is crucial for prenatal growth and the epigenetic state at this locus is environmentally labile. Recent studies have implicated maternal factors, including folate intake and smoking, in the regulation of DNA methylation at this locus, although data are often conflicting in the direction and magnitude of effect. Most studies have focused on single tissues and on one or two differentially-methylated regions (DMRs) regulating IGF2/H19 expression. In this study, we investigated the relationship between multiple shared and non-shared gestational/maternal factors and DNA methylation at four IGF2/H19 DMRs in five newborn cell types from 67 pairs of monozygotic and 49 pairs of dizygotic twins. Data on maternal and non shared supply line factors were collected during the second and third trimesters of pregnancy and DNA methylation was measured via mass spectrometry using Sequenom MassArray EpiTyper analysis. Our exploratory approach showed that the site of umbilical cord insertion into the placenta in monochorionic twins has the strongest positive association with methylation in all IGF2/H19 DMRs (p<0.05). Further, evidence for tissue- and locus-specific effects were observed, emphasizing that responsiveness to environmental exposures in utero cannot be generalized across genes and tissues, potentially accounting for the lack of consistency in previous findings. Such complexity in responsiveness to environmental exposures in utero has implications for all epigenetic studies investigating the developmental origins of health and disease. PMID- 23917822 TI - Factors associated with packed red blood cell transfusions in premature infants in an intensive care unit. AB - OBJECTIVE: This study analyzed the factors that are associated with the need for packed red blood cell transfusions in premature infants in a neonatal intensive care unit. METHODS: This study is a cross-sectional study of secondary data from premature infants who were admitted to a neonatal intensive care unit between 2008 and 2010. Premature infants with low birth weight were included. Packed red blood cell transfusion was the dependent variable. Pearson's Chi-square or Fisher's exact tests were used for data analysis, and the median, minimum, and maximum values were calculated. Prevalence ratios were calculated using the Poisson regression and Pearson correlation coefficient. Linear regression analyses were performed. P < 0.05 was considered to be significant. RESULTS: We examined 254 premature infants, and 39.4% of this sample received packed red blood cells. Transfusions were 70% less prevalent in premature infants who were born at >32 weeks of gestation, and 191% more prevalent in infants who exhibited late-onset neonatal sepsis. The number of transfusions per patient was negatively correlated with gestational age and positively correlated with late-onset neonatal sepsis. A gestational age <32 weeks and late-onset neonatal sepsis explained 45% of the transfusions (p<0.0001). CONCLUSIONS: Premature infants with a gestational age <32 weeks and who developed late-onset neonatal sepsis exhibited a greater need for packed red blood cell transfusions. PMID- 23917823 TI - Incidence and primary causes of unplanned extubation in a neonatal intensive care unit. AB - OBJECTIVE: This study established the incidence and primary causes of unplanned extubation in newborns in the neonatal intensive care units of the Hospital Sofia Feldman, Belo Horizonte (Minas Gerais). METHODS: This retrospective study was conducted between July 1, 2009 and April 30, 2010. Unplanned extubations and their primary causes were assessed using an adverse events form. The following variables were assessed: gender, corrected age, present weight, duration of mechanical ventilation time, and motives/causes of the event on the day of the unplanned extubation event. RESULTS: Fifty-four unplanned extubations occurred, which corresponded to an incidence of 1.0 event/100 days of mechanical ventilation. This rate was higher among newborns with a corrected age of 30 to 36 weeks and weight < 1,000 g. The primary causes of unplanned extubations included patient agitation, inappropriate handling of patients during the performance of procedures, and inappropriate fixation and positioning of the endotracheal tube. CONCLUSION: The incidence of unplanned extubation in the investigated neonatal intensive care units was low during the study period compared to previously reported data. Nevertheless, the assessment of the quality of procedures, the continuous follow-up of newborns, and the monitoring of the causes of extubation are required to further reduce this incidence. PMID- 23917824 TI - Urinary electrolyte monitoring in critically ill patients: a preliminary observational study. AB - OBJECTIVE: Intensive care unit survivors and non-survivors have distinct acid base profiles. The kidney's regulation of urinary electrolytes and the urinary strong ion difference plays a major role in acid-base homeostasis. The aim of this study was to evaluate the potential utility of daily spot urinary electrolyte measurement in acid-base and renal function monitoring. METHODS: We prospectively recorded daily plasma acid-base parameters and traditional markers of renal function in parallel with spot urinary electrolyte measurements in patients with urinary catheters admitted to our intensive care unit. Patients who remained in the intensive care unit for at least 4 days with a urinary catheter were included in the study. RESULTS: Of the 50 patients included in the study, 22% died during their intensive care unit stay. The incidence of acute kidney injury was significantly higher in non-survivors during the 4-day observation period (64% vs. 18% in survivors). Urinary chloride and sodium were lower and urinary strong ion difference was higher on day 1 in patients who developed acute kidney injury among both survivors and non-survivors. Both groups had similar urine output, although non-survivors had persistently higher urinary strong ion difference on all days. Survivors had a progressive improvement in metabolic acid base profile due to increases in the plasma strong ion difference and decreases in weak acids. These changes were concomitant with decreases in urinary strong ion difference. In non-survivors, acid-base parameters did not significantly change during follow-up. CONCLUSIONS: Daily assessment of spot urinary electrolytes and strong ion difference are useful components of acid-base and renal function evaluations in critically ill patients, having distinct profiles between intensive care unit survivors and non-survivors. PMID- 23917825 TI - Mortality assessment in patients with severe acute pancreatitis: a comparative study of specific and general severity indices. AB - OBJECTIVE: This study compared the general and specific severity indices to assess the prognosis of severe acute pancreatitis at a polyvalent intensive care unit. METHODS: This retrospective study included 108 patients who were diagnosed with severe acute pancreatitis from July 1, 1999 to March 31, 2012. Their demographic and clinical data were collected, and the following severity indices were calculated: Ranson, Osborne, Blamey and Imrie, Balthazar, POP, APACHE II, SAPS II, and SOFA. The discriminative power of these indices with regard to mortality at the intensive care unit and hospital was assessed using the area under the ROC curve. RESULTS: The demographic data of the surviving and deceased patients did not significantly differ at baseline. The mortality rates were 27% and 39% at the intensive care unit and hospital, respectively. The severity indices that exhibited the greatest discriminative power with regard to mortality at the intensive care unit and hospital were the POP 0, POP 24, SOFA (at admission, 24 hours, 48 hours, and discharge), SAPS II, and APACHE II. CONCLUSION: The POP performed better than the other indices (aROC>0.8) at admission and 24 hours later (as originally described). The general physiological dysfunction indices also exhibited reasonable discriminative power (aROC=0.75 0.8), which was unlike the remaining pancreatitis specific indices, whose discriminative power was lower. PMID- 23917826 TI - Routine chest radiography in intensive care: impact on decision-making. AB - OBJECTIVE: This study determined the prevalence of clinical abnormalities in chest radiographs and its relationship with decision-making in intensive care. METHODS: This prospective cohort study involved nonconsecutive patients who were admitted to the intensive care unit at the Hospital Universitario Professor Polydoro Ernani de Sao Thiago of the Universidade Federal de Santa Catarina. Imaging tests in the intensive care unit (ICU) were assessed daily between February and May 2011 and divided according to the reason for hospitalization, the type of test requested, anatomical segment under assessment and the purpose of the request. The imaging tests were interpreted by intensivists and subsequently divided according to the detected abnormalities and changes in medical care. The chi-squared test was used for statistical analysis. RESULTS: The study sample included 106 patients. A total of 447 imaging tests were assessed, 425 of which were anteroposterior chest radiographs. An average of 4.01 radiographs per patient was obtained. Among the requested radiographs, 79.3% were normal, and 35.2% of abnormal radiographs did not prompt changes in medical care. CONCLUSION: Most of the radiographs performed in the intensive care unit exhibited no statistically significant clinical alterations, and the radiographs that revealed abnormalities did not necessarily lead to changes in medical care. PMID- 23917827 TI - Is the intention to donate organs influenced by the public's understanding of brain death? AB - OBJECTIVE: To evaluate the influence of the understanding of brain death in relation to organ donation in patients from the Marco School Health Center, which is linked to the Universidade do Estado do Para. METHODS: A total of 136 patients were interviewed based on a research protocol. The interview results were subsequently analyzed with regard to the understanding of brain death and organ donation in addition to the collection of sociodemographic data. RESULTS: The majority of patients were female and were in favor of organ donation, with a mean age of 39 years being observed. Only 19.9% of the patients understood the meaning of brain death, and 85.3% believed that physicians may be mistaken in confirming the status of brain death of a patient, while 18.4% trusted the diagnosis of brain death. A statistically significant (p < 0.01) correlation was observed between the degree of confidence in the diagnosis of brain death and the person's agreement to donate his/her organs after death. CONCLUSION: The majority of the population under study did not understand the meaning of brain death and had a low degree of confidence in the diagnosis of brain death. This lack of understanding and confidence negatively influences the desire to donate organs. PMID- 23917828 TI - Nutritional support and outcomes in critically ill patients after one week in the intensive care unit. AB - OBJECTIVE: This study evaluated the relationship between nutritional intake and protein and caloric requirements and observed clinical outcomes on the 7th day of intensive care unit stay. METHODS: This was a retrospective cohort study of 126 patients who were admitted to the intensive care unit for >7 days. The patients were categorized according to the adequacy of energy and protein intake in relation to requirements (a >60% Adequate Intake Group and a <60% Inadequate Intake Group). The length of stay, ventilator free time and mortality in the intensive care unit and hospital were evaluated. RESULTS: Enteral nutrition was used in 95.6% of the 126 included patients, and nutrition was initiated 41 hours after admission to the intensive care unit. The adequacy of intake was 84% for energy and 72.5% for protein. No differences in the length of stay [16 (11-23) versus 15 (11-21) days, p=0.862], ventilator free time [2 (0-7) versus 3 (0-6) days, p=0.985] or mortality in the intensive care unit [12 (41.4%) versus 38 (39.1%), p=0.831] and hospital [15 (51.7%) versus 44 (45.4%), p=0.348] were observed between the adequate and inadequate energy intake groups, respectively. Similar results in protein intake and the length of hospital stay [15 (12-21) versus 15 (11-21) days, p=0.996], ventilator free time [2 (0-7) versus 3 (0-6) days, p=0.846], and mortality in the intensive care unit [15 (28.3%) versus 35 (47.9%), p=0.536)] and hospital [18 (52.9%) versus 41 (44.6%), p=0.262] were observed between groups. CONCLUSION: The results did not establish that energy and protein intakes of greater or less than 60% of nutritional requirements were reliable dividers of clinical outcomes. PMID- 23917829 TI - Nutritional requirements of the critically ill patient. AB - OBJECTIVE: Given the inaccessibility of indirect calorimetry, intensive care units generally use predictive equations or recommendations that are established by international societies to determine energy expenditure. The aim of the present study was to compare the energy expenditure of critically ill patients, as determined using indirect calorimetry, to the values obtained using the Harris Benedict equation. METHODS: A retrospective observational study was conducted at the Intensive Care Unit 1 of the Centro Hospitalar do Porto. The energy requirements of hospitalized critically ill patients as determined using indirect calorimetry were assessed between January 2003 and April 2012. The accuracy (+/- 10% difference between the measured and estimated values), the mean differences and the limits of agreement were determined for the studied equations. RESULTS: Eighty-five patients were assessed using 288 indirect calorimetry measurements. The following energy requirement values were obtained for the different methods: 1,753.98+/-391.13 kcal/day (24.48 +/- 5.95 kcal/kg/day) for indirect calorimetry and 1,504.11 +/- 266.99 kcal/day (20.72+/-2.43 kcal/kg/day) for the Harris Benedict equation. The equation had a precision of 31.76% with a mean difference of -259.86 kcal/day and limits of agreement between -858.84 and 339.12 kcal/day. Sex (p=0.023), temperature (p=0.009) and body mass index (p<0.001) were found to significantly affect energy expenditure. CONCLUSION: The Harris-Benedict equation is inaccurate and tends to underestimate energy expenditure. In addition, the Harris-Benedict equation is associated with significant differences between the predicted and true energy expenditure at an individual level. PMID- 23917830 TI - Use of non-invasive ventilation in acute pulmonary edema and chronic obstructive pulmonary disease exacerbation in emergency medicine: predictors of failure. AB - OBJECTIVE: This study analyzed acute respiratory failure caused by acute pulmonary edema, as well as chronic obstructive pulmonary disease exacerbation, that was treated with non-invasive mechanical ventilation to identify the factors that are associated with the success or failure non-invasive mechanical ventilation in urgent and emergency service. METHODS: This study was a prospective, descriptive and analytical study. We included patients of both genders aged >18 years who used non-invasive mechanical ventilation due to acute respiratory failure that was secondary to acute pulmonary edema or chronic obstructive pulmonary disease exacerbation. Patients with acute respiratory failure that was secondary to pathologies other than acute pulmonary edema and chronic obstructive pulmonary disease or who presented with contraindications for the technique were excluded. Expiratory pressures between 5 and 8 cmH2O and inspiratory pressures between 10 and 12 cmH2O were used. Supplemental oxygen maintained peripheral oxygen saturation at >90%. The primary outcome was endotracheal intubation. RESULTS: A total of 152 patients were included. The median non-invasive mechanical ventilation time was 6 hours (range 1 - 32 hours) for chronic obstructive pulmonary disease patients (n=60) and 5 hours (range 2 - 32 hours) for acute pulmonary edema patients (n=92). Most (75.7%) patients progressed successfully. However, reduced APACHE II scores and lower peripheral oxygen saturation were observed. These results were statistically significant in patients who progressed to intubation (p<0.001). BiPAP (Bi-level Positive Airway Pressure portable ventilator), as continuous positive airway pressure use increased the probability of endotracheal intubation 2.3 times (p=0.032). Patients with acute pulmonary edema and elevated GCS scores also increased the probability of success. CONCLUSION: Respiratory frequency >25 rpm, higher APACHE II scores, BiPAP use and chronic obstructive pulmonary disease diagnosis were associated with endotracheal intubation. Higher GCS and SpO2 values were associated with NIV success. Non-invasive mechanical ventilation can be used in emergency services in acute respiratory failure cases caused by acute pulmonary edema and chronic obstructive pulmonary disease exacerbation, but patients with variables related to a higher percentage of endotracheal intubation should be specially monitored. PMID- 23917831 TI - Bleeding in non-ST-segment elevation acute coronary syndrome. AB - The development of antiplatelet and antithrombotic therapies, in addition to interventionist strategy, has resulted in great improvements in the outcomes of patients with non-ST-segment elevation acute coronary syndrome. Parallel to therapeutic advances, bleeding, which can be induced during management, increases the risk of recurrent ischemia, myocardial infarction and death. The present literature review describes the benefits and bleeding risks of each medication or intervention strategy and suggests guidelines for managing these patients. PMID- 23917832 TI - CD4+CD25+ T lymphocytes and regulation of the immune system: perspectives for a pathophysiological understanding of sepsis. AB - The systemic inflammatory response represents the core pathogenic event of sepsis, underlying clinical manifestations and laboratory findings in patients. Numerous studies have shown that CD4+CD25+ T lymphocytes, also known as regulatory T lymphocytes (Treg), participate in the development of sepsis due to their ability to suppress the immune response. The present article discusses the role of Treg lymphocytes in sepsis based on a specific search strategy (Latin American and Caribbean Health Sciences / Literatura Latino-americana e do Caribe em Ciencias da Saude - LILACS, PubMed, and Scientific Electronic Library Online - SciELO) focusing on two main topics: the participation of Treg cells in inflammation and immunity as well as perspectives in the computational physiological investigation of sepsis. PMID- 23917833 TI - Plasmapheresis as a therapeutic approach for hypertriglyceridemia-induced acute pancreatitis. AB - Acute pancreatitis is an inflammatory condition that is clinically manifested by abdominal pain and elevated serum levels of pancreatic enzymes. Hypertriglyceridemia is the third most common cause of acute pancreatitis. The present report aimed to describe a case of hypertriglyceridemia-induced acute pancreatitis, where the therapeutic approach was plasmapheresis. A 48-year-old female patient was admitted to the hospital with complaints of "severe abdominal pain". She reported the onset of such symptoms as nausea, vomiting and abdominal pain with a burning feeling in the epigastric area. The patient denied having a fever. The initial examination revealed that she was obese, oriented, tachypneic, normotensive, tachycardic, dehydrated, afebrile, anicteric and acyanotic and had normal color. Her abdomen was distended with bowel sounds, tympanic and diffusely painful, which was mostly in the supramesocolic compartment. The initial laboratory exams showed 10.932 mg/dL triglycerides, 1.548 mg/dL cholesterol, 226 mg/dL amylase and 899 mg/dL lipase. The abdominal computed tomography exhibited increased pancreatic volume (Balthazar E). The patient's condition worsened, and she was sent to the intensive care center. Plasmapheresis was performed with no complications. On the 14th day after admission, the patient was discharged from the intensive care center and was sent to the gastroenterology ward, where an oral diet was resumed with good acceptance. The patient progressed well and was discharged from the hospital on the 25th day after admission. High triglyceride levels are necessary to cause pancreatitis, and it is important to exclude the most common causes. Importantly, the therapeutic approach reduced the high hypertriglyceridemia quickly, thereby avoiding tissue damage. PMID- 23917834 TI - Meningitis as a complication of infective endocarditis. AB - Although approximately 30% of patients with endocarditis present with neurological complications, the development of meningitis in these patients is rare. This case report describes a female patient who developed meningitis as a complication of mitral valve endocarditis, and surgery was required for this patient due to acute heart failure resulting from the rupture of the chordae tendineae. PMID- 23917835 TI - The incidence of delirium in patients pretreated with statins who remain in an intensive care unit after cardiac surgery. PMID- 23917836 TI - Virus occupational exposure in solid waste processing facilities. AB - It is well known that workers involved in the management of solid waste are at risk of exposure to bioaerosol, which is generally studied in relation to bacteria, fungi, and endotoxins. However, to date, there have been no reports on the incidence of work-related infectious diseases. To determine if occupational exposure to viruses occurs upon exposure to waste-related activities, monitoring was carried out in a landfill, a waste recycling plant, an incineration plant, and a waste collection vehicles. Air and surfaces were sampled and analyzed for torque teno virus (TTV), human adenovirus (HAdV), norovirus, rotavirus, and enterovirus using polymerase chain reaction (PCR)-based techniques. Positivity was confirmed by sequencing and quantification with real-time PCR; infectivity was also tested for culturable viruses. Samples were analyzed in parallel for mean total bacterial and fungi counts in both the summer and winter. In total, 30% (12/40) of air and 13.5% (5/37) of surface samples collected in plants were positive for HAdV and TTV. Among the eight HAdV-positive samples, six (75%), revealed in landfill and recycling plant air and in incinerator and waste vehicles surfaces, were able to replicate in cell culture and were subsequently confirmed as infective. The frequency of detection of virus-positive samples was similar in both seasons, but with evident differences in the type of virus detected: TTV and HAdV were more frequently detected in the summer and winter, respectively. The area of highest viral contamination was the paper selection landfill. Fungi and bacterial contamination did not correlate with viral presence or concentration. In conclusion, we evidence that working with solid and liquid waste can lead to infectious viruses, included in Group 2 of the European Directive 90/679/CEE pathogens list; thus, further investigation on the sources and routes of contamination is needed in order to assess the occupational risk. PMID- 23917837 TI - Haunted with and hunting for viruses. PMID- 23917838 TI - Emerging infectious diseases associated with bat viruses. AB - Bats play important roles as pollen disseminators and pest predators. However, recent interest has focused on their role as natural reservoirs of pathogens associated with emerging infectious diseases. Prior to the outbreak of severe acute respiratory syndrome (SARS), about 60 bat virus species had been reported. The number of identified bat viruses has dramatically increased since the initial SARS outbreak, and most are putative novel virus species or genotypes. Serious infectious diseases caused by previously identified bat viruses continue to emerge throughout in Asia, Australia, Africa and America. Intriguingly, bats infected by these different viruses seldom display clinical symptoms of illness. The pathogenesis and potential threat of bat-borne viruses to public health remains largely unknown. This review provides a brief overview of bat viruses associated with emerging human infectious diseases. PMID- 23917839 TI - A novel human coronavirus: Middle East respiratory syndrome human coronavirus. AB - In 2012, a novel coronavirus, initially named as human coronavirus EMC (HCoV-EMC) but recently renamed as Middle East respiratory syndrome human coronavirus (MERS CoV), was identified in patients who suffered severe acute respiratory infection and subsequent renal failure that resulted in death. Ongoing epidemiological investigations together with retrospective studies have found 61 laboratory confirmed cases of infection with this novel coronavirus, including 34 deaths to date. This novel coronavirus is culturable and two complete genome sequences are now available. Furthermore, molecular detection and indirect immunofluorescence assay have been developed. The present paper summarises the limited recent advances of this novel human coronavirus, including its discovery, genomic characterisation and detection. PMID- 23917840 TI - New strategy for virus discovery: viruses identified in human feces in the last decade. AB - Emerging and re-emerging viruses continue to surface all over the world. Some of these viruses have the potential for rapid and global spread with high morbidity and mortality, such as the SARS coronavirus outbreak. It is extremely urgent and important to identify a novel virus near-instantaneously to develop an active preventive and/or control strategy. As a culture-independent approach, viral metagenomics has been widely used to investigate highly divergent and completely new viruses in humans, animals, and even environmental samples in the past decade. A new model of Koch's postulates, named the metagenomic Koch's postulates, has provided guidance for the study of the pathogenicity of novel viruses. This review explains the viral metagenomics strategy for virus discovery and describes viruses discovered in human feces in the past 10 years using this approach. This review also addresses issues related to the metagenomic Koch's postulates and the challenges for virus discovery in the future. PMID- 23917841 TI - An emerging hemorrhagic fever in China caused by a novel bunyavirus SFTSV. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever in rural areas of China and is caused by a new bunyavirus, SFTSV, named after the disease. The transmission vectors and animal hosts of SFTSV are unclear. Ticks are the most likely transmission vectors and domestic animals, including goats, dogs, and cattle, are potential amplifying hosts of SFTSV. The clinical symptoms of SFTS are nonspecific, but major symptoms include fever, gastrointestinal symptoms, myalgia, dizziness, joint pain, chills, and regional lymphadenopathy. The most common abnormalities in laboratory test results are thrombocytopenia (95%), leukocytopenia (86%), and elevated levels of serum alanine aminotransferase, aspartate aminotransferase, creatine kinase, and lactate dehydrogenase. The fatality rate for SFTS is 12% on average, and the annual incidence of the disease is approximately five per 100000 of the rural population. PMID- 23917842 TI - Duck egg drop syndrome virus: an emerging Tembusu-related flavivirus in China. AB - Duck egg drop syndrome virus (DEDSV) is a newly emerging pathogenic flavivirus isolated from ducks in China. DEDSV infection mainly results in severe egg drop syndrome in domestic poultry, which leads to huge economic losses. Thus, the discovery of ways and means to combat DEDSV is urgent. Since 2010, a remarkable amount of progress concerning DEDSV research has been achieved. Here, we review current knowledge on the epidemiology, symptomatology, and pathology of DEDSV. A detailed dissection of the viral genome and polyprotein sequences, comparative analysis of viral antigenicity and the corresponding potential immunity against the virus are also summarized. Current findings indicate that DEDSV should be a distinct species from Tembusu virus. Moreover, the adaption of DEDSV in wildlife and its high homology to pathogenic flaviviruses (e.g., West Nile virus, Japanese encephalitis virus, and dengue virus), illustrate its reemergence and potential to become a zoonotic pathogen that should not be overlooked. Detailed insight into the antigenicity and corresponding immunity against the virus is of clear significance for the development of vaccines and antiviral drugs specific for DEDSV. PMID- 23917843 TI - Newly discovered insect RNA viruses in China. AB - Insects are a group of arthropods and the largest group of animals on Earth, with over one million species described to date. Like other life forms, insects suffer from viruses that cause disease and death. Viruses that are pathogenic to beneficial insects cause dramatic economic losses on agriculture. In contrast, viruses that are pathogenic to insect pests can be exploited as attractive biological control agents. All of these factors have led to an explosion in the amount of research into insect viruses in recent years, generating impressive quantities of information on the molecular and cellular biology of these viruses. Due to the wide variety of insect viruses, a better understanding of these viruses will expand our overall knowledge of their virology. Here, we review studies of several newly discovered RNA insect viruses in China. PMID- 23917844 TI - The synthesis and biological testing of bacilysin analogues. AB - A series of compounds based on the structure of bacilysin were synthesised and tested for antibacterial activity. The key steps in the syntheses are the coupling of an iodide to a diketopiperazine (DKP) and mono-lactim ether scaffold, respectively. The diastereoselectivity of the coupling reactions was dependant on the scaffold, with selectivity for DKP of about 4:1 and mono-lactim ether exceeding 98:2. Subsequent elaboration of the compounds to give open chain dipeptides and DKPs that mimic the structure of bacilysin but substitute the epoxy ketone for a saturated or unsaturated ketone is described. Overall yield from coupling to final product was between 5 and 21 %, with the yield of the saturated products notably higher. The open chain dipeptides demonstrated moderate antibacterial and antifungal activity. PMID- 23917845 TI - Cross-linking and mass spectrometry methodologies to facilitate structural biology: finding a path through the maze. AB - Multiprotein complexes, rather than individual proteins, make up a large part of the biological macromolecular machinery of a cell. Understanding the structure and organization of these complexes is critical to understanding cellular function. Chemical cross-linking coupled with mass spectrometry is emerging as a complementary technique to traditional structural biology methods and can provide low-resolution structural information for a multitude of purposes, such as distance constraints in computational modeling of protein complexes. In this review, we discuss the experimental considerations for successful application of chemical cross-linking-mass spectrometry in biological studies and highlight three examples of such studies from the recent literature. These examples (as well as many others) illustrate the utility of a chemical cross-linking-mass spectrometry approach in facilitating structural analysis of large and challenging complexes. PMID- 23917846 TI - Parkinson disease: Long-term levodopa exposure may increase risk of neuropathy in patients with PD. PMID- 23917847 TI - Stroke: Is thrombolysis safe in anticoagulated ischaemic stroke? PMID- 23917848 TI - Pain: Quantitative sensory testing--a tool for daily practice? PMID- 23917849 TI - Outcome predictors for status epilepticus--what really counts. AB - In adult patients with status epilepticus (SE)-a life-threatening state of ongoing or repetitive seizures--the current evidence regarding outcome prediction is based on clinical, biochemical and EEG determinants. These predictors of outcome involve clinical features such as age, history of prior seizures or epilepsy, SE aetiology, level of consciousness, and seizure type at SE onset. The clinical risk-benefit calculation between the danger of undertreated persistent seizure activity and, conversely, the potential damage from unwarranted aggressive treatments remains a constant challenge. Improved knowledge of outcome determinants, as well as increased availability of reliable outcome prediction models early in the course of SE, is paramount for optimization of treatment of patients who develop this disorder. In this Review, we discuss the major prognostic determinants of outcome in SE. Through consideration of studies that provide measures of association between predictors of SE outcome and death, we propose a detailed--but as yet unvalidated--paradigm for assessment of these predictors during the course of SE. Such an algorithm could guide the organization of results from existing trials and provide direction with regard to the parameters that should be monitored in future studies of SE. PMID- 23917851 TI - Comparison of open lateral release and transarticular lateral release in distal chevron metatarsal osteotomy for hallux valgus correction. AB - PURPOSE: The aim of this study was to investigate the difference in clinical and radiographic outcomes between conventional open lateral soft tissue release (OLSTR) and transarticular lateral soft tissue release (TLSTR) in patients undergoing distal chevron metatarsal osteotomy (DCMO) for hallux valgus (HV) correction. METHODS: This study included weight-bearing anteroposterior radiographs of 138 patients (185 feet) with HV that underwent DCMO and Akin phalangeal osteotomy at a mean age of 51.7 years (21-74) with a mean 26 months of follow-up between June 2004 and June 2010. Patients were classified into two groups: OLSTR as group 1 (84 feet) and TLSTR as group 2 (101 feet). We evaluated clinical and radiographic outcomes between the two groups using the American Orthopaedic Foot and Ankle Society hallux score, visual analogue scale pain score, hallux valgus angle, intermetatarsal angle and complications, pre- and post-operatively. RESULTS: There were no significant differences between the two groups except for post-operative complications such as first metatarsophalangeal joint (MTPJ) stiffness (group 1) and post-operative hallux varus (group 2). CONCLUSIONS: Clinical and radiographic outcomes between OLSTR and TLSTR in HV correction using DCMO were not significantly different except for post-operative limitation of motion of the first MTPJ and hallux varus tendency. Different precautions should be taken into account when choosing the type of lateral soft tissue release due to possible complications associated with each technique. PMID- 23917852 TI - Reviewing subchondral cartilage surgery: considerations for standardised and outcome predictable cartilage remodelling: a technical note. AB - PURPOSE: The potential of subchondral mesenchymal stem cell stimulation (MSS) for cartilage repair has led to the widespread use of microfracture as a first line treatment for full thickness articular cartilage defects. Recent focus on the effects of subchondral bone during cartilage injury and repair has expanded the understanding of the strengths and limitations in MSS and opened new pathways for potential improvement. Comparative studies have shown that bone marrow access has positive implications for pluripotential cell recruitment, repair quality and quantity, i.e. deeper channels elicited better cartilage fill, more hyaline cartilage character with higher type II collagen content and lower type I collagen content compared to shallow marrow access. METHODS: A subchondral needling procedure using standardised and thin subchondral perforations deep into the subarticular bone marrow making the MSS more consistent with the latest developments in subchondral cartilage remodelling is proposed. RESULTS: As this is a novel method clinical studies have been initiated to evaluate the procedure especially compared to microfracturing. However, the first case studies and follow-ups indicate that specific drills facilitate reaching the subchondral bone marrow while the needle size makes perforation of the subchondral bone easier and more predictable. Clinical results of the first group of patients seem to compare well to microfracturing. CONCLUSION: The authors suggest a new method for a standardised procedure using a new perforating device. Advances in MSS by subchondral bone marrow perforation are discussed. It remains to be determined by clinical studies how this method compares to microfracturing. The subchondral needling offers the surgeon and the investigator a method that facilitates comparison studies because of its defined depth of subchondral penetration and needle size. PMID- 23917850 TI - 25 years of neuroimaging in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease for which a precise cause has not yet been identified. Standard CT or MRI evaluation does not demonstrate gross structural nervous system changes in ALS, so conventional neuroimaging techniques have provided little insight into the pathophysiology of this disease. Advanced neuroimaging techniques--such as structural MRI, diffusion tensor imaging and proton magnetic resonance spectroscopy--allow evaluation of alterations of the nervous system in ALS. These alterations include focal loss of grey and white matter and reductions in white matter tract integrity, as well as changes in neural networks and in the chemistry, metabolism and receptor distribution in the brain. Given their potential for investigation of both brain structure and function, advanced neuroimaging methods offer important opportunities to improve diagnosis, guide prognosis, and direct future treatment strategies in ALS. In this article, we review the contributions made by various advanced neuroimaging techniques to our understanding of the impact of ALS on different brain regions, and the potential role of such measures in biomarker development. PMID- 23917853 TI - Unilateral versus bilateral instrumented transforaminal lumbar interbody fusion in two-level degenerative lumbar disorders: a prospective randomised study. AB - PURPOSE: The aim of this study was to analyse the clinical and radiological outcomes of unilateral versus bilateral instrumented TLIF in two-level degenerative lumbar disorders. METHODS: A prospective randomised clinical study was performed from January 2008 to May 2011. Sixty-eight consecutive patients with severe low back pain and radicular pain were divided randomly into the unilateral (n = 33) or bilateral (n = 35) pedicle screw fixation group based on a random number list. Operative time, blood loss, duration of hospital stay, fusion rate, complication rate and implant costs were recorded and analysed statistically. Visual analog scale (VAS) scores, Oswestry Disability Index (ODI), and SF-36 were used to assess the preoperative and postoperative clinical results in the two groups. RESULTS: No differences were observed between the two groups with respect to demographic data. The patients of the two groups had significant improvement in functional outcome compared to preoperatively. There was no significant difference comparing fusion rate, complication rate and duration of hospital stay between the two groups at postoperative follow-up (P > 0.05). However, compared with the bilateral pedicle screw group, a significant decrease occurred in operative time, blood loss and implant costs in the unilateral group. CONCLUSION: Two-level unilateral instrumented TLIF is an effective and safe method with reduced operative time and blood loss for multiple-level lumbar diseases. But it is imperative that the larger cage should be appropriately positioned to support the contralateral part of the anterior column by crossing the midline of the vertebral body. PMID- 23917854 TI - Comparison of the short-term and long-term results of the Ponseti method in the treatment of idiopathic pes equinovarus. AB - PURPOSE: Congenital club foot is one of the most common birth defects involving the musculoskeletal system. At present two methods are used for the treatment of this deformity: French and Ponseti method. The purpose of this study was to compare the short-term (up to three years) and long-term (three to seven years) results of treatment with the Ponseti method. METHODS: A total of 195 consecutive infants (143 boys and 52 girls) with idiopathic club foot treated with the Ponseti method in the period of 2005-2012 were included in this study; the total number of feet was 303. The severity of the foot deformity was classified according to Dimeglio. When relapse occurred up until three years of age, we started with the casting again. If conservative treatment was unsuccessful we proceeded to surgical treatment. RESULTS: Primary correction was attained in all cases. Surgical correction of relapses was performed in 30 % of patients according to the Ponseti method (re-tenotomy of the Achilles tendon and transposition of the tibialis anterior) and in 70 % by alternative techniques. The number of relapses indicated for surgery increased with increasing period of follow-up: whereas in patients where the treatment started already in 2005 relapses occurred in 72 %, in patients included in 2011 the number of recurrences only reached 3 %. CONCLUSIONS: It follows from our results that it is impossible to cure all club feet with casting, tenotomy of the Achilles tendon and transposition of the tibialis anterior only. PMID- 23917855 TI - Prosthetic infection: improvement of diagnostic procedures using 16S ribosomal deoxyribonucleic acid polymerase chain reaction. AB - PURPOSE: Prosthetic infection is the worst complication in joint arthroplasty. The diagnostic procedure is time consuming and in many cases unrewarding. The aim of this investigation was to raise the sensitivity of the diagnostic procedure. METHODS: Altogether, 229 implants were removed from 229 patients. Complete data from 157 patients could be analysed. On explantation of the respective arthroplasty, tissue was removed, puncture fluid aspirated and biofilm scratched from the implant surface with a surgical knife. Specimens were investigated with conventional culture methods and with 16S ribosomal DNA (rDNA) polymerase chain reaction (PCR) and sequencing. RESULTS: In 123 cases, no pathogen could be identified by routine culture methods. In three of these culture-negative cases, bacteria could be identified with 16S rDNA sequencing of the removed biofilm. In 34 cases, bacteria could be identified with culture methods. In two of these cases, sequencing detected additional pathogens. CONCLUSIONS: The process of 16S ribosomal deoxyribonucleic acid polymerase chain reaction (rDNA PCR) and sequencing of biofilm removed from the explanted prosthesis is an important addition to conventional culture methods in prosthetic joint infection. Polymerase chain reaction detects additional pathogens and improves diagnostic sensitivity. The examination of tissue, puncture fluid and biofilm should be performed in cases of prosthesis loosening and explantation. PMID- 23917856 TI - Changes in and shortcomings of drug stockpiling, vaccine development and related policies during outbreaks of avian influenza A H5N1, H1N1, and H7N9 among humans. AB - The purpose of this paper is to provide a reference for the future stockpiling of drugs and developing vaccines for treatment of emerging infectious diseases by summarizing the status of drug stockpiling, vaccine development, and related policies during three major outbreaks of avian influenza among humans (H5N1 in 2003, H1N1 in 2009, and H7N9 in 2013). Documents regarding drug stockpiling and vaccine development during three influenza outbreaks have been reviewed. Results indicated that the response to pandemic influenza outbreaks has improved markedly in terms of stockpiles of antivirals and vaccine development. These improvements also suggest advances in related policy planning. These trends also foreshadow better prospects for prevention and control of emerging infectious diseases. However, the rationality of drug stockpiling and international cooperation still needs to be enhanced. PMID- 23917857 TI - A new phenoxazine derivative isolated from marine sediment actinomycetes, Nocardiopsis sp. 236. AB - During screening of marine actinomycetes for anti-mycobacterial activity, a new phenoxazine derivative (1) was isolated, along with 6-phenazinediol (2), 6 methoxy-1-phenazinol (3), nocardamin (4), and 3-pyridinecarboxylic acid (5), from a culture of Nocardiopsis sp. 236 collected from the west Pacific. The chemical structure of 1 was established on the basis of 1D-, 2D-NMR, and HRQ-TOF MS data. All compounds were evaluated for their anti-mycobacterial activity in vitro, and only compounds 2 and 3 exhibited weak activity. PMID- 23917858 TI - Effects of Gosha-jinki-gan (Chinese herbal medicine: Niu-Che-Sen-Qi-Wan) on hyperinsulinemia and hypertriglyceridemia in prediabetic Zucker fatty rats. AB - The Chinese herbal medicine, Goshajinki-gan (GJ) (Niu-Che-Sen-Qi-Wan), has been widely used for treating patients with melalgia, lower back pain, numbness, and diabetic neuropathy. We investigated the effects of GJ on the regulation of serum insulin and triglyceride levels in obese Zucker fatty rats (fa/fa; ZFR). We administrated GJ to 6-week-old ZFR and non-obese lean rats (LR) for 12 weeks. Body weight and serum glucose, insulin, total cholesterol, and triglyceride levels were significantly increased at 18 weeks in ZFR as compared to the LR. GJ treatment in ZFR significantly suppressed elevation in serum glucose, insulin, and triglyceride levels, but no significant differences were observed in body weight and serum cholesterol levels in the ZFR group with GJ treatment compared to the ZFR group without GJ treatment. These results suggest that GJ may improve hyperinsulinemia and hypertriglyceridemia in ZFR and that GJ may be useful for preventing or delaying the onset of diabetes mellitus in a pre-diabetic state. PMID- 23917859 TI - Chemopreventive effects of combination of honokiol and magnolol with alpha santalol on skin cancer developments. AB - alpha-Santalol is active component of sandalwood oil and has been shown to have chemopreventive effects against chemically and UVB-induced skin cancer development in mice. alpha-Santalol is also shown to have skin permeation enhancing effects. Honokiol and magnolol isolated from Magnolia officinalis bark extract have also been shown to have chemopreventive effects against chemically and UVB-induced skin cancer in mice. This study was conducted to investigate the combination effects of alpha-santalol, honokiol and magnolol to study any additive/synergistic effects to lower the doses required for chemoprevention. Pretreatment of combinations of alpha-santalol with honokiol and magnolol significantly decreased tumor multiplicity upto 75% than control, alpha-santalol, honokiol and magnolol alone in SKH-1 mice. Combination of alpha-santalol with honokiol and magnolol also decreased cell viability, proliferation, and enhanced apotosis in comparison to alpha-santalol, honokiol and magnolol alone in Human epidrmoid carcinoma A431 cells. Overall, the results of present study indicated combinations of alpha-santalol with honokiol and magnolol could provide chemoprevention of skin cancer at lower doses than given alone. PMID- 23917860 TI - Evaluation of in vitro mutagenicity and genotoxicity of magnetite nanoparticles. AB - For successful application of nanomaterials in bioscience, it is essential to understand the biological fate and potential toxicity of nanoparticles. The aim of this study is to evaluate the genetic safety of magnetite nanoparticles (MNPs) (Fe(3)O(4)) in order to provide their diverse applications in life sciences, such as drug development, protein detection, and gene delivery. Concentrations of 10 ppm, 30 ppm, and 70 ppm (10-70 MUg/mL) of the MNPs of 8.0 +/- 2.0 nm were used. Characterization of MNPs was done with transmission electron microscopy (TEM), X Ray Diffractometry (XRD) and a vibrating sample magnetometer (VSM). The MNPs mutagenic potential was evaluated using the Salmonella Ames test with Salmonella strains TA100, TA2638, TA102, and TA98 in the presence and the absence of metabolic activation with S9-liver extract. Genetic mutations at the chromosomal level and extent of DNA damage using the alkaline Comet assay were applied to peripheral blood lymphocytes and HEK-293 cell lines respectively. There were significant changes in the results of the Salmonella mutagenicity test at the 70 ppm concentration of MNPs which might reflect their mutagenic activity at higher concentrations. Cytogenetic evaluation revealed the absence of genetic mutations at the chromosomal level. The extent of DNA damage quantified by Comet assay and the mutagenicity study using Ames test were significantly correlated for the MNPs. Our results indicated that magnetite nanoparticles with the defined physicochemical properties caused apparent toxicity at higher concentrations of 30 ppm and 70 ppm without chromosomal abnormalities under the experimental conditions of this study. PMID- 23917861 TI - The first inhibitor-based fluorescent imaging probe for aminopeptidase N. AB - Holtke and his co-workers firstly reported the synthesis and characterization of an inhibitor-based fluorescent imaging probe for aminopeptidase N. This fluorescent probe demonstrated high binding affinity to APN and could specifically bind to APN high expressed cells, thus revealed the distribution of APN. As a milestone, this outstanding work provided a useful tool to understand APN pathophysiology. PMID- 23917862 TI - Rare disease patients in China anticipate the sunlight of legislation. AB - It is estimated that there are over ten million rare disease patients in China currently. Due to a lack of effective drugs and reimbursement regulations for medical expenses the diseases bring most patients enormous physical suffering and psychological despair. Past experience in other countries such as the United States, Japan, and the European Union have shown that legislation is the critical step to improve the miserable situation of rare disease patients. Laws and regulations for rare diseases in these countries prescribe a series of incentives for research and development of orphan drugs which turn out to obviously allow these drugs to flourish. Legislation has also established a drug reimbursement system to reduce the medical burden of the patients. These measures effectively protect the rights and interests of patients with rare diseases. In China, legislation for rare diseases has begun to attract the attention of authorities. It is anticipated that relevant laws and regulations will be established as early as possible to provide safeguards for rare disease patients in China. PMID- 23917863 TI - Design and implementation of disaster recovery and business continuity solution for radiology PACS. AB - In the digital era of radiology, picture archiving and communication system (PACS) has a pivotal role in retrieving and storing the images. Integration of PACS with all the health care information systems e.g., health information system, radiology information system, and electronic medical record has greatly improved access to patient data at anytime and anywhere throughout the entire enterprise. In such an integrated setting, seamless operation depends critically on maintaining data integrity and continuous access for all. Any failure in hardware or software could interrupt the workflow or data and consequently, would risk serious impact to patient care. Thus, any large-scale PACS now have an indispensable requirement to include deployment of a disaster recovery plan to ensure secure sources of data. This paper presents our experience with designing and implementing a disaster recovery and business continuity plan. The selected architecture with two servers in each site (local and disaster recovery (DR) site) provides four different scenarios to continue running and maintain end user service. The implemented DR at University Hospitals Health System now permits continuous access to the PACS application and its contained images for radiologists, other clinicians, and patients alike. PMID- 23917864 TI - An optimization based on simulation approach to the patient admission scheduling problem: diagnostic imaging department case study. AB - The growing influx of patients in healthcare providers is the result of an aging population and emerging self-consciousness about health. In order to guarantee the welfare of all the healthcare stakeholders, it is mandatory to implement methodologies that optimize the healthcare providers' efficiency while increasing patient throughput and reducing patient's total waiting time. This paper presents a case study of a conventional radiology workflow analysis in a Portuguese healthcare provider. Modeling tools were applied to define the existing workflow. Re-engineered workflows were analyzed using the developed simulation tool. The integration of modeling and simulation tools allowed the identification of system bottlenecks. The new workflow of an imaging department entails a reduction of 41 % of the total completion time. PMID- 23917865 TI - Ptychography--a label free, high-contrast imaging technique for live cells using quantitative phase information. AB - Cell imaging often relies on synthetic or genetic fluorescent labels, to provide contrast which can be far from ideal for imaging cells in their in vivo state. We report on the biological application of a, label-free, high contrast microscopy technique known as ptychography, in which the image producing step is transferred from the microscope lens to a high-speed phase retrieval algorithm. We demonstrate that this technology is appropriate for label-free imaging of adherent cells and is particularly suitable for reporting cellular changes such as mitosis, apoptosis and cell differentiation. The high contrast, artefact-free, focus-free information rich images allow dividing cells to be distinguished from non-dividing cells by a greater than two-fold increase in cell contrast, and we demonstrate this technique is suitable for downstream automated cell segmentation and analysis. PMID- 23917874 TI - Performance of Biopsy Needle With Therapeutic Injection System to Prevent Bleeding Complications. AB - Renal disease is epidemic in the United States with approximately 8 * 106 people having chronic kidney disease. Renal biopsies are widely used to provide essential diagnostic information to physicians. However, the risk of bleeding complications possibly leading to life-threatening situations results in the contra-indication of biopsy in certain patient populations. Safer renal biopsies will allow more accurate diagnosis and better management of this epidemic health problem. We report the preclinical testing of a novel biopsy device called the therapeutic injection system (TIS). The device introduces a third stage to the standard two-stage side-cut percutaneous biopsy process. The third stage is designed to reduce bleeding complications by injecting a hemostatic plug at the time of biopsy. Laboratory evaluation and preliminary in vivo animal testing using an anticoagulated porcine model of the TIS and Bard Monopty(r) (Bard Medical, Covington, GA) control device were performed. The hemostatic material Gelfoam(r) (Pfizer, Brussels, Belgium) was selected as the active material comprising the hemostatic plugs. The performance of two composite plugs, one composed of polyvinyl alcohol (PVA) combined in 2:1 and 12:1 ratios with the hemostatic material, and one plug composed of 100[Formula: see text] hemostatic material were tested. Stroke sequence and hemostatic plug deployment were verified by sequential firing of the TIS biopsy needle into clear gelatin and ex vivo bovine kidney specimens. In vivo trials with porcine specimens revealed a significant reduction in blood loss (8.1 [Formula: see text] 3.9 ml, control versus 1.9 [Formula: see text] 1.6 ml, 12:1 PVA/hemostatic, TIS, [Formula: see text] = 0.01, [Formula: see text] = 6). The 100[Formula: see text] hemostatic plug showed a substantial and immediate reduction in blood loss (9.2 ml, control versus 0.0 ml, TIS, [Formula: see text] = 1). The prototype device was shown to work repeatedly and reliably in laboratory trials. Initial results show promise in this approach to control post biopsy bleeding. This solution maintains the simplicity and directness of the percutaneous approach, while not significantly changing the standard percutaneous biopsy procedure. PMID- 23917876 TI - Localization of CGRP receptor components, CGRP, and receptor binding sites in human and rhesus cerebellar cortex. AB - The cerebellum is classically considered to be mainly involved in motor processing, but studies have suggested several other functions, including pain processing. Calcitonin-gene-related peptide (CGRP) is a neuropeptide involved in migraine pathology, where there is elevated release of CGRP during migraine attacks and CGRP receptor antagonists have antimigraine efficacy. In the present study, we examined CGRP and CGRP receptor binding sites and protein expression in primate cerebellar cortex. Additionally, mRNA expression of the CGRP receptor components, calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1), was examined. In addition, expression of procalcitonin was studied. We observed high [(3)H]MK-3207 (CGRP receptor antagonist) binding densities in the molecular layer of rhesus cerebellar cortex; however, due to the limit of resolution of the autoradiographic image the exact cellular localization could not be determined. Similarly, [(125)I]CGRP binding was observed in the molecular layer and Purkinje cell layer of human cerebellum. CLR and RAMP1 mRNA was expressed within the Purkinje cell layer and some expression was found in the molecular layer. Immunofluorescence revealed expression of CGRP, CLR, and RAMP1 in the Purkinje cells and in cells in the molecular layer. Procalcitonin was found in the same localization. Recent research in the biology of cerebellum indicates that it may have a role in nociception. For the first time we have identified CGRP and CGRP receptor binding sites together with CGRP receptor expression through protein and mRNA localization in primate cerebellar cortex. These results point toward a functional role of CGRP in cerebellum. Further efforts are needed to evaluate this. PMID- 23917877 TI - Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century. AB - Cancer is a heterogeneous disease manifest in many forms. Tumor histopathology can differ significantly among patients and cellular heterogeneity within tumors is common. A primary goal of cancer biologists is to better understand tumorigenesis and cancer progression; however, the complex nature of tumors has posed a substantial challenge to unlocking cancer's secrets. The cancer stem cell (CSC) paradigm for the pathobiology of solid tumors appropriately acknowledges phenotypic and functional tumor cell heterogeneity observed in solid tumors and accounts for the disconnect between drug approval based on response and the general inability of approved therapies to meaningfully impact survival due to their failure to eradicate these most important of cellular targets. First proposed to exist decades ago, CSC have only recently begun to be precisely identified due to technical advancements that facilitate identification, isolation, and interrogation of distinct tumor cell subpopulations with differing ability to form and perpetuate tumors. Precise identification of CSC populations and the complete hierarchy of cells within solid tumors will facilitate more accurate characterization of patient subtypes and ultimately contribute to more personalized and effective therapies. Rapid advancement in the understanding of tumor biology as it exists in patients requires cooperation among institutions, surgeons, pathologists, cancer biologists and patients alike, primarily because this translational research is best done with patient-derived tissue grown in the xenograft setting as patient-derived xenografts. This review calls for a broader change in the approaches taken to study cancer pathobiology, highlights what implications the CSC paradigm has for pathologists and cancer biologists alike, and calls for greater collaboration between institutions, physicians and scientists in order to more rapidly advance our collective understanding of cancer. PMID- 23917878 TI - Linking metabolism and epigenetic regulation in development of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most common form of cancer globally and is rarely curable once detected. The 5-year survival rate of patients diagnosed with late-stage HCC may be as low as 27%. HCC is a cancer largely driven by epigenetic changes that arise from exposure to exogenous environmental factors rather than coding sequence mutations. The liver is susceptible to effects from Hepatitis C and Hepatitis B viruses, exposure to aflatoxin and continuous excessive consumption of alcohol. The liver is a highly metabolic organ balancing many vital biochemical processes; exposure to any of the above environmental factors is associated with loss of liver function and is a major risk factor for the development of HCC. Emerging studies aim to examine the underlying metabolic processes that are abrogated in cancer and lead to the altered flux and availability of key metabolites important for epigenetic processes. Metabolites have been shown to act as substrates for many canonical epigenetic regulators. These enzymes are responsible for regulating histone modification, DNA methylation and micro RNA expression. By studying the impact of altered liver metabolism, we may better understand the long-term epigenetic processes, which lead to the development and progression of HCC. PMID- 23917879 TI - Urinary tract obstruction in the mouse: the kinetics of distal nephron injury. AB - Congenital urinary tract obstruction is the single most important cause of childhood chronic kidney disease. We have previously demonstrated that human and primate fetal obstruction impairs the development, differentiation, and maturation of the kidney. Research using postnatal rodent models has primarily focused upon the role of proximal tubular injury, with few reports of collecting duct system pathology or the suitability of the postnatal models for examining injury to the distal nephron. We have employed the mouse unilateral ureteric obstruction (UUO) model and examined time points ranging from 1 to 14 days of obstruction. Many of the key features of fetal collecting duct injury are replicated in the postnatal mouse model of obstruction. Obstruction causes a sixfold increase in myofibroblast accumulation, two- to threefold dilatation of tubules of the distal nephron, 65% reduction of principal cell aquaporin 2 expression, 75% reduction of collecting duct intercalated cell abundance, and disruption of E-cadherin- and betacatenin-mediated collecting duct epithelial adhesion. Notably, these features are shared by the distal and connecting tubules. This work confirms that distal nephron pathology is a significant component of postnatal mouse UUO. We have highlighted the utility of this model for investigating collecting duct and distal tubule injury and for identifying the underlying mechanisms of the distal nephron's contribution to the repair and fibrosis. PMID- 23917880 TI - Cutaneous manifestations of endemic mycoses. AB - All of the endemic mycoses have cutaneous and mucocutaneous manifestations that are most commonly seen when patients have disseminated infection. Biopsy of skin lesions is simple and safe and can assist in making a timely diagnosis of disseminated infection. Primary cutaneous inoculation infection has been reported with all of the endemic mycoses, but is rare. In this situation, a nodule or ulcer occurs at the inoculation site, is often accompanied by lymphangitis and regional lymphadenopathy, and systemic symptoms and signs as almost always absent. Mucosal lesions are common with disseminated histoplasmosis, but also have been described in patients who have disseminated blastomycosis and coccidioidomycosis. Biopsy is essential to rule out cancer and allows a rapid diagnosis of the endemic fungal infection. PMID- 23917881 TI - Transition pathway and its free-energy profile: a protocol for protein folding simulations. AB - We propose a protocol that provides a systematic definition of reaction coordinate and related free-energy profile as the function of temperature for the protein-folding simulation. First, using action-derived molecular dynamics (ADMD), we investigate the dynamic folding pathway model of a protein between a fixed extended conformation and a compact conformation. We choose the pathway model to be the reaction coordinate, and the folding and unfolding processes are characterized by the ADMD step index, in contrast to the common a priori reaction coordinate as used in conventional studies. Second, we calculate free-energy profile as the function of temperature, by employing the replica-exchange molecular dynamics (REMD) method. The current method provides efficient exploration of conformational space and proper characterization of protein folding/unfolding dynamics from/to an arbitrary extended conformation. We demonstrate that combination of the two simulation methods, ADMD and REMD, provides understanding on molecular conformational changes in proteins. The protocol is tested on a small protein, penta-peptide of met-enkephalin. For the neuropeptide met-enkephalin system, folded, extended, and intermediate sates are well-defined through the free-energy profile over the reaction coordinate. Results are consistent with those in the literature. PMID- 23917882 TI - Acetylcholinesterase reactivators (HI-6, obidoxime, trimedoxime, K027, K075, K127, K203, K282): structural evaluation of human serum albumin binding and absorption kinetics. AB - Acetylcholinesterase (AChE) reactivators (oximes) are compounds predominantly targeting the active site of the enzyme. Toxic effects of organophosphates nerve agents (OPNAs) are primarily related to their covalent binding to AChE and butyrylcholinesterase (BChE), critical detoxification enzymes in the blood and in the central nervous system (CNS). After exposure to OPNAs, accumulation of acetylcholine (ACh) overstimulates receptors and blocks neuromuscular junction transmission resulting in CNS toxicity. Current efforts at treatments for OPNA exposure are focused on non-quaternary reactivators, monoisonitrosoacetone oximes (MINA), and diacylmonoxime reactivators (DAM). However, so far only quaternary oximes have been approved for use in cases of OPNA intoxication. Five acetylcholinesterase reactivator candidates (K027, K075, K127, K203, K282) are presented here, together with pharmacokinetic data (plasma concentration, human serum albumin binding potency). Pharmacokinetic curves based on intramuscular application of the tested compounds are given, with binding information and an evaluation of structural relationships. Human Serum Albumin (HSA) binding studies have not yet been performed on any acetylcholinesterase reactivators, and correlations between structure, concentration curves and binding are vital for further development. HSA bindings of the tested compounds were 1% (HI-6), 7% (obidoxime), 6% (trimedoxime), and 5%, 10%, 4%, 15%, and 12% for K027, K075, K127, K203, and K282, respectively. PMID- 23917883 TI - Adverse events during treatment of drug-resistant tuberculosis: a comparison between patients with or without human immunodeficiency virus co-infection. AB - INTRODUCTION: In settings such as Namibia with a high prevalence of human immunodeficiency virus (HIV) and drug-resistant (DR) tuberculosis (TB) co infection, interactions and adverse events associated with second-line anti-TB and antiretroviral medicines pose a unique challenge in the treatment of both infections. OBJECTIVE: The main objective of this study was to compare the absolute risks and risk factors for commonly observed adverse events (occurring in >20 % of patients) during DR-TB treatment in HIV-infected and HIV-uninfected patients. METHODS: This was a retrospective cohort analysis of patients treated for DR-TB between January 2008 and February 2010 at the Kondja DR-TB ward in Walvis Bay, Namibia. Data were anonymously collected from patients' treatment records, using a structured form. The data were then analyzed using descriptive statistics, while 2 * 2 contingency tables stratified by HIV status were employed to examine specific risk factor and adverse event relationships, using Epi Info 3.4.3 statistical software. Eighteen adverse events were studied but, because of the small sample size of patients, only the four most frequent ones (occurring in >20 % of patients) were included in the risk factor analysis. The risk factors were a treatment period of <4 weeks; treatment with any highly active antiretroviral therapy (HAART) regimen; specific treatment with a zidovudine (AZT)-based HAART regimen, a cycloserine-based DR-TB regimen or an amikacin-based DR-TB regimen; female gender; baseline body weight <= 45 kg; and age 30 >= years. RESULTS: Of the 57 DR-TB patients who were included in the analysis, 31 (53 %) were co-infected with HIV. When stratified by HIV status, DR-TB patients had similar exposure to specific DR-TB medicines and comparable demographic and clinical characteristics, except for age, as HIV-infected patients were on average 6.5 years older than HIV-uninfected patients (P = 0.007). Of the 18 studied adverse events, tinnitus (40 %), joint pain (26 %), hearing loss (23 %) and nausea (21 %) were the four most commonly observed events. Only for abdominal pain was there a statistically significant difference in the risk of occurrence between HIV-infected patients and HIV-uninfected patients (26 versus 4 %, P = 0.02). The risk ratios (RRs) for the association between treatment with a cycloserine-based DR-TB regimen and occurrence of joint pain did not differ much between HIV-infected and HIV-uninfected patients (RR 4.3 in HIV-infected patients, P = 0.03; RR 5 in HIV-uninfected patients, P = 0.08). Similarly, although some differences in the RRs were observed between the two HIV status groups, the differences were not statistically significant for tinnitus, hearing loss or nausea. In some instances, HIV status appeared to modify the effect of the association of some of the risk factors and adverse event occurrence, but the wide and overlapping confidence intervals were inconclusive. CONCLUSION: Generally, the absolute risks and risk factors for adverse events were similar between HIV-infected and HIV-uninfected patients treated for DR-TB in our Namibian cohort of 57 patients. Although our findings of comparable adverse event risks between DR-TB and DR-TB/HIV co-infected patients are encouraging, they are inconclusive because of the low statistical power of our study. We recommend a prospective study with a larger sample size that would increase the power and therefore the confidence in the results. PMID- 23917884 TI - The oxidative toxicity of Ag and ZnO nanoparticles towards the aquatic plant Spirodela punctuta and the role of testing media parameters. AB - The toxicity effects of silver (nAg) and zinc oxide (nZnO) engineered nanoparticles (ENPs) on the duckweed Spirodela punctuta were studied to investigate the potential risks posed by these ENPs towards higher aquatic plants. The influence of media abiotic factors on the stability of the ENPs was also evaluated. Marked agglomeration of ENPs was observed after introduction into testing media whereby large particles settled out of suspension and accumulated at the bottom of testing vessels. The high ionic strength (IS) promoted agglomeration of ENPs because it reduced the inter-particle repulsion caused by a reduction in their surface charge. Low dissolution was observed for nAg, reaching only 0.015% at 1000 mg L(-1), whilst improved dissolution was observed for nZnO, only falling below analytical quantification at 0.1 mg L(-1) and lower. The quantification of free radicals namely, reactive oxygen and nitrogen species (ROS/RNS) and hydrogen peroxide (H2O2), indicated the induction of oxidative stress in plants exposed to the ENPs. A definite dose influence was observed for ROS/RNS volumes in plants exposed to nZnO for 14 days, a response not always observed. The total antioxidant capacity (TAC) and superoxide dismutase (SOD) activity in plants indicated varying degrees of oxidative toxicity caused by exposure to ENPs. This toxicity was driven mainly by particulates in plants exposed to nAg, whilst dissolved Zn(2+) was the main driver for toxicity in plants exposed to nZnO. Our findings suggest that the toxicity of nAg and nZnO could be caused by both the particulates and ionic forms, as modified by media properties. PMID- 23917891 TI - Structurally coloured secondary particles composed of black and white colloidal particles. AB - This study investigated the colourful secondary particles formed by controlling the aggregation states of colloidal silica particles and the enhancement of the structural colouration of the secondary particles caused by adding black particles. We obtained glossy, partially structurally coloured secondary particles in the absence of NaCl, but matte, whitish secondary particles were obtained in the presence of NaCl. When a small amount of carbon black was incorporated into both types of secondary particles, the incoherent multiple scattering of light from the amorphous region was considerably reduced. However, the peak intensities in the reflection spectra, caused by Bragg reflection and by coherent single wavelength scattering, were only slightly decreased. Consequently, a brighter structural colour of these secondary particles was observed with the naked eye. Furthermore, when magnetite was added as a black particle, the coloured secondary particles could be moved and collected by applying an external magnetic field. PMID- 23917892 TI - [Dexmedetomidine]. AB - Dexmedetomidine is a highly selective alpha2-receptor agonist with sedative, analgetic and anxiolytic effects. It is chemically related to clonidine and has been an authorized drug in Europe since September 2011. Dexmedetomidine enables a level of sedation in which mechanically ventilated patients may be woken by verbal stimulation (Richmond agitation sedation scale RASS 0--3). In this respect dexmedetomidine achieves the same desired effect as propofol and midazolam; however, in direct comparison to a sedation regime with benzodiazepines, dexmedetomidine reduces the prevalence, duration and severity of delirium in intensive care. Patients sedated by dexmedetomidine can statistically be extubated earlier and an influence on duration of stay in the intensive care unit (ICU) has not been shown. Daily therapy costs are approximately 5 times higher than those of propofol but an objective standpoint in relation to clinical cost efficiency is unattainable. PMID- 23917893 TI - [Validity of admission diagnoses as process-driving criteria : influence on length of stay and consultation rate in emergency departments]. AB - BACKGROUND: Primary care physicians and specialists often refer patients to the emergency department with a specific diagnosis and request for admission. Such an external diagnosis frequently influences the initial evaluation in the emergency department. The present study aimed to evaluate the accuracy of such external diagnoses and to assess the consequences of incorrect diagnoses on length of stay and number of specialty consultations in the emergency department. MATERIAL AND METHODS: This was a prospective observational study over the course of 3 months in the emergency department of a tertiary care center. External admission diagnoses made by primary care physicians and specialists were categorized as "accurate", "partially accurate" and "inaccurate". A special analysis of the external admission diagnosed was performed for patients admitted directly to an intermediary care unit and intensive care unit or patients who were transferred directly from the emergency department to the operating room. RESULTS: Data for 784 patients were analyzed. Patients were on average 63.1 +/- 19.5 years old (minimum-maximum 18-97 years, median 68 years) and 54 % were male. After emergency department evaluation and treatment 57.8 % of external diagnoses were categorized as accurate, 23.6 % as partially accurate and 18.6 % as inaccurate. Patients with partially accurate and inaccurate diagnoses had a 3 and 6.5 times higher rate of specialty consultations in the emergency department, respectively, when compared with patients with an accurate diagnosis (number of specialty consultations n = 0: 77.3 % vs. 54.1 % vs. 92.9 %, p < 0.05; n = 1: 20.0 % vs. 40.4 % vs. 6.2 %, p < 0.05; n = 2: 2.7 % vs. 5.5 % vs. 0.9 %, p < 0.05, respectively. Patients with an accurate diagnosis had a shorter total length of stay than patients with a partially accurate or inaccurate diagnosis [mean +/- SD (min-max; median): 192 +/- 108 min (10-707 min; 181 min) vs. 246 +/- 126 min (27 1,026 min; 214 min) vs. 258 +/- 138 min (22-700 min; 232 min), p < 0.001], respectively. Out of 85 patients admitted directly to an intermediary care unit, intensive care unit and patients who were transferred directly from the emergency department to the operating room the diagnosis was accurate, partially accurate and inaccurate in 56.5 %, 24.7 % and 18.8 %, respectively. CONCLUSIONS: Admission diagnoses made by primary care physicians and specialists who subsequently refer patients to the emergency department are subject to certain inaccuracies. Inaccurate admission diagnoses are associated with an increased length of stay and a considerably higher rate of specialty consultation in the emergency department. Standardized operating procedures, treatment algorithms and triage systems are important to identify such incorrect diagnoses so that these patients can undergo appropriate diagnostic investigation and treatment. PMID- 23917895 TI - [Acute respiratory distress syndrome and septic cardiomyopathy : successful application of veno-venoarterial extracorporeal membrane oxygenation]. AB - A 30-year-old patient was admitted to hospital with fever and respiratory insufficiency due to community acquired pneumonia. Within a few days the patient developed septic cardiomyopathy and severe acute respiratory distress syndrome (ARDS) which deteriorated under conventional mechanical ventilation. Peripheral venoarterial extracorporeal membrane oxygenation (va-ECMO) was initiated by the retrieval team of an ARDS/ECMO centre at a paO2/FIO2 ratio of 73 mmHg and a left ventricular ejection fraction (EF) of 10 %. After 12 h va-ECMO was converted to veno-venoarterial ECMO (vva-ECMO) for improvement of pulmonary and systemic oxygenation. Left ventricular function improved (EF 45 %) 36 h after starting ECMO and the patient was weaned from vva-ECMO and converted to vv-ECMO. The patient was weaned successfully from vv-ECMO after 5 additional days and transferred back to the referring hospital for weaning from the ventilator. PMID- 23917896 TI - [Point-of-care-based hemotherapy]. PMID- 23917894 TI - Report on a study of fires with smoke gas development : determination of blood cyanide levels, clinical signs and laboratory values in victims. AB - BACKGROUND: This is a report on an international non-interventional study of patients exposed to fires with smoke development in closed rooms. The objective of the study was to document clinical symptoms, relevant laboratory values and blood cyanide concentrations from fire victims in order to confirm or rule out presumptive correlations between the individual parameters. MATERIALS AND METHODS: The study was conducted in five European countries with patients being included if they presented with the characteristic clinical signs, such as soot deposits and altered neurological status. Venous blood samples were taken from victims prior to administration of an antidote in all cases and determination of cyanide concentration was performed in a central laboratory using high performance liquid chromatography. RESULTS: Data from 102 patients (62 % male, average age 49 years) were included in the evaluation with no blood samples being available for analysis from 2 patients. In 25 patients the blood cyanide concentration was below the limit of detection of 1.2 MUmol/l. Cyanide levels between 1.2 and 10 MUmol/l were measured in 54 patients, 7 patients had values between 10 and 20 MUmol/l, 4 patients between 20 and 40 MUmol/l while levels above 40 MUmol/l were determined in 10 patients. The results of the study could not demonstrate that the cyanide level was influenced either by the interval between smoke exposure and blood sampling or the duration presence at the fire scene. The following clinical signs or laboratory values were recorded as relevant for increased and possibly toxic cyanide levels: respiratory arrest, dyspnea, resuscitation requirement, tracheal intubation, respiratory support measures, low Glasgow coma scale (GCS) score and respiratory frequency. A correlation between cyanide concentration and the total amount of soot deposits on the face and neck, in the oral cavity and in expectoration was confirmed. A correlation between cyanide and carboxyhemoglobin (COHb) levels in the blood of fire victims was also confirmed. CONCLUSIONS: As long as it is not possible to immediately determine the blood cyanide concentration in patients exposed to fire with smoke development, a decreased GCS score, soot deposits particularly in expectoration, dyspnea and convulsions are to be regarded as risk markers for intoxication. In their presence immediate administration of hydroxocobalamin as an antidote is recommended. PMID- 23917897 TI - Uncontrolled bleeding in patients with major abdominal trauma. AB - Haemodynamically unstability after severe abdominal injuries requires a new therapeutic strategy. European guidelines recommend: reduced time, non-invasive investigations, avoid massive volemic replacement before surgery. The primary aim of Damage Control Resuscitation protocol is to prevent the lethal triad: hypothermia, acidosis and coagulopathy. The treatment includes contemporary: permissive hypotension, haemostatic resuscitation, and Damage Control Surgery (DCS). Systolic pressure below the physiological limits maximize the benefits of resuscitation and haemostasis, decreasing vessel clots expulsion. Haemostatic resuscitation uses blood components and substitutes, to allow volemic replacement and to avoid trauma-induced coagulopathy (25% - 30% of complex trauma). The use of PRBCs and plasma 1 to 1 is an independent survival predictor in patients undergoing DCS. Military haemostatic resuscitation protocol suggests massive transfusion using 10 or more PRBCs during 24 or 6 hours if 3 or more triggers are present: pressure > 90, hemoglobin > 11 g, temperature < 35.5 degrees C, INR > 1.5, base deficit = 4,000 g]). Final models were stratified by prepregnancy body mass index (underweight, normal weight, overweight, or obese) and adjusted for maternal age, education, race/ethnicity, smoking status, parity, and marital status. Overall, 62% of the sample had excessive weight gain and 15% had inadequate weight gain. Women with excessive weight gain were more likely to deliver a HBW infant; this relationship was observed for women in all prepregnancy weight categories. Among women with underweight or normal weight prior to pregnancy, those with inadequate weight gain during pregnancy were more likely to deliver a LBW infant. Among the low-income population of Hawaii, women with GWG within the range recommended in the 2009 IOM guidelines had better birthweight outcomes than those with GWG outside the recommended range. Further study is needed to identify optimal GWG goals for women with an obese BMI prior to pregnancy. PMID- 23917899 TI - The SUMO system: a master organizer of nuclear protein assemblies. AB - Cellular signaling pathways largely depend on the plasticity of multiprotein complexes. A central mechanism that assures the coordinated assembly and disassembly of protein complexes is the reversible post-translational modification of the individual components for example by phosphorylation, acetylation, or ubiquitylation. Accumulating evidence indicates that the small ubiquitin-related modifier (SUMO) system is another master organizer of protein complexes. Here, we will focus on the role of SUMO in the regulation of nuclear protein complexes that are involved in chromatin remodeling, double-strand break repair, and ribosome biogenesis. On the basis of these selected pathways, we will summarize current ideas of SUMO signaling, including the concept of group modification and the intersection of the ubiquitin and SUMO pathways. PMID- 23917901 TI - Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. AB - This report updates US Public Health Service recommendations for the management of healthcare personnel (HCP) who experience occupational exposure to blood and/or other body fluids that might contain human immunodeficiency virus (HIV). Although the principles of exposure management remain unchanged, recommended HIV postexposure prophylaxis (PEP) regimens and the duration of HIV follow-up testing for exposed personnel have been updated. This report emphasizes the importance of primary prevention strategies, the prompt reporting and management of occupational exposures, adherence to recommended HIV PEP regimens when indicated for an exposure, expert consultation in management of exposures, follow-up of exposed HCP to improve adherence to PEP, and careful monitoring for adverse events related to treatment, as well as for virologic, immunologic, and serologic signs of infection. To ensure timely postexposure management and administration of HIV PEP, clinicians should consider occupational exposures as urgent medical concerns, and institutions should take steps to ensure that staff are aware of both the importance of and the institutional mechanisms available for reporting and seeking care for such exposures. The following is a summary of recommendations: (1) PEP is recommended when occupational exposures to HIV occur; (2) the HIV status of the exposure source patient should be determined, if possible, to guide need for HIV PEP; (3) PEP medication regimens should be started as soon as possible after occupational exposure to HIV, and they should be continued for a 4-week duration; (4) new recommendation-PEP medication regimens should contain 3 (or more) antiretroviral drugs (listed in Appendix A ) for all occupational exposures to HIV; (5) expert consultation is recommended for any occupational exposures to HIV and at a minimum for situations described in Box 1 ; (6) close follow-up for exposed personnel ( Box 2 ) should be provided that includes counseling, baseline and follow-up HIV testing, and monitoring for drug toxicity; follow-up appointments should begin within 72 hours of an HIV exposure; and (7) new recommendation-if a newer fourth-generation combination HIV p24 antigen-HIV antibody test is utilized for follow-up HIV testing of exposed HCP, HIV testing may be concluded 4 months after exposure ( Box 2 ); if a newer testing platform is not available, follow-up HIV testing is typically concluded 6 months after an HIV exposure. PMID- 23917902 TI - Incidence trends in pathogen-specific central line-associated bloodstream infections in US intensive care units, 1990-2010. AB - OBJECTIVE: To quantify historical trends in rates of central line-associated bloodstream infections (CLABSIs) in US intensive care units (ICUs) caused by major pathogen groups, including Candida spp., Enterococcus spp., specified gram negative rods, and Staphylococcus aureus. DESIGN: Active surveillance in a cohort of participating ICUs through the Centers for Disease Control and Prevention, the National Nosocomial Infections Surveillance system during 1990-2004, and the National Healthcare Safety Network during 2006-2010. Setting. ICUs. Participants. Patients who were admitted to participating ICUs. RESULTS: The CLABSI incidence density rate for S. aureus decreased annually starting in 2002 and remained lower than for other pathogen groups. Since 2006, the annual decrease for S. aureus CLABSIs in nonpediatric ICU types was -18.3% (95% confidence interval [CI], 20.8% to -15.8%), whereas the incidence density rate for S. aureus among pediatric ICUs did not change. The annual decrease for all ICUs combined since 2006 was -17.8% (95% CI, -19.4% to -16.1%) for Enterococcus spp., -16.4% (95% CI, -18.2% to -14.7%) for gram-negative rods, and -13.5% (95% CI, -15.4% to -11.5%) for Candida spp. CONCLUSIONS: Patterns of ICU CLABSI incidence density rates among major pathogen groups have changed considerably during recent decades. CLABSI incidence declined steeply since 2006, except for CLABSI due to S. aureus in pediatric ICUs. There is a need to better understand CLABSIs that still do occur, on the basis of microbiological and patient characteristics. New prevention approaches may be needed in addition to central line insertion and maintenance practices. PMID- 23917903 TI - Electronic documentation of central venous catheter-days: validation is essential. AB - BACKGROUND: Measurement of central line-associated bloodstream infection (CLABSI) rates outside of intensive care units is challenged by the difficulty in reliably determining central venous catheter (CVC) use. The National Healthcare Safety Network (NHSN) allows for use of electronic data for determination of CVC-days, but validation of electronic data has not been studied systematically. OBJECTIVE: To design and validate a process to reliably measure CVC-days outside of the intensive care units that leverages electronic documentation. METHODS: Thirty four inpatient wards at 2 academic hospitals using a common electronic platform for nursing documentation were studied. Electronic queries were created to capture patient and CVC information, and tools and processes for tracking and reporting errors in documentation were developed. Strategies to validate electronic data included comparisons with manual CVC-day determinations and automated data validation using customized tools. Interventions included redesign of documentation interface, real-time audit with feedback of errors, and education. The primary outcome was patient-level total error rate in electronic CVC-day measurement compared with manually counted CVC-days. RESULTS: At baseline, there were a mean (+/- standard deviation) of [Formula: see text] electronic CVC-day errors (omission and commission errors summed and counted equally) per manually counted CVC-day. After several process improvement cycles over 7 months, the error rate decreased to <0.05 errors per CVC-day and remained at or below this level for 2 years. CONCLUSIONS: Baseline electronic CVC-day counts had a high error rate. Stepwise interventions reduced errors to consistently low levels. Validation of electronic calculation of CVC-days is essential to ensure accuracy, particularly if these data will be used for interinstitutional comparison. PMID- 23917904 TI - The risk of bloodstream infection associated with peripherally inserted central catheters compared with central venous catheters in adults: a systematic review and meta-analysis. AB - BACKGROUND: Peripherally inserted central catheters (PICCs) are associated with central line-associated bloodstream infection (CLABSI). The magnitude of this risk relative to central venous catheters (CVCs) is unknown. OBJECTIVE: To compare risk of CLABSI between PICCs and CVCs. METHODS: MEDLINE, CinAHL, Scopus, EmBASE, and Cochrane CENTRAL were searched. Full-text studies comparing the risk of CLABSI between PICCs and CVCs were included. Studies involving adults 18 years of age or older who underwent insertion of a PICC or a CVC and reported CLABSI were included in our analysis. Studies were evaluated using the Downs and Black scale for risk of bias. Random effects meta-analyses were used to generate summary estimates of CLABSI risk in patients with PICCs versus CVCs. RESULTS: Of 1,185 studies identified, 23 studies involving 57,250 patients met eligibility criteria. Twenty of 23 eligible studies reported the total number of CLABSI episodes in patients with PICCs and CVCs. Pooled meta-analyses of these studies revealed that PICCs were associated with a lower risk of CLABSI than were CVCs (relative risk [RR], 0.62; 95% confidence interval [CI], 0.40-0.94). Statistical heterogeneity prompted subgroup analysis, which demonstrated that CLABSI reduction was greatest in outpatients (RR [95% CI], 0.22 [0.18-0.27]) compared with hospitalized patients who received PICCs (RR [95% CI], 0.73 [0.54-0.98]). Thirteen of the included 23 studies reported CLABSI per catheter-day. Within these studies, PICC-related CLABSI occurred as frequently as CLABSI from CVCs (incidence rate ratio [95% CI], 0.91 [0.46-1.79]). LIMITATIONS: Only 1 randomized trial met inclusion criteria. CLABSI definition and infection prevention strategies were variably reported. Few studies reported infections by catheter days. CONCLUSIONS: Although PICCs are associated with a lower risk of CLABSI than CVCs in outpatients, hospitalized patients may be just as likely to experience CLABSI with PICCs as with CVCs. Consideration of risks and benefits before PICC use in inpatient settings is warranted. PMID- 23917905 TI - Automated measures of hand hygiene compliance among healthcare workers using ultrasound: validation and a randomized controlled trial. AB - OBJECTIVE: The primary objective of this study was to validate a novel method of assessing hand hygiene compliance using ultrasound transmitters in patient zones and staff tagged with receivers. The secondary objective was to assess the impact of audio reminders and quantified individual feedback. DESIGN: An observational comparison against manual assessment followed by assessment using an open-label randomized control method. SETTING: Patient zones were established in 3 wards of 2 large teaching hospitals, including 88 general and 18 intensive care unit ward beds. PARTICIPANTS: Consented regular ward nursing, medical, and allied health staff. METHODS: Concordance between 40 hours of manual observation using trained hand hygiene auditors and automated measures of opportunities and compliance. Subsequent measured interventions were reminder beeps and written individual feedback. RESULTS: When compared with manual observations, ultrasound monitoring underestimated percentage compliances by a nonsignificant mean (95% confidence interval [CI]) difference of 5.2% (-20.1% to 9.8%; [Formula: see text]). After the intervention, adjusted multivariate analysis showed mean (95% CI) overall compliance in the intervention arm was 6.8% (2.5%-11.1%; [Formula: see text]) higher than in the control arm. Results stratified by compliance at entry and exit showed that the effect of intervention was stronger for compliance at exit than at entry. CONCLUSIONS: Our automated measure of hand hygiene compliance is valid when compared with the traditional gold standard of manual observations. As an interventional tool, ultrasound-based automated hand hygiene audits have significant benefit that can be built upon with enhancements and find increasing acceptance with time. PMID- 23917906 TI - Overcoming patient barriers to discussing physician hand hygiene: do patients prefer electronic reminders to other methods? AB - BACKGROUND: Despite agreement that handwashing decreases hospital-acquired infections (HAIs), physician hand hygiene remains suboptimal. Interventions to empower patients to discuss handwashing have had variable success. OBJECTIVE: To understand patient perceived barriers to discussing physician hand hygiene and to determine whether patients prefer electronic alerts over printed information as an intervention to discuss physician handwashing. DESIGN: Cross-sectional study of 250 medical/surgical patients at an academic medical center. RESULTS: Ninety six percent of patients had heard of HAIs. Ninety-six percent of patients thought it was important for physicians to clean their hands before touching anything in a patient's room. The majority of patients (78%) believed patients should remind physicians to clean their hands. Thirty-two percent of patients observed physician hand hygiene noncompliance. In multivariate analysis, predictors of not speaking up regarding physician hand hygiene included never having worked in health care (odds ratio [OR], 2.8 [95% confidence interval (CI), 1.5-5.1]), not observing a physician clean hands before touching the patient (OR, 2.4 [95% CI, 1.3-4.4]), and not thinking patients should have to remind physicians to clean hands (OR, 5.5 [95% CI, 2.4-12.7]). Ninety-three percent of patients favored electronic device reminders over printed information as an intervention to encourage patients to discuss hand hygiene with their doctors. CONCLUSIONS: The strongest predictor of not challenging a doctor to clean their hands was not believing it was the patient's role to do so. Patients prefer electronic device reminders to printed information as an aid in overcoming barriers to discussing hand hygiene with physicians. PMID- 23917907 TI - Issues in understanding the impact of the Needlestick Safety and Prevention Act on hospital sharps injuries. AB - OBJECTIVE: Measuring the effect of the Needlestick Safety and Prevention Act (NSPA) is challenging. No agreement exists on a common denominator for calculating injury rates. Does it make a difference? How are the law and safety engineered devices related? What is the effect on injuries and costs? This study examines those issues in assessing the impact of the legislation on hospital worker percutaneous injuries. METHODS: Using a historic prospective design, we analyzed injury data from 85 hospitals. Injury rates were calculated per 100 full time equivalents, 100 staffed beds, and 100 admissions each year from 1995 to 2005. We compared changes for each denominator. We measured the proportion of the injury rate attributed to safety-engineered devices. Finally, we estimated a national change in injuries and associated costs. RESULTS: For all denominators, a precipitous drop in injury rates of greater than one-third ([Formula: see text]) occurred in 2001, immediately following the legislation. The decrease was sustained through 2005. Concomitant with the decrease in rates, the proportion of injuries from safety-engineered devices nearly tripled ([Formula: see text]) across all denominators. We estimated annual reductions of more than 100,000 sharps injuries at a cost savings of $69-$415 million. CONCLUSIONS: While the data cannot demonstrate cause and effect, the evidence suggests a reduction in hospital worker injury rates related to the NSPA, regardless of denominator. It also suggests an association between the increase in safety-engineered devices and the reduction in overall injury rates. The decreases observed translate into significant reductions in injuries and associated costs. PMID- 23917908 TI - Secular trends in gram-negative resistance among urinary tract infection hospitalizations in the United States, 2000-2009. AB - OBJECTIVE: Urinary tract infections (UTIs) are common among hospitalized patients. Selection of an appropriate antibiotic for this infection requires knowledge of both its general microbiology and the epidemiology of drug-resistant organisms. We sought to determine secular trends in UTI hospitalizations that involve gram-negative (GN) multidrug-resistant Pseudomonas aeruginosa (MDR-PA), extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (EC) and Klebsiella pneumoniae (KP), and carbapenem-resistant Enterobacteriaceae (CRE). DESIGN: Survey. PATIENTS: Patients with UTI in US hospitals between 2000 and 2009. METHODS: We first derived the total number of UTI hospitalizations in the United States from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample database years 2000-2009. Based on a literature review, we then determined what proportion of all UTIs arise due to each of the organisms of interest, irrespective of resistance pattern. Finally, we assessed the prevalence of resistance within each pathogen based on the Eurofins Surveillance Network database 2000-2009. Susceptibility patterns served as phenotypic surrogates for resistance. RESULTS: Between 2000 and 2009, the frequency of UTI hospitalizations increased by approximately 50%, from 53 to 77 cases per 1,000 hospitalizations. Infections due to all GN bacteria followed a similar trajectory, whereas those caused by resistant GN pathogens increased by approximately 50% (MDR-PA) to approximately 300% (ESBL). CRE emerged and reached 0.5 cases per 1,000 hospitalizations in this 10-year period. CONCLUSIONS: The epidemiology and microbiology of GN UTI hospitalizations has shifted over the past decade. The proportion of all hospitalizations involving this infection has climbed. Resistant GN bacteria are becoming more prevalent and are implicated in an increasing proportion of UTIs among hospitalized patients. PMID- 23917910 TI - Prevalence and risk factors associated with vancomycin-resistant Staphylococcus aureus precursor organism colonization among patients with chronic lower extremity wounds in Southeastern Michigan. AB - BACKGROUND: Of the 13 US vancomycin-resistant Staphylococcus aureus (VRSA) cases, 8 were identified in southeastern Michigan, primarily in patients with chronic lower-extremity wounds. VRSA infections develop when the vanA gene from vancomycin-resistant enterococcus (VRE) transfers to S. aureus. Inc18-like plasmids in VRE and pSK41-like plasmids in S. aureus appear to be important precursors to this transfer. OBJECTIVE: Identify the prevalence of VRSA precursor organisms. DESIGN: Prospective cohort with embedded case-control study. PARTICIPANTS: Southeastern Michigan adults with chronic lower-extremity wounds. METHODS: Adults presenting to 3 southeastern Michigan medical centers during the period February 15 through March 4, 2011, with chronic lower-extremity wounds had wound, nares, and perirectal swab specimens cultured for S. aureus and VRE, which were tested for pSK41-like and Inc18-like plasmids by polymerase chain reaction. We interviewed participants and reviewed clinical records. Risk factors for pSK41 positive S. aureus were assessed among all study participants (cohort analysis) and among only S. aureus-colonized participants (case-control analysis). RESULTS: Of 179 participants with wound cultures, 26% were colonized with methicillin susceptible S. aureus, 27% were colonized with methicillin-resistant S. aureus, and 4% were colonized with VRE, although only 17% consented to perirectal culture. Six participants (3%) had pSK41-positive S. aureus, and none had Inc18 positive VRE. Having chronic wounds for over 2 years was associated with pSK41 positive S. aureus colonization in both analyses. CONCLUSIONS: Colonization with VRSA precursor organisms was rare. Having long-standing chronic wounds was a risk factor for pSK41-positive S. aureus colonization. Additional investigation into the prevalence of VRSA precursors among a larger cohort of patients is warranted. PMID- 23917909 TI - Predictors and molecular epidemiology of community-onset extended-spectrum beta lactamase-producing Escherichia coli infection in a Midwestern community. AB - OBJECTIVE: To identify predictors of community-onset extended-spectrum beta lactamase (ESBL)-producing Escherichia coli infection. DESIGN: Prospective case control study. SETTING: Acute care hospitals and ambulatory clinics in the Chicago, Illinois, region. PATIENTS: Adults with E. coli clinical isolates cultured in ambulatory settings or within 48 hours of hospital admission. METHODS: Cases were patients with ESBL-producing E. coli clinical isolates cultured in ambulatory settings or within 48 hours of admission, and controls were patients with non-ESBL-producing E. coli isolates, matched to cases by specimen, location, and date. Clinical variables were ascertained through interviews and medical record review. Molecular methods were used to identify ESBL types, sequence type ST131, and aac(6')-Ib-cr. RESULTS: We enrolled 94 cases and 158 controls. Multivariate risk factors for ESBL-producing E. coli infection included travel to India in the past year (odds ratio [OR], 14.40 [95% confidence interval (CI), 2.92-70.95]), ciprofloxacin use (OR, 3.92 [95% CI, 1.90-8.1]), and age (OR, 1.04 [95% CI, 1.02-1.06]). Case isolates exhibited high prevalence of CTX-M-15 (78%), ST131 (50%), and aac(6')-Ib-cr (66% of isolates with CTX-M-15). CONCLUSIONS: Providers should be aware of the increased risk of ESBL-producing E. coli infection among returned travelers, especially those from India. PMID- 23917911 TI - Detection of mixed populations of Clostridium difficile from symptomatic patients using capillary-based polymerase chain reaction ribotyping. AB - OBJECTIVE: To investigate the simultaneous occurrence of more than 1 Clostridium difficile ribotype in patients' stool samples at the time of diagnostic testing. METHODS: Stool samples submitted for diagnostic testing for the presence of toxigenic C. difficile were obtained for 102 unique patients. A total of 95 single colonies of C. difficile per stool sample were isolated on selective media, subcultured alongside negative (uninoculated) controls, and polymerase chain reaction (PCR) ribotyped using capillary gel electrophoresis. RESULTS: Capillary-based PCR ribotyping was successful for 9,335 C. difficile isolates, yielding a median of 93 characterized isolates per stool sample (range, 69-95). More than 1 C. difficile ribotype was present in 16 of 102 (16%) C. difficile infection (CDI) cases; 2 of the 16 mixtures were composed of at least 3 ribotypes, while the remaining 14 were composed of at least 2. CONCLUSIONS: Deep sampling of patient stool samples coupled with capillary-based PCR ribotyping identified a high rate of mixed CDI cases compared with previous estimates. Studies seeking to quantify the clinical significance of particular C. difficile ribotypes should account for mixed cases of disease. PMID- 23917912 TI - Prevalence and predictors of compliance with discontinuation of airborne isolation in patients with suspected pulmonary tuberculosis. AB - OBJECTIVE: Examine the use of airborne isolation by identifying reasons for nontimely discontinuation and predictors of compliance with Centers for Disease Control and Prevention (CDC) guidelines. Compliance with guidelines should result in timely (within 48 hours) discontinuation of isolation in patients without infectious pulmonary tuberculosis (TB). DESIGN: Retrospective, observational study. SETTING: A private, university-affiliated, tertiary-care medical center. PATIENTS: All patients in airborne isolation for suspected pulmonary TB from June through December 2011. METHOD: Chart reviews were performed to identify airborne isolation practices and delayed (greater than 48 hours) or very delayed (greater than 72 hours) discontinuation. We used descriptive statistics and logistic regression to determine independent predictors of nontimely discontinuation of isolation. RESULTS: We identified 113 patients (mean age +/- standard deviation, [Formula: see text] years; male sex, 75.2%; white race, 15.9%; mean collection interval +/- standard deviation, [Formula: see text] hours). Delayed and very delayed isolation discontinuation was noted in 81% and 49% of patients, respectively. No significant differences in demographic characteristics and clinical characteristics were identified between groups. Predictors of timely (within 48 hours) airborne isolation discontinuation included use of alternate diagnosis for discontinuation of isolation ([Formula: see text]), early infectious diseases (ID) consultation ([Formula: see text]), pulmonary consultation ([Formula: see text]), average sputum collection interval less than 24 hours ([Formula: see text]), and need for more than 1 induced sputum specimen ([Formula: see text]). Adjusting for potential confounders, pulmonary consultation (odds ratio [OR] [95% confidence interval (CI)], 0.14 [0.03-0.58]), alternate diagnosis for discontinuation of isolation (OR [95% CI], 4.5 [1.3 15.8]), and early ID consultation (OR [95% CI], 4.0 [1.1-14.8]) were independently associated with timely discontinuation. CONCLUSIONS: Timely airborne isolation discontinuation occurs in only 18.6% of cases and is an opportunity for cost savings, improved efficiency, and potentially patient safety and satisfaction. PMID- 23917913 TI - Modification of antimicrobial prophylaxis based on rectal culture results to prevent fluoroquinolone-resistant Escherichia coli infections after prostate biopsy. AB - For patients undergoing transrectal ultrasound-guided biopsy of the prostate (TRUBP), use of rectal screening culture results to guide antimicrobial prophylaxis was effective for prevention of fluoroquinolone-resistant Escherichia coli infections. In practice, elimination of infections after TRUBP required the rectal screening protocol and addition of gentamicin for patients missing prior screening. PMID- 23917914 TI - Pokes, pathogens, and primum non nocere: prudent prophylaxis protocols for prostate biopsy. PMID- 23917915 TI - Early onset versus late onset peripherally inserted central venous catheter infections: an analysis of risk factors and microbiology. AB - The risks and microbiology for peripherally inserted central catheters (PICCs) are less well described than those for traditional central catheters, particularly as they pertain to duration of catheterization. We compared patients with early- and late-onset PICC bloodstream infections at our institution and found significant differences in microbiologic etiologies. PMID- 23917916 TI - Comparison of total hospital-acquired bloodstream infections to central line associated bloodstream infections and implications for outcome measures in infection control. AB - The validity of the central line-associated bloodstream infection (CLABSI) measure is compromised by subjectivity. We observed significant decreases in both CLABSIs and total hospital-acquired bloodstream infections (BSIs) following a CLABSI prevention intervention in adult intensive care units. Total hospital acquired BSIs could be explored as an adjunct, objective CLABSI measure. PMID- 23917917 TI - Effect of varying the number and location of alcohol-based hand rub dispensers on usage in a general inpatient medical unit. AB - We sequentially increased the number of wall-mounted alcohol-based hand rub dispensers in a small medical unit to evaluate effects on hand hygiene performance. Above a certain point, addition of more dispensers did not increase hand hygiene frequency, which appeared to be influenced more by location than by total number of dispensers. PMID- 23917918 TI - Can matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) enhance antimicrobial stewardship efforts in the acute care setting? AB - We evaluated 222 hospitalized patients whose clinical isolates were tested using standard methods and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF). MALDI-TOF could have reduced time to appropriate therapy for 28.8% and 44.6% patients based on the treating physician's choices and stewardship team recommendations, respectively. Clinicians should be aware of scenarios in which MALDI-TOF can optimize antibiotic therapy. PMID- 23917919 TI - The environment and healthcare-acquired infections: why accurate reporting and evaluation of biological plausibility are important. PMID- 23917920 TI - Reply to Harbarth et al. PMID- 23917921 TI - Impact of the 2013 revised Centers for Disease Control and Prevention central line-associated bloodstream infection (CLABSI) surveillance definition on inpatient hospital CLABSI rates: is it enough? PMID- 23917922 TI - The English North-South divide: risk factors for cardiovascular disease accounting for cross-sectional socio-economic position. AB - AIMS: Given a North-South divide in mortality in England, we aimed to assess the extent of a North-South divide in risk factors for cardiovascular disease (CVD), controlling for markers of socio-economic position (SEP). METHODS: We undertook cross-sectional analyses using respondents from the 2006 Health Survey for England. We assessed mean systolic blood pressure, total cholesterol, body mass index (BMI) and smoking prevalence in the two regions. We built nested regression models adding demographic factors, SEP indicators, behavioural risk factors, vascular disease status and CVD preventive medications stepwise into each model. We examined interactions between region, age and gender. RESULTS: Controlling for demographic variables, we found a northern excess in systolic blood pressure (+1.95mmHg (SE = 0.40)), BMI (0.40kgm(-2) (SE = 0.12)) and smoking prevalence (5.6% (SE = 1.1)). The difference in smoking prevalence was entirely abolished by markers of SEP. Systolic blood pressure and BMI differences were attenuated by SEP, behavioural and disease indicators, but remained (+1.63mmHg (SE = 0.41) and 0.25kgm(-2) (SE = 0.12), respectively). However, they were lost after adjustment for preventive medication. The North-South divide in systolic blood pressure was attributed to differences in men and younger-to-middle-aged groups. Northern respondents were more physically active, especially younger men. CONCLUSIONS: English North-South differences in smoking can be explained through adverse, cross-sectional SEP. Northern excesses in blood pressure and BMI may be associated with differential clinical management. Risk factor differences may, in part, explain a previously found North-South divide in mortality. Further exploration of geographic inequalities, concentrating on the impact of healthcare, may be warranted. PMID- 23917923 TI - How do you prefer your resuscitation solution?: Do you want a little bit more salt? PMID- 23917924 TI - Importance of intensive care professionals for organ donation and transplantation. PMID- 23917925 TI - Moving beyond the assessment of mortality and severity of diseases in critical patients: we are just getting started... PMID- 23917926 TI - Do endotracheal tubes with suction above the cuff decrease the rate of ventilator associated pneumonia, and are they cost-effective? PMID- 23917927 TI - Intensive care provision: a global problem. PMID- 23917928 TI - Volume replacement with saline solutions during pancreatitis in rats and the hepatic profiles of apoptotic proteins and heat-shock proteins. AB - OBJECTIVE: Liver failure can occur as a consequence of the systemic inflammation after acute pancreatitis. We assessed the effect of volume repositioning with hypertonic saline solution or normal saline on hepatic cytokine production and the expression of heat-shock proteins and apoptotic proteins after acute pancreatitis. METHODS: Wistar rats were divided in four groups: C - control animals that were not subjected to insult or treatment; NT - animals that were subjected to acute pancreatitis and received no treatment; normal saline - animals that were subjected to acute pancreatitis and received normal saline (NaCl 0.9%); and HS - animals that were subjected to acute pancreatitis and received hypertonic saline solution (NaCl 7.5%). Acute pancreatitis was induced by retrograde transduodenal infusion of 2.5% sodium taurocholate into the pancreatic duct. At 4, 12 and 24 h following acute pancreatitis induction, TNF alpha, IL-1-beta, IL-6 and IL-10, caspase-2 and -7, Apaf-1, AIF and HSP60 and 90 were analyzed in the liver. RESULTS: Casp2 decreased in the normal saline and hypertonic saline groups (p<0.05 versus. C) at 12 h. Apaf-1, AIF and HSP90 remained unchanged. At 4 h, Casp7 increased in the NT group (p<0.01 versus C), although it remained at the baseline levels in the reperfused groups. HSP60 increased in all of the groups at 4 h (p< 0.001 vs. C). However, the hypertonic saline group showed lower expression of HSP60 than the normal saline group (p<0.05). Hypertonic saline solution maintained the production of cytokines at normal levels. Volume reperfusion with normal or hypertonic saline significantly modulated the expression of Casp7. CONCLUSION: Volume replacement with hypertonic or normal saline was effective in reducing caspase 7. However, only hypertonic solution was capable of regulating cytokine production and HSP60 expression at all time points. PMID- 23917929 TI - A managed protocol for treatment of deceased potential donors reduces the incidence of cardiac arrest before organ explant. AB - OBJECTIVE: To assess the effect of the application of a managed protocol for the maintenance care of deceased potential multiple organ donors at two hospitals. METHODS: A before (Phase 1)/after (Phase 2) study conducted at two general hospitals, which included consecutively potential donors admitted to two intensive care units. In Phase 1 (16 months), the data were collected retrospectively, and the maintenance care measures of the potential donors were instituted by the intensivists. In Phase 2 (12 months), the data collection was prospective, and a managed protocol was used for maintenance care. The two phases were compared in terms of their demographic variables, physiological variables at diagnosis of brain death and the end of the process, time to performance of brain death confirmatory test and end of the process, adherence to bundles of maintenance care essential measures, losses due to cardiac arrest, family refusal, contraindications, and the conversion rate of potential into actual donors. Student's t- and chi-square tests were used, and p-value < 0.05 was considered to be significant. RESULTS: A total of 42 potential donors were identified (18 in Phase 1 and 24 in Phase 2). The time interval between the first clinical assessment and the recovery decreased in Phase 2 (Phase 1: 35.0+/-15.5 hours versus Phase 2: 24.6+/-6.2 hours; p = 0.023). Adherence increased to 10 out of the 19 essential items of maintenance care, and losses due to cardiac arrest also decreased in Phase 2 (Phase 1: 27.8 versus 0% in Phase 2; p = 0.006), while the convertion rate increased (Phase 1: 44.4 versus 75% in Phase 2; p = 0.044). The losses due to family refusal and medical contraindication did not vary. CONCLUSION: The adoption of a managed protocol focused on the application of essential measures for the care of potential deceased donors might reduce the loss of potential donors due to cardiac arrest. PMID- 23917930 TI - Quality of life before admission to the intensive care unit. AB - OBJECTIVE: To examine the reliability of the SF-36 general health questionnaire when used to evaluate the health status of critically ill patients before admission to intensive care and to measure their health-related quality of life prior to admission and its relation to severity of illness and length of stay in the intensive care unit. METHODS: Prospective cohort study conducted in the intensive care unit of a public teaching hospital. Over three months, communicative and oriented patients were interviewed within the first 72 hours of intensive care unit admission; 91 individuals participated. The APACHE II score was used to assess severity of illness, and the SF-36 questionnaire was used to measure health-related quality of life. RESULTS: The reliability of SF-36 was verified in all dimensions using Cronbach's alpha coefficient. In six dimensions of eight domains the value exceeded 0.70. The average SF-36 scores of the health related quality of life dimensions for the patients before admission to intensive care unit were 57.8 for physical functioning, 32.4 for role-physical, 53.0 for bodily pain, 63.2 for general health, 50.6 for vitality, 56.2 for social functioning, 54.6 for role-emotional and 60.3 for mental health. The correlations between severity of illness and length of stay and the health-related quality of life scores were very low, ranging from -0.152 to 0.175 and -0.158 to 0.152, respectively, which were not statistically significant. CONCLUSION: In the sample studied, the SF-36 demonstrated good reliability when used to measure health related quality of life in critically ill patients before admission to the intensive care unit. The worst score was role-physical and the best was general health. Health-related quality of life of patients before admission was not correlated with severity of illness or length of stay in the intensive care unit. PMID- 23917931 TI - Diabetes mellitus and impaired glucose tolerance are underdiagnosed in intensive care units. AB - OBJECTIVE: To evaluate the presence of diabetes mellitus and impaired glucose tolerance in intensive care unit inpatients. METHODS: The study included patients in post-surgical care for elective and emergency surgery and excluded those patients with known diabetes mellitus. To diagnose prior serum glucose level disorders, we considered the value of glycated hemoglobin (HbA1c) at the time of admission, classifying the patients as normal (<5.7%), glucose intolerant (5.7 6.4%) or diabetic (>6.4%). During the first 3 days of the patient's hospital stay, glycemic control and clinical complications were assessed. Mortality was monitored for 28 days. For the statistical analyses, chi-square, ANOVA, student's t, Kruskal-Wallis or Mann Whitney tests were used. RESULTS: Thirty patients were included in the present study, 53% of whom were women; the patients had a mean age of 53.4+/-19.7 years and an APACHE II score of 13.6+/-6.6. The majority of patients were admitted for severe sepsis or septic shock followed by post operative care for elective surgery, oncological surgery, multiple traumas and emergency surgery. When classifying these patients according to HbA1c, despite the absence of a prior history of diabetes mellitus, only 13.3% had a normal HbA1c level, 23.3% had levels compatible with the diagnosis of diabetes mellitus and 63.3% had levels compatible with impaired glucose tolerance. We found a significant association between the diagnosis of diabetes mellitus or impaired glucose tolerance and the use of vasoactive drugs (p=0.04). CONCLUSION: A high prevalence of undiagnosed diabetes mellitus and impaired glucose tolerance was observed in inpatients at a general intensive care unit. PMID- 23917932 TI - Influence on prognosis and prevalence of stress hyperglycemia in a cohort of patients with acute coronary syndrome. AB - OBJECTIVE: To demonstrate the prevalence of stress hyperglycemia in a cohort of patients with acute coronary syndrome and to determine the correlation of stress hyperglycemia with death, heart failure and/or left ventricular systolic dysfunction during the intrahospital phase. METHODS: A prospective initial cohort study of hospitalized patients with acute coronary syndrome with or without ST segment elevation. The groups were compared to demonstrate the correlation between stress hyperglycemia and cardiovascular events. The chi-square test or Fisher's exact test and student's t-test were used to compare the groups with and without stress hyperglycemia. The variables with p<0.20 in the univariate analysis were submitted to logistic regression. RESULTS: In total, 363 patients with an average age of 12.45 +/- 62.06 were studied. There was a predominance of males (64.2%). In total, 96 patients (26.4%) presented with stress hyperglycemia. There were no differences between the groups with or without stress hyperglycemia. The area under the ROC curve was 0.67 for the relationship between stress hyperglycemia and the composite outcome heart failure, left ventricular systolic dysfunction or death at the end of the hospital admission. The ROC curve proved that stress hyperglycemia was the predictor of the composite outcome (death, heart failure and/or ventricular dysfunction). The multivariate analysis did not indicate age, stress hyperglycemia or admission heart rate as risk factors. CONCLUSION: Stress hyperglycemia was common in the studied sample. In the univariate analysis, the presence of stress hyperglycemia was associated with such events as death, heart failure and/or intrahospital ventricular dysfunction in patients with acute coronary syndrome. PMID- 23917933 TI - Financial impact of nosocomial infections in the intensive care units of a charitable hospital in Minas Gerais, Brazil. AB - OBJECTIVE: Infections in intensive care units are often associated with a high morbidity and mortality in addition to high costs. An analysis of these aspects can assist in optimizing the allocation of relevant financial resources. METHODS: This retrospective study analyzed the hospital administration and quality in intensive care medical databases [Sistema de Gestao Hospitalar (SGH)] and RM Janus(r). A cost analysis was performed by evaluating the medical products and materials used in direct medical care. The costs are reported in the Brazilian national currency (Real). The cost and length of stay analyses were performed for all the costs studied. The median was used to determine the costs involved. Costs were also adjusted by the patients' length of stay in the intensive care unit. RESULTS: In total, 974 individuals were analyzed, of which 51% were male, and the mean age was 57+/-18.24 years. There were 87 patients (8.9%) identified who had nosocomial infections associated with the intensive care unit. The median cost per admission and the length of stay for all the patients sampled were R$1.257,53 and 3 days, respectively. Compared to the patients without an infection, the patients with an infection had longer hospital stays (15 [11-25] versus 3 [2-6] days, p<0.01), increased costs per patient in the intensive care unit (median R$9.763,78 [5445.64 - 18,007.90] versus R$1.093,94 [416.14 - 2755.90], p<0.01) and increased costs per day of hospitalization in the intensive care unit (R$618,00 [407.81 - 838.69] versus R$359,00 [174.59 - 719.12], p<0.01). CONCLUSION: Nosocomial infections associated with the intensive care unit were determinants of increased costs and longer hospital stays. However, the study design did not allow us to evaluate specific aspects of cause and effect. PMID- 23917934 TI - Relative adrenal insufficiency as a predictor of disease severity and mortality in severe septic shock. AB - OBJECTIVE: To evaluate if cortisol responses to 250 ug of intravenously administered adrenocorticotropic hormone are related to disease severity and, hence, mortality. METHODS: This is a retrospective study in a medical-surgical intensive care unit of a university hospital. We studied 69 consecutive patients with septic shock over a 1-yr period; these patients underwent a short 250-ug adrenocorticotropic hormone test because they exhibited >6 hours of progressive hemodynamic instability requiring repeated fluid challenges and vasopressor treatment to maintain blood pressure. The test was performed by intravenously injecting 250 ug of synthetic adrenocorticotropic hormone and measuring cortisol immediately before injection, 30 minutes post-injection and 60 minutes post injection. RESULTS: The mean APACHE II score was 22+/-7. The intensive care unit mortality rate at day 28 was 55%. Median baseline cortisol levels (19 [11-27] ug/dL versus 24 [18-34] ug/dL, p=0.047) and median baseline cortisol/albumin ratios (7.6 [4.6-12.3] versus 13.9 [8.8-18.5]; p=0.01) were lower in survivors than in non-survivors. Responders and non-responders had similar baseline clinical data and outcomes. The variables that were significantly correlated with outcome based on the area under the ROC curves (AUC) were APACHE II (AUC=0.67 [0.535 to 0.781]), baseline cortisol (ug/dl) (AUC=0.662 [0.536 to 0.773], peak cortisol (ug/dl) (AUC=0.642 [0.515 to 0.755]) and baseline cortisol/albumin (AUC=0.75 [0.621 to 0.849]). CONCLUSIONS: Increased basal cortisol is associated with mortality and disease severity. Cortisol responses upon adrenocorticotropic hormone stimulation were not related to outcome. The cortisol/albumin ratio does not predict unfavorable outcomes better than total cortisol levels or help to improve the accuracy of the adrenocorticotropic hormone test. PMID- 23917935 TI - The use of 2% chlorhexidine gel and toothbrushing for oral hygiene of patients receiving mechanical ventilation: effects on ventilator-associated pneumonia. AB - OBJECTIVE: To evaluate the effects of oral chlorhexidine hygiene with toothbrushing on the rate of ventilator-associated pneumonia in a mixed population of critically ill patients under prolonged mechanical ventilation. METHODS: Prospective, randomized, and placebo-controlled pilot study. Patients who were receiving mechanical ventilation, had been admitted less than 24 hours prior, and were anticipated to require mechanical ventilation for more than 72 hours were included in the study. The patients were randomly divided into one of the following groups: chlorhexidine hygiene with toothbrushing or a placebo group (gel with the same color and consistency and toothbrushing). RESULTS: The planned interim analysis was conducted using 52 patients, and the study was terminated prematurely. In total, 28 patients were included in the chlorhexidine / toothbrushing group, and 24 patients were included in the placebo group. Ventilator-associated pneumonia occurred in 45.8% of the placebo group and in 64.3% of the chlorhexidine hygiene with toothbrushing group (RR=1.4; 95% CI=0.83 2.34; p=0.29). CONCLUSION: Because the study was terminated due to futility, it was not possible to evaluate the impact of oral hygiene using 2% chlorhexidine and toothbrushing on the incidence of ventilator-associated pneumonia in this heterogeneous population of critical patients receiving long-term mechanical ventilation, and no beneficial effect was observed for this intervention. PMID- 23917936 TI - Noninvasive ventilation in acute respiratory failure from respiratory syncytial virus bronchiolitis. AB - OBJECTIVES: The present study focused on respiratory syncytial virus bronchiolitis with respiratory failure. The aim of the study was to determine whether noninvasive ventilation reduces the need for endotracheal intubation or slows the clinical progression of acute respiratory syncytial virus bronchiolitis by reducing the incidence of infectious complications. METHODS: The present study was a retrospective cohort study. Cohort A was comprised of children who were admitted to the pediatric intensive and special care unit from 2003-2005 before starting noninvasive ventilation; cohort B was comprised of children who were admitted to the pediatric intensive and special care unit from 2006-2008 after starting noninvasive ventilation. With the exception of noninvasive ventilation, the therapeutic support was the same for the two groups. All children who were diagnosed with respiratory syncytial virus bronchiolitis and respiratory failure between November 2003 and March 2008 were included in the cohort. Demographic, clinical and blood gas variables were analyzed. RESULTS: A total of 162 children were included; 75% of the subjects were less than 3 months old. Group A included 64 children, and group B included 98 children. In group B, 34 of the children required noninvasive ventilation. The distributions of the variables age, preterm birth, congenital heart disease, cerebral palsy and chronic lung disease were similar between the two groups. On admission, the data for blood gas analysis and the number of apneas were not significantly different between the groups. In group B, fewer children required invasive ventilation (group A: 12/64 versus group B: 7/98; p=0.02), and there was a reduction in the number of cases of bacterial pneumonia (group A: 19/64 versus group B: 12/98; p=0.008). There was no record of mortality in either of the groups. CONCLUSION: By comparing children with the same disease both before and after noninvasive ventilation was used for ventilation support, we verified a reduction in infectious complications and cases requiring intubation. PMID- 23917937 TI - Nosocomial infections in a neonatal intensive care unit in South Brazil. AB - OBJECTIVE: The aim of this study was to describe the incidence and epidemiology of nosocomial infection in newborns who were admitted to a neonatal intensive care unit in a hospital in south Santa Catarina, Brazil. METHODS: A prospective cohort study was conducted for 1 year among 239 neonates who remained as in patients 48 hours after admission. The criteria that were used to diagnose infection were in accordance with the Centers for Disease Control and Prevention and the National Health Surveillance Agency. RESULTS: The incidence of nosocomial infection was 45.8%. The primary reasons for admission were primary bloodstream infection (80.7%) and pneumonia (6.7%). Coagulase-negative Staphylococcus was the most commonly identified agent in the blood cultures and in the hospital unit. Prematurity was the most prevalent reason for admission. The general mortality rate was 12.1%, and mortality from nosocomial infection was 33.8%. CONCLUSIONS: The incidence of nosocomial infection in the hospital unit was higher than rates that have been reported in other national studies. The major types of nosocomial infection were primary bloodstream infection and pneumonia. PMID- 23917938 TI - Epidemiological characteristics and deaths of premature infants in a referral hospital for high-risk pregnancies. AB - OBJECTIVE: To analyze the process of care provided to premature infants in a neonatal intensive care unit and the factors associated with their mortality. METHODS: Cross-sectional retrospective study of premature infants in an intensive care unit between 2008 and 2010. The characteristics of the mothers and premature infants were described, and a bivariate analysis was performed on the following characteristics: the study period and the "death" outcome (hospital, neonatal and early) using Pearson's chi-square test, Fisher's exact test or a chi-square test for linear trends. Bivariate and multivariable logistic regression analyses were performed using a stepwise backward logistic regression method between the variables with p<0.20 and the "death" outcome. A p value <0.05 was considered to be significant. RESULTS: In total, 293 preterm infants were studied. Increased access to complementary tests (transfontanellar ultrasound and Doppler echocardiogram) and breastfeeding rates were indicators of improving care. Mortality was concentrated in the neonatal period, especially in the early neonatal period, and was associated with extreme prematurity, small size for gestational age and an Apgar score <7 at 5 minutes after birth. The late-onset sepsis was also associated with a greater chance of neonatal death, and antenatal corticosteroids were protective against neonatal and early deaths. CONCLUSIONS: Although these results are comparable to previous findings regarding mortality among premature infants in Brazil, the study emphasizes the need to implement strategies that promote breastfeeding and reduce neonatal mortality and its early component. PMID- 23917939 TI - Plasmodium falciparum malaria: proteomic studies. AB - Despite advances in treatment and campaigns for prevention and control of malaria on the various continents where it is still rampant, this disease remains significantly relevant to the contemporary world. Plasmodium falciparum is the organism that is mainly responsible for severe malaria, which is characterized by disturbances in different organs and systems, with possibly fatal outcomes. Although incipient, proteomic studies of malaria have yielded favorable prospects for elucidating the biological aspects of Plasmodium as well as the pathophysiological, diagnostic, prophylactic, and therapeutic mechanisms of the disease. Thus, the aim of the present article is to present a brief review of the applications of proteomic analysis in P. falciparum malaria. PMID- 23917940 TI - Impact of supra-cuff suction on ventilator-associated pneumonia prevention. AB - Critically ill patients are intubated or tracheostomized because, in most cases, these individuals require invasive mechanical ventilation. The cannulae that are used include the cuff, which can act as a reservoir for oropharyngeal secretions, predisposing to ventilator-associated pneumonia. Studies have revealed that the suction of subglottic secretions through the dorsal suction lumen above the endotracheal tube cuff delays the onset and reduces the incidence of ventilator associated pneumonia. The aim of this review is to assess published studies regarding the significance of using suction with a supra-cuff device for the prevention of ventilator-associated pneumonia in critically ill patients treated with orotracheal intubation or tracheostomy. Therefore, by searching national and international databases, a literature review was undertaken of studies published between the years 1986 and 2011. Few results were found relating the suction of subglottic secretions to decreased duration of mechanical ventilation and length of stay in the intensive care unit. The suction of subglottic secretions is ineffective in decreasing mortality but is effective in reducing the incidence of early-onset ventilator-associated pneumonia and hospital costs. Techniques involving continuous suction of subglottic secretions may be particularly efficient in removing secretions; however, intermittent suction appears to be the least harmful method. In conclusion, cannulae with a supra-cuff suction device enable the aspiration of subglottic secretions, providing benefits to critically ill patients by reducing the incidence of ventilator-associated pneumonia and, consequently, hospital costs - with no large-scale adverse effects. PMID- 23917941 TI - Vascular access through the intraosseous route in pediatric emergencies. AB - Obtaining venous access in critically ill children is an essential procedure to restore blood volume and administer drugs during pediatric emergencies. The first option for vascular access is through a peripheral vein puncture. If this route cannot be used or if a prolonged period of access is necessary, then the intraosseous route is an effective option for rapid and safe venous access. The present work is a descriptive and exploratory literature review. The study's aim was to describe the techniques, professional responsibilities, and care related to obtaining venous access via the intraosseous route in pediatric emergencies. We selected 22 articles (published between 2000 and 2011) that were available in the Latin American and Caribbean Health Sciences (LILACS) and MEDLINE databases and the SciELO electronic library, in addition to the current protocol of cardiopulmonary resuscitation from the American Heart Association (2010). After the literature search, data were pooled and grouped into the following categories of analysis: historical aspects and physiological principles; indications, benefits, and contraindications; professional assignments; technical principles; care during the access; and possible complications. The results of the present study revealed that the intraosseous route is considered the main secondary option for vascular access during the emergency response because the technique is quick and easily executed, presents several non-collapsible puncture sites, and enables the rapid and effective administration of drugs and fluid replacement. PMID- 23917942 TI - Acute respiratory failure caused by organizing pneumonia secondary to antineoplastic therapy for non-Hodgkin's lymphoma. AB - Interstitial lung diseases belong to a group of diseases that typically exhibit a subacute or chronic progression but that may cause acute respiratory failure. The male patient, who was 37 years of age and undergoing therapy for non-Hodgkin's lymphoma, was admitted with cough, fever, dyspnea and acute hypoxemic respiratory failure. Mechanical ventilation and antibiotic therapy were initiated but were associated with unfavorable progression. Thoracic computed tomography showed bilateral pulmonary "ground glass" opacities. Methylprednisolone pulse therapy was initiated with satisfactory response because the patient had used three drugs related to organizing pneumonia (cyclophosphamide, doxorubicin and rituximab), and the clinical and radiological symptoms were suggestive. Organizing pneumonia may be idiopathic or linked to collagen diseases, drugs and cancer and usually responds to corticosteroid therapy. The diagnosis was anatomopathological, but the patient's clinical condition precluded performing a lung biopsy. Organizing pneumonia should be a differential diagnosis in patients with apparent pneumonia and a progression that is unfavorable to antimicrobial treatment. PMID- 23917943 TI - The anatomy of a community health center system-level intervention for intimate partner violence. AB - The US Preventive Services Task Force (USPSTF) now recommends screening for intimate partner violence (IPV) as part of routine preventive services for women. However, there is a lack of clarity as to the most effective methods of screening and referral. We conducted a 3-year community-based mixed-method participatory research project involving four community health centers that serve as safety net medical providers for a predominately indigent urban population. The project involved preparatory work, a multifaceted systems-level demonstration project, and a sustainability period with provider/staff debriefing. The goal was to determine if a low-tech system-level intervention would result in an increase in IPV detection and response in an urban community health center. Results highlight the challenges, but also the opportunities, for implementing the new USPSTF guidelines to screen all women of childbearing years for intimate partner violence in resource-limited primary care settings. PMID- 23917944 TI - Predation of Alouatta puruensis by Boa constrictor. AB - Reports of successful predator attacks on primates are rare. Primates from all major radiations are particularly susceptible to raptors, carnivores, and snakes. Among New World primates, reports of snake predation are limited to medium- and small-bodied species. Here, we report the first documented case of successful predation of an atelid by a snake-an adult female Purus red howler monkey, Alouatta puruensis, that was subdued by a ca. 2-m-long Boa constrictor in an arboreal setting at a height of 7.5 m above the ground. The victim belonged to a group composed of six individuals (one adult male, two adult females, two juveniles, and one infant) that inhabited a ca. 2.5-ha forest fragment in the State of Rondonia, western Brazilian Amazon. The boa applied the species' typical hunting behavior of striking and immediately coiling around its prey and then killing it through constriction (probably in less than 5 min), but the entire restraint period lasted 38 min. The attack occurred around noon. The howler was swallowed head-first in 76 min. The only group member to respond to the distress vocalization emitted by the victim was the other adult female, which was closest to the location where the attack occurred. This female ran toward the snake, also vocalizing, and hit it with her hands several times, but the snake did not react and she moved off to a nearby tree from where she watched most of the interaction. The remaining group members stayed resting at a height approximately 15 m above the victim in a nearby tree without showing any overt signs of stress, except for a single whimper vocalization. This event indicates that even large bodied atelids are vulnerable to predation by large snakes and suggests that B. constrictor may be a more common predator of primates. PMID- 23917947 TI - Identification of differentially expressed microRNAs across the developing human brain. AB - We present a spatio-temporal assessment of microRNA (miRNA) expression throughout early human brain development. We assessed the prefrontal cortex, hippocampus and cerebellum of 18 normal human donor brains spanning infancy through adolescence by RNA-seq. We discovered differentially expressed miRNAs and broad miRNA patterns across both temporal and spatial dimensions, and between male and female prefrontal cortex. Putative target genes of the differentially expressed miRNAs were identified, which demonstrated functional enrichment for transcription regulation, synaptogenesis and other basic intracellular processes. Sex-biased miRNAs also targeted genes related to Wnt and transforming growth factor-beta pathways. The differentially expressed miRNA targets were highly enriched for gene sets related to autism, schizophrenia, bipolar disorder and depression, but not neurodegenerative diseases, epilepsy or other adult-onset psychiatric diseases. Our results suggest critical roles for the identified miRNAs in transcriptional networks of the developing human brain and neurodevelopmental disorders. PMID- 23917948 TI - Association study of the estrogen receptor gene ESR1 with postpartum depression- a pilot study. AB - Perinatal mood disorders, such as postpartum depression (PPD), are costly for society, with potentially serious consequences for mother and child. While multiple genes appear to play a role in PPD susceptibility, the contributions of specific genetic variations remain unclear. Previously implicated as a candidate gene, the estrogen receptor alpha gene (ESR1) is a key player in mediating hormonal differences during pregnancy and the postpartum period. This study addresses genetic factors in perinatal mood disorders, testing nine polymorphisms in ESR1. Two hundred fifty-seven postpartum women were screened for mood disorders, including 52 women with PPD and 32 without any symptoms of mood disorders. We detected a significant association for the upstream TA microsatellite repeat with Edinburgh Postnatal Depression Scale scores (p = 0.007). The same variant was also associated with the occurrence of PPD. Separately, 11 candidate functional polymorphisms in 7 additional genes were genotyped to investigate gene-gene interaction with the ESR1 TA repeat, identifying a potential interaction with the serotonin transporter. Our results support a role for ESR1 in the etiology of PPD, possibly through the modulation of serotonin signaling. Our findings for ESR1 could have broad implications for other disorders and therapies that involve estrogens. PMID- 23917946 TI - Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders. AB - Recently discovered genome-wide rare copy number variants (CNVs) have unprecedented levels of statistical association with many developmental neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, intellectual disability and attention deficit hyperactivity disorder. However, as CNVs often include multiple genes, causal genes responsible for CNV-associated diagnoses and traits are still poorly understood. Mouse models of CNVs are in use to delve into the precise mechanisms through which CNVs contribute to disorders and associated traits. Based on human and mouse model studies on rare CNVs within human chromosome 22q11.2, we propose that alterations of a distinct set of multiple, noncontiguous genes encoded in this chromosomal region, in concert with modulatory impacts of genetic background and environmental factors, variably shift the probabilities of phenotypes along a predetermined developmental trajectory. This model can be further extended to the study of other CNVs and may serve as a guide to help characterize the impact of genes in developmental neuropsychiatric disorders. PMID- 23917949 TI - The bilateral anatomical variation of the sural nerve and a review of relevant literature. AB - The sural nerve is a sensory nerve, usually formed in the distal part of the leg by the union of the lateral sural cutaneous nerve or the communicating fibular branch with the medial sural cutaneous nerve. The aim of this paper is to present a case of a variant formation of the sural nerve and a review of the literature related to this case. During the dissection of an adult male cadaver, the medial sural cutaneous nerve and communicating fibular branch, after respectively deriving from the tibial and common fibular nerve, were noticed to continue their course without any formation of a unique nerve trunk on the posterior side of both lower limbs. A transverse communicating branch, connecting these two nerves, was present in both legs. As the sural nerve is of significant diagnostic and therapeutic importance, detailed knowledge of the sural nerve's anatomy and its contributing nerves is also of great importance. PMID- 23917951 TI - Non-dopaminergic treatments for motor control in Parkinson's disease. AB - The pathological processes underlying Parkinson's disease (PD) involve more than dopamine cell loss within the midbrain. These non-dopaminergic neurotransmitters include noradrenergic, serotonergic, glutamatergic, and cholinergic systems within cortical, brainstem and basal ganglia regions. Several non-dopaminergic treatments are now in clinical use to treat motor symptoms of PD, or are being evaluated as potential therapies. Agents for symptomatic monotherapy and as adjunct to dopaminergic therapies for motor symptoms include adenosine A2A antagonists and the mixed monoamine-B inhibitor (MAO-BI) and glutamate release agent safinamide. The largest area of potential use for non-dopaminergic drugs is as add-on therapy for motor fluctuations. Thus adenosine A2A antagonists, safinamide, and the antiepileptic agent zonisamide can extend the duration of action of levodopa. To reduce levodopa-induced dyskinesia, drugs that target overactive glutamatergic neurotransmission can be used, and include the non selective N-methyl D-aspartate antagonist amantadine. More recently, selective metabotropic glutamate receptor (mGluR5) antagonists are being evaluated in phase II randomized controlled trials. Serotonergic agents acting as 5-HT2A/2C antagonists, such as the atypical antipsychotic clozapine, may also reduce dyskinesia. 5-HT1A agonists theoretically can reduce dyskinesia, but in practice, may also worsen PD motor symptoms, and so clinical applicability has not yet been shown. Noradrenergic alpha2A antagonism using fipamezole can potentially reduce dyskinesia. Several non-dopaminergic agents have also been investigated to reduce non-levodopa-responsive motor symptoms such as gait and tremor. Thus the cholinesterase inhibitor donepezil showed mild benefit in gait, while the predominantly noradrenergic re-uptake inhibitor methylphenidate had conflicting results in advanced PD subjects. Tremor in PD may respond to muscarinic M4 cholinergic antagonists (anticholinergics), but tolerability is often poor. Alternatives include beta-adrenergic antagonists such as propranolol. Other options include 5-HT2A antagonists, and drugs that have mixed binding properties involving serotonin and acetylcholine, such as clozapine and the antidepressant mirtazapine, can be effective in reducing PD tremor. Many other non-dopaminergic agents are in preclinical and phase I/II early stages of study, and the reader is directed to recent reviews. While levodopa remains the most effective agent to treat motor symptoms in PD, the overall approach to using non-dopaminergic drugs in PD is to reduce reliance on levodopa and to target non-levodopa-responsive symptoms. PMID- 23917952 TI - A contact line pinning based microfluidic platform for modelling physiological flows. AB - This work introduces a contact line pinning based microfluidic platform for the generation of interstitial and intramural flows within a three dimensional (3D) microenvironment for cellular behaviour studies. A contact line pinning method was used to confine a natively derived biomatrix, collagen, in microfluidic channels without walls. By patterning collagen in designated wall-less channels, we demonstrated and validated the intramural flows through a microfluidic channel bounded by a monolayer of endothelial cells (mimic of a vascular vessel), as well as slow interstitial flows within a cell laden collagen matrix using the same microfluidic platform. The contact line pinning method ensured the generation of an engineered endothelial tube with straight walls, and spatially uniform interstitial fluid flows through the cell embedded 3D collagen matrix. Using this device, we demonstrated that the breast tumour cells' (MDA-MB-231 cell line) morphology and motility were modulated by the interstitial flows, and the motility of a sub-population of the cells was enhanced by the presence of the flow. The presented microfluidic platform provides a basic framework for studies of cellular behaviour including cell transmigration, growth, and adhesion under well controlled interstitial and intramural flows, and within a physiologically realistic 3D co-culture setting. PMID- 23917953 TI - Self-Expanding Stent and Delivery System for Aortic Valve Replacement. AB - Currently, aortic valve replacement procedures require a sternotomy and use of cardiopulmonary bypass (CPB) to arrest the heart and provide a bloodless field in which to operate. A less invasive alternative to open heart surgery is transapical or transcatheter aortic valve replacement (TAVR), already emerging as a feasible treatment for patients with high surgical risk. The bioprosthetic valves are delivered via catheters using transarterial or transapical approaches and are implanted within diseased aortic valves. This paper reports the development of a new self-expanding stent for minimally invasive aortic valve replacement and its delivery device for the transapical approach under real-time magnetic resonance imaging (MRI) guidance. Made of nitinol, the new stent is designed to implant and embed a commercially available bioprosthetic aortic valve in aortic root. An MRI passive marker was affixed onto the stent and an MRI active marker to the delivery device. These capabilities were tested in ex vivo and in vivo experiments. Radial resistive force, chronic outward force, and the integrity of bioprosthesis on stent were measured through custom design dedicated test equipment. In vivo experimental evaluation was done using a porcine large animal model. Both ex vivo and in vivo experiment results indicate that the self expanding stent provides adequate reinforcement of the bioprosthetic aortic valve and it is easier to implant the valve in the correct position. The orientation and positioning of the implanted valve is more precise and predictable with the help of the passive marker on stent and the active marker on delivery device. The new self-expanding nitinol stent was designed to exert a constant radial force and, therefore, a better fixation of the prosthesis in the aorta, which would result in better preservation of long-term heart function. The passive marker affixed on the stent and active marker embedded in the delivery devices helps to achieve precise orientation and positioning of the stent under MRI guidance. The design allows the stent to be retracted in the delivery device with a snaring catheter if necessary. Histopathology reports reveal that the stent is biocompatible and fully functional. All the stented bioprosthesis appeared to be properly seated in the aortic root. PMID- 23917950 TI - Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. AB - The 13th St Gallen International Breast Cancer Conference (2013) Expert Panel reviewed and endorsed substantial new evidence on aspects of the local and regional therapies for early breast cancer, supporting less extensive surgery to the axilla and shorter durations of radiation therapy. It refined its earlier approach to the classification and management of luminal disease in the absence of amplification or overexpression of the Human Epidermal growth factor Receptor 2 (HER2) oncogene, while retaining essentially unchanged recommendations for the systemic adjuvant therapy of HER2-positive and 'triple-negative' disease. The Panel again accepted that conventional clinico-pathological factors provided a surrogate subtype classification, while noting that in those areas of the world where multi-gene molecular assays are readily available many clinicians prefer to base chemotherapy decisions for patients with luminal disease on these genomic results rather than the surrogate subtype definitions. Several multi-gene molecular assays were recognized as providing accurate and reproducible prognostic information, and in some cases prediction of response to chemotherapy. Cost and availability preclude their application in many environments at the present time. Broad treatment recommendations are presented. Such recommendations do not imply that each Panel member agrees: indeed, among more than 100 questions, only one (trastuzumab duration) commanded 100% agreement. The various recommendations in fact carried differing degrees of support, as reflected in the nuanced wording of the text below and in the votes recorded in supplementary Appendix S1, available at Annals of Oncology online. Detailed decisions on treatment will as always involve clinical consideration of disease extent, host factors, patient preferences and social and economic constraints. PMID- 23917954 TI - Spondyloarthritis. Treat-to-target in spondyloarthritis--do we have a plan? AB - Clinicians now have the therapies and outcome tools to implement treat-to-target strategies aimed at achieving and maintaining adequate function and control of symptoms in spondyloarthritis and psoriatic arthritis. However, validation of surrogate markers of structural progression is a prerequisite for treat-to-target strategies aimed at improving long-term outcomes such as joint damage. PMID- 23917955 TI - Rheumatoid arthritis. Assessment of CVD in patients with RA by strain imaging. PMID- 23917956 TI - Inflammation. Fetal bone growth directly and locally impaired by IL-6. PMID- 23917957 TI - The pulmonary tissue damage associated with the aspiration of gelatinizers in rats. AB - Various gelatinizers, which facilitate oral ingestion, are employed in patients with dysphagia. The purpose of this study was to histologically clarify the influence of various gelatinizers on the lung, using rats. We administered 0.2 ml/kg of 0.1% xanthangam, a 0.25% commercially available xanthangam gelatinizer, 0.35% iota-carrageenan, 0.5% kappa-carrageenan, 1% gelatin, 0.15% agar, physiological saline, tap water, and isopropanolpurified 0.1% xanthangam/0.35% iota-carrageenan into the trachea of 8- to 9-week-old male SD rats. The lungs were extirpated after 24 and 72 hours. Neutrophil infiltration in the alveolar space was expressed as the mean number of neutrophils in 30 randomly selected high-power fields. In the xanthangam (451.0 +/- 204.0 cells) -, and the iota carrageenan (424.4 +/- 257.2) treated groups, the neutrophil counts after 24 hours was significantly greater than in the physiological saline (33.0 +/- 22.6) treated group (p < 0.05). In the available xanthangam gelatinizer (290.0 +/- 86.8) -treated group was no significant difference in the physiological saline treated group. In the isopropanol-purified xanthangam (90.2 +/- 42.3)-treated group, the neutrophil counts after 24 hours were significantly smaller than in the nonpurified xanthangam -treated group.These results suggest that lung tissue inflammatory response-inducing features depend on the type of gelatinizer. On the other hand, purification reduces the lung-damaging features of xanthangam. PMID- 23917958 TI - Efficient in vivo delivery of antisense oligonucleotide to choroid plexus. AB - The choroid plexus (CP) is present on the ventricular walls of the brain, produces cerebrospinal fluid (CSF), contains many blood vessels, and is a major functional component of the blood-CSF barrier. The CP is an important site in the pathophysiology of various neurological diseases, including Alzheimer's disease and meningeal amyloidosis. We performed gene silencing in the CP in vivo by using an antisense oligonucleotide (ASO). A short ASO of length 12 nucleotides was intravenously injected into rats. The ASO was not delivered to neurons or glia in the central nervous system, but was successfully delivered into the CP, and resulted in a significant reduction of endogenous target gene expression in epithelial cells within the CP. Although the mechanism of uptake of the ASO by the CP was not elucidated, the ASO bound to albumin in vivo, and the distribution of ASO delivery was similar to that of albumin delivery. These findings suggest that we inhibited target gene expression in the epithelial cells of the CP via albumin-ASO conjugates. This strategy should be useful for investigations of the function of CP, and for the development of new gene-silencing therapies for diseases with pathophysiology related to the CP. PMID- 23917959 TI - The generation of induced pluripotent stem cells from a patient with KCNH2 G603D, without LQT2 disease associated symptom. AB - The long QT syndrome type 2 (LQT2) is inheritable life threatening arrhythmic disorder and one of the most common genetic variants in long QT syndrome. There are some indications for treatment of the patients with LQT2 but it is impossible to completely prevent fatal arrhythmia. To develop novel therapy for the patients with LQT2, it has been desired to generate diseasespecific and patient-specific disease model. Human induced pluripotent stem (iPS) cells are somatic cell derived pluripotent stem cells with infinite proliferation ability and multipotency. Patient-specific iPS cells can be derived from patient somatic cells, have all genomic information encoded in patient's genome including mutation and all SNPs, and can be ideal disease models of the patients. To generate disease model for LQT2 by iPS cells, we should firstly generate iPS cells from the patient with LQT2 and confirm the genomic mutation in iPS cells. In this study, we showed the successful generation of iPS cells from a patient with KCNH2 G603D mutation. The patient specific iPS cells properly expressed stem cell markers, such as NANOG and OCT3/4. We also confirmed that the KCNH2 G603D (G1808A) mutation was taken over in patient specific iPS cells. These patient specific iPS cells may contribute to the future analysis for disease pathogenesis and drug innovation. PMID- 23917960 TI - Correlation between doctor's belief on the patient's self-determination and medical outcomes in obtaining informed consent. AB - We employed a questionnaire survey to assess attitudes toward informed consent (IC) among hospital doctors. Based on the result of the correlation analysis, the following two hypotheses were identified. The first hypothesis is that "the doctor's belief that the patient's self-determination is possible promotes cure of illness by obtaining IC." The second hypothesis is that "the doctor's belief that the patient's self-determination is possible has a positive influence on patient's quality of life by obtaining IC." We clarified the rationale for explaining these two hypotheses by applying cross tabulation analysis, discriminant analysis and principal component analysis (PCA). The doctors were divided into two groups in terms of their position on the patient's self determination. One group of doctors believed the possibility of patient's self determination, and the other did not. Through our statistical analyses, the characteristics that discriminate these two groups were identified. It was revealed that the former group placed a great importance on the hospitality value, while the latter placed an importance on the service value. Agreement or rejection of the concept of IC has been demonstrated as a key distinguishing factor between the two groups. The results of PCA showed that the doctor's belief on the patient's self-determination in obtaining IC had a significant effect on medical outcomes, and the two above-mentioned hypotheses were revealed. PMID- 23917961 TI - Changes in the psychological characteristics of oral cancer patients in the perioperative period: a quantitative evaluation. AB - We examined the changes in psychological distress and quality of life (QOL) during the perioperative period in oral cancer patients undergoing surgery and investigated the relationship between patient's psychological distress and QOL. Methods. Fifty patients participated. The Hospital Anxiety and Depression Scale (HADS; Japanese version), as a psychological test and the Functional Assessment of Cancer Therapy General (FACT-G); and Head and Neck (FACT-H&N), as quality of life (QOL) surveys were administered preoperatively, after surgery, and 1 month after leaving the hospital. Results. Anxiety was highest pre-operation and depression was highest post-operation, but improvements in both were seen post discharge. At the pre-operation time point, anxiety and depression low-score groups had significantly high scores on Emotional well-being and Functional well being. At the post-operation time point, anxiety and depression low-score groups had significantly high scores on all QOL subscales. Conclusion. Providing psychological support while considering anxiety might be particularly useful preoperatively whereas providing psychological support while considering depression might be particularly useful postoperatively. PMID- 23917962 TI - Amrubicin as second-line and beyond treatment for platinum-refractory advanced thymic carcinoma. AB - OBJECTIVE: Thymic carcinoma is a rare mediastinal neoplasm, and the prognosis of patients with advanced thymic carcinoma is poor. No standard chemotherapeutic regimen has yet been established for the disease. This is the first report to evaluate the role of amrubicin, a novel anthracycline anticancer drug, in second line and beyond treatment for patients with platinum-refractory advanced thymic carcinoma. METHODS: This study was a review of thymic carcinoma patients who had received amrubicin monotherapy between June 2003 and December 2011 for the progression of disease previously treated with platinum-based chemotherapy. Amrubicin was administered at 35 or 40 mg/m(2) for three consecutive days every 3 weeks, until progression. RESULTS: Nine patients with recurrent thymic carcinoma were registered. Their median age was 61 years (range 45-72), and the patients included five males and four females. All nine patients had Masaoka's Stage IVb disease. There were three squamous cell carcinomas, one adenocarcinoma, one small cell carcinoma and two other histological types. The mean number of chemotherapy cycles was five (range 2-13). Grade 3 or higher toxicities included mainly neutropenia (55.5%), anemia (25.0%) and febrile neutropenia (11.1%). No treatment related deaths were observed. The response rate was 44.4% (95% confidence interval: 19-73). The median progression-free survival after the amrubicin monotherapy was 4.9 months, while the median overall survival was 6.4 months. CONCLUSIONS: Single-agent amrubicin was found to be potentially useful as second line and beyond chemotherapy for patients with advanced thymic carcinoma. Further multi-institutional prospective studies are warranted. PMID- 23917963 TI - [Drug therapy of infectious diarrhea. Part 2: Chronic diarrhea]. AB - Diarrheal diseases are among the most common diseases worldwide. In this review the current treatment recommendations for acute (Part 1) and chronic (Part 2) infectious diarrhea are summarized and typical enteropathogens are discussed. The second part of the article describes chronic diarrhea, its related pathogens and treatment. In contrast to acute diarrhea which is mainly caused by viral and typical bacterial pathogens, chronic diarrhea has mainly non-infectious origins. Protozoal pathogens, such as Giardia lamblia and Entamoeba histolytica in particular are found and more rarely bacterial pathogens, such as Tropheryma whipplei. Opportunistic pathogens cause diarrhea in immunocompromised patients, such as in HIV patients. In these patients cytomegalovirus (CMV) colitis or infections with Cryptosporidium spp., Cyclospora cayetanensis, Isospora belli or microsporidia have to be considered. Besides targeted specific antimicrobial therapy, anti-retroviral drugs improving the underlying immunosuppression and thus the reconstitution of the adaptive immune response remain a cornerstone of the treatment in HIV-positive patients. PMID- 23917964 TI - A supramolecular approach to fabricate highly emissive smart materials. AB - The aromatic chromophores, for example, perylene diimides (PDIs) are well known for their desirable absorption and emission properties. However, their stacking nature hinders the exploitation of these properties and further applications. To fabricate emissive aggregates or solid-state materials, it has been common practice to decrease the degree of stacking of PDIs by incorporating substituents into the parent aromatic ring. However, such practice often involves difficultorganic synthesis with multiple steps. A supramolecular approach is established here to fabricate highly fluorescent and responsive soft materials, which has greatly decreases the number of required synthetic steps and also allows for a system with switchable photophysical properties. The highly fluorescent smart material exhibits great adaptivity and can be used as a supramolecular sensor for the rapid detection of spermine with high sensitivity and selectivity, which is crucial for the early diagnosis of malignant tumors. PMID- 23917965 TI - Marks of autopsy and identification of victims of human rights violations exhumed from cemeteries: the case of the Spanish Civil War (1936-1939). AB - The presence of autopsy marks in human skeletal remains indicates a medicolegal procedure related to ascertaining the cause and manner of death. We present here four cases where signs of autopsy were observed in the remains recovered from mass graves and cemeteries of prisoners from the Spanish Civil War (1936-1939), victims of extrajudicial executions, and of death in prison, respectively. With respect to the former, historical evidence indicate that during the first weeks after the coup, official removal of cadavers and autopsy procedures were carried out to the first victims of extrajudicial killings, whose corpses were found abandoned in the road. Once the civil war was established and systematic extrajudicial killings were systematic, official military orders were issued to stop standard forensic proceedings. Therefore, autopsy marks observed in the remains exhumed from mass graves located in cemeteries may be indicative of an earlier chronology of the killings, and this information proved to be relevant for the identification process in one of the cases presented. In a cemetery of political prisoners, autopsy signs were also observed in two skeletal remains and in the official records of two prisoners, a corroboration of information also relevant for the identification process. These findings indicate that autopsy marks can be found in the remains of victims of human rights violations exhumed from cemeteries. Skeletal and archival information could be useful for the identification process in other cases of large-scale violence, where the first victims of extrajudicial executions were buried unidentified in cemeteries after autopsy procedures. PMID- 23917966 TI - Radiofrequency ablation is a valuable therapeutic option in the treatment of liver metastases from gastrointestinal stromal tumors. PMID- 23917967 TI - Association of paraoxonase 1 gene polymorphism and enzyme activity with carotid plaque in rheumatoid arthritis. AB - OBJECTIVE: To investigate the relationship of genetic and biochemical determinants of paraoxonase 1 activity to carotid plaque as a surrogate marker of cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). METHODS: The relationships between paraoxonase 1 activity, PON1 genotype (for the functional polymorphism at position 192), and carotid plaque presence were determined in 168 RA patients. After an overnight fast, blood was collected for lipoprotein analysis, and paraoxonase 1 activity was measured using paraoxon as the substrate. The PON1 Q192R genotype was determined for all patients. Lipoprotein cholesterol levels, traditional CV risk factors, medication use, and RA disease characteristics were assessed for all patients. RESULTS: Paraoxonase 1 activity values in the RA patients were highest for the RR genotype, intermediate for the QR genotype, and lowest for the QQ genotype (P < 0.0001). Compared to patients with either the QQ genotype or the QR genotype, patients with the RR genotype demonstrated decreased risk of carotid plaque on multivariate analysis, controlling for traditional CV risk factors, high-sensitivity C-reactive protein levels, prednisone use, and cholesterol-lowering medication use (P < 0.05). Additional multivariate logistic regression analysis controlling for the above factors also revealed a significant association of plasma paraoxonase 1 activity with carotid plaque in RA patients. Lower plasma paraoxonase 1 activity was associated with increased risk of carotid plaque (P < 0.05). CONCLUSION: The current findings suggest a relationship of the genetic determinants and activity of paraoxonase 1 to CV risk in RA patients, as assessed by the presence or absence of carotid plaque. Further CV outcome studies are warranted to validate the utility of paraoxonase 1 as a biomarker of CV risk in patients with RA. PMID- 23917968 TI - Constipation in critically ill patients: much more than we imagine. PMID- 23917969 TI - Increasing the awareness of delirium in critically ill patients. PMID- 23917970 TI - How to prepare and submit abstracts for scientific meetings. AB - The presentation of study results is a key step in scientific research, and submitting an abstract to a meeting is often the first form of public communication. Meeting abstracts have a defined structure that is similar to abstracts for scientific articles, with an introduction, the objective, methods, results and conclusions. However, abstracts for meetings are not presented as part of a full article and, therefore, must contain the necessary and most relevant data. In this article, we detail their structure and include tips to make them technically correct. PMID- 23917971 TI - Defining ventilator-associated pneumonia: a (de)construction concept. PMID- 23917972 TI - Incidence of constipation in an intensive care unit. AB - OBJECTIVES: To evaluate the incidence of constipation in critical patients on enteral nutrition in a hospital intensive care unit and to correlate this incidence with the variables found for critical patients. METHODS: The present investigation was a retrospective analytical study conducted in the intensive care unit of Hospital Regional da Asa Norte (DF) via the analysis of medical records of patients admitted during the period from January to December 2011. Data on the incidence of constipation and enteral nutritional support, gastrointestinal changes, stool frequency, ventilatory support, and outcomes were collected and analyzed. RESULTS: The initial sample consisted of 127 patients admitted to the unit during the period from January to December 2011. Eighty-four patients were excluded, and the final sample consisted of 43 patients. The incidence of constipation, defined as no bowel movement during the first 4 days of hospitalization, was 72% (n=31). The patients were divided into a control group and a constipated group. The group of constipated patients reached the caloric target, on average, at 6.5 days, and the control group reached the caloric target in 5.6 days (p=0.51). Constipation was not associated with the length of hospital stay, suspension of nutritional support, or outcome of hospitalization. There was an association between evacuation during hospitalization and a longer duration of hospitalization for a subgroup of patients who did not evacuate during the entire period (p=0.009). CONCLUSION: The incidence of constipation in the unit studied was 72%. Only the absence of evacuation during hospitalization was associated with longer hospital stays. Constipation was not associated with the length of hospital stay, suspension of nutritional support, or outcome of hospitalization. PMID- 23917973 TI - Evaluation of functional independence after discharge from the intensive care unit. AB - OBJECTIVE: 1) To evaluate the functional independence measures immediately after discharge from an intensive care unit and to compare these values with the FIMs 30 days after that period. 2) To evaluate the possible associated risk factors. METHODS: The present investigation was a prospective cohort study that included individuals who were discharged from the intensive care unit and underwent physiotherapy in the unit. Functional independence was evaluated using the functional independence measure immediately upon discharge from the intensive care unit and 30 days thereafter via a phone call. The patients were admitted to the Hospital Santa Clara intensive care unit during the period from May 2011 to August 2011. RESULTS: During the predetermined period of data collection, 44 patients met the criteria for inclusion in the study. The mean age of the patients was 55.4+/-10.5 years. Twenty-seven of the subjects were female, and 15 patients were admitted due to pulmonary disease. The patients exhibited an functional independence measure of 84.1+/-24.2. When this measure was compared to the measure at 30 days after discharge, there was improvement across the functional independence variables except for that concerned with sphincter control. There were no significant differences when comparing the gender, age, clinical diagnosis, length of stay in the intensive care unit, duration of mechanical ventilation, and the presence of sepsis during this period. CONCLUSION: Functional independence, as evaluated by the functional independence measure scale, was improved at 30 days after discharge from the intensive care unit, but it was not possible to define the potentially related factors. PMID- 23917974 TI - The performance of a rapid response team in the management of code yellow events at a university hospital. AB - OBJECTIVE: To describe the epidemiological data of the clinical instability events in patients attended to by the rapid response team and to identify prognostic factors. METHODS: This was a longitudinal study, performed from January to July 2010, with an adult inpatient population in a hospital environment. The data collected regarding the code yellow service included the criteria of the clinical instability, the drug and non-drug therapies administered and the activities and procedures performed. The outcomes evaluated were the need for intensive care unit admission and the hospital mortality rates. A level of p=0.05 was considered to be significant. RESULTS: A total of 150 code yellow events that occurred in 104 patients were evaluated. The most common causes were related to acute respiratory insufficiency with hypoxia or a change in the respiratory rate and a concern of the team about the patient's clinical condition. It was necessary to request a transfer to the intensive care unit in 80 of the 150 cases (53.3%). It was necessary to perform 42 procedures. The most frequent procedures were orotracheal intubation and the insertion of a central venous catheter. The patients who were in critical condition and had to wait for an intensive care unit bed had a higher risk of death compared to the other patients (hazard ratio: 3.12; 95% CI: 1.80-5.40; p<0.001). CONCLUSIONS: There are patients in critical condition that require expert intensive care in the regular ward unit hospital beds. The events that most frequently led to the code yellow activation were related to hemodynamic and respiratory support. The interventions performed indicate the need for a physician on the team. The situation of pent-up demand is associated with a higher mortality rate. PMID- 23917975 TI - Translation, adaptation, and validation of the Sunderland Scale and the Cubbin & Jackson Revised Scale in Portuguese. AB - OBJECTIVE: To Translate into Portuguese and evaluate the measuring properties of the Sunderland Scale and the Cubbin & Jackson Revised Scale, which are instruments for evaluating the risk of developing pressure ulcers during intensive care. METHODS: This study included the process of translation and adaptation of the scales to the Portuguese language, as well as the validation of these tools. To assess the reliability, Cronbach alpha values of 0.702 to 0.708 were identified for the Sunderland Scale and the Cubbin & Jackson Revised Scale, respectively. The validation criteria (predictive) were performed comparatively with the Braden Scale (gold standard), and the main measurements evaluated were sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve, which were calculated based on cutoff points. RESULTS: The Sunderland Scale exhibited 60% sensitivity, 86.7% specificity, 47.4% positive predictive value, 91.5% negative predictive value, and 0.86 for the area under the curve. The Cubbin & Jackson Revised Scale exhibited 73.3% sensitivity, 86.7% specificity, 52.4% positive predictive value, 94.2% negative predictive value, and 0.91 for the area under the curve. The Braden scale exhibited 100% sensitivity, 5.3% specificity, 17.4% positive predictive value, 100% negative predictive value, and 0.72 for the area under the curve. CONCLUSIONS: Both tools demonstrated reliability and validity for this sample. The Cubbin & Jackson Revised Scale yielded better predictive values for the development of pressure ulcers during intensive care. PMID- 23917976 TI - Effects of educational intervention on adherence to the technical recommendations for tracheobronchial aspiration in patients admitted to an intensive care unit. AB - OBJECTIVE: To evaluate the effectiveness of an educational intervention on healthcare professionals' adherence to the technical recommendations for tracheobronchial aspiration in intensive care unit patients. METHODS: A quasi experimental study was performed to evaluate intensive care unit professionals' adherence to the tracheobronchial aspiration technical recommendations in intensive care unit patients both before and after a theoretical and practical educational intervention. Comparisons were performed using the chi-square test, and the significance level was set to p<0.05. RESULTS: A total of 124 procedures, pre- and post-intervention, were observed. Increased adherence was observed in the following actions: the use of personal protective equipment (p=0.01); precaution when opening the catheter package (p<0.001); the use of a sterile glove on the dominant hand to remove the catheter (p=0.003); the contact of the sterile glove with the catheter only (p<0.001); the execution of circular movements during the catheter removal (p<0.001); wrapping the catheter in the sterile glove at the end of the procedure (p=0.003); the use of distilled water, opened at the start of the procedure, to wash the connection latex (p=0.002); the disposal of the leftover distilled water at the end of the procedure (p<0.001); and the performance of the aspiration technique procedures (p<0.001). CONCLUSION: There was a low adherence by health professionals to the preventive measures against hospital infection, indicating the need to implement educational strategies. The educational intervention used was shown to be effective in increasing adherence to the technical recommendations for tracheobronchial aspiration. PMID- 23917977 TI - Severe virus influenza A H1N1 related pneumonia and community-acquired pneumonia: differences in the evolution. AB - OBJECTIVE: To analyze the clinical, laboratory and evolution data of patients with severe influenza A H1N1 pneumonia and compare the data with that of patients with severe community-acquired bacterial pneumonia. METHODS: Cohort and retrospective study. All patients admitted to the intensive care unit between May 2009 and December 2010 with a diagnosis of severe pneumonia caused by the influenza A H1N1 virus were included in the study. Thirty patients with severe community-acquired pneumonia admitted within the same period were used as a control group. Severe community-acquired pneumonia was defined as the presence of at least one major severity criteria (ventilator or vasopressor use) or two minor criteria. RESULTS: The data of 45 patients were evaluated. Of these patients, 15 were infected with H1N1. When compared to the group with community-acquired pneumonia, patients from the H1N1 group had significantly lower leukocyte counts on admission (6,728+/-4,070 versus 16,038+/-7,863; p<0.05) and lower C-reactive protein levels (Day 2: 15.1+/-8.1 versus 22.1+/-10.9 mg/dL; p<0.05). The PaO2/FiO2 ratio values were lower in the first week in patients with H1N1. Patients who did not survive the H1N1 severe pneumonia had significantly higher levels of C-reactive protein and higher serum creatinine levels compared with patients who survived. The mortality rate was significantly higher in the H1N1 group than in the control group (53% versus 20%; p=0.056, respectivelly). CONCLUSION: Differences in the leukocyte count, C-reactive protein concentrations and oxygenation profiles may contribute to the diagnosis and prognosis of patients with severe influenza A H1N1 virus-related pneumonia and community acquired pneumonia. PMID- 23917978 TI - Acute kidney injury in critically ill patients with lung disease: kidney-lung crosstalk. AB - OBJECTIVE: To examine the factors associated with acute kidney injury and outcome in patients with lung disease. METHODS: A prospective study was conducted with 100 consecutive patients admitted to a respiratory intensive care unit in Fortaleza (CE), Brazil. The risk factors for acute kidney injury and mortality were investigated in a group of patients with lung diseases. RESULTS: The mean age of the study population was 57 years, and 50% were male. The incidence of acute kidney injury was higher in patients with PaO2/FiO2<200 mmHg (54% versus 23.7%; p=0.02). Death was observed in 40 cases and the rate of mortality of the acute kidney injury group was higher (62.8% versus 27.6%; p=0.01). The independent factor that was found to be associated with acute kidney injury was PaO2/FiO2<200 mmHg (p=0.01), and the independent risk factors for death were PEEP at admission (OR: 3.6; 95%CI: 1.3-9.6; p=0.009) and need for hemodialysis (OR: 7.9; 95%CI: 2.2-28.3; p=0.001). CONCLUSION: There was a higher mortality rate in the acute kidney injury group. Increased mortality was associated with mechanical ventilation, high PEEP, urea and need for dialysis. Further studies must be performed to better establish the relationship between kidney and lung injury and its impact on patient outcome. PMID- 23917979 TI - Delirium in intensive care: an under-diagnosed reality. AB - Delirium occurs in up to 80% of patients admitted to intensive care units. Although under-diagnosed, delirium is associated with a significant increase in morbidity and mortality in critical patients. Here, we review the main risk factors, clinical manifestations and preventative and therapeutic approaches (pharmacological and non-pharmacological) for this illness. PMID- 23917980 TI - Delirium rating scales in critically ill patients: a systematic literature review. AB - OBJECTIVE: To identify scales that can establish a quantitative assessment of delirium symptoms in critically ill patients through a systematic review. METHODS: Studies that evaluated delirium stratification scales in patients hospitalized in intensive care units were selected in a search performed in the MedLine database. Validation studies of these scales and their target patient populations were analyzed, and we identified the examiner and the signs and symptoms evaluated. In addition, the duration of the application and the sensitivity and specificity of each scale were assessed. RESULTS: Six scales were identified: the Delirium Detection Score, the Cognitive Test of Delirium, the Memorial Delirium Assessment Scale, the Intensive Care Delirium Screening Checklist, The Neelon and Champagne Confusion Scale and the Delirium Rating Scale Revised-98. CONCLUSION: The scales identified allow the stratification and monitoring of critically ill patients with delirium. Among the six scales, the most studied and best suited for use in the intensive care units was the Intensive Care Delirium Screening. PMID- 23917981 TI - Perceptions and practices regarding delirium, sedation and analgesia in critically ill patients: a narrative review. AB - A significant number of landmark studies have been published in the last decade that increase the current knowledge on sedation for critically ill patients. Therefore, many practices that were considered standard of care are now outdated. Oversedation has been shown to be hazardous, and light sedation and no-sedation protocols are associated with better patient outcomes. Delirium is increasingly recognized as a major form of acute brain dysfunction that is associated with higher mortality, longer duration of mechanical ventilation and longer lengths of stay in the intensive care unit and hospital. Despite all the available evidence, translating research into bedside care is a daunting task. International surveys have shown that practices such as sedation interruption and titration are performed only in the minority of cases. Implementing best practices is a major challenge that must also be addressed in the new guidelines. In this review, we summarize the findings of sedation and delirium research over the last years. We also discuss the gap between evidence and clinical practice and highlight ways to implement best practices at the bedside. PMID- 23917982 TI - Drug-nutrient interactions in the intensive care unit: literature review and current recommendations. AB - OBJECTIVE: To describe the interactions between drugs and nutrients and their frequency in the intensive care unit and to assess the professional team's awareness regarding this subject. METHODS: The keywords "drug interactions" and "nutrition therapy" were searched in the PubMed (specifically MeSH) electronic database. The studies were systematically reviewed for descriptions of the types of interactions between drugs and nutrients, including their frequency and consequences. RESULTS: Sixty-seven articles were found. Among these, 20 articles were appropriate for the methodology adopted and accomplished the objectives of the study. Of these 20 articles, 14 articles described interactions between drugs and enteral nutrition, three described interactions between drugs and parenteral nutrition, and three described the importance and care required to avoid such interactions. CONCLUSIONS: The literature about drug and nutrient interactions is limited and suggests the inability of health care teams to recognize the potential for these interactions. Possibly, the elaboration of a protocol to evaluate drug-nutrient interactions will increase the safety and efficacy of therapeutics. PMID- 23917983 TI - Use of femoral vein catheters for the assessment of perfusion parameters. AB - The use of central venous oxygen saturation (SvcO2) and arterial lactate in the diagnosis of severe tissue hypoperfusion is well established, and the optimization of these parameters is currently under investigation, particularly in patients with severe sepsis/septic shock. However, the only place for deep venous puncture or the first choice for puncture is often the femoral vein. Although venous saturation obtained from blood sampling from this catheter, instead of SvcO2, has already been used in the diagnosis of severe tissue hypoperfusion, little is known about the accuracy of the results. The venous lactate in place of arterial puncture has also been used to guide therapeutic decisions. We conducted this literature review to seek evidence on the correlation and concordance of parameters obtained by collecting femoral venous blood gases in relation to SvcO2 and arterial lactate. Few studies in the literature have evaluated the use of femoral venous oxygen saturation (SvfO2) or venous lactate. The results obtained thus far demonstrate no adequate agreement between SvfO2 and SvcO2, which limits the clinical use of SvfO2. However, the apparent strong correlation between arterial and peripheral and central venous lactate values suggests that venous lactate obtained from the femoral vein could eventually be used instead of arterial lactate, although there is insufficient evidence on which to base this procedure at this time. PMID- 23917984 TI - Spontaneous acute subdural hematoma and intracerebral hemorrhage in a patient with thrombotic microangiopathy during pregnancy. AB - Preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low-platelet count), and acute fatty liver of pregnancy are the main causes of thrombotic microangiopathy and evere liver dysfunction during pregnancy and represent different manifestations of the same pathological continuum. The case of a 35 week pregnant woman who was admitted to an intensive care unit immediately after a Cesarean section due to fetal death and the presence of nausea, vomiting, and jaundice is reported. Postpartum preeclampsia and acute fatty liver of pregnancy were diagnosed. The patient developed an acute subdural hematoma and an intracerebral hemorrhage, which were subjected to neurosurgical treatment. The patient died from refractory hemolytic anemia and spontaneous bleeding of multiple organs. Preeclampsia HELLP syndrome, and acute fatty liver of pregnancy might overlap and be associated with potentially fatal complications, including intracranial hemorrhage, as in the present case. Early detection and diagnosis are crucial to ensure management and treatment success. PMID- 23917986 TI - Functional switching and stability of regulatory T cells. AB - It is widely accepted that the primary immune system contains a subpopulation of cells, known as regulatory T cells whose function is to regulate the immune response. There is conflicting biological evidence regarding the ability of regulatory cells to lose their regulatory capabilities and turn into immune promoting cells. In this paper, we develop mathematical models to investigate the effects of regulatory T cell switching on the immune response. Depending on environmental conditions, regulatory T cells may transition, becoming effector T cells that are immunostimulatory rather than immunoregulatory. We consider this mechanism both in the context of a simple, ordinary differential equation (ODE) model and in the context of a more biologically detailed, delay differential equation (DDE) model of the primary immune response. It is shown that models that incorporate such a mechanism express the usual characteristics of an immune response (expansion, contraction, and memory phases), while being more robust with respect to T cell precursor frequencies. We characterize the affects of regulatory T cell switching on the peak magnitude of the immune response and identify a biologically testable range for the switching parameter. We conclude that regulatory T cell switching may play a key role in controlling immune contraction. PMID- 23917987 TI - The self-regulation model of sexual offending: intermediate outcomes and posttreatment recidivism. AB - The self-regulation model (SRM) is a nine-phase, four-pathway offense process model designed specifically for sexual offenders that is now being applied to the treatment of this group in many settings and jurisdictions. In the present prospective study, we evaluated the validity and utility of the SRM in a sample of 275 adult male sexual offenders treated within the Correctional Service of Canada. Results indicated that participation in treatment resulted in moderate to large sized improvements from pretreatment to posttreatment on a dynamic risk assessment measure and several self-reported treatment targets. These changes were, in some cases, differentially associated with self-regulation pathways, suggesting that offense pathway is a clinically relevant variable when evaluating treatment change and in conceptualizing sexual offender treatment. In terms of outcome, individuals following the approach pathways, particularly the approach automatic pathway, demonstrated higher failure rates than individuals following avoidant pathways. However, many of these differences were less pronounced when taking risk for recidivism into account. Implications of these findings for the effective assessment and rehabilitation of sexual offenders are discussed. PMID- 23917985 TI - A prevalence study of IgG4-related ophthalmic disease in Japan. AB - PURPOSE: Immunoglobulin (Ig)G4-related ophthalmic disease belongs to a category of ocular adnexal lymphoproliferative disorders, the most frequent group of orbital tumors and simulating lesions. The aim of this study was to elucidate the number of IgG4-related diseases of orbital lymphoproliferative disorders and correlate ages and sex of such patients from 18 centers in Japan. METHODS: One thousand and fourteen patients with orbital lymphoproliferative disorders were enrolled in this study. All had pathologically diagnosed lymphoproliferative disorders with surgical samples of ocular adnexal tissue. Patients with conjunctival lesions and intraocular lymphoma were excluded. RESULTS: Of the 1,014 cases of orbital lymphoproliferative disorders 404 (39.8 %) had extranodal mucosa-associated lymphoid tissue (MALT) lymphoma, 156 (15.4 %) had other malignant lymphomas, 191 (18.8 %) had non-IgG4 orbital inflammation, 219 (21.6 %) had IgG4-related orbital inflammation, and 44 (4.3 %) had IgG4-positive MALT lymphoma. Median age of the IgG4-related orbital inflammation group was 62 years, which is significantly lower than that of the MALT lymphoma group (median 66 years) and higher than the non-IgG4 orbital inflammation group (median 57 years). The male/female ratio was 105/114 in the IgG4-related orbital inflammation group. CONCLUSIONS: Nearly a quarter of orbital lymphoproliferative disorders in Japan are related to IgG4. PMID- 23917988 TI - A yeast one-hybrid and microfluidics-based pipeline to map mammalian gene regulatory networks. AB - The comprehensive mapping of gene promoters and enhancers has significantly improved our understanding of how the mammalian regulatory genome is organized. An important challenge is to elucidate how these regulatory elements contribute to gene expression by identifying their trans-regulatory inputs. Here, we present the generation of a mouse-specific transcription factor (TF) open-reading frame clone library and its implementation in yeast one-hybrid assays to enable large scale protein-DNA interaction detection with mouse regulatory elements. Once specific interactions are identified, we then use a microfluidics-based method to validate and precisely map them within the respective DNA sequences. Using well described regulatory elements as well as orphan enhancers, we show that this cross-platform pipeline characterizes known and uncovers many novel TF-DNA interactions. In addition, we provide evidence that several of these novel interactions are relevant in vivo and aid in elucidating the regulatory architecture of enhancers. PMID- 23917989 TI - Bacterial cheating drives the population dynamics of cooperative antibiotic resistance plasmids. AB - Inactivation of beta-lactam antibiotics by resistant bacteria is a 'cooperative' behavior that may allow sensitive bacteria to survive antibiotic treatment. However, the factors that determine the fraction of resistant cells in the bacterial population remain unclear, indicating a fundamental gap in our understanding of how antibiotic resistance evolves. Here, we experimentally track the spread of a plasmid that encodes a beta-lactamase enzyme through the bacterial population. We find that independent of the initial fraction of resistant cells, the population settles to an equilibrium fraction proportional to the antibiotic concentration divided by the cell density. A simple model explains this behavior, successfully predicting a data collapse over two orders of magnitude in antibiotic concentration. This model also successfully predicts that adding a commonly used beta-lactamase inhibitor will lead to the spread of resistance, highlighting the need to incorporate social dynamics into the study of antibiotic resistance. PMID- 23917990 TI - The effect of geometric variations in posterior-stabilized knee designs on motion characteristics measured in a knee loading machine. AB - BACKGROUND: In different posterior-stabilized (PS) total knees, there are considerable variations in condylar surface radii and cam-post geometry. To what extent these variations affect kinematics is not known. Furthermore, there are no clearly defined ideal kinematics for a total knee. QUESTIONS/PURPOSES: The purposes of this study were to determine (1) what the kinematic differences are caused by geometrical variations between PS total knee designs in use today; and (2) what design characteristics will produce kinematics that closely resemble that of the normal anatomic knee. METHODS: Four current PS designs with different geometries and one experimental asymmetric PS design, with a relatively conforming medial side, were tested in a purpose-built machine. The machine applied combinations of compressive, shear, and torque forces at a sequence of flexion angles to represent a range of everyday activities, consistent with the ASTM standard test for measuring constraint. The femorotibial contact points, the neutral path of motion, and the AP and internal-external laxities were used as the kinematic indicators. RESULTS: The PS designs showed major differences in motion characteristics among themselves and with motion data from anatomic knees determined in a previous study. Abnormalities in the current designs included symmetric mediolateral motion, susceptibility to excessive AP medial laxity, and reduced laxity in high flexion. The asymmetric-guided motion design alleviated some but not all of the abnormalities. CONCLUSIONS: Current PS designs showed kinematic abnormalities to a greater or lesser extent. An asymmetric design may provide a path to achieving a closer match to anatomic kinematics. CLINICAL RELEVANCE: One criterion for the evaluation of PS total knees is how closely the kinematics of the prosthesis resemble that of the anatomic knee, because this is likely to affect the quality of function. PMID- 23917992 TI - Reply to the letter to the editor: hip resurfacing does not improve proprioception compared with THA. PMID- 23917991 TI - Intra- and interobserver reliability of the Eaton classification for trapeziometacarpal arthritis: a systematic review. AB - BACKGROUND: Trapeziometacarpal, or thumb carpometacarpal (CMC), arthritis is a common problem with a variety of treatment options. Although widely used, the Eaton radiographic staging system for CMC arthritis is of questionable clinical utility, as disease severity does not predictably correlate with symptoms or treatment recommendations. A possible reason for this is that the classification itself may not be reliable, but the literature on this has not, to our knowledge, been systematically reviewed. QUESTIONS/PURPOSES: We therefore performed a systematic review to determine the intra- and interobserver reliability of the Eaton staging system. METHODS: We systematically reviewed English-language studies published between 1973 and 2013 to assess the degree of intra- and interobserver reliability of the Eaton classification for determining the stage of trapeziometacarpal joint arthritis and pantrapezial arthritis based on plain radiographic imaging. Search engines included: PubMed, Scopus((r)), and CINAHL. Four studies, which included a total of 163 patients, met our inclusion criteria and were evaluated. The level of evidence of the studies included in this analysis was determined using the Oxford Centre for Evidence Based Medicine Levels of Evidence Classification by two independent observers. RESULTS: A limited number of studies have been performed to assess intra- and interobserver reliability of the Eaton classification system. The four studies included were determined to be Level 3b. These studies collectively indicate that the Eaton classification demonstrates poor to fair interobserver reliability (kappa values: 0.11-0.56) and fair to moderate intraobserver reliability (kappa values: 0.54 0.657). CONCLUSIONS: Review of the literature demonstrates that radiographs assist in the assessment of CMC joint disease, but there is not a reliable system for classification of disease severity. Currently, diagnosis and treatment of thumb CMC arthritis are based on the surgeon's qualitative assessment combining history, physical examination, and radiographic evaluation. Inconsistent agreement using the current common radiographic classification system suggests a need for better radiographic tools to quantify disease severity. PMID- 23917993 TI - Validation of the Brazilian version of the musculoskeletal tumor society rating scale for lower extremity bone sarcoma. AB - BACKGROUND: The Musculoskeletal Tumor Society (MSTS) rating scale is an English language instrument used worldwide to assess functional evaluation of patients with musculoskeletal cancer. Despite its use in several studies in English speaking countries, its validity for assessing patients in other languages is unknown. The translation and validation of widely used scales can facilitate the comparison across international patient samples. OBJECTIVES/PURPOSES: The objectives of this study were (1) to translate and culturally adapt the MSTS rating scale for functional evaluation in patients with lower extremity bone sarcomas to Brazilian Portuguese; (2) analyze its factor structure; and (3) test the reliability and (4) validity of this instrument. METHOD: The MSTS rating scale for lower limbs was translated from English into Brazilian Portuguese. Translations were synthesized, translated back into English, and reviewed by a multidisciplinary committee for further implementation. The questionnaire was administered to 67 patients treated for malignant lower extremity bone tumors who were submitted to limb salvage surgery or amputation. They also completed a Brazilian version of the Toronto Extremity Salvage Score (TESS). Psychometric properties were analyzed including factor structure analysis, internal consistency, interobserver reliability, test-retest reliability, and construct validity (by comparing the adapted MSTS with TESS and discriminant validity). RESULTS: The MSTS rating scale for lower limbs was translated and culturally adapted to Brazilian Portuguese. The MSTS-BR proved to be adequate with only one latent dimension. The scale was also found to be reliable in a population that speaks Brazilian Portuguese showing good internal consistency (Cronbach's alpha = 0.84) and reliability (test-retest reliability and interobserver agreement of 0.92 and 0.98, respectively). Validity of the Brazilian MSTS rating scale was proved by moderate with TESS and good discriminant validity. CONCLUSIONS: The Brazilian version of the MSTS rating scale was translated and validated. It is a reliable tool to assess functional outcome in patients with lower extremity bone sarcomas. It can be used for functional evaluation of Brazilian patients and crosscultural comparisons. PMID- 23917994 TI - The value of valgus stress radiographs in the workup for medial unicompartmental arthritis. AB - BACKGROUND: High tibial osteotomy and unicompartmental knee arthroplasty are surgical treatment options for unicompartmental knee arthritis; these procedures are indicated for patients who do not have severe arthritis in the lateral compartment. Valgus stress radiographs sometimes are used to make this evaluation, but this test has not been critically evaluated. QUESTIONS/PURPOSES: We sought to determine (1) whether valgus stress radiographs help to evaluate the integrity of the cartilage in the lateral compartment in patients undergoing TKA for noninflammatory arthritis, and (2) whether valgus stress radiographs can identify patients whose varus deformity is correctable. METHODS: We reviewed preoperative hip-to-ankle standing radiographs, AP standing radiographs, and valgus stress radiographs of 84 patients (91 knees) who underwent TKA for varus knee arthritis between July 2010 and January 2012. Valgus stress radiographs were obtained with the patient supine with the knee 20 degrees flexed and a firm manual valgus force was applied through the knee. On valgus stress radiographs, the lateral compartment joint space width and the corrected mechanical alignment were measured. Intraoperative cartilage assessment (Outerbridge grade) was compared with lateral compartment joint space width. Knees with mechanical leg alignment of 3 degrees varus to 3 degrees valgus on valgus stress radiographs were considered correctable deformities. RESULTS: The lateral compartment joint space width on valgus stress radiographs did not correlate with the intraoperative Outerbridge grading of the lateral compartment cartilage (rs = 0.154; p = 0.146). The majority of knees (93%; 55 of 59) with 10 degrees or less mechanical varus on hip-to-ankle standing radiographs were correctable within the range of 3 degrees varus to 3 degrees valgus. CONCLUSIONS: Valgus stress radiographs provided no added benefit to the radiographic assessment of the lateral compartment cartilage and regarding the correctability of the varus deformity. PMID- 23917995 TI - Hydrogen bonding to the cysteine ligand of superoxide reductase: acid-base control of the reaction intermediates. AB - Superoxide reductase (SOR) is a non-heme iron metalloenzyme that detoxifies superoxide radical in microorganisms. Its active site consists of an unusual non heme Fe(2+) center in a [His4Cys1] square pyramidal pentacoordination, with the axial cysteine ligand proposed to be an essential feature in catalysis. Two NH peptide groups from isoleucine 118 and histidine 119 establish hydrogen bonds involving the sulfur ligand (Desulfoarculus baarsii SOR numbering). To investigate the catalytic role of these hydrogen bonds, the isoleucine 118 residue of the SOR from Desulfoarculus baarsii was mutated into alanine, aspartate, or serine residues. Resonance Raman spectroscopy showed that the mutations specifically induced an increase of the strength of the Fe(3+)-S(Cys) and S-Cbeta(Cys) bonds as well as a change in conformation of the cysteinyl side chain, which was associated with the alteration of the NH hydrogen bonding involving the sulfur ligand. The effects of the isoleucine mutations on the reactivity of SOR with O2 (*-) were investigated by pulse radiolysis. These studies showed that the mutations induced a specific increase of the pK a of the first reaction intermediate, recently proposed to be an Fe(2+)-O2 (*-) species. These data were supported by density functional theory calculations conducted on three models of the Fe(2+)-O2 (*-) intermediate, with one, two, or no hydrogen bonds involving the sulfur ligand. Our results demonstrated that the hydrogen bonds between the NH (peptide) and the cysteine ligand tightly control the rate of protonation of the Fe(2+)-O2 (*-) reaction intermediate to form an Fe(3+)-OOH species. PMID- 23917997 TI - Psychopathology and academic performance, social well-being, and social preference at school: the TRAILS study. AB - Psychopathology during adolescence has been associated with poor academic performance, low social well-being, and low social preference by peers at school. However, previous research has not accounted for comorbid psychopathology, informant-specific associations between psychopathology and functioning, and gender and age differences. This study addresses these limitations by examining adolescents' psychopathology and functioning at school, reported by child, parent, teacher, and peers during primary and secondary school in a large Dutch longitudinal cohort study (N = 2230). Teacher reports of psychopathology, especially regarding attention problems and withdrawn/depressed problems, followed by parent reports regarding hyperactivity, were most strongly associated with academic performance. The same held for social preference which was associated with teacher and parent ratings of withdrawn/depressed problems and hyperactivity. In contrast, social well-being was best predicted by child reports (at primary school) of affective problems. In girls, the association between ADHD problems and poor academic performance was stronger than in boys and conduct problems were more often associated with poor school functioning in general. These findings can help identify adolescents at risk for poor functioning and design interventions that effectively reduce or prevent poor school functioning. PMID- 23917999 TI - Congenital granular cell tumor with uncommon clinical behavior. AB - OBJECTIVES/HYPOTHESIS: Congenital granular cell tumor (CGCT), also known as congenital epulis, is a rare benign mesenchymal tumor of the oral cavity. We report of a 3 years and 7 months old female patient undergoing surgical excision of an oral tumor. Subsequent histological and immunohistological investigations within the clinical course led to the diagnosis of CGCT. However, clinical findings in this case, such as primary onset and an untypical location within the oral cavity, clearly stand in contrast to those usually found in CGCT, resulting in an exceptional case not previously described in the literature. PMID- 23917998 TI - Microfluidic electroporation for cellular analysis and delivery. AB - Electroporation is a simple yet powerful technique for breaching the cell membrane barrier. The applications of electroporation can be generally divided into two categories: the release of intracellular proteins, nucleic acids and other metabolites for analysis and the delivery of exogenous reagents such as genes, drugs and nanoparticles with therapeutic purposes or for cellular manipulation. In this review, we go over the basic physics associated with cell electroporation and highlight recent technological advances on microfluidic platforms for conducting electroporation. Within the context of its working mechanism, we summarize the accumulated knowledge on how the parameters of electroporation affect its performance for various tasks. We discuss various strategies and designs for conducting electroporation at the microscale and then focus on analysis of intracellular contents and delivery of exogenous agents as two major applications of the technique. Finally, an outlook for future applications of microfluidic electroporation in increasingly diverse utilities is presented. PMID- 23918000 TI - Demonstrating measurement equivalence of the electronic and paper formats of the Urticaria Patient Daily Diary in patients with chronic idiopathic urticaria. AB - BACKGROUND: The Urticaria Patient Daily Diary (UPDD), originally developed on paper, is a measure of key symptoms of chronic idiopathic urticaria (CIU). The development of the electronic version (eUPDD) involved moderate modifications to the appearance of the paper version. OBJECTIVE: This study assessed the measurement equivalence of the electronic and paper versions of the UPDD in a sample of patients with CIU. METHODS: This was a cross-over study of patients with moderate-severe CIU refractory to H1 antihistamines. Patients were randomized to either the eUPDD followed by the paper UPDD or vice versa. The UPDD includes morning and evening questions; both sets were administered together in this study. An hour-long filler task was given between paper and electronic administrations. Patients with stable symptoms between the two assessments were included in the analyses. Cohen's kappa coefficients and intraclass correlation coefficients (ICC) were computed as applicable to assess equivalence. RESULTS: A total of 91 patients participated (mean age 43 years, 79.1 % female). Symptoms were stable between assessments for 67-74 (74-81 %) patients (varied by symptom). Kappa coefficients ranged from 0.82 to 1.00 for the individual UPDD items. For the Urticaria Activity Score (the sum of the 'itch severity' and 'number of hives' item scores) the ICC was 0.90 for the morning (Wilcoxon p = 0.331) and 0.95 for the evening (Wilcoxon p = 0.836). CONCLUSIONS: All test-retest statistics in this study were well above the accepted threshold, indicating excellent agreement between the two administration methods. Findings support the measurement equivalence of the electronic and paper versions of the UPDD to measure CIU symptoms. PMID- 23918002 TI - Fabrication of ultra-thin nanostructured bimetallic foils by Accumulative Roll Bonding and Asymmetric Rolling. AB - This paper reports a new technique that combines the features of Accumulative Roll Bonding (ARB) and Asymmetric Rolling (AR). This technique has been developed to enable production of ultra-thin bimetallic foils. Initially, 1.5 mm thick AA1050 and AA6061 foils were roll-bonded using ARB at 200 degrees C, with 50% reduction. The resulting 1.5 mm bimetallic foil was subsequently thinned to 0.04 mm through four AR passes at room temperature. The speed ratio between the upper and lower AR rolls was 1:1.3. The tensile strength of the bimetallic foil was seen to increase with reduction in thickness. The ductility of the foil was seen to reduce upon decreasing the foil thickness from 1.5 mm to 0.14 mm, but increase upon further reduction in thickness from 0.14 mm to 0.04 mm. The grain size was about 140 nm for the AA6061 layer and 235 nm for the AA1050 layer, after the third AR pass. PMID- 23918001 TI - Is there a role for nitric oxide in methamphetamine-induced dopamine terminal degeneration? AB - Methamphetamine (METH) abuse results in long-term damage to the dopaminergic system, manifesting as decreases in dopamine (DA) tissue content, DA transporter binding, as well as tyrosine hydroxylase and vesicular monoamine transporter immunostaining. However, the exact cascade of events that ultimately result in this damage has not been clearly elucidated. One factor that has been heavily implicated in METH-induced DA terminal degeneration is the production of nitric oxide (NO). Unfortunately, many of the studies attempting to clarify the role of NO in METH-induced neurotoxicity have been confounded by issues such as the disruption of METH-induced hyperthermia, preventing the formation of strong conclusions. As a result, there is a body of work suggesting that NO is sufficient for METH-induced neurotoxicity, while other studies suggest that NO does not play a role in METH-induced degeneration of DA nerve terminals. This review summarizes the existing studies investigating the role of NO in METH induced neurotoxicity, and argues that while NO may be necessary for METH-induced neurotoxicity, it is not sufficient. Finally, important areas of future investigation are highlighted and discussed. PMID- 23918003 TI - Postoperative laryngeal symptoms in a general surgery setting. Clinical study. AB - INTRODUCTION: Vocal cord injuries (VI), postoperative hoarseness (PH), dysphonia (DN), dysphagia (DG) and sore throat (ST) are common complications after general anesthesia; there is actually a lack of consensus to support the proper timing for post-operative laryngoscopy that is reliable to support the diagnosis of laryngeal or vocal fold lesions after surgery and there are no valid studies about the entity of laryngeal trauma in oro-tracheal intubation. Aim of our study is to evaluate the statistical relation between anatomic, anesthesiological and surgical variables in the case of PH, DG or impaired voice register. MATERIALS AND METHODS: 50 patients (30 thyroidectomies, 8 videolaparoscopic cholecistectomies, 2 right emicolectomies, 2 left emicolectomies, 1 gastrectomy, 1 hemorrhoidectomy, 1 nefrectomy, 1 diagnostic videothoracoscopy, 1 superior right lung lobectomy, 1 appendicectomy, 1 incisional hernia repair, 1 low anterior rectal resection, 1 radical hysterectomy) underwent clinical evaluation and direct laryngoscopy before surgery, within 6 hours, after 72 hours and after 30 days, to evaluate motility and breathing space, phonatory motility, true and false vocal folds and arytenoids oedema. We evaluated also mean age (56.6 +/- 3.6 years), male:female ratio (1:1.5), cigarette smoke (20%), atopic comorbidity (17/50 = 34%), Mallampati class (32% 1, 38% 2, 26% 3, 2% 4), mean duration of intubation (159 minutes, range 50 - 405 minutes), Cormack-Lehane score (34% 1, 22% 2, 22% 3, 2% 4), difficult intubation in 9 cases (18%). No complication during the laryngoscopy were registered. We investigated the statistic relationship between pre and intraoperative variables and laryngeal symptoms and lesions. RESULTS: In our experience, statistically significant relations were found in prevalence of vocal folds oedema in smokers (p < 0.005), self limiting DG and DN in younger patients (p < 0.005) and in thyroidectomy (p < 0.01), DG after thyroidectomy (p < 0.01). The short preoperative use of steroids and antihistaminic to prevent allergic reactions appears not related to reduction or prevention of DN, DG, PH and ST. No statistical relation in incidence of postoperative complications was found for the prolonged intubation, gastro esophageal reflux, BURP manoeuvre (backward upward right sided pressure) and Mallampati and Cormack-Lehane class more than 2, maintenance with sevoflurane 2% and use of stilet. CONCLUSIONS: Direct laryngoscopy is essential for the detection of arytenoid lesions after orotracheal intubation for general anesthesia. In our opinion, a part of temporary post-operative DN or PH is due to monolateral or bilateral arytenoids oedema, secondary to prolonged or difficult orotracheal intubation, valuable with laryngoscopy 72 hours after surgery. Is necessary to adjunct these complications in the surgical informed consensus scheme. PMID- 23918004 TI - Patients with Parkinson's disease and scans with (predominant) ipsilateral dopaminergic deficit. PMID- 23918005 TI - Cerium ammonium nitrate (CAN)-catalyzed four-component one-pot synthesis of multi substituted pyrano[2,3-c] pyrazoles under ultrasound irradiation. AB - A convenient and efficient synthesis of multi-substituted dihydropyrano[2,3 c]pyrazole derivatives is reported. The four-component reaction of 4 hydrazinobenzoic acid, beta-keto esters, aromatic aldehydes, and malononitrile using 10 mol% CAN catalyst in water under ultrasound irradiation produced the target compounds in good-to-excellent yields. This method has advantages over conventional methods in being economic, non-toxic, and environmentally compatible due to its use of efficient and eco-friendly CAN catalyst and water solvent. PMID- 23918006 TI - Electromagnetic tracking system with reduced distortion using quadratic excitation. AB - PURPOSE: Electromagnetic tracking systems, frequently used in minimally invasive surgery, are affected by conductive distorters. The influence of conductive distorters on electromagnetic tracking system accuracy can be reduced through magnetic field modifications. This approach was developed and tested. METHODS: The voltage induced directly by the emitting coil in the sensing coil without additional influence by the conductive distorter depends on the first derivative of the voltage on the emitting coil. The voltage which is induced indirectly by the emitting coil across the conductive distorter in the sensing coil, however, depends on the second derivative of the voltage on the emitting coil. The electromagnetic tracking system takes advantage of this difference by supplying the emitting coil with a quadratic excitation voltage. The method is adaptive relative to the amount of distortion cause by the conductive distorters. This approach is evaluated with an experimental setup of the electromagnetic tracking system. RESULTS: In vitro testing showed that the maximal error decreased from 10.9 to 3.8 mm when the quadratic voltage was used to excite the emitting coil instead of the sinusoidal voltage. Furthermore, the root mean square error in the proximity of the aluminum disk used as a conductive distorter was reduced from 3.5 to 1.6 mm when the electromagnetic tracking system used the quadratic instead of sinusoidal excitation. CONCLUSIONS: Electromagnetic tracking with quadratic excitation is immune to the effects of a conductive distorter, especially compared with sinusoidal excitation of the emitting coil. Quadratic excitation of electromagnetic tracking for computer-assisted surgery is promising for clinical applications. PMID- 23918007 TI - Regulation of GSK3beta-FBXW7-JUNB axis. PMID- 23918008 TI - Teaching and Research in the preparation of future professionals. PMID- 23918009 TI - Teaching of the Integrated Management of Childhood Illness strategy in undergraduate nursing programs. AB - OBJECTIVE: To describe and analyze the teaching of the Integrated Management of Childhood Illness (IMCI) strategy on Brazilian undergraduate nursing programs. METHOD: Integrating an international multicentric study, a cross-sectional online survey was conducted between May and October 2010 with 571 undergraduate nursing programs in Brazil RESULTS: Responses were received from 142 programs, 75% private and 25% public. 64% of them included the IMCI strategy in the theoretical content, and 50% of the programs included IMCI as part of the students' practical experience. The locations most used for practical teaching were primary health care units. The 'treatment' module was taught by the fewest number of programs, and few programs had access to the IMCI instructional manuals. All programs used exams for evaluation, and private institutions were more likely to include class participation as part of the evaluation. Teaching staff in public institutions were more likely to have received training in teaching IMCI. CONCLUSION: In spite of the relevance of the IMCI strategy in care of the child, its content is not addressed in all undergraduate programs in Brazil, and many programs do not have access to the IMCI teaching manuals and have not provide training in IMCI to their teaching staff. PMID- 23918010 TI - Emotional competencies in the process of teaching and learning in nursing, from the perspective of the neurosciences. AB - OBJECTIVE: to investigate aspects of the interaction which occurs between feeling and learning from the perspective of the neurosciences. METHOD: research with a qualitative approach, of the case study type, undertaken in Brazilian public nursing colleges. The research subjects were lecturers and students. The techniques of use of a questionnaire, individual interviews and a focus group were used in data collection. RESULTS: knowledge of cerebral functioning and the functioning of different structures involved in the learning of cognitive, technical, emotional and relational competences can help the lecturer in her task of teaching. CONCLUSIONS: we can outline the difficulties of learning and need, as lecturers, to develop teaching strategies based in the new knowledge from the neurosciences so as to maximize the students' learning. This new knowledge brings elements which contribute to the teacher's training, facilitate the process for the person learning, and make teaching more pleasurable. PMID- 23918011 TI - Expansion of higher education in Brazil: increase in the number of Undergraduate Nursing courses. AB - OBJECTIVE: This study analyzed the increase in the number of undergraduate nursing courses during the last two decades due to the expansion of higher education in Brazil. METHOD: A records-based research concerning the legal frameworks that have driven this movement and a quantitative research that described the increase in the number of professional nursing courses. Data were analyzed using thematic content analysis (qualitative) and descriptive statistics (quantitative). RESULTS: the political-ideological argument present in the regulatory documents, which points out higher education as a possibility to change the current social scenario, has not been reflected in the professional nursing field. The expansion of nursing courses has been unfolding in a disorderly manner and is concentrated in the private sector, with geographical inequality in the distribution of these courses. CONCLUSION: There does not seem to be a concern with the local needs and with a connection among education, research and extension, which compromises the quality of the education provided to future nurses. PMID- 23918012 TI - Current status of Complementary Therapies in Spain in nursing degree. AB - OBJECTIVE: Describe the current situation of complementary therapies in nursing education in schools and nursing schools in Spain. METHOD: Descriptive study. Study population all faculties andschools ascribed to Spain. Data collection through observation sheet. Analysis units Curricula. Variables (credits, course type, location, type of therapy). Descriptive analysis of relative and absolute data using Excel spreadsheet. RESULTS: Most of the faculties and schoolsofnursingscrutinized the subject of Complementary Therapies has disappeared and those that aparace is an optional subject. CONCLUSION: Complementary Therapies training in Spain is deficient because it is not collected as a core subject and / or obligatory. The absence of Complementary Therapies in the curriculum, questions such as their value in training, conceptualization which teachers, the impact on quality of care, training of teachers responsible for teaching the subject, as well as the number of credits and the course being in the degree of Grado. PMID- 23918013 TI - Association between moment of the undergraduate course and cardiovascular risk factors in university students. AB - AIM: This study aimed to verify the association between moment of the undergraduate course and cardiovascular risk factors in a representative sample of university students. METHODS: A total of 1,599 university students (1,197 freshmen and 402 seniors) were investigated for the following risk factors: insufficient practice of physical activity, tobacco and alcohol consumption, poor eating habits, excess body weight, increased waist circumference and elevated arterial pressure. Information regarding the practice of physical activity were obtained using the International Physical Activity Questionnaire (IPAQ) instrument, the behaviors using the Youth Risk Behavior Surveillance, and the socio-environmental information using the methodology of the Associacao Brasileira de Empresas de Pesquisa (Brazilian Association of Research Companies). RESULTS: A significantly higher probability of presenting the following risk factors was verified among the senior students: insufficient practice of physical activity, smoked, consumed alcohol or drank alcohol in excess within the last thirty days. CONCLUSION: The results suggest that students closer to the end of the undergraduate course show a higher possibility of presenting some cardiovascular risk factors than those just entering the university environment. Therefore, prevention programs and health promotion during the undergraduate course should be investigated. PMID- 23918014 TI - Nursing values as social practice: a qualitative meta-synthesis. AB - OBJECTIVE: to identify values which structure and guide nursing as social practice. METHOD: qualitative meta-synthesis. RESULTS: three concepts were identified: The tension between technique, organization and ethics in the nurse's practice; Historical carry-overs of the values which run through nursing practice; Attention to ethics, to reform of the health system, and to the humanization of care. These led to the synthesis of the principal variables 'planning' and 'care', which represent, respectively, guiding values of the technical-operative and ethical-moral elements of the social practice of nursing. CONCLUSION: these values are articulated through the prism of ordering so as to care well. Their recognition contributed to a better understanding of the process of health care and nursing care. PMID- 23918015 TI - Adaptation and validation of the Patient Expectations and Satisfaction with Prenatal Care instrument among Brazilian pregnant women. AB - OBJECTIVE: to adapt and validate the Patient Expectations and Satisfaction with Prenatal Care instrument for use in Brazil. It contains 41 items divided into two dimensions: expectations and satisfaction. The adapted version was submitted to analysis for stability, convergent construct validity, and internal consistency (Cronbach's alpha) for distinct groups and dimensions. METHOD: 119 pregnant women receiving prenatal care were interviewed and 26 of these women answered the instrument twice (retest). Internal consistency was appropriate (Cronbach's alpha >= 0.70); test-retest presented strong correlation (r=0.82; p<0.001) for the domain expectations and moderate correlation (r=0.66; p<0.001) for the satisfaction domain. The analysis confirmed that the instrument's adapted version is valid in the studied group. RESULTS: there is strong evidence for the validity and reliability of the instrument's adaptation. CONCLUSION: the instrument needs to be tested in groups of pregnant women with different social characteristics. PMID- 23918016 TI - Maternal mortality due to hemorrhage in Brazil. AB - OBJECTIVE: to analyze the rates of maternal mortality due to hemorrhage identified in Brazil from 1997 to 2009. METHODS: the time series and population data from the Brazilian Health Ministry, Mortality Information System and Live Birth Information System were examined. From the Mortality Information System, we initially selected all reported deaths of women between 10 and 49 years old, which occurred from January 1, 1997 to December 31, 2009 in Brazil, recorded as a "maternal death". RESULTS: during the research period, 22,281 maternal deaths were identified, among which 3,179 were due to hemorrhage, accounting for 14.26% of the total deaths. The highest rates of maternal mortality were found in the North and Northeast areas of Brazil. CONCLUSIONS: the Brazilian scenario shows regional inequalities regarding maternal mortality. It presents hemorrhaging as a symptom and not as a cause of death. PMID- 23918017 TI - Constraints and/or determinants of return to sexual activity in the puerperium. AB - OBJECTIVE: to identify factors which constrain or determine the return to sexual activity in the puerperium. METHOD: exploratory and descriptive study undertaken in a university hospital in the South of Brazil. Fifteen women who had recently given birth, who received a consultation with the nurse in the period August - October 2011, took part in the study. Data was collected after the consultation had finished through semi-structured interviews, in which the women who had recently given birth were asked about the return to sexual activity and the feelings involved in this process. RESULTS: the principal determinant/constraint for return to sexual activity in the post-natal period was the fear of a new pregnancy. Fear of feeling pain, permission from the health professional, shame of their own bodies and changes in libido emerged as constraining and/or determinant factors in the thematic analysis. CONCLUSION: it is considered fundamental for the issue of contraception to be addressed with the woman/couple during the pre-natal consultation, so that there may be opportunities for reflection and dialog prior to the critical time itself. PMID- 23918018 TI - Social representations of mothers about gestational hypertension and premature birth. AB - OBJECTIVE: To identify the meanings attributed by mothers to hypertensive disorders of pregnancy (HDPs) and their consequences, such as premature birth and hospitalization of the infant in the neonatal intensive care unit (NICU). METHOD: A qualitative study, based on the Central Nucleus Theory, with 70 women who had hypertensive disorders of pregnancy and preterm delivery. We used the technique of free word association (FWAT) with three stimuli: high blood pressure during pregnancy, prematurity and NICU. RESULTS: We obtained 1007 evocations, distributed as follows: high blood pressure during pregnancy (335) prematurity (333) and NICU (339). These constituted three thematic units: representation of HDPs, prematurity and the NICU. The categories death and negative aspects were inherent to the three units analyzed, followed by coping strategies and needs for care present in HDPs and prematurity. CONCLUSION: The study had death as its central nucleus, and highlighted the subjective aspects present in the high risk pregnancy and postpartum cycle. It is hoped that this research will contribute to qualifying nursing care for women confronting the problem of HDPs, so that they can cope with less impacts from the adverse effects of high risk pregnancy and birth. PMID- 23918019 TI - Prevalence of pre-frailty for the component of gait speed in older adults. AB - OBJECTIVE: to investigate pre-frailty and the factors associated with this condition, taking into account the measurements of the older adults' gait speed. METHOD: participants were selected by means of inclusion/exclusion criteria and a cognitive tracking test. The sample was calculated based on the estimation of populational proportion and made up of 195 older adults who were using a Primary Health-Care Center in Curitiba in the state of Parana. Data was collected using a socio-demographic/clinical questionnaire and the gait speed test. RESULTS: pre frailty for gait speed has moderate prevalence (27.3%), and is associated with the 60 - 69 years age range, a low level of schooling, not feeling oneself to be alone, using anti-hypertensives, having cardiovascular disease and being overweight. CONCLUSION: it is considered relevant to identify those older adults with pre-frailty, as this creates the possibility for immediate intervention with the aim of stabilizing the picture. There is a significant shortage of studies on the syndrome of frailty in Brazilian older adults, principally referring to components in isolation. Given that gerontological nursing is at an early stage regarding this issue, it is understood that the identification of the prevalence must be the key point of the research on the matter. PMID- 23918020 TI - Variables related to the anticipated support for care in community-dwelling older adults. AB - OBJECTIVE: to compare the anticipated support for care, living arrangements and variables related to health as functions of gender and age in older adults in the community. METHOD: data was used from the Research network "Frailty in Brazilian Older Adults" (FIBRA network), sample for Campinas (n=671) analyses of data description and comparison were made. RESULT: compared to the men, the women are in worse socio-demographic conditions and have poorer perception of their health and dependency and lower expectations of support for care; those who have expectations anticipate receiving help from only one person. Advanced age was related to lower incapacity percentages and the majority of the older adults assess their health as good or very good, irrespective of their age, although the women predominate in the group composed of those who assess their own health as bad or very bad. CONCLUSION: this study guides the nurse in identifying older adults in situations of risk of lack of support for care and indicates the need for interventions aiming at giving support to this group. PMID- 23918021 TI - Old age and elderly people: social representations of adolescent students. AB - OBJECTIVE: to know the main elements of social representations about elderly people and old age among adolescents at a public high school. METHOD: 172 adolescents between 14 and 19 years of age participated. The free evocation of words technique was applied through the terms elderly and old age. RESULTS: The main elements of the representations significantly designed for elderly people were: respect and disrespect, 78; experience, 49; care, 32; wisdom, 23; fragility, 19. For old age: disease, 51; retirement, 27; experience, 27; wisdom, 19; wrinkles, 17. The social representations of adolescents are strongly marked by physical, psychological and social aspects, with positive and negative aspects about old age. CONCLUSION: Participatory health education activities are needed to make adolescents critically reflect on and the condition of elderly people in contemporary society. PMID- 23918022 TI - Factors associated with bullying at nurses' workplaces. AB - OBJECTIVE: To identify nurses who are subject to workplace bullying and its associated factors. METHOD: Descriptive and exploratory study with a quantitative approach. The sample consisted of 199 nurses working in public and private sectors (N=388). For data collection, a graphic socio-professional questionnaire and the Leymann Inventory Psychological Terrorization were used, both in print or electronic format (May/September 2010). RESULTS: According to the data collected, 11.56% of the participants had been subject to bullying. Multivariate analysis showed that having children, working at Public Healthcare Units, working at an institution for a period between one and three years, currently dealing with acts of bullying and to feel bullied are risk factors for bullying. CONCLUSION: This study permitted a better understanding of the factors associated with bullying; however, a research based on samples of Brazilian nurses is only the first step to evaluate other factors of influence related to the organizational context. PMID- 23918023 TI - Professional nursing practice: environment and emotional exhaustion among intensive care nurses. AB - OBJECTIVE: to evaluate the characteristics of the professional nursing practice environment and its relationship with burnout, perception of quality of care, job satisfaction and the intention to leave the job in the next 12 months. METHOD: cross-sectional study with a quantitative approach to data. The sample was composed of 129 nurses working in adult Intensive Care Units from a region in the interior of Sao Paulo, Brazil. RESULTS: The structural equation modeling, using path analysis, revealed that characteristics of the environment influence job satisfaction, perception of quality of care, and having an intention to leave their job, when mediated by emotional exhaustion. Nurses with limited autonomy, poor control over their practice, and poor relationships with physicians, experience a greater level of emotional exhaustion, which can negatively influence their perception of quality of care, job satisfaction and an intention to abandon their jobs. CONCLUSION: the mediating role of emotional exhaustion may negatively influence care delivery. Therefore, there is a need to adopt strategies to minimize this condition among nurses. PMID- 23918024 TI - Nursing work at night in palliative oncology care. AB - OBJECTIVE: to understand the meaning baccalaureate nurses and nursing technicians attribute to night work in the context of clinical palliative oncology nursing care services, as well as how nursing works to attend to clients and caregivers' needs in this period. METHOD: in this exploratory and qualitative study, grounded theory was used. Seven nurses and four nursing technicians were interviewed, who composed two sample groups. Nine categories were produced and, in their comparative content analysis, a knowledge emphasis was evidenced with implications for nighttime nursing work. In this study, these aspects were discussed in two of the categories, which are: to describe care practice in order to understand nursing care management and to point out the difficulties in care practice and nursing care management. RESULTS: The results evidence the complexity in the nighttime care context, considering the clients' clinical conditions and clients and caregivers' psychological demands, mainly because of the threat of death. CONCLUSION: The team attempts to respond to these needs through communication, but reveals a lack of assistential services and an overload. Interdisciplinarity is a palliative care premise, favoring holistic care delivery, and cannot be neglected at, which requires attention and investment to develop better practices. PMID- 23918025 TI - The importance of communication in pediatric oncology palliative care: focus on Humanistic Nursing Theory. AB - OBJECTIVE: to investigate and analyze communication in palliative care contexts from the perspective of nurses, based on Humanistic Nursing Theory. METHOD: this is a field study with a qualitative approach, in which ten nurses working in the pediatric oncology unit of a Brazilian public hospital participated. Semi structured interviews were used to collect data. The testimonies were qualitatively analyzed using Humanistic Nursing Theory and based on the five phases of Nursing Phenomenology. RESULTS: two thematic categories emerged from the analysis of the study's empirical material: "strategy to humanize nursing care, with an emphasis on relieving the child's suffering" and "strategy to strengthen ties of trust established between nurse and child." CONCLUSION: communication is an efficacious element in the care provided to the child with cancer and is extremely important to promoting palliative care when it is based on Humanistic Nursing Theory. PMID- 23918026 TI - Comparison of the quality of life among persons with lung cancer, before and after the chemotherapy treatment. AB - OBJECTIVE: this prospective study aimed to assess the quality of life related to health (QLRH) of patients with lung cancer after chemotherapy treatment. METHOD: The QLRH was assessed using the questionnaires Quality-of-Life Questionnaire-Core 30 (QLQ-C30) and Lung Cancer Module (LC13), version 3.0. RESULTS: the sample was made up of 11 women and 19 men, with an average age of 68 years (51-87 years). After the chemotherapy treatment, the authors observed a clinically-relevant improvement in general quality of life, as well as in the symptoms of dyspnea, insomnia, hemoptysis, cough, thoracic pain, pain in the arm/shoulder, and financial difficulty. There was a worsening on the functional scale which assesses role performance and symptoms of fatigue, nausea and vomiting, sensory neuropathy, pain in other parts, constipation, loss of appetite and alopecia. CONCLUSION: although the patients have an improvement of their QLRH and symptoms related to the lung cancer after the chemotherapy treatment, there was a worsening of the symptoms which resulted from the toxicity of the chemotherapy medications. PMID- 23918027 TI - Quality of life of severe sepsis survivors after hospital discharge. AB - AIMS: to evaluate the quality of life in severe sepsis survivors, using specific QoL questionnaires: the EuroQol-5 Dimensions and the Visual Analogue Scale (EQ VAS). METHOD: This case-control study was performed in patients discharged from a teaching hospital after being admitted to the ICU with severe sepsis. Medical records from 349 patients were retrieved from the hospital sepsis registry. Each patient with sepsis was considered as a case. Patients who were admitted immediately after the sepsis episode were considered as controls, provided that they did not have sepsis and survived the ICU admission. This specific study population included 100 patients. RESULTS: The sepsis group showed higher mortality at 1 year compared with critically ill patients. However, the control group showed no sepsis. Older patients (>60 years) in the sepsis group had a significantly higher prevalence of problems. There were no differences in EQ-VAS between respondents from both groups. CONCLUSIONS: After discharge from ICU, sepsis survivors of sepsis had a higher mortality rate than critically ill patients without sepsis. Older patients with sepsis had more moderate and severe problems in all five quality of life dimensions evaluated. PMID- 23918028 TI - Warmed intravenous infusion for controlling intraoperative hypothermia. AB - OBJECTIVE: to verify the effectiveness of warmed intravenous infusion for hypothermia prevention in patients during the intraoperative period. METHOD: experimental, comparative, field, prospective and quantitative study undertaken at a federal public hospital. The sample was composed of 60 adults, included based on the criteria of axillary temperature between 36oC and 37.1oC and surgical abdominal access, divided into control and experimental groups, using the systematic probability sampling technique. RESULTS: 22 patients (73.4%) from both groups left the operating room with hypothermia, that is, with temperatures below 36oC (p=1.0000). The operating room temperature when patients arrived and patients' temperature when they arrived at the operating room were statistically significant to affect the occurrence of hypothermia. CONCLUSION: the planning and implementation of nursing interventions carried out by baccalaureate nurses are essential for preventing hypothermia and maintaining perioperative normothermia. PMID- 23918029 TI - The APACHE II measured on patients' discharge from the Intensive Care Unit in the prediction of mortality. AB - OBJECTIVE: to analyze the performance of the Acute Physiology and Chronic Health Evaluation (APACHE II), measured based on the data from the last 24 hours of hospitalization in ICU, for patients transferred to the wards. METHOD: an observational, prospective and quantitative study using the data from 355 patients admitted to the ICU between January and July 2010, who were transferred to the wards. RESULTS: the discriminatory power of the AII-OUT prognostic index showed a statistically significant area beneath the ROC curve. The mortality observed in the sample was slightly greater than that predicted by the AII-OUT, with a Standardized Mortality Ratio of 1.12. In the calibration curve the linear regression analysis showed the R2 value to be statistically significant. CONCLUSION: the AII-OUT could predict mortality after discharge from ICU, with the observed mortality being slightly greater than that predicted, which shows good discrimination and good calibration. This system was shown to be useful for stratifying the patients at greater risk of death after discharge from ICU. This fact deserves special attention from health professionals, particularly nurses, in managing human and technological resources for this group of patients. PMID- 23918030 TI - Cardiovascular risk assessment in hypertensive patients. AB - OBJECTIVE: to assess cardiovascular risk by means of the traditional Framingham score and the version modified through the incorporation of emerging risk factors, such as family history of acute myocardial infarction, metabolic syndrome and chronic kidney disease. METHOD: participants were 50 hypertensive patients under outpatient treatment. The clinical data were collected through a semi-structured interview and the laboratory data from patients' histories. RESULTS: it was verified that the traditional Framingham score was predominantly low (74%), with 14% showing medium risk and 12% high risk. After the inclusion of emerging risk factors, the chance of a coronary event was low in 22% of the cases, medium in 56% and high in 22%. CONCLUSIONS: the comparison between the traditional Framingham risk score and the modified version demonstrated a significant difference in the cardiovascular risk classification, whose correlation shows discreet agreement between the two scales. Lifestyle elements seem to play a determinant role in the increase in cardiovascular risk levels. PMID- 23918031 TI - Chronic subdural hematoma - an up-to-date concept. AB - Chronic subdural hematoma (CSDH) is prevalent among elderly populations worldwide, and its mysterious pathogenesis has been discussed in the literature for decades. The issues remaining to be solved in regard to CSDH include the initiating events; the bleeding into the subdural space and the formation of the outer and inner membranes, its development; increase and liquefaction of hematoma, the optimal treatments, and the natural history. The pathophysiology is becoming more clear due to recent findings from computed tomography studies and human models of CSDH. In this work, we review previous studies on CSDH and present a new integrated concept about the development of this common condition after head injuries. PMID- 23918032 TI - [Posttraumatic dystrophy. Diagnosis and therapy after distal radius fractures and hand injuries]. AB - BACKGROUND: Posttraumatic dystrophy manifests as signs and symptoms of endothelial dysfunction in the microcirculation with pronounced involvement of arteriovenous (AV) anastomosis. PATIENTS AND METHODS: Blood gas analysis was performed in 28 patients with persistent painful swelling 6-14 weeks after distal radius fracture or hand injury. The patients showed higher levels of venous oxygenation on the affected side in comparison to the contralateral arm. Furthermore, an increased perfusion and an AV shunt situation were proven by radionuclide angiography. These findings correlate with insufficient oxygen utilization by the tissue (dystrophy = capillary malperfusion). Pathophysiologically, complex processes must be assumed which require a multimodal therapy and treatment focuses on open AV shunts. RESULTS: The disastrous consequences of hand dystrophy (loss of function due to fibrosis) could be prevented in all patients. Statistical analyses between affected and normal hands showed significant differences. CONCLUSION: Posttraumatic dystrophy needs early detection for successful therapy and should not be identified under the umbrella term "complex regional pain syndrome" (CRPS). PMID- 23918033 TI - Deciphering serology to understand the ecology of infectious diseases in wildlife. AB - The ecology of infectious disease in wildlife has become a pivotal theme in animal and public health. Studies of infectious disease ecology rely on robust surveillance of pathogens in reservoir hosts, often based on serology, which is the detection of specific antibodies in the blood and is used to infer infection history. However, serological data can be inaccurate for inference to infection history for a variety of reasons. Two major aspects in any serological test can substantially impact results and interpretation of antibody prevalence data: cross-reactivity and cut-off thresholds used to discriminate positive and negative reactions. Given the ubiquitous use of serology as a tool for surveillance and epidemiological modeling of wildlife diseases, it is imperative to consider the strengths and limitations of serological test methodologies and interpretation of results, particularly when using data that may affect management and policy for the prevention and control of infectious diseases in wildlife. Greater consideration of population age structure and cohort representation, serological test suitability and standardized sample collection protocols can ensure that reliable data are obtained for downstream modeling applications to characterize, and evaluate interventions for, wildlife disease systems. PMID- 23918034 TI - Genome-wide association study (GWAS) for molar-incisor hypomineralization (MIH). AB - OBJECTIVES: This genome-wide association study (GWAS) investigated the relationship between molar-incisor hypomineralization (MIH) and possible genetic loci. Clinical and genetic data from the 10-year follow-up of 668 children from the Munich GINI-plus and LISA-plus birth cohort studies were analyzed. MATERIAL AND METHODS: The dental examinations included the diagnosis of MIH according to the criteria of the European Academy of Paediatric Dentistry (EAPD). Children with MIH were categorized as those with a minimum of one hypomineralized first permanent molar. A GWAS was implemented following a quality-control step and an additive genetic effect was assumed. RESULTS: A total of 2,013,491 single nucleotide polymorphisms (SNPs) were available for analysis. Rs13058467, which is located near the SCUBE1 gene on chromosome 22 (p < 3.72E-7), was identified as a possible locus linked to MIH when using a threshold of p value <1E-6. CONCLUSIONS: After considering the limitations of the present study (e.g., limited sample size and lack of an independent replication sample), it can be concluded that (1) replication analyses in an independent cohort study are strongly recommended and (2) large-scale and well-powered studies are needed to investigate a possible genetic link to MIH. PMID- 23918036 TI - Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis. AB - OBJECTIVES: High levels of vascular endothelial growth factor (VEGF), a key angiogenic factor, are present in patients with systemic sclerosis (SSc), but its role in the pathogenesis of fibrosis and its contribution to the disturbed angiogenesis of SSc remains hypothetical. METHODS: Mono (+/-) and double (+/+) VEGF transgenic (tg) mice and their wildtype (wt) controls were analysed. The bleomycin model was applied to VEGF tg mice to evaluate effects of VEGF under proinflammatory conditions. Additionally, tight skin (TSK) 1/VEGF+/+ mice were generated to mimic later non-inflammatory stages of SSc. RESULTS: VEGF+/+, but not VEGF+/- tg mice, spontaneously developed significant skin fibrosis, indicating profibrotic effect of VEGF in a gene-dosing manner. In the proinflammatory bleomycin model, the profibrotic effect became more pronounced with induction of skin fibrosis in VEGF+/- tg mice and even more enhanced fibrosis in VEGF+/+ tg mice. Analysis in TSK1/VEGF+/+ mice showed similar profibrotic effects of VEGF also under non-inflammatory in vivo conditions. In vitro analysis revealed that VEGF is able to directly induce collagen synthesis in dermal fibroblasts. Additionally, there was an inverse gene-dosing effect on the efficacy of angiogenesis in that a higher number of microvessels was observed in VEGF+/- tg mice than in VEGF+/+ tg mice. CONCLUSIONS: These data provide the first evidence for VEGF as a novel molecular link between fibrosis and vasculopathy in the pathogenesis of SSc. They suggest that high levels of VEGF potently induce fibrosis in inflammatory and non-inflammatory stages, and also contribute to the relatively insufficient angiogenesis characteristic for SSc. PMID- 23918038 TI - An in-plane optofluidic microchip for focal point control. AB - A polydimethylsiloxane (PDMS) optofluidic microfluidic chip comprising a tunable optofluidic in-plane biconvex microlens and a tunable optofluidic in-plane microprism is proposed for controlling the focal length and deviation angle of a light beam. In the proposed device, the microlens comprises an expansion chamber containing a high refractive index stream sandwiched between two low refractive index streams. Meanwhile, the microprism comprises a triangular chamber filled with two liquids, one with a higher refractive index than that of PDMS and the other a lower refractive index than that of PDMS. It is shown that the radius of curvature (and therefore the focal length) of the microlens can be adjusted by controlling the flow rate ratio of the core and cladding streams. In addition, it is shown that the deviation angle of the light ray exiting the microprism depends on the refractive indices of the two working fluids, the apex angle of the prism chamber, and the flow rate ratio of the two working fluids. In general, the results show that the biconvex microlens enables the focal length to be adjusted in the range of 2.9-7.6 mm when using benzothiazole and ethylene glycol-ethanol as the core and cladding fluids, respectively. Moreover, a deviation angle range of -6.2 degrees to 22.3 degrees can be achieved when using a microprism chamber with an apex angle of 90 degrees and benzothiazole and DI water as the working fluids. The integrated optofluidic chip therefore can manipulate the focal length and deviation angle of a light beam by adjusting the relative flow rates of fluids. PMID- 23918037 TI - Long-term safety and efficacy of certolizumab pegol in combination with methotrexate in the treatment of rheumatoid arthritis: 5-year results from the RAPID 1 trial and open-label extension. AB - OBJECTIVES: To examine the safety and efficacy of 5-year administration of certolizumab pegol (CZP)+methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: Eligible patients from the Rheumatoid Arthritis Prevention of Structural Damage (RAPID)1 randomised controlled trial (RCT) were treated in open-label extension (OLE) with CZP 400 mg every other week (Q2W), reduced to 200 mg Q2W after >=6 months, +MTX. Combined safety data from RCT and OLE are presented from initiation of CZP treatment to 12 wks post last visit in patients receiving >=1 dose of CZP (Safety population, N=958). Efficacy data are presented to start of first site closure (wk 256 of CZP treatment: 52 wks in RCT+204 wks in OLE) for all patients randomised to receive CZP (intent-to-treat (ITT) population, N=783) and CZP patients who completed the 52 wk RCT and enrolled into OLE (wk 52 CZP completers, N=508). Disease Activity Score (DAS)28 (Erythrocyte Sedimentation Rate (ESR)), American College of Rheumatology Criteria (ACR) 20/50/70, Health Assessment Questionnaire - Disability Index (HAQ-DI), and patient retention (Kaplan-Meier analysis) were assessed. RESULTS: Overall event rate per 100 patient-years (ER) of adverse events (AEs) was 290.4, most frequently: urinary tract infections (ER=7.9), nasopharyngitis (ER=7.3) and upper respiratory tract infections (ER=7.3). ER of serious AEs was 20.3 (infections=5.9, malignancies=1.2). 21 patients (2.2%) experienced an AE resulting in death (incidence rate=0.6). At wk 256 of treatment, 55.3% of the CZP ITT population were estimated to remain on treatment (68.7% if solely withdrawals due to AE or lack of efficacy were considered). In wk 52 CZP completers and CZP ITT population, DAS28 (ESR) remission rates and improvements from baseline were sustained to wk 256. CONCLUSIONS: CZP+MTX treatment provided a favourable risk benefit profile over 5 years in patients with active RA. No new safety signals were identified. PMID- 23918035 TI - Biologic and oral disease-modifying antirheumatic drug monotherapy in rheumatoid arthritis. AB - Clinical evidence demonstrates coadministration of tumour necrosis factor inhibitor (TNFi) agents and methotrexate (MTX) is more efficacious than administration of TNFi agents alone in patients with rheumatoid arthritis, leading to the perception that coadministration of MTX with all biologic agents or oral disease-modifying antirheumatic drugs is necessary for maximum efficacy. Real-life registry data reveal approximately one-third of patients taking biologic agents use them as monotherapy. Additionally, an analysis of healthcare claims data showed that when MTX was prescribed in conjunction with a biologic agent, as many as 58% of patients did not collect the MTX prescription. Given this discrepancy between perception and real life, we conducted a review of the peer-reviewed literature and rheumatology medical congress abstracts to determine whether data support biologic monotherapy as a treatment option for patients with rheumatoid arthritis. Our analysis suggests only for tocilizumab is there evidence that the efficacy of biologic monotherapy is comparable with combination therapy with MTX. PMID- 23918039 TI - Heat Transfer Investigation of Air Flow in Microtubes-Part II: Scale and Axial Conduction Effects. AB - In this paper, the scale effects are specifically addressed by conducting experiments with air flow in different microtubes. Three stainless steel tubes of 962, 308, and 83 MUm inner diameter (ID) are investigated for friction factor, and the first two are investigated for heat transfer. Viscous heating effects are studied in the laminar as well as turbulent flow regimes by varying the air flow rate. The axial conduction effects in microtubes are experimentally explored for the first time by comparing the heat transfer in SS304 tube with a 910 MUm ID/2005 MUm outer diameter nickel tube specifically fabricated using an electrodeposition technique. After carefully accounting for the variable heat losses along the tube length, it is seen that the viscous heating and the axial conduction effects become more important at microscale and the present models are able to predict these effects accurately. It is concluded that neglecting these effects is the main source of discrepancies in the data reported in the earlier literature. PMID- 23918040 TI - Celiac disease and chronic liver disease: is there a relationship? AB - Celiac disease is a multisystem disease, and the liver is affected in a subset of patients. We herein present a case series of 25 patients with celiac disease who had evidence of cirrhosis of the liver. We retrospectively reviewed the case records of patients with celiac disease having concomitant cirrhosis. The diagnosis of celiac disease was made on the basis of the modified European Society of Pediatric Gastroenterology, Hepatology, and Nutrition criteria. Of 25 patients (nine males; mean age 28.8 +/- 16.6 years) with celiac disease and cirrhosis, 17 patients presented predominantly with cirrhosis, while 8 presented primarily with celiac disease. Five patients had known cause of cirrhosis (autoimmune hepatitis, three; PBC, one; hepatic venous outflow tract obstruction, one); the remaining 20 were cryptogenic. Gluten-free diet led to improvement in diarrhea and anemia and to a better control of ascites and other features of liver failure. Some patients with cryptogenic cirrhosis have coexistent celiac disease, and they show response to gluten-free diet. Patients with cryptogenic cirrhosis should be screened for celiac disease. PMID- 23918042 TI - Liquid crystal self-templating approach to ultrastrong and tough biomimic composites. AB - Materials with both high strength and toughness are in great demand for a wide range of applications, requiring strict design of ingredients and hierarchically ordered architecture from nano- to macro-scale. Nacre achieves such a target in the long natural evolution by alternative alignment of inorganic nanoplatelets and biomacromolecules. To mimic nacre, various strategies were developed, approaching nacre-comparable performance in limited size. How to remarkably exceed nacre in both property and size is a key issue to further the advancement of composites. Here we present liquid crystal self-templating methodology to make the next generation of ultrastrong and tough nacre-mimics continuously. The hierarchically assembled composites show the highest tensile strength (652 MPa) among nacre mimics, five to eight times as high as that of nacre (80-135 MPa), and excellent ductility with toughness of 18 MJ m(-3), one to two orders of magnitude greater than that of nacre (0.1 ~ 1.8 MJ m(-3)). PMID- 23918043 TI - BDNF and TNF-alpha polymorphisms in memory. AB - Here, we investigate the genetic basis of human memory in healthy individuals and the potential role of two polymorphisms, previously implicated in memory function. We have explored aspects of retrospective and prospective memory including semantic, short term, working and long-term memory in conjunction with brain derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF alpha). The memory scores for healthy individuals in the population were obtained for each memory type and the population was genotyped via restriction fragment length polymorphism for the BDNF rs6265 (Val66Met) SNP and via pyrosequencing for the TNF-alpha rs113325588 SNP. Using univariate ANOVA, a significant association of the BDNF polymorphism with visual and spatial memory retention and a significant association of the TNF-alpha polymorphism was observed with spatial memory retention. In addition, a significant interactive effect between BDNF and TNF-alpha polymorphisms was observed in spatial memory retention. In practice visual memory involves spatial information and the two memory systems work together, however our data demonstrate that individuals with the Val/Val BDNF genotype have poorer visual memory but higher spatial memory retention, indicating a level of interaction between TNF-alpha and BDNF in spatial memory retention. This is the first study to use genetic analysis to determine the interaction between BDNF and TNF-alpha in relation to memory in normal adults and provides important information regarding the effect of genetic determinants and gene interactions on human memory. PMID- 23918044 TI - A multicenter phase II study of belotecan, a new camptothecin analogue, in elderly patients with previously untreated, extensive-stage small cell lung cancer. AB - PURPOSE: Belotecan is a new camptothecin analogue and a potent topoisomerase I inhibitor. The aim of this phase II study was to investigate the efficacy and toxicity of belotecan in previously untreated elderly patients with small cell lung cancer (SCLC). METHODS: A total of 26 patients, aged >=65 years, with previously untreated, extensive-stage SCLC were enrolled in the study. Belotecan was administered by daily intravenous infusion at 0.5 mg/m(2)/day for 5 consecutive days every 3 weeks. RESULTS: The overall response rate and disease control rate of chemotherapy on an intention-to-treat basis were 35 and 54 %, respectively. The median overall survival was 6.4 months, and the median time to progression was 2.8 months. The most common toxicity was hematologic. Grade 3 or 4 neutropenia occurred in 80.8 % of patients, and grade 3 or 4 thrombocytopenia in 15.3 %. Non-hematologic toxic effects of grade 3 or 4 were uncommon. CONCLUSION: Belotecan had modest efficacy and well-tolerated toxicity in previously untreated, elderly SCLC patients. Single belotecan could be a promising treatment option, considering its lower toxicity in elderly patients who are unsuitable candidates for platinum plus etoposide chemotherapy. PMID- 23918045 TI - SCD1 activity in muscle increases triglyceride PUFA content, exercise capacity, and PPARdelta expression in mice. AB - Stearoyl-CoA desaturase (SCD)1 converts saturated fatty acids into monounsaturated fatty acids. Using muscle overexpression, we sought to determine the role of SCD1 expression in glucose and lipid metabolism and its effects on exercise capacity in mice. Wild-type C57Bl/6 (WT) and SCD1 muscle transgenic (SCD1-Tg) mice were generated, and expression of the SCD1 transgene was restricted to skeletal muscle. SCD1 overexpression was associated with increased triglyceride (TG) content. The fatty acid composition of the muscle revealed a significant increase in polyunsaturated fatty acid (PUFA) content of TG, including linoleate (18:2n6). Untrained SCD1-Tg mice also displayed significantly increased treadmill exercise capacity (WT = 6.6 +/- 3 min, Tg = 71.9 +/- 9.5 min; P = 0.0009). SCD1-Tg mice had decreased fasting plasma glucose, glucose transporter (GLUT)1 mRNA, fatty acid oxidation, mitochondrial content, and increased peroxisome proliferator-activated receptor (PPAR)delta and Pgc-1 protein expression in skeletal muscle. In vitro studies in C2C12 myocytes revealed that linoleate (18:2n6) and not oleate (18:1n9) caused a 3-fold increase in PPARdelta and a 9-fold increase in CPT-1b with a subsequent increase in fat oxidation. The present model suggests that increasing delta-9 desaturase activity of muscle increases metabolic function, exercise capacity, and lipid oxidation likely through increased PUFA content, which increases PPARdelta expression and activity. However, the mechanism of action that results in increased PUFA content of SCD1-Tg mice remains to be elucidated. PMID- 23918046 TI - Heritability of metabolic syndrome traits in a large population-based sample. AB - Heritability estimates of metabolic syndrome traits vary widely across studies. Some studies have suggested that the contribution of genes may vary with age or sex. We estimated the heritability of 11 metabolic syndrome-related traits and height as a function of age and sex in a large population-based sample of twin families (N = 2,792-27,021, for different traits). A moderate-to-high heritability was found for all traits [from H(2) = 0.47 (insulin) to H(2) = 0.78 (BMI)]. The broad-sense heritability (H(2)) showed little variation between age groups in women; it differed somewhat more in men (e.g., for glucose, H(2) = 0.61 in young females, H(2) = 0.56 in older females, H(2) = 0.64 in young males, and H(2)= 0.27 in older males). While nonadditive genetic effects explained little variation in the younger subjects, nonadditive genetic effects became more important at a greater age. Our findings show that in an unselected sample (age range, ~18-98 years), the genetic contribution to individual differences in metabolic syndrome traits is moderate to large in both sexes and across age. Although the prevalence of the metabolic syndrome has greatly increased in the past decades due to lifestyle changes, our study indicates that most of the variation in metabolic syndrome traits between individuals is due to genetic differences. PMID- 23918048 TI - Use of pressure-volume loops for physiological assessment of adult laryngotracheal stenosis. AB - OBJECTIVES/HYPOTHESIS: To assess the utility of intraoperative pressure-volume curves as an objective method of physiological disease stratification and outcomes assessment in adult laryngotracheal stenosis. STUDY DESIGN: Prospective observational study. METHODS: We prospectively studied 42 tracheotomy-free patients undergoing endoscopic laryngotracheoplasty over 18 months. Patient and lesion characteristics were obtained. Dyspnea severity was assessed using the Medical Research Council scale. Preoperative spirometry and intraoperative pulmonary compliance were recorded. RESULTS: There were 19 male and 23 female patients, and the mean age at treatment was 44 +/- 16 years. There were 14 Myer Cotton 1 lesions and 14 and 13 patients had grade 2 or 3 stenoses, respectively. Pulmonary compliance was strongly correlated with anatomical stenosis severity (r = 0.8, P < .0001) and perceptual dyspnea severity (r = 0.73, P < .0001). The strengths of correlation between pulmonary compliance and anatomical stenosis severity was significantly greater than those between forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and peak expiratory flow. The strength of correlation between pulmonary compliance and perceptual dyspnea severity was significantly greater than those between FEV1 and FVC with perceptual dyspnea severity. The two independent determinants of pulmonary compliance were Myer-Cotton stenosis severity (P < .0001) and patient age (P = .013). CONCLUSIONS: Pulmonary compliance provides an objective measure of physiological airway impairment. It correlates well with anatomical disease severity and perceptual dyspnea severity. Its more widespread use in adult patients and research into its utility in pediatric airway stenosis is recommended. PMID- 23918047 TI - Binding of a pleurotolysin ortholog from Pleurotus eryngii to sphingomyelin and cholesterol-rich membrane domains. AB - A mixture of sphingomyelin (SM) and cholesterol (Chol) exhibits a characteristic lipid raft domain of the cell membranes that provides a platform to which various signal molecules as well as virus and bacterial proteins are recruited. Several proteins capable of specifically binding either SM or Chol have been reported. However, proteins that selectively bind to SM/Chol mixtures are less well characterized. In our screening for proteins specifically binding to SM/Chol liposomes, we identified a novel ortholog of Pleurotus ostreatus, pleurotolysin (Ply)A, from the extract of edible mushroom Pleurotus eryngii, named PlyA2. Enhanced green fluorescent protein (EGFP)-conjugated PlyA2 bound to SM/Chol but not to phosphatidylcholine/Chol liposomes. Cell surface labeling of PlyA2-EGFP was abolished after sphingomyelinase as well as methyl-beta-cyclodextrin treatment, removing SM and Chol, respectively, indicating that PlyA2-EGFP specifically binds cell surface SM/Chol rafts. Tryptophan to alanine point mutation of PlyA2 revealed the importance of C-terminal tryptophan residues for SM/Chol binding. Our results indicate that PlyA2-EGFP is a novel protein probe to label SM/Chol lipid domains both in cell and model membranes. PMID- 23918049 TI - Pediatric health care quality measures: considerations for pharmacotherapy. AB - Measuring the quality use of medicines can be conceptualized as a mechanism for understanding appropriate use, underuse, overuse, or misuse. For pediatric pharmacotherapy, measuring the quality use of medicines requires awareness of the differences in health care between children and adults and the differences in the quality and quantity of science that supports evidence-based practice in pediatric health care compared with adult health care. Here we use the Pediatric Quality Measures Program that arose from the Children's Health Insurance Program Reauthorization Act in the United States to illustrate the challenges in developing quality measures of pediatric pharmacotherapy. The challenges are primarily twofold: (i) weak evidence base for the specific pharmacotherapy in children and (ii) limited data to calculate the measure. A weak evidence base must often be weighed against the importance of the topic if the quality measure is intended to address a known quality of care or public health problem. Limited data because of insufficient amount or inappropriate type will affect implementation of the measure and its eventual usefulness. Methods to meet these challenges often depend on the priorities of and the tools available to end users. Health information technology is emerging as a tool to improve quality measurement but presents additional challenges. PMID- 23918050 TI - Introducing a standard method for experimental determination of the solvent response in laser pump, X-ray probe time-resolved wide-angle X-ray scattering experiments on systems in solution. AB - In time-resolved laser pump, X-ray probe wide-angle X-ray scattering experiments on systems in solution the structural response of the system is accompanied by a solvent response. The solvent response is caused by reorganization of the bulk solvent following the laser pump event, and in order to extract the structural information of the solute, the solvent response has to be treated. Methodologies capable of doing so include both theoretical modelling and experimental determination of the solvent response. In the work presented here, we have investigated how to obtain a reproducible solvent response-the solvent term experimentally when applying laser pump, X-ray probe time-resolved wide-angle X ray scattering. The solvent term describes difference scattering arising from the structural response of the solvent to changes in the hydrodynamic parameters: pressure, temperature and density. We present results based on NIR and dye mediated solvent heating, and demonstrate that the solvent response is independent of the heating method. The NIR heating is shown to be rendered unusable by higher order effects under certain experimental conditions, while the dye mediated solvent heating is demonstrated to exhibit first order behaviour with respect to the amount of energy deposited in the solution. We introduce a standardized method for recording solvent responses in laser pump, X-ray probe time-resolved X-ray wide-angle scattering experiments by using dye mediated solvent heating. Furthermore, we have generated a library of solvent terms, which can be used to describe the solvent term in any TRWAXS experiment, and made it available online. PMID- 23918051 TI - [Population mobility and HIV]. PMID- 23918052 TI - [Factors influencing Central America's civil society organization's capacity to provide AIDS related care]. AB - OBJECTIVE: To analyze the capacities of Central American civil society organizations (CSOs) to implement HIV prevention and care strategies in mobile groups within the HIV Mesoamerican Project. MATERIALS AND METHODS: During the year 2008, 14 key actors of nine Central American civil society organizations participating in the Mesoamerican Project were interviewed. The information collected was systematized using Atlas-TI software, and content analysis was performed according to its categories and dimensions. RESULTS: These items were a contribution to capacity: the previous work of CSOs allowed the sensibilization of population and authorities to STD-HIV and to the implemented program; the coordination with government and other involved actors. LIMITATIONS: a good but informal coordination with the government; the worsening economic situation reduced available resources; attended communities are isolated and unsecure. CONCLUSION: To improve the capacities of CSOs in developing this type of project, it is recommended: that an initial community diagnosis be performed in order to better adapt the proposed interventions; to improve administrative efficiency; to formalize collaborative links with the government; and to seek counseling in the development of HIV prevention strategies that consider population mobility. PMID- 23918053 TI - [Cost-benefit analysis: HIV/AIDS prevention in migrants in Central America]. AB - OBJECTIVE: To quantify the costs and benefits of three HIV prevention interventions in migrants in Central America: voluntary counseling and testing, treatment of sexually transmitted infections, and condom distribution. MATERIALS AND METHODS: The methods were: a) identification and quantification of costs; b) quantification of benefits, defined as the potential savings in antiretroviral treatment of HIV cases prevented; and c) estimation of the cost-benefit ratio. RESULTS: The model estimated that 9, 21 and 8 cases of HIV were prevented by voluntary counseling and testing, treatment for sexually transmitted infections and condom distribution per 10 000 migrants, respectively. In Panama, condom distribution and treatment for sexually transmitted infections had a return of US$131/USD and US$69.8/USD. Returns in El Salvador were US$2.0/USD and US$42.3/USD in voluntary counseling and testing and condom distribution, respectively. CONCLUSION: The potential savings on prevention have a large variation between countries. Nevertheless, the cost-benefit estimates suggest that the HIV prevention programs in Central America can potentially result in monetary savings in the long run. PMID- 23918054 TI - [STI and HIV prevention in female sex workers at border communities in Central America]. AB - OBJECTIVE: To analyze access to STI and HIV prevention services for female sex workers in border communities of Central America. MATERIALS AND METHODS: A quasi experimental study was carried out in a non-random sample of 558 sex workers, in border communities with and without prevention interventions related to information on human rights, sexual behavior and access to information on prevention/transmission, condoms, HIV testing, contraception, healthcare and condom use. A descriptive analysis of these variables was done and a logistic regression model was used, in order to identify factors associated with condom use. RESULTS: Female sex workers of communities with intervention had greater access to information on prevention (99 vs 87%), condoms (98 vs 75%), HIV testing (89 vs 61%), contraception (74 vs 65%), gynecological services (83 vs 57%), and condom use with clients, 3.9 (IC:1.2-12.7), compared to workers in communities without intervention. CONCLUSIONS: The observed differences must be considered in a more general framework related to sociocultural characteristics and population mobility in border contexts, as well as to the organization of healthcare services. PMID- 23918055 TI - [Prevention of HIV among youth from Central American border communities]. AB - OBJECTIVE: To examine factors associated to prevention, STI/HIV medical attention and respect for people living with HIV/AIDS (PLWHA) among youth in Central American border communities. MATERIALS AND METHODS: Cross-sectional analysis of a non-probabilistic sample (n=716) in border communities with and without preventive and medical care STI/ HIV interventions. Variables associated with having access to information, respect to PLWHA; HIV/STD tests, condom use and medical care were identified. RESULTS: Youth in communities with interventions have higher levels of information regarding STI/HIV, attitudes of respect toward PLWHA (94.1 vs. 75.3%) and access to HIV tests (50.8 vs. 14.7%). 52% of youngsters had intercourse. Condom use was higher among those who participated in preventive actions (60.5 vs. 50.9%) and those with international mobility (70.6 vs. 51.9%). 8.8% had STI symptoms; only 55% sought medical attention. CONCLUSION: Community interventions are associated with higher levels of information, respect for the rights of PLWHA and access to tests among youth; condom use is related to direct participation in program interventions. PMID- 23918056 TI - [Population mobility and HIV: an experience of regional cooperation in Central America and Mexico]. PMID- 23918057 TI - [Sexually transmitted infections: profile of care in border areas of Central America (2007-2010)]. AB - OBJECTIVE: To analyze the profile of care for sexually transmitted infections (STIs) in health centers in border areas of Central America during 2007-2010. MATERIALS AND METHODS: Cross-sectional study in a sample of 3 357 patients. Doctors were trained and medicines, condoms and HIV testing (basic package of care [BPC]) were supplied. Sample was characterized according to sociodemographic variables. Factors associated with the probability of receiving the BPC were identified. RESULTS: Sixty six percent were 25-59 years old, and 93.2% were women. The most frequently diagnosed syndrome was vaginal discharge associated with candidiasis, bacterial vaginosis, trichomoniasis and gonorrhea. Sixty six percent of prescriptions were adhered to the international recommendations. Only 10% received the complete BPC.The likelihood of receiving it was lower in women. CONCLUSIONS: It is not enough to increase service delivery capacity to change care practices. These are deeply rooted in the sociocultural context. Highlights gendered medical practices that adversely affect the profile of care. PMID- 23918058 TI - [Central American migrants' sexual experiences and rights in their transit to the USA]. AB - OBJECTIVES: To explore the causes and circumstances that determine the way in which migrants experience their sexuality and how this impacts their sexual rights. MATERIALS AND METHODS: Qualitative study conducted between April 2009 and July 2010 in Chiapas, Oaxaca, San Luis Potosi, and Tamaulipas. We conducted 22 in depth interviews to migrants in transit and to ten different key actors. For the analysis we used elements of grounded theory. RESULTS: Migrants know and identify the risks they may encounter in their transit but have scarce access to services to effectively exercise their sexual and reproductive rights. Their vulnerability makes them internalize and accept the violence enacted on them as part of their destiny and as what they must suffer in order to reach the USA. CONCLUSIONS: Violence, including sexual violence, determines much of the experiences of their transit through Mexico. Differences between groups and between male and female migrants are determined by gender inequalities and power. PMID- 23918059 TI - Systematic review of HIV prevalence studies among key populations in Latin America and the Caribbean. AB - OBJECTIVE: This systematic review aims to synthesize articles, abstracts and reports of HIV prevalence studies conducted among men who have sex with men (MSM) and female sex workers (FSW) in Latin America and the Caribbean (LAC). MATERIALS AND METHODS: Authors searched online databases and collected gray literature on HIV prevalence among MSM and FSW from LAC. Year, location, sampling methodology, study design, sample size, HIV prevalence and confidence intervals were abstracted. RESULTS: A total of 73 studies, dating from 1986 to 2010 were included.The median prevalences for MSM and FSW were 10.6% (interquartile range: 7.4- 17.4) and 2.6% (IQR: 0.6 -4.2), respectively. Variability was high, especially for MSM. The majority of studies recruited participants using convenience methods. CONCLUSION: HIV prevalence among MSM was higher than that among FSW. Sampling techniques should be standardized for future studies, prioritizing probability methods. PMID- 23918060 TI - [An application of the strategy results cycle to HIV/AIDS strategic planning in Latin America]. AB - OBJECTIVE: To describe the Strategy Results Cycle (SRC), a model that approaches planning as an ongoing cycle of seven phases that continually responds and adapts to existing evidence. MATERIALS AND METHODS: Reliable sources were used for the preparation of databases and expenditure-costing data for resources needs analysis. The planning process 6-9 months to complete a national strategic plan that was informed by evidence, focused on results and costed. RESULTS: Knowledge transfer facilitated national leadership and stakeholders' participation. Between 2007 and 2011, 13 of 16 countries adopted the Strategy Results Cycle model. The evidence supported the identification of results and the expenditure-costing analysis improved budget allocation efficiency. CONCLUSION: The SRC facilitated purposeful participation and added value to previous planning approaches by connecting "thinking" and "doing" which resulted in national strategic plans that are designed by stakeholders, relevant to local conditions, and can guide implementation and resource mobilization. PMID- 23918061 TI - Long term, stable brain machine interface performance using local field potentials and multiunit spikes. AB - OBJECTIVE: Brain machine interfaces (BMIs) have the potential to restore movement to people with paralysis. However, a clinically-viable BMI must enable consistently accurate control over time spans ranging from years to decades, which has not yet been demonstrated. Most BMIs that use single-unit spikes as inputs will experience degraded performance over time without frequent decoder re training. Two other signals, local field potentials (LFPs) and multi-unit spikes (MSPs), may offer greater reliability over long periods and better performance stability than single-unit spikes. Here, we demonstrate that LFPs can be used in a biomimetic BMI to control a computer cursor. APPROACH: We implanted two rhesus macaques with intracortical microelectrodes in primary motor cortex. We recorded LFP and MSP signals from the monkeys while they performed a continuous reaching task, moving a cursor to randomly-placed targets on a computer screen. We then used the LFP and MSP signals to construct biomimetic decoders for control of the cursor. MAIN RESULTS: Both monkeys achieved high-performance, continuous control that remained stable or improved over nearly 12 months using an LFP decoder that was not retrained or adapted. In parallel, the monkeys used MSPs to control a BMI without retraining or adaptation and had similar or better performance, and that predominantly remained stable over more than six months. In contrast to their stable online control, both LFP and MSP signals showed substantial variability when used offline to predict hand movements. SIGNIFICANCE: Our results suggest that the monkeys were able to stabilize the relationship between neural activity and cursor movement during online BMI control, despite variability in the relationship between neural activity and hand movements. PMID- 23918062 TI - Bridging the genotyping gap: using genotyping by sequencing (GBS) to add high density SNP markers and new value to traditional bi-parental mapping and breeding populations. AB - Genotyping by sequencing (GBS) is the latest application of next-generation sequencing protocols for the purposes of discovering and genotyping SNPs in a variety of crop species and populations. Unlike other high-density genotyping technologies which have mainly been applied to general interest "reference" genomes, the low cost of GBS makes it an attractive means of saturating mapping and breeding populations with a high density of SNP markers. One barrier to the widespread use of GBS has been the difficulty of the bioinformatics analysis as the approach is accompanied by a high number of erroneous SNP calls which are not easily diagnosed or corrected. In this study, we use a 384-plex GBS protocol to add 30,984 markers to an indica (IR64) * japonica (Azucena) mapping population consisting of 176 recombinant inbred lines of rice (Oryza sativa) and we release our imputation and error correction pipeline to address initial GBS data sparsity and error, and streamline the process of adding SNPs to RIL populations. Using the final imputed and corrected dataset of 30,984 markers, we were able to map recombination hot and cold spots and regions of segregation distortion across the genome with a high degree of accuracy, thus identifying regions of the genome containing putative sterility loci. We mapped QTL for leaf width and aluminum tolerance, and were able to identify additional QTL for both phenotypes when using the full set of 30,984 SNPs that were not identified using a subset of only 1,464 SNPs, including a previously unreported QTL for aluminum tolerance located directly within a recombination hotspot on chromosome 1. These results suggest that adding a high density of SNP markers to a mapping or breeding population through GBS has a great value for numerous applications in rice breeding and genetics research. PMID- 23918063 TI - Candidate loci for phenology and fruitfulness contributing to the phenotypic variability observed in grapevine. AB - KEY MESSAGE: In this study, we identified several genes, which potentially contribute to phenological variation in the grapevine. This may help to maintain consistent yield and suitability of particular varieties in future climatic conditions. The timing of major developmental events in fruit crops differs with cultivar, weather conditions and ecological site. This plasticity results also in diverse levels of fruitfulness. Identifying the genetic factors responsible for phenology and fertility variation may help to improve these traits to better match future climates. Two Vitis vinifera populations, an F1 progeny of Syrah * Pinot Noir and a phenological core collection composed of 163 cultivars, were evaluated for phenology and fertility subtraits during three to six growing seasons in the same geographical location. The phenotypic variability in the core collection mostly overlapped with that observed in the F1 progeny and several accessions had exceeding values of phenological response. The progeny population was used together with SSR and SNP markers to map quantitative trait loci (QTLs). This allowed us to detect nine QTLs related to budburst, flowering beginning, the onset of ripening (veraison) and total fertility, explaining from 8 to 44 % of phenotypic variation. A genomic region on chromosome 15 was associated with budburst and veraison and two QTLs for fruitfulness were located on chromosomes 3 and 18. Several genes potentially affecting fertility and the timing of fruit development were proposed, based on their position and putative function. Allelic variation at these candidate loci may be explored by sampling accessions from the core collection. PMID- 23918066 TI - Random walk analysis of ranging patterns of sympatric langurs in a complex resource landscape. AB - The identification of random walk models to characterize the movement patterns of social groups of primates, and the behavioral processes that give rise to such movement patterns, remain open questions in movement ecology. Movement patterns characterized by a power-law tail with exponent between 1 and 3 (Levy flight) occur when animals forage on scarce, randomly distributed resources. For primates and similar foragers with memory processes, movements resembling Levy flights emerge when feeding trees (targets) are randomly distributed and the trunk size distribution of targets follows a power-law. We tested three competing random walk models to describe movement patterns of two langur species. We found a truncated power law to be the most suitable model. The power-law model was poorly supported by the data and hence we found no support for Levy-flight-like behavior. Moreover, the spatial distribution of feeding trees and the probability distribution of feeding tree size differed from values suggested to result in Levy-flight-like patterns. We identify intraspecific territoriality, foraging behavior, and the spatial and size distribution of food patches as plausible mechanisms that may have given rise to the observed movement patterns. PMID- 23918065 TI - Variation at the vernalisation genes Vrn-H1 and Vrn-H2 determines growth and yield stability in barley (Hordeum vulgare) grown under dryland conditions in Syria. AB - KEY MESSAGE: Spring growth in barley controlled by natural variation at Vrn-H1 and Vrn-H2 improved yield stability in marginal Syrian environments. The objective of the present study was to identify QTL influencing agronomic performance in rain-fed Mediterranean environments in a recombinant inbred line (RIL) population, ARKE derived from the Syrian barley landrace, Arta and the Australian feed cultivar, Keel. The population was field tested for agronomic performance at two locations in Syria for 4 years with two sowing dates, in autumn and winter. Genotypic variability in yield of the RIL population was mainly affected by year-to-year variation presumably caused by inter-annual differences in rainfall distribution. The spring growth habit and early flowering inherited from the Australian cultivar Keel increased plant height and biomass and improved yield stability in Syrian environments. QTL for yield and biomass coincided with the map location of flowering time genes, in particular the vernalisation genes Vrn-H1 and Vrn-H2. In marginal environments with terminal drought, the Vrn-H1 allele inherited from Keel improved final biomass and yield. Under changing climate conditions, such as shorter winters, reduced rainfall, and early summer drought, spring barley might thus outperform the traditional vernalisation-sensitive Syrian landraces. We present the ARKE population as a valuable genetic resource to further elucidate the genetics of drought adaptation of barley in the field. PMID- 23918064 TI - Cbf14 copy number variation in the A, B, and D genomes of diploid and polyploid wheat. AB - Freezing tolerance and winter hardiness are complex traits. In the Triticeae, two loci on the group 5 chromosome homoeologs are repeatedly identified as having major effects on these traits. Recently, we found that segments of the genomic region at one of these loci, Frost resistance-2 (Fr-2) is copy number variable in barley. Freezing-tolerant winter-hardy genotypes have greater tandem copy numbers of the genomic region encompassing the C-repeat binding factor genes Cbf2A and Cbf4B at Fr-H2 than the less freezing-tolerant nonwinter-hardy genotypes. Here we report that in wheat the Cbf14 gene at Fr-2 is copy number variable. Using DNA blot hybridizations, we estimated copy numbers of Cbf14 across the different genomes of diploid and polyploid wheat. Copy numbers of Cbf14 are lower in the B genome than in the A and D genomes across all ploidy levels. Among hexaploid red wheats, winter genotypes harbor greater Cbf14 copy numbers than spring genotypes. Cbf14 copy numbers also vary across the red winter wheats such that hard wheats harbor greater copy numbers than soft wheats. Analysis of hexaploid wheat chromosome 5 substitution lines indicates that Cbf14 copy numbers in the introgressions are stable in the different backgrounds. Taken together our data suggest that higher copy number states existed in the diploid wild ancestors prior to the polyploidization events and that the loss of Cbf14 copies occurred in the cultivated germplasm. PMID- 23918067 TI - Launching into adulthood from institutional care with a serious mental health condition. AB - This qualitative study explores the experiences of emerging adults with serious mental health conditions (e.g., bipolar disorder, posttraumatic stress disorder) before and after they emancipate from the child welfare system and exit a transitional living program. Sixteen participants were interviewed before and 13 were interviewed after aging out. Findings suggest that transitional living programs services were appreciated for the relationships and safety net they fostered. Future plans were positive, but vague, and worries about the future were prevalent. Struggles with independence post-emancipation were common despite adult service use. Additional research is needed to understand how to best support these at-risk emerging adults. PMID- 23918068 TI - Medical diplomacy and global mental health: from community and national institutions to regional centers of excellence. AB - We explore how regional medical diplomacy can increase funding for global mental health initiatives. Interventions for infectious diseases have dominated medical diplomacy by focusing on security concerns. The global mental health movement has adopted similar strategies, but unsuccessfully since mental illnesses do not cause international epidemics. Instead, realpolitik arguments may increase funding by prioritizing economic productivity and regional diplomacy based on cultural ties to advance mental health services and research at the community level. In South Asia, initiatives to train personnel and provide refugee services offer a foundation for regional centers of excellence. This model can be expanded elsewhere. PMID- 23918069 TI - Overview and management of cardiac adverse events associated with tyrosine kinase inhibitors. AB - BACKGROUND: Small-molecule tyrosine kinase inhibitors (TKIs) may provide an effective therapeutic option in patients with hematologic malignancies and solid tumors. However, cardiovascular (CV) events, including hypertension, heart failure, left ventricular systolic dysfunction, and QT prolongation, have emerged as potential adverse events (AEs) with TKI therapy. PURPOSE: We review what is known about the mechanism of action of CV AEs associated with TKI use and discuss therapeutic interventions that may prevent and manage these events in clinical practice. METHODS: References for this review were identified through searches of PubMed and Medline databases, and only papers published in English were considered. Search terms included "cardiac," "cardiovascular," "cancer," and "kinase inhibitor." Related links in the databases were reviewed, along with relevant published guidelines. RESULTS: Although the link between rising blood pressure (BP) and CV AEs is observed but not proven, good clinical practice supports an aggressive policy on proper long-term BP management. There are insufficient data from randomized controlled clinical trials to show indisputably that aggressive or effective heart failure therapy in patients receiving TKIs will fundamentally change outcomes; however, clinical practice suggests that this is an effective long-term approach. Recognizing that QT prolongation is associated with TKI use facilitates identification of patients at high risk for this CV AE and increases awareness of the need for routine electrocardiograms and electrolyte monitoring for those receiving TKI treatment. CONCLUSION: Regular monitoring, early recognition, and appropriate interventions for CV AEs can help more patients derive the benefit of long-term TKI therapy. PMID- 23918071 TI - Screening for lung cancer with low-dose computed tomography. PMID- 23918070 TI - Second-Line Therapy for Advanced NSCLC. AB - Most patients with lung cancer have non-small cell lung cancer (NSCLC) subtype and have advanced disease at the time of diagnosis. Improvements in both first line and subsequent therapies are allowing longer survival and enhanced quality of life for these patients. The median overall survival observed in many second line trials is approximately 9 months, and many patients receive further therapy after second-line therapy. The cytotoxic agents pemetrexed and docetaxel and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib are standard second-line therapies. For patients with EGFR mutation, a TKI is the favored second-line therapy if not already used in first-line therapy. For patients without the EGFR mutation, TKIs are an option, but many oncologists favor cytotoxic therapy. The inhibitor of the EML4/ALK fusion protein, crizotinib, has recently become a standard second-line treatment for patients with the gene rearrangement and has promise for patients with the ROS1 rearrangement. PMID- 23918072 TI - Epidemiology and intermediate-term outcomes of open- and closed-globe injuries in traumatic childhood cataract. AB - PURPOSE: To study epidemiology and intermediate-term outcomes of open- and closed globe injuries (CGI) in traumatic childhood cataract. METHODS: In this retrospective interventional case series, demographic parameters and history including type of injury of 57 children younger than 16 years with traumatic cataract were recorded; ocular examination included best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, and posterior segment evaluation. Patients underwent cataract surgery with or without intraocular lens (IOL) implantation. Main surgical outcomes at 6 months comprised BCVA, residual refractive spherical error (SE), and postoperative complications, namely visual axis opacification (VAO) and amblyopia. RESULTS: Bow and arrow was the most common causal agent. Open-globe injury (OGI) was 3 times more frequent than CGI. There was a significant visual gain from baseline in both groups after cataract surgery (p<0.001); residual SE was greater in OGI (1.6 +/- 0.95 SD) compared to blunt trauma (0.8 +/- 0.55 SD; p = 0.001). Incidence of corneal scarring, iris distortion, posterior synechiae, and intraoperative posterior capsular tear was greater with OGI (p<0.05). A total of 86% of patients were rehabilitated with a primary/secondary IOL. Single-piece IOL implantation rate (p = 0.004) was significantly greater in CGI, with no statistical difference for in-the-bag IOL (p = 0.053) and IOL implantation rate (p = 0.16). Final BCVA was significantly better for in-the-bag IOL implantation compared to sulcus fixation. Postoperative complications included amblyopia (51%) and VAO (12%). CONCLUSIONS: Bow and arrow injury caused the maximum cases of traumatic cataract; cataract extraction resulted in significant visual improvement; and CGI tended to have better prognosis in pediatric traumatic cataracts. PMID- 23918073 TI - Effect of axial length on retinal nerve fiber layer thickness in children. AB - PURPOSE: To investigate the effect of axial length on peripapillary retinal nerve fiber layer (RNFL) thickness in myopic, hyperopic, and emmetropic eyes in children by Cirrus HD spectral-domain optical coherence tomography (OCT). METHODS: Subjects were divided into 3 groups according to their refractive status: myopic (n = 36), emmetropic (n = 30), and hyperopic (n = 28) eyes. The RNFL thickness measurements were taken from the superior, inferior, nasal, and temporal quadrants in the peripapillary region by Cirrus HD OCT. Axial length was also determined for each patient. RESULTS: The myopic eyes had thinner average RNFL and RNFLs of temporal, superior, nasal, and inferior quadrants than the hyperopic eyes (p1<0.001, p2 = 0.004, p3 = 0.011, p4 = 0.006, p5 = 0.033, respectively). In addition, average peripapillary RNFL thickness and RNFL thicknesses of all quadrants had significant negative correlations with axial length. On the other hand, after applying modified Littmann formula for correction of magnification effect, the differences among the 3 groups disappeared (all p>0.05). CONCLUSIONS: We have shown that axial length and accordingly refractive status influenced peripapillary RNFL thickness measurements by Cirrus HD OCT in children. Therefore, to make a correct diagnosis of glaucoma or other optic neuropathies in children, either axial length-induced magnification effect should be corrected by ophthalmologists or the current Cirrus HD OCT database should be revised taking axial length into consideration. PMID- 23918074 TI - Consecutive exotropia: risk factor analysis and management outcomes. AB - PURPOSE: To report the frequency of risk factors and outcomes of consecutive exotropia (XT) following bimedial rectus recession (BMR) for the treatment of childhood esotropia (ET). METHODS: Ninety-eight patients with ET, who underwent only BMR between 1996 and 2007, were included in this study. Predictors of the development of consecutive XT and treatment outcomes were compared between groups (group 1, cases with consecutive XT; group 2, cases without consecutive XT). RESULTS: Mean follow-up time after BMR surgery was 7.23 +/- 3.62 years. There was no significant difference between the groups in terms of age, preoperative angle of near deviation, follow-up time, or refraction for both eyes (p>0.05 for all). The differences regarding preoperative angle of distance deviation (p = 0.009), presence of inferior oblique overaction (p = 0.023), amount of BMR (p = 0.028), and postoperative adduction limitation (p<0.0001) between the groups were statistically significant. However, only preoperative angle of distance deviation and presence of postoperative adduction limitation were independent risk factors for the development of consecutive XT (p = 0.043, p = 0.007, respectively). CONCLUSIONS: Postoperative adduction limitation should alert physicians to the increased risk of developing consecutive XT in the long-term follow-up after BMR for the treatment of childhood ET. PMID- 23918075 TI - Surgical treatment of total bilateral ankyloblepharon in a child: unusual case report. AB - PURPOSE: To report on the efficacy of surgical management of total bilateral ankyloblepharon in a child. METHODS: An 8-year-old African girl from Burundi presented with complete lid-corneo-conjunctival adhesion in both eyes, dating back 6 years. Preoperative ultrasound evaluation of anterior and posterior segment was detected. Electrophysiologic examinations showed low responses. Surgery was performed with scarring tissue removal through manual cleavage in order to separate tarsal conjunctiva and corneal stroma, followed by multiple human amniotic membrane grafts on the cornea, the entire bulbar surface, and fornices. RESULTS: Ankyloblepharon removal, excellent width of fornices, and lid motility recovery were obtained. Nevertheless, corneal stroma remained cloudy. The patient's visual acuity reached hand movements perception at 6 months follow up. CONCLUSIONS: Even in the presence of deep deprivation amblyopia, total ankyloblepharon surgical removal and anatomic restoration of ocular surface is mandatory in children. Subsequent surgery including corneal keratoplasty or keratoprosthesis implant should be taken into consideration after an accurate evaluation of the cost/benefit ratio. Furthermore, these young patients could be enrolled in specific visual rehabilitation programs to enhance residual visual abilities. PMID- 23918076 TI - Ophthalmologic findings in a pediatric cochlear implant population. AB - PURPOSE: To report ocular findings in a cohort of children requiring pediatric cochlear implant and to evaluate the usefulness of routine ophthalmologic examination in such children. METHODS: This was a prospective study of ophthalmologic assessment of 47 consecutive children aged 10 months to 12 years from the cochlear implant program of our hospital. RESULTS: All children underwent complete ocular assessment consisting of orthoptic and ophthalmo-logic examination, including cycloplegic refraction. A total of 18 children (38.3%) had some form of ocular abnormality, with the majority (14 patients, 29.8%) having refractive errors. Hypermetropia was the most common refractive error (21.3%), followed by astigmatism (8.5%). Strabismus was found in 6 patients, with esotropia being the most common type. Other ocular findings included ptosis (1 patient) and epicanthal folds (3 patients). During the follow-up period, 9 children were fitted with glasses, 3 underwent occlusion therapy, 2 underwent strabismus surgery, and 1 underwent ptosis surgery. CONCLUSIONS: Thorough orthoptic and ophthalmologic examination is useful for ensuring optimal visual function in children undergoing cochlear implantation. PMID- 23918078 TI - A case report of very late stent thrombosis observed simultaneously in all three vessels 5 years after sirolimus-eluting stent implantation. AB - A 67-year-old man with recent myocardial infarction underwent a total of five sirolimus-eluting stents (SES) implantation for three vessels stage by stage. A follow-up angiography showed no significant restenosis except one in the side branch. Thereafter, he had remained asymptomatic. Sixty-six months later, he had an acute myocardial infarction with cardiogenic shock due to simultaneous 3 vessel very late stent thrombosis (VLST). After successful percutaneous coronary intervention, final angiography revealed serious peri-stent contrast staining along with positive remodeling and grade V stent fracture. This rare case illustrates simultaneous 3-vessel VLST, associating with multiple SES-related problems, under continuation of aspirin and cilostazol. PMID- 23918077 TI - MRSI of the medial temporal lobe at 7 T in explosive blast mild traumatic brain injury. AB - PURPOSE: Up to 19% of veterans returning from the wars in Iraq and Afghanistan have a history of mild traumatic brain injury with 70% associated with blast exposure. Tragically, 20-50% of this group reports persistent symptoms, including memory loss. Unfortunately, routine clinical imaging is typically normal, making diagnosis and clinical management difficult. The goal of this work was to develop methods to acquire hippocampal MRSI at 7 T and evaluate their sensitivity to detect injury in veterans with mild traumatic brain injury. METHODS: At 7 T, hippocampal MRSI measurements are limited by: (1) poor B(0) homogeneity; (2) insufficient B(1)(+) strength and homogeneity; and (3) chemical shift dispersion artifacts. To overcofme these limitations we: (1) used third degree B(0) shimming; (2) an inductively decoupled transceiver array with radiofrequency shimming; and (3) a volume localized single slice sequence using radiofrequency shimming-based outer volume suppression. RESULTS: In 20 controls and 25 veterans with mild traumatic brain injury due to blast exposure with memory impairment, hippocampal N-acetyl aspartate to choline (P < 0.001) and N-acetyl aspartate to creatine (P < 0.001) were decreased in comparison to control subjects. CONCLUSION: With the appropriate methods robust spectroscopic imaging of the hippocampus can be carried out at 7 T. MRSI at 7 T can detect hippocampal injury in veterans with mild traumatic brain injury. PMID- 23918079 TI - In vitro ceramic scaffold mineralization: comparison between histological and micro-computed tomographical analysis. AB - The porous structure of beta-tricalcium phosphate (beta-TCP) scaffolds was assessed by conventional histomorphometry and micro-computed tomography (micro CT) to evaluate the substitutability of time-consuming histomorphometry by rapid micro-CT. Extracellular matrix mineralization on human mesenchymal stem cell seeded beta-TCP scaffolds was scanned by means of micro-CT after 6 weeks in cultivation and evaluated morphometrically. For the histomorphometric analysis, undecalcified sections were prepared in the mediosagittal plane of the cylindrical tissue-engineered constructs. The sections were scanned at a nominal resolution of 8 MUm and stained with von Kossa and Toluidine Blue. Pores were analyzed with both methods for morphometrical parameters such as horizontal/vertical diameter and pore/mineralized tissue area. Results showed highly significant correlations between histomorphometry and micro-CT for pore horizontal length (r = 0.95), pore vertical length (r = 0.96), pore area (r = 0.97), and mineralized tissue area (r = 0.82). Mean percentage differences between histomorphometry and micro-CT measurements ranged from 1.4% (pore vertical diameter) to 14.0% (area of mineralized tissue). With its high image precision, micro-CT qualifies as an additional tool for endpoint evaluation measurements of mineralized tissue development within tissue-engineered constructs also in ceramic scaffolds. PMID- 23918080 TI - The effect of visual and sensory performance on head impact biomechanics in college football players. AB - The development of prevention strategies is critical to address the rising prevalence of sport-related concussions. Visual and sensory performance may influence an individual's ability to interpret environmental cues, anticipate opponents' actions, and create appropriate motor responses limiting the severity of an impending head impact. The purpose of this study was to determine the relationship between traditional and visual sensory reaction time measures, and the association between visual and sensory performance and head impact severity in college football players. Thirty-eight collegiate football players participated in the study. We used real-time data collection instrumentation to record head impact biomechanics during games and practices. Our findings reveal no significant correlations between reaction time on traditional and visual sensory measures. We found a significant association between head impact severity and level of visual and sensory performance for multiple assessments, with low visual and sensory performers sustaining a higher number of severe head impacts. Our findings reveal a link between level of visual and sensory performance and head impact biomechanics. Future research will allow clinicians to have the most appropriate testing batteries to identify at-risk athletes and create interventions to decrease their risk of injurious head impacts. PMID- 23918081 TI - Susceptibility to corrosion and in vitro biocompatibility of a laser-welded composite orthodontic arch wire. AB - Composite arch-wire (CoAW) is an arch wire formed by solder connection of nickel titanium shape memory alloy and stainless steel wire. The purpose of the present study was to investigate the biocompatibility of CoAW as an important foundation for its clinical application. The electrochemical corrosion and ion release behavior of CoAW upon immersion in solutions simulating oral cavity conditions were measured to evaluate the corrosion behavior of CoAW. Murine L-929 cells were co-cultured with CoAW extract to evaluate the cytotoxicity of the corrosion products in vitro. Polarization tests indicated that CoAW is resistant to corrosion in the tested artificial saliva (AS)-based solutions (chloric solution, simple AS, fluorinated AS, and protein-containing AS), and the amount of toxic copper ions released after immersion was lower than average daily dietary intake levels. The cytotoxicity experiments demonstrated the in vitro biocompatibility of CoAW. Based on the combined advantages of its base materials CoAW, with its resistance to biocorrosion and in vitro cytocompatibility, is a promising alternative material for use in orthodontic fixation applications. PMID- 23918082 TI - A cold-adapted and organic solvent-tolerant lipase from a psychrotrophic bacterium Pseudomonas sp. strain YY31: identification, cloning, and characterization. AB - A novel cold-adapted lipase (designated as LipYY31) was obtained from a psychrotrophic Pseudomonas sp. YY31. The strain YY31 was gram-negative, rod shaped, motile by means of one polar flagellum, and exhibited chemotaxis toward oil droplets under a microscope. The strain displayed remarkable degradation of edible oil and fat even at 5 degrees C. The LipYY31 DNA fragment contains an open reading frame of 1,410 bp which encoded a protein of 470 amino acids with an estimated molecular mass of 49,584 Da. LipYY31 showed high sequence similarity to those of subfamily Iota.3 lipase and had a conserved GXSXG motif around the catalytic Ser residue. Its optimal temperature was 25-30 degrees C, and it retained 20-40 % of its activity at 0-5 degrees C. The optimal pH value was 8.0. The activity was strongly inhibited by Cd(2+), Zn(2+), EDTA and was highly dependent on Ca(2+). Tricaprin and p-nitrophenyl caprate were the most favorable substrates among the triglycerides and p-nitrophenyl esters, respectively. LipYY31 also had high activity towards natural substrates including edible vegetable oils and animal fat. Furthermore, LipYY31 was very active and stable in the presence of several detergents and organic solvents. In particular, the lipase exhibited high stability against organic solvents such as methanol, ethanol, and isopropanol. PMID- 23918083 TI - Breast cancer metastases to the pancreas. AB - INTRODUCTION: The pancreas can serve as the destination for metastatic spread of malignancies from multiple organ sites. Breast cancer metastases to the pancreas are part of this spectrum and surgeons evaluate such patients as part of their practice. Uniform clinical guidelines for these cases do not exist and care is primarily driven by the personal experience of the treating surgeon. DISCUSSION: We present two patients with breast cancer metastases to their pancreas and review their workup and clinical management in light of our experience and the existing published literature. We propose that metastatic disease to the pancreas has to remain in the differential diagnosis for any patient with a new pancreatic mass and prior cancer history. Surgical resection is a viable treatment option for patients with isolated metastatic disease to the pancreas if the underlying biology of the metastatic tumor is favorable. PMID- 23918086 TI - Organs on Chips 2013. PMID- 23918084 TI - Acute and elective laparoscopic resection for complicated sigmoid diverticulitis: clinical and histological outcome. AB - BACKGROUND: Surgical treatment of acute complicated sigmoid diverticulitis is still under debate while elective treatment of recurrent diverticulitis has proven benefits. The aim of this study was to evaluate the clinical and histological outcome of acute and elective laparoscopic sigmoid colectomy in patients with diverticulitis. METHODS: A retrospective review was conducted where 197 patients were analyzed undergoing laparoscopic sigmoid resection for acute complicated diverticulitis and recurrent diverticulitis. Single-stage laparoscopic resection and primary anastomosis were routinely performed using a 3 trocar technique. Recorded data included age, sex, American Society of Anesthesiologists (ASA)-score, operative time, duration of hospital stay, complications, and histological results. RESULTS: Ninety-one patients received laparoscopy for acute diverticular disease (group I) and 93 patients underwent elective laparoscopic sigmoid resection for diverticulitis (group II). M/F ratio was 49:42 for group I and 37:56 for group II. Mean operative time and hospital stay was similar in both groups. Majority of patients were ASA II in both groups. Rate of minor complications was 14.3 % in group I and 7.5 % in group II. Major complications were 2.2 % for acute treatment and 4.3 % for elective resections. No anastomotic leakage and no mortality occurred. In 32.3 % of the patients of elective group II, destruction of the colonic wall with pericolic abscess, fistulization, or fibrinoid purulent peritonitis were identified. CONCLUSIONS: Laparoscopic surgery for acute diverticular disease is safe and effective. Continuing bowl inflammations in histological specimens justify sigmoid resection in elective patients, but more effective pre-operative parameters need to be found to identify patients that would benefit from surgery during the initial episode. PMID- 23918085 TI - Weight loss interventions for morbidly obese patients with compensated cirrhosis: a Markov decision analysis model. AB - Many transplant centers require that patients maintain a BMI below 40 kg/m(2) in order to be eligible for listing, rendering many morbidly obese patients with end stage liver disease unable to access liver transplantation as a method of treatment. In order to determine the safest and most efficacious weight loss regimen in this challenging population, Roux-en-Y gastric bypass (RYGB), adjustable gastric banding (AGB), and diet and exercise were modeled to assess their impact on life expectancy in morbidly obese patients with cirrhosis. A Markov state transition model was developed to assess the survival benefit of undergoing RYGB, AGB, or 1 year of diet and exercise in morbidly obese patients with compensated cirrhosis. A base case analysis of no weight loss intervention in a 45-year-old patient with compensated cirrhosis and a BMI of 45 kg/m(2) revealed an average survival of 7.93 years. The average survival for the weight loss simulations was 9.14, 8.84, and 8.16 years for RYGB, AGB, and diet and exercise, respectively. In morbidly obese patients with compensated cirrhosis, RYGB allows patients to lose more weight more rapidly than is probable with either AGB or diet and exercise, thus having the greatest impact on survival. PMID- 23918087 TI - Abundance and diversity of archaeal accA gene in hot springs in Yunnan Province, China. AB - It has been suggested that archaea carrying the accA gene, encoding the alpha subunit of the acetyl CoA carboxylase, autotrophically fix CO2 using the 3 hydroxypropionate/4-hydroxybutyrate pathway in low-temperature environments (e.g., soils, oceans). However, little new information has come to light regarding the occurrence of archaeal accA genes in high-temperature ecosystems. In this study, we investigated the abundance and diversity of archaeal accA gene in hot springs in Yunnan Province, China, using DNA- and RNA-based phylogenetic analyses and quantitative polymerase chain reaction. The results showed that archaeal accA genes were present and expressed in the investigated Yunnan hot springs with a wide range of temperatures (66-96 degrees C) and pH (4.3-9.0). The majority of the amplified archaeal accA gene sequences were affiliated with the ThAOA/HWCG III [thermophilic ammonia-oxidizing archaea (AOA)/hot water crenarchaeotic group III]. The archaeal accA gene abundance was very close to that of AOA amoA gene, encoding the alpha subunit of ammonia monooxygenase. These data suggest that AOA in terrestrial hot springs might acquire energy from ammonia oxidation coupled with CO2 fixation using the 3-hydroxypropionate/4 hydroxybutyrate pathway. PMID- 23918088 TI - Hepatic involvement in pediatric patients with paracoccidioidomycosis: a clinical and laboratory study. AB - The liver is one of the organs most affected by paracoccidioidomycosis, a systemic mycosis endemic in some Latin American countries. The majority of articles focused on adult populations and failed to describe any detailed experience of liver abnormalities in pediatric patients. Therefore, the aim of this study was to describe the frequency and characteristics of liver involvement in children with paracoccidioidomycosis. This study comprised 102 patients less than 16 years of age (median 104.3 months) diagnosed with paracoccidioidomycosis from 1980 to 2010. Diagnosis was established by the identification of fungus. Forty-one patients had liver involvement. The main clinical features were generalized lymph node enlargement (39/41), weight loss (34/41) and fever 32/41). Approximately, one-third of the patients had jaundice. Patients with hepatic involvement were younger. A predominant elevation of canalicular enzymes occurred. There was a statistically significant difference in albumin (p < 0.001) and hemoglobin (p = 0.002) values between patients with and without liver involvement, and the lowest values were found in the former group. Cutoff levels of albumin (<3.05 g/dL) and hemoglobin (<9.2 g/dL) can be used to infer hepatic involvement. Hypoalbuminemia (median 2.4 g/dl) is more severe in patients with hepatic involvement and may indicate a worse liver function or complication of the disease (intestinal lymphangiectasia). Deaths (6) occurred only among patients with liver involvement. Particular clinical and laboratory characteristics are present in pediatric patients with hepatic involvement. Younger patients and those with severe hypoalbuminemia are more likely to present liver involvement by Paracoccidioides brasiliensis. PMID- 23918089 TI - Canine gastrointestinal pythiosis treatment by combined antifungal and immunotherapy and review of published studies. AB - Pythium insidiosum is an oomycete, a fungal like microorganism, which infects mammals, causing pythiosis in animals and humans, especially in tropical and subtropical regions around the world. The treatment for this infection is very difficult, and therapeutic options commonly comprise surgery, immunotherapy and antimicrobial drugs. The present report describes the clinical healing of a dog with gastrointestinal pythiosis by treatment with a combination of antifungals and immunotherapy, as well as reviews the cases reported in the literature that used some type of therapy for canine pythiosis. A 2.5-year-old male beagle initially showed sporadic vomiting episodes, and this symptom became more frequent 5 months after the onset of clinical signs. Celiotomy procedure found thickness of the stomach wall extending to the pylorus and duodenum. A biopsy was performed, and the diagnosis of pythiosis was made by mycological, histopathological analyses and molecular identification. Therapy was based on an association of terbinafine plus itraconazole during 12 months and immunotherapy for 2.5 months. The healing of the dog reported here allows us to propose the use of immunotherapy associated with antifungal therapy to treat canine gastrointestinal pythiosis. However, additional studies should be performed on a larger number of patients to establish a standard treatment protocol for canine pythiosis. PMID- 23918090 TI - Microsporum canis infection in three familial cases with tinea capitis and tinea corporis. AB - We report a familial infection caused by Microsporum canis. The first two patients were a 30-year-old female and her son, a 5-year-old boy, who came in contact with a pet dog at a farm house. The boy then suffered from hair loss for 3 months. There were circular and patchy alopecia with diffuse scaling on his scalp. Meanwhile, his mother also developed patchy erythema and scaling on her face. Several weeks later, the boy's sister, a 4-year-old girl, was noted to have inconspicuous scaly plaques in the center of her scalp. The development of tinea capitis in the two children and tinea corporis in their mother were diagnosed based on the positive KOH examination. Morphologic characteristics and sequencing of the internal transcribed spacers 1 and 2, amplified from primary culture isolates, confirmed that their infections were caused by the zoophilic M. canis. Repetitive sequence-based molecular typing using the DiversiLab system secreted enzymatic activity analysis, and antifungal susceptibility indicated that these isolates might share the same source. The boy and girl were cured by the treatment with oral itraconazole and topical naftifine-ketoconazole cream after washing the hair with 2 % ketoconazole shampoo, and their mother was successfully treated by terbinafine orally in combination with topical application of naftifine-ketoconazole cream. PMID- 23918091 TI - Method of conditional moments (MCM) for the Chemical Master Equation: a unified framework for the method of moments and hybrid stochastic-deterministic models. AB - The time-evolution of continuous-time discrete-state biochemical processes is governed by the Chemical Master Equation (CME), which describes the probability of the molecular counts of each chemical species. As the corresponding number of discrete states is, for most processes, large, a direct numerical simulation of the CME is in general infeasible. In this paper we introduce the method of conditional moments (MCM), a novel approximation method for the solution of the CME. The MCM employs a discrete stochastic description for low-copy number species and a moment-based description for medium/high-copy number species. The moments of the medium/high-copy number species are conditioned on the state of the low abundance species, which allows us to capture complex correlation structures arising, e.g., for multi-attractor and oscillatory systems. We prove that the MCM provides a generalization of previous approximations of the CME based on hybrid modeling and moment-based methods. Furthermore, it improves upon these existing methods, as we illustrate using a model for the dynamics of stochastic single-gene expression. This application example shows that due to the more general structure, the MCM allows for the approximation of multi-modal distributions. PMID- 23918092 TI - Characterising eye movement dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome. AB - BACKGROUND: People who suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report that their eye movements are sluggish and that they have difficulties tracking moving objects. However, descriptions of these visual problems are based solely on patients' self-reports of their subjective visual experiences, and there is a distinct lack of empirical evidence to objectively verify their claims. This paper presents the first experimental research to objectively examine eye movements in those suffering from ME/CFS. METHODS: Patients were assessed for ME/CFS symptoms and were compared to age, gender, and education matched controls for their ability to generate saccades and smooth pursuit eye movements. RESULTS: Patients and controls exhibited similar error rates and saccade latencies (response times) on prosaccade and antisaccade tasks. Patients showed relatively intact ability to accurately fixate the target (prosaccades), but were impaired when required to focus accurately in a specific position opposite the target (antisaccades). Patients were most markedly impaired when required to direct their gaze as closely as possible to a smoothly moving target (smooth pursuit). CONCLUSIONS: It is hypothesised that the effects of ME/CFS can be overcome briefly for completion of saccades, but that continuous pursuit activity (accurately tracking a moving object), even for a short time period, highlights dysfunctional eye movement behaviour in ME/CFS patients. Future smooth pursuit research may elucidate and improve diagnosis of ME/CFS. PMID- 23918093 TI - Retinal outer layer thickness increases after vitrectomy for epiretinal membrane, and visual improvement positively correlates with photoreceptor outer segment length. AB - PURPOSE: To investigate postoperative thickness changes in the retinal layers in eyes with epiretinal membrane (ERM). Correlations between these changes and visual outcomes were also examined. METHODS: Retrospective review of 25 eyes (24 patients) that had undergone pars plana vitrectomy for ERM and had a postoperative follow-up period >=6 months. Optical coherence tomography (6 * 6 mm macular thickness map) was used to measure mean thickness of the inner and outer retinal layers 1 week and 1, 3, and 6 months following surgery. Photoreceptor outer segment (PROS) length was evaluated manually, and used to assess the association between best-corrected visual acuity (BCVA) and retinal layer thickness at the fovea. RESULTS: At 1 week and 1, 3, and 6 months, retinal layer thickness was 388, 377, 362, and 352 MUm for the whole layer; 133, 115, 107, and 101 MUm for the inner layer; 138, 145, 147, and 148 MUm for the outer layer; and 28, 35, 36, and 40 MUm for the PROS length, respectively. In comparison to 1-week data, the inner layers were significantly thinner at 1 month and later, as was the thickness of the entire retina. Outer layer thickness and PROS length were also significantly thicker at these time points. Six months following surgery, BCVA was significantly correlated with an elongated PROS length (R = 0.49, P = 0.01). CONCLUSION: Retinal outer layer thickness significantly increased following pars plana vitrectomy for ERM. Visual improvement was positively correlated with PROS length recovery. PMID- 23918094 TI - Five-year results of photodynamic therapy with and without supplementary antivascular endothelial growth factor treatment for polypoidal choroidal vasculopathy. AB - BACKGROUND: To clarify the long-term efficacy of photodynamic therapy (PDT) in patients with symptomatic polypoidal choroidal vasculopathy (PCV). METHODS: We retrospectively reviewed 60 naive eyes of 59 patients (45 men, 14 women; mean age, 73.8 years) treated with full-fluence PDT (PDT group) and followed for at least 60 months. Retreatment was either antivascular endothelial growth factor (VEGF) therapy or intravitreal triamcinolone acetonide if PDT alone was ineffective (supplemental retreatment group). RESULTS: The mean logarithm of the minimum angle of resolution best-corrected visual acuity (BCVA) levels at baseline and 60 months were 0.66 and 0.71, respectively. The mean change at 60 months was a decrease of 0.50 line. In the PDT group (36 eyes), the mean BCVAs at baseline and month 60 were 0.73 and 0.68, respectively (p = 0.60). In the supplemental retreatment group (24 eyes), the mean BCVAs at baseline and month 60 were 0.55 and 0.74, respectively (p = 0.076). The percentage of eyes with decreased BCVA at the time of the additional anti-VEGF treatment was significantly (p = 0.031) higher than at month 60. The risk factors identified by multiple regression analysis with a significant decrease in BCVA at month 60 were a large greatest linear dimension (GLD), classic choroidal neovascularization at baseline, and a hemorrhage over the arcade vessels after PDT. CONCLUSIONS: The efficacy of PDT for PCV depends on the GLD. Twenty-four of the 60 eyes needed additional treatment other than only PDT during 60 months of follow-up. Additional anti-VEGF treatment may help maintain the BCVA of patients with exudative or anatomic recurrence. PMID- 23918096 TI - Primary care and upfront computed tomography scanning in the diagnosis of chronic rhinosinusitis: a cost-based decision analysis. AB - OBJECTIVES/HYPOTHESIS: To diagnose chronic rhinosinusitis (CRS), current guidelines require either endoscopic or computed tomography (CT) findings of sinus disease. To a primary care physician, this means a referral to an otolaryngologist or obtaining a CT scan. Unfortunately, the sensitivity of endoscopy for detecting CRS is low, and examination by the Otolaryngologist may not yield a definitive diagnosis. This leaves CT scanning. However, this is contradicted by recommendations to limit CT scanning for only preoperative planning purposes due to cost concerns. This study aims to provide an evidence based cost-efficient recommendation for primary care practice. STUDY DESIGN: Health care economics-based decision analysis model. METHODS: A cost-based decision analysis based on literature-reported probabilities and Medicare costs was constructed for two scenarios: 1) primary care physicians who are comfortable initiating first-line treatment for chronic rhinosinusitis, rhinitis, and atypical facial pain; and 2) primary care physicians who are less comfortable with medical management of these conditions. RESULTS: Under both scenarios and the extremes of sensitivity analysis, upfront CT scanning provides cost-efficient diagnosis over presuming a diagnosis of chronic rhinosinusitis. Primary care physicians who attempt first-line treatment can expect $503 (range = $296-$761) saved per patient. Meanwhile, primary care physicians who prefer to refer may expect $326 (range = $299-$353) saved per patient. CONCLUSIONS: In all scenarios, confirming diagnosis with CT scanning prior to treatment or referral is more cost efficient than presuming a diagnosis of CRS based on symptoms alone. PMID- 23918095 TI - Shared space, separate processes: Neural activation patterns for auditory description and visual object naming in healthy adults. AB - Historically, both clinicians and cognitive scientists have used visual object naming measures to study naming, and lesion-type studies have implicated the left posterior, temporo-parietal region as a critical component of naming circuitry. However, recent results from behavioral and cortical stimulation studies using auditory description naming as well as visual object naming in left temporal lobe epilepsy patients suggest that discrete sites in anterior temporal cortex are critical for description naming, whereas posterior temporal regions mediate both visual object naming and description naming. To determine whether this task specificity reflects normal cerebral organization and processing, 13 healthy adults performed description naming and visual naming during functional neuroimaging. In addition to standard univariate analysis, multivariate, ordinal trend analysis examined the network character of the regions involved in task specific naming. Univariate analysis indicated posterior temporal activation for both visual naming and description naming, whereas multivariate analysis revealed broader networks for both tasks, with both overlapping and task-specific regions, as well as task-related differences in the way the tasks utilized common regions. Additionally, multivariate analysis revealed unique, task-specific, regionally covarying activation patterns that were strikingly consistent in all 13 subjects for visual naming and 12/13 subjects for description naming. Results suggest a common neural substrate, yet differentiable neural processes underlying visual naming and description naming in neurologically intact individuals. These findings support the use of both types of tasks for clinical assessment and may have application in the treatment of neurologically based naming deficits. Inc. PMID- 23918097 TI - Creating clinical practice guidelines: problems and solutions. PMID- 23918098 TI - Asymmetric dimethylarginine: a disease marker for asthma? PMID- 23918099 TI - Three cheers for the crumbling silo: the lesson of how a minor procedure can have a major impact. PMID- 23918100 TI - Should the newer oral anticoagulants be withheld from patients with valvular AF? PMID- 23918102 TI - Point: Are the best patient outcomes achieved when ICU bundles are rigorously adhered to? Yes. PMID- 23918103 TI - Counterpoint: Are the best patient outcomes achieved when ICU bundles are rigorously adhered to? No. PMID- 23918104 TI - Rebuttal from Drs Dellinger and Townsend. PMID- 23918105 TI - Rebuttal from Dr Marik et al. PMID- 23918106 TI - Creating clinical practice guidelines we can trust, use, and share: a new era is imminent. AB - Standards and guidance for developing trustworthy clinical practice guidelines are now available, and a number of leading guidelines adhere to the key standards. Even current trustworthy guidelines, however, generally suffer from a cumbersome development process, suboptimal presentation formats, inefficient dissemination to clinicians at the point of care, high risk of becoming quickly outdated, and suboptimal facilitation of shared decision-making with patients. To address these limitations, we have--in our innovative research program and nonprofit organization, MAGIC (Making GRADE the Irresistible Choice)--constructed a conceptual framework and tools to facilitate the creation, dissemination, and dynamic updating of trustworthy guidelines. We have developed an online application that constitutes an authoring and publication platform that allows guideline content to be written and structured in a database, published directly on our web platform or exported in a computer-interpretable language (eg, XML) enabling dissemination through a wide range of outputs that include electronic medical record systems, web portals, and applications for smartphones/tablets. Modifications in guidelines, such as recommendation updates, will lead to automatic alterations in these outputs with minimal additional labor for guideline authors and publishers, greatly facilitating dynamic updating of guidelines. Semiautomated creation of a new generation of decision aids linked to guideline recommendations should facilitate face-to-face shared decision-making in the clinical encounter. We invite guideline organizations to partner with us (www.magicproject.org) to apply and further improve the tools for their purposes. This work will result in clinical practice guidelines that we cannot only trust, but also easily share and use. PMID- 23918107 TI - The airway microbiome and disease. AB - Although traditionally thought to be sterile, accumulating evidence now supports the concept that our airways harbor a microbiome. Thus far, studies have focused upon characterizing the bacterial constituents of the airway microbiome in both healthy and diseased lungs, but what perhaps provides the greatest impetus for the exploration of the airway microbiome is that different bacterial phyla appear to dominate diseased as compared with healthy lungs. As yet, there is very limited evidence supporting a functional role for the airway microbiome, but continued research in this direction is likely to provide such evidence, particularly considering the progress that has been made in understanding host microbe mutualism in the intestinal tract. In this review, we highlight the major advances that have been made discovering and describing the airway microbiome, discuss the experimental evidence that supports a functional role for the microbiome in health and disease, and propose how this emerging field is going to impact clinical practice. PMID- 23918109 TI - "Pills" and the air passages. AB - Aspiration of a medication in the airways in any form produces a variety of adverse effects, both local and systemic. Furthermore, specific reaction of the airways to each type of pill strongly affects the outcome. It is crucial for pulmonologists and emergency medicine specialists to acknowledge this clinical entity. In addition, airways have been increasingly used to deliver medications such as insulin and prostacycline. These aerosolized medications can also cause local as well as systemic side effects. We review the local and systemic reactions of these "pills" accessing the airways either by incidental aspiration or iatrogenic administration. We address clinical presentation, mechanism of injury, diagnosis, and management of complications of these pills in the air passages. PMID- 23918110 TI - Endobronchial valve placement and balloon occlusion for persistent air leak: procedure overview and new current procedural terminology codes for 2013. AB - Unidirectional endobronchial valves, originally studied for potential treatment of emphysema, have emerged as a useful intervention for patients with persistent air leak from the lung. The procedure is accomplished via bronchoscopy in a patient who already has a chest tube in place for management of the air leak. It uses an occluding balloon to determine the specific airway(s) leading to the leak by impact on airflow and subsequent placement of removable valve(s) in one or more segment or subsegments to decrease flow across the leak to allow for healing of the fistula. Specific US Food and Drug Administration-approved criteria for placement and removal of these valves via a Humanitarian Device Exemption are discussed along with reported outcomes. Current Procedural Terminology codes effective for 2013 that are specific to the procedure are reviewed. PMID- 23918111 TI - Seizure-induced acute urate nephropathy: case report and review. AB - Urate nephropathy is observed primarily in patients treated for malignancy, but several other predisposing conditions are recognized. We report a case in which urate nephropathy complicated status epilepticus and review the literature regarding previous similar cases. In addition, we discuss current views of the pathophysiology of acute kidney injury due to urate nephropathy. This case illustrates the value of carefully examining the urine of patients with acute kidney injury to identify causes that may have a specific treatment. PMID- 23918108 TI - WHO's in second?: A practical review of World Health Organization group 2 pulmonary hypertension. AB - World Health Organization (WHO) group 2 pulmonary hypertension (PH) due to left side heart disease (ie, heart failure or left-sided valvular heart disease) is the most common form of PH in western countries. Distinguishing patients with WHO group 2 PH, particularly the subset of patients with PH due to heart failure with preserved ejection fraction (HFpEF), from those with WHO group 1 pulmonary arterial hypertension (PAH) is challenging. Separating the two conditions is of vital importance because treatment strategies differ completely. Furthermore, therapies that are indicated for WHO group 1 PAH may be harmful in patients with WHO group 2 PH. We review the somewhat confusing PH nomenclature and the WHO classification system and rationale behind it. We then focus on left-side heart disorders that cause PH. An aging population and advances in the medical management of common cardiovascular disorders have caused the prevalence of heart failure to rise significantly, with more than one-half of patients having HFpEF. We review contemporary studies that focus on clinical and echocardiographic findings that help to distinguish HFpEF from PAH in the patient with PH. We discuss the typical, and sometimes atypical, hemodynamic profiles that characterize these two groups, review challenges in the interpretation of data obtained by right-sided heart catheterization, and highlight special maneuvers that may be required for accurate diagnosis. Finally, we review the largely disappointing studies on the use of PAH-specific therapies in patients with WHO group 2 PH, including the use of prostacyclins, endothelin receptor antagonists, and the more promising phosphodiesterase-5 inhibitors. PMID- 23918112 TI - Uncommon pulmonary presentation of IgG4-related disease in a 15-year-old boy. AB - IgG4-related disease was first described in adults with autoimmune pancreatitis but is now known to affect multiple organs. Lung involvement has never been described in children to our knowledge. Here, we report an adolescent presenting with recurrent dry cough and hemoptysis who was found to have venous ectasia in the left upper lobe, and diffuse bronchiectasis. Sustained high levels of IgG4 (1,090 mg/dL) were found, and the endobronchial biopsy revealed a marked infiltration of plasma cells producing IgG4 (ratio of IgG4 plasma cells to IgG plasma cells >50%). This unique case highlights the occurrence of IgG4-related disease in a child and underscores the importance of careful scrutiny of all investigations in complex pediatric respiratory cases. PMID- 23918113 TI - Management of hyponatremia in the ICU. AB - Hyponatremia is common in critical care units. Avoidance of neurologic injury requires a clear understanding of why the serum sodium (Na) concentration falls and why it rises, how the brain responds to a changing serum Na concentration, and what the goals of therapy should be. A 4 to 6 mEq/L increase in serum Na concentration is sufficient to treat life-threatening cerebral edema caused by acute hyponatremia. In chronic (> 48 h), severe (< 120 mEq/L) hyponatremia, correction by > 8 to 10 mEq/L/d risks iatrogenic osmotic demyelination syndrome (ODS); therefore, a 4 to 6 mEq/L daily increase in serum Na concentration should be the goal in most patients. With the possible exception of hyponatremia caused by heart failure or hepatic cirrhosis, a rapid initial increase in serum Na for severe symptoms and avoidance of overcorrection are best achieved with 3% saline given in either a peripheral or central vein. Inadvertent overcorrection can be avoided in high-risk patients with chronic hyponatremia by administration of desmopressin to prevent excessive urinary water losses. In patients with hyponatremia with oliguric kidney failure, controlled correction can be achieved with modified hemodialysis or continuous renal replacement therapies. ODS is potentially reversible, even in severely affected patients who are quadriplegic, unresponsive, and ventilator dependent. Supportive care should be offered several weeks before concluding that the condition is hopeless. PMID- 23918114 TI - Maximizing positive airway pressure adherence in adults: a common-sense approach. AB - Positive airway pressure (PAP) therapy is considered the most efficacious treatment of obstructive sleep apnea (OSA), especially moderate to severe OSA, and remains the most commonly prescribed. Yet suboptimal adherence presents a challenge to sleep-medicine clinicians. The purpose of the current review is to highlight the efficacy of published interventions to improve PAP adherence and to suggest a patient-centered clinical approach to enhancing PAP usage. PMID- 23918115 TI - Progressive dyspnea complicated by fever and massive hemoptysis in a 61-year-old man with extremity chondrosarcoma. PMID- 23918116 TI - A 71-year-old man with fever, productive cough, and tree-in-bud pattern on chest CT scan. PMID- 23918117 TI - A 49-year-old man with acute pulmonary hypertension post lung transplantation. PMID- 23918122 TI - Link between short sleep and obesity in humans: a matter of age? PMID- 23918124 TI - Hyperimmune IV immunoglobulin treatment of 2009 influenza A(H1N1). PMID- 23918123 TI - Response. PMID- 23918125 TI - Response. PMID- 23918126 TI - CPAP in obstructive sleep apnea and atrial flutter-fibrillation: is this truly two for the price of one? PMID- 23918127 TI - Response. PMID- 23918128 TI - N2 nodal involvement in multiple primary lung cancer: really an exclusion criterion? PMID- 23918129 TI - Response. PMID- 23918130 TI - Antibiotic use in COPD exacerbations. PMID- 23918131 TI - Response. PMID- 23918132 TI - When pharmacies cause harm. PMID- 23918133 TI - Response. PMID- 23918134 TI - Simulation-based bronchoscopy training. PMID- 23918135 TI - Response. PMID- 23918136 TI - Obstructive sleep apnea and sodium intake: what is the mechanism? PMID- 23918137 TI - Response. PMID- 23918144 TI - Worsening dyspnea and cough following thoracentesis. PMID- 23918146 TI - Deciphering the complex: methodological overview of statistical models to derive OMICS-based biomarkers. AB - Recent technological advances in molecular biology have given rise to numerous large-scale datasets whose analysis imposes serious methodological challenges mainly relating to the size and complex structure of the data. Considerable experience in analyzing such data has been gained over the past decade, mainly in genetics, from the Genome-Wide Association Study era, and more recently in transcriptomics and metabolomics. Building upon the corresponding literature, we provide here a nontechnical overview of well-established methods used to analyze OMICS data within three main types of regression-based approaches: univariate models including multiple testing correction strategies, dimension reduction techniques, and variable selection models. Our methodological description focuses on methods for which ready-to-use implementations are available. We describe the main underlying assumptions, the main features, and advantages and limitations of each of the models. This descriptive summary constitutes a useful tool for driving methodological choices while analyzing OMICS data, especially in environmental epidemiology, where the emergence of the exposome concept clearly calls for unified methods to analyze marginally and jointly complex exposure and OMICS datasets. PMID- 23918145 TI - Modulation of p75(NTR) prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats. AB - AIMS/HYPOTHESIS: Diabetic retinopathy is characterised by early blood-retina barrier (BRB) breakdown and neurodegeneration. Diabetes causes imbalance of nerve growth factor (NGF), leading to accumulation of the NGF precursor (proNGF), as well as the NGF receptor, p75 neurotrophin receptor (p75(NTR)), suggesting a possible pathological role of the proNGF-p75(NTR) axis in the diabetic retina. To date, the role of this axis in diabetes-induced retinal inflammation and BRB breakdown has not been explored. We hypothesised that modulating p75(NTR) would prevent diabetes- and proNGF-induced retinal inflammation and BRB breakdown. METHODS: Diabetes was induced by streptozotocin in wild-type and p75(NTR) knockout (p75KO) mice. After 5 weeks, the expression of inflammatory mediators, ganglion cell loss and BRB breakdown were determined. Cleavage-resistant proNGF was overexpressed in rodent retinas with and without p75(NTR) short hairpin RNA or with pharmacological inhibitors. In vitro, the effects of proNGF were investigated in retinal Muller glial cell line (rMC-1) and primary Muller cells. RESULTS: Deletion of p75(NTR) blunted the diabetes-induced decrease in retinal NGF expression and increases in proNGF, nuclear factor kappaB (NFkappaB), p NFkappaB and TNF-alpha. Deletion of p75(NTR) also abrogated diabetes-induced glial fibrillary acidic protein expression, ganglion cell loss and vascular permeability. Inhibited expression or cleavage of p75(NTR) blunted proNGF-induced retinal inflammation and vascular permeability. In vitro, proNGF induced p75(NTR) dependent production of inflammatory mediators in primary wild-type Muller and rMC-1 cultures, but not in p75KO Muller cells. CONCLUSIONS/INTERPRETATION: The proNGF-p75(NTR) axis contributes to retinal inflammation and vascular dysfunction in the rodent diabetic retina. These findings underscore the importance of p75(NTR) as a novel regulator of inflammation and potential therapeutic target in diabetic retinopathy. PMID- 23918147 TI - MR-based hypoxia measures in human glioma. AB - Hypoxia plays a central role in tumor stem cell genesis and is related to a more malignant tumor phenotype, therapy resistance (e.g. in anti-angiogenic therapies) and radio-insensitivity. Reliable hypoxia imaging would provide crucial metabolic information in the diagnostic work-up of brain tumors. In this study, we applied a novel BOLD-based MRI method for the measurement of relative oxygen extraction fraction (rOEF) in glioma patients and investigated potential benefits and drawbacks. Forty-five glioma patients were examined preoperatively in a pilot study on a 3T MR scanner. rOEF was calculated from quantitative transverse relaxation rates (T2, T2*) and cerebral blood volume (CBV) using a quantitative BOLD approach. rOEF maps were assessed visually and by means of a volume of interest (VOI) analysis. In six cases, MRI-targeted biopsy samples were analyzed using HIF-1alpha-immunohistochemistry. rOEF maps could be obtained with a diagnostic quality. Focal spots with high rOEF values were observed in the majority of high-grade tumors but in none of the low-grade tumors. VOI analysis revealed potentially hypoxic tumor regions with high rOEF in contrast-enhancing tumor regions as well as in the non-enhancing infiltration zone. Systematic bias was found as a result of non-BOLD susceptibility effects (T2*) and contrast agent leakage affecting CBV. Histological samples demonstrated reasonable correspondence between MRI characteristics and HIF-1alpha-staining. The presented method of rOEF imaging is a promising tool for the metabolic characterization of human glioma. For the interpretation of rOEF maps, confounding factors must be considered, with a special focus on CBV measurements in the presence of contrast agent leakage. Further validation involving a bigger cohort and extended immuno histochemical correlation is required. PMID- 23918149 TI - Iron deficiency anaemia in young males: do gastrointestinal symptoms and haemoglobin level affect diagnostic yield? PMID- 23918148 TI - Selective activation of the human tibial and common peroneal nerves with a flat interface nerve electrode. AB - OBJECTIVE: Electrical stimulation has been shown effective in restoring basic lower extremity motor function in individuals with paralysis. We tested the hypothesis that a flat interface nerve electrode (FINE) placed around the human tibial or common peroneal nerve above the knee can selectively activate each of the most important muscles these nerves innervate for use in a neuroprosthesis to control ankle motion. APPROACH: During intraoperative trials involving three subjects, an eight-contact FINE was placed around the tibial and/or common peroneal nerve, proximal to the popliteal fossa. The FINE's ability to selectively recruit muscles innervated by these nerves was assessed. Data were used to estimate the potential to restore active plantarflexion or dorsiflexion while balancing inversion and eversion using a biomechanical simulation. MAIN RESULTS: With minimal spillover to non-targets, at least three of the four targets in the tibial nerve, including two of the three muscles constituting the triceps surae, were independently and selectively recruited in all subjects. As acceptable levels of spillover increased, recruitment of the target muscles increased. Selective activation of muscles innervated by the peroneal nerve was more challenging. SIGNIFICANCE: Estimated joint moments suggest that plantarflexion sufficient for propulsion during stance phase of gait and dorsiflexion sufficient to prevent foot drop during swing can be achieved, accompanied by a small but tolerable inversion or eversion moment. PMID- 23918151 TI - Extracorporeal hepatic resection and autotransplantation using temporary portocaval shunt provides an improved solution for conventionally unresectable HCC. PMID- 23918150 TI - Apamin attenuated cerulein-induced acute pancreatitis by inhibition of JNK pathway in mice. AB - BACKGROUND/AIM: We have previously reported that bee venom (BV) has a protective role against acute pancreatitis (AP). However, the effects of apamin, the major compound of BV, on AP have not been determined. The aim of this study was to evaluate the effects of apamin on cerulein-induced AP. METHODS: AP was induced via intraperitoneal injection of supramaximal concentrations of the stable cholecystokinin analogue cerulein (50 MUg/kg) every hour for 6 times. In the apamin treatment group, apamin was administered subcutaneously (10, 50, or 100 MUg/kg) at both 18 and 1 h before the first cerulein injection. The mice were sacrificed at 6 h after the final cerulein injection. Blood samples were obtained to determine serum amylase and lipase levels, as well as cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examination, myeloperoxidase (MPO) assay, and real-time reverse transcription polymerase chain reaction. Furthermore, we isolated the pancreatic acinar cells to specify the role of apamin in AP. RESULTS: Pre-treatment with apamin inhibited histological damage, pancreatic weight/body weight ratio, serum level of amylase and lipase, MPO activity, and cytokine production. In addition, apamin treatment significantly inhibited cerulein-induced pancreatic acinar cell death. Furthermore, apamin treatment inhibited the cerulein-induced activation of c-Jun NH2-terminal kinases (JNK). CONCLUSIONS: These results could suggest that apamin could protect against AP by inhibition of JNK activation. PMID- 23918152 TI - Does modified Braun enteroenterostomy improve alkaline reflux gastritis and marginal ulcer after pancreaticoduodenectomy? AB - BACKGROUND: The safety of pancreaticoduodenectomy has improved significantly. However, alkaline reflux gastritis and marginal ulcer are two substantial problems after pancreaticoduodenectomy. AIMS: To identify whether Child reconstruction with a modified Braun enteroenterostomy decreases the incidence of alkaline reflux gastritis and marginal ulcer after pancreaticoduodenectomy better than Roux-en-Y reconstruction. METHODS: Data on 57 consecutive patients who underwent standard pancreaticoduodenectomy between January 1, 2008 and January 31, 2012 were collected prospectively. Data on early and late complications of the Child reconstruction with a modified Braun enteroenterostomy and Roux-en-Y were gathered. The risk factors of alkaline reflux gastritis and marginal ulcer were also investigated by using univariate and multivariate analyses. RESULTS: Twenty-five patients received Roux-en-Y and 32 underwent Child reconstruction with a modified Braun enteroenterostomy. Early complications after the two reconstruction methods were insignificant. Significant differences in terms of later postoperative morbidity (P = 0.01) and change in body mass index (P = 0.03) were found 12 months after pancreaticoduodenectomy. No significant difference for alkaline reflux gastritis was observed between the two methods (14.8 vs. 28.6 %, P = 0.24). Marginal ulcer occurred significantly lower in patients with the modified reconstruction than in those with Roux-en-Y reconstruction (11.1 vs. 47.6 %, P = 0.01). Peptic ulcer history, diabetes mellitus, and reconstruction type had a significant effect on marginal ulcer formation. CONCLUSIONS: Child reconstruction with a modified Braun enteroenterostomy offers an advantage with respect to marginal ulcer after standard pancreaticoduodenectomy, potentially decreasing the incidence of alkaline reflux gastritis as effectively as Roux-en-Y reconstruction. PMID- 23918153 TI - Single nucleotide polymorphisms of caudal type homeobox 1 and 2 are associated with Barrett's esophagus. AB - BACKGROUND: Barrett's esophagus (BE), the premalignant lesion of esophageal adenocarcinoma, is believed to develop as a result of chronic gastroesophageal reflux disease (GERD). Approximately 10 % of subjects with GERD progress to BE. Genetic, epigenetic and other risk factors may contribute to this inter individual variability. Caudal type homeobox 1 (Cdx1) and Caudal type homeobox 2 (Cdx2) play important regulatory roles in the development of human BE. AIMS: To determine associations between Cdx1 and Cdx2 single nucleotide polymorphisms (SNPs) and BE. METHODS: Genomic DNA was extracted from blood samples collected from BE (n = 109) and GERD (n = 223) patients for genotyping of 5 SNPs each of Cdx1 and Cdx2 using TaqMan allelic discrimination assays. Odds ratios and 95 % confidence intervals of SNPs and haplotypes were calculated with a logistic regression model adjusted for factors including age, sex and hiatal hernia. Interactions between genetic variants and these three risk factors were also analyzed. RESULTS: Older age (>=50 years), male sex and hiatal hernia were significantly associated with BE (P < 0.001). Five variants of Cdx1 SNPs (rs3776082, rs717746 and rs3776083), one Cdx1 haplotype, and three variants of Cdx2 SNPs (rs4769585 and rs3812863) were associated with BE (P < 0.05). Statistically significant interactions were detected between most of these SNPs and the three risk factors (P < 0.05). CONCLUSION: Certain SNPs of Cdx1 and Cdx2 and their interactions with other risk factors are associated with BE, and may contribute to human susceptibility to BE. PMID- 23918154 TI - Relationship of cardiac sympathetic nerve innervation and excitability to cardiac hypertrophy in very elderly male hypertensive patients. AB - INTRODUCTION: Our study aimed to disclose the relationship of cardiac sympathetic nerve innervation and excitability to myocardial hypertrophy in very old elderly male hypertensive patients with low serum testosterone level. METHODS: A total of 80 elderly male hypertensive patients aged from 80 to 95 years were recruited. Heart rate variability is determined by 24 h dynamic electrocardiogram and heart rate variability analysis system. Cardiac function and left ventricular mass index were determined using color Doppler ultrasound. RESULTS: Standard deviation of all normal sinus R-R intervals over 24 h (SDNN) significantly decreased in hypertensive cardiac hypertrophy patients as compared with those without cardiac hypertrophy. SDANN and Standard deviation of the average normal sinus R-R intervals for all 5-min segment index, time-domain index reflecting sympathetic nerve tension, obviously decreased and LFnu and LFnu/HFnu, frequency-domain index representing sympathetic nerve excitability, significantly increased in hypertensive cardiac hypertrophy patients as compared with those without cardiac hypertrophy. Myocardial norepinephrine content significantly increased while tyrosine hydroxylase expression significantly lowered in hypertensive cardiac hypertrophy patients, and a negative correlation between myocardial tyrosine hydroxylase expression and myocardial norepinephrine content was present. Serum total testosterone level decreased in hypertensive cardiac hypertrophy patients and was an independent risk factor for the increase in myocardial norepinephrine content and decrease in tyrosine hydroxylase expression. CONCLUSIONS: These data confirm that cardiac sympathetic nerve hypoinnervation and relative increase in cardiac sympathetic nerve excitability are closely related to cardiac hypertrophy in very old hypertensive patients. A lower serum total testosterone level was the independent risk factor of cardiac sympathetic nerve hypoinnervation and relative increase in excitability in very old male hypertensive patients. PMID- 23918155 TI - Clinical management of hypertension in pregnancy. Practical recommendations from the Italian Society of Hypertension (SIIA). [corrected]. PMID- 23918156 TI - Growth hormone, gender and face shape in Prader-Willi syndrome. AB - Prader-Willi syndrome is a neurodevelopmental disorder resulting from the absence of expression of paternally expressed gene(s) in a highly imprinted region of chromosome 15q11-13. The physical phenotype includes evidence of growth retardation due to relative growth hormone deficiency, small hands and feet, a failure of normal secondary sexual development, and a facial appearance including narrow bifrontal diameter, almond-shaped palpebral fissures, narrow nasal root, and thin upper vermilion with downturned corners of the mouth. Anecdotally, the face of individuals with PWS receiving hGH treatment is said to "normalize." We used dense surface modelling and shape signature techniques to analyze 3D photogrammetric images of the faces of 72 affected and 388 unaffected individuals. We confirmed that adults with Prader-Willi syndrome who had never received human growth supplementation displayed known characteristic facial features. Facial growth was significantly reduced in these adults, especially in males. We demonstrated that following human growth hormone (hGH) supplementation, vertical facial growth of affected individuals falls within the normal range. However, lateral and periorbital face shape and nose shape differences in affected children who have received hGH therapy remain sufficiently strong to be significantly discriminating in comparisons with age-sex matched, unaffected individuals. Finally, we produced evidence that age at initiation and length of treatment with hGH do not appear to play a role in normalization or in consistent alteration of the face shape of affected individuals. This is the first study to provide objective shape analysis of craniofacial effects of hGH therapy in Prader Willi syndrome. PMID- 23918157 TI - Molecular etiology of hearing impairment associated with nonsyndromic enlarged vestibular aqueduct in East China. AB - Recessive mutations in SLC26A4 and in rarer cases double heterozygous mutations of FOXI1/SLC26A4 and KCNJ10/SLC26A4 lead to hearing impairment associated with enlarged vestibular aqueduct (EVA), the most common inner ear malformation. In our large cohort study, we addressed several important questions to the molecular etiology of this disorder. The overall prevalence of SLC26A4 mutations in nonsyndromic childhood sensorineural hearing loss (11.2%, 37/330) were determined by sequencing of SLC26A4 in 330 hearing impaired children who did not undergo inner ear radiologic imaging prior to their genetic test. The penetrance of EVA in bi-allelic SLC26A4 mutation carriers (100%, 37/37) was determined by follow-up computed tomography scanning. Combined with the study of 140 additional probands diagnosed with nonsyndromic EVA, we characterized the mutation spectrum of SLC26A4 in East China, which consisted of 19 novel SLC26A4 mutations and differed from those reported in other regions of China. PMID- 23918158 TI - Sexual violence and mental health symptoms among National Guard and Reserve soldiers. AB - BACKGROUND: Reserve and National Guard (NG) soldiers report disproportionate mental health problems relative to active duty military upon returning from the Iraq and Afghanistan conflicts. However, few studies have examined whether exposure to particular types of traumatic events (e.g., lifetime sexual violence) is associated with this increased burden of psychopathology. OBJECTIVE: The current study examined the prevalence of lifetime sexual violence exposure as well as the adjusted odds and population attributable fraction of psychopathology associated with sexual violence in a large sample of male and female Reserve and NG soldiers. DESIGN: Baseline structured telephone interviews were conducted in 2009. PARTICIPANTS: 1,030 Reserve (23 % female) and 973 NG (15 % female) soldiers. MAIN MEASURES: Four items assessed lifetime and deployment-related sexual violence. Probable lifetime and past-year posttraumatic stress disorder (PTSD) and depression were assessed with the PTSD Checklist and the Patient Health Questionnaire, respectively. KEY RESULTS: Lifetime sexual violence prevalence was 37.4 % and 27.6 % among Reserve and NG women, and 4.3 % and 3.7 % among Reserve and NG men, respectively. Recent deployment-related sexual violence ranged from 1.4 to 2.6 % for women and 0 % for men. Regression analyses indicated that the adjusted odds of probable past-year and lifetime PTSD and depression were 1.2 to 3.5 times greater among those reporting sexual violence relative to non-victims. The proportion of probable lifetime PTSD and depression attributable to sexual violence was 45.2 % and 16.6 %, respectively, in the Reserves, and 10.3 % and 6.2 %, respectively, in the NG. CONCLUSIONS: Lifetime sexual violence prevalence was high among female soldiers, with approximately one-third of Reserve and National Guard women reporting a history. The majority of sexual violence was not related to the most recent deployment; however, sexual violence contributed to a high burden of psychopathology. Findings emphasize a need to screen for lifetime sexual violence and associated mental disorders in military samples. PMID- 23918159 TI - Reflections on compassion in the midst of violence. PMID- 23918161 TI - The mentor. PMID- 23918160 TI - Psychometric properties of the brief health literacy screen in clinical practice. AB - BACKGROUND: The three-item Brief Health Literacy Screen (BHLS) has been validated in research settings, but not in routine practice, administered by clinical personnel. OBJECTIVE: As part of the Health Literacy Screening (HEALS) study, we evaluated psychometric properties of the BHLS to validate its administration by clinical nurses in both clinic and hospital settings. PARTICIPANTS: Beginning in October 2010, nurses in clinics and the hospital at an academic medical center have administered the BHLS during patient intake and recorded responses in the electronic health record. MEASURES: Trained research assistants (RAs) administered the short Test of Functional Health Literacy in Adults (S-TOFHLA) and re-administered the BHLS to convenience samples of hospital and clinic patients. Analyses included tests of internal consistency reliability, inter administrator reliability, and concurrent validity by comparing the nurse administered versus RA-administered BHLS scores (BHLS-RN and BHLS-RA, respectively) to the S-TOFHLA. KEY RESULTS: Cronbach's alpha for the BHLS-RN was 0.80 among hospital patients (N = 498) and 0.76 among clinic patients (N = 295), indicating high internal consistency reliability. Intraclass correlation between the BHLS-RN and BHLS-RA among clinic patients was 0.77 (95 % CI 0.71-0.82) and 0.49 (95 % CI 0.40-0.58) among hospital patients. BHLS-RN scores correlated significantly with BHLS-RA scores (r = 0.33 among hospital patients; r = 0.62 among clinic patients), and with S-TOFHLA scores (r = 0.35 among both hospital and clinic patients), providing evidence of inter-administrator reliability and concurrent validity. In regression models, BHLS-RN scores were significant predictors of S-TOFHLA scores after adjustment for age, education, gender, and race. Area under the receiver operating characteristic curve for BHLS-RN to predict adequate health literacy on the S-TOFHLA was 0.71 in the hospital and 0.76 in the clinic. CONCLUSIONS: The BHLS, administered by nurses during routine clinical care, demonstrates adequate reliability and validity to be used as a health literacy measure. PMID- 23918163 TI - Crack Identification of Cantilever Plates Based on a Kriging Surrogate Model. AB - This work presents an effective method to identify the tip locations of an internal crack in cantilever plates based on a Kriging surrogate model. Samples of varying crack parameters (tip locations) and their corresponding root mean square (RMS) of random responses are used to construct the initial Kriging surrogate model. Moreover, the pseudo excitation method (PEM) is employed to speed up the spectral analysis. For identifying crack parameters based on the constructed Kriging model, a robust stochastic particle swarm optimization (SPSO) algorithm is adopted for enhancing the global searching ability. To improve the accuracy of the surrogate model without using extensive samples, a small number of samples are first used. Then an optimal point-adding process is carried out to reduce computational cost. Numerical studies of a cantilever plate with an internal crack are performed. The effectiveness and efficiency of this method are demonstrated by the identified results. The effect of initial sampling size on the precision of the identified results is also investigated. PMID- 23918162 TI - Challenges faced by patients with low socioeconomic status during the post hospital transition. AB - BACKGROUND: Patients with low socioeconomic status (low-SES) are at risk for poor outcomes during the post-hospital transition. Few prior studies explore perceived reasons for poor outcomes from the perspectives of these high-risk patients. OBJECTIVE: We explored low-SES patients' perceptions of hospitalization, discharge and post-hospital transition in order to generate hypotheses and identify common experiences during this transition. DESIGN: We conducted a qualitative study using in-depth semi-structured interviewing. PARTICIPANTS: We interviewed 65 patients who were: 1) uninsured, insured by Medicaid or dually eligible for Medicaid and Medicare; 2) residents of five low-income ZIP codes; 3) had capacity or a caregiver who could be interviewed as a proxy; and 4) hospitalized on the general medicine or cardiology services of two academically affiliated urban hospitals. APPROACH: Our interview guide investigated patients' perceptions of hospitalization, discharge and the post-hospital transition, and their performance of recommended post-hospital health behaviors related to: 1) experience of hospitalization and discharge; 2) external constraints on patients' ability to execute discharge instructions; 3) salience of health behaviors; and 4) self-efficacy to execute discharge instructions. We used a modified grounded theory approach to analysis. KEY RESULTS: We identified six themes that low-SES patients shared in their narratives of hospitalization, discharge and post hospital transition. These were: 1) powerlessness during hospitalization due to illness and socioeconomic factors; 2) misalignment of patient and care team goals; 3) lack of saliency of health behaviors due to competing issues; 4) socioeconomic constraints on patients' ability to perform recommended behaviors; 5) abandonment after discharge; and 6) loss of self-efficacy resulting from failure to perform recommended behaviors. CONCLUSIONS: Low-SES patients describe discharge goals that are confusing, unrealistic in the face of significant socioeconomic constraints, and in conflict with their own immediate goals. We hypothesize that this goal misalignment leads to a cycle of low achievement and loss of self-efficacy that may underlie poor post-hospital outcomes among low-SES patients. PMID- 23918164 TI - Development of a Semi-Active Electromagnetic Vibration Absorber and Its Experimental Study. AB - In this work, a semiactive electromagnetic vibration absorber has been developed based on a proposed electromagnetic stiffness adjustable spring model, which presents a new solution for adjusting stiffness in the field of vibration absorber devices. Simulation study on the electromagnetic spring has been performed to determine the structural parameter of the semiactive vibration absorber. An experimental rig is also built up to investigate its practical vibration control effectiveness. Firstly, the finite element model of the test bench is used to analyze its vibration characteristics. Then, the vibration reduction effect is predicted through the simulation analysis, from which the optimal control positions are found. Finally, the experimental studies are also conducted, and the results show that this semiactive electromagnetic vibration absorber has a frequency adjustment range from 21 Hz to 25 Hz, in which considerable vibration reduction from 5 dB to 10 dB can be achieved. PMID- 23918165 TI - Dual-Functional Energy-Harvesting and Vibration Control: Electromagnetic Resonant Shunt Series Tuned Mass Dampers. AB - This paper proposes a novel retrofittable approach for dual-functional energy harvesting and robust vibration control by integrating the tuned mass damper (TMD) and electromagnetic shunted resonant damping. The viscous dissipative element between the TMD and primary system is replaced by an electromagnetic transducer shunted with a resonant RLC circuit. An efficient gradient based numeric method is presented for the parameter optimization in the control framework for vibration suppression and energy harvesting. A case study is performed based on the Taipei 101 TMD. It is found that by tuning the TMD resonance and circuit resonance close to that of the primary structure, the electromagnetic resonant-shunt TMD achieves the enhanced effectiveness and robustness of double-mass series TMDs, without suffering from the significantly amplified motion stroke. It is also observed that the parameters and performances optimized for vibration suppression are close to those optimized for energy harvesting, and the performance is not sensitive to the resistance of the charging circuit or electrical load. PMID- 23918166 TI - Fluoride promotes viability and differentiation of osteoblast-like Saos-2 cells via BMP/Smads signaling pathway. AB - The BMP/Smad signaling pathway plays an important role in the viability and differentiation of osteoblast; however, it is not clear whether this pathway is involved in the fluoride-induced osteoblast differentiation. In this study, we investigated the role of BMP/Smad signaling pathway in fluoride-induced osteoblast-like Saos-2 cells differentiation. Cells were exposed to fluoride of different concentrations (0, 0.1, 0.2, 0.4, 0.8, and 1.6 mM), and cell proliferation was determined using WST assays. The expression of osteoblast marker genes such as osteocalcin (BGP) and bone alkaline phosphatase (BALP) were detected by qRT-PCR. We found that fluoride enhanced the proliferation of Saos-2 cells in a dose-dependent manner and 0.2 mM of fluoride resulted in a higher expression of osteoblast marker genes. In addition, immunofluorescence analysis showed that the promotion effects of 0.2 mM of fluoride on Saos-2 cells differentiation were associated with the activation of the BMP/Smad pathway. Expression of phosphorylated Smad1/5(p-Smad1/5) was higher in cells exposed to 0.2 mM of fluoride. Plasmid expression vectors encoding the short hairpin RNA (shRNA) targeting Smad4 gene were used to block the BMP/Smad pathway, which resulted in a significantly reduced expression of BGP and BALP as well as their corresponding mRNA. The mRNA levels after transfection remained low even in the presence of fluoride. The present results reveal that BMP/Smad signaling pathway was altered during the period of osteogenesis, and that the activities of p Smad1/5 were required for Saos-2 cells viability and differentiation induced by fluoride. PMID- 23918167 TI - A preliminary study of a Peruvian diet using dietary analysis and hair mineral content as indicators. AB - Observations among former American residents living long-term in Peru suggested that hair health improved while in Peru. To determine if a Peruvian diet correlates with hair composition, dietary intake of nutrients and mineral content of hair were measured among Peruvian and matched US residents. Selected foods from Peru were also analyzed for mineral and antioxidant content and compared with equivalent foods available in the USA. Statistically significant differences between Peruvian and US residents' hair were found for sodium (decreased in Peru, p = 0.007) and vanadium (decreased in Peru, p = 0.03). Differences in hair composition between residencies may be explained by lower dietary sodium and vanadium intake among Peruvian residents or by lower concentrations of these minerals in Peruvian drinking water. Many significant mineral differences were also identified between Peruvian foods and their US equivalents. Although no statistically significant correlations between dietary intake and hair mineral content were found, results indicate that a Peruvian diet contributes differently to hair composition than a US diet. More research is needed to elucidate the link between a Peruvian diet and specific aspects of hair health. PMID- 23918168 TI - A genetically encoded sulfotyrosine for VHR function research. PMID- 23918169 TI - Development of an algorithm for identifying rheumatoid arthritis in the Korean National Health Insurance claims database. AB - This study aimed to develop an identification algorithm for validating the International Classification of Diseases-Tenth diagnostic codes for rheumatoid arthritis (RA) in the Korean National Health Insurance (NHI) claims database. An individual copayment beneficiaries program for rare and intractable diseases, including seropositive RA (M05), began in South Korea in July 2009. Patients registered in this system pay only 10 % of their total medical costs, but registration requires an official report from a doctor documenting that the patient fulfills the 1987 ACR criteria. We regarded patients registered in this system as gold standard RA and examined the validity of several algorithms to define RA diagnosis using diagnostic codes and prescription data. We constructed nine algorithms using two highly specific prescriptions (positive predictive value >90 % and specificity >90 %) and one prescription with high sensitivity (>80 %) and accuracy (>75 %). A total of 59,823 RA patients were included in this validation study. Among them, 50,082 (83.7 %) were registered in the individual copayment beneficiaries program and considered true RA. We tested nine algorithms that incorporated two specific regimens [biologics and leflunomide alone, methotrexate plus leflunomide, or more than 3 disease-modifying anti-rheumatic drugs (DMARDs)] and one sensitive drug (any non-steroidal anti-inflammatory drug (NSAID), any DMARD, or any NSAID plus any DMARD). The algorithm that included biologics, more than 3 DMARDs, and any DMARD yielded the highest accuracy (91.4 %). Patients with RA diagnostic codes with prescription of biologics or any DMARD can be considered as accurate cases of RA in Korean NHI claims database. PMID- 23918170 TI - A practical guide to multiplexed mass cytometry. AB - Recent advances in inductively coupled plasma mass spectrometry (ICP-MS) as applied in mass cytometry, enabled its broad applicability to life science research. Mass cytometry enables the high-dimensional characterization of cellular systems by simultaneously measuring dozens of metal isotope reporter labeled antibodies bound to cell components. With the ability to simultaneously interrogate an unprecedented number of molecular components on a per cell basis, it offers the possibility to gain better understanding of single cell biology in heterogeneous samples. To upscale this single cell information to screening approaches by mass cytometry, a cell-based multiplexing technique, called mass tag cellular barcoding (MCB), was developed. MCB enables the simultaneous analysis of multiple cell samples by using n metal ion tags to multiplex up to 2 (n) samples. Different mass tag combinations are used to label individual cell samples with a unique mass barcode that allows multiple samples to be combined and immunostained together for a single analysis on the mass cytometer. Taken together, MCB enables increased sample throughput, reduces antibody consumption, and increases the overall data quality. In this chapter, we describe the MCB to array the samples in a 96-well format that allows for medium-scale profiling/screening experiments to be run on a standard mass cytometer. PMID- 23918171 TI - Modulation of small GTPases by Legionella. AB - The pathogenic bacterium Legionella pneumophila interacts intimately with signaling molecules during the infection of eukaryotic host cells. Among a diverse set of regulatory molecules, host small GTPases appear to be prominent and significant targets. Small GTPases are molecular switches that regulate cellular signaling via their respective nucleotide-bound states: When bound to GDP, they are inactive, but become activated upon binding to GTP. Legionella secretes specific bacterial proteins into the cytosol of the host cell that most prominently modulate the activities of small GTPases involved in vesicular trafficking, but probably also other G-proteins. The master regulators of vesicular trafficking, i.e., Rab and Arf proteins, are majorly targeted G proteins of Legionella proteins, and among these, Rab1 experiences the most diverse modifications. Generally, the activities of small GTPases are modulated by GDP/GTP exchange (activation), GTP hydrolysis (deactivation), membrane recruitment, post-translational modifications (phosphocholination, adenylylation), and tight and competitive binding. Here, we discuss the consequences and molecular details of the modulation of small GTPases for the infection by Legionella, with a special but not exclusive focus on Rab and Arf proteins. PMID- 23918172 TI - Phosphoinositide lipids and the Legionella pathogen vacuole. AB - Subversion of vesicle trafficking is vital for intracellular survival of Legionella pneumophila within host cells. L. pneumophila produces several type IV translocated effector proteins that modify components of the phagosomal membrane, in particular the phosphoinositide (PI) lipids. Within eukaryotic cells PIs co define subcellular compartments and membrane dynamics. The generation, half-life, and localization of PI lipids are not only tightly regulated by the host cell, but also targeted and modulated by a number of L. pneumophila effectors. These effectors either anchor to PIs, directly modify the lipids, or recruit PI metabolizing enzymes to the LCV membrane. Together, PI-subverting L. pneumophila effectors act jointly to promote the formation of a replication-permissive niche inside the host. PMID- 23918174 TI - Modulation of the ubiquitination machinery by Legionella. AB - The bacterial pathogen Legionella pneumophila manipulates its intracellular fate by co-opting host processes. Using bacterial proteins translocated into host cells, L. pneumophila targets pathways shared by unicellular protozoa and higher eukaryotes. In eukaryotes, an important mechanism that regulates numerous cellular processes, including those designed to kill invading microorganisms, is ubiquitination. Post-translational modification of proteins with ubiquitin is a highly regulated process that either targets proteins for degradation or modifies their activity. It is emerging that L. pneumophila possesses functional mimics of eukaryotic E3 ubiquitin ligases that function with the host ubiquitination machinery to select and modify substrates for polyubiquitination. L. pneumophila proteins have been identified that ubiquitinate both host and bacterial proteins, and ubiquitination of the bacterial protein SidH results in its degradation by the host proteasome. This pathway allows L. pneumophila to temporally regulate effector function inside host cells, and facilitates optimal L. pneumophila replication by undefined mechanisms. This review will focus on our current knowledge of the proteins used by L. pneumophila to co-opt the host ubiquitination machinery, and current progress toward understanding the ubiquitin mediated processes manipulated by L. pneumophila to facilitate intracellular survival and propagation. PMID- 23918175 TI - Host lipidation: a mechanism for spatial regulation of Legionella effectors. AB - Bacterial pathogens have evolved the capacity to translocate proteins into the cytosol of infected cells to manipulate host processes. How do pathogens regulate spatially these bacterial effector proteins once they are released into the host cell? One mechanism, which is used by Legionella and other bacterial pathogens, is to encode effectors that mimic the substrates of eukaryotic lipid transferases. In this review we discuss three membrane-targeting pathways in eukaryotes that are exploited by Legionella and other pathogens-prenylation, palmitoylation, and myristoylation. Lipidation of bacterial substrates primes the effectors for coincidence detection-mediated targeting onto membrane-bound organelles by increasing membrane affinity. Intracellular membrane-targeting strategies that exploit protein fatty acylation and prenylation direct bacterial effectors to compartments where their target substrates reside and thus are critical for effector function. PMID- 23918173 TI - Host signal transduction and protein kinases implicated in Legionella infection. AB - Modulation of the phosphorylation status of proteins by both kinases and phosphatases plays an important role in cellular signal transduction. Challenge of host cells by Legionella pneumophila manipulates the phosphorylation state of multiple host factors. These changes play roles in bacterial uptake, vacuole modification, cellular survival, and the immune response. In addition to modification by host cell kinases in response to the bacterium, L. pneumophila translocates bacterial kinases into the host cell that may contribute to further signaling modifications. Proper regulation of host cell signaling by L. pneumophila is necessary for its ability to replicate intracellulary, while avoiding host defenses. PMID- 23918176 TI - Effector translocation by the Legionella Dot/Icm type IV secretion system. AB - Legionella pneumophila is an opportunistic pathogen responsible for Legionnaires' disease. This bacterium survives and replicates within phagocytes by bypassing their bactericidal activity. Intracellular replication of L. pneumophila requires the Dot/Icm type IV secretion system made of approximately 27 proteins that presumably traverses the bacterial and phagosomal membranes. The perturbation of the host killing ability largely is mediated by the collective functions of the protein substrates injected into host cells via the Dot/Icm transporter. Proper protein translocation by Dot/Icm is determined by a number of factors, including signals recognizable by the translocator, chaperones that may facilitate the proper folding of substrates and transcriptional regulation and protein stability that determine the abundance and temporal transfer of the substrates. Although a large number of Dot/Icm substrates have been identified, investigation to understand the translocation is ongoing. Here we summarized the recent advancements in our understanding of the factors that determine the protein translocation activity of the Dot/Icm transporter. PMID- 23918177 TI - The Legionella pneumophila two-component regulatory systems that participate in the regulation of Icm/Dot effectors. AB - Legionella pneumophila, the causative agent of Legionnaires' disease, actively manipulates intracellular processes to establish a replication niche inside their host cells. The establishment of its replication niche requires a functional Icm/Dot type IV secretion system which translocates about 300 effector proteins into the host cells during infection. This enormous number of effectors should be coordinated at the level of gene expression, in order to be expressed and translocated at the correct time and appropriate amounts. One of the predominant ways in bacteria to regulate virulence gene expression is by the use of two component systems (TCSs). To date, four TCSs have been shown to be involved in the regulation of Icm/Dot effector-encoding genes: The PmrAB and CpxRA TCSs that directly control, and the LetAS and LqsRS TCSs that indirectly control the level of expression of effector-encoding genes. According to our current knowledge, these four TCSs control the expression of about 70 effector-encoding genes. The regulation by different TCSs divides the effectors into groups of co-regulated effector-encoding genes that are probably co-expressed at a similar time during infection and might perform related functions. In addition, examples of interplay between these TCSs were already reported indicating that they form part of a regulatory network that orchestrates the expression of L. pneumophila effector encoding genes during infection. PMID- 23918178 TI - Facets of small RNA-mediated regulation in Legionella pneumophila. AB - Legionella pneumophila is a water-borne pathogen that causes a severe lung infection in humans. It is able to replicate inside amoeba in the water environment, and inside lung macrophages in humans. Efficient regulation of gene expression is critical for responding to the conditions that L. pneumophila encounters and for intracellular multiplication in host cells. In the last two decades, many reports have contributed to our understanding of the critical importance of small regulatory RNAs (sRNAs) in the regulatory network of bacterial species. This report presents the current state of knowledge about the sRNAs expressed by L. pneumophila and discusses a few regulatory pathways in which sRNAs should be involved in this pathogen. PMID- 23918179 TI - Mouse models of Legionnaires' disease. AB - Legionella pneumophila is an accidental respiratory pathogen of humans that provokes a robust inflammatory response upon infection. While most people exposed to L. pneumophila will clear the infection, certain groups with underlying susceptibility will develop Legionnaires' disease. Mice, like most humans, are inherently resistant to L. pneumophila and infection of most inbred strains reflects the response of immune competent people to L. pneumophila exposure. Hence, the use of mouse models of L. pneumophila infection has taught us a great deal about the innate and adaptive factors that lead to successful clearance of the pathogen and avoidance of Legionnaires' disease. At the same time, L. pneumophila has provided new insight into innate immunity in general and is now a model pathogen with which to study acute lung inflammation and inflammasome activation. This chapter will explore the history and use of the mouse model of L. pneumophila infection and examine what we know about the innate and adaptive factors that contribute to the control of L. pneumophila in the mouse lung. PMID- 23918180 TI - Shooting movies of signaling network dynamics with multiparametric cytometry. AB - Single-cell technologies like mass cytometry enable researchers to comprehensively monitor signaling network responses in the context of heterogeneous cell populations. Cell-to-cell variability, the possibly nonlinear topology of signaling processes, and the destructive nature of mass cytometry necessitate nontrivial computational approaches to reconstruct and sensibly describe signaling dynamics. Modeling of signaling states depends on a set of coherent examples, that is, a set of cell events representing the same cell state. This requirement is frequently compromized by process asynchrony phenomena or nonlinear process topologies. We discuss various computational deconvolution approaches to define molecular process coordinates and enable compilation of coherent data sets for cell state inference. In addition to the conceptual presentation of these approaches, we discuss the application of these methods to modeling of TRAIL-induced apoptosis. Due to their generic applicability these computational approaches will contribute to the elucidation of dynamic intracellular signaling networks in various settings. The resulting signaling maps constitute a promising source for novel interventions and are expected to be particularly valuable in clinical settings. PMID- 23918181 TI - Structural instability and emergence of the biodiversity. AB - In the framework of population dynamics, we start from the logistic equation describing the evolution of one species with limited food supply. A split device allows us to consider the population as two sub-populations x and y evolving analogously. The dynamical system has a one-parameter family of equilibria which is structurally unstable. Then small perturbations of the system (describing functional or ethological differentiations between the sub-species) lead in general to a new system involving a fast and a slow dynamics with a finite number of equilibria. In simple situations where the differentiation is clearly either an advantage or an inconvenience for one of the subspecies, the stable equilibrium amounts to extinction of the disadvantaged subspecies (elementary Darwinism). Oppositely more complex differentiations (involving both advantages and inconveniences) often lead to stable equilibria with well-defined non zero proportions of the sub-populations (preservation of the biodiversity). Other examples are concerned with symbiosis-like differentiations, leading to preservation, whereas the opposite case (mutual nuisances) has an unstable equilibrium and lead to extinction of one or the other subspecies according to the initial conditions. The case of a scission into three subspecies is more rich in consequences. In certain cases, predator-prey relations lead to auto organization phenomena with stable diversity-preserving diversity. Cases of instability are also possible, leading to orbits tending towards a poly cycle.This implies some kind of pseudo-extinction: this amounts to "pseudo periodic-like" orbits with "pseudo-periods" larger and larger, tending to infinity; each pseudo-period contains parts where one of the sub-populations practically vanish. Other non-linear perturbations lead to stable orbits. PMID- 23918182 TI - Evaluation of intraoperative cone beam computed tomography and optical drill tracking in temporal bone surgery. AB - OBJECTIVES/HYPOTHESIS: A prototype system for intraoperative cone beam computed tomography (CBCT) imaging has been developed and augmented with real time optical tracking of a surgical drill. We hypothesize that this system provides sufficient accuracy for guidance of temporal bone surgery. STUDY DESIGN: Basic research. METHODS: Measurements of drill localization accuracy using CBCT imaging were obtained with a custom three-dimensional calibration object. Integrated CBCT imaging and drill tracking were prospectively evaluated on 12 cadaver temporal bones. Six inexperienced and six experienced surgeons conducted four surgical tasks: cortical mastoidectomy, posterior tympanotomy, cochleostomy, and a translabyrinthine approach to the internal auditory canal. Questionnaires provided expert feedback on tracking accuracy and system usability. RESULTS: Target registration error measurements of drill tracking accuracy and precision yielded a mean of 0.76 mm, a maximum of 1.30 mm, and a standard deviation of 0.21 mm. Anatomical landmark identification tasks (e.g., facial nerve, incus, semicircular canals, cochlea) provided additional validation of system accuracy. The usability and utility of the guidance system were positively rated by both groups of surgeons, with further modifications underway to improve tracking line of sight and registration workflow. Experienced but in particular inexperienced surgeons indicated significant benefits in cases involving extensive disease, abnormal anatomy, and loss of anatomical landmarks. CONCLUSIONS: The integration of intraoperative CBCT imaging with optical tracking provides sufficient accuracy to localize anatomical structures within the temporal bone using an otological drill. Future studies will explore the role of this technology in complex oncological resections, in surgery for congenital anomalies, and as a tool for teaching. PMID- 23918183 TI - Cloning of a sesquiterpene synthase from Lavandula x intermedia glandular trichomes. AB - The essential oil (EO) of Lavandula is dominated by monoterpenes, but can also contain small amounts of sesquiterpenes, depending on species and environmental conditions. For example, the sesquiterpene 9-epi-caryophyllene can make up to 8 % of the EO in a few species, including those commercially propagated for EO production. Here, we report the cloning and functional characterization of 9-epi caryophyllene synthase (LiCPS) from the glandular trichomes of Lavandula x intermedia, cv. Grosso. The 1,617 bp open reading frame of LiCPS, which did not encode a transit peptide, was expressed in Escherichia coli and the recombinant protein purified by Ni-NTA agarose affinity chromatography. The ca. 60 kDa recombinant protein specifically converted farnesyl diphosphate to 9-epi caryophyllene. LiCPS also produced a few monoterpenes when assayed with the monoterpene precursor geranyl diphosphate (GPP), but--unlike most monoterpene synthases--was not able to derive detectable amounts of any products from the cis isomer of GPP, neryl diphosphate. The LiCPS transcripts accumulated in developing L. x intermedia flowers and were highly enriched in glandular trichomes, but were not detected in leaves suggesting that the transcriptional expression of this gene is spatially and developmentally regulated. PMID- 23918185 TI - Three-dimensional echocardiography is essential for intraoperative assessment of mitral regurgitation. PMID- 23918184 TI - Modified expression of an auxin-responsive rice CC-type glutaredoxin gene affects multiple abiotic stress responses. AB - Glutaredoxins (GRXs) are the ubiquitous oxidoreductase enzymes, which play an important role in defense against various stresses. Here, we report the role of a CC-type GRX gene from rice, OsGRX8, in abiotic stress tolerance. OsGRX8 protein was found to be localized in nucleus and cytosol and its gene expression is induced by various stress conditions and plant hormone auxin. The over-expression of OsGRX8 in Arabidopsis plants conferred reduced sensitivity to auxin and stress hormone, abscisic acid. In addition, the transgenic Arabidopsis plants exhibited enhanced tolerance to various abiotic stresses, including salinity, osmotic and oxidative stress. Further, the transgenic RNAi rice plants exhibited increased susceptibility to various abiotic stresses, which further confirmed the role of OsGRX8 in abiotic stress responses. The microarray data analysis revealed that expression of a large number of auxin-responsive, known stress-associated and transcription factor encoding genes was altered in GRX transgenic Arabidopsis plants in response to exogenous auxin and stress conditions as compared to wild type plants. Altogether, these findings suggest the role of OsGRX8 in regulating abiotic stress response and may be used to engineer stress tolerance in crop plants. PMID- 23918186 TI - Three-dimensional echocardiography is not essential for intraoperative assessment of mitral regurgitation. PMID- 23918187 TI - Optimal programming of implantable cardiac-defibrillators. PMID- 23918188 TI - ECG Response: August 6, 2013. Isorhythmic dissociation. PMID- 23918189 TI - Para-aortic lymphoma simulating mycotic abdominal aortic aneurysm. PMID- 23918190 TI - First in human transapical implantation of an inverted transcatheter aortic valve prosthesis to treat native mitral valve stenosis. PMID- 23918192 TI - Letter by Coffey et al regarding article, "Estimating deaths from cardiovascular disease: a review of global methodologies of mortality measurement". PMID- 23918193 TI - Behavioral reactivity to emotion challenge is associated with cortisol reactivity and regulation at 7, 15, and 24 months of age. AB - Emotionally arousing stimuli have been largely unsuccessful in eliciting cortisol responses in young children. Whether or not emotion challenge will elicit a cortisol response, however, may in part be determined by the extent to which the tasks elicit behavioral reactivity and regulation. We examined relations of behavioral reactivity and regulation to emotional arousal in the context of fear and frustration to the cortisol response at 7, 15, and 24 months of age in a low income, rural population based sample of 1,292 families followed longitudinally from birth. At each age, children participated in fear and frustration inducing tasks, and cortisol samples were taken at three time points (before the tasks began, 20 min following peak emotional arousal or after the series of tasks ended, and 40 min after peak arousal or the tasks ended) in order to capture both increases (reactivity) and subsequent decreases (regulation) in the cortisol response. Using multilevel models, we predicted the cortisol response from measures of behavioral reactivity and regulation. At 7 months of age, cortisol reactivity and recovery were related to behavioral reactivity during a frustration-eliciting task and marginally related to behavioral reactivity during a fear-eliciting task. At 15 and 24 months of age, however, cortisol reactivity and recovery were related only to behavioral reactivity during a fear-eliciting task. Results indicate that while behavioral reactivity is predictive of whether or not infants and young children will exhibit a cortisol response to emotionally arousing tasks, behavioral and cortisol reactivity are not necessarily coupled. PMID- 23918194 TI - The role of nerve monitoring to predict postoperative recurrent laryngeal nerve function in thyroid and parathyroid surgery. AB - OBJECTIVES/HYPOTHESIS: To determine the role and efficacy of intraoperative recurrent laryngeal nerve (RLN) stimulation in the prediction of early and permanent postoperative nerve function in thyroid and parathyroid surgery. STUDY DESIGN: A retrospective review of thyroid and parathyroid surgeries was performed with calculation of sensitivity and specificity of the response of intraoperative stimulation for different pathological groups. METHODS: Normal electromyography (EMG) response with 0.5 mAmp stimulation was considered a positive stimulation response with postoperative function determined by laryngoscopy. No EMG response at >1-2 mAmps was considered a negative response. The rates of early and permanent paralysis, as well as sensitivity, specificity, and positive and negative predictive values for postoperative nerve function were calculated for separate pathological groups. RESULTS: The number of nerves at risk analyzed was 909. The overall early and permanent paralysis rates were 3.1% and 1.2%, respectively, with the highest rate being for Grave's disease cases. The overall sensitivity was 98.4%. The specificity was lower at 62.5% but acceptable in thyroid carcinoma and Grave's disease patients. The majority of nerves with a positive stimulation result and postoperative paralysis on laryngoscopy recovered function in 3 to 12 weeks, showing positive stimulation to be a good predictor of eventual recovery. CONCLUSIONS: Stimulation of the RLN during thyroid and parathyroid surgery is a useful tool in predicting postoperative RLN function. The sensitivity of stimulation is high, showing positive stimulation to be an excellent predictor of normal nerve function. Negative stimulation is more predictive of paralysis in cases of thyroid carcinoma and Grave's disease. LEVEL OF EVIDENCE: 2b. PMID- 23918195 TI - Use transition between illegal drugs among Brazilian university students. AB - PURPOSE: The aim of the present study was to test whether the first use of an illicit drug increases the chance of first use of other illicit drugs. METHOD: The transitions from the first use of a drug to the first use of another drug were analyzed. Comparisons were made between first drug users and non-users. Survival analysis methods were used to compare the cumulative probability of second drug use after adjusting for socio-demographic covariates and the intermediate use of alcohol and/or tobacco. A total of 12,721 Brazilian university students participated in this study. RESULTS: Inhalants and marijuana were used prior to the use of several other drugs, whereas the opposite pattern was not found. Ecstasy was used before other drugs in several instances. Other well-examined drugs, such as amphetamines, cocaine and hallucinogens, were used both before and after other illicit drugs without any marked predominance for either of the two roles. CONCLUSIONS: This study supports the role of the use of marijuana and inhalants almost exclusively before the use of other illicit drugs, whereas the use of ecstasy has an opposite role. These roles could be linked to the prevalence of lifetime use and whether individuals were at an earlier or later age during experimentation. PMID- 23918196 TI - Does depression experienced by mothers leads to a decline in marital quality: a 21-year longitudinal study. AB - PURPOSE: Marital conflict and/or marital breakdown are known pathways to the onset of depression. Few studies however have examined the possibility that depression can lead to a decrease in marital quality and an increase in marital breakdown. Depression may be an important pathway to a decline in martial quality. METHODS: A birth cohort study with women (mothers) recruited early in pregnancy and followed for 21 years. Using repeated measures analysis for four waves of data collection we use GEE to examine the extent to which symptoms of depression predict subsequent poor martial quality in women and poor marital quality predicts subsequent depression. RESULTS: A bidirectional association between poor marital quality and depression is observed. After removing those who had pre-existing poor marital quality we note that depression predicts subsequent poor martial quality. Similarly, we note that poor marital quality predicts subsequent depression. These associations are all statistically significant and of a similar magnitude. CONCLUSION: Over the maternal reproductive life course there is a long-term trajectory of reduced marital quality and increased depression. Maternal depression is as likely to lead to a decline in marital quality as poor martial quality is likely to lead to increased levels of depression. There may be a need to develop intervention programmes to reduce this long-term pattern of change. PMID- 23918197 TI - Defining multiple criteria for meaningful outcome in routine outcome measurement using the Health of the Nation Outcome Scales. AB - PURPOSE: Using the reliable and clinically significant change approach, we aimed to identify meaningful outcome indicators for the Health of the Nation Outcome Scales (HoNOS) and to combine them in a single model. We applied these indicators to the 1-year outcome of two large samples of people attending community mental health services in Italy (cohort 1) and the Netherlands (cohort 2). METHODS: Data were drawn from two studies on routine outcome assessment. The criteria for meaningful outcome were defined on both study cohorts and both language versions of the scale. The model combined (a) two criteria for adequate change (at least 4 or 8 points change), (b) two cut-offs for clinically significant change (a total score of 10 was the threshold between mild and moderate illness, 13 between moderate and severe illness), and (c) a method for classifying stable subjects in three degrees of severity (stable in mild, moderate or severe illness). Results were compared with those given by the effect size (ES) and analysis of variance and covariance (ANOVA and ANCOVA). RESULTS: For the proposed approach the outcome of cohort 1 was better than cohort 2, with 65-67% of its subjects showing a positive outcome compared to only 45-46%. The other reference methods (ES and ANOVA), however, showed a greater improvement for cohort 2. ANCOVA indicated that the differences were due to regression to the mean (RTM) which showed opposite effects across the two cohorts. CONCLUSIONS: The proposed approach proved valuable and generalizable for interpreting outcome on HoNOS, scarcely influenced by the RTM effect. Its introduction could benefit outcome evaluation and management. PMID- 23918198 TI - Neonatal microglia come of age for inflammatory pain. PMID- 23918199 TI - Thinking of anything else does not always reduce pain: it depends on timing. PMID- 23918200 TI - Comment on Ng et al.: 'Laypersons' expectations of recovery and beliefs about whiplash injury: a cross-cultural comparison between Australians and Singaporeans'. PMID- 23918201 TI - Authors' reply to the comment by Ferrari. PMID- 23918202 TI - Effectiveness of pseudoephedrine as adjunctive therapy for neurogenic shock after acute spinal cord injury: a case series. AB - STUDY OBJECTIVE: To evaluate the effectiveness of pseudoephedrine as adjunctive therapy for neurogenic shock in patients with acute spinal cord injury (SCI). DESIGN: Case series. SETTING: Academic medical center. PATIENTS: Thirty-eight patients admitted to the trauma intensive care unit between September 2005 and October 2012 with an acute SCI and who received more than 1 day of pseudoephedrine for one or more of the following: treatment of bradycardia (heart rate <= 50 beats/min), treatment of hypotension (systolic blood pressure < 90 mm Hg), or were receiving intravenous vasopressor support. MEASUREMENTS AND MAIN RESULTS: The effect of adjunctive pseudoephedrine (PSE) was categorized as a success if vasopressors were discontinued after the initiation of PSE or improvement in the number of episodes of bradycardia was noted after the initiation of PSE as evidenced by decreased use of atropine. The effect of pseudoephedrine was categorized as a failure if it did not meet one of the criteria for success. The effect of pseudoephedrine was categorized as inconclusive if there were confounding factors such as vasopressors being restarted for another indication after initial discontinuation. Pseudoephedrine was successful in 31/38 (82%) patients, failed in 2/38 (5%) patients, and had inconclusive results in 5/38 (13%) patients. The mean +/- SD time to successful weaning of intravenous vasopressors was 7 +/- 7 days. Daily maximum pseudoephedrine doses ranged from 60-720 mg. Mean +/- SD duration of pseudoephedrine therapy was 32 +/- 23 days (range 2-135 days), with 64.5% of surviving patients discharged while receiving pseudoephedrine. CONCLUSION: These data suggest that pseudoephedrine is an effective adjunctive therapy in facilitating the discontinuation of intravenous vasopressors and/or atropine in patients with acute SCI with neurogenic shock, although patients will typically require long durations of therapy. PMID- 23918203 TI - Assessment of therapeutic potential of amantadine in methamphetamine induced neurotoxicity. AB - Methamphetamine epidemic has a broad impact on world's health care system. Its abusive potential and neurotoxic effects remain a challenge for the anti addiction therapies. In addition to oxidative stress, mitochondrial dysfunction and apoptosis, excitotoxicity is also involved in methamphetamine induced neurotoxicity. The N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to be one of the predominant mediators of excitotoxicity. There is growing evidence that NMDA receptor antagonists could be one of the therapeutic options to manage excitotoxicity. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was found to possess NMDA antagonistic properties and has shown to release dopamine from the nerve terminals. The current study aimed to evaluate the effect of amantadine pre-treatment against methamphetamine induced neurotoxicity. Results showed that methamphetamine treatment had depleted striatal dopamine, generated of reactive oxygen species and decreased activity of complex I in the mitochondria. Interestingly, amantadine, at high dose (10 mg/kg), did not prevent dopamine depletion moreover it exacerbated the behavioral manifestations of methamphetamine toxicity such as akinesia and catalepsy. Only lower dose of amantadine (1 mg/kg) produced significant scavenging of the reactive oxygen species induced by methamphetamine. Overall results from the present study suggest that amantadine should not be used concomitantly with methamphetamine as it may results in excessive neurotoxicity. PMID- 23918205 TI - An online EEG BCI based on covert visuospatial attention in absence of exogenous stimulation. AB - OBJECTIVE: In this work we present--for the first time--the online operation of an electroencephalogram (EEG) brain-computer interface (BCI) system based on covert visuospatial attention (CVSA), without relying on any evoked responses. Electrophysiological correlates of pure top-down CVSA have only recently been proposed as a control signal for BCI. Such systems are expected to share the ease of use of stimulus-driven BCIs (e.g. P300, steady state visually evoked potential) with the autonomy afforded by decoding voluntary modulations of ongoing activity (e.g. motor imagery). APPROACH: Eight healthy subjects participated in the study. EEG signals were acquired with an active 64-channel system. The classification method was based on a time-dependent approach tuned to capture the most discriminant spectral features of the temporal evolution of attentional processes. The system was used by all subjects over two days without retraining, to verify its robustness and reliability. MAIN RESULTS: We report a mean online accuracy across the group of 70.6 +/- 1.5%, and 88.8 +/- 5.8% for the best subject. Half of the participants produced stable features over the entire duration of the study. Additionally, we explain drops in performance in subjects showing stable features in terms of known electrophysiological correlates of fatigue, suggesting the prospect of online monitoring of mental states in BCI systems. SIGNIFICANCE: This work represents the first demonstration of the feasibility of an online EEG BCI based on CVSA. The results achieved suggest the CVSA BCI as a promising alternative to standard BCI modalities. PMID- 23918204 TI - Reactive oxygen species from human astrocytes induced functional impairment and oxidative damage. AB - Reactive oxygen species (ROS) have been shown to be a contributor to aging and disease. ROS also serve as a trigger switch for signaling cascades leading to corresponding cellular and molecular events. In the central nervous system (CNS), microglial cells are likely the main source of ROS production. However, activated astrocytes also appear to be capable of generating ROS. In this study we investigated ROS production in human astrocytes stimulated with interleukin (IL) 1beta and interferon (IFN)-gamma and its potential harmful effects. Although IFN gamma alone had no effect, it potentiated IL-1beta-induced ROS production in a time-dependent manner. One of the sources of ROS in IL-1beta-activated astrocytes was from increased superoxide production in mitochondria accompanied by enhanced manganese superoxide dismutase and inhibited catalase expression. NADPH oxidase (NOX) may also contribute to ROS production as astrocytes express NOX isoforms. Glutamate uptake, which represents one of the most important methods of astrocytes to prevent excitotoxicity, was down-regulated in IL-1beta-activated astrocytes, and was further suppressed in the presence of IFN-gamma; IFN-gamma itself exerted minimal effect. Elevated levels of 8-isoprostane in IL-1beta +/- IFN-gamma-activated human astrocytes indicate downstream lipid peroxidation. Pretreatment with diphenyleneiodonium abolished the IL-1beta +/- IFN-gamma induced ROS production, restored glutamate uptake function and reduced 8 isoprostane to near control levels suggesting that ROS contributes to the dysfunction of activated astrocytes. These results support the notion that dampening activated human astrocytes to maintain the redox homeostasis is vital to preserve their neuroprotective potential in the CNS. PMID- 23918206 TI - Topical secretoneurin gene therapy accelerates diabetic wound healing by interaction between heparan-sulfate proteoglycans and basic FGF. AB - Diabetic foot ulcers represent a therapeutic problem of high clinical relevance. Reduced vascular supply, neuropathy and diminished expression of growth factors strongly contribute to wound healing impairment in diabetes. Secretoneurin, an angiogenic neuropeptide, has been shown to improve tissue perfusion in different animal models by increasing the amount of vessels in affected areas. Therefore, topical secretoneurin gene therapy was tested in a full thickness wound healing model in diabetic db/db mice. Secretoneurin significantly accelerated wound closure in these mice and immunohistochemistry revealed higher capillary and arteriole density in the wounded area compared to control mice. In-vitro, the mechanism of action of secretoneurin on human dermal microvascular endothelial cells was evaluated in normal and diabetic cells. Secretoneurin shows positive effects on in vitro angiogenesis, proliferation and apoptosis of these cells in a basic fibroblast growth factor dependent manner. A small molecular weight inhibitor revealed fibroblast growth factor receptor 3 as the main receptor for secretoneurin mediated effects. Additionally, we could identify heparan-sulfates as important co-factor of secretoneurin induced binding of basic fibroblast growth factor to human dermal endothelial cells. We suggest topical secretoneurin plasmid therapy as new tool for delayed wound healing in patients suffering from diabetes. PMID- 23918208 TI - Learning and memory in children with Noonan syndrome. AB - Genetic syndromes resulting from molecular alterations of the RAS-MAPK signaling cascade have become the focus of heightened interest among behavioral scientists due to discoveries that proteins within this pathway play an important role in memory formation and consolidation. Individuals with Noonan syndrome (NS), caused by germline mutations in the RAS-MAPK pathway, exhibit wide variability in cognitive and memory skills. The current study aimed to characterize memory deficits that occur in some affected individuals as a key step toward understanding the neurocognitive effects of dysregulated Ras signaling. Learning and memory skills were assessed among 29 children and adolescents with NS using the Wide Range Assessment of Memory and Learning, Second Edition. Performance across subdomains (verbal memory, visual memory and working memory) was compared, as well as the effect of response type (free recall vs. recognition). For immediate memory, children with NS performed significantly better on verbal memory tasks than on visual memory or working memory tasks. For delayed memory, verbal free recall tasks that depend heavily on prefrontal-hippocampal networks were more challenging than recognition tasks that rely on more distributed temporal cortical regions. Additionally, verbal information presented in context was more easily retained than that presented in a rote format. The current study contributes to our knowledge of the effects of dysregulated RAS-MAPK signaling on the brain and behavior. Continued research on neurocognitive skills in NS has the potential to generate a novel conceptualization of how learning disabilities can arise from altered molecular processes within a specific biological pathway. PMID- 23918207 TI - Characterization of early neovascular response to acute lung ischemia using simultaneous (19)F/ (1)H MR molecular imaging. AB - Angiogenesis is an important constituent of many inflammatory pulmonary diseases, which has been unappreciated until recently. Early neovascular expansion in the lungs in preclinical models and patients is very difficult to assess noninvasively, particularly quantitatively. The present study demonstrated that (19)F/(1)H MR molecular imaging with alphavbeta3-targeted perfluorocarbon nanoparticles can be used to directly measure neovascularity in a rat left pulmonary artery ligation (LPAL) model, which was employed to create pulmonary ischemia and induce angiogenesis. In rats 3 days after LPAL, simultaneous (19)F/(1)H MR imaging at 3T revealed a marked (19)F signal in animals 2 h following alphavbeta3-targeted perfluorocarbon nanoparticles [(19)F signal (normalized to background) = 0.80 +/- 0.2] that was greater (p = 0.007) than the non-targeted (0.30 +/- 0.04) and the sham-operated (0.07 +/- 0.09) control groups. Almost no (19)F signal was found in control right lung with any treatment. Competitive blockade of the integrin-targeted particles greatly decreased the (19)F signal (p = 0.002) and was equivalent to the non-targeted control group. Fluorescent and light microscopy illustrated heavy decorating of vessel walls in and around large bronchi and large pulmonary vessels. Focal segmental regions of neovessel expansion were also noted in the lung periphery. Our results demonstrate that (19)F/(1)H MR molecular imaging with alphavbeta3 targeted perfluorocarbon nanoparticles provides a means to assess the extent of systemic neovascularization in the lung. PMID- 23918209 TI - Serum C-peptide levels as an independent predictor of diabetes mellitus mortality in non-diabetic individuals. PMID- 23918210 TI - High cystatin C levels predict severe retinopathy in type 2 diabetes patients. PMID- 23918211 TI - Does desloratadine alter the serum levels of montelukast when administered in a fixed-dose combination? AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to investigate the serum levels of montelukast when administered alone or in combination with desloratadine. STUDY DESIGN: A prospective crossover study. METHODS: Twenty-three healthy volunteers were investigated in two sessions. Volunteers were given 10 mg of montelukast orally with 250 mL water in the first session. The same subjects were given 10 mg of montelukast in fixed combination with 5 mg desloratadine 10 days after first session. Blood samples were collected 2, 3, and 4 hours after drug administration, and kept at -80 degrees C after both applications. Plasma samples were analyzed for montelukast concentration. RESULTS: Mean concentration values of both groups were not statistically different (P > .05), but the differences were statistically significant according to time (P < .05). Statistically significant difference was not found between the groups according to the area under curve on the basis of both marginal and cumulative values for all different time intervals (P > .05). CONCLUSIONS: The absorption rate of montelukast was not altered when administered with desloratadine. This study suggested that desloratadine does not influence the bioavailability of montelukast, and their combination therapy can be used safely. PMID- 23918212 TI - Fenofibrate increases serum vaspin by upregulating its expression in adipose tissue. AB - Fenofibrate is a peroxisome proliferator-activated receptor-alpha that has been clinically used to treat dyslipidemia and insulin resistance. To better understand the molecular mechanisms underlying fenofibrate action, we investigated whether fenofibrate affects serum levels of vaspin, an adipocytokine that has recently been shown to link obesity and insulin resistance. Fenofibrate treatment significantly increased serum vaspin levels of dyslipidemic patients, which correlated with reduced body weight and increased insulin sensitivity. To elucidate the biochemical mechanisms of fenofibrate action, we investigated the effect of fenofibrate on vaspin mRNA and protein expressions in obese rats. Fenofibrate greatly increased vaspin mRNA and protein levels in visceral adipose tissue consisting of retroperitoneal, mesenteric, and periepididymal adipose tissue but not in the subcutaneous adipose tissue, which correlated with increased serum vaspin levels and increased insulin sensitivity in obese rats. Consistent with a direct effect on vaspin expression, fenofibrate treatment significantly increased the mRNA and protein expression levels of vaspin in 3T3 L1 adipocytes. Together, our results demonstrate for the first time that fenofibrate upregulates vaspin expression in dyslipidemic human subjects and suggest that upregulation of vaspin expression in adipocytes may provide a mechanism by which fenofibrate improves insulin sensitivity in dyslipidemic patients. PMID- 23918213 TI - The role of temporal delay and repeated prospective memory cue exposure on the deactivation of completed intentions. AB - Previous studies have shown that completed prospective memory (PM) intentions entail aftereffects in terms of ongoing-task-performance decrements in trials containing repeated PM cues which previously served as PM cues triggering the intended action. Previous research reported that PM aftereffects decrease over time, thus revealing a specific time course of PM aftereffects. In the present study, we tested two accounts for this pattern, assuming either that the decline of aftereffects is related to the temporal distance to PM task completion or may be a result of the repeated exposure of repeated PM cues in the ongoing task. In three experiments, we manipulated both the temporal distance to PM task completion and the frequency of repeated PM cues and demonstrated that aftereffects of completed intentions declined with repeated exposure of formerly relevant PM cues. In addition, effects of repeated exposure were not only limited to the repetition of specific PM-cue exemplars but also generalized to other semantically related PM cues within the PM-cue category. Together, findings show that decreased aftereffects of completed intentions are not related to the temporal duration of the subsequent test block, but crucially depend on the repeated exposure of the previously relevant PM cues. PMID- 23918215 TI - Potential for autoimmune pathogenesis of Rift Valley Fever virus retinitis. AB - Rift Valley Fever (RVF) is a significant threat to human health because it can progress to retinitis, encephalitis, and hemorrhagic fever. The timing of onset of Rift Valley Fever virus (RVFV) retinitis suggests an autoimmune origin. To determine whether RVFV retinitis is associated with increased levels of IgG against retinal tissue, we measured and compared levels of IgG against healthy human eye tissue by immunohistochemical analysis. We found that serum samples from RVFV-exposed Kenyans with retinitis (n = 8) were slightly more likely to have antibodies against retinal tissue than control populations, but the correlation was not statistically significant. Further investigation into the possible immune pathogenesis of RVFV retinitis could lead to improved therapies to prevent or treat this severe complication. PMID- 23918214 TI - Communication between neuronal somata and satellite glial cells in sensory ganglia. AB - Studies of the structural organization and functions of the cell body of a neuron (soma) and its surrounding satellite glial cells (SGCs) in sensory ganglia have led to the realization that SGCs actively participate in the information processing of sensory signals from afferent terminals to the spinal cord. SGCs use a variety ways to communicate with each other and with their enwrapped soma. Changes in this communication under injurious conditions often lead to abnormal pain conditions. "What are the mechanisms underlying the neuronal soma and SGC communication in sensory ganglia?" and "how do tissue or nerve injuries affect the communication?" are the main questions addressed in this review. PMID- 23918216 TI - Phylogeography of Aedes aegypti (yellow fever mosquito) in South Florida: mtDNA evidence for human-aided dispersal. AB - The invasive dengue vector Aedes aegypti has persisted for > 200 years in South Florida in the United States. We tested the hypotheses that Florida's landscape creates dispersal barriers and corridors and that long-distance human-aided dispersal structures populations of Ae. aegypti. We evaluated the phylogeography of 362 individuals from Florida's East and West Coasts with a 760-bp (418- and 342-bp fragments of ND5 and ND4, respectively) mitochondrial sequence. Populations from these two coasts were not significantly differentiated, suggesting that limited urbanization in central Florida is not a strong barrier to gene flow. Evidence for long-distance dispersal between Ft. Lauderdale and the West and Ft. Myers and the East indicates the importance of human-aided dispersal. West Coast populations showed no genetic differentiation, indicating that West Coast rivers and bays did not significantly impede gene flow. Phylogeographic analysis of haplotypes showed two distinct matrilines with no geographic patterns, suggesting multiple introductions or balancing selection. PMID- 23918217 TI - Cross-sectional study to assess risk factors for leishmaniasis in an endemic region in Sri Lanka. AB - Sri Lanka reports significantly more cutaneous leishmaniasis (CL) cases than visceral leishmaniasis (VL) cases, both of which are caused by Leishmania donovani MON-37. A cross-sectional study conducted in an area with a high prevalence of CL prevalent included 954 participants of an estimated population of 61,674 to estimate the number of CL cases, ascertain whether there is a pool of asymptomatic VL cases, and identify risk factors for transmission. A total of 31 cases of CL were identified, of whom 21 were previously diagnosed and 10 were new cases. Using rK39 rapid diagnostic test to detect antibodies against Leishmania spp., we found that only one person was seropositive but did not have clinical symptoms of CL or VL, which indicated low transmission of VL in this area. chi(2) test, independent sample t-test, and multivariate analysis of sociodemographic and spatial distribution of environmental risk factors showed that living near paddy fields is associated with increased risk for transmission of CL (P <= 0.01). PMID- 23918219 TI - Outcome of a multimodality approach to the management of idiopathic subglottic stenosis. AB - OBJECTIVES/HYPOTHESIS: To assess the results of treating idiopathic subglottic stenosis (ISS), determine predictors of treatment success and outcome, and better define roles and limitations of endoscopic and open surgery. STUDY DESIGN: Prospective observational study. METHODS: Fifty-four consecutive patients were treated between 2004 and 2012. Patient, stenosis and treatment details, complications, open surgery rates, and outcomes were recorded. Regression analyses were used to identify predictors of endoscopic treatment success; treatment frequency; and functional outcomes in airway, dyspnea, voice, and swallowing domains. RESULTS: All patients were female and mean age at diagnosis was 48 +/- 12 years. Symptoms-to-diagnosis latency was 21 +/- 20 months. There were 10 concomitant glottic and subglottic stenoses. Most lesions were Myer Cotton grade 3 (48%). Overall, 78% of patients were managed endoscopically. Treatment included intralesional corticosteroids, laser surgery, balloon dilation, and temporary silastic stenting in selected cases. Annual intervention rate was 1.07 +/- 0.79. Mean follow-up was 45 months. Factors associated with intervention frequency were stenosis location and severity. Twelve patients underwent anteroposterior laryngotracheal reconstruction with biological inhibition. This resulted in disease remission in all patients with subglottic stenosis, and in most patients with concomitant glottic and subglottic stenosis. Patients with total laryngotracheal stenosis required ongoing treatment for glottic disease. All patients maintained prosthesis-free airways, but in one patient this required a laryngectomy. Most patients achieved good functional outcomes. Stenosis location was the only independent predictor of dyspnea and voice outcomes. CONCLUSIONS: ISS can be effectively treated with endoscopic surgery or a bespoke open reconstructive procedure that does not compromise on female voice quality. LEVEL OF EVIDENCE: 4. PMID- 23918218 TI - Imaging features of sporadic breast cancer in women under 40 years old: 97 cases. AB - OBJECTIVES: To evaluate characteristic features of mammography, ultrasound and magnetic resonance imaging (MRI) of sporadic breast cancer in women <40 years and to determine correlations with pathological and biological factors. METHODS: A retrospective review of radiological, clinicopathological and biological features of sporadic breast cancers for women under 40 years at our institution between 2007-2012 covering 91 patients. Mammography was available for 97 lesions, ultrasound for 94 and MRI for 38. RESULTS: The most common imaging features were masses, nearly all classified BI-RADS 4 or 5. On mammography microcalcifications alone accounted for 31 %, all suspicious. There were 42.6 % luminal B, 24.5 % luminal A, 19.1 % HER2-enriched and 10.6 % triple-negative (TN) tumours by immunohistochemistry. HER2 overexpression was correlated with the presence of calcifications at mammography (P = 0.03). TN cancers more often had an oval shape and abrupt interface at ultrasound and rim enhancement on MRI. MRI features were suspicious for all cancers and rim enhancement of a mass was a significant predictor of triple-negative tumours (P = 0.01). CONCLUSIONS: The imaging characteristics of cancers in patients under 40 years without proven gene mutations do not differ from their older counterparts, but appear correlated to phenotypic profiles, which have a different distribution in young women compared to the general population. PMID- 23918221 TI - DFT studies of conversion of methyl chloride and three substituted chloromethyl tetrahydrofuran derivatives during reaction with trimethylamine. AB - B3LYP/6-31+G level computations were performed for the formation of four trimethylammonium salts in the reaction of methyl chloride (1a), (S)-1,4-andydro 5-chloro-2,3,5-trideoxypentitol (2a), (2S,5S)-2,5-andydro-6-chloro-1,3,4,6 tetradeoxyhexitol (3a) and methyl 5-chloro-2,3,5-trideoxy-beta-D-pentofuranoside (4a) with trimethylamine. All the structures were fully optimized in the gas phase, in chloroform and water. In addition, B3LYP/6-311++G and MPW1K/6-31+G level calculations were carried out to estimate activation barrier heights in the gas phase. A detailed description of all stationary points is presented, and the conformational behavior of the THF ring is discussed. B3LYP and MPW1K activation barriers indicate the reaction between methyl chloride and trimethylamine to be the fastest, whereas reaction 4 is the slowest one, both in the gas phase and in solvents. THF ring conformation changes were observed for reactions 2 and 3 along the reaction pathway, whereas it was almost unchanged for reaction 4, in the gas phase. In the case of reactions 2 and 3, different shapes of the THF ring were found for the transition state geometry in the gas phase and in water. The (5) E >E 4 and (3) E->E 5 conformational changes were observed for reactions 2 and 3, respectively. PMID- 23918220 TI - Towards a more desirable dry powder inhaler formulation: large spray-dried mannitol microspheres outperform small microspheres. AB - PURPOSE: To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aerolizer((r))) in the case of a model drug (i.e. albuterol sulphate) formulated with spray dried mannitol carrier particles with homogeneous shape and solid-state form but different sizes. METHODS: Spray dried mannitol (SDM) particles were characterized in terms of size, surface area, morphology, water content, solid-state, density and electrostatic charge by a novel approach. DPI formulations composed of SDM and albuterol sulphate (AS) were prepared and evaluated in terms of drug content homogeneity and in vitro aerosolization performance. RESULTS: All SDM particles generated similar fine particle fractions of AS. Formulations consisting of larger SDM particles demonstrated better drug content homogeneity, reduced amounts of drug loss and reduced oropharyngeal deposition. Comparing different SDM products demonstrated that SDM powders with relatively poorer flowability, wider size distributions and higher charge density generated DPI formulations with poorer drug content homogeneity and deposited higher amount of drug on the inhaler, mouthpiece adaptor and throat. DPI formulation total desirability increased linearly with the mean diameter of SDM. CONCLUSION: Particle shape and solid-state form of mannitol could dominate over carrier size, bulk density, flowability and charge in terms of determining the aerosolization behaviour of AS formulated with mannitol carrier, at least within the experimental protocols applied in the present study. PMID- 23918222 TI - Theoretical study on the adsorption of phenol on activated carbon using density functional theory. AB - Density functional theory (DFT) calculations performed at the PBE/DZP level using the DFT-D2 method were utilized to investigate the adsorption of phenol on pristine activated carbon (AC) and on activated carbon functionalized with OH, CHO, or COOH groups. Over the pristine AC, the phenol molecule undergoes weak physical adsorption due to van der Waals interactions between the aromatic part of the phenol and the basal planes of the AC. Among the three functional groups used to functionalize the AC, the carboxylic group was found to interact most strongly with the hydroxyl group of phenol. These results suggest that functionalized AC-COOH has great potential for use in environmental applications as an adsorbent of phenol molecules in aqueous phases. PMID- 23918223 TI - Effects of trimethylaluminium and tetrakis(ethylmethylamino) hafnium in the early stages of the atomic-layer-deposition of aluminum oxide and hafnium oxide on hydroxylated GaN nanoclusters. AB - We calculate the interactions of two atomic layer deposition (ALD) reactants, trimethylaluminium (TMA) and tetrakis(ethylmethylamino) hafnium (TEMAH) with the hydroxylated Ga-face of GaN clusters when aluminum oxide and hafnium oxide, respectively, are being deposited. The GaN clusters are suitable as testbeds for the actual Ga-face on practical GaN nanocrystals of importance not only in electronics but for several other applications in nanotechnology. We find that TMA spontaneously interacts with hydroxylated GaN; however it does not follow the atomic layer deposition reaction path unless there is an excess in potential energy introduced in the clusters at the beginning of the optimization, for instance, using larger bond lengths of various bonds in the initial structures. TEMAH also does not interact with hydroxylated GaN, unless there is an excess in potential energy. The formation of a Ga-N(CH3)(CH2CH3) bond during the ALD of HfO2 using TEMAH as the reactant without breaking the Hf-N bond could be the key part of the mechanism behind the formation of an interface layer at the HfO2/GaN interface. PMID- 23918224 TI - A comparison of diamino- and diamidocarbenes toward dimerization. AB - In this study, we compare the dimerization of N,N'-diamidocarbene with that of N heterocyclic carbene (NHC). Less interaction occurred between the filled lone pair of nitrogen and the unfilled lone pair of the carbenic center for a N,N' diamdiocarbene than did in a saturated NHC because of the resonance between the lone pair of nitrogen and a carbonyl group. Therefore, a N,N'-diamidocarbene exhibits less singlet-triplet splitting. The less singlet-triplet splitting in a heterocyclic carbene containing nitrogen, the more exothermic the dimerization, which is consistent with the conclusion of Thiel et al. (Chem Phys Lett 217:11 16, 1994). PMID- 23918225 TI - Oral presentations and posters of the XL Annual ESAO Congress - 11-14 September 2013, Glasgow, Scotland (UK). PMID- 23918226 TI - A radical opposition in body weight control. PMID- 23918227 TI - Testis specific gene expression drives disease progression and Rituximab resistance in lymphoma. PMID- 23918230 TI - An experimental investigation of the effect of a justice violation on pain experience and expression among individuals with high and low just world beliefs. AB - BACKGROUND: Perceptions of injustice are linked with poorer physical and psychological outcomes in the context of pain and injury. Violations of injustice can arise out of violations of just world belief (JWB). However, no study has yet examined whether JWB moderates the effect of justice violation on pain experience. METHODS: The current study examined the effect of an experimental justice violation on acute pain outcomes and whether JWB moderated this effect. Participants completed the JWB scale and then engaged in two cold pressor tasks (CPT). Half the participants were told that the second CPT immersion was part of standard protocol; the other half were told that the painful procedure had to be repeated due to experimenter negligence. Participants provided report of pain intensity following each CPT immersion. Video records of participants undergoing the CPT were coded for presence and duration of pain behaviour. RESULTS: Exposure to the justice violation resulted in elevated pain intensity from the first to the second immersion only among participants with high JWB. For participants with low JWB and participants in the control condition, there was no significant difference in pain intensity across immersions. Control participants showed a decrease in pain behaviour from the first to the second immersion. In the negligence/ justice violation condition, reductions in pain behaviour were observed only among participants with low JWB. CONCLUSIONS: Our results indicate that individuals with high JWB may show particularly adverse reactions in response to justice violations in the context of acute pain experience. PMID- 23918228 TI - IgA EGFR antibodies mediate tumour killing in vivo. AB - Currently all approved anti-cancer therapeutic monoclonal antibodies (mAbs) are of the IgG isotype, which rely on Fcgamma receptors (FcgammaRs) to recruit cellular effector functions. In vitro studies showed that targeting of FcalphaRI (CD89) by bispecific antibodies (bsAbs) or recombinant IgA resulted in more effective elimination of tumour cells by myeloid effector cells than targeting of FcgammaR. Here we studied the in vivo anti-tumour activity of IgA EGFR antibodies generated using the variable sequences of the chimeric EGFR antibody cetuximab. Using FcalphaRI transgenic mice, we demonstrated significant in vivo anti-tumour activity of IgA2 EGFR against A431 cells in peritoneal and lung xenograft models, as well as against B16F10-EGFR cells in a lung metastasis model in immunocompetent mice. IgA2 EGFR was more effective than cetuximab in a short-term syngeneic peritoneal model using EGFR-transfected Ba/F3 target cells. The in vivo cytotoxic activity of IgA2 EGFR was mediated by macrophages and was significantly decreased in the absence of FcalphaRI. These results support the potential of targeting FcalphaRI for effective antibody therapy of cancer. PMID- 23918231 TI - Study on the in vitro effects of the mixtures of polycyclic aromatic hydrocarbons (PAHs) and heavy metals on ethoxyresorufin-O-deethylase (EROD) activity in Mossambica tilapia liver. AB - This paper reports in vitro effects of individual heavy metals (Cd(2+), Cu(2+) and Hg(2+)), and PAHs, including benzo[a]pyrene(BaP), indeno[1,2,3-cd]pyrene (IP) and fluoranthene (FL), and their mixtures on ethoxyresorufin-O-deethylase (EROD) activities using a plate-reader method. The results showed that all three metals inhibited EROD activity, while BaP/IP significantly induced the enzyme. However, FL alone decreased EROD activity. Moreover, co-treatment with BaP/IP and heavy metals inhibited PAH-induced EROD activities, while combined exposure to FL and heavy metals induced FL-inhibited EROD activities. PMID- 23918232 TI - Divergent immunomodulatory effects of extracts and phenolic compounds from the fern Osmunda japonica Thunb. AB - OBJECTIVE: To study possible immunobiological potential of Osmunda japonica Thunb. METHODS: Immunomodulatory effects of ethanol extracts prepared from rhizomes of O. japonica and phenolic compounds isolated from the extracts were investigated under the in vitro conditions using the rat peritoneal cells (2*10(6)/mL; 24 h culture). Biosynthesis of nitric oxide (NO) was assayed by Griess reagent, production of prostaglandin E2 (PGE2) and secretion of cytokines were determined by enzyme-linked immunoabsorbent assay. RESULTS: The extracts activated dose dependently, with the onset at 2.5-5 MUmol/L concentrations, the high output NO production, and secretion of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). Mild enhancement of NO was produced by the aldehyde-type phenolics 4 hydroxybenzaldehyde and 3,4-hydroxybenzaldehyde. In contrasts, the acetone-type phenolics 4-hydroxybenzalacetone and 3,4-hydroxybenzalacetone inhibited production of immune mediators including cytokines (TNF-alpha, IL-1beta, IL-6), NO, and PGE2. The 3,4-hydroxybenzalacetone was more effective than 4 hydroxybenzaldehyde. The IC50s estimates ranged within the interval of 5-10 MUmol/L. No signs of cytotoxicity were observed up to the 50 MUmol/L concentration of the compounds. CONCLUSION: Phenolic compounds contained in medicinal herb Osmunda japonica possess distinct immunomodulatory activity. PMID- 23918233 TI - Biomedical mechanisms of blood stasis syndrome of coronary heart disease by systems biology approaches. AB - The prevalence of coronary heart disease (CHD) is increasing, and has been a severe burden on society and family worldwide. New ideas need to be achieved for developing more efficacious and safe therapies to treat CHD. Chinese medicine (CM) uses multicomponent drugs to prevent disease and ameliorate symptoms based on patients' different syndromes. The benefit of CM in CHD has recently been proven by increasing clinical evidence. More importantly, linking CM syndrome differentiation and biomedical diagnosis might provide innovative thinking for treating CHD. According to epidemiological investigations, blood stasis syndrome (BSS) is the major type of syndrome in CHD. Investigating the biomedical mechanisms of BSS of CHD is a topic of CM research. Because the holistic perspective of systems biology is well matched with CM, the application of omics techniques and other integrative approaches appears inherently appropriate. A wide range of omics techniques, including transcriptomics and proteomics, have been used in studies of BSS of CHD to search for a common ground of understanding. These approaches could be useful for understanding BSS of CHD from clinical and biological viewpoints. Nevertheless, current studies mainly contain results from a single approach, and they have not achieved the holistic, systematic and integrative concept of system biology. Therefore, we discuss the progress and challenges in exploring the biomedical mechanisms of BSS of CHD by systems biology approaches. With further development of systems biology, a better platform to study BSS of CHD may be provided, and biomarkers for BSS of CHD and therapeutic targets may be found. The study of BSS of CHD by systems biology approaches will also be beneficial for developing personalized treatment for BSS of CHD patients. PMID- 23918234 TI - A systematic review and meta-analysis of type 2 diabetes mellitus treatment based on the "three-typed syndrome differentiation" theory in Chinese medicine. AB - OBJECTIVE: To evaluate the efficacy and safety of "Three-Typed Syndrome Differentiation" (TTSD) in treating type 2 diabetes mellitus patients. METHODS: A systematic review and meta-analysis was done based on the clinical diabetes treatment literature of the "TTSD". Overseas databases like the PubMed/MEDLINE, EMBASE, Cochrane Library and Cochrane Central Register of Controlled Clinical Trials, and China databases like China Biology Medicine Disc (CBM), Chinese national Knowledge Infrastructure (CNKI), Wanfang database, and VIP database, without limitation on language, were included with the time limitation from Jan 1982 to Dec 2012 by retrieval of relative original clinical research articles. RESULTS: Nineteen articles where contains 1,840 diabetes patients were obtained, in which no adverse reactions were reported. Of these, 14 literatures involved the effect of fasting blood glucose (FBG), 10 involved that of postprandial 2-h blood glucose (P2hBG), and 19 involved the overall efficacy based on the national Chinese medicine (CM) diagnosis and treatment standard of diabetes. All the meta analysis results prefer to the "TTSD" groups (CM+Western medicine Based on TTSD). The results show that, beside the efficacy of Western medicine, the concentrations of FBG and P2hBG in "TTSD" groups continue to drop with statistical significance. For "TTSD" groups, the FBG subsequently dropped 1.03 mmol/L, 95%CI [1.24,0.82] P <0.00001), the P2hBG subsequently dropped 1.09 mmol/L, 95% CI [1.61, 0.57] (P <0.0001), and the overall efficacies benefit 3.46 times those of Western medicine alone, 95% CI [2.67,4.48] (P <0.00001). CONCLUSIONS: The CM by the diagnosis and treatment of type 2 diabetes based on TTSD might be safe and effective, and could better improve both blood glucose and the overall status of patients, including symptoms. PMID- 23918235 TI - Yiqixue buganshen recipe regulates the expression of integrin alphanubeta3 in the endometrium of controlled ovarian hyperstimulation mice. AB - OBJECTIVE: To observe the effect of Yiqixue Buganshen recipe(, YBR) on the expression of integrin alphanubeta3 in the endometrium of controlled ovarian hyperstimulation mice. METHODS: A total of 180 mice were divided into three groups: model group, treatment group and control group. The treatment and model groups were intraperitoneally injected with gonadotropin-releasing hormone analogue for 7 days; pregnant mare serum gonadotropin was also injected on the 7th day. After 48 h, human chorionic gonadotropin was injected. The control group was injected with an equal volume of saline at the same time. From the start of the experiment, the treatment group was intragastrically administered Jinghouzengzhi Recipe() and Cuhuangti Recipe(). The model group and the control group were intragastrically administered an equal volume of saline. Real-time reverse transcription polymerase chain reaction and Western blotting were used to detect the mRNA and protein expression of integrin alphanubeta3 in mouse endometrium. RESULTS: Integrin alphanubeta3 was expressed in mouse endometrium in all groups. Integrin alphabetabeta3 expression increased gradually along with pregnancy, progressing from pregnant day (Pd) 1. Integrin alphanubeta3 expression significantly increased on Pd 4, then began to decrease on Pd 6. Integrin alphanubeta3 expression in the treatment group was higher than in the model group, and the difference was statistically significant (P <0.05). The difference between the treatment group and the control group was not statistically significant (P >0.05). CONCLUSION: YBR improves endometrial receptivity, and may play an important role in embryonic implantation. PMID- 23918236 TI - Self-reported causes for referral to dental treatment under general anaesthesia (DGA): a cross-sectional survey. AB - AIM: To determine causes leading to dental care under general anaesthesia (DGA) in public health care reported by the patients or the parents/caregivers. STUDY DESIGN: All the patients referred to DGA at the Municipal Health Centre, Oulu, Finland, during 10 months were invited to participate in the present cross sectional survey. They were sent a questionnaire on indications for referral to DGA, dental fear, possible reasons for it as well as prior treatment of dental fear. For measuring overall dental fear, the modified Corah dental anxiety scale (MCDAS) and visual analogue scale (VAS) forms were also included in the questionnaire. RESULTS: The most common self-reported indication for referral to DGA was dental fear (63.9%). For children and adolescents (<18 years), need for extensive care was the second most common reported cause. The great majority of the respondents reported having dental fear (90.8%). Dental fear was more common among females than males, but the difference between the genders was not statistically significant. The most common cause for dental fear was earlier negative experiences in dental care (51.9%). The mean MCDAS score was 19.0 (SD 5.7; 5-25) indicating severe dental anxiety. An increasing trend towards older age groups could be seen in VAS scores reporting fear of pain, needles, scaling, scolding by the dentist, extractions, as well as endodontic treatment. Dental fear had been taken into consideration in dental treatment preceding DGA. CONCLUSION: Dental fear is the most common self-reported indication for referral to DGA and should be taken into consideration. PMID- 23918237 TI - Mandibular block success rate in relation to needle insertion and position: a self-report survey. AB - AIM: To evaluate possible associations between successful mandibular block injection and location of penetrating the oral mucosa, location of injection on the ramus and the needle insertion length. STUDY DESIGN: The study consisted of 101 dentists, of whom, 33 were oral surgeons, 33 certified paediatric dentists and 35 general dental practitioners. The dentists were asked to estimate their rate of success in mandibular block injections, defined as the proportion of their patients for whom only a single carpule was necessary, and to indicate the needle insertion length and the location of the injection on a photograph of a ramus and on a photograph of the oral mucosa. RESULTS: Injecting a single carpule for achieving full anaesthesia in 90% or more of their patients was reported by 79.3 and 57.8% of the dentists treating children and adults, respectively. Of practitioners treating children, experienced dentists (>5 years in occupation) reported higher success rates than did inexperienced ones (p = 0.05). A positive correlation was found between failure rate reported in children, shorter length of the inserted needle (R = 0.356, p = 0.001) and injecting at the central (superior inferior dimension) most anterior quarters of the ramus (p = 0.006; odd ratio = 3.9375). Routine waiting period of more than 5 min after the injection and before operative treatment was associated with higher rates of failure (p = 0.042, chi(2) = 6.335). No correlation was found between the success rates of mandibular block injection and the location of penetrating the oral mucosa in children (p = 0.94), adults (p = 0.57), or between success rates and the target location on the ramus in adults (p = 0.42). STATISTICS: chi(2) test was used to determine the significance of differences among proportions and t test for continuous variables. Pearson's correlation analysis was used to analyse the correlation between the length of the needle inserted in children and adults by the same dentist. CONCLUSIONS: Shorter needle insertion lengths and targeting the injecting to the most anterior quarters of the ramus were positively correlated with failure of anaesthesia in children, according to dentists' reports. A routine waiting period of over 5 min did not increase the success rates of mandibular block injection. PMID- 23918238 TI - Effects of Fuel Temperature on Injection Process and Combustion of Dimethyl Ether Engine. AB - To investigate the effects of fuel temperature on the injection process in the fuel-injection pipe and the combustion characteristics of compression ignition (CI) engine, tests on a four stroke, direct injection dimethyl ether (DME) engine were conducted. Experimental results show that as the fuel temperature increases from 20 to 40 degrees C, the sound speed is decreased by 12.2%, the peak line pressure at pump and nozzle sides are decreased by 7.2% and 5.6%, respectively. Meanwhile, the injection timing is retarded by 2.2 degrees CA and the injection duration is extended by 0.8 degrees CA. Accordingly, the ignition delay and the combustion duration are extended by 0.7 degrees CA and 4.0 degrees CA, respectively. The cylinder peak pressure is decreased by 5.4%. As a result, the effective thermal efficiency is decreased, especially for temperature above 40 degrees C. Before beginning an experiment, the fuel properties of DME, including the density, the bulk modulus, and the sound speed were calculated by "ThermoData." The calculated result of sound speed is consistent with the experimental results. PMID- 23918239 TI - Risk of arrhythmias associated with ipratropium bromide in children, adolescents, and young adults with asthma: a nested case-control study. AB - STUDY OBJECTIVE: To evaluate the risk of arrhythmias associated with inhaled anticholinergic (IAC) use in young patients with asthma. DESIGN: Population-based nested case-control study. DATABASE: IMS LifeLink Health Plan Claims Database. PATIENTS: Patients 5-24 years of age who were diagnosed with asthma and were new users of asthma controller medications were identified between July 1997 and April 2010. Cases were newly diagnosed with arrhythmia and were matched with up to 10 controls based on age, gender, geographic region, and quarter and year of first controller medication dispensing. MEASUREMENTS AND MAIN RESULTS: Exposure to IACs was determined in the 180 days prior to the event date, defined as date of arrhythmia claim. Active use was defined as sufficient days' supply of a prescription to extend through the event date. Among 283,429 patients with asthma, 7656 cases were matched to 76,304 controls. Most of those included were female (58.8%) and 12 years or older (73.3%). Active exposure of IACs was observed in 0.69% of cases and 0.18% of controls. Active use was associated with a 1.56-fold increase in arrhythmia risk compared with nonactive users or nonusers (adjusted odds ratio [ORadj ] 1.56, 95% confidence interval [CI] 1.08-2.25]). Risk was highest among active users of ipratropium (ORadj 1.59, 95% CI 1.08 2.33). Active high-dose users of IACs (more than 0.114 mg of ipratropium equivalents) had a 69% increase in risk (ORadj 1.69, 95% CI 1.10-2.59), whereas the added risk for active users receiving low-dose IACs (0.114 mg of ipratropium equivalents or less) was not statistically significant (ORadj 1.22, 95% CI 0.53 2.65). CONCLUSION: Use of ipratropium bromide was associated with an increased risk of arrhythmias in 12-24-year-old patients with asthma. PMID- 23918240 TI - Deletion of 14.7 Mb 2q32.3q33.3 with a marfanoid phenotype and hypothyroidism. AB - Interstitial 2q deletions are very rare chromosome abnormalities. The 2q32q33 deletion was proposed as a distinct entity with characteristic phenotype. Most patients have feeding problems, growth restriction, moderate to severe developmental delay, speech delay or lack of speech, high, prominent forehead, thin sparse hair, teeth abnormalities and a high or cleft palate. We report on another rare case of interstitial 2q33 deletion found during routine karyotyping and further characterized by the use of a genomic SNP array. The patient presented here has a "Marfanoid" phenotype, hypothyroidism, and a marked tactile hypersensitivity. We concluded that hypothyroidism might be caused by the deletion of the CD28 and/or CTLA4 genes; also cardiological monitoring of patients with the deletion including BMPR2 may be considered in order to prevent the possible medical complications associated with pulmonary hypertension. PMID- 23918241 TI - Upregulation of microRNA-203 is associated with advanced tumor progression and poor prognosis in epithelial ovarian cancer. AB - MicroRNA-203 (miR-203), possessing tumor suppressive or promotive activities, has been found to be downregulated or upregulated in different cancer types. The purpose of this study was to investigate whether the increased expression of miR 203 can be used as a noninvasive diagnostic and prognostic biomarker in epithelial ovarian cancer (EOC). Real-time quantitative PCR was performed to detect the expression levels of miR-203 in EOC tissues. The expression levels of miR-203 were significantly higher in EOC tissues compared to adjacent non cancerous tissues (p < 0.001). High expression of miR-203 was observed in 65.38 % (102/156) of EOC. In addition, high miR-203 expression was found to be closely correlated with advanced FIGO stage (p < 0.001), higher histological grade (p = 0.02), lymph node involvement (p < 0.001), and positive recurrence (p < 0.001). Moreover, high miR-203 expression was correlated with shorter overall survival (p < 0.001) and shorter progression-free survival (p < 0.001) of EOC patients. Furthermore, multivariate analysis showed that the status of miR-203 expression was an independent predictor for both overall survival and progression-free survival in EOC. These findings provide the convincing evidence for the first time that the upregulation of miR-203 may serve as a novel molecular marker to predict the aggressive tumor progression and unfavorable prognosis of EOC patients. PMID- 23918242 TI - p14(ARF) methylation is a common event in the pathogenesis and progression of myxoid and pleomorphic liposarcoma. AB - Liposarcoma represents the most frequent group of soft tissue sarcomas. The group can be divided into three different classes: (1) differentiated/undifferentiated (WDLPS/DDLPS), (2) myxoid/round cell (MLPS/RCLPS) and (3) pleomorphic liposarcoma (PLS). It has become apparent that p53-p14 and Rb-p16 pathways play important roles in the pathogenesis of various sarcoma types. Molecular studies of the genes involved in these two pathways showed wide variations between the liposarcoma subtypes or even within the same subtype. We sought to examine mutational status of p53 and methylation status of p16 (INK4a) /p14 (ARF) genes in primary and recurrent liposarcoma tumors. There were twelve myxoid (12/18, 66.7 %) and six pleomorphic liposarcoma (6/18, 33.3 %) samples. Immunohistochemical analysis revealed that p53 protein was overexpressed in 3/12 MLPS (25 %) and 6/6 PLS (100 %). Mutational analysis showed that 2/11 MLPS (18.2 %) and 2/6 PLS (33.3 %) contained mutated p53 gene. On the other hand, 3/18 samples (16.7 %) had methylated p16 promoter. However, the frequencies of the p14 (ARF) gene methylation were 83.3 % (10/12) and 50 % (3/6) in myxoid and pleomorphic group, respectively. Overall, 15 out of 18 (83.3 %) samples had either p53 gene mutation or methylated p14 (ARF) promoter. The results from the current study suggest significant impact of the p14 (ARF) gene methylation on the pathogenesis and progression of myxoid and to a lesser extent pleomorphic liposarcoma. Despite the limited number of samples, our study points to necessity of further investigation of p53-p14 and Rb-p16 pathways in liposarcoma. PMID- 23918243 TI - Smoking behaviors in a community-based cohort of HIV-infected indigent adults. AB - We conducted a longitudinal study of a community-based cohort of HIV-infected indigent adults to examine smoking behaviors and factors associated with quitting. We assessed "hardcore" smoking behaviors associated with a low probability of quitting. Of the 296 participants, 218 were current smokers (73.6 %). The prevalence of "hardcore" smoking was high: 59.6 % smoked >=15 cigarettes per day, and 67.3 % were daily smokers. During the study interval, 20.6 % made at least one quit attempt. Of these, 53.3 % were abstinent at 6 months. The successful quit rate over 2 years was 4.6 %. Illegal substance use (adjusted odds ratio, AOR 0.2, 95 % CI 0.1-0.6) and smoking within 30 min of waking (AOR 0.2, 95 % CI 0.1-0.7) were associated with lower likelihood of making a quit attempt. Interventions that reduce nicotine dependence prior to smoking cessation and those that are integrated with substance use treatment may be effective for this population. PMID- 23918244 TI - Methadone maintenance therapy decreases the rate of antiretroviral therapy discontinuation among HIV-positive illicit drug users. AB - We sought to examine whether methadone maintenance therapy (MMT) decreased rates of antiretroviral therapy (ART) discontinuation and was associated with plasma HIV RNA responses among a cohort of illicit drug users. Cumulative ART discontinuation rates were estimated using Kaplan-Meier methods and factors independently associated with ART discontinuation were identified using Cox proportional hazards regression. Engagement in MMT was negatively and independently associated with ART discontinuation [Adjusted Relative Hazard = 0.67 (95 % CI 0.54-0.83); p < 0.001]. Among participants receiving ART and MMT, 81.6 % of plasma HIV-1 RNA assessments were <500 copies/mL, while 65.81 % of HIV 1 RNA assessments among those prescribed ART without MMT were <500 copies/mL (p < 0.001). These results demonstrate that engagement in MMT conferred a protective benefit against ART discontinuation and was associated with a significant increase in plasma HIV RNA suppression among HIV-infected opioid-dependent drug users. PMID- 23918246 TI - MeltDB 2.0-advances of the metabolomics software system. AB - MOTIVATION: The research area metabolomics achieved tremendous popularity and development in the last couple of years. Owing to its unique interdisciplinarity, it requires to combine knowledge from various scientific disciplines. Advances in the high-throughput technology and the consequently growing quality and quantity of data put new demands on applied analytical and computational methods. Exploration of finally generated and analyzed datasets furthermore relies on powerful tools for data mining and visualization. RESULTS: To cover and keep up with these requirements, we have created MeltDB 2.0, a next-generation web application addressing storage, sharing, standardization, integration and analysis of metabolomics experiments. New features improve both efficiency and effectivity of the entire processing pipeline of chromatographic raw data from pre-processing to the derivation of new biological knowledge. First, the generation of high-quality metabolic datasets has been vastly simplified. Second, the new statistics tool box allows to investigate these datasets according to a wide spectrum of scientific and explorative questions. AVAILABILITY: The system is publicly available at https://meltdb.cebitec.uni-bielefeld.de. A login is required but freely available. PMID- 23918245 TI - Guidelines on processing and reporting of prostate biopsies: the 2013 update of the pathology committee of the European Randomized Study of Screening for Prostate Cancer (ERSPC). AB - The histopathological examination of a prostate biopsy is the basis of prostate cancer diagnostics. Prostate cancer grade and extent of cancer in the diagnostic biopsy are important determinants of patient management. Quality of the prostate biopsy and its processing may influence the outcome of the histopathological evaluation. Further, an unambiguous and concise pathology reporting is essential for an appropriate clinical decision process. Since our initial report in 2003, there have been several practice changes, including the increased uptake of follow-up biopsies of patients who are under active surveillance, increasingly taken under guidance of MRI, or who underwent a prostate-sparing therapy. Therefore, we investigated the literature on the current pathology practices and recommendations with regard to prostate biopsy processing and reporting, both at initial diagnosis and in the context of follow-up biopsies in order to update our guidelines on the optimal processing and reporting of prostate biopsies. PMID- 23918247 TI - CellMissy: a tool for management, storage and analysis of cell migration data produced in wound healing-like assays. AB - SUMMARY: Automated image processing has allowed cell migration research to evolve to a high-throughput research field. As a consequence, there is now an unmet need for data management in this domain. The absence of a generic management system for the quantitative data generated in cell migration assays results in each dataset being treated in isolation, making data comparison across experiments difficult. Moreover, by integrating quality control and analysis capabilities into such a data management system, the common practice of having to manually transfer data across different downstream analysis tools will be markedly sped up and made more robust. In addition, access to a data management solution creates gateways for data standardization, meta-analysis and structured public data dissemination. We here present CellMissy, a cross-platform data management system for cell migration data with a focus on wound healing data. CellMissy simplifies and automates data management, storage and analysis from the initial experimental set-up to data exploration. AVAILABILITY AND IMPLEMENTATION: CellMissy is a cross platform open-source software developed in Java. Source code and cross-platform binaries are freely available under the Apache2 open source license at http://cellmissy.googlecode.com. PMID- 23918248 TI - Pclust: protein network visualization highlighting experimental data. AB - SUMMARY: One approach to infer functions of new proteins from their homologs utilizes visualization of an all-against-all pairwise similarity network (A2ApsN) that exploits the speed of BLAST and avoids the complexity of multiple sequence alignment. However, identifying functions of the protein clusters in A2ApsN is never trivial, due to a lack of linking characterized proteins to their relevant information in current software packages. Given the database errors introduced by automatic annotation transfer, functional deduction should be made from proteins with experimental studies, i.e. 'reference proteins'. Here, we present a web server, termed Pclust, which provides a user-friendly interface to visualize the A2ApsN, placing emphasis on such 'reference proteins' and providing access to their full information in source databases, e.g. articles in PubMed. The identification of 'reference proteins' and the ease of cross-database linkage will facilitate understanding the functions of protein clusters in the network, thus promoting interpretation of proteins of interest. AVAILABILITY: The Pclust server is freely available at http://prodata.swmed.edu/pclust PMID- 23918249 TI - The BioPAX Validator. AB - SUMMARY: BioPAX is a community-developed standard language for biological pathway data. A key functionality required for efficient BioPAX data exchange is validation-detecting errors and inconsistencies in BioPAX documents. The BioPAX Validator is a command-line tool, Java library and online web service for BioPAX that performs >100 classes of consistency checks. AVAILABILITY AND IMPLEMENTATION: The validator recognizes common syntactic errors and semantic inconsistencies and reports them in a customizable human readable format. It can also automatically fix some errors and normalize BioPAX data. Since its release, the validator has become a critical tool for the pathway informatics community, detecting thousands of errors and helping substantially increase the conformity and uniformity of BioPAX-formatted data. The BioPAX Validator is open source and released under LGPL v3 license. All sources, binaries and documentation can be found at sf.net/p/biopax, and the latest stable version of the web application is available at biopax.org/validator. PMID- 23918250 TI - Scaffold network generator: a tool for mining molecular structures. AB - SUMMARY: Scaffold network generator (SNG) is an open-source command-line utility that computes the hierarchical network of scaffolds that define a large set of input molecules. Scaffold networks are useful for visualizing, analysing and understanding the chemical data that is increasingly available through large public repositories like PubChem. For example, some groups have used scaffold networks to identify missed-actives in high-throughput screens of small molecules with bioassays. Substantially improving on existing software, SNG is robust enough to work on millions of molecules at a time with a simple command-line interface. AVAILABILITY AND IMPLEMENTATION: SNG is accessible at http://swami.wustl.edu/sng PMID- 23918251 TI - Distilled single-cell genome sequencing and de novo assembly for sparse microbial communities. AB - MOTIVATION: Identification of every single genome present in a microbial sample is an important and challenging task with crucial applications. It is challenging because there are typically millions of cells in a microbial sample, the vast majority of which elude cultivation. The most accurate method to date is exhaustive single-cell sequencing using multiple displacement amplification, which is simply intractable for a large number of cells. However, there is hope for breaking this barrier, as the number of different cell types with distinct genome sequences is usually much smaller than the number of cells. RESULTS: Here, we present a novel divide and conquer method to sequence and de novo assemble all distinct genomes present in a microbial sample with a sequencing cost and computational complexity proportional to the number of genome types, rather than the number of cells. The method is implemented in a tool called Squeezambler. We evaluated Squeezambler on simulated data. The proposed divide and conquer method successfully reduces the cost of sequencing in comparison with the naive exhaustive approach. AVAILABILITY: Squeezambler and datasets are available at http://compbio.cs.wayne.edu/software/squeezambler/. PMID- 23918252 TI - A distance-based test of association between paired heterogeneous genomic data. AB - MOTIVATION: Due to rapid technological advances, a wide range of different measurements can be obtained from a given biological sample including single nucleotide polymorphisms, copy number variation, gene expression levels, DNA methylation and proteomic profiles. Each of these distinct measurements provides the means to characterize a certain aspect of biological diversity, and a fundamental problem of broad interest concerns the discovery of shared patterns of variation across different data types. Such data types are heterogeneous in the sense that they represent measurements taken at different scales or represented by different data structures. RESULTS: We propose a distance-based statistical test, the generalized RV (GRV) test, to assess whether there is a common and non-random pattern of variability between paired biological measurements obtained from the same random sample. The measurements enter the test through the use of two distance measures, which can be chosen to capture a particular aspect of the data. An approximate null distribution is proposed to compute P-values in closed-form and without the need to perform costly Monte Carlo permutation procedures. Compared with the classical Mantel test for association between distance matrices, the GRV test has been found to be more powerful in a number of simulation settings. We also demonstrate how the GRV test can be used to detect biological pathways in which genetic variability is associated to variation in gene expression levels in an ovarian cancer sample, and present results obtained from two independent cohorts. AVAILABILITY: R code to compute the GRV test is freely available from http://www2.imperial.ac.uk/~gmontana PMID- 23918253 TI - SOX17 is expressed in regenerating oligodendrocytes in experimental models of demyelination and in multiple sclerosis. AB - We have previously demonstrated that Sox17 expression is prominent at developmental stages corresponding to oligodendrocyte progenitor cell (OPC) cycle exit and onset of differentiation, and that Sox17 promotes initiation of OPC differentiation. In this study, we examined Sox17 expression and regulation under pathological conditions, particularly in two animal models of demyelination/remyelination and in post-mortem multiple sclerosis (MS) brain lesions. We found that the number of Sox17 expressing cells was significantly increased in lysolecithin (LPC)-induced lesions of the mouse spinal cord between 7 and 30 days post-injection, as compared with controls. Sox17 immunoreactivity was predominantly detected in Olig2(+) and CC1(+) oligodendrocytes and rarely in NG2(+) OPCs. The highest density of Sox17(+) oligodendrocytes was observed at 2 weeks after LPC injection, coinciding with OPC differentiation. Consistent with these findings, in cuprizone-treated mice, Sox17 expression was highest in newly generated and in maturing CC1(+) oligodendrocytes, but low in NG2(+) OPCs during the demyelination and remyelination phases. In MS tissue, Sox17 was primarily detected in actively demyelinating lesions and periplaque white matter. Sox17 immunoreactivity was co-localized with NOGO-A+ post-mitotic oligodendrocytes both in active MS lesions and periplaque white matter. Taken together, our data: (i) demonstrate that Sox17 expression is highest in newly generated oligodendrocytes under pathological conditions and could be used as a marker of oligodendrocyte regeneration, and (ii) are suggestive of Sox17 playing a critical role in oligodendrocyte differentiation and lesion repair. PMID- 23918254 TI - Wild boar (Sus scrofa) as a bioindicator of organochlorine compound contamination in terrestrial ecosystems of West Pomerania Province, NW Poland. AB - The aim of this study was to detect the presence and determine the residue levels of DDT, lindane, endrin and polychlorinated biphenyls (PCBs) in the liver of wild boars from the area of West Pomerania, NW Poland; to determine the activity of glutathione S-transferase (GST) as a biomarker of biological response and to assess the toxicological risk for consumers of the wild boar offal. The presence of pesticide residues and PCBs was found in all examined liver samples. The highest concentration was observed for endrin, and then, the descending order was PCBs >DDTs >lindane >dl-PCBs. The mean hepatic concentrations of endrin, PCBs, DDTs and lindane were 117.28, 78.59, 67.95 and 7.24 ng/g lipid weight, respectively. Among the dioxin-like PCB congeners, 118 and 156 were dominant in liver samples. The mean toxic equivalent (TEQ) level calculated for dl-PCBs was 2.10 +/- 1.11 pg WHO-PCB-TEQ/g. There was a statistically significant (p < 0.05) negative correlation between the concentration of lindane, DDTs and PCBs (as a sum of indicator congeners) in the liver and in the activity of GST. However, GST activities showed no significant correlation with any of the dl-PCBs. In five boar liver samples, the levels of certain organochlorine compounds exceeded the maximum residue levels (MRLs). In one sample, the MRLs were exceeded simultaneously for PCBs, endrin and DDTs and in another one-for endrin and DDTs. In the remaining three samples, only PCB levels were exceeded. PMID- 23918255 TI - Patient safety in the cardiac operating room: human factors and teamwork: a scientific statement from the American Heart Association. PMID- 23918256 TI - Let's clear the air for casino patrons and employees. PMID- 23918257 TI - Changes in ambulance calls after implementation of a smoke-free law and its extension to casinos. AB - BACKGROUND: Casinos are often exempted from legislation mandating smoke-free environments, potentially putting employees and patrons at risk for adverse events triggered by secondhand smoke exposure. METHODS AND RESULTS: We used an interrupted time series analysis of ambulance calls not originating and originating from casinos in Gilpin County, Colorado, a rural Colorado county with a large casino presence, from January 2000 through December 2012 to determine whether there was a change in ambulance calls originating from casinos when a state smoke-free law was extended to include them. Initial implementation of the smoke-free law (which exempted casinos) was followed by a significant 22.8% drop in ambulance calls (incidence rate ratio, 0.772; 95% confidence interval, 0.685 0.871; P<0.001) from locations other than casinos but no significant change in calls from casinos (P>0.9). The law requiring smoke-free casinos taking effect was followed by a 19.1% (incidence rate ratio, 0.809; 95% confidence interval, 0.724-0.905; P<0.001) drop in ambulance calls from casinos but no change in calls originating outside casinos (P>0.1). CONCLUSIONS: The observation that ambulance calls not coming from casinos dropped when the smoke-free law was initially implemented (excluding casinos) with no change in calls from casinos, followed by a comparable drop in calls originating from casinos (but not calls from elsewhere) when the law was extended to casinos, suggests that the important effects of secondhand smoke exposure occur acutely. These results also suggest that exempting casinos from smoke-free laws means that more people will suffer medical emergencies. PMID- 23918258 TI - Waveform efficiency analysis of auditory nerve fiber stimulation for cochlear implants. AB - Evaluation of the electrical stimulation efficiency of various stimulating waveforms is an important issue for efficient neural stimulator design. Concerning the implantable micro devices design, it is also necessary to consider the feasibility of hardware implementation of the desired waveforms. In this paper, the charge, power and energy efficiency of four waveforms (i.e. square, rising ramp, triangular and rising ramp-decaying exponential) in various durations have been simulated and evaluated based on the computational model of the auditory nerve fibers. Moreover, for a fair comparison of their feasibility, a fully integrated current generator circuit has been developed so that the desired stimulating waveforms can be generated. The simulation results show that stimulation with the square waveforms is a proper choice in short and intermediate durations while the rising ramp-decaying exponential or triangular waveforms can be employed for long durations. PMID- 23918259 TI - The impact of biofilm-producing bacteria on chronic bacterial prostatitis treatment: results from a longitudinal cohort study. AB - PURPOSE: We aim to evaluate the role of biofilm-producing bacteria in the clinical response to antibiotic therapy among patients affected by chronic bacterial prostatitis (CBP). METHODS: All patients attending our centre from January to December 2008 due to prostatitis-like symptoms with a positive Meares Stamey test were enroled. The clinical symptoms were assessed according to the NIH-CPSI, and the bacterial strains isolated from the patients enroled were identified and tested for antibiotic sensitivity using cards of the Vitek II semi automated System for Microbiology (BioMerieux). Quantitative bacterial slime production was assessed by the Christensen microwell assay. All patients were treated with fluoroquinolones for 4 weeks and reevaluated clinically and microbiologically after 3 months. RESULTS: One hundred and sixteen patients were enroled, and 150 bacterial strains were isolated from all patients. About 85 % of these strains were strong or moderate biofilm producers. Patients with strong or moderate biofilm-producing bacteria had a higher NIH-CPSI symptom score than those without biofilm-producing bacteria (mean 17.6 +/- 5.6 vs. 14.1 +/- 3.3; p = 0.0009). At the follow-up, 68 patients (58.6 %) had negative microbiological tests, but only 11 (9.48 %) reported a reduction in NIH-CPSI score. Improvement of symptoms was found statistically significantly less frequent in patients with biofilm-producing bacteria than in those without (p = 0.03). Ultrastructural analysis showed cellular forms in active replication with aberrant morphology of unknown cause and confirmed strong slime production with consistent bacterial stratification. CONCLUSION: In our CBP population, biofilm-producing bacteria were commonly found and had a significant negative impact on the clinical response to antibiotic therapy. PMID- 23918261 TI - Regrowth of the adenoids after coblation adenoidectomy: cephalometric analysis. AB - OBJECTIVES/HYPOTHESIS: To analyze the prevalence of adenoid regrowth at 1 year after coblation adenoidectomy using cephalometric radiography. STUDY DESIGN: Retrospective analysis. METHODS: One hundred eighty-eight children who underwent adenoidectomy from June 2006 through September 2010 were included. Demographic data, preoperative size of palatine tonsils, presence of allergic rhinitis, concurrent operation of recurrent middle ear effusion, and preoperative and postoperative Korean version of Obstructive Sleep Apnea-18 (KOSA-18) scores were analyzed. The size of the adenoids was measured three times in all the children by lateral cephalometry; preoperatively, at 1 month after adenoidectomy to observe adenoid residual; and at 1 year after surgery to observe adenoid regrowth. RESULTS: The adenoid regrowth at 1 year after adenoidectomy was observed in 25 children (13.3%), and the adenoid residual at 1 month after surgery was observed in 11 children (5.9%) in the cephalometry. Seven of the 11 children with residual disease (63.6%) had adenoid regrowth at 1 year. The regrowth group was significantly younger than no regrowth group, and the preoperative adenoids were larger in regrowth group than in no regrowth group. The symptoms of sleep disordered breathing recurred in two patients and they had revision adenoidectomy. CONCLUSION: The regrowth rate of the adenoids at 1 year was not low. However, most of the patients were asymptomatic. The adenoid residual at 1 month contributed to regrowth at 1 year, and the risk factors of the adenoid regrowth were younger age and larger initial size of the adenoids. LEVEL OF EVIDENCE: 2b. PMID- 23918260 TI - OsbZIP71, a bZIP transcription factor, confers salinity and drought tolerance in rice. AB - The bZIP transcription factor (TF) family plays an important role in the abscisic acid (ABA) signaling pathway of abiotic stress in plants. We here report the cloning and characterization of OsbZIP71, which encodes a rice bZIP TF. Functional analysis showed that OsbZIP71 is a nuclear-localized protein that specifically binds to the G-box motif, but has no transcriptional activity both in yeast and rice protoplasts. In yeast two-hybrid assays, OsbZIP71 can form both homodimers and heterodimers with Group C members of the bZIP gene family. Expression of OsbZIP71 was strongly induced by drought, polyethylene glycol (PEG), and ABA treatments, but repressed by salt treatment. OsbZIP71 overexpressing (p35S::OsbZIP71) rice significantly improved tolerance to drought, salt and PEG osmotic stresses. In contrast, RNAi knockdown transgenic lines were much more sensitive to salt, PEG osmotic stresses, and also ABA treatment. Inducible expression (RD29A::OsbZIP71) lines were significantly improved their tolerance to PEG osmotic stresses, but hypersensitivity to salt, and insensitivity to ABA. Real-time PCR analysis revealed that the abiotic stress related genes, OsVHA-B, OsNHX1, COR413-TM1, and OsMyb4, were up-regulated in overexpressing lines, while these same genes were down-regulated in RNAi lines. Chromatin immunoprecipitation analysis confirmed that OsbZIP71 directly binds the promoters of OsNHX1 and COR413-TM1 in vivo. These results suggest that OsbZIP71 may play an important role in ABA-mediated drought and salt tolerance in rice. PMID- 23918262 TI - Long-term in vivo impedance changes of subretinal microelectrodes implanted in dystrophic P23H rats. AB - Retinal prostheses are being developed to restore vision in blind patients with photoreceptor degeneration. Electrodes arrays were subretinally implanted in transgenic P23H rats with their photoreceptors degenerated. Electrical stability of the implants was evaluated by long-term monitoring of their impedance changes. Electrode impedances were found to increase by two log units over a three weeks period whereas no impedance increase was noted when the implants were located in the vitreous. In case of hemorrhage or major fibrous reactions, the impedance continued to increase steadily. After explantation, it recovered its initial value indicating no deterioration of the implant. Although the glial cell layer at the surface of the subretinal space was slightly larger, no major glial reaction was seen in direct contact to the implant. These results indicate that no functional testing should be considered before at least three weeks post implantation. PMID- 23918263 TI - Nutrition in kidney transplantation. AB - Organ transplantation has progressively established itself as the preferred therapy for many end-stage organ failures. However, many of these chronic diseases and their treatments can negatively affect nutritional status, leading to malnutrition and mineral deficiencies.Nutritional status is an important determinant of the clinical outcome of kidney transplant recipients.Malnutrition and obesity may represent a contraindication to transplantation in many cases and may increase the risk of postoperative complications after the transplantation. Nutritional support in kidney transplant recipients is challenging, since it must take into account the pre-transplant nutritional status, the side effects of immunosuppression, the function of the transplanted graft, the presence of infection, and the general status of the patient at the time of the transplantation.With these considerations in mind, we reviewed current literature on the impact of nutritional status on the outcome of kidney transplantation. PMID- 23918264 TI - Nanoporous activated carbon beads and monolithic columns as effective hemoadsorbents for inflammatory cytokines. AB - The aim of the present study was to develop and investigate nanoporous activated carbon materials for their ability to adsorb inflammatory cytokines directly from blood, for a range of therapeutic applications, including: systemic inflammatory response syndrome (SIRS) related to sepsis, cardio-pulmonary by-pass surgery, or ischemic reperfusion injury. Building on the previously established relationship between the porous structure of beaded polymer-derived activated carbon and its capacity to adsorb inflammatory molecules, we have developed and characterized monolithic porous carbon columns produced from the same polymer precursor matrix as carbon microbeads. The monolithic columns developed were assessed for their ability to adsorb inflammatory molecules from blood in a circulating system. Preliminary findings demonstrated good removal of the inflammatory cytokines IL-8 (100% removal), IL-6 (80% removal), and TNF (51% removal) from blood. The efficiency of cleansing is dependent on the size of the adsorbed molecule and the porous structure of the monolith, highlighting their potential for use as a hemoadsorption device. PMID- 23918265 TI - Using the Impella 5.0 with a right axillary artery approach as bridge to long term mechanical circulatory assistance. AB - PURPOSE: Impella 5.0 is a short-term left ventricle assist device (LVAD), inserted retrograde into the left ventricle across the aortic valve through a surgical peripheral access. Impella has been utilized for various indications but in the setting of bridge-to-bridge application there are limited reports. METHODS: We performed a retrospective observational analysis of Impella utilization at our institution as bridge to long-term LVADs. The primary end point was survival during Impella support. RESULTS: Between December 2010 and February 2012, we implanted 20 Impella in patients with cardiogenic shock and, among these, 5 were implanted as bridge to long-term LVADs. In this latter group, mean age at the time of implantation was 44 +/- 15.6 (range 27-68) years and there was a prevalence of males (80%). Etiology of cardiogenic shock was: decompensated anthracycline-induced cardiomyopathy (n = 1), myocardial infarction (n = 4). There was no major bleeding requiring surgical revision or infectious complications at the right axillary access. One patient required Impella replacement due to a pump stop. After a mean period of 14.2 +/- 9.0 (range 6-27) days of Impella support, patients were switched to a long-term LVAD (Jarvik 2000, n = 2; HeartMate II, n = 3). One patient died 70 days after implantation of the long-term LVAD due to multi-organ failure, while the remaining patients are still alive after a mean period of follow-up of 108.6 +/- 66.2 (range 19-191) days. CONCLUSIONS: Our experience shows that an Impella 5.0 implanted through the right axillary artery approach is a valid option as bridge to long-term LVADs. PMID- 23918266 TI - Fixation and mounting of porcine aortic valves for use in mock circuits. AB - PURPOSE: Investigations of the circulatory system in vitro use mock circuits that require valves to mimic the cardiac situation. Whereas mechanical valves increase water hammer effects due to inherent stiffness and do not allow the use of pressure lines or catheters, bioprosthetic valves are expensive and of limited durability in test fluids. Therefore, we developed a cheap, fast, alternative method to mount valves obtained from the slaughterhouse in mock circuits. METHODS: Porcine aortic roots were obtained from the abattoir and used either in native condition or after fixation. Fixation was performed at a constant retrograde pressure to ensure closed valve position. Fixation time was 4 h in a 0.5%-glutaraldehyde phosphate buffer. The fixed valves were molded into a modular mock circulation connector using a fast curing silicone. Valve functionality was evaluated in a pulsatile setting (cardiac output = 4.7 l/min, heart rate = 80 beats/min) and compared before and after fixation. Leaflet motion was recorded with a high-speed camera and valve insufficiency was quantified by leakage flow under steady pressure application (80 mmHg). RESULTS: Under physiological conditions the aortic valves showed almost equal leaflet motion in native and fixed conditions. However, the leaflets of the native valves showed lower stiffness and more fluttering during systole than the fixed specimens. Under retrograde pressure, fresh and fixed valves showed small leakage flows of <30 ml/min. CONCLUSIONS: The new mounting and fixation procedure is a fast method to fabricate low cost biologic valves for the use in mock circuits. PMID- 23918267 TI - Trends in therapeutic plasma exchange: a single-center evaluation. AB - PURPOSE: The quality of evidence supporting the use of therapeutic plasma exchange (TPE) in the treatment of individual diseases and disorders is often limited. Since we have experienced a growing variety of indications in our center we decided to make an inventory of our TPE population. METHODS: Single-center retrospective inventory of adult TPE-patients during a 7-year period to determine the evolution of indications for TPE, the response to treatment, and the existing evidence supporting TPE in specified settings. RESULTS: During a period of 84 months, 72 patients underwent 638 sessions of TPE in 91 episodes. There was no shift in frequency of TPE or level of indication. Our population consisted of 69 patients. A level I indication was seen in 41 patients (59.4%), while 14 (20.3%) had a level II indication, 8 (11.6%) had a level III indication, one had a level IV indication (1.4%) and 5 patients suffered from a condition not mentioned in the guidelines (7.2%). The response rate was inversely correlated with the level of evidence after exclusion of these 5 patients (category I 97.6%, category II 71.4%, category III 50%, category IV 0% response, p<0.01). CONCLUSIONS: There was no shift in frequency of TPE or level of indication in our center. Controversial indications should be carefully evaluated on an individual basis and a trial of TPE cannot be solely ruled out because of lack of evidence. PMID- 23918268 TI - Prevalence and management of anemia in hemodialysis patients in a Brazilian population of predominantly African descent. AB - BACKGROUND/OBJECTIVE: Findings from the international DOPPS indicated a rise in hemoglobin levels for patients on maintenance hemodialysis (MHD) for more than 180 days across many countries with more than 60% with hemoglobin >=11 g/dl. However, the situation of anemia control for a large contingent of the hemodialysis population remains unknown. Studies in the United States indicate that hemoglobin level is lower for African Americans on MHD, but studies in other populations of African descent are lacking. We investigated the prevalence of, and associated factors for, hemoglobin <11 g/dl in MHD patients from the Brazilian city with the largest proportion of African descendants outside Africa. METHODS: Cross-sectional study of 1,263 MHD patients enrolled in the Prospective Study of the Prognosis of Chronic Hemodialysis Patients (PROHEMO) in Salvador, Brazil 2005-2009. RESULTS: 88.0% black or mixed race; age 49.0 +/- 14.7 years; 96.6% receiving erythropoietin, median = 6,000 units/week. In patients on MHD for more than 180 days, 67.4% had hemoglobin <11 g/dl. Factors associated with hemoglobin<11 g/dl were MHD by catheter (odds ratio (OR) = 3.03, 95% confidence interval (CI) = 1.43-6.42), hospitalization in prior 3 months (OR = 2.14, 95% CI = 1.20-3.83), transferrin saturation <20% (OR = 1.49, 95% CI = 1.05-2.12) and higher malnutrition-inflammation score (OR = 1.58 per each log-transformed unit, 95% CI = 1.14-2.19). CONCLUSIONS: The results suggest that iron deficiency, insufficient erythropoietin dose, catheter use, malnutrition-inflammation, and problems associated with hospitalization are explanations for the high prevalence of hemoglobin below the guideline target in MHD patients from a large African descent Brazilian population. These results have implications for understanding the lower hemoglobin concentration in MHD populations of African descent. PMID- 23918269 TI - The impact of inflammatory factors associated with primary arteriovenous failure. AB - PURPOSE: Very scarce data exist regarding the relationship between differential white blood cell (WBC) counts and primary arteriovenous fistula (AVF) failure. Thus, the current study aimed to investigate the specific relationship between primary AVF failure and differential WBC counts.? METHODS: Sociodemographic, clinical, and laboratory parameters including automatically determined complete blood counts of the patients (from medical records and hospital charts) prior to AVF fistula surgery were recorded. Primary AVF failure was described as a complication of the AVF before the first successful cannulation for HD treatment.? RESULTS: In total 94 patients (Male/Female: 49/45, Aged: 50.9 +/- 15.0 years) were included. Ferritin, high sensitive C-reactive protein (hs-crp), total WBC count, neutrophil count, red cell distribution width (RDW) were higher in patients with primary AVF failure compared to patients without primary AVF failure. Logistic regression analysis showed that presence of diabetes (OR = 3.654, p = 0.035), RDW (OR = 0.449, p = 0.033) and ferritin (OR = 1.097, p = 0.021) were independently related with primary AVF failure.? CONCLUSIONS: Neither total WBC counts nor WBC subtypes were related with primary AVF failure. Higher RDW and ferritin levels had a prognostic value for development of primary AVF failure. PMID- 23918270 TI - Co-culture of human bone marrow stromal cells with endothelial cells alters gene expression profiles. AB - The intricate relationship between angiogenesis and osteogenesis in vivo must be replicated in bone tissue engineering constructs to ensure the formation of a functional vascular network to support successful bone formation. Although communication between bone marrow stromal cells (MSC) and endothelial cells (EC) is recognized as one of the most important cellular interactions in bone regeneration, the underlying mechanisms of this biological process are not well understood. The purpose of this study was to analyze global gene expression associated with intercellular communication between MSC and EC using HumanWG-6 v3.0 expression BeadChips with a one-channel platform system (Illumina, San Diego, CA, USA). Each array contains more than 48,000 probes derived from human genes. A global map of MSC gene expression was generated following co-culture of MSC with EC for 5 and 15 days, in a direct-contact model. The map was used to determine relative alterations in functional processes and pathways. Co-culturing EC with MSC up-regulated genes related to angiogenesis as von Willebrand factor, platelet/endothelial cell adhesion molecule-1, cadherin 5, angiopoietin-related protein 4, and cell surface antigen CD34, and genes playing important roles in osteogenesis as alkaline phosphatase, FK506 binding protein 5, and bone morphogenetic protein. These findings clearly demonstrated that EC had a significant impact on MSC, particularly the bidirectional regulation of angiogenesis and osteogenesis. Moreover, cell-matrix interactions and TGF-beta signal pathways were implicated for a crucial role in endothelial, cell-induced gene regulation in MSCs. A detailed study of the functional correlates of the microarray data is warranted to explore cellular and molecular interactions of importance in bone tissue engineering. PMID- 23918271 TI - Continuous blood purification ameliorates endothelial hyperpermeability in SAP patients with MODS by regulating tight junction proteins via ROCK. AB - BACKGROUND: Excessive activation of inflammatory mediator cascade during severe acute pancreatitis (SAP) is a major cause of multiple organ dysfunction and is associated with a high mortality. Recently, more and more studies have shown that continuous blood purification (CBP) could improve the prognosis of patients with multiple organ dysfunction syndrome (MODS), but the exact mechanism is still unclear. Many researchers have found that the disruption of tight junction barrier was an important factor for endothelial hyperpermeability, which played a key role in the pathogenesis of MODS. Previously, we found CBP could attenuate endothelial hyperpermeability in SAP patients with lung injury through regulating cytoskeleton reorganization mediated by RhoA/ROCK. However, the effect of CBP on the change of tight junction proteins in SAP patients with MODS was still unknown. This study aimed to investigate the role of tight junctions in endothelial hyperpermeability in SAP patients with MODS using an in vitro model, and the effect of CBP on tight junction barrier.? METHODS: Before CBP and after CBP, blood samples were collected to observe hepatic and renal function, and arterial blood gas, while the APACHE II score was calculated to evaluate the severity of patients. To test whether RhoA/ROCK signaling pathway was involved, human umbilical vein endothelial cells (HUVECs) were exposed to serum samples taken from patients at specific time points during CBP, or preincubated with ROCK inhibitor, Y-27632, followed by treatment with serum. Then, the changes in endothelial cell permeability and the expression and distribution of tight junction proteins occludin and claudin-1 were observed. ? RESULTS: Compared with before CBP, the APACHE II score, serum creatinine and alanine aminotransferase decreased significantly, while PaO2/FiO2 increased significantly after CBP. Meanwhile, endothelial permeability induced by serum from patients significantly increased, while the expression of tight junction proteins occludin and claudin-1 significantly decreased, and severe disruption of occludin and claudin-1 was found in these cells. However, pretreated with Rho-kinase inhibitor, Y-27632 could lessen all of these abnormalities, and in a dose-dependent way. Endothelial hyperpermeability, the abnormal expression and distribution of occludin and claudin-1 were attenuated in HUVECs treated with serum from patients after CBP treatment. ? CONCLUSIONS: The abnormality of tight junctions mediated by ROCK was an important mechanism for endothelial hyperpermeability induced by serum from SAP patients with MODS. CBP could ameliorate the disorganization and redistribution of tight junction proteins, hence improve the endothelial permeability. PMID- 23918272 TI - Novel approach for bacteremia detection in patients with end-stage renal failure undergoing hemodialysis. AB - Severe systemic infections are one of the leading causes of death in patients with end-stage renal disease and are often associated with hospitalization. Since bacteria can be identified in used hemofilters in an ICU setting, it was investigated whether this method might be useful in patients undergoing regular intermittent hemodialysis. By analyzing used hemodialyzers in (n = 13) patients, we identified systemic bacteremia in two patients (15.4%) while corresponding blood cultures were negative. In two further patients, positive microbiological findings from hemodialyzers appeared to be of unclear clinical relevance. Cultures from hemodialyzers might be an add-on approach for the identification of bacteria in the blood stream of patients undergoing regular intermittent hemodialysis. PMID- 23918273 TI - Effects of mechanical and chemical stimuli on differentiation of human adipose derived stem cells into endothelial cells. AB - It has been hypothesized that application of the micromechanical environment that target cells experience in vivo enhances functionality of differentiated cells. Vascular endothelial cells, functioning at the interface of the blood-vessel wall, are vital to the performance of the cardiovascular system. They are subject to shear and tensile stresses induced by blood flow and pressure, respectively. This study investigated effects of shear/tensile stresses on endothelial differentiation of adipose-derived mesenchymal stem cells (ASCs) utilizing a custom-made bioreactor capable of applying both shear and tensile stresses. The loading values of 10% cyclic stretch, 0-2.5 dyn/cm2 cyclic shear stress, and combined loadings were used. To examine the extent of mechanical and chemical stimuli in acquisition of endothelial characteristics by ASCs, the expression of three major endothelial genes were quantified when ASCs were treated by three loading regimes and endothelial growth factor for three different durations (1, 2, and 7 days). In general, cyclic stretch decreased expression of FLK-1 and vWF, while cyclic shear elevated expression levels. The combined loading regime had minor effects on the expression of the two markers. All types of loadings significantly enhanced the expression level of VE-cadherin with the most prominent increase by combined loading. It was concluded that applying different loading regimes assists in adjusting the expression level of endothelial markers to achieve functional endothelial cells for cardiovascular engineering. PMID- 23918274 TI - Insulin independence after islet transplantation through an indwelling catheter in the right gastric vein. AB - BACKGROUND: Current islet transplantation approaches have various defects. This study was to investigate the feasibility and safety of an indwelling catheter in the right gastric vein for intra-hepatic islet transplantation. METHODS: Twenty patients had islet transplants through the indwelling catheter in the right gastric vein. The catheters were placed into the portal vein trunk using open surgery. While monitored with Doppler ultrasound, the islet suspensions were infused after the catheter location was confirmed in the trunk of the portal vein. The catheter was kept indwelling and secured to the skin for optional subsequent infusions and flushed with heparinized saline once per day to avoid peri-catheter thrombosis. After one month, the catheter was removed. Adverse effects and transplant efficacy parameters were observed. RESULTS: Insulin independence was finally achieved in 17 patients; 11 patients received a second infusion. The mean surgical duration was 55 +/- 7 minutes and the hemorrhage volume was approximately 40 +/- 11 mL. No significant change in portal pressure was observed (before infusion 2.9 +/- 1.5 cm H2O, after infusion 2.6 +/- 1.7 cm H2O, p>0.05). However, peak systolic velocity (PRV) of the hepatic artery after infusion was markedly higher than that before infusion (35.1 +/- 10.7 cm/s vs. 68.5 +/- 46.2 cm/s, p<0.01). Neither infection nor severe hemorrhage was found after surgery. CONCLUSIONS: It is feasible, convenient, and safe to use an indwelling catheter in the right gastric vein for islet transplantation. PMID- 23918275 TI - Central closed chest implantation of extracorporeal membrane oxygenation to prevent limb ischemia. AB - PURPOSE: Extracorporeal membrane oxygenation (ECMO) support is a widely accepted treatment option for patients with cardiogenic shock, but it is still related to a high incidence of severe complications and death. We present an alternative implantation technique to prevent life-threatening vascular complications.? METHODS: Between January 2008 and January 2011, a total of 28 patients with acute myocardial failure and consecutive cardiogenic shock required ECMO as supportive treatment. Pre-implantation procedures were isolated CABG, CABG combined with mitral valve reconstruction or ventricular septal defect closure, respectively. The implantation of ECMO was performed by connecting the ascending aorta via an 8 mm Dacron prosthesis with the arterial line and percutaneous puncture of the femoral vein. The chest was closed after installation of ECMO was completed. The arterial line was directed subxyphoidally and removal was possible without thoracotomy.? RESULTS: Average support duration was 8.7 +/- 3.9 days. An additional intra-aortic balloon pump was used in 23 patients (89.3%). Cerebrovascular events occurred in 21.4% and gastrointestinal complications in 9.1%. Acute renal failure was treated with continuous renal replacement therapy in 64.3%. In eight cases a systemic infection had to be treated. One patient with pre-existing severe peripheral arterial disease suffered from limb malperfusion, requiring leg amputation. Twelve patients were successfully weaned from ECMO and 8 patients (28.6%) were discharged from hospital. ? CONCLUSIONS: This alternative cannulation strategy offers effective cardiopulmonary support while minimizing the risk of limb hypo- or hyperperfusion without requiring reopening of the thorax. PMID- 23918276 TI - The removal of serum hepcidin by different dialysis membranes. AB - PURPOSE: Hepcidin has been suspected to be associated with anemia of chronic disease, which is commonly observed in patients with maintenance hemodialysis (MHD). As almost of hepcidin is bounded to protein, it is essential to clarify which kind of dialysis membrane can remove it efficiently. METHODS: Ex vivo study: 50 mL of whole blood from healthy volunteers were circulated for 2 h in a microcircuit with mini-dialyzers (acrylonitrile-co-methallyl sulfonate (AN69) or polysulfone (PS)) without ultrafiltration. We measured hepcidin-25 levels at 0, 60, and 120 min in the blood samples. In vivo study: Blood samples were taken from 28 MHD patients at the start and end of HD sessions with PS or AN69. We measured serum levels of hepcidin 20, 22, and 25 by liquid chromatography tandem mass spectrometry, and also measured serum levels of urea nitrogen (UN), beta2microglobulin (MG). RESULTS: Ex vivo study: Although serum hepcidin 25 levels increased after the ex vivo session with PS, they significantly decreased with AN69. In vivo study: The reduction ratio of beta2MG by PS was significantly higher than that of AN69. On the other hand, there was no significant difference in the reduction ratio of hepcidin 20, 22, and 25 between PS and AN69. CONCLUSIONS: Both super-flux PS and AN69 similarly removed hepcidin 20 22, and 25. HD with PS might achieve a high removal ratio of hepcidin by enhanced diffusion performance and an increased clearance of small molecule solutes. On the other hand, AN69 might remove hepcidin by adsorption. PMID- 23918277 TI - Hiatal hernia following total gastrectomy with Roux-en-Y reconstruction. AB - Hiatal hernias after total gastrectomy for advanced gastric cancer are very rare. We review a case of a 44-year-old male who presented with dyspnea and chest pain 2 days after total gastrectomy, lower esophagectomy, and splenectomy with retrocolic Roux-en-Y reconstruction approached by a left thoracoabdominal incision for gastric cancer at the cardia. Plain and cross-sectional imaging identified a large hiatal hernia protruding into the right thorax containing left sided transverse colon and small intestine. Our patient underwent a laparotomy, and after hernia reduction the hiatal defect was repaired by direct suturing. He experienced anastomotic leakage and right pyothorax, but recovered. The potential cause is discussed here and the published literature on this rare complication is reviewed briefly. PMID- 23918278 TI - Solid-state NMR analysis of a boron-containing pharmaceutical hydrochloride salt. AB - A novel crystalline form of the boron-containing antibacterial drug (S)-3 (aminomethyl)-7-(3-hydroxypropoxy)benzo[c] [1,2]oxaborol-1(3H)-ol hydrochloride is studied by solid-state nuclear magnetic resonance (SSNMR) and single-crystal X ray diffraction techniques. After determination of the crystal structure by X-ray diffraction, SSNMR spectroscopy of this form is performed to obtain structural information using experimental approaches based on dipolar correlation, chemical shift analysis, and quadrupolar interaction analysis. 1H SSNMR experiments at 16.4 T using magic-angle spinning (MAS) and homonuclear dipolar decoupling, 2D SSNMR experiments based on (1)H-(13)C and (1)H-(11)B dipolar heteronuclear correlation, and density functional theory (DFT) calculations are combined in a novel approach to obtain a nearly complete assignment of the (1)H spectrum of this crystalline phase. (11)B and (35)Cl chemical shift and quadrupolar parameters are obtained using the analysis of MAS spectra and are found to be accurately reproduced using DFT calculations. NMR chemical shielding and electric field gradient parameters obtained using these methods are related to hydrogen bonding trends in the crystal structure. The results illustrate the increasing capability of SSNMR techniques involving (1)H, (11)B, and (35)Cl SSNMR in the analysis of the crystal structure of a pharmaceutical compound containing covalently bonded boron. PMID- 23918279 TI - Iron deficiency after Roux-en-Y gastric bypass: insufficient iron absorption from oral iron supplements. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) may reduce the absorption of iron, but the extent to which this absorption is impeded is largely unknown. First, we determined the prevalence of iron deficiency following RYGB and explored the risk factors for its development. Second, we examined to what extent oral iron supplements are absorbed after RYGB. METHODS: Monocentric retrospective study in 164 patients (123 females, 41 males; mean age 43 years) who underwent RYGB between January 2006 and November 2010 was done. Pre- and postoperative data on gender, age, BMI, serum levels of iron, ferritin, hemoglobin, vitamin B12, 25 hydroxy vitamin D, and use of proton pump inhibitors and H2 antagonists were collected. Generalized linear mixed models were used for the analysis of the data. In 23 patients who developed iron deficiency after surgery, an oral challenge test with 100 mg FeSO4 . 7H2O was performed. RESULTS: Following RYGB, 52 (42.3 %) female patients and 9 male (22.0 %) patients developed iron deficiency (serum ferritin concentration <= 20 MUg/L). The prevalence of iron deficiency was significantly higher in females than males (p = 0.0170). Young age (p = 0.0120), poor preoperative iron status (p = 0.0004), vitamin B12 deficiency (p = 0.0009), and increasing time after surgery (p < 0.0001) were also associated with iron deficiency. In the oral iron challenge test, only one patient out of 23 showed sufficient iron absorption. CONCLUSIONS: Iron deficiency is extremely frequent after RYGB and is linked with different risk factors. Iron supplementation seems essential, but the effect of oral tablets may be limited as absorption of oral iron supplements is insufficient post-RYGB. PMID- 23918280 TI - Algorithm for the management of ventral hernia in morbidly obese patients. PMID- 23918281 TI - Response to "Algorithm for management of ventral hernia in morbidly obese patients". PMID- 23918283 TI - The lysosome: from waste bag to potential therapeutic target. AB - Lysosomes are ubiquitous membrane-bound intracellular organelles with an acidic interior. They are central for degradation and recycling of macromolecules delivered by endocytosis, phagocytosis, and autophagy. In contrast to the rather simplified view of lysosomes as waste bags, nowadays lysosomes are recognized as advanced organelles involved in many cellular processes and are considered crucial regulators of cell homeostasis. The function of lysosomes is critically dependent on soluble lysosomal hydrolases (e.g. cathepsins) as well as lysosomal membrane proteins (e.g. lysosome-associated membrane proteins). This review focuses on lysosomal involvement in digestion of intra- and extracellular material, plasma membrane repair, cholesterol homeostasis, and cell death. Regulation of lysosomal biogenesis and function via the transcription factor EB (TFEB) will also be discussed. In addition, lysosomal contribution to diseases, including lysosomal storage disorders, neurodegenerative disorders, cancer, and cardiovascular diseases, is presented. PMID- 23918282 TI - Fasting and meal-suppressed ghrelin levels before and after intragastric balloons and balloon-induced weight loss. AB - BACKGROUND: Intragastric balloons may be an option for obese patients with weight loss failure. Its mode of action remains enigmatic. We hypothesised depressed fasting ghrelin concentrations and enhanced meal suppression of ghrelin secretion by the gastric fundus through balloon contact and balloon-induced delayed gastric emptying. METHODS: Patients were randomised to a 13-week period of sham or balloon treatment, followed by a 13-week period of balloon treatment in everyone. Blood samples for ghrelin measurement were taken in the fasting state and every 15 min for 1 h after a breakfast meal at the start, after 13 weeks and after 26 weeks. Patients filled out scales to assess satiety and kept a food diary. RESULTS: Forty obese patients (BMI 43.1 kg/m(2)) participated. At the start, fasting ghrelin values were low with a blunted ghrelin response to a test meal. The presence of a balloon had no influence on fasting or meal-suppressed ghrelin concentrations. Despite a weight loss of 10 % after 13 weeks and 15 % after 26 weeks, fasting ghrelin concentrations did not change; neither did the ghrelin response to a meal. No relation was found between ghrelin and insulin, satiety, intermeal interval, the number of meals or subsequent energy intake. Ghrelin concentrations were more suppressed with greater weight loss or with balloons located in the fundus. CONCLUSIONS: Ghrelin concentrations did not change by balloon treatment after 13 and 26 weeks and, unexpectedly, did not rise despite substantial weight loss and negative energy balance. This suppression might be of benefit in the maintenance of weight loss but could not be ascribed to the balloon treatment. PMID- 23918284 TI - Heterogeneity of Ca2+ handling among and within Golgi compartments. AB - The Golgi apparatus (GA) is a dynamic intracellular Ca(2+) store endowed with complex Ca(2+) homeostatic mechanisms in part distinct from those of the endoplasmic reticulum (ER). We describe the generation of a novel fluorescent Ca(2+) probe selectively targeted to the medial-Golgi. We demonstrate that in the medial-Golgi: (i) Ca(2+) accumulation takes advantage of two distinct pumps, the sarco/endoplasmic reticulum Ca(2+) ATPase and the secretory pathway Ca(2+) ATPase1; (ii) activation of IP3 or ryanodine receptors causes Ca(2+) release, while no functional two-pore channel was found; (iii) luminal Ca(2+) concentration appears higher than that of the trans-Golgi, but lower than that of the ER, suggesting the existence of a cis- to trans-Golgi Ca(2+) concentration gradient. Thus, the GA represents a Ca(2+) store of high complexity where, despite the continuous flow of membranes and luminal contents, each sub compartment maintains its Ca(2+) identity with specific Ca(2+) homeostatic characteristics. The functional role of such micro-heterogeneity in GA Ca(2+) handling is discussed. PMID- 23918285 TI - Is the short messaging service feasible to improve adherence to tuberculosis care? A cross-sectional study. AB - BACKGROUND: The short messaging service (SMS) is supposed to improve adherence of TB patients to regular treatment. METHODS: A cross-sectional study using survey questionnaires and in-depth interviews was performed with pulmonary TB patients to identify the feasibility of SMS reminders and determinants of mobile phone utilization. RESULTS: The rates of mobile ownership and messages usage were 91.1% and 80.4% respectively, and 81% held favorable opinion on SMS reminders. Gender, age, education level and income profile were likely to be influencing factors. CONCLUSION: The SMS reminder system was feasible to initiate given high access to mobile phones and positive views. Features of service users should be considered when implementing SMS interventions. PMID- 23918286 TI - Enteric pathogens in HIV infected and HIV uninfected individuals with diarrhea in Pune. AB - BACKGROUND: Diarrhea in HIV infected individuals is a common complication seen in about 90% of patients in developing countries. The objective of this study was to identify enteric pathogens in HIV infected and HIV uninfected individuals in Pune. METHOD: This study was conducted from January 2009 to May 2010 on 331 consecutive patients presenting with diarrhea admitted at Naidu Municipal Corporation Hospital, Pune and processed using conventional methods. RESULTS: Intestinal parasitic pathogens were detected in 60% (39/65) of HIV infected and 14.3 (38/266) of HIV uninfected individuals. Bacterial pathogens were detected in 34% (22/65) of HIV infected individuals and 28.2% (75/266) of the HIV uninfected individuals. The common enteric pathogens detected in HIV infected individuals were Cystoisospora belli (28%, 18/65) followed by Cryprotosporidium parvum (12%, 8/65). In HIV uninfected individuals Entamoeba histolytica (7.1%, 19/266) followed by Shigella flexnari (4.9%, 13/266) were the most common pathogens. The difference in detection of enteric parasites in HIV infected individuals and HIV uninfected individuals was found to be significant (p < 0.01). CONCLUSIONS: Intestinal parasitic pathogens are more common in HIV infected antiretroviral therapy naive patients. Early detection of enteric pathogens by routine examination of stool samples will help in the management and to improve the quality of life for HIV infected individuals. PMID- 23918287 TI - The importance of rehabilitation after lower limb fractures in elderly osteoporotic patients. AB - Improving rehabilitation strategies after lower limb fractures among elderly patients is an urgent public health challenge due to the increasing proportion of older population and therefore the raised number of falls and fractures. Due to their strategic positioning, physiatrists should aim not only to improve functional outcomes after acute fracture treatment but also to address the underlying osteoporotic condition in order to prevent the devastating socioeconomic consequences of osteoporotic fractures. PMID- 23918288 TI - SEOM clinical guidelines for the treatment of non-small cell lung cancer (NSCLC) 2013. AB - Lung cancer remains the most commonly diagnosed cancer worldwide and the leading cause of cancer-related mortality. More than 80 % of all newly diagnosed cases of lung cancer are non-small cell lung cancer (NSCLC). Despite recent advances, 40 % of patients still have advanced disease at the moment of diagnosis. Clinical information, pathological diagnosis and molecular assessment are needed to guide the systemic therapy, whereas discussion within an experienced team is key to adequately select the most appropriate multidisciplinary strategies. The purpose of this article is to provide updated recommendations for the management of these patients. PMID- 23918289 TI - The effect of cancer stage and treatment modality on quality of life in oropharyngeal cancer. AB - OBJECTIVES/HYPOTHESIS: To examine changes in health-related quality of life among oropharyngeal cancer patients by stages and across treatment types among advanced cancer patients. STUDY DESIGN: Individual prospective cohort study. METHODS: All newly diagnosed patients with oropharyngeal cancer treated with curative intent were routinely assessed. The European Organization for Research and Treatment of Cancer (EORTC) both the Main Module quality-of-life questionnaire (QLQ-C30) and the Head and Neck Cancer (HNC) Module (QLQ-H&N35) were administered at diagnosis and 3, 6, and 12 months thereafter. Complete case analysis was used following assessment of missing data. The proportion of patients with clinically significant deterioration (changes of >= 10 points) from baseline were calculated for each follow-up time point and compared by stage (I/II vs. III/IV) and then treatment type (chemotherapy and radiotherapy [CRT] vs. surgery and postoperative radiotherapy [S&PORT]). RESULTS: Deterioration in most domains was most frequent for stage III/IV patients at 3 months (both modules), whereas stage I/II patients experienced this at 6 months (QLQ-C30) and 12 months (H&N35). Among stage III/IV patients, this happened at all time points for S&PORT patients (QLQ-C30) versus 12 months for CRT patients (H&N35). The number of patients reporting deterioration was lower for most domains at 12 months compared to earlier periods, although dry mouth remained a problem for most patients (60%-85% across treatment/stage groups). CONCLUSIONS: Our preliminary findings suggest that general and disease-specific deterioration is of most concern for stage I/II patients at 6 and 12 months and at 3 months for advanced cancer patients. For stage III/IV patients receiving S&PORT, general deterioration remains a problem after diagnosis, whereas for CRT patients, disease-specific deterioration is of most concern at 12 months. PMID- 23918290 TI - Second family with the Boston-type craniosynostosis syndrome: novel mutation and expansion of the clinical spectrum. AB - Craniosynostosis, caused by early fusion of one or more cranial sutures, can affect the coronal or lambdoid sutures, or include premature fusion of the sagittal (scaphocephaly) or metopic suture (trigonocephaly). Often occurring as isolated finding, their co-existence in a craniosynostosis syndrome is infrequent. We describe a four-generation family with variable expression of a craniosynostosis phenotype with scaphocephaly and a particularly severe trigonocephaly. Molecular analysis revealed a missense mutation in the MSX2 associated with the Boston-type craniosynostosis syndrome-affecting the same amino-acid residue as in the original Boston family. Besides unique features such as the cranial sutures involved, minor limb abnormalities and incomplete penetrance, our patients share with the original family autosomal dominant inheritance and the presence of multiple endocranial erosions on CT imaging. Though these findings appear to be important diagnostic clues for MSX2-related craniosynostosis, it is noteworthy that the first affected generation in this family presented merely with isolated sagittal or unicoronal craniosynostosis and cutaneous syndactyly. Molecular analysis of MSX2 should therefore be considered in patients with isolated scaphocephaly/unicoronal synostosis, especially in the presence of a family history for craniosynostosis or syndactyly. PMID- 23918291 TI - Pertuzumab: a new targeted therapy for HER2-positive metastatic breast cancer. AB - Trastuzumab, a humanized monoclonal antibody, has become an important targeted therapy for patients with all stages of human epidermal growth factor receptor-2 (HER2)-positive breast cancer. However, primary and acquired resistance to trastuzumab remains a significant problem. Pertuzumab, a humanized monoclonal antibody that binds to a domain of the HER2 receptor separate from trastuzumab, may have the potential to overcome trastuzumab resistance. Clinical trials have shown that pertuzumab can be effectively combined with other biologic therapy or chemotherapy in patients with metastatic HER2-positive breast cancer. Pertuzumab is relatively well tolerated with minimal increases in hematologic and cardiac toxicity observed when added to trastuzumab and/or docetaxel. In addition to becoming the standard of care in combination with docetaxel and trastuzumab in patients with newly diagnosed HER2-positive metastatic breast cancer, clinical trials continue to evaluate pertuzumab in combination with other targeted therapy, chemotherapy, and in patients with early stage breast cancer. These trials will help to further determine the role of pertuzumab in the treatment of HER2-positive breast cancer. PMID- 23918292 TI - Religious congregations and social justice participation: a multilevel examination of social processes and leadership. AB - Religious congregations have potential to be mediating structures for social justice participation. However, research has yet to examine the specific social processes or leadership characteristics within congregations that may promote social justice participation. In this study, we use data from 176,901 participants nested within 1,938 congregations to test how social processes (i.e., religious attendance at worship services, extra-worship participation, bonding social capital, a congregational norm for justice) and leadership characteristics (i.e., leader modeling of justice, horizontal leadership style) predict personal social justice involvement through the congregation (i.e., participation in social justice activities sponsored by the congregation) as well as personal social justice involvement outside the congregation (i.e., participation in social justice activities not sponsored by the congregation). We use multilevel logistic regression to examine these social processes and leadership characteristics at both individual and congregational levels of analysis. Results showed distinct patterns of associations at individual and congregational levels of analysis and that different social processes and leadership characteristics predicted personal social justice participation through or outside the congregation. These findings reveal the importance of social processes and leadership characteristics in understanding how congregations may mediate social justice participation. Implications for community psychology research and practiced also are discussed. PMID- 23918293 TI - [Arthroscopic correction of extra-articular subspinal impingement in the hip joint]. AB - We report the case of symptomatic extra-articular subspinal impingement in the hip joint caused by a pathological contact between the anterior inferior iliac spine (AIIS) and the femoral neck. A 28-year-old patient presented with activity related inguinal pain on the right side and a positive anterior impingement test in the clinical examination. Radiological examinations revealed a hypertrophic AIIS with caudal extension below the acetabulum. After a positive injection test confirmed the AIIS as the origin of the pain, arthroscopic correction with partial resection of the AIIS was performed resulting in significant pain relief and improved range of motion. PMID- 23918294 TI - The relationship between selected socioeconomic factors and basic anthropometric parameters of school-aged children and adolescents in Poland. AB - The aim of the present paper was to examine the associations between anthropometric parameters, overweight, obesity, and socioeconomic status (SES) of children and adolescents in Poland. Data were collected in the "Elaboration of reference blood pressure ranges for children and adolescents in Poland" OLAF PL0080 (OLAF) study, a nationally representative survey on growth and blood pressure references for children and adolescents aged 7-18 years. Body height, weight, and waist circumference (WC) were measured, and body mass index (BMI) was calculated. Anthropometric parameters were standardized for age and gender and expressed as z-scores. Statistical analyses were conducted on 10,950 children and adolescents whose parents provided socioeconomic questionnaires. The associations between anthropometric parameters, overweight (including obesity), and SES were analyzed using multiple regression and multiple logistic regression. The height was positively associated with higher levels of maternal education and, in the case of girls, also with paternal education. Higher level of income per capita, but not the highest, was associated with higher weight, BMI, and WC and, in the case of boys, also tall stature. The height, weight, BMI, and waist were significantly inversely associated with number of children in the family. Lower number of children in the family and higher level of income, but not the highest, increased odds of overweight and obesity. In the case of girls, the odds of obesity decreased with paternal higher level of education. CONCLUSION: The social position associated with parents' education, better environment, and SES correlate with body height and weight of a child. However, it is associated with higher risk of overweight and abdominal obesity. PMID- 23918295 TI - A rapid plasma neutrophil gelatinase-associated lipocalin assay for diagnosis of acute pyelonephritis in infants with acute febrile urinary tract infections: a preliminary study. AB - In infants with febrile urinary tract infection (UTI), the accurate rapid diagnosis of acute pyelonephritis (APN) would be valuable because early aggressive treatment reduces the risk of renal scarring. The objective of the study was to evaluate whether rapid plasma neutrophil gelatinase-associated lipocalin (NGAL) assay could be used as a diagnostic biomarker of renal parenchymal injury in infants with acute febrile UTI to distinguish APN at the bedside. This prospective observational study included 47 infants, who were admitted with a first episode of acute febrile UTI. Total UTI group was divided into the Cortical defect (UTI-CD, n = 24) group and Non-cortical defect (UTI-ND, n = 23) group, according to the result of renal scan. For the Control group, 15 infants who presented a febrile episode without any focus of bacterial infection were included. On admission, the median NGAL level (106.5 [60-476] ng/mL) in the UTI-CD group was significantly higher than that (60 [60-196] ng/mL) in the UTI-ND group and that (60 [60-197] ng/mL) in the Control group and was significantly decreased to 60 [60-306] ng/mL after an antibiotic treatment. The area under the receiver operating characteristic curves was 0.748 (95 % CI, 0.610-0.887; P = 0.003) for NGAL levels and 0.724 (95 % CI, 0.579-0.868; P = 0.009) for CRP levels. The best cutoff of NGAL level for detection of APN was founded to be 61.0 ng/mL (sensitivity, 75.0 %; specificity, 78.3 %). Although not a stand-alone test, the rapid determination of plasma NGAL level provides valuable information quickly, concerning the distinction of APN, for determining the clinical course of acute febrile UTI. PMID- 23918296 TI - A lump in an arm. PMID- 23918297 TI - Young male soccer players exhibit additional bone mineral acquisition during the peripubertal period: 1-year longitudinal study. AB - The aim of this study was to determine whether soccer could have different bone benefits in prepubescent and pubescent boys. We investigated 76 boys aged 10 to 13 years during a 1-year study. All boys were prepubescent at the beginning of the study (T0); pubescent status was determined by a complete 24-h urine hormonal assay of FSH-LH, with LH <= 0.31 IU/24 h and FSH <= 2.19 IU/24 h corresponding to prepubescent Tanner stage I and with 0.31 < LH < 0.95 IU/24 h and 1.57 < FSH < 3.77 IU/24 h corresponding to pubescent Tanner stage II. At the end of the study (T1), 35 boys remained prepubescent (22 soccer players (F1) and 13 controls (C1)), and 41 boys had entered puberty (26 soccer players (F2) and 15 controls (C2)). Soccer players completed 2 to 5 h of training plus one competition game per week during the school year, and controls only had physical education at school. Bone mineral content (BMC) was measured at T0 and T1 by DPX in the lumbar spine, total hip, and whole body (WB) for a comparison between soccer players and controls. At T0, no BMC difference was found between F1 and C1, but BMC was higher in F2 than C2 in WB and weight-bearing sites. At T1, BMC was higher in WB and weight-bearing sites in both F1 and F2 compared to their respective controls. Between T0 and T1, soccer induced a BMC gain at weight-bearing sites in both F1 and F2 compared to C1 and C2, respectively. The soccer-related bone gain was greater in WB and weight-bearing (the lumbar spine, total hip, and supporting leg) and non-weight-bearing bones (dominant arm and nondominant arm) in boys who became pubescent than in boys who remained prepubescent. In conclusion, 1-year study in young male soccer players demonstrates that the process of bone accretion at the very early phase of puberty is more intensely stimulated by the combination of physical exercise and sexual impregnation than by one of these factors alone. PMID- 23918299 TI - Regulation of photosynthesis during heterocyst differentiation in Anabaena sp. strain PCC 7120 investigated in vivo at single-cell level by chlorophyll fluorescence kinetic microscopy. AB - Changes of photosynthetic activity in vivo of individual heterocysts and vegetative cells in the diazotrophic cyanobacterium Anabaena sp. strain PCC 7120 during the course of diazotrophic acclimation were determined using fluorescence kinetic microscopy (FKM). Distinct phases of stress and acclimation following nitrogen step-down were observed. The first was a period of perception, in which the cells used their internally stored nitrogen without detectable loss of PS II activity or pigments. In the second, the stress phase of nitrogen limitation, the cell differentiation occurred and an abrupt decline of fluorescence yield was observed. This decline in fluorescence was not paralleled by a corresponding decline in photosynthetic pigment content and PS II activity. Both maximal quantum yield and sustained electron flow were not altered in vegetative cells, only in the forming heterocysts. The third, acclimation phase started first in the differentiating heterocysts with a recovery of PS II photochemical yields [Formula: see text] Afterwards, the onset of nitrogenase activity was observed, followed by the restoration of antenna pigments in the vegetative cells, but not in the heterocysts. Surprisingly, mature heterocysts were found to have an intact PS II as judged by photochemical yields, but a strongly reduced PS II-associated antenna as judged by decreased F 0. The possible importance of the functional PS II in heterocysts is discussed. Also, the FKM approach allowed to follow in vivo and evaluate the heterogeneity in photosynthetic performance among individual vegetative cells as well as heterocysts in the course of diazotrophic acclimation. Some cells along the filament (so-called "superbright cells") were observed to display transiently increased fluorescence yield, which apparently proceeded by apoptosis. PMID- 23918300 TI - YKL-40 expression could be a poor prognostic marker in the breast cancer tissue. AB - YKL-40 is a glycoprotein involved in cellular growth, migration, and the inflammatory process. Elevation in serum levels of YKL-40 has been associated with worse prognosis in various cancers, including breast cancer. Given that the clinical significance of YKL-40 expression in breast cancer tissue is unclear, we aimed to determine the prognostic value of YKL-40 expression in breast cancer tissue using immunohistochemistry. We performed tissue microarray (TMA) analysis of 425 breast cancer tissues collected during operation. Immunohistochemical staining was performed to measure expression of YKL-40 and several breast cancer biomarkers, such as aldehyde dehyadrogenase1, TGF-beta, and Gli-1 as well as hormonal receptor and Her-2/neu status. Statistical analysis of the relationship of YKL-40 expression with clinicopathological characteristics was performed for 390 TMA samples. YKL-40 was expressed to varying degrees in 84.9% of breast cancer tissues. YKL-40 expression was correlated with estrogen receptor and progesterone receptor negativity and was positively correlated with TGF-beta and Gli-1 expression. Strong YKL-40 expression was associated with a larger proportion of Her-2/neu-enriched and basal-like tumors. The results of this study demonstrate that YKL-40 expression in breast cancer tissues is associated with hormone receptor negativity and Her-2/neu-enriched molecular subtypes of breast cancer, and therefore could be considered a poor prognostic predictor. PMID- 23918302 TI - Cell surface nucleolin is crucial in the activation of the CXCL12/CXCR4 signaling pathway. AB - Recently, CXCL12-CXCR4 has been focused on therapeutic strategies for papillary thyroid carcinoma (PTC) and other cancers. At the same time, cell surface nucleolin is also over-expressed in PTC and others. Interestingly, a few reports suggest that either CXCR4 or cell surface nucleolin is a co-receptor for HIV-1 entry into CD4+ T cells, which indicates that there is a relationship between CXCR4 and nucleolin. In this study, antibody and siRNA were used to identify effects of cell surface nucleolin and CXCR4 on cell signaling; soft-agar colony formation assay and Transwell assay were used to determine roles of nucleolin and CXCR4 in cell proliferation and migration. Importantly, co-immunoprecipitation was used to demonstrate the relationship between CXCR4 and nucleolin. Results showed CXCR4 and nucleolin were co-expressed in PTC cell line K1, B-CPAP, and TPC 1. Either cell surface nucleolin or CXCR4 was necessary to prompt extracellular signal-regulated kinase phosphorylation. When blocked, CXCR4 or nucleolin can significantly affect TPC-1 proliferation and migration (p < 0.01). Co immunoprecipitation analysis identified that nucleolin can bind and interact with CXCR4 to activate CXCR4 signaling. This study suggests that nucleolin is crucial in the activation of CXCR4 signaling, which affects cell growth, migration, and invasiveness. Further, nucleolin may interact with other receptors. Our study also offers new ideas for cancer therapy. PMID- 23918301 TI - Association between an insertion/deletion polymorphism within 3'UTR of SGSM3 and risk of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, and multiple host genetic factors are believed to contribute to HCC development. The small G protein signaling modulator 3 (SGSM3) has been shown to be associated with small G protein coupled receptor signal transduction pathway, suggesting a potential role in HCC susceptibility. We carried out a case-control study in a Chinese population (502 cases and 513 controls) to determine whether the 4-bp insertion/deletion polymorphism (rs56228771) in 3' untranslated region of SGSM3 could affect HCC susceptibility. Logistic regression analysis showed that compared with the del/del genotype, the ins/del genotype of rs56228771 was associated with a significantly decreased risk of HCC [adjusted odd ratio = 0.55, 95% confidence interval (CI) = 0.42-0.73, P = 1.93 * 10(-5)]. The combined ins/del + ins/ins genotypes contributed to a 45% decreased HCC risk (95% CI = 0.42-0.73, P = 1.03 * 10(-5)). This protective trend was more prominent in the HBsAg-negative subgroup. Furthermore, in vivo experiments showed that mRNA levels of SGSM3 from HCC tumor tissues and adjacent non-HCC tissues were correlated with rs56228771 genotypes. Tissue samples with ins/ins genotype have the highest level of SGSM3, which are 2.85-3.00-fold and 1.46-1.57-fold higher than that with ins/del and del/del genotype, respectively. Similar results were also observed with four common hepatoma cell lines in vitro. In addition, compared with HCC tissues, significantly higher SGSM3 expression was observed in adjacent non-HCC tissues (fold change = 2.48), implying its tumor suppressor roles in HCC. Bioinformatics prediction showed that the insertion allele disrupted a binding site for microRNA (miRNA)-151-5p, which would upregulate SGSM3. Taken together, we provided initial evidence that rs56228771 may contribute to hepatocarcinogenesis, possibly by affecting SGSM3 expression through a miRNA mediated regulation. The replication of our studies in other populations and functional analysis will further strengthen the underlining mechanism. PMID- 23918303 TI - Genetic polymorphisms in XRCC1 gene and susceptibility to glioma in Chinese Han population. AB - Glioma is the most common type of primary brain malignancy in adults. The X-ray repair cross-complementing group 1 (XRCC1) is an important candidate gene for influencing the pathogenesis of glioma. This study aimed to evaluate the potential association between XRCC1 genetic polymorphisms and glioma susceptibility. This case-control study was conducted in Chinese Han populations consisting of 620 glioma cases and 630 cancer-free controls. XRCC1 genetic polymorphisms were detected by the polymerase chain reaction-restriction fragment length polymorphism and verified using DNA sequencing methods. The c.910A>G and c.1779C>G genetic polymorphisms were identified in this study. Our data suggested that the genotypes/alleles of these two genetic polymorphisms were statistically associated with the increased risk of glioma. As for c.910A>G, the risk of glioma for genotype GG was significantly higher than wild genotype AA (odds ratio (OR) = 1.98, 95% confidence interval (CI) 1.33-2.94, P = 0.001). As for c.1779C>G, the genotype GG was statistically associated with the increased risk of glioma compared to wild genotype CC (OR = 1.80, 95% CI 1.17-2.78, P = 0.007). Both of alleles G in c.910A>G and c.1779C>G may contribute to glioma susceptibility (G versus (vs.) A, OR = 1.30, 95% CI 1.09-1.54, P = 0.003; G vs. C, OR = 1.19, 95% CI 1.00-1.42, P = 0.045). Our findings indicate that the c.910A>G and c.1779C>G genetic polymorphisms are associated with the susceptibility to glioma in Chinese Han populations and might be used as molecular markers for evaluating glioma risk. PMID- 23918298 TI - Pathobiology and management of prostate cancer-induced bone pain: recent insights and future treatments. AB - Prostate cancer (PCa) has a high propensity for metastasis to bone. Despite the availability of multiple treatment options for relief of PCa-induced bone pain (PCIBP), satisfactory relief of intractable pain in patients with advanced bony metastases is challenging for the clinicians because currently available analgesic drugs are often limited by poor efficacy and/or dose-limiting side effects. Rodent models developed in the past decade show that the pathobiology of PCIBP comprises elements of inflammatory, neuropathic and ischemic pain arising from ectopic sprouting and sensitization of sensory nerve fibres within PCa invaded bones. In addition, at the cellular level, PCIBP is underpinned by dynamic cross talk between metastatic PCa cells, cellular components of the bone matrix, factors associated with the bone microenvironment as well as peripheral components of the somatosensory system. These insights are aligned with the clinical management of PCIBP involving use of a multimodal treatment approach comprising analgesic agents (opioids, NSAIDs), radiotherapy, radioisotopes, cancer chemotherapy agents and bisphosphonates. However, a major drawback of most rodent models of PCIBP is their short-term applicability due to ethical concerns. Thus, it has been difficult to gain insight into the mal(adaptive) neuroplastic changes occurring at multiple levels of the somatosensory system that likely contribute to intractable pain at the advanced stages of metastatic disease. Specifically, the functional responsiveness of noxious circuitry as well as the neurochemical signature of a broad array of pro-hyperalgesic mediators in the dorsal root ganglia and spinal cord of rodent models of PCIBP is relatively poorly characterized. Hence, recent work from our laboratory to develop a protocol for an optimized rat model of PCIBP will enable these knowledge gaps to be addressed as well as identification of novel targets for drug discovery programs aimed at producing new analgesics for the improved relief of intractable PCIBP. PMID- 23918304 TI - Prognostic significance of sphingosine kinase 2 expression in non-small cell lung cancer. AB - Sphingosine kinase 2 (SphK2) as a conserved lipid kinase has not been thoroughly elucidated in non-small cell lung cancer (NSCLC). The aim of the present study was to evaluate the expression of SphK2 in NSCLC tissues and to determine its correlation with clinicopathologic characteristics and its impact on patient prognosis. We assessed the expression of SphK2 and proliferating cell nuclear antigen (PCNA) (as a proliferative index) by immunohistochemistry in 180 NSCLC patient's formalin-fixed paraffin-embedded tissue blocks. Relationship between the expression of SphK2 and PCNA and various clinicopathological features in these patients was evaluated. We detected that expression of SphK2 was gradually upregulated from normal, metaplasia/dysplasia tissues to NSCLC tissues. At the same time, PCNA expression followed a similar pattern. Statistical analysis showed that expression of SphK2 in NSCLC tissues was strongly associated with PCNA expression, histology grade, live vaccine strain invasion, lymph node status, clinical stage, tumors size, and histology type. Patients with SphK2 overexpression in their tissues had lower overall survival (OS) and disease-free survival (DFS) rates than those with low SphK2 expression. Using uni- and multivariate analysis, we found that SphK2 overexpression was an independent prognostic factor for both OS and DFS. The expression of SphK2 parallels the progression of NSCLC, and SphK2 overexpression may represent a novel and potentially independent biomarker for the prognosis of patients with NSCLC. PMID- 23918305 TI - Notch and TGF-beta/Smad3 pathways are involved in the interaction between cancer cells and cancer-associated fibroblasts in papillary thyroid carcinoma. AB - Accumulating evidence suggests that cancer-associated stromal fibroblasts (CAFs) contribute to tumor growth by actively communicating with cancer cells. Our aim was to identify the signaling pathways that are involved in tumor-stromal cell interactions in human papillary thyroid carcinoma (PTC). Immunohistochemical analyses were performed with 127 archived formalin-fixed and paraffin-embedded thyroid tissue samples that included 70 cases of PTC, 35 cases of nodular goiter (NG), and 22 cases of normal thyroid tissues. The results showed that the expression levels of Notch1, transforming growth factor beta (TGF-beta1), and p Smad3 in PTC cells and alpha-smooth muscle actin (alpha-SMA) in the stroma of PTC were all significantly higher than in NG and normal thyroid tissues. Further analysis showed that in PTC, higher expression levels of Notch1 and TGF-beta1 were closely related with lymph node metastasis (P < 0.05), whereas for alpha-SMA and p-Smad3, the percent expression increased significantly with advanced tumor stages (P < 0.05). Correlation analysis revealed that TGF-beta1 expression increased with increased Notch1 and p-Smad3 levels in PTC cells (P < 0.05). Moreover, a significant correlation was found between higher TGF-beta1 expression in PTC cells and increased alpha-SMA levels in the fibroblasts surrounding the cancer cells (P < 0.05). We identified TGF-beta1 as an important factor from PTC cells that act in a paracrine manner to influence the activation of stromal fibroblasts. These data suggest that the activation of Notch and TGF-beta/Smad3 pathways in cancer cells influence tumor growth. Moreover, cancer cell-derived TGF-beta ligands also affect stromal cells in a paracrine fashion and enhance tumor growth. PMID- 23918306 TI - Clinicopathological significance of SLP-2 overexpression in human gallbladder cancer. AB - Several studies have indicated that overexpression of stomatin-like protein 2 (SLP-2) has been identified in several types of cancer. However, its role and clinical relevance in gallbladder cancer (GBC) is unknown. The purpose of this study was to reveal the prognostic significance of SLP-2 in GBC. The SLP-2 expression was examined at mRNA and protein levels by real-time quantitative polymerase chain reaction (qRT-PCR), and immunohistochemistry in GBC tissues and adjacent noncancerous tissues. Statistical analyses were applied to test the associations between SLP-2 expression, clinicopathologic factors, and prognosis. Immunohistochemistry and qRT-PCR showed that the protein and mRNA expression levels of SLP-2 were both significantly higher in GBC tissues than in adjacent noncancerous tissues. In addition, immunohistochemistry analysis showed that SLP 2 expression was significantly correlated with histological grade (P <0.001), pathologic T stage (P = 0.019), clinical stage (P = 0.001), and lymph node metastasis (P = 0.026). The Kaplan-Meier survival curves indicated that patients with high expression of SLP-2 had shorter overall survival than those with low expression (P <0.001). Meanwhile, the Cox multivariate analysis indicated that high expressions of SLP-2 were an independent prognostic factor for patients with GBC. These data showed that SLP-2 may play an important role in human GBC tumorigenesis, and SLP-2 might serve as a novel prognostic marker in human GBC. PMID- 23918307 TI - Association between the Thr241Met polymorphism of X-ray repair cross complementing group 3 gene and glioma risk: evidence from a meta-analysis based on 4,136 cases and 5,233 controls. AB - Genetic polymorphism of X-ray repair cross-complementing group 3 (XRCC3) Thr241Met has been implicated to alter the risk of glioma, but the results are controversial. Medline, PubMed, Embase, and Cochrane Library databases were independently searched by two investigators up to 13 July 2013. Summary odds ratios (OR) and 95% confidence interval (CI) for Thr241Met polymorphism and prostate cancer were calculated. Statistical analysis was performed with the software program Stata 12.0. A total of 10 independent studies, including 4,136 cases and 5,233 controls, were identified. Our analysis suggested that Thr241Met was not associated with glioma risk in overall population. In the subgroup analysis, we detected no significant association between Thr241Met polymorphism and glioma risk in different descent populations. Subgroup analysis was held by source of controls, significant association was found between this polymorphism and glioma risk for population-based studies (homozygote model: OR = 1.747, 95% CI = 1.123-2.717, Ph = 0.059, I(2) = 59.7%; recessive model, OR = 1.455, 95% CI = 1.179-1.795, Ph = 0.111, I(2) = 50.1%; allele model, OR = 1.258, 95% CI = 1.010 1.566, Ph = 0.011, I(2) = 72.9%). This meta-analysis showed the evidence that XRCC3 Thr241Met polymorphism was associated with a low risk of glioma development. PMID- 23918308 TI - XPC gene polymorphisms contribute to bladder cancer susceptibility: a meta analysis. AB - Numerous studies have investigated the association between three polymorphisms (Lys939Gln, Ala499Val and PAT-/+) of Xeroderma pigmentosum group C (XPC) gene and bladder cancer susceptibility; however, the findings are inconclusive. In order to acquire a more precise estimation of the relationship, we performed a meta analysis based on 10 studies including 3,934 cases and 4,269 controls for Lys939Gln, five studies including 2,113 cases and 2,249 controls for Ala499Val, and seven studies including 2,834 cases and 3,048 controls for PAT-/+ polymorphism. We searched publications from EMBASE, MEDLINE, and Chinese Biomedical. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using either fixed-effects or random-effects model according to the between study heterogeneity. We found that all studied polymorphisms were individually associated with increased overall cancer risks, as shown by ORs (95% CIs) below: the Lys939Gln (Gln/Gln vs. Lys/Lys: OR = 1.39, 95% CI = 1.08-1.79; recessive model: OR = 1.42, 95% CI = 1.11-1.83; and allele comparing: OR = 1.12, 95% CI = 1.003-1.24), the Ala499Val (Val/Val vs. Ala/Ala: OR = 1.82, 95% CI = 1.19-2.79; recessive model: OR = 1.70, 95% CI = 1.18-2.46; and allele comparing: OR = 1.23, 95% CI = 1.01-1.50), and the PAT-/+ (+/+ vs. -/-: OR = 1.36, 95% CI = 1.03-1.79 and recessive model: OR = 1.34, 95% CI = 1.06-1.70). Furthermore, stratification analyses demonstrated an increased risk for Asian populations as to the Lys939Gln and PAT-/+ whereas for Caucasian populations as to the Ala499Val polymorphism in the homozygous and recessive models. Despite some limitations, this meta-analysis suggests that XPC polymorphisms are associated with bladder cancer risk, but this association warrants further validation in well-designed studies with large sample sizes. PMID- 23918309 TI - Association between cytochrome P450 1A1 MspI polymorphism and endometrial cancer risk: a meta-analysis. AB - Many studies proposed that cytochrome P450 1A1 (CYP1A1) MspI polymorphism may be associated with endometrial cancer risk, but the findings from previous studies reported conflicting results. A meta-analysis of all relevant studies was performed to get a comprehensive assessment of the association between CYP1A1 MspI polymorphism and endometrial cancer risk. Eligible studies were searched in PubMed and China National Knowledge Infrastructure databases. The pooled odds ratios (ORs) with the corresponding 95 % confidence intervals (95 % CIs) were calculated to evaluate the association. Twelve studies with a total of 2,111 cases and 2,894 controls were finally included into the meta-analysis. Overall, meta-analysis of a total of 12 studies showed that there was no obvious association between CYP1A1 MspI polymorphism and endometrial cancer risk (ORC vs. T = 0.97, 95 % CI 0.77-1.22, P OR = 0.808; ORCC vs. TT = 1.00, 95 % CI 0.57-1.76, P OR = 0.994; ORCC vs. TT/TC = 0.88, 95 % CI 0.65-1.20, P OR = 0.425; ORCC/TC vs. TT = 0.98, 95 % CI 0.74-1.29, P OR = 0.861). Subgroup analyses by ethnicity further showed that there was no obvious association between CYP1A1 MspI polymorphism and endometrial cancer risk in both Caucasians and Asians. There was no obvious risk of publication bias. Therefore, the meta-analysis suggests that CYP1A1 MspI polymorphism is not associated with endometrial cancer risk. PMID- 23918310 TI - Thrombomodulin mediates the progression of epithelial ovarian cancer cells. AB - Thrombomodulin (TM), a natural anticoagulation factor, maintains circulation homeostasis in endothelial cells. TM has additional roles in modulating inflammation, thrombosis, and carcinogenesis. However, there is little information on the role of TM in the progression and metastasis of ovarian cancer. RNA silencing and cDNA expression vectors were used to manipulate target gene expression in ovarian cancer cells. Cell growth and migration were evaluated by an MTT assay, a wound-healing migration assay, a transwell migration assay, and a biosensor system. In this study, we found that TM silencing may enhance the growth rate of cells. The migratory ability of ovarian cancer cells was enhanced dramatically after TM silencing. TM overexpression in ovarian cells suppressed the proliferation and migration capability. Furthermore, we found that skov-3 cells treated with TM shRNA expressed high levels of fibronectin and vimentin and that the expression of these markers correlated positively with their migratory ability. Our results demonstrate that TM expression may regulate cell growth and migration in ovarian cancer cells. This finding suggests that TM may be a novel prognostic and therapeutic target for ovarian cancer. PMID- 23918311 TI - Mothers under stress? Hatching sex ratio in relation to maternal baseline corticosterone in the common tern (Sterna hirundo). AB - Sex ratio of progeny should be balanced if costs and benefits of rearing sons and daughters are equal. However, shifts in sex ratio have been demonstrated across bird species and it was suggested that females are able to adjust the primary sex ratio. One possible mechanism is the glucocorticoid corticosterone which rises under stressful conditions and can be deposited into egg yolk by mothers. We analysed primary sex ratio of common terns Sterna hirundo from 2006 to 2008 and related it to maternal baseline corticosterone level, laying date and year. Therefore, we took 101 blood samples of 71 breeding females via blood sucking bugs, a method with negligible stress for the birds. Sex ratio did not differ from parity in any of the analysed years, which were characterized by poor food availability and breeding success. Only within 1 year there was a tendency for more females in the last hatched chick. Neither corticosterone level nor laying date or year showed an influence on hatching sex ratio. The negative result concerning primary sex ratio and maternal baseline corticosterone level might suggest conditions to be good enough for mothers to prevent them from depositing high levels of corticosterone into eggs. PMID- 23918312 TI - Blue colour preference in honeybees distracts visual attention for learning closed shapes. AB - Spatial vision is an important cue for how honeybees (Apis mellifera) find flowers, and previous work has suggested that spatial learning in free-flying bees is exclusively mediated by achromatic input to the green photoreceptor channel. However, some data suggested that bees may be able to use alternative channels for shape processing, and recent work shows conditioning type and training length can significantly influence bee learning and cue use. We thus tested the honeybees' ability to discriminate between two closed shapes considering either absolute or differential conditioning, and using eight stimuli differing in their spectral characteristics. Consistent with previous work, green contrast enabled reliable shape learning for both types of conditioning, but surprisingly, we found that bees trained with appetitive-aversive differential conditioning could additionally use colour and/or UV contrast to enable shape discrimination. Interestingly, we found that a high blue contrast initially interferes with bee shape learning, probably due to the bees innate preference for blue colours, but with increasing experience bees can learn a variety of spectral and/or colour cues to facilitate spatial learning. Thus, the relationship between bee pollinators and the spatial and spectral cues that they use to find rewarding flowers appears to be a more rich visual environment than previously thought. PMID- 23918313 TI - Development and evaluation of paclitaxel nanoparticles using a quality-by-design approach. AB - The aims of this study were to develop and characterize paclitaxel nanoparticles, to identify and control critical sources of variability in the process, and to understand the impact of formulation and process parameters on the critical quality attributes (CQAs) using a quality-by-design (QbD) approach. For this, a risk assessment study was performed with various formulation and process parameters to determine their impact on CQAs of nanoparticles, which were determined to be average particle size, zeta potential, and encapsulation efficiency. Potential risk factors were identified using an Ishikawa diagram and screened by Plackett-Burman design and finally nanoparticles were optimized using Box-Behnken design. The optimized formulation was further characterized by Fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy, atomic force microscopy, and gas chromatography. It was observed that paclitaxel transformed from crystalline state to amorphous state while totally encapsulating into the nanoparticles. The nanoparticles were spherical, smooth, and homogenous with no dichloromethane residue. In vitro cytotoxicity test showed that the developed nanoparticles are more efficient than free paclitaxel in terms of antitumor activity (more than 25%). In conclusion, this study demonstrated that understanding formulation and process parameters with the philosophy of QbD is useful for the optimization of complex drug delivery systems. PMID- 23918314 TI - Mannitol for acute traumatic brain injury. AB - BACKGROUND: Mannitol is sometimes effective in reversing acute brain swelling, but its effectiveness in the ongoing management of severe head injury remains unclear. There is evidence that, in prolonged dosage, mannitol may pass from the blood into the brain, where it might cause increased intracranial pressure. OBJECTIVES: To assess the effects of different mannitol therapy regimens, of mannitol compared to other intracranial pressure (ICP) lowering agents, and to quantify the effectiveness of mannitol administration given at other stages following acute traumatic brain injury. SEARCH METHODS: We searched the Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library), MEDLINE (OvidSP), EMBASE (OvidSP), ISI Web of Science (SCI-EXPANDED & CPCI-S) and PubMed. We checked reference lists of trials and review articles, and contacted authors of trials. The search was updated on the 20th April 2009. SELECTION CRITERIA: Randomised controlled trials of mannitol, in patients with acute traumatic brain injury of any severity. The comparison group could be placebo-controlled, no drug, different dose, or different drug. We excluded cross-over trials, and trials where the intervention was started more than eight weeks after injury. DATA COLLECTION AND ANALYSIS: We independently rated quality of allocation concealment and extracted the data. Relative risks (RR) and 95% confidence intervals (CI) were calculated for each trial on an intention to treat basis. MAIN RESULTS: We identified four eligible randomised controlled trials. One trial compared ICP-directed therapy to 'standard care' (RR for death = 0.83; 95% CI 0.47 to 1.46). One trial compared mannitol to pentobarbital (RR for death = 0.85; 95% CI 0.52 to 1.38). One trial compared mannitol to hypertonic saline (RR for death = 1.25; 95% CI 0.47 to 3.33). One trial tested the effectiveness of pre hospital administration of mannitol against placebo (RR for death = 1.75; 95% CI 0.48 to 6.38). AUTHORS' CONCLUSIONS: Mannitol therapy for raised ICP may have a beneficial effect on mortality when compared to pentobarbital treatment, but may have a detrimental effect on mortality when compared to hypertonic saline. ICP directed treatment shows a small beneficial effect compared to treatment directed by neurological signs and physiological indicators. There are insufficient data on the effectiveness of pre-hospital administration of mannitol. PMID- 23918315 TI - Implication of the chemokine CCL2 in trigeminal nociception and traumatic neuropathic orofacial pain. AB - BACKGROUND: Chemokine (C-C motif) ligand 2 (CCL2) participates in different mechanisms contributing to the spinal cord inflammation and pain development after sciatic nerve injury. Recent data also support its role in orofacial thermal hypersensitivity, although its implication in different phases of trigeminal pain emergence is unclear. We assessed the importance of CCL2 signalling in biochemical and behavioural alterations during the early and late stages following chronic constriction injury of infraorbital nerve (ION-CCI), a model of peripheral traumatic trigeminal pain. METHODS: After evaluating the consequences of CCL2 intracisternal injection in naive rats, we determined the expression changes for CCL2, inflammatory and glia activation markers in the somatosensory trigeminal complex (STC) and trigeminal ganglia (TG) after ION-CCI. The role of CCL2 signalling was assessed using pre-emptive or 'curative' intracisternal treatment with specific CCL2 receptor antagonist - INCB3344. RESULTS: Exogenous CCL2 evoked spontaneous behaviour reminiscent of orofacial pain and marked mechanical hypersensitivity, associated with increased expression of proinflammatory cytokines and glial markers in STC and TG. CCL2-evoked changes were prevented by the co-administration of INCB3344. Two weeks after ION-CCI, mRNA for CCL2, glial and inflammatory markers were up-regulated, and CCL2 immunoreactivity accumulated in central and ganglionic tissues. At this time, repeated intracisternal administration of INCB3344 did not attenuate the ION-CCI associated behavioural nor biochemical changes. By contrast, pre-emptive INCB3344 treatment delayed the emergence of trigeminal mechanical allodynia and associated biochemical alterations. CONCLUSIONS: Our data suggest that CCL2 is involved principally in the early events accompanying the ION lesion rather than in long term alterations and the maintenance of trigeminal mechanical hypersensitivity. PMID- 23918316 TI - Structure-activity relationship studies of pyrrolone antimalarial agents. AB - Previously reported pyrrolones, such as TDR32570, exhibited potential as antimalarial agents; however, while these compounds have potent antimalarial activity, they suffer from poor aqueous solubility and metabolic instability. Here, further structure-activity relationship studies are described that aimed to solve the developability issues associated with this series of compounds. In particular, further modifications to the lead pyrrolone, involving replacement of a phenyl ring with a piperidine and removal of a potentially metabolically labile ester by a scaffold hop, gave rise to derivatives with improved in vitro antimalarial activities against Plasmodium falciparum K1, a chloroquine- and pyrimethamine-resistant parasite strain, with some derivatives exhibiting good selectivity for parasite over mammalian (L6) cells. Three representative compounds were selected for evaluation in a rodent model of malaria infection, and the best compound showed improved ability to decrease parasitaemia and a slight increase in survival. PMID- 23918317 TI - A case of spontaneous chylous pericardial effusion in Poland syndrome. AB - Chylous pericardial effusion is an uncommon entity that is most commonly associated with post-cardiac surgery, in particular aortic valve and minimally invasive cardiac surgery. Post-radiation therapy, infection, mediastinal neoplasm, lymphoma and a small group of idiopathic, spontaneous chylous pericardial effusion have also been reported as the causes. Here, we report a rare case of pericardial effusion secondary to chylous fistula in a 63-year-old man with Poland syndrome. The case highlights an unusual thoracic duct anomaly as a cause of our reported chylous pericardial effusion. PMID- 23918318 TI - Midterm outcomes of sutureless technique for postoperative pulmonary venous stenosis. AB - BACKGROUND: The efficacy of a sutureless technique for postoperative pulmonary venous stenosis (PVS) following repair of total anomalous pulmonary venous connection (TAPVC) has been reported, though detailed clinical advantages remain unclear. We retrospectively reviewed our surgical experience, and compared outcomes between conventional procedures and a sutureless technique. METHODS: For relief of postoperative PVS after TAPVC repair, five patients underwent a conventional procedure, such as orifice cutback or resection of a proliferated intima, from 1999 to 2004 (Conventional group, 4 males, median 93 days old, 3.6 kg), then seven underwent a sutureless technique (Sutureless group, 5 males, 119 days old, 3.4 kg) from 2005 to 2011. Patients with a functional single ventricle were excluded. There were no significant differences regarding patient characteristics. Follow-up examinations were completed in all patients. RESULTS: The rate for cumulative survival at 5 years was 60 % in the Conventional group and 71.4 % in the Sutureless group. Re-stenosis after relief of PVS occurred in 100 % (10/10) of patients in the Conventional group and 31.6 % (6/19) of patients in the Sutureless group (p = 0.0088). For bilateral venous stenosis patients, the survival rate was 66.7 % (4/6) in the Sutureless group and 0 % (0/2) in the Conventional group (p = 0.10). Out of three patients who developed whole 4-vein stenosis, only one in the Sutureless group survived. CONCLUSIONS: Although overall survival rate was similar in both groups, the Sutureless technique for postoperative PVS following TAPVC repair successfully rescued more pulmonary veins without re-stenosis than conventional procedures. Further follow-up may demonstrate therapeutic advantages. PMID- 23918320 TI - Fibrodysplasia ossificans progressiva: three Indian patients with mutation in the ACVR1 gene. AB - Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by ectopic bone formation involving the connective tissues leading to severe skeletal manifestations. The genetic defect in this disorder has not been characterized in Indian patients till date. The authors report three cases of FOP along with the molecular defects identified in them. Exon 4 of the ACVR1 gene was amplified and analysed by sequencing. All three cases revealed common heterozygous mutation i.e., c.617(G>A). Identification of this mutation would lead to decrease in misdiagnosis and subsequent iatrogenic harm caused to these children by unnecessary surgical procedures. Also, mutation detection would provide an opportunity for prenatal diagnosis. PMID- 23918321 TI - Bardet-Biedl syndrome with urogenital sinus presenting with acute renal failure in a neonate. AB - This is a case report of Bardet-Biedl syndrome with a urogenital sinus and an ectopic right ureter presenting with acute renal failure in the neonatal period in a female baby. Acute renal failure in these patients is commonly known to occur around 5-7 y of age and neonatal presentation is extremely rare. PMID- 23918319 TI - Retinal regeneration in adult zebrafish requires regulation of TGFbeta signaling. AB - Muller glia are the resident radial glia in the vertebrate retina. The response of mammalian Muller glia to retinal damage often results in a glial scar and no functional replacement of lost neurons. Adult zebrafish Muller glia, in contrast, are considered tissue-specific stem cells that can self-renew and generate neurogenic progenitors to regenerate all retinal neurons after damage. Here, we demonstrate that regulation of TGFbeta signaling by the corepressors Tgif1 and Six3b is critical for the proliferative response to photoreceptor destruction in the adult zebrafish retina. When function of these corepressors is disrupted, Muller glia and their progeny proliferate less, leading to a significant reduction in photoreceptor regeneration. Tgif1 expression and regulation of TGFbeta signaling are implicated in the function of several types of stem cells, but this is the first demonstration that this regulatory network is necessary for regeneration of neurons. PMID- 23918322 TI - Knowledge, attitude and performance of IMNCI trained nursing personnel: an evaluative survey. AB - OBJECTIVE: A cross-sectional survey of nursing personnel's knowledge, attitude and their consultations with sick children under 5 y of age, at specified levels of health care in terms of IMNCI guidelines, was conducted at six community health centers (CHC) of a selected district of Haryana, India. METHODS: Total enumeration technique was used to assess knowledge and attitude of 183 IMNCI trained nursing personnel towards the training programme using a pretested structured questionnaire. Total 236 consultations of sick children presenting to the facilities made by conveniently selected 65 nursing personnel were also observed. RESULTS: Majority of nursing personnel had good knowledge 94 (51.4 %) and excellent attitude 98 (53.55 %) scores related to IMNCI programme. Nursing personnel performed best in assessing sick children (2 mo-5 y) in areas of fever (89.7 %, CI 96.9-79.7), cough (89.2 %, CI 96.7-81.6), and identifying treatment (89.1 %, CI 96.7-83.7). Their performance in identifying classifications related to diarrhea (74.1 %, CI 84.7-62.8), malnutrition (67.2 %, CI 78.6-59.0), anemia (77.3 %, CI 87.5-70.0), immunization (78.9 % CI 88.8-71.8) and feeding problem (75.9 %, CI 86.3-66.9) was relatively less. Similarly, in assessing young infants (0-2 mo) performance of nursing personnel was best in the areas of possible serious bacterial infection (PSBI) (88.1 %, CI 99.1-87.3), and identifying the treatment (86.7 %, CI 94.9-80.2) and low in dehydration (70.8 %, CI81.8-52.6), feeding problem (50.5 %, CI 62.7-40.9), feeding assessment (50.6 %, CI 62.8 39.8), and immunization (70 %, CI 81.1-61.2). CONCLUSIONS: IMNCI trained nursing personnel have good knowledge and attitude towards child care and their performance can be improved further with drills, exercises and supervised practices. PMID- 23918323 TI - Corrosive substance ingestion in children. AB - OBJECTIVES: To evaluate children who ingested corrosive substances, in terms of demographic features, nature of ingested substances, clinical findings, management and complications. METHODS: A total of 1709 cases aged between 0 and 16 y who ingested corrosive substance were analyzed retrospectively by evaluating the medical records of the patients. RESULTS: The mean age of the cases was 35.23 +/- 30.65 mo and male:female ratio was 1.45. Forty one percent of corrosive substances causing intoxication contained NaOH. Thirty percent of the families consisted of 5 or more members. Fourteen percent of the mothers were illiterate. Stricture formation was observed in 29 (1.69 %) of the cases during follow-up. In 79.31 % of those cases alkaline substance ingestion was responsible for stricture development. It was found that stricture formation occurred more frequently among cases who were older than 5 y of age and this finding was statistically significant (p = 0.001). CONCLUSIONS: The cases older than 5 y of age with the diagnosis of grade 2b esophagitis must be followed up closely for the stricture formation. In order to protect children from corrosive ingestion, importance must be given to preventive measures such as education of families, keeping and storing these agents out of the reach of children and providing safety caps for these products. PMID- 23918324 TI - Verbal memory functioning in adolescents and young adults with Costello syndrome: evidence for relative preservation in recognition memory. AB - Costello syndrome (CS) is a rare genetic disorder caused by germline mutations in the HRAS proto-oncogene which belongs to the family of syndromes called rasopathies. HRAS plays a key role in synaptic long-term potentiation (LTP) and memory formation. Prior research has found impaired recall memory in CS despite enhancement in LTP that would predict memory preservation. Based on findings in other rasopathies, we hypothesized that the memory deficit in CS would be specific to recall, and that recognition memory would show relative preservation. Memory was tested using word-list learning and story memory tasks with both recall and recognition trials, a design that allowed us to examine these processes separately. Participants were 11 adolescents and young adults with molecularly confirmed CS, all of whom fell in the mild to moderate range of intellectual disability. Results indicated a clear dissociation between verbal recall, which was impaired (M = 69 +/- 14), and recognition memory, which was relatively intact (M = 86 +/- 14). Story recognition was highly correlated with listening comprehension (r = 0.986), which also fell in the low-average range (M = 80 +/- 12.9). Performance on other measures of linguistic ability and academic skills was impaired. The findings suggest relatively preserved recognition memory that also provides some support for verbal comprehension. This is the first report of relatively normal performance in a cognitive domain in CS. Further research is needed to better understand the mechanisms by which altered RAS-MAPK signaling affects neuronal plasticity and memory processes in the brain. PMID- 23918325 TI - Preparation of 2 nm gold nanoparticles for in vitro and in vivo applications. AB - Gold nanoparticles have been a versatile tool in recent years for the exploration of biological systems. However, challenges with purification and adequate surface coverage limit the biocompatibility of gold nanoparticles. Here, we describe a detailed procedure for the synthesis, purification, and functionalization of biologically compatible gold nanoparticles for in vitro and in vivo studies. PMID- 23918326 TI - DNA conjugation to nanoparticles. AB - Nanoparticle-DNA (NP-DNA) conjugates have been highlighted due to their versatility in diverse science and engineering fields. The protocol of DNA conjugation to gold nanoparticles (AuNPs), which are among the most popular NPs in bio-applications, is thus described here. This protocol also includes ligand exchange of AuNP to make AuNPs suitable for conjugation process and a fluorescence technique to evaluate the average number of DNA strands attached to single AuNP. PMID- 23918327 TI - Conjugation of nanoparticles to proteins. AB - Nanoparticle-protein conjugates hold great promise in biomedical applications. Diverse strategies have been developed to link nanoparticles to proteins. This chapter describes a method to assemble and purify nanoparticle-protein conjugates. First, stable and biocompatible 1.5 nm gold nanoparticles are synthesized. Conjugation of the nanoparticle to the protein is then achieved via two different approaches that do not require heavy chemical modifications or cloning: cysteine-gold covalent bonding, or electrostatic attachment of the nanoparticle to charged groups of the protein. Co-functionalization of the nanoparticle with PEG thiols is recommended to help protein folding. Finally, structural characterization is performed with circular dichroism, as this spectroscopy technique has proven to be effective at examining protein secondary structure in nanoparticle-protein conjugates. PMID- 23918328 TI - Water-solubilization and functionalization of semiconductor quantum dots. AB - Semiconductor quantum dots (QDs) are highly fluorescent nanocrystals that have abundant potential for uses in biological imaging and sensing. However, the best materials are synthesized in hydrophobic surfactants that prevent direct aqueous solubilization. While several methods have been developed to impart water solubility, an aqueous QD dispersion has no inherent useful purpose and must be functionalized further. Due to the colloidal nature of QD dispersions, traditional methods of chemical conjugation in water either have low yields or cause irreversible precipitation of the sample. Here, we describe several methods to water-solubilize QDs and further functionalize the materials with chemical and/or biological vectors. PMID- 23918329 TI - Synthesizing and modifying peptides for chemoselective ligation and assembly into quantum dot-peptide bioconjugates. AB - Quantum dots (QDs) are well-established as photoluminescent nanoparticle probes for in vitro or in vivo imaging, sensing, and even drug delivery. A critical component of this research is the need to reliably conjugate peptides, proteins, oligonucleotides, and other biomolecules to QDs in a controlled manner. In this chapter, we describe the conjugation of peptides to CdSe/ZnS QDs using a combination of polyhistidine self-assembly and hydrazone ligation. The former is a high-affinity interaction with the inorganic surface of the QD; the latter is a highly efficient and chemoselective reaction that occurs between 4-formylbenzoyl (4FB) and 2-hydrazinonicotinoyl (HYNIC) moieties. Two methods are presented for modifying peptides with these functional groups: (1) solid phase peptide synthesis; and (2) solution phase modification of pre-synthesized, commercial peptides. We further describe the aniline-catalyzed ligation of 4FB- and HYNIC modified peptides, in the presence of a fluorescent label on the latter peptide, as well as subsequent assembly of the ligated peptide to water-soluble QDs. Many technical elements of these protocols can be extended to labeling peptides with other small molecule reagents. Overall, the bioconjugate chemistry is robust, selective, and modular, thereby potentiating the controlled conjugation of QDs with a diverse array of biomolecules for various applications. PMID- 23918330 TI - Reliable methods for silica coating of Au nanoparticles. AB - The inherent properties of silica, such as optical transparency, high biocompatibility, chemical and colloidal stability, controllable porosity, and easy surface modification, provide silica materials with a tremendous potential in biomedicine. Therefore, the coating of Au nanoparticles with silica largely contributes to enhance the important applications of metal nanoparticles in biomedicine. We describe in this chapter a number of reliable strategies that have been reported for silica coating of different types of Au nanoparticles. All descriptions are based on tested protocols and are expected to provide a reference for scientists with an interest in this field. PMID- 23918332 TI - Functionalization protocols of silicon micro/nano-mechanical biosensors. AB - Functionalization is a key element in biodetection technologies such as micro/nano-mechanical sensors. Since assay sensitivity and stability drastically depends on a proper bioreceptor immobilization, the sensing surface must be first chemically modified with uniform, well-packed, and robust layers. Here, we describe three functionalization protocols that we developed for the surface modification with amino, aldehyde, and carboxyl groups of micro/nano-mechanical biosensors. PMID- 23918331 TI - Surface modifications by polymers for biomolecule conjugation. AB - Polymeric coatings, usually referred as tridimensional chemistries, provide homogenous surface derivatization methods presenting a high reactive group concentration and resulting in an increased binding capacity of targets. Furthermore, they act as linkers distributing the bound probe also in the axial position, thus causing a faster reaction with the target involved in biomolecular recognition and can be engineered to custom tailor their properties for specific applications. Most approaches which aim at attaching polymers to a surface use a system where the polymer carries an "anchor" group either as an end group or in a side chain. This anchor group can reacts with appropriate sites at the substrate surface, thus yielding surface-attached monolayers of polymer molecules (termed "grafting to"). Another technique is to carry out a polymerization reaction in the presence of a substrate onto which monomers had been attached leading to the so called "grafting from" approach. In this chapter, protocols to functionalize glass and silicon surfaces by "grafting to" as well as by "grafting-from" approach are shown using copolymers made of N,N-dimethylacrylamide (DMA) or Glycidyl methacrylate (GMA) as the polymer backbone, N-acryloyloxysuccinimide (NAS) as reactive group, and 3-(trimethoxysilyl)propyl methacrylate (MAPS) or 3 mercaptopropyl trimethoxy silane (MPS) as anchoring groups. PMID- 23918333 TI - Stability and aggregation assays of nanoparticles in biological media. AB - Colloidal stability of nanoparticles in biological media is crucial to preserve their utility as aggregation often leads to undesirable biological response. A quantitative measurement of nanoparticles aggregation in solution would provide a valuable assessment of colloidal stability of bio-nano interfaces after surface functionalization. Here, we develop a quantitative technique based on optical absorption to assay the colloidal stability of plasmonic nanoparticles functionalized with different amphiphilic surface ligands in biologically relevant media. PMID- 23918334 TI - Electrochemical measurements of DNA melting on surfaces. AB - Thermal denaturation, or melting, measurements are a classic technique for analysis of thermodynamics of nucleic base driven associations in solution, as well as of interactions between nucleic acids and small molecule ligands such as drugs or carcinogens. Performed on surface-immobilized DNA films, this well established technique can help understand how energetics of surface hybridization relate to those in solution, as well as provide high-throughput platforms for screening of small molecule ligands. Here we describe methods for measuring DNA melting transitions at solid/liquid interfaces with focus on the role of immobilization chemistry, including a common "immobilization-through-self assembly" approach that is effective at moderate temperatures, and a thermo stable approach based on polymer-supported DNA monolayers that can be used at elevated temperatures. We also discuss conditions necessary for reversible measurements, as signified by superimposition of the association (cooling) and dissociation (heating) transitions of immobilized DNA strands. PMID- 23918335 TI - Formation and characterization of the nanoparticle-protein corona. AB - Over the last decade the existence of "the corona," a natural interface between nanomaterials and living matter in biological milieu, evolved from a vague concept into broadly recognized fact. This robust shell arises (to some extent) on the surface of all nanoparticles (NPs), even the ones designed to avoid its formation upon contact with biological fluids and confers a biological identity to the nanomaterials such that they can engage with cellular machinery. The NP corona consists of those proteins (and other biomolecules such as lipids and sugars) residing on the NP surface for a sufficient timescale to influence the NP's properties and interactions with living systems. This chapter aims to provide simple protocols, as well as notes on potential pitfalls, to help researchers to perform basic experiments in this field as the basis for a more mechanistic approach to study and understand NP-protein corona complexes. This work has been supported by INSPIRE (Integrated NanoScience Platform for Ireland) funded by the Irish Government's Programme for Research in Third Level Institutions, Cycle 4, National Development Plan 2007-2013, and 3MICRON (NMP-2009 LA-245572), NAMDIATREAM (NMP4-LA-2010-246479) and QualityNano (INFRA-2010-262163) funded by the European Commission 7th Framework Programme. PMID- 23918336 TI - Electrophoretic implementation of the solution-depletion method for measuring protein adsorption, adsorption kinetics, and adsorption competition among multiple proteins in solution. AB - The venerable solution-depletion method is perhaps the most unambiguous method of measuring solute adsorption from solution to solid particles, requiring neither complex instrumentation nor associated interpretive theory. We describe herein an SDS-gel electrophoresis implementation of the solution--depletion method for measuring protein adsorption and protein-adsorption kinetics. Silanized-glass particles with different surface chemistry/energy and hydrophobic sepharose-based chromatographic media are used as example adsorbents. Electrophoretic separation enables quantification of adsorption competition among multiple proteins in solution for the same adsorbent surface, demonstrated herein by adsorption- competition kinetics from binary solution. PMID- 23918337 TI - Hyperspectral microscopy for characterization of gold nanoparticles in biological media and cells for toxicity assessment. AB - Nanoparticles (NPs) are being implemented in a wide range of applications, and it is critical to proactively investigate their toxicity. Due to the extensive range of NPs being produced, in vitro studies are a valuable approach for toxicity screening. Key information required to support in vitro toxicity assessments include NP stability in biologically relevant media and fate once exposed to cells. Hyperspectral microscopy is a sensitive, real-time technique that combines the use of microscopy and spectroscopy for the measurement of the reflectance spectrum at individual pixels in a micrograph. This method has been used extensively for molecular imaging with plasmonic NPs as contrast agents (Aaron et al., Opt Express 16:2153-2167, 2008; Kumar et al., Nano Lett 7:1338-1343, 2007; Wax and Sokolov, Laser Photon Rev 3:146-158, 2009; Curry et al., Opt Express 14:6535-6542, 2006; Curry et al., J Biomed Opt 13:014022, 2008; Cognet et al., Proc Natl Acad Sci U S A 100:11350-11355, 2003; Sokolov et al., Cancer Res 63:1999-2004, 2003; Sonnichsen et al., Nat Biotechnol 23:741-745, 2005; Nusz et al., Anal Chem 80:984-989, 2008) and/or sensors (Nusz et al., Anal Chem 80:984 989, 2008; Ungureanu et al., Sens Actuators B 150:529-536, 2010; McFarland and Van Duyne, Nano Lett 3:1057-1062, 2003; Galush et al., Nano Lett 9:2077-2082, 2009; El-Sayed et al., Nano Lett 5:829-834, 2005). Here we describe an approach for using hyperspectral microscopy to characterize the agglomeration and stability of plasmonic NPs in biological media and their interactions with cells. PMID- 23918338 TI - Immunocytochemistry, electron tomography, and energy dispersive X-ray spectroscopy (EDXS) on cryosections of human cancer cells doped with stimuli responsive polymeric nanogels loaded with iron oxide nanoparticles. AB - The cryosectioning technique is an alternative method for preparing biological material for Transmission Electron Microscopy (TEM). We have applied this technique to study the mechanism of cell internalization of stimuli-responsive polymeric nanogels exploited as cargo nanovectors. With respect to conventional TEM processing, cryosectioning technique better preserves the morphology of solvent-sensitive nanogels and enhances the visibility of membrane-bounded organelles inside the cell cytoplasm. In this chapter we describe the protocols we have established to perform Electron Microscopy (EM)-immunocytochemistry, Electron Tomography (ET), and Energy Dispersive X-ray Spectroscopy (EDXS) chemical analysis in Scanning TEM (STEM) on cryosections of HeLa cells treated with pH-responsive nanogels hosting short interference RNA (siRNAs) and iron oxide nanoparticles (IONPs). PMID- 23918339 TI - Zwitterion siloxane to passivate silica against nonspecific protein adsorption. AB - Passivating surfaces against protein adsorption is important for many biotechnological applications. Current approaches have been exploiting the use of zwitterions instead of poly(ethylene glycol) (PEG). Commonly used zwitterions are polymeric and are grafted onto surfaces using specialized polymerization techniques. Here we describe the synthesis of a monomeric zwitterion siloxane and its covalent attachment to silica surfaces (nanoparticle and planar) in a one-pot one-step aqueous method requiring no catalyst. PMID- 23918340 TI - Preparation and characterization of DNA block copolymer assemblies loaded with nanoparticles. AB - We have recently developed a universal procedure to functionalize inorganic nanoparticles with a dense layer of DNA through the self-assembly of DNA block copolymers and nanoparticles. This functionalization strategy allows one to combine the useful physical properties of inorganic nanoparticle with the enhanced DNA binding properties that originate from the high surface DNA density. In particular, the hybrid nanostructures exhibit orders of magnitude higher binding constants than regular DNA strands. This chapter presents a detailed protocol for the preparation and characterization of DNA block copolymer assemblies loaded with nanoparticles. PMID- 23918341 TI - Polyaspartic acid coated iron oxide nanoprobes for PET/MRI imaging. AB - Iron oxide nanoparticles, due to their exceptional magnetic property, biocompatibility, and biodegradability, have long been studied as contrast agents for magnetic resonance imaging (Xie et al., Curr Med Chem 16(10):1278-1294, 2009; Xie et al., Adv Drug deliv Rev 62(11):1064-1079, 2010). While previous applications mostly target reticuloendothelial system (RES) organs such as liver and lymph nodes, recent efforts have been made to impart targeting peptides or antibodies onto particle surface to enable site-specific targeting after systemic administration (Xie et al., Adv Drug Deliv Rev 62(11):1064-1079, 2010; Cai and Chen, Small 3(11):1840-1854, 2007; Corot et al., Adv Drug Deliv Rev 58 (14):1471 1504, 2006; Xie et al., Acc Chem Res 44(10):883-892). Moreover, other imaging functionalities can be loaded onto nanoparticles to achieve multimodality imaging probes (Cai and Chen, Small 3(11):1840-1854, 2007; Lee et al., J Nucl Med Soc Nucl Med 49(8):1371-1379, 2008). In this protocol, we describe the procedure of constructing an iron oxide nanoparticle (IONP)-based probe with high affinity towards integrin alphavbeta3 for positron emission tomography (PET) and magnetic resonance imaging (MRI) dual modality imaging. The related characterizations and validation experiments, including particle concentration determination, Prussian blue staining, animal model preparation, and in vivo PET/MRI imaging will also be discussed. PMID- 23918342 TI - Ligand synthesis and passivation for silver and large gold nanoparticles for single-particle-based sensing and spectroscopy. AB - Silver and large gold nanoparticles are more efficient scatterers than smaller particles, which can be advantageous for a variety of single-particle-based sensing and spectroscopic applications. The increased susceptibility to surface oxidation and the larger surface area of these particles, however, present challenges to colloid stability and controllable bio-conjugation strategies. In this chapter, ligand syntheses and particle passivation procedures for yielding stable and bio-conjugatable colloids of silver and large gold nanoparticles are described. PMID- 23918343 TI - Noncovalent intracellular drug delivery of hydrophobic drugs on Au NPs. AB - The successful delivery of hydrophobic drugs to cellular targets continues to present challenges to the pharmaceutical industry. The advances made by nanotechnology have generated new avenues for selectively loading, delivering, and targeting these drugs to their biological targets without compromising efficacy. Here, we describe how gold nanoparticles (Au NPs) functionalized with polyethylene glycol (PEG) can be evaluated for the delivery of hydrophobic drugs in aqueous systems. Specifically, we describe Au NP synthesis, ligand exchange, and delivery evaluation at-the-bench for screening of potential drug candidates. PMID- 23918344 TI - Modification of carbon nanotubes for gene delivery vectors. AB - The surface modification of carbon nanotubes (CNTs) can be tailored to allow the formation of a complex between these potential carriers with DNA. In this chapter, protocols developed in our lab to prepare transfection vectors through the modification of MWCNTs are described. The protocol includes sections focused on the reduction of CNTs length, protocols to increase the dispersability of CNTs and finally, protocols for surface modification to attach through electrostatic interactions DNA to the CNTs. PMID- 23918346 TI - Stabilizing gold nanoparticle bioconjugates in physiological conditions by PEGylation. AB - Stability of gold nanoparticles (AuNPs) is often compromised in physiological conditions. The loss of colloidal stability might lead to undesired biological responses for drug delivery nanosystems. Here a methodology to confer additional stability to the AuNPs by the addition of PEG is presented. Also, protocols to prepare and characterize the composition and conformation of mixed layers with PEG and alkanethiols are described here. Finally, methods to assay the stability of the link between the NP conjugates and a model drug are shown. PMID- 23918345 TI - Lipid-based nanoparticles as nonviral gene delivery vectors. AB - Efficient delivery of nucleic acids into cells is a promising technique to modulate cellular gene expression for therapeutic and research applications. Cationic lipid-based liposomes represent one of the most intensively studied and employed nonviral vectors. They are positively charged at physiological pH and spontaneously self-assemble with polyanionic nucleic acids forming nanoscaled complexes named lipoplexes. Here, we draft a simple protocol for the development, characterization, optimization, and screening of liposomal formulations for in vitro gene delivery. In particular, we report as a practical example a quick method to formulate and extrude nanometer-sized unilamellar cationic vesicles composed of DOTAP as cationic lipid and DOPE as zwitterionic helper lipid at 1:1 molar ratio. The physico-chemical characterization of liposomes and lipoplexes involves the measurement of mean diameter and overall surface charge using Dynamic Light Scattering (DLS) and Laser Doppler Microelectrophoresis. The outlined transfection procedure takes into account several experimental parameters affecting the in vitro performance of gene delivery systems, paying special attention to the charge ratio (CR). Gene delivery effectiveness is evaluated both in terms of transfection efficiency and cytotoxicity of the vector to find the optimal transfection conditions. Importantly, the proposed protocol can be easily shifted to different types of nonviral vectors. PMID- 23918347 TI - Solution of Inverse Kinematics for 6R Robot Manipulators With Offset Wrist Based on Geometric Algebra. AB - In this paper, we present an efficient method based on geometric algebra for computing the solutions to the inverse kinematics problem (IKP) of the 6R robot manipulators with offset wrist. Due to the fact that there exist some difficulties to solve the inverse kinematics problem when the kinematics equations are complex, highly nonlinear, coupled and multiple solutions in terms of these robot manipulators stated mathematically, we apply the theory of Geometric Algebra to the kinematic modeling of 6R robot manipulators simply and generate closed-form kinematics equations, reformulate the problem as a generalized eigenvalue problem with symbolic elimination technique, and then yield 16 solutions. Finally, a spray painting robot, which conforms to the type of robot manipulators, is used as an example of implementation for the effectiveness and real-time of this method. The experimental results show that this method has a large advantage over the classical methods on geometric intuition, computation and real-time, and can be directly extended to all serial robot manipulators and completely automatized, which provides a new tool on the analysis and application of general robot manipulators. PMID- 23918348 TI - Serine/threonine kinases and E2-ubiquitin conjugating enzymes in Planctomycetes: unexpected findings. AB - The regulation of signal transduction by phosphorylation and ubiquitination is essential to ensure the correct behavior of eukaryotic cells. We searched for protein families involved in such signaling in several eukaryotic species and in a limited set of prokaryotes, where two members of the Planctomycetes phylum were included as they exhibit eukaryote-like features (Gemmata obscuriglobus and Pirellula staleyi). We identified sequences homologous to eukaryotic serine/threonine kinases (STKs) and E2-ubiquitin conjugating enzymes in the two Planctomycetes species. To extend these analyses to the Planctomycetes/Verrucomicrobia/Chlamydia super-phylum, we performed comparative analyses using domains from kinases, phosphatases and GTPases that serve as signaling signatures, and we analyzed their distributions. We found substantial differences in kinome densities with regards to other prokaryote clades and among the groups in the Planctomycetes/Verrucomicrobia/Chlamydia super-phylum. In addition, we identified the presence of classic eukaryotic E2-conjugating ubiquitin proteins in prokaryotes, these having previously believed to exist only in eukaryotes. Our phylogenetic analyses of the STKs signature domains and E2 enzymes suggest the existence of horizontal gene transfer. PMID- 23918349 TI - Cetuximab-induced skin exanthema: prophylactic and reactive skin therapy are equally effective. AB - PURPOSE: Treatment with cetuximab is accompanied by the development of an acneiform follicular skin exanthema in more than 80 % of patients. Severe exanthema (grade III/IV) develops in about 9-19 % of patients with the necessity of cetuximab dose reduction or cessation. METHODS: The study presented was a retrospective analysis of 50 gastrointestinal cancer patients treated with cetuximab in combination with either FOLFIRI or FOLFOX. One cohort of 15 patients received an in-house reactive skin protocol upon development of an exanthema. A second cohort of 15 patients received a skin prophylaxis starting with the first dose of cetuximab before clinical signs of toxicity. A third historic group of 20 patients had received no skin prophylaxis or reactive treatment. RESULTS: 19/20 patients of the historic group developed a skin exanthema. Grade III/IV exanthema was observed six times. Forty percent discontinued cetuximab therapy. The average time to exanthema onset was 14.7 days. Applying the reactive skin protocol after the first occurrence of an exanthema, the exanthema was downgraded as follows: No patients developed grade IV degrees exanthema, and two patients developed a grade II/III exanthema. In the majority of cases, the reactive skin protocol controlled the exanthema (grade 0-I degrees ). No dose reductions in cetuximab were necessary. Applying the prophylactic skin protocol starting at the beginning of cetuximab application was not superior to the reactive skin protocol. CONCLUSIONS: Cetuximab-induced skin exanthema can be coped with a reactive protocol equally effective as compared to a prophylactic skin treatment. A prospective study with higher patient numbers is planned. PMID- 23918350 TI - Intraocular malignant melanoma of the choroid presenting as orbital cellulitis. AB - We report a case of choroidal melanoma with features suggestive of orbital cellulitis. A 24-year-old Asian Indian male presented with a 20-day history of sudden loss of vision in the right eye. Edematous eyelids with complete mechanical ptosis, complete ophthalmoplegia, gross proptosis accompanied by massive chemosis, and prolapse of the inferior forniceal conjunctiva were noted. He denied perception of light in the right eye. The left eye was unremarkable. B scan ultrasonography of the right eye showed a large dome-shaped mass filling the posterior segment suggestive of choroidal melanoma. Computed tomography confirmed those findings and showed no extraocular tumor extension. The patient was conservatively treated with systemic steroids following which the inflammation subsided. He underwent enucleation of the right eye and a diagnosis of spindle A cell choroidal melanoma was confirmed by histopathological examination. Although rare, orbital cellulitis is one of the presenting features of choroidal melanoma. Uveal melanoma-associated orbital cellulitis can be well controlled with systemic steroids, does not always indicate extraocular tumor extension, and can occur in spindle A cell melanomas. PMID- 23918351 TI - Brain-derived neurotrophic factor is upregulated in the cervical dorsal root ganglia and spinal cord and contributes to the maintenance of pain from facet joint injury in the rat. AB - The facet joint is commonly associated with neck and low back pain and is susceptible to loading-induced injury. Although tensile loading of the cervical facet joint has been associated with inflammation and neuronal hyperexcitability, the mechanisms of joint loading-induced pain remain unknown. Altered brain derived neurotrophic factor (BDNF) levels are associated with a host of painful conditions, but the role of BDNF in loading-induced joint pain remains undefined. Separate groups of rats underwent a painful cervical facet joint distraction or a sham procedure. Bilateral forepaw mechanical hypersensitivity was assessed and BDNF mRNA and protein levels were quantified in the dorsal root ganglion (DRG) and spinal cord at days 1 and 7. Facet joint distraction induced significant (P < 0.001) mechanical hypersensitivity at both time points. Painful joint distraction did not alter BDNF mRNA in the DRG compared with sham levels but did significantly increase (P < 0.016) BDNF protein expression over sham in the DRG at day 7. Painful distraction also significantly increased BDNF mRNA (P = 0.031) and protein expression (P = 0.047) over sham responses in the spinal cord at day 7. In a separate study, intrathecal administration of the BDNF-sequestering molecule trkB-Fc on day 5 after injury partially attenuated behavioral sensitivity after joint distraction and reduced pERK in the spinal cord at day 7 (P < 0.045). Changes in BDNF after painful facet joint injury and the effect of spinal BDNF sequestration in partially reducing pain suggest that BDNF signaling contributes to the maintenance of loading-induced facet pain but that additional cellular responses are also likely involved. PMID- 23918352 TI - Value of electroneurography as a prognostic indicator for recovery in acute severe inflammatory facial paralysis: a prospective study of Bell's palsy and Ramsay Hunt syndrome. AB - OBJECTIVES/HYPOTHESIS: To evaluate the prognostic and predictive value of electroneuronography (ENoG) in acute severe inflammatory facial paralysis, including Bell's palsy and Ramsay Hunt syndrome (RHS). STUDY DESIGN: Prospective observational study. METHODS: Patients with acute severe facial paralysis of House-Brackmann (H-B) grade IV or worse and diagnosed with Bell's palsy or RHS were enrolled from August 2007 to July 2011. After treatment with oral corticosteroid, antiviral agent, and protective eye care, patients were followed up until recovery or 12 months from onset. RESULTS: Sixty-six patients with Bell's palsy and 22 with RHS were included. Multiple logistic regression analysis showed significant effect of ENoG value on recovery in both Bell's palsy and RHS. Values of ENoG were significantly worse in RHS than Bell's palsy. Chance of early recovery within 6 weeks after correction of ENoG effect was still significantly worse in RHS. Logistic regression analysis showed 90% chance of recovery within 6 months, expected with ENoG values of 69.2% degeneration (Bell's palsy) and 59.3% (RHS). The receiver operating characteristics (ROC) curves showed ENoG values of 82.5% (Bell's palsy) and 78.0% (RHS) as a critical cutoff value of nonrecovery until 1 year, with the best sensitivity and specificity. CONCLUSIONS: A higher chance of recovery was expected with better ENoG in Bell's palsy and RHS. Based on our data, nonrecovery is predicted in patients with ENoG value greater than 82.5% in Bell's palsy, and 78% in RHS. LEVEL OF EVIDENCE: 4. PMID- 23918353 TI - Minimum of the order parameter fluctuations of seismicity before major earthquakes in Japan. AB - It has been shown that some dynamic features hidden in the time series of complex systems can be uncovered if we analyze them in a time domain called natural time chi. The order parameter of seismicity introduced in this time domain is the variance of chi weighted for normalized energy of each earthquake. Here, we analyze the Japan seismic catalog in natural time from January 1, 1984 to March 11, 2011, the day of the M9 Tohoku earthquake, by considering a sliding natural time window of fixed length comprised of the number of events that would occur in a few months. We find that the fluctuations of the order parameter of seismicity exhibit distinct minima a few months before all of the shallow earthquakes of magnitude 7.6 or larger that occurred during this 27-y period in the Japanese area. Among the minima, the minimum before the M9 Tohoku earthquake was the deepest. It appears that there are two kinds of minima, namely precursory and nonprecursory, to large earthquakes. PMID- 23918354 TI - Search strategy has influenced the discovery rate of human viruses. AB - A widely held concern is that the pace of infectious disease emergence has been increasing. We have analyzed the rate of discovery of pathogenic viruses, the preeminent source of newly discovered causes of human disease, from 1897 through 2010. The rate was highest during 1950-1969, after which it moderated. This general picture masks two distinct trends: for arthropod-borne viruses, which comprised 39% of pathogenic viruses, the discovery rate peaked at three per year during 1960-1969, but subsequently fell nearly to zero by 1980; however, the rate of discovery of nonarboviruses remained stable at about two per year from 1950 through 2010. The period of highest arbovirus discovery coincided with a comprehensive program supported by The Rockefeller Foundation of isolating viruses from humans, animals, and arthropod vectors at field stations in Latin America, Africa, and India. The productivity of this strategy illustrates the importance of location, approach, long-term commitment, and sponsorship in the discovery of emerging pathogens. PMID- 23918355 TI - Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. AB - The future of safe cell-based therapy rests on overcoming teratoma/tumor formation, in particular when using human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Because the presence of a few remaining undifferentiated hPSCs can cause undesirable teratomas after transplantation, complete removal of these cells with no/minimal damage to differentiated cells is a prerequisite for clinical application of hPSC-based therapy. Having identified a unique hESC signature of pro- and antiapoptotic gene expression profile, we hypothesized that targeting hPSC-specific antiapoptotic factor(s) (i.e., survivin or Bcl10) represents an efficient strategy to selectively eliminate pluripotent cells with teratoma potential. Here we report the successful identification of small molecules that can effectively inhibit these antiapoptotic factors, leading to selective and efficient removal of pluripotent stem cells through apoptotic cell death. In particular, a single treatment of hESC-derived mixed population with chemical inhibitors of survivin (e.g., quercetin or YM155) induced selective and complete cell death of undifferentiated hPSCs. In contrast, differentiated cell types (e.g., dopamine neurons and smooth-muscle cells) derived from hPSCs survived well and maintained their functionality. We found that quercetin-induced selective cell death is caused by mitochondrial accumulation of p53 and is sufficient to prevent teratoma formation after transplantation of hESC- or hiPSC derived cells. Taken together, these results provide the "proof of concept" that small-molecule targeting of hPSC-specific antiapoptotic pathway(s) is a viable strategy to prevent tumor formation by selectively eliminating remaining undifferentiated pluripotent cells for safe hPSC-based therapy. PMID- 23918356 TI - Target specificity among canonical nuclear poly(A) polymerases in plants modulates organ growth and pathogen response. AB - Polyadenylation of pre-mRNAs is critical for efficient nuclear export, stability, and translation of the mature mRNAs, and thus for gene expression. The bulk of pre-mRNAs are processed by canonical nuclear poly(A) polymerase (PAPS). Both vertebrate and higher-plant genomes encode more than one isoform of this enzyme, and these are coexpressed in different tissues. However, in neither case is it known whether the isoforms fulfill different functions or polyadenylate distinct subsets of pre-mRNAs. Here we show that the three canonical nuclear PAPS isoforms in Arabidopsis are functionally specialized owing to their evolutionarily divergent C-terminal domains. A strong loss-of-function mutation in PAPS1 causes a male gametophytic defect, whereas a weak allele leads to reduced leaf growth that results in part from a constitutive pathogen response. By contrast, plants lacking both PAPS2 and PAPS4 function are viable with wild-type leaf growth. Polyadenylation of SMALL AUXIN UP RNA (SAUR) mRNAs depends specifically on PAPS1 function. The resulting reduction in SAUR activity in paps1 mutants contributes to their reduced leaf growth, providing a causal link between polyadenylation of specific pre-mRNAs by a particular PAPS isoform and plant growth. This suggests the existence of an additional layer of regulation in plant and possibly vertebrate gene expression, whereby the relative activities of canonical nuclear PAPS isoforms control de novo synthesized poly(A) tail length and hence expression of specific subsets of mRNAs. PMID- 23918358 TI - Experiments on the role of deleterious mutations as stepping stones in adaptive evolution. AB - Many evolutionary studies assume that deleterious mutations necessarily impede adaptive evolution. However, a later mutation that is conditionally beneficial may interact with a deleterious predecessor before it is eliminated, thereby providing access to adaptations that might otherwise be inaccessible. It is unknown whether such sign-epistatic recoveries are inconsequential events or an important factor in evolution, owing to the difficulty of monitoring the effects and fates of all mutations during experiments with biological organisms. Here, we used digital organisms to compare the extent of adaptive evolution in populations when deleterious mutations were disallowed with control populations in which such mutations were allowed. Significantly higher fitness levels were achieved over the long term in the control populations because some of the deleterious mutations served as stepping stones across otherwise impassable fitness valleys. As a consequence, initially deleterious mutations facilitated the evolution of complex, beneficial functions. We also examined the effects of disallowing neutral mutations, of varying the mutation rate, and of sexual recombination. Populations evolving without neutral mutations were able to leverage deleterious and compensatory mutation pairs to overcome, at least partially, the absence of neutral mutations. Substantially raising or lowering the mutation rate reduced or eliminated the long-term benefit of deleterious mutations, but introducing recombination did not. Our work demonstrates that deleterious mutations can play an important role in adaptive evolution under at least some conditions. PMID- 23918359 TI - Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. AB - Transgenic mice expressing the mouse interleukin 33 (IL-33) gene driven by a keratin 14 promoter were generated. The skin-selective expression of the IL-33 gene was enhanced, and intense immunofluorescence for IL-33 was evident in the nuclei of the epidermis. Spontaneous itchy dermatitis developed in those mice at 6-8 wk of age in specific pathogen-free conditions. In the lesional skin, the epidermis was thickened and the eosinophils were infiltrated with increased expression of the eosinophil peroxidase and major basic protein genes. Mast cells were also abundant there, and blood histamine and total IgE levels were high. Those phenotypes closely resemble the features of atopic dermatitis. In peripheral blood and lesional skin, IL-5, IL-13, regulated upon activation, normally T-expressed, and presumably secreted (RANTES)/CCL5, and Eotaxin 1/CCL11 were increased, whereas TNF-alpha, IFN-gamma, and thymic stromal lymphopoietin (TSLP) were unaltered. Furthermore, the proportion of group 2 innate lymphoid cells (ILC2s), which produce IL-5, were significantly increased in the lesional skin, peripheral blood, and regional lymph nodes. The dermatitis with eosinophil infiltration was improved by the administration of an anti-IL-5 antibody. These results suggest that the expression of IL-33 in the skin activates an immune response involving ILC2 and that this process might play a crucial role in the pathogenesis of allergic inflammation that is characteristic of atopic dermatitis. PMID- 23918357 TI - Proteasome activator complex PA28 identified as an accessible target in prostate cancer by in vivo selection of human antibodies. AB - Antibody cancer therapies rely on systemically accessible targets and suitable antibodies that exert a functional activity or deliver a payload to the tumor site. Here, we present proof-of-principle of in vivo selection of human antibodies in tumor-bearing mice that identified a tumor-specific antibody able to deliver a payload and unveils the target antigen. By using an ex vivo enrichment process against freshly disaggregated tumors to purge the repertoire, in combination with in vivo biopanning at optimized phage circulation time, we have identified a human domain antibody capable of mediating selective localization of phage to human prostate cancer xenografts. Affinity chromatography followed by mass spectrometry analysis showed that the antibody recognizes the proteasome activator complex PA28. The specificity of soluble antibody was confirmed by demonstrating its binding to the active human PA28alphabeta complex. Whereas systemically administered control phage was confined in the lumen of blood vessels of both normal tissues and tumors, the selected phage spread from tumor vessels into the perivascular tumor parenchyma. In these areas, the selected phage partially colocalized with PA28 complex. Furthermore, we found that the expression of the alpha subunit of PA28 [proteasome activator complex subunit 1 (PSME1)] is elevated in primary and metastatic human prostate cancer and used anti-PSME1 antibodies to show that PSME1 is an accessible marker in mouse xenograft tumors. These results support the use of PA28 as a tumor marker and a potential target for therapeutic intervention in prostate cancer. PMID- 23918360 TI - Release of arsenic to deep groundwater in the Mekong Delta, Vietnam, linked to pumping-induced land subsidence. AB - Deep aquifers in South and Southeast Asia are increasingly exploited as presumed sources of pathogen- and arsenic-free water, although little is known of the processes that may compromise their long-term viability. We analyze a large area (>1,000 km(2)) of the Mekong Delta, Vietnam, in which arsenic is found pervasively in deep, Pliocene-Miocene-age aquifers, where nearly 900 wells at depths of 200-500 m are contaminated. There, intensive groundwater extraction is causing land subsidence of up to 3 cm/y as measured using satellite-based radar images from 2007 to 2010 and consistent with transient 3D aquifer simulations showing similar subsidence rates and total subsidence of up to 27 cm since 1988. We propose a previously unrecognized mechanism in which deep groundwater extraction is causing interbedded clays to compact and expel water containing dissolved arsenic or arsenic-mobilizing solutes (e.g., dissolved organic carbon and competing ions) to deep aquifers over decades. The implication for the broader Mekong Delta region, and potentially others like it across Asia, is that deep, untreated groundwater will not necessarily remain a safe source of drinking water. PMID- 23918361 TI - Optical imaging of the chorioretinal vasculature in the living human eye. AB - Detailed visualization of microvascular changes in the human retina is clinically limited by the capabilities of angiography imaging, a 2D fundus photograph that requires an intravenous injection of fluorescent dye. Whereas current angiography methods enable visualization of some retinal capillary detail, they do not adequately reveal the choriocapillaris or other microvascular features beneath the retina. We have developed a noninvasive microvascular imaging technique called phase-variance optical coherence tomography (pvOCT), which identifies vasculature three dimensionally through analysis of data acquired with OCT systems. The pvOCT imaging method is not only capable of generating capillary perfusion maps for the retina, but it can also use the 3D capabilities to segment the data in depth to isolate vasculature in different layers of the retina and choroid. This paper demonstrates some of the capabilities of pvOCT imaging of the anterior layers of choroidal vasculature of a healthy normal eye as well as of eyes with geographic atrophy (GA) secondary to age-related macular degeneration. The pvOCT data presented permit digital segmentation to produce 2D depth-resolved images of the retinal vasculature, the choriocapillaris, and the vessels in Sattler's and Haller's layers. Comparisons are presented between en face projections of pvOCT data within the superficial choroid and clinical angiography images for regions of GA. Abnormalities and vascular dropout observed within the choriocapillaris for pvOCT are compared with regional GA progression. The capability of pvOCT imaging of the microvasculature of the choriocapillaris and the anterior choroidal vasculature has the potential to become a unique tool to evaluate therapies and understand the underlying mechanisms of age-related macular degeneration progression. PMID- 23918362 TI - Interferon regulatory factor 3 controls interleukin-17 expression in CD8 T lymphocytes. AB - IFN regulatory factor (IRF) 3 plays a key role in innate responses against viruses. Herein we assessed its contribution to T-cell activation. We observed that poly(I:C)-induced IRF3 activation in CD8 T cells represses IL-17 expression in a type I IFN-independent fashion. Even in the absence of poly(I:C), polyclonally activated naive IRF3(-/-) CD8 T cells expressed high levels of IL-17 and IL-23R in comparison with wild-type cells. Furthermore, IRF3(-/-) OT1 cells adoptively transferred into wild-type hosts also produced higher IL-17 levels upon immunization than their wild-type counterparts. This phenotype could be reversed by ectopic expression of IRF3, confirming that this effect is intrinsic to T cells. We show that IRF3 directly interacts with RORgammat in the cytoplasm through its IRF interaction domain and limits its ability to bind and transactivate the IL-17 promoter. These observations uncover an unexpected role of IRF3 in the control of CD8 T-cell polarization. PMID- 23918363 TI - Enabling enhanced emission and low-threshold lasing of organic molecules using special Fano resonances of macroscopic photonic crystals. AB - The nature of light interaction with matter can be dramatically altered in optical cavities, often inducing nonclassical behavior. In solid-state systems, excitons need to be spatially incorporated within nanostructured cavities to achieve such behavior. Although fascinating phenomena have been observed with inorganic nanostructures, the incorporation of organic molecules into the typically inorganic cavity is more challenging. Here, we present a unique optofluidic platform comprising organic molecules in solution suspended on a photonic crystal surface, which supports macroscopic Fano resonances and allows strong and tunable interactions with the molecules anywhere along the surface. We develop a theoretical framework of this system and present a rigorous comparison with experimental measurements, showing dramatic spectral and angular enhancement of emission. We then demonstrate that these enhancement mechanisms enable lasing of only a 100-nm thin layer of diluted solution of organic molecules with substantially reduced threshold intensity, which has important implications for organic light-emitting devices and molecular sensing. PMID- 23918364 TI - Odor representations in the olfactory bulb evolve after the first breath and persist as an odor afterimage. AB - Rodents can discriminate odors in one breath, and mammalian olfaction research has thus focused on the first breath. However, sensory representations dynamically change during and after stimuli. To investigate these dynamics, we recorded spike trains from the olfactory bulb of awake, head-fixed mice and found that some mitral cells' odor representations changed following the first breath and others continued after odor cessation. Population analysis revealed that these postodor responses contained odor- and concentration-specific information- an odor afterimage. Using calcium imaging, we found that most olfactory glomerular activity was restricted to the odor presentation, implying that the afterimage is not primarily peripheral. The odor afterimage was not dependent on odorant physicochemical properties. To artificially induce aftereffects, we photostimulated mitral cells using channelrhodopsin and recorded centrally maintained persistent activity. The strength and persistence of the afterimage was dependent on the duration of both artificial and natural stimulation. In summary, we show that the odor representation evolves after the first breath and that there is a centrally maintained odor afterimage, similar to other sensory systems. These dynamics may help identify novel odorants in complex environments. PMID- 23918365 TI - Comparative studies of Munc18c and Munc18-1 reveal conserved and divergent mechanisms of Sec1/Munc18 proteins. AB - Sec1/Munc18 (SM) family proteins are essential for every vesicle fusion pathway. The best-characterized SM protein is the synaptic factor Munc18-1, but it remains unclear whether its functions represent conserved mechanisms of SM proteins or specialized activities in neurotransmitter release. To address this question, we dissected Munc18c, a functionally distinct SM protein involved in nonsynaptic exocytic pathways. We discovered that Munc18c binds to the trans-SNARE (soluble N ethylmaleimide-sensitive factor attachment protein receptor) complex and strongly accelerates the fusion rate. Further analysis suggests that Munc18c recognizes both vesicle-rooted SNARE and target membrane-associated SNAREs, and promotes trans-SNARE zippering at the postdocking stage of the fusion reaction. The stimulation of fusion by Munc18c is specific to its cognate SNARE isoforms. Because Munc18-1 regulates fusion in a similar manner, we conclude that one conserved function of SM proteins is to bind their cognate trans-SNARE complexes and accelerate fusion kinetics. Munc18c also binds syntaxin-4 monomer but does not block target membrane-associated SNARE assembly, in agreement with our observation that six- to eightfold increases in Munc18c expression do not inhibit insulin-stimulated glucose uptake in adipocytes. Thus, the inhibitory "closed" syntaxin binding mode demonstrated for Munc18-1 is not conserved in Munc18c. Unexpectedly, we found that Munc18c recognizes the N-terminal region of the vesicle-rooted SNARE, whereas Munc18-1 requires the C-terminal sequences, suggesting that the architecture of the SNARE/SM complex likely differs across fusion pathways. Together, these comparative studies of two distinct SM proteins reveal conserved as well as divergent mechanisms of SM family proteins in intracellular vesicle fusion. PMID- 23918366 TI - Influence of early-life nutrition on mortality and reproductive success during a subsequent famine in a preindustrial population. AB - Individuals with insufficient nutrition during development often experience poorer later-life health and evolutionary fitness. The Predictive Adaptive Response (PAR) hypothesis proposes that poor early-life nutrition induces physiological changes that maximize fitness in similar environments in adulthood and that metabolic diseases result when individuals experiencing poor nutrition during development subsequently encounter good nutrition in adulthood. However, although cohort studies have shown that famine exposure in utero reduces health in favorable later-life conditions, no study on humans has demonstrated the predicted fitness benefit under low later-life nutrition, leaving the evolutionary origins of such plasticity unexplored. Taking advantage of a well documented famine and unique datasets of individual life histories and crop yields from two preindustrial Finnish populations, we provide a test of key predictions of the PAR hypothesis. Known individuals from fifty cohorts were followed from birth until the famine, where we analyzed their survival and reproductive success in relation to the crop yields around birth. We were also able to test whether the long-term effects of early-life nutrition differed between individuals of varying socioeconomic status. We found that, contrary to predictions of the PAR hypothesis, individuals experiencing low early-life crop yields showed lower survival and fertility during the famine than individuals experiencing high early-life crop yields. These effects were more pronounced among young individuals and those of low socioeconomic status. Our results do not support the hypothesis that PARs should have been favored by natural selection and suggest that alternative models may need to be invoked to explain the epidemiology of metabolic diseases. PMID- 23918367 TI - Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth. AB - Placental growth factor (PlGF) remodels tumor vasculatures toward a normalized phenotype, which affects tumor growth, invasion and drug responses. However, the coordinative and spatiotemporal relation between PlGF and VEGF in modulation of tumor angiogenesis and vascular remodeling is less understood. Here we report that PlGF positively and negatively modulate tumor growth, angiogenesis, and vascular remodeling through a VEGF-dependent mechanism. In two independent tumor models, we show that PlGF inhibited tumor growth and angiogenesis and displayed a marked vascular remodeling effect, leading to normalized microvessels with infrequent vascular branches and increased perivascular cell coverage. Surprisingly, elimination of VEGF gene (i.e., VEGF-null) in PlGF-expressing tumors resulted in (i) accelerated tumor growth rates and angiogenesis and (ii) complete attenuation of PlGF-induced vascular normalization. Thus, PlGF positively and negatively modulates tumor growth, angiogenesis, and vascular remodeling through VEGF-dependent spatiotemporal mechanisms. Our data uncover molecular mechanisms underlying the complex interplay between PlGF and VEGF in modulation of tumor growth and angiogenesis, and have conceptual implication for antiangiogenic cancer therapy. PMID- 23918368 TI - Subset of heat-shock transcription factors required for the early response of Arabidopsis to excess light. AB - Sunlight provides energy for photosynthesis and is essential for nearly all life on earth. However, too much or too little light or rapidly fluctuating light conditions cause stress to plants. Rapid changes in the amount of light are perceived as a change in the reduced/oxidized (redox) state of photosynthetic electron transport components in chloroplasts. However, how this generates a signal that is relayed to changes in nuclear gene expression is not well understood. We modified redox state in the reference plant, Arabidopsis thaliana, using either excess light or low light plus the herbicide DBMIB (2,5-dibromo-3 methyl-6-isopropyl-p-benzoquinone), a well-known inhibitor of photosynthetic electron transport. Modification of redox state caused a change in expression of a common set of about 750 genes, many of which are known stress-responsive genes. Among the most highly enriched promoter elements in the induced gene set were heat-shock elements (HSEs), known motifs that change gene expression in response to high temperature in many systems. We show that HSEs from the promoter of the ASCORBATE PEROXIDASE 2 (APX2) gene were necessary and sufficient for APX2 expression in conditions of excess light, or under low light plus the herbicide. We tested APX2 expression phenotypes in overexpression and loss-of-function mutants of 15 Arabidopsis A-type heat-shock transcription factors (HSFs), and identified HSFA1D, HSFA2, and HSFA3 as key factors regulating APX2 expression in diverse stress conditions. Excess light regulates both the subcellular location of HSFA1D and its biochemical properties, making it a key early component of the excess light stress network of plants. PMID- 23918369 TI - Efficient influenza A virus replication in the respiratory tract requires signals from TLR7 and RIG-I. AB - Induction of a proinflammatory response is the hallmark of host innate defense against invading pathogens. Host recognition of influenza A virus (IAV) infection relies on pattern-recognition receptors, including Toll-like receptor 7 (TLR7) and retinoic acid inducible gene-1 (RIG-I) for the activation of innate-immune responses. Here, we show that following a physiological low dose of IAV infection, viral sensing by either TLR7 or RIG-I induces a proinflammatory program that promotes viral replication. Transfer of bronchoalveolar lavage from infected wild-type mice into the airway of mice deficient in TLR7 and RIG-I pathways was sufficient to restore viral replication efficiency. Comparison of IAV-infected cells revealed that inflammatory mediators elicited by TLR7 and RIG I signaling recruit viral target cells to the airway, thereby enhancing viral load within the respiratory tract. Our data suggest that IAV uses physiological levels of inflammatory responses for its replicative advantage and highlight the complex interplay between viruses and the host innate-immune responses. PMID- 23918370 TI - From the Cover: Neutralization of terminal differentiation in gliomagenesis. AB - An immature state of cellular differentiation--characterized by stem cell-like tendencies and impaired differentiation--is a hallmark of cancer. Using glioblastoma multiforme (GBM) as a model system, we sought to determine whether molecular determinants that drive cells toward terminal differentiation are also genetically targeted in carcinogenesis and whether neutralizing such genes also plays an active role to reinforce the impaired differentiation state and promote malignancy. To that end, we screened 71 genes with known roles in promoting nervous system development that also sustain copy number loss in GBM through antineoplastic assay and identified A2BP1 (ataxin 2 binding protein 1, Rbfox1), an RNA-binding and splicing regulator that is deleted in 10% of GBM cases. Integrated in silico analysis of GBM profiles to elucidate the A2BP1 pathway and its role in glioma identified myelin transcription factor 1-like (Myt1L) as a direct transcriptional regulator of A2BP1. Reintroduction of A2BP1 or Myt1L in GBM cell lines and glioma stem cells profoundly inhibited tumorigenesis in multiple assays, and conversely, shRNA-mediated knockdown of A2BP1 or Myt1L in premalignant neural stem cells compromised neuronal lineage differentiation and promoted orthotopic tumor formation. On the mechanistic level, with the top represented downstream target TPM1 as an illustrative example, we demonstrated that, among its multiple functions, A2BP1 serves to regulate TPM1's alternative splicing to promote cytoskeletal organization and terminal differentiation and suppress malignancy. Thus, in addition to the activation of self-renewal pathways, the neutralization of genetic programs that drive cells toward terminal differentiation may also promote immature and highly plastic developmental states that contribute to the aggressive malignant properties of GBM. PMID- 23918371 TI - Inhibitory role of the transcription repressor Gfi1 in the generation of thymus derived regulatory T cells. AB - Foxp3(+) regulatory T (T(reg)) cells are essential for the maintenance of self tolerance and immune homeostasis. The majority of T(reg) cells is generated in the thymus as a specific subset of CD4(+) T cells, known as thymus-derived or natural T(reg) (nT(reg)) cells, in response to signals from T-cell receptors, costimulatory molecules, and cytokines. Recent studies have identified intracellular signaling and transcriptional pathways that link these signals to Foxp3 induction, but how the production of these extrinsic factors is controlled remains poorly understood. Here, we report that the transcription repressor growth factor independent 1 (Gfi1) has a key inhibitory role in the generation of nT(reg) cells by a noncell-autonomous mechanism. T cell-specific deletion of Gfi1 results in aberrant expansion of thymic nT(reg) cells and increased production of cytokines. In particular, IL-2 overproduction plays an important role in driving the expansion of nT(reg) cells. In contrast, although Gfi1 deficiency elevated thymocyte apoptosis, Gfi1 repressed nT(reg) generation independently of its prosurvival effect. Consistent with an inhibitory role of Gfi1 in this process, loss of Gfi1 dampens antitumor immunity. These data point to a previously unrecognized extrinsic control mechanism that negatively shapes thymic generation of nT(reg) cells. PMID- 23918372 TI - Newborn chickens generate invariant object representations at the onset of visual object experience. AB - To recognize objects quickly and accurately, mature visual systems build invariant object representations that generalize across a range of novel viewing conditions (e.g., changes in viewpoint). To date, however, the origins of this core cognitive ability have not yet been established. To examine how invariant object recognition develops in a newborn visual system, I raised chickens from birth for 2 weeks within controlled-rearing chambers. These chambers provided complete control over all visual object experiences. In the first week of life, subjects' visual object experience was limited to a single virtual object rotating through a 60 degrees viewpoint range. In the second week of life, I examined whether subjects could recognize that virtual object from novel viewpoints. Newborn chickens were able to generate viewpoint-invariant representations that supported object recognition across large, novel, and complex changes in the object's appearance. Thus, newborn visual systems can begin building invariant object representations at the onset of visual object experience. These abstract representations can be generated from sparse data, in this case from a visual world containing a single virtual object seen from a limited range of viewpoints. This study shows that powerful, robust, and invariant object recognition machinery is an inherent feature of the newborn brain. PMID- 23918373 TI - Understanding metropolitan patterns of daily encounters. AB - Understanding of the mechanisms driving our daily face-to-face encounters is still limited; the field lacks large-scale datasets describing both individual behaviors and their collective interactions. However, here, with the help of travel smart card data, we uncover such encounter mechanisms and structures by constructing a time-resolved in-vehicle social encounter network on public buses in a city (about 5 million residents). Using a population scale dataset, we find physical encounters display reproducible temporal patterns, indicating that repeated encounters are regular and identical. On an individual scale, we find that collective regularities dominate distinct encounters' bounded nature. An individual's encounter capability is rooted in his/her daily behavioral regularity, explaining the emergence of "familiar strangers" in daily life. Strikingly, we find individuals with repeated encounters are not grouped into small communities, but become strongly connected over time, resulting in a large, but imperceptible, small-world contact network or "structure of co-presence" across the whole metropolitan area. Revealing the encounter pattern and identifying this large-scale contact network are crucial to understanding the dynamics in patterns of social acquaintances, collective human behaviors, and- particularly--disclosing the impact of human behavior on various diffusion/spreading processes. PMID- 23918374 TI - ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer. AB - Combinatorial activation of PI3-kinase and RAS signaling occurs frequently in advanced prostate cancer and is associated with adverse patient outcome. We now report that the oncogenic Ets variant 4 (Etv4) promotes prostate cancer metastasis in response to coactivation of PI3-kinase and Ras signaling pathways in a genetically engineered mouse model of highly penetrant, metastatic prostate cancer. Using an inducible Cre driver to simultaneously inactivate Pten while activating oncogenic Kras and a fluorescent reporter allele in the prostate epithelium, we performed lineage tracing in vivo to define the temporal and spatial occurrence of prostate tumors, disseminated tumor cells, and metastases. These analyses revealed that though disseminated tumors cells arise early following the initial occurrence of prostate tumors, there is a significant temporal lag in metastasis, which is temporally coincident with the up-regulation of Etv4 expression in primary tumors. Functional studies showed that knockdown of Etv4 in a metastatic cell line derived from the mouse model abrogates the metastatic phenotype but does not affect tumor growth. Notably, expression and activation of ETV4, but not other oncogenic ETS genes, is correlated with activation of both PI3-kinase and Ras signaling in human prostate tumors and metastases. Our findings indicate that ETV4 promotes metastasis in prostate tumors that have activation of PI3-kinase and Ras signaling, and therefore, ETV4 represents a potential target of therapeutic intervention for metastatic prostate cancer. PMID- 23918375 TI - Prevalent mechanism of membrane bridging by synaptotagmin-1. AB - Synaptotagmin-1 functions as a Ca(2+) sensor in neurotransmitter release through its two C2 domains (the C2A and C2B domain). The ability of synaptotagmin-1 to bridge two membranes is likely crucial for its function, enabling cooperation with the soluble N-ethylmaleimide sensitive factor adaptor protein receptors (SNAREs) in membrane fusion, but two bridging mechanisms have been proposed. A highly soluble synaptotagmin-1 fragment containing both domains (C2AB) was shown to bind simultaneously to two membranes via the Ca(2+)-binding loops at the top of both domains and basic residues at the bottom of the C2B domain (direct bridging mechanism). In contrast, a longer fragment including a linker sequence (lnC2AB) was found to aggregate in solution and was proposed to bridge membranes through trans interactions between lnC2AB oligomers bound to each membrane via the Ca(2+)-binding loops, with no contact of the bottom of the C2B domain with the membranes. We now show that lnC2AB containing impurities indeed aggregates in solution, but properly purified lnC2AB is highly soluble. Moreover, cryo-EM images reveal that a majority of lnC2AB molecules bridge membranes directly. Fluorescence spectroscopy indicates that the bottom of the C2B domain contacts the membrane in a sizeable population of molecules of both membrane-bound C2AB and membrane-bound lnC2AB. NMR data on nanodiscs show that a fraction of C2AB molecules bind to membranes with antiparallel orientations of the C2 domains. Together with previous studies, these results show that direct bridging constitutes the prevalent mechanism of membrane bridging by both C2AB and lnC2AB, suggesting that this mechanism underlies the function of synaptotagmin-1 in neurotransmitter release. PMID- 23918376 TI - Brief meditation training induces smoking reduction. AB - More than 5 million deaths a year are attributable to tobacco smoking, but attempts to help people either quit or reduce their smoking often fail, perhaps in part because the intention to quit activates brain networks related to craving. We recruited participants interested in general stress reduction and randomly assigned them to meditation training or a relaxation training control. Among smokers, 2 wk of meditation training (5 h in total) produced a significant reduction in smoking of 60%; no reduction was found in the relaxation control. Resting-state brain scans showed increased activity for the meditation group in the anterior cingulate and prefrontal cortex, brain areas related to self control. These results suggest that brief meditation training improves self control capacity and reduces smoking. PMID- 23918377 TI - Generation of hair cells in neonatal mice by beta-catenin overexpression in Lgr5 positive cochlear progenitors. AB - Mammalian hair cells do not regenerate, and their loss is a major cause of deafness. We recently identified leucine-rich repeat containing, G-protein coupled receptor 5 (Lgr5)-expressing cochlear supporting cells with the capacity for self-renewal and hair cell differentiation in vitro. We found that these cells, a subset of cochlear supporting cells, were responsive to Wnt signaling. Here we asked whether these Lgr5-positive cells, despite their lack of contribution to hair cell replacement after degenerative loss, could be driven by forced expression of beta-catenin to act as hair cell progenitors in vivo. We showed that forced stabilization of beta-catenin in supporting cells in neonatal animals resulted in proliferation of supporting cells and generation of hair cells. Although beta-catenin expression was increased by genetic means in all supporting cells, entry to the cell cycle and differentiation to hair cells of the normally postmitotic cells was restricted to the Lgr5-positive population. Our finding suggests that Wnt/beta-catenin can drive Lgr5-positive cells to act as hair cell progenitors, even after their exit from the cell cycle and apparent establishment of cell fate. PMID- 23918378 TI - Structure of N-linked oligosaccharides attached to chlorovirus PBCV-1 major capsid protein reveals unusual class of complex N-glycans. AB - The major capsid protein Vp54 from the prototype chlorovirus Paramecium bursaria chlorella virus 1 (PBCV-1) contains four Asn-linked glycans. The structure of the four N-linked oligosaccharides and the type of substitution at each glycosylation site was determined by chemical, spectroscopic, and spectrometric analyses. Vp54 glycosylation is unusual in many ways, including: (i) unlike most viruses, PBCV-1 encodes most, if not all, of the machinery to glycosylate its major capsid protein; (ii) the glycans are attached to the protein by a beta-glucose linkage; (iii) the Asn-linked glycans are not located in a typical N-X-(T/S) consensus site; and (iv) the process probably occurs in the cytoplasm. The four glycoforms share a common core structure, and the differences are related to the nonstoichiometric presence of two monosaccharides. The most abundant glycoform consists of nine neutral monosaccharide residues, organized in a highly branched fashion. Among the most distinctive features of the glycoforms are (i) a dimethylated rhamnose as the capping residue of the main chain, (ii) a hyperbranched fucose unit, and (iii) two rhamnose residues with opposite absolute configurations. These glycoforms differ from what has been reported so far in the three domains of life. Considering that chloroviruses and other members of the family Phycodnaviridae may have a long evolutionary history, we suggest that the chlorovirus glycosylation pathway is ancient, possibly existing before the development of the endoplasmic reticulum and Golgi pathway, and involves still unexplored mechanisms. PMID- 23918379 TI - Forebrain dopamine neurons project down to a brainstem region controlling locomotion. AB - The contribution of dopamine (DA) to locomotor control is traditionally attributed to ascending dopaminergic projections from the substantia nigra pars compacta and the ventral tegmental area to the basal ganglia, which in turn project down to the mesencephalic locomotor region (MLR), a brainstem region controlling locomotion in vertebrates. However, a dopaminergic innervation of the pedunculopontine nucleus, considered part of the MLR, was recently identified in the monkey. The origin and role of this dopaminergic input are unknown. We addressed these questions in a basal vertebrate, the lamprey. Here we report a functional descending dopaminergic pathway from the posterior tuberculum (PT; homologous to the substantia nigra pars compacta and/or ventral tegmental area of mammals) to the MLR. By using triple labeling, we found that dopaminergic cells from the PT not only project an ascending pathway to the striatum, but send a descending projection to the MLR. In an isolated brain preparation, PT stimulation elicited excitatory synaptic inputs into patch-clamped MLR cells, accompanied by activity in reticulospinal cells. By using voltammetry coupled with electrophysiological recordings, we demonstrate that PT stimulation evoked DA release in the MLR, together with the activation of reticulospinal cells. In a semi-intact preparation, stimulation of the PT elicited reticulospinal activity together with locomotor movements. Microinjections of a D1 antagonist in the MLR decreased the locomotor output elicited by PT stimulation, whereas injection of DA had an opposite effect. It appears that this descending dopaminergic pathway has a modulatory role on MLR cells that are known to receive glutamatergic projections and promotes locomotor output. PMID- 23918380 TI - The Great Recession, genetic sensitivity, and maternal harsh parenting. AB - Using data from the Fragile Families and Child Wellbeing Study, this study examined the effects of the Great Recession on maternal harsh parenting. We found that changes in macroeconomic conditions, rather than current conditions, affected harsh parenting, that declines in macroeconomic conditions had a stronger impact on harsh parenting than improvements in conditions, and that mothers' responses to adverse economic conditions were moderated by the DRD2 Taq1A genotype. We found no evidence of a moderating effect for two other, less well-studied SNPs from the DRD4 and DAT1 genes. PMID- 23918381 TI - Polo kinase Cdc5 is a central regulator of meiosis I. AB - During meiosis, two consecutive rounds of chromosome segregation yield four haploid gametes from one diploid cell. The Polo kinase Cdc5 is required for meiotic progression, but how Cdc5 coordinates multiple cell-cycle events during meiosis I is not understood. Here we show that CDC5-dependent phosphorylation of Rec8, a subunit of the cohesin complex that links sister chromatids, is required for efficient cohesin removal from chromosome arms, which is a prerequisite for meiosis I chromosome segregation. CDC5 also establishes conditions for centromeric cohesin removal during meiosis II by promoting the degradation of Spo13, a protein that protects centromeric cohesin during meiosis I. Despite CDC5's central role in meiosis I, the protein kinase is dispensable during meiosis II and does not even phosphorylate its meiosis I targets during the second meiotic division. We conclude that Cdc5 has evolved into a master regulator of the unique meiosis I chromosome segregation pattern. PMID- 23918382 TI - Arf guanine nucleotide-exchange factors BIG1 and BIG2 regulate nonmuscle myosin IIA activity by anchoring myosin phosphatase complex. AB - Brefeldin A-inhibited guanine nucleotide-exchange factors BIG1 and BIG2 activate, through their Sec7 domains, ADP ribosylation factors (Arfs) by accelerating the replacement of Arf-bound GDP with GTP for initiation of vesicular transport or activation of specific enzymes that modify important phospholipids. They are also implicated in regulation of cell polarization and actin dynamics for directed migration. Reciprocal coimmunoprecipitation of endogenous HeLa cell BIG1 and BIG2 with myosin IIA was demonstrably independent of Arf guanine nucleotide-exchange factor activity, because effects of BIG1 and BIG2 depletion were reversed by overexpression of the cognate BIG molecule C-terminal sequence that follows the Arf activation site. Selective depletion of BIG1 or BIG2 enhanced specific phosphorylation of myosin regulatory light chain (T18/S19) and F-actin content, which impaired cell migration in Transwell assays. Our data are clear evidence of these newly recognized functions for BIG1 and BIG2 in transduction or integration of mechanical signals from integrin adhesions and myosin IIA-dependent actin dynamics. Thus, by anchoring or scaffolding the assembly, organization, and efficient operation of multimolecular myosin phosphatase complexes that include myosin IIA, protein phosphatase 1delta, and myosin phosphatase-targeting subunit 1, BIG1 and BIG2 serve to integrate diverse biophysical and biochemical events in cells. PMID- 23918383 TI - An allele of the crm gene blocks cyanobacterial circadian rhythms. AB - The SasA-RpaA two-component system constitutes a key output pathway of the cyanobacterial Kai circadian oscillator. To date, rhythm of phycobilisome associated (rpaA) is the only gene other than kaiA, kaiB, and kaiC, which encode the oscillator itself, whose mutation causes completely arrhythmic gene expression. Here we report a unique transposon insertion allele in a small ORF located immediately upstream of rpaA in Synechococcus elongatus PCC 7942 termed crm (for circadian rhythmicity modulator), which results in arrhythmic promoter activity but does not affect steady-state levels of RpaA. The crm ORF complements the defect when expressed in trans, but only if it can be translated, suggesting that crm encodes a small protein. The crm1 insertion allele phenotypes are distinct from those of an rpaA null; crm1 mutants are able to grow in a light:dark cycle and have no detectable oscillations of KaiC phosphorylation, whereas low-amplitude KaiC phosphorylation rhythms persist in the absence of RpaA. Levels of phosphorylated RpaA in vivo measured over time are significantly altered compared with WT in the crm1 mutant as well as in the absence of KaiC. Taken together, these results are consistent with the hypothesis that the Crm polypeptide modulates a circadian-specific activity of RpaA. PMID- 23918384 TI - Population genomics reveals a possible history of backcrossing and recombination in the gynogenetic fish Poecilia formosa. AB - Unisexual sperm-dependent vertebrates are of hybrid origins, rare, and predicted to be short-lived as a result of several challenges arising from their mode of reproduction. In particular, because of a lack of recombination, clonal species are predicted to have a low potential to respond to natural selection. However, many unisexual sperm-dependent species persist, and assessing the genetic diversity present in these species is fundamental to understanding how they avoid extinction. We used population genomic methods to assess genotypic variation within the unisexual fish Poecilia formosa. Measures of admixture and population differentiation, as well as clustering analyses, indicate that the genomes of individuals of P. formosa are admixed and intermediate between Poecilia latipinna and Poecilia mexicana, consistent with the hypothesis of their hybrid origins. Bayesian genomic cline analyses indicate that about 12% of sampled loci exhibit patterns consistent with inheritance from only one parent. The estimation of observed heterozygosity clearly suggests that P. formosa is not comprised of direct descendants of a single nonrecombining asexual F1 hybrid individual. Additionally, the estimation of observed heterozygosity provides support for the hypothesis that the history of this unisexual species has included backcrossing with the parent species before the onset of gynogenesis. We also document high levels of variation among asexual individuals, which is attributable to recombination (historical or ongoing) and the accumulation of mutations. The high genetic variation suggests that this unisexual vertebrate has more potential to respond to natural selection than if they were frozen F1 hybrids. PMID- 23918385 TI - Conditionals by inversion provide a universal method for the generation of conditional alleles. AB - Conditional mutagenesis is becoming a method of choice for studying gene function, but constructing conditional alleles is often laborious, limited by target gene structure, and at times, prone to incomplete conditional ablation. To address these issues, we developed a technology termed conditionals by inversion (COIN). Before activation, COINs contain an inverted module (COIN module) that lies inertly within the antisense strand of a resident gene. When inverted into the sense strand by a site-specific recombinase, the COIN module causes termination of the target gene's transcription and simultaneously provides a reporter for tracking this event. COIN modules can be inserted into natural introns (intronic COINs) or directly into coding exons as part of an artificial intron (exonic COINs), greatly simplifying allele design and increasing flexibility over previous conditional KO approaches. Detailed analysis of over 20 COIN alleles establishes the reliability of the method and its broad applicability to any gene, regardless of exon-intron structure. Our extensive testing provides rules that help ensure success of this approach and also explains why other currently available conditional approaches often fail to function optimally. Finally, the ability to split exons using the COIN's artificial intron opens up engineering modalities for the generation of multifunctional alleles. PMID- 23918386 TI - Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons. AB - Presenilin (PS) plays a central role in the pathogenesis of Alzheimer's disease, and loss of PS causes progressive memory impairment and age-related neurodegeneration in the mouse cerebral cortex. In hippocampal neurons, PS is essential for neurotransmitter release, NMDA receptor-mediated responses, and long-term potentiation. PS is also involved in the regulation of calcium homeostasis, although the precise site of its action is less clear. Here we investigate the mechanism by which PS regulates synaptic function and calcium homeostasis using acute hippocampal slices from PS conditional knockout mice and primary cultured postnatal hippocampal neurons, in which PS is inducibly inactivated. Using two different calcium probes, Fura-2 and Mag-Fura-2, we found that inactivation of PS in primary hippocampal neurons does not affect calcium concentration in the endoplasmic reticulum. Rather, in the absence of PS, levels of ryanodine receptor (RyR) are reduced in the hippocampus, measured by Western analysis and radioligand binding assay, although the mRNA expression is unaffected. RyR-mediated function is also impaired, as indicated by reduced RyR agonist-induced calcium release from the ER and RyR-mediated synaptic responses in the absence of PS. Furthermore, knockdown of RyR expression in wild-type hippocampal neurons by two independent shRNAs to levels comparable with the RyR protein reduction in PS-deficient hippocampal neurons mimics the defects exhibited in calcium homeostasis and presynaptic function. Collectively, our findings show that PS regulates calcium homeostasis and synaptic function via RyR and suggest that disruption of intracellular calcium homeostasis may be an early pathogenic event leading to presynaptic dysfunction in Alzheimer's disease. PMID- 23918387 TI - Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system. AB - A simple and robust method for targeted mutagenesis in zebrafish has long been sought. Previous methods generate monoallelic mutations in the germ line of F0 animals, usually delaying homozygosity for the mutation to the F2 generation. Generation of robust biallelic mutations in the F0 would allow for phenotypic analysis directly in injected animals. Recently the type II prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas) system has been adapted to serve as a targeted genome mutagenesis tool. Here we report an improved CRISPR/Cas system in zebrafish with custom guide RNAs and a zebrafish codon-optimized Cas9 protein that efficiently targeted a reporter transgene Tg(-5.1mnx1:egfp) and four endogenous loci (tyr, golden, mitfa, and ddx19). Mutagenesis rates reached 75-99%, indicating that most cells contained biallelic mutations. Recessive null-like phenotypes were observed in four of the five targeting cases, supporting high rates of biallelic gene disruption. We also observed efficient germ-line transmission of the Cas9-induced mutations. Finally, five genomic loci can be targeted simultaneously, resulting in multiple loss-of-function phenotypes in the same injected fish. This CRISPR/Cas9 system represents a highly effective and scalable gene knockout method in zebrafish and has the potential for applications in other model organisms. PMID- 23918388 TI - Hippo pathway effector Yap promotes cardiac regeneration. AB - The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 (Taz) exhibit gene dosage dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process. PMID- 23918389 TI - Host-related metabolic cues affect colonization strategies of a root endophyte. AB - The mechanisms underpinning broad compatibility in root symbiosis are largely unexplored. The generalist root endophyte Piriformospora indica establishes long lasting interactions with morphologically and biochemically different hosts, stimulating their growth, alleviating salt stress, and inducing local and systemic resistance to pathogens. Cytological studies and global investigations of fungal transcriptional responses to colonization of barley and Arabidopsis at different symbiotic stages identified host-dependent colonization strategies and host-specifically induced effector candidates. Here, we show that in Arabidopsis, P. indica establishes and maintains biotrophic nutrition within living epidermal cells, whereas in barley the symbiont undergoes a nutritional switch to saprotrophy that is associated with the production of secondary thinner hyphae in dead cortex cells. Consistent with a diversified trophic behavior and with the occurrence of nitrogen deficiency at the onset of saprotrophy in barley, fungal genes encoding hydrolytic enzymes and nutrient transporters were highly induced in this host but not in Arabidopsis. Silencing of the high-affinity ammonium transporter PiAMT1 gene, whose transcripts are accumulating during nitrogen starvation and in barley, resulted in enhanced colonization of this host, whereas it had no effect on the colonization of Arabidopsis. Increased levels of free amino acids and reduced enzymatic activity for the cell-death marker VPE (vacuolar-processing enzyme) in colonized barley roots coincided with an extended biotrophic lifestyle of P. indica upon silencing of PiAMT1. This suggests that PiAmt1 functions as a nitrogen sensor mediating the signal that triggers the in planta activation of the saprotrophic program. Thus, host-related metabolic cues affect the expression of P. indica's alternative lifestyles. PMID- 23918390 TI - Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2. AB - Mechanotransduction in the mammalian auditory system depends on mechanosensitive channels in the hair bundles that project from the apical surface of the sensory hair cells. Individual stereocilia within each bundle contain a core of tightly packed actin filaments, whose length is dynamically regulated during development and in the adult. We show that the actin-binding protein epidermal growth factor receptor pathway substrate 8 (Eps8)L2, a member of the Eps8-like protein family, is a newly identified hair bundle protein that is localized at the tips of stereocilia of both cochlear and vestibular hair cells. It has a spatiotemporal expression pattern that complements that of Eps8. In the cochlea, whereas Eps8 is essential for the initial elongation of stereocilia, Eps8L2 is required for their maintenance in adult hair cells. In the absence of both proteins, the ordered staircase structure of the hair bundle in the cochlea decays. In contrast to the early profound hearing loss associated with an absence of Eps8, Eps8L2 null mutant mice exhibit a late-onset, progressive hearing loss that is directly linked to a gradual deterioration in hair bundle morphology. We conclude that Eps8L2 is required for the long-term maintenance of the staircase structure and mechanosensory function of auditory hair bundles. It complements the developmental role of Eps8 and is a candidate gene for progressive age-related hearing loss. PMID- 23918391 TI - R-loop formation at Snord116 mediates topotecan inhibition of Ube3a-antisense and allele-specific chromatin decondensation. AB - Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are oppositely imprinted autism-spectrum disorders with known genetic bases, but complex epigenetic mechanisms underlie their pathogenesis. The PWS/AS locus on 15q11-q13 is regulated by an imprinting control region that is maternally methylated and silenced. The PWS imprinting control region is the promoter for a one megabase paternal transcript encoding the ubiquitous protein-coding Snrpn gene and multiple neuron-specific noncoding RNAs, including the PWS-related Snord116 repetitive locus of small nucleolar RNAs and host genes, and the antisense transcript to AS-causing ubiquitin ligase encoding Ube3a (Ube3a-ATS). Neuron specific transcriptional progression through Ube3a-ATS correlates with paternal Ube3a silencing and chromatin decondensation. Interestingly, topoisomerase inhibitors, including topotecan, were recently identified in an unbiased drug screen for compounds that could reverse the silent paternal allele of Ube3a in neurons, but the mechanism of topotecan action on the PWS/AS locus is unknown. Here, we demonstrate that topotecan treatment stabilizes the formation of RNA:DNA hybrids (R loops) at G-skewed repeat elements within paternal Snord116, corresponding to increased chromatin decondensation and inhibition of Ube3a-ATS expression. Neural precursor cells from paternal Snord116 deletion mice exhibit increased Ube3a-ATS levels in differentiated neurons and show a reduced effect of topotecan compared with wild-type neurons. These results demonstrate that the AS candidate drug topotecan acts predominantly through stabilizing R loops and chromatin decondensation at the paternally expressed PWS Snord116 locus. Our study holds promise for targeted therapies to the Snord116 locus for both AS and PWS. PMID- 23918392 TI - Unifying model for molecular determinants of the preselection Vbeta repertoire. AB - The primary antigen receptor repertoire is sculpted by the process of V(D)J recombination, which must strike a balance between diversification and favoring gene segments with specialized functions. The precise determinants of how often gene segments are chosen to complete variable region coding exons remain elusive. We quantified Vbeta use in the preselection Tcrb repertoire and report relative contributions of 13 distinct features that may shape their recombination efficiencies, including transcription, chromatin environment, spatial proximity to their DbetaJbeta targets, and predicted quality of recombination signal sequences (RSSs). We show that, in contrast to functional Vbeta gene segments, all pseudo-Vbeta segments are sequestered in transcriptionally silent chromatin, which effectively suppresses wasteful recombination. Importantly, computational analyses provide a unifying model, revealing a minimum set of five parameters that are predictive of Vbeta use, dominated by chromatin modifications associated with transcription, but largely independent of precise spatial proximity to DbetaJbeta clusters. This learned model-building strategy may be useful in predicting the relative contributions of epigenetic, spatial, and RSS features in shaping preselection V repertoires at other antigen receptor loci. Ultimately, such models may also predict how designed or naturally occurring alterations of these loci perturb the preselection use of variable gene segments. PMID- 23918393 TI - Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells. AB - Neural precursor cells of the central nervous system undergo successive temporal waves of terminal division, each of which is soon followed by the onset of cell differentiation. The organ of Corti in the mammalian cochlea develops differently, such that precursors at the apex are the first to exit from the cell cycle but the last to begin differentiating as mechanosensory hair cells. Using a tissue-specific knockout approach in mice, we show that this unique temporal pattern of sensory cell development requires that the adjacent auditory (spiral) ganglion serve as a source of the signaling molecule Sonic hedgehog (Shh). In the absence of this signaling, the cochlear duct is shortened, sensory hair cell precursors exit from the cell cycle prematurely, and hair cell differentiation closely follows cell cycle exit in a similar apical-to-basal direction. The dynamic relationship between the restriction of Shh expression in the developing spiral ganglion and its proximity to regions of the growing cochlear duct dictates the timing of terminal mitosis of hair cell precursors and their subsequent differentiation. PMID- 23918394 TI - Ventral premammillary nucleus as a critical sensory relay to the maternal aggression network. AB - Maternal aggression is under the control of a wide variety of factors that prime the females for aggression or trigger the aggressive event. Maternal attacks are triggered by the perception of sensory cues from the intruder, and here we have identified a site in the hypothalamus of lactating rats that is highly responsive to the male intruder--the ventral premammillary nucleus (PMv). The PMv is heavily targeted by the medial amygdalar nucleus, and we used lesion and immediate-early gene studies to test our working hypothesis that the PMv signals the presence of a male intruder and transfers this information to the network organizing maternal aggression. PMv-lesioned dams exhibit significantly reduced maternal aggression, without affecting maternal care. The Fos analysis revealed that PMv influences the activation of hypothalamic and septal sites shown to be mobilized during maternal aggression, including the medial preoptic nucleus (likely to represent an important locus to integrate priming stimuli critical for maternal aggression), the caudal two-thirds of the hypothalamic attack area (comprising the ventrolateral part of the ventromedial hypothalamic nucleus and the adjacent tuberal region of the lateral hypothalamic area, critical for the expression of maternal aggression), and the ventral part of the anterior bed nuclei of the stria terminalis (presently discussed as being involved in controlling neuroendocrine and autonomic responses accompanying maternal aggression). These findings reveal an important role for the PMv in detecting the male intruder and how this nucleus modulates the network controlling maternal aggression. PMID- 23918395 TI - Sphingosine 1-phosphate receptor 3 regulates recruitment of anti-inflammatory monocytes to microvessels during implant arteriogenesis. AB - Endothelial cells play significant roles in conditioning tissues after injury by the production and secretion of angiocrine factors. At least two distinct subsets of monocytes, CD45(+)CD11b(+)Gr1(+)Ly6C(+) inflammatory and CD45(+)CD11b(+)Gr1( )Ly6C(-) anti-inflammatory monocytes, respond differentially to these angiocrine factors and promote pathogen/debris clearance and arteriogenesis/tissue regeneration, respectively. We demonstrate here that local sphingosine 1 phosphate receptor 3 (S1P3) agonism recruits anti-inflammatory monocytes to remodeling vessels. Poly(lactic-co-glycolic acid) thin films were used to deliver FTY720, an S1P1/3 agonist, to inflamed and ischemic tissues, which resulted in a reduction in proinflammatory cytokine secretion and an increase in regenerative cytokine secretion. The altered balance of cytokine secretion results in preferential recruitment of anti-inflammatory monocytes from circulation. The chemotaxis of these cells, which express more S1P3 than inflammatory monocytes, toward SDF-1alpha was also enhanced with FTY720 treatment, but not in S1P3 knockout cells. FTY720 delivery enhanced arteriolar diameter expansion and increased length density of the local vasculature. This work establishes a role for S1P receptor signaling in the local conditioning of tissues by angiocrine factors that preferentially recruit regenerative monocytes that can enhance healing outcomes, tissue regeneration, and biomaterial implant functionality. PMID- 23918397 TI - State-dependent climate sensitivity in past warm climates and its implications for future climate projections. AB - Projections of future climate depend critically on refined estimates of climate sensitivity. Recent progress in temperature proxies dramatically increases the magnitude of warming reconstructed from early Paleogene greenhouse climates and demands a close examination of the forcing and feedback mechanisms that maintained this warmth and the broad dynamic range that these paleoclimate records attest to. Here, we show that several complementary resolutions to these questions are possible in the context of model simulations using modern and early Paleogene configurations. We find that (i) changes in boundary conditions representative of slow "Earth system" feedbacks play an important role in maintaining elevated early Paleogene temperatures, (ii) radiative forcing by carbon dioxide deviates significantly from pure logarithmic behavior at concentrations relevant for simulation of the early Paleogene, and (iii) fast or "Charney" climate sensitivity in this model increases sharply as the climate warms. Thus, increased forcing and increased slow and fast sensitivity can all play a substantial role in maintaining early Paleogene warmth. This poses an equifinality problem: The same climate can be maintained by a different mix of these ingredients; however, at present, the mix cannot be constrained directly from climate proxy data. The implications of strongly state-dependent fast sensitivity reach far beyond the early Paleogene. The study of past warm climates may not narrow uncertainty in future climate projections in coming centuries because fast climate sensitivity may itself be state-dependent, but proxies and models are both consistent with significant increases in fast sensitivity with increasing temperature. PMID- 23918396 TI - Convergent Ca2+ and Zn2+ signaling regulates apoptotic Kv2.1 K+ currents. AB - A simultaneous increase in cytosolic Zn(2+) and Ca(2+) accompanies the initiation of neuronal cell death signaling cascades. However, the molecular convergence points of cellular processes activated by these cations are poorly understood. Here, we show that Ca(2+)-dependent activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is required for a cell death-enabling process previously shown to also depend on Zn(2+). We have reported that oxidant-induced intraneuronal Zn(2+) liberation triggers a syntaxin-dependent incorporation of Kv2.1 voltage-gated potassium channels into the plasma membrane. This channel insertion can be detected as a marked enhancement of delayed rectifier K(+) currents in voltage clamp measurements observed at least 3 h following a short exposure to an apoptogenic stimulus. This current increase is the process responsible for the cytoplasmic loss of K(+) that enables protease and nuclease activation during apoptosis. In the present study, we demonstrate that an oxidative stimulus also promotes intracellular Ca(2+) release and activation of CaMKII, which, in turn, modulates the ability of syntaxin to interact with Kv2.1. Pharmacological or molecular inhibition of CaMKII prevents the K(+) current enhancement observed following oxidative injury and, importantly, significantly increases neuronal viability. These findings reveal a previously unrecognized cooperative convergence of Ca(2+)- and Zn(2+)-mediated injurious signaling pathways, providing a potentially unique target for therapeutic intervention in neurodegenerative conditions associated with oxidative stress. PMID- 23918398 TI - Statistically accurate low-order models for uncertainty quantification in turbulent dynamical systems. AB - A framework for low-order predictive statistical modeling and uncertainty quantification in turbulent dynamical systems is developed here. These reduced order, modified quasilinear Gaussian (ROMQG) algorithms apply to turbulent dynamical systems in which there is significant linear instability or linear nonnormal dynamics in the unperturbed system and energy-conserving nonlinear interactions that transfer energy from the unstable modes to the stable modes where dissipation occurs, resulting in a statistical steady state; such turbulent dynamical systems are ubiquitous in geophysical and engineering turbulence. The ROMQG method involves constructing a low-order, nonlinear, dynamical system for the mean and covariance statistics in the reduced subspace that has the unperturbed statistics as a stable fixed point and optimally incorporates the indirect effect of non-Gaussian third-order statistics for the unperturbed system in a systematic calibration stage. This calibration procedure is achieved through information involving only the mean and covariance statistics for the unperturbed equilibrium. The performance of the ROMQG algorithm is assessed on two stringent test cases: the 40-mode Lorenz 96 model mimicking midlatitude atmospheric turbulence and two-layer baroclinic models for high-latitude ocean turbulence with over 125,000 degrees of freedom. In the Lorenz 96 model, the ROMQG algorithm with just a single mode captures the transient response to random or deterministic forcing. For the baroclinic ocean turbulence models, the inexpensive ROMQG algorithm with 252 modes, less than 0.2% of the total, captures the nonlinear response of the energy, the heat flux, and even the one-dimensional energy and heat flux spectra. PMID- 23918399 TI - PICK1 interacts with PACSIN to regulate AMPA receptor internalization and cerebellar long-term depression. AB - The dynamic trafficking of AMPA receptors (AMPARs) into and out of synapses is crucial for synaptic transmission, plasticity, learning, and memory. The protein interacting with C-kinase 1 (PICK1) directly interacts with GluA2/3 subunits of the AMPARs. Although the role of PICK1 in regulating AMPAR trafficking and multiple forms of synaptic plasticity is known, the exact molecular mechanisms underlying this process remain unclear. Here, we report a unique interaction between PICK1 and all three members of the protein kinase C and casein kinase II substrate in neurons (PACSIN) family and show that they form a complex with AMPARs. Our results reveal that knockdown of the neuronal-specific protein, PACSIN1, leads to a significant reduction in AMPAR internalization following the activation of NMDA receptors in hippocampal neurons. The interaction between PICK1 and PACSIN1 is regulated by PACSIN1 phosphorylation within the variable region and is required for AMPAR endocytosis. Similarly, the binding of PICK1 to the ubiquitously expressed PACSIN2 is also regulated by the homologous phosphorylation sites within the PACSIN2-variable region. Genetic deletion of PACSIN2, which is highly expressed in Purkinje cells, eliminates cerebellar long term depression. This deficit can be fully rescued by overexpressing wild-type PACSIN2, but not by a PACSIN2 phosphomimetic mutant, which does not bind PICK1 efficiently. Taken together, our data demonstrate that the interaction of PICK1 and PACSIN is required for the activity-dependent internalization of AMPARs and for the expression of long-term depression in the cerebellum. PMID- 23918400 TI - TNFSF15 inhibits vasculogenesis by regulating relative levels of membrane-bound and soluble isoforms of VEGF receptor 1. AB - Mouse bone marrow-derived Lin(-)-Sca-1(+) endothelial progenitor cell (EPC) has pluripotent abilities such as supporting neovascularization. Vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) (Flt1) recognizes various VEGF isoforms and is critically implicated in a wide range of physiological and pathological settings, including vasculogenesis. Mouse EPC expresses two isoforms of VEGFR1: mFlt1, which transmits ligand-induced signals; and sFlt1, which acts as a negative regulator by sequestering ligands of VEGF receptors. How the relative levels of mFlt1 and sFlt1 are regulated is not yet clear. We report here that tumor necrosis factor superfamily 15 (TNFSF15) (also known as VEGI or TL1A), an endothelial cell-secreted cytokine, simultaneously promotes mFlt1 degradation and up-regulates sFlt1 expression in EPC, giving rise to disruption of VEGF- or PlGF induced activation of eNOS and MAPK p38 and effective inhibition of VEGF-driven, EPC-supported vasculogenesis in a murine Matrigel implant model. TNFSF15 treatment of EPC cultures facilitates Akt deactivation-dependent, ubiquitin assisted degradation of mFlt1 and stimulates sFlt1 expression by activating the PKC, Src, and Erk1/2 signaling pathway. Additionally, TNFSF15 promotes alternative splicing of the Flt1 gene in favor of sFlt1 production by down regulating nuclear protein Jumonji domain-containing protein 6 (Jmjd6), thus alleviating Jmjd6-inhibited sFlt1 expression. These findings indicate that TNFSF15 is a key component of a molecular mechanism that negatively modulates EPC supported vasculogenesis through regulation of the relative levels of mFlt1 and sFlt1 in EPC. PMID- 23918402 TI - Time-dependent climate sensitivity and the legacy of anthropogenic greenhouse gas emissions. AB - Climate sensitivity measures the response of Earth's surface temperature to changes in forcing. The response depends on various climate processes that feed back on the initial forcing on different timescales. Understanding climate sensitivity is fundamental to reconstructing Earth's climatic history as well as predicting future climate change. On timescales shorter than centuries, only fast climate feedbacks including water vapor, lapse rate, clouds, and snow/sea ice albedo are usually considered. However, on timescales longer than millennia, the generally higher Earth system sensitivity becomes relevant, including changes in ice sheets, vegetation, ocean circulation, biogeochemical cycling, etc. Here, I introduce the time-dependent climate sensitivity, which unifies fast-feedback and Earth system sensitivity. I show that warming projections, which include a time dependent climate sensitivity, exhibit an enhanced feedback between surface warming and ocean CO2 solubility, which in turn leads to higher atmospheric CO2 levels and further warming. Compared with earlier studies, my results predict a much longer lifetime of human-induced future warming (23,000-165,000 y), which increases the likelihood of large ice sheet melting and major sea level rise. The main point regarding the legacy of anthropogenic greenhouse gas emissions is that, even if the fast-feedback sensitivity is no more than 3 K per CO2 doubling, there will likely be additional long-term warming from slow climate feedbacks. Time-dependent climate sensitivity also helps explaining intense and prolonged warming in response to massive carbon release as documented for past events such as the Paleocene-Eocene Thermal Maximum. PMID- 23918401 TI - On-chip phenotypic analysis of inflammatory monocytes in atherogenesis and myocardial infarction. AB - Monocyte recruitment to inflamed arterial endothelium initiates plaque formation and drives progression of atherosclerosis. Three distinct monocyte subsets are detected in circulation (CD14(++)CD16(-), CD14(++)CD16(+), and CD14(+)CD16(++)), and each may play distinct roles during atherogenesis and myocardial infarction. We studied a range of subjects that included otherwise healthy patients with elevated serum triglyceride levels to patients presenting with acute myocardial infarction. Our objective was to correlate an individual's risk with the activation state of each monocyte subset as a function of changes in adhesion receptor expression using flow cytometric quantitation of integrins and l selectin membrane expression. A microfluidic-based laboratory-on-a-chip was developed to quantify the adhesion efficiency of monocytes sheared in whole blood on vascular cell adhesion molecule-1, while characterizing adhesion receptor expression and topography on captured monocytes. CD14(++)CD16(+) monocytes adhered with sevenfold higher efficiency than other subsets, and in patients with myocardial infarction the capture efficiency of this subset was double that for healthy subjects. In patients with hypertriglyceridemia, this increase in monocyte adhesion was attributable to CD14(++)CD16(+) uptake of triglyceride-rich lipoproteins and subsequent signaling via a Phospholipase C-dependent mechanism to increase CD11c expression, very late antigen-4 function, and integrin coclustering within focal adhesive sites on vascular cell adhesion molecule-1. In summary, we introduce a unique laboratory-on-a-chip method for quantifying the activation state of monocyte subsets. These experiments reveal that CD11c/CD18 is an inducible integrin whose expression correlates with a monocyte inflammatory state in subjects at risk for atherogenesis and in patients with myocardial infarction. PMID- 23918403 TI - Ultraconserved words and Eurasiatic? The "faces in the fire" of language prehistory. PMID- 23918404 TI - Short, frequent words are more likely to appear genetically related by chance. PMID- 23918405 TI - Development of the rat larynx: a histological study. AB - OBJECTIVES/HYPOTHESIS: To evaluate and describe the cartilaginous and muscular development of the rat larynx. STUDY DESIGN: Histologic evaluation. METHODS: The larynges of Sprague Dawley rats of embryonic day (E) 13, 15, 17, 19, 21, postnatal day 0, 14, and adult of 250 gm were collected. Four larynges of each age were harvested, cut into 15-MUm serial sections, stained with hematoxylin and eosin, and evaluated under light microscopy. Representative digital images were recorded and evaluated at the preglottic (supraglottic in humans), glottic, and postglottic (subglottic in humans) levels. RESULTS: Brachial arches were observed at E13. At E17, immature structures of the larynx, including skeletal muscle, cartilage, and the lumen were identifiable. Chondrification and muscle formation were clearly seen by E19. The muscular and cartilagenous components of the larynx were well established by E21. During the span between birth and adult maturation, the size of the larynx increased from a height of 1.10 mm to 2.90 mm, and from a width of 1.80 mm to 5.40 mm, and from a length of 1.38 mm to 4.77 mm in the stained section. Although developed at E21, the laryngeal structures continued to grow by approximately 30%. CONCLUSION: Rat laryngeal development parallels that in mice and humans. In the rat, at E17 immature structures of the larynx are identifiable, they are well developed at birth and grow by approximately 30% into adulthood. Understanding the chronology and morphology of the embryogenesis of the rat laryngeal musculature is essential and will allow for further evaluation of the embryologic innervation of these muscles. PMID- 23918406 TI - Bacterial bioeffectors modify bioactive profile and increase isoflavone content in soybean sprouts (Glycine max var Osumi). AB - The effect of two bacterial strains to enhance bioactive contents (total phenolic compounds, total flavonoid compounds and isoflavones) and antioxidant activity on 3-day-old soybean sprouts were investigated. To identify bacterial determinants responsible for these effects, viable and UV-treated strains were delivered to wounded seeds at different concentration. Multivariate analysis performed with all the evaluated parameters indicated the different effectiveness of Stenotrophomonas maltophilia N5.18 and Pseudomonas fluorescens N21.4 based on different structural and metabolic determinants for each. N21.4 increased total phenolics and isoflavones from the genistein family, while N5.18 triggered biosynthesis of daidzein and genistein families coupled to a decrease in total phenolics, suggesting different molecular targets in the phenilpropanoid pathway. Only extracts from N5.18 treated seeds showed an improved antioxidant activity according to the beta-carotene bleaching prevention method. In summary, bioeffectors from both bacterial strains are effective tools to improve soybean sprouts quality; structural elicitors from N5.18 also enhanced antioxidant activity, being the best alternative for further development of a biotechnological procedure. PMID- 23918407 TI - A virus-encoded potassium ion channel is a structural protein in the chlorovirus Paramecium bursaria chlorella virus 1 virion. AB - Most chloroviruses encode small K(+) channels, which are functional in electrophysiological assays. The experimental finding that initial steps in viral infection exhibit the same sensitivity to channel inhibitors as the viral K(+) channels has led to the hypothesis that the channels are structural proteins located in the internal membrane of the virus particles. This hypothesis was questioned recently because proteomic studies failed to detect the channel protein in virions of the prototype chlorovirus Paramecium bursaria chlorella virus 1 (PBCV-1). Here, we used a mAb raised against the functional K(+) channel from chlorovirus MA-1D to search for the viral K(+) channel in the virus particle. The results showed that the antibody was specific and bound to the tetrameric channel on the extracellular side. The antibody reacted in a virus specific manner with protein extracts from chloroviruses that encoded channels similar to that from MA-1D. There was no cross-reactivity with chloroviruses that encoded more diverse channels or with a chlorovirus that lacked a K(+) channel gene. Together with electron microscopic imaging, which revealed labelling of individual virus particles with the channel antibody, these results establish that the viral particles contain an active K(+) channel, presumably located in the lipid membrane that surrounds the DNA in the mature virions. PMID- 23918408 TI - Identification and characterization of a novel paramyxovirus, porcine parainfluenza virus 1, from deceased pigs. AB - We describe the discovery and characterization of a novel paramyxovirus, porcine parainfluenza virus 1 (PPIV-1), from swine. The virus was detected in 12 (3.1 %) of 386 nasopharyngeal and two (0.7 %) of 303 rectal swab samples from 386 deceased pigs by reverse transcription-PCR, with viral loads of up to 10(6) copies ml(-1). Complete genome sequencing and phylogenetic analysis showed that PPIV-1 represented a novel paramyxovirus within the genus Respirovirus, being most closely related to human parainfluenza virus 1 (HPIV-1) and Sendai virus (SeV). In contrast to HPIV-1, PPIV-1 possessed a mRNA editing function in the phosphoprotein gene. Moreover, PPIV-1 was unique among respiroviruses in having two G residues instead of three to five G residues following the A6 run at the editing site. Nevertheless, PPIV-1, HPIV-1 and SeV share common genomic features and may belong to a separate group within the genus Respirovirus. The presence of PPIV-1 in mainly respiratory samples suggests a possible association with respiratory disease, similar to HPIV-1 and SeV. PMID- 23918409 TI - Impact of study design on the evaluation of inhaled and intranasal corticosteroids' effect on hypothalamic-pituitary-adrenal axis function, part I: general overview of HPA axis study design. AB - Inhaled and intranasal corticosteroids (ICS and INS) are among the mainstays of the treatment for asthma and allergic rhinitis, respectively, and also carry the potential to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Several important factors affect the interpretability of trials investigating the impact of ICS and INS on the HPA axis. This paper reviews 106 published clinical trials, peer-reviewed articles, and New Drug Application reviews of approved ICS and INS, using MEDLINE and Drugs@FDA database. The trials included in this review evaluated the potential impact on HPA axis function of eight approved single ingredient ICS and INS (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone furoate, flucticasone propionate, mometasone furoate, and triamcinolone acetonide) and combination products containing these ingredients. The most commonly utilized design was blinded, placebo controlled, and short term (<6 weeks) for adult trials and blinded, placebo controlled, and long term (>=6 weeks) for pediatric trials. Factors potentially affecting trial results include the choice of dose, dosing duration, assay sensitivity, statistical methodology, and the study population evaluated (patients or healthy volunteers). All of these factors have the potential to affect the level of adrenal suppression detected. In conclusion, to be informative, a HPA axis study should be well designed and carefully implemented to minimize variability in results and improve the overall interpretability of data obtained. PMID- 23918410 TI - Edible protein energy return on investment ratio (ep-EROI) for Spanish seafood products. AB - Life cycle assessment (LCA) has developed into a useful methodology to assess energy consumption of fishing fleets and their derived seafood products, as well as the associated environmental burdens. In this study, however, the life cycle inventory data is used to provide a dimensionless ratio between energy inputs and the energy provided by the fish: the edible protein energy return on investment (ep-EROI). The main objective was to perform a critical comparison of seafood products landed in Galicia (NW Spain) in terms of ep-EROI. The combination of energy return on investment (EROI) with LCA, the latter having standardized mechanisms regarding data acquisition and system boundary delimitation, allowed a reduction of uncertainties in EROI estimations. Results allow a deeper understanding of the energy efficiency in the Galician fishing sector, showing that small pelagic species present the highest ep-EROI values if captured using specific fishing techniques. Finally, results are expected to provide useful guidelines for policy support in the EU's Common Fisheries Policy. PMID- 23918411 TI - A call for urgent monitoring of food and water security based on relevant indicators for the Arctic. AB - This perspective paper argues for an urgent need to monitor a set of 12 concrete, measurable indicators of food and water security in the Arctic over time. Such a quantitative indicator approach may be viewed as representing a reductionist rather than a holistic perspective, but is nevertheless necessary for actually knowing what reality aspects to monitor in order to accurately understand, quantify, and be able to project critical changes to food and water security of both indigenous and non-indigenous people in the Arctic. More relevant indicators may be developed in the future, taking us further toward reconciliation between reductionist and holistic approaches to change assessment and understanding. However, the potential of such further development to improved holistic change assessment is not an argument not to urgently start to monitor and quantify the changes in food and water security indicators that are immediately available and adequate for the Arctic context. PMID- 23918412 TI - Pikeperch (Sander lucioperca (L.)) in decline: high mortality of three populations in the northern Baltic Sea. AB - The development of three pikeperch (Sander lucioperca (L.)) populations in the northern Baltic Sea was monitored using standardized multimesh gillnets in 1995 2009. Declining trends in the abundances of pikeperch over 40 cm total length, low numbers of individuals older than 6 years, and high mortality rates were observed in all three populations. In the site with the largest commercial catches per unit area and a rapidly increased colony of great cormorants (Phalacrocorax carbo sinensis Blumenbach 1798), also the abundance of pikeperch below 40 cm total length and year-class strength showed declining trends. The adverse population level changes did not correlate with changes in water quality or eutrophication status. Together, the results suggest that in all study sites fisheries are harvesting a large proportion of the pikeperch soon after or even before reaching the maturity, and that predation from great cormorants may increase mortality of juveniles. Pikeperch is important not only for fisheries but also for ecosystem functioning, and our results point at the need for further management measures to ensure viable populations in the areas studied. PMID- 23918413 TI - Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response. AB - OBJECTIVE: Rituximab, a monoclonal antibody specifically targeting CD20, induces B cell depletion and is effective in the treatment of rheumatoid arthritis (RA). This study was undertaken to evaluate whether routine monitoring of lymphocyte subpopulations, especially T cells, may be useful in patients receiving rituximab for RA. METHODS: We examined data on all RA patients receiving rituximab between July 2007 and November 2012 in our center. Peripheral blood CD3+, CD4+, CD8+, CD3 CD56+, and CD19+ lymphocyte counts before and during the first course of rituximab were measured by flow cytometry. The Mann-Whitney nonparametric test was used to compare lymphocyte subpopulation counts before and during treatment. RESULTS: Data on 52 patients were examined. Rituximab induced unexpected and substantial depletion of T cells, mainly CD4+ cells, in most patients. The CD4+ cell count decreased by a mean +/- SD of 37 +/- 33% as compared to baseline at week 12, reaching <200 cells/MUl in 3 patients. Importantly, lack of CD4+ cell depletion was associated with no clinical response. Therefore, the mechanism of action of rituximab may depend at least in part on T cells. CONCLUSION: Rituximab induces substantial T cell depletion, mainly of CD4+ cells, which is associated with the clinical response in RA. Routine monitoring of T cells may be useful in the clinical setting of RA. PMID- 23918414 TI - Operative treatment and outcome of unstable distal radial fractures using a palmar T-miniplate at a non-specialized institution. AB - Treatment options for displaced distal radial fractures are still a controversial topic of discussion. Although good results for the palmar plating of high-volume centers have been published, evidence of its successful use in smaller institutions is still lacking. We report the clinical and radiological results of the treatment for 84 distal radial fractures with a single 2.4-mm T-miniplate in an institution performing <30 procedures per year. According to the AO classification system, there were 30 A, 5 B, and 49 C fractures with a patients mean age of 64 years. After a minimum of 12-month follow-up, we found very good and good results according to the Gardland and Sarmiento scores and a DASH of 5.6. Only five patients were classified as having a moderate outcome. A remaining intra-articular step-off of more than 1 mm was seen in 15 patients. In a comparison of grip strength between the injured and uninjured hands, we saw a difference of 6.8 % less on the injured side. We saw two instances of tendon rupture and one of tendon irritation due to prominent dorsal screws and necessitating revision surgery. Flexor tendon irritation was noted in one patient, requiring a second operation. Modern treatment for distal radial fractures can be performed successfully and with good clinical outcome in smaller institutions. Based on the high and increasing incidence of distal radial fractures, there is no need to transfer these patients into high-volume centers. Level of evidence Case study, Level IV. PMID- 23918415 TI - N-substituted 1,2-dihydroquinolines as anticancer agents: electronic control of redox stability, assessment of antiproliferative effects, and mechanistic insights. AB - Redox chemotherapy: Antiproliferative activities of a series of N-substituted 1,2 dihydroquinolines capable of causing redox imbalance in cancer cells are presented. Detailed studies showed that these derivatives arrest the cell cycle in the G2/M phase and induce apoptosis through an intrinsic pathway characterized by loss of mitochondrial membrane potential, DNA fragmentation, cytochrome c release, and activation of caspases 9 and 3. PMID- 23918416 TI - Interstitial 12p13.1 deletion involving GRIN2B in three patients with intellectual disability. AB - We report on three patients presenting moderate intellectual disability, delayed language acquisition, and mild facial dysmorphia. Array-CGH studies revealed overlapping interstitial 12p13.1 microdeletions encompassing all or part of GRIN2B. GRIN2B encodes the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. This receptor is a heteromeric glutamate-activated ion channel, present throughout the central nervous system. It plays a critical role in corticogenesis, neuronal migration, and synaptogenesis during brain development. GRIN2B alterations, including mutation and gene disruption by apparently balanced chromosomal rearrangements, have been described in patients with intellectual disability and autism spectrum disorder. We report here on the first cases of GRIN2B deletion, enlarging the spectrum of GRIN2B abnormalities. Our findings confirm the involvement of this gene in neurodevelopmental disorders. (c) 2013 Wiley Periodicals, Inc. PMID- 23918417 TI - Historical overview of transposable element research. AB - Research on transposable elements began nearly 100 years ago with classical genetic experiments. Remarkably, many of the activities of transposable elements, such as the ability to transpose, to induce chromosome rearrangements, to undergo cycles of activity and inactivity, and to affect expression of neighboring genes, were described by geneticists long before transposons were molecularly isolated. This chapter traces the historical roots of transposable element research, describing the scientists, their observations, and interpretations as they sought to understand the enigma of transposable elements. PMID- 23918418 TI - Distinguishing variable phenotypes from variegation caused by transposon activities. AB - Variable phenotypes are common in nature and in laboratory materials. Guidelines and illustrations are presented to help distinguish developmental, environmental, disease, and somatic recombination-generated variation from the phenotypes caused by transposable elements. PMID- 23918419 TI - Using transposons for genetic mosaic analysis of plant development. AB - Genetic mosaics, or chimeras, are individual organisms composed of cells or tissues of two or more distinct genotypes. They are experimentally useful for addressing several key biological questions. These include fate mapping through analysis of marked clonal lineages, analyzing cell or tissue interactions such as the induction of developmental events, and analyzing whether a gene acts cell autonomously. Genetic mosaics can arise in many ways, including through the action of transposable elements. Naturally occurring transposons can generate genetic mosaics by somatically inserting into a gene to cause a mutant sector, somatically excising from a mutant gene to create a revertant wild-type sector, or causing chromosomal breaks or rearrangements leading to loss of a gene or genes. Transposons have also been cleverly engineered to allow the generation of marked somatic sectors, sometimes in controlled ways. Here we review ways in which transposon-induced genetic mosaics have been used experimentally, the various methods that have been used, and general considerations for designing genetic mosaic studies using transposon methods. PMID- 23918420 TI - Survey of natural and transgenic gene markers used to monitor transposon activity. AB - Marker genes have played a critical role in the discovery of plant transposable elements, our understanding of transposon biology, and the utility of transposable elements as tools in functional genomics. Marker traits in model plants have been useful to detect transposable elements and to study the dynamics of transposition. Transposon-induced changes in the sequence of marker genes and consequently their expression have contributed to our understanding of molecular mechanisms of transposition and associated genome rearrangements. Further, marker genes that have been cloned and are compatible in heterologous systems have found versatile utility in the design of DNA constructs that have enabled us to understand the finer details of transposition mechanisms, and also allowed the use of transposon-based tools for functional genomics. This chapter traces the role of marker traits and marker genes (endogenous and transgenic) in various plant systems, and their contributions to the advancement of transposon biology over the past several decades. PMID- 23918421 TI - Molecular biology of maize Ac/Ds elements: an overview. AB - Maize Activator (Ac) is one of the prototype transposable elements of the hAT transposon superfamily, members of which were identified in plants, fungi, and animals. The autonomous Ac and nonautonomous Dissociation (Ds) elements are mobilized by the single transposase protein encoded by Ac. To date Ac/Ds transposons were shown to be functional in approximately 20 plant species and have become the most widely used transposable elements for gene tagging and functional genomics approaches in plants. In this chapter we review the biology, regulation, and transposition mechanism of Ac/Ds elements in maize and heterologous plants. We discuss the parameters that are known to influence the functionality and transposition efficiency of Ac/Ds transposons and need to be considered when designing Ac transposase expression constructs and Ds elements for application in heterologous plant species. PMID- 23918422 TI - Gene tagging with engineered Ds elements in maize. AB - We describe here protocols for isolating genes in maize using Dissociation (Ds) transposons marked with a green fluorescent protein (GFP) transgene. The introduced marker enables the phenotypic scoring of the nonautonomous element and the anchoring of unique primers on the element to facilitate the isolation of the adjacent DNA by PCR. Transposons such as Ds transpose preferentially to sites closely linked to the Ds-launching platform. Based on this transposition behavior, a genetic resource is being created to mobilize a modified Ds element from different starting sites in the genome. Enough transgenic lines are being generated to cover most of the maize genome, allowing the targeted tagging of most genes from a Ds-launching platform located nearby. PMID- 23918423 TI - Plant regeneration methods for rapid generation of a large scale Ds transposant population in rice. AB - To mutagenize rice genomes, a two-element system is utilized. This system comprises an immobile Ac element driven by the CaMV 35S promoter, and a gene trap Ds carrying a partial intron with alternative splice acceptors fused to the GUS coding region. Rapid, large-scale generation of a Ds transposant population was achieved using a plant regeneration procedure involving the tissue culture of seed-derived calli carrying Ac and Ds elements. During tissue cultures, Ds mobility accompanies changes in methylation patterns of a terminal region of Ds, where over 70% of plants contained independent Ds insertions. In the transposon population, around 12% of plants expressed GUS at the early seedling stage. A flanking-sequence-tag (FST) database has been established by cloning over 19,968 Ds insertion sites and the Ds map shows relatively uniform distribution across the rice chromosomes. PMID- 23918424 TI - Isolation of sequences flanking Ac insertion sites by Ac casting. AB - Localizing Ac insertions is a fundamental task in studying Ac-induced mutation and chromosomal rearrangements involving Ac elements. Researchers may sometimes be faced with the situation in which the sequence flanking one side of an Ac/Ds element is known, but the other flank is unknown. Or, a researcher may have a small sequence surrounding the Ac/Ds insertion site and needs to obtain additional flanking genomic sequences. One way to rapidly clone unknown Ac/Ds flanking sequences is via a PCR-based method termed Ac casting. This approach utilizes the somatic transposition activity of Ac during plant development, and provides an efficient means for short-range genome walking. Here we describe the principle of Ac casting, and show how it can be applied to isolate Ac macrotransposon insertion sites. PMID- 23918425 TI - Regulation of the Mutator system of transposons in maize. AB - The Mutator system has proved to be an invaluable tool for elucidating gene function via insertional mutagenesis. Its high copy number, high transposition frequency, relative lack of insertion specificity, and ease of use has made it the preferred method for gene tagging in maize. Recent advances in high throughput sequencing of insertion sites, combined with the availability of large numbers of pre-mutagenized and sequence-indexed stocks, ensure that this resource will only be more useful in the years ahead. Muk is a locus that can silence Mu active lines, making it possible to ameliorate the phenotypic effects of high numbers of active Mu transposons and reduce the copy number of these elements during introgressions. PMID- 23918426 TI - Using MuDR/Mu transposons in directed tagging strategies. AB - An introduction to MuDR/Mu transposons as mutagens is provided along with protocols for using these elements to tag maize genes. Selection for retention of Mutator activity is described as well as details for establishing and screening tagging populations efficiently. PMID- 23918427 TI - Genetic and molecular analyses of UniformMu transposon insertion lines. AB - The UniformMu transposon population is a large public resource for reverse genetics and functional genomics of maize. Users access the collection of UniformMu genetic stocks that are freely distributed by the Maize Cooperation Stock Center using online tools maintained at MaizeGDB.org. Genetic and molecular analyses of UniformMu stocks (UFMu insertion lines) typically require development of genotyping assays that use a gene-specific polymerase chain reaction (PCR) to follow segregation of transposon insertions in genes of interest. Here we describe methods for accessing the resource and recommended protocols for genotyping of transposon insertion alleles. PMID- 23918428 TI - Digestion-ligation-amplification (DLA): a simple genome walking method to amplify unknown sequences flanking mutator (Mu) transposons and thereby facilitate gene cloning. AB - Digestion-ligation-amplification (DLA), a novel PCR-based genome walking method, was developed to amplify unknown sequences flanking known sequences of interest. DLA specifically overcomes the problems associated with amplifying genomic sequences flanking high copy number transposons in large genomes. Two DLA-based strategies, MuClone and DLA-454, were developed to isolate Mu-tagged alleles. MuClone allows for the amplification of DNA flanking subsets of the numerous Mu transposons in the genome using unique three-nucleotide tags at the 3'-ends of primers, simplifying the identification of flanking sequences that co-segregate with mutant phenotypes caused by Mu insertions. DLA-454, which combines DLA with 454 pyrosequencing, permits the efficient amplification and sequencing of Mu flanking regions in a high-throughput manner. PMID- 23918429 TI - Molecular genetics and epigenetics of CACTA elements. AB - The CACTA transposons, so named for a highly conserved motif at element ends, comprise one of the most abundant superfamilies of Class 2 (cut-and-paste) plant transposons. CACTA transposons characteristically include subterminal sequences of several hundred nucleotides containing closely spaced direct and inverted repeats of a short, conserved sequence of 14-15 bp. The Supressor-mutator (Spm) transposon, identified and subjected to detailed genetic analysis by Barbara McClintock, remains the paradigmatic element of the CACTA family. The Spm transposon encodes two proteins required for transposition, the transposase (TnpD) and a regulatory protein (TnpA) that binds to the subterminal repeats. Spm expression is subject to both genetic and epigenetic regulation. The Spm-encoded TnpA serves as an activator of the epigenetically inactivated, methylated Spm, stimulating both transient and heritable activation of the transposon. TnpA also serves as a negative regulator of the demethylated active element promoter and is required, in addition to the TnpD, for transposition. PMID- 23918430 TI - Activation tagging using the maize En-I transposon system for the identification of abiotic stress resistance genes in Arabidopsis. AB - Activation tagging is a high-throughput method of overexpressing genes by using an enhancer present in insertion sequences that are randomly inserted in the genome to enhance the expression of adjacent genes. Gain-of-function approaches are advantageous to identify the functions of redundant genes that are not identifiable by knockout (KO) mutations, and for identification of phenotypes with small effects, which are enhanced by activation. An activation tag (ATag) library of 800 lines was generated in Arabidopsis ecotype Columbia using the En-I (Spm) transposon system. The ATag lines were used in a forward genetics strategy to identify novel genes that confer resistance/tolerance to abiotic stresses. The ATag lines were screened for altered drought and salt stress response phenotypes using quantitative assays for biomass accumulation under stress, revealing a number of resistant and sensitive ATag mutants. PMID- 23918431 TI - Reverse genetics in rice using Tos17. AB - Transposon of Oryza sativa 17 (Tos17), a Ty1-Copia Class I retroelement, is one of the few active retroelements identified in rice, the main cereal crop of human consumption and the model genome for cereals. Tos17 exists in two copies in the standard Nipponbare japonica genome (n = 12 and 379 Mb). Tos17 copies are inactive in the plant grown under normal conditions. However, the copy located on chromosome 7 can be activated upon tissue culture. Plants regenerated from 3- and 5-month-old tissue cultures harbor, respectively, an average of 3.5 and 8 newly transposed copies that are stably inserted at new positions in the genome. Due to its favorable features, Tos17 has been extensively used for insertion mutagenesis of the model genome and 31,403 sequence indexed inserts harbored by regenerants/T DNA plants are available in the databases. The corresponding seed stocks can be ordered from the laboratories which generated them. Both forward genetics and reverse genetics approaches using these lines have allowed the deciphering of gene function in rice. We report here two protocols for ascertaining the presence of a Tos17 insertion in a gene of interest among R2/T2 seeds received from Tos17 mutant stock centers: The first protocol is PCR-based and allows the identification of azygous, heterozygous and homozygous plants among progenies segregating the insertion. The second protocol is based on DNA blot analysis and can be used to identify homozygous plants carrying the Tos17 copy responsible for gene disruption while cleaning the mutant background from other unwitting mutagen inserts. PMID- 23918432 TI - Identification and applications of the Petunia class II Act1/dTph1 transposable element system. AB - Transposable genetic elements are considered to be ubiquitous. Despite this, their mutagenic capacity has been exploited in only a few species. The main plant species are maize, Antirrhinum, and Petunia. Representatives of all three major groups of class II elements, viz., hAT-, CACTA- and Mutator-like elements, have been identified in Petunia. Here we focus on the research "history" of the Petunia two-element Act1-dTph1 system and the development of its application in forward- and reverse-genetics studies. PMID- 23918433 TI - Transposon display: a versatile method for transposon tagging. AB - Transposon tagging has been used successfully in a range of organisms for the cloning of mutants of interest. In species containing high copy numbers of transposable elements combined with a high transposition rate, forward cloning can be quite challenging and requires specific high-resolution methods. Here we detail an updated version of the Transposon Display technique, which allows visualization of large numbers of transposon-flanking sequences simultaneously in a highly robust and reproducible manner. This strategy was developed for the analysis of the transpositional behavior of the dTph1 transposon and for the forward cloning of mutants, particularly in the Petunia W138 background, individuals of which can contain >200 copies of the endogenous dTph1 element. The method is derived from the AFLP technique and can in principle easily be adapted to any system. PMID- 23918434 TI - Massive indexed parallel identification of transposon flanking sequences. AB - The large scale sequencing of insertion element flanking sequences has revolutionized reverse genetics in plant research: Insertion mutants can now simply be identified in silico by BLAST searching the resulting flanking sequence databases. The development of next-generation sequencing technologies has further facilitated the creation of flanking sequence collections derived from entire mutant populations. Here we describe a highly efficient and widely applicable method that we developed to amplify, sequence, and identify dTph1 transposon flanking sequences from a library of 1000 Petunia W138 individuals simultaneously. PMID- 23918435 TI - Use of Next Generation Sequencing (NGS) technologies for the genome-wide detection of transposition. AB - Plant transposable elements are ubiquitous in eukaryotes. Their propensity to densely populate the genomes of many plants and animal species has put them in the focus of both structural and functional genomics. Although a number of bioinformatic software have been recently developed for the annotation of TEs in sequenced genomes, there are very few computational tools strictly dedicated to the identification of active TEs using genome-wide approaches. In this paper, we describe SearchTESV, a pipeline that we have developed to detect Transposable Elements-associated structural variants (TEASVs) using Next Generation Sequencing (NGS) technologies. PMID- 23918436 TI - Overview of repeat annotation and de novo repeat identification. AB - The availability of a large amount of genomic sequences has provided unique opportunities for understanding the composition and dynamics of transposable elements (TEs) in plants. As the cost of sequencing declines, the genomic sequences of most crop plants will be available within the next few years. Thus, the annotation of genomic sequences, rather than sequence availability, will become the "bottleneck" for genome study. Since TEs are the largest component of most plant genomes, the automation of TE identification and classification is essential for future genome annotation as well as characterization of TEs. In this chapter, the functions and mechanisms of different repeat finding tools are reviewed, with a focus on de novo repeat identification programs. In addition, this chapter covers the further processing of results from de novo identification programs and the construction of repeat libraries for downstream genome analyses. PMID- 23918437 TI - Computational methods for identification of DNA transposons. AB - The initial identification of transposable elements (TEs) was attributed to the activity of DNA transposable elements, which are prevalent in plants. Unlike RNA elements, which accumulate in the gene-poor heterochromatic regions, most DNA elements are located in the gene rich regions and many of them carry genes or gene fragments. As such, DNA elements have a more intimate relationship with genes and may have an immediate impact on gene expression and gene function. DNA elements are structurally distinct from RNA elements and most of them have terminal inverted repeats (TIRs). Such structural features have been used to identify the relevant elements from genomic sequences. Among the DNA elements in plants, the most abundant type is the miniature inverted repeat transposable elements (MITEs). This chapter discusses the methods to identify MITEs, Helitrons, and other DNA transposable elements. PMID- 23918438 TI - TEnest 2.0: computational annotation and visualization of nested transposable elements. AB - Grass genomes harbor a diverse and complex content of repeated sequences. Most of these repeats occur as abundant transposable elements (TEs), which present unique challenges to sequence, assemble, and annotate genomes. Multiple copies of Long Terminal Repeat (LTR) retrotransposons can hinder sequence assembly and also cause problems with gene annotation. TEs can also contain protein-encoding genes, the ancient remnants of which can mislead gene identification software if not correctly masked. Hence, accurate assembly is crucial for gene annotation. We present TEnest v2.0. TEnest computationally annotates and chronologically displays nested transposable elements. Utilizing organism-specific TE databases as a reference for reconstructing degraded TEs to their ancestral state, annotation of repeats is accomplished by iterative sequence alignment. Subsequently, an output consisting of a graphical display of the chronological nesting structure and coordinate positions of all TE insertions is the result. Both linux command line and Web versions of the TEnest software are available at www.wiselab.org and www.plantgdb.org/tool/, respectively. PMID- 23918439 TI - Transoral robotic surgery for the treatment of T1-T2 carcinoma of the larynx: preliminary study. AB - OBJECTIVES/HYPOTHESIS: To determine the feasibility and the preliminary oncological results of transoral robotic surgery (TORS) for the treatment of early stage laryngeal tumors. STUDY DESIGN: Retrospective single center study. METHODS: We reviewed the medical records of 23 patients who underwent TORS for the treatment of T1 or T2 laryngeal squamous cell carcinoma between August 2009 and March 2012. RESULTS: Laryngeal tumors were involving the glottis (13 cases) and the supraglottis (10 cases). They were classified T1 N0 in 16 cases, T2 N0 in four cases, and T2 N+ in three cases. The median TORS operative time was 60 minutes (ranging from 30 to 118 minutes). The median hospitalization time was 7.5 days. Histopathological examination of the resected tumors confirmed 14 cases in which the margins were clear, four cases in which the surgical margins were close (less than 1 mm), one case in which the margins were microscopically positive, and in four cases margins status were not able to be recorded. A tracheostomy was carried out for three patients, and 11 patients got a nasogastric feeding tube postoperatively. The local recurrence rate was 8.7% (2/ 23 cases), and in both cases the recurrence occurred in the anterior commissure area only. The overall larynx preservation rate was 95,7% (22/ 23 cases). CONCLUSION: In this preliminary study, we demonstrated that laryngeal TORS is feasible and may result in oncological results comparable with other treatment strategies, including laser CO2 surgery. This innovative approach needs to be evaluated through randomized multi-institutional trial. LEVEL OF EVIDENCE: 4. PMID- 23918440 TI - Savant syndrome: realities, myths and misconceptions. AB - It was 126 years ago that Down first described savant syndrome as a specific condition and 70 years ago that Kanner first described Early Infantile Autism. While as many as one in ten autistic persons have savant abilities, such special skills occur in other CNS conditions as well such that approximately 50 % of cases of savant syndrome have autism as the underlying developmental disability and 50 % are associated with other disabilities. This paper sorts out realities from myths and misconceptions about both savant syndrome and autism spectrum disorders (ASD) that have developed through the years. The reality is that low IQ is not necessarily an accompaniment of savant syndrome; in some cases IQ can be superior. Also, savants can be creative, rather than just duplicative, and the skills increase over time on a continuum from duplication, to improvisation to creation, rather than diminishing or suddenly disappearing. Genius and prodigy exist separate from savant syndrome and not all such highly gifted persons have Asperger's Disorder. This paper also emphasizes the critical importance of separating 'autistic-like' symptoms from ASD especially in children when the savant ability presents as hyperlexia (children who read early) or as Einstein syndrome (children who speak late), or have impaired vision (Blindisms) because prognosis and outcome are very different when that careful distinction is made. In those cases the term 'outgrowing autism' might be mistakenly applied when in fact the child did not have ASD in the first place. PMID- 23918441 TI - Visual attention to competing social and object images by preschool children with autism spectrum disorder. AB - Eye tracking studies of young children with autism spectrum disorder (ASD) report a reduction in social attention and an increase in visual attention to non-social stimuli, including objects related to circumscribed interests (CI) (e.g., trains). In the current study, fifteen preschoolers with ASD and 15 typically developing controls matched on gender and age (range 24-62 months) were eye tracked while viewing a paired preference task of face and object stimuli. While co-varying verbal and nonverbal developmental quotients, preschoolers with ASD were similar to controls in their visual attention to faces presented with objects unrelated to CI, but attended significantly less than controls to faces presented with CI-related objects. This was consistent across three metrics: preference, prioritization and duration. Social attention in preschoolers with ASD therefore appears modulated by salience of competing non-social stimuli, which may affect the development of both social and non-social characteristics of the disorder. PMID- 23918442 TI - Complete inclusion of adaptive rowing only 1000 m ahead. AB - Adaptive rowing (AR) at the Paralympic level is accessible for rowers with physical disability. AR was included for the first time in the Beijing 2008 Paralympic Games. Racing distance for all AR events is currently 1000 m, which impedes public recognition of this sport and leads to many organisational challenges during the inclusive World Rowing Championships. The aim of this report was to discuss the feasibility of increasing AR race distance to 2000 m from a sports injury and athletic health perspective. As limited data on injury and illness risks exist in AR, knowledge and experiences had to be taken from other Paralympic sports. The anticipated duration of 2000 m AR competitions is either comparable or considerably lower than that of the other Paralympic disciplines with similar characteristics. AR has inherent injury and health risks especially within thorax, shoulders and low back region, but they are not expected to be significantly modified by increased racing times. Specific considerations need to be taken into account for athletes with a spinal cord injury, like in other sport disciplines. There are no distinctive contra indications for AR events of 2000 m based on the current literature review and a 10-year experience in this sport. Long-term follow-ups are needed to understand fully the injury and health risk associated with AR and to develop appropriate prevention strategies. PMID- 23918443 TI - The predictive validity of a single leg bridge test for hamstring injuries in Australian Rules Football Players. AB - BACKGROUND: Hamstring muscle strain injuries (HMSI) are the greatest injury problem in kicking sports such as Australian Rules Football. Reduced hamstring muscle strength is commonly perceived to be a risk factor for hamstring injury; however, evidence is inconclusive. Testing hamstring strength with the hip and knee at functional angles and assessing endurance parameters may be more relevant for examining the risk of hamstring injury. OBJECTIVE: The primary aim of this prospective study was to examine if reduced hamstring muscle strength assessed with the single leg hamstring bridge (SLHB) was a risk factor for hamstring injury. METHODS: Hamstring muscle strength of 482 amateur and semielite players from 16 football clubs, mean age 20.7 (range 16-34 years), was tested during the 2011 preseason. Players were then monitored throughout the 2011 playing season for HMSI. RESULTS: A total of 28 hamstring injuries, 16 right and 12 left, were recorded. Players who sustained a right HMSI during the season had a significantly lower mean right SLHB score (p=0.029), were older (p=0.002) and were more likely to have sustained a past right hamstring injury (p=0.02) or right knee injury (p=0.035). For left-sided hamstring injury, the injured group was more likely to be left leg dominant (p=0.001), older athletes (p=0.002) and there was a trend towards a history of left hamstring injury (p=0.07). CONCLUSIONS: This study demonstrated a significant deficit in preseason SLHB scores on the right leg of players that subsequently sustained a right-sided hamstring injury. Age, previous knee injury and a history of hamstring injury were other risk factors supported in this study. Low hamstring strength appears to be a risk factor for hamstring injury; however, due to the confounding variables and low injury rate in this study, further studies are required. PMID- 23918444 TI - A systematic review of shockwave therapies in soft tissue conditions: focusing on the evidence. AB - BACKGROUND: 'Shock wave' therapies are now extensively used in the treatment of musculoskeletal injuries. This systematic review summarises the evidence base for the use of these modalities. METHODS: A thorough search of the literature was performed to identify studies of adequate quality to assess the evidence base for shockwave therapies on pain in specific soft tissue injuries. Both focused extracorporeal shockwave therapy (F-ESWT) and radial pulse therapy (RPT) were examined. RESULTS: 23 appropriate studies were identified. There is evidence for the benefit of F-ESWT and of RPT in a number of soft tissue musculoskeletal conditions, and evidence that both treatment modalities are safe. There is evidence that F-ESWT is effective in the treatment of plantar fasciitis, calcific tendinitis, and that RPT is effective in plantar fasciitis. Where benefit is seen in F-ESWT, it appears to be dose dependent, with greater success seen with higher dose regimes. There is low level evidence for lack of benefit of low-dose F-ESWT and RPT in non-calcific rotator cuff disease and mixed evidence in lateral epicondylitis. PMID- 23918445 TI - Effectiveness of an educational video on concussion knowledge in minor league hockey players: a cluster randomised controlled trial. AB - BACKGROUND: With the heightened awareness of concussions in all sports, the development and implementation of effective prevention strategies are necessary. Education has been advocated as an effective injury prevention intervention. PURPOSE: To examine the effectiveness of the 'Smart Hockey: More Safety, More Fun' video on knowledge transfer among minor league hockey players. STUDY DESIGN: Cluster-randomised controlled trial. METHODS: A total of 267 participants from two age divisions and competitive levels were assigned to either a video or no video group. The video was shown (or not shown) to the entire team as a result of random assignment. To evaluate the effectiveness of the educational video, questionnaires specific to concussion knowledge and players' attitudes and behaviours were completed. RESULTS: There was a significant increase in the players' concussion knowledge scores immediately following exposure to the video (F(1,103)=27.00, p<0.001). However, concussion knowledge at 2 months was not significantly different between the video and no-video groups, after controlling for prior knowledge level, age and competitive level (F(1,115)=0.41, p=0.523). Similarly, players' attitudes and behaviour scores at 2 months did not differ between groups (F(1,115)=0.41, p=0.507). CONCLUSIONS: We were able to show that a single viewing of an educational video in hockey could immediately improve knowledge about concussion but that this effect was transient and lost at 2-month follow-up. Future prevention endeavours in hockey and other sports should attempt to incorporate strategies and modalities to enhance knowledge retention. PMID- 23918446 TI - Determining if telomeres matter in colon cancer initiation or progression. PMID- 23918447 TI - Extensive telomere erosion in the initiation of colorectal adenomas and its association with chromosomal instability. AB - BACKGROUND: Telomere shortening, dysfunction, and fusion may facilitate the acquisition of large-scale genomic rearrangements, driving clonal evolution and tumor progression. The relative contribution that telomere dysfunction and/or APC mutation play in the chromosome instability that occurs during colorectal tumorigenesis is not clear. METHODS: We used high-resolution telomere length and fusion analysis to analyze 85 adenomatous colorectal polyps obtained from 10 patients with familial adenomatous polyposis and a panel of 50 colorectal carcinomas with patient-matched normal colonic mucosa. Telomerase activity was determined using the telomeric repeat amplification protocol. Array-CGH was used to detect large-scale genomic rearrangements. Pearson correlation and Student t test were used, and all statistical tests were two-sided. RESULTS: Despite the presence of telomerase activity, we observed apparent telomere shortening in colorectal polyps that correlated with large-scale genomic rearrangements (P < .0001) but was independent of polyp size and indistinguishable from that observed in colorectal carcinomas (P = .82). We also observed apparent lengthening of telomeres in both polyps and carcinomas. The extensive differences in mean telomere length of up to 4.6kb between patient-matched normal mucosa and polyps were too large to be accounted for by replicative telomere erosion alone. Telomere fusion events were detected in both polyps and carcinomas; the mutational spectrum accompanying fusion was consistent with alternative nonhomologous end joining. CONCLUSIONS: Telomere length distributions observed in colorectal polyps reflect the telomere length composition of the normal originating cells from which clonal growth was initiated. Originating cells containing both short telomeres and APC mutations may give rise to polyps that exhibit short telomeres and are prone to telomere dysfunction, driving genomic instability and progression to malignancy. J Natl Cancer Inst;2013;105:1202-1211. PMID- 23918449 TI - Evidence of mechanism of action of anti-inflammatory/antinociceptive activities of acacetin. AB - BACKGROUND: Acacetin is a bioflavonoid with pharmacological properties such as antinociceptive/anti-inflammatory activities. However, scientific evidence of its spectrum activity and mechanisms of action is unknown. METHODS: Acacetin administered via i.p. was assessed using several nociceptive experimental models such as the writhing test, the formalin test and carrageenan paw oedema in the thermal plantar tests (Hargreaves method) in mice, as well as the pain-induced functional impairment model in rat (PIFIR model). RESULTS: Acacetin produced a significant and dose-dependent inhibition of the writhes with an ED50 = 20 mg/kg. Furthermore, acacetin inhibited licking and shaking associated with nociceptive behaviour mainly in the inflammatory phase of the formalin test. No significant differences were observed in the plantar test in mice, but a minor response was obtained in the PIFIR model. Animals receiving pre-treatment of WAY100635 (0.1 mg/kg, s.c.), flumazenil (3 mg/kg, i.p.) or naloxone (1 mg/kg, i.p.) partially reduced the antinociceptive response of acacetin in the writhing test. Presence of the inhibitors in the NO-cGMP-K(+) channel pathway did not modify the antinociceptive effect of acacetin in the writhing or the formalin test. CONCLUSIONS: Our data showed that systemic administration of acacetin decreased visceral and inflammatory nociception and prevented the formalin-induced oedema. In the mechanism of the acacetin antinociceptive effect, 5-HT1A, GABA/BDZs and opioid receptors but not the NO-cGMP-K(+) channel pathway seem to be involved. The data presented prove acacetin to be potentially useful in the therapy of pain related diseases. PMID- 23918450 TI - Feasibility and kinetic characteristics of (68)Ga-NOTA-RGD PET for in vivo atherosclerosis imaging. AB - OBJECTIVE: In this study, the feasibility and kinetic characteristics of the (68)Ga-NOTA-RGD, a recently developed RGD peptide agent, were investigated for atherosclerosis imaging in comparison with (18)FDG. METHODS: ApoE(-/-) mice were fed a high-fat diet for more than 20 weeks. To evaluate the feasibility, tissue uptakes of (68)Ga-NOTA-RGD and (18)FDG in the major organs were measured and compared between ApoE(-/-) and control mice. Animal PET imaging was also performed and relative uptake values in the thoracic aorta were compared between ApoE(-/-) and control mice. In humans, the kinetic characteristics and feasibility of (68)Ga-NOTA-RGD PET were assessed in 4 patients with known coronary artery disease. RESULTS: In the tissue uptake study, the thoracic aorta showed higher uptake in ApoE(-/-) than in control mice with both (68)Ga-NOTA-RGD and (18)FDG (P < 0.001). On PET scans, the relative uptake values of the thoracic aorta were significantly higher in ApoE(-/-) with both (68)Ga-NOTA-RGD (P = 0.024) and (18)FDG (P = 0.038). In human PET, the appropriateness of reversible binding model and Logan plotting was clearly demonstrated. The aorta-to-jugular ratios were measured up to 1.25 and showed a tendency to correlate with the serum high-sensitivity C-reactive protein level (r = 0.899, P = 0.102). CONCLUSIONS: (68)Ga-NOTA-RGD has potential as an in vivo atherosclerosis imaging agent. However, the lower imaging contrast and sensitivity of (68)Ga-NOTA-RGD PET compared with (18)FDG PET may be a limitation for clinical application. PMID- 23918451 TI - Exercise modifies alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor expression in striatopallidal neurons in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-lesioned mouse. AB - The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid-type glutamate receptor (AMPAR) plays a critical role in modulating experience-dependent neuroplasticity, and alterations in AMPAR expression may underlie synaptic dysfunction and disease pathophysiology. Using the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) mouse model of dopamine (DA) depletion, our previous work showed exercise increases total GluA2 subunit expression and the contribution of GluA2-containing channels in MPTP mice. The purpose of this study was to determine whether exercise-dependent changes in AMPAR expression after MPTP are specific to the striatopallidal (D2 R) or striatonigral (D1 R) medium spiny neuron (MSN) striatal projection pathways. Drd2 -eGFP-BAC transgenic mice were used to delineate differences in AMPAR expression between striatal D2 R-MSNs and D1 R-MSNs. Striatal AMPAR expression was assessed by immunohistochemical (IHC) staining, Western immunoblotting (WB) of preparations enriched for postsynaptic density (PSD), and alterations in the current-voltage relationship of MSNs. We found DA depletion results in the emergence of GluA2-lacking AMPARs selectively in striatopallidal D2 R-MSNs and that exercise reverses this effect in MPTP mice. Exercise-induced changes in AMPAR channels observed after DA depletion were associated with alterations in GluA1 and GluA2 subunit expression in postsynaptic protein, D2 R-MSN cell surface expression, and restoration of corticostriatal plasticity. Mechanisms regulating experience-dependent changes in AMPAR expression may provide innovative therapeutic targets to increase the efficacy of treatments for basal ganglia disorders, including Parkinson's disease. PMID- 23918452 TI - Microglial polarization and plasticity: evidence from organotypic hippocampal slice cultures. AB - Increasing evidence indicates that "functional plasticity" is not solely a neuronal attribute but a hallmark of microglial cells, the main brain resident macrophage population. Far from being a univocal phenomenon, microglial activation can originate a plethora of functional phenotypes, encompassing the classic M1 proinflammatory and the alternative M2 anti-inflammatory phenotypes. This concept overturns the popular view of microglial activation as a synonym of neurotoxicity and neurogenesis failure in brain disorders. The characterization of the alternative programs is a matter of intense investigation, but still scarce information is available on the course of microglial activation, on the reversibility of the different commitments and on the capability of preserving molecular memory of previous priming stimuli. By using organotypic hippocampal slice cultures as a model, we developed paradigms of stimulation aimed at shedding light on some of these aspects. We show that persistent stimulation of TLR4 signaling promotes an anti-inflammatory response and microglial polarization toward M2-like phenotype. Moreover, acute and chronic preconditioning regimens permanently affect the capability to respond to a later challenge, suggesting the onset of mechanisms of molecular memory. Similar phenomena could occur in the intact brain and differently affect the vulnerability of mature and newborn neurons to noxious signals. PMID- 23918453 TI - The impact of comorbidity on Health-Related Quality of Life among cancer survivors: analyses of data from the PROFILES registry. AB - PURPOSE: The aim of this study was to assess the difference in explained variance of Health-Related Quality of Life (HRQoL) between comorbidity, sociodemographic characteristics and cancer characteristics. This association was assessed among thyroid cancer, colorectal cancer, and (non-)Hodgkin's lymphoma patients. METHODS: Data from three large population-based surveys on survivors of thyroid cancer, colorectal cancer, and (non-)Hodgkin's lymphoma were used. Cancer specific HRQoL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) of which physical function, emotional function, fatigue, and pain were included in the analyses. Comorbidity was assessed using the Self-reported Comorbidity Questionnaire. The association between comorbidity and HRQoL was assessed with multivariate linear regression models. Semi-partial R (2) was reported to assess the amount of variance in HRQoL explained by comorbidity in comparison with sociodemographic and cancer characteristics. RESULTS: In total, 3,792 cancer survivors were included in this analysis. The variance in HRQoL subscales explained by comorbidity was higher compared with sociodemographic and cancer characteristics for physical function (11-17 vs. 2-4 and 1-2 %, respectively) and emotional function (7-17 vs. 1-3 and 1-3 %, respectively), regardless of cancer type. In addition, comorbidity explained 7-20 and 11-13 % of the variance in pain and fatigue, respectively, compared to 0-4 % for both sociodemographic and cancer characteristics. Osteoarthritis and back pain were strongly associated with physical function and pain, while depression was strongly associated with emotional function. Depression and back pain were strongly associated with fatigue. CONCLUSIONS: This study showed that comorbidity explained more variance in physical and emotional function, pain, and fatigue in comparison with sociodemographic and cancer characteristics in cancer survivors, regardless of cancer type. Our findings emphasize the importance of adjusting for the presence of comorbid diseases when assessing HRQoL in cancer survivors. IMPLICATION FOR CANCER SURVIVORS: Cancer survivors suffering from comorbid diseases experience lower levels of health-related quality of life. Clinicians should become more aware of the impact of comorbidity on HRQoL and provide necessary psychological support to assist self-management of comorbid diseases. PMID- 23918454 TI - Health-related quality of life in young men with testicular cancer: validation of the Cancer Assessment for Young Adults (CAYA). AB - BACKGROUND: Patient-reported outcome instruments are needed to measure health related quality of life (HRQOL) in young adults with cancer. The purpose of this project was to establish a conceptual model and measurement instrument for assessment of HRQOL in young men with testicular cancer. METHODS: Patient interviews and a literature review were used to develop a conceptual framework of biopsychosocial domains of cancer-related quality of life and an initial pool of questionnaire items. Items were piloted and refined. Revised items were administered to a sample (N = 171) of young (ages 18-29) men with testicular cancer and repeated 4 weeks later. Rasch measurement methods guided item reduction and scale construction. Traditional psychometric analyses were also performed to allow for comparison with existing measures. RESULTS: The conceptual framework included seven biopsychosocial domains: physical, sexual, intrapersonal, cognitive-emotional, social-relational, educational-vocational avocational, and spiritual to form independent scales of the resulting questionnaire, the Cancer Assessment for Young Adults-Testicular (CAYA-T). Each scale fulfilled Rasch and traditional psychometric criteria (i.e., person separation index, 0.34-0.82; Cronbach's alpha, 0.70-0.91; and an expected pattern of convergent and discriminant validity correlations). CONCLUSIONS: The CAYA-T can be used to assess HRQOL across a comprehensive set of domains as identified by young men with cancer. It passes strict psychometric criteria and has potential as a useful research and clinical tool. IMPLICATIONS FOR CANCER SURVIVORS: The CAYA-T has potential research and clinical value for addressing inter-related aspects of HRQOL in young adult men with cancer. The measure may assist with assessing and monitoring HRQOL across a range of domains and contributing to more comprehensive assessment of biopsychosocial needs of young adults. PMID- 23918455 TI - Pathological study of otitis media with effusion after treatment with intranasal pulmonary surfactant. AB - OBJECTIVES/HYPOTHESIS: To evaluate the histopathological effect of intranasal pulmonary surfactant (PS) on the eustachian tube (ET) in guinea pigs with otitis media with effusion (OME). STUDY DESIGN: Randomized control trial. METHODS: Nonviable heat-killed Hemophilus influenzae solution was injected into the tympanum of guinea pigs by a trans-eardrum approach to establish OME. Guinea pigs were divided into four groups: normal controls (group A), untreated OME (group B), saline-treated (group C), PS-treated (group D). The response threshold of the guinea pigs was measured by auditory brainstem response (ABR), and data were analyzed by one-way analysis of variance. The histopathological changes in the osseous, cartilaginous, and muscular portions of the ET were observed systematically by light microscopy. RESULTS: The ABR threshold in OME group B was raised significantly compared with normal group (A). The response in saline treated group C was not statistically significantly different compared with OME group B. Seven days after intranasal dripping of pulmonary surfactant in PS treated group D, the response threshold showed at statistically significant decrease compared with OME B and saline-treated C groups. In OME group B and saline-treated group C, mucosa showed swelling with goblet cell hyperplasia, and cilia were irregularly arranged. In PS-treated group D, there was slight mucosal swelling with fewer goblet cells, and cilia were regularly arranged, similar to the normal group A. CONCLUSIONS: The findings of the study indicate that intranasal pulmonary surfactant drops have protective and hyposecretory effects on the mucociliary system of the ET in guinea pigs suffering from OME. PMID- 23918456 TI - Pharmacokinetic study of adenosine diphosphate-encapsulated liposomes coated with fibrinogen gamma-chain dodecapeptide as a synthetic platelet substitute in an anticancer drug-induced thrombocytopenia rat model. AB - A fibrinogen gamma-chain (dodecapeptide HHLGGAKQAGDV, H12)-coated, adenosine diphosphate (ADP)-encapsulated liposome [H12-(ADP)-liposome] was designed to achieve optimal performance as a homeostatic agent and expected as a synthetic platelet alternative. For the purpose of efficient function as platelet substitute, H12-(ADP)-liposomes should potentially have both acceptable pharmacokinetic and biodegradable properties under conditions of an adaptation disease including thrombocytopenia induced by anticancer drugs. The aim of this study was to characterize the pharmacokinetics of H12-(ADP)-liposomes in busulphan-induced thrombocytopenic rats using (14) C, (3) H double radiolabeled H12-(ADP)-liposomes, in which the encapsulated ADP and liposomal membrane (cholesterol) were labeled with (14) C and (3) H, respectively. After the administration of H12-(ADP)-liposomes, they were determined to be mainly distributed to the liver and spleen and disappeared from organs within 7 days after injection. The encapsulated ADP was mainly eliminated in the urine, whereas the outer membrane (cholesterol) was mainly eliminated in feces. The successive dispositions of the H12-(ADP)-liposomes were similar in both normal and thrombocytopenic rats. However, the kinetics of H12-(ADP)-liposomes in thrombocytopenic rats was more rapid, compared with the corresponding values for normal rats. These findings, which well reflect the clinical features of patients with anticancer drug-induced thrombocytopenia, provide useful information for the development of the H12-(ADP)-liposomes for future clinical use. PMID- 23918457 TI - Population pharmacokinetic analysis of linezolid in low body weight patients with renal dysfunction. AB - Linezolid has antibacterial activity against aerobic Gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA). Adjustment of the dose of linezolid has been proposed to be unnecessary in patients with reduced renal function. However, platelet counts and hemoglobin levels were shown to be significantly lower in such patients than in patients with normal renal function. The population pharmacokinetic (PPK) of linezolid was investigated in MRSA infected patients with renal dysfunction. Linezolid concentrations in serum were measured by high-performance liquid chromatography. PPK analysis was performed in the nonlinear mixed effects model (NONMEM) computer program. In the final PPK model, total body weight (TBW), estimated glomerular filtration rate (eGFR), hemoglobin (HB), and alanine amino transferase (ALT) were influential covariates on total body clearance (CL), and the volume of distribution (Vd) was affected by TBW, which was expressed as CL (L/h) = 0.00327 * TBW * eGFR(0.428) * HB(0.502) * 0.283 (ALT >= 100 IU/L) and CL (L/h) = 0.00327 * TBW * eGFR(0.428) * HB(0.502) (ALT < 100 IU/L), Vd (L) = 1.310 * TBW. The PPK parameters of linezolid obtained here are useful for the optimal use of linezolid with similar patient population characteristics. PMID- 23918458 TI - Prevalence of Beckwith-Wiedemann syndrome in North West of Italy. AB - Although Beckwith-Wiedemann syndrome (BWS, OMIM #130650) is the most common genetic overgrowth disorder, data on its epidemiology are scanty and the estimates of its occurrence show wide variability. The aim of this study is to assess its prevalence in Piedmont Region (Italy). We included in the study all patients diagnosed with BWS born in Piedmont from 1997 to 2009 through a search in the Italian Registry for Rare Diseases. This source was further validated with data from the network of Regional Clinical Genetics services and surveys in extra regional Clinical Genetics centres, laboratories and the Italian BWS patients association. All cases were further ascertained through physical exam, medical history and specific molecular tests. The search identified 46 clear-cut cases of BWS born across the 13-year period, providing a prevalence of 1:10 340 live births (95% confidence interval 1:7,752-13,698 live births). Among the 41 patients who underwent molecular tests, 70.7% were positive, showing hypomethylation of the IC2 imprinting center (29.3%), paternal chromosome 11 uniparental disomy (pUPD11, 24.4%), IC1 hypermethylation (14.6%), CDKN1c mutation (2.4%), whereas 29.3% had negative molecular tests. The study provides an approximate BWS prevalence of 1:10,000 live birth, the highest reported to date. PMID- 23918459 TI - Development and optimization of on-line 2-dimensional chromatographic approaches for eliminating matrix effects and improving bioanalysis of peptides in human plasma using UHPLC-MS/MS. AB - Online 2-dimensional chromatographic approaches for eliminating matrix effects and optimizing bioanalysis of peptides using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) were studied. Three therapeutic peptides (octreotide, desmopressin, and vasopressin) were selected as model analytes. Human plasma was precipitated with acetonitrile; peptides were analyzed on C(8), C(18), Phenyl and HILIC ACQUITY UPLC columns. For simpler online clean-up applications, a C(18) pre-column was coupled to the analytical column via a switching valve. For more complex heart-cutting applications, two analytical columns were used with optional online dilution to refocus the analyte peaks prior to the second dimension separation. This allows the use of MS incompatible mobile phases, such as TFA, in the first dimension separation. Online clean-up effectiveness was investigated by monitoring phospholipids. Flushing direction, mobile phase composition, flow rate and transfer window were evaluated. Phospholipids were readily retained on reversed-phase columns, and the peptides were reproducibly transferred, individually or as a group, to the second column using appropriate transfer windows. The best peak shapes were obtained when the second dimension column was more retentive (e.g. C(18) vs. C(8)). However, C(8) to HILIC gave broad unresolved peaks due to mobile phase mismatch. Trapped phospholipids were efficiently removed from either guard columns or first dimensional columns by forward- or back-flushing at high flows; however, back flushing was more efficient with lower flow rates on larger columns. PMID- 23918460 TI - Elemental composition validation from stored waveform inverse Fourier transform (SWIFT) isolation FT-ICR MS isotopic fine structure. AB - Elemental composition assignment confidence in mass spectrometry is typically assessed by monoisotopic mass accuracy. For a given mass accuracy, resolution and detection of other isotopologues can further narrow the number of possible elemental compositions. However, such measurements require ultrahigh resolving power and high dynamic range, particularly for compounds containing low numbers of nitrogen and oxygen (both (15)N and (18)O occur at less than 0.4% natural abundance). Here, we demonstrate validation of molecular formula assignment from isotopic fine structure, based on ultrahigh resolution broadband Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Dynamic range is enhanced by external quadrupole and internal stored waveform inverse Fourier transform (SWIFT) isolation to facilitate detection of low abundance heavy atom isotopologues. PMID- 23918461 TI - Chemical derivatization of peptide carboxyl groups for highly efficient electron transfer dissociation. AB - The carboxyl groups of tryptic peptides were derivatized with a tertiary or quaternary amine labeling reagent to generate more highly charged peptide ions that fragment efficiently by electron transfer dissociation (ETD). All peptide carboxyl groups-aspartic and glutamic acid side-chains as well as C-termini-were derivatized with an average reaction efficiency of 99 %. This nearly complete labeling avoids making complex peptide mixtures even more complex because of partially-labeled products, and it allows the use of static modifications during database searching. Alkyl tertiary amines were found to be the optimal labeling reagent among the four types tested. Charge states are substantially higher for derivatized peptides: a modified tryptic digest of bovine serum albumin (BSA) generates ~90% of its precursor ions with z > 2, compared with less than 40 % for the unmodified sample. The increased charge density of modified peptide ions yields highly efficient ETD fragmentation, leading to many additional peptide identifications and higher sequence coverage (e.g., 70 % for modified versus only 43 % for unmodified BSA). The utility of this labeling strategy was demonstrated on a tryptic digest of ribosomal proteins isolated from yeast cells. Peptide derivatization of this sample produced an increase in the number of identified proteins, a >50 % increase in the sequence coverage of these proteins, and a doubling of the number of peptide spectral matches. This carboxyl derivatization strategy greatly improves proteome coverage obtained from ETD-MS/MS of tryptic digests, and we anticipate that it will also enhance identification and localization of post-translational modifications. PMID- 23918462 TI - Non-direct sequence ions in the tandem mass spectrometry of protonated peptide amides--an energy-resolved study. AB - The fragmentation reactions of the MH(+) ions of Leu-enkephalin amide and a variety of heptapeptide amides have been studied in detail as a function of collision energy using a QqToF beam type mass spectrometer. The initial fragmentation of the protonated amides involves primarily formation of bn ions, including significant loss of NH3 from the MH(+) ions. Further fragmentation of these bn ions occurs following macrocyclization/ring opening leading in many cases to bn ions with permuted sequences and, thus, to formation of non-direct sequence ions. The importance of these non-direct sequence ions increases markedly with increasing collision energy, making peptide sequence determination difficult, if not impossible, at higher collision energies. PMID- 23918463 TI - Comparative validation of the WOMAC osteoarthritis and Lequesne algofunctional indices in Greek patients with hip or knee osteoarthritis. AB - PURPOSE: To comparatively evaluate the reliability and validity of the Western Ontario and McMaster (WOMAC) and the Lequesne algofunctional indices in Greek patients with hip or knee osteoarthritis (OA). METHODS: The Greek versions of WOMAC LK 3.1 and Lequesne indices were administered to 97 outpatients with OA. Internal consistency reliability was assessed by Cronbach's alpha and item-scale correlations. Test-retest reliability was examined with intraclass correlations. Patients were also asked to complete the Short Form 36 (SF-36) and a Visual Analog Scale capturing strength of pain, in order to assess construct validity. Additional demographic and clinical data were also recorded to evaluate further associations. RESULTS: Cronbach's alpha values of the WOMAC ranged between 0.92 and 0.98 for hip and 0.89-0.97 for knee OA. The respective values for Lequesne were 0.63-0.74 and 0.74-0.80. Item-scale correlations confirmed the superiority of WOMAC with respect to internal consistency reliability. Intraclass correlations were 0.79-0.97 and 0.57-0.98 for hip and 0.86-0.97 and 0.82-0.97 for knee OA, for WOMAC and Lequesne, respectively. The two indices showed high correlations with comparable subscales of SF-36 and the Visual Analog Scale. Significant relationships were identified for age, body mass index, duration of disease, duration of stiffness and radiographic classification. CONCLUSIONS: Our findings, in samples of knee and hip OA patients, indicate that the WOMAC index demonstrates better internal consistency reliability than the Lequesne counterpart, as well as equivalent test-retest reliability and construct validity. PMID- 23918464 TI - The heat is on: room temperature affects laboratory equipment--an observational study. AB - OBJECTIVE: To evaluate the effect of ambient room temperature on equipment typically used in in vitro fertilization (IVF). DESIGN: We set the control temperature of the room to 20 degrees C (+/-0.3) and used CIMScan probes to record temperatures of the following equipment: six microscope heating stages, four incubators, five slide warmers and three heating blocks. We then increased the room temperature to 26 degrees C (+/-0.3) or decreased it to 17 degrees C (+/-0.3) and monitored the same equipment again. We wanted to determine what role, if any, changing room temperature has on equipment temperature fluctuation. RESULTS: There was a direct relationship between room temperature and equipment temperature stability. When room temperature increased or decreased, equipment temperature reacted in a corresponding manner. Statistical differences between equipment were found when the room temperature changed. What is also noteworthy is that temperature of equipment responded within 5 min to a change in room temperature. CONCLUSIONS: Clearly, it is necessary to be aware of the affect of room temperature on equipment when performing assisted reproductive procedures. Room and equipment temperatures should be monitored faithfully and adjusted as frequently as needed, so that consistent culture conditions can be maintained. If more stringent temperature control can be achieved, human assisted reproduction success rates may improve. PMID- 23918465 TI - Does the type of cleft palate contribute to the need for secondary surgery? A national perspective. AB - OBJECTIVES/HYPOTHESIS: To determine whether the type of cleft palate is associated with a need for secondary surgery (oronasal fistula repair, speech surgery) after primary cleft palate repair. STUDY DESIGN: Retrospective analysis of a national pediatric database (2009 Kids' Inpatient Database). METHODS: We identified two distinct cohorts of children who underwent primary and secondary (revision) cleft palate repairs, respectively, from a national, pediatric database (2009 Kids' Inpatient Database). Revision ratios for each cleft palate diagnosis were calculated to identify diagnoses with higher rates of revision. Revision ratio was calculated by dividing the relative frequency of each diagnosis in the secondary repair cohort by the corresponding relative frequency in the primary repair cohort. RESULTS: In 2009, there were 1942 cases of primary cleft palate repair in the 44 states participating in the KID's inpatient database. Fifty-two percent (n=1018) were male. The average age at the time of surgery was 13.36 months. In the same year secondary cleft palate procedures were performed on 724 different patients, 54% (n=388) were males. The average age for secondary procedures was 59 months. Cleft lip and palate diagnoses had higher revision rate ratios (1.92) compared to cleft palate only (0.54) P <0.05. CONCLUSION: Children with an initial diagnosis of cleft lip and palate, which is more severe than cleft palate only, have comparatively higher rates of secondary cleft palate procedures than children with cleft palate only. LEVEL OF EVIDENCE: N/A. PMID- 23918466 TI - Bioactivation and toxicity of acetaminophen in a rat hepatocyte micropatterned coculture system. AB - We have recently shown that primary rat hepatocytes organized in micropatterned cocultures with murine embryonic fibroblasts (HepatoPacTM) maintain high levels of liver functions for at least 4 weeks. In this study, rat HepatoPac was assessed for its utility to study chemical bioactivation and associated hepatocellular toxicity. Treatment of HepatoPac cultures with acetaminophen (APAP) over a range of concentrations (0-15 mM) was initiated at 1, 2, 3, or 4 weeks followed by the assessment of morphological and functional endpoints. Consistent and reproducible concentration-dependent effects on hepatocyte structure, viability, and basic functions were observed over the 4-week period, and were exacerbated by depleting glutathione using buthionine sulfoximine or inducing CYP3A using dexamethasone, presumably due to increased reactive metabolite-induced stress and adduct formation. In conclusion, the results from this study demonstrate that rat HepatoPac represents a structurally and functionally stable hepatic model system to assess the long-term effects of bioactivated compounds. PMID- 23918467 TI - Motor development skills of 1- to 4-year-old Iranian children with early treated phenylketonuria. AB - Objective : To gauge the gross and fine motor development of early treated phenylketonuria (ETPKU) in children in the age range of 1-4 years. Methods : A cross-sectional analytic study was conducted in PKU clinics (reference clinics for PKU follow-up), Tehran, Iran. Seventy children with ETPKU were selected as the case group for the study. ETPKU children were those with early and continuous treatment with a phenylalanine-restricted diet (the mean of blood phenylalanine level during the recent 6 months was 2-6 mg/dL or 120-360 MUmol/L). Also, 100 healthy and normal children matched with the ETPKU group for age were randomly selected from 4 kindergartens in four parts of Tehran as a control group. The measurements consisted of a demographic questionnaire, Peabody Developmental Motor Scale-2 (PDMS-2), and pediatrician assessment. Motor quotients were determined by PDMS-2 and then compared in both groups by two independent samples t-test. Results : The mean ages in case and control group were 28.5 (+/- 11.6) and 29.7 (+/- 11.3) months, respectively. Comparison of the mean fine, gross, and total developmental motor quotients (DMQs) showed statistically significant differences between the two groups (p < 0.05). The fine and total DMQs of ETPKU children were also correlated with age. In addition, there was a negative correlation between the phenylalanine level and fine (p < 0.001) and total (p = 0.001) DMQs. Conclusion : It seems that ETPKU Iranian children, regardless of following a phenylalanine-restricted diet or not, have lower motor development. It is recommended to plan programs for early detection and intervention of developmental delays in these children. PMID- 23918468 TI - Papilloedema secondary to a spinal paraganglioma. AB - An asymptomatic 72-year-old man presented with bilateral papilloedema. Cranial CT imaging was normal, but lumbar puncture found an opening pressure of 320 mmH2O (120-250) with raised cerebrospinal fluid protein, increased red blood cells and xanthochromia. MR scan of spine showed a cauda equina tumour, histologically defined as a paraganglioma. The papilloedema resolved after surgery. PMID- 23918469 TI - Functional analysis of novel polymorphisms in the human SLCO1A2 gene that encodes the transporter OATP1A2. AB - The solute carrier organic anion transporting polypeptide 1A2 (OATP1A2, SLCO1A2) is implicated in the cellular influx of a number of drugs. We identified five novel single nucleotide polymorphisms (SNPs) in coding exons of the SLCO1A2 gene in a cohort of subjects: G550A, G553A, G673A, A775C, and G862A, that encoded the OATP1A2 variants E184K, D185N, V255I, T259P, and D288N, respectively. The function and expression of these variant transporters were assessed in HEK-293 cells. We found that the novel variants, E184K, D185N, T259P, and D288N, were associated with impaired estrone-3-sulfate, imatinib, and methotrexate transport (~20-50% of wild-type control); function was retained by OATP1A2-V255I. From biotinylation assays, the decreased function of these variants was due, at least in part, to impaired plasma membrane expression. The four loss-of-function variants were studied further using mutagenesis to produce variants that encode residues with different charges or steric properties. From immunoblotting, the replacement of negatively charged residues at amino acid positions 184 and 185 impaired membrane expression, while either a positive or negative charge at residue 288 supported the correct membrane targeting of OATP1A2. Replacement of T259 with bulky residues disrupted transporter stability. From molecular models, E184, D185, and D288 were located near several charged residues such that intramolecular ionic interactions may stabilize the transporter structure. Individuals who carry these novel SNPs in the SLCO1A2 gene may be at risk from impaired efficacy or enhanced toxicity during treatment with drugs that are substrates for OATP1A2. PMID- 23918470 TI - NOSH-aspirin (NBS-1120), a novel nitric oxide and hydrogen sulfide releasing hybrid, attenuates neuroinflammation induced by microglial and astrocytic activation: a new candidate for treatment of neurodegenerative disorders. AB - Hydrogen sulfide (H2 S) and nitric oxide (NO) have been described as gasotransmitters. Anti-inflammatory activity in the central and peripheral nervous systems may be one of their functions. Previously we demonstrated that several SH(-) donors including H2 S-releasing aspirin (S-ASA) exhibited anti inflammatory and neuroprotective activity in vitro against toxins released by activated microglia and astrocytes. Here we report that NOSH-ASA, an NO- and H2 S releasing hybrid of aspirin, has a significantly greater anti-inflammatory and neuroprotective effect than S-ASA or NO-ASA. When activated by LPS/IFNgamma, human microglia and THP-1 cells release materials that are toxic to differentiated SH-SY5Y cells. These phenomena also occur with IFNgamma-stimulated human astroglia and U373 cells. When the cells were treated with the S-ASA or NO ASA, there was a significant enhancement of neuroprotection. However, NOSH-ASA had significantly more potent protection properties than NO-ASA or S-ASA. The effect was concentration-dependent, as well as incubation time-dependent. Such treatment not only reduced the release of the TNFalpha and IL-6, but also attenuated activation of P38 MAPK and NFkappaB proteins. All the compounds tested were not harmful when applied directly to SH-SY5Y cells. These data suggest that NOSH-ASA has significant anti-inflammatory properties and may be a new candidate for treating neurodegenerative disorders that have a prominent neuroinflammatory component such as Alzheimer disease and Parkinson disease. PMID- 23918471 TI - Computational Coupled Method for Multiscale and Phase Analysis. AB - On micro scale the constitutions of porous media are effected by other constitutions, so their behaviors are very complex and it is hard to derive theoretical formulations as well as to simulate on macro scale. For decades, in order to escape this complication, the phenomenological approaches in a field of multiscale methods have been extensively researched by many material scientists and engineers. Their theoretical approaches are based on the hierarchical multiscale methods using a priori knowledge on a smaller scale; however it has a drawback that an information loss can be occurred. Recently, according to a development of the core technologies of computer, the ways of multiscale are extended to a direct multiscale approach called the concurrent multiscale method. This approach is not necessary to deal with complex mathematical formulations, but it is noted as an important factor: development of computational coupling algorithms between constitutions in a porous medium. In this work, we attempt to develop coupling algorithms in different numerical methods finite element method (FEM), smoothed particle hydrodynamics (SPH) and discrete element method (DEM). Using this coupling algorithm, fluid flow, movement of solid particle, and contact forces between solid domains are computed via proposed discrete element which is based on SPH, FEM, and DEM. In addition, a mixed FEM on continuum level and discrete element model with SPH particles on discontinuum level is introduced, and proposed coupling algorithm is verified through numerical simulation. PMID- 23918472 TI - Biochemical and morphological characterization of A2BP1 in neuronal tissue. AB - A2BP1 is considered to regulate alternative splicing of important neuronal transcripts and has been implicated in a variety of neurological and developmental disorders. A2BP1 was found in neuronal cells and was analyzed biochemically and morphologically. In this study, we prepared a specific antibody against A2BP1, anti-A2BP1, and carried out protein expression and localization analyses of A2BP1 in rat and mouse tissues. By Western blotting, A2BP1 showed tissue-dependent expression profiles and was expressed in a developmental-stage dependent manner in the brain. A2BP1 was detected at high levels in neocortex and cerebellum in the rat brain. Immunohistochemical analyses demonstrated that A2BP1 was highly expressed in differentiated neurons but not in mitotically active progenitor cells in the cerebral cortex during developmental stages. In cortical neurons, A2BP1 had accumulated mainly in the nucleus and diffusely distributed in the cell body and dendrites. In differentiated primary cultured rat hippocampal neurons, although A2BP1 was enriched in the nucleus and diffusely distributed in the cytoplasm, it was found in a punctate distribution adjacent to synapses. The results suggest that in neuronal tissues A2BP1 plays important roles, which are regulated in a spatiotemporal manner. PMID- 23918473 TI - Negative parenting behavior and childhood oppositional defiant disorder: differential moderation by positive and negative peer regard. AB - Although negative parenting behavior and peer status are independently associated with childhood conduct problems (e.g., oppositional defiant disorder (ODD)), relatively little is known about their interplay, particularly in relation to differentiated measures of positive and negative peer regard. To improve the specificity of the association of negative parenting behavior and peer factors with ODD, we explored the potential interaction of parenting and peer status in a sample of 169 five-to ten-year-old ethnically diverse children with and without attention-deficit/hyperactivity disorder (ADHD) assessed using multiple measures (i.e., rating scales, interview) and informants (i.e., parents, teachers). Controlling for children's age, sex, number of ADHD symptoms, and parents' race ethnicity, peer acceptance inversely predicted and inconsistent discipline, harsh punishment, and peer rejection were each positively associated with ODD symptom severity. Interactive influences were also evident such that inconsistent discipline and harsh punishment each predicted elevated ODD but only among children experiencing low peer acceptance or high peer rejection. These findings suggest that supportive environments, including peer acceptance, may protect children from negative outcomes associated with inconsistent discipline and harsh punishment. Findings are integrated with theories of social support, and we additionally consider implications for intervention and prevention. PMID- 23918474 TI - COL2A1 gene disruption by a balanced translocation t(12;15)(q13;q22.2) in familial Stickler syndrome. PMID- 23918475 TI - Disruptive technology roils the health care landscape. PMID- 23918476 TI - Are human genes patentable? The Supreme Court says yes and no. PMID- 23918477 TI - Hospital electronic health information exchange grew substantially in 2008-12. AB - Electronic health information exchange can improve care coordination for patients by enabling more timely and complete sharing of clinical information among providers and hospitals. Approaches to health information exchange have expanded in recent years with the growth in entities such as regional health information organizations (HIOs) and the increased adoption of electronic health record (EHR) systems. However, little is known about the extent of exchange activity in US hospitals. Using national surveys of hospitals, we found that between 2008 and 2012, hospitals' electronic exchange of health information with other providers increased significantly, regardless of provider type, organizational affiliation, or type of clinical information. In 2012 nearly six in ten hospitals actively exchanged electronic health information with providers and hospitals outside their organization, an increase of 41 percent since 2008. EHR adoption and HIO participation were associated with significantly greater hospital exchange activity, but exchanges with providers outside the organization and exchanges of clinical care summaries and medication lists remained limited. New and ongoing policy initiatives and payment reforms may accelerate the electronic exchange of health information by creating new data exchange options, defining standards for interoperability, and creating payment incentives for information sharing across organizational boundaries. PMID- 23918478 TI - Some hospitals are falling behind in meeting 'meaningful use' criteria and could be vulnerable to penalties in 2015. AB - With nearly $30 billion in incentives available, it is critical to know to what extent US hospitals have been able to respond to those incentives by adopting electronic health record (EHR) systems that meet Medicare's criteria for their "meaningful use." Medicare has provided aggregate incentive payment data, but still missing is an understanding of how these payments are distributed across hospital types and years. Our analysis of Medicare data found a substantial increase in the percentage of hospitals receiving EHR incentive payments between 2011 (17.4 percent) and 2012 (36.8 percent). However, this increase was not uniform across all hospitals, and the overall proportion of hospitals receiving a payment for meaningful use was low. Critical-access, smaller, and publicly owned or nonprofit hospitals appeared to be at particular risk for failing to meet Medicare's meaningful-use criteria, and the overall proportion of hospitals receiving a payment for meaningful use was low. Starting in 2015, hospitals that fail to meet the criteria will be subject to financial penalties. To address the needs of institutions in danger of incurring these penalties, policy makers could implement targeted grant programs and provide additional information technology workforce support. In addition, the capacity of EHR system vendors should be carefully monitored to ensure that these institutions have access to the technology they need. PMID- 23918479 TI - Electronic communication improves access, but barriers to its widespread adoption remain. AB - Because electronic communication is quick, convenient, and inexpensive for most patients, care that is truly patient centered should promote the use of such communication between patients and providers, even using it as a substitute for office visits when clinically appropriate. Despite the potential benefits of electronic communication, fewer than 7 percent of providers used it in 2008. To learn from the experiences of providers that have widely incorporated electronic communication into patient care, we interviewed leaders of twenty-one medical groups that use it extensively with patients. We also interviewed staff in six of those groups. Electronic communication was widely perceived to be a safe, effective, and efficient means of communication that improves patient satisfaction and saves patients time but that increases the volume of physician work unless office visits are reduced. Practice redesign and new payment methods are likely necessary for electronic communication to be more widely used in patient care. PMID- 23918480 TI - Root cause analysis reports help identify common factors in delayed diagnosis and treatment of outpatients. AB - Delays in diagnosis and treatment are widely considered to be threats to outpatient safety. However, few studies have identified and described what factors contribute to delays that might result in patient harm in the outpatient setting. We analyzed 111 root cause analysis reports that investigated such delays and were submitted to the Veterans Affairs National Center for Patient Safety in the period 2005-12. The most common contributing factors noted in the reports included coordination problems resulting from inadequate follow-up planning, delayed scheduling for unspecified reasons, inadequate tracking of test results, and the absence of a system to track patients in need of short-term follow-up. Other contributing factors were team-level decision-making problems resulting from miscommunication of urgency between providers and providers' lack of awareness of or knowledge about a patient's situation; and communication failures among providers, patients, and other health care team members. Our findings suggest that to support care goals in the Affordable Care Act and the National Quality Strategy, even relatively sophisticated electronic health record systems will require enhancements. At the same time, policy initiatives should support programs to implement, and perhaps reward the use of, more rigorous interprofessional teamwork principles to improve outpatient communication and coordination. PMID- 23918481 TI - Independent practice associations and physician-hospital organizations can improve care management for smaller practices. AB - Pay-for-performance, public reporting, and accountable care organization programs place pressures on physicians to use health information technology and organized care management processes to improve the care they provide. But physician practices that are not large may lack the resources and size to implement such processes. We used data from a unique national survey of 1,164 practices with fewer than twenty physicians to provide the first information available on the extent to which independent practice associations (IPAs) and physician-hospital organizations (PHOs) might make it possible for these smaller practices to share resources to improve care. Nearly a quarter of the practices participated in an IPA or a PHO that accounted for a significant proportion of their patients. On average, practices participating in these organizations provided nearly three times as many care management processes for patients with chronic conditions as nonparticipating practices did (10.4 versus 3.8). Half of these processes were provided only by IPAs or PHOs. These organizations may provide a way for small and medium-size practices to systematically improve care and participate in accountable care organizations. PMID- 23918482 TI - High physician concern about malpractice risk predicts more aggressive diagnostic testing in office-based practice. AB - Despite widespread agreement that physicians who practice defensive medicine drive up health care costs, the extent to which defensive medicine increases costs is unclear. The differences in findings to date stem in part from the use of two distinct approaches for assessing physicians' perceived malpractice risk. In this study we used an alternative strategy: We linked physicians' responses regarding their levels of malpractice concern as reported in the 2008 Health Tracking Physician Survey to Medicare Parts A and B claims for the patients they treated during the study period, 2007-09. We found that physicians who reported a high level of malpractice concern were most likely to engage in practices that would be considered defensive when diagnosing patients who visited their offices with new complaints of chest pain, headache, or lower back pain. No consistent relationship was seen, however, when state-level indicators of malpractice risk replaced self-rated concern. Reducing defensive medicine may require approaches focused on physicians' perceptions of legal risk and the underlying factors driving those perceptions. PMID- 23918483 TI - Increases in consumer cost sharing redirect patient volumes and reduce hospital prices for orthopedic surgery. AB - Some employers are implementing reference-pricing benefit designs, which establish limits on the amount they will pay for some procedures covered by employer-sponsored insurance. Employees are required to pay the difference between the employer's contribution limit and the actual price received by the hospital. These initiatives encourage patients to select low-price facilities and indirectly encourage facilities to reduce prices to increase patient volume. We evaluated the impact of reference pricing on the use of and prices paid for knee and hip replacement surgery by members of the California Public Employees' Retirement System (CalPERS) from 2008 to 2012, using enrollees in Anthem Blue Cross as a comparison group. In the first year after implementation, surgical volumes for CalPERS members increased by 21.2 percent at low-price facilities and decreased by 34.3 percent at high-price facilities. Prices charged to CalPERS members declined by 5.6 percent at low-price facilities and by 34.3 percent at high-price facilities. Our analysis indicates that in 2011 reference pricing accounted for $2.8 million in savings for CalPERS and $0.3 million in lower cost sharing for CalPERS members. PMID- 23918484 TI - Low-socioeconomic-status enrollees in high-deductible plans reduced high-severity emergency care. AB - One-third of US workers now have high-deductible health plans, and those numbers are expected to grow in 2014 as implementation of the Affordable Care Act continues. There is concern that high-deductible health plans might cause enrollees of low socioeconomic status to forgo emergency care as a result of burdensome out-of-pocket costs. We analyzed emergency department (ED) visits and hospitalizations over two years among enrollees insured in high-deductible plans through small employers in Massachusetts. We found that plan members of low socioeconomic status experienced 25-30 percent reductions in high-severity ED visits over both years, while hospitalizations declined by 23 percent in year 1 but rose again in year 2. Similar trends were not found among high-deductible plan members of high socioeconomic status. Our findings suggest that plan members of low socioeconomic status at small firms responded inappropriately to high deductible plans and that initial reductions in high-severity ED visits might have increased the need for subsequent hospitalizations. Policy makers and employers should consider proactive strategies to educate high-deductible plan members about their benefit structures or identify members at higher risk of avoiding needed care. They should also consider implementing means-based deductibles. PMID- 23918485 TI - Transitional care cut hospital readmissions for North Carolina Medicaid patients with complex chronic conditions. AB - Recurrent hospitalizations represent a substantial and often preventable human and financial burden in the United States. In 2008 North Carolina initiated a statewide population-based transitional care initiative to prevent recurrent hospitalizations among high-risk Medicaid recipients with complex chronic medical conditions. In a study of patients hospitalized during 2010-11, we found that those who received transitional care were 20 percent less likely to experience a readmission during the subsequent year, compared to clinically similar patients who received usual care. Benefits of the intervention were greatest among patients with the highest readmission risk. One readmission was averted for every six patients who received transitional care services and one for every three of the highest-risk patients. This study suggests that locally embedded, targeted care coordination interventions can effectively reduce hospitalizations for high risk populations. PMID- 23918486 TI - Satisfaction with Massachusetts nursing home care was generally high during 2005 09, with some variability across facilities. AB - Since 2005 Massachusetts has publicly reported results from biennial surveys of satisfaction with nursing homes, completed by responsible parties for residents, to promote consumer-centered care. Our analysis of the results from 2005, 2007, and 2009 revealed generally high satisfaction with care, which remained stable over time. On a scale of 1 to 5 (from very dissatisfied to very satisfied), average satisfaction with overall care was 4.22-4.31, and satisfaction that overall residents' needs were met was 4.09-4.16. Around 90 percent of respondents would recommend the facility. Satisfaction ratings varied considerably across facilities, with higher scores associated with higher nursing staffing levels, fewer deficiency citations, and nonprofit or government ownership. Scores for six domains of care were, in general, closely associated with satisfaction scores. However, family members seemed less satisfied with the physical and social activities available to residents and with the food and meals served than with such attributes as the physical environment. Our findings suggest that including the consumer's perspective would improve the Centers for Medicare and Medicaid Services' current nursing home reporting efforts. However, refinements may be necessary to detect the impact of consumer reporting on the quality of patient centered care. PMID- 23918487 TI - Regulatory neutrality is essential to establishing a level playing field for accountable care organizations. AB - Accountable care organizations (ACOs) are among the most widely discussed models for encouraging movement away from fee-for-service payment arrangements. Although ACOs have the potential to slow health spending growth and improve quality of care, regulating them poses special challenges. Regulations, particularly those that affect both ACOs and Medicare Advantage plans, could inadvertently favor or disfavor certain kinds of providers or payers. Such favoritism could drive efficient organizations from the market and thus increase costs or reduce quality of and access to care. To avoid this type of outcome, we propose a general principle: Regulation of ACOs should strive to preserve a level playing field among different kinds of organizations seeking the same cost, quality, and access objectives. This is known as regulatory neutrality. We describe the implications of regulatory neutrality in four key areas: antitrust, financial solvency regulation, Medicare governance requirements, and Medicare payment models. We also discuss issues relating to short-term versus long-term perspectives--to promote the goal of regulatory neutrality and allow the most efficient organizations to prevail in the marketplace. PMID- 23918488 TI - An improved approach to measuring drug innovation finds steady rates of first-in class pharmaceuticals, 1987-2011. AB - For more than a decade, industry analysts and policy makers have raised concerns about declining pharmaceutical innovation, citing declining numbers of new molecular entities (NMEs) approved in the United States each year. Yet there is little consensus on whether this is the best measure of "innovation." We examined NME approvals during 1987-2011 and propose the three distinct subcategories of NMEs--first-in-class, advance-in-class, and addition-to-class--to provide more nuanced and informative insights into underlying trends. We found that trends in NME approvals were largely driven by addition-to-class, or "me too," drug approvals, while first-in-class approvals remained fairly steady over the study period. Moreover, the higher proportion of first-in-class drug approvals over the most recent decade is an encouraging sign of the health of the industry as a whole. PMID- 23918489 TI - UnitedHealthcare experience illustrates how payers can enable patient engagement. AB - Patient engagement is crucial to better outcomes and a high-performing health system, but efforts to support it often focus narrowly on the role of physicians and other care providers. Such efforts miss payers' unique capabilities to help patients achieve better health. Using the experience of UnitedHealthcare, a large national payer, this article demonstrates how health plans can analyze and present information to both patients and providers to help close gaps in care; share detailed quality and cost information to inform patients' choice of providers; and offer treatment decision support and value-based benefit designs to help guide choices of diagnostic tests and therapies. As an employer, UnitedHealth Group has used these strategies along with an "earn-back" program that provides positive financial incentives through reduced premiums to employees who adopt healthful habits. UnitedHealth's experience provides lessons for other payers and for Medicare and Medicaid, which have had minimal involvement with demand-side strategies and could benefit from efforts to promote activated beneficiaries. PMID- 23918490 TI - HealthPartners adopts community business model to deepen focus on nonclinical factors of health outcomes. AB - Clinical care contributes only 20 percent to overall health outcomes, according to a population health model developed at the University of Wisconsin. Factors contributing to the remainder include lifestyle behaviors, the physical environment, and social and economic forces--all generally considered outside the realm of care. In 2010 Minnesota-based HealthPartners decided to target nonclinical community health factors as a formal part of its strategic business plan to improve public health in the Twin Cities area. The strategy included creating partnerships with businesses and institutions that are generally unaccustomed to working together or considering how their actions could help improve community health. This article describes efforts to promote healthy eating in schools, reduce the stigma of mental illness, improve end-of-life decision making, and strengthen an inner-city neighborhood. Although still in their early stages, the partnerships can serve as encouragement for organizations inside and outside health care that are considering undertaking similar efforts in their markets. PMID- 23918491 TI - Provider performance measures in private and public programs: achieving meaningful alignment with flexibility to innovate. AB - In recent years there has been a significant expansion in the use of provider performance measures for quality improvement, payment, and public reporting. Using data from a survey of health plans, we characterize the use of such performance measures by private payers. We also compare the use of these measures among selected private and public programs. We studied twenty-three health plans with 121 million commercial enrollees--66 percent of the national commercial enrollment. The health plans reported using 546 distinct performance measures. There was much variation in the use of performance measures in both private and public payment and care delivery programs, despite common areas of focus that included cardiovascular conditions, diabetes, and preventive services. We conclude that policy makers and stakeholders who seek less variability in the use of performance measures to increase consistency should balance this goal with the need for flexibility to meet the needs of specific populations and promote innovation. PMID- 23918493 TI - In the safety net: a tale of ticking clocks and tricky diagnoses. PMID- 23918492 TI - A call for evidence-based medical treatment of opioid dependence in the United States and Canada. AB - Despite decades of experience treating heroin or prescription opioid dependence with methadone or buprenorphine--two forms of opioid substitution therapy--gaps remain between current practices and evidence-based standards in both Canada and the United States. This is largely because of regulatory constraints and pervasive suboptimal clinical practices. Fewer than 10 percent of all people dependent on opioids in the United States are receiving substitution treatment, although the proportion may increase with expanded health insurance coverage as a result of the Affordable Care Act. In light of the accumulated evidence, we recommend eliminating restrictions on office-based methadone prescribing in the United States; reducing financial barriers to treatment, such as varying levels of copayment in Canada and the United States; reducing reliance on less effective and potentially unsafe opioid detoxification; and evaluating and creating mechanisms to integrate emerging treatments. Taking these steps can greatly reduce the harms of opioid dependence by maximizing the individual and public health benefits of treatment. PMID- 23918494 TI - Grantwatch. PMID- 23918496 TI - Workplace wellness programs. PMID- 23918497 TI - The effect of workplace wellness programs. PMID- 23918498 TI - Workplace wellness: the authors reply. PMID- 23918499 TI - Integrating social supports into medical care. PMID- 23918500 TI - Social supports: the authors reply. PMID- 23918501 TI - Nurse practitioners and Israeli health care. PMID- 23918502 TI - Israeli health care: the author replies. PMID- 23918504 TI - New challenges in dental and oral health care. PMID- 23918505 TI - Discharge and bad taste. PMID- 23918503 TI - Varicella zoster virus vasculopathy: clinical features and pathogenesis. AB - Varicella zoster virus (VZV) vasculopathy is caused by productive virus infection of cerebral arteries, leading to inflammation, pathological vascular remodeling, and ischemic or hemorrhagic stroke. VZV vasculopathy occurs in immunocompetent and immunocompromised individuals and involves both large and small vessels. MRI abnormalities include more deep-seated than superficial lesions, particularly at gray-white matter junctions, and lesions may enhance. Diagnosis is challenging, since stroke can occur months after zoster rash and in the absence of rash or CSF pleocytosis. The best virological test for diagnosis is detection of anti-VZV IgG antibody in the CSF. Pathological studies of VZV-infected arteries from patients with VZV vasculopathy reveal that the arterial adventitia is the initial site of infection, after which virus spreads transmuraly towards the lumen. Histological and immunohistochemical studies of VZV-infected arteries show a thickened intima, disrupted internal elastic lamina, and loss of smooth muscle cells, that likely contribute to weakening of the vessel wall and occlusion. Early in disease, VZV infected arteries contain CD4+ and CD8+ T cells, macrophages, and rare B cells, in addition to abundant neutrophils in early disease. Importantly, perivascular inflammatory cells underlie the areas of thickened intima, raising the possibility that soluble factors secreted by these cells contribute to arterial remodeling. This review discusses the clinical features of VZV vasculopathy and potential mechanisms of VZV-induced cerebrovascular remodeling and stroke. PMID- 23918506 TI - Impact of excessive occlusal load on successfully-osseointegrated dental implants: a literature review. AB - The aim of the present study was to review the available evidence on the response of the peri-implant bone when subjected to excessive occlusal forces. The search strategy included papers published in English in the Medline database and the Wiley Online Library from January 1991 to December 2011. Experimental or review papers reporting the conditions of the peri-implant bone of dental implants submitted to excessive occlusal loading in the presence of a controlled oral hygiene regime were eligible for inclusion. The knowledge regarding the response of the peri-implant bone when the dental implant is excessively loaded is limited, and the level of evidence is poor. With animal experimental studies showing conflicting results, it is unclear whether occlusal overload might cause marginal bone loss or total loss of osseointegration to already osseointegrated dental implants when the applied load exceeds the biologically-acceptable limit. This biological limit is also unknown. Furthermore, higher remodeling activity of the peri-implant bone is found around implants subjected to high loading forces. PMID- 23918507 TI - Development of hydrophobized alginate hydrogels for the vessel-simulating flow through cell and their usage for biorelevant drug-eluting stent testing. AB - The vessel-simulating flow-through cell (vFTC) has been used to examine release and distribution from drug-eluting stents in an in vitro model adapted to the stent placement in vivo. The aim of this study was to examine the effect of the admixture of different hydrophobic additives to the vessel wall simulating hydrogel compartment on release and distribution from model substance-coated stents. Four alginate-based gel formulations containing reversed-phase column microparticles LiChroprep(r) RP-18 or medium-chain triglycerides in form of preprocessed oil-in-water emulsions Lipofundin(r) MCT in different concentrations were successfully developed. Alginate and modified gels were characterized regarding the distribution coefficient for the fluorescent model substances, fluorescein and triamterene, and release as well as distribution of model substances from coated stents were investigated in the vFTC. Distribution coefficients for the hydrophobic model substance triamterene and the hydrophobized gel formulations were up to four times higher than for the reference gel. However, comparison of the obtained release profiles yielded no major differences in dissolution and distribution behavior for both fluorescent model substances (fluorescein, triamterene). Comparison of the test results with mathematically modeled data acquired using finite element methods demonstrated a good agreement between modeled data and experimental results indicating that gel hydrophobicity will only influence release in cases of fast releasing stent coatings. PMID- 23918508 TI - Sodium valproate sensitizes non-small lung cancer A549 cells to gammadelta T-cell mediated killing through upregulating the expression of MICA. AB - Major histocompatibility complex (MHC) class I chain-related protein A (MICA) is involved in gammadelta T-cell recognition of target tumor cells. The aim of this study was to investigate the feasibility of utilization of sodium valproate (VPA), a histone deacetylase inhibitor, to sensitize non-small cell lung cancer A549 cells to gammadelta T-cell-mediated killing. VPA induced a dose-dependent increase in the mRNA and protein expression of MICA in A549 cells. gammadelta T cells showed cytotoxicity to A549 cells, which was increased by about 50% in the presence of VPA. The concomitant addition of MICA antibody significantly attenuated the VPA-mediated sensitization to gammadelta T-cell killing. VPA enhanced the cleavage of caspase-3 and caspase-9 in A549 cells cocultured with gammadelta T cells, and such enhancement was reversed by the MICA antibody. In conclusion, VPA sensitizes tumor cells to gammadelta T-cell-mediated cytotoxicity through the upregulation of MICA and may thus have benefits in improving gammadelta T-cell-based cancer immunotherapy. PMID- 23918509 TI - A prospective study of 113 deep neck infections managed using a clinical practice guideline. AB - OBJECTIVES/HYPOTHESIS: Retropharyngeal abscesses are a difficult to diagnose condition in children. Though some children with such abscesses can be managed with intravenous (IV) antibiotics alone, our group has argued that surgical drainage is the gold standard for safe management and likely leads to shorter hospital stays. We present prospective data on children with retropharyngeal infections who were managed according to a clinical practice guideline that emphasizes reliance on computed tomography and prompt surgical drainage when pus is felt to be present. STUDY DESIGN: Prospective observational study at a tertiary care children's hospital. METHODS: Children were included in the study if a retropharyngeal infection was suspected and they were treated according to the clinical guideline between July 2001 and March 2004. RESULTS: Of 111 children in the study, 73 were ultimately treated with incision and drainage. There was no long-term morbidity or mortality. Surgical patients were more likely to require an intensive care unit (ICU) admission than patients managed with IV antibiotics alone (26.0% vs. 5.3%, P < .01) and on average cost nearly $8,000 more ($22,071 and $14,950; P < .01). However, these results may be biased, as patients requiring surgery were younger, which likely influenced the decision for ICU admission. CONCLUSIONS: It is possible to treat pediatric retropharyngeal infections according to our clinical guideline with nearly zero long-term morbidity and mortality. Our data showed good outcomes for both groups, and substantially higher costs for patients treated surgically. These results cannot be regarded as definitive, because surgery was consistently advised for all patients with suspected pus, and because the surgical group was younger than the nonsurgical group. PMID- 23918510 TI - Raising the ante in anti-counterfeit drug legislation. PMID- 23918511 TI - Right-sided pyriform sinus fistula in an adult. AB - Pyriform sinus fistula is important despite its rarity, as it can induce a recurrent neck abscess. Most of the reported cases occur in children and the majority affect only the left side. We report a patient with a pyriform sinus fistula of the right neck in an adult, which was successfully treated by surgery. The aetiology of this entity is also discussed herein. PMID- 23918512 TI - Fatal cerebral air embolism related to an air flight. AB - A patient with chronic obstructive pulmonary disease developed a cough, loss of consciousness, and convulsions during an air flight. Chest radiography showed a large lung bulla. Computed tomography of the brain showed intraparenchymal air and bilateral cerebral infarcts. The findings were compatible with cerebral air embolism, most likely predisposed to by lung bulla and an air flight. The underlying pathology and possible treatment are discussed. PMID- 23918513 TI - Mad honey poisoning mimicking acute myocardial infarction. AB - We report a case of acute poisoning in a 48-year-old man who presented with chest pain, abdominal pain, dizziness, sweatiness, blurred vision, and severe hypotension after ingestion of honey. His electrocardiogram showed sinus bradycardia and transient ST elevation. He made a good recovery after treatment with atropine and close monitoring. Grayanotoxin was detected in his urine and the honey he ingested, which confirmed a diagnosis of mad honey poisoning. This is a condition prevalent in the Black Sea region around Turkey but rarely seen locally. Although mad honey poisoning is life-threatening, early use of atropine is life-saving. Such poisoning may present with ST elevation in the electrocardiogram and symptoms mimicking acute myocardial infarction. It is therefore essential for clinicians to recognise this unusual form of poisoning and avoid the disastrous use of thrombolytic therapy. PMID- 23918514 TI - A patient with congenital hyperlactataemia and Leigh syndrome: an uncommon mitochondrial variant. AB - We report an uncommon mitochondrial variant in a baby girl with congenital hyperlactataemia and Leigh syndrome. The patient presented with a single episode of generalised clonic convulsion at day 19, and was found to have isolated and persistent hyperlactataemia ranging from 3.34 to 9.26 mmol/L. She had elevated serum lactate-to-pyruvate ratios of up to 35 and high plasma alanine concentration, indicative of a respiratory chain defect. At the age of 8 months, she developed evolving neurological and imaging features compatible with Leigh syndrome. Genetic testing for common mitochondrial DNA mutations, large mitochondrial DNA deletions, and selected nuclear genes was negative. Further analysis of lymphocyte mitochondrial DNA by sequencing revealed an uncommon heteroplasmic variant, NC_012920.1(MT-ND5):m.13094T>C (p.Val253Ala), which was previously shown to reduce complex I activity. In patients in whom there was a high suspicion of mitochondrial disorder, entire mitochondrial DNA analysis may be warranted if initial screening of common mitochondrial DNA mutations is negative. PMID- 23918515 TI - Early consideration of anti-NMDAR encephalitis in unexplained encephalopathy. AB - With the identification of anti-NMDAR (N-methyl-D-aspartate receptor) antibody, the spectrum of anti-NMDAR encephalitis has been expanding. The condition is also increasingly recognised in children, though younger patients are less likely to have tumours, while behavioural and speech problems, seizures, and abnormal movements are common early presenting features. Here we present yet another case with subtle, non-specific clinical symptoms that responded promptly to intravenous immunoglobulin. We believe this illustrates the importance of considering this uncommon differential diagnosis in the management of unexplained neurological conditions. PMID- 23918516 TI - A target annular rash in an atopic neonate. PMID- 23918517 TI - Mounier-Kuhn syndrome: an unusual underlying cause for chronic coughs and recurrent pneumonias. PMID- 23918518 TI - Effect of prostaglandin E2 on myometrial electrical activity in women undergoing induction of labor. AB - OBJECTIVE: To investigate the effect of prostaglandin E2 (PGE2) on electrical uterine activity using a novel uterine muscle electromyography device in patients undergoing induction of labor. STUDY DESIGN: Electrical uterine myography (EUM) was prospectively measured using a noninvasive nine channels recorder in 31 women undergoing induction of labor with vaginal PGE2 tablets. Women were monitored before and up to 12 hours after vaginal PGE2 application. EUM index was defined as mean electrical activity of the uterine muscle over a period of 10 minutes measured in units of microjoule (uJ, uWs). RESULTS: The EUM index was not increased significantly during the first 2 hours following PGE2 application (overall increase of 5.3 +/- 60.1%, p = 0.7). Peak EUM activity was observed during 2 to 8 hours following PGE2 application, which represented a statistically significant increase compared with the EUM index before PGE2 application (3.3 +/- 0.5 uJ vs. 2.5 +/- 0.95 uJ, p = 0.01), and with the EUM index 0 to 2 hours following PGE2 application (3.3 +/- 0.5 uJ vs. 2.3 +/- 0.9 uJ, p = 0.004). CONCLUSION: The data suggests that in women undergoing labor induction with PGE2, uterine activity peaks 2 to 8 hours following PGE2 application. This information may provide more insight into the mechanism of PGE2 action. PMID- 23918519 TI - Stillbirth gestational age as a predictor of recurrence risk. AB - OBJECTIVE: We evaluated risk of subsequent stillbirth (SB) according to gestational age at initial SB. STUDY DESIGN: We retrospectively reviewed a cohort of women delivering a singleton SB with at least one subsequent pregnancy. Relative risks (RRs) were calculated using an initial SB gestational age of 36 to < 40 weeks as the referent. Multivariable logistic regression accounted for potential confounders. RESULTS: In all, 2,887 mothers and 5,090 subsequent births met inclusion criteria. For the immediately next pregnancy, the linear trend for gestational age was not significant (RR 0.41; 95% confidence interval [CI] 0.03 to 5.53). However, women with index SBs occurring between 20 and 23(6/7) weeks' gestation had a RR for subsequent stillbirth of 2.9 (95% CI 1.2 to 7.1). When including subsequent pregnancies, the test for trend for gestational age was nonsignificant (RR 1.5; 95% CI 0.3 to 8.7). However, women suffering a stillbirth between 20(0/7) and 23(6/7) weeks' gestation in the index pregnancy had an almost threefold increase in the risk of subsequent stillbirth. Women suffering an index stillbirth between 28(0/7) and 31(6/7) weeks' and after 40 weeks' gestation had a 2.5- to 3.5-fold increased risk of subsequent SB. CONCLUSIONS: Gestational age at initial SB predicts risk of recurrent SB. This effect is most pronounced in women with very preterm or with postterm pregnancies. PMID- 23918520 TI - Application of transcutaneous carbon dioxide tension monitoring with low electrode temperatures in premature infants in the early postnatal period. AB - OBJECTIVE: The aim of this article is to evaluate the accuracy, precision, and safety of transcutaneous carbon dioxide tension (TcPCO2) monitoring at different electrode temperatures in preterm infants in the early postnatal period. STUDY DESIGN: A total of 26 neonates with a median birth weight of 974 g (432-1,694 g) and gestational age of 28.0 weeks (26.1-31.3 weeks) were studied in the first 5 days of life. A total of 252 simultaneous pairs (TcPCO2 and arterial carbon dioxide tension [PaCO2]) were analyzed at 38, 39, and 40 degrees C at 26 and 27 weeks, and at 38, 39, 40, and 42 degrees C at 28 to 31 weeks. RESULTS: The mean difference of TcPCO2 and PaCO2 (bias) increased from 3.93 mm Hg at 42 degrees C to 5.64 mm Hg at 40 degrees C, 6.58 mm Hg at 39 degrees C, and 6.07 mm Hg at 38 degrees C. Standard deviation (SD) of the bias increased from 4.17 mm Hg at 42 degrees C to 4.76 mm Hg at 40 degrees C, 5.29 mm Hg at 39 degrees C, and 5.07 mm Hg at 38 degrees C. Adverse skin lesions were not observed. CONCLUSION: TcPCO2 measurements are the most accurate and precise at an electrode temperature of 42 degrees C. However, in premature babies, monitoring at 38, 39, and 40 degrees C is possible provided a bias correction of 6 mm Hg and SD of 5 mm Hg are applied. PMID- 23918521 TI - Engaging expectant parents to receive Tdap vaccination. AB - OBJECTIVE: To assess the acceptability of a Tdap vaccination program for partners of pregnant women. STUDY DESIGN: Pregnant women and their partners were enrolled in a prospective acceptability study. For partners absent during the initial encounter, an introductory letter inviting the partner to participate was sent home. Tetanus and diphtheria toxoids and acellular pertussis vaccine (Tdap) was offered to vaccine-eligible partners while vaccine-eligible pregnant women were offered Tdap immediately postpartum, as per national recommendations at the time the study was conducted. Tdap acceptance was defined as vaccination during study participation. RESULTS: A total of 69 pregnant women and 63 partners were enrolled. Excluding the 19 partners reporting prior receipt, 61.4% of partners (27/44) accepted Tdap during the study. Those who enrolled following the introductory letter were more likely to accept Tdap than those enrolled at the initial encounter (84 vs. 44%, p = 0.005). Excluding the 29 pregnant women reporting prior receipt, 65% (26/40) received Tdap postpartum. Demographic factors and vaccine beliefs were not associated with Tdap acceptance. CONCLUSION: Tdap vaccination for partners of pregnant women during prenatal care is acceptable. Large-scale implementation would require substantial interest and willingness of obstetrician-gynecologists to administer Tdap not only to pregnant women but also to their partners. Such a program would provide improved "cocooning" of vulnerable infants against pertussis. PMID- 23918522 TI - Postpartum depression in mothers of infants in neonatal intensive care unit: risk factors and management strategies. AB - OBJECTIVE: The aim of this study is to assess incidence, risk factors, and management strategies for Postpartum depression (PPD) in mothers of neonatal intensive care unit (NICU) infants. STUDY DESIGN: A total of 131 mothers completed the study assessment tool (Edinburgh Postnatal Depression Scale with additional questions). Score of 10 or above was considered to indicate risk for PPD (subclinical depression). Risk factors were examined with particular emphasis on length of stay (LOS). RESULTS: Approximately 19.1% of mothers experienced (subclinical) PPD. Depression during current and previous pregnancy, and problems with current delivery were strong predicting risk factors for PPD. As the LOS increased beyond 2 weeks, the odds of PPD risks initially increased, then leveled off, and then decreased after 31 days. CONCLUSION: We recommend that the mothers of NICU infants be routinely screened for PPD and aggressively treated. PMID- 23918523 TI - Association between weight gain during pregnancy and pregnancy outcomes after dietary and lifestyle interventions: a meta-analysis. AB - OBJECTIVES: Lifestyle interventions in obese pregnant women reduce adverse maternal outcomes of pregnancy. However, the association between weight change due to interventions and the actual reduction in complications is unknown. The objective of this study was to determine the association between gestational weight gain (GWG) and the rate of pregnancy complications. STUDY DESIGN: The authors included randomized controlled trials (RCTs) assessing the effect of lifestyle interventions during pregnancy on GWG and adverse maternal and fetal outcomes. For each outcome they assessed the association between GWG and the risk of adverse pregnancy outcomes. RESULTS: They analyzed data of 23 RCTs (4,990 women). Increased GWG was associated with a nonsignificant increase in the incidence of preeclampsia (PE) (0.2% per gained kg, 95% confidence interval [CI] 0.5 to 0.9%, p > 0.05), gestational diabetes (GDM) (0.3% per gained kg, 95% CI 0.5 to 1.0%, p > 0.05), and induction of labor (IOL) (1.5% per gained kg, 95% CI 0.9 to 3.9%, p > 0.05). CONCLUSIONS: Reduction in GWG due to lifestyle interventions in pregnancy had statistically nonsignificant effects on lowering the incidence of PE, GDM, and IOL. Possibly, the beneficial effect of lifestyle interventions on pregnancy outcomes is due to an effect independent of the reduction of GWG. PMID- 23918524 TI - Extensive regenerative plasticity among adult NG2-glia populations is exclusively based on self-renewal. AB - NG2-glia are known to proliferate in the adult brain, however the extent of their mitotic and regenerative capacity and particularly their adult origin is uncertain. By employing a paradigm of mitotic blockade in conjunction with genetic fate tracing we demonstrate that intracerebroventricular mitotic blocker infusion leads to wide-spread and complete ablation of NG2-glial cells in the hypothalamus and other periventricular brain regions. However, despite the extensive glia loss, parenchymal NG2-glia coverage is fully restored to pretreatment levels within two weeks. We further reveal that in response to mitotic blocker treatment, NG2-glia bordering the ablated territories start to express the stem cell marker nestin, divide and migrate to replace the lost cells. Importantly, the migration front of repopulating NG2-glia invariably proceeds from the distal parenchyma towards the ventricles, ruling out contributions of the subventricular zone neurogenic niche or the corresponding area of the third ventricle as source of new NG2-glia. NG2-CreER-based fate tracing further substantiates that NG2-glia which have been spared from mitotic blockade are the sole source of regenerating NG2-glia. Collectively, our data reveals that all adult NG2-glia retain the ability to divide and that they are capable of fully restoring parenchymal NG2-glia coverage after wide-spread NG2 cell loss, indicating complete self-sufficiency in maintaining NG2-glia population levels in the adult brain. PMID- 23918525 TI - ADAM15 adds to apoptosis resistance of synovial fibroblasts by modulating focal adhesion kinase signaling. AB - OBJECTIVE: To study the contribution of ADAM15, a disintegrin metalloproteinase that is up-regulated in the rheumatoid arthritis (RA) synovial membrane, to the characteristic resistance of RA synovial fibroblasts (RASFs) to apoptosis induction by genotoxic stress or stimulation with proapoptotic FasL, which is present at high concentrations in RA synovial fluid. METHODS: Caspase 3/7 activity and the total apoptosis rate in RASFs upon exposure to the DNA-damaging agent camptothecin or FasL were determined using enzyme assays and annexin V staining. Phosphorylated signaling proteins were analyzed by immunoblotting. RNA interference was used to silence ADAM15 expression. NF-kappaB activity was determined by enzyme-linked immunosorbent assay. RESULTS: RASFs displayed significantly higher caspase 3/7 activity upon camptothecin and FasL exposure when ADAM15 had been down-regulated by specific small interfering RNAs. Upon FasL stimulation, RASFs phosphorylated focal adhesion kinase (FAK) and c-Src (Src), and activated phosphatidylinositol 3-kinase as well as the transcription factor NF-kappaB. This ADAM15-dependent, FasL-induced activation of antiapoptotic kinases and NF-kappaB was demonstrated by a marked reduction of apoptosis upon knockdown of ADAM15 protein expression. Inhibitors specifically interfering with FAK and Src signaling, such as FAK inhibitor 14 and dasatinib, potently induce apoptosis in RASFs, with significant enhancement by the silencing of ADAM15. CONCLUSION: ADAM15 contributes to apoptosis resistance in RASFs by activating the Src/FAK pathway upon FasL exposure, rendering the FAK/Src signaling pathway an interesting target for potential therapeutic intervention in RA. PMID- 23918526 TI - Characteristics of glass ionomer cements composed of glass powders in CaO-SrO-ZnO SiO2 system prepared by two different synthetic routes. AB - Glass ionomer cements (GICs) are composed of an acid degradable glass, polyacrylic acid and water. Sol-gel processing to prepare the glass phase has certain advantages, such as the ability to employ lower synthesis temperatures than melt quenching and glasses that are reported to have higher purity. A previous study reported the effects of glass synthesis route on GIC fabrication. However, in that study, the sol-gel derived glass exhibited a reduced concentration of cations. This study investigates increasing the cation content of a sol-gel derived glass, 12CaO.4SrO.36ZnO.48SiO2 (molar ratio) by heating before aging to reduce dissolution of cations. This glass was prepared by both sol-gel and melt-quenched routes. GICs were subsequently prepared using both glasses. The resultant cement based on the sol-gel derived glass had a shorter working time than the cement based on the melt-quenched one. Contrary to this, setting time was considerably longer for the cement based on the sol-gel derived glass than for the cement based on the melt-quenched one. The cements based on the sol-gel derived glass were stronger in both compression and biaxial flexure than the cements prepared from the melt-quenched glass. The differences in setting and mechanical properties were associated with both cation content in the glass phase and the different surface area of the resultant cements. PMID- 23918527 TI - The influence of target stoichiometry on early cell adhesion of co-sputtered calcium-phosphate surfaces. AB - The nature of the initial interaction between calcium phosphate (Ca-P) thin films and osteoblasts can be influenced by a number of different properties including the phase, crystallinity, stoichiometry and composition of the surface. There is still a strong interest in developing and studying Ca-P surfaces that have the ability to accurately control the osteoblast response. Radio frequency (RF) magnetron sputtering is a technique that allows for accurate control of the properties of deposited Ca-P coatings and has been studied extensively because of this fact. In this work, Ca-P coatings were co-deposited using RF magnetron sputtering in order to study the effect of changing the target stoichiometry on the initial in vitro behavior of MG63 osteoblast-like cells. The samples produced were analysed both as-deposited and after thermal annealing to 500 degrees C. After annealing XPS analyses of the samples co-deposited using tricalcium phosphate (TCP) materials gave a Ca/P ratio of 1.71 +/- 0.01, as compared to those co-deposited from hydroxyapatite (HA) materials, with a Ca/P of 1.82 +/- 0.06. In addition to this, the curve fitted XPS data indicated the presence of low levels of carbonate in the coatings. Despite this the XRD results for all of the annealed coatings were shown to be characteristic of pure HA with a preferred 002 orientation. The atomic force microscopy results also highlighted that both types of coatings had surface features of a similar size (200-220 nm). Both surfaces exhibited a degree of surface degradation, even after 1 h of cell culture. However, the TCP derived surfaces showed an enhanced osteoblastic cell response in terms of cell adhesion and cell proliferation in the earlier stages of cell culture than the surfaces deposited from HA. An improvement in the initial cell attachment and a potential for increased cell proliferation rates is viewed as a highly advantageous result in relation to controlling the osteoblast response on these surfaces. PMID- 23918528 TI - Osteogenesis imperfecta in adults: phenotypic characteristics and response to treatment in an Irish cohort. AB - BACKGROUND: Osteogenesis imperfecta (OI) is a heritable disorder of variable phenotype that is characterised by bone fragility and frequent fractures, with deformities and short stature in more severe cases. AIMS: We sought to review the response to treatment in a cohort of adult patients with OI. METHODS: Charts of 16 patients with OI attending a metabolic bone disease clinic were reviewed, particularly with respect to the response to treatment using bisphosphonates and recombinant human parathyroid hormone (rhPTH). The response to treatment was assessed by monitoring bone mineral density (BMD) and bone turnover markers (BTMs). RESULTS: In response to bisphosphonate therapy, median (range) BMD increased at the spine by 15.1(6.9-43.7) %. In response to rhPTH in 2 cases, spinal BMD increased by 40.3 and 27.2 %. CONCLUSION: OI is debilitating disorder, but the course of the disease may be altered by treatment that increases BMD such as bisphosphonates and rhPTH. Both serial BMD and BTM aid in assessing response to intervention. Further study is needed with regard to fracture prevention. PMID- 23918529 TI - Patients satisfaction with warfarin and willingness to switch to dabigatran: a patient survey. AB - Warfarin is an anticoagulant medication that is challenging to manage. Dabigatran has been approved by the FDA for stroke and systemic embolism prevention in non valvular atrial fibrillation as an alternative to warfarin. Dabigatran does not require routine monitoring, has an established dose, and lacks many of the drug, herbal, and food interactions that afflict warfarin. To evaluate patients' satisfaction with their current warfarin treatment and their opinion on switching to a newly marketed medication (dabigatran) through a brief survey. Two separate surveys were administered to (1) evaluate the patients' opinion of their warfarin therapy and (2) evaluate their thoughts on switching to a newer anticoagulant. Responses were recorded on a rating scale of 1-5; 1 being the least and 5 being the highest. Study was conducted at the Georgia Regents Health System (GRHS) pharmacy-based anticoagulation clinic. Two hundred sixty patients on warfarin treatment were enrolled. Patients expressed high satisfaction with warfarin treatment (4.7 +/- 0.78). However, a vast majority of the patients were willing to switch to an agent that: requires less frequent follow-up visits (3.9 +/- 1.35); lacks interaction with food and/or beverage (4.1 +/- 1.25); is as efficacious as warfarin (3.7 +/- 1.38). Patients expressed that out-of-pocket cost would be a major barrier to switch to this new medication (1.3 +/- 0.58). Patients are satisfied with their warfarin treatment but willing to consider a new anticoagulant. Cost was highlighted as the most significant barrier. Efficacy, dietary freedom and less frequent visits are the major factors affecting the patients' decision. PMID- 23918530 TI - Screening for lung cancer: the US studies. AB - Efforts in lung cancer screening with chest X-ray (CXR) and sputum cytology in the 1970s and 1980s were negative. In the ensuing decade, the early lung cancer action project (ELCAP), and the Mayo screening study showed the promise of low dose CT. These and other studies led to the National lung screening study (NLST), which showed definitively that low-dose spiral computed tomography had a measurable impact on mortality and could be justified as a tool for lung cancer screening. This review examines the results of past and recent studies of lung cancer screening. PMID- 23918531 TI - Can pillar suturing promote efficacy of adenotonsillectomy for pediatric OSAS? A prospective randomized controlled trial. AB - OBJECTIVES/HYPOTHESIS: Pediatric obstructive sleep apnea syndrome (OSAS) is a common disorder with serious clinical implications if left untreated. The recommended initial treatment for pediatric patients with obstructive sleep apnea syndrome (OSAS) is adenotonsillectomy. However, recent reports have shown variable surgical results with adenotonsillectomy in the treatment of pediatric OSAS. STUDY DESIGN: Prospective, controlled study. METHODS: From April 2007 to August 2010, 24 participants were assigned alternatively to either adenotonsillectomy with pillar suturing (intervention group) or adenotonsillectomy alone (control group). RESULT: The average improvement in apnea hypopnea index (AHI) was 42.6% in the control group and 79.9% in the intervention group (P=0.037). The success rate was 50% in the control group and 91.6% in the intervention group (P=0.034). Six patients (50%) in the intervention group achieved complete resolution of pediatric OSAS, as defined by an AHI <1/hour, compared to 2 patients (16.7%) in the control group (P=0.097). CONCLUSION: Adenotonsillectomy with pillar suturing showed significant improvement in treating pediatric patients with OSAS compared to adenotonsillectomy alone. The procedure is simple and safe. LEVEL OF EVIDENCE: 4. PMID- 23918532 TI - H infinity Estimation for Stochastic Time Delays in Networked Control Systems by Partly Unknown Transition Probabilities of Markovian Chains. AB - This paper is concerned with the problem of Hinfinity estimation for networked control systems. Time delays and packet dropouts are considered simultaneously. The occurrence probability of each time delay is considered. The packet dropouts have the Bernoulli distributions. The system is modeled as Markovian jump linear systems with partly unknown transition probability. State observer is designed to estimate the practical state with Hinfinity feature. The estimation problem is cast into a set of linear matrix inequalities. An example is provided to illustrate the effectiveness and applicability of the proposed method. PMID- 23918533 TI - Hepatitis B virus reverse transcriptase mutations in treatment Naive chronic hepatitis B patients. AB - Mutations in the reverse transcriptase (RT) region of the hepatitis B virus (HBV) genome lead to decreased susceptibility to nucleos(t)ide analogs approved for treatment of HBV infection. The aim of this study was to detect and analyze pre existing HBV RT mutations in treatment naive patients with chronic hepatitis B. Seventy one chronic HBV treatment naive patients were enrolled from January 2009 to June 2011. HBV RT sequence analysis was done by using direct bidirectional sequencing of semi-nested PCR products. HBV genotypes were determined by multiplex PCR. Genotype D was found in 64 patients (90.1%) followed by genotype C and A which were present in 5 (7.0%) and 2 (2.8%) patients respectively. The results of the RT sequence analysis showed mutations in 34 (47.9%) patients. The rtH248N mutation was the most common mutation, accounting for 47.1% patients. Other common mutations included rtD263E/S, rtM129L, rtF122L/V/I, rtS135Y/H, rtQ149K, rtL91I, rtH126R, rtC256S/G, rtY257W, rtS259T and rtE271D, which were present in 26.5% (9/34), 29.4% (10/34), 20.6% (7/34), 20.6% (7/34), 20.6% (7/34), 17.6% (6/34), 14.7% (5/34), 14.7% (5/34), 11.8% (4/34), 11.8% (4/34) and 11.8% (4/34) patients respectively. The known primary drug resistance mutations were found in 3 (8.8%) patients. The present study shows the presence of RT amino acid substitutions in treatment-naive patients with chronic hepatitis B, which may decrease susceptibility to available oral antiviral drugs. On the basis of the finding of this study, genotypic testing is recommended before the start of therapy in naive patients, so that suitable antiviral drugs can be prescribed. PMID- 23918534 TI - Prevalence of IL-28B and ITPA genotypes in Chinese Han population infected persistently with hepatitis C virus genotype 6 or HCV-1. AB - The geographic distribution, demographics, epidemiology, host factors, and clinical characteristics of persistent HCV-6 infection in China need further characterization. This multicenter study enrolled 63 patients with persistent HCV 6 infection and 63 patients with persistent HCV-1 infection as controls. Blood biochemistry, quantitation of HCV RNA levels, and identification of host IL-28B genotypes (rs12979860, rs8099917, and rs12980275) and ITPA genotype (rs1127354) were performed to estimate potential variability in host factors that may affect response to treatment. The mean HCV-6 RNA level (3.8E6 IU/ml) was significantly higher than that in patients infected with HCV-1 (1.7E6 IU/ml; P < 0.001). Patients persistently infected with HCV-6 had a high prevalence of IL-28B rs12979860 CC genotype (92.1%), rs8099917 TT genotype (93.7%), and rs12980275 AA genotype (90.5%). Their prevalence in patients infected with HCV-1 was only modestly lower (82.5%, 84.1%, and 82.5%, respectively; P > 0.05). The inosine triphosphate pyrophosphatase (ITPA) SNP rs1127354 CC genotype was present in 66.7% of patients infected with HCV-6, comparable to that of patients infected with HCV-1 (65.1%; P > 0.05). There were no differences in the liver function, proportion of hepatic cirrhosis patients or patients with increased serum glucose between these two groups. Persistent HCV-6 infection in Chinese Han is found mainly in the southern China. Chinese Han with chronic HCV-1 or HCV-6 infection have IL-28B genotypes, suggesting responsiveness to interferon-based pharmacotherapy. Most patients (67%) possess the ITPA genotype associated with susceptibility to ribavirin-induced hemolysis. The routes of transmission for HCV 6 genotype were more diversified than HCV-1 genotype. The outbreak of HCV-6 infection through blood transfusion progressed faster than HCV-1. PMID- 23918535 TI - Hepatitis C genotype distribution and homology among geographically disparate injecting drug users in Afghanistan. AB - Hepatitis C virus (HCV) prevalence is high among injecting drug users in Afghanistan, but transmission dynamics are poorly understood. Samples from HCV infected injecting drug users were sequenced to determine circulating genotypes and potential transmission linkages. Serum samples were obtained from injecting drug user participants in Hirat, Jalalabad, and Mazar-i-Sharif between 2006 and 2008 with reactive anti-HCV rapid tests. Specimens with detected HCV viremia were amplified and underwent sequence analysis. Of 113 samples evaluated, 25 samples (35.2%) were only typeable in NS5B, nine samples (12.7%) were only typeable in CE1, and 37 samples (52.1%) were genotyped in both regions. Of those with typeable HCV, all were Afghan males with a mean age of 31.1 (standard deviation [SD] +/- 8.0) years and mean duration of injecting of 3.9 (SD +/- 4.3) years. Most reported residence outside Afghanistan in the last decade (90.1%) and prior incarceration (76.8%). HCV genotypes detected were: 1a, (35.2%, n = 25), 3a (62.0%, n = 44), and 1b (2.8%, n = 2). Cluster formation was detected in NS5B and CE1 and were generally from within the same city. All participants within clusters reported being a refugee in Iran compared to 93.5% of those outside clusters. Only 22.2% (4/11) of those within clusters had been refugees in Pakistan and these four individuals had also been refugees in Iran. Predominance of genotype 3a and the association between HCV viremia and having been a refugee in Iran potentially reflects migration between Afghanistan and Iran among IDUs from Mazar-i-Sharif and Hirat and carry implications for harm reduction programs for this migratory population. PMID- 23918536 TI - Serum apolipoprotein B-100 concentration predicts the virological response to pegylated interferon plus ribavirin combination therapy in patients infected with chronic hepatitis C virus genotype 1b. AB - Host lipoprotein metabolism is associated closely with the life cycle of hepatitis C virus (HCV), and serum lipid profiles have been linked to the response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy. Polymorphisms in the human IL28B gene and amino acid substitutions in the core and interferon sensitivity-determining region (ISDR) in NS5A of HCV genotype 1b (G1b) were also shown to strongly affect the outcome of Peg-IFN plus RBV therapy. In this study, an observational cohort study was performed in 247 HCV G1b infected patients to investigate whether the response to Peg-IFN and RBV combination therapy in these patients is independently associated with the level of lipid factors, especially apolipoprotein B-100 (apoB-100), an obligatory structural component of very low density lipoprotein and low density lipoprotein. The multivariate logistic analysis subsequently identified apoB-100 (odds ratio (OR), 1.602; 95% confidence interval (CI), 1.046-2.456), alpha-fetoprotein (OR, 0.764; 95% CI, 0.610-0.958), non-wild-type ISDR (OR, 5.617; 95% CI, 1.274 24.754), and the rs8099917 major genotype (OR, 34.188; 95% CI, 10.225-114.308) as independent factors affecting rapid initial virological response (decline in HCV RNA levels by >=3-log10 at week 4). While lipid factors were not independent predictors of complete early or sustained virological response, the serum apoB 100 level was an independent factor for sustained virological response in patients carrying the rs8099917 hetero/minor genotype. Together, we conclude that serum apoB-100 concentrations could predict virological response to Peg-IFN plus RBV combination therapy in patients infected with HCV G1b, especially in those with the rs8099917 hetero/minor genotype. PMID- 23918537 TI - Kinetics of relapse after pegylated interferon and ribavirin therapy for chronic hepatitis C. AB - To optimize standard treatment of chronic hepatitis C in responder patients who have achieved undetectable viral load, a prospective study was conducted to determine the factors and kinetics of virologic relapse. Responder patients were monitored 2, 4, 8, 12, 16, and 24 weeks after the end of treatment with pegylated interferon and ribavirin. Forty-seven of the 154 patients (30.5%) relapsed. Relapse was significantly associated with absence of rapid virologic response (RVR), retreatment, higher baseline viral load, older age, and lower weight-based dose of pegylated interferon. Relapse was more frequent in patients failing to achieve a RVR after receiving pegylated interferon alpha 2a < 2.5 ug/week or alpha 2b < 1.5 ug/week (P = 0.002). Among patients infected with hepatitis C virus (HCV) genotype 1 with non-CC IL-28B polymorphism (rs12979860), viral decay during treatment was lower in relapsers (P = 0.003 at week 4). Relapse was detected at weeks 2, 4, 8, and 12 after the end of treatment for 5, 8, 10, and 6 patients infected with HCV genotype 1, respectively. Positive predictive values for sustained virologic response were 70.9%, 80.2%, 91.9%, and 98.8% at weeks 2, 4, 8, and 12, respectively. Only one patient relapsed beyond 24 weeks. Closer follow-up and treatment adaptation in patients failing to achieve RVR may decrease the relapse rate in slower responders and heavier patients. Monitoring viral load as early as 1 month after the end of treatment could be useful to assess virologic response. PMID- 23918538 TI - Serum prolactin levels and prolactin mRNA expression in peripheral blood mononuclear cells in hepatitis C virus infection. AB - Prolactin is not only a pituitary hormone but an immunoregulatory hormone secreted from lymphocytes. Prolactin induction in relation to hepatitis C virus (HCV) infection has not been elucidated. The serum levels of prolactin were examined in 232 HCV-infected subjects positive for anti-HCV antibody and 65 healthy controls negative for it, who were recruited in the cohort study. The prolactin mRNAs were measured in peripheral blood mononuclear cells (PBMCs) of eleven healthy volunteers including five men and six women before and after stimulation by HCV in vitro. The serum level of prolactin and prolactin mRNA in PBMCs were measured by chemiluminescence immunoassay and real-time PCR, respectively. The serum levels of prolactin were significantly higher in the HCV infected subjects (median: 7.5, IQR: 5.7-10.9 ng/ml) than in the controls (median: 5.6, IQR: 4.4-8.3 ng/ml) (P < 0.01). They were significantly higher in HCV-infected males (median: 8.0, IQR: 5.9-11.8 ng/ml) than in the controls (median: 4.8, IQR: 4.2-5.9 ng/ml) (P < 0.001), however, the difference was not significant between HCV-infected females (median: 7.3, IQR: 5.6-10.5 ng/ml) and the controls (median: 6.4, IQR: 5.3-9.8 ng/ml). The mRNA expression of prolactin was induced in PBMCs of all males, but it was induced in PBMCs of the two of six females examined in vitro. These results suggest that the serum level of prolactin is higher in HCV-infected males than in healthy males, and that HCV infection induces the mRNA expression of prolactin in PBMCs that is more apparent in male than in females. PMID- 23918539 TI - Genetic variation in NOS2A is associated with a sustained virological response to peginterferon plus ribavirin therapy for chronic hepatitis C in Taiwanese Chinese. AB - This study aimed to evaluate whether genetic polymorphisms of the inducible nitric oxide synthase (iNOS) gene NOS2A could be associated with a sustained virological response (SVR) among patients infected with hepatitis C virus genotypes 1 and 2 (HCV-1 and HCV-2) who were treated with peginterferon plus ribavirin (PEG-IFNalpha-RBV). We analyzed the associations between SVR to PEG IFNalpha-RBV therapy and two single nucleotide polymorphisms (SNPs) in NOS2A. This study included Taiwanese Chinese patients infected with either HCV-1 (n = 265) or HCV-2 (n = 195) with or without a SVR. Among the NOS2A SNPs examined, the combination of genotypes A/A and A/G of rs2248814 was inversely correlated with SVR in patients infected with HCV-1 (P = 0.0048), particularly in males (P = 0.0281). This effect was not observed in patients infected with HCV-2. The AC NOS2A haplotype comprising two SNPs (rs2248814 and rs2072324) was found to be associated with SVR, and its presence may decrease the chances for a successful outcome of treatment of patients infected with HCV-1 (P = 0.0053). HCV-1 infected patients who carried the A-C diplotype will have a lower success rate of achieving a SVR (P = 0.0117). In addition, a multivariate logistic regression model for predicting a SVR revealed that the presence of the A-C diplotype interactively affected the outcome of PEG-IFNalpha-RBV treatment. The presence of NOS2A SNPs and the association with SVR showed that NOS2A polymorphisms may influence the therapeutic outcomes of patients infected with HCV-1 under standard of care treatment. PMID- 23918540 TI - Regulation of p14ARF expression by HPV-18 E6 variants. AB - A common causative agent for uterine cervical cancer is the human papillomavirus type 18 (HPV-18) which has three phylogenic variants: Asian-Amerindian, European, and African. Each variant shows significant molecular differences in the E6 gene. E6 oncoprotein is a negative regulator of tumor suppressor protein p53, hence, this oncoprotein indirectly regulates the expression of tumor-suppressor p14(ARF) . p14(ARF) and p16(INK4A) genes are overexpressed in--and have been proposed as markers for--HPV-related cervical cancer. In order to dissect the role of E6 on the regulation of p14(ARF) expression, separating it from that of other intervening factors, transfection of E6 variants to MCF-7 cells was performed, assessing cDNA transcript levels by RT-PCR, whereas p14(ARF) and p53 expression were evaluated by immunocytochemistry and Western blot. E6 transfected cells differentially expressed transcripts of two molecular forms: E6 and E6*. The ratio of these two forms varied with the transfected E6 variant. With the Asian Amerindian variant, the ratio was E6 > E6*, whereas with the European and the African the ratio was E6* > E6. As expected with the E6* construct, E6* transcripts were solely observed. In addition, when E6 > E6* and p53 expression was low, p14(ARF) was high and when E6* > E6 and p53 expression was high, p14(ARF) was low. In conclusion, each E6 variant distinctively affects p53 levels and consequently p14(ARF) expression, finding that could be related with the differences in oncogenic effect of infection with the diverse high-risk HPV variants. PMID- 23918541 TI - Simple and rapid human papillomavirus genotyping method by restriction fragment length polymorphism analysis with two restriction enzymes. AB - Cervical cancer, the third most common cancer that affects women worldwide, is caused by the human papillomavirus (HPV) and is treatable when detected at an early stage. To date, more than 100 different HPV types have been described, and the development of simple, low-cost, and accurate methods to distinguish HPV genotypes is highly warranted. In this study, an HPV genotyping assay based on polymerase chain reaction (PCR) was evaluated. This method involved the use of MY09/11 primers followed by restriction fragment length polymorphism (RFLP) analysis with the restriction enzymes HpyCH4V and NlaIII. Cervical specimens preserved using CytoRich Blue fluid were collected from 1,134 female volunteers for HPV detection, and 1,111 valid samples were amplified using PCR. The PCR method was sensitive enough to detect 25 copies of HPV18, and three copies of HPV16. Out of 202 PCR-positive samples, HPV genotypes were determined in 189 samples (93.6%) by this RFLP method. Results were then evaluated further by capillary sequencing method. Concordant results between the two tests were as high as 96.0%. Thirteen samples, which tested negative with RFLP, were verified as non-specific amplifications with PCR. In conclusion, this PCR-RFLP method using restriction enzymes HpyCH4V and NlaIII is simple, non-labor intensive, and is applicable for the inexpensive determination of HPV genotypes in clinical samples. PMID- 23918542 TI - Use of the NucliSENS EasyQ HPV assay in the management of cervical intraepithelial neoplasia. AB - Persistent infection by high-risk human papillomavirus is a necessary cause for cervical cancer. DNA-based human papillomavirus (HPV) assays show high sensitivity but poor specificity in detecting high-grade cervical lesions. Assays detecting mRNA of the oncoproteins E6 and E7 show higher specificity but lack either detection of all high-risk genotypes or the ability to specify the detected genotypes. The aim of this study was to evaluate the clinical performance of the NucliSENS EasyQ HPV assay in comparison with the Hybrid Capture 2 test (HC2) and the CLART Human Papillomavirus 2 assay (CLART), using a clinical cut-off of cervical intraepithelial neoplasia grade 2 or worse. In the 554 studied women, the lowest HPV positivity rate was detected for NucliSENS EasyQ HPV assay (55.1%), while HC2 and CLART showed similar results (HC2: 77.4%; CLART: 78.0%). In comparison with the other tests, the NucliSENS EasyQ HPV assay showed a lower clinical sensitivity (79.3% vs. 96.4% for HC2 and 95.9% for CLART) but a higher clinical specificity (72.6% vs. 42.8% for HC2 and 42.5% for CLART). Detection of E6/E7 mRNA transcripts may provide a higher specificity for cervical intraepithelial neoplasia grade 2 lesions or worse, since the oncogenic potential of HPV infection depends on the over-expression of these two oncoproteins. PMID- 23918543 TI - Prospective evaluation of E6/E7 mRNA detection by the NucliSENS Easy Q HPV assay in a stepwise protocol. AB - The objective of the study was to evaluate prospectively the added value of E6/E7 mRNA detection in a stepwise protocol. A total of 1,422 samples were collected over a period of 17 months. The samples were referred for human papillomavirus (HPV) genotyping if they showed cytological evidence of atypical squamous cells of undetermined significance, low- or high-grade squamous intraepithelial lesion. If one or more of HPV types 16, 18, 31, 33, or 45 were present, mRNA was analyzed by the NucliSENS EasyQ HPV assay. The genotypical distribution of high-risk HPV was very heterogeneous; HPV 16, 18, 31, 33, and 45 represented 20.2%, 3.4%, 10.8%, 3.4%, and 3.8% of HPV-positive samples, respectively. Follow-up data were available for 35 patients. Although over the half (51.4%) of follow-up samples showing HPV DNA/mRNA consensus evolved to cervical intraepithelial neoplastic lesions, 25.7% showed no progression to neoplasia despite mRNA positivity. However, the major concern was the group (14.3%) that showed progression to cervical intraepithelial neoplasia despite mRNA negativity: all but one of these cases had a high-risk HPV genotype other than the five included in the NucliSENS EasyQ HPV assay. Markedly, 66.7% of the discordant samples between colposcopy and histology that underestimated the degree of cervical dysplasia were found in this group. Close monitoring of high-risk HPV DNA-positive/mRNA-negative cases remains necessary, which leads to questions about the added value of the evaluated protocol. PMID- 23918544 TI - Development of duplex real-time RT-PCR based on Taqman technology for detecting simultaneously the genome of pan-enterovirus and enterovirus 71. AB - Human enterovirus (EV) 71 is the main etiological agent of hand, foot, and mouth disease (HFMD). It is associated with neurological complications, and caused fatalities during recent outbreaks in the Asia-Pacific region. Infections caused by EV71 could lead to many complications, ranging from brainstem encephalitis to pulmonary oedema, resulting in high mortality. In this study, a duplex real-time RT-PCR assay was developed in order to simultaneously detect pan-EV and EV71. EV71-specific primers and probes were designed based on the highly conserved VP1 region of EV71. Five EV71 strains were detected as positive, and no positive fluorescence signal was observed in the duplex real-time RT-PCR for other viral RNA, which showed 100% specificity for the selected panel, and no cross-reactions were observed in this duplex real-time RT-PCR. The EV71-specific duplex real-time RT-PCR was more sensitive than conventional RT-PCR, and detected viral titers that were 10-fold lower than those measured by the latter. Of the 381 HFMD clinical specimens, 196 (51.4%) cases were pan-EV-positive, of which 170 (86.7%) were EV71-positive when tested by pan-EV and EV71-specific duplex real-time RT PCR. EV71-specific duplex real-time RT-PCR offers a rapid and sensitive method to detect EV71 from clinical specimens, and will allow quarantine measures to be taken more effectively during outbreaks. PMID- 23918545 TI - Frequency of enterovirus detection in blood samples of neonates admitted to hospital with sepsis-like illness in Kuwait. AB - This study investigated the role of enteroviruses in sepsis-like illness among neonates in Kuwait. Serum samples from 139 consecutive neonates presenting with sepsis-like illness during a three and a half-year-period whose blood cultures were negative for bacterial pathogens were tested. Enterovirus RNA was detected by single-step reverse-transcription PCR (RT-PCR). Specific genotypes were identified by direct DNA sequencing of enteroviral genome. Serotype-specific antibodies in serum samples from some selected patients were detected by virus neutralization test using coxsackievirus B types (CBVs). All 139 neonates presented with sepsis-like illness and blood samples were uniformly negative for aerobic/anaerobic bacterial cultures. Fifty-six (40%) neonates had further complications of sepsis including carditis (n = 34) and multi-organ involvement (n = 22). Enterovirus RNA was detected by RT-PCR in 34 of 139 (24%) serum samples which is among the highest frequency reported so far in non-epidemic settings. Genotyping identified CBVs as most common enteroviruses, causing 19 of 34 (56%) enteroviral sepsis episodes in neonates. Of 34 carditis cases, 18 were positive for CBVs by serotyping including all 10 enterovirus RNA-positive samples. Only one fatality was observed due to liver failure in a neonate with hepatitis. Our data showed that enteroviruses are responsible for 24% of neonatal sepsis cases due to non-bacterial causes in Kuwait. The data indicate that enteroviruses should be considered in the differential diagnosis of sepsis-like illness among neonates, particularly those with negative blood cultures for bacterial pathogens. PMID- 23918546 TI - Molecular epidemiology of JCV genotypes in patients and healthy subjects from Northern Italy. AB - Very little is known about JCV infection and genotype distribution with respect to the different demographic and clinical characteristics of the Italian population. A cross-sectional study was carried out on the prevalence of JCV genotypes in 323 Caucasian subjects (mean age: 37.5 years, range: 2-70 years). Urine samples from 200 immunocompromised patients, including patients affected by Multiple Sclerosis (MS), Human Immunodeficiency Virus (HIV), colon cancer, inflammatory diseases and Progressive Multifocal Leukoencephalopathy (PML), and 123 immunocompetent individuals were tested by quantitative real time PCR. Sequencing of the JCV viral protein 1 (VP1) and transcriptional control region (TCR) was performed. In this series, the overall prevalence of JCV excretion was 32.8% without significant differences between males and females. JCV was detected in 39.5% of patients and in 22% of healthy individuals (P = 0.004). The most prevalent JCV genotype excreted was genotype 1 (69.8%), followed by genotype 2 (22.6%) and genotype 4 (7.5%). Distribution of genotypes between patients and healthy subjects showed a statistically significant difference for the type 1 compared to the other variants (P < 0.01). Of note, JCV genotype 2 was found to be associated to young patients (P = 0.0001) and to patients treated with immunomodulator drugs (P = 0.0001), but not to PML subjects. The non-pathogenic archetype IIS (singular, insert) form was present in all JCV strains detected. This result allows to hypothesize a possible JCV genotype selection in response to pressure by immunomodulatory drugs. PMID- 23918547 TI - Detection and molecular characterisation of noroviruses in hospitalised children in Malawi, 1997-2007. AB - Despite the increasing recognition of noroviruses as major pathogens associated with community-acquired diarrhoea in children, there are few studies from Africa. Long-term surveillance studies of rotavirus gastroenteritis in Malawian children have provided an opportunity to undertake a study of the importance and epidemiological features of norovirus infection in this population. Faecal specimens were collected from children <5 years of age admitted to hospital with acute diarrhoea, as well as from a comparison group of diarrhoea-free children, in Blantyre, Malawi between 1997 and 2007. Norovirus was detected using real-time PCR and strains genotyped by nucleotide sequence analysis. Norovirus was detected in 220/1,941 (11.3%) faecal specimens, comprising genogroup GI (1.8%), GII (9.4%) and mixed GI/GII (0.1%). The median age of children with norovirus was 6 months (range, 0-48 months). Norovirus was detected throughout the year, with peaks at the end of the rainy season (March) and towards the end of the dry season (August November). Norovirus GII.4 was the most commonly detected genotype accounting for 70% of strains characterised, followed by GII.2 (6%), GII.6 (4%) and GII.12 (4%). Sub typing of GII.4 noroviruses demonstrated local circulation of strains prior to their subsequent detection in association with global epidemics of gastroenteritis. The prevalence of norovirus in children without diarrhoea was similar to the level in cases. This largest study to date of norovirus infection in African children indicates the potential role of paediatric surveillance in predicting the emergence of norovirus strains with global epidemic potential. PMID- 23918548 TI - Male-produced sex pheromone of the carrion beetles, Oxelytrum discicolle and its attraction to food sources. AB - Carrion beetles are part of the great diversity of insects collected on cadavers. In Brazil, beetles of the genus Oxelytrum have great forensic importance in post mortem interval (PMI) estimation. We investigated the system of chemical communication in the attraction of these necrophagous beetles. Gas chromatographic analysis (GC) of female and male aeration extracts revealed the presence of two male-specific compounds, produced in a ratio of 94:6. Bioassays showed that the combination of male produced volatiles and the odor of a food source (carcass volatiles) were attractive to females. Mass and infrared spectral analyses of the male-specific compounds suggested that they were both unsaturated hydrocarbons. Several micro-derivatizations were carried out with the natural products, and the target structures were identified as (Z)-1,8-heptadecadiene (major) and 1-heptadecene (minor). The structure of the minor component was assigned by co-injection with a commercial standard. A seven-step synthesis was developed to synthesize (Z)-1,8-heptadiene, which co-eluted with the major natural product on three different GC stationary phases. Y-tube olfactometer assays showed that the mixture of synthetic standards in the naturally occurring proportion was slightly attractive to females. The results contribute both to the understanding of the chemical ecology of O. discicolle and to its potential to improve the accuracy of PMI estimation. PMID- 23918550 TI - Salient stimuli capture attention and action. AB - Reaction times in a visual search task increase when an irrelevant but salient stimulus is presented. Recently, the hypothesis that the increase in reaction times was due to attentional capture by the salient distractor has been disputed. We devised a task in which a search display was shown after observers had initiated a reaching movement toward a touch screen. In a display of vertical bars, observers had to touch the oblique target while ignoring a salient color singleton. Because the hand was moving when the display appeared, reach trajectories revealed the current selection for action. We observed that salient but irrelevant stimuli changed the reach trajectory at the same time as the target was selected, about 270 ms after movement onset. The change in direction was corrected after another 160 ms. In a second experiment, we compared manual selection of color and orientation targets and observed that selection occurred earlier for color than for orientation targets. Salient stimuli support faster selection than do less salient stimuli. Under the assumption that attentional selection for action and perception are based on a common mechanism, our results suggest that attention is indeed captured by salient stimuli. PMID- 23918549 TI - Is minimal residual lymph node disease in papillary thyroid cancer of prognostic impact? An analysis of the epithelial cell adhesion molecule EpCAM in lymph nodes of 40 pN0 patients. AB - This study was aimed to assess the extend of nodal microdissemination in patients with pN0 papillary thyroid carcinoma (PTC) using immunohistochemical analysis. In early stage PTC both, systematic lymphadenectomy as well as radio iodine treatment, aimed to eliminate occult nodal tumor involvement, are under controversial debate, since little is known about the extend of lymphatic microdissemination in these patients. Formalin embedded samples of the resected lymph nodes were systematically screened for the presence of disseminated tumor cells using immunohistochemistry (monoclonal antibody Ber-EP4). Clinical and histopathological parameters as well as the post-operative course were recorded. Survival data were analysed by the Kaplan-Meier method and the log rank test. Overall 321 lymph nodes of 40 patients were screened immunohistochemically. In 12.5% of the patients disseminated occult tumor cells were diagnosed. In addition to tumor resection 90% of the patients underwent adjuvant radio-iodine treatment. The mean observation period in our collective was 72 months. The detection of disseminated tumor cells did not correlate with clinicopathologic risk parameters and did not have significant influence on the prognosis of these patients. Immunohistochemical analysis enables the detection of disseminated tumor cells in patients with pN0 PTC. This finding seems to support the application of adjuvant radio iodine, even in early tumor stages. PMID- 23918551 TI - An electrophysiological study of the object-based correspondence effect: is the effect triggered by an intended grasping action? AB - We examined Goslin, Dixon, Fischer, Cangelosi, and Ellis's (Psychological Science 23:152-157, 2012) claim that the object-based correspondence effect (i.e., faster keypress responses when the orientation of an object's graspable part corresponds with the response location than when it does not) is the result of object-based attention (vision-action binding). In Experiment 1, participants determined the category of a centrally located object (kitchen utensil vs. tool), as in Goslin et al.'s study. The handle orientation (left vs. right) did or did not correspond with the response location (left vs. right). We found no correspondence effect on the response times (RTs) for either category. The effect was also not evident in the P1 and N1 components of the event-related potentials, which are thought to reflect the allocation of early visual attention. This finding was replicated in Experiment 2 for centrally located objects, even when the object was presented 45 times (33 more times than in Exp. 1). Critically, the correspondence effects on RTs, P1s, and N1s emerged only when the object was presented peripherally, so that the object handle was clearly located to the left or right of fixation. Experiment 3 provided further evidence that the effect was observed only for the base-centered objects, in which the handle was clearly positioned to the left or right of center. These findings contradict those of Goslin et al. and provide no evidence that an intended grasping action modulates visual attention. Instead, the findings support the spatial-coding account of the object-based correspondence effect. PMID- 23918552 TI - Reconciling conflicting electrophysiological findings on the guidance of attention by working memory. AB - Maintaining a representation in working memory has been proposed to be sufficient for the execution of top-down attentional control. Two recent electrophysiological studies that recorded event-related potentials (ERPs) during similar paradigms have tested this proposal, but have reported contradictory findings. The goal of the present study was to reconcile these previous reports. To this end, we used the stimuli from one study (Kumar, Soto, & Humphreys, 2009) combined with the task manipulations from the other (Carlisle & Woodman, 2011b). We found that when an item matching a working memory representation was presented in a visual search array, we could use ERPs to quantify the size of the covert attention effect. When the working memory matches were consistently task irrelevant, we observed a weak attentional bias to these items. However, when the same item indicated the location of the search target, we found that the covert attention effect was approximately four times larger. This shows that simply maintaining a representation in working memory is not equivalent to having a top down attentional set for that item. Our findings indicate that high-level goals mediate the relationship between the contents of working memory and perceptual attention. PMID- 23918553 TI - Expression kinetics of chicken beta2-microglobulin and Class I MHC in vitro and in vivo during Marek's disease viral infections. AB - Marek's disease virus (MDV) is a highly cell-associated herpesvirus that causes a disease in chickens characterized by tumor formation and immunosuppression. The changes of major histocompatibility complex (MHC) expression in different MDV infected cells are not completely understood. In this study, we investigated the expression of the Class I MHC and beta2-microglobulin (beta2m) genes in response to MDV infection at different time points by real-time PCR. In both in vitro and in vivo, the expression levels of Class I MHC and beta2m genes were upregulated during early MDV infections in comparison to control cells; We also found that the expression of Class I MHC gene was downregulated in BudR (5-bromo-2' deoxyuridine)-treated MSB1 cells at 48 h and MDV-infected chicken embryo fibroblast cells (CEF) at 120 and 168 h post infection (hpi); Furthermore, compared to control groups, Class I MHC and beta2m expression levels were downregulated in peripheral blood lymphocytes (PBLC) from MDV-infected chickens at 14 and 28 days post infection (dpi); Interestingly, both Class I MHC and beta2m gene expression levels increased again in PBLC from MDV RB1B-infected chickens at 35 dpi, in which MDV was in the latent or transformed infection stages. In addition, Class I MHC expression was clearly decreased in MDV-infected CEF at 120 hpi although beta2m expression was significantly increased. These changes in Class I MHC and beta2m gene expression might provide more insights into host-virus interaction. PMID- 23918554 TI - Stent evaluation with optical coherence tomography. AB - Optical coherence tomography (OCT) has been recently applied to investigate coronary artery disease in interventional cardiology. Compared to intravascular ultrasound, OCT is able to visualize various vascular structures more clearly with higher resolution. Several validation studies have shown that OCT is more accurate in evaluating neointimal tissue after coronary stent implantation than intravascular ultrasound. Novel findings on OCT evaluation include the detection of strut coverage and the characterization of neointimal tissue in an in-vivo setting. In a previous study, neointimal healing of stent strut was pathologically the most important factor associated with stent thrombosis, a fatal complication, in patients treated with drug-eluting stent (DES). Recently, OCT-defined coverage of a stent strut was proposed to be related with clinical safety in DES-treated patients. Neoatherosclerosis is an atheromatous change of neointimal tissue within the stented segment. Clinical studies using OCT revealed neoatherosclerosis contributed to late-phase luminal narrowing after stent implantation. Like de novo native coronary lesions, the clinical presentation of OCT-derived neoatherosclerosis varied from stable angina to acute coronary syndrome including late stent thrombosis. Thus, early identification of neoatherosclerosis with OCT may predict clinical deterioration in patients treated with coronary stent. Additionally, intravascular OCT evaluation provides additive information about the performance of coronary stent. In the near future, new advances in OCT technology will help reduce complications with stent therapy and accelerating in the study of interventional cardiology. PMID- 23918555 TI - Outcome predictors for intestinal Behcet's disease. AB - Behcet's disease (BD) is a multisystem inflammatory disorder that presents as recurrent oral and genital ulcers in conjunction with other dermatological and ocular manifestations. The prevalence of BD is higher in Middle and East Asia than in Western countries. Intestinal BD is a specific subtype of BD, characterized by intestinal ulcers and associated gastrointestinal symptoms. Similar to inflammatory bowel disease, intestinal BD exhibits a fluctuating disease course with repeated episodes of relapse and remission that necessitate adequate maintenance therapy after achievement of clinical remission. Medical treatment of intestinal BD is largely empirical since well-controlled studies have been difficult to perform due to the heterogeneity and rarity of the disease. To date, 5-aminosalicylic acid, systemic corticosteroids, and immunosuppressants have been used anecdotally to treat intestinal BD. The clinical course of intestinal BD shows considerable variability, and the exact point at which more potent agents such as immunosuppressants should be used has not yet been elucidated. Given the difficulty in predicting which patients will experience complicated disease courses and the fact that these drugs are related with certain risk resulting from immunosuppression, proper identification of prognostic factors in intestinal BD may allow physicians to implement tailored medical therapy and individualized patient monitoring based on risk stratification. In this review, the impact of baseline characteristics on the long-term course of intestinal BD, prognostic factors during various medical therapies, and outcome predictors related to surgery will be discussed. PMID- 23918556 TI - Comparison of drainage volume of chronic subdural hematoma according to drainage catheter type. AB - PURPOSE: To assess the therapeutic value of two different drainage catheters in treating chronic subdural hematoma (CSDH). MATERIALS AND METHODS: Two types of drainage catheters can be used to treat CSDH according to the position of holes in the catheter: open-type or closed-type catheter. In this retrospective study, 199 total patients with CSDH were reviewed according to catheter type. Among them, 84 patients were and 113 in the closed-type group (holes positioned within the distal- most 1 cm of the catheter). The surgeon selected the catheter type. Total drainage volume, initial drainage volume within 2 days, percentage of initial drainage volume per total drainage volume, duration of catheter insertion, and reoperation rate were compared. RESULTS: Total drainage volume was not different between the two groups (p=0.333). The initial drainage volume within 2 days was larger in the open-type group than closed-type group (p=0.024), but the percentage of initial drainage volume per total drainage volume was not different (p=0.354). The duration of catheter insertion was shorter in the open type group than closed-type group (p=0.015). The reoperation rate of CSDH was also higher in the open-type group than closed-type group (p=0.004). CONCLUSION: CSDH drainage with an open-type catheter is faster compared with a closed-type catheter, but total drainage volume is similar and reoperation rate is higher. Therefore, the open-type catheter for CSDH drainage has limited clinical value. PMID- 23918557 TI - Prevalence and geographic distribution of herniated intervertebral disc in Korean 19-year-old male from 2008 to 2009: a study based on Korean conscription national and geographic prevalence of herniated intervertebral disc in Korean 19YO male-. AB - PURPOSE: This study was to determine the prevalence of herniated intervertebral disc (HIVD) among Korean 19-year-old male in a large national sample and to compare the prevalence across geographic regions based on the data of conscription. MATERIALS AND METHODS: We analyzed the conscription data of 615508 cases who were 19-year-old male, given an examination for conscription at nationwide Korean Military Manpower Administration from January 2008 to December 2009. Prevalence was determined by dividing the number of cases by the number of persons enrolled for 2 years. The analyses included of a cross-tabulations and nonparametric chi-square to compare the prevalence according to geographic region, disc severity, and conscription year. RESULTS: The prevalence of HIVD among 19-year-old male was 0.47%. Seoul had the highest prevalence of HIVD (total HIVD was 0.60%, and severe HIVD was 0.44%). The prevalence of HIVD was lower in Jeollabuk- do and Jeollanam-do (total HIVD was 0.25-0.27%, and severe HIVD was 0.16-0.17%). Annual prevalence of HIVD was slightly decreased in 2009, but geographic distribution annually was not different. CONCLUSION: In Korean 19-year old male, the national prevalence of adolescent HIVD was 0.60%, but different geographic distribution was observed. It is quite possible that secondary contributing factor(s) interfere with the different geographic prevalence of HIVD. PMID- 23918558 TI - Outcome of transcatheter closure of oval shaped atrial septal defect with amplatzer septal occluder. AB - PURPOSE: For the successful completion of transcatheter closure of atrial septal defects with the Amplatzer septal occluder, shape of the defects should be considered prior to selecting the device. The purpose of this study is to evaluate the results of a transcatheter closure of oval shaped atrial septal defect. MATERIALS AND METHODS: From November 2009 until November 2011, cardiac computed tomography was performed on 69 patients who needed a transcatheter closure of atrial septal defect. We defined an oval shaped atrial septal defect as the ratio of the shortest diameter to the longest diameter <= 0.75 measured using computed tomography. A trans-thoracic echocardiogram was performed one day after and six months after. RESULTS: The transcatheter closure of atrial septal defect was performed successfully in 24 patients in the ovoid group and 45 patients in the circular group. There were no serious complications in both groups and the complete closure rate at 6 months later was 92.3% in the ovoid group and 93.1% in the circular group (p>0.05). The differences between the device size to the longest diameter of the defect and the ratios of the device size to the longest diameter were significantly smaller in the ovoid group (1.8 +/- 2.8 vs. 3.7 +/- 2.6 and 1.1 +/- 0.1 vs. 1.2 +/- 0.2). CONCLUSION: Transcatheter closure of an oval shaped atrial septal defect was found to be safe with the smaller Amplatzer septal occluder device when compared with circular atrial septal defects. PMID- 23918559 TI - Standardized approaches to syncope evaluation for reducing hospital admissions and costs in overcrowded emergency departments. AB - PURPOSE: The evaluation of syncope is often disorganized and ineffective. The objective of this study was to examine whether implementation of a standardized emergency department (ED) protocol improves the quality of syncope evaluation. MATERIALS AND METHODS: This study was a prospective, non-randomized study conducted at a 1900-bed, tertiary teaching hospital in South Korea. We compared two specific periods, including a 12-month observation period (control group, January- December 2009) and a 10-month intervention period after the implementation of standardized approaches, comprising risk stratification, hospital order sets and establishment of a syncope observational unit (intervention group, March-December 2010). Primary end points were hospital admission rates and medical costs related to syncope evaluation. RESULTS: A total of 244 patients were enrolled in this study (116 patients in the control group and 128 patients in the intervention group). The admission rate decreased by 8.3% in the intervention group (adjusted odds ratio 0.31, 95% confidence interval 0.13 0.70, p=0.005). There was a cost reduction of about 30% during the intervention period [369000 Korean won (KRW), interquartile range (IQR) 240000-602000 KRW], compared with the control period (542000 KRW, IQR 316000-1185000 KRW). The length of stay in the ED was also reduced in the intervention group (median: 4.6 hours vs. 3.4 hours). CONCLUSION: Standardized approaches to syncope evaluation reduced hospital admissions, medical costs and length of stay in the overcrowded emergency department of a tertiary teaching hospital in South Korea. PMID- 23918560 TI - Optimal anticoagulation during off pump coronary artery bypass in patients recently exposed to clopidogrel. AB - PURPOSE: The aim of this study was to find an optimal range of activated clotting time (ACT) during off-pump coronary artery bypass surgery (OPCAB) yielding ischemic protection without the risk of hemorrhagic complications in patients with recent exposure to dual antiplatelet therapy. MATERIALS AND METHODS: Three hundred and five patients who received aspirin and clopidogrel within 7 days of isolated multi-vessel OPCAB were retrospectively studied. Combined hemorrhagic and ischemic outcome was defined as the occurrence of 1 of the following: significant perioperative bleeding (>30% of estimated blood volume), transfusion of packed red blood cell (pRBC) >= 2 U, or myocardial infarction (MI). This was compared in relation to the tertile distribution of the time-weighted average ACT 212-291 sec (first tertile), 292-334 sec (second tertile), 335-485 sec (third tertile). RESULTS: The amount of perioperative blood loss was 937 +/- 313 mL, 1014 +/- 340 mL, and 1076 +/- 383 mL, respectively (p=0.022). Significantly more patients in the third tertile developed MI (4%, 4%, and 12%, respectively, p=0.034). The incidence of significant perioperative blood loss and transfusion of pRBC >= 2 U were lower in the first tertile than those of other tertiles without statistical significance. In the multivariate analysis, the first tertile was associated with a 52% risk reduction of combined hemorrhagic and ischemic outcomes (95% confidence interval: 0.25-0.92, p= 0.027). CONCLUSION: A lower degree of anticoagulation with a reduced initial heparin loading dose should be carefully considered for patients undergoing OPCAB who have recently been exposed to clopidogrel. PMID- 23918561 TI - Reduced food intake is the major contributor to the protective effect of rimonabant on islet in established obesity-associated type 2 diabetes. AB - PURPOSE: Although the presence of cannabinoid type 1 (CB1) receptor in islets has been reported, the major contributor to the protective effect of rimonabant on islet morphology is unknown. We determined whether the protective effect of rimonabant on pancreatic islet morphology is valid in established diabetes and also whether any effect was independent of decreased food intake. MATERIALS AND METHODS: After diabetes was confirmed, Otsuka Long-Evans Tokushima Fatty rats, aged 32 weeks, were treated with rimonabant (30 mg/kg/d, rimonabant group) for 6 weeks. Metabolic profiles and islet morphology of rats treated with rimonabant were compared with those of controls without treatment (control group), a pair fed control group, and rats treated with rosiglitazone (4 mg/kg/d, rosiglitazone group). RESULTS: Compared to the control group, rats treated with rimonabant exhibited reduced glycated albumin levels (p<0.001), islet fibrosis (p<0.01), and improved glucose tolerance (p< 0.05), with no differences from the pair-fed control group. The retroperitoneal adipose tissue mass was lower in the rimonabant group than those of the pair-fed control and rosiglitazone groups (p<0.05). Rimonabant, pair-fed control, and rosiglitazone groups showed decreased insulin resistance and increased adiponectin, with no differences between the rimonabant and pair-fed control groups. CONCLUSION: Rimonabant had a protective effect on islet morphology in vivo even in established diabetes. However, the protective effect was also reproduced by pair-feeding. Thus, the results of this study did not support the significance of islet CB1 receptors in islet protection with rimonabant in established obesity-associated type 2 diabetes. PMID- 23918562 TI - Effect of 45 degrees reclining sitting posture on swallowing in patients with dysphagia. AB - PURPOSE: To determine the effect of a 45 degrees reclining sitting posture on swallowing in patients with dysphagia. MATERIALS AND METHODS: Thirty-four patients with dysphagia were evaluated. Videofluoroscopic swallowing study was performed for each patient in 90 degrees upright and in 45 degrees reclining sitting posture. Patients swallowed 5 types of boluses twice: sequentially 2 mL thin liquid, 5 mL thin liquid, thick liquid, yogurt, and cooked rice. Data such as the penetration-aspiration scale (PAS), oral transit time (OTT), pharyngeal delay time (PDT), pharyngeal transit time (PTT), residue in valleculae and pyriform sinuses, premature bolus loss, and nasal penetration were obtained. RESULTS: The mean PAS on the 2 mL thin liquid decreased significantly in the 45 degrees reclining sitting posture (p=0.007). The mean PAS on 5 mL thin liquid in the 45 degrees reclining sitting posture showed decreasing tendency. The residue in valleculae decreased significantly for all boluses in the 45 degrees reclining sitting posture (p<0.001, p=0.002, p=0.003, p<0.001, p=0.020, respectively). The residue in pyriform sinuses increased significantly on 5 mL thin liquid, thick liquid, and yogurt (p=0.031, p=0.020, p=0.002, respectively). There were no significant differences in OTT, PDT, PTT, premature bolus loss, and nasal penetration between both postures. CONCLUSION: PAS on 2 mL thin liquid and residue in valleculae on all types of boluses were decreased in a 45 degrees reclining sitting posture. Therefore, we believe that the 45 degrees reclining sitting posture on swallowing is beneficial for the patients with penetration or aspiration on small amounts of thin liquid and large amounts of residue in valleculae. PMID- 23918563 TI - Late-presenting congenital diaphragmatic hernia in children: the experience of single institution in Korea. AB - PURPOSE: Late-presenting congenital diaphragmatic hernia (CDH) beyond the neonatal period is rare and often misdiagnosed, with delayed treatment. MATERIALS AND METHODS: We retrospectively reviewed our experience with late-presenting CDH over 30 years at a single institution to determine the characteristics of late presenting CDH for early diagnosis. RESULTS: Seven patients had operations due to late-presenting CHD in our institution over 30 years. The patients' ages ranged from 2.5 months to 16 years. There were six boys and one girl. Five hernias were left-sided, one was right-sided and one was a retrosternal hernia. All patients had normal intestinal rotation. Non-specific gastrointestinal or respiratory symptoms and signs were usually presented. Intestinal malrotations were absent; therefore, only organs adjacent to the defect or relatively movable organs such as the small bowel and transverse colon were herniated. Two cases were accompanied by stomach herniation with the volvulus and liver, respectively. The duration from presentation to diagnosis varied from 5 days to 1 year. Diagnoses were made by chest X-ray, upper gastrointestinal series and chest computed tomography. All patients underwent primary repair with interrupted non-absorbable sutures by a transabdominal approach. None had postoperative complications. The follow-up period in six patients ranged from 4 months to 20 years (median 3.8 years). There was no recurrence in any of the patients on follow-up. CONCLUSION: A high index of suspicion is important for the diagnosis of late-presenting CDH because it can be a life-threatening condition such as CDH with a gastric volvulus. Early diagnosis and appropriate treatment can lead to a good prognosis. PMID- 23918564 TI - Sendai F/HN viroplexes for efficient transfection of leukemic T cells. AB - PURPOSE: Most chemical transfection reagents are ineffective for the transfection of cells in suspension, such as leukemic cell and stem cell lineages. We developed two different types of viroplexes, cationic Sendai F/HN viroplexes (CSVs) and protamine sulfate-condensed cationic Sendai F/HN viroplexes (PCSVs) for the efficient transfection of T-leukemic cells. MATERIALS AND METHODS: The viroplex systems were prepared by reconstitution of fusogenic Sendai F/HN proteins in DMKE (O,O'-dimyristyl-N-lysyl glutamate) cationic liposomes. The viroplexes were further optimized for plasmid DNA and siRNA delivery to suspension cells. The particle size and surface charge of the viroplexes were analyzed with a zeta-sizer. Transfection of plasmid DNA (pDNA) and small interfering RNA (siRNA) by CSVs or PCSV was evaluated by measurement of transgene expression, confocal microscopy, FACS, and RT-PCR. RESULTS: The optimized CSVs and PCSVs exhibited enhanced gene and siRNA delivery in the tested suspension cell lines (Jurkat cells and CEM cells), compared with conventional cationic liposomes. In the case of pDNA transfection, the CSVs and PCSVs show at least 10 fold and 100-fold higher transgene expression compared with DMKE lipoplexes (or lipofectamine 2000), respectively. The CSVs showed more effective siRNA delivery to the suspension cells than cationic liposomes, as assessed by confocal microscopy, FACS, and RT-PCR. The effective transfection by the CSVs and PCSVs is presumably due to fusogenic activity of F/HN proteins resulting in facilitated internalization of pDNA and siRNA. CONCLUSION: This study suggests that Sendai F/HN viroplexes can be widely applicable for the transfection of pDNA and siRNA to suspension cell lines. PMID- 23918565 TI - NAD(P)H: quinone oxidoreductase 1 and NRH:quinone oxidoreductase 2 polymorphisms in papillary thyroid microcarcinoma: correlation with phenotype. AB - PURPOSE: NAD(P)H:Quinone Oxidoreductase 1 (NQO1) C609T missense variant (NQO1*2) and 29 basepair (bp)-insertion/deletion (I29/D) polymorphism of the NRH:Quinone Oxidoreductase 2 (NQO2) gene promoter have been proposed as predictive and prognostic factors for cancer development and progression. The purpose of this study is to investigate the relationship between NQO1/NQO2 genotype and clinico pathological features of papillary thyroid microcarcinoma (PTMC). MATERIALS AND METHODS: Genomic DNA was isolated from 243 patients; and clinical data were retrospectively analyzed. NQO1*2 and tri-allelic polymorphism of NQO2 were investigated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. RESULTS: PTMC with NQO1*2 frequently exhibited extra-thyroidal extension as compared to PTMC with wild-type NQO1 (p=0.039). There was a significant relationship between I29/I29 homozygosity of NQO2 and lymph node metastasis (p=0.042). Multivariate analysis showed that the I29/I29 genotype was associated with an increased risk of lymph node metastasis (OR, 2.24; 95% CI, 1.10-4.56; p=0.026). CONCLUSION: NQO1*2 and I29 allele of the NQO2 are associated with aggressive clinical phenotypes of PTMC, and the I29 allele represents a putative prognostic marker for PTMC. PMID- 23918566 TI - Prognostic factors for patients with bone-only metastasis in breast cancer. AB - PURPOSE: Bone is the most frequent site of metastasis among breast cancer patients. We investigated prognostic factors affecting survival following bone only metastasis in breast cancer patients. MATERIALS AND METHODS: The medical records of breast cancer patients who were treated and followed at Gangnam Severance Hospital retrospectively reviewed to identify patients with bone-only metastasis. RESULTS: The median time from the diagnosis of bone-only metastasis to the last follow-up or death was 55.2 [95% confidence interval (CI), 38.6-71.9] months. The Kaplan-Meier overall survival estimate at 10 years for all patients was 34.9%. In the multivariate Cox regression model, bisphosphonate treatment [hazard ratio=0.18; 95% CI, 0.07-0.43], estrogen receptor positivity (hazard ratio=0.51; 95% CI, 0.28-0.94), and solitary bone metastasis (hazard ratio=0.32; 95% CI, 0.14-0.72) were significantly associated with longer overall survival in the bone-only recurrence group. Among the treatment modalities, only bisphosphonate treatment was identified as a significant prognostic factor. CONCLUSION: Identifying the factors influencing breast cancer mortality after bone-only metastasis will help clarify the clinical course and improve the treatment outcome for patients with breast cancer and bone-only metastasis. Bisphosphonates, as a significant prognostic factor, warrant further investigation. PMID- 23918567 TI - Feasibility of sorafenib combined with local radiotherapy in advanced hepatocellular carcinoma. AB - PURPOSE: Sorafenib is an effective systemic agent for advanced hepatocellular carcinoma. To increase its efficacy, we evaluated the feasibility and benefit of sorafenib combined with radiotherapy. MATERIALS AND METHODS: From July 2007 to July 2011, 31 patients were treated with a daily dose of 800 mg of sorafenib and radiotherapy. Among them, 13 patients who received radiotherapy on the bone metastasis were excluded. Thirteen patients received 30-54 Gy of radiotherapy on the primary tumor (primary group) and 5 patients received 30-58.4 Gy on the measurable metastatic lesions (measurable metastasis group). Tumor responses at 1 month after the completion of radiotherapy and overall survival were evaluated. RESULTS: The in-field response rate was 100% in the primary group and 60% in the measurable metastasis group. A decrease of more than 80% in the tumor marker alpha-fetoprotein was observed in 7 patients in the primary group (54%). Toxicities of grades 3-4 were hand-foot syndrome in 3 (17%) patients, duodenal bleeding in 1 (6%) patient, thrombocytopenia in 3 (17%) patients and elevation of aspartate transaminase in 1 (6%) patient. The median overall survival was 7.8 months (95% confidence interval, 3.0-12.6). CONCLUSION: The combined treatment of sorafenib and radiotherapy was feasible and induced substantial tumor responses in the target lesions. The results of this study emphasize the importance of individualized approach in the management of advanced hepatocellular carcinoma and encourage the initiation of a controlled clinical trial. PMID- 23918568 TI - Growth inhibition of hepatocellular carcinoma Huh7 cells by Lactobacillus casei extract. AB - PURPOSE: Lactobacillus casei (L. casei) is known to exert anti-proliferation effects on many types of cancer cells. However, the effect of L. casei on liver cancer has not been reported. Accordingly, the aim of this study was to determine the anti-cancer effect of L. casei extract on Huh7 cells. MATERIALS AND METHODS: L. casei ATCC393 extract was prepared and purified. After the treatment of L. casei extract on Huh7 cells, cell viability, cell cycle arrest and cell death were analyzed by flow cytometry. The expression levels of tumor necrosis factor alpha receptor 1 (TNFR1) and death receptor 3 (DR3) mRNA related with extrinsic apoptosis were assessed by reverse transcription polymerase chain reaction. Additionally, P21 and P27 cell cycle proteins as well as Caspase-3, -8, -9, phospho-Bad and Bcl-2 apoptosis proteins were analyzed by western blot analysis. To determine the effect of L. casei extract on cancer stem-like cells, we analyzed changes in side population fraction through flow cytometry. RESULTS: The cell viability of Huh7 cells treated with L. casei extract was decreased by 77%, potentially owing to increases in the rates of Huh7 cells arrested in the G2/M phase (3% increase) and that underwent apoptosis (6% increase). The expression levels of TNFR1 and DR3 mRNA, as well as P21 and P27 cell cycle proteins, were increased. Meanwhile, the expressions of caspase-8, -9, phospho-Bad and Bcl-2 proteins decreased. However, in the case of side population cells, no remarkable changes were observed. CONCLUSION: L. casei extract exerts a potent anti-tumor effect on the viability of liver cancer cells, although not on cancer stem-like cells. PMID- 23918569 TI - Proteinuria as a risk factor for mortality in patients with colorectal cancer. AB - PURPOSE: We investigated the effects of proteinuria and renal insufficiency on all-cause mortality in patients with colorectal cancer, with special emphasis on cancer staging and cancer-related deaths. MATERIALS AND METHODS: We retrospectively studied a cohort of patients with colorectal cancer. In protocol 1, patients were classified into four groups based on the operability of cancer and proteinuria: group 1, early-stage cancer patients (colorectal cancer stage <= 3) without proteinuria; group 2, early-stage cancer patients with proteinuria; group 3, advanced-stage cancer patients without proteinuria (colorectal cancer stage=4); and group 4, advanced- stage cancer patients with proteinuria. In protocol 2, patients were classified into four similar groups based on cancer staging and renal insufficiency (eGFR <60 mL/min/1.73 m(2)). Between January 1, 1998 and December 31, 2009, 3379 patients were enrolled in this cohort and followed until May 1, 2012 or until death. RESULTS: The number of patients with proteinuria was 495 (14.6%). The prevalence of proteinuria was higher in advanced stage cancer (n=151, 22.3%) than in early-stage cancer patients (n=344, 12.7%). After adjusting for age, gender and other clinical variables, the proteinuric, early-stage cancer group was shown to be associated with an adjusted hazard ratio of 1.67 and a 95% confidence interval of 1.38-2.01, compared with non-proteinuric early-stage cancer patients. However, renal insufficiency was not associated with colorectal cancer mortality. CONCLUSION: Proteinuria is an important risk factor for cancer mortality, especially in relatively early colorectal cancer. PMID- 23918570 TI - Role of prostate volume in the early detection of prostate cancer in a cohort with slowly increasing prostate specific antigen. AB - PURPOSE: To investigate the relationship between prostate volume and the increased risk for being diagnosed with prostate cancer (PCa) in men with slowly increasing prostate specific antigen (PSA). MATERIALS AND METHODS: A cohort of 1035 men who visited our hospital's health promotion center and were checked for serum PSA levels more than two times between January 2001 and November 2011 were included. Among them, 116 patients had a change in PSA levels from less than 4 ng/mL to more than 4 ng/mL and underwent transrectal ultrasound guided prostate biopsy. Median age was 55.9 years and 26 (22.4%) had PCa. We compared the initial PSA level, the last PSA level, age, prostate volume, PSA density (PSAD), PSA velocity, and follow-up period between men with and without PCa. The mean follow- up period was 83.7 months. RESULTS: Significant predictive factors for the detection of prostate cancer identified by univariate analysis were prostate volume, follow-up period and PSAD. In the multivariate analysis, prostate volume (p<0.001, odds ratio: 0.890) was the most significant factor for the detection of prostate cancer. In the receiver operator characteristic curve of prostate volume, area under curve was 0.724. At the cut-off value of 28.8 mL for prostate volume, the sensitivity and specificity were 61.1% and 73.1% respectively. CONCLUSION: In men with PSA values more than 4 ng/mL during the follow-up period, a small prostate volume was the most important factor in early detection of prostate cancer. PMID- 23918571 TI - Outcomes of Gleason Score <= 8 among high risk prostate cancer treated with 125I low dose rate brachytherapy based multimodal therapy. AB - PURPOSE: To investigate the role of low dose rate (LDR) brachytherapy-based multimodal therapy in high-risk prostate cancer (PCa) and analyze its optimal indications. MATERIALS AND METHODS: We reviewed the records of 50 high-risk PCa patients [clinical stage >= T2c, prostate-specific antigen (PSA) >20 ng/mL, or biopsy Gleason score >= 8] who had undergone 125I LDR brachytherapy since April 2007. We excluded those with a follow-up period <3 years. Biochemical recurrence (BCR) followed the Phoenix definition. BCR-free survival rates were compared between the patients with Gleason score >= 9 and Gleason score <= 8. RESULTS: The mean initial PSA was 22.1 ng/mL, and mean D90 was 244.3 Gy. During a median follow- up of 39.2 months, biochemical control was obtained in 72% (36/50) of the total patients; The estimated 3-year BCR-free survival was 92% for the patients with biopsy Gleason scores <= 8, and 40% for those with Gleason scores >= 9 (p<0.001). In Cox multivariate analysis, only Gleason score >= 9 was observed to be significantly associated with BCR (p=0.021). Acute and late grade >= 3 toxicities were observed in 20% (10/50) and 36% (18/50) patients, respectively. CONCLUSION: Our results showed that 125I LDR brachytherapy-based multimodal therapy in high-risk PCa produced encouraging relatively long-term results among the Asian population, especially in patients with Gleason score <= 8. Despite small number of subjects, biopsy Gleason score >= 9 was a significant predictor of BCR among high risk PCa patients after brachytherapy. PMID- 23918572 TI - Evaluation of quality of life with the chronic obstructive pulmonary disease assessment test in chronic obstructive pulmonary disease and the effect of dyspnea on disease-specific quality of life in these patients. AB - PURPOSE: The chronic obstructive pulmonary disease (COPD) assessment test (CAT) was recently introduced for use in assessing disease-specific quality of life and follow-up of patients with COPD. The purpose of this study was to evaluate the effect of the dyspnea on disease-specific quality of life detected by CAT score in patients with COPD. MATERIALS AND METHODS: In this study, 90 stable patients with COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria were included. The level of dyspnea was assessed with the Medical Research Council (MRC) dyspnea scale, and disease-specific quality of life was assessed with CAT score. RESULTS: The mean +/- SD age was 68.5 +/- 10.9 (range 41-97) years. A significant relationship was established between CAT score, MRC dyspnea scale score and GOLD stage in patients with COPD. There was also a positive correlation between dyspnea scale scores and GOLD stage in the patients (p<0.001), as well as positive correlation between CAT score and dyspnea scale score (p<0.001). CAT score showed a significant correlation with hospitalization and exacerbations (p<0.05). CONCLUSION: Dyspnea is an important symptom that may impact quality of life in patients with COPD. CAT was shown to be a simple, fast and intelligible measurement of disease-specific quality of life, and was correlated with levels of dyspnea in patients with COPD. PMID- 23918573 TI - A simple and efficient multiplex PCR assay for the identification of Mycobacterium genus and Mycobacterium tuberculosis complex to the species level. AB - PURPOSE: The Mycobacterium tuberculosis complex comprises M. tuberculosis, M. bovis, M. bovis bacillus Calmette-Guerin (BCG) and M. africanum, and causes tuberculosis in humans and animals. Identification of Mycobacterium spp. and M. tuberculosis complex to the species level is important for practical use in microbiological laboratories, in addition to optimal treatment and public health. MATERIALS AND METHODS: A novel multiplex PCR assay targeting a conserved rpoB sequence in Mycobacteria spp., as well as regions of difference (RD) 1 and RD8, was developed and evaluated using 37 reference strains and 178 clinical isolates. RESULTS: All mycobacterial strains produced a 518-bp product (rpoB), while other bacteria produced no product. Virulent M. tuberculosis complex strains, M. tuberculosis, M. bovis and M. africanum, produced a 254-bp product (RD1), while M. bovis BCG, M. microti and nontuberculous mycobacteria produced no RD1 region product. Additionally, M. tuberculosis and M. africanum produced a 150-bp product (RD8), while M. bovis and M. bovis BCG produced a 360-bp product (deleted form of RD8). M. microti and nontuberculous mycobacteria produced no RD8 region product. This assay identified all Mycobacterium spp. and all M. tuberculosis complex strains to the species level. CONCLUSION: The multiplex PCR assay of the present study could be implemented as a routine test in microbiology laboratories, and may contribute to more effective treatment and surveillance of tuberculosis stemming from the M. tuberculosis complex. PMID- 23918574 TI - Treatment response and adverse reactions in older tuberculosis patients with immunocompromising comorbidities. AB - PURPOSE: The aim of this study was to elucidate the effects of immunocompromising comorbidities on treatment response and adverse reactions in older tuberculosis (TB) patients. MATERIALS AND METHODS: The medical records of 182 patients older than 65 years with proven TB by positive culture of Mycobacterium tuberculosis and with available drug susceptibility tests were reviewed retrospectively. These patients were subsequently assigned to either the comorbidity group (n=78) or non comorbidity group (n=104) depending on whether they had immunocompromising comorbidities. RESULTS: The mean durations of treatment were 9.9 +/- 3.3 months in the comorbidity group and 9.3 +/- 3.2 months in the non-comorbidity group (p=0.21). M. tuberculosis culture results converted to negative in most patients with available follow-up cultures at two months after treatment. The successful treatment rates were 94.9% and 98.9% in the comorbidity and non-comorbidity groups, respectively (p=0.30). The most common side effects of anti-TB treatment were skin rash/pruritus (13% in the comorbidity group vs. 11% in the non comorbidity group, p=0.79), gastro-intestinal problems (14% vs. 9%, p=0.25) and hepatotoxicity (14% vs. 7%, p=0.09). CONCLUSION: The present study shows that the successful treatment rate for TB is high and that immunocompromising comorbidities have no effect on the response to treatment and adverse effects in older TB patients. PMID- 23918575 TI - Posaconazole treatment in Korea: single-center experience over 5 years. AB - PURPOSE: Posaconazole is a second-generation triazole with a broad spectrum. However, there is a lack of data to support a significant role for posaconazole in the treatment of invasive fungal infection (IFI), especially in Korea. Until recently, posaconazole was available only through the Korean Orphan Drug Center. This study was designed to review the use of posaconazole at a single-center in Korea. MATERIALS AND METHODS: Data from patients who received posaconazole treatment at Catholic Blood and Marrow Transplantation Center were retrospectively reviewed between January 2007 and September 2012. RESULTS: A total of 11 cases (3 males and 8 females, median age 52 years) received posaconazole. Five patients were given the drug for mucormycosis, two for invasive aspergillosis, and four for unspecified IFI for which galactomannan (GM) assays were negative. The treatment duration ranged from 4-250 days. Three patients received posaconazole for management refractory IFI, two for intolerance of previous antifungal therapy, and six for long-term maintenance treatment. The overall successful response rate to posaconazole was 55% (six of eleven patients). Five of eleven patients died during the study period. However, only one death was attributed to the progression of IFI. None of the patients discontinued posaconazole therapy due to adverse events. CONCLUSION: Posaconazole is an attractive oral antifungal agent for salvage treatment of IFI, particularly upon diagnosis of mucormycosis or in cases in which mucormycosis cannot be ruled out due to a negative GM. PMID- 23918576 TI - Clinical significance of serum CA-125 in Korean females with ascites. AB - PURPOSE: Mycobacterium tuberculosis is endemic in Korea. Because tuberculous peritonitis is characterized by ascites, abdominal pain, abdominal mass and elevation of serum CA-125, it can be confused with ovarian malignancies. The aim of this study was to evaluate the significance of serum CA-125 level in the differential diagnosis of tuberculous peritonitis and ovarian malignancy in a Mycobacterium tuberculosis-endemic area. MATERIALS AND METHODS: The medical records of patients diagnosed with tuberculous peritonitis (n=48) or epithelial ovarian malignancy (n=370) at Samsung Medical Center from January 2000 to October 2009 were retrospectively reviewed. RESULTS: Median serum CA-125 level in the epithelial ovarian cancer group was significantly higher than that in the tuberculous peritonitis group (p <= 0.01). Only one patient (2.1%) in the tuberculous peritonitis group had a serum CA-125 level over 2000 U/mL. However, 109 patients (29.5%) in the epithelial ovarian cancer group had a serum CA-125 level over 2000 U/mL. At the CA-125 ranges of 400 to 599 and 600 to 799, the proportions of those with tuberculous peritonitis were 24% and 21.9%, respectively. At a serum CA-125 level over 1000 U/mL, however, the proportion of tuberculous peritonitis was much lower (2.1%). CONCLUSION: Tuberculous peritonitis should be considered in the evaluation of female patients with ascites and high serum CA-125. PMID- 23918577 TI - Modified mandibulotomy technique to reduce postoperative complications: 5-year results. AB - PURPOSE: To review the 5-year outcomes of our modified mandibulotomy technique. Retrospective review of a tertiary level oral cancer center. MATERIALS AND METHODS: During a 5-year period, 30 patients who had a uniform surgical technique consisting of a lower lip-splitting, modified stair-step osteotomy with thin saw blade and osteotome after plate-precontouring and combination fixation with monocortical osteosynthesis (miniplate) and bicortical osteosynthesis (maxiplate and bicortical screws), with at least 14 months postoperative follow-up, were selected and reviewed retrospectively. RESULTS: There were 8 women and 22 men with an average age of 56.5 years. All the patients involved malignancies were squamous cell carcinoma. The main primary sites of the those who underwent a mandibulotomy were the tonsil, the base of tongue, the oral tongue, the retromolar pad area, and others. Others included buccal cheek, floor of mouth, and soft palate. 23 patients received postoperative radiation therapy, and among whom 8 patients also received chemotherapy. Total four (13%) mandibulotomy related complications occurred, only two (6.7%) requiring additional operation under general anesthesia. CONCLUSION: Our modified mandibulotomy meets the criteria for an ideal mandibulotomy technique relatively well because it requires no intermaxillary fixation, can precise preserve the occlusion in a precise way, allows early function, requires no secondary procedures, and has few complications. PMID- 23918578 TI - Efficacy of combination of meloxicam and pregabalin for pain in knee osteoarthritis. AB - PURPOSE: Osteoarthritic pain is largely considered to be inflammatory pain. Sensory nerve fibers innervating the knee have been shown to be significantly damaged in rat models of knee osteoarthritis (OA) in which the subchondral bone junction is destroyed, and this induces neuropathic pain (NP). Pregabalin was developed as a pain killer for NP; however, there are no reports on pregabalin use in OA patients. The purpose of this study was to investigate the efficacy of pregabalin for pain in OA patients. MATERIALS AND METHODS: Eighty-nine knee OA patients were evaluated in this randomized prospective study. Patients were divided into meloxicam, pregabalin, and meloxicam+pregabalin groups. Pain scores were evaluated before and 4 weeks after drug application using a visual analogue scale (VAS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Pain scales among groups were compared using a Kruskal-Wallis test. RESULTS: Before drug application, there was no significant difference in VAS and WOMAC scores among the three groups (p>0.05). Significant pain relief was seen in the meloxicam+pregabalin group in VAS at 1, 2, and 4 weeks, and WOMAC score at 4 weeks, compared with the other groups (p<0.05). No significant pain relief was seen in the meloxicam only group in VAS during 4 weeks and WOMAC score at 4 weeks compared with the pregabalin only group (p>0.05). CONCLUSION: Meloxicam+pregabalin was effective for pain in OA patients. This finding suggests that OA pain is a combination of inflammatory and NP. PMID- 23918579 TI - Comparison of preoperative and postoperative ocular biometry in eyes with phakic intraocular lens implantations. AB - PURPOSE: To compare preoperative and postoperative ocular biometry in patients with iris-fixated phakic intraocular lens (pIOLs): Artisan and Artiflex. MATERIALS AND METHODS: This study included 40 eyes with Artisan and 36 eyes with Artiflex pIOL implants. Anterior chamber depth (ACD) and axial length (AL) were measured by applanation ultrasonography (A-scan) and partial coherence interferometry (IOLMaster) preoperatively and 3 months after pIOL implantation. RESULTS: ACD measurements after Artisan or Artiflex pIOL implantation were smaller than preoperative measurements. Specifically, the difference after Artisan pIOL implantation was -1.07 +/- 0.17 mm by A-scan and -0.08 +/- 0.08 mm by IOLMaster. The difference after Artiflex pIOL implantation was -1.31 +/- 0.15 mm by A-scan and -0.05 +/- 0.07 mm by IOLMaster. After Artisan pIOL implantation, differences in AL measurements by A-scan were insignificant (difference: -0.03 +/ 0.15 mm), whereas postoperative AL measurements by IOLMaster were significantly longer than preoperative measurements (difference: 0.12 +/- 0.07 mm). After Artiflex pIOL implantation, AL measurements by both A-scan and IOLMaster were significantly longer than preoperative measurements (difference: 0.09 +/- 0.16 mm by A-scan and 0.07 +/- 0.10 mm by IOLMaster). In the Artiflex group, differences in AL measurements by A-scan correlated with the central thickness of the Artiflex pIOL. CONCLUSION: ACD and AL measurements were influenced by iris fixated phakic IOL implantation. PMID- 23918580 TI - Kidney function in living donors undergoing nephrectomy by sevoflurane or desflurane anesthesia. AB - PURPOSE: Although there is no clinical evidence of nephrotoxicity with the volatile anesthetics currently used in general anesthesia, a better agent should be needed in terms of preserving postoperative renal function in living kidney donors who have only single remaining kidney. The purpose of the current retrospective, single-center study was to evaluate and compare renal function of living kidney donors after nephrectomy under either sevoflurane or desflurane anesthesia. MATERIALS AND METHODS: From January 2006 through December 2011, a total of 228 donors undergoing video assisted minilaparotomy surgery nephrectomy for kidney donation were retrospectively enrolled in the current study. The donors were categorized into a sevoflurane group or desflurane group based on the type of volatile anesthetic used. We collected laboratory data from the patients preoperatively, immediately after the operation, on the first postoperative day and on the third postoperative day. We also compared renal function of the kidney donors after donor nephrectomy by comparing creatinine level and estimated glomerular filtration rate (eGFR). RESULTS: The decrease in renal function after surgery in both groups was the most prominent on the first postoperative day. There were no significant differences between the two groups in postoperative changes of creatinine or eGFR. CONCLUSION: Sevoflurane and desflurane can be used safely as volatile anesthetics in donors undergoing nephrectomy. PMID- 23918581 TI - Risk assessment of postoperative nausea and vomiting in the intravenous patient controlled analgesia environment: predictive values of the Apfel's simplified risk score for identification of high-risk patients. AB - PURPOSE: Opioid-based intravenous patient-controlled analgesia (IV PCA) is popular method of postoperative pain control, but many patients suffer from IV PCA-related postoperative nausea and vomiting (PONV). In this retrospective observational study, we have determined independent predictors of IV PCA-related PONV and predictive values of the Apfel's simplified risk score in pursuance of identifying high-risk patients. MATERIALS AND METHODS: We analyzed 7000 patients who received IV PCA with background infusion after elective surgery. Patients who maintained IV PCA for a postoperative period of 48 hr (completion group, n=6128) were compared with those who have discontinued IV PCA within 48 hr of surgery due to intractable PONV (cessation group, n=872). Patients, anesthetics, and surgical factors known for predicting PONV were evaluated by logistic regression analysis to identify independent predictors of IV PCA related intractable PONV. RESULTS: In a stepwise multivariate analysis, weight, background infusion dose of fentanyl, addition of ketolorac to PCA, duration of anesthesia, general anesthesia, head and neck surgery, and Apfel's simplified risk score were revealed as independent risk factors for intractable PONV followed by the cessation of IV PCA. In addition, Apfel's simplified risk score, which demonstrated the highest odds ratio among the predictors, was strongly correlated with the cessation rate of IV PCA. CONCLUSION: Multimodal prophylactic antiemetic strategies and dose reduction of opioids may be considered as strategies for the prevention of PONV with the use of IV PCA, especially in patients with high Apfel's simplified risk scores. PMID- 23918582 TI - Detection of methicillin-resistant Staphylococcus aureus in healthcare workers using real-time polymerase chain reaction. AB - Healthcare-associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have recently become an important issue for healthcare facilities due to high rates of infection, mortality, and high treatment costs. We investigated the frequency of MRSA in healthcare workers (HCWs) via nasal carriage and assessed the performance of the LightCycler(r) MRSA Advanced test. We tested nasal swabs from the anterior nares of participating HCWs at an intensive care unit. Nasal swabs were identified as S. aureus, methicillin sensitive or methicillin-resistant coagulase-negative staphylococci (MSCoNS or MRCoNS), or MRSA by using conventional culture and the LightCycler(r) MRSA Advanced test. Of the 142 HCWs who participated in this study, only 11 participants (7.8%) were MRSA-positive by conventional culture and MRSA ID, and 24 (16.9%) were positive for mecA by real time polymerase chain reaction (PCR). In terms of diagnostic performance, the LightCycler(r) MRSA Advanced test had a sensitivity of 100%, a specificity of 90.1%, a positive predictive value of 45.8%, and a negative predictive value of 100% compared with conventional culture method. The detection limit of the LightCycler(r) MRSA Advanced test was 10(3) colony/mL. We concluded that real-time PCR was able to rapidly and sensitively detect MRSA in HCWs. However, MRSA must be confirmed by culture due to false positivity. PMID- 23918583 TI - IgG4-related sclerosing disease involving the superior vena cava and the atrial septum of the heart. AB - A 55-year-old woman presented with frequent episodes of syncope due to sinus pauses. During ambulatory Holter monitoring, atrial fibrillation and first-degree atrioventricular nodal block were observed. Magnetic resonance imaging and CT scans showed a tumor-like mass from the superior vena cava to the right atrial septum. Open chest cardiac biopsy was performed. The tumor was composed of proliferating IgG4-positive plasma cells and lymphocytes with surrounding sclerosis. The patient was diagnosed with IgG4-related sclerosing disease. Because of frequent sinus pauses and syncope, a permanent pacemaker was implanted. The cardiac mass was inoperable, but it did not progress during the one-year follow-up. PMID- 23918584 TI - Spurious elevation of glucose concentration during administration of high dose of ascorbic acid in a patient with type 2 diabetes on hemodialysis. AB - We describe herein a case of life-threatening hypoglycemia due to spurious elevation of glucose concentration during the administration of ascorbic acid in a type 2 diabetic patient. A 31-year-old female was admitted for proliferative diabetic retinopathy treatment and prescribed high dose ascorbic acid. During hospitalization, she suddenly lost her consciousness and her glucose concentration was 291 mg/dL, measured using self-monitoring blood glucose (SMBG) device, while venous blood glucose concentration was 12 mg/dL. After intravenous injection of 50% glucose solution, the patient became alert. We reasoned that glucose measurement by SMBG device was interfered by ascorbic acid. Physicians should be aware of this interference; high dose ascorbic acid may cause spurious elevation of glucose concentration when measuring with SMBG devices. PMID- 23918585 TI - Familial occurrence of pulmonary embolism after intravenous, adipose tissue derived stem cell therapy. AB - The therapeutic potential of human multipotent mesenchymal stromal cells, especially human adipose tissue-derived stem cells (hASC), is promising. However, there are concerns about the safety of infusion of hASC in human. Recently, we have experienced pulmonary embolism and infarct among family members who have taken multiple infusions of intravenous autologous hASC therapy. A 41-year-old man presented with chest pain for one month. Chest CT showed multiple pulmonary artery embolism and infarct at right lung. Serum D-dimer was 0.8 MUg/mL (normal; 0-0.5 MUg/mL). He had received intravenous autologous adipose tissue-derived stem cell therapy for cervical herniated intervertebral disc three times (one, two, and three months prior to the visit). His parents also received the same therapy five times and their chest CT also showed multiple pulmonary embolism. These cases represent artificial pulmonary embolisms and infarct after IV injection of hASC. Follow-up chest CT showed spontaneous resolution of lesions in all three patients. PMID- 23918586 TI - Human infection of Salmonella matadi in Korea. PMID- 23918587 TI - Mastoid cavity obliteration and Vibrant Soundbridge implantation for patients with mixed hearing loss. AB - OBJECTIVES/HYPOTHESIS: To review the results of obliteration of a preexisting mastoid cavity with abdominal fat and Vibrant Soundbridge implantation in patients with mixed hearing loss (MHL) and to compare the data with results of Vibrant Soundbridge implantation in patients with MHL without mastoid cavity and with pure sensorineural hearing loss (SNHL). STUDY DESIGN: Retrospective chart analysis of 10 patients (10 ears) with MHL and preexisting mastoid cavity, 18 patients (19 ears) with MHL alone and nine patients (10 ears) with SNHL treated in one tertiary referral center. METHODS: Vibrant Soundbridge implantation and obliteration in case a mastoid cavity existed previously. Pure tone audiometry (average air-bone gap, average functional gain), speech audiometry (Freiburg Monosyllabic Test) and complication rate were main outcome measures. RESULTS: Postoperative average air-bone gap was -15.1 +/- 21.2 dB in patients with MHL with mastoid cavity obliteration, -7.2 +/- 11.4 dB in patients with MHL without mastoid cavity, and -5.7 +/- 11.2 dB in patients with SNHL. Average functional gain was 40.0 +/- 23.5 dB, 39.7 +/- 12.1 dB, and 9.5 +/- 10.6 dB. Postoperative speech discrimination rate was 77.9 +/- 20.8%, 83.3 +/- 13.6%, and 83.6 +/- 6.3%. No severe intraoperative or postoperative complications were noted. CONCLUSIONS: Mastoid cavity obliteration during Vibrant Soundbridge implantation in patients with MHL and preexisting mastoid cavity is a safe procedure. The audiometric results are satisfying and comparable to those of other patient groups implanted with the same device. LEVEL OF EVIDENCE: 4. PMID- 23918588 TI - Effects of resveratrol in patients with type 2 diabetes mellitus on skeletal muscle SIRT1 expression and energy expenditure. AB - OBJECTIVES: The primary aims of the study were to examine the effect of resveratrol on skeletal muscle SIRT1 expression and energy expenditure in subjects with Type 2 diabetes mellitus (T2DM). BACKGROUND: Animal and in vivo studies indicate that resveratrol increases SIRT1 expression that stimulates PGC1alpha activity. Subsequent upregulation of AMPK and GLUT4 expression are associated with improved insulin sensitivity in peripheral tissues. METHODS: Ten subjects with T2DM were randomized in a double-blind fashion to receive 3g resveratrol or placebo daily for 12 weeks. Secondary outcomes include measures of AMPK, p-AMPK and GLUT4 expression levels, energy expenditure, physical activity levels, distribution of abdominal adipose tissue and skeletal muscle fiber type composition, body weight, HbA1c, plasma lipid subfraction, adiponectin levels, and insulin sensitivity. RESULTS: There was a significant increase in both SIRT1 expression (2.01 vs. 0.86 arbitrary units [AU], p = .016) and p-AMPK to AMPK expression ratio (2.04 vs. 0.79 AU, p = .032) in the resveratrol group compared with the placebo group. Although the percentage of absolute change (8.6 vs. 13.9%, p = .033) and percentage of predicted resting metabolic rate (RMR; 7.8 vs. -13.9%, p = .013) were increased following resveratrol, there was a significant reduction in average daily activity (-38 vs. 43.2%, p = .028) and step counts ( 39.5 vs. 11.8%, p = .047) when compared with placebo. CONCLUSIONS: In patients with T2DM, treatment with resveratrol regulates energy expenditure through increased skeletal muscle SIRT1 and AMPK expression. These findings indicate that resveratrol may have beneficial exercise-mimetic effects in patients with T2DM. PMID- 23918589 TI - A genome-wide association study reveals ARL15, a novel non-HLA susceptibility gene for rheumatoid arthritis in North Indians. AB - OBJECTIVE: Genome-wide association studies (GWAS) and their subsequent meta analyses have changed the landscape of genetics in rheumatoid arthritis (RA) by uncovering several novel genes. Such studies are heavily weighted by samples from Caucasian populations, but they explain only a small proportion of total heritability. Our previous studies in genetically distinct North Indian RA cohorts have demonstrated apparent allelic/genetic heterogeneity between North Indian and Western populations, warranting GWAS in non-European populations. We undertook this study to detect additional disease-associated loci that may be collectively important in the presence or absence of genes with a major effect. METHODS: High-quality genotypes for >600,000 single-nucleotide polymorphisms (SNPs) in 706 RA patients and 761 controls from North India were generated in the discovery stage. Twelve SNPs showing suggestive association (P < 5 * 10(-5)) were then tested in an independent cohort of 927 RA patients and 1,148 controls. Additional disease-associated loci were determined using support vector machine (SVM) analyses. Fine-mapping of novel loci was performed by using imputation. RESULTS: In addition to the expected association of the HLA locus with RA, we identified association with a novel intronic SNP of ARL15 (rs255758) on chromosome 5 (Pcombined = 6.57 * 10(-6); odds ratio 1.42). Genotype-phenotype correlation by assaying adiponectin levels demonstrated the functional significance of this novel gene in disease pathogenesis. SVM analysis confirmed this association along with that of a few more replication stage genes. CONCLUSION: In this first GWAS of RA among North Indians, ARL15 emerged as a novel genetic risk factor in addition to the classic HLA locus, which suggests that population-specific genetic loci as well as those shared between Asian and European populations contribute to RA etiology. Furthermore, our study reveals the potential of machine learning methods in unraveling gene-gene interactions using GWAS data. PMID- 23918591 TI - Development of the short form of the Korean Health Literacy Scale for the elderly. AB - We developed and examined a shortened form of the Korean Health Literacy Scale (KHLS) with a sample of 543 elderly in South Korea. Rasch analysis of the KHLS was conducted to examine the unidimensionality of the scale, along with a confirmatory factor analysis to evaluate both the item fit and item difficulty. Based on these data the KHLS was narrowed down to 12 of the original 24 items (7 comprehension and numeracy questions and 5 health-related questions). The internal consistency of the resulting short form (S-KHLS) was 0.80. The S-KHLS is a short and reliable scale for testing the health literacy skills of elderly Korean adults. PMID- 23918590 TI - Which biomarkers are effective for identifying Th2-driven inflammation in asthma? AB - Recognition of asthma as a heterogeneous disease revealed different potential molecular targets and urged the development of targeted, customized treatment modalities. Evidence was provided for different inflammatory subsets of asthma and more recently, further refined to T helper (Th)2-high and Th2-low subphenotypes with different responsiveness to standard and targeted pharmacotherapy. Given these differences in immunology and pathophysiology, proof of concept studies of novel treatment modalities for asthma should be performed in adequate, well-defined phenotypes. In this review, we describe both existing and novel biomarkers of Th2-inflammation in asthma that can be applied to classify asthma subphenotypes in clinical studies and for treatment monitoring. PMID- 23918592 TI - Three patients resembling Teebi-Shaltout syndrome. AB - Teebi-Shaltout syndrome (TSS) was first reported by Teebi and Shaltout in 1989. This entity is proposed to be inherited in autosomal recessive manner. The clinical features include characteristic facial features, ectodermal dysplasia, camptodactyly, and caudal appendage. Only one additional paper reporting four additional cases has been published since the first description. Clinical features common to all previously affected individuals diagnosed with TSS are craniofacial, orodental-ectodermal, and skeletal. This report summarizes and discusses the findings of three additional patients from two unrelated families with findings similar to TSS. These findings may be present in a genetically and phenotypically heterogeneous group of disorders similar to TSS. Presence of consanguinity and similarly affected siblings of both genders suggests autosomal recessive inheritance. PMID- 23918593 TI - [What do medical students think of family medicine? Results of an online cross sectional study in the federal state of Baden-Wuerttemberg]. AB - BACKGROUND: In the context of physician shortages, critical factors influencing career choice need to be better understood. The aim of this study was to explore experiences students have had with family medicine in order to develop additional strategies for recruiting family medicine trainees. METHODS: Students from the five medical faculties in the federal state of Baden-Wuerttemberg were invited to participate in an online-survey via email. A purpose-built questionnaire was used. In addition to descriptive statistics, analysis included linear partial correlations controlled for age, gender, and semester, which were calculated between the variable "I believe family medicine is an attractive job" and the 31 variables of the survey. Linear regression was used to analyze the influence of experiences with family medicine and statements about family medicine to the perception of family medicine as an attractive specialty. RESULTS: 1299 students participated in the survey. About half of the participants (49.7 %) considered working as a primary care physician to be attractive or partly attractive. 49.6 % of students reported positive experiences with family medicine as a patient and 33.1 % as a family member. 24.3 % reported positive experiences during the compulsory 1-2 weeks general practice internship and 18.1 % during a four weeks elective placement. For 302 participants (23.3 %), family medicine is presented positively in the media. 178 (13.7 %) consider family medicine to have high importance in both undergraduate and postgraduate education. Positive influences on judging attractiveness of family medicine were: own experience with family medicine as a clinical elective (rpart= + 0.450), own experience with family medicine as a patient (rpart= + 0.218), perception that family medicine offers a diversified working day (rpart= + 0.259), and perception that family medicine offers a good salary (rpart= + 0.242). CONCLUSION: To enable students during undergraduate studies to have practical experience with family medicine seems to be an important influence on judging family medicine attractive. PMID- 23918594 TI - Squarylium-triazine dyad as a highly sensitive photoradical generator for red light. AB - New dyads, based on squarylium dye and substituted-triazine, were synthesized that exhibit an intramolecular photodissociative electron-transfer reaction. The compounds were used as a red-light photoradical generator. The photochemical activity of the dyad was compared to the corresponding unlinked systems (S+T) by determining the rate constant of electron transfer. The efficiency of the radical generation from the dyad compared to the unlinked system was demonstrated by measuring the maximum rate of free radical polymerization of acrylates in film. An excellent relationship between the rate of electron transfer and the rate of polymerization was found, evidencing the interest of this new approach to efficiently produce radicals under red light. PMID- 23918595 TI - Diagnosis and treatment of traumatic optic neuropathy with carotid artery cavernous segment pseudoaneurysm. AB - OBJECTIVES/HYPOTHESIS: To summarize our experience in diagnosis of carotid cavernous segment pseudoaneurysm in patients with traumatic optic neuropathy, and to make recommendations for treatment. STUDY DESIGN: Retrospective study. METHODS: Clinical data of 133 cases with traumatic optic neuropathy (TON) were reviewed. The diagnosis and treatment of four cases with carotid cavernous segment pseudoaneurysm (PSA) were analyzed. RESULTS: The incidence of traumatic optic neuropathy with pseudoaneurysm for this group of patients was 3.01% (4/133). Preliminary screening was performed with vascular-enhanced computed tomography (CT) scan, and was further confirmed by digital subtraction angiography (DSA). Among the four cases with pseudoaneurysm, three cases were successfully treated with vascular embolization. In one of the three cases, coil embolization was employed; and in the other two cases stent embolization was performed. The pseudoaneurysm disappeared after embolization, and nosebleeds subsided without significant complications. All four patients did not undergo nasal endoscopic optic nerve decompression. There was no recurrence of nose bleeding after embolization in the following 1 to 12 months, and in one case the patient's vision improved from no light perception to perceiving hand movement. CONCLUSIONS: There is a possibility of fatal epistaxis for traumatic optic neuropathy with carotid artery cavernous segment pseudoaneurysm. Endoscopic optic nerve decompression treatment (EOND) is not suitable for these cases; instead, it is recommended that patients with traumatic optic neuropathy go through vascular enhanced computed tomography screening. Suspected cases should be diagnosed by digital subtraction angiography and be treated by embolization in a timely manner, with stent vascular interventional embolization being the ideal choice. PMID- 23918596 TI - Photophysical properties of some flavones probes in homogeneous media. AB - Photophysical properties of five hydroxyflavones (HF) (some typical models of flavonols), (3 - HF, 6 - HF, 7-HF, 3, 6 - diHF and 3, 7 - diHF) were studied in homogeneous media by means of UV-vis and steady-state and time resolved fluorescence spectroscopies. Their absorption and fluorescence characteristics based on the flavonols structure are presented and discussed. It was found that the fluorescence of the flavonols depends on the nature of the solvent and on their molecular structure, especially on the position and the number of the -OH groups of the substituted phenyl ring. Attention is paid to the number of the -OH groups that influence the excited-state intramolecular proton transfer (ESIPT) process. The fluorescence quantum yield and the lifetime of the flavonols in heterogeneous media have been also determined. The results are discussed with relevance to the flavonols as sensitive fluorescence probe and to their microenvironments in the systems of biological interest and especially in a typical protein environment. PMID- 23918597 TI - A novel colorimetric and off-on fluorescent chemosensor for cr(3+) in aqueous solution and its application in live cell imaging. AB - A novel colorimetric and off-on fluorescent chemosensor 2 was designed and synthesized, which showed reversible and highly selective and sensitive recognition toward Cr(3+) over other examined metal ions in aqueous solution. Upon addition of Cr(3+), the solution of chemosensor 2 resulted in a color change from colorless to obvious pink color, these significant changes in color could be used for naked-eye detection. Chemosensor 2 exhibited a stable response for Cr(3+) in the range 0-10 MUM with a detection limit of 1 ppm. Furthermore, fluorescence imaging experiments of Cr(3+) ions in living MGC803 cells demonstrated its value of practical applications in biological systems. PMID- 23918598 TI - Synthesis and optical properties of various thienyl derivatives of pyrene. AB - A series of various thienyl derivatives of pyrene were synthesized by Stille cross-coupling procedure. Their structures were characterized by (1)H NMR, (13)C NMR and elemental analysis. The spectroscopic characteristics were investigated by UV-vis absorption and fluorescence spectra. Based on quantum chemical calculations, the energy levels of investigated molecules with respect to the pyrene molecule were also discussed. PMID- 23918599 TI - Did I turn off the gas? Reality monitoring of everyday actions. AB - Failing to remember whether we performed, or merely imagined performing, an everyday action can occasionally be inconvenient, but in some circumstances it can have potentially dangerous consequences. In this fMRI study, we investigated the brain activity patterns, and objective and subjective behavioral measures, associated with recollecting such everyday actions. We used an ecologically valid "reality-monitoring" paradigm in which participants performed, or imagined performing, specified actions with real objects drawn from one of two boxes. Lateral brain areas, including prefrontal cortex, were active when participants recollected both the actions that had been associated with objects and the locations from which they had been drawn, consistent with a general role in source recollection. By contrast, medial prefrontal and motor regions made more specific contributions, with supplementary motor cortex activity being associated with recollection decisions about actions but not locations, and medial prefrontal cortex exhibiting greater activity when remembering performed rather than imagined actions. These results support a theoretical interpretation of reality monitoring that entails the fine-grained discrimination between multiple forms of internally and externally generated information. PMID- 23918600 TI - The time course of episodic associative retrieval: electrophysiological correlates of cued recall of unimodal and crossmodal pair-associate learning. AB - Little is known about the time course of processes supporting episodic cued recall. To examine these processes, we recorded event-related scalp electrical potentials during episodic cued recall following pair-associate learning of unimodal object-picture pairs and crossmodal object-picture and sound pairs. Successful cued recall of unimodal associates was characterized by markedly early scalp potential differences over frontal areas, while cued recall of both unimodal and crossmodal associates were reflected by subsequent differences recorded over frontal and parietal areas. Notably, unimodal cued recall success divergences over frontal areas were apparent in a time window generally assumed to reflect the operation of familiarity but not recollection processes, raising the possibility that retrieval success effects in that temporal window may reflect additional mnemonic processes beyond familiarity. Furthermore, parietal scalp potential recall success differences, which did not distinguish between crossmodal and unimodal tasks, seemingly support attentional or buffer accounts of posterior parietal mnemonic function but appear to constrain signal accumulation, expectation, or representational accounts. PMID- 23918602 TI - The winning formulation: the development of paclitaxel in pancreatic cancer. AB - Paclitaxel has wide application in anticancer therapy but was never considered an efficacious agent in pancreatic cancer. A review of the experience with the Cremaphor formulation hinted at paclitaxel's activity in pancreatic cancer, but the early development was hampered by significant toxicities such as neutropenia and infection at clinically tolerable doses. However, such efficacy was confirmed in the recently completed phase III Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), in which the addition of nab-paclitaxel to gemcitabine significantly improved the survival of patients with metastatic pancreatic cancer. Several other Cremaphor-free formulations of paclitaxel had also been evaluated in pancreatic cancer, and the reasons for the success of the albumin nanoparticulate are examined here. In the era of biologic and molecularly targeted agents, the success of nab-paclitaxel in recalcitrant pancreatic cancer is a timely reminder of the importance and relevance of pharmacology and novel drug delivery technology in the development of anticancer drugs. PMID- 23918601 TI - Relationship of mammographic density and gene expression: analysis of normal breast tissue surrounding breast cancer. AB - PURPOSE: Previous studies of breast tissue gene expression have shown that the extratumoral microenvironment has substantial variability across individuals, some of which can be attributed to epidemiologic factors. To evaluate how mammographic density and breast tissue composition relate to extratumoral microenvironment gene expression, we used data on 121 patients with breast cancer from the population-based Polish Women's Breast Cancer Study. EXPERIMENTAL DESIGN: Breast cancer cases were classified on the basis of a previously reported, biologically defined extratumoral gene expression signature with two subtypes: an Active subtype, which is associated with high expression of genes related to fibrosis and wound response, and an Inactive subtype, which has high expression of cellular adhesion genes. Mammographic density of the contralateral breast was assessed using pretreatment mammograms and a quantitative, reliable computer-assisted thresholding method. Breast tissue composition was evaluated on the basis of digital image analysis of tissue sections. RESULTS: The Inactive extratumoral subtype was associated with significantly higher percentage mammographic density (PD) and dense area (DA) in univariate analysis (PD: P = 0.001; DA: P = 0.049) and in multivariable analyses adjusted for age and body mass index (PD: P = 0.004; DA: P = 0.049). Inactive/higher mammographic density tissue was characterized by a significantly higher percentage of stroma and a significantly lower percentage of adipose tissue, with no significant change in epithelial content. Analysis of published gene expression signatures suggested that Inactive/higher mammographic density tissue expressed increased estrogen response and decreased TGF-beta signaling. CONCLUSIONS: By linking novel molecular phenotypes with mammographic density, our results indicate that mammographic density reflects broad transcriptional changes, including changes in both epithelia- and stroma-derived signaling. PMID- 23918604 TI - A pharmacogenetic predictive model for paclitaxel clearance based on the DMET platform. AB - PURPOSE: Paclitaxel is used in the treatment of solid tumors and displays high interindividual variation in exposure. Low paclitaxel clearance could lead to increased toxicity during treatment. We present a genetic prediction model identifying patients with low paclitaxel clearance, based on the drug metabolizing enzyme and transporter (DMET)-platform, capable of detecting 1,936 genetic variants in 225 metabolizing enzyme and drug transporter genes. EXPERIMENTAL DESIGN: In 270 paclitaxel-treated patients, unbound plasma concentrations were determined and pharmacokinetic parameters were estimated from a previously developed population pharmacokinetic model (NONMEM). Patients were divided into a training- and validation set. Genetic variants determined by the DMET platform were selected from the training set to be included in the prediction model when they were associated with low paclitaxel clearance (1 SD below mean clearance) and subsequently tested in the validation set. RESULTS: A genetic prediction model including 14 single-nucleotide polymorphisms (SNP) was developed on the training set. In the validation set, this model yielded a sensitivity of 95%, identifying most patients with low paclitaxel clearance correctly. The positive predictive value of the model was only 22%. The model remained associated with low clearance after multivariate analysis, correcting for age, gender, and hemoglobin levels at baseline (P = 0.02). CONCLUSIONS: In this first large-sized application of the DMET-platform for paclitaxel, we identified a 14 SNP model with high sensitivity to identify patients with low paclitaxel clearance. However, due to the low positive predictive value we conclude that genetic variability encoded in the DMET-chip alone does not sufficiently explain paclitaxel clearance. PMID- 23918603 TI - Integration of metabolomics and transcriptomics revealed a fatty acid network exerting growth inhibitory effects in human pancreatic cancer. AB - PURPOSE: To identify metabolic pathways that are perturbed in pancreatic ductal adenocarcinoma (PDAC), we investigated gene-metabolite networks with integration of metabolomics and transcriptomics. EXPERIMENTAL DESIGN: We conducted global metabolite profiling analysis on two independent cohorts of resected PDAC cases to identify critical metabolites alteration that may contribute to the progression of pancreatic cancer. We then searched for gene surrogates that were significantly correlated with the key metabolites, by integrating metabolite and gene expression profiles. RESULTS: Fifty-five metabolites were consistently altered in tumors as compared with adjacent nontumor tissues in a test cohort (N = 33) and an independent validation cohort (N = 31). Weighted network analysis revealed a unique set of free fatty acids (FFA) that were highly coregulated and decreased in PDAC. Pathway analysis of 157 differentially expressed gene surrogates revealed a significantly altered lipid metabolism network, including key lipolytic enzymes PNLIP, CLPS, PNLIPRP1, and PNLIPRP2. Gene expressions of these lipases were significantly decreased in pancreatic tumors as compared with nontumor tissues, leading to reduced FFAs. More importantly, a lower gene expression of PNLIP in tumors was associated with poorer survival in two independent cohorts. We further showed that two saturated FFAs, palmitate and stearate, significantly induced TRAIL expression, triggered apoptosis, and inhibited proliferation in pancreatic cancer cells. CONCLUSIONS: Our results suggest that impairment in a lipolytic pathway involving lipases, and a unique set of FFAs, may play an important role in the development and progression of pancreatic cancer and provide potential targets for therapeutic intervention. PMID- 23918605 TI - Long-term survival in primary glioblastoma with versus without isocitrate dehydrogenase mutations. AB - PURPOSE: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II and III gliomas, but rare in primary glioblastomas, and associated with longer survival. EXPERIMENTAL DESIGN: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival >36 months (LTS-36), including 33 patients surviving >60 months (LTS-60), with 257 patients surviving <36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques. RESULTS: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment. CONCLUSIONS: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified. PMID- 23918606 TI - Dual blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) pathways synergistically inhibits rhabdomyosarcoma cell growth in vitro and in vivo. AB - PURPOSE: To provide rationale for using phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathway inhibitors to treat rhabdomyosarcomas, a major cause of pediatric and adolescent cancer deaths. EXPERIMENTAL DESIGN: The prevalence of PI3K/MAPK pathway activation in rhabdomyosarcoma clinical samples was assessed using immunohistochemistry. Compensatory signaling and cross-talk between PI3K/MAPK pathways was determined in rhabdomyosarcoma cell lines following p110alpha short hairpin RNA-mediated depletion. Pharmacologic inhibition of reprogrammed signaling in stable p110alpha knockdown lines was used to determine the target-inhibition profile inducing maximal growth inhibition. The in vitro and in vivo efficacy of inhibitors of TORC1/2 (AZD8055), MEK (AZD6244), and P13K/mTOR (NVP-BEZ235) was evaluated alone and in pairwise combinations. RESULTS: PI3K pathway activation was seen in 82.5% rhabdomyosarcomas with coactivated MAPK in 36% and 46% of alveolar and embryonal subtypes, respectively. p110alpha knockdown in cell lines over the short and long term was associated with compensatory expression of other p110 isoforms, activation of the MAPK pathway, and cross-talk to reactivate the PI3K pathway. Combinations of PI3K pathway and MAP-ERK kinase (MEK) inhibitors synergistically inhibited cell growth in vitro. Treatment of RD cells with AZD8055 plus AZD6244 blocked reciprocal pathway activation, as evidenced by reduced AKT/ERK/S6 phosphorylation. In vivo, the synergistic effect on growth and changes in pharmacodynamic biomarkers was recapitulated using the AZD8055/AZD6244 combination but not NVP-BEZ235/AZD6244. Pharmacokinetic analysis provided evidence of drug-drug interaction with both combinations. CONCLUSIONS: Dual PI3K/MAPK pathway activation and compensatory signaling in both rhabdomyosarcoma subtypes predict a lack of clinical efficacy for single agents targeting either pathway, supporting a therapeutic strategy combining a TORC1/2 with a MEK inhibitor. PMID- 23918607 TI - TMPRSS2-ERG status is not prognostic following prostate cancer radiotherapy: implications for fusion status and DSB repair. AB - BACKGROUND: Preclinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers, may be a surrogate for DNA repair status and therefore a biomarker for DNA-damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). METHODS: Pretreatment biopsies from two cohorts of patients with intermediate risk prostate cancer [T1/T2, Gleason score (GS) < 8, prostate-specific antigen (PSA) < 20 ng/mL; >7 years follow-up] were analyzed: (i) 126 patients [comparative genomic hybridization (CGH) cohort] with DNA samples assayed by array CGH (aCGH) for the TMPRSS2-ERG fusion; and (ii) 118 patients [immunohistochemical (IHC) cohort] whose biopsy samples were scored within a defined tissue microarray (TMA) immunostained for ERG overexpression (known surrogate for TMPRSS2-ERG fusion). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir + 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using a Cox proportional hazards model. RESULTS: TMPRSS2-ERG fusion by aCGH was identified in 27 (21%) of the cases in the CGH cohort, and ERG overexpression was found in 59 (50%) patients in the IHC cohort. In both cohorts, TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analysis. CONCLUSIONS: In two similarly treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these prostate cancers have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response. PMID- 23918608 TI - A growing abdominal problem. PMID- 23918609 TI - Doctors should listen to the whole patient: don't forget the stethoscope in neurological examination. PMID- 23918610 TI - Waking up to the effects of fatigue in doctors. PMID- 23918611 TI - Use of beta blockers during surgery may have caused 10,000 deaths in the UK. PMID- 23918612 TI - Phase 2 study of a high dose of 186Re-HEDP for bone pain palliation in patients with widespread skeletal metastases. AB - (186)Re-1-hydroxyethylidene-1,1-diphosphonate (HEDP) is an attractive radiopharmaceutical for the treatment of bone pain arising from skeletal metastatic lesions. Currently, (186)Re-HEDP is most commonly used in European countries. The aim of this study was to investigate the palliative efficacy and adverse effects of (186)Re-HEDP in patients with different types of cancers and skeletal bone pain. METHODS: Nineteen (8 male, 11 female) patients with various cancers (breast, prostate, renal cell carcinoma, colon, and neuroendocrine tumors) and painful bone metastases were included in the study. A dose of 1,480 3,330 MBq (40-90 mCi) of (186)Re-HEDP was administered intravenously. The patients' level of pain relief was assessed by the Visual Analog Scale for 8 wk after treatment and by a weekly blood cell count to evaluate for hematologic toxicity. RESULTS: The overall response rate was 89.5%, and the mean pain score assessed by the Visual Analog Scale was reduced from 9.1 to 5.3 after 1 wk (P = 0.003). No adverse effects were reported by patients during intravenous administration or for up to 24 h after administration. A flare reaction was seen in 63.2% of patients, mainly during days 1-3, and lasted for 2-4 d. There was no significant correlation between the response to therapy and the flare reactions (P > 0.05). The nadir of platelet reduction occurred at the fourth or fifth week and led to platelet infusion in only 4 patients with a low baseline platelet count and diffuse skeletal metastases. Bone marrow suppression occurred in patients receiving higher doses, but no clinical problems were seen except in 2 patients who required packed cell transfusion similar to their prior transfusions. CONCLUSION: (186)Re-HEDP is an effective radiopharmaceutical for the palliative treatment of metastatic bone pain and has minimal adverse effects. PMID- 23918613 TI - Variability of total lesion glycolysis by 18F-FDG-positive tissue thresholding in lung cancer. AB - The aim of this work was to assess the variability of total lesion glycolysis (TLG) measurements in lung cancer patients, obtained with fixed percentages of the maximum standardized uptake value (SUVmax) thresholds. METHODS: Thirteen lesions (10 patients) were analyzed in 10 successive 2.5-min frames of an (18)F FDG PET dynamic acquisition obtained between 60 and 110 min after injection. (18)F-FDG-positive lesion volume, associated average SUV (SUVmean), and TLG (volume * SUVmean) were assessed in each frame using thresholds of 40%, 50%, 60%, 70%, and 80%. For each threshold, the average relative SD of TLG, leading to relative measurement error and repeatability, was calculated over the lesion series. The dependence of TLG variability on volume and SUVmean variability was also assessed. RESULTS: The average relative SD of TLG correlated strongly with threshold: 1.0866 * exp(0.0472 * threshold) (r = 0.999; P < 0.01). For the 40% threshold, average TLG over the series was 225.9 g (range, 41.7-1,086.3), relative measurement error and repeatability were 14.5%-20.4% (95% confidence interval), and no significant difference was found between TLG and volume variability. For the other thresholds, TLG variability was significantly lower or greater than volume or SUVmean variability, respectively. CONCLUSION: In current clinical practice, a formula allows quick estimation of TLG variability for any percentage of the SUVmax threshold: the higher the threshold the greater the TLG variability. PMID- 23918614 TI - Radiation public health emergencies, community resilience, and the role of nuclear medicine technologists. PMID- 23918615 TI - Adjustment of overestimated CT-based attenuation correction on bone SPECT/CT after hip-resurfacing arthroplasty. AB - SPECT/CT has made it possible to perform attenuation correction easily. However, CT-based attenuation correction (CTAC) is overestimated when metal is inside the body. The aim of this investigation was to create and test a new attenuation correction formula for CTAC that decreases the overestimation caused by an artificial femoral head and hip joint. METHODS: We tested the usefulness of the new formula in a phantom study. The phantom contained "bones" made from gypsum. The components were placed in the phantom, the point source was placed both near metal and away from metal, and the counts were compared to verify the usefulness of the new attenuation correction formula. The new formula included use of thresholds to prevent the overestimation caused by proximity to metal. RESULTS: With the standard formula, the maximum overestimation was 18% for a 22-cm artificial hip joint placed in the acetabular roof. With the new formula, using 2 thresholds, the overestimation decreased to 4%. CONCLUSION: The new attenuation correction formula helps provide more correct data in SPECT/CT examinations of patients with metallic implants. PMID- 23918616 TI - PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case-control study in a population with relatively low folate intake. AB - The PCMT1 gene encodes the protein repair enzyme protein-L-isoaspartate (D aspartate) O-methyltransferase, which is known to protect certain neural cells against Bax-induced apoptosis. Previous studies have produced inconsistent results regarding the effects of PCMT1 (rs4816 and rs4552) polymorphisms on neural tube defects (NTDs). Reduced maternal plasma folate levels and/or elevated homocysteine (Hcy) levels are considered to be risk factors for NTDs. In order to clarify the key factors contributing to the apparent discrepancy and investigate gene-environment interaction, we conducted a case-control study including 121 cases and 146 matched controls to investigate the association between the two PCMT1 polymorphisms in fetuses and the risk of NTDs in the Chinese population of Lvliang, which has low folate intake. Maternal plasma folate and Hcy levels were also measured, and the interaction between fetal PCMT1 gene status and maternal folate metabolites was assessed. Maternal plasma folate concentrations in the NTD group were lower than in controls (10.23 vs. 13.08 nmol/L, adjusted P = 0.059), and Hcy concentrations were significantly higher (14.46 vs. 11.65 MUmol/L, adjusted P = 0.026). Fetuses carrying the rs4816 AG + GG genotype, combined with higher maternal plasma Hcy, had a 6.46-fold (95 % CI 1.15-36.46) increased risk of anencephaly. The results of this study imply that the fetal PCMT1 rs4816 polymorphism may play only a weak role in NTD formation and that gene-environment interactions might be more significant. PMID- 23918617 TI - Active women before/after an intervention designed to restore menstrual function: resting metabolic rate and comparison of four methods to quantify energy expenditure and energy availability. AB - It is hypothesized that exercise-related menstrual dysfunction (ExMD) results from low energy availability (EA), defined as energy intake (EI)--exercise energy expenditure (EEE). When EI is too low, resting metabolic rate (RMR) may be reduced to conserve energy. PURPOSE: To measure changes in RMR and EA, using four methods to quantify EEE, before/after a 6-month diet intervention aimed at restoring menses in women with ExMD; eumenorrheic (Eumen) active controls (n = 9) were also measured. METHODS: Active women with ExMD (n = 8) consumed +360 kcal/d (supplement) for 6 months; RMR was measured 2 times at 0 months/6 months. EI and total energy expenditure (TEE) were estimated using 7-day diet/activity records, with EA assessed using four methods to quantify EEE. RESULTS: At baseline, groups did not differ for age, gynecological age, body weight, lean/fat mass, VO2max, EI and EA, but mean TEE was higher in ExMD (58.3 +/- 4.4 kcal/ kgFFM/d; Eumen = 50.6 +/- 2.4; p < .001) and energy balance (EB) more negative (-10.3 +/- 6.9 kcal/kgFFM/d; Eumen=-3.0 +/- 9.7; p = .049). RMR was higher in ExMD (31.3 +/- 1.8 kcal/kgFFM/d) vs. Eumen (29.1 +/- 1.9; p < .02). The intervention increased weight (1.6 +/- 2.0 kg; p = .029), but there were no significant changes in EA (0 month range = 28.2-36.7 kcal/kgFFM/d; 6-month range = 30.0-45.4; p > .05), EB (6 months = -0.7 +/- 15.1 kcal/kgFFM/d) or RMR (0 months = 1515 +/- 142; 6 months = 1522 +/- 134 kcal/d). Assessment of EA varied dramatically (~30%) by method used. CONCLUSIONS: For the ExMD group, EI and weight increased with +360 kcal/d for 6 months, but there were no significant changes in EB, EA or RMR. No threshold EA value was associated with ExMD. Future research should include TEE, EB and clearly quantifying EEE (e.g.,>4 MET) if EA is measured. PMID- 23918618 TI - Biologic agents in islet transplantation. AB - Islet transplantation is today an accepted modality for treating selected patients with frequent hypoglycemic events or severe glycemic lability. Despite tremendous progress in islet isolation, culture, and preservation, clinical use is still restricted to a limited subset, and lifelong immunosuppression is required. Issues surrounding limited islet revascularization and immune destruction remain. One of the major challenges is to prevent alloreactivity and recurrence of autoimmunity against beta-cells. These two hurdles can be effectively reduced by immunosuppressive therapy combining induction and maintenance treatments. The introduction of highly potent and selective biologic agents has significantly reduced the frequency of acute rejection and has prolonged graft survival, while minimizing the complications of this therapeutic scheme. This review will address the most important biological agents used in islet transplantation. We provide a historical perspective of their introduction into clinical practice and their role in current clinical protocols, aiming at improved engraftment efficiency, increased long-term survival, and better overall results of clinical islet transplantation. PMID- 23918620 TI - Favorable long-term outcomes of endoscopic submucosal dissection for locally recurrent early gastric cancer after endoscopic resection. AB - BACKGROUND AND STUDY AIM: Close observation after noncurative endoscopic resection for early gastric cancer (EGC) is an acceptable option if a positive horizontal margin or piecemeal resection of differentiated-type adenocarcinoma is the only noncurative factor. When locally recurrent EGC is subsequently detected, endoscopic submucosal dissection (ESD) may be performed, although only limited research has been reported regarding the outcomes. We aimed to evaluate the effectiveness, safety, and long-term clinical outcomes of ESD performed for locally recurrent EGC. PATIENTS AND METHODS: Endoscopic resection was performed in 3704 patients with a total of 4216 EGC lesions between January 1997 and December 2011 at our institution. During this period, 95 patients with 95 locally recurrent EGCs following their endoscopic resection underwent ESD performed by experts, which we retrospectively reviewed. The prior endoscopic resection procedures were endoscopic mucosal resection in 75 cases and ESD in 20. RESULTS: Of the 95 cases, en bloc resection was achieved in 90.5 %, R0 resection in 84.2 %, and curative resection in 81.1 %. Median procedure time was 70 minutes; no bleeding requiring blood transfusion was seen. There were six perforations (6.3 %), with one necessitating emergency surgery. Within a median follow-up period of 76.4 months (range, 10.5 - 170.0 months), second local recurrences occurred in three patients. Five-year overall and disease-specific survival rates were 92.8 % and 100 %, respectively. CONCLUSIONS: ESD was safe and effective with favorable long-term clinical outcomes for locally recurrent EGC following endoscopic resection. PMID- 23918619 TI - Usefulness of pancreatic duct wire-guided endoscopic papillectomy for ampullary adenoma for preventing post-procedure pancreatitis. AB - BACKGROUND AND STUDY AIMS: After endoscopic papillectomy, pancreatic duct stenting is important in preventing pancreatitis, but duct cannulation can be difficult following conventional snare resection. Pancreatic duct wire-guided endoscopic snaring before resection can reduce the post-procedure stenting failure rate. We evaluated the usefulness of this approach. PATIENTS AND METHODS: Pancreatic duct wire-guided endoscopic papillectomy was performed in 72 patients with ampullary adenoma. The snare loop was passed over a guide wire inserted into the pancreatic duct. After resection, a pancreatic stent was immediately placed along or alongside the guide wire. RESULTS: Pancreatic duct stenting was successful in all patients after endoscopic papillectomy. Post-procedure pancreatitis occurred in 6/72 (8 %), but was mild and resolved with conservative treatment. Complete endoscopic resection of ampullary adenoma was achieved in 65/72 (90 %), with en bloc resection in 60/72 (83 %). There was no procedure associated mortality. Follow-up (mean 23.7 months) showed recurrence in 5/65 (8 %) who had undergone complete resection. CONCLUSIONS: Pancreatic duct wire-guided endoscopic snare papillectomy for ampullary adenoma effectively facilitated pancreatic duct stenting to prevent severe post-procedure pancreatitis. PMID- 23918621 TI - A large-scale multicenter study of long-term outcomes after endoscopic resection for submucosal invasive colorectal cancer. AB - BACKGROUND AND STUDY AIMS: Patients with submucosal invasive colorectal cancer (SM-CRC) treated with endoscopic resection who are at low risk of lymph node metastasis and local recurrence may be followed up with observation alone, while additional surgery is recommended for those with high risk features. However, the long-term outcomes that these strategies offer are still unclear. The objective of our study was to retrospectively evaluate the long-term outcomes of patients with SM-CRC managed with endoscopic resection. PATIENTS AND METHODS: We retrospectively analyzed all patients with SM-CRC treated by endoscopic resection at six institutions between 2000 and 2007. SM-CRCs with (i) negative vertical margin, (ii) well or moderately differentiated adenocarcinoma, (iii) absence of lymphovascular invasion, and (iv) invasion depth < 1000 um were classified as low risk. Patients with SM-CRCs without these characteristics were classified as high risk. Outcomes were assessed by 5-year recurrence-free survival (RFS) and recurrence rate. RESULTS: During the study period, 428 patients with SM-CRC (low risk, 126; high risk, 302) who underwent endoscopic resection as their first treatment were enrolled (median follow-up 61 months). Among the 120 patients with low risk features treated by endoscopic resection alone, the 5-year RFS and recurrence rates were 98 % and 0.8 %, respectively. Of the 302 patients with high risk features, 196 underwent additional surgery and 106 were managed with endoscopic resection alone. For those who underwent additional surgery, the 5 year RFS and recurrence rates were 97 % and 3.6 %, respectively. Among the 106 patients managed with endoscopic resection alone, RFS and recurrence rates were 89 % (P < 0.05 vs. low risk patients treated by endoscopic resection alone) and 6.6 % (P < 0.05), respectively. CONCLUSIONS: Endoscopic resection alone is adequate for the management of patients with SM-CRC and low risk features. However, in those patients with SM-CRC and high risk features, surgery should be considered in addition to endoscopic resection. PMID- 23918622 TI - Study designs to compare new colonoscopic techniques: clinical considerations, data analysis, and sample size calculations. AB - BACKGROUND AND STUDY AIMS: Novel imaging techniques need to be evaluated for their ability to improve the detection of polyps. Critical appraisal of reported studies reveals remarkable differences in study designs, despite their similar objectives. The aim of the current study was to compare frequently used study designs for their required sample size to detect relevant differences in polyp detection rates. PATIENTS AND METHODS: Three commonly reported study designs were compared: design 1, the parallel randomized design; design 2, the randomized cross-over design with direct removal of polyps; and design 3, the randomized cross-over design without direct removal of polyps. A total of five different scenarios were analyzed per study design, representing a variety of clinical settings. Each scenario was repeated 1000 times for each study design and the sample size that produced a significant result per study design in each scenario was recorded. RESULTS: In many scenarios, study design 1 required 10-15 times more patients to reach the same statistical power of 80% compared with study design 2. Further reductions in sample size could be achieved when study design 3 was used, although this design is limited by its impracticality. CONCLUSIONS: The randomized parallel design requires a larger sample size to achieve equivalent power to the cross-over design. Researchers should carefully consider whether the latter design could be used instead, as it requires a lower number of subjects, although it may be more cumbersome for patients, endoscopists, and researchers. PMID- 23918623 TI - Hearing preservation and speech perception outcomes with electric-acoustic stimulation after 12 months of listening experience. AB - OBJECTIVES/HYPOTHESIS: To report on single-center data of an FDA-approved clinical trial on the objective benefits of cochlear implantation and subsequent ipsilateral Electric-Acoustic Stimulation (EAS). STUDY DESIGN: Single-center data from a prospective, multicenter clinical trial. METHODS: Eighteen subjects completed the 12-month EAS evaluation and were included in this evaluation. Each patient underwent cochlear implantation using a standardized hearing preservation approach. Both hearing preservation and speech perception abilities were evaluated at various intervals. Speech testing included performance measures obtained in quiet (CNC words) and noise (adaptive CUNY protocol) in three listening conditions: hearing aid (HA) alone, cochlear implant (CI) only, and combined ipsilateral EAS. RESULTS: Various levels of hearing preservation were achieved with cochleostomy and round-window surgical approaches in 17 of the 18 subjects. Mean CNC word scores at the 12-month interval were 14.9 +/- 12.1, 45.3 +/- 15.4, and 70.7 +/- 11.7% correct in the HA only, CI only, and EAS conditions, respectively. Average CUNY scores at 0 dB SNR were 14.6 +/- 17.2, 47.1 +/- 22.1, and 72.2 +/- 21.5 for the three test conditions obtained after 12 months. CONCLUSIONS: Data obtained during this clinical trial correlate well with previous reports. Hearing preservation appears successful in a high number of subjects, and combined EAS offers excellent speech perception abilities in quiet and in noise. LEVEL OF EVIDENCE: 4. PMID- 23918624 TI - Second harmonic microscopic imaging and spectroscopic characterization in prostate pathological tissue. AB - Second harmonic microscopic imaging and spectroscopy technology has become a powerful tool for biomedical studies, especially in cancer research. In this paper, second harmonic generation in benign prostatic hyperplasia (BPH) and prostate cancer (PC) tissues in mouse model (C57BL6) have been reported. Excitated samples with different wavelength near-infrared laser from 780 to 850 nm we found that second harmonic signals from BPH nuclei stronger than that from PC, and a wavelength sensitivity was also observed in this experiment. Providing useful help for prostate malignancy diagnosis and identifying tissue components on clinic. PMID- 23918625 TI - Unprecedented electron-poor octahedral Ta(6) clusters in a solid-state compound: synthesis, characterisations and theoretical investigations of Cs(2)BaTa(6)Br(15)O(3). AB - The crystal structure of Cs2BaTa6Br15O3 has been elucidated by using synchrotron X-ray powder diffraction and absorption experiments. It is built from edge bridged octahedral [(Ta6Bri9Oi3)Bra6]4- cluster units with a singular poor metallic electron (ME) count equal to thirteen. This leads to a paramagnetic behaviour related to one unpaired electron. The arrangement of the Ta6 clusters is similar to that of Cs2LaTa6Br15O3 exhibiting 14-MEs per [(Ta6Bri9Oi3)Bra6]5- motif. The poorer electron-count cluster presents longer metal-metal distances as foreseen according to the electronic structure of edge-bridged hexanuclear cluster. Density functional theory (DFT) calculations on molecular models were used to rationalise the structural properties of 13- and 14-ME clusters. Periodic DFT calculations demonstrate that the electronic structure of these solid-state compounds is related to those of the discrete octahedral units. Oxygen-barium interactions seem to prevent the geometry of the octahedral cluster to strongly distort, allowing stabilisation of this unprecedented electron-poor Ta6 cluster in the solid state. PMID- 23918626 TI - Development of fragment-based n-FABS NMR screening applied to the membrane enzyme FAAH. AB - Despite the recognized importance of membrane proteins as pharmaceutical targets, the reliable identification of fragment hits that are able to bind these proteins is still a major challenge. Among different 19F NMR spectroscopic methods, n fluorine atoms for biochemical screening (n-FABS) is a highly sensitive technique that has been used efficiently for fragment screening, but its application for membrane enzymes has not been reported yet. Herein, we present the first successful application of n-FABS to the discovery of novel fragment hits, targeting the membrane-bound enzyme fatty acid amide hydrolase (FAAH), using a library of fluorinated fragments generated based on the different local environment of fluorine concept. The use of the recombinant fusion protein MBP FAAH and the design of compound 11 as a suitable novel fluorinated substrate analogue allowed n-FABS screening to be efficiently performed using a very small amount of enzyme. Notably, we have identified 19 novel fragment hits that inhibit FAAH with a median effective concentration (IC50) in the low mM-MUM range. To the best of our knowledge, these results represent the first application of a 19F NMR fragment-based functional assay to a membrane protein. PMID- 23918627 TI - What is chosen first, the hand used for reaching or the target that is reached? AB - Models of information processing generally assume that stimuli are processed before actions are selected, at least in typical laboratory experiments where stimuli are presented and responses follow. In everyday life, however, there are generally fewer constraints on the ordering of decisions pertaining to stimuli and actions. This raises the question of which sorts of decisions normally precede which others. To address this question, we asked participants to aim for either of two targets with either hand on the basis of whichever combination seemed easiest. We analyzed the choices made in this free condition with choices made when the hand was specified or when the target was specified. We found that a model assuming similar selection processes in the hand-specified condition and the free condition provided the best account for the data. The data accord with the hypothesis that hand was generally chosen first in the free-choice condition. PMID- 23918628 TI - Erratum to: Changes in specialists' perspectives on cancer genetic testing, prophylactic surgery and insurance discrimination: then and now. AB - Erratum to: J Genet Counsel DOI 10.1007/s10897-013-9625-z . In the "Funding" section, the company HRA was incorrectly referred to as HSR. The full name of the company is "HRA- Healthcare Research & Analytics." PMID- 23918629 TI - Use of the lymphocyte count as a diagnostic screen in adults with suspected Epstein-Barr virus infectious mononucleosis. AB - OBJECTIVES/HYPOTHESIS: To evaluate the predictive diagnostic accuracy of the lymphocyte count in Epstein-Barr virus-related infectious mononucleosis (IM). STUDY DESIGN: Retrospective case note and blood results review within a university-affiliated teaching hospital. METHODS: A retrospective review of 726 patients undergoing full blood count and Monospot testing was undertaken. Monospot testing outcomes were compared with the lymphocyte count, examining for significant statistical correlations. RESULTS: With a lymphocyte count of <=4 * 10(9) /L, 99% of patients had an associated negative Monospot result (sensitivity of 84% and specificity of 94%). A group subanalysis of the population older than 18 years with a lymphocyte count <=4 * 10(9) /L revealed that 100% were Monospot negative (sensitivity of 100% and specificity of 97%). A lymphocyte count of <=4 * 10(9) /L correlated significantly with a negative Monospot result. CONCLUSIONS: A lymphocyte count of <=4 * 10(9) /L appears to be a highly reliable predictor of a negative Monospot result, particularly in the population aged >18 years. Pediatric patients, and adults with strongly suggestive symptoms and signs of IM, should still undergo Monospot testing. However, in adults with more subtle symptoms and signs, representing the vast majority, Monospot testing should be restricted to those with a lymphocyte count >4 * 10(9) /L. LEVEL OF EVIDENCE: NA PMID- 23918631 TI - Co-occurrence of 22q11 deletion syndrome and HDR syndrome. AB - 22q11 deletion syndrome is one of the most common chromosomal deletion syndromes and is usually caused by a 1.5-3.0 Mb deletion at chromosome 22q11.2. It is characterized by hypocalcemia resulting from hypoplasia of the parathyroid glands, hypoplasia of the thymus, and defects of the cardiac outflow tract. We encountered a Japanese boy presenting with an unusually severe phenotype of 22q11 deletion syndrome, including progressive renal failure and severe intellectual disabilities. Diagnostic testing using fluorescent in situ hybridization revealed deletion of the 22q11 region, but this did not explain the additional complications. Copy number analysis was therefore performed using whole genome single nucleotide polymorphism (SNP) assay, which identified an additional de novo deletion at 10p14. This region is the locus for hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome caused by haploinsufficiency of GATA3. Together, these two syndromes sufficiently explain the patient's phenotype. This is the first known case report of the co-occurrence of 22q11 deletion syndrome and HDR syndrome. As the two syndromes overlap clinically, this study indicates the importance of carrying out careful clinical and genetic assessment of patients with atypical clinical phenotypes or unique complications. Unbiased genetic analysis using whole genome copy number SNP arrays is especially useful for detecting such rare double mutations. PMID- 23918632 TI - Comparison between conidia and blastospores of Esteya vermicola, an endoparasitic fungus of the pinewood nematode, Bursaphelenchus xylophilus. AB - Esteya vermicola, an endoparasitic fungus of Bursaphelenchus xylophilus, the pinewood nematode (PWN), exhibits great potential as a biological control agent against this nematode. E. vermicola produces blastospores in liquid media and aerial conidia on solid media. The agent was mass-produced using two kinds of culture media: S (50 % wheat bran and 50 % pine wood powder), L (0.5 g wheat bran and 0.5 g pinewood powder in 200 ml of potato dextrose broth), and two controls: SC (potato dextrose agar), LC (potato dextrose broth). Yields, multiple stress tolerance, storage life, new generation conidial number, and PWN mortality rates of the spores were measured in each of these four media and compared. The spore yields, new generation conidial number, and nematode mortality rates of blastospores were higher than those of conidia. Nevertheless, the conidia had a higher germination rate than the blastospores during the storage process and multiple stress treatments. Considering the number of spores surviving from the process of the storage and multiple stress treatments per unit of mass media, the blastospores from L survived most. Comprehensive analysis indicates that the L culture medium is the most optimal medium for mass production relatively. PMID- 23918630 TI - Diagnosing and characterizing coronary artery disease in women: developments in noninvasive and invasive imaging techniques. AB - Cardiovascular disease is the leading cause of death in men and women in the USA; yet, coronary artery disease (CAD) continues to be underrecognized and underdiagnosed in women. Noninvasive and invasive imaging techniques are constantly being developed in order to more accurately assess CAD. At the same time, the impact of gender on the interpretation and accuracy of these studies is still being elucidated. Furthermore, new imaging techniques have improved our understanding of CAD pathophysiology and progression and have begun to reveal gender differences in the development of CAD. This article will review current imaging techniques and their application to diagnosing and understanding CAD in women. PMID- 23918633 TI - Primer evaluation and adaption for cost-efficient SYBR Green-based qPCR and its applicability for specific quantification of methanogens. AB - In the present study nine promising primer sets, targeting Archaea and methanogenic Archaea in particular, were evaluated in silico, in vitro and in situ concerning specificity, accuracy and applicability in end-point (ep-) and especially quantitative (q-)PCR research. The main goal was to adapt and evaluate already adapted primer sets, which were partially designed in combination with TaqMan probes, in substantially cheaper SYBR Green-based qPCR applications. An initial 16S rRNA gene bank-based in silico evaluation revealed high coverage potentials for all primers within targeted groups, ranging from 71 to 90%, except the Methanosaeta specific set showing a low potential of 37%. Mentionable cross reacting potentials could be detected for the Methanothermobacter, Methanomicrobiales and Methanoculleus sets. The in vitro evaluation with selected reference organisms revealed a specific behavior for most primer sets, while the Methanosarcina and Methanothermobacter sets showed most problematic cross reactions in epPCR application. We were able to show that primers for detecting the total archaeal community, methanogenic orders Methanosarcinales, Methanobacteriales, Methanococcales and the genus Methanoculleus performed in a highly specific way and allowed an accurate quantification of targeted organisms without the use of expensive TaqMan probes. However, primer pairs designed for detecting Methanomicrobiales, Methanothermobacter, Methanosarcina and Methanosaeta are not suitable for SYBR Green applications. The reliability of in situ quantifications was assessed for a typical methanogenic community, derived from a thermophilic fermenter, and confirmed via denaturing gradient gel band quantification and sequencing. Thereby, we revealed high abundances of methanogenic Archaea, mainly comprising Methanoculleus and Methanosarcinales, while Methanobacteriales only formed a minor fraction. PMID- 23918634 TI - 2-Ureido-4-pyrimidone-based hydrogels with multiple responses. AB - Functionalisation of poly[2-(dimethylamino)ethyl methacrylate] (a responsive methacrylate) with light-activatable 2-ureido-4-pyrimidone units allows a supramolecular hydrogel to be obtained that combines temperature, light and pH response with self-healing properties. Whereas the self-healing properties of this system were described previously, this report focuses on its response to different external stimuli, which is studied by quartz crystal microbalance analysis of thin films of the material. Reversible collapse with increasing temperature, reversible swelling with decreasing pH and irreversible shrinkage with UV exposure are demonstrated. These three stimuli are combined to have externally gated or tuned responses. Thermo-induced swelling and shrinkage can be reversibly inhibited by changing the pH and irreversibly regulated by exposure to light of different doses. These materials represent the first general strategy to obtain responsive self-healing hydrogels in which the response and the self healing properties are decoupled from each other and can be tuned independently. PMID- 23918635 TI - Dietary regimens of athletes competing at the Delhi 2010 Commonwealth Games. AB - The aim of this study was to investigate the dietary regimens reported by athletes competing at a major international competition and report whether these were based on nutrient composition, religious beliefs, cultural eating style, food intolerance or avoidance of certain ingredients. A questionnaire was randomly distributed to 351 athletes in the main dining hall of the athletes' village over the three main meal periods during the Delhi 2010 Commonwealth Games (23rd Sept-14th Oct, 2010). The majority (n = 218, 62%) of athletes reported following one or more dietary regimens, with 50% (n = 174) following a diet based on the nutrient composition of the food. Significantly more athletes from weight category and aesthetic sports (28%, p = .005) and from power/sprint sports (41%, p = .004) followed low fat and high protein regimens respectively. Other specialized dietary regimens were followed by 33% of participants, with avoidance of red meat (13%), vegetarian (7%), Halal (6%), and low lactose regimens (5%) reported most frequently. Significantly more athletes from non-Western regions followed a vegetarian diet (p < .001), while more vegetarians reported avoiding additives (p = .013) and wheat (p <= .001). A Western style of eating was the most commonly reported cultural regimen (72% of total with 23% from non-Western regions). Those following a Western diet were significantly more likely to report following a regimen based on nutrient composition (p = .02). As a high proportion of athletes from differing countries and sports follow specialized dietary regimens, caterers and organizers should ensure that adequate nutrition support and food items are available at similar events. PMID- 23918636 TI - Ethnic-specific genetic analyses in rheumatoid arthritis: incremental gains but valuable contributions to the big picture. PMID- 23918637 TI - Effects of tadalafil on ischemia/reperfusion injury in rat brain. AB - Cerebral ischemia-reperfusion (I/R) injury is caused by lack of blood supply to the brain. The accumulation of toxic products such as reactive oxygen species (ROS) occurs on reperfusion, when the occlusion is removed. The resulting oxidative stress results in the initiation of pathways leading to necrotic and apoptotic cell death. Tadalafil (TAD) prevents the accumulation of ROS and increases antioxidant cellular protective mechanisms. The aim of this study was to investigate the effect of TAD treatment against short-term global brain I/R injury in rats. The study was carried out on 30 Wistar-albino rats, which were divided into three groups including a control group (n = 10), an I/R group (n = 10) and an I/R + TAD group (n = 10) (2 mg/kg/day for 4 days before ischemia). At the end of the experiment, tissue samples were collected for both biochemical and histopathological analyses. Malondialdehyde was significantly lower in the TAD administered group (9.06 +/- 0.15) than in the I/R group (p < 0.05). However, no significant difference was observed in nitric oxide levels in the TAD administered group compared to the I/R group. The mean superoxide dismutase level was significantly higher in the I/R-TAD group than the I/R group. There was no statistically significant difference in glutathione peroxidase levels in I/R + TAD group compared to I/R group. Histopathologically, TAD-administered group provided significant morphological improvement compared to the I/R group. We concluded that TAD prevented I/R-induced neurotoxicity as shown by obtained biochemical and histopathological findings. PMID- 23918640 TI - Seizures after decompressive hemicraniectomy for ischaemic stroke. AB - OBJECTIVE: The risk of seizures after malignant middle cerebral artery (MCA) infarction with decompressive hemicraniectomy (DHC) is uncertain. Also unknown is how this complication influences survivors' recovery and quality of life. METHODS: We retrospectively reviewed medical charts of all patients admitted to Harborview Medical Center between 1 January 2002 and 31 June 2011 for space occupying MCA ischaemic stroke and who underwent DHC. Survivors and their surrogates were invited to participate in a telephone or in-person interview. RESULTS: Fifty-five patients were followed for a median of 311 days (IQR 134 727). Twenty-seven patients (49%) had seizures, 25 (45%) developed epilepsy and 21 (38%) achieved moderate disability or better (modified Rankin Scale score <=3) by 1 year after stroke onset. The only factor significantly associated with seizure occurrence was male gender. Median time from stroke to first seizure was 222 days, with a cluster of first seizures within weeks after cranioplasty; only two of the first seizures occurred right around the time of stroke onset. Follow up time was significantly longer for patients with seizures (605 days, IQR 297 882) than for those without (221 days, IQR 104-335). Of the 20 patients interviewed, 12 achieved moderate disability or better, 15 experienced a seizure with 6 indicating the seizure was a major drawback. Regardless, all 20 would have chosen DHC again. CONCLUSIONS: In this case series, patients were at high risk of developing seizures after malignant MCA stroke with DHC, especially after cranioplasty. Assuming these findings are replicated, means should be sought to reduce the occurrence of this complication. PMID- 23918641 TI - The endoscopic approach to a fourth branchial pouch sinus presenting in an adult. AB - Fourth branchial complex anomalies are rare and typically present in neonates or adolescents. Surgical management via open excision is the traditional approach to prevent recurrence. However, endoscopic sinus cauterization has recently been reported as a less invasive alternative. The current case report represents the first published account of a fourth branchial pouch presenting in an adult patient effectively managed through endoscopic excision. We compare this method to open excision and endoscopic ablative techniques. PMID- 23918643 TI - Influence of perfluorinated end groups on the SFRD of [Pt(cod)Me(C(n)F(2n+1))] onto porous Al(2)O(3) in CO(2) under reductive conditions. AB - The optimized synthesis of a range of cyclooctadiene-stabilized Pt complexes that contained different perfluoro-alkane chains, [Pt(cod)Me(Cn F2n+1 )], is presented. These metal-organic compounds were employed in the so-called supercritical fluid reactive deposition (SFRD) in CO2 under reductive conditions to generate metallic nanoparticles on aluminum oxide as a porous support. Thus, Al2 O3 -supported Pt nanoparticles with a narrow particle-size distribution were obtained. At a reduction pressure of 15.5 MPa and a temperature of 353 K, particle diameters of d50 =2.3-2.8 nm were generated. Decreasing the pressure during the reduction reaction led to slightly larger particles whilst decreasing the amount of organometallic precursor in CO2 yielded a decrease in the particle size from x50 =3.2 nm to 2.6 nm and a particle-size distribution of 2.2 nm. Furthermore, substitution of the CH3 end group by the Cn F2n+1 end groups led to a significant drop in Pt loading of about 50 %. Within the series of perfluorinated end groups that were considered, the Pt complex that contained a branched perfluoro-isopropyl group showed the most-interesting results when compared to the control precursor, [Pt(cod)Me2 ] (1). PMID- 23918642 TI - Acute heart failure: patient characteristics and pathophysiology. AB - The number of hospitalizations for acute heart failure (HF) continues to increase and it remains the most common discharge diagnosis among Medicare beneficiaries. Prognosis after hospitalization for HF is poor, with high in-hospital mortality and even higher post-discharge mortality and rehospitalization rates. It is a complex clinical syndrome that varies widely with respect to clinical presentation and underlying pathophysiology. This paper reviews what is documented in the literature regarding the known pathophysiologic mechanisms reported in patients hospitalized for HF. PMID- 23918644 TI - Development of a new method using narrow band imaging for taste assessment. AB - OBJECTIVES/HYPOTHESIS: The observation of fungiform papillae is a useful objective taste examination. The purpose of this study is to develop a new method using narrow band imaging for assessment of taste function. STUDY DESIGN: Using a narrow band imaging endoscope, we assessed the number and blood vessel morphology of fungiform papillae and compared with the gustatory threshold by the filter paper disc test. METHODS: The number of fungiform papillae was counted in 20 mm(2) , and blood vessels in fungiform papillae were evaluated morphologically by a five-point scoring system in 11 patients who had undergone middle ear surgery. The filter taste disc test was performed simultaneously to obtain the gustatory threshold and was compared with the number and blood vessel morphology of fungiform papillae. RESULTS: Using a narrow band imaging endoscope, we could clearly detect not only fungiform papillae but also blood vessel morphology. There was a significant correlation between the values of the number of papillae and blood vessel morphology. Moreover, these two parameters revealed a significant inverse correlation with gustatory function. As expected, both parameters on the affected side were significant lower than those on the unaffected side in patients. CONCLUSIONS: The assessment of fungiform papillae using narrow band imaging endoscopy is easy, highly sensitive, and reliable; therefore, it might be useful as an objective examination of taste function. LEVEL OF EVIDENCE: N/A. PMID- 23918645 TI - Beyond demographics: differences in patient activation across new immigrant, diverse language subgroups. AB - The federal government promotes "patient-centered medical homes" to plan care with respect to patients' cultures and values and support patients' self-care efforts. To promote self-care, the medical home would be best utilized by activated, engaged patients. The objective of this study was to measure and compare patient activation scores in English-, Spanish-, and Haitian Creole speaking patients seen at an inner-city hospital ambulatory care practice. Patient activation was measured using the patient activation measure (PAM). Mean PAM scores and activation levels differed according to survey language (p < 0.001). US-born participants had higher mean PAM scores than persons born outside of the US. Participants living in the US longer had higher mean PAM scores than participants newer to the US. Levels of activation and mean PAM scores increased with greater comfort reading, speaking, and thinking in English. The mean PAM (SD) score of 61.5 (16.5) for Haitian Creole-speaking Caribbean Blacks was significantly lower than the mean PAM score of 68.8 (15.6) for English-speaking Caribbean Blacks (p value = 0.006). Although mean PAM scores did not significantly differ between Haitian Creole and Spanish speakers, PAM stages differed according to language of survey completion (p < 0.001), with a greater percentage of Haitian Creole speakers being categorized as stage 1 (least activated) as well as stage 4 (most activated). Spanish and Haitian Creole speakers have lower mean PAM scores than English speakers. Mean PAM scores did not differ between Hispanics and non-Hispanics or according to race, illustrating the need to examine the role of language and culture on patient activation. PMID- 23918646 TI - Synthesis and negative inotropic effects evaluation of 7-substituted-4,5-dihydro [1,2,4]oxadiazolo[4,3-a]quinolin-1-ones. AB - A series of 7-alkoxy-4,5-dihydro-[1,2,4]oxadiazolo[4,3-a]quinolin-1-ones was synthesized and their negative inotropic effects were evaluated by measuring the left atrium stroke volume in isolated rabbit heart preparations. All compounds moderated the cardiac workload by decreasing heart rate and contractility (inotropic effects). Among them, compound 6 was found to be best potent with a 28.89 +/- 1.91 % decrease in the stroke volume at a concentration of 3 * 10(-5) M in our in vitro study. PMID- 23918647 TI - A cross-sectional study of factors related to gastrointestinal drug use in Korean adolescents. AB - Adolescence is critical in the habituation of diverse lifestyles and is a base for future physical well-being. Although gastrointestinal disorders are frequently reported in adolescents, studies related to GI drug use or related factors in Korean adolescents are rare. Thus, this study examined Korean adolescents for the use of GI drugs for abdominal symptoms and analyzed the associated factors. This cross-sectional study was done with a total of 2,416 students who completed a given questionnaire. The health-related questions included GI medication intake, smoking, alcohol, caffeine, regular exercise, self cognitive health level, GI symptom, non-steroidal anti-inflammatory drugs (NSAIDs) intake, and sleep problems. In questions about GI medication intake, drugs included digestives and antacids. And the intake of GI drugs more than once during the past 1 month was regarded as taking GI drugs. The sociodemographic questions included age, gender, grade, number of close friends, extracurricular activities, and school performance. The overall prevalence for taking GI drugs, including antacids and digestives, was 17.4 %. When students taking GI drugs were compared with those not taking GI drugs, the former group showed higher rates of girls (P < 0.001) and participants in extracurricular activities (P < 0.05) than the latter group. Factors including alcohol, caffeine, self-cognitive health levels, and GI symptoms showed statistical significance with the rate of GI drug intake. The rate of GI drug intake in NSAID users was 2.7 times higher than that in non-users (P < 0.001). The prevalence rate of every sleep problem was higher in students taking GI medications except snoring, witnessed apnea, and teeth grinding. From the multiple regression, it was found that gender (female), extracurricular activities, alcohol intake, self-cognitive health levels, NSAIDs intake, and nightmares were related factors to GI drug intake. Based on the results, it was conclude that encouragement to build healthy lifestyle habits in adolescents is very important for their academic performances and health status in adulthood. PMID- 23918648 TI - Ginsenoside Rc modulates Akt/FoxO1 pathways and suppresses oxidative stress. AB - Ginsenoside Rc (Rc), a protopanaxadiol type ginsenoside, is the active component mainly responsible for the therapeutic and pharmacologic properties of ginseng, which are derived from its suppression of superoxide-induced free radicals. Forkhead box O (FoxO1) regulates various genes involved in cellular metabolism related to cell death and response to oxidative stress, and Rc is known to prevent FoxO1 phosphorylation by activation of PI3K/Akt and subsequent inhibition of AMP-activated protein kinase (AMPK) in cells exposed to tert butylhydroperoxide (t-BHP). In the current study, we attempted the mechanism of increased catalase expression by Rc through inhibition of FoxO1 activation resulting from t-BHP-induced production of reactive species (RS). We found that overexpression of catalase induced by Rc resulted in suppression of RS production in kidney human embryo kidney 293T cells (HEK293T) cells, and that oxidative stress induced activation of PI3K/Akt and inhibition of the AMPK pathway and FoxO1 phosphorylation, leading to down-regulation of catalase, a FoxO1-targeting gene. In addition, treatment of HEK293T cells with Rc resulted in cAMP-response element-binding protein (CREB)-binding protein (CBP) regulated FoxO1 acetylation. Our results suggest that Rc modulates FoxO1 phosphorylation through activation of PI3K/Akt and inhibition of AMPK and FoxO1 acetylation through interaction with CBP and SIRT1, and that this leads to upregulation of catalase under conditions of oxidative stress. PMID- 23918649 TI - New leads for DPP IV inhibition: structure-based pharmacophore mapping and virtual screening study. AB - Dipeptidyl peptidase IV (DPP IV) is an attractive target for the development of new antidiabetic drugs. DPP IV inhibitors improve glycemic control by preventing the rapid inactivation of the incretin hormones; glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide. In the current study, virtual screening, using 2D and 3D filters implemented in a hierarchical cascade, was employed to identify new DPP IV inhibitors. Co-crystallized ligands, with potent DPP IV-inhibitory activities, were utilized to generate structure-based pharmacophore models using DS Visualizer software. The derived pharmacophore maps were validated using in-house built database containing active and inactive DPP IV inhibitors. Subsequently, the optimum validated pharmacophore model was used as a search query against two 3D-databases (NCI and in-house built drug databases). Further hit filtration was carried out employing 2D virtual filters based on Lipinski's rule of 5; number of rotatable bonds and other physicochemical filters. 3D filter using high-throughput molecular docking was also applied. As a result, 5 novel DPP IV inhibitors were discovered as potential lead compounds and later confirmed via in vitro bioassay. PMID- 23918650 TI - Screening of multiple drugs of abuse and metabolites in urine using LC/MS/MS with polarity switching electrospray ionization. AB - A recent trend in urine drug testing in forensic and clinical toxicology has been the simultaneous determination of different chemical groups of target drugs, which are selected based on their local popularity. Rapid multiple drug analysis, made possible by the use of liquid chromatography-tandem mass spectrometry (LC/MS/MS), has become more widely used, especially in workplace drug testing. Therefore, in the present study, a method for simultaneously analyzing 35 drugs of abuse and relevant metabolites that are most prevalent in Korea, using LC/MS/MS with polarity switching electrospray ionization, was developed and validated. The drugs and metabolites in urine were extracted by using mixed mode strong cation exchange polymeric solid phase extraction cartridges after enzymatic hydrolysis and were then injected into the LC/MS/MS system. The validation results for selectivity, linearity, intra- and inter-assay precision and accuracy for this method were satisfactory, while the results for matrix effects and recovery showed significant variance among the urine samples from different sources. The limits of detection ranged from 0.1 to 10 ng/ml and the limits of quantification were from 1 to 10 ng/ml. To reduce the matrix effects in authentic samples, two different quantitative approaches were compared: quantification using calibration standards prepared by the drug-free pooled urine matrix and quantification using the standard addition. Of these, the latter method was found to be the most suitable. The method developed in this study will be very useful for forensic and clinical toxicology laboratories to adopt for monitoring the inappropriate use of controlled drugs. PMID- 23918651 TI - Inhibition of mitotic clonal expansion mediates fisetin-exerted prevention of adipocyte differentiation in 3T3-L1 cells. AB - Adipocytes are the key player in adipose tissue inflammation and subsequent systemic insulin resistance and its development involves complex process of proliferation and differentiation of preadipocytes. Fistein, a polyphenol flavonoid, is known to exert anti-inflammatory, anti-carcinogenic and anti diabetic effects. In this study, we aimed to investigate the effect of fisetin on adipocyte proliferation and differentiation in 3T3-L1 preadipocyte cell line and its mechanism of action. We found that fisetin inhibits adipocyte differentiation in a concentration dependent manner, which were evidenced by Oil Red O staining and the protein expression of mature adipocyte marker genes fatty acid synthase and peroxisome proliferator-activated receptor gamma. Moreover, the proliferation of preadipocytes was also markedly suppressed by treatment of fisetin for 24 and 48 h in the differentiation medium. We also found that fisetin inhibition of adipocyte differentiation was largely due to the effect on mitotic clonal expansion. Fisetin suppression of preadipocyte proliferation at early stage of differentiation was accompanied by the changes of expression of a series of cell cycle regulatory proteins. Altogether, our results suggest that the inhibition of adipocyte differentiation by fisetin may be at least in part mediated by cell cycle arrest during adipogenesis. PMID- 23918652 TI - Blue toes and a new pair of shoes--challenges in diagnosis and treatment of acute myelogenous leukemia. PMID- 23918653 TI - Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure. AB - The NR5A1 gene encodes for steroidogenic factor 1, a nuclear receptor that regulates proper adrenal and gonadal development and function. Mutations identified by NR5A1 sequencing have been associated with disorders of sex development (DSD), ranging from sex reversal to severe hypospadias in 46,XY patients and premature ovarian failure (POF) in 46,XX patients. Previous reports have identified four families with a history of both 46,XY DSD and 46,XX POF carrying segregating NR5A1 sequence mutations. Recently, three 46,XY DSD sporadic cases with NR5A1 microdeletions have been reported. Here, we identify the first NR5A1 microdeletion transmitted in a pedigree with both 46,XY DSD and 46,XX POF. A 46,XY individual with DSD due to gonadal dysgenesis was born to a young mother who developed POF. Array CGH analysis revealed a maternally inherited 0.23 Mb microdeletion of chromosome 9q33.3, including the NR5A1 gene. Based on this finding, we screened patients with unexplained 46,XY DSD (n = 11), proximal hypospadias (n = 21) and 46,XX POF (n = 36) for possible NR5A1 copy-number variations (CNVs) via multiplex ligation-dependent probe amplification (MLPA), but did not identify any additional CNVs involving NR5A1. These data suggest that NR5A1 CNVs are an infrequent cause of these disorders but that array CGH and MLPA are useful genomic screening tools to uncover the genetic basis of such unexplained cases. This case is the first report of a familial NR5A1 CNV transmitting in a pedigree, causing both the male and female phenotypes associated with NR5A1 mutations, and the first report of a NR5A1 CNV associated with POF. PMID- 23918654 TI - Dual-modality micro-positron emission tomography/computed tomography and near infrared fluorescence imaging of EphB4 in orthotopic glioblastoma xenograft models. AB - PURPOSE: In glioblastoma, EphB4 receptors, a member of the largest family of receptor tyrosine kinases, are overexpressed in both tumor cells and angiogenic blood vessels. The purpose of this study was to examine whether the EphB4-binding peptide TNYL-RAW labeled with both (64)Cu and near-infrared fluorescence dye Cy5.5 could be used as a molecular imaging agent for dual-modality positron emission tomography/computed tomography [PET/CT] and optical imaging of human glioblastoma in orthotopic brain tumor models. MATERIALS AND METHODS: TNYL-RAW was conjugated to Cy5.5 and the radiometal chelator 1,4,7,10-tetraazadodecane N,N',N",N'''-tetraacetic acid. The conjugate was then labeled with (64)Cu for in vitro binding and in vivo dual MUPET/CT and optical imaging studies in nude mice implanted with EphB4-expressing U251 and EphB4-negative U87 human glioblastoma cells. Tumors and brains were removed at the end of the imaging sessions for immunohistochemical staining and fluorescence microscopic examinations. RESULTS: MUPET/CT and near-infrared optical imaging clearly showed specific uptake of the dual-labeled TNYL-RAW peptide in both U251 and U87 tumors in the brains of the nude mice after intravenous injection of the peptide. In U251 tumors, the Cy5.5 labeled peptide colocalized with both tumor blood vessels and tumor cells; in U87 tumors, the tracer colocalized only with tumor blood vessels, not with tumor cells. CONCLUSIONS: Dual-labeled EphB4-specific peptide could be used as a noninvasive molecular imaging agent for PET/CT and optical imaging of glioblastoma owing to its ability to bind to both EphB4-expressing angiogenic blood vessels and EphB4-expressing tumor cells. PMID- 23918655 TI - Probing charge transfer in benzodifuran-C60 dumbbell-type electron donor-acceptor conjugates: ground- and excited-state assays. AB - Rigid electron donor-acceptor conjugates (1-3) that combine pi-extended benzodifurans as electron donors and C60 molecules as electron acceptors with different linkers have been synthesized and investigated with respect to intramolecular charge-transfer events. Electrochemistry, fluorescence, and transient absorption measurements revealed tunable and structure-dependent charge transfer processes in the ground and excited states. Our experimental findings are underpinned by density-functional theory calculations. PMID- 23918656 TI - The effects of beta-alanine supplementation on performance: a systematic review of the literature. AB - PURPOSE: To critically review the methodological quality and synthesize information from systematic reviews and high quality studies on the effects of beta alanine (BA) on exercise and athletic performance. METHODS: A search strategy was developed in accordance with the standards for the reporting of scientific literature via systematic reviews. Five databases were thoroughly searched from inception to November 2012. Inclusion criteria were English language, human studies, used BA to increase exercise or athletic performance, systematic reviews or randomized controlled trials and were published in a peer reviewed journal. Included studies were systematically graded for their methodological quality by rotating pairs of reviewers and the results were qualitatively synthesized. RESULTS: One systematic review and 19 randomized trials were included in this review. There is one systematic review with several methodological weaknesses that limit the confidence in its results. There are moderate to high quality studies that appear to support that BA may increase power output and working capacity, decrease the feeling of fatigue and exhaustion, and have of positive effect on body composition and carnosine content. The reporting of side effects from BA supplementation in the athletic population was generally under-reported. CONCLUSIONS: There appears to be some evidence from this review that supplementation with BA may increase athletic performance. However, there is insufficient evidence examining the safety of BA supplementation and its side effects. It is therefore recommended to err on the side of caution in using BA as an ergogenic aid until there is sufficient evidence confirming its safety. PMID- 23918657 TI - Transient receptor potential ankyrin 1 receptor stimulation by hydrogen peroxide is critical to trigger pain during monosodium urate-induced inflammation in rodents. AB - OBJECTIVE: Gout is a common cause of inflammatory arthritis and is provoked by the accumulation of monosodium urate (MSU) crystals. However, the underlying mechanisms of the pain associated with acute attacks of gout are poorly understood. The aim of this study was to evaluate the role of transient receptor potential ankyrin 1 (TRPA-1) and TRPA-1 stimulants, such as H2 O2 , in a rodent model of MSU-induced inflammation. METHODS: MSU or H2 O2 was injected into the hind paws of rodents or applied in cultured sensory neurons, and the intracellular calcium response was measured in vitro. Inflammatory or nociceptive responses in vivo were evaluated using pharmacologic, genetic, or biochemical tools and methods. RESULTS: TRPA-1 antagonism, TRPA-1 gene deletion, or pretreatment of peptidergic TRP-expressing primary sensory neurons with capsaicin markedly decreased MSU-induced nociception and edema. In addition to these neurogenic effects, MSU increased H2 O2 levels in the injected tissue, an effect that was abolished by the H2 O2 -detoxifying enzyme catalase. H2 O2 , but not MSU, directly stimulated sensory neurons through the activation of TRPA-1. The nociceptive responses evoked by MSU or H2 O2 injection were attenuated by the reducing agent dithiothreitol. In addition, MSU injection increased the expression of TRPA-1 and TRP vanilloid channel 1 (TRPV-1) and also enhanced cellular infiltration and interleukin-1beta levels, and these effects were blocked by TRPA-1 antagonism. CONCLUSION: Our results suggest that MSU injection increases tissue H2 O2 , thereby stimulating TRPA-1 on sensory nerve endings to produce inflammation and nociception. TRPV-1, by a previously unknown mechanism, also contributes to these responses. PMID- 23918658 TI - Repeat-associated non-ATG (RAN) translation in neurological disease. AB - Well-established rules of translational initiation have been used as a cornerstone in molecular biology to understand gene expression and to frame fundamental questions on what proteins a cell synthesizes, how proteins work and to predict the consequences of mutations. For a group of neurological diseases caused by the abnormal expansion of short segments of DNA (e.g. CAG*CTG repeats), mutations within or outside of predicted coding and non-coding regions are thought to cause disease by protein gain- or loss-of-function or RNA gain-of function mechanisms. In contrast to these predictions, the recent discovery of repeat-associated non-ATG (RAN) translation showed expansion mutations can express homopolymeric expansion proteins in all three reading frames without an AUG start codon. This unanticipated, non-canonical type of protein translation is length-and hairpin-dependent, takes place without frameshifting or RNA editing and occurs across a variety of repeat motifs. To date, RAN proteins have been reported in spinocerebellar ataxia type 8 (SCA8), myotonic dystrophy type 1 (DM1), fragile X tremor ataxia syndrome (FXTAS) and C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). In this article, we review what is currently known about RAN translation and recent progress toward understanding its contribution to disease. PMID- 23918659 TI - Vps33b pathogenic mutations preferentially affect VIPAS39/SPE-39-positive endosomes. AB - Mutations in Vps33 isoforms cause pigment dilution in mice (Vps33a, buff) and Drosophila (car) and the neurogenic arthrogryposis, renal dysfunction and cholestasis syndrome in humans (ARC1, VPS33B). The later disease is also caused by mutations in VIPAS39, (Vps33b interacting protein, apical-basolateral polarity regulator, SPE-39 homolog; ARC2), a protein that interacts with the HOmotypic fusion and Protein Sorting (HOPS) complex, a tether necessary for endosome lysosome traffic. These syndromes offer insight into fundamental endosome traffic processes unique to metazoans. However, the molecular and cellular mechanisms underlying these mutant phenotypes remain poorly understood. Here we investigate interactions of wild-type and disease-causing mutations in VIPAS39/SPE-39 and Vps33b by yeast two hybrid, immunoprecipitation and quantitative fluorescent microscopy. We find that although few mutations prevent interaction between VIPAS39/SPE-39 and Vps33b, some mutants fragment VIPAS39/SPE-39-positive endosomes, but all mutants alter the subcellular localization of Vps33b to VIPAS39/SPE-39-positive endosomes. Our data suggest that the ARC syndrome may result through impaired VIPAS39/SPE-39 and Vps33b-dependent endosomal maturation or fusion. PMID- 23918661 TI - Moving forward: cystic fibrosis gene therapy. AB - Since cloning of the CFTR gene more than 20 years ago a large number of pre clinical and clinical CF gene therapy studies have been performed and a vast amount of information and know-how has been generated. Here, we will review key studies with a particular emphasis on clinical findings. We have learnt that the lung is a more difficult target than originally anticipated, and we describe the strength and weaknesses of the most commonly used airway gene transfer agents (GTAs). In our view, one of the most significant developments in recent years is the generation of lentiviral vectors, which efficiently transduce lung tissue. However, focused and co-ordinated efforts assessing lentiviral vector safety and scaling up of production will be required to move this vector into clinical lung gene therapy studies. PMID- 23918660 TI - Age-associated epigenetic drift: implications, and a case of epigenetic thrift? AB - It is now well established that the genomic landscape of DNA methylation (DNAm) gets altered as a function of age, a process we here call 'epigenetic drift'. The biological, functional, clinical and evolutionary significance of this epigenetic drift, however, remains unclear. We here provide a brief review of epigenetic drift, focusing on the potential implications for ageing, stem cell biology and disease risk prediction. It has been demonstrated that epigenetic drift affects most of the genome, suggesting a global deregulation of DNAm patterns with age. A component of this drift is tissue-specific, allowing remarkably accurate age predictive models to be constructed. Another component is tissue-independent, targeting stem cell differentiation pathways and affecting stem cells, which may explain the observed decline of stem cell function with age. Age-associated increases in DNAm target developmental genes, overlapping those associated with environmental disease risk factors and with disease itself, notably cancer. In particular, cancers and precursor cancer lesions exhibit aggravated age DNAm signatures. Epigenetic drift is also influenced by genetic factors. Thus, drift emerges as a promising biomarker for premature or biological ageing, and could potentially be used in geriatrics for disease risk prediction. Finally, we propose, in the context of human evolution, that epigenetic drift may represent a case of epigenetic thrift, or bet-hedging. In summary, this review demonstrates the growing importance of the 'ageing epigenome', with potentially far-reaching implications for understanding the effect of age on stem cell function and differentiation, as well as for disease prevention. PMID- 23918662 TI - Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease. AB - Mutations in ABCA4 cause Stargardt disease and other blinding autosomal recessive retinal disorders. However, sequencing of the complete coding sequence in patients with clinical features of Stargardt disease sometimes fails to detect one or both mutations. For example, among 208 individuals with clear clinical evidence of ABCA4 disease ascertained at a single institution, 28 had only one disease-causing allele identified in the exons and splice junctions of the primary retinal transcript of the gene. Haplotype analysis of these 28 probands revealed 3 haplotypes shared among ten families, suggesting that 18 of the 28 missing alleles were rare enough to be present only once in the cohort. We hypothesized that mutations near rare alternate splice junctions in ABCA4 might cause disease by increasing the probability of mis-splicing at these sites. Next generation sequencing of RNA extracted from human donor eyes revealed more than a dozen alternate exons that are occasionally incorporated into the ABCA4 transcript in normal human retina. We sequenced the genomic DNA containing 15 of these minor exons in the 28 one-allele subjects and observed five instances of two different variations in the splice signals of exon 36.1 that were not present in normal individuals (P < 10(-6)). Analysis of RNA obtained from the keratinocytes of patients with these mutations revealed the predicted alternate transcript. This study illustrates the utility of RNA sequence analysis of human donor tissue and patient-derived cell lines to identify mutations that would be undetectable by exome sequencing. PMID- 23918663 TI - CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly. AB - Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference, reduction in the size of the cerebral cortex with otherwise grossly normal brain structure and variable intellectual disability. MCPH is caused by mutations of 11 different genes which code for proteins implicated in cell division and cell cycle regulation. We studied a consanguineous eight generation family from Pakistan with ten microcephalic children using homozygosity mapping and found a new MCPH locus at HSA 7q21.11-q21.3. Sanger sequencing of the most relevant candidate genes in this region revealed a homozygous single nucleotide substitution c.589G>A in CDK6, which encodes cyclin dependent kinase 6. The mutation changes a highly conserved alanine at position 197 into threonine (p.Ala197Thr). Post hoc whole-exome sequencing corroborated this mutation's identification as the causal variant. CDK6 is an important protein for the control of the cell cycle and differentiation of various cell types. We show here for the first time that CDK6 associates with the centrosome during mitosis; however, this was not observed in patient fibroblasts. Moreover, the mutant primary fibroblasts exhibited supernumerary centrosomes, disorganized microtubules and mitotic spindles, an increased centrosome nucleus distance, reduced cell proliferation and impaired cell motility and polarity. Upon ectopic expression of the mutant protein and knockdown of CDK6 through shRNA, we noted similar effects. We propose that the identified CDK6 mutation leads to reduced cell proliferation and impairs the correct functioning of the centrosome in microtubule organization and its positioning near the nucleus which are key determinants during neurogenesis. PMID- 23918664 TI - Isometric and swallowing tongue strength in healthy adults. AB - OBJECTIVES/HYPOTHESIS: The tongue contributes to a safe swallow. It facilitates bolus control during mastication, maintains a bolus in the oral cavity to prevent premature entry of the bolus into the hypopharynx, and helps generate pressure in the hypopharynx during swallowing. This study examined isometric tongue strength and tongue pressure measured during swallowing in healthy young and older adults. STUDY DESIGN: Prospective group design. METHODS: One hundred twenty-six healthy individuals who were recruited as part of a larger study on swallowing participated in this study. Participants were divided into three age groups: 20 to 40 years, 41 to 60 years, and >=61 years. A KayPentax Digital Swallowing Workstation with an air-filled bulb array was placed on the tongue of each participant (anterior to posterior). Participants completed three isometric tongue presses and three swallows. RESULTS: Repeated measures analyses of variance revealed a significant main effect of age (P = .01) and gender by tongue bulb location interaction (P = .02) for isometric tongue strength. That is, older adults had lower isometric tongue strength than young adults, and females had a greater difference between anterior and posterior tongue strength than males. Tongue strength during swallowing yielded significantly greater anterior versus posterior tongue pressure. CONCLUSIONS: This study comprises one of the largest in terms of number of healthy participants reported to date and confirms previous findings that isometric tongue strength decreases with age. Furthermore, given young and older adults generate similar swallowing pressures, swallowing is a submaximal strength activity, yet older adults have less functional reserve. LEVEL OF EVIDENCE: 4. PMID- 23918665 TI - Potential role of epigenetic mechanisms in the regulation of drug metabolism and transport. AB - This is a report of a symposium on the potential role of epigenetic mechanisms in the control of drug disposition sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2013 meeting in Boston, MA, April 21, 2013. Epigenetics is a rapidly evolving area, and recent studies have revealed that expression of drug-metabolizing enzymes and transporters is regulated by epigenetic factors, including histone modification, DNA methylation, and noncoding RNAs. The symposium speakers provided an overview of genetic and epigenetic mechanisms underlying variable drug metabolism and drug response, as well as the implications for personalized medicine. Considerable insight into the epigenetic mechanisms in differential regulation of the dioxin-inducible drug and carcinogen-metabolizing enzymes CYP1A1 and 1B1 was provided. The role of noncoding microRNAs in the control of drug metabolism and disposition through targeting of cytochrome P450 (P450) enzymes and ATP-binding cassette membrane transporters was discussed. In addition, potential effects of xenobiotics on chromatin interactions and epigenomics, as well as the possible role of long noncoding RNAs in regulation of P450s during liver maturation were presented. PMID- 23918666 TI - Evaluation of rhesus monkey and guinea pig hepatic cytosol fractions as models for human aldehyde oxidase. AB - Aldehyde oxidase (AOX) is a cytosolic enzyme expressed across a wide range of species, including guinea pig and rhesus monkey. These species are believed to be the best preclinical models for studying human AOX-mediated metabolism. We compared AOX activity in rhesus monkeys, guinea pigs, and humans using phthalazine and N-[2-(dimethylamino)ethyl]acridone-4-carboxamide (DACA) as substrates and raloxifene as an inhibitor. Michaelis-Menten kinetics was observed for phthalazine oxidation in rhesus monkey, guinea pig, and human liver cytosol, whereas substrate inhibition was seen with DACA oxidase activity in all three livers. Raloxifene inhibited phthalazine and DACA oxidase activity uncompetitively in guinea pig, whereas mixed-mode inhibition was seen in rhesus monkey. Our analysis of the primary sequence alignment of rhesus monkey, guinea pig, and human aldehyde oxidase isoform 1 (AOX1) along with homology modeling has led to the identification of several amino acid residue differences within the active site and substrate entrance channel of AOX1. We speculate that some of these residues might be responsible for the differences observed in activity. Overall, our data indicate that rhesus monkeys and guinea pigs would overestimate intrinsic clearance in humans and would be unsuitable to use as animal models. Our study also showed that AOX metabolism in species is substrate-dependent and no single animal model can be reliably used to predict every drug response in humans. PMID- 23918667 TI - Utility of in vitro systems and preclinical data for the prediction of human intestinal first-pass metabolism during drug discovery and preclinical development. AB - A growing awareness of the risks associated with extensive intestinal metabolism has triggered an interest in developing robust methods for its quantitative assessment. This study explored the utility of intestinal S9 fractions, human liver microsomes, and recombinant cytochromes P450 to quantify CYP3A-mediated intestinal extraction in humans for a selection of marketed drugs that are predominantly metabolized by CYP3A4. A simple competing rates model is used to estimate the fraction of drug escaping gut wall metabolism (fg) from in vitro intrinsic clearance in humans. The fg values extrapolated from the three in vitro systems used in this study, together with literature-derived fg from human intestinal microsomes, were validated against fg extracted from human in vivo pharmacokinetic (PK) profiles using a generic whole-body physiologically-based pharmacokinetic (PBPK) model. The utility of the rat as a model for human CYP3A mediated intestinal metabolism was also evaluated. Human fg from PBPK compares well with that from the grapefruit juice method, justifying its use for the evaluation of human in vitro systems. Predictive performance of all human in vitro systems was comparable [root mean square error (RMSE) = 0.22-0.27; n = 10]. Rat fg derived from in vivo PK profiles using PBPK has the lowest RMSE (0.19; n = 11) for the prediction of human fg for the selected compounds, most of which have a fraction absorbed close to 1. On the basis of these evaluations, the combined use of fg from human in vitro systems and rats is recommended for the estimation of CYP3A4-mediated intestinal metabolism in lead optimization and preclinical development phases. PMID- 23918668 TI - Protective effect of dimethyl sulfoxide on stricture formation in corrosive esophageal burns in rats. AB - INTRODUCTION: The aim of this study was to investigate the effects of dimethyl sulfoxide (DMSO) on stricture formation in corrosive esophageal burns. MATERIALS AND METHODS: A total of 21 male rats were divided equally into three groups. In Group 1 (burn) and Group 2 (burn + DMSO) burns were induced in the distal esophagi with a 30% NaOH solution. In Group 3 (control), a saline solution was applied to the esophageal lumen. In Group 2, DMSO was administered intraperitoneally (3 mg/kg) 15 minutes after the burn was induced and then every 24 hours for 7 days. All rats were humanely killed at the end of Day 22. Distal esophagi were harvested for analysis. The stenosis index (SI) and histopathologic damage score were evaluated in addition to malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) levels. RESULTS: DMSO significantly decreased the levels of MDA, NO, TNF-alpha, and IL-6 in the rats with burned esophagi. Furthermore, the SI and histopathologic scores decreased significantly in the burn + DMSO group relative to the burn group (p < 0.05). CONCLUSIONS: Our results suggest that DMSO can decrease the occurrence of stricture formation and could represent a beneficial alternative therapy for the treatment of corrosive esophagitis. PMID- 23918669 TI - Treatment of tracheomalacia with aortopexy in children in Glasgow. AB - OBJECTIVE: The aim of this study was to assess outcomes of infants and children undergoing aortopexy and to try and establish which children would derive the greatest benefit from this complex intervention. Materials and METHODS: This is a retrospective case series in a pediatric tertiary referral hospital between 1993 and 2012. A case sheet review was performed to collect demographic data and identify outcomes for each child. The effects of the subtype of tracheomalacia, weight at surgery, symptoms at presentation, surgical approach, and preoperative ventilation were considered. RESULTS: There were 30 children who underwent aortopexy during the study period. Of the 30 children in the study, 21 children (70%) were male. The gestational age at birth ranged between 25 and 41 weeks (9 children [30%] were preterm). Age at surgery was between 2 and 140 weeks (mean; 31.5 weeks, median; 26 weeks). The onset of symptoms was between birth and 18 months (mean; 3.8 months, median; 3.5 months). The presenting symptoms were stridor (n = 9; 30%), failed extubation (n = 4; 13%), death attacks (n = 8; 27%), and cyanosis (n = 9; 30%). The underlying pathology was primary in 10 children (33%) and secondary in 18 children. The diagnosis was made by bronchoscopy in 26 children (93%). Imaging was performed in 25 children (83%). Aortopexy in our institution is performed by general pediatric surgeons (n = 8; 27%) and cardiothoracic surgeons (n = 22; 73%). In the immediately postoperative period, 25 children (83%) were thriving. Of the children that required another procedure; 1 child was reintubated (3%), 2 children had a tracheostomy (6%), 1 child had a stent (3%), and 2 children died (6%). Clinical follow-up of these children was between 1 month and 12 years. Long term, in 22 children (73%) were asymptomatic. CONCLUSION: There were no clinical predictors of outcome identified, but aortopexy is a safe effective procedure for children with severe tracheomalacia. PMID- 23918670 TI - To split or not to split: colostomy complications for anorectal malformations or hirschsprung disease: a single center experience and a systematic review of the literature. AB - INTRODUCTION: The aim of this article is to identify the ideal type and location of colostomy in children with colorectal disease. PATIENTS AND METHODS: A retrospective case study of children with an anorectal malformation who received a colostomy, born between January 1990 and July 2012. Furthermore, a systematic literature search on colostomies in neonates with an anorectal malformation or Hirschsprung disease. Colostomies were classified as loop or split colostomies in the transverse or sigmoid colon. Outcome measures were mortality and complications such as prolapse, technical difficulties with the reconstruction, urinary tract infections, and others. RESULTS: The mortality rate in the 180 children with anorectal malformation was 6%, and none of them were directly related to stoma formation or closure. The overall complication rate was 23% and the specific rates for the two types of procedures and the two locations of the colostomy did not differ (p = 0.389 and p = 0.667, respectively). All prolapses (n = 22) occurred in loop colostomies in the transverse colon. One colostomy required revision because of insufficient length for the reconstruction. Urinary tract infections were not documented. A total of eight studies were included in the systematic review (1982-2011; 2,954 patients). Mortality ranged between 0.1 and 11%. Loop colostomies had more complications than split colostomies (63 vs. 45%; p = 0.007), mainly prolapse (18 vs. 6%; p < 0.001). Overall complication rate differed between transverse en sigmoid colostomies (62 vs. 51%, p = 0.006), and prolapse occurred more often in the transverse colon (23 vs. 7%; p < 0.001). Revision because of insufficient length during the reconstruction was needed in 0 to 6%. Two studies reported on urinary tract infections which are as follows: One showed no difference between loop or split colostomies, whereas the other showed frequent episodes of urinary tract infections in 64% of the loop colostomies. CONCLUSIONS: The complication to be avoided in transverse colostomies is prolapse and the surgical technique should be modified accordingly. The procedure of split sigmoid colostomy is meticulous, and the risk of insufficient length for the reconstruction remains. PMID- 23918671 TI - European Commission orders France to lift ban on acne pill. PMID- 23918672 TI - Baby food giants accused of wooing mothers in India off breastfeeding. PMID- 23918673 TI - Democrats denounce "unprecedented" efforts by Republicans to block health law. PMID- 23918675 TI - Molecular and crystal structure diversity, and physical properties of tetrathiafulvalene derivatives substituted with various aryl groups through sulfur bridges. AB - A library of tetrathiafulvalene (TTF) derivatives (TTF-1-TTF-47) bearing aryl groups attached through sulfur bridges has been created. The peripheral aryl groups exert a significant influence on both the electronic and crystallographic properties of the resulting TTFs. These TTFs display broad absorption bands at 400-500 nm caused by intramolecular charge-transfer transitions between the aryl groups and central TTF core, and their first redox potentials increase with increasing electron-withdrawing ability of the aryl groups. In their crystal structures (22 examples), the central TTF cores adopt various conformations, including chair, half-chair, boat, and planar conformations. Moreover, the peripheral aryl groups exhibit multiple alignment modes with respect to the central TTF core, caused by their rotation about the two C-S bonds of the sulfur bridges. The packing motifs of these TTFs depend on both the nature of the aryl groups and their spatial alignment modes. Driven by intermolecular van der Waals forces and pi-pi interactions between the aryl groups and between the aryl groups and the TTF core, these TTFs adopt various packing structures. As a typical example, TTF-14, an achiral molecule, adopts a helical chain stack through intermolecular atomic close contacts. Moreover, the molecular geometries and packing motifs of these TTFs are sensitive to environmental variation, as exemplified by TTF-28, which adopts three distinct crystal modifications with diverse molecular geometries and stacking modes under different crystallization conditions. This work indicates that these TTFs are potential candidates as electronic materials, as well as functional building blocks for supramolecular assembly. PMID- 23918674 TI - Reproductive and maternal healthcare needs of HIV infected women. AB - Advances in HIV treatment and prevention of mother to child transmission have effectively reduced mortality and morbidity for women living with HIV and significantly reduced new infections in infants. Women living with HIV require comprehensive, integrated clinical services to address their reproductive and maternal healthcare needs. Guidelines for safer conception counseling with fertile couples recommend discussing fertility and childbearing, addressing contraception with those not wishing to conceive, and clarification of strategies to conceive for those wishing to do so. Services pre-conception to postpartum should emphasize HIV testing for mother, partner and infant, encourage the maintenance of medication adherence and promote engagement and retention in care, and ensure supportive and non-judgmental patient education by healthcare providers. Behavioral, psychosocial and healthcare factors can have profound effects on pregnancy outcomes, and male involvement and enhanced provider involvement throughout the reproductive process has been recommended to reduce transmission and enhance medication adherence and uptake. PMID- 23918676 TI - C4.4A highly expressed in HER2-positive human breast cancers may indicate a good prognosis. AB - BACKGROUND: The aim of our study was to investigate the association of C4.4A expression in breast tumors with both patients' clinicopathological characteristics and outcomes in order to clarify the significance of C4.4A in breast cancer. METHODS: Primary breast cancer patients (n = 125, stage I-III) who had undergone breast mastectomy or breast-conserving surgery at our hospital between 2005 and 2011 were recruited for this study. Tumor samples were obtained from surgical specimens and expression status of C4.4A, estrogen receptors, progesterone receptors, human epidermal growth factor receptor 2 (HER2) and Ki67 was analyzed immunohistochemically, while HER2 amplification was examined using fluorescence in situ hybridization. RESULTS: Multivariate analysis showed that HER2 positivity was the only independent predictive factor for C4.4A expression (odds ratio 5.31, 95 % confidence interval 2.04-15.72; P < 0.001). Univariate prognostic analysis of the relationship between C4.4A and disease-free survival showed that survival of patients with C4.4A-positive tumors was longer than that of patients with C4.4A-negative tumors in the HER2-positive subset (P = 0.004) while there was no significant difference in patient outcome according to C4.4A status for total patients (median observation period 37 months, range 1-92 months; P = 0.223). CONCLUSIONS: We established a positive relationship between C4.4A and HER2 status, suggesting that C4.4A expression may be a prognostic factor for HER2-positive breast cancer patients. PMID- 23918677 TI - Collagenopathy with a phenotype resembling Silver-Russell syndrome phenotype. PMID- 23918678 TI - The mandate for quality: an invitation to be part of the solution. PMID- 23918679 TI - Associations between allergies and risk of hematologic malignancies: results from the VITamins and lifestyle cohort study. AB - Immune dysregulations associated with allergies may affect cancer cell biology but studies on the relationship between allergies and risk of hematologic malignancies (HM) yielded inconsistent results. Herein, we used the vitamins and Lifestyle (VITAL) cohort to examine this association. From 2000 to 2002, 66,212 participants, aged 50-76, completed a baseline questionnaire on cancer risk factors, medical conditions, allergies, and asthma. Through 2009, incident HMs (n = 681) were identified via linkage to the surveillance, epidemiology, and end results cancer registry. After adjustment for factors possibly associated with HMs, a history of airborne allergy was associated with increased risk of HMs (hazard ratio [HR] = 1.19 [95% confidence interval: 1.01-1.41], P = 0.039) in Cox proportional hazards models. This association was limited to allergies to plants/grass/trees (HR = 1.26 [1.05-1.50], P = 0.011) and was strongest for some mature B-cell lymphomas (HR = 1.50 [1.14-2.00], P = 0.005). Gender-stratified analyses revealed that the associations between airborne allergies overall and those to plants, grass, and trees were only seen in women (HR = 1.47 [1.14-1.91], P = 0.004; and HR = 1.73 [1.32-2.25], P < 0.001) but not men (HR = 1.03 [0.82 1.29], P = 0.782; and HR = 0.99 [0.77-1.27], P = 0.960). Together, our study indicates a moderately increased risk of HMs in women but not men with a history of allergies to airborne allergens, especially to plant, grass, or trees. PMID- 23918680 TI - Comment on: "cost-utility analysis of duloxetine in osteoarthritis: a US private payer perspective". PMID- 23918681 TI - LC-MS/MS method for the determination of agomelatine in human plasma and its application to a pharmacokinetic study. AB - A sensitive and selective LC-MS/MS method for the determination of agomelatine in human plasma was developed and validated. After simple liquid-liquid extraction, the analytes were separated on a Zorbax SB-C18 column (150 * 2.1 mm i.d., 5 um) with an isocratic mobile phase consisting of 5 mm ammonium acetate solution (containing 0.1% formic acid) and methanol (30:70, v/v) at a flow-rate of 0.3 mL/min. The MS acquisition was performed in multiple reaction monitoring mode with a positive electrospray ionization source. The mass transitions monitored were m/z 244.1 -> 185.3 and m/z 285.2 -> 193.2 for agomelatine and internal standard, respectively. The methods were validated for selectivity, carry-over, matrix effects, calibration curves, accuracy and precision, extraction recoveries, dilution integrity and stability. The validated method was successfully applied to a pharmacokinetic study of agomelatine in Chinese volunteers following a single oral dose of 25 mg agomelatine tablet. PMID- 23918682 TI - Circulating periostin levels do not differ between postmenopausal women with normal and low bone mass and are not affected by zoledronic acid treatment. AB - Periostin is a secreted extracellular matrix protein preferentially expressed in bone by osteocytes and periosteal osteoblasts. Reduced periostin expression may affect osteoblast differentiation and collagen type I synthesis and predispose to osteoporosis and increased fracture risk. We aimed to evaluate circulating periostin levels in postmenopausal women with low bone mass, their possible correlations with clinical and laboratory parameters, as well as the 3-month effect of zoledronic acid. Serum samples for periostin, 25-hydroxyvitamin D, parathyroid hormone (PTH), C-terminal telopeptide of type I collagen (CTx), and total alkaline phosphatase (tALP) were obtained from 46 postmenopausal women with low bone mass at baseline and 3 months after zoledronic acid infusion and from 30 age-matched, postmenopausal controls with normal bone mass at baseline. There was no difference in periostin levels between women with normal and low bone mass (250+/-15 vs. 272+/-14 ng/ml, respectively; p=0.279). Periostin remained essentially unchanged after zoledronic acid infusion (262+/-18 ng/ml; p=0.130). Serum periostin levels at baseline were not affected by previous bisphosphonate treatment, and were correlated only to tALP (rs=0.351; p=0.018). In multiple linear regression analysis, tALP (B=3.17; 95% CI=0.59-5.79; p=0.018) was associated with serum periostin levels at baseline, independently from previous anti-osteoporotic treatment, age, body mass index, and 25-hydroxyvitamin D. In conclusion, serum periostin levels do not differ between postmenopausal women with normal and low bone mass and are not affected by zoledronic acid treatment. Women with higher tALP have independently higher periostin levels. PMID- 23918683 TI - Altered chemokine Th1/Th2 balance in Addison's disease: relationship with hydrocortisone dosing and quality of life. AB - The adrenalitis found in autoimmune Addison's disease (AAD) is considered having a Th1-driven pathogenesis. Circulating Th1- and Th2-associated chemokines responsible for the trafficking of leukocytes to inflammatory sites are markers for the Th1/Th2 balance. The aim of the study was to assess if the same daily hydrocortisone dose of 30 mg given in either 2 or 4 doses to patients with AAD could affect the Th1/Th2 balance of circulating chemokines.Fifteen patients (6 women) with AAD were included in this randomised, placebo controlled, double blind cross-over study. Samples for chemokines, Th1-associated (CXCL10, CXCL11) and Th2-associated (CCL17, CCL22), were drawn 5 times during a 24-h period at the end of each treatment period and analysed with Luminex. Seven control subjects did the same diurnal blood sampling once. Subjects with AAD had higher median diurnal levels of the Th1-associated chemokines than controls, CXCL10 [43 (33-56) pg/ml vs. 22 (19-34) pg/ml, p<0.01] and CXCL11 [37 (29-48) pg/ml vs. 16 (9-24) pg/ml, p<0.001], whereas no significant difference was found regarding the Th2 related chemokines. Similar chemokine levels were found when the same hydrocortisone dose of 30 mg was divided in 2 or 4 doses. Levels of CXCL11 correlated negatively with scores of SF-36 domains (high score indicate better health) of General Health (GH) and total score for Physical Component Summary (PCS), and these negative correlations were most pronounced at 04:00 h on the 2 dose regimen. Patients with AAD have a dominant Th1 chemokine profile that partially correlates to reduced quality of life. PMID- 23918684 TI - Decreased serum T3 after an exercise session is independent of glucocorticoid peak. AB - Physical exercise increases serum glucocorticoids, which is believed to be involved in the fall of T3 after high intensity exercise. The objective was to evaluate whether a physical exercise session alters the thyroid economy and adrenal axis in humans, and the possible role of corticosteroids in thyroid function disturbance. Active but not athlete subjects were enrolled in an open field competition and cortisol, TSH, T3, and T4 were measured before and after the race. To give new insights into the mechanisms underlying the changes in thyroid economy after exercise, we used a rat model to evaluate the impact of blocking corticosterone synthesis during treadmill exercise by metyrapone administration. Cortisol levels increased 1.5-fold (from 28.2+/-3.8 to 42.2+/-2.2 MUg/dl; p<0.05), while serum T3 decreased by 13% (from 115+/-5 to 99+/-5 MUg/dl; p<0.05) 6 h after the race in humans. Also, in rats, glucocorticoid increased by 2-fold while T3 decreased 15% after exercise session (p<0.05). However, the complete blockage of corticosterone peak did not impair serum T3 decrease observed in rats submitted to exercise. Interestingly, the lack of corticosterone peak led not only to lower serum T3, but also to decreased serum T4, indicating that corticosterone might be fundamental for the maintenance of serum thyroid hormone levels after high intensity exercise. Although cortisol increases and T3 decreases after high intensity exercise in both humans and rats, it does not seem to be a cause-effect response since pharmacological blockage of corticosterone peak does not modulate T3 response. PMID- 23918685 TI - Increased cardiovascular risk in South African patients with Addison's disease. AB - Patients with Addison's disease (AD) are believed to be at risk for cardiovascular disease (CVD). South Africa, like the rest of the developing world is experiencing an increase in CVD and patients with AD may be at double the risk of their peers. We wished to explore AD patients' CVD risk factors. A cross sectional nationwide study in South Africa of patients with AD was conducted. A cohort of 147 patients with AD and 147 healthy control subjects were matched by age, gender, ethnicity, and BMI as far as was possible. Lipoproteins and highly sensitive C-reactive-protein (hs-CRP) were the main outcome measures. AD patients had significantly higher triglycerides; (p=0.001), lower HDLC (p<0.001), higher hs-CRP (p<0.001), and more small dense LDL; (p=0.002) than controls. Nonesterified fatty acids were lower in patients (p<0.001). Approximately 65% [95% confidence interval (CI 55.6-72.4%)] had hypercholesterolaemia, 75% (CI 64.8 81.2%) had low HDLC, and 75% (CI 68.0-84.1%) had a higher LDLC. Thirteen percent of AD patients had diabetes mellitus, but none of the risk factors differed from the nondiabetics. Only HDLC correlated positively with daily hydrocortisone dose (r=0.32; p=0.005). In conclusion dyslipidaemia is common in South African AD patients; CVD risk assessment and intervention are probably warranted in the management of these patients. PMID- 23918686 TI - A pilot study evaluating 99mTc-anti-TNF-alpha scintigraphy in graves' ophtalmopathy patients with different clinical activity score. AB - The present study describes the preliminary results of the use of 99mTc-anti-TNF alpha scintigraphy as a new diagnostic approach to evaluate patients presenting with Graves' ophthalmopathy (GO). Patients (n=25) presenting at different inflammatory stages of GO and 10 healthy volunteers underwent 99mTc-anti-TNF alpha scintigraphy. Images were obtained 15 min after the intravenous injection of 370 MBq (10 mCi) 99mTc-anti-TNF-alpha. Planar images were obtained in a 256*256 matrix (each lasting 5 min) and single photon emission computed tomography (SPECT) scan lasting 13 min. Regions of interest (ROI) were drawn on the orbit and cerebral hemispheres. The uptake of 99m Tc-anti-TNF-alpha in these regions was compared and positive scintigraphy established when the ROI was >2.5. In addition, uptake for each positive exam was scored as either slight (2.6-5.1), moderate (5.2-7.6), or high (>7.6). In this pilot study, 69 orbits were evaluated (1 patient had only 1 eye), and 27 had a positive CAS (>=3/7). Scintigraphies were positive in 38 orbits. Comparing the results of the exams with CAS, a high sensitivity and negative predictive values were determined for scintigraphy (96.3% and 96.7%, respectively). However, the specificity and the positive predictive values were 71.4% and 68.4%, respectively, with an accuracy of 81.2%. The exclusion of examinations that were slightly positive from the analysis resulted in an improvement in test accuracy (95.5%). The preliminary results suggest that 99mTc-anti-TNF-alpha scintigraphy is a promising procedure for the evaluation of active orbital inflammation in GO. PMID- 23918687 TI - CD40L stimulates the crosstalk between adipocytes and inflammatory cells. AB - Macrophages and lymphocytes are implicated in obesity-related adipose tissue inflammation via interactions with adipocytes. Co-stimulatory systems, especially the CD40-CD40L system, play an important role in T cell activation and inflammatory reactions. CD40L was recently shown to promote adipose tissue inflammation in vivo, yet, the mechanisms underlying its function in the intercellular communication between inflammatory cells and adipocytes remain not entirely clear. Here we found that adipocyte stimulation with CD40L increased the expression of CD40, as well as of chemokines, such as MCP-1, CCL4, or CCL5, whereas adipocyte CD40 expression was also stimulated by TNF but not palmitate. Moreover, conditioned media of CD40L-pretreated adipocytes provoked elevated migration of mononuclear cells and increased the expression of inflammatory genes in bone marrow derived mononuclear phagocytes (BMDM) shifting them to an M1-like pro-inflammatory phenotype. Nonetheless, the CD40/CD40L interaction did not contribute to the adhesion between adipocytes and T cells. Together, CD40L stimulates adipocyte chemokine expression, thereby attracting monocytes/macrophages into the adipose tissue. Moreover, CD40L stimulation of adipocytes likely promotes macrophage M1 polarization in the adipose tissue and thereby perpetuation of adipose tissue inflammation. PMID- 23918688 TI - Caloric restriction followed by high fat feeding predisposes to oxidative stress in skeletal muscle mitochondria. AB - The purpose of the present study was to assess the impact of previous period of caloric restriction on energy balance and skeletal muscle mitochondrial energetics in response to high-fat (HF) diet. To this end, 1 group of rats was subjected to 2 weeks of caloric restriction with nonpurified diet and then fed HF diet (430 kJ metabolizable energy/day) for 1 week, while the second group was fed ad libitum with nonpurified diet for 2 weeks and then fed HF diet (430 kJ metabolizable energy/day) for 1 week. Body composition, energy balance, and glucose homeostasis were measured. Mitochondrial mass, oxidative capacity and efficiency, parameters of oxidative stress, and antioxidant defense were evaluated in subsarcolemmal and intermyofibrillar mitochondria from skeletal muscle. Body energy and lipid content, plasma insulin, and metabolic efficiency were significantly higher, while energy expenditure significantly decreased, in food-restricted rats fed HF diet compared to controls. Mitochondrial efficiency and oxidative damage in skeletal muscle were significantly increased, while antioxidant defence was significantly lower in food-restricted rats fed HF diet, compared with controls. Finally, food-restricted rats fed HF diet exhibited significant reduction in subsarcolemmal mitochondrial mass. In conclusion, caloric restriction elicits higher mitochondrial efficiency and predisposes skeletal muscle to high fat-induced oxidative damage, which in turn could lead to impaired glucose homeostasis in food-restricted rats fed HF diet. PMID- 23918689 TI - Decrease of hyperglycemia by syringaldehyde in diabetic rats. AB - Syringaldehyde is one of the active principles from the stems of Hibiscus taiwanensis (Malvaceae) that has been mentioned to lower hyperglycemia. However, the potential mechanisms for this action of syringaldehyde remain obscure. In the present study, we used streptozotocin to induce diabetic rats (STZ-diabetic rats) as type 1-like diabetic rats and fed fructose-rich chow to rats as type 2-like diabetic rats. Then, we performed the postprandial glucose test and applied the hyperinsulinemic euglycemic clamp to investigate the actions of syringaldehyde. Also, the changes of gene expressions of enzyme relating to glucose homeostasis in muscle and liver were characterized. Syringaldehyde significantly decreased the postprandial plasma glucose in rats, while the plasma insulin was not modified by syringaldehyde. The glucose infusion rate (GIR) in fructose chow-fed rats using hyperinsulinemic euglycemic clamp was markedly improved by syringaldehyde. Additionally, repeated administration of syringaldehyde for 3 days in STZ-diabetic rats resulted in a marked reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression in liver and an increased expression of glucose transporter subtype 4 (GLUT 4) in skeletal muscle. Our results suggest that syringaldehyde may increase glucose utilization to lower hyperglycemia in diabetic rats. PMID- 23918690 TI - Liver glucagon receptors (GluR): effect of exercise and fasting on binding characteristics, GluR-mRNA, and GluR protein content in rats. AB - The purpose of the study was to investigate the effects of acute exercise and fasting on glucagon receptor (GluR) binding characteristics, GluR-mRNA, and protein content in rat liver. Liver homogenates were prepared and plasma membranes were purified by aqueous 2-phase affinity partitioning in rats fed at rest (control) and after 180 min of swimming exercise and 24 h of fasting (7 rats/group). Saturation curve of plasma membranes incubated with [125I]-glucagon showed significant higher GluR density following exercise and fasting than in the control group (8.19+/-0.29 and 8.01+/-0.65 vs. 3.09+/-0.12 pmol/mg of proteins, respectively). When compared to control rats, GluR Kd was also higher following exercise and fasting (0.46+/-0.05 and 0.56+/-0.13 vs. 0.33+/-0.05 nM, respectively; significantly different for fasting only). Expression of GluR-mRNA and protein content were both significantly higher (~100% and ~90%, respectively) following the 24-h fast than in the control rats, but not following exercise. These results, in line with the literature showing an increased sensitivity of the liver to glucagon following exercise and fasting, indicate that an increased density of GluR on plasma membranes can be obtained by 2 complementary mechanisms: externalization of pre-existing GluR from intracellular pools operative in response to the prolonged exercise, and de novo synthesis of GluR operative only in response to fasting. The reduction in plasma insulin concentration and/or depletion of liver glycogen stores, which results from both prolonged exercise and fasting, could be involved in the control of these mechanisms. PMID- 23918691 TI - Treatment with the nitric oxide donor SNP increases triiodothyronine levels in hyper- and hypothyroid Sprague-Dawley rats. AB - Nitric oxide pathway might play a crucial role in the pathophysiology of thyroid dysfunctions. This study aimed to investigate the impact of nitric oxide (NO) on hypothyroid and hyperthyroid Sprague-Dawley rats under controlled diet. Furthermore, the effects of the nitric oxide donor sodium nitroprusside (SNP) on thyroid dysfunctions were also assessed. Sprague-Dawley rats (n=107) were subdivided into normal diet and high-fat diet (HFD) groups and grouped into controls, hypothyroid, hyperthyroid, and SNP treated groups. Hypothyroidism was induced through propylthiouracil, whereas hyperthyroidism by triiodothyronine (T3). After 12 weeks of T3 treatment, serum nitric oxides (NOX), endogenous asymmetric dimethylarginine (ADMA), body weight and food intake were analyzed. Hypothyroid rats showed decreased serum T3 levels, hyperthyroid rats increased T3 compared to controls. Diet had no impact on T3. Thyroid dysfunctions were accompanied by changes in calorie intake and body weight. Serum NOX was significantly reduced in normal diet hypothyroid rats. SNP administration compensated the decrease and markedly increased T3. NO synthase inhibitor ADMA levels were significantly higher in the HFD control group than in the normal diet controls. ADMA was declined in both hypothyroid groups and increased in normal diet hyperthyroid rats. An association of thyroid dysfunctions with reduced bioavailability of NO and alterations of ADMA levels could be established. Treatment with the NO donor SNP resulted in an increase of serum T3 levels. These results demonstrate that the NO pathway is implicated in thyroid dysfunctions, which may be of clinical relevance. PMID- 23918692 TI - Combination therapy of steroids and antivirals improves the recovery rate in patients with severe Bell's palsy. PMID- 23918693 TI - Four-dimensional computed tomographic angiography of an arteriovenous fistula in the neck. AB - Arteriovenous fistula (AVF), a type of vascular anomaly, is a relatively uncommon disease characterized by abnormal connections between the arterial and venous systems. Recently, remarkable advances in four-dimensional computed tomographic angiography (4D-CTA) have enabled detailed analysis of the hemodynamic features of vascular anomalies, which cannot be achieved by conventional imaging modalities. We report a case of AVF in a 59-year-old female presenting as a right neck mass. Using reconstructed animations from various viewing angles, 4D-CTA could clearly visualize not only a mass but the feeding artery and draining vein from the mass. 4D-CTA was useful for the diagnosis of AVF and to determine the surgical strategy preoperatively. PMID- 23918694 TI - Periarticular bone loss in antigen-induced arthritis. AB - OBJECTIVE: Bone loss in arthritis is a complex process characterized by bone erosions and periarticular and generalized bone loss. The antigen-induced arthritis (AIA) model is mainly used to study synovitis and joint destruction, including bone erosions; however, periarticular bone loss has been less extensively investigated. The objectives of this study were to characterize and establish AIA as a model for periarticular bone loss, and to determine the importance of NADPH oxidase 2 (NOX-2)-derived reactive oxygen species (ROS) in periarticular bone loss. METHODS: Arthritis was induced in mice by local injection of antigen in one knee; the other knee was used as a nonarthritis control. At study termination, the knees were collected for histologic assessment. Periarticular bone mineral density (BMD) was investigated by peripheral quantitative computed tomography. Flow cytometric analyses were performed using synovial and bone marrow cells. RESULTS: AIA resulted in decreased periarticular trabecular BMD and increased frequencies of preosteoclasts, neutrophils, and monocytes in the arthritic synovial tissue. Arthritis induction resulted in an increased capability to produce ROS. However, induction of arthritis in Ncf1 / mice, which lack NOX-2-derived ROS, and control mice resulted in similar reductions in periarticular trabecular BMD. CONCLUSION: The initiation of AIA resulted in periarticular bone loss associated with local effects on inflammatory cells and osteoclasts. Furthermore, based on our observations using this model, we conclude that NOX-2-derived ROS production is not essential for inflammation-mediated periarticular bone loss. Thus, AIA can be used as a model to investigate the pathogenesis of local inflammation-mediated bone loss. PMID- 23918695 TI - Clinical characteristics and therapeutic response of objective tinnitus due to middle ear myoclonus: a large case series. AB - OBJECTIVES/HYPOTHESIS: To evaluate the clinical characteristics and therapeutic response of tinnitus due to middle ear myoclonus (MEM) and to suggest appropriate diagnostic methods. STUDY DESIGN: Retrospective chart review. METHODS: This study included 58 patients with tinnitus diagnosed with MEM, who were seen from January 2004 to July 2011. Clinical and audiological characteristics were investigated. The therapeutic responses to counseling, medical therapy, and surgical therapy were evaluated. RESULTS: Patients had a mean age of 29.8 years (range, 6-70 years), 20.7% (n = 12) were <10 years old, 39.7% (n = 23) were <20 years old, 74.1% (n = 43) were <40 years old, and 5.2% (n = 3) were >=60 years old. Remembered stressful events or noise exposure were associated with the onset of MEM in 51.8% (n = 30) and 27.6% (n = 16) of patients, respectively. The most frequent nature of the tinnitus was a crackling sound. MEM associated with forceful eyelid closure was observed in 15% of patients. Impedance audiogram and otoendoscopic examinations of the tympanic membrane were helpful tools for diagnosing MEM. With medical therapy, more than 75% of patients exhibited complete or partial remission of their tinnitus. Patients with intractable MEM who underwent sectioning of the middle ear tendons had very good outcomes. CONCLUSIONS: Tinnitus due to middle ear myoclonus seems to occur in young patients and to be related to stress or noise. Information about the clinical characteristics and therapeutic response of this less-common type of tinnitus will help to ensure early and appropriate diagnosis and treatment of these patients. LEVEL OF EVIDENCE: 4. PMID- 23918696 TI - Pain over time and its effects on life in thalassemia. AB - Pain reports have become increasingly common and problematic in thalassemia. As patients are living longer,there is a growing need to study pain and to explore its impact on patient lives. The Brief Pain Inventory(BPI) was used quarterly to assess pain and pain interference in patients with thalassemia in North America.The Medical Outcomes Study 36-Item Short Form Health Survey and the Hospital Anxiety and Depression Scale were used to assess quality of life, anxiety and depression. Of the 252 participants, 56% reported pain at least once over the course of this study, with 32% reporting severe pain (>=7/10); 16% reported pain at all four visits. Increased pain severity significantly interfered with daily life (P< 0.001; regression analysis) and participants with more sites of pain showed an increase in the amount of daily activities affected by pain(P50.001). Participants reporting more visits with pain reported a significantly higher impact on affective and physical function (P< 0.001). Physical quality of life decreased with increasing numbers of visits with pain (P< 0.001). Those who reported one or more sites of pain showed increased symptoms of both depression(P< 0.001) and anxiety (P50.003). Participants reporting at least two visits with pain had higher symptoms of anxiety (P50.002) and those with at least three visits reported higher symptoms of depression(P50.003). Pain is prevalent in thalassemia and is often a chronic condition that interferes with life. The study highlights the significance of pain in thalassemia and its impact, which should be considered in future research and treatments. PMID- 23918697 TI - Dirt bikes injuries in children. AB - INTRODUCTION: Dirt bike riding is becoming a more popular recreational activity among children. Injuries associated with this recreational activity did not gain attention in the medical literature. The purpose of this study is to assess orthopedic injuries associated with dirt bike riding. METHODS: We retrospectively studied injuries occurring in children less than 18 years old, while riding dirt bikes, that required admission to the trauma department in our level one trauma center during the period 2000-2010. RESULTS: There were 24 admissions (23 patients). The mean age was 13. Fourteen patients had brain injuries. Six patients had abdominal injuries. One patient died shortly after arriving to the emergency department. Fourteen patients had face and neck injuries. The average injury severity score was 8.5. Thirteen patients' admissions (54 %) had orthopedic fractures. Five of 13 patients (38 %) suffered more than one fracture. Eight patients needed orthopedic intervention (seven of these were in operating room under general anesthesia and one in the emergency department under conscious sedation). Femur fracture was the most common cause for performing surgery in this group of patients. CONCLUSION: Riding dirt bikes is not a safe recreational activity. Orthopedic injuries constitute a major component of the injuries affecting children riding dirt bikes. Orthopedic surgeons (being responsible for treating most of these children) have the obligation to warn the community against the possible dangers facing children who ride dirt bikes. PMID- 23918698 TI - Second study on valsartan is threatened with retraction over alleged data manipulation. PMID- 23918699 TI - Lixisenatide: a review of its use in patients with type 2 diabetes mellitus. AB - Lixisenatide (Lyxumia((r))) is a glucagon-like peptide-1 receptor agonist that acts in a glucose-dependent manner to improve glycemic control in adult patients with type 2 diabetes mellitus. Subcutaneous once-daily prandial lixisenatide is indicated for the treatment of adult patients with type 2 diabetes to achieve glycemic control in combination with oral antihyperglycemic drugs (OADs) and/or basal insulin when these antihyperglycemic drugs do not provide adequate glycemic control. In an extensive phase III clinical trial program, lixisenatide once daily in combination with OADs and/or basal insulin for 24 weeks improved glycemic control, had beneficial effects on bodyweight, and was generally well tolerated in adult patients with inadequately controlled type 2 diabetes despite treatment with OADs and/or basal insulin. At 24 weeks, in terms of the primary efficacy endpoint of each trial, combination therapy with lixisenatide was associated with better efficacy than placebo in patients inadequately controlled on OADs and/or basal insulin, was shown to be noninferior to exenatide in patients inadequately controlled on background metformin therapy, and showed similar efficacy to sitagliptin in patients inadequately controlled on background metformin therapy. Further clinical experience/post-marketing surveillance studies and long-term safety data, along with pharmacoeconomic analyses, are required to fully define the position of lixisenatide in relation to other antihyperglycemics. In the meantime, once-daily prandial lixisenatide in combination with OADs and/or basal insulin (plus diet and exercise) is an effective option for improving glycemic control in adult patients with type 2 diabetes, including in patients where bodyweight loss is an essential component in their management. PMID- 23918700 TI - On metrics. PMID- 23918702 TI - Editor's Note: Expression of transforming growth factor beta 1 in lung tissue during cardiopulmonary bypass-induced lung injury in dogs by Wang et al. (epub ahead of print). PMID- 23918703 TI - Age-related change in renal corticomedullary differentiation: evaluation with noncontrast-enhanced steady-state free precession (SSFP) MRI with spatially selective inversion pulse using variable inversion time. AB - PURPOSE: To evaluate age-related change in renal corticomedullary differentiation and renal cortical thickness by means of noncontrast-enhanced steady-state free precession (SSFP) magnetic resonance imaging (MRI) with spatially selective inversion recovery (IR) pulse. MATERIALS AND METHODS: The Institutional Review Board of our hospital approved this retrospective study and patient informed consent was waived. This study included 48 patients without renal diseases who underwent noncontrast-enhanced SSFP MRI with spatially selective IR pulse using variable inversion times (TIs) (700-1500 msec). The signal intensity of renal cortex and medulla were measured to calculate renal corticomedullary contrast ratio. Additionally, renal cortical thickness was measured. RESULTS: The renal corticomedullary junction was clearly depicted in all patients. The mean cortical thickness was 3.9 +/- 0.83 mm. The mean corticomedullary contrast ratio was 4.7 +/- 1.4. There was a negative correlation between optimal TI for the best visualization of renal corticomedullary differentiation and age (r = -0.378; P = 0.001). However, there was no significant correlation between renal corticomedullary contrast ratio and age (r = 0.187; P = 0.20). Similarly, no significant correlation was observed between renal cortical thickness and age (r = 0.054; P = 0.712). CONCLUSION: In the normal kidney, noncontrast-enhanced SSFP MRI with spatially selective IR pulse can be used to assess renal corticomedullary differentiation and cortical thickness without the influence of aging, although optimal TI values for the best visualization of renal corticomedullary junction were shortened with aging. PMID- 23918704 TI - Two Somali half-siblings with CHST3-related chondrodysplasia illustrating the phenotypic spectrum and intrafamilial variability. AB - Deficiency of carbohydrate sulfotransferase 3 (CHST3; also known as chondroitin-6 sulfotranferase) has been associated with a phenotype of severe chondrodysplasia and progressive spinal involvement. Recent reports indicate that affected individuals initially present with neonatal multiple joint dislocations. We describe a 14-year-old Somali patient and her 3-year-old maternal half-brother with novel homozygous CHST3 mutations. The proband presented at the age 51/2 years with short stature and genua valga. Her clinical course was characterized by rapid progression of spinal deformities and large joint contractures. Her half brother presented at birth with bilateral knee dislocation and talipes equinovarus. This report of a Somali family with CHST3-related chondrodysplasia illustrates the intrafamilial variability in phenotypic expression of this rare disorder. (c) 2013 Wiley Periodicals, Inc. PMID- 23918705 TI - Clinical images: enchondromatosis (Ollier disease). PMID- 23918706 TI - Immune deficiencies in children: an overview. AB - Primary immune deficiencies (PIDs) are disorders of the immune system that result in increased susceptibility to infectious disease, autoimmunity and malignancy. They are challenging to paediatricians as they can present anytime from birth to adolescence with a wide variety of signs and symptoms. It is important to diagnose PIDs promptly, especially more severe forms to prevent significant morbidity and mortality. However, significant challenges exist in deciding which children to investigate and when. We aim to give a basic understanding of the human immune system, the different presentations in a child that should alert a paediatrician about the possibility of PID and the possible underlying diagnosis. Additionally, we have developed a framework for a stepwise approach to investigating these children. PMID- 23918707 TI - Obesity and the risk of chronic rhinosinusitis, allergic rhinitis, and acute otitis media in school-age children. AB - OBJECTIVES/HYPOTHESIS: To determine if obesity is a significant risk factor for acute otitis media (AOM), allergic rhinitis (AR), or chronic rhinosinusitis (CRS) in children and to understand the potential otolaryngological implications of childhood obesity. STUDY DESIGN: Cross-Sectional Analysis. METHODS: The 2006 and 2008 the Medical Expenditure Panel Survey was utilized to identify school-aged children with AOM, AR, and/or CRS. Risk factors for the diagnoses extracted included standard demographics and the presence or absence of obesity. Multivariate analyses were conducted for associations between childhood obesity and AOM, AR, and CRS. RESULTS: 42.1 million (95% CI, 40.4-44.2) school-age children (unweighted N = 10623) were sampled in 2006 and 2008. There was a slight male predominance (51.0% [95% CI, 49.8-52.2]). Of these patients, 2.2 million (95% CI 1.9-2.4) received a diagnosis of AOM, 4.0 million (95% CI 3.6-4.4) received a diagnosis of AR, and 1.7 million (95% CI 1.4-1.9) received a diagnosis of CRS. Approximately 9.3 million (95% CI 8.7-10.0) children were obese, representing 22.2% (95% CI 21.0-23.3) of the U.S. population (age 6-17). Utilizing an adjusted multivariate model, childhood obesity was found to be associated with AOM (odds ratio, 1.44; [95% CI 1.08-1.93]; P = 0.033). Significant associations between obesity and AR (OR 1.14; [95% CI 0.88-1.47]; P = 0.60) or obesity and CRS (OR0.73; [95% CI 0.48-1.10]; P = 0.79) were not identified. CONCLUSION: Childhood obesity appears to be associated with the development of AOM; however, an association between obesity and AR or CRS was not demonstrated. Given that in the United States nearly one-fourth of all children seeking health care are obese, these data may have important preventative care implications. LEVEL OF EVIDENCE: 2C. PMID- 23918708 TI - Otorhinolaryngological patient injuries in Finland. AB - OBJECTIVES/HYPOTHESIS: Otorhinolaryngology (ORL) is considered a specialty associated with few serious patient injuries. Research data that support this belief are, however, scarce. We analyzed claims associated with ORL to determine the number of Finnish cases and the possible common denominators. STUDY DESIGN: Register study of ORL cases in the Patient Insurance Centre (PIC), the Regional State Administrative Agencies (RSAA), and the National Supervisory Authority for Welfare and Care (Valvira) during the years 2004 to 2008. METHODS: These three agencies are the main actors in the field of patient injury in Finland. We analyzed compensated ORL patient injury cases from the PIC and cases associated with the ORL specialty for Valvira and RSAA from 2004 to 2008 and surveyed patient treatment files, statements from specialists, and compensation decisions. RESULTS: Injuries were usually associated with operations; three patients who experienced injuries during these procedures died. Common ORL operations such as tonsillectomy, septoplasty, and paranasal sinus surgery were most often associated with compensated injuries. Serious injuries were few, with a total of 110 out of 422 (26.1%) claims compensated by the PIC. Of the 110 compensated cases, 30 (27.3%) were related to tumor surgery. The most usual compensated case had iatrogenic nerve injury affecting the facial or trigeminal nerves. Of the compensated cases, 79 (71.8%) were treated by specialists, 15 (13.6%) by residents, and the rest by other medical professionals. CONCLUSIONS: Patient injuries in ORL are seldom severe and are strongly associated with surgery. A typical compensated injury was one that occurred in a central hospital during working hours. LEVEL OF EVIDENCE: N/A. PMID- 23918709 TI - Quantum rotation and translation of hydrogen molecules encapsulated inside C60: temperature dependence of inelastic neutron scattering spectra. AB - The quantum dynamics of a hydrogen molecule encapsulated inside the cage of a C60 fullerene molecule is investigated using inelastic neutron scattering (INS). The emphasis is on the temperature dependence of the INS spectra which were recorded using time-of-flight spectrometers. The hydrogen endofullerene system is highly quantum mechanical, exhibiting both translational and rotational quantization. The profound influence of the Pauli exclusion principle is revealed through nuclear spin isomerism. INS is shown to be exceptionally able to drive transitions between ortho-hydrogen and para-hydrogen which are spin-forbidden to photon spectroscopies. Spectra in the temperature range 1.6<=T<=280 K are presented, and examples are given which demonstrate how the temperature dependence of the INS peak amplitudes can provide an effective tool for assigning the transitions. It is also shown in a preliminary investigation how the temperature dependence may conceivably be used to probe crystal field effects and inter-fullerene interactions. PMID- 23918710 TI - Nuclear spin isomers of guest molecules in H2@C60, H2O@C60 and other endofullerenes. AB - Spectroscopic studies of recently synthesized endofullerenes, in which H2, H2O and other atoms and small molecules are trapped in cages of carbon atoms, have shown that although the trapped molecules interact relatively weakly with the internal environment they are nevertheless susceptible to appropriately applied external perturbations. These properties have been exploited to isolate and study samples of H2 in C60 and other fullerenes that are highly enriched in the para spin isomer. Several strategies for spin-isomer enrichment, potential extensions to other endofullerenes and possible applications of these materials are discussed. PMID- 23918711 TI - Recognition of hydrogen isotopomers by an open-cage fullerene. AB - We present our study on the recognition of hydrogen isotopes by an open-cage fullerene through determination of binding affinity of isotopes H2/HD/D2 with the open-cage fullerene and comparison of their relative molecular sizes through kinetic-isotope-release experiments. We took advantage of isotope H2/D2 exchange that generated an equilibrium mixture of H2/HD/D2 in a stainless steel autoclave to conduct high-pressure hydrogen insertion into an open-cage fullerene. The equilibrium constants of three isotopes with the open-cage fullerene were determined at various pressures and temperatures. Our results show a higher equilibrium constant for HD into open-cage fullerene than the other two isotopomers, which is consistent with its dipolar nature. D2 molecule generally binds stronger than H2 because of its heavier mass; however, the affinity for H2 becomes larger than D2 at lower temperature, when size effect becomes dominant. We further investigated the kinetics of H2/HD/D2 release from open-cage fullerene, proving their relative escaping rates. D2 was found to be the smallest and H2 the largest molecule. This notion has not only supported the observed inversion of relative binding affinities between H2 and D2, but also demonstrated that comparison of size difference of single molecules through non-convalent kinetic-isotope effect was applicable. PMID- 23918712 TI - HD in C60: theoretical prediction of the inelastic neutron scattering spectrum and its temperature dependence. AB - We report rigorous quantum calculations of the inelastic neutron scattering (INS) spectra of HD@C60, over a range of temperatures from 0 to 240 K and for two incident neutron wavelengths used in recent experimental investigations. The computations were performed using our newly developed methodology, which incorporates the coupled five-dimensional translation-rotation (T-R) eigenstates of the guest molecule as the initial and final states of the INS transitions, and yields highly detailed spectra. Depending on the incident neutron wavelength, the number of computed INS transitions varies from almost 500 to over 2000. The low temperature INS spectra display the fingerprints of the coupling between the translational and rotational motions of the entrapped HD molecule, which is responsible for the characteristic splitting patterns of the T-R energy levels. INS transitions from the ground T-R state of HD to certain sublevels of excited T R multiplets have zero intensity and are absent from the spectra. This surprising finding is explained by the new INS selection rule introduced here. The calculated spectra exhibit strong temperature dependence. As the temperature increases, numerous new peaks appear, arising from the transitions originating in excited T-R states which become populated. Our calculations show that the higher temperature features typically comprise two or more transitions close in energy and with similar intensities, interspersed with numerous other transitions whose intensities are negligible. This implies that accurately calculated energies and intensities of INS transitions which our methodology provides will be indispensable for reliable interpretation and assignment of the experimental spectra of HD@C60 and related systems at higher temperatures. PMID- 23918713 TI - Infrared spectroscopy of small-molecule endofullerenes. AB - Hydrogen is one of the few molecules that has been incarcerated in the molecular cage of C60 to form the endohedral supramolecular complex H2@C60. In this confinement, hydrogen acquires new properties. Its translation motion, within the C60 cavity, becomes quantized, is correlated with its rotation and breaks inversion symmetry that induces infrared (IR) activity of H2. We apply IR spectroscopy to study the dynamics of hydrogen isotopologues H2, D2 and HD incarcerated in C60. The translation and rotation modes appear as side bands to the hydrogen vibration mode in the mid-IR part of the absorption spectrum. Because of the large mass difference of hydrogen and C60 and the high symmetry of C60 the problem is almost identical to a vibrating rotor moving in a three dimensional spherical potential. We derive potential, rotation, vibration and dipole moment parameters from the analysis of the IR absorption spectra. Our results were used to derive the parameters of a pairwise additive five dimensional potential energy surface for H2@C60. The same parameters were used to predict H2 energies inside C70. We compare the predicted energies and the low temperature IR absorption spectra of H2@C70. PMID- 23918714 TI - Predicting the paramagnet-enhanced NMR relaxation of H2 encapsulated in endofullerene nitroxides by density-functional theory calculations. AB - We have investigated the structure and nuclear magnetic resonance (NMR) spectroscopic properties of some dihydrogen endofullerene nitroxides by means of density-functional theory (DFT) calculations. Quantum versus classical roto translational dynamics of H2 have been characterized and compared. Geometrical parameters and hyperfine couplings calculated by DFT have been input to the Solomon-Bloembergen equations to predict the enhancement of the NMR longitudinal relaxation of H2 due to coupling with the unpaired electron. Estimating the rotational correlation time via computed molecular volumes leads to a fair agreement with experiment for the simplest derivative; the estimate is considerably improved by recourse to the calculation of the diffusion tensor. For the other more flexible congeners, the agreement is less good, which may be due to an insufficient sampling of the conformational space. In all cases, relaxation by Fermi contact and Curie mechanisms is predicted to be negligible. PMID- 23918715 TI - Molecular surgical synthesis of H2@C60: recollections. AB - The first synthesis of endohedral fullerene containing molecular hydrogen, H2@C60, is briefly summarized. The synthesis was conducted according to what we call the 'molecular surgical method', that is, opening a hole on a C60 surface, enlargement of the hole, insertion of a guest species and enclosure of the hole without loss of the encapsulated guest. The entire process involves three chemical reactions to open the hole and four reactions to gradually reduce the hole size and finally close the hole. The total yield of the product, H2@C60, based on consumed C60 was 9%. The encapsulated molecule of hydrogen exhibited a 6 ppm upfield-shifted 1H NMR signal when compared with free hydrogen, indicating the aromaticity at the inner centre of the C60 cage. PMID- 23918716 TI - Anisotropic nuclear spin interactions in H2O@C60 determined by solid-state NMR. AB - We report a solid-state NMR study of the anisotropic nuclear spin interactions in H2O@C60 at room temperature. We find evidence of significant dipole-dipole interactions between the water protons, and also a proton chemical shift anisotropy (CSA) interaction. The principal axes of these interaction tensors are found to be perpendicular. The magnitude of the CSA is too large to be explained by a model in which the water molecules are partially aligned with respect to an external axis. The evidence indicates that the observed CSA is caused by a distortion of the geometry or electronic structure of the fullerene cages, in response to the presence of the endohedral water. PMID- 23918717 TI - Spectroscopy of light-molecule endofullerenes. AB - Molecular endofullerenes are supramolecular systems consisting of fullerene cages encapsulating small molecules. Although most early examples consist of encapsulated metal clusters, recently developed synthetic routes have provided endofullerenes with non-metallic guest molecules in high purity and macroscopic quantities. The encapsulated light molecule behaves as a confined quantum rotor, displaying rotational quantization as well as translational quantization, and a rich coupling between the translational and rotational degrees of freedom. Furthermore, many encapsulated molecules display spin isomerism. Spectroscopies such as inelastic neutron scattering, nuclear magnetic resonance and infrared spectroscopy may be used to obtain information on the quantized energy level structure and spin isomerism of the guest molecules. It is also possible to study the influence of the guest molecules on the cages, and to explore the communication between the guest molecules and the molecular environment outside the cage. PMID- 23918718 TI - Probing the C60 triplet state coupling to nuclear spins inside and out. AB - The photoexcitation of functionalized fullerenes to their paramagnetic triplet electronic state can be studied by pulsed electron paramagnetic resonance (EPR) spectroscopy, whereas the interactions of this state with the surrounding nuclear spins can be observed by a related technique: electron nuclear double resonance (ENDOR). In this study, we present EPR and ENDOR studies on a functionalized exohedral fullerene system, dimethyl[9-hydro (C60-Ih)[5,6]fulleren-1(9H) yl]phosphonate (DMHFP), where the triplet electron spin has been used to hyperpolarize, couple and measure two nuclear spins. We go on to discuss the extension of these methods to study a new class of endohedral fullerenes filled with small molecules, such as H2@C60, and we relate the results to density functional calculations. PMID- 23918719 TI - Rates and energetics of intramolecular electron transfer processes in conjugated metallofullerenes. AB - In this paper, we report on the design, redox potentials, excited state energies and radical ion pair state energies in electron donor-acceptor conjugates comprising the electron-donating pi-extended tetrathiafulvalene and several electron-accepting fullerenes. To this end, we contrast an empty fullerene, that is, C60, with two endohedral metallofullerenes, that is, open-shell La@C82 and closed-shell La2@C80, in terms of charge separation and charge recombination dynamics. PMID- 23918720 TI - Nanolaboratories: physics and chemistry of small-molecule endofullerenes. AB - This Theo Murphy Meeting Issue contains papers presented at a Discussion Meeting held at the Kavli Centre of the Royal Society in March 2012. The meeting brought together a wide variety of scientists working on different aspects of small molecule endofullerenes--those intriguing chemical systems in which small molecules such as H2 or H2O are encapsulated in tiny carbon cages. PMID- 23918722 TI - Systematic review and meta-analysis of the efficacy and safety of perampanel in the treatment of partial-onset epilepsy. AB - INTRODUCTION: Perampanel is a first-in-class antiepileptic drug approved for adjunctive treatment of partial-onset seizure in patients aged 12 years or older. Published randomised controlled trials (RCTs) had small sample sizes, and meta analyses have included too few studies to draw conclusive results for the assessment of tolerability, efficacy and safety of perampanel. There is a need to conduct a meta-analysis with a larger dataset and an appropriate study design. OBJECTIVE: The aim of this study was to systematically review the efficacy and safety of perampanel in the treatment of partial-onset epilepsy. METHODS: Electronic and clinical trials databases were searched for RCTs of perampanel published up to March 2013. Outcomes of interest were 50 % responder rates, seizure freedom, treatment-emergent adverse events (TEAEs) and incidence of withdrawal. Meta-analysis was performed to investigate the outcomes of interest. RESULTS: Five RCTs with a total of 1,678 subjects were included. The 50 % responder rates were significantly greater in patients receiving 4, 8 and 12 mg perampanel versus placebo, with risk ratios of 1.54 (95 % CI 1.11-2.13), 1.80 (95 % CI 1.38-2.35) and 1.72 (95 % CI 1.17-2.52), respectively. There was no statistical evidence of a difference in seizure freedom between 8 or 12 mg perampanel and placebo. Of the five commonly reported TEAEs included, both dizziness and somnolence were statistically associated with 8 mg perampanel, whilst dizziness was statistically associated with 12 mg perampanel. Incidences of withdrawal due to adverse events were significantly higher in the 8 mg and 12 mg perampanel groups versus placebo. CONCLUSION: The use of perampanel resulted in a statistically significant reduction of seizure frequency with respect to the 50 % responder rate in patients with partial-onset epilepsy. Perampanel is well tolerated at 4 mg and reasonably tolerated at 8 and 12 mg. Further clinical and pharmacovigilance studies are required to investigate the long-term efficacy and safety of perampanel in the management of other types of epilepsy. PMID- 23918723 TI - [General principles of tumour biology in visceral surgery]. AB - Within the last decade, there has been a tremendous progress in understanding the molecular basis of cancer. In particular, the development and the characteristic features of cancer cells are being increasingly understood. The understanding of these molecular characteristics is mandatory for the development of novel, targeted therapeutic strategies and their integration into clinical practice. In addition, tumour genetics play a critically important role for hereditary cancer syndromes, with respect to both diagnostics and clinical decision-making. The aim of this review is to highlight general principles of tumour genetics from a visceral surgeon's point of view, although a comprehensive summary of all aspects would be beyond the scope of this article due to the complexity of the topic. PMID- 23918724 TI - [3D Virtual Reality Laparoscopic Simulation in Surgical Education - Results of a Pilot Study]. AB - BACKGROUND: The use of three-dimensional imaging in laparoscopy is a growing issue and has led to 3D systems in laparoscopic simulation. Studies on box trainers have shown differing results concerning the benefit of 3D imaging. There are currently no studies analysing 3D imaging in virtual reality laparoscopy (VRL). MATERIALS AND METHODS: Five surgical fellows, 10 surgical residents and 29 undergraduate medical students performed abstract and procedural tasks on a VRL simulator using conventional 2D and 3D imaging in a randomised order. RESULTS: No significant differences between the two imaging systems were shown for students or medical professionals. Participants who preferred three-dimensional imaging showed significantly better results in 2D as wells as in 3D imaging. DISCUSSION: First results on three-dimensional imaging on box trainers showed different results. Some studies resulted in an advantage of 3D imaging for laparoscopic novices. This study did not confirm the superiority of 3D imaging over conventional 2D imaging in a VRL simulator. CONCLUSION: In the present study on 3D imaging on a VRL simulator there was no significant advantage for 3D imaging compared to conventional 2D imaging. PMID- 23918725 TI - [Metaanalysis of EVAR versus open repair for patients undergoing elective repair of abdominal aortic aneurysms]. AB - INTRODUCTION: Elective endovascular abdominal aneurysm repair (EVAR) has become established in the past 20 years as a therapy option for infrarenal abdominal aortic aneurysms (AAA). Even so the benefits of EVAR over open aneurysm repair (OR) are still being discussed controversially. MATERIALS AND METHODS: A random effects meta-analysis model was used to compare the surgical outcome of EVAR with that of open operations. The end points were evaluated comparatively by use of the Peto odds ratio (Peto OR) and weighted mean differences (WMD). Four prospective randomised studies (EVAR-1, DREAM, OVER, ACE) with a total of 2747 patients (EVAR 1381, OR 1366) were included in the metaanalysis. RESULTS: In comparison to OR, EVAR was associated with a significantly reduced 30-day mortality rate (Peto OR: 0.373; p<0.001). In addition, there was a statistically significant advantage of EVAR over OR with regard to aneurysm-associated mortality (Peto OR: 0.589, p=0.013) and the length of hospital stay (SD in mean: 0.494; p<0.001). In contrast OR exhibited a lower re-intervention rate than EVAR (Peto OR: 1.843, p<0.001). On consideration of long-term survival (Peto OR: 0,977; p=0.826) and health-related quality of life there were no statistically significant differences between the two therapeutic options (SD in mean: - 0.032, p=0.481). CONCLUSIONS: In spite of the clinical heterogeneity of the studies included in the metaanalysis, the data indicate that EVAR has a marked benefit with regard to surgical mortality. In the long-term course this advantage in survival is lost but this is not due to the aneurysm-associated mortality. PMID- 23918726 TI - [Principles of Teaching in Surgery - State of the Art]. AB - Ten to 15 years ago the number of applications for a surgical residency position was very much larger than the positions available. Today, this situation has clearly reversed itself as indicated through a noticeable deficit in recruits. The decision to become a surgeon has become more uncommon. This can be blamed upon not only the demotivatingly viewed "work-life imbalance" associated with being a surgeon, but also on the basically non-inspiring training process during medical school. Due to the fact that university educators/instructors are not fundamentally trained teachers, they often fail in their capacity to convey their extensive knowledge to medical students and potentially future surgical residents. The quality of primary as well as postgraduate training is an important central factor in the effort to once again restore the attractive image of surgery within the realm of the medical disciplines. This paper presents an overview of the basic modern training concepts by which every surgeon should be able to effectively convey knowledge and practical skills. Furthermore, this work should inspire a more intensive interest in clinical graduate and postgraduate education. Due to the hand in hand relationship, this manuscript does not differentiate between student teaching and postgraduate training. PMID- 23918727 TI - [The role of peroral endoscopic myotomy (POEM) in achalasia]. AB - Achalasia is a rare motility disorder of the oesophagus. Classic achalasia is characterised by a lack of propulsive peristalsis of the distal oesophagus and incomplete relaxation of the lower oesophageal sphincter (LES). Traditionally achalasia is treated either endoscopically by pneumatic balloon dilatation or laparoscopically by Heller's myotomy. Both therapeutic procedures show a comparable effectiveness. Recently, peroral endoscopic myotomy was introduced as a new definitive treatment option. So far, this minimally invasive therapy was evaluated in a few clinical studies only. In this survey, peroral endoscopic myotomy is presented and compared to the well established surgical treatment. The diagnosis of achalasia is based on the patient's medical history and analysis of symptoms and particularly on oesophageal manometry. In addition, a barium swallow (oesophagram) and upper endoscopy are performed to rule out other reasons causing dysphagia. The patient's complaints should be recorded by use of a symptoms score. The POEM procedure starts with an incision of the mucosa at the level of the mid-oesophagus. Then, a submucosal tunnel is created distally passing approximately 2 cm over the oesophagogastric junction. After this step, myotomy of (at least) the circular muscle bundle of the distal oesophagus is performed and should be extended to a distance of 2 cm over the cardiac. Finally the mucosal entry site at the level of the mid-oesophagus is closed with endoscopic clips. First results of this technique are very promising with significant symptom relief and reduction of the mean LES pressure. In conclusion, POEM is a new, minimally invasive therapeutic option for the treatment of oesophageal achalasia. First results are very promising; long-term results and results of comparative clinical trials with established treatment methods must be awaited. PMID- 23918728 TI - Copy number variations of complement component C4 are associated with Behcet's disease but not with ankylosing spondylitis associated with acute anterior uveitis. AB - OBJECTIVE: Complement component C4 copy number variations are associated with various inflammatory diseases. This study was undertaken to investigate whether copy number variations of C4 are also involved in the pathogenesis of Behcet's disease (BD). METHODS: Gene expression was examined by enzyme-linked immunosorbent assay (ELISA) or real-time polymerase chain reaction (PCR). Copy number variations of C4 isotypes (C4A and C4B) were detected by real-time PCR in 905 patients with BD, 205 patients with ankylosing spondylitis (AS) and acute anterior uveitis, and 1,238 controls. The activation of CD4+ T cells was analyzed by flow cytometry, and cytokine production was detected by ELISA. RESULTS: Protein expression of total C4 in serum was significantly increased in patients with active BD compared with those with inactive BD or controls (Bonferroni corrected P [Pcorr ] = 1.64 * 10(-4) and Pcorr = 0.037, respectively), but not in patients with AS and acute anterior uveitis. Copy number variation analysis identified a significantly increased frequency of more than 2 copies of C4A in BD patients (P = 1.65 * 10(-7) , odds ratio [OR] 2.84). HLA-B51, which is located on the same chromosome as C4, showed a strong association with BD in the Han Chinese population (P = 8.90 * 10(-65) , OR 5.05), but logistic regression showed that C4A copy number variation was an independent risk factor for BD. A significantly increased expression of C4A was observed in the high copy number groups (>2 copies or 2 copies) versus the low copy number group (Pcorr = 0.019 and Pcorr = 0.044, respectively). Increased production of interleukin-6 (IL-6) was also observed in the high C4A copy number group (Pcorr = 0.037). No effect of C4 copy number variation on the expression of T cell activation markers was detected. CONCLUSION: Our findings indicate that a high copy number of C4A confers risk for BD by modulating the expression of C4A and enhancing IL-6 production. PMID- 23918729 TI - Brain magnetic resonance imaging findings in Smith-Lemli-Opitz syndrome. AB - Smith-Lemli-Opitz syndrome (SLOS) is a neurodevelopmental disorder caused by inborn errors of cholesterol metabolism resulting from mutations in 7 dehydrocholesterol reductase (DHCR7). There are only a few studies describing the brain imaging findings in SLOS. This study examines the prevalence of magnetic resonance imaging (MRI) abnormalities in the largest cohort of patients with SLOS to date. Fifty-five individuals with SLOS (27 M, 28 F) between age 0.17 years and 25.4 years (mean = 6.2, SD = 5.8) received a total of 173 brain MRI scans (mean = 3.1 per subject) on a 1.5T GE scanner between September 1998 and December 2003, or on a 3T Philips scanner between October 2010 and September 2012; all exams were performed at the Clinical Center of the National Institutes of Health. We performed a retrospective review of these imaging studies for both major and minor brain anomalies. Aberrant MRI findings were observed in 53 of 55 (96%) SLOS patients, with abnormalities of the septum pellucidum the most frequent (42/55, 76%) finding. Abnormalities of the corpus callosum were found in 38 of 55 (69%) patients. Other findings included cerebral atrophy, cerebellar atrophy, colpocephaly, white matter lesions, arachnoid cysts, Dandy-Walker variant, and type I Chiari malformation. Significant correlations were observed when comparing MRI findings with sterol levels and somatic malformations. Individuals with SLOS commonly have anomalies involving the midline and para-midline structures of the brain. Further studies are required to examine the relationship between structural brain abnormalities and neurodevelopmental disability in SLOS. PMID- 23918730 TI - An exploration of factors predicting malnutrition in patients with advanced head and neck cancer. AB - OBJECTIVES/HYPOTHESIS: Malnutrition is common among head and neck cancer patients and negatively impacts on survival and quality of life. This study aimed to identify predictors of malnutrition at time of diagnosis in order to identify patients at risk and enable early nutritional support and prevent malnutrition. MATERIALS AND METHOD: A total of 134 patients with advanced oral and pharyngeal cancer were included in the study. Weight, body mass index (BMI), fat free mass (FFM), dysphagia, and quality of life were measured at diagnosis and after 6 months. Two definitions for malnutrition were applied: >10% weight loss and BMI <20 after 6 months. RESULTS: Six months after diagnosis, 66% of the patients were malnourished as per the >10% weight loss definition, and 26% of the patients were malnourished as per the BMI < 20 weight loss definition. In multivariate analysis, low BMI followed by low FFM and dysphagia were the strongest predictors for malnutrition using BMI <20. Chemotherapy and high BMI at diagnosis were the strongest predictors of malnutrition using the 10% weight loss definition. For patients treated with chemotherapy, the risk for malnutrition was very high both for patients with normal BMI (67%) and for patients with BMI 30 (89%). CONCLUSION: Unintended weight loss more than 10% seems to be the most reasonable definition of malnutrition for identifying predictors of this in head and neck cancer patients. The weight loss correlated significantly to a loss of FFM. Treatment with chemotherapy was a strong predictor, as was a high BMI at time of diagnosis. This is an important finding since overweight patients might not be considered at high risk for developing malnutrition, and consequently nutritional support for them might be delayed. PMID- 23918731 TI - Radionuclide Imaging of Infection and Inflammation: A Pictorial Case-Based Atlas. PMID- 23918732 TI - Reply: Value of 99mTc-macroaggregated albumin SPECT for radioembolization treatment planning. PMID- 23918733 TI - Interobserver agreement of qualitative analysis and tumor delineation of 18F fluoromisonidazole and 3'-deoxy-3'-18F-fluorothymidine PET images in lung cancer. AB - As the preparation phase of a multicenter clinical trial using (18)F-fluoro-2 deoxy-d-glucose ((18)F-FDG), (18)F-fluoromisonidazole ((18)F-FMISO), and 3'-deoxy 3'-(18)F-fluorothymidine ((18)F-FLT) in non-small cell lung cancer (NSCLC) patients, we investigated whether 18 nuclear medicine centers would score tracer uptake intensity similarly and define hypoxic and proliferative volumes for 1 patient and we compared different segmentation methods. METHODS: Ten (18)F-FDG, ten (18)F-FMISO, and ten (18)F-FLT PET/CT examinations were performed before and during curative-intent radiotherapy in 5 patients with NSCLC. The gold standards for uptake intensity and volume delineation were defined by experts. The between center agreement (18 nuclear medicine departments connected with a dedicated network, SFMN-net [French Society of Nuclear Medicine]) in the scoring of uptake intensity (5-level scale, then divided into 2 levels: 0, normal; 1, abnormal) was quantified by kappa-coefficients (kappa). The volumes defined by different physicians were compared by overlap and kappa. The uptake areas were delineated with 22 different methods of segmentation, based on fixed or adaptive thresholds of standardized uptake value (SUV). RESULTS: For uptake intensity, the kappa values between centers were, respectively, 0.59 for (18)F-FDG, 0.43 for (18)F FMISO, and 0.44 for (18)F-FLT using the 5-level scale; the values were 0.81 for (18)F-FDG and 0.77 for both (18)F-FMISO and (18)F-FLT using the 2-level scale. The mean overlap and mean kappa between observers were 0.13 and 0.19, respectively, for (18)F-FMISO and 0.2 and 0.3, respectively, for (18)F-FLT. The segmentation methods yielded significantly different volumes for (18)F-FMISO and (18)F-FLT (P < 0.001). In comparison with physicians, the best method found was 1.5 * maximum SUV (SUVmax) of the aorta for (18)F-FMISO and 1.3 * SUVmax of the muscle for (18)F-FLT. The methods using the SUV of 1.4 and the method using 1.5 * the SUVmax of the aorta could be used for (18)F-FMISO and (18)F-FLT. Moreover, for (18)F-FLT, 2 other methods (adaptive threshold based on 1.5 or 1.6 * muscle SUVmax) could be used. CONCLUSION: The reproducibility of the visual analyses of (18)F-FMISO and (18)F-FLT PET/CT images was demonstrated using a 2-level scale across 18 centers, but the interobserver agreement was low for the (18)F-FMISO and (18)F-FLT volume measurements. Our data support the use of a fixed threshold (1.4) or an adaptive threshold using the aorta background to delineate the volume of increased (18)F-FMISO or (18)F-FLT uptake. With respect to the low tumor-on background ratio of these tracers, we suggest the use of a fixed threshold (1.4). PMID- 23918734 TI - Radiobiologic optimization of combination radiopharmaceutical therapy applied to myeloablative treatment of non-Hodgkin lymphoma. AB - Combination treatment is a hallmark of cancer therapy. Although the rationale for combination radiopharmaceutical therapy was described in the mid-1990s, such treatment strategies have only been implemented clinically recently and without a rigorous methodology for treatment optimization. Radiobiologic and quantitative imaging-based dosimetry tools are now available that enable rational implementation of combined targeted radiopharmaceutical therapy. Optimal implementation should simultaneously account for radiobiologic normal-organ tolerance while optimizing the ratio of 2 different radiopharmaceuticals required to maximize tumor control. We have developed such a methodology and applied it to hypothetical myeloablative treatment of non-Hodgkin lymphoma (NHL) patients using (131)I-tositumomab and (90)Y-ibritumomab tiuxetan. METHODS: The range of potential administered activities (AAs) is limited by the normal-organ maximum tolerated biologic effective doses (MTBEDs) arising from the combined radiopharmaceuticals. Dose-limiting normal organs are expected to be the lungs for (131)I-tositumomab and the liver for (90)Y-ibritumomab tiuxetan in myeloablative NHL treatment regimens. By plotting the limiting normal-organ constraints as a function of the AAs and calculating tumor biologic effective dose (BED) along the normal-organ MTBED limits, we obtained the optimal combination of activities. The model was tested using previously acquired patient normal-organ and tumor kinetic data and MTBED values taken from the literature. RESULTS: The average AA value based solely on normal-organ constraints was 19.0 +/- 8.2 GBq (range, 3.9-36.9 GBq) for (131)I-tositumomab and 2.77 +/- 1.64 GBq (range, 0.42-7.54 GBq) for (90)Y-ibritumomab tiuxetan. Tumor BED optimization results were calculated and plotted as a function of AA for 5 different cases, established using patient normal-organ kinetics for the 2 radiopharmaceuticals. Results included AA ranges that would deliver 95% of the maximum tumor BED, allowing for informed inclusion of clinical considerations, such as a maximum allowable (131)I administration. CONCLUSION: A rational approach for combination radiopharmaceutical treatment has been developed within the framework of a proven 3-dimensional (3D) personalized dosimetry software, 3D-RD, and applied to the myeloablative treatment of NHL. We anticipate that combined radioisotope therapy will ultimately supplant single radioisotope therapy, much as combination chemotherapy has substantially replaced single-agent chemotherapy. PMID- 23918735 TI - Determination of the in vivo selectivity of a new kappa-opioid receptor antagonist PET tracer 11C-LY2795050 in the rhesus monkey. AB - (11)C-LY2795050 is a novel kappa-selective antagonist PET tracer. The in vitro binding affinities (Ki) of LY2795050 at the kappa-opioid (KOR) and MU-opioid (MOR) receptors are 0.72 and 25.8 nM, respectively. Thus, the in vitro KOR/MOR binding selectivity is about 36:1. Our goal in this study was to determine the in vivo selectivity of this new KOR antagonist tracer in the monkey. METHODS: To estimate the ED50 value (dose of a compound [or drug] that gives 50% occupancy of the target receptor) of LY2795050 at the MOR and KOR sites, 2 series of blocking experiments were performed in 3 rhesus monkeys using (11)C-LY2795050 and (11)C carfentanil with coinjections of various doses of unlabeled LY2795050. Kinetic modeling was applied to calculate regional binding potential (BP(ND)), and 1- and 2-site binding curves were fitted to these data to measure (11)C-LY2795050 binding selectivity. RESULTS: The LY2795050 ED50 at MOR was 119 MUg/kg based on a 1-site model for (11)C-carfentanil. The 1-site binding model was also deemed sufficient to describe the specific binding of (11)C-LY2795050 at KOR. The ED50 at KOR estimated from the 1-site model was 15.6 MUg/kg. Thus, the ED50 ratio for MOR:KOR was 7.6. CONCLUSION: The in vivo selectivity of (11)C-LY2795050 for KOR over MOR is 7.6. (11)C-LY2795050 has 4.7-fold-lower selectivity at KOR over MOR in vivo as compared with in vitro. Nevertheless, on the basis of our finding in vivo, 88% of the PET-observed specific binding of (11)C-LY2795050 under baseline conditions will be due to binding of the tracer at the KOR site in a region with similar prevalence of KOR and MOR. (11)C-LY2795050 is sufficiently selective for KOR over MOR in vivo to be considered an appropriate probe for studying the KOR with PET. PMID- 23918736 TI - Hypermetabolism in 18F-FDG PET predicts favorable outcome following decompressive surgery in patients with degenerative cervical myelopathy. AB - The aim of this study was to prospectively assess the regional changes of glucose metabolism of the cervical spinal cord in patients with degenerative cervical spine stenosis and symptomatic cervical myelopathy after decompressive surgery using (18)F-FDG PET. METHODS: Twenty patients with symptomatic degenerative monosegmental cervical stenosis with neuroradiologic signs of spinal cord compression underwent decompressive surgery. The clinical course using a functional status score (Japanese Orthopedic Association [JOA] score), (18)F-FDG uptake, and MR imaging were assessed before and at follow-up 12 mo after surgery. Pre- and postoperative changes of (18)F-FDG PET were correlated to the patients' clinical outcome. RESULTS: Ten patients demonstrated preoperatively a focally increased (18)F-FDG uptake at the level of the stenosis. At follow-up, the uptake declined significantly (P = 0.008), and a significant improvement of JOA scores (P < 0.001) could be observed. The remaining 10 patients were characterized preoperatively by an inconspicuous glucose uptake at the level of cord compression in combination with a poststenotic decrease of (18)F-FDG uptake. At follow-up, both JOA scores and (18)F-FDG uptake changed insignificantly. CONCLUSION: Focal glucose hypermetabolism at the level of cervical spinal cord compression may predict an improved outcome after surgical decompression. Thus, this finding on (18)F-FDG PET suggests a functional damage in a reversible phase of cervical myelopathy. PMID- 23918737 TI - Subsequent malignancies and their effect on survival in patients with retinoblastoma. AB - BACKGROUND: As cure rates for retinoblastoma have improved, it is clear that patients with hereditary retinoblastoma experience increased risk of subsequent malignant neoplasms (SMNs). METHODS: Using the Surveillance, Epidemiology and End Results (SEER) database, we evaluated risk of SMNs in survivors or retinoblastoma. Standardized mortality ratios (SMRs) were calculated to compare number of deaths observed to the expected number for the cohort. Cumulative incidence of SMNs and standardized incidence ratios (SIRs) of observed to expected SMNs were calculated RESULTS: A total of 595 patients were included in the analysis. Cumulative incidence of secondary malignancy at 30 years for patients with unilateral and bilateral disease was 1.7% and 28.5%, respectively (P < 0.001). SIRs of subsequent malignancies for patients with unilateral and bilateral disease were 2.1 (95% CI = 0.6-5.4) and 38.3 (95% CI = 24.3-57.5), respectively. Patients with bilateral disease treated with and without radiotherapy both experienced an increased risk of SMNs (SIRs = 45.9, 95% CI = 26.8-73.6 and 27.3, 95% CI = 10.0-59.4, respectively). The most common cause of death for the patients with bilateral disease was subsequent malignancy (52% of deaths). Beginning in the 1990s, there was a significant decrease in the use of radiotherapy as 30.5% of patients received radiotherapy in the 1980s compared to 2.6% after 1999 (P < 0.001). CONCLUSIONS: Survivors of bilateral retinoblastoma experience an increased risk of SMNs which adversely affects survival. The use of radiotherapy in the management of retinoblastoma has declined; however, patients with bilateral disease remain at an increased risk of subsequent cancers. PMID- 23918738 TI - Wirksamkeit und Vertraglichkeit eines pflanzlichen Arzneimittels mit Kapuzinerkressenkraut und Meerrettich bei akuter Sinusitis, akuter Bronchitis und akuter Blasenentzundung im Vergleich zu anderen Therapien unter den Bedingungen der taglichen Praxis. PMID- 23918739 TI - Multiple lupus-associated ITGAM variants alter Mac-1 functions on neutrophils. AB - OBJECTIVE: Multiple studies have demonstrated that single-nucleotide polymorphisms (SNPs) in the ITGAM locus (including the nonsynonymous SNPs rs1143679, rs1143678, and rs1143683) are associated with systemic lupus erythematosus (SLE). ITGAM encodes the protein CD11b, a subunit of the beta2 integrin Mac-1. The purpose of this study was to determine the effects of ITGAM genetic variation on the biologic functions of neutrophil Mac-1. METHODS: Neutrophils from ITGAM-genotyped and -sequenced healthy donors were isolated for functional studies. The phagocytic capacity of neutrophil ITGAM variants was probed with complement-coated erythrocytes, serum-treated zymosan, heat-treated zymosan, and IgG-coated erythrocytes. The adhesion capacity of ITGAM variants, in adhering to either purified intercellular adhesion molecule 1 or tumor necrosis factor alpha-stimulated endothelial cells, was assessed in a flow chamber. Expression levels of total CD11b and activation of CD11b were assessed by flow cytometry. RESULTS: Mac-1-mediated neutrophil phagocytosis, determined in cultures with 2 different complement-coated particles, was significantly reduced in individuals with nonsynonymous variant alleles of ITGAM. This reduction in phagocytosis was related to variation at either rs1143679 (in the beta-propeller region) or rs1143678/rs1143683 (highly linked SNPs in the cytoplasmic/calf-1 regions). Phagocytosis mediated by Fcgamma receptors was also significantly reduced in donors with variant ITGAM alleles. Similarly, firm adhesion of neutrophils was significantly reduced in individuals with variant ITGAM alleles. These functional alterations were not attributable to differences in total receptor expression or activation. CONCLUSION: The nonsynonymous ITGAM variants rs1143679 and rs1143678/rs113683 contribute to altered Mac-1 function on neutrophils. These results underscore the need to consider multiple nonsynonymous SNPs when assessing the functional consequences of ITGAM variation on immune cell processes and the risk of SLE. PMID- 23918740 TI - Sleep quality and disease severity in patients with chronic rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: To evaluate sleep quality in patients with chronic rhinosinusitis (CRS) using a validated outcome measure and to compare measures of CRS disease severity with sleep dysfunction. STUDY DESIGN: Cross-sectional evaluation of a multi-center cohort. METHODS: According to the 2007 Adult Sinusitis Guidelines, patients with CRS were prospectively enrolled from four academic, tertiary care centers across North America. Each subject completed the Pittsburgh Sleep Quality Index (PSQI) instrument, in addition to CRS-specific measures of quality-of-life (QOL), endoscopy, computed tomography (CT), and olfaction. Patient demographics, comorbid conditions, and clinical measures of disease severity were compared between patients with "good" (PSQI; <=5) and "poor" (PSQI; > 5) sleep quality. RESULTS: Patients (n = 268) reported a mean PSQI score of 9.4 (range: 0-21). Seventy-five percent of patients reported PSQI scores above the traditional cutoff, indicating poor sleep quality. Patients with poor sleep quality were found to have significantly worse QOL scores on both the Rhinosinusitis Disability Index (P < 0.001) and 22-item Sinonasal Outcome Test (P < 0.001). No significant differences in average endoscopy, CT, or olfactory function scores were found between patients with good or poor sleep quality. Tobacco smokers reported worse average PSQI total scores compared to nonsmokers (P = 0.030). Patients reporting poor sleep were more likely to have a history of depression, even after controlling for gender (P = 0.020). CONCLUSION: The majority of patients with CRS have a poor quality of sleep, as measured by the PSQI survey. Poor sleep quality is significantly associated with CRS-specific QOL, gender, comorbid depression, and tobacco use, but not CT score or endoscopy grade. LEVEL OF EVIDENCE: 2b. PMID- 23918741 TI - Prognostic markers in stage I oral cavity squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: Early-stage oral squamous cell carcinoma (OSCC) treatment is based on anatomic location, clinical TNM staging, and histological grade. It is a heterogeneous disease group. Classification of patients with OSCC by immunohistochemical analysis of established oncoproteins and evaluate disease course was our primary objective. Characterization of stage I OSCC patients in Southwest Finland was our secondary objective. STUDY DESIGN: Immunohistochemical analysis of tumor specimens and retrospective analysis of patient data of the patient treated in Turku University Hospital for T1N0M0 OSCC during the years 2000-2004. METHODS: Paraffin-embedded tumor specimens from 35 OSCC patients were collected and analyzed for HIF-1alpha, CD44, p16, Ki67, and podoplanin by immunohistochemistry and correlated with clinical findings. RESULTS: Tumoral CD44 and HIF1-alpha expression levels, in combination, predicted 5-year disease-free survival. Reduced expression of CD44 and elevated expression of HIF1-alpha is associated with the lowest probability of disease-free survival compared to the population as a whole (P < .001 in Kaplan-Meier analysis). Patients with grade I tumors demonstrated improved disease-specific survival compared to those with grade II tumors (P = .027). No association was seen between p16 expression, Ki67 labeling index, or podoplanin expression and prognosis in our 35 specimens. CONCLUSIONS: HIF-1alpha and CD44 immunohistochemical detection could potentially serve as a prognostic tool in therapy selection for early-stage OSCC. LEVEL OF EVIDENCE: 2b. PMID- 23918742 TI - Material loss at the taper junction of retrieved large head metal-on-metal total hip replacements. AB - It has been speculated that material loss, either as corrosion or wear, at the head-stem taper junction is implicated in the high revision rates reported for metal-on-metal total hip replacements. We measured the volume of material loss from the taper and bearing surfaces of retrieved devices, and investigated the associations with blood metal ion levels and the diagnosis of a cystic or solid pseudotumor. The median volumes of material lost from the female and male taper surfaces were 2.0 and 0.29 mm(3) , respectively, while the median volumes of wear from the cup and head bearing surfaces were 1.94 and 3.44 mm(3) , respectively. Material loss from the female taper was similar to that from the acetabular bearing surface (p = 0.55), but significantly less than that from the femoral bearing surface (p < 0.001). Material loss from the male taper was less than that from both bearing surfaces (p < 0.001). Multivariable analysis demonstrated no significant correlations between the volume of material lost from the taper surfaces and either blood cobalt or chromium ions, or the presence of pseudotumor. While a substantial volume of material is lost at the taper junction, the clinical significance of this debris remains unclear. PMID- 23918743 TI - A method to account for track overlap in CR-39 detectors. AB - Solid-state nuclear track detectors are commonly used for the detection of indoor radon levels. However, despite numerous advantages, this technique still presents many unsolved problems. An important source of error is represented by the reduction in the detection efficiency due to overlapping tracks, which results in a sensible underestimation of the radon levels. This paper presents a new experimental procedure to address the effect of overlapping tracks by establishing a relationship between the detection efficiency and the number of detected tracks. Experimental data have been collected at the radon chamber of the Istituto Nazionale di Metrologia delle Radiazioni Ionizzanti (INMRI), at the ENEA centre in Casaccia, using CR-39 detectors provided by Radosys Ltd. It has been proved that the method, applied to the experimental settings of this study, gives reliable results up to 7607 kBq h m(-3). Finally, the method has been validated through a Monte Carlo simulation, exploring a wide range of radon exposure. PMID- 23918744 TI - Optimising radiographic bitewing examination to adult and juvenile patients through the use of anthropomorphic phantoms. AB - Four anthropomorphic phantoms (an adult male, an adult female, a 10-y-old child and a 5-y-old child) were exposed to bitewing radiographs at film and digital settings using both rectangular and round collimation. Optically stimulated dosemeters were used. For children, average organ doses were <40 uGy and the organs with the highest doses were the salivary glands, parotid, oral mucosa, skin and extrathoracic airway. For adults, average organ doses were <200 uGy. Highest adult doses were to the salivary glands, oral mucosa and skin. Effective doses ranged from 1.5 to 1.8 uSv for children and from 2.6 to 3.6 uSv for adults when optimised technique factors were employed, including digital receptors, rectangular collimation, size-appropriate exposure times and proper clinical judgment. Optimised doses were a fraction of the natural daily background exposure. Therefore, predictions of hypothetical cancer incidence or detriment in patient populations exposed to such low doses are highly speculative and should be discouraged. PMID- 23918745 TI - Ototoxicity of aluminum acetate/benzethonium chloride otic solution in the chinchilla animal model. AB - OBJECTIVES/HYPOTHESIS: To determine the ototoxic potential of aluminum acetate (0.5%)/benzethonium chloride (0.03%) otic solution in the chinchilla animal model. STUDY DESIGN: A randomized, prospective, controlled study was conducted in the chinchilla animal model. METHODS: Fourteen female chinchillas were used. After an incision was made in each tympanic membrane, baseline auditory brainstem response measurements were performed at 16, 20, and 25 kHz. One ear was randomized to receive aluminum acetate (0.5%)/benzethonium chloride (0.03%), whereas the other ear served as the control and received 0.9% NaCl. Solutions were applied transtympanically once a day for 3 consecutive days. Postapplication auditory brainstem response measurements were done at day 7 and day 30. In half of the animals, scanning electron microscopy was done following the last auditory brainstem response measurement. RESULTS: A statistically significant difference was found between the mean threshold shifts in the experimental and control ears at all frequencies on both 7 and 30 days postapplication (P < .02). Increased ossification of the cochleae was seen in experimental ears (n = 12). Scanning electron microscopy study demonstrated outer hair cell damage and/or loss in the experimental ears. No significant morphological changes were detected on scanning electron microscopy obtained from the control ears. CONCLUSIONS: Application of aluminum acetate (0.5%)/benzethonium chloride (0.03%) otic solution causes hearing loss in chinchillas when a tympanic membrane perforation exists. Further studies are needed to test the effect of this otic solution on hearing. LEVEL OF EVIDENCE: 4. PMID- 23918746 TI - Small intragenic deletion in FOXP2 associated with childhood apraxia of speech and dysarthria. AB - Relatively little is known about the neurobiological basis of speech disorders although genetic determinants are increasingly recognized. The first gene for primary speech disorder was FOXP2, identified in a large, informative family with verbal and oral dyspraxia. Subsequently, many de novo and familial cases with a severe speech disorder associated with FOXP2 mutations have been reported. These mutations include sequencing alterations, translocations, uniparental disomy, and genomic copy number variants. We studied eight probands with speech disorder and their families. Family members were phenotyped using a comprehensive assessment of speech, oral motor function, language, literacy skills, and cognition. Coding regions of FOXP2 were screened to identify novel variants. Segregation of the variant was determined in the probands' families. Variants were identified in two probands. One child with severe motor speech disorder had a small de novo intragenic FOXP2 deletion. His phenotype included features of childhood apraxia of speech and dysarthria, oral motor dyspraxia, receptive and expressive language disorder, and literacy difficulties. The other variant was found in a family in two of three family members with stuttering, and also in the mother with oral motor impairment. This variant was considered a benign polymorphism as it was predicted to be non-pathogenic with in silico tools and found in database controls. This is the first report of a small intragenic deletion of FOXP2 that is likely to be the cause of severe motor speech disorder associated with language and literacy problems. PMID- 23918747 TI - De novo complex X chromosome rearrangement unmasking maternally inherited CSF2RA deletion in a girl with pulmonary alveolar proteinosis. AB - We report on a 3-year-old girl with a de novo complex X chromosome rearrangement associated with congenital pulmonary alveolar proteinosis (PAP) and short stature. Array comparative genome hybridization and FISH analyses contributed to characterize the complex rearrangement consisting of a 7.37 Mb terminal deletion of Xp22.33p22.2, a 17.3 Mb interstitial inverted duplication of Xp22.2p21.3, and a 10.14 Mb duplication of Xq27.3q28. PCR analysis of microsatellite markers supported a paternal origin of the X chromosome rearrangement. A pre-meiotic two step mechanism may explain the occurrence of this complex X rearrangement: an inverted duplication deletion event on Xp, and duplication of the Xq27.3qter region through a telomere capture event stabilizing the broken chromosome Xp end. The girl has also inherited from her healthy mother an X chromosome with a colony stimulating factor 2 receptor, alpha (CSF2RA) gene deletion. Consistent with the recessive mode of inheritance, the de novo paternal Xp22.33p22.2 deletion combined to the maternally inherited CSF2RA gene deletion led to homozygous deletion of CSF2RA and PAP diagnosis in the girl. The Xp deletion encompasses the pseudoautosomal region 1 (PAR1) which contains genes that escape X inactivation. Short stature homeobox (SHOX) haploinsufficiency explains growth retardation. Absence of other symptoms in relation to the X deletion/amplification is most probably due to skewed X inactivation. Finally, inherited deletions may unmask rare pathogenic genomic rearrangement and contribute to clinical phenotypes by a recessive mode of gene action. PMID- 23918748 TI - Endothelial nitric oxide synthase, cyclooxygenase-2, and essential hypertension: is there an interaction? PMID- 23918750 TI - Angiotensin-(1-7)-induced renal vasodilation in hypertensive humans is attenuated by low sodium intake and angiotensin II co-infusion. AB - Current evidence suggests that angiotensin-(1-7) plays an important role in the regulation of tissue blood flow. This evidence, however, is restricted to studies in animals and human forearm. Therefore, we studied the effects of intrarenal angiotensin-(1-7) infusion on renal blood flow in hypertensive humans. To assess the influence of renin-angiotensin system activity, sodium intake was varied and co-infusion with angiotensin II was performed in a subgroup. In 57 hypertensive patients who were scheduled for renal angiography, renal blood flow was measured ((133)Xenon washout method) before and during intrarenal infusion of angiotensin (1-7) (3 incremental doses: 0.27, 0.9, and 2.7 ng/kg per minute). Patients were randomized into low or high sodium intake. These 2 groups of patients received angiotensin-(1-7), with or without intrarenal co-infusion of angiotensin II (0.3 ng/kg per minute). Angiotensin-(1-7) infusion resulted in intrarenal vasodilation in patients adhering to a sodium-rich diet. This vasodilatory effect of angiotensin-(1-7) was clearly attenuated by low sodium intake, angiotensin II co infusion, or both. Regression analyses showed that the prevailing renin concentration was the only independent predictor of angiotensin-(1-7)-induced renal vasodilation. In conclusion, angiotensin-(1-7) induces renal vasodilation in hypertensive humans, but the effect of angiotensin-(1-7) is clearly attenuated by low sodium intake and co-infusion of angiotensin II. This supports the hypothesis that angiotensin-(1-7) induced renal vasodilation depends on the degree of renin-angiotensin-system activation. PMID- 23918749 TI - Hypoxia-inducible factor-1alpha in vascular smooth muscle regulates blood pressure homeostasis through a peroxisome proliferator-activated receptor-gamma angiotensin II receptor type 1 axis. AB - Hypertension is a major worldwide health issue for which only a small proportion of cases have a known mechanistic pathogenesis. Of the defined causes, none have been directly linked to heightened vasoconstrictor responsiveness, despite the fact that vasomotor tone in resistance vessels is a fundamental determinant of blood pressure. Here, we reported a previously undescribed role for smooth muscle hypoxia-inducible factor-1alpha (HIF-1alpha) in controlling blood pressure homeostasis. The lack of HIF-1alpha in smooth muscle caused hypertension in vivo and hyperresponsiveness of resistance vessels to angiotensin II stimulation ex vivo. These data correlated with an increased expression of angiotensin II receptor type I in the vasculature. Specifically, we show that HIF-1alpha, through peroxisome proliferator-activated receptor-gamma, reciprocally defined angiotensin II receptor type I levels in the vessel wall. Indeed, pharmacological blockade of angiotensin II receptor type I by telmisartan abolished the hypertensive phenotype in smooth muscle cell-HIF-1alpha-KO mice. These data revealed a determinant role of a smooth muscle HIF-1alpha/peroxisome proliferator activated receptor-gamma/angiotensin II receptor type I axis in controlling vasomotor responsiveness and highlighted an important pathway, the alterations of which may be critical in a variety of hypertensive-based clinical settings. PMID- 23918751 TI - Potassium channel openers increase aortic elastic fiber formation and reverse the genetically determined elastin deficit in the BN rat. AB - Hypertension is a cardiovascular disorder that appears in more than half of the patients with Williams-Beuren syndrome, hemizygous for the elastin gene among 26 to 28 other genes. It was shown that the antihypertensive drug minoxidil, an ATP dependent potassium channel opener, enhances elastic fiber formation; however, no wide clinical application was developed because of its adverse side effects. The Brown Norway rat was used here as an arterial elastin-deficient model. We tested 3 different potassium channel openers, minoxidil, diazoxide, and pinacidil, and 1 potassium channel blocker, glibenclamide, on cultured smooth muscle cells from Brown Norway rat aorta. All tested potassium channel openers increased mRNAs encoding proteins and enzymes involved in elastic fiber formation, whereas glibenclamide had the opposite effect. The higher steady-state level of tropoelastin mRNA in minoxidil-treated cells was attributable to an increase in both transcription and mRNA stability. Treatment of Brown Norway rats for 10 weeks with minoxidil or diazoxide increased elastic fiber content and decreased cell number in the aortic media, without changing collagen content. The minoxidil induced cardiac hypertrophy was reduced when animals simultaneously received irbesartan, an angiotensin II-receptor antagonist. This side effect of minoxidil was not observed in diazoxide-treated animals. In conclusion, diazoxide, causing less undesirable side effects than minoxidil, or coadministration of minoxidil and irbesartan, increases elastic fiber content, decreases cell number in the aorta and, thus, could be suitable for treating vascular pathologies characterized by diminished arterial elastin content and simultaneous hypertension. PMID- 23918753 TI - Do optimal antihypertensive drug regimens allow blood pressure normalization in all patients with resistant hypertension? PMID- 23918752 TI - Prevalence of optimal treatment regimens in patients with apparent treatment resistant hypertension based on office blood pressure in a community-based practice network. AB - Hypertensive patients with clinical blood pressure (BP) uncontrolled on >=3 antihypertensive medications (ie, apparent treatment-resistant hypertension [aTRH]) comprise ~28% to 30% of all uncontrolled patients in the United States. However, the proportion receiving these medications in optimal doses is unknown; aTRH is used because treatment adherence and measurement artifacts were not available in electronic record data from our >200 community-based clinics Outpatient Quality Improvement Network. This study sought to define the proportion of uncontrolled hypertensives with aTRH on optimal regimens and clinical factors associated with optimal therapy. During 2007-2010, 468 877 hypertensive patients met inclusion criteria. BP <140/<90 mm Hg defined control. Multivariable logistic regression was used to assess variables independently associated with optimal therapy (prescription of diuretic and >=2 other BP medications at >=50% of maximum recommended hypertension doses). Among 468 877 hypertensives, 147 635 (31.5%) were uncontrolled; among uncontrolled hypertensives, 44 684 were prescribed >=3 BP medications (30.3%), of whom 22 189 (15.0%) were prescribed optimal therapy. Clinical factors independently associated with optimal BP therapy included black race (odds ratio, 1.40 [95% confidence interval, 1.32-1.49]), chronic kidney disease (1.31 [1.25-1.38]), diabetes mellitus (1.30 [1.24-1.37]), and coronary heart disease risk equivalent status (1.29 [1.14-1.46]). Clinicians more often prescribe optimal therapy for aTRH when cardiovascular risk is greater and treatment goals lower. Approximately 1 in 7 of all uncontrolled hypertensives and 1 in 2 with uncontrolled aTRH are prescribed >=3 BP medications in optimal regimens. Prescribing more optimal pharmacotherapy for uncontrolled hypertensives including aTRH, confirmed with out of-office BP, could improve hypertension control. PMID- 23918754 TI - Hypertensive disorders of pregnancy and cardiometabolic health in adolescent offspring. AB - An accumulating body of evidence suggests that offspring of mothers with preeclampsia have higher blood pressure during childhood and young adulthood compared with women without preeclampsia. However, the evidence with regard to offspring glucose metabolism and lipids is more scant. We examined whether maternal hypertensive disorders of pregnancy (preeclampsia and gestational hypertension) are associated with a range of cardiometabolic health measures in adolescent offspring. We included data for mother-offspring pairs from a United Kingdom prospective birth cohort (the Avon Longitudinal Study of Parents and Children). Repeat antenatal clinic measures of blood pressure and proteinuria (median 14 and 11, respectively) were used to ascertain maternal preeclampsia (n=53) and gestational hypertension (n=431). Offspring had blood pressure (n=4438), and fasting lipids, insulin, and glucose (n=2888) measured at a mean age of 17 years. There was no strong evidence of differences in fasting insulin, glucose, or lipid concentrations. Systolic and diastolic blood pressures were higher in offspring of mothers with gestational hypertension (mean difference, 2.06 mm Hg; 95% confidence interval, 1.28-2.84 and 1.11 mm Hg; 95% confidence interval, 0.54-1.69, respectively) and preeclampsia (1.12 mm Hg; 95% confidence interval, -0.89-3.12 and 1.71 mm Hg; 95% confidence interval, 0.23-3.17, respectively) compared with offspring of mothers without hypertensive disorders of pregnancy, adjusting for potential confounders (age, sex, maternal age at delivery, household social class, prepregnancy body mass index, parity, and smoking in pregnancy). Results suggest a specific association between maternal hypertensive disorders of pregnancy and offspring blood pressure that may be driven by genetics or familial nongenetic risk factors particular to blood pressure. PMID- 23918755 TI - Effectiveness of adrenalectomy and aldosterone antagonists for long-term treatment of primary aldosteronism. PMID- 23918756 TI - Behavioural interventions to reduce sexual risk for HIV in heterosexual couples: a meta-analysis. AB - OBJECTIVES: The current study was conducted to synthesise evaluations of couple based HIV prevention interventions, assess the efficacy of these interventions in reducing sexual risk, and identify moderators of intervention efficacy. METHODS: A comprehensive literature search identified 29 interventions (22 reports; N=5168 couples) that met the inclusion criteria, including enrolment of both members of a heterosexual couple, measurement of condom use at baseline and follow-up, and sufficient statistical information to calculate effect sizes. Effect sizes were analysed using fixed-effects and random-effects assumptions; factors related to intervention efficacy were identified using metaregression. RESULTS: Overall, there were significant increases in condom use from baseline to follow-up (d+=0.78, 95% CI 0.48 to 1.09) and significant decreases in partner concurrency (d+=0.37, 95% CI 0.13 to 0.60). Condom use increased to a greater extent when studies were conducted toward the beginning of the epidemic, were located in countries scoring lower on the Human Development Index, enrolled serodiscordant couples, and delivered intervention content in multiple contexts. Couples who had been together longer, reported higher incidence of sexually transmitted infection, were provided voluntary counselling and testing, and provided outcome measures during face-to-face interviews also reported larger increases in condom use. CONCLUSIONS: Couple-based interventions are efficacious in reducing unprotected sex within the context of romantic relationships. Future research should continue to improve risk reduction for couples. PMID- 23918757 TI - Dynamic relationship of left-ventricular dyssynchrony and contractile reserve in patients undergoing cardiac resynchronization therapy. AB - AIMS: Contradicting reports have been published regarding the relation between a dobutamine-induced increase in either cardiac dyssynchrony or left-ventricular ejection fraction (LVEF) and the response to cardiac resynchronization therapy (CRT). Using apical rocking (ApRock) as surrogate dyssynchrony parameter, we investigated the dobutamine stress echocardiography (DSE)-induced changes in left ventricular (LV) dyssynchrony and LVEF and their potential pathophysiological interdependence. METHODS AND RESULTS: Fifty-eight guideline-selected CRT candidates were prospectively enrolled for low-dose DSE. Dyssynchrony was quantified by the amplitude of ApRock. An LVEF increase during stress of >5% was regarded significant. Scar burden was assessed by magnetic resonance imaging. Mean follow-up after CRT implantation was 41 +/- 13 months for the occurrence of cardiac death. ApRock during DSE predicted CRT response (AUC 0.88, 95% CI 0.77 0.99, P < 0.001) and correlated inversely with changes in EF (r = -0.6, P < 0.001). Left-ventricular ejection fraction changes during DSE were not associated with CRT response (P = 0.082). Linear regression analysis revealed an inverse association of LVEF changes during DSE with both, total scar burden (B = -2.67, 95CI -3.77 to -1.56, P < 0.001) and the DSE-induced change in ApRock amplitude (B = -1.23, 95% CI -1.53 to -0.94, P < 0.001). Kaplan-Meier analysis revealed that DSE-induced increase in ApRock, but not LVEF, was associated with improved long term survival. CONCLUSION: During low-dose DSE in CRT candidates with baseline dyssynchrony, myocardial contractile reserve predominantly results in more dyssynchrony, but less in an increase in LVEF. Dyssynchrony at baseline and its dobutamine-induced changes are predictive of both response and long-term survival following CRT. PMID- 23918758 TI - Twiddler syndrome causing an inappropriate implantable cardioverter-defibrillator shock. PMID- 23918759 TI - A very-late migrated coronary stent mimicking aortic root vegetation. PMID- 23918760 TI - Major regional disparities in outcomes after sudden cardiac arrest during sports. AB - AIMS: Characteristics of sudden cardiac arrest (SCA) during sports offers a novel (and unexplored) setting to assess factors associated with disparities in outcomes across regions. METHODS AND RESULTS: From a prospective 5-year community based French registry concerning SCA during sports in 10-75 year-olds, we evaluated whether outcomes differed significantly between geographic regions. We then determined the extent to which variations in community-related early interventions were associated with regional variations in survival. Among 820 SCA cases studied, overall survival at hospital discharge was 15.7% (95% confidence interval, 13.2-18.2%), with considerable regional disparities (from 3.4 to 42.6%, P < 0.001). Major differences were noted regarding bystander initiation of cardiopulmonary resuscitation (15.3-80.9%, P < 0.001) and presence of initial shockable rhythm (28.6-79.1%, P < 0.001), with higher values of these being associated with better survival rates. The proportion of survivors with favourable neurological outcome at discharge was fairly uniform among survival groups (CPC-1/2, varying from 77.4 to 90.0%, P = 0.83). No difference was observed regarding subjects' characteristics and circumstances of SCA occurrence, including delays in resuscitation (collapse-to-call period). With a comparable in hospital mortality (P = 0.44), survival at hospital discharge was highly correlated with that at hospital admission (regional variations from 7.4 to 75.0%, P < 0.001). CONCLUSION: Major regional disparities exist in survival rates (up to 10-fold) after SCA during sports. SCA cases from regions with the highest levels of bystander resuscitation had the best survival rates to hospital admission and discharge. PMID- 23918761 TI - Change of obstruction level during drug-induced sleep endoscopy according to sedation depth in obstructive sleep apnea. AB - OBJECTIVES/HYPOTHESIS: We evaluated the change in upper airway collapse according to the depth of sedation during drug-induced sleep endoscopy (DISE), as well as characteristics possibly associated with that change. STUDY DESIGN: Prospective, single center, observational study. METHODS: Twenty-nine patients with upper airway collapse were twice evaluated using DISE according to the depth of sedation, as confirmed by the bispectral index (BIS), which is a measure of the level of consciousness. Changes in the site and degree of obstruction according to the change in sedation depth at the retropalatal and the retroglossal levels were evaluated. The possible contributing factors of this change were explored. RESULTS: As DISE sedation deepened, the upper airway became narrower in 37% of patients at the retropalatal level and in 44.8% of patients at the retroglossal level. No clinical, polysomnographic, or cephalometric variables showed any association with the change in the degree of retroglossal airway narrowing, with the exception of mouth breathing during DISE. CONCLUSIONS: The degree of upper airway narrowing can be aggravated according to the sedation depth. The monitoring of sedation depth during DISE is critical, especially in patients with mouth breathing. PMID- 23918762 TI - Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3 methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1. AB - 3-Methylglutaconic aciduria (3-MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3-MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3-MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2-6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the disease MEGDHEL syndrome. PMID- 23918763 TI - Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis. AB - Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis. PMID- 23918764 TI - mHealth: a mechanism to deliver more accessible, more effective mental health care. AB - The increased popularity and functionality of mobile devices has a number of implications for the delivery of mental health services. Effective use of mobile applications has the potential to (a) increase access to evidence-based care; (b) better inform consumers of care and more actively engage them in treatment; (c) increase the use of evidence-based practices; and (d) enhance care after formal treatment has concluded. The current paper presents an overview of the many potential uses of mobile applications as a means to facilitate ongoing care at various stages of treatment. Examples of current mobile applications in behavioural treatment and research are described, and the implications of such uses are discussed. Finally, we provide recommendations for methods to include mobile applications into current treatment and outline future directions for evaluation. KEY PRACTITIONER MESSAGE: Mobile devices are becoming increasingly common among the adult population and have tremendous potential to advance clinical care. Mobile applications have the potential to enhance clinical care at stages of treatment-from engaging patients in clinical care to facilitating adherence to practices and in maintaining treatment gains. Research is needed to validate the efficacy and effectiveness of mobile applications in clinical practice. Research on such devices must incorporate assessments of usability and adherence in addition to their incremental benefit to treatment. PMID- 23918765 TI - A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations. AB - Nuclear-encoded disorders of mitochondrial translation are clinically and genetically heterogeneous. Genetic causes include defects of mitochondrial aminoacyl-tRNA synthetases, and factors required for initiation, elongation and termination of protein synthesis as well as ribosome recycling. We report on a new case of myopathy, lactic acidosis and sideroblastic anemia (MLASA) syndrome caused by defective mitochondrial tyrosyl aminoacylation. The patient presented at 1 year with anemia initially attributed to iron deficiency. Bone marrow aspirate at 5 years revealed ringed sideroblasts but transfusion dependency did not occur until 11 years. Other clinical features included lactic acidosis, poor weight gain, hypertrophic cardiomyopathy and severe myopathy leading to respiratory failure necessitating ventilatory support. Long-range PCR excluded mitochondrial DNA rearrangements. Clinical diagnosis of MLASA prompted direct sequence analysis of the YARS2 gene encoding the mitochondrial tyrosyl-tRNA synthetase, which revealed homozygosity for a known pathogenic mutation, c.156C>G;p.F52L. Comparison with four previously reported cases demonstrated remarkable clinical homogeneity. First line investigation of MLASA should include direct sequence analysis of YARS2 and PUS1 (encoding a tRNA modification factor) rather than muscle biopsy. Early genetic diagnosis is essential for counseling and to facilitate appropriate supportive therapy. Reasons for segregation of specific clinical phenotypes with particular mitochondrial aminoacyl tRNA synthetase defects remain unknown. PMID- 23918766 TI - A retrospective review comparing the treatment outcomes of emergency lung resection for massive haemoptysis with and without preoperative bronchial artery embolization. AB - OBJECTIVES: The objective of this review was to determine the feasibility of emergency lung resection for massive haemoptysis without preoperative bronchial artery embolization (BAE). The potential for fatal recurrent haemoptysis following BAE may be avoided if surgery is undertaken instead. Furthermore, if the outcomes for emergency lung resection with and without BAE are equivalent, it may be advisable to bypass BAE and proceed directly to resection. METHODS: A retrospective review of case records from January 2005 to October 2007 of patients admitted to the Department of Cardiothoracic Surgery with massive haemoptysis deemed suitable for emergency lung resection was undertaken. Following urgent clinical evaluation, emergency lung resection with or without preoperative BAE was undertaken. If BAE was selected, the timing of lung resection was dependent upon the presence of recurrent haemoptysis. RESULTS: Sixty-one patients with massive haemoptysis were deemed suitable for emergency lung resection. Forty-one patients had lung resection without BAE. One patient (2%) had recurrent minor haemoptysis after surgery. Other complications included 2 deaths, 1 post-resection empyema thoracis and 1 deep thoracotomy wound infection. Twenty patients underwent surgery following BAE. Fifteen (75%) patients had recurrent haemoptysis after BAE. None developed recurrent haemoptysis after surgery. Other complications included 1 death and 2 post resection empyema thoraces. CONCLUSIONS: This retrospective study suggests that emergency lung resection is feasible in appropriately selected patients presenting with radiologically localized disease and massive haemoptysis. These data also suggest that BAE is probably best utilized as a temporizing measure in patients unsuitable for emergency lung resection. PMID- 23918767 TI - Surgical management of malignant tumours invading the inferior vena cava. AB - OBJECTIVES: The management of malignant tumours invading the inferior vena cava (IVC) generally requires a high-risk surgery with low long-term benefits. Surgical treatment with resection and/or embolectomy of the IVC may, however, be beneficial in selected patients. We describe our experience with regard to patient selection, operative technique and outcomes through a standardized and simplified approach. METHODS: Between 1996 and 2012, 37 patients underwent extended resection of malignant tumours invading the IVC. Tumour infiltration was located at the hepatic and suprahepatic segment in 23 patients (62%), the renal segment in 6 (16%), and the infrarenal segment in 8 (24%). Fourteen patients (38%) had right heart involvement, of whom 5 had a tumour thrombus located in the pulmonary arteries (PA). RESULTS: All the patients underwent a median laparotomy. A sternotomy with full liver mobilization was performed for tumours involving the PA, or the retrohepatic or supradiaphragmatic IVC. Cardiopulmonary bypass was performed in 15 patients (41%), with deep hypothermic circulatory arrest (DHCA) in 5 (14%). The 30-day mortality rate was 5.4%. The 1-, 5- and 10-year survival rates were 68.1, 45.7 and 40%, respectively, with a median survival of 18 months. Incomplete resection (R1 or R2) was the only parameter found to have a significant negative effect on survival (P = 0.003). CONCLUSIONS: Radical resection of malignant tumours invading the IVC is feasible in carefully selected patients and may require CPB with or without DHCA. Morbidity and mortality are low and the survival rates acceptable, particularly in patients with complete resection of the tumour. PMID- 23918768 TI - One-stage repair in complex multisegmental thoracic aneurysmal disease: results of a multicentre study. AB - OBJECTIVES: Patients with thoracic aneurysmal disease involving the arch and the descending or thoracoabdominal aorta may require more than one surgical intervention. The results of one-stage repair using a hybrid stent-graft in the frozen elephant trunk manner are presented. METHODS: Between January 2005 and March 2012, 113 (age 67 +/- 10 years) of 358 registered patients in the International E-Vita Open Registry were operated on for combined arch and descending and thoracoabdominal aortic aneurysm. Thirty-one (27%) patients had a previous cardiothoracic, abdominal aortic surgery or endovascular repair. The E Vita Open hybrid stent-graft was used in all cases. Postoperatively and during the follow-up (100%), aortic image examinations were performed. RESULTS: Combined arch replacement and antegrade stent-grafting distally (graft diameter 34 +/- 4 mm) were performed under selective cerebral perfusion (72 +/- 27 min) and hypothermic visceral ischaemia (65 +/- 27 min). Postoperatively, aneurysm exclusion was completely and partially achieved in 80% and 20%, respectively. In hospital mortality and survival rate after 5 years were 12% (13 of 113) and 78%, respectively. Latest aortic imaging demonstrated 93% complete aneurysm exclusion. Freedom from secondary endovascular intervention and open surgery were 88 and 90%, respectively. CONCLUSIONS: In multisegmental thoracic aneurysmal disease, combined arch replacement with distal repair by a hybrid stent-graft enables one stage treatment with acceptable mortality. Aneurysm exclusion by the stent-graft seems to be primarily curative and allows easier access for distal open or endovascular reintervention. PMID- 23918769 TI - Thoracoscopic 360 degree apical pleurodesis with turned-over parietal pleura. AB - Apical pleurodesis procedures, in addition to the resection of bullae or blebs, proved to lower the recurrence rate in spontaneous pneumothoraces. Here, we describe our thoracoscopic technique of making a 360 degrees apical pleurodesis. After resecting responsible bullae or blebs thoracoscopically, we dissect the parietal pleura off the chest wall up, turn it over on the mediastinal side, clip it on the mediastinal pleura and place the lung apex against the rough surface to promote extensive apical pleurodesis. The technique has been performed for 18 patients so far and no late recurrence of pneumothorax has been noted. PMID- 23918770 TI - Long- and short-term intravital imaging reveals differential spatiotemporal recruitment and function of myelomonocytic cells after spinal cord injury. AB - After spinal cord injury (SCI), resident and peripheral myelomonocytic cells are recruited to the injury site and play a role in injury progression. These cells are important for clearing cellular debris, and can modulate the retraction and growth of axons in vitro. However, their precise spatiotemporal recruitment dynamics is unknown, and their respective roles after SCI remain heavily debated. Using chronic, quantitative intravital two-photon microscopy of adult mice with SCI, here we show that infiltrating lysozyme M (LysM(+)) and resident CD11c(+) myelomonocytic cells have distinct spatiotemporal recruitment profiles, and exhibit changes in morphology, motility, phagocytic activity and axon interaction patterns over time. This study provides the first in vivo description of the influx of inflammatory and resident myelomonocytic cells into the injured spinal cord and their interactions with cut axons, and underscores the importance of precise timing and targeting of specific cell populations in developing therapies for SCI. PMID- 23918771 TI - Interlimb communication to the knee flexors during walking in humans. AB - A strong coordination between the two legs is important for maintaining a symmetric gait pattern and adapting to changes in the external environment. In humans as well as animals, receptors arising from the quadriceps muscle group influence the activation of ipsilateral muscles. Moreover, strong contralateral spinal connections arising from quadriceps and hamstring afferents have been shown in animal models. Therefore, the aims of the present study were to assess if such connections also exist in humans and to elucidate on the possible pathways. Contralateral reflex responses were investigated in the right leg following unexpected unilateral knee joint rotations during locomotion in either the flexion or extension direction. Strong reflex responses in the contralateral biceps femoris (cBF) muscle with a mean onset latency of 76 +/- 6 ms were evoked only from ipsilateral knee extension joint rotations in the late stance phase. To investigate the contribution of a transcortical pathway to this response, transcranial magnetic and electrical stimulation were applied. Motor evoked potentials elicited by transcranial magnetic stimulation, but not transcranial electrical stimulation, were facilitated when elicited at the time of the cBF response to a greater extent than the algebraic sum of the cBF reflex and motor evoked potentials elicited separately, indicating that a transcortical pathway probably contributes to this interlimb reflex. The cBF reflex response may therefore be integrated with other sensory input, allowing for responses that are more flexible. We hypothesize that the cBF reflex response may be a preparation of the contralateral leg for early load bearing, slowing the forward progression of the body to maintain dynamic equilibrium during walking. PMID- 23918772 TI - Defining the neurocircuitry of exercise hyperpnoea. AB - One hundred years ago in this journal, Krogh and Lindhard published a seminal paper highlighting the importance of the brain in the control of breathing during exercise. This symposium report reviews the historical developments that have taken place since 1913, and attempts to place the detailed neurocircuitry thought to underpin exercise hyperpnoea into context by focusing on key structures that might form the command network. With the advent of enhanced neuroimaging and functional neurosurgical techniques, a unique window of opportunity has recently arisen to target potential circuits in humans. Animal studies have identified a priori sites of interest in mid-brain structures, in particular the subthalamic locomotor region (subthalamic nucleus, STN) and the periaqueductal grey (PAG), which have now been recorded from in humans during exercise. When all data are viewed in an integrative manner, the PAG, in particular the lateral PAG, and aspects of the dorsal lateral PAG, appear to be key communicating circuitry for 'central command'. Moreover, the PAG also fulfils many requirements of a command centre. It has functional connectivity to higher centres (dorsal lateral prefrontal cortex) and the basal ganglia (in particular, the STN), and receives a sensory input from contracting muscle, but, importantly, it sends efferent information to brainstem nuclei involved in cardiorespiratory control. PMID- 23918773 TI - Exposure to cocaine regulates inhibitory synaptic transmission from the ventral tegmental area to the nucleus accumbens. AB - Synaptic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) make up the backbone of the brain reward pathway, a neural circuit that mediates behavioural responses elicited by natural rewards as well as by cocaine and other drugs of abuse. In addition to the well-known modulatory dopaminergic projection, the VTA also provides fast excitatory and inhibitory synaptic input to the NAc, directly regulating NAc medium spiny neurons (MSNs). However, the cellular nature of VTA-to-NAc fast synaptic transmission and its roles in drug-induced adaptations are not well understood. Using viral-mediated in vivo expression of channelrhodopsin 2, the present study dissected fast excitatory and inhibitory synaptic transmission from the VTA to NAc MSNs in rats. Our results suggest that, following repeated exposure to cocaine (15 mg kg(-1) day(-1) * 5 days, i.p., 1 or 21 day withdrawal), a presynaptic enhancement of excitatory transmission and suppression of inhibitory transmission occurred at different withdrawal time points at VTA-to-NAc core synapses. In contrast, no postsynaptic alterations were detected at either type of synapse. These results suggest that changes in VTA-to-NAc fast excitatory and inhibitory synaptic transmissions may contribute to cocaine-induced alteration of the brain reward circuitry. PMID- 23918775 TI - Inflammatory cytokines in chronic heart failure: interleukin-8 is associated with adverse outcome. Results from CORONA. AB - AIM: We investigated the ability of prototypical inflammatory cytokines to predict clinical outcomes in a large population of patients with chronic systolic heart failure (HF). METHODS AND RESULTS: Serum levels of tumour necrosis factor alpha (TNF-alpha), soluble TNF receptors type I and II (sTNF-RI and sTNF-RII), and the chemokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) were analysed in 1464 patients with chronic ischaemic systolic HF in the CORONA study, aged >= 60 years, in NYHA class II-IV, and related to the primary endpoint (n = 320), as well as any coronary event (n = 255), all-cause mortality (n = 329), cardiovascular (CV) mortality (n = 268), and the composite endpoint hospitalization from worsening heart failure (WHF) or CV mortality (n = 547). TNF alpha, sTNF-RI, sTNF-RII, and IL-8, but not MCP-1, were independent predictors of all endpoints except the coronary endpoint in multivariable models including conventional clinical variables. After further adjustment for estimated glomerular filtration rate, the ApoB/ApoA-1 ratio, NT-proBNP, and high sensitivity C-reactive protein, only IL-8 remained a significant predictor of all endpoints (except the coronary endpoint), while sTNF- RI remained independently associated with CV mortality. Adding IL-8 to the full model led to a significant improvement in net reclassification for all-cause mortality and CV hospitalization, but only a borderline significant improvement for the primary endpoint, CV mortality, and the composite endpoint WHF hospitalization or CV mortality. CONCLUSION: Our study supports a relationship between IL-8 and outcomes in patients with chronic HF. However, the clinical usefulness of IL-8 as a biomarker in an unselected HF population is at present unclear. PMID- 23918774 TI - AMP-activated protein kinase regulates nicotinamide phosphoribosyl transferase expression in skeletal muscle. AB - Deacetylases such as sirtuins (SIRTs) convert NAD to nicotinamide (NAM). Nicotinamide phosphoribosyl transferase (Nampt) is the rate-limiting enzyme in the NAD salvage pathway responsible for converting NAM to NAD to maintain cellular redox state. Activation of AMP-activated protein kinase (AMPK) increases SIRT activity by elevating NAD levels. As NAM directly inhibits SIRTs, increased Nampt activation or expression could be a metabolic stress response. Evidence suggests that AMPK regulates Nampt mRNA content, but whether repeated AMPK activation is necessary for increasing Nampt protein levels is unknown. To this end, we assessed whether exercise training- or 5-amino-1-beta-D-ribofuranosyl imidazole-4-carboxamide (AICAR)-mediated increases in skeletal muscle Nampt abundance are AMPK dependent. One-legged knee-extensor exercise training in humans increased Nampt protein by 16% (P < 0.05) in the trained, but not the untrained leg. Moreover, increases in Nampt mRNA following acute exercise or AICAR treatment (P < 0.05 for both) were maintained in mouse skeletal muscle lacking a functional AMPK alpha2 subunit. Nampt protein was reduced in skeletal muscle of sedentary AMPK alpha2 kinase dead (KD), but 6.5 weeks of endurance exercise training increased skeletal muscle Nampt protein to a similar extent in both wild-type (WT) (24%) and AMPK alpha2 KD (18%) mice. In contrast, 4 weeks of daily AICAR treatment increased Nampt protein in skeletal muscle in WT mice (27%), but this effect did not occur in AMPK alpha2 KD mice. In conclusion, functional alpha2-containing AMPK heterotrimers are required for elevation of skeletal muscle Nampt protein, but not mRNA induction. These findings suggest AMPK plays a post-translational role in the regulation of skeletal muscle Nampt protein abundance, and further indicate that the regulation of cellular energy charge and nutrient sensing is mechanistically related. PMID- 23918776 TI - Can coronary calcium scoring and computed tomography angiography serve as a gatekeeper for invasive coronary angiography in patients with new-onset heart failure? PMID- 23918777 TI - Leptospiral LruA is required for virulence and modulates an interaction with mammalian apolipoprotein AI. AB - Leptospirosis is a worldwide zoonosis caused by spirochetes of the genus Leptospira. While understanding of pathogenesis remains limited, the development of mutagenesis in Leptospira has provided a powerful tool for identifying novel virulence factors. LruA is a lipoprotein that has been implicated in leptospiral uveitis as a target of the immune response. In this study, two lruA mutants, M754 and M765, generated by transposon mutagenesis from Leptospira interrogans serovar Manilae, were characterized. In M754, the transposon inserted in the middle of lruA, resulting in no detectable expression of LruA. In M765, the transposon inserted toward the 3' end of the gene, resulting in expression of a truncated protein. LruA was demonstrated to be on the cell surface in M765 and the wild type (WT). M754, but not M765, was attenuated in a hamster model of acute infection. A search for differential binding to human serum proteins identified a serum protein of around 30 kDa bound to the wild type and the LruA deletion mutant (M754), but not to the LruA truncation mutant (M765). Two-dimensional separation of proteins from leptospiral cells incubated with guinea pig serum identified the 28-kDa apolipoprotein A-I (ApoA-I) as a major mammalian serum protein that binds Leptospira in vitro. Interestingly, M754 (with no detectable LruA) bound more ApoA-I than did the LruA-expressing strains Manilae wild type and M765. Our data thus identify LruA as a surface-exposed leptospiral virulence factor that contributes to leptospiral pathogenesis, possibly by modulating cellular interactions with serum protein ApoA-I. PMID- 23918778 TI - Deletion of arcD in Streptococcus pneumoniae D39 impairs its capsule and attenuates virulence. AB - The arginine deiminase system (ADS) is associated with arginine catabolism and plays a role in virulence of several pathogenic bacteria. In Streptococcus pneumoniae, the ADS genes exist as a locus consisting of arcABCDT. A recent genome-wide mutagenesis approach revealed that both arcD and arcT are potentially essential in a chinchilla otitis media (OM) model. In the present study, we generated DeltaarcD, DeltaarcT, and DeltaarcDT mutants by homologous recombination and evaluated their infectivity. Our results showed that only arcD, and not arcT, of an OM isolate is required during chinchilla middle ear infection. Additionally, D39 DeltaarcD exhibited enhanced nasopharyngeal colonization and was attenuated in both mouse pneumonia and bacteremia models. In vitro, D39 DeltaarcD displayed enhanced adherence to A549 epithelial cells and increased phagocytosis by J774A.1 macrophages compared to those with the parental strain. This mutant also exhibited an impaired capsule, as detected using electron microscopy, immunofluorescence, and a capsule assay. We demonstrated that the capsule defect in the D39 DeltaarcD mutant may not be associated with a deficiency in arginine but rather is likely caused by a loss of interaction between the capsule and the transmembrane protein ArcD. PMID- 23918779 TI - Contribution of secretory antibodies to intestinal mucosal immunity against Helicobacter pylori. AB - The natural immune response to Helicobacter pylori neither clears infection nor prevents reinfection. However, the ability of secretory antibodies to influence the course of H. pylori infection has not been determined. We compared the natural progression of H. pylori infection in wild-type C57BL/6 mice with that in mice lacking the polymeric immunoglobulin receptor (pIgR) that is essential for the secretion of polymeric antibody across mucosal surfaces. H. pylori SS1 infected wild-type and pIgR knockout (KO) mice were sampled longitudinally for gastrointestinal bacterial load, antibody response, and histological changes. The gastric bacterial loads of wild-type and pIgR KO mice remained constant and comparable at up to 3 months postinfection (mpi) despite SS1-reactive secretory IgA in the intestinal contents of wild-type mice at that time. Conversely, abundant duodenal colonization of pIgR KO animals contrasted with the near-total eradication of H. pylori from the intestine of wild-type animals by 3 mpi. H. pylori was cultured only from the duodenum of those animals in which colonization in the distal gastric antrum was of sufficient density for immunohistological detection. By 6 mpi, the gastric load of H. pylori in wild-type mice was significantly lower than in pIgR KO animals. While there was no corresponding difference between the two mouse strains in gastric pathology results at 6 mpi, reductions in gastric bacterial load correlated with increased gastric inflammation together with an intestinal secretory antibody response in wild-type mice. Together, these results suggest that naturally produced secretory antibodies can modulate the progress of H. pylori infection, particularly in the duodenum. PMID- 23918780 TI - Leishmania amazonensis amastigotes trigger neutrophil activation but resist neutrophil microbicidal mechanisms. AB - Neutrophils are the first cells to infiltrate to the site of Leishmania promastigote infection, and these cells help to reduce parasite burden shortly after infection is initiated. Several clinical reports indicate that neutrophil recruitment is sustained over the course of leishmaniasis, and amastigote-laden neutrophils have been isolated from chronically infected patients and experimentally infected animals. The goal of this study was to compare how thioglycolate-elicited murine neutrophils respond to L. amazonensis metacyclic promastigotes and amastigotes derived from axenic cultures or from the lesions of infected mice. Neutrophils efficiently internalized both amastigote and promastigote forms of the parasite, and phagocytosis was enhanced in lipopolysaccharide (LPS)-activated neutrophils or when parasites were opsonized in serum from infected mice. Parasite uptake resulted in neutrophil activation, oxidative burst, and accelerated neutrophil death. While promastigotes triggered the release of tumor necrosis factor alpha (TNF-alpha), uptake of amastigotes preferentially resulted in the secretion of interleukin-10 (IL-10) from neutrophils. Finally, the majority of promastigotes were killed by neutrophils, while axenic culture- and lesion-derived amastigotes were highly resistant to neutrophil microbicidal mechanisms. This study indicates that neutrophils exhibit distinct responses to promastigote and amastigote infection. Our findings have important implications for determining the impact of sustained neutrophil recruitment and amastigote-neutrophil interactions during the late phase of cutaneous leishmaniasis. PMID- 23918781 TI - Reduced virulence of the Vibrio cholerae fadD mutant is due to induction of the extracytoplasmic stress response. AB - Vibrio cholerae, an important human intestinal pathogen, is responsible for the diarrheal disease cholera. The pathogenesis of V. cholerae is a highly coordinated process that involves diverse regulatory factors. It has recently been demonstrated that disruption of the V. cholerae fadD gene, encoding a long chain fatty acyl coenzyme A (acyl-CoA) ligase, drastically reduces expression of the major virulence genes and in vivo lethality of this important human pathogen. This effect was due to reduced membrane localization of the central virulence regulator TcpP. In this study, the reason for the impaired membrane localization of TcpP in the fadD mutant was investigated. We demonstrate that extracytoplasmic stress is induced in the V. cholerae DeltafadD strain. In response to the extracytoplasmic stress, the integral membrane protease RseP is activated and degrades the membrane-localized TcpP in the fadD mutant strain. Indeed, disruption of the rseP gene in a fadD mutant background restored membrane localization of TcpP and expression of the downstream virulence genes toxT, ctxA, and tcpA. Increased expression of the sigma(E) regulon genes in ethanol-treated wild-type V. cholerae indicated that ethanol exposure could induce an extracytoplasmic stress response in V. cholerae. Ethanol treatment also led to activation of the RseP protease activity and resulted in degradation of membrane localized TcpP and subsequent reduction in expression of the virulence genes. Taken together, these results suggest that extracytoplasmic stress response per se reduces virulence of V. cholerae by impairing membrane localization of TcpP. PMID- 23918782 TI - Characterization of botulinum neurotoxin A subtypes 1 through 5 by investigation of activities in mice, in neuronal cell cultures, and in vitro. AB - Botulinum neurotoxins (BoNTs) are synthesized by Clostridium botulinum and exist as seven immunologically distinct serotypes designated A through G. For most serotypes, several subtypes have now been described based on nominal differences in the amino acid sequences. BoNT/A1 is the most well-characterized subtype of the BoNT/A serotype, and many of its properties, including its potency, its prevalence as a food poison, and its utility as a pharmaceutical, have been thoroughly studied. In contrast, much remains unknown of the other BoNT/A subtypes. In this study, BoNT/A subtype 1 (BoNT/A1) to BoNT/A5 were characterized utilizing a mouse bioassay, an in vitro cleavage assay, and several neuronal cell based assays. The data indicate that BoNT/A1 to -5 have distinct in vitro and in vivo toxicological properties and that, unlike those for BoNT/A1, the neuronal and mouse results for BoNT/A2 to -5 do not correlate with their enzymatic activity. These results indicate that BoNT/A1 to -5 have distinct characteristics, which are of importance for a greater understanding of botulism and for pharmaceutical applications. PMID- 23918783 TI - Requirement and redundancy of the Src family kinases Fyn and Lyn in perforin dependent killing of Cryptococcus neoformans by NK cells. AB - Natural killer (NK) cells directly recognize and kill fungi, such as the pathogenic fungus Cryptococcus neoformans, via cytolytic mechanisms. However, the precise signaling pathways governing this NK cell microbicidal activity and the implications for fungal recognition are still unknown. Previously, it was reported that NK cell anticryptococcal activity is mediated through a conserved phosphatidylinositol 3-kinase-extracellular signal-regulated kinase 1/2 (PI3K ERK1/2) pathway. Using YT (a human NK-like cell line) and primary human NK cells, we sought to identify the upstream, receptor-proximal signaling elements that led to fungal cytolysis. We demonstrate that Src family kinases were activated in response to C. neoformans. Furthermore, pharmacologic inhibition with an Src kinase inhibitor blocked C. neoformans-induced downstream activation of PI3K and ERK1/2 and abrogated cryptococcal killing. At the same time, the inhibitor disrupted the polarization of perforin-containing granules toward the NK cell cryptococcal synapse but had no effect on conjugate formation between the organism and the NK cell. Finally, small interfering RNA (siRNA) double (but not single) knockdown of two Src family kinases, Fyn and Lyn, blocked cryptococcal killing. Together these data demonstrate a mechanism whereby the Src family kinases, Fyn and Lyn, redundantly mediate anticryptococcal activity through the activation of PI3K and ERK1/2, which in turn facilitates killing by inducing the polarization of perforin-containing granules to the NK cell-cryptococcal synapse. PMID- 23918784 TI - New role for DCR-1/dicer in Caenorhabditis elegans innate immunity against the highly virulent bacterium Bacillus thuringiensis DB27. AB - Bacillus thuringiensis produces toxins that target invertebrates, including Caenorhabditis elegans. Virulence of Bacillus strains is often highly specific, such that B. thuringiensis strain DB27 is highly pathogenic to C. elegans but shows no virulence for another model nematode, Pristionchus pacificus. To uncover the underlying mechanisms of the differential responses of the two nematodes to B. thuringiensis DB27 and to reveal the C. elegans defense mechanisms against this pathogen, we conducted a genetic screen for C. elegans mutants resistant to B. thuringiensis DB27. Here, we describe a B. thuringiensis DB27-resistant C. elegans mutant that is identical to nasp-1, which encodes the C. elegans homolog of the nuclear-autoantigenic-sperm protein. Gene expression analysis indicated a substantial overlap between the genes downregulated in the nasp-1 mutant and targets of C. elegans dcr-1/Dicer, suggesting that dcr-1 is repressed in nasp-1 mutants, which was confirmed by quantitative PCR. Consistent with this, the nasp 1 mutant exhibits RNA interference (RNAi) deficiency and reduced longevity similar to those of a dcr-1 mutant. Building on these surprising findings, we further explored a potential role for dcr-1 in C. elegans innate immunity. We show that dcr-1 mutant alleles deficient in microRNA (miRNA) processing, but not those deficient only in RNAi, are resistant to B. thuringiensis DB27. Furthermore, dcr-1 overexpression rescues the nasp-1 mutant's resistance, suggesting that repression of dcr-1 determines the nasp-1 mutant's resistance. Additionally, we identified the collagen-encoding gene col-92 as one of the downstream effectors of nasp-1 that play an important role in resistance to DB27. Taken together, these results uncover a previously unknown role for DCR-1/Dicer in C. elegans antibacterial immunity that is largely associated with miRNA processing. PMID- 23918786 TI - Pseudomonas guguanensis sp. nov., a gammaproteobacterium isolated from a hot spring. AB - An aerobic, Gram-stain-negative, rod-shaped bacterium (designated strain CC G9A(T)), motile by a polar-flagellum, was isolated from a hot spring water sample in Taiwan. Strain CC-G9A(T) could grow at 20-42 degrees C, pH 6.0-10.0 and tolerate up to 7% (w/v) NaCl. The 16S rRNA gene sequence analysis of strain CC G9A(T) showed pairwise sequence similarity to Pseudomonas mendocina LMG 1223(T) (97.7%), Pseudomonas alcaligenes ATCC 14909(T) (97.8 %), Pseudomonas alcaliphila DSM 17744(T) (97.8 %), Pseudomonas toyotomiensis JCM 15604(T) (97.6 %), Pseudomonas oleovorans subsp. lubricantis DSM 21016(T) (97.6 %) and Pseudomonas argentinensis BCRC 17807(T) (97.5 %), and lower sequence similarity to other species of the genus Pseudomonas. According to DNA-DNA association analysis, the relatedness of strain CC-G9A(T) to P. mendocina BCRC 10458(T), P. alcaliphila DSM 17744(T), P. alcaligenes BCRC 11893(T), P. oleovorans subsp. lubricantis DSM 21016(T), P. argentinensis BCRC 17807(T) and P. oleovorans subsp. oleovorans BCRC 11902 was 55.1+/-3.1, 13.7+/-1.5, 14.1+/-1.8, 58.5+/-1.1, 28.9+/-2.0 and 28.6+/ 1.8 %, respectively. The evolutionary trees reconstructed based on 16S rRNA, gyrB and rpoB gene sequences revealed varying phylogenetic neighbourhoods of strain CC G9A(T) with regard to the most closely related type strains. The predominant quinone system was ubiquinone (Q-9) and the DNA G+C content was 64.3+/-1.3 mol%. The major fatty acids were C10 : 0 3-OH, C12 : 0, C12 : 0 3-OH, C16 : 0 and summed features 3 and 8 consisting of C16 : 1omega7c/C16 : 1omega6c and C18 : 1omega7c/C18 : 1omega6c, respectively. The major polar lipids were diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine and phosphatidylglycerol. According to distinct phylogenetic, phenotypic and chemotaxonomic features, strain CC-G9A(T) is proposed to represent a novel species within the genus Pseudomonas for which the name Pseudomonas guguanensis sp. nov. is proposed. The type strain is CC-G9A(T) ( = BCRC 80438(T) = JCM 18416(T)). PMID- 23918787 TI - Pseudomonas guangdongensis sp. nov., isolated from an electroactive biofilm, and emended description of the genus Pseudomonas Migula 1894. AB - A Gram-negative, straight to slightly curved rod-shaped bacterium, motile with peritrichous flagella, designated SgZ-6(T), was isolated from an electroactive biofilm and was characterized by means of a polyphasic approach. Growth occurred with 0-5.0 % (w/v) NaCl (optimum 1 %), at pH 6.0-10.0 (optimum pH 7.0) and at 10 42 degrees C (optimum 30 degrees C) in trypticase soya broth. Phylogenetic analyses based on the 16S rRNA and gyrB genes identified the isolate as a member of a novel species of the genus Pseudomonas. Strain SgZ-6(T) exhibited the highest 16S rRNA gene sequence similarity to 'Pseudomonas linyingensis' CGMCC 1.10701 (97.5 %), followed by Pseudomonas sagittaria JCM 18195(T) (97.4 %), P. oleovorans subsp. lubricantis DSM 21016(T) (96.6 %), P. tuomuerensis JCM 14085(T) (96.5 %) and P. alcaliphila JCM 10630(T) (96.4 %). Strain SgZ-6(T) showed the highest gyrB gene sequence similarity of 93.7 % to 'P. linyingensis' CGMCC 1.10701 among all type strains of genus Pseudomonas. DNA-DNA pairing studies showed that strain SgZ-6(T) displayed 47.1 and 40.3 % relatedness to 'P. linyingensis' CGMCC 1.10701 and P. sagittaria JCM 18195(T), respectively. The major isoprenoid quinone was ubiquinone 9 (Q-9). The whole-cell fatty acids consisted mainly of summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c), C16 : 0 and summed feature 8 (C18 : 1omega6c and/or C18 : 1omega7c). The DNA G+C content of the genomic DNA was 68.1 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain SgZ-6(T) is proposed to represent a novel species of the genus Pseudomonas, for which the name Pseudomonas guangdongensis sp. nov. is proposed. The type strain is SgZ-6(T) ( = CCTCC AB 2012022(T) = KACC 16606(T)). An emended description of the genus Pseudomonas is also proposed. PMID- 23918788 TI - Trichonympha burlesquei n. sp. from Reticulitermes virginicus and evidence against a cosmopolitan distribution of Trichonympha agilis in many termite hosts. AB - Historically, symbiotic protists in termite hindguts have been considered to be the same species if they are morphologically similar, even if they are found in different host species. For example, the first-described hindgut and hypermastigote parabasalian, Trichonympha agilis (Leidy, 1877) has since been documented in six species of Reticulitermes, in addition to the original discovery in Reticulitermes flavipes. Here we revisit one of these, Reticulitermes virginicus, using molecular phylogenetic analysis from single-cell isolates and show that the Trichonympha in R. virginicus is distinct from isolates in the type host and describe this novel species as Trichonympha burlesquei n. sp. We also show the molecular diversity of Trichonympha from the type host R. flavipes is greater than supposed, itself probably representing more than one species. All of this is consistent with recent data suggesting a major underestimate of termite symbiont diversity. PMID- 23918785 TI - CD30 is required for activation of a unique subset of interleukin-17A-producing gammadelta T cells in innate immunity against Mycobacterium bovis Bacillus Calmette-Guerin infection. AB - Interleukin-17A (IL-17A)-producing gammadelta T cells are known to be activated following Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection. Here, we show that CD30, a member of the tumor necrosis factor (TNF) receptor superfamily, is important for activation of IL-17A-producing gammadelta T cells after BCG infection. Vgamma1(-) Vgamma4(-) gammadelta T cells preferentially expressing Vgamma6/Vdelta1 genes were identified as the major source of IL-17A in the peritoneal cavity during the early stage of BCG infection. The number of IL-17A producing Vgamma1(-) Vgamma4(-) gammadelta T cells bearing Vgamma6 increased in peritoneal exudate cells (PEC) of wild-type (WT) mice but not in those of CD30 knockout (KO) mice in response to BCG infection. Consistently, CD30 ligand (CD30L) or CD30 expression, predominantly by Vgamma1(-) Vgamma4(-) gammadelta T cells, was rapidly upregulated after BCG infection. Inhibition of CD30L/CD30 signaling by in vivo administration of a soluble CD30 and immunoglobulin fusion protein (CD30-Ig) severely impaired activation of IL-17A-producing Vgamma1(-) Vgamma4(-) gammadelta T cells in WT mice, while stimulating CD30L/CD30 signaling by in vivo administration of agonistic anti-CD30 monoclonal antibody (MAb) restored IL-17A production by Vgamma1(-) Vgamma4(-) gammadelta T cells in CD30L KO mice after BCG infection. These results suggest that CD30 signaling plays an important role in the activation of IL-17A-producing Vgamma1(-) Vgamma4(-) gammadelta T cells bearing Vgamma6 at an early stage of BCG infection. PMID- 23918789 TI - The time course of exit and entrance block during cryoballoon pulmonary vein isolation. AB - AIMS: The dynamic time course of entrance and exit block during pulmonary vein isolation (PVI) is unknown. The purpose of this series was to dynamically evaluate the manifestation of entrance and exit conduction block during simultaneous circumferential PVI. METHODS AND RESULTS: Pacing manoeuvres were performed during cryoballoon ablation of left-sided pulmonary veins (PVs) in 30 consecutive patients with a history of drug-refractory paroxysmal atrial fibrillation. At the onset of ablation continuous pacing was performed from the PV at a cycle length of 600 ms until the appearance of exit block. Once exit block was demonstrated, uninterrupted pacing was immediately transitioned to the distal coronary sinus (CS) catheter and continued at 600 ms throughout the rest of the cryoapplication. The timing of exit block, entrance block, and corresponding cryoballoon temperature were noted for all patients. In the 45 PVs when real-time PV recordings were available during cryothermal ablation, the presence of exit block was reliably demonstrated to precede entrance block (P < 0.0001) by a median of 5 s [interquartile range (IQR) 3, 12; median temperature at isolation -39 degrees C (IQR -30, -45); nadir ablation temperature -53 degrees C (IQR -48, -59)]. In all cases, when uninterrupted pacing was transitioned from the PV to the distal CS, entrance conduction from the left atrium to PV remained intact. CONCLUSION: Circumferential PV ablation results in progressive PVI, beginning with unidirectional exit block, and followed by entrance block. As exit block reliably precedes entrance block, we are able to provide justification for the exclusive use of entrance conduction block as the endpoint of cryoballoon based PVI. PMID- 23918790 TI - The impact of haemodialysis on the outcomes of catheter ablation in patients with paroxysmal atrial fibrillation. AB - AIMS: The outcomes of catheter ablation (CA) in patients with paroxysmal atrial fibrillation (PAF) who are undergoing haemodialysis (HD) have not been fully elucidated. This study aimed to determine the impact of HD on CA outcome in these patients. METHODS AND RESULTS: We examined 1364 consecutive PAF patients (mean age, 61 +/- 10 years) who underwent CA, including 32 (2.3%) patients undergoing HD. The patients undergoing HD had a significantly lower body mass index (P < 0.0001), higher CHADS2 score (P = 0.006), and higher prevalence of structural heart disease (P < 0.0001), hypertension (P = 0.002), and congestive heart failure (P = 0.02). Echocardiography indicated a larger left atrial diameter (P < 0.0001) and left ventricular diameter (P = 0.0002) in the HD patients. Haemodialysis was a significant predictor of AF recurrence (hazard ratio 2.56; 95% confidence interval 1.56-4.03; P = 0.0004) in the overall population. Sinus rhythm maintenance rates in the HD patients at 1, 3, and 5 years were 42.3, 37.6, and 19.7%, respectively, after the first procedure, and 64.7, 54.9, and 47.1%, respectively, after the final procedure (median, 2; range, 1-2 procedures); these rates were significantly lower than those in the non-HD patients (P < 0.0001). The 5-year survival rate was 78.1% in the HD patients. CONCLUSION: Haemodialysis was significantly associated with AF recurrence after CA for PAF. However, an ~50% success rate for sinus rhythm maintenance without antiarrhythmic drug therapy in HD patients suggested that CA could be an option for the treatment of AF. PMID- 23918791 TI - Early mortality in prophylactic implantable cardioverter-defibrillator recipients: development and validation of a clinical risk score. AB - AIMS: To reduce sudden cardiac death, implantable cardioverter-defibrillators (ICDs) are indicated in patients with ischaemic and non-ischaemic dilated cardiomyopathy and a left ventricular ejection fraction (LVEF) <=35%. Current guidelines do not recommend device therapy in patients with a life expectancy <1 year since benefit in these patients is low. In this study, we evaluated the incidence and predictors of early mortality (<1 year after implantation) in a consecutive primary prevention population. METHODS AND RESULTS: Analysis was performed on a prediction and validation cohort. The primary endpoint was all cause mortality at 1 year. The prediction cohort comprised 861 prophylactic ICD recipients with ischaemic cardiomyopathy or dilated cardiomyopathy from the Academic Medical Center (Amsterdam) and Thorax Center Twente (Enschede). Detailed clinical data were collected. After multivariate analysis, a risk score was developed based on age >=75 years, LVEF <= 20%, history of atrial fibrillation, and estimated glomerular filtration rate (eGFR) <=30 mL/min/1.73 m(2). Using these predictors, a low (<=1 factor), intermediate (2 factors), and high (>=3 factors) risk group could be identified with 1-year mortality of, respectively, 3.4, 10.9, and 38.9% (P< 0.01). Afterwards, the risk score was validated in 706 primary prevention patients from the Erasmus Medical Center (Rotterdam). One-year mortality was, respectively, 2.5, 13.2, and 46.3% (all P< 0.01). CONCLUSION: A simple risk score based on age, LVEF, eGFR, and atrial fibrillation can identify patients at low, intermediate, and high risk for early mortality after ICD implantation. This may be helpful in the risk assessment of ICD candidates. PMID- 23918792 TI - Treatment of obstructive sleep apnoea improves metabolic conditions and prevents initiation of antiarrhythmic therapy in a patient with atrial fibrillation. PMID- 23918794 TI - Arcobacter anaerophilus sp. nov., isolated from an estuarine sediment and emended description of the genus Arcobacter. AB - Two strains (JC83, JC84(T)) of obligately anaerobic, H2S-producing bacteria were isolated from estuarine sediment samples collected from Gangasagar, West Bengal, India. Cells were Gram-stain-negative, non-motile rods. Both strains were positive for oxidase, negative for catalase, hydrolysed casein, reduced nitrate and utilized citrate. Both strains grew chemoorganoheterotrophically with optimal pH of 7-8 (range 7-10) and at 30 degrees C (range 25-37 degrees C). C16 : 1omega7c, C18 : 1omega7c, C16 : 0 and C12 : 0 were the major fatty acids of both strains with minor amounts of C14 : 0, C12 : 0 3-OH and C18 : 0. Polar lipids of both strains included diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylcholine, phosphatidylinositol, an unidentified aminolipid (AL2), an unidentified phospholipid (PL2) and an unidentified lipid (L3). MK-6 was the major respiratory quinone. The DNA G+C content of strains JC83 and JC84(T) was 25.0 and 24.6 mol%, respectively. The strains showed DNA reassociation >85 % (86.0+/-0.5 %) (based on DNA-DNA hybridization). Based on 16S rRNA gene sequence analysis, both strains were identified as belonging to the family Campylobacteraceae of the class Epsilonproteobacteria with Arcobacter marinus CL-S1(T) (95.4 % sequence similarity) as their closest phylogenetic neighbour. On the basis of morphological, physiological and chemotaxonomic characteristics as well as phylogenetic analysis, strains JC83 and JC84(T) are considered to represent a novel species, for which the name Arcobacter anaerophilus sp. nov. is proposed. The type strain is JC84(T) ( = KCTC 15071(T) = MTCC 10956(T) = DSM 24636(T)). An emended description of the genus Arcobacter is provided. PMID- 23918793 TI - The invisible arm of immunity in common cancer chemoprevention agents. AB - Immunoprevention refers to a strategy of preventing pathogen-associated and spontaneous cancers through the use of vaccines, antibodies, and immune modulators. Immune modulators function by enhancing the endogenous ability of the immune system to monitor for malignancy, so-called "immunosurveillance." There is growing evidence that many of the most promising cancer chemoprevention agents including aspirin, COX-2 inhibitors, aromatase inhibitors, and bisphosphonates mediate their effects, in part, by enhancing immunosurveillance and reversing the immune evasive mechanisms that premalignant lesions use. In the following review, we introduce critical components of the human immune surveillance system dendritic cells, T cells, and immune suppressive cells-and discuss the emerging data suggesting that common chemoprevention agents may modulate the function of these immunologic cells. PMID- 23918795 TI - Intestinimonas butyriciproducens gen. nov., sp. nov., a butyrate-producing bacterium from the mouse intestine. AB - A Gram-positive, spore-forming, non-motile, strictly anaerobic rod-shaped bacterium was isolated from the caecal content of a TNF(deltaARE) mouse. The isolate, referred to as strain SRB-521-5-I(T), was originally cultured on a reduced agar medium containing yeast extract, rumen fluid and lactic acid as main energy and carbon sources. Phylogenetic analysis of partial 16S rRNA genes revealed that the species most closely related to strain SRB-521-5-I(T) were Flavonifractor plautii and Pseudoflavonifractor capillosus (<95 % sequence similarity; 1436 bp). In contrast to F. plautii and P. capillosus, strain SRB-521 5-I(T) contained a substantial amount of C18 : 0 dimethylacetal. Additional major fatty acids were C14 : 0 methyl ester, C16 : 0 dimethylacetal and C18 : 0 aldehyde. Strain SRB-521-5-I(T) differed in its enzyme profile from F. plautii and P. capillosus by being positive for dextrin, maltotriose, turanose, dl-lactic acid and d-lactic acid methyl ester but negative for d-fructose. In reduced Wilkins-Chalgren-Anaerobe broth, strain SRB-521-5-I(T) produced approximately 8 mM butyrate and 4 mM acetate. In contrast to F. plautii, the strain did not metabolize flavonoids. It showed intermediate resistance towards the antibiotics ciprofloxacin, colistin and tetracycline. Based on genotypic and phenotypic characteristics, we propose the name Intestinimonas butyriciproducens gen. nov., sp. nov. to accommodate strain SRB-521-5-I(T) ( = DSM 26588(T) = CCUG 63529(T)) as the type strain. PMID- 23918796 TI - Complementary populations of human adipose CD34+ progenitor cells promote growth, angiogenesis, and metastasis of breast cancer. AB - Obesity is associated with an increased frequency, morbidity, and mortality of several types of neoplastic diseases, including postmenopausal breast cancer. We found that human adipose tissue contains two populations of progenitors with cooperative roles in breast cancer. CD45(-)CD34(+)CD31(+)CD13(-)CCRL2(+) endothelial cells can generate mature endothelial cells and capillaries. Their cancer-promoting effect in the breast was limited in the absence of CD45( )CD34(+)CD31(-)CD13(+)CD140b(+) mesenchymal progenitors/adipose stromal cells (ASC), which generated pericytes and were more efficient than endothelial cells in promoting local tumor growth. Both endothelial cells and ASCs induced epithelial-to-mesenchymal transition (EMT) gene expression in luminal breast cancer cells. Endothelial cells (but not ASCs) migrated to lymph nodes and to contralateral nascent breast cancer lesions where they generated new vessels. In vitro and in vivo, endothelial cells were more efficient than ASCs in promoting tumor migration and in inducing metastases. Granulocyte colony-stimulating factor (G-CSF) effectively mobilized endothelial cells (but not ASCs), and the addition of chemotherapy and/or of CXCR4 inhibitors did not increase endothelial cell or ASC blood mobilization. Our findings suggest that adipose tissue progenitor cells cooperate in driving progression and metastatic spread of breast cancer. PMID- 23918797 TI - Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110alpha inhibitor potently blocks PI3K signaling and growth of HER2+ breast cancers. AB - We examined the effects of LJM716, an HER3 (ERBB3) neutralizing antibody that inhibits ligand-induced and ligand-independent HER3 dimerization, as a single agent and in combination with BYL719, an ATP competitive p110alpha-specific inhibitor, against HER2-overexpressing breast and gastric cancers. Treatment with LJM716 reduced HER2-HER3 and HER3-p85 dimers, P-HER3 and P-AKT, both in vitro and in vivo. Treatment with LJM716 alone markedly reduced growth of BT474 xenografts. The combination of LJM716/lapatinib/trastuzumab significantly improved survival of mice with BT474 xenografts compared with lapatinib/trastuzumab (P = 0.0012). LJM716 and BYL719 synergistically inhibited growth in a panel of HER2+ and PIK3CA mutant cell lines. The combination also inhibited P-AKT in HER2-overexpressing breast cancer cells and growth of HER2+ NCI-N87 gastric cancer xenografts more potently than LJM716 or BYL719 alone. Trastuzumab-resistant HER2+/PIK3CA mutant MDA453 xenografts regressed completely after 3 weeks of therapy with LJM716 and BYL719, whereas either single agent inhibited growth only partially. Finally, mice with BT474 xenografts treated with trastuzumab/LJM716, trastuzumab/BYL719, LJM716/BYL719, or trastuzumab/LJM716/BYL719 exhibited similar rates of tumor regression after 3 weeks of treatment. Thirty weeks after treatment discontinuation, 14% of mice were treated with trastuzumab/LJM716/BYL719, whereas >80% in all other treatment groups were sacrificed due to a recurrent large tumor burden (P = 0.0066). These data suggest that dual blockade of the HER2 signaling network with an HER3 antibody that inhibits HER2-HER3 dimers in combination with a p110alpha-specific inhibitor in the absence of a direct HER2 antagonist is an effective treatment approach against HER2-overexpressing cancers. PMID- 23918798 TI - Cohort profile: the Amirkola Health and Ageing Project (AHAP). AB - This is the first comprehensive cohort study of the health of older people ever conducted in Iran. The aim of this project is to investigate the health status of older people in Amirkola in the northern part of Iran, near the Caspian Sea. The Amirkola Health and Ageing Project (AHAP) is mainly concerned with geriatric medical problems, such as falling, bone fragility and fractures, cognitive impairment and dementia, poor mobility and functional dependence. It is planned that all participants will be re-examined after 2 years. Data are collected via questionnaire, examinations and venepuncture. AHAP started in April 2011 and 1616 participants had been seen by 18 July 2012, the end of the baseline stage of this study. The participation rate was 72.3%. The prevalence of self-reported hypertension (41.2%) and diabetes mellitus (23.3%) are high. Only 14.4% of older people considered their health as excellent or good in comparison with others at this age. The prevalence of osteoporosis (T score<=-2.5) was 57.4% in women and 16.1% in men, and 38.2 % of older people were vitamin D deficient (<20 ng/ml). Researchers interested in using the information are invited to contact the principal investigator Seyed Reza Hosseini (hosseinim46@yahoo.com). PMID- 23918799 TI - Autophagy negatively regulates early axon growth in cortical neurons. AB - Neurite growth requires neurite extension and retraction, which are associated with protein degradation. Autophagy is a conserved bulk degradation pathway that regulates several cellular processes. However, little is known about autophagic regulation during early neurite growth. In this study, we investigated whether autophagy was involved in early neurite growth and how it regulated neurite growth in primary cortical neurons. Components of autophagy were expressed and autophagy was activated during early neurite growth. Interestingly, inhibition of autophagy by atg7 small interfering RNA (siRNA) caused elongation of axons, while activation of autophagy by rapamycin suppressed axon growth. Surprisingly, inhibition of autophagy reduced the protein level of RhoA. Moreover, expression of RhoA suppressed axon overelongation mediated by autophagy inhibition, whereas inhibition of the RhoA signaling pathway by Y-27632 recovered rapamycin-mediated suppression of axon growth. Interestingly, hnRNP-Q1, which negatively regulates RhoA, accumulated in autophagy-deficient neurons, while its protein level was reduced by autophagy activation. Overall, our study suggests that autophagy negatively regulates axon extension via the RhoA-ROCK pathway by regulating hnRNP Q1 in primary cortical neurons. Therefore, autophagy might serve as a fine-tuning mechanism to regulate early axon extension. PMID- 23918800 TI - Molecular mechanism of SLC5A8 inactivation in breast cancer. AB - SLC5A8 is a putative tumor suppressor that is inactivated in more than 10 different types of cancer, but neither the oncogenic signaling responsible for SLC5A8 inactivation nor the functional relevance of SLC5A8 loss to tumor growth has been elucidated. Here, we identify oncogenic HRAS (HRAS(G12V)) as a potent mediator of SLC5A8 silencing in human nontransformed normal mammary epithelial cell lines and in mouse mammary tumors through DNMT1. Further, we demonstrate that loss of Slc5a8 increases cancer-initiating stem cell formation and promotes mammary tumorigenesis and lung metastasis in an HRAS-driven murine model of mammary tumors. Mammary-gland-specific overexpression of Slc5a8 (mouse mammary tumor virus-Slc5a8 transgenic mice), as well as induction of endogenous Slc5a8 in mice with inhibitors of DNA methylation, protects against HRAS-driven mammary tumors. Collectively, our results provide the tumor-suppressive role of SLC5A8 and identify the oncogenic HRAS as a mediator of tumor-associated silencing of this tumor suppressor in mammary glands. These findings suggest that pharmacological approaches to reactivate SLC5A8 expression in tumor cells have potential as a novel therapeutic strategy for breast cancer treatment. PMID- 23918801 TI - The PR/SET domain zinc finger protein Prdm4 regulates gene expression in embryonic stem cells but plays a nonessential role in the developing mouse embryo. AB - Prdm4 is a highly conserved member of the Prdm family of PR/SET domain zinc finger proteins. Many well-studied Prdm family members play critical roles in development and display striking loss-of-function phenotypes. Prdm4 functional contributions have yet to be characterized. Here, we describe its widespread expression in the early embryo and adult tissues. We demonstrate that DNA binding is exclusively mediated by the Prdm4 zinc finger domain, and we characterize its tripartite consensus sequence via SELEX (systematic evolution of ligands by exponential enrichment) and ChIP-seq (chromatin immunoprecipitation-sequencing) experiments. In embryonic stem cells (ESCs), Prdm4 regulates key pluripotency and differentiation pathways. Two independent strategies, namely, targeted deletion of the zinc finger domain and generation of a EUCOMM LacZ reporter allele, resulted in functional null alleles. However, homozygous mutant embryos develop normally and adults are healthy and fertile. Collectively, these results strongly suggest that Prdm4 functions redundantly with other transcriptional partners to cooperatively regulate gene expression in the embryo and adult animal. PMID- 23918802 TI - Epigenetic regulation of autophagy by the methyltransferase G9a. AB - Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although the cytoplasmic machinery that orchestrates autophagy induction during starvation, hypoxia, or receptor stimulation has been widely studied, the key epigenetic events that initiate and maintain the autophagy process remain unknown. Here we show that the methyltransferase G9a coordinates the transcriptional activation of key regulators of autophagosome formation by remodeling the chromatin landscape. Pharmacological inhibition or RNA interference (RNAi)-mediated suppression of G9a induces LC3B expression and lipidation that is dependent on RNA synthesis, protein translation, and the methyltransferase activity of G9a. Under normal conditions, G9a associates with the LC3B, WIPI1, and DOR gene promoters, epigenetically repressing them. However, G9a and G9a-repressive histone marks are removed during starvation and receptor-stimulated activation of naive T cells, two physiological inducers of macroautophagy. Moreover, we show that the c-Jun N terminal kinase (JNK) pathway is involved in the regulation of autophagy gene expression during naive-T-cell activation. Together, these findings reveal that G9a directly represses genes known to participate in the autophagic process and that inhibition of G9a-mediated epigenetic repression represents an important regulatory mechanism during autophagy. PMID- 23918803 TI - Emerging roles of competing endogenous RNAs in cancer: insights from the regulation of PTEN. AB - The capacity of noncoding RNA to regulate gene expression in health and disease is epitomized by the microRNAs, small ~22-nucleotide RNAs that target mRNAs to repress their translation into protein. Recently a previously unrecognized gene regulatory layer has emerged, characterized by the ability of a wide range of RNA transcripts to vie for microRNA binding and alleviate the repressive effect of microRNAs on their mRNA targets. Termed competing endogenous RNAs (ceRNAs), these participate in a microRNA-dependent cross talk, producing robust networks that when perturbed may lead to cancer. To date, the tumor suppressor PTEN has been most extensively validated as competing with a variety of ceRNAs in different cancers: reducing these ceRNAs appears to reduce PTEN levels, tipping cells toward cancer progression. In this review we look at ceRNA networks in cancer, their characteristics, and constituent parts, focusing on the insights that can be gained from the studies conducted on PTEN. We also explore the conditions that facilitate ceRNA cross talk, proposing that the disruption of these conditions may represent a general phenomenon in carcinogenesis. PMID- 23918804 TI - Tetrahymena telomerase holoenzyme assembly, activation, and inhibition by domains of the p50 central hub. AB - The eukaryotic reverse transcriptase, telomerase, adds tandem telomeric repeats to chromosome ends to promote genome stability. The fully assembled telomerase holoenzyme contains a ribonucleoprotein (RNP) catalytic core and additional proteins that modulate the ability of the RNP catalytic core to elongate telomeres. Electron microscopy (EM) structures of Tetrahymena telomerase holoenzyme revealed a central location of the relatively uncharacterized p50 subunit. Here we have investigated the biochemical and structural basis for p50 function. We have shown that the p50-bound RNP catalytic core has a relatively low rate of tandem repeat synthesis but high processivity of repeat addition, indicative of high stability of enzyme-product interaction. The rate of tandem repeat synthesis is enhanced by p50-dependent recruitment of the holoenzyme single-stranded DNA binding subunit, Teb1. An N-terminal p50 domain is sufficient to stimulate tandem repeat synthesis and bridge the RNP catalytic core, Teb1, and the p75 subunit of the holoenzyme subcomplex p75/p19/p45. In cells, the N terminal p50 domain assembles a complete holoenzyme that is functional for telomere maintenance, albeit at shortened telomere lengths. Also, in EM structures of holoenzymes, only the N-terminal domain of p50 is visible. Our findings provide new insights about subunit and domain interactions and functions within the Tetrahymena telomerase holoenzyme. PMID- 23918805 TI - Serine-threonine kinase receptor-associated protein (STRAP) regulates translation of type I collagen mRNAs. AB - Type I collagen is the most abundant protein in the human body and is composed of two alpha1(I) and one alpha2(I) polypeptides which assemble into a triple helix. For the proper assembly of the collagen triple helix, the individual polypeptides must be translated in coordination. Here, we show that serine-threonine kinase receptor-associated protein (STRAP) is tethered to collagen mRNAs by interaction with LARP6. LARP6 is a protein which directly binds the 5' stem-loop (5'SL) present in collagen alpha1(I) and alpha2(I) mRNAs, but it interacts with STRAP with its C-terminal domain, which is not involved in binding 5'SL. Being tethered to collagen mRNAs, STRAP prevents unrestricted translation, primarily that of collagen alpha2(I) mRNAs, by interacting with eukaryotic translation initiation factor 4A (eIF4A). In the absence of STRAP, more collagen alpha2(I) mRNA can be pulled down with eIF4A, and collagen alpha2(I) mRNA is unrestrictedly loaded onto the polysomes. This results in an imbalance of synthesis of alpha1(I) and alpha2(I) polypeptides, in hypermodifications of alpha1(I) polypeptide, and in inefficient assembly of the polypeptides into a collagen trimer and their secretion as monomers. These defects can be partially restored by supplementing STRAP. Thus, we discovered STRAP as a novel regulator of the coordinated translation of collagen mRNAs. PMID- 23918806 TI - Expression of polycomb targets predicts breast cancer prognosis. AB - Global changes in the epigenome are increasingly being appreciated as key events in cancer progression. The pathogenic role of enhancer of zeste homolog 2 (EZH2) has been connected to its histone 3 lysine 27 (H3K27) methyltransferase activity and gene repression; however, little is known about relationship of changes in expression of EZH2 target genes to cancer characteristics and patient prognosis. Here we show that through expression analysis of genomic regions with H3K27 trimethylation (H3K27me3) and EZH2 binding, breast cancer patients can be stratified into good and poor prognostic groups independent of known cancer gene signatures. The EZH2-bound regions were downregulated in tumors characterized by aggressive behavior, high expression of cell cycle genes, and low expression of developmental and cell adhesion genes. Depletion of EZH2 in breast cancer cells significantly increased expression of the top altered genes, decreased proliferation, and improved cell adhesion, indicating a critical role played by EZH2 in determining the cancer phenotype. PMID- 23918807 TI - A feedback loop consisting of microRNA 23a/27a and the beta-like globin suppressors KLF3 and SP1 regulates globin gene expression. AB - The developmental stage-specific expression of the human beta-like globin genes has been studied for decades, and many transcriptional factors as well as other important cis elements have been identified. However, little is known about the microRNAs that potentially regulate beta-like globin gene expression directly or indirectly during erythropoiesis. In this study, we show that microRNA 23a (miR 23a) and miR-27a promote beta-like globin gene expression in K562 cells and primary erythroid cells through targeting of the transcription factors KLF3 and SP1. Intriguingly, miR-23a and miR-27a further enhance the transcription of beta like globin genes through repression of KLF3 and SP1 binding to the beta-like globin gene locus during erythroid differentiation. Moreover, KLF3 can bind to the promoter of the miR-23a~27a~24-2 cluster and suppress this microRNA cluster expression. Hence, a positive feedback loop comprised of KLF3 and miR-23a promotes the expression of beta-like globin genes and the miR-23a~27a~24-2 cluster during erythropoiesis. PMID- 23918808 TI - Complete genome sequence of Streptococcus dysgalactiae subsp. equisimilis 167 carrying Lancefield group C antigen and comparative genomics of S. dysgalactiae subsp. equisimilis strains. AB - Streptococcus dysgalactiae subsp. equisimilis (SDSE) is an emerging human pathogen that causes life-threatening invasive infections such as streptococcal toxic shock syndrome. Recent epidemiological studies reveal that invasive SDSE infections have been increasing in Asia, Europe, and the United States. Almost all SDSE carry Lancefield group G or C antigen. We have determined the complete genome sequence of a human group C SDSE 167 strain. A comparison of its sequence with that of four SDSE strains, three in Lancefield group G and one in Lancefield group A, showed approximately 90% coverage. Most regions showing little or no homology were located in the prophages. There was no evidence of massive rearrangement in the genome of SDSE 167. Bayesian phylogeny using entire genome sequences showed that the most recent common ancestor of the five SDSE strains appeared 446 years ago. Interestingly, we found that SDSE 167 harbors sugar metabolizing enzymes in a unique region and streptodornase in the phage region, which presumably contribute to the degradation of host tissues and the prompted covRS mutation, respectively. A comparison of these five SDSE strains, which differ in Lancefield group antigens, revealed a gene cluster presumably responsible for the synthesis of the antigenic determinant. These results may provide the basis for molecular epidemiological research of SDSE. PMID- 23918809 TI - Evolution along the mutation gradient in the dynamic mitochondrial genome of salamanders. AB - Mitochondria are intracellular organelles where oxidative phosphorylation is carried out to complete ATP synthesis. Mitochondria have their own genome; in metazoans, this is a small, circular molecule encoding 13 electron transport proteins, 22 tRNAs, and 2 rRNAs. In invertebrates, mitochondrial gene rearrangement is common, and it is correlated with increased substitution rates. In vertebrates, mitochondrial gene rearrangement is rare, and its relationship to substitution rate remains unexplored. Mitochondrial genes can also show spatial variation in substitution rates around the genome due to the mechanism of mtDNA replication, which produces a mutation gradient. To date, however, the strength of the mutation gradient and whether movement along the gradient in rearranged (or otherwise modified) genomes impacts genic substitution rates remain unexplored in the majority of vertebrates. Salamanders include both normal mitochondrial genomes and independently derived rearrangements and expansions, providing a rare opportunity to test the effects of large-scale changes to genome architecture on vertebrate mitochondrial gene sequence evolution. We show that: 1) rearranged/expanded genomes have higher substitution rates; 2) most genes in rearranged/expanded genomes maintain their position along the mutation gradient, substitution rates of the genes that do move are unaffected by their new position, and the gradient in salamanders is weak; and 3) genomic rearrangements/expansions occur independent of levels of selective constraint on genes. Together, our results demonstrate that large-scale changes to genome architecture impact mitochondrial gene evolution in predictable ways; however, despite these impacts, the same functional constraints act on mitochondrial protein-coding genes in both modified and normal genomes. PMID- 23918810 TI - Small, smaller, smallest: the origins and evolution of ancient dual symbioses in a Phloem-feeding insect. AB - Many insects rely on bacterial symbionts with tiny genomes specialized for provisioning nutrients lacking in host diets. Xylem sap and phloem sap are both deficient as insect diets, but differ dramatically in nutrient content, potentially affecting symbiont genome evolution. For sap-feeding insects, sequenced symbiont genomes are available only for phloem-feeding examples from the suborder Sternorrhyncha and xylem-feeding examples from the suborder Auchenorrhyncha, confounding comparisons. We sequenced genomes of the obligate symbionts, Sulcia muelleri and Nasuia deltocephalinicola, of the phloem-feeding pest insect, Macrosteles quadrilineatus (Auchenorrhyncha: Cicadellidae). Our results reveal that Nasuia-ALF has the smallest bacterial genome yet sequenced (112 kb), and that the Sulcia-ALF genome (190 kb) is smaller than that of Sulcia in other insect lineages. Together, these symbionts retain the capability to synthesize the 10 essential amino acids, as observed for several symbiont pairs from xylem-feeding Auchenorrhyncha. Nasuia retains genes enabling synthesis of two amino acids, DNA replication, transcription, and translation. Both symbionts have lost genes underlying ATP synthesis through oxidative phosphorylation, possibly as a consequence of the enriched sugar content of phloem. Shared genomic features, including reassignment of the UGA codon from Stop to tryptophan, and phylogenetic results suggest that Nasuia-ALF is most closely related to Zinderia, the betaproteobacterial symbiont of spittlebugs. Thus, Nasuia/Zinderia and Sulcia likely represent ancient associates that have co-resided in hosts since the divergence of leafhoppers and spittlebugs >200 Ma, and possibly since the origin of the Auchenorrhyncha, >260 Ma. PMID- 23918811 TI - Interactions affected by arginine methylation in the yeast protein-protein interaction network. AB - Protein-protein interactions can be modulated by the methylation of arginine residues. As a means of testing this, we recently described a conditional two hybrid system, based on the bacterial adenylate cyclase (BACTH) system. Here, we have used this conditional two-hybrid system to explore the effect of arginine methylation in modulating protein-protein interactions in a subset of the Saccharomyces cerevisiae arginine methylproteome network. Interactions between the yeast hub protein Npl3 and yeast proteins Air2, Ded1, Gbp2, Snp1, and Yra1 were first validated in the absence of methylation. The major yeast arginine methyltransferase Hmt1 was subsequently included in the conditional two-hybrid assay, initially to determine the degree of methylation that occurs. Proteins Snp1 and Yra1 were confirmed as Hmt1 substrates, with five and two novel arginine methylation sites mapped by ETD LC-MS/MS on these proteins, respectively. Proteins Ded1 and Gbp2, previously predicted but not confirmed as substrates of Hmt1, were also found to be methylated with five and seven sites mapped respectively. Air2 was found to be a novel substrate of Hmt1 with two sites mapped. Finally, we investigated the interactions of Npl3 with the five interaction partners in the presence of active Hmt1 and in the presence of Hmt1 with a G68R inactivation mutation. We found that the interaction between Npl3 and Air2, and Npl3 and Ded1, were significantly increased in the presence of active Hmt1; the interaction of Npl3 and Snp1 showed a similar degree of increase in interaction but this was not statistically significant. The interactions of Npl3 and Gbp2, along with Npl3 and Yra1, were not significantly increased or decreased by methylation. We conclude that methylarginine may be a widespread means by which the interactions of proteins are modulated. PMID- 23918812 TI - LuciPHOr: algorithm for phosphorylation site localization with false localization rate estimation using modified target-decoy approach. AB - The localization of phosphorylation sites in peptide sequences is a challenging problem in large-scale phosphoproteomics analysis. The intense neutral loss peaks and the coexistence of multiple serine/threonine and/or tyrosine residues are limiting factors for objectively scoring site patterns across thousands of peptides. Various computational approaches for phosphorylation site localization have been proposed, including Ascore, Mascot Delta score, and ProteinProspector, yet few address direct estimation of the false localization rate (FLR) in each experiment. Here we propose LuciPHOr, a modified target-decoy-based approach that uses mass accuracy and peak intensities for site localization scoring and FLR estimation. Accurate estimation of the FLR is a difficult task at the individual site level because the degree of uncertainty in localization varies significantly across different peptides. LuciPHOr carries out simultaneous localization on all candidate sites in each peptide and estimates the FLR based on the target-decoy framework, where decoy phosphopeptides generated by placing artificial phosphorylation(s) on non-candidate residues compete with the non-decoy phosphopeptides. LuciPHOr also reports approximate site-level confidence scores for all candidate sites as a means to localize additional sites from multiphosphorylated peptides in which localization can be partially achieved. Unlike the existing tools, LuciPHOr is compatible with any search engine output processed through the Trans-Proteomic Pipeline. We evaluated the performance of LuciPHOr in terms of the sensitivity and accuracy of FLR estimates using two synthetic phosphopeptide libraries and a phosphoproteomic dataset generated from complex mouse brain samples. PMID- 23918813 TI - Concerns about eroding the ethical barrier to in vitro eugenics: lessons from the hESC debate. AB - In his discussion of in vitrogametogenesis, Rob Sparrow claims that an ethical barrier to development of this technology is that many jurisdictions currently prohibit the practice of creating embryos solely for the purpose of research. However, he suggests that this ethical barrier will soon be eroded, in view of the fact that in vitro gametogenesis could serve as a powerful new technology to overcome infertility. In this commentary, I argue that Sparrow is being overly optimistic in his analysis here. I claim that the debate over so-called compromise positions in the human embryonic stem cell debate suggests that the purpose of the research for which a research embryo is created is unlikely to be considered as having any significant bearing on the moral permissibility of the practice for those who oppose it. Even though in vitro gametogenesis could serve as a powerful new technology to overcome infertility, I argue that opponents of the practice of creating embryos solely for research purposes would still view the creation of research embryos that the development of in vitro gametogenesis would require, as being incompatible with affording the embryo proper moral respect. I conclude by suggesting that Sparrow's analysis of the potential benefits of in vitro gametogenesis provides us with further reasons to scrutinise the unconvincing arguments that are often cited in favour of prohibiting the practice of creating embryos solely for research purposes. PMID- 23918814 TI - The sea of the pro-life movement: a brief response to 'Reflections on the Kermit Gosnell Controversy'. PMID- 23918815 TI - Would you terminate a pregnancy affected by sickle cell disease? Analysis of views of patients in Cameroon. AB - Sickle cell disease (SCD) is a debilitating illness that affects quality of life and life expectancy for patients. In Cameroon, it is now possible to opt for termination of an affected pregnancy (TAP) where the fetus is found to be affected by SCD. Our earlier studies found that, contrary to the views of Cameroonian physicians, a majority of parents with their children suffering from SCD would choose to abort if the fetuses were found to be affected. What have not yet been investigated are the views of people suffering from/living with SCD. We used a quantitative sociological method, with administered structured questionnaires, to study the attitudes of adult patients suffering from SCD on prenatal genetic diagnosis (PND) and possible TAP. The majority of the 89 participants were urban dwellers (84.3%), women (57.3%), Christian (95.5%) and single (90.9%), with a secondary/tertiary education (79.5%). The majority (89.2%) would consider PND for SCD; almost half (48.5%) would reject TAP while 40.9% would consider it. Respondents who rejected TAP claimed mostly ethical reasons (78.1%) while those who found TAP acceptable cited fear of having an affected child (88.9%) and the poor quality of the affected child's health (81.5%). Cameroonian patients with SCD are generally supportive of PND and a remarkably high number of patients living with SCD reported that they would consider terminating a pregnancy based on their assessment of the future well-being of the child. Research is required to investigate the burden of SCD on families and their quality of life. PMID- 23918816 TI - Systemic alteration of cell-surface and secreted glycoprotein expression in malignant breast cancer cell lines. AB - Breast cancer cell lines express fewer transmembrane and secreted glycoproteins than nonmalignant ones. The objective of these experiments was to characterize the changes in the expression of several hundred glycoproteins quantitatively. Secreted and cell-surface glycoproteins were isolated using a glycoprotein capture protocol and then identified by tandem mass spectrometry. Glycoproteins expressed by a group of cell lines originating from malignant tumors of the breast were compared with those expressed by a nonmalignant set. The average number of spectral counts (proportional to relative protein abundance) and the total number of glycopeptides in the malignant samples were reduced to about two thirds of the level in the nonmalignant samples. Most glycoproteins were expressed at a different level in the malignant samples, with nearly as many increasing as decreasing. The glycoproteins with reduced expression accounted for a larger change in spectral counts, and hence for the net loss of spectral counts in the malignant lines. Similar results were found when the glycoproteins were studied via identified glycosylation sites only, or through identified sites together with non-glycopeptides. The overall reduction is largely due to the loss of integrins, laminins and other proteins that form or interact with the basement membrane. PMID- 23918817 TI - Ideology and disease identity: the politics of rickets, 1929-1982. AB - How can we assess the reciprocal impacts of politics and medicine in the contemporary period? Using the example of rickets in twentieth century Britain, I will explore the ways in which a preventable, curable non-infectious disease came to have enormous political significance, first as a symbol of socioeconomic inequality, then as evidence of racial and ethnic health disparities. Between the 1920s and 1980s, clinicians, researchers, health workers, members of Parliament and later Britain's growing South Asian ethnic communities repeatedly confronted the British state with evidence of persistent nutritional deficiency among the British poor and British Asians. Drawing on bitter memories of the 'Hungry Thirties', postwar rickets-so often described as a 'Victorian' disease-became a high-profile sign of what was variously constructed as a failure of the Welfare State; or of the political parties charged with its protection; or of ethnically Asian migrants and their descendants to adapt to British life and norms. Here I will argue that rickets prompted such consternation not because of its severity, the cost of its treatment, or even its prevalence; but because of the ease with which it was politicised. I will explore the ways in which this condition was envisioned, defined and addressed as Britain moved from the postwar consensus to Thatcherism, and as Britain's diverse South Asian communities developed from migrant enclaves to settled multigenerational ethnic communities. PMID- 23918818 TI - Salmonella enterica serovar Typhimurium BaeSR two-component system positively regulates sodA in response to ciprofloxacin. AB - In response to antibiotics, bacteria activate regulatory systems that control the expression of genes that participate in detoxifying these compounds, like multidrug efflux systems. We previously demonstrated that the BaeSR two-component system from Salmonella enterica serovar Typhimurium (S. Typhimurium) participates in the detection of ciprofloxacin, a bactericidal antibiotic, and in the positive regulation of mdtA, an efflux pump implicated in antibiotic resistance. In the present work, we provide further evidence for a role of the S. Typhimurium BaeSR two-component system in response to ciprofloxacin treatment and show that it regulates sodA expression. We demonstrate that, in the absence of BaeSR, the transcript levels of sodA and the activity of its gene product are lower. Using electrophoretic mobility shift assays and transcriptional fusions, we demonstrate that BaeR regulates sodA by a direct interaction with the promoter region. PMID- 23918820 TI - Broadening the vision: a case for community-based psychoanalysis in the context of usual practice. AB - A case is made for community-based psychoanalysis as part of usual psychoanalytic practice. A safe community is first defined psychodynamically, after which three variations are presented on the community-based style and qualities and modes of practice compared with individual psychoanalytic therapy and psychoanalysis. Three community case studies, from Jamaica and the U.S., are then presented to illustrate and lend depth and aliveness to the theory. Finally, a plea is made for a community-based initiative in preventive physical and mental health care that uses schools as a basic site for addressing the causes and cure of socially and economically costly community problems, creating healthy individuals through each turn of the pre-K through twelfth grade school cycle. PMID- 23918819 TI - Transcriptional regulation of CXCR4 in prostate cancer: significance of TMPRSS2 ERG fusions. AB - CXCR4 is a chemokine receptor that mediates invasion and metastasis. CXCR4 expression is transcriptionally regulated in cancer cells and is associated with aggressive prostate cancer phenotypes. Previously, we and others have shown that the transcription factor ERG regulates CXCR4 expression in prostate cancer cells and that androgens modulate CXCR4 expression via increasing ERG expression. Herein, the molecular mechanisms of ERG-mediated CXCR4 promoter activation, phosphorylation of ERG by intracellular kinases and subsequent CXCR4 expression, as well as the status of ERG and CXCR4 in human prostate cancer specimens were investigated. Using multiple molecular strategies, it was demonstrated that (i) ERG expressed in TMPRSS2-ERG fusion positive VCaP cells selectively binds to specific ERG/Ets bindings sites in the CXCR4 promoter; (ii) distal binding sites mediate promoter activation; (iii) exogenously expressed ERG promotes CXCR4 expression; (iv) ERG is phosphorylated at Serine-81 and -215, by both IKK and Akt kinases, and Akt mediates CXCR4 expression; (v) ERG-induced CXCR4 drives CXCL12 dependent adhesion to fibronectin; and (vi) ERG and CXCR4 were coexpressed in human prostate cancer tissue, consistent with ERG-mediated transcriptional activation of CXCR4. These data demonstrate that ERG activates CXCR4 expression by binding to specific ERG/Ets responsive elements and via intracellular kinases that phosphorylate ERG at discrete serine residues. IMPLICATIONS: These findings provide a mechanistic link between TMPRSS2-ERG translocations and intracellular kinase-mediated phosphorylation of ERG on enhanced metastasis of tumor cells via CXCR4 expression and function in prostate cancer cells. PMID- 23918821 TI - Enactment and the emergence of new relational organization. AB - Enactments are investigated from the process-oriented focus of our therapeutic approach. By embedding their occurrence within the on-going flow of nonlinear dyadic process, we focus on the subtle back-and-forth between patient and analyst, as well as the importance of what we call now moments. An alternative to the dissociative self-state model is offered that emphasizes implicit memory processes in bodily comportment and style of relating with others. We suggest that change occurs through the emergence of new relational (i.e., procedural) skills within a therapeutic relationship that is self-organizing at more inclusive levels. Treating enactment as an emergent property of the dyad means not concentrating on the level of the individual components of a system. Rather, it means regarding enactment as a property of the entire system, without which there would be no emergent property. Going forward, we suggest use of the term relational apprehension in referring to the complex process of grasping a gestalt of relational meaning as an integration of perceptions, feelings, images and imaginings, sensations, fantasies, thoughts, and intuitions. Two brief case vignettes from the literature are discussed in order to illustrate this view. PMID- 23918822 TI - Commentary on Kernberg's "suicide prevention for psychoanalytic institutes and societies". PMID- 23918823 TI - "Action" in psychoanalysis: a comparison between adult and adolescent analysis. Panel Report. PMID- 23918826 TI - J. Todd Dean on Lewis Kirshner. PMID- 23918827 TI - Lewis Kirshner responds to J. Todd Dean. PMID- 23918828 TI - Jonathan Lear responds to J. Todd Dean. PMID- 23918829 TI - Stephen Sonnenberg on Sidney Phillips: Paul Gray's Narrowing Scope. PMID- 23918830 TI - Lawrence Friedman responds to J. Todd Dean. PMID- 23918831 TI - Chemotherapy counteracts metastatic dissemination induced by antiangiogenic treatment in mice. AB - The development of resistance and progressive disease after treatment with angiogenesis inhibitors is becoming a controversial issue. We investigated the experimental conditions that cause multireceptor tyrosine kinase inhibitors (RTKI) to augment metastasis and whether opportune combinations with chemotherapy could counteract this effect. The renal Renca-luc tumor was transplanted orthotopically in the kidney of Balb/c mice, which then were or were not nephrectomized. The Lewis Lung carcinoma (LLC) was transplanted in the tibial muscle of C57/Bl6 mice. Treatment with the RTKI sunitinib started at different stages of tumor progression, mimicking neoadjuvant or adjuvant settings. Combination studies with paclitaxel, doxorubicin, cisplatin, gemcitabine, and topotecan were done on the LLC model, using opportune regimens. In a neoadjuvant setting, sunitinib inhibited Renca-luc tumor growth, prolonging survival despite an increase in lung metastasis; treatment after primary tumor surgery (adjuvant setting) or on established metastasis prolonged survival and decreased metastasis. Sunitinib increased lung metastasis from mice bearing early-stage LLC, but did not affect established metastases (no acceleration) from advanced tumors. Combinations with doxorubicin, topotecan, gemcitabine, but not cisplatin and paclitaxel, counteracted the increase in metastasis from LLC, partly reflecting their antitumor activity. Histology analysis after sunitinib confirmed tumor vascular changes and increased hypoxia. Topotecan at suboptimal daily doses reduced sunitinib-related metastasis, reducing tumor hypoxia. Tyrosine kinase inhibitors, as sunitinib, can have adverse malignant effects mainly in the neoadjuvant setting. The addition of chemotherapy might influence metastasis, depending on each drug mechanism of action and its regimen of administration. PMID- 23918832 TI - Prognostic role of lemur tyrosine kinase-3 germline polymorphisms in adjuvant gastric cancer in Japan and the United States. AB - Lemur tyrosine kinase-3 (LMTK3) was recently identified as an estrogen receptor (ER)-alpha modulator related to endocrine therapy resistance, and its polymorphisms rs9989661 (T>C) T/T genotype and rs8108419 (G>A) G/G or A/G genotype predicted improved outcomes in breast cancer. Because different predominant ER distributions link to breast and gastric cancer and little is known of the prognostic role of LMTK3 in gastric cancer, this study was carried out to clarify the prognostic role of these polymorphisms in gastric cancer. One hundred and sixty-nine Japanese and 137 U.S. patients with localized gastric adenocarcinoma were enrolled. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA sequencing. Overall, these polymorphisms were not associated with survival in both cohorts. When gender was considered, in multivariate analysis, harboring rs9989661 T/T genotype was associated with disease-free survival [HR, 4.37; 95% confidence interval (CI), 2.08-9.18; P < 0.0001] and overall survival (OS; HR, 3.69; 95% CI, 1.65-8.24; P = 0.0014) in the Japanese males and time to recurrence (HR, 7.29; 95% CI, 1.07 49.80; P = 0.043) in the U.S. females. Meanwhile, harboring rs8108419 G/G genotype was associated with OS in the Japanese females (HR, 3.04; 95% CI, 1.08 8.56; P = 0.035) and the U.S. males (HR, 3.39; 95% CI, 1.31-8.80; P = 0.012). The prognostic role of these polymorphisms may be negative in gastric cancer. These findings suggest that the estrogen pathway may play a prognostic role in patients with gastric cancer but this may be dependent on the regional differences both in physiology and genetic alterations of gastric cancer. PMID- 23918834 TI - A novel ATP1A2 gene mutation in familial hemiplegic migraine and epilepsy. AB - BACKGROUND: Familial hemiplegic migraine (FHM) is a rare autosomal dominant migraine subtype, characterized by fully reversible motor weakness as a specific symptom of aura. Mutations in the ion transportation coding genes CACNA1A , ATP1A2 and SCN1A are responsible for the FHM phenotype. Moreover, some mutations in ATP1A2 or SCN1A also may lead to epilepsy. CASE: Here we report on a three generation family with five patients having a novel ATP1A2 mutation on exon 19, causing guanine-to-adenine substitution (c.2620G>A, p.Gly874Ser) that co segregated in the five living relatives with migraine, four of whom had hemiplegic migraine. Moreover, three patients presented with epilepsy, one of whom had generalized epilepsy with febrile seizures plus (GEFS+). CONCLUSIONS: The present study provides further evidence on the involvement of ATP1A2 mutations in both migraine and epilepsy, underlying the relevance of genetic analysis in families with a comorbidity of both disorders. PMID- 23918833 TI - Subtype-specific MEK-PI3 kinase feedback as a therapeutic target in pancreatic adenocarcinoma. AB - Mutations in the KRAS oncogene are dominant features in pancreatic ductal adenocarcinoma (PDA). Because KRAS itself is considered "undruggable," targeting pathways downstream of KRAS are being explored as a rational therapeutic strategy. We investigated the consequences of MAP-ERK kinase (MEK) inhibition in a large PDA cell line panel. Inhibition of MEK activated phosphoinositide 3 kinase in an EGF receptor (EGFR)-dependent fashion and combinations of MEK and EGFR inhibitors synergistically induced apoptosis. This combinatorial effect was observed in the epithelial but not mesenchymal subtype of PDA. RNA expression analysis revealed predictors of susceptibility to the combination, including E cadherin, HER3, and the miR200-family of microRNAs, whereas expression of the transcription factor ZEB1 was associated with resistance to the drug combination. Knockdown of HER3 in epithelial-type and ZEB1 in mesenchymal-type PDA cell lines resulted in sensitization to the combination of MEK and EGFR inhibitors. Thus, our findings suggest a new, subtype-specific, and personalized therapeutic strategy for pancreatic cancer. PMID- 23918835 TI - What can data mining teach us about triptan safety that we don't already know? PMID- 23918836 TI - Definitions need to be consistent with the facts. Reply to Parisi et al. PMID- 23918837 TI - Altered brain metabolism in vestibular migraine: comparison of interictal and ictal findings. AB - BACKGROUND: Vestibular symptoms/signs frequently coexist with migraine, but the mechanisms of migraine-related vestibular dysfunction remain to be elucidated. This study aimed to determine altered brain metabolism in vestibular migraine. METHODS: Two patients with vestibular migraine underwent (18)F-fluorodeoxy glucose (FDG) positron-emission tomography (PET) during and between attacks of vestibular migraine in addition to detailed neurotological evaluation. We analyzed the regional brain metabolism of the patients in comparison with that of age-matched healthy controls in each patient. We also compared ictal with interictal FDG PET using a subtraction method. RESULTS: During the attacks, both patients showed an activation of the bilateral cerebellum and frontal cortices, and deactivation of the bilateral posterior parietal and occipitotemporal areas. One patient also showed hypermetabolism in the dorsal pons and midbrain, right posterior insula, and right temporal cortex while the other patient had an additional activation of the left temporal cortex. Compared with interictal images, ictal PET showed increased metabolism in the bilateral cerebellum, frontal cortices, temporal cortex, posterior insula, and thalami. CONCLUSION: During the attacks of vestibular migraine, the increased metabolism in the temporo-parieto-insular areas and bilateral thalami indicates activation of the vestibulo-thalamo-cortical pathway, and decreased metabolism in the occipital cortex may represent reciprocal inhibition between the visual and vestibular systems. PMID- 23918838 TI - Programming exercise intensity in patients on beta-blocker treatment: the importance of choosing an appropriate method. AB - AIM: To verify the usefulness of current recommended level of target exercise heart rate (HR) and of different HR-based methods for calculating target HR in patients with and without beta-blocker treatment. METHODS: We studied 53 patients not treated with beta-blocker and 159 patients on beta-blocker treatment. All patients underwent a maximal exercise test with gas analysis, and first ventilatory threshold (VT1 or aerobic threshold), second ventilatory threshold (VT2 or anaerobic threshold), time of exercise, maximum load, metabolic parameters, HR at rest (HRrest), HRpeak, HR at VT1 (HRVT1) and at VT2 (HRVT2), and 75, 80, and 85% of HRmax (HR75%, HR80%, HR85%) were calculated. Exercise HR was also determined using the Karvonen formula, applying 60, 70, and 80% of the heart rate reserve (HRR) (HRKarv0.6, HRKarv0.7, and HRKarv0.8). RESULTS: This study included 102 patients on a beta-blocker and 39 not treated with negative cronotropic effect drugs. Maximum load, metabolic parameters, HRrest, HRpeak, HRVT1, and HRVT2 were significantly lower in patients on beta-blocker treatment. The proportion of patients with a HR75%, HR80%, HR85%, HRKarv0.6, HRKarv0.7, and HRKarv0.8 VT2 was very high and depended on whether patients were on beta-blocker treatment. CONCLUSIONS: Prescribed exercise intensity should be within VT1 and VT2, so that the efficacy and safety is guaranteed. If determining VT1 and VT2 is not possible, HR-based methods can be used, but with caution. In fact, there will be always a proportion of patients training below VT1 or above VT2. On the other hand, recommendations for patients on a beta-blocker should be different from patients not receiving a beta-blocker. Patients not treated with a beta-blocker should exercise at HRKarv0.7 or at HR85%. In patients on a beta blocker, we recommend preferentially a target HR of HRKarv0.6 or HR80%. PMID- 23918839 TI - Cumulative impact of axial, structural, and repolarization ECG findings on long term cardiovascular mortality among healthy individuals in Japan: National Integrated Project for Prospective Observation of Non-Communicable Disease and its Trends in the Aged, 1980 and 1990. AB - AIMS: Various cohort studies have shown a close association between long-term cardiovascular disease (CVD) outcomes and individual electrocardiographic (ECG) abnormalities such as axial, structural, and repolarization changes. The combined effect of these ECG abnormalities, each assumed to be benign, has not been thoroughly investigated. METHODS AND RESULTS: Community-dwelling Japanese residents from the National Integrated Project for Perspective Observation of Non Communicable Disease and its Trends in the Aged, 1980-2004 and 1990-2005 (NIPPON DATA80 and 90), were included in this study. Baseline ECG findings were classified using the Minnesota Code and categorized into axial (left axis deviation, clockwise rotation), structural (left ventricular hypertrophy, atrial enlargement), and repolarization (minor and major ST-T changes) abnormalities. The hazard ratios of the cumulative impacts of ECG findings on long-term CVD death were estimated by stratified Cox proportional hazard models, including adjustments for cohort strata. In all, 16,816 participants were evaluated. The average age was 51.2 +/- 13.5 years; 42.7% participants were male. The duration of follow up was 300,924 person-years (mean 17.9 +/- 5.8 years); there were 1218 CVD deaths during that time. Overall, 4203 participants (25.0%) had one or more categorical ECG abnormalities: 3648 (21.7%) had a single abnormality, and 555 (3.3%) had two or more. The risk of CVD mortality increased as the number of abnormalities accumulated (single abnormality HR 1.29, 95% CI 1.13-1.48; >=2 abnormalities HR 2.10, 95% CI 1.73-2.53). CONCLUSIONS: Individual ECG abnormalities had an additive effect in predicting CVD outcome risk in our large scale cohort study. PMID- 23918840 TI - Metabolic syndrome, diabetes mellitus, or both and cardiovascular risk in outpatients with or at risk for atherothrombosis. AB - BACKGROUND: The incidence of metabolic syndrome (MetS), diabetes mellitus (DM), and their coexistence is increasing but whether MetS increases cardiovascular risk beyond component risk factors is controversial. DESIGN: We compared the risk of cardiovascular death, myocardial infarction, or stroke among patients with MetS, newly detected DM, established DM, or coexistent MetS and DM in the global REduction of Atherothrombosis for Continued Health (REACH) registry. METHODS: Outpatients with or at risk for atherothrombosis were recruited between 1 December 2003 and 31 December 2004 and followed up to 4 years for cardiovascular events. Risk was compared in patients with or without MetS or DM after adjustment for age, sex, risk factors, vascular disease, fasting blood glucose, therapy, and region. RESULTS: Among 44,548 REACH participants, 17,887 (40%) were without MetS or DM; 6459 had MetS (15%); 12,059 had established DM (27%); 7503 had both (17%); and 640 had newly detected DM (1%). Presence of MetS was not associated with higher cardiovascular events (12.6%, adjusted HR 0.98, 95% CI 0.89-1.08). In addition, once DM was evident, patients with coexistent MetS had similar increased risk (16.1%, adjusted HR 1.33, 95% CI 1.21-1.47) as DM alone (16.7%, adjusted HR 1.36, 95% CI 1.24-1.48). Newly detected DM was associated with increased cardiovascular risk (18.5%, adjusted HR 1.26, 95% CI 1.02-1.57), similar to longstanding DM. MetS was associated with incident DM (adjusted OR 1.94). CONCLUSIONS: In the REACH registry, presence of newly detected DM but not metabolic syndrome was associated with an increased risk of cardiovascular events. PMID- 23918842 TI - Cardiac rehabilitation programmes reduce vascular risk. PMID- 23918841 TI - Changes in hospitalization rates for acute coronary syndrome after a two-phase comprehensive smoking ban. AB - AIMS: The impact of a comprehensive stepwise smoking ban (2007 and 2008) was assessed by analysing the hospitalization rate for acute coronary syndrome (ACS) in France, between 2003 and 2009. METHODS AND RESULTS: Between 2003 and 2009, 867,164 hospitalizations for ACS were observed among about 23 million administrative reports. The age-and gender-standardized hospitalization rates were calculated and their variation before and after the smoking ban implementation was investigated by Poisson regression that included the ACS seasonal variations and the historical trend. The hospitalization rate decreased by 12.8% (from 269 to 235/100,000) with a significant historical trend reduction (p < 0.10(-3)) in all groups, but in young women. After adjusting for linear trend, reductions linked to the ban remained not significant in all groups: relative risk (RR) from 0.96 (95% CI 0.91-1.01) in men older than 55 years to 0.99 (95% CI 0.93-1.04) in men aged 55 years or less after the first phase, and from 0.96 (95% CI 0.89-1.04) in men older than 55 years to 1.03 (95% CI 0.94 1.12) in women older than 65 years after the second phase of the ban. CONCLUSIONS: This study did not demonstrate a significant effect of a two-phases smoking ban on ACS hospitalization rate. A steadily decrease of this rate over the 7-year period, the past preventive measures in France leading to low levels of passive smoking, and the significant increase in active smoking during the studied period may explain this result. Our study highlights the difficulty of proving an effect of smoking bans in a country with an already low ACS incidence. PMID- 23918843 TI - Patient satisfaction with participation in a randomized exercise trial: effects of randomization and a usual care posttrial exercise program. AB - BACKGROUND: Participation in an exercise trial is a major commitment for cancer survivors, but few exercise trials have evaluated patient satisfaction with trial participation. PURPOSE: To examine patient satisfaction with participation in the Healthy Exercise for Lymphoma Patients (HELP) Trial and to explore possible determinants. METHODS: The HELP Trial randomized 122 lymphoma patients to 12 weeks of supervised aerobic exercise training (AET; n = 60) or to usual care (UC; n = 62), with the option of participating in a 4-week posttrial exercise program. At the 6-month follow-up assessment, participants evaluated their overall trial satisfaction. RESULTS: Personal satisfaction with trial participation was strongly influenced by group assignment with participants randomized to AET reporting participation to be more rewarding (p < 0.001) and personally useful (p < 0.001) than participants randomized to UC. UC participants who completed the optional 4-week posttrial exercise program reported participation to be more rewarding (p = 0.008) and personally useful (p < 0.001) than UC participants who declined the program. LIMITATIONS: The study is limited by the lack of a validated measure of participant satisfaction, and the fact that the offer of participation in the posttrial exercise program to the UC group was not randomized. CONCLUSIONS: Lymphoma patients randomized to UC viewed it as less rewarding and personally useful despite being offered a 4-week posttrial exercise program. UC participants who completed the 4-week program reported personal satisfaction levels similar to the AET group; however, the causal direction of this association is unknown. Researchers should continue to evaluate participant satisfaction in exercise trials. PMID- 23918844 TI - Millennium Development Goals national targets are moving targets and the results will not be known until well after the deadline of 2015. PMID- 23918845 TI - Revisiting the discourse on accomplishing MDG-4. PMID- 23918846 TI - To the Editors of The Lancet: Professor Lustig's plague serum. PMID- 23918847 TI - Commentary: An experimental theatre for vaccines--Bombay in the time of plague. PMID- 23918848 TI - Commentary: N.H. Choksy and serum therapy. PMID- 23918849 TI - The Kaya HDSS, Burkina Faso: a platform for epidemiological studies and health programme evaluation. AB - The Kaya Health and Demographic Surveillance System (Kaya HDSS) is located in the North Central region of Burkina Faso in the Kaya health district. The main purposes of the Kaya HDSS are to study demographic, infectious and chronic disease indicators in the district, to observe changes in health over time, evaluate health programmes and to provide a basis for policy decisions and capacity building in order to enhance the health of the community. Kaya HDSS was established in late 2007 following a baseline census of the population of the HDSS area. Homes were visited every 6 months to collect demographic information and data on morbidity and mortality. A verbal autopsy questionnaire is used to collect information on the causes of death. The Kaya HDSS reached 64,480 residents in 10,587 households by the end of 2011, with an average of 6.1 +/- 4.3 persons per household. The site is 70% urban and 30% rural. The population is 51.8% female. Over 55% of deaths occur outside health facilities. Malaria is the leading cause of death, primarily affecting children under 5 years of age (44%) and those 5 to 14 years old (36%). The Kaya HDSS data can be obtained by sending a request via the HDSS website (http://kaya-hdss.org/). PMID- 23918850 TI - Effectiveness of demand and supply side interventions in promoting institutional deliveries--a quasi-experimental trial from rural north India. AB - BACKGROUND: We assessed the differential and sequential effects of a Government of India conditional cash transfer scheme for the socio-economically disadvantaged (Janani Suraksha Yojana; JSY) and the strengthening of the primary health centre (PHC) network to provide 24/7 obstetric care in promoting institutional deliveries. METHODS: This study used 7796 births from the Ballabgarh Health and Demographic Surveillance Site between April 2006 and March 2010 when both schemes were implemented in a staggered manner. The multiple baseline design took advantage of interventions separated by time and geographical zone to compute difference in differences in the rate of institutional deliveries. Logistic regression was used to estimate increases in the odds of institutional deliveries after adjustment for caste and maternal education. RESULTS: Compared with villages with poor access, institutional deliveries nearly doubled among villages with access to 24/7 delivery services; odds ratio (OR) 1.9 [95% confidence interval (CI): 1.3, 2.6]. Introduction of JSY in villages with poor access resulted in a 1.4-fold (95% CI: 1.1, 1.8) increase in institutional deliveries and a 1.1-fold (95% CI: 0.9, 1.4) increase in villages served by PHCs 24/7. However, the introduction of PHC 24/7 care to villages served by JSY doubled the rate of institutional deliveries; OR 2.1 (95% CI: 1.5, 2.8). Among the disadvantaged, institutional deliveries increased by 34.4%, compared with 24.8% among the non-disadvantaged. Introduction of PHC 24/7 care in this group increased institutional deliveries 4-fold; OR 4.2 (95% CI: 1.9, 9.0) compared with 3-fold for JSY alone; OR 3.2 (95% CI: 1.8, 5.6). CONCLUSIONS: Both demand and supply side strategies are effective and promote equity. Improving service delivery in a population previously primed by demand side intervention appears to be the most useful. PMID- 23918851 TI - Peak flow as a predictor of cause-specific mortality in China: results from a 15 year prospective study of ~170,000 men. AB - BACKGROUND: Forced expiratory volume in one second (FEV1) is inversely associated with mortality in Western populations, but few studies have assessed the associations of peak expiratory flow (PEF) with subsequent cause-specific mortality, or have used populations in developing countries, including China, for such assessments. METHODS: A prospective cohort study followed ~ 170,000 Chinese men ranging in age from 40-69 years at baseline (1990-1991) for 15 years. In the study, height-adjusted PEF (h-PEF), which was uncorrelated with height, was calculated by dividing PEF by height. Hazard ratios (HR) for cause-specific mortality and h-PEF, adjusted for age, area of residence, smoking, and education, were calculated through Cox regression analyses. RESULTS: Of the original study population, 7068 men died from respiratory causes (non-neoplastic) and 22 490 died from other causes (including 1591 from lung cancer, 5469 from other cancers, and 10 460 from cardiovascular disease) before reaching the age of 85 years. Respiratory mortality was strongly and inversely associated with h-PEF. For h-PEF >= 250 L/min, the association was log-linear, with a hazard ratio (HR) of 1.29 (95% CI: 1.25-1.34) per 100 L/min reduction in h-PEF. The association was stronger but not log-linear for lower values of h-PEF. Mortality from combined other causes was also inversely associated with h-PEF, and the association was log-linear for all values of h-PEF, declining with follow-up, with HRs per 100 L/min reduction in h-PEF of 1.13 (1.10-1.15), 1.08 (1.06-1.11), and 1.06 (1.03 1.08) in three consecutive 5-year follow-up periods. Specifically, lower values of h-PEF were associated with higher mortality from cardiovascular disease and lung cancer, but not from other cancers. CONCLUSIONS: A lower value of h-PEF was associated with increased mortality from respiratory and other causes, including lung cancer and cardiovascular disease, but its associations with the other causes of death declined across the follow-up period. PMID- 23918854 TI - Matched designs and causal diagrams. AB - We use causal diagrams to illustrate the consequences of matching and the appropriate handling of matched variables in cohort and case-control studies. The matching process generally forces certain variables to be independent despite their being connected in the causal diagram, a phenomenon known as unfaithfulness. We show how causal diagrams can be used to visualize many previous results about matched studies. Cohort matching can prevent confounding by the matched variables, but censoring or other missing data and further adjustment may necessitate control of matching variables. Case-control matching generally does not prevent confounding by the matched variables, and control of matching variables may be necessary even if those were not confounders initially. Matching on variables that are affected by the exposure and the outcome, or intermediates between the exposure and the outcome, will ordinarily produce irremediable bias. PMID- 23918855 TI - Population health and status of epidemiology: WHO European Region I. AB - BACKGROUND: This article of the International Epidemiological Association commissioned paper series stocktakes the population health and status of epidemiology in 21 of the 53 countries of the WHO European Region. By United Nations geographical classification, these countries belong to Eastern Europe, Western Asia and South-Central Asia. METHODS: Published data were used to describe population health indicators and risk factors. Epidemiological training and research was assessed based on author knowledge, information searches and E mail survey of experts. Bibliometric analyses determined epidemiological publication outputs. RESULTS: Between-country differences in life expectancy, amount and profile of disease burden and prevalence of risk factors are marked. Epidemiological training is affected by ongoing structural reforms of educational systems. Training is advanced in Israel and several Eastern European countries. Epidemiological research is mainly university-based in most countries, but predominantly conducted by governmental research institutes in several countries of the former Soviet Union. Funding is generally external and limited, partially due to competition from and prioritization of biomedical research. Multiple relevant professional societies exist, especially in Poland, the Czech Republic and Hungary. Few of the region's 39 epidemiological academic journals have international currency. The number of epidemiological publications per population is highest for Israel and lowest for South-Central Asian countries. CONCLUSIONS: Epidemiological capacity will continue to be heterogeneous across the region and depend more on countries' individual historical, social, political and economic conditions and contexts than their epidemiologists' successive efforts. National and international research funding, and within- and between-country collaborations should be enhanced, especially for South-Central Asian countries. PMID- 23918853 TI - Within-person variability in calculated risk factors: comparing the aetiological association of adiposity ratios with risk of coronary heart disease. AB - BACKGROUND: Within-person variability in measured values of a risk factor can bias its association with disease. We investigated the extent of regression dilution bias in calculated variables and its implications for comparing the aetiological associations of risk factors. METHODS: Using a numerical illustration and repeats from 42,300 individuals (12 cohorts), we estimated regression dilution ratios (RDRs) in calculated risk factors [body-mass index (BMI), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR)] and in their components (height, weight, waist circumference, and hip circumference), assuming the long-term average exposure to be of interest. Error-corrected hazard ratios (HRs) for risk of coronary heart disease (CHD) were compared across adiposity measures per standard-deviation (SD) change in: (i) baseline and (ii) error corrected levels. RESULTS: RDRs in calculated risk factors depend strongly on the RDRs, correlation, and comparative distributions of the components of these risk factors. For measures of adiposity, the RDR was lower for WHR [RDR: 0.72 (95% confidence interval 0.65-0.80)] than for either of its components [waist circumference: 0.87 (0.85-0.90); hip circumference: 0.90 (0.86-0.93) or for BMI: 0.96 (0.93-0.98) and WHtR: 0.87 (0.85-0.90)], predominantly because of the stronger correlation and more similar distributions observed between waist circumference and hip circumference than between height and weight or between waist circumference and height. Error-corrected HRs for BMI, waist circumference, WHR, and WHtR, were respectively 1.24, 1.30, 1.44, and 1.32 per SD change in baseline levels of these variables, and 1.24, 1.27, 1.35, and 1.30 per SD change in error-corrected levels. CONCLUSIONS: The extent of within-person variability relative to between-person variability in calculated risk factors can be considerably larger (or smaller) than in its components. Aetiological associations of risk factors should be compared through the use of error corrected HRs per SD change in error-corrected levels of these risk factors. PMID- 23918856 TI - Commentary: Secondhand smoke causes disease everywhere, including mental health care settings. PMID- 23918857 TI - Commentary: The uptake of human papillomavirus vaccination: the power of belief. PMID- 23918852 TI - Alcohol consumption in 0.5 million people from 10 diverse regions of China: prevalence, patterns and socio-demographic and health-related correlates. AB - BACKGROUND: Drinking alcohol has a long tradition in Chinese culture. However, data on the prevalence and patterns of alcohol consumption in China, and its main correlates, are limited. METHODS: During 2004-08 the China Kadoorie Biobank recruited 512,891 men and women aged 30-79 years from 10 urban and rural areas of China. Detailed information on alcohol consumption was collected using a standardized questionnaire, and related to socio-demographic, physical and behavioural characteristics in men and women separately. RESULTS: Overall, 76% of men and 36% of women reported drinking some alcohol during the past 12 months, with 33% of men and 2% of women drinking at least weekly; the prevalence of weekly drinking in men varied from 7% to 51% across the 10 study areas. Mean consumption was 286 g/week and was higher in those with less education. Most weekly drinkers habitually drank spirits, although this varied by area, and beer consumption was highest among younger drinkers; 37% of male weekly drinkers (12% of all men) reported weekly heavy drinking episodes, with the prevalence highest in younger men. Drinking alcohol was positively correlated with regular smoking, blood pressure and heart rate. Among male weekly drinkers, each 20 g/day alcohol consumed was associated with 2 mmHg higher systolic blood pressure. Potential indicators of problem drinking were reported by 24% of male weekly drinkers. CONCLUSION: The prevalence and patterns of drinking in China differ greatly by age, sex and geographical region. Alcohol consumption is associated with a number of unfavourable health behaviours and characteristics. PMID- 23918861 TI - NeuroInterp: a method for facilitating neuroimaging research on cerebral malaria. PMID- 23918862 TI - Giant left middle fossa VII nerve schwannoma associated with amnesia. AB - The facial nerve is the third most frequent location of intracranial schwannomas, with facial paresis the most common sign.(1,2) A 77-year-old woman presented with amnesia; the Mini-Mental State Examination score was 26, with normal cranial nerve function. A giant multicystic VII nerve schwannoma was identified in the left middle fossa, with components of the tumor in the temporal bone facial canal, geniculate ganglion, and internal auditory canal (figure). Compression of the hippocampus may have accounted for the clinical presentation. The middle fossa component of the tumor was resected for mass effect relief, with iatrogenic facial palsy. PMID- 23918863 TI - Pearls and oy-sters: central fourth nerve palsies. PMID- 23918864 TI - Stroke prognostication using age and NIH Stroke Scale: SPAN-100. PMID- 23918866 TI - Pearls and oysters: transient Horner syndrome associated with autonomic dysreflexia. PMID- 23918867 TI - Teaching NeuroImages: reversible cognitive impairment with bithalamic lesions caused by a dural arteriovenous fistula. PMID- 23918868 TI - Teaching NeuroImages: Terson syndrome in cortical venous sinus thrombosis. PMID- 23918869 TI - Soaring aspirations: lessons from my mentors and colleagues: the Weisenfeld award. PMID- 23918870 TI - Introducing David Epstein, the 2013 recipient of the Weisenfeld award. PMID- 23918871 TI - Opioid growth factor - opioid growth factor receptor axis inhibits proliferation of triple negative breast cancer. AB - Triple negative breast cancer (TNBC) represents approximately 15% of the newly diagnosed cancers worldwide and is characterized by tissue lacking in estrogen, progesterone and human epidermal growth factor receptors. TNBC disproportionately affects younger women and women of colour, and new treatments are needed. The opioid growth factor (OGF) - opioid growth factor receptor (OGFr) axis is a determinant of cell proliferation in neoplasia, and OGF is an endogenously produced pentapeptide that inhibits cell replication by interacting with OGFr and upregulating cyclin-dependent inhibitory kinase pathways thus reducing DNA synthesis. In these studies we investigated the presence and function of the OGF OGFr axis in two human TNBC cell lines, as well as in breast cancer cell lines containing hormonal receptors. TNBC cell lines MDA-MD-231 and BT-20, as well as human breast cancer cells SK-BR-3 and MCF-7, were examined for the presence of pentapeptide and receptors, as well as their response to OGF. Specificity of peptide and receptor was confirmed by antibody neutralization and molecular studies to knockdown classical receptor protein. The requirement for protein transcription and translation and RNA transcription were investigated. Growth of TNBC cells in the presence of OGF and standard of care chemotherapeutic agent paclitaxel was evaluated to determine both efficacy and protective effects against toxicity. OGF treatment inhibited TNBC cells in a dosage related, receptor mediated, and reversible manner. OGF was the specific endogenous opioid to inhibit cell proliferation, and this was mediated by p21 cyclin dependent inhibitory kinase pathways, and required protein and RNA synthesis. OGFr was the specific receptor involved; both peptide and receptor were detected in all four cell lines. OGF treatment inhibited growth of all cancer cell lines evaluated, and reduced cell death in cultures exposed to paclitaxel. The OGF-OGFr axis is present and functioning in TNBC cell lines, and provides a novel biological pathway as potential therapy. PMID- 23918872 TI - Recombinant adeno-associated virus-mediated transfer of shRNA against Notch3 ameliorates hepatic fibrosis in rats. AB - Liver fibrosis, a wound healing process following all kinds of liver injuries, is characterized by excessive deposition of extracellular matrix (ECM). Our previous study revealed that Notch3 might participate in liver fibrogenesis by regulating the activation of hepatic stellate cells (HSCs). The aim of this study was to assess the effects of Notch3 shRNA on hepatic fibrosis in a rat model induced by carbon tetrachloride (CCl4) and to clarify the mechanisms underlying those effects. Recombinant adeno-associated virus type 1 (rAAV1) vector carrying Notch3 shRNA (rAAV1-Notch3-shRNA) was generated and transferred to rat livers via the tail vein. The expression of Notch3, Jagged1, Hes1 and alpha-SMA were detected by real-time RT-PCR and immunofluorescence. The effects of rAAV1-Notch3-shRNA on fibrosis was investigated by pathological and immunohistochemical examination. Our findings showed that Notch3, Jagged1, Hes1 and alpha-SMA were downregulated. This downregulation was accompanied by improved hepatic fibrosis after the inhibition of Notch3 in vivo. rAAV1-Notch3-shRNA treatment reversed the epithelial-mesenchymal transition (EMT) in fibrotic livers by decreasing the expression of transforming growth factor beta1 (TGF-beta1) and vimentin in a line with the increased expression of E-cadherin. The inhibition of Notch3 was not found to play a role in hepatocyte proliferation. Rather, it inhibited hepatocyte apoptosis in vivo to some extent. The results of the present study suggest that the inhibition of Notch3 can protect hepatocytes from undergoing apoptosis and attenuate liver fibrogenesis. This may be a viable therapeutic option for hepatic fibrosis. PMID- 23918874 TI - Soy extracts suppressed iodine uptake and stimulated the production of autoimmunogen in rat thyrocytes. AB - Soy consumption is associated with thyroid disorders such as hypothyroidism, goiter, and autoimmune thyroid disease (ATD) as well as increased iodine requirement in certain cases. However, the anti-thyroid component(s) in soy are yet to be identified and the molecular mechanism(s) involved remain unclear. This study examined the effects of soy isoflavones (ISF) on iodide uptake and expression of thyroglobulin (Tg) and sodium/iodide symporter (NIS) in thyrocytes. Fischer rat thyroid cells (FRTL) were treated with Novasoy (a soy alcohol extract containing 30% ISF) or major ISF aglycones or glycosides for 24 h. Iodide uptake was measured by a colorimetric assay. The protein level of Tg and NIS was measured by Western blotting. Cytotoxicity of tested compounds was determined by the MTT cell proliferation assay. Iodide uptake in FRTL cells was dose dependently suppressed by Novasoy added into the cell culture (10, 25, or 50 ug/mL, P < 0.05). However, neither the major ISF aglycones nor glycosides alone or in combination had similar effects. Novasoy (up to 200 ug/mL) had no cytotoxic effect. Novasoy (1, 10, and 50 ug/mL) and genistein (1 and 10 uM) markedly increased the protein content of a 40 kDa Tg fragment (P40, a known autoimmunogen) and non-glycosylated NIS in the FRTL cells (P < 0.05). Overall, this study demonstrated that the alcohol soluble component(s) other than the major ISF in soy remarkably inhibited iodide uptake in the FRTL cells. Soy ISF, particularly genistein, induced the production of P40, which might be responsible for the higher incidence of ATD reported in soy infant formula-fed children. PMID- 23918873 TI - Concentrated fish oil (Lovaza(R)) extends lifespan and attenuates kidney disease in lupus-prone short-lived (NZBxNZW)F1 mice. AB - A growing number of reports indicate that anti-inflammatory actions of fish oil (FO) are beneficial against systemic lupus erythematosus (SLE). However, the majority of pre-clinical studies were performed using 5-20% FO, which is higher than the clinically relevant dose for lupus patients. The present study was performed in order to determine the effective low dose of FDA-approved concentrated FO (Lovaza(r)) compared to the commonly used FO-18/12 (18 Eicosapentaenoic acid [EPA]/12-Docosahexaenoic acid [DHA]). We examined the dose dependent response of Lovaza(r) (1% and 4%) on an SLE mouse strain (NZBxNZW)F1 and compared the same with 1% and 4% placebo, as well as 4% FO-18/12, maintaining standard chow as the control. Results show for the first time that 1% Lovaza(r) extends maximal lifespan (517 d) and 4% Lovaza(r) significantly extends both the median (502 d) and maximal (600 d) life span of (NZBxNZW)F1 mice. In contrast, FO 18/12 extends only median lifespan (410 d) compared to standard chow diet (301 d). Additionally, 4% Lovaza(r) significantly decreased anti-dsDNA antibodies, reduced glomerulonephritis and attenuated lipopolysaccharide-induced pro inflammatory cytokines (IL-1beta, IL-6, TNF-alpha) in splenocytes compared to placebo. 4% Lovaza(r) was also shown to reduce the expression of inflammatory cytokines, including IL-1beta, IL-6 and TNF-alpha, while increasing renal anti oxidant enzymes in comparison to placebo. Notably, NFkappaB activation and p65 nuclear translocation were lowered by 4% Lovaza(r) compared to placebo. These data indicate that 1% Lovaza(r) is beneficial, but 4% Lovaza(r) is more effective in suppressing glomerulonephritis and extending life span of SLE-prone short lived mice, possibly via reducing inflammation signaling and modulating oxidative stress. PMID- 23918875 TI - Reconstitution of anti-allergic activities of PG102 derived from Actinidia arguta by combining synthetic chemical compounds. AB - PG102, a water-soluble extract from an edible fruit, Actinidia arguta, has previously been shown to control various factors involved in allergy pathogenesis. It was investigated whether the original activities of PG102 could be reconstituted by mixing chemical compounds present in PG102. Six compounds present in PG102 were, individually or in the form of mixtures, tested for their effects on the expression of various Th2 cytokines and inflammatory mediators in the cell-based assay. Each chemical inhibited IL-4 expression to varying degrees. The chemical compounds were combined at a ratio present in PG102, resulting in two formulations, CQMIIH and CQM, consisting of all or the first three of the following chemicals, citric, quinic, and malic acids, myo-inositol, isoquercitrin, and 5-hydroxymethyl-2-furaldehyde. The mixtures reconstituted original activities of PG102 to a significant level. In the murine asthma model, CQM ameliorated asthmatic symptoms and significantly decreased the level of IgE and IL-5. The decreased phosphorylation of ERK1/2 was observed in cells and mice treated with PG102 and the mixtures. Our data indicated that the substantial portion of PG102's anti-allergic activities could be reconstituted, in vitro and in vivo, by mixing six chemical compounds, suggesting the possibility of developing a new type of anti-allergic agent. This approach may be useful for developing chemically defined functional products from complex botanical extracts. PMID- 23918876 TI - Ovarian hormone withdrawal in prepubertal developmental stage does not prevent thymic involution in rats. AB - The study was undertaken to assess the effects of ovarian hormone withdrawal in prepubertal age on thymopoiesis in 2- (young) and 11-month-old (middle-aged) rats. In ovariectomized (Ox) rats, irrespective of age, thymic weight and cellularity were greater than in age-matched controls, but the values of both parameters exhibited the age-related decline. In addition, although thymopoietic efficiency was increased in both groups of Ox rats when compared with age-matched controls, thymopoiesis exhibited the age-related decline mirrored in the lower numbers of both CD4+ and CD8+ recent thymic emigrants in peripheral blood. This reflected the prethymic changes affecting bone marrow progenitor generation/entry and the thymic alterations encompassing the impaired progenitor progression through early pre-T-cell receptor developmental stages (defined by CD45RC/CD2 expression) and, possibly, a more pronounced decrease in the proliferation of the most mature thymocytes. Apart from the changes at thymocyte level, in Ox rats the age-related alterations in thymic stroma (substantiated in a prominent loss of thymic epithelial cells) were registered. Ovariectomy-induced changes in thymic lymphoid and epithelial component, most probably, influenced each other leading to the increase in thymic expression of interleukin-6 and interleukin-7 mRNAs along with time after ovariectomy. Collectively, the study showed that the withdrawal of ovarian hormones in prepubertal age increases the efficiency of thymopoiesis in young adult rats, but does not prevent decline in thymopoiesis occurring with age. PMID- 23918877 TI - Neurochemical and behavioural impact of C18 fatty acids in male mice postweaning. AB - Dietary components, particularly essential fatty acids, affect the expression and maintenance of normal physiological phenotypes. However, the influence of C18 fatty acids that are abundantly present in the normal diet is unclear. We focused on the behavioural and neurochemical effects of C18 fatty acids during postweaning development in male mice. An AIN-93G diet supplemented with 8% stearic acid (C18:0), 3% oleic acid (C18:1), 3% linoleic acid (C18:2) or 3% alpha linolenic acid (C18:3) was provided from four weeks of age for eight weeks. At 12 weeks of age, novel exploratory behaviour and social interaction tests were carried out. One week after the last behavioural test, the brain of each mouse was removed. The frequency of social interactive behaviour was decreased by approximately 70% in the C18:0 group compared to the basal diet group, but there was no difference in cumulative time. The frequency of social interaction showed a positive correlation to cumulative time in mice fed with the experimental diets except for C18:0. Dietary C18 fatty acids following weaning had no impact on brain fatty acid composition except for the C18:3 diet. Furthermore, the neurochemical properties to be especially noted were that choline acetyltransferase activity was absolutely higher in C18:0 diet-fed mice than in the other groups, especially in the frontal cortex where it was 1.7-fold higher than in the basal diet-fed group. The present results reveal a significant possibility of neurochemical and behavioural effects of dietary fatty acids, and saturated fatty acids are of special importance during the postweaning period. PMID- 23918878 TI - Anti-fibrotic effect of Cordyceps sinensis polysaccharide: Inhibiting HSC activation, TGF-beta1/Smad signalling, MMPs and TIMPs. AB - Cordyceps sinensis has been used to treat liver disease in traditional Chinese medicine for thousands of years. Polysaccharide extracted from cultured Cordyceps sinensis mycelia (CS-PS) is the major active components of cordyceps sinensis with anti-liver injury effects. In the present study, the effects of CS-PS on hepatic stellate cell (HSC) activation, transforming growth factor-beta1 (TGF beta1)/Smad pathway, as well as matrix metalloproteinase (MMP) 2, MMP9 and tissue inhibitor of metalloproteinase (TIMP) 1, TIMP2, were investigated in liver fibrosis in rats induced by carbon tetrachloride (CCl4). Colchicine was used as a positive control. The effect of CS-PS inhibition liver injury and fibrosis was confirmed by decreasing serum alanine aminotransferase, aspartate aminotransferase, total bilirubin, hepatic hydroxyproline and increasing serum albumin, as well as alleviation of histological changes, which was comparable to that of colchicine. With CS-PS treatment, hepatic alpha-smooth muscle actin, TGF beta1, TGF-beta1 receptor (TbetaR)-I, TbetaR-II, p-Smad2, p-Smad3 and TIMP2 proteins expression were down-regulated comparing to that in CCl4 group. The activities of MMP2 and MMP9 in liver tissue were also inhibited in CS-PS-treated group. It is indicated that the effects of CS-PS anti-liver fibrosis are probably associated with the inhibition on HSC activation, TGF-beta1/Smads signalling pathway, as well as MMP2, MMP9 activity and TIMP2 expression. PMID- 23918879 TI - Erythropoietin promotes the repair effect of acute kidney injury by bone-marrow mesenchymal stem cells transplantation. AB - Bone-marrow mesenchymal stem cells (BMSCs) transplantation is effective for acute kidney injury (AKI) repair but with limited efficiency. In the present study, BMSCs marked by bromodeoxyuridine (BrdU) were transplanted to the AKI mouse model with erythropoietin (EPO) being subcutaneously injected. The blood urea nitrogen (BUN) and serum creatinine (Scr) levels, pathological changes, distribution of BMSCs, expressions of the cytokeratin 18 (CK18) and the stromal cell-derived factor 1 (SDF-1) in the nephridial tissues were measured. The directional migration of BMSCs to the AKI microenvironment in vitro was also tested. The results showed that BMSCs transplantation or EPO injection alone decreased the BUN and Scr levels and the acute tubular necrosis (ATN) scoring in varied degrees. The combination of these decreased the above indicators' levels significantly. BrdU(+) cells (BMSCs) were observed in the AKI nephridial tissues, and CK18 expressed in the cytoplasm of these cells. EPO injection increased the proportion of BrdU(+) cells with the enhanced expression of SDF-1 in the AKI nephridial tissues. EPO increased the migrating number of BMSCs to the AKI microenvironment in vitro, and additional anti-SDF-1 treatment with SDF-1 antibody neutralized this effect. Our results showed that EPO increased the number of the transplanted BMSCs in the injured nephridial tissues and enhanced the AKI repair effect of BMSCs transplantation. The enhanced kidney-homing efficiency for BMSCs mediated by the SDF-1/CXCR4 pathway is one of the possible mechanisms for EPO performance. PMID- 23918880 TI - Effect of mesenchymal stem cells on renal injury in rats with severe acute pancreatitis. AB - The aim of this study was to preliminarily investigate the effect of bone marrow mesenchymal stem cells (MSCs) on structural change of capillary endothelial barrier and expression variation of aquaporin 1 (AQP1) in kidney at the onset of renal injury caused by severe acute pancreatitis (SAP). Ninety male Sprague Dawley (SD) rats were divided into the control group, the SAP group in which animals received induction of SAP and the MSCs-treated group in which SAP-induced animals were injected with MSCs. They were further subdivided according to the time point that the animals were killed; 6 h, 12 h and 24 h after the closure of the incision, serum, pancreatic and renal samples were collected, respectively. The level of serum amylase (AMY), creatinine (Cr) and blood urea nitrogen (BUN) were analysed, the change of pancreatic histology was assessed, the structural change of the renal interstitial capillaries was evaluated using the transmission electron microscope (TEM) and the location and expression of AQP1 in kidney were analysed using immunohistochemistry, quantitative polymerase chain reaction and Western blot. The outcomes showed that the level of serum AMY, Cr, BUN elevated, the damage of pancreatic tissue and renal capillary endothelial barrier was aggravated and the expression of AQP1 was reduced significantly after induced pancreatitis. But after treatments with MSCs, the elevation of AMY, Cr and BUN was inhibited, the damage of pancreatic tissue and renal interstitial capillary barrier was alleviated and the down-regulation of AQP1 was reversed. In summary, the MSCs therapy could alleviate renal injury in rats with SAP, the mechanism of which might be related to reduction of the damage to renal interstitial capillary endothelial barrier, and up-expression of AQP1 in kidney. PMID- 23918881 TI - Overexpressions of HO-1/HO-1G143H in C57/B6J mice affect melanoma B16F10 lung metastases rather than change the survival rate of mice-bearing tumours. AB - Heme oxygenase-1 (HO-1) is often upregulated in tumour tissues and endows tumour cells with cytoprotection and antiapoptosis. It is worthy of note that some people show higher activity of HO-1 and some anti-cancer therapies could induce HO-1 expression in normal tissues, but the effect of HO-1 of normal tissues on tumours among these people remains unknown. To assess the effect of HO-1 of normal tissues on tumour progressiveness, we investigated the growth, metastasis and angiogenic potential of murine melanoma B16F10 cells in transgenic mice overexpressing HO-1 and its negative dominant mutant HO-1G143H, respectively. The results demonstrated that neither overexpression of HO-1 nor overexpression of HO 1G143H in normal tissues could significantly change the survival rate of tumour bearing mice, but HO-1 overexpression could inhibit lung metastases and HO-1G143H could significantly promote lung metastases. Meanwhile, the leukocytes infiltration was reduced and angiogenesis was promoted in tumours in mice overexpressing HO-1, but the opposite was true in mice overexpressing HO-1G143H. Our findings suggested that overexpression of HO-1 might be conducive to patients bearing melanoma metastasis. PMID- 23918882 TI - Role of HO-1 in protective effect of electro-acupuncture against endotoxin shock induced acute lung injury in rabbits. AB - Heme oxygenase (HO)-1 has been reported to play a great role in attenuating lung injury during endotoxic shock in our previous research. Although electro acupuncture has been explored to reduce oxidative stress and decrease inflammatory reaction in animals with endotoxic shock, the mechanism of this effect is still unclear. The aim of this study was to determine whether HO-1 is involved in the effect of electro-acupuncture on the injured lung during endotoxic shock in rabbits. Sixty New England white rabbits were randomly divided into groups C, Z, ES, EA, AP, and EAZ. Before inducing endotoxic shock, group ES received no electro-acupuncture, while group EA received electro-acupuncture at ST36 (zusanli) and BL13 (feishu) acupoints on both sides for five days and group AP received electro-acupuncture (EA) stimulation at a non-acupoint. Groups ES, AP, EA, and EAZ received LPS to replicate the experimental model of injured lung induced by endotoxic shock, and electro-acupuncture was performed throughout the procedure with the same parameter. Groups EAZ and Z received the HO-1 inhibitor, ZnPP-IX, intraperitoneally. The animals were sacrificed by blood-letting at 6 h after LPS administration. The blood samples were collected for serum examination, and the lungs were removed for pathology examination, detection of alveolaer epithelial cell apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling assay (TUNEL assay), determination of wet to dry ratio, measurement of Evans blue (EB) contents, and determination of HO-1protein and mRNA expression. According to the results, EA at ST36 and BL13 could increase the expression of HO-1. At the same time, index of quantitative assessment (IQA) score and the number of TUNEL-positive cells decreased, while electro-acupuncture at the other points did not exert this effect, and pretreatment with ZnPP-IX in group EAZ suppressed the efficacy of electro-acupuncture preconditioning. In summary, electro-acupuncture stimulation at ST36 and BL13, while not the non acupoint, could attenuate the lung injury during the endotoxic shock, and this effect was due to increased expression of HO-1. PMID- 23918883 TI - Effects of non-surgical periodontal treatment on the L-arginine-nitric oxide pathway and oxidative status in platelets. AB - Several studies have suggested an increase of cardiovascular disease (CVD) risk on periodontitis patients. An enhancement has been demonstrated on both platelet activation and oxidative stress on periodontitis patients, which may contribute for this association. Therefore, the aim of this study was to evaluate the effects of non-surgical periodontal treatment on the l-arginine-nitric oxide (NO) cyclic guanosine monophosphate (cGMP) pathway and oxidative status in platelets. A total of eight periodontitis patients and eight controls were included in this study. Clinical, laboratory and experimental evaluations were performed on baseline and 90 days after periodontal treatment (except for western blot analysis). The clinical periodontal evaluation included measurements of probing pocket depth (PPD), clinical attachment loss (CAL), % of sites with plaque and % of sites with bleeding on probing. We evaluated: l-[(3)H]arginine influx; nitric oxide synthase (NOS) and arginase enzymes activity and expression; expression of guanylate cyclase and phosphodiesterase-5 enzymes; cGMP levels; platelet aggregation; oxidative status through superoxide dismutase (SOD) and catalase activities, and measurement of reactive oxygen species (ROS) levels and C reactive protein (CRP) levels. The initial results showed an activation of both l arginine influx and via system y (+ )L associated with reduced intraplatelet cGMP levels in periodontitis patients and increased systemic levels of CRP. After periodontal treatment, there was a significant reduction of the % of sites with PPD 4-5mm, % of sites with CAL 4-5 mm, and an enhancement in cGMP levels and SOD activity. Moreover, CRP levels were reduced after treatment. Therefore, alterations in the intraplatelet l-arginine-NO-cGMP pathway and oxidant antioxidant balance associated with a systemic inflammatory response may lead to platelet dysfunction, which may contribute to a higher risk of CVD in periodontitis. PMID- 23918885 TI - Men on the move: a pilot program to increase physical activity among African American men. AB - Despite the important contribution increasing physical activity levels may play in reducing chronic disease morbidity and mortality, there is a paucity of interventions and research indicating how to improve physical activity levels in African American men. Men on the Move was a pilot study to increase African American men's levels of physical activity by improving access to age and ability appropriate, male-focused physical activity opportunities and facilitating access to social support from male peers. Forty-one African American men ages 35 to 70 enrolled (mean age = 53.8). Groups of 5 to 10 men met once a week with a certified personal trainer for 10 weeks. Each meeting addressed barriers to physical activity, provided men with community resources, and incorporated activities that promoted flexibility, strength, balance, and conditioning. Improvements (p < .05) were detected for the following outcome measures: perceived self-efficacy to sustain physical activity, endurance, overall health status, and stress level. Physiological and fitness outcome measures improved, although not to significant levels. Whereas 40% of the men met the recommendation of 150 minutes of moderate or vigorous physical activity weekly at baseline, 68% of the men met this recommendation by the end of the project. These positive results attest to the feasibility of successfully engaging middle-aged and older African American men in a physical activity intervention, and our findings demonstrate the initial efficacy of this intervention approach. More research is needed that includes a more intensive intervention and one that helps motivate men to be physically active outside of the structured, small-group sessions. PMID- 23918886 TI - Use of urine testing in outpatients treated for urinary tract infection. AB - OBJECTIVE: To characterize urine test use in ambulatory, antibiotic-treated pediatric urinary tract infection (UTI). METHODS: We studied children <18 years who had an outpatient UTI and a temporally associated antibiotic prescription from 2002 through 2007 by using a large claims database, Innovus i3. We evaluated urine-testing trends and performed multivariable logistic regression to assess for factors associated with urine culture use. RESULTS: Of 40 603 treated UTI episodes in 28 678 children, urinalysis was performed in 76%, and urine culture in 57%; 32% of children <2 years had no urinalysis or culture performed for an antibiotic-treated UTI episode. Urine culture use decreased during the study period from 60% to 54% (P < .001). We observed variation in urine culture use with age (<2 years: odds ratio [OR] 1.0, 95% confidence interval [CI] 0.9-1.1; 2 5 years: OR 1.3, 95% CI 1.2-1.4; 6-12 years: OR 1.3, 95% CI 1.2-1.4, compared with 13-17 years); gender (boys: OR 0.8, 95% CI 0.8-0.9); and specialty (pediatrics: OR 2.6, 95% CI 2.5-2.8; emergency medicine, OR 1.2, 95% CI 1.1-1.3; urology: OR 0.5, 95% CI 0.4-0.6, compared with family/internal medicine). Recent antibiotic exposure (OR 1.1, 95% CI 1.1-1.2) and empirical broad-spectrum prescription (OR 1.2, 95% CI 1.1-1.2) were associated with urine culture use, whereas previous UTI and urologic anomalies were not. CONCLUSIONS: Providers often do not obtain urine tests when prescribing antibiotics for outpatient pediatric UTI. Variation in urine culture use was observed based on age, gender, and physician specialty. Additional research is necessary to determine the implications of empirical antibiotic prescription for pediatric UTI without confirmatory urine testing. PMID- 23918887 TI - Parent and child cigarette use: a longitudinal, multigenerational study. AB - OBJECTIVES: Using longitudinal data from the multigenerational Youth Development Study (YDS), this article documents how parents' long-term smoking trajectories are associated with adolescent children's likelihood of smoking. Prospective data from the parents (from age 14-38 years) enable unique comparisons of the parents' and children's smoking behavior, as well as that of siblings. METHODS: Smoking trajectories are constructed using latent class analysis for the original YDS cohort (n = 1010). Multigenerational longitudinal data from 214 parents and 314 offspring ages 11 years and older are then analyzed by using logistic regression with cluster-corrected SEs. RESULTS: Four latent smoking trajectories emerged among the original cohort: stable nonsmokers (54%), early-onset light smokers who quit/reduce (16%), late-onset persistent smokers (14%), and early-onset persistent heavy smokers (16%). Although 8% of children of stable nonsmokers smoked in the last year, the other groups' children had much higher percentages, ranging from 23% to 29%. Multivariate logistic regression models confirm that these significant differences were robust to the inclusion of myriad child- and parent-level measures (for which child age and grade point average [GPA] are significant predictors). Older sibling smoking, however, mediated the link between parental heavy smoking and child smoking. CONCLUSIONS: Even in an era of declining rates of teenage cigarette use in the United States, children of current and former smokers face an elevated risk of smoking. Prevention efforts to weaken intergenerational associations should consider parents' long-term cigarette use, as well as the smoking behavior of older siblings in the household. PMID- 23918888 TI - Outcomes of children with severe bronchopulmonary dysplasia who were ventilator dependent at home. AB - OBJECTIVE: To describe the incidence and outcomes of children with chronic respiratory failure secondary to severe bronchopulmonary dysplasia (BPD) on chronic positive pressure ventilation (PPV) via tracheostomy at home. METHODS: We retrospectively reviewed medical charts of patients with severe BPD who were PPV dependent at home and who were enrolled in a university-affiliated home ventilator program between 1984 and 2010. We excluded patients with other comorbidities that could contribute to the development of chronic respiratory failure. We reported the incidence of these children in Indiana and cumulative incidences of survival, liberation from PPV, and decannulation. RESULTS: Over 27 years, 628 children were cared for in our home ventilator program. Of these, 102 patients met inclusion criteria: 83 (81.4%) were alive and 19 (18.6%) were deceased. Sixty-nine patients (67.6%) were liberated from PPV, and 97.1% of them were weaned before their fifth birthday, with a median age at liberation of 24 months (interquartile range, 19-33). Similarly, 60 patients (58.8%) were decannulated, of which 96.7% completed this process before their sixth birthday, with a median age at decannulation of 37.5 months (interquartile range, 31.5-45). The incidence of children with chronic respiratory failure secondary to BPD who were PPV-dependent at home in Indiana was 1.23 per 100 000 live births in 1984 and increased to 4.77 per 100 000 live births in 2010. CONCLUSIONS: Although extreme prematurity associated with severe BPD necessitating PPV at home carries significant risks of morbidity and mortality, successful liberation from mechanical ventilation and decannulation are likely to occur. PMID- 23918889 TI - Use of conventional and novel smokeless tobacco products among US adolescents. AB - OBJECTIVES: To assess the prevalence and correlates of use of conventional and novel smokeless tobacco products among a national sample of US middle and high school students. METHODS: Data from the 2011 National Youth Tobacco Survey were analyzed to determine national estimates of current use of conventional ("chewing tobacco", "snuff," or "dip"), novel ("snus" and "dissolvable tobacco products"), and any smokeless tobacco products (novel and/or conventional products) within the past 30 days. RESULTS: The overall prevalence of current use of any smokeless tobacco product was 5.6% (n = 960). Among all students, 5.0% used chewing tobacco, snuff, or dip; 1.9% used snus; and 0.3% used dissolvable tobacco products. Among users of any smokeless tobacco, 64.0% used only conventional products, 26.8% were concurrent users of novel plus conventional products, whereas 9.2% exclusively used novel products. Approximately 72.1% of current any smokeless tobacco users concurrently smoked combustible tobacco products, and only 40.1% expressed an intention to quit all tobacco use. Regression analyses indicated that peer (adjusted odds ratio [aOR]: 9.56; 95% confidence interval [CI]: 7.14-12.80) and household (aOR: 3.32; 95% CI: 2.23-4.95) smokeless tobacco use were associated with smokeless tobacco use, whereas believing that all forms of tobacco are harmful was protective (aOR: 0.55; 95% CI: 0.38-0.79). CONCLUSIONS: Conventional smokeless tobacco products remain the predominant form of smokeless tobacco use. Most users of novel smokeless tobacco products also concurrently smoked combustible tobacco products. Smokeless tobacco use was associated with lower perception of harm from all tobacco products and protobacco social influences, indicating the need to change youth perceptions about the use of all tobacco products and to engage pediatricians in tobacco use prevention and cessation interventions. PMID- 23918890 TI - Cost-effectiveness of routine screening for critical congenital heart disease in US newborns. AB - OBJECTIVES: Clinical evidence indicates newborn critical congenital heart disease (CCHD) screening through pulse oximetry is lifesaving. In 2011, CCHD was added to the US Recommended Uniform Screening Panel for newborns. Several states have implemented or are considering screening mandates. This study aimed to estimate the cost-effectiveness of routine screening among US newborns unsuspected of having CCHD. METHODS: We developed a cohort model with a time horizon of infancy to estimate the inpatient medical costs and health benefits of CCHD screening. Model inputs were derived from new estimates of hospital screening costs and inpatient care for infants with late-detected CCHD, defined as no diagnosis at the birth hospital. We estimated the number of newborns with CCHD detected at birth hospitals and life-years saved with routine screening compared with no screening. RESULTS: Screening was estimated to incur an additional cost of $6.28 per newborn, with incremental costs of $20 862 per newborn with CCHD detected at birth hospitals and $40 385 per life-year gained (2011 US dollars). We estimated 1189 more newborns with CCHD would be identified at birth hospitals and 20 infant deaths averted annually with screening. Another 1975 false-positive results not associated with CCHD were estimated to occur, although these results had a minimal impact on total estimated costs. CONCLUSIONS: This study provides the first US cost-effectiveness analysis of CCHD screening in the United States could be reasonably cost-effective. We anticipate data from states that have recently approved or initiated CCHD screening will become available over the next few years to refine these projections. PMID- 23918892 TI - Breastfeeding keratosis: this frictional keratosis of newborns may mimic thrush. AB - We report the first example, to our knowledge, of a frictional keratosis from exuberant sucking in a breastfeeding infant. A 2-month-old girl was referred for evaluation of a well-demarcated, nonsloughing white keratotic plaque of the lower lip mucosa, just inside the vermilion border. The plaque had a slightly irregular surface, had no surrounding erythema, and was the only such plaque in the mouth. It had been present for at least 3 weeks and had been unsuccessfully treated by her pediatrician via oral Mycostatin (nystatin). Her parents sought a second opinion when the infant was prescribed a full course of oral Diflucan (fluconazole). A cytopathology smear (Papanicolaou test) revealed abundant mature keratinocytes with no evidence of Candida. The mother admitted that the infant "worked hard" at sucking during breastfeeding and continued sucking long after feeding. The parents were unaware of any other habit or potential irritation of the lips. After 3 months of age the infant's sucking pattern became more "normal" and the keratosis disappeared; it did not recur during 3 years of follow-up. We propose the term "breastfeeding keratosis" for this entity. PMID- 23918891 TI - Rapid changes in American family life: consequences for child health and pediatric practice. AB - Pediatricians are in the unique position of being on the front line of care for children and having access to their families. This article presents both a rationale and the evidence base for identifying the family characteristics and processes that affect child health and suggests approaches that pediatricians can implement to improve the care of children, using data from 3 recent reports of the Institute of Medicine and National Research Council, as well as other recent family research. Evidence regarding the impact on child health of 3 family factors in particular (family composition and living arrangements, family routines, and parental depression) is highlighted, and implications for pediatric practice are described. PMID- 23918893 TI - Asthma during pregnancy and clinical outcomes in offspring: a national cohort study. AB - BACKGROUND AND OBJECTIVE: Maternal asthma is a common pregnancy complication, with adverse short-term effects for the offspring. The objective was to determine whether asthma during pregnancy is a risk factor of offspring diseases. METHODS: We studied pregnant women from the Danish National Birth Cohort (births: 1996 2002; prospective data) giving birth to live singletons (n = 66 712 mother-child pairs), with 4145 (6.2%) women suffering from asthma during pregnancy. We estimated the associations between asthma during pregnancy and offspring diseases (International Classification of Diseases, 10th Revision diagnoses from national registries), controlling for potential confounders and validating findings by secondary analyses. RESULTS: Offspring median age at end of follow-up was 6.2 (3.6-8.9) years. Asthma was associated with an increased offspring risk of infectious and parasitic diseases (hazard ratio [HR] 1.34; 95% confidence interval [CI] 1.23-1.46), diseases of the nervous system (HR 1.43; CI 1.18-1.73), ear (HR 1.33; CI 1.19-1.48), respiratory system (HR 1.43; CI 1.34-1.52), and skin (HR 1.39; CI 1.20-1.60), and potentially (not confirmed in secondary analyses) of endocrine and metabolic disorders (HR 1.26; CI 1.02-1.55), diseases of the digestive system (HR 1.17; CI 1.04-1.32), and malformations (odds ratio 1.13; CI 1.01-1.26), but not of neoplasms, mental disorders, or diseases of the blood and immune system, circulatory system, musculoskeletal system, and genitourinary system. CONCLUSIONS: To the best of our knowledge, this is the first comprehensive study of the associations between asthma during pregnancy and a wide spectrum of offspring diseases. In line with previous data on selected outcomes, asthma during pregnancy may be a risk factor for numerous offspring diseases, suggesting that careful monitoring of women with asthma during pregnancy and their offspring is important. PMID- 23918894 TI - Striving for meaningful policies to reduce sugar-sweetened beverage intake among young children. PMID- 23918895 TI - A case report of obsessive-compulsive disorder following acute disseminated encephalomyelitis. AB - We present a case of a boy who developed obsessive-compulsive disorder (OCD) shortly after an episode of acute disseminated encephalomyelitis (ADEM). To our knowledge, this is the first report of the development of OCD in a child who has had ADEM. This presentation is consistent with our understanding of OCD as a complex genetic disease involving the cerebral white matter tracts, and may indicate a potential pathway for the development of OCD in genetically vulnerable individuals or a shared trigger for the development of pediatric acute-onset neuropsychiatric syndrome and ADEM. PMID- 23918896 TI - Blood cultures in the evaluation of uncomplicated skin and soft tissue infections. AB - BACKGROUND: Blood cultures are often obtained in children hospitalized with skin and soft tissue infections (SSTIs). Because little evidence exists to validate this practice, we examined the yield of blood cultures in the evaluation of immunocompetent children with SSTIs. METHODS: Medical records were reviewed for all children admitted between January 1, 2007 and December 31, 2009 after emergency department evaluation and diagnosis of cellulitis or abscess. We compared patients with SSTIs (n = 482) with those with complicated SSTIs (cSSTIs; n = 98). A cSSTI was defined as surgical or traumatic wound infection, need for surgical intervention, or infected ulcers or burns. The SSTI group included patients without complicating factors. RESULTS: None of the patients in the SSTI group had a positive blood culture. In the cSSTI group, 12.5% of blood cultures were positive. The mean length of hospital stay (LOHS) of children with SSTIs was shorter than that of those with cSSTIs (P < .001). In the SSTI group, obtaining a blood culture was associated with a higher mean LOHS (P = .044). CONCLUSIONS: Blood cultures are not useful in evaluating immunocompetent children who are admitted to the hospital with uncomplicated SSTIs, and they are associated with a nearly 1-day increase in mean LOHS. PMID- 23918897 TI - Sugar-sweetened beverages and weight gain in 2- to 5-year-old children. AB - BACKGROUND AND OBJECTIVE: Although sugar-sweetened beverage (SSB) consumption has been tightly linked to weight status among older children, the data regarding these relationships in children aged 2 to 5 years have been mixed. Our objective was to evaluate longitudinal and cross-sectional relationships between SSB consumption and weight status among children aged 2 to 5 years. METHODS: We assessed SSB consumption and BMI z scores among 9600 children followed in the Early Childhood Longitudinal Survey--Birth Cohort, using linear and logistic regression and adjusting for race/ethnicity, socioeconomic status, mother's BMI, and television viewing. RESULTS: Higher rates of SSB consumption were associated with higher BMI z scores among children age 4 (P < .05) and 5 (P < .001) but not yet at 2 years. Children aged 5 years who drank SSB regularly (compared with infrequent/nondrinkers) had a higher odds ratio for being obese (1.43, confidence interval 1.10-1.85, P < .01). In prospective analysis, children drinking SSB at 2 years (compared with infrequent/nondrinkers) had a greater subsequent increase in BMI z score over the ensuing 2 years (P < .05). CONCLUSIONS: Similar to what is seen among older children, children aged 2 to 5 years drinking SSB demonstrate both prospective and cross-sectional correlations with higher BMI z score. Pediatricians and parents should discourage SSB consumption to help avoid potential unhealthy weight gain in young children. From a public health standpoint, strong consideration should be made toward policy changes leading to decreases in SSB consumption among children. PMID- 23918898 TI - Risk-adjusted hospital outcomes for children's surgery. AB - BACKGROUND The American College of Surgeons National Surgical Quality Improvement Program-Pediatric was initiated in 2008 to drive quality improvement in children's surgery. Low mortality and morbidity in previous analyses limited differentiation of hospital performance. METHODS: Participating institutions included children's units within general hospitals and free-standing children's hospitals. Cases selected by Current Procedural Terminology codes encompassed procedures within pediatric general, otolaryngologic, orthopedic, urologic, plastic, neurologic, thoracic, and gynecologic surgery. Trained personnel abstracted demographic, surgical profile, preoperative, intraoperative, and postoperative variables. Incorporating procedure-specific risk, hierarchical models for 30-day mortality and morbidities were developed with significant predictors identified by stepwise logistic regression. Reliability was estimated to assess the balance of information versus error within models. RESULTS: In 2011, 46 281 patients from 43 hospitals were accrued; 1467 codes were aggregated into 226 groupings. Overall mortality was 0.3%, composite morbidity 5.8%, and surgical site infection (SSI) 1.8%. Hierarchical models revealed outlier hospitals with above or below expected performance for composite morbidity in the entire cohort, pediatric abdominal subgroup, and spine subgroup; SSI in the entire cohort and pediatric abdominal subgroup; and urinary tract infection in the entire cohort. Based on reliability estimates, mortality discriminates performance poorly due to very low event rate; however, reliable model construction for composite morbidity and SSI that differentiate institutions is feasible. CONCLUSIONS: The National Surgical Quality Improvement Program Pediatric expansion has yielded risk-adjusted models to differentiate hospital performance in composite and specific morbidities. However, mortality has low utility as a children's surgery performance indicator. Programmatic improvements have resulted in actionable data. PMID- 23918899 TI - Visual processing in adolescents born extremely low birth weight and/or extremely preterm. AB - BACKGROUND AND OBJECTIVES: Ocular growth and development differs between preterm and term-born infants and may cause long-term negative consequences for visual function, but contemporary data on long-term visual outcomes in representative samples of the highest risk extremely low birth weight (ELBW, <1000 g birth weight) or extremely preterm (EP, <28 weeks' gestation) survivors are lacking. Our objective was to compare visual functioning between ELBW/EP and normal birth weight (NBW, >2499 g birth weight) control adolescents. METHODS: Geographically determined cohort study of 228 consecutive ELBW/EP survivors born in the state of Victoria in 1991 and 1992, and 166 randomly selected NBW controls assessed between 14 and 20 years of age. Visual acuity, stereopsis, convergence, color perception, and visual perception were assessed and contrasted between groups. RESULTS: ELBW/EP subjects had significantly worse visual acuity with habitual correction in both the left and right eyes, and for the best eye (P < .001). The ELBW/EP adolescents also exhibited poorer stereopsis, odds ratio (OR) 3.22 (95% confidence interval [CI] 1.78 to 5.84), and convergence, OR 2.76 (CI 1.32 to 5.75) than controls, and more problems with visual perception, OR 3.09 (CI 1.67 to 5.71) after habitual correction. CONCLUSIONS: Despite advances in medical care improving the survival rate of high-risk ELBW/EP infants, visual morbidity is still relatively high compared with controls in late adolescence. PMID- 23918901 TI - Pathogen infection trial increases the secretion of proteins localized in the endoplasmic reticulum body of Arabidopsis. PMID- 23918900 TI - Identification of a probable pore-forming domain in the multimeric vacuolar anion channel AtALMT9. AB - Aluminum-activated malate transporters (ALMTs) form an important family of anion channels involved in fundamental physiological processes in plants. Because of their importance, the role of ALMTs in plant physiology is studied extensively. In contrast, the structural basis of their functional properties is largely unknown. This lack of information limits the understanding of the functional and physiological differences between ALMTs and their impact on anion transport in plants. This study aimed at investigating the structural organization of the transmembrane domain of the Arabidopsis (Arabidopsis thaliana) vacuolar channel AtALMT9. For that purpose, we performed a large-scale mutagenesis analysis and found two residues that form a salt bridge between the first and second putative transmembrane alpha-helices (TMalpha1 and TMalpha2). Furthermore, using a combination of pharmacological and mutagenesis approaches, we identified citrate as an "open channel blocker" of AtALMT9 and used this tool to examine the inhibition sensitivity of different point mutants of highly conserved amino acid residues. By this means, we found a stretch within the cytosolic moiety of the TMalpha5 that is a probable pore-forming domain. Moreover, using a citrate insensitive AtALMT9 mutant and biochemical approaches, we could demonstrate that AtALMT9 forms a multimeric complex that is supposedly composed of four subunits. In summary, our data provide, to our knowledge, the first evidence about the structural organization of an ion channel of the ALMT family. We suggest that AtALMT9 is a tetramer and that the TMalpha5 domains of the subunits contribute to form the pore of this anion channel. PMID- 23918902 TI - Association between endothelial nitric oxide synthase gene polymorphism (-786T>C) and interleukin-6 in acute coronary syndrome. AB - Atherosclerosis is morphologically an inflammatory disease, where endothelial dysfunction plays a key role in all the stages. The nitric oxide (NO) synthase 3 (NOS3) gene is responsible for the synthesis of endothelial NO synthase (eNOS) in humans and some genetic polymorphisms are considered "polymorphisms associated with risk" for the development of coronary artery diseases, such as acute coronary syndrome. Thus, the present study aimed to evaluate the influence of the -786T>C polymorphism of the eNOS gene on inflammatory and oxidative process. A prospective cohort study of 125 consecutive patients with clinical diagnosis of non-ST-elevation acute coronary syndromes was conducted. Patients were assessed using a standardized questionnaire. Blood samples were drawn to measure serum levels of high-sensitivity C-reactive protein, soluble CD40 ligand, interleukin-6 (IL-6), N-terminal prohormone of brain natriuretic peptide, immunoglobulin G antibodies against oxidized low-density lipoprotein. The genotypes for the 786T>C polymorphism in the 5'-flanking region of eNOS gene were determined. The 786C allele was found in 92 of 250 alleles (38.8%). No statistical association was observed between demographic and clinical characteristics and distribution of eNOS-786T>C polymorphism. We found that -786CC was associated with lower levels of IL-6. No significant differences were observed between the distribution of 786T>C polymorphism and other investigated markers. PMID- 23918903 TI - Supramolecular ferric porphyrins and a cyclodextrin dimer as antidotes for cyanide poisoning. AB - OBJECTIVES: This study aimed to evaluate the antidotal effect of a newly developed supramolecular complex, ferric porphyrins and a cyclodextrin dimer (Fe(III)PIm3CD), that possess a higher binding constant and quicker binding rate to cyanide ions than those of hydroxocobalamin (OHCbl) in the presence of serum protein. METHODS: First, in vitro cytochrome activity and cell viability were evaluated in murine fibroblast cells cultured with various doses of Fe(III)PIm3CD and potassium cyanide (KCN). Next, BALB/c mice were pretreated with intravenous OHCbl (0.23 mmol/kg), Fe(III)PIm3CD (0.23 mmol/kg), or saline and then received KCN (lethal dose 100% (LD100): 0.23 mmol/kg) through a stomach tube. Finally, as a resuscitation model, KCN-induced apnea was treated with a bolus injection of an equimolar dose of antidotes followed by a slow infusion of the same reagent. RESULTS: Fe(III)PIm3CD showed dose-dependent antidotal effects in vitro. Pretreatment with Fe(III) PIm3CD prevented KCN-induced apnea significantly better than OHCbl. Resuscitation with Fe(III)PIm3CD resulted in an earlier resumption of respiration than that seen with OHCbl. However, 24-h survival was similar among the treatments (Fe(III)PIm3CD, nine of nine mice; OHCbl, eight of nine mice). CONCLUSION: Fe(III)PIm3CD exerted significant antidotal effects on cyanide toxicity in vitro and in vivo, with a potency equal in the mortality of cyanide poisoned mice or superior in the respiratory status during an acute phase to those of OHCbl. PMID- 23918904 TI - The DNA methyl transferase inhibitor, 5'-aza-2-deoxycitidine, enhances the apoptotic effect of Mevastatin in human leukemia HL-60 cells. AB - Statins induce antiproliferative effects and apoptotic response in various cancer cell types. Moreover, they also sensitize tumor cell lines from different origins to many agents. We aimed to investigate possible effects of Mevastatin (Mev) alone and sequential treatment of 5'-aza-2-deoxycitidine (DAC) and Mev on HL-60 cell line using XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5 carboxanilide) assay, lactate dehydrogenase release assay, flourescence microscopy, DNA fragmentation analysis, determination of DNA synthesis rate, and active caspase-3 assay. Messenger RNA (mRNA) expression of apoptotic and antiapoptotic genes were also evaluated by semiquantitative reverse transcription polymerase chain reaction (RT-PCR) for BAX, BCL2, and XIAP genes and quantitative Real-time PCR for CASP3, CASP8, and CASP9 genes. We showed that treatment with Mev alone and DAC followed by Mev resulted in apoptotic response in a time- and dose-dependent manner. We also found that pretreatment with DAC sensitized HL-60 cells to Mev and caused more apoptotic cell death than Mev-alone treatment via caspase-3 activation and DNA fragmentation. Moreover, sequential addition of Mev after DAC diminished DNA synthesis rate more effectively than Mev-alone treatment. Furthermore, DAC pretreatment significantly increased CASP3 and CASP9 mRNA expression even with lower doses of Mev. BAX, BCL2, and XIAP gene mRNA levels were also found to be changed in the presence of DAC and Mev. Determination of the exact molecular effects of statins and DAC would allow us to identify new molecular targets to develop more effective treatment regimens for cancer. PMID- 23918905 TI - Paget Cells in Endometrial and Endocervical Curettings in a Patient With Recurrent Vulvar Paget's Disease. AB - INTRODUCTION: Paget's disease of the vulva is a rare malignancy primarily affecting Caucasian women in their seventh to eighth decades. Most patients experience an indolent disease course and undergo surgical excision for disease control. Although progression to invasive adenocarcinoma is rare, recurrence is common because of the difficulty of achieving negative surgical margins. CASE PRESENTATION: We report a case of a 73-year-old woman with a long-standing history of recurrent vulvar Paget's disease who presented with postmenopausal bleeding. Workup revealed extensive endocervical involvement by Paget's disease, resulting in Paget cells on endocervical curettage, as well as endometrial curettage (because of cervical contamination). CONCLUSION: Extensive endocervical involvement by vulvar Paget's disease can occur despite multiple reexcisions and topical therapy. The presence of Paget cells on endometrial and endocervical curettings, particularly in patients without visible vulvar or cervical lesions, should raise suspicion of endocervical involvement and prompt further evaluation of disease extension. PMID- 23918906 TI - The geriatrician and geriatric psychiatrist workforce in Texas: characteristics, challenges, and policy implications. AB - OBJECTIVE: This study provides a current analysis of the size and characteristics of the board-certified geriatrician and geriatric psychiatrist workforce in Texas, and thereby its capacity to meet increasing health needs of elders. METHOD: Secondary data on Texas board-certified geriatricians and geriatric psychiatrists from American Board of Medical Specialties database were analyzed. RESULTS: The study found 1 geriatrician per 5,132 elders, and 1 geriatric psychiatrist per 21,327 elders, in Texas. Over 62% of geriatricians had active certification, 30% were females and the average age was 55.2 years. Rural geriatricians were disproportionately scarce (p < .001). DISCUSSION: The study indicated a serious shortage of board-certified geriatricians and geriatric psychiatrists in Texas. This shortage is worse than that at the national level, and more marked along the Texas-Mexico border and counties lacking large health facilities. Addressing this workforce deficiency requires improvements in the geriatric training pipeline, reimbursements, and practice environments. PMID- 23918908 TI - Osteopathic Research Conference 2013: "From Bench to Bedside". PMID- 23918909 TI - The effect of OMT on postoperative medical and functional recovery of coronary artery bypass graft patients. PMID- 23918910 TI - Relighting the fire in our bellies. PMID- 23918911 TI - Mathematical analysis of the flow of hyaluronic acid around fascia during manual therapy motions. AB - CONTEXT: More research is needed to understand the flow characteristics of hyaluronic acid (HA) during motions used in osteopathic manipulative treatment and other manual therapies. OBJECTIVE: To apply a 3-dimensional mathematical model to explore the relationship between the 3 manual therapy motions (constant sliding, perpendicular vibration, and tangential oscillation) and the flow characteristics of HA below the fascial layer. METHODS: The Squeeze Film Lubrication theory of fluid mechanics for flow between 2 plates was used, as well as the Navier-Stokes equations. RESULTS: The fluid pressure of HA increased substantially as fascia was deformed during manual therapies. There was a higher rate of pressure during tangential oscillation and perpendicular vibration than during constant sliding. This variation of pressure caused HA to flow near the edges of the fascial area under manipulation, and this flow resulted in greater lubrication. The pressure generated in the fluid between the muscle and the fascia during osteopathic manipulative treatment causes the fluid gap to increase. Consequently, the thickness between 2 fascial layers increases as well. Thus, the presence of a thicker fluid gap can improve the sliding system and permit the muscles to work more efficiently. CONCLUSION: The mathematical model employed by the authors suggests that inclusion of perpendicular vibration and tangential oscillation may increase the action of the treatment in the extracellular matrix, providing additional benefits in manual therapies that currently use only constant sliding motions. PMID- 23918912 TI - Exercise during pregnancy: the role of obstetric providers. AB - CONTEXT: Obstetric providers are logical choices for conveying information about physical activity to their pregnant patients. However, research regarding obstetric providers counseling pregnant patients about physical activity is sparse. OBJECTIVES: To investigate the association between obstetric providers discussing exercise with their pregnant patients and patients' exercise behaviors and to explore factors related to obstetric providers discussing exercise and other health behaviors (tobacco use, alcohol use, and nutrition) with their patients. METHODS: We received completed surveys from 238 pregnant women and 31 obstetric providers at 12 obstetrician offices. The offices were located throughout the United States and were heterogeneous in regards to patient insurance coverage, number of patients treated per month, and percentage of patients with complications. RESULTS: Women who were "more careful about eating healthy" (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.2-8.0) and who discussed exercise with their obstetric provider (OR, 2.2; 95% CI, 1.1-4.3) were more likely to "maintain or increase exercise" during pregnancy than those who were not conscientious about their diets and those who did not discuss exercise with their obstetric provider, respectively. The odds of obstetric providers discussing exercise with pregnant patients increased 7-fold (OR, 7.1; 95% CI, 1.4 37.3) for each health behavior the obstetric provider discussed with the patient. CONCLUSION: Patient discussions with obstetric providers about exercise and patient attention to eating habits are associated with exercising during pregnancy. A more multibehavioral approach by obstetric providers may improve the likelihood that patients exercise during pregnancy. PMID- 23918913 TI - Caring for patients with chronic pain: pearls and pitfalls. AB - Chronic, nonmalignant pain is a substantial public health problem in the United States. Research over the past 2 decades has defined chronic pain by using a "biopsychosocial model" that considers a patient's biology and psychological makeup in the context of his or her social and cultural milieu. Whereas this model addresses the pathology of chronic pain, it also places many demands on the physician, who is expected to assess and manage chronic pain safely and successfully. There is a growing body of evidence suggesting that opioids can be effective in the management of chronic pain, but there has also been a rise in opioid-related overdoses and deaths. Clinicians should be aware of assessment tools that may be used to evaluate the risk of opioid abuse. A basic understanding of chronic pain pathophysiology and a uniform approach to patient care can satisfy the needs of both patients and physicians. PMID- 23918914 TI - Incorporating simulation technology into a neurology clerkship. AB - Simulation-based medical education is growing in use and popularity in various settings and specialties. A literature review yields scant information about the use of simulation-based medical education in neurology, however. The specialty of neurology presents an interesting challenge to the field of simulation-based medical education because of the inability of even the most advanced mannequins to mimic a focal neurologic deficit. The authors present simulator protocols for status epilepticus and acute stroke that use a high-fidelity mannequin despite its inability to mimic a focal neurologic deficit. These protocols are used in the training of third- and fourth-year medical students during their neurology clerkship at Penn State College of Medicine. The authors also provide a review of the pertinent literature. PMID- 23918915 TI - Conservative approach to tardive dyskinesia-induced neck and upper back pain. AB - The management of schizophrenia typically involves the use of antipsychotics (neuroleptics). Use of such medications, however, can result in tardive dyskinesia, or the involuntary contracture of muscles, and associated symptomatic somatic dysfunction. The authors present a case of a 29-year-old woman who presented to a family medicine clinic for ongoing management of schizophrenia with noticeable tardive dyskinesia and complaints of neck and upper back pain. Conventional management of tardive dyskinesia involves either a change in or reduction of the offending antipsychotic. In the present case, the patient received osteopathic manipulative treatment in addition to conventional care for the management of her neck and upper back pain. Although not curative, osteopathic manipulative treatment can provide palliative relief for patients with tardive dyskinesia. PMID- 23918916 TI - Fibrous dysplasia of the craniofacial bones. PMID- 23918917 TI - One of ours. PMID- 23918919 TI - Stratified high-throughput screening sets enable flexible screening strategies from a single plated collection. AB - Customized compound picking and plating of very large corporate screening decks (many 100,000s) for high-throughput screening is generally restricted, both from a time and cost perspective. Here we present a stratified screening deck with accompanying plating design for use with very large corporate compound collections. The deck is plated as a whole, but copies for screening can be downsized flexibly and quickly on the fly, without the need for repicking of physical samples. We show that such downsized sets maximize returns and yield results superior to randomly picked subsets of the same size. For the proposed stratified plating design, structurally diverse subsets that cover the full collection in terms of compound diversity and favorable compound properties can be produced economically and quickly from the full set of master plates. The design was implemented globally at AstraZeneca in 2009 and has enabled substantial cost-saving in screening campaigns, as set size requirements can be met on a per-screen basis, using a single, preplated master deck. PMID- 23918920 TI - An HTS-compatible 3D colony formation assay to identify tumor-specific chemotherapeutics. AB - There has been increasing interest in the development of cellular behavior models that take advantage of three-dimensional (3D) cell culture. To enable assessment of differential perturbagen impacts on cell growth in 2D and 3D, we have miniaturized and adapted for high-throughput screening (HTS) the soft agar colony formation assay, employing a laser-scanning cytometer to image and quantify multiple cell types simultaneously. The assay is HTS compatible, providing high quality, image-based, replicable data for multiple, co-cultured cell types. As proof of concept, we subjected colorectal carcinoma colonies in 3D soft agar to a mini screen of 1528 natural product compounds. Hit compounds from the primary screen were rescreened in an HTS 3D co-culture matrix containing colon stromal cells and cancer cells. By combining tumor cells and normal, nontransformed colon epithelial cells in one primary screening assay, we were able to obtain differential IC50 data, thereby distinguishing tumor-specific compounds from general cytotoxic compounds. Moreover, we were able to identify compounds that antagonized tumor colony formation in 3D only, highlighting the importance of this assay in identifying agents that interfere with 3D tumor structural growth. This screening platform provides a fast, simple, and robust method for identification of tumor-specific agents in a biologically relevant microenvironment. PMID- 23918921 TI - Self-Reported Preconception Care of HIV-Positive Women of Reproductive Potential: A Retrospective Study. AB - OBJECTIVES: We determined the proportion and correlates of self-reported pregnancy planning discussions (that is preconception counseling) that HIV positive women reported to their family physicians (FPs), HIV specialists, and obstetrician/gynecologists (OB/Gyns). METHODS: In a cross-sectional substudy, HIV positive women of reproductive potential were asked whether their care providers discussed pregnancy planning. Logistic regression was used to calculate odds ratios for the correlates of preconception counseling. RESULTS: A total of 431 eligible participants (median age 38, interquartile range = 32-43) reported having discussion with a physician (92% FP, 96% HIV specialists, and 45% OB/Gyns). In all, 34%, 41%, and 38% had their pregnancy planning discussion with FP, HIV specialist, and Ob/Gyns, respectively; 51% overall. In the multivariable model, significant correlates of preconception counseling were age (P = .02), marital status (P < .01), number of years living in Canada (P < .001), and age of youngest child (P < .01). CONCLUSIONS: Preconception care in our cohort was suboptimal. We recommend that counseling on healthy preconception should be part of routine HIV care. PMID- 23918922 TI - Reducing the variability of compound management delivery using visual management systems. AB - The globalization and externalization of a pharmaceutical company's research and development (R&D) places considerable demands on its underpinning compound management (CM) capability. More robust CM workflows are needed to support higher demands and cross-continent supply chains. The tracking and visibility of compound orders progressing through CM processes has become crucial to ensure prompt and reliable delivery to customers and project timelines worldwide. AstraZeneca at Alderley Park UK has successfully introduced and integrated a visual management system into its CM processes to support the company's global R&D strategy. A simple, low-cost approach has been employed to track solid processing and solubilization orders. This reduced variability and end-to-end cycle times by decreasing waiting time between processing steps. The visual tracking system has been quick to implement, adaptable to change, and able to be owned and run by delivery teams. Introduction of the visual tracking system has resulted in significant improvements in order processing, both in terms of variability and speed. The percentage of orders processed within 24 h rose from 81.5% to 92.5%, and reductions of 50% and 17.5% in the average processing time were seen for solid dispense and solubilization orders, respectively. PMID- 23918923 TI - Dysregulation of the immune system in Aicardi-Goutieres syndrome: another example in a TREX1-mutated patient. AB - Aicardi-Goutieres syndrome (AGS) is a rare genetic encephalopathy characterized by neurological and extraneurological involvement. A clinical overlap between AGS and systemic lupus erythematosus (SLE) has been reported. We describe an AGS patient who developed autoimmune manifestations: thyroiditis, cANCA positivity, antiphospholipid antibodies and cerebral ischemia. This first description of antiphospholipid syndrome in a TREX1-mutated patient further expands the clinical spectrum of AGS. Although the clinical overlap with SLE may indicate common pathogenic mechanisms, the autoimmune manifestations in AGS are so extensive that we suggest they should be considered a clinical feature of the disease, rather than a sign of coexistent SLE. PMID- 23918924 TI - Histamine induces ATP release from human subcutaneous fibroblasts, via pannexin-1 hemichannels, leading to Ca2+ mobilization and cell proliferation. AB - Changes in the regulation of connective tissue ATP-mediated mechano-transduction and remodeling may be an important link to the pathogenesis of chronic pain. It has been demonstrated that mast cell-derived histamine plays an important role in painful fibrotic diseases. Here we analyzed the involvement of ATP in the response of human subcutaneous fibroblasts to histamine. Acute histamine application caused a rise in intracellular Ca(2+) ([Ca(2+)]i) and ATP release from human subcutaneous fibroblasts via H1 receptor activation. Histamine-induced [Ca(2+)]i rise was partially attenuated by apyrase, an enzyme that inactivates extracellular ATP, and by blocking P2 purinoceptors with pyridoxal phosphate-6 azo(benzene-2,4-disulfonic acid) tetrasodium salt and reactive blue 2. [Ca(2+)]i accumulation caused by histamine was also reduced upon blocking pannexin-1 hemichannels with (10)Panx, probenecid, or carbenoxolone but not when connexin hemichannels were inhibited with mefloquine or 2-octanol. Brefeldin A, an inhibitor of vesicular exocytosis, also did not block histamine-induced [Ca(2+)]i mobilization. Prolonged exposure of human subcutaneous fibroblast cultures to histamine favored cell growth and type I collagen synthesis via the activation of H1 receptor. This effect was mimicked by ATP and its metabolite, ADP, whereas the selective P2Y1 receptor antagonist, MRS2179, partially attenuated histamine induced cell growth and type I collagen production. Expression of pannexin-1 and ADP-sensitive P2Y1 receptor on human subcutaneous fibroblasts was confirmed by immunofluorescence confocal microscopy and Western blot analysis. In conclusion, histamine induces ATP release from human subcutaneous fibroblasts, via pannexin-1 hemichannels, leading to [Ca(2+)]i mobilization and cell growth through the cooperation of H1 and P2 (probably P2Y1) receptors. PMID- 23918925 TI - A stable bacterial peroxidase with novel halogenating activity and an autocatalytically linked heme prosthetic group. AB - Reconstructing the phylogenetic relationships of the main evolutionary lines of the mammalian peroxidases lactoperoxidase and myeloperoxidase revealed the presence of novel bacterial heme peroxidase subfamilies. Here, for the first time, an ancestral bacterial heme peroxidase is shown to possess a very high bromide oxidation activity (besides conventional peroxidase activity). The recombinant protein allowed monitoring of the autocatalytic peroxide-driven formation of covalent heme to protein bonds. Thereby, the high spin ferric rhombic heme spectrum became similar to lactoperoxidase, the standard reduction potential of the Fe(III)/Fe(II) couple shifted to more positive values (-145 +/- 10 mV at pH 7), and the conformational and thermal stability of the protein increased significantly. We discuss structure-function relationships of this new peroxidase in relation to its mammalian counterparts and ask for its putative physiological role. PMID- 23918926 TI - Protein phosphatase 2A enables expression of interleukin 17 (IL-17) through chromatin remodeling. AB - Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase involved in essential cellular functions. T cells from patients with systemic lupus erythematosus (SLE) express high levels of the catalytic subunit of PP2A (PP2Ac). A mouse overexpressing PP2Ac in T cells develops glomerulonephritis in an IL-17-dependent manner. Here, using microarray analyses, we demonstrate that increased expression of PP2Ac grants T cells the capacity to produce an array of proinflammatory effector molecules. Because IL-17 is important in the expression of glomerulonephritis, we studied the mechanism through which PP2Ac dysregulation facilitates its production. We report that PP2Ac is involved in the regulation of the Il17 locus by enhancing histone 3 acetylation through a mechanism that involves activation of interferon regulatory factor 4. Increased histone 3 acetylation of the Il17 locus is shared between T cells of PP2Ac transgenic mice and patients with SLE. We propose that, by promoting the inflammatory capacity of T cells, PP2Ac dysregulation contributes to the pathogenesis of SLE. PMID- 23918927 TI - Human T cell activation results in extracellular signal-regulated kinase (ERK) calcineurin-dependent exposure of Tn antigen on the cell surface and binding of the macrophage galactose-type lectin (MGL). AB - The C-type lectin macrophage galactose-type lectin (MGL) exerts an immunosuppressive role reflected by its interaction with terminal GalNAc moieties, such as the Tn antigen, on CD45 of effector T cells, thereby down regulating T cell receptor signaling, cytokine responses, and induction of T cell death. Here, we provide evidence for the pathways that control the specific expression of GalNAc moieties on human CD4(+) T cells. GalNAc epitopes were readily detectable on the cell surface after T cell activation and required de novo protein synthesis. Expression of GalNAc-containing MGL ligands was completely dependent on PKC and did not involve NF-kappaB. Instead, activation of the downstream ERK MAPK pathway led to decreased mRNA levels and activity of the core 1 beta3GalT enzyme and its chaperone Cosmc, favoring the expression of Tn antigen. In conclusion, expression of GalNAc moieties mirrors the T cell activation status, and thus only highly stimulated T cells are prone to the suppressive action of MGL. PMID- 23918928 TI - Furin is the primary in vivo convertase of angiopoietin-like 3 and endothelial lipase in hepatocytes. AB - The proprotein convertases (PCs) furin, PC5/6, and PACE4 exhibit unique and/or complementary functions. Their knock-out (KO) in mice resulted in strong and specific phenotypes demonstrating that, in vivo, these PCs are unique and essential during development. However, they also exhibit redundant functions. Liver angiopoietin-like 3 (ANGPTL3) inhibits lipolysis by binding to lipoprotein lipases. It is found in the plasma as full length and truncated forms. The latter is more active and generated by cleavage at a furin-like site. Endothelial lipase (EL) binds heparin sulfate proteoglycans on cell surfaces and catalyzes the hydrolysis of HDL phospholipids. EL activity is regulated by two endogenous inhibitors, ANGPTL3 and ANGPTL4, and by PCs that inactivate EL through cleavage releasing the N-terminal catalytic and C-terminal lipid-binding domains. Herein, because furin and PC5/6 complete KOs are lethal, we used mice lacking furin or PC5/6 specifically in hepatocytes (hKO) or mice completely lacking PACE4. In primary hepatocytes, ANGPTL3 was processed into a shorter form of ANGPTL3 intracellularly by furin only, and extracellularly mainly by PACE4. In vivo, the absence of furin in hepatocytes reduced by ~50% the circulating levels of cleaved ANGPTL3, while the lack of PACE4 had only a minor effect. Analysis of the EL processing in primary hepatocytes and in vivo revealed that it is mostly cleaved by furin. However, the lack of furin or PC5/6 in hepatocytes and complete PACE4 KO did not appreciably modify plasma HDL levels or EL activity. Thus, inhibition of furin in liver would not be expected to modify the plasma lipid profiles. PMID- 23918929 TI - The vitamin K oxidoreductase is a multimer that efficiently reduces vitamin K epoxide to hydroquinone to allow vitamin K-dependent protein carboxylation. AB - The vitamin K oxidoreductase (VKORC1) recycles vitamin K to support the activation of vitamin K-dependent (VKD) proteins, which have diverse functions that include hemostasis and calcification. VKD proteins are activated by Glu carboxylation, which depends upon the oxygenation of vitamin K hydroquinone (KH2). The vitamin K epoxide (KO) product is recycled by two reactions, i.e. KO reduction to vitamin K quinone (K) and then to KH2, and recent studies have called into question whether VKORC1 reduces K to KH2. Analysis in insect cells lacking endogenous carboxylation components showed that r-VKORC1 reduces KO to efficiently drive carboxylation, indicating KH2 production. Direct detection of the vitamin K reaction products is confounded by KH2 oxidation, and we therefore developed a new assay that stabilized KH2 and allowed quantitation. Purified VKORC1 analyzed in this assay showed efficient KO to KH2 reduction. Studies in 293 cells expressing tagged r-VKORC1 revealed that VKORC1 is a multimer, most likely a dimer. A monomer can only perform one reaction, and a dimer is therefore interesting in explaining how VKORC1 accomplishes both reactions. An inactive mutant (VKORC1(C132A/C135A)) was dominant negative in heterodimers with wild type VKORC1, resulting in decreased KO reduction in cells and carboxylation in vitro. The results are significant regarding human VKORC1 mutations, as warfarin resistant patients have mutant and wild type VKORC1 alleles. A VKORC1 dimer indicates a mixed population of homodimers and heterodimers that may have different functional properties, and VKORC1 reduction may therefore be more complex in these patients than appreciated previously. PMID- 23918931 TI - Listeria monocytogenes aguA1, but not aguA2, encodes a functional agmatine deiminase: biochemical characterization of its catalytic properties and roles in acid tolerance. AB - Listeria monocytogenes is adaptable to low pH environments and therefore crosses the intestinal barrier to establish systemic infections. L. monocytogenes aguA1 and aguA2 encode putative agmatine deiminases (AgDIs) AguA1 and AguA2. Transcription of aguA1 and aguA2 was significantly induced at pH 5.0. Deletion of aguA1 significantly impaired its survival both in gastric fluid at pH 2.5 and in mouse stomach, whereas aguA2 deletion did not show significant defect of survival in gastric fluid. With agmatine as the sole substrate, AguA1 expressed in Escherichia coli was optimal at 25 degrees C and over a wide range of pH from 3.5 to 10.5. Recombinant AguA2 showed no deiminase activity. Site-directed mutagenesis revealed that all nine AguA1 mutants completely lost enzymatic activity. AguA2 acquired AgDI activity only when Cys-157 was mutated to glycine. AguA1 mutation at the same site, G157C, also inactivated the enzyme. Thus, we have discovered Gly-157 as a novel residue other than the known catalytic triad (Cys-His-Glu/Asp) in L. monocytogenes that is critical for enzyme activity. Of the two putative AgDIs, we conclude that only AguA1 functionally participates in the AgDI pathway and mediates acid tolerance in L. monocytogenes. PMID- 23918930 TI - Forkhead box O1 (FOXO1) protein, but not p53, contributes to robust induction of p21 expression in fasted mice. AB - Reporter mice that enable the activity of the endogenous p21 promoter to be dynamically monitored in real time in vivo and under a variety of experimental conditions revealed ubiquitous p21 expression in mouse organs including the brain. Low light bioluminescence microscopy was employed to localize p21 expression to specific regions of the brain. Interestingly, p21 expression was observed in the paraventricular, arcuate, and dorsomedial nuclei of the hypothalamus, regions that detect nutrient levels in the blood stream and signal metabolic actions throughout the body. These results suggested a link between p21 expression and metabolic regulation. We found that short-term food deprivation (fasting) potently induced p21 expression in tissues involved in metabolic regulation including liver, pancreas and hypothalamic nuclei. Conditional reporter mice were generated that enabled hepatocyte-specific expression of p21 to be monitored in vivo. Bioluminescence imaging demonstrated that fasting induced a 7-fold increase in p21 expression in livers of reporter mice and Western blotting demonstrated an increase in protein levels as well. The ability of fasting to induce p21 expression was found to be independent of p53 but dependent on FOXO1. Finally, occupancy of the endogenous p21 promoter by FOXO1 was observed in the livers of fasted but not fed mice. Thus, fasting promotes loading of FOXO1 onto the p21 promoter to induce p21 expression in hepatocytes. PMID- 23918932 TI - Metabolite regulation of nucleo-cytosolic trafficking of carbohydrate response element-binding protein (ChREBP): role of ketone bodies. AB - The carbohydrate response element-binding protein (ChREBP) is a glucose responsive transcription factor that plays a critical role in converting excess carbohydrate to storage fat in liver. In response to changing glucose levels, ChREBP activity is regulated by nucleo-cytoplasmic shuttling of ChREBP via interactions with 14-3-3 proteins and importins. The nuclear/cytosol trafficking is regulated partly by phosphorylation/dephosphorylation of serine 196 mediated by cAMP-dependent protein kinase and protein phosphatase. We show here that protein-free extracts of starved and high fat-fed livers contain metabolites that activate interaction of ChREBP.14-3-3 and inhibit the ChREBP/importin alpha interaction, resulting in cytosolic localization. These metabolites were identified as beta-hydroxybutyrate and acetoacetate. Nuclear localization of GFP ChREBP is rapidly inhibited in hepatocytes incubated in beta-hydroxybutyrate or fatty acids, and the observed inhibition is closely correlated with the production of ketone bodies. These observations show that ketone bodies play an important role in the regulation of ChREBP activity by restricting ChREBP localization to the cytoplasm, thus inhibiting fat synthesis during periods of ketosis. PMID- 23918933 TI - Regulatory interaction between NBS1 and DNMT1 responding to DNA damage. AB - NBS1 is the causative gene product of Nijmegen breakage syndrome (NBS), a recessive genetic disorder resulting in chromosomal instability and immunodeficiency. We isolated DNMT1 cDNA by two-hybrid screening by using NBS1 as bait to study its function in DNA replication and damage checkpoint. DNMT1 encodes DNA methyltransferase 1, which maintains the genomic methylation pattern and also regulates the checkpoint pathway via interactions with various factors, such as CHK1, p53, Rb and ATM. The interaction between NBS1 and DNMT1 was observed under conditions of hydroxyl urea treatment, resulting in replication stall and mitomycin C treatment resulting in DNA damage. Additionally, we mapped their binding regions to the N-terminus of NBS1 (including the forkhead associated domain) and amino acids 1401-1503 in the target recognition domain in the C-terminus of DNMT1. Under DNA replication stall conditions, DNMT1 was recruited to the survivin promoter by p53, and it repressed survivin expression via hetrochromatin formation; this regulation was dependent on the NBS1 genotype. These results suggest that DNMT1 function in the regulatory response is controlled by NBS1. PMID- 23918934 TI - Bob Goldstein: cell biology by way of development. Interviewed by Caitlin Sedwick. PMID- 23918935 TI - Macrophages in pancreatic cancer: starting things off on the wrong track. AB - Chronic inflammation drives initiation and progression of many malignancies, including pancreatic cancer. In this issue, Liou et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201301001) report that inflammatory macrophages are major players in the earliest stages of pancreatic cancer. They show that paracrine signals from the macrophages activate the nuclear factor kappaB transcriptional program in normal pancreatic acinar cells, resulting in acinar ductal metaplasia, a dedifferentiated state that is poised for oncogenic transformation. PMID- 23918937 TI - Microtubule severing by the katanin complex is activated by PPFR-1-dependent MEI 1 dephosphorylation. AB - Katanin is an evolutionarily conserved microtubule (MT)-severing complex implicated in multiple aspects of MT dynamics. In Caenorhabditis elegans, the katanin homologue MEI-1 is required for meiosis, but must be inactivated before mitosis. Here we show that PPFR-1, a regulatory subunit of a trimeric protein phosphatase 4 complex, enhanced katanin MT-severing activity during C. elegans meiosis. Loss of ppfr-1, similarly to the inactivation of MT severing, caused a specific defect in meiosis II spindle disassembly. We show that a fraction of PPFR-1 was degraded after meiosis, contributing to katanin inactivation. PPFR-1 interacted with MEL-26, the substrate recognition subunit of the CUL-3 RING E3 ligase (CRL3(MEL-26)), which also targeted MEI-1 for post-meiotic degradation. Reversible protein phosphorylation of MEI-1 may ensure temporal activation of the katanin complex during meiosis, whereas CRL3(MEL-26)-mediated degradation of both MEI-1 and its activator PPFR-1 ensure efficient katanin inactivation in the transition to mitosis. PMID- 23918936 TI - Cryo-electron tomography: the challenge of doing structural biology in situ. AB - Electron microscopy played a key role in establishing cell biology as a discipline, by producing fundamental insights into cellular organization and ultrastructure. Many seminal discoveries were made possible by the development of new sample preparation methods and imaging modalities. Recent technical advances include sample vitrification that faithfully preserves molecular structures, three-dimensional imaging by electron tomography, and improved image-processing methods. These new techniques have enabled the extraction of high fidelity structural information and are beginning to reveal the macromolecular organization of unperturbed cellular environments. PMID- 23918938 TI - Coordination of adjacent domains mediates TACC3-ch-TOG-clathrin assembly and mitotic spindle binding. AB - A complex of transforming acidic coiled-coil protein 3 (TACC3), colonic and hepatic tumor overexpressed gene (ch-TOG), and clathrin has been implicated in mitotic spindle assembly and in the stabilization of kinetochore fibers by cross linking microtubules. It is unclear how this complex binds microtubules and how the proteins in the complex interact with one another. TACC3 and clathrin have each been proposed to be the spindle recruitment factor. We have mapped the interactions within the complex and show that TACC3 and clathrin were interdependent for spindle recruitment, having to interact in order for either to be recruited to the spindle. The N-terminal domain of clathrin and the TACC domain of TACC3 in tandem made a microtubule interaction surface, coordinated by TACC3-clathrin binding. A dileucine motif and Aurora A-phosphorylated serine 558 on TACC3 bound to the "ankle" of clathrin. The other interaction within the complex involved a stutter in the TACC3 coiled-coil and a proposed novel sixth TOG domain in ch-TOG, which was required for microtubule localization of ch-TOG but not TACC3-clathrin. PMID- 23918940 TI - CCM1-ICAP-1 complex controls beta1 integrin-dependent endothelial contractility and fibronectin remodeling. AB - The endothelial CCM complex regulates blood vessel stability and permeability. Loss-of-function mutations in CCM genes are responsible for human cerebral cavernous malformations (CCMs), which are characterized by clusters of hemorrhagic dilated capillaries composed of endothelium lacking mural cells and altered sub-endothelial extracellular matrix (ECM). Association of the CCM1/2 complex with ICAP-1, an inhibitor of beta1 integrin, prompted us to investigate whether the CCM complex interferes with integrin signaling. We demonstrate that CCM1/2 loss resulted in ICAP-1 destabilization, which increased beta1 integrin activation and led to increased RhoA-dependent contractility. The resulting abnormal distribution of forces led to aberrant ECM remodeling around lesions of CCM1- and CCM2-deficient mice. ICAP-1-deficient vessels displayed similar defects. We demonstrate that a positive feedback loop between the aberrant ECM and internal cellular tension led to decreased endothelial barrier function. Our data support that up-regulation of beta1 integrin activation participates in the progression of CCM lesions by destabilizing intercellular junctions through increased cell contractility and aberrant ECM remodeling. PMID- 23918939 TI - Lissencephaly-1 promotes the recruitment of dynein and dynactin to transported mRNAs. AB - Microtubule-based transport mediates the sorting and dispersal of many cellular components and pathogens. However, the mechanisms by which motor complexes are recruited to and regulated on different cargos remain poorly understood. Here we describe a large-scale biochemical screen for novel factors associated with RNA localization signals mediating minus end-directed mRNA transport during Drosophila development. We identified the protein Lissencephaly-1 (Lis1) and found that minus-end travel distances of localizing transcripts are dramatically reduced in lis1 mutant embryos. Surprisingly, given its well-documented role in regulating dynein mechanochemistry, we uncovered an important requirement for Lis1 in promoting the recruitment of dynein and its accessory complex dynactin to RNA localization complexes. Furthermore, we provide evidence that Lis1 levels regulate the overall association of dynein with dynactin. Our data therefore reveal a critical role for Lis1 within the mRNA localization machinery and suggest a model in which Lis1 facilitates motor complex association with cargos by promoting the interaction of dynein with dynactin. PMID- 23918941 TI - Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-kappaB and MMPs. AB - In response to inflammation, pancreatic acinar cells can undergo acinar-to-ductal metaplasia (ADM), a reprogramming event that induces transdifferentiation to a ductlike phenotype and, in the context of additional oncogenic stimulation, contributes to development of pancreatic cancer. The signaling mechanisms underlying pancreatitis-inducing ADM are largely undefined. Our results provide evidence that macrophages infiltrating the pancreas drive this transdifferentiation process. We identify the macrophage-secreted inflammatory cytokines RANTES and tumor necrosis factor alpha (TNF) as mediators of such signaling. Both RANTES and TNF induce ADM through activation of nuclear factor kappaB and its target genes involved in regulating survival, proliferation, and degradation of extracellular matrix. In particular, we identify matrix metalloproteinases (MMPs) as targets that drive ADM and provide in vivo data suggesting that MMP inhibitors may be efficiently applied to block pancreatitis induced ADM in therapy. PMID- 23918942 TI - Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. AB - PURPOSE: To evaluate the association between cumulative duration of metformin use after prostate cancer (PC) diagnosis and all-cause and PC-specific mortality among patients with diabetes. PATIENTS AND METHODS: We used a population-based retrospective cohort design. Data were obtained from several Ontario health care administrative databases. Within a cohort of men older than age 66 years with incident diabetes who subsequently developed PC, we examined the effect of duration of antidiabetic medication exposure after PC diagnosis on all-cause and PC-specific mortality. Crude and adjusted hazard ratios (HRs) were calculated by using a time-varying Cox proportional hazard model to estimate effects. RESULTS: The cohort consisted of 3,837 patients. Median age at diagnosis of PC was 75 years (interquartile range [IQR], 72 to 79 years). During a median follow-up of 4.64 years (IQR, 2.7 to 7.1 years), 1,343 (35%) died, and 291 patients (7.6%) died as a result of PC. Cumulative duration of metformin treatment after PC diagnosis was associated with a significant decreased risk of PC-specific and all cause mortality in a dose-dependent fashion. Adjusted HR for PC-specific mortality was 0.76 (95% CI, 0.64 to 0.89) for each additional 6 months of metformin use. The association with all-cause mortality was also significant but declined over time from an HR of 0.76 in the first 6 months to 0.93 between 24 and 30 months. There was no relationship between cumulative use of other antidiabetic drugs and either outcome. CONCLUSION: Increased cumulative duration of metformin exposure after PC diagnosis was associated with decreases in both all-cause and PC-specific mortality among diabetic men. PMID- 23918943 TI - DNA methylation signatures for prediction of biochemical recurrence after radical prostatectomy of clinically localized prostate cancer. AB - PURPOSE: Diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, causing overtreatment of indolent PC and risk of delayed treatment of aggressive PC. Here, we identify six novel candidate DNA methylation markers for PC with promising diagnostic and prognostic potential. METHODS: Microarray-based screening and bisulfite sequencing of 20 nonmalignant and 29 PC tissue specimens were used to identify new candidate DNA hypermethylation markers for PC. Diagnostic and prognostic potential was evaluated in 35 nonmalignant prostate tissue samples, 293 radical prostatectomy (RP) samples (cohort 1, training), and 114 malignant RP samples (cohort 2, validation) collected in Denmark, Switzerland, Germany, and Finland. Sensitivity and specificity for PC were evaluated by receiver operating characteristic analyses. Correlations between DNA methylation levels and biochemical recurrence were assessed using log-rank tests and univariate and multivariate Cox regression analyses. RESULTS: Hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B was highly cancer specific (area under the curve, 0.89 to 0.98). Furthermore, high C1orf114 methylation was significantly (P < .05) associated with biochemical recurrence in multivariate analysis in cohort 1 (hazard ratio [HR], 3.10; 95% CI, 1.89 to 5.09) and was successfully validated in cohort 2 (HR, 3.27; 95% CI, 1.17 to 9.12). Moreover, a significant (P < .05) three-gene prognostic methylation signature (AOX1/C1orf114/HAPLN3), classifying patients into low- and high-methylation subgroups, was trained in cohort 1 (HR, 1.91; 95% CI, 1.26 to 2.90) and validated in cohort 2 (HR, 2.33; 95% CI, 1.31 to 4.13). CONCLUSION: We identified six novel candidate DNA methylation markers for PC. C1orf114 hypermethylation and a three gene methylation signature were independent predictors of time to biochemical recurrence after RP in two PC patient cohorts. PMID- 23918945 TI - Sirolimus reduces cutaneous squamous cell carcinomas in transplantation recipients. PMID- 23918944 TI - Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. AB - PURPOSE: To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. METHODS: Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up. RESULTS: Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases). CONCLUSION: This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses. PMID- 23918946 TI - Chemotherapy versus autologous stem-cell transplantation for the treatment of transformed follicular lymphoma in the rituximab era. PMID- 23918947 TI - Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. AB - PURPOSE: Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAF(V600E/K) mutation-positive metastatic melanoma (mut(+) MM). PATIENTS AND METHODS: Histologically confirmed patients with stage IV BRAF(V600E/K) mut(+) MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was investigator-assessed overall response rate in BRAF(V600E) mut(+) MM patients. Secondary end points included progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and the evaluation of cfDNA as a predictor of clinical outcome. RESULTS: Seventy-six patients with BRAF(V600E) and 16 patients with BRAF(V600K) mut(+) MM were enrolled onto the study. In the BRAF(V600E) group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five patients (7%) with complete responses. Two patients (13%) with BRAF(V600K) mut(+) MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAF(V600E) and BRAF(V600K) groups, median PFS was 6.3 months and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted response rate and PFS in BRAF(V600E) mut(+) MM patients. CONCLUSION: Dabrafenib was well tolerated and clinically active in patients with BRAF(V600E/K) mut(+) MM. cfDNA may be a useful prognostic and response marker in future studies. PMID- 23918948 TI - The time is ripe for a randomized trial of metformin in clinically localized prostate cancer. PMID- 23918949 TI - Aromatase inhibitors and safety: clinical or statistical significance? PMID- 23918950 TI - Optimal sequence of tamoxifen and aromatase inhibitors to prevent bone loss. PMID- 23918951 TI - Second allograft for hematologic relapse of acute leukemia after first allogeneic stem-cell transplantation from related and unrelated donors: the role of donor change. AB - PURPOSE: To evaluate the role of a second allogeneic hematopoietic stem-cell transplantation (HSCT2) given for relapsed acute leukemia (AL) after related or unrelated first hematopoietic stem-cell transplantation (HSCT1) and to analyze the role of donor change for HSCT2 in both settings. PATIENTS AND METHODS: We performed a retrospective registry study on 179 HSCT2s given for relapse after HSCT1 from matched related donors (n = 75) or unrelated donors (n = 104), using identical or alternative donors for HSCT2. Separate analyses were performed according to donor at HSCT1. RESULTS: Independent of donor, 74% of patients achieved complete remission after HSCT2, and half of these patients experienced relapse again. Overall survival (OS) at 2 years was 25% +/- 4% (39% +/- 7% after related HSCT2; 19% +/- 4% after unrelated HSCT2). Long-term survivors were observed even after two unrelated HSCT2s. Multivariate analysis for OS from HSCT2 confirmed established risk factors (remission duration after HSCT1: hazard ratio [HR], 2.37; 95% CI, 1.61 to 3.46; P < .001; stage at HSCT2: HR, 0.53; 95% CI, 0.34 to 0.83; P = .006). Outcome of HSCT2 was better after related HSCT1 than after unrelated HSCT1 (2-year OS: 37% +/- 6% v 16% +/- 4%, respectively; HR, 0.68; 95% CI, 0.47 to 0.98; P = .042, multivariate Cox regression). After both related and unrelated HSCT1, selecting a new donor for HSCT2 did not result in a relevant improvement in OS compared with HSCT2 from the original donor; however, donor change was not detrimental either. CONCLUSION: After relapse from allogeneic HSCT1, HSCT2 can induce 2-year OS in approximately 25% of patients. Unrelated HSCT2 is feasible after related and unrelated HSCT1. Donor change for HSCT2 is a valid option. However, a clear advantage in terms of OS could not be demonstrated. PMID- 23918952 TI - Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. AB - PURPOSE: Patients with metastatic gastric cancer (mGC) who do not respond to or who experience progression with second-line chemotherapy have no treatment options that clearly confer a survival benefit. This trial investigated the safety and efficacy of apatinib, an inhibitor of vascular endothelial growth factor receptor, as a treatment option for heavily pretreated patients with mGC. PATIENTS AND METHODS: Patients who experienced treatment failure with at least two chemotherapeutic regimens were randomly assigned to receive placebo (group A), apatinib 850 mg once daily (group B), or apatinib 425 mg twice daily (group C). RESULTS: We enrolled 144 patients onto this study. In groups A, B, and C, the median overall survival (OS) times were 2.50 months (95% CI, 1.87 to 3.70 months), 4.83 months (95% CI, 4.03 to 5.97 months), and 4.27 months (95% CI, 3.83 to 4.77 months), respectively, and the median progression-free survival (PFS) times were 1.40 months (95% CI, 1.20 to 1.83 months), 3.67 months (95% CI, 2.17 to 6.80 months), and 3.20 months (95% CI, 2.37 to 4.53 months), respectively. There were statistically significant differences between the apatinib and placebo groups for both PFS (P < .001) and OS (P < .001 and P = .0017). Nine patients had a partial response (three patients in group B and six patients in group C). Toxicities were tolerable or could be clinically managed. The most common grade 3 to 4 adverse events were hand-foot syndrome and hypertension. Hematologic toxicities were moderate, and grade 3 to 4 hematologic toxicities were rare. CONCLUSION: Apatinib showed improved PFS and OS in heavily pretreated patients with mGC who had experienced treatment failure with two or more chemotherapy regimens. PMID- 23918953 TI - Randomized controlled trial of Mindfulness-based cancer recovery versus supportive expressive group therapy for distressed survivors of breast cancer. AB - PURPOSE: To compare the efficacy of the following two empirically supported group interventions to help distressed survivors of breast cancer cope: mindfulness based cancer recovery (MBCR) and supportive-expressive group therapy (SET). PATIENTS AND METHODS: This multisite, randomized controlled trial assigned 271 distressed survivors of stage I to III breast cancer to MBCR, SET, or a 1-day stress management control condition. MBCR focused on training in mindfulness meditation and gentle yoga, whereas SET focused on emotional expression and group support. Both intervention groups included 18 hours of professional contact. Measures were collected at baseline and after intervention by assessors blind to study condition. Primary outcome measures were mood and diurnal salivary cortisol slopes. Secondary outcomes were stress symptoms, quality of life, and social support. RESULTS: Using linear mixed-effects models, in intent-to-treat analyses, cortisol slopes were maintained over time in both SET (P = .002) and MBCR (P = .011) groups relative to the control group, whose cortisol slopes became flatter. Women in MBCR improved more over time on stress symptoms compared with women in both the SET (P = .009) and control (P = .024) groups. Per-protocol analyses showed greater improvements in the MBCR group in quality of life compared with the control group (P = .005) and in social support compared with the SET group (P = .012). CONCLUSION: In the largest trial to date, MBCR was superior for improving stress levels, quality of life and social support [CORRECTED] for distressed survivors of breast cancer. Both SET and MBCR also resulted in more normative diurnal cortisol profiles than the control condition. The clinical implications of this finding require further investigation. PMID- 23918954 TI - Loss of epidermal Evi/Wls results in a phenotype resembling psoriasiform dermatitis. AB - Cells of the epidermis renew constantly from germinal layer stem cells. Although epithelial cell differentiation has been studied in great detail and the role of Wnt signaling in this process is well described, the contribution of epidermal Wnt secretion in epithelial cell homeostasis remains poorly understood. To analyze the role of Wnt proteins in this process, we created a conditional knockout allele of the Wnt cargo receptor Evi/Gpr177/Wntless and studied mice that lacked Evi expression in the epidermis. We found that K14-Cre, Evi-LOF mice lost their hair during the first hair cycle, showing a reddish skin with impaired skin barrier function. Expression profiling of mutant and wild-type skin revealed up-regulation of inflammation-associated genes. Furthermore, we found that Evi expression in psoriatic skin biopsies is down-regulated, suggesting that Evi deficient mice developed skin lesions that resemble human psoriasis. Immune cell infiltration was detected in Evi-LOF skin. Interestingly, an age-dependent depletion of dendritic epidermal T cells (DETCs) and an infiltration of gammadelta(low) T cells in Evi mutant epidermis was observed. Collectively, the described inflammatory skin phenotype in Evi-deficient mice revealed an essential role of Wnt secretion in maintaining normal skin homeostasis by enabling a balanced epidermal-dermal cross talk, which affects immune cell recruitment and DETC survival. PMID- 23918955 TI - The microtubule-associated protein DCAMKL1 regulates osteoblast function via repression of Runx2. AB - Osteoblasts are responsible for the formation and mineralization of the skeleton. To identify novel regulators of osteoblast differentiation, we conducted an unbiased forward genetic screen using a lentiviral-based shRNA library. This functional genomics analysis led to the identification of the microtubule associated protein DCAMKL1 (Doublecortin-like and CAM kinase-like 1) as a novel regulator of osteogenesis. Mice with a targeted disruption of Dcamkl1 displayed elevated bone mass secondary to increased bone formation by osteoblasts. Molecular experiments demonstrated that DCAMKL1 represses osteoblast activation by antagonizing Runx2, the master transcription factor in osteoblasts. Key elements of the cleidocranial dysplasia phenotype observed in Runx2(+/-) mice are reversed by the introduction of a Dcamkl1-null allele. Our results establish a genetic linkage between these two proteins in vivo and demonstrate that DCAMKL1 is a physiologically relevant regulator of anabolic bone formation. PMID- 23918957 TI - Global calcium transducer P-type Ca2+-ATPases open new avenues for agriculture by regulating stress signalling. AB - Food security is in danger under the continuous growing threat of various stresses including climate change and global warming, which ultimately leads to a reduction in crop yields. Calcium plays a very important role in many signal transduction pathways including stress signalling. Different extracellular stimuli trigger increases in cytosolic calcium, which is detrimental to plants. To cope with such stresses, plants need to develop efficient efflux mechanisms to maintain ionic homeostasis. The Ca(2+)-ATPases are members of the P-type ATPase superfamily, which perform many fundamental processes in organisms by actively transporting ions across cellular membranes. In recent years, many studies have revealed that, as well as efflux mechanisms, Ca(2+)-ATPases also play critical roles in sensing calcium fluctuations and relaying downstream signals by activating definitive targets, thus modulating corresponding metabolic pathways. As calcium-activated calmodulin (CaM) is reported to play vital roles in stress tolerance, the presence of a unique CaM-binding site in type IIB Ca(2+)-ATPases indicates their potential role in biotic as well as abiotic stress tolerance. The key roles of Ca(2+)-ATPases in transport systems and stress signalling in cellular homeostasis are addressed in this review. A complete understanding of plant defence mechanisms under stress will allow bioengineering of improved crop plants, which will be crucial for food security currently observed worldwide in the context of global climate changes. Overall, this article covers classification, evolution, structural aspects of Ca(2+)-ATPases, and their emerging roles in plant stress signalling. PMID- 23918956 TI - Origin, trafficking, and intraepithelial fate of gut-tropic T cells. AB - The small intestine epithelium (SI-Ep) harbors millions of unconventional (gammadelta and CD4(-) CD8(-) NK1.1(-) TCRalphabeta) and conventional (CD8alphabeta and CD4) T cells, designated intraepithelial lymphocytes (IELs). Here, we identified the circulating pool of SI-Ep-tropic T cells and studied their capacity to colonize the SI-Ep under steady-state conditions in SPF mice. Developmentally regulated levels of alpha4beta7 endowed recent thymic emigrants (RTEs) of unconventional types with higher SI-Ep tropism than their conventional homologues. SI-Ep-tropic RTEs, which in all lineages emerged naive, homed to the SI-Ep, but this environment was inadequate to stimulate them to cycle. In contrast, conventional and, unexpectedly, unconventional T cells, particularly Vgamma7(+) (hallmark of gammadelta IELs), previously stimulated to cycle in the gut-associated lymphoid tissue (GALT), proliferated in the SI-Ep. Cycling unconventional SI-Ep immigrants divided far more efficiently than their conventional homologues, thereby becoming predominant. This difference impacted on acquisition of high Granzyme B content, which required extensive proliferation. In conclusion, SI-Ep-tropic T cells follow a thymus-SI-Ep or a GALT-SI-Ep pathway, the latter generating highly competitive immigrants that are the sole precursors of cytotoxic IELs. These events occur continuously as part of the normal IEL dynamics. PMID- 23918958 TI - High mature grain phytase activity in the Triticeae has evolved by duplication followed by neofunctionalization of the purple acid phosphatase phytase (PAPhy) gene. AB - The phytase activity in food and feedstuffs is an important nutritional parameter. Members of the Triticeae tribe accumulate purple acid phosphatase phytases (PAPhy) during grain filling. This accumulation elevates mature grain phytase activities (MGPA) up to levels between ~650 FTU/kg for barley and 6000 FTU/kg for rye. This is notably more than other cereals. For instance, rice, maize, and oat have MGPAs below 100 FTU/kg. The cloning and characterization of the PAPhy gene complement from wheat, barley, rye, einkorn, and Aegilops tauschii is reported here. The Triticeae PAPhy genes generally consist of a set of paralogues, PAPhy_a and PAPhy_b, and have been mapped to Triticeae chromosomes 5 and 3, respectively. The promoters share a conserved core but the PAPhy_a promoter have acquired a novel cis-acting regulatory element for expression during grain filling while the PAPhy_b promoter has maintained the archaic function and drives expression during germination. Brachypodium is the only sequenced Poaceae sharing the PAPhy duplication. As for the Triticeae, the duplication is reflected in a high MGPA of ~4200 FTU/kg in Brachypodium. The sequence conservation of the paralogous loci on Brachypodium chromosomes 1 and 2 does not extend beyond the PAPhy gene. The results indicate that a single-gene segmental duplication may have enabled the evolution of high MGPA by creating functional redundancy of the parent PAPhy gene. This implies that similar MGPA levels may be out of reach in breeding programs for some Poaceae, e.g. maize and rice, whereas Triticeae breeders should focus on PAPhy_a. PMID- 23918960 TI - Shifts in stomatal traits following the domestication of plant species. AB - Stomata are the major gates regulating substrate availability for photosynthesis and water loss. Although both processes are critical to yield and to resource-use efficiency, we lack a comprehensive picture on how domestication and further breeding have impacted on leaf stomata. To fill this gap, stomatal sizes and densities were screened in cultivated and wild ancestor representatives of a uniquely large group of 24 herbaceous crops. Anatomical data and gas-exchange models were combined to compute maximum potential conductance to water, separately for upper and lower leaf sides. The evolution of maximum conductance under domestication was diverse. Several crops increased, others decreased (noticeably high-conductance species), and others kept a similar potential conductance following domestication. It was found that the contribution of upper leaf sides to maximum conductance was statistically higher in cultivated than in wild ancestors. For crops showing this response, reduced stomatal density in the lower side of domesticated leaves was responsible for the observed 'adaxialization' of conductance. Increases in the size of stomata at the upper epidermis played a comparatively minor role. Nevertheless, this overall response was varied in magnitude and direction, signalling crop-wise specificities. Observed patterns reflect only potential conductances based on anatomical traits and should be used with care until actual physiological outcomes are measured. Together with advancements in the developmental genetics of stomata, our findings might hint at new breeding avenues, focused on stomata distribution. Provided urgent needs for increasing yields, the opportunities of enhancing traits of the physiological relevance of stomata should not be ignored. PMID- 23918959 TI - TaCPK2-A, a calcium-dependent protein kinase gene that is required for wheat powdery mildew resistance enhances bacterial blight resistance in transgenic rice. AB - Calcium-dependent protein kinases (CPKs) are important Ca2+ signalling components involved in complex immune and stress signalling networks; but the knowledge of CPK gene functions in the hexaploid wheat is limited. Previously, TaCPK2 was shown to be inducible by powdery mildew (Blumeria graminis tritici, Bgt) infection in wheat. Here, its functions in disease resistance are characterized further. This study shows the presence of defence-response and cold-response cis elements on the promoters of the A subgenome homoeologue (TaCPK2-A) and D subgenome homoeologue (TaCPK2-D), respectively. Their expression patterns were then confirmed by quantitative real-time PCR (qRT-PCR) using genome-specific primers, where TaCPK2-A was induced by Bgt treatment while TaCPK2-D mainly responded to cold treatment. Downregulation of TaCPK2-A by virus-induced gene silencing (VIGS) causes loss of resistance to Bgt in resistant wheat lines, indicating that TaCPK2-A is required for powdery mildew resistance. Furthermore, overexpression of TaCPK2-A in rice enhanced bacterial blight (Xanthomonas oryzae pv. oryzae, Xoo) resistance. qRT-PCR analysis showed that overexpression of TaCPK2-A in rice promoted the expression of OsWRKY45-1, a transcription factor involved in both fungal and bacterial resistance by regulating jasmonic acid and salicylic acid signalling genes. The opposite effect was found in wheat TaCPK2-A VIGS plants, where the homologue of OsWRKY45-1 was significantly repressed. These data suggest that modulation of WRKY45-1 and associated defence-response genes by CPK2 genes may be the common mechanism for multiple disease resistance in grass species, which may have undergone subfunctionalization in promoters before the formation of hexaploid wheat. PMID- 23918961 TI - Putative p24 complexes in Arabidopsis contain members of the delta and beta subfamilies and cycle in the early secretory pathway. AB - p24 proteins are a family of type I membrane proteins localized to compartments of the early secretory pathway and to coat protein I (COPI)- and COPII-coated vesicles. They can be classified, by sequence homology, into four subfamilies, named p24alpha, p24beta, p24gamma, and p24delta. In contrast to animals and fungi, plants contain only members of the p24beta and p24delta subfamilies, the latter probably including two different subclasses. It has previously been shown that transiently expressed red fluorescent protein (RFP)-p24delta5 (p24delta1 subclass) localizes to the endoplasmic reticulum (ER) at steady state as a consequence of highly efficient COPI-based recycling from the Golgi apparatus. It is now shown that transiently expressed RFP-p24delta9 (p24delta2 subclass) also localizes to the ER. In contrast, transiently expressed green fluorescent protein (GFP)-p24beta3 mainly localizes to the Golgi apparatus (as p24beta2) and exits the ER in a COPII-dependent manner. Immunogold electron microscopy in Arabidopsis root tip cells using specific antibodies shows that endogenous p24delta9 localizes mainly to the ER but also partially to the cis-Golgi. In contrast, endogenous p24beta3 mainly localizes to the Golgi apparatus. By a combination of experiments using transient expression, knock-out mutants, and co immunoprecipitation, it is proposed that Arabidopsis p24 proteins form different heteromeric complexes (including members of the beta and delta subfamilies) which are important for their stability and their coupled trafficking at the ER-Golgi interface. Evidence is also provided for a role for p24delta5 in retrograde Golgi ER transport of the KDEL-receptor ERD2. PMID- 23918962 TI - The effects of free-air CO2 enrichment (FACE) on carbon and nitrogen accumulation in grains of rice (Oryza sativa L.). AB - Rising atmospheric CO2 concentrations will probably increase rice (Oryza sativa L.) yield but decrease grain nitrogen (GN) concentration. Grains attached to different positions in the panicles differ greatly in weight and quality, but their responses to elevated CO2 (e[CO2]) are poorly understood, which limits our understanding of the mechanisms of yield enhancement and quality degradation. Thus a free-air CO2 enrichment experiment was conducted to examine the effects of e[CO2] on grain mass (GM), grain carbon (GC), and GN accumulation in the spikelets attached to the upper primary rachis branch (superior spikelets; SS) and those attached to the lower secondary rachis (inferior spikelets; IS). e[CO2] stimulated the rice yield by 13% but decreased the N concentration in the panicle by 7% when averaged over two levels of N fertilizations (P < 0.01). The responses of SS and IS to e[CO2] were different particularly under higher N supply. For SS, e[CO2] decreased GN by 24% (P < 0.01) but did not affect GM. For IS, e[CO2] increased GM by 13% (P < 0.05) but GN was not affected. The reduction of GN due to e[CO2] started to appear at the beginning of grain filling. These results suggest that future [CO2] levels probably stimulate the grain growth of IS, most of which are not marketable due to limited size, at the expense of GN reduction in SS. Translocation of N from SS to IS may be a possible mechanism for reduction in GN of SS. This may degrade the grain quality of marketable rice under e[CO2]. PMID- 23918963 TI - Leaf proteome alterations in the context of physiological and morphological responses to drought and heat stress in barley (Hordeum vulgare L.). AB - The objective of this study was to identify barley leaf proteins differentially regulated in response to drought and heat and the combined stresses in context of the morphological and physiological changes that also occur. The Syrian landrace Arta and the Australian cultivar Keel were subjected to drought, high temperature, or a combination of both treatments starting at heading. Changes in the leaf proteome were identified using differential gel electrophoresis and mass spectrometry. The drought treatment caused strong reductions of biomass and yield, while photosynthetic performance and the proteome were not significantly changed. In contrast, the heat treatment and the combination of heat and drought reduced photosynthetic performance and caused changes of the leaf proteome. The proteomic analysis identified 99 protein spots differentially regulated in response to heat treatment, 14 of which were regulated in a genotype-specific manner. Differentially regulated proteins predominantly had functions in photosynthesis, but also in detoxification, energy metabolism, and protein biosynthesis. The analysis indicated that de novo protein biosynthesis, protein quality control mediated by chaperones and proteases, and the use of alternative energy resources, i.e. glycolysis, play important roles in adaptation to heat stress. In addition, genetic variation identified in the proteome, in plant growth and photosynthetic performance in response to drought and heat represent stress adaption mechanisms to be exploited in future crop breeding efforts. PMID- 23918964 TI - The potato suberin feruloyl transferase FHT which accumulates in the phellogen is induced by wounding and regulated by abscisic and salicylic acids. AB - The present study provides new insights on the role of the potato (Solanum tuberosum) suberin feruloyl transferase FHT in native and wound tissues, leading to conclusions about hitherto unknown properties of the phellogen. In agreement with the enzymatic role of FHT, it is shown that its transcriptional activation and protein accumulation are specific to tissues that undergo suberization such as the root boundary layers of the exodermis and the endodermis, along with the tuber periderm. Remarkably, FHT expression and protein accumulation within the periderm is restricted to the phellogen derivative cells with phellem identity. FHT levels in the periderm are at their peak near harvest during periderm maturation, with the phellogen becoming meristematically inactive and declining thereafter. However, periderm FHT levels remain high for several months after harvest, suggesting that the inactive phellogen retains the capacity to synthesize ferulate esters. Tissue wounding induces FHT expression and the protein accumulates from the first stages of the healing process onwards. FHT is up-regulated by abscisic acid and down-regulated by salicylic acid, emphasizing the complex regulation of suberin synthesis and wound healing. These findings open up new prospects important for the clarification of the suberization process and yield important information with regard to the skin quality of potatoes. PMID- 23918965 TI - Pattern of iron distribution in maternal and filial tissues in wheat grains with contrasting levels of iron. AB - Iron insufficiency is a worldwide problem in human diets. In cereals like wheat, the bran layer of the grains is an important source of iron. However, the dietary availability of iron in wheat flour is limited due to the loss of the iron-rich bran during milling and processing and the presence of anti-nutrients like phytic acid that keep iron strongly chelated in the grain. The present study investigated the localization of iron and phosphorus in grain tissues of wheat genotypes with contrasting grain iron content using synchrotron-based micro-X-ray fluorescence (micro-XRF) and micro-proton-induced X-ray emission (micro-PIXE). X ray absorption near-edge spectroscopy (XANES) was employed to determine the proportion of divalent and trivalent forms of Fe in the grains. It revealed the abundance of oxygen, phosphorus, and sulphur in the local chemical environment of Fe in grains, as Fe-O-P-R and Fe-O-S-R coordination. Contrasting differences were noticed in tissue-specific relative localization of Fe, P, and S among the different genotypes, suggesting a possible effect of localization pattern on iron bioavailability. The current study reports the shift in iron distribution from maternal to filial tissues of grains during the evolution of wheat from its wild relatives to the present-day cultivated varieties, and thus suggests the value of detailed physical localization studies in varietal improvement programmes for food crops. PMID- 23918967 TI - Auxin induces redox regulation of ascorbate peroxidase 1 activity by S nitrosylation/denitrosylation balance resulting in changes of root growth pattern in Arabidopsis. AB - S-Nitrosylation of Cys residues is one of the molecular mechanisms driven by nitric oxide (NO) for regulating biological functions of key proteins. While the studies on S-nitrosylation of Cys residues have served for identifying SNO proteomes, the physiological relevance of protein S-nitrosylation/denitrosylation remains poorly understood. In this study, it is shown that auxin influences the balance of S-nitrosylated/denitrosylated proteins in roots of Arabidopsis seedlings. 2D-PAGE allowed the identification of ascorbate peroxidase 1 (APX1) as target of auxin-induced denitrosylation in roots. Auxin causes APX1 denitrosylation and partial inhibition of APX1 activity in Arabidopsis roots. In agreement, the S-nitrosylated form of recombinant APX1 expressed in Escherichia coli is more active than the denitrosylated form. Consistently, Arabidopsis apx1 mutants have increased H2O2 accumulation in roots, shorter roots, and less sensitivity to auxin than the wild type. It is postulated that an auxin-regulated counterbalance of APX1 S-nitrosylation/denitrosylation contributes to a fine tuned control of root development and determination of root architecture. PMID- 23918966 TI - Sequence variations of the partially dominant DELLA gene Rht-B1c in wheat and their functional impacts. AB - Rht-B1c, allelic to the DELLA protein-encoding gene Rht-B1a, is a natural mutation documented in common wheat (Triticum aestivum). It confers variation to a number of traits related to cell and plant morphology, seed dormancy, and photosynthesis. The present study was conducted to examine the sequence variations of Rht-B1c and their functional impacts. The results showed that Rht B1c was partially dominant or co-dominant for plant height, and exhibited an increased dwarfing effect. At the sequence level, Rht-B1c differed from Rht-B1a by one 2kb Veju retrotransposon insertion, three coding region single nucleotide polymorphisms (SNPs), one 197bp insertion, and four SNPs in the 1kb upstream sequence. Haplotype investigations, association analyses, transient expression assays, and expression profiling showed that the Veju insertion was primarily responsible for the extreme dwarfing effect. It was found that the Veju insertion changed processing of the Rht-B1c transcripts and resulted in DELLA motif primary structure disruption. Expression assays showed that Rht-B1c caused reduction of total Rht-1 transcript levels, and up-regulation of GATA-like transcription factors and genes positively regulated by these factors, suggesting that one way in which Rht-1 proteins affect plant growth and development is through GATA-like transcription factor regulation. PMID- 23918968 TI - OsAP65, a rice aspartic protease, is essential for male fertility and plays a role in pollen germination and pollen tube growth. AB - Aspartic proteases (APs) comprise a large proteolytic enzyme family widely distributed in animals, microbes, viruses, and plants. The rice genome encodes 96 APs, of which only a few have been functionally characterized. Here, the identification and characterization of a novel AP gene, OsAP65, which plays an indispensable role in pollen tube growth in rice, is reported. The T-DNA insertion line of OsAP65 caused severe segregation distortion. In the progeny derived from an individual heterozygous for the T-DNA insertion, the wild type and T-DNA-carrying heterozygote segregated at a ratio close to 1:1, while homozygotes of disrupted OsAP65 (OsAP65-/-) were not recovered. Reciprocal crosses between heterozygotes and wild-type plants demonstrated that the mutant alleles could not be transmitted through the male gamete. Examination of the anthers from heterozygous plants revealed that the mutant pollen matured normally, but did not germinate or elongate. OsAP65 was expressed in various tissues and the transcript level in heterozygous plants was about half of the amount measured in the wild-type plants. The subcellular localization showed that OsAP65 is a pre-vacuolar compartment (PVC) protein. These results indicated that OsAP65 was essential for rice pollen germination and tube growth. PMID- 23918969 TI - Nitric oxide controls nitrate and ammonium assimilation in Chlamydomonas reinhardtii. AB - Nitrate and ammonium are major inorganic nitrogen sources for plants and algae. These compounds are assimilated by means of finely regulated processes at transcriptional and post-translational levels. In Chlamydomonas, the expression of several genes involved in high-affinity ammonium (AMT1.1, AMT1.2) and nitrate transport (NRT2.1) as well as nitrate reduction (NIA1) are downregulated by ammonium through a nitric oxide (NO)-dependent mechanism. At the post translational level, nitrate/nitrite uptake and nitrate reductase (NR) are also inhibited by ammonium, but the mechanisms implicated in this regulation are scarcely known. In this work, the effect of NO on nitrate assimilation and the high-affinity ammonium uptake was addressed. NO inhibited the high-affinity uptake of ammonium and nitrate/nitrite, as well as the NR activity, in a reversible form. In contrast, nitrite reductase and glutamine synthetase activities were not affected. The in vivo and in vitro studies suggested that NR enzyme is inhibited by NO in a mediated process that requires the cell integrity. These data highlight a role of NO in inorganic nitrogen assimilation and suggest that this signalling molecule is an important regulator for the first steps of the pathway. PMID- 23918970 TI - HYL1 is required for establishment of stamen architecture with four microsporangia in Arabidopsis. AB - The stamen produces pollen grains for pollination in higher plants. Coordinated development of four microsporangia in the stamen is essential for normal fertility. The roles of miR165/166-directed pathways in the establishment of adaxial-abaxial polarity have been well defined in leaves. However, the molecular mechanism underlying the adaxial-abaxial polarity of the stamen is elusive. Here it is reported that HYPONASTIC LEAVES1 (HYL1), a general regulator of microRNA (miRNA) biogenesis, plays an essential role in establishing the stamen architecture of the four microsporangia in Arabidopsis thaliana. In stamens, HYL1 and miR165/6 expression are progressively restricted to the lateral region, microsporangia, microspore mother cells, and microspores, whereas HD-ZIP III genes are preferentially expressed in the middle region, vascular bundle, and stomium. Loss of HYL1 leads to the formation of two rather than four microsporangia in each stamen. In the stamen of the hyl1 mutant, miR165/6 accumulation is reduced, whereas miR165/6-targeted HD-ZIP III genes are up regulated and FILAMENTOUS FLOWER (FIL) is down-regulated; and, specifically, REVOLUTA (REV) is overexpressed in the adaxial region and FIL is underexpressed in the abaxial regions, concomitant with the aberrance of the two inner microsporangia and partial adaxialization of the connectives. Genetic analysis reveals that FIL works downstream of HYL1, and the defects in hyl1 stamens are partially rescued by rev-9 or phv-5 phb-6 alleles. These results suggest that HYL1 modulates inner microsporangia and stamen architecture by repression of HD ZIP III genes and promotion of the FIL gene through miR165/6. Thus, the role of HYL1 in establishment of stamen architecture provides insight into the molecular mechanism of male fertility. PMID- 23918971 TI - Proper gibberellin localization in vascular tissue is required to regulate adventitious root development in tobacco. AB - Bioactive gibberellins (GAs) are involved in many developmental aspects of the life cycle of plants, acting either directly or through interaction with other hormones. Accumulating evidence suggests that GAs have an important effect on root growth; however, there is currently little information on the specific regulatory mechanism of GAs during adventitious root development. A study was conducted on tobacco (Nicotiana tabacum) plants for altered rates of biosynthesis, catabolism, and GA signalling constitutively or in specific tissues using a transgenic approach. In the present study, PtGA20ox, PtGA2ox1, and PtGAI were overexpressed under the control of the 35S promoter, vascular cambium specific promoter (LMX5), or root meristem-specific promoter (TobRB7), respectively. Evidence is provided that the precise localization of bioactive GA in the stem but not in the roots is required to regulate adventitious root development in tobacco. High levels of GA negatively regulate the early initiation step of root formation through interactions with auxin, while a proper and mobile GA signal is required for the emergence and subsequent long-term elongation of established primordia. The results demonstrated that GAs have an inhibitory effect on adventitious root formation but a stimulatory effect on root elongation. PMID- 23918972 TI - The Arabidopsis small GTPase AtRAC7/ROP9 is a modulator of auxin and abscisic acid signalling. AB - Rac-like GTPases or Rho-related GTPases from plants (RAC/ROPs) are important components of hormone signalling pathways in plants. Based on phylogeny, several groups can be distinguished, and the underlying premise is that members of different groups perform distinct functions in the plant. AtRAC7/ROP9 is phylogenetically unique among 11 Arabidopsis RAC/ROPs, and here it was shown that it functions as a modulator of auxin and abscisic acid (ABA) signalling, a dual role not previously assigned to these small GTPases. Plants with reduced levels of AtRAC7/ROP9 had increased sensitivity to auxin and were less sensitive to ABA. On the other hand, overexpressing AtRAC7/ROP9 activated ABA-induced gene expression but repressed auxin-induced gene expression. In addition, both hormones regulated the activity of the AtRAC7/ROP9 promoter, suggesting a feedback mechanism to modulate the signalling output from the AtRAC7/ROP9 controlled molecular switch. High levels of AtRAC7/ROP9 were detected specifically in embryos and lateral roots, underscoring the important role of this protein during embryo development and lateral root formation. These results place AtRAC7/ROP9 as an important signal transducer in recently described pathways that integrate auxin and ABA signalling in the plant. PMID- 23918974 TI - Amplified NKG2C+ NK cells in cytomegalovirus (CMV) infection preferentially express killer cell Ig-like receptor 2DL: functional impact in controlling CMV infected dendritic cells. AB - CMV infection represents a major complication in hematopoietic stem cell transplantation, which compromises graft outcome. Downregulation of HLA class I expression is one mechanism by which CMV evades T cell-mediated immune detection, rendering infected cells vulnerable to killer cell Ig-like receptor (KIR)(+) NK cells. In this study, we observed that the amplified NKG2C(+) NK cell population observed specifically in CMV seropositive individuals mainly expressed KIR2DL receptors. We have shown that HLA class I expression was downregulated on CMV infected immature dendritic cells (iDCs), which escape to HLA-A2-pp65-specific T lymphocytes but strongly trigger the degranulation of KIR2D(+) NK cells. CMV infection conferred a vulnerability of C2C2(+) iDCs to educated KIR2DL1(+) and KIR2DL3(+) NK cell subsets. Alloreactivity of KIR2DL1(+) NK cell subsets against C1C1(+) iDCs was maintained independently of CMV infection. Unexpectedly, CMV infected C1C1(+) iDCs did not activate KIR2DL3(+) NK cell reactivity, suggesting a potential CMV evasion to KIR2DL3 NK cell recognition. Altogether, the coexpression of KIR and NKG2C on expanded NK cell subsets could be related to a functional contribution of KIR in CMV infection and should be investigated in hematopoietic stem cell transplantation, in which the beneficial impact of CMV infection has been reported on the graft-versus-leukemia effect. PMID- 23918973 TI - Activation of p38alpha in T cells regulates the intestinal host defense against attaching and effacing bacterial infections. AB - Intestinal infections by attaching and effacing (A/E) bacterial pathogens cause severe colitis and bloody diarrhea. Although p38alpha in intestinal epithelial cells (IEC) plays an important role in promoting protection against A/E bacteria by regulating T cell recruitment, its impact on immune responses remains unclear. In this study, we show that activation of p38alpha in T cells is critical for the clearance of the A/E pathogen Citrobacter rodentium. Mice deficient of p38alpha in T cells, but not in macrophages or dendritic cells, were impaired in clearing C. rodentium. Expression of inflammatory cytokines such as IFN-gamma by p38alpha deficient T cells was reduced, which further reduced the expression of inflammatory cytokines, chemokines, and antimicrobial peptide by IECs and led to reduced infiltration of T cells into the infected colon. Administration of IFN gamma activated the mucosal immunity to C. rodentium infection by increasing the expression of inflammation genes and the recruitment of T cells to the site of infection. Thus, p38alpha contributes to host defense against A/E pathogen infection by regulating the expression of inflammatory cytokines that activate host defense pathways in IECs. PMID- 23918975 TI - Multistage T cell-dendritic cell interactions control optimal CD4 T cell activation through the ADAP-SKAP55-signaling module. AB - The Ag-specific interactions between T cells and dendritic cells progress through dynamic contact stages in vivo consisting of early long-term stable contacts and later confined, yet motile, short-lived contacts. The signaling pathways that control in vivo interaction dynamics between T cells and dendritic cells during priming remain undefined. Adhesion and degranulation promoting adapter protein (ADAP) is a multifunctional adapter that regulates "inside-out" signaling from the TCR to integrins. Using two-photon microscopy, we demonstrate that, in the absence of ADAP, CD4 T cells make fewer early-stage stable contacts with Ag-laden dendritic cells, and the interactions are characterized by brief repetitive contacts. Furthermore, ADAP-deficient T cells show reduced contacts at the late motile contact phase and display less confinement around dendritic cells. The altered T cell interaction dynamics in the absence of ADAP are associated with defective early proliferation and attenuated TCR signaling in vivo. Regulation of multistage contact behaviors and optimal T cell signaling involves the interaction of ADAP with the adapter src kinase-associated phosphoprotein of 55 kDa (SKAP55). Thus, integrin activation by the ADAP-SKAP55-signaling module controls the stability and duration of T cell-dendritic cell contacts during the progressive phases necessary for optimal T cell activation. PMID- 23918978 TI - Immunization with a chimera consisting of the B subunit of Shiga toxin type 2 and brucella lumazine synthase confers total protection against Shiga toxins in mice. AB - The striking feature of enterohemorrhagic Escherichia coli (EHEC) infections is the production of Shiga toxins (Stx) implicated in the development of the life threatening hemolytic uremic syndrome. Despite the magnitude of the social impact of EHEC infections, no licensed vaccine or effective therapy is available for human use. One of the biggest challenges is to develop an effective and safe immunogen to ensure nontoxicity, as well as a strong input to the immune system to induce long-lasting, high-affinity Abs with anti-Stx-neutralizing capacity. The enzyme lumazine synthase from Brucella spp. (BLS) is a highly stable dimer of pentamers and a scaffold with enormous plasticity on which to display foreign Ags. Taking into account the advantages of BLS and the potential capacity of the B subunit of Stx2 to induce Abs that prevent Stx2 toxicity by blocking its entrance into the host cells, we engineered a new immunogen by inserting the B subunit of Stx2 at the amino termini of BLS. The resulting chimera demonstrated a strong capacity to induce a long-lasting humoral immune response in mice. The chimera induced Abs with high neutralizing capacity for Stx2 and its variants. Moreover, immunized mice were completely protected against i.v. Stx2 challenge, and weaned mice receiving an oral challenge with EHEC were completely protected by the transference of immune sera. We conclude that this novel immunogen represents a promising candidate for vaccine or Ab development with preventive or therapeutic ends, for use in hemolytic uremic syndrome-endemic areas or during future outbreaks caused by pathogenic strains of Stx-producing E. coli. PMID- 23918977 TI - Induction of HIV-1 broad neutralizing antibodies in 2F5 knock-in mice: selection against membrane proximal external region-associated autoreactivity limits T dependent responses. AB - A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs). Using a knock-in (KI) model of 2F5, a human HIV-1 gp41 membrane proximal external region (MPER)-specific BnAb, we previously demonstrated that a key obstacle to BnAb induction is clonal deletion of BnAb-expressing B cells. In this study of this model, we provide a proof-of-principle that robust serum neutralizing IgG responses can be induced from pre-existing, residual, self reactive BnAb-expressing B cells in vivo using a structurally compatible gp41 MPER immunogen. Furthermore, in CD40L-deficient 2F5 KI mice, we demonstrate that these BnAb responses are elicited via a type II T-independent pathway, coinciding with expansion and activation of transitional splenic B cells specific for 2F5's nominal gp41 MPER-binding epitope (containing the 2F5 neutralization domain ELDKWA). In contrast, constitutive production of nonneutralizing serum IgGs in 2F5 KI mice is T dependent and originates from a subset of splenic mature B2 cells that have lost their ability to bind 2F5's gp41 MPER epitope. These results suggest that residual, mature B cells expressing autoreactive BnAbs, like 2F5 as BCR, may be limited in their ability to participate in T-dependent responses by purifying selection that selectively eliminates reactivity for neutralization epitope-containing/mimicked host Ags. PMID- 23918979 TI - Negative charges in the flexible N-terminal domain of Rho GDP-dissociation inhibitors (RhoGDIs) regulate the targeting of the RhoGDI-Rac1 complex to membranes. AB - In its resting state, Rho GDP-dissociation inhibitor (RhoGDI) alpha forms a soluble cytoplasmic heterodimer with the GDP-bound form of Rac. Upon stimulation, the dissociation of RhoGDIalpha from the RhoGDIalpha-Rac complex is a mandatory step for Rac activation; however, this mechanism is poorly understood. In this study, we examined how the cytoplasm/membrane cycles of the RhoGDI-Rac complex are regulated, as well as where RhoGDI dissociates from the RhoGDI-Rac complex, during FcgammaR-mediated phagocytosis. The negatively charged and flexible N terminus (25 residues) of RhoGDIalpha, particularly its second negative amino acid cluster possessing five negatively charged amino acids, was a pivotal regulator in the cytoplasm/membrane cycles of the RhoGDI-Rac complex. We also found that RhoGDIalpha translocated to the phagosomes as a RhoGDIalpha-Rac1 complex, and this translocation was mediated by an interaction between the polybasic motif in the C terminus of Rac1 and anionic phospholipids produced on phagosomes, such as phosphatidic acid, that is, by a phagosome-targeting mechanism of Rac1. Thus, we demonstrated that the targeting/accumulation of the RhoGDIalpha-Rac1 complex to phagosomes is regulated by a balance between three factors: 1) the negatively charged and flexible N-terminal of RhoGDIalpha, 2) the binding affinity of RhoGDIalpha for Rac1, and 3) anionic phospholipids produced on phagosomes. Moreover, we demonstrated that the mechanism of targeting/accumulation of the RhoGDIalpha-Rac1 complex is also applicable for the RhoGDIbeta-Rac1 complex. PMID- 23918976 TI - Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus. AB - Loss-of-function mutations in the Fas death receptor or its ligand result in a lymphoproliferative syndrome and exacerbate clinical disease in most lupus-prone strains of mice. One exception is mice injected with 2,6,10,14 tetramethylpentadecane (TMPD), a hydrocarbon oil commonly known as pristane, which induces systemic lupus erythematosus-like disease. Although Fas/Fas ligand (FasL) interactions have been strongly implicated in the activation-induced cell death of both lymphocytes and other APCs, FasL can also trigger the production of proinflammatory cytokines. FasL is a transmembrane protein with a matrix metalloproteinase cleavage site in the ectodomain. Matrix metalloproteinase cleavage inactivates membrane-bound FasL and releases a soluble form reported to have both antagonist and agonist activity. To better understand the impact of FasL cleavage on both the proapoptotic and proinflammatory activity of FasL, its cleavage site was deleted through targeted mutation to produce the deleted cleavage site (DeltaCS) mouse line. DeltaCS mice express higher levels of membrane-bound FasL than do wild-type mice and fail to release soluble FasL. To determine to what extent FasL promotes inflammation in lupus mice, TMPD-injected FasL-deficient and DeltaCS BALB/c mice were compared with control TMPD-injected BALB/c mice. We found that FasL deficiency significantly reduced the early inflammatory exudate induced by TMPD injection. In contrast, DeltaCS mice developed a markedly exacerbated disease profile associated with a higher frequency of splenic neutrophils and macrophages, a profound change in anti nuclear Ab specificity, and markedly increased proteinuria and kidney pathology compared with controls. These results demonstrate that FasL promotes inflammation in TMPD-induced autoimmunity, and its cleavage limits FasL proinflammatory activity. PMID- 23918980 TI - Paradoxical effect of cortistatin treatment and its deficiency on experimental autoimmune encephalomyelitis. AB - Cortistatin is a cyclic-neuropeptide produced by brain cortex and immune cells that shows potent anti-inflammatory activity. In this article, we investigated the effect of cortistatin in two models of experimental autoimmune encephalomyelitis (EAE) that mirror chronic and relapsing-remitting multiple sclerosis. A short-term systemic treatment with cortistatin reduced clinical severity and incidence of EAE, the appearance of inflammatory infiltrates in spinal cord, and the subsequent demyelination and axonal damage. This effect was associated with a reduction of the two deleterious components of the disease, namely, the autoimmune and inflammatory response. Cortistatin decreased the presence/activation of encephalitogenic Th1 and Th17 cells in periphery and nervous system, and downregulated various inflammatory mediators, whereas it increased the number of regulatory T cells with suppressive effects on the encephalitogenic response. Moreover, cortistatin regulated glial activity and favored an active program of neuroprotection/regeneration. We further used cortistatin-deficient mice to investigate the role of endogenous cortistatin in the control of immune responses. Surprisingly, cortistatin-deficient mice were partially resistant to EAE and other inflammatory disorders, despite showing competent inflammatory/autoreactive responses. This unexpected phenotype was associated with elevated circulating glucocorticoids and an anxiety-like behavior. Our findings provide a powerful rationale for the assessment of the efficacy of cortistatin as a novel multimodal therapeutic approach to treat multiple sclerosis and identify cortistatin as a key endogenous component of neuroimmune system. PMID- 23918982 TI - Notch signaling regulates follicular helper T cell differentiation. AB - Follicular helper T (TFH) cells are specialized in providing help for B cell differentiation and Ab secretion. Several positive and negative regulators of TFH cell differentiation have been described but their control is not fully understood. In this study, we show that Notch signaling in T cells is a major player in the development and function of TFH cells. T cell-specific gene ablation of Notch1 and Notch2 impaired differentiation of TFH cells in draining lymph nodes of mice immunized with T-dependent Ags or infected with parasites. Impaired TFH cell differentiation correlated with deficient germinal center development and the absence of high-affinity Abs. The impact of loss of Notch on TFH cell differentiation was largely independent of its effect on IL-4. These results show a previously unknown role for Notch in the regulation of TFH cell differentiation and function with implications for the control of this T cell population. PMID- 23918981 TI - Two phases of inflammatory mediator production defined by the study of IRAK2 and IRAK1 knock-in mice. AB - The roles of IL-1R-associated kinase (IRAK)2 and IRAK1 in cytokine production were investigated using immune cells from knock-in mice expressing the TNFR associated factor 6 (TRAF6) binding-defective mutant IRAK2[E525A] or the catalytically inactive IRAK1[D359A] mutant. In bone marrow-derived macrophages (BMDMs), the IRAK2-TRAF6 interaction was required for the late (2-8 h) but not the early phase (0-2 h) of il6 and tnfa mRNA production, and hence for IL-6 and TNF-alpha secretion by TLR agonists that signal via MyD88. Loss of the IRAK2 TRAF6 interaction had little effect on the MyD88-dependent production of anti inflammatory molecules produced during the early phase, such as Dual Specificity Phosphatase 1, and a modest effect on IL-10 secretion. The LPS/TLR4-stimulated production of il6 and tnfa mRNA and IL-6 and TNF-alpha secretion was hardly affected, because the Toll/IL-1R domain-containing adapter-inducing IFN-beta (TRIF) signaling pathway was used instead of the IRAK2-TRAF6 interaction to sustain late-phase mRNA production. IRAK1 catalytic activity was not rate limiting for il6, tnfa, or il10 mRNA production or the secretion of these cytokines by BMDMs, but IFN-beta mRNA induction by TLR7 and TLR9 agonists was greatly delayed in plasmacytoid dendritic cells (pDCs) from IRAK1[D359A] mice. In contrast, IFN-beta mRNA production was little affected in pDCs from IRAK2[E525A] mice, but subsequent IFN-alpha mRNA production and IFN-alpha secretion were reduced. IFN-beta and IFN-alpha production were abolished in pDCs from IRAK1[D359A] * IRAK2[E525A] double knock-in mice. Our results establish that the IRAK2-TRAF6 interaction is rate limiting for the late, but not the early phase of cytokine production in BMDM and pDCs, and that the IRAK2-TRAF6 interaction is needed to sustain IkappaB-inducing kinase beta activity during prolonged activation of the MyD88 signaling network. [corrected] PMID- 23918984 TI - Enhancer of zeste homolog 2 is a negative regulator of mitochondria-mediated innate immune responses. AB - The intracellular RIG-I-like receptors recognize 5'-triphosphate viral genomic RNA and initiate the production of cytokines through mitochondria adaptor VISA. The regulation of this signal pathway is largely unknown. In this study, we report that the histone methyltransferase enhancer of zeste homolog 2 (EZH2) inhibits RIG-I signal pathway in an methyltransferase-independent manner. Knockdown EZH2 expression enhances VISA-induced activation of IFN-beta promoter and NF-kappaB signaling. Cytosolic distributed EZH2 colocalizes with VISA and binds to its caspase recruitment domain (CARD), thus blocking its association with RIG-I. During the infection of influenza A virus (IAV) strain A/WSN/33 (WSN), EZH2 translocates to RIG-I and continuously interferes the interaction between RIG-I and VISA. Both N and C termini of EZH2 interact with VISA and attenuate its downstream signaling. WSN virus infection-induced expression of TNF alpha, IFN-beta, and IL-8 is inhibited by EZH2 and its catalytic dead form DeltaSET. EZH2 overexpression facilitates the replications of IAV strains WSN and A/Puerto Rico/8/34 influenza virus. Knockdown EZH2 expression activates infection induced IFN-beta transcription and inhibits virus replication. We further provided evidence to show that pharmacological disruption of EZH2 expression by its inhibitor 3-deazaneplanocin A activates innate immune responses and attenuates the replication of WSN virus in HeLa, MDCK, and mouse primary bone marrow-derived macrophages, but not in IFN-deficient Vero cells. Collectively, these results revealed that EZH2 binds to VISA and interferes with the interaction between VISA and RIG-I. Targeting EZH2 activates mitochondria mediated antiviral innate immune responses, and thus represses the replication of IAV in cells. PMID- 23918983 TI - Divergent immunomodulating effects of probiotics on T cell responses to oral attenuated human rotavirus vaccine and virulent human rotavirus infection in a neonatal gnotobiotic piglet disease model. AB - Rotaviruses (RVs) are a leading cause of childhood diarrhea. Current oral vaccines are not effective in impoverished countries where the vaccine is needed most. Therefore, alternative affordable strategies are urgently needed. Probiotics can alleviate diarrhea in children and enhance specific systemic and mucosal Ab responses, but the T cell responses are undefined. In this study, we elucidated the T cell and cytokine responses to attenuated human RV (AttHRV) and virulent human RV (HRV) in gnotobiotic pigs colonized with probiotics (Lactobacillus rhamnosus strain GG [LGG] and Bifidobacterium lactis Bb12 [Bb12]), mimicking gut commensals in breastfed infants. Neonatal gnotobiotic pigs are the only animal model susceptible to HRV diarrhea. Probiotic colonized and nonvaccinated (Probiotic) pigs had lower diarrhea and reduced virus shedding postchallenge compared with noncolonized and nonvaccinated pigs (Control). Higher protection in the Probiotic group coincided with higher ileal T regulatory cells (Tregs) before and after challenge, and higher serum TGF-beta and lower serum and biliary proinflammatory cytokines postchallenge. Probiotic colonization in vaccinated pigs enhanced innate serum IFN-alpha, splenic and circulatory IFN gamma-producing T cells, and serum Th1 cytokines, but reduced serum Th2 cytokines compared with noncolonized vaccinated pigs (Vac). Thus, LGG+Bb12 induced systemic Th1 immunostimulatory effects on oral AttHRV vaccine that coincided with lower diarrhea severity and reduced virus shedding postchallenge in Vac+Pro compared with Vac pigs. Previously unreported intestinal CD8 Tregs were induced in vaccinated groups postchallenge. Thus, probiotics LGG+Bb12 exert divergent immunomodulating effects, with enhanced Th1 responses to oral AttHRV vaccine, whereas inducing Treg responses to virulent HRV. PMID- 23918987 TI - TWEAK inhibits TRAF2-mediated CD40 signaling by destabilization of CD40 signaling complexes. AB - We found recently that TNF-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible-14 (Fn14) by virtue of their strong capability to reduce the freely available cytoplasmic pool of TNFR-associated factor (TRAF)2 and cellular inhibitors of apoptosis (cIAPs) antagonize the functions of these molecules in TNFR1 signaling, resulting in sensitization for apoptosis and inhibition of classical NF-kappaB signaling. In this study, we demonstrate that priming of cells with TWEAK also interferes with activation of the classical NF kappaB pathway by CD40. Likewise, there was strong inhibition of CD40 ligand (CD40L)-induced activation of MAPKs in TWEAK-primed cells. FACS analysis and CD40L binding studies revealed unchanged CD40 expression and normal CD40L-CD40 interaction in TWEAK-primed cells. CD40L immunoprecipitates, however, showed severely reduced amounts of CD40 and CD40-associated proteins, indicating impaired formation or reduced stability of CD40L-CD40 signaling complexes. The previously described inhibitory effect of TWEAK on TNFR1 signaling has been traced back to reduced activity of the TNFR1-associated TRAF2-cIAP1/2 ubiquitinase complex and did not affect the stability of the immunoprecipitable TNFR1 receptor complex. Thus, the inhibitory effect of TWEAK on CD40 signaling must be based at least partly on other mechanisms. In line with this, signaling by the CD40-related TRAF2-interacting receptor TNFR2 was also attenuated but still immunoprecipitable in TWEAK-primed cells. Collectively, we show that Fn14 activation by soluble TWEAK impairs CD40L-CD40 signaling complex formation and inhibits CD40 signaling and thus identify the Fn14-TWEAK system as a potential novel regulator of CD40-related cellular functions. PMID- 23918985 TI - Soluble CD80 restores T cell activation and overcomes tumor cell programmed death ligand 1-mediated immune suppression. AB - Many tumor cells escape anti-tumor immunity through their expression of programmed death ligand-1 (PDL1 or B7-H1), which interacts with T cell-expressed PD1 and results in T cell apoptosis. We previously reported that transfection of human tumor cells with a membrane-bound form of the human costimulatory molecule CD80 prevented PD1 binding and restored T cell activation. We now report that a membrane-bound form of murine CD80 similarly reduces PDL1-PD1-mediated suppression by mouse tumor cells and that a soluble protein consisting of the extracellular domains of human or mouse CD80 fused to the Fc domain of IgG1 (CD80 Fc) overcomes PDL1-mediated suppression by human and mouse tumor cells, respectively. T cell activation experiments with human and mouse tumor cells indicate that CD80-Fc facilitates T cell activation by binding to PDL1 to inhibit PDL1-PD1 interactions and by costimulating through CD28. CD80-Fc is more effective in preventing PD1-PDL1-mediated suppression and restoring T cell activation compared with treatment with mAb to either PD1 or PDL1. These studies identify CD80-Fc as an alternative and potentially more efficacious therapeutic agent for overcoming PDL1-induced immune suppression and facilitating tumor specific immunity. PMID- 23918986 TI - Programmed death-1 is a marker for abnormal distribution of naive/memory T cell subsets in HIV-1 infection. AB - Chronic activation of T cells is a hallmark of HIV-1 infection and plays an important role in disease progression. We previously showed that the engagement of the inhibitory receptor programmed death (PD)-1 on HIV-1-specific CD4(+) and CD8(+) T cells leads to their functional exhaustion in vitro. However, little is known about the impact of PD-1 expression on the turnover and maturation status of T cells during the course of the disease. In this study, we show that PD-1 is upregulated on all T cell subsets, including naive, central memory, and transitional memory T cells in HIV-1-infected subjects. PD-1 is expressed at similar levels on most CD4(+) T cells during the acute and the chronic phase of disease and identifies cells that have recently entered the cell cycle. In contrast, PD-1 expression is dramatically increased in CD8(+) T cells during the transition from acute to chronic infection, and this is associated with reduced levels of cell proliferation. The failure to downregulate expression of PD-1 in most T cells during chronic HIV-1 infection is associated with persistent alterations in the distribution of T cell subsets and is associated with impaired responses to IL-7. Our findings identify PD-1 as a marker for aberrant distribution of T cell subsets in HIV-1 infection. PMID- 23918989 TI - Receptor-interacting protein 2 gene silencing attenuates allergic airway inflammation. AB - Persistent activation of NF-kappaB has been associated with the development of asthma. Receptor-interacting protein 2 (Rip2) is a transcriptional product of NF kappaB activation. It is an adaptor protein with serine/threonine kinase activity and has been shown to positively regulate NF-kappaB activity. We investigated potential protective effects of Rip2 gene silencing using small interfering RNA (siRNA) in an OVA-induced mouse asthma model. Rip2 protein level was found to be upregulated in allergic airway inflammation. A potent and selective Rip2 siRNA given intratracheally knocked down Rip2 expression in OVA-challenged lungs and reduced OVA-induced increases in total and eosinophil counts, and IL-4, IL-5, IL 13, IL-1beta, IL-33, and eotaxin levels in bronchoalveolar lavage fluid. Rip2 silencing blocked OVA-induced inflammatory cell infiltration and mucus hypersecretion as observed in lung sections, and mRNA expression of ICAM-1, VCAM 1, E-selectin, RANTES, IL-17, IL-33, thymic stromal lymphopoietin, inducible NO synthase, and MUC5ac in lung tissues. In addition, elevation of serum OVA specific IgE level in mouse asthma model was markedly suppressed by Rip2 siRNA, together with reduced IL-4, IL-5, and IL-13 production in lymph node cultures. Furthermore, Rip2 siRNA-treated mice produced significantly less airway hyperresponsiveness induced by methacholine. Mechanistically, Rip2 siRNA was found to enhance cytosolic level of IkappaBalpha and block p65 nuclear translocation and DNA-binding activity in lung tissues from OVA-challenged mice. Taken together, our findings clearly show that knockdown of Rip2 by gene silencing ameliorates experimental allergic airway inflammation, probably via interruption of NF-kappaB activity, confirming Rip2 a novel therapeutic target for the treatment of allergic asthma. PMID- 23918988 TI - Peritoneal cavity regulatory B cells (B10 cells) modulate IFN-gamma+CD4+ T cell numbers during colitis development in mice. AB - The spleen regulatory B cell subset with the functional capacity to express IL-10 (B10 cells) modulates both immune responses and autoimmune disease severity. However, the peritoneal cavity also contains relatively high frequencies of functionally defined IL-10-competent B10 cells. In this study, peritoneal cavity B10 cells shared similar cell surface phenotypes with their spleen counterparts. However, peritoneal cavity B10 cells were 10-fold more frequent among B cells than occurred within the spleen, intestinal tract, or mesenteric lymph nodes and were present at higher proportions among the phenotypically defined peritoneal B1a > B1b > B2 cell subpopulations. The development or localization of B10 cells within the peritoneal cavity was not dependent on the presence of commensal microbiota, T cells, IL-10 or B10 cell IL-10 production, or differences between their fetal liver or adult bone marrow progenitor cell origins. The BCR repertoire of peritoneal cavity B10 cells was diverse, as occurs in the spleen, and predominantly included germline-encoded VH and VL regions commonly found in either the conventional or B1 B cell compartments. Thereby, the capacity to produce IL-10 appears to be an intrinsic functional property acquired by clonally diverse B cells. Importantly, IL-10 production by peritoneal cavity B cells significantly reduced disease severity in spontaneous and induced models of colitis by regulating neutrophil infiltration, colitogenic CD4(+) T cell activation, and proinflammatory cytokine production during colitis onset. Thus, the numerically small B10 cell subset within the peritoneal cavity has regulatory function and is important for maintaining homeostasis within gastrointestinal tissues and the immune system. PMID- 23918990 TI - The C-type lectin receptor DCIR is crucial for the development of experimental cerebral malaria. AB - Cerebral malaria (CM) is the most severe complication of malaria. The murine Plasmodium berghei ANKA (PbA) infection model has helped to identify crucial players in the pathogenesis of CM. However, the role of pattern recognition receptors in innate immunity to CM induction is still poorly understood. C-type lectin receptors (CLRs) represent a family of pattern recognition receptors that recognize carbohydrate structures on pathogens and self-Ags often in a Ca(2+) dependent manner. In this study, we investigated the role of the CLR dendritic cell immunoreceptor (DCIR) in the genesis of CM. Using the murine PbA infection, we show in this article that DCIR is essential for the development of CM. Although PbA infection led to 80% CM in wild-type C57BL/6 mice, DCIR-deficient mice were highly protected with only 15% CM development. In accordance with the reduced CM incidence in DCIR(-/-) mice, CD8(+) T cell sequestration was markedly reduced in brains of PbA-infected DCIR(-/-) mice, which was accompanied by reduced brain inflammation. Reduced T cell sequestration in the brain was caused by decreased TNF-alpha levels in sera, as well as a modulated activation of CD4(+) and CD8(+) T cells in spleen of PbA-infected DCIR(-/-) mice. This study indicates that DCIR is critically involved in CM induction, thus highlighting the importance of this CLR in innate immunity during malaria infection. PMID- 23918991 TI - Characterization of ultrananocrystalline diamond microsensors for in vivo dopamine detection. AB - We show the technical feasibility of coating and micro patterning boron-doped ultrananocrystalline diamond (UNCD(r)) on metal microwires and of applying them as microsensors for the detection of dopamine in vivo using fast-scan cyclic voltammetry. UNCD electrode surface consistently generated electrochemical signals with high signal-to-noise ratio of >800 using potassium ferrocyanide ferricyanide redox couple. Parylene patterned UNCD microelectrodes were effectively applied to detect dopamine reliably in vitro using flow injection analysis with a detection limit of 27 nM and in the striatum of the anesthetized rat during electrical stimulation of dopamine neurons. PMID- 23918992 TI - Kinase detection with gallium nitride based high electron mobility transistors. AB - A label-free kinase detection system was fabricated by the adsorption of gold nanoparticles functionalized with kinase inhibitor onto AlGaN/GaN high electron mobility transistors (HEMTs). The HEMTs were operated near threshold voltage due to the greatest sensitivity in this operational region. The Au NP/HEMT biosensor system electrically detected 1 pM SRC kinase in ionic solutions. These results are pertinent to drug development applications associated with kinase sensing. PMID- 23918993 TI - Drug interactions in dermatology: what the dermatologist should know. AB - A drug interaction is a process by which a drug or any other substance interacts with another drug and affects its activity by increasing or decreasing its effect, causing a side effect or producing a new effect unrelated to the effect of either. Interactions may be of various types-drug-drug interactions, drug-food interactions, drug-medical condition interactions, or drug-herb interactions. Interactions may occur by single or multiple mechanisms. They may occur in vivo or in vitro (pharmaceutical reactions). In vivo interactions may be further subdivided into pharmacodynamic or pharmacokinetic reactions. Topical drug interactions which may be agonistic or antagonistic may occur between two drugs applied topically or between a topical and a systemic drug. Topical drug-food interaction (for example, grape fruit juice and cyclosporine) and drug-disease interactions (for example, topical corticosteroid and aloe vera) may also occur. It is important for the dermatologist to be aware of such interactions to avoid complications of therapy in day-to-day practice. PMID- 23918995 TI - White lesions in the oral cavity: a clinicopathological study from a tertiary care dermatology centre in kerala, India. AB - CONTEXT: White lesions in the oral cavity may be benign, pre-malignant or malignant. There are no signs and symptoms which can reliably predict whether a leukoplakia will undergo malignant change or not. Many systemic conditions appear initially in the oral cavity and prompt diagnosis and management can help in minimizing disease progression and organ destruction. AIM: The aim of the paper was to study the clinical and histopathological patterns of white lesions in the oral cavity presented at the study setting and to study the factors associated with the histopathological patterns of the lesions. SETTINGS AND DESIGN: A hospital based cross-sectional study of patients with white lesions in the oral cavity attending the Department of Dermatology and Venereology, Medical College, Thiruvananthapuram was done. MATERIALS AND METHODS: After taking a detailed history, microscopic examination of Potassium hydroxide smear and an oral biopsy with histopathologial examination was done. RESULTS: Out of the 50 patients in the study, clinically the diagnoses made were Lichen planus (32 patients; 64%), Frictional Keratosis (4;8%), Dysplasia (2;4%), Oral Hairy Leukoplakia (1;2%), Pemphigus Vulgaris (2;4%), Cutaneous Lupus Erythematosus (1;2%), Oral Submucous fibrosis (3;6%) and Oral Candidiasis alone (5;10%). Out of the 45 patients who had undergone biopsy, 25 (55.6%) had Lichen planus, 9 (20%) had Frictional Keratosis and mild Dysplasia was found in 4 (8.9%) patients. CONCLUSION: The measure of agreement between the clinical and pathological diagnosis was only 32%. Older age, difficulty in opening the mouth, consumption of non-smoked tobacco, site of the lesion (gingival, floor of mouth or lingual vestibule) and presence of tenderness on the lesion were significantly associated with Dysplasia. PMID- 23918996 TI - Analysis of diagnostic criteria in adamantiades-behcet disease: a retrospective study. AB - Adamantiades-Behcet's disease (ABD) is a chronic-relapsing, inflammatory and multi-systemic disease. Any organ or system may be involved: ABD presents a great variety of cutaneous and mucosal lesions, ocular manifestations, central and peripheral nervous system abnormalities, joint as well as gastrointestinal involvement. Since clear pathognomonic clinical features and laboratory tests are lacking, the diagnosis of ABD mainly relies on the characteristic clinical features. Several sets of diagnostic criteria have been used. The International Study Group for Behcet Disease (ISGBD) in 1990 formulated a set of criteria to warrant uniformity of both diagnosis and classification. Therefore, in 2006, a new set was proposed by the International Team for the Revision of the International Criteria for Behcet's Disease (ITR-ICBD) not only to uniform the previous criteria but also to establish best accuracy, along with an optimum sensivity and specificity. The aims of this study are both to analyze the clinical features of ABD patients and to validate the ISGBD and ITR-ICDB criteria for the diagnosis of ABD in our cohort. PMID- 23918997 TI - Pseudolymphomatous folliculitis: a distinctive cutaneous lymphoid hyperplasia. AB - Pseudolymphomatous folliculitis (PLF) was first described in 1986 as a distinct variant of pseudolymphoma, characterized by a dense lymphoid infiltrate and accompanied by hyperplastic hair follicles. Here in we report a case of PLF presenting as an erythematous plaque with pustules and satellite lesions on forehead in an otherwise healthy adult male patient. PMID- 23918994 TI - Systemic sclerosis: current concepts in pathogenesis and therapeutic aspects of dermatological manifestations. AB - Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disease with protean clinical manifestations. Recent advances in understanding the pathogenic mechanisms have led to development of target-oriented and vasomodulatory drugs which play a pivotal role in treating various dermatological manifestations. An exhaustive literature search was done using Medline, Embase, and Cochrane library to review the recent concepts regarding pathogenesis and evidence-based treatment of salient dermatological manifestations. The concept of shared genetic risk factors for the development of autoimmune diseases is seen in SSc. It is divided into fibroproliferative and inflammatory groups based on genome-wide molecular profiling. Genetic, infectious, and environmental factors play a key role; vascular injury, fibrosis, and immune activation are the chief pathogenic factors. Vitamin D deficiency has been documented in SSc and correlates with the severity of skin involvement. Skin sclerosis, Raynaud's phenomenon (RP) with digital vasculopathies, pigmentation, calcinosis, and leg ulcers affect the patient's quality of life. Immunosuppressives, biologicals, and hematopoietic stem cell transplantation are efficacious in skin sclerosis. Endothelin A receptor antagonists, calcium-channel blockers, angiotensin receptor inhibitors, prostacyclin analogs, and phosphodiesterase type 5 (PDE-5) inhibitors are the mainstay in RP and digital vasculopathies. Pigmentation in SSc has been attributed to melanogenic potential of endothelin-1 (ET-1); the role of ET 1 antagonists and vitamin D analogs needs to be investigated. Sexual dysfunction in both male and female patients has been attributed to vasculopathy and fibrosis, wherein PDE-5 inhibitors are found to be useful. The future concepts of treating SSc may be based on the gene expression signature. PMID- 23918998 TI - Kojic Acid vis-a-vis its Combinations with Hydroquinone and Betamethasone Valerate in Melasma: A Randomized, Single Blind, Comparative Study of Efficacy and Safety. AB - BACKGROUND: Melasma is a relatively common, acquired symmetric hypermelanosis characterized by irregular light to gray-brown macules involving sun-exposed areas. Kojic acid, with its depigmenting potential due to tyrosinase inhibition and suppression of melanogenesis, has become a vital component of the dermatologists' armamentarium against melasma. AIM: To study and compare the efficacy of kojic acid 1% alone, vis-a-vis its separate combinations with 2% hydroquinone or 0.1% betamethasone valerate and a combination of all these three agents with respect to the duration of symptoms and level of pigmentation in the therapy of melasma. MATERIALS AND METHODS: Eighty patients from a single tertiary care center objectively assessed by calculating the melasma area severity index (MASI) and randomized (simple randomization) into four parallel groups (A, B, C, and D) of 20 each were prescribed once daily local application at night, (participants blinded regarding the difference in identity of interventions), as follows: Group A - kojic acid 1% cream. Group B - kojic acid 1% and hydroquinone 2% cream. Group C - kojic acid 1% and betamethasone valerate 0.1% cream. Group D kojic acid 1%, hydroquinone 2%, and betamethasone valerate 0.1% cream. Strict photoprotection and use of a SPF 15 sunscreen was advised during the day. Patients were evaluated every 2 weeks and a fall in MASI score was calculated at the end of the study period of 12 weeks by the same investigator. RESULTS: The response was compared according to percentage decrease in MASI score. Efficacy was evaluated among the groups at the end of 3 months using bivariate analysis and calculated by using the paired 't' test. The clinical efficacy of group B was the highest followed closely by group D and group A, that of group C being the lowest. CONCLUSION: Kojic acid in synergy with hydroquinone is a superior depigmenting agent as compared with other combinations. PMID- 23918999 TI - Unilateral Nevus of Ota with Bilateral Nevus of Ito and Palatal Lesion: A Case Report with a Proposed Clinical Modification of Tanino's Classification. AB - Nevus of Ota and nevus of Ito are rare dermal melanocytoses. Nevus of Ota may be very rarely associated with the nevus of Ito and other extra cutaneous features. Both nevi are similar in all respect apart from the area of distribution. Bilateral distribution of nevus of Ito is seldom reported in the literature. A 24 year-old male patient reported with nevus of Ota of the right side of his face since his infancy and nevus of Ito on both shoulder regions since early childhood. He had bluish lesions on the right side of his hard palate. Systemic examination was normal. Relevant laboratory investigations were non contributory. The histopathological examination of the skin from the affected areas showed the presence of elongated dendritic dermal melanocytes. The present case is the first report of an association of bilateral nevus of Ito with nevus of Ota and palatal lesions. Tanino classified Nevus of Ota into four groups. As both the nevi are similar in all respect except the area of distribution, a minor modification of the existing Tanino's classification to incorporate the nevus of Ito into the classification for the Ota's nevus may be appropriate. PMID- 23919000 TI - Psoriasiform dermatoses: microscopic approach. AB - Psoriasiform dermatoses often pose challenges to both dermatologists and pathologists alike. With proper clinicopathologic correlation and a systematic approach, it is possible to arrive at a specific diagnosis in most cases. This article attempts to outline a practical, step-wise method of looking at these cases and highlights some important clues in individual conditions. PMID- 23919001 TI - A Study of Various Histopathological Features and their Relevance in Pathogenesis of Psoriasis. AB - BACKGROUND: The pathogenesis of psoriasis is still to be fully unraveled. The immunological theory with T cells at the centre of attraction and peripherally acting cytokines are the present favourites among aetiopathological factors. Histopathology of the skin lesions offers a good study model to understand the pathogenesis of this complex disease. AIMS: To study the various histopathological parameters of psoriatic lesions, and to establish their correlation with the pathogenesis of the disorder. MATERIALS AND METHODS: Eighty eight consecutive histopathologically proven cases of psoriasis were included in the study. Eight common histopathological parameters of psoriasis present in these biopsies were assessed and graded. We then statistically analyzed the relationship of the factors with one another and attempted to establish a better understanding of the pathogenesis of disease. RESULTS: Significant correlations were found between degree of epidermal hyperplasia and inflammatory infiltrate, grade of inflammation and pustules of Kogoj, inflammatory infiltrate and grade of capillary proliferation as also between epidermal hyperplasia and the presence of parakeratosis. CONCLUSION: The study suggests that the immunopathogenesis of psoriasis is predominantly based on the inflammatory response. This is in consonance with other studies which have suggested that psoriasis is primarily a T lymphocyte based disease. Several treatment modalities are now based on this concept and it is hoped that the future treatment modalities will focus on the central role of inflammatory cells in the pathogenesis of this enigmatic disease. PMID- 23919002 TI - Retraction notice. PMID- 23919004 TI - Polyamine metabolism changes in psoriasis. AB - INTRODUCTION: Polyamines - putrescine, spermidine and spermine are polycationic compounds ubiquitous for all living organisms. They are essential for the cell growth and differentiation, the control of cell cycle progress, apoptosis, and cancerogenesis. Accumulated scientific evidence suggests the central role of polyamines in the process of keratinocytic proliferation, differentiation, and regulation. OBJECTIVE: To elucidate the polyamine metabolic changes that occur in benign keratinocytic proliferation. Fifty eight patients were enrolled in the study, 31 with plaque-form of psoriasis vulgaris, which had been referred to as a model of benign keratinocytic proliferation, and 27-healthy controls. MATERIALS AND METHODS: An original, innovative chromatographic method was used to detect the levels of putrescine, spermidine, and spermine in all skin samples. RESULTS: Were significantly proven (P < 0.05). No difference was found between the polyamines levels of non-lesional psoriatic skin and healthy controls. Psoriatic lesions showed a two-time higher concentration of all polyamines in lesional, compared to non-lesional skin. Spermine had the highest concentration and highest proliferation trend, which demonstrated the importance of propylamine synthesis in the pathogenesis of psoriasis. Spermine highest concentrations suggested the leading role of adenosine methionine decarboxylase (AMDC) in the pathogenesis of benign keratinocytic proliferations. CONCLUSIONS: Non-lesional skin in psoriatic patients did not show latent changes in polyamine metabolism. Psoriatic lesions demontrated two-time higher levels of the most essential biogenic polyamines compared to healthy controls. The highest level of spermine proved the crucial role of AMDC in the polyamine metabolism changes in psoriasis. Future therapeutic approaches should be focused on reduction of exogenic spermine intake, utilizing new spermine blockers, and synthesis of AMDC inhibitors. PMID- 23919005 TI - Finger nail pitting in psoriasis and its relation with different variables. AB - Incidence of pitting, vary considerably in different types of psoriasis. In clinical practice, toe nail examination is inconvenient. There are inadequate studies which show relation of nail pitting with duration and severity of the disease. The objective was to examine the incidence of finger nail pitting in all types of cutaneous psoriasis and its relation with different variables. This is a clinico-epidemiological study. A careful clinical examination of finger nails was done in day time. Severity of disease was calculated by psoriasis area severity index (PASI). Statistical analysis was done using Microcomputer statistics software (MSTAT). In study group, 621 patients and in control group 350 people were taken. Finger nail pitting was present in 37% (total number was < 20 in 17%; 20-60 in 8% and > 60 in 12%) in study group. In control group, it was present in 10% (in all cases total number was < 20). In < 1 year duration group, pitting was present in 32% of cases, while in > 1 year duration group it was 40.5%. In mild psoriasis, pitting was present in 34.2%, while in severe cases it was 47.6%. Finger nail pitting is an important nail finding in psoriasis and its incidence increases with duration and severity of disease. PMID- 23919003 TI - Metabolic syndrome and skin: psoriasis and beyond. AB - Metabolic syndrome (Met S) is a clustering of risk factors comprising of abdominal obesity, dyslipidemia, elevated blood pressure, and abnormal glucose tolerance. The prevalence of Met S has been increasing in the last few years throughout the world. Psoriasis has consistently been associated with Met S as well as its various components. However, the association is no longer limited to psoriasis alone. Various dermatological conditions such as lichen planus, androgenetic alopecia, systemic lupus erythematosus, skin tags, acanthosis nigricans, and even cutaneous malignancies have also been found to be associated with this syndrome. Though chronic inflammation is thought to be the bridging link, the role of oxidative stress and endocrine abnormalities has recently been proposed in bringing them together. PMID- 23919006 TI - Is psoriasis a new cutaneous marker for metabolic syndrome? A study in Indian patients. PMID- 23919007 TI - Prevalence of metabolic syndrome in South Indian patients with psoriasis vulgaris and the relation between disease severity and metabolic syndrome: a hospital based case-control study or cross-sectional study? PMID- 23919008 TI - Authors' reply. PMID- 23919009 TI - More Robust Evidence and Safety Checks are Required Before Autologous Serum Therapy as Treatment for Chronic Urticaria can be Recommended. PMID- 23919010 TI - Authors' reply. PMID- 23919012 TI - Multiple nodular swellings in an adult male. PMID- 23919011 TI - Verrucous squamous cell carcinoma of vulva simulating multiple epidermal inclusion cysts. PMID- 23919013 TI - Curious translucent papules over vitiliginous patches. PMID- 23919014 TI - Chronic idiopathic urticaria and thyroid autoimmunity: perplexing association. AB - BACKGROUND: Autologous serum skin test (ASST) is the most commonly used laboratory test to differentiate chronic autoimmune urticaria patients from chronic idiopathic urticaria patients without autoantibodies. Thyroid autoimmunity is the original paradigm for autoimmune disease in general and many previous studies show increased prevalence of thyroid autoantibodies and deranged thyroid hormone profile in chronic idiopathic urticaria patients. AIM: To find the association between thyroid autoimmunity and chronic autoimmune urticaria, if any. MATERIALS AND METHODS: The chronic idiopathic urticaria patients were divided into two subgroups based on autologous serum skin test. Thyroid autoantibodies were estimated in 40 patients each of ASST positive and ASST negative groups. Further, thyroid hormone profile was done in cases with significant titers of thyroid autoantibodies. Forty patients, who had never suffered from urticaria, represented the control group. RESULTS: The prevalence of thyroid autoantibodies did not differ significantly among the ASST positive (20%) and ASST negative patients (15%). The control group had low prevalence of these autoantibodies (5%). CONCLUSION: The almost equal prevalence of thyroid autoantibodies in two subgroups of chronic idiopathic urticaria patients suggests possibly the same etiopathogenesis of the two subgroups. The two subgroups probably form a continuum, or even may be the same entity. PMID- 23919015 TI - Reduced P53 Staining in Actinic Keratosis is Associated with Squamous Cell Carcinoma: A Preliminary Study. AB - BACKGROUND: Actinic keratosis (AK) is a cutaneous neoplasm caused by prolonged sun exposure, and may progress into squamous cell carcinoma (SCC). The p53 gene plays a central role in the development of SCC, and mutations in this gene are found in 90% of SCC and up to 100% of AK cases. OBJECTIVE: To identify AK cases that are highly susceptible to developing SCC. MATERIALS AND METHODS: Fifty-six AK cases were classified into two groups: AK adjacent to "normal" skin and AK adjacent to SCC. The groups were compared based on epithelial atypia, inflammation, solar elastosis, histopathological AK classification and p53 protein expression. RESULTS: Of the 56 AK cases analyzed, 23% were associated with SCC. The types of AK observed were classified as follows: common, hypertrophic, atrophic, acantholytic, pigmented and bowenoid. SCC was associated with common and hypertrophic AK, and p53 staining was observed in 78% of AK cases. The mean difference in p53 immunopositivity between common AK cases associated with SCC (17%) and not associated with SCC (45.4%) was significant (p=0.011). CONCLUSIONS: Hypertrophic and common AK are associated with SCC, and the low percentage of p53 immunopositivity in the common type indicates a greater probability of developing into SCC. PMID- 23919016 TI - Soy allergy in patients suffering from atopic dermatitis. AB - AIM: The evaluation of soy allergy in patients over 14 years of age suffering from atopic dermatitis. The evaluation of the correlation to the occurence of peanut and pollen allergy. MATERIALS AND METHODS: Altogether 175 persons suffering from atopic dermatitis were included in the study: Specific IgE, skin prick tests, atopy patch tests to soy, history and food allergy to peanut and pollen allergy were evaluated. RESULTS: The early allergic reaction to soy was recorded in 2.8% patients. Sensitization to soy was found in another 27.2% patients with no clinical manifestation after soy ingestion. The correlation between the positive results of examinations to soy and between the occurence of peanut and pollen allergy was confirmed in statistics. CONCLUSION: Almost one third of patients suffering from atopic dermatitis are sensitized to soy without clinical symptoms. The early allergic reaction to soy occur in minority of patients suffering from atopic dermatitis. PMID- 23919017 TI - Cerebrospinal Fluid Abnormalities in HIV-Negative Patients with Secondary and Early Latent Syphilis and Serum VDRL >= 1:32. AB - BACKGROUND: Syphilis is caused by a spirochete Treponema pallidum. Invasion of the central nervous system (CNS) by T. pallidum may appear early during the course of disease. The diagnosis of confirmed neurosyphilis is based on the reactive Venereal Disease Research Laboratory (VDRL) in cerebrospinal fluid (CSF). Recent studies indicated that serum RPR >= 1:32 are associated with higher risk of reactivity of CSF VDRL. AIMS: The main aim of the current study was to assess cerebrospinal fluid serological and biochemical abnormalities in HIV negative subjects with secondary and early latent syphilis and serum VDRL >= 1:32. MATERIALS AND METHODS: Clinical and laboratory data of 33 HIV-negative patients with secondary and early latent syphilis, with the serum VDRL titer >= 1:32, who underwent a lumbar puncture and were treated in Department of Dermatology at Jagiellonian University School of Medicine in Cracow, were collected. RESULTS: Clinical examination revealed no symptoms of CNS involvement in all patients. 18% (n = 6) of patients met the criteria of confirmed neurosyphilis (reactive CSF-VDRL). In 14 (42%) patients CSF WBC count >= 5/ul was found, and in 13 (39%) subjects there was elevated CSF protein concentration (>= 45 mg/dL). 10 patients had CSF WBC count >= 5/ul and/or elevated CSF protein concentration (>= 45 mg/dL) but CSF-VDRL was not reactive. CONCLUSIONS: Indications for CSF examination in HIV-negative patients with early syphilis are the subject of discussion. It seems that all patients with syphilis and with CSF abnormalities (reactive serological tests, elevated CSF WBC count, elevated protein concentration) should be treated according to protocols for neurosyphilis. But there is a need for identification of biomarkes in order to identify a group of patients with syphilis, in whom risk of such abnormalities is high. PMID- 23919018 TI - Phototherapy in Vitiligo: Assessing the Compliance, Response and Patient's Perception about Disease and Treatment. AB - CONTEXT: Vitiligo is a chronic, benign, but emotionally frustrating autoimmune disorder of depigmentation, with an incidence of 0.25-2.5% in India, the treatment of which is equally frustrating to the patient, as well as the doctor. Phototherapy is the first line treatment in many cases, which needs to be given at frequent sittings for long periods of time. As there is no satisfactory, short term treatment, many vitiligo patients, though enthusiastic in the beginning, become defaulters after a few weeks or months. AIMS: This study was conducted to assess the compliance to phototherapy (PUVA and NB-UVB), determine the reasons for non-compliance, to calculate the overall response to phototherapy and to know about the patients' perception about improvement of lesions. MATERIALS AND METHODS: All files of the patients who attended phototherapy for Vitiligo in the department for a period of 4 years from January 2007 were analyzed and the patients were contacted via mail or telephone and were made to answer questionnaire regarding their disease. CONCLUSIONS: At the end of this retrospective questionnaire based study we concluded that only a quarter of the patients underwent regular phototherapy, among which the younger patients and those with widespread disease and facial lesions were more compliant. Educational status and sex had no impact on default status. PMID- 23919019 TI - The Evaluation of the Impact of Age, Skin Tags, Metabolic Syndrome, Body Mass Index, and Smoking on Homocysteine, Endothelin-1, High-sensitive C-reactive Protein, and on the Heart. AB - BACKGROUND: Skin tags (STs) are small, pedunculated skin-colored or brown papules that occur around any site where skin folds occur. The literature is short of comprehensive and controlled clinical studies aimed to evaluate the atherogenic risk factors in patients with STs. AIM OF WORK: The aim of this study is to evaluate the impact of age, STs, metabolic syndrome (METs), body mass index (BMI), and smoking on homocysteine (Hcy), endothelin-1 (ET-1), high-sensitive C reactive protein (Hs-CRP), and on cardiovascular diseases. MATERIALS AND METHODS: This study included 30 cardiac patients with STs, 30 non-cardiac patients with STs, and 30 healthy controls with neither heart disease nor STs. History of smoking, measurement of height, weight, BMI, waist circumference (WC), blood pressure, STs number, color, acanthosis nigricans, estimation of serum level of fasting glucose, triglycerides (TGs), cholesterol, high-dense lipoproteins (HDL), Hcy, ET-1, Hs-CRP, and the presence of the METs were elicited in the three groups. RESULTS: Regarding the Hcy, ET-1, and Hs-CRP, the cardiac-STs group showed the highest levels and the control group showed the least (P < 0.001). The percents of patients with METs were 56.7% in the cardiac-STs, 40% in the non cardiac-STs, and 0% in the control group (P < 0.001). Mean BMI exceeded the limit of obesity in the cardiac-STs group (30.9 +/- 3.9) and the non-cardiac-STs group (32.6 +/- 6) and was normal in the control group (24.7 +/- 2.8). Hyperpigmented STs were present in 66.7% of the cardiac-STs group. Multivariate regression analysis for the independent effectors on Hcy level were the presence of STs (P < 0.001), METs (P = 0.001), and BMI (P = 0.024). Regarding ET-1, the effectors were the presence of STs and METs (P = 0.032). For Hs-CRP, effectors were the presence of STs (P < 0.001) and smoking (P = 0.040). Multivariate logistic regression of the predictors of cardiac disease showed that the independent predictors of the occurrence of cardiac disease were BMI (P < 0.001), STs (P = 0.002), and METs (P = 0.037). CONCLUSION: STs may act as a physical sign of underlying raised cardiac atherogenic factors. This may indicates an ongoing risk on coronary circulation which may indicate further corrective action, hopefully early enough. The association of ST with obesity and METs represents a Bermuda Triangle that act against the heart. PMID- 23919020 TI - No Evidence of Human Papillomaviruses in Non-genital Seborrheic Keratosis. AB - BACKGROUND: Seborrheic keratosis (SK) is a benign epidermal tumor of unknown etiology. Because of its wart-like morphology, Human papillomaviruses (HPVs) have been suggested as a possible causative agent. Viral involvement, however, has not been confirmed yet despite research and the association between HPVs and seborrheic keratosis has not been studied among Iranian population by PCR. OBJECTIVES: The aim of this case-control study was to evaluate the presence of HPVs DNA in non-genital SK by PCR. MATERIALS AND METHODS: Fifty biopsy specimens obtained from patients with non-genital SK and 50 controls were analyzed using polymerase chain reaction (PCR). RESULTS: No HPVs DNA was detected by PCR within the tissue extracts from paraffin-embedded SK samples, while one of the controls was HPVs DNA positive. The age range of the patients was 20 to 82 yrs (mean = 52). Twenty-eight patients (56%) were males and 22 patients (44%) were females. The most common anatomic site was the face. Histopathologic changes due to viral infection such as koilocytosis (10%), dyskeratosis (66%), mitosis (28%), and parakeratosis (88%) were evident within the lesions. The most common histologic type was acanthotic type. CONCLUSION: Our results showed that there is no association between HPVs and seborrheic keratosis in investigated subjects. PMID- 23919021 TI - A clinical study of the cutaneous manifestations of hypothyroidism in kashmir valley. AB - BACKGROUND: Thyroid disorders are known to involve all the organ systems of the body, the skin being no exception. The association of thyroid disorders with cutaneous manifestations is complex. Both hypothyroidism and hyperthyroidism are known to cause these changes. AIMS: The present study was designed to ascertain the varied cutaneous manifestations of hypothyroidism. MATERIALS AND METHODS: This study was a hospital based clinical study conducted in collaboration with the Endocrinology Division (Department of Medicine) of SMHS Hospital (associated teaching hospital of Government Medical College Srinagar), over a period of one year, from May 2010 to May 2011. Four hundred and sixty consecutive diagnosed cases of hypothyroidism constituted the subject material for the study and were evaluated for the presence of any cutaneous manifestation. RESULTS: In our study group of 460 patients, there were 416 females and 44 male patients. The predominant cutaneous symptom in our hypothyroid patients was dry coarse skin (65.22%), followed by hair loss (42.6%) and puffy edema (38.48%). The most common cutaneous sign observed in hypothyroid patients was xerosis (57.17%), followed by diffuse hair loss (46.09%), altered skin texture (31.74%), coarse scalp hair (29.35%) and puffy face (28.69%). CONCLUSIONS: The interaction between thyroid gland and skin is of profound clinical importance in dermatological practice. So, dermatologists need to be cognizant of the ways in which these two organs interact. PMID- 23919022 TI - 308-nm Excimer Lamp for the Treatment of Alopecia Areata: Clinical Trial on 16 Cases. AB - BACKGROUND: Alopecia areata (AA) is considered as a T-cell mediated autoimmune disorder. The 308-nm excimer laser is thought to be capable of inducing T-cell apoptosis in vitro, suggesting that the 308-nm excimer lamp (not laser) might be effective for the treatment of AA. We examined the effectiveness of the 308-nm excimer lamp for treating AA. MATERIALS AND METHODS: We treated 16 patients with single AA and multiple AA (MAA). The lesions were irradiated with a 308-nm excimer lamp at 2-week intervals. RESULTS: Hair regrowth was observed in 14 patients. Among them, 10 patients showed more than 50% hair re-growth. Our results suggested that the 308-nm excimer lamp system is effective and safe for the treatment of single AA and MAA. CONCLUSION: Our results suggest that the 308 nm excimer lamp is a good therapeutic alternative without serious side effect for treating AA. PMID- 23919023 TI - Cutaneous syringoma: a clinicopathologic study of 34 new cases and review of the literature. AB - BACKGROUND: Syringoma is a benign adnexal tumor derived from intraepidermal eccrine duct. AIM: The aim of the study is to report the experience concerning syringoma by reviewing the clinical and histopathologic features of a series of 34 histologically diagnosed syringoma patients observed over a period of six years. MATERIALS AND METHODS: Thirty-four patients were sorted into two groups, localized and generalized syringoma, according to the Friedman and Butler classification. Different histopathologic findings were recorded in specially designed questionnaires for further analysis. RESULTS: Ninety-seven percent of the patients were females with the mean age of 27.6 years. The mean duration of the lesions before the presentations was six years. The diagnosis of syringoma was only considered in 23 patients (67.6%) and was the initial diagnosis in only 13 (38.2%) patients. All histological findings were seen more common in our cases. in comparison to the documented cases in the literature. Clear cell change of epithelial eccrine cells was 85.2% and there was no difference in the histopathological findings in the two groups. Our patients with generalized syringoma (GS) had a considerable lower age of onset than the ones with localized syringoma (LS) (P = 0.027). CONCLUSION: Our patients with generalized syringoma were younger than the ones with localized syringoma. Distribution of the generalized syringoma was mainly in the chest and neck followed by the forearms whereas localized syringoma was mostly confined to the face, axilla and genitalia. There were also some conditions associated with our cases including sarcoidosis, calcinosis cutis and basal cell carcinoma. PMID- 23919024 TI - Expression of Inflammatory Biomarkers from Cultured Sebocytes was Influenced by Treatment with Vitamin D. AB - BACKGROUND: Inflammatory cytokines are the key factor in the pathophysiology of acne. It is well known that keratinocytes synthesize many kinds of inflammatory cytokines. In addition, it is reported that inflammatory cytokines are also expressed from sebocytes, which originate from the same stem cells with keratinocytes. AIM: To clarify changes in the expression of inflammatory biomarkers from cultured sebocytes after treatment with vitamin D. MATERIALS AND METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was done to measure changes in the expression of inflammatory biomarkers, including interleukin-1beta (IL-1beta), IL-6, IL-8, and tumor necrosis factor-alpha (TNF alpha), and several subtypes of matrix metalloproteinases (MMPs) after treatment of a group of cultured sebocytes with vitamin D. Vitamin D receptor (VDR) small interfering RNA (siRNA) was added in the other group of cultured sebocytes to assure the role of vitamin D on the expression of inflammatory biomarkers. Enzyme linked immunosorbent assay (ELISA) was also performed in the vitamin D-treated sebocytes. RESULTS: Cultured sebocytes showed non-significant changes in the gene expression of inflammatory biomarkers after treatment with vitamin D. In cultured sebocytes treated with a VDR siRNA, the expression of inflammatory biomarkers was not blocked after treatment with vitamin D. ELISA showed a significant decrease in the expression of IL-6, IL-8, and MMP-9, but a significant increase in the expression of MMP-1 and MMP-3, after treatment with vitamin D (10(-6) M). CONCLUSION: Expression of inflammatory biomarkers is influenced by treatment with vitamin D in cultured sebocytes, but not through VDR. PMID- 23919025 TI - Aminolevulinic Acid-photodynamic therapy of Basal cell carcinoma and factors affecting the response to treatment: a clinical trial. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common type of skin cancer in humans. Photodynamic therapy (PDT) is a non-invasive therapeutic modality that may be considered as a valuable treatment option for BCC. This study was designed with the aim of evaluating the efficacy of PDT in treatment of BCC and factors that may affect the response rate. MATERIALS AND METHODS: This clinical trial was conducted on 12 patients (28 BCC lesions) who were treated with aminulevulinic acid (ALA)-PDT, monthly, up to 6 sessions and the clinical response, cosmetic results, and possible side effects were evaluated. RESULTS: The study was performed on 28 BCC lesions from 12 patients. Complete response was achieved in 9 (32.1%) lesions. Complete response rate was higher in younger patients (P < 0.01) and those with smaller lesions (P < 0.001). Superficial type also had significant higher response rate (P < 0.05). Patients with history of radiotherapy for the treatment of tinea capitis in childhood showed less response (P < 0.05). Cosmetic results were excellent or good in 77.5% cases. After 6 months of follow-up, none of the resolved lesions recurred. CONCLUSION: PDT would be a good therapeutic option in treatment of BCC with acceptable efficacy and low side effects. Younger patients, superficial BCCs, and smaller lesions show better response to ALA-PDT. History of radiotherapy may be associated with a lower response rate. PMID- 23919026 TI - Teenage patients with ingrown toenails: treatment with partial matrix excision or segmental phenolization. AB - BACKGROUND: Ingrown toenails (IT) is a very common problem leading to significant associated morbidity. The articles related to phenolization for matrix removal in teenagers with IT are not enough in the foot surgery literature. AIMS: To compare the postoperative recovery periods, complication rate, and tolerability of partial matrix excision and segmental phenolization in teenagers with IT. MATERIALS AND METHODS: Thirty-nine patients (13-17 years) with 48 IT were randomly divided into two groups and were treated with partial matrix excision (Group I) and segmental phenolization (Group II). We assessed the recurrence rates, postoperative complications, duration of analgesic usage, and time to return to daily activities. RESULTS: There was no significant difference between the demographic and clinical data of the two groups. Three patients in Group I and two patients in Group II experienced moderate pain postoperatively. These patients used analgesics for 3 days. The rates of postoperative complications and recurrences between the two groups showed no statistically significant difference (P = 0.688). The time to return to normal daily activities was significantly shorter in Group II patients than in Group I patients (P < 0.05). CONCLUSIONS: Partial matrix excision is a very safe model of therapy in the surgical treatment of teenagers with IT. It has low recurrence rate and minimal postoperative morbidity. We concluded that segmental phenolization is also as safe as partial matrix excision in the treatment of IT and patients return to their daily activities in less time with this treatment modality. PMID- 23919027 TI - Intra-hepatic Cholestasis of Pregnancy: A Comprehensive Review. AB - Intra-hepatic cholestasis of pregnancy is a cholestatic disorder characterized by i) pruritus, with onset in the third trimester of pregnancy, without any primary skin lesions, ii) elevated fasting serum bile acids > 10 MUmol/L (and elevated serum transaminases), iii) spontaneous relief of signs and symptoms within two to three weeks after delivery, and iv) absence of other disease that cause pruritus and jaundice. It is believed to be a multi-factorial disease with interplay between genetic, environmental and hormonal factors. Incidence is between 0.02% to 2.4% of all pregnancies; with wide geographical variations. Maternal prognosis is usually good but can result in adverse fetal outcomes like meconium staining of amniotic fluid, fetal bradycardia and even fetal loss. Response to anti histaminic is poor. Of all the medical therapies that have been described for the treatment for IHCP, ursodeoxycholic acid has the best response in relieving pruritus in mother, and probably has a role in preventing even the perinatal complications. Timely diagnosis and treatment is urged in order to prevent fetal complications and an early delivery between 37 to 38 weeks should be contemplated in severe cases, especially once fetal lung maturity is attained. PMID- 23919028 TI - Civatte bodies: a diagnostic clue. PMID- 23919029 TI - Bitemporal scalp, lip and tongue necrosis in giant cell arteritis: a rare presentation. AB - A 74-year-old man was presented with fever, bilateral throbbing temporoparietal headache, jaw claudication, and bilateral loss of vision. On examination, he had bilateral scalp necrosis with impending necrosis of lip and tongue. Temporal artery biopsy was done, and it was compatible with active temporal arteritis. This is one of the rare presentations of giant cell arteritis where there is simultaneous necrosis of scalp, lip, and tongue, and to the best of our knowledge, it is the first case reported from India. PMID- 23919030 TI - Tender skin nodules in a newborn. AB - Subcutaneous fat necrosis of infancy is a rare disorder of subcutaneous adipose tissue that is sometimes complicated by hypercalcemia. Complete resolution is common. From the pediatrician's point of view, the disease is a rare but important cause of inconsolable cry in a newborn. PMID- 23919031 TI - Cutis laxa: a report of two interesting cases. AB - Cutis laxa is a rare disease that may be either inherited or acquired. The acquired form is rarer than the inherited form. Pathogenesis of this disease is largely unknown. Two cases of acquired cutis laxa are reported here and neither of them had any systemic involvement or any history of drug intake. One of them had localized disease with history of preceding cutaneous inflammation. The other patient with generalized lesion lacked any history of preceding illness. The patient with localized lesion was treated satisfactorily by reconstructive surgery. The other patient had generalized involvement, for which no satisfactory treatment could be offered. PMID- 23919032 TI - Ganglion cell like cells, diagnostic dilemma. AB - We report a case of cutaneous swelling found on the left anterior axillary fold of a 41-year-old man. Gross examination of specimen excised from the dermis showed a well-circumscribed nodule histologically composed of spindle cells with interspersed ganglion cell like cells. On hematoxylin and eosine (H and E) staining it was diagnosed as ganglioneuroma. Ganglioneuromas are rare, benign, fully differentiated tumors that contain mature schwann cells, ganglion cells, fibrous tissue, and nerve fibers. They are commonly found along the paravertebral sympathetic ganglia and sometimes in the adrenal medulla. However primary cutaneous ganglioneuroma is an extremely rare tumor. Immunohistochemical workup revealed a fibroblastic origin and hence the case was diagnosed as fibromatosis with ganglion cell like fibroblasts. This case report suggests that the features considered diagnostic of ganglioneuromas can occur in other cutaneous lesions and, therefore, this diagnosis cannot be offered only on the basis of H and E. PMID- 23919033 TI - A generalized, non-pruritic variant of lichen amyloidosis: a case report and a brief review. AB - Lichen amyloidosis (LA) has been considered a highly pruritic dermatosis, and the deposition of fibrillar material has generally been considered to be secondary to the scratching. Focal epidermal damage and chronic scratching have been implicated as the pathogenetic factors in the occurrence of LA, although they may not be able to explain the occurrence of a widespread variant of this dermatosis. There are few case reports describing the occurrence of a non-pruritic variant of LA. We hereby report a case of non-pruritic, generalized variant of lichen amyloidosis. PMID- 23919034 TI - Case reports of incontinentia pigmenti in males. AB - Incontinentia pigmenti is an X-linked dominant disorder, which is fatal in males, and majority of cases reported are in females. Here, we report 2 cases of males with incontinentia pigmenti. Case 1 has progressed through the classical stages of IP, giving history of vesicular and verrucous lesions and has presented with hyperpigmentation in whorled pattern. Case 2 has vesicular lesions in a linear distribution on the legs along with classical histopathological findings. PMID- 23919035 TI - Recurrent ulcers: a diagnostic challenge. PMID- 23919036 TI - Psoriasis occurring as a koebner phenomenon over keloids. PMID- 23919037 TI - Multiple squamous cell carcinoma over lichen simplex chronicus: a rare entity. PMID- 23919038 TI - Erythema annulare centrifugum: deep variant with vasculitis like histopathology. PMID- 23919039 TI - A case of senear-usher syndrome. PMID- 23919040 TI - Erythema gyratum repens like figurate erythema responding to topical steroid in an healthy individual. PMID- 23919041 TI - Topical timolol: a safer alternative for complicated and un-complicated infantile hemangiomas. PMID- 23919042 TI - Nevus lipomatosus cutaneous superficialis associated with trichofolliculoma on the lower leg. PMID- 23919043 TI - Follicular occlusion triad associated with reticulate pigmentary disorder: is there a genetic linkage? PMID- 23919044 TI - A particularly bothersome umbilical nodule. PMID- 23919045 TI - A 54-year-old female with skin lesions and history of renal cell carcinoma. PMID- 23919046 TI - Getting to zero: Possibility or propoganda? AB - The world is now in the fourth decade of a pandemic that united all the nations more than any other calamities or policies. The numbers with relation to HIV are falling consistently. Unfortunately the funding is also decreasing. In the current uncertain economic environment, the Joint United Nations Programme on HIV and AIDS (UNAIDS) has set a very ambitious target of reducing HIV to zero by 2015. There are strategies that are good and cost-effective and, if used appropriately, will give remarkable results. No new innovations have recently been discovered related to HIV. More molecular level studies are needed besides strengthening the existing strategies. We need money for all these activities and it should not stop coming. The paper reviews the success of HIV program in India and also foresees the challenges lying ahead of us in "getting to zero." PMID- 23919047 TI - Profile of HIV seroconcordant/discordant couples a clinic based study at Vadodara, India. AB - BACKGROUND: Heterosexual transmission of HIV among married couples is the commonest mode of transmission seen in India. Intramarital transmission is associated with several challenges which need to be further researched. AIM: To study level of seroconcordance and serodiscordance among HIV positive couples and factors affecting intramarital sexual transmission in terms of safe sexual practice, and the presence of Sexually transmitted infections (STI)/circumcision. MATERIALS AND METHODS: Ninety-one monogamous married cohabiting HIV-positive cases (index cases) attending Department of Skin and Venereology, Medical College Baroda, from January 2009 to August 2009 were studied. Their spouses were tested for HIV. A structured proforma was used to study various factors like condom use, circumcision, and the presence of sexually transmitted infections. RESULTS: Ninety-one monogamous married cohabiting HIV-positive cases were included in the study and considered as index cases. There were 51 males and 40 females. On testing their spouses for HIV, both the spouses were positive in 55 couples giving rise to 60% seroconcordance rate. Out of 55 seroconcordant couples, male spouses used condom in 16 cases (29%). Out of 36 serodiscordant couples 17 male spouses (47%) used condom. Evidence of STD was observed in one of the spouses in 6 out of 55 seroconcordant couples and 6 out of 36 serodiscordant couples. Thus, out of 91 couples one of the partners was having STI in 12 couples. Overall rate of circumcision was 12.2%. CONCLUSION: The prevention of transmission of HIV to the HIV negative partner is of paramount importance. Serodiscordant couples, specially the HIV negative female partner is at higher risk. Less acceptability of condoms among married couples may be one of the factors responsible in transmission. Further studies are needed to explore other risk factors associated with HIV transmission in discordant couples. PMID- 23919048 TI - Partner notification and treatment Institute of Venereology-experience. AB - INTRODUCTION: There has been a significant increase in general awareness about Sexually transmitted diseases (STD's) among the general public. However, rates of partner notification and treatment which are an integral part of STD awareness is still questionable. METHODOLOGY AND RESULTS: We analyzed the statistics for prevalence of partner notification (which is about 52%) as well as the possible reasons for non-compliance. An overview of various ways of partner notification has been given as patient delivered partner medication (PDPM) and patient based partner referral (PBPR) of which PDPM is the most acceptable and effective method worldwide. PMID- 23919049 TI - Study of sexual behavior and prevalence of STIs/RTIs and HIV among female workers of textile industries in Surat city, Gujarat, India. AB - BACKGROUND: Surat city is vulnerable to transmission of sexually transmitted infections (STIs)/HIV due to its huge migratory population in diamond and textile industries. Females working in textile industries were not receiving focused intervention although they were at high risk of acquiring STIs/HIV. OBJECTIVE: The present study was conducted to know the prevalence of various STIs and HIV among the group of female textile workers in Surat city. The findings of the study will be helpful for policy decision makers to address the issues of a specific vulnerable group. MATERIALS AND METHODS: A total 257 female workers in various textile markets were enrolled in the present study. Data were collected by the help of a pre-tested questionnaire and analysis was done by using Microsoft Excel and the EPI Info software. RESULT: Overall prevalence of various STIs/RTIs (reproductive tract infections) was 16.73%, whereas HIV positivity was 1.17%. Bacterial vaginosis and candidiasis were the most common infections. CONCLUSION: Groups such as female textile workers need to be taken care of especially to enhance the HIV prevention and control activities in Surat city, which would help in breaking the chain of transmission. PMID- 23919050 TI - Pattern of mucocutaneous manifestations in human immunodeficiency virus-positive patients in North India. AB - BACKGROUND: Mucocutaneous diseases are among the first-recognized clinical manifestations of acquired immune deficiency syndrome. They function as visual markers in assessing the progression of human immunodeficiency virus (HIV) infection. Given the relative ease of examination of skin, its evaluation remains an important tool in the diagnosis of HIV infection. OBJECTIVE: To determine the pattern of mucocutaneous manifestations in HIV-positive patients and to correlate their presence with CD4 counts. MATERIALS AND METHODS: This cross-sectional study included 352 HIV-infected patients seen at PGIMER, Chandigarh, India, over a period of 1 year. The patients were screened for mucocutaneous disorders by an experienced dermatologist. The patients were classified into different stages according to the World Health Organization clinical and immunological staging system. RESULTS: The most prevalent infection was candidiasis, seen in 57 patients (16.2%). Prevalence of candidiasis, dermatophytosis, herpes simplex, herpes zoster, molluscum contagiosum (MC), seborrheic dermatitis, adverse drug reaction, nail pigmentation, xerosis and diffuse hair loss differed statistically according to the clinical stages of HIV infection. There was a statistically significant association between immunological stages of HIV infection and dermatophytosis. CONCLUSION: Results of our study suggest that mucocutaneous findings occur throughout the course of HIV infection. Dermatoses like MC and dermatophytosis show an inverse relation with CD4 cell count, and these dermatoses can be used as a proxy indicator of advanced immunosuppression to start highly active anti-retroviral therapy in the absence of facilities to carry out CD4 cell count. PMID- 23919051 TI - Trichomoniasis: How do we diagnose in a resource poor setting? AB - BACKGROUND: Diagnosis of Trichomonas vaginalis vaginalis infection based solely on clinical symptoms and signs is unreliable because the spectrum of infection is broad and other sexually transmitted pathogens cause similar signs and symptoms. AIMS: Our study was undertaken to study the frequency of T. vaginalis infection in women presenting with vaginal discharge, to characterize the clinical features, and to study the sensitivity and specificity of microbiological investigations in the diagnosis of the same. MATERIALS AND METHODS: This was a hospital-based descriptive study done on 400 female patients with vaginal discharge attending the Gynecology out-patient department (OPD) of JIPMER, Puducherry, from May 2010 to July 2011. Women of age between 20 years and 50 years presenting with vaginal discharge irrespective of marital status, were included, and detailed history was elicited and thorough examination was performed. RESULTS: In 400 women presenting with vaginal discharge from Gynecology out-patient department (OPD) included in the study, T. vaginalis infection was found in 27 (6.75%) women. The risk factors for trichomoniasis included history of pre- or extramarital sexual contact in the woman or her partner, symptomatic partner, and alcohol consumption. A positive association with pelvic inflammatory disease was also observed. The most frequent symptoms included lower abdominal pain, dysuria, and dyspareunia. Combining of Whiff test, pH > 4.5, and pus cells in Gram-stained smear, the specificity in diagnosing the infection (97.3%) approached that of the reference standard, i.e., culture. On combining wet mount with Papanicolaou smear, the sensitivity increased to 92.6%, which was higher than that individually done. CONCLUSION: To conclude, diagnosis of T. vaginalis infection based solely on clinical symptoms and signs is unreliable, and combination of simple laboratory tests increases the diagnostic performance close to the reference standard (culture), especially in resource poor settings. PMID- 23919052 TI - Herpes genitalis - Topical zinc sulfate: An alternative therapeutic and modality. AB - BACKGROUND: Herpes genitalis is one of the commonest sexually transmitted infections in the world caused by herpes simplex virus (HSV) 1 and 2. All herpes viruses show latency. Herpes genitalis caused by HSV-1 and HSV-2 is recurrent in 55 and 90% of case respectively. AIMS: To comparatively evaluate the therapeutic efficacy of topical zinc sulfate (ZnSO4) in varying concentrations in herpes genitalis. MATERIALS AND METHODS: Ninety patients clinically diagnosed as herpes genitalis and confirmed by Tzanck test were taken up for study and divided into 3 groups of 30 patients each which were applied topical ZnSO4 in concentrations of 1%, 2% and 4% respectively for 3 months. Ten patients of herpes genitalis were kept as control in whom only distilled water was applied. Patients were followed up for a total period of 6 months for any recurrences. RESULTS: Ten patients of group 1 (1% ZnSO4) showed recurrence, 6 patients in group 2 (2% ZnSO4) and only one patient in group 3 (4% ZnSO4) showed recurrence. In the control group, 8 out of 10 patients showed recurrence. No serious side effects were seen in all 3 groups. CONCLUSION: Topical ZnSO4 has been found to be an effective therapeutic modality not only for treatment but also for prolonging remissions in herpes genitalis. Topical 4% ZnSO4 has been found to be most efficacious out of the three concentrations, without any side effects. PMID- 23919053 TI - Observance of Kassowitz law-late congenital syphilis: Palatal perforation and saddle nose deformity as presenting features. AB - Late congenital syphilis refers to the people with syphilis from the age of 2 to 30 years. We report a case of late congenital syphilis in a 9 year old girl with perforation of palate and saddle nose deformity. Kassowitz law was also observed (if a woman with untreated syphilis has series of pregnancies, the likelihood of infection of the fetus in later pregnancies becomes less). Venereal Disease Research Laboratory (VDRL) and Treponema pallidum hemagglutination (TPHA) were reactive. Computed tomography (CT) scan of paranasal sinus showed maxillary and nasal polyps. The case reported here is a rare presentation of late congenital syphilis with perforation of palate and saddle nose deformity. PMID- 23919054 TI - Pseudoepitheliomatous keratotic and micaceous balanitis with malignant transformation. AB - Pseudoepitheliomatous, keratotic and micaceous balanitis (PKMB) is a non-venereal and extremely rare pre-malignant condition characterized by silvery white plaque with micaceous scaling on glans seen in elderly uncircumcised men. Symptoms include phimosis, pain, and interference with sexual activity. Herein we present a young, 40-year-old male with PKMB of 5 years duration with deviation of urinary stream and histology showing acanthosis, hyperkeratosis with features of cellular atypia and abnormal mitosis suggestive of malignant transformation. PMID- 23919055 TI - Squamous cell carcinoma of penis with bullous pemphigoid masquerading as lymphogranuloma venereum. AB - We report a case of a 60-year old unmarried male who presented with multiple ulcers and foul smelling discharge from the groin since 4 months and multiple tense bullae over the trunk of 1 month duration. Groove sign was present. Investigations for lymphogranuloma venereum (LGV) and other sexually transmitted diseases were negative. Histopathology from the ulcer in the groin and growth in the penis revealed squamous cell carcinoma (SCC). Skin biopsy of bulla was diagnostic of bullous pemphigoid (BP). We report a rare case of SCC masquerading as LGV with BP occurring as a paraneoplastic phenomenon. PMID- 23919056 TI - Perianal pseudoverrucous papules and nodules. AB - Perianal pseudoverrucous papules and nodules (PPPN) is a rare entity attributed to chronic irritation. We came across this entity in a case of spina bifida. A 14 year old girl having spina bifida at L3 presented with complaints of multiple asymptomatic whitish lesions on the inner aspect of thighs and labia majora since early childhood. She had incontinence of stool and urine since birth. Cutaneous examination revealed multiple 3-12 mm flat topped moist papules, few verrucous nodules, some of these lesions coalesced to form plaques at the perianal area extending upto the labia majora. On histology marked epidermal hyperplasia and pale keratinocytes in the epidermis was seen. This confirmed the diagnosis of PPPN. This rare condition can be mistaken with sexually transmitted diseases leading to unnecessary investigations and treatment. PMID- 23919057 TI - Late onset Warfarin induced skin necrosis in human immunodeficiency virus infected patient with pulmonary tuberculosis. AB - The incidence of Warfarin-induced skin necrosis (WISN) is very low 0.01-0.10%. The majority of the WISN cases appear between day 3 and 6 of onset of Warfarin therapy. The cases of late onset WISN are rarely seen. We report a case of late onset WISN in a young human immunodeficiency virus positive female patient with thrombotic pulmonary embolism and reactivation of pulmonary tuberculosis. PMID- 23919058 TI - Congenital syphilis, still a reality. AB - Congenital syphilis is a potentially serious pathology affecting newborns of infected mothers. Even one case of congenital syphilis is a sentinel public health event, since timely diagnosis and treatment of syphilis infected pregnant woman should prevent transmission almost entirely. Here, we are reporting a case of early symptomatic congenital syphilis presented with severe desquamating papulosquamous lesions over multiple body parts along with erosive lesions around oral cavity and nostrils. PMID- 23919059 TI - Assessment of oral health status and Treatment needs of HIV/AIDS patients visiting Government Hospitals and Rehabilitation centers in Banglore city. PMID- 23919060 TI - Father to child transmission of human immunodeficiency virus disease while sero discordant status of the mother is maintained. PMID- 23919061 TI - Nine years' follow-up of successful implementation of PPTCT program in Government Medical College, Dhule, Maharashtra. PMID- 23919062 TI - Behcet's disease simulating secondary syphilis in an HIV-infected patient. PMID- 23919063 TI - Genital tract infection of women in Southern Orissa with special reference to pelvic inflammatory disease. PMID- 23919064 TI - Assessing the preparedness of the community for rendering home-based care for HIV/AIDS patients by a using a qualitative tool. PMID- 23919065 TI - The role of fluorodeoxyglucose positron emission tomography-computerized tomography in resolving therapeutic dilemmas in pediatric Hodgkin lymphoma. AB - INTRODUCTION: Hodgkin lymphoma (HL) is a highly curable lymphoma with cure rates of over 80% and even higher with limited stage disease. Computerized tomography (CT) scan is currently the recommended modality in staging and assessment of response to therapy in patients with HL. However, CT has its limitations. This study describes our experience with patients of HL where fluorodeoxyglucose positron emission tomography (FDG-PET)-CT scan helped decide further management, after completion of chemotherapy. METHODOLOGY: This is a retrospective review of the records of children diagnosed with HL at our center. Patients with post treatment CT scan showing evidence of residual disease, who underwent FDG-PET-CT for deciding further management, were included in the study. RESULTS: Thirty one patients were diagnosed with HL during this period. Nine patients were eligible and underwent PET-CT. In 8 out of 9 patients, PET-CT showed no scan evidence of active disease. In one patient, FDG-PET-CT carried out after completion of chemotherapy showed evidence of active disease and was given radiotherapy. CONCLUSION: FDG-PET-CT is a promising modality in deciding further management when there is discordance between the post-treatment CT scan and clinical condition of the patient with HL thus avoiding unnecessary chemotherapy/radiotherapy. PMID- 23919066 TI - Detecting primary bladder cancer using delayed (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography imaging after forced diuresis. AB - OBJECTIVE: The aim of this study was to evaluate the use of delayed pelvic (18)F 2-fluoro-2-deoxy-D-glucose-positron emission tomography combined with the computed tomography (FDG-PET/CT) imaging, according to a standardized protocol including, pre-hydration and forced diuresis, for the detection of primary bladder cancer. MATERIALS AND METHODS: We evaluated 38 consecutive patients with primary cT1-4 bladder cancer. They underwent standard FDG-PET/CT followed by delayed pelvic imaging after administration of 20 mg furosemide intravenously and extra oral water intake of 0.5 L. Two observers, blinded for patient data, scored both image sets for tumor visibility using a 3-point ordinal scale: (1) negative; (2) indeterminate; (3) positive. FDG-PET/CT findings were compared with histopathology and/or follow-up imaging. RESULTS: The procedure was completed successfully in 37/38 patients and the reference standard revealed a bladder tumor in 26/37 patients. Delayed PET/CT images showed reduction of urinary bladder activity to (near) background levels in 17 of 37 cases (45.9%). Standard PET/CT detected hyper-metabolic bladder lesions in 15/37 patients (40.5%) of which 8 were indeterminate. Delayed FDG-PET/CT showed hyper-metabolic bladder lesions in 30/37 (81.1%) patients, of which 5 were indeterminate. When indeterminate lesions were considered positive, the sensitivity of standard and delayed PET/CT was 46% versus 88%, respectively. The specificity was 72% versus 36%. When indeterminate lesions were considered negative, the sensitivity of standard and delayed PET/CT was 23% and 85%. The specificity was 93% versus 73%. CONCLUSIONS: Our data suggest that delayed pelvic FDG-PET/CT imaging after forced detects more primary bladder tumors than standard FDG-PET/CT protocols. However, indeterminate bladder lesions on delayed PET/CT remain a problem and should be interpreted cautiously in order to avoid false positive results. PMID- 23919067 TI - Utility of negative oral contrast (milk with 4% fat) in PET-CT studies. AB - AIMS: The aim of this study was to evaluate whether low-attenuation oral contrast agent (milk with 4% fat) in PET-CT gastrointestinal studies(GIT) improves the diagnostic accuracy. JUSTIFICATION FOR THE STUDY: Traditional high-contrast oral agents like iodine solutions, and barium suspensions which due to overcorrection problems in PET-CT interpretation lowers the accuracy of diagnosis. Traditional low-attenuation oral contrast agents are water, air, fat containing agents used with 12.5% corn oil and polyethylene glycol. Volumen is a 0.1% barium suspension and has found favor in visualization of mural features as well as for GIT distension. Milk with 4% fat content has also been tested out in radiological studies and found to be as effective as Volumen. As the former is more easily available, palatable, and acceptable especially, by children it needed to be tested in the visualization of the GIT in the PET-CT scenario. MATERIALS AND METHODS: Total of 112 patients were divided into 3 groups. Group I: No intervention (18 subjects) Group II: Water (55 subjects): All these patients had 500-750 ml of water 5-10 min before PET examination. Group III: Milk (39 subjects) 500 ml of milk (4% fat content with no additives) was given 40-45 min after 18F-Fluorodeoxyglucose (FDG) injection and another 500 ml 5 min before scan was started. For patients intolerant to milk the same procedure was carried out with soya milk. Group IV comparison with data with Volumen. RESULTS: CRITERIA FOR EVALUATION OF GUT DISTENSION ON CT IMAGES: (0) No distension, (1) 1 cm distension, (2) 1-2 cm distension, (3) >2 cm distension. For the study analysis, % of patients with criteria 2 and 3 were considered as good visualization. Stomach distension was16%, 47%, 88%, 75% in Gr1-4 respectively, Duodenum-11%, 27% 88%, 86%, Jejunum-33%, 49%, 89%, 76%(*) Ileum-40%, 77%, 82%, 80%(*) and Colon 55%, 58%, 7 4%. Visualization of bowel wall with enhancement of stomach, duodenum, jejunum, and ileum and proximal colon was significantly better with milk than with water or no intervention. Intensity of FDG uptake was mild to moderate with no overcorrection in normal bowel loops and in patients with GIT lesions. Gaseous distension was not increased with milk as an oral contrast agent. Images of patients with bowel tumor was well-delineated with milk administration as the FDG uptake ratio of tumor to gut was high. CONCLUSION: Distension and visualization of the stomach, duodenum, jejunum, and proximal bowel was significantly improved with milk as a low-attenuation contrast agent. Intensity of FDG uptake was not significantly increased in normal gut and delineation of tumor with increased FDG uptake was improved as overcorrection was minimal. PMID- 23919068 TI - Utility of single photon emission computed tomography/computed tomography imaging in evaluation of chronic low back pain. AB - INTRODUCTION: Abnormal morphologic findings in imaging were thought to explain the etiology of low back pain (LBP). However, it is now known that variety of morphologic abnormalities is noted even in asymptomatic individuals. Single photon emission computed tomography/computed tomography (SPECT/CT) could be used to differentiate incidental findings from clinically significant findings. OBJECTIVE: This study was performed to define the SPECT/CT patterns in patients with LBP and to correlate these with clinical and magnetic resonance imaging (MRI) findings. MATERIALS AND METHODS: Thirty adult patients with LBP of duration 3 months or more were prospectively evaluated in this study. Patients with known or suspected malignancy, trauma or infectious processes were excluded. A detailed history of sensory and motor symptoms and neurologic examination was performed. All the patients were subjected to MRI and bone scintigraphy with hybrid SPECT/CT of the lumbo-sacral spine within 1 month of each other. The patients were classified into those with and without neurologic symptoms, activity limitation. The findings of clinical examination and imaging were compared. MRI and SPECT/CT findings were also compared. RESULTS: Thirty patients (18 men and 12 women; mean age 38 years; range 17-64 years) were eligible for the study. Clinically, 14 of 30 (46%) had neurologic signs and or symptoms. Six of the 30 patients (20%) had positive straight leg raising test (SLRT). Twenty-two of the 30 patients (73%) had SPECT abnormality. Most frequent SPECT/CT abnormality was tracer uptake in the anterior part of vertebral body with osteophytes/sclerotic changes. Significant positive agreement was noted between this finding and MRI evidence of degenerative disc disease. Only 13% of patients had more than one abnormality in SPECT. All 30 patients had MRI abnormalities. The most frequent abnormality was degenerative disc disease and facet joint arthropathy. MRI showed single intervertebral disc abnormality in 36% of the patients and more than one intervertebral disc abnormality in remaining 64% patients. Fifteen of the 30 patients had facet joint arthropathy. 60% of these patients had involvement of more than one level facet joints while 38% had associated inter vertebral disc disease. 83% of the patients with positive SLRT had SPECT and MRI abnormalities. 100% of patients with neurologic symptoms had SPECT and MRI abnormalities. CONCLUSION: Addition of hybrid SPECT/CT data will help differentiate incidental from significant MRI abnormalities as all patients with LBP have MRI abnormalities and most have MRI abnormalities at multiple sites. Tracer uptake in the anterior part of the vertebral body represents degenerative disc disease. MRI is sensitive and SPECT/CT is specific for facet joint arthropathy. Both investigations are best used complementary to each other. PMID- 23919069 TI - Diagnosis of bone infection by complementary role of technetium-99m MDP and technetium-99m hexamethylpropylene-amineoxime-leukocytes. AB - PURPOSE: Valuate complementary role of (99m)Tc-MDP bone scan and (99m)Technetium hexamethylpropylene-amineoxime ((99m)Tc-HMPAO) labeled leukocyte scintigraphy in diagnosis of bone infection. PATIENTS AND METHODS: NINETY ONE SITES SUSPECTED TO HAVE BONE INFECTION WERE DIVIDED IN TO TWO GROUPS: Group I 49 sites with current endo-prothesis; and group II 42 sites with no prosthesis. All patients were subjected to serial images of (99m)Tc-HMPAO labeled leukocyte ((99m)Tc-white blood cells (WBCs)), triple phase bone scan ((99m)Tc-MDP) and plain X-ray, in addition to clinical and bacteriological assessment, together with follow-up. RESULTS: The overall sensitivity (Sn) was found to be 34.9%, 95.4%, and 86% for plain X-ray, (99m)Tc-MDP, and (99m)Tc-WBCs respectively. Concerning specificity (Sp) was found to be 47.9%, 45.8%, and 91.7% respectively for the three imaging modalities. (99m)Tc-WBCs showed better Sn, Sp, and accuracy in group I (95%, 93.1% and 93.9%, respectively) compared to 40%, 41.4%, and 40.8% for plain X-ray and 90%, 62%, and 73.5% respectively for (99m)Tc-MDP. On the other hand, (99m)Tc MDP proved to have best Sn 100% versus 78.3% and 30.4% for (99m)Tc-WBCs and plain X-ray respectively. Yet, Sp and accuracy was found to best for (99m)Tc-WBCs (89.5% and 83.3% respectively) compared to 57.9% and 42.9% for plain X-ray and 21.1% and 64.3% for (99m)Tc-MDP. CONCLUSION: Combined imaging with (99m)Tc-WBCs and (99m)Tc-MDP proved to be effective in early detection of bone infection in the presence or absence of prosthesis. PMID- 23919070 TI - Higher events rate in patients with a normal gated myocardial perfusion imaging with dipyridamole than exercise: "Run for reliability". AB - OBJECTIVE: The aim of this is to evaluate the negative predictive value (NPV) of a normal gated myocardial perfusion imaging (NGMPI) with exercise and dipyridamole in a propensity matched population. MATERIALS AND METHODS: This is a prospective study conducted at Nuclear Cardiology Department of Karachi Institute of Heart Diseases, Karachi from December 2008 until June 2010. A total of 809 patients with a NGMPI with adequate exercise (558/809) or dipyridamole (251/809) stress were included and followed-up for 12-30 months (mean 24 +/- 3 months) for fatal or non-fatal myocardial infarctions (MI). RESULTS: Mean ejection fraction (%), end diastolic volume (ml), and end systolic volume (ml) in exercise and dipyridamole cohorts were (72 +/- 08, 66 +/- 11), (68 +/- 13, 81 +/- 17), and (19 +/- 11, 26 +/- 12) respectively. On follow-up, in dipyridamole cohort 2 fatal and 6 non-fatal MIs were reported. While in exercise cohort only 2 non-fatal MIs were reported. The NPV of a NGMPI with exercise was 99.7% (95% confidence interval [CI] 98.93-99.96%) with an event rate of 0.3% (95% CI; 0.03-0.6%) and annualized event rate of 0.15%. The NPV of NGMPI with dipyridamole was 96.80% (95% CI; 2.2 4.3%) with an event rate of 3.2% (95% CI; 1.39-3.83%) and annualized event rate of approximately 1.6%. Event free survival for dipyridamole group was significantly lower than exercise analyzed by Log-rank test (14.509, P < 0.001). CONCLUSION: A NGMPI with dipyridamole stress has higher event rate (low-NPV) as compared with exercise and this raises concern over its credibility to label these patients into low-risk group. PMID- 23919071 TI - A comparison of deconvolution and the Rutland-Patlak plot in parenchymal renal uptake rate. AB - INTRODUCTION: Deconvolution and the Rutland-Patlak (R-P) plot are two of the most commonly used methods for analyzing dynamic radionuclide renography. Both methods allow estimation of absolute and relative renal uptake of radiopharmaceutical and of its rate of transit through the kidney. MATERIALS AND METHODS: Seventeen patients (32 kidneys) were referred for further evaluation by renal scanning. All patients were positioned supine with their backs to the scintillation gamma camera, so that the kidneys and the heart are both in the field of view. Approximately 5-7 mCi of (99m)Tc-DTPA (diethylinetriamine penta-acetic acid) in about 0.5 ml of saline is injected intravenously and sequential 20 s frames were acquired, the study on each patient lasts for approximately 20 min. The time activity curves of the parenchymal region of interest of each kidney, as well as the heart were obtained for analysis. The data were then analyzed with deconvolution and the R-P plot. RESULTS: A strong positive association (n = 32; r = 0.83; R (2) = 0.68) was found between the values that obtained by applying the two methods. Bland-Altman statistical analysis demonstrated that ninety seven percent of the values in the study (31 cases from 32 cases, 97% of the cases) were within limits of agreement (mean +/- 1.96 standard deviation). CONCLUSION: We believe that R-P analysis method is expected to be more reproducible than iterative deconvolution method, because the deconvolution technique (the iterative method) relies heavily on the accuracy of the first point analyzed, as any errors are carried forward into the calculations of all the subsequent points, whereas R-P technique is based on an initial analysis of the data by means of the R-P plot, and it can be considered as an alternative technique to find and calculate the renal uptake rate. PMID- 23919072 TI - Unusual presentation of oesophageal carcinoma with adrenal metastasis. AB - Adrenal gland is a common site of metastasis in many cancers but it is very rare in oesophageal carcinoma. We report one such case found to have adrenal metastasis on follow-up PET/computed tomography scan. PMID- 23919073 TI - Hypermetabolic subcutaneous fat in patients on highly active anti-retroviral therapy treatment: Subtle finding with implications. AB - Lipodystrophy (LD) is a serious complication of highly active anti-retroviral therapy, characterized by peripheral fat wasting, central adiposity and metabolic changes. Since the disfiguration caused by LD is permanent, the focus of management is on early detection to arrest progression. We report a case where ancillary finding of increased fluorine-18 fluoro-2-deoxyglucose (F-18 FDG) uptake in the sub-cutaneous fat helped early detection of LD and led to early intervention to arrest progression. Though F-18 FDG positron emission tomography/computed tomography scan is not recommended to diagnose LD, conscious reporting of this finding when present can greatly influence patient management. PMID- 23919074 TI - Primary extradural non-hodgkin's lymphoma. AB - A 67-year-old male presented to our institute with history of paraparesis with decreased sensation and loss of bladder and bowel control. The diagnostic work up revealed an extradural mass at spinal level D7-D12. He had laminectomy and the tumor was sub totally resected. Histological examination revealed non-hodgkin's lymphoma (NHL). The patient was worked up for disease anywhere else in the body and was confirmed to have primary extradural non-hodgkin's lymphoma. PMID- 23919075 TI - Diffusely increased thyroidal uptake of F-18 fluorodeoxyglucose in a patient with non-Hodgkin's lymphoma and Graves' disease. AB - Increased uptake of F-18 fluorodeoxyglucose (FDG) has been reported in thyroiditis and hypothyroidism. The authors present a case where increased FDG uptake in the thyroid was subsequently corroborated with a pertechnetate scan and thyroid hormone levels to diagnose previously undetected Graves' disease in a patient of non-Hodgkin's lymphoma being followed-up with positron emission tomography for disease recurrence. PMID- 23919076 TI - Disseminated metastatic penile squamous cell carcinoma detected by fluorodeoxyglucose PET/computerized tomography. AB - Penile cancer is an uncommon malignancy which of the management depends on the clinical stage and location of the lesion. Positron emission tomography/computerized tomography (PET/CT) is a promising method for detection of distant metastatic lesions and therapeutic strategy planning. Here, we report a case of penile squamous cell carcinoma of 57-year-old male patient, was referred to PET/CT department for investigation of metastases. There were significantly increased fluoro-18 fluorodeoxyglucose activities in supradiaphragmatic and infradiaphragmatic lymphatic stations. PMID- 23919077 TI - Post re-anastomosis demonstration of regain in function in non-visualized upper half of kidney in a dual arterial allogenic renal graft on renal scintigraphy. AB - A young male patient with end stage renal disease underwent renal allograft having dual arterial supply. Immediate post-operative urine output dropped, an urgent Technetium-99m-mercaptoacetyltriglycine ((99m)Tc-MAG3) renogram revealed non-visualized upper-half and the preserved perfusion and parenchymal function of the small transplant kidney. Patient was re-explored and re-anastomosis was performed. A renogram at 24h post re-anastomosis revealed increase in the size of renal allograft, with preserved perfusion to the upper-half of transplant. Transplant kidney biopsy of the Upper-half showed acute tubular necrosis. 99mTc MAG3renogram at 10 days post re-vascularization remains unchanged with persistent improvement at 2 months follow-up. We conclude that early recognition of renal functional loss allows early management and the high probability of salvaging the renal function. PMID- 23919078 TI - Promising role of single photon emission computed tomography/computed tomography in Meckel's scan. AB - Meckel's scan is a common procedure performed in nuclear medicine. Single-photon emission computed tomography/computed tomography (SPECT/CT) in a suspected case of heterotopic location of gastric mucosa can increase the accuracy of its anatomic localization. We present two suspected cases of Meckel's diverticulum in, which SPECT/CT co-registration has helped in better localization of the pathology. PMID- 23919079 TI - Sacrococcygeal chordoma: Increased (99m)Tc methylene diphosphonate uptake on single photon emission computed tomography/computed tomography bone scintigraphy. AB - Chordoma is a malignant tumor arising from the remnants of the notochord, and is the most frequent primitive tumor of the sacrum. While most sacral tumors show increased concentration of bone-seeking radiopharmaceuticals, chordomas usually exhibit decreased uptake. The authors present an image of a sacrococcygeal chordoma with osteolysis and increased uptake of 99mTc methylene diphosphonate on planar and single photon emission computed tomography/computed tomography bone scintigraphy. PMID- 23919080 TI - Touraine-Solente-Gole syndrome: The complete form needs to be recognized. AB - The primary hypertrophic osteoarthropathy (HOA) (pachydermoperiostosis) is a rare hereditary disease characterized by skin manifestations (pachydermia), digital clubbing and proliferation of periosteum (periostitis) with sub-periosteal new bone formation. We describe here a case who presented with seborrheic dermatitis and joint pain of both hands on work up matched satisfactorily with the complete form of primary HOA. The identification of secondary form being relatively common among clinicians and hence the importance of recognizing the primary form, which is a difficult to treat condition is discussed here. PMID- 23919081 TI - Non-osseous uptake on Tc99m methylene diphosphonate in multiple muscles confirmed on SPECT/computed tomography. AB - A 55-year-old female presented with complaints of pain in the left hip radiating to the left lower limb since 1 year. Computed tomography (CT) abdomen and pelvis revealed bony destruction of pubic symphysis with associated soft tissue component suspicious of infective or metastatic etiology. Magnetic resonance imaging Lumbo-sacral spine performed later revealed altered bone marrow signal in sacral 1-3 vertebrae. Wholebody bone scan with 25 mCi of Tc-99m methylene diphosphonate (MDP) was performed, which revealed multiple skeletal metastases and extraosseous soft tissue uptake was seen involving multiple muscles. We performed single photon emission tomography single photon emission computed tomography (SPECT)/computed tomography (CT) images to precisely delineate the muscle involved and noted calcification on CT images in one of the muscle at site of Tc-99m MDP uptake, no definite calcification was noted in the other muscles. Thus, the final diagnosis was multiple skeletal metastasis with metastatic calcification in multiple muscle from an unknown primary. PMID- 23919082 TI - Lymphoscintigraphy with single-photon emission computed tomography/computed tomography is useful for determining the site of chyle leakage after esophagectomy. AB - We describe the case of chylothorax after esophagectomy for esophageal carcinoma. Lymphoscintigraphy with Tc-99m-human serum albumin-diethylenetriaminepentaacetic acid showed an abnormal radioisotope accumulation on the left side of the thoracic duct. Single-photon emission computed tomography (SPECT) combined with computed tomography (CT) revealed a hot spot directly on the site at, which the thoracic duct was ligated during surgery, which was the suggested site of chyle leakage. We emphasize that lymphoscintigraphy with SPECT/CT is very useful tool for accurately identifying the site of the chyle leakage. PMID- 23919083 TI - Fluorine-18 fluoro-2-deoxyglucose positron emission tomography/computed tomography in a case of suspected primary pericardial mesothelioma. PMID- 23919084 TI - Single photon emission computed tomography in detection of anterior cruciate ligament tear. PMID- 23919085 TI - SARP: A Novel Algorithm to Assess Compositional Biases in Protein Sequences. AB - The composition of a defined set of subunits (nucleotides, amino acids) is one of the key features of biological sequences. Compositional biases are local shifts in amino acid or nucleotide frequencies that can occur as an adaptation of an organism to an extreme ecological niche, or as the signature of a specific function or localization of the corresponding protein. The calculation of probability is a method for annotating compositional bias and providing accurate detection of biased subsequences. Here, we present a Sequence Analysis based on the Ranking of Probabilities (SARP), a novel algorithm for the annotation of compositional biases based on ranking subsequences by their probabilities. SARP provides the same accuracy as the previously published Lower Probability Subsequences (LPS) algorithm but performs at an approximately 230-fold faster rate. It can be recommended for use when working with large datasets to reduce the time and resources required. PMID- 23919086 TI - Effect of microemulsions on transdermal delivery of citalopram: optimization studies using mixture design and response surface methodology. AB - The aim of this study was to evaluate the potential of microemulsions as a drug vehicle for transdermal delivery of citalopram. A computerized statistical technique of response surface methodology with mixture design was used to investigate and optimize the influence of the formulation compositions including a mixture of Brij 30/Brij 35 surfactants (at a ratio of 4:1, 20%-30%), isopropyl alcohol (20%-30%), and distilled water (40%-50%) on the properties of the drug loaded microemulsions, including permeation rate (flux) and lag time. When microemulsions were used as a vehicle, the drug permeation rate increased significantly and the lag time shortened significantly when compared with the aqueous control of 40% isopropyl alcohol solution containing 3% citalopram, demonstrating that microemulsions are a promising vehicle for transdermal application. With regard to the pharmacokinetic parameters of citalopram, the flux required for the transdermal delivery system was about 1280 MUg per hour. The microemulsions loaded with citalopram 3% and 10% showed respective flux rates of 179.6 MUg/cm(2) and 513.8 MUg/cm(2) per hour, indicating that the study formulation could provide effective therapeutic concentrations over a practical application area. The animal study showed that the optimized formulation (F15) containing 3% citalopram with an application area of 3.46 cm(2) is able to reach a minimum effective therapeutic concentration with no erythematous reaction. PMID- 23919087 TI - Visual perception of axes of head rotation. AB - Registration of ego-motion is important to accurately navigate through space. Movements of the head and eye relative to space are registered through the vestibular system and optical flow, respectively. Here, we address three questions concerning the visual registration of self-rotation. (1) Eye-in-head movements provide a link between the motion signals received by sensors in the moving eye and sensors in the moving head. How are these signals combined into an ego-rotation percept? We combined optic flow of simulated forward and rotational motion of the eye with different levels of eye-in-head rotation for a stationary head. We dissociated simulated gaze rotation and head rotation by different levels of eye-in-head pursuit. We found that perceived rotation matches simulated head- not gaze-rotation. This rejects a model for perceived self-rotation that relies on the rotation of the gaze line. Rather, eye-in-head signals serve to transform the optic flow's rotation information, that specifies rotation of the scene relative to the eye, into a rotation relative to the head. This suggests that transformed visual self-rotation signals may combine with vestibular signals. (2) Do transformed visual self-rotation signals reflect the arrangement of the semi-circular canals (SCC)? Previously, we found sub-regions within MST and V6(+) that respond to the speed of the simulated head rotation. Here, we re analyzed those Blood oxygenated level-dependent (BOLD) signals for the presence of a spatial dissociation related to the axes of visually simulated head rotation, such as have been found in sub-cortical regions of various animals. Contrary, we found a rather uniform BOLD response to simulated rotation along the three SCC axes. (3) We investigated if subject's sensitivity to the direction of the head rotation axis shows SCC axes specifcity. We found that sensitivity to head rotation is rather uniformly distributed, suggesting that in human cortex, visuo-vestibular integration is not arranged into the SCC frame. PMID- 23919088 TI - A fast statistical significance test for baseline correction and comparative analysis in phase locking. AB - Human perception, cognition, and action are supported by a complex network of interconnected brain regions. There is an increasing interest in measuring and characterizing these networks as a function of time and frequency, and inter areal phase locking is often used to reveal these networks. This measure assesses the consistency of phase angles between the electrophysiological activity in two areas at a specific time and frequency. Non-invasively, the signals from which phase locking is computed can be measured with magnetoencephalography (MEG) and electroencephalography (EEG). However, due to the lack of spatial specificity of reconstructed source signals in MEG and EEG, inter-areal phase locking may be confounded by false positives resulting from crosstalk. Traditional phase locking estimates assume that no phase locking exists when the distribution of phase angles is uniform. However, this conjecture is not true when crosstalk is present. We propose a novel method to improve the reliability of the phase locking measure by sampling phase angles from a baseline, such as from a prestimulus period or from resting-state data, and by contrasting this distribution against one observed during the time period of interest. PMID- 23919089 TI - Presence of glucose, xylose, and glycerol fermenting bacteria in the deep biosphere of the former Homestake gold mine, South Dakota. AB - Eight fermentative bacterial strains were isolated from mixed enrichment cultures of a composite soil sample collected at 1.34 km depth from the former Homestake gold mine in Lead, SD, USA. Phylogenetic analysis of their 16S rRNA gene sequences revealed that these isolates were affiliated with the phylum Firmicutes belonging to genera Bacillus and Clostridium. Batch fermentation studies demonstrated that isolates had the ability to ferment glucose, xylose, or glycerol to industrially valuable products such as ethanol and 1,3-propanediol (PDO). Ethanol was detected as the major fermentation end product in glucose fermenting cultures at pH 10 with yields of 0.205-0.304 g of ethanol/g of glucose. While a xylose-fermenting strain yielded 0.189 g of ethanol/g of xylose and 0.585 g of acetic acid/g of xylose at the end of fermentation. At pH 7, glycerol-fermenting isolates produced PDO (0.323-0.458 g of PDO/g of glycerol) and ethanol (0.284-0.350 g of ethanol/g of glycerol) as major end products while acetic acid and succinic acid were identified as minor by-products in fermentation broths. These results suggest that the deep biosphere of the former Homestake gold mine harbors bacterial strains which could be used in bio-based production of ethanol and PDO. PMID- 23919090 TI - Effects of redox state on the efficient uptake of cell permeable Peptide in Mammalian cells. AB - We investigated whether a cell-penetrating peptide linked via a disulfide bond to a fluorophore-labeled cargo peptide can be used to interrogate changes in cellular redox state. A fluorescence resonance energy transfer (FRET) pair was constructed so that the cargo peptide was labeled with fluorescein amidite (FAM) and the cell-penetrating peptide was attached to a quencher. Incubation of cells in culture with the FRET construct was visualized using live-cell, time-lapse imaging, which demonstrated earlier cellular uptake of the construct when cells were treated with the reducing agent n-acetylcysteine (NAC). The FRET peptide construct was easily detected in cells cultured in 96-well plates using a plate reader. Treatment of cells with various classes of reducing or oxidizing agents resulted in an increase or decrease in FAM fluorescence, respectively. Changes in FAM fluorescence correlated significantly with redox-sensitive green fluorescent protein ratios in cells treated with hydrogen peroxide but not NAC. Detection of relative changes in cellular redox state was enhanced by the fact that uptake of the cell-penetrating peptide occurred more quickly in relatively reduced compared with oxidized cells. We conclude that cell-penetrating peptides coupled via disulfide bonds to detectable cargo is a novel and specific approach for assessment of relative changes in cellular thiol redox state. PMID- 23919091 TI - Discrimination of Enterobacteriaceae and Non-fermenting Gram Negative Bacilli by MALDI-TOF Mass Spectrometry. AB - Discrimination of Enterobacteriaceae and Non-fermenting Gram Negative Bacilli by MALDI-TOF Mass Spectrometry Matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) has proven to be an effective identification tool in medical microbiology. Discrimination to subspecies or serovar level has been found to be challenging using commercially available identification software. By forming our own reference database and using alternative analysis methods, we could reliably identify all implemented Enterobacteriaceae and non-fermenting gram negative bacilli by MALDI-TOF MS and even succeeded to distinguish Shigella sonnei from Escherichia coli (E. coli) and Salmonella enterica spp. enterica serovar Enteritidis from Salmonella enterica spp. enterica serovar Typhimurium. Furthermore, the method showed the ability to separate Enterohemorrhagic E. coli (EHEC) and Enteropathogenic E. coli (EPEC) from non-enteropathogenic E. coli. PMID- 23919092 TI - The Efficacy of Continuous Versus Intermittent Celecoxib Treatment in Osteoarthritis Patients with Body Mass Index >=30 and <30 kg/m(2.). AB - OBJECTIVE: Characterize the effect of body mass index (BMI) on the efficacy of continuous daily celecoxib treatment compared with intermittent celecoxib treatment. METHODS: Prespecified exploratory analysis of a 24-week, double-blind, parallel-group, randomized, multicenter international study. 858 patients with knee or hip osteoarthritis (OA) were randomized to receive celecoxib 200 mg daily either as continuous or intermittent treatment. Efficacy was measured by Western Ontario and McMaster Universities Arthritis Index (WOMAC) total and subscale scores and the number of flare events. RESULTS: Least squares mean increases (worsening) in WOMAC total scores were significantly less in the continuous treatment group than in the intermittent treatment group in patients with a BMI <30 kg/m(2) (1.33 vs 4.85; p=0.016) and in patients with a BMI >=30 kg/m(2) (1.84 vs 5.12; p=0.019). There was a greater worsening in patients with a BMI >=30 kg/m(2) than in those with a BMI <30 kg/m(2) in both the continuous and intermittent groups. Fewer flares were reported in the continuous treatment group than in the intermittent group in patients with a BMI <30 kg/m(2) (0.55 vs 0.88; p<0.0001) and >=30 kg/m(2) (0.54 vs 0.97; p<0.0001). There were no differences in adverse events in the two BMI groups. CONCLUSIONS: Continuous celecoxib treatment was significantly more efficacious than intermittent use in patients with a BMI <30 kg/m(2) compared with obese patients (>=30 kg/m(2)) as assessed by WOMAC total scores and the number of flares. These data suggest that including weight loss as part of a treatment regimen for obese OA patients could be important. PMID- 23919093 TI - Intra-articular hyaluronic Acid as treatment in elderly and middle-aged patients with knee osteoarthritis. AB - INTRODUCTION: Osteoarthritis is the most common age-related degenerative joint disease. It affects all the joints containing hyaline cartilage. Knee osteoarthritis is the most cumbersome in terms of prevalence and disability. The aim of this study to evaluate the efficacy of intra-articular hyaluronic acid in patients with knee osteoarthritis with regard to joint pain and function, as well as patient satisfaction, assessed at one month and at one year, and by age group. METHODS: In this prospective randomised study, 172 patients who were diagnosed knee OA and who received three consecutive intra-articular injections of HA weekly were included. Patients 65 years of age or older were accepted as the "elderly group", and those under 65 were accepted as the "middle-aged group". Clinical evaluations of efficacy and safety were conducted at the beginning of the study, one month after the third injection, and one year after the third injection. RESULTS: In the two groups, the intragroup analysis revealed significant improvements following injection when compared with preinjection values. According to the last followup controls (after 12 months) in the middle aged group, VAS activity pain, VAS rest pain, WOMAC physical function, and WOMAC pain values were found to be statistically lower when compared with pre-injection values. In the elderly group, no statistically significant differences were found between pre-injection and after 12 months. CONCLUSION: We can conclude that intra articular joint HA injections are effective in both young and old patients with OA with regard to pain and functional status over a short-term period. Further, HA injections in patients younger than 65 years can be planned for a one-year period. PMID- 23919094 TI - Acute infection in total knee arthroplasty: diagnosis and treatment. AB - Infection is one of the most serious complications after total knee arthroplasty (TKA). The current incidence of prosthetic knee infection is 1-3%, depending on the series(.) For treatment and control to be more cost effective, multidisciplinary groups made up of professionals from different specialities who can work together to eradicate these kinds of infections need to be assembled. About the microbiology, Staphylococcus aureus and coagulase-negative staphylococcus were among the most frequent microorganisms involved (74%). Anamnesis and clinical examination are of primary importance in order to determine whether the problem may point to a possible acute septic complication. The first diagnosis may then be supported by increased CRP and ESR levels. The surgical treatment for a chronic prosthetic knee infection has been perfectly defined and standardized, and consists in a two-stage implant revision process. In contrast, the treatment for acute prosthetic knee infection is currently under debate. Considering the different surgical techniques that already exist, surgical debridement with conservation of the prosthesis and polythene revision appears to be an attractive option for both surgeon and patient, as it is less aggressive than the two-stage revision process and has lower initial costs. The different results obtained from this technique, along with prognosis factors and conclusions to keep in mind when it is indicated for an acute prosthetic infection, whether post-operative or haematogenous, will be analysed by the authors. PMID- 23919095 TI - Is there still a place for continuous closed irrigation in the management of periprosthetic total knee infection? AB - In recent decades, many technical improvements have been achieved in the use of prosthetic joints, and the risk of infection has been greatly reduced, to current rates of 0.4-2.0% following primary knee replacement. However, the increasing rate of joint replacements being performed means that the absolute number of such infections remains significant and poses substantial costs to healthcare systems worldwide. Accordingly, further strategies to treat and prevent total joint infections should be investigated. Infections following knee replacements can compromise the function and durability of arthroplasty. When these infections occur during the immediate postoperative period, irrigation and debridement with component retention can be attempted to salvage the implant. This is an attractive, cheap, low-morbidity treatment for periprosthetic knee infection. However, the results published regarding this procedure are uneven; some studies report the eradication of prosthetic joint infection by debridement alone in 70 90% of cases but conversely, others have reported a high failure rate for this procedure, averaging 68% (61-82%). The difference could be attributed in part to the multiplicity of variables that may influence the success of the procedure. One such is that of treatment with a continuous irrigation system, which has the theoretical advantage of enabling the administration of antimicrobial agents, as well as the drainage of debris and blood clots. The objective of this study is to elucidate the overall efficacy of irrigation and debridement with prosthesis retention in infected total knee arthroplasty and to determine whether the addition of a continuous irrigation system influences this efficacy. PMID- 23919096 TI - Special issues involving periprosthetic infection in immunodeficiency patients. AB - Chronic systemic illnesses such as diabetes mellitus, chronic kidney disease (CKD), liver cirrhosis, neoplasia, etc. have been clearly associated with high rates of SWI. However, the exact mechanisms underlying these observations are still under investigation. Chronic kidney disease (CKD) is a growing problem in our society. Many of these patients will require an arthroplasty and it appears that the prosthetic infection risk for these types of patients is much higher than in the normal population. The risk of complications due to infection seems to be lower in patients with kidney transplants than in patients undergoing haemodialysis. Both prophylaxis and treatment of infection in patients with CKD should be carried out with a strict monitoring of potentially nephrotoxic antibiotics. The literature on the prognosis and risk of infection in patients with haematopoietic stem cell transplant is scarce and occasionally contradictory. The optimal time for the surgery should be determined by taking into account the immunological state of the patient and should be avoided, as much as possible, during the first year after the HSCT. Child's classification system is the most widely used method of stratifying the surgical risk for patients with cirrhosis; the infection appeared to be associated in a statistically significant way with advanced age and a Child B pre-operative classification. The prevention of prosthetic joint infections in HIV-infected patients should not be significantly different from the prevention for any other patient. Those patients that receive adequate antiretroviral treatment and periodic laboratory control show infection rates and periprosthetic complications that are similar to those for patients not affected by HIV. Therefore, the patient's level of immunodeficiency is the most important prognostic factor for prosthetic infection. The particular immunological condition of these patients can lead to infections due to particular microorganisms that immunocompetent patients do not have to deal with. Of all possibilities, because of their frequency and difficulty to treat, infections caused by methicillin-resistant S. aureus and fungus are highlighted. PMID- 23919097 TI - Management of infection after intramedullary nailing of long bone fractures: treatment protocols and outcomes. AB - Implant related sepsis is a relatively unusual complication of intra-medullary nail fixation of long bone fractures. Depending on the extent of infection, timing of diagnosis and progress of fracture union, different treatment strategies have been developed. The aim of this review article is to collect and analyze the existing evidence about the incidence and management of infection following IM nailing of long bone fractures and to recommend treatment algorithms that could be valuable in everyday clinical practice. After searching the P u b M e d /Medline databases, 1270 articles were found related to the topic during the last 20 years. The final review included 28 articles that fulfilled the inclusion criteria. Only a few prospective studies exist to report on the management of infection following IM nailing of long-bone fractures. In general, stage I (early) infections only require antibiotic administration with/without debridement. Stage II (delayed) infections can be successfully treated with debridement, IM reaming, antibiotic nails, and administration of antibiotics. Infected non-unions are best treated with exchange nailing, antibiotic administration and when infection has been eradicated with graft implantation if it is needed. Debridement, exchange nailing and systemic administration of antibiotics is the best indication for stage III (late) infections, while stage III infected non-unions can successfully be treated with nail removal and Ilizarov frame, especially when large bone defects exist. PMID- 23919098 TI - Periprosthetic shoulder infection. AB - Shoulder arthroplasty is considered the most effective surgical procedure for endstage shoulder pain from different causes including osteoarthritis, cuff-tear arthropathy, trauma, and tumors. Although uncommon and less frequent than knee or hip periprosthetic infection, periprosthetic shoulder infection represents a devastating complication and, despite treatment, is associated with unsatisfactory results. The most commonly identified microorganisms in periprosthetic shoulder infections are Staphylococcus aureus, coagulase-negative Staphylococci and Propionibacterium acnes. Diagnosis is not always easy and mainly derives from the integration of clinical symptoms, laboratory exams, radiological studies and microbiological swabs. Different options are available for treatment, including antibiotic therapy, lavage and debridement with retention of the prosthesis, one-stage reimplantation, two-stage reimplantation with antibiotic-impregnated cement spacer and resection arthroplasty. The aim of this review is to describe the current knowledge regarding risk factors, etiology, diagnosis and treatment of periprosthetic shoulder infection. PMID- 23919099 TI - Nurses' perceived barriers to and facilitators of research utilization in mainland china: a cross-sectional survey. AB - Despite the drive towards evidence-based practice, the extent to which research evidence is being implemented in nursing practice is unclear, particularly in developing countries. This study was to assess the levels of perceived barriers to and facilitators of research utilization in practice among Chinese nurses and inter-relationships between these barriers and facilitators and their socio demographic characteristics. A cross-sectional, descriptive survey was conducted in 2011 with 743 registered nurses randomly selected from four general hospitals in China. They completed the Barriers to Research Utilization and Facilitators of Research Utilization scales. Correlation tests were used to test the relationships between the nurses' perceived barriers and facilitators, their demographic characteristics and research training and involvement. The Chinese nurses' level of perceived barriers was moderate on average and lower than that in previous research. Among the 10 top-ranked items, six were from the subscale 'Organizational Characteristics'. Their perceived barriers were correlated positively with age and post-registration experience and negatively with research training undertaken. Junior diplomatic nurses reported a significantly higher degree of barriers than those senior ones with postgraduate education. Higher and more diverse barriers to research utilization in practice are perceived by Chinese nurses than those in Western countries and they are associated with a few socio-demographic factors. Future research on these barriers/facilitators and their relationships with occupational and socio-cultural factors in Chinese and other Asian nurses is recommended. PMID- 23919100 TI - A hydrodynamic focusing microchannel based on micro-weir shear lift force. AB - A novel microflow cytometer is proposed in which the particles are focused in the horizontal and vertical directions by means of the Saffman shear lift force generated within a micro-weir microchannel. The proposed device is fabricated on stress-relieved glass substrates and is characterized both numerically and experimentally using fluorescent particles with diameters of 5 MUm and 10 MUm, respectively. The numerical results show that the micro-weir structures confine the particle stream to the center of the microchannel without the need for a shear flow. Moreover, the experimental results show that the particles emerging from the micro-weir microchannel pass through the detection region in a one-by one fashion. The focusing effect of the micro-weir microchannel is quantified by computing the normalized variance of the optical detection signal intensity. It is shown that the focusing performance of the micro-weir structure is equal to 99.76% and 99.57% for the 5-MUm and 10-MUm beads, respectively. Overall, the results presented in this study confirm that the proposed microcytometer enables the reliable sorting and counting of particles with different diameters. PMID- 23919101 TI - Primary amelanotic melanoma of the rectum mimicking adenocarcinoma. AB - PATIENT: Male, 55 FINAL DIAGNOSIS: Melanoma Symptoms: Worsening constipation * tenesmus * weight loss MEDICATION: - Clinical Procedure: Chemoradiation therapy Specialty: Oncology. OBJECTIVE: Challenging differential diagnosis. BACKGROUND: Malignant melanoma is usually readily diagnosed by the presence of melanin granules. Although amelanotic melanoma contains a few melanin granules, it is often difficult to differentiate from non-epithelial malignant tumors. Immunohistochemical staining may be needed to diagnose the condition. CASE REPORT: This report describes a case of amelanotic melanoma of the rectum, which was originally suspected to be an adenocarcinoma, but was subsequently correctly diagnosed by immunohistochemical staining with HMB-45 antibody and by the presence of S-100 protein. A pinkish-red ulceroproliferative growth was located about 7 cm from the anal verge. The patient was treated by laparoscopic low anterior resection. CONCLUSIONS: Very few cases of amelanotic melanoma of rectum have been reported in the literature and there is only limited clinical experience with this disease. It appears to be a highly lethal tumor and may need much more aggressive treatment than that used for carcinoma of the rectum. PMID- 23919102 TI - A near fatal case of pathological skin picking. AB - PATIENT: Female, 51 FINAL DIAGNOSIS: Patological skin picking Symptoms: Aphasia * headache * hemiparesis * incontinence MEDICATION: - Clinical Procedure: - Specialty: Dermatology. OBJECTIVE: Challenging differential diagnosis. BACKGROUND: Pathological skin picking (PSP) disorder is characterized by repetitive and compulsive picking of the skin resulting in tissue damage. PSP has been shown to affect 5.4% of a community sample, 4% of college students, and 2% of patients seen in a dermatology clinic. It can be associated with significant disfigurement. The diagnosis requires obtaining a careful history and high clinical suspicion. CASE REPORT: We report a previously healthy 51-year-old Caucasian female with a history of "acne" who presented with new onset right sided hemiparesis, mild aphasia and an episode of incontinence. She had memory loss of the prior few days. She also complained of a four-day history of intense headaches and dizziness. CT and MRI of the head showed encephalomalacia involving the left frontal and parietal lobes. Further history from the patient revealed that the patient had been picking at her forehead with a sewing needle and later with a long knitting needle. CONCLUSIONS: PSP is a prevalent disorder, which can have potentially serious health consequences. Besides potential disfigurement and scarring, PSP can have significant morbidity and mortality. Early diagnosis and appropriate treatment by clinicians are essential to prevent potentially fatal consequences. PMID- 23919103 TI - "Bath salts" induced severe reversible cardiomyopathy. AB - PATIENT: Male, 27 FINAL DIAGNOSIS: Bath salt induced cardiomyopathy Symptoms: Agitation * fever * pedal edema MEDICATION: Intravenous nor-epinephrine for less than 6 hours Clinical Procedure: - Specialty: Internal medicine * cardiology. OBJECTIVE: Unusual clinical course. BACKGROUND: "Bath salts" is the street name for a group of recently identified and increasingly abused stimulant synthetic cathinones that are associated with multiple systemic effects. We present a case of a patient who developed reversible dilated cardiomyopathy secondary to their use. CASE REPORT: A 27 year old male with no past medical history was brought to emergency department with agitation. He had been inhaling and intravenously injecting "bath salts", containing a mephedrone/Methylenedioxypyrovalerone (MDPV) combination. On presentation, he was tachycardic, hypotensive and febrile. His initial labs showed an elevated white count, creatinine and creatinine phosphokinase levels. His erythrocyte sedimentation rate; C-reactive protein; urinalysis; urine drug screen; Human Immunodeficiency Virus, hepatitis, coxsackie, and influenza serology were normal. EKG showed sinus tachycardia. An echocardiogram was done which showed dilated cardiomyopathy with an ejection fraction (EF) of 15-20% and global hypokinesia. A left heart catheterization was done and was negative for coronary artery disease. At a 20 week follow up, he had stopped abusing bath salts and was asymptomatic. A repeat echocardiogram showed an EF of 52%. COCNLUSIONS: Bath salts (MDPV, mephedrone) are synthetic cathinones with amphetamine/cocaine like properties with potential cardiotoxic effects. Cardiovascular manifestations reported include tachycardia, hypertension, myocardial infarction, arrhythmias and cardiac arrest. "Bath salts" can also cause severe reversible dilated cardiomyopathy. Prior to diagnosis, other causes of cardiomyopathy including ischemic, infectious, familial, immunological, metabolic and cytotoxic may need to be ruled out; as was done in our patient. PMID- 23919104 TI - Hilar cholangiocarcinoma. AB - Hilar cholangiocarcinoma (HC) is a rare tumor. It accounts for 2/3 of the tumors of the biliary tract. Untreated, prognosis is very poor. Surgery is the only therapy that offers the possibility of cure but is technically very complex. With recent improvements in the therapeutic strategies applied by multidisciplinary teams, survival rates in the different series currently range from 25% to 45%. A group of experts devoted to HC (pathologists, gastroenterologists, radiologists, surgeons and oncologists) have reviewed and updated every open question in HC in a special issue. PMID- 23919105 TI - Radiological diagnosis and staging of hilar cholangiocarcinoma. AB - Hilar cholangiocarcinoma is a rare malignant tumor arising from the epithelium of the bile ducts. Surgery is still the only chance of potentially curative treatment in patients with perihilar cholangiocarcinoma. However, radical resection requires aggressive surgical strategies that should be tailored optimally according to the location, size and vascular invasion of the tumors. Accurate diagnosis and staging of these tumors is therefore critical for optimal treatment planning and for determining a prognosis. Multidetector computed tomography (MDCT), magnetic resonance imaging (MRI) and MR cholangiography are useful tools, both to diagnose and stage hilar cholangiocarcinoma. Modern imaging techniques allow accurate detection of the level of obstruction and the longitudinal and radial spread of the tumor. In addition, high-resolution MDCT and MR provide specific radiographic features to determine vascular involvement of anatomic structures, such as the hepatic artery or the portal vein, which are critical to decide the surgical strategy. Finally, radiological staging allows detection of patients with distant metastasis in the liver or peritoneum who will not benefit from a surgical approach. PMID- 23919106 TI - Laparoscopic staging in hilar cholangiocarcinoma: Is it still justified? AB - Radical resection remains the only potential curative therapy for hilar cholangiocarcinoma (HCCA). The aim of staging laparoscopic (SL) is to identify patients with previously undetected advanced disease who will not benefit from surgical palliation and therefore avoid unnecessary laparotomies. The accuracy of non-invasive imaging techniques has significantly improved during the last years. As a consequence, the diagnostic yield of SL of biliary tract malignancy should have decreased proportionally. At the same time, some authors have recently questioned the value of laparoscopic ultrasound (LUS) as a complement of SL. In this setting, the precise role of SL and LUS in the preoperative workup of HCCA remains unclear. As it seems undoubtedly clear that its efficacy has decreased in the last decades, there is a general consensus that the universal use of SL shouldn't be recommended anymore; SL should be performed only in selected patients with higher risk of holding unresectable disease (T2/T3 or Bismuth type 3/4 and patients with suspicion of metastases). It would also be recommended in patients with potentially resectable disease who would need preoperative invasive procedures. Finally, SL should be performed preceding laparotomy in one session. Further studies on the benefit of SL and LUS in this subset of HCCA patients are warranted. PMID- 23919107 TI - Risk factors and classifications of hilar cholangiocarcinoma. AB - Cholangiocarcinoma is the second most common primary malignant tumor of the liver. Perihilar cholangiocarcinoma or Klatskin tumor represents more than 50% of all biliary tract cholangiocarcinomas. A wide range of risk factors have been identified among patients with Perihilar cholangiocarcinoma including advanced age, male gender, primary sclerosing cholangitis, choledochal cysts, cholelithiasis, cholecystitis, parasitic infection (Opisthorchis viverrini and Clonorchis sinensis), inflammatory bowel disease, alcoholic cirrhosis, nonalcoholic cirrhosis, chronic pancreatitis and metabolic syndrome. Various classifications have been used to describe the pathologic and radiologic appearance of cholangiocarcinoma. The three systems most commonly used to evaluate Perihilar cholangiocarcinoma are the Bismuth-Corlette (BC) system, the Memorial Sloan-Kettering Cancer Center and the TNM classification. The BC classification provides preoperative assessment of local spread. The Memorial Sloan-Kettering cancer center proposes a staging system according to three factors related to local tumor extent: the location and extent of bile duct involvement, the presence or absence of portal venous invasion, and the presence or absence of hepatic lobar atrophy. The TNM classification, besides the usual descriptors, tumor, node and metastases, provides additional information concerning the possibility for the residual tumor (R) and the histological grade (G). Recently, in 2011, a new consensus classification for the Perihilar cholangiocarcinoma had been published. The consensus was organised by the European Hepato-Pancreato-Biliary Association which identified the need for a new staging system for this type of tumors. The classification includes information concerning biliary or vascular (portal or arterial) involvement, lymph node status or metastases, but also other essential aspects related to the surgical risk, such as remnant hepatic volume or the possibility of underlying disease. PMID- 23919108 TI - Principles of surgical resection in hilar cholangiocarcinoma. AB - The aim of this article is to describe the surgical techniques for the treatment of hilar cholangiocarcinoma (HC). Resection with microscopically negative margin (R0) is the only way to cure patients with HC. Today, resection of the caudate lobe and part of segment IV, combined with a right or left hepatectomy, bile duct resection, lymphadenectomy of the hepatic hilum and sometimes vascular resection, is the standard surgical procedure for HC. Intraoperative frozen-section examination of proximal and distal biliary margins is necessary to confirm the suitability of resection. Although lymphadenectomy probably has little direct effect on survival, inaccurate staging information may influence post resection treatment recommendations. Aggressive venous and arterial resections should be undertaken in selected cases to achieve a R0 resection. The concept of "no-touch proposed" in 1999 by Neuhaus et al combine an extended right hepatectomy with systematic portal vein resection and caudate lobectomy avoiding hilar dissection and possible intraoperative microscopic dissemination of cancer cells. More recently minor liver resections have been proposed for treatment of HC. As the hilar bifurcation of the bile ducts is near to liver segments IV, V and I, adequate liver resection of these segments together with the bile ducts can result in cure. PMID- 23919109 TI - Outcome of surgical resection in Klatskin tumors. AB - Cholangiocarcinomas are the second most frequent primary hepatic malignancy, and make up from 5% to 30% of malignant hepatic tumours. Hilar cholangiocarcinoma (HCC) is the most common type, and accounts for approximately 60% to 67% of all cholangiocarcinoma cases. There is not a staging system that permits us to compare all series and extract some conclusions to increase the long-survival rate in this dismal disease. Neither the extension of resection, according to the sort of HCC, is a closed topic. Some authors defend limited resection (mesohepatectomy with S1, S1 plus S4b-S5, local excision for papillary tumours, etc.) while others insist in the compulsoriness of an extended hepatic resection with portal vein bifurcation removed to reach cure. As there is not an ideal adjuvant therapy, R1 resection can be justified to prolong the survival rate. Morbidity and mortality rates changed along the last decade, but variability is the rule, with morbidity and mortality rates ranging from 14% to 76% and from 0% to 19%, respectively. CONCLUSION: Surgical resection continues to be the main treatment of HCC. Negative resection margins achieved with major hepatic resections are associated with improved outcome. Preresectional management with biliary drainage, portal vein embolization and staging laparoscopy should be considered in selected patients. Additional evidence is needed to fully define the role of orthotopic liver transplant. Portal and lymph node involvement worsen the prognosis and long-term survival, and surgery is the only option that can lengthen it. Improvements in adjuvant therapy are essential for improving long term outcome. Furthermore, the lack of effective chemotherapy drugs and radiotherapy approaches leads us to can consider R1 resection as an option, because operated patients have a longer survival rate than those who not undergo surgery. PMID- 23919110 TI - Pathological aspects of so called "hilar cholangiocarcinoma". AB - Cholangiocarcinoma (CC) arising from the large intrahepatic bile ducts and extrahepatic hilar bile ducts share clinicopathological features and have been called hilar and perihilar CC as a group. However, "hilar and perihilar CC" are also used to refer exclusively to the intrahepatic hilar type CC or, more commonly, the extrahepatic hilar CC. Grossly, a major distinction can be made between papillary and non-papillary tumors. Histologically, most hilar CCs are well to moderately differentiated conventional type (biliary) carcinomas. Immunohistochemically, CK7, CK20, CEA and MUC1 are normally expressed, being MUC2 positive in less than 50% of cases. Two main premalignant lesions are known: biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the biliary tract (IPNB). IPNB includes the lesions previously named biliary papillomatosis and papillary carcinoma. A series of 29 resected hilar CC from our archives is reviewed. Most (82.8%) were conventional type adenocarcinomas, mostly well to moderately differentiated, although with a broad morphological spectrum; three cases exhibited a poorly differentiated cell component resembling signet ring cells. IPNB was observed in 5 (17.2%), four of them with an associated invasive carcinoma. A clear cell type carcinoma, an adenosquamous carcinoma and two gastric foveolar type carcinomas were observed. PMID- 23919111 TI - Chemotherapy for cholangiocarcinoma: An update. AB - Cholangiocarcinomas (bile duct cancers) are a heterogeneous group of malignancies arising from the epithelial cells of the intrahepatic, perihilar and extrahepatic bile ducts. Patients diagnosed with cholangiocarcinoma must be evaluated by a multidisciplinary team and be treated with individualized management. First of all, it is very important to define the potential resectability of the tumor because surgery is the main therapeutic option for these patients. Overall, cholangiocarcinomas have a very poor prognosis. The 5-year survival rate is 5% 10%. In cases with a potentially curative surgery, 5-year survival rates of 25% 30% are reported. Therefore, it is necessary to increase the cure rate from surgery, exploring the survival benefit of any adjuvant strategy. It is difficult to clarify the role of adjuvant treatment in localized and locally advanced cholangiocarcinomas. There are limited data and the role of adjuvant chemotherapy/chemoradiation in patients with resected biliary tract cancer is poorly defined. The most relevant studies in the adjuvant setting are one from Japan, the well known ESPAC-3 and BILCAP from the United Kingdom and a meta analysis. We show the results of these trials. According to medical oncology guidelines, postoperative adjuvant therapy is widely recommended for all patients with intrahepatic or extrahepatic cholangiocarcinoma who have microscopically positive resection margins, as well as for those with a complete resection but node-positive disease. Clinical trials are ongoing. The locally advanced cholangiocarcinoma setting includes a heterogeneous mix of patients: (1) patients who have had surgery but with macroscopic residual disease; (2) patients with locally recurrent disease after potentially curative treatment; and (3) patients with locally unresectable disease at presentation. In these patients, surgery is not an option and chemoradiation therapy can prolong overall survival and provide control of symptoms due to local tumor effects. Nowadays, no neoadjuvant therapy can be considered a standard approach for the treatment of patients with cholangiocarcinoma. There are promising results and randomized trials are needed in patients with a metastatic cholangiocarcinoma. In systemic therapy, no single drug or combination has consistently increased median survival beyond the expected 8-12 mo. It is always recommended that patients enrol in clinical trials. Clinical trials have shown that the more standard chemotherapy for a first line regimen of gemcitabine plus cisplatin (or oxaliplatin as a potentially better tolerated agent) is superior to gemcitabine alone. Leucovorin-modulated 5 fluorouracil, capecitabine monotherapy or single agent gemcitabine are reasonable options for patients with a borderline performance status. After progression in patients with an adequate performance status, active regimens that could be considered include gemcitabine plus capecitabine, or erlotinib plus bevacizumab, for second line treatment. PMID- 23919112 TI - Magnetic Heating of Nanoparticles: The Importance of Particle Clustering to Achieve Therapeutic Temperatures. AB - Hyperthermia therapy for cancer treatment seeks to destroy tumors through heating alone or combined with other therapies at elevated temperatures between 41.8 and 48 degrees C. Various forms of cell death including apoptosis and necrosis occur depending on temperature and heating time. Effective tumoricidal effects can also be produced by inducing damage to the tissue vasculature and stroma; however, surrounding normal tissue must be spared to a large extent. Magnetic nanoparticles have been under experimental investigation in recent years as a means to provide a favorable therapeutic ratio for local hyperthermia; however, practical numerical models that can be used to study the underlying mechanisms in realistic geometries have not previously appeared to our knowledge. Useful numerical modeling of these experiments is made extremely difficult by the many orders of magnitude in the geometries: from nanometers to centimeters. What has been missing is a practical numerical modeling approach that can be used to more deeply understand the experiments. We develop and present numerical models that reveal the extent and dominance of the local heat transfer boundary conditions, and provide a new approach that may simplify the numerical problem sufficiently to make ordinary computing machinery capable of generating useful predictions. The objectives of this paper are to place the discussion in a convenient interchangeable classical electromagnetic formulation, and to develop useful engineering approximations to the larger multiscale numerical modeling problem that can potentially be used in experiment evaluation; and eventually, may prove useful in treatment planning. We cast the basic heating mechanisms in the framework of classical electromagnetic field theory and provide calibrating analytical calculations and preliminary experimental results on BNF-Starch(r) nanoparticles in a mouse tumor model for perspective. PMID- 23919113 TI - An overview of the Charcot foot pathophysiology. AB - Charcot arthropathy of the foot is a rare but devastating complication of diabetes that remains to be a challenging issue for the foot and ankle surgeons. Charcot foot fails to be an obvious diagnostic option that comes to mind, even in a pathognomonic clinical appearance. The rarity of the disorder, more common pathologies that mimic the condition, and the self-limiting prognosis deviate the clinician from the right diagnosis. The clinical challenges in the diagnosis of Charcot foot require in-depth investigations of its enigmatic nature to establish useful guidelines. Yet, this goal seems to be beyond reach, without a holistic view of the immense literature concerning the pathophysiology of the disorder. The primary objective of this article is to put together and review the recent advancements about the etiology and intrinsic mechanisms of diabetic Charcot foot. PMID- 23919114 TI - Conservative and surgical treatment of the chronic Charcot foot and ankle. AB - Charcot neuroarthropathy (CN) is a severe joint disease in the foot and ankle that can result in fracture, permanent deformity, and limb loss. It is a serious and potentially limb-threatening lower-extremity late complication of diabetes mellitus. The aim of this manuscript was to evaluate modern concepts of chronic CN through a review of the available literature and to integrate a perspective of management from the authors' extensive experience. PMID- 23919116 TI - Iranian science shows world's fastest growth: ranks 17th in science production in 2012. PMID- 23919115 TI - Human wound infections caused by Neisseria animaloris and Neisseria zoodegmatis, former CDC Group EF-4a and EF-4b. AB - BACKGROUND: Neisseria animaloris and Neisseria zoodegmatis, former CDC Group EF 4a and -4b, are considered to be rare zoonotic pathogens, usually associated with dog or cat bites. The aim of the study was to phenotypicaly characterize 13 EF-4 isolates from wound infections, determine their antibiotic susceptibility and to follow the clinical outcome of the patients. METHODS: 13 of the EF-4 isolates were cultured on agar plates. Conventional biochemical tests and the Biolog system were used for phenotypical identification. An arbitrary primed polymerase chain reaction (AP-PCR) was carried out to determine the genetic profiles. Minimum inhibitory concentration (MIC) values were determined for different antibiotics were determined. According to this, clinical data for the patients were recorded. RESULTS: 11 isolates were identified as N. animaloris and 2 as N. zoodegmatis due to the production of arginine dihydrolase. A majority of the patients had a history of dog bite. In 6 cases only grewth of N. animaloris or zoodegmatis was registered. When a patient received antibiotic treatment the most common drug of choice was penicillin V. Only 3 patients received treatment for which the isolated EF-4 bacterium was fully susceptible. CONCLUSION: Human infections involving N. animaloris and N. zoodegmatis usually present themselves as local wound infection, but severe complications can occur. Despite their pathogenic potentia, l N. animaloris and N. zoodegmatis are often misidentified, dismissed as skin contaminants or not recognized at all. Due to the fact that N. animaloris and N. zoodegmatis are significant pathogens in animal bites, physicians should keep these bacteria in mind when choosing antibiotic therapy. PMID- 23919117 TI - The Role of Different Supplements in Expression Level of Monoclonal Antibody against Human CD20. AB - BACKGROUND: Recombinant monoclonal antibodies have been marketed in last three decades as the major therapeutic proteins against different cancers. However choosing a proper medium and supplements to reach the high expression is a challenging step. Despite of commercial serum free and chemically defined media, there are still numerous researches seeking the optimum media to gain higher expression titer. Selecting the best basal media followed by proper supplementation to increase the cell density and expression titer needs proper and accurate investigation. METHODS: In this study, we have determined the expression titer of monoclonal antibody against human CD20 using soy extract, Essential Amino Acid, Non-Essential Amino Acid, Panexin NTS, Peptone, Yeast extract, Insulin-transferrin selenite, Human Serum Albumin, Bovine Serum Albumin, Lipid, and two commercially available supplements, Power and Xtreme feed. In each experiment, the expression level was compared with a well defined media, ProCHO5, RPMI 1640 and DMEM-F12. RESULTS: It has been shown that supplementing the ProCHO5 basal medium with 10% power feed or combination of 5% PanexinNTS,1.5 g/L yeast and 1.5g/L peptone results in the best production levels with 450 and 425 mg/L of anti CD20 mAb expression level, respectively. CONCLUSION: Panexin NTS, yeast and peptone cane be proper supplement for fed-batch cell culture instead of commercial Power feed supplement which is a cost effective way to increase expression level. And thereby ProCHO5 may be replaced with common media such as RPMI 1640 and DMEM-F12. PMID- 23919118 TI - Predictions of Protein-Protein Interfaces within Membrane Protein Complexes. AB - BACKGROUND: Prediction of interaction sites within the membrane protein complexes using the sequence data is of a great importance, because it would find applications in modification of molecules transport through membrane, signaling pathways and drug targets of many diseases. Nevertheless, it has gained little attention from the protein structural bioinformatics community. METHODS: In this study, a wide variety of prediction and classification tools were applied to distinguish the residues at the interfaces of membrane proteins from those not in the interfaces. RESULTS: The tuned SVM model achieved the high accuracy of 86.95% and the AUC of 0.812 which outperforms the results of the only previous similar study. Nevertheless, prediction performances obtained using most employed models cannot be used in applied fields and needs more effort to improve. CONCLUSION: Considering the variety of the applied tools in this study, the present investigation could be a good starting point to develop more efficient tools to predict the membrane protein interaction site residues. PMID- 23919119 TI - Effect of Oral Supplementation of Biogenic Selenium Nanoparticles on White Blood Cell Profile of BALB/c Mice and Mice Exposed to X-ray Radiation. AB - BACKGROUND: Radiation therapy is an effective method used for treatment of many types of cancers. However, this method can cause unwanted side effects such as bone marrow suppression. In this study, the effect of oral administration of biogenic selenium nanoparticles (SeNPs) on total and differentiated white cells profile of BALB/c mice exposed to X-ray radiation was investigated and compared with non-irradiated mice. METHODS: Sixty female BALB/c mice between six to eight weeks olds were divided into 4 test and control groups in two categories of normal and irradiated mice. In normal mice SeNPs administration was started from the day 0 and followed for a month. Irradiated mice were divided into three groups and were exposed to doses of 2, 4 and 8 Gy. After 72 hr of irradiation, the SeNPs treatment was started and continued for a month. Total and differentiated blood cells counts of both irradiated and non-irradiated groups were monitored during 30 days and the obtained results were compared. Also, the deposition of Se in different tissues and blood serum of normal mice was determined in normal mice after 30 days period of supplementation. RESULTS: In normal mice an increase in the count of neutrophils was observed after 30 days of supplementation. In irradiated mice, SeNPs supplementation led to increase in both lymphocytes and neutrophils counts especially in mice exposed to 2 and 4 Gys radiation. CONCLUSION: Radiotherapy is categorized as an invasive method which can cause tissue damage and suppress the host immune defense. A restore of lymphocytes which was observed after SeNPs supplementation in irradiated mice can be highly interesting and provide cellular immunity against malignant diseases or other bacterial or fungal infections after radiotherapy. PMID- 23919120 TI - Cloning and Expression of Functional Reteplase in Escherichia coli TOP10. AB - BACKGROUND: Production of tissue Plasminogen Activator protein (t-PA) in prokaryotes systems has many problems such as the lack of active protein production, multiple purification steps, and renaturation process which has been shown to be costly and time-consuming. METHODS: In this study, reteplase which is the nonglycosylated active domain of t-PA was used to transform TOP10 Escherichia coli (E. coli) bacteria to resolve some of the above mentioned problems. Reteplase cDNA was ligated into pBAD/gIII plasmid which allowed secretion of this protein into the periplasmic space and would allow the correct formation of disulfide bonds in protein structure. The presence of reteplase cDNA in pBAD/gIII plasmid was confirmed by restriction digestion and sequencing. After induction of the expression of this protein by adding 0.0002% L-Arabinose to the medium, the proteins in periplasmic space as well as the inclusion bodies formed inside the cell were extracted. Subsequently, these proteins were purified and detected by Western blot method. RESULTS: Our results showed that the amount of reteplase extracted from periplasmic space was much lower than the extracted inclusion bodies and large quantities of the recombinant protein were present as inclusion bodies. Therefore, it was more efficient to use inclusion body extraction method for protein isolation and purification. CONCLUSION: We produced active reteplase after its expression in E. coli TOP10 and isolation of inclusion bodies produced the best results for purification and extraction of this protein. PMID- 23919121 TI - Overexpression and Purification of C-terminal Fragment of the Passenger Domain of Hap Protein from Nontypeable Haemophilus influenzae in a Highly Optimized Escherichia coli Expression System. AB - BACKGROUND: Nontypeable Haemophilus influenzae (NTHi) is a common cause of respiratory tract disease and initiates infection by colonization in nasopharynx. The Haemophilus influenzae (H. influenzae) Hap adhesin is an auto transporter protein that promotes initial interaction with human epithelial cells. Hap protein contains a 110 kDa internal passenger domain called "HapS" and a 45 kDa C terminal translocator domain called "Hapbeta". Hap adhesive activity has been recently reported to be connected to its Cell Binding Domain (CBD) which resides within the 311 C-terminal residues of the internal passenger domain of the protein. Furthermore, immunization with this CBD protein has been shown to prevent bacterial nasopharynx colonization in animal models. METHODS: To provide enough amounts of pure HapS protein for vaccine studies, we sought to develop a highly optimized system to overexpress and purify the protein in large quantities. To this end, pET24a-cbd plasmid harboring cbd sequence from NTHi ATCC49766 was constructed and its expression was optimized by testing various expression parameters such as growth media, induction temperature, IPTG inducer concentration, induction stage and duration. SDS-PAGE and Western-blotting were used for protein analysis and confirmation and eventually the expressed protein was easily purified via immobilized metal affinity chromatography (IMAC) using Ni NTA columns. RESULTS: The highest expression level of target protein was achieved when CBD expressing E. coli BL21 (DE3) cells were grown at 37 degrees C in 2xTY medium with 1.0 mM IPTG at mid-log phase (OD600 nm equal to 0.6) for 5 hrs. Amino acid sequence alignment of expressed CBD protein with 3 previously published CBD amino acid sequences were more than %97 identical and antigenicity plot analysis further revealed 9 antigenic domains which appeared to be well conserved among different analyzed CBD sequences. CONCLUSION: Due to the presence of high similarity among CBD from NTHi ATCC49766 and other NTHi strains, CBD protein expressed here sounds to be theoretically ideal as a universal candidate for being used in vaccine studies against NTHi strains of various geographical areas. Further investigations to corroborate the potency of this protein as a vaccine candidate are under process. PMID- 23919122 TI - Production of cloned mice by nuclear transfer of cumulus cells. AB - BACKGROUND: Over the past several years, mammals have been successfully cloned by either the splitting of an early stage embryo or nuclear transfer of adult somatic cells (NT) into oocytes. Although it has been 15 years since the generation of the first cloned mammals from somatic cells by NT, the success rate for producing live offspring by this technique is low regardless of the cell type and animal species used. However, these techniques have the potential to be important tools for future research in basic biology. In the present study, we described our experiences in producing successfully cloned mouse using NT method and piezo-actuated micromanipulator. METHODS: B6D2F1 mice, 8-12 weeks old, were superovulated with injections of 5 IU of pregnant mare serum gonadotropin and 5 IU of human chorionic gonadotropin administered 48 hr apart. Enucleation and donor nuclei cumulus cell injection were performed with a piezo-actuated micromanipulator after which activation and trichostatin A treatment were used for reconstructed oocytes. Two-cell stage cloned embryos that developed in the mWM medium were transferred into the oviducts of pseudopregnant NMRI mice. RESULTS: Of 367 oocytes collected, 131 (69%) developed into 2-cell stage embryos. Of these, 5 (1%) live pups were successfully delivered. We used NMRI foster mother to raise the pups by lactation. One adult cloned mouse was mated, after which she delivered and raised normal offspring. CONCLUSION: For mouse cloning, the present study also successfully tested the capability of somatic cell nuclear transfer SCNT using a piezo unit. PMID- 23919123 TI - A Novel Approach for High Level Expression of Soluble Recombinant Human Parathyroid Hormone (rhPTH 1-34) in Escherichia coli. AB - BACKGROUND: Parathyroid hormone (PTH) secreted by parathyroid glands regulates the metabolism of calcium and phosphorus in bone and kidney. Thereby, it can stimulate bone formation, and is a promising agent in the treatment of osteoporosis. Mature form of PTH consists of 84 amino acids; however, the first 34 residues of PTH cover the majority of hormonal action. METHODS: In this study, the fusion form of highly soluble rhPTH was expressed at high level in Escherichia coli (E. coli). His6-thioredoxin as an extension for rhPTH improves the solubility of inclusion body. His6-thioredoxin-hPTH (1-34) was ligated into pET32a expression vector. The insertion of 5 amino acids (Asp-Asp-Asp-Asp-Lys) in the N-terminal of PTH made this protein to be digestable specifically by enterokinase enzyme. The fusion form of rhPTH was harvested and purified by immobilized affinity chromatography followed by digestion with enterokinase. Digested rhPTH was purified by applying on size exclusion and ion exchange chromatography to get the highest purity. RESULTS: The mass spectroscopy analysis shows rhPTH molecular weight was 4117.5 Da. The purity was measured by HPLC column which showed more than 97%. Bioassay analysis of rhPTH was performed on rat sarcoma cell UMR-106 in parallel with commercially available rhPTH, Forteo. The result was measured through immunofluorescence detection kit. The data showed that the potency of rhPTH was comparable with commercially available medicine. CONCLUSION: Thioredoxin was applied as a fusion partner for production of highly soluble rhPTH. This specific fusion partner increased protein solubility and decreased protease reactivity. Purification process was optimized for high recovery and for purity more than 99%. As its biological activity is comparable with marketed drug, this protein is qualified for biopharmaceutical usage. PMID- 23919124 TI - Vignettes from the field of mathematical biology: the application of mathematics to biology and medicine. AB - The application of mathematical models in biology and medicine has a long history. From the sparse number of papers in the first half of the twentieth century with a few scientists working in the field it has become vast with thousands of active researchers. We give a brief, and far from definitive history, of how some parts of the field have developed and how the type of research has changed. We describe in more detail just two examples of specific models which are directly related to real biological problems, namely animal coat patterns and the growth and image enhancement of glioblastoma brain tumours. PMID- 23919125 TI - Turing's theory of morphogenesis of 1952 and the subsequent discovery of the crucial role of local self-enhancement and long-range inhibition. AB - In his pioneering work, Alan Turing showed that de novo pattern formation is possible if two substances interact that differ in their diffusion range. Since then, we have shown that pattern formation is possible if, and only if, a self enhancing reaction is coupled with an antagonistic process of longer range. Knowing this crucial condition has enabled us to include nonlinear interactions, which are required to design molecularly realistic interactions. Different reaction schemes and their relation to Turing's proposal are discussed and compared with more recent observations on the molecular-genetic level. The antagonistic reaction may be accomplished by an inhibitor that is produced in the activated region or by a depletion of a component that is used up during the self enhancing reaction. The autocatalysis may be realized by an inhibition of an inhibition. Activating molecules can be processed into molecules that have an inhibiting function; patterning of the Wnt pathway is proposed to depend on such a mechanism. Three-component systems, as discussed in Turing's paper, are shown to play a major role in the generation of highly dynamic patterns that never reach a stable state. PMID- 23919126 TI - Chemical morphogenesis: recent experimental advances in reaction-diffusion system design and control. AB - In his seminal 1952 paper, Alan Turing predicted that diffusion could spontaneously drive an initially uniform solution of reacting chemicals to develop stable spatially periodic concentration patterns. It took nearly 40 years before the first two unquestionable experimental demonstrations of such reaction diffusion patterns could be made in isothermal single phase reaction systems. The number of these examples stagnated for nearly 20 years. We recently proposed a design method that made their number increase to six in less than 3 years. In this report, we formally justify our original semi-empirical method and support the approach with numerical simulations based on a simple but realistic kinetic model. To retain a number of basic properties of real spatial reactors but keep calculations to a minimal complexity, we introduce a new way to collapse the confined spatial direction of these reactors. Contrary to similar reduced descriptions, we take into account the effect of the geometric size in the confinement direction and the influence of the differences in the diffusion coefficient on exchange rates of species with their feed environment. We experimentally support the method by the observation of stationary patterns in red-ox reactions not based on oxihalogen chemistry. Emphasis is also brought on how one of these new systems can process different initial conditions and memorize them in the form of localized patterns of different geometries. PMID- 23919128 TI - Wing vein patterns of the Hemiptera insect Orosanga japonicus differ among individuals. AB - Although Turing's reaction-diffusion model (RD model) has been gradually accepted among biologists, application of the model is still limited. Accumulated experimental studies have shown that the morphogen gradient model can explain most patterning phenomena in embryogenesis. These experiments have been performed only in a few model animals. Therefore, it is not clear whether the discovered principle of the mechanism is generally applicable. The wing venation pattern of Drosophila melanogaster is largely determined by the morphogen gradient mechanism. We found that the gradient model cannot be applied to some other species. In the Hemiptera insect Orosanga japonicus, each individual has a unique pattern. Veins of O. japonicus extend radially from the proximal region and bifurcate to add the veins in the distal region. Interestingly, the bifurcation points are almost random and the vein number at the wing edge differs with wing size. However, the spacing between the veins is maintained evenly. Computer simulation of the RD model showed these properties do not fit the morphogen gradient model, but perfectly fit the RD model. This result suggests that the RD model may explain phenomena to which the morphogen gradient mechanism is currently believed to apply. PMID- 23919127 TI - Towards an integrated experimental-theoretical approach for assessing the mechanistic basis of hair and feather morphogenesis. AB - In his seminal 1952 paper, 'The Chemical Basis of Morphogenesis', Alan Turing lays down a milestone in the application of theoretical approaches to understand complex biological processes. His deceptively simple demonstration that a system of reacting and diffusing chemicals could, under certain conditions, generate spatial patterning out of homogeneity provided an elegant solution to the problem of how one of nature's most intricate events occurs: the emergence of structure and form in the developing embryo. The molecular revolution that has taken place during the six decades following this landmark publication has now placed this generation of theoreticians and biologists in an excellent position to rigorously test the theory and, encouragingly, a number of systems have emerged that appear to conform to some of Turing's fundamental ideas. In this paper, we describe the history and more recent integration between experiment and theory in one of the key models for understanding pattern formation: the emergence of feathers and hair in the skins of birds and mammals. PMID- 23919129 TI - Turing's model for biological pattern formation and the robustness problem. AB - One of the fundamental questions in developmental biology is how the vast range of pattern and structure we observe in nature emerges from an almost uniformly homogeneous fertilized egg. In particular, the mechanisms by which biological systems maintain robustness, despite being subject to numerous sources of noise, are shrouded in mystery. Postulating plausible theoretical models of biological heterogeneity is not only difficult, but it is also further complicated by the problem of generating robustness, i.e. once we can generate a pattern, how do we ensure that this pattern is consistently reproducible in the face of perturbations to the domain, reaction time scale, boundary conditions and so forth. In this paper, not only do we review the basic properties of Turing's theory, we highlight the successes and pitfalls of using it as a model for biological systems, and discuss emerging developments in the area. PMID- 23919130 TI - Computing by molecular self-assembly. AB - The paper reviews two computing models by DNA self-assembly whose proof of principal have recently been experimentally confirmed. The first model incorporates DNA nano-devices and triple crossover DNA molecules to algorithmically arrange non-DNA species. This is achieved by simulating a finite state automaton with output where golden nanoparticles are assembled to read-out the result. In the second model, a complex DNA molecule representing a graph emerges as a solution of a computational problem. This supports the idea that in molecular self-assembly computing, it may be necessary to develop the notion of shape processing besides the classical approach through symbol processing. PMID- 23919131 TI - Towards quantum simulations of biological information flow. AB - Recent advances in the spectroscopy of biomolecules have highlighted the possibility of quantum coherence playing an active role in biological energy transport. The revelation that quantum coherence can survive in the hot and wet environment of biology has generated a lively debate across both the physics and biology communities. In particular, it remains unclear to what extent non-trivial quantum effects are used in biology and what advantage, if any, they afford. We propose an analogue quantum simulator, based on currently available techniques in ultra-cold atom physics, to study a model of energy and electron transport based on the Holstein Hamiltonian. By simulating the salient aspects of a biological system in a tunable laboratory set-up, we hope to gain insight into the validity of several theoretical models of biological quantum transport in a variety of relevant parameter regimes. PMID- 23919132 TI - An age-size reaction norm yields insight into environmental interactions affecting life-history traits: a factorial study of larval development in the malaria mosquito Anopheles gambiae sensu stricto. AB - Environmental factors frequently act nonindependently to determine growth and development of insects. Because age and size at maturity strongly influence population dynamics, interaction effects among environmental variables complicate the task of predicting dynamics of insect populations under novel conditions. We reared larvae of the African malaria mosquito Anopheles gambiae sensu stricto (s.s.) under three factors relevant to changes in climate and land use: food level, water depth, and temperature. Each factor was held at two levels in a fully crossed design, for eight experimental treatments. Larval survival, larval development time, and adult size (wing length) were measured to indicate the importance of interaction effects upon population-level processes. For age and size at emergence, but not survival, significant interaction effects were detected for all three factors, in addition to sex. Some of these interaction effects can be understood as consequences of how the different factors influence energy usage in the context of a nonindependent relationship between age and size. Experimentally assessing interaction effects for all potential future sets of conditions is intractable. However, considering how different factors affect energy usage within the context of an insect's evolved developmental program can provide insight into the causes of complex environmental effects on populations. PMID- 23919133 TI - A detachable mobile and adjustable telemetry system. AB - Many traditional mobile telemetry systems require permanently mounting a rod through the cabin of a vehicle to serve as the mast for a directional antenna. In this article we present an alternative to this configuration by providing a platform that can be placed atop the vehicle in which the antenna mast can be mounted and controlled from the cabin of the vehicle. Thereby making this design a viable option for researchers who share vehicles with others that may not approve of permanent vehicle modifications such as placing a hole in the roof of the vehicle as required by traditional mobile configurations. We tested the precision and accuracy of detachable mobile and adjustable telemetry system (DMATS) in an urban park with varying terrain, tree stands, overhead wires, and other structures that can contribute to signal deflection. We placed three radiocollars 50 m apart and 1.2 m above the ground then established three testing stations ~280 m from the location of the radiocollars. The DMATS platform required 12 h for completion and cost $1059 USD. Four technicians were randomly assigned radio collars to triangulate using DMATS and a handheld telemetry system. We used a one-way analysis of variance (ANOVA) with a Scheffe post hoc test to compare error ellipses between azimuths taken using DMATS and the hand held system. Average error ellipses for all testers was 1.96 +/- 1.22 ha. No significant differences were found between error ellipses of testers (P = 0.292). Our design, the DMATS, does not require any vehicle modification; thereby, making this a viable option for researchers sharing vehicles with others that may not approve of permanent vehicle alterations. PMID- 23919134 TI - No evidence of sperm conjugate formation in an Australian mouse bearing sperm with three hooks. AB - Sperm conjugation occurs when two or more sperm physically unite for motility or transport through the female reproductive tract. In many muroid rodent species, sperm conjugates have been shown to form by a single, conspicuous apical hook located on the sperm head. These sperm "trains" have been reported to be highly variable in size and, despite all the heads pointing in roughly the same direction, exhibit a relatively disordered arrangement. In some species, sperm "trains" have been shown to enhance sperm swimming speed, and thus have been suggested to be advantageous in sperm competition. Here, we assessed the behavior of sperm in the sandy inland mouse (Pseudomys hermannsburgensis), a muroid rodent that bears sperm with three apical hooks. First, we accrued genetic evidence of multiple paternity within "wild" litters to unequivocally show that sperm competition does occur in this species. Following this we utilized both in vitro and in vivo methodologies to determine whether sandy inland mouse sperm conjugate to form motile trains. Our observations of in vitro preparations of active sperm revealed that sandy inland mouse sperm exhibit rapid, progressive motility as individual cells only. Similarly, histological sections of the reproductive tracts of mated females revealed no in vivo evidence of sperm conjugate formation. We conclude that the unique, three-hooked morphology of the sandy inland mouse sperm does not facilitate the formation of motile conjugates, and discuss our findings in relation to the different hypotheses for the evolution of the muroid rodent hook/s. PMID- 23919135 TI - Phenological indices of avian reproduction: cryptic shifts and prediction across large spatial and temporal scales. AB - Climate change-induced shifts in phenology have important demographic consequences, and are frequently used to assess species' sensitivity to climate change. Therefore, developing accurate phenological predictions is an important step in modeling species' responses to climate change. The ability of such phenological models to predict effects at larger spatial and temporal scales has rarely been assessed. It is also not clear whether the most frequently used phenological index, namely the average date of a phenological event across a population, adequately captures phenological shifts in the distribution of events across the season. We use the long-tailed tit Aegithalos caudatus (Fig. 1) as a case study to explore these issues. We use an intensive 17-year local study to model mean breeding date and test the capacity of this local model to predict phenology at larger spatial and temporal scales. We assess whether local models of breeding initiation, termination, and renesting reveal phenological shifts and responses to climate not detected by a standard phenological index, that is, population average lay date. These models take predation timing/intensity into account. The locally-derived model performs well at predicting phenology at the national scale over several decades, at both high and low temperatures. In the local model, a trend toward warmer Aprils is associated with a significant advance in termination dates, probably in response to phenological shifts in food supply. This results in a 33% reduction in breeding season length over 17 years - a substantial loss of reproductive opportunity that is not detected by the index of population average lay date. We show that standard phenological indices can fail to detect patterns indicative of negative climatic effects, potentially biasing assessments of species' vulnerability to climate change. More positively, we demonstrate the potential of detailed local studies for developing broader scale predictive models of future phenological shifts. PMID- 23919137 TI - Getting the biggest birch for the bang: restoring and expanding upland birchwoods in the Scottish Highlands by managing red deer. AB - High deer populations threaten the conservation value of woodlands and grasslands, but predicting the success of deer culling, in terms of allowing vegetation to recover, is difficult. Numerical simulation modeling is one approach to gain insight into the outcomes of management scenarios. We develop a spatially explicit model to predict the responses of Betula spp. to red deer (Cervus elaphus) and land management in the Scottish Highlands. Our model integrates a Bayesian stochastic stage-based matrix model within the framework of a widely used individual-based forest simulation model, using data collected along spatial and temporal gradients in deer browsing. By initializing our model with the historical spatial locations of trees, we find that densities of juvenile trees (<3 m tall) predicted after 9-13 years closely match counts observed in the field. This is among the first tests of the accuracy of a dynamical simulation model for predicting the responses of tree regeneration to herbivores. We then test the relative importance of deer browsing, ground cover vegetation, and seed availability in facilitating landscape-level birch regeneration using simulations in which we varied these three variables. We find that deer primarily control transitions of birch to taller (>3 m) height tiers over 30 years, but regeneration also requires suitable ground cover for seedling establishment. Densities of adult seed sources did not influence regeneration, nor did an active management scenario where we altered the spatial configuration of adults by creating "woodland islets". Our results show that managers interested in maximizing tree regeneration cannot simply reduce deer densities but must also improve ground cover for seedling establishment, and the model we develop now enables managers to quantify explicitly how much both these factors need to be altered. More broadly, our findings emphasize the need for land managers to consider the impacts of large herbivores rather than their densities. PMID- 23919136 TI - MHC class II B diversity in blue tits: a preliminary study. AB - In this study, we partly characterize major histocompatibility complex (MHC) class II B in the blue tit (Cyanistes caeruleus). A total of 22 individuals from three different European locations: Spain, The Netherlands, and Sweden were screened for MHC allelic diversity. The MHC genes were investigated using both PCR-based methods and unamplified genomic DNA with restriction fragment length polymorphism (RFLP) and southern blots. A total of 13 different exon 2 sequences were obtained independently from DNA and/or RNA, thus confirming gene transcription and likely functionality of the genes. Nine out of 13 alleles were found in more than one country, and two alleles appeared in all countries. Positive selection was detected in the region coding for the peptide binding region (PBR). A maximum of three alleles per individual was detected by sequencing and the RFLP pattern consisted of 4-7 fragments, indicating a minimum number of 2-4 loci per individual. A phylogenetic analysis, demonstrated that the blue tit sequences are divergent compared to sequences from other passerines resembling a different MHC lineage than those possessed by most passerines studied to date. PMID- 23919138 TI - Manta Matcher: automated photographic identification of manta rays using keypoint features. AB - For species which bear unique markings, such as natural spot patterning, field work has become increasingly more reliant on visual identification to recognize and catalog particular specimens or to monitor individuals within populations. While many species of interest exhibit characteristic markings that in principle allow individuals to be identified from photographs, scientists are often faced with the task of matching observations against databases of hundreds or thousands of images. We present a novel technique for automated identification of manta rays (Manta alfredi and Manta birostris) by means of a pattern-matching algorithm applied to images of their ventral surface area. Automated visual identification has recently been developed for several species. However, such methods are typically limited to animals that can be photographed above water, or whose markings exhibit high contrast and appear in regular constellations. While manta rays bear natural patterning across their ventral surface, these patterns vary greatly in their size, shape, contrast, and spatial distribution. Our method is the first to have proven successful at achieving high matching accuracies on a large corpus of manta ray images taken under challenging underwater conditions. Our method is based on automated extraction and matching of keypoint features using the Scale-Invariant Feature Transform (SIFT) algorithm. In order to cope with the considerable variation in quality of underwater photographs, we also incorporate preprocessing and image enhancement steps. Furthermore, we use a novel pattern-matching approach that results in better accuracy than the standard SIFT approach and other alternative methods. We present quantitative evaluation results on a data set of 720 images of manta rays taken under widely different conditions. We describe a novel automated pattern representation and matching method that can be used to identify individual manta rays from photographs. The method has been incorporated into a website (mantamatcher.org) which will serve as a global resource for ecological and conservation research. It will allow researchers to manage and track sightings data to establish important life history parameters as well as determine other ecological data such as abundance, range, movement patterns, and structure of manta ray populations across the world. PMID- 23919139 TI - Delimiting shades of gray: phylogeography of the Northern Fulmar, Fulmarus glacialis. AB - The Northern Fulmar (Fulmarus glacialis) is a common tube-nosed seabird with a disjunct Holarctic range. Taxonomic divisions within the Northern Fulmar have historically been muddled by geographical variation notably including highly polymorphic plumage. Recent molecular analyses (i.e., DNA barcoding) have suggested that genetic divergence between Atlantic and Pacific populations could be on par with those typically observed between species. We employ a multigene phylogenetic analysis to better explore the level of genetic divergence between these populations and to test an old hypothesis on the origin of the modern distribution of color morphs across their range. Additionally, we test whether mutations in the melanocortin-1 receptor gene (MC1R) are associated with dark plumage in the Northern Fulmar. We confirmed that mitochondrial lineages in the Atlantic and Pacific populations are highly divergent, but nuclear markers revealed incomplete lineage sorting. Genetic divergence between these populations is consistent with that observed between many species of Procellariiformes and we recommend elevating these two forms to separate species. We also find that MC1R variation is not associated with color morph but rather is better explained by geographical divergence. PMID- 23919140 TI - Adaptive divergence in body size overrides the effects of plasticity across natural habitats in the brown trout. AB - The evolution of life-history traits is characterized by trade-offs between different selection pressures, as well as plasticity across environmental conditions. Yet, studies on local adaptation are often performed under artificial conditions, leaving two issues unexplored: (i) how consistent are laboratory inferred local adaptations under natural conditions and (ii) how much phenotypic variation is attributed to phenotypic plasticity and to adaptive evolution, respectively, across environmental conditions? We reared fish from six locally adapted (domesticated and wild) populations of anadromous brown trout (Salmo trutta) in one semi-natural and three natural streams and recorded a key life history trait (body size at the end of first growth season). We found that population-specific reaction norms were close to parallel across different streams and Q ST was similar - and larger than F ST - within all streams, indicating a consistency of local adaptation in body size across natural environments. The amount of variation explained by population origin exceeded the variation across stream environments, indicating that genetic effects derived from adaptive processes have a stronger effect on phenotypic variation than plasticity induced by environmental conditions. These results suggest that plasticity does not "swamp" the phenotypic variation, and that selection may thus be efficient in generating genetic change. PMID- 23919141 TI - Selection on the Drosophila seminal fluid protein Acp62F. AB - Sperm competition and sexual conflict are thought to underlie the rapid evolution of reproductive proteins in many taxa. While comparative data are generally consistent with these hypotheses, few manipulative tests have been conducted and those that have provided contradictory results in some cases. Here, we use both comparative and experimental techniques to investigate the evolution of the Drosophila melanogaster seminal fluid protein Acp62F, a protease inhibitor for which extensive functional tests have yielded ambiguous results. Using between species sequence comparisons, we show that Acp62F has been subject to recurrent positive selection. In addition, we experimentally evolved populations polymorphic for an Acp62F null allele over eight generations, manipulating the opportunities for natural and sexual selection. We found that the Acp62F null allele increased in frequency in the presence of natural selection, with no effect of sexual selection. PMID- 23919142 TI - Alternative forms for genomic clines. AB - Understanding factors regulating hybrid fitness and gene exchange is a major research challenge for evolutionary biology. Genomic cline analysis has been used to evaluate alternative patterns of introgression, but only two models have been used widely and the approach has generally lacked a hypothesis testing framework for distinguishing effects of selection and drift. I propose two alternative cline models, implement multivariate outlier detection to identify markers associated with hybrid fitness, and simulate hybrid zone dynamics to evaluate the signatures of different modes of selection. Analysis of simulated data shows that previous approaches are prone to false positives (multinomial regression) or relatively insensitive to outlier loci affected by selection (Barton's concordance). The new, theory-based logit-logistic cline model is generally best at detecting loci affecting hybrid fitness. Although some generalizations can be made about different modes of selection, there is no one-to-one correspondence between pattern and process. These new methods will enhance our ability to extract important information about the genetics of reproductive isolation and hybrid fitness. However, much remains to be done to relate statistical patterns to particular evolutionary processes. The methods described here are implemented in a freely available package "HIest" for the R statistical software (CRAN; http://cran.r-project.org/). PMID- 23919143 TI - Flexibility and constraints in the molt schedule of long-distance migratory shorebirds: causes and consequences. AB - Molt is a major component of the annual cycle of birds, the timing and extent of which can affect body condition, survival, and future reproductive success through carry-over effects. The way in which molt is fitted into the annual cycle seems to be a somewhat neglected area which is both of interest and of importance. Study of the causes of annual variation in the timing of molt and its potential consequence in long-distance migratory birds was examined using the Curlew Sandpiper, Calidris ferruginea, as a model species. Using the maximum likelihood molt models of Underhill and Zucchini (1988, Ibis 130:358-372), the relationship between annual variability in the start dates of molt at the population level with conditions on the breeding area was explored. Adult males typically started early in years when temperature in June on the Arctic breeding grounds were high compared to cold years while adult females molted later in years of high breeding success and/or warm July temperature and vice versa. When molt started later, the duration was often shorter, indicating that late completion of molt might have fitness consequences, probably jeopardizing survival. Evidence of this was seen in the low body condition of birds in years when molt was completed late. The results indicate that these migratory shorebirds follow a fine-tuned annual life cycle, and disturbances at a certain stage can alter next biological events through carry-over effects. PMID- 23919144 TI - Evidence of maternal effects on temperature preference in side-blotched lizards: implications for evolutionary response to climate change. AB - Natural populations respond to selection pressures like increasing local temperatures in many ways, including plasticity and adaptation. To predict the response of ectotherms like lizards to local temperature increase, it is essential to estimate phenotypic variation in and determine the heritability of temperature-related traits like average field body temperature (T b) and preferred temperature (T p). We measured T p of Uta stansburiana in a laboratory thermal gradient and assessed the contribution of sex, reproductive status and throat color genotype to phenotypic variation in T b of adult lizards. Females had higher T p than males. However, they temporarily preferred lower temperature when gravid than when nongravid. Using a nested half-sib design for genetic crosses in the laboratory, we estimated relative contributions of additive genetic variation and maternal effects to T p of hatchlings. Our results show that maternal effects, but not additive genetic variation, influence T p of hatchlings in U. stansburiana. Maternal T p and the presence or absence of blue throat color alleles significantly influenced T p of hatchlings. We discuss ecological and evolutionary consequences of these maternal effects in the context of rapid climate change and natural selection that we measure on progeny survival to maturity as a function of maternal T p. PMID- 23919145 TI - Developmental trajectories and breakdown in F1 interpopulation hybrids of Tribolium castaneum. AB - When hybrid inviability is an indirect by-product of local adaptation, we expect its degree of severity between pairs of populations to vary and to be sensitive to the environment. While complete reciprocal hybrid inviability is the outcome of the gradual process of local adaptation, it is not representative of the process of accumulation of incompatibility. In the flour beetle, Tribolium castaneum, some pairs of populations exhibit complete, reciprocal F1 hybrid incompatibility while other pairs are fully or partially compatible. We characterize this naturally occurring variation in the degree and timing of expression of the hybrid incompatible phenotype to better understand the number of genes or developmental processes contributing to speciation. We assessed the morphological and developmental variation in four Tribolium castaneum populations and their 12 possible F1 hybrids at each life-history stage from egg to adult. We find that the rate of hybrid larval development is affected in all interpopulation crosses, including those eventually producing viable, fertile adults. Hybrid incompatibility manifests early in development as changes in the duration of instars and diminished success in the transition between instars are relative to the parent populations. Parent populations with similar developmental profiles may produce hybrids with disrupted development. The degree and timing of expression of hybrid inviability depends upon populations crossed, direction of the cross, and environment in which hybrids are raised. Our findings suggest that the coordinated expression of genes involved in transitional periods of development is the underlying cause of hybrid incompatibility in this species. PMID- 23919146 TI - Foraging area fidelity for Kemp's ridleys in the Gulf of Mexico. AB - For many marine species, locations of key foraging areas are not well defined. We used satellite telemetry and switching state-space modeling (SSM) to identify distinct foraging areas used by Kemp's ridley turtles (Lepidochelys kempii) tagged after nesting during 1998-2011 at Padre Island National Seashore, Texas, USA (PAIS; N = 22), and Rancho Nuevo, Tamaulipas, Mexico (RN; N = 9). Overall, turtles traveled a mean distance of 793.1 km (+/-347.8 SD) to foraging sites, where 24 of 31 turtles showed foraging area fidelity (FAF) over time (N = 22 in USA, N = 2 in Mexico). Multiple turtles foraged along their migratory route, prior to arrival at their "final" foraging sites. We identified new foraging "hotspots" where adult female Kemp's ridley turtles spent 44% of their time during tracking (i.e., 2641/6009 tracking days in foraging mode). Nearshore Gulf of Mexico waters served as foraging habitat for all turtles tracked in this study; final foraging sites were located in water <68 m deep and a mean distance of 33.2 km (+/-25.3 SD) from the nearest mainland coast. Distance to release site, distance to mainland shore, annual mean sea surface temperature, bathymetry, and net primary production were significant predictors of sites where turtles spent large numbers of days in foraging mode. Spatial similarity of particular foraging sites selected by different turtles over the 13-year tracking period indicates that these areas represent critical foraging habitat, particularly in waters off Louisiana. Furthermore, the wide distribution of foraging sites indicates that a foraging corridor exists for Kemp's ridleys in the Gulf. Our results highlight the need for further study of environmental and bathymetric components of foraging sites and prey resources contained therein, as well as international cooperation to protect essential at-sea foraging habitats for this imperiled species. PMID- 23919147 TI - Interspecific synchrony of seabird population growth rate and breeding success. AB - Environmental variability can destabilize communities by causing correlated interspecific fluctuations that weaken the portfolio effect, yet evidence of such a mechanism is rare in natural systems. Here, we ask whether the population dynamics of similar sympatric species of a seabird breeding community are synchronized, and if these species have similar exceptional responses to environmental variation. We used a 24-year time series of the breeding success and population growth rate of a marine top predator species group to assess the degree of synchrony between species demography. We then developed a novel method to examine the species group - all species combined - response to environmental variability, in particular, whether multiple species experience similar, pronounced fluctuations in their demography. Multiple species were positively correlated in breeding success and growth rate. Evidence of "exceptional" years was found, where the species group experienced pronounced fluctuations in their demography. The synchronous response of the species group was negatively correlated with winter sea surface temperature of the preceding year for both growth rate and breeding success. We present evidence for synchronous, exceptional responses of a species group that are driven by environmental variation. Such species covariation destabilizes communities by reducing the portfolio effect, and such exceptional responses may increase the risk of a state change in this community. Our understanding of the future responses to environmental change requires an increased focus on the short-term fluctuations in demography that are driven by extreme environmental variability. PMID- 23919148 TI - Covariation and repeatability of male mating effort and mating preferences in a promiscuous fish. AB - Although mate choice by males does occur in nature, our understanding of its importance in driving evolutionary change remains limited compared with that for female mate choice. Recent theoretical models have shown that the evolution of male mate choice is more likely when individual variation in male mating effort and mating preferences exist and positively covary within populations. However, relatively little is known about the nature of such variation and its maintenance within natural populations. Here, using the Trinidadian guppy (Poecilia reticulata) as a model study system, we report that mating effort and mating preferences in males, based on female body length (a strong correlate of fecundity), positively covary and are significantly variable among subjects. Individual males are thus consistent, but not unanimous, in their mate choice. Both individual mating effort (including courtship effort) and mating preference were significantly repeatable. These novel findings support the assumptions and predictions of recent evolutionary models of male mate choice, and are consistent with the presence of additive genetic variation for male mate choice based on female size in our study population and thus with the opportunity for selection and further evolution of large female body size through male mate choice. PMID- 23919149 TI - The use of on-animal acoustical recording devices for studying animal behavior. AB - Audio recordings made from free-ranging animals can be used to investigate aspects of physiology, behavior, and ecology through acoustic signal processing. On-animal acoustical monitoring applications allow continuous remote data collection, and can serve to address questions across temporal and spatial scales. We report on the design of an inexpensive collar-mounted recording device and present data on the activity budget of wild mule deer (Odocoileus hemionus) derived from these devices applied for a 2-week period. Over 3300 h of acoustical recordings were collected from 10 deer on their winter range in a natural gas extraction field in northwestern Colorado. Analysis of a subset of the data indicated deer spent approximately 33.5% of their time browsing, 20.8% of their time processing food through mastication, and nearly 38.3% of their time digesting through rumination, with marked differences in diel patterning of these activities. Systematic auditory vigilance was a salient activity when masticating, and these data offer options for quantifying wildlife responses to varying listening conditions and predation risk. These results (validated using direct observation) demonstrate that acoustical monitoring is a viable and accurate method for characterizing individual time budgets and behaviors of ungulates, and may provide new insight into the ways external forces affect wildlife behavior. PMID- 23919150 TI - Alternative trait combinations and secondary resource partitioning in sexually selected color polymorphism. AB - Resource partitioning within a species, trophic polymorphism is hypothesized to evolve by disruptive selection when intraspecific competition for certain resources is severe. However, in this study, we reported the secondary partitioning of oviposition resources without resource competition in the damselfly Ischnura senegalensis. In this species, females show color polymorphism that has been evolved as counteradaptation against sexual conflict. One of the female morphs is a blue-green (andromorph, male-like morph), whereas the other morph is brown (gynomorph). These female morphs showed alternative preferences for oviposition resources (plant tissues); andromorphs used fresh (greenish) plant tissues, whereas gynomorphs used decaying (brownish) plants tissues, suggesting that they chose oviposition resources on which they are more cryptic. In addition, the two-color morphs had different egg morphologies. Andromorphs have smaller and more elongated eggs, which seemed to adapt to hard substrates compared with those of gynomorphs. The resource partitioning in this species is achieved by morphological and behavioral differences between the color morphs that allow them to effectively exploit different resources. Resource partitioning in this system may be a by-product of phenotypic integration with body color that has been sexually selected, suggesting an overlooked mechanism of the evolution of resource partitioning. Finally, we discuss the evolutionary and ecological consequences of such resource partitioning. PMID- 23919151 TI - Individual heterogeneity in reproductive rates and cost of reproduction in a long lived vertebrate. AB - Individual variation in reproductive success is a key feature of evolution, but also has important implications for predicting population responses to variable environments. Although such individual variation in reproductive outcomes has been reported in numerous studies, most analyses to date have not considered whether these realized differences were due to latent individual heterogeneity in reproduction or merely random chance causing different outcomes among like individuals. Furthermore, latent heterogeneity in fitness components might be expressed differently in contrasted environmental conditions, an issue that has only rarely been investigated. Here, we assessed (i) the potential existence of latent individual heterogeneity and (ii) the nature of its expression (fixed vs. variable) in a population of female Weddell seals (Leptonychotes weddellii), using a hierarchical modeling approach on a 30-year mark-recapture data set consisting of 954 individual encounter histories. We found strong support for the existence of latent individual heterogeneity in the population, with "robust" individuals expected to produce twice as many pups as "frail" individuals. Moreover, the expression of individual heterogeneity appeared consistent, with only mild evidence that it might be amplified when environmental conditions are severe. Finally, the explicit modeling of individual heterogeneity allowed us to detect a substantial cost of reproduction that was not evidenced when the heterogeneity was ignored. PMID- 23919152 TI - Evidence for no sexual isolation between Drosophila albomicans and D. nasuta. AB - Sexual isolation, the reduced tendency to mate, is one of the reproductive barriers that prevent gene flow between different species. Various species specific signals during courtship contribute to sexual isolation between species. Drosophila albomicans and D. nasuta are closely related species of the nasuta subgroup within the Drosophila immigrans group and are distributed in allopatry. We analyzed mating behavior and courtship as well as cuticular hydrocarbon profiles within and between species. Here, we report that these two species randomly mated with each other. We did not observe any sexual isolation between species or between strains within species by multiple-choice tests. Significant difference in the courtship index was detected between these two species, but males and females of both species showed no discrimination against heterospecific partners. Significant quantitative variations in cuticular hydrocarbons between these two species were also found, but the cuticular hydrocarbons appear to play a negligible role in both courtship and sexual isolation between these two species. In contrast to the evident postzygotic isolation, the lack of sexual isolation between these two species suggests that the evolution of premating isolation may lag behind that of the intergenomic incompatibility, which might be driven by intragenomic conflicts. PMID- 23919153 TI - Genetic structure of the white-footed mouse in the context of the emergence of Lyme disease in southern Quebec. AB - The white-footed mouse (Peromyscus leucopus) has expanded its northern limit into southern Quebec over the last few decades. P. leucopus is a great disperser and colonizer and is of particular interest because it is considered a primary reservoir for the spirochete bacterium that causes Lyme disease. There is no current information on the gene flow between mouse populations on the mountains and forest fragments found scattered throughout the Monteregie region in southern Quebec, and whether various landscape barriers have an effect on their dispersal. We conducted a population genetics analysis on eleven P. leucopus populations using eleven microsatellite markers and showed that isolation by distance was weak, yet barriers were effective. The agricultural matrix had the least effect on gene flow, whereas highways and main rivers were effective barriers. The abundance of ticks collected from mice varied within the study area. Both ticks and mice were screened for the presence of the spirochete bacterium Borrelia burgdorferi, and we predicted areas of greater risk for Lyme disease. Merging our results with ongoing Lyme disease surveillance programs will help determine the future threat of this disease in Quebec, and will contribute toward disease prevention and management strategies throughout fragmented landscapes in southern Canada. PMID- 23919154 TI - Inbreeding reveals mode of past selection on male reproductive characters in Drosophila melanogaster. AB - Directional dominance is a prerequisite of inbreeding depression. Directionality arises when selection drives alleles that increase fitness to fixation and eliminates dominant deleterious alleles, while deleterious recessives are hidden from it and maintained at low frequencies. Traits under directional selection (i.e., fitness traits) are expected to show directional dominance and therefore an increased susceptibility to inbreeding depression. In contrast, traits under stabilizing selection or weakly linked to fitness are predicted to exhibit little to-no inbreeding depression. Here, we quantify the extent of inbreeding depression in a range of male reproductive characters and then infer the mode of past selection on them. The use of transgenic populations of Drosophila melanogaster with red or green fluorescent-tagged sperm heads permitted in vivo discrimination of sperm from competing males and quantification of characteristics of ejaculate composition, performance, and fate. We found that male attractiveness (mating latency) and competitive fertilization success (P2) both show some inbreeding depression, suggesting they may have been under directional selection, whereas sperm length showed no inbreeding depression suggesting a history of stabilizing selection. However, despite having measured several sperm quality and quantity traits, our data did not allow us to discern the mechanism underlying the lowered competitive fertilization success of inbred (f = 0.50) males. PMID- 23919155 TI - Evolutionary dynamics of giant viruses and their virophages. AB - Giant viruses contain large genomes, encode many proteins atypical for viruses, replicate in large viral factories, and tend to infect protists. The giant virus replication factories can in turn be infected by so called virophages, which are smaller viruses that negatively impact giant virus replication. An example is Mimiviruses that infect the protist Acanthamoeba and that are themselves infected by the virophage Sputnik. This study examines the evolutionary dynamics of this system, using mathematical models. While the models suggest that the virophage population will evolve to increasing degrees of giant virus inhibition, it further suggests that this renders the virophage population prone to extinction due to dynamic instabilities over wide parameter ranges. Implications and conditions required to avoid extinction are discussed. Another interesting result is that virophage presence can fundamentally alter the evolutionary course of the giant virus. While the giant virus is predicted to evolve toward increasing its basic reproductive ratio in the absence of the virophage, the opposite is true in its presence. Therefore, virophages can not only benefit the host population directly by inhibiting the giant viruses but also indirectly by causing giant viruses to evolve toward weaker phenotypes. Experimental tests for this model are suggested. PMID- 23919156 TI - Genotypic and phenotypic variation in transmission traits of a complex life cycle parasite. AB - Characterizing genetic variation in parasite transmission traits and its contribution to parasite vigor is essential for understanding the evolution of parasite life-history traits. We measured genetic variation in output, activity, survival, and infection success of clonal transmission stages (cercaria larvae) of a complex life cycle parasite (Diplostomum pseudospathaceum). We further tested if variation in host nutritional stage had an effect on these traits by keeping hosts on limited or ad libitum diet. The traits we measured were highly variable among parasite genotypes indicating significant genetic variation in these life-history traits. Traits were also phenotypically variable, for example, there was significant variation in the measured traits over time within each genotype. However, host nutritional stage had no effect on the parasite traits suggesting that a short-term reduction in host resources was not limiting the cercarial output or performance. Overall, these results suggest significant interclonal and phenotypic variation in parasite transmission traits that are not affected by host nutritional status. PMID- 23919157 TI - Can endopolyploidy explain body size variation within and between castes in ants? AB - Endoreduplication is the process by which the nuclear genome is repeatedly replicated without mitotic cell division, resulting in nuclei that contain numerous additional genome copies. Endoreduplication occurs widely throughout Eucarya and is particularly common in angiosperms and insects. Although endoreduplication is an important process in the terminal differentiation of some specialized cell types, and often increases cell size and metabolism, the direct effects of increasing nuclear ploidy on cell function are not well resolved. Here, we examine if endoreduplication may play a role in body size and/or caste differentiation in ants. Nuclear ploidy was measured by flow cytometry of whole individuals (providing the basis for overall body size patterns) and individual body segments for multiple polymorphic ant species. We used cell cycle values, interpreted as the mean number of endocycles performed by each cell in the sample, as our measure of overall endoreduplication. Among females of four polymorphic ant species, endoreduplication was positively related with size within the worker caste, but was not related to caste generally in two species where we also examined queens. Additionally, abdomens had the greatest endoreduplication of all body parts regardless of caste or size. We also found that males, having derived from haploid unfertilized eggs, had the highest rates of endoreduplication and may compensate for their haploid origin by performing an additional endocycle relative to females. These results suggest that endoreduplication may play a role in body size variation in eusocial insects and the development of some segment-specific tissues. PMID- 23919158 TI - An ecological genetic delineation of local seed-source provenance for ecological restoration. AB - An increasingly important practical application of the analysis of spatial genetic structure within plant species is to help define the extent of local provenance seed collection zones that minimize negative impacts in ecological restoration programs. Here, we derive seed sourcing guidelines from a novel range wide assessment of spatial genetic structure of 24 populations of Banksia menziesii (Proteaceae), a widely distributed Western Australian tree of significance in local ecological restoration programs. An analysis of molecular variance (AMOVA) of 100 amplified fragment length polymorphism (AFLP) markers revealed significant genetic differentiation among populations (PhiPT = 0.18). Pairwise population genetic dissimilarity was correlated with geographic distance, but not environmental distance derived from 15 climate variables, suggesting overall neutrality of these markers with regard to these climate variables. Nevertheless, Bayesian outlier analysis identified four markers potentially under selection, although these were not correlated with the climate variables. We calculated a global R-statistic using analysis of similarities (ANOSIM) to test the statistical significance of population differentiation and to infer a threshold seed collection zone distance of ~60 km (all markers) and 100 km (outlier markers) when genetic distance was regressed against geographic distance. Population pairs separated by >60 km were, on average, twice as likely to be significantly genetically differentiated than population pairs separated by <60 km, suggesting that habitat-matched sites within a 30-km radius around a restoration site genetically defines a local provenance seed collection zone for B. menziesii. Our approach is a novel probability-based practical solution for the delineation of a local seed collection zone to minimize negative genetic impacts in ecological restoration. PMID- 23919159 TI - QTL affecting fitness of hybrids between wild and cultivated soybeans in experimental fields. AB - The objective of this study was to identify quantitative trait loci (QTL) affecting fitness of hybrids between wild soybean (Glycine soja) and cultivated soybean (Glycine max). Seed dormancy and seed number, both of which are important for fitness, were evaluated by testing artificial hybrids of G. soja * G. max in a multiple-site field trial. Generally, the fitness of the F1 hybrids and hybrid derivatives from self-pollination was lower than that of G. soja due to loss of seed dormancy, whereas the fitness of hybrid derivatives with higher proportions of G. soja genetic background was comparable with that of G. soja. These differences were genetically dissected into QTL for each population. Three QTLs for seed dormancy and one QTL for total seed number were detected in the F2 progenies of two diverse cross combinations. At those four QTLs, the G. max alleles reduced seed number and severely reduced seed survival during the winter, suggesting that major genes acquired during soybean adaptation to cultivation have a selective disadvantage in natural habitats. In progenies with a higher proportion of G. soja genetic background, the genetic effects of the G. max alleles were not expressed as phenotypes because the G. soja alleles were dominant over the G. max alleles. Considering the highly inbreeding nature of these species, most hybrid derivatives would disappear quickly in early self pollinating generations in natural habitats because of the low fitness of plants carrying G. max alleles. PMID- 23919160 TI - Demographic patterns of a widespread long-lived tree are associated with rainfall and disturbances along rainfall gradients in SE Australia. AB - Predicting species distributions with changing climate has often relied on climatic variables, but increasingly there is recognition that disturbance regimes should also be included in distribution models. We examined how changes in rainfall and disturbances along climatic gradients determined demographic patterns in a widespread and long-lived tree species, Callitris glaucophylla in SE Australia. We examined recruitment since 1950 in relation to annual (200-600 mm) and seasonal (summer, uniform, winter) rainfall gradients, edaphic factors (topography), and disturbance regimes (vertebrate grazing [tenure and species], fire). A switch from recruitment success to failure occurred at 405 mm mean annual rainfall, coincident with a change in grazing regime. Recruitment was lowest on farms with rabbits below 405 mm rainfall (mean = 0-0.89 cohorts) and highest on less-disturbed tenures with no rabbits above 405 mm rainfall (mean = 3.25 cohorts). Moderate levels of recruitment occurred where farms had no rabbits or less disturbed tenures had rabbits above and below 405 mm rainfall (mean = 1.71-1.77 cohorts). These results show that low annual rainfall and high levels of introduced grazing has led to aging, contracting populations, while higher annual rainfall with low levels of grazing has led to younger, expanding populations. This study demonstrates how demographic patterns vary with rainfall and spatial variations in disturbances, which are linked in complex ways to climatic gradients. Predicting changes in tree distribution with climate change requires knowledge of how rainfall and key disturbances (tenure, vertebrate grazing) will shift along climatic gradients. PMID- 23919161 TI - Female mate preferences for male body size and shape promote sexual isolation in threespine sticklebacks. AB - Female mate preferences for ecologically relevant traits may enhance natural selection, leading to rapid divergence. They may also forge a link between mate choice within species and sexual isolation between species. Here, we examine female mate preference for two ecologically important traits: body size and body shape. We measured female preferences within and between species of benthic, limnetic, and anadromous threespine sticklebacks (Gasterosteus aculeatus species complex). We found that mate preferences differed between species and between contexts (i.e., within vs. between species). Within species, anadromous females preferred males that were deep bodied for their size, benthic females preferred larger males (as measured by centroid size), and limnetic females preferred males that were more limnetic shaped. In heterospecific mating trials between benthics and limnetics, limnetic females continued to prefer males that were more limnetic like in shape when presented with benthic males. Benthic females showed no preferences for size when presented with limnetic males. These results show that females use ecologically relevant traits to select mates in all three species and that female preference has diverged between species. These results suggest that sexual selection may act in concert with natural selection on stickleback size and shape. Further, our results suggest that female preferences may track adaptation to local environments and contribute to sexual isolation between benthic and limnetic sticklebacks. PMID- 23919162 TI - Condition-dependent expression of pre- and postcopulatory sexual traits in guppies. AB - Female choice can impose persistent directional selection on male sexually selected traits, yet such traits often exhibit high levels of phenotypic variation. One explanation for this paradox is that if sexually selected traits are costly, only the fittest males are able to acquire and allocate the resources required for their expression. Furthermore, because male condition is dependent on resource allocation, condition dependence in sexual traits is expected to underlie trade-offs between reproduction and other life-history functions. In this study we test these ideas by experimentally manipulating diet quality (carotenoid levels) and quantity in the guppy (Poecilia reticulata), a livebearing freshwater fish that is an important model for understanding relationships between pre- and post-copulatory sexually selected traits. Specifically, we test for condition dependence in the expression of pre- and postcopulatory sexual traits (behavior, ornamentation, sperm traits) and determine whether diet manipulation mediates relationships among these traits. Consistent with prior work we found a significant effect of diet quantity on the expression of both pre- and postcopulatory male traits; diet-restricted males performed fewer sexual behaviors and exhibited significant reductions in color ornamentation, sperm quality, sperm number, and sperm length than those fed ad libitum. However, contrary to our expectations, we found no significant effect of carotenoid manipulation on the expression of any of these traits, and no evidence for a trade-off in resource allocation between pre- and postcopulatory episodes of sexual selection. Our results further underscore the sensitivity of behavioral, ornamental, and ejaculate traits to dietary stress, and highlight the important role of condition dependence in maintaining the high variability in male sexual traits. PMID- 23919163 TI - Host-parasite genotypic interactions in the honey bee: the dynamics of diversity. AB - Parasites are thought to be a major driving force shaping genetic variation in their host, and are suggested to be a significant reason for the maintenance of sexual reproduction. A leading hypothesis for the occurrence of multiple mating (polyandry) in social insects is that the genetic diversity generated within colonies through this behavior promotes disease resistance. This benefit is likely to be particularly significant when colonies are exposed to multiple species and strains of parasites, but host-parasite genotypic interactions in social insects are little known. We investigated this using honey bees, which are naturally polyandrous and consequently produce genetically diverse colonies containing multiple genotypes (patrilines), and which are also known to host multiple strains of various parasite species. We found that host genotypes differed significantly in their resistance to different strains of the obligate fungal parasite that causes chalkbrood disease, while genotypic variation in resistance to the facultative fungal parasite that causes stonebrood disease was less pronounced. Our results show that genetic variation in disease resistance depends in part on the parasite genotype, as well as species, with the latter most likely relating to differences in parasite life history and host-parasite coevolution. Our results suggest that the selection pressure from genetically diverse parasites might be an important driving force in the evolution of polyandry, a mechanism that generates significant genetic diversity in social insects. PMID- 23919164 TI - The evolution of costly acquired immune memory. AB - A key feature of the vertebrate adaptive immune system is acquired immune memory, whereby hosts launch a faster and heightened response when challenged by previously encountered pathogens, preventing full infection. Here, we use a mathematical model to explore the role of ecological and epidemiological processes in shaping selection for costly acquired immune memory. Applying the framework of adaptive dynamics to the classic SIR (Susceptible-Infected Recovered) epidemiological model, we focus on the conditions that may lead hosts to evolve high levels of immunity. Linking our work to previous theory, we show how investment in immune memory may be greatest at long or intermediate host lifespans depending on whether immunity is long lasting. High initial costs to gain immunity are also found to be essential for a highly effective immune memory. We also find that high disease infectivity and sterility, but intermediate virulence and immune period, increase selection for immunity. Diversity in host populations through evolutionary branching is found to be possible but only for a limited range of parameter space. Our model suggests that specific ecological and epidemiological conditions have to be met for acquired immune memory to evolve. PMID- 23919165 TI - Estimating resource selection with count data. AB - Resource selection functions (RSFs) are typically estimated by comparing covariates at a discrete set of "used" locations to those from an "available" set of locations. This RSF approach treats the response as binary and does not account for intensity of use among habitat units where locations were recorded. Advances in global positioning system (GPS) technology allow animal location data to be collected at fine spatiotemporal scales and have increased the size and correlation of data used in RSF analyses. We suggest that a more contemporary approach to analyzing such data is to model intensity of use, which can be estimated for one or more animals by relating the relative frequency of locations in a set of sampling units to the habitat characteristics of those units with count-based regression and, in particular, negative binomial (NB) regression. We demonstrate this NB RSF approach with location data collected from 10 GPS collared Rocky Mountain elk (Cervus elaphus) in the Starkey Experimental Forest and Range enclosure. We discuss modeling assumptions and show how RSF estimation with NB regression can easily accommodate contemporary research needs, including: analysis of large GPS data sets, computational ease, accounting for among-animal variation, and interpretation of model covariates. We recommend the NB approach because of its conceptual and computational simplicity, and the fact that estimates of intensity of use are unbiased in the face of temporally correlated animal location data. PMID- 23919166 TI - Evidence for parallel adaptation to climate across the natural range of Arabidopsis thaliana. AB - How organisms adapt to different climate habitats is a key question in evolutionary ecology and biological conservation. Species distributions are often determined by climate suitability. Consequently, the anthropogenic impact on earth's climate is of key concern to conservation efforts because of our relatively poor understanding of the ability of populations to track and evolve to climate change. Here, we investigate the ability of Arabidopsis thaliana to occupy climate space by quantifying the extent to which different climate regimes are accessible to different A. thaliana genotypes using publicly available data from a large-scale genotyping project and from a worldwide climate database. The genetic distance calculated from 149 single-nucleotide polymorphisms (SNPs) among 60 lineages of A. thaliana was compared to the corresponding climate distance among collection localities calculated from nine different climatic factors. A. thaliana was found to be highly labile when adapting to novel climate space, suggesting that populations may experience few constraints when adapting to changing climates. Our results also provide evidence of a parallel or convergent evolution on the molecular level supporting recent generalizations regarding the genetics of adaptation. PMID- 23919167 TI - Inferences of evolutionary history of a widely distributed mangrove species, Bruguiera gymnorrhiza, in the Indo-West Pacific region. AB - Inference of genetic structure and demographic history is fundamental issue in evolutionary biology. We examined the levels and patterns of genetic variation of a widespread mangrove species in the Indo-West Pacific region, Bruguiera gymnorrhiza, using ten nuclear gene regions. Genetic variation of individual populations covering its distribution range was low, but as the entire species it was comparable to other plant species. Genetic differentiation among the investigated populations was high. They could be divided into two genetic clusters: the West and East clusters of the Malay Peninsula. Our results indicated that these two genetic clusters derived from their ancestral population whose effective size of which was much larger compared to the two extant clusters. The point estimate of speciation time between B. gymnorrhiza and Bruguiera sexangula was two times older than that of divergence time between the two clusters. Migration from the West cluster to the East cluster was much higher than the opposite direction but both estimated migration rates were low. The past Sundaland and/or the present Malay Peninsula are likely to prevent gene flow between the West and East clusters and function as a geographical or land barrier. PMID- 23919168 TI - Lake Malawi cichlid evolution along a benthic/limnetic axis. AB - Divergence along a benthic to limnetic habitat axis is ubiquitous in aquatic systems. However, this type of habitat divergence has largely been examined in low diversity, high latitude lake systems. In this study, we examined the importance of benthic and limnetic divergence within the incredibly species-rich radiation of Lake Malawi cichlid fishes. Using novel phylogenetic reconstructions, we provided a series of hypotheses regarding the evolutionary relationships among 24 benthic and limnetic species that suggests divergence along this axis has occurred multiple times within Lake Malawi cichlids. Because pectoral fin morphology is often associated with divergence along this habitat axis in other fish groups, we investigated divergence in pectoral fin muscles in these benthic and limnetic cichlid species. We showed that the eight pectoral fin muscles and fin area generally tended to evolve in a tightly correlated manner in the Lake Malawi cichlids. Additionally, we found that larger pectoral fin muscles are strongly associated with the independent evolution of the benthic feeding habit across this group of fish. Evolutionary specialization along a benthic/limnetic axis has occurred multiple times within this tropical lake radiation and has produced repeated convergent matching between exploitation of water column habitats and locomotory morphology. PMID- 23919169 TI - Reconstructing shifts in vital rates driven by long-term environmental change: a new demographic method based on readily available data. AB - Frequently, vital rates are driven by directional, long-term environmental changes. Many of these are of great importance, such as land degradation, climate change, and succession. Traditional demographic methods assume a constant or stationary environment, and thus are inappropriate to analyze populations subject to these changes. They also require repeat surveys of the individuals as change unfolds. Methods for reconstructing such lengthy processes are needed. We present a model that, based on a time series of population size structures and densities, reconstructs the impact of directional environmental changes on vital rates. The model uses integral projection models and maximum likelihood to identify the rates that best reconstructs the time series. The procedure was validated with artificial and real data. The former involved simulated species with widely different demographic behaviors. The latter used a chronosequence of populations of an endangered cactus subject to increasing anthropogenic disturbance. In our simulations, the vital rates and their change were always reconstructed accurately. Nevertheless, the model frequently produced alternative results. The use of coarse knowledge of the species' biology (whether vital rates increase or decrease with size or their plausible values) allowed the correct rates to be identified with a 90% success rate. With real data, the model correctly reconstructed the effects of disturbance on vital rates. These effects were previously known from two populations for which demographic data were available. Our procedure seems robust, as the data violated several of the model's assumptions. Thus, time series of size structures and densities contain the necessary information to reconstruct changing vital rates. However, additional biological knowledge may be required to provide reliable results. Because time series of size structures and densities are available for many species or can be rapidly generated, our model can contribute to understand populations that face highly pressing environmental problems. PMID- 23919170 TI - Estimating home-range size: when to include a third dimension? AB - Most studies dealing with home ranges consider the study areas as if they were totally flat, working only in two dimensions, when in reality they are irregular surfaces displayed in three dimensions. By disregarding the third dimension (i.e., topography), the size of home ranges underestimates the surface actually occupied by the animal, potentially leading to misinterpretations of the animals' ecological needs. We explored the influence of considering the third dimension in the estimation of home-range size by modeling the variation between the planimetric and topographic estimates at several spatial scales. Our results revealed that planimetric approaches underestimate home-range size estimations, which range from nearly zero up to 22%. The difference between planimetric and topographic estimates of home-ranges sizes produced highly robust models using the average slope as the sole independent factor. Moreover, our models suggest that planimetric estimates in areas with an average slope of 16.3 degrees (+/ 0.4) or more will incur in errors >=5%. Alternatively, the altitudinal range can be used as an indicator of the need to include topography in home-range estimates. Our results confirmed that home-range estimates could be significantly biased when topography is disregarded. We suggest that study areas where home range studies will be performed should firstly be scoped for its altitudinal range, which can serve as an indicator for the need for posterior use of average slope values to model the surface area used and/or available for the studied animals. PMID- 23919171 TI - Assessing the cryptic invasion of a domestic conspecific: American mink in their native range. AB - Control of invasions is facilitated by their early detection, but this may be difficult when invasions are cryptic due to similarity between invaders and native species. Domesticated conspecifics offer an interesting example of cryptic invasions because they have the ability to hybridize with their native counterparts, and can thus facilitate the introgression of maladaptive genes. We assessed the cryptic invasion of escaped domestic American mink (Neovison vison) within their native range. Feral mink are a known alien invader in many parts of the world, but invasion of their native range is not well understood. We genetically profiled 233 captive domestic mink from different farms in Ontario, Canada and 299 free-ranging mink from Ontario, and used assignments tests to ascertain genetic ancestries of free-ranging animals. We found that 18% of free ranging mink were either escaped domestic animals or hybrids, and a tree regression showed that these domestic genotypes were most likely to occur south of a latitude of 43.13 degrees N, within the distribution of mink farms in Ontario. Thus, domestic mink appear not to have established populations in Ontario in locations without fur farms. We suspect that maladaptation of domestic mink and outbreeding depression of hybrid and introgressed mink have limited their spread. Mink farm density and proximity to mink farms were not important predictors of domestic genotypes but rather, certain mink farms appeared to be important sources of escaped domestic animals. Our results show that not all mink farms are equal with respect to biosecurity, and thus that the spread of domestic genotypes can be mitigated by improved biosecurity. PMID- 23919172 TI - Quantifying the biomass of parasites to understand their role in aquatic communities. AB - By infecting multiple host species and acting as a food resource, parasites can affect food web topography and contribute to ecosystem energy transfer. Owing to the remarkable secondary production of some taxa, parasite biomass - although cryptic - can be comparable to other invertebrate and vertebrate groups. More resolved estimates of parasite biomass are therefore needed to understand parasite interactions, their consequences for host fitness, and potential influences on ecosystem energetics. We developed an approach to quantify the masses of helminth parasites and compared our results with those of biovolume based approaches. Specifically, we massed larval and adult parasites representing 13 species and five life stages of trematodes and cestodes from snail and amphibian hosts. We used a replicated regression approach to quantify dry mass and compared these values with indirect biovolume estimates to test the validity of density assumptions. Our technique provided precise estimates (R (2) from 0.69 to 0.98) of biomass across a wide range of parasite morphotypes and sizes. Individual parasites ranged in mass from 0.368 +/- 0.041 to 320 +/- 98.1 MUg. Among trematodes, adult parasites tended to be the largest followed by rediae, with nonclonal larval stages (metacercariae and cercariae) as the smallest. Among similar morphotypes, direct estimates of dry mass and the traditional biovolume technique provided generally comparable estimates (although important exceptions also emerged). Finally, we present generalized length-mass regression equations to calculate trematode mass from length measurements, and discuss the most efficient use of limited numbers of parasites. By providing a novel method of directly estimating parasite biomass while also helping to validate more traditional methods involving length-mass conversion, our findings aim to facilitate future investigations into the ecological significance of parasites, particularly with respect to ecosystem energetics. In addition, this novel technique can be applied to a wide range of difficult-to-mass organisms. PMID- 23919173 TI - Genetic by environment interactions affect plant-soil linkages. AB - The role of plant intraspecific variation in plant-soil linkages is poorly understood, especially in the context of natural environmental variation, but has important implications in evolutionary ecology. We utilized three 18- to 21-year old common gardens across an elevational gradient, planted with replicates of five Populus angustifolia genotypes each, to address the hypothesis that tree genotype (G), environment (E), and G * E interactions would affect soil carbon and nitrogen dynamics beneath individual trees. We found that soil nitrogen and carbon varied by over 50% and 62%, respectively, across all common garden environments. We found that plant leaf litter (but not root) traits vary by genotype and environment while soil nutrient pools demonstrated genotype, environment, and sometimes G * E interactions, while process rates (net N mineralization and net nitrification) demonstrated G * E interactions. Plasticity in tree growth and litter chemistry was significantly related to the variation in soil nutrient pools and processes across environments, reflecting tight plant soil linkages. These data overall suggest that plant genetic variation can have differential affects on carbon storage and nitrogen cycling, with implications for understanding the role of genetic variation in plant-soil feedback as well as management plans for conservation and restoration of forest habitats with a changing climate. PMID- 23919175 TI - Using GPS telemetry to validate least-cost modeling of gray squirrel (Sciurus carolinensis) movement within a fragmented landscape. AB - In Britain, the population of native red squirrels Sciurus vulgaris has suffered population declines and local extinctions. Interspecific resource competition and disease spread by the invasive gray squirrel Sciurus carolinensis are the main factors behind the decline. Gray squirrels have adapted to the British landscape so efficiently that they are widely distributed. Knowledge on how gray squirrels are using the landscape matrix and being able to predict their movements will aid management. This study is the first to use global positioning system (GPS) collars on wild gray squirrels to accurately record movements and land cover use within the landscape matrix. This data were used to validate Geographical Information System (GIS) least-cost model predictions of movements and provided much needed information on gray squirrel movement pathways and network use. Buffered least-cost paths and least-cost corridors provide predictions of the most probable movements through the landscape and are seen to perform better than the more expansive least-cost networks which include all possible movements. Applying the knowledge and methodologies gained to current gray squirrel expansion areas, such as Scotland and in Italy, will aid in the prediction of potential movement areas and therefore management of the invasive gray squirrel. The methodologies presented in this study could potentially be used in any landscape and on numerous species. PMID- 23919174 TI - Changes in the genetic structure of Atlantic salmon populations over four decades reveal substantial impacts of stocking and potential resiliency. AB - While the stocking of captive-bred fish has been occurring for decades and has had substantial immediate genetic and evolutionary impacts on wild populations, its long-term consequences have only been weakly investigated. Here, we conducted a spatiotemporal analysis of 1428 Atlantic salmon sampled from 1965 to 2006 in 25 populations throughout France to investigate the influence of stocking on the neutral genetic structure in wild Atlantic salmon (Salmo salar) populations. On the basis of the analysis of 11 microsatellite loci, we found that the overall genetic structure among populations dramatically decreased over the period studied. Admixture rates among populations were highly variable, ranging from a nearly undetectable contribution from donor stocks to total replacement of the native gene pool, suggesting extremely variable impacts of stocking. Depending on population, admixture rates either increased, remained stable, or decreased in samples collected between 1998 and 2006 compared to samples from 1965 to 1987, suggesting either rising, long-lasting or short-term impacts of stocking. We discuss the potential mechanisms contributing to this variability, including the reduced fitness of stocked fish and persistence of wild locally adapted individuals. PMID- 23919176 TI - Recent physical connections may explain weak genetic structure in western Alaskan chum salmon (Oncorhynchus keta) populations. AB - Low genetic divergence at neutral loci among populations is often the result of high levels of contemporary gene flow. Western Alaskan summer-run chum salmon (Oncorhynchus keta) populations demonstrate weak genetic structure, but invoking contemporary gene flow as the basis for the low divergence is problematic because salmon home to their natal streams and some of the populations are thousands of kilometers apart. We used genotypes from microsatellite and single nucleotide polymorphism loci to investigate alternative explanations for the current genetic structure of chum salmon populations from western Alaska. We also estimated current levels of gene flow among Kuskokwim River populations. Our results suggest that weak genetic structure is best explained by physical connections that occurred after the Holocene Thermal Maximum among the Yukon, Kuskokwim, and Nushagak drainages that allowed gene flow to occur among now distant populations. PMID- 23919177 TI - A new method for identifying rapid decline dynamics in wild vertebrate populations. AB - Tracking trends in the abundance of wildlife populations is a sensitive method for assessing biodiversity change due to the short time-lag between human pressures and corresponding shifts in population trends. This study tests for proposed associations between different types of human pressures and wildlife population abundance decline-curves and introduces a method to distinguish decline trajectories from natural fluctuations in population time-series. First, we simulated typical mammalian population time-series under different human pressure types and intensities and identified significant distinctions in population dynamics. Based on the concavity of the smoothed population trend and the algebraic function which was the closest fit to the data, we determined those differences in decline dynamics that were consistently attributable to each pressure type. We examined the robustness of the attribution of pressure type to population decline dynamics under more realistic conditions by simulating populations under different levels of environmental stochasticity and time-series data quality. Finally, we applied our newly developed method to 124 wildlife population time-series and investigated how those threat types diagnosed by our method compare to the specific threatening processes reported for those populations. We show how wildlife population decline curves can be used to discern between broad categories of pressure or threat types, but do not work for detailed threat attributions. More usefully, we find that differences in population decline curves can reliably identify populations where pressure is increasing over time, even when data quality is poor, and propose this method as a cost-effective technique for prioritizing conservation actions between populations. PMID- 23919179 TI - Recruitment of transcription complexes to enhancers and the role of enhancer transcription. AB - Enhancer elements regulate the tissue- and developmental-stage-specific expression of genes. Recent estimates suggest that there are more than 50,000 enhancers in mammalian cells. At least a subset of enhancers has been shown to recruit RNA polymerase II transcription complexes and to generate enhancer transcripts. Here, we provide an overview of enhancer function and discuss how transcription of enhancers or enhancer-generated transcripts could contribute to the regulation of gene expression during development and differentiation. PMID- 23919181 TI - Knowledge, attitude and practices of women towards breast cancer in benin city, Nigeria. AB - BACKGROUND: Breast cancer is the principal cause of cancer deaths among women worldwide. African women in comparison with their low incidence of cancer, disproportionately bear a high cancer mortality rate. AIM: The study was aimed at investigating level of breast cancer awareness, attitudes and practices towards early detection strategies. SUBJECTS AND METHODS: The study was conducted in Oredo municipal council of Benin city and adopted a descriptive cross sectional design. Purposive, stratified and simple random sampling were used to select 365 women from 9 health facilities in 6 wards of the municipality. Self-administered questionnaires were used. Analysis was done using Social Science Statistical Package, version 16 (United States, 2007) (country of make and if). Test of associations employed chi square statistical tool with level of significance generally taken at 0.05. RESULTS: About 90.5% (314/347) knew about breast cancer, but only about 49.71% (172/347) knew up to 3 breast cancer risk factors. A total of 65.2% (226/347) could identify up to two breast cancer signs and symptoms. While about 56.5% (195/347) knew at least one early detection strategy, it was however only about 17.73% (61/347) that practiced regularly at least one of the early detective procedures. Practice of early detection strategies was significantly associated with knowledge (P = 0.01 respectively). CONCLUSION: The result shows that while substantial number still remains ignorant of breast cancer issues, a good number of those who have knowledge were yet to translate knowledge and attitudes into practice. PMID- 23919180 TI - Association between Periodontal Status, Oral Hygiene Status and Tooth Wear among Adult Male Population in Benin City, Nigeria. AB - BACKGROUND: The association between periodontal status, oral hygiene status and severity of tooth wear lesion varies from community to community and also from occupation to occupation. AIM: To determine the association between periodontal status, oral hygiene status and tooth wear among the adult male population in Benin City, Nigeria. SUBJECTS AND METHODS: This study was conducted among 65 male drivers, aged 25-64 years, with a mean age of 48.6 (9.1) years in an organized private motor park in Benin City between November 2011 and January 2012. The data collected through interview and clinical oral examination were age, educational status, driving experience, oral hygiene status, periodontal status and severity of tooth wear. RESULTS: In this study, 13.8% (9/65) and 1.5% (1/65) of the participants had 4-5 mm and >=6 mm periodontal pockets, respectively. A total of 15.4% (10/65) of the participants had poor oral hygiene status and 58.5% (38/65) of the participants had tooth wear lesion, with 15.8% (9/65) being severe tooth wear lesions (score 3). Participants with poorer oral hygiene and more severe tooth wear lesions significantly exhibited poorer periodontal status. There also existed a significant association between oral hygiene status and the severity of tooth wear lesion among the participants in this study. CONCLUSION: Data from this study revealed a statistically significant association between periodontal status, oral hygiene status and severity of tooth wear lesion among the participants. PMID- 23919182 TI - Mandibular fractures at veer chandra singh garhwali government medical science and research institute, garhwal region, uttarakhand, India: a retrospective study. AB - BACKGROUND: Mandibular fractures constitute a substantial proportion of cases of maxillofacial trauma. Demographic data related to mandibular fractures are difficult to evaluate because of many variables associated with the studies. The information is as diverse as the countries and the people who inhabit them. AIM: This is a retrospective study designed to determine the site distribution, associated fracture and causes of mandibular fractures in patients presenting to the trauma centre of Veer Chandra Singh Garhwali Government Medical Science and Research Institute, Uttarakhand, India. MATERIALS AND METHODS: Records of 121 patients with confirmed mandibular fractures presenting over a three year period (i.e., 1(st) January 2008 to 31(st) December 2010). Data obtained from record included age, sex, site of fracture and causes. RESULTS: There were 48/121 (39.6%) males and 73/121 (60.3%) females. The most predominant age group of fracture was found to be 21-30 (53/121-43.8%) followed by 11-20 (25/121-20.6%). In this study history of fall was the most common cause of mandibular fracture (66/121-54.5%), followed by road traffic accidents (45/121-37.1%), fights and assault (08/121-6.6%) and industrial accidents (02/121-1.6%). In our study most of the patients suffered from fracture in the parasymphysis (35/139-25.1%) and angle region (32/139-23.0%) followed by body (30/139-21.5%), condyle (21/139 15.1%), symphysis (19/139-13.7%), and ramus (02/121-1.4%) area. CONCLUSION: In this study mandibular fractures were more prevalent in females especially during the second and third decade of life. History of fall was the most predominant cause of mandibular fracture. The most frequently affected sites were parasymphysis and angle. PMID- 23919183 TI - An appraisal of the management of ectopic pregnancy in a nigerian tertiary hospital. AB - BACKGROUND: Ectopic pregnancy has remained a significant cause of maternal morbidity and mortality especially in the sub Saharan Africa. A periodic appraisal of its management is paramount. AIM: To determine the incidence and associated risk factors, for ectopic pregnancy, review available treatment modalities and suggest interventions to reduce its prevalence, morbidity and mortality. MATERIALS AND METHODS: A cross sectional study with retrolective data collection of all cases of ectopic pregnancy managed in Nnamdi Azikiwe University Teaching Hospital, Nnewi, south-east Nigeria between 1(st) January, 2002 and 31(st) December, 2011 was undertaken. Analysis was carried out using Epi-info 2008 version 3.5.1. RESULTS: During the study period, there were a total 98 cases of ectopic pregnancies out of 8,811 deliveries and 1884 gynecological admissions, giving an incidence of 0.9% of all attendants or 1 in 90 deliveries and 5.2% of all gynecological admissions. Only 94.9% (93/98) case files were retrieved and were used in the final analysis. The mean age of the patients was 30.1 (0.7) years while the mean gestational age at presentations was 7.4 weeks. Previous induced abortion, 37.5% (36/93) was the commonest associated risk factor, followed by pelvic infections, 35.5% (33/93). The recurrence rate was 6.5% (6/93). Majority, 80.6% (75/93) presented with abdominal pain and 35.8% (33/93) presented with vaginal bleeding. Up to 88.2% (82/93) had salpingectomy while only 2.5% (2/93) were successfully managed medically with methotrexate therapy following diagnosis with transvaginal ultrasound Missed diagnosis of ectopic pregnancy occurred in 16.1% (15/93). There was no maternal death. CONCLUSION: Ectopic pregnancy has remained an important gynecological condition in our center. The common identifiable risk factors were induced abortion and pelvic infection. Early first trimester transvaginal ultrasound should be offered to all women for early diagnosis. PMID- 23919185 TI - Unsafe injection practices: a potential weapon for the outbreak of blood borne viruses in the community. AB - BACKGROUND: Unsafe injection practices are common in developing nations. Such practices, through contaminated needles and syringes, place injection recipient, healthcare workers and the community at large at risk of infection with blood borne viruses. AIM: An attempt was made to briefly describe an acute hepatitis outbreak that occurred in Gujarat, India, due to unsafe injection practices with a brief review of the literature. SUBJECTS AND METHODS: An outbreak of acute hepatitis occurred in February-March 2009 in the Sabarkantha district of Gujarat in India. Blood samples were collected randomly from 25 cases, admitted in the local hospital during the ongoing outbreak. Screening was done using an immunoassay analyzer (Cobas e411; Roche Diagnostics, Indianapolis, IN, USA) for hepatitis B surface antigen (HBsAg), IgM and total antibodies to hepatitis B core antigen (HBc), hepatitis B e antigen (HBeAg) and antibody to HBe, antibodies to HCV, HIV and IgM antibodies to hepatitis A virus (HAV), as per the manufacturer's protocol. RESULTS: Gross and continuous use of contaminated needle and syringes were responsible for this outbreak as all the patients gave history of receiving injections about 2-3 months prior to the development of clinical signs and symptoms, from one particular doctor. Mean age of the patients was 33.4 years (SD 12.9 years). Seventeen of these patients were males and eight were females. All patients were hepatitis B surface antigen positive, with median levels as 35,450 IU/mL (IQR 450-2,49,750 IU/mL). IgM HBc was positive in 22/25 (88%). HBe Ag was positive in 11 patients (44%). The median HBV DNA level was 2.6 * 10(4) IU/mL (IQR 1.18 * 10(2) to 6.7 * 10(6) IU/mL). No significant co-infection with other hepatitis viruses existed. All isolates were genotype D. CONCLUSIONS: The findings emphasize the role of unsafe injection practices in the community outbreak of hepatitis B infection, need to start routine surveillance system and increase awareness in health care workers regarding safe injection practices. PMID- 23919184 TI - Overweight and obesity and related factors in urban Iranian population aged between 20 to 84 years. AB - BACKGROUND: Obesity is one of the most common health problems in the world and is assuming epidemic proportions in both developed and developing countries. AIM: The present study aimed to provide population-based data on the prevalence of obesity and estimation the risk of some of demographic factors associated with obesity. SUBJECTS AND METHODS: From May 2007 through December 2008, we conducted a community-based cross-sectional survey on 3,000 males and females (age >= 20 years) in Tehran province. Respondents were asked to give their height and weight in the questionnaire. Body mass index (BMI) is recognized as the measure of overall obesity and calculated as body weight divided by the square body height in meters (kg/m(2)). RESULTS: The overall prevalence of overweight and obesity was 34.1% (924/2708) and 15.4% (417/2708). The combined prevalence of both overweight and obesity was 51.2% (1387/2708) in males and 57.5% (1557/2708) in females. The mean (SD) BMI for the total population studied was 26.14 (4.71) and it was higher in women than in men (P < 0.001). The overall prevalence of overweight and obesity was 39.5% (376/952) and 11.7% (111/952) in men and 36.9% (548/1458) and 20.6% (306/1458) in women. The multivariate-adjusted odds ratios of obesity showed that higher ages, females, married and low educated subjects had more chance to being obese. CONCLUSION: This population-based cross-sectional survey indicates that the prevalence of overweight and obesity are moderately high in the general Iranian population and must be considered as a significant public health problem at national level especially among women. PMID- 23919186 TI - Comparison of research productivity between metro and non-metro cities in a biomedical journal from India. AB - BACKGROUND: The research productivity of a place depends on doctors, patients and available infrastructure to carry research activities. AIMS: We aimed to study the publishing trends and research productivity of metro and non-metro cities in the Journal of the Association of Physi cians of India (JAPI). MATERIALS AND METHODS: Bibliometric analysis of research articles published in JAPI between 2000 and 2011was undertaken. The four types of articles (original articles including brief reports, case reports, correspondence and pictorial image) were studied for research productivity. They were analyzed according to subspecialty, publication times and type of research work from both places. Comparison between groups was done using Fisher exact and Mann-Whitney U test. Descriptive statistics were used and a P < 0.05 was considered significant. RESULTS: Of a total of 2977 articles, 1798 were available for analysis. Metros published 46% (825/1798) and non-metros 54% (973/1798). Original articles and case reports constituted 3/4(th) of the published literature from both places. Pictorial images were seen more from non-metro cities (P = 0.03). Mumbai and Delhi were leading from the metros, whereas Varanasi and Chandigarh were leading from the non-metro places. Endocrinology, Neurology, Cardiology and Infectious Diseases constituted the top four subspecialties from both places. Neurology articles were published more from non-metros (P = 0.03). The timelines from submission to publication varied between 12 and 15 months, and were lesser for articles from the metros (P = 0.01). CONCLUSIONS: Metros and non-metro cities are comparable in publishing trends and research productivity. Places with post-graduate institutes contribute majority of the research articles. Faster publication timelines from metros indicate better manuscript content and preparation. PMID- 23919187 TI - Do women presenting for first and second-trimester abortion differ socio demographically? AB - BACKGROUND: To identify the socio-demographic differences between a sample of women who present for first-trimester and second-trimester abortion. AIM: To determine whether women presenting late (in the second trimester) for abortion differ socio-demographically from those presenting early (in the first trimester). MATERIALS AND METHODS: Data over 4 years for women presenting for second-trimester abortion were collected from the records of Family Planning Clinic at a public tertiary level teaching hospital in India. Eighty-four cases were analysed. The case presenting for first-trimester abortion after each second trimester abortion was included for comparison. Information was gathered concerning age, parity, educational background, employment status, educational background of the husband, family expenditure and religion. Data were statistically analysed and significance determined using logistic regression analysis. RESULTS: Second-trimester abortions represented 2% (84/4254) of all abortions in the study period. More women of higher age (P = 0.03) and parity (P = 0.02) and higher educational status (P = 0.04) presented for second-trimester abortion as compared to first-trimester abortion. The occupational status of the woman, husband's educational background, monthly family expenditure per person and religion did not significantly influence the time of presentation for abortion. CONCLUSION: Second-trimester abortions are associated with both increasing age and parity and higher education. This group of educated, older and multiparous women should be one of those targeted for counseling to reduce the risks associated with second trimester abortion. PMID- 23919188 TI - Serum leptin level in women with polycystic ovary syndrome: correlation with adiposity, insulin, and circulating testosterone. AB - BACKGROUND: Leptin, an adipocyte-derived hormone encoded by 'ob' gene, serves as a link relaying metabolic signals to the neuronal networks in the brain to modulate hypothalamo-pituitary-ovarian axis. Circulating leptin correlates strongly with obesity, which is frequently associated with polycystic ovarian syndrome (PCOS), a major form of dysovulatory infertility in women, characterized by endocrine abnormalities such as hyperandrogenism and inappropriate LH secretion. PCOS is also often associated with insulin resistance and hyperinsulinemia, features that are linked to leptin and its receptors. However, the relationship between leptin and gonadotropins, androgens, and insulin in PCOS is still controversial. AIM: Present investigation attempts to evaluate the interrelationship between serum leptin level with body mass index, insulin and with circulating testosterone in PCOS women. SUBJECTS AND METHODS: Women diagnosed with either tubal block/male factor infertility (Control; n = 18) and with PCOS (n = 16), enrolled for in vitro fertilization and embryo transfer (IVF ET), were recruited for this study. All were reviewed for body mass index (BMI), endocrine milieu (including pituitary gonadotropins, TSH, prolactin, gonadal steroids, and insulin) and for circulating serum leptin. Interpretation of data was done using PRISM Statistical Software Package (PRISM Version 4.03@1992-2005; GraphPad Software Inc). RESULTS: Positive correlation was observed between serum leptin, BMI, and insulin in both the groups. Mean BMI, LH, and LH: FSH ratios were found elevated in the PCOS population. PCOS women also had significantly elevated androgens and fasting levels of insulin. CONCLUSION: Hyperleptinemia in PCOS women appears to be due to the positive correlation between serum leptin, BMI, and insulin. PMID- 23919189 TI - Percutaneous k-wire fixation for femur shaft fractures in children: a treatment concepts for developing countries. AB - BACKGROUND: Fractures shaft femur is a major cause of morbidity and mortality in patients with lower extremity injuries. AIMS: The aim of this study was to evaluate the efficacy of intramedullary Kirschner wires for the treatment of femoral shaft fracture in children. SUBJECTS AND METHODS: This prospective study was conducted in the Department of Orthopaedic surgery in M. M. Medical College from June 2005 to June 2010. Sixty eight children with a mean age of 7.7 years (range, 2-14 years) were recruited from Emergency and out patient department having closed fracture of femoral shaft. All patients were operated under general anesthesia. All patients were followed for twelve months. RESULTS: Out of sixty eight patients, sixty four patients underwent union in 42 to 70 days with a mean of 56 days. Touch down weight bearing was started on 2(nd) post-operative day. Complications found in four patients who had insignificant delayed union which were united next three weeks. Intramedullary Kirschner-wires were removed after an average of five months without any complications. The results were excellent in 94.1% (64/68) and good in 5.8% (4/68). CONCLUSION: This technique is simple, quick to perform, safe and reliable and avoids prolonged hospitalization with good results and is economical. PMID- 23919190 TI - Attendance and achievement in medicine: investigating the impact of attendance policies on academic performance of medical students. AB - BACKGROUND: The attendance mandate for the medical course in Melaka Manipal Medical College, Manipal, India was increased from 75% to 90% based on the assumption that the mandatory increase will improve the students' performance. AIMS: To find out whether there is any correlation between class attendance and academic performance. SUBJECTS AND METHODS: This was an institution based retrospective analytical study. Students who have completed Phase I (first two and a half years) of the MBBS course were included in the study. Student marks and attendance, from the database were obtained from three random batches, each, from two clusters A and B respectively. Those who had a mandatory attendance requirement of 75% belonged to A (n = 243), and those who had a mandatory attendance percentage of 90% belonged to B (n = 360). Statistical analyses performed included, Pearson 2 tailed correlation to correlate class attendance with student performance; Cluster analysis to classify group average in a similarity matrix; t-test to determine significance of difference in percentage of students who attained 100% when the college changed mandatory attendance from 75% to 90%; Mann-Whitney test to find out if there was a better performance in university exam when attendance policy changed. RESULTS: There was a significant correlation between attendance and the students who passed in the University exam. The number of students in the pass category was maximum (>90%) compared to students in distinction and failed categories. Percentage of students with 100% attendance rose from 4% (n = 10) to 11% (n = 40) when the mandatory attendance was increased from 75% to 90%. CONCLUSIONS: Attendance policy correlated with better academic performance. Reducing absenteeism, probably contributed to the improved academic performance of the students. But the link between attendance and best and worst performances could not be predicted because of small numbers in every batch. PMID- 23919191 TI - Pattern of sexually transmitted infections: a profile from a sexually transmitted infections clinic of a tertiary care hospital of eastern India. AB - BACKGROUND: Sexually transmitted infections (STIs) are public health problems, which significantly increase the risk of HIV transmission. A proper understanding of the pattern of STIs in different geographical regions is important for proper planning of STI control. AIMS: To determine the pattern of sexually transmitted diseases in a tertiary care hospital in Eastern India. SUBJECTS AND METHODS: This is a hospital-based, cross-sectional study done in a tertiary care hospital of Eastern India. All the consecutive patients attending the STI clinic of a tertiary care hospital from January 2011 to December 2011 were included in the study, irrespective of age and sex. Thorough history was taken; proper clinical examination and relevant laboratory investigations were done. STIs were categorized in different syndromes as depicted by National AIDS Control Organization(NACO) in the syndromic management of STIs. The STIs, which were not included in the syndromic management, were also identified by clinical features and investigations. Partner notification and condom promotion was done. The statistical analysis used was Chi-square test using Medcalc(R) statistical software Version 9.3 (Belgium). RESULTS: The commonest STI was genital herpes. Viral STIs like genital herpes, condyloma acuminata, molluscum contagiosum were more prevalent than the non-viral ones like genital ulcer disease non-herpetic, syphilis. STIs which were not included in the syndromic management like molluscum contagiosum, condyloma acuminata, genital scabies were common. HIV seropositivity in the study population (4.2%) was more than the NACO estimate. Condom promotion, partner notification, and partner management was not adequate. Occurrence of venereophobia was found to be significantly higher in male than in female attendees of STI clinic. CONCLUSIONS: The trend for viral STIs is increasing while that for bacterial STIs is decreasing. Proper training of the health care providers regarding minor STIs, condom promotion, partner notification and partner management, counseling regarding venereophobia should be undertaken to make STI control programs successful. PMID- 23919192 TI - Hydatidiform mole: A Review of Management Outcomes in a Tertiary Hospital in South-East Nigeria. AB - BACKGROUND: Hydatidiform mole (molar pregnancy) is the pre-malignant form of gestational trophoblastic neoplasia. It is of clinical and epidemiological interest because of its significant complication in pregnancy. AIM: This study was to determine the incidence, risk factors, clinical presentations, diagnosis, treatment options, and outcomes of molar pregnancy in a Nigerian tertiary health institution. MATERIALS AND METHODS: A 10-year retrospective study of patients with molar pregnancy managed at the hospital from 1(st) July 2001 to 30(th) June 2010 was undertaken. RESULTS: There were 34 cases of molar pregnancy, out of a total delivery of 7,579, giving an incidence of 0.4% or 1 in 223 deliveries. The mean age of the patients was 31.3 (8.7) years, and 29.0% (9/31) of the patients were nulliparous. The mean gestational age of the patients at presentation was 14.7 (3.5) weeks. The most common presenting symptom was abnormal vaginal bleeding, 93.5% (29/31), while anemia was the commonest complication seen in 96.8% (30/31) of patients. Almost all the patients (93.5%) had suction evacuation while 6.5% (2/31) had hysterectomy. As many as 6.5% (2/31) of patients had post evacuation chemotherapy while 87.1% (27/31) patients had follow-up contraception. As many as 64.5% (20/31) of patients had complete follow-up for less than 6 months. The case fatality rate was 9.7%. CONCLUSION: Molar pregnancy has remained an important cause of maternal morbidity and mortality in our hospital, and the incidence was high. There is need for early recognition, timely referral, prompt and proper treatment of this condition. Adequate follow-up of the patients should be reinforced. PMID- 23919193 TI - Self-Reported Use of Complementary and Alternative Medicine among the Health Care Consumers at a Tertiary Care Center in Ajman, United Arab Emirates. AB - BACKGROUND: Complementary and alternative medicine (CAM) covers a wide range of approaches, including herbal medicine, manual healing techniques, traditional therapies and mind-body interventions. CAM is widely used throughout the world to treat a variety of illnesses and to maintain health. AIM: Complementary and alternative medicine (CAM) is popular across the world, and is widely practiced. Utilization pattern and reasons for use and non-use among patients attending a tertiary care center are assessed in this study. SUBJECTS AND METHODS: One hundred and thirty-five patients of different nationalities, above the age of 18 years, Gulf Medical College Hospital and Research Centre, Ajman, UAE, were interviewed using an open-ended structured questionnaire. In addition to socio demographic characteristics, the acceptability, utilization pattern and reasons for use and non-use were elicited from the participants after obtaining consent from them. PASW 18 version was used to perform Chi-square test and descriptive statistics. RESULTS: Among the 135 participants were 20-81 years old, those from the Far East used most 85.7% (6/7), then Pakistan 38.5% (15/39) and India 23% (16/70). The most common system used was homeopathy. Physicians advised 28.2% (11/39) of users, whereas others used non-medical information. Around 71.8% (28/39) reported good outcome for themselves and family; however, only 10% (4/39) recommended it to others. Most of the users, 75% (101/135), were not sure whether CAM was based on scientific evidence, while 18% (24/135) felt it was. Good previous experience and less treatment complications were the most common reasons for using CAM and non-use due to lack of knowledge or need. CONCLUSION: About one third of the seekers of modern medicine care also use CAM, and mostly without physician advice; hence, the importance of discussing the same while taking the clinical history. In view of the belief that CAM has fewer side-effects, there is even more need for physician-initiated discussion. PMID- 23919194 TI - Antibiotic prescriptions in critically-ill patients: a latin american experience. AB - BACKGROUND: It is widely acknowledged that the presence of infection is an important outcome determinant for intensive care unit (ICU) patients. In fact, antibiotics are one of the most common therapies administered in the ICU settings. AIM: To evaluate the current usage of antibiotics in Latin American ICUs. SUBJECTS AND METHODS: A one-day p-oint prevalence study to investigate the patterns of antibiotic was undertaken in 72 Latin American (LA) ICUs. Data was analyzed using the Statistix 8 statistical software, version 2.0 (USA). Results were expressed as proportions. When applicable, two tailed hypothesis testing for difference in proportions was used (Proportion Test); a P value of <0.05 was considered significant. RESULTS: Of 704 patients admitted, 359 received antibiotic treatment on the day of the study (51%), of which 167/359 cases (46.5%) were due to hospital-acquired infections. The most frequent infection reorted was nosocomial pneumonia (74/359, 21%). Only in 264/359 patients (73.5%), cultures before starting antibiotic treatment were performed. Thirty-eight percent of the isolated microorganisms were Enterobacteriaceae extended-spectrum beta-lactamase-producing, 11% methicillin-resistant Staphylococcus aureus and 10% carbapenems-resistant non-fermentative Gram-negatives. The antibiotics most frequently prescribed were carbapenems (125/359, 35%), alone or in combination with vancomycin or other antibiotic. There were no significant differences in the "restricted" antibiotic prescription (carbapenems, vancomycin, piperacillin tazobactam, broad-spectrum cephalosporins, fluoroquinolones, tigecycline and linezolid) between patients with APACHE II score at the beginning of the antibiotic treatment <15 [83/114 (72.5%)] and >=15 [179/245 (73%)] (P = 0.96). Only 29% of the antibiotic treatments were cultured directed (104/359). CONCLUSION: Carbapenems (alone or in combination) were the most frequently prescribed antibiotics in LA ICUs. However, the problem of carbapenem resistance in LA requires that physicians improve the use of this class of antibiotics. Our findings show that our web-based method for collection of one-day point prevalence was implemented successfully. However, based on the limitations of the model used, the results of this study must be taken with caution. PMID- 23919195 TI - Mechanisms of hip fracture in owerri, Nigeria, and its associated variables. AB - BACKGROUND: Hip fracture has been associated with various risk factors, including osteoporosis, excessive alcohol consumption, physical inactivity, visual impairment, aging, sex, rural/urban inhabitation, race and climatic variations. Mechanisms of hip fractures in many parts of the world have been documented, and include road traffic accident (RTA), gunshot injury, fall from heights and many others. There is paucity of such documentation in Owerri, Nigeria. AIM: This study was designed to investigate the mechanism of hip fractures in Owerri, Nigeria, and to determine its prevailing factors. MATERIALS AND METHODS: The study was conducted in hospitals located in Owerri, Nigeria. Cases of hip fracture were identified from the medical register while data were sourced from the medical record department for hip fractures that occurred between 1(st) January 2002 and 31(st) December 2008 for patients resident in Owerri and aged between 10 years and above. RESULTS: The study uncovered a total of 105 cases of hip fractures over the study period in 65% (n = 68) males and 35% (n = 37) females. Proportion of hip fractures as a result of fragility fracture mechanisms was significantly higher in females than in the males (P < 0.001), while the reverse was the case for RTA mechanisms. In the same vein, proportion of hip fractures as a result of moderate trauma mechanisms was significantly higher in the elderly than in the young patients (P < 0.001), while the reverse was the case for RTA mechanisms. CONCLUSION: Mechanism of hip fractures in Owerri, Nigeria, can be associated with gender and age. RTA had the largest single contributory mechanism of hip fractures in Owerri. Therefore, public health campaigns and promotions should be created to reduce the influence of RTA on hip fracture among this population. Among the elderly population, hip fracture was mostly sustained from fragility trauma mechanisms, suggesting that osteoporosis is a major contributory factor of hip fracture among this population. PMID- 23919196 TI - Can Chronoscopic Reading in Whole Body Reaction Time be a Tool in Detecting Cognitive Dysfunction in Hypertensives? Findings from a Case Control Study. AB - BACKGROUND: Hypertension on a long-term basis can cause target organ damage, especially the central nervous system, which can affect cognition. It is known that difference between simple and choice reaction time (RT) implies time required for cognition. Although delayed RTs indicate involvement of cognition, they cannot quantify how much time is required for cognition. AIM: Recording chronoscpic RT to quantify time required for cognition in hypertensives and compare them with controls. SUBJECTS AND METHODS: This is a hospital-based case control study conducted (August 2010 to January 2011) on 118 subjects attending an outpatient department using visual and whole body reaction timers having criteria of age and hypertensive condition, compared with an equal number of age- and sex-matched controls. Statistical analysis was carried out by Independent t test and duration of hypertension was correlated with whole body choice reaction time (WBCRT) C1 using Pearson's correlation. Predictive value of WBCRT C1 was calculated by using the receiver operating characteristic curve. RESULTS: The WBCRT C1 562.6 (108) ms was more delayed among hypertensives compared with controls 523.5(98.8) ms. There was no significant correlation between duration of hypertension and WBCRT C1 (r = -0.064). The best cut-off value for WBCRT C1when predicting cognitive dysfunction in hypertensive patients was 538.5 ms (sensitivity 76.2%, specificity 50%). CONCLUSIONS: WBCRT C1 can be a quantitative measurement of cognition. It can be used as a screening tool to detect cognitive dysfunction. PMID- 23919197 TI - Fungal infections in intensive care unit: challenges in diagnosis and management. AB - Infections have almost become an inseparable part of the intensive care units throughout the globe in spite of numerous advancements in diagnostic and therapeutic interventions. With advances in critical care medicine and introduction of broad-spectrum antibiotics, the incidence of invasive fungal infections in intensive care is on the rise, especially in patients with immunosuppression. The aim of this review is to collect recent information about various types of invasive fungal infections prevalent in the intensive care unit, the problems in their diagnosis and recent trends in their management. A thorough literature search was made in PubMed and Google using the following keywords for our search: Invasive fungal infection, antifungal therapy in intensive care unit, candidiasis. The major fungi implicated worldwide are Candida and Aspergillus spp., followed by Cryptococcus, Histoplasma, etc., in endemic areas. These produce a wide variety of infections that are difficult to diagnose as most of the diagnosing tests are non-specific and the culture takes a long time. An early suspicion of fungal infection with institution of appropriate antifungal therapy is mandatory for a positive outcome and to prevent development of invasive fungal infection. PMID- 23919199 TI - The neglected. AB - The dividing line between non-communicable and communicable disease is quite blurred. This has been explained through an analogy between neglected tropical diseases (NTDs) and spatial neglect. The electronic databases such as MEDLINE, Tropical Diseases Research Division at the WHO and Google Scholar were consulted and reference lists of articles were searched for relevant material. Spatial neglect is a common complication following stroke. Both NTDs and spatial neglect demonstrate a preference for space and pose challenges in control and management. Although they may appear to be different entities, at least three NTDs (Chagas disease, neurocysticercosis, and schistosomiasis) have been implicated as risk factors for stroke (and thence spatial neglect). This makes NTDs an issue of international concern, unrestricted to the tropics, and too important to be neglected. PMID- 23919198 TI - Applications of stem cells in interdisciplinary dentistry and beyond: an overview. AB - In medicine stem cell-based treatments are being used in conditions like Parkinson's disease, neural degeneration following brain injury, cardiovascular diseases, diabetes, and autoimmune diseases. In dentistry, recent exciting discoveries have isolated dental stem cells from the pulp of the deciduous and permanent teeth, from the periodontal ligament, and an associated healthy tooth structure, to cure a number of diseases. The aim of the study was to review the applications of stem cells in various fields of dentistry, with emphasis on its banking, and to understand how dental stem cells can be used for regeneration of oral and non-oral tissues conversely. A Medline search was done including the international literature published between 1989 and 2011. It was restricted to English language articles and published work of past researchers including in vitro and in vivo studies. Google search on dental stem cell banking was also done. Our understanding of mesenchymal stem cells (MSC) in the tissue engineering of systemic, dental, oral, and craniofacial structures has advanced tremendously. Dental professionals have the opportunity to make their patients aware of these new sources of stem cells that can be stored for future use, as new therapies are developed for a range of diseases and injuries. Recent findings and scientific research articles support the use of MSC autologously within teeth and other accessible tissue harvested from oral cavity without immunorejection. A future development of the application of stem cells in interdisciplinary dentistry requires a comprehensive research program. PMID- 23919200 TI - Coexistence of pheochromocytoma with abdominal aortic aneurysm: an untold association. AB - Pheochromocytomas have been described in association with rare vascular abnormalities, most common of them being renal artery stenosis. A 45-year-old woman was admitted to our hospital with complaints of headache, sweating, anxiety, dizziness, nausea, vomiting and severe hypertension. For the last several days, she was having a dull aching abdominal pain with a palpable, pulsatile, expansile and non-tender mass in the epigastric region. Hypertension was confirmed biochemically to result from excess catecholamine production. Abdominal computed tomography revealed the presence of a right adrenal pheochromocytoma. Magnetic resonance imaging of the abdomen demonstrated an abdominal aortic aneurysm (AAA) of maximum transverse diameter of 4.5 cm with 3 cm lumen. Surgical removal of pheochromocytoma resulted in normalization of blood pressure to normal. Because of the asymptomatic 4.5 cm aneurysm, our patient was advised for periodic follow-up. To our belief, this is the first such case report emanating from India, citing this rare association between pheochromocytoma and AAA. It is concluded that when the two diseases occur simultaneously, both must be diagnosed accurately and treated adequately. Possible mechanisms of such an uncommon association are also discussed. PMID- 23919201 TI - Pediatric Precursor B-cell Lymphoblastic Lymphoma Presenting with Extensive Skeletal Lesions. AB - Lymphoblastic lymphoma (LL) of the B cell type is uncommon, and extranodal presentation is even rarer. It is difficult to suspect this diagnosis without clinically obvious lymph nodal mass or bone marrow involvement. A 3-year-old girl presented with progressive pain and swelling of the right knee joint of 3 months duration. Radiograph revealed expansile lytic lesion at the supracondylar area of the right femur; with pathological fracture and multiple lytic areas in both femora. She neither had lymphadenopathy nor organomegaly. Her blood counts, peripheral smear examination and bone marrow examination were normal. Right supracondylar biopsy revealed diagnosis of a precursor B cell LL. Computerized tomography scan revealed a hypodense, poorly enhancing lesion in the left adnexal region. Although rare, precursor B-cell LL may present with extensive bone lesions. Early and accurate diagnosis of this entity is very important due to its high cure rates. PMID- 23919202 TI - Unusual branching pattern of axillary artery associated with the high origin of ulnar artery. AB - Axillary artery is a continuation of subclavian artery, extending from the outer border of first rib to the lower border of teres major muscle. During routine dissection for the undergraduate medical students, a rare variations was seen in an approximately 55-year-old male cadaver. This case showed a variation in branching pattern of right axillary and subscapular arteries. The subscapular artery originated from 2(nd) part of axillary artery, gave origin to posterior circumflex humeral and lateral thoracic arteries in addition to its normal branches. The ulnar artery originated from the 3(rd) part of the axillary artery, just above the lower border of teres major muscle. The variant ulnar artery passed deep to the median cubital vein, bicipital aponeurosis, and tendon of palmaris longus muscle. Then, it passed superficial to flexor digitorum superficialis muscle and flexor retinaculum to enter the palm. In the palm, it formed the superficial palmar arch. This variant ulnar artery was much smaller in caliber than the radial artery. PMID- 23919203 TI - A synchronous presentation of two different ovarian tumors: a rare occurrence. AB - Approximately 60% of all ovarian tumors are epithelial in origin, and these neoplasms are thought to arise from the ovarian surface epithelium or small epithelial inclusion cysts. Surface epithelium is capable of differentiating into serous (tubal), mucinous, endometrioid or transitional epithelium. Serous and mucinous cystadenomas are the most common epithelial tumors and, together, account for about 30% of ovarian tumors We report a case of a 29-year-old lady P1L1 presenting with the chief complaints of pain abdomen off and on since the last 1 year. Ultrasonography revealed normal uterus with enlarged right ovary, with a cyst measuring 46 mm * 36 mm * 55 mm showing internal echoes with volume of 50 cc., left ovary also enlarged with multiple well-defined cysts measuring 34 mm * 44 mm * 69 mm with volume of 55 cc and the largest cyst measuring 37 mm. Bilateral ovarian cystectomy was done and sent for histopathology. To our surprise, both the ovaries revealed different histopathological pictures, with the right ovary revealing serous cystadenoma and the left ovary showing mucinous cystadenoma. This rare occurrence has never been reported so far in the literature to the best of our knowledge. PMID- 23919204 TI - Twin tooth on either side: a case report of bilateral gemination. AB - Gemination is an anomaly caused by a single tooth germ that attempted to divide during its development, resulting in a bifid crown. They are found more frequently in the primary than in the permanent dentition unilaterally, but bilateral gemination is very rare. It is caused by complex interactions among a variety of genetic and environmental factors. This developmental anomaly may cause clinical problems including esthetic impairment, periodontal problems, caries, and tooth crowding. Here, we report a unique case of bilateral gemination of permanent maxillary central incisors. PMID- 23919205 TI - An unusual presentation of perforated intrauterine contraceptive device. AB - Contraception is an essential component of sexual and reproductive health issues, especially in Nigeria, which has a high fertility rate. The intrauterine contraceptive device (IUCD) is one of the most frequently used contraceptive methods. Countless researches have helped establish the fact that an intrauterine device IUCD is a safe and effective contraceptive method for most women regardless of their health status. However, many complications associated with the IUCD have also been described. In this report, we present an unusual complication of the IUCD in which the device perforated the uterus and migrated to the ileum, with the IUCD string still visible per vaginum. PMID- 23919206 TI - Prosthodontic management of hypohidrotic ectodermal dysplasia with anodontia: a case report in pediatric patient and review of literature. AB - Ectodermal dysplasias are rare hereditary disorders characterized by abnormal development of certain tissues and structures of ectodermal origin. The condition is important for dentists as it affects teeth resulting in hypodontia or anodontia and dentist plays an important role in rehabilitation of the patient. Affected young children with anodontia not only have difficulties in eating and speaking but can also feel that they look different from their contemporaries. Well-fitting and functioning prosthesis could be a great help during their schooling years as it will improve appearance and thus boost their self confidence. We report a case of hypohidrotic ectodermal dysplasia in an 8-year old boy who exhibited anodontia and was successfully rehabilitated with conventional complete dentures in both maxillary and mandibular arches. The aim of the treatment was to improve psychological development apart from promoting better functioning of the stomatognathic system. PMID- 23919207 TI - Mycobacterium tuberculosis pyomyositis in an infant. AB - Mycobacterium tuberculosis is endemic to many parts of the world. It may have variable clinical presentations, especially in the pediatric age group. Presented here is the case of a 9-month old infant who was referred for infectious disease opinion when his thigh induration failed to improve after surgical drainage and a course of oral antibiotic therapy. Mycobacterial PCR on the operative sample fluid was found to be positive; and mycobacterial culture grew M. tuberculosis. He received 9 months of treatment with anti-TB medications, with excellent results and complete recovery. This is the first report of TB pyomyositis in an infant; and highlights the need to have a high index of suspicion for unusual organisms when conventional therapy fails to demonstrate expected results. PMID- 23919209 TI - Juvenile aggressive ossifying fibroma of the maxilla: a case report and review of the literature. AB - Juvenile aggressive ossifying fibroma is a rare benign but locally aggressive tumor with high recurrent potentials. Juvenile aggressive ossifying fibroma poses diagnostic challenges because of its rapidly growing nature. A 7-years-old female child presented to the pediatric unit of our institution with a 9-month history of right maxillary tumor. An initial diagnosis of Burkitt's lymphoma was made and the child has several courses of chemotherapy without adequate histologic confirmation., She was later referred to the maxillofacial unit where the appropriate diagnosis and treatment were instituted. The importance of early recognition and adequate management is highlighted. PMID- 23919208 TI - Compound odontoma in deciduous dentition. AB - Odontomas are benign tumors containing all the components of the odontogenic tissue. Disturbances in tooth eruption are one of the most common complications associated with odontomas. They are generally asymptomatic and are usually seen in second and third decades of life, rarely seen below 10 years of age. Herewith, we report an unusual occurrence of compound odontoma in a 4-year-old child visualized as a swelling of the cortical bone in the anterior maxilla. PMID- 23919210 TI - Joubert syndrome: the molar tooth sign of the mid-brain. AB - Joubert syndrome (JS) is a very rare, autosomal-recessive condition. It is characterized by agenesis of cerebellar vermis, abnormal eye movements with nystagmus, episodes of hyperpnea and apnea, delayed generalized motor development, retinal coloboma and dystrophy and, sometimes, multicystic kidney disease. The importance of recognizing JS is related to the outcome and its potential complications. Prenatal diagnosis by ultarsonography and antenatal magnetic resonance imaging (MRI) is also possible. We have diagnosed a case of JS in a male infant with history of delayed mental and motor milestone development, history of abnormal breathing pattern, abnormal limb movement, generalized hypotonia and abnormal head movements with nystagmus. MRI showed hypoplastic cerebellar vermis with hypoplasia of the superior cerebellar peduncle resembling the "Molar Tooth Sign" in the mid-brain. PMID- 23919211 TI - Defensive medicine: a bane to healthcare. PMID- 23919212 TI - Lurking Dangers Behind Overuse of Lamivudine to Treat Non-HIV Hepatitis B Patients in Africa. PMID- 23919213 TI - Steroid ulcers: Any news? AB - Steroid ulcers, although a common feature in experimental studies, seldom develop in clinical practice, as observed by the meta-analyses carried out in the 90s. Corticosteroids alone become ulcerogenic only if treatment lasts longer than one month and the total administered dose exceeds 1000 mg. On the other hand concomitant intake of non-steroidal anti-inflammatory drugs results in a synergistic, highly damaging effect on the gastroduodenal mucosa. Thus, despite the survival of the steroid ulcer myth in the medical culture, pharmacological protection against steroid-induced peptic ulcers is a rare necessity while the best prophylactic strategy still remains to be determined. PMID- 23919215 TI - Are medical ethics universal or culture specific. AB - In our society and culture where family is of utmost importance, sometimes I wonder how much of a doctor's duty is to the patient and how much is to the whole family. As a medical student, I remember being told by my professors that we should treat the patient as a whole and not focus on just one problem or organ system. Similarly when practicing medicine in Pakistan, one cannot treat the patient alone and ignore the family. How much should relatives' wishes be taken into account when dealing with a patient Don't patients have a right to their medical information When, how, and by whom can that right be waived What role does culture play when debating medical ethics. PMID- 23919214 TI - Inflammatory bowel disease: An archetype disorder of outer environment sensor systems. AB - The pathogenesis of the two inflammatory bowel diseases (IBDs) phenotypes ulcerative colitis (UC) and Crohn's disease (CD) has remained elusive, thus frustrating attempts at defining a cure. IBD often presents as a complex inflammatory process wherein colon lesions (UC) or widespread ulceration and fissure (CD) might be accompanied by ancillary extra-intestinal manifestations involving the eye, skin, joints or liver, but also by full-blown "autoimmune" disorders from psoriasis and multiple sclerosis to rheumatoid arthritis; attempts at unraveling a link or a hierarchical order in these entities have proven almost fruitless. More recently, the input of genetics has suggested that the IBDs might be multi-organ inflammatory processes, elicited by a large number of low penetrance susceptibility genes, with environmental factors needed to induce full blown disease. At a noteworthy exception to this rule, the description of the nucleotide-oligomerization domain (NOD) gene mutations in CD came at the beginning of the 2000s: the NOD-LRR are part of a highly conserved microbial sensor system which respond to bacterial peptidoglycans by mounting an inflammatory response. At least in Caucasian patients, the prevalently loss-of function mutation of NOD permitted to unexpectedly define CD as an immune deficiency state, and upon its recent description in apparently unrelated disorders such as the Blau syndrome (a granulomatous pediatric syndrome), and perhaps in psoriasis and chronic obstructive pulmonary disorders, has contributed to revolutionize our view of IBD and CD in particular. The latter affection, together with psoriasis and chronic pulmonary disease can now be included into a newly identified category named "barrier organ disease", wherein a barrier organ is defined as a large mucosal or epithelial surface with an abundant metagenomic microbial population and an underneath reactive tissue, the whole structure being in contact with the outer environment and capable to react to it. Personalized treatments and empowerment of research across different disease phenotypes should be the advantages of this novel mindset. PMID- 23919216 TI - Emerging causes of iron deficiency anemia refractory to oral iron supplementation. AB - While oral iron supplementation is commonly used throughout many clinical setting, treatment with intravenous (IV) iron has historically been reserved for specific settings, such as chronic kidney disease, gynecologic issues, and anemia associated with cancer and its treatments. However, the use of IV iron has begun to gain popularity in the treatment of iron deficiency anemia (IDA) associated with two conditions that are being seen more frequently than in years past: patients who are status post gastric bypass procedure and those with inflammatory bowel disease (IBD). The Roux-en-Y procedure involves connecting a gastric pouch to the jejunum, creating a blind loop consisting of distal stomach, duodenum, and proximal jejunum that connects to the Roux limb to form a common tract. IDA occurs in 6%-50% of patients who have undergone a gastric bypass, the etiology being multifactorial. The proximal gastric pouch, the primary site of gastric acid secretion, is bypassed, resulting in a decreased ability to metabolize molecular iron. Once metabolized, most iron is absorbed in the duodenum, which is entirely bypassed. After undergoing bypass procedures, most patients significantly limit their intake of red meat, another factor contributing to post bypass IDA. Chronic anemia occurs in approximately 1/3 of patients who suffer from IBD, and almost half of all IBD patients are iron deficient. IBD leads to IDA through multiple mechanisms, including chronic intestinal blood loss, decreased absorption capabilities of the duodenum secondary to inflammation, and an inability of many IBD patients to tolerate the side effects of oral ferrous sulfate. In this study, we reviewed the charts of all patients who received IV iron at Sylvester Comprehensive Cancer Center/University of Miami Hospital Clinic from January 2007 to May 2012. The most common indications for IV iron were for issues related to cancer and its treatment (21.9%), IBD (20.1%), and gastric bypass (15.0%). Of the 262 patients who received IV iron, 230 received iron sucrose and 36 received iron dextran. While doses of 100, 200, 300, and 400 mg of iron sucrose were given, 100 and 200 mg were by far the most common dosages used, 122 and 120 times, respectively. The number of dosages of iron sucrose given ranged from 1 to 46, with a mean of 5.5 and a median of 4 doses. The average dose of iron dextran given was 870.5 mg, with 1000 mg being the most common dosage used. Most patients (22 of 36) who received iron dextran only received one dose. While patients with traditional indications for IV iron, such as gynecologic issues and kidney disease, still were represented in this study, we expect to see a continued increase in physicians using IV iron for emerging gastrointestinal indications, especially considering the increased safety of new low-molecular formulations. PMID- 23919217 TI - Association of ITPA polymorphism with outcomes of peginterferon-alpha plus ribavirin combination therapy. AB - AIM: To analyzed the association between inosine triphosphatase (ITPA) (rs1127354) genotypes and sustained virological response (SVR) rates in peginterferon (Peg-IFN)alpha + ribavirin (RBV) treatment. METHODS: Patients who underwent Peg-IFNalpha + RBV combination therapy were enrolled (n = 120) and they had no history of other IFN-based treatments. Variation in hemoglobin levels during therapy, cumulative reduction of RBV dose, frequency of treatment withdrawal, and SVR rates were investigated in each ITPA genotype. RESULTS: In patients with ITPA CC genotype, hemoglobin decline was significantly greater and the percentage of patients in whom total RBV dose was < 60% of standard and/or treatment was withdrawn was significantly higher compared with CA/AA genotype. However, SVR rates were equivalent between CC and CA/AA genotypes, and within a subset of patients with Interleukin 28B (IL28B) (rs8099917) TT genotype, SVR rates tended to be higher in patients with ITPA CC genotype, although the difference was not significant. CONCLUSION: ITPA CC genotype was a disadvantageous factor for Peg-IFNalpha + RBV treatment in relation to completion rates and RBV dose. However, CC genotype was not inferior to CA/AA genotype for SVR rates. When full-length treatment is accomplished, it is plausible that more SVR is achieved in patients with ITPA CC variant, especially in a background of IL28B TT genotype. PMID- 23919218 TI - Outcome of patients with primary sclerosing cholangitis and ulcerative colitis undergoing colectomy. AB - AIM: To study the outcomes of primary sclerosing cholangitis (PSC) patients with ulcerative colitis (UC) undergoing colectomy. METHODS: We identified 193 patients with PSC and UC undergoing colectomy at the Mayo Clinic (Rochester, MN, United States), between January 1, 1995 and December 31, 2008 using a computerized record system. Eighty-nine patients were excluded due to unclear diagnosis, liver transplantation prior to colectomy, age less than 18 years, inadequate follow-up data or known cases of cholangiocarcinoma. We retrospectively reviewed data from patient medical records. Clinical information, date of colectomy, preoperative and follow-up liver tests and pathological findings of the colon were reviewed. The Mayo risk score at baseline was calculated to obtain survival estimates for up to 4 years of follow-up. The primary endpoint was defined by the presence of all-cause mortality and/or liver decompensation requiring liver transplantation. All patients who did not have a clinical note on December 31, 2008 were considered as patients with an incomplete follow-up unless they reached a study endpoint (death or underwent liver transplantation) prior to that date. The study was approved by the Institutional Review Boards of the Mayo Clinic. RESULTS: Of the 2441 patients with PSC observed in this period, 104 patients (4.3%) had UC and underwent colectomy and were included. The median age was 43.2 years, and 67% were male. The leading indications for colectomy were severe colonic inflammation (49%), the presence of colonic dysplasia during routine surveillance (42%) and bowel perforation (3%). Twenty-six patients were lost to follow-up after a median duration of 3.9 years. The remaining 78 patients included 52 patients (66.7%) who were followed for a median duration of 5.5 years and 26 patients (33.3%) who developed primary endpoints including death (n = 13) or underwent liver transplantation (n = 13) with a median follow up of 2.6 years. For the secondary endpoint, the liver complications within 1 mo following the colectomy were found in 9 patients (8.6%) and included worsening liver tests (n = 3), liver failure requiring liver transplantation (n = 2), acute cholangitis (n = 3) and right hepatic vein thrombosis with hepatic infarct (n = 1). A multivariate logistic analysis demonstrated that only lower platelet count and lower albumin level preoperatively were significantly associated with more primary endpoints (OR = 0.99 and 0.05 respectively). CONCLUSION: One third of patients with PSC and UC undergoing colectomy died or underwent liver transplantation within 2.6 years. PSC patients with lower platelet counts and lower albumin levels were significantly more likely to have a poorer outcome. PMID- 23919220 TI - Diarrhoea in a patient with metastatic melanoma: Ipilimumab ileocolitis treated with infliximab. AB - Administration of ipilimumab, a cytotoxic T-lymphocyte associated antigen-4 blocking monoclonal antibody, leads to enhancement of the anti-tumor T-cell respons and as a result shows a significant survival benefit in metastatic melanoma patients. Therefore patients are currently receiving this promising therapy as a second-line strategy. Unfortunately, by activation of the T-cell immune response, ipilimumab therapy may lead to an unwanted induction of different autoimmune phenomena. Diarrhoea and colitis occur in up to one third of patients. Here we present a case of ipilimumab induced ileocolitis which was successfully treated with infliximab, an anti-tumor necrosis factor monoclonal antibody, after corticosteroid therapy failure. Although formal trials are lacking, recently publicated series suggest that infusional therapy of infliximab is effective in ipilimumab induced ileocolitis. PMID- 23919219 TI - Reduced esophageal cancer incidence in statin users, particularly with cyclo oxygenase inhibition. AB - AIM: To examine the association between statin use and the development of esophageal cancer METHODS: We performed a systematic review and meta-analysis. Multiple databases (Pubmed, EMBASE, Cochrane Library, Web of Science, Wiley Interscience and Google Scholar) were systematically searched for studies reporting the association of statin use and the development of esophageal cancer. Literature searching and data abstraction were performed independently by two separate researchers. The quality of studies reviewed was evaluated using the Newcastle-Ottawa Quality assessment scale. Meta-analysis on the relationship between statin use and cancer incidence was performed. The effect of the combination of statin plus a cyclo-oxygenase inhibitor was also examined. RESULTS: Eleven studies met eligibility criteria, 9 high and 2 medium quality. All were observational studies. Studies examining adenocarcinoma development in Barrett's esophagus included 317 cancers and 1999 controls, population-based studies examining all esophageal cancers included 371203 cancers and 6083150 controls. In the Barrett's population the use of statins (OR = 0.57; 95%CI: 0.43 0.75) and cyclo-oxygenase inhibitors (OR = 0.59; 95%CI: 0.45-0.77) were independently associated with a reduced incidence of adenocarcinoma. Combined use of a statin plus cyclo-oxygenase inhibitor was associated with an even lower adenocarcinoma incidence (OR = 0.26; 95%CI: 0.1-0.68). There was more heterogeneity in the population-based studies but pooled adjusted data showed that statin use was associated with a lower incidence of all combined esophageal cancers (OR = 0.81; 95%CI: 0.75-0.88). CONCLUSION: Statin use in patients with Barrett's oesophagus is associated with a significantly lower incidence of adenocarcinoma. The chemopreventive actions of statins, especially combined with cyclo-oxygenase inhibitors deserve further exploration. PMID- 23919221 TI - [Guinea worm--the last step toward extinction?]. PMID- 23919222 TI - New goals in sight to reduce poverty and hunger. PMID- 23919223 TI - Latin American countries crack down on junk food. PMID- 23919224 TI - The authors respond to: Complications following pulmonary lobectomy: the role of helmet noninvasive ventilation. PMID- 23919225 TI - The authors respond to: Noninvasive mechanical ventilation and helmet after lung resection: oxygenation improvement: a small step or a large step? PMID- 23919226 TI - The authors respond to: High-flow nasal cannula oxygen therapy in the emergency department: welcome, but selection should be the first step. PMID- 23919227 TI - A thunderclap headache. PMID- 23919228 TI - For Georgy I. Eskin--on the occasion of his 80th birthday. PMID- 23919230 TI - Antidepressant drugs and infectious disease. AB - Clostridium difficile (C.difficile) infection (CDI) is a common and clinically significant cause of diarrhea associated with the use of antibiotic drugs. Two observational studies have suggested that antidepressant drug use is associated with an increased risk of developing CDI. Because of the potential public health significance of this finding, this article critically evaluates the methodology of these studies and provides evidence to question the plausibility and validity of this finding. The safety of antidepressant and other psychotropic drugs should not be taken for granted, but studies that receive media attention may cause harm if their findings are not valid and they result in a reluctance to use these drugs for treating serious mental disorders. PMID- 23919229 TI - Hepatitis B and C virus infection among hemodialysis patients in Yogyakarta, Indonesia: Prevalence and molecular evidence for nosocomial transmission. AB - Hemodialysis patients are at an increased risk of acquiring hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. However, the prevalence of hepatitis viral infection and its genotype distribution among hemodialysis patients in Indonesia are unclear. In order to investigate these issues and the possibility of nosocomial transmission, 161 hemodialysis patients and 35 staff members at one of the hemodialysis unit in Yogyakarta, Indonesia, were tested for serological and virological markers of both viruses. HBV surface antigen (HBsAg) was detected in 18 patients (11.2%) and in two staff members (5.7%). Anti-HCV was detected in 130 patients (80.7%) but not in any staff members. Occult HBV and HCV infection were detected in 21 (14.7%) and 4 (12.9%) patients, respectively. The overall prevalence rates of HBV and HCV infection among patients were 24.2% and 83.2%, respectively. HCV infection was independently associated with hemodialysis duration and the number of blood transfusions. Phylogenetic analysis revealed that 23 of 39 tested HBV strains (59%) were genotype B, 11 (28.2%) were genotype C, and 5 (12.8%) were genotype A. HCV genotype 1a was dominant (95%) among 100 tested HCV strains. Nosocomial transmission was suspected because the genotype distribution differed from that of the general population in Indonesia, and because the viral genomes of several strains were identical. These findings suggest that HBV and HCV infection is common among hemodialysis patients in Yogyakarta, and probably occurs through nosocomial infection. Implementation of strict infection-control programs is necessary in hemodialysis units in Indonesia. PMID- 23919232 TI - First impressions of a global gathering. PMID- 23919231 TI - Human endurance and the heart at altitude. AB - Human endurance, both at altitude and at sea level, depends upon the ability of the subject to transport oxygen from the atmosphere to the working tissues. Many physiological processes were involved in oxygen transport, including the oxygen cost of breathing, the ventilation of alveolar gas, diffusion in the lungs, blood transport, and diffusion within the tissues. At sea level, the blood transport term (effectively the product of haemoglobin level and maximum cardiac out) offers the major resistance to oxygen uptake. At moderate altitudes, such as Denver (5000 ft) and Mexico City (7350 ft), alveolar ventilation (measured under STPD conditions) is well maintained, and the normal shape of the oxygen dissociation curve increases the effective solubility of oxygen in the blood stream, partially compensating for the increasing resistance offered by the pulmonary diffusion/blood transport interaction. However, if unacclimatized men are exposed acutely to an altitude of 7350 ft, their maximum oxygen intake is decreased by at least 8-10%, and there is a corresponding loss of performance in endurance events. The average sedentary indi vidual notices nothing more than a little breathlessness at this altitude, probably because in sub-maximum exercise, compensation is readily achieved by an increase of ventilation (measured at body temperature and pressure) and pulse rate. With more prolonged residence at altitude, compensation is also affected by adjustment of buffering systems and an increase of haemoglobin level. The altitude of Mexico City is rather critical from the physiological standpoint; at higher altitudes, compensation is no longer possible by increase of ventilation and use of the normal oxygen dissociation characteristics of haemoglobin. The pulmonary diffusion/blood transport resistance becomes increasingly significant, arterial saturation falls, and there is a progressive loss of maximum oxygen intake. Above 10,000 ft, the problem is compounded by the danger that unaccustomed severe exertion may induce pulmonary oedema. PMID- 23919233 TI - Caring for the uncared-for needs of others. PMID- 23919234 TI - Aged care: restraint case lessons must be heeded. PMID- 23919235 TI - Economic factors trump refugee women's needs. PMID- 23919236 TI - Nurse censured for lack of respect towards a patient. PMID- 23919237 TI - Francis: implications for midwives. AB - The final report of the Mid Staffordshire hospital Trust enquiry has recently been released (Francis 2013). Following this, the current Government produced Patients first and foremost (DH 2013) as a response. These reports will have a wide impact on the NHS and throughout health care. The purpose of this article is to explore some of the implications for midwives and the maternity services PMID- 23919238 TI - Film forming microbial biopolymers for commercial applications--a review. AB - Microorganisms synthesize intracellular, structural and extracellular polymers also referred to as biopolymers for their function and survival. These biopolymers play specific roles as energy reserve materials, protective agents, aid in cell functioning, the establishment of symbiosis, osmotic adaptation and support the microbial genera to function, adapt, multiply and survive efficiently under changing environmental conditions. Viscosifying, gelling and film forming properties of these have been exploited for specific significant applications in food and allied industries. Intensive research activities and recent achievements in relevant and important research fields of global interest regarding film forming microbial biopolymers is the subject of this review. Microbial polymers such as pullulan, kefiran, bacterial cellulose (BC), gellan and levan are placed under the category of exopolysaccharides (EPS) and have several other functional properties including film formation, which can be used for various applications in food and allied industries. In addition to EPS, innumerable bacterial genera are found to synthesis carbon energy reserves in their cells known as polyhydroxyalkanoates (PHAs), microbial polyesters, which can be extruded into films with excellent moisture and oxygen barrier properties. Blow moldable biopolymers like PHA along with polylactic acid (PLA) synthesized chemically in vitro using lactic acid (LA), which is produced by LA bacteria through fermentation, are projected as biodegradable polymers of the future for packaging applications. Designing and creating of new property based on requirements through controlled synthesis can lead to improvement in properties of existing polysaccharides and create novel biopolymers of great commercial interest and value for wider applications. Incorporation of antimicrobials such as bacteriocins or silver and copper nanoparticles can enhance the functionality of polymer films especially in food packaging applications either in the form of coatings or wrappings. Use of EPS in combinations to obtain desired properties can be evaluated to increase the application range. Controlled release of active compounds, bioactive protection and resistance to water can be investigated while developing new technologies to improve the film properties of active packaging and coatings. An holistic approach may be adopted in developing an economical and biodegradable packaging material with acceptable properties. An interdisciplinary approach with new innovations can lead to the development of new composites of these biopolymers to enhance the application range. This current review focuses on linking and consolidation of recent research activities on the production and applications of film forming microbial polymers like EPS, PHA and PLA for commercial applications. PMID- 23919239 TI - Cyclodextrin-based hydrogels toward improved wound dressings. AB - Optimal wound dressings should be capable of mechanical wound protection and also facilitate the healing process via maintenance of suitable environmental conditions and the controlled delivery of bioactive molecules. Hydrogels present suitable properties for wound-dressing applications such as good biocompatibility, together with a high water content, the latter of which is important for the maintenance of a moist environment and ready removal from the wound with a minimal level of associated pain. However, their properties as drug delivery systems can be improved by the use of cyclodextrins as cross-linking agents. Cyclodextrins have been extensively used as "carriers" on food, textile, cosmetic and, most especially, in the pharmaceutical industry in view of their powerful complexation abilities and biocompatibilities, together with further desirable characteristics. The conjugation of cyclodextrins with hydrogels may allow the achievement of an optimal wound-dressing material, because the hydrogel component will maintain the moist environment required for the healing process, and the cyclodextrin moiety has the ability to protect and modulate the release of bioactive molecules. Therefore, this review aims to gather information regarding cyclodextrin-based hydrogels for possible wound-dressing applications. PMID- 23919240 TI - A methodological combined framework for roadmapping biosensor research: a fault tree analysis approach within a strategic technology evaluation frame. AB - Biosensor technology began in the 1960s to revolutionize instrumentation and measurement. Despite the glucose sensor market success that revolutionized medical diagnostics, and artificial pancreas promise currently the approval stage, the industry is reluctant to capitalize on other relevant university produced knowledge and innovation. On the other hand, the scientific literature is extensive and persisting, while the number of university-hosted biosensor groups is growing. Considering the limited marketability of biosensors compared to the available research output, the biosensor field has been used by the present authors as a suitable paradigm for developing a methodological combined framework for "roadmapping" university research output in this discipline. This framework adopts the basic principles of the Analytic Hierarchy Process (AHP), replacing the lower level of technology alternatives with internal barriers (drawbacks, limitations, disadvantages), modeled through fault tree analysis (FTA) relying on fuzzy reasoning to count for uncertainty. The proposed methodology is validated retrospectively using ion selective field effect transistor (ISFET) - based biosensors as a case example, and then implemented prospectively membrane biosensors, putting an emphasis on the manufacturability issues. The analysis performed the trajectory of membrane platforms differently than the available market roadmaps that, considering the vast industrial experience in tailoring and handling crystallic forms, suggest the technology path of biomimetic and synthetic materials. The results presented herein indicate that future trajectories lie along with nanotechnology, and especially nanofabrication and nano-bioinformatics, and focused, more on the science-path, that is, on controlling the natural process of self-assembly and the thermodynamics of bioelement-lipid interaction. This retained the nature-derived sensitivity of the biosensor platform, pointing out the differences between the scope of academic research and the market viewpoint. PMID- 23919241 TI - Current and future trends for biofilm reactors for fermentation processes. AB - Biofilms in the environment can both cause detrimental and beneficial effects. However, their use in bioreactors provides many advantages including lesser tendencies to develop membrane fouling and lower required capital costs, their higher biomass density and operation stability, contribution to resistance of microorganisms, etc. Biofilm formation occurs naturally by the attachment of microbial cells to the support without use of any chemicals agent in biofilm reactors. Biofilm reactors have been studied and commercially used for waste water treatment and bench and pilot-scale production of value-added products in the past decades. It is important to understand the fundamentals of biofilm formation, physical and chemical properties of a biofilm matrix to run the biofilm reactor at optimum conditions. This review includes the principles of biofilm formation; properties of a biofilm matrix and their roles in the biofilm formation; factors that improve the biofilm formation, such as support materials; advantages and disadvantages of biofilm reactors; and industrial applications of biofilm reactors. PMID- 23919242 TI - Glycosylation: impact, control and improvement during therapeutic protein production. AB - The emergence of the biopharmaceutical industry represented a major revolution for modern medicine, through the development of recombinant therapeutic proteins that brought new hope for many patients with previously untreatable diseases. There is a ever-growing demand for these therapeutics that forces a constant technological evolution to increase product yields while simultaneously reducing costs. However, the process changes made for this purpose may also affect the quality of the product, a factor that was initially overlooked but which is now a major focus of concern. Of the many properties determining product quality, glycosylation is regarded as one of the most important, influencing, for example, the biological activity, serum half-life and immunogenicity of the protein. Consequently, monitoring and control of glycosylation is now critical in biopharmaceutical manufacturing and a requirement of regulatory agencies. A rapid evolution is being observed in this context, concerning the influence of glycosylation in the efficacy of different therapeutic proteins, the impact on glycosylation of a diversity of parameters/processes involved in therapeutic protein production, the analytical methodologies employed for glycosylation monitoring and control, as well as strategies that are being explored to use this property to improve therapeutic protein efficacy (glycoengineering). This work reviews the main findings on these subjects, providing an up-to-date source of information to support further studies. PMID- 23919243 TI - Prevalence and classification of rhinitis in the elderly: a nationwide survey in Portugal. AB - BACKGROUND: Nationwide epidemiologic data on rhinitis in the elderly do not exist. This study aimed to estimate the prevalence of rhinitis in the population aged 65 years or above in mainland Portugal and to characterize and classify rhinitis in this age group. METHODS: Cross-sectional, nationwide, population based survey of citizens aged 65 years or above, living in mainland Portugal. Current rhinitis (CR) was defined as the presence of at least two symptoms: 'repeated sneezing and itchy nose', 'blocked nose for more than one whole hour', or 'runny nose when not having a cold or flu', either usually or in the last 12 months. Rhinitis severity was assessed using a visual analogue scale; rhinitis was classified according to ARIA. RESULTS: Data were obtained from 3678 responders (92.5% response rate). The prevalence of CR was 29.8% (95% confidence interval (CI): 28.4%-31.3%): 49.1% had mild intermittent, 7.0% mild persistent, 27.5% moderate-severe intermittent, and 16.4% moderate-severe persistent rhinitis. Only 38.6% of patients with CR had been physician diagnosed and 38.7% were under treatment for this disease in the previous year. Allergic conjunctivitis symptoms were referred by 68.6% of subjects with CR (rhinoconjunctivitis population prevalence, 20.5% (95% CI: 19.2%-21.8%)). CONCLUSIONS: Rhinitis and rhinoconjunctivitis are common but underdiagnosed and undertreated diseases in the geriatric population. This was the first nationwide epidemiological survey classifying rhinitis according to ARIA guidelines in this age group. More than 40% of old-age patients presented moderate-severe disease. PMID- 23919244 TI - Synthesis and biological evaluation of alpha-galactosylceramide analogues with heteroaromatic rings and varying positions of a phenyl group in the sphingosine backbone. AB - We designed and synthesized seven alpha-GalCer analogues with a pyrazole moiety and varying positions of a phenyl group in the sphingosine backbone to polarize cytokine secretion. On the basis of in vitro and in vivo biological evaluations, we found that analogue 5 induced greater polarization toward Th2 and greater secretion of the immunomodulatory cytokine, IL-4, over secretion of pro inflammatory cytokines, IFN-gamma and IL-17. Treatment of a single dose of analogue 5 markedly ameliorated disease pathogenesis in an animal model of an inflammatory demyelinating disease of the central nervous system, compared to that of KRN7000 (1). Therefore, this new alpha-GalCer analogue 5 is a novel iNKT ligand that stimulates the selective secretion of anti-inflammatory cytokines and regulates autoimmune diseases by reducing Th1 and Th17 responses. PMID- 23919245 TI - High-resolution electron spectroscopy and rotational conformers of group 6 metal (Cr, Mo, and W) bis(mesitylene) sandwich complexes. AB - Group 6 metal-bis(mesitylene) sandwich complexes are produced by interactions between the laser-vaporized metal atoms and mesitylene vapor in a pulsed molecular beam source, identified by photoionization time-of-flight mass spectrometry, and studied by pulsed-field ionization zero-electron kinetic energy spectroscopy and density functional theory calculations. Although transition metal-bis(arene) sandwich complexes may adopt eclipsed and staggered conformations, the group 6 metal-bis(mesitylene) complexes are determined to be in the eclipsed form. In this form, rotational conformers with methyl group dihedral angles of 0 and 60 degrees are identified for the Cr complex, whereas the 0 degrees rotamer is observed for the Mo and W species. The 0 degrees rotamer is in a C(2v) symmetry with the neutral ground state of (1)A1 and the singly positive charged ion state of (2)A1. The 60 degrees rotamer is in a C(i) symmetry with the neutral ground state of (1)A(g) and the ion state of (2)A(g). Partial conversion of the 60 to 0 degrees rotamer is observed from He to He/Ar supersonic expansion for Cr-bis(mesitylene). The unsuccessful observation of the 60 degrees rotamer for the Mo and W complexes is the result of its complete conversion to the 0 degrees rotamer in both He and He/Ar expansions. The adiabatic ionization energies of the 0 degrees rotamers of the three complexes are in the order of Cr-bis(mesitylene) < W-bis(mesitylene) < Mo-bis(mesitylene), which is different from that of the metal atoms. These metal-bis(mesitylene) complexes have lower ionization energies than the corresponding metal bis(benzene) and -bis(toluene) species. PMID- 23919246 TI - Feasibility of endoscopic retrograde cholangiopancreatography in healthy cats. AB - Cats are predisposed to diseases of the biliary tract and the exocrine pancreas and these can be challenging to diagnose. In humans and dogs > 10 kg, endoscopic retrograde cholangiopancreatography (ERCP) has been successfully used to diagnose some of these disorders. The purpose of our study was to determine whether ERCP would also be feasible in cats using a pediatric duodenoscope. Four purpose-bred, clinically healthy, castrated domestic shorthair cats participated in two studies. Study 1 compared standard white light endoscopy with chromoendoscopy for localizing the major duodenal papilla. In Study 2 ERCP was performed. Repeated clinical examinations and measurements of serum feline pancreatic lipase immunoreactivity (fPLI) were performed before and up to 18 hours after interventions on all cats. Chromoendoscopy was subjectively judged to be superior for localizing the major papilla. Insertion of the ERCP catheter was best accomplished when cats were in dorsal recumbency. Complete ERCP was successful in two cats. In the other cats, either retrograde cholangiography or pancreatography was possible. Serum fPLI concentrations increased temporarily in two cats during Study 2 when measured immediately, 2, 4, and 18 h after ERCP. Peak fPLI concentrations were detected either immediately after ERCP or 2 h later. No clinical signs of complications were observed within 18 h after the procedures. Findings indicated that ERCP is technically demanding but feasible in healthy cats. Future studies need to determine whether the temporary increases in serum fPLI concentrations are clinically important and to investigate the utility of ERCP in feline patients. PMID- 23919247 TI - Infectious aortitis in a liver transplant recipient. AB - The development of an abdominal aortic aneurysm secondary to infectious aortitis following solid organ transplantation is a rare event that in the absence of surgical intervention, can lead to uncontrolled sepsis, catastrophic hemorrhage and death. Arterial allografts have been a viable surgical option for the past 30 years, although operative modalities have undergone a paradigm shift in recent years. We describe the first case in the literature of a liver transplant recipient who developed an infrarenal aortic aneurysm secondary to Salmonella bacteraemia, which was treated successfully with aortic allograft transplantation. PMID- 23919248 TI - The prevalence of the honeybee brood pathogens Ascosphaera apis, Paenibacillus larvae and Melissococcus plutonius in Spanish apiaries determined with a new multiplex PCR assay. AB - The microorganisms Ascosphaera apis, Paenibacillus larvae and Melissococcus plutonius are the three most important pathogens that affect honeybee brood. The aim of the present study was to evaluate the prevalence of these pathogens in honeybee colonies and to elucidate their role in the honeybee colony losses in Spain. In order to get it, a multiplex polymerase chain reaction (PCR) assay was developed to simultaneously amplify the16S ribosomal ribonucleic acid (rRNA) gene of P. larvae and M. plutonius, and the 5.8S rRNA gene of A. apis. The multiplex PCR assay provides a quick and specific tool that successfully detected the three infectious pathogens (P. larvae, M. plutonius and A. apis) in brood and adult honeybee samples without the need for microbiological culture. This technique was then used to evaluate the prevalence of these pathogens in Spanish honeybee colonies in 2006 and 2007, revealing our results a low prevalence of these pathogens in most of the geographic areas studied. PMID- 23919249 TI - Efficacy and safety of Wilate in paediatric VWD patients under 6 years of age - results of a prospective multicentre clinical study including recovery information. AB - Treatment with exogenous von Willebrand factor (VWF) is indicated in patients with von Willebrand disease (VWD) in whom treatment with 1-deamino-8-d-arginine vasopressin/desmopressin is contraindicated. Wilate is a new generation plasma derived concentrate of native VWF and coagulation factor VIII (FVIII) (in a physiological 1:1 ratio) developed for the treatment of VWD. This is the first study to report safety, efficacy and in vivo recovery (IVR) data from 15 paediatric patients less than 6 years of age who received Wilate for either prophylaxis, on-demand treatment or for treatment in surgical procedures during a prospective open-label trial (VWD type 1: 5, type 2A: 1, type 2B: 2, type 3: 6, unknown type: 1 patients). Analysis of IVR for VWF and FVIII suggested an appropriate and consistent rise in coagulation activity after Wilate administration. Overall efficacy was rated as excellent or good for 99.7% [prophylactic infusions] and 100% [bleeding episodes/surgical procedures]. More than 82% of bleeding episodes resolved after 1 day of treatment, and a Wilate dosage of 20-50 IU kg(-1) was sufficient to achieve haemostasis in 97% of bleeding episodes. All surgical procedures were successfully managed with Wilate. No thromboembolic events were observed during the study, and no patient developed anti-VWF antibodies or FVIII inhibitors. In conclusion, this study confirms both the expected IVR profile in paediatric patients and the excellent efficacy, tolerability and safety profile of Wilate observed previously in adults. Wilate showed excellent efficacy in the treatment of bleeding when used prophylactically or on-demand, and in the treatment of surgical procedures. PMID- 23919250 TI - Pd(0)-catalyzed sequential C-N bond formation via allylic and aromatic C-H amination of alpha-methylstyrenes with diaziridinone. AB - A novel Pd(0)-catalyzed sequential C-N bond formation process via allylic and aromatic C-H amination of alpha-methylstyrenes with di-tert-butyldiaziridinone, giving spirocyclic indolines in good yields, is described. Four C-N bonds and one spiro quaternary carbon are generated in a single operation. PMID- 23919251 TI - Enamel matrix derivative: protein components and osteoinductive properties. AB - BACKGROUND: Although enamel matrix derivative (EMD) has demonstrated the ability to promote angiogenesis and osteogenesis both in vitro and in vivo, the specific elements within the EMD compound responsible for these effects remain unknown. METHODS: Nine different protein pools from a commercially produced EMD were collected based on molecular weight. Six of these pools, along with the complete EMD unfractionated compound and positive and negative controls, were tested for their ability to induce bone formation in a calvarial induction assay. Immunocytochemistry of phosphorylated SMAD1/5/8 (phospho-SMAD), osterix, and vascular endothelial growth factor A (VEGF-A) was carried out at selected time points. Finally, proteomic analysis was completed to determine the specific protein-peptide content of the various osteoinductive pools. RESULTS: One of the lower-molecular-weight pools tested, pool 7, showed bone induction responses significantly greater than those of the other pools and the complete EMD compound and was concentration dependent. Dynamic bone formation rate analysis demonstrated that pool 7 was optimally active at the 5- to 10-MUg concentration. It was demonstrated that EMD and pool 7 induced phospho-SMAD, osterix, and VEGF A, which is indicative of increased bone morphogenetic protein (BMP) signaling. Proteomic composition analysis demonstrated that pool 7 had the highest concentration of the biologically active amelogenin-leucine-rich amelogenin peptide and ameloblastin 17-kDa peptides. CONCLUSIONS: These studies demonstrate that the low-molecular-weight protein pools (7 to 17 kDa) within EMD have greater osteoinductive potential than the commercially available complete EMD compound and that the mechanism of action, in part, is through increased BMP signaling and increased osterix and VEGF-A. With this information, selected components of EMD can now be formulated for optimal osteo- and angio-genesis. PMID- 23919252 TI - Clinical relevance of the (S)-citalopram-omeprazole interaction in geriatric patients. PMID- 23919253 TI - Controlling microstructure of pentacene derivatives by solution processing: impact of structural anisotropy on optoelectronic properties. AB - The consideration of anisotropic structural properties and their impact on optoelectronic properties in small-molecule thin films is vital to understand the performance of devices incorporating crystalline organic semiconductors. Here we report on the important relationship between structural and optoelectronic anisotropy in aligned, functionalized-pentacene thin films fabricated using the solution-based zone-casting technique. The microstructure of thin films composed of 6,13-bis(triisopropylsilylethynyl)pentacene (TIPS-pentacene) and 6,13 bis(triethylsilylethynyl)pentacene (TES-pentacene) is systematically controlled by varying the casting speed. By controlling the structural alignment, we were able to experimentally decouple, for the first time in these films, an intramolecular absorption transition dipole (at ~440 nm) oriented close to the pentacene short axis and an intermolecular absorption transition dipole (at ~695 nm) oriented predominantly along the conjugated pentacene-pentacene core stacking axis (crystallographic a-axis) in both films. Using the intermolecular absorption as a signature for intermolecular delocalization, much higher optical dichroism was obtained in TES-pentacene (16 +/- 6) than TIPS-pentacene (3.2 +/- 0.1), which was attributed to the 1D packing structure of TES-pentacene compared to the 2D packing structure of TIPS-pentacene. This result was also supported by field effect mobility anisotropy measurements of the films, with TES-pentacene exhibiting a higher anisotropy (~21-47, depending on the casting speed) than TIPS pentacene (~3-10). PMID- 23919254 TI - Spatial variation buffers temporal fluctuations in early juvenile survival for an endangered Pacific salmon. AB - Spatial, phenotypic and genetic diversity at relatively small scales can buffer species against large-scale processes such as climate change that tend to synchronize populations and increase temporal variability in overall abundance or production. This portfolio effect generally results in improved biological and economic outcomes for managed species. Previous evidence for the portfolio effect in salmonids has arisen from examinations of time series of adult abundance, but we lack evidence of spatial buffering of temporal variability in demographic rates such as survival of juveniles during their first year of life. We therefore use density-dependent population models with multiple random effects to represent synchronous (similar among populations) and asynchronous (different among populations) temporal variability as well as spatial variability in survival. These are fitted to 25 years of survey data for breeding adults and surviving juveniles from 15 demographically distinct populations of Chinook salmon (Oncorhynchus tshawytscha) within a single metapopulation in the Snake River in Idaho, USA. Model selection identifies the most support for the model that included both synchronous and asynchronous temporal variability, in addition to spatial variability. Asynchronous variability (log-SD = 0.55) is approximately equal in magnitude to synchronous temporal variability (log-SD = 0.67), but much lower than spatial variability (log-SD = 1.11). We also show that the pairwise correlation coefficient, a common measure of population synchrony, is approximated by the estimated ratio of shared and total variance, where both approaches yield a synchrony estimate of 0.59. We therefore find evidence for spatial buffering of temporal variability in early juvenile survival, although between-population variability that persists over time is also large. We conclude that spatial variation decreases interannual changes in overall juvenile production, which suggests that conservation and restoration of spatial diversity will improve population persistence for this metapopulation. However, the exact magnitude of spatial buffering depends upon demographic parameters such as adult survival that may vary among populations and is proposed as an area of future research using hierarchical life cycle models. We recommend that future sampling of this metapopulation employ a repeated-measure sampling design to improve estimation of early juvenile carrying capacity. PMID- 23919255 TI - Collision tumors of the sella: coexistence of pituitary adenoma and craniopharyngioma in the sellar region. AB - Collision tumors of the sellar region are relatively uncommon and consist mainly of more than one type of pituitary adenoma or a cyst or cystic tumor. The association of a pituitary adenoma and a craniopharyngioma is particularly rare. This study describes a rare occurrence in which a pituitary adenoma and a craniopharyngioma coexisted in the sellar region. The case involves a 47-year-old woman who underwent transsphenoidal surgery with subtotal tumor resection and reoperation using an interhemispheric transcallosal approach for total microsurgical resection of the tumor because the visual acuity in her left eye had re-deteriorated. Histopathological and immunohistochemical examinations of the excised tissue revealed a pituitary adenoma in the first operation and a craniopharyngioma in the second operation. Retrospective analysis found the coexistence of a pituitary adenoma and a craniopharyngioma, known as a collision tumor. Instead of the transsphenoidal approach, a craniotomy should be performed, to explore the suprasellar region. PMID- 23919256 TI - Long-term performance and stability of molecular shotgun lipidomic analysis of human plasma samples. AB - The stability of the lipid concentration levels in shotgun lipidomics analysis was tracked over a period of 3.5 years. Concentration levels in several lipid classes, such as phospholipids, were determined in human plasma lipid extracts. Impact of the following factors on the analysis was investigated: sample amount, internal standard amount, and sample dilution factor. Moreover, the reproducibility of lipid profiles obtained in both polarity modes was evaluated. Total number of samples analyzed was approximately 6800 and 7300 samples in negative and positive ion modes, respectively, out of which 610 and 639 instrument control samples were used in stability calculations. The assessed shotgun lipidomics approach showed to be remarkably robust and reproducible, requiring no batch corrections. Coefficients of variation (CVs) of lipid mean concentration measured with optimized analytical parameters were typically less than 15%. The high reproducibility indicated that no lipid degradation occurred during the monitored time period. PMID- 23919257 TI - Manifestations of food protein induced gastrointestinal allergies presenting to a single tertiary paediatric gastroenterology unit. AB - BACKGROUND: Food protein induced gastrointestinal allergies are difficult to characterise due to the delayed nature of this allergy and absence of simple diagnostic tests. Diagnosis is based on an allergy focused history which can be challenging and often yields ambiguous results. We therefore set out to describe a group of children with this delayed type allergy, to provide an overview on typical profile, symptoms and management strategies. METHODS: This retrospective analysis was performed at Great Ormond Street Children's Hospital. Medical notes were included from 2002 - 2009 where a documented medical diagnosis of food protein induced gastrointestinal allergies was confirmed by an elimination diet with resolution of symptoms, followed by reintroduction with reoccurrence of symptoms. Age of onset of symptoms, diagnosis, current elimination diets and food elimination at time of diagnosis and co-morbidities were collected and parents were phoned again at the time of data collection to ascertain current allergy status. RESULTS: Data from 437 children were analysis. The majority (67.7%) of children had an atopic family history and 41.5% had atopic dermatitis at an early age. The most common diagnosis included, non-IgE mediated gastrointestinal food allergy (n = 189) and allergic enterocolitis (n = 154) with symptoms of: vomiting (57.8%), back-arching and screaming (50%), constipation (44.6%), diarrhoea (81%), abdominal pain (89.9%), abdominal bloating (73.9%) and rectal bleeding (38.5%). The majority of patients were initially managed with a milk, soy, egg and wheat free diet (41.7%). At a median age of 8 years, 24.7% of children still required to eliminate some of the food allergens. CONCLUSIONS: This large retrospective study on children with food induced gastrointestinal allergies highlights the variety of symptoms and treatment modalities used in these children. However, further prospective studies are required in this area of food allergy. PMID- 23919258 TI - Short-term storage and swim-up selection do not affect the x/y ratio in equine spermatozoa. AB - The standard procedure of artificial insemination with fresh equine spermatozoa involves short-term storage (to 48 h at 5 degrees C). This procedure is accompanied by a gradual loss of sperm viability. The aim of this study was to investigate whether the X/Y ratio of equine spermatozoa is affected by short-term storage and the swim-up procedure. We used a standard protocol, for short-term storage (0, 24 and 48 h at 5 degrees C) of stallion semen diluted in the commercial extender EquiProTM (Minitub GmbH, Tiefenbach, Germany). After each set up storage period, the motile fraction of sperm cells was selected by the swim-up method. The X/Y ratio was evaluated by fluorescence in situ hybridization (FISH) in the fresh, non-selected sperm, and in motile spermatozoa selected after each of the storage periods. Molecular probes for the equine chromosomes X and Y were used. The X/Y ratio in all sperm samples analysed in this study (fresh and stored) was not different from the theoretical 1 : 1 value. The incidence of chromosomally abnormal sperm cells in the fresh (0.28%) and motile (0.13%) sperm samples was not significantly different. The two approaches (sperm storage up to 48 h and the swim-up procedure) applied to this study did not affect the X/Y ratio in the motile fraction of equine spermatozoa. This finding does not conform to phenomena described for human and cattle. For this reason, the finding may imply species-related differences. PMID- 23919260 TI - Field-based approach for assessing the impact of treated pulp and paper mill effluent on endogenous metabolites of fathead minnows (Pimephales promelas). AB - A field-based metabolomic study was conducted during a shutdown of a pulp and paper mill (PPM) to assess the impacts of treated PPM effluent on endogenous polar metabolites in fathead minnow (FHM; Pimephales promelas) livers. Caged male and female FHMs were deployed at a Great Lakes area of concern during multiple periods (pre-, during, and post-shutdown) near the outflow for a wastewater treatment plant. Influent to this plant is typically 40% PPM effluent by volume. Additional FHMs were exposed to reference lake water under laboratory conditions. A bioassay using T47D-KBluc cells showed that estrogenic activity of receiving water near the outflow declined by 46% during the shutdown. We then used (1)H NMR spectroscopy and principal component analysis to profile abundances of hepatic endogenous metabolites for FHMs. Profiles for males deployed pre-shutdown in receiving water were significantly different from those for laboratory-control males. Profiles were not significantly different for males deployed during the shutdown, but they were significant again for those deployed post-shutdown. Impacts of treated effluent from this PPM were sex-specific, as differences among profiles of females were largely nonsignificant. Thus, we demonstrate the potential utility of field-based metabolomics for performing biologically based exposure monitoring and evaluating remediation efforts occurring throughout the Great Lakes and other ecosystems. PMID- 23919261 TI - Fighting on the side of life: a special issue on suicide in bipolar disorder. PMID- 23919262 TI - Scrutinizing skinfield melanin patterns in young Caucasian women. AB - INTRODUCTION: When using adequate wavelength illumination and high resolution recordings, Caucasian skin color appears uneven. The patterns of faint mosaic melanoderma (FMM) are diverse and possibly related to the risk of skin cancer development. AREAS COVERED: The current peer-reviewed publications about objective methods quantifying FMM are revisited. The images from the Visioscan(r) and Visioface(r) Quick devices are computerized in order to record the ultraviolet light-enhanced visualization (ULEV) and the color-enhanced visualization (CEV) of the skin. Previously published data regarding the FMM are gathered in 20 odd Caucasian women. Seven FMM patterns are distinguished. They appear expressed differently according to body regions, but the mean gray level appears more uniform. EXPERT OPINION: The combination of larger subclinical melanotic macules and ivory spots during early adulthood is apparently associated with an increased risk for non-melanoma skin cancers. PMID- 23919263 TI - Novel candidate genes influencing natural variation in potato tuber cold sweetening identified by comparative proteomics and association mapping. AB - BACKGROUND: Higher plants evolved various strategies to adapt to chilling conditions. Among other transcriptional and metabolic responses to cold temperatures plants accumulate a range of solutes including sugars. The accumulation of the reducing sugars glucose and fructose in mature potato tubers during exposure to cold temperatures is referred to as cold induced sweetening (CIS). The molecular basis of CIS in potato tubers is of interest not only in basic research on plant adaptation to environmental stress but also in applied research, since high amounts of reducing sugars affect negatively the quality of processed food products such as potato chips. CIS-tolerance varies considerably among potato cultivars. Our objective was to identify by an unbiased approach genes and cellular processes influencing natural variation of tuber sugar content before and during cold storage in potato cultivars used in breeding programs. We compared by two-dimensional polyacrylamide gel electrophoresis the tuber proteomes of cultivars highly diverse for CIS. DNA polymorphisms in genomic sequences encoding differentially expressed proteins were tested for association with tuber starch content, starch yield and processing quality. RESULTS: Pronounced natural variation of CIS was detected in tubers of a population of 40 tetraploid potato cultivars. Significant differences in protein expression were detected between CIS-tolerant and CIS-sensitive cultivars before the onset as well as during cold storage. Identifiable differential proteins corresponded to protease inhibitors, patatins, heat shock proteins, lipoxygenase, phospholipase A1 and leucine aminopeptidase (Lap). Association mapping based on single nucleotide polymorphisms supported a role of Lap in the natural variation of the quantitative traits tuber starch and sugar content. CONCLUSIONS: The combination of comparative proteomics and association genetics led to the discovery of novel candidate genes for influencing the natural variation of quantitative traits in potato tubers. One such gene was a leucine aminopeptidase not considered so far to play a role in starch sugar interconversion. Novel SNP's diagnostic for increased tuber starch content, starch yield and chip quality were identified, which are useful for selecting improved potato processing cultivars. PMID- 23919266 TI - The association between mild cognitive impairment and doing housework. AB - OBJECTIVES: The ability to perform instrumental activities of daily living (IADL) is thought to be relatively intact for people with mild cognitive impairment (MCI). Doing housework as part of IADL is an important skill needed for older people to live independently and successfully. A limited number of studies explore the association between MCI and doing housework. The aim of this study was to assess the association between MCI and doing housework among old people. METHOD: The study employed a community-based, cross-sectional design. A total of 1773 older people residents, aged 60 and over, were randomly recruited in the Suzhou area, and they underwent the Montreal cognitive assessment (MoCA) for screening MCI in 2009. Participants were required to complete a questionnaire, which was comprised of their demographic information, health status, and life style, to evaluate the associations between MCI and these factors. RESULTS: About 13% of the respondents were found to have MCI. People with MCI are found to be less healthy and live unhealthy lifestyles. After adjusting confounding factors, a significant association was observed between MCI and not doing housework (Odds ratio (OR) = 1.64; 95% confidence interval (CI) = 1.17-2.30). CONCLUSIONS: MCI is associated with doing less housework. The deterioration in the ability to do housework is a potentially important indicator of evolving cognitive impairment in some old people. PMID- 23919264 TI - Cardio-metabolic risk factors and prehypertension in persons without diabetes, hypertension, and cardiovascular disease. AB - BACKGROUND: Prehypertension has been shown to be an early risk factor of cardiovascular disease (CVD). We investigated the prevalence and pattern of cardiometabolic risk factors in prehypertension in three ethnic Asian populations in Singapore. METHODS: We examined data from Chinese (n=1177), Malay (n=774), and Indian (n=985) adults aged 40-80 years who participated in three independent population based studies conducted from 2004-2011 in Singapore who were free of diabetes, hypertension and previous CVD. Prehypertension was defined as systolic blood pressure (BP) 120-139 mm Hg or diastolic BP 80-89 mm Hg. Random blood glucose, glycated haemoglobin (HbA1c), body mass index (BMI), triglycerides, low density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol were examined as indicators of adverse cardiometabolic profile. The association between metabolic variables and prehypertension was examined using logistic regression models adjusting for potential confounders. RESULTS: The prevalence of prehypertension was 59.8% (Chinese), 68.9% (Malays) and 57.7% Indians. Higher levels of blood glucose, HbA1c and BMI were significantly associated with prehypertension in all three ethnic groups, odds ratio (95% confidence interval) of prehypertension in Chinese, Malays and Indians were: 1.42 (1.10, 1.83), 1.53 (1.05, 2.24), 1.49 (1.13, 1.98) for high-glucose; 3.50 (1.01, 12.18), 3.72 (1.29, 10.75), 2.79 (1.31, 5.94) for high-HbA1c; 1.86 (1.34, 2.56), 2.96 (2.10, 4.18), 1.68 (1.28, 2.20) for high-BMI. In addition, higher levels of LDL cholesterol in Chinese and higher levels of triglycerides were significantly associated with prehypertension. These associations persisted when metabolic variables were analysed as continuous variables. CONCLUSIONS: Higher levels of blood glucose, HbA1c and BMI were associated with prehypertension in all three ethnic groups in Singapore. Screening for prehypertension and lifestyle modifications could potentially reduce the burden of CVD in otherwise healthy Asian adults living in Singapore. PMID- 23919265 TI - Genotype-phenotype correlations in recessive RYR1-related myopathies. AB - BACKGROUND: RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia, and genotype-phenotype patterns have emerged from the study of these mutations that have contributed to the understanding of disease pathogenesis. The recent availability of genetic testing for the entire RYR1 coding sequence has led to a dramatic expansion in the identification of recessive mutations in core myopathies and other congenital myopathies. To date, no clear patterns have been identified in these recessive mutations, though no systematic examination has yet been performed. METHODS: In this study, we investigated genotype-phenotype correlations in a large combined cohort of unpublished (n = 14) and previously reported (n = 92) recessive RYR1 cases. RESULTS: Overall examination of this cohort revealed nearly 50% of cases to be non-core myopathy related. Our most significant finding was that hypomorphic mutations (mutations expected to diminish RyR1 expression) were enriched in patients with severe clinical phenotypes. We also determined that hypomorphic mutations were more likely to be encountered in non-central core myopathies. With analysis of the location of non hypomorphic mutations, we found that missense mutations were generally enriched in the MH/CCD hotspots and specifically enriched in the selectivity filter of the channel pore. CONCLUSIONS: These results support a hypothesis that loss of protein function is a key predictive disease parameter. In addition, they suggest that decreased RyR1 expression may dictate non-core related pathology though, data on protein expression was limited and should be confirmed in a larger cohort. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis in recessive core myopathies. Overall, our findings represent a comprehensive analysis of genotype-phenotype associations in recessive RYR1-myopathies. PMID- 23919267 TI - Public opinion regarding utilization of assisted reproductive technology (ART) in obese women. AB - BACKGROUND: There have been calls to restrict access to fertility treatment in women above a certain body mass index (BMI). It is important to consider public expectations before formulating policy. The study objective was to assess public opinion regarding provision of assisted reproductive technology (ART) to obese (BMI>30 kg/m(2)) women in the United States. The study was conducted through an Internet-based survey of U.S. residents ages 18-75. METHODS: Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression to describe predictors of response based on demographic characteristics. RESULTS: Of the 1049 respondents, 60.7% support the use of ART in obese women. Adjusting for age and gender, the odds of support were over twice as high in participants with BMI>40 kg/m(2) as in normal-weight respondents (OR=2.87, 95% CI=1.28-6.44). Fifty-five percent of participants supported a BMI limit for access to ART. Both increasing education (p-value=0.02) and BMI (p-value=0.01) were inversely associated with support of a BMI limit. Individuals who had themselves used ART were also less likely (OR=0.27, 95% CI=0.07--0.99) to support a BMI limit. CONCLUSIONS: In an Internet-based survey, participants who are in favor of ART are likely to support its use among obese women. More than 50% of these respondents also support implementation of a BMI limit for access to these services. PMID- 23919268 TI - Giant left atrial appandage thrombus due to atrial fibrillation: successful treatment with warfarin. PMID- 23919270 TI - Conjugated estrogens for the treatment of menopausal symptoms: a review of safety data. AB - INTRODUCTION: Conjugated equine estrogens (CEE) are widely used for the treatment of menopausal symptoms, such as vasomotor symptoms and vulvovaginal atrophy, and for the prevention of bone loss, in postmenopausal women. The safety profile of CEE has been extensively published over the past 20 years. AREAS COVERED: Data from randomized controlled trials and from observational studies on the effects of CEE on the risk of breast cancer, endometrial cancer or hyperplasia, other cancers, cardiovascular outcomes, and cognitive function are reviewed. When used alone, CEE are not associated with an increased risk of breast cancer and may be associated with reduced mortality. The risk of cardiovascular events with CEE may be reduced in women who are more recently postmenopausal. EXPERT OPINION: Numerous clinical studies have evaluated the safety of CEE. The data reviewed in this article describe the breast, endometrial, and cardiovascular safety of unopposed CEE. International recommendations describe CEE as the menopausal symptom treatment of choice, particularly in young or recently postmenopausal hysterectomized women. PMID- 23919271 TI - Correction: Expression of Hox genes during regeneration of nereid polychaete Alitta virens (Annelida, Lophotrochozoa). PMID- 23919272 TI - Elevated central venous pressure is associated with impairment of microcirculatory blood flow in sepsis: a hypothesis generating post hoc analysis. AB - BACKGROUND: Microcirculatory driving pressure is defined as the difference between post-arteriolar and venular pressure. In previous research, an absence of correlation between mean arterial blood pressure (MAP) and microcirculatory perfusion has been observed. However, the microcirculation may be considered as a low pressure compartment with capillary pressure closer to venous than to arterial pressure. From this perspective, it is conceivable that central venous pressure (CVP) plays a more important role in determination of capillary perfusion. We aimed to explore associations between CVP and microcirculatory perfusion. METHODS: We performed a post-hoc analysis of a prospective study in septic patients who were resuscitated according a strict non-CVP guided treatment protocol. Simultaneous measurements of hemodynamics and sublingual Sidestream Dark Field imaging were obtained 0 and 30 minutes after fulfillment of resuscitation goals. Data were examined for differences in microcirculatory variables for CVP <= or > 12 mmHg and its evolution over time, as well as for predictors of a microvascular flow index (MFI) < 2.6. RESULTS: In 70 patients with a mean APACHE II score of 21, 140 simultaneous measurements of CVP and sublingual microcirculation (vessels < 20 umeter) were obtained. (MFI) and the percentage of perfused small vessels (PPV) were significantly lower in the 'high' CVP (> 12 mmHg) group as compared to patients in the 'low' CVP (<=12 mmHg) group (1.4 +/- 0.9 vs. 1.9 +/- 0.9, P = 0.006; and 88 +/- 21% vs. 95 +/- 8%, P = 0.006 respectively). Perfusion pressure (MAP-CVP) and cardiac output did not differ significantly between both CVP groups. From time point 0 to 30 minutes, a significant increase in MFI (from 1.6 +/- 0.6 to 1.8 +/- 0.9, P = 0.027) but not in PPV, was observed, while CVP and perfusion pressure significantly decreased in the same period. In a multivariate model CVP > 12 mmHg was the only significant predictor for a capillary MFI < 2.6 (Odds ratio 2.5 (95% confidence interval 1.1 5.8), P = 0.026). CONCLUSION: We observed a significant association between a higher CVP and impairment of microcirculatory blood flow. Further research is needed to elaborate on our hypothesis generating findings that an elevated CVP may act as an outflow obstruction of organ perfusion. PMID- 23919273 TI - The cross-domain correlates of subjective age in Chinese oldest-old. AB - OBJECTIVES: This study examined subjective age and its cross-domain correlates in Chinese oldest-old. METHOD: We conducted a secondary data analysis using cross sectional data drawn from the 2006 Sample Survey on the Aged Population in Urban/Rural China, which consisted of a sample of 860 community-dwelling Chinese older adults aged 85 years and above. RESULTS: A small percentage (8%) of the oldest-old participants reported that they did not feel old. Binary logistic regression analyses revealed that urban living, better physical and self-reported cognitive functioning and mental health were all related to not feeling old, whereas chronological age was found to have no association with subjective age when controlling for indicators of physical and self-reported cognitive functioning. CONCLUSION: The findings revealed the key roles of functional limitations and mental health in the construction of subjective age in Chinese oldest-old. The possible cross-cultural similarity in the links of subjective age to mental health and physical functioning in later life suggests that maintaining a youthful subjective age may have adaptive value for the oldest-old and contribute to their successful aging. PMID- 23919275 TI - Promoting universal financial protection: how the Thai universal coverage scheme was designed to ensure equity. AB - BACKGROUND: Empirical evidence demonstrates that the Thai Universal Coverage Scheme (UCS) has improved equity of health financing and provided a relatively high level of financial risk protection. Several UCS design features contribute to these outcomes: a tax-financed scheme, a comprehensive benefit package and gradual extension of coverage to illnesses that can lead to catastrophic household costs, and capacity of the National Health Security Office (NHSO) to mobilise adequate resources. This study assesses the policy processes related to making decisions on these features. METHODS: The study employs qualitative methods including reviews of relevant documents, in-depth interviews of 25 key informants, and triangulation amongst information sources. RESULTS: Continued political and financial commitments to the UCS, despite political rivalry, played a key role. The Thai Rak Thai (TRT)-led coalition government introduced UCS; staying in power 8 of the 11 years between 2001 and 2011 was long enough to nurture and strengthen the UCS and overcome resistance from various opponents. Prime Minister Surayud's government, replacing the ousted TRT government, introduced universal renal replacement therapy, which deepened financial risk protection.Commitment to their manifesto and fiscal capacity pushed the TRT to adopt a general tax-financed universal scheme; collecting premiums from people engaged in the informal sector was neither politically palatable nor technically feasible. The relatively stable tenure of NHSO Secretary Generals and the chairs of the Financing and the Benefit Package subcommittees provided a platform for continued deepening of financial risk protection. NHSO exerted monopsonistic purchasing power to control prices, resulting in greater patient access and better systems efficiency than might have been the case with a different design.The approach of proposing an annual per capita budget changed the conventional line-item programme budgeting system by basing negotiations between the Bureau of Budget, the NHSO and other stakeholders on evidence of service utilization and unit costs. CONCLUSIONS: Future success of Thai UCS requires coverage of effective interventions that address primary and secondary prevention of non-communicable diseases and long-term care policies in view of epidemiologic and demographic transitions. Lessons for other countries include the importance of continued political support, evidence informed decisions, and a capable purchaser organization. PMID- 23919274 TI - Ursodeoxycholic acid counteracts celecoxib in reduction of duodenal polyps in patients with familial adenomatous polyposis: a multicentre, randomized controlled trial. AB - BACKGROUND: Due to prophylactic colectomy, mortality in patients with familial adenomatous polyposis (FAP) has changed, with duodenal cancer currently being the main cause of death. Although celecoxib reduces duodenal polyp density in patients with FAP, its long-term use may increase the risk of cardiovascular events and alternatives need to be explored. Preclinical studies suggest that the combination of celecoxib with ursodeoxycholic acid (UDCA) is a potentially effective strategy. We performed a randomized, double-blind, placebo-controlled trial to investigate the effect of celecoxib and UDCA co-treatment on duodenal adenomatosis in patients with FAP. METHODS: Patients with FAP received celecoxib (400 mg twice daily) and UDCA (1000-2000 mg daily, ~20-30 mg/kg/day, n=19) or celecoxib and placebo (n=18) orally for 6 months. Primary outcome was drug efficacy, assessed by comparing duodenal polyp density at pre- and post intervention by blinded review of endoscopic recordings. As secondary outcomes, cell proliferation, apoptosis, and COX-2 levels in normal duodenal mucosa were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction. RESULTS: In intention-to-treat analysis, deceased polyp density was observed after celecoxib/placebo treatment (p=0.029), whereas increased polyp density was observed after celecoxib/UDCA treatment (p=0.014). The difference in change in duodenal polyp density was statistically significant between the groups (p=0.011). No changes in secondary outcomes were observed. Thirty patients (81%) reported one or more adverse events, 16 patients (84%, Common Toxicity Criteria for Adverse Events version 3.0 (CTCAE) grade 1-3) treated with celecoxib/UDCA and 14 patients (78%, CTCAE grade 1-2) treated with celecoxib/placebo. Nine patients (24%) discontinued intervention prematurely, 5 patients (26%) treated with celecoxib/UDCA and 4 patients (22%) treated with celecoxib/placebo. CONCLUSIONS: Celecoxib reduces duodenal polyp density in patients with FAP, and unexpectedly, high dose UDCA co-treatment counteracts this effect. The benefit of long term use of celecoxib for duodenal cancer prevention needs to be weighed against the (risk of) adverse events. TRIAL REGISTRATION: http://ClinicalTrials.gov, identifier NCT00808743. PMID- 23919276 TI - Size-dependent velocity map photoelectron imaging of nanosized ammonia aerosol particles. AB - The size dependence of the band position, the bandwidth, and the asymmetry parameter in the valence photoelectron spectrum of ammonia clusters and ultrafine ammonia aerosol particles is investigated for aggregates with diameters up to ~7 nm. The neutral aggregates are ionized by single photons at 13.318 eV from a tabletop vacuum ultraviolet laser. The photoelectrons are detected in a velocity map imaging photoelectron spectrometer. The size distributions of the neutral aggregates are determined independently using the Na-doping method. Up to clusters with a few tens of molecules, the first ionization energy (value at band maximum) decreases, the width of the lowest band in the photoelectron spectrum broadens, and the corresponding asymmetry parameter decreases with increasing cluster size. Constant ("plateau") values of these parameters are found for larger aggregates, which might be explained by a predominantly noncrystalline structure of these aggregates with an average coordination similar to that of the liquid. This explanation is in agreement with previous infrared studies and theoretical predictions. PMID- 23919277 TI - Stabilized cyclopropane analogs of the splicing inhibitor FD-895. AB - Targeting the spliceosome with small molecule inhibitors provides a new avenue to target cancer by intercepting alternate splicing pathways. Although our understanding of alternate mRNA splicing remains poorly understood, it provides an escape pathway for many cancers resistant to current therapeutics. These findings have encouraged recent academic and industrial efforts to develop natural product spliceosome inhibitors, including FD-895 (1a), pladienolide B (1b), and pladienolide D (1c), into next-generation anticancer drugs. The present study describes the application of semisynthesis and total synthesis to reveal key structure-activity relationships for the spliceosome inhibition by 1a. This information is applied to deliver new analogs with improved stability and potent activity at inhibiting splicing in patient derived cell lines. PMID- 23919278 TI - beta-blockers: a new role in cancer chemotherapy? AB - beta-blockers are a class of drugs that are widely used in treating cardiac, respiratory and other ailments. They act by blocking beta-adrenergic receptor mediated signaling. Studies in various cancers have shown that patients taking a beta-blocker have higher survival and lower recurrence and metastasis rates. This is supported by several preclinical and in vitro studies showing that adrenergic activation modulates apoptosis, promotes angiogenesis and other cancer hallmarks, and these effects can be abrogated by beta-blockers. These studies provide a rationale for the use of beta-blockers as adjuvants with cancer chemotherapy. However, all published studies so far are retrospective and most do not take into account the specific beta-blocker used or address which is most likely to benefit cancer patients. The published epidemiological studies are correlative and have not examined the adrenergic receptor status of the tumors. Knowledge of the beta adrenergic receptor status of tumor cells is essential in choosing the best beta blocker for adjuvant therapy. A comprehensive, prospective study is necessary to definitively prove the utility of using beta-blockers with chemotherapy and to identify the specific beta-blocker most likely to benefit patients with cancer. PMID- 23919280 TI - Magnetite nanoparticle-induced fluorescence quenching of adenosine triphosphate BODIPY Conjugates: application to adenosine triphosphate and pyrophosphate sensing. AB - We report that magnetite nanoparticles (Fe3O4 NPs) act as an efficient quencher for boron dipyrromethene-conjugated adenosine 5'-triphosphate (BODIPY-ATP) that is highly fluorescent in bulk solution. BODIPY-ATP molecules attached to the surface of Fe3O4 NPs through the coordination between the triphosphate group of BODIPY-ATP and Fe(3+)/Fe(2+) on the NP surface. The formed complexes induced an apparent reduction in the BODIPY-ATP fluorescence resulting from an oxidative photoinduced electron transfer (PET) from the BODIPY-ATP excited state to an unfilled d shell of Fe(3+)/Fe(2+) on the NP surface. A comparison of the Stern Volmer quenching constant between Fe(3+) and Fe(2+) suggests that Fe(3+) on the NP surface dominantly controls this quenching process. The efficiency for Fe3O4 NP-induced fluorescence quenching of the BODIPY-ATP was enhanced by increasing the concentration of Fe3O4 NPs and lowering the pH of the solution to below 6.0. We found that pyrophosphate and ATP compete with BODIPY-ATP for binding to Fe3O4 NPs. Thus, we amplified BODIPY-ATP fluorescence in the presence of increasing the pyrophosphate and ATP concentration; the detection limits at a signal-to-noise ratio of 3 for pyrophosphate and ATP were determined to be 7 and 30 nM, respectively. The Fe3O4 NP-based competitive binding assay detected ATP and pyrophosphate in only 5 min. The selectivity of this assay for ATP over metal ions, amino acids, and adenosine analogues is particularly high. The practicality of using the developed method to determine ATP in a single drop of blood is also validated. PMID- 23919281 TI - Reductive cleavage of aryl O-carbamates to phenols by the Schwartz reagent. Expedient link to the directed ortho metalation strategy. AB - A general, mild, and efficient method for the reductive cleavage of aryl O carbamates to phenols, 1 -> 2 using the Schwartz reagent is reported. The method is selective, tolerating a large number of functional groups; may be carried out by direct or by an economical in situ procedure; and, notably, establishes a synthetic connection to the directed ortho metalation strategy (Figure 1 ) allowing new entries into difficult to prepare contiguously substituted aromatics and heteroaromatics. PMID- 23919282 TI - Oral contraceptive pills for endometriosis after conservative surgery: a systematic review and meta-analysis. AB - To assess the effects of oral contraceptive pills (OCPs) for endometriosis in women after conservative surgery, we performed a search of PubMed, Embase, ISI Web of Science, Cochrane Library, Scidirect, Chinese VIP, CNKI and WANGFANG database. Randomized controlled trials (RCTs) of OCPs in postoperative medical therapy for endometriosis were collected. Articles published as of January 2013 with no language restriction were identified using defined keywords, and 15 studies comprising 1850 patients were included. There was a significantly higher rate of total endometriosis remission [OR = 2.55, 95% CI (1.68, 3.86), p < 0.00001] and a lower rate of recurrence [OR = 0.31, 95% CI (0.22, 0.45), p < 0.00001] in the OCPs group compared with surgery alone. There appears to be no statistical difference in pregnancy rates between the OCPs group as compared with surgery alone or other hormonal drug treatments in infertility patients. As for the rate of recurrence and complete remission, there were no statistical differences among OCPs and gestrinone, mifepristone or GnRH-a groups. However, OCPs users had less side effects that were more mild as compared with patients using other hormonal treatments. PMID- 23919283 TI - "If It's Not Working, Why Would They Be Testing It?": mental models of HIV vaccine trials and preventive misconception among men who have sex with men in India. AB - BACKGROUND: Informed consent based on comprehension of potential risks and benefits is fundamental to the ethical conduct of clinical research. We explored mental models of candidate HIV vaccines and clinical trials that may impact on the feasibility and ethics of biomedical HIV prevention trials among men who have sex with men (MSM) in India. METHODS: A community-based research project was designed and implemented in partnership with community-based organizations serving MSM in Chennai and Mumbai. We conducted 12 focus groups (n=68) with diverse MSM and 14 key informant interviews with MSM community leaders/service providers using a semi-structured interview guide to explore knowledge and beliefs about HIV vaccines and clinical trials. Focus groups (60-90 minutes) and interviews (45-60 minutes) were conducted in participants' native language (Tamil in Chennai; Marathi or Hindi in Mumbai), audio-taped, transcribed and translated into English. We explored focus group and interview data using thematic analysis and a constant comparative method, with a focus on mental models of HIV vaccines and clinical trials. RESULTS: A mental model of HIV vaccine-induced seropositivity as "having HIV" resulted in fears of vaccine-induced infection and HIV stigma. Some participants feared inactivated vaccines might "drink blood" and "come alive". Pervasive preventive misconception was based on a mental model of prevention trials as interventions, overestimation of likely efficacy of candidate vaccines and likelihood of being assigned to the experimental group, with expectations of protective benefits and decreased condom use. Widespread misunderstanding and lack of acceptance of placebo and random assignment supported perceptions of clinical trials as "cheating". Key informants expressed concerns that volunteers from vulnerable Indian communities were being used as "experimental rats" to benefit high-income countries. CONCLUSIONS: Evidence informed interventions that engage with shared mental models among potential trial volunteers, along with policies and funding mechanisms that ensure local access to products that demonstrate efficacy in trials, may support the safe and ethical implementation of HIV vaccine trials in India. PMID- 23919285 TI - Infrared imaging of the crime scene: possibilities and pitfalls. AB - All objects radiate infrared energy invisible to the human eye, which can be imaged by infrared cameras, visualizing differences in temperature and/or emissivity of objects. Infrared imaging is an emerging technique for forensic investigators. The rapid, nondestructive, and noncontact features of infrared imaging indicate its suitability for many forensic applications, ranging from the estimation of time of death to the detection of blood stains on dark backgrounds. This paper provides an overview of the principles and instrumentation involved in infrared imaging. Difficulties concerning the image interpretation due to different radiation sources and different emissivity values within a scene are addressed. Finally, reported forensic applications are reviewed and supported by practical illustrations. When introduced in forensic casework, infrared imaging can help investigators to detect, to visualize, and to identify useful evidence nondestructively. PMID- 23919286 TI - Epigenetic contributions to hormonally-mediated sexual differentiation of the brain. AB - It has been long established that hormones exert enduring influences on the developing brain that direct the reproductive response in adulthood, although the cellular mechanisms by which organisational effects are maintained have not been determined satisfactorily. Recent interest in epigenetic modifications to the nervous system has highlighted the potential for hormone-induced changes to the genome that could endure for the lifespan but not be transmitted to the next generation. Preliminary evidence suggests that this is indeed possible because sex differences in the histone code and in the methylation of CpGs in the promoters of specific genes have been identified and, at times, functionally correlated with behaviour. The present review provides an overview of epigenetic processes and discusses the current state-of-the-art, and also identifies future directions. PMID- 23919287 TI - Relationship between frontostriatal morphology and executive function deficits in bipolar I disorder following a first manic episode: data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM). AB - OBJECTIVES: Executive function impairments are a core feature of bipolar I disorder (BD-I), not only present during acute episodes but also persisting following remission of mood symptoms. Despite advances in knowledge regarding the neural basis of executive functions in healthy subjects, research into morphological abnormalities underlying the deficits in BD-I is lacking. METHODS: Patients with BD-I within three months of sustained remission from their first manic episode (n = 41) underwent neuropsychological testing and a 3T magnetic resonance imaging scan and were compared to healthy subjects matched for age, sex, and premorbid IQ (n = 30). Group dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) and caudate volumes were examined and analyzed for relationships with the average score from three computerized tests of executive function: Spatial Working Memory, Stockings of Cambridge, and Intradimensional/Extradimensional Shift. RESULTS: Right caudate volumes were enlarged in patients (z = 3.57, p < 0.05 corrected). No differences in DLPFC volumes were found. Patients showed large deficits in executive function relative to healthy subjects (d = -0.92, p < 0.001). While in healthy subjects, a larger right (r = +0.39, p < 0.05) and left (r = +0.44, p < 0.05) caudate was associated with better executive function score, in patients, larger right (r = -0.36, p < 0.05) and left (r = -0.34, p < 0.05) volumes correlated with poorer performance. CONCLUSIONS: Although the etiology of gray matter changes is unknown, volume increases in the right caudate may be an important factor underlying executive function impairments during remission in patients with BD-I. PMID- 23919288 TI - The Italian experience with octopolar perc-paddle leads. AB - OBJECTIVE: The aim of this study is to evaluate the efficacy of spinal cord stimulation using octopolar perc-paddle leads (S-Series, St. Jude Medical, St. Paul, MN, USA) introduced percutaneously with St. Jude Medical's Epiducer Lead Delivery System in patients suffering from low back and leg pain. MATERIALS AND METHOD: We performed a retrospective review of patients implanted from 2009 to 2012 in Italy. Seventy-six patients were initially enrolled in the study. The patients' follow-up varies from 12 to 30 months. RESULTS: Seventy-one patients, 60 suffering from failed back surgery syndrome and 11 from spinal stenosis, reported significant improvement in pain symptoms and good paresthesia coverage of the affected regions. Pain reduction according to the Numerical Rating Scale ranged from 55% to 63%. The use of this new device appears to enhance the recruitment of the fibers of the lumbar region to obtain a reduction of the energy required for the stimulation and a more pleasant stimulation reported by patients. CONCLUSION: The possibility of using a percutaneous paddle lead, reducing the surgical aggressiveness but taking advantage of a different electric field and a better recruitment of the fibers of the lumbar region, has allowed pain therapists to be more effective in the treatment of these patients. The use of this device system suggests that the percutaneous paddle placement is safe and effective. PMID- 23919289 TI - Spread and change in stress resistance of Shiga toxin-producing Escherichia coli O157 on fungal colonies. AB - To elucidate the effect of fungal hyphae on the behaviour of Shiga toxin producing Escherichia coli (STEC) O157, the spread and change in stress resistance of the bacterium were evaluated after coculture with 11 species of food-related fungi including fermentation starters. Spread distances of STEC O157 varied depending on the co-cultured fungal species, and the motile bacterial strain spread for longer distances than the non-motile strain. The population of STEC O157 increased when co-cultured on colonies of nine fungal species but decreased on colonies of Emericella nidulans and Aspergillus ochraceus. Confocal scanning microscopy visualization of green fluorescent protein-tagged STEC O157 on fungal hyphae revealed that the bacterium colonized in the water film that existed on and between hyphae. To investigate the physiological changes in STEC O157 caused by co-culturing with fungi, the bacterium was harvested after 7 days of co-culturing and tested for acid resistance. After co-culture with eight fungal species, STEC O157 showed greater acid resistance compared to those cultured without fungi. Our results indicate that fungal hyphae can spread the contamination of STEC O157 and can also enhance the stress resistance of the bacteria. PMID- 23919290 TI - Stereoselective synthesis of beta-alkylated alpha-amino acids via palladium catalyzed alkylation of unactivated methylene C(sp3)-H bonds with primary alkyl halides. AB - We report a new set of reactions based on the Pd-catalyzed alkylation of methylene C(sp(3))-H bonds of aliphatic quinolyl carboxamides with alpha haloacetate and methyl iodide and applications in the stereoselective synthesis of various beta-alkylated alpha-amino acids. These reactions represent the first generally applicable method for the catalytic alkylation of unconstrained and unactivated methylene C-H bonds with high synthetic relevance. When applied with simple isotope-enriched reagents, they also provide a convenient and powerful means to site-selectively incorporate isotopes into the carbon scaffolds of amino acid compounds. PMID- 23919291 TI - Third trimester amniocentesis for diagnosis of inherited bleeding disorders prior to delivery. AB - X-linked and autosomally inherited bleeding disorders confer a risk of foetal intracranial haemorrhage during delivery. Conventional prenatal diagnosis involving chorionic villus sampling or early amniocentesis is primarily aimed at offering the choice of pregnancy termination. Currently, non-invasive procedures, involving analysis of free foetal DNA in the maternal circulation, are restricted to gender determination, and are of limited value in women at risk of carrying a foetus with a bleeding disorder. These limitations, together with the rising proportion of women shown to be carrying an affected foetus, who decide to continue the pregnancy, have led to the development of prenatal mutation identification via late amniocentesis after 34 weeks of gestation, with the sole aim of directing delivery management. Although this approach has been documented in some cases of potential foetal anomaly, there are no previous reports of its use in women with heritable bleeding disorders. We report a single-centre experience of this technique in managing nine such deliveries. Of these, three showed an affected foetus, five showed an unaffected foetus and in one case no result could be obtained. In the three affected cases and the one with the inconclusive result restrictive birth plans were implemented, whereas the five unaffected cases underwent routine obstetric management; with one delivery necessitating interventions which would have been contraindicated if foetal status had not been determined. Late amniocentesis is a safe technique for guiding delivery management in women with bleeding disorders where the mutation is known. PMID- 23919292 TI - Onset and persistence of respiratory/allergic symptoms in preschoolers: new insights from the PARIS birth cohort. AB - BACKGROUND: The natural course of childhood asthma and allergy is complex and not fully understood. We aimed to identify phenotypes based upon the time course of respiratory/allergic symptoms throughout preschool years. METHODS: As part of the PARIS cohort, symptoms of wheezing, dry night cough, rhinitis and dermatitis were collected annually from birth to age 4 years. K-means clustering was used to group into phenotypes children with similar symptoms trajectories over the study period. Associations of phenotypes with IgE sensitization and risk factors were studied using multinomial logistic regression. RESULTS: Besides a group with low prevalence of symptoms considered as reference (n = 1236, 49.0%), four distinct respiratory/allergic phenotypes were identified: two transient [transient rhinitis phenotype (n = 295, 11.7%), transient wheeze phenotype (n = 399, 15.8%)], without any relation with IgE sensitization, and two persistent [cough/rhinitis phenotype (n = 284, 11.3%), dermatitis phenotype (n = 308, 12.2%)], associated with IgE sensitization. Transient rhinitis phenotype was only associated with tobacco smoke exposure, which could irritate the airways. Transient wheeze phenotype was related to male sex and contact with other children (older siblings, day care attendance). Lastly, risk factors for both IgE associated phenotypes encompassed parental history of allergy, potential exposure to allergens and stress, known to be associated with the development of allergic diseases. CONCLUSION: This study provides evidence for the existence of different respiratory/allergic phenotypes before school age. The fact that they differ in terms of sensitization and risk factors reinforces the plausibility of distinct phenotypes, potentially linked to irritation and infections for the transient phenotypes and to allergy for the persistent phenotypes. PMID- 23919293 TI - Early embryonic determination of the sexual dimorphism in segment number in geophilomorph centipedes. AB - BACKGROUND: Most geophilomorph centipedes show intraspecific variability in the number of leg-bearing segments. This intraspecific variability generally has a component that is related to sex, with females having on average more segments than males. Neither the developmental basis nor the adaptive role of this dimorphism is known. RESULTS: To determine when this sexual dimorphism in segment number is established, we have followed the development of Strigamia maritima embryos from the onset of segmentation to the first post-embryonic stage where we could determine the sex morphologically. We find that males and females differ in segment number by Stage 6.1, a point during embryogenesis when segment addition pauses while the embryo undergoes large-scale movements. We have confirmed this pattern by establishing a molecular method to determine the sex of single embryos, utilising duplex PCR amplification for Y chromosomal and autosomal sequences. This confirms that male embryos have a modal number of 43 segments visible at Stage 6, while females have 45. In our Strigamia population, adult males have a modal number of 47 leg-bearing segments, and females have 49. This implies that the sexual dimorphism in segment number is determined before the addition of the last leg-bearing segments and the terminal genital segments. CONCLUSIONS: Sexual dimorphism in segment number is not associated with terminal segment differentiation, but must instead be related to some earlier process during segment patterning. The dimorphism may be associated with a difference in the rate and/or duration of segment addition during the main phase of rapid segment addition that precedes embryonic Stage 6. This suggests that the adaptive role, if any, of the dimorphism is likely to be related to segment number per se, and not to sexual differentiation of the terminal region. PMID- 23919294 TI - Maternal trait personality and breastfeeding duration: the importance of confidence and social support. AB - AIM: To explore associations among breastfeeding duration, maternal personality and maternal attitudes and experiences of breastfeeding. BACKGROUND: Understanding influences on breastfeeding initiation and duration is critical to increasing breastfeeding rates and supporting new mothers. Maternal characteristics such as self-efficacy, knowledge and confidence are known to enable women to breastfeed, but little is known about the influence of maternal trait personality on breastfeeding. DESIGN: An exploratory cross-sectional survey. METHOD: A total of 602 mothers with an infant aged 6-12 months old completed a self-report questionnaire examining maternal trait personality, breastfeeding duration and attitudes and experiences of breastfeeding. Data were collected between March-June 2009. RESULTS: Mothers who reported high levels of extraversion, emotional stability and conscientiousness were significantly more likely to initiate and continue breastfeeding for a longer duration. Attitudes and experiences significantly associated with these personality traits such as perceived difficulties and lack of support may explain these patterns. For example, characteristics associated with introversion and anxiety may prevent women from seeking support or challenging negative attitudes of others at this critical time. CONCLUSION: Understanding the influence of maternal personality may thus be a useful tool in antenatal support to recognize women who may need extra, directed support while facilitating discussion of potential barriers to breastfeeding. PMID- 23919295 TI - Methanogenesis facilitated by geobiochemical iron cycle in a novel syntrophic methanogenic microbial community. AB - Production and emission of methane have been increasing concerns due to its significant effect on global climate change and the carbon cycle. Here we report facilitated methane production from acetate by a novel community of methanogens and acetate oxidizing bacteria in the presence of poorly crystalline akaganeite slurry. Comparative analyses showed that methanogenesis was significantly enhanced by added akaganeite and acetate was mostly stoichiometrically converted to methane. Electrons produced from anaerobic acetate oxidation are transferred to akaganeite nanorods that likely prompt the transformation into goethite nanofibers through a series of biogeochemical processes of soluble Fe(II) readsorption and Fe(III) reprecipitation. The methanogenic archaea likely harness the biotransformation of akaganeite to goethite by the Fe(III)-Fe(II) cycle to facilitate production of methane. These results provide new insights into biogeochemistry of iron minerals and methanogenesis in the environment, as well as the development of sustainable methods for microbial methane production. PMID- 23919296 TI - Generalist solutions to complex problems: generating practice-based evidence--the example of managing multi-morbidity. AB - BACKGROUND: A growing proportion of people are living with long term conditions. The majority have more than one. Dealing with multi-morbidity is a complex problem for health systems: for those designing and implementing healthcare as well as for those providing the evidence informing practice. Yet the concept of multi-morbidity (the presence of >2 diseases) is a product of the design of health care systems which define health care need on the basis of disease status. So does the solution lie in an alternative model of healthcare? DISCUSSION: Strengthening generalist practice has been proposed as part of the solution to tackling multi-morbidity. Generalism is a professional philosophy of practice, deeply known to many practitioners, and described as expertise in whole person medicine. But generalism lacks the evidence base needed by policy makers and planners to support service redesign. The challenge is to fill this practice research gap in order to critically explore if and when generalist care offers a robust alternative to management of this complex problem. We need practice-based evidence to fill this gap. By recognising generalist practice as a 'complex intervention' (intervening in a complex system), we outline an approach to evaluate impact using action-research principles. We highlight the implications for those who both commission and undertake research in order to tackle this problem. SUMMARY: Answers to the complex problem of multi-morbidity won't come from doing more of the same. We need to change systems of care, and so the systems for generating evidence to support that care. This paper contributes to that work through outlining a process for generating practice-based evidence of generalist solutions to the complex problem of person-centred care for people with multi-morbidity. PMID- 23919297 TI - The interaction between human enteroviruses and type I IFN signaling pathway. AB - Human enteroviruses (HEV), very common and important human pathogens, cause infections in diverse ways. Recently, the large epidemic of HFMD caused by HEV infection became a growing threat to public health in China. As the first line of immune response, the type I interferon (IFN-alpha/beta) pathway plays an essential role in antiviral infection, particularly in limiting both the early and late stages of infection. Because of co-evolution with the host, the viruses have evolved multiple strategies to evade or subvert the host immunity to ensure their survival. In this paper, we systematically reviewed and summarized the interaction between HEV infections and host type I IFN responses. We firstly described the recent findings of HEV recognition and IFN induction, specifically on host pattern-recognition receptors (PRRs) in HEV infection. Then we discussed the antiviral effect of IFN in HEV infection. Finally, we timely summarized the mechanisms of HEV to circumvent the IFN responses. Clarification of the complexity in this battle may provide us new strategies for prevention and antiviral treatment. PMID- 23919298 TI - The contractile vacuole complex of protists--new cues to function and biogenesis. AB - The contractile vacuole complex (CVC) of freshwater protists sequesters the excess of water and ions (Ca(2+)) for exocytosis cycles at the pore. Sequestration is based on a chemiosmotic proton gradient produced by a V-type H(+)-ATPase. So far, many pieces of information available have not been combined to a comprehensive view on CVC biogenesis and function. One main function now appears as follows. Ca(2+)-release channels, type inositol 1,4,5-trisphosphate receptors (InsP3R), may serve for fine-tuning of local cytosolic Ca(2+) concentration and mediate numerous membrane-to-membrane interactions within the tubular spongiome meshwork. Such activity is suggested by the occurrence of organelle-specific soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) and Ras-related in brain (Rab) proteins, which may regulate functional requirements. For tubulation, F-Bin-amphiphysin-Rvs (F-BAR) proteins are available. In addition, there is indirect evidence for the occurrence of H(+)/Ca(2+) exchangers (to sequester Ca(2+)) and mechanosensitive Ca(2+)-channels (for signaling the filling sate). The periodic activity of the CVC may be regulated by the mechanosensitive Ca(2+)-channels. Such channels are known to colocalize with and to be functionally supported by stomatins, which were recently detected in the CVC. A Kif18-related kinesin motor protein might control the length of radial arms. Two additional InsP3-related channels and several SNAREs are associated with the pore. De novo organelle biogenesis occurs under epigenetic control during mitotic activity and may involve the assembly of gamma tubulin, centrin, calmodulin and a never in mitosis A-type (NIMA) kinase - components also engaged in mitotic processes. PMID- 23919299 TI - The shikimate pathway: review of amino acid sequence, function and three dimensional structures of the enzymes. AB - The aromatic compounds such as aromatic amino acids, vitamin K and ubiquinone are important prerequisites for the metabolism of an organism. All organisms can synthesize these aromatic metabolites through shikimate pathway, except for mammals which are dependent on their diet for these compounds. The pathway converts phosphoenolpyruvate and erythrose 4-phosphate to chorismate through seven enzymatically catalyzed steps and chorismate serves as a precursor for the synthesis of variety of aromatic compounds. These enzymes have shown to play a vital role for the viability of microorganisms and thus are suggested to present attractive molecular targets for the design of novel antimicrobial drugs. This review focuses on the seven enzymes of the shikimate pathway, highlighting their primary sequences, functions and three-dimensional structures. The understanding of their active site amino acid maps, functions and three-dimensional structures will provide a framework on which the rational design of antimicrobial drugs would be based. Comparing the full length amino acid sequences and the X-ray crystal structures of these enzymes from bacteria, fungi and plant sources would contribute in designing a specific drug and/or in developing broad-spectrum compounds with efficacy against a variety of pathogens. PMID- 23919300 TI - Normothermic machine perfusion of discarded liver grafts. PMID- 23919302 TI - Gender dysphoria: the lived experience TRANS. Directed by Chris Arnold and produced by Mark Schoen, 2012, 93 minutes. DVD, $29.90-$125.00. TRANS, 244 South Main Street, New Hope, PA 18938; http://www.transthemovie.com. PMID- 23919301 TI - What Hispanic parents do to encourage and discourage 3-5 year old children to be active: a qualitative study using nominal group technique. AB - PURPOSE: Hispanic preschoolers are less active than their non-Hispanic peers. As part of a feasibility study to assess environmental and parenting influences on preschooler physical activity (PA) (Ninos Activos), the aim of this study was to identify what parents do to encourage or discourage PA among Hispanic 3-5 year old children to inform the development of a new PA parenting practice instrument and future interventions to increase PA among Hispanic youth. METHODS: Nominal Group Technique (NGT), a structured multi-step group procedure, was used to elicit and prioritize responses from 10 groups of Hispanic parents regarding what parents do to encourage (5 groups) or discourage (5 groups) preschool aged children to be active. Five groups consisted of parents with low education (less than high school) and 5 with high education (high school or greater) distributed between the two NGT questions. RESULTS: Ten NGT groups (n = 74, range 4-11/group) generated 20-46 and 42-69 responses/group for practices that encourage or discourage PA respectively. Eight to 18 responses/group were elected as the most likely to encourage or discourage PA. Parental engagement in child activities, modeling PA, and feeding the child well were identified as parenting practices that encourage child PA. Allowing TV and videogame use, psychological control, physical or emotional abuse, and lack of parental engagement emerged as parenting practices that discourage children from being active. There were few differences in the pattern of responses by education level. CONCLUSIONS: Parents identified ways they encourage and discourage 3-5 year-olds from PA, suggesting both are important targets for interventions. These will inform the development of a new PA parenting practice scale to be further evaluated. Further research should explore the role parents play in discouraging child PA, especially in using psychological control or submitting children to abuse, which were new findings in this study. PMID- 23919303 TI - Novel 1H-pyrrolo[2,3-b]pyridine derivative nortopsentin analogues: synthesis and antitumor activity in peritoneal mesothelioma experimental models. AB - In this study, we describe the synthesis of new nortopsentin analogues, 1H pyrrolo[2,3-b]pyridine derivatives and their biological effects in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rare and rapidly fatal disease, poorly responsive to conventional therapies. The three most active compounds, 1f (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3-thiazol-4-yl]-1H pyrrolo[2,3-b]pyridine), 3f (3-[2-(1H-indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H pyrrolo[2,3-b]pyridine), and 1l (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3 thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b] pyridine), which were shown to act as cyclin-dependent kinase 1 inhibitors, consistently reduced DMPM cell proliferation and induced a caspase-dependent apoptotic response, with a concomitant reduction of the expression of the active Thr(34)-phosphorylated form of the antiapoptotic protein survivin. Moreover, the combined treatment of DMPM cells with 3f derivative and paclitaxel produced a synergistic cytotoxic effect, which was paralleled by an enhanced apoptotic response. In the mouse model, i.p. administration of 1f, 3f, and 1l derivatives was effective, resulting in a significant tumor volume inhibition of DMPM xenografts (range, 58-75%) at well tolerated doses, and two complete responses were observed in each treatment group. PMID- 23919304 TI - Asymmetric bromine-lithium exchange: application toward the synthesis of natural product. AB - Asymmetric bromine-lithium exchange has been successfully employed to synthesize bicoumarin chiral building blocks of (+)-isokotanin A and (-)-kotanin in good yields and with an excellent level of enantioselectivity. This is the first reported example of formal syntheses, using this direct methodology, leading to the single (M)-atropoisomer of (+)-isokotanin A and (-)-kotanin building blocks, without any resolution step. PMID- 23919305 TI - Effect of TRPV1 channel on the proliferation and apoptosis in asthmatic rat airway smooth muscle cells. AB - BACKGROUND: Hyperplasia of airway smooth muscle cells (ASMC) is a major contributor to airway remodeling in asthma. Transient receptor potential vanilloid 1 (TRPV1) is an important channel to mediate Ca(2+) influx. This study explores the expression of TRPV1 channel and its effect on the proliferation and apoptosis in rat ASMC, in order to find a new target to treat airway remodeling in asthma. METHODS: Rats were sensitized and challenged with ovalbumin to replicate asthmatic models. Proliferating cell nuclear antigen (PCNA) was detected by immunohistochemistry. Reverse transcriptase-polymerase chain reaction, immunocytochemistry, and Western blot were used to detect the mRNA and protein expression of TRPV1 channel. Intracellular calcium ([Ca(2+)]i) was detected using confocal fluorescence Ca(2+) imaging. [(3)H] thymidine incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were used to observe the DNA synthesis and proliferation. TUNEL assay was used to detect the apoptosis of ASMC. RESULTS: (1) The expression of PCNA was significantly increased in intact asthmatic rat ASMC. (2) The expression of TRPV1 channel was significantly increased in asthmatic rat ASMC. (3) [Ca(2+)]i in ASMC of the asthmatic group was significantly increased. After treatment with TRPV1 agonist capsaicin (CAP), [Ca(2+)]i was further increased, whereas [Ca(2+)]i was decreased after administration of TRPV1 antagonist capsazepine (CPZ) in ASMC of the asthmatic group. (4) The DNA synthesis and absorbance of MTT were significantly increased, while apoptosis was significantly decreased in asthmatic ASMC. CAP further enhanced proliferation and decreased apoptosis. CPZ significantly inhibited the effect of CAP in asthmatic ASMC. CONCLUSION: TRPV1 channel was involved in the regulation of proliferation and apoptosis in asthmatic ASMC. PMID- 23919307 TI - The prevalence of late-life mania: a review. AB - OBJECTIVES: Since there is a worldwide steady increase in the number of individuals living longer and an expected increase in the number of older adults who will be diagnosed with bipolar disorder, there is a growing need to better understand late-life mania. We provide in this review a report of published studies focusing on the prevalence of late-life mania in the community and in senior psychiatric care facilities. METHODS: We conducted a search of PubMed and Psychinfo databases using combinations of the keywords bipolar, manic/a, manic depression, elderly, and older including English-language reports presenting quantitative data on the prevalence of mania in adults over the age of 50 years. RESULTS: Eighteen out of 188 potentially eligible studies met our inclusion criteria, with most studies focusing on psychiatric inpatient samples. The overall prevalence of late-life mania was estimated to be 6.0% in the reported 1,519 older psychiatric inpatients. In elderly inpatients with bipolar disorder, the mean prevalence of late-onset mania was 44.2%. For other relevant care facilities, no firm conclusions could be drawn. CONCLUSIONS: Late-life mania is not rare in older psychiatric inpatients and late-onset mania is associated with increased somatic comorbidity in patients aged 50 years and older. Several hypotheses regarding the relationship between somatic illness and late-life mania in the elderly have been proposed and studies on this relationship and the prevalence of late-life mania in different senior psychiatric care facilities deserve specific attention in future research projects. PMID- 23919306 TI - A mutation in the c-fos gene associated with congenital generalized lipodystrophy. AB - BACKGROUND: Congenital generalized lipodystrophy (CGL) or Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare genetic syndrome characterized by the absence of adipose tissue. As CGL is thought to be related to malfunctions in adipocyte development, genes involved in the mechanisms of adipocyte biology and maintenance or differentiation of adipocytes, especially transcription factors are candidates. Several genes (BSCL1-4) were found to be associated to the syndrome but not all CGL patients carry mutations in these genes. METHODS AND RESULTS: In a patient with CGL and insulin resistance we investigated the known candidate genes but the patient did not carry a relevant mutation. Analyses of the insulin activated signal transduction pathways in isolated fibroblasts of the patient revealed a postreceptor defect altering expression of the immediate early gene c-fos. Sequence analyses revealed a novel homozygous point mutation (c.-439, T->A) in the patients' c-fos promoter. The point mutation was located upstream of the well characterized promoter elements in a region with no homology to any known cis-elements. The identified mutation was not detected in a total of n=319 non lipodystrophic probands. In vitro analyses revealed that the mutation facilitates the formation of a novel and specific protein/DNA complex. Using mass spectrometry we identified the proteins of this novel complex. Cellular investigations demonstrate that the wild type c-fos promoter can reconstitute the signaling defect in the patient, excluding further upstream signaling alterations, and vice versa the investigations with the c-fos promoter containing the identified mutation generally reduce basal and inducible c-fos transcription activity. As a consequence of the identified point mutation gene expression including c-Fos targeted genes is significantly altered, shown exemplified in cells of the patient. CONCLUSION: The immediate-early gene c-fos is one essential transcription factor to initiate adipocyte differentiation. According to the role of c-fos in adipocyte differentiation our findings of a mutation that initiates a repression mechanism at c-fos promoter features the hypothesis that diminished c fos expression might play a role in CGL by interfering with adipocyte development. PMID- 23919308 TI - Characterization of field and vaccine infectious bursal disease viruses from Nigeria revealing possible virulence and regional markers in the VP2 minor hydrophilic peaks. AB - Outbreaks of infectious bursal disease in vaccinated chicken flocks are frequent in Nigeria. For the control of infectious bursal disease, live vaccines based on foreign infectious bursal disease virus (IBDV) strains are used. The present study investigated the phylogenetic relationship between field and vaccine IBDV strains from northwestern Nigeria. Thirty field IBDV strains and three commercial vaccines strains were characterized through sequencing the VP2 hypervariable region. In addition, the complete genome segment A coding region for two vaccines and two field strains was sequenced. The deduced amino acid sequences (position 212 to 331) of IBDV strains from Nigeria and other regions of the world were aligned and possible regional and virulence markers were identified associated with VP2 minor hydrophilic peaks. Reversion to virulence of a vaccine strain with a Q to L mutation at position 253 was observed. Phylogenetic analyses revealed a unique cluster of northwest Nigerian field IBDV strains alone or related to imported characterized classical and very virulent IBDV vaccines. The results suggest that when IBDV strains spread from their region of origin to a different region they mutate alongside indigenous field strains but may retain their identity on the VP2 region. PMID- 23919309 TI - Determination of rate constants of N-alkylation of primary amines by 1H NMR spectroscopy. AB - Macromolecules containing N-diazeniumdiolates of secondary amines are proposed scaffolds for controlled nitrogen oxide (NO) release medical applications. Preparation of these compounds often involves converting primary amine groups to secondary amine groups through N-alkylation. However, N-alkylation results in not only secondary amines but tertiary amines as well. Only N-diazeniumdiolates of secondary amines are suitable for controlled NO release; therefore, the yield of secondary amines is crucial to the total NO load of the carrier. In this paper, (1)H NMR spectroscopy was used to estimate the rate constants for formation of secondary amine (k1) and tertiary amine (k2) for alkylation reagents such as propylene oxide (PO), methyl acrylate (MA), and acrylonitrile (ACN). At room temperature, the ratio of k2/k1 for the three reactions was found to be around 0.50, 0.026, and 0.0072. PMID- 23919310 TI - DNA damage caused by chronic transgenerational exposure to low dose gamma radiation in Medaka fish ( Oryzias latipes ). AB - The effect of transgenerational exposure to low dose rate (2.4 and 21 mGy/day) gamma irradiation on the yield of DNA double-strand breaks and oxidized guanine (8-hydroxyguanine) has been studied in the muscle and liver tissue of a model organism, the Japanese medaka fish. We found the level of unrepaired 8 hydroxyguanine in muscle tissue increased nonlinearly over four generations and the pattern of this change depended on the radiation dose rate, suggesting that our treatment protocols initiated genomic instability and an adaptive response as the generations progressed. The yield of unrepaired double-strand breaks did not vary significantly among successive generations in muscle tissue in contrast to liver tissue in which it varied in a nonlinear manner. The 8-hydroxyguanine and DSB radiation yields were significantly higher at 2.4 mGy/day than at 21 mGy/day in both muscle and liver tissue in all generations. These data are consistent with the hypothesis of a threshold for radiation-induced activation of DNA repair systems below which tissue levels of DNA repair enzymes remain unchanged, leading to the accumulation of unrepaired damage at very low doses and dose rates. PMID- 23919311 TI - Cardiac injury after 10 gy total body irradiation: indirect role of effects on abdominal organs. AB - The objective of this study was to determine whether radiation-induced injury to the heart after 10 Gy total body irradiation (TBI) is direct or indirect. Young male WAG/RijCmcr rats received a 10 Gy single dose using TBI, upper hemi-body (UHB) irradiation, lower hemi-body (LHB) irradiation, TBI with the kidneys shielded or LHB irradiation with the intestines shielded. Age-matched, sham irradiated rats served as controls. The lipid profile, kidney injury, heart and liver morphology and cardiac function were determined up to 120 days after irradiation. LHB, but not UHB irradiation, increased the risk factors for cardiac disease as well as the occurrence of cardiac and kidney injury in a way that was quantitatively and qualitatively similar to that observed after TBI. Shielding of the kidneys prevented the increases in risk factors for cardiac disease. Shielding of the intestines did not prevent the increases in risk factors for cardiac disease. There was no histological evidence of liver injury 120 days after irradiation. Injury to the heart from irradiation appears to be indirect, supporting the notion that injury to abdominal organs, principally the kidneys, is responsible for the increased risk factors for and the occurrence of cardiac disease after TBI and LHB irradiation. PMID- 23919312 TI - Mitigation of radiation-induced damage by targeting EGFR in noncancerous human epithelial cells. AB - Methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate (CDDO-Me) is an antioxidative, anti-inflammatory modulator, which activates the nuclear factor-erythroid 2 related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. While CDDO-Me has radioprotective activity through Nrf2 activation in vitro and in vivo, its ability to mitigate radiation-induced damage when provided after irradiation has not been studied. Here we investigated whether CDDO-Me mitigates ionizing radiation (IR)-induced DNA damage in immortalized normal human colonic epithelial cells (HCECs) and bronchial epithelial cells (HBECs). DNA damage and clonogenic survival were assessed after treatment with CDDO-Me postirradiation. We observed that treatment with CDDO-Me within 30 min after irradiation improved both DNA damage repair and clonogenic survival independently of Nrf2. CDDO-Me activates the epidermal growth factor receptor (EGFR) related DNA repair responses. In the presence of CDDO-Me, EGFR is phosphorylated and translocates into the nucleus where it interacts with DNA-PKcs. CDDO-Me-mediated mitigation activity can be abrogated through depletion of EGFR, ectopic overexpression of mutant EGFR or inhibition of DNA-PKcs. While post-treatment of CDDO-Me protected noncancerous HCECs and HBECs against IR, cancer cells (HCT116 and MCF7) were not protected by CDDO-Me. These results suggest that targeting EGFR using CDDO-Me is a promising radiation mitigator with potential utility for first responders to nuclear accidents. PMID- 23919313 TI - Kinetics of drug selection systems in mouse embryonic stem cells. AB - BACKGROUND: Stable expression of transgenes is an important technique to analyze gene function. Various drug resistance genes, such as neo, pac, hph, zeo, bsd, and hisD, have been equally used as selection markers to isolate a transfectant without considering their dose-dependent characters. RESULTS: We quantitatively measured the variation of transgene expression levels in mouse embryonic stem (mES) cells, using a series of bi-cistronic expression vectors that contain Egfp expression cassette linked to each drug resistant gene via IRES with titration of the selective drugs, and found that the transgene expression levels achieved in each system with this vector design are in order, in which pac and zeo show sharp selection of transfectants with homogenously high expression levels. We also showed the importance of the choice of the drug selection system in gene-trap or gene targeting according to this order. CONCLUSIONS: The results of the present study clearly demonstrated that an appropriate choice of the drug resistance gene(s) is critical for a proper design of the experimental strategy. PMID- 23919314 TI - Predicting outcome in peripheral nerve stimulation for chronic neuropathic pain. AB - OBJECTIVE: The aim of the study was to investigate the predictive value of percutaneous electrical nerve stimulation (PENS) in peripheral nerve stimulation (PNS) for chronic neuropathic pain. MATERIALS AND METHODS: Twelve patients being evaluated for PNS for chronic neuropathic pain were included in this survey. Stimulation with acupuncture needles was applied with continuous high frequency stimulation. Position, polarity, frequency and amperage threshold of perception, and adverse effects were noted. Additional stimulation side effects were documented. A StimScore was developed to evaluate effects in a standardized manner. This StimScore comprises coverage of the painful area, therapeutic range, and amperage required for successful stimulation. StimScore was determined during PENS, during test stimulation, and under final stimulation. RESULTS: PNS was well tolerated by all patients. Seven of the 12 patients (58%) were classified as successfully treated, and 5/12 patients (42%) as unsuccessful. The mean overall pain reduction in the first group was 4.0 points (SD = 2.87, P = 0.010) and 2.4 points (SD = 1.29, P = 0.014), respectively, on the visual analogue scale. In the successful stimulation group, a mean StimScore of 13.14 (SD 11.19-15.0) was calculated vs. 10.4 (95% CI 8.52-12.28) in the unsuccessful stimulation group (P = 0.033, 95% CI = 0.265-5.220). CONCLUSIONS: Predicting response to PNS is crucial to reduce the number of patients implanted in vain. To adopt PENS via electroacupuncture needles as a percutaneous simulation method for PNS seemed to be feasible. The technique presented herein bears the potential to improve patient selection combined with reduced invasiveness. The presented results are encouraging and deliver a starting point for further trials. PMID- 23919315 TI - Sudden unexpected death due to Graves' disease during physical altercation. AB - We report a case of a 30-year-old woman who suddenly collapsed after having a physical altercation with her husband. Despite immediate resuscitation, she died on arrival at the hospital. The victim's parents requested an autopsy because they believed that their daughter was killed by her husband. Postmortem examination revealed that the victim had a diffusely enlarged thyroid gland and cardiomegaly with left ventricular hypertrophy. There was no evidence of significant trauma on the body. Further postmortem thyroid function tests and review of her medical history indicated that her death was due to Graves' disease. To the best of our knowledge, this is the first case reported of sudden death due to cardiac arrhythmia from Graves' disease induced by physical and emotional stress associated with the criminal activity of another person. The autopsy findings are described. In addition, the literature is reviewed and the significance of postmortem evaluation of thyroid hormones in the cases of sudden death is discussed. PMID- 23919317 TI - Rethinking data collection and signal processing. 2. Preserving the temporal fidelity of electrochemical measurements. AB - Direct electrochemical measurements of biological events are often challenging because of the low signal relative to the magnitude of the background and noise. When choosing a data processing approach, the frequency and phase content of the data must be considered. Here, we employ a zero-phase (infinite impulse response (IIR)) filter to remove the noise from the analytical signal, while preserving the phase content. In fast-scan cyclic voltammetry, the frequency content of the signal is a function of the scan rate of the applied waveform. Fourier analysis was used to develop a relationship between scan rate and the filter cutoff frequency to maximize the reduction in noise, while not altering the true nature of the analytical signal. The zero-phase filter has the same effect as traditional filters with regards to increasing the signal-to-noise ratio. Because the zero-phase filter does not introduce a change to DeltaEpeak, the heterogeneous electron rate transfer constant (0.10 cm/s) for ferrocene is calculated accurately. The zero-phase filter also improves electrochemical analysis of signaling molecules that have their oxidation potential close to the switching potential. Lastly, a quantitative approach to filtering amperometric traces of exocytosis based on the rise time was developed. PMID- 23919316 TI - Engineering of recombinant Escherichia coli cells co-expressing poly-gamma glutamic acid (gamma-PGA) synthetase and glutamate racemase for differential yielding of gamma-PGA. AB - Poly-gamma-glutamic acid (gamma-PGA) is a promising environmental-friendly material with outstanding water solubility, biocompatibility and degradability. However, it is tough to determine the relationship between functional synthetic enzyme and the strains' yield or substrate dependency. We cloned gamma-PGA synthetase genes pgsBCA and glutamate racemase gene racE from both L-glutamate dependent gamma-PGA-producing Bacillus licheniformis NK-03 and L-glutamate independent B. amyloliquefaciens LL3 strains. The deduced RacE and PgsA from the two strains shared the identity of 84.5% and 78.53%, while PgsB and PgsC possessed greater similarity with 93.13% and 93.96%. The induced co-expression of pgsBCA and racE showed that the engineered Escherichia coli strains had the capacity of synthesizing gamma-PGA, and LL3 derived PgsBCA had higher catalytic activity and enhanced productivity than NK-03 in Luria-Bertani medium containing glucose or L-glutamate. However, the differential effect was weakened when providing sufficient immediateness L-glutamate substrate, that is, the supply of substrate could be served as the ascendance upon gamma-PGA production. Furthermore, RacE integration could enhance gamma-PGA yield through improving the preferred d-glutamate content. This is the first report about co-expression of pgsBCA and racE from the two Bacillus strains, which will be of great value for the determination of the biosynthetic mechanism of gamma-PGA. PMID- 23919318 TI - A systematic review of MR imaging as a tool for evaluating haemophilic arthropathy in children. AB - Our purposes were to determine: (i) whether there is direct evidence that currently available MRI techniques are accurate for early diagnosis of pathological findings in haemophilic arthropathy; (ii) whether there is an MRI scoring system that best correlates with clinical/radiological constructs for evaluation of haemophilic arthropathy; (iii) whether there is an MRI scoring system that best correlates with clinical/radiological constructs for evaluation of haemophilic arthropathy. Articles were screened using MEDLINE (n = 566), EMBASE (n = 201), and the Cochrane Library (n = 1). Two independent reviewers assessed articles for inclusion under the overarching purposes of the review by using the Standards for Reporting of Diagnostic Accuracy (STARD) tool, and the quality of the studies were graded using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. The electronic literature search retrieved 777 references (after duplicates were removed). A total of 32 studies were chosen for inclusion from the results of the search and review of bibliographical references. Using the STARD tool, seven studies were of excellent quality of reporting, and using the QUADAS-2 tool, 10 studies were judged to be of adequate quality. There is 'fair' evidence to recommend MRI as an accurate test for detecting evidence of haemophilic arthropathy and the use of second or third generation MRI scales for assessing haemophilic arthropathy. However, there is no evidence that screening of early intra-articular soft tissue bleed with MRI improves the functional status of joints over time. PMID- 23919320 TI - Falls in the general elderly population: a 3- and 6- year prospective study of risk factors using data from the longitudinal population study 'Good ageing in Skane'. AB - BACKGROUND: Accidental falls in the elderly are a major health problem, despite extensive research on risk factors and prevention. Only a limited number of multifactorial, long-term prospective studies have been performed on risk factors for falls in the general elderly population. The aim of this study was to identify risk factors predicting falls in a general elderly population after three and six years, using a prospective design. METHODS: The prevalence of 38 risk factors was recorded at a baseline assessment of 1763 subjects (aged 60-93 years). The incidence of one or more falls was recorded after three and six years. The predicted risk of falling, after exposure to the various risk factors, was analysed in a multiple logistic regression model, adjusted for age and sex, and presented as odds ratios (OR). A principal component analysis (PCA), including the statistical significant factors, was also performed to identify thematic, uncorrelated components associated with falls. RESULTS: The use of neuroleptics (OR 3.30, 95% CI: 1.15-9.43), heart failure with symptoms (OR 1.88, 95% CI: 1.17-3.04) and low walking speed (OR 1.77, 95% CI: 1.28-2.46) were prominent individual risk factors for falls. In the PCA, three main components predicting falls were identified: reduced mobility, OR 2.12 (95% CI 1.54-2.91), heart dysfunction, OR 1.66 (95% CI 1.26-2.20) and functional impairment including nocturia, OR 1.38 (95% CI 1.01-1.88). CONCLUSIONS: Three main components predicting falls were identified in a general elderly population after three and six years: reduced mobility, heart dysfunction and functional impairment including nocturia. The use of neuroleptic drugs was also a prominent individual risk factor, although the prevalence was low. Heart failure with symptoms was a significant risk factor for falls and may be of clinical importance as the prevalence of this condition in the elderly is increasing worldwide. There is need for further research on the relation between heart failure and falls in the elderly, as the treatment for this condition is poorly documented in this demographic. The findings of this study may be valuable in the development of intervention programmes aimed at sustainable, long-term reduction of falls in the elderly. PMID- 23919321 TI - A longitudinal study of coping strategies in men receiving radiotherapy and neo adjuvant androgen deprivation for prostate cancer: a quantitative and qualitative study. AB - AIM: This paper reports a study on how men cope with the side-effects of radiotherapy and neo-adjuvant androgen deprivation for prostate cancer up to 1 year after treatment. BACKGROUND: With early detection and improved treatments, prostate cancer survivors are living longer with the disease and the side-effects of treatment. How they cope affects their long-term physical and mental health. DESIGN: A prospective, longitudinal, exploratory design using both qualitative and quantitative methods was used in this study. METHOD: Between September 2006 September 2007 149 men who were about to undergo radical radiotherapy +/- androgen deprivation for localized prostate cancer in Northern Ireland were recruited to the study. They completed the Brief Cope scale at four time-points. RESULTS: Acceptance, positive reframing, emotional support, planning and, just getting on with it, were the most common ways of coping. Fewer men used coping strategies less at 6 months and 1 year after radiotherapy in comparison to pre treatment and 4-6 weeks after radiotherapy. Interviews with these men demonstrated that men adapted to a new norm, with the support of their wives/partners and did not readily seek professional help. A minority of men used alcohol, behavioural disengagement and self blame as ways of coping. CONCLUSION: Men used a variety of ways of coping to help them deal with radiotherapy and neo adjuvant androgen deprivation for up to 12 months after radiotherapy. Interventions need to be developed to take account of the specific needs of partners of men with prostate cancer and single men who have prostate cancer. PMID- 23919322 TI - Gender differences in heterosexual college students' conceptualizations and indicators of sexual consent: implications for contemporary sexual assault prevention education. AB - Because sexual assault is often defined in terms of nonconsent, many prevention efforts focus on promoting the clear communication of consent as a mechanism to reduce assault. Yet little research has specifically examined how sexual consent is being conceptualized by heterosexual college students. In this study, 185 Midwestern U.S. college students provided responses to open-ended questions addressing how they define, communicate, and interpret sexual consent and nonconsent. The study aimed to assess how college students define and communicate consent, with particular attention to gender differences in consent. Results indicated no gender differences in defining consent. However, there were significant differences in how men and women indicated their own consent and nonconsent, with women reporting more verbal strategies than men and men reporting more nonverbal strategies than women, and in how they interpreted their partner's consent and nonconsent, with men relying more on nonverbal indicators of consent than women. Such gender differences may help to explain some misunderstandings or misinterpretations of consent or agreement to engage in sexual activity, which could partially contribute to the occurrence of acquaintance rape; thus, a better understanding of consent has important implications for developing sexual assault prevention initiatives. PMID- 23919323 TI - Isoflurane post-treatment improves pulmonary vascular permeability via upregulation of heme oxygenase-1. AB - Isoflurane (ISO) has been shown to attenuate acute lung injury (ALI). Induction of heme oxygenase-1 (HO-1) and suppression of inducible nitric oxide synthase (iNOS) expression provide cytoprotection in lung and vascular injury. The aim of this study was to investigate the effect of post-treatment with isoflurane on lung vascular permeability and the role of HO-1 in an ALI rat model induced by cecal ligation and puncture (CLP). Male Sprague-Dawley rats were randomly assigned to one of four groups: sham group, sham rats post-treated with vehicle (Sham); CLP group, CLP rats post-treated with vehicle (CLP); ISO group, CLP rats post-treated with isoflurane (ISO); and ZnPP group, CLP rats injected with zinc protoporphyrin IX (ZnPP), a competitive inhibitor of HO-1, 1 hour before the operation, and post-treated with isoflurane (ZnPP). Isoflurane (1.4%) was administered 2 hour after CLP. At 24 hour after CLP, the extent of ALI was evaluated by lung wet/dry ratio, Evans blue dye (EBD) extravasation, lung permeability index (LPI), as well as histological and immunohistochemical examinations. We also determined pulmonary iNOS and HO-1 expression. Compared with the CLP group, the isoflurane post-treatment group showed improved pulmonary microvascular permeability as detected by EBD extravasation, LPI, as well as histological and immunohistochemical examinations. Furthermore, isoflurane decreased iNOS and increased HO-1 expression in lung tissue. Pretreatment with ZnPP prevented the protective effects of isoflurane in rats. These findings indicate that the protective role of isoflurane post-conditioning against CLP induced lung injury may be associated with its role in upregulating HO-1 in ALI. PMID- 23919324 TI - Application of molecular genetics method for differentiating Martes zibellina L. heart from its adulterants in traditional Chinese medicine based on mitochondrial cytochrome b gene. AB - The use of Martes zibellina L. heart as a famous kind of traditional Chinese medicine has been documented for many years in China. Identification of its authenticity as raw materials became a key in controlling of herbal preparations. In this study, the characteristics of mitochondrial cytochrome b (Cyt b) gene from four species of Martes were explored, and a specific molecular genetics technique for identifying the heart of M. zibellina L. in addition to some close relatives from their counterfeits was established. The bioinformatics was carried out to design the primers for the Cyt b gene based on the different species of Martes. PCR and sequencing technology were performed. The mt DNA was extracted from all of fresh M. zibellina L., Martes melampus. Martes flavigula. Martes martes heart samples and dry M. zibellina L. heart powder through the modified alkaline extracting method in addition to its counterfeits including the chicken heart, duck heart, goose heart, rabbit heart and Mustela vison. The complete mt DNA was separated from all samples used in the study, and the Cyt b gene with 310 bp segments was amplified only from M. zibellina L. heart as DNA template by the PCR technique. The sequencing indicated that the segment amplified by the PCR was homologous with the species of M. zibellina in GenBank. The data revealed that the primers and selected segment could be used as the genetic markers to identify M. zibellina L. heart from its counterfeits among different animal species. PMID- 23919325 TI - Population genetic structure of Siniperca chuatsi in the middle reach of the Yangtze River inferred from mitochondrial DNA and microsatellite loci. AB - The Chinese mandarin fish (Siniperca chuatsi) is currently one of the most important economic freshwater fish in China, whereas the wild resource has declined dramatically in recent years. In this study, we examined the genetic structure and diversity of five populations from the middle reach of the Yangtze River using mitochondrial cytochrome b sequences and microsatellite markers. This research revealed high genetic diversity and low genetic differentiation of S. chuatsi from these regions. The pairwise Fst values of the two markers showed low and no-significant differentiation among populations. AMOVA analysis of two markers and the haplotype genealogy of the Cytb gene confirmed these results. The STRUCTURE analysis of the microsatellite marker implied that the dam upon the tributary of the Yangtze River blocked the gene flow among those regions. This research will be useful in breeding programs and conservation management of this species. PMID- 23919326 TI - Complete mitochondrial genome of the Japanese wobbegong Orectolobus japonicus (Orectolobiformes: Orectolobidae). AB - The complete mitochondrial genome of the Japanese wobbegong Orectolobus japonicus was presented in this study. It is 16,706 bp in length with the typical gene composition and arrangement in the mitochondrial genome of vertebrates. The overall base composition is 32.6% A, 24.0% C, 13.3% G and 30.1% T. Two start codons (ATG and GTG) and two stop codons (TAG and TAA) were found in protein coding genes. The tRNA-Ser2 lacks the dihydrouridine arm and cannot be folded into a typical cloverleaf structure. One termination associated sequence (TAS) and three conserved sequence blocks (CSB1-3) were found in the control region. PMID- 23919327 TI - Integrated wall stress: a new methodological approach to assess ventricular workload and myocardial contractile reserve. AB - BACKGROUND: Wall stress is a useful concept to understand the progression of ventricular remodeling. We measured cumulative LV wall stress throughout the cardiac cycle over unit time and tested whether this "integrated wall stress (IWS)" would provide a reliable marker of total ventricular workload. METHODS AND RESULTS: We applied IWS to mice after experimental myocardial infarction (MI) and sham-operated mice, both at rest and under dobutamine stimulation. Small infarcts were created so as not to cause subsequent overt hemodynamic decompensation. IWS was calculated over one minute through simultaneous measurement of LV internal diameter and wall thickness by echocardiography and LV pressure by LV catheterization. At rest, the MI group showed concentric LV hypertrophy pattern with preserved LV cavity size, LV systolic function, and IWS comparable with the sham group. Dobutamine stimulation induced a dose-dependent increase in IWS in MI mice, but not in sham mice; MI mice mainly increased heart rate, whereas sham mice increased LV systolic and diastolic function. IWS showed good correlation with a product of peak-systolic wall stress and heart rate. We postulate that this increase in IWS in post-MI mice represents limited myocardial contractile reserve. CONCLUSION: We hereby propose that IWS provides a useful estimate of total ventricular workload in the mouse model and that increased IWS indicates limited LV myocardial contractile reserve. PMID- 23919328 TI - A four-year pathology review of the near total face transplant. AB - In December of 2008, our institution performed a near total face transplant. The patient was monitored for signs of rejection assessed by paired skin and mucosa biopsies. The results of histological review of 120 biopsies collected during the first 4 years posttransplant are discussed. All biopsies were stained with hematoxylin and eosin, periodic acid-Schiff, immunohistochemical and TUNEL assays and graded using the Banff 2007 classification. Grade III rejection was diagnosed clinically at weeks 45 and 66, posttransplant; week 45 was determined as folliculitis while the erythema episode at week 66 confirmed an acute rejection (AR) that required hospitalization. The mucosa frequently showed interface inflammation without clinical signs of rejection and was not present in skin biopsies. In all, 34 of the 45 mucosal biopsies (75%) showed these interface changes. Clinical symptoms concurred with skin pathology in two grade III rejections. The mucosa showed histologic signs of rejection more frequently, which may indicate: increased mucosal sensitivity to rejection, a different type or subtype of AR that is specific to the mucosa, or a nonspecific process such as a drug effect. With more data and world experience, the diagnosis of face transplant rejection will be better defined and the Banff classification enhanced. PMID- 23919329 TI - Comparison of HIV-related vulnerabilities between former child soldiers and children never abducted by the LRA in northern Uganda. AB - BACKGROUND: Thousands of former child soldiers who were abducted during the prolonged conflict in northern Uganda have returned to their home communities. Programmes that facilitate their successful reintegration continue to face a number of challenges. Although there is increasing knowledge of the dynamics of HIV infection during conflict, far less is known about its prevalence and implications for population health in the post-conflict period. This study investigated the effects of abduction on the prevalence of HIV and HIV-risk behaviours among young people in Gulu District, northern Uganda. An understanding of abduction experiences and HIV-risk behaviours is vital to both the development of effective reintegration programming for former child soldiers and the design of appropriate HIV prevention interventions for all young people. METHODS: In 2010, we conducted a cross-sectional study of 2 sub-counties in Gulu District. A demographic and behavioural survey was interview-administered to a purposively selected sample of 384 transit camp residents aged 15-29. Biological specimens were collected for HIV rapid testing in the field and confirmatory laboratory testing. Descriptive statistics were used to describe characteristics of abduction. Additionally, a gender-stratified bivariate analysis compared abductees' and non-abductees' HIV risk profiles. RESULTS: Of the 384 participants, 107 (28%) were former child soldiers (61% were young men and 39% were young women). The median age of participants was 20 and median age at abduction was 13. HIV prevalence was similar among former abductees and non abductees (12% vs. 13%; p = 0.824), with no differences observed by gender. With respect to differences in HIV vulnerability, our bivariate analysis identified greater risky sexual behaviours in the past year for former abductees than non abductees, but there were no differences between the two groups' survival/livelihood activities and food insufficiency experiences, both overall and by gender. The analysis further revealed that young northern Ugandans in general are in desperate need of education, skills development, and support for victims of sexual violence. CONCLUSIONS: This study persuasively demonstrates that all young people in northern Ugandan have been similarly affected by HIV infection during war and displacement. Post-conflict programme planners must therefore abandon rudimentary targeting practices based on abductees as a high profile category. Instead, they must develop evidence-based HIV interventions that are commensurate with young people's specific needs. As such programmes will be less stigmatizing, more oriented to self-selection, and more inclusive, they will effectively reach the most vulnerable young people in northern Uganda. PMID- 23919330 TI - Development, validation, and initial results of the Angioedema Activity Score. AB - BACKGROUND: Recurrent angioedema (RecA) is a frequent clinical problem characterized by suddenly occurring cutaneous and/or mucosal swellings. Depending on their location, RecA may be painful, hindering, disfiguring, or even life threatening. The assessment of disease activity in affected patients is important to guide treatment decisions. Currently, however, there is no standardized and validated outcome measure available to do so. OBJECTIVE: To develop and validate the first specific patient-reported outcome instrument to assess disease activity in RecA patients, the Angioedema Activity Score (AAS). METHODS: After a set of potential AAS items was developed, item evaluation and reduction were performed by means of impact analysis, factor analysis, regression analysis, and by checking for face validity. In addition, the items of the final AAS questionnaire were tested for their validity and reliability during a 12-week validation study. RESULTS: In total, data from 110 and 80 RecA patients were used during the AAS item evaluation and validation phase, respectively. The resulting AAS consisted of five items and was found to have a one-dimensional structure and excellent internal consistency. It correlated well with other measures of disease activity and quality-of-life impairment, thus demonstrating its convergent validity. In addition, the known-groups validity and test-retest reliability of the AAS were found to be good. CONCLUSIONS: The AAS is the first validated and reliable tool to determine disease activity in RecA patients, and it may serve as a valuable instrument in future clinical studies and routine patient care. PMID- 23919331 TI - Toward integrated and sustainable prevention against diabetes in rural China: study rationale and protocol of eCROPS. AB - BACKGROUND: Being an intermediate stage in the development of diabetes, pre diabetics were estimated as high as 14% to 63% in China and one to three quarters of them will develop into diabetes within 10 years. It is well established that the risk of diabetes progression can be modified substantially and a whole range of proven guidelines, protocols and methodologies are available. Unfortunately, most proven interventions are seldom used in daily practice and this is especially true in resource poor rural China. This project aims at demonstrating that an evolutionary intervention package featuring low cost, integration with routine services, cultural sensitization and self-optimization, is effective and sustainable in preventing diabetes. METHODS/DESIGN: This project utilizes a quasi cluster randomized controlled trial and a batched implementation strategy in which villages are recruited in 7 blocks within 7 consecutive years respectively. Block 0 involves 3 villages and provides an opportunity for piloting and refining primitive intervention methodologies and protocols. The following 6 blocks consist of 14 villages each and serve as intervention arm; while all the villages not yet started intervention form the control arm. For each block, measurement happens at baseline and every 12 months (for plasma glucose) or monthly (for body weight and blood pressure) after baseline. These arrangements enable documentation of up to 6 years of consecutive measures and detection of lower incidence of progression into diabetes, improved body max index and blood pressure, and increased service use and involvement in healthy dietary and physical activities among pre-diabetics receiving the experimental intervention compared to themselves at baseline or those in the delayed-intervention control condition. DISCUSSION: China has a long history of separating disease prevention and treatment systems and there is a clear need to leverages key success factors in a synergetic way toward integrated and sustainable diabetes prevention. This project is owned and managed by local health authorities and utilizes available resources. It introduces a package of long-term incentives, establishes ongoing mechanisms for continuous capacity building and quality improvement, and builds up an operational cycle for catalyzing similar efforts in the local prefecture even throughout rural China. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN66772711. PMID- 23919332 TI - Hyperleukocytosis and leukocytapheresis in acute leukaemias: experience from a single centre and review of the literature of leukocytapheresis in acute myeloid leukaemia. AB - BACKGROUND: Hyperleukocytosis is usually defined as leukocyte count >100 * 10(9) L(-1) and can be seen in newly diagnosed leukaemias. Hyperleukocytic leukaemia is associated with a risk of organ failure and early death secondary to leukostasis. Mechanical removal of leukocytes by the apheresis technique, leukocytapheresis, is a therapeutic option in these patients. METHODS: During a 16-year period, 16 patients were treated with leukocytapheresis (35 apheresis procedures) for hyperleukocytosis/leukostasis. We present our experience, and in addition we review previous studies of hyperleukocytosis/leukocytapheresis in patients with acute myeloid leukaemia (AML). RESULTS: We used a highly standardised approach for leukocytapheresis in leukaemia patients with hyperleukocytosis. The average leukocytapheresis number for each patient was 2.2 (range 1-6). Median leukocyte count before apheresis was 309 * 10(9) L(-1) (range 104-935); the mean leukocyte count reduction was 71%, corresponding to a mean absolute reduction of 219 * 10(9) L(-1). No serious side effects were seen during or immediately after apheresis. CONCLUSIONS: The data suggest that our standardised technique for leukocytapheresis effectively reduced the peripheral blood leukaemia cell counts. Previous studies in AML also support the conclusion that this is a safe and effective procedure for the treatment of a potentially life-threatening complication, but apheresis should always be combined with early chemotherapy. PMID- 23919333 TI - The double misfortune: time to improve off-label immune intervention. PMID- 23919334 TI - Advances in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation in the presence of identifiable risk factors. Inflammation is the central pathological feature in the pathogenesis of COPD. In addition to its pulmonary effects, COPD is associated with significant extrapulmonary manifestations, including ischaemic heart disease, osteoporosis, stroke and diabetes. Anxiety and depression are also common. Spirometry remains the gold standard diagnostic tool. Pharmacologic and non-pharmacologic therapy can improve symptoms, quality of life and exercise capacity and, through their effects on reducing exacerbations, have the potential to modify disease progression. Bronchodilators are the mainstay of pharmacotherapy, with guidelines recommending a stepwise escalating approach. Smoking cessation is paramount in managing COPD, with promotion of physical activity and pulmonary rehabilitation being other key factors in management. Comorbidities should be actively sought and managed in their own right. Given the chronicity and progressive nature of COPD, ongoing monitoring and support with timely discussion of advanced-care planning and end of-life issues are recommended. PMID- 23919335 TI - Experience with low-dose rituximab in off-label indications at two tertiary hospitals. AB - BACKGROUND: Rituximab is a monoclonal antibody directed against B cells and is increasingly used to treat a variety of autoimmune conditions. Most published evidence reporting the successful use of rituximab in off-label indications has empirically used a high-dose regimen (either 375 mg/m(2) weekly for 4 weeks, or 1000 mg * 2), which is the approved course of treatment for lymphoma and rheumatoid arthritis patients. AIMS: The aims of this report are to review the indications, outcomes and adverse events of low-dose (500 mg twice, given 1-2 weeks apart), off-label use of rituximab in our institutions, and to review the available evidence. METHODS: We performed a retrospective audit of the off-label use of low-dose rituximab at two university teaching, tertiary referral hospitals, from mid-2008 until the end of 2011. RESULTS: Off-label rituximab was given to 52 patients (53 indications) across a heterogeneous group of autoimmune conditions. Outcomes were known for 46 conditions (affecting 45 patients), and of these, complete responses were observed in 16 (35%) conditions and a further 19 (41%) had a partial response. There was no response to rituximab in 11 (24%) patients. There were eight significant adverse events, mostly related to infectious complications. CONCLUSION: This case series suggests that low-dose courses of rituximab can be used off-label to treat several severe and/or refractory immunological disorders with a reasonable safety profile; however, further trials are required in many off-label indications. PMID- 23919336 TI - Alignment: a conceptual shift from adherence. AB - Developing a treatment plan with a patient is one of the cornerstones of clinical medicine. The current concept of adherence, a conceptual shift away from the notion of compliance, connotes an agreement to and implementation of a plan. There are, however, myriad causes that can impinge on whether or not a treatment plan is followed through. The current clinical usage of the word 'adherence' tends to focus on the ultimate behaviour of the patient, and as such the factors acting on the behaviour may escape attention. We propose the concept of treatment 'alignment'. The term 'alignment' conveys an image of the patient and clinician in the context of a range of factors that must 'line up' to maximise the chances of a treatment plan being successfully implemented. PMID- 23919337 TI - Inpatient palliative care consultation for patients with glioblastoma in a tertiary hospital. AB - Glioblastoma (GBM) is an uncommon disease with significant mortality and morbidity, but there is a lack of published evidence on palliative care involvement with this population. This audit highlights the heavy symptom burden, extensive allied health involvement and discharge outcomes of GBM inpatients referred to the palliative care service at The Royal Melbourne Hospital. This information can provide an important framework for further research and also supports the role of multidisciplinary palliative care in the care of patients with GBM. PMID- 23919338 TI - Diabetic ketoacidosis secondary to L-asparaginase in acute lymphoblastic leukaemia. AB - We describe a case of severe hyperglycaemia resulting in diabetic ketoacidosis secondary to L-asparaginase. There are few reports of this potentially life threatening complication, particularly in the English literature. Awareness and recognition of this preventable and manageable problem will improve safe delivery of this anti-leukaemic drug. PMID- 23919339 TI - Successful endoscopic ultrasound-guided ethanol ablation of multiple insulinomas accompanied with multiple endocrine neoplasia type 1. PMID- 23919340 TI - Pseudohypercalcaemia in a patient with newly diagnosed Waldenstrom macroglobinaemia. PMID- 23919341 TI - Anticoagulation-associated upper gastrointestinal haemorrhage. PMID- 23919342 TI - Addition of etoposide to standard acute myeloid leukaemia induction chemotherapy does not improve survival. PMID- 23919343 TI - Neutropenia is rare in patients receiving continuous infusions of vancomycin in an Australian Hospital in the Home setting. PMID- 23919344 TI - A formalised, more considered and ethical approach to resuscitation. PMID- 23919345 TI - Cardiopulmonary resuscitation: should it be the default option? PMID- 23919346 TI - Author reply: To PMID 22646807. PMID- 23919347 TI - Development of a practical, asymmetric synthesis of the hepatitis C virus protease inhibitor MK-5172. AB - The development of a practical, asymmetric synthesis of the hepatitis C virus (HCV) protease inhibitor MK-5172 (1), an 18-membered macrocycle, is described. PMID- 23919348 TI - Spinal cord stimulation for treatment of leg pain associated with lumbar spinal stenosis. AB - OBJECTIVE: Spinal cord stimulation (SCS) is expected to have analgesic effects in patients with neuropathic pain, ischemic pain, or mixed pain. The type of leg pain caused by lumbar spinal stenosis (LSS) is considered as mixed pain, which is expected to respond to SCS. However, there is no established view on the usefulness of SCS in the management of this type of pain. Therefore, we aimed at evaluating the efficacy of SCS against leg pain associated with LSS. MATERIALS AND METHODS: Data were collected retrospectively for the period from January 2003 to December 2011 from 91 patients with LSS-associated leg pain enrolled to the SCS trial. SCS implantation was performed in patients who responded to the trial and desired to receive this therapy. RESULTS: The response rate (percentage of patients showing 50% or greater alleviation of pain) in the trial was 65% (59/91 patients). SCS implantation was performed on 41 patients. The percentage of patients who showed a good response (definition is SCS continued for one year or longer after implantation) was 95% (39/41). CONCLUSION: SCS seemed to be effective against leg pain associated with LSS. Thus, SCS should be actively adopted in indicated patients as a method of treatment intermediate between conservative therapy and surgical therapy. PMID- 23919349 TI - Nongenomic effect of levothyroxine on the synchronous electrical activity of the spinal dorsal horn in the rat. AB - Levothyroxine (T4) has a well-known effect on the central nervous system (CNS). This effect requires hours of latency by genetic pathway. We tested for short latency nongenomic effects of T4 superfusion on the spinal dorsal horn (DH) evaluating lumbar somatosensory evoked potentials in rats. T4 increased N and P wave amplitudes and N wave area under the curve, but reduced P wave duration and N-P interval, suggesting that T4 exerts both excitatory and synchronizing effects on DH interneurons in less than 300 s, thus, providing evidence of nongenomic effects of T4 on DH. PMID- 23919350 TI - Tetramethylammonium hydroxide as a reagent for complex mixture analysis by negative ion electrospray ionization mass spectrometry. AB - Ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) enables the direct characterization of complex mixtures without prior fractionation. High mass resolution can distinguish peaks separated by as little as 1.1 mDa), and high mass accuracy enables assignment of elemental compositions in mixtures that contain tens of thousands of individual components (crude oil). Negative electrospray ionization (ESI) is particularly useful for the speciation of the most acidic petroleum components that are implicated in oil production and processing problems. Here, we replace conventional ammonium hydroxide by tetramethylammonium hydroxide (TMAH, a much stronger base, with higher solubility in toluene) to more uniformly deprotonate acidic components of complex mixtures by negative ESI FTICR MS. The detailed compositional analysis of four crude oils (light to heavy, from different geographical locations) reveals that TMAH reagent accesses 1.5-6 times as many elemental compositions, spanning a much wider range of chemical classes than does NH4OH. For example, TMAH reagent produces abundant negative electrosprayed ions from less acidic and neutral species that are in low abundance or absent with NH4OH reagent. More importantly, the increased compositional coverage of TMAH-modified solvent systems maintains, or even surpasses, the compositional information for the most acidic species. The method is not limited to petroleum-derived materials and could be applied to the analysis of dissolved organic matter, coal, lipids, and other naturally occurring compositionally complex organic mixtures. PMID- 23919351 TI - Toxicity and mutagenicity of Gulf of Mexico waters during and after the deepwater horizon oil spill. AB - The Deepwater Horizon oil spill is unparalleled among environmental hydrocarbon releases, because of the tremendous volume of oil, the additional contamination by dispersant, and the oceanic depth at which this release occurred. Here, we present data on general toxicity and mutagenicity of upper water column waters and, to a lesser degree, sediment porewater of the Northeastern Gulf of Mexico (NEGOM) and west Florida shelf (WFS) at the time of the Deepwater Horizon oil spill in 2010 and thereafter. During a research cruise in August 2010, analysis of water collected in the NEGOM indicated that samples of 3 of 14 (21%) stations were toxic to bacteria based on the Microtox assay, 4 of 13 (34%) were toxic to phytoplankton via the QwikLite assay, and 6 of 14 (43%) showed DNA damaging activity using the lambda-Microscreen Prophage induction assay. The Microtox and Microscreen assays indicated that the degree of toxicity was correlated to total petroleum hydrocarbon concentration. Long-term monitoring of stations on the NEGOM and the WFS was undertaken by 8 and 6 cruises to these areas, respectively. Microtox toxicity was nearly totally absent by December 2010 in the Northeastern Gulf of Mexico (3 of 8 cruises with one positive station). In contrast, QwikLite toxicity assay yielded positives at each cruise, often at multiple stations or depths, indicating the greater sensitivity of the QwikLite assay to environmental factors. The Microscreen mutagenicity assays indicated that certain water column samples overlying the WFS were mutagenic at least 1.5 years after capping the Macondo well. Similarly, sediment porewater samples taken from 1000, 1200, and 1400 m from the slope off the WFS in June 2011 were also highly genotoxic. Our observations are consistent with a portion of the dispersed oil from the Macondo well area advecting to the southeast and upwelling onto the WFS, although other explanations exist. Organisms in contact with these waters might experience DNA damage that could lead to mutation and heritable alterations to the community pangenome. Such mutagenic interactions might not become apparent in higher organisms for years. PMID- 23919352 TI - Photo-induced conformational flexibility in single solution-phase peridinin chlorophyll-proteins. AB - The peridinin-chlorophyll-protein (PCP) is an accessory light-harvesting complex found in red-tide dinoflagellates. PCP absorbs photons primarily in the blue green spectral region via peridinin (Per) carotenoid pigments which then transfer excitations to chlorophyll (Chl) and ultimately downstream to photosystem II (PSII). Whereas the ultrafast dynamics of PCP are well-studied, much less is known about slower protein dynamics on time scales of milliseconds and seconds. Previous single-molecule studies of spectral emission and intensity have attached PCP to surfaces, but the native environment of PCP is in the lumen, meaning that a surface-attached environment could perturb its native conformations. To address this concern, we use the anti-Brownian electrokinetic (ABEL) trap to study single PCP monomers in solution for several seconds each. We measure, for the first time, simultaneous single-molecule intensity, lifetime, and spectral emission shifts for each trapped PCP monomer. The rate of reversible spectral redshifts depends linearly on irradiance over a factor of 30, indicating a light-induced mechanism which we attribute to a protein conformational change. Independent of these spectral shifts, our measurements of intensity and lifetime show reversible Chl quenching. In contrast to previous work, we show that this quenching cannot result from isolated photobleaching of Chl. These independent mechanisms arise from distinct conformational changes which maintain relatively stable fluorescence emission. PMID- 23919353 TI - Polypharmacology - foe or friend? AB - Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy. PMID- 23919354 TI - Fatal case of a 27-year-old male after taking iboga in withdrawal treatment: GC MS/MS determination of ibogaine and ibogamine in iboga roots and postmortem biological material. AB - We report the case of a man who died twelve hours after ingesting powdered iboga root, commonly taken for its stimulant and hallucinogenic properties. Ibogaine and ibogamine were quantified in the powder ingested and the victim's body fluids by GC-MS/MS after liquid-liquid extraction (Toxi-tubes A((r))). The concentrations of ibogaine measured in the blood samples taken at the scene and in the peripheral blood, urine, and gastric fluid samples taken during the autopsy were 0.65, 1.27, 1.7, and 53.5 MUg/mL, while the iboga content in the powder was 7.2%. Moreover, systematic toxicological analyses of biological samples showed the presence of diazepam and methadone in therapeutic concentrations. Death was attributed to the ingestion of a substantial quantity of iboga in the context of simultaneous methadone and diazepam consumption. PMID- 23919355 TI - Implementing haemophilia care in Senegal, West Africa. AB - Despite significant progres on haemophilia care in developed world, this disease remains unknown in many sub-Saharan African countries. The objectives of this article were to report Senegalese experience on the management of haemophilia care through 18 years of follow-up. This cohort study included 140 patients (127 haemophilia A, 13 haemophilia B), followed in Dakar's haemophilia treatment centre from 1995 to 2012. Our study reported a prevalence of 2.3/100,000 male births, accounting for 11.6% of what is expected in Senegal. From the period 1995 2003 to 2004-2012, significant progress was seen including 67.9% increase in new patient's identification, 11.3 years reduction in mean age at diagnosis (from 15.5 to 4.2 years), lower mortality rate (from 15.3% to 6.8%) and age at death evolved from 6.5 to 23.3 years. Of the 50 haemophilia A patients who were tested for inhibitor presence, 10 were positive (eight severe and two moderate) that is prevalence of 20%. All patients were low responders since inhibitor titre was between 1.5 and 3.8 BU. Disabilities were seen in 36.5% of patients above 20 years old who had musculoskeletal sequels and 39% had no scholar or professional activities in our setting. Implementing haemophilia care in sub-Saharan Africa is a great challenge as this disease is not yet counted in national health problems in many countries. Lessons learned from this study show a significant improvement in diagnosis and prognosis parameters. This emphasizes the needs to set up such follow-up initiatives and to enhance medical and lay cooperation for better results. PMID- 23919356 TI - Polymyxin-B endotoxin removal device: making the point on mechanisms of action, clinical effectiveness and possible future applications: review. AB - In this review, we focus on current information on the apheresis procedures for endotoxins removal with Polymyxin B cartridges (PMX). This device has been designed in 2003 in Japan in order to take advantage of the antibiotic effects of Polymyxins on Gram negative bacteria and endotoxins, by-passing the toxicity shown by the intravenous administration. Although its mechanisms of action are nowadays well-known, we felt the need to sum up all the someway scattered information giving an overall sight on the entire process that brings Polymyxins molecules to function as powerful detergents of the endotoxins from the blood flow. Since the first experiences on humans, over one hundred studies have been published about the clinical use of this device. Even if some of them were limited in number of patients and compliance to international standards, they all converged in showing a highly positive impact of PMX on the improvement of clinic condition and outcome. Recently, more significant and large experiences confirmed the benefits of this treatment on hemodynamic, PaO2/FiO2 ratio, APACHE and SOFA scores and outcome at 28 days even on different typologies of sepsis cases, such as in transplanted patients. Summarizing, this relatively new procedure has proven to be a promising tool against Gram negative and endotoxin sepsis, combining clinical and outcome improvements with a fair cost/effectiveness ratio. Given that, there's still need of wider and more structured clinical studies that could steady the use of this device and widen its fields of applications. PMID- 23919357 TI - Publishing "Invisible" and "Abandoned" clinical trials: a commitment for CTS. PMID- 23919358 TI - Creating a worldview and permissive microenvironment for translational sciences. PMID- 23919359 TI - Research mentor training: initiatives of the University of Wisconsin Institute for Clinical and Translational Research. PMID- 23919360 TI - Faculty perceptions of how community-engaged research is valued in tenure, promotion, and retention decisions. AB - PURPOSE: We assessed the perceptions of community core faculty in academic medical center institutions that received Clinical and Translational Science Awards (CTSA) about how these institutions consider community-engaged scholarship (CES) when tenure, promotion, and retention decisions are made. METHOD: An assessment tool was adapted to create an 18-item survey that was sent during November and December 2011 via the Internet to the 369 members of the community engagement core mailing list of the CTSA. RESULTS: Fifty-nine responses were received which represented 37 of the possible 60 different funded institutions. The mean score was 48.14 (SD = 11.18); range of 23-74; and Cronbach's alpha was .91 About half reported that support for CES and its inclusion in the academic decision process increased since the institution was awarded a CTSA. Open-ended responses indicated some confusion with terminology although a definition of CES had been provided in the instrument instructions. CONCLUSION: Respondents overall agreed there was moderate support for CES in tenure, promotion, and retention decisions which may have been influenced by the CTSA application requirements. This survey could be used to identify if there are differences in institutional and departments and measure changes over time. PMID- 23919361 TI - A dynamical approach toward understanding mechanisms of team science: change, kinship, tension, and heritage in a transdisciplinary team. AB - Since the concept of team science gained recognition among biomedical researchers, social scientists have been challenged with investigating evidence of team mechanisms and functional dynamics within transdisciplinary teams. Identification of these mechanisms has lacked substantial research using grounded theory models to adequately describe their dynamical qualities. Research trends continue to favor the measurement of teams by isolating occurrences of production over relational mechanistic team tendencies. This study uses a social constructionist-grounded multilevel mixed methods approach to identify social dynamics and mechanisms within a transdisciplinary team. A National Institutes of Health-funded research team served as a sample. Data from observations, interviews, and focus groups were qualitatively coded to generate micro/meso level analyses. Social mechanisms operative within this biomedical scientific team were identified. Dynamics that support such mechanisms were documented and explored. Through theoretical and emergent coding, four social mechanisms dominated in the analysis-change, kinship, tension, and heritage. Each contains relational social dynamics. This micro/meso level study suggests such mechanisms and dynamics are key features of team science and as such can inform problems of integration, praxis, and engagement in teams. PMID- 23919362 TI - Observational study of contracts processing at 29 CTSA sites. AB - We measured contracts final negotiation (FN) and full execution (FE) times using shared definitions in a prospective observational study of management of contracts for clinical trials at 29 CTSA institutions. Median FN and FE times were reached in 39 and 91 days, respectively; mean times for FN and FE were 55 and 103 days, respectively. Individual site medians ranged from 3 to 116 days for FN and 34 to 197 days for FE. The use of master agreements (MAs) and previously negotiated terms (PNTs) was associated with significant reduction of FN times by a mean of 33 days (p < 0) and 22 days (p < 0.001), respectively. PNTs, but not MAs, were associated with significantly reduced FE time (22 days, p < 0.007). Gap analysis revealed a gap of 22 days between contracts negotiation and Institutional Review Board (IRB) review and intervals of 33 days (contracts) and 48 days (IRB review) during which the process steps were being conducted alone, suggesting a potential benefit with parallel processing. These baseline data support a plan to investigate root causes of prolonged study start-up time by examining causes of variation and outliers. PMID- 23919363 TI - Thinking about health-related outcomes: what do we need evidence about? AB - BACKGROUND: There is an urgent need for efficient, equitable interventions across the disease spectrum from prevention to palliative care. To identify and prioritize such interventions, evidence of effectiveness important to potential constituents is needed on outcomes relevant to them. METHODS: To inform practice and policy, evidence is needed on actionable, harmonized outcomes which are feasible to collect in most settings and relevant to citizens, practitioners, and decision makers. We propose that increased priority should be given to certain outcomes that are infrequently collected across multiple domains. RESULTS: A modification of a logic model of health outcomes by Proctor et al. is used to propose key domains and measures of implementation, service delivery, biomarkers, and health and functioning outcomes. Recommendations are made to give increased priority to implementation (especially reach, resource requirements/costs; and fidelity/adaptation); Institute of Medicine service delivery categories of equity and safety; and patient reported health and functioning outcomes. CONCLUSIONS: Implications of this outcomes framework include that biomarkers are not always the most important or relevant outcomes; that harmonized, pragmatic, and actionable measures are needed for each of these types of outcomes, and that significant changes in training and review of grants and publications are needed. PMID- 23919364 TI - Community representatives' involvement in Clinical and Translational Science Awardee activities. AB - OBJECTIVES: To understand the formal roles of community representatives (CRs) in Clinical and Translational Science Awardee (CTSA) activities, to evaluate the extent of integration into the organizational and governance structures and to identify barriers to effective integration. METHODS: The inventory tool was distributed to each of the 60 CTSAs using a secure web application. RESULTS: Forty-seven (78%) completed the inventory. The mean number of CRs per CTSA is 21.4 (SD: 14.8). Most CTSAs had community advisory boards (89%) and 94% included CRs in Community Engagement (CE) cores. Only 11% reported a CR being a member of the CTSA leadership team and 19% reported that CRs advise core programs beyond CE. CRs are compensated by 79% of CTSAs. Mean annual compensation is $753 (median: $400). Compensation directly correlated with the number of hours that CRs worked in CTSA activities (r = 0.64; P = 0.001). CONCLUSIONS: This inventory allows CTSAs to better understand how CRs have engaged in activities and brings attention to the limited representation among cores and in leadership roles. CTSAs should, with substantive input from CRs, develop strategies to provide the resources and compensation necessary to better integrate the community in CTSA activities and fully realize the goals of the CTSA vision. PMID- 23919365 TI - Partnership between CTSI and business schools can promote best practices for core facilities and resources. AB - Biomedical research enterprises require a large number of core facilities and resources to supply the infrastructure necessary for translational research. Maintaining the financial viability and promoting efficiency in an academic environment can be particularly challenging for medical schools and universities. The Indiana Clinical and Translational Sciences Institute sought to improve core and service programs through a partnership with the Indiana University Kelley School of Business. The program paired teams of Masters of Business Administration students with cores and programs that self-identified the need for assistance in project management, financial management, marketing, or resource efficiency. The projects were developed by CTSI project managers and business school faculty using service-learning principles to ensure learning for students who also received course credit for their participation. With three years of experience, the program demonstrates a successful partnership that improves clinical research infrastructure by promoting business best practices and providing a valued learning experience for business students. PMID- 23919366 TI - Evaluation guidelines for the Clinical and Translational Science Awards (CTSAs). AB - The National Center for Advancing Translational Sciences (NCATS), a part of the National Institutes of Health, currently funds the Clinical and Translational Science Awards (CTSAs), a national consortium of 61 medical research institutions in 30 states and the District of Columbia. The program seeks to transform the way biomedical research is conducted, speed the translation of laboratory discoveries into treatments for patients, engage communities in clinical research efforts, and train a new generation of clinical and translational researchers. An endeavor as ambitious and complex as the CTSA program requires high-quality evaluations in order to show that the program is well implemented, efficiently managed, and demonstrably effective. In this paper, the Evaluation Key Function Committee of the CTSA Consortium presents an overall framework for evaluating the CTSA program and offers policies to guide the evaluation work. The guidelines set forth are designed to serve as a tool for education within the CTSA community by illuminating key issues and practices that should be considered during evaluation planning, implementation, and utilization. Additionally, these guidelines can provide a basis for ongoing discussions about how the principles articulated in this paper can most effectively be translated into operational reality. PMID- 23919367 TI - Relationships hold the key to trustworthy and productive translational science: recommendations for expanding community engagement in biomedical research. AB - Good relationships between research institutions and communities are an essential, but often neglected, part of the infrastructure of translational science. In an effort to create greater interest among translational science researchers in cultivating relationships with community members, we report the results of a workshop we convened to learn how relationships vital to research are best created and sustained. We highlight common barriers and challenges that hinder relationships. We also provide recommendations that individual research institutions and teams can use to expand and strengthen their relationships with community members. The improved relationships between universities and communities that could result from their implementation should build greater public trust in biomedical research, lead to a stronger commitment to see it succeed, and engender shared values and commitments that will give rise to new rewards, recognition and admonishment to sustain those values and commitments over time, all of which would facilitate translational science. PMID- 23919368 TI - Using AI to understand key success features in evolving CTSAs. AB - A vital role for Clinical and Translational Science Award (CTSA) evaluators is to first identify and then articulate the necessary change processes that support the research infrastructures and achieve synergies needed to improve health through research. The use of qualitative evaluation strategies to compliment quantitative tracking measures (e.g., number of grants/publications) is an essential but under-utilized approach in CTSA evaluations. The Clinical and Translational Science Institute of Southeast Wisconsin implemented a qualitative evaluation approach using appreciative inquiry (AI) that has revealed three critical features associated with CTSA infrastructure transformation success: developing open communication, creating opportunities for proactive collaboration, and ongoing attainment of milestones at the key function group level. These findings are consistent with Bolman & Deal's four interacting hallmarks of successful organizations: structural (infrastructure), political (power distribution; organizational politics), human resource (facilitating change among humans necessary for continued success), and symbolic (visions and aspirations). Data gathered through this longitudinal AI approach illuminates how these change features progress over time as CTSA funded organizations successfully create the multiinstitutional infrastructures to connect laboratory discoveries with the diagnosis and treatment of human disease. PMID- 23919369 TI - Evaluating various areas of process improvement in an effort to improve clinical research: discussions from the 2012 Clinical Translational Science Award (CTSA) Clinical Research Management workshop. AB - Emphasis has been placed on assessing the efficiency of clinical and translational research as part of the National Institutes of Health (NIH) goal to "improve human health." Improvements identified and implemented by individual organizations cannot address the research infrastructure needs of all clinical and translational research conducted. NIH's National Center for Advancing Translational Sciences (NCATS) has brought together 61 Clinical and Translational Science Award (CTSA) sites creating a virtual national laboratory that reflects the diversity and breadth of academic medical centers to collectively improve clinical and translational science. The annual Clinical Research Management workshop is organized by the CTSA consortium with participation from CTSA awardees, NIH, and others with an interest in clinical research management. The primary objective of the workshop is to disseminate information that improves clinical research management although the specific objectives of each workshop evolve within the consortium. The fifth annual workshop entitled "Learning by doing; applying evidence-based tools to re-engineer clinical research management" took place in June 2012. The primary objective of the 2012 workshop was to utilize data to evaluate, modify, and improve clinical research management. This report provides a brief summary of the workshop proceedings and the major themes discussed among the participants. PMID- 23919370 TI - Cross-sectional evidence for a stress-negative affect pathway to substance use among sexual minority girls. AB - Sexual minority girls (SMGs) are four times more likely to engage in substance use than are heterosexual girls. A better understanding of the explanatory mechanisms of this disparity is needed to inform prevention and intervention programs. The goal of this study was to conduct a preliminary test of a "stress negative affect" pathway by examining gay-related victimization and depression as mediators of substance use among SMGs. Adolescent girls (N = 156, 41% SMGs) were recruited from two urban adolescent medicine clinics to participate in an NIH funded study of adolescent substance use. The average age was 17.0 years old and 57% were nonwhite. Mediation analyses were conducted in a multiple regression framework using SPSS and a mediation macro utilizing bias-corrected bootstrapping. Four models were estimated to test mediated pathways from sexual orientation to gay-related victimization (Mediator 1), to depression symptoms (Mediator 2), and then to each of four substance use variables: cigarettes, marijuana, alcohol, and heavy alcohol use. Significant mediated pathways (mediation tests with 95% CIs) were found for cigarette, alcohol and heavy alcohol use outcome variables. Results provide preliminary support for the minority stress hypothesis and the stress-negative affect pathway, and may inform the development of future prevention and intervention programs. PMID- 23919371 TI - Statistical evaluation of the use of concurrent controls in treatment screening studies. AB - A well-designed pilot study can advance science by providing essential preliminary data to support or motivate further research, refine study logistics, and demonstrate proof of concept. Often, the outcomes of such studies can be quantified by a success/failure dichotomy. For example, a novel compound may show activation of a neural pathway, or it may not. When an intervention's efficacy is quantified using a dichotomous outcome, probability mass functions can be enumerated to determine the probability that the observed result from a pilot study supports further evaluation of the intervention since there is only a finite, and often small, number of sample configurations possible. The purpose of this research was to determine the probability of an "efficacy signal" for pilot studies using one- and two-sample pilot study designs. Efficacy signal was defined as the probability of observing a more favorable response proportion relative to a historical control (one-sample setting) or to a concurrent control (two-sample setting). An enumeration study (exact simulation) was conducted to calculate the efficacy signal probability. One-sample study designs yielded higher probability of determining an efficacy signal than the two-sample setting; however, sampling variation must be accounted for. A 68% score confidence interval is recommended for this purpose. PMID- 23919373 TI - Multi-drug resistant toxigenic Vibrio cholerae O1 is persistent in water sources in New Bell-Douala, Cameroon. AB - BACKGROUND: Cholera has been endemic in Douala, since 1971 when it was first recorded in Cameroon. Outbreaks have often started in slum areas of the city including New Bell. Despite the devastating nature of outbreaks, always resulting in high mortality and morbidity, a paucity of information exists on the reservoirs of the causative agent, V. cholerae, and factors maintaining its persistence. This has complicated disease prevention, resulting in frequent outbreaks of cholera. We investigated water sources in New Bell for contamination with V. cholerae O1 with pathogenic potential, to highlight their role in disease transmission. Antibiotic susceptibility pattern of isolates and the environmental factors maintaining its persistence were investigated. METHOD: Water samples from various sources (taps, dug wells, streams) were analyzed for contamination with V. cholerae O1 using standard methods. Antibiotic susceptibility was determined by disc diffusion method. Pathogenic potential of isolates was determined by analyzing for genes for cholera toxin (ctx), toxin co-regulated pilus (tcpA), and zonula occludens toxin (zot) by PCR. Physico-chemical characteristics of water (pH, temperature and salinity) were investigated using standard methods. The Spearman's Rank correlation was used to analyze the relationship between physico chemical factors and the occurrence of V. cholerae O1. Differences were considered significant at P<=0.05. RESULTS: Twenty-five V. cholerae O1 strains were isolated from stream and well samples in both dry and rainy seasons. Twenty three (92%) isolates were multidrug resistant. All isolates had genes for at least one virulence factor. Cholera toxin gene was detected in 7 isolates. Of the 15 isolates positive for tcpA gene, two had Classical type tcpA while 13 had tcpA El Tor. All tcpA Classical positive isolates were positive for ctx gene. Isolates were grouped into nine genotypes based on the genes analyzed. pH and salinity significantly correlated with isolation of V. cholerae O1. CONCLUSION: Multidrug resistant Vibrio cholerae O1 with pathogenic potential is present in some wells and streams in study area. pH and salinity are among the factors maintaining the persistence of the organism. Findings indicate an urgent need for potable water supply in study area and in addition, regular disinfection of water from contaminated sources to prevent outbreak of cholera. PMID- 23919375 TI - Tracking retention and transport of ultrafine polystyrene in an asthmatic mouse model using positron emission tomography. AB - Upon exposure to particulates, asthmatic individuals are more susceptible to deleterious health effects and increased morbidity and mortality when compared to healthy individuals. These effects are not limited to the respiratory system; increases in acute cardiovascular events have been observed. The development of extrapulmonary illnesses has led to interest in determining whether particles move out of the lungs and whether transport of particles differs for asthmatic individuals. Differences in particle deposition and retention in asthmatic versus normal subjects have been explored in the literature using the gamma camera, a two-dimensional imaging technique. Herein we report the deposition and fate of (64)Cu-labeled 100 nm polystyrene particles in a mouse model of asthma using positron emission tomography (PET). All animals were handled humanely under an approved protocol (UC Davis Institutional Animal Care and Use Committee). Particles were administered by intratracheal instillation and animals were imaged over 48 hours using PET. Biodistribution was determined from images using Regions of Interest (ROI) analysis. After 48 hours, for the asthmatic animals, we observed that ~28% of the initial dose is cleared from the lungs; particle accumulation in small amounts is evident in the GI (gastrointestinal) tract, liver, and bladder. This decrease in lung retention is significantly different when compared to the normal mouse (~11%DD), which showed minimal particle transport out of the lung (P < 0.001). This study indicates that ultrafine particles (UFP) undergo enhanced transport out of the lungs in an asthma model. This observed transport may facilitate the adverse peripheral effects associated with particulate exposure. PMID- 23919374 TI - Evaluation of a subject specific dual-transmit approach for improving B1 field homogeneity in cardiovascular magnetic resonance at 3T. AB - BACKGROUND: Radiofrequency (RF) shading artifacts degrade image quality while performing cardiovascular magnetic resonance (CMR) at higher field strengths. In this article, we sought to evaluate the effect of local RF (B1 field) shimming by using a dual-source-transmit RF system for cardiac cine imaging and to systematically evaluate the effect of subject body type on the B1 field with and without local RF shimming. METHODS: We obtained cardiac images from 37 subjects (including 11 patients) by using dual-transmit 3T CMR. B1 maps with and without subject-specific local RF shimming (exploiting the independent control of transmit amplitude and phase of the 2 RF transmitters) were obtained. Metrics quantifying B1 field homogeneity were calculated and compared with subject body habitus. RESULTS: Local RF shimming across the region encompassed by the heart increased the mean flip angle (MU) in that area (88.5 +/- 15.2% vs. 81.2 +/- 13.3%; P = 0.0014), reduced the B1 field variation by 42.2 +/- 13%, and significantly improved the percentage of voxels closer to MU (39% and 82% more voxels were closer to +/- 10% and +/- 5% of MU, respectively) when compared with no RF shimming. B1 homogeneity was independent of subject body type (body surface area [BSA], body mass index [BMI] or anterior-posterior/right-left patient width ratio [AP/RL]). Subject specific RF (B1) shimming with a dual-transmit system improved local RF homogeneity across all body types. CONCLUSION: With or without RF shimming, cardiac B1 field homogeneity does not depend on body type, as characterized by BMI, BSA, and AP/RL. For all body types studied, cardiac B1 field homogeneity was significantly improved by performing local RF shimming with 2 independent RF-transmit channels. This finding indicates the need for subject specific RF shimming. PMID- 23919376 TI - Orange juice and cancer chemoprevention. AB - Orange juice (OJ) is among the most consumed fruit juices worldwide, and its chemopreventive action is fairly addressed in the literature. This review critically presents the available evidence linking OJ with cancer chemoprevention and on discussing the putative mechanisms and negative health effects. The chemopreventive action of OJ is related to its effect on metabolic enzymes and its antiinflammatory, cytoprotective/apoptotic, hormonal, cell signaling modulating, antioxidant, and antigenotoxic effects. Most studies on OJ are in vitro, and few are conducted in vivo. Results from in vitro studies must be interpreted carefully because these findings do not consider in vivo bioavailability. However, such results are useful for studying the impact of different processing and storage methods on OJ's chemopreventive effect. Evidence of OJ's chemoprevention in humans is limited. OJ is antimutagenic in bacteria and antigenotoxic in humans and rodents. Studies using rodent cancer models showed that OJ is cancer chemopreventive, influencing either the induction stage or the promotion stage. The composition and, therefore, the chemopreventive action of OJ might be influenced by different cultivars, climates, extraction methods, packaging, storage temperatures, and shelf lives, among other factors. Epidemiological studies and randomized controlled intervention studies in humans evaluating the chemopreventive effect of OJ, taking into consideration variability in OJ composition, are needed. PMID- 23919377 TI - Identification of a linear epitope recognized by a monoclonal antibody directed to the heterogeneous nucleoriboprotein A2. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disorder, characterized by progressive joint destruction and disability. Classical autoantibodies of RA are rheumatoid factors and citrulline antibodies. Patients positive for these autoantibodies are usually associated with a progressive disease course. A subgroup of RA patients does not express citrulline antibodies, instead are approximately 35% of these anti-citrulline-negative patients reported to express autoantibodies to the heterogeneous nucleoriboprotein A2, a ribonucleoprotein involved in RNA transport and processing also referred to as RA33. In the absence of citrulline antibodies, RA33 antibodies have been suggested to be associated with a milder disease course. In this study we screened the reactivity of a monoclonal antibody to RA33-derived peptides by modified enzyme-linked immunosorbent assays (ELISA). Terminally truncated resin-bound peptides were applied for determination of the functional epitope necessary for antibody recognition. In addition, screening of substituted peptides by modified ELISA identified amino acids necessary for antibody reactivity. A potential epitope was identified in the region 71-79 (PHSIDGRVV), where the amino acids Ser, Ile and Asp were found to be essential for antibody reactivity. These amino acids were found to contribute to the antibody-antigen interface through side-chain interactions, possibly in combination with a positively charged amino acid in position 77. Moreover, the amino acids in the N-terminal end (Pro and His) were found to contribute to the interface through backbone contributions. No notable reactivity was found with RA-positive patient sera, thus screening of RA33 antibodies does not seem to be a supplementary for the diagnosis of RA. PMID- 23919378 TI - Biophysical and structural characterization of the recombinant human eIF3L. AB - The eukaryotic translation initiation factor 3, subunit L (eIF3L) is one of the subunits of the eIF3 complex, an accessory protein of the Polymerase I enzyme and may have an important role in the Flavivirus replication by interaction with a viral non-structural 5 protein. Considering the importance of eIF3L in a diversity of cellular functions, we have produced the recombinant full-length eIF3L protein in Escherichia coli and performed spectroscopic and in silico analyses to gain insights into its hydrodynamic behavior and structure. Dynamic light scattering showed that eIF3L behaves as monomer when it is not interacting with other molecular partners. Circular dichroism experiments showed a typical spectrum of alpha-helical protein for eIF3L, which is supported by sequence-based predictions of secondary structure and the 3D in silico model. The molecular docking with the K subunit of the eIF3 complex revealed a strong interaction. It was also predicted several potential interaction sites in eIF3L, indicating that the protein is likely capable of interacting with other molecules as experimentally shown in other functional studies. Moreover, bioinformatics analyses showed approximately 8 putative phosphorylation sites and one possible N glycosylation site, suggesting its regulation by post-translational modifications. The production of the eIF3L protein in E. coli and structural information gained in this study can be instrumental for target-based drug design and inhibitors against Flavivirus replication and to shed light on the molecular mechanisms involved in the eukaryotic translation initiation. PMID- 23919379 TI - Construction, expression and characterization of a single chain variable fragment antibody against human myostatin. AB - Myostatin plays negative roles in muscle development. To block the inhibitory effects of myostatin on myogenesis, a 759 bp single chain variable fragment antibody (scFv) against myostatin was constructed and expressed in Escherichia coli. ELISA detection showed that the scFv could bind to myostatin, and change of the scFv N-terminal peptides decreased its binding affinity. MTT assay and cell morphology demonstrated that the cell number and viability of the C2C12 myoblast were enhanced by the scFv. Meanwhile, the scFv significantly inhibited the myostatin-induced expression of cyclin-dependent kinase inhibitor p21 and Smad binding element-luciferase activity. H2O2 increased the expression of Muscle RING Finger 1 (MuRF1) and Muscle Atrophy F-box (MAFbx) in myoblasts as well as myostatin and MuRF1 in myotubes, and the scFv significantly decreased the H2O2 elevated expression of these genes. Conclusively, the scFv we developed could antagonize the inhibitory effects of myostatin on myogenesis through Smad pathway and regulation of p21, MuRF1 and MAFbx gene expression. The scFv may have application in the therapy of muscular dystrophy and improvement of animal meat production. PMID- 23919380 TI - Challenges and strategies in the administration of a population based mortality follow-back survey design. AB - Population-based mortality follow-back survey designs have been used to collect information concerning end-of-life care from bereaved family members in several countries. In Canada, this design was recently employed to gather population based information about the end-of-life care experience among adults in Nova Scotia as perceived by the decedent's family. In this article we describe challenges that emerged during the implementation of the study design and discuss resolutions strategies to help overcome them. Challenges encountered included the inability to directly contact potential participants, difficulties ascertaining eligibility, mailing strategy complications and the overall effect of these issues on response rate and subsequent sample size. Although not all challenges were amenable to resolution, strategies implemented proved beneficial to the overall process and resulted in surpassing the targeted sample size. The inability to directly contact potential participants is an increasing reality and limitations associated with this process best acknowledged during study development. Future studies should also consider addressing participant concerns pertaining to their eligibility and use of a more cost effective mailing strategy. PMID- 23919381 TI - Outcomes of adult dual kidney transplants by KDRI in the United States. AB - UNOS guidelines provide inadequate discriminatory criteria for kidneys that should be transplanted as single (SKT) versus dual (DKT). We evaluated the utility of the kidney donor risk index (KDRI) to define kidneys with better outcomes when transplanted as dual. Using SRTR data from 1995 to 2010 of de novo KTX recipients of adult deceased-donor kidneys, we examined outcomes of SKT and DKT stratified by KDRI group <=1.4 (n = 49 294), 1.41-1.8 (n = 15 674), 1.81-2.2 (n = 6523) and >2.2 (n = 2791). DKT of kidneys with KDRI >2.2 was associated with significantly better overall graft survival [adjusted hazard ratio (aHR) 0.83, 95% confidence interval (CI) 0.72-0.96] compared to single kidneys with KDRI >2.2. DKT was associated with significantly decreased odds of delayed graft function (top 2 KDRI categories) and significantly decreased odds of 1-year serum creatinine level >2 mg/dL (top 3 KDRI categories). Among SKT and DKT from KDRI >2.2 there were 16.1 and 13.9 graft losses per 100 patient follow-up years, respectively. KDRI >2.2 is a useful discriminatory cut-off for the determination of graft survival benefit with the use of DKT; however, the benefit of increased graft years was less than half of single kidneys from donors in the same KDRI range. PMID- 23919382 TI - Health information technology in nursing homes: why and how? PMID- 23919383 TI - Cancer detection and management in patients with haemophilia: a retrospective European multicentre study. AB - Lymphomas or hepatocarcinomas related to blood-borne transmitted diseases are well-known malignancies in persons with haemophilia (PWH). However, rising life expectancy has increased the number of PWH suffering from other malignancies. This study aimed to collect cancer occurrence data in PWH followed in five European haemophilia treatment centres (Brussels, Geneva, Marseille, Montpellier and Paris-Bicetre) over the last 10 years and to analyse some particular features of cancer occurring in PWH. In total, 45 malignancies were diagnosed in 1067 PWH. The most common malignancies were hepatocellular carcinoma (12/45) and urogenital tract tumours (9/45). Bleeding at presentation or changes in bleeding pattern was indicative of cancer in four patients. Three patients with mild haemophilia developed anti-factor VIII inhibitors after intensive substitution therapy prior to surgery or invasive procedures. There was no bleeding associated with chemotherapy or radiotherapy. A few bleeding complications occurred following invasive (3/39) or surgical procedures (2/27) as a result of insufficient hemostatic coverage or in spite of adequate substitution. No bleeding was noted after liver or prostate biopsies. Following cancer diagnosis, five patients were switched from on-demand to prolonged prophylaxis substitution. In the majority of cases, the standard cancer treatment protocol was not modified on account of concomitant haemophilia. Thus, oncological treatments are not contraindicated and should not be withheld in PWH assuming that adequate haemostasis correction is undertaken. As shown by our study results, a change in bleeding pattern in adult PWH should raise suspicion of a malignancy. Intensive substitution must be considered a risk factor for inhibitor development. PMID- 23919385 TI - Resilient ageing: a concept analysis. AB - AIM: This paper is a report of an analysis of the concept resilient ageing. Unique in comparison with other healthy ageing concepts, resilient ageing can be applied to all older people, regardless of age or affliction. BACKGROUND: The state of global population expansion in older people over the next 50 years calls for increased health promotion research efforts to ensure the maintenance of health and optimal quality of life for all older people. DATA SOURCES: Literature for this concept analysis was retrieved from several databases, CINAHL, PubMed PsycINFO, for the years 1990-2012. DESIGN: Rodgers's evolutionary method of concept analysis was used because of its applicability to concepts that are still evolving. METHODS: An integrative research review methodology was applied to peer reviewed journal articles (n = 46) for an inductive analysis of the concept of resilient ageing. RESULTS: The antecedents, defining attributes, and consequence of resilient ageing were identified. Antecedents to resilient ageing were found to be adversity and protective factors, while the core attributes include coping, hardiness and self-concept. The consequence of the process of resilient ageing was optimal quality of life. Sense of coherence was found to be the surrogate term. The results obtained were further substantiated using Antonovsky's (1979) theory of salutogenesis. CONCLUSION: A theoretical definition and a model of resilient ageing were developed. In addition, a discussion was provided on the practice, policy and research implications for promoting the development of protective factors and resilient ageing. PMID- 23919384 TI - Individual patient data systematic review and meta-analysis of optic nerve sheath diameter ultrasonography for detecting raised intracranial pressure: protocol of the ONSD research group. AB - BACKGROUND: The purpose of the optic nerve sheath diameter (ONSD) research group project is to establish an individual patient-level database from high quality studies of ONSD ultrasonography for the detection of raised intracranial pressure (ICP), and to perform a systematic review and an individual patient data meta analysis (IPDMA), which will provide a cutoff value to help physicians making decisions and encourage further research. Previous meta-analyses were able to assess the diagnostic accuracy of ONSD ultrasonography in detecting raised ICP but failed to determine a precise cutoff value. Thus, the ONSD research group was founded to synthesize data from several recent studies on the subject and to provide evidence on the diagnostic accuracy of ONSD ultrasonography in detecting raised ICP. METHODS: This IPDMA will be conducted in different phases. First, we will systematically search for eligible studies. To be eligible, studies must have compared ONSD ultrasonography to invasive intracranial devices, the current reference standard for diagnosing raised ICP. Subsequently, we will assess the quality of studies included based on the QUADAS-2 tool, and then collect and validate individual patient data. The objectives of the primary analyses will be to assess the diagnostic accuracy of ONSD ultrasonography and to determine a precise cutoff value for detecting raised ICP. Secondly, we will construct a logistic regression model to assess whether patient and study characteristics influence diagnostic accuracy. DISCUSSION: We believe that this IPD MA will provide the most reliable basis for the assessment of diagnostic accuracy of ONSD ultrasonography for detecting raised ICP and to provide a cutoff value. We also hope that the creation of the ONSD research group will encourage further study. TRIAL REGISTRATION: PROSPERO registration number: CRD42012003072. PMID- 23919386 TI - Hydrothermal synthesis of zinc oxide nanoparticles using rice as soft biotemplate. AB - BACKGROUND: Rice as a renewable, abundant bio-resource with unique characteristics can be used as a bio-template to synthesize various functional nanomaterials. Therefore, the effect of uncooked rice flour as bio-template on physico-chemical properties, especially the morphology of zinc oxide nanostructures was investigated in this study. The ZnO particles were synthesized through hydrothermal-biotemplate method using zinc acetate-sodium hydroxide and uncooked rice flour at various ratios as precursors at 120 degrees C for 18 hours. RESULTS: The results indicate that rice as a bio-template can be used to modify the shape and size of zinc oxide particles. Different morphologies, namely flake-, flower-, rose-, star- and rod-like structures were obtained with particle size at micro- and nanometer range. Pore size and texture of the resulting zinc oxide particles were found to be template-dependent and the resulting specific surface area enhanced compared to the zinc oxide synthesized without rice under the same conditions. However, optical property particularly the band gap energy is generally quite similar. CONCLUSION: Pure zinc oxide crystals were successfully synthesized using rice flour as biotemplate at various ratios of zinc salt to rice. The size- and shape-controlled capability of rice to assemble the ZnO particles can be employed for further useful practical applications. PMID- 23919387 TI - Fast and accurate detection of multiple quantitative trait Loci. AB - We present a new computational scheme that enables efficient and reliable quantitative trait loci (QTL) scans for experimental populations. Using a standard brute-force exhaustive search effectively prohibits accurate QTL scans involving more than two loci to be performed in practice, at least if permutation testing is used to determine significance. Some more elaborate global optimization approaches, for example, DIRECT have been adopted earlier to QTL search problems. Dramatic speedups have been reported for high-dimensional scans. However, since a heuristic termination criterion must be used in these types of algorithms, the accuracy of the optimization process cannot be guaranteed. Indeed, earlier results show that a small bias in the significance thresholds is sometimes introduced. Our new optimization scheme, PruneDIRECT, is based on an analysis leading to a computable (Lipschitz) bound on the slope of a transformed objective function. The bound is derived for both infinite- and finite-size populations. Introducing a Lipschitz bound in DIRECT leads to an algorithm related to classical Lipschitz optimization. Regions in the search space can be permanently excluded (pruned) during the optimization process. Heuristic termination criteria can thus be avoided. Hence, PruneDIRECT has a well-defined error bound and can in practice be guaranteed to be equivalent to a corresponding exhaustive search. We present simulation results that show that for simultaneous mapping of three QTLS using permutation testing, PruneDIRECT is typically more than 50 times faster than exhaustive search. The speedup is higher for stronger QTL. This could be used to quickly detect strong candidate eQTL networks. PMID- 23919388 TI - Fast matching of transcription factor motifs using generalized position weight matrix models. AB - The problem of finding the locations in DNA sequences that match a given motif describing the binding specificities of a transcription factor (TF) has many applications in computational biology. This problem has been extensively studied when the position weight matrix (PWM) model is used to represent motifs. We investigate it under the feature motif model, a generalization of the PWM model that does not assume independence between positions in the pattern while being compatible with the original PWM. We present a new method for finding the binding sites of a transcription factor in a DNA sequence when the feature motif model is used to describe transcription factor binding specificities. The experimental results on random and real data show that the search algorithm is fast in practice. PMID- 23919389 TI - Challenges of using polyethylene passive samplers to determine dissolved concentrations of parent and alkylated PAHs under cold and saline conditions. AB - Passive samplers can be useful tools for determining truly dissolved concentrations of organic contaminants in the water. Polyethylene (PE) samplers were validated for measuring polycyclic aromatic hydrocarbons (PAHs), with a focus on alkylated PAHs that can dominate in an oil spill. Equilibrium partition coefficients between water and PE passive samplers (KPEw) were measured for 41 PAHs both at ambient conditions (20 degrees C, no salt) and down to -15 degrees C with up to 245 psu present in ice brine. For each additional alkylated carbon, log KPEw increased by an average of 0.40 (+/-0.20) log units, close to predictions. The increase per aromatic carbon was only 0.33 (+/-0.02) log units. Apparent PE-water distributions of pyrene and deuterated pyrene (performance reference compound) were within 0.1 log unit for all experiments at 20 and 2 degrees C but started to diverge by 0.8 log units at -4 degrees C (100 psu) and by 3.1 log units at -15 degrees C (245 psu). The delay in equilibrating PAHs in these experiments was dominated by increases in the water viscosity, which, in turn, affected both the aqueous diffusivities of the PAHs and the thickness of the water boundary layer. In a simulated marine oil spill in the laboratory, PE based results were within a factor of 2 of conventional sampling results for the most abundant PAHs. PMID- 23919390 TI - DNA barcoding in Mexico: an introduction. AB - DNA barcoding has become an important current scientific trend to the understanding of the world biodiversity. In the case of mega-diverse hot spots like Mexico, this technique represents an important tool for taxonomists, allowing them to concentrate in highlighted species by the barcodes instead of analyzing entire sets of specimens. This tendency resulted in the creation of a national network named Mexican Barcode of Life (MEXBOL) which main goals are to train students, and to promote the interaction and collective work among researchers interested in this topic. As a result, the number of records in the Barcode of Life Database (BOLD) for some groups, such as the Mammalia, Actinopterygii, Polychaeta, Branchiopoda, Ostracoda, Maxillopoda, Nematoda, Pinophyta, Ascomycota and Basidiomycota place Mexico among the top ten countries in the generation of these data. This special number presents only few of the many interesting findings in this region of the world, after the use of this technique and its integration with other methodologies. PMID- 23919391 TI - A study of the anatomic changes and dosimetric consequences in adaptive CRT of non-small-cell lung cancer using deformable CT and CBCT image registration. AB - The aim of this study is to evaluate anatomic lung tumor changes and dosimetric consequences utilizing the deformable daily kilovolt (KV) cone-beam computer tomography (CBCT) image registration. Five patients diagnosed with NSCLC were treated with three-dimensional conformal radiotherapy (3D CRT) and 10 daily KV CBCT image sets were acquired for each patient. Each CBCT image and plan CT were imported into the deformable image registration (DIR) system. The plan CT image was deformed by the DIR system and a new contour on CBCT was obtained by using the auto-contouring function of the DIR. These contours were individually marked as CBCT f1, CBCT f2,..., and CBCT f10, and imported into a treatment planning system (TPS). The daily CBCT plan was individually generated with the same planning criteria based on new contours. These plans were individually marked as CBCTp1, CBCTp2,..., and CBCTp10, followed by generating a dose accumulation plan (DA plan) in original pCT image contour sets by adding all CBCT plans using Varian Eclipse TPS. The maximum, minimum and mean doses to the plan target volume (PTV) in the 5 DA plans were the same with the CT plans. However, the volume of radiation 5, 10, 20, 30, and 50 Gy of the total lungs in DA plans were less than those of the CT plans. The maximum dose of the spinal cord in the DA plans were average 27.96% less than the CT plans. The mean dose for the left, right, and total lungs in the DA plans were reduced by 13.80%, 23.65%, and 12.96%, respectively. The adaptive 3D CRT based on the deformable registration can reduce the dose to the lung and the spinal cord with the same PTV dose coverage. Moreover, it provides a method for further adaptive radiotherapy exploration. PMID- 23919392 TI - Multiple infections and cancer: implications in epidemiology. AB - Approximately 18% of the global cancer burden has been attributed to infectious agents, with estimates ranging from 7% in developed countries to about 22% in developing countries. Chronic infections caused by the hepatitis B and C viruses, human papilloma viruses (HPV), and Helicobacter pylori (H. pylori) are reported to be responsible for approximately 15% of all human cancers. Interestingly, although many of the infectious agents that have been associated with cancer- such as HPV, Epstein-Barr virus (EBV), and H. pylori--are highly prevalent in the world, most infected individuals do not develop cancer but remain lifelong carriers. Malignancies associated with infectious agents may result from prolonged latency as a result of chronic infections. Pathogenic infections are necessary but are not sufficient for cancer initiation or progression. Cancer initiation may require additional cofactors, including secondary infections. Therefore, in patients with chronic infection with one agent, secondary co infection with another agent may serve as an important co-factor that may cause cancer initiation and progression. Additionally, opportunistic co-infections could significantly inhibit response to cancer treatment and increase cancer mortality. Co-infections are relatively common in areas with a high prevalence of infectious agents, especially in developing countries. These co-infections can cause an imbalance in the host immune system by affecting persistence of and susceptibility to malignant infections. Several articles have been published that focus on infectious agents and cancer. In this article, we discuss the role of infectious agents in malignancies, highlight the role of multiple/co-infections in cancer etiology, and review implications for cancer epidemiology. PMID- 23919393 TI - MicroRNA-145 function as a cell growth repressor by directly targeting c-Myc in human ovarian cancer. AB - MiR-145 is reported to be significantly down-regulated in ovarian cancer. This study was aimed at elucidating the roles of miR-145 in regulating the biological behavior of epithelial ovarian cancer (EOC) cells. In this report, we find out that up-regulation of miR-145 in OVCAR-3 and SKOV-3 cells inhibit cell proliferation and promote cell apoptosis. We show that miR-145 directly target the c-Myc 3'-UTR. Moreover, ectopic expression of c-Myc reduces the inhibition of cell proliferation caused by miR-145 transfection. Cell cycle assay showed that up-regulation of miR-145 reduces S phase population, and restoration of c-Myc can rescue this reduction. These findings indicate that miR-145 inhibits cell proliferation and promotes cell apoptosis by targeting c-Myc 3'-UTR. Therefore, the result indicated that miR- 145 could be used as a potential therapeutic target in ovarian cancer. PMID- 23919394 TI - Potential usefulness of baculovirus-mediated sodium-iodide symporter reporter gene as non-invasively gene therapy monitoring in liver cancer cells: an in vitro evaluation. AB - Primary liver cancer has one of the highest mortality rates of all cancers, and the main current treatments have a poor prognosis. This study aims to examine the efficiency of baculovirus vectors for transducing target gene into liver cancer cells and to evaluate the feasibility of using baculovirus vectors to deliver the sodium-iodide symporter (NIS) gene as a reporter gene through co-vector administration approach to monitor the expression of the target therapeutic gene in liver cancer gene therapy. We constructed (green fluorescent protein) GFP- and NIS-expressing baculovirus vectors (Bac-GFP and Bac-NIS), and measured the baculovirus transduction efficiency in HepG2 cells and other tumor cells (A549, SW1116 and 8505C), and it showed that the transduction efficiency and target gene expression level rose with increasing viral multiplicity of infection (MOI) in HepG2 cells, and HepG2 cells had a significantly higher transduction efficiency (60.8% at MOI = 200) than other tumor cells. Moreover, the baculovirus transduction was not cytotoxic to HepG2 cells at a higher MOI (MOI 5 400). We also performed dynamic iodide uptake trials, and found that Bac-NIS-transduced HepG2 cells exhibited efficient iodide uptake which could be inhibited by sodium perchlorate (NaClO4). And we measured the correlation of fluorescent intensities and 125I uptake amount in HepG2 cells after co-vector administration with Bac-NIS and Bac-GFP at different MOIs, and found a high correlation coefficient (r(2) = 0.8447), which provides a good basis for successfully evaluating the feasibility of baculovirus-mediated NIS reporter gene monitoring target gene expression in liver cancer therapy. Therefore, this study indicates that baculovirus vector is a potential vehicle for delivering therapeutic genes in studying liver cancer cells. And it is feasible to use a baculovirus vector to deliver NIS gene as a reporter gene to monitor the expression of target genes. It therefore provides an effective approach and a good basis for future baculovirus-mediated therapeutic gene delivering or therapeutic gene expression monitoring in liver cancer cells studies. PMID- 23919395 TI - Performance evaluations of demons and free form deformation algorithms for the liver region. AB - We investigated the influence of breathing motion on radiation therapy according to four- dimensional computed tomography (4D-CT) technology and indicated the registration of 4D-CT images was significant. The demons algorithm in two interpolation modes was compared to the FFD model algorithm to register the different phase images of 4D-CT in tumor tracking, using iodipin as verification. Linear interpolation was used in both mode 1 and mode 2. Mode 1 set outside pixels to nearest pixel, while mode 2 set outside pixels to zero. We used normalized mutual information (NMI), sum of squared differences, modified Hausdorff-distance, and registration speed to evaluate the performance of each algorithm. The average NMI after demons registration method in mode 1 improved 1.76% and 4.75% when compared to mode 2 and FFD model algorithm, respectively. Further, the modified Hausdorff-distance was no different between demons modes 1 and 2, but mode 1 was 15.2% lower than FFD. Finally, demons algorithm has the absolute advantage in registration speed. The demons algorithm in mode 1 was therefore found to be much more suitable for the registration of 4D-CT images. The subtractions of floating images and reference image before and after registration by demons further verified that influence of breathing motion cannot be ignored and the demons registration method is feasible. PMID- 23919396 TI - Design and testing of indigenous cost effective three dimensional radiation field analyser (3D RFA). AB - The aim of the study is to design and validate an indigenous three dimensional Radiation Field Analyser (3D RFA). The feed system made for X, Y and Z axis movements is of lead screw with deep ball bearing mechanism made up of stain less steel driven by stepper motors with accuracy less than 0.5 mm. The telescopic column lifting unit was designed using linear actuation technology for lifting the water phantom. The acrylic phantom with dimensions of 800 x 750 x 570 mm was made with thickness of 15 mm. The software was developed in visual basic programming language, classified into two types, viz. beam analyzer software and beam acquisition software. The premeasurement checks were performed as per TG 106 recommendations. The physical parameters of photon PDDs such as Dmax, D10, D20 and Quality Index (QI), and the electron PDDs such as R50, Rp, E0, Epo and X-ray contamination values can be obtained instantaneously by using the developed RFA system. Also the results for profile data such as field size, central axis deviation, penumbra, flatness and symmetry calculated according to various protocols can be obtained for both photon and electron beams. The result of PDDs for photon beams were compared with BJR25 supplement values and the profile data were compared with TG 40 recommendation. The results were in agreement with standard protocols. PMID- 23919397 TI - Preoperative intensity modulated radiation therapy for retroperitoneal sarcoma. AB - The use of intensity modulated radiation therapy (IMRT) has allowed for the administration of high doses to retroperitoneal sarcomas (RSTS) while limiting toxicity to adjacent organs. The purpose of our study is to assess the outcome and toxicities of patients with RSTS treated with neo-adjuvant external beam radiation (EBRT) therapy using IMRT. This is a retrospective study of 21 patients treated with preoperative IMRT for primary or recurrent RSTS between 2005 and 2011. Overall survival (OS) and local recurrence free survival (LRFS) were computed using the Kaplan-Meier method (log-rank test). Acute and chronic toxicities were assessed using the CTCAE v. 3 criteria. The actuarial 2 and 3 year OS was 66% for both and the 5-year OS was 51%. As for LRFS it was 57% at 2 and 3-year and 51% for the 5-year LRFS. Factors predictive for local control were microscopically negative margins (p = 0.022), a median tumor diameter <15 cm (p = 0.007) and pathology of liposarcoma (p = 0.021). Furthermore, patients treated for recurrent disease fared worse (p = 0.04) in local control than patients treated for primary disease. As for OS, patients treated for Grade 1 histology had a better outcome (p 5 0.05). EBRT was generally well tolerated. Acute gastrointestinal (GI) Grade 1 or 2 toxicities occurred in 33% of patients and one patient had unexplained post-radiation Grade 2 fever that resolved after tumor resection. As for chronic toxicities 24% of our patients presented Grade 1 GI toxicity and one patient presented Grade 3 small bowel stenosis not clearly due to radiation toxicity. Despite the location and volume of the tumors treated, preoperative IMRT was very well tolerated in our patients with retroperitoneal sarcoma. Unfortunately local recurrences remain common and dose escalation is to be considered. PMID- 23919398 TI - Dosimetric evaluation of magnetic resonance imaging-based intracavitary brachytherapy for cervical cancer. AB - The purpose of this study was to evaluate the dosimetric benefit of magnetic resonance imaging (MRI)-based dose adaptation in intracavitary brachytherapy (ICR) for cervical cancer. Dose-volume histograms were compared between matched conventional and optimized plans in 22 patients who were treated by MRI-based ICR. Doses to organs-at-risk (OAR) and dose covering 90% of high-risk clinical target volume (HR-CTV) were evaluated to compare OAR sparing and target coverage, respectively. The probability of RTOG rectal toxicity grade of >=2 in the 22 patients was estimated based on the prediction model generated from previous three-dimensional CT-based ICR data. After optimization, doses to OAR showed a statistically significant decrease. The reduction percentage (reduced dose by optimization x 100/dose in the conventional plan) was higher in patients with HR CTV >20 cc than in patients with HR-CTV >20 cc in the rectum. In patients with HR CTV <= 20 cc, the mean probability of RTOG rectal toxicity grade >= 2 was 67.6% for the conventional plan and 47.8% for the optimized plan, based on the prediction model. In conclusion, dose adaptation by MRI-based ICR for cervical cancer resulted in significant dose reduction to the rectum, especially in patients with HR-CTV <= 20 cc. PMID- 23919399 TI - Optimization of the formulation for preparing Lactobacillus casei loaded whey protein-Ca-alginate microparticles using full-factorial design. AB - CONTEXT: This article presents specific approach for microencapsulation of Lactobacillus casei using emulsion method followed by additional coating with whey protein. METHODS: Experimental design was employed using polynomial regression model at 2nd level with three independent variables, concentrations of alginate, whey protein and CaCl2. Physicochemical, biopharmaceutical and biological properties were investigated. RESULTS: In 11 series generated, negatively charged microparticles were obtained, with size 6.99-9.88 um, Ca content 0.29-0.47 mg per 10 mg microparticles, and viability of the probiotic 9.30-10.87 log10CFU/g. The viability after 24 hours in simulated gastrointestinal conditions was between 3.60 and 8.32 log10CFU/g. DISCUSSION: Optimal formulation of the microparticles that ensures survival of the probiotic and achieves controlled delivery was determined: 2.5% (w/w) alginate, 3% (w/w) CaCl2 and 3% (w/w) whey protein. CONCLUSION: The advantageous properties of the L. casei loaded microparticles make them suitable for incorporation in functional food and/or pharmaceutical products. PMID- 23919400 TI - Structural consequences of cysteinylation of Cu/Zn-superoxide dismutase. AB - The metalloenzyme Cu/Zn-superoxide dismutase (SOD1) catalyzes the reduction of superoxide anions into molecular oxygen and hydrogen peroxide. Hydrogen peroxide can oxidize SOD1, resulting in aberrant protein conformational changes, disruption of SOD1 function, and DNA damage. Cells may have evolved mechanisms of regulation that prevent such oxidation. We observed that cysteinylation of cysteine 111 (Cys111) of SOD1 prevents oxidation by peroxide (DOI 10.1021/bi4006122 ). In this article, we characterize cysteinylated SOD1 using differential scanning fluorometry and X-ray crystallography. The stoichiometry of binding was one cysteine per SOD1 dimer, and there does not appear to be free volume for a second cysteine without disrupting the dimer interface. Much of the three-dimensional structure of SOD1 is unaffected by cysteinylation. However, local conformational changes are observed in the cysteinylated monomer that include changes in conformation of the electrostatic loop (loop VII; residues 133 144) and the dimer interface (loop VI; residues 102-115). In addition, our data shows how cysteinylation precludes oxidation of cysteine 111 and suggests possible cross-talk between the dimer interface and the electrostatic loop. PMID- 23919401 TI - Minimum alveolar concentration of desflurane with caudal analgesia for laryngeal mask airway removal in anesthetized children. AB - BACKGROUND: Regional blocks have been shown to decrease the requirement of anesthetic agents. This study was conducted to determine the optimal endtidal concentrations of desflurane for removal of Laryngeal mask airway in children in presence of caudal block. METHODS: Twenty-two children of ASA status I between the age group of 2-10 year undergoing infraumbilical surgery were enrolled in the study. General anesthesia was induced with sevoflurane and oxygen given via mask and laryngeal mask airway inserted. Caudal injection of bupivacaine 0.25%, 1 ml.kg(-1) was administered according to Armitage regimen. Desflurane was used for maintenance of anesthesia. Predecided endtidal concentration of desflurane was maintained for 10 min at the end of surgery and laryngeal mask airway removed. Target concentration in the next patient was thereafter determined by the Dixon up-down method (with 0.5% as a step size). 5% endtidal concentration was kept as the starting concentration. If removal of laryngeal mask airway was not associated with any coughing, teeth clenching, gross purposeful movement, breath holding or laryngospasm, during or within 1 min after removal, it was considered as successful. RESULTS: In the presence of caudal analgesia, endtidal concentration of desflurane required for successful laryngeal mask airway removal in 50% (ED50) children was 3.39 +/- 0.38% by Dixon's method. CONCLUSION: Laryngeal mask airway can be successfully removed in 50% of anesthetized children without coughing, moving, or any other airway complications at an endtidal desflurane concentration of 3.4% in the presence of caudal analgesia. PMID- 23919402 TI - Improving hand hygiene compliance in the emergency department: getting to the point. AB - BACKGROUND: The emergency department (ED) represents an environment with a high density of invasive, and thus, infection-prone procedures. The two primary goals of this study were (1) to define the number of hand-rubs needed for an individual patient care at the ED and (2) to optimize hand hygiene (HH) compliance without increasing workload. METHODS: Prospective tri-phase (6-week observation phases interrupted by two 6-week interventions) before after study to determine opportunities for and compliance with HH (WHO definition). Standard operating procedures (SOPs) were optimized for invasive procedures during two predefined intervention periods (phases I and II) to improve workflow practices and thus compliance with HH. RESULTS: 378 patient cases were evaluated with 5674 opportunities for hand rubs (HR) and 1664 HR performed. Compliance significantly increased from 21% (545/2603) to 29% (467/1607), and finally 45% (652/1464; all p<0.001) in phases 1, 2, and 3, respectively. The number of HR needed for one patient care significantly decreased from 22 to 13 for the non-surgical and from 13 to 7 for the surgical patients (both p<0.001) due to improved workflow practices after implementing SOPs. In parallel, the number of HR performed increased from 3 to 5 for non-surgical (p<0.001) and from 2 to 3 for surgical patients (p=0.317). Avoidable opportunities as well as glove usage instead of HR significantly decreased by 70% and 73%, respectively. CONCLUSIONS: Our study provides the first detailed data on HH in an ED setting. Importantly, HH compliance improved significantly without increasing workload. PMID- 23919403 TI - Experimental effect of shots caused by projectiles fired from air guns with kinetic energy below 17 J. AB - Pursuant to the Polish Weapons and Ammunitions Law (Legal Gazette No 53/1999 item 549 with subsequent amendments), air guns with kinetic energy of the fired projectiles below 17 J are not regarded as weapons. The aim of the study was to assess the potential effect of shots caused by projectiles of various mass and structure fired from air guns with kinetic energy below 17 J on human soft tissues. As a model of soft tissue, we used 20% gelatin blocks. After shooting, we measured the depth of gelatin block penetration by pellets fired from various distances and compared these results with autopsy findings. The results demonstrated that examined pneumatic guns may cause serious injuries, including damage to the pleura, pericardium, liver, spleen, kidneys, femoral artery, and thoracic and abdominal aorta. Experiment shown that gelatin blocks do not reflect fully the properties of the human body. PMID- 23919404 TI - Elective versus emergency abdominal surgery following cardiac transplantation: a Victorian state transplant service experience. AB - BACKGROUND: Heart transplant patients constitute a unique patient cohort with multiple risk factors predictive of poor surgical outcome. The Alfred Hospital offers the only heart transplant service in Victoria, Australia. This article presents The Alfred Hospital's experience with outcomes of abdominal operations in the heart transplant patient population. METHODS: The statewide cardiothoracic registry was cross-referenced with The Alfred Hospital's electronic hospital database to identify heart transplant patients who had undergone abdominal surgery from 2002 to November 2012. Patients who met the inclusion criteria were evaluated in two groups: elective and emergency surgical settings. In the emergency group, risk factors recorded for poor surgical outcome were high-dose immunosuppression therapy, diabetes and other conventional vascular risk factors. Outcome measures assessed in both groups were length of stay, readmission within 30 days and 1-year mortality. RESULTS: Twelve patients were identified who underwent 13 abdominal operations. Eight were elective cases and five were emergent abdominal operations. The mean length of stay was shorter in the elective group than the emergency group (2.5 days versus 21.3 days). There was one readmission within 30 days, and no mortality at 1 year following elective surgery. In the emergency surgery group, two patients were readmitted within 30 days post-operatively, and there were two deaths observed in this group. CONCLUSION: The Alfred Hospital experience demonstrates that elective abdominal surgery following heart transplantation can be performed safely. Emergent surgery in this group of patients, however, is associated with poorer outcomes. PMID- 23919405 TI - The effects of pre versus post workout supplementation of creatine monohydrate on body composition and strength. AB - BACKGROUND: Chronic supplementation with creatine monohydrate has been shown to promote increases in total intramuscular creatine, phosphocreatine, skeletal muscle mass, lean body mass and muscle fiber size. Furthermore, there is robust evidence that muscular strength and power will also increase after supplementing with creatine. However, it is not known if the timing of creatine supplementation will affect the adaptive response to exercise. Thus, the purpose of this investigation was to determine the difference between pre versus post exercise supplementation of creatine on measures of body composition and strength. METHODS: Nineteen healthy recreational male bodybuilders (mean +/- SD; age: 23.1 +/- 2.9; height: 166.0 +/- 23.2 cm; weight: 80.18 +/- 10.43 kg) participated in this study. Subjects were randomly assigned to one of the following groups: PRE SUPP or POST-SUPP workout supplementation of creatine (5 grams). The PRE-SUPP group consumed 5 grams of creatine immediately before exercise. On the other hand, the POST-SUPP group consumed 5 grams immediately after exercise. Subjects trained on average five days per week for four weeks. Subjects consumed the supplement on the two non-training days at their convenience. Subjects performed a periodized, split-routine, bodybuilding workout five days per week (Chest shoulders-triceps; Back-biceps, Legs, etc.). Body composition (Bod Pod(r)) and 1 RM bench press (BP) were determined. Diet logs were collected and analyzed (one random day per week; four total days analyzed). RESULTS: 2x2 ANOVA results - There was a significant time effect for fat-free mass (FFM) (F = 19.9; p = 0.001) and BP (F = 18.9; p < 0.001), however, fat mass (FM) and body weight did not reach significance. While there were trends, no significant interactions were found. However, using magnitude-based inference, supplementation with creatine post workout is possibly more beneficial in comparison to pre workout supplementation with regards to FFM, FM and 1-RM BP. The mean change in the PRE SUPP and POST-SUPP groups for body weight (BW kg), FFM (kg), FM (kg) and 1-RM bench press (kg) were as follows, respectively: Mean +/- SD; BW: 0.4 +/- 2.2 vs. 0.8 +/- 0.9; FFM: 0.9 +/- 1.8 vs. 2.0 +/- 1.2; FM: -0.1 +/- 2.0 vs. -1.2 +/- 1.6; Bench Press 1-RM: 6.6 +/- 8.2 vs. 7.6 +/- 6.1. Qualitative inference represents the likelihood that the true value will have the observed magnitude. Furthermore, there were no differences in caloric or macronutrient intake between the groups. CONCLUSIONS: Creatine supplementation plus resistance exercise increases fat-free mass and strength. Based on the magnitude inferences it appears that consuming creatine immediately post-workout is superior to pre-workout vis a vis body composition and strength. PMID- 23919406 TI - Current status of the research and development of diacylglycerol O acyltransferase 1 (DGAT1) inhibitors. AB - Diacylglycerol O-acyltransferase 1 (DGAT1) has recently become a highly interesting target for metabolic disorders as well as for hepatitis C virus (HCV). DGAT1 processes diacylglycerol to triglycerides in the final step of resynthesis for the absorption of fat across the intestine. Pharmaceutical companies have developed many novel inhibitors of DGAT1, several of which have reached the clinic. Proof of target engagement was achieved with the observation of reduced triglycerides upon treatment of humans with DGAT1 inhibitors; however, there were gastrointestinal adverse events such as nausea, diarrhea, and vomiting. These adverse events have been reported with multiple compounds and are possibly linked to the target because of the recent identification of a human cohort deficient in DGAT1. Clinical studies are continuing in a trial to treat patients with an orphan indication for familial chylomicronemia. The full potential of DGAT1 as a therapeutic target will need to overcome observed clinical adverse events, which are possibly mechanism based. The widespread use of DGAT1 inhibitors will ultimately depend upon a better understanding of how to improve the GI tolerability of these agents. PMID- 23919407 TI - Technology as system innovation: a key informant interview study of the application of the diffusion of innovation model to telecare. AB - PURPOSE: To identify and explore factors that influence adoption, implementation and continued use of telecare technologies. METHOD: As part of the Assistive Technologies for Healthy Living in Elders: Needs Assessment by Ethnography (ATHENE) project, 16 semi-structured interviews were conducted with key participants from organisations involved in developing and providing telecare technologies and services. Data were analysed thematically, using a conceptual model of diffusion of innovations. RESULTS: Participants identified numerous interacting factors that facilitated or hindered adoption and use. As predicted by the model, these related variously to the technology, individual adopters, the process of social influence, the innovativeness and readiness of organisations, implementation and routinisation processes following initial adoption, and the nature and strength of linkages between these elements. Key issues included (i) the complexity and uniqueness of the "user system", (ii) the ongoing work needed to support telecare use beyond initial adoption, and (iii) the relatively weak links that typically exist between users of telecare technologies and the organisations who design and distribute them. CONCLUSIONS: Telecare is not merely a technology but a complex innovation requiring input from, and coordination between, people and organisations. To promote adoption and use, these contextual factors must be specified, understood and addressed. PMID- 23919408 TI - Proposal of a personal mobility vehicle capable of traversing rough terrain. AB - PURPOSE: Personal mobility vehicles (PMVs) are now being actively developed. Most PMVs are wheel-driven, a mode of transport notable for its efficiency. However, such vehicles tend to have little mobility over rough terrain. We propose a new type of PMV, a vehicle that traverses relatively smooth terrain by wheel but is capable of negotiating rough terrain by using its wheel mechanisms as legs. METHOD: The PMV we propose is intended to provide its user with a degree of outdoor mobility in daily urban life, say when going to a neighbourhood shop or simply taking a stroll. We do not consider elevators and other infrastructural elements that should be barrier-free, but rather focus on unimproved terrains that act as barriers to transport; for example, the steps that often act as de facto boundaries around building entrances. RESULTS: We developed a new type of PMV and implemented a new algorithm to realize the capability to move on rough terrain. We experimentally compared the capability of a commercially available PMV and the developed PMV. CONCLUSIONS: Through an experiment involving the traversing of a representative terrain and a comparative experiment using a stock PMV, we demonstrated the features of the proposed PMV. IMPLICATIONS FOR REHABILITATION: We developed a single-seat personal mobility vehicle, the RT Mover PType 3, which is capable of traversing steps and other unimproved terrain often found within an urban environment. RT-Mover PType 3 can handle oblique slopes and other terrain that can be quite difficult to negotiate with a conventional electric wheelchair, thus enabling individuals with impaired mobility to move freely about urban environments. The current vehicle is primarily intended for the active elderly and other individuals in fairly good health, although, through further research and development, we do hope to extend its usefulness to those with substantial mobility impairments. PMID- 23919409 TI - Cognitive support technologies for people with TBI: current usage and challenges experienced. AB - PURPOSE: We investigated the current use of off-the-shelf cognitive support technologies (CSTs) by individuals with traumatic brain injury (TBI), the challenges they and their caregivers face when using these technologies, the functional areas where support is needed, and their current experience in learning new technologies. METHOD: We conducted two focus groups with participants with TBI and their caregivers. Focus group interactions were captured using recordings and a court reporter. Transcripts were analyzed qualitatively. RESULTS: We identified three core themes - consumer and caregiver self-reported needs for support, how support is used on a daily basis and consumer and caregiver attitudes towards the use of support by types of support. We also inferred implications for design of CSTs. CONCLUSIONS: Individuals with TBI use consumer available technologies to support cognition. The design of most of these devices is not targeted to meet the needs of people with TBI, and they can be challenging to use independently, but individuals and their caregivers still benefit from their use by embedding technology as one type of support within a broader support network that includes personal assistance. IMPLICATIONS FOR REHABILITATION: People with traumatic brain injury (TBI) are attempting to use a wide range of consumer available technologies to support cognition, although not always successfully. One important role for rehabilitation providers could be helping people with TBI use these technologies with more accuracy and success. People with TBI note that an important element in adopting new technology is good training in its use. Cognitive support technologies (CSTs) are one part of broader network of supports. People with TBI and their caregivers desire independence but do not want to lose the human element that can be provided by a caregiver. New technologies should be implemented with an understanding of an individual's broader support network. Psychosocial aspects of TBI need to be considered when designing and implementing CSTs. In particular, rehabilitation providers need to address the anxiety that many people with TBI experience, including fear about forgetting and their need for early, repeated reminders so they can prepare for upcoming events. PMID- 23919411 TI - Status of ten self-etch adhesives for bonding to dentin of primary teeth. AB - OBJECTIVE: Aim of this in vitro study was to compare self-etch adhesives regarding microtensile bond strength (MU-TBS) to dentin of primary teeth. METHODS: Fifty freshly extracted primary molars were ground to expose caries-free dentin. Specimens were bonded with ten self-etch adhesives (iBond self etch/Heraeus, Xeno V+/Dentsply, G-Bond, Gaenial Bond/GC, BeautiBond/Shofu, AdheSE One F/Ivoclar Vivadent, Adper Easy Bond/3M ESPE, Clearfil SE Bond/Kuraray, OptiBond XTR/KerrHawe, Prime&Bond NT/Dentsply). After 24-h storage (distilled water, 37 degrees C), resin-dentin beams were cut and 848 resin-dentin sticks were subjected to MU-TBS tests. Fracture analysis was carried out at 40* magnification under a fluorescence microscope and under a SEM. RESULTS: Three adhesives (iBond SE, Clearfil SE Bond, Prime&Bond NT) did not suffer pre-test failures (PTF). AdheSE One F revealed the largest portion of PTF (28%; P < 0.05). Clearfil SE Bond and OptiBond XTR exhibited more cohesive fractures than the other adhesives (77.3% vs 64.8%; P < 0.05). iBond SE, Gaenial Bond, Clearfil SE, and OptiBond XTR achieved MU-TBS of >60 MPa, whereas Xeno V+ and AdheSE One F ranged only at ~20 MPa (P < 0.05). CONCLUSION: Within the limits of this study, the self-etch adhesives under investigation proved different extents of initial MU-TBS to primary dentin with iBond SE, Gaenial Bond, Clearfil SE, and OptiBond XTR having been most successful. PMID- 23919410 TI - Strongyloides stercoralis transmission by kidney transplantation in two recipients from a common donor. AB - Strongyloides stercoralis hyperinfection in an immunocompromised host has a high mortality rate but may initially present with nonspecific pulmonary and gastrointestinal symptoms. Donor-derived S. stercoralis by kidney transplantation is an uncommon diagnosis and difficult to prove. We report two renal allograft recipients on different immunosuppressive maintenance regimens that developed strongyloidiasis after transplantation from the same donor. Recipient 1 presented with a small bowel obstruction. Larvae were demonstrated on a duodenal biopsy and isolated from gastric, pulmonary, and stool samples. Serologic testing for S. stercoralis was negative at a referral laboratory but positive at the Centers for Disease Control. The patient's hospital course was complicated by a hyperinfection syndrome requiring subcutaneous ivermectin due to malabsorption. Recipient 1 survived but the allograft failed. Recipient 2 had larvae detected in stool samples after complaints of diarrhea and was treated. On retrospective testing for S. stercoralis, pretransplant serum collected from the donor and Recipient 1 was positive and negative, respectively. Donor-derived strongyloidiasis by renal transplantation is a preventable disease that may be affected by the immunosuppressive maintenance regimen. Subcutaneous ivermectin is an option in the setting of malabsorption. Finally, routine screening for S. stercoralis infection in donors from endemic areas may prevent future complications. PMID- 23919412 TI - Fibre post adaptation and bond strength in oval canals. AB - AIM: To evaluate ex vivo the bond strength and adaptation of fibre posts with oval and circular cross sections luted in oval canals with post spaces prepared using dedicated drills or ultrasonic tips. METHODOLOGY: Forty extracted premolars with oval canals were root filled, then randomly divided into four groups according to the post space preparation device and the shape of the luted fibre post: dedicated drill + round post, dedicated drill + oval post, ultrasonic tip + round post and ultrasonic tip + oval post. Posts were cemented with a self adhesive cement (RelyX Unicem 2; 3M ESPE). Samples were sectioned in 1-mm-thick slices and observed under a microscope, and the area occupied by the post within the post space area was calculated. Bond strength was then measured using a push out test, and the failure modes were evaluated with a stereomicroscope at 40* magnification. Fibre post adaptation and push-out test results were evaluated by analysis of variance (P < 0.05). RESULTS: Fibre posts, both round and oval, were better adapted to the apical region of the post space (P = 0.001). In oval canals, the bond strength was significantly higher in coronal regions, when the post space was prepared with a dedicated drill and an oval post was luted (P < 0.0001). Adhesive failures between cement and post were the most frequent type of failure in all groups. CONCLUSIONS: Circular and oval posts achieved similar adaptation to oval canals, but the use of ultrasonic tips and round posts resulted in reduced bond strength values. PMID- 23919413 TI - Concentrated arabinoxylan but not concentrated beta-glucan in wheat bread has similar effects on postprandial insulin as whole-grain rye in porto-arterial catheterized pigs. AB - The acute glycemic effects of concentrated dietary fibers (DF) versus whole-grain rye were studied in porto-arterial catheterized pigs. Two white wheat breads with wheat arabinoxylan (AX) or oat beta-glucan (BG), two rye breads with intact rye kernels (RK) or milled rye (GR), and a low DF white wheat bread were fed to six pigs in a randomized crossover design. Blood profiles were collected for 4 h after feeding. Glucose absorption was reduced in pigs fed the AX bread at 60 min postprandial (3.1 mmol/min for AX compared to 9.4 mmol/min for WF, P = 0.02) and insulin secretion was lowered at 30 min postprandial for AX and GR (74.4 and 129 pmol/min for AX and GR, respectively, compared to 738 pmol/min for WF, P < 0.04). In conclusion, the GR and AX breads were most effective in improving insulin economy, suggesting that arabinoxylan from wheat and rye induces similar outcomes in the metabolic response. PMID- 23919414 TI - Ovariectomy induces osteoporosis in the maxillary alveolar bone: an in vivo micro CT and histomorphometric analysis in rats. AB - OBJECTIVE: To investigate whether porotic changes occur in maxillary alveolar bone in ovariectomized rats. METHODS: Thirty-two 6-week-old female Sprague-Dawley rats were divided into an ovariectomy group (OVX) and a sham-ovariectomy group (sham). Twelve weeks after surgery, maxillae of 16 rats (eight OVX and eight sham) were analyzed by micro-CT. Inter-radicular alveolar bone of the maxillary first molar was reconstructed and analyzed. The remaining 16 maxillae were used for histochemistry, including hematoxylin-eosin staining and tartrate-resistant acid phosphatase enzyme staining. RESULTS: Three-dimensional reconstructed images of the irregular alveolar bone showed an intuitive view of porotic changes in the OVX group. The alveolar bone in OVX rats had a porous microarchitecture including lower bone mass and a looser structure of more widely separated trabeculae. Bone mineral density (BMD), bone volume fraction (BV/TV), and trabecular thickness (Tb.Th.) were significantly lower in the OVX group than those in the sham group (P < 0.05). Trabecular separation (Tb.Sp.) increased significantly in the OVX rats compared to the sham rats (P < 0.05). Histomorphometric analysis of alveolar bone also revealed porotic changes in the OVX rats. Bone area ratio significantly decreased in the OVX group compared with the sham group (P < 0.01). There were also more osteoclasts present in the alveolar bone of OVX rats compared to sham rats (P < 0.05). CONCLUSION: Ovariectomy induces osteoporosis in maxillary alveolar bone in rats, which may be related to the increased number of osteoclasts. PMID- 23919415 TI - Neurodegenerative changes initiated by presynaptic dysfunction. AB - alpha-Synucleinopathies are a subgroup of neurodegenerative diseases including dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Pathologically, these disorders can be characterized by the presence of intraneuronal aggregates composed mainly of alpha-synuclein (alphaSyn), which are called Lewy bodies and Lewy neurites. Recent report showed that more than 90% of alphaSyn aggregates are present in the form of very small deposits in presynaptic terminals of the affected neurons in DLB. However, the mechanisms responsible for presynaptic accumulation of abnormal alphaSyn remain unclear. In this article, we review recent findings on the involvement of presynaptic dysfunction in the initiation of neuronal dysfunctional changes. This review highlights that the presynaptic failure can be a potential trigger of the dying-back neuronal death in neurodegenerative diseases. PMID- 23919417 TI - Healthcare's "big data" challenge. PMID- 23919416 TI - Prevalence and diagnostic stability of ADHD and ODD in Turkish children: a 4-year longitudinal study. AB - BACKGROUND: This study was designed to assess the prevalence of Attention Deficit/Hyperactivity Disorder (ADHD) and Oppositional Defiant Disorder (ODD) in a representative sample of second grade students from a country in a region where no previous rates are available (Turkey). The second aim is to evaluate the differences in ADHD and ODD prevalence rates among four different waves with one year gap in reassessments. METHOD: Sixteen schools were randomly selected and stratified according to socioeconomic classes. The DSM-IV Disruptive Behavior Disorders Rating Scale (T-DSM-IV-S) was delivered to parents and teachers for screening in around 1500 children. Screen positive cases and matched controls were extensively assessed using the K-SADS-PL and a scale to assess impairment criterion. The sample was reassessed in the second, third and fourth waves with the same methodology. RESULTS: The prevalence rates of ADHD in the four waves were respectively 13.38%, 12.53%, 12.22% and 12.91%. The ODD prevalence was found to be 3.77% in the first wave, 0.96% in the second, 5.41% in the third and 5.35% in the fourth wave. Mean ODD prevalence was found to be 3.87%. CONCLUSIONS: The prevalence rates of ADHD in the four waves were remarkably higher than the worldwide pooled childhood prevalence. ADHD diagnosis was quite stable in reassessments after one, two and three years. A mean ODD prevalence consistent with the worldwide-pooled prevalence was found; but diagnostic stability was much lower compared to ADHD. PMID- 23919418 TI - Previously unrecognized trends in diabetes consumption clusters in medicare. AB - OBJECTIVE: To examine the annual cost profiles of Medicare beneficiaries with diabetes to identify patterns in their consumption of benefits. METHODS: Retrospective expenditure data were collected from Medicare records. Beneficiaries with diabetes were grouped into 5 consumption clusters ranging from "crisis consumers" at the high end to "low consumers" at the low end. RESULTS: The percentages of beneficiaries and expenditures for the consumption clusters remained generally constant from year to year. As expected, most of Medicare's budget each year was spent on crisis, heavy, and moderate consumers. However, a notable proportion of low and light consumers from one year go on to become crisis and heavy consumers in subsequent years. A review of total 2001 through 2006 inpatient costs for the year 2000 clusters revealed that 47% of these costs were for year 2000 low and light consumers and only 27% were for year 2000 crisis and heavy consumers. CONCLUSIONS: This analysis revealed previously unrecognized trends, whereby a notable proportion of low and light consumers during one year went on to become crisis and heavy consumers in subsequent years, representing a large proportion of inpatient costs. These findings have important implications for disease management programs, which typically focus intervention efforts exclusively on crisis and heavy consumers. PMID- 23919419 TI - Healthcare system effects of pay-for-performance for smoking status documentation. AB - OBJECTIVES: To evaluate the impact on smoking status documentation of a payer sponsored pay-for-performance (P4P) incentive that targeted a minority of an integrated healthcare delivery system's patients. STUDY DESIGN: Three commercial insurers simultaneously adopted P4P incentives to document smoking status of their members with 3 chronic diseases. The healthcare system responded by adding a smoking status reminder to all patients' electronic health records (EHRs). We measured change in smoking status documentation before (2008-2009) and after (2010-2011) P4P implementation by patient P4P eligibility. METHODS: The P4P eligible patients were compared primarily with a subset of non-P4P-eligible patients who resembled P4P-eligible patients and also with all non-P4P-eligible patients. Multivariate models adjusted for patient and provider characteristics and accounted for provider-level clustering and preimplementation trends. RESULTS: Documentation increased from 48% of 207,471 patients before P4P to 71% of 227,574 patients after P4P. Improvement from 56% to 83% occurred among P4P eligible patients (adjusted odds ratio [AOR], 3.6; 95% confidence interval [CI], 2.9-4.5) and from 56% to 80% among the comparable subset of non-P4P-eligible patients (AOR, 3.0; 95% CI, 2.3-3.9). The difference in improvement between groups was significant (AOR, 1.3; 95% CI, 1.1-1.4; P = .009). CONCLUSIONS: A P4P incentive targeting a minority of a healthcare system's patients stimulated adoption of a system wide EHR reminder and improved smoking status documentation overall. Combining a P4P incentive with an EHR reminder might help healthcare systems improve treatment delivery for smokers and meet "meaningful use" standards for EHRs. PMID- 23919420 TI - Change in claims-based diabetes medications is a diabetes improvement indicator. AB - BACKGROUND: Because laboratory test results are less available to researchers than claims data, a claims-based indicator of diabetes improvement would be valuable. OBJECTIVES: To determine whether a decrease in medication use for diabetes parallels clinical improvement in glycemic control. STUDY DESIGN: This was a retrospective cohort study using up to 3.5 years of pharmacy and laboratory data from 1 private insurer. Data included 104 patients with diabetes who underwent bariatric surgery and had at least 1 glycated hemoglobin (A1C) test before and after surgery. METHODS: We assigned each A1C test to a 90-day interval before or after surgery. Medication availability was noted for the midpoint of the interval (on insulin, on oral medications, count of medications). Each subject could contribute 1 presurgery and up to 3 postsurgery observations. We recorded the changes in A1C test results and medication use from the presurgery to the postsurgery period. Using the A1C test as the reference standard, positive and negative predictive values of medication-based indicators were calculated. RESULTS: After bariatric surgery, A1C test values decreased by more than 1% and the count of unique medications decreased by 0.6. All 3 medication-based indicators had high positive predictive values (0.85) and low negative predictive values (0.20), and count of medications had better performance than the other indicators. CONCLUSIONS: Without clinical information, a decrease in use of medications can serve as a proxy for clinical improvement. Validation of results in other settings is needed. PMID- 23919421 TI - Risk bearing and use of fee-for-service billing among accountable care organizations. AB - OBJECTIVES: To determine the willingness of accountable care organizations (ACOs) to bear financial risk for the healthcare they provide. DESIGN AND METHODS: Structured interviews conducted between January and June 2012 with 57 ACOs led by hospitals and physician groups located throughout the United States. Findings are based on the 38 ACOs that were actively providing care under an ACO payment arrangement at the time of the interview. RESULTS: Among these ACOs, 71% cover a portion of their ACO population with contracts that put the ACOs at some financial risk, while 45% have risk-based contracts for their entire ACO population. Payments based on fee-for-service (FFS) billing still dominate, as 92% of ACOs use FFS-based billing for at least a portion of their ACO population and 71% are fully reimbursed using FFS-based billing. CONCLUSIONS: Under the auspices of an ACO, providers are accepting some financial risk for their accountable care patient population. There is still strong reliance on FFS-based billing methods as providers experiment with different payment models. PMID- 23919422 TI - Encouraging value-based insurance designs in state health insurance exchanges. AB - OBJECTIVES: One of the main goals of the Affordable Care Act (ACA) is to control the costs of US healthcare. Channeling patients toward more effective services is one of many approaches being used to control costs while improving health outcomes. This paper reviews value-based insurance design (VBID) concepts and discusses options for states to encourage these designs in the new health insurance exchanges (HIEs). METHODS: We reviewed the literature on VBID as well as the text of the ACA for descriptions of how VBID might be encouraged through the new state health insurance exchanges. RESULTS: States, under healthcare reform, are allowed to promote the use of VBID designs in their exchanges. There are 4 broad approaches a state HIE could pursue with regard to VBID, ranging from establishing a process for recommending high- or low-value services and requiring plans to adhere to the recommendations, to offering no guidance to plans. The evidence surrounding how well VBID designs work is growing, but it is still limited. To date there is no evidence that reducing or eliminating copays for preventive services cuts costs in the long term. However, modeling does suggest the potential for such long-term savings,so states should proceed with caution. CONCLUSIONS: Modifying copays, even in small amounts, can send signals to patients about the relative value of drugs and services. However, long-term savings will likely result from higher copays on low-value services. The leadership of each exchange has a unique opportunity to reshape the insurance benefit landscape in its state to improve value and invest in prevention. PMID- 23919423 TI - Analysis of EGFR, EML4-ALK, KRAS, and c-MET mutations in Chinese lung adenocarcinoma patients. AB - INTRODUCTION: Mutation analysis of cancer driver genes is helpful for determining an optimal treatment strategy. We evaluated mutations in four driver genes, namely epidermal growth factor receptor (EGFR), Kirsten ras oncogene (KRAS), c MET, and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), in Chinese lung adenocarcinoma patients from Hunan Province. METHODS: We enrolled 110 lung adenocarcinoma patients in a single institution. EGFR and KRAS mutations were examined by direct sequencing, the EML4-ALK fusion gene was analyzed by fluorescence in situ hybridization, and c-MET amplification and c-Met protein expression were detected by quantitative PCR and immunohistochemistry, respectively. RESULTS: EGFR and KRAS mutations were observed in 52.7% (58/110) and 3.6% (4/106) of patients, respectively. c-MET amplification was detected in 5.5% (6/110) of patients. In addition, 30% (33/110) of the cases expressed c-Met protein, including all of the patients harboring c MET amplification. Ten percent (11/110) of patients harbored the EML4-ALK fusion gene, and the frequency of ALK rearrangement was higher than that of other cohort analyses involving patients from other regions in China. Almost all of these gene mutations were exclusive except that in two female non-smoking patients, who harbored an EGFR mutation and EML4-ALK rearrangement simultaneously. In total, 70% of patients in the study harbored one of the four gene mutations. CONCLUSIONS: Most Chinese lung adenocarcinoma patients harbor driver gene mutations, among which ALK rearrangements were more common in Hunan patients than in previously reported populations. Future clinical trials should be conducted to determine the safety and efficacy of drug combination targeting different driver mutations. PMID- 23919424 TI - Correlative assessment of fecal indicators using human mitochondrial DNA as a direct marker. AB - Identifying the source of surface water fecal contamination is paramount to mitigating pollution and risk to human health. Fecal bacteria such as E. coli have been staple indicator organisms for over a century, however there remains uncertainty with E. coli-based metrics since these bacteria are abundant in the environment. The relationships between the presence of direct indicator of human waste (human mitochondrial DNA), human-specific Bacteroidales, and E. coli were studied for water samples taken from an urban creek system (Duck Creek Watershed, Cincinnati, OH) impacted by combined sewer overflows. Logistic regression analysis shows that human-specific Bacteroidales correlates much more closely to human mitochondrial DNA (R = 0.62) relative to E. coli (R = 0.33). We also examine the speciation of Bacteroidales within the Duck Creek Watershed using next-generation sequencing technology (Ion Torrent) and show the most numerous populations to be associated with sewage. Here we demonstrate that human-specific Bacteroidales closely follow the dynamics of human mitochondrial DNA concentration changes, indicating that these obligate anaerobes are more accurate than E. coli for fecal source tracking, lending further support to risk overestimation using coliforms, especially fecal coliforms and E. coli. PMID- 23919425 TI - DNA barcoding of bark and ambrosia beetles reveals excessive NUMTs and consistent east-west divergence across Palearctic forests. AB - A comprehensive DNA barcoding library is very useful for rapid identification and detection of invasive pest species. We tested the performance of species identification in the economically most damaging group of wood-boring insects - the bark and ambrosia beetles - with particular focus on broad geographical sampling across the boreal Palearctic forests. Neighbour-joining and Bayesian analyses of cytochrome oxidase I (COI) sequences from 151 species in 40 genera revealed high congruence between morphology-based identification and sequence clusters. Inconsistencies with morphological identifications included the discovery of a likely cryptic Nearctic species of Dryocoetes autographus, the possible hybrid origin of shared mitochondrial haplotypes in Pityophthorus micrographus and P. pityographus, and a possible paraphyletic Xyleborinus saxeseni. The first record of Orthotomicus suturalis in North America was confirmed by DNA barcoding. The mitochondrial data also revealed consistent divergence across the Palearctic or Holarctic, confirmed in part by data from the large ribosomal subunit (28S). Some populations had considerable variation in the mitochondrial barcoding marker, but were invariant in the nuclear ribosomal marker. These findings must be viewed in light of the high number of nuclear insertions of mitochondrial DNA (NUMTs) detected in eight bark beetle species, suggesting the possible presence of additional cryptic NUMTs. The occurrence of paralogous COI copies, hybridization or cryptic speciation demands a stronger focus on data quality assessment in the construction of DNA barcoding databases. PMID- 23919427 TI - Multiple exosites distributed across the three domains of streptokinase co operate to generate high catalytic rates in the streptokinase-plasmin activator complex. AB - To examine the global function of the key surface-exposed loops of streptokinase, bearing substrate-specific exosites, namely, the 88-97 loop in the alpha domain, the 170 loop in the beta domain, and the coiled-coil region (Leu321-Asn338) in the gamma domain, mutagenic as well as peptide inhibition studies were carried out. Peptides corresponded to the primary structure of an exosite, either individual or stoichiometric mixtures of various disulfide-constrained synthetic peptide(s) inhibited plasminogen activation by streptokinase. Remarkably, pronounced inhibition of substrate plasminogen activation by the preformed streptokinase-plasmin activator complex was observed when complementary mixtures of different peptides were used compared to the same overall concentrations of individual peptides, suggesting co-operative interactions between the exosites. This observation was confirmed with streptokinase variants mutated at one, two, or three sites simultaneously. The single/double/triple exosite mutants of streptokinase showed a nonadditive, synergistic decline in kcat for substrate plasminogen activation in the order single > double > triple exosite mutant. Under the same conditions, zymogen activation by the various mutants remained essentially native- like in terms of nonproteolytic activation of partner plasminogen. Multisite mutants also retain affinity to form 1:1 stoichiometric activator complexes with plasmin when probed through sensitive equilibrium fluorescence studies. Thus, the present results strongly support a model of streptokinase action, wherein catalysis by the streptokinase-plasmin complex operates through a distributed network of substrate-interacting exosites resident across all three domains of the cofactor protein. PMID- 23919428 TI - The determinants of successful RF ablation - is measurement of tissue contact the next step? AB - The assessment of tissue contact is an area undergoing much research as a means of improving the outcomes of cardiac radiofrequency ablation. This review provides an overview of RF ablation with specific reference to the relevance of good tissue contact to adequate RF lesion formation. An up-to-date review of the clinical evidence is provided, and recent patents of novel contact-sensing technologies in the field of cardiac RF ablation are presented. PMID- 23919426 TI - Qingfei Xiaoyan Wan alleviates asthma through multi-target network regulation. AB - BACKGROUND: Qingfei Xiaoyan Wan (QFXY), a traditional Chinese formula, is widely used for relieving cough, asthma, upper respiratory tract infection, bronchitis, pneumonia, and etc. in clinic. Comparing with other anti-asthma drugs, it is characterised with moderate and persistent efficacy as well as few side effects, however, the underlying action mechanism still remains elusive. This study aimed to identify QFXY multi-target network regulation as an asthma controller. METHODS: This study established asthma model induced by histamine phosphate and acetylcholine chloride (His&Ach) in guinea pigs, which then were administered orally with QFXY. Hematoxylin-Eosin staining sections were applied for evaluating QFXY effect. In both Model and QFXY groups, customized microarrays and 2D electrophoresis were adopted to detect differentially expressed genes (diff genes) and proteins (diff proteins) respectively, and some diff proteins were identified with MALDI-TOF/MS. The checked diff genes and proteins underwent Cluster, GO and KEGG analysis. Based on GAD and HPRD databases, QFXY-asthma target regulation network was constructed. RESULTS: His&Ach-induced asthma model of guinea pigs was established. HE sections presented anti-inflammation and anti remodelling effects of QFXY. Comparing with the Model group, 55 diff genes and 6 diff proteins were identified in QFXY group. Validation by qPCR and Western blot showed the microarray and 2D data reliable. Furthermore, QFXY-asthma target regulation network was achieved. CONCLUSIONS: A primarily combined genomic and proteomic screening of QFXY targets displayed a series of candidate genes and proteins, which indicated that the effect of QFXY relied on the combined mechanism, anti-inflammation and anti-remodelling, as well as influencing signal transduction in vivo. PMID- 23919429 TI - Patents and heart valve surgery - II: tissue valves. AB - Valvular heart disease affects millions of Americans yearly and currently requires surgical intervention to repair or replace the defective valves. Through a close-knit collaboration between physicians, scientists and biomedical engineers, a vast degree of research and development has been aimed towards the optimization of prosthetic heart valves. Although various methods have made fantastic strides in producing durable prostheses, the therapeutic efficacy of prosthetic valves is inherently limited by a dependency upon lifelong anticoagulant regimens for recipients - a difficult challenge for many in clinical setting. Thus, biological tissue valves have been developed to circumvent vascular and immunemediated complications by incorporating biological materials to mimic native valves while still maintaining a necessary level of structural integrity. Over the past decade, a multitude of patents pertaining to the refinement of designs as well as the advancement in methodologies and technologies associated with biological tissue valves have been issued. This review seeks to chronicle and characterize such patents in an effort to track the past, present, and future progress as well as project the trajectory of tissue valves in the years to come. PMID- 23919430 TI - Does a yellow filter improve visual object categorization in normal aging? AB - Previous studies have shown that a yellow filter (CPF450) can increase contrast, motion sensitivity, vergence, and accommodation. We investigated whether a yellow filter can reduce age-related visual deficits. We tested two groups of 60 observers (mean age 24 vs. 72) in an object categorization task. Grayscale photographs of natural objects and artifacts were displayed either centrally or peripherally (21 degrees ) at low (8%) or medium (30%) contrast. There were three filter conditions (no filter, placebo filter, and yellow filter). Both groups of observers performed similarly on central and medium-contrast pictures. The deleterious effects of reduced contrast and eccentricity were stronger in elderly individuals. Moreover, the yellow filter globally improved the speed of categorization for the elderly participants. The decrease in response time in the yellow filter condition was larger when the stimuli were displayed peripherally in both groups. A yellow filter should be considered as a potential means for visual improvement in normal aging. PMID- 23919431 TI - The use of near-infrared photography to image fired bullets and cartridge cases. AB - An imaging technique that is capable of reducing glare, reflection, and shadows can greatly assist the process of toolmarks comparison. In this work, a camera with near-infrared (near-IR) photographic capabilities was fitted with an IR filter, mounted to a stereomicroscope, and used to capture images of toolmarks on fired bullets and cartridge cases. Fluorescent, white light-emitting diode (LED), and halogen light sources were compared for use with the camera. Test-fired bullets and cartridge cases from different makes and models of firearms were photographed under either near-IR or visible light. With visual comparisons, near IR images and visible light images were comparable. The use of near-IR photography did not reveal more details and could not effectively eliminate reflections and glare associated with visible light photography. Near-IR photography showed little advantages in manual examination of fired evidence when it was compared with visible light (regular) photography. PMID- 23919432 TI - Efficacy of subtenon block in infants - a comparison with intravenous fentanyl for perioperative analgesia in infantile cataract surgery. AB - BACKGROUND: General anesthesia with opioids provides good perioperative analgesia in infantile ocular surgeries but is associated with the risk of respiratory depression and postoperative emesis. This study aimed to assess the effectiveness of subtenon block for providing perioperative analgesia in infants undergoing cataract surgeries. METHODS: In this prospective, randomized, controlled, double blinded trial, 63 infants of ASA grade I and II (1-12 months) were recruited to receive either subtenon block (Group SB) or 1 MUg.kg(-1) i.v. fentanyl (Group F) after induction of anesthesia. Primary outcome was the number of infants requiring rescue analgesia during 4-h study period before discharge of the infants. Secondary outcomes assessed were CRIES pain score, incidence of oculocardiac reflex, surgical difficulty, and incidence of postoperative emesis. RESULTS: The number of infants requiring rescue analgesia during 4-h study period was significantly less in Group SB (n = 6/32, 18.8%) compared to Group F (n = 14/31, 45.2%, P = 0.032). CRIES scores were significantly lower at and after 40 min compared to immediate postoperative period in Group F while these were comparable at all time intervals in Group SB. CRIES scores were significantly lower in Group SB compared to Group F at all time intervals except at 1 h. The incidence of oculocardiac reflex and the postoperative emesis were comparable in both the groups. CONCLUSION: Subtenon block is an effective superior technique for postoperative analgesia compared to intravenous fentanyl in infants undergoing cataract surgery. PMID- 23919433 TI - Active and passive maternal smoking during pregnancy and birth outcomes: the Kyushu Okinawa maternal and child health study. AB - BACKGROUND: In Western countries, active maternal smoking during pregnancy is recognized as the most important preventable risk factor for adverse birth outcomes. However, the effect of passive maternal smoking is less clear and has not been extensively studied. In Japan, there has been only one epidemiological study which examined the effects of active smoking during early pregnancy on birth outcomes although the effects of passive smoking were not assessed. METHODS: Study subjects were 1565 mothers with singleton pregnancies and the babies born from these pregnancies. Data on active maternal smoking status in the first, second, and third trimesters and maternal environmental tobacco smoke (ETS) exposure at home and work were collected with self-administered questionnaires. RESULTS: Compared with children born to mothers who had never smoked during pregnancy, children born to mothers who had smoked throughout their pregnancy had a significantly increased risk of small-for-gestational-age (SGA) (adjusted odd ratio [OR] = 2.87; 95% confidence interval: 1.11 - 6.56). However, active maternal smoking only in the first trimester and active maternal smoking in the second and/or third trimesters but not throughout pregnancy were not significantly associated with SGA. With regard to the risk of preterm birth, the adjusted ORs for the above-mentioned three categories were not significant; however, the positive linear trend was significant (P for trend = 0.048). No significant association was found between active maternal smoking during pregnancy and the risk of low birth weight. There was a significant inverse relationship between active maternal smoking during pregnancy and birth weight; newborns of mothers who had smoked throughout pregnancy had an adjusted mean birth weight reduction of 169.6 g. When classifying babies by gender, a significant positive association between active maternal smoking throughout pregnancy and the risk of SGA was found only in male newborns, however, the interaction was not significant. Maternal ETS exposure at home or work was not significantly associated with any birth outcomes. CONCLUSIONS: This is the first study in Japan to show that active maternal smoking throughout pregnancy, but not during the first trimester, is significantly associated with an increased risk of SGA and a decrease in birth weight. Thus, women who smoke should quit smoking as soon as possible after conception. PMID- 23919434 TI - Agricultural soil and drilosphere as reservoirs of new and unusual assimilators of 2,4-dichlorophenol carbon. AB - 2,4-Dichlorophenol (2,4-DCP) is a potential soil and groundwater contaminant. Earthworms modulate growth and activities of soil microbiota. Thus, active 2,4 DCP degraders in agricultural soil and drilosphere (i.e. burrow walls, gut content and cast) were identified by comparative amplicon pyrosequencing-based 16S rRNA stable isotope probing in soil columns. In situ relevant concentrations of [U-(13) C]2,4-DCP were consumed in soil within 19 and 41 days in the presence and absence of the endogeic earthworm Aporrectodea caliginosa, respectively. [U (14) C]2,4-DCP mineralization was higher in cast, burrow wall and soil from columns with than without earthworms. [U-(14) C]2,4-DCP mineralization was lowest in gut contents. Data indicated a strong impact of earthworms on the active microbial community. Novosphingobium, Comamonas and Desulfitobacterium sp. assimilated 2,4-DCP-[(13)C] in the absence of earthworms. Pseudomonas, Flavobacterium and Clostridium sp. assimilated 2,4-DCP-[(13)C] in the drilosphere. Novosphingobium- and Variovorax-related taxa dominated [U-(13)C]2,4 DCP consumers in soil slurries with drilosphere and bulk soil material. 16S rRNA sequences suggested species level novelty. The collective data demonstrates that new Bacteroidetes and Alphaproteobacteria/Betaproteobacteria were involved in 2,4 DCP-C transformation and indicated that diverse and hitherto unknown microbes associated with carbon flow from 2,4-DCP are shaped by earthworms. PMID- 23919435 TI - Feasibility and Efficacy of an Addiction Treatment Program in Patients With Upper Aerodigestive Tract Cancer. AB - Background: Continuing to smoke or to drink after the treatment of an upper aerodigestive tract (UADT) cancer is known to worsen the prognosis. We assessed the feasibility and efficacy of an addiction treatment program integrated into the cancer treatment. Method: In four units devoted to UADT tumors, we proposed an addiction treatment to all patients still drinking or smoking at the end of the cancer treatment; the abstinence rate was assessed 6 and 12 months later. Results: One hundred and sixteen patients were included. Among the 73 patients still drinking and/or smoking at the end of the cancer treatment, 46.6% accepted an addiction treatment. In the latter, abstinence rate was increased, 52.2% versus 31.03% ( p = .07) at M12. In patients both drinking and smoking, addiction treatment doubled the rate of abstinence of both products (31% vs. 14%). Conclusion: Offering addiction treatment to patients with UADT cancer improves abstinence rate and helps maintain long-term withdrawal. PMID- 23919436 TI - Push-out bond strength of MTA with antiwashout gel or resins. AB - AIM: Assessment of the push-out bond strength of four MTA-based formulations for use as root-end filling materials. METHODOLOGY: MTA Plus mixed with (i) water ('MTA-W'); (ii) a proprietary water-based antiwashout gel ('MTA-AW'); (iii) Superbond C&B chemically curing resin ('MTA-Chem'); and (iv) Heliobond light curing resin ('MTA-Light') was tested. Root slices 3 mm thick human had a 1.5 mm diameter hole drilled centrally and were treated with 17% EDTA for 60s. Forty specimens divided into groups 1-4 were prepared and filled with MTA-W, MTA-AW, MTA-Chem and MTA-Light, respectively. Groups 3 and 4 were etched with 37% phosphoric acid for 60s, and bonding agent was applied to the dentine surface. Specimens were stored for 28 days in Hanks' Balanced Salt Solution at 37 degrees C. Push-out strength was tested with a punch and die (punch diameter 1.3 mm, die diameter 2.0 mm, punch speed 1 mm min(-1)). Stereomicroscopy was used to classify failure mode (adhesive, cohesive or mixed type). RESULTS: The resulting push-out strengths were 5.1 MPa (MTA-W), 4.3 MPa (MTA-AW), 4.7 MPa (MTA-Chem) and 11.0 MPa (MTA-Light). MTA-W had higher push-out strength than MTA-AW (P = 0.022). The same was noted for MTA-Light relative to the other materials (P < 0.05). All materials exhibited adequate push-out strengths compared with MTA-W. Failure was predominantly mixed, except for MTA-Chem (predominantly adhesive). CONCLUSIONS: All materials exhibited adequate push-out strength. Previous studies have shown the new formulations have additional advantages including increased washout resistance and faster setting time, making them promising for future dental applications. PMID- 23919438 TI - Identification, characterization and analysis of expression of genes encoding arylalkylamine N-acetyltransferases in the pea aphid Acyrthosiphon pisum. AB - Most organisms exhibit some kind of rhythmicity in their behaviour and/or physiology as an adaptation to the cyclical movements of the Earth. In addition to circadian rhythms, many organisms have an annual rhythmicity in certain activities, such as reproduction, migration or induction of diapause. Current knowledge of the molecular basis controlling seasonal rhythmicity, especially in insects, is scarce. One element that seems to play an essential role in the maintenance of both circadian and seasonal rhythms in vertebrates is the hormone melatonin. In vertebrates, the limiting enzyme in its synthesis is the arylalkylamine N-acetyltransferase (AANAT). Melatonin is also present in insects but the precise biochemical pathway and the enzymes involved in its synthesis are unknown. Insects possess phylogenetically distant arylalkylamine N acetyltransferases but their involvement in melatonin synthesis still needs to be fully demonstrated. Aphids have a seasonally rhythmical life cycle, reproducing parthenogenetically by viviparity in favourable seasons but, in unfavourable seasons, they produce a single generation of sexual individuals. The length of the photoperiod is the main environmental factor that controls the mode of reproduction in aphids. Taking advantage of the availability of the genome of the aphid Acyrthosiphon pisum, we searched for genes encoding aphid arylalkylamine N acetyltransferase homologues that could be candidates for participation in seasonal rhythmicity. We identified four AANAT genes, of which at least two (Ap AANAT1 and Ap-AANAT3) showed highly significant variation in transcription levels depending on the photoperiod conditions. These results are discussed in the context of how seasonality can be controlled in aphids. PMID- 23919437 TI - Polyreactive antibodies developing amidst humoral rejection of human kidney grafts bind apoptotic cells and activate complement. AB - Antibody mediated rejection (AMR) is associated with a variety of graft-reactive antibodies following kidney transplant. To characterize these antibodies, we immortalized 107 B cell clones from a patient with AMR. In a previous study, we showed that six clones were reacting to multiple self-antigens as well as to HLA and MICA for two of them, thus displaying a pattern of polyreactivity. We show here that all six polyreactive clones also reacted to apoptotic but not viable cells. More generally we observed a nearly perfect overlap between polyreactivity and reactivity to apoptotic cells. Functionally, polyreactive antibodies can activate complement, resulting in the deposition of C3d and C4d at the surface of target cells. Testing the serum of 88 kidney transplant recipients revealed a significantly higher IgG reactivity to apoptotic cells in AMR patients than in patients with stable graft function. Moreover, total IgG purified from AMR patients had increased complement activating properties compared to IgG from non AMR patients. Overall, our studies show the development of polyreactive antibodies cross-reactive to apoptotic cells during AMR. Further studies are now warranted to determine their contribution to the detection of C4d in graft biopsies as well as their role in the pathophysiology of AMR. PMID- 23919439 TI - Relationship of pulmonary function response to ozone exposure and capsaicin cough sensitivity. AB - CONTEXT: Challenge studies in humans have shown considerable interindividual variability in pulmonary impairment across ozone exposure. OBJECTIVE: Since previous results suggested effect modulation by neural mechanism, we investigated sensory C-fiber reactivity in relationship to ozone-triggered response pattern. METHODS: Cough reflex thresholds reflecting C-fiber sensitivity were evaluated by capsaicin single breath dose-response method. Capsaicin concentrations triggering, respectively, two and five or more coughs (C2, C5) were recorded. Sixteen healthy subjects were randomly exposed in an intermittent exercise protocol to ozone concentrations of 240 and 40 ppb (sham exposure). Ozone responsiveness was defined by a decrease in forced expiratory volume in 1 s (FEV(1)) of more than 5%. RESULTS: Based on a dichotomous classification, subjects with enhanced reactivity to ozone had lower cough thresholds than non responders (C2, p = 0.035; C5, p = 0.086). Over all, we could demonstrate relationships between capsaicin sensitivity and ozone-triggered changes in FEV(1), peak expiratory flow and maximal expiratory flow at 50% vital capacity but not in specific airway resistance. CONCLUSION: Our results suggest that capsaicin challenge tests might be useful to characterize subjects with enhanced pulmonary function response towards inhalant irritants. PMID- 23919440 TI - Comment on "Regional particle size dependent deposition of inhaled aerosols in rats and mice" by Kuehl et al. PMID- 23919442 TI - Nanoscale crystal imperfection-induced characterization changes of manganite nanolayers with various crystallographic textures. AB - (La,Sr)MnO3 (LSMO) nanolayers with various crystallographic textures were grown on the sapphire substrate with and without In2O3 epitaxial buffering. The LSMO nanolayer with In2O3 epitaxial buffering has a (110) preferred orientation. However, the nanolayer without buffering shows a highly (100)-oriented texture. Detailed microstructure analyses show that the LSMO nanolayer with In2O3 epitaxial buffering has a high degree of nanoscale disordered regions (such as subgrain boundaries and incoherent heterointerfaces) in the film. These structural inhomogeneities caused a low degree of ferromagnetic ordering in LSMO with In2O3 epitaxial buffering, which leads to a lower saturation magnetization value and Curie temperature, and higher coercivity and resistivity. PMID- 23919441 TI - The effect of acute exposure to coarse particulate matter air pollution in a rural location on circulating endothelial progenitor cells: results from a randomized controlled study. AB - CONTEXT: Fine particulate matter (PM) air pollution has been associated with alterations in circulating endothelial progenitor cell (EPC) levels, which may be one mechanism whereby exposures promote cardiovascular diseases. However, the impact of coarse PM on EPCs is unknown. OBJECTIVE: We aimed to determine the effect of acute exposure to coarse concentrated ambient particles (CAP) on circulating EPC levels. METHODS: Thirty-two adults (25.9 +/- 6.6 years) were exposed to coarse CAP (76.2 +/- 51.5 MUg m(-3)) in a rural location and filtered air (FA) for 2 h in a randomized double-blind crossover study. Peripheral venous blood was collected 2 and 20 h post-exposures for circulating EPC (n = 21), white blood cell (n = 24) and vascular endothelial growth factor (VEGF) (n = 16-19) levels. The changes between exposures were compared by matched Wilcoxon signed rank tests. RESULTS: Circulating EPC levels were elevated 2 [108.29 (6.24-249.71) EPC mL(-1); median (25th-75th percentiles), p = 0.052] and 20 h [106.86 (52.91 278.35) EPC mL(-1), p = 0.008] post-CAP exposure compared to the same time points following FA [38.47 (0.00-84.83) and 50.16 (0.00-104.79) EPC mL(-1)]. VEGF and white blood cell (WBC) levels did not differ between exposures. CONCLUSIONS: Brief inhalation of coarse PM from a rural location elicited an increase in EPCs that persisted for at least 20 h. The underlying mechanism responsible may reflect a systemic reaction to an acute "endothelial injury" and/or a circulating EPC response to sympathetic nervous system activation. PMID- 23919444 TI - Budget impact analysis of 8 hormonal contraceptive options. AB - OBJECTIVES: To develop a model comparing costs of 8 hormonal contraceptives and determine whether acquisition costs for implants and intrauterine devices (IUDs) were offset by decreased pregnancy-related costs over a 3-year time horizon from a managed care perspective. STUDY DESIGN: A model was developed to assess the budget impact of branded or generic oral contraceptives (OCs), quarterly intramuscular depot medroxyprogesterone, etonogestrel/ethinyl estradiol vaginal ring, etonogestrel implant, levonorgestrel IUD, norelgestromin/ethinyl estradiol transdermal contraceptive, and ethinyl estradiol/levonorgestrel extended-cycle OC. METHODS: Major variables included drug costs, typical use failure rates, discontinuation rates, and pregnancy costs. The base case assessed costs for 1000 women initiating each of the hormonal contraceptives. RESULTS: The etonogestrel implant and levonorgestrel IUD resulted in the fewest pregnancies, 63 and 85, respectively, and the least cost, $1.75 million and $2.0 million, respectively. In comparison, generic OC users accounted for a total of 243 pregnancies and $3.4 million in costs. At the end of year 1, costs for the etonogestrel implant ($800,471) and levonorgestrel IUD ($949,721) were already lower than those for generic OCs ($1,146,890). Sensitivity analysis showed that the cost of pregnancies, not product acquisition cost, was the primary cost driver. CONCLUSIONS: Higher initial acquisition costs for the etonogestrel implant and levonorgestrel IUD were offset within 1 year by lower contraceptive failure rates and consequent pregnancy costs. Thus, after accounting for typical use failure rates of contraceptive products, the etonogestrel implant and levonorgestrel IUD emerged as the least expensive hormonal contraceptives. PMID- 23919443 TI - Nicotine is more addictive, not more cognitively therapeutic in a neurodevelopmental model of schizophrenia produced by neonatal ventral hippocampal lesions. AB - Nicotine dependence is the leading cause of death in the United States. However, research on high rates of nicotine use in mental illness has primarily explained this co-morbidity as reflecting nicotine's therapeutic benefits, especially for cognitive symptoms, equating smoking with 'self-medication'. We used a leading neurodevelopmental model of mental illness in rats to prospectively test the alternative possibility that nicotine dependence pervades mental illness because nicotine is simply more addictive in mentally ill brains that involve developmental hippocampal dysfunction. Neonatal ventral hippocampal lesions (NVHL) have previously been demonstrated to produce post-adolescent-onset, pharmacological, neurobiological and cognitive-deficit features of schizophrenia. Here, we show that NVHLs increase adult nicotine self-administration, potentiating acquisition-intake, total nicotine consumed and drug seeking. Behavioral sensitization to nicotine in adolescence prior to self-administration is not accentuated by NVHLs in contrast to increased nicotine self-administration and behavioral sensitization documented in adult NVHL rats, suggesting periadolescent neurodevelopmental onset of nicotine addiction vulnerability in the NVHL model. Delivering a nicotine regimen approximating the exposure used in the sensitization and self-administration experiments (i.e. as a treatment) to adult rats did not specifically reverse NVHL-induced cortical-hippocampal dependent cognitive deficits and actually worsened cognitive efficiency after nicotine treatment stopped, generating deficits that resemble those due to NVHLs. These findings represent the first prospective evidence demonstrating a causal link between disease processes in schizophrenia and nicotine addiction. Developmental cortical-temporal limbic dysfunction in mental illness may thus amplify nicotine's reinforcing effects and addiction risk and severity, even while producing cognitive deficits that are not specifically or substantially reversible with nicotine. PMID- 23919445 TI - Physician assistants and their intent to retire. AB - OBJECTIVES: To determine predictors of physician assistants (PAs) to retire or to permanently leave clinical practice. The intent was to create a measure of retention and attrition for purposes of forecasting PA supply. STUDY DESIGN: All PAs 55 years or older who were nationally certified in 2011 were surveyed. METHODS: Statistical analysis included descriptive measures utilizing means, standard deviations, range, and proportions for all survey questions. Univariable analysis using chi2 test for the categorical variables determined gender differences in participants' intent to retire. A studentized t test analysis for continuous variables was used to compare differences across genders. The estimated time interval until retirement was calculated using reported values from participants and then subtracting their projected retirement age from current age. The same calculation was used for estimating PA career length from date of graduation to retirement. For all analyses, a P value < .05 was considered statistically significant. RESULTS: A total of 12,005 were eligible and surveyed online; 4767 responded (38%). The mean age was 60 years and the years in clinical practice was 25. When asked to predict a retirement date or age, the mean duration of working beyond age 55 years was 12 years (range 5 to 21). Most respondents reported being confident they were on track to retire with an adequate income. The significant differences that emerged were that men were more confident than women in preparing to retire, having enough money for medical expenses, and being able to live comfortably in retirement. Men more than women stated that, if forced to retire, they were more confident in the preparation to do so. CONCLUSIONS: PAs 55 years and older report they are likely to delay retirement from practice until age 67 years, on average. Women were less confident than men in retirement preparation. This age prediction expands career projections and refines forecasting models for the profession. Correlations based on expectation-action chain of events should be developed by periodically measuring how often intent and reality coalesce. PMID- 23919446 TI - The patient-centered medical home in the Veterans Health Administration. AB - BACKGROUND: The Veterans Health Administration (VHA) is the largest integrated US health system to implement the patient-centered medical home. The Patient Aligned Care Team (PACT) initiative (implemented 2010-2014) aims to achieve team based care, improved access, and care management for more than 5 million primary care patients nationwide. OBJECTIVES: To describe PACT and evaluate interim changes in PACT-related care processes. STUDY DESIGN: Data from the VHA Corporate Data Warehouse were obtained from April 2009 (pre- PACT) to September 2012. All patients assigned to a primary care provider (PCP) at all VHA facilities were included. METHODS: Nonparametric tests of trend across time points. RESULTS: VHA increased primary care staff levels from April 2010 to December 2011 (2.3 to 3.0 staff per PCP full-time equivalent). In-person PCP visit rates slightly decreased from April 2009 to April 2012 (53 to 43 per 100 patients per calendar quarter; P < .01), while in-person nurse encounter rates remained steady. Large increases were seen in phone encounters (2.7 to 28.8 per 100 patients per quarter; P < .01), enhanced personal health record use (3% to 13% of patients enrolled), and electronic messaging to providers (0.01% to 2.3% of patients per quarter). Post hospitalization follow-up improved (6.6% to 61% of VA hospital discharges), but home telemonitoring (0.8% to 1.4% of patients) and group visits (0.2 to 0.65 per 100 patients per quarter; P < .01) grew slowly. CONCLUSIONS: Thirty months into PACT, primary care staff levels and phone and electronic encounters have greatly increased; other changes have been positive but slower. PMID- 23919447 TI - Early results from the hospital Electronic Health Record Incentive Programs. AB - OBJECTIVES: To assess the level of hospital participation in the first 18 months of the Medicare and Medicaid Electronic Health Record (EHR) Incentive Programs, and to identify whether vulnerable hospitals lag behind. STUDY DESIGN: Retrospective study of participation among the 4938 Medicare-certified hospitals from the beginning of the incentive payment period (June 2011) through December 2012. METHODS: We used multivariate models to examine which types of hospitals qualified for financial incentives either through attesting to meaningful use of EHRs or by meeting the "Adopt-Implement-Upgrade" (AIU) option that requires demonstrating progress toward achieving meaningful use. We focused on small, Critical Access, and safety-net hospitals. RESULTS: We found that more than 75% of all eligible US hospitals have qualified for financial incentives in the first 18 months of the program. Nearly two-thirds of these hospitals (52% of all hospitals) attested to meaningful use while the remaining one-third (24% of all hospitals) were paid under the AIU option only. Small hospitals were less likely than large hospitals to qualify for incentive payments (odds ratio [OR] = 0.49, 95% confidence interval [CI] 0.36-0.68; P < .001 across categories). Critical Access hospitals also had lower odds of incentive payment (OR = 0.69, 95% CI 0.57 0.84, P < .001). Safety-net hospitals were more likely to qualify for payments overall (OR = 2.51; 95% CI 1.92-3.38, P < .001), but did so primarily through AIU. CONCLUSIONS: There is broad participation in the federally led incentive program to promote nationwide EHR uptake. Lower rates of participation among smaller hospitals and Critical Access hospitals merit close monitoring to ensure that broad adoption is achieved. PMID- 23919448 TI - Optimization of cytarabine (ARA-C) therapy for acute myeloid leukemia. AB - Cytarabine (cytosine arabinoside) is one of the most effective drugs for the treatment of acute myeloid leukemia. The standard dose of cytarabine used to treat this leukemia is 100 mg per square meter. In an attempt to improve the effectiveness of cytarabine against acute myeloid leukemia, a high-dose treatment (3,000 mg per square meter) was introduced into therapy. The side effects of high dose cytarabine was a major concern, especially its neurological toxicity. A review of recent clinical trials indicates that this high-dose cytarabine can be replaced by the intermediate-dose of 1,000 mg per square meter without loss of efficacy and with less toxicity. This is an important step to improve the efficacy of cytarabine for the treatment of acute myeloid leukemia. Despite the improvements in the therapy for this leukemia, the current overall survival rate for adult patients is less than 30%. To optimize the cytarabine therapy, it is important to determine how some leukemic stem cells survive treatment. Preclinical data suggest that survival of the leukemic stem cells could be due to the long 12 hour interval between infusions of cytarabine, which permits some leukemic cells to escape its S phase specific action. Among the other factors that can lead to leukemic cell survival are the high levels in the liver and spleen of cytidine deaminase, the enzyme that inactivates cytarabine and drug resistance due to deficiency in deoxycytidine kinase, the enzyme that activates the prodrug, cytarabine. Several approaches are proposed in this commentary to overcome these impediments with the goal of increasing the effectiveness of cytarabine for the treatment of acute myeloid leukemia. PMID- 23919449 TI - Exploring variation of antibiotic resistance genes in activated sludge over a four-year period through a metagenomic approach. AB - In this study, the profiles of ARGs in activated sludge from the Shatin WWTP of Hong Kong were investigated using metagenomic analysis over a four-year period. Forty giga base pairs of metagenomic data were generated from eight activated sludge samples collected biannually at two seasons (winter and summer) from July 2007 to January 2011. A structured database of ARGs was proposed and constructed to facilitate the classification of ARGs in the collected samples from metagenomic data using a customized script. Analysis of the data showed the existence of a broad-spectrum of different ARGs, some of which have never been reported in activated sludge before. The most abundant ARGs were aminoglycoside and tetracycline resistance genes, followed by resistance genes of sulfonamide, multidrug, and chloramphenicol. Seasonal fluctuations were observed for 3 types of ARGs, that is, resistance genes of tetracycline, sulfonamide, and vancomycin. The abundances of these resistance genes were generally higher in the samples collected in the winters than the samples collected in the contiguous summer. Further analyses were carried out for the presence of subtypes of ARGs for aminoglycoside, tetracycline, and beta-lactam. The abundances of some ARGs subtypes were inconsistent with those reported in previous studies of activated sludge using the PCR approach. Statistical analyses showed that the activated sludge data sets from this study can be distinguished from other types of samples based on their ARGs profiles. Furthermore, the results of this study demonstrate that a high throughput-based metagenomic approach combined with a structured database of ARGs provides a powerful tool for a comprehensive survey of the various ARGs not only in the activated sludge of a WWTP but in other environmental samples as well. Thus, the profiling of ARGs in other ecologically important environmental matrixes may help elucidate those environmental factors contributing to the spread of ARGs. PMID- 23919451 TI - RNA-Seq analysis and targeted mutagenesis for improved free fatty acid production in an engineered cyanobacterium. AB - BACKGROUND: High-energy-density biofuels are typically derived from the fatty acid pathway, thus establishing free fatty acids (FFAs) as important fuel precursors. FFA production using photosynthetic microorganisms like cyanobacteria allows for direct conversion of carbon dioxide into fuel precursors. Recent studies investigating cyanobacterial FFA production have demonstrated the potential of this process, yet FFA production was also shown to have negative physiological effects on the cyanobacterial host, ultimately limiting high yields of FFAs. RESULTS: Cyanobacterial FFA production was shown to generate reactive oxygen species (ROS) and lead to increased cell membrane permeability. To identify genetic targets that may mitigate these toxic effects, RNA-seq analysis was used to investigate the host response of Synechococcus elongatus PCC 7942. Stress response, nitrogen metabolism, photosynthesis, and protein folding genes were up-regulated during FFA production while genes involved in carbon and hydrogen metabolisms were down-regulated. Select genes were targeted for mutagenesis to confirm their role in mitigating FFA toxicity. Gene knockout of two porins and the overexpression of ROS-degrading proteins and hypothetical proteins reduced the toxic effects of FFA production, allowing for improved growth, physiology, and FFA yields. Comparative transcriptomics, analyzing gene expression changes associated with FFA production and other stress conditions, identified additional key genes involved in cyanobacterial stress response. CONCLUSIONS: A total of 15 gene targets were identified to reduce the toxic effects of FFA production. While single-gene targeted mutagenesis led to minor increases in FFA production, the combination of these targeted mutations may yield additional improvement, advancing the development of high-energy-density fuels derived from cyanobacteria. PMID- 23919450 TI - Thrombin induces epithelial-mesenchymal transition via PAR-1, PKC, and ERK1/2 pathways in A549 cells. AB - Thrombin activates protease-activated receptor (PAR)-1 and induces a myofibroblast phenotype in normal lung fibroblasts. The origins of myofibroblasts are resident fibroblasts, fibrocytes, and epithelial-mesenchymal transition (EMT). We investigated the effects of thrombin, an important mediator of interstitial lung fibrosis, on EMT in A549 human alveolar epithelial cells. We show that thrombin induced EMT and collagen I secretion through the activation of PAR-1, and PKC and ERK1/2 phosphorylation in A549 cells. These effects were largely prevented by a specific PAR-1 antagonist, short interfering RNA (siRNA) directed against PAR-1, or specific PKCalpha/beta, delta, and epsilon inhibitors. These data indicated that interaction with thrombin and alveolar epithelial cells might directly contribute to the pathogenesis of pulmonary fibrosis through EMT. Targeting PAR-1 on the pulmonary epithelium or specific inhibitors to PKCalpha/beta, delta, and epsilon might stop the fibrotic processes in human idiopathic pulmonary fibrosis by preventing thrombin-induced EMT. PMID- 23919452 TI - Deaths involving methylenedioxypyrovalerone (MDPV) in Upper East Tennessee. AB - Two deaths involving 3, 4-methylenedioxypyrovalerone (MDPV) are reported. MDPV is a synthetic cathinone stimulant found in "bath salts" with neurological and cardiovascular toxicity. Biological specimens were analyzed for MDPV by GC/MS and LC/MS. A White man was found dead with signs of nausea and vomiting after repeatedly abusing bath salts during a weekend binge. Femoral venous blood and urine had MDPV concentrations of 39 ng/mL and 760 ng/mL. The second fatality was a White man with a history of drug and bath salt abuse found dead at a scene in total disarray after exhibiting fits of anger and psychotic behavior. Femoral venous blood and urine had MDPV concentrations of 130 ng/mL and 3800 ng/mL. The blood and urine MDPV concentrations are within the reported recreational concentration ranges (blood 24-241 ng/mL and urine 34-3900 ng/mL). Both decedents' deaths were attributed to relevant natural causes in a setting of MDPV abuse. PMID- 23919453 TI - Presence of preoperative diastolic dysfunction predicts postoperative pulmonary edema and cardiovascular complications in patients undergoing noncardiac surgery. AB - OBJECTIVE: The aim of this study was to evaluate the impact of left ventricular diastolic dysfunction on predicting postoperative pulmonary edema and major cardiovascular events (MACE) in patients who underwent low- or intermediate-risk noncardiac surgery. METHODS: A total of 692 patients aged >60 years who underwent transthoracic echocardiography (TTE) before undergoing elective low- or intermediate-risk noncardiac surgery were prospectively enrolled. The medical history and TTE variables were assessed. Each patient was clinically evaluated for postoperative pulmonary edema and MACE. The presence of postoperative pulmonary edema and MACE were evaluated during a 30-day follow-up period after surgery. RESULTS: We identified 166 patients with pulmonary edema and 49 patients with MACE. After adjusting for clinical and TTE variables, multivariate analysis demonstrated that a ratio of early transmitral flow velocity to early diastolic velocity of the mitral annulus (E/e') >15, pulmonary artery systolic pressure (PASP) >=35 mmHg, and left ventricular hypertrophy (LVH) were significantly associated with postoperative pulmonary edema (E/e', P < 0.001: PASP, P = 0.005; LVH, P = 0.017). The multivariate analysis for MACE after adjusting for clinical risk factors indicated that MACE were significantly associated with an E/e' > 15 (P < 0.001). CONCLUSION: E/e' > 15, PASP elevation, and LVH on preoperative TTE predicted postoperative pulmonary edema, and E/e' > 15 predicted MACE in the patients who underwent low- or intermediate-risk noncardiac surgery. Thus, we believe that clinicians need to be cautious when providing perioperative care to patients with high E/e' ratios who are indicated for TTE. PMID- 23919454 TI - A novel fluorescence assay and catalytic properties of Crh1 and Crh2 yeast cell wall transglycosylases. AB - The mechanical properties of fungal cell walls are largely determined by composition and mutual cross-linking of their macromolecular components. Previous work showed that the Crh proteins are required for the formation of cross-links between chitin and glucan at the Saccharomyces cerevisiae cell wall. In the present study, the proteins encoded by CRH1 and CRH2 were heterologously expressed in Pichia pastoris and a sensitive fluorescence in vitro soluble assay was devised for determination of their transglycosylating activities. Both proteins act as chitin transglycosylases; they use soluble chitin derivatives, such as carboxymethyl chitin, glycol-chitin and/or N-acetyl chito oligosaccharides of DP (degree of polymerization)>=5 as the oligoglycosyl donors, and oligosaccharides derived from chitin, beta-(1,3)-glucan (laminarin) and beta (1,6)-glucan (pustulan), fluorescently labelled with sulforhodamine or FITC as acceptors. The minimal number of intact hexopyranose units required by Crh1 and/or Crh2 in the molecule of the acceptor oligosaccharide was two and the effectivity of the acceptor increased with the increasing length of its oligosaccharide chain. Products of the transglycosylation reactions were hybrid molecules composed of the acceptor and portions of carboxymethyl chitin attached to its non-reducing end. Both proteins exhibited a weak chitinolytic activity in different assays whereby the ratio of endo- compared with exo-chitinase activity was approximately 4-fold higher in Crh1 than in Crh2. The pH optimum of both enzymes was 3.5 and the optimum temperature was 37 degrees C. The results obtained in vitro with different fluorescently labelled oligosaccharides as artificial chitin acceptors corroborated well with those observed in vivo. PMID- 23919455 TI - Anesthesia and Duchenne or Becker muscular dystrophy: review of 117 anesthetic exposures. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are associated with life-threatening perioperative complications, including rhabdomyolysis, hyperkalemia, and hyperthermia. Current recommendations contraindicate use of succinylcholine and volatile anesthetics; however, the latter recommendation remains controversial. OBJECTIVE: To review the perioperative outcomes of patients with DMD and BMD. METHODS: We reviewed records of patients with DMD or BMD who underwent anesthetic management at our institution from January 1990 through December 2011. RESULTS: We identified 47 patients (DMD, 37; BMD, 10) who underwent 117 anesthetic exposures (DMD, 101; BMD, 16). Volatile anesthetic agents were used 66 times (DMD, 59; BMD, 7). One patient with undiagnosed BMD received succinylcholine and developed acute rhabdomyolysis and hyperkalemic cardiac arrest. All other major complications were attributed to the procedure (i.e., large bleeding), to preexisting comorbidities (i.e., respiratory failure, cardiac disease), or to both. CONCLUSIONS: Use of succinylcholine in children with dystrophinopathy is contraindicated. These patients have significant comorbidities and are frequently undergoing extensive operations; complications related to these factors can develop, as evidenced by our series. These complications may occur with use of volatile and nonvolatile anesthetics. However, because most of our patients were older than 8 years at the time of surgery, our observation cannot be generalized to younger dystrophin-deficient children. PMID- 23919456 TI - Three dimensional multiphoton imaging of fresh and whole mount developing mouse mammary glands. AB - BACKGROUND: The applications of multiphoton microscopy for deep tissue imaging in basic and clinical research are ever increasing, supplementing confocal imaging of the surface layers of cells in tissue. However, imaging living tissue is made difficult by the light scattering properties of the tissue, and this is extraordinarily apparent in the mouse mammary gland which contains a stroma filled with fat cells surrounding the ductal epithelium. Whole mount mammary glands stained with Carmine Alum are easily archived for later reference and readily viewed using bright field microscopy to observe branching architecture of the ductal network. Here, we report on the advantages of multiphoton imaging of whole mount mammary glands. Chief among them is that optical sectioning of the terminal end bud (TEB) and ductal epithelium allows the appreciation of abnormalities in structure that are very difficult to ascertain using either bright field imaging of the stained gland or the conventional approach of hematoxylin and eosin staining of fixed and paraffin-embedded sections. A second advantage is the detail afforded by second harmonic generation (SHG) in which collagen fiber orientation and abundance can be observed. METHODS: GFP-mouse mammary glands were imaged live or after whole mount preparation using a Zeiss LSM510/META/NLO multiphoton microscope with the purpose of obtaining high resolution images with 3D content, and evaluating any structural alterations induced by whole mount preparation. We describe a simple means for using a commercial confocal/ multiphoton microscope equipped with a Ti-Sapphire laser to simultaneously image Carmine Alum fluorescence and collagen fiber networks by SHG with laser excitation set to 860 nm. Identical terminal end buds (TEBs) were compared before and after fixation, staining, and whole mount preparation and structure of collagen networks and TEB morphologies were determined. Flexibility in excitation and emission filters was explored using the META detector for spectral emission scanning. Backward scattered or reflected SHG (SHG-B) was detected using a conventional confocal detector with maximum aperture and forward scattered or transmitted SHG (SHG-F) detected using a non-descanned detector. RESULTS: We show here that the developing mammary gland is encased in a thin but dense layer of collagen fibers. Sparse collagen layers are also interspersed between stromal layers of fat cells surrounding TEBs. At the margins, TEBs approach the outer collagen layer but do not penetrate it. Abnormal mammary glands from an HAI-1 transgenic FVB mouse model were found to contain TEBs with abnormal pockets of cells forming extra lumens and zones of continuous lateral bud formation interspersed with sparse collagen fibers. CONCLUSIONS: Collagen fibril arrangement and TEB structure is well preserved during the whole mount procedure and light scattering is reduced dramatically by extracting fat resulting in improved 3D structure, particularly for SHG signals originating from collagen. In addition to providing a bright signal, Carmine Alum stained whole mount slides can be imaged retrospectively such as performed for the HAI-1 mouse gland revealing new aspects of abnormal TEB morphology. These studies demonstrated the intimate contact, but relatively sparse abundance of collagen fibrils adjacent to normal and abnormal TEBS in the developing mammary gland and the ability to obtain these high resolution details subject to the discussed limitations. Our studies demonstrated that the TEB architecture is essentially unchanged after processing. PMID- 23919457 TI - Validating the use of colouration patterns for individual recognition in the worm pipefish using a novel set of microsatellite markers. AB - In studies of behaviour, ecology and evolution, identification of individual organisms can be an invaluable tool, capable of unravelling otherwise cryptic information regarding group structure, movement patterns, population size and mating strategies. The use of natural markings is arguably the least invasive method for identification. However, to be truly useful natural markings must be sufficiently variable to allow for unique identification, while being stable enough to permit long-term studies. Non-invasive marking techniques are especially important in fishes of the Family Syngnathidae (pipefishes, seahorses and seadragons), as many of these taxa are of conservation concern or used extensively in studies of sexual selection. Here, we assessed the reliability of natural markings as a character for individual identification in a wild population of Nerophis lumbriciformis by comparing results from natural markings to individual genetic assignments based on eight novel microsatellite loci. We also established a minimally invasive method based on epithelial cell swabbing to sample DNA. All pipefish used in the validation of natural markings, independently of sex or time between recaptures, were individually recognized through facial colouration patterns. Their identities were verified by the observation of the same multilocus genotype at every sampling event for each individual that was identified on the basis of natural markings. Successful recaptures of previously swabbed pipefish indicated that this process probably did not induce an elevated rate of mortality. Also, the recapture of newly pregnant males showed that swabbing did not affect reproductive behaviour. PMID- 23919458 TI - Shikonin suppresses ERK 1/2 phosphorylation during the early stages of adipocyte differentiation in 3T3-L1 cells. AB - BACKGROUND: The naphthoquinone pigment, shikonin, is a major component of Lithospermum erythrorhizon and has been shown to have various biological functions, including antimicrobial, anti-inflammatory, and antitumor effects. In this study, we investigated the effect of shikonin on adipocyte differentiation and its mechanism of action in 3T3-L1 cells. METHODS: To investigate the effects of shikonin on adipocyte differentiation, 3T3-L1 cells were induced to differentiate using 3-isobutyl-1-methylzanthine, dexamethasone, and insulin (MDI) for 8 days in the presence of 0-2 MUM shikonin. Oil Red O staining was performed to determine the lipid accumulation in 3T3-L1 cells. To elucidate the anti adipogenic mechanism of shikonin, adipogenic transcription factors, the phosphorylation levels of ERK, and adipogenic gene expression were analyzed by Western blotting and quantitative real-time PCR. To further confirm that shikonin inhibits adipogenic differentiation through downregulation of ERK 1/2 activity, 3T3-L1 cells were treated with shikonin in the presence of FGF-2, an activator, or PD98059, an inhibitor, of the ERK1/2 signaling pathway. RESULTS: Shikonin effectively suppressed adipogenesis and downregulated the protein levels of 2 major transcription factors, PPARgamma and C/EBPalpha, as well as the adipocyte specific gene aP2 in a dose-dependent manner. qRT-PCR analysis revealed that shikonin inhibited mRNA expression of adipogenesis-related genes, such as PPARgamma, C/EBPalpha, and aP2. Adipocyte differentiation was mediated by ERK 1/2 phosphorylation, which was confirmed by pretreatment with PD98059 (an ERK 1/2 inhibitor) or FGF-2 (an ERK 1/2 activator). The phosphorylation of ERK1/2 during the early stages of adipogenesis in 3T3-L1 cells was inhibited by shikonin. We also confirmed that FGF-2-stimulated ERK 1/2 activity was attenuated by shikonin. CONCLUSIONS: These results demonstrate that shikonin inhibits adipogenic differentiation via suppression of the ERK signaling pathway during the early stages of adipogenesis. PMID- 23919459 TI - Pulmonary immune responses to Aspergillus fumigatus in an immunocompetent mouse model of repeated exposures. AB - Aspergillus fumigatus is a filamentous fungus that produces abundant pigmented conidia. Several fungal components have been identified as virulence factors, including melanin; however, the impact of these factors in a repeated exposure model resembling natural environmental exposures remains unknown. This study examined the role of fungal melanin in the stimulation of pulmonary immune responses using immunocompetent BALB/c mice in a multiple exposure model. It compared conidia from wild-type A. fumigatus to two melanin mutants of the same strain, Deltaarp2 (tan) or Deltaalb1 (white). Mass spectrometry-based analysis of conidial extracts demonstrated that there was little difference in the protein fingerprint profiles between the three strains. Field emission scanning electron microscopy demonstrated that the immunologically inert Rodlet A layer remained intact in melanin-deficient conidia. Thus, the primary difference between the strains was the extent of melanization. Histopathology indicated that each A. fumigatus strain induced lung inflammation, regardless of the extent of melanization. In mice exposed to Deltaalb1 conidia, an increase in airway eosinophils and a decrease in neutrophils and CD8(+) IL-17(+) (Tc17) cells were observed. Additionally, it was shown that melanin mutant conidia were more rapidly cleared from the lungs than wild-type conidia. These data suggest that the presence of fungal melanin may modulate the pulmonary immune response in a mouse model of repeated exposures to A. fumigatus conidia. PMID- 23919461 TI - bam Lipoproteins Assemble BamA in vitro. AB - The Bam machine assembles beta-barrel membrane proteins into the outer membranes of Gram-negative bacteria. The central component of the Bam complex, BamA, is a beta-barrel that is conserved in prokaryotes and eukaryotes. We have previously reported an in vitro assay for studying the assembly of beta-barrel proteins by the Bam complex and now apply this assay to identify the specific components that are required for BamA assembly. We establish that BamB and BamD, two lipoprotein components of the complex, bind to the unfolded BamA substrate and are sufficient to accelerate its assembly into the membrane. PMID- 23919462 TI - Effects of unconditioned stimulus intensity and fear extinction on subsequent sleep architecture in an afternoon nap. AB - Impaired fear extinction and disturbed sleep coincide in post-traumatic stress disorder (PTSD), but the nature of this relationship is unclear. Rapid eye movement (REM) sleep deprivation impairs fear extinction recall in rodents and young healthy subjects, and animal models have demonstrated both disrupted sleep after fear conditioning and normalized sleep after extinction learning. As a correlation between unconditioned stimulus (US) responding and subsequent sleep architecture has been observed in healthy subjects, the goal of this study was to test whether US intensity would causally affect subsequent sleep. Twenty-four young healthy subjects underwent a fear conditioning session with skin conductance response measurements before an afternoon session of polysomnographically recorded sleep (up to 120 min) in the sleep laboratory. Two factors were manipulated experimentally in a 2 * 2 design: US (electrical shock) was set at high or low intensity, and subjects did or did not receive an extinction session after fear conditioning. We observed that neither factor affected REM sleep amount, that high US intensity nominally increased sleep fragmentation (more Stage 1 sleep, stage shifts and wake after sleep onset), and that extinction increased Stage 4 amount. Moreover, reduced Stage 1 and increased Stage 4 and REM sleep were associated with subjective sleep quality of the afternoon nap. These results provide evidence for the notion that US intensity and extinction affect subsequent sleep architecture in young healthy subjects, which may provide a translational bridge from findings in animal studies to correlations observed in PTSD patients. PMID- 23919460 TI - Immunogenicity of therapeutic proteins: influence of aggregation. AB - The elicitation of anti-drug antibodies (ADA) against biotherapeutics can have detrimental effects on drug safety, efficacy, and pharmacokinetics. The immunogenicity of biotherapeutics is, therefore, an important issue. There is evidence that protein aggregation can result in enhanced immunogenicity; however, the precise immunological and biochemical mechanisms responsible are poorly defined. In the context of biotherapeutic drug development and safety assessment, understanding the mechanisms underlying aggregate immunogenicity is of considerable interest. This review provides an overview of the phenomenon of protein aggregation, the production of unwanted aggregates during bioprocessing, and how the immune response to aggregated protein differs from that provoked by non-aggregated protein. Of particular interest is the nature of the interaction of aggregates with the immune system and how subsequent ADA responses are induced. Pathways considered here include 'classical' activation of the immune system involving antigen presenting cells and, alternatively, the breakdown of B cell tolerance. Additionally, methods available to screen for aggregation and immunogenicity will be described. With an increased understanding of aggregation enhanced immune responses, it may be possible to develop improved manufacturing and screening processes to avoid, or at least reduce, the problems associated with ADA. PMID- 23919463 TI - Pulmonary drug delivery. PMID- 23919464 TI - Overcoming the undesirable properties of dry-powder inhalers with novel engineered mannitol particles. PMID- 23919465 TI - Re-engineering the early development process for pulmonary drug-delivery products. PMID- 23919466 TI - Pirfenidone in respirable powder form for the treatment of pulmonary fibrosis: a safer alternative to the current oral delivery system? PMID- 23919469 TI - Interview with Peter J Barnes. PMID- 23919470 TI - Ask the experts: the benefits and challenges of pulmonary drug delivery. AB - The field of pulmonary drug delivery is ever progressing with technological advances in inhaler device design, the development of increasingly sophisticated techniques in targeted delivery and new opportunities in drug formulation, largely as a product of the rapidly advancing area of nanotechnology. Though pulmonary administration offers numerous advantages in terms of both local and systemic drug delivery, the translation of inhaled drugs from bench-to-bedside presents an ongoing challenge. Hannah Coaker, Assistant Commissioning Editor, spoke to six experts and discussed their motivations for becoming involved in the field, major obstacles in aerosol drug development and the evolving area of pulmonary drug delivery. PMID- 23919472 TI - Effect of processing history on the surface interfacial properties of budesonide in carrier-based dry-powder inhalers. AB - Influence of air-jet micronization, post-micronization conditioning and storage on the surface properties of budesonide in dry-powder inhaler formulations was investigated. Crystalline budesonide was air jet-micronized and conditioned using organic vapor. Particle engineering was also used to fabricate respirable particles of budesonide. Surface imaging by atomic force microscopy suggested that micronized material possessed process-induced surface disorder, which relaxed upon conditioning with organic vapor. Particle engineered material was devoid of such surface disorder. Surface interfacial properties of all batches were different and correlated to in vitro fine particle delivery. The surface properties and in vitro performance of the conditioned material changed upon storage of the budesonide at 44% relative humidity and 25 degrees C, while the micronized and particle-engineered material remained stable. These data suggest that processing conditions of budesonide affected the surface properties of the material, which was demonstrated to have direct affect on dry-powder inhaler formulation performance. PMID- 23919471 TI - Biopharmaceutical in vitro characterization of CPZEN-45, a drug candidate for inhalation therapy of tuberculosis. AB - BACKGROUND: The caprazamycin derivative, CPZEN-45 has previously demonstrated antitubercular activity against Mycobacterium tuberculosis H37Rv. Here, the authors report a basic biopharmaceutical characterization of the compound focusing on in vitro permeability and cytotoxicity, with respect to the suitability of CPZEN-45 hydrochloride for inhalation treatment of tuberculosis. RESULTS: MTT assays confirmed that CPZEN-45 HCl had no acute cytotoxic effects up to 3 mg/ml. In transport studies, apparent permeability coefficients of CPZEN-45 HCl across Calu-3 monolayers in absorptive and secretive directions were 0.43 +/- 0.20 * 10(-6) cm/s and 0.38 +/- 0.12 * 10(-6) cm/s, respectively. Across ATI-like monolayers, apparent permeability values were 12.10 +/- 4.31 * 10(-6) cm/s and 8.50 +/- 1.83 * 10(-6) cm/s. CPZEN-45 HCl formed colloidal complexes at concentrations above 0.38 mg/ml; however, these complexes were not micelles, as assessed by Orange OT encapsulation assay. CONCLUSION: CPZEN-45 is an interesting new drug candidate with potential to be used in aerosol therapy of tuberculosis. PMID- 23919473 TI - Device factors affecting pulmonary delivery of dry powders. AB - The use of orally inhaled dry powder technologies is one way of delivering medicines to the lung for treating local conditions or for achieving systemic effect. These involve dry powder formulations containing an active pharmaceutical ingredient together with inhaler devices. These powder/device systems enable patients to inhale and aerosolize the medicine into suitably sized particles that deposit in the lung. Several inhaler centric aspects of these delivery systems are presented and discussed in context of new product development. Case examples are provided to highlight several inhaler aspects and to guide development of powder/inhaler systems. PMID- 23919475 TI - Electrostatics in pharmaceutical aerosols for inhalation. AB - Electrostatics continues to play an important role in pharmaceutical aerosols for inhalation. Despite its ubiquitous nature, the charging process is complex and not well understood. Nonetheless, significant advances in the past few years continue to improve understanding and lead to better control of electrostatics. The purpose of this critical review is to present an overview of the literature, with an emphasis on how electrostatic charge can be useful in improving pulmonary drug delivery. PMID- 23919476 TI - Improved laboratory test methods for orally inhaled products. AB - Existing pharmacopeial methods for the in vitro testing of orally inhaled products (OIPs) are simplified representations of clinical reality, as their objective is to provide metrics that are discriminating of product quality. Attempts to correlate measures such as fine particle fraction <5 um aerodynamic diameter with in vivo measures of lung deposition have therefore been notoriously difficult to achieve. Although particle imaging-based techniques may be helpful to link in vitro to in vivo data as surrogates for clinical responses, a reappraisal of the purposes for laboratory-based testing of OIPs is required. This article provides guidance on approaches that may be helpful to develop clinically appropriate methods to assess OIP performance in the laboratory, with the ultimate goal of developing robust in vitro-in vivo relationships for the major inhaled drug classes. PMID- 23919477 TI - Mechanisms of absorption and elimination of drugs administered by inhalation. AB - Pulmonary drug delivery is an effective route for local or systemic drug administration. However, compared with other routes of administration, there is a scarcity of information on how drugs are absorbed from the lung. The different cell composition lining the airways and alveoli makes this task extremely complicated. Lung cell lines and primary culture cells are useful in studying the absorption mechanisms. However, it is imperative that these cell cultures express essential features required to study these mechanisms such as intact tight junctions and transporters. In vivo, the drug has to face defensive physical and immunological barriers such as mucociliary clearance and alveolar macrophages. Knowledge of the physicochemical properties of the drug and aerosol formulation is required. All of these factors interact together leading to either successful drug deposition followed by absorption or drug elimination. These aspects concerning drug transport in the lung are addressed in this review. PMID- 23919478 TI - Liposomal formulations for inhalation. AB - No marketed inhaled products currently use sustained release formulations such as liposomes to enhance drug disposition in the lung, but that may soon change. This review focuses on the interaction between liposomal formulations and the inhalation technology used to deliver them as aerosols. There have been a number of dated reviews evaluating nebulization of liposomes. While the information they shared is still accurate, this paper incorporates data from more recent publications to review the factors that affect aerosol performance. Recent reviews have comprehensively covered the development of dry powder liposomes for aerosolization and only the key aspects of those technologies will be summarized. There are now at least two inhaled liposomal products in late-stage clinical development: ARIKACE((r)) (Insmed, NJ, USA), a liposomal amikacin, and PulmaquinTM (Aradigm Corp., CA, USA), a liposomal ciprofloxacin, both of which treat a variety of patient populations with lung infections. This review also highlights the safety of inhaled liposomes and summarizes the clinical experience with liposomal formulations for pulmonary application. PMID- 23919474 TI - Delivery and performance of surfactant replacement therapies to treat pulmonary disorders. AB - Lung surfactant is crucial for optimal pulmonary function throughout life. An absence or deficiency of surfactant can affect the surfactant pool leading to respiratory distress. Even if the coupling between surfactant dysfunction and the underlying disease is not always well understood, using exogenous surfactants as replacement is usually a standard therapeutic option in respiratory distress. Exogenous surfactants have been extensively studied in animal models and clinical trials. The present article provides an update on the evolution of surfactant therapy, types of surfactant treatment, and development of newer-generation surfactants. The differences in the performance between various surfactants are highlighted and advanced research that has been conducted so far in developing the optimal delivery of surfactant is discussed. PMID- 23919480 TI - American crows as carriers of vancomycin-resistant enterococci with vanA gene. AB - We studied the vanA-carrying vancomycin-resistant enterococci (VRE) isolated from American crows in the United States during the winter 2011/2012. Faecal samples from crows were cultured selectively for VRE and characterized. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were used to examine epidemiological relationships of vanA-containing VRE. Isolates were tested in vitro for their ability to horizontally transfer the vancomycin resistance trait. VRE with the vanA gene were found in 15 (2.5%) of 590 crows samples, from which we obtained 22 different isolates. Enterococcal species were Enterococcus faecium (14) and E. faecalis (8). One, two and 19 isolates originated from Kansas, New York State and Massachusetts, respectively. Based on MLST analysis, E. faecium isolates were grouped as ST18 (6 isolates), ST555 (2), and novel types ST749 (1), ST750 (3), ST751 (1), ST752 (1). Enterococcus faecalis isolates belonged to ST6 (1), ST16 (3) and ST179 (4). All isolates were able to transfer the vancomycin resistance trait via filter mating with very high transfer range. Clinically important enterococci with the vanA gene occur in faeces of wild American crows throughout the United States. These migrating birds may contribute to the dissemination of VRE in environment over large distances. [Correction added after first online publication on 06 August 2013: The number of E. faecium ST752 isolate is now amended to '1', consistent with that shown in the 'Results' section and Figure 2.]. PMID- 23919481 TI - Polloidal chains from self-assembly of flattened particles. AB - Chains of micrometer-size colloidal particles have been self-assembled that are flexible, mechanically stable, and observable in optical microscopy. The chains sometimes have more than 30 particles, and we call them "polloidal chains". A key aspect of the work is the careful modeling of the interparticle forces between partially flattened polystyrene spheres. This modeling helped us to identify a narrow window of system conditions that produce interparticle physical bonds with a bond energy greater than 15kT, as well as a gap of fluid between particles that enables freely rotating bonds and flexible chains. The formation of the chains is well-modeled using linear condensation growth from classical polymer theory, suggesting that the chains might be used experimentally as large-scale, relatively slow moving models for polymer chains. PMID- 23919482 TI - Native chemical ligation at Asx-Cys, Glx-Cys: chemical synthesis and high resolution X-ray structure of ShK toxin by racemic protein crystallography. AB - We have re-examined the utility of native chemical ligation at -Gln/Glu-Cys- [Glx Cys] and -Asn/Asp-Cys- [Asx-Cys] sites. Using the improved thioaryl catalyst 4 mercaptophenylacetic acid (MPAA), native chemical ligation could be performed at Gln-Cys- and Asn-Cys- sites without side reactions. After optimization, ligation at a -Glu-Cys- site could also be used as a ligation site, with minimal levels of byproduct formation. However, -Asp-Cys- is not appropriate for use as a site for native chemical ligation because of formation of significant amounts of beta linked byproduct. The feasibility of native chemical ligation at -Gln-Cys- enabled a convergent total chemical synthesis of the enantiomeric forms of the ShK toxin protein molecule. The D-ShK protein molecule was ~50,000-fold less active in blocking the Kv1.3 channel than the L-ShK protein molecule. Racemic protein crystallography was used to obtain high-resolution X-ray diffraction data for ShK toxin. The structure was solved by direct methods and showed significant differences from the previously reported NMR structures in some regions of the ShK protein molecule. PMID- 23919483 TI - Differential striatal dopamine responses following oral alcohol in individuals at varying risk for dependence. AB - BACKGROUND: The neurobiology of risk for alcohol use disorders (AUDs) remains poorly understood. Individual differences in vulnerability, though, have been indicated by subjective responses to alcohol ingestion and personality traits. METHODS: To investigate the relationship between these features and striatal dopamine (DA) responses to alcohol, we studied 26 healthy young social drinkers (21.3 +/- 3.0 years old; 10.7 +/- 8.8 drinks/wk) at varying risk for alcoholism. Each participant received 2 positron emission tomography [(11) C]raclopride scans after administration of either placebo or oral alcohol (1 ml/kg body weight of 94% alcohol, 0.75 g/kg) in a randomized and counterbalanced design. RESULTS: Subjects with high-risk subjective responses to alcohol had more family members with AUDs, greater alcohol use problems, and, in response to the alcohol challenge, significant decreases in [(11) C]raclopride binding indicative of increased extracellular DA. In contrast, low-risk subjects exhibited increases in [(11) C]raclopride binding in response to alcohol. The results were similar when risk groups were based on personality traits, although statistically less robust. CONCLUSIONS: Changes in striatal DA in response to alcohol ingestion may be a neurobiological marker of vulnerability to AUDs. PMID- 23919484 TI - Chemotherapy for osteosarcoma - where does it come from? What is it? Where is it going? AB - INTRODUCTION: Although chemotherapy is currently indispensable for the treatment of osteosarcoma, chemotherapy for this rare cancer has not been developed based on multicentre randomised prospective trials with many subjects. The therapeutic outcomes of chemotherapy have been improved in large part through the efforts and innovation of physicians who treated patients with osteosarcoma and conducted detailed examinations of a small number of subjects. It is important to understand how chemotherapy for osteosarcoma has changed to achieve further development. AREAS COVERED: This article discusses the changes in chemotherapy for osteosarcoma, including adjuvant and neoadjuvant chemotherapy, and focuses on four key anticancer drugs: methotrexate, adriamycin, cisplatin, and ifosfamide. This article also discusses the problems of research on osteosarcoma treatment, from the perspective of osteosarcoma as a rare disease, and the challenges to be addressed. EXPERT OPINION: Approximately 30 years have passed since the key anticancer drugs were introduced. The development of new therapeutic drugs for osteosarcoma has stagnated. Given that osteosarcoma is a rare cancer, it would be difficult to expect that drug development will be led by pharmaceutical companies. Thus, it is very important to create a system for more efficient drug development based on innovations from various academic and medical institutions. PMID- 23919485 TI - fat facets induces polyubiquitination of Imd and inhibits the innate immune response in Drosophila. AB - The IMD pathway is one of the major regulators of the innate immune response in Drosophila. Although extensive analysis of the IMD pathway has been carried out, precise mechanisms for how each target gene of the pathway is down-regulated remain to be clarified. Here, we carried out genetic screening and found that fat facets (faf), which encodes a deubiquitinating enzyme, inhibited the expression of the target genes of the IMD pathway. Overexpression of faf suppressed the infection-induced expression of Diptericin and increased susceptibility to bacterial infection in flies, whereas faf loss-of-function mutants decreased susceptibility. Time course analysis revealed that specific subsets of the target genes of the IMD pathway were affected by faf. Biochemical analysis showed that Faf made a complex with Imd, and both Faf and Imd were polyubiquitinated when they were co-overexpressed. Given that faf-dependent Imd polyubiquitination did not seem to cause protein degradation of Imd, Faf might inhibit the IMD pathway by modulating the state of Imd ubiquitination and/or stability. PMID- 23919487 TI - Module 1: the environment. PMID- 23919486 TI - Pretransplant sensitization against angiotensin II type 1 receptor is a risk factor for acute rejection and graft loss. AB - The angiotensin II type 1 receptor (AT1R) is an emerging target of functional non HLA antibodies (Ab). We examined the potential of determining the degree of presensitization against AT1R as a risk factor for graft survival and acute rejection (AR). The study included 599 kidney recipients between 1998 and 2007. Serum samples were analyzed in a blinded fashion for anti-AT1R antibodies (AT1R Abs) using a quantitative solid-phase assay. A threshold of AT1R-Ab levels was statistically determined at 10 U based on the time to graft failure. An extended Cox model determined risk factors for occurrence of graft failure and a first AR episode. AT1R-Abs >10 U were detected in 283 patients (47.2%) before transplantation. Patients who had a level of AT1R-Abs >10 U had a 2.6-fold higher risk of graft failure from 3 years posttransplantation onwards (p = 0.0005) and a 1.9-fold higher risk of experiencing an AR episode within the first 4 months of transplantation (p = 0.0393). Antibody-mediated rejection (AMR) accounted for 1/3 of AR, whereby 71.4% of them were associated with >10 U of pretransplant AT1R Abs. Pretransplant anti-AT1R-Abs are an independent risk factor for long-term graft loss in association with a higher risk of early AR episodes. PMID- 23919488 TI - Module 2: policy and value-based purchasing. PMID- 23919489 TI - Module 3: measuring quality in the quality enterprise. PMID- 23919490 TI - Module 4: the quality enterprise and VBP principles--case studies. PMID- 23919491 TI - Module 5: what's next? PMID- 23919492 TI - The quality enterprise: Q and A with the "nation's" chief pharmacist, Rear Admiral Scott F. Giberson. PMID- 23919493 TI - Stability of amine-functionalized cellulose during temperature-vacuum-swing cycling for CO2 capture from air. AB - The stability of amine-functionalized nanofibrilated cellulose sorbent for direct air capture of CO2 is investigated during temperature-vacuum-swing (TVS) cycling. The presence of O2 at 90 degrees C degrades the sorbent, reducing its CO2 adsorption capacity by 30% after 15 h of treatment in moist air with a dew point of 22 degrees C. In contrast, exposure to moist CO2 at 90 degrees C with a dew point of 22 degrees C does not deteriorate its CO2 adsorption capacity after 15 h. Performing 100 TVS consecutive cycles, with CO2 adsorption from ambient air containing 400-530 ppm CO2 at 30 degrees C and 60% relative humidity and with CO2 desorption at 90 degrees C and 30 mbar, resulted in a reduction of the equilibrium CO2 adsorption capacity by maximum 5%. The average CO2 adsorption capacity during TVS cyclic operation is 0.90 mmol CO2/g. PMID- 23919494 TI - A cost-effectiveness analysis of respiratory syncytial virus (RSV) prophylaxis in infants in the United Kingdom. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of respiratory infection that is highly prevalent in infants. Severe cases of RSV infection require hospitalisation; this is most likely to occur in infant populations at high risk. The study assesses the cost-effectiveness of palivizumab versus no prophylaxis in infants at high risk of hospitalisation with RSV in the United Kingdom (UK). METHODS: A decision tree model was developed to reflect the clinical pathway of infants at high risk of severe RSV infection who receive either prophylaxis with palivizumab or no prophylaxis. The main outcome was the incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were performed to assess the degree of uncertainty surrounding the results. A threshold analysis considered the impact of clinical and environmental risk factors on the cost-effectiveness in the subgroup of preterm infants 33-35 weeks gestational age (wGA). RESULTS: Prophylaxis with palivizumab compared with no prophylaxis is associated with the following ICERs; L33,216 for infants with congenital heart disease; L19,168 for infants with chronic lung disease; L3,845 for preterm infants < 29 wGA; L30,205 for preterm infants 29-32 wGA; and L99,056 for preterm infants 33-35 wGA. One-way sensitivity analysis suggests that these results are highly sensitive to the input data. Threshold analysis in the preterm 33-35 wGA subgroup demonstrates that an adjusted RSV-hospitalisation baseline risk of 17.94% or higher would result in an ICER below the L30,000 per quality-adjusted life-year threshold. DISCUSSION: Palivizumab is cost-effective compared to no prophylaxis in the United Kingdom in many of the subgroups considered, showing that palivizumab would be a cost effective use of National Health Service resources. PMID- 23919495 TI - Selection and validation of reference genes for quantitative gene expression studies by real-time PCR in eggplant (Solanum melongena L). AB - BACKGROUND: Analysis of gene expression patterns leads to functional understanding of biological processes. Quantitative real-time PCR has become the most commonly used technique for in-depth studies of gene expression. To quantify variation in specific gene expression, accurate and reliable normalization across different samples and tissues is necessary. This can be achieved by selecting one or more suitable reference genes to compare the target mRNA transcript levels. In the present work, we illustrate the first evaluation of potential internal control or reference genes across different developmental stages of eggplant for reliable quantification of transcripts by real-time PCR. RESULTS: We have evaluated the stability in expression of six candidate reference genes (18s rRNA, APRT, GAPDH, Cyclophilin, Actin, and RuBP) in a set of tissues representing six developmental stages of eggplant. The candidate genes were cloned from cDNA and analysed by real-time PCR. The expression data analyzed by three statistical methods (geNorm, NormFinder and BestKeeper) identified 18s rRNA, Cyclophilin and APRT as the most stable and suitable reference genes in eggplant. This was further confirmed in four different varieties, two representative lines of transgenic eggplant as well as in nematode infected eggplant. CONCLUSION: 18s rRNA, Cyclophilin and APRT have been found to be appropriate for the normalization of real-time PCR data for gene expression studies in eggplant. PMID- 23919496 TI - Modified microwave method for the synthesis of visible light-responsive TiO2/MWCNTs nanocatalysts. AB - Recently, TiO2/multi-walled carbon nanotube (MWCNT) hybrid nanocatalysts have been a subject of high interest due to their excellent structures, large surface areas and peculiar optical properties, which enhance their photocatalytic performance. In this work, a modified microwave technique was used to rapidly synthesise a TiO2/MWCNT nanocatalyst with a large surface area. X-ray powder diffraction, field-emission scanning electron microscopy, transmission electron microscopy and Brunauer-Emmett-Teller measurements were used to characterise the structure, morphology and the surface area of the sample. The photocatalytic activity of the hybrid nanocatalysts was evaluated through a comparison of the degradation of methylene blue dye under irradiation with ultraviolet and visible light. The results showed that the TiO2/MWCNT hybrid nanocatalysts degraded 34.9% of the methylene blue (MB) under irradiation with ultraviolet light, whereas 96.3% of the MB was degraded under irradiation with visible light. PMID- 23919497 TI - A mechanism for epithelial-mesenchymal transition and anoikis resistance in breast cancer triggered by zinc channel ZIP6 and STAT3 (signal transducer and activator of transcription 3). AB - Genes involved in normal developmental processes attract attention as mediators of tumour progression as they facilitate migration of tumour cells. EMT (epithelial-mesenchymal transition), an essential part of embryonic development, tissue remodelling and wound repair, is crucial for tumour metastasis. Previously, zinc transporter ZIP6 [SLC39A6; solute carrier family 39 (zinc transporter), member 6; also known as LIV-1) was linked to EMT in zebrafish gastrulation through a STAT3 (signal transducer and activator of transcription 3) mechanism, resulting in nuclear localization of transcription factor Snail. In the present study, we show that zinc transporter ZIP6 is transcriptionally induced by STAT3 and unprecedented among zinc transporters, and is activated by N terminal cleavage which triggers ZIP6 plasma membrane location and zinc influx. This zinc influx inactivates GSK-3beta (glycogen synthase kinase 3beta), either indirectly or directly via Akt or GSK-3beta respectively, resulting in activation of Snail, which remains in the nucleus and acts as a transcriptional repressor of E-cadherin (epithelial cadherin), CDH1, causing cell rounding and detachment. This was mirrored by ZIP6-transfected cells which underwent EMT, detached from monolayers and exhibited resistance to anoikis by their ability to continue proliferating even after detachment. Our results indicate a causative role for ZIP6 in cell motility and migration, providing ZIP6 as a new target for prediction of clinical cancer spread and also suggesting a ZIP6-dependent mechanism of tumour metastasis. PMID- 23919499 TI - Associations between tumor necrosis factor alpha gene -238 G/A and -308 G/A polymorphisms and the risk of pneumoconiosis: update of a meta-analysis. AB - OBJECTIVES: Tumor necrosis factor alpha (TNF-alpha) gene (-238 G/A [rs361525] and -308 G/A [rs1800629]) polymorphisms have been extensively studied in relation to various diseases, several epidemiologic studies have been performed to investigate the associations of TNF-alpha gene polymorphisms with pneumoconiosis; however, the results of these studies were not entirely consistent. In an effort to clarify earlier inconclusive results, we performed this meta-analysis of case control genetic association studies. METHODS: We identified eligible studies by searching the relevant databases, including PubMed, Embase, Web of Science, CBMdisc, CNKI, and Google Scholar, until February 15, 2013. Additionally, hand searching of the references of identified articles were performed. Heterogeneity and publication bias across studies were determined and the meta-analysis was performed by Stata 11.0. RESULTS: Fourteen articles involving 20 studies were included in the final meta-analysis, covering a total of 1935 pneumoconiosis cases and 3753 controls. The results showed evidence for significant association between TNF-alpha gene -308 G/A polymorphism and pneumoconiosis risk, suggesting that TNF-alpha gene -308 A allele may be a risk factor for pneumoconiosis (for A allele vs. G allele: OR = 1.41, 95% CI = 1.10-1.81, p = 0.01; for A/A + G/A vs. G/G: OR = 1.52, 95% CI = 1.21-1.91, p < 0.01). For TNF-alpha gene -238 G/A polymorphism, no significant association was found between this genetic variation and pneumoconiosis risk. CONCLUSIONS: This meta-analysis indicates that TNF-alpha gene -308 G/A polymorphism is associated with an increased pneumoconiosis risk. PMID- 23919498 TI - Screening for phenotype selective activity in multidrug resistant cells identifies a novel tubulin active agent insensitive to common forms of cancer drug resistance. AB - BACKGROUND: Drug resistance is a common cause of treatment failure in cancer patients and encompasses a multitude of different mechanisms. The aim of the present study was to identify drugs effective on multidrug resistant cells. METHODS: The RPMI 8226 myeloma cell line and its multidrug resistant subline 8226/Dox40 was screened for cytotoxicity in response to 3,000 chemically diverse compounds using a fluorometric cytotoxicity assay (FMCA). Follow-up profiling was subsequently performed using various cellular and biochemical assays. RESULTS: One compound, designated VLX40, demonstrated a higher activity against 8226/Dox40 cells compared to its parental counterpart. VLX40 induced delayed cell death with apoptotic features. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. Strong connections to tubulin inhibitors and microtubule cytoskeleton were retrieved. The mechanistic hypothesis of VLX40 acting as a tubulin inhibitor was confirmed by direct measurements of interaction with tubulin polymerization using a biochemical assay and supported by demonstration of G2/M cell cycle arrest. When tested against a broad panel of primary cultures of patient tumor cells (PCPTC) representing different forms of leukemia and solid tumors, VLX40 displayed high activity against both myeloid and lymphoid leukemias in contrast to the reference compound vincristine to which myeloid blast cells are often insensitive. Significant in vivo activity was confirmed in myeloid U-937 cells implanted subcutaneously in mice using the hollow fiber model. CONCLUSIONS: The results indicate that VLX40 may be a useful prototype for development of novel tubulin active agents that are insensitive to common mechanisms of cancer drug resistance. PMID- 23919500 TI - Individual and familial factors associated with metabolic control in children with type 1 diabetes. AB - BACKGROUND: The aim of this study was to determine the individual and familial factors associated with metabolic control in children with type 1 diabetes (T1DM). METHODS: The study was performed in 93 children with T1DM between the ages of 3 and 19 years. Children and their families completed questionnaires on sociodemographics and data associated with diabetes. Medical information from the charts was also recorded. RESULTS: Older age, longer diabetes duration and higher hospitalization rate for acute complications were positively associated with poor metabolic control. Good school performance, regular hospital visits, young maternal age, high paternal education level and fewer numbers of siblings were found to be negatively associated with poor metabolic control. CONCLUSIONS: Multiple individual and family-level factors are associated with metabolic control. These data may aid in identification of diabetic children and adolescents who have a higher risk of poor metabolic control. PMID- 23919501 TI - Analysis of the quality of hospital information systems Audit Trails. AB - BACKGROUND: Audit Trails (AT) are fundamental to information security in order to guarantee access traceability but can also be used to improve Health information System's (HIS) quality namely to assess how they are used or misused. This paper aims at analysing the existence and quality of AT, describing scenarios in hospitals and making some recommendations to improve the quality of information. METHODS: The responsibles of HIS for eight Portuguese hospitals were contacted in order to arrange an interview about the importance of AT and to collect audit trail data from their HIS. Five institutions agreed to participate in this study; four of them accepted to be interviewed, and four sent AT data. The interviews were performed in 2011 and audit trail data sent in 2011 and 2012. Each AT was evaluated and compared in relation to data quality standards, namely for completeness, comprehensibility, traceability among others. Only one of the AT had enough information for us to apply a consistency evaluation by modelling user behaviour. RESULTS: The interviewees in these hospitals only knew a few AT (average of 1 AT per hospital in an estimate of 21 existing HIS), although they all recognize some advantages of analysing AT. Four hospitals sent a total of 7 AT - 2 from Radiology Information System (RIS), 2 from Picture Archiving and Communication System (PACS), 3 from Patient Records. Three of the AT were understandable and three of the AT were complete. The AT from the patient records are better structured and more complete than the RIS/PACS. CONCLUSIONS: Existing AT do not have enough quality to guarantee traceability or be used in HIS improvement. Its quality reflects the importance given to them by the CIO of healthcare institutions. Existing standards (e.g. ASTM:E2147, ISO/TS 18308:2004, ISO/IEC 27001:2006) are still not broadly used in Portugal. PMID- 23919502 TI - Differences between juvenile offenders with and without intellectual disabilities in the importance of static and dynamic risk factors for recidivism. AB - BACKGROUND: Juvenile offenders with intellectual disability (ID) have been largely ignored in the literature of risk assessment, while they are overrepresented in the criminal justice system, and ID is a risk factor for juvenile delinquency and recidivism. The aim of this study was to examine whether there are differences between juvenile offenders with and without ID in the impact of risk factors for recidivism. Both the impact of static and dynamic risk factors were examined. Static risk factors were examined in the criminal history domain and dynamic risk factors were examined in the domains of family, school, use of free time, friends, alcohol/drugs, attitude, aggression and skills. This knowledge is important for both assessment and treatment of juvenile offenders with ID. METHOD: The sample consisted of adolescents who appeared before the courts for a criminal act and for whom the Washington State Juvenile Court Assessment (WSJCA) was completed. The group of ID juvenile offenders (n = 102) consisted of juvenile offenders with a formal diagnosis of ID, which means a full scale IQ of less than 70, coupled with significant deficits in adaptive behaviour, with childhood onset. The juveniles of this group are special education students or they have a formal diagnosis of a special education need. The group without ID (n = 526), was a random sample of all juvenile offenders without a formal diagnosis of ID. RESULTS: No differences were found between juvenile offenders with and without ID in the impact of risk factors on recidivism in most domains. However, in the skills domain, the relations between all risk factors and recidivism were significantly stronger in adolescents without ID than in adolescents with ID. Although not or only borderline statistically significant, these risk factors were all negatively related to recidivism in adolescents with ID, whereas these risk factors were significantly and positively related to recidivism in adolescents without ID. CONCLUSIONS: There are few differences between juvenile offenders with and without ID in the impact of risk factors for recidivism, suggesting that the same assessment methods can be used for juvenile offenders with and without ID. There were, however, differences between juvenile offenders with and without ID in the skills domain. What these differences mean for the treatment of juvenile offenders is yet to be determined. For now it is important to be aware of potential negative (side) effects on recidivism when skills training is offered to juvenile offenders with ID. PMID- 23919503 TI - A prospective study of the patterns and dynamics of colonization with Candida spp. in very low birth weight neonates. AB - BACKGROUND: Knowledge of fungal colonization patterns in very low birth weight infants (VLBWI) admitted to the neonatal intensive care unit (NICU) is essential in understanding the process of fungal infections in neonates. We analyzed prospectively, during 2009-2010, the patterns and dynamics of fungal colonization in VLBWI, including timing, colonization sites, and species involved. METHODS: Weekly skin, oropharynx, and rectum/stool surveillance fungal cultures were collected from admission until discharge in VLBWI in the NICU. None received antifungal prophylaxis. RESULTS: Overall, 118 VLBWI provided 1723 samples; 34 (29%) had 104 positive samples at least once during the first 10 hospitalization weeks. Thirty-nine (33%) weighed < 1000 g; 68 were delivered by cesarean section. Candida albicans (57/104, 55%) and Candida parapsilosis (26/104, 25%) were the main fungi isolated. Eight (24%) VLBWI were colonized during the first week and 23 (68%) during the second week. No differences in colonization were recorded between cesarean section and vaginally delivered VLBWI. The colonization risk at least once during the first 10 weeks was 23% for skin, 14% for oropharynx, 27% for rectum/stool, and 38% for any anatomic site sampled. Persistent colonization was recorded in 5/34 (15%), while transient colonization was found in 14/34 (41%) VLBWI; 16/34 (47%) were discharged or died colonized with Candida spp. Candidemia was diagnosed in 4 (3%) VLBWI and previous/simultaneous colonization was found in 3/4. CONCLUSIONS: The cumulative risk of colonization, at any sampled site and at least once during follow-up, was high. Initial colonization occurred most often during the first 2 weeks of life. Colonization dynamics were characterized by various persistence, disappearance, and recolonization patterns. Candidemia was rare. PMID- 23919506 TI - Formation of heterogeneous polymer films via simultaneous or sequential depositions of soluble and insoluble monomers onto ionic liquids. AB - In this paper, we studied the formation of heterogeneous polymer films on ionic liquid (IL) substrates via the simultaneous or sequential depositions of monomers that are either soluble or insoluble in the liquid. We found that the insoluble monomer 1H,1H,2H,2H-perfluorodecyl acrylate (PFDA) only polymerizes at the IL surface, while the soluble monomer ethylene glycol diacrylate (EGDA) can polymerize at both the IL surface and within the bulk liquid. The polymer chains that form within the bulk liquid entrap IL as they integrate into the polymer film formed at the IL surface, resulting in heterogeneous films that contain IL on the bottom side. Varying the order in which the soluble and insoluble monomers were introduced into the system led to different film structures. When the insoluble monomer was introduced first, a film formed at the surface and the soluble monomer then diffused through this film and polymerized within the bulk, leading to a sandwich structure. When the soluble monomer was introduced first, a layered film was formed whose structure followed the order in which the monomers were introduced. When the two monomers were introduced simultaneously, the soluble monomer polymerized in the bulk while a copolymer film formed at the surface. This study provides an understanding of how to control the composition of layered polymer films deposited onto IL substrates in order to develop new composite materials for separation and electrochemical applications. PMID- 23919504 TI - Aeromonas spp.: ubiquitous or specialized bugs? AB - The genus Aeromonas comprises ubiquitous bacteria that are known to play several roles in the environment. These bacteria were first described as fish pathogens, but their presence was documented in other reservoirs, such as animals and humans. Today, these bacteria are described as emerging pathogens, but their effective role in human pathogenicity is still controversial. In addition, their taxonomy is heavily debated, as species distinction is often difficult to achieve. To study the interspecies relationships and to investigate their connection with the environment, a multilocus sequence typing scheme previously developed for Aeromonas spp. was applied to 258 strains, and the genetic data were analysed by population software. Sampling was a fundamental step, including several of the main sources of Aeromonas: fish, food products and human cases of disease. The objective was to characterize the isolates and to find potential associations among them according to the following: species, sharing of virulence factors, source and adaptation to a specific habitat. The strains were characterized and demonstrated exceptionally high nucleotide variability in the Aeromonas genus. Among the sampled sources, different species distributions were found, highlighting the occurrence of adaptation processes towards specific habitats. PMID- 23919507 TI - Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: comparison, efficacy and safety. AB - INTRODUCTION: Dipeptidyl peptidase (DPP)-4 inhibitors belong to one class of drugs that have been approved for treatment of type 2 diabetes (T2D) based on the glucose-lowering actions of the gastrointestinal hormone glucagon-like peptide (GLP)-1. Several different compounds are now available, and although their mechanism of action (inhibition of the catalytic activity of DPP-4) is the same, there are fundamental differences between them. AREAS COVERED: The authors discuss the differences between different DPP-4 inhibitors and review their therapeutic efficacy and key safety data. The literature covered includes original studies and meta-analyses identified in PubMed, recent abstracts presented at major diabetes scientific conferences, and clinical trials registered at ClinicalTrials.gov. EXPERT OPINION: Although there are some differences in the pharmacokinetic and pharmacodynamic profiles of the different DPP-4 inhibitors, all are small orally active compounds with broadly similar HbA1c-lowering efficacy. They improve glycaemic control in T2D, without increasing the risk of hypoglycaemia or causing weight gain. They can be used as monotherapy or in combination with other anti-diabetic therapies, including insulin, regardless of renal or hepatic function, and are efficacious across the spectrum of patients with T2D, including those with long-standing disease duration. DPP-4 inhibitors may also have beneficial effects beyond glycaemic control, although this remains to be demonstrated in purpose-designed clinical trials. PMID- 23919505 TI - rFN/Cad-11-modified collagen type II biomimetic interface promotes the adhesion and chondrogenic differentiation of mesenchymal stem cells. AB - Properties of the cell-material interface are determining factors in the successful function of cells for cartilage tissue engineering. Currently, cell adhesion is commonly promoted through the use of polypeptides; however, due to their lack of complementary or modulatory domains, polypeptides must be modified to improve their ability to promote adhesion. In this study, we utilized the principle of matrix-based biomimetic modification and a recombinant protein, which spans fragments 7-10 of fibronectin module III (heterophilic motif) and extracellular domains 1-2 of cadherin-11 (rFN/Cad-11) (homophilic motif), to modify the interface of collagen type II (Col II) sponges. We showed that the designed material was able to stimulate cell proliferation and promote better chondrogenic differentiation of rabbit mesenchymal stem cells (MSCs) in vitro than both the FN modified surfaces and the negative control. Further, the Col II/rFN/Cad-11-MSCs composite stimulated cartilage formation in vivo; the chondrogenic effect of Col II alone was much less significant. These results suggested that the rFN/Cad-11-modified collagen type II biomimetic interface has dual biological functions of promoting adhesion and stimulating chondrogenic differentiation. This substance, thus, may serve as an ideal scaffold material for cartilage tissue engineering, enhancing repair of injured cartilage in vivo. PMID- 23919508 TI - Mutual abrasion of endocardial leads: analysis of explanted leads. AB - BACKGROUND: Abrasion of the outer insulation in crush syndrome and in the pocket region is a common cause of endocardial lead failure. Lead fracture at the level of the tricuspid valve has also been described. METHODS AND RESULTS: We examined 1,212 endocardial leads removed percutaneously from 700 patients. The average time the leads had been in place was 77.3 +/- 55.9 months. Macroscopic examination revealed abrasion of the outer insulation with exposure of the metal conductor in the intracardiac parts of 199 leads removed from 177 patients. Lead abrasion was confirmed by examination with an optical microscope. Multivariate analysis showed that the phenomenon was associated with the number of extracted leads, the time the leads had been in place, infections of the cardiovascular electronic device, location of the lead in the coronary sinus, and excessive lead length. CONCLUSION: We conclude that the described mechanical abrasion of the outer lead insulation in the heart chambers could result from mutual friction. It is highly likely that intracardiac lead abrasion might play a role in the formation of intracardiac vegetation and lead-dependent endocarditis. PMID- 23919509 TI - Ebi alleviates excessive growth signaling through multiple epigenetic functions in Drosophila. AB - As multicellular organisms develop, many cells permanently stop dividing and undergo terminal differentiation. The G1 phase of the cell cycle is thought to be the critical decision point for differentiation. Many growth factors, such as epidermal growth factor, are involved in regulating the G1 to S phase transition, and aberrant activation of growth factor signaling is one of the critical causes of tumor formation. Therefore, each cell must have proper mechanisms to suppress inappropriate/excessive activation of growth factor signaling, but the underlying molecular mechanisms remain undefined. Here, we found that ebi, a Drosophila homologue of genes encoding transducin-beta-like 1 and transducin-beta-like 1 related protein, mitigated excess growth stimulation by taking advantage of its distinct epigenetic functions. Ebi acted as a corepressor of transcription by forming a complex with retinoblastoma family protein (RBF), a Drosophila homologue of retinoblastoma, and regulating the expression of specific target genes of the Rbf/E2F pathway. Furthermore, ebi also sustained expression of certain genes, including Rbf, encoding factors that inhibit progression out of G1. Our genetic studies suggest that the antagonistic function of ebi against the Polycomb group silencing complex plays a role in the G1/S phase transition. PMID- 23919510 TI - 5 years after tragedy: an update on organ procurement travel in Michigan. PMID- 23919511 TI - National health insurance, social influence and antenatal care use in Ghana. AB - The study explores the importance of social influence and the availability of health insurance on maternal care utilization in Ghana through the use of antenatal care services. A number of studies have found that access to health insurance plays a critical role in women's decision to utilize antenatal care services. However, little is known about the role that social forces play in this decision. This study uses village-level data from the 2008 Ghana Demographic and Health Survey to investigate the effects of health insurance and social influences on the intensity of antenatal care utilization by Ghanaian women. Using GIS information at the village level, we employ a spatial lag regression model in this study. Results indicate that, controlling for a host of socioeconomic and geographical factors, women who have health insurance appear to use more antenatal services than women who do not. In addition, the intensity of antenatal visits appears to be spatially correlated among the survey villages, implying that there may be some social influences that affect a woman's decision to utilize antenatal care. A reason for this may be that women who benefit from antenatal care through positive pregnancy outcomes may pass this information along to their peers who also increase their use of these services in response. Traditional/Cultural leaders as "gate-keepers" may be useful in the dissemination of maternal health care information. Public health officials may also explore the possibility of disseminating information relating to maternal care services via the mass media. PMID- 23919513 TI - Solution-solid-solid mechanism: superionic conductors catalyze nanowire growth. AB - The catalytic mechanism offers an efficient tool to produce crystalline semiconductor nanowires, in which the choice, state, and structure of catalysts are active research issues of much interest. Here we report a novel solution solid-solid (SSS) mechanism for nanowire growth catalyzed by solid-phase superionic conductor nanocrystals in low-temperature solution. The preparation of Ag2Se-catalyzed ZnSe nanowires at 100-210 degrees C is exampled to elucidate the SSS model, which can be extendable to grow other II-VI semiconductor (e.g., CdSe, ZnS, and CdS) nanowires by the catalysis of nanoscale superionic-phase silver or copper(I) chalcogenides (Ag2Se, Ag2S, and Cu2S). The exceptional catalytic ability of these superionic conductors originates from their structure characteristics, known for high-density vacancies and fast mobility of silver or copper(I) cations in the rigid sublattice of Se(2-) or S(2-) ions. Insights into the SSS mechanism are provided based on the formation of solid solution and the solid-state ion diffusion/transport at solid-solid interface between catalyst and nanowire. PMID- 23919512 TI - Identification of novel key amino acids at the interface of the transmembrane domains of human BST-2 and HIV-1 Vpu. AB - BACKGROUND: BST-2 (bone marrow stromal cell antigen 2) is an interferon-inducible protein that inhibits virus release by tethering viral particles to the cell surface. This antiviral activity of BST-2 is antagonized by HIV-1 accessory protein Vpu. Vpu physically interacts with BST-2 through their mutual transmembrane (TM) domains. In this study, we utilized the BRET assay and molecular dynamics (MD) simulation method to further characterize the interaction of BST-2 and Vpu. RESULTS: Amino acids I34, L37, P40 and L41 in the TM domain of BST-2, and L11, A18 and W22 in the TM domain of Vpu were identified to be critical for the interaction between BST-2 and Vpu. The residues P40 in the TM domain of BST-2 and L11 in the TM domain of Vpu were shown, for the first time, to be important for their interaction. Furthermore, triple-amino-acid substitutions, 14-16 (AII to VAA) and 26-28 (IIE to AAA) in Vpu TM, not the single-residue mutation, profoundly disrupted BST-2/Vpu interaction. The results of MD simulation revealed significant conformational changes of the BST-2/Vpu complex as a result of mutating P40 of BST-2 and L11, 14-16 (AII to VAA) and 26 28 (IIE to AAA) of Vpu. In addition, disrupting the interaction between BST-2 and Vpu rendered BST-2 resistant to Vpu antagonization. CONCLUSIONS: Through use of the BRET assay, we identified novel key residues P40 in the TM domain of BST-2 and L11 in the TM domain of Vpu that are important for their interaction. These results add new insights into the molecular mechanism behind BST-2 antagonization by HIV-1 Vpu. PMID- 23919514 TI - Concept of pharmacogenomics and future considerations. PMID- 23919515 TI - Mixed-function oxidases and esterases associated with permethrin, deltamethrin and bendiocarb resistance in Anopheles gambiae s.l. in the south-north transect Benin, West Africa. AB - BACKGROUND: Insecticide resistance monitoring is essential to help national programmers to implement more effective and sustainable malaria control strategies in endemic countries. The current study aimed at an exploring the involvement of detoxifying enzymes in the insecticide phenotype resistance in Anopheles gambiae s.l.from Benin, in order to guide future malaria vector control interventions. METHODS: Larvae and pupae of Anopheles gambiae s.l. mosquitoes were collected from the breeding sites in Oueme, Atacora and Alibori provinces. CDC susceptibility tests were conducted on unfed female mosquitoes aged 2-5 days old. CDC bioassays were performed with stock solutions of permethrin (21.5 MUg per bottle), deltamethrin (12.5 MUg per bottle) and bendiocarb (12.5 MUg per bottle). CDC biochemical assays using synergists were also conducted to assess the metabolic resistance. RESULTS: The susceptibility of Anopheles gambiae Agbalilame and Kandi populations to permethrin and deltamethrin respectively, increased significantly when synergized by PBO, suggesting an implication of mono oxygenases in resistance of Anopheles gambiae s.l. to pyrethroid. Esterases may play a role in bendiocarb resistance in Anopheles gambiae Tanguieta. CONCLUSION: Synergists partially restored susceptibility to pyrethroid and carbamate insecticides and might help mitigate the impact of vector resistance in Anopheles gambiae Agbalilame, Kandi and Tanguieta populations. However, additional vector control tools are needed to further impact on malaria transmission in such settings.This will improve the implementation and management of future control programs against this important malaria vector in Benin and in Africa in general. PMID- 23919517 TI - DNA methylation errors in imprinting disorders and assisted reproductive technology. AB - There have been increased incident reports of rare imprinting disorders associated with assisted reproductive technology (ART). ART is an important treatment for infertile people of reproductive age and is increasingly common. The identification of epigenetic changes at imprinted loci in ART infants has led to the suggestion that the techniques themselves may predispose embryos to acquisition of imprinting errors and disease. It is still unknown, however, at what point(s) these imprinting errors arise, or the risk factors. In this review it was hypothesized that the particular steps of the ART process may be prone to induction of imprinting methylation errors during gametogenesis, fertilization and early embryonic development. In addition, imprinting diseases and their causes are explained. Moreover, using a Japanese nationwide epidemiological study of imprinting diseases, their association with ART is determined. Epigenetic studies are required to understand the pathogenesis of this association; the ART related risk factor(s); and the precautions that can be taken to prevent the occurrence of these syndromes. It is hoped that the constitution of children born after ART will indicate the safest and most ethical approach to use, which will be invaluable for the future development of standard ART treatment. PMID- 23919516 TI - Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice. AB - BACKGROUND: Akt is a serine/threonine kinase that mediates signaling downstream of tyrosine kinase receptors like the type I insulin-like growth factor receptor (IGF-IR). In fact, we have previously shown that mammary tumors induced by elevated expression of the IGF-IR are associated with hyperactivation of Akt. However, there are three mammalian isoforms of Akt (Akt1, Akt2 and Akt3) and these isoforms regulate distinct physiologic properties within cells. In this manuscript, the impact of disrupting Akt1 or Akt2 in mammary tumors induced by IGF-IR overexpression were examined to determine whether specific Akt isoforms regulate different aspects of mammary tumorigenesis. METHODS: Akt1 and Akt2 levels were stably ablated in mammary tumors of MTB-IGFIR transgenic mice by crossing MTB-IGFIR transgenic mice with either Akt1(-/-) or Akt2(-/-) mice. Tumor onset, growth rate, and metastasis were determined. RESULTS: Ablation of Akt1 or Akt2 significantly delayed tumor onset and tumor growth rate but did not significantly alter lung metastasis. Despite the absence of Akt1 or Akt2, mammary tumors that developed in the MTB-IGFIR mice maintained detectable levels of phosphorylated Akt. Disruption of Akt1 or Akt2 did not affect cell morphology or the expression of luminal or basal cytokeratins in mammary tumors. CONCLUSIONS: Although loss of Akt1 or Akt2 significantly inhibited mammary tumor onset and growth rates the effects were less dramatic than anticipated. Despite the complete loss of Akt1 or Akt2, the level of total phosphorylated Akt remained largely unaffected in the mammary tumors suggesting that loss of one Akt isoform is compensated by enhanced activation of the remaining Akt isoforms. These findings indicate that therapeutic strategies targeting the activation of individual Akt isoforms will prove less effective than simultaneously inhibiting the activity of all three Akt isoforms for the treatment of breast cancer. PMID- 23919518 TI - Care pathways across the primary-hospital care continuum: using the multi-level framework in explaining care coordination. AB - BACKGROUND: Care pathways are widely used in hospitals for a structured and detailed planning of the care process. There is a growing interest in extending care pathways into primary care to improve quality of care by increasing care coordination. Evidence is sparse about the relationship between care pathways and care coordination.The multi-level framework explores care coordination across organizations and states that (inter)organizational mechanisms have an effect on the relationships between healthcare professionals, resulting in quality and efficiency of care.The aim of this study was to assess the extent to which care pathways support or create elements of the multi-level framework necessary to improve care coordination across the primary-hospital care continuum. METHODS: This study is an in-depth analysis of five existing local community projects located in four different regions in Flanders (Belgium) to determine whether the available empirical evidence supported or refuted the theoretical expectations from the multi-level framework. Data were gathered using mixed methods, including structured face-to-face interviews, participant observations, documentation and a focus group. Multiple cases were analyzed performing a cross case synthesis to strengthen the results. RESULTS: The development of a care pathway across the primary-hospital care continuum, supported by a step-by-step scenario, led to the use of existing and newly constructed structures, data monitoring and the development of information tools. The construction and use of these inter organizational mechanisms had a positive effect on exchanging information, formulating and sharing goals, defining and knowing each other's roles, expectations and competences and building qualitative relationships. CONCLUSION: Care pathways across the primary-hospital care continuum enhance the components of care coordination. PMID- 23919519 TI - Assessment on the occupational exposure of manufacturing workers to Dechlorane Plus through blood and hair analysis. AB - Dechlorane Plus (DP), as a widely used flame retardant in different electrical and textile applications, has recently attracted great concern around the world. The present study investigated the DP levels and distribution in human samples from a DP manufacturing plant and a nearby area in east China. The DP concentrations ranged from 89.8 to 2958 ng/g lipid weight in whole blood and 4.08 to 2159 ng/g dry weight in hair. For the workers engaged in DP manufacturing process, their DP levels were significantly higher than those in most of the other two control groups from the nearby area. The values of anti-DP fractional abundance (fanti ratio) were commonly lower in the human samples from both the manufacturing plant and nearby area compared with those in the commercial products, and excretion as well as biotransformation are possible reasons for stereoselective accumulation of the syn-DP isomer in humans. Furthermore, a significantly positive relationship (p < 0.05) was obtained between (i) the concentrations (and fanti) in the paired blood and hair samples, indicating a similar distribution pattern of the two DP isomers in the paired samples; (ii) the DP levels in human body and the exposure time (p < 0.05), which suggests that further assessment could be needed to investigate potential long-term risks to the occupational population. PMID- 23919520 TI - Effect of surface compositional heterogeneities and microphase segregation of fluorinated amphiphilic copolymers on antifouling performance. AB - In this paper, a series of fluorinated amphiphilic copolymers composed of 2 perfluorooctylethyl methacrylate (FMA) and 2-hydroxyethyl methacrylate (HEMA) monomers were prepared, and their surface properties and antifouling performance were investigated. Bovine serum albumin (BSA) and human plasma fibrinogen (HFg) were used as model proteins to study protein adsorption onto the fluorinated amphiphilic surfaces. All the fluorinated amphiphilic surfaces exhibit excellent resistant performance of protein adsorption measured by X-ray photoelectron spectroscopy (XPS). The surface compositional heterogeneities on the molecular scale play an important role in the antifouling properties. It was found that the copolymers exhibited better antifouling properties than the corresponding homopolymers did, when the percentage of hydrophilic hydroxyl groups is from 4% to 7% and the percentage of hydrophobic fluorinated moieties is from 4% to 14% on the surface. In addition, the protein molecular size scale and the pattern of microphase segregation domains on the surface strongly affect the protein adsorption behaviors. These results demonstrate the desirable protein-resistant performance from the fluorinated amphiphilic copolymers and provide deeper insight of the effect of surface compositional heterogeneity and microphase segregation on the protein adsorption behaviors. PMID- 23919521 TI - Validating the Clinical Use of the Modified Huddart and Bodenham Scoring System for Outcome in Cleft Lip and/or Palate. AB - OBJECTIVE: The aim of this study was to validate the clinical use of the modified Huddart and Bodenham scoring system for the measurement of maxillary arch constriction in children born with cleft lip and/or palate. DESIGN: The study design consisted of a reliability assessment between clinical and study model scoring. SETTING: The study was carried out in cleft clinics at three hospital based orthodontic units. PARTICIPANTS: A total of 53 subjects were recruited when attending routine clinic appointments and gave informed consent to participate. INTERVENTION: The modified Huddart and Bodenham scoring system was applied to study models for 53 subjects by all examiners; whereas, one examiner scored 53 subjects clinically, the other two examiners scored 25 and 28 subjects, respectively, on two occasions at least 1 month apart. MAIN OUTCOME MEASURE: Reliability of modified Huddart and Bodenham scoring clinically and on study models was compared. RESULTS: When scoring clinically with the modified Huddart and Bodenham index on two occasions, the intraexaminer and interexaminer intraclass correlation coefficients (ICC) indicated a high level of repeatability and reliability (ICC range, 0.941 to 0.989). The Bland-Altman plots did not show any areas of systematic bias. The ICC between clinical and model scores for each examiner ranged between 0.923 and 0.959. The Bland-Altman plots did not show any areas of systematic bias. The ICC between clinical and model scores for each examiner ranged between 0.923 and 0.959. Canines had lower reliability than molars and incisors. CONCLUSIONS: There was excellent intraexaminer and interexaminer agreement both on study models and in the intraoral scoring using the modified Huddart and Bodenham index. In addition, there was a high degree of correlation between study model and clinical scores using this index. PMID- 23919522 TI - To the editor:. PMID- 23919523 TI - Molar volumes of ethylcyclohexane and butyronitrile glasses resulting from vapor deposition: dependence on deposition temperature and comparison to alkylbenzenes. AB - Molar volumes (Vm) of vapor-deposited ethylcyclohexane (ECH) and butyronitrile (BN, sometimes called butanenitrile) glasses were studied as a function of deposition temperature (Td). ECH glasses deposited at Td sufficiently below their glass-transition temperature (Tg) exhibited changes in Vm on heating similarly to alkylbenzenes. At Td close to Tg, ECH formed dense glasses as alkylbenzenes do, although these glasses were only slightly more dense than its supercooled liquid (SCL) states at the same temperatures. For BN, no indication of the formation of dense glasses was observed even at Td close to Tg, and the variations in Vm with the temperature elevation were different from those of alkylbenzenes. Analysis of the initial Vm of the deposited glasses of different compounds demonstrated that its Td-dependence was well correlated with the steepness index (m) of the corresponding SCL. Quantum-chemical calculations concerning dimer formation by the studied compounds showed that the hydrogen bond between a C-H bond in the alkyl group and pi-electrons in the phenyl ring stabilizes the alkylbenzene dimers, suggesting the possibility of the dense glass formation and large m of these compounds. The small m value of BN was also discussed on the basis of the calculation results. PMID- 23919524 TI - Trace element, oxidant, and antioxidant enzyme values in blood of children with refractory epilepsy. AB - PURPOSE: The aim of this study is to evaluate the serum levels of some trace elements, oxidants, and antioxidants in children with intractable epilepsy compared to healthy children. PATIENTS AND METHODS: In a case-control study, 40 children (24 males and 16 females) suffering from refractory generalized epileptic seizures were compared with 40 sex- and age-matched healthy children serve as a control group. Serum selenium (Se), zinc (Zn), copper (Cu), and plasma malondialdehyde (MDA) as well as erythrocyte glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) values were measured in the patients and controls. RESULTS: Plasma MDA values of the patient group were significantly ( p < 0.001) higher than those in control. Serum Zn, Se, and erythrocyte GSH-Px values of the patient group are significantly ( p < 0.001) lower than those in control, although there is no statistical difference in Cu and SOD values. CONCLUSION: Plasma MDA, erythrocyte GSH-Px, and trace elements Zn and Se may play an important role in the pathogenesis of intractable epilepsy in children. PMID- 23919525 TI - Microglia in juvenile neuronal ceroid lipofuscinosis are primed toward a pro inflammatory phenotype. AB - Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3. Regions of microglial activation precede and predict areas of neuronal loss in JNCL; however, the functional role of activated microglia remains to be defined. The inflammasome is a key molecular pathway for activating pro-IL-1beta in microglia, and IL-1beta is elevated in the brains of JNCL patients and can induce neuronal cell death. Here, we utilized primary microglia isolated from CLN3(Deltaex7/8) mutant and wild-type (WT) mice to examine the impact of CLN3 mutation on microglial activation and inflammasome function. Treatment with neuronal lysates and ceramide, a lipid intermediate elevated in the JNCL brain, led to inflammasome activation and IL 1beta release in CLN3(Deltaex7/8) microglia but not WT cells, as well as increased expression of additional pro-inflammatory mediators. Similar effects were observed following either TNF-alpha or IL-1beta treatment, suggesting that CLN3(Deltaex7/8) microglia exist in primed state and hyper-respond to several inflammatory stimuli compared to WT cells. CLN3(Deltaex7/8) microglia displayed constitutive caspase-1 activity that when blocked led to increased glutamate release that coincided with hemichannel opening. Conditioned medium from activated CLN3(Deltaex7/8) or WT microglia induced significant cell death in CLN3(Deltaex7/8) but not WT neurons, demonstrating that intrinsically diseased CLN3(Deltaex7/8) neurons are less equipped to withstand cytotoxic insults generated by activated microglia. Collectively, aberrant microglial activation may contribute to the pathological chain of events leading to neurodegeneration during later stages of JNCL. PMID- 23919526 TI - Spirometry results (FEV1 and FVC) in young Bantu men from Tanzania vs environmental and family characteristics. AB - OBJECTIVES: The aim of this paper was to examine the extent to which socioeconomic factors, anthropological data and somatic indices influenced the results of spirometric measurements (FEV1 and FVC) in Tanzanian youth. MATERIALS AND METHODS: The population studied were young black Bantu men aged 12.8-24.0 years. Analysis was performed for the whole data set (n = 255), as well as separately for two age groups: under 17.5 years (n = 168) and 17.5 + (n = 87). A backward stepwise multiple regression analysis was performed for FEV1 and FVC as dependent variables on socioeconomic and anthropometric data. RESULTS: Multiple regression analysis for the whole group revealed that the socioeconomic and anthropometric data under analysis accounted for 38% of the variation in FEV1. In addition the analysis demonstrated that 34% of the variation in FVC could be accounted for by the variables used in the regression. A significant impact in explaining the variability of FVC was exhibited by the thorax mobility, financial situation of the participants and Pignet-Verwaecka Index. CONCLUSION: Analysis of the data indicates the significant role of selected socio-economic factors on the development of the biological specimens investigated. There were no perceptible pathologies, and the results can be treated as a credible interpretation of the influence exerted by the environment in which the teenagers under study grew up. PMID- 23919527 TI - Designing CXCL8-based decoy proteins with strong anti-inflammatory activity in vivo. AB - IL (interleukin)-8 [CXCL8 (CXC chemokine ligand 8)] exerts its role in inflammation by triggering neutrophils via its specific GPCRs (G-protein-coupled receptors), CXCR1 (CXC chemokine receptor 1) and CXCR2, for which additional binding to endothelial HS-GAGs (heparan sulphate-glycosaminoglycans) is required. We present here a novel approach for blocking the CXCL8-related inflammatory cascade by generating dominant-negative CXCL8 mutants with improved GAG-binding affinity and knocked-out CXCR1/CXCR2 activity. These non-signalling CXCL8 decoy proteins are able to displace WT (wild-type) CXCL8 and to prevent CXCR1/CXCR2 signalling thereby interfering with the inflammatory response. We have designed 14 CXCL8 mutants that we subdivided into three classes according to number and site of mutations. The decoys were characterized by IFTs (isothermal fluorescence titrations) and SPR (surface plasmon resonance) to determine GAG affinity. Protein stability and structural changes were evaluated by far-UV CD spectroscopy and knocked-out GPCR response was shown by Boyden chamber and Ca2+ release assays. From these experiments, CXCL8(Delta6F17KF21KE70KN71K) emerged with the most promising in vitro characteristics. This mutant was therefore further investigated in a murine model of mBSA (methylated BSA)-induced arthritis in mice where it showed strong anti-inflammatory activity. Based on these results, we propose that dominant-negative CXCL8 decoy proteins are a promising class of novel biopharmaceuticals with high therapeutic potential in inflammatory diseases. PMID- 23919528 TI - Complete genome of a new Firmicutes species belonging to the dominant human colonic microbiota ('Ruminococcus bicirculans') reveals two chromosomes and a selective capacity to utilize plant glucans. AB - The recently isolated bacterial strain 80/3 represents one of the most abundant 16S rRNA phylotypes detected in the healthy human large intestine and belongs to the Ruminococcaceae family of Firmicutes. The completed genome sequence reported here is the first for a member of this important family of bacteria from the human colon. The genome comprises two large chromosomes of 2.24 and 0.73 Mbp, leading us to propose the name Ruminococcus bicirculans for this new species. Analysis of the carbohydrate active enzyme complement suggests an ability to utilize certain hemicelluloses, especially beta-glucans and xyloglucan, for growth that was confirmed experimentally. The enzymatic machinery enabling the degradation of cellulose and xylan by related cellulolytic ruminococci is however lacking in this species. While the genome indicated the capacity to synthesize purines, pyrimidines and all 20 amino acids, only genes for the synthesis of nicotinate, NAD+, NADP+ and coenzyme A were detected among the essential vitamins and co-factors, resulting in multiple growth requirements. In vivo, these growth factors must be supplied from the diet, host or other gut microorganisms. Other features of ecological interest include two type IV pilins, multiple extracytoplasmic function-sigma factors, a urease and a bile salt hydrolase. PMID- 23919529 TI - Golden goal controls dendrite elongation and branching of multidendritic arborization neurons in Drosophila. AB - Precise refinement of axonal and dendritic patterns is essential for the maturation of functional neuronal circuits. Although several transmembrane molecules have been shown to control the development of both axons and dendrites, the molecular mechanisms that regulate these different processes are poorly understood. Golden Goal (Gogo) is one of the molecules that are known to control the development of axons in the Drosophila visual system. In this study, we analyzed Gogo function in dendritic field formation of dorsal multidendritic arborization (md-da) neurons of the Drosophila Peripheral Nervous System. We showed that Gogo is required to restrain the growth of ddaC dendrites toward the midline in the embryo. During larval stages, Gogo promotes dendritic branching of the complex classIV ddaC neurons. However, over-expression of Gogo restrained dendritic branch formation in ddaC neurons, and this phenotype was enhanced by co over-expression with Flamingo (Fmi), a partner of Gogo in axon guidance. These results suggest Gogo plays important roles in maintaining homeostasis of dendritic branching. Like axons, the cytoplasmic part of Gogo is required for its function in dendritic tree formation, suggesting that Gogo conveys information from extracellular cues to intracellular molecules that control dendrite development. PMID- 23919530 TI - Brominated and fluorinated organic pollutants in the breast milk of first-time Irish mothers: is there a relationship to levels in food? AB - Brominated flame retardants - polybrominated diphenyl ethers (PBDEs), polybrominated biphenyls (PBBs), hexabromocyclododecane (HBCD) and others - have been measured in 11 pooled breast milk samples from 109 first-time mothers in Ireland. Additionally, the study has measured levels of polybrominated dibenzo-p dioxins and furans (PBDD/Fs), mixed halogenated dioxins (PXCC/Fs) and biphenyls (PXBs), polychlorinated naphthalenes (PCNs) and perfluoroalkylated substances (PFAS) in these samples. The mean sum of 19 PBDEs including BDE-209 was 4.85 ng g(-1) fat, which is comparable with that found in other European countries. BDE 47, BDE-153, BDE-209, BDE-99 and BDE-100 were found at the highest concentrations. The only PBBs detected consistently were BB-77, BB-126 and BB 153, with highest concentrations being found for BB-153 (mean = 0.13 ng g(-1) fat). The mean sum of HBCD enantiomers was 3.52 ng g(-1) fat, with alpha-HBCD representing over 70% of the total. Of the other brominated flame retardants - tetrabromobisphenol-A (TBBP-A), hexabromobenzene (HBB), decabromodiphenylethane (DBDPE) and bis(2,4,6-tribromophenoxyethane) (BTBPE) - examined, only TBBP-A was detected above the limit of detection (LOD), in two of the 11 pools analysed. All measured PBDF congeners were observed (at 0.02-0.91 pg g(-1) fat), but 2,3,7,8 tetrabromo-dibenzodioxin (TeBDD) was the only PBDD detected, with a mean concentration of 0.09 pg g(-1) fat. The occurrence of the mixed chlorinated/brominated dibenzodioxins, dibenzofurans and biphenyls, 2-B-3,7,8 CDD, 2,3-B-7,8-CDF, 4-B-2,3,7,8-CDF, PXB 105, PXB 118, PXB 126 and PCB 156 in breast milk in the current study may indicate that levels of these contaminants are increasing in the environment. Polychlorinated naphthalenes were detected in all samples, but not perfluorooctane sulfonate (PFOS) and other PFAS. The pattern of occurrence of these brominated and fluorinated persistent organic pollutants (POPs) in Irish breast milk shows a general relationship to their occurrence in food, as reported in a number of surveillance studies carried out by the Food Safety Authority of Ireland. PMID- 23919532 TI - Organic monolayers from 1-alkynes covalently attached to chromium nitride: alkyl and fluoroalkyl termination. AB - Strategies to modify chromium nitride (CrN) surfaces are important because of the increasing applications of these materials in various areas such as hybrid electronics, medical implants, diffusion barrier layers, corrosion inhibition, and wettability control. The present work presents the first surface immobilization of alkyl and perfluoro-alkyl (from C6 to C18) chains onto CrN substrates using appropriately functionalized 1-alkynes, yielding covalently bound, high-density organic monolayers with excellent hydrophobic properties and a high degree of short-range order. The obtained monolayers were characterized in detail by water contact angle, X-ray photoelectron spectroscopy (XPS), ellipsometry, and infrared reflection absorption spectroscopy (IRRAS). PMID- 23919533 TI - Successful treatment of chronic HCV infection should not preclude kidney donation to an HCV negative recipient. PMID- 23919534 TI - Clinical importance of renal calyceal microlithiasis in children. AB - BACKGROUND: Renal calyceal microlithiasis refers to a hyperechogenic spot in renal calyces <3 mm in diameter detected on renal sonography. These spots possibly represent the first step in calculus formation. The aim of this study was to analyze the clinical presentation, predisposing factors, prognosis and clinical importance of these hyperechogenic spots in renal calyces, renal calyceal microlithiasis, during childhood. METHODS: The data of 292 children (135 girls, 157 boys) with microlithiasis diagnosed between January 1998 and December 2010 were evaluated retrospectively. Demographic data, serum biochemistry, urinary metabolic factors, and renal sonography results were obtained from patient files. A total of 228 patients were re-evaluated at least 6 months after the first observation of renal calyceal microlithiasis and at 6-12 month intervals thereafter. RESULTS: Mean age was 16.8 +/- 14.9 months, and mean follow up duration was 14.6 +/- 5.9 months. Presenting symptoms were abdominal or flank pain (41.1%), hematuria (35.6%), dysuria (24.7%) and urinary tract infection (34.6%). Previous ultrasounds were normal in 35% of the children. Metabolic and anatomic abnormalities were found in 55.5% and 17.8%, respectively. Hypercalciuria was the most common metabolic abnormality (88.9%). Among 228 patients who had been re-evaluated, microlithiasis disappeared in 37.7%; decreased in number or size in 23.7%; progressed to renal stone formation in 10.6%; increased in number of microlithiasis in 19.0%; and remained unchanged on radiology in 9.0%. CONCLUSION: Renal calyceal microlithiasis represents a spectrum of clinical situations and underlying metabolic abnormalities that need further investigation in children. PMID- 23919535 TI - Directing self-assembly of DNA nanotubes using programmable seeds. AB - Control over when and where nanostructures arise is essential for the self assembly of dynamic or multicomponent devices. We design and construct a DNA origami seed for the control of DAE-E tile DNA nanotube assembly. Seeds greatly accelerate nanotube nucleation and growth because they serve as nanotube nucleation templates. Seeds also control nanotube circumference. Simulations predict nanotube growth rates and suggest a small nucleation barrier remains when nanotubes grow from seeds. PMID- 23919536 TI - The role of chemotherapy in managing chronic lymphocytic leukemia: optimizing combinations with targeted therapy. AB - For many years, alkylating agents were the standard treatment for chronic lymphocytic leukemia (CLL). The advent of purine analogs improved response rates, but not overall survival, and although the monoclonal antibody rituximab is generally active against B-cell malignancies, it has demonstrated limited benefits as monotherapy for the treatment of CLL. However, specific combinations of chemotherapy, antibodies and targeted therapies have demonstrated additive or synergistic activity in CLL cells and deliver substantial clinical benefits. A greater understanding of the actions of chemotherapies and targeted agents on cellular pathways will advance the development of rationally designed combinations corresponding to individual patients' disease profiles. PMID- 23919537 TI - Tear fluid proteomics multimarkers for diabetic retinopathy screening. AB - BACKGROUND: The aim of the project was to develop a novel method for diabetic retinopathy screening based on the examination of tear fluid biomarker changes. In order to evaluate the usability of protein biomarkers for pre-screening purposes several different approaches were used, including machine learning algorithms. METHODS: All persons involved in the study had diabetes. Diabetic retinopathy (DR) was diagnosed by capturing 7-field fundus images, evaluated by two independent ophthalmologists. 165 eyes were examined (from 119 patients), 55 were diagnosed healthy and 110 images showed signs of DR. Tear samples were taken from all eyes and state-of-the-art nano-HPLC coupled ESI-MS/MS mass spectrometry protein identification was performed on all samples. Applicability of protein biomarkers was evaluated by six different optimally parameterized machine learning algorithms: Support Vector Machine, Recursive Partitioning, Random Forest, Naive Bayes, Logistic Regression, K-Nearest Neighbor. RESULTS: Out of the six investigated machine learning algorithms the result of Recursive Partitioning proved to be the most accurate. The performance of the system realizing the above algorithm reached 74% sensitivity and 48% specificity. CONCLUSIONS: Protein biomarkers selected and classified with machine learning algorithms alone are at present not recommended for screening purposes because of low specificity and sensitivity values. This tool can be potentially used to improve the results of image processing methods as a complementary tool in automatic or semiautomatic systems. PMID- 23919538 TI - Comorbid psychopathology and stress mediate the relationship between autistic traits and repetitive behaviours in adults with autism. AB - BACKGROUND: Comorbid psychopathology and stress were considered possible mediators that may explain the relationship between some autistic traits and repetitive behaviours. The current study sought to examine the mediational effects of comorbid psychopathology, executive dysfunctions and stress in the relationship between some autistic traits and repetitive behaviours. METHOD: A battery of questionnaires including measures of autistic traits, repetitive behaviours, stress, executive dysfunctions and comorbid psychopathology were administered to a sample of adults with autism and intellectual disabilities (n = 43). RESULTS: We found that when taken as set dimensions of comorbidity, dysexecutive functioning and stress mediated or explained the effects of autistic symptoms on repetitive behaviour. The total model explained 60% of the variation in repetitive behaviours (R = 0.60; F = 13.64, P < 0.001). The results are discussed in the light of pertinent previous research and their clinical implications, and suggestions for future research are provided. CONCLUSIONS: According to the investigated model, increased levels of comorbid psychopathology and stress explained the relationships between repetitive/restrictive behaviours and autistic traits in adults with autism, while executive functioning did not contribute to that relationship. PMID- 23919539 TI - Migration of South African health workers: the extent to which financial considerations influence internal flows and external movements. AB - BACKGROUND: The loss of human resource capacity has had a severe impact on the health system in South Africa. This study investigates the causes of migration focussing on the role of salaries and benefits. Health professionals from public, private and non-governmental (NGO) health facilities located in selected peri urban and urban areas in KwaZulu-Natal, South Africa were surveyed about their current positions and attitudes toward migration. METHODS: The study uses cross sectional data collected in 2009. A total of 694 health professionals (430 in the public sector, 133 in the NGO sector and 131 in the private sector) were surveyed. An additional 11 health professionals were purposively selected for in depth interviews. Odds ratios with 95% confidence intervals were calculated to determine whether salaries influenced HWs decisions to migrate. RESULTS: HWs decision to move was not positively associated with lower salaries. It was found, instead, that the consideration to move was determined by other factors including age, levels of stress experienced and the extent to which they were satisfied at their current place of work. CONCLUSIONS: The OSD appears to have lowered the risk of HWs migrating due to low salaries. However, the results also indicate that the South African Department of Health needs to improve working conditions for HWs within the public health sector to assist in retention. PMID- 23919540 TI - How to get started with a systematic review in epidemiology: an introductory guide for early career researchers. AB - BACKGROUND: Systematic review is a powerful research tool which aims to identify and synthesize all evidence relevant to a research question. The approach taken is much like that used in a scientific experiment, with high priority given to the transparency and reproducibility of the methods used and to handling all evidence in a consistent manner.Early career researchers may find themselves in a position where they decide to undertake a systematic review, for example it may form part or all of a PhD thesis. Those with no prior experience of systematic review may need considerable support and direction getting started with such a project. Here we set out in simple terms how to get started with a systematic review. DISCUSSION: Advice is given on matters such as developing a review protocol, searching using databases and other methods, data extraction, risk of bias assessment and data synthesis including meta-analysis. Signposts to further information and useful resources are also given. CONCLUSION: A well-conducted systematic review benefits the scientific field by providing a summary of existing evidence and highlighting unanswered questions. For the individual, undertaking a systematic review is also a great opportunity to improve skills in critical appraisal and in synthesising evidence. PMID- 23919541 TI - Cation-induced hydrogels of cellulose nanofibrils with tunable moduli. AB - Cellulose nanofibrils are biocompatible nanomaterials derived from sustainable natural sources. We report hydrogelation of carboxylated cellulose nanofibrils with divalent or trivalent cations (Ca(2+), Zn(2+), Cu(2+), Al(3+), and Fe(3+)) and subsequent formation of interconnected porous nanofibril networks. The gels were investigated by dynamic viscoelastic measurements. The storage moduli of the gels are strongly related to valency of the metal cations and their binding strength with carboxylate groups on the nanofibrils. Hydrogel moduli may be tuned by appropriate choice of cation. Cation-carboxylate interactions are proposed to initiate gelation by screening of the repulsive charges on the nanofibrils and to dominate gel properties through ionic cross-linking. Binding energies of cations with carboxylate groups were calculated from molecular models developed for nanofibril surfaces to validate the correlation and provide further insight into the cross-linked structures. The cellulose nanofibril-based hydrogels may have a variety of biomedical and other applications, taking advantage of their biocompatibility, high porosity, high surface area, and durability in water and organic solvents. PMID- 23919542 TI - Facile and efficient one-pot synthesis of benzimidazoles using lanthanum chloride. AB - BACKGROUND: We report the synthesis of benzimidazoles using lanthanum chloride as an efficient catalyst. One-pot synthesis of 2-substituted benzimidazole derivatives from o-phenylenediamine and a variety of aldehydes were developed under mild reaction conditions. RESULTS: We have examined the effect of different solvents using the same reaction conditions. The yield of the product varied with the nature of the solvents, and better conversion and easy isolation of products were found with acetonitrile. In a similar manner, the reaction with o phenylenediamine and 3,4,5-trimethoxybenzaldehyde was carried out without any solvents. The observation shows that the reaction was not brought into completion, even after starting for a period of 9 h, and the reaction mixture showed a number of spots in thin-layer chromatography. CONCLUSIONS: In conclusion, lanthanum chloride has been employed as a novel and efficient catalyst for the synthesis of benzimidazoles in good yields from o phenylenediamine and a wide variety of aldehydes. All of the reactions were carried out in the presence of lanthanum chloride (10 mol%) in acetonitrile at room temperature. PMID- 23919543 TI - Total synthesis of the cytotoxic anhydrophytosphingosine pachastrissamine (jaspine B). AB - A short, 8-step synthesis of the marine natural product pachastrissamine has been developed that relies on a diastereoselective aldol reaction between a suitably protected hydantoin and an optically enriched alpha-chloroaldehyde. This synthetic route provides new opportunities for exploring structure activity relationships within this family of natural products. PMID- 23919544 TI - Gene expression of fathead minnows (Pimephales promelas) exposed to two types of treated municipal wastewater effluents. AB - Contaminants of emerging concern (CECs) in treated municipal effluents have the potential to adversely impact exposed organisms prompting elevated public concern. Using transcriptomic tools, we investigated changes in gene expression and cellular pathways in the liver of male fathead minnows (Pimephales promelas) exposed to 5% concentrations of full secondary-treated (HTP) or advanced primary treated (PL) municipal wastewater effluents containing CECs. Gene expression changes were associated with apical end points (plasma vitellogenin and changes in secondary sexual characteristics). Of 32 effluent CECs analyzed, 28 were detected including pharmaceuticals, personal care products, hormones, and industrial compounds. Exposure to both effluents produced significantly higher levels of plasma VTG and changes in secondary sexual characteristics (e.g., ovipositor development). Transcript patterns differed between effluents, with <10% agreement in the detected response (e.g., altered production of transcripts involved in xenobiotic detoxification, oxidative stress, and apoptosis were observed following exposure to both effluents). Exposure to PL effluent caused changes in transcription of genes involved in metabolic pathways (e.g., lipid transport and steroid metabolism). Exposure to HTP effluent affected transcripts involved in signaling pathways (e.g., focal adhesion assembly and extracellular matrix). The results suggest a potential association between some transcriptomic changes and physiological responses following effluent exposure. This study identified responses in pathways not previously implicated in exposure to complex chemical mixtures containing CECs, which are consistent with effluent exposure (e.g., oxidative stress) in addition to other pathway responses specific to the effluent type. PMID- 23919545 TI - The promise of sulfated synthetic small molecules as modulators of glycosaminoglycan function. PMID- 23919546 TI - Fluorescent ligands for G protein-coupled receptors: illuminating receptor-ligand interactions for drug discovery. PMID- 23919548 TI - Interview with James Bradner. Interviewed by Hannah Coaker. AB - James E Bradner is an Assistant Professor in Medicine at Harvard Medical School (MA, USA) as well as a Staff Physician in the Division of Hematologic Malignancies at Dana-Farber Cancer Institute (MA, USA). The present research focus of the Bradner laboratory concerns the discovery and optimization of prototype drugs targeting cancer gene regulation. The clinical objective of the Bradner group is to deliver novel therapeutics for human clinical investigation in hematologic diseases. Bradner's awards and honors include the Damon Runyon Rachleff Innovation Award, the Smith Family Award for Excellence in Biomedical Research, the Dunkin' Donuts Rising Star Award and the HMS Distinguished Excellence in Teaching Award. He is a member of the American Society of Clinical Investigation, the American Society of Hematology, the American Chemical Society and the American Association of Cancer Research. His recent research has been published in Nature, Cell, Nature Chemical Biology and the Journal of the American Chemical Society. He has authored more than 20 US Patent applications, licensed to five pharmaceutical companies, and is a scientific founder of Acetylon Pharmaceuticals, SHAPE Pharmaceuticals, Tensha Therapeutics and Syros Pharmaceuticals. Bradner received his AB from Harvard University, his MD from the University of Chicago (IL, USA) and a MMS from Harvard Medical School. He completed his postgraduate training in Internal Medicine at Brigham & Women's Hospital (MA, USA), followed by a fellowship in Medical Oncology and Hematology at Dana-Farber Cancer Institute. Following additional post-doctoral training in Chemistry at Harvard University and the Broad Institute (MA, USA) with Professor Stuart Schreiber, Bradner joined the research faculty of Dana-Farber in 2008. Interview conducted by Hannah Coaker, Assistant Commissioning Editor. PMID- 23919549 TI - A green approach toward quinoxalines and bis-quinoxalines and their biological evaluation against A431, human skin cancer cell lines. AB - BACKGROUND: The objective of this study was to develop a practical green procedure to synthesize quinoxalines and bis-quinoxalines and evaluate their inhibitory effects on the viability of A431 human epidermoid carcinoma cells. METHOD: A series of quinoxaline and bis-quinoxaline derivatives have been designed and synthesized following a microwave-assisted and bismuth nitrate catalyzed eco-friendly route. A detailed comparison has been made between microwave-induced protocol with the reactions occurred at room temperature. The structure of the compounds have been elucidated by various spectroscopic methods and finally confirmed by x-ray crystallographic analyses. RESULTS: Two quinoxaline derivatives, compounds 6 and 12 have demonstrated inhibitory effects on the viability of A431 human epidermoid carcinoma cells when compared with HaCaT nontumorigenic human keratinocyte cells. CONCLUSION: Notably, compound 6 inhibits Stat3 phosphorylation/activation in A431 skin cancer cells. PMID- 23919550 TI - Insights on how the Mycobacterium tuberculosis heme uptake pathway can be used as a drug target. AB - Mycobacterium tuberculosis (Mtb) acquires non-heme iron through salicylate derived siderophores termed mycobactins whereas heme iron is obtained through a cascade of heme uptake proteins. Three proteins are proposed to mediate Mtb heme iron uptake, a secreted heme transporter (Rv0203), and MmpL3 and MmpL11, which are potential transmembrane heme transfer proteins. Furthermore, MhuD, a cytoplasmic heme-degrading enzyme, has been identified. Rv0203, MmpL3 and MmpL11 are mycobacteria-specific proteins, making them excellent drug targets. Importantly, MmpL3, a necessary protein, has also been implicated in trehalose monomycolate export. Recent drug-discovery efforts revealed that MmpL3 is the target of several compounds with antimycobacterial activity. Inhibition of the Mtb heme uptake pathway has yet to be explored. We propose that inhibitor design could focus on heme analogs, with the goal of blocking specific steps of this pathway. In addition, heme uptake could be hijacked as a method of importing drugs into the mycobacterial cytosol. PMID- 23919552 TI - Development of small molecules to target the IgE:FcepsilonRI protein-protein interaction in allergies. AB - The protein-protein interaction (PPI) between IgE and its high-affinity receptor (FcepsilonRI) is a key component of the allergic response. Inhibiting the IgE:FcepsilonRI PPI is an attractive strategy for therapeutic intervention and the development of allergy treatments. This PPI has been validated as a viable target by the monoclonal anti-IgE antibody omalizumab (Xolair((r))), which has demonstrated clinical efficacy when prescribed to treat moderate-to-severe asthma and hay fever, but small molecules would be a more convenient form of treatment. Cyclic peptides, small proteins and a natural product have all been developed to target the IgE:FcepsilonRI PPI, and these will be discussed in this review. Targeting the IgE:FcepsilonRI complex with small molecules presents various challenges, some of which are inherent in all PPI targets but some of which are unique to this system, which presents great opportunities for the development of new therapeutics for the treatment of allergies. PMID- 23919551 TI - A review of ceramide analogs as potential anticancer agents. AB - Ceramide serves as a central mediator in sphingolipid metabolism and signaling pathways, regulating many fundamental cellular responses. It is referred to as a 'tumor suppressor lipid', since it powerfully potentiates signaling events that drive apoptosis, cell cycle arrest, and autophagic responses. In the typical cancer cell, ceramide levels and signaling are usually suppressed by overexpression of ceramide-metabolizing enzymes or downregulation of ceramide generating enzymes. However, chemotherapeutic drugs as well as radiotherapy increase intracellular ceramide levels, while exogenously treating cancer cells with short-chain ceramides leads to anticancer effects. All evidence currently points to the fact that the upregulation of ceramide levels is a promising anticancer strategy. In this review, we exhibit many anticancer ceramide analogs as downstream receptor agonists and ceramide-metabolizing enzyme inhibitors. PMID- 23919554 TI - Modulating nitric oxide signaling in the CNS for Alzheimer's disease therapy. AB - Nitric oxide (NO)/solube GC (sGC)/cGMP signaling is important for modulating synaptic transmission and plasticity in the hippocampus and cerebral cortex, which are critical for learning and memory. Physiological concentrations of NO also elicit anti-apoptotic/prosurvival effects against various neurotoxic challenges and brain insults through multiple mechanisms. Depression of the NO/sGC pathway is a feature of Alzheimer's disease (AD), attributed to amyloid beta neuropathology, and altered expression and activity of NOS, sGC and PDE enzymes. Different classes of NO-releasing hybrid drugs, including nomethiazoles, NO-NSAIDs and NO-acetylcholinesterase inhibitors were designed to deliver low concentrations of exogenous NO to the CNS while targeting other underlying disease mechanisms, such as excitotoxicity, neuro-inflammation and acetylcholine deficiency, respectively. Incorporating a NO-donating moiety may also reduce gastrointestinal and liver toxicity of the parent drugs. Progress has also been made in targeting downstream sGC and PDE enzymes. The PDE9 inhibitor PF-04447943 has completed Phase II clinical trials for AD. The search for effective NO donating hybrid drugs, CNS-targeting sGC stimulators/activators and selective PDE inhibitors is an important goal for pharmacotherapy that manipulates NO biochemical pathways involved in cognitive function and neuroprotection. Rigorous preclinical validation of target engagement, and optimization of pharmacokinetic and toxicity profiles are likely to advance more drug candidates into clinical trials for mild cognitive impairment and early stage AD. PMID- 23919553 TI - Hemozoin and antimalarial drug discovery. AB - Recent initiatives to develop more effective and affordable drugs, controlling mosquitoes and development of a preventative vaccine have been launched with the goal of completely eradicating malaria. To this end, Novartis (Surrey, UK) and GlaxoSmithKline (Middlesex, UK) screened their chemical libraries of approximately two million small molecules for antimalarial properties, which resulted in a set of over 20,000 'highly druggable' initial hits. Efforts in academia are centered on specific pathway targets. One such high-throughput screening effort has been focused on hemozoin formation, a unique heme detoxification pathway found in the malaria parasite. This review discusses the current approaches and limitations of high-throughput screening discovery of hemozoin inhibitors. In the future, new methods must be developed to validate the mechanism of action of these hit compounds within the parasite. PMID- 23919556 TI - Influence of phospholipid composition on self-assembly and energy-transfer efficiency in networks of light-harvesting 2 complexes. AB - In the photosynthetic membrane of purple bacteria networks of light-harvesting 2 (LH2) complexes capture the sunlight and transfer the excitation energy. In order to investigate the mutual relationship between the supramolecular organization of the pigment-protein complexes and their biological function, the LH2 complexes were reconstituted into three types of phospholipid membranes, consisting of L alpha-phosphatidylglycerol (PG), L-alpha-phosphatidylcholine (PC), and L-alpha phosphatidylethanolamine (PE)/PG/cardiolipin (CL). Atomic force microscopy (AFM) revealed that the type of phospholipids had a crucial influence on the clustering tendency of the LH2 complexes increased from PG over PC to PE/PG/CL, where the LH2 complexes formed large, densely packed clusters. Time-resolved spectroscopy uncovered a strong quenching of the LH2 fluorescence that is ascribed to singlet singlet and singlet-triplet annihilation by an efficient energy transfer between the LH2 complexes in the artificial membrane systems. Quantitative analysis reveals that the intercomplex energy transfer efficiency varies strongly as a function of the morphology of the nanostructure, namely in the order PE/PG/CL > PC > PG, which is in line with the clustering tendency of LH2 observed by AFM. These results suggest a strong influence of the phospholipids on the self assembly of LH2 complexes into networks and concomitantly on the intercomplex energy transfer efficiency. PMID- 23919557 TI - What is the impact of hypogammaglobulinemia on the rate of infections and survival in solid organ transplantation? A meta-analysis. AB - Hypogammaglobulinemia has been described after solid organ transplantation and has been associated with increased risk of infections. The aim of the study was to evaluate the rate of severe hypogammaglobulinemia and its relationship with the risk of infections during the first year posttransplantation. Eighteen studies (1756 patients) that evaluated hypogammaglobulinemia and posttransplant infections were included. The data were pooled using the DerSimonian and Laird random-effects model. Q statistic method was used to assess statistical heterogeneity. Within the first year posttransplantation, the rate of hypogammaglobulinemia (IgG < 700 mg/dL) was 45% (95% CI: 0.34-0.55; Q = 330.1, p < 0.0001), the rate of mild hypogammaglobulinemia (IgG = 400-700 mg/dL) was 39% (95% CI: 0.22-0.56; Q = 210.09, p < 0.0001) and the rate of severe hypogammaglobulinemia (IgG < 400 mg/dL) was 15% (95% CI: 0.08-0.22; Q = 50.15, p < 0.0001). The rate of hypogammaglobulinemia by allograft type: heart 49% (21% 78%; Q = 131.16, p < 0.0001); kidney 40% (30%-49%; Q = 24.55, p = 0.0002); liver 16% (0.001%-35%; Q = 14.31, p = 0.0002) and lung 63% (53%-74%; Q = 6.85, p = 0.08). The odds of respiratory infection (OR = 4.83; 95% CI: 1.66-14.05; p = 0.004; I(2) = 0%), CMV (OR = 2.40; 95% CI: 1.16-4.96; p = 0.02; I(2) = 26.66%), Aspergillus (OR = 8.19; 95% CI: 2.38-28.21; p = 0.0009; I(2) = 17.02%) and other fungal infections (OR = 3.69; 95% CI: 1.11-12.33; p = 0.03; I(2) = 0%) for patients with IgG < 400 mg/dL were higher than the odds for patients with IgG > 400 mg/dL. The odds for 1-year all-cause mortality for severe hypogammaglobulinemia group was 21.91 times higher than those for IgG > 400 mg/dL group (95% CI: 2.49-192.55; p = 0.005; I(2) = 0%). Severe hypogammaglobulinemia during the first year posttransplantation significantly increased the risk of CMV, fungal and respiratory infections, and was associated with higher 1-year all cause mortality. PMID- 23919558 TI - Solution-focused brief therapy from the perspective of clients with long-term physical health conditions. AB - As long-term physical health conditions are becoming increasingly prevalent in our society, interventions are needed to help individuals live as well as possible. The research explores participants' experiences of solution-focused brief therapy (SFBT) with a view to determining helpful aspects of this. Eleven service users were interviewed, and interviews were analysed using inductive thematic analysis. Participants' responsibility for change and the strengths and resources they possessed were highlighted, along with the focus within therapy on goals. A number of specific SFBT techniques that were perceived as helpful during therapy were described such as reframing, competence talk and reflectiveness, as well as other factors that enabled engagement with the psychologist. PMID- 23919559 TI - Three-dimensional mapping of quantum wells in a GaN/InGaN core-shell nanowire light-emitting diode array. AB - Correlated atom probe tomography, cross-sectional scanning transmission electron microscopy, and cathodoluminescence spectroscopy are used to analyze InGaN/GaN multiquantum wells (QWs) in nanowire array light-emitting diodes (LEDs). Tomographic analysis of the In distribution, interface morphology, and dopant clustering reveals material quality comparable to that of planar LED QWs. The position-dependent CL emission wavelength of the nonpolar side-facet QWs and semipolar top QWs is correlated with In composition. PMID- 23919560 TI - Neuroinflammation in Alzheimer's disease: an understanding of physiology and pathology. AB - Alzheimer's disease (AD) is a devastative neurodegenerative disorder with complex etiology. Neuroinflammation has been found to be an underlying cause of the disease, although it demonstrates significant defensive role and renders the brain immunologically secured. This review focuses on the physiology and pathology of this crucial biological process and the diverse factors involved in and acting in a concerted manner to play a pivotal role either in the physiology or pathology of the disease. We used Pubmed, Pubmed Central, and Medline databases for a period of 3 months. It also summarizes the recent advances in neuroinflammation in both in vitro and in vivo. This review eventually warrants further studies on animal models of AD to unravel the complete pathophysiology of the disease and also accentuates the burgeoning need to protect astrocytes which can become a substantial therapeutic avenue. PMID- 23919561 TI - Universal access to HIV treatment in the context of vulnerability: female farm workers in Zimbabwe. AB - In this study we extend the theoretical and empirical debate on gender justice regarding universal access to antiretroviral therapy. In many circumstances, debates about human rights and HIV/AIDS are premised on the view that universal access to primary health care improves the multiple health burdens of those infected by the epidemic. We argue that ''universal access'' does not always benefit those in marginalized positions in society. Female farm workers living in rural, marginalized spaces at the intersection of systems of social inequality and oppression shape the way in which they experience access to antiretroviral drugs. PMID- 23919562 TI - Influence of mobbing (workplace bullying) on depressive symptoms: a longitudinal study among employees working with people with intellectual disabilities. AB - BACKGROUND: The problem of mobbing has attracted a great deal of attention over the past few years. This concern has increased the study of the phenomena, which has resulted in many scientific publications. Mobbing has been characterised as an emerging risk at work. The aim of this longitudinal study was to analyse the influence of mobbing on depressive symptoms in a sample of employees working with people with intellectual disabilities (ID). METHOD: The sample consisted of 372 Spanish employees working with people with ID at 61 job centres in the Valencian Community (Spain). Seventy-nine (21.2%) participants were men, and 293 were (78.8%) women. Mobbing was evaluated by the Mobbing-UNIPSICO scale, and depressive symptoms were measured using the Zung Self Rating Depression Scale. Using analyses of variance (anova), we tested the differences in depressive symptoms according to the mobbing criteria indicated by Leymann, that is, frequency and duration at Time 1 and Time 2. RESULTS: Employees who met the mobbing criteria: frequency (at least once a week) and duration (at least 6 months) at the two study times presented significantly higher levels of depressive symptoms than employees who met mobbing criteria at Time 1, but did not meet any criteria for mobbing at Time 2, and employees who did not meet any criteria for mobbing at Time 1 or Time 2. CONCLUSIONS: We conclude that permanence of mobbing from Time 1 to Time 2 increases depressive symptoms. PMID- 23919564 TI - Structural and equilibrium effects of the surface passivant on the stability of Au nanorods. AB - Au nanomaterials are well-known for their optical properties, where Au nanorods have demonstrated unique capabilities because of their readily tunable size and shape. Unfortunately, functionalization of the material surface is challenging because of their lack of stability after only a few purification cycles. Here, we demonstrate that enhanced Au-nanorod stability can be achieved by purifying the materials using dilute cetyltrimethylammonium bromide (CTAB) wash solutions. To this end, purifying the materials in such a manner shifts the passivant on/off equilibrium to maintain surfactant adsorption to the metal surface, leading to enhanced stability. Interestingly, from this study, a bimodal distribution of Au nanorods was evident, where one species was prone to bulk aggregation, whereas the second population remained stable in solution. This likely arose from defects within the CTAB bilayer at the nanorod surface, resulting in selective material aggregation. For this, those structures with high numbers of defects aggregated, whereas nanorods with a more pristine bilayer remained stable. Coating of the Au nanorods using polyelectrolytes was also explored for enhanced stability, where the composition of the anionic polymer played an important role in controlling materials stability. Taken together, these results demonstrate that the stability of Au nanorods can be directly tuned by the solvent-exposed surface structure, which could be manipulated to allow for the extensive material functionalization that is required for the generation of nanoplatforms with multiple applications. PMID- 23919565 TI - Use of instrumental acoustic parameters of winegrape seeds as possible predictors of extractable phenolic compounds. AB - The use of instrumental acoustic parameters produced during a compression test as reliable predictors of the extractable phenolic composition in intact winegrape seeds, determined by reference chemical methods, was evaluated by means of the analytical performance of calibration models. These models were developed only for those phenolic compounds most significantly and strongly correlated with the acoustic parameters. The analytical performance of the models was expressed in terms of standard error of cross-validation (SECV) and residual predictive interquartile amplitude (RPIQ), among other statistics. Several acoustic parameters showed satisfactory predictive accuracy for the percentage of galloylation in the terminal units, the content of (-)-epicatechin, and the mean degree of polymerization. Most of the reliable models developed are fairly recommended not for quantitative purposes but for fast screening (SECV% < 19, 1.6 < RPIQ < 2.1). PMID- 23919566 TI - Risk factors for persistence of asthma in children: 10-year follow-up. AB - OBJECTIVE: Risk factors related to the outcome of childhood asthma are not yet well established. We aimed to investigate the long-term outcome for children with asthma to determine the risk factors in predicting persistence of disease. METHODS: Sixty-two children with asthma were evaluated retrospectively at the end of a 10-year follow-up. Patients were asked to complete a questionnaire requesting clinical information, and underwent physical examination, skin prick testing, a pulmonary function test and bronchial provocation testing. Immunologic parameters evaluated were allergen-specific IgE and IgG4 levels, and allergen induced generation of CD4(+)CD25(+) cells. RESULTS: Mean age at final assessment was 15.9 +/- 3.6 years, and duration of follow-up was 10.30 +/- 1.27 years. Fifty percent of patients outgrew their asthma during the 10-year follow-up period. All the non-atopic patients outgrew their disease during the study period, whereas 67% of atopic patients did not. We identified two risk factors independently related to the persistence of symptoms: presence of bronchial hyper responsiveness and presence of rhinitis. Atopic children who were in remission demonstrated significantly higher allergen-induced CD4(+)CD25(+) T cells compared to healthy controls. CONCLUSIONS: Atopy, presence of rhinitis, positive and presence of bronchial hyper-reactivity are important risk factors for the persistence of asthma in children. Allergen-induced CD4(+)CD25(+) T cells were higher in the atopic children who outgrew their disease, implicating an immunological mechanism of asthma remission in children. PMID- 23919567 TI - Mechanism of cholesterol-assisted oligomeric channel formation by a short Alzheimer beta-amyloid peptide. AB - Alzheimer beta-amyloid (Abeta) peptides can self-organize into oligomeric ion channels with high neurotoxicity potential. Cholesterol is believed to play a key role in this process, but the molecular mechanisms linking cholesterol and amyloid channel formation have so far remained elusive. Here, we show that the short Abeta22-35 peptide, which encompasses the cholesterol-binding domain of Abeta, induces a specific increase of Ca(2+) levels in neural cells. This effect is neither observed in calcium-free medium nor in cholesterol-depleted cells, and is inhibited by zinc, a blocker of amyloid channel activity. Double mutations V24G/K28G and N27R/K28R in Abeta22-35 modify cholesterol binding and abrogate channel formation. Molecular dynamic simulations suggest that cholesterol induces a tilted alpha-helical topology of Abeta22-35. This facilitates the establishment of an inter-peptide hydrogen bond network involving Asn-27 and Lys-28, a key step in the octamerization of Abeta22-35 which proceeds gradually until the formation of a perfect annular channel in a phosphatidylcholine membrane. Overall, these data give mechanistic insights into the role of cholesterol in amyloid channel formation, opening up new therapeutic options for Alzheimer's disease. Abeta22-35 peptide, which encompasses the cholesterol binding domain of Abeta, induces a specific increase of Ca(2+) level in neural cells. Double mutations V24G/K28G and N27R/K28R modify cholesterol binding and abrogate channels formation. Molecular dynamic simulations suggest that cholesterol induces a tilted alpha-helical peptide topology facilitating the formation of annular octameric channels, as schematically shown in the graphic (with a hydrogen bond shown in green for two vicinal peptides). Overall, the data give insights into the role of cholesterol in amyloid channel formation and open up new therapeutic options for Alzheimer's disease. PMID- 23919568 TI - An improved autocidal gravid ovitrap for the control and surveillance of Aedes aegypti. AB - BACKGROUND: Limited success has been achieved using traditional vector control methods to prevent the transmission of dengue viruses. Integrated control programs incorporating alternative tools, such as gravid ovitraps (lethal ovitraps and sticky ovitraps) may provide greater potential for monitoring and reducing vector populations and dengue virus transmission. We had developed an autocidal gravid ovitrap (AGO) as a simple, low-cost device for surveillance and control of Ae. aegypti without the use of pesticides that does not require servicing for an extended period of time. The purpose of our study was to improve the efficacy and efficiency of this device. METHODS: Competitive assays were performed in the laboratory and an outdoor cage to evaluate whether modifications to the structure and appearance of our original trap design (AGO-A), and the addition of an olfactory bait (hay infusion), improve trap function. The performance of a modified trap design (AGO-B) was then assessed and compared with conventional ovitraps in a series of field tests in San Juan City, Puerto Rico. Generalized linear mixed models were used to analyze adult Ae. aegypti capture data from the laboratory, outdoor cage and field experiments. RESULTS: Increasing the size of the trap entrance, altering the color of trap components, and increasing the volume/surface area of the aqueous bait significantly improved the performance of the AGO in the outdoor cage. In a subsequent field comparison, captures of Ae. aegypti females were 3.7 fold greater in the improved trap (AGO B), compared with the original design (AGO-A). An infusion bait produced "in situ" significantly improved capture rates of the improved trap under both semi natural and field conditions. Semi-weekly collections of Ae. aegypti females in the AGO-B were significantly correlated with cumulative rainfall 8 to 28 days prior to sampling, whereas egg collections in paired conventional ovitraps were not. When vector abundance was low, the AGO-B provided greater sensitivity and precision as a surveillance device, compared with paired conventional ovitraps. CONCLUSIONS: The AGO-B can be used to efficiently attract and capture gravid Ae. aegypti females for more than 8 weeks without the need for trap maintenance. PMID- 23919569 TI - Environmental monitoring using next generation sequencing: rapid identification of macroinvertebrate bioindicator species. AB - INTRODUCTION: Invertebrate communities are central to many environmental monitoring programs. In freshwater ecosystems, aquatic macroinvertebrates are collected, identified and then used to infer ecosystem condition. Yet the key step of species identification is often not taken, as it requires a high level of taxonomic expertise, which is lacking in most organizations, or species cannot be identified as they are morphologically cryptic or represent little known groups. Identifying species using DNA sequences can overcome many of these issues; with the power of next generation sequencing (NGS), using DNA sequences for routine monitoring becomes feasible. RESULTS: In this study, we test if NGS can be used to identify species from field-collected samples in an important bioindicator group, the Chironomidae. We show that Cytochrome oxidase I (COI) and Cytochrome B (CytB) sequences provide accurate DNA barcodes for chironomid species. We then develop a NGS analysis pipeline to identifying species using megablast searches of high quality sequences generated using 454 pyrosequencing against comprehensive reference libraries of Sanger-sequenced voucher specimens. We find that 454 generated COI sequences successfully identified up to 96% of species in samples, but this increased up to 99% when combined with CytB sequences. Accurate identification depends on having at least five sequences for a species; below this level species not expected in samples were detected. Incorrect incorporation of some multiplex identifiers (MID's) used to tag samples was a likely cause, and most errors could be detected when using MID tags on forward and reverse primers. We also found a strong quantitative relationship between the number of 454 sequences and individuals showing that it may be possible to estimate the abundance of species from 454 pyrosequencing data. CONCLUSIONS: Next generation sequencing using two genes was successful for identifying chironomid species. However, when detecting species from 454 pyrosequencing data sets it was critical to include known individuals for quality control and to establish thresholds for detecting species. The NGS approach developed here can lead to routine species level diagnostic monitoring of aquatic ecosystems. PMID- 23919570 TI - A six year retrospective review of occipital nerve stimulation practice- controversies and challenges of an emerging technique for treating refractory headache syndromes. AB - BACKGROUND: A retrospective review of patients treated with Occipital Nerve Stimulation (ONS) at two large tertiary referral centres has been audited in order to optimise future treatment pathways. METHODS: Patient's medical records were retrospectively reviewed, and each patient was contacted by a trained headache expert to confirm clinical diagnosis and system efficacy. Results were compared to reported outcomes in current literature on ONS for primary headaches. RESULTS: Twenty-five patients underwent a trial of ONS between January 2007 and December 2012, and 23 patients went on to have permanent implantation of ONS. All 23 patients reached one-year follow/up, and 14 of them (61%) exceeded two years of follow-up. Seventeen of the 23 had refractory chronic migraine (rCM), and 3 refractory occipital neuralgia (ON). 11 of the 19 rCM patients had been referred with an incorrect headache diagnosis. Nine of the rCM patients (53%) reported 50% or more reduction in headache pain intensity and or frequency at long term follow up (11-77 months). All 3 ON patients reported more than 50% reduction in pain intensity and/or frequency at 28-31 months. Ten (43%) subjects underwent surgical revision after an average of 11 +/- 7 months from permanent implantation - in 90% of cases due to lead problems. Seven patients attended a specifically designed, multi-disciplinary, two-week pre-implant programme and showed improved scores across all measured psychological and functional parameters independent of response to subsequent ONS. CONCLUSIONS: Our retrospective review: 1) confirms the long-term ONS success rate in refractory chronic headaches, consistent with previously published studies; 2) suggests that some headaches types may respond better to ONS than others (ON vs CM); 3) calls into question the role of trial stimulation in ONS; 4) confirms the high rate of complications related to the equipment not originally designed for ONS; 5) emphasises the need for specialist multidisciplinary care in these patients. PMID- 23919571 TI - A preliminary profile of Australian women accessing doula care: findings from the Australian Longitudinal Study on Women's Health. AB - Despite growing interest and controversy regarding the value of doulas in contemporary maternity care, little is known about the profile of women who choose to involve a doula in their care team. This preliminary analysis indicates that women's attitudes towards maternity care may influence their use of a doula more so than demographic factors. Further research examining these issues in more detail is needed for all those involved in maternity care to ensure safe maternal and fetal outcomes. PMID- 23919563 TI - RNA polymerase II transcription elongation control. PMID- 23919572 TI - Gold nanoparticles synthesized by Geobacillus sp. strain ID17 a thermophilic bacterium isolated from Deception Island, Antarctica. AB - BACKGROUND: The use of microorganisms in the synthesis of nanoparticles emerges as an eco-friendly and exciting approach, for production of nanoparticles due to its low energy requirement, environmental compatibility, reduced costs of manufacture, scalability, and nanoparticle stabilization compared with the chemical synthesis. RESULTS: The production of gold nanoparticles by the thermophilic bacterium Geobacillus sp. strain ID17 is reported in this study. Cells exposed to Au3+ turned from colourless into an intense purple colour. This change of colour indicates the accumulation of intracellular gold nanoparticles. Elemental analysis of particles composition was verified using TEM and EDX analysis. The intracellular localization and particles size were verified by TEM showing two different types of particles of predominant quasi-hexagonal shape with size ranging from 5-50 nm. The mayority of them were between 10-20 nm in size. FT-IR was utilized to characterize the chemical surface of gold nanoparticles. This assay supports the idea of a protein type of compound on the surface of biosynthesized gold nanoparticles. Reductase activity involved in the synthesis of gold nanoparticles has been previously reported to be present in others microorganisms. This reduction using NADH as substrate was tested in ID17. Crude extracts of the microorganism could catalyze the NADH-dependent Au3+ reduction. CONCLUSIONS: Our results strongly suggest that the biosynthesis of gold nanoparticles by ID17 is mediated by enzymes and NADH as a cofactor for this biological transformation. PMID- 23919574 TI - Retraction of highly enantioselective radical addition to N-benzoyl hydrazones using chiral ammonium salts. PMID- 23919573 TI - The effectiveness and cost-effectiveness of the Family Nurse Partnership home visiting programme for first time teenage mothers in England: a protocol for the Building Blocks randomised controlled trial. AB - BACKGROUND: The Nurse Family Partnership programme was developed in the USA where it is made available to pregnant young mothers in some socially deprived geographic areas. The related Family Nurse Partnership programme was introduced in England by the Department of Health in 2006 with the aim of improving outcomes for the health, wellbeing and social circumstances of young first-time mothers and their children. METHODS / DESIGN: This multi-centre individually randomised controlled trial will recruit 1600 participants from 18 Primary Care Trusts in England, United Kingdom. The trial will evaluate the effectiveness of Family Nurse Partnership programme and usual care versus usual care for nulliparous pregnant women aged 19 or under, recruited by 24 weeks gestation and followed until the child's second birthday. Data will be collected from participants at baseline, 34-36 weeks gestation, 6, 12, 18 and 24 months following birth. Routine clinical data will be collected from maternity, primary care and hospital episodes statistics. Four primary outcomes are to be reported from the trial: birth weight; prenatal tobacco use; child emergency attendances and/or admissions within two years of birth; second pregnancy within two years of first birth. DISCUSSION: This trial will evaluate the effectiveness and cost effectiveness of the Family Nurse Partnership in England. The findings will provide evidence on pregnancy and early childhood programme outcomes for policy makers, health professionals and potential recipients in three domains (pregnancy and birth, child health and development, and parental life course and self-sufficiency) up to the child's second birthday. TRIAL REGISTRATION: Trial registration number: ISRCTN23019866. PMID- 23919575 TI - Routine use of Staphylococcus aureus rapid diagnostic test in patients with suspected ventilator-associated pneumonia. AB - INTRODUCTION: In patients with ventilator-associated pneumonia (VAP), administration of an appropriate empirical antimicrobial treatment is associated with improved outcomes, leading to the prescription of broad-spectrum antibiotics, including a drug active against methicillin resistant Staphylococcus aureus (MRSA). In order to avoid the overuse of antibiotics, the present study aimed to evaluate the technical characteristics of a rapid diagnostic test (Cepheid Xpert assay) in patients with suspected VAP. METHODS: From June 2011 to June 2012, in patients with suspected VAP, a sample from the bronchialalveolar lavage (BAL) or miniBAL was tested in a point-of-care laboratory for a rapid diagnostic test of methicillin susceptible Staphylococcus aureus (MSSA) and MRSA. Then, the result was compared to the quantitative culture with a threshold at 104 colony-forming units per milliliter for bronchoalveolar lavage and 103 colony forming units per milliliter for minibronchoalveolar lavage. The study was performed in three intensive care units at two institutions. RESULTS: Four hundred, twenty-two samples from 328 patients were analyzed. The culture of 6 (1.1%) and 28 (6.5%) samples were positive for MRSA and MSSA. The test was not interpretable in 41 (9.3%) patients. The negative predictive values of the rapid detection test were 99.7% (98.1 to 99.9%) and 99.8% (98.7 to 99.9%) for MSSA and MRSA, respectively. CONCLUSION: The rapid diagnostic test is reliable in excluding the presence of MSSA and MRSA in the samples of patients with suspected VAP. Its utility should be regarded depending on the prevalence of MRSA. PMID- 23919576 TI - National Japanese survey of thrombolytic therapy selection for coronary aneurysm: intracoronary thrombolysis or intravenous coronary thrombolysis in patients with Kawasaki disease. AB - BACKGROUND: Thrombolytic therapy for coronary aneurysm thrombosis of Kawasaki disease (KD) includes antiplatelet and anticoagulants, i.v. coronary thrombolysis (IVCT), and i.c. thrombolysis (ICT). Therapeutic methods, drugs and doses vary among medical facilities. METHODS AND RESULTS: A nationwide survey of thrombolytic therapy was conducted under the auspices of the Ministry of Health, Labour and Welfare Research Program to Intractable Diseases Research Grants. A secondary survey targeted 14 facilities conducting thrombolytic therapy during a 5 year period (2004-2009). The primary survey investigated performance of thrombolytic therapy for 23 KD patients at 14 facilities, and of these, five with acute myocardial infarction had received ICT and combined therapy. The secondary survey investigated the pre-treatment condition of aneurysm and thrombosis and actual treatment methods. ICT was effective for small thrombi (<= 10 mm), while IVCT was effective even for giant thrombi (>10 mm). ICT was also effective for thrombi within several hours after formation. CONCLUSION: In the present nationwide survey, thrombolytic therapy was more effective in cases of a shorter duration between thrombus formation and the start of treatment. It was found that many facilities used only IVCT for thrombus alone. Medications given to KD children did not cause serious hemorrhagic complications, unlike in adults. Although doses exceeded recommended levels in many cases, the only complications were nasal bleeding and fever. PMID- 23919577 TI - DNA-templated silver nanoclusters for fluorescence turn-on assay of acetylcholinesterase activity. AB - We have developed a fluorescence turn-on assay using DNA-templated silver nanoclusters (Ag NCs) (i.e., 12 polycytosine-templated silver nanoclusters, dC12 Ag NCs), which is amenable to rapid, ultrasensitive assay of acetylcholinesterase (AChE). The detection mechanism is based on the concept, that is, AChE hydrolyzes the acetylthiocholine (ATCh) chloride to produce thiocholine (TCh). Subsequently, TCh sensitively and rapidly reacts with dC12-Ag NCs via Ag-S bond forming and enhances the fluorescence of dC12-Ag NCs. Using dC12-Ag NCs, detection of TCh has a linear concentration range of 2.0 nM to 16.0 nM and a detection limit of 0.3 nM. Due to the sensitive and rapid fluorescence turn-on response of dC12-Ag NCs to TCh, AChE with activity as low as 0.5 * 10(-4) U/mL (signal/noise = 3) can be analyzed with a dynamic range of 0.1 to 1.25 * 10(-3) U/mL. The promising application of the proposed method in AChE inhibitor screening was demonstrated. AChE concentrations were determined in human blood red cell (RBC) membranes from clinical specimens using dC12-Ag NCs, and the quantitative results were validated with Ellman's method. Aside from the ease of manufacture, reduction of matrix effect, and low background noise, the continuous detection format and detection sensitivity can open up to wider applications to AChE activity assay in neurobiology, toxicology, and pharmacology, among other fields. PMID- 23919578 TI - Trunk isometric force production parameters during erector spinae muscle vibration at different frequencies. AB - BACKGROUND: Vibration is known to alter proprioceptive afferents and create a tonic vibration reflex. The control of force and its variability are often considered determinants of motor performance and neuromuscular control. However, the effect of vibration on paraspinal muscle control and force production remains to be determined. METHODS: Twenty-one healthy adults were asked to perform isometric trunk flexion and extension torque at 60% of their maximal voluntary isometric contraction, under three different vibration conditions: no vibration, vibration frequencies of 30 Hz and 80 Hz. Eighteen isometric contractions were performed under each condition without any feedback. Mechanical vibrations were applied bilaterally over the lumbar erector spinae muscles while participants were in neutral standing position. Time to peak torque (TPT), variable error (VE) as well as constant error (CE) and absolute error (AE) in peak torque were calculated and compared between conditions. RESULTS: The main finding suggests that erector spinae muscle vibration significantly decreases the accuracy in a trunk extension isometric force reproduction task. There was no difference between both vibration frequencies with regard to force production parameters. Antagonist muscles do not seem to be directly affected by vibration stimulation when performing a trunk isometric task. CONCLUSIONS: The results suggest that acute erector spinae muscle vibration interferes with torque generation sequence of the trunk by distorting proprioceptive information in healthy participants. PMID- 23919579 TI - Bioassay-guided investigation of two Monarda essential oils as repellents of yellow fever mosquito Aedes aegypti. AB - As part of an ongoing research program to identify active mosquito repellents, Monarda bradburiana Beck and Monarda fistulosa L. essential oils showed good repellent activity with minimum effective dosages (MED) of 0.055 +/- 0.036 and 0.078 +/- 0.027 mg/cm(2), respectively, compared to reference standard N,N diethyl-3-methylbenzamide (DEET) (0.039 +/- 0.014 mg/cm(2)). Systematic bioassay guided fractionation of essential oils of both Monarda species was performed to identify the active repellent compounds, and isolated pure compounds were individually tested for repellency. Of the isolated compounds, carvacrol, thymol, eugenol, and carvacrol methyl ether were found to be the repellent compounds with MEDs in the range of 0.013-0.063 mg/cm(2). Active repellent compounds were also tested for larvicidal activity against 1-day-old Aedes aegypti larvae. Thymol was the best larvicide among the tested individual compounds (LD50 of 13.9 ppm). None of the individual compounds showed cytotoxicity against mammalian cells; however, the essential oils were toxic to all cell lines. PMID- 23919580 TI - Analysis of self-selection bias in a population-based cohort study of autism spectrum disorders. AB - BACKGROUND: This study examined potential self-selection bias in a large pregnancy cohort by comparing exposure-outcome associations from the cohort to similar associations obtained from nationwide registry data. The outcome under study was specialist-confirmed diagnosis of autism spectrum disorders (ASDs). METHODS: The cohort sample (n = 89 836) was derived from the population-based prospective Norwegian Mother and Child Cohort Study and its substudy of ASDs, the Autism Birth Cohort (ABC) study. The nationwide registry data were derived from the Medical Birth Registry of Norway (n = 507 856). The children were born in 1999-2007, and seven prenatal and perinatal exposures were selected for analyses. RESULTS: ASDs were reported for 234 (0.26%) children in the cohort and 2072 (0.41%) in the nationwide population. Compared with the nationwide population, the cohort had an under-representation of the youngest women (<25 years), those who had single status, mothers who smoked during pregnancy, and non-users of prenatal folic acid supplements. The ratios of the adjusted odds ratios (ORs) in the cohort over the adjusted ORs in the nationwide population were as follows; primipara pregnancy: 1.39/1.22, prenatal folic acid use: 0.85/0.86, prenatal smoking: 1.20/1.17, preterm birth (<37 weeks): 1.48/1.42, low birthweight (<2500 g): 1.60/1.58, male sex: 4.39/4.59 (unadjusted only); and caesarean section history: 1.03/1.04. CONCLUSIONS: Associations estimated between ASDs and perinatal and prenatal exposures in the cohort are close to those estimated in the nationwide population. Self-selection does not appear to compromise validity of exposure-outcome associations in the ABC study. PMID- 23919581 TI - Linking environmental variability to village-scale malaria transmission using a simple immunity model. AB - BACKGROUND: Individuals continuously exposed to malaria gradually acquire immunity that protects from severe disease and high levels of parasitization. Acquired immunity has been incorporated into numerous models of malaria transmission of varying levels of complexity (e.g. Bull World Health Organ 50:347, 1974; Am J Trop Med Hyg 75:19, 2006; Math Biosci 90:385-396, 1988). Most such models require prescribing inputs of mosquito biting rates or other entomological or epidemiological information. Here, we present a model with a novel structure that uses environmental controls of mosquito population dynamics to simulate the mosquito biting rates, malaria prevalence as well as variability in protective immunity of the population. METHODS: A simple model of acquired immunity to malaria is presented and tested within the framework of the Hydrology, Entomology and Malaria Transmission Simulator (HYDREMATS), a coupled hydrology and agent-based entomology model. The combined model uses environmental data including rainfall, temperature, and topography to simulate malaria prevalence and level of acquired immunity in the human population. The model is used to demonstrate the effect of acquired immunity on malaria prevalence in two Niger villages that are hydrologically and entomologically very different. Simulations are conducted for the year 2006 and compared to malaria prevalence observations collected from the two villages. RESULTS: Blood smear samples from children show no clear difference in malaria prevalence between the two villages despite pronounced differences in observed mosquito abundance. The similarity in prevalence is attributed to the moderating effect of acquired immunity, which depends on prior exposure to the parasite through infectious bites - and thus the hydrologically determined mosquito abundance. Modelling the level of acquired immunity can affect village vulnerability to climatic anomalies. CONCLUSIONS: The model presented has a novel structure constituting a mechanistic link between spatial and temporal environmental variability and village-scale malaria transmission. Incorporating acquired immunity into the model has allowed simulation of prevalence in the two villages, and isolation of the effects of acquired immunity in dampening the difference in prevalence between the two villages. Without these effects, the difference in prevalence between the two villages would have been significantly larger in response to the large differences in mosquito populations and the associated biting rates. PMID- 23919582 TI - The neuroprotective activity of the amyloid precursor protein against traumatic brain injury is mediated via the heparin binding site in residues 96-110. AB - We have previously shown that following traumatic brain injury (TBI) the presence of the amyloid precursor protein (APP) may be neuroprotective. APP knockout mice have increased neuronal death and worse cognitive and motor outcomes following TBI, which is rescued by treatment with exogenous sAPPalpha (the secreted ectodomain of APP generated by alpha-secretase cleavage). Two neuroprotective regions were identified in sAPPalpha, the N and C-terminal domains D1 and D6a/E2 respectively. As both D1 and D6a/E2 contain heparin binding activity it was hypothesized that this is responsible for the neuroprotective activity. In this study, we focused on the heparin binding site, encompassed by residues 96-110 in D1, which has previously been shown to have neurotrophic properties. We found that treatment with APP96-110 rescued motor and cognitive deficits in APP-/- mice following focal TBI. APP96-110 also provided neuroprotection in Sprague-Dawley rats following diffuse TBI. Treatment with APP96-110 significantly improved functional outcome as well as preserve histological cellular morphology in APP-/- mice following focal controlled cortical impact injury. Furthermore, following administration of APP96-110 in rats after diffuse impact acceleration TBI, motor and cognitive outcomes were significantly improved and axonal injury reduced. These data define the heparin binding site in the D1 domain of sAPPalpha, represented by the sequence APP96-110, as the neuroprotective site to confer neuroprotection following TBI. The product of alpha-secretase cleavage of the amyloid precursor protein, sAPPalpha is neuroprotective following traumatic brain injury (TBI). Of interest was whether this neuroprotective activity could be further delineated to a heparin binding region within sAPPalpha, corresponding to the region APP96-110 (see diagram demonstrating the domain structure of sAPPalpha). Indeed treatment with APP96-110 improved functional outcome following TBI, an effect that was not seen with a mutated version of the peptide that had reduced heparin binding affinity. PMID- 23919583 TI - Sleep-related and non-sleep-related migraine: interictal sleep quality, arousals and pain thresholds. AB - BACKGROUND: The mechanisms associating sleep and migraine are unknown. No previous polysomnographic (PSG) or pain-threshold (PT) study has compared patients with sleep-related migraine attacks (SM), non-sleep related migraine attacks (NSM) and healthy controls. METHODS: We have performed a blinded, prospective exploratory study with case-control design. Thirty-four healthy controls, 15 patients with SM and 18 patients with NSM had interictal PSG heat-, cold- and pressure PT (HPT, CPT, PPT) recordings and completed diary- and questionnaire on sleep and headache related aspects. RESULTS: NSM patients had more slow-wave sleep (SWS) and more K-bursts than SM patients (K-bursts: p = 0.023 and SWS: p = 0.030) and controls (K-bursts: p = 0.009 and SWS: 0.041). NSM patients also had lower HPT and CPT than controls (p = 0.026 and p = 0.021). In addition, SM patients had more awakenings and less D-bursts than controls (p = 0.025 and p = 0.041). CONCLUSION: SM- and NSM patients differed in objective-, but not subjective sleep quality. NSM patients had PSG findings indicating foregoing sleep deprivation. As foregoing sleep times were normal, a relative sleep deficit might explain reduced PT among NSM patients. The SM patients had signs of slightly disturbed sleep. PMID- 23919585 TI - High-throughput genomics in sorghum: from whole-genome resequencing to a SNP screening array. AB - With its small, diploid and completely sequenced genome, sorghum (Sorghum bicolor L. Moench) is highly amenable to genomics-based breeding approaches. Here, we describe the development and testing of a robust single-nucleotide polymorphism (SNP) array platform that enables polymorphism screening for genome-wide and trait-linked polymorphisms in genetically diverse S. bicolor populations. Whole genome sequences with 6* to 12* coverage from five genetically diverse S. bicolor genotypes, including three sweet sorghums and two grain sorghums, were aligned to the sorghum reference genome. From over 1 million high-quality SNPs, we selected 2124 Infinium Type II SNPs that were informative in all six source genomes, gave an optimal Assay Design Tool (ADT) score, had allele frequencies of 50% in the six genotypes and were evenly spaced throughout the S. bicolor genome. Furthermore, by phenotype-based pool sequencing, we selected an additional 876 SNPs with a phenotypic association to early-stage chilling tolerance, a key trait for European sorghum breeding. The 3000 attempted bead types were used to populate half of a dual-species Illumina iSelect SNP array. The array was tested using 564 Sorghum spp. genotypes, including offspring from four unrelated recombinant inbred line (RIL) and F2 populations and a genetic diversity collection. A high call rate of over 80% enabled validation of 2620 robust and polymorphic sorghum SNPs, underlining the efficiency of the array development scheme for whole-genome SNP selection and screening, with diverse applications including genetic mapping, genome-wide association studies and genomic selection. PMID- 23919584 TI - HNO enhances SERCA2a activity and cardiomyocyte function by promoting redox dependent phospholamban oligomerization. AB - AIMS: Nitroxyl (HNO) interacts with thiols to act as a redox-sensitive modulator of protein function. It enhances sarcoplasmic reticular Ca(2+) uptake and myofilament Ca(2+) sensitivity, improving cardiac contractility. This activity has led to clinical testing of HNO donors for heart failure. Here we tested whether HNO alters the inhibitory interaction between phospholamban (PLN) and the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) in a redox-dependent manner, improving Ca(2+) handling in isolated myocytes/hearts. RESULTS: Ventriculocytes, sarcoplasmic reticulum (SR) vesicles, and whole hearts were isolated from control (wildtype [WT]) or PLN knockout (pln(-/-)) mice. Compared to WT, pln(-/-) myocytes displayed enhanced resting sarcomere shortening, peak Ca(2+) transient, and blunted beta-adrenergic responsiveness. HNO stimulated shortening, relaxation, and Ca(2+) transient in WT cardiomyocytes, and evoked positive inotropy/lusitropy in intact hearts. These changes were markedly blunted in pln( /-) cells/hearts. HNO enhanced SR Ca(2+) uptake in WT but not pln(-/-) SR vesicles. Spectroscopic studies in insect cell microsomes expressing SERCA2a+/ PLN showed that HNO increased Ca(2+)-dependent SERCA2a conformational flexibility but only when PLN was present. In cardiomyocytes, HNO achieved this effect by stabilizing PLN in an oligomeric disulfide bond-dependent configuration, decreasing the amount of free inhibitory monomeric PLN available. INNOVATION: HNO dependent redox changes in myocyte PLN oligomerization relieve PLN inhibition of SERCA2a. CONCLUSIONS: PLN plays a central role in HNO-induced enhancement of SERCA2a activity, leading to increased inotropy/lusitropy in intact myocytes and hearts. PLN remains physically associated with SERCA2a; however, less monomeric PLN is available resulting in decreased inhibition of the enzyme. These findings offer new avenues to improve Ca(2+) handling in failing hearts. PMID- 23919587 TI - Insulin sensitivity and secretion in Arab Americans with glucose intolerance. AB - BACKGROUND: This study examined the pathophysiological abnormalities in Arab Americans with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). SUBJECTS AND METHODS: Homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of insulin secretion (HOMA-%beta), and the Matsuda Insulin Sensitivity Index composite (ISIcomposite) were calculated from the fasting and stimulated glucose and insulin concentrations measured during the oral glucose tolerance test in a population-based, representative, cross-sectional sample of randomly selected Arab Americans. RESULTS: In total, 497 individuals (42+/-14 years old; 40% males; body mass index [BMI], 29+/-6 kg/m(2)) were studied. Multivariate linear regression models were performed to compare HOMA-IR, HOMA-%beta, and ISIcomposite among individuals with normal glucose tolerance (NGT) (n=191) versus isolated IFG (n=136), isolated IGT (n=22), combined IFG/IGT (n=43), and diabetes (n=105). Compared with individuals with NGT (2.9+/-1.6), HOMA-IR progressively increased in individuals with isolated IFG (4.8+/-2.7, P<0.001), combined IFG/IGT (6.0+/-4.3, P<0.001), and diabetes (9.7+/ 8.3, P<0.001) but not in those with isolated IGT (3.0+/-1.7, P=0.87). After adjustment for sex and BMI, these associations remained unchanged. Whole-body insulin sensitivity as measured by ISIcomposite was significantly lower in individuals with isolated IFG (3.9+/-2.3, P<0.001), isolated IGT (2.8+/-1.5, P<0.001), combined IFG/IGT (1.9+/-1.1, P<0.001), and diabetes (1.6+/-1.1, P<0.001) compared with those with NGT (6.1+/-3.5). HOMA-%beta was significantly lower in diabetes (113.7+/-124.9, P<0.001) compared with NGT (161.3+/-92.0). After adjustment for age, sex, and BMI, isolated IFG (146.6+/-80.2) was also significantly associated with a decline in HOMA-%beta relative to NGT (P=0.005). CONCLUSIONS: This study suggests that differences in the underlying metabolic defects leading to diabetes in Arab Americans with IFG and/or IGT exist and may require different strategies for the prevention of diabetes. PMID- 23919588 TI - Neutrophil-to-lymphocyte ratio as a quick and reliable predictive marker to diagnose the severity of diabetic retinopathy. AB - INTRODUCTION: Diabetic retinopathy (DR) is the most common complication and cause of visual impairment in diabetes patients. The pathogenesis is not fully understood, but several studies have suggested that inflammation plays an important role. The neutrophil-to-lymphocyte ratio (NLR) was defined as a novel potential marker to determine inflammation. We aimed to evaluate the relationship between DR and inflammation by using NLR. PATIENTS AND METHODS: The study was included 58 patients diagnosed with type 2 diabetes mellitus. Twenty-four of them had DR. The control group was composed of 52 age- and sex-matched healthy subjects. Retinopathy was graded using the International Clinical Diabetic Retinopathy Disease Severity Scale. RESULTS: NLR values of the diabetes patients were significantly higher than those of the healthy control group (P<0.001), and NLR levels of the patients with DR were higher than those of the patients without DR (P<0.001). In addition, NLR values were correlated with the presence of DR and DR grades (r=0.466, P<0.001; and r=0.630, P<0.001, respectively). CONCLUSIONS: According to our knowledge, this is the first study investigating the relationship between NLR, which is an inflammatory marker, and DR and its severity. Our results suggest that while evaluating diabetes patients in terms of DR, higher NLR values may be a remarkable marker. PMID- 23919586 TI - A nanobody binding to non-amyloidogenic regions of the protein human lysozyme enhances partial unfolding but inhibits amyloid fibril formation. AB - We report the effects of the interaction of two camelid antibody fragments, generally called nanobodies, namely cAb-HuL5 and a stabilized and more aggregation-resistant variant cAb-HuL5G obtained by protein engineering, on the properties of two amyloidogenic variants of human lysozyme, I56T and D67H, whose deposition in vital organs including the liver, kidney, and spleen is associated with a familial non-neuropathic systemic amyloidosis. Both NMR spectroscopy and X ray crystallographic studies reveal that cAb-HuL5 binds to the alpha-domain, one of the two lobes of the native lysozyme structure. The binding of cAb-HuL5/cAb HuL5G strongly inhibits fibril formation by the amyloidogenic variants; it does not, however, suppress the locally transient cooperative unfolding transitions, characteristic of these variants, in which the beta-domain and the C-helix unfold and which represents key early intermediate species in the formation of amyloid fibrils. Therefore, unlike two other nanobodies previously described, cAb HuL5/cAb-HuL5G does not inhibit fibril formation via the restoration of the global cooperativity of the native structure of the lysozyme variants to that characteristic of the wild-type protein. Instead, it inhibits a subsequent step in the assembly of the fibrils, involving the unfolding and structural reorganization of the alpha-domain. These results show that nanobodies can protect against the formation of pathogenic aggregates at different stages in the structural transition of a protein from the soluble native state into amyloid fibrils, illustrating their value as structural probes to study the molecular mechanisms of amyloid fibril formation. Combined with their amenability to protein engineering techniques to improve their stability and solubility, these findings support the suggestion that nanobodies can potentially be developed as therapeutics to combat protein misfolding diseases. PMID- 23919589 TI - A novel mathematical model detecting early individual changes of insulin resistance. AB - BACKGROUND: Insulin resistance (IR) and hyperinsulinemia as well as obesity play a key role in the metabolic syndrome (MetS), type 2 diabetes (T2D), and associated cardiovascular disease. Unfortunately, IR and hyperinsulinemia are often diagnosed late (i.e., when the MetS is already clinically evident). An earlier diagnosis of IR would be desirable to reduce its clinical consequences, in particular in view of the increasing prevalence of obesity and diabetes conditions. For this purpose, we developed a mathematical model capable of detecting early onset of IR through small variations of insulin sensitivity, glucose effectiveness, and first- or second-phase responses. MATERIALS AND METHODS: Murine models provide controlled conditions to study various stages of IR. Various degrees of hypercholesterolemia, obesity, IR, and atherosclerosis were induced in low-density lipoprotein receptor-deficient mice by feeding them cholesterol- or sucrose-rich diets. IR was assessed by oral glucose tolerance tests. Controls included animals fed exclusively, or switched back to, regular chow. A nonlinear mathematical model of the order of 5 was developed by refining Bergman's "Minimal Model" and then applied to experimental data. RESULTS: Different metabolic constellations consistently corresponded to specific and close-meshed changes in model parameters. Reduced second-phase glucose sensitivity characterized an early impaired glucose tolerance. Later stages showed an increased first-phase glucose sensitivity compensating for decreased insulin sensitivity. Finally, T2D was associated with both first- and second phase sensitivities close to zero. CONCLUSIONS: The new mathematical model detected various insulin-sensitive or -resistant metabolic stages of IR. It can therefore be implemented for quantitative metabolic risk assessment and may be of therapeutic value by anticipating the start of therapeutic interventions. PMID- 23919590 TI - Developments in Meyers' lactamization methodology: en route to bi(hetero)aryl structures with defined axial chirality. AB - Highly atroposelective Meyers' lactamization promoted by pivalic acid under microwave irradiation is reported which allows the construction of nonracemic substituted-dibenzo(di)azepine derivatives through a center to axial chirality transfer principle, controlling the otherwise configurationally labile biaryl axis. This approach provides a straightforward entry to enantioenriched analogues of biorelevant architectures. PMID- 23919591 TI - Novel passive sampling device for measuring sediment-water diffusion fluxes of hydrophobic organic chemicals. AB - Molecular diffusion across the sediment-water interface, as one of the key geochemical processes, dictates whether a sediment is a source or sink of chemicals, providing useful data in designing remedial actions. Despite ample previous efforts in quantifying sediment-water diffusion fluxes, the resulting methods are largely unsatisfactory. Herein, we introduce a novel passive sampling device capable of measuring vertical profiles of chemical concentrations near the sediment-water interface, from which diffusion fluxes can be calculated based on a model that we developed. In laboratory testing, diffusion fluxes (0.032-310 ng m(-2) d(-1)) of dichlorodiphenyltrichloroethane and its metabolites obtained from the present sampling device were consistent with those (0.38-610 ng m(-2) d(-1)) determined by using a conventional active sampling method, solid-phase extraction/liquid-liquid extraction. Field deployment of the sampling device yielded individual diffusion fluxes of p,p'-DDD, p,p'-DDE, p,p'-DDMU, o,p'-DDMU, p,p'-DDNU, and p,p'-DBP in the range of 5.9-150 ng m(-2) d(-1), which were comparable to those (5.5-85 ng m(-2) d(-1)) obtained with a benthic chamber. Moreover, diffusion fluxes of p,p'-DDT and o,p'-DDT obtained with the sampling device were negative; i.e., the sediment is acting as a sink for these chemicals, while that could not be found using the benthic chamber. Thus, the passive sampling device can provide better information about the movement of chemicals through the sediment and overlying water for the choice of remedial strategies. PMID- 23919592 TI - Intra-abdominal fat is related to metabolic syndrome and non-alcoholic fat liver disease in obese youth. AB - BACKGROUND: Previous studies have shown an association between adiposity, especially intra-abdominal adipose tissue, and hemodynamic/metabolic comorbidities in adults, however it is not clear in pediatric population. The aim of the study was to analyze the relationship between non-alcoholic fatty liver disease (NAFLD) and components of metabolic syndrome (MS) with values of intra abdominal (IAAT) and subcutaneous (SCAT) adipose tissue in obese children and adolescents. METHODS: Cross-sectional study. SUBJECTS: 182 obese sedentary children and adolescents (aged 6 to 16 y), identified by the body mass index (BMI). MEASUREMENTS: Body composition and trunk fat by dual-energy X-ray absorptiometry- DXA; lipid profile, blood pressure and pubertal stage were also assessed. NAFLD was classified as absent (0), mild (1), moderate (2) and severe (3), and intra-abdominal and subcutaneous abdominal fat thickness were identified by ultrasound. The MS was identified according to the cut offs proposed by World Health Organization adapted for children and adolescents. The chi-square test was used to compare categorical variables, and the binary logistic regression indicated the magnitude of the associations adjusted by potential cofounders (sex, age, maturation, NAFLD and HOMA-IR). RESULTS: Higher quartile of SCAT was associated with elevated blood pressure (p = 0.015), but not associated with NAFLD (p = 0.665). Higher IAAT was positively associated with increased dyslipidemia (p = 0.001), MS (p = 0.013) and NAFLD (p = 0.005). Intermediate (p = 0.007) and highest (p = 0.001) quartile of IAAT were also associated with dyslipidemia, independently of age, sex, maturation, NAFLD and HOMA-IR (homeostatic model assessment-insulin resistance). CONCLUSION: Obese children and adolescents, with higher IAAT are more prone to develop MS and NAFLD than those with higher values of SCAT, independent of possible confounding variables. PMID- 23919593 TI - High attack rate for malaria through irregular migration routes to a country on verge of elimination. AB - Irregular migration in the form of human smuggling and human trafficking is recognized as a global public health issue. Thirty-two cases of Plasmodium falciparum were detected in 534 irregular migrants returning to Sri Lanka via failed human smuggling routes from West Africa in 2012, contributing to the largest burden of imported cases in Sri Lanka as it entered elimination phase. Beyond the criminality and human rights abuse, irregular migration plays an important, but often forgotten, pathway for malaria re-introduction. Active surveillance of the growing numbers of irregular migrant flows becomes an important strategy as Sri Lanka advances towards goals of malaria elimination. PMID- 23919594 TI - Clinical evaluation of a first trimester algorithm predicting the risk of hypertensive disease of pregnancy. AB - BACKGROUND: The aim of this study is to validate the Fetal Medicine Foundation (FMF) multiple logistic regression algorithm for prediction of risk of pre eclampsia in an Australian population. This model, which predicts risk using the population rate of pre-eclampsia, a variety of demographic factors, mean maternal arterial blood pressure (MAP), uterine artery PI (UtA PI) and pregnancy associated plasma protein A (PAPP-A), has been shown to predict early-onset pre eclampsia (delivery prior to 34 weeks) in 95% of women at a 10% false-positive rate. METHODS: All women who attended first trimester screening at the Royal Prince Alfred Hospital had their body mass index (BMI), MAP and UtA PI assessed in addition to factors traditionally used to assess aneuploidy (including PAPP-A MoM). After delivery, risks of early-onset (delivery prior to 34 weeks) pre eclampsia, late pre-eclampsia and gestational hypertension were calculated using the FMF risk algorithm. RESULTS: A total of 3099 women were screened and delivered locally. 3066 (98.9%) women had all data to perform pre-eclampsia screening available. This included 3014 (98.3%) women with a live birth, where risks of early pre-eclampsia were calculated. Twelve women were delivered before 34 weeks because of early pre-eclampsia with a prevalence of early pre-eclampsia of 1 in 256 pregnancies. Risks generated through the use of maternal history, MAP, UtA PI and PAPP-A detected 41.7 and 91.7% of early pre-eclampsia at a false positive rate of 5 and 10%, respectively. CONCLUSIONS: This study shows that the FMF early pre-eclampsia algorithm is effective in an Australian population. PMID- 23919596 TI - Electroassisted transfer of vertical silicon wire arrays using a sacrificial porous silicon layer. AB - An electroassisted method is developed to transfer silicon (Si) wire arrays from the Si wafers on which they are grown to other substrates while maintaining their original properties and vertical alignment. First, electroassisted etching is used to form a sacrificial porous Si layer underneath the Si wires. Second, the porous Si layer is separated from the Si wafer by electropolishing, enabling the separation and transfer of the Si wires. The method is further expanded to develop a current-induced metal-assisted chemical etching technique for the facile and rapid synthesis of Si nanowires with axially modulated porosity. PMID- 23919595 TI - Buprenorphine implants for treatment of opioid dependence: randomized comparison to placebo and sublingual buprenorphine/naloxone. AB - AIMS: To evaluate the safety and efficacy of buprenorphine implants (BI) versus placebo implants (PI) for the treatment of opioid dependence. A secondary aim compared BI to open-label sublingual buprenorphine/naloxone tablets (BNX). DESIGN: Randomized, double-blind, placebo-controlled trial. Subjects received either four buprenorphine implants (80 mg/implant) (n = 114), four placebo implants (n = 54) or open-label BNX (12-16 mg/day) (n = 119). SETTING: Twenty addiction treatment centers. PARTICIPANTS: Adult out-patients (ages 18-65) with DSM-IV-TR opioid dependence. MEASUREMENTS: The primary efficacy end-point was the percentage of urine samples negative for opioids collected from weeks 1 to 24, examined as a cumulative distribution function (CDF). FINDINGS: The BI CDF was significantly different from placebo (P < 0.0001). Mean [95% confidence interval (CI)] proportions of urines negative for opioids were: BI = 31.2% (25.3, 37.1) and PI = 13.4% (8.3, 18.6). BI subjects had a higher study completion rate relative to placebo (64 versus 26%, P < 0.0001), lower clinician-rated (P < 0.0001) and patient-rated (P < 0.0001) withdrawal, lower patient-ratings of craving (P < 0.0001) and better subjects' (P = 0.031) and clinicians' (P = 0.022) global ratings of improvement. BI also resulted in significantly lower cocaine use (P = 0.0016). Minor implant-site reactions were comparable in the buprenorphine [27.2% (31 of 114)] and placebo groups [25.9% (14 of 54)]. BI were non-inferior to BNX on percentage of urines negative for opioids [mean (95% CI) = 33.5 (27.3, 39.6); 95% CI for the difference of proportions = (-10.7, 6.2)]. CONCLUSIONS: Compared with placebo, buprenorphine implants result in significantly less frequent opioid use and are non-inferior to sublingual buprenorphine/naloxone tablets. PMID- 23919597 TI - Effect of initial dialysis access on post-transplant outcome. PMID- 23919598 TI - Does different wording of a global oral health question provide different results? AB - OBJECTIVE: Focusing on 70-year-old adults in Sweden and guided by the conceptual framework of International Classification of Impairments, Disabilities and Handicaps (ICIDH), the purpose of this study was to examine the extent to which socio-demographic characteristics, self-reported oral disease and social/psychological/physical oral health outcome variables are associated with two global measures of self-assessed satisfaction with oral health in Swedish 70 year-olds and if there is a degree of discordance between these global questions. BACKGROUND: It has become an important task to create a simple way to measure self-perceived oral health. In these attempts to find practical ways to measure health, the 'global oral health question' is a possible tool to measure self rated oral health, but there is limited knowledge about how important the wording of this question is. MATERIALS AND METHODS: In 2012, a questionnaire was mailed to all persons born in 1942 in two Swedish counties, Orebro (T) and Ostergotland (E). The total population of 70-year-olds amounted to 7889. Bivariate analyses were conducted by cross-tabulation and Chi-square statistics. Multivariate analyses were conducted using binary multiple logistic regression. RESULTS: The two global oral health question of 70-year-olds in Sweden was mainly explained by the number of teeth (OR=5.6 and 5.2), chewing capacity (OR=6.9 and 4.2), satisfaction with dental appearance (OR=19.8 and 17.3) and Oral Impact on Daily Performance (OIDP) (OR=3.5 and 3.9). CONCLUSION: Regardless of the wording, it seems that the concept of a global oral health question has the same main determinants. PMID- 23919599 TI - Sex-specific associations of variants in regulatory regions of NADPH oxidase-2 (CYBB) and glutathione peroxidase 4 (GPX4) genes with kidney disease in type 1 diabetes. AB - Oxidative stress is involved in the pathophysiology of diabetic nephropathy. The superoxide-generating nicotinamide adenine dinucleotide phosphate-oxidase 2 (NOX2, encoded by the CYBB gene) and the antioxidant enzyme glutathione peroxidase 4 (GPX4) play opposing roles in the balance of cellular redox status. In the present study, we investigated associations of single nucleotide polymorphisms (SNPs) in the regulatory regions of CYBB and GPX4 with kidney disease in patients with type 1 diabetes. Two functional SNPs, rs6610650 (CYBB promoter region, chromosome X) and rs713041 (GPX4 3'untranslated region, chromosome 19), were genotyped in 451 patients with type 1 diabetes from a Brazilian cohort (diabetic nephropathy: 44.6%) and in 945 French/Belgian patients with type 1 diabetes from Genesis and GENEDIAB cohorts (diabetic nephropathy: 62.3%). The minor A-allele of CYBB rs6610650 was associated with lower estimated glomerular filtration rate (eGFR) in Brazilian women, and with the prevalence of established/advanced nephropathy in French/Belgian women (odds ratio 1.75, 95% CI 1.11-2.78, p = 0.016). The minor T-allele of GPX4 rs713041 was inversely associated with the prevalence of established/advanced nephropathy in Brazilian men (odds ratio 0.30, 95% CI 0.13-0.68, p = 0.004), and associated with higher eGFR in French/Belgian men. In conclusion, these heterogeneous results suggest that neither CYBB nor GPX4 are major genetic determinants of diabetic nephropathy, but nevertheless, they could modulate in a gender-specific manner the risk for renal disease in patients with type 1 diabetes. PMID- 23919600 TI - Cu salt ink formulation for printed electronics using photonic sintering. AB - We formulate copper salt (copper formate/acetate/oleate) precursor inks for photonic sintering using high-intensity pulsed light (HIPL) based on the ink's light absorption ability. The inks can be developed through controllable crystal field splitting states (i.e., the ligand weights and their coordination around the metal centers). The inks' light absorption properties are extremely sensitive to the carbon chain lengths of the ligands, and the ink colors can drastically change. From the relationship between the ratios of C/Cu and the required sintering energies, it is possible to ascertain that the integral absorbance coefficients are strongly correlated with the photonic sintering behavior. These results suggest that the ink absorbance properties are the most important factors in photosintering. The wires formed by sintered copper formate complex ink via the HIPL method showed good electronic conduction, achieving a low resistivity of 5.6 * 10(-5) Omega cm. However, the resistivity of the wires increased with increasing contains carbon chain length of the inks, suggesting that large amounts of residual carbon have negative effects on both the wire's surface morphology and the electrical conductivity. We find in this study that high light absorptivity and low carbon inks would lead to a lower environmental load in future by reducing both energy usage and carbon oxide gas emissions. PMID- 23919601 TI - Eosinophil-targeted therapy: not the panacea for antibody-mediated rejection? PMID- 23919602 TI - Is Dirofilaria repens endemic in the Havelland district in Brandenburg, Germany? AB - In Brandenburg, northeastern Germany, an outbreak of zoonotic Dirofilaria repens in a sledge dog kennel was detected in January, 2012. Using the modified Knott test, 8 out of 28 adult dogs were microfilaria positive. A D. repens-specific PCR based on the internal transcribed spacer 2 region detected filarial DNA in 11 of these dogs. Northeastern Germany is currently considered to be free of Dirofilaria. The 39% prevalence within the kennel and the fact that the dogs transiently stayed in endemic areas only during the winter suggest that autochthonous infections occurred. Analysis of weather data shows that extrinsic development of Dirofilaria was continuously possible in the summers of 1994-2012, thus allowing active transmission within the area. PMID- 23919603 TI - The epidemic West Nile virus strain in Greece was a recent introduction. AB - To estimate the prevalence of West Nile virus (WNV) immunoglobulin G (IgG) antibodies in residents of northern Greece before the large outbreak of 2010, stored serum samples collected during 2003-2004 from 626 apparently healthy residents of northern Greece were tested. A seroprevalence of 0.62% was detected, with no statistically significant differences among the various prefectures, gender, and age groups, suggesting that the lineage 2 WNV strain that caused the outbreaks for 3 consecutive years was introduced recently. Data from the present study can be used as a threshold in future comparisons with respective data after the outbreaks to estimate and assess the public health impact, as well as for WNV evolutionary studies. PMID- 23919604 TI - Lobomycosis: risk of zoonotic transmission from dolphins to humans. AB - Lobomycosis, a fungal disease of the skin and subcutaneous tissues caused by Lacazia loboi, is sometimes referred to as a zoonotic disease because it affects only specific delphinidae and humans; however, the evidence that it can be transferred directly to humans from dolphins is weak. Dolphins have also been postulated to be responsible for an apparent geographic expansion of the disease in humans. Morphological and molecular differences between the human and dolphin organisms, differences in geographic distribution of the diseases between dolphins and humans, the existence of only a single documented case of presumed zoonotic transmission, and anecdotal evidence of lack of transmission to humans following accidental inoculation of tissue from infected dolphins do not support the hypothesis that dolphins infected with L. loboi represent a zoonotic hazard for humans. In addition, the lack of human cases in communities adjacent to coastal estuaries with a high prevalence of lobomycosis in dolphins, such as the Indian River Lagoon in Florida (IRL), suggests that direct or indirect transmission of L. loboi from dolphins to humans occurs rarely, if at all. Nonetheless, attention to personal hygiene and general principals of infection control are always appropriate when handling tissues from an animal with a presumptive diagnosis of a mycotic or fungal disease. PMID- 23919606 TI - Persistence of anti-West Nile virus-specific antibodies among asymptomatic blood donors in northeastern Italy. AB - The development and persistence of anti-West Nile Virus (WNV) immunoglobulin G (IgG)- and IgM-specific antibodies were investigated in 68 asymptomatic blood donors (BDs) previously tested as positive between October, 2008, and September, 2009, and living in northeastern Italy. Our study showed that WNV-specific IgG titers became negative (41%) or decreased (33%) in a large percentage of BDs, while they increased in a smaller percentage (10%); 16% of BDs showed no titer variation. Reversion to seronegative status within a short time frame suggests that WNV surveillance should be maintained year after year. PMID- 23919605 TI - West Nile Virus equine serosurvey in the Czech and Slovak republics. AB - A serological survey for West Nile virus (WNV) infection involved 395 horses from 43 administrative districts of the Czech Republic (163 animals) and 29 districts of Slovakia (232 animals), sampled between 2008 and 2011. Using a plaque reduction neutralization microtest, antibodies to WNV were not detected in any horse from the Czech Republic, whereas 19 nonvaccinated horses from Slovakia had specific antibodies to WNV (no cross-reactions were observed with tick-borne encephalitis and Usutu flaviviruses in those animals). The seropositivity rate of nonvaccinated horses in Slovakia was 8.3% (95% confidence interval [CI] 4.7 11.9%), and autochthonous local infection with WNV occurred at least in 11, i.e., 4.8% (95% CI 2.0-7.6%) of the animals. All seropositive horses lived in six lowland districts of southern Slovakia; overall, 15.1% (95% CI 8.8-21.4%) of 126 nonvaccinated horses were seropositive in those districts, situated relatively closely to the border with Hungary, i.e., the country where WNV disease cases have been reported in birds, horses and humans since 2003. PMID- 23919607 TI - Eastern equine encephalitis virus: high seroprevalence in horses from Southern Quebec, Canada, 2012. AB - Eastern equine encephalitis virus (EEEV) is a highly pathogenic arbovirus that infects humans, horses, and other animals. There has been a significant increase in EEEV activity in southeastern Canada since 2008. Few data are available regarding nonlethal EEEV infections in mammals, and consequently the distribution and pathogenicity spectrum of EEEV infections in these hosts is poorly understood. This cross-sectional study focuses on the evaluation of viral activity in southern Quebec's horses by seroprevalence estimation. A total of 196 horses, 18 months and older, which had never been vaccinated against EEEV and have never traveled outside Canada, were sampled from 92 barns distributed throughout three administrative regions of southern Quebec. Blood samples were taken from each horse and titrated for EEEV antibodies by plaque reduction neutralization test (PRNT). Equine population vaccination coverage was estimated by surveying horse owners and equine practitioners. PRNT results revealed an EEEV seroprevalence up to 8.7%, with 95% confidence limits ranging from 4.4% to 13.0%. Vaccination coverage was estimated to be at least 79%. Our study reveals for the first time in Canada a measure of EEEV seroprevalence in horses. High seroprevalence in unvaccinated animals challenges the perception that EEEV is a highly lethal pathogen in horses. Monitoring high-risk vector-borne infections such as EEEV in animal populations can be an important element of a public health surveillance strategy, population risk assessment and early detection of epidemics. PMID- 23919608 TI - Arboviral surveillance of field-collected mosquitoes reveals circulation of West Nile virus lineage 1 strains in Eastern Thrace, Turkey. AB - INTRODUCTION: Arbovirus screening in invertebrate vectors is an important component of the vector-borne disease surveillance programs. Turkey has been shown to harbor medically important mosquito-borne arboviruses such as West Nile Virus (WNV). However, limited information about infections in vectors are currently available. This study was performed to provide preliminary data from Eastern Thrace region, Turkey, where no arbovirus vector surveillance has previously been performed. MATERIALS AND METHODS: Mosquito sampling was undertaken at 23 sites in Edirne province during July, 2012. All specimens were identified morphologically, and selected individuals were subjected to DNA barcoding via cytochrome c oxidase I (COI) sequencing. Consensus PCR for Flavivirus, Alphavirus, and Phlebovirus genera and WNV-specific nested and real time reverse transcription PCR were employed for mosquito pool screening and/or confirmation. Viral sequences detected in pools were characterized via sequencing. RESULTS: A total of 9261 mosquitoes were captured and distributed into 232 pools from the following species: Ochlerotatus caspius (90.9%), Culex pipiens sensu lato (s.l.) (4.7%), Anopheles pseudopictus (3%), and Anopheles maculipennis s.l. (1.3%). Specimens morphologically classified as Cx. pipiens s.l. were identified as Cx. pipiens pipiens via barcoding. Thirty-seven mosquito pools (15.9%) were positive in pan-flavivirus and WNV-specific assays. Viral sequences in positive pools were characterized as WNV lineage 1 clade 1a and demonstrated 1-4% divergence. No flavivirus sequences other than WNV were detected in the mosquito pools. WNV infection rates in Oc. caspius and Cx. pipiens s.l. pools were 15.6% and 36.3%, respectively. Comparison of current and previously identified WNV sequences from Turkey revealed 94.00-96.34% similarity. DISCUSSION: WNV RNA was identified for the first time in Cx. pipiens s.l. and Oc. caspius mosquitoes in Eastern Thrace, Turkey. Our findings indicate the circulation of WNV lineage 1 strains in potential vector species and provide an epidemiological link between WNV activity in mosquitoes and vertebrate infections. PMID- 23919609 TI - Detection and early warning of West Nile Virus circulation in Central Macedonia, Greece, using sentinel chickens and mosquitoes. AB - Following the West Nile Virus (WNV) epidemic in 2010 in Central Macedonia, Greece, which resulted in 197 human neuroinvasive disease cases, we determined the seasonal appearance and prevalence of the virus in 2011 by testing weekly for WNV genomic RNA in mosquitoes collected in carbon dioxide-baited traps, and for anti-WNV antibodies in sentinel chickens. Preliminary findings of the surveillance program regarding the circulation of "Nea Santa-Greece-2010" in sentinel chickens were rapidly communicated to public health authorities. In the present article, the full 2011 data produced by this surveillance program are presented. We detected enzootic circulation of WNV in chickens 1 month prior to the onset of the first human cases in 2011. Culex pipiens and Cx. modestus were abundant throughout the sampling period and at all sites of increased transmission. Molecular identification and phylogenetic analysis of WNV isolates from two chickens and one Cx. pipiens mosquito pool suggested that: (1) the virulent "Nea Santa-Greece-2010" WNV lineage 2 strain responsible for the 2010 epidemic was actively circulating in 2011, and (2) all Greek isolates belong to a distinct recent evolutionary clade. In Europe, where numerous strains of different virulence coexist, sequencing information for WNV is important for phylogeography and identification of virulent strains for human health risk assessment. PMID- 23919610 TI - Fabrication and characterization of dual function nanoscale pH-scanning ion conductance microscopy (SICM) probes for high resolution pH mapping. AB - The easy fabrication and use of nanoscale dual function pH-scanning ion conductance microscopy (SICM) probes is reported. These probes incorporate an iridium oxide coated carbon electrode for pH measurement and an SICM barrel for distance control, enabling simultaneous pH and topography mapping. These pH-SICM probes were fabricated rapidly from laser pulled theta quartz pipets, with the pH electrode prepared by in situ carbon filling of one of the barrels by the pyrolytic decomposition of butane, followed by electrodeposition of a thin layer of hydrous iridium oxide. The other barrel was filled with an electrolyte solution and Ag/AgCl electrode as part of a conductance cell for SICM. The fabricated probes, with pH and SICM sensing elements typically on the 100 nm scale, were characterized by scanning electron microscopy, energy-dispersive X ray spectroscopy, and various electrochemical measurements. They showed a linear super-Nernstian pH response over a range of pH (pH 2-10). The capability of the pH-SICM probe was demonstrated by detecting both pH and topographical changes during the dissolution of a calcite microcrystal in aqueous solution. This system illustrates the quantitative nature of pH-SICM imaging, because the dissolution process changes the crystal height and interfacial pH (compared to bulk), and each is sensitive to the rate. Both measurements reveal similar dissolution rates, which are in agreement with previously reported literature values measured by classical bulk methods. PMID- 23919611 TI - What do patients with glaucoma think about personal health records? AB - PURPOSE: Putting patients in control of their records is one way of promoting patient centred care and patients with chronic health problems may benefit most from personal health records (PHRs). Glaucoma management is often complicated by incomplete understanding and poor adherence to treatment, two areas which a PHR may help to address. This study aimed to discover what patients with glaucoma think about PHRs and what type of information a glaucoma PHR should contain. METHODS: A consultation exercise using a focus group approach involving 71 participants was undertaken to discuss if a PHR would be useful and what it would be like. Narrative data were collected through written notes and an online forum in addition to transcripts of the focus group feedback session and individual interviews. Recordings were transcribed and analysed with simple thematic analysis facilitated by NVivo software (www.qsrinternational.com). RESULTS: The consultation exercise indicated enthusiasm for PHRs. Views varied on the best format, some participants strongly favoured electronic records and others preferred a low-tech, paper based format. A comprehensive dataset of 24 items was developed which highlighted areas which are not covered by existing guidance to developers. A model for how PHRs may be useful as an education tool in clinical practice was devised. CONCLUSIONS: Asking patients what they thought about a glaucoma PHR raised challenging questions and adds perspective to predominantly clinician led development. Listening and responding to such viewpoints is fundamental to developing more patient centred PHRs which may act both as health record and self-care educational tool to promote more holistic, efficient glaucoma care. PMID- 23919612 TI - Glycinyl-histidinyl-serine (GHS), a novel rapeseed protein-derived peptide has blood pressure-lowering effect in spontaneously hypertensive rats. AB - A novel antihypertensive peptide (Gly-His-Ser or GHS) with dual inhibition of angiotensin I-converting enzyme (ACE) and renin activities was isolated from the 3 kDa membrane ultrafiltration permeate of a pepsin+pancreatin rapeseed protein digest. The IC50 values of GHS were 0.52 +/- 0.01 mg/mL and 0.32 +/- 0.01 mg/mL for ACE and renin inhibitions, respectively, which are 1.5 times the ACE inhibition and 3.5 times the renin inhibition of the 3 kDa permeate. Oral administration (30 mg/kg body weight) to spontaneously hypertensive rats showed GHS to be an effective hypotensive agent with maximum blood pressure reduction of -17.29 +/- 2.47 mmHg after 6 h. In contrast, the 3 kDa permeate exhibited a maximum of -21.29 +/- 9.29 mmHg after 4 h, although at a relatively higher dose of 100 mg/kg body weight). GHS inhibited ACE and renin activities noncompetitively, but the renin inhibition became uncompetitive at a higher peptide concentration. PMID- 23919613 TI - Unesterified docosahexaenoic acid is protective in neuroinflammation. AB - Docosahexaenoic acid (22:6n-3) is the major brain n-3 polyunsaturated fatty acid and it is possible that docosahexaenoic acid is anti-inflammatory in the brain as it is known to be in other tissues. Using a combination of models including the fat-1 transgenic mouse, chronic dietary n-3 polyunsaturated fatty acid modulation in transgenic and wild-type mice, and acute direct brain infusion, we demonstrated that unesterified docosahexaenoic acid attenuates neuroinflammation initiated by intracerebroventricular lipopolysaccharide. Hippocampal neuroinflammation was assessed by gene expression and immunohistochemistry. Furthermore, docosahexaenoic acid protected against lipopolysaccharide-induced neuronal loss. Acute intracerebroventricular infusion of unesterified docosahexaenoic acid or its 12/15-lipoxygenase product and precursor to protectins and resolvins, 17S-hydroperoxy-docosahexaenoic acid, mimics anti neuroinflammatory aspects of chronically increased unesterified docosahexaenoic acid. LC-MS/MS revealed that neuroprotectin D1 and several other docosahexaenoic acid-derived specialized pro-resolving mediators are present in the hippocampus. Acute intracerebroventricular infusion of 17S-hydroperoxy-docosahexaenoic acid increases hippocampal neuroprotectin D1 levels concomitant to attenuating neuroinflammation. These results show that unesterified docosahexaenoic acid is protective in a lipopolysaccharide-initiated mouse model of acute neuroinflammation, at least in part, via its conversion to specialized pro resolving mediators; these docosahexaenoic acid stores may provide novel targets for the prevention and treatment(s) of neurological disorders with a neuroinflammatory component. Our study shows that chronically increased brain unesterified DHA levels, but not solely phospholipid DHA levels, attenuate neuroinflammation. Similar attenuations occur with acute increases in brain unesterified DHA or 17S-HpDHA levels, highlighting the importance of an available pool of precursor unesterified DHA for the production of enzymatically derived specialized pro-resolving mediators that are critical in the regulation of neuroinflammation. PMID- 23919614 TI - Establishment of cell lines with increased susceptibility to EV71/CA16 by stable overexpression of SCARB2. AB - BACKGROUND: Human enterovirus type 71 (EV71) and Coxsackievirus A group type 16 (CA16) belong to human Enterovirus species A of the family Picornaviridae. These viruses are recognized as the major pathogens responsible for epidemics of hand foot-mouth disease (HFMD), which presents with fever and vesicular eruptions of palms, soles of the feet or mouth. Human scavenger receptor class B, member 2 (SCARB2) has been identified as the receptor for both EV71 and CA16, as overexpression of SCARB2 in cells can enhance virus replication significantly. METHODS: In this study, we used a lentivirus packaging vector to transduce the SCARB2 gene into human embryonic kidney cells (293), human rhabdomyosarcoma cells (RD) and African green monkey kidney cells (Vero) to create stable expression lines. Expression of SCARB2 in the resulting three transgenic cell lines was confirmed by real-time RT-PCR, immunofluorescence and flow cytometry. RESULTS: Levels of SCARB2 mRNA determined by real-time RT-PCR in 293-SCARB2 (293S) or RD SCARB2 (RDS) transgenic cell lines were approximately 2 * 10(2) times higher than those in 293 and RD cells, respectively, and three times higher in Vero-SCARB2 (VeroS) than in Vero cells. Furthermore, EV71 and CA16 virus titers in 293S and RDS cells were 10(2)-10(3)-fold higher (detected in RD cell) than those in the parental cells, and a 10-fold higher titer of EV71 was achieved in VeroS cells compared with that in Vero cells. CONCLUSIONS: We established for the first time three cell lines stably overexpressing SCARB2, which showed drastic increases in susceptibility to EV71/CA16 infection. These optimal cell lines may be utilized to develop inactivated vaccines for EV71/CA16 and facilitate rapid detection and isolation of HFMD pathogens or other Enterovirus serotypes. Furthermore, these stable cell lines also can serve as tools to facilitate drug screenings as well as molecular studies on virus-host interactions and pathogenesis of causative agents for HFMD. PMID- 23919616 TI - Association of APOA5 -1131T>C polymorphism and serum lipid levels in patients with type 2 diabetes. AB - Significant abnormalities in lipid metabolism are frequently present in patients with type 2 diabetes mellitus (T2DM). Hypertriglyceridemia, a highly proatherogenic state, is associated with increased risk of coronary artery disease. Genetic polymorphism APOA5 -1131T>C has been recognized as a significant contributor to hypertriglyceridemia in both healthy and diabetic populations. The aim of the study was to investigate the association of APOA5 -1131T>C polymorphism with the serum levels of triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol in patients with T2DM. In total, 234 DNA samples from patients with T2DM were genotyped using the PCR-RFLP method. Serum lipid levels were measured using standard laboratory methods. Obtained APOA5 -1131T>C genotype frequencies were 89% (T/T) and 11% (T/C+C/C). There was no significant association between APOA5 -1131T>C genotypes and triglyceride levels (1.90 mM [1.32-2.74] vs. 1.78 mM [1.54-3.05] for T/T vs. T/C+C/C genotype; p=0.553), HDL cholesterol levels (1.30 mM [1.10-1.40] vs. 1.30 mM [1.05-1.40] for T/T vs. T/C+C/C; p=0.534), and LDL cholesterol levels (3.1 mM [2.3-3.8] vs. 3.0 mM [2.2-3.5] for T/T vs. T/C+C/C; p=0.313). Our results suggest that hypertriglyceridemia in patients with T2DM is not likely to be associated with the APOA5 -1131T>C polymorphism. PMID- 23919615 TI - ERK-associated changes in E2F4 phosphorylation, localization and transcriptional activity during mitogenic stimulation in human intestinal epithelial crypt cells. AB - BACKGROUND: The transcription factor E2F4 controls proliferation of normal and cancerous intestinal epithelial cells. E2F4 localization in normal human intestinal epithelial cells (HIEC) is cell cycle-dependent, being cytoplasmic in quiescent differentiated cells but nuclear in proliferative cells. However, the intracellular signaling mechanisms regulating such E2F4 localization remain unknown. RESULTS: Treatment of quiescent HIEC with serum induced ERK1/2 activation, E2F4 phosphorylation, E2F4 nuclear translocation and G1/S phase transition while inhibition of MEK/ERK signaling by U0126 prevented these events. Stimulation of HIEC with epidermal growth factor (EGF) also led to the activation of ERK1/2 but, in contrast to serum or lysophosphatidic acid (LPA), EGF failed to induce E2F4 phosphorylation, E2F4 nuclear translocation and G1/S phase transition. Furthermore, Akt and GSK3beta phosphorylation levels were markedly enhanced in serum- or LPA-stimulated HIEC but not by EGF. Importantly, E2F4 phosphorylation, E2F4 nuclear translocation and G1/S phase transition were all observed in response to EGF when GSK3 activity was concomitantly inhibited by SB216763. Finally, E2F4 was found to be overexpressed, phosphorylated and nuclear localized in epithelial cells from human colorectal adenomas exhibiting mutations in APC and KRAS or BRAF genes, known to deregulate GSK3/beta-catenin and MEK/ERK signaling, respectively. CONCLUSIONS: The present results indicate that MEK/ERK activation and GSK3 inhibition are both required for E2F4 phosphorylation as well as its nuclear translocation and S phase entry in HIEC. This finding suggests that dysregulated E2F4 nuclear localization may be an instigating event leading to hyperproliferation and hence, of tumor initiation and promotion in the colon and rectum. PMID- 23919617 TI - Helix formation by alanine-based peptides in pure water and electrolyte solutions: insights from molecular dynamics simulations. AB - Specific ion effects on oligopeptide conformations in solution are attracting strong research attention, because of their impact on the protein-folding problem and on several important biological-biotechnological applications. In this work, we have addressed specific effects of electrolytes on the tendency of oligopeptides toward formation and propagation of helical segments. We have used replica-exchange molecular dynamics (REMD) simulations to study the conformations of two short hydrophobic peptides [Ace-(AAQAA)3-Nme (AQ), and Ace-A8-Nme (A8)] in pure water and in aqueous solutions of sodium chloride (NaCl) and sodium iodide (NaI) with concentrations of 1 and 3 M. The average helicities of the AQ peptide have been analyzed to yield Lifson-Roig (LR) parameters for helix nucleation and helix propagation. The salt dependence of these parameters suggests that electrolytes tend to stabilize the helical conformations of short peptides by enhancing the helix nucleation parameter. The helical conformations of longer oligopeptides are destabilized in the presence of salts, however, because the helix propagation parameters are reduced by electrolytes. On top of this general trend, we observe a significant specific salt effect in these simulations. The hydrophobic iodide ion in NaI solutions has a high affinity for the peptide backbone, which reflects itself in an enhanced helix nucleation and a reduced helix propagation parameter with respect to pure water or NaCl solutions. The present work thus explains the computational evidence that electrolytes tend to stabilize the compact conformations of short peptides and destabilize them for longer peptides, and it also sheds additional light on the specific salt effects on compact peptide conformations. PMID- 23919618 TI - Cervical varicosities and placenta praevia. AB - INTRODUCTION: Cervical varicosities (CVs) have been reported infrequently in pregnancy and have been associated with significant antepartum and postpartum haemorrhage. The most common association with CVs in pregnancy in the literature is placenta praevia. AIMS: To further investigate the association between placenta praevia and CVs. METHODS: A retrospective audit of all cases of placenta praevia that had an ultrasound in the Feto-Maternal Unit at Liverpool Hospital over the period January 2001 to January 2012. Patient outcomes were obtained from the hospital paper and electronic medical records, including mode of delivery and blood loss. RESULTS: Eighty-four cases of placenta praevia were identified, and 78 had saved images that were reviewed. 51 of these 78 cases had transvaginal ultrasound (TVUS) images, which identified nine further cases of cervical varicosities. All cases of CVs were complicated by APH and delivered by caesarean section. There was no significant difference in the blood loss at delivery between the placenta praevia with CVs and those without (925 vs 870 mLs P = 0.3877). CONCLUSIONS: Cervical varicosities are not as rare as the literature would suggest. The clinical relevance of the additional finding of CV on TVUS in cases of placenta praevia is questionable. PMID- 23919619 TI - Glutathione peroxidase 7 utilizes hydrogen peroxide generated by Ero1alpha to promote oxidative protein folding. AB - AIMS: Ero1 flavoproteins catalyze oxidative folding in the endoplasmic reticulum (ER), consuming oxygen and generating hydrogen peroxide (H2O2). The ER-localized glutathione peroxidase 7 (GPx7) shows protein disulfide isomerase (PDI)-dependent peroxidase activity in vitro. Our work aims at identifying the physiological role of GPx7 in the Ero1alpha/PDI oxidative folding pathway and at dissecting the reaction mechanisms of GPx7. RESULTS: Our data show that GPx7 can utilize Ero1alpha-produced H2O2 to accelerate oxidative folding of substrates both in vitro and in vivo. H2O2 oxidizes Cys57 of GPx7 to sulfenic acid, which can be resolved by Cys86 to form an intramolecular disulfide bond. Both the disulfide form and sulfenic acid form of GPx7 can oxidize PDI for catalyzing oxidative folding. GPx7 prefers to interact with the a domain of PDI, and intramolecular cooperation between the two redox-active sites of PDI increases the activity of the Ero1alpha/GPx7/PDI triad. INNOVATION: Our in vitro and in vivo evidence provides mechanistic insights into how cells consume potentially harmful H2O2 while optimizing oxidative protein folding via the Ero1alpha/GPx7/PDI triad. Cys57 can promote PDI oxidation in two ways, and Cys86 emerges as a novel noncanonical resolving cysteine. CONCLUSION: GPx7 promotes oxidative protein folding, directly utilizing Ero1alpha-generated H2O2 in the early secretory compartment. Thus, the Ero1alpha/GPx7/PDI triad generates two disulfide bonds and two H2O molecules at the expense of a single O2 molecule. PMID- 23919620 TI - Genetic characterization of Toxoplasma gondii from pigs from different localities in China by PCR-RFLP. AB - BACKGROUND: Toxoplasma gondii is a widely prevalent protozoan parasite that causes serious toxoplasmosis in humans and animals. The present study aimed to determine the genetic diversity of T. gondii isolates from pigs in Jiangxi, Sichuan, Guangdong Provinces and Chongqing Municipality in China using multilocous polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technology. METHODS: A total of 38 DNA samples were extracted from hilar lymph nodes of pigs with suspected toxoplasmosis, and were detected for the presence of T. gondii by semi-nested PCR of B1 gene. The positive DNA samples were typed at 11 genetic markers, including 10 nuclear loci, namely, SAG1, 5' SAG2 and 3'-SAG2, alternative SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and an apicoplast locus Apico. RESULTS: Twenty-five of the 38 DNA samples were T. gondii B1 gene positive. Complete genotyping data for all loci could be obtained for 17 of the 25 samples. Two genotypes were revealed (ToxoDB PCR-RFLP genotypes #9 and #3). Sixteen samples belong to genotype #9 which is the major lineage in mainland China and one sample belongs to genotype #3 which is Type II variant. CONCLUSIONS: To our knowledge, this is the first report of genetic typing of T. gondii isolates from pigs in Jiangxi, Sichuan Province and Chongqing Municipality, and the first report of ToxoDB #3 T. gondii from pigs in China. These results have implications for the prevention and control of foodborne toxoplasmosis in humans. PMID- 23919621 TI - A systematic review of studies assessing the association between adherence to smoking cessation medication and treatment success. AB - AIMS: Lack of adherence to smoking cessation medication regimens is assumed to play a significant role in limiting their effectiveness. This study aimed to assess evidence for this assumption. METHODS: A systematic search was conducted, supplemented by expert consultation, of papers reporting on randomized trials and observational studies examining the association between adherence to cessation medication and the success of quit attempts. To rule out reverse causality, only studies where adherence was assessed prior to relapse were included. Five studies met the inclusion criteria and results were extracted independently by two researchers. Heterogeneity between studies precluded a pooled analysis of the data. RESULTS: Studies varied widely with regard to both the definition of adherence and outcome measures. The included studies only addressed adherence to nicotine replacement therapy. One study of lozenge use found that the amount of medication used between 1 and 2 weeks after the quit date predicted abstinence at 6 weeks [adjusted odds ratio (OR) for 'high' versus 'low' lozenge use 1.25; 95% confidence interval (CI) = 1.05-1.50; P < 0.02]. Similarly, one study found a significant impact of oral nicotine consumption during the first week on abstinence at 4 weeks (adjusted OR per additional mg/day = 1.05; CI = 1.01-1.10). Another study found that participants using nicotine replacement therapy for at least 5 weeks were significantly more likely to self-report continuous abstinence at 6 months. The remaining two studies failed to find a significant effect of treatment duration on outcome at 1 and 2 years but had very low power to detect such an effect. CONCLUSIONS: There is modest evidence to support the assumption that lack of adherence to nicotine replacement therapy regimens undermines effectiveness in clinical studies. PMID- 23919623 TI - Effects of pulsed Nd:YAG laser on tensile bond strength and caries resistance of human enamel. AB - This study aims to evaluate the effects of pulsed Nd:YAG laser on the tensile bond strength (TBS) of resin to human enamel and caries resistance of human enamel. A total of 201 human premolars were used in this in vitro study. A flat enamel surface greater than 4 * 4 mm in area was prepared on each specimen using a low-speed cutting machine under a water coolant. Twenty-one specimens were divided into seven groups for morphology observations with no treatment, 35% phosphoric acid etching (30 seconds), and laser irradiation (30 seconds) of pulsed Nd:YAG laser with five different laser-parameter combinations. Another 100 specimens were used for TBS testing. They were embedded in self-cured acrylic resin and randomly divided into 10 groups. After enamel surface pretreatments according to the group design, resin was applied. The TBS values were tested using a universal testing machine. The other 80 specimens were randomly divided into eight groups for acid resistance evaluation. Scanning electron microscope (SEM) results showed that the enamel surfaces treated with 1.5 W/20 Hz and 2.0 W/20 Hz showed more etching-like appearance than those with other laser-parameter combinations. The laser-parameter combinations of 1.5 W/15 Hz and 1.5 W/20 Hz were found to be efficient for the TBS test. The mean TBS value of 14.45 +/- 1.67 MPa in the laser irradiated group was significantly higher than that in the untreated group (3.48 +/- 0.35 MPa) but lower than that in the 35% phosphoric acid group (21.50 +/- 3.02 MPa). The highest mean TBS value of 26.64 +/- 5.22 MPa was identified in the combination group (laser irradiation and then acid etching). Acid resistance evaluation showed that the pulsed Nd:YAG laser was efficient in preventing enamel demineralization. The SEM results of the fractured enamel surfaces, resin/enamel interfaces, and demineralization depths were consistent with those of the TBS test and the acid resistance evaluation. Pulsed Nd:YAG laser as an enamel surface pretreatment method presents a potential clinical application, especially for the caries-susceptible population or individuals with recently bleached teeth. PMID- 23919622 TI - Impact of nutritional supplementation on immune response, body mass index and bioelectrical impedance in HIV-positive patients starting antiretroviral therapy. AB - BACKGROUND: Challenges to HIV care in resource limited settings (RLS) include malnutrition. Limited evidence supports the benefit of nutritional supplementation when starting antiretroviral therapy (ART) in RLS. METHODS: Randomized controlled pilot study. HIV-positive ART-naive adults with self reported weight loss were randomized to receive ART plus FutureLife porridge nutritional supplement (NS) (388 kcal/day) or ART alone (Controls) for 6 months. Patients returned for monthly assessments and blood was drawn at enrolment and 6 months on ART. Differences in body composition, biochemical and laboratory parameters were estimated at 6 months on treatment. RESULTS: Of the 36 randomized patients, 26 completed the 6 month follow-up (11 NS vs 15 Controls). At enrolment, groups were similar in terms of age, gender, body mass index (BMI) and bioelectrical impedance. NS patients had a lower median CD4 count (60 cells/mm3 [IQR 12-105 vs. 107 cells/mm3 [IQR 63-165]; p = 0.149) and hemoglobin (10.3 g/dL [IQR 9.0-11.3] vs. 13.1 g/dL [IQR 11.1-14.7]; p = 0.001). CONCLUSION: Preliminary results are encouraging and suggest that NS taken concurrently with ART can promote weight gain, improve immune response and improve physical activity in HIV positive patients that present at ART initiation with weight loss. PMID- 23919624 TI - Accomplishing esthetics using enamel microabrasion and bleaching-a case report. AB - This case report describes the sequential steps that were used to treat unesthetic, white, hard-texture enamel stains of unknown etiology. A tapered fine diamond bur was used to remove superficial enamel followed by the use of an enamel microabrasion compound Opalustre (Ultradent Products Inc). This technique removed the stains and was followed by polishing with a fluoride paste to restore the enamel to a smooth finish. The teeth were subsequently bleached with carbamide peroxide (Opalescence 10%, Ultradent Products), which achieved the patient's desired esthetic results. PMID- 23919626 TI - Direct observation of charge-carrier heating at WZ-ZB InP nanowire heterojunctions. AB - We have investigated the dynamics of hot charge carriers in InP nanowire ensembles containing a range of densities of zinc-blende inclusions along the otherwise wurtzite nanowires. From time-dependent photoluminescence spectra, we extract the temperature of the charge carriers as a function of time after nonresonant excitation. We find that charge-carrier temperature initially decreases rapidly with time in accordance with efficient heat transfer to lattice vibrations. However, cooling rates are subsequently slowed and are significantly lower for nanowires containing a higher density of stacking faults. We conclude that the transfer of charges across the type II interface is followed by release of additional energy to the lattice, which raises the phonon bath temperature above equilibrium and impedes the carrier cooling occurring through interaction with such phonons. These results demonstrate that type II heterointerfaces in semiconductor nanowires can sustain a hot charge-carrier distribution over an extended time period. In photovoltaic applications, such heterointerfaces may hence both reduce recombination rates and limit energy losses by allowing hot carrier harvesting. PMID- 23919625 TI - Internet-based interventions for eating disorders in adults: a systematic review. AB - BACKGROUND: This systematic review evaluates the efficacy of internet-based interventions for the treatment of different eating disorders in adults. METHOD: A search for peer reviewed journal articles detailing Randomised Control Trials (RCT) and Controlled Trials (CT) addressing participants with eating disorders aged at least 16 was completed in the electronic databases Web of Science, PsycInfo and PubMed. The quality of the included articles was assessed, results were reviewed and effect sizes and corresponding confidence intervals were calculated. RESULTS: Eight studies, including a total of N = 609 participants, fulfilled the selection criteria and were included. The majority of treatments applied in these studies were based on CBT principles. Six studies described guided self-help interventions that showed significant symptom reduction in terms of primary and secondary outcomes regarding eating behaviour and abstinence rates. These studies produced significant medium to high effect sizes both within and between the groups after utilisation of guided self-help programs or a self help book backed up with supportive e-mails. The two remaining studies utilised a specific writing task or e-mail therapy that did not follow a structured treatment program. Here, no significant effects could be found. Treatment dropout rates ranged from 9% to 47.2%. Furthermore, reductions in other symptoms, for example depression and anxiety, and an increase in quality of life were found by four studies. CONCLUSIONS: Overall, the results support the value of internet based interventions that use guided self-help to tackle eating disorders, but further research is needed due to the heterogeneity of the studies. PMID- 23919627 TI - Toxicogenomic responses of zebrafish embryos/larvae to tris(1,3-dichloro-2 propyl) phosphate (TDCPP) reveal possible molecular mechanisms of developmental toxicity. AB - Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is frequently present in indoor dust and can be detected in human milk. In order to evaluate the effects of TDCPP on vertebrate development, zebrafish embryos/larvae were used as an animal model to examine developmental phenotypes and explore possible mechanisms of toxicity by employing microarrays and iTRAQ labeling quantitative proteomics. The results demonstrated that treatment with TDCPP (3 MUM) from 0.75 h postfertilization (hpf) inhibited cell rearrangement at 4 hpf, caused delay in epiboly at 5.7 and 8.5 hpf, and led to abnormal development (e.g., short tail, reduced body size) and lethality between 14 and 45 hpf, which might be related with altered expression of genes regulating embryogenesis. Furthermore, trunk curvature was observed as the main phenotype in 96 hpf zebrafish larvae exposed to 1 or 3 MUM TDCPP, possibly by changing somite formation and expression of proteins related to fast muscle and cartilage development. Collectively, our results suggest that exposure to TDCPP causes developmental toxicity in vertebrates and warrant the need for studies to evaluate the potential health risks of TDCPP to developing human embryos/infants/children, due to its frequent presence in indoor dust and potential for human exposure. PMID- 23919628 TI - Eosinophils are not required for the induction and maintenance of an alloantibody response. AB - Eosinophil-produced cytokines have been shown to participate in the maintenance of antigen-specific plasma cells (PC) in bone marrow (BM), suggesting that eosinophils are required in the development and/or maintenance of alloantibody responses posttransplant. To test this hypothesis, we sensitized eosinophil deficient DeltadblGATA1 mice and wild-type (WT) control mice with allogeneic splenocytes or with allogeneic heart grafts and compared the kinetics and titers of serum donor-specific antibodies (DSA), as well as BM and spleen CD130 + B220 low PC populations between groups. Spleen cells from naive DeltadblGATA1 BALB/c mice contained higher percentages of PC than WT without detectable differences in BM PCs. After sensitization with allogeneic splenocytes, BALB/c DeltadblGATA1 mice contained fewer BM PCs but more splenic PCs compared to controls. These differences were associated with modestly lower titers of serum DSA 4 and 12 weeks after sensitization but secondary immunizations induced similar increases in both groups. Moreover, the kinetics and strength of DSA did not differ in WT and DeltadblGATA1 BALB/c mice transplanted with B6 cardiac allografts, nor did they differ in transplanted DeltadblGATA1 and WT mice on a B6 background. Therefore, eosinophils are not required for alloantibody formation or maintenance in mice and are thus unlikely to be effective targets for antibody desensitization. PMID- 23919629 TI - Clinical, cytologic, and histologic features of a mammary micropapillary carcinoma in a dog. AB - Mammary invasive micropapillary carcinoma is a rare variant of mammary carcinoma that was recently recognized in dogs. The cytologic features and biologic behavior of such neoplasms in dogs have not yet been widely discussed in the veterinary literature. We report the clinical, cytologic, and histologic features of a canine micropapillary carcinoma in a 13-year-old female mongrel dog. The mammary region presented with extreme local pain, severe edema and erythema, and multifocal epidermal ulceration, which is typical for an inflammatory mammary carcinoma. Fine-needle aspirates were highly cellular and consisted of individual cells and papillary cell clusters with characteristics of malignant epithelial cells. Histologic examination revealed neoplastic cells arranged in small papillae without fibrovascular cores, sometimes inside clear lymphatic spaces, indicating lymphovascular invasion. Regional lymph node evaluation revealed metastatic cells. Due to deteriorating clinical condition the dog was euthanatized 5 months after mastectomy. At necropsy, metastatic neoplastic mammary cells were found in popliteal and mediastinal lymph nodes, the right femoral biceps muscle, liver, heart, lungs, and urinary bladder. PMID- 23919630 TI - Tuning the size and properties of ClyA nanopores assisted by directed evolution. AB - Nanopores have recently emerged as powerful tools in single-molecule investigations. Biological nanopores, however, have drawbacks, including a fixed size and limited stability in lipid bilayers. Inspired by the great success of directed evolution approaches in tailoring enzyme properties, in this work we evolved Cytolysin A from Salmonella typhi (ClyA) to a high level of soluble expression and desired electrical properties in lipid bilayers. Evolved ClyA nanopores remained open up to -150 mV applied potential, which allowed the detailed characterization of folded proteins by ionic current recordings. Remarkably, we also found that ClyA forms several nanopore species; among which we could isolate and characterize three nanopore types most likely corresponding to the 12mer, 13mer, and 14mer oligomeric forms of ClyA. Protein current blockades to the three ClyA nanopores showed that subnanometer variations in the diameter of nanopores greatly affect the recognition of analyte proteins. PMID- 23919631 TI - Enzyme-modified carbon-fiber microelectrode for the quantification of dynamic fluctuations of nonelectroactive analytes using fast-scan cyclic voltammetry. AB - Neurotransmission occurs on a millisecond time scale, but conventional methods for monitoring nonelectroactive neurochemicals are limited by slow sampling rates. Despite a significant global market, a sensor capable of measuring the dynamics of rapidly fluctuating, nonelectroactive molecules at a single recording site with high sensitivity, electrochemical selectivity, and a subsecond response time is still lacking. To address this need, we have enabled the real-time detection of dynamic glucose fluctuations in live brain tissue using background subtracted, fast-scan cyclic voltammetry. The novel microbiosensor consists of a simple carbon fiber surface modified with an electrodeposited chitosan hydrogel encapsulating glucose oxidase. The selectivity afforded by voltammetry enables quantitative and qualitative measurements of enzymatically generated H2O2 without the need for additional strategies to eliminate interfering agents. The microbiosensors possess a sensitivity and limit of detection for glucose of 19.4 +/- 0.2 nA mM(-1) and 13.1 +/- 0.7 MUM, respectively. They are stable, even under deviations from physiological normoxic conditions, and show minimal interference from endogenous electroactive substances. Using this approach, we have quantitatively and selectively monitored pharmacologically evoked glucose fluctuations with unprecedented chemical and spatial resolution. Furthermore, this novel biosensing strategy is widely applicable to the immobilization of any H2O2 producing enzyme, enabling rapid monitoring of many nonelectroactive enzyme substrates. PMID- 23919632 TI - Willingness to pay to prevent chemotherapy induced nausea and vomiting among patients with breast, lung, or colorectal cancer. AB - OBJECTIVE: Understanding the value patients place on avoiding various aspects of chemotherapy induced nausea and vomiting (CINV) can help medical professionals assess whether current and emerging treatments are acceptable based on their costs and expected effects. Little is known, however, about the value patients place on avoiding various aspects of CINV. The current study helps fill this gap in the literature. METHODS: 301 patients completed a discrete-choice conjoint survey. Patients viewed 25 conjoint tasks, each containing two descriptions of CINV, and indicated which they preferred. The descriptions combined levels from eight CINV attributes (likelihood of nausea, duration of nausea, severity of nausea, likelihood of vomiting, duration of vomiting, severity of vomiting, need to seek treatment for dehydration, and out-of-pocket treatment costs). RESULTS: Cost contributed more to patient choices than any other single attribute. The combined effect of the likelihood, duration, and severity attributes for nausea, however, was a stronger driver of patient choices than cost, as was the combined effect of the likelihood, duration, and severity attributes for vomiting. The nausea attributes also were a stronger driver of patient choices than the vomiting attributes. Patients were willing to pay to avoid increases in all attributes, except likelihood of vomiting, where the result was not statistically different from zero. Willingness-to-pay varied by income, disease stage, Eastern Cooperative Oncology Group performance status, chemotherapy status, and whether patients worked while on chemotherapy. LIMITATIONS: Although the study used a convenience sample, data were collected from several geographically dispersed U.S. oncology clinics. CONCLUSIONS: Several antiemetics are now available at different price points. This study assesses the value patients place on their benefits and may be used to inform decisions about the management of CINV. PMID- 23919633 TI - Effects of gradual versus sudden training on the cognitive demand required while learning a novel locomotor task. AB - The cognitive demand required for a range of locomotor tasks has been described for a variety of populations. However, the effect of different training strategies on the cognitive demand required while learning novel locomotor tasks is not well understood and may inform physical rehabilitation. The authors examined whether two training strategies, gradual and sudden training, influenced the cognitive demand required while practicing a novel locomotor task, asymmetric split-belt treadmill walking. Simple reaction times and whole-body kinematics were recorded throughout practice. Gradual training resulted in significantly lower reaction times during much of training, suggesting that gradual training is less cognitively demanding than sudden training, possibly due to a reduction in error feedback or movement planning demands. PMID- 23919634 TI - Alcohol dispersions of calcium hydroxide nanoparticles for stone conservation. AB - Alcohol dispersions of Ca(OH)2 nanoparticles, the so-called nanolimes, are emerging as an effective conservation material for the consolidation of stone, mortars, and plasters present in old masonry and/or mural paintings. To better understand how this treatment operates, to optimize its performance and broaden its applications, here we study the nano and microstructural characteristics, carbonation behavior, and consolidation efficacy of colloidal alcohol dispersions of Ca(OH)2 nanoparticles produced by both homogeneous (commercial nanolime) and heterogeneous phase synthesis (aged slaked lime and carbide lime putties). We observe that the alcohol not only provides a high colloidal stability to Ca(OH)2 particles, but also affects the kinetics of carbonation and CaCO3 polymorph selection. This is due to the pseudomorphic replacement of Ca(OH)2 particles by calcium alkoxides upon reaction with ethanol or 2-propanol. The extent of this replacement reaction depends on Ca(OH)2 size and time. Hydrolysis of alkoxides speeds up the carbonation process and increases the CaCO3 yield. The higher degree of transformation into calcium alkoxide of both the commercial nanolime and the carbide lime fosters metastable vaterite formation, while calcite precipitation is promoted upon carbonation of the aged slaked lime due its lower reactivity, which limits calcium alkoxide formation. A higher consolidation efficacy in terms of strength gain of treated porous stone is achieved in the latter case, despite the fact that the carbonation is much faster and reaches a higher yield in the former ones. Formation of alkoxides, which has been neglected in previous studies, needs to be considered when applying nanolime treatments. These results show that the use Ca(OH)2 nanoparticle dispersions prepared with either aged slaked lime or carbide lime putties is an economical and effective conservation alternative to commercial nanolimes produced by homogeneous phase synthesis. Ultimately, this study contributes to show that nanotechnology can help saving the built and sculptural heritage. PMID- 23919635 TI - Studies on the flavone glycosides from Fructus Kochiae. AB - A series of flavone glycosides were isolated from Fructus Kochiae for the first time, including two new flavone glycosides. The structures were established by interpretation of their spectroscopic data. Two new flavone glycosides are quercetin 3-O-beta-d-apiofuranosyl-(1 -> 2)-beta-d-galactopyranosyl-7-O-beta-d glucopyranoside (1) and quercetin 3-O-alpha-l-rhamnopyranosyl-(1 -> 6)-beta-d galactopyranosyl-7-O-beta-d-sophoroside (2). The others are quercetin 7-O-beta-d glucopyranoside (3), quercetin 3-O-beta-d-apiofuranosyl-(1 -> 2)-beta-d galactopyranoside (4), quercetin 3-O-beta-d-galactopyranosyl-7-O-beta-d glucopyranoside (5), and quercetin 7-O-beta-d-sophoroside (6). PMID- 23919636 TI - Vesicular GABA transporter (VGAT) transports beta-alanine. AB - Vesicular GABA transporter (VGAT) is expressed in GABAergic and glycinergic neurons, and is responsible for vesicular storage and subsequent exocytosis of these inhibitory amino acids. In this study, we show that VGAT recognizes beta alanine as a substrate. Proteoliposomes containing purified VGAT transport beta alanine using Deltapsi but not DeltapH as a driving force. The Deltapsi-driven beta-alanine uptake requires Cl(-). VGAT also facilitates Cl(-) uptake in the presence of beta-alanine. A previously described VGAT mutant (Glu213Ala) that disrupts GABA and glycine transport similarly abrogates beta-alanine uptake. These findings indicated that VGAT transports beta-alanine through a mechanism similar to those for GABA and glycine, and functions as a vesicular beta-alanine transporter. Vesicular GABA transporter (VGAT) is expressed in GABAergic and glycinergic neurons, and is responsible for vesicular storage and subsequent exocytosis of these inhibitory amino acids. In the present study, we showed that proteoliposomes containing purified VGAT transport beta-alanine using Deltapsi as a driving force. VGAT also facilitates Cl(-) uptake. Our findings indicated that VGAT functions as a vesicular beta-alanine transporter. PMID- 23919637 TI - Estimating DNA polymorphism from next generation sequencing data with high error rate by dual sequencing applications. AB - BACKGROUND: As the error rate is high and the distribution of errors across sites is non-uniform in next generation sequencing (NGS) data, it has been a challenge to estimate DNA polymorphism (theta) accurately from NGS data. RESULTS: By computer simulations, we compare the two methods of data acquisition - sequencing each diploid individual separately and sequencing the pooled sample. Under the current NGS error rate, sequencing each individual separately offers little advantage unless the coverage per individual is high (>20X). We hence propose a new method for estimating theta from pooled samples that have been subjected to two separate rounds of DNA sequencing. Since errors from the two sequencing applications are usually non-overlapping, it is possible to separate low frequency polymorphisms from sequencing errors. Simulation results show that the dual applications method is reliable even when the error rate is high and theta is low. CONCLUSIONS: In studies of natural populations where the sequencing coverage is usually modest (~2X per individual), the dual applications method on pooled samples should be a reasonable choice. PMID- 23919638 TI - Dietary glutamine supplementation prevents mucosal injury and modulates intestinal epithelial restitution following acetic acid induced intestinal injury in rats. AB - Beneficial effects of glutamine (GLN) have been described in many gastrointestinal disorders. The aim of the present study was to evaluate the preventative effect of oral GLN supplementation against acetic acid (AA) induced intestinal injury in a rat. Male Sprague-Dawley rats were divided into four experimental groups: control (CONTR) rats underwent laparotomy, control-glutamine (CONTR-GLN) rats were treated with enteral glutamine given in drinking water (2%) 48 hours before and five days following laparotomy, AA rats underwent laparotomy and injection of AA into an isolated jejunal loop, and acetic acid-glutamine (AA GLN) rats underwent AA-induced injury and were treated with enteral GLN 48 hours before and 5 days following laparotomy. Intestinal mucosal damage (Park's injury score), mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined five days following intestinal injury. Western blotting was used to determine p-ERK and bax protein levels. AA-induced intestinal injury resulted in a significantly increased intestinal injury score with concomitant inhibition of cell turnover (reduced proliferation and enhanced apoptosis). Treatment with dietary GLN supplementation resulted in a decreased intestinal injury score with concomitant stimulation of cell turnover (enhanced proliferation and reduced apoptosis). In conclusion, pre-treatment with oral GLN prevents mucosal injury and improves intestinal recovery following AA-induced intestinal injury in rats. PMID- 23919639 TI - Reaction of water with (radicals in) plasma polymerized allyl alcohol (and formation of OH-rich polymer layers). AB - The pulsed plasma polymerization of allyl alcohol was employed under the aspect of maximal retention of OH groups and the formation of a regular polymer structure. It should be noted that earlier investigations on plasma polymers deposited from allyl alcohol did not show extensive postplasma addition of oxygen and water vapor from ambient air during storage, measuring the elemental O/C ratio by means of X-ray photoelectron spectroscopy (XPS).The identification of OH groups in the plasma polymerized polymer using FTIR spectroscopy was such an indicator for fragmentation. The peak area of OH groups in the film which was stored was increased by about 20% compared to that measured ("in situ"). These phenomenons reflected that moisture and O2 in air played an important role in scavenging the free radicals. The addition of water and more specifically chemical bonding of OH of water in the deposited plasma polymer may serve as an indicator for monomer fragmentation, poly recombination, and the remaining radicals responsible for film formation. Moreover, the dielectric measurements show that the plasma deposited films are not thermally stable but undergo a postplasma chemical reaction during heating, where the reaction kinetics depends on pressure. PMID- 23919641 TI - Narrative environments and the capacity of disability narratives to motivate leisure-time physical activity among individuals with spinal cord injury. AB - PURPOSE: Few individuals with spinal cord injury (SCI) engage in the recommended amount of leisure time physical activity (LTPA). Yet little is known about how, and why, active individuals engage in specific types of LTPA. This study explored how a unique narrative environment and disability narratives motivated individuals with SCI to engage in LTPA. METHOD: Fourteen individuals with SCI from a physical activity program participated in approximately hour-long interviews. Interviews were then subjected to a narrative analysis. RESULTS: Individuals who used a restitution narrative (n = 6) were motivated to engage in functional LTPA because of the desire to maintain the body and restore the past self. The individual who used the chaos narrative (n = 1) preferred solitary LTPA as exposure to others with SCI was a constant reminder of the lost, pre-injury self. Individuals who used a quest narrative (n = 7) explored LTPA options that fit with their interests; these individuals were open to new types of LTPA, such as sport and outdoor recreation. CONCLUSION: The plot of three disability narratives can all motivate the pursuit of LTPA; however, not all types of LTPA are seen as equal. LTPA interventions can be enhanced through the lessons learned from this unique type of environment. IMPLICATIONS FOR REHABILITATION: Despite individuals' views about their disability, they can still be motivated to engage in routine LTPA. Different theoretical determinants, such as health or social benefits, hold different relevance for LTPA among individuals with differing disability narratives. The environment provided by practitioners can therefore elicit some stories of SCI while stifling others. Open narrative environment will attract individuals to listen and maintain involvement in LTPA. PMID- 23919642 TI - Reporting about disability evaluation in European countries. AB - PURPOSE: To compare the official requirements of the content of disability evaluation for social insurance across Europe and to explore how the International Classification of Functioning, Disability and Health is currently applied, using the rights and obligations of people with disabilities towards society as frame of reference. METHODS: Survey. We used a semi-structured questionnaire to interview members of the European Union of Medicine in Assurance and Social Security (EUMASS), who are central medical advisors in social insurance systems in their country. We performed two email follow-up rounds to complete and verify responses. RESULTS: Fifteen respondents from 15 countries participated. In all countries, medical examiners are required to report about a claimant's working capacity and prognosis. In 14 countries, medical reports ought to contain information about socio-medical history and feasible interventions to improve the claimant's health status. The format of medical reporting on working capacity varies widely (free text, semi- and fully structured reports). One country makes a reference to the ICF in their reports on working capacity, others consider doing so. CONCLUSION: Official requirements on medical reporting about disability in social insurance across Europe follow the frame of four features: work capacity, socio-medical history, feasibility of intervention and prognosis of disability. There is an increasing trend to make formal or informal reference to the ICF in the reports about working capacity. The four features and the ICF may provide common references across countries to describe disability evaluation, facilitating national and international research. Implications for Rehabilitation Reporting about disability in social insurance in different countries is about work capacity, social medical history, feasibility of intervention and prognosis of disability. Formats of reporting on work capacity vary among countries, from free text to semi-structured report forms to fully structured and scaled report forms of working capacity. The ICF could serve as a reference for describing work capacity, provided the ICF contains all necessary categories. PMID- 23919643 TI - Change of residence and functional status within three months and one year following hip fracture surgery. AB - PURPOSE: To study the recovery of patients in terms of 18 activities of daily living and change of residence within the year following a hip fracture. METHOD: This prospective cohort study was carried out in a trauma service of an acute hospital in southern Spain including 159 patients with a hip fracture, 65 years or older and allowed weight-bearing after surgery. Patients or their relatives were interviewed about their residential status and functional level at pre fracture, three months and one year after surgery, using the Functional Independence Measure. RESULTS: Losses of function for the main activities affected were, at the first month, third month and one year relative to the pre fracture status, 50%, 25% and 12%, respectively, for locomotion, 40%, 25% and 20%, respectively, for mobility and 27%, 17% and 15%, respectively, for self care (p < 0.001). Residential status changed mostly for patients who lived in their own home (73% before fracture to 58% at one year). CONCLUSIONS: The loss of independence in the first year after a hip fracture is substantial for specific activities. Recovery mainly takes place during the first three months after surgery. Change of residence mostly involved those patients who lived alone in their own home at pre-fracture. Implications for Rehabilitation One year after fracture, patients did not recover their previous function, and the activities most affected at the one-year follow-up were: dressing lower body, bathing/showering, transfer bathtub/shower and walking up/down stairs. After a hip fracture, most recovery of the function happens within the first three months, though some functional activities continue recovering over the first year. Rehabilitation programs cannot be based only on mobility activities, the recovery of other daily living activities should also be included. PMID- 23919644 TI - Physical and rehabilitation medicine training center in Split, Croatia: striving to achieve excellence in education of a rehabilitation team. AB - PURPOSE: The aim of this manuscript is to describe recent changes in rehabilitation medicine education in Croatia, and to highlight the effort that was made at University of Split School of Medicine, as well as at University Hospital Split in order to improve training in rehabilitation medicine. METHOD: Critical collection and study of pertinent data on evolvement and present state of physical and rehabilitation medicine (PRM) education in Croatia. RESULTS: Education in physical medicine and rehabilitation in Croatia was mainly focused on rheumatology rather than rehabilitation. In order to satisfy the new standards set for quality of rehabilitation medicine national curriculum reform was made for medical students, specialist and physiotherapists and new rehabilitation medicine training centers were established throughout the country. CONCLUSIONS: Academic setting such as PRM training center Split enables education for different health professionals at the same place and time, which provides opportunities for learning about competencies of other team members and development of future collaboration. Also, a uniform approach to education in rehabilitation medicine is provided for all health professionals. All of this sets a solid foundation for education of integrated rehabilitation team and achieving excellence in contemporary Croatian PRM. Implications for Rehabilitation In order to achieve high quality rehabilitation it is necessary to make education accessible to all rehabilitation team members. Implementation of rehabilitation principles in undergraduate education sets a good foundation for the development of postgraduate and specialty training in rehabilitation medicine. Academic setting such as physical and rehabilitation medicine training center Split provides a uniform approach to education in rehabilitation medicine for all health professionals. PMID- 23919640 TI - Rho/Rho-associated coiled-coil forming kinase pathway as therapeutic targets for statins in atherosclerosis. AB - SIGNIFICANCE: The 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors or statins are important therapeutic agents for lowering serum cholesterol levels. However, recent studies suggest that statins may exert atheroprotective effects beyond cholesterol lowering. These so-called "pleiotropic effects" include effects of statins on vascular and inflammatory cells. Thus, it is important to understand whether other signaling pathways that are involved in atherosclerosis could be targets of statins, and if so, whether individuals with "overactivity" of these pathways could benefit from statin therapy, regardless of serum cholesterol level. RECENT ADVANCES: Statins inhibit the synthesis of isoprenoids, which are important for the function of the Rho/Rho-associated coiled-coil containing kinase (ROCK) pathway. Indeed, recent studies suggest that inhibition of the Rho/ROCK pathway by statins could lead to improved endothelial function and decreased vascular inflammation and atherosclerosis. Thus, the Rho/ROCK pathway has emerged as an important target of statin therapy for reducing atherosclerosis and possibly cardiovascular disease. CRITICAL ISSUES: Because atherosclerosis is both a lipid and an inflammatory disease, it is important to understand how inhibition of Rho/ROCK pathway could contribute to statins' antiatherosclerotic effects. FUTURE DIRECTIONS: The role of ROCKs (ROCK1 and ROCK2) in endothelial, smooth muscle, and inflammatory cells needs to be determined in the context of atherogenesis. This could lead to the development of specific ROCK1 or ROCK2 inhibitors, which could have greater therapeutic benefits with less toxicity. Also, clinical trials will need to be performed to determine whether inhibition of ROCKs, with and without statins, could lead to further reduction in atherosclerosis and cardiovascular disease. PMID- 23919645 TI - Experiences of African nurses and the perception of their managers in the NHS. AB - AIM: This study aims to explore experiences of racism, discrimination and equality of opportunity among black African nurses and their managers' perspective on these issues. BACKGROUND: International nurse migration has brought increased diversity in the nursing workforce internationally. These nurses have reported negative experiences associated with their integration in host nations. The UK has a long history of international nurse recruitment, which has been associated with experiences of racism and discrimination towards these nurses despite various equality Acts. Experiences of black African nurses and perceptions of their managers are good indicators of how effective these equality Acts have been. METHOD: A qualitative approach was used to gain an insight into black nurses' experiences and those of their managers in the UK National Health Service. FINDINGS: Nurses and managers reported that black African nurses face racism, discrimination and lack of equal opportunities in the British National Health Service. CONCLUSION: Racism and discrimination towards black and ethnic minority nurses are present in the National Health Service despite equality Acts. Robust measures to combat racism and discrimination are urgently needed. IMPLICATIONS FOR NURSING MANAGEMENT: Managers need to be aware that good policies can be misinterpreted and disadvantage minorities, and should therefore take steps to promote good practice. PMID- 23919646 TI - L1 norm based common spatial patterns decomposition for scalp EEG BCI. AB - BACKGROUND: Brain computer interfaces (BCI) is one of the most popular branches in biomedical engineering. It aims at constructing a communication between the disabled persons and the auxiliary equipments in order to improve the patients' life. In motor imagery (MI) based BCI, one of the popular feature extraction strategies is Common Spatial Patterns (CSP). In practical BCI situation, scalp EEG inevitably has the outlier and artifacts introduced by ocular, head motion or the loose contact of electrodes in scalp EEG recordings. Because outlier and artifacts are usually observed with large amplitude, when CSP is solved in view of L2 norm, the effect of outlier and artifacts will be exaggerated due to the imposing of square to outliers, which will finally influence the MI based BCI performance. While L1 norm will lower the outlier effects as proved in other application fields like EEG inverse problem, face recognition, etc. METHODS: In this paper, we present a new CSP implementation using the L1 norm technique, instead of the L2 norm, to solve the eigen problem for spatial filter estimation with aim to improve the robustness of CSP to outliers. To evaluate the performance of our method, we applied our method as well as the standard CSP and the regularized CSP with Tikhonov regularization (TR-CSP), on both the peer BCI dataset with simulated outliers and the dataset from the MI BCI system developed in our group. The McNemar test is used to investigate whether the difference among the three CSPs is of statistical significance. RESULTS: The results of both the simulation and real BCI datasets consistently reveal that the proposed method has much higher classification accuracies than the conventional CSP and the TR CSP. CONCLUSIONS: By combining L1 norm based Eigen decomposition into Common Spatial Patterns, the proposed approach can effectively improve the robustness of BCI system to EEG outliers and thus be potential for the actual MI BCI application, where outliers are inevitably introduced into EEG recordings. PMID- 23919647 TI - Effects of radioiodine administration on serum concentrations of matrix metalloproteinases, adiponectin and thrombospondin-1. AB - BACKGROUND: In order to assess safety of radioactive iodine administration in the treatment of thyrotoxicosis, we measured concentrations of matrix metalloproteinase-2 (MMP-2), its main inhibitor - TIMP-2 (tissue inhibitor of MMP 2), matrix metalloproteinase-9 (MMP-9), its main inhibitor - TIMP-1, adiponectin, as well as pro-inflammatory and procancerogenic thrombospondin-1 (TSP-1). DESIGN AND PATIENTS: The study involved 23 patients treated with radioiodine for thyrotoxicosis. Serum concentrations of TSH, free T4, free T3, MMP-2, MMP-9, TIMP 1, TIMP-2, total adiponectin and TSP-1 were measured by immunoassays just before radioiodine administration (visit 1), and subsequently, after 7 days (visit 2), 3 months (visit 3), 6 to 8 months (visit 4) and 15-18 months after radioiodine administration (visit 5). RESULTS: There were no acute changes in serum concentrations of MMP-2, MMP-9, TIMP-1, TIMP-2, adiponectin and TSP-1 (visit 1 vs. 2). Subsequently, there was an increase in MMP-2 (from 393+/-106 ng/ml to 774+/-424 ng/ml), TIMP-1 (from 177+/-76 ng/ml to 296+/-118 ng/ml), and adiponectin (from 16442+/-9490 ng/ml to 23518+/-9840 ng/ml), visit 1 to 5, respectively (p < 0.01). Further analysis revealed no significant change in MMP 2/TIMP-2 ratio, but there was a significant decrease in MMP-9/TIMP-1 ratio (p < 0.05), suggestive of possible decrease in free MMP-9 concentrations. CONCLUSIONS: Our data reveal a significant and sustained increase in serum adiponectin, as well as possible decrease of free MMP-9 concentration after radioiodine administration. In contrast, there was no significant change of TSP-1. This might indicate overall safety of radioiodine treatment of thyrotoxicosis in terms of the risks of subsequent cardiovascular and neoplastic disease. PMID- 23919648 TI - Immunomodulation of alveolar epithelial cells by Mycobacterium tuberculosis phosphatidylinositol mannosides results in apoptosis. AB - During intracellular residence in macrophages, mycobacterial lipids, namely phosphatidylinositol mannosides (PIM) and lipoarabinomannans, are expelled in the lung milieu to interact with host cells. PIM include a group of essential lipid components of Mycobacterium tuberculosis (M. tb) cell wall. Given that PIM function as mycobacterial adhesins for binding to host cells, the present study explored the consequences of interaction of M. tb PIM with alveolar epithelial cells (AEC). A 24-h PIM exposure at a concentration of 10 MUg/mL to AEC conferred cytolysis to AEC via induction of apoptosis, suggesting their potential to alter alveolar epithelium integrity. The results also reflected that type I like AEC are more sensitive to cytolysis than type II AEC. PIM-treated AEC exhibited significant production of reactive oxygen species (ROS) and an immunosuppressive cytokine transforming growth factor-beta (TGF-beta) in the culture supernatants. Although AEC displayed constitutive mRNA transcripts for toll-like receptors (TLR2 and 4) as well as chemokines (IL-8 and MCP-1), no significant change in their expression was observed upon PIM treatment. Collectively, these results offer insights into PIM potential as M. tb virulence factor that might promote mycobacterial dissemination by causing cytolysis of AEC via increased production of ROS and TGF-beta. PMID- 23919649 TI - Innovative approach for benzene degradation using hybrid surface/packed-bed discharge plasmas. AB - An innovative plasma reactor, which generates hybrid surface/packed-bed discharge (HSPBD) plasmas, was employed for the degradation of benzene. The HSPBD reactor was found to display remarkably better benzene degradation, mineralization, and energy performance than surface or packed-bed discharge reactors alone. The degradation efficiency, CO2 selectivity, and energy yield in the HSPBD reactor were 21%, 11%, and 3.9 g kWh-1 higher, respectively, than in a surface discharge reactor and 30%, 21%, and 5.5 g kWh-1 higher, respectively, than in a packed-bed discharge reactor operated at 280 J L-1. Particularly, the benzene degradation in the HSPBD reactor exhibited an unambiguous synergistic enhancement rather than a simple additive effect using the surface discharge and packed-bed discharge reactors. Moreover, in the HSPBD reactor, the formation of byproducts, such as NO2, was suppressed, while O3 was promoted. The use of N2 as the carrier gas was found to be effective for benzene degradation because of the fast reaction rate of N2(A3?u+) with benzene, and oxygen species derived from the dissociation of O2 were found to be significant in the mineralization process. Thus, the addition of O2 to N2 allows for efficient degradation of benzene, and the optimized amount of O2 was determined to be 3%. PMID- 23919650 TI - Generalized pruritic eruption in a 78-year-old man. PMID- 23919651 TI - Prevalence and association of perceived stress, substance use and behavioral addictions: a cross-sectional study among university students in France, 2009 2011. AB - BACKGROUND: University students face multiple stressors such as academic overload, constant pressure to succeed, competition with peers as well as concerns about the future. Stress should not be considered on its own, but should be associated with potential risk behaviors leading to onset of substance use and related problems heightened during the university period. The aim of this study was to determine the prevalence of main substance use and behavioral addictions among students in higher education in France and to examine the relationship with perceived stress. METHODS: A self-administered questionnaire was filled out by university student volunteers from Upper Normandy (France) either by anonymous online questionnaire or by paper questionnaire. Data collected included socio economic characteristics, Perceived Stress Scale (PSS), substance use (tobacco, alcohol, and cannabis) and hazardous behaviors: alcohol abuse problems, smoking, consumption of cannabis, eating disorders, and cyber addiction. RESULTS: A total of 1876 students were included. Mean PSS score was 15.9 (standard deviation = 7.2). Highly stressed students (4th quartile) were compared with lesser stressed students (1st quartile). A positive relation was observed between female gender, regular smokers, alcohol abuse problems, risk of cyberaddiction and especially eating disorders (AOR = 5.45, 95% CI = 3.42-8.69), and increasing PSS score. PSS score however, was not significantly related to the curriculum, regular alcohol use, drunkenness or binge drinking even after additional controlling for use of other substances. We found a significant negative association between stress and practice of sport: students with the most physical activity were less likely to report perceived stress (4th quartile: AOR = 0.57, 95% CI = 0.39-0.80). CONCLUSIONS: This cross-sectional study among university students in France revealed that perceived stress was associated not only with known risks such as alcohol misuse, but also with new risks such as eating disorders and cyber addiction. These results could help to develop preventive interventions focussing on these risk behaviors and subsequently improving stress coping capacity in this high-risk population. PMID- 23919652 TI - Mitochondrial energetics is impaired in vivo in aged skeletal muscle. AB - With aging, most skeletal muscles undergo a progressive loss of mass and strength, a process termed sarcopenia. Aging-related defects in mitochondrial energetics have been proposed to be causally involved in sarcopenia. However, changes in muscle mitochondrial oxidative phosphorylation with aging remain a highly controversial issue, creating a pressing need for integrative approaches to determine whether mitochondrial bioenergetics are impaired in aged skeletal muscle. To address this issue, mitochondrial bioenergetics was first investigated in vivo in the gastrocnemius muscle of adult (6 months) and aged (21 months) male Wistar rats by combining a modular control analysis approach with (31) P magnetic resonance spectroscopy measurements of energetic metabolites. Using this innovative approach, we revealed that the in vivo responsiveness ('elasticity') of mitochondrial oxidative phosphorylation to contraction-induced increase in ATP demand is significantly reduced in aged skeletal muscle, a reduction especially pronounced under low contractile activities. In line with this in vivo aging related defect in mitochondrial energetics, we found that the mitochondrial affinity for ADP is significantly decreased in mitochondria isolated from aged skeletal muscle. Collectively, the results of this study demonstrate that mitochondrial bioenergetics are effectively altered in vivo in aged skeletal muscle and provide a novel cellular basis for this phenomenon. PMID- 23919653 TI - Antifouling glycocalyx-mimetic peptoids. AB - The glycocalyx of the cell is composed of highly hydrated saccharidic groups conjugated to protein and lipid cores. Although components of the glycocalyx are important in cell-cell interactions and other specific biological recognition events, a fundamental role of the glycocalyx is the inhibition of nonspecific interactions at the cell surface. Inspired by glycoproteins present in the glycocalyx, we describe a new class of synthetic antifouling polymer composed of saccharide containing N-substituted polypeptide (glycopeptoid). Grafting of glycopeptoids to a solid surface resulted in a biomimetic shielding layer that dramatically reduced nonspecific protein, fibroblast, and bacterial cell attachment. All-atom molecular dynamics simulation of grafted glycopeptoids revealed an aqueous interface enriched in highly hydrated saccharide residues. In comparison to saccharide-free peptoids, the interfacial saccharide residues of glycopeptoids formed a higher number of hydrogen bonds with water molecules. Moreover, these hydrogen bonds displayed a longer persistence time, which we believe contributed to fouling resistance by impeding interactions with biomolecules. Our findings suggest that the fouling resistance of glycopeptoids can be explained by the presence of both a 'water barrier' effect associated with the hydrated saccharide residues as well as steric hindrance from the polymer backbone. PMID- 23919655 TI - Energies of the adsorption of functional groups to calcium carbonate polymorphs: the importance of -OH and -COOH groups. AB - The adsorption behavior of calcium carbonate is an important factor in many processes in nature, industry, and biological systems. We determined and compared the adsorption energies for a series of small molecules of different sizes and polarities (i.e., water, several alcohols, and acetic acid) on three synthetic CaCO3 polymorphs (calcite, aragonite, and vaterite). We measured isosteric heats of adsorption from vapor adsorption isotherms for 273 < T < 293 K, and we used XRD and SEM to confirm that samples did not change phase during the experiments. Density functional calculations and molecular dynamics simulations complemented the experimental results and aided interpretation. Alcohols with molecular mass greater than that of methanol bind more strongly to the calcium carbonate polymorphs than water and acetic acid. The adsorption energies for the alcohols are typical of chemisorption and indicate alcohol displacement of water from calcium carbonate surfaces. This explains why organisms favor biomolecules that contain alcohol functional groups (-OH) to control which polymorph they use, the crystal face and orientation, and the particle shape and size in biomineralization processes. This new insight is also very useful in understanding organic molecule adsorption mechanisms in soils, sediments, and rocks, which is important for predicting the behavior of mineral-fluid interactions when the challenge is to remediate contaminated groundwater aquifers or to produce oil and gas from reservoirs. PMID- 23919654 TI - Characterization of the aggregation responses of camel platelets. AB - BACKGROUND: Despite evidence of active hemostasis, camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation. OBJECTIVES: The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists, and to characterize the receptor that mediates the aggregation response to adenosine diphosphate (ADP), the most potent agonist for camel platelets known so far. METHODS: Aggregation studies were performed with platelet-rich plasma (PRP) in response to multiple doses or combinations of ADP, epinephrine (EPN), collagen, and arachidonic acid (AA). Aggregation responses to ADP were performed before and after the addition of the ADP receptor (P2Y12) antagonist Clopidogrel. RESULTS: Camel platelets responded to ADP at doses higher than the standard dose for human platelets, and to combinations of EPN and other agonists, while no aggregation was elicited with EPN or AA alone. Clopidogrel blocked the ADP induced aggregation responses in a dose-dependent fashion in vitro. CONCLUSIONS: Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP, but not AA or EPN. Irreversible aggregation of camel platelets could also be triggered by a combination of EPN and ADP, and collagen and AA. Inhibition with clopidogrel suggests that camel platelets express the ADP receptor, P2Y12. Understanding platelet function in camels will add to the understanding of platelet function in health and disease. PMID- 23919656 TI - Self-assembly of diblock polythiophenes with discotic liquid crystals on side chains for the formation of a highly ordered nanowire morphology. AB - Diblock copolymers bearing a triphenylene (TP) discotic liquid crystals moiety, poly(3-hexylthiophene)-block-poly[3-(10-(2,3,6,7,10 pentakis(hexyloxy)triphenylen)-decyloxy)thiophene] (P3HT-b-P3TPT), was successfully synthesized by Grignard metathesis polymerization. The self assembled nanowire structures of these diblock copolymers have been investigated by atomic force microscopy and transmission electron microscopy. The domain size and crystallinity of the nanostructures can be easily controlled by tuning the P3HT/P3TPT block ratio and by employing different annealing processes such as thermal and solvent annealing. The results of X-ray diffraction indicate that both intermolecular interactions and mesogen packing are essential for the formation of nanostructures in the diblock copolymers. Although the block ratio of P3HT and P3TPT comes to 9:1 and the copolymer undergoes solvent annealing followed by thermal treatment, an optimal crystalline nanowire with a size of 16.9 nm is formed. In addition, solar cells based on these copolymers as electron donors in combination with [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM) or N,N'-di(2-ethylhexyl)perylene-3,4,9,10-tetracarboxylbisimide (PDI) as electron acceptors have been constructed, and the effect of the nanomorphology on device performance has been investigated. PMID- 23919657 TI - High-resolution fractionation after gas chromatography for effect-directed analysis. AB - This research presents an analytical technology for highly efficient, high resolution, and high-yield fractionation of compounds after gas chromatography (GC) separations. The technology is straightforward, does not require sophisticated cold traps or adsorbent traps, and allows collecting large numbers of fractions during a GC run. The technology is based on direct infusion of a carrier solvent at the end of the GC column, where infusion takes place in the GC oven. Pentane and hexane used as carrier solvent showed good results. Acetonitrile also showed good results as a more polar carrier solvent. Development and optimization of the technology is described, followed by demonstration in a high-throughput effect directed analysis setting toward dioxin receptor bioactivity. The GC fractionation setup was capable of collecting fractions in the second range. As a result, fractionated compounds could be collected into one or two fractions when 6.5 s resolution fractionation was performed. Subsequently, mixtures containing polycyclic aromatic hydrocarbons, of which some are bioactive toward the dioxin receptor, were profiled with a mammalian gene reporter assay. After fractionation into 96-well plates, we used our new approach for direct cell seeding onto the fractions prior to assaying which allowed dioxin receptor bioactivity to be measured directly after fractionation. The current technology represents a great advance in effect directed analysis for environmental screening worldwide as it allows combining the preferred analytical separation technology for often non-polar environmental pollutants with environmentally relevant bioassays, in high resolution. PMID- 23919658 TI - Periostin increases migration and proliferation of human periodontal ligament fibroblasts challenged by tumor necrosis factor -alpha and Porphyromonas gingivalis lipopolysaccharides. AB - BACKGROUND: In the chronic established periodontal lesion, the proliferation and migration potential of periodontal ligament (PDL) cells are significantly compromised. Thus, the progressive loss of tissue integrity is favored and normal healing and regeneration compromised. Periostin, a known PDL marker, modulates cell-matrix interactions, cell behavior, as well as the matrix biomechanics and PDL homeostasis. OBJECTIVE: To evaluate whether periostin restores the regenerative potential of PDL cells in terms of proliferation, migration, and activation of survival signaling pathways after being challenged by Porphyromonas gingivalis lipopolysaccharides and tumor necrosis factor alpha alpha. METHODS: Human PDL (hPDL) cells were cultured under different conditions: control, periostin (50 or 100 ng/mL), and fibroblast growth factor 2 (10 ng/mL) to evaluate cell proliferation (by Ki67), cell migration (by scratch assays) and PI3K/AKT/mTOR pathway activation (by western blot analyses of total AKT, phospho AKT and PS6). A different set of cultures was challenged by adding tumor necrosis factor alpha alpha (10 ng/mL) and P. gingivalis lipopolysaccharides (200 ng/mL) to evaluate the effects of periostin as described above. RESULTS: Periostin significantly increased cell proliferation (twofold), migration (especially at earlier time points and low dose) and activation of survival signaling pathway (higher phosphorylation of AKT and PS6). Furthermore, periostin promoted similar cellular effects even after being challenged with proinflammatory cytokines and bacterial virulence factors. CONCLUSION: Periostin acts as an important modulator of hPDL cell-matrix dynamics. It modulates hPDL proliferation, migration and PI3K/AKT/mTOR pathway. It also helps in overcoming the altered biological phenotype that chronic exposure to periodontal pathogens and proinflammatory cytokines produce in hPDL cells. PMID- 23919659 TI - Two new alkaloids from Corydalis humosa. AB - Two new alkaloids, named 1,1-dimethyl-6-methoxy-7-hydroxyl-1,2,3,4 tetrahydroisoquinoline (1) and (1R)-(4-hydroxybenzyl)-7-hydroxyl-8-O-beta-d glucopyranosyl-1,2,3,4-tetrahydroisoquinoline (2), together with 11 known compounds (3-13), were isolated from the tubers of Corydalis humosa. Their structures were elucidated on the basis of their spectroscopic and chemical evidence. PMID- 23919660 TI - Comparing online adjustments to distance and direction in fast pointing movements. AB - It has been suggested that movements are planned in terms of direction and distance. If so, online adjustments to changes in the direction and distance of the movements may also differ. The authors therefore investigated whether fast online movement adjustments are the same for perturbations of the direction and of the distance. While subjects made fast pointing movements, the authors perturbed either target direction or distance or both shortly after movement initiation. Both kinds of perturbations resulted in accurate online adjustments. The latency and intensity of corrections for distance and direction perturbations were quite similar. This suggests that there might be one mechanism controlling both distance and direction perturbations. PMID- 23919661 TI - Safeguarding in medication administration: understanding pre-registration nursing students' survey response to patient safety and peer reporting issues. AB - AIM: To explore nursing students' experiences of patient safety and peer reporting using hypothetical medication administration scenarios. BACKGROUND: Pre registration nurse training is tasked with the preparation of students able to provide safe, high quality nursing care. How students' contextualise teaching related to patient safety, risk recognition and management in the clinical setting is less clear. METHOD: A total of 321 third year students enrolled in the final semester of an adult branch pre-registration nursing programme in 2011 in a UK university were surveyed. Using free texts, the questionnaire contained hypothetical medication administration scenarios where patient safety could potentially be at risk. Students' qualitative responses were analysed using thematic analysis. FINDINGS: The response rate was 58% (n = 186). Four themes were identified from the scenarios: (1) Protecting patient safety (2) Willingness to compromise; (3) Avoiding responsibility; (4) Consequences from my actions. CONCLUSION: The findings underscore the importance of contextual teaching about risk management, practical techniques for error management and leadership for optimal patient safety in nursing curricula. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers are role models for nursing students in the clinical setting. Nursing management must lead, by example, the patient safety agenda in the clinical setting. PMID- 23919662 TI - Manipulating the growth kinetics of vapor-liquid-solid propagated Ge nanowires. AB - This article describes an innovative approach in which bimetallic alloy seeds of AuxAg1-x are used to enhance the growth kinetics of Ge nanowires, via a vapor liquid-solid (VLS) growth technique. The decreased equilibrium concentration and increased supersaturation of Ge in the liquid alloy seeds, compared to pure Au seeds, results in favorable growth kinetics and the realization of high-aspect ratio millimeter-long Ge nanowires. Also detailed is the manifestation of the Gibbs-Thompson effect resulting in diameter-dependent nanowire growth rates as a function of the Au-Ag-Ge eutectic composition. Significantly, AuxAg1-x alloy seeds lower the critical diameter of the Ge nanowires in this liquid-seeded growth approach. In situ TEM heating experiments established the correlation between the growth kinetics and equilibrium eutectic compositions in the ternary growth systems. The fundamental insights of nanowire growth demonstrated with the ternary eutectic alloys opens up opportunities to engineer the aspect ratio and morphology of a range of semiconductor nanowires. PMID- 23919663 TI - Atrial fibrillation and anticoagulation management: a wake-up call to practitioners, patients, and policymakers. PMID- 23919664 TI - Sources of bias in measures of allele-specific expression derived from RNA sequence data aligned to a single reference genome. AB - BACKGROUND: RNA-seq can be used to measure allele-specific expression (ASE) by assigning sequence reads to individual alleles; however, relative ASE is systematically biased when sequence reads are aligned to a single reference genome. Aligning sequence reads to both parental genomes can eliminate this bias, but this approach is not always practical, especially for non-model organisms. To improve accuracy of ASE measured using a single reference genome, we identified properties of differentiating sites responsible for biased measures of relative ASE. RESULTS: We found that clusters of differentiating sites prevented sequence reads from an alternate allele from aligning to the reference genome, causing a bias in relative ASE favoring the reference allele. This bias increased with greater sequence divergence between alleles. Increasing the number of mismatches allowed when aligning sequence reads to the reference genome and restricting analysis to genomic regions with fewer differentiating sites than the number of mismatches allowed almost completely eliminated this systematic bias. Accuracy of allelic abundance was increased further by excluding differentiating sites within sequence reads that could not be aligned uniquely within the genome (imperfect mappability) and reads that overlapped one or more insertions or deletions (indels) between alleles. CONCLUSIONS: After aligning sequence reads to a single reference genome, excluding differentiating sites with at least as many neighboring differentiating sites as the number of mismatches allowed, imperfect mappability, and/or an indel(s) nearby resulted in measures of allelic abundance comparable to those derived from aligning sequence reads to both parental genomes. PMID- 23919665 TI - Rac1-mediated effects of HMG-CoA reductase inhibitors (statins) in cardiovascular disease. AB - SIGNIFICANCE: HMG-CoA reductase inhibitors (statins) lower serum cholesterol concentrations and are beneficial in the primary and secondary prevention of coronary heart disease. The positive clinical effects have only partially been reproduced with other lipid-lowering interventions suggesting potential statin effects in addition to cholesterol lowering. In experimental models, direct beneficial cardiovascular effects that are mediated by the inhibition of isoprenoids have been documented, which serve as lipid attachments for intracellular signaling molecules such as small Rho guanosine triphosphate binding proteins, whose membrane localization and function are dependent on isoprenylation. RECENT ADVANCES: Rac1 GTPase is an established master regulator of cell motility through the cortical actin reorganization and of reactive oxygen species generation through the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. CRITICAL ISSUES: Observations in cells, animals, and humans have implicated the activation of Rac1 GTPase as a key component of cardiovascular pathologies, including the endothelial dysfunction, cardiac hypertrophy and fibrosis, atrial fibrillation, stroke, hypertension, and chronic kidney disease. However, the underlying signal transduction remains incompletely understood. FUTURE DIRECTIONS: Based on the recent advance made in Rac1 research in the cardiovascular system by using mouse models with transgenic overexpression of activated Rac1 or conditional knockout, as well as Rac1 specific small molecule inhibitor NSC 23766, the improved understanding of the Rac1-mediated effects statins may help to identify novel therapeutic targets and strategies. PMID- 23919666 TI - Imputation method for lifetime exposure assessment in air pollution epidemiologic studies. AB - BACKGROUND: Environmental epidemiology, when focused on the life course of exposure to a specific pollutant, requires historical exposure estimates that are difficult to obtain for the full time period due to gaps in the historical record, especially in earlier years. We show that these gaps can be filled by applying multiple imputation methods to a formal risk equation that incorporates lifetime exposure. We also address challenges that arise, including choice of imputation method, potential bias in regression coefficients, and uncertainty in age-at-exposure sensitivities. METHODS: During time periods when parameters needed in the risk equation are missing for an individual, the parameters are filled by an imputation model using group level information or interpolation. A random component is added to match the variance found in the estimates for study subjects not needing imputation. The process is repeated to obtain multiple data sets, whose regressions against health data can be combined statistically to develop confidence limits using Rubin's rules to account for the uncertainty introduced by the imputations. To test for possible recall bias between cases and controls, which can occur when historical residence location is obtained by interview, and which can lead to misclassification of imputed exposure by disease status, we introduce an "incompleteness index," equal to the percentage of dose imputed (PDI) for a subject. "Effective doses" can be computed using different functional dependencies of relative risk on age of exposure, allowing intercomparison of different risk models. To illustrate our approach, we quantify lifetime exposure (dose) from traffic air pollution in an established case control study on Long Island, New York, where considerable in-migration occurred over a period of many decades. RESULTS: The major result is the described approach to imputation. The illustrative example revealed potential recall bias, suggesting that regressions against health data should be done as a function of PDI to check for consistency of results. The 1% of study subjects who lived for long durations near heavily trafficked intersections, had very high cumulative exposures. Thus, imputation methods must be designed to reproduce non-standard distributions. CONCLUSIONS: Our approach meets a number of methodological challenges to extending historical exposure reconstruction over a lifetime and shows promise for environmental epidemiology. Application to assessment of breast cancer risks will be reported in a subsequent manuscript. PMID- 23919667 TI - A prospective, randomised study of a novel transforming methacrylate dressing compared with a silver-containing sodium carboxymethylcellulose dressing on partial-thickness skin graft donor sites in burn patients. AB - This prospective, randomised study compares a new transforming methacrylate dressing (TMD) with a silver-containing carboxymethylcellulose dressing (CMC-Ag) after application to split-thickness skin graft (STSG) donor sites. This was an unblinded, non-inferiority, between-patient, comparison study that involved patients admitted to a single-centre burn unit who required two skin graft donor sites. Each patient's donor sites were covered immediately after surgery: one donor site with TMD and the other with CMC-Ag. The donor sites were evaluated until healing or until 24 days post-application, whichever came first. Study endpoints were time to healing, daily pain scores, number of dressing changes, patient comfort and physicians' and patients' willingness to use the dressings in the future. Nineteen patients had both the dressings applied. No statistically significant difference was noted in time to healing between the two dressings (14.2 days using TMD compared with 13.2 days using CMC-Ag). When pain scores were compared, TMD resulted in statistically significantly less pain at three different time periods (2-5 days, 6-10 days and 11-15 days; P < 0.001 at all time periods). Patients also reported greater comfort with TMD (P < 0.001). Users rated TMD as being less easy to use because of the time and technique required for application. Reductions in pain and increased patient comfort with the use of the TMD dressing, compared with CMC-Ag, were seen as clinical benefits as these are the major issues in donor site management. PMID- 23919668 TI - Contrast-agent enhancement in ex vivo flat-panel computed tomography of locally advanced laryngeal cancer. AB - CONCLUSION: Visualization of cartilage invasion in ex vivo laryngectomy specimens was improved by flat-panel volumetric computed tomography (fpvCT) after diffusion of contrast agents. A prospective study to assess the specificity and sensitivity of this new method is warranted. OBJECTIVES: Cartilage invasion is a criterion for staging laryngeal squamous cell carcinoma. Contrast-enhanced CT is routinely used for assessing cartilage invasion. However, the sensitivities and specificities given for this method in the literature vary, and there is a need for improvement of this staging method. The objective of our pilot study was to determine cartilage invasion with fpvCT after contrast agent diffusion. METHODS: Three patients underwent preoperative CT and total laryngectomy. The excised larynges were immediately scanned with an fpvCT scanner, without contrast enhancement. Additional fpvCT scans were performed after incubation of the larynges in one of three different contrast agents for 24 and 48 h. The results from presurgical conventional scans, fpvCT scans, and histological examination - as the gold standard - were compared. RESULTS: We demonstrated the feasibility of ex vivo contrast enhancement of laryngeal tissues by diffusion, with a subsequent increase in contrast enhancement and improved visualization of cartilage invasion in fpvCT scans. Histology confirmed the fpvCT results. PMID- 23919669 TI - Analysis of prognostic factors of endoscopic optic nerve decompression in traumatic blindness. AB - CONCLUSIONS: Hemorrhage within the ethmoid and/or sphenoid sinus and an interval between the time of injury and the time of operation exceeding 3 days are the risk factors for the visual prognosis of traumatic blindness. OBJECTIVES: To investigate the therapeutic efficacy of endoscopic optic nerve decompression in the treatment of traumatic blindness and to evaluate the relevant prognostic factors. METHODS: Eighty-five cases of traumatic blindness were analyzed retrospectively. Univariate analysis and multiple logistic regression were performed to evaluate potential prognostic factors. RESULTS: The overall rate of vision acuity improvement was 44.7% (38 of 85). Univariate analysis indicated that hemorrhage within the ethmoid and/or sphenoid sinus was significantly associated with unrecovered visual acuity. However, multiple logistic regression analysis identified that an interval between the time of injury and the time of operation exceeding 3 days, and hemorrhage within the ethmoid and/or sphenoid sinus were significantly correlated with the efficacy of treatment of traumatic blindness. PMID- 23919670 TI - Salvage of recurrent hypopharyngeal carcinoma after primary curative treatment. AB - CONCLUSIONS: There was a moderate chance of cure after surgical salvage of recurrent hypopharyngeal squamous cell carcinoma (SCC). However, surgical salvage was only feasible for early recurrent tumor. Close follow-up surveillance to detect early recurrence is essential after primary treatment of patients. OBJECTIVES: Despite improvements in surgery, radiotherapy, and chemotherapy, hypopharyngeal SCC has one of the worst prognoses among head and neck malignant diseases. To improve the overall survival and cure rates in patients with hypopharyngeal SCC, the management of recurrent disease as well as initial treatment is important. In this study, the efficacy and results of salvage treatment of recurrent hypopharyngeal SCC after primary curative treatment were evaluated. METHODS: The management outcomes of 49 patients who were treated for recurrent hypopharyngeal SCC between January 2002 and December 2010 at Kyushu University Hospital were reviewed. RESULTS: The median time for detection of recurrence from the initial curative treatment was 10.3 months (range 2.1-61.1 months). The total salvage rates of recurrence were 45% (local, 85%; locoregional, 100%; regional, 23%; distant, 19%). The 1- and 3-year tumor-free actuarial survival rates of those patients who received salvage surgery followed by chemotherapy and/or radiotherapy were 96% and 79%, respectively. There was no 3-year survivor among the patients who received only chemotherapy and/or radiotherapy. PMID- 23919671 TI - IDEAS for a healthy baby--reducing disparities in use of publicly reported quality data: study protocol for a randomized controlled trial. AB - BACKGROUND: Publicly reported performance on quality measures is intended to enable patients to make more informed choices. Despite the growing availability of these reports, patients' use remains limited and disparities exist. Low health literacy and numeracy are two barriers that may contribute to these disparities. Patient navigators have helped patients overcome barriers such as these in other areas, such as cancer care and may prove useful for overcoming barriers to using publicly reported quality data. METHODS/DESIGN: The goals of this study are: to determine the efficacy of a patient navigator intervention to assist low-income pregnant women in the use of publicly available information about quality of care when choosing a pediatrician; to evaluate the relative importance of factors influencing women's choice of pediatric practices; to evaluate the effect of the intervention on patient engagement in management of their own and their child's health care; and to assess variation in efficacy of the intervention for sub groups based on parity, age, and race/ethnicity. English speaking women ages 16 to 50 attending a prenatal clinic at a large urban medical center will be randomized to receive an in-person navigator intervention or an informational pamphlet control between 20 to 34 weeks of gestation. The intervention will include in-person guided use of the Massachusetts Health Quality Partners website, which reports pediatric practices' performance on quality measures and patient experience. The primary study outcomes will be the mean scores on a) clinical quality and b) patient experience measures. DISCUSSION: Successful completion of the study aims will yield important new knowledge about the value of guided website navigation as a strategy to increase the impact of publicly reported quality data and to reduce disparities in use of these data. TRIAL REGISTRATION: ClinicalTrials.gov #NCT01784575. PMID- 23919673 TI - Chiroptical inversion in helical Si-Si bond polymer aggregates. AB - To elucidate the factors involved in the chiroptical properties of polymer aggregates composed of helical building blocks, a series of rigid rod helical poly[alkyl-(S)-2-methylbutylsilane]s (achiral alkyl side chains = ethyl, n propyl, n-butyl, n-pentyl, n-hexyl) have been investigated. It was found that the chiroptical sign in the circular dichroism (CD) spectra of the polysilane aggregates depends on the achiral side chain length and cosolvent fraction. Concerning the achiral side chains, the n-propyl group was of a critical length for solvent-dependent chiroptical inversion on aggregation. This unique side chain length-dependent chiroptical inversion was theoretically predictable by using the novel approach of combining the cholesteric hard-core model and exciton chirality method. The latter was also investigated theoretically by Gaussian 03 (TD-DFT, B3LYP, 6-31G(d) basis set) calculations applied to two spatially arranged helical Si-Si bonded decamer models. PMID- 23919672 TI - Participants' perceptions of a knowledge-brokering strategy to facilitate evidence-informed policy-making in Fiji. AB - BACKGROUND: Evidence-informed policy-making (EIPM) is optimal when evidence producers (researchers) and policy developers work collaboratively to ensure the production and use of the best available evidence. This paper examined participants' perceptions of knowledge-brokering strategies used in the TROPIC (Translational Research in Obesity Prevention in Communities) project to facilitate the use of obesity-related evidence in policy development in Fiji. METHOD: Knowledge-brokers delivered a 12-18 month programme comprising workshops targeting EIPM skills and practical support for developing evidence-informed policy briefs to reduce obesity. The programme was tailored to each of the six participating organizations. Knowledge-brokering strategies included negotiating topics that were aligned to the goals of individual organizations, monitoring and evaluating time-management skills, accommodating other organizational and individual priorities, delivering practical sessions on use of appropriate research tools and supporting individual writing of policy briefs. Two qualitative methods were used to examine individuals' perceptions of skills obtained, opportunities afforded by the TROPIC project, facilitators and inhibiters to planned policy brief development and suggestions for improved programme delivery. Forty-nine participants completed an electronic word table and then participated in a semi-structured interview. An independent interviewer conducted structured interviews with a high-ranking officer in each organization to examine their perceptions of TROPIC engagement strategies. Data were analyzed descriptively and thematically, with the first author and another experienced qualitative researcher analyzing data sets separately, and then combining analyses. RESULTS: Many participants believed that they had increased their skills in acquiring, assessing, adapting and applying evidence, writing policy briefs and presenting evidence-based arguments to higher levels. Many participants preferred one-to-one meetings to group activities to ensure early resolution of developing issues and to refine policy briefs. Perceived barriers to EIPM were lack of knowledge about data sources, inadequate time to develop evidence-informed briefs, and insufficient resources for accessing and managing evidence. CONCLUSION: An innovative knowledge-brokering approach utilizing skill development and mentorship facilitated individual EIPM skills and policy brief development. The TROPIC model could stimulate evidence-based policy action relating to obesity prevention and other policy areas in other Pacific countries and elsewhere. PMID- 23919674 TI - An overview of adjuvant formulations and delivery systems. AB - Adjuvants may promote immune responses: by recruiting professional antigen presenting cells (APCs) to the vaccination site, increasing the delivery of antigens to APCs, or by activating APCs to produce cytokines and by triggering T cell responses. Aluminium salts have been effective at promoting protective humoral immunity; however, they are not effective in generating cell-mediated immunity. A number of different approaches have been developed to potentiate immune response and they have been partially successful. Research has been conducted into vaccine delivery systems (VDS); enhancing cross-presentation by targeting antigens to (APCs). Antigen discovery has increased over the past decade, and consequently, it has accelerated vaccine development demanding a new generation of VDS that combines different types of adjuvants into specific formulations with greater activity. The new approaches offer a wide spectrum of opportunities in vaccine research with direct applications in the near future. PMID- 23919675 TI - Identification and systematic annotation of tissue-specific differentially methylated regions using the Illumina 450k array. AB - BACKGROUND: DNA methylation has been recognized as a key mechanism in cell differentiation. Various studies have compared tissues to characterize epigenetically regulated genomic regions, but due to differences in study design and focus there still is no consensus as to the annotation of genomic regions predominantly involved in tissue-specific methylation. We used a new algorithm to identify and annotate tissue-specific differentially methylated regions (tDMRs) from Illumina 450k chip data for four peripheral tissues (blood, saliva, buccal swabs and hair follicles) and six internal tissues (liver, muscle, pancreas, subcutaneous fat, omentum and spleen with matched blood samples). RESULTS: The majority of tDMRs, in both relative and absolute terms, occurred in CpG-poor regions. Further analysis revealed that these regions were associated with alternative transcription events (alternative first exons, mutually exclusive exons and cassette exons). Only a minority of tDMRs mapped to gene-body CpG islands (13%) or CpG islands shores (25%) suggesting a less prominent role for these regions than indicated previously. Implementation of ENCODE annotations showed enrichment of tDMRs in DNase hypersensitive sites and transcription factor binding sites. Despite the predominance of tissue differences, inter-individual differences in DNA methylation in internal tissues were correlated with those for blood for a subset of CpG sites in a locus- and tissue-specific manner. CONCLUSIONS: We conclude that tDMRs preferentially occur in CpG-poor regions and are associated with alternative transcription. Furthermore, our data suggest the utility of creating an atlas cataloguing variably methylated regions in internal tissues that correlate to DNA methylation measured in easy accessible peripheral tissues. PMID- 23919676 TI - Moiety-linkage map reveals selective nonbisphosphonate inhibitors of human geranylgeranyl diphosphate synthase. AB - Bisphosphonates are potent inhibitors of farnesyl pyrophosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS). Current bisphosphonate drugs (e.g., Fosamax and Zometa) are highly efficacious in the treatment of bone diseases such as osteoporosis, Paget's disease, and tumor-induced osteolysis, but they are often less potent in blood and soft-tissue due to their phosphate moieties. The discovery of nonbisphosphonate inhibitors of FPPS and/or GGPPS for the treatment of bone diseases and cancers is, therefore, a current goal. Here, we propose a moiety-linkage-based method, combining a site-moiety map with chemical structure rules (CSRs), to discover nonbisphosphonate inhibitors from thousands of commercially available compounds and known crystal structures. Our moiety-linkage map reveals the binding mechanisms and inhibitory efficacies of 51 human GGPPS (hGGPPS) inhibitors. To the best of our knowledge, we are the first team to discover two novel selective nonbisphosphonate inhibitors, which bind to the inhibitory site of hGGPPS, using CSRs and site-moiety maps. These two compounds can be considered as a novel lead for the potent inhibitors of hGGPPS for the treatment of cancers and mevalonate-pathway diseases. Moreover, based on our moiety-linkage map, we identified two key residues of hGGPPS, K202, and K212, which play an important role for the inhibitory effect of zoledronate (IC50 = 3.4 MUM and 2.4 MUM, respectively). This result suggests that our method can discover specific hGGPPS inhibitors across multiple prenyltransferases. These results show that the compounds that highly fit our moiety-linkage map often inhibit hGGPPS activity and induce tumor cell apoptosis. We believe that our method is useful for discovering potential inhibitors and binding mechanisms for pharmaceutical targets. PMID- 23919678 TI - Designing heterogeneous chemical composition on hierarchical structured copper substrates for the fabrication of superhydrophobic surfaces with controlled adhesion. AB - Controlling water adhesion is important for superhydrophobic surfaces in many applications. Compared with numerous researches about the effect of microstructures on the surface adhesion, research relating to the influence of surface chemical composition on the surface adhesion is extremely rare. Herein, a new strategy for preparation of tunable adhesive superhydrophobic surfaces through designing heterogeneous chemical composition (hydrophobic/hydrophilic) on the rough substrate is reported, and the influence of surface chemical composition on the surface adhesion are examined. The surfaces were prepared through self-assembling of mixed thiol (containing both HS(CH2)9CH3 and HS(CH2)11OH) on the hierarchical structured copper substrates. By simply controlling the concentration of HS(CH2)11OH in the modified solution, tunable adhesive superhydrophobic surfaces can be obtained. The adhesive force of the surfaces can be increased from extreme low (about 8 MUN) to very high (about 65 MUN). The following two reasons can be used to explain the tunable effect: one is the number of hydrogen bond for the variation of surface chemical composition; and the other is the variation of contact area between the water droplet and surface because of the capillary effect that results from the combined effect of hydrophilic hydroxyl groups and microstructures on the surface. Noticeably, water droplets with different pH (2-12) have similar contact angles and adhesive forces on the surfaces, indicating that these surfaces are chemical resistant to acid and alkali. Moreover, the as-prepared surfaces were also used as the reaction substrates and applied in the droplet-based microreactor for the detection of vitamin C. This report provides a new method for preparation of superhydrophobic surfaces with tunable adhesion, which could not only help us further understand the principle for the fabrication of tunable adhesive superhydrophobic surfaces, but also potentially be used in many important applications, such as microfluidic devices and chemical microreactors. PMID- 23919677 TI - Calpain cleavage and inactivation of the sodium calcium exchanger-3 occur downstream of Abeta in Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by pathological deposits of beta-amyloid (Abeta) in senile plaques, intracellular neurofibrillary tangles (NFTs) comprising hyperphosphorylated aggregated tau, synaptic dysfunction and neuronal death. Substantial evidence indicates that disrupted neuronal calcium homeostasis is an early event in AD that could mediate synaptic dysfunction and neuronal toxicity. Sodium calcium exchangers (NCXs) play important roles in regulating intracellular calcium, and accumulating data suggests that reduced NCX function, following aberrant proteolytic cleavage of these exchangers, may contribute to neurodegeneration. Here, we show that elevated calpain, but not caspase-3, activity is a prominent feature of AD brain. In addition, we observe increased calpain-mediated cleavage of NCX3, but not a related family member NCX1, in AD brain relative to unaffected tissue and that from other neurodegenerative conditions. Moreover, the extent of NCX3 proteolysis correlated significantly with amounts of Abeta1-42. We also show that exposure of primary cortical neurons to oligomeric Abeta1-42 results in calpain-dependent cleavage of NCX3, and we demonstrate that loss of NCX3 function is associated with Abeta toxicity. Our findings suggest that Abeta mediates calpain cleavage of NCX3 in AD brain and therefore that reduced NCX3 activity could contribute to the sustained increases in intraneuronal calcium concentrations that are associated with synaptic and neuronal dysfunction in AD. PMID- 23919679 TI - The effects of work alienation on organisational commitment, work effort and work to-family enrichment. AB - AIM: The aim of this study was to analyse the effects of work alienation on organisational commitment, work effort and work-to-family enrichment. BACKGROUND: There is substantial research on the effects of work alienation on passive job performance, such as organisational commitment. However, studies analysing work alienation on active performance, such as work effort, and outside work, such as work-to-family enrichment, are scarce. METHOD: Two dimensions of work alienation are considered: powerlessness and meaninglessness. Hypotheses are tested using surveys collected among a national sample of midwives in the Netherlands (respondents: 790, response rate 61%). RESULT: the findings indicate that work alienation (powerlessness and meaninglessness) influence organisational commitment, work effort and--to a lesser extent--work-to-family enrichment. High work meaninglessness, in particular, has negative effects on these outcomes. CONCLUSION: When people feel that they have no influence in their work (hence, when they feel 'powerless') and especially when the feel that their work is not worthwhile (when they feel 'meaningless') this has substantial negative effects. IMPLICATIONS FOR NURSING MANAGEMENT: Managers should increase the meaningfulness that people attach to their work, thereby maintaining a high-quality workforce. Possible strategies include: (1) improving person-job fit, (2) developing high quality relationships, (3) better communicating the results people help to deliver. PMID- 23919680 TI - Dramatic inundation changes of China's two largest freshwater lakes linked to the Three Gorges Dam. AB - Ever since its planning in the 1990s, the Three Gorges Dam (TGD) caused endless debate in China on its potential impacts on the environment and humans. However, to date, synoptic assessment of environmental changes and their potential linkage with the TGD is still lacking. Here, we combine remote sensing, meteorological, and hydrological observations to investigate the potential influence of the TGD on the downstream freshwater lakes. A 10 year Moderate Resolution Imaging Spectroradiometer (MODIS) time series from 2000 to 2009 revealed significantly decreasing trends (3.3 and 3.6%/year) in the inundation areas of the two largest freshwater lakes of China (Poyang Lake and Dongting Lake) downstream of the TGD since its impoundment in 2003, after which both relative humidity and surface runoff coefficient of the lakes' drainages also dropped dramatically. These environmental changes appear to be linked to the TGD. PMID- 23919681 TI - Evaluation of automated assays for immunoglobulin G, M, and A measurements in dog and cat serum. AB - BACKGROUND: Measurements of immunoglobulins (Igs) in companion animals can be useful to detect deficiencies of the humoral immune system, that can be associated with opportunistic or chronic infections, or other immune-mediated disorders including B-cell neoplasms. OBJECTIVE: The purpose of this study was to evaluate commercially available automated immunoturbidimetric assays designed for human IgG, M, and A measurements in canine and feline serum using species specific calibrators. METHODS: Canine and feline serum samples with different IgG, M, and A concentrations were used for the analytical validation of the assays. Intra- and inter-assay precision, linearity under dilution, spiking recovery, and limit of detection were determined. In addition, effects of lipemia, hemolysis, and bilirubinemia were evaluated. Finally, Ig concentrations were determined in small groups of diseased dogs and cats, and compared with healthy groups. RESULTS: Spiking recovery and linearity under dilution tests showed that the assays measured Igs in canine and feline serum samples precisely and accurately. Intra- and inter-assay imprecisions were lower than 15% in all cases. Significantly higher IgG, IgM, and IgA levels were observed in dogs with leishmaniasis, while dogs with pyometra showed a statistically significant increase in IgM and IgA concentrations in comparison with healthy dogs. Significantly higher IgG and IgM levels were observed in FIV-infected cats compared with healthy ones. CONCLUSIONS: The automated human Ig assays showed adequate precision and accuracy with serum samples from dogs and cats. Also, they were able to discriminate different concentrations of Igs in healthy and diseased animals. PMID- 23919683 TI - Direct electroanalytical method for alternative assessment of global antioxidant capacity using microchannel electrodes. AB - A new electroanalytical method for the characterization of global antioxidant capacity is proposed based on chronoamperometric responses monitored at microchannel band electrodes. This approach does not require any titrating species, biological elements, or precalibration curves. A thin-layer regime is established at the working electrode according to the geometry of the device and hydrodynamic flow rate. Under these conditions, the currents are directly proportional to the total concentration of antioxidants and do not depend on their respective diffusion coefficients. Measurements were performed with synthetic solutions and mixtures of four antioxidants used as sample tests: trolox, ascorbic acid, gallic acid, and caffeic acid. Operating potentials were selected at the formal potentials of some reactive oxygen species to simulate their oxidative attacks. The very good agreement obtained between simulations and experimental data validated this new electroanalytical procedure. These results pave the way for the concept of innovative sensor-type microfluidic devices for alternative determination of antioxidant capacity. PMID- 23919682 TI - Complement alternative pathway genetic variation and Dengue infection in the Thai population. AB - Dengue disease is a mosquito-borne infection caused by Dengue virus. Infection may be asymptomatic or variably manifest as mild Dengue fever (DF) to the most severe form, Dengue haemorrhagic fever (DHF). Mechanisms that influence disease severity are not understood. Complement, an integral component of the immune system, is activated during Dengue infection and the degree of activation increases with disease severity. Activation of the complement alternative pathway is influenced by polymorphisms within activation (factor B rs12614/rs641153, C3 rs2230199) and regulatory [complement factor H (CFH) rs800292] proteins, collectively termed a complotype. Here, we tested the hypothesis that the complotype influences disease severity during secondary Dengue infection. In addition to the complotype, we also assessed two other disease-associated CFH polymorphisms (rs1061170, rs3753394) and a structural polymorphism within the CFH protein family. We did not detect any significant association between the examined polymorphisms and Dengue infection severity in the Thai population. However, the minor allele frequencies of the factor B and C3 polymorphisms were less than 10%, so our study was not sufficiently powered to detect an association at these loci. We were also unable to detect a direct interaction between CFH and Dengue NS1 using both recombinant NS1 and DV2-infected culture supernatants. We conclude that the complotype does not influence secondary Dengue infection severity in the Thai population. PMID- 23919684 TI - A new kaempferol trioside from Silphium perfoliatum. AB - A new apiose-containing kaempferol trioside, kaempferol-3-O-alpha-L-rhamnosyl (1''' -> 6")-O-beta-D-galactopyranosyl-7-O-beta-D-apiofuranoside, along with 16 known compounds, were isolated from 50% acetone extract of Silphium perfoliatum L. Their structures were elucidated by acid hydrolysis and spectroscopic techniques including UV, IR, MS, 1H, 13C, and 2D-NMR. In addition, the pharmacological activity of compound 1 was tested with HepG2 and Balb/c mice (splenic lymphocytes and thymic lymphocytes) in vitro, and it exhibited inhibitory effect on the proliferation of HepG2 cells and showed the immunosuppressive activity. PMID- 23919685 TI - General practice: unity in diversity. PMID- 23919686 TI - General practice patients in the emergency department. PMID- 23919687 TI - Planned homebirth in Australia. PMID- 23919688 TI - Challenges of transition to adult health services for patients with rare diseases. PMID- 23919691 TI - Our first National Primary Health Care Strategy: 3 years on, what change for general practice? PMID- 23919692 TI - Involuntary treatment of drug and alcohol dependence in New South Wales: an old Act and a new direction. PMID- 23919693 TI - Vitamin B12 and folate tests: the ongoing need to determine appropriate use and public funding. PMID- 23919694 TI - Vitamin B12 and folate tests: interpret with care. PMID- 23919695 TI - Financial incentives for childhood immunisation - a unique but changing Australian initiative. PMID- 23919696 TI - Why can't we get permanent general practitioners for our country town? PMID- 23919697 TI - Telehealth and equitable access to health care. PMID- 23919698 TI - Gestational diabetes needs to be managed. PMID- 23919699 TI - Gestational diabetes needs to be managed. PMID- 23919700 TI - Gestational diabetes needs to be managed. Reply. PMID- 23919701 TI - Controversy grows over redefinition of gestational diabetes. PMID- 23919702 TI - Over 150 potentially low-value health care practices: an Australian study. PMID- 23919703 TI - Over 150 potentially low-value health care practices: an Australian study. PMID- 23919704 TI - Over 150 potentially low-value health care practices: an Australian study. Reply. PMID- 23919705 TI - Salicylate elimination diets in children: is food restriction supported by the evidence? AB - A review of case notes from our Sydney-based paediatric allergy services, between 1 January 2003 and 31 December 2011, identified 74 children who had been prescribed diets that eliminated foods containing natural salicylates before attending our clinics. The most common indications for starting the diets were eczema (34/74) and behavioural disturbances (17/74) including attention deficit hyperactivity disorder (ADHD). We could find no peer-reviewed evidence to support the efficacy of salicylate elimination diets in managing these diseases. We do not prescribe these diets, and in a survey of European and North American food allergy experts, only 1/23 respondents used a similar diet for eczema, with none of the respondents using salicylate elimination to treat ADHD. A high proportion (31/66) of children suffered adverse outcomes, including nutritional deficiencies and food aversion, with four children developing eating disorders. We could find no published evidence to support the safety of these diets in children. While this uncontrolled study does not prove a causal relationship between salicylate elimination diets and harm, the frequency of adverse events appears high, and in the absence of evidence of safety or efficacy, we cannot recommend the use of these diets in children. PMID- 23919706 TI - Salicylate elimination diets in children. PMID- 23919707 TI - The changing face of cardiovascular care in Australia. PMID- 23919708 TI - Primary prevention of cardiovascular disease: new guidelines, technologies and therapies. AB - A trend in primary prevention of cardiovascular disease (CVD) has been a move away from managing isolated risk factors, such as hypertension and dyslipidaemia, towards assessment and management of absolute CVD risk. In Australian guidelines, absolute CVD risk is calculated as the probability of a stroke, transient ischaemic attack, myocardial infarction, angina, peripheral arterial disease or heart failure occurring within the next 5 2013s. Absolute CVD risk should be regularly assessed in patients aged 45 2013s or older (35 2013s or older in Aboriginal and Torres Strait Islander people) using the Australian absolute CVD risk calculator (http://www.cvdcheck.org.au). For patients currently taking a blood pressure (BP)-lowering or lipid-lowering agent, pretreatment values should be used to calculate risk. Patients at high absolute risk of CVD (> 15% over 5 2013s) should be treated with both BP-lowering and lipid-lowering agents, unless contraindicated or clinically inappropriate. For patients at moderate absolute risk of CVD (10%-15%) treatment with a BP-lowering and/or a lipid-lowering agent should be considered if the risk remains elevated after lifestyle interventions, BP is >= 160/100 mmHg, there is a family history of premature CVD, or the patient is of South Asian, Middle Eastern, Maori, Pacific Islander, Aboriginal or Torres Strait Islander ethnicity. BP measurements taken using an oscillometric device can be used to approximate mean daytime ambulatory BP. PMID- 23919709 TI - Quantifying the proportion of general practice and low-acuity patients in the emergency department. AB - OBJECTIVE: To accurately estimate the proportion of patients presenting to the emergency department (ED) who may have been suitable to be seen in general practice. DESIGN: Using data sourced from the Emergency Department Information Systems for the calendar 2013s 2009 to 2011 at three major tertiary hospitals in Perth, Western Australia, we compared four methods for calculating general practice-type patients. These were the validated Sprivulis method, the widely used Australasian College for Emergency Medicine method, a discharge diagnosis method developed by the Tasmanian Department of Human and Health Services, and the Australian Institute of Health and Welfare (AIHW) method. MAIN OUTCOME MEASURE: General practice-type patient attendances to EDs, estimated using the four methods. RESULTS: All methods except the AIHW method showed that 10%-12% of patients attending tertiary EDs in Perth may have been suitable for general practice. These attendances comprised 3%-5% of total ED length of stay. The AIHW method produced different results (general practice-type patients accounted for about 25% of attendances, comprising 10%-11% of total ED length of stay). General practice-type patient attendances were not evenly distributed across the week, with proportionally more patients presenting during weekday daytime (08:00-17:00) and proportionally fewer overnight (00:00-08:00). This suggests that it is not a lack of general practitioners that drives patients to the ED, as weekday working hours are the time of greatest GP availability. CONCLUSION: The estimated proportion of general practice-type patients attending the EDs of Perth's major hospitals is 10%-12%, and this accounts for < 5% of the total ED length of stay. The AIHW methodology overestimates the actual proportion of general practice-type patient attendances. PMID- 23919710 TI - Publicly funded homebirth in Australia: a review of maternal and neonatal outcomes over 6 years. AB - OBJECTIVE: To report maternal and neonatal outcomes for Australian women planning a publicly funded homebirth from 2005 to 2010. DESIGN, SETTING AND SUBJECTS: Retrospective analysis of data on women who planned a homebirth and on their babies. Data for 2005-2010 (or from the commencement of a program to 2010) were requested from the 12 publicly funded homebirth programs in place at the time. MAIN OUTCOME MEASURES: Maternal outcomes (mortality; place and mode of birth; perineal trauma; type of management of the third stage of labour; postpartum haemorrhage; transfer to hospital); and neonatal outcomes (early mortality; Apgar score at 5 minutes; birthweight; breastfeeding initially and at 6 weeks; significant morbidity; transfer to hospital; admission to a special care nursery). RESULTS: Nine publicly funded homebirth programs in Australia provided data accounting for 97% of births in these programs during the period studied. Of the 1807 women who intended to give birth at home at the onset of labour, 1521 (84%) did so. 315 (17%) were transferred to hospital during labour or within one week of giving birth. The rate of stillbirth and early neonatal death was 3.3 per 1000 births; when deaths because of expected fetal anomalies were excluded it was 1.7 per 1000 births. The rate of normal vaginal birth was 90%. CONCLUSION: This study provides the first national evaluation of a significant proportion of women choosing publicly funded homebirth in Australia; however, the sample size does not have sufficient power to draw a conclusion about safety. More research is warranted into the safety of alternative places of birth within Australia. PMID- 23919711 TI - Perceptions of precautionary labelling among parents of children with food allergy and anaphylaxis. AB - OBJECTIVE: To examine the behaviour and perception of parents of food-allergic children with and without a history of anaphylaxis in relation to precautionary labelling on packaged foods and to understand consumers' perception of the "may be present" statement advocated by VITAL (voluntary incidental trace allergen labelling). DESIGN, SETTING AND PARTICIPANTS: Questionnaire-based study of parents of a consecutive series of 497 children who attended the Department of Allergy and Immunology at the Royal Children's Hospital, Melbourne, from 1 August to 31 October 2011, of whom 293 met our criteria of having an existing medically diagnosed food allergy, and of whom 246 had enough information provided to be included in our analysis. MAIN OUTCOME MEASURES: Parents' responses about their behaviour and perceptions relating to precautionary food labels, and a comparison between parents of children with a past history of anaphylaxis and those with a past history of mild to moderate IgE allergic reactions. RESULTS: Avoidance of foods with precautionary labels differed depending on the wording of the precautionary statement, with 74 parents (65%) ignoring the statement "made in the same factory" compared with 24 (22%) for "may be present". There was no evidence of a difference in participants' behaviour or perceptions depending on whether or not their child had a history of anaphylaxis. CONCLUSIONS: Consumers are choosing a gradient level of risk based on the wording of the precautionary statements and appear to be complacent about precautionary labelling. Many statements are now being disregarded by a sizeable proportion of parents of food allergic children, including those caring for children with a past history of anaphylaxis. This may be due to inadequacies in food labelling legislation. Policies that promote greater clarity and consistent use of precautionary statements may help to deal with this complacency. PMID- 23919712 TI - Sevenfold rise in likelihood of pertussis test requests in a stable set of Australian general practice encounters, 2000-2011. AB - OBJECTIVE: To better understand the role that diagnostic test-ordering behaviour of general practitioners has on current pertussis epidemiology in Australia. DESIGN AND SETTING: Analysis of Australian general practice encounter data (from the Bettering the Evaluation and Care of Health [BEACH] program) on 13 "pertussis related problem" (PRP) codes that were most likely to result in a pertussis laboratory test request and Australian pertussis notifications data (from the National Notifiable Diseases Surveillance System [NNDSS]) for the period April 2000 to March 2011. MAIN OUTCOME MEASURES: The change in the proportion of PRP general practice encounters with a pertussis test request between 2000 and 2011, and the change in national pertussis notifications over the same period. RESULTS: The proportion of PRP encounters resulting in a pertussis test request increased from 0.25% between April 2000 and March 2004 to 1.71% between April 2010 and March 2011 (odds ratio, 7.0; 95% CI, 5.5-8.8). The BEACH data on pertussis testing and NNDSS data on pertussis notifications were highly correlated (r = 0.99), and the notification data mirrored the likelihood of a pertussis test request in general practice. The proportion of NNDSS pertussis notifications with a polymerase chain reaction (PCR)-confirmed diagnosis increased from 16.3% between April 2000 and March 2004 to 65.3% between April 2010 and March 2011. CONCLUSION: An increase in pertussis testing following recognition of early epidemic cases may have led to identification of previously undetected infections, resulting in a further increase in notified disease and awareness among GPs. The changing likelihood of being tested may also be due to expanding availability and use of PCR testing in Australia. PMID- 23919713 TI - A pilgrim's progress: severe Rickettsia conorii infection complicated by gangrene. PMID- 23919714 TI - Reflections. The Drover's Wife. PMID- 23919715 TI - Remote supervision in postgraduate training: a personal view. PMID- 23919718 TI - Differential response of human gingival fibroblasts to titanium- and titanium zirconium-modified surfaces. AB - BACKGROUND AND OBJECTIVE: Gingival fibroblasts are responsible for the constant adaptation, wound healing and regeneration of gingival connective tissue. New titanium-zirconium (TiZr) abutment surfaces have been designed to improve soft tissue integration and reduce implant failure compared with titanium (Ti). The aim of the present study was first to characterize a primary human gingival fibroblast (HGF) model and secondly to evaluate their differential response to Ti and TiZr polished (P), machined (M) and machined + acid-etched (modMA) surfaces, respectively. MATERIAL AND METHODS: HGF were cultured on tissue culture plastic or on the different Ti and TiZr surfaces. Cell morphology was evaluated through confocal and scanning electron microscopy. A wound healing assay was performed to evaluate the capacity of HGF to close a scratch. The expression of genes was evaluated by real-time RT-PCR, addressing: (i) extracellular matrix organization and turnover; (ii) inflammation; (iii) cell adhesion and structure; and (iv) wound healing. Finally, cells on Ti/TiZr surfaces were immunostained with anti ITGB3 antibodies to analyze integrin beta3 production. Matrix metalloproteinase-1 (MMP1) and inhibitor of metallopeptidases-1 (TIMP1) production were analyzed by enzyme-linked immunosorbent assays. RESULTS: On tissue culture plastic, HGF showed no differences between donors on cell proliferation and on the ability for wound closure; alpha-smooth muscle actin was overexpressed on scratched monolayers. The differentiation profile showed increased production of extracellular matrix components. Ti and TiZr showed similar biocompatibility with HGF. TiZr increased integrin-beta3 mRNA and protein levels, compared with Ti. Cells on TiZr surfaces showed higher MMP1 protein than Ti surfaces, although similar TIMP1 protein production. In this in vitro experiment, P and M surfaces from both Ti and TiZr showed better HGF growth than modMA. CONCLUSION: Taking into account the better mechanical properties and bioactivity of TiZr compared with Ti, the results of the present study show that TiZr is a potential clinical candidate for soft tissue integration and implant success. PMID- 23919719 TI - Dynamic air layer on textured superhydrophobic surfaces. AB - We provide an experimental demonstration that a novel macroscopic, dynamic continuous air layer or plastron can be sustained indefinitely on textured superhydrophobic surfaces in air-supersaturated water by a natural gas influx mechanism. This type of plastron is an intermediate state between Leidenfrost vapor layers on superheated surfaces and the equilibrium Cassie-Baxter wetting state on textured superhydrophobic surfaces. We show that such a plastron can be sustained on the surface of a centimeter-sized superhydrophobic sphere immersed in heated water and variations of its dynamic behavior with air saturation of the water can be regulated by rapid changes of the water temperature. The simple experimental setup allows for quantification of the air flux into the plastron and identification of the air transport model of the plastron growth. Both the observed growth dynamics of such plastrons and millimeter-sized air bubbles seeded on the hydrophilic surface under identical air-supersaturated solution conditions are consistent with the predictions of a well-mixed gas transport model. PMID- 23919720 TI - Dually active silicon nanowire transistors and circuits with equal electron and hole transport. AB - We present novel multifunctional nanocircuits built from nanowire transistors that uniquely feature equal electron and hole conduction. Thereby, the mandatory requirement to yield energy efficient circuits with a single type of transistor is shown for the first time. Contrary to any transistor reported up to date, regardless of the technology and semiconductor materials employed, the dually active silicon nanowire channels shown here exhibit an ideal symmetry of current voltage device characteristics for electron (n-type) and hole (p-type) conduction as evaluated in terms of comparable currents, turn-on threshold voltages, and switching slopes. The key enabler to symmetry is the selective tunability of the tunneling transmission of charge carriers as rendered by the combination of the nanometer-scale dimensions of the junctions and the application of radially compressive strain. To prove the advantage of this concept we integrated dually active transistors into cascadable and multifunctional one-dimensional circuit strings. The nanocircuits confirm energy efficient switching and can further be electrically configured to provide four different types of operation modes compared to a single one when employing conventional electronics with the same amount of transistors. PMID- 23919721 TI - Cost-effectiveness of a pentavalent rotavirus vaccine in Japan. AB - OBJECTIVE: To evaluate the impact of universal vaccination with a pentavalent rotavirus vaccine (RV5) on the healthcare burden and costs associated with rotavirus gastroenteritis (RGE) in Japan. METHODS: The model included a hypothetical cohort of 1,091,156 children followed for their first 5 years of life. In the absence of universal vaccination, there were 19 deaths, 78,000 hospitalizations, and 678,000 outpatient visits due to RGE. The efficacy of RV5 is based on international clinical trial data, which was similar to the efficacy observed in clinical trials conducted in Japan. The primary outcome measure is the cost per quality-adjusted-life-year (QALY) gained. In the base case, the QALY loss per 1000 RGE episodes included 2.2 for children and 1.8 per parent. RESULTS: Universal vaccination is projected to reduce hospitalizations by 92%, outpatient visits by 74%, and work-loss days by 73%. For the base case analysis, the total vaccination cost was Y26 billion. The estimated reduction in medical costs was Y16 billion. Of 2500 QALYs gained with the vaccination program, approximately half are directly attributed to the child. In the base case analysis, the incremental cost-effectiveness ratio (ICER) for vaccination vs. no vaccination is Y4 million and Y2 million per quality-adjusted life year (QALY) gained from the healthcare payer and societal perspectives, respectively. The ICERs are Y8 million and Y4 million if parental disutilities are excluded. KEY LIMITATION: The QALY decrements for children and parents were evaluated using different instruments, and the QALY decrements do not vary based on episode severity. Given the interdependence between children and their parents, excluding parental disutilities may under-estimate the impact of RGE. CONCLUSION: Universal vaccination with RV5 in Japan is projected to have a substantial public health impact and may be cost-effective from both the payer and societal perspectives if parental disutilities are included in the cost-effectiveness ratios. PMID- 23919722 TI - Local and systemic neutrophilic inflammation in patients with lung cancer and chronic obstructive pulmonary disease. AB - BACKGROUND: Recent investigations suggest that neutrophils play an important role in the immune response to lung cancer as well as chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the amount of neutrophils and markers of their activity in lung cancer and COPD and in coexistence of these two diseases. METHODS: In total, 267 persons were included in the study: 139 patients with lung cancer, 55 patients with lung cancer and COPD, 40 patients with COPD, and 33 healthy subjects. Peripheral blood and BAL fluid samples were obtained for cell count analysis and determination of NE, MPO levels and ROS production. NE and MPO levels in the serum and BAL fluid were determined by ELISA. ROS production was analyzed by flow cytometer. RESULTS: The percentage, cell count of neutrophils and neutrophil to lymphocyte ratio in the peripheral blood were significantly higher in lung cancer patients with or without COPD compared to COPD patients or healthy individuals (P < 0.05). The percentage and cell count of neutrophils in BAL fluid were significantly lower in patients with lung cancer with or without COPD than in patients with COPD (P < 0.05). However, BAL fluid and serum levels of both NE and MPO were significantly higher in patients with lung cancer than COPD patients or healthy individuals (P < 0.05). Neutrophils produced higher amounts of ROS in patients with lung cancer with or without COPD compared with COPD patients or healthy individuals (P < 0.05). CONCLUSIONS: The results from this study demonstrate higher degree of local and systemic neutrophilic inflammation in patients with lung cancer (with or without COPD) than in patients with COPD. PMID- 23919723 TI - Kruppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts. AB - BACKGROUND: Kruppel-like factor 4 (KLF4) is a member of the KLF family of transcription factors and regulates proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers including colorectal cancer. We previously showed that KLF4 inhibits cell cycle progression following DNA damage and that mouse embryonic fibroblasts (MEFs) null for Klf4 are genetically unstable, as evidenced by increased rates of cell proliferation, and the presence of DNA double strand breaks (DSBs), centrosome amplification, chromosome aberrations and aneuploidy. METHODS: To determine whether re-expression of Klf4 corrects the observed genetic instability in MEFs null for Klf4 (Klf4(-/-)), we transfected Klf4(-/-)MEFs with Klf4-expressing plasmids and compared the results to wild type (Klf4(+/+)) and untransfected or mock-transfected Klf4(-/-)MEFs. RESULTS: We show that overexpression of Klf4 in Klf4(-/-)MEFs reduced cell proliferation rates and the proportion of cells with DSBs, abnormal centrosome numbers, aneuploidy and micronuclei. In addition, Klf4-transfected Klf4(-/-)MEFs exhibited a more robust DNA damage repair response as demonstrated by the greater rate in disappearance of gamma-H2AX and 53BP1 foci following gamma-irradiation. CONCLUSION: Taken together these findings provide evidence that KLF4 plays a crucial role in the maintenance of genetic stability by modulating the DNA damage response and repair processes. PMID- 23919724 TI - Superoxide mediates acute liver injury in irradiated mice lacking sirtuin 3. AB - AIMS: This study determined whether acute radiation-induced liver injury seen in Sirtuin3(-/-) mice after exposure to Cs-137 gamma-rays was mediated by superoxide anion (O2(*-)). RESULTS: Male wild-type (WT) and SIRT3(-/-) mice were given 2*2 Gy whole-body radiation doses separated by 24 h and livers were harvested 20 h after the second dose. Ex vivo measurements in fresh frozen liver sections demonstrated 50% increases in dihydroethidium oxidation from SIRT3(-/-) animals, relative to WT animals, before irradiation, but this increase was not detected 20 h after radiation exposure. In addition, irradiated livers from SIRT3(-/-) animals showed significant hydropic degeneration, loss of MitoTracker Green FM staining, increased immunohistochemical staining for 3-nitrotyrosine, loss of Ki67 staining, and increased mitochondrial localization of p53. These parameters of radiation-induced injury were significantly attenuated by an intraperitoneal injection of 2 mg/kg of the highly specific superoxide dismutase mimic, GC4401, 30 min before each fraction. INNOVATION: Sirtuin 3 (SIRT3) is believed to regulate mitochondrial oxidative metabolism and antioxidant defenses in response to acute radiation-induced liver injury. This work provides strong evidence for the causal role of O2(*-) in the liver injury process initiated by whole-body irradiation in SIRT3(-/-) mice. CONCLUSION: These results support the hypothesis that O2(*-) mediates acute liver injury in SIRT3(-/-) animals exposed to whole body gamma-radiation and suggest that GC4401 could be used as a radio-protective compound in vivo. PMID- 23919725 TI - ISPTM: an iterative search algorithm for systematic identification of post translational modifications from complex proteome mixtures. AB - Identifying protein post-translational modifications (PTMs) from tandem mass spectrometry data of complex proteome mixtures is a highly challenging task. Here we present a new strategy, named iterative search for identifying PTMs (ISPTM), for tackling this challenge. The ISPTM approach consists of a basic search with no variable modification, followed by iterative searches of many PTMs using a small number of them (usually two) in each search. The performance of the ISPTM approach was evaluated on mixtures of 70 synthetic peptides with known modifications, on an 18-protein standard mixture with unknown modifications and on real, complex biological samples of mouse nuclear matrix proteins with unknown modifications. ISPTM revealed that many chemical PTMs were introduced by urea and iodoacetamide during sample preparation and many biological PTMs, including dimethylation of arginine and lysine, were significantly activated by Adriamycin treatment in nuclear matrix associated proteins. ISPTM increased the MS/MS spectral identification rate substantially, displayed significantly better sensitivity for systematic PTM identification compared with that of the conventional all-in-one search approach, and offered PTM identification results that were complementary to InsPecT and MODa, both of which are established PTM identification algorithms. In summary, ISPTM is a new and powerful tool for unbiased identification of many different PTMs with high confidence from complex proteome mixtures. PMID- 23919726 TI - Description and molecular differentiation of a new Staphylocystoides (Cyclophyllidea: Hymenolepididae) from the dusky shrew Sorex monticolus in Southeast Alaska. AB - Staphylocystoides gulyaevi n. sp. is described based on specimens obtained from the dusky shrew Sorex monticolus collected on Sukkwan Island, southeast Alaska. Staphylocystoides gulyaevi n. sp. is compared with other North American members of the genus having 10 rostellar hooks. The new species is morphologically similar to Staphylocystoides parvissima and Staphylocystoides asketus. The uterus in S. gulyaevi n. sp. develops much more rapidly, and a well-developed uterus appears abruptly after it is barely visible in a previous proglottid. In S. parvissima the uterus grows gradually, and its early development is seen in several proglottids. At the level of pre-gravid proglottids the uterus of S. gulyaevi n. sp. occupies only the middle field of the proglottid, while in S. parvissima it fills the whole proglottid including lateral fields. The rostellar hooks in the new species are significantly smaller in size than in S. asketus. Additionally, the new species has fewer proglottids than S. asketus, while having a similar strobila length. Molecular comparison, using 3 genes (28s rDNA, cox1, and nad1), between S. gulyaevi n. sp. and S. parvissima, further corroborates the status of S. gulyaevi n. sp. as a new species. The new species is the seventh species of Staphylocystoides found in North America and the first cestode or any helminth reported from shrews in southeast Alaska. PMID- 23919727 TI - Tailoring a response to youth binge drinking in an Aboriginal Australian community: a grounded theory study. AB - BACKGROUND: While Aboriginal Australian health providers prioritise identification of local community health needs and strategies, they do not always have the opportunity to access or interpret evidence-based literature to inform health improvement innovations. Research partnerships are therefore important when designing or modifying Aboriginal Australian health improvement initiatives and their evaluation. However, there are few models that outline the pragmatic steps by which research partners negotiate to develop, implement and evaluate community-based initiatives. The objective of this paper is to provide a theoretical model of the tailoring of health improvement initiatives by Aboriginal community-based service providers and partner university researchers. It draws from the case of the Beat da Binge community-initiated youth binge drinking harm reduction project in Yarrabah. METHODS: A theoretical model was developed using the constructivist grounded theory methods of concurrent sampling, data collection and analysis. Data was obtained from the recordings of reflective Community-Based Participatory Research (CBPR) processes with Aboriginal community partners and young people, and university researchers. CBPR data was supplemented with interviews with theoretically sampled project participants. The transcripts of CBPR recordings and interviews were imported into NVIVO and coded to identify categories and theoretical constructs. The identified categories were then developed into higher order concepts and the relationships between concepts identified until the central purpose of those involved in the project and the core process that facilitated that purpose were identified. RESULTS: The tailored alcohol harm reduction project resulted in clarification of the underlying local determinants of binge drinking, and a shift in the project design from a social marketing awareness campaign (based on short term events) to a more robust advocacy for youth mentoring into education, employment and training. The community-based process undertaken by the research partnership to tailor the design, implementation and evaluation of the project was theorised as a model incorporating four overlapping stages of negotiating knowledges and meanings to tailor a community response. CONCLUSIONS: The theoretical model can be applied in spaces where local Aboriginal and scientific knowledges meet to support the tailored design, implementation and evaluation of other health improvement projects, particularly those that originate from Aboriginal communities themselves. PMID- 23919728 TI - Pressure ulcer knowledge of registered nurses, assistant nurses and student nurses: a descriptive, comparative multicentre study in Sweden. AB - The aim of this study was to describe and compare the knowledge of registered nurses (RNs), assistant nurses (ANs) and student nurses (SNs) about preventing pressure ulcers (PUs). PU prevention behaviours in the clinical practice of RNs and ANs were also explored. A descriptive, comparative multicentre study was performed. Hospital wards and universities from four Swedish county councils participated. In total, 415 participants (RN, AN and SN) completed the Pressure Ulcer Knowledge Assessment Tool. The mean knowledge score for the sample was 58.9%. The highest scores were found in the themes 'nutrition' (83.1%) and 'risk assessment' (75.7%). The lowest scores were found in the themes 'reduction in the amount of pressure and shear' (47.5%) and 'classification and observation' (55.5%). RNs and SNs had higher scores than ANs on 'aetiology and causes'. SNs had higher scores than RNs and ANs on 'nutrition'. It has been concluded that there is a knowledge deficit in PU prevention among nursing staff in Sweden. A major educational campaign needs to be undertaken both in hospital settings and in nursing education. PMID- 23919730 TI - Sysmex UF-1000i performance for screening yeasts in urine. AB - We tested the capacity of the Sysmex UF-1000i system to detect yeasts in urine by screening a total of 22 132 urine samples received for culture in our microbiology laboratory during 1 year. We also analyzed different dilutions of previously filtered urine inoculated with a strain of Candida albicans. With clinical samples, a single cut-off point of 50 yeast-like cells (YLCs)/MUL detected candiduria >=10 000 colony forming units (CFU)/mL and >100 000 CFU/mL with a sensitivity of 87.3%/95.4%, a specificity of 97%, a negative predictive value of 95.9%, and a positive predictive value of 9.3%/5.7%. With the simulated samples, a linear relationship was observed between the dilution factor and the number of cells detected by UF-1000i. This instrument appears to be able to reliably rule out candiduria of a magnitude of at least 10 000 CFU/mL and facilitate urine sample screening, thereby providing fast results. The Sysmex UF1000i system can be adapted for candiduria screening by the use of an appropriate YLCs/MUL cut-off point that takes account of the prevalence of candiduria in the population. PMID- 23919729 TI - The distinct expression patterns of claudin-2, -6, and -11 between human gastric neoplasms and adjacent non-neoplastic tissues. AB - BACKGROUND: Cancers have a multifactorial etiology a part of which is genetic. Recent data indicate that expression of the tight junction claudin proteins is involved in the etiology and progression of cancer. METHODS: To explore the correlations of the tight junction proteins claudin-2,-6, and -11 in the pathogenesis and clinical behavior of gastric cancer, 40 gastric cancer tissues and 28 samples of non-neoplastic tissues adjacent to the tumors were examined for expression of claudin-2,-6, and -11 by streptavidin-perosidase immunohistochemical staining method. RESULTS: The positive expression rates of claudin-2 in gastric cancer tissues and adjacent tissues were 25% and 68% respectively (P<0.001). The positive expression rates of claudin-6 in gastric cancer tissues and adjacent tissues were 55% and 79% respectively (P=0.045<0.05). In contrast, the positive expression rates of claudin-11 in gastric cancer tissues and gastric cancer adjacent tissues were 80% and 46% (P=0.004<0.01). Thus in our study, the expression of claudin-2, and claudin-6 was down regulated in gastric cancer tissue while the expression of claudin-11 was up regulated. Correlations between claudin expression and clinical behavior were not observed. CONCLUSION: Our study provides the first evidence that claudin-2,-6, and -11 protein expression varies between human gastric cancers and adjacent non neoplastic tissues. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5470513569630744. PMID- 23919731 TI - Is there any interaction of resistin and adiponectin levels with protein-energy wasting among patients with chronic kidney disease. AB - The aim of this study was to evaluate the effects of adipocytokines including adiponectin, leptin, resistin, neuropeptide Y and ghrelin in chronic kidney disease (CKD) patients on appearance of protein-energy wasting (PEW). One hundred fifty patients with mean age of 45.4 +/- 15.9 years, without active infections or chronic inflammatory conditions were recruited into the study. Study groups were control group (consisting of 30 healthy volunteers with normal kidney functions), hemodialysis group, predialysis group, peritoneal dialysis group and kidney transplant group. Fasting morning serum leptin, ghrelin, acylated ghrelin, neuropeptide Y, adiponectin, resistin levels of all of the groups were measured. Anthropometric and nutritional assessments of all patients were obtained. Diagnosis of PEW was made according to definition recommended by the International Society of Renal Nutrition and Metabolism. Presence of PEW in hemodialysis (23.3%) and peritoneal dialysis (26.7%) groups were significantly higher than those of predialysis (3.3%), and transplantation (0%) groups. Adiponectin and resistin levels in predialysis, peritoneal dialysis and hemodialysis patients were significantly higher than control group (p: 0.0001). This study had given significant positive correlations between presence of PEW and serum resistin (r: 0.267, p: 0.001), and serum adiponectin levels (r: 0.349, p: 0.0001). There were no relationship between presence of PEW and ghrelin, acylated-ghrelin, neuropeptide Y, and leptin levels of the groups. CKD patients except transplant patients had higher adiponectin and resistin levels than control group. PEW was found to be linearly correlated with resistin and adiponectin. High serum resistin and adiponectin levels might have a role in development of PEW among dialysis patients. PMID- 23919732 TI - Bioconcentration of organic contaminants in Daphnia resting eggs. AB - Organic contaminants detected in sediments from Lake Greifensee and other compounds falling in the log Dow range from 1 to 7 were selected to study the bioconcentration of organic contaminants in sediments in Daphnia resting eggs (ephippia). Our results show that octocrylene, tonalide, triclocarban, and other personal care products, along with pesticides and biocides can accumulate in ephippia with log BCF values up to 3. Data on the uptake and depuration kinetics show a better fit toward a two compartment organism model over a single compartment model due to the differences in ephippial egg content in the environment. The obtained BCFs correlate with hydrophobicity for neutral compounds. Independence between BCF and hydrophobicity was observed for partially ionized compounds with log Dow values around 1. Internal concentrations in ephippia in the environment were predicted based on sediment concentrations using the equilibrium partitioning model and calculated BCFs. Estimated internal concentration values ranged between 1 and 68,000 MUg/kglip with triclocarban having the highest internal concentrations followed by tonalide and triclosan. The outcomes indicate that contaminants can be taken up by ephippia from the water column or the pore water in the sediment and might influence fitness and sexual reproduction in the aquatic key species of the genus Daphnia. PMID- 23919733 TI - Outcomes of fetal listed patients awaiting heart transplantation. AB - HTx in neonates is mainstay therapy for those with severe cardiomyopathies and congenital heart disease. Fetal listing for HTx has been proposed as a way to increase the potential window for a donor with outcomes predicted to be similar to the neonatal population. Data from the PHTS, a prospective multicenter study, were used to examine the outcomes of fetuses listed between 1993 and 2009. Four thousand three hundred and sixty-five children were listed for HTx during this period. Fetuses comprised 1% and neonates 19.8% of listed patients. In those patients listed as fetus and transplanted, the median wait time from listing to HTx was 55 days (range 4-255), with a median of 25 days (range 0-233) after birth. By six months post-listing, a higher proportion of fetal listed patients had undergone HTx with a lower waitlist mortality when compared with neonate. There was no significant difference in survival following HTx between the two group (p = 0.4). While the results of this study may be less applicable to current practice due to changes in referrals for fetal listing, they do indicate that fetal listing can be a reasonable option. These results are of particular interest at the present time given the ongoing public discourse on the proposed elimination of fetal listing within UNOS. PMID- 23919734 TI - Automated, high-throughput IgG-antibody glycoprofiling platform. AB - One of today's key challenges is the ability to decode the functions of complex carbohydrates in various biological contexts. To generate high-quality glycomics data in a high-throughput fashion, we developed a robotized and low-cost N-glycan analysis platform for glycoprofiling of immunoglobulin G antibodies (IgG), which are central players of the immune system and of vital importance in the biopharmaceutical industry. The key features include (a) rapid IgG affinity purification and sample concentration, (b) protein denaturation and glycan release on a multiwell filtration device, (c) glycan purification on solid supported hydrazide, and (d) glycan quantification by ultra performance liquid chromatography. The sample preparation workflow was automated using a robotic liquid-handling workstation, allowing the preparation of 96 samples (or multiples thereof) in 22 h with excellent reproducibility and, thus, should greatly facilitate biomarker discovery and glycosylation monitoring of therapeutic IgGs. PMID- 23919735 TI - Characterizing amosamine biosynthesis in amicetin reveals AmiG as a reversible retaining glycosyltransferase. AB - The antibacterial and antiviral agent amicetin is a disaccharide nucleoside antibiotic featuring a unique alpha-(1->4)-glycoside bond between amosamine and amicetose, characteristic of a retaining glycosylation. In this study, two key steps for amosamine biosynthesis were investigated: the N-methyltransferase AmiH was demonstrated to be requisite for the dimethylation in amosamine, and the glycosyltransferase AmiG was shown to be necessary for amosaminylation. Biochemical and kinetic characterization of AmiG revealed for the first time the catalytic reversibility of a retaining glycosyltransferase involved in secondary metabolite biosynthesis. AmiG displayed substrate flexibility by utilizing five additional sugar nucleotides as surrogate donors. AmiG was also amenable to sugar and aglycon exchange reactions. This study indicates that AmiG is a potential catalyst for diversifying nucleoside antibiotics and paves the way for mechanistic studies of a natural-product retaining glycosyltransferase. PMID- 23919736 TI - Is an increase in skin temperature predictive of neuropathic foot ulceration in people with diabetes? A systematic review and meta-analysis. AB - INTRODUCTION: The aim of this systematic review was to evaluate the strength of the existing research to answer the question: Is an increase in skin temperature predictive of neuropathic foot ulceration in people with diabetes? METHODS: This study is a systematic review and meta-analysis of temperature-monitoring in the prediction and prevention of diabetic foot ulceration. Two investigators conducted a literature search for all relevant articles from 1960 until July 2011. During this process the following data bases were searched: MEDLINE, Science Direct, AMED, Australian Medical Index, APAIS-Health, ATSIhealth, EMBASE, Web of Science and OneSearch. Keywords used in this search included diabetes, foot complications, ulceration, temperature-monitoring, prediction and prevention. RESULTS: Results of the meta-analysis support the theory that an increase in skin temperature is predictive of foot ulceration when compared with the same site on the contralateral limb. The theory that there is a mean norm foot temperature which can be used as a benchmark to monitor pathological change was unsupported by this meta-analysis. CONCLUSIONS: The conclusions derived from this review are based on the best available scientific evidence in this field. It is intended that the results of this study will improve clinical decision-making and encourage the appropriate measures used to predict and prevent ulceration in people with diabetes at high risk of foot complications. Based on quality studies in this area, the results of this review have indicated that the use of temperature-monitoring is an effective way to predict, and thus prevent, diabetic foot ulceration. PMID- 23919737 TI - Is obesity a possible modifier of periodontal disease as a chronic inflammatory process? A case-control study. AB - BACKGROUND AND OBJECTIVE: This cross-sectional case-control study was conducted to provide a comparative evaluation of clinical periodontal measurements, together with serum levels of certain bioactive peptides and inflammatory cytokines, in relation to obesity. For this purpose, clinical periodontal measurements and the levels of serum leptin, adiponectin, interleukin-6 (IL-6), C reactive protein and soluble intercellular adhesion molecule-1 of obese female individuals and their nonobese counterparts were compared. MATERIAL AND METHODS: Sixty obese (body mass index (BMI) > 30) and 31 nonobese (BMI < 30) female subjects were recruited for the present study. Before any periodontal intervention, serum samples were obtained and full-mouth clinical periodontal measurements were recorded at six sites per tooth. ELISA was used for the biochemical analysis. Data were tested statistically. RESULTS: Clinical attachment level was significantly higher in the obese group compared with the nonobese control group (p < 0.05). Serum levels of leptin and IL-6 were significantly higher in the obese group (p < 0.05). BMI correlated with the serum levels of inflammatory molecules (p < 0.05), but not with clinical periodontal parameters, in the obese group. CONCLUSION: In conclusion, obesity does not seem to have a prominent effect on clinical periodontal parameters but it does have many correlations with circulating inflammatory molecules. As suggested in the literature, increased levels of leptin and IL-6 in the obese group might be one explanation for a possible relationship between obesity and periodontal disease. A prospective study is warranted to clarify, in greater detail, the effects of obesity on periodontal health. PMID- 23919738 TI - Development and validation of a patient-reported outcome instrument in partial responders to proton pump inhibitors. AB - OBJECTIVE: The Reflux Symptom Questionnaire 7-day recall (RESQ-7) was developed, in line with the US Food and Drug Administration (FDA) guidelines, to address the need for a patient-reported outcome (PRO) instrument assessing symptoms specifically in patients with gastroesophageal reflux disease (GERD) who are only partially responsive to proton pump inhibitor (PPI) therapy. MATERIALS AND METHODS: The RESQ-7 was constructed using patient interviews and expert consensus. The instrument was psychometrically validated in a clinical trial setting in patients with persistent GERD symptoms despite PPI therapy. RESULTS: Evaluation of content validity yielded a 13-item structure for the RESQ-7, incorporating symptoms overlooked by existing GERD questionnaires, such as hoarseness, cough, difficulty swallowing and burping. Principal component analysis suggested a four-domain structure. All domains had a high inter-item correlation (Cronbach's alpha lower 95% confidence limits: 0.77-0.87 for intensity; 0.72-0.82 for frequency). Test-retest reliability was fair-to-good or excellent (intraclass correlation coefficient lower 95% confidence limits: 0.70 0.78 for intensity; 0.65-0.75 for frequency). Convergent and discriminant validity were confirmed by correlation comparisons with the Gastrointestinal Symptom Rating Scale. DISCUSSION: The RESQ-7 demonstrated good content validity and psychometric properties in patients with GERD and a partial response to PPIs. The weekly recall makes the RESQ-7 appropriate for use in routine clinical care. The authors believe that it is the first instrument to be developed specifically for patients with a partial response to PPI therapy in line with FDA guidelines on PROs (ClinicalTrials.gov identifier: NCT00703534). PMID- 23919739 TI - Large thermoelectric power factor enhancement observed in InAs nanowires. AB - We report the observation of a thermoelectric power factor in InAs nanowires that exceeds that predicted by a single-band bulk model by up to an order of magnitude at temperatures below about 20 K. We attribute this enhancement effect not to the long-predicted 1D subband effects but to quantum-dot-like states that form in electrostatically nonuniform nanowires as a result of interference between propagating states and 0D resonances. PMID- 23919740 TI - Comparison of circulating tumour necrosis factor superfamily cytokines in periodontitis patients undergoing supportive therapy: a case-controlled cross sectional study comparing smokers and non-smokers in health and disease. AB - BACKGROUND: B-cells are prominent immune cells in established periodontitis lesions. Tumour necrosis factor superfamily (TNFSF) cytokines play roles in supporting B-cell function as well as bone re-modelling. The influence of smoking on factors that support B-cell function in periodontitis remains unclear. AIM: To investigate plasma concentrations of TNF (TNSF1A), soluble receptor activator of nuclear-factor Kappa-B ligand (sRANKL/TNFSF11), a proliferation-inducing ligand (APRIL/TNFSF13), B-cell activating factor (BAFF/TNFSF13B) and Osteoprotegerin (OPG/TNFRSF11B) in smokers and non-smokers with and without chronic periodontitis MATERIALS & METHODS: Plasma concentrations of TNFSF and OPG were evaluated in 200 systemically healthy subjects divided into four groups: non-smokers with periodontitis (n = 101), smokers with periodontitis (n = 55), healthy non-smokers (n = 27) and healthy smokers (n = 17). RESULTS: Periodontitis patients had significantly higher plasma sRANKL, TNF, APRIL and BAFF and lower OPG than healthy subjects (p < 0.01). TNF and sRANKL were significantly greater in smokers with periodontitis (p = 0.011, p = 0.001) and OPG concentrations significantly lower (p = 0.001), whereas APRIL or BAFF were little changed. Plasma APRIL, BAFF, sRANKL and TNF correlated with probing depth and clinical attachment loss. CONCLUSION: TNFSF cytokines correlate with periodontitis disease severity. However, only TNF, sRANKL and OPG levels were altered by cigarette smoking. APRIL and BAFF appear as good indicators of disease severity. PMID- 23919741 TI - Effect of mechanical instability of polymer scaffolds on cell adhesion. AB - The adhesion of fibroblast on polymer bilayers composed of a glassy polystyrene (PS) prepared on top of a rubbery polyisoprene (PI) was studied. Since the top PS layer is not build on a glassy, or firm, foundation, the system becomes mechanically unstable with decreasing thickness of the PS layer. When the PS film was thinner than 25 nm, the number of cells adhered to the surface decreased and the cells could not spread well. On a parallel experiment, the same cell adhesion behavior was observed on plasma-treated PS/PI bilayer films, where in this case, the surface was more hydrophilic than that of the intact films. In addition, the fluorescence microscopic observations revealed that the formation of F-actin filaments in fibroblasts attached to the thicker PS/PI bilayer films was greater than those using the thinner PS/PI bilayer films. On the other hand, the thickness dependence of the cell adhesion behavior was not observed for the PS monolayer films. Taking into account that the amount of adsorbed protein molecules evaluated by a quartz crystal microbalance method was independent of the PS layer thickness of the bilayer films, our results indicate that cells, unlike protein molecules, could sense a mechanical instability of the scaffold. PMID- 23919742 TI - Prognostic value of amplitude-integrated electroencephalography in neonates with hypernatremic dehydration. AB - OBJECTIVES: Hypernatremic dehydration in neonates is a condition that develops due to inadequate fluid intake and it may lead to cerebral damage. We aimed to determine whether there was an association between serum sodium levels on admission and aEEG patterns and prognosis, as well as any association between aEEG findings and survival rates and long-term prognosis. METHOD: The present study included all term infants hospitalized for hypernatremic dehydration in between January 2010 and May 2011. Infants were monitored by aEEG. At 2 years of age, we performed a detailed evaluation to assess the impact of hypernatremic dehydration on the neurodevelopmental outcome. RESULTS: Twenty-one infants were admitted to the neonatal intensive care unit for hypernatremic dehydration. A correlation was found between increased serum sodium levels and aEEG abnormalities. Neurodevelopmental assessment was available for 17 of the 21 infants. The results revealed that hypernatremic dehydration did not adversely affect the long-term outcomes. CONCLUSION: The follow-up of newborns after discharge is key to determine the risks associated with hypernatremic dehydration. Our results suggest that hypernatremic dehydration had no impact on the long-term outcome. In addition, continuous aEEG monitoring could provide information regarding early prognosis and mortality. PMID- 23919743 TI - Adipose tissue-derived stem cells in clinical applications. AB - INTRODUCTION: In the past decade human adipose tissue has been identified as a source of multipotent stem cells. Adipose tissue derived stem cells (ASCs) are characterised by immunosuppressive properties and low immunogenicity. Therefore, they can be used in regenerative medicine, as well as applied to induce graft tolerance or prevent autoimmunity. ASCs can be easily harvested with low morbidity, which is their main advantage over mesenchymal stem cells (MSCs) derived from other sources. AREAS COVERED: The review focuses on reported clinical applications of ASCs and discusses technical approaches of their isolation and processing. The differences in phenotype and differentiation preferences between ASCs and other MSCs that may affect the choice of a particular cell type for the future therapy are also described. EXPERT OPINION: ASCs seem to be the perfect tool for regenerative medicine and immunosuppressive cellular therapies. Nevertheless, there are some tasks that should be addressed by the future studies: i) ASCs require better characterisation; a set of markers determining ASCs should be clearly defined; ii) there is need for more studies on safety of reconstructive therapies with ASCs in cancer patients (e.g., after mastectomy); iii) release criteria should be determined for freshly isolated and ex vivo expanded ASCs designed for clinical applications. PMID- 23919744 TI - Anticancer agent ukrain and bortezomib combination is synergistic in 4T1 breast cancer cells. AB - The identification and in-depth understanding of intracellular signalling pathways led to the synthesis and discovery of many agents targeting cancer cells. In this study, we investigated for the first time the effect of anticancer agent ukrain as a single agent or in combination with cisplatin, etoposide, 5 fluorouracil, quercetin and bortezomib in 4T1 breast cancer and B16F10 melanoma cells. It was found that ukrain is cytotoxic and apoptotic in 4T1 breast carcinoma and B16F10 melanoma cells when given alone. The IC50 value of ukrain in 4T1 cells was found as 40 +/- 6.8 MUM and that in B16F10 cells as 76 +/- 10 MUM. It was then found that apoptosis can be induced in 4T1 breast cancer cells in a dose-dependent manner in response to ukrain treatment, based on DNA fragmentation evidence. The induction of apoptosis was corroborated by the analysis of cleavage products of caspase-3 in 4T1 cells using Western blot technique. When ukrain was tested in combination with cisplatin and etoposide, no significant enhancement of cytotoxicity was detected as compared with single agent treatments. Similarly, 5 fluorouracil and quercetin also did not potentiate the cytotoxic effects of ukrain in 4T1 cells. Finally, we examined the effect of various concentrations of ukrain in combination with 10 nM bortezomib in 4T1 cells. Determination of combination index values showed that bortezomib potentiated the effect of ukrain. And the combination was found to cause synergistic cell death. The lowest combination index detected was 0.57 which was obtained when the cells were treated with 10 nM bortezomib + 100 MUM ukrain. Likewise, when cells were treated with different doses of bortezomib in the presence of 25 MUM ukrain, synergism was similarly detected between the two drugs in a dose-dependent manner. Altogether, the results presented here suggest that the combination of ukrain + bortezomib may be further evaluated and tested in clinical settings. PMID- 23919745 TI - Assessment of nutritional status in cancer--the relationship between body composition and pharmacokinetics. AB - Several nutritional assessment tools have been used in oncology settings to monitor nutritional status and its associated prognostic significance. Body composition is fundamental for the assessment of nutritional status. Recently, the use of accurate and precise body composition tools has significantly added to the value of nutritional assessment in this clinical setting. Computerized tomography (CT) is an example of a technique which provides state-of-the-art assessment of body composition. With use of CT images, a great variability in body composition of cancer patients has been identified even in people with identical body weight or body mass index. Severe muscle depletion (sarcopenia) has emerged as a prevalent body composition phenotype which is predictive of poor functional status, shorter time to tumor progression, shorter survival, and higher incidence of dose-limiting toxicity. Variability in body composition of cancer patients may be a source of disparities in the metabolism of cytotoxic agents. Future clinical trials investigating dose reductions in patients with sarcopenia and dose-escalating studies based on pre-treatment body composition assessment have the potential to alter cancer treatment paradigms. PMID- 23919746 TI - beta-Hydroxy-beta-methylbutyrate as a countermeasure for cancer cachexia: a cellular and molecular rationale. AB - Cancer cachexia is a life-threatening condition characterized by involuntary body weight loss and skeletal muscle wasting. In addition to being associated with poor prognosis and reduced survival, patients with cachexia exhibit a critical loss of physical function that impinges upon their ability to perform basic activities of daily living. Consequently, there is a loss of independence and a drastically reduced quality of life. Despite being a major unmet medical need of patients, very few treatment options exist. Maintaining muscle mass represents an important objective in the cancer patient trajectory not only because it relates to one's capacity to perform activities of daily living, but also because muscle preservation may be a critical determinant of survival while in a tumor-bearing state. In this regard, research has been directed towards identifying countermeasures effective in preserving muscle. With respect to nutritional approaches, administration of the leucine metabolite beta-hydroxy-beta methylbutyrate (HMB) could be a viable component in multi-modal therapies targeting cancer cachexia. Evidence suggests that HMB treatment promotes regenerative events (i.e. myogenic program), suppresses protein degradation, and activates signaling pathways preceding protein synthesis and skeletal muscle growth. HMB therefore, could conceivably act on key regulatory events driving cancer cachexia, thereby favoring muscle growth/preservation. In this review, we take a mechanistic approach in making a case for the use of HMB provision as a possible therapeutic strategy for cancer cachexia by highlighting the cellular and molecular aspects of HMB function. PMID- 23919747 TI - Soy and its isoflavones: the truth behind the science in breast cancer. AB - Epidemiological and migratory evidence suggests that dietary soy consumption can lower the risk for breast cancer. The role of soy isoflavones in cancer prevention and promotion is somewhat unclear. There are two views in terms of soy isoflavones and breast cancer. One line of evidence suggests that soy and its isoflavones have exhibited cancer-preventive properties including lengthening the menstrual cycle, altering estrogen metabolism away from cancerous compounds, and demonstrating anti-proliferative properties in vivo. On the contrary, isoflavones found in soy products are suggested to behave as weak estrogens and as such, much speculation surrounds the influence of soy and/or its isoflavones on hormone receptor-positive cancers. The objective of this review is to present the latest knowledge regarding the role of soy and its isoflavones with the development and advancement of breast cancer, the safety of soy isoflavones for breast cancer survivors, and a comparison of the carcinogenic effects in animal models following soy isoflavone and estrogen administration. This review compares and contrasts literature in terms of the anti-cancer and cancer-promoting effects of soy isoflavones and estrogen in humans and animal models. In conclusion, current human and animal data provide evidence for several anticancer properties of soy and/or its isoflavones. Although the specific quantities and constituents responsible for the observed anti-cancer effects have not been elucidated, it appears that soy isoflavones do not function as an estrogen, but rather exhibit anti-estrogenic properties. However, their metabolism differs between humans and animals and therefore the outcomes of animal studies may not be applicable to humans. The majority of breast cancer cases are hormone-receptor-positive; therefore, soy isoflavones should be considered a potential anti-cancer therapeutic agent and warrant further investigation. PMID- 23919748 TI - Omega-3 polyunsaturated fatty acids and cancer. AB - While the anticancer effect of omega-3 polyunsaturated fatty acids (omega-3 fatty acids), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has been the subject of intense study, our understanding regarding the underlying mechanisms of omega-3 fatty acids against cancer is still limited. Recent studies describing the cancer protective effect of EPA and DHA have sparked a renewed interest in using these fatty acids for cancer prevention and treatment. Here, we summarize the significance of omega- 3 fatty acids in the initiation and progression of cancer, and review the complex mechanisms by which EPA and DHA are thought to have anticancer activities during cancer development. It is concluded that omega-3 fatty acids may exert their anticancer actions by influencing multiple targets implicated in various stages of cancer development, including cell proliferation, cell survival, angiogenesis, inflammation, metastasis and epigenetic abnormalities that are crucial to the onset and progression of cancer. PMID- 23919750 TI - Evaluating the plausibility of prebiotic multistage syntheses. PMID- 23919749 TI - Effects of simulated microgravity on primary human NK cells. AB - The deleterious effects of microgravity on lymphocytes have been demonstrated in previous studies. However, research on the effects of microgravity on human natural killer (NK) cells remains exceedingly limited. In this study, we demonstrated that NK cell cytotoxicity was significantly decreased under simulated microgravity (SMG) conditions (p<0.05). Several processes, including apoptosis, receptor expression, and cytokine secretion, were investigated in human NK cells under SMG. We observed decreased cytotoxicity, concurrent with increased apoptosis and necrosis, in NK cells after exposure to SMG (p<0.05). Additionally, interferon (IFN)-gamma and perforin expression decreased significantly, and the expression of granzyme-B was only slightly reduced. Meanwhile, SMG selectively inhibited the expression of certain surface receptors on NK cells. Specifically, the expression of NKG2A and NKG2D were significantly downregulated under SMG, but the expression of NKp30 and NKp44 was not affected. We also found that interleukin (IL)-15 alone or in combination with IL-12 could counteract the inhibition of NK cell cytotoxicity under SMG. Our findings indicate that human NK cells were sensitive to SMG, as reflected by their decreased cytotoxicity. Factors such as increased early apoptosis and late apoptosis/necrosis and the decreased expression of INF-gamma, cytolytic proteins, and cell surface receptors may be responsible for the loss of cytotoxicity in human NK cells under SMG. A combination of IL-12 and IL-15 may be useful as a therapeutic strategy for overcoming the effects of microgravity on human NK cells during long space missions. PMID- 23919751 TI - Neurotoxic potential of lunar and martian dust: influence on em, proton gradient, active transport, and binding of glutamate in rat brain nerve terminals. AB - The harmful effects of lunar dust (LD) on directly exposed tissues are documented in the literature, whereas researchers are only recently beginning to consider its effects on indirectly exposed tissues. During inhalation, nano-/microsized particles are efficiently deposited in nasal, tracheobronchial, and alveolar regions and transported to the central nervous system. The neurotoxic potential of LD and martian dust (MD) has not yet been assessed. Glutamate is the main excitatory neurotransmitter involved in most aspects of normal brain function, whereas disturbances in glutamate homeostasis contribute to the pathogenesis of major neurological disorders. The research was focused on the analysis of the effects of LD/MD simulants (JSC-1a/JSC, derived from volcanic ash) on the key characteristics of glutamatergic neurotransmission. The average size of LD and MD particles (even minor fractions) before and after sonication was determined by dynamic light scattering. With the use of radiolabeled l-[(14)C]glutamate, it was shown that there is an increase in l-[(14)C]glutamate binding to isolated rat brain nerve terminals (synaptosomes) in low [Na(+)] media and at low temperature in the presence of LD. MD caused significantly lesser changes under the same conditions, whereas nanoparticles of magnetite had no effect at all. Fluorimetric experiments with potential-sensitive dye rhodamine 6G and pH-sensitive dye acridine orange showed that the potential of the plasma membrane of the nerve terminals and acidification of synaptic vesicles were not altered by LD/MD (and nanoparticles of magnetite). Thus, the unique effect of LD to increase glutamate binding to the nerve terminals was shown. This can have deleterious effects on extracellular glutamate homeostasis in the central nervous system and cause alterations in the ambient level of glutamate, which is extremely important for proper synaptic transmission. During a long-term mission, a combination of constant irritation due to dust particles, inflammation, stress, low gravity and microgravity, radiation, UV, and so on may consequently change the effects of the dust and aggravate neurological consequences. PMID- 23919752 TI - High burden of hepatitis B infection in Northern Uganda: results of a population based survey. AB - BACKGROUND: Worldwide 2 billion people are exposed to hepatitis B infection, 350 million have chronic infection, 65 million in sub-Saharan Africa. Uganda is highly endemic with 10% national prevalence of hepatitis B infection, rates varying across the country from 4% in the southwest and 25% in the Northeast. Childhood vaccination was rolled out in 2002, the effect of which on the burden of hepatitis B has not been examined. We determined the prevalence and risk factors for hepatitis B infection in the Northern Uganda Municipality of Gulu. METHODS: We carried out a cross-sectional, population-based survey. The study population included those found at home at the time of recruitment. Data on demographics, wealth index, cultural and behavioral factors, vaccination and health education on hepatitis B were collected. Hepatitis B infection (Hepatitis B surface antigen positive) and lifetime exposure (anti-hepatitis B core antibody positive) were measured. Analysis was done in 2 age groups, 1-14 years, 14 years and more. Associations between predictors and HBV infection were assessed. RESULTS: Information on 790 respondents were analyzed. Overall, 139/790 (17.6%) had hepatitis B infection and 572/790 (72.4%) lifetime exposure. In the younger age group 16/73 (21.9%) had hepatitis B infection and 35/73 (48%) lifetime exposure. Increasing wealth was protective for infection (OR 0.46 per quartile, 95% CI=0.26-0.82, p=0.009), while older age was protective for lifetime exposure (OR 2.70 per age group, 95% CI 1.03-7.07, p=0.043). In the older age group, overall hepatitis B infection was seen in 123/717 (17.2%) and lifetime exposure in 537/717 (74.9%). The female sex (OR 0.63, 95% CI=0.42-0.98, p=0.032) and increasing age (OR 0.76 per age group, 95% CI=0.64-0.91, p=0.003) were factors associated with infection. For lifetime exposure, increasing number of lifetime sexual partners was a risk factor (OR 1.19 per partner category, 95% CI=1.04 1.38, p=0.012). CONCLUSIONS: We found a high prevalence of hepatitis B infection and lifetime exposures to hepatitis B in this northern Uganda Municipality. Targeted vaccination of susceptible adults and improving existing childhood vaccinations and provision of treatment for those with infection will play roles in reducing the high prevalence rates seen in the population. PMID- 23919753 TI - Cigarette smoke induces epithelial to mesenchymal transition and increases the metastatic ability of breast cancer cells. AB - BACKGROUND: Recent epidemiological studies demonstrate that both active and involuntary exposure to tobacco smoke increase the risk of breast cancer. Little is known, however, about the molecular mechanisms by which continuous, long term exposure to tobacco smoke contributes to breast carcinogenesis because most previous studies have focused on short term treatment models. In this work we have set out to investigate the progressive transforming effects of tobacco smoke on non-tumorigenic mammary epithelial cells and breast cancer cells using in vitro and in vivo models of chronic cigarette smoke exposure. RESULTS: We show that both non-tumorigenic (MCF 10A, MCF-12A) and tumorigenic (MCF7) breast epithelial cells exposed to cigarette smoke acquire mesenchymal properties such as fibroblastoid morphology, increased anchorage-independent growth, and increased motility and invasiveness. Moreover, transplantation experiments in mice demonstrate that treatment with cigarette smoke extract renders MCF 10A cells more capable to survive and colonize the mammary ducts and MCF7 cells more prone to metastasize from a subcutaneous injection site, independent of cigarette smoke effects on the host and stromal environment. The extent of transformation and the resulting phenotype thus appear to be associated with the differentiation state of the cells at the time of exposure. Analysis by flow cytometry showed that treatment with CSE leads to the emergence of a CD44(hi)/CD24(low) population in MCF 10A cells and of CD44+ and CD49f + MCF7 cells, indicating that cigarette smoke causes the emergence of cell populations bearing markers of self-renewing stem-like cells. The phenotypical alterations induced by cigarette smoke are accompanied by numerous changes in gene expression that are associated with epithelial to mesenchymal transition and tumorigenesis. CONCLUSIONS: Our results indicate that exposure to cigarette smoke leads to a more aggressive and transformed phenotype in human mammary epithelial cells and that the differentiation state of the cell at the time of exposure may be an important determinant in the phenotype of the final transformed state. PMID- 23919754 TI - Myxoinflammatory fibroblastic sarcoma in children and adolescents: clinicopathologic aspects of a rare neoplasm. AB - Myxoinflammatory fibroblastic sarcoma (MIFS), originally described as a low-grade malignant soft-tissue tumor in adults, has recently been reported in children and in non-acral sites. This report describes the clinicopathologic features of a series of 5 MIFS in children and adolescents (3 males, 2 females), ranging in age from 5 to 17 years (mean, 13 years). These tumors presented as small, superficial, slowly growing soft-tissues masses of the scalp, neck, middle finger, forearm, and thigh. Histologically, the tumors were composed of spindled and plump polygonal cells with prominent nuclear pleomorphism, nuclear pseudoinclusions; large eosinophilic nucleoli; myxoid foci intermingled with spindled foci; and an accompanying inflammatory infiltrate of lymphocytes, plasma cells, and variable neutrophils. Immunohistochemical analysis revealed variable reactivity for CD34 and smooth muscle actin in the tumor cells. Genetic analysis in 3 cases showed no rearrangements of TGFBR3 or MGEA5. Follow up in 4 cases revealed no recurrence or metastasis. These 5 cases of childhood and adolescent MIFS demonstrate an expanded age range and topographic distribution and a favorable outcome. The differential diagnosis and importance of recognizing this rare neoplasm in young patients are discussed. PMID- 23919755 TI - Inhibition of Mycoplasma pneumoniae growth by FDA-approved anticancer and antiviral nucleoside and nucleobase analogs. AB - BACKGROUND: Mycoplasma pneumoniae (Mpn) is a human pathogen that causes acute and chronic respiratory diseases and has been linked to many extrapulmonary diseases. Due to the lack of cell wall, Mpn is resistant to antibiotics targeting cell wall synthesis such as penicillin. During the last 10 years macrolide-resistant Mpn strains have been frequently reported in Asian countries and have been spreading to Europe and the United States. Therefore, new antibiotics are needed. In this study, 30 FDA-approved anticancer or antiviral drugs were screened for inhibitory effects on Mpn growth and selected analogs were further characterized by inhibition of target enzymes and metabolism of radiolabeled substrates. RESULTS: Sixteen drugs showed varying inhibitory effects and seven showed strong inhibition of Mpn growth. The anticancer drug 6-thioguanine had a MIC (minimum inhibitory concentration required to cause 90% of growth inhibition) value of 0.20 MUg ml(-1), whereas trifluorothymidine, gemcitabine and dipyridamole had MIC values of approximately 2 MUg ml(-1). In wild type Mpn culture the presence of 6 thioguanine and dipyridamole strongly inhibited the uptake and metabolism of hypoxanthine and guanine while gemcitabine inhibited the uptake and metabolism of all nucleobases and thymidine. Trifluorothymidine and 5-fluorodeoxyuridine, however, stimulated the uptake and incorporation of radiolabeled thymidine and this stimulation was due to induction of thymidine kinase activity. Furthermore, Mpn hypoxanthine guanine phosphoribosyl transferase (HPRT) was cloned, expressed, and characterized. The 6-thioguanine, but not other purine analogs, strongly inhibited HPRT, which may in part explain the observed growth inhibition. Trifluorothymidine and 5-fluorodeoxyuridine were shown to be good substrates and inhibitors for thymidine kinase from human and Mycoplasma sources. CONCLUSION: We have shown that several anticancer and antiviral nucleoside and nucleobase analogs are potent inhibitors of Mpn growth and that the mechanism of inhibition are most likely due to inhibition of enzymes in the nucleotide biosynthesis pathway and nucleoside transporter. Our results suggest that enzymes in Mycoplasma nucleotide biosynthesis are potential targets for future design of antibiotics against Mycoplasma infection. PMID- 23919756 TI - Cytotoxicity of silver dressings-time to rethink and react. PMID- 23919758 TI - Discovery and biophysical characterization of 2-amino-oxadiazoles as novel antagonists of PqsR, an important regulator of Pseudomonas aeruginosa virulence. AB - The human pathogen Pseudomonas aeruginosa employs alkyl quinolones for cell-to cell communication. The Pseudomonas quinolone signal (PQS) regulates various virulence factors via interaction with the transcriptional regulator PqsR. Therefore, we consider the development of PqsR antagonists a novel strategy to limit the pathogenicity of P. aeruginosa. A fragment identification approach using surface plasmon resonance screening led to the discovery of chemically diverse PqsR ligands. The optimization of the most promising hit (5) resulted in the oxadiazole-2-amine 37 showing pure antagonistic activity in Escherichia coli (EC50 = 7.5 MUM) and P. aeruginosa (EC50 = 38.5 MUM) reporter gene assays. 37 was able to diminish the production of the PQS precursor HHQ in a PqsH-deficient P. aeruginosa mutant. The level of the major virulence factor pyocyanin was significantly reduced in wild-type P. aeruginosa. In addition, site-directed mutagenesis in combination with isothermal titration calorimetry and NMR INPHARMA experiments revealed that the identified ligands bind to the same site of PqsR by adopting different binding modes. These findings will be utilized in a future fragment-growing approach aiming at novel therapeutic options for the treatment of P. aeruginosa infections. PMID- 23919759 TI - Bronchiolitis obliterans associated with Stevens-Johnson Syndrome: histopathological bronchial reconstruction of the whole lung and immunohistochemical study. AB - This study presents an extremely rare case of constrictive bronchiolitis obliterans (BO) associated with Stevens-Johnson Syndrome (SJS) provides the morphological and immunohistochemical features using histopathological bronchial reconstruction technique. A 27-year-old female developed progressive dyspnea after SJS induced by taking amoxicillin at the age of 10. Finally, she died of exacerbation of type II respiratory failure after 17 years from clinically diagnosed as having BO. Macroscopic bronchial reconstruction of the whole lungs at autopsy showed the beginning of bronchial obliterations was in the 4th to 5th branches, numbering from each segmental bronchus. Once they were obliterated, the distal and proximal bronchi were dilated. Microscopic bronchial reconstruction demonstrated the localization of obliteration was mainly from small bronchi to membranous bronchioli with intermittent airway luminal narrowing or obliteration. Moreover, CD3-, CD20-, and CD68-positive cells were found in the BO lesions. CD34 and D2-40-positive cells were mainly distributed in the peribronchiolar lesions and bronchiolar lumens, respectively. SMA- and TGF-beta-positive cells were seen in the fibrous tissue of BO lesions. THE VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1071703140102601. PMID- 23919760 TI - Incidence of community-acquired methicillin-resistant Staphylococcus aureus carrying Pantone-Valentine leucocidin gene at a referral hospital in United Arab Emirates. AB - Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging pathogen in hospitalized patients worldwide. The present study was undertaken to identify CA-MRSA in hospitalized patients in a 350-bed tertiary care hospital in Sharjah, UAE over a 2-year period from January 2011 to December 2012. CA-MRSA was defined based on identification within first 48 h of admission in the hospital. Staphylococcal cassette chromosome (SCC) mec typing of the CA MRSA isolates was carried out by multiplex polymerase chain reaction (PCR). Detection of PVL and mecA genes was done by PCR using the GenoType((r)) MRSA test system (Hain Lifescience). Patient's clinical data and antimicrobial susceptibility pattern of the CA-MRSA isolates were also evaluated. Fifty seven of the 187 MRSA isolates were identified as CA-MRSA. All the CA-MRSA strains in our study belonged to SCCmecIV type and were positive for both PVL and mecA genes. The patients with CA-MRSA infections were young (median age, 32 years) and the majority of infections involved the skin and soft tissue (36%). Antimicrobial susceptibility pattern of the CA-MRSA isolates showed a better susceptibility profile to the non-beta-lactam antimicrobials with the exception of ciprofloxacin having 28% resistance. This study evidently strengthens the recent observation of an increase in CA-MRSA emergence among hospitalized patients in the UAE. PMID- 23919761 TI - Synthesis, spectroscopic properties, and photoinduced CO-release studies of functionalized ruthenium(II) polypyridyl complexes: versatile building blocks for development of CORM-peptide nucleic acid bioconjugates. AB - A series of ruthenium(II) dicarbonyl complexes of formula [RuCl2(L)(CO)2] (L = bpy(CH3,CH3) = 4,4'-dimethyl-2,2'-bipyridine, bpy(CH3,CHO) = 4'-methyl-2,2' bipyridine-4-carboxyaldehyde, bpy(CH3,COOH) = 4'-methyl-2,2'-bipyridine-4 carboxylic acid, CppH = 2-(pyridin-2-yl)pyrimidine-4-carboxylic acid, dppzcH = dipyrido[3,2-a:2',3'-c]phenazine-11-carboxylic acid), and [RuCl(L)(CO)2](+) (L = tpy(COOH) = 6-(2,2':6',2"-terpyridine-4'-yloxy)hexanoic acid) has been synthesized. In addition, a high-yield synthesis of a peptide nucleic acid (PNA) monomer containing the 2-(pyridin-2-yl)pyrimidine ligand was also developed, and this compound was used to prepare the first Ru(II) dicarbonyl complex, [RuCl2(Cpp L-PNA)(CO)2],(Cpp-L-PNA = tert-butyl-N-[2-(N-9 fluorenylmethoxycarbonyl)aminoethyl]-N-[6-(2-(pyridin-2-yl)pyrimidine-4 carboxamido)hexanoyl]glycinate) attached to a PNA monomer backbone. Such metal complex PNA-bioconjugates are attracting profound interest for biosensing and biomedical applications. Characterization of all complexes has been undertaken by IR and NMR spectroscopy, mass spectrometry, elemental analysis, and UV-vis spectroscopy. Investigation of the CO-release properties of the Ru(II) complexes in water/dimethyl sulfoxide (49:1) using the myoglobin assay showed that they are stable under physiological conditions in the dark for at least 60 min and most of them even for up to 15 h. In contrast, photoinduced CO release was observed upon illumination at 365 nm, the low-energy shoulder of the main absorption maximum centered around 300 nm, establishing these compounds as a new class of PhotoCORMs. While the two 2,2'-bipyridine complexes release 1 equiv of CO per mole of complex, the terpyridine, 2-(2'-pyridyl)pyrimidine, and dipyrido[3,2 a:2',3'-c]phenazine complexes are less effective CO releasers. Attachment of the 2-(2'-pyridyl)pyrimidine complex to a PNA backbone as in [RuCl2(Cpp-L-PNA)CO2] did not significantly change the spectroscopic or CO-release properties compared to the parent complex. Thus, a novel class of Ru(II)-based PhotoCORMs has been established which can be coupled to carrier delivery vectors such as PNA to facilitate cellular uptake without loss of the inherent CORM properties of the parent compound. PMID- 23919763 TI - Application of exonuclease III-aided target recycling in flow cytometry: DNA detection sensitivity enhanced by orders of magnitude. AB - DNA-functionalized microspheres in conjugation with flow cytometry detection are widely used for high-throughput nucleic acid assays. Although such assays are rapid and capable of simultaneous analysis of multiple nucleic acid analytes in a single test, the intrinsic limitation in sensitivity remains challenging. Here we report a simple, highly sensitive, and reproducible method based on Exonuclease III-aided target recycling technique applied for DNA quantification in flow cytometry. By loading a high density of Cy5-labeled probe DNA on microspheres (15 MUm), we achieved hitherto unreported DNA detection limit of 3.2 pM in flow cytometry bead assay, enhancing the sensitivity by a factor of over 56.8 compared to the conventional direct hybridization bead assay. Furthermore, we evaluated multiplexing capability by simultaneous detections of two target DNAs with FAM and Cy5 reporter conjugated probes. Therefore, the novel Exonuclease III amplified flow cytometry bead assay has great potential for the rapid, sensitive, and accurate detection and quantification of nucleic acids in clinical diagnosis and biomedical research. PMID- 23919762 TI - Antibody depletion for the treatment of crossmatch-positive pediatric heart transplant recipients. AB - Sensitization to HLA is a risk factor for adverse outcomes after heart transplantation. Requiring a negative prospective CM results in longer waiting times and increased waitlist mortality. We report outcomes in a cohort of sensitized children who underwent transplant despite a positive CDC CM+ using a protocol of antibody depletion at time of transplant, followed by serial IVIG administration. All patients <21 yrs old who underwent heart transplantation at Boston Children's Hospital from 1/1998 to 1/2011 were included. We compared freedom from allograft loss, allograft rejection, and serious infection between CM+ and CM- recipients. Of 134 patients in the cohort, 33 (25%) were sensitized prior to transplantation and 12 (9%) received a CM+ heart transplant. Serious infection in the first post-transplant year was more prevalent in the CM+ patients compared with CM- patients (50% vs. 16%; p = 0.005), as was HD-AMR (50% vs. 2%; p < 0.001). There was no difference in freedom from allograft loss or any rejection. At our center, children transplanted despite a positive CM had acceptable allograft survival and risk of any rejection, but a higher risk of HD AMR and serious infection. PMID- 23919764 TI - A metafluid exhibiting strong optical magnetism. AB - Advances in the field of metamaterials have enabled unprecedented control of light-matter interactions. Metamaterial constituents support high-frequency electric and magnetic dipoles, which can be used as building blocks for new materials capable of negative refraction, electromagnetic cloaking, strong visible-frequency circular dichroism, and enhancing magnetic or chiral transitions in ions and molecules. While all metamaterials to date have existed in the solid-state, considerable interest has emerged in designing a colloidal metamaterial or "metafluid". Such metafluids would combine the advantages of solution-based processing with facile integration into conventional optical components. Here we demonstrate the colloidal synthesis of an isotropic metafluid that exhibits a strong magnetic response at visible frequencies. Protein-antibody interactions are used to direct the solution-phase self-assembly of discrete metamolecules comprised of silver nanoparticles tightly packed around a single dielectric core. The electric and magnetic response of individual metamolecules and the bulk metamaterial solution are directly probed with optical scattering and spectroscopy. Effective medium calculations indicate that the bulk metamaterial exhibits a negative effective permeability and a negative refractive index at modest fill factors. This metafluid can be synthesized in large-quantity and high-quality and may accelerate development of advanced nanophotonic and metamaterial devices. PMID- 23919765 TI - Process evaluation of podiatric treatment of patients with forefoot pain. AB - BACKGROUND: Foot pain is a common problem for people aged 50 and over and occurs more often in women than in men. About 60% of the foot problems are forefoot problems and slightly more than half of these patients seek medical help, mainly in the form of podiatric care. Podiatric treatment of forefoot problems is known to be heterogeneous. The aims of the present study are to describe the podiatric treatment of patients with forefoot pain and to evaluate the podiatric examination and treatment using an expert panel. METHOD: We invited twenty-five randomly selected subjects with forefoot problems who had received podiatric treatment in a pragmatic randomised clinical trial to participate in an analysis of their treatment by an expert panel. The panel retrospectively established the cause of the foot problem as well as the therapeutic goals and evaluated the treatment. These findings were compared to those reported by the treating podiatrist. RESULTS: Two fundamentally different approaches were found in approach of podiatric examination; a functional approach (n =13) and a non functional approach (n =12). In nine cases the expert panel agreed with the cause recorded by the podiatrist. In five other cases the expert panel concluded that the treatment of the podiatrist was not consistent with the cause of the problem recorded by the podiatrist. Of the 10 patients for whom the podiatrist had recorded to have given shoe advice, only two were able to recollect the proper advice. Three patients did not remember receiving advice at all. CONCLUSION: In this study almost half of the podiatrists worked according to a non-functional approach where the other half (like the expert panel) chose a functional strategy that analyses the underlying problem. Fundamental differences in treatment plans and thus heterogeneous treatments could be a consequence. PMID- 23919766 TI - Effect of PEGylation on ligand-based targeting of drug carriers to the vascular wall in blood flow. AB - The blood vessel wall plays a prominent role in the development of many life threatening diseases and as such is an attractive target for treatment. To target diseased tissue, particulate drug carriers often have their surfaces modified with antibodies or epitopes specific to vascular wall-expressed molecules, along with poly(ethylene glycol) (PEG) to improve carrier blood circulation time. However, little is known about the effect of poly(ethylene glycol) on carrier adhesion dynamics-specifically in blood flow. Here we examine the influence of different molecular weight PEG spacers on particle adhesion in blood flow. Anti ICAM-1 or Sialyl Lewis(a) were grafted onto polystyrene 2 MUm and 500 nm spheres via PEG spacers and perfused in blood over activated endothelial cells at physiological shear conditions. PEG spacers were shown to improve, reduce, or have no effect on the binding density of targeted-carriers depending on the PEG surface conformation, shear rate, and targeting moiety. PMID- 23919767 TI - Impact of arterial microcalcification of the vascular access on cardiovascular mortality in hemodialysis patients. AB - Gross vascular calcification seen on imaging studies is common in hemodialysis (HD) patients, and is a significant predictor for cardiovascular mortality in HD patients. We have reported that arterial microcalcification (AMiC) of the vascular access is associated with increased aortic stiffness. This study investigated the impact of vascular access AMiC on cardiovascular mortality in HD patients. The study included 149 HD patients (mean age: 59.1 +/- 13.9 years, 86 men and 63 women, 65.8% diabetic) who underwent vascular access surgery. Radial or brachial artery specimens were obtained intraoperatively, and pathologic examination was performed using von Kossa stain to identify AMiC. We compared all cause and cardiovascular mortality between patients with and without AMiC. The mean follow-up was 37.8 +/- 34.5 months, and AMiC was present in 38.8% (n = 57) of patients. The presence of diabetes (odds ratio: 16.49, 95% confidence interval: 1.81-150.36, P = 0.013) was the only independent risk factor for vascular access AMiC. During the observational period, there were 27 cardiovascular deaths. Kaplan-Meier analysis showed an increased cardiovascular mortality risk (log rank = 4.83, P = 0.028) in AMiC patients, and Cox regression analysis confirmed that AMiC was an independent predictor for cardiovascular mortality (hazard ratio: 2.35, 95% confidence interval: 1.09-5.09, P = 0.030). In conclusion, vascular access AMiC is a strong risk factor for cardiovascular mortality in HD patients. PMID- 23919768 TI - Resilient brain aging: characterization of discordance between Alzheimer's disease pathology and cognition. AB - BACKGROUND: Although it is now evident that normal cognition can occur despite significant AD pathology, few studies have attempted to characterize this discordance, or examine factors that may contribute to resilient brain aging in the setting of AD pathology. METHODS: More than 2,000 older persons underwent annual evaluation as part of participation in the Religious Orders Study or Rush Memory Aging Project. A total of 966 subjects who had brain autopsy and comprehensive cognitive testing proximate to death were analyzed. Resilience was quantified as a continuous measure using linear regression modeling, where global cognition was entered as a dependent variable and global pathology was an independent variable. Studentized residuals generated from the model represented the discordance between cognition and pathology, and served as measure of resilience. The relation of resilience index to known risk factors for AD and related variables was examined. RESULTS: Multivariate regression models that adjusted for demographic variables revealed significant associations for early life socioeconomic status, reading ability, APOE-epsilon4 status, and past cognitive activity. A stepwise regression model retained reading level (estimate = 0.10, SE = 0.02; p< 0.0001) and past cognitive activity (estimate = 0.27, SE = 0.09; p = 0.002), suggesting the potential mediating role of these variables for resilience. CONCLUSIONS: The construct of resilient brain aging can provide a framework for quantifying the discordance between cognition and pathology, and help identify factors that may mediate this relationship. PMID- 23919770 TI - Epidemiology and etiology of Alzheimer's disease: from genetic to non-genetic factors. AB - At present, the etiology of Alzheimer's disease (AD) is still unclear, but both genetic and non-genetic factors are thought to take part in the etiopathogenesis of AD. Epidemiologic researches revealed that genetic factors played a decisive role in the development of both early-onset AD (EOAD) and late-onset AD (LOAD). The mutations in APP, PSEN1 and PSEN2 are inherited in a Mendelian fashion and directly lead to the EOAD, while recent genome-wide association studies have identified numbers of risky genes, which influences the susceptibility to LOAD. Although genetic factors are inherited and fixed, non-genetic factors, such as occupational exposures (exposure to pesticides, electromagnetic fields, organic solvents and volatile anesthetics), pre-existing medical conditions (cerebrovascular disease, hypertension, diabetes, dyslipidemia, traumatic brain injury, depression and cancer) and lifestyle factors (smoking, consumptions of alcohol and coffee, body mass index, physical activity and cognitive activity), are partly environmentally-determined. Timely interventions targeted at these non genetic risk factors may offer opportunities for prevention and treatment of AD. In the future, more high-quality and large-sample epidemiologic studies are needed to identify risk factors for AD, and the interaction models between genetic and non-genetic risk factors required further investigation. In addition, public health campaigns targeted at modification of non-genetic risk factors should be developed among population at high risk of AD. PMID- 23919769 TI - Impact of apolipoprotein E on Alzheimer's disease. AB - A key feature of Alzheimer's disease (AD) is deposition of extracellular amyloid plaque comprised chiefly of the amyloid beta (Abeta) peptide. Studies of Abeta have shown that it may be catabolized by proteolysis or cleared from brain via members of the low-density lipoprotein receptor family. Alternatively, Abeta can undergo a conformational transition from alpha-helix to beta-sheet, a conformer that displays a propensity to self-associate, oligomerize and form fibrils. Furthermore, beta- sheet conformers catalyze conversion of other alpha-helical Abeta peptides to beta-sheet, feeding the oligomer and fibril assembly process. A factor that influences the fate of Abeta in the extracellular space is apolipoprotein (apo) E. Polymorphism at position 112 or 158 in apoE give rise to three major isoforms. One isoform in particular, apoE4 (Arg at 112 and 158), has generated considerable interest since the discovery that it is the major genetic risk factor for development of late onset AD. Despite this striking correlation, the molecular mechanism underlying apoE4's association with AD remains unclear. A tertiary structural feature distinguishing apoE4 from apoE2 and apoE3, termed domain interaction, is postulated to affect the conformation and orientation of its' two independently folded domains. This feature has the potential to influence apoE4's interaction with Abeta, its sensitivity to proteolysis or its lipid accrual and receptor binding activities. Thus, domain interaction may constitute the principal molecular feature of apoE4 that predisposes carriers to late onset AD. By understanding the contribution of apoE4 to AD at the molecular level new therapeutic or prevention strategies will emerge. PMID- 23919772 TI - Progression of Alzheimer-type neurofibrillary tangles is related to the proximodistal segments of the hemispheric arteries. AB - In Alzheimer's disease (AD), neurofibrillary degeneration in the hemispheres starts in the limbic and paralimbic regions prior to those in the isocortical ones but factors determining the progression of these changes are unknown. Previous studies have shown that migration of extracellular substances (volume transmission) driven by arterial pulse pressure waves from the cerebrospinal fluid (CSF) towards the brain parenchyma occurs earlier in these limbic and paralimbic cortices located around the basal cisterns containing the proximal segments of the main hemispheric arteries than in the isocortex. Considering this similarity, the aim of our study was to examine the relation between the proximal segments of the main hemispheric arteries and the development and spread of neurofibrillary tangles (NFTs) in limbic and early isocortical Braaks' stages. Blocks following proximosdistal levels of the anterior and middle cerebral arteries containing areas of the cingulate and insular cortices, respectively, were dissected and NFTs were counted. In both regions, the density of NFTs decreased in parallel with the proximodistal segments of the accompanying arteries. Our results show that neurofibrillary degeneration in AD is related to the proximodistal levels of the main hemispheric arteries and raise the possibility that this effect is mediated by volume transmission from the CSF into the brain. PMID- 23919771 TI - Pupil response biomarkers distinguish amyloid precursor protein mutation carriers from non-carriers. AB - CONTEXT: Alzheimer's disease (AD) is usually only diagnosed many years after pathology begins. Earlier detection would allow emerging interventions to have a greater chance to preserve healthy brain function. A rare form of Alzheimer's disease, caused by autosomal-dominant mutations, affects carriers with 100% certainty and at a younger age specific to their mutation. Studying families with these mutations allows a unique investigation of the temporal sequence of biomarker changes in Alzheimer's disease. OBJECTIVE: To determine whether the pupil flash response (PFR), previously reported to be altered in sporadic Alzheimer's disease, is different in pre-symptomatic mutation carriers. DESIGN: Researchers blinded to participant mutation status collected pupil response data from cognitively normal participants in the Dominantly Inherited Alzheimer's Network (DIAN) Study during 2010-2011. SETTING: The pupil response was examined at the McCusker Alzheimer's Research Foundation in Perth, Western Australia. PARTICIPANTS: Participants were from a single family harboring an Amyloid-Beta Precursor Protein genetic mutation (APPGlu693Gln). Six carriers and six non carriers were available for pupil testing (age 43.0+/-8.3 years old, 2 males and 10 females, 4 with hypertension). MAIN OUTCOME MEASURE: Pupil response parameter comparison between mutation carriers and non-carriers. RESULTS: 75% recovery time was longer in mutation carriers (p<0.0003, ROC AUC 1.000, Sensitivity 100%, Specificity 100%) and percentage recovery 3.5 seconds after stimulus was less in mutation carriers (p<0.006, ROC AUC 1.000, Sensitivity 100%, Specificity 100%). CONCLUSIONS: PFR changes occur pre-symptomatically in autosomal dominant AD mutation carriers, supporting further investigation of PFR for early detection of AD. PMID- 23919774 TI - Multipotent, permeable drug ASS234 inhibits Abeta aggregation, possesses antioxidant properties and protects from Abeta-induced apoptosis in vitro. AB - Amyloid beta (Abeta) aggregation and deposition is a key pathological hallmark of AD. Growing evidence suggests that neurotoxicity of this peptide is related to the formation of toxic oligomeric aggregates. Therefore, a deeply investigated therapeutic strategy comes at present from blocking the formation of these species to non-toxic aggregates. Among other considered strategies, the multi target approach has been proposed as a more suitable potential therapy, precisely due to the multifactorial nature of AD. In this context, we recently identified ASS234, a novel compound that possesses a significant multipotent profile since it is able to inhibit cholinesterase and monoamine oxidase enzymes as well as to interfere in Abeta aggregation process. In this work, we investigated more in detail the effects of ASS234 on Abeta aggregation and toxicity in vitro as well as we explored its ability to penetrate to the CNS. We report that ASS234 inhibited Abeta1-42 self-aggregation more efficiently than that of Abeta1-40, limiting the formation of fibrillar and oligomeric species. Additionally, ASS234 completely blocked the aggregation mediated by AChE of both Abeta1-42 and Abeta1 40, showing a dual binding site to AChE. Interestingly, ASS234 significantly reduced Abeta1-42-mediated toxicity in SH-SY5Y human neuroblastoma cells through the prevention of the mitochondrial apoptosis pathway activation. Also importantly, we observed a significant ability of ASS234 to capture free-radical species in vitro as well as a potent effect in preventing the Abeta1-42-induced depletion of antioxidant enzymes (catalase and SOD-1). Finally, we report the capability of ASS234 to cross the bloodbrain barrier. Overall, our in vitro results show that ASS234 may have an impact on different processes involved in AD pathogenesis and provide evidences that it has encouraging attributes as a therapeutic lead compound. PMID- 23919773 TI - Elevated Abeta42 in aged, non-demented individuals with cerebral atherosclerosis. AB - The beta-secretase, BACE1, generates beta-amyloid (Abeta), a major hallmark of Alzheimer's disease (AD) pathology. The elevation of BACE1 levels in brains of AD patients may play a role in initiating or propagating disease. BACE1 levels are increased under low energy or low oxygen conditions, which may occur in individuals with impaired circulation in the brain. We compared levels of BACE1 in the brains of aged, non-demented individuals with high or low levels of atherosclerosis in the circle of Willis, and found that while there is no change in BACE1, Abeta42 levels are elevated in the high atherosclerosis group. PMID- 23919775 TI - Application of multimodal MR imaging on studying Alzheimer's disease: a survey. AB - The aim of this review is to summarize the current magnetic resonance imaging (MRI) variants applied on the studies of Alzheimer's disease (AD). Experimental findings, advantages and disadvantages, and the prospect of every individual technique will be presented. MRI can be used to investigate the change of the brain in terms of volume, function, white matter track orientation and even mechanical properties and metabolic concentration.Results from volumetric and morphological analysis indicated that the hippocampus reduced by approximately 18%-24% or 3%-4% annually. Functional MRI (fMRI) detected the blood oxygen level dependent (BOLD) signaland suggested thatmedial temporal lobe (MTL) such as hippocampus and entorhinal cortex reduced at the early stage of AD, and frontal, temporal, and parietal cortices at the later stage. In diffusion tensor imaging (DTI), the white matter fiber track integrity is measured but the results are inconsistent. Besides,magnetic resonance spectroscopy (MRS), chemical shift imaging (CSI), arterial spin labeling (ASL), magnetic resonance elastography (MRE) and susceptibility weighted imaging (SWI) will also be included in this review. PMID- 23919776 TI - Alzheimer's Disease is Associated with Increased Risk of Osteoporosis: The Chongqing Aging Study. AB - OBJECTIVE: The aim of this study was to analyze the relationship between Alzheimer's disease (AD) and a risk of osteoporosis in the elderly cohort of Chongqing, China. METHODS: A prospective study with 6 years of follow-up in 1802 patients aged 60- 75 was conducted from January 2007 to June 2013. Dual energy X ray absorptiometry was utilized to evaluate bone mineral density (BMD). Their cognitive function was detected using the Chinese version of the Mini-Mental State Examination (MMSE) and a detection of the instrumental activities of daily living (ADL). Cox proportional hazards models were used to detect the association between AD and the risk of osteoporosis. RESULTS: After adjusting for age, female, AD, 25-hydroxyvitamine D (25(OH)D), smoking, drinking and stroke, AD (Hazard ratio, HR 2.48, 95%CI 1.66-2.94), age (HR 1.36, 95% CI 1.14-1.60), female (HR 1.39, 95% CI 1.17-1.65), 25(OH)D (HR1.34, 95%CI 1.11-1.59), current smoking (HR 1.27, 95%CI 1.22-1.43), daily drinking (HR 1.33, 95%CI 1.11-1.52) and stroke (HR 1.26, 95%CI 1.14-1.58) were associated with increased risk of osteoporosis. In osteoporosis fracture group, osteoporosis with AD was more common than osteoporosis with normal cognition function. CONCLUSIONS: AD was associated with an increased risk of osteoporosis in the elderly cohort of Chongqing, China. PMID- 23919777 TI - Monoclonal versus polyclonal anti-D in the treatment of ITP. AB - Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder caused by low numbers of platelets generally due to the production of anti-platelet antibodies. One effective treatment for ITP patients who express the RhD antigen on their red blood cells has been the use of blood donor-derived pooled polyclonal anti-D. Although anti-D has served us well, it needs to be replaced with a recombinant product. While the mechanism of action of anti-D in ITP remains highly speculative, this has not thwarted attempts to replace anti-D with a monoclonal product. Although a single attempt at a monoclonal antibody was not successful in the 1990s for the treatment of ITP, more recent efforts in mouse models of ITP and ITP patients now show that monoclonal antibodies can be successful in ITP. These studies also finally help substantiate the concept that it is unlikely that contaminants in the original donor-derived preparations mediate the major ameliorative activity of anti-D in ITP. PMID- 23919779 TI - Frontlines: stormy weather. PMID- 23919778 TI - Threading polyintercalators with extremely slow dissociation rates and extended DNA binding sites. AB - The development of small molecules that bind DNA sequence specifically has the potential to modulate gene expression in a general way. One mode of DNA binding is intercalation, or the insertion of molecules between DNA base pairs. We have developed a modular polyintercalation system in which intercalating naphthalene diimide (NDI) units are connected by flexible linkers that alternate between the minor and major grooves of DNA when bound. We recently reported a threading tetraintercalator with a dissociation half-life of 16 days, the longest reported to date, from its preferred 14 bp binding site. Herein, three new tetraintercalator derivatives were synthesized with one, two, and three additional methylene units in the central major groove-binding linker. These molecules displayed dissociation half-lives of 57, 27, and 18 days, respectively, from the 14 bp site. The optimal major groove-binding linker was used in the design of an NDI hexaintercalator that was analyzed by gel-shift assays, DNase I footprinting, and UV-vis spectroscopy. The hexaintercalator bound its entire 22 bp binding site, the longest reported specific binding site for a synthetic, non nucleic acid-based DNA binding molecule, but with a significantly faster dissociation rate compared to the tetraintercalators. PMID- 23919785 TI - When disaster strikes is your hospital ready? PMID- 23919786 TI - Perspective: thorniest issues in healthcare. PMID- 23919787 TI - Developing mobile biomedical apps. PMID- 23919788 TI - Eliminate the fear factor: how to get the most out of work meetings. PMID- 23919789 TI - The case for biomed involvement in purchasing. PMID- 23919790 TI - A doctor's crusade to improve patient safety. PMID- 23919791 TI - Implementing a video integration system in hybrid operating rooms. PMID- 23919792 TI - Improving your equipment intake process. PMID- 23919793 TI - Biological safety cabinets. PMID- 23919795 TI - A role for BMETs in supporting robot-assisted surgery. PMID- 23919796 TI - A guaranteed way to succeed in your career. PMID- 23919797 TI - Lack of correlation between age and/or gender with the force utilized in cleaning an anesthesia machine. AB - Several human factors influence the cleaning of reusable medical devices and equipment. This study evaluated whether a correlation exists between age and/or gender of a person cleaning, with the force applied to remove artificial blood soil on the surface of an anesthesia machine. The findings from this study may be used to increase our understanding of human factors in the cleaning of reusable medical equipment and suggest improvements in equipment design to address issues of concern. PMID- 23919798 TI - Ophthalmic viscoelastic devices as a cleaning challenge. AB - Common practice when validating the cleaning of medical devices is to employ clinically relevant test soils as a challenge to the cleaning process. During use, medical devices may come into contact with a variety of materials that are difficult to clean. One example of this is the use of ophthalmic viscoelastic devices (OVDs) in cataract surgery. This study evaluated the effectiveness of a procedure for cleaning the lumens of a phacoemulsification handpiece using two different OVDs as test soils. The results of this study demonstrate that effective cleaning of the aspiration and irrigation lumens of a phacoemulsification handpiece may be achieved if the manufacturer's recommended cleaning procedures are followed. PMID- 23919800 TI - Predictors of non-exclusive breastfeeding at 6 months among rural mothers in east Ethiopia: a community-based analytical cross-sectional study. AB - BACKGROUND: Exclusive breastfeeding in infants aged under six months is a simple and cost-effective feeding method that ensures better infant and child survival and boosts the achievement of child related Millennium Development Goals in the developing world. Identifying factors associated with good breastfeeding practice helps to increase its coverage and maximize its advantages through improved advocacy. The objective of this study was to identify the predictors of non exclusive breastfeeding in the rural areas of eastern Ethiopia. METHODS: A community-based analytical cross-sectional study was conducted on mother/caregiver-child pairs in east Ethiopia from July to August 2011. Data on infant feeding practices were collected by trained interviewers who used a pretested and structured questionnaire. Odds ratio with a 95% confidence interval was estimated for the predictors of non-exclusive breastfeeding using the multivariable logistic regression. RESULTS: The prevalence of non-exclusive breastfeeding in infants aged under six months, was 28.3%. Non-exclusive breastfeeding was more likely to be practiced by mothers who were not married at the moment [AOR (95% CI) = 2.6 (1.1, 6.0)], mothers who had no access to health facility [AOR (95% CI) = 2.9 (1.9, 4.3)], and mothers whose knowledge about infant and young child feeding practices was low [AOR (95% CI) = 3.4 (2.4, 4.7)]. CONCLUSION: Non-exclusive breastfeeding was more common among mothers with no marital relationships, poor access to health facilities, and inadequate knowledge about infant and young child feeding practices. Family support, education, and behavior change communication on infant feeding, especially on exclusive breastfeeding, at the community level may improve the knowledge, behavior, and practice of mothers on optimal infant and young child feeding practices. PMID- 23919801 TI - Laboratory assessment of the antifouling potential of a soluble-matrix paint laced with the natural compound polygodial. AB - Polygodial is a potent and selective inhibitor of ascidian metamorphosis that shows promise for controlling fouling by ascidians in bivalve aquaculture. The current study examined the potency of, and associated effects of seawater exposure on, a rosin-based soluble-matrix paint laced with 0.08-160 ng polygodial g(-1) wet paint matrix. Paint-coated surfaces were soaked in seawater for 0, 2, 4 or 12 weeks prior to screening for antifouling activity using a bioassay based on the nuisance ascidian Ciona savignyi Herdman. Mortality was greater (mean 50% lethal concentration: 5 +/- 2 ng g(-1); mean 75% lethal concentration: 17 +/- 4 ng g(-1)) and metamorphosis was inhibited (mean 50% anti-metamorphic concentration: 2 +/- 0.4 ng g(-1); mean 75% anti-metamorphic concentration: 15 +/ 10 ng g(-1)) in C. savignyi larvae exposed to polygodial-laced soluble-matrix paints, relative to control paints without polygodial. Soaking in seawater prior to testing reduced the efficacy of the formulation up to nearly 12-fold, but even after soaking for 12 weeks paints laced with polygodial at 160 ng g(-1) wet paint matrix prevented ?90% of the larvae of C. savignyi from completing metamorphosis. The outcome of this experiment provides a positive first step in evaluating the suitability of polygodial-laced soluble-matrix paints for use in aquaculture. PMID- 23919802 TI - A comparison of obstetrical outcomes with labor induction agents used at term. AB - OBJECTIVE: To compare the obstetrical outcomes of term pregnancies induced with one of four commonly used labor induction agents. METHODS: This is a retrospective cohort study of induced deliveries between 1 August 1995 and 31 December 2007 occurring at the Los Angeles County + University of Southern California Medical Center. Viable, singleton, term pregnancies undergoing induction were identified. Exclusion criteria included gestational age less than 37 weeks, previous cesarean delivery, breech presentation, stillbirth, premature rupture of membranes, and fetal anomaly. Induction methods studied were oxytocin, misoprostol, dinoprostone and Foley catheter. Our primary outcome was cesarean delivery rate among the four induction agents. Secondary outcomes included rate of failed induction, obstetrical complications, and immediate neonatal complications. RESULTS: A total of 3707 women were included in the study (1486 nulliparous; 2221 multiparous). Outcomes were compared across induction methods using Chi-square Tests (Pearson or Fisher's, as appropriate). Among the nulliparous patients, there was no statistical difference among the four induction agents with regards to cesarean delivery rate (p = 0.51), frequency of failed inductions (p = 0.49), the cesarean delivery frequency for "fetal distress" (p = 0.82) and five minute Apgar score <7 (p = 0.24). Among parous patients, the cesarean delivery rate varied significantly by induction method (p < 0.001), being lowest among those receiving misoprostol (10%). Those receiving oxytocin and transcervical Foley catheter had cesarean rates of 22%, followed by dinoprostone at 18%. The rate of failed inductions was 2% among those receiving misoprostol, compared to 7-8% among those in the other groups (p < 0.01). Although cases of "fetal distress" between the four induction agents was not significantly different amongst multipara women, the cesarean delivery indication for "fetal distress" was higher among multipara receiving misoprostol (p = 0.004). There was no difference among the different induction agents with regards to five minute Apgar <7 (p = 0.34). CONCLUSION: Among nulliparous women, all induction methods have similar rate of cesarean delivery. The use of misoprostol appears to be associated with a lower risk of cesarean birth among parous women induced at our institution. PMID- 23919803 TI - Monitoring drug self-aggregation and potential for promiscuity in off-target in vitro pharmacology screens by a practical NMR strategy. AB - A simple NMR assay was applied to monitor the tendency of compounds to self aggregate in aqueous media. The observation of unusual spectral trends as a function of compound concentration appears to be signatory of the formation of self-assemblies. (1)H NMR resonances of aggregating compounds were sensitive to the presence of a range of molecular assemblies in solution including large molecular-size entities, smaller multimers, and mixtures of assembled species. The direct observation of aggregates via unusual NMR spectra also correlated with promiscuous behavior of molecules in off-target in vitro pharmacology assays. This empirical assay can have utility for predicting compound promiscuity and should complement predictive methods that principally rely on the computing of descriptors such as lipophilicity (cLogP) and topological surface area (TPSA). This assay should serve as a practical tool for medicinal chemists to monitor compound attributes in aqueous solution and various pharmacologically relevant media, as demonstrated herein. PMID- 23919804 TI - Regioselective hydrothiolation of alkynes by sulfonyl hydrazides using organic ionic base-Bronsted acid. AB - A practical and novel approach has been developed for the synthesis of vinyl sulfides by the reaction of sulfonyl hydrazides with aryl/heteroarylacetylenes using a DBU-based ionic liquid. The system offers a new sulfur source for hydrothiolation and is endowed with green credentials. PMID- 23919805 TI - Scanning electrochemical microscopy: using the potentiometric mode of SECM to study the mixed potential arising from two independent redox processes. AB - This study demonstrates how the potentiometric mode of the scanning electrochemical microscope (SECM) can be used to sensitively probe and alter the mixed potential due to two independent redox processes provided that the transport of one of the species involved is controlled by diffusion. This is illustrated with the discharge of hydrogen from nanostructured Pd hydride films deposited on the SECM tip. In deareated buffered solutions the open circuit potential of the PdH in equilibrium between its beta and alpha phases (OCP(beta >alpha)) does not depend on the tip-substrate distance while in aerated conditions it is found to be controlled by hindered diffusion of oxygen. Chronopotentiometric and amperometric measurements at several tip-substrate distances reveal how the flux of oxygen toward the Pd hydride film determines its potential. Linear sweep voltammetry shows that the polarization resistance increases when the tip approaches an inert substrate. The SECM methodology also demonstrates how dissolved oxygen affects the rate of hydrogen extraction from the Pd lattice. Over a wide potential window, the highly reactive nanostructure promotes the reduction of oxygen which rapidly discharges hydrogen from the PdH. The flux of oxygen toward the tip can be adjusted via hindered diffusion. Approaching the substrate decreases the flux of oxygen, lengthens the hydrogen discharge, and shifts OCP(beta->alpha) negatively. The results are consistent with a mixed potential due to the rate of oxygen reduction balancing that of the hydride oxidation. The methodology is generic and applicable to other mixed potential processes in corrosion or catalysis. PMID- 23919806 TI - Upregulation of Ying Yang 1 (YY1) suppresses esophageal squamous cell carcinoma development through heme oxygenase-1. AB - Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignancies worldwide. Ying Yang 1 (YY1), a ubiquitously expressed GLI-Kruppel zinc finger transcription factor, plays a regulatory role in a variety of fundamental biological processes, such as embryonic development, growth, apoptosis, differentiation and oncogenic transformation. The purpose of this study was to investigate the expression of YY1 in normal and cancerous esophageal tissues and its function in ESCC development. We found that the expression of YY1 mRNA was significantly increased in the tumor tissues, compared with the para-tissues or normal esophageal tissues. The increased expression of YY1 in tumor samples was further confirmed by immunohistochemistry. Furthermore, the overexpression of YY1 conferred radioresistance to the ESCC TE-1 cells and resulted in markedly reduced cell proliferation. Accordingly, the small interfering RNA-mediated silencing of YY1 expression in TE-1 cells resulted in increased proliferation by enhancing the binding of P21 to Cyclin D1 and CDK4, a protein complex known to mediate cell cycle progression. Moreover, besides P21, heme oxygenase-1 (HO-1) was identified as a YY1 downstream effector, as YY1 stimulated HO-1 expression in esophageal cancer cells. YY1 mediated biological function through transcription of HO-1. Forced expression of HO-1 could moderately suppress proliferation of TE-1 cells. The expression of YY1 significantly correlated with that of HO-1 in ESCC tissues. Taken together, we demonstrated overexpression of YY1 in esophageal carcinoma and identified HO-1 as its target. PMID- 23919807 TI - Chlamydia trachomatis homotypic inclusion fusion is promoted by host microtubule trafficking. AB - BACKGROUND: The developmental cycle of the obligate intracellular pathogen Chlamydia is dependant on the formation of a unique intracellular niche termed the chlamydial inclusion. The inclusion is a membrane bound vacuole derived from host cytoplasmic membrane and is modified significantly by the insertion of chlamydial proteins. A unique property of the inclusion is its propensity for homotypic fusion. The vast majority of cells infected with multiple chlamydial elementary bodies (EBs) contain only a single mature inclusion. The chlamydial protein IncA is required for fusion, however the host process involved are uncharacterized. RESULTS: Here, through live imaging studies, we determined that the nascent inclusions clustered tightly at the cell microtubule organizing center (MTOC) where they eventually fused to form a single inclusion. We established that factors involved in trafficking were required for efficient fusion as both disruption of the microtubule network and inhibition of microtubule trafficking reduced the efficiency of fusion. Additionally, fusion occurred at multiple sites in the cell and was delayed when the microtubule minus ends were either no longer anchored at a single MTOC or when a cell possessed multiple MTOCs. CONCLUSIONS: The data presented demonstrates that efficient homotypic fusion requires the inclusions to be in close proximity and that this proximity is dependent on chlamydial microtubule trafficking to the minus ends of microtubules. PMID- 23919808 TI - Study of Health and Activity in Preschool Environments (SHAPES): study protocol for a randomized trial evaluating a multi-component physical activity intervention in preschool children. AB - BACKGROUND: Physical inactivity is a recognized public health concern. Inadequate proportions of children in the U.S, including those of preschool age, are meeting physical activity recommendations. In response to low numbers of preschool children attaining appropriate physical activity levels, combined with the large number of young children who attend preschool, researchers have identified the need to devise interventions to increase physical activity at preschools. However, few multi-component interventions to increase physical activity in preschool children exist. The aims of this study were to observe the effects of a multi-component intervention on physical activity, sedentary behavior, and physical activity energy expenditure in 3-5 year-old children; identify factors that associate with change in those variables; and evaluate the process of implementing the multi-component intervention. The purpose of this manuscript is to describe the study design and intervention protocol. METHODS/DESIGN: The overall design of the Study of Health and Activity in Preschool Environments (SHAPES) was a two-year randomized trial (nested cohort design), with two conditions, two measurement occasions, and preschool serving as the unit of analysis. Sixteen schools (eight intervention and eight control) were enrolled. The intervention protocol was based on the social ecological model and included four main components: (a) indoor physical activity ("move inside"), (b) recess ("move outside"), (c) daily lessons ("move to learn"), and (d) social environment. Components were implemented using teacher and administrator trainings and workshops, site support visits, newsletters, and self-monitoring methods. Outcomes included accelerometer assessment of physical activity, sedentary behavior, and physical activity energy expenditure; weight status; and demographic factors; family/home social and physical environment; and parental characteristics. An extensive process evaluation battery was also used to monitor dose delivered by interventionists, completeness of intervention component delivery by teachers, and fidelity of teachers' implementation. DISCUSSION: The study will address important gaps relative to increasing physical activity in preschool children. Few studies to date have incorporated a multi-component approach, rigorous measurement protocol, and thorough evaluation of intervention implementation. PMID- 23919809 TI - Comparison between survey radiography, B-mode ultrasonography, contrast-enhanced ultrasonography and contrast-enhanced multi-detector computed tomography findings in dogs with acute abdominal signs. AB - Contrast-enhanced multi-detector computed tomography (CE-MDCT) is used routinely in evaluating human patients with acute abdominal symptoms. Contrast-enhanced ultrasound (CEUS) continues to be in its infancy as it relates to evaluation of the acute abdomen. The purpose of this study was to compare survey radiography, B mode ultrasound, CEUS, and CE-MDCT findings in canine patients presenting with acute abdominal signs; with a focus on the ability to differentiate surgical from non-surgical conditions. Nineteen dogs were prospectively enrolled. Inclusion required a clinical diagnosis of acute abdominal signs and confirmed surgical or non-surgical causes for the clinical signs. Agreement for the majority of recorded imaging features was at least moderate. There was poor agreement in the identification of pneumoperitoneum and in the comparison of pancreatic lesion dimensions for B-mode vs. CEUS. The CT feature of fat stranding was detected in cases including, but not limited to, gastric neoplasia with perforation, pancreatitis, and small intestinal foreign body. Ultrasound underestimated the size and number of specific lesions when compared with CE-MDCT. Contrast-enhanced ultrasound was successful in detecting bowel and pancreatic perfusion deficits that CE-MDCT failed to identify. Accuracy for differentiation of surgical vs. non surgical conditions was high for all modalities; 100%, 94%, and 94% for CE-MDCT, ultrasonography and survey radiography respectively. Findings indicated that CE MDCT is an accurate screening test for differentiating surgical from non-surgical acute abdominal conditions in dogs. Focused CEUS following CE-MDCT or B-mode ultrasonography may be beneficial for identifying potentially significant hypoperfused lesions. PMID- 23919810 TI - Micronutrient deficiencies in pediatric and young adult intestinal transplant patients. AB - Intestinal transplant recipients are at risk of micronutrient deficiency due to the slow process of post-transplant adaptation. Another contributing factor is calcineurin inhibitor-induced renal tubular dysfunction. Patients are typically supplemented with micronutrients during PN; however, the risk of deficiency may persist even after a successful transition to FEN. The goal was to determine the prevalence of, and associated risk factors for, iron, zinc, magnesium, phosphorus, selenium, copper, folate, and vitamins A, D, E, and B12 deficiency in pediatric intestinal transplant recipients after successful transition to FEN. A retrospective review of prospectively collected data from children who underwent intestinal transplantation at Cincinnati Children's Hospital Medical Center was done. Deficiencies of various micronutrients were defined using the hospital reference values. Twenty-one intestinal transplant recipients, aged one to 23 yr, who were successfully transitioned to FEN were included in the study. The prevalence of micronutrient deficiency was 95.2%. The common deficient micronutrients were iron (94.7%) and magnesium (90.5%). Age <= 10 yr (p = 0.002) and tube feeding (p = 0.02) were significant risk factors for micronutrient deficiencies. Pediatric intestinal transplant recipients have a high risk of micronutrient and mineral deficiencies. These deficiencies were more common among younger patients and those who received jejunal feeding. PMID- 23919811 TI - Changing trends and serotype distribution of Shigella species in Beijing from 1994 to 2010. AB - Shigella species are a common cause of acute diarrheal disease in China. In this study, we characterized the changing trends and serotype distribution of Shigella species in Beijing from 1994 to 2010. A total of 5999 Shigella strains were isolated and serotyped from the 302nd Hospital in Beijing. The annual number of Shigella isolates reached a peak (n = 1192; 19.84%) in 1996 and then decreased annually, reaching the lowest point (n = 24; 0.41%) in 2010. S. flexneri 2a and S. sonnei were the most frequently isolated Shigella, with their respective isolates making up 53.3% and 27.6% of the total. Isolates of S. flexneri 4c, 4a, and x made up 3% respectively of the total isolates. Significant decreases in percentage of S. flexneri over time were observed. S. sonnei surpassed S. flexneri 2a as the predominant serotype in 2000. Most isolates were recovered from July to September; 13.6% of the isolates were recovered from children aged 0 to 5 years, and 16% were recovered from those aged 21 to 25 years. S. flexneri 2a and 5 were recovered mostly from males (33.41%, p < 0.001; and 0.46%, p < 0.001%; respectively), whereas S. flexneri 2b and 6, and S. sonnei were most often isolated from females. Continuous monitoring of Shigella showed that all 4 species and 27 serotypes were present in Beijing, China, during the study period. The emergence of S. sonnei and the overall decreasing isolation rate of Shigella in Beijing can potentially aid in the development of vaccine and control strategies for shigellosis in the city. PMID- 23919813 TI - Not different is not the same as the same: how can we tell? PMID- 23919812 TI - Long-term orange juice consumption is associated with low LDL-cholesterol and apolipoprotein B in normal and moderately hypercholesterolemic subjects. AB - BACKGROUND: This study investigated the hypothesis that long-term orange juice consumption (>= 12 months) was associated with low risk factors for cardiovascular disease in adult men and women with normal and moderately high cholesterol blood levels. METHODS: The sample consisted of 103 men (18-66 y) and 26 women (18-65 y); all were employees of an orange juice factory with daily access to free orange juice. The results showed that 41% of the individuals consumed 2 cups (480 mL) of orange juice per day for at least twelve months, while 59% of the volunteers are non-consumers of orange juice. RESULTS: Orange juice consumers with normal serum lipid levels had significantly lower total cholesterol (-11%, p <0.001), LDL-cholesterol (-18%, p < 0.001), apolipoprotein B (apo B) (-12%, p < 0.01) and LDL/HDL ratio (-12%, p < 0.04) in comparison to non consumers, as did the consumers with moderate hypercholesterolemia: lower total cholesterol (-5%, p <0.02), LDL-cholesterol (-12%, p <0.03), apolipoprotein B ( 12%, p <0.01) and LDL/HDL ratio (-16%, p <0.05) in comparison the non-consumers counterparts. Serum levels of homocysteine, HDL- cholesterol and apolipoprotein A 1, body composition and the dietary intake of food energy and macronutrients did not differ among orange juice consumers and non-consumers, but vitamin C and folate intake was higher in orange juice consumers. CONCLUSION: Long-term orange juice consumers had lower levels of total cholesterol, LDL-cholesterol, apo B and LDL/HDL ratio and an improvement of folate and vitamin C in their diet. PMID- 23919815 TI - Using disodium monohydrogen phosphate to prepare a phosphate-enriched hemodialysate. PMID- 23919814 TI - Structure of biodegradable films at aqueous surfaces: X-ray diffraction and spectroscopy studies of polylactides and tyrosine-derived polycarbonates. AB - Three representative polymers of increasing modulus, poly(d,l-lactic acid), PDLLA, poly(desaminotyrosyl-tyrosine ethyl ester carbonate), PDTEC, and the same polymer with iodinated DTE segments, PI2DTEC, were characterized by surface pressure versus area (Pi-A) isotherms and surface sensitive X-ray diffraction techniques. Films of 10-100 A thickness were prepared for these studies by spreading dilute polymer solutions at air-water interfaces. The general properties of the isotherms and the Flory exponents, determined from the isotherms, vary in accordance with the increasing modulus of PDLLA, PDTEC, PI2DTEC, respectively. The analysis of in situ X-ray reflectivity and grazing incidence X-ray diffraction (GIXD) measurements from films at aqueous surfaces provides a morphological picture that is consistent with the modulus of the polymers, and to a large extent, with their packing in their dry-bulk state. Large absorption of X-rays by iodine enabled X-ray spectroscopic studies under near-total-reflection conditions to determine the iodine distribution in the PI2DTEC film and complement the structural model derived from reflectivity and GIXD. These structural studies lay the foundation for future studies of polymer protein interactions at aqueous interfaces. PMID- 23919816 TI - Bone quality assessment in routine dental implant treatment among Brazilian and Swedish specialists. AB - OBJECTIVES: To investigate the interpretation and assessment of bone quality among Brazilian and Swedish specialist performing implant treatment. MATERIAL AND METHODS: A questionnaire was developed containing open and closed questions on attitudes, knowledge, and understanding of diagnostic methods for bone quality assessment. The questionnaire was sent by mail to dental implant specialists in Brazil while the Swedish version was Web-based and sent to specialists in periodontology and maxillofacial surgery. The response rate in the Brazilian group was 15.4% and in the Swedish group 36.5%. RESULTS: Most respondents in both groups considered bone quality to be an important parameter for implant treatment outcome. Among Swedish specialists, bone quality, however, was considered to be of low relevance. The most popular method for assessing bone quality among Swedish specialists was the hand-felt perception of drilling resistance followed by radiography. The Brazilian specialists more often used peak insertion torque. Most respondents classified bone quality, and both groups used the classification proposed by Lekholm & Zarb (Tissue-Integratedprosthesis: Osseointegration in Clinical Dentistry, 1985, Quintessence, Chicago) most frequently. CONCLUSION: Specialists in both countries considered bone quality to be an important parameter for implant treatment outcome, but there was no consensus neither on what bone quality means nor on how to assess bone quality. PMID- 23919817 TI - First-principles study of microporous magnets M-MOF-74 (M = Ni, Co, Fe, Mn): the role of metal centers. AB - A clear understanding of the origin of magnetism in metal-organic frameworks (MOFs) would provide useful insight for tuning the electromagnetic properties of MOFs and finding new applications. In the present study, first-principles calculations show that the open paramagnetic metal sites in three-dimensional porous magnets M-MOF-74 (M = Ni, Co, Fe, Mn) favor high-spin electronic arrangement. Fe- and Co-MOF-74 exhibit ferromagnetic (FM) features and significantly distinct energy gaps between spin-up and spin-down channels in metastable states. After replacement of the Co center with a Ni ion, the FM feature was exhibited for the stable state since the "extra" valence electron was filled in the spin-down 3d bands to shift the Fermi level to higher energy. In contrast, after removal of one valence electron (i.e., replacement of the Fe center with Mn atoms), the energy gap was significantly enlarged and an antiferromagnetic (AFM) feature will be discerned. PMID- 23919818 TI - Physical and virtual screening methods for marine toxins and drug discovery targeting nicotinic acetylcholine receptors. AB - INTRODUCTION: Nicotinic acetylcholine receptors (nAChRs) have been extensively studied because of their importance in physiological processes and their involvement in a number of muscle and neuronal human pathologies. However, the role of specific subtypes remains poorly understood due to the lack of selective nAChR probes. During the last decade, drug design strategies have been powered by a wide variety of natural compounds with diverse chemical structures, and by the structural characterization of several nAChRs structural homologs. AREAS COVERED: In this review, the authors present a short overview of nAChRs, and some natural sources of bioactive molecules targeting these receptors. The authors provide an emphasis on alpha-conotoxins from Conus venoms, which provide the most diverse selective antagonists of nAChRs known to date, as well briefly discussing macrocyclic imine toxins. The authors, furthermore, review valuable radioactive and non-radioactive methods used for discovering novel ligands targeting nAChRs and highlight high-throughput developments in receptor-binding and electrophysiological assays. Finally, the authors review the molecular modeling approaches used in the last few years with an aim to provide an overview of their potential to identify and optimize selective nAChR ligands. EXPERT OPINION: Recent years have provided new valuable techniques for the detection and identification of new nAChRs ligands, along with an increasing use of different molecular modeling tools. This furthering of knowledge has had an impact on the design and discovery of more potent and selective nAChRs ligands. There is still however a lack of high-resolution structural information that will require new developments. PMID- 23919819 TI - Genetic polymorphisms of XRCC1 gene and susceptibility to gastric cancer in Chinese Han population. AB - This study aims to evaluate whether the c.1471G > A and c.1686C > G genetic polymorphisms of XRCC1 gene influencing gastric cancer susceptibility. A total of 813 subjects with Chinese Han ethnicity were enrolled. Our data suggest that the allele and genotype frequencies are significantly different from gastric cancer patients with cancer-free controls. We find that c.1471G > A and c.1686C > G genetic polymorphisms statistically increase the risk of gastric cancer. Our findings indicate these two genetic polymorphisms are related with the susceptibility to gastric cancer, and could be used as molecular markers for detecting gastric cancer in Chinese Han ethnicity. PMID- 23919820 TI - Dynamics of telomere length in different age groups in a Latvian population. AB - The shortening of telomeres with ageing is a well-documented observation; however, the reported number of nucleotides in telomeres varies between different laboratories and studies. Such variability is likely caused by ethnic differences between the populations studied. Until now, there were no studies that investigated the variability of telomere length in a senescent Latvian population of the most common mitochondrial haplogroups, defined as H (45%), U (25%), Y chromosomal N1c (40%) and R1a1 (40%). Telomere length was determined in 121 individuals in different age groups, including a control group containing individuals of 20-40 years old and groups of individuals between 60-70 years old, 71-80 years old, 81-90 years old, and above 90 years old. Telomere length was determined using the Southern blot telomeric restriction fragment assay (TRF). Decreased telomere length with ageing was confirmed, but a comparison of centenarians and individuals between 60-90 years of age did not demonstrate a significant difference in telomere length. However, significant variability in telomere length was observed in the control group, indicating probable rapid telomere shortening in some individuals that could lead up to development of health status decline appearing with ageing. Telomere length measured in mononuclear blood cells (MNC) was compared with the telomere length measured in whole peripheral white blood cells (WBC) using TRF. Telomere length in MNC was longer than in WBC for the control group with individuals 20 to 40 years old; in contrast, for the group of individuals aged 65 to 85 years old, measured telomere length was shorter in MNC when compared to WBC. PMID- 23919821 TI - Random walk on a leash: a simple single-molecule diffusion model for surface tethered redox molecules with flexible linkers. AB - We develop a random walk model to simulate the Brownian motion and the electrochemical response of a single molecule confined to an electrode surface via a flexible molecular tether. We use our simple model, which requires no prior knowledge of the physics of the molecular tether, to predict and better understand the voltammetric response of surface-confined redox molecules when motion of the redox molecule becomes important. The single molecule is confined to a hemispherical volume with a maximum radius determined by the flexible molecular tether (5-20 nm) and is allowed to undergo true three-dimensional diffusion. Distance- and potential-dependent electron transfer probabilities are evaluated throughout the simulations to generate cyclic voltammograms of the model system. We find that at sufficiently slow cyclic voltammetric scan rates the electrochemical reaction behaves like an adsorbed redox molecule with no mass transfer limitation; thus, the peak current is proportional to the scan rate. Conversely, at faster scan rates the diffusional motion of the molecule limits the simulated peak current, which exhibits a linear dependence on the square root of the scan rate. The switch between these two limiting regimes occurs when the diffusion layer thickness, (2Dt)(1/2), is ~10 times the tether length. Finally, we find that our model predicts the voltammetric behavior of a redox-active methylene blue tethered to an electrode surface via short flexible single stranded, polythymine DNAs, allowing the estimation of diffusion coefficients for the end-tethered molecule. PMID- 23919823 TI - Deriving indicators for breast conserving surgery using finite element analysis. AB - Breast conserving therapy (BCT), comprising a complete surgical excision of the tumour (partial mastectomy) with post-operative radiotherapy to the remaining breast tissue, is feasible for most women undergoing treatment for breast cancer. The goal of BCT is to achieve local control of the cancer, as well as to preserve a breast that satisfies a woman's cosmetic concerns. Although most women undergo partial mastectomy with satisfactory cosmetic results, in many patients the remaining breast is left with major cosmetic defects including concave deformities, distortion of the nipple-areolar complex, asymmetry and changes in tissue density characterised by excessive density associated with parenchymal scarring, as well as breast pain. There are currently no tools, other than surgical experience and judgement, which can predict the impact of partial mastectomy on the contour, the deformity of the treated breast and the mechanical stress that it induces. In this study, we use a finite element model to execute virtual surgery and carry out a sensitivity analysis on the resection location, the resection size, the breast tissue mechanical property and the different post surgery recovery stage. We output the result in two different built-in indicators labelled as the cosmetic and the functional indicators. This study used the breast model for three women with breast cancer who have been elected to undergo BCT and are being treated at the Methodist Hospital in Houston, TX. The goal of this study was to propose a first glimpse of the key parameter leading to satisfactory post-BCT cosmetic results. PMID- 23919824 TI - Ligand-protein interactions of selective casein kinase 1delta inhibitors. AB - Casein kinase 1delta (CK1delta) and 1epsilon (CK1epsilon) are believed to be necessary enzymes for the regulation of circadian rhythms in all mammals. On the basis of our previously published work demonstrating a CK1epsilon-preferring compound to be an ineffective circadian clock modulator, we have synthesized a series of pyrazole-substitued pyridine inhibitors, selective for the CK1delta isoform. Additionally, using structure-based drug design, we have been able to exploit differences in the hinge region between CK1delta and p38 to find selective inhibitors that have minimal p38 activity. The SAR, brain exposure, and the effect of these inhibitors on mouse circadian rhythms are described. The in vivo evaluation of these inhibitors demonstrates that selective inhibition of CK1delta at sufficient central exposure levels is capable of modulating circadian rhythms. PMID- 23919825 TI - Low Usutu virus seroprevalence in four zoological gardens in central Europe. AB - BACKGROUND: Usutu virus (USUV), a mosquito-borne flavivirus of the Japanese encephalitis virus antigenic group, caused bird die-offs in Austria, Hungary and Switzerland between 2001 and 2009. While the zoological gardens of Vienna and Zurich recorded USUV-associated mortality in different species of birds during this period, incidences in Budapest were limited to areas outside the zoo, and in the greater Basel area avian mortality due to USUV infection was not observed at all. The objectives of this investigation were to gain insight into USUV infection dynamics in captive birds in zoos with varying degrees of virus exposure and to study differences in susceptibility to USUV of different species of birds. RESULTS: 372 bird sera were collected between October 2006 and August 2007. The samples were tested in parallel by hemagglutination inhibition (HI) and 90% plaque reduction neutralization tests (PRNT-90). 8.75%, 5.3% and 6.59% of birds in the zoos of Vienna, Zurich and Basel, respectively, showed USUV-specific antibodies by PRNT-90. No antibodies to USUV were detected in birds of the Budapest zoo. The order Strigiformes (owls) exhibited the highest USUV seroprevalence, compared to other orders of birds. CONCLUSIONS: USUV seems not to pose an imminent threat to zoo bird populations in central Europe at the moment. Depending on a variety of especially environmental factors, however, this may change at any time in the (near) future, as experienced with West Nile virus (WNV). It is therefore strongly suggested to continue with combined WNV and USUV surveillance activities in affected areas. PMID- 23919826 TI - Routine cervical length and fetal fibronectin screening in asymptomatic twin pregnancies: is there clinical benefit? AB - OBJECTIVE: To determine whether routine cervical length (CL) and fetal fibronectin (fFN) screening is associated with improved clinical outcomes in asymptomatic patients with twin pregnancies. STUDY DESIGN: We compared outcomes between two large cohorts of twin pregnancies who delivered in New York City from 2003 to 2012. One cohort (n = 532) was managed by a single group practice, delivered at one large academic medical center, and underwent routine serial CL and fFN screening. The second cohort (n = 456) delivered at a second large academic center and only underwent CL and fFN testing as clinically indicated. Outcomes measured include cerclage placement, preterm birth (PTB), spontaneous PTB (sPTB), and antenatal corticosteroid (ACS) exposure. RESULTS: Rates of cerclage placement, PTB, and SPTB were similar between the two groups. However, routine CL and fFN screening was associated with improved rates of ACS exposure in patients who delivered <34 weeks (91.3% versus 74.7%, p = 0.005) and 34-36 6/7 weeks (41.3% versus 13.9%, p < 0.001) without increased ACS exposure in women who delivered at term. In patients who delivered <34 weeks, routine CL and fFN screening was significantly associated with improved rates of ACS exposure within 1-14 days of delivery and within 1-7 days of delivery. CONCLUSION: In twin pregnancies, routine CL and fFN screening does not reduce the risk of PTB or SPTB. However, the routine use of these tests is associated with significantly improved ACS exposure and timing for women who deliver preterm without increasing ACS exposure to women who deliver at term. PMID- 23919827 TI - Clinical and genetic characteristics of Chinese patients with hereditary haemorrhagic telangiectasia-associated pulmonary hypertension. AB - BACKGROUND: Mutations in activin receptor-like kinase-1 (ACVRL-1) or endoglin (ENG) are mostly identified in patients with hereditary haemorrhagic telangiectasia (HHT) associated with pulmonary hypertension (PH), but have not yet been studied in Chinese patients. MATERIAL AND METHODS: In this study, we investigated the clinical and molecular genetic features of Chinese patients with HHT-associated PH and analysed genotype/phenotype correlations in 14 probands and their relatives. Mutation analyses in ACVRL-1, bone morphogenetic protein receptor type 2 (BMPR2) and ENG were performed in 14 Chinese Han patients with HHT-associated PH. RESULTS: The overall mutation rate was 71.4%, including 8 ACVRL-1 mutations and 2 ENG mutations, 6 of which were novel. Six patients were identified with arteriovenous malformations (AVMs), including four patients with pulmonary AVMs and two patients with liver AVMs. Five of the patients with AVMs were identified with mutations. Most patients received targeted therapy for PH. CONCLUSIONS: Our findings have revealed the clinical phenotype and molecular genetic features of HHT-associated PH in Chinese Han patients and indicate that mutations of ACVRL-1 and ENG are genetic predisposing factors in Chinese patients. Our data further addressed clinical management and have provided limited experience in treating this group of disorders. PMID- 23919828 TI - Communication factors-promising targets in osteoporosis treatment. AB - Osteoporosis is one of the most serious under-diagnosed and under-treated recessive diseases, leading to increased mortality and morbidity as well as huge economic burden. The fundamental reason for the occurrence of osteoporosis lies in the disequilibrium between bone resorption mediated by osteoclasts and bone formation mediated by osteoblasts. Osteoclast-osteoblast communication plays important roles in the maintenance of hemeostasis. In this review, we present the detailed mechanisms of this communication, including modes of diffusible paracrine factors, cell-cell direct contact and cell-bone matrix interaction. We demonstrate that osteoclasts (or osteoblasts) could not only secrete cytokines, growth factors, chemokines and function in a paracrine manner, but also express molecules on their membranes to bind to the receptors on osteoblasts (or osteoclasts) to transduce bidirectional signals. Moreover, growth factors and cytokines deliberated from bone matrix during bone resorption could also regulate the function of both osteoblasts and osteoclasts. This review gives the latest knowledge of communication factors, some of which are emerging as novel therapeutic targets for future development of antiosteoporotic drugs. PMID- 23919829 TI - Protection against hyperoxia-induced lung fibrosis by KGF-induced MSCs mobilization in neonatal rats. AB - MSCs have been shown to improve functional and pathological outcome in lung fibrosis. However, low in vivo cell engraftment of the transplanted cells limits their overall effectiveness. KGF (also known as FGF-7) is a critical mediator of pulmonary epithelial repair through stimulation of epithelial cell proliferation. However, the role of KGF in MSCs and its therapeutic effects have not been identified. In this study, we investigated the effect of KGF on MSCs and its preventive role in hyperoxia-induced fibrosis in neonatal rats. Neonatal rats exposed to normoxia or hyperoxia were randomly assigned to receive intraperitoneal injections of normal saline (PL), MSCs, or KGF pretreated MSCs on the fourth day of exposure. Our results showed that as compared to PL, while MSCs attenuated lung fibrosis, KGF pretreated MSCs exhibited enhanced preventive effect against lung fibrosis. This effect was partly attributed to enhanced mobilization of MSCs to the fibrotic lungs. In addition, the SHH signaling pathway, which is associated with the differentiation of stem cells was activated by KGF. Our data suggest that MSCs, especially KGF preconditioned MSCs, can attenuate lung fibrosis and KGF may regulate the MSCs behavior by activating SHH pathway. PMID- 23919830 TI - Imaging diagnosis--extrahepatic biliary tract obstruction secondary to a biliary foreign body in a cat. AB - An 11-year-old, neutered female British Shorthair cat was referred with a 4-week history of abdominal pain and vomiting. Abdominal ultrasonography revealed a dilated common bile duct containing a spindle-shaped structure with several reflecting interfaces. Differentials that were considered included an intraluminal foreign body, or helminth parasites within the common bile duct. Surgical exploration of the abdominal cavity demonstrated the presence of two grass awns obstructing the common bile duct. Anomalies of the portal vasculature were noted during surgery and were considered an incidental finding. The clinical signs resolved following surgical removal of the grass awns. PMID- 23919831 TI - Three-stage biochemical selection: cloning of prototype class IIS/IIC/IIG restriction endonuclease-methyltransferase TsoI from the thermophile Thermus scotoductus. AB - BACKGROUND: In continuing our research into the new family of bifunctional restriction endonucleases (REases), we describe the cloning of the tsoIRM gene. Currently, the family includes six thermostable enzymes: TaqII, Tth111II, TthHB27I, TspGWI, TspDTI, TsoI, isolated from various Thermus sp. and two thermolabile enzymes: RpaI and CchII, isolated from mesophilic bacteria Rhodopseudomonas palustris and Chlorobium chlorochromatii, respectively. The enzymes have several properties in common. They are large proteins (molecular size app. 120 kDa), coded by fused genes, with the REase and methyltransferase (MTase) in a single polypeptide, where both activities are affected by S adenosylmethionine (SAM). They recognize similar asymmetric cognate sites and cleave at a distance of 11/9 nt from the recognition site. Thus far, we have cloned and characterised TaqII, Tth111II, TthHB27I, TspGWI and TspDTI. RESULTS: TsoI REase, which originate from thermophilic Thermus scotoductus RFL4 (T. scotoductus), was cloned in Escherichia coli (E. coli) using two rounds of biochemical selection of the T. scotoductus genomic library for the TsoI methylation phenotype. DNA sequencing of restriction-resistant clones revealed the common open reading frame (ORF) of 3348 bp, coding for a large polypeptide of 1116 aminoacid (aa) residues, which exhibited a high level of similarity to Tth111II (50% identity, 60% similarity). The ORF was PCR-amplified, subcloned into a pET21 derivative under the control of a T7 promoter and was subjected to the third round of biochemical selection in order to isolate error-free clones. Induction experiments resulted in synthesis of an app. 125 kDa protein, exhibiting TsoI-specific DNA cleavage. Also, the wild-type (wt) protein was purified and reaction optima were determined. CONCLUSIONS: Previously we identified and cloned the Thermus family RM genes using a specially developed method based on partial proteolysis of thermostable REases. In the case of TsoI the classic biochemical selection method was successful, probably because of the substantially lower optimal reaction temperature of TsoI (app. 10-15 degrees C). That allowed for sufficient MTase activity in vivo in recombinant E. coli. Interestingly, TsoI originates from bacteria with a high optimum growth temperature of 67 degrees C, which indicates that not all bacterial enzymes match an organism's thermophilic nature, and yet remain functional cell components. Besides basic research advances, the cloning and characterisation of the new prototype REase from the Thermus sp. family enzymes is also of practical importance in gene manipulation technology, as it extends the range of available DNA cleavage specificities. PMID- 23919832 TI - Expected and unexpected transformations of manganese(III) tris(4 nitrophenyl)corrole. AB - The synthesis and characterization of manganese complexes of 5,10,15-tris(4 nitrophenyl) corrole in different oxidation states are described. Adoption of established protocols for the synthesis of (nitrido)manganese(V) complexes led to the expected corrole derivative as a minor product, accompanied by nitrogen atom insertion into the macrocycle. The major product was fully characterized via the combination of spectroscopy and X-ray crystallography as (nitrido)manganese(V) 6 azahemiporphycene. PMID- 23919833 TI - Impact of dissociation constant on the detection sensitivity of polymerization based signal amplification reactions. AB - Many studies have demonstrated the concept of using free-radical polymerization reactions to provide signal amplification so that molecular recognition events indicative of disease states may be detected in a simple and low-cost manner. We provide the first systematic study of how the dissociation constant impacts detection sensitivity in these assays, having chosen a range of dissociation constants (nanomolar to picomolar) that is typical of those encountered in molecular diagnostic applications that detect protein-protein binding events. In addition, we use experimental results to validate a mass-action kinetic model that may be used to predict assay performance as an alternative or supplement to the empirical approach to developing new polymerization-based amplification assays that has characterized the field to date. PMID- 23919834 TI - A transition-metal-free synthesis of arylcarboxyamides from aryl diazonium salts and isocyanides. AB - A transition-metal-free carboxyamidation process, using aryl diazonium tetrafluoroborates and isocyanides under mild conditions, has been developed. This novel conversion was initiated by a base and solvent induced aryl radical, followed by radical addition to isocyanide and single electron transfer (SET) oxidation, affording the corresponding arylcarboxyamide upon hydration of the nitrilium intermediate. PMID- 23919836 TI - Anti-correlated cortical networks of intrinsic connectivity in the rat brain. AB - In humans, resting-state blood oxygen level-dependent (BOLD) signals in the default mode network (DMN) are temporally anti-correlated with those from a lateral cortical network involving the frontal eye fields, secondary somatosensory and posterior insular cortices. Here, we demonstrate the existence of an analogous lateral cortical network in the rat brain, extending laterally from anterior secondary sensorimotor regions to the insular cortex and exhibiting low-frequency BOLD fluctuations that are temporally anti-correlated with a midline "DMN-like" network comprising posterior/anterior cingulate and prefrontal cortices. The primary nexus for this anti-correlation relationship was the anterior secondary motor cortex, close to regions that have been identified with frontal eye fields in the rat brain. The anti-correlation relationship was corroborated after global signal removal, underscoring this finding as a robust property of the functional connectivity signature in the rat brain. These anti correlated networks demonstrate strong anatomical homology to networks identified in human and monkey connectivity studies, extend the known preserved functional connectivity relationships between rodent and primates, and support the use of resting-state functional magnetic resonance imaging as a translational imaging method between rat models and humans. PMID- 23919837 TI - Different interfacial behaviors of N- and C-terminus cysteine-modified cecropin P1 chemically immobilized onto polymer surface. AB - Sum frequency generation (SFG) vibrational spectroscopy and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) were used to investigate the orientation of N-terminus cysteine-modified cecropin P1 (cCP1) at the polystyrene maleimide (PS-MA)/peptide phosphate buffer solution interface. The cCP1 cysteine group reacts with the maleimide group on the PS-MA surface to chemically immobilize cCP1. Previously, we found that the C-terminus cysteine modified cecropin P1 (CP1c) molecules exhibit a multiple-orientation distribution at the PS-MA/peptide phosphate buffer solution interface, due to simultaneous physical adsorption and chemical immobilization of CP1c on the PS-MA surface. Differently, in this research, it was found that the interfacial orientation of cCP1 molecules varied from a horizontal orientation to the "tilting" orientation to the "standing up" orientation and then to the "multiple-orientation" distribution as the peptide concentration increased from 0.19 to 3.74 MUM. This research shows the different interaction mechanisms between CP1c and PS-MA and between cCP1 and PS-MA. PMID- 23919835 TI - Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon. AB - Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose-response and a small therapeutic window, treatment with coumarin derivatives is challenging. Certain polymorphisms in CYP2C9 and VKORC1 are associated with lower dose requirements and a higher risk of bleeding. In this review we describe the use of different coumarin derivatives, pharmacokinetic characteristics of these drugs and differences amongst the coumarins. We also describe the current clinical challenges and the role of pharmacogenetic factors. These genetic factors are used to develop dosing algorithms and can be used to predict the right coumarin dose. The effectiveness of this new dosing strategy is currently being investigated in clinical trials. PMID- 23919838 TI - C-reactive protein and incident diabetes in patients with arterial disease. AB - INTRODUCTION: Systemic low-grade inflammation, as measured by high-sensitive C reactive protein (hsCRP), may contribute to the risk of type 2 diabetes in patients with manifest arterial disease. METHODS: Cohort study in 4072 patients with manifest arterial disease without diabetes. The relation between quartiles of hsCRP and type 2 diabetes was assessed with Cox regression analyses, taking age, smoking and blood pressure-lowering medication and lipid-lowering medication into account. Insulin resistance was estimated with homeostasis model of insulin resistance (HOMA-IR). In exploratory models, adjustments were performed for body mass index (BMI) and visceral and subcutaneous adipose tissue thickness. RESULTS: During a median follow-up of 5.0 (IQR 2.5-8.2) years, 288 subjects developed diabetes. High hsCRP was independently associated with incident diabetes (Q4 vs. Q1 males: HR 1.62; 95% CI 1.06-2.48; females: HR 3.12; 95% CI 1.57-6.21). HOMA-IR at baseline is related to hsCRP plasma levels (Q4 vs. Q1: males: beta 0.27; 95% CI 0.19-0.36; females: beta 0.35; 95% CI 0.22-0.48). The risk of diabetes associated with hsCRP was abolished in males (Q4 vs. 1 HR 1.23; 95% CI 0.80-1.88) and attenuated in females (Q4 vs. 1 HR 2.32; 95% CI 1.14-4.75) after adding BMI to the model, but not modified by statin use (P for interaction: 0.61). CONCLUSIONS: Patients with manifest arterial disease with high hsCRP plasma levels are at increased risk to develop type 2 diabetes and are more insulin resistant as compared to those with low hsCRP levels. This increase in risk is more pronounced in females than in males and is not modified by statin use. PMID- 23919840 TI - Well-circumscribed type of intramuscular lipoma in the chest wall. AB - A tumor shadow was identified in the chest X-ray of a 40-year-old Korean man and he was referred to our hospital. The computed tomographic (CT) scan of his chest showed a 3-cm rounded pleural-based mass lesion with calcification, which was growing into the intercostal muscles. Thoracoscopic surgery was performed to resect the tumor. From the histological findings, the tumor was diagnosed as an intramuscular lipoma. The patient displayed no evidence of recurrence for more than 18 months. As well-circumscribed type of intramuscular lipoma is a rare tumor, we report this case with a literature review in this paper. PMID- 23919839 TI - An economic evaluation for prevention of diabetes mellitus in a developing country: a modelling study. AB - BACKGROUND: The serious consequences of diabetes mellitus, and the subsequent economic burden, call for urgent preventative action in developing countries. This study explores the clinical and economic outcomes of strategies that could potentially prevent diabetes based on Chinese circumstances. It aims to provide indicators for the long-term allocation of healthcare resources for authorities in developing countries. METHODS: A representative sample of Chinese adults was used to create a simulated population of 20,000 people aged 25 years and above. The hybrid decision tree Markov model was developed to compare the long-term clinical and economic outcomes of four simulated diabetes prevention strategies with a control group, where no prevention applied. These preventive strategies were the following: (i) one-off screening for undiagnosed diabetes and impaired glucose tolerance (IGT), with lifestyle interventions on diet, (ii) on exercise, (iii) on diet combined exercise (duo-intervention) respectively in those with IGT, and (iv) one-off screening alone. Independent age-specific models were simulated based on diverse incidences of diabetes, mortalities and health utilities. The reported outcomes were the following: the remaining survival years, the quality-adjusted life years (QALYs) per diabetes or IGT subjects, societal costs per simulated subject and the comparisons between preventions and control over 40 years. Sensitivity analyses were performed based on variations of all assumptions, in addition to the performance and the compliance of screening. RESULTS: Compared with the control group, all simulated screening programmes prolonged life expectancy at the initiation ages of 25 and 40 years, postponed the onset of diabetes and increased QALYs at every initiation age. Along with an assumption of six years intervention, prevention programmes were associated with cost-saving compared with the control group, especially in the population aged 25 years. The savings were at least US$2017 per subject, but no statistically significant difference was observed among the intervention strategies within each age groups. The cost savings were reduced when screening was affected by poor performance and noncompliance. CONCLUSIONS: Developing countries have few effective strategies to manage the prevention of diabetes. One-off screening for undiagnosed diabetes and IGT, with appropriate lifestyle interventions for those with IGT are cost saving in China, especially in young adults. PMID- 23919841 TI - Forkhead box protein C2 contributes to invasion and metastasis of extrahepatic cholangiocarcinoma, resulting in a poor prognosis. AB - Extrahepatic cholangiocarcinoma (EHCC) is a cancer with a poor prognosis, and the postoperative survival of patients depends on the existence of invasion and metastasis. The epithelial-to-mesenchymal transition (EMT) is an important step in EHCC invasion and metastasis. Forkhead box protein C2 (FOXC2) is a transcription factor that has been reported to induce the EMT. Therefore we examined the correlation between FOXC2 expression and clinical pathological factors, and analysed the function of FOXC2. The expression of FOXC2 in 77 EHCC cases was investigated by immunohistochemical staining, and the relationship between FOXC2 expression and clinicopathological factor was assessed. Knockdown by small interfering RNA (siRNA) was performed to determine the roles of FOXC2 in EHCC cell line. FOXC2 expression correlated with lymph node metastasis (P = 0.0205). Patients in the high FOXC2 expression group had a poorer prognosis than the patients in the low FOXC2 expression group. Moreover, FOXC2 knockdown inhibited cell motility and invasion, and decreased the expression of EMT markers (N-cadherin, and matrix metalloproteinase (MMP) -2) and Angiopietin-2 (Ang-2). The EMT inducer FOXC2 contributes to a poor prognosis and cancer progression. FOXC2 may be a promising molecular target for regulating EHCC metastasis. PMID- 23919843 TI - Meeting report: 2nd international conference: antibody incompatible transplantation and transplant infectious disease. AB - The 2nd International Conference on Antibody Incompatible Transplantation and Transplant Infectious Disease took place at the University of Warwick on 23rd and 24th November 2012. The aims of the meeting were to discuss the pertinent clinical and laboratory issues surrounding antibody incompatible transplantation and to provide a contemporary analysis of transplant infectious disease. This report summarises the key points discussed at the meeting. PMID- 23919842 TI - Association between APOE, SCARB1, PPARalpha polymorphisms and serum lipids in a population of Lithuanian adults. AB - BACKGROUND: Dyslipidemia is one of several known risk factors for coronary heart disease, a leading cause of death in Lithuania. Blood lipid levels are influenced by multiple genetic and environmental factors. Epidemiological studies demonstrated the impact of nutrition on lipid levels within the Lithuanian population although the role of genetic factors for dyslipidemias has not yet been studied. The objective of this study was to assess the distribution of the APOE, SCARB1, PPARalpha genotypes in the Lithuanian adult population and to determine the relationship of these genotypes with dyslipidemia. METHODS: A cross sectional health survey was carried out in a representative random sample of the Lithuanian population aged 25-64 (n=1030). A variety of single-nucleotide polymorphisms (SNPs) of the APOE (rs429358 and rs7412), SCARB1 (rs5888) and PPARalpha (rs1800206) genes were assessed using real-time polymerase chain reaction. Serum lipids were determined using enzymatic methods. RESULTS/PRINCIPAL FINDINGS: Men and women with the APOE2 genotype had the lowest level of total and low-density lipoprotein cholesterol (LDL-C). Men with the APOE2 genotype had significantly higher levels of triglycerides (TG) than those with the APOE3 genotype. In men, the carriers of the APOE4 genotype had higher odds ratios (OR) of reduced (<1.0 mmol/L) high density lipoprotein cholesterol (HDL-C) levels versus APOE3 carriers (OR=1.98; 95% CI=1.05-3.74). The odds of having elevated (>1.7 mmol/L) TG levels was significantly lower in SCARB1 genotype CT carriers compared to men with the SCARB1 genotype CC (OR=0.50; 95% CI=0.31-0.79). In men, carriers of the PPARalpha genotype CG had higher OR of elevated TG levels versus carriers of PPARalpha genotype CC (OR=2.67; 95% CI=1.15-6.16). The odds of having high LDL-C levels were lower in women with the APOE2 genotype as compared to APOE3 genotype carriers (OR=0.35; 95% CI=0.22-0.57). CONCLUSIONS/SIGNIFICANCE: Our data suggest a gender difference in the associations between APOE, SCARB1, PPARalpha genotypes and lipid levels. In men, the APOE4 genotype and PPARalpha genotype CG were correlated with an atherogenic lipid profile while the SCARB1 genotype CT had an atheroprotective effect. In women, APOE2 carriers had the lowest odds of high LDL-C. PMID- 23919844 TI - Enhanced recovery programmes: do these have a role in gynaecology? AB - Enhanced recovery (ER) has become increasingly ubiquitous in most surgical specialities and its use is gathering pace. It has been proven to be a safe and effective means of managing patients perioperatively, while also improving patient outcomes, and its use in gynaecology has recently been supported by the Royal College of Obstetricians and Gynaecologists (RCOG). ER is gaining popularity, despite being a diversion from the traditional surgical approach, demanding an orchestration of primary, secondary, social and auxillary care teams to work effectively. ER has been heralded as improving clinical outcomes and patient satisfaction, while simultaneously allowing increased patient turnover. This has potentially massive impacts on service provision within the NHS and is likely to become a proof of concept that the NHS can adapt. ER can be championed as a flexible and contemporary healthcare model, which can be improved as patients' needs and NHS resources change. PMID- 23919845 TI - Renal angiomyolipoma and lymphangioleiomyomatosis in pregnancy. AB - This is a literature review for management of angiomyolipoma (AML), lymphangioleiomyomatosis (LAM) and tuberous sclerosis (TS) during pregnancy, prompted by a case of a 23-year-old woman who presented with generalised itching at 31 weeks' gestation and was found to have a large vascular retroperitoneal mass in the lower pole of the left kidney. Magnetic resonance imaging (MRI) was suggestive of angiomyolipoma with multiple large aneurysms and haemorrhage within the tumour. She was delivered at 38 weeks by elective caesarean section, to avoid the risk of rupture and bleeding from the aneurysms during labour. Further imaging, with MR angiogram, computed tomography (CT) of the abdomen and pelvis and high resolution CT (HRCT) of the chest, confirmed lymphangioleiomyomatosis with left AML. She had embolisation of the AML performed twice, 8 weeks apart after delivery and subsequently had a left nephrectomy. PMID- 23919847 TI - Training the trainees: an evaluation exercise using the TLH and BSO model. AB - Our aim was to evaluate surgical training in gynaecological oncology by assessing the time required by a trainee to complete a single laparoscopic gynaecologic oncological operation. A total of 135 patients with a BMI < 40 kg/m2, diagnosed with endometrial cancer, underwent a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy (TLH and BSO). Patients in Group I (n = 78) were operated on by a consultant gynaecological oncology surgeon and in Group II (n = 57) by sub-specialist trainees (SSTs). The mean patient age and BMI was 63.5 years and 29.6 kg/m2, respectively, in Group I and 64.5 years and 29.9 kg/m2, respectively, in Group II. Median operating times for Groups I and II were 58 and 90 min, respectively (p < 0.05). Furthermore, significant improvement was noted when comparing the average operating time between the first and second half of SST training. Even experienced gynaecological trainees take significantly longer to perform a reproducible laparoscopic operation. At the completion of training, an SST demonstrates improvement with respect to operation duration but is still not as fast as the trainer. PMID- 23919848 TI - Foundation doctors' views of medical professionalism. AB - The views of Foundation Years 1 and 2 doctors on medical professionalism were investigated using focus groups, in respect of definitions and components, teaching, learning and assessment. They were able to define and identify the components of medical professionalism, as well as components that could be taught. They felt medical professionalism was poorly taught and assessed. They recognised the dangers the online environment posed to medical professionalism but felt public expectations for doctors could at times be unrealistic. The profile, teaching and assessment of medical professionalism need to be improved. This can be achieved by teaching and assessing it as a standalone entity rather that within medical ethics as it is currently taught, and raising its profile to that of academic subjects. PMID- 23919849 TI - Characteristics of women with nausea and vomiting of pregnancy who chose to continue compassionate use of placebo after a randomised trial. AB - The placebo effect has not been characterised in pregnant women suffering from nausea and vomiting of pregnancy (NVP). Our aim was to characterise determinants of the placebo effect in women treated with placebo for NVP. We analysed data from a multicentre, double blind randomised controlled trial of Diclectin (delayed release doxylamine and pyridoxine) vs placebo for the treatment of NVP. A total of 127 women in the placebo arm and 130 in the active arm provided evaluable data for this analysis. Women who chose to continue placebo on a compassionate basis (n = 41) had significantly better improvement in symptoms of NVP and higher Wellbeing scores than those who did not ask to continue compassionate use. Results were similar in the active drug arm. The request to continue compassionate use of either placebo or active drug could be predicted by greater improvement in symptoms of NVP during the trial period. PMID- 23919850 TI - Early clinical characteristics and pregnancy outcomes of patients with influenza A (H1N1) infection requiring mechanical ventilation during pregnancy. AB - The early clinical characteristics and pregnancy outcomes of H1N1-infected pregnant women with or without mechanical ventilation were compared. In H1N1 infected pregnant women with mechanical ventilation, the gestational age was greater, the early oxygenation index was lower and early-stage pneumonic lesions were wider than patients without mechanical ventilation. Moreover, compared with the non-mechanical ventilation group, the incidence of the adverse pregnancy outcomes was higher in the mechanical ventilation group. PMID- 23919851 TI - A comparative study of positive rate of placental alpha-microglobulin-1 test in pre-term pregnant women with and without uterine contraction. AB - The aim of this study was to compare positive placental alpha-microglobulin-1 (PAMG-1) test rates with clinical significance of pre-term pregnant women, intact membrane with and without uterine contraction. A prospective analytic study was performed including 100 pre-term pregnant women with intact membranes. Patients were classified into two groups, patients with uterine contraction (n = 50) and patients without contraction (n = 50). Conventional standard methods were performed to exclude rupture of membranes. PAMG-1 test was performed. Positive results of the tests and clinical significance (including time from test to delivery, route of delivery and outcomes of the fetuses) were determined. PAMG-1 positive rate was 10% (5/50) and 0% in contraction group and no contraction group, respectively (p = 0.028). Gestational age at delivery and test-to-delivery interval were less in contraction group than those in no-contraction group. When compared between positive test (n = 5) and negative test (n = 45) in pre-term contraction. Test-to-delivery interval was shorter positive group (20 vs. 720 h, p = 0.025). In conclusion, in pre-term pregnant women with intact membranes, PAMG 1 test rates are more positive in cases of uterine contraction. Pre-term pregnant women in labour with a positive PAMG-1 test had a significantly shorter test-to delivery interval than those with a negative test. PMID- 23919852 TI - Maternal and perinatal outcome in pregnancies complicated by uterine cervical prolapse. AB - Uterine cervical prolapse is extremely rare during pregnancy and may predispose patients to serious complications, including maternal death. Four patients are presented here: two patients had pre-existing prolapse and the other two developed prolapse during pregnancy. All the patients required hospitalisation due to threatened pre-term labour. Two patients were delivered via caesarean section at term due to obstetrical complications, but the others delivered spontaneously. In a case of uterine cervical prolapse lasting until term, hospitalisation with bed rest, anti-tocolytic agents and genital hygiene may protect the cervix, resulting in favourable maternal and fetal prognoses. PMID- 23919853 TI - Effect of the Foley catheter and synchronous low dose misoprostol administration on cervical ripening: a randomised controlled trial. AB - This randomised controlled trial was carried out over a 14-month period in a tertiary health institution in Nigeria, to determine the effectiveness of Foley catheter and synchronous low dose misoprostol for pre-labour cervical ripening. Term pregnant women with unfavourable cervices (Bishop's score < 6) requiring cervical ripening/induction of labour were assigned randomly into three groups: Group A, transcervical Foley catheter was used synchronously with low dose intravaginal misoprostol; Group B, transcervical Foley catheter alone was used and Group C, low dose intravaginal misoprostol alone was used. The time to achieve a favourable cervical status as well as vaginal delivery was significantly shorter in the synchronous group than in the control groups (p < 0.05). The synchronous use of Foley catheter and misoprostol is very effective in cervical ripening and should be considered in clinical situations where there is need to hasten vaginal delivery in the presence of an unripe cervix. PMID- 23919854 TI - Perinatal outcome of pre-eclampsia in parous women. AB - Women with a second and recurrent pre-eclampsia pregnancy have more adverse pregnancy outcomes compared with women with pre-eclampsia in the first pregnancy. A retrospective cohort study was performed to compare the clinical characteristics and perinatal outcomes of pre-eclampsia in parous women who had complicated pre-eclampsia in previous pregnancies (n = 69) and uncomplicated pre eclampsia in previous pregnancies (n = 312) from 2006 to 2010, in the Fujian Maternity and Child Health Hospital. No statistical significant differences were observed between the two groups in terms of: maternal age, admission blood pressure and BMI; prenatal care times, hospitalisation time, laboratory results and incident rates of complications. The incident and delivery weeks were earlier and the renal injury, caesarean section and small for gestational age (SGA) incidence rates were higher in recurrent pre-eclampsia women. Women with recurrent pre-eclampsia had adverse perinatal outcomes when compared with parous women with pre-eclampsia who had not had pre-eclampsia in prior pregnancies. PMID- 23919855 TI - Obstetric hysterectomy: trend and outcome in Ile-Ife, Nigeria. AB - Worldwide, the incidence of obstetric hysterectomy is expected to be on the decline due to improvements in obstetric care. This hospital-based 10-year review (2001-10) was performed to determine its incidence and outcome in Ile-Ife, Nigeria. The trend was determined by comparing the current incidence with that from two previous studies from the same centre. There were 58 obstetric hysterectomies and 15,194 deliveries during the review period, giving a rate of 3.8/1,000 deliveries. A rising trend was observed in the obstetric hysterectomy rate in Ile-Ife over two decades (1990-2010). Uterine rupture was the commonest indication (60%). Postoperative complications such as sepsis, vesico-vaginal fistula and renal failure affected 34.5% of the patients. Maternal and fetal case fatality rates were 18.2% and 43.6%, respectively. The obstetric hysterectomy rate in Ile-Ife is high and the trend is rising. Universal access to skilled birth attendance is advocated to reduce uterine rupture and consequently obstetric hysterectomy. PMID- 23919856 TI - Hormonal and histological changes in the ovaries with high-doses of methylprednisolone administration for acute spinal cord injury: an experimental study. AB - This study was conducted to investigate the hormonal and histological changes in the ovaries with high doses of methylprednisolone administration for acute spinal cord injury (SCI). Group I (trauma group, eight rats) were subjected to laminectomy and SCI but received no treatment. Group II (steroid group, eight rats) were subjected to SCI and received methylprednisolone (30 mg/kg, intraperitoneally). Group III (control group, six rats) underwent a sham operation without trauma and treatment. Malondialdehyde (MDA) levels were significantly decreased in Group II (p < 0.05). The scores of histopathological damage of the ovaries in the three groups were found to be statistically comparable (p > 0.05). Serum anti-Mullerian hormone (AMH) levels in the steroid group was significantly lower compared with the control group (p < 0.05). High dose methylprednisolone administration may effect ovarian reserve with reversible ovarian damage and can resolve lipid peroxidation in rats with spinal cord injury. PMID- 23919857 TI - Effects of a combined oral contraceptive containing oestradiol valerate/dienogest on hormone withdrawal-associated symptoms: results from the multicentre, randomised, double-blind, active-controlled HARMONY II study. AB - The objective of this multicentre, randomised, double-blind study was to compare a combined oral contraceptive (COC) containing oestradiol valerate/dienogest (E2V/DNG) administered in a dynamic dosing regimen with a monophasic COC containing ethinyloestradiol/levonorgestrel (EE/LNG), with regard to their ability to reduce the frequency and intensity of headache and pelvic pain in women with hormone withdrawal-associated symptoms (HWAS). Women aged 18-50 years received E2V/DNG in an oestrogen step-down and progestin step-up regimen (26/2 regimen; n = 223) or EE 20 MUg/LNG 100 MUg (21/7 regimen; n = 218) over six cycles. Headache and pelvic pain were assessed using a visual analogue scale (VAS) during cycle days 22-28. Rescue medication use was also assessed. E2V/DNG was superior to EE/LNG with regard to reducing the frequency and intensity of headache and pelvic pain from baseline to cycle 6 (change from baseline in the average of the three highest VAS values [mean +/- standard deviation]: 47.7 +/- 29.4 vs 34.5 +/- 25.7 mm, respectively; p < 0.0001). The use of rescue medication was also significantly reduced with E2V/DNG compared with EE/LNG (p < 0.05). E2V/DNG may be a good option for women who experience HWAS with traditional 21/7 day regimen COCs. PMID- 23919858 TI - Differences in omega-3 and fatty acid profiles between patients with endometriosis and those with a functional ovarian cyst. AB - Endometriosis is a chronic inflammatory gynaecological disease. Problems associated with endometriosis include dysmenorrhoea, dyspareunia and infertility. We evaluated the omega-3 and fatty acid profiles in erythrocytes and tissues in patients with endometriosis (n = 10) or a functional ovarian cyst (n = 12), using a food frequency questionnaire that included questions about 117 food items typical of Korean meals. Erythrocyte levels of 20:5n3 and 22:6n3, the omega-3 index, and n-3 PUFA were significantly higher, and the n-6:n-3 ratio was significantly lower in the endometriosis group than in the functional ovarian cyst group. The functional ovarian cyst group consumed significantly more fruit than the group with endometriosis. PMID- 23919859 TI - Women's satisfaction with early home medical abortion with telephone follow-up: a questionnaire-based study in the U.K. AB - A questionnaire-based study was undertaken to assess women's satisfaction with the home medical abortion service. Over a 15-month period, questionnaires were conducted at 24 h and 2 weeks following the procedure. A total of 127 women took part in the study and filled in a questionnaire at 24 h, with 77 completing the questionnaire at 2 weeks. At 24 h, over 95% of women who responded, agreed or strongly agreed that they felt prepared for the pain and bleeding that they experienced at home. At 2 weeks, 97.3% of respondents felt that they had had enough information and knew what to expect, and were therefore satisfied with the procedure. Only 15% of women were lost to clinical follow-up at 2 weeks. The majority of women are satisfied with the home medical abortion service. These high satisfaction rates are maintained at 2 weeks. Telephone follow-up 2 weeks after the abortion was safe and effective. PMID- 23919860 TI - Morbidity from unsafe termination of pregnancy in South Africa. AB - The Termination of Pregnancy (TOP) Act in South Africa (SA) allows women to request TOP for social reasons. A retrospective record review was done on all (85) women who were admitted with complications arising from TOP over a 1-year period in 2008, at the Charlottee Maxeke Johannesburg Academic (CMJA) Hospital, SA. The demography, methods and place of TOP, presenting complications and final management was discussed. Morbidity such as severe blood loss (39%), sepsis (26%), multiple organ dysfunctions (4%) and organ injuries (5%) were observed. A correct guideline for TOP was followed in only 33% of women. Self-induced TOP remained common practice. There is a need for accelerated training among healthcare workers providing TOP in SA to prevent this costly and preventable maternal morbidity. PMID- 23919861 TI - Prospective evaluation of 125 consecutive laparoscopic myomectomies. AB - With technological advancement and increasing skill in minimal access surgery, laparoscopic myomectomy is increasingly performed for the management of symptomatic fibroids in appropriately selected women. We present a series of 125 consecutive laparoscopic myomectomies to assess whether the number, size and location of fibroids affect the length of hospital stay. Total of 462 myomas were removed from 125 patients. The mean size of fibroids removed was 7.6 cm and the mean number of fibroids was 3.69. None of our patients had major intraoperative complication involving bladder or bowel. Our laparotomy conversion rate was 1.6% (2 out of 125). There was no significant difference based on size, number or weight of fibroids removed in relation to the day of discharge in our series. We conclude that the size and number of fibroids removed do not affect the day of discharge. PMID- 23919862 TI - A comparison of abdominal and vaginal hysterectomies in Benghazi, Libya. AB - We performed a comparative study between abdominal and vaginal hysterectomies using clinical data from Al-Jamhouria hospital (one of the largest maternity hospitals in Eastern Libya). Various parameters were taken into consideration: the rates of each type (and their subtypes); average age of patients; indications; causes; postoperative complications; and duration of stay in the hospital afterwards. Conclusions and recommendations were drawn from the results of this study. In light of the aforementioned parameters, it was found that: (1) abdominal hysterectomies were more common than vaginal hysterectomies (p < 0.001); (2) patients admitted for abdominal hysterectomies are younger than those admitted for vaginal hysterectomies (p < 0.001); (3) the most common indication for an abdominal hysterectomy was menstrual disturbances, while for vaginal hysterectomies it was vaginal prolapse; (4) the histopathological cause for abdominal and vaginal hysterectomies were observed and the most common were found to be leiomyomas and atrophic endometrium; (5) there was no significant difference between the two routes in terms of postoperative complications; (6) patients who were admitted for abdominal hysterectomies spent a longer amount of time in the hospital (p < 0.01). It was concluded that efforts should be made to further pursue vaginal and laparoscopic hysterectomies as a viable option to the more conventional abdominal route. PMID- 23919863 TI - Cervical cancer screening among Michigan women: 'The Special Cancer Behavioral Risk Factor Survey', 2004-2008. AB - The burden of cervical cancer remains greater among minority women. The purpose of this study was to evaluate racial/ethnic disparities in cervical cancer screening among minority women in Michigan. Data from 8,023 women (>= 40 years) surveyed in the 2004-2008 Michigan Special Cancer Behavioral Risk Factor Survey were used to assess racial/ethnic differences in cervical cancer screening, knowledge and beliefs. Unexpectedly, African-American and Hispanic women reported being screened for cervical cancer at rates similar to, or higher than, Whites. Women demonstrated limited knowledge of cervical cancer risk factors and its signs/symptoms. Most minority women were more likely than Whites to believe in the importance of cervical screening, with Hispanic women more likely to support HPV vaccination. Differential utilisation of screening does not explain the disproportionately high rates of cervical cancer among minorities. Future research should examine disparities in the follow-up of abnormal cervical results and receipt of treatment. PMID- 23919864 TI - Loop electrosurgical excision procedure for the treatment of cervical intraepithelial neoplasia: how much excision is enough? AB - This is a retrospective observational study to compare outcomes in patients with cervical intraepithelial neoplasia (CIN) treated with loop electrosurgical excision procedure (LEEP) using combined ectocervical/endocervical resection vs ectocervical resection alone. We demonstrated that additional endocervical resection during loop electrosurgical excision procedure did not significantly lower the risk of subsequent recurrence compared with ectocervical resection alone, in the treatment of CIN. With current published data supporting subsequent increased adverse effects of LEEP on future obstetrical outcomes, endocervical excision should be applied selectively. We recommend that additional endocervical excision should be reserved only for patients with a strong suspicion of underlying endocervical canal involvement based on colposcopic assessment or in patients with unsatisfactory colposcopy, where it is essential to evaluate the endocervical canal. PMID- 23919865 TI - Intra-areolar polythelia in pregnancy: a rare anomaly. PMID- 23919866 TI - Reflection of paternal tuberous sclerosis in the fetus: cardiac rhabdomyoma. PMID- 23919867 TI - Rupture of renal angiomyolipoma in pregnancy. PMID- 23919868 TI - Second trimester rupture in a retroflexed, scarred uterus. PMID- 23919869 TI - Seizures presenting in pregnancy: eclampsia or something else? PMID- 23919870 TI - Feasibility of successful pregnancies in women with spinal injury. PMID- 23919871 TI - Pelvic abscess following frozen embryo transfer. PMID- 23919872 TI - A case of fallopian tube entrapment in a caesarean section scar. PMID- 23919873 TI - Unusual adnexal masses in adolescents and young women: massive ovarian oedema. PMID- 23919874 TI - A rare case of bilateral ovarian fibroma presenting as Meigs syndrome. PMID- 23919875 TI - Strumal carcinoid ovary with mucinous cystadenoma presenting as a large abdominal mass and increased tumour marker level. PMID- 23919876 TI - Small cell carcinoma of the uterine cervix metastasising to the cerebellum. PMID- 23919877 TI - Isolated muscle metastasis of cervical cancer. PMID- 23919878 TI - A large primary vaginal leiomyosarcoma diagnosed postoperatively and uterine leiomyomas treated with surgery and chemotherapy. PMID- 23919879 TI - Re: Qureshi NS. 2013. Examiners' perceptions of the objective structured clinical examination in colposcopy. Journal of obstetrics and gynaecology 33:188-190. PMID- 23919880 TI - Re: Lemon TI, Lampard R, Shah RD, Stone BA. PMID- 23919881 TI - Clinical features and management of closed injury of the cervical trachea due to blunt trauma. AB - BACKGROUND: We retrospectively reviewed the presentation, diagnosis, treatment, and outcomes of patients with closed injury of the cervical trachea. We evaluated factors that improve diagnosis and treatment, reduce mortality, and avoid tracheal stenosis. METHODS: We reviewed the clinical data of 17 patients with closed injury of the cervical trachea. All patients underwent CT scanning or endoscopy, tracheal exploration, low tracheotomy, and tracheal repair. RESULTS: In 12 patients, breathing, phonation, and swallowing functions had returned to normal at 2 weeks. In three patients, breathing and swallowing functions had recovered at 2 weeks, but hoarseness continued. In two patients, tracheal stenosis prevented extubation and required further surgery; in these patients breathing and swallowing functions had recovered at 6 months. CONCLUSIONS: Closed injury of the cervical trachea may cause airway obstruction and is potentially life-threatening. Early diagnosis and repair to restore structure and function are important to ensure survival and avoid tracheal stenosis. PMID- 23919882 TI - Design and optimization of drugs used to treat copper deficiency. AB - INTRODUCTION: Copper is an essential element in the human organism. Furthermore, copper deficiency is rare; however, the hematologic manifestations associated with copper deficiency, such as anemia, leukopenia, neutropenia, myeloneuropathy and osteoporosis, are well known. AREAS COVERED: The authors present an overview of the various commercially available drugs used in the treatment of copper deficiency. Furthermore, the authors offer a description of copper complexes, as potential pharmaceutically active compounds, that can be used in the design of new formulations with therapeutic potential. EXPERT OPINION: Progress in the synthesis of new metallo-organic complexes (such as the copper-pullulan complex) and the chelated form of copper have provided new avenues for drug design that combat copper deficiency. The copper-pullulan complex, as an active compound, has been designed in its solid dosage form, and its optimization in the treatment of copper deficiency has been furthered through advancements in experimental design methodology. The authors believe that the numerous ongoing studies, evaluating the synthesis of these complexes, should produce new additions to the copper deficiency therapeutic armamentarium in the future. PMID- 23919884 TI - Synthesis of [closo-B12(OH)11NH3]-: a new heterobifunctional dodecaborane scaffold for drug delivery applications. AB - Effective utilization of [closo-B12H12](2-) derivatives in targeted drug delivery applications depends upon an efficient strategy to differentiate at least one of the 12 vertices on the B12(2-) core. Precursor molecules must also be able to withstand the initial harsh hydrogen peroxide treatment necessary for hydroxylation of the B-H vertices. We report here a method for preparation of the ammonio derivative [closo-B12(OH)11NH3](-) and also demonstrate its utility in construction of a targeted drug delivery scaffold. Treatment of the precursor [closo-B12H11NH3](-) with hydrogen peroxide gives the corresponding nitro derivative [closo-B12(OH)11NO2](2-) in good yield. The nitro group is easily reduced with hydrogen over a Raney nickel catalyst to produce [closo B12(OH)11NH3](-). The 11 hydroxyl groups can then be readily converted to carbonates or carbamates. As a proof-of-principle of its utility as a drug delivery system, we used the resulting vertex-differentiated ammonio derivative to construct a platinated pro-drug possessing 11 copies of a carboplatin analogue conjugated to the B12(2-) core via carbamate linkage and a fluorescein molecule attached at the remaining vertex by an amide linkage. In vitro cytotoxicity assays demonstrated that activity of an untagged analog was similar to carboplatin against platinum-sensitive A459 cells and higher than carboplatin against platinum-resistant SK-OV-3 cells. Further fluorescence microscopy revealed that the fluorescein-tagged pro-drug localizes to the nuclei of A459 cells. PMID- 23919883 TI - Anomalous N-glycan structures with an internal fucose branched to GlcA and GlcN residues isolated from a mollusk shell-forming fluid. AB - This report describes the structural details of a unique N-linked valence epitope on the major protein within the extrapallial (EP) fluid of the mollusk, Mytilus edulis. Fluids from this area are considered to be responsible for shell expansion by a self-assembly process that provides an organic framework for the growth of CaCO3 crystals. Previous reports from our laboratories have described the purification and amino acid sequence of this EP protein, which was found to be a glycoprotein (EPG) of approximately 28 KDa with 14.3% carbohydrate on a single N-linked consensus site. Described herein is the de novo sequence of the major glycan and its glycomers. The sequence was determined by ion trap sequential mass spectrometry (ITMS(n)) resolving structure by tracking precursor product relationships through successive rounds of collision induced disassociation (CID), thereby spatially resolving linkage and branching details within the confines of the ion trap. Three major glycomers were detected, each possessing a 6-linked fucosylated N-linked core. Two glycans possessed four and five identical antennae, while the third possessed four antennas, but with an additional methylfucose 2-linked to the glucuronic acid moiety, forming a pentasaccharide. The tetrasaccharide structure was: 4-O-methyl-GlcA(1-4)[GlcNAc(1 3)]Fuc(1-4)GlcNAc, while the pentasaccharide was shown to be as follows: mono-O methyl-Fuc(1-2)-4-O-methyl-GlcA(1-4)[GlcNAc(1-3)]Fuc(1-4)GlcNAc. Samples were differentially deuteriomethylated (CD3/CH3) to localize indigenous methylation, further analyzed by high resolution mass spectrometry (HRMS) to confirm monomer compositions, and finally gas chromatography mass spectrometry (GC-MS) to assign structural and stereoisomers. The interfacial shell surface location of this major extrapallial glycoprotein, its calcium and heavy metal binding properties and unique structure suggests a probable role in shell formation and possibly metal ion detoxification. A closely related terminal tetrasaccharide structure has been reported in spermatozoan glycolipids of freshwater bivalves. PMID- 23919885 TI - Abuse-deterrent formulations of opioid analgesics. PMID- 23919886 TI - Methionine improves the performance and breast muscle growth of broilers with lower hatching weight by altering the expression of genes associated with the insulin-like growth factor-I signalling pathway. AB - The present study aimed to investigate the responses of broilers with different hatching weights (HW) to dietary methionine (Met). A total of 192 1-d-old Arbor Acres broiler chicks with different HW (heavy: 48.3 (sem 0.1) g and light: 41.7 (sem 0.1) g) were allocated to a 2 (HW) * 2 (Met) factorial arrangement with six replicates of eight chicks. Control starter (1-21 d) and finisher (22-42 d) diets contained 0.50 and 0.43 % Met, respectively. Corresponding values for a high-Met treatment were 0.60 and 0.53 %. Light chicks had poorer (P< 0.05) growth performance and breast muscle weight and lower (P< 0.05) insulin-like growth factor-I (IGF-I) concentration and mRNA level in breast muscle than heavy chicks when both were fed the control diets. High-Met diets improved performance and promoted breast muscle growth and IGF-I concentration in light chicks (P< 0.05). Increased IGF-I and target of rapamycin (TOR) mRNA levels as well as decreased eIF4E-binding protein 1 (4EBP1), atrogin-1 and forkhead box O 4 (FOXO4) mRNA levels were induced by high-Met diets in light chicks (P< 0.05). In conclusion, the Met requirement of broilers might depend on their HW and Met levels used in the control diets in the present study were adequate for heavy chicks but inadequate for light chicks, resulting in poorer performance and breast muscle growth, which were improved by increasing dietary Met supply presumably through alterations in IGF-I synthesis and gene expression of the TOR/4EBP1 and FOXO4/atrogin-1 pathway. PMID- 23919887 TI - The effect of low-level laser on bone healing in critical size defects treated with or without autogenous bone graft: an experimental study in rat calvaria. AB - OBJECTIVE: The objective of this study was to evaluate the effect of low-level laser (LLL) on bone healing process in surgically created critical size defects in rat calvaria treated with or without autogenous bone graft (AB). MATERIAL AND METHODS: The study was conducted on 40 male rats (Rattusnorvegicus, albinus, Wistar), weighing 250-300 g. For accomplishment of the experimental procedures, the rats were anesthetized with an intramuscular injection of xylazine (0.02 ml/kg) and ketamine hydrochloride (0.4 ml/kg). Acritical size defect with 5-mm diameter was created. The animals were divided into four groups: Group C (Control filled with blood clot), Group LLL, Group AB (autogenous bone graft), Group AB + LLL (autogenous bone graft and LLL). The animals treated with LLL received applications of LLL at the infrared spectrum wavelength (lambda = 810 nm) and energy density of 6 J/cm(2) per point, 60 s per point, adding up to five points on the entire created defect. The animals were euthanized at 30 days postoperatively. After decalcification, each specimen was longitudinally divided into two blocks, exactly along the center of the original surgical defect, processed and embedded in paraffin. Longitudinal serial sections with 6-MUm thickness were made, initiating from the center of the original surgical defect. The sections were stained with hematoxylin and eosin (HE) for light microscopy analysis for histomorphometric analysis. RESULTS: Group C presented smaller quantity of new bone formation than Groups LLL (P < 0.01), AB (P < 0.01), and AB + LLL (P < 0.01). CONCLUSIONS: Utilization of LLL favored the healing process in rat calvaria. The quantity of new bone formation with use of the LLL was similar to the autogenous bone graft. PMID- 23919888 TI - An examination of linking hypotheses drawn from the perceptual consequences of experimentally induced changes in neural circuitry. AB - Because targeted early experiential manipulations alter both perception and the response properties of particular cells in the striate cortex, they have been used as evidence for linking hypotheses between the two. However, such hypotheses assume that the effects of the early biased visual input are restricted to just the specific cell population and/or visual areas of interest and that the neural populations that contribute to the visual perception itself do not change. To examine this assumption, we measured the consequences for vision of an extended period of early monocular deprivation (MD) on a kitten (from 19 to 219 days of age) that began well before, and extended beyond, bilateral ablation of visual cortical areas 17 and 18 at 132 days of age. In agreement with previous work, the lesion reduced visual acuity by only a factor of two indicating that the neural sites, other than cortical areas 17 and 18, that support vision in their absence have good spatial resolution. However, these sites appear to be affected profoundly by MD as the effects on vision were just as severe as those observed following MD imposed on normal animals. The pervasive effects of selected early visual deprivation across many cortical areas reported here and elsewhere, together with the potential for perception to be mediated at a different neural site following deprivation than after typical rearing, points to a need for caution in the use of data from early experiential manipulations for formulation of linking hypotheses. PMID- 23919889 TI - Olanzapine depot formulation in rat: a step forward in modelling antipsychotic induced metabolic adverse effects. AB - Rats are used as animal models in the study of antipsychotic-induced metabolic adverse effects, with oral drug administration yielding hyperphagia, weight gain and, in some cases, lipogenic effects. However, the rapid half-life of these drugs in rats, in combination with development of drug tolerance after a few weeks of treatment, has limited the validity of the model. In order to prevent fluctuating drug serum concentrations seen with daily repeated administrations, we injected female rats with a single intramuscular dose of long-acting olanzapine formulation. The olanzapine depot injection yielded plasma olanzapine concentrations in the range of those achieved in patients, and induced changes in metabolic parameters similar to those previously observed with oral administration, including increased food intake, weight gain and elevated plasma triglycerides. Moreover, the sensitivity to olanzapine was maintained beyond the 2-3 wk of weight gain observed with oral administration. In a separate olanzapine depot experiment, we aimed to clarify the role of hypothalamic AMP-activated protein kinase (AMPK) in olanzapine-induced weight gain, which has been subject to debate. Adenovirus-mediated inhibition of AMPK was performed in the arcuate (ARC) or the ventromedial hypothalamic (VMH) nuclei in female rats, with subsequent injection of olanzapine depot solution. Inhibition of AMPK in the ARC, but not in the VMH, attenuated the weight-inducing effect of olanzapine, suggesting an important role for ARC-specific AMPK activation in mediating the orexigenic potential of olanzapine. Taken together, olanzapine depot formulation provides an improved mode of drug administration, preventing fluctuating plasma concentrations, reducing handling stress and opening up possibilities to perform complex mechanistic studies. PMID- 23919890 TI - A finite element model of the face including an orthotropic skin model under in vivo tension. AB - Computer models of the human face have the potential to be used as powerful tools in surgery simulation and animation development applications. While existing models accurately represent various anatomical features of the face, the representation of the skin and soft tissues is very simplified. A computer model of the face is proposed in which the skin is represented by an orthotropic hyperelastic constitutive model. The in vivo tension inherent in skin is also represented in the model. The model was tested by simulating several facial expressions by activating appropriate orofacial and jaw muscles. Previous experiments calculated the change in orientation of the long axis of elliptical wounds on patients' faces for wide opening of the mouth and an open-mouth smile (both 30(o)). These results were compared with the average change of maximum principal stress direction in the skin calculated in the face model for wide opening of the mouth (18(o)) and an open-mouth smile (25(o)). The displacements of landmarks on the face for four facial expressions were compared with experimental measurements in the literature. The corner of the mouth in the model experienced the largest displacement for each facial expression (~11-14 mm). The simulated landmark displacements were within a standard deviation of the measured displacements. Increasing the skin stiffness and skin tension generally resulted in a reduction in landmark displacements upon facial expression. PMID- 23919891 TI - Micropollutant dynamics in Vidy Bay--a coupled hydrodynamic-photolysis model to assess the spatial extent of ecotoxicological risk. AB - The direct discharge of effluent wastewater into Vidy Bay (Lake Geneva) results in the formation of an effluent plume with locally high concentrations of wastewater-derived micropollutants. The micropollutant hotspots above the wastewater outfall present a potential ecotoxicological risk, yet the spatial extent of the plume and the associated ecotoxicological risk zone remain unclear. This work combines the two main processes affecting the spreading of the plume, namely dilution of micropollutants due to mixing and degradation by photolysis, into a coupled hydrodynamic-photolysis model, with which we estimated the spatial extent of the risk zone in Vidy Bay. The concentration of micropollutants around the wastewater outfall was simulated for typical wind scenarios and seasons relevant to Vidy Bay, and the resulting ecotoxicological risk was evaluated. Specifically, we determined the direct and indirect photolysis rate constants for 24 wastewater-derived micropollutants and implemented these in a hydrodynamic particle tracking model, which tracked the movement of water parcels from the wastewater outfall. Simulations showed that owing to thermal stratification, the zone of ecotoxicological risk is largest in summer and extends horizontally over 300 m from the outfall. Photolysis processes contribute to reducing the plume extent mainly under unstratified conditions when the plume surfaces. Moreover, it was shown that only a few compounds, mainly antibiotics, dominate the total ecotoxicological risk. PMID- 23919892 TI - Total synthesis of lysergic acid. AB - A total synthesis of lysergic acid was accomplished. Key features of our synthesis include stereoselective construction of the stereogenic centers at the allylic positions by using the Evans aldol reaction, and a sequential process with a ring-closing metathesis and an intramolecular Heck reaction to construct the C and D rings. PMID- 23919893 TI - Characterization of micro- and mesoporous materials using accelerated dynamics adsorption. AB - Porosimetry is a fundamental characterization technique used in development of new porous materials for catalysis, membrane separation, and adsorptive gas storage. Conventional methods like nitrogen and argon adsorption at cryogenic temperatures suffer from slow adsorption dynamics especially for microporous materials. In addition, CO2, the other common probe, is only useful for micropore characterization unless being compressed to exceedingly high pressures to cover all required adsorption pressures. Here, we investigated the effect of adsorption temperature, pressure, and type of probe molecule on the adsorption dynamics. Methyl chloride (MeCl) was used as the probe molecule, and measurements were conducted near room temperature under nonisothermal condition and subatmospheric pressure. A pressure control algorithm was proposed to accelerate adsorption dynamics by manipulating the chemical potential of the gas. Collected adsorption data are transformed into pore size distribution profiles using the Horvath Kavazoe (HK), Saito-Foley (SF), and modified Kelvin methods revised for MeCl. Our study shows that the proposed algorithm significantly speeds up the rate of data collection without compromising the accuracy of the measurements. On average, the adsorption rates on carbonaceous and aluminosilicate samples were accelerated by at least a factor of 4-5. PMID- 23919895 TI - Migraine genetics: Part II. AB - Migraine clusters in families and is considered to be a strongly heritable disorder. Hemiplegic migraine is a rare subtype of migraine with aura that may occur as a familial or a sporadic condition. Three genes have been identified studying families with familial hemiplegic migraine (FHM). The first FHM gene that was identified is CACNA1A. A second gene, FHM2, has been mapped to chromosome 1 q 21-23. The defect is a new mutation in the alpha2 subunit of the Na/K pump (ATP1A2). A third gene (FHM3) has been linked to chromosome 2q24. It is due to a missense mutation in gene SCN1A (Gln1489Lys), which encodes an alpha1 subunit of a neuronal voltage-gated Na+ channel. Genome-wide association studies have identified many non-coding variants associated with common diseases and traits, like migraine. These variants are concentrated in regulatory DNA marked by deoxyribonuclease I hypersensitive sites. A role has been suggested for the two-pore domain potassium channel, TWIK-related spinal cord potassium channel. TWIK-related spinal cord potassium channel is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine. PMID- 23919894 TI - Uptake and transport of superparamagnetic iron oxide nanoparticles through human brain capillary endothelial cells. AB - The blood-brain barrier (BBB) formed by brain capillary endothelial cells (BCECs) constitutes a firm physical, chemical, and immunological barrier, making the brain accessible to only a few percent of potential drugs intended for treatment inside the central nervous system. With the purpose of overcoming the restraints of the BBB by allowing the transport of drugs, siRNA, or DNA into the brain, a novel approach is to use superparamagnetic iron oxide nanoparticles (SPIONs) as drug carriers. The aim of this study was to investigate the ability of fluorescent SPIONs to pass through human brain microvascular endothelial cells facilitated by an external magnet. The ability of SPIONs to penetrate the barrier was shown to be significantly stronger in the presence of an external magnetic force in an in vitro BBB model. Hence, particles added to the luminal side of the in vitro BBB model were found in astrocytes cocultured at a remote distance on the abluminal side, indicating that particles were transported through the barrier and taken up by astrocytes. Addition of the SPIONs to the culture medium did not negatively affect the viability of the endothelial cells. The magnetic force-mediated dragging of SPIONs through BCECs may denote a novel mechanism for the delivery of drugs to the brain. PMID- 23919896 TI - Organ-specific remodeling of the Arabidopsis transcriptome in response to spaceflight. AB - BACKGROUND: Spaceflight presents a novel environment that is outside the evolutionary experience of terrestrial organisms. Full activation of the International Space Station as a science platform complete with sophisticated plant growth chambers, laboratory benches, and procedures for effective sample return, has enabled a new level of research capability and hypothesis testing in this unique environment. The opportunity to examine the strategies of environmental sensing in spaceflight, which includes the absence of unit gravity, provides a unique insight into the balance of influence among abiotic cues directing plant growth and development: including gravity, light, and touch. The data presented here correlate morphological and transcriptome data from replicated spaceflight experiments. RESULTS: The transcriptome of Arabidopsis thaliana demonstrated organ-specific changes in response to spaceflight, with 480 genes showing significant changes in expression in spaceflight plants compared with ground controls by at least 1.9-fold, and 58 by more than 7-fold. Leaves, hypocotyls, and roots each displayed unique patterns of response, yet many gene functions within the responses are related. Particularly represented across the dataset were genes associated with cell architecture and growth hormone signaling; processes that would not be anticipated to be altered in microgravity yet may correlate with morphological changes observed in spaceflight plants. As examples, differential expression of genes involved with touch, cell wall remodeling, root hairs, and cell expansion may correlate with spaceflight associated root skewing, while differential expression of auxin-related and other gravity-signaling genes seemingly correlates with the microgravity of spaceflight. Although functionally related genes were differentially represented in leaves, hypocotyls, and roots, the expression of individual genes varied substantially across organ types, indicating that there is no single response to spaceflight. Rather, each organ employed its own response tactics within a shared strategy, largely involving cell wall architecture. CONCLUSIONS: Spaceflight appears to initiate cellular remodeling throughout the plant, yet specific strategies of the response are distinct among specific organs of the plant. Further, these data illustrate that in the absence of gravity plants rely on other environmental cues to initiate the morphological responses essential to successful growth and development, and that the basis for that engagement lies in the differential expression of genes in an organ-specific manner that maximizes the utilization of these signals--such as the up-regulation of genes associated with light-sensing in roots. PMID- 23919897 TI - Relationship between health-related quality of life, and acute care re-admissions and survival in older adults with chronic illness. AB - BACKGROUND: Australia's ageing population means that there is increasing emphasis on developing innovative models of health care delivery for older adults. The assessment of the most appropriate mix of services and measurement of their impact on patient outcomes is challenging. The aim of this evaluation was to describe the health related quality of life (HRQoL) of older adults with complex needs and to explore the relationship between HRQoL, readmission to acute care and survival. METHODS: The study was conducted in metropolitan Melbourne, Australia; participants were recruited from a cohort of older adults enrolled in a multidisciplinary case management service. HRQoL was measured at enrolment into the case-management service using The Assessment of Quality of Life (AQoL) instrument. In 2007-2009, participating service clinicians approached their patients and asked for consent to study participation. Administrative databases were used to obtain data on comorbidities (Charlson Comorbidity Index) at enrolment, and follow-up data on acute care readmissions over 12 months and five year mortality. HRQoL was compared to aged-matched norms using Welch's approximate t-tests. Univariate and multivariate logistic regression models were used to explore which patient factors were predictive of readmissions and mortality. RESULTS: There were 210 study participants, mean age 78 years, 67% were female. Participants reported significantly worse HRQoL than age-matched population norms with a mean AQOL of 0.30 (SD 0.27). Seventy-eight (38%) participants were readmitted over 12-months and 5-year mortality was 65 (31%). Multivariate regression found that an AQOL utility score <0.37 (OR 1.95, 95%CI, 1.03 - 3.70), and a Charlson Comorbidity Index >=6 (OR 4.89, 95%CI 2.37 - 10.09) were predictive of readmission. Multivariate analysis demonstrated that age >=80 years (OR 7.15, 95%CI, 1.83 - 28.02), and Charlson Comorbidity Index >=6 (OR 6.00, 95%CI, 2.82 - 12.79) were predictive of death. CONCLUSION: This study confirms that the AQoL instrument is a robust measure of HRQoL in older community dwelling adults with chronic illness. Lower self-reported HRQoL was associated with an increased risk of readmission independently of comorbidity and kind of service provided, but was not an independent predictor of five-year mortality. PMID- 23919898 TI - The possibility that requiring high-dose olanzapine cannot be explained by pharmacokinetics in the treatment of acute-phase schizophrenia. AB - We examined clinical characteristics including serum olanzapine concentrations for acute schizophrenia patients who required above conventional doses. We performed a rater-blinded, randomized clinical trial in 12 psychiatric emergency sites. Eligible patients were 18-64 years old and met diagnostic criteria for schizophrenia, acute schizophrenia-like psychotic disorder, or schizoaffective disorder. A total of 42 patients were randomly assigned by means of sealed envelopes to receive risperidone (3-12 mg/day; n=20) and olanzapine (10-40 mg/day; n=22), with follow-up at 8 weeks. The Negative score of the Positive and Negative Syndrome Scale was significantly higher in patients who required high doses than in patients who responded to conventional doses. Serum olanzapine concentrations at the time of oral 20mg/day could be obtained from 5 out of 7 patients who subsequently required high-dose olanzapine. All values were more than 30 ng/mL after 11-16 h from dosing to sample collection, and the mean value was 47.876 (S.D. 21.546) ng/mL. Such concentrations are appropriate with respect to a therapeutic range of 20-50 ng/mL. The present study has shown evidence that the reason for requiring high-dose olanzapine cannot be explained by pharmacokinetics in the treatment of acute-phase schizophrenia. PMID- 23919899 TI - Current cannabis use and age of psychosis onset: a gender-mediated relationship? Results from an 8-year FEP incidence study in Bologna. AB - This study examined the relationship between gender, illicit drug use and age of onset of psychosis. We analysed data from an epidemiologically based cohort of 160 subjects with first-episode psychosis from community mental health centers. Cannabis was associated with an earlier onset of psychosis compared to other drugs, especially among women. PMID- 23919900 TI - Evolutionary conservation of mammalian sperm proteins associates with overall, not tyrosine, phosphorylation in human spermatozoa. AB - We investigated possible associations between sequence evolution of mammalian sperm proteins and their phosphorylation status in humans. As a reference, spermatozoa from three normozoospermic men were analyzed combining two dimensional gel electrophoresis, immunoblotting, and mass spectrometry. We identified 99 sperm proteins (thereof 42 newly described) and determined the phosphorylation status for most of them. Sequence evolution was studied across six mammalian species using nonsynonymous/synonymous rate ratios (dN/dS) and amino acid distances. Site-specific purifying selection was assessed employing average ratios of evolutionary rates at phosphorylated versus nonphosphorylated amino acids (alpha). According to our data, mammalian sperm proteins do not show statistically significant sequence conservation difference, no matter if the human ortholog is a phosphoprotein with or without tyrosine (Y) phosphorylation. In contrast, overall phosphorylation of human sperm proteins, i.e., phosphorylation at serine (S), threonine (T), and/or Y residues, associates with above-average conservation of sequences. Complementary investigations suggest that numerous protein-protein interactants constrain sequence evolution of sperm phosphoproteins. Although our findings reject a special relevance of Y phosphorylation for sperm functioning, they still indicate that overall phosphorylation substantially contributes to proper functioning of sperm proteins. Hence, phosphorylated sperm proteins might be considered as prime candidates for diagnosis and treatment of reduced male fertility. PMID- 23919901 TI - Comparative kinetics of Qi site inhibitors of cytochrome bc1 complex: picomolar antimycin and micromolar cyazofamid. AB - Antimycin and cyazofamid are specific inhibitors of the mitochondrial respiratory chain and bind to the Qi site of the cytochrome bc1 complex. With the aim to understand the detailed molecular inhibition mechanism of Qi inhibitors, we performed a comparative investigation of the inhibitory kinetics of them against the porcine bc1 complex. The results showed that antimycin is a slow tight binding inhibitor of succinate-cytochrome c reductase (SCR) with Ki = 0.033 +/- 0.00027 nm and non-competitive inhibition with respect to cytochrome c. Cyazofamid is a classical inhibitor of SCR with Ki = 12.90 +/- 0.91 MUm and a non-competitive inhibitor with respect to cytochrome c. Both of them show competitive inhibition with respect to substrate DBH2 . Further molecular docking and quantum mechanics calculations were performed. The results showed that antimycin underwent significant conformational change upon the binding. The energy barrier between the conformations in the crystal and in the binding pocket is ~13.63 kcal/mol. Antimycin formed an H-bond with Asp228 and two water-bridged H-bonds with Lys227 and His201, whereas cyazofamid formed only one H-bond with Asp228. The conformational change and the different hydrogen bonding network might account for why antimycin is a slow tight-binding inhibitor, whereas cyazofamid is a classic inhibitor. PMID- 23919902 TI - Behavioral profile of adults with Prader-Willi syndrome: correlations with individual and environmental variables. AB - BACKGROUND: Maladaptive behavior has been reported as a phenotypical feature in Prader-Willi syndrome (PWS). It severely limits social adaptation and the quality of life of children and adults with the syndrome. Different factors have been linked with the intensity and form of these behavioral disturbances but there is no consensus about the cause. Consequently, there is still controversy regarding management strategies and there is a need for new data. METHODS: The behavior of 100 adults with PWS attending a dedicated center was assessed using the Developmental Behavior Checklist for Adults (DBC-A) and the PWS-specific Hyperphagia Questionnaire. The DBC-A was completed separately by trained caregivers at the center and relatives or caregivers in a natural setting. Genotype, gender, age, degree of obesity and cognitive impairment were analyzed as variables with a hypothetical influence on behavioral features. RESULTS: Patients showed a relatively high rate of behavioral disturbances other than hyperphagia. Disruptive and social relating were the highest scoring DBC-A subscales whereas anxiety/antisocial and self-absorbed were the lowest. When hospital caregiver and natural caregiver scores were compared, scores for the latter were higher for all subscales except for disruptive and anxiety/antisocial. These effects of institutional management were underlined. In the DBC-A, 22 items have descriptive indications of PWS behavior and were used for further comparisons and correlation analysis. In contrast to previous reports, rates of disturbed behavior were lower in patients with a deletion genotype. However, the behavioral profile was similar for both genotypes. No differences were found in any measurement when comparing type I and type II deletions. The other analyzed variables showed little relevance. CONCLUSIONS: Significant rates of behavioral disorders were highlighted and their typology described in a large cohort of adults with PWS. The deletion genotype was related to a lower severity of symptoms. Some major behavioral problems, such as hyperphagia, may be well controlled if living circumstances are adapted to the specific requirements of individuals with PWS. PMID- 23919903 TI - Urinary tract infections caused by community-acquired extended-spectrum beta lactamase-producing and nonproducing bacteria: a comparative study. AB - OBJECTIVE: To study the clinical characteristics and associated risk factors of urinary tract infections (UTIs) caused by community-acquired extended-spectrum beta-lactamase (CA-ESBL)-producing Enterobacteriaceae. STUDY DESIGN: A case control study at a large community hospital in northern Israel, comparing children who had UTI due to CA-ESBL (n = 25) and CA non-ESBL (n = 125) in 2008 2011. Data were collected from medical charts, telephonic questionnaires administered to all participants, and groups were compared. RESULTS: During the study period, the yearly incidence of CA-ESBL UTI increased significantly. There were no significant differences between the CA-ESBL and CA non-ESBL groups in demographics and clinical outcome. Compared with CA non-ESBL UTI, children with CA-ESBL UTI had a longer hospital stay (5.9 +/- 3.3 vs 3.9 +/- 2.3 days; P = .003) and higher rates of recent hospitalization (28% vs 4%; P = .001), previous UTI (40% vs 13%; P = .003), urinary tract anomalies (32% vs 5%; P < .001), UTI prophylaxis with cephalexin (32% vs 2%; P < .005), and aminoglycoside resistance. In a multivariate analysis, UTI prophylaxis (OR 12.5 [CI 2.7-58]), recent hospitalization (OR 4.8 [CI 1.1-21]), and Klebsiella spp. UTI (OR 4.7 [CI 1.3 17]), were risk factors for CA-ESBL UTI. CONCLUSIONS: Children prescribed UTI prophylaxis (due to urinary tract anomalies or recurrent UTI) with cephalexin and those with previous hospitalizations are at increased risk for CA-ESBL UTI. Although not associated with higher rates of complications, the multidrug resistant phenotype of CA-ESBL isolates poses a challenge in choosing appropriate empiric and definitive therapy and prolongs hospital stay. PMID- 23919904 TI - A population-based cohort study of breastfeeding according to gestational age at term delivery. AB - OBJECTIVE: Because breastfeeding is the optimal form of infant feeding, this study was conducted to determine the effect of gestational age on breastfeeding in term infants. STUDY DESIGN: A retrospective population-based cohort study of singleton/twin hospital births was conducted in Ontario, Canada between April 1, 2009, and March 31, 2010. Multivariate logistic regression was used to determine the adjusted effect of gestational age on breastfeeding. RESULTS: Our study population comprised 92,364 infants, of whom 80,297 (86.9%) were exclusively or partially breastfed at the time of hospital discharge. Multivariate logistic regression analyses demonstrated that early-term infants had lower odds of being breastfed compared with infants born at 41 weeks gestation (40 weeks: aOR, 0.93; 95% CI, 0.86-0.99; 39 weeks: aOR, 0.87; 95% CI, 0.81-0.93; 38 weeks: aOR, 0.81; 95% CI, 0.75-0.88; 37 weeks: aOR, 0.74; 95% CI, 0.67-0.82). CONCLUSION: Using a population-based approach, we found that infants born at 40, 39, 38, and 37 weeks gestation had increasingly lower odds of being breastfed compared with infants born at 41 weeks. Clinicians need to be made aware of the differences in outcomes of infants delivered at early and late term, so that appropriate breastfeeding support can be provided to women at risk for not breastfeeding. PMID- 23919905 TI - Perinatal transmission of hepatitis C virus. PMID- 23919907 TI - Role of pediatricians in fostering resilience in parents of children with autism spectrum disorders. PMID- 23919906 TI - Children with both asthma and depression are at risk for heightened inflammation. AB - OBJECTIVE: To test whether children and adolescents with co-occurring asthma and depression are at risk for elevated inflammation-concurrently and at the next assessment. STUDY DESIGN: Up to 6 yearly assessments per person from the prospective, population-based Great Smoky Mountains Study (N = 1420) were used, covering children in the community aged 10-16 years old. High-sensitivity C reactive protein (CRP) was assayed from annual bloodspot collections and provided indicators of elevated inflammation at CRP > 1, CRP > 2, and CRP > 3 mg/L. Depression was assessed with the Child and Adolescent Psychiatric Assessment. Asthma was assessed using a form adapted from the Centers for Disease Control and Prevention National Health Interview Survey. RESULTS: Controlling common covariates of CRP, the co-occurrence of asthma and depression predicted heightened CRP-concurrently and at the next assessment. In turn, elevated CRP was relatively stable from one assessment to the next. CONCLUSIONS: The co-occurrence of asthma and depression in childhood poses a risk for substantially elevated inflammation concurrently and over time, which could contribute to pathophysiological processes involved in the development of additional chronic diseases and also to asthma--related morbidity and mortality. PMID- 23919908 TI - Advanced glycation endproducts in children with diabetes. AB - OBJECTIVES: To estimate skin content of advanced glycation endproducts (AGEs) by measurements of skin intrinsic fluorescence (SIF) from youth with diabetes in comparison with a population of youth and adults without diabetes. STUDY DESIGN: Using a specialized instrument, skin AGEs were estimated from skin auto fluorescence induced at 420 nm and corrected for skin pigmentation (SIF420[kx0.5, km0.5]) in children with types 1 and 2 diabetes, as well as children and adults without diabetes. The effect of age, sex, ethnicity, and diabetes status on SIF420[kx0.5, km0.5] was analyzed. RESULTS: SIF420[kx0.5, km0.5] increased with chronologic age and was higher in children with diabetes compared with children without diabetes (P = .0001). SIF420[kx0.5, km0.5] from 43% of children with type 1 diabetes and 55% with type 2 diabetes overlapped the range of adults without diabetes. SIF420[kx0.5, km0.5] was higher in girls than boys in patients with diabetes patients. However, there was no effect of sex or race on SIF420[kx0.5, km0.5] in subjects without diabetes. CONCLUSIONS: After 4-6 years' exposure to diabetes, many children will have precociously high estimates of skin AGEs, comparable with levels that would naturally accumulate only after ~25 years of chronologic aging. Potentially, this technology identifies children who are at increased risk for complications. PMID- 23919909 TI - Anti-N-methyl-D-aspartate receptor encephalitis and parvovirus B19: A possible link? PMID- 23919910 TI - Imaging a peaked pupil in a traumatic open globe injury. PMID- 23919911 TI - An objective method for assessing adherence to prophylaxis in adults with severe haemophilia. AB - Severe haemophilia is often managed by prophylactic factor infusions in developed countries. The benefits of secondary prophylaxis in adults are currently being studied and adherence to the prescribed prophylactic factor regimen is vital to decreasing bleeding episodes. The aim of this study was to measure discrepancy between the physicians' prescription for prophylactic factor usage, and the actual factor usage obtained through infusion logs. During this method subjects with severe haemophilia A or B (FVIII or FIX <=2%), from a single haemophilia clinic with complete medical and infusion records from July 01, 2009 to June 30, 2011, were evaluated. Continuous prophylaxis >=4 weeks were included in the analysis. A scoring system for adherence to prescribed dosing and frequency was developed. A global scale of adherence was performed by two independent nurses using visual analogue scale. Thirty-one subjects, all with haemophilia A, with a median age of 26 years (range 18-56) were included. Results showed that the median (IQR) adherence rate to prescribed frequency and dosage, respectively, was 76% (67;85) and 93% (73;97). In multivariate analysis, only the length of time on prophylaxis during the study period showed a positive correlation with adherence whereas age, number of co-infections, number of bleeds and number of joints with chronic arthropathy did not. Global nursing assessments were in general agreement with the score. In conclusion, we observed a moderately good level of adherence based on score and by the nurse global assessment. Better adherence was found in subjects with longer exposure to prophylaxis. PMID- 23919912 TI - Lipid emulsions in parenteral nutrition: current applications and future developments. AB - INTRODUCTION: A parenteral lipid emulsion (LE), used as a key source of energy, essential fatty acids (FAs), and fat-soluble vitamins, is an integral part of a parenteral nutrition (PN) regimen. The conventional LEs, such as soybean oil (SO) based emulsions, have caused concerns about the potential adverse effects involving oxidative stress, inflammation, and immune response probably because of undesirable FA composition. AREAS COVERED: Recently, alternative LEs, optimizing the FA composition with partial substitution of SO with medium-chain triglyceride (MCT), olive oil (OO), and fish oil (FO), have been developed and applied in clinical practice. This review summarizes the characteristics and beneficial clinical effects of alternative parenteral LEs in critically ill, pediatric, and long-term PN patients. EXPERT OPINION: More clinical data from sufficiently high powered studies are required to characterize the integral biological properties of alternative LEs for further selection to fit individual needs and disease characteristics. Simultaneously, potential lipid sources with desirable FA compositions and biological properties should be selected to develop new therapeutic LEs. As supplements to current parenteral lipids, the new LEs with different therapeutic effects are expected to fit specified subpopulations of patients with different diseases. Great efforts should be devoted to the development of parenteral LEs. PMID- 23919913 TI - Five patients with melanosis of the nipple and areola clinically mimicking melanoma. AB - BACKGROUND: Pigmented lesions on the nipple and areola concern patients and physicians as melanoma and pigmented mammary Paget's disease must be considered in the differential diagnoses. There have been only six case reports of melanosis of the nipple and areola in the medical literature yet five cases presented to our department in a 26-month period. METHOD: Five women aged between 26 and 34 years presented with pigmentation of the areola and/or nipple. Two patients were pregnant and one also had vitiligo. All lesions were solitary, eccentrically located with a sharp but irregular contour, and homogeneous pigmentation. Dermoscopy was performed and reassuring features included light to dark brown cobblestone pigmentation with ring-like structures and reticulation. Blue-white veil and irregular centred black dots were not seen. Histology confirmed melanosis of the nipple and areola. CONCLUSION: Melanosis of the nipple and areola is probably significantly underreported in the medical literature and, based on our experience, is likely to be the most common cause of pigmentation at this site. Considering this, benign condition on clinical and dermoscopic features should lead to biopsy rather than excision to confirm the diagnosis. Further reports of the dermoscopic features will help to define this condition further. PMID- 23919914 TI - Indirect comparison analysis of efficacy and safety between olanzapine and aripiprazole for schizophrenia. AB - AIMS: Indirect comparison (IC) and direct comparison (DC) between aripiprazole and olanzapine for schizophrenia were conducted to compare their efficacy and safety. The objective was to determine the usability of IC and consistency of results delivered by the two comparisons. Factors that might influence the inconsistency of results were also investigated. METHODS: ICs and DCs were conducted using the change from baseline of the Positive and Negative Syndrome Scale (PANSS) total score as an efficacy endpoint and the dropout rate was selected as a safety endpoint. Placebo and risperidone were used as common comparators for ICs. RESULTS: A literature search identified 20 articles. The efficacy analysis gave results on the mean difference in PANSS change (95% CI) of -5.72 (-10.22, -1.22) in ICs using placebo as a common comparator and -7.41 ( 15.96, 1.14) in DCs. When using risperidone as a common comparator, it was -9.15 (-20.12, 1.82). In rate ratio analysis of the all cause dropout rate, the IC result was 1.17 (0.83, 1.65) using placebo as a common comparator and 1.56 (0.57, 4.26) using risperidone as a common comparator. Both analyses gave consistent results between ICs and DCs. A slightly lower estimated value was observed in ICs using placebo. CONCLUSIONS: This study demonstrated that ICs between olanzapine and aripiprazole can deliver results consistent with those of DCs. It is also suggested that the selection of a common comparator is important when control group bias is suspected in the data set. PMID- 23919915 TI - Synthesis, characterization, and electron-transfer processes in indium ferrocenyl containing porphyrins and their fullerene adducts. AB - Three new indium(III) tetra- and penta(ferrocenyl)-substituted porphyrins of the general formula XInTFcP [X = Cl(-), OH(-), or Fc(-); TFcP = 5,10,15,20 tetraferrocenylporphyrin(2-); Fc = ferrocene] have been prepared and characterized by UV-vis, magnetic circular dichroism (MCD), (1)H, (13)C, 2D, and variable-temperature NMR spectroscopy, as well as elemental analysis. Molecular structures of the ClInTFcP, FcInTFcP, and FcInTFcP@4C60 complexes were determined by X-ray crystallography with the last compound being not only the first example of a C60 adduct to the organometallic porphyrins but also the first structure in which organometallic porphyrin antennas intercalated into four electron-transfer channels. The electronic structures and relative energies of individual atropisomers, as well as prospective electron-transfer properties of fullerene adducts of XInTFcP complexes, were investigated by the Density Functional Theory (DFT) approach. Redox properties of XInTFcP complexes were investigated using electrochemical (CV and DPV), spectroelectrochemical, and chemical oxidation approaches. Electrochemical experiments conducted in low-polarity solvent using noncoordinating electrolyte were crucial for the sequential oxidation of ferrocene substituents in XInTFcP compounds. In agreement with DFT calculations, the axial ferrocene ligand in FcInTFcP, with direct In-C sigma-bond has a 240 mV lower oxidation potential compared to the first oxidation potential for equatorial ferrocene substituents connected to the porphyrin core. The first equatorial ferrocene oxidation process in all XInTFcP complexes is separated by at least 150 mV from the next three ferrocene based oxidations. The second, third, and fourth redox processes in the ferrocene region are more closely spaced. The addition of the bulky axial ferrocene ligand results in significantly larger rotational barriers for equatorial ferrocene substituents in FcInTFcP compared to the other complexes and leads to better defined redox waves in cyclic voltammetry (CV) and differential pulse voltammetry (DPV) experiments. Mixed valence compounds of the general formula [XInTFcP](n+) (n = 1, 2) were observed and characterized by spectroelectrochemical and chemical oxidation approaches. In all cases, the presence of the intense intervalence charge transfer (IVCT) bands associated with the oxidation of a single equatorial ferrocene substituent were detected in the NIR region confirming the presence of the iron-based mixed valence species and suggesting long-range metal-metal coupling in the target systems. The resulting data from the mixed-valence [XInTFcP](n+) (n = 1, 2) complexes matched very closely to the previously reported MTFcP and metal-free poly(ferrocenyl)porphyrins and were assigned as Robin and Day Class II mixed valence compounds. PMID- 23919916 TI - Symmetry-amplified J splittings for quadrupolar spin pairs: a solid-state NMR probe of homoatomic covalent bonds. AB - Chemically informative J couplings between pairs of quadrupolar nuclei in dimetallic and dimetalloid coordination motifs are measured using J-resolved solid-state NMR experiments. It is shown that the application of a double-quantum filter is necessary to observe the J splittings and that, under these conditions, only a simple doublet is expected. Interestingly, the splitting is amplified if the spins are magnetically equivalent, making it possible to measure highly precise J couplings and unambiguously probe the symmetry of the molecule. This is demonstrated experimentally by chemically breaking the symmetry about a pair of boron spins by reaction with an N-heterocyclic carbene to form a beta-borylation reagent. The results show that the J coupling is a sensitive probe of bonding in diboron compounds and that the J values quantify the weakening of the B-B bond which occurs when forming an sp(2)-sp(3) diboron compound, which is relevant to their reactivity. Due to the prevalence of quadrupolar nuclei among transition metals, this work also provides a new approach to probe metal-metal bonding; results for Mn2(CO)10 are provided as an example. PMID- 23919917 TI - Easy monitoring of velocity fields in microfluidic devices using spatiotemporal image correlation spectroscopy. AB - Spatiotemporal image correlation spectroscopy (STICS) is a simple and powerful technique, well established as a tool to probe protein dynamics in cells. Recently, its potential as a tool to map velocity fields in lab-on-a-chip systems was discussed. However, the lack of studies on its performance has prevented its use for microfluidics applications. Here, we systematically and quantitatively explore STICS microvelocimetry in microfluidic devices. We exploit a simple experimental setup, based on a standard bright-field inverted microscope (no fluorescence required) and a high-fps camera, and apply STICS to map liquid flow in polydimethylsiloxane (PDMS) microchannels. Our data demonstrates optimal 2D velocimetry up to 10 mm/s flow and spatial resolution down to 5 MUm. PMID- 23919918 TI - Breaking barriers to interoperability: assigning spatially and temporally unique identifiers to spaces and buildings. AB - The real estate industry routinely uses specialized information systems for functions, including design, construction, facilities management, brokerage, tax assessment, and utilities. These systems are mature and effective within vertically integrated market segments. However, new questions are reaching across these traditional information silos. For example, buyers may be interested in evaluating the design, energy efficiency characteristics, and operational performance of a commercial building. This requires the integration of information across multiple databases held by different institutions. Today, this type of data integration is difficult to automate and propone to errors due, in part, to the lack of generally accepted building and spaces identifiers. Moving forward, the real estate industry needs a new mechanism to assign identifiers for whole buildings and interior spaces for the purpose of interoperability, data exchange, and integration. This paper describes a systematic process to identify activities occurring at building or within interior spaces to provide a foundation for exchange and interoperability. We demonstrate the application of the approach with a prototype Web application. This concept and demonstration illustrate the elements of a practical interoperability framework that can increase productivity, create new business opportunities, and reduce errors, waste, and redundancy. PMID- 23919919 TI - Bone cement-enhanced sternal closure technique in cardiac surgery: effects on sternal union, pain and life quality. AB - BACKGROUND: Median sternotomy provides excellent access to all mediastinal structures in patients undergoing conventional cardiovascular surgery. Although this incision technique is associated with relatively lower complication rates, certain complications such as the sternal dehiscence may pose serious health consequences. In this regard, considerable effort has been paid to develop techniques aiming to improve sternal healing and to enhance postoperative recovery after conventional cardiac surgery. Among these, kryptonite bone cement, a biocompatible polymer with improved mechanical properties when combined with a standard wire cerclage, represents a promising novel approach that may help prevent sternal dehiscence. In this study, the effects of this particular type of bone cement on sternal healing, postoperative pain, and quality of life have been evaluated. METHODS: Kryptonite bone cement enhanced sternal closure was employed in a total of 100 patients undergoing conventional cardiac surgery between November 2009 and June 2012. Of these patients, 50 expressed their willingness to participate in this study. Each participant underwent a computerized tomography imaging for the radiological assessment of sternal healing. Pain and life quality of these patients have been evaluated by Wong-Baker faces pain scale and SF-36 health survey questionnaire, respectively. RESULTS: Mean duration of follow-up was 20.14 +/- 7.36 months (range: 10-32). Mean age and body mass index were 71.32 +/- 7.23 years (range: 55-85) and 28.34 +/- 2.62 (21-34) kg/m2, respectively. Elderly patients (>=70), females and those with chronic obstructive pulmonary disease (COPD) comprised 64%, 26% and 40% of the study population, respectively. No patients had findings suggestive of dehiscence on CT images. No patients reported severe pain (i.e. all patients had a Wong-Baker faces pain scale score <4). Elderly (>= 70 yr) subjects had better quality of life scores as compared to the remaining group of patients (< 70 yr) according to SF-36 Health Survey results. Vitality and emotional role scores were lower (63.5 +/- 25.5, p = 0.018 and 41.7 +/- 23.3, p = 0.001, respectively) in female patients. Patients with COPD had lower quality of life scores than those without COPD, particularly with respect to general health scores (73.3 +/- 18.5; p = 0.012). CONCLUSIONS: Kryptonite bone cement, when combined with a standard wire cerclage, enhances mechanical strength, prevents sternal dehiscence, reduces postoperative pain and improves quality of life after conventional cardiac surgery. Long-term studies are warranted to better define the role of kryptonite bone cement in the prevention of sternal dehiscence. PMID- 23919920 TI - Low serum enterolactone concentration is associated with low colonic Lactobacillus-Enterococcus counts in men but is not affected by a synbiotic mixture in a randomised, placebo-controlled, double-blind, cross-over intervention study. AB - The aims of the present study were to assess the possible differences in faecal microbiota between men with a low serum enterolactone concentration and those with a high concentration, and to investigate the impact of a synbiotic mixture on serum enterolactone concentration in men with a low concentration. We compared faecal microbiota between ten men with the lowest serum enterolactone concentration and ten men with the highest concentration at recruitment (n 84). Furthermore, we carried out a randomised, double-blind, placebo-controlled, cross over intervention study (6-week intervention periods and 4-week washout period) to investigate the impact of a synbiotic mixture (two Lactobacillus strains, one Bifidobacterium strain, one Propionibacterium strain and galacto-oligosaccharides (32 g/l)) on serum enterolactone concentration in fifty-two men who had a concentration < 20 nmol/l. Serum sensitive C-reactive protein (CRP) concentration was measured at the end of the first intervention period. Men with a low serum enterolactone concentration when compared with those with a high concentration had less faecal bacteria, especially those belonging to the Lactobacillus Enterococcus group (median 8.2 (interquartile range 7.8-8.4) log10 colony-forming units/g v. median 8.8 (interquartile range 8.5-8.9) log10 colony-forming units/g, P= 0.009). The synbiotic mixture that was used did not have a significant effect on serum enterolactone (synbiotic v. placebo ratio 0.96 (95 % CI 0.76, 1.22), P= 0.724) or serum sensitive CRP (synbiotic v. placebo ratio 0.99 (95 % CI 0.74, 1.33), P= 0.954) concentration. Men with a low serum enterolactone concentration harbour less colonic bacteria, especially those belonging to the Lactobacillus Enterococcus group. A synbiotic mixture does not increase serum enterolactone concentration. PMID- 23919921 TI - Introduction: exploring the organizational, social, and cultural context of bioethics. PMID- 23919922 TI - DNA-repair in mild cognitive impairment and Alzheimer's disease. AB - While the pathogenesis of the sporadic form of Alzheimer disease (late onset Alzheimer disease, LOAD) is not fully understood, it seems to be clear that a combination of genetic and environmental factors are involved and influence the course of the disease. Among these factors, elevated levels of oxidative stress have been recognized and individual differences in the capacity to deal with DNA damage caused by its effects have been the subject of numerous studies. This review summarizes the research on DNA repair proteins and genes in the context of LOAD pathogenesis and its possible prodromal stage, mild cognitive impairment (MCI). The current status of the research in this field is discussed with respect to methodological issues which might have compromised the outcome of some studies and future directions of investigation on this subject are depicted. PMID- 23919923 TI - Chromatin structure in double strand break repair. AB - Cells are under constant assault by endogenous and environmental DNA damaging agents. DNA double strand breaks (DSBs) sever entire chromosomes and pose a major threat to genome integrity as a result of chromosomal fragment loss or chromosomal rearrangements. Exogenous factors such as ionizing radiation, crosslinking agents, and topoisomerase poisons, contribute to break formation. DSBs are associated with oxidative metabolism, form during the normal S phase, when replication forks collapse and are generated during physiological processes such as V(D)J recombination, yeast mating type switching and meiosis. It is estimated that in mammalian cells ~10 DSBs per cell are formed daily. If left unrepaired DSBs can lead to cell death or deregulated growth, and cancer development. Cellular response to DSB damage includes mechanisms to halt the progression of the cell cycle and to restore the structure of the broken chromosome. Changes in chromatin adjacent to DNA break sites are instrumental to the DNA damage response (DDR) with two apparent ends: to control compaction and to bind repair and signaling molecules to the lesion. Here, we review the key findings related to each of these functions and examine their cross-talk. PMID- 23919924 TI - The impact of a hand therapy screening and management clinic for patients referred for surgical opinion in an Australian public hospital. AB - STUDY DESIGN: Retrospective cohort study. PURPOSE: To measure the impact of initial treatment by a hand therapist of people referred to a hand surgeon for common hand conditions. METHODS: This retrospective cohort study included 224 patients with Carpal Tunnel Syndrome, Trigger Finger/Thumb, de Quervain's tenosynovitis, and trapeziometacarpal osteoarthrosis. All were invited to attend for assessment and non-operative treatment and were followed up for at least one year. Between groups comparisons for who attended (N = 164) and those who did not (N = 60) were conducted. RESULTS: 40.8% of the non-operative treatment group and 65% of the no treatment group underwent surgery, which was statistically significant (p = 0.02). Univariate analysis found that the variable "attending non-operative treatment" was able to predict those who did not have surgery (p = 0.02). Multivariate analysis using logistic regression also showed that this was the only significant predictor of not progressing to surgery (p = 0.001). CONCLUSIONS: Assessment and treatment by a non-operative provider were associated with a decrease in the rate of operative treatment. Prospective, randomized studies could help determine if this observed difference is related to the treatment approach. PMID- 23919925 TI - Patterned biofilm formation reveals a mechanism for structural heterogeneity in bacterial biofilms. AB - Bacterial biofilms are ubiquitous and are the major cause of chronic infections in humans and persistent biofouling in industry. Despite the significance of bacterial biofilms, the mechanism of biofilm formation and associated drug tolerance is still not fully understood. A major challenge in biofilm research is the intrinsic heterogeneity in the biofilm structure, which leads to temporal and spatial variation in cell density and gene expression. To understand and control such structural heterogeneity, surfaces with patterned functional alkanthiols were used in this study to obtain Escherichia coli cell clusters with systematically varied cluster size and distance between clusters. The results from quantitative imaging analysis revealed an interesting phenomenon in which multicellular connections can be formed between cell clusters depending on the size of interacting clusters and the distance between them. In addition, significant differences in patterned biofilm formation were observed between wild type E. coli RP437 and some of its isogenic mutants, indicating that certain cellular and genetic factors are involved in interactions among cell clusters. In particular, autoinducer-2-mediated quorum sensing was found to be important. Collectively, these results provide missing information that links cell-to-cell signaling and interaction among cell clusters to the structural organization of bacterial biofilms. PMID- 23919926 TI - Analysis of TAp73-dependent signaling via omics technologies. AB - Transactivation-proficient (TA) p73 is a transcription factor belonging to the p53 family, which regulates a variety of biological processes, including neurogenesis, differentiation, apoptosis, and DNA damage checkpoint response. In the present study, we adopted multiple Omics approaches, based upon the simultaneous application of metabolomics, lipidomics, and proteomics, in order to dissect the intracellular pathways activated by p73. As cellular model, we utilized a clone of the human osteosarcoma SAOS-2 cell line that allows the expression of TAp73alpha in an inducible manner. We found that TAp73alpha promoted mitochondrial activity (accumulation of metabolic intermediates and up regulation of proteins related to the Krebs cycle), boosted glutathione homeostasis, increased arginine-citrulline-NO metabolism, altered purine synthesis, and promoted the pentose phosphate pathway toward NADPH accumulation for reducing and biosynthetic purposes. Indeed, lipid metabolism was driven toward the accumulation and oxidation of long-chain fatty acids with pro apoptotic potential. In parallel, the expression of TAp73alpha was accompanied by the dephosphorylation of key proteins of the mitotic spindle assembly checkpoint. In conclusion, the obtained results confirm existing evidence from transcriptomics analyses and suggest a role for TAp73alpha in the regulation of cellular metabolism, cell survival, and cell growth. PMID- 23919927 TI - Glycogen synthase kinase-3beta haploinsufficiency lengthens the circadian locomotor activity period in mice. AB - The mood stabiliser drug lithium has been reported to impact circadian rhythms in vertebrates. Among several putative therapeutic molecular targets, direct inhibition of glycogen synthase kinase-3 beta (GSK3beta) by lithium has been proposed to underlie its effects on circadian physiology. Here we study the effect of GSK3beta haploinsufficiency on the circadian locomotor activity in mice during a free-running period in comparison to wildtype littermates (WT). Mice were housed individually to record their circadian wheel running activity and were entrained to a 12h light/12h dark cycle for 14 days and then placed under constant darkness for 14 days to allow free-running. During the free-running phase, the circadian locomotor activity period of GSK3beta(+/-) was significantly lengthened (23.83+/-0.05h) when compared to the WT mice (23.54+/-0.10h; p=0.0374). No significant difference in locomotor activity was observed. Knowing that GSK3beta interacts with most of the core clock components, these data suggest that GSK3beta acts as a critical intrinsic regulator of the circadian clock and plays an important role in regulating its period in response to lithium treatment. PMID- 23919928 TI - Adverse drug reactions and off-label and unlicensed medicines in children: a prospective cohort study of unplanned admissions to a paediatric hospital. AB - AIMS: To examine the impact of off-label and unlicensed (OLUL) prescribing on adverse drug reactions (ADRs) causing unplanned admissions to a paediatric hospital. METHODS: Prescription data from a 12 month prospective cohort study of ADRs detected in children admitted to a paediatric hospital were scrutinized. The relative risk for off-label and unlicensed medicines being implicated in an ADR was calculated. Logistic regression analyses were carried out with exposure to off-label and unlicensed medicines and number of off-label and unlicensed medicines administered as predictor variables. RESULTS: Off-label and unlicensed medicines were more likely to be implicated in an ADR than authorized medicines (relative risk 1.67, 95% CI 1.38, 2.02, P < 0.001). There was a 25% increase in ADR risk (95% CI 1.16, 1.35, P < 0.001) with each additional authorized medicine and 23% (95% CI 1.10, 1.36, P < 0.001) with each additional off-label or unlicensed medicine. Logistic regression analysis focusing on non-oncology patients demonstrated that the number of authorized medicines (odds ratio 1.33, 95% CI 1.23, 1.44, P < 0.001), but not the number of off-label and unlicensed medicine courses, was a predictor of ADR risk. CONCLUSIONS: In a heterogeneous population of children admitted to a secondary/tertiary hospital, off-label and unlicensed medicines are more likely to be implicated in an ADR than authorized medicines. This was largely driven by ADRs related to drugs used in oncological practice, where the usage of off-label or unlicensed medicines was associated with a higher ADR risk than in non-oncological areas. PMID- 23919930 TI - Severe FX deficiency caused by a homozygous double deletion involving F10 and PROZ genes. PMID- 23919931 TI - Chloride ion-pairing with Ru(II) polypyridyl compounds in dichloromethane. AB - Chloride ion-pairing with a series of four dicationic Ru(II) polypyridyl compounds of the general form [Ru(bpy)3-x(deeb)x](PF6)2, where bpy is 2,2' bipyridine and deeb is 4,4'-diethylester-2,2'-bipyridine, was observed in dichloromethane solution. The heteroleptic compounds [Ru(bpy)2(deeb)](2+) and [Ru(bpy)(deeb)2](2+) were found to be far less sensitive to ligand loss photochemistry than were the homoleptic compounds [Ru(bpy)3](2+) and [Ru(deeb)3](2+) and were thus quantified in most detail. X-ray crystal structure and (1)H NMR analysis showed that, when present, the C-3/C-3' position of bpy was the preferred site for adduct formation with chloride. Ion-pairing was manifest in UV-visible absorption spectral changes observed during titrations with TBACl, where TBA is tetrabutyl ammonium. A modified Benesi-Hildebrand analysis yielded equilibrium constants for ion-pairing that ranged from 13 700 to 64 000 M(-1) and increased with the number of deeb ligands present. A Job plot indicated a 2:1 chloride-to-ruthenium complex ratio in the ion-paired state. The chloride ion was found to decrease both the excited state lifetime and the quantum yield for photoluminescence. Nonlinear Stern-Volmer plots were observed that plateaued at high chloride concentrations. The radiative rate constants decreased and the nonradiative rate constants increased with chloride concentration in a manner consistent with theory for radiative rate constants and the energy gap law. Equilibrium constants for excited state ion-pairing abstracted from such data were found to be significantly larger than that measured for the ground state. Photophysical studies of hydroxide and bromide ion-pairing with [Ru(bpy)2(deeb)](2+) are also reported. PMID- 23919929 TI - Vitamin E: a dark horse at the crossroad of cancer management. AB - It appears that the story on vitamin E and its role in human health remains incomplete. It is apparent that vitamin E supplementation involves many variables, some of which include its uptake from the intestine, the preference for alpha-tocopherol, transport by tocopherol specific proteins and lipid transporters and the differential metabolism of different vitamin E isoforms. The fundamental differences within population genetics can have significant implications for the effect that dietary supplementation might have on human health. When evaluating the efficacy of vitamin E prophylactic or therapeutic use in previous and future studies, it is critical to consider dosage to be administered, form of vitamin E and source (such as whether from synthetic or purified from natural sources). Further studies are needed to determine the effects of all vitamin E isoforms on cell growth, tumorigenicity, to clarify its possible use as an adjuvant to existing chemotherapeutics. The Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study Group and Selenium and Vitamin E Cancer Prevention Trial (SELECT) studies along with the numerous studies of vitamin E should help guide the next chapter of vitamin E research. PMID- 23919932 TI - Generalized eruptive keratoacanthoma: proposed diagnostic criteria and therapeutic evaluation. AB - Generalized eruptive keratoacanthoma (GEKA) of Grzybowski is a sporadically occurring, extremely rare variant of keratoacanthoma characterized clinically by severely pruritic, generalized eruption of numerous small follicular papules, often with a central keratotic plug, and histologically by typical features of solitary keratoacanthoma. Despite the continuous addition of new case reports, no definite diagnostic criteria have been established, and an optimum treatment is not yet determined. Herein, we review the different aspects of this rare entity, including pathogenesis, clinical and histopathological features, differential diagnosis, course and prognosis. Different therapeutic approaches and their impact on the course and prognosis of the disease are also evaluated and presented. We propose two sets of diagnostic criteria to define the disease more precisely and to avoid overlapping and confusion with other types of multiple keratoacanthoma. The first set comprises constant clinical and histopathological features that almost always present in every case and the second set includes variable features that were reported in some patients, and to which any emerging finding could be added to avoid missing cases. Although different therapeutic options have been used, either as single agents or in combinations, there is no standard therapy for GEKA and the disease still represents a therapeutic challenge. PMID- 23919934 TI - [Hospital admission of nursing home residents: evidence based orientation for general practitioners could save not just costs]. PMID- 23919935 TI - [Urolithiasis]. PMID- 23919937 TI - [Allergies to betalactam-antibiotics: when and how to evaluate?]. AB - When there is the suspicion of an allergic reaction to betalactam-antibiotics, the allergological evaluation is an important tool to confirm the allergy and to test alternative medicaments. As all the testing methods for the allergologic evaluation (cutaneous tests and in-vitro tests) don't have a high sensitivity, a broad case report and the former documentation of the symptoms and diagnostic findings are essential, to enable a high significance of the examination and to assess the indication for the provocation test which is the gold standard in many cases. The documentation of the time flow is basic, to differentiate between immediate reactions (hours after intake) and nonimmediate reactions (several days after intake). The diagnostic evaluation not later than after six months increases the prospects for a successful allergic evaluation. PMID- 23919938 TI - [Practical aspects of the treatment of Parkinson's disease]. AB - Correct diagnosis is the main problem at the beginning of Parkinson's disease. Treatment is symptomatic and begins with levodopa or dopamine agonists, depending on age and neuropsychiatric symptoms. When many drug intakes are necessary or major non-motor problems are present, the situation becomes complex and requires individual treatment plans including non-pharmacological therapies. Deep brain stimulation is an option when a satisfactory mobility cannot be reached without inacceptable side effects. PMID- 23919939 TI - [Acute hospital admissions among nursing home residents--benefits and potential harms]. AB - Nursing home residents are often referred by their general practitioners to the emergency department or to a geriatric hospital. Hospitalization is mainly perceived as a burden by elderly people; it may also contribute to a reduction of their mental abilities and functional decline. Reasons for admitting patients from nursing homes include infections, exacerbation of pre-existing cardiovascular disease and falls. GP presence in the nursing home, qualified nursing staff, early diagnosis of infections or acute on chronic episodes of e. g. heart failure and appropriate management of chronic diseases are essential to avoid unnecessary hospitalizations. Furthermore, physicians should identify palliative situations in a timely manner and should be familiar with the patients' preferences regarding hospitalization and place of death. PMID- 23919940 TI - [What the internist needs to know about pacemakers]. AB - In Switzerland, in 2011, 4463 patients underwent pacemaker implantation. This review article focusses on basic pacemaker functions, some fundamental remarks on pacemaker therapy and especially indications and pacemaker models. The current guidelines for PM indications date from the years 2007 [1] and 2008 [2] and form the basis of this article. Very rare indications (congenital heart disease, bradycardia after heart transplantation) are not discussed. Each year, new pacemaker models are released that provide advanced diagnostic features (e. g. detailed heart rate memory, 1:1 ECG recordings). However, these features do not significantly change everyday practice. An innovation with clinical impact is the "MRI-safe" system that has been introduced about a year ago. PMID- 23919941 TI - [Not a tropical, but a non the less exotic fever]. AB - We describe a 26-year-old male patient with fever and elevated inflammatory markers of three months duration plus an initial episode of encephalitis. Since intensive search for infectious diseases gave no positive results and ANA and ANCA titers were negative, Still's disease was assumed. But as the patient developed a nodular erythema, polyarteritis nodosa (PAN) was revealed by histopathology. The case underlines, that PAN presents mostly with general symptoms. Therefore, the diagnosis is difficult. An encephalitis is a seldom manifestation of PAN. PMID- 23919943 TI - [Not Available]. PMID- 23919944 TI - [Not Available]. PMID- 23919946 TI - [CME-ORL 9: Sore throat para-laryngeal right]. PMID- 23919948 TI - Enhanced HSP30 and HSP70 accumulation in Xenopus cells subjected to concurrent sodium arsenite and cadmium chloride stress. AB - Heat shock proteins (HSPs) are molecular chaperones that aid in protein folding, translocation and in preventing stress-induced protein aggregation. The present study examined the effect of simultaneous sodium arsenite and cadmium chloride treatment on the pattern of HSP30 and HSP70 accumulation in A6 kidney epithelial cells of the frog, Xenopus laevis. Immunoblot analysis revealed that HSP30 and HSP70 accumulation in concurrent stressor treatments were significantly higher than the sum of HSP30 or HSP70 accumulation in individual treatments. This finding suggested a synergistic action between sodium arsenite and cadmium chloride. KNK437 inhibitor studies indicated that the combined stressor-induced accumulation of HSPs may be regulated, at least in part, at the level of transcription. Immunocytochemistry revealed that simultaneous treatment of cells with the two stressors induced HSP30 accumulation primarily in the cytoplasm in a punctate pattern with some dysregulation of F-actin structure. Increased ubiquitinated protein accumulation was observed with combined sodium arsenite and cadmium chloride treatment compared to individual stressors suggesting an impairment of the ubiquitin proteasome degradation system. The addition of a mild heat shock further enhanced the accumulation of HSP30 and HSP70 in response to relatively low concentrations of sodium arsenite plus cadmium chloride. PMID- 23919949 TI - Major distinctions in the antioxidant responses in liver and kidney of Cd(2+) treated common carp (Cyprinus carpio). AB - This study is related to the accumulation of Cd(2+), its effects on oxidative stress biomarkers and its role in macromolecule damage in liver and kidney of common carp. We present evidence of an increased ratio of reduced to oxidized glutathione (GSH/GSSG) in both organs after 10 mg/L Cd(2+) exposure, with different underlying biological mechanisms and consequences. In the liver, the expressions and/or activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase increased to cope with the Cd(2+)-generated toxic effects during the first 48 h of treatment. In contrast, none of these selected antioxidant markers was significantly altered in the kidney, whereas the expression of glutathione synthetase was upregulated. These results suggest that the major defense mechanism provoked by Cd(2+) exposure involves the regeneration of GSH in the liver, while its de novo synthesis predominates in the kidney. High levels of accumulation of Cd(2+) and peroxynitrite anion (ONOO(-)) were detected in the kidney; the major consequences of ONOO(-) toxicity were enhanced lipid peroxidation and GSH depletion. The accumulation of ONOO(-) in the kidney suggests intensive production of NO and the development of nitrosative stress. In the liver the level of hydrogen peroxide was elevated. PMID- 23919950 TI - Montreal Cognitive Assessment and Mini-Mental State Examination performance in patients with mild-to-moderate dementia with Lewy bodies, Alzheimer's disease, and normal participants in Taiwan. AB - BACKGROUND: The aim of this study was to examine and test the sensitivity, specificity, and threshold scores of the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) and determine those that best correspond to a clinical diagnosis of dementia with Lewy bodies (DLB). METHODS: Sixty-seven Alzheimer's disease (AD), 36 DLB, and 62 healthy participants without dementia (NC), aged 60 to 90, were enrolled. All three groups took the MoCA and MMSE tests at the same time. The Cochran-Mantel-Haenszel tests and receiver operating characteristics curve analysis were used to compare the different neuropsychological test results among the groups. RESULTS: The cut-off point of the MoCA for AD was 21/22 with a sensitivity of 95.5% and a specificity of 82.3% (area under the curve (AUC): 0.945), and the cut-off point for DLB was 22/23 with a sensitivity of 91.7% and a specificity of 80.6% (AUC: 0.932). For the MMSE, the cut-off points for AD and for DLB from NC were all 24/25, with a sensitivity of 88.1% and a specificity of 85.5% for AD (AUC: 0.92), and a sensitivity of 77.8% and a specificity of 85.5% for DLB (AUC: 0.895). After controlling sex, age, and education, AD and DLB had lower scores in all MoCA subscales than the NC group (p < 0.05), except for the orientation and naming in DLB. In addition, AD had a lower score in the MoCA orientation (p = 0.03) and short-term memory (p = 0.02) than did DLB. CONCLUSIONS: The MoCA is a more sensitive instrument than the MMSE to screen AD or DLB patients from non-dementia cases. PMID- 23919951 TI - Subclinical thyroid disease. AB - INTRODUCTION: Subclinical thyroid disease is a common finding on testing of thyroid function and its management remains controversial. SOURCE OF DATA: Epidemiological data from large population studies from USA and Europe. AREAS OF AGREEMENT: There is an increased risk of progression to overt hypothyroidism or hyperthyroidism. The treatment of mild thyroid failure is of importance in optimizing pregnancy outcome. AREAS OF CONTROVERSY: Diagnostic criteria differ and there is variation between management guidelines. The difference was found in long-term clinical outcomes between endogenous and exogenous subclinical hyperthyroidism. GROWING POINTS: Meta-analyses have provided epidemiological data in cardiovascular mortality and morbidity in subclinical thyroid disease. Increased use of echocardiography and bone markers in identifying those who benefit from intervention. AREAS TIMELY FOR DEVELOPING RESEARCH: A randomized controlled trial to identify those subjects identified from screening programmes that benefit from intervention in terms of morbidity and mortality. PMID- 23919952 TI - Design of synthetic biological logic circuits based on evolutionary algorithm. AB - The construction of an artificial biological logic circuit using systematic strategy is recognised as one of the most important topics for the development of synthetic biology. In this study, a real-structured genetic algorithm (RSGA), which combines general advantages of the traditional real genetic algorithm with those of the structured genetic algorithm, is proposed to deal with the biological logic circuit design problem. A general model with the cis-regulatory input function and appropriate promoter activity functions is proposed to synthesise a wide variety of fundamental logic gates such as NOT, Buffer, AND, OR, NAND, NOR and XOR. The results obtained can be extended to synthesise advanced combinational and sequential logic circuits by topologically distinct connections. The resulting optimal design of these logic gates and circuits are established via the RSGA. The in silico computer-based modelling technology has been verified showing its great advantages in the purpose. PMID- 23919953 TI - Multiscale modelling of coupled Ca2+ channels using coloured stochastic Petri nets. AB - Stochastic modelling of coupled Ca2+ channels is a challenge, especially when the coupling of the channels, as determined by their spatial arrangement relative to each other, has to be considered at multiple spatial scales. In this study, the authors address this problem using coloured stochastic Petri nets (SPNc) as high level description to generate continuous-time Markov chains. The authors develop several models with increasing complexity. They first apply SPNc to model single clusters of coupled Ca2+ channels arranged in a regular or irregular lattice, where they describe how to represent the geometrical arrangement of Ca2+ channels relative to each other using colours. They then apply this modelling idea to construct more complex models by modelling spatially arranged clusters of channels. The authors' models can be easily reproduced and adapted to different scenarios. PMID- 23919954 TI - Quantitative analysis of the effects of iododeoxyuridine and ionising radiation treatment on the cell cycle dynamics of DNA mismatch repair deficient human colorectal cancer cells. AB - DNA mismatch repair (MMR) is involved in processing DNA damage following treatment with ionising radiation (IR) and various classes of chemotherapy drugs including iododeoxyuridine (IUdR), a known radiosensitiser. In this study, the authors have developed asynchronous probabilistic cell cycle models to assess the isolated effects of IUdR and IR and the combined effects of IUdR + IR treatments on MMR damage processing. The authors used both synchronous and asynchronous MMR proficient/MMR-deficient cell populations and followed treated cells for up to two cell cycle times. They have observed and quantified differential cell cycle responses to MMR damage processing following IR and IUdR + IR treatments, principally in the duration of both G1 and G2/M cell cycle phases. The models presented in this work form the foundation for the development of an approach to maximise the therapeutic index for IR and IUdR + IR treatments in MMR-deficient (damage tolerant) cancers. PMID- 23919955 TI - Profile and predictors of global distress: can the DT guide nursing practice in prostate cancer? AB - OBJECTIVE: This study examines the ability of the distress thermometer to accurately identify patients with higher symptoms, unmet needs and psychological morbidity. METHODS: Baseline data collected as part of a randomized controlled trial evaluating a nurse-led supportive care intervention for men with prostate cancer commencing radiotherapy at a specialist cancer hospital in Melbourne, Australia. Measures assessed global distress (DT), anxious and depressive symptomatology (HADS), prostate-cancer specific quality of life (EPIC-26), unmet supportive care needs (SCNS-SF34R) and cancer treatment-related concerns (CATS). Following descriptive and correlational analysis, hierarchical multiple regression was employed to examine the contribution of variable sets to explaining variance in DT scores. RESULTS: Less than 20% of men reported DT scores of 4 or higher, indicating overall low distress. The DT accurately identified almost all men reporting HADS score indicative of anxious or depressive symptomatology, suggesting it accurately identifies psychological morbidity. Importantly, the DT identified a further group of distressed men, not identified by HADS, whose distress related to unmet needs and prostate cancer specific issues, indicating the DT is superior in identifying other forms of distress. While the hierarchical multiple regression confirmed anxious and depressive symptomatology as the best predictor of distress score, many other scales are also good predictors of DT scores, supporting the argument that distress is multi-determined. SIGNIFICANCE OF RESULTS: Nurses can be confident that the DT accurately identifies patients with psychological morbidity and importantly identifies other patients with distress who may require intervention. A distress score of 4 or higher identified participants with higher physical symptomatology, higher unmet needs, more concerns about treatment and poorer quality of life. The low prevalence of distress reaching cut off scores suggests nurses would not be overwhelmed by the outcomes of screening and could use the score to prioritise the patients who need greater attention at entry to radiotherapy services. PMID- 23919956 TI - A rare association of leiomyosarcoma with squamous cell carcinoma of the larynx: two cases. AB - OBJECTIVE: To discuss the histopathogenesis and treatment choices for synchronous tumours of the larynx. CASE REPORTS: We present two cases of synchronous laryngeal leiomyosarcoma and squamous cell carcinoma. The first case was an early stage tumour and the second an advanced-stage tumour of the larynx. Selection of adequate treatment for synchronous tumours is difficult because of different spreading rates and metastatic patterns. Treatment choices for both the primary tumour site and the neck should be related to the stage of the squamous component of the tumour. CONCLUSION: In such cases, the tumour location, tumour stage and lymphatic metastases must be carefully evaluated in order to make the optimum treatment choice. Treatment evaluation of the neck should be related to the stage of the squamous component of these synchronous tumours. Partial laryngectomy techniques may be preferred if the extent of the disease permits. PMID- 23919959 TI - Proposed reclassification of Pasteurella lymphangitidis Sneath & Stevens 1990 as Yersinia pseudotuberculosis. AB - The 16S rRNA gene sequences of Pasteurella lymphangitidis, Yersinia pseudotuberculosis and Yersinia pestis were found to be identical and multilocus sequence analysis could not discriminate between the three species. The susceptibility to a Y. pseudotuberculosis phage and the presence of the Y. pseudotuberculosis-specific invasin gene in P. lymphangitidis indicate that the latter should be reclassified as Y. pseudotuberculosis. PMID- 23919960 TI - Lactobacillus silagei sp. nov., isolated from orchardgrass silage. AB - A Gram-reaction-positive, facultatively anaerobic, non-spore-forming and catalase negative rod-shaped bacterial strain, designated IWT126(T), was isolated from orchardgrass (Dactylis glomerata L.) silage preserved in Hachimantai, Iwate, Japan. The isolate showed growth at 15-45 degrees C, pH 3.5-7.5 and with 4.0 % (w/v) NaCl. The cell wall peptidoglycan did not contain meso-diaminopimelic acid, and the DNA G+C content was 45.6 mol%. The major cellular fatty acids were C16 : 0 and C19 : 1 cyclo 9,10. Based on 16S rRNA gene sequence similarity, strain IWT126(T) was classified as a member of the genus Lactobacillus and was most closely related to Lactobacillus odoratitofui YIT 11304(T) (98.7 %), Lactobacillus similis JCM 2765(T) (98.5 %), Lactobacillus collinoides JCM 1123(T) (97.6 %), Lactobacillus paracollinoides DSM 15502(T) (97.6 %) and Lactobacillus kimchicus DCY51(T) (96.9 %). Based on sequence analysis of the phenylalanyl-tRNA synthase alpha-subunit (pheS) gene, strain IWT126(T) was well separated from its phylogenetic neighbours in the genus Lactobacillus. Based on physiological, biochemical and genotypic results, as well as low DNA-DNA relatedness to recognized phylogenetic relatives in the genus Lactobacillus, classification of strain IWT126(T) as a representive of a novel species named Lactobacillus silagei sp. nov. is proposed. The type strain is IWT126(T) ( = JCM 19001(T) = DSM 27022(T)). PMID- 23919961 TI - Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity. AB - The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress. PMID- 23919962 TI - Elastin-derived peptides are new regulators of insulin resistance development in mice. AB - Although it has long been established that the extracellular matrix acts as a mechanical support, its degradation products, which mainly accumulate during aging, have also been demonstrated to play an important role in cell physiology and the development of cardiovascular and metabolic diseases. In the current study, we show that elastin-derived peptides (EDPs) may be involved in the development of insulin resistance (IRES) in mice. In chow-fed mice, acute or chronic intravenous injections of EDPs induced hyperglycemic effects associated with glucose uptake reduction and IRES in skeletal muscle, liver, and adipose tissue. Based on in vivo, in vitro, and in silico approaches, we propose that this IRES is due to interaction between the insulin receptor (IR) and the neuraminidase-1 subunit of the elastin receptor complex triggered by EDPs. This interplay was correlated with decreased sialic acid levels on the beta-chain of the IR and reduction of IR signaling. In conclusion, this is the first study to demonstrate that EDPs, which mainly accumulate with aging, may be involved in the insidious development of IRES. PMID- 23919963 TI - Rhein protects pancreatic beta-cells from dynamin-related protein-1-mediated mitochondrial fission and cell apoptosis under hyperglycemia. AB - Rhein, an anthraquinone compound isolated from rhubarb, has been shown to improve glucose metabolism disorders in diabetic mice. The mechanism underlying the protective effect of rhein, however, remains unknown. Here, we demonstrate that rhein can protect the pancreatic beta-cells against hyperglycemia-induced cell apoptosis through stabilizing mitochondrial morphology. Oral administration of rhein for 8 or 16 weeks in db/db mice significantly reduced fasting blood glucose (FBG) level and improved glucose tolerance. Cell apoptosis assay using both pancreatic sections and cultured pancreatic beta-cells indicated that rhein strongly inhibited beta-cell apoptosis. Morphological study showed that rhein was mainly localized at beta-cell mitochondria and rhein could preserve mitochondrial ultrastructure by abolishing hyperglycemia-induced mitochondrial fission protein dynamin-related protein 1 (Drp1) expression. Western blot and functional analysis confirmed that rhein protected the pancreatic beta-cells against hyperglycemia induced apoptosis via suppressing mitochondrial Drp1 level. Finally, mechanistic study further suggested that decreased Drp1 level by rhein might be due to its effect on reducing cellular reactive oxygen species. Taken together, our study demonstrates for the first time that rhein can serve as a novel therapeutic agent for hyperglycemia treatment and rhein protects pancreatic beta-cells from apoptosis by blocking the hyperglycemia-induced Drp1 expression. PMID- 23919964 TI - Concomitant high-grade prostatic intraepithelial neoplasia is associated with good prognosis factors and oncologic outcome after radical prostatectomy. AB - OBJECTIVES: To assess correlations between concomitant high-grade prostatic intraepithelial neoplasia (HGPIN), pathological features and oncologic outcomes after radical prostatectomy (RP). MATERIAL AND METHODS: We prospectively collected a single-institution database of 2,351 patients who underwent RP between 1998 and 2011. RESULTS: 1,272 (54.1%) patients had HGPIN on specimens. The mean follow-up was 28 months. Presence of HGPIN was significantly associated with a favorable preoperative risk status and with pathological factors of poor prognosis in RP specimens. Patients without HGPIN had a worse biochemical recurrence-free survival compared with those with HGPIN in RP specimen (log-rank test: p = 0.015). The 3-year RFS rate was 73.9% for the HGPIN group versus 67.2%. The absence of HGPIN was also significantly correlated with the use of androgen deprivation treatment during the follow-up (p < 0.001). In Cox multivariate analysis, taking into account the other prognostic pathological factors, HGPIN was not an independent predictive factor for PSA failure (p = 0.868). CONCLUSION: HGPIN is associated with factors of good prognosis but fails to show independent significance when classical pathological prognostic factors are taken into account. PMID- 23919965 TI - How couples' experiences prior to the start of infertility treatment with donor gametes influence the disclosure decision. AB - AIMS: To explore couples' experiences in the preconception phase of infertility treatment with donor gametes and how this may influence the disclosure process to the offspring and/or others. METHODS: In-depth interviews with 10 recipient couples were analyzed using a grounded theory approach. RESULTS: In the context of their infertility and a culture in which definitions of gender and family are fundamentally biologically based, participants reconsidered the significance and meaning of genetics, and social connectedness in family-building and parenthood. When couples emphasized the similarities with the biologically based definitions of parenthood and family, the question of disclosing the donor conception to the offspring seemed less relevant. When couples adapted their view on families and parenthood to an alternative family formation, long-term consequences became more relevant, including the disclosure question. Support from others was needed to manage the challenges of this stage, but this could be in conflict with their decision of non-disclosing the donor conception to the potential offspring. CONCLUSIONS: This study highlights the importance of couples' experiences in the preconception phase for their disclosure process. The treatment of infertility and a future-oriented, family-building approach should be addressed in a fertility program with donor gametes and valued as complementary. PMID- 23919966 TI - Preliminary study of themes of meaning and psychosocial service use among informal cancer caregivers. AB - OBJECTIVE: The burden experienced by informal caregivers (ICs) of patients with advanced cancer is well documented. ICs are at risk for anxiety and depression, as well as existential concerns that arise when a loved one is facing a terminal illness. Few psychosocial interventions focus on existential concerns of ICs. However, a growing body of literature indicates that finding meaning in the experience of being an IC for a person with cancer has the potential to buffer against burden. The purpose of this study was to collect preliminary descriptive data regarding caregiver burden, meaning, and psychosocial service use to inform the adaptation of a meaning-centered intervention for ICs. METHOD: Twenty-five caregivers and 32 patients completed brief, anonymous questionnaires that asked about their role as a caregiver or their perception of their loved one as a caregiver, caregiver burden, and psychosocial service use. RESULTS: Caregivers and patients identified anxiety and depression as top correlates of burden experienced by caregivers, whereas guilt, issues with role/sense of identity, and self-care were additional areas of concern. The majority of caregivers were not receiving psychosocial services, although they almost unanimously reported desiring services. A greater proportion of patients than caregivers believed that an intervention designed to enhance meaning would ameliorate burden, but, nevertheless, close to three quarters of caregivers reported interest in participating in such an intervention. SIGNIFICANCE OF RESULTS: These study findings provide further support for, at a minimum, engaging ICs of persons with advanced cancer in interventions that address existential issues, mental health, self-care, and service use. Such interventions are likely to improve the quality of life of both patients with cancer and their ICs. PMID- 23919968 TI - The added value of 18F-fluorodeoxyglucose positron emission tomography computed tomography in patients with neck lymph node metastases from an unknown primary malignancy. AB - BACKGROUND: The search for a primary malignancy in patients with a metastatic cervical lymph node is challenging yet ultimately of utmost clinical importance. This study evaluated the efficacy of positron emission tomography computed tomography in detecting the occult primary, within the context of a tertiary referral centre head and neck cancer multidisciplinary team tumour board meeting. METHODS: Thirty-two patients (23 men and 9 women; mean and median age, 61 years) with a metastatic cervical lymph node of unknown primary origin, after clinical examination and magnetic resonance imaging, underwent positron emission tomography computed tomography. RESULTS: The primary tumour detection rate was 50 per cent (16/32). Positron emission tomography computed tomography had a sensitivity of 94 per cent (16/17) and a specificity of 67 per cent (10/15). Combining these results with those of 10 earlier studies of similar patients gave an overall detection rate of 37 per cent. CONCLUSION: Positron emission tomography computed tomography has become an important imaging modality. To date, it has the highest primary tumour detection rate, for head and neck cancer patients presenting with cervical lymph node metastases from an unknown primary. PMID- 23919967 TI - The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes. AB - Castrate-Resistant Prostate Cancer (CRPC) is characterized by persistent androgen receptor-driven tumor growth in the apparent absence of systemic androgens. Current evidence suggests that CRPC cells can produce their own androgens from endogenous sterol precursors that act in an intracrine manner to stimulate tumor growth. The mechanisms by which CRPC cells become steroidogenic during tumor progression are not well defined. Herein we describe a novel link between the elevated cholesterol phenotype of CRPC and the TERE1 tumor suppressor protein, a prenyltransferase that synthesizes vitamin K-2, which is a potent endogenous ligand for the SXR nuclear hormone receptor. We show that 50% of primary and metastatic prostate cancer specimens exhibit a loss of TERE1 expression and we establish a correlation between TERE1 expression and cholesterol in the LnCaP-C81 steroidogenic cell model of the CRPC. LnCaP-C81 cells also lack TERE1 protein, and show elevated cholesterol synthetic rates, higher steady state levels of cholesterol, and increased expression of enzymes in the de novo cholesterol biosynthetic pathways than the non-steroidogenic prostate cancer cells. C81 cells also show decreased expression of the SXR nuclear hormone receptor and a panel of directly regulated SXR target genes that govern cholesterol efflux and steroid catabolism. Thus, a combination of increased synthesis, along with decreased efflux and catabolism likely underlies the CRPC phenotype: SXR might coordinately regulate this phenotype. Moreover, TERE1 controls synthesis of vitamin K-2, which is a potent endogenous ligand for SXR activation, strongly suggesting a link between TERE1 levels, K-2 synthesis and SXR target gene regulation. We demonstrate that following ectopic TERE1 expression or induction of endogenous TERE1, the elevated cholesterol levels in C81 cells are reduced. Moreover, reconstitution of TERE1 expression in C81 cells reactivates SXR and switches on a suite of SXR target genes that coordinately promote both cholesterol efflux and androgen catabolism. Thus, loss of TERE1 during tumor progression reduces K-2 levels resulting in reduced transcription of SXR target genes. We propose that TERE1 controls the CPRC phenotype by regulating the endogenous levels of Vitamin K-2 and hence the transcriptional control of a suite of steroidogenic genes via the SXR receptor. These data implicate the TERE1 protein as a previously unrecognized link affecting cholesterol and androgen accumulation that could govern acquisition of the CRPC phenotype. PMID- 23919969 TI - Extracorporeal life support with an integrated left ventricular vent in children with a low cardiac output. AB - BACKGROUND: The aim of this study was to evaluate our experience in central extracorporeal life support with an integrated left ventricular vent in children with cardiac failure. METHODS: Eight children acquired extracorporeal life support with a left ventricular vent, either after cardiac surgery (n = 4) or during an acute cardiac illness (n = 4). The ascending aorta and right atrium were cannulated. The left ventricular vent was inserted through the right superior pulmonary vein and connected to the venous line on the extracorporeal life support such that active left heart decompression was achieved. RESULTS: No patient died while on support, seven patients were successfully weaned from it and one patient was transitioned to a biventricular assist device. The median length of support was 6 days (range 5-10 days). One patient died while in the hospital, despite successful weaning from extracorporeal life support. No intra cardiac thrombus or embolic stroke was observed. No patient developed relevant intracranial bleeding resulting in neurological dysfunction during and after extracorporeal life support. CONCLUSIONS: In case of a low cardiac output and an insufficient inter-atrial shunt, additional left ventricular decompression via a vent could help avoid left heart distension and might promote myocardial recovery. In pulmonary dysfunction, separate blood gas analyses from the venous cannula and the left ventricular vent help detect possible coronary hypoxia when the left ventricle begins to recover. We recommend the use of central extracorporeal life support with an integrated left ventricular vent in children with intractable cardiac failure. PMID- 23919970 TI - [Identity--solidarity]. PMID- 23919971 TI - Understanding diversity of hepatic metabolism and related adaptations in the early lactating dairy cow. AB - The onset of lactation in dairy cows represents a major metabolic challenge that involves large adaptations in glucose, fatty acid, and mineral metabolism to support lactation and to avoid metabolic dysfunction. The complex system of adaptation can differ considerably between cows, and may have a genetic base. In the present review, the variation in adaptive reactions in dairy cows is discussed. In these studies, the liver being a key metabolic regulator for understanding the variation in adaptive performance of the dairy cow was the main focus of research. Liver function was evaluated through gene expression measurements; to explain the associated phenotypic variability and to identify descriptors for metabolic robustness in dairy cows. Hence, the identified genes involved act as a connecting link between the genotype encoded on the DNA and the phenotypic expression of the target factors at a protein level. The integration of phenotypic data, including gene expression profiles, and genomic data will facilitate a better characterization of the complex interplay between these levels, and will improve the genetic understanding necessary to unravel a certain trait or multi-trait such as metabolic robustness in dairy cows. PMID- 23919972 TI - [Mastitis management in Swiss dairy farms with udder health problems]. AB - The objective of this study was to describe the udder health management in Swiss dairy herds with udder health problems. One hundred dairy herds with a yield corrected somatic cell count of 200'000 to 300'000 cells/ml during 2010 were selected. Data concerning farm structure, housing system, milking technique, milking procedures, dry-cow and mastitis management were collected during farm visits between September and December 2011. In addition, quarter milk samples were collected for bacteriological culturing from cows with a composite somatic cell count >= 150'000 cells/ml. The highest quarter level prevalence was 12.3 % for C. bovis. Eighty-two percent of the pipeline milking machines in tie-stalls and 88 % of the milking parlours fulfilled the criteria for the vacuum drop, and only 74 % of the pipeline milking machines met the criteria of the 10-l-water test. Eighty-five percent of the farms changed their milk liners too late. The correct order of teat preparation before cluster attachment was carried out by 37 % of the farmers only. With these results, Swiss dairy farmers and herd health veterinarians can be directed to common mistakes in mastitis management. The data will be used for future information campaigns to improve udder health in Swiss dairy farms. PMID- 23919973 TI - [Disturbances of water metabolism in two dogs and one cat with central nervous system disorders]. AB - Hypernatremia due to different pathophysiological mechanisms results in a rise in plasma osmolality. Dependent on its severity and on the speed of its development hyperosmolality can be life-threatening. This article describes 2 dogs and 1 cat with central nervous system disorders (adenoma of the pituitary gland, cerebral trauma). All patients developed normovolemic hypernatremia due to pituitary gland and hypothalamus dysfunction, respectively. Plasma sodium concentrations ranged from 163 to 185 mmol/l. Neurological examinations revealed lethargy, disturbances of consciousness, and ataxia, respectively. The dogs had to be euthanased due to the grave prognosis, the cat with cerebral trauma survived. PMID- 23919974 TI - Anaesthesia with medetomidine-ketamine-isoflurane with and without midazolam, in eight captive chimpanzees (Pan troglodytes) premedicated with oral zuclopenthixol. AB - In 8 captive adult chimpanzees of various ages premedicated with oral zuclopenthixol anaesthesia was induced intramuscularly with a combination of medetomidine and ketamine (40 or 50 ug/kg and 5 mg/kg, IM, respectively), with and without midazolam (0.05 mg/kg), and maintained with isoflurane in oxygen. At the end of the procedure, sedation was reversed with atipamezole (0.25 mg/kg, IM) and sarmazenil (0.005 mg/kg, IM) when midazolam had been administered. Oral zuclopenthixol resulted in tranquillization of the whole group and only one animal required a second dart injection to achieve adequately deep anaesthesia. Effective and reliable anaesthesia was achieved in all apes; the depth of hypnosis was stable and sudden arousal did not occur. Physiological parameters remained within normal ranges in the majority of the animals; however, manageable anaesthesia-related complications, namely apnoea after darting, hypotension, hypoventilation, hypoxemia and prolonged recovery, occurred in 6 out of 8 animals. The use of monitoring devices was essential to guarantee adequate management of these complications. PMID- 23919978 TI - Thoughts from an old clinician on the art and science of delivering bad news. PMID- 23919979 TI - Patient self-assessment in discriminating the more obstructed side in nasal breathing. AB - BACKGROUND: Correlating patient perception of nasal obstruction sidedness to causative anatomy is important in surgical planning. The accuracy of patient perceived asymmetry of nasal obstruction, as regards objective measures, is described. METHODS: Cross-sectional study of patients undergoing nasal airflow assessment. Unilateral obstruction was assessed using visual analogue scale scores and anterior rhinomanometry, without decongestion. Subjective obstruction asymmetry was defined using either the absolute score difference (right vs left) or the minimal clinically important difference, derived statistically. Correlation between subjective and objective obstruction measures was assessed. RESULTS: In 145 patients (mean age +/- standard deviation, 42.8 +/- 16.6 years; 54.5 per cent female), objective obstruction was right-sided in 32.4 per cent, left-sided in 36.6 per cent and symmetrical in 31.0 per cent. Subjective perception of obstruction sidedness had a sensitivity and specificity of 86.9 and 41.1 per cent, respectively, using the minimal clinically important difference. Positive predictive value was 59.4 per cent using absolute score difference and 53.7 per cent using minimal clinically important difference. Receiver operator characteristic curve analysis indicated correlation between subjective and objective measures (p < 0.001). CONCLUSION: Subjective perception of nasal obstruction asymmetry has limited accuracy. Corroboration with objective airway assessment may be helpful in patients whose symptoms are incongruous with clinical findings. PMID- 23919980 TI - Website visitors asking questions online to lung cancer specialists: what do they want to know? AB - BACKGROUND: In 2003 the Dutch Lung Cancer Information Centre (Longkanker Informatie Centrum) launched a website containing information on lung cancer accessible to anyone. OBJECTIVE: Our study aim was to inventorize the information needs of the visitors of this website by analyzing the questions they asked the lung cancer specialists in the websites interactive section "Ask the Physician". METHODS: The first 2000 questions posted up until May 2006 have been classified by visitors' wish, type of required information, identity, gender, and phase during treatment course. RESULTS: Our results show that 1893 (1158/1893, 61%) of the questions were asked by a loved one/caregiver and (239/1893 13%) by patients. 1 out of 3 questions was asked by a daughter/grand-daughter. Most questions concerned specific information on lung cancer and lung cancer course (817/1893, 43%). The most inquired specific information topics were therapy side effects, diagnostics, general information on lung cancer, and regular therapy. Furthermore, questioners wanted to verify their own doctor's information (122/1893, 6%), a diagnosis (267/1893, 14%), and a prognosis (204/1893, 11%). CONCLUSIONS: Lung cancer patients and their caregivers asked the most questions in the interactive website section. The most frequently requested information was more detailed information. These include specific information on lung cancer (regular therapy, diagnostics, and disease symptoms), verification of what the doctor has said, diagnosis, and prognosis. Most of the requested information could have been obtained from treating specialists, indicating that current information supply to lung cancer patients and their caregivers may not be matching their needs sufficiently. The further implementation of an online dialogue with lung cancer specialists might be a solution. PMID- 23919982 TI - The Wilson Effect: the increase in heritability of IQ with age. AB - Ronald Wilson presented the first clear and compelling evidence that the heritability of IQ increases with age. We propose to call the phenomenon 'The Wilson Effect' and we document the effect diagrammatically with key twin and adoption studies, including twins reared apart, that have been carried out at various ages and in a large number of different settings. The results show that the heritability of IQ reaches an asymptote at about 0.80 at 18-20 years of age and continuing at that level well into adulthood. In the aggregate, the studies also confirm that shared environmental influence decreases across age, approximating about 0.10 at 18-20 years of age and continuing at that level into adulthood. These conclusions apply to the Westernized industrial democracies in which most of the studies have been carried out. PMID- 23919981 TI - Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells. AB - Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with poor overall survival. Constitutive as well as cytokine-initiated activation of PI3K/Akt/mTOR signaling is a common feature of AML patients, and inhibition of this pathway is considered as a possible therapeutic strategy in AML. Human AML cells and different stromal cell populations were cultured under highly standardized in vitro conditions. We investigated the effects of mTOR inhibitors (rapamycin and temsirolimus) and PI3K inhibitors (GDC-0941 and 3-methyladenin (3 MA)) on cell proliferation and the constitutive release of angioregulatory mediators by AML and stromal cells. Primary human AML cells were heterogeneous, though most patients showed high CXCL8 levels and detectable release of CXCL10, Ang-1, HGF and MMP-9. Hierarchical clustering analysis showed that disruption of PI3K/Akt/mTOR pathways decreased AML cell release of CXCL8-11 for a large subset of patients, whereas the effects on other mediators were divergent. Various stromal cells (endothelial cells, fibroblasts, cells with osteoblastic phenotype) also showed constitutive release of angioregulatory mediators, and inhibitors of both the PI3K and mTOR pathway had anti-proliferative effects on stromal cells and resulted in decreased release of these angioregulatory mediators. PI3K and mTOR inhibitors can decrease constitutive cytokine release both by AML and stromal cells, suggesting potential direct and indirect antileukemic effects. PMID- 23919983 TI - Laryngotracheal reconstruction for relapsing polychondritis: case report and review of the literature. AB - BACKGROUND: Relapsing polychondritis is a multi-system autoimmune disease characterised by the inflammation and destruction of cartilaginous structures. The most common sites are the pinna, nose, laryngotracheobronchial tree and peripheral joints. Airway involvement occurs in up to half of patients affected, at any disease stage. It is the most severe and life-threatening aspect of the disease, and proves to be a therapeutic challenge. OBJECTIVES: This article reports our experience of performing laryngotracheal reconstruction in a patient with relapsing polychondritis. A review of the literature is presented, with a focused discussion of airway treatment options. METHODS: Laryngotracheal reconstruction for relapsing polychondritis was performed using hyoid bone pedicled on sternohyoid muscle. CONCLUSION: Airway management in relapsing polychondritis can improve quality of life and palliate patients effectively. PMID- 23919984 TI - Neural correlates of attentional bias in addiction. AB - A small but growing neuroimaging literature has begun to examine the neural mechanisms underlying the difficulty that substance-use dependent (SUD) groups have with ignoring salient, drug-related stimuli. Drug-related attentional bias appears to implicate the countermanding forces of cognitive control and reward salience. Basic cognitive neuroscience research suggests that ignoring emotionally evocative stimuli in our environment requires both up-regulation of control networks and down-regulation of processing in emotion and reward regions. Research to date suggests that attentional biases for drug-related stimuli emerge from a failure to sufficiently increase control of attention over salient, but task-irrelevant stimuli. While SUD samples have typically shown increased activity in the cognitive control regions (ie, lateral prefrontal and dorsal anterior cingulate), during attentional bias such increases appear to have been insufficient for the concomitant increases in processing by the emotion/reward regions (ie, amygdala, insula, and striatum). Given the potential contribution of attentional biases to perpetuating drug use and the development of interventions (both pharmaceutical and cognitive-behavioral) to treat biases, understanding the neural basis of successfully reducing bias remains an important, but as yet unanswered, question for our field. PMID- 23919985 TI - Severity of hematuria effects resolution in patients treated with hyperbaric oxygen therapy for radiation-induced hematuria. AB - INTRODUCTION: We investigated the differences between prostate cancer patients with radiation-induced hematuria treated with hyperbaric oxygen (HBO) therapy that did or did not have a resolution of hematuria. MATERIALS AND METHODS: We performed a retrospective review of prostate cancer patients with radiation induced hematuria who underwent HBO from April 2000 to March 2010. We performed an analysis of demographic data and severity of hematuria in those who had resolution of or persistent hematuria. Additionally, prostate-specific antigen (PSA) data were also obtained during the study period. RESULTS: Overall, 11/22 men had resolution of hematuria after HBO therapy with a median follow-up of 2.2 (0.35-13.6) years. The Radiation Therapy Oncology Group (RTOG) grade of hematuria is predictive of final hematuria outcome (resolution vs. persistent) after HBO (p = 0.026). No significant PSA changes were noted before and after HBO therapy. CONCLUSIONS: The RTOG hematuria grade is associated with the resolution of hematuria after HBO therapy for radiation-induced hematuria in men treated for prostate cancer. This information may be helpful during shared medical decision making regarding utility of HBO therapy in the context of severity of hematuria. PMID- 23919986 TI - Independent sex chromosome evolution in lower vertebrates: a molecular cytogenetic overview in the Erythrinidae fish family. AB - The Erythrinidae fish family is an excellent model for analyzing the evolution of sex chromosomes. Different stages of sex chromosome differentiation from homomorphic to highly differentiated ones can be found among the species of this family. Here, whole chromosome painting, together with the cytogenetic mapping of repetitive DNAs, highlighted the evolutionary relationships of the sex chromosomes among different erythrinid species and genera. It was demonstrated that the sex chromosomes can follow distinct evolutionary pathways inside this family. Reciprocal hybridizations with whole sex chromosome probes revealed that different autosomal pairs have evolved as the sex pair, even among closely related species. In addition, distinct origins and different patterns of differentiation were found for the same type of sex chromosome system. These features expose the high plasticity of the sex chromosome evolution in lower vertebrates, in contrast to that occurring in higher ones. A possible role of this sex chromosome turnover in the speciation processes is also discussed. PMID- 23919988 TI - Highlights from the 11th International Family Nursing Conference, Minneapolis, Minnesota, USA, June 19-22, 2013. PMID- 23919987 TI - An analysis of online evaluations on a physician rating website: evidence from a German public reporting instrument. AB - BACKGROUND: Physician rating websites (PRW) have been gaining in popularity among patients who are seeking a physician. However, little evidence is available on the number, distribution, or trend of evaluations on PRWs. Furthermore, there is no published evidence available that analyzes the characteristics of the patients who provide ratings on PRWs. OBJECTIVE: The objective of the study was to analyze all physician evaluations that were posted on the German PRW, jameda, in 2012. METHODS: Data from the German PRW, jameda, from 2012 were analyzed and contained 127,192 ratings of 53,585 physicians from 107,148 patients. Information included medical specialty and gender of the physician, age, gender, and health insurance status of the patient, as well as the results of the physician ratings. Statistical analysis was carried out using the median test and Kendall Tau-b test. RESULTS: Thirty-seven percent of all German physicians were rated on jameda in 2012. Nearly half of those physicians were rated once, and less than 2% were rated more than ten times (mean number of ratings 2.37, SD 3.17). About one third of all rated physicians were female. Rating patients were mostly female (60%), between 30-50 years (51%) and covered by Statutory Health Insurance (83%). A mean of 1.19 evaluations per patient could be calculated (SD 0.778). Most of the rated medical specialties were orthopedists, dermatologists, and gynecologists. Two thirds of all ratings could be assigned to the best category, "very good". Female physicians had significantly better ratings than did their male colleagues (P<.001). Additionally, significant rating differences existed between medical specialties (P<.001). It could further be shown that older patients gave better ratings than did their younger counterparts (P<.001). The same was true for patients covered by private health insurance; they gave more favorable evaluations than did patients covered by statutory health insurance (P<.001). No significant rating differences could be detected between female and male patients (P=.505). The likelihood of a good rating was shown to increase with a rising number of both physician and patient ratings. CONCLUSIONS: Our findings are mostly in line with those published for PRWs from the United States. It could be shown that most of the ratings were positive, and differences existed regarding sociodemographic characteristics of both physicians and patients. An increase in the usage of PRWs might contribute to reducing the lack of publicly available information on physician quality. However, it remains unclear whether PRWs have the potential to reflect the quality of care offered by individual health care providers. Further research should assess in more detail the motivation of patients who rate their physicians online. PMID- 23919989 TI - MinKyoung Song, PhD, RN, FNP-BC, appointed as Dr. Suzanne Feetham Inaugural Professor, University of Michigan School of Nursing. PMID- 23919990 TI - Peggy Simpson, RN, PhD: Excellence in Nursing Research Award. PMID- 23919991 TI - Variation in prevalence and intensity of two avian ectoparasites in a polluted area. AB - We counted the numbers of pupae of two ectoparasitic flies (Protocalliphora sp. and Ornithomyia sp.) in the nests of a passerine bird, the pied flycatcher (Ficedula hypoleuca) to find out if their prevalence or intensity are affected by long-term environmental pollution by a copper smelter and whether such an interaction would have impacts on birds' breeding success. Fecal metal concentrations of F. hypoleuca nestlings were used to explore direct association between metal levels and parasite prevalence, but we also included other explanatory factors in our analysis, such as timing of breeding, brood size, ambient temperature, habitat quality and host population density. We found that environmental pollution decreased the prevalence of Protocalliphora via changed habitat quality but did not affect the prevalence of Ornithomyia. The prevalence of neither ectoparasite was, however, directly related to ambient metal levels. Both ectoparasites showed higher prevalence when ambient temperature during the nestling period was high, emphasizing the potential of climate change to modify host-parasite relationships. The prevalence of Ornithomyia was further highest in dense F. hypoleuca populations and late broods. Nestling survival decreased with increasing infestation intensity of Ornithomyia while no association was found for Protocalliphora. Despite relatively low numbers and overall weak effect of parasites on survival, the possible delayed and/or sublethal effects of these ectoparasites call for further studies. Our results suggest that pollution related effects on avian ectoparasite numbers are species-specific and reflect habitat changes rather than direct toxic effect of heavy metals. PMID- 23919992 TI - Disclosure of a mental health problem in the employment context: qualitative study of beliefs and experiences. AB - Aims. Decisions regarding disclosure of a mental health problem are complex and can involve reconciling conflicting needs and values. This article provides a qualitative account of the beliefs and experiences of mental health service users regarding disclosure in employment contexts. Methods. Total sample of 45 individuals were interviewed in two study phases. In phase one, semi-structured interviews were carried out with 15 mental health service users. The transcripts were analysed using interpretative phenomenological analysis (IPA). In phase two, identified themes were further explored through interviews with mental health service users (n = 30) in three employment contexts: in paid employment (n = 10); in study or voluntary work (n = 10); and currently unemployed (n = 10). These were analysed using directed content analysis. Results. Four super-ordinate themes were drawn from phase one analysis: (1) public understanding of mental health problems; (2) the employment context; (3) personal impact of labelling and (4) disclosure needs. These themes were reflective of the content of phase two interviews. Conclusions. Greater emphasis needs to be placed on considering the societal, employment and interpersonal influences which form the basis for disclosure beliefs and experiences. PMID- 23919993 TI - Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. AB - Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways and network connections mediating acute lung injury, using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model pathogen. We utilized a time course of matched virologic, pathological, and transcriptomic data within a novel methodological framework that can detect pathway enrichment among key highly connected network genes. This unbiased approach produced a high-priority list of 4 genes in one pathway out of over 3,500 genes that were differentially expressed following SARS-CoV infection. With these data, we predicted that the urokinase and other wound repair pathways would regulate lethal versus sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway for SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation, and pathological disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways regulating pathological disease outcomes, including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, such as SARS-CoV. IMPORTANCE: Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and 2003, and infected patients developed an atypical pneumonia, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) leading to pulmonary fibrosis and death. We identified sets of differentially expressed genes that contribute to ALI and ARDS using lethal and sublethal SARS-CoV infection models. Mathematical prioritization of our gene sets identified the urokinase and extracellular matrix remodeling pathways as the most enriched pathways. By infecting Serpine1-knockout mice, we showed that the urokinase pathway had a significant effect on both lung pathology and overall SARS-CoV pathogenesis. These results demonstrate the effective use of unbiased modeling techniques for identification of high-priority host targets that regulate disease outcomes. Similar transcriptional signatures were noted in 1918 and 2009 H1N1 influenza virus-infected mice, suggesting a common, potentially treatable mechanism in development of virus-induced ALI. PMID- 23919994 TI - Unique features of a Pseudomonas aeruginosa alpha2-macroglobulin homolog. AB - Human pathogens frequently use protein mimicry to manipulate host cells in order to promote their survival. Here we show that the opportunistic pathogen Pseudomonas aeruginosa synthesizes a structural homolog of the human alpha2 macroglobulin, a large-spectrum protease inhibitor and important player of innate immunity. Small-angle X-ray scattering analysis demonstrated that the fold of P. aeruginosa MagD (PA4489) is similar to that of the human macroglobulin and undergoes a conformational modification upon binding of human neutrophil elastase. MagD synthesis is under the control of a general virulence regulatory pathway including the inner membrane sensor RetS and the RNA-binding protein RsmA, and MagD undergoes cleavage from a 165-kDa to a 100-kDa form in all clinical isolates tested. Fractionation and immunoprecipitation experiments showed that MagD is translocated to the bacterial periplasm and resides within the inner membrane in a complex with three other molecular partners, MagA, MagB, and MagF, all of them encoded by the same six-gene genetic element. Inactivation of the whole 10-kb operon on the PAO1 genome resulted in mislocalization of uncleaved, in trans-provided MagD as well as its rapid degradation. Thus, pathogenic bacteria have acquired a homolog of human macroglobulin that plays roles in host-pathogen interactions potentially through recognition of host proteases and/or antimicrobial peptides; it is thus essential for bacterial defense. IMPORTANCE: The pathogenesis of Pseudomonas aeruginosa is multifactorial and relies on surface-associated and secreted proteins with different toxic activities. Here we show that the bacterium synthesizes a 160-kDa structural homolog of the human large-spectrum protease inhibitor alpha2-macroglobulin. The bacterial protein is localized in the periplasm and is associated with the inner membrane through the formation of a multimolecular complex. Its synthesis is coregulated at the posttranscriptional level with other virulence determinants, suggesting that it has a role in bacterial pathogenicity and/or in defense against the host immune system. Thus, this new P. aeruginosa macromolecular complex may represent a future target for antibacterial developments. PMID- 23919995 TI - Acinetobacter baumannii strain M2 produces type IV pili which play a role in natural transformation and twitching motility but not surface-associated motility. AB - Acinetobacter baumannii is a Gram-negative, opportunistic pathogen. Recently, multiple A. baumannii genomes have been sequenced; these data have led to the identification of many genes predicted to encode proteins required for the biogenesis of type IV pili (TFP). However, there is no experimental evidence demonstrating that A. baumannii strains actually produce functional TFP. Here, we demonstrated that A. baumannii strain M2 is naturally transformable and capable of twitching motility, two classical TFP-associated phenotypes. Strains were constructed with mutations in pilA, pilD, and pilT, genes whose products have been well characterized in other systems. These mutants were no longer naturally transformable and did not exhibit twitching motility. These TFP-associated phenotypes were restored when these mutations were complemented. More PilA was detected on the surface of the pilT mutant than the parental strain, and TFP were visualized on the pilT mutant by transmission electron microscopy. Thus, A. baumannii produces functional TFP and utilizes TFP for both natural transformation and twitching motility. Several investigators have hypothesized that TFP might be responsible, in part, for the flagellum-independent surface associated motility exhibited by many A. baumannii clinical isolates. We demonstrated that surface-associated motility was not dependent on the products of the pilA, pilD, and pilT genes and, by correlation, TFP. The identification of functional TFP in A. baumannii lays the foundation for future work determining the role of TFP in models of virulence that partially recapitulate human disease. IMPORTANCE: Several investigators have documented the presence of genes predicted to encode proteins required for the biogenesis of TFP in many A. baumannii genomes. Furthermore, some have speculated that TFP may play a role in the unique surface-associated motility phenotype exhibited by many A. baumannii clinical isolates, yet there has been no experimental evidence to prove this. Unfortunately, progress in understanding the biology and virulence of A. baumannii has been slowed by the difficulty of constructing and complementing mutations in this species. Strain M2, a recently characterized clinical isolate, is amenable to genetic manipulation. We have established a reproducible system for the generation of marked and/or unmarked mutations using a modified recombineering strategy as well as a genetic complementation system utilizing a modified mini-Tn7 element in strain M2. Using this strategy, we demonstrated that strain M2 produces TFP and that TFP are not required for surface-associated motility exhibited by strain M2. PMID- 23919996 TI - Structure and evolution of chlorate reduction composite transposons. AB - The genes for chlorate reduction in six bacterial strains were analyzed in order to gain insight into the metabolism. A newly isolated chlorate-reducing bacterium (Shewanella algae ACDC) and three previously isolated strains (Ideonella dechloratans, Pseudomonas sp. strain PK, and Dechloromarinus chlorophilus NSS) were genome sequenced and compared to published sequences (Alicycliphilus denitrificans BC plasmid pALIDE01 and Pseudomonas chloritidismutans AW-1). De novo assembly of genomes failed to join regions adjacent to genes involved in chlorate reduction, suggesting the presence of repeat regions. Using a bioinformatics approach and finishing PCRs to connect fragmented contigs, we discovered that chlorate reduction genes are flanked by insertion sequences, forming composite transposons in all four newly sequenced strains. These insertion sequences delineate regions with the potential to move horizontally and define a set of genes that may be important for chlorate reduction. In addition to core metabolic components, we have highlighted several such genes through comparative analysis and visualization. Phylogenetic analysis places chlorate reductase within a functionally diverse clade of type II dimethyl sulfoxide (DMSO) reductases, part of a larger family of enzymes with reactivity toward chlorate. Nucleotide-level forensics of regions surrounding chlorite dismutase (cld), as well as its phylogenetic clustering in a betaproteobacterial Cld clade, indicate that cld has been mobilized at least once from a perchlorate reducer to build chlorate respiration. IMPORTANCE: Genome sequencing has identified, for the first time, chlorate reduction composite transposons. These transposons are constructed with flanking insertion sequences that differ in type and orientation between organisms, indicating that this mobile element has formed multiple times and is important for dissemination. Apart from core metabolic enzymes, very little is known about the genetic factors involved in chlorate reduction. Comparative analysis has identified several genes that may also be important, but the relative absence of accessory genes suggests that this mobile metabolism relies on host systems for electron transport, regulation, and cofactor synthesis. Phylogenetic analysis of Cld and ClrA provides support for the hypothesis that chlorate reduction was built multiple times from type II dimethyl sulfoxide (DMSO) reductases and cld. In at least one case, cld has been coopted from a perchlorate reduction island for this purpose. This work is a significant step toward understanding the genetics and evolution of chlorate reduction. PMID- 23919997 TI - Small-molecule inhibitors of toxT expression in Vibrio cholerae. AB - Vibrio cholerae, a Gram-negative bacterium, infects humans and causes cholera, a severe disease characterized by vomiting and diarrhea. These symptoms are primarily caused by cholera toxin (CT), whose production by V. cholerae is tightly regulated by the virulence cascade. In this study, we designed and carried out a high-throughput chemical genetic screen to identify inhibitors of the virulence cascade. We identified three compounds, which we named toxtazin A and toxtazin B and B', representing two novel classes of toxT transcription inhibitors. All three compounds reduce production of both CT and the toxin coregulated pilus (TCP), an important colonization factor. We present evidence that toxtazin A works at the level of the toxT promoter and that toxtazins B and B' work at the level of the tcpP promoter. Treatment with toxtazin B results in a 100-fold reduction in colonization in an infant mouse model of infection, though toxtazin A did not reduce colonization at the concentrations tested. These results add to the growing body of literature indicating that small-molecule inhibitors of virulence genes could be developed to treat infections, as alternatives to antibiotics become increasingly needed. IMPORTANCE: V. cholerae caused more than 580,000 infections worldwide in 2011 alone (WHO, Wkly. Epidemiol. Rec. 87:289-304, 2012). Cholera is treated with an oral rehydration therapy consisting of water, glucose, and electrolytes. However, as V. cholerae is transmitted via contaminated water, treatment can be difficult for communities whose water source is contaminated. In this study, we address the need for new therapeutic approaches by targeting the production of the main virulence factor, cholera toxin (CT). The high-throughput screen presented here led to the identification of two novel classes of inhibitors of the virulence cascade in V. cholerae, toxtazin A and toxtazins B and B'. We demonstrate that (i) small molecule inhibitors of virulence gene production can be identified in a high throughput screen, (ii) targeting virulence gene production is an effective therapeutic strategy, and (iii) small-molecule inhibitors can uncover unknown layers of gene regulation, even in well-studied regulatory cascades. PMID- 23919998 TI - Influence of vaginal bacteria and D- and L-lactic acid isomers on vaginal extracellular matrix metalloproteinase inducer: implications for protection against upper genital tract infections. AB - We evaluated levels of vaginal extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase (MMP-8) in vaginal secretions in relation to the composition of vaginal bacterial communities and D- and L-lactic acid levels. The composition of vaginal bacterial communities in 46 women was determined by pyrosequencing the V1 to V3 region of 16S rRNA genes. Lactobacilli were dominant in 71.3% of the women, followed by Gardnerella (17.4%), Streptococcus (8.7%), and Enterococcus (2.2%). Of the lactobacillus-dominated communities, 51.5% were dominated by Lactobacillus crispatus, 36.4% by Lactobacillus iners, and 6.1% each by Lactobacillus gasseri and Lactobacillus jensenii. Concentrations of L-lactic acid were slightly higher in lactobacillus dominated vaginal samples, but most differences were not statistically significant. D-Lactic acid levels were higher in samples containing L. crispatus than in those with L. iners (P<0.0001) or Gardnerella (P=0.0002). The relative proportion of D-lactic acid in vaginal communities dominated by species of lactobacilli was in concordance with the proportions found in axenic cultures of the various species grown in vitro. Levels of L-lactic acid (P<0.0001) and the ratio of L-lactic acid to D-lactic acid (P=0.0060), but not concentrations of D lactic acid, were also correlated with EMMPRIN concentrations. Moreover, vaginal concentrations of EMMPRIN and MMP-8 levels were highly correlated (P<0.0001). Taken together, the data suggest the relative proportion of L- to D-lactic acid isomers in the vagina may influence the extent of local EMMPRIN production and subsequent induction of MMP-8. The expression of these proteins may help determine the ability of bacteria to transverse the cervix and initiate upper genital tract infections. IMPORTANCE: A large proportion of preterm births (>50%) result from infections caused by bacteria originating in the vagina, which requires that they traverse the cervix. Factors that influence susceptibility to these infections are not well understood; however, there is evidence that matrix metalloproteinase (MMP-8) is known to alter the integrity of the cervix. In this work, we show that concentrations of vaginal extracellular matrix metalloproteinase inducer (EMMPRIN) are influenced by members of the vaginal microbial community and concentrations of D- or L-lactic acid isomers in vaginal secretions. Elevated levels of D-lactic acid and the ratio of D- to L-lactic acid influence EMMPRIN concentrations as well as MMP-8 levels. Thus, isomers of lactic acid may function as signaling molecules that alter host gene expression and influence risk of infection-related preterm birth. PMID- 23919999 TI - Structure-informed design of an enzymatically inactive vaccine component for group A Streptococcus. AB - Streptococcus pyogenes (group A Streptococcus [GAS]) causes ~700 million human infections/year, resulting in >500,000 deaths. There is no commercial GAS vaccine available. The GAS surface protein arginine deiminase (ADI) protects mice against a lethal challenge. ADI is an enzyme that converts arginine to citrulline and ammonia. Administration of a GAS vaccine preparation containing wild-type ADI, a protein with inherent enzymatic activity, may present a safety risk. In an approach intended to maximize the vaccine safety of GAS ADI, X-ray crystallography and structural immunogenic epitope mapping were used to inform vaccine design. This study aimed to knock out ADI enzyme activity without disrupting the three-dimensional structure or the recognition of immunogenic epitopes. We determined the crystal structure of ADI at 2.5 A resolution and used it to select a number of amino acid residues for mutagenesis to alanine (D166, E220, H275, D277, and C401). Each mutant protein displayed abrogated activity, and three of the mutant proteins (those with the D166A, H275A, and D277A mutations) possessed a secondary structure and oligomerization state equivalent to those of the wild type, produced high-titer antisera, and avoided disruption of B-cell epitopes of ADI. In addition, antisera raised against the D166A and D277A mutant proteins bound to the GAS cell surface. The inactivated D166A and D277A mutant ADIs are ideal for inclusion in a GAS vaccine preparation. There is no human ortholog of ADI, and we confirm that despite limited structural similarity in the active-site region to human peptidyl ADI 4 (PAD4), ADI does not functionally mimic PAD4 and antiserum raised against GAS ADI does not recognize human PAD4. IMPORTANCE: We present an example of structural biology informing human vaccine design. We previously showed that the administration of the enzyme arginine deiminase (ADI) to mice protected the mice against infection with multiple GAS serotypes. In this study, we determined the structure of GAS ADI and used this information to improve the vaccine safety of GAS ADI. Catalytically inactive mutant forms of ADI retained structure, recognition by antisera, and immunogenic epitopes, rendering them ideal for inclusion in GAS vaccine preparations. This example of structural biology informing vaccine design may underpin the formulation of a safe and efficacious GAS vaccine. PMID- 23920000 TI - The novel mutation p.Trp147Arg of the steroidogenic acute regulatory protein causes classic lipoid congenital adrenal hyperplasia with adrenal insufficiency and 46,XY disorder of sex development. AB - BACKGROUND: The steroidogenic acute regulatory protein (StAR) is essential for steroidogenesis by mediating cholesterol transfer into mitochondria. Inactivating StAR mutations cause lipoid congenital adrenal hyperplasia. OBJECTIVE AND METHODS: To identify causative mutations in a patient presenting with adrenal failure during early infancy. The objective was to study the functional and structural consequences of the novel StAR mutation p.Trp147Arg in a Turkish patient detected in compound heterozygosity with the p.Glu169Lys mutation. RESULTS: Transient in vitro expression of the mutant proteins together with P450 side-chain cleavage enzyme, adrenodoxin, and adrenodoxin reductase yielded severely diminished cholesterol conversion of the p.Trp147Arg mutant. The previously described p.Glu169Lys mutant led to significantly lower cholesterol conversion than wild-type StAR protein. As derived from three-dimensional protein modeling, the residue W147 is stabilizing the C-terminal helix in a closed conformation hereby acting as gatekeeper of the ligand cavity of StAR. CONCLUSIONS: The novel mutation p.Trp147Arg causes primary adrenal insufficiency and complete sex reversal in the 46,XY patient. Clinical disease, in vitro studies and three-dimensional protein modeling of the mutation p.Trp147Arg underscore the relevance of this highly conserved residue for StAR protein function. PMID- 23920001 TI - In vivo porcine model for practicing retrograde intrarenal surgery. AB - OBJECTIVES: To examine the feasibility of retrograde intrarenal surgery (RIRS) in a porcine model. MATERIALS AND METHODS: Female pigs (n = 3) were placed in a dorsal lithotomy position under general anesthesia, and stone material was inserted into the renal pelvis of the pigs. The bladder was entered with a cystoscope, and a 0.038-inch hydrophilic guidewire was passed into the renal pelvis. Following successful placement of the guidewire, a ureteral access sheath (9.5/11.5 Fr) was placed to allow for optimal visualization. A 7.5-Fr flexible ureteroscope (Karl Storz Flex-X2) and a 200-MUm laser fiber were used for lithotripsy. When basketing was deemed necessary, zero-tipped nitinol stone baskets were used. Trainees then practiced all these manipulations on the model. RESULTS: Urologists with moderate experience in advanced endourologic surgery were trained using this model. However, there were some surgical difficulties due to the urinary system anatomy of the pig. Intravaginal location of the urethra, bladder neck location of the ureters, tight ureteric orifices, tortuous ureters, longitudinally elongated renal pelvis, narrow infundibulopelvic angle and shallow calices made the passage of the instruments and maneuverability of the flexible ureteroscope more difficult than in a human model. CONCLUSIONS: Despite some difficulties, our porcine model was very effective, because all the trainees successfully practiced the RIRS manipulations on this model. PMID- 23920002 TI - Doppler ultrasound examination of multiple sclerosis patients and control participants: inter-observer agreement and association with disease. AB - OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) has been proposed as a major risk factor for multiple sclerosis (MS). The aim of this study was to assess inter-observer agreement between two ultrasound examiners and to compare findings in MS patients and control participants. METHODS: A prospective, blinded, controlled study of MS patients diagnosed within 2 years (MS <= 2, n = 39), patients diagnosed more than 10 years ago (MS > 10, n = 43) and age- and sex matched control participants (n = 40). Ultrasound examinations were performed by two independent examiners. CCSVI criteria 1, 3, 4 and 5 as proposed by Zamboni were explored: (1) reflux in the internal jugular (IJV) and vertebral veins (VV), (3) IJV cross-sectional area (CSA) <=0.3 cm(2), (4) absence of flow in IJV and VV, and (5) reverted postural control of venous outflow. RESULTS: Criteria 1, 4 and 5 were met in less than 10% of the MS patients and control participants as studied by both examiners. The level of inter-observer agreement was poor for all parameters except assessment of the CSA of IJV at the thyroid level. Findings meeting CCSVI criterion 3 (CSA <= 0.3 cm(2)) were observed in 18/40 (45%) of the control participants, in 24/37 (65%) of MS <= 2 patients (p = 0.09 vs. control participants) and in 30/43 (70%) of the MS > 10 patients (p = 0.022 vs. control participants). CONCLUSIONS: The feasibility of the CCSVI criteria for common use is questionable because of low inter-observer agreement. Small-calibre IJVs meeting the CCSVI criterion 3 appear common in both Finnish control participants and MS patients, but the clinical significance of this finding is questionable. PMID- 23920003 TI - Evaluating the predictive ability of sweat chloride. PMID- 23920004 TI - The use of rescripting imagery for people with psychosis who hear voices. AB - BACKGROUND: Image rescripting can be helpful in reducing the distress associated with intrusive images or memories across a range of disorders. Existing studies using imagery rescripting with people with psychosis have not included people who hear voices. AIMS: This study aimed to explore the use of image rescripting with people with psychosis who have intrusive images or memories and hear voices. METHOD: This study used a one-off image rescripting session, using an A-B design with four participants with psychosis who were attending adult mental health community services. RESULTS: Clinically significant reductions in distress, negative affect and reduced conviction in the beliefs associated with the imagery were reported at 1-week follow-up and maintained for three of the four participants at 1-month follow-up. CONCLUSIONS: The study offers early indications that image rescripting can be used as a treatment approach for people with psychosis. Exploring visual imagery and rescripting visual memories where appropriate may be a useful extension of cognitive behavioural therapy for psychosis (CBTp). PMID- 23920005 TI - T helper subsets in Sjogren's syndrome and IgG4-related dacryoadenitis and sialoadenitis: a critical review. AB - IgG4-related disease (IgG4-RD) is a systemic disease characterized by the elevation of serum IgG4 and infiltration of IgG4-positive plasma cells in multiple target organs, including the pancreas, kidney, biliary tract and salivary glands. In contrast, Mikulicz's disease (MD) has been considered a subtype of Sjogren's syndrome (SS) based on histopathological similarities. However, it is now recognized that MD is an IgG4-RD distinguishable from SS and called as IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS). Regarding immunological aspects, it is generally accepted that CD4+ T helper (Th) cells play a crucial role in the pathogenesis of SS. Since it is well known that IgG4 is induced by Th2 cytokines such as interleukin (IL)-4 and IL-13, IgG4-DS is speculated to be a unique inflammatory disorder characterized by Th2 immune reactions. However, the involvement of Th cells in the pathogenesis of IgG4-DS remains to be clarified. Exploring the role of Th cell subsets in IgG4-DS is a highly promising field of investigation. In this review, we focus on the selective localization and respective functions of Th cell subsets and discuss the differences between SS and IgG4-DS to clarify the pathogenic mechanisms of these diseases. PMID- 23920006 TI - Portal for Families Overcoming Neurodevelopmental Disorders (PFOND): Implementation of a Software Framework for Facilitated Community Website Creation by Nontechnical Volunteers. AB - BACKGROUND: The Portal for Families Overcoming Neurodevelopmental Disorders (PFOND) provides a structured Internet interface for the sharing of information with individuals struggling with the consequences of rare developmental disorders. Large disease-impacted communities can support fundraising organizations that disseminate Web-based information through elegant websites run by professional staff. Such quality resources for families challenged by rare disorders are infrequently produced and, when available, are often dependent upon the continued efforts of a single individual. OBJECTIVE: The project endeavors to create an intuitive Web-based software system that allows a volunteer with limited technical computer skills to produce a useful rare disease website in a short time period. Such a system should provide access to emerging news and research findings, facilitate community participation, present summary information about the disorder, and allow for transient management by volunteers who are likely to change periodically. METHODS: The prototype portal was implemented using the WordPress software system with both existing and customized supplementary plug-in software modules. Gamification scoring features were implemented in a module, allowing editors to measure progress. The system was installed on a Linux-based computer server, accessible across the Internet through standard Web browsers. RESULTS: A prototype PFOND system was implemented and tested. The prototype system features a structured organization with distinct partitions for background information, recent publications, and community discussions. The software design allows volunteer editors to create a themed website, implement a limited set of topic pages, and connect the software to dynamic RSS feeds providing information about recent news or advances. The prototype was assessed by a fraction of the disease sites developed (8 out of 27), including Aarskog-Scott syndrome, Aniridia, Adams-Oliver syndrome, Cat Eye syndrome, Kabuki syndrome, Leigh syndrome, Peters anomaly, and Rothmund-Thomson syndrome. The editor progress score was used to measure performance for a portion of sites. CONCLUSIONS: The PFOND system provides a convenient and structured Internet resource for the facilitated creation of information resources for families confronted by rare disorders. The system empowers volunteers to participate in the creation of quality content, while allowing for the inevitable turnover of contributors over time. The next phase of PFOND development will focus on volunteer participation in system development and community engagement. PMID- 23920007 TI - The effects of hyperbaric air and hyperbaric oxygen on blood-brain barrier integrity in rats. AB - Hyperbaric oxygen (HBO) treatment yields conflicting results on blood-brain barrier (BBB) integrity under various pathological conditions and the effects of HBO on healthy brain is poorly understood. In this experimental study, the effects of HBO on BBB integrity were investigated in comparison with hyperbaric air (HBA) in intact rats. Four sessions of HBA or HBO were applied to intact rats in 24h. BBB integrity was functionally and structurally evaluated by determining extravasation of Evans blue (EB) dye and horseradish peroxidase (HRP) tracers. In immunohistochemical evaluation, relative staining intensity for occludin, a tight junction (TJ) protein, and aquaporin 4 (AQP4), a water-channel protein, was detected in the barrier type of microvessels of brain by image analysis. BBB permeability to EB dye significantly increased in animals in HBO treatment group compared to those in HBA and control groups (p<0.05). The immunoreactivity of occludin, a tight junction protein, remained essentially unaltered in capillaries of hippocampus in all groups. In animals exposed to HBO, AQP4 immunoreactivity significantly increased in parietal cortex compared to those in HBA and control groups (p<0.01). Ultrastructurally, frequent vesicles containing HRP reaction products were observed in capillary endothelial cells in cerebral cortex and hippocampus of rats subjected to both HBA and HBO. Our results indicate that the HBO administration to intact rats increased BBB permeability to both EB and HRP while HBA increased only HRP extravasation in these animals. The results of this study suggest that HBA also impairs the BBB integrity in intact rats as well as HBO. PMID- 23920008 TI - Reduced apoptosis by combining normobaric oxygenation with ethanol in transient ischemic stroke. AB - BACKGROUND AND PURPOSE: The effect of normobaric oxygen (NBO) on apoptosis remains controversial. The present study evaluated the effect of NBO on ischemia induced apoptosis and assessed the potential for improved outcomes by combining NBO administration with another neuroprotective agent, ethanol, in a rat stroke model. METHODS: Rats were subjected to right middle cerebral artery occlusion (MCAO) for 2h. At the onset of reperfusion, ischemic animals received either NBO (2h duration), an intraperitoneal injection of ethanol (1.0g/kg), or both NBO and ethanol. Extent of brain injury was determined by infarct volume, neurological deficit, and apoptotic cell death. Expression of pro- and anti-apoptotic proteins was evaluated through Western immunoblotting. RESULTS: Given alone, NBO and ethanol each slightly (p<0.05) reduced infarct volume to 38% and 37%, respectively, as compared to the impressive reduction of 51% (p<0.01) seen with combined NBO-ethanol administration. Neurologic deficits were also significantly reduced by 48% with combined NBO-ethanol therapy, as compared to lesser reductions of 24% and 23% with NBO or ethanol, respectively. Combined NBO-ethanol therapy decreased apoptotic cell death by 49%, as compared to 31% with NBO and 30% with ethanol. Similarly, combination therapy significantly increased expression of anti-apoptotic factors (Bcl-2 and Bcl-xL) and significantly reduced expression of pro-apoptotic proteins (BAX, Caspase-3, and AIF), as compared to the minimal or nil protein expression changes elicited by NBO or ethanol alone. CONCLUSIONS: In rats subjected to ischemic stroke, NBO administration salvages ischemic brain tissue through evidenced decrease in apoptotic cell death. Combined NBO therapy with ethanol administration greatly improves both degree of neuroprotection and associated apoptosis. PMID- 23920010 TI - Self-organization in Pd/W(110): interplay between surface structure and stress. AB - It has recently been shown that submonolayer Pd on W(110) forms highly ordered linear mesoscopic stripes at high temperatures. The stripes display an internal Pd superstructure with a nano-scale periodicity along the direction perpendicular to the periodicity of the stripes. The same type of superstructure is also observed in a wide range of temperatures below the stripe formation temperature. We present a combined experimental and theoretical study of this superstructure of Pd on W(110) and investigate its influence on the appearance of the linear mesoscopic stripes. By means of low-energy electron diffraction and low-energy electron microscopy we show that it has a far more peculiar dependence on temperature and coverage than expected from a regular surface reconstruction. Using density-functional theory, we model the Pd superstructures as periodic vacancy-line type configurations and investigate their energetics and elastic properties. From our calculated surface stresses and anisotropies for the vacancy line configurations, and based on the continuum elasticity theory, we demonstrate quantitatively that the vacancy-line type of structure is a prerequisite for the formation of the linear mesoscopic stripes. Moreover, we show that the physics driving the formation of the internal superstructure is very similar to the one at play in forming the mesoscopic stripes themselves. PMID- 23920009 TI - Functional somatotopy revealed across multiple cortical regions using a model of complex motor task. AB - The primary motor cortex (M1) possesses a functional somatotopic structure representations of adjacent within-limb joints overlap to facilitate coordination while maintaining discrete centers for individuated movement. We examined whether similar organization exists across other sensorimotor cortices. Twenty-four right handed healthy subjects underwent functional magnetic resonance imaging (fMRI) while tracking complex targets with flexion/extension at right finger, elbow and ankle separately. Activation related to each joint at false discovery rate of 0.005 served as its representation across multiple regions. Within each region, we identified the center of mass (COM) for each representation, and the overlap between the representations of within-limb (finger and elbow) and between-limb joints (finger and ankle). Somatosensory (S1) and premotor cortices (PMC) demonstrated greater distinction of COM and minimal overlap for within- and between-limb representations. In contrast, M1 and supplementary motor area (SMA) showed more integrative somatotopy with higher sharing for within-limb representations. Superior and inferior parietal lobule (SPL and IPL) possessed both types of structure. Some clusters exhibited extensive overlap of within- and between-limb representations, while others showed discrete COMs for within-limb representations. Our results help to infer hierarchy in motor control. Areas such as S1 may be associated with individuated movements, while M1 may be more integrative for coordinated motion; parietal associative regions may allow switch between both modes of control. Such hierarchy creates redundant opportunities to exploit in stroke rehabilitation. The use of complex rather than traditionally used simple movements was integral to illustrating comprehensive somatotopic structure; complex tasks can potentially help to understand cortical representation of skill and learning-related plasticity. PMID- 23920011 TI - Exposure to herpes simplex virus, type 1 and reduced cognitive function. AB - Herpes simplex virus, type 1 (HSV-1) causes cold sores, keratitis and rarely, fatal encephalitis. The infection is lifelong, with sensory ganglia serving as reservoirs of latent infection. Recently, exposure to HSV-1 has also been repeatedly associated with reduced cognitive function among healthy individuals without prior encephalitis. Though HSV-1 does not elevate risk for schizophrenia (SZ) per se, exposure is likewise associated with impaired cognitive functions among SZ patients. The range of cognitive changes observed in HSV-1 exposed persons has not been investigated systematically, nor is it known whether interaction between HSV-1 exposure and SZ related factors contributes to the impairment among SZ patients. Persons with or without schizophrenia/schizophreniform disorder (N = 298 total, DSM IV criteria) were assessed for HSV-1 exposure using serum HSV-1 antibody titers. The Penn Computerized Neurocognitive battery was used to assess eight cognitive domains with respect to accuracy and speed. There were no significant case-control differences in HSV-1 exposure. The SZ/schizophreniform disorder cases were significantly impaired in all cognitive domains compared with the controls. HSV-1 exposure was also associated with reduced cognitive function in the entire sample, but the magnitude of the effects and their patterns differed from the SZ related changes. Further, statistically significant interactions between HSV-1 exposure and SZ case status were not detected. HSV-1 exposure does not elevate risk for SZ, but it is associated with reduced function in specific cognitive domains regardless of SZ diagnostic status. An 'epidiagnostic' model for the association is proposed to explain the results. PMID- 23920013 TI - Prehospital unassisted assessment of stroke severity using telemedicine: a feasibility study. AB - BACKGROUND AND PURPOSE: We evaluated the feasibility and the reliability of remote stroke severity quantification in the prehospital setting using the Unassisted TeleStroke Scale (UTSS) via a telestroke ambulance system and a fourth generation mobile network. METHODS: The technical feasibility and the reliability of the UTSS were studied in healthy volunteers mimicking 41 stroke syndromes during ambulance transportation. RESULTS: Except for 1 issue, high-quality telestroke assessment was feasible in all scenarios. The mean examination time for the UTSS was 3.1 minutes (SD, 0.4). The UTSS showed excellent intrarater and interrater variability (rho=0.98 and 0.97; P<0.001), as well as excellent internal consistency and rater agreement. Adequate concurrent validity can be derived from the strong correlation between the UTSS and the National Institutes of Health Stroke Scale (rho=0.90; P<0.001). CONCLUSIONS: Remote assessment of stroke severity in fast-moving ambulances using a system dedicated to prehospital telemedicine, 4G technology, and the UTSS is feasible and reliable. PMID- 23920012 TI - Recommendations on angiographic revascularization grading standards for acute ischemic stroke: a consensus statement. PMID- 23920014 TI - Susceptibility-weighted imaging is more reliable than T2*-weighted gradient recalled echo MRI for detecting microbleeds. AB - BACKGROUND AND PURPOSE: We investigated the sensitivity and reliability of MRI susceptibility-weighted imaging (SWI) compared with routine MRI T2*-weighted gradient-recalled echo (GRE) for cerebral microbleed (CMB) detection. METHODS: We used data from a prospective study of cerebral amyloid angiopathy (n=9; mean age, 71+/-8.3) and healthy non-cerebral amyloid angiopathy controls (n=22; mean age, 68+/-6.3). Three raters (labeled 1, 2, and 3) independently interpreted the GRE and SWI sequences (using the phase-filtered magnitude image) blinded to clinical information. RESULTS: In 9 cerebral amyloid angiopathy cases, the raters identified 1146 total CMBs on GRE and 1432 CMBs on SWI. In 22 healthy control subjects, the raters identified >=1 CMBs in 6/22 on GRE (total 9 CMBs) and 5/22 on SWI (total 19 CMBs). Among cerebral amyloid angiopathy cases, the reliability between raters for CMB counts was good for SWI (intraclass correlation coefficient, 0.87) but only moderate for GRE (intraclass correlation coefficient, 0.52). In controls, agreement on the presence or absence of CMBs in controls was moderate to good on both SWI (kappa coefficient ranged from 0.57 to 0.74 across the 3 combinations of rater pairs) and GRE (kappa range, 0.31 to 0.70). A review of 114 hypointensities identified as possible CMBs indicated that increased detection and reliability on SWI was related to both increased contrast and higher resolution, allowing better discrimination of CMBs from the background and better anatomic differentiation from pial vessels. CONCLUSIONS: SWI confers greater reliability as well as greater sensitivity for CMB detection compared with GRE, and should be the preferred sequence for quantifying CMB counts. PMID- 23920015 TI - External validation of the secondary intracerebral hemorrhage score in The Netherlands. AB - BACKGROUND AND PURPOSE: We aimed to validate externally in a setting outside the United States the secondary intracerebral hemorrhage (ICH) score that was developed to predict the probability of macrovascular causes in patients with nontraumatic ICH. METHODS: Patients with nontraumatic ICH admitted to the University Medical Center Utrecht, the Netherlands, between 2003 and 2011 were included if an angiographic examination, neurosurgical inspection, or pathological examination had been performed. Secondary ICH score performance was assessed by calibration (agreement between predicted and observed outcomes) and discrimination (separation of those with and without macrovascular cause). RESULTS: Forty-eight of 204 patients (23.5%) had a macrovascular cause. The secondary ICH score showed modest calibration (P=0.06) and modest discriminative ability (c-statistic 0.73; 95% confidence interval, 0.65-0.80). Discrimination improved slightly using only noncontrast computed tomography categorization (c statistic 0.79; 95% confidence interval, 0.72-0.86). CONCLUSIONS: The discriminative ability and calibration of the secondary ICH score are moderate in a university hospital setting outside the United States. Clues on noncontrast computed tomography are the strongest predictor of a macrovascular cause in patients with ICH. PMID- 23920016 TI - Imaging of contrast medium extravasation in anticoagulation-associated intracerebral hemorrhage with dual-energy computed tomography. AB - BACKGROUND AND PURPOSE: Contrast medium extravasation (CE) in intracerebral hemorrhage (ICH) is a marker of ongoing bleeding and a predictor of hematoma expansion. The aims of the study were to establish an ICH model in which CE can be quantified, characterized in ICH during warfarin and dabigatran anticoagulation, and to evaluate effects of prothrombin complex concentrates on CE in warfarin-associated ICH. METHODS: CD1-mice were pretreated orally with warfarin, dabigatran, or vehicle. Prothrombin complex concentrates were administered in a subgroup of warfarin-treated mice. ICH was induced by stereotactic injection of collagenase VIIs into the right striatum. Contrast agent (350 MUL Isovue 370 mg/mL) was injected intravenously after ICH induction (2-3.5 hours). Thirty minutes later, mice were euthanized, and CE was measured by quantifying the iodine content in the hematoma using dual-energy computed tomography. RESULTS: The optimal time point for contrast injection was found to be 3 hours after ICH induction, allowing detection of both an increase and a decrease of CE using dual-energy computed tomography. CE was higher in the warfarin group compared with the controls (P=0.002). There was no significant difference in CE between dabigatran-treated mice and controls. CE was higher in the sham-treated warfarin group than in the prothrombin complex concentrates treated warfarin group (P<0.001). CONCLUSIONS: Dual-energy computed tomography allows quantifying CE, as a marker of ongoing bleeding, in a model of anticoagulation-associated ICH. Dabigatran induces less CE in ICH than warfarin and consequently reduces risks of hematoma expansion. This constitutes a potential safety advantage of dabigatran over warfarin. Nevertheless, in case of warfarin anticoagulation, prothrombin complex concentrates reduce this side effect. PMID- 23920017 TI - Refining angiographic biomarkers of revascularization: improving outcome prediction after intra-arterial therapy. AB - BACKGROUND AND PURPOSE: Angiographic revascularization grading after intra arterial stroke therapy is limited by poor standardization, making it unclear which scale is optimal for predicting outcome. Using recently standardized criteria, we sought to compare the prognostic performance of 2 commonly used reperfusion scales. METHODS: Inclusion criteria for this multicenter retrospective study were acute ischemic stroke attributable to middle cerebral artery M1 occlusion, intra-arterial therapy, and 90-day modified Rankin scale score. Post-intra-arterial therapy reperfusion was graded using the Thrombolysis in Myocardial Infarction (TIMI) and Modified Thrombolysis in Cerebral Infarction (mTICI) scales. The scales were compared for prediction of clinical outcome using receiver-operating characteristic analysis. RESULTS: Of 308 patients, mean age was 65 years, and median National Institutes of Health Stroke Scale score was 17. The mean time from stroke onset to groin puncture was 305 minutes. There was no difference in the time to treatment between patients grouped by final TIMI (ie, 0 versus 1 versus 2 versus 3) or mTICI grades (ie, 0 versus 1 versus 2a versus 2b versus 3). Good outcome (modified Rankin scale, 0-2) was achieved in 32.5% of patients, and mortality rate was 25.3% at 90 days. There was a 6.3% rate of parenchymal hematoma type 2. In receiver-operating characteristic analysis, mTICI was superior to TIMI for predicting 90-day modified Rankin scale 0 to 2 (c statistic: 0.74 versus 0.68; P<0.0001). The optimal threshold for identifying a good outcome was mTICI 2b to 3 (sensitivity 78.0%; specificity 66.1%). CONCLUSIONS: mTICI is superior to TIMI for predicting clinical outcome after intra-arterial therapy. mTICI 2b to 3 is the optimal biomarker for procedural success. PMID- 23920018 TI - Vascularization pattern after ischemic stroke is different in control versus diabetic rats: relevance to stroke recovery. AB - BACKGROUND AND PURPOSE: Pre-existing diabetes mellitus worsens brain functionality in ischemic stroke. We have previously shown that type 2 diabetic rats exhibit enhanced dysfunctional cerebral neovascularization and when these rats are subjected to cerebral ischemic reperfusion injury develop hemorrhagic transformation and greater neurological deficits. However, our knowledge of vascular and functional plasticity during the recovery phase of diabetic stroke is limited. This study tested the hypothesis that vascular repair is impaired in the poststroke period in diabetes mellitus, and this is associated with poor sensorimotor and cognitive function. We further hypothesized that glycemic control prevents impaired vascularization and improves functional outcome in diabetes mellitus. METHODS: Vascularization was assessed in the ipsilateral and contralateral hemispheres in control, diabetes mellitus and diabetes mellitus plus metformin groups 14 days after ischemic reperfusion injury, as well as in respective sham controls. Three-dimensional reconstruction of the fluorescein isothiocyanate (FITC)-stained vasculature was achieved by confocal microscopy, and stereological parameters, including vascular volume and surface area, were measured. Astrogliosis was determined by glial fibrillary acidic protein staining. The relative rates of sensorimotor recovery, cognitive decline, and spontaneous activity were assessed. RESULTS: Vascular density in the peri-infarct area was significantly reduced in diabetes mellitus, whereas there was reparative neovascularization in control rats. Astroglial swelling and reactivity were more pronounced in diabetic stroke compared with control stroke. Diabetes mellitus blunted sensorimotor recovery and also exacerbated anxiety-like symptoms and cognitive deficits. Glycemic control started after stroke partially prevented these changes. CONCLUSIONS: Diabetes mellitus impairs poststroke reparative neovascularization and impedes the recovery. Glycemic control after stroke can improve neurovascular repair and improve functional outcome. PMID- 23920019 TI - Population-based study of disability and institutionalization after transient ischemic attack and stroke: 10-year results of the Oxford Vascular Study. AB - BACKGROUND AND PURPOSE: Long-term outcome information after transient ischemic attack (TIA) and stroke is required to help plan and allocate care services. We evaluated the impact of TIA and stroke on disability and institutionalization over 5 years using data from a population-based study. METHODS: Patients from a UK population-based cohort study (Oxford Vascular Study) were recruited from 2002 to 2007 and followed up to 2012. Patients were followed up at 1, 6, 12, 24, and 60 months postevent and assessed using the modified Rankin scale. A multivariate regression analysis was performed to assess the predictors of disability postevent. RESULTS: A total of 748 index stroke and 440 TIA cases were studied. For patients with TIA, disability levels increased from 14% (63 of 440) premorbidly to 23% (60 of 256) at 5 years (P=0.002), with occurrence of subsequent stroke being a major predictor of disability. For stroke survivors, the proportion disabled (modified Rankin scale >2) increased from 21% (154 of 748) premorbidly to 43% (273 of 634) at 1 month (P<0.001), with 39% (132 of 339) of survivors disabled 5 years after stroke. Five years postevent, 70% (483 of 690) of patients with stroke and 48% (179 of 375) of patients with TIA were either dead or disabled. The 5-year risk of care home institutionalization was 11% after TIA and 19% after stroke. The average 5-year cost per institutionalized patient was $99,831 (SD, 67 020) for TIA and $125,359 (SD, 91 121) for stroke. CONCLUSIONS: Our results show that 70% of patients with stroke are either dead or disabled 5 years after the event. Thus, there remains considerable scope for improvements in acute treatment and secondary prevention to reduce postevent disability and institutionalization. PMID- 23920021 TI - An economic evaluation of public programs for internationalization: the case of the Diagnostic Program in Spain. AB - This paper evaluates the Diagnostic Program in Spain which is a publicly funded program to promote internationalization of companies located in Andalusia (south of Spain). The methodology used is the propensity score-matching. The treatment group consists of companies which participated in the Program until 2008. The control group has companies which planned to participate in the Program but had not done so up to that date. The response variable measures the ratio of export to total sales for each company. Four covariates have been taken into account: activity, location, sales and number of employees. The analysis leads to the conclusion that the companies that participated in the Program improved their ratio of exports to total sales by about 10 percentage points. PMID- 23920020 TI - Brain imaging and cognitive predictors of stroke and Alzheimer disease in the Framingham Heart Study. AB - BACKGROUND AND PURPOSE: Exposure to vascular risk factors has a gradual deleterious effect on brain MRI and cognitive measures. We explored whether a pattern of these measures exists that predicts stroke and Alzheimer disease (AD) risk. METHODS: A cognitive battery was administered to 1679 dementia and stroke free Framingham offspring (age, >55 years; mean, 65.7+/-7.0) between 1999 and 2004; participants were also free of other neurological conditions that could affect cognition and >90% also had brain MRI examination. We related cognitive and MRI measures to risks of incident stroke and AD <=10 years of follow-up. As a secondary analysis, we explored these associations in The Framingham Heart Study original cohort (mean age, 67.5+/-7.3 and 84.8+/-3.3 years at the cognitive assessment and MRI examination, respectively). RESULTS: A total of 55 Offspring participants sustained strokes and 31 developed AD. Offspring who scored <1.5 SD below predicted mean scores, for age and education, on an executive function test, had a higher risk of future stroke (hazard ratio [HR], 2.27; 95% confidence interval [CI], 1.06-4.85) and AD (HR, 3.60; 95% CI, 1.52-8.52); additional cognitive tests also predicted AD. Participants with low (<20 percentile) total brain volume and high (>20 percentile) white matter hyperintensity volume had a higher risk of stroke (HR, 1.97; 95% CI, 1.03-3.77 and HR, 2.74; 95% CI, 1.51 5.00, respectively) but not AD. Hippocampal volume at the bottom quintile predicted AD in the offspring and original cohorts (HR, 4.41; 95% CI, 2.00-9.72 and HR, 2.37; 95% CI, 1.12-5.00, respectively). A stepwise increase in stroke risk was apparent with increasing numbers of these cognitive and imaging markers. CONCLUSIONS: Specific patterns of cognitive and brain structural measures observed even in early aging predict stroke risk and may serve as biomarkers for risk prediction. PMID- 23920022 TI - Facultative and obligate parasite communities exhibit different network properties. AB - Network theory is gaining momentum as a descriptive tool in community ecology. Because organisms with the same lifestyle can still exhibit ecological differences, it is crucial to determine the scale at which networks should be described. Here we show that networks of hosts (mammals) and parasites (ectoparasitic gamasid mites) differ when either facultative or obligatory parasites only are considered. More importantly, the structure of these networks is opposed, with obligatory parasites networks being more modular, and facultative parasites networks being more nested. Our results have consequences for the way we define which species to include in ecological networks, which we discuss in the light of community ecology and epidemiology. PMID- 23920023 TI - Validating and Improving Injury Burden Estimates Study: the Injury-VIBES study protocol. AB - BACKGROUND: Priority setting, identification of unmet and changing healthcare needs, service and policy planning, and the capacity to evaluate the impact of health interventions requires valid and reliable methods for quantifying disease and injury burden. The methodology developed for the Global Burden of Disease (GBD) studies has been adopted to estimate the burden of disease in national, regional and global projects. However, there has been little validation of the methods for estimating injury burden using empirical data. OBJECTIVE: To provide valid estimates of the burden of non-fatal injury using empirical data. SETTING: Data from prospective cohort studies of injury outcomes undertaken in the UK, USA, Australia, New Zealand and The Netherlands. DESIGN AND PARTICIPANTS: Meta analysis of deidentified, patient-level data from over 40 000 injured participants in six prospective cohort studies: Victorian State Trauma Registry, Victorian Orthopaedic Trauma Outcomes Registry, UK Burden of Injury study, Prospective Outcomes of Injury study, National Study on Costs and Outcomes of Trauma and the Dutch Injury Patient Survey. ANALYSIS: Data will be systematically analysed to evaluate and refine injury classification, development of disability weights, establishing the duration of disability and handling of cases with more than one injury in burden estimates. Developed methods will be applied to incidence data to compare and contrast various methods for estimating non-fatal injury burden. CONTRIBUTION TO THE FIELD: The findings of this international collaboration have the capacity to drive how injury burden is measured for future GBD estimates and for individual country or region-specific studies. PMID- 23920024 TI - Persons with multiple disabilities increase adaptive responding and control inadequate posture or behavior through programs based on microswitch-cluster technology. AB - Study I used typical microswitch-cluster programs to promote adaptive responding (i.e., object manipulation) and reduce inappropriate head or head-trunk forward leaning with a boy and a woman with multiple disabilities. Optic, tilt, and vibration microswitches were used to record their adaptive responses while optic and tilt microswitches monitored their posture. The study included an ABB(1)AB(1) sequence, in which A represented baseline phases, B represented an intervention phase in which adaptive responses were always followed by preferred stimulation, and B(1) represented intervention phases in which the adaptive responses led to preferred stimulation only if the inappropriate posture was absent. Study II assessed a non-typical, new microswitch-cluster program to promote two adaptive responses (i.e., mouth cleaning to reduce drooling effects and object assembling) with a man with multiple disabilities. Initially, the man received preferred stimulation for each cleaning response. Then, he received stimulation only if mouth cleaning was preceded by object assembling. The results of Study I showed that both participants had large increases in adaptive responding and a drastic reduction in inappropriate posture during the B(1) phases and a 2-week post intervention check. The results of Study II showed that the man learned to control drooling effects through mouth cleaning and used object assembling to extend constructive engagement and interspace cleaning responses functionally. The practical implications of the findings are discussed. PMID- 23920025 TI - Using developmental trajectories to examine verbal and visuospatial short-term memory development in children and adolescents with Williams and Down syndromes. AB - Williams (WS) and Down (DS) syndromes have been associated with specifically compromised short-term memory (STM) subsystems. Individuals with WS have shown impairments in visuospatial STM, while individuals with DS have often shown problems with the recall of verbal material. However, studies have not usually compared the development of STM skills in these domains, in these populations. The present study employed a cross-sectional developmental trajectories approach, plotting verbal and visuospatial STM performance against more general cognitive and chronological development, to investigate how the domain-specific skills of individuals with WS and DS may change as development progresses, as well as whether the difference between STM skill domains increases, in either group, as development progresses. Typically developing children, of broadly similar cognitive ability to the clinical groups, were also included. Planned between- and within-group comparisons were carried out. Individuals with WS and DS both showed the domain-specific STM weaknesses in overall performance that were expected based on the respective cognitive profiles. However, skills in both groups developed, according to general cognitive development, at similar rates to those of the TD group. In addition, no significant developmental divergence between STM domains was observed in either clinical group according to mental age or chronological age, although the general pattern of findings indicated that the influence of the latter variable across STM domains, particularly in WS, might merit further investigation. PMID- 23920026 TI - Interaction of child disability and stressful life events in predicting maternal psychological health. Results of an area-based study of very preterm infants at two years corrected age. AB - This study aimed at exploring the relationship between severe neuromotor and/or sensory disability in very preterm infants assessed at 2 years corrected age and their mothers' psychological health. Data on 581 Italian singletons born at 22-31 weeks of gestation in five Italian regions and their mothers were analyzed. Maternal psychological distress was measured through the General Health Questionnaire short version (GHQ-12). The prevalence of any maternal distress (GHQ scores >= 2) and of clinical distress (scores >= 5) were 31.3% and 8.1% respectively. At multivariable analysis, we found a statistically significant association between child's disability and mothers' GHQ scoring >= 5 (OR 3.45, 95% CI 1.07-11.15). Also lower maternal education appeared to increase the likelihood of psychological distress (OR 1.38, 95% CI 1.14-1.66). The impact of child disability was weaker in women who had experienced additional stressful life events since delivery, pointing to the existence of a "ceiling" effect. Maternal psychological assessment and support should be included in follow-up programs targeting very preterm infants. PMID- 23920027 TI - Does format matter for comprehension of a facial affective scale and a numeric scale for pain by adults with Down syndrome? AB - People with intellectual disabilities are at high risk for pain and have communication difficulties. Facial and numeric scales for self-report may aid pain identification. It was examined whether the comprehension of a facial affective scale and a numeric scale for pain in adults with Down syndrome (DS) varies with presentation format. Adults with DS were included (N=106, mild to severe ID, mean age 37 years), both with (N=57) and without (N=49) physical conditions that may cause pain or discomfort. The Facial Affect Scale (FAS) and a numeric rating scale (NRS) were compared. One subgroup of participants (N=50) had to choose the two items within each format to indicate 'least pain' and 'most pain'. The other subgroup of participants (N=56) had to order three faces of the FAS from 'least pain' to 'most pain', and to answer questions about the magnitude of numbers for the NRS. Comprehension percentages were compared between two subgroups. More participants understood the FAS than the NRS, irrespective of the presentation format. The comprehension percentage for the FAS did not differ between the least-most extremities format and the ordering/magnitude format. In contrast, comprehension percentages for the NRS differed significantly between the least-most extremities format (61%) and the ordering/magnitude format (32%). The inclusion of ordering and magnitude in a presentation format is essential to assess thorough comprehension of facial and numeric scales for self-reported pain. The use of this format does not influence the number of adults with DS who pass the comprehension test for the FAS, but reduces the number of adults with DS who pass the comprehension test for the NRS. PMID- 23920028 TI - Mothers of children with developmental disabilities: stress in early and middle childhood. AB - Using a sample of 219 families of children with (n=94) and without (n=125) developmental disabilities, this study examined the longitudinal perspectives of maternal stress in early (ages 3-5) and middle childhood (ages 6-13) and its relationship to mothers' and children's characteristics. Multivariate latent curve models indicated that maternal stress remained high and stable with minimal individual variation in early childhood, but declined with significant individual variation in middle childhood. Maternal stress at the beginning of middle childhood was associated with earlier maternal stress, as well as children's behavioral problems and social skills. The trajectory of maternal stress across middle childhood was related to children's behavioral problems. Implications for interventions are discussed. PMID- 23920030 TI - Reply: To PMID 23270865. PMID- 23920029 TI - Procedural learning is impaired in dyslexia: evidence from a meta-analysis of serial reaction time studies. AB - A number of studies have investigated procedural learning in dyslexia using serial reaction time (SRT) tasks. Overall, the results have been mixed, with evidence of both impaired and intact learning reported. We undertook a systematic search of studies that examined procedural learning using SRT tasks, and synthesized the data using meta-analysis. A total of 14 studies were identified, representing data from 314 individuals with dyslexia and 317 typically developing control participants. The results indicate that, on average, individuals with dyslexia have worse procedural learning abilities than controls, as indexed by sequence learning on the SRT task. The average weighted standardized mean difference (the effect size) was found to be 0.449 (CI95: .204, .693), and was significant (p<.001). However, moderate levels of heterogeneity were found between study-level effect sizes. Meta-regression analyses indicated that studies with older participants that used SRT tasks with second order conditional sequences, or with older participants that used sequences that were presented a large number of times, were associated with smaller effect sizes. These associations are discussed with respect to compensatory and delayed memory systems in dyslexia. PMID- 23920031 TI - Aggressive hydration with lactated Ringer's solution reduces pancreatitis after endoscopic retrograde cholangiopancreatography. AB - BACKGROUND & AIMS: Pancreatitis is the most common serious complication of endoscopic retrograde cholangiopancreatography (ERCP). We performed a pilot study to determine whether aggressive periprocedural hydration with lactated Ringer's solution reduces the incidence of pancreatitis after ERCP. METHODS: Patients who underwent first-time ERCP were randomly assigned to groups (2:1) that received aggressive hydration with lactated Ringer's solution (3 mL/kg/h during the procedure, a 20-mL/kg bolus after the procedure, and 3 mL/kg/h for 8 hours after the procedure, n = 39) or standard hydration with the same solution (1.5 mL/kg/h during and for 8 hours after procedure, n = 23). Serum levels of amylase, visual analogue pain scores (scale of 0-10), and volume overload were assessed at baseline and 2, 8, and 24 hours after ERCP. The primary end point, post-ERCP pancreatitis, was defined as hyperamylasemia (level of amylase >3 times the upper limit of normal) and increased epigastric pain (>=3 points on visual analogue scale) persisting for >=24 hours after the procedure. Secondary end points included hyperamylasemia, increased pain, and volume overload. RESULTS: None of the patients who received aggressive hydration developed post-ERCP pancreatitis, compared with 17% of patients who received standard hydration (P = .016). Hyperamylasemia developed in 23% of patients who received aggressive hydration vs 39% of those who received standard hydration (P = .116, nonsignificant); increased epigastric pain developed in 8% of patients who received aggressive hydration vs 22% of those who received standard hydration (P = .146, nonsignificant). No patients had evidence of volume overload. CONCLUSIONS: On the basis of a pilot study, aggressive intravenous hydration with lactated Ringer's solution appears to reduce the development of post-ERCP pancreatitis and is not associated with volume overload. ClinicalTrials.gov, Number: NCT 01758549. PMID- 23920032 TI - Cancer risk after resection of polypoid dysplasia in patients with longstanding ulcerative colitis: a meta-analysis. AB - BACKGROUND & AIMS: American and European guidelines propose complete endoscopic resection of polypoid dysplasia (adenomas or adenoma-like masses) in patients with longstanding colitis, with close endoscopic follow-up. The incidence of cancer after detection of flat low-grade dysplasia or dysplasia-associated lesion or mass is estimated at 14 cases/1000 years of patient follow-up. However, the risk for polypoid dysplasia has not been determined with precision. We investigated the risk of cancer after endoscopic resection of polypoid dysplasia in patients with ulcerative colitis. METHODS: MEDLINE, EMBASE, PubMed, and the Cochrane library were searched for studies of patients with colitis and resected polypoid dysplasia, with reports of colonoscopic follow-up and data on cancers detected. Outcomes from included articles were pooled to provide a single combined estimate of outcomes by using Poisson regression. RESULTS: Of 425 articles retrieved, we analyzed data from 10 studies, comprising 376 patients with colitis and polypoid dysplasia with a combined 1704 years of follow-up. A mean of 2.8 colonoscopies were performed for each patient after the index procedure (range, 0-15 colonoscopies). The pooled incidence of cancer was 5.3 cases (95% confidence interval, 2.7-10.1 cases)/1000 years of patient follow-up. There was no evidence of heterogeneity or publication bias. The pooled rate of any dysplasia was 65 cases (95% confidence interval, 54-78 cases)/1000 patient years. CONCLUSION: Patients with colitis have a low risk of colorectal cancer after resection of polypoid dysplasia; these findings support the current strategy of resection and surveillance. However, these patients have a 10-fold greater risk of developing any dysplasia than colorectal cancer and should undergo close endoscopic follow-up. PMID- 23920033 TI - Pathogenesis, diagnosis, and management of gastric ischemia. AB - BACKGROUND & AIMS: Gastric ischemia is infrequently reported in the medical literature and under-recognized clinically and histopathologically. Various medical terms are used to describe gastric ischemia. We define and review the pathogenesis, diagnosis, and management of gastric ischemia. METHODS: We describe 6 cases of gastric ischemia. We discuss features of the gastric vascular supply and review literature on this disorder. RESULTS: Gastric ischemia results from diffuse or localized vascular insufficiency caused by etiologies such as systemic hypotension, vasculitis, or disseminated thromboembolism. The disorder is managed by fluid resuscitation, nasogastric tube placement (for intermittent air and fluid aspiration, to prevent or reduce gastric distention), aggressive acid reduction (via intravenous administration of proton pump inhibitors), and selective use of broad-spectrum antibiotics for patients with sepsis or gastric pneumatosis. CONCLUSIONS: Gastric ischemia has a poor prognosis. Early diagnosis is required for appropriate patient management. PMID- 23920034 TI - Endoscopic duodenal-jejunal bypass liner rapidly improves plasma parameters of nonalcoholic fatty liver disease. AB - Bariatric surgery reduces nonalcoholic fatty liver disease (NAFLD). We investigated the effects of duodenal-jejunal bypass liner (DJBL), nonsurgical bariatric device, on plasma parameters of NAFLD. Seventeen obese subjects with type 2 diabetes received the DJBL for 24 weeks. Before, during, and after DJBL implantation, we determined plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (gamma-GT), albumin, caspase-cleaved cytokeratin-18 (CK-18), and liver fatty acid-binding protein (L FABP). At baseline, subjects had increased levels of AST (35 +/- 4 IU/L), ALT (54 +/- 5 IU/L), and gamma-GT (66 +/- 14 IU/L), compared with healthy individuals; subjects' mean concentrations of caspase-cleaved CK-18 and L-FABP were 214.4 +/- 35.6 U/L and 29.3 +/- 2.6 ng/mL, respectively. Three months after implantation of DJBL, all NAFLD-related parameters had decreased from baseline (AST, 28 +/- 3 IU/L; ALT, 32 +/- 2 IU/L; gamma-GT, 44 +/-7 IU/L; caspase-cleaved CK-18, 140.6 +/ 16.3U/L; and L-FABP, 18.2 +/- 1.5 ng/mL; all P < .05). After 6 months, levels of ALT and gamma-GT had further decreased (ALT, 28 +/- 2 IU/L and gamma-GT, 35 +/- 5 IU/L), whereas levels of AST, caspase-cleaved CK-18, and L-FABP had stabilized (P = not significant). Six months after DJBLs were removed, levels of ALT (37 +/- 3 IU/L), gamma-GT (42 +/- 5 IU/L), and caspase-cleaved CK-18 (124.5 +/- 12.5U/L) were still reduced (P < .05), whereas AST and L-FABP had returned to near baseline levels (P = not significant). Therefore, in obese subjects, DJBL reduces plasma parameters of NAFLD. ClinicalTrials.gov, Number: NCT00985114. PMID- 23920035 TI - Gastroesophageal reflux does not alter effects of body mass index on risk of esophageal adenocarcinoma. AB - BACKGROUND & AIMS: A history of high body mass index (BMI) is associated strongly with a risk of esophageal adenocarcinoma (EAC). We investigated whether gastroesophageal reflux is involved in this association. METHODS: We analyzed data from a population-based Swedish nationwide study of patients with a new diagnosis of EAC (n = 189) or gastroesophageal junction adenocarcinoma (n = 262), and matched controls (n = 816), from 1995 through 1997. Our analysis included data on BMI 20 years before study inclusion; maximum adult BMI; frequency, severity, and duration of gastroesophageal reflux symptoms; tumor features; and covariates (sex, age, smoking, alcohol, fruit and vegetable intake, and socioeconomic status). We conducted stratified analyses and synergy tests, adjusting for covariates. RESULTS: Odds ratios (ORs) for EAC among subjects with a BMI of 25 or higher 20 years before inclusion, compared with those with a BMI less than 25, did not differ significantly, without or with adjustment for gastroesophageal reflux frequency (OR, 3.1; 95% confidence interval [CI], 2.2 4.4; and OR, 3.3; 95% CI, 2.2-4.8, respectively), severity (OR, 3.3; 95% CI, 2.2 4.8), or duration (OR, 3.2; 95% CI, 2.2-4.7). However, there were interactions between BMI and categories of gastroesophageal reflux. BMI appeared to have the largest effect on gastroesophageal reflux frequency (synergy index, 8.9; 95% CI, 2.3-34.1 for maximum BMI; and gastroesophageal reflux >3 times/wk). CONCLUSIONS: Based on a population-based study, the association between BMI and EAC does not appear to be affected by symptomatic gastroesophageal reflux, although there appears to be synergy between BMI and reflux. PMID- 23920036 TI - Assessment of changes in immune measures of multiple sclerosis patients treated with laquinimod. AB - Laquinimod is a novel orally active agent with immunomodulatory properties that was shown to be effective in suppressing disease activity in relapsing-remitting multiple sclerosis patients. Though many mechanisms of action of laquinimod have been described, little is known about the in vivo effects of laquinimod on the functionality of circulating human peripheral blood mononuclear cell populations. We assessed both phenotypical and functional measures of PBMC in a prospective longitudinal analysis comparing laquinimod and placebo treated cohorts. We determined that there were no significant changes in the relative proportion of T cells, B-cells, monocytes & macrophages, NK-cells, dendritic cells or FoxP3(+) CD25(hi) T-regs in laquinimod treated patients. There were also no significant differences in the proliferative response to PHA or tetanus antigen, or in the inflammatory cytokine bias of these responses. These data demonstrated that there were no significant changes in immune function of PBMC in patients receiving two years of continuous laquinimod therapy who retained a full complement of the major populations of circulating PBMC and retained their capacity to respond to immunologic stimuli. PMID- 23920037 TI - The effects of lipoplex formulation variables on the protein corona and comparisons with in vitro transfection efficiency. AB - The use of lipoplexes for the intracellular delivery of nucleic acids typically involves the optimization of several parameters that are known to affect delivery. Researchers commonly vary charge ratio, and often incorporate different amounts of helper lipids (e.g., cholesterol) to optimize formulations for transfection in cell culture and in vivo. The results of such experiments are often interpreted in the context of nuclease resistance and cell association, but effects on the protein corona are usually not considered. While many studies have demonstrated that lipoplex structure and function can be dramatically compromised in the presence of serum, little attention has been paid to the adsorption of specific proteins and how this might be affected by formulation parameters. In this study, we characterize changes in the protein corona that occur as DOTAP based lipoplexes are formulated with different amounts of cholesterol and prepared at different charge ratios. Our results demonstrate a significant effect of lipid composition on both total protein adsorption as well as the individual proteins from fetal calf serum that are associated with lipoplexes. In addition, we show that PEGylation increases protein adsorption with our formulations; effects that depend on the type of PEG conjugate employed in the lipoplex. Attempts to identify a specific protein responsible for enhancing transfection were unsuccessful. PMID- 23920038 TI - In vitro and in vivo mapping of drug release after laser ablation thermal therapy with doxorubicin-loaded hollow gold nanoshells using fluorescence and photoacoustic imaging. AB - Doxorubicin-loaded hollow gold nanoshells (Dox@PEG-HAuNS) increase the efficacy of photothermal ablation (PTA) not only by mediating efficient PTA but also through chemotherapy, and therefore have potential utility for local anticancer therapy. However, in vivo real-time monitoring of Dox release and temperature achieved during the laser ablation technique has not been previously demonstrated before. In this study, we used fluorescence optical imaging to map the release of Dox from Dox@PEG-HAuNS and photoacoustic imaging to monitor the tumor temperature achieved during near-infrared laser-induced photothermal heating in vitro and in vivo. In vitro, treatment with a 3-W laser was sufficient to initiate the release of Dox from Dox@PEG-HAuNS (1:3:1 wt/wt, 1.32 * 10(12)particles/mL). Laser powers of 3 and 6W achieved ablative temperatures of more than 50 degrees C. In 4T1 tumor-bearing nude mice that received intratumoral or intravenous injections of Dox@PEG-HAuNS, fluorescence optical imaging (emission wavelength = 600 nm, excitation wavelength = 500 nm) revealed that the fluorescence intensity in surface laser-treated tumors 24h after treatment was significantly higher than that in untreated tumors (p = 0.015 for intratumoral, p = 0.008 for intravenous). Similar results were obtained using an interstitial laser to irradiate tumors following the intravenous injection of Dox@PEG-HAuNS (p = 0.002 at t = 24h). Photoacoustic imaging (acquisition wavelength = 800 nm) revealed that laser treatment caused a substantial increase in tumor temperature, from 37 degrees C to ablative temperatures of more than 50 degrees C. Ex vivo analysis revealed that the fluorescence intensity of laser-treated tumors was twice as high as that of untreated tumors (p = 0.009). Histological analysis confirmed that intratumoral injection of Dox@PEG-HAuNS and laser treatment caused significantly more tumor necrosis compared to tumors that were not treated with laser (p<0.001). On the basis of these findings, we conclude that fluorescence optical imaging and photoacoustic imaging are promising approaches to assessing Dox release and monitoring temperature, respectively, after Dox@PEG-HAuNS-mediated thermal ablation therapy. PMID- 23920040 TI - Physical and sociopsychological characteristics of older community residents with mild cognitive impairment as assessed by the Japanese version of the Montreal Cognitive Assessment. AB - BACKGROUND: Although mild cognitive impairment (MCI) criteria are disputable, characterizing various aspects of operational MCI (O-MCI) may lead to a better understanding of potential modulators of cognitive decline and contribute to more effective public health strategies. The aim of the study is to examine characteristics of community-dwelling elderly people with MCI assessed using Japanese version of Montreal Cognitive Assessment (MoCA-J). METHODS: A total of 913 community-dwelling Japanese (65-84 years) participated in health examinations in Tokyo, 2011. The MoCA-J, Mini-Mental State Examination (MMSE), and other physical and mental tests were conducted. Excluded were those with <24 MMSE scores. Those with <26 in MoCA-J were divided into 2 subgroups, (A) participants independent of instrumental activities of daily living (IADL) and no memory complaints and (B) participants independent of IADL with memory complaints or partially dependent on IADL with/without memory complaints. Those with >=26 in MoCA-J and subgroup (A) of MCI were the normal controls (NCs, 57.4%), and subgroup (B) of MCI was O-MCI, 36.5%. We compared each variable between NC and O MCI, using logistic regression analysis, adjusted for gender and age. RESULTS: The majority of all the groups were independent of IADL. The O-MCI characteristics were increased depressive symptom, worse self-rated health, lower systolic blood pressure, poorer intellectual activities, no hobbies, weaker grip strength, and slower than usual walking speed compared to the NC group. CONCLUSIONS: Older persons with O-MCI defined by MoCA-J have partially decreased cognition and physical and sociopsychological functions. PMID- 23920039 TI - Biodistribution and bioimaging studies of hybrid paclitaxel nanocrystals: lessons learned of the EPR effect and image-guided drug delivery. AB - Paclitaxel (PTX) nanocrystals (200 nm) were produced by crystallization from a solution. Antitumor efficacy and toxicity were examined through a survival study in a human HT-29 colon cancer xenograft murine model. The antitumor activity of the nanocrystal treatments was comparable with that by the conventional solubilization formulation (Taxol(r)), but yielded less toxicity as indicated by the result of a survival study. Tritium-labeled PTX nanocrystals were further produced with a near infrared (NIR) fluorescent dye physically integrated in the crystal lattice. Biodistribution and tumor accumulation of the tritium-labeled PTX nanocrystals were determined immediately after intravenous administration and up to 48 h by scintillation counting. Whole-body optical imaging of animals was concurrently carried out; fluorescent intensities were also measured from excised tumors and major organs of euthanized animals. It was found that drug accumulation in the tumor was less than 1% of 20mg/kg intravenous dose. Qualitatively correlation was identified between the biodistribution determined by using tritium-labeled particles and that using optical imaging, but quantitative divergence existed. The divergent results suggest possible ways to improve the design of hybrid nanocrystals for cancer therapy and diagnosis. The study also raises questions of the general role of the enhanced permeability and retention (EPR) effect in tumor targeting and the effectiveness of bioimaging, specifically for theranostics, in tracking drug distribution and pharmacokinetics. PMID- 23920041 TI - DYRK1A overexpression decreases plasma lecithin:cholesterol acyltransferase activity and apolipoprotein A-I levels. AB - BACKGROUND AND AIMS: Down syndrome is caused by trisomy of all or part of human chromosome 21. Individuals with Down syndrome present some metabolic abnormalities involving lipoproteins, notably lower high-density lipoprotein levels associated with altered lecithin:cholesterol acyltransferase activity and apolipoprotein A-I levels. DYRK1A is a kinase overexpressed in Down syndrome that can activate the STAT3 pathway, which is involved in lecithin:cholesterol acyltransferase expression. Therefore, we characterized the role of DYRK1A overexpression on lecithin:cholesterol acyltransferase activity and expression in mouse models. METHODS: Effects of Dyrk1a overexpression were examined in mice overexpressing Dyrk1a by ELISA, chemical analyses and Western blotting. RESULTS: Overexpression of DYRK1A decreased plasma lecithin:cholesterol acyltransferase activity and hepatic STAT3 activation, which was associated with activation of SHP2, a tyrosine phosphatase. Although hepatic apolipoprotein E and D levels were increased in mice overexpressing DYRK1A, decreased plasma lecithin:cholesterol acyltransferase activity was associated with decreased hepatic and plasma apolipoprotein A-I levels. High-density lipoprotein-cholesterol levels were also decreased in plasma despite similar total cholesterol and non-high-density lipoprotein-cholesterol levels. CONCLUSIONS: We identified the role of DYRK1A overexpression on altered lipoprotein metabolism. PMID- 23920042 TI - Development of MLPA for human ACAT1 gene and identification of a heterozygous Alu mediated deletion of exons 3 and 4 in a patient with mitochondrial acetoacetyl CoA thiolase (T2) deficiency. AB - Mitochondrial acetoacetyl-CoA thiolase deficiency is an autosomal recessive disorder, characterized by intermittent ketoacidosis. We developed a multiplex ligation-dependent probe amplification method for mutation detection in the ACAT1 gene, which encodes this enzyme, and validated it using DNAs from two previously reported patients having partial deletion and duplication in this gene. Using this method, we identified a heterozygous deletion including exons 3-4 in a third patient, likely due to Alu-mediated non-equal homologous recombination between Alu sequences. PMID- 23920043 TI - Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool. AB - Recent expansion of our knowledge on epigenetic changes strongly suggests that not only nuclear DNA (nDNA), but also mitochondrial DNA (mtDNA) may be subjected to epigenetic modifications related to disease development, environmental exposure, drug treatment and aging. Thus, mtDNA methylation is attracting increasing attention as a potential biomarker for the detection and diagnosis of diseases and the understanding of cellular behavior in particular conditions. In this paper we review the current advances in mtDNA methylation studies with particular attention to the evidences of mtDNA methylation changes in diseases and physiological conditions so far investigated. Technological advances for the analysis of epigenetic variations are promising tools to provide insights into methylation of mtDNA with similar resolution levels as those reached for nDNA. However, many aspects related to mtDNA methylation are still unclear. More studies are needed to understand whether and how changes in mtDNA methylation patterns, global and gene specific, are associated to diseases or risk factors. PMID- 23920044 TI - Expanding the clinical phenotype at the 3q13.31 locus with a new case of microdeletion and first characterization of the reciprocal duplication. AB - Congenital deletions at the 3q13.31 locus have been recently described as a novel microdeletion syndrome characterized by developmental delay, postnatal overgrowth, hypoplastic male genitalia and characteristic facial features. A common critical region of overlapping of 580kb was delineated including two strong candidate genes for developmental delay: DRD3 and ZBTB20. In this report, we describe a new case of 3q13.31 microdeletion identified by array-CGH in a 16year-old girl sharing clinical features commonly observed in the 3q13.31 microdeletion syndrome. This girl had a microdeletion of 7.39Mb spanning the common critical region of overlapping. More interestingly, we report for the first time the existence of a microduplication reciprocal to the microdeletion syndrome. This familial 2.76Mb microduplication identified by array-CGH was carried by two brothers and their father. The phenotype shared by the brothers resembled the phenotype related to the 3q13.31 microdeletion syndrome including especially severe intellectual disability, developmental delay, behavioral abnormalities and obesity. This microduplication involves three strong candidate genes for the developmental delay ZBTB20, LSAMP and GAP43. Further molecular characterization showed that DRD3, another strong candidate gene for developmental delay, was not included in the duplicated region. However, a dosage alteration of this gene cannot be completely excluded as the duplication was inverted at proximity of this gene, as revealed by FISH analysis. Finally, we hypothesized that the phenotype shared by the two brothers could be related to a gene dosage imbalance even if gene expression could not be measured in relevant tissues such as brain or adipocytes. PMID- 23920045 TI - Lethal phenotype in conditional late-onset arginase 1 deficiency in the mouse. AB - Human arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia, which lead to neurological impairment with spasticity, loss of ambulation, seizures, and severe mental and growth retardation; uncommonly, patients suffer early death from this disorder. In a murine targeted knockout model, onset of the phenotypic abnormality is heralded by weight loss at around day 15, and death occurs typically by postnatal day 17 with hyperargininemia and markedly elevated ammonia. This discrepancy between the more attenuated juvenile-onset human disease and the lethal neonatal murine model has remained suboptimal for studying and developing therapy for the more common presentation of arginase deficiency. These investigations aimed to address this issue by creating an adult conditional knockout mouse to determine whether later onset of arginase deficiency also resulted in lethality. Animal survival and ammonia levels, body weight, circulating amino acids, and tissue arginase levels were examined as outcome parameters after widespread Cre-recombinase activation in a conditional knockout model of arginase 1 deficiency. One hundred percent of adult female and 70% of adult male mice died an average of 21.0 and 21.6 days, respectively, after the initiation of tamoxifen administration. Animals demonstrated elevated circulating ammonia and arginine at the onset of phenotypic abnormalities. In addition, brain and liver amino acids demonstrated abnormalities. These studies demonstrate that (a) the absence of arginase in adult animals results in a disease profile (leading to death) similar to that of the targeted knockout and (b) the phenotypic abnormalities seen in the juvenile onset model are not exclusive to the age of the animal but instead to the biochemistry of the disorder. This adult model will be useful for developing gene and cell-based therapies for this disorder that will not be limited by the small animal size of neonatal therapy and for developing a better understanding of the characteristics of hyperargininemia. PMID- 23920046 TI - Mitochondrial respiratory chain disease discrimination by retrospective cohort analysis of blood metabolites. AB - Diagnosing primary mitochondrial respiratory chain (RC) dysfunction has long relied on invasive tissue biopsies, since no blood-based biomarker has been shown to have sufficiently high sensitivity and specificity across the myriad of individual clinical presentations. We sought to determine whether cohort-level evaluation of commonly obtained blood analytes might reveal consistent patterns to discriminate a heterogenous group of primary mitochondrial RC disease subjects both from control individuals and from subjects with pyruvate dehydrogenase deficiency. METHODS: Following IRB approval, 62 biochemical analyte concentrations or ratios were retrospectively analyzed in three well-defined and intentionally heterogeneous subject cohorts reflective of clinical practice: [1] Primary mitochondrial disease (n=19); [2] pyruvate dehydrogenase deficiency (n=4); and [3] controls (n=27). Blood analyte categories included comprehensive chemistry profile, creatine kinase, lipoprotein profile, lactate, pyruvate, and plasma amino acid profile. Non-parametric analyses were used to compare the median of each analyte level between cohorts. RESULTS: Disease cohorts differed significantly in their median levels of triglycerides, lactate, pyruvate, and multiple individual plasma amino acids. Primary mitochondrial disease was significantly discriminated at the cohort level from pyruvate dehydrogenase deficiency by greater pyruvate and alanine elevation in pyruvate dehydrogenase deficiency, as well as significantly increased branched chain amino acid (BCAA) levels and increased ratios of individual BCAAs to glutamate in mitochondrial disease. In addition, significant elevation of median blood triglyceride level was seen in the primary mitochondrial disease cohort. CONCLUSIONS: Blood metabolite profile analysis can discriminate a heterogeneous cohort of primary mitochondrial disease both from controls and from pyruvate dehydrogenase deficiency. Elevated BCAA levels, either absolutely or when considered relative to the level of glutamate, are common metabolic sequelae of primary mitochondrial RC disease. Prospective study is needed to validate observed plasma metabolite alterations as a potential biomarker of disease both in larger cohorts and at the individual subject level. PMID- 23920047 TI - Various roles of Th cytokine mRNA expression in different forms of glomerulonephritis. AB - BACKGROUND: Kidney disease is characterized by injurious immune responses to self or foreign antigens. The development and maintenance of immune responses generally involves activation of T lymphocytes. We evaluated mRNA expression patterns of T-cell cytokines to identify the principal Th-cell subset involved in the development of antineutrophil cytoplasmic antigen-associated pauci-immune crescentic glomerulonephritis (ANCAGN), membranoproliferative glomerulonephritis (MPGN), and membranous nephropathy (MN). METHODS: Kidney biopsy specimens from ANCAGN (17), MPGN (11), and MN (14) patients were evaluated for mRNA expression of various T-cell cytokines. RESULTS: Interferon-gamma mRNA expression was detected in both ANCAGN and MPGN, but not in MN patients. Furthermore, mRNA expression of interleukin (IL)-12, a Th1-associated cytokine, was lower in MN patients than in ANCAGN and MPGN patients. In contrast, a significantly higher expression of IL-4 and IL-5 was observed in MN than in ANCAGN and MPGN patients. In the analyses of Th17-associated cytokine expression, a significantly higher expression of IL-6 and IL-17 was observed in ANCAGN than in MPGN and MN patients. No significant differences were observed in the expression of these cytokines between MPGN and MN patients. With regard to Treg-associated cytokines, a significantly higher IL-10 expression was observed in MN than in ANCAGN patients, and a significantly higher transforming growth factor-beta expression was observed in MN than in ANCAGN and MPGN patients. Similarly, Foxp3 expression was significantly higher in MN. CONCLUSION: Th1 and Th17 immune responses in ANCAGN, the Th1 response in MPGN, and Th2 and Treg responses in MN patients may be integral for the distinct histological features of these diseases. PMID- 23920048 TI - Controlled ovarian stimulation using a long gonadotropin-releasing hormone antagonist protocol: a proof of concept and feasibility study. AB - BACKGROUND/AIMS: To evaluate the feasibility of a long protocol of controlled ovarian stimulation prior to in vitro fertilization (IVF) and embryo transfer with a gonadotropin-releasing hormone (GnRH) antagonist used for pituitary and ovarian suppression. METHODS: Thirty patients undergoing IVF/intracytoplasmic sperm injection were randomized into two groups. The control group (n = 16) received a standard flexible GnRH antagonist protocol. Ovarian stimulation consisted of 225 IU/day of recombinant follicle-stimulating hormone for 5 days, followed by 225 IU/day of human menopausal gonadotropin until human chorionic gonadotropin (hCG) administration. The study group (n = 14) received 0.25 mg of GnRH antagonist daily for 7 days, thereafter, upon confirmation of pituitary and ovarian suppression, ovarian stimulation was commenced with the same protocol as used in the control group. Hormone and follicle dynamics, as well as laboratory characteristics and cycle outcome, were compared for both groups. RESULTS: Both groups were comparable in baseline characteristics. Pituitary and ovarian suppression were effectively achieved in 12/14 patients in the study group. The duration of ovarian stimulation and gonadotropin consumption were similar in both groups, as was also the number and size of follicles on hCG day. CONCLUSION: The results of our study confirm the feasibility of a long GnRH antagonist protocol. This regimen could become another option to optimize GnRH antagonist protocols, and should thus be further explored. PMID- 23920049 TI - Fourteenth International Medical Chemical Defence Conference 2013 "Translation of experimental research for improved treatment of chemical warfare agents". PMID- 23920050 TI - Core schemas across the continuum of psychosis: a comparison of clinical and non clinical groups. AB - BACKGROUND: Research suggests that core schemas are important in both the development and maintenance of psychosis. AIMS: The aim of the study was to investigate and compare core schemas in four groups along the continuum of psychosis and examine the relationships between schemas and positive psychotic symptomatology. METHOD: A measure of core schemas was distributed to 20 individuals experiencing first-episode psychosis (FEP), 113 individuals with "at risk mental states" (ARMS), 28 participants forming a help-seeking clinical group (HSC), and 30 non-help-seeking individuals who endorse some psychotic-like experiences (NH). RESULTS: The clinical groups scored significantly higher than the NH group for negative beliefs about self and about others. No significant effects of group on positive beliefs about others were found. For positive beliefs about the self, the NH group scored significantly higher than the clinical groups. Furthermore, negative beliefs about self and others were related to positive psychotic symptomatology and to distress related to those experiences. CONCLUSIONS: Negative evaluations of the self and others appear to be characteristic of the appraisals of people seeking help for psychosis and psychosis-like experiences. The results support the literature that suggests that self-esteem should be a target for intervention. Future research would benefit from including comparison groups of people experiencing chronic psychosis and people who do not have any psychotic-like experiences. PMID- 23920051 TI - Measurement of characteristic prompt gamma rays emitted from oxygen and carbon in tissue-equivalent samples during proton beam irradiation. AB - The purpose of this work was to characterize how prompt gamma (PG) emission from tissue changes as a function of carbon and oxygen concentration, and to assess the feasibility of determining elemental concentration in tissues irradiated with proton beams. For this study, four tissue-equivalent water-sucrose samples with differing densities and concentrations of carbon, hydrogen, and oxygen were irradiated with a 48 MeV proton pencil beam. The PG spectrum emitted from each sample was measured using a high-purity germanium detector, and the absolute detection efficiency of the detector, average beam current, and delivered dose distribution were also measured. Changes to the total PG emission from (12)C (4.44 MeV) and (16)O (6.13 MeV) per incident proton and per Gray of absorbed dose were characterized as a function of carbon and oxygen concentration in the sample. The intensity of the 4.44 MeV PG emission per incident proton was found to be nearly constant for all samples regardless of their carbon concentration. However, we found that the 6.13 MeV PG emission increased linearly with the total amount (in grams) of oxygen irradiated in the sample. From the measured PG data, we determined that 1.64 * 10(7) oxygen PGs were emitted per gram of oxygen irradiated per Gray of absorbed dose delivered with a 48 MeV proton beam. These results indicate that the 6.13 MeV PG emission from (16)O is proportional to the concentration of oxygen in tissue irradiated with proton beams, showing that it is possible to determine the concentration of oxygen within tissues irradiated with proton beams by measuring (16)O PG emission. PMID- 23920052 TI - Differential brain effects of laser and needle acupuncture at LR8 using functional MRI. AB - OBJECTIVE: While needle acupuncture is a well-accepted technique, laser acupuncture is being increasingly used in clinical practice. The differential effects of the two techniques are of interest. We examine this in relation to brain effects of activation of LR8, a putative acupuncture point for depression, using functional MRI (fMRI). METHODS: Sixteen healthy participants were randomised to receive low intensity laser acupuncture to LR8 on one side and needle acupuncture to the contralateral LR8. Stimulation was in an on-off block design and brain patterns were recorded under fMRI. RESULTS: Significant activation occurred in the left precuneus during laser acupuncture compared with needle acupuncture and significant activation occurred in the left precentral gyrus during needle acupuncture compared with laser acupuncture. CONCLUSIONS: Laser and needle acupuncture at LR8 in healthy participants produced different brain patterns. Laser acupuncture activated the precuneus relevant to mood in the posterior default mode network while needle acupuncture activated the parietal cortical region associated with the primary motor cortex. Further investigations are warranted to evaluate the clinical relevance of these effects. PMID- 23920053 TI - Identification of a novel chitin-binding spore wall protein (NbSWP12) with a BAR 2 domain from Nosema bombycis (microsporidia). AB - The spore wall of Nosema bombycis plays an important role in microsporidian pathogenesis. Protein fractions from germinated spore coats were analysed by two dimensional polyacrylamide gel electrophoresis and MALDI-TOF/TOF mass spectrometry. Three protein spots were identified as the hypothetical spore wall protein NbHSWP12. A BAR-2 domain (e-value: 1.35e-03) was identified in the protein, and an N-terminal protein-heparin interaction motif, a potential N glycosylation site, and 16 phosphorylation sites primarily activated by protein kinase C were also predicted. The sequence analysis suggested that Nbhswp12 and its homologous genes are widely distributed among microsporidia. Additionally, Nbhswp12 gene homologues share similar sequence features. An indirect immunofluorescence analysis showed that NbHSWP12 localized to the spore wall, and thus we renamed it spore wall protein 12 (NbSWP12). Moreover, NbSWP12 could adhere to deproteinized N. bombycis chitin coats that were obtained by hot alkaline treatment. This novel N. bombycis spore wall protein may function in a structural capacity to facilitate microsporidial spore maintenance. PMID- 23920054 TI - Ribosomal and mitochondrial DNA analysis of Trichuridae nematodes of carnivores and small mammals. AB - Several species of Trichuridae nematodes can infect dogs, cats and wild mammals. The diagnosis of these infections relies on the microscopic identification of eggs which are characterized by a similar "lemon" shape and polar plugs in all Trichuridae. Thus, morphological diagnosis to species level is challenging. The use of biomolecular diagnostic methods is desirable but very little genetic data are known from Trichuridae of carnivores and small mammals. The aim of this work was to genetically characterize several species of Trichuridae that can affect dogs, cats and wild mammals, as a basis to develop molecular diagnostic tests. Specimens (adult worms or eggs) of Eucoleus aerophilus (syn. Capillaria aerophila), Eucoleus boehmi (syn. Capillaria boehmi), Pearsonema plica (syn. Capillaria plica), Aonchotheca putorii (syn. Capillaria putorii), Calodium hepaticum (syn. Capillaria hepatica), Calodium splenaecum (syn. Capillaria splenaeca) and Trichuris vulpis were obtained from carcasses of red foxes, feces of dogs, the liver of a vole and from the spleen of Crocidura sp. Parts of the small subunit rRNA (18S rRNA) gene and of the mitochondrial cytochrome c oxidase subunit I (cox 1 mtDNA) gene were amplified from the above mentioned nematodes, yielding the first 18S rRNA gene sequences of all the capillariid nematodes and the first cox 1 mtDNA sequences of E. boehmi, P. plica, C. hepaticum, A. putorii and T. vulpis. The 18S rRNA gene is highly conserved among the different species and not suitable as a target for specific diagnostic oligonucleotides. However, these sequences contribute to a better understanding of the complex taxonomic relations among Trichuridae. Indeed, a dendrogram based on the 18S rRNA gene locus supports the latest taxonomic revision. Interspecies divergence was much higher at the cox 1 mtDNA gene locus, rendering it suitable for DNA barcoding and particularly valuable in resolving closely related species. Furthermore, the mitochondrial genetic markers defined in the present study are useful to develop Trichuridae species-specific primers. PMID- 23920055 TI - CD95 (FAS) and CD178 (FASL) induce the apoptosis of CD4+ and CD8+ cells isolated from the peripheral blood and spleen of dogs naturally infected with Leishmania spp. AB - Infected dogs are urban reservoirs of Leishmania chagasi, which is a causative agent of visceral leishmaniasis (VL). Dogs exhibit immune suppression during the course of this disease, and lymphocyte apoptosis is involved in this process. To investigate apoptosis and the expression levels of FAS-FAS-associated death domain protein (CD95 or APO-1), FASL-FAS ligand protein (CD178), and TRAIL-TNF related apoptosis-inducing ligand (CD253) receptors in peripheral blood mononuclear cells and spleen leukocytes from 38 symptomatic dogs with moderate VL and 25 healthy dogs were evaluated by flow cytometry. The apoptosis rate of blood and splenic CD4+ and CD8+ cells was higher in infected dogs than in healthy dogs. The expression levels of FAS and FASL in blood and splenic CD4+ cells were lower in infected dogs than in healthy dogs. FAS expression in CD8+ cells was higher in infected dogs than in healthy dogs; in contrast, FASL expression was lower in infected dogs. The expression of the TRAIL receptor increased only in splenic CD8+ cells from infected dogs. The FAS and FAS-L blocking antibodies confirmed the importance of these receptors in apoptosis. Our results enhance the current understanding of the immune response in dogs infected with L. chagasi, facilitating the future development of therapeutic interventions to reduce lymphocyte depletion. PMID- 23920056 TI - Longitudinal analysis of serological tests officially adopted by the Brazilian Ministry of Health for the diagnosis of canine visceral leishmaniasis in dogs vaccinated with Leishmune(r). AB - Development of vaccines against canine visceral leishmaniasis (CVL) may provide a prophylactic barrier, but antibody response detected by standard diagnostic techniques may not separate vaccinated from naturally infected dogs. Moreover, anti-Leishmania antibody levels in vaccinated dogs may be detectable for months. Accordingly, the aim of the present study was to comparatively evaluate an "in house" ELISA with three serological tests officially adopted by the Brazilian Ministry of Health for the diagnosis of CVL in dogs vaccinated with Leishmune((r)). A total of 18 mongrel dogs were submitted to a complete protocol of the vaccine, monitored and evaluated in 5 times (T0-T4) up to 180 days after T0. Twenty-one days after the first dose (T1), 50% of the dogs were seropositive by the "in-house" ELISA and 5.5% by IFAT, while by the official ELISA and DPP((r)) CVL rapid test all dogs tested negative. At time T2, 42 days after of the first dose, 100%, 83.3%, 11.1%, and 5.5% of the dogs were seropositive by the "in-house" ELISA, IFAT, official ELISA kit and the DPP((r)) CVL rapid test, respectively. Ninety days after the first dose (T3), 100%, 83.3%, 72.2% and 33.3% of the dogs were seropositive by the "in-house" ELISA, official ELISA kit, IFAT, and the DPP((r)) CVL rapid test, respectively. Finally, at time T4, 88.8%, 33.3%, 11.1% and 5.5% of the dogs were seropositive by the "in-house" ELISA, official ELISA kit, DPP((r)) CVL rapid test and IFAT, respectively. In conclusion, dogs vaccinated with Leishmune((r)) cross-react by an "in-house" ELISA and by the three official Brazilian serological tests for the diagnosis of canine visceral leishmaniasis up to six months after the first vaccine dose, and may be mistakenly diagnosed and removed. PMID- 23920057 TI - The diminished interhemispheric connectivity correlates with negative symptoms and cognitive impairment in first-episode schizophrenia. AB - BACKGROUND: Previous studies imply that interhemispheric disconnectivity plays a more important role on information processing in schizophrenia. However, the role of the aberrant interhemispheric connection in the pathophysiology of this disorder remains unclear. Recently, resting-state functional Magnetic Resonance Imaging (fMRI) has reported to have potentials of mapping functional interactions between pairs of brain hemispheres. METHODS: Resting-state whole-brain functional connectivity analyses were performed on 41 schizophrenia patients and 33 healthy controls. RESULTS: The first-episode schizophrenia patients showed significant aberrant interhemispheric connection in the globus pallidus, medial frontal gyrus and inferior temporal gyrus. The correlation of Wechsler Adult Intelligence Scale scores with odds ratio of the aberrant interhemispheric connections revealed positive correlation in the pallidum (rho=0.335, p=.003) and medial frontal gyrus (rho=0.260, p=.025). The connection in the pallidum was also positively correlated with duration of illness (rho=-0.407, p=.009). Whereas, the aberrant interhemispheric connection in the inferior temporal gyrus was positively correlated with scores of Scale for the Assessment of Negative Symptoms (rho=0.393, p=.012). CONCLUSION: The present study provides fMRI evidence for the aberrant interhemispheric resting-state functional connectivity within resting state networks in first-episode schizophrenia patients. These aberrant interhemispheric connections, in particular the pallidum, due to its anatomical and functional connectivities, may be the primary disturbance for cognitive impairment, negative symptoms and chronicity of schizophrenia. PMID- 23920060 TI - Acute cardiogenic pulmonary edema induced by severe hypoglycemia--a rare case report. PMID- 23920059 TI - SSRIs versus exercise training for depression in chronic heart failure: a meta analysis of randomized controlled trials. PMID- 23920058 TI - Residual conduction after pulmonary vein isolation with a circular multielectrode radiofrequency ablation catheter: the role of adenosine and orciprenalin during a prolonged observation time. AB - INTRODUCTION: Recurrences after pulmonary vein isolation (PVI) in patients (pts) with paroxysmal atrial fibrillation (AF) are mostly due to PV reconnection. The effect of adenosine, orciprenalin and their combination on left atrial PV conduction after PVI with a phased radiofrequency (RF) circular multielectrode ablation catheter (Pulmonary Vein Ablation Catheter, PVAC) was prospectively evaluated during a prolonged waiting time. In addition, it was assessed whether pharmacological reconnection characterizes veins requiring use of an irrigated catheter. METHODS AND RESULTS: In 116 consecutive pts [age 62 (IQR:52,68) years, 46% female], PVI was achieved with the PVAC alone in 114/116 (98%) pts and 461/464 (99%) veins after a median of 26 (IQR:22,32) applications delivering 1782 s (IQR:1518,2197) of RF. Mostly transient PV reconnections were observed in 40/116 (34%) pts and 57/464 (12%) PVs, a median of 44 (IQR:30,58) min after initial isolation. Adenosine, alone (43/57, 75%) or during orciprenalin infusion (7/57, 12%), unmasked residual conduction in the majority of veins (50/57, 88%). Additional PVAC applications less frequently achieved permanent isolation in veins showing reconnection compared to those that didn't (52/57, 91% vs. 404/407, 99%; P < .001). All PVs that could not be isolated with the PVAC were successfully treated with a standard irrigated catheter. CONCLUSIONS: After apparent PVI with the PVAC, drug-challenge after prolonged observation unmasked residual PV conduction in a significant number of pts, and adenosine was the most effective strategy. Drug-induced PV reconnection was difficult to treat with the PVAC. Whether this strategy improves clinical outcome of PVI with phased RF needs to be investigated. PMID- 23920061 TI - The impact of drug-related QT prolongation on FDA regulatory decisions. PMID- 23920062 TI - Pleuropericardial effusion: a diagnostic conundrum. PMID- 23920063 TI - Erythropoietin combined with ACE inhibitor prevents heart remodeling in 5/6 nephrectomized rats independently of blood pressure and kidney function. AB - BACKGROUND: Cardiovascular disease is the primary cause of mortality in patients with chronic kidney disease (CKD). Heart remodeling in CKD comprises mainly interstitial fibrosis and capillary loss. Beyond correcting renal anemia, erythropoietin (Epo) has potentially beneficial pleiotropic effects on heart remodeling. METHODS: 12-week-old male Sprague-Dawley rats were randomized to 5/6 nephrectomy (NX) or sham operation (sham-op); subsequently, they received murine Epo (2.5 MUg/kg/week), enalapril (12 mg/kg/day), Epo + enalapril, Epo + dihydralazine (25 mg/kg/day), or vehicle. Heart function and morphology was assessed after 16 weeks of treatment. RESULTS: Compared with sham-op (81.2%), left ventricle fractional shortening was reduced in vehicle-treated NX (66.3%) and this was ameliorated by Epo (72.6%) and even prevented by enalapril (80.6%). Capillary length density was lower and the area of fibrosis more marked in vehicle-treated NX compared to sham-op. Capillary rarefaction and heart fibrosis were prevented in NX treated with Epo + enalapril and reduced in NX treated with enalapril and Epo + dihydralazine. Despite higher blood pressure, treatment with Epo reduced heart fibrosis but failed to prevent capillary loss. In parallel, expression of the p47phox NADPH oxidase was higher in untreated NX and was effectively reduced in NX treated with Epo + enalapril. Under basal conditions there was no difference between the groups regarding myocardial hypoxia as reflected by pimonidazole staining. CONCLUSION: Epo in combination with enalapril caused additive reduction of cardiac fibrosis and microvessel disease in 5/6 nephrectomized rats presumably by decreasing myocardial oxidative stress. PMID- 23920065 TI - Relationship between erectile dysfunction and silent coronary artery disease: detection with multidetector computed tomography coronary angiography. AB - AIM: Our aim was to determine the relationship between erectile dysfunction (ED) and silent coronary artery disease (CAD) by multidetector computed tomography (MDCT) coronary angiography. METHODS: Thirty consecutive men with nonhormonal and nonpsychogenic ED and with no cardiac symptoms were evaluated. Medical history, physical examination and laboratory investigation were performed. The five-item brief form of the International Index of Erectile Function (IIEF-5) was performed for evaluation of ED. The Agatston score (AS) was determined from MDCT images under beta blockade to induce bradycardia. The MDCT coronary angiography findings were evaluated by two radiologists blinded to the clinical findings. Patients were classified into three categories (mild, moderate and severe ED) according to IIEF-5 scores and into five categories (very low, low, moderate, moderately high and high CAD risk) according to the AS. RESULTS: Mean age was 58.3 +/- 8.7 years (46-79). 6 patients had hypertriglyceridemia, 4 had hypercholesterolemia and 4 had hyperglycemia. All patients had normal early morning testosterone levels. Regarding IIEF-5 scores, none of them had mild ED, 14 had moderate ED and 16 had severe ED. Of the 14 patients with moderate ED, 21.4% had low and 28.5% had moderate CAD risk regarding AS. Of the 16 patients with severe ED, 25% had moderate, 31.2% had moderately high and 25% had high CAD risk regarding AS. Increasing age was a risk factor for high AS (p = 0.045). There was a significant correlation between AS and ED severity (p = 0.01). CONCLUSIONS: ED and CAD often coexist. MDCT coronary angiography can detect coronary lesions and allow appropriate medical intervention. PMID- 23920064 TI - The skinny on cocaine: insights into eating behavior and body weight in cocaine dependent men. AB - There is a general assumption that weight loss associated with cocaine use reflects its appetite suppressing properties. We sought to determine whether this was justified by characterizing, in detail, alterations in dietary food intake and body composition in actively using cocaine-dependent individuals. We conducted a cross-sectional case-control comparison of 65 male volunteers from the local community, half of whom satisfied the DSM-IV-TR criteria for cocaine dependence (n=35) while the other half had no personal or family history of a psychiatric disorder, including substance abuse (n=30). Assessments were made of eating behavior and dietary food intake, estimation of body composition, and measurement of plasma leptin. Although cocaine users reported significantly higher levels of dietary fat and carbohydrates as well as patterns of uncontrolled eating, their fat mass was significantly reduced compared with their non-drug using peers. Levels of leptin were associated with fat mass, and with the duration of stimulant use. Tobacco smoking status or concomitant use of medication did not affect the significance of the results. Weight changes in cocaine users reflect fundamental perturbations in fat regulation. These are likely to be overlooked in clinical practice but may produce significant health problems when cocaine use is discontinued during recovery. PMID- 23920066 TI - Falling short in organized dentistry: a call for increased diversity. PMID- 23920067 TI - WHO recognizes oral diseases in action plan for noncommunicable diseases. PMID- 23920068 TI - CDA advocacy: making a difference in oral health care. PMID- 23920069 TI - Does breastfeeding increase risk of early childhood caries? PMID- 23920070 TI - New CDA position statement on dental patients with orthopedic implants. PMID- 23920072 TI - Determining position of the inferior alveolar nerve via anatomical dissection and micro-computed tomography in preparation for dental implants. AB - BACKGROUND: The inferior alveolar nerve courses anteriorly within the mandibular canal, providing sensory nerve supply to the mandibular teeth, the buccal mucosa, the gingiva, and the soft tissues of the lower lip and chin. To avoid damage to this nerve and resulting sensory disturbances, its exact location must be known before placement of a dental implant. Imaging modalities currently used to visualize the position of the inferior alveolar nerve may be inaccurate. This study was undertaken to determine the accuracy of micro-computed tomography (micro-CT) for determining the position of this nerve. METHODS: Micro-CT images of 16 cadaveric hemimandibles were acquired at a slice thickness of 154 um. Each hemimandible was then sectioned at 6 predetermined locations between the ramus and the mental foramen, to yield 5 corticocancellous bone specimens. The superior, inferior, buccal and lingual distances for bone surrounding the mandibular canal were measured by direct digital caliper and compared with corresponding micro-CT measurements obtained by 3-dimensional visualization and modelling software. RESULTS: There was substantial variability in the vertical position of the inferior alveolar nerve, depending on the length of time since tooth loss and the movement of the nerve from the lingual to buccal position as it courses from the posterior to the anterior aspect of the mandible. However, digital caliper and corresponding micro-CT measurements of the thickness of bone surrounding the inferior alveolar nerve were highly consistent, and no significant differences were detected between the two methods of measurement. CLINICAL SIGNIFICANCE: The findings reported here confirm the accuracy of micro CT in determining the location of the inferior alveolar nerve during planning for placement of dental implants in the human mandible. PMID- 23920074 TI - Managing postoperative pain following periodontal surgery. PMID- 23920073 TI - C-terminal cross-linking telopeptide as a serologic marker for bisphosphonate related osteonecrosis of the jaw: review of 2 cases. AB - With the increasing use of the bisphosphonate class of drugs, dental professionals are encountering more cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ). The C-terminal cross-linking telopeptide (CTX) assay is a serologic test to predict the risk of BRONJ. This paper examines the effectiveness of CTX as a biochemical marker for BRONJ and its utility to the dentist in establishing appropriate treatment plans for patients with a history of bisphosphonate use. Alternative means of assessing the risk of BRONJ are discussed, and 2 case vignettes are presented to demonstrate dental treatment planning for patients with a history of bisphosphonate use, in the context of specific CTX results. PMID- 23920075 TI - Implications of Dabigatran, a direct thrombin inhibitor, for oral surgery practice. AB - Direct thrombin inhibitors, specifically orally administered dabigatran etexilate, are emerging as alternatives to warfarin for anticoagulation in the management of atrial fibrillation and venous thromboembolism. The risk associated with bleeding events while taking dabigatran has been documented in multiple randomized controlled trials, but to date, no studies have focused on the risk of bleeding after dental extraction. Extraction of teeth is one of the most common surgical procedures and may cause significant bleeding, so a thorough understanding of the pharmacology of anticoagulant medications is required to prevent complications. With the increasing use of direct thrombin inhibitors, the safe management of patients taking these anticoagulants must be delineated. This review compares dabigatran and warfarin, especially in terms of their effects on dental and oral surgery practice, and examines best management of these patients in light of the existing literature. PMID- 23920076 TI - Factors modulating effective chest compressions in the neonatal period. AB - The need for chest compressions in the newborn is a rare occurrence. The methods employed for delivery of chest compressions have been poorly researched. Techniques that have been studied include compression:ventilation ratios, thumb versus finger method of delivering compressions, depth of compression, site on chest of compression, synchrony or asynchrony of breaths with compressions, and modalities to improve the compression technique and consistency. Although still in its early days, an evidence-based guideline for chest compressions is beginning to take shape. PMID- 23920077 TI - Novel approach to epicardial pacemaker implantation in patients with limited venous access. AB - BACKGROUND: Limited venous access in certain patients increases the procedural risk and complexity of conventional transvenous pacemaker implantation. OBJECTIVE: The purpose of this study was to determine a minimally invasive epicardial approach using pericardial reflections for dual-chamber pacemaker implantation in patients with limited venous access. METHODS: Between June 2006 and November 2011, 15 patients underwent epicardial pacemaker implantation. Procedures were performed through a minimally invasive subxiphoid approach and pericardial window with subsequent fluoroscopy-assisted lead placement. Mean patient age was 46.4 +/- 15.3 years (9 male [(60.0%], 6 female [40.0%]). The new surgical approach was used in patients determined to have limited venous access due to multiple abandoned leads in 5 (33.3%), venous occlusion in 3 (20.0%), intravascular retention of lead fragments from prior extraction in 3 (20.0%), tricuspid valve vegetation currently under treatment in 2 (13.3%), and unrepaired intracardiac defects in 2 (13.3%). RESULTS: All procedures were successful with no perioperative complications or early deaths. Mean operating time for isolated pacemaker implantation was 231.7 +/- 33.5 minutes. Lead placement on the superior aspect of right atrium, through the transverse sinus, was possible in 12 patients. In the remaining 3 patients, the atrial lead was implanted on the left atrium through the oblique sinus, the postcaval recess, or the left pulmonary vein recess. None of the patients displayed pacing or sensing dysfunction, and all parameters remained stable throughout the follow-up period of 36.8 +/- 25.1 months. CONCLUSION: Epicardial pacemaker implantation through pericardial reflections is an effective alternative therapy for those patients requiring physiologic pacing in whom venous access is limited. PMID- 23920078 TI - Postmarket surveillance and returned product analysis: success but not transparency. PMID- 23920079 TI - Dosimetric effect by shallow air cavities in high energy electron beams. AB - This study evaluates the dosimetric impact caused by an air cavity located at 2 mm depth from the top surface in a PMMA phantom irradiated by electron beams produced by a Siemens Primus linear accelerator. A systematic evaluation of the effect related to the cavity area and thickness as well as to the electron beam energy was performed by using Monte Carlo simulations (EGSnrc code), Pencil Beam algorithm and Gafchromic EBT2 films. A home-PMMA phantom with the same geometry as the simulated one was specifically constructed for the measurements. Our results indicate that the presence of the cavity causes an increase (up to 70%) of the dose maximum value as well as a shift forward of the position of the depth dose curve, compared to the homogeneous one. Pronounced dose discontinuities in the regions close to the lateral cavity edges are observed. The shape and magnitude of these discontinuities change with the dimension of the cavity. It is also found that the cavity effect is more pronounced (6%) for the 12 MeV electron beam and the presence of cavities with large thickness and small area introduces more significant variations (up to 70%) on the depth-dose curves. Overall, the Gafchromic EBT2 film measurements were found in agreement within 3% with Monte Carlo calculations and predict well the fine details of the dosimetric change near the cavity interface. The Pencil Beam calculations underestimate the dose up to 40% compared to Monte Carlo simulations; in particular for the largest cavity thickness (2.8 cm). PMID- 23920080 TI - Bike helmets: a reply to replies. PMID- 23920081 TI - Kinetic modeling of low density lipoprotein oxidation in arterial wall and its application in atherosclerotic lesions prediction. AB - Oxidation of low-density lipoprotein (LDL) is one of the major factors in atherogenic process. Trapped oxidized LDL (Ox-LDL) in the subendothelial matrix is taken up by macrophage and leads to foam cell generation creating the first step in atherosclerosis development. Many researchers have studied LDL oxidation using in vitro cell-induced LDL oxidation model. The present study provides a kinetic model for LDL oxidation in intima layer that can be used in modeling of atherosclerotic lesions development. This is accomplished by considering lipid peroxidation kinetic in LDL through a system of elementary reactions. In comparison, characteristics of our proposed kinetic model are consistent with the results of previous experimental models from other researches. Furthermore, our proposed LDL oxidation model is added to the mass transfer equation in order to predict the LDL concentration distribution in intima layer which is usually difficult to measure experimentally. According to the results, LDL oxidation kinetic constant is an important parameter that affects LDL concentration in intima layer so that existence of antioxidants that is responsible for the reduction of initiating rates and prevention of radical formations, have increased the concentration of LDL in intima by reducing the LDL oxidation rate. PMID- 23920082 TI - An efficient synthesis of 4alpha- and 4beta-hydroxy- 7-dehydrocholesterol, biomarkers for patients with and animal models of the Smith-Lemli-Opitz syndrome. AB - A highly efficient and improved method for the preparation of stereoisomeric 4alpha- and 4beta-hydroxy-7-dehydrocholesterol has been developed. These oxysterols are atypical precursors of cholesterol found to be present in increased concentrations in brain, liver, and serum of animals treated with AY9944, an inhibitor of 3beta-hydroxysterol-Delta(7)-reductase (Dhcr7). AY9944 treated rats are considered a model for Smith-Lemli-Opitz syndrome (SLOS). The principal reactions involved were (1) cis-4alpha,5alpha-dihydroxylation of the allylic 3beta-acetoxy-Delta(4) intermediate with in situ generated RuO4 and subsequent dehydration with SOCl2, (2) direct 4beta-hydroxylation of cholesterol with selenium dioxide, and (3) regioselective dehydrogenation at C-7/-8 of the resulting 4alpha- and 4beta-hydroxylated derivatives with 1,3-dibromo-5,5 dimethylhydantoin/azobisisobutyronitrile, followed by tetrabutyl ammonium bromide/tetrabutyl ammonium fluoride. Chemical instability of these 4 hydroxylated 7-dehydrocholesterols when exposed to UV light, heat or in an acidic medium is briefly discussed. PMID- 23920083 TI - The role of angiogenic and antiangiogenic factors in the second trimester in the prediction of preeclampsia in pregnant women with type 1 diabetes. AB - OBJECTIVE: To assess the association between circulating angiogenic and antiangiogenic factors in the second trimester and risk of preeclampsia in women with type 1 diabetes. RESEARCH DESIGN AND METHODS: Maternal plasma concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin (sEng) were available at 26 weeks of gestation in 540 women with type 1 diabetes enrolled in the Diabetes and Preeclampsia Intervention Trial. RESULTS: Preeclampsia developed in 17% of pregnancies (n = 94). At 26 weeks of gestation, women in whom preeclampsia developed later had significantly lower PlGF (median [interquartile range]: 231 pg/mL [120-423] vs. 365 pg/mL [237 582]; P < 0.001), higher sFlt-1 (1,522 pg/mL [1,108-3,393] vs. 1,193 pg/mL [844 1,630] P < 0.001), and higher sEng (6.2 ng/mL [4.9-7.9] vs. 5.1 ng/mL[(4.3-6.2]; P < 0.001) compared with women who did not have preeclampsia. In addition, the ratio of PlGF to sEng was significantly lower (40 [17-71] vs. 71 [44-114]; P < 0.001) and the ratio of sFlt-1 to PlGF was significantly higher (6.3 [3.4-15.7] vs. 3.1 [1.8-5.8]; P < 0.001) in women who later developed preeclampsia. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to a logistic model containing established risk factors (area under the curve [AUC], 0.813) significantly improved the predictive value (AUC, 0.850 and 0.846, respectively; P < 0.01) and significantly improved reclassification according to the integrated discrimination improvement index (IDI) (IDI scores 0.086 and 0.065, respectively; P < 0.001). CONCLUSIONS: These data suggest that angiogenic and antiangiogenic factors measured during the second trimester are predictive of preeclampsia in women with type 1 diabetes. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to established clinical risk factors significantly improves the prediction of preeclampsia in women with type 1 diabetes. PMID- 23920084 TI - Oxidative stress and response in relation to coronary artery disease in type 1 diabetes. AB - OBJECTIVE: Although oxidative stress (OxS) is thought to contribute to atherosclerosis and coronary artery disease (CAD), little is known about the variability in an individual's ability to respond to OxS. Therefore, we assessed potential indices of response to OxS and evaluated whether they modify the association between OxS and CAD. RESEARCH DESIGN AND METHODS: We evaluated plasma alpha- and gamma-tocopherol per unit cholesterol (potential response markers); urinary 15-isoprostane F2t per milligram creatinine (isoprostane [IsoP], a potential stress marker); and the alpha-tocopherol-to-IsoP ratio (as a measure of response to stress), measured three times during 20 years of follow-up, in relation to CAD incidence in a cohort with childhood-onset type 1 diabetes (n = 658; mean age at baseline, 28 years; duration of diabetes, 19 years). Participants with three samples (blood and either 24-h or overnight urine) available before the onset of CAD or the end of follow-up (n = 356) were selected for study. RESULTS: In multivariable mixed models, alpha-tocopherol over time was inversely associated with CAD (beta = -0.27; P = 0.02), whereas a direct association was observed for IsoP (beta = 0.0008; P = 0.06). Moreover, the alpha tocopherol-to-IsoP ratio was strongly and inversely related to CAD incidence (beta = -0.72; P = 0.003), whereas in a separate model including alpha-tocopherol and IsoP, both biomarkers maintained statistical significance. No association was observed for gamma-tocopherol (beta = -0.22; P = 0.54). CONCLUSIONS: These data suggest that a greater potential capability (alpha-tocopherol) to respond to OxS (urinary IsoP) relates to CAD incidence. PMID- 23920085 TI - Alterations to bone mineral composition as an early indication of osteomyelitis in the diabetic foot. AB - OBJECTIVE: Osteomyelitis in the diabetic foot is a major risk factor for amputation, but there is a limited understanding of early-stage infection, impeding limb-preserving diagnoses. We hypothesized that bone composition measurements provide insight into the early pathophysiology of diabetic osteomyelitis. RESEARCH DESIGN AND METHODS: Compositional analysis by Raman spectroscopy was performed on bone specimens from patients with a clinical diagnosis of osteomyelitis in the foot requiring surgical intervention as either a biopsy (n = 6) or an amputation (n = 11). RESULTS: An unexpected result was the discovery of pathological calcium phosphate minerals in addition to normal bone mineral. Dicalcium phosphate dihydrate, also called brushite, and uncarbonated apatite were found to be exclusively associated with infected bone. CONCLUSIONS: Compositional measurements provided a unique insight into the pathophysiology of osteomyelitis in diabetic foot ulcers. At-patient identification of pathological minerals by Raman spectroscopy may serve as an early-stage diagnostic approach. PMID- 23920086 TI - Diabetes and end-stage renal disease synergistically contribute to increased incidence of cardiovascular events: a nationwide follow-up study during 1998 2009. AB - OBJECTIVE This study aimed to investigate the effect of interaction of diabetes and end-stage renal disease (ESRD) on the risks of cardiovascular (CV) events. RESEARCH DESIGN AND METHODS By using two representative national cohorts, we determined the age- and sex-specific incidences and 20-year risks of incident CV events, including acute myocardial infarction (AMI), stroke, and congestive heart failure (CHF), stratified by the presence of diabetes, de novo diabetes after ESRD, or ESRD. Individuals were excluded if age <18 years or if previous CV events or malignancies were present before enrollment. Cox proportional hazards models were also constructed with adjustments for competing risk of mortality. RESULTS A total 648,851 non-ESRD individuals and 71,397 ESRD patients, including 53,342 and 34,754 diabetic patients, respectively, were followed up during 1998 2009. A monotonic risk pattern of CV-related incidences was noted with the presence of diabetes, ESRD, or both, respectively, after stratification by age and sex. De novo diabetes showed similar increased risks for CV incidences, especially AMI and stroke. There is a multiplicatively synergistic effect of diabetes and ESRD for CV-related risks, especially for AMI and stroke, of which the adjusted hazard ratios (aHRs) were 5.24 (95% CI 4.83-5.68) and 2.43 (2.32 2.55), respectively, in comparison with people without diabetes or ESRD; de novo diabetes after ESRD had similar effects with aHRs of 4.12 (3.49-4.87) and 1.75 (1.57-1.95), respectively. CONCLUSIONS Diabetes and ESRD synergistically increase risks of CV events. Proactive screening and control for diabetes in patients with ESRD should be built into our daily practice. PMID- 23920087 TI - Unwanted sexual experiences and cognitive appraisals that evoke mental contamination. AB - BACKGROUND: Mental contamination is a psychological sense of contamination that involves an internal, emotional feeling of dirtiness that may be evoked by unwanted thoughts and images, such as sexual assaults. AIMS: This study aimed to investigate which types of unwanted sexual experiences evoke the strongest mental contamination, and to test the hypothesis that cognitive appraisals of an unwanted sexual experience predict indices of mental contamination (i.e. feeling of dirtiness, urge to wash, internal negative emotions, and external negative emotions). METHOD: 148 female participants were asked to recall their most distressing unwanted sexual experiences. Indices of mental contamination and cognitive appraisals of the experience were then assessed. RESULTS: Our findings indicated that individuals recalling experiences related to rape felt more intense feelings of dirtiness than individuals recalling other types of unwanted sexual experience, such as verbal sexual assault, visual sexual assault, and forcible touching/frottage. In addition, hierarchical regression analyses demonstrated that a cognitive appraisal of perceived violation predicted all of the indices of mental contamination after controlling anxiety, depression, and fear of contact contamination. CONCLUSIONS: The present study demonstrated that an individual is at greatest risk of mental contamination if she has experienced rape/attempted rape, and if she makes a cognitive appraisal of violation regarding the incident. PMID- 23920088 TI - The finch epidemic strain of Trichomonas gallinae is predominant in British non passerines. AB - Avian trichomonosis, caused by the flagellated protozoan Trichomonas gallinae, is a recently emerged infectious disease of British passerines. The aetiological agent, a clonal epidemic strain of the parasite, has caused unprecedented finch mortality and population-level declines in Britain and has since spread to continental Europe. To better understand the potential origin of this epidemic and to further investigate its host range, T. gallinae DNA extracts were collected from parasite culture and tissue samples from a range of avian species in Britain. Sequence typing at the ITS1/5.8S rRNA/ITS2 region resolved three distinct ITS region types circulating in free-ranging British birds. Subtyping by sequence analyses at the Fe-hydrogenase gene demonstrated further strain variation within these ITS region types. The UK finch epidemic strain was preponderant amongst columbids sampled, however, wide strain diversity was encountered in isolates from a relatively small number of pigeons, suggesting further strains present in columbid populations across the UK are yet to be identified. Fe-hydrogenase gene sequence data in isolates from birds of prey with disease were predominantly identical to the UK finch epidemic strain, demonstrating its presence as a virulent strain in UK birds of prey since at least 2009. PMID- 23920089 TI - Real-time temperature estimation and monitoring of HIFU ablation through a combined modeling and passive acoustic mapping approach. AB - Passive acoustic mapping (PAM) has been recently demonstrated as a method of monitoring focused ultrasound therapy by reconstructing the emissions created by inertially cavitating bubbles (Jensen et al 2012 Radiology 262 252-61). The published method sums energy emitted by cavitation from the focal region within the tissue and uses a threshold to determine when sufficient energy has been delivered for ablation. The present work builds on this approach to provide a high-intensity focused ultrasound (HIFU) treatment monitoring software that displays both real-time temperature maps and a prediction of the ablated tissue region. This is achieved by determining heat deposition from two sources: (i) acoustic absorption of the primary HIFU beam which is calculated via a nonlinear model, and (ii) absorption of energy from bubble acoustic emissions which is estimated from measurements. The two sources of heat are used as inputs to the bioheat equation that gives an estimate of the temperature of the tissue as well as estimates of tissue ablation. The method has been applied to ex vivo ox liver samples and the estimated temperature is compared to the measured temperature and shows good agreement, capturing the effect of cavitation-enhanced heating on temperature evolution. In conclusion, it is demonstrated that by using PAM and predictions of heating it is possible to produce an evolving estimate of cell death during exposure in order to guide treatment for monitoring ablative HIFU therapy. PMID- 23920090 TI - Fluorescence correlation spectroscopy analysis for accurate determination of proportion of doubly labeled DNA in fluorescent DNA pool for quantitative biochemical assays. AB - Fluorescent double-stranded DNA (dsDNA) molecules labeled at both ends are commonly produced by annealing of complementary single-stranded DNA (ssDNA) molecules, labeled with fluorescent dyes at the same (3' or 5') end. Because the labeling efficiency of ssDNA is smaller than 100%, the resulting dsDNA have two, one or are without a dye. Existing methods are insufficient to measure the percentage of the doubly-labeled dsDNA component in the fluorescent DNA sample and it is even difficult to distinguish the doubly-labeled DNA component from the singly-labeled component. Accurate measurement of the percentage of such doubly labeled dsDNA component is a critical prerequisite for quantitative biochemical measurements, which has puzzled scientists for decades. We established a fluorescence correlation spectroscopy (FCS) system to measure the percentage of doubly labeled dsDNA (PDL) in the total fluorescent dsDNA pool. The method is based on comparative analysis of the given sample and a reference dsDNA sample prepared by adding certain amount of unlabeled ssDNA into the original ssDNA solution. From FCS autocorrelation functions, we obtain the number of fluorescent dsDNA molecules in the focal volume of the confocal microscope and PDL. We also calculate the labeling efficiency of ssDNA. The method requires minimal amount of material. The samples have the concentration of DNA in the nano-molar/L range and the volume of tens of microliters. We verify our method by using restriction enzyme Hind III to cleave the fluorescent dsDNA. The kinetics of the reaction depends strongly on PDL, a critical parameter for quantitative biochemical measurements. PMID- 23920091 TI - Real-time and non-invasive impedimetric monitoring of cell proliferation and chemosensitivity in a perfusion 3D cell culture microfluidic chip. AB - A perfusion three-dimensional (3D) cell culture microfluidic chip has been developed for real-time and non-invasive impedimetric monitoring of cell proliferation and chemosensitivity. In this study, human oral cancer cells (OEC M1) were encapsulated in 3D agarose scaffold and cultured in a miniaturized chamber under perfusion of tested substance. This setting provides a more in vitro physiologically relevant microenvironment to better mimic the complex in vivo microenvironment. A pair of vertical electrodes was embedded at the opposite sidewalls of the culture chamber for the on-site impedance measurement. Cell density in the 3D construct was shown to be proportional to the impedance magnitude of the entire construct. Therefore, perfusion 3D cell culture was performed for up to 5 days and cell proliferation can be monitored by the impedimetric analysis. Moreover, real-time impedimetric monitoring of cell viability under the perfusion of anti-cancer drug in different concentrations was conducted and the impedance magnitude was directly correlated with the cell viability. From the confirmation of the endpoint cell viability assays, a concentration-dependent effect was shown; however, the response of cell viability during the drug treatment was able to be traced by the impedance measurement. The experimental results showed that cell proliferation and chemosensitivity in 3D cell culture format can be monitored by impedance measurement. This microfluidic chip has a high potential to develop a powerful analytical platform for cancer research. PMID- 23920092 TI - Electrochemical sensing interfaces with tunable porosity for nonenzymatic glucose detection: a Cu foam case. AB - It is widely thought in electro-biochemical analysis that the sensing interfaces play a key role in the enzymeless detection of biomolecules like glucose, ascorbic acid, dopamine and uric acid. On the way to maximize the anti-poisoning sensitivity of nonenzymatic electrochemical glucose sensors as well as achieve favorable selectivity, we propose here a porous interface fabricated by a facile but effective approach for glucose monitoring in alkaline media containing dissolved oxygen. The sensing interface based on porous Cu foams is directly formed on a homemade disposable screen-printed carbon electrode (SPCE) substrate by electrodeposition assisted with hydrogen evolution simultaneously, and its porosity can be easily tailored through adjusting deposition conditions for the optimal electrocatalytic oxidation of glucose molecules. SEM and BET studies show that the generated Cu foam possesses robust hierarchical porous architectures with greatly enhanced surface area and pore volume, beneficial for the unimpeded mobility of glucose and reaction products. Cyclic voltammetric tests indicate that a diffusion-controlled glucose electro-oxidation reaction occurs at the Cu foam electrode at around +0.35 V vs. Ag/AgCl in 0.1 M NaOH. Chronoamperometric results obtained under optimized conditions reveal that the proposed sensor exhibits desired poison resistance ability in the presence of chloride ions and significant selectivity to glucose, providing fascinating sensitivities of 2.57 and 1.81 mA cm(-2) mM(-1) for glucose in the linear concentration ranges of 2-80 MUM and 0.1-5 mM, respectively. The limit of detection is calculated to be as low as 0.98 MUM according to the signal-to-noise ratio of three. In addition, the fabricated sensing interface shows attractive reproducibility (RSD of 5.1% and 7.0% for 15 repeated measurements on a sensor and for measurements on 15 prepared sensors, respectively) and outstanding long-term stability (less than 5% loss in sensitivity over 1 month) for glucose detection. The application of the Cu foam based sensor for monitoring glucose in practical samples is also successfully demonstrated. PMID- 23920093 TI - Pharmacokinetics of amphotericin B lipid complex in critically ill patients undergoing continuous venovenous haemodiafiltration. AB - The objective of this study was to examine the effect of continuous venovenous haemodiafiltration (CVVHDF) on the pharmacokinetics of amphotericin B (AmB) in critically ill patients following administration of amphotericin B lipid complex (ABLC). Plasma and ultrafiltrate (UF) samples were collected from patients administered ABLC and either receiving or not receiving CVVHDF. Pharmacokinetic (PK) analysis was performed on eight profiles from patients receiving CVVHDF and six profiles from patients not receiving CVVHDF. For patients receiving CVVHDF, the following median PK data were calculated: area under the concentration-time curve (AUC) = 13.9 h.MUg/mL, volume of distribution at steady state (V(ss)) = 1476L and drug clearance (CL) = 27.4 L/h; for patients not receiving CVVHDF, the corresponding median PK data were 11.5 h MUg/mL, 2048 L and 43.7 L/h, respectively. The median half-lives calculated during the dosage interval (t(1/2int)) were 30.9 h and 32.5 h on and off CVVHDF, respectively, and the total range of t(1/2int) values was 15.6-180.4 h. Observed median peak concentrations on Day 1 were 0.563 MUg/mL and 0.468 MUg/mL in patients on and off CVVHDF, respectively. From AmB present in the UF, clearance via CVVHDF contributed<1% of total plasma clearance. The AmB concentration-time profiles for patients administered ABLC on and off CVVHDF were compared and no statistically significant differences in AUC, CL, t(1/2int) and V(ss) were observed. In conclusion, CVVHDF had no clinically significant effect on the pharmacokinetics of AmB following administration of ABLC. PMID- 23920095 TI - [The modern paradigm of Rheumatoid Arthritis]. PMID- 23920094 TI - Multicomponent antibiotic substances produced by fermentation: implications for regulatory authorities, critically ill patients and generics. AB - Teicoplanin and polymyxin E (colistin) are antibiotics consisting of multiple, closely related subcomponents, produced by fermentation. The principal components comprise a complex mixture of chemically related, active substances (teicoplanin A(2-1)-A(2-5) and polymyxin E(1-2), respectively), which might be required to be present in specific ratios to ensure optimal antibacterial and clinical efficacy. These subcomponents differ in their fatty acid and amino acid composition and, as such, the lipophilic and protein binding characteristics differ between components. This has therapeutic implications for critically ill patients, as the volume of distribution of the teicoplanin A2 and polymyxin E analogues at the onset of an intravenous infusion may impact on expected pharmacokinetics and influence outcome. PMID- 23920096 TI - [The toxicity of venom of Bothrops (Rhinocerophris) alternatus in different areas of Cordoba State in Argentina]. AB - Snake venoms can show biochemical and toxicological variability even in specimens from the same specie. The geographical localization of the snakes is one of the factors that can influence those variations. By these reasons the venom from specimens of Bothrops (Rhinocerophis) alternatus ("crucera", "yararagrande"), one of the snakes of highest medical importance in Argentina, from three different regions of Cordoba was studied. Lehtal potency, hemorrhagic, coagulant on plasma and thrombin like activities as well as the electrophoretic patterns of venom from snakes of Calamuchita, Traslasierras and the East of the province were determined. The venom from the snakes of the three regions showed the characteristic activities of the venom of the majority of Bothrops, causing hemorrhage, hemostatic disturbances acting on plasma or directly on fibrinogen with a "thrombin like activity". The different samples were very similar regarding their biochemical characteristics and toxic potencies at difference of previous observations on venoms from the same specie in different regions of other provinces fro Argentina. Bivalent antivenom, the one used by the Provincial Ministry of Health to treat the bothropic accidents, neutralized in all the cases the toxic activities of the venom in very similar range of neutralizing potency. PMID- 23920097 TI - Risk factors associated with infection in tibial open fractures. AB - BACKGROUND: The objective of the treatment of open fracture is to prevent infection, stabilize the bones, and restore function. However, infection is the most important step in achieving the latter aims. OBJECTIVE: The objective of the current paper is to find risk factors associated with infection in a sample of tibial open fractures. PATIENTS AND METHODS: A retrospective analysis was carried out. The study included all patients who underwent to tibial open fracture treatment in the Hospital Geral Roberto Santos-HGRS, Salvador, Bahia, Brasil, from March to October, 2009. Patients under the age of eight, with multiple fractures or suffering from systemic or bone disease were excluded. Clinical and demographic data were collected and Patient outcomes were divided into two groups: Group 1 comprises those without infection whereas group 2 comprises those with lesions which became infected. The two groups were evaluated in search for associated factors that could lead to infection. RESULTS: We studied 50 patients. Our overall infection rate was 14 (28%; CI95%=15.5-40.5). Infection was significantly associated with place of trauma (OR 3.78; CI95%=1.4-5.5; p=0.02), and time delay superior to 24 hours (OR 3.4; CI95%=1.4-20.8; p=0.03). Fractures graded as Gustilo I, II and IIIA had a lower chance for infection compared to Gustilo IIIB and IIIC (OR 4.32; CI95%=1.3-19.1; p=0.01). Fractures graded Tscherne III and IV had a higher chance for infection, and it was the most significant isolated factor (OR 8.07; CI95%=2.4-47.1; pp<0.00). CONCLUSIONS: We confirmed the relationships between infection with Gustilo classification and as well as between infection and trauma from the countryside of Bahia State. We also presented a new relationship between soft tissue and infection, and another relating time delay of more than 12 hours with infection. PMID- 23920098 TI - [Incidence and risk factors of endoleak in endovascular aortic aneurysm repair]. AB - BACKGROUND: endovascular aneurysm repair (EVAR) reduces morbidity and hospital stay compaired with open surgical repair. Endoleak is a common complication of the procedure. The resulting increase of pressure within the sac may expand the aneurysm with the following risk of rupture. The aim of this study was to recognize the incidence of endoleak in tomographic controls of the patients who underwent endovascular repair at our hospital as well as identify the risk factors associated with this complication. METHODS: all consecutive patients who underwent endovascular aneurysm repair at our hospital between 2008, February until 2012, February were restrospectively enrolled in the study, excluding those who were lost at follow-up. 43 patients were included, aged 70.5 +/- 6 (men: 88%). The endpoint was endoleak incidence at 1, 6, 12th months after the intervention in the control tomography, and its association with underlying risk factors: hypertension, Smoking, chronic obstructive pulmonary desease and the diameter of the aneurysm. RESULTS: eleven (11%) patients developed endoleak (type I 9%, type III 2%). All were infrarrenal aortic aneurysms. The anteroposterior diameter of the aneurysm (more than 60 mm) showed a trend toward statistical significance as a risk factor (30% vs. 6%; p:0.073). No relationship was found with gender, age, COPD, smoking or hypertension. CONCLUSION: endoleak after endovascular aneurysm repair is a common complication. The size of the aneurysm might be a risk factor of the event. PMID- 23920099 TI - [Diabetes and pregnancy: maternal and perinatal results in Materno Neonatal Hospital]. PMID- 23920100 TI - [Polycystic ovary syndrome: physiopathology review]. AB - Polycystic ovary syndrome (PCOS), the most common gynecological endocrinopathy in women of reproductive age, is characterized by hyperandrogenism, chronic anovulation and /or polycystic ovaries. Although the cause of PCOS is still unknown, there are several hypotheses attempting to explain the primary defect; the most commonly accepted is insulin resistance. Due to its high prevalence, the patients have increased risk of developing metabolic and cardiovascular alterations. The compensatory hyperinsulinemia contributes to hyperandrogenism in different ways: by stimulating ovarian androgen synthesis and inhibiting hepatic production of sex hormone binding globulin. From the study of the intrauterine environment in recent years it has been suggested that PCOS may have an origin in utero associated with prenatal exposure to androgens. The aim of this paper is to review the main mechanisms proposed to cause the syndrome. PMID- 23920101 TI - [Pulmonary carcinomatous lymphangitis: presentation as acute pneumopathy. Report of two cases]. AB - INTRODUCTION: Carcinomatous lymphangitis of the lung accounts for 6-8% of lung's metastases. There are evidence that it can be a treatable condition with an impact on progression of dyspnea and radiographic lesions, and survival improvement. Two cases are reported, with the aim of increase the clinical suspicion at compatible cases. METHODS: Case 1: woman 32 years old. Progressive dyspnea and cough two weeks ago, without antibiotic response. Tachypnea, increase of respiratory work, basal crackles. Respiratory failure. Radiography: basal alveolointerstitial opacities. Treatment for severe community-acquired pneumonia is started. She evolves unfavorably, with need of MRA and fatal outcome. Case 2: woman 46 years old. Progressive dyspnea and cough from one week ago. Tachypnea, diffuse crackles. Respiratory failure. Radiography: diffuse nodular interstitialradiopacity, with radiopacy lesion in right apex. HRCT: nodular thickening of interlobular septum and peribrochovascular interstitial. Treatment for tuberculosis of the lung is started. She evolves unfavorably, with need of MRA and fatal outcome. In both cases a lung biopsy was performed, diagnosing carcinomatous lymphangitis. DISCUSSION: Two cases are reported, with acute afebrilepneumopathyin young patients, whose manifestations guided to treatment of respiratory infection, and evolved quickly to refractory hypoxemic respiratory failure with need of MRA and fatal outcome. CONCLUSION: Carcinomatous lymphangitis of the lung should be included as a differential diagnosis of cases of acute lung pathology, especially when there was an unfavorable evolution under antibiotics or have excluded more common etiologies. PMID- 23920102 TI - [Medical and patient relationship]. PMID- 23920103 TI - Effect of body image on gestational weight gain in overweight and obese women. AB - PROBLEM OR BACKGROUND: There is little information available describing how women who are overweight or obese in pregnancy perceive their bodies, and in particular the effect of body image dissatisfaction on gestational weight gain. QUESTION: To describe how women who are overweight or obese in pregnancy perceive their body, and the effect of body image on gestational weight gain. METHODS: This prospective nested cohort study evaluated self estimation of body weight, preferred body shape, dieting behavior, satisfaction with body weight and shape, and gestational weight gain in pregnant women who were overweight or obese, through self-completed questionnaire in early pregnancy in South Australia from October 2010 to February 2012. FINDINGS: Of the 442 women who completed the questionnaire, 25.8% correctly identified their BMI, with 70.1% under-estimating and 4.1% over-estimating their BMI. Women who were obese were significantly less likely to correctly identify their BMI, as were younger women. Women who incorrectly identified their BMI were significantly more likely to have higher gestational weight gain (P<0.001). Approximately 45% of women indicated dissatisfaction with their weight or body shape, with this being more common in women of higher parity and higher BMI. Dissatisfaction was significantly related to gestational weight gain. CONCLUSION: Women who report increasing dissatisfaction with their body size and shape are more likely to gain excessive weight during pregnancy. Further research should explore insights about maternal body image and diet related behaviors. PMID- 23920104 TI - Low birthweight and premature birth are risk factors for podocytopenia and focal segmental glomerulosclerosis. AB - BACKGROUND: Recent reports suggest that low birthweight (LBW) is a risk factor for kidney diseases, including focal segmental glomerulosclerosis (FSGS), although the underlying pathological mechanism remains unknown. Podocyte loss triggers glomerulosclerosis; however, whether FSGS in LBW children is associated with podocytopenia is unclear. METHODS: We reviewed the birthweights and gestational age of all patients who underwent renal biopsies from 1995 to 2011 at our Institute. Sixteen patients had FSGS, of which 6 (37.5%) had LBW; this LBW rate was significantly higher than the overall LBW rate in Japan (9.7%). The incidence of LBW was also high in patients with minimal change nephrotic syndrome (MCNS; 12.5%). The glomerular cell numbers in biopsy sections were calculated using computer image analysis and compared with FSGS of normal birthweight (NBW FSGS). Biopsy specimens from age-matched patients with MCNS were also compared. Wilms' tumor-1 (WT1) immunohistochemistry was performed to enumerate the podocytes. RESULTS: All patients in the LBW-FSGS group were also preterm, with an average gestational age of 25.8 weeks. The number of podocytes per glomerulus in the LBW-FSGS patients was 34 and 24% lower as compared to that in the MCNS patients (p < 0.01) and the NBW-FSGS patients (p < 0.05), respectively. Similar results were observed for the WT1-positive glomerular cell number. CONCLUSION: LBW and premature birth were associated with FSGS development. The possibility that LBW and premature birth may be predisposing factors for severe podocytopenia in children with FSGS warrants further investigation. PMID- 23920105 TI - Bioconcentration of triclosan and methyl-triclosan in marine mussels (Mytilus galloprovincialis) under laboratory conditions and in metropolitan waters of Gulf St Vincent, South Australia. AB - The anti-microbial agent triclosan (TCS), and its derivative methyl-triclosan (Me TCS), are discharged with treated effluents from wastewater treatment plants to receiving environments. We investigated the bioconcentration of TCS and Me-TCS in mussels (Mytilus galloprovincialis) exposed to TCS (100 ng L(-1)) for 30 days in seawater aquaria (19+/-2 degrees C) with fresh phytoplankton as a food source. Bioconcentration increased with time reaching a steady-state around 24-30 days. The bioconcentration factor (log BCF) for TCS were 2.81 L kg(-1) (dry weight) and 4.13 L kg(-1), when lipid normalised concentrations were used. Mussels were also deployed in cages at four marine locations receiving effluents from WWTPs. The mean (+/-SD) TCS and Me-TCS concentrations for mussels from these sites were 9.87 (+/-1.34) and 6.99 (+/-2.44) MUg kg(-1). The study showed that mussels can be a useful tool for monitoring pollution of TCS and Me-TCS in marine and estuarine environments. PMID- 23920107 TI - Optimizing the use of intravenous therapy in internal medicine. AB - BACKGROUND: We aimed to evaluate the impact of physicians' educational programs in the reduction of inappropriate intravenous lines in internal medicine. METHODS: Fifty-six French internal medicine units were enrolled in a nationwide, prospective, blinded, randomized controlled trial. Forms describing the patients with an intravenous line and internal medicine department characteristics were filled out on 2 separate days in January and April 2007. Following the first visit, all units were randomly assigned to either a specific education program on the appropriate indications of an intravenous line, during February and March 2007, or no training (control group). The Investigators' Committee then blindly evaluated the clinical relevance of the intravenous line according to pre established criteria. The primary outcome was the percentage of inappropriate intravenous lines. RESULTS: During January 2007, intravenous lines were used in 475 (24.9%) of the 1910 hospitalized patients. Of these, 80 (16.8%) were considered inappropriate. In April 2007, 416 (22.8%) of the 1823 hospitalized patients received an intravenous line, which was considered in 10.2% (21/205) of patients managed by trained physicians, versus 16.6% (35/211) of patients in the control group (relative difference 39%; 95% confidence interval, -0.6-13.3; P = .05). Reduced intravenous administration of fluids, antibiotics, and analgesics accounted for the observed decrease. CONCLUSION: The use of a simple education program reduced the rate of inappropriate intravenous lines by almost 40% in an internal medicine setting (NCT01633307). PMID- 23920106 TI - Catalog of mRNA expression patterns for DNA methylating and demethylating genes in developing mouse lower urinary tract. AB - The mouse prostate develops from a component of the lower urinary tract (LUT) known as the urogenital sinus (UGS). This process requires androgens and signaling between mesenchyme and epithelium. Little is known about DNA methylation during prostate development, including which factors are expressed, whether their expression changes over time, and if DNA methylation contributes to androgen signaling or influences signaling between mesenchyme and epithelium. We used in situ hybridization to evaluate the spatial and temporal expression pattern of mRNAs which encode proteins responsible for establishing, maintaining or remodeling DNA methylation. These include DNA methyltransferases, DNA deaminases, DNA glycosylases, base excision repair and mismatch repair pathway members. The mRNA expression patterns were compared between male and female LUT prior to prostatic bud formation (14.5 days post coitus (dpc)), during prostatic bud formation (17.5 dpc) and during prostatic branching morphogenesis (postnatal day (P) 5). We found dramatic changes in the patterns of these mRNAs over the course of prostate development and identified examples of sexually dimorphic mRNA expression. Future investigation into how DNA methylation patterns are established, maintained and remodeled during the course of embryonic prostatic bud formation may provide insight into prostate morphogenesis and disease. PMID- 23920108 TI - Antibodies biotinylated using a synthetic Z-domain from protein A provide stringent in situ protein detection. AB - Antibody-based protein profiling on a global scale using immunohistochemistry constitutes an emerging strategy for mapping of the human proteome, which is crucial for an increased understanding of biological processes in the cell. Immunohistochemistry is often performed indirectly using secondary antibodies for detection, with the benefit of signal amplification. Direct immunohistochemistry instead brings the advantage of multiplexing; however, it requires labeling of the primary antibody. Many antibody-labeling kits do not specifically target IgG and may therefore cause labeling of stabilizing proteins present in the antibody solution. A new conjugation method has been developed that utilizes a modified Z domain of protein A (ZBPA) to specifically target the Fc part of antibodies. The aim of the present study was to compare the ZBPA conjugation method and a commercially available labeling kit, Lightning-Link, for in situ protein detection. Fourteen antibodies were biotinylated with each method and stained using immunohistochemistry. For all antibodies tested, ZBPA biotinylation resulted in distinct immunoreactivity without off-target staining, regardless of the presence of stabilizing proteins in the buffer, whereas the majority of the Lightning-Link biotinylated antibodies displayed a characteristic pattern of nonspecific staining. We conclude that biotinylated ZBPA domain provides a stringent method for antibody biotinylation, advantageous for in situ protein detection in tissues. PMID- 23920110 TI - Sphingomyelin patches on pancreatic beta-cells are indicative of insulin secretory capacity. AB - The establishment and validation of specific markers on the surfaces of pancreatic beta-cells would have a significant impact on the development of agents that specifically target these cells for imaging and/or image-guided therapy in diabetes patient samples. We have recently described unique, cholesterol-stabilized sphingomyelin (SM) patches on the surfaces of beta-cells using the IC2 antibody. To further investigate the utility of SM patches as a unique beta-cell biomarker, we embarked on the current study to correlate the expression of this antigen with the insulin secretory capacity of beta-cells in tissue samples from patients and animals with type 1 and type 2 diabetes and compared this with samples from normal subjects. We found that the locations of SM patches were consistent with the insulin status of islets in all tissues studied. Using immunohistochemistry and staining with an IC2 antibody, we demonstrated a direct correlation between the reduced expression of SM patches and insulin production in diabetic individuals, indicating that the former could potentially serve as a functional biomarker of beta-cells. We believe that our results have significant implications for the further development of ligands with SM specificity for the non-invasive functional assessment of beta-cells and/or for targeted therapeutic delivery in diabetic patients. PMID- 23920109 TI - Cryptochrome in sponges: a key molecule linking photoreception with phototransduction. AB - Sponges (phylum: Porifera) react to external light or mechanical signals with contractile or metabolic reactions and are devoid of any nervous or muscular system. Furthermore, elements of a photoreception/phototransduction system exist in those animals. Recently, a cryptochrome-based photoreceptor system has been discovered in the demosponge. The assumption that in sponges the siliceous skeleton acts as a substitution for the lack of a nervous system and allows light signals to be transmitted through its glass fiber network is supported by the findings that the first spicules are efficient light waveguides and the second sponges have the enzymatic machinery for the generation of light. Now, we have identified/cloned in Suberites domuncula two additional potential molecules of the sponge cryptochrome photoreception system, the guanine nucleotide-binding protein beta subunit, related to beta-transducin, and the nitric oxide synthase (NOS)-interacting protein. Cryptochrome and NOSIP are light-inducible genes. The studies show that the NOS inhibitor L-NMMA impairs both morphogenesis and motility of the cells. Finally, we report that the function of primmorphs to produce reactive nitrogen species can be abolished by a NOS inhibitor. We propose that the sponge cryptochrome-based photoreception system, through which photon signals are converted into radicals, is coupled to the NOS apparatus. PMID- 23920111 TI - TSNA exposure from cigarette smoking: 18 years of urinary NNAL excretion data. AB - The objective of this work was to characterize trends over time in urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) among cigarette smokers in the US. We identified 35 studies presenting data that either reported, or could be converted to, common units of total urinary NNAL excretion as pmol/mg creatinine. The studies spanned 18years, reported urinary NNAL excretion estimates for 61 defined populations, and included a combined total of 3941 study participants. Analyses show that urinary NNAL excretion trends downward with study publication year, and the trend is statistically significant. The trend does not appear to be accounted for by a reduction in cigarettes smoked per day by study participants over the same time period. This trend is consistent with reductions in tobacco specific nitrosamine (TSNA) levels in both cigarette tobacco filler and mainstream cigarette smoke observed over the past decade and with efforts by the tobacco industry and the agricultural community to reduce levels of TSNAs in tobacco and cigarette smoke. PMID- 23920112 TI - Kleptomania in patients with neuro-Behcet's disease. AB - OBJECTIVE: This study was conducted to characterize the prevalence and clinical features of kleptomania, an impulse control disorder, in patients with Behcet's disease involving the central nervous system. SUBJECTS AND METHODS: Medical records of 350 patients with neuro-Behcet's disease were evaluated, and clinical and neuropsychological features of patients with kleptomania were noted. RESULTS: Of the 350 neuro-Behcet's disease patients 6 (1.7%) had presented with symptoms that fulfilled the criteria of kleptomania according to the revised 4th version of the Diagnostic and Statistical Manual of Mental Disorders. The 6 patients (5 men, 1 woman) had parenchymal lesions and had developed kleptomania during remission. Magnetic resonance imaging done on the 6 patients before the onset of kleptomania mostly revealed brainstem lesions. Psychiatric assessment did not show any comorbid psychiatric disorders and neuropsychological evaluation showed executive dysfunction in all patients. CONCLUSION: The 6 patients with kleptomania had developed a frontal lobe syndrome. PMID- 23920113 TI - A mechanically coupled reaction-diffusion model for predicting the response of breast tumors to neoadjuvant chemotherapy. AB - There is currently a paucity of reliable techniques for predicting the response of breast tumors to neoadjuvant chemotherapy. The standard approach is to monitor gross changes in tumor size as measured by physical exam and/or conventional imaging, but these methods generally do not show whether a tumor is responding until the patient has received many treatment cycles. One promising approach to address this clinical need is to integrate quantitative in vivo imaging data into biomathematical models of tumor growth in order to predict eventual response based on early measurements during therapy. In this work, we illustrate a novel biomechanical mathematical modeling approach in which contrast enhanced and diffusion weighted magnetic resonance imaging data acquired before and after the first cycle of neoadjuvant therapy are used to calibrate a patient-specific response model which subsequently is used to predict patient outcome at the conclusion of therapy. We present a modification of the reaction-diffusion tumor growth model whereby mechanical coupling to the surrounding tissue stiffness is incorporated via restricted cell diffusion. We use simulations and experimental data to illustrate how incorporating tissue mechanical properties leads to qualitatively and quantitatively different tumor growth patterns than when such properties are ignored. We apply the approach to patient data in a preliminary dataset of eight patients exhibiting a varying degree of responsiveness to neoadjuvant therapy, and we show that the mechanically coupled reaction-diffusion tumor growth model, when projected forward, more accurately predicts residual tumor burden at the conclusion of therapy than the non-mechanically coupled model. The mechanically coupled model predictions exhibit a significant correlation with data observations (PCC = 0.84, p < 0.01), and show a statistically significant >4 fold reduction in model/data error (p = 0.02) as compared to the non-mechanically coupled model. PMID- 23920114 TI - Do male and female gammarids defend themselves differently during chemical stress? AB - To investigate xenobiotic impacts on organism physiology, several studies involve biomarker assessment. However, most studies do not take into account the toxic effect on both males and females. Here, we have investigated the influence of gender on the detoxification response (reduced glutathione, metallothionein, gamma-glutamylcystein ligase and carotenoid), energy reserves (protein, lipids and glycogen) and biomarker of toxic effects (malondialdehyde) in Gammarus roeseli exposed to cadmium. A principal component analysis revealed that G. roeseli males and females were differently impacted by cadmium. We observed lower malondialdehyde levels in females than in males, whatever the condition tested (i.e. control, 2 and 8 MUg CdL(-1)), although the pattern of responses of control and exposures to 2 or 8 MUgL(-1) was the same for both genders. Results could be linked to apparently more effective detoxification displayed by females than by males. Protein concentrations were unchanged in both genders, lipids contents were always significantly decreased and glycogen contents decreased only in females. This study supports the importance of taking into account the gender in ecotoxicological studies to have an overview of xenobiotics effects on a population. PMID- 23920115 TI - Hippocampal lateralization and memory in children and adults. AB - The neural organization of cognitive processes, particularly hemispheric lateralization, changes throughout childhood and adolescence. Differences in the neural basis of relational memory between children and adults are not well characterized. In this study we used magnetoencephalography to observe the lateralization differences of hippocampal activation in children and adults during performance of a relational memory task, transverse patterning (TP). The TP task was paired with an elemental control task, which does not depend upon the hippocampus. We contrasted two hypotheses; the compensation hypothesis would suggest that more bilateral activation in children would lead to better TP performance, whereas the maturation hypothesis would predict that a more adult like right-lateralized pattern of hippocampal activation would lead to better performance. Mean-centered partial least squares analysis was used to determine unique patterns of brain activation specific to each task per group, while diminishing activation that is consistent across tasks. Our findings support the maturation hypothesis that a more adult-like pattern of increased right hippocampal lateralization in children leads to superior performance on the TP task. We also found dynamic changes of lateralization throughout the time course for all three groups, suggesting that caution is needed when interpreting conclusions about brain lateralization. PMID- 23920117 TI - A core transcriptional network composed of Pax2/8, Gata3 and Lim1 regulates key players of pro/mesonephros morphogenesis. AB - Translating the developmental program encoded in the genome into cellular and morphogenetic functions requires the deployment of elaborate gene regulatory networks (GRNs). GRNs are especially crucial at the onset of organ development where a few regulatory signals establish the different programs required for tissue organization. In the renal system primordium (the pro/mesonephros), important regulators have been identified but their hierarchical and regulatory organization is still elusive. Here, we have performed a detailed analysis of the GRN underlying mouse pro/mesonephros development. We find that a core regulatory subcircuit composed of Pax2/8, Gata3 and Lim1 turns on a deeper layer of transcriptional regulators while activating effector genes responsible for cell signaling and tissue organization. Among the genes directly affected by the core components are the key developmental molecules Nephronectin (Npnt) and Plac8. Hence, the pro/mesonephros GRN links together several essential genes regulating tissue morphogenesis. This renal GRN sheds new light on the disease group Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) in that gene mutations are expected to generate different phenotypic outcomes as a consequence of regulatory network deficiencies rather than threshold effects from single genes. PMID- 23920116 TI - Knockdown of fbxl10/kdm2bb rescues chd7 morphant phenotype in a zebrafish model of CHARGE syndrome. AB - CHARGE syndrome is a sporadic autosomal-dominant genetic disorder characterized by a complex array of birth defects so named for its cardinal features of ocular coloboma, heart defects, choanal atresia, growth retardation, genital abnormalities, and ear abnormalities. Approximately two-thirds of individuals clinically diagnosed with CHARGE syndrome have heterozygous loss-of-function mutations in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7), an ATP-dependent chromatin remodeler. To examine the role of Chd7 in development, a zebrafish model was generated through morpholino (MO)-mediated targeting of the zebrafish chd7 transcript. High doses of chd7 MO induce lethality early in embryonic development. However, low dose-injected embryos are viable, and by 4 days post-fertilization, morphant fish display multiple defects in organ systems analogous to those affected in humans with CHARGE syndrome. The chd7 morphants show elevated expression of several potent cell-cycle inhibitors including ink4ab (p16/p15), p21 and p27, accompanied by reduced cell proliferation. We also show that Chd7 is required for proper organization of neural crest-derived craniofacial cartilage structures. Strikingly, MO-mediated knockdown of the jumonji domain-containing histone demethylase fbxl10/kdm2bb, a repressor of ribosomal RNA (rRNA) genes, rescues cell proliferation and cartilage defects in chd7 morphant embryos and can lead to complete rescue of the CHARGE syndrome phenotype. These results indicate that CHARGE-like phenotypes in zebrafish can be mitigated through modulation of fbxl10 levels and implicate FBXL10 as a possible therapeutic target in CHARGE syndrome. PMID- 23920118 TI - Aetiological overlap between obsessive-compulsive and depressive symptoms: a longitudinal twin study in adolescents and adults. AB - BACKGROUND: Depression is commonly co-morbid with obsessive-compulsive disorder (OCD). However, it is unknown whether depression is a functional consequence of OCD or whether these disorders share a common genetic aetiology. This longitudinal twin study compared these two hypotheses. METHOD: Data were drawn from a longitudinal sample of adolescent twins and siblings (n = 2651; Genesis 12 19 study) and from a cross-sectional sample of adult twins (n = 4920). The longitudinal phenotypic associations between OCD symptoms (OCS) and depressive symptoms were examined using a cross-lag model. Multivariate twin analyses were performed to explore the genetic and environmental contributions to the cross sectional and longitudinal relationship between OCS and depressive symptoms. RESULTS: In the longitudinal phenotypic analyses, OCS at time 1 (wave 2 of the Genesis 12-19 study) predicted depressive symptoms at time 2 (wave 3 of the Genesis 12-19 study) to a similar extent to which depressive symptoms at time 1 predicted OCS at time 2. Cross-sectional twin analyses in both samples indicated that common genetic factors explained 52-65% of the phenotypic correlation between OCS and depressive symptoms. The proportion of the phenotypic correlation due to common non-shared environmental factors was considerably smaller (35%). In the adolescent sample, the longitudinal association between OCS at time 1 and subsequent depressive symptoms was accounted for by the genetic association between OCS and depressive symptoms at time 1. There was no significant environmental association between OCS and later depressive symptoms. CONCLUSIONS: The present findings show that OCS and depressive symptoms co-occur primarily due to shared genetic factors and suggest that genetic, rather than environmental, effects account for the longitudinal relationship between OCS and depressive symptoms. PMID- 23920119 TI - Optimisation of single-phase dry-thermophilic anaerobic digestion under high organic loading rates of industrial municipal solid waste: population dynamics. AB - Different high feed organic loading rates (OLRs) (from 5.7 g to 46.0 g TVS/l/d) or hydraulic retention times (HRTs) (from 15 d to 2 d) in single-phase dry thermophilic anaerobic digestion (AD) of organic fraction municipal solid waste (OFMSW) were investigated. The specific gas production (SGP) values (0.25-0.53 m(3)/kg TVS) and the percentages of Eubacteria, Archaea, H2-utilising methanogens (HUMs) and acetate-utilising methanogens (AUMs) were stable within the ranges 80.2-91.1%, 12.4-18.5%, 4.4-9.8% and 5.5-10.9%, respectively. A HUM/AUM ratio greater than 0.7 seems to be necessary to maintain very low partial pressures of H2 required for dry AD process. Increasing OLR resulted in an increase in all the populations, except for propionate-utilising acetogens (PUAs). Optimal conditions were obtained at 3d HRT (OLR=30.7 g TVS/l/d), which is lower than the doubling time of acetogens and methanogens. The methane production (MP) was clearly higher than those reported in AD of OFMSW. PMID- 23920120 TI - Effect of temperature on lignin-derived inhibition studied with three structurally different cellobiohydrolases. AB - Non-productive enzyme adsorption onto lignin inhibits enzymatic hydrolysis of lignocellulosic biomass. Three cellobiohydrolases, Trichoderma reesei Cel7A (TrCel7A) and two engineered fusion enzymes, with distinctive modular structures and temperature stabilities were employed to study the effect of temperature on inhibition arising from non-productive cellulase adsorption. The fusion enzymes, TeCel7A-CBM1 and TeCel7A-CBM3, were composed of a thermostable Talaromyces emersonii Cel7A (TeCel7A) catalytic domain fused to a carbohydrate-binding module (CBM) either from family 1 or from family 3. With all studied enzymes, increase in temperature was found to increase the inhibitory effect of supplemented lignin in the enzymatic hydrolysis of microcrystalline cellulose. However, for the different enzymes, lignin-derived inhibition emerged at different temperatures. Low binding onto lignin and thermostable structure were characteristic for the most lignin-tolerant enzyme, TeCel7A-CBM1, whereas TrCel7A was most susceptible to lignin especially at elevated temperature (55 degrees C). PMID- 23920121 TI - Effect of salt additives on protein partition in polyethylene glycol-sodium sulfate aqueous two-phase systems. AB - Partitioning of 15 proteins in polyethylene glycol (PEG)-sodium sulfate aqueous two-phase systems (ATPS) formed by PEG of two different molecular weights, PEG 600 and PEG-8000 in the presence of different buffers at pH7.4 was studied. The effect of two salt additives (NaCl and NaSCN) on the protein partition behavior was examined. The salt effects on protein partitioning were analyzed by using the Collander solvent regression relationship between the proteins partition coefficients in ATPS with and without salt additives. The results obtained show that the concentration of buffer as well as the presence and concentration of salt additives affects the protein partition behavior. Analysis of ATPS in terms of the differences between the relative hydrophobicity and electrostatic properties of the phases does not explain the protein partition behavior. The differences between protein partitioning in PEG-600-salt and PEG-8000-salt ATPS cannot be explained by the protein size or polymer excluded volume effect. It is suggested that the protein-ion and protein-solvent interactions in the phases of ATPS are primarily important for protein partitioning. PMID- 23920122 TI - Prediction of antidepressant treatment response from gray matter volume across diagnostic categories. AB - Dysfunctional limbic, paralimbic and prefrontal brain circuits represent neural substrates of major depression that are targeted by pharmacotherapy. In a high resolution structural magnetic resonance imaging (MRI) study we investigated the potential of variability of the cortex volume to predict the response to antidepressant treatment among patients with major depression. We enrolled 167 patients participating in the Munich Antidepressant Response Signature (MARS) study and employed voxel based morphometry to investigate covariation of gray matter (GM) maps with changes of depression severity over 5 weeks. Larger left hippocampal and bilateral posterior cingulate GM volumes and lower right temporolateral GM volumes were associated with beneficial treatment response. Subcallosal/orbitofrontal GM volumes were associated with treatment response mainly through gender-by-region interactions. A hippocampal/temporolateral composite marker proved robust in both first episode and recurrent unipolar patients and in bipolar patients. Compared with 92 healthy controls, abnormally low volumes were only detected in the left hippocampal area, particularly in recurrent unipolar patients. These findings indicate that variability of the cortex volume of specific brain areas is associated with different response to antidepressants. In addition, hippocampal findings recursively link together unfavorable treatment response and progressive hippocampal structural changes in recurrent depression. PMID- 23920123 TI - Interleukin-1beta induced by Helicobacter pylori infection enhances mouse gastric carcinogenesis. AB - Interleukin-1beta (Il1b) is considered to be involved in Helicobacter pylori (HP) induced human gastric carcinogenesis, while the role of its polymorphisms in gastric cancer susceptibility remains controversial. Here, we aimed to clarify the role of HP infection-induced IL1B in gastric inflammation and carcinogenesis using Il1b(-/-) (Il1b-null) mice. In gastric mucosa of the Il1b(+/+) (WT) mice, HP infection induced Il1b expression and severe inflammation. In contrast, in Il1b-null mice, recruitment of neutrophils and macrophages by HP infection was markedly suppressed. In a carcinogenicity test, the multiplicity of gastric tumors was significantly suppressed in theIl1b-null mice (58% of WT; P<0.005). Mechanistically, HP infection induced NF-kappaB activation both in the inflammatory and epithelial cells in gastric mucosae, and the activation was attenuated in the Il1b-null mice. Accordingly, increased proliferation and decreased apoptosis of gastric epithelial cells induced by HP infection in the WT mice were attenuated in the Il1b-null mice. These results demonstrated that the IL1B physiologically induced by HP infection enhanced gastric carcinogenesis by affecting both inflammatory and epithelial cells. PMID- 23920125 TI - Down-regulation and aberrant cytoplasmic expression of GLTSCR2 in prostatic adenocarcinomas. AB - GLTSCR2 is a nuclear/nucleolar protein that translocates to the nucleoplasm, suppressed and mutated in human cancers. Our aim in this study was to investigate whether downregulation or cytoplasmic expression of GLTSCR2 has any pathological significance in prostatic cancer development or progression. In this study we show that GLTSCR2 is suppressed in prostatic cancers and its expression is significantly associated with Gleason's scores. Furthermore, we investigated the pathogenetic mechanism of downregulation and cytoplasmic expression of GLTSCR2 in development or progression of prostatic cancers. Taken together, our results indicate that GLTSCR2 functions as a tumor suppressor in prostatic adenocarcinomas. PMID- 23920124 TI - Guggulsterone decreases proliferation and metastatic behavior of pancreatic cancer cells by modulating JAK/STAT and Src/FAK signaling. AB - Inadequate efficacy, high toxicity and drug resistance associated with existing chemotherapeutic agents mandate a need for novel therapeutic strategies for highly aggressive Pancreatic Cancer (PC). Guggulsterone (GS) exhibits potent anti proliferative effects against various cancer cells and has emerged as an attractive candidate for use in complementary or preventive cancer therapies. However, the knowledge regarding the therapeutic potential of GS in PC is still limited and needs to be explored. We studied the effect of GS on PC cell growth, motility and invasion and elucidated the molecular mechanisms associated with its anti-tumor effects. Treatment of Capan1 and CD18/HPAF PC cells with GS resulted in dose- and time-dependent growth inhibition and decreased colony formation. Further, GS treatment induced apoptosis and cell cycle arrest as assessed by Annexin-V assay and FACS analysis. Increased apoptosis following GS treatment was accompanied with Bad dephosphorylation and its translocation to the mitochondria, increased Caspase-3 activation, decreased Cyclin D1, Bcl-2 and xIAP expression. Additionally, GS treatment decreased motility and invasion of PC cells by disrupting cytoskeletal organization, inhibiting activation of FAK and Src signaling and decreased MMP9 expression. More importantly, GS treatment decreased mucin MUC4 expression in Capan1 and CD18/HPAF cells through transcriptional regulation by inhibiting Jak/STAT pathway. In conclusion, our results support the utility of GS as a potential therapeutic agent for lethal PC. PMID- 23920126 TI - A novel antibody-like TCRgammadelta-Ig fusion protein exhibits antitumor activity against human ovarian carcinoma. AB - TCRgamma9delta2(OT3) is a tumor-specific TCR with an unique complementarity determining region 3 (CDR3) sequence, referred to as OT3, in its delta2 chain. This region was identified in tumor-infiltrating lymphocytes (TILs) from human ovarian epithelial carcinoma. We demonstrated that TCRgamma9delta2(OT3)-Fc, a fusion protein composed of the complete extracellular domains of the gamma9 and delta2 chains linked to the Fc domains of human IgG1, exhibited successful binding to multiple human carcinoma cell lines. In vitro, TCRgamma9delta2(OT3)-Fc mediated cell killing via antibody-dependent cellular cytotoxicity (ADCC) in a dose-dependent manner. In vivo, TCRgamma9delta2(OT3)-Fc significantly inhibited tumor growth and enhanced survival in human ovarian carcinoma xenograft models. Our findings suggest that the TCRgamma9delta2(OT3)-Fc fusion protein possesses both the antigen-recognition properties of TCR gammadelta and the Fc-mediated effector functions of the antibody. PMID- 23920127 TI - Immune microenvironment profiles of tumor immune equilibrium and immune escape states of mouse sarcoma. AB - Cancer immunoediting consists of three distinct phases: elimination, equilibrium and escape. Here, for the first time, we investigated the immune microenvironment profiles of tumor immune equilibrium and immune escape states in 3' methylcholanthrene-induced murine sarcoma model. Our study indicates the relative balance of monocytic MDSCs and antitumor immunity cells (especially CTLs, NK cells and gammadeltaT cells) may involve in maintaining tumor cells in a state of immune-mediated dormancy. In addition, high percentages of Treg cells and PMN MDSCs are associated with the tumor immune escape state - mice with progressing sarcomas. In summary, the relative balance of immune effector cells and suppressive populations in the tumor microenvironment may involve in determining the fate of tumors. PMID- 23920128 TI - [High mortality of meningococcal group C disease in adults in the Seville province, Spain (2008-2012)]. PMID- 23920130 TI - Human seminal fibronectin fragmentation patterns and their domain immunoreactivities in leucocytospermic patients. AB - The aim of the work was to analyse fibronectin (FN) domain immunoreactivities and profiles of FN fragmentation in seminal plasmas of fertile normozoospermic and infertile leucocytospermic male patients. ELISA with domain-specific monoclonal antibodies and immunoblotting were used in these measurements. Immunoblotting of normal and leucocytospermic seminal plasmas revealed the presence of twelve FN bands of ~70-196kDa with nearly identical FN profiles under reducing and non reducing conditions. The epitopes of the cell-, fibrin-, collagen-binding FN domains and the extra domain A (EDA) FN segment retained the ability to bind their specific monoclonal antibodies, whereas the fibrin-heparin domain (N terminal end) and the area around the disulfide bridges (C-terminal end) of the FN polypeptide did not show any reactivities with their respective specific antibodies. The mean values of cell- (338.4+/-138.4 and 398.3+/-310mgL(-1)), fibrin- (79.1+/-38.5 and 145.2+/-188.8mgL(-1)) and collagen-binding (19+/-19.8 and 50.9+/-73.4mgL(-1)) FN domain immunoreactivities and the relative amount of (EDA)FN did not show any significant differences between the normal and leucocytospermic groups. The high values of standard deviations for the FN domain immunoreactivities in the leucocytospermic group probably results from different aetiology of leucocytospermia. The profile of FN fragmentation and alterations of FN domain immunoreactivities in seminal plasma may influence their engagement in the fertilisation process. The analysis of seminal FN molecular status would be helpful for selecting the highest quality spermatozoa for use in assisted reproduction techniques. PMID- 23920129 TI - Cortical encoding of pitch contour changes in cochlear implant users: a mismatch negativity study. AB - A better understanding of melodic pitch perception in cochlear implants (CIs) may guide signal processing and/or rehabilitation techniques to improve music perception and appreciation in CI patients. In this study, the mismatch negativity (MMN) in response to infrequent changes in 5-tone pitch contours was obtained in CI users and normal-hearing (NH) listeners. Melodic contour identification (MCI) was also measured. Results showed that MCI performance was poorer in CI than in NH subjects; the MMNs were missing in all CI subjects for the 1-semitone contours. The MMNs with the 5-semitone contours were observed in a smaller proportion of CI than NH subjects. Results suggest that encoding of pitch contour changes in CI users appears to be degraded, most likely due to the limited pitch cues provided by the CI and deafness-related compromise of brain substrates. PMID- 23920131 TI - Clinical effectiveness of aripiprazole in short-term treatment of tic disorder in children and adolescents: a naturalistic study. AB - BACKGROUND/PURPOSE: The purpose of this study was to evaluate the effectiveness and tolerability of aripiprazole in short-term treatment of children and adolescents with tic disorder (TD). METHODS: This was a 14-week, prospective, open-label flexible dose trial of aripiprazole. We enrolled patients with TD aged between 4 years and 18 years. They received aripiprazole (dose: 2.5 mg/day) initially, which was then adjusted according to clinical response. The severity was assessed by the Yale Global Tic Severity Score (YGTSS) at 0, 2, 6, 10, and 14 weeks. The linear mixed models were used for evaluation of the YGTSSs at each follow-up, which were compared with baseline scores. RESULTS: Eighty-one patients were enrolled in this study. Nine patients withdrew from the study with complaints of adverse side effects. Of the remaining 72 patients, 15 patients discontinued medications prematurely due to being free of symptoms for over 2 weeks. Two patients discontinued medications due to no significant improvement. The mean scores had significantly decreased since the 2nd week (p < 0.01). The mean reduction was 51.0% in the motor tic scores, 67.1% in the vocal tic scores, and 70.0% in the total YGTSSs. The common adverse effects were sedation (32.1%) and increased appetite (22.2%). A slight increase in average body weight was noted, from 32.7 to 33.7 kg (+1.0 kg, p < 0.05). CONCLUSION: Aripiprazole is effective for short-term treatment of TD, especially vocal tics, in children and adolescents with mild adverse effects. However, further double-blind trials against placebo or other medications are needed to verify the efficacy of aripiprazole in the pharmacotherapy of TD. PMID- 23920132 TI - Comparison and reproducibility of nuchal translucency measurements using two dimensional and volume nuchal translucency ultrasound: a prospective study. AB - OBJECTIVE: To assess the reproducibility and feasibility of automated nuchal translucency (NT) measurement (Volume NT(c)) in comparison to the two-dimensional (2D) manual approach. The Volume NT technique reveals the correct midsagittal plane automatically and measures the NT at the maximum distance with minimal manipulation. METHODS: In this prospective study, 70 patients underwent NT screening. All standard 2D (standard NT) images and 3D volumes were acquired with an Accuvix V20 Prestige. Off-line measurements of the 3D volumes, manual (manual box NT) and automated (Volume NT) were performed by experienced and nonexperienced operators. Intertechnique and intra- and interobserver agreement were evaluated. RESULTS: Eleven of 70 cases were excluded due to missing data or aberrant position. The Volume NT program was successful in 83.8% of the cases. Acceptable levels of intraobserver agreement were found for all techniques. The Volume NT technique underestimated NT by 0.21 mm (p < 0.0001) in comparison to standard NT. Between-observer agreement for manual box NT was best for the experienced operators. For Volume NT, the results for between-observer agreement were more ambiguous. CONCLUSIONS: The Volume NT program improves standardization of NT measuring. The technique is reproducible and comparable to the 2D manual approach, particularly for inexperienced sonographers. Further technique refinement should reduce any underestimation. PMID- 23920134 TI - Impulse control disorder in a patient with X-linked dystonia-parkinsonism after bilateral pallidal deep brain stimulation. PMID- 23920135 TI - Predictive value of the smell identification test for nigrostriatal dopaminergic depletion in Korean tremor patients. AB - BACKGROUND: The predictive value of Cross-Cultural Smell Identification Test for nigrostriatal dopaminergic depletion in Korean tremor patients has yet to be assessed. METHODS: Three hundred nineteen drug-naive patients who visited our clinic for the diagnosis of their tremor, and took both Cross-Cultural Smell Identification Test and dopamine transporter PET were included in the data analysis. Visual grading of each PET image was performed by two independent neurologists. RESULTS: Smell test scores were significantly correlated to the striatal dopaminergic activity (Kendall's taub = -0.291, p < 0.001). However, smell test score alone appeared to have relatively weak power for predicting dopaminergic depletion (area under the curve = 0.693). Multivariate logistic regression model with inclusion of the patient's age and symptom duration as independent variables enhanced predictive power for dopaminergic depletion (area under the curve = 0.812). CONCLUSIONS: These results demonstrated that Cross Cultural Smell Identification Test measurements alone may be insufficient to predict striatal dopaminergic depletion in Korean tremor patients. PMID- 23920136 TI - [Acute myocardial infarction in women. Initial characteristics, management and early outcome. The FAST-MI registry]. AB - AIM: To assess gender differences in characteristics, management, and hospital outcomes in patients participating in the French FAST-MI 2010 registry. POPULATION: Three thousand and seventy-nine patients hospitalised for ST elevation (STEMI) or non-ST-elevation (NSTEMI) myocardial infarction in 213 French centres during a 1-month period at the end of 2010. RESULTS: Women account for 27% of the population and more frequently present with NSTEMI. They are 9 years older than men on average, although 25% of women with STEMI are less than 60 years of age. Management of STEMI is similar, after adjustment for baseline characteristics. However, fewer women are treated with primary percutaneous coronary angioplasty. In NSTEMI, although use of coronary angiography is similar, fewer women get treated with angioplasty. Most medications are used in a similar way in men and women, except thienopyridines, with fewer women receive prasugrel. After adjustment, in-hospital mortality is similar for men and women. CONCLUSION: Myocardial infarction is not specific to men: one out of four patients admitted for myocardial infarction is a woman. Initial management is rather similar for men and women, after taking into account differences in baseline characteristics. Percutaneous coronary angioplasty, however, remains less frequently used in women. In-hospital complications have become rarer and do not differ according to sex. PMID- 23920137 TI - Associations of dietary habits, physical activity and cognitive views with gestational diabetes mellitus among Chinese women. AB - OBJECTIVE: To evaluate the relationship between dietary habits, physical activity and cognitive views and the risk of gestational diabetes mellitus (GDM) in Chinese women. DESIGN: A cross-sectional study to explore the potential risk factors of GMD through the International Physical Activity Questionnaire, an FFQ and a self-designed structured questionnaire, respectively. SETTING: Guangzhou, Guangdong Province, China. SUBJECTS: Chinese pregnant women (n 571) who underwent a 75-g oral glucose tolerance test at their 24th to 28th gestational week. RESULTS: Thirteen per cent of the investigated women were identified as having GDM, and an increased intake of local featured foods and lower physical activity were observed in the GDM-positive group v. the GDM-negative group. Women who regarded early-pregnancy morning sickness as relevant to fetal abnormalities and those with unlimited dietary intake after the ending of morning sickness both had an increased risk for GDM (P = 0.018 and P = 0.038, respectively). After multiple logistic regression analysis, cognitive views for unlimited food intake subsequent to morning sickness, increased consumption of energy-dense snack foods and high-glycaemic-index fruits were strongly associated with the risk of GDM (OR = 1.911, P = 0.032; OR = 1.050, P = 0.001; and OR = 1.002, P = 0.017, respectively). CONCLUSIONS: Local featured foods and incorrect cognitive views on pregnancy-related health were closely related to the risk of GDM in Chinese women. Intensive health education about pregnancy physiology and reasonable dietary and physical exercise behaviours should be strengthened for the control of GDM. PMID- 23920139 TI - Commentary: Poverty and cardiovascular disease in India: do we need more evidence for action? PMID- 23920133 TI - An rpoD gene sequence based evaluation of cultured Pseudomonas diversity on different growth media. AB - The last decade has shown an increased interest in the utilization of bacteria for applications ranging from bioremediation to wastewater purification and promotion of plant growth. In order to extend the current number of micro organism mediated applications, a continued quest for new agents is required. This study focused on the genus Pseudomonas, which is known to harbour strains with a very diverse set of interesting properties. The aim was to identify growth media that allow retrieval of a high Pseudomonas diversity, as such increasing the chance of isolating isolates with beneficial properties. Three cultivation media: trypticase soy agar (TSA), potato dextrose agar (PDA) and Pseudomonas isolation agar (PIA) were evaluated for their abilities to grow Pseudomonas strains. TSA and PDA were found to generate the largest Pseudomonas diversity. However, communities obtained with both media overlapped. Communities obtained with PIA, on the other hand, were unique. This indicated that the largest diversity is obtained by sampling from either PDA or TSA and from PIA in parallel. To evaluate biodiversity of the isolated Pseudomonas members on the media, an appropriate biomarker had to be identified. Hence, an introductory investigation of the taxonomic resolution of the 16S rRNA, rpoD, gyrB and rpoB genes was performed. The rpoD gene sequences not only had a high phylogenetic content and the highest taxonomic resolution amongst the genes investigated, it also had a gene phylogeny that related well with that of the 16S rRNA gene. PMID- 23920138 TI - The structure of the symptoms of major depression: exploratory and confirmatory factor analysis in depressed Han Chinese women. AB - BACKGROUND: The symptoms of major depression (MD) are clinically diverse. Do they form coherent factors that might clarify the underlying nature of this important psychiatric syndrome? METHOD: Symptoms at lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ?30 years with recurrent DSM-IV MD. Exploratory factor analysis (EFA) and confirmatoryfactor analysis (CFA) were performed in Mplus in random split-half samples. RESULTS: The preliminary EFA results were consistently supported by the findings from CFA. Analyses of the nine DSM-IV MD symptomatic A criteria revealed two factors loading on: (i) general depressive symptoms; and (ii) guilt/suicidal ideation. Examining 14 disaggregated DSM-IV criteria revealed three factors reflecting: (i) weight/appetite disturbance; (ii) general depressive symptoms; and (iii) sleep disturbance. Using all symptoms (n = 27), we identified five factors that reflected: (i) weight/appetite symptoms; (ii) general retarded depressive symptoms; (iii) atypical vegetative symptoms; (iv) suicidality/hopelessness; and (v) symptoms of agitation and anxiety. CONCLUSIONS: MD is a clinically complex syndrome with several underlying correlated symptom dimensions. In addition to a general depressive symptom factor, a complete picture must include factors reflecting typical/atypical vegetative symptoms, cognitive symptoms (hopelessness/suicidal ideation), and an agitated symptom factor characterized by anxiety, guilt, helplessness and irritability. Prior cross-cultural studies, factor analyses of MD in Western populations and empirical findings in this sample showing risk factor profiles similar to those seen in Western populations suggest that our results are likely to be broadly representative of the human depressive syndrome. PMID- 23920140 TI - Life expectancy and national income in Europe, 1900-2008: an update of Preston's analysis. AB - BACKGROUND: In the past, upward shifts of the so-called Preston curve, which relates life expectancy to national income, have contributed importantly to worldwide increases in life expectancy. These shifts were due to rapid diffusion of knowledge and technology for infectious disease control from high-income to low-income countries. We assessed to what extent life expectancy growth in Europe has been accompanied by upward shifts in the relation between national income and life expectancy in later parts of the 20th century, when progress in cardiovascular disease control was the main driver of life expectancy growth. METHODS: Data on national income (gross domestic product per capita, in 1990 international dollars), life expectancy and cause-specific mortality covering the period 1900-2008 were extracted from international data banks. (Change in) life expectancy and age-standardized mortality was regressed on (change in) national income, and the regression parameters were used to estimate the contribution to rising life expectancy and declining mortality in Europe as a whole of changes in national income vs shifts in the relation between national income and health outcomes. RESULTS: Large upward shifts in the relation between national income and life expectancy only occurred before 1960, and were due to rapid declines in mortality from infectious diseases which were independent of rises in national income. These shifts account for between two-thirds and four-fifths of the increase in life expectancy in Europe as a whole during this period. After 1960, upward shifts in the relation between national income and life expectancy were much smaller, and contributed only between one-quarter and one-half to the increase in life expectancy in Europe as a whole. During the latter period, declines in mortality from cardiovascular disease were mainly attributable to increases in national income. CONCLUSIONS: In contrast to earlier periods, recent life expectancy growth in European countries appears to have been dependent on their economic growth. More rapid diffusion of knowledge and technology for cardiovascular disease control from higher- to lower-income countries in Europe may be needed to close the East-West life expectancy gap, but it is unlikely that this can be achieved in the absence of more equal economic conditions. PMID- 23920142 TI - Perinatal risk factors for suicide in young adults in Taiwan. AB - BACKGROUND: We investigated the association of early life social factors-maternal age, single motherhood, socioeconomic position, birth order and family size-with future risk of suicide in Taiwan. METHODS: Using a nested case-control design, we used linked data from Taiwan's Birth Registry (1978-93) and Taiwan's Death Registry (1993-2008) and identified 3984 suicides aged 15-30 years. For each suicide, 30 controls matched by age and sex were randomly selected, using incidence density sampling. Conditional logistic regression models were estimated to assess the association of early life risk factors with suicide. RESULTS: Younger maternal age (<25 years), single motherhood, lower paternal educational level and higher birth order were independently associated with increased risk of suicide. Stratified analyses suggest that lower paternal educational level was associated with male, but not female suicide risk (Pinteraction=0.02). Single motherhood was a stronger risk factor for suicide in female than in male offspring [odds ratios (95% confidence interval)=2.30 (1.47, 3.58) vs. 1.50 (1.01, 2.20), Pinteraction=0.12]. There was a suggestion that in families with large sibship size (>=4 siblings), the excess in suicide risk was greater among later born daughters compared with later born sons (Pinteraction=0.05). CONCLUSIONS: Our findings provide support for the results of European studies, suggesting that early life social circumstances influence future risk of suicide. Factors specific to Taiwanese culture, such as a preference for male offspring, may have influenced gender-specific patterns of risk. PMID- 23920141 TI - Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries. AB - BACKGROUND: Low- and middle-income countries continue to experience a large burden of stunting; 148 million children were estimated to be stunted, around 30 40% of all children in 2011. In many of these countries, foetal growth restriction (FGR) is common, as is subsequent growth faltering in the first 2 years. Although there is agreement that stunting involves both prenatal and postnatal growth failure, the extent to which FGR contributes to stunting and other indicators of nutritional status is uncertain. METHODS: Using extant longitudinal birth cohorts (n=19) with data on birthweight, gestational age and child anthropometry (12-60 months), we estimated study-specific and pooled risk estimates of stunting, wasting and underweight by small-for-gestational age (SGA) and preterm birth. RESULTS: We grouped children according to four combinations of SGA and gestational age: adequate size-for-gestational age (AGA) and preterm; SGA and term; SGA and preterm; and AGA and term (the reference group). Relative to AGA and term, the OR (95% confidence interval) for stunting associated with AGA and preterm, SGA and term, and SGA and preterm was 1.93 (1.71, 2.18), 2.43 (2.22, 2.66) and 4.51 (3.42, 5.93), respectively. A similar magnitude of risk was also observed for wasting and underweight. Low birthweight was associated with 2.5-3.5 fold higher odds of wasting, stunting and underweight. The population attributable risk for overall SGA for outcomes of childhood stunting and wasting was 20% and 30%, respectively. CONCLUSIONS: This analysis estimates that childhood undernutrition may have its origins in the foetal period, suggesting a need to intervene early, ideally during pregnancy, with interventions known to reduce FGR and preterm birth. PMID- 23920143 TI - Toxic effects of mercury on PSI and PSII activities, membrane potential and transthylakoid proton gradient in Microsorium pteropus. AB - Mercury (Hg) is one of the top toxic metals in environment and it poses a great risk to organisms. This study aimed to elucidate the toxic effects of Hg(2+) on energy conversion of photosystem I (PSI) and photosystem II (PSII), membrane potential and proton gradient of Microsorium pteropus (an aquatic plant species). Contents of chlorophyll a, chlorophyll b and carotenoids, quantum yield and electron transfer of PSI and PSII of M. pteropus exposed to various concentrations of Hg(2+) were measured. With increasing Hg(2+) concentration, quantum yield and electron transport of PSI [Y(I) and ETR(I)] and PSII [Y(II) and ETR(II)] decreased whereas limitation of donor side of PSI [Y(ND)] increased. At ?165MUgL(-1) Hg(2+), quantum yield of non-light-induced non-photochemical fluorescence quenching in PSII [Y(NO)] significantly increased but quantum yield of light-induced non-photochemical fluorescence quenching [Y(NPQ)] decreased. Membrane potential (Deltapsi) and proton gradient (DeltapH) of M. pteropus were reduced significantly at 330MUg L(-1) Hg(2+) compared to control. Mercury exposure affected multiple sites in PSII and PSI of M. pteropus. PMID- 23920144 TI - Epithelial membrane protein 3 is frequently shown as promoter methylation and functions as a tumor suppressor gene in non-small cell lung cancer. AB - Epithelial membrane protein 3 (EMP3) is a typical member of the epithelial membrane protein (EMP) family which has been reported to be a tumor suppressor gene in neuroblastomas and gliomas and recently reported to be commonly repressed in esophageal squamous cell carcinoma (ESCC) cell lines. However, the expression and clinical significance of EMP3 protein in lung cancer have not yet been elucidated. In this article, we detected that the expression of EMP3 in non-small cell lung cancer was significantly lower than the expression of normal lung tissues (P < 0.01) by western blot. EMP3 expression in Lung cancer was significantly related to p-TNM stage (P < 0.05) and EMP3 was negatively correlated with proliferation marker Ki67(r = -0.775; P < 0.01), However, no significant correlations were found between EMP3 and other clinical parameters. The post-recurrent survival after radical surgery was poorer in lung cancer patients with lower EMP3 expression (P < 0.01). While in vitro, following release from serum starvation of A549 NSCLC cell, the expression of EMP3 was deregulated. Thus, our finding suggests that EMP3 may be a tumor suppressor gene at the late step of lung cancer, and EMP3 may be a potential prognostic marker and therapeutic target of NSCLC. PMID- 23920145 TI - Oxidative stress-induced cyclin D1 depletion and its role in cell cycle processing. AB - BACKGROUND: Cyclin D1 is immediately down-regulated in response to reactive oxygen species (ROS) and implicated in the induction of cell cycle arrest in G2 phase by an unknown mechanism. Either treatment with a protease inhibitor alone or expression of protease-resistant cyclin D1 T286A resulted in only a partial relief from the ROS-induced cell cycle arrest, indicating the presence of an additional control mechanism. METHODS: Cells were exposed to hydrogen peroxide (H2O2), and analyzed to assess the changes in cyclin D1 level and its effects on cell cycle processing by kinase assay, de novo synthesis, gene silencing, and polysomal analysis, etc. RESULTS: Exposure of cells to excessive H2O2 induced ubiquitin-dependent proteasomal degradation of cyclin D1, which was subsequently followed by translational repression. This dual control mechanism was found to contribute to the induction of cell cycle arrest in G2 phase under oxidative stress. Silencing of an eIF2alpha kinase PERK significantly retarded cyclin D1 depletion, and contributed largely to rescuing cells from G2 arrest. Also the cyclin D1 level was found to be correlated with Chk1 activity. CONCLUSIONS: In addition to an immediate removal of the pre-existing cyclin D1 under oxidative stress, the following translational repression appear to be required for ensuring full depletion of cyclin D1 and cell cycle arrest. Oxidative stress-induced cyclin D1 depletion is linked to the regulation of G2/M transit via the Chk1-Cdc2 DNA damage checkpoint pathway. GENERAL SIGNIFICANCE: The control of cyclin D1 is a gate keeping program to protect cells from severe oxidative damages. PMID- 23920146 TI - Gestational protein restriction delays prostate morphogenesis in male rats. AB - Maternal malnutrition due to a low-protein diet is associated with functional disorders in adulthood, which may be related to embryonic development failures. The effects of gestational protein restriction on prostate morphogenesis in male offspring were investigated. Pregnant rat dams were divided into normoprotein (NP; fed a normal diet containing 17% protein) and hypoprotein (LP; fed a diet containing 6% protein) groups. On the day of birth (PND1), anogenital distance and bodyweight were measured in male pups. Seven males per experimental group (one male per litter) were killed, and the pelvic urethra was evaluated. LP offspring showed a significant reduction in bodyweight and anogenital distance on PND1. On three-dimensional reconstruction of the prostate, the number of prostatic buds was lower in LP than in NP males. Mesenchymal cells surrounding the buds were androgen-receptor positive, and the quantity and intensity of nucleus immunoreactivity was decreased in LP. The proliferation index was lower in LP than in NP prostatic buds. Immunoreactivity for alpha-actin in mesenchymal cells and that for epidermal growth factor receptor in epithelial cells was higher in NP than in LP. Our findings demonstrate that maternal protein restriction delays prostatic morphogenesis, probably because of considerable disruption in the epithelium-mesenchyme interaction. PMID- 23920148 TI - Conservatively managed fetal goiter: an alternative to in utero therapy. AB - Fetal goiter may arise from a variety of etiologies including iodine deficiency, overtreatment of maternal Graves' disease, inappropriate maternal thyroid replacement and, rarely, congenital hypothyroidism. Fetal goiter is often associated with a retroflexed neck and polyhydramnios, raising concerns regarding airway obstruction in such cases. Prior reports have advocated for cordocentesis and intra-amniotic thyroid hormone therapy in order to confirm the diagnosis of fetal thyroid dysfunction, reduce the size of the fetal goiter, reduce polyhydramnios, aid with the assistance of maternal thyroid hormone therapy and reduce fetal malpresentation. We report two cases of conservatively managed fetal goiter, one resulting in a vaginal delivery, and no evidence of postnatal respiratory distress despite the presence of polyhydramnios and a retroflexed neck on prenatal ultrasound. PMID- 23920149 TI - Exposure to traumatic experiences is associated with abnormal neural mechanism during charitable donation. AB - Previous studies suggested that posttraumatic stress disorder (PTSD) might be associated with dysfunctional reward processing. At present, little is known about the neural mechanisms of reward-related processing during a charitable donation task in trauma survivors who do not go on to develop PTSD. We used functional magnetic resonance imaging (fMRI) to investigate the neural basis of charitable donation in non-PTSD survivors of the Sichuan earthquake. Results showed that activations in the striatum of trauma survivors were reduced in both the low donation (donated a small amount to the Red Cross) and the high donation conditions (donated a large amount to the Red Cross) compared with the healthy controls. Furthermore, the trauma survivors also exhibited less activity in the insula than the healthy controls in the high donation condition. These findings suggest that abnormal reward-related activations might be associated with dysfunctions in the reward pathway of trauma survivors. Also, we discuss the possibility that traumatic experiences attenuate the reactivity of reward-related brain areas to positive emotions (as induced by advantageous donations). PMID- 23920150 TI - In vitro clearance and hemocompatibility assessment of ultrathin nanoporous silicon membranes for hemodialysis applications using human whole blood. AB - BACKGROUND/AIMS: Recent advances in nanotechnology have made it possible to mass produce ultrathin silicon membranes with pore sizes in the range of nanometers. In this study, we investigate the possibility of employing ultrathin nanoporous silicon membranes with pore diameters of 5 and 20 nm for dialysis of human whole blood by performing in vitro clearance and hemocompatibility assessments. METHODS: A mini blood dialyzer is fabricated by mounting nanoporous silicon membranes on a Teflon structure. Clearance is calculated based on the concentration of sodium, chloride, ionized calcium, total CO2, glucose, creatinine and hematocrit measured before and after dialysis. Blood activation is assessed by flow cytometry. RESULTS: Blood contact with the nanoporous membranes induces considerable leukocyte activation. Coating of the membranes with polyethylene glycol significantly improves hemocompatibility without blocking the nanopores. CONCLUSION: Silicon nanoporous membranes are potential candidates for fabrication of miniaturized blood dialyzers. Their mechanical strength and hemocompatibility can be further improved. PMID- 23920151 TI - Patterns of sociodemographic and food practice characteristics in relation to fruit and vegetable consumption in children: results from the U.K. National Diet and Nutrition Survey Rolling Programme (2008-2010). AB - OBJECTIVE: Few studies have considered the combined effects of home-related determinants on children's diet. The present study investigated independent associations between sociodemographic and food practice (SFP) characteristics and fruit and vegetable consumption in U.K. children and the combined effects of SFP on consumption using pattern analysis. DESIGN: Diet was assessed using 4 d food diaries, SFP were collected using computer-assisted personal interview. Linear regressions were used to test associations; principal component analysis was used to identify patterns of SFP characteristics. Regression of fruit (g/d) and vegetables (g/d) v. component scores of each pattern were performed. SETTING: U.K. National Diet and Nutrition Survey Rolling Programme (2008-2010). SUBJECTS: Children aged 1.5-10 years (n 642). RESULTS: Significant associations were found between fruit and vegetable consumption and household socio-economic status. Pattern 1, which was positively correlated with household structure characteristics, was associated with increased fruit consumption (P < 0.001). Pattern 2, characterised by positive correlations for socio-economic status, fruit availability and organic food purchase, and negatively correlated with household size and the number of children per household, was associated with higher fruit and vegetable consumption (both P < 0.001). Pattern 3, characterised by high frequency of eating out and eating takeaway, was associated with a lower consumption of both fruit (P < 0.012) and vegetables (P < 0.023). CONCLUSIONS: Patterns of SFP determinants may be more informative than individual characteristics in relation to dietary outcomes. Results have public health implications on the healthfulness of meals eaten out of home and in takeaways, as well as the need to reduce diet inequality in larger households with lower socio economic status. PMID- 23920152 TI - Bacterial-binding chitosan microspheres for gastric infection treatment and prevention. AB - Helicobacter pylori (H. pylori) colonizes the gastric mucosa of over 50% of the world population, causing several pathologies, such as gastric ulcers and gastric cancer. Since current antibiotic treatments are inefficient in 20% of cases alternative therapies are needed. This work reports the ability of chitosan microspheres to adhere to H. pylori and prevent/remove H. pylori colonization. Adhesion of H. pylori strains with different functional adhesins (BabA and/or SabA) to chitosan microspheres (diameter 167 +/- 27 MUm) occurs at both pH 2.6 and 6.0, but is higher at pH 6.0. Bacterial adhesion to a gastric cell line expressing sialylated carbohydrates (SabA receptors) was performed at the same pH values using H. pylori strains with and without SabA. At both pH values addition of microspheres to gastric cells before and after pre-incubation with H. pylori decreased bacterial adhesion to cells. Furthermore, the chitosan microspheres were non-cytotoxic. These findings reveal the potential of chitosan microspheres as an alternative or complementary treatment for H. pylori gastric eradication or prevention of H. pylori colonization. PMID- 23920153 TI - Validity and reliability of a German version of the Neck Disability Index (NDI G). AB - The Neck Disability Index (NDI) is a widely used questionnaire in the assessment of disability of neck patients. The aim of this study was to translate the NDI according to established guidelines into German (NDI-G) and to test the psychometric properties. Patients with acute (ACU) and chronic neck pain (CHR) and a healthy control group (HCG) completed the NDI-G twice with a mean test retest interval of 3 days. The total score of NDI-G showed high reliability (Intraclass correlation coefficient (ICC2,1) = 0.92) and a high Cronbach's alpha (alpha = 0.96). The minimal detectable change was 7 points. The Bland-Altman plot revealed a small positive systematic error of 1.02 points. The Kruskal-Wallis test showed significant differences in the NDI-G total score among the three groups (chi(2) = 29.77, p < 0.001). Mann-Whitney U tests showed significant differences in the total score between ACU and HCG (p < 0.001), and CHR and HCG (p < 0.001). The factor analysis of NDI-G yielded 2 factors that together explained 67% of the variance. Spearman's phi coefficients showed no correlation between the NDI-G total score and the visual analogue scale (VAS) in the ACU group (phi = 0.23, p = 0.40), and a moderate correlation in the CHR group (phi = 0.55, p = 0.03). The item analysis of the NDI-G revealed moderate to good reliability for all items. Only the item 'work' could differentiate between the ACU and CHR group. The NDI-G emerged from this study as a valid and reliable assessment. Its psychometric properties are comparable with the original version. Thus, the NDI-G is recommended for research and clinical settings in neck pain in German speaking countries. PMID- 23920154 TI - The measurement of corneal thickness from center to limbus in vivo in C57BL/6 and BALB/c mice using two-photon imaging. AB - The mouse corneal thickness is very important for research into the fields of eye disease. However, the in vivo corneal thickness for the entire cornea from the pupil to the limbus was not determined. We measured in vivo corneal layer thicknesses in different corneal areas, from the central cornea to the limbus, in the widely used inbred C57BL/6 and BALB/c mouse strains using two-photon (2 PH) imaging. Eight corneas of the C57BL/6 or BALB/c were scanned using a 2 PH laser scanning fluorescence microscopy system. A total of 14 thicknesses of the different corneal layers, from different corneal regions, were measured using image processing software. In both C57BL/6 and BALB/c mice, the thickness of the corneal layers was inhomogeneous in different areas of the cornea, and all of the layers had their minimum thickness at the limbus. In C57BL/6 mice, the thickness of the corneal layers gradually increased from the central to the paracentral cornea, peaked at the fifth measurement point in the paracentral area, and decreased from this point to the limbus. In BALB/c mice, the thickness of the entire cornea and corneal epithelium had its maximum at the central cornea and gradually decreased from the central cornea to the peripheral cornea and to the limbus. The thickness of the corneal stroma and endothelium had its maximum at the fourth measurement point in the paracentral cornea and gradually decreased from the paracentral cornea to the limbus. The ratio of epithelial thickness to the total corneal thickness gradually decreased from the central cornea to the limbus in both C57BL/6 and BALB/c mice. The minimum ratio was observed at the fourteenth measurement point in both C57BL/6 and BALB/c mice. The ratio of stromal and endothelial to the total corneal thickness gradually increased from the central cornea to the limbus in both C57BL/6 and BALB/c mice. The maximum ratio was observed at the fourteenth measurement point in C57BL/6 mice. The ratio at the first eight measurement points was significantly lower in BALB/c than in C57BL/6 mice (P < 0.05). Our study demonstrated that the thickness of the entire cornea, the corneal epithelium, the corneal stroma and the endothelium was inhomogeneous in different areas of the cornea. Moreover, all of the layers exhibited a minimum thickness at the limbus in both C57BL/6 and BALB/c mice. Furthermore, the corneal thickness in different areas varied between C57BL/6 and BALB/c mice, and the variation in thickness with respect to corneal location for these strains was dissimilar. When using the mouse as an animal model to examine the cornea, it is important to note the differences between humans and mice. PMID- 23920156 TI - Resumptive elements aid comprehension of object relative clauses: evidence from Persian. AB - The current study investigated the role of resumption in the interpretation of object relative clauses (RCs) in Persian-speaking children. Sixty-four (N=64) children aged 3;2-6;0 (M=4;8) completed a referent selection task that tested their comprehension of subject RCs, gapped object RCs, and object RCs containing either a resumptive pronoun or an object clitic. The results showed that the presence of a resumptive element (pronoun or clitic) had a facilitative effect on children's processing of object RCs. In both cases object RCs with resumptive elements were interpreted more accurately than gapped subject and object RCs, suggesting that resumptive elements ease processing burden in syntactically complex contexts because they provide local cues to thematic role assignment. PMID- 23920155 TI - Regulation of GABA content by glucose in the chick retina. AB - Some visual information is processed in the retina by gamma-aminobutyric acid (GABA) signaling. Once retinal degeneration and visual impairment caused by diabetic retinopathy (DR) are affecting an increasing number of people worldwide, and the disease is characterized by hyper- and hypoglycemic events, the authors aimed to investigate how retinal GABA cell content is affected by variations in glucose availability. Using the ex vivo chick retinas exposed to different glucose concentrations, we observed that amacrine cells from both inner nuclear layer (INL) and ganglion cell layer (GCL) as well as their processes in the inner plexiform layer (IPL) released GABA through GABA transporter-1 (GAT-1) after 30 min of glucose deprivation. Extending this insult to 60 min triggered a permanent loss of GABA-positive amacrine cells, caused swelling of IPL and cell death. High glucose (35 mM) for 30 min induced an increment in GABA immunolabeling in both outer and inner retina. Further, glucose deprivation effects could not be reverted by basal glucose levels and high glucose did not prevent GABA loss upon a glucose deprivation insult. Therefore, GABA cell content is differently affected by short-term variations in glucose availability. While high glucose modulates outer and inner GABAergic circuits, glucose deprivation affects mainly the inner retina. Also, consecutive alteration in glucose supply was not able to rescue basal GABA content. Therefore, glucose oscillations interfering with GABAergic retinal functioning during early stages of retinopathies should be further investigated. PMID- 23920157 TI - 3D element imaging using NSECT for the detection of renal cancer: a simulation study in MCNP. AB - This work describes a simulation study investigating the application of neutron stimulated emission computed tomography (NSECT) for noninvasive 3D imaging of renal cancer in vivo. Using MCNP5 simulations, we describe a method of diagnosing renal cancer in the body by mapping the 3D distribution of elements present in tumors using the NSECT technique. A human phantom containing the kidneys and other major organs was modeled in MCNP5. The element composition of each organ was based on values reported in literature. The two kidneys were modeled to contain elements reported in renal cell carcinoma (RCC) and healthy kidney tissue. Simulated NSECT scans were executed to determine the 3D element distribution of the phantom body. Elements specific to RCC and healthy kidney tissue were then analyzed to identify the locations of the diseased and healthy kidneys and generate tomographic images of the tumor. The extent of the RCC lesion inside the kidney was determined using 3D volume rendering. A similar procedure was used to generate images of each individual organ in the body. Six isotopes were studied in this work - (32)S, (12)C, (23)Na, (14)N, (31)P and (39)K. The results demonstrated that through a single NSECT scan performed in vivo, it is possible to identify the location of the kidneys and other organs within the body, determine the extent of the tumor within the organ, and to quantify the differences between cancer and healthy tissue-related isotopes with p <= 0.05. All of the images demonstrated appropriate concentration changes between the organs, with some discrepancy observed in (31)P, (39)K and (23)Na. The discrepancies were likely due to the low concentration of the elements in the tissue that were below the current detection sensitivity of the NSECT technique. PMID- 23920158 TI - Developmental changes in BDNF protein in the song control nuclei of zebra finches. AB - The zebra finch song system provides an excellent model to study the mechanisms underlying the development of sex difference in brain structure and function. Only male zebra finches sing and the brain nuclei controlling song learning and production are considerably larger than in females. Sexual differentiation may in part be regulated by estrogen, but other molecules including neurotrophic factors likely also affect masculinization. Brain derived neurotrophic factor (BDNF) plays a crucial role in numerous aspects of vertebrate brain development and function, including neurogenesis, cell survival, growth of axonal projections, synaptogenesis and processes linked to learning and memory. The current study investigated the expression of BDNF protein in juvenile males and females at four ages, as well as in adults, to begin to evaluate the potential roles of endogenous BDNF in particular stages of structural and functional development of the song system. In both HVC and the robust nucleus of the arcopallium (RA), males had more BDNF+ cells than females. The number of immunopositive cells increased in males and decreased in females as they matured, in a pattern generally consistent with a role for BDNF in sensorimotor integration of song learning. In addition, in HVC (but not RA) the ratio of mature BDNF compared to its precursor proBDNF was greater in adult males than those at post-hatching day 25, indicating a region-specific shift in the relative availability of the two forms. Collectively, the data suggest that changes in BDNF protein expression across development may be associated with song system maturation, particularly during the sensorimotor integration of masculine vocalizations. PMID- 23920160 TI - Thyroid storm: an updated review. AB - Thyroid storm, an endocrine emergency first described in 1926, remains a diagnostic and therapeutic challenge. No laboratory abnormalities are specific to thyroid storm, and the available scoring system is based on the clinical criteria. The exact mechanisms underlying the development of thyroid storm from uncomplicated hyperthyroidism are not well understood. A heightened response to thyroid hormone is often incriminated along with increased or abrupt availability of free hormones. Patients exhibit exaggerated signs and symptoms of hyperthyroidism and varying degrees of organ decompensation. Treatment should be initiated promptly targeting all steps of thyroid hormone formation, release, and action. Patients who fail medical therapy should be treated with therapeutic plasma exchange or thyroidectomy. The mortality of thyroid storm is currently reported at 10%. Patients who have survived thyroid storm should receive definite therapy for their underlying hyperthyroidism to avoid any recurrence of this potentially fatal condition. PMID- 23920161 TI - Granulocyte transfusion therapy. AB - Bacterial and fungal infections continue to be a major cause of morbidity and mortality in severely neutropenic patients undergoing aggressive chemotherapy regimens or hematopoietic stem cell transplantation. Traditional granulocyte transfusion therapy, a logical approach in treating these infections, has been available for many years, and several controlled studies have shown this therapy to be useful. However, granulocyte transfusion therapy fell out of favor because the results were not clinically impressive, and adverse results were reported. These disappointing results were felt to be, in part, because of the low doses of granulocytes provided. More recent studies have attempted to increase the numbers of transfused cells by stimulating normal granulocyte donors with G-CSF (+/ corticosteroids). With these techniques, the number of granulocytes transfused can be increased 3-4 fold. The cells have been shown to circulate in recipients, and daily transfusions are capable of maintaining normal or near-normal blood neutrophil counts in previously severely neutropenic patients. The cells appear to function normally by a variety of in vitro and in vivo tests. Clinical benefit, as defined by survival or clearance of infection, has not been definitively determined. Results of an ongoing randomized controlled clinical trial should be available in the near future. PMID- 23920162 TI - Quantitative analysis of carbon in silicon carbide coated with carbon. AB - Nonconductive specimens for scanning electron microscopy or X-ray microanalysis are coated with conductive carbon in order to reduce charging. But carbon film absorbs X-ray fluxes causing errors in measuring chemical composition. Especially when the carbon content is measured, carbon coating not only blocks X-rays but also becomes a source of carbon X-rays. It is thus necessary to determine how much errors are induced by carbon coating, and how thick coating is allowed for the accurate measurement. In this study, quantitative analysis of carbon on silicon carbide with carbon coating films was attempted by electron probe microanalyzer. It was found that measured carbon content increased in a nonlinear manner up to 40% with a film thickness, whereas silicon content decreased slightly. Carbon X-ray intensity was determined by computer simulation, which increased in a linear manner with the thickness. The discrepancy was due to a nucleation and growth of islands and thus a change of density with a thickening of coating film. PMID- 23920159 TI - Mechanisms of transgenerational inheritance of addictive-like behaviors. AB - Genetic factors are implicated in the heritability of drug abuse. However, even with advances in current technology no specific genes have been identified that are critical for the transmission of drug-induced phenotypes to subsequent generations. It is now evident that epigenetic factors contribute to disease heritability and represent a link between genes and the environment. Recently, epigenetic mechanisms have been shown to underlie drug-induced structural, synaptic, and behavioral plasticity by coordinating the expression of gene networks within the brain. Therefore, the epigenome provides a direct mechanism for drugs of abuse to influence the genetic events involved in the development of addiction as well as its heritability to subsequent generations. In this review we discuss the mechanisms underlying intergenerational epigenetic transmission, highlight studies that demonstrate this phenomenon with particular attention to the field of addiction, and identify gaps for future studies. PMID- 23920163 TI - The effect of atomic mass on the physical spatial resolution in EBSD. AB - In this study, bicrystals of silver (Ag) and aluminum (Al) were used to investigate the physical spatial resolution of the electron backscatter diffraction system combining a digital image correlation method. Furthermore, the effect of the accelerating voltage and probe current was investigated on the physical spatial resolution of the lateral and longitudinal resolutions for Ag and Al, respectively. The lateral and longitudinal resolutions show high dependency on the accelerating voltage for a low atomic mass material of Al, In addition, these are almost independent of the accelerating voltage for a high atomic mass material of Ag. Moreover, the probe current does not play any role on both the lateral and longitudinal resolutions. The best lateral resolutions for Al and Ag are 40.5 and 12.1 nm at 10 kV and 1 nA, respectively. The best longitudinal resolutions of 23.2 and 80 nm were obtained at 10 kV and 1 nA for Al and Ag, respectively. PMID- 23920164 TI - Microstructure characterization of ZK60 magnesium alloys using TEM and HR-EBSD. AB - ZK60 (Mg-Zn-Zr) alloys exhibited a variation in precipitates with aging, and their mechanical properties also changed. Microindentation tests were carried out on two types of ZK60 alloys of solid solution (T4) and peak aging (T6). Microstructure and texture evolution during indentation was investigated using electron backscatter diffraction. Twinning occurred near the indentation marks in most grains. It was found that tensile twinning was dominant, and two twin variants were usually observed. Texture and microstructure evolution by twinning and slip activation was further examined by uniaxial compression test with strain. The initial random orientation gradually changed into basal fibers with strain. Some grains with nonbasal orientations aligned with the loading direction easily underwent twinning followed by slip deformation. Other grains near basal orientations revealed only slip deformation. PMID- 23920165 TI - Phase analysis on dual-phase steel using band slope of electron backscatter diffraction pattern. AB - A quantitative and automated phase analysis of dual-phase (DP) steel using electron backscatter diffraction (EBSD) was attempted. A ferrite-martensite DP microstructure was produced by intercritical annealing and quenching. An EBSD map of the microstructure was obtained and post-processed for phase discrimination. Band slope (BS), which was a measure of pattern quality, exhibited much stronger phase contrast than another conventional one, band contrast. Owing to high sensitivity to lattice defect and little orientation dependence, BS provided handiness in finding a threshold for phase discrimination. Its grain average gave a superior result on the discrimination and volume fraction measurement of the constituent phases in the DP steel. PMID- 23920166 TI - Quantification of ridging in ferritic stainless steel sheets by electron backscattered diffraction R-value maps. AB - In ferritic stainless steel (FSS), undesirable surface defects of ridging appear during deep drawing. The formation of these defects is attributed to the inhomogeneous distribution of orientations of individual grains. In the present work, a new electron backscattered diffraction R(alpha)-value map was introduced, and the dependence of the tensile directions on the formation of ridging in an FSS sheet was discussed using this map. The results showed that large grain colonies in the R(alpha)-value maps lead to the formation of severe ridging in an FSS sheet. PMID- 23920167 TI - Statistical analysis on static recrystallization texture evolution in cold-rolled AZ31 magnesium alloy sheet. AB - Cast AZ31B-H24 magnesium alloy, comprising Mg with 3.27 wt% Al and 0.96 wt% Zn, was cold rolled and subsequently annealed. Global texture evolutions in the specimens were observed by X-ray diffractometry after the thermomechanical processing. Image-based microstructure and texture for the deformed, recrystallized, and grown grains were observed by electron backscattered diffractometry. Recrystallized grains could be distinguished from deformed ones by analyzing grain orientation spread. Split basal texture of ca. +/-10-15 degrees in the rolling direction was observed in the cold-rolled sample. Recrystallized grains had widely spread basal poles at nucleation stage; strong {0001} basal texture developed with grain growth during annealing. PMID- 23920168 TI - Direct observation of cationic ordering in double perovskite Sr2FeReO6 crystals. AB - Two kinds of Sr2FeReO6 (SFRO) samples, pristine SFRO and Re-excess SFRO, were prepared and we visualized the local atomic structure in terms of cationic ordering in the prepared SFRO samples via high-angle annular dark-field (HAADF) scanning transmission electron microscopy (STEM). HAADF-STEM results demonstrated the high degree of cationic ordering maintains in both the pristine SFRO and Re excess SFRO samples. On the other hand, defective structures such as antiphase boundary and Re-deficient phase were observed dominantly in the pristine SFRO, and thus the poor magnetic property in the pristine SFRO is attributed to those defective structures related with the frustrated Fe/Re ordering. PMID- 23920169 TI - Characterization of Sc2O3&CeO2-stabilized ZrO2 powders via co-precipitation or hydrothermal synthesis. AB - As the presence of Sc2O3 and CeO2 is known to largely enhance the ionic conductivity in the temperature range of 600-800 degrees C, compared with the conventional yttria-stabilized ZrO2, Sc2O3&CeO2-stabilized ZrO2 provide its applicability as electrolytes in solid oxide fuel cells. The current study introduces the methodology to synthesize Sc2O3&CeO2-stabilized ZrO2 powders by using co-precipitation technique or high-temperature hydrothermal reaction, and further describes the structural characterization of the zirconia powders synthesized by the above-mentioned two methods. The co-precipitation technique was found to allow obtaining powders of cubic phase, whereas high-temperature hydrothermal synthesis results in the presence of a monoclinic phase as well. The scanning transmission electron microscope observations also confirm that the size of the synthesized ZrO2 powders in this study is found to be much smaller than that of commercially available powders. PMID- 23920170 TI - Amorphization induced by focused ion beam milling in metallic and electronic materials. AB - Focused ion beam (FIB) milling using high-energy gallium ions is widely used in the preparation of specimens for transmission electron microscopy (TEM). However, the energetic ion beam induces amorphization on the edge of specimens during milling, resulting in a mischievous influence on the clearness of high-quality transmission electron micrographs. In this work, the amorphization induced by the FIB milling was investigated by TEM for three kinds of materials, metallic materials in bulk shape, and semiconductive and electronic ceramic materials as a substrate for the deposition of thin films. PMID- 23920171 TI - The mechanism of {113} defect formation in silicon: clustering of interstitial vacancy pairs studied by in situ high-resolution electron microscope irradiation. AB - We report the direct visualization of point defect clustering in {113} planes of silicon crystal using a transmission electron microscope, which was supported by structural modeling and high-resolution electron microscope image simulations. In the initial stage an accumulation of nonbonded interstitial-vacancy (I-V) pairs stacked at a distance of 7.68 A along neighboring atomic chains located on the {113} plane takes place. Further broadening of the {113} defect across its plane is due to the formation of planar fourfold coordinated defects (FFCDs) perpendicular to chains accumulating I-V pairs. Closely packed FFCDs create a sequence of eightfold rings in the {113} plane, providing sites for additional interstitials. As a result, the perfect interstitial chains are built on the {113} plane to create an equilibrium structure. Self-ordering of point defects driven by their nonisotropic strain fields is assumed to be the main force for point defect clustering in the {113} plane under the existence of an energy barrier for their recombination. PMID- 23920172 TI - In situ transmission electron microscopy imaging of electromigration in platinum nanowires. AB - In situ transmission electron microscopy was performed on the electromigration in platinum (Pt) nanowires (14 nm thick, 200 nm wide, and 300 nm long) with and without feedback control. Using the feedback control mode, symmetric electrodes are obtained and the gap usually forms at the center of the Pt nanowire. Without feedback control, asymmetric electrodes are formed, and the gap can occur at any position along the wire. The three-dimensional gap geometries of the electrodes in the Pt nanowire were determined using high-angle annular dark-field scanning transmission electron microscopy; the thickness of the nanowire is reduced from 14 nm to only a few atoms at the edge with a gap of about 5-10 nm. PMID- 23920173 TI - In situ heating transmission electron microscopy observation of nanoeutectic lamellar structure in Sn-Ag-Cu alloy on Au under-bump metallization. AB - We investigated the microstructural evolution of Sn(96.4)Ag(2.8)Cu(0.8) solder through in situ heating transmission electron microscopy observations. As soldered bump consisted of seven layers, containing the nanoeutectic lamella structure of AuSn and Au5Sn phases, and the polygonal grains of AuSn2 and AuSn4, on Au-plated Cu bond pads. Here, we found that there are two nanoeutectic lamellar layers with lamella spacing of 40 and 250 nm. By in situ heating above 140 degrees C, the nanoeutectic lamella of AuSn and Au5Sn was decomposed with structural degradation by sphering and coarsening processes of the lamellar interface. At the third layer neighboring to the lamella layer, on the other hand, Au5Sn particles with a zig-zag shape in AuSn matrix became spherical and were finally dissipated in order to minimize the interface energy between two phases. In the other layers except both lamella layers, polycrystal grains of AuSn2 and AuSn4 grew by normal grain growth during in situ heating. The high interface energy of nanoeutectic lamella and polygonal nanograins, which are formed by rapid solidification, acted as a principal driving force on the microstructural change during the in situ heating. PMID- 23920174 TI - Electron holography study of the charging effect in microfibrils of sciatic nerve tissues. AB - The charging effects of microfibrils of sciatic nerve tissues due to electron irradiation are investigated using electron holography. The phenomenon that the charging effects are enhanced with an increase of electron intensity is visualized through direct observations of the electric potential distribution around the specimen. The electric potential at the surface of the specimen could be quantitatively evaluated by simulation, which takes into account the reference wave modulation due to the long-range electric field. PMID- 23920175 TI - Meso-scale transmission electron microscope tomography applied for wax distribution in toner particles. AB - Distribution of wax in laser printer toner was observed using an ultra-high voltage (UHV) and a medium-voltage transmission electron microscope (TEM). As the radius of the wax spans a hundred to greater than a thousand nanometers, its three-dimensional recognition via TEM requires large depth of focus (DOF) for a volumetric specimen. A tomogram with a series of the captured images would allow the determination of their spatial distribution. In this study, bright-field (BF) images acquired with UHV-TEM at a high tilt angle prevented the construction of the tomogram. Conversely, the Z-contrast images acquired by the medium-voltage TEM produced a successful tomogram. The spatial resolution for both is discussed, illustrating that the image degradation was primarily caused by beam divergence of the Z-contrast image and the combination of DOF and chromatic aberration of the BF image from the UHV-TEM. PMID- 23920176 TI - Precipitates in Nb and Nb-V microalloyed X80 pipeline steel. AB - Precipitates in two X80 pipeline steels were studied by transmission electron microscopy equipped with an energy filtering system. The steels are microalloyed with niobium and niobium-vanadium (Nb-V), respectively, and produced by continuous hot rolling. Besides the precipitates TiN and (Ti, Nb) (C, N), which were 10-100 nm in size, a large number of precipitates smaller than 10 nm distributed in the two steels have been observed. In the Nb-V microalloyed steel, only a few titanium nitrides covered by vanadium compounds on the surface have been observed. It is inferred that the vanadium exists mainly in the matrix as a solid solution element. The fact has been accepted that there was no contribution to the precipitation strengthening of the X80 steel by adding 0.04-0.06% vanadium under the present production process. By contrast, the toughness of the Nb-V steel is deteriorated. Therefore, a better toughness property of the Nb microalloyed X80 results from the optimum microalloying composition design and the suitable accelerating cooling after hot rolling. PMID- 23920177 TI - Detection and determination of solute carbon in grain interior to correlate with the overall carbon content and grain size in ultra-low-carbon steel. AB - In this study, every effort was exerted to determine and accumulate data to correlate microstructural and compositional elements in ultra-low-carbon (ULC) steels to variation of carbon content (12-44 ppm), manganese (0.18-0.36%), and sulfur (0.0066-0.001%). Quantitative analysis of the ULC steel using optical microscope, scanning electron microscope, transmission electron microscope, and three-dimensional atom probe revealed the decrease of grain size and dislocation density with the increase of carbon contents and/or increase of the final delivery temperature. For a given carbon content, the grain interior carbon concentration increases as the grain size increases. PMID- 23920178 TI - The effects of maintaining temperature in annealing heat treatment for an FSWed 6061-T6 Al alloy. AB - The technological development of all kinds of lightweight transportation devices including vehicles, aircraft, ships, etc. has progressed markedly with the demand for energy saving and environmental protection. Aluminum alloy is in the spotlight as it is a suitable environmentally friendly material. However, deformation is a major problem during the welding process because aluminum alloy has a large thermal expansion coefficient. In addition, it is known that its corrosion resistance is excellent; nevertheless, in practice, considerable corrosion is generated and this is a major problem. To solve this problem, the friction stir welding (FSW) technology is applied extensively at various industrial fields as a new welding technique. This method involves a process in which materials are joined by frictional heat and physical force. Therefore, we evaluated improvements in mechanical properties and corrosion resistance through annealing heat treatment after FSW. The electrochemical experiment did not show a significant difference. However, the microstructure observation showed defectless, fine crystal particles, indicating excellent properties at 200-225 degrees C. PMID- 23920179 TI - An investigation on the optimum corrosion protection potential for minimization of cavitation damage using the potentiostatic method in seawater. AB - In this study, we replaced the expensive blade material with an aluminum-bronze alloy that has excellent corrosion resistance and cavitation characteristics and developed the corrosion protection method to improve durability using an electrochemical method. The objective of this study was to identify the electrochemical corrosion protection conditions to minimize cavitation damage due to generating hydrogen gas (2H2O + 2e- -> 2OH- + H2) by means of hydrogen overvoltage before the impact pressure of the cavity is transferred to the surface. In the constant potential experiment under the cavitation environment, the energy was reflected or cancelled out by collision of the cavities with the hydrogen gas generated by the hydrogen overvoltage. As a result, the optimal corrosion prevention potential in the dynamic state is assumed to be the range of -1.4 to -1.7 V, which is the range at which active polarization took place. PMID- 23920180 TI - Scale-bridging analysis on deformation behavior of high-nitrogen austenitic steels. AB - Scale-bridging analysis on deformation behavior of high-nitrogen austenitic Fe 18Cr-10Mn-(0.39 and 0.69)N steels was performed by neutron diffraction, electron backscattered diffraction (EBSD), and transmission electron microscopy (TEM). Two important modes of deformation were identified depending on the nitrogen content: deformation twinning in the 0.69 N alloy and strain-induced martensitic transformation in the 0.39 N alloy. The phase fraction and deformation faulting probabilities were evaluated based on analyses of peak shift and asymmetry of neutron diffraction profiles. Semi in situ EBSD measurement was performed to investigate the orientation dependence of deformation microstructure and it showed that the variants of epsilon martensite as well as twin showed strong orientation dependence with respect to tensile axis. TEM observation showed that deformation twin with a {111} mathematical left angle bracket 112 mathematical right angle bracket crystallographic component was predominant in the 0.69 N alloy whereas two types of strain-induced martensites (epsilon and alpha' martensites) were observed in the 0.39 N alloy. It can be concluded that scale bridging analysis using neutron diffraction, EBSD, and TEM can yield a comprehensive understanding of the deformation mechanism of nitrogen-alloyed austenitic steels. PMID- 23920181 TI - A quantitative evaluation of microstructure by electron back-scattered diffraction pattern quality variations. AB - Band contrast (BC) is a qualitative measure of electron back-scattered diffraction (EBSD), which is derived from the intensity of the Kikuchi bands. The BC is dependent upon several factors including scanning electron microscope measurement parameters, EBSD camera setup, and the specimen itself (lattice defect and grain orientation). In this study, the effective factors for BC variations and the feasibility of using BC variations for the quantification of microstructure evolutions have been investigated. In addition, the effects of the lattice defect and the grain orientation on the BC variations are studied. Next, a shear-deformed microstructure of 316L stainless steel, which contains nanosized grains and a large portion of twin boundaries, is revealed by BC map and histogram. Recovery and recrystallization of shear-deformed 316L stainless steel are displayed by BC variations during isothermal annealing at 700 and 800 degrees C, respectively. It is observed that the BC turns bright as the shear-deformed crystal structure is recovered or recrystallized. PMID- 23920182 TI - Transmission electron microscopy characterization of thermomechanically treated Al3Ti-(8, 10, 15)% Cr intermetallics. AB - The ordered L12-type Al3Ti-(8, 10, 15)% Cr intermetallic compounds, namely, Al67Ti25Cr8, Al66Ti24Cr10, and Al59Ti26Cr15, were prepared by induction melting followed by thermomechanical treatment. Their microstructure, compositional variation, and crystal structure were characterized using X-ray diffraction, optical microscopy, and scanning and transmission electron microscopy equipped with energy-dispersive spectroscopy. The Al67Ti25Cr8 alloy consisted of the L12 Al3Ti matrix and precipitates of alpha2-Ti3Al, D022-Al3Ti, and gamma-TiAl. The Al66Ti24Cr10 and Al59Ti26Cr15 alloys consisted of the L12-Al3Ti matrix and grains of alpha-TiAl and beta-Cr. PMID- 23920183 TI - Effect of creep stress on the microstructure of 9-12% Cr steel for rotor materials. AB - High-chromium heat-resistant steel has been widely used as the key material to improve the condition of steam pressure and temperature in the modern high efficiency power plants. Despite the use of the steel above 550 degrees C for several decades, its major failure is owing to the creep fracture. In this study, the effect of creep stress on the microstructure in 9-12% Cr steel has been investigated microscopically, and it is clarified that the creep stress enhances precipitation of Laves phase and influences the lath width and dislocation density in lath interior. PMID- 23920184 TI - Composition fluctuation of in and well-width fluctuation in InGaN/GaN multiple quantum wells in light-emitting diode devices. AB - In this paper, we have observed an atomic-scale structure and compositional variation at the interface of the InGaN/GaN multi-quantum wells (MQW) by both scanning transmission electron microscopy (STEM) using high-angle annular dark field mode and atom probe tomography (APT). The iso-concentration analysis of APT results revealed that the roughness of InGaN/GaN interface increased as the MQW layers were filled up, and that the upper interface of MQW (GaN/InGaN to the p GaN side) was much rougher than that of the lower interface (InGaN/GaN tot he n GaN side). On the basis of experimental results, it is suggested that the formation of interface roughness can affect the quantum efficiency of InGaN-based light-emitting diodes. PMID- 23920185 TI - Microstructural study on Kirkendall void formation in Sn-containing/Cu solder joints during solid-state aging. AB - Kirkendall void formation at the solder/metallization interface is an important reliability concern for Cu conductors and under-bump metallization in microelectronic packaging industry, whose mechanism is still hard to be understood for different individual cases. In the present work, two typical solder/Cu-diffusing couples, eutectic SnIn/Cu and SnBi/Cu, were studied by scanning/transmission electron microscopy to investigate the microstructural evolution and voiding process after soldering and then solid-state aging. It was concluded that Kirkendall voids formed between two sublayers within Cu2(In,Sn) phase in eutectic SnIn/Cu solder joint, whereas they appeared at the Cu3Sn/Cu interface or within Cu3Sn for eutectic SnBi/Cu solder joint. Besides the effect of impurity elements, the morphological difference within one intermetallic compound layer could change the diffusing rates of reactive species, hence resulting in void formation in the reaction zone. PMID- 23920186 TI - Electron energy loss spectroscopy characterization of TANOS (TaN/Al2O3/Si3N4/SiO2/Si) stacks. AB - The interfacial layer between the Al2O3 layer and the Si3N4 layer formed after postdeposition annealing (PDA) of TaN/Al2O3/Si3N4/SiO2/Si (TANOS) stacks was investigated using transmission electron microscopy (TEM), scanning transmission electron microscopy, and electron energy loss spectroscopy (EELS). From the result of the TEM analysis, it was found that the 2-nm-thick interface layer between Al2O3 and Si3N4 layers was amorphous. The high-loss EELS analysis showed that the phases of the interfacial layer weakly bound together instead of the substoichiometric silicon oxide and amorphous Al2O3 near the bottom interface of the crystalline Al2O3. The low-loss EELS analysis showed that aluminum existed in metallic state at the interface. Therefore, we speculated that SiO(x)N(y) could be formed by oxidation of Si3N4 during PDA and that metallic aluminum could be formed by the decomposition of weakly bound amorphous Al2O3 during electron irradiation. These complicated reactions near the interface could induce oxygen deficiency in the Al2O3 layer and finally degrade the retention properties of TANOS stacks. PMID- 23920187 TI - Enhanced morphological and thermal stabilities of nickel germanide with an ultrathin tantalum layer studied by ex situ and in situ transmission electron microscopy. AB - The formation and morphological evolution of germanides formed in a ternary Ni/Ta interlayer/Ge system were examined by ex situ and in situ annealing experiments. The Ni germanide film formed in the Ni/Ta-interlayer/Ge system maintained continuity up to 550 degrees C, whereas agglomeration of the Ni germanide occurred in the Ni/Ge system without Ta-interlayer. Through microstructural and chemical analysis of the Ni/Ta-interlayer/Ge system during and after in situ annealing in a transmission electron microscope, it was confirmed that the Ta atoms remained uniformly on the top of the newly formed Ni germanide layer during the diffusion reaction. Consequently, the agglomeration of the Ni germanide film was retarded and the thermal stability was improved by the Ta incorporation. PMID- 23920188 TI - Microstructure characterization of defects in cubic silicon carbide using transmission electron microscopy. AB - Microstructures of 3C-SiC grown by chemical vapor deposition (CVD) technique on undulant silicon substrate and a further developed technique called switch-back epitaxy (SBE) were studied using transmission electron microscopy (TEM). In case of the CVD sample, the density of the stacking faults was found to be significantly decreasing along growth direction. Sites of collision of stacking faults were observed using high-resolution transmission electron microscopy. Some of the stacking faults were observed to have disappeared after colliding into each other. The stacking faults were identified to be on the same type of plane and had the same type of displacement vector not only in CVD and SBE but also in the epitaxial layer on the SBE SiC samples. PMID- 23920189 TI - Identification of local phase of nanoscale BaTiO3 powders by high-resolution electron energy loss spectroscopy. AB - The electron energy loss spectroscopy (EELS) technique was applied to investigate the local variation in the phase of barium titanate (BaTiO3) ceramics. It was found that the fine structure of the titanium L2,3 edge and their satellite peaks were sensitively varied with the tetragonal-cubic phase transition. The peak splitting of Ti-L3 edge of tetragonal-phased BaTiO3 ceramics was widened because of the increased crystal field effect compared with that of cubic-phased BaTiO3. In case of nanoscale BaTiO3 powders, the L3 edge splitting of the core region was found to be smaller than that of the shell region. The energy gap between peaks t2g and eg varied from 2.36 to 1.94 eV with changing the probe position from 1 to 20 nm from the surface. These results suggest that the EELS technique can be used to identify the local phase of sintered BaTiO3 ceramics. PMID- 23920190 TI - Spatial distribution of dislocations in relation to a substructure in high quality GaN film. AB - The dislocation distribution of high-quality single-crystal gallium nitride (GaN) films grown by the hybrid vapor phase epitaxy was analyzed. This study examined the domain structure of GaN from the dislocation distribution on the macroscale by optical microscopy. The surface structure of GaN consisted of domains with microcolumns as the substructure. The inner domains contained a lower density of dislocations but a large number of these dislocations were observed along the domain boundaries. The existence of a domain boundary structure doubly increased the total dislocation density. PMID- 23920191 TI - Interfacial structure and electrical properties of transparent conducting ZnO thin films on polymer substrates. AB - The effects of polymer substrates on the interfacial structure and the thermal stability of Ga-doped ZnO (GZO) thin films were investigated. The GZO thin films were deposited on polyethylene terephthalate (PET) and polyethylene naphthalate (PEN) substrates by rf-magnetron sputtering at room temperature, and thermal stability tests of the GZO thin films on the polymer substrates were performed at 150 degrees C up to 8 h in air. Electrical and structural characterizations of the GZO thin films on the PET and the PEN substrates were carried out, and the origins of the stable interfacial structure and the improved thermal stability of the GZO thin film on the PEN substrate were discussed. PMID- 23920192 TI - Analytical electron microscopy of W-core beta-SiC fibers for use in an SiC-based composite material for fusion applications. AB - In this work, the interactions between tungsten (W) and silicon carbide (SiC) in Sigma SiC fibers at high temperatures were characterized using scanning and transmission electron microscopy. These fibers could have the potential for use in fusion-related applications owing to their high thermal conductivity compared with pure SiC-based fibers. The as-received fibers were composed of a 100-MUm thick shell of radially textured beta-SiC grains and a 15-MUm-thick tungsten core, composed of a few hundreds of nm-sized elongated tungsten grains. The interfaces between the tungsten and the SiC and the SiC and the outer coatings were sharp and smooth. After heat treatment at 1,600 degrees C for 3 h in Ar, the tungsten core reacted with SiC to form a rough interface surface. Inside the core, W5Si3, W3Si, and W2C phases were detected using energy-dispersive X-ray spectroscopy and electron-diffraction techniques. The mechanical properties of the fibers deteriorate after the heat treatment. PMID- 23920193 TI - Extraction of quantitative parameters for describing the microstructure of solid oxide fuel cells. AB - Digital quantification of a two-dimensional structure was applied to a GDC(Gd2O3 doped CeO2)/LSM(La0.85Sr0.15MnO3) composite cathode employed for solid oxide fuel cells. With the aid of high-resolution imaging capability based on secondary and backscattered electron images, two-dimensional electron micrographs were converted to digital binary files using an image processing tool combined with the line intercept method. Statistical analysis combined with a metallurgical tool was employed to determine microstructural factors, i.e., volume fraction, size distribution, and interconnectivity. The current work reports the quantification of the two-dimensional structural images of GDC/LSM composites applicable to solid oxide fuel cells, with the aim of obtaining the volume fraction, size distribution, and interconnectivity as functions of composite composition. The volume fractions of the solid constituent phases exhibit compositional dependence in cathodes; however, LSM interconnectivity increases gradually as a function of LSM composition, whereas that of GDC decreases significantly at 50 wt% LSM. PMID- 23920194 TI - Microstructural characterization of high indium-composition InXGa1-XN epilayers grown on c-plane sapphire substrates. AB - The growth of high-quality indium (In)-rich In(X)Ga(1-X)N alloys is technologically important for applications to attain highly efficient green light emitting diodes and solar cells. However, phase separation and composition modulation in In-rich In(X )Ga(1-X)N alloys are inevitable phenomena that degrade the crystal quality of In-rich In(X)Ga(1-X)N layers. Composition modulations were observed in the In-rich In(X)Ga(1-X)N layers with various In compositions. The In composition modulation in the In X Ga1-X N alloys formed in samples with In compositions exceeding 47%. The misfit strain between the InGaN layer and the GaN buffer retarded the composition modulation, which resulted in the formation of modulated regions 100 nm above the In(0.67)Ga(0.33)N/GaN interface. The composition modulations were formed on the specific crystallographic planes of both the {0001} and {0114} planes of InGaN. PMID- 23920195 TI - Microstructural analysis of dehydrogenation products of the Ca(BH4)2-MgH2 composite. AB - The microstructural analysis of the dehydrogenation products of the Ca(BH4)2-MgH2 composite was performed using transmission electron microscopy. It was found that nanocrystalline CaB6 crystallites formed as a dehydrogenation product throughout the areas where the signals of Ca and Mg were simultaneously detected, in addition to relatively coarse Mg crystallites. The uniform distribution of the nanocrystalline CaB6 crystallites appears to play a key role in the rehydrogenation of the dehydrogenation products, which implies that microstructure is a crucial factor determining the reversibility of reactive hydride composites. PMID- 23920196 TI - Provenance study through analysis of microstructural characteristics using an optical microscope and scanning electron microscopy for Goryeo celadon excavated from the seabed. AB - This paper aims at identifying the provenance of Goryeo celadons by understanding its microstructural characteristics, such as particles, blisters, forms and amount of pores, and the presence of crystal formation, bodies, and glazes and its boundary, using an optical microscope and scanning electron microscopy (SEM). The analysis of the reproduced samples shows that the glazed layer of the sherd fired at higher temperatures has lower viscosity and therefore it encourages the blisters to be combined together and the layer to become more transparent. In addition, the result showed that the vitrification and melting process of clay minerals such as feldspars and quartzs on the bodies was accelerated for those samples. To factor such characteristics of the microstructure and apply it to the sherds, the samples could be divided into six categories based on status, such as small particles with many small pores or mainly large and small circular pores in the bodies, only a limited number of varied sized blisters in the glazes, and a few blisters and needle-shaped crystals on the boundary surface. In conclusion, the analysis of the microstructural characteristics using an optical microscope and SEM have proven to be useful as a categorizing reference factor in a provenance study on Goryeo celadons. PMID- 23920197 TI - Study of the painting methods of mural paintings in ancient tombs of Goguryeo using scanning electron microscope. AB - Disputes on the painting methods of Goguryeo murals can mainly be categorized into whether the murals adapted eastern secco or western fresco; however, the murals have their own unique methods as well. There are different viewpoints among experts on interpreting the painting methods. This study involved the creation of research samples to discover the painting methods under dispute and may help discover the methods based on scanning electron microscopy energy dispersive X-ray spectroscopy (SEM-EDX) studies. Goguryeo murals introduced pseudo-fresco rather than buon fresco methods. Unlike fresco techniques in the West, Goguryeo painters mixed traditional soft binders and adapted typical secco painting techniques for paintings, borders, and corrections after drying. The disputed issues may be resolved by these techniques, and samples may be produced based on the analyzed data. Therefore, many questions can finally be answered through SEM-EDX elemental mapping. PMID- 23920198 TI - A new method for measurement of the vitrification rate of earthenware texture by scanning electron microscope. AB - A new method for determining the vitrification rate of pottery depending on the firing temperature was devised using secondary electron images (SEI) of scanning electron microscope (SEM). Several tests were performed to establish the appropriate operating conditions of SEM and reproducibility as well as to examine the applicability of the method. The grayscale values converted from each pixel of SEI were used to determine the vitrification rate of pottery, which in our study were artificially fired specimens composed of three types of clay. A comparison between the vitrification rate value and appearance temperature of minerals shows that mullite formation starts at 1,100 degrees C, during which the vitrification rate rapidly increases by over 10%. In consequence, the result presented here demonstrates that the new method can be applied to estimate the firing temperature of pottery. PMID- 23920199 TI - Characterization of white and black deposits on the surface of Korean stone cultural heritages. AB - White and black deposits have been frequently observed on the surface of Korean stone cultural heritages, and they are considered as damage factors in both conservation and esthetic points of view. In order to set up the appropriate conservation remedy, it is important to know their origins, characteristics, and compositions. In this study, optical and scanning electron microscopes (SEMs) equipped with an energy-dispersive spectrometer (EDS) and X-ray diffractometer were employed to determine the white and black deposits. It was found that both deposits consisted mainly of calcium carbonate (calcite) and calcium sulfate (gypsum). The calcite and gypsum were characterized by bladed, rhombohedral, tabular, and amorphous morphologies under a SEM. The black deposit was not only composed of calcite or gypsum, but also accompanied amorphous and irregular matrix. SEM-EDS analysis revealed an abundance of silicon, aluminum, iron, phosphorus, and carbon on the matrix, which were major elements of soil, atmospheric deposits, and organisms. The white deposit, on the other hand, barely contained those coloring substances. These salts and deposited substances were caused by chemical reaction and physical adhesion between rock-forming minerals, lime mortar, sulfur in polluted air environment, soil dust, and microorganisms. PMID- 23920200 TI - Three-dimensional imaging of cerebellar mossy fiber rosettes by ion-abrasion scanning electron microscopy. AB - The detailed knowledge of the three-dimensional (3D) organization of the nervous tissue provides essential information on its functional elucidation. We used serial block-face scanning electron microscopy with focused ion beam (FIB) milling to reveal 3D morphologies of the mossy fiber rosettes in the mice cerebellum. Three-week-old C57 black mice were perfused with a fixative of 1% paraformaldehyde/1% glutaraldehyde in phosphate buffer; the cerebellum was osmicated and embedded in the Araldite. The block containing granule cell layer was sliced with FIB and observed by field-emission scanning electron microscopy. The contrast of backscattered electron image of the block-face was similar to that of transmission electron microscopy and processed using 3D visualization software for further analysis. The mossy fiber rosettes on each image were segmented and rendered to visualize the 3D model. The complete 3D characters of the mossy fiber rosette could be browsed on the A-Works, in-house software, and some preliminary quantitative data on synapse of the rosette could be extracted from these models. Thanks to the development of two-beam imaging and optimized software, we could get 3D information on cerebellar mossy fiber rosettes with ease and speedily, which would be an additive choice to explore 3D structures of the nervous systems and their networks. PMID- 23920201 TI - Adaptive phenotypic plasticity of Siberian elm in response to drought stress: increased stomatal pore depth. AB - Leaf stomatal characteristics of Siberian elm (Ulmus pumila) were investigated by electron microscopy and white light scanning interferometry. On the basis of average annual precipitations, two types of tree specimens were collected from Korea, China, and Mongolia: (1) trees under normal environmental conditions and (2) trees under arid conditions. Field emission scanning electron microscopy revealed oval-shaped stomata on the lower surface, and they were ca. 20 MUm in width. In-lens secondary electron imaging showed differences in electron density and stomatal pore depth between the two types. According to the line profile analysis by white light scanning interferometry, stomata under arid conditions appeared to have higher levels of the stomatal pore depth than ones under normal conditions. Focused ion beam-field emission electron microscopy supported the increased stomatal pore depth with the increasing drought stress gradient. These results suggest that complementary microscopy can be employed to unravel the adaptive phenotypic plasticity of Siberian elm in response to drought stress. PMID- 23920202 TI - Rapid method for electron tomographic reconstruction and three-dimensional modeling of the murine synapse using an automated fiducial marker-free system. AB - Electron tomography (ET) has recently afforded new insights into neuronal architecture. However, the tedious process of sample preparation, image acquisition, alignment, back projection, and additional segmentation process of ET repels beginners. We have tried Hitachi's commercial packages integrated with a Hitachi H-7650 TEM to examine the potential of using an automated fiducial-less approach for our own neuroscience research. Semi-thick sections (200-300 nm) were cut from blocks of fixed mouse (C57BL) cerebellum and prepared for ET. Sets of images were collected automatically as each section was tilted by 2 degrees increments (+/-60 degrees ). "Virtual" image volumes were computationally reconstructed in three dimension (3D) with the EMIP software using either the commonly used "weighted back-projection" (WBP) method or "topography-based reconstruction" (TBR) algorithm for comparison. Computed tomograms using the TBR were more precisely reconstructed compared with the WBP method. Following reconstruction, the image volumes were imported into the 3D editing software A View and segmented according to synaptic organization. The detailed synaptic components were revealed by very thin virtual image slices; 3D models of synapse structure could be constructed efficiently. Overall, this simplified system provided us with a graspable tool for pursuing ET studies in neuroscience. PMID- 23920203 TI - Three-dimensional structure of Drosophila testis tip: the spatial relation between dividing cells. AB - At the apical tip of Drosophila testis, there is a stem cell niche known as the proliferation center, where the stem cells are maintained by hub cell cluster for the regulation of differentiation and proliferation. Germline stem cells go through mitosis four times from one primary spermatogonial cell to the 16-cell stage before the maturation. The cells derived from the same germline stem cell are located within one cyst, an enclosed system by two cyst cells, and they are connected by the intercellular bridges called ring canals. In this study, the three-dimensional (3D) structure of Drosophila testis tip was reconstructed from serial sections. The size of cells at each stage was compared in volume from the 3D structure. The stages of cells in a cyst could be distinguishable exactly by counting the cells linked with intercellular bridges in 3D-reconstructed structure. The cysts containing the same stage cells appeared in the horizontal plane. Both the germline stem cell directly attached to the hub cell and the spermatogonial cells detached from the hub cell were divided at the almost perpendicular direction to the spermatogonial cell layers. The dividing phase in one cyst was delayed gradually through the cytoplasmic region of intercellular bridge. PMID- 23920204 TI - Extraction of three-dimensional information of biological membranous tissue with scanning confocal infrared laser microscope tomography. AB - The "LEXT" confocal laser scanning microscope has been used for the three dimensional (3D) imaging of the surface of specimens, especially in materials science fields, by the penetration of near-infrared (NIR) light without mechanical cutting, deposition, or other specimen pretreatment. Noninvasive investigation of various biological tissues such as human spinal dura mater, rat aorta, and cornea without the dehydration process was successfully carried out with the "LEXT," in order to access both surface and internal topographic images of the biological structures at a good status of the wet tissue such as in vivo, especially in measuring tissue thickness. The confocal NIR laser microscopy offers the viable means to visualize tissue architecture and its thickness in microdomain to integrate 3D images efficiently. We believe that the "LEXT" has a good application for biological researchers to study biomaterials, and it would be useful as a diagnostic tool in the near future. PMID- 23920205 TI - Microscopic and spectroscopic analyses of Pt-decorated carbon nanowires formed on carbon fiber paper. AB - We report the synthesis of carbon nanowires (CNWs) via chemical vapor deposition using catalytic decomposition of ethanol on nanosized transition metals such as Co, Fe, and Ni. Dip-coating process was used for the formation of catalytic nanoparticles, inducing the growth of CNWs on the surface of the carbon fiber paper (CFP). The liquid ethanol used as carbon source was atomized by an ultrasonic atomizer and subsequently flowed into the reactor that was heated up to a synthesis temperature of 600-700 degrees C. Microscopic images show that CNWs of <50 nm were densely synthesized on the surface of the CFP. Raman spectra reveal that a higher synthesis temperature leads to the growth of higher crystalline CNWs. In addition, we demonstrate the successful decoration of platinum nanoparticles on the surface of the prepared CNWs/CFP using the electrochemical deposition technique. PMID- 23920206 TI - Oxidation mechanism of nickel oxide/carbon nanotube composite. AB - The oxidation mechanism and thermal stability of nickel oxide (NiO)/carbon nanotube (CNT) composites were investigated by examining composites with different NiO contents by thermogravimetric analysis and transmission electron microscopy (TEM). NiO acts as a catalyst in the oxidation of CNT in the composite. CNTs can be oxidized, even in a vacuum, by reducing NiO to nickel at temperatures lower than the normal oxidation temperature of CNTs. This phase transition was confirmed directly by in situ heating TEM observations. In air, reduction by CNT occurs simultaneously with reoxidation by gaseous O2 molecules, and NiO maintains its phase. The thermal stability decreased with increasing NiO content because of defects in the CNT generated by the NiO loading. PMID- 23920207 TI - Features of the ISO-25498: method of selected area electron diffraction analysis in transmission electron microscopy. AB - International standard ISO-25498 specifies the method of selected area electron diffraction (SAED) analysis in TEM. It is applicable to the acquisition of SAED patterns, indexing the patterns and calibration of diffraction constant. Several features of this standard are introduced. As an example of the applications, phosphide with nanometer scale in a low-carbon steel produced by compact strip production process was analyzed by SAED and EDX. The phosphide precipitates in the steel are identified as M x P, where x is 2-3 and M is Fe, Ti, Cr, or Ni. It possesses a hexagonal lattice with lattice parameter a = 0.609 nm and c = 0.351 nm. PMID- 23920208 TI - Rapid in vitro corrosion induced by crack-like pathway in biodegradable Mg-10% Ca alloy. AB - The in vitro corrosion mechanism of the biodegradable cast Mg-10% Ca binary alloy in Hanks' solution was evaluated through transmission electron microscopy observations. The corrosion behavior depends strongly on the microstructural peculiarity of Mg2Ca phase surrounding the island-like primary Mg phase and the fast corrosion induced by the interdiffusion of O and Ca via the Mg2Ca phase of lamellar structure. At the corrosion front, we found that a nanosized crack-like pathway was formed along the interface between the Mg2Ca phase and the primary Mg phase. Through the crack-like pathway, O and Ca are atomically exchanged each other and then the corroded Mg2Ca phase was transformed to Mg oxides. The in vitro corrosion by the exchange of Ca and O at the nanosized pathway led to the rapid bulk corrosion in the Mg-Ca alloys. PMID- 23920210 TI - Correlation between spirometry values and pulmonary artery pressure in young healthy subjects. AB - BACKGROUND: Pulmonary hypertension is frequently associated with parenchymal lung disease. We evaluated the association between spirometry values and pulmonary artery systolic pressure (PASP) in young subjects without lung disease METHODS: : We studied applicants to the Israeli Air Force, who undergo routine evaluation that includes resting spirometry and echocardiography. Applicants with overt lung disease were excluded. All echocardiographic studies performed in the years 1994 through 2010 (n = 6,598) were screened, and files that included PASP and spirometry values were analyzed for the association between PASP and FVC, FEV1, FEV1/FVC, peak expiratory flow, and forced expiratory flow during the middle half of the FVC maneuver. RESULTS: Of the 647 air force applicants who underwent echocardiography in which PASP was measurable and had spirometry data, 607 (94%) were male, and their average age was 18.16 +/- 0.73 years. Mean PASP was 26.4 +/- 5.2 mm Hg (range 10-41 mm Hg). None of the spirometry values significantly correlated with PASP. CONCLUSIONS: PASP in young healthy subjects is not significantly associated with spirometry values. Lung mechanics probably do not contribute significantly to PASP in this population. PMID- 23920209 TI - Sexual risk after HIV diagnosis: a comparison of pre-ART individuals with CD4>500 cells/ul and ART-eligible individuals in a HIV treatment and care programme in rural KwaZulu-Natal, South Africa. AB - INTRODUCTION: Little is known about people diagnosed as HIV-positive who access HIV care early in their disease. In pre-ART studies published to date, only a minority of the participants have CD4>500 cells/ul. METHODS: This cross-sectional study compared individuals presenting for HIV care with CD4>500 cells/ul, "pre ART" (N=247), with individuals who had CD4<200 cells/ul or WHO Stage IV, "ART eligible" (N=385). Baseline characteristics were contrasted between the two groups and logistic regression models used to explore group differences in: (a) being sexually active in the last month; (b) disclosure of HIV status to current partner; (c) knowing the HIV status of one's current partner; and (d) condom use at last sex. RESULTS: Pre-ART and ART-eligible individuals were similar in terms of a wide range of socio-demographic characteristics. Controlling for gender, only current sexual behaviour and HIV-testing history were significantly different between ART groups. In multivariable models, participants in the pre ART group were twice as likely to be sexually active in the last month, OR 2.06 95% CI (1.32, 3.21), and to know their partner's status, OR 1.95 (1.18, 3.22) compared to those in the ART-eligible group. Self-reported disclosure of HIV status to current sexual partner (71%), condom use at last sex (61%) and HIV concordancy within relationships were not significantly different between the two ART groups. Overall, 39% of the study participants reported knowing that they were in concordant HIV-positive relationships. Fifty-five percent of all participants reported not knowing their partner's HIV status, only half of whom reported using a condom at last sex. Pre-ART individuals were significantly less likely to have tested HIV-positive for the first time in the last year and to have tested for sickness-related reasons than the ART-eligible group. CONCLUSIONS: Reported sexual risk behaviours by pre-ART individuals with CD4>500 cells/ul suggest a continued risk of onward HIV transmission. There is a need for positive prevention efforts to target this group given that current treatment guidelines do not provide them with ART. Strengthening support regarding disclosure, partner HIV testing and consistent condom use, and further promotion of HIV testing in the community to assist earlier diagnosis are urgently required. PMID- 23920211 TI - Polysomnograph chart view by patients: a new educational strategy to improve CPAP adherence in sleep apnea therapy. AB - BACKGROUND: CPAP is currently the treatment of choice for obstructive sleep apnea syndrome, but therapy adherence is poor. Many educational trials have been proposed to increase CPAP adherence. We tested the hypothesis that polysomnograph chart viewing by patients would improve CPAP adherence. METHODS: A controlled parallel group study was performed with 206 newly diagnosed obstructive sleep apnea syndrome patients, randomized into 2 groups (n = 103 each): standard support group, and educational support group. Each educational support group subject viewed 2 consecutive polysomnograms on the computer screen: the first recorded during a standard diagnostic overnight polysomnography, and the second during a full-night polysomnography with nasal CPAP. The subject's attention was drawn only to the flow and oxyhemoglobin saturation curves. Clinical outcomes were assessed via polysomnography at CPAP initiation and after 1, 3, and 12 months. RESULTS: After 12 months of CPAP, 76% of the educational support group and 52% of the standard support group returned for a follow-up visit (P < .001). Statistical significance had already been reached after 1 and 3 months. Moreover, CPAP use (measured as hours of use per night) was higher in the educational support group at each control visit. CONCLUSIONS: Polysomnograph chart viewing by obstructive sleep apnea patients can increase CPAP adherence, as evaluated by rate of return for the follow-up visit and mean nightly CPAP use. PMID- 23920212 TI - Reference equation for the 2-minute walk test in adults and the elderly. AB - BACKGROUND: The 2-min walk test (2MWT) has been used in several health conditions, but the interpretation of its results is limited due to a lack of reference values. The aim of this study was to establish a reference equation to predict the distance walked (DW) in the 2MWT for healthy adults and the elderly and to test its reproducibility. METHODS: We evaluated 390 healthy subjects (195 male), 18-89 y old, with normal spirometry and no history of previous chronic diseases. Two 2MWTs were performed on the same day, 30 min apart. To test the reliability of the prediction equation, 70 subjects (35 male) were prospectively included in the study. RESULTS: Men walked farther than women (221 [202-240] vs 199 [164-222] m, respectively; P < .0001). Significant correlations were observed between DW and age (r = -0.50), weight (r = 0.23), height (r = 0.40), and gender (r = 0.35) (P < .001 for all). Age and gender persisted in the model to predict DW (R(2) = 0.51). There was no difference between the DW by the subjects (197 [182-216] m) and that estimated by the prediction equation (197 [179-222] m) (P = .68). CONCLUSIONS: We established a prediction equation that may be used as a reference to interpret performance on the 2MWT of adults and the elderly with different health conditions. PMID- 23920213 TI - In vitro evaluation of positive expiratory pressure devices attached to nebulizers. AB - BACKGROUND: Patients with cystic fibrosis perform airway clearance techniques and receive nebulized medications on a regular basis. Some positive expiratory pressure (PEP) devices allow concomitant administration of aerosol. I hypothesized that this practice alters the aerosol characteristics and patient dose. I compared the aerosol characteristics and patient dose of nebulized albuterol from 2 types of nebulizer, alone and when connected to different PEP and vibratory PEP devices. METHODS: Three units of a continuous-output nebulizer (Up-Draft II Opti-Neb) and 3 units of a breath-enhanced nebulizer (LC Plus) were tested alone and connected to PEP devices (Acapella Choice, Acapella Duet, and EzPAP for Up-Draft II Opti-Neb, and Pari PEP at 2 different settings, and Pari PEP S system with the LC Plus). Aerosol characteristics were evaluated with a cooled cascade impaction technique. The nebulizers were loaded with 2.5 mg/3 mL albuterol solution and operated for 4 min at 6 L/min (wall air). Patient dose was evaluated with simulated breathing patterns for a child, small adult, and large adult. Albuterol was assayed via spectrophotometry. RESULTS: Connecting the LC Plus to the PEP devices did not change the aerosol characteristics or patient dose. Connecting the Up-Draft II Opti-Neb to the PEP devices significantly reduced the mass median aerodynamic diameter, from 4.13 MUm to 3.72 MUm with EzPAP (P = .02), 1.24 MUm with Acapella Choice (P < .001), and 1.22 MUm with Acapella Duet (P < .001). The total amount of albuterol captured by the impactor decreased when connected to either Acapella Choice (65%) or Acapella Duet (69%), with 17-25% retained in the PEP devices. Patient dose decreased by 76% and 84% when connected to Acapella Choice and Acapella Duet, respectively. CONCLUSIONS: Concomitant use of nebulizer and PEP or vibratory PEP devices that obstruct the aerosol pathway significantly decrease the aerosol particle size and the patient dose. PMID- 23920214 TI - Scintigraphic assessment of radio-aerosol pulmonary deposition with the acapella positive expiratory pressure device and various nebulizer configurations. AB - BACKGROUND: The Acapella device produces high-frequency oscillations and positive expiratory pressure to promote bronchial secretion clearance. Its performance during aerosol delivery has not been described. We evaluated the effect of nebulizer and Acapella configuration on pulmonary deposition of radio-tagged aerosol in healthy subjects. METHODS: Ten healthy male subjects (mean age 24.4 +/ 2.2 y) participated in a crossover study that compared pulmonary delivery of 4 mL of technetium-99m-labeled diethylene triamine penta-acetic acid (25 mCi) and 0.9% saline solution via jet nebulizer. We tested 3 configurations: nebulizer attached to the distal end of the Acapella; nebulizer placed between the mouthpiece and the Acapella; and nebulizer alone (control). With scintigraphy we measured radio-aerosol deposition in 6 lung regions: upper, middle, lower, central, intermediate, and peripheral. RESULTS: Deposition was similar between the right and left lungs, with no significant differences between device configurations. Lung deposition was less with the nebulizer attached to the Acapella than with nebulizer between the mouthpiece and the Acapella (P = .001, for both lungs) or without the Acapella (P = .003 and P = .001 for the right and left lungs, respectively). There was no significant difference between the setup without Acapella and the setup with the nebulizer between the mouthpiece and the Acapella (P = .001, for both lungs). On the vertical axis, deposition was lower with the nebulizer attached to the distal end of the Acapella than with the nebulizer between the mouthpiece and the Acapella (upper region P < .001, middle region P = .001, lower region P = .003), and lower with the nebulizer attached to the distal end of the Acapella than with the setup without Acapella (upper and middle region both P = .001, lower region P = .002), with up to a 3-fold difference in the middle and lower regions. On the central-peripheral axis, deposition was lower with the nebulizer attached to the distal end of the Acapella than with the nebulizer between the mouthpiece and the Acapella (central region P < .001, peripheral region P < .001), and lower with the nebulizer attached to the distal end of the Acapella than with the setup without Acapella (central and peripheral regions both P = .002), with differences of 3-4-fold between the central and peripheral regions. CONCLUSIONS: Placing the nebulizer distal to the Acapella, as recommended by the manufacturer, decreased intrapulmonary deposition, compared to placing the nebulizer between the Acapella and the patient airway, or delivering aerosol without the Acapella in the circuit. (ClinicalTrials.gov NCT01102166). PMID- 23920215 TI - In vitro evaluation of radio-labeled aerosol delivery via a variable-flow infant CPAP system. AB - BACKGROUND: Nasal CPAP is widely used in neonatal ICUs. Aerosolized medications such as inhaled steroids and beta agonists are commonly administered in-line through nasal CPAP, especially to infants with bronchopulmonary dysplasia. We hypothesized that aerosol delivery to the lungs via variable-flow nasal CPAP in an in vitro model would be unreliable, and that the delivery would depend on the position of the aerosol generator within the nasal CPAP circuit. METHODS: We used a system that employed a test lung placed in a plastic jar and subjected to negative pressure. Simulated inspiration effort was measured with a heated-wire anemometer. We used technetium-99m-labeled diethylene triamine penta-acetic acid as our aerosol. The nebulizer was placed either close to the humidifier or close to the nasal prongs in the circuit, and patient effort was simulated with a minute ventilation of 0.4 L/min. RESULTS: Relative aerosol delivery to the infant test lung with the nebulizer close to the humidifier was extremely low (0.3 +/- 0.4%), whereas placing the nebulizer close to the nasal prongs resulted in significantly (P < .001) improved delivery (21 +/- 11%). Major areas of aerosol deposition with the nebulizer close to the humidifier versus close to the nasal prongs were: nebulizer (10 +/- 4% vs 33 +/- 13%, P < .001), exhalation limb (9 +/ 17% vs 26 +/- 30%, P = .23), and generator tubing (21 +/- 11% vs 19 +/- 20%, P = .86). Placing the nebulizer close to the humidifier resulted in 59 +/- 8% of the aerosol being deposited in the inhalation tubing along the heater wire. CONCLUSIONS: Isotope delivery from an aerosol generator placed near the humidifier on variable-flow nasal CPAP was negligible in this in vitro setup; however, such delivery was significantly improved by locating the aerosol generator closer to the nasal CPAP interface. PMID- 23920216 TI - Histopathology and exercise: a winning combination in pulmonary fibrosis: a case report. AB - The diffuse parenchymal lung diseases form a heterogeneous group of disorders characterized by varying degrees of inflammation and fibrosis involving the space between epithelial and endothelial basement membranes. Among the diffuse parenchymal lung diseases of unknown etiology, one of the most common is usual interstitial pneumonia/idiopathic pulmonary fibrosis, which carries the worst prognosis. In contrast, nonspecific interstitial pneumonia, which belongs to the same diffuse parenchymal lung disease group, has a more favorable prognosis. Based on the relative amount of inflammation and fibrosis observed on lung biopsies, at least 2 nonspecific interstitial pneumonia patterns have been suggested: cellular and fibrosing. The long-term prognosis is excellent for patients with nonspecific interstitial pneumonia with a cellular pattern, as compared to patients with a fibrosing pattern. We describe here a patient with nonspecific interstitial pneumonia with a fibrosing pattern in a highly practiced runner, showing an unexpectedly long-term favorable course, and consider the possible role of exercise in the diagnosis and clinical course of the disease. This case reinforces the evidence that exercise training, which is a principal component of pulmonary rehabilitation, may have clinically important effects on functional exercise capacity, especially if it is delivered early in the course of the disease. PMID- 23920217 TI - Broncholithiasis secondary to pulmonary actinomycosis. AB - We report a case of broncholithiasis secondary to pulmonary actinomycosis. Broncholithiasis has occasionally been reported in association with actinomycosis, but it is unclear if actinomycosis leads to lymph node calcification with subsequent erosion into the airway, producing a broncholith, or if an existing generic broncholith is secondarily colonized with Actinomyces. The patient had post-obstruction pneumonia, and computed tomography showed calcified nodules obstructing the bronchus intermedius and distal necrotizing pneumonia. The nodules included sulfur granules containing Gram-positive branching filamentous organisms consistent with Actinomyces. The finding of Actinomyces throughout the broncholith is strong evidence that the etiology of the broncholithiasis was a primary pulmonary Actinomyces infection. PMID- 23920218 TI - Profile of evidence-based practice among respiratory therapists in Taiwan. AB - BACKGROUND: Evidence-based practice (EBP) has been proposed as a core competence to improve healthcare quality. The profile of EBP among respiratory therapists (RTs) has not been explored. We investigated how RTs in Taiwan perceive the implementation of EBP. METHODS: We surveyed RTs in Taiwan's regional hospitals during a 4-month period in 2011. RESULTS: A majority of RTs were aware of EBP (88.0%). Although most RTs held a favorable impression of EBP, their knowledge of and skill in EBP implementation were deficient. Only half of the RTs had implemented EBP. Insufficient convenient kits (59.1%), deficient designated personnel (50.0%), and lack of time (45.5%) were major barriers to implementing EBP. RTs rated MEDLINE as the most commonly used evidence-based retrieval database, followed by UpToDate, the Cochrane Library, MD Consult, ProQuest, CINAHL, DynaMed, and Micromedex. Multivariate regression analyses demonstrated sufficient skill in EBP and use of online databases as favorable factors for implementing EBP. In contrast, barriers of time constraint and insufficient knowledge were unfavorable factors for the implementation of EBP. CONCLUSIONS: EBP is not widespread among RTs in Taiwan. We have identified important factors in the implementation of EBP. The data provide valuable evidence for plotting strategies for disseminating EBP implementation. PMID- 23920219 TI - Insights into insulin-mediated regulation of CYP2E1: miR-132/-212 targeting of CYP2E1 and role of phosphatidylinositol 3-kinase, Akt (protein kinase B), mammalian target of rapamycin signaling in regulating miR-132/-212 and miR-122/ 181a expression in primary cultured rat hepatocytes. AB - Several microRNAs (miRNAs) were selected for characterization of their response to insulin signaling based on in silico predictions of targeting CYP2E1 mRNA and previous reports implicating their role in hepatic metabolism and disease. CYP2E1 expression decreases with increasing insulin concentration and has been shown to be regulated by the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. In primary cultured rat hepatocytes, insulin at 0.1, 1.0, and 10 nM elevated miRNA-132 and -212 expression ~2- and 1.8-fold, respectively, whereas expression of miRNA-181a and 122 increased ~1.6- and 1.4-fold, respectively. In contrast, insulin failed to alter significantly the expression of miRNA let-7a. Mechanistic studies using inhibitors of PI3-K, Akt, and mTOR were used to examine the role of the insulin signaling pathway on miR expression and resulted in significant suppression of the insulin-mediated elevation of miR-132, miR-212, and miR-122 levels, with a lesser effect observed for miR-181a. Targeting of the rat CYP2E1 3'-untranslated region (UTR) by miR-132 and -212 was demonstrated with an in vitro luciferase reporter assay. These data show that insulin, which regulates CYP2E1 through the PI3-K, Akt, mTOR signaling pathway, also regulates the expression of miRs that target the 3'-UTR of CYP 2E1 mRNA and are involved in the regulation of hepatic metabolism and disease. PMID- 23920221 TI - Substrate-dependent inhibition of organic anion transporting polypeptide 1B1: comparative analysis with prototypical probe substrates estradiol-17beta glucuronide, estrone-3-sulfate, and sulfobromophthalein. AB - Organic anion transporting polypeptide (OATP) 1B1 plays an important role in the hepatic uptake of many drugs, and the evaluation of OATP1B1-mediated drug-drug interactions (DDIs) is emphasized in the latest DDI (draft) guidance documents from U.S. and E.U. regulatory agencies. It has been suggested that some OATP1B1 inhibitors show a discrepancy in their inhibitory potential, depending on the substrates used in the cell-based assay. In this study, inhibitory effects of 14 compounds on the OATP1B1-mediated uptake of the prototypical substrates [3H]estradiol-17beta-glucuronide (E2G), [3H]estrone-3-sulfate (E1S), and [3H]sulfobromophthalein (BSP) were studied in OATP1B1-transfected cells. Inhibitory potencies of tested compounds varied depending on the substrates. Ritonavir, gemfibrozil, and erythromycin caused remarkable substrate-dependent inhibition with up to 117-, 14-, and 13-fold difference in their IC50 values, respectively. Also, the clinically relevant OATP inhibitors rifampin and cyclosporin A exhibited up to 12- and 6-fold variation in their IC50 values, respectively. Regardless of the inhibitors tested, the most potent OATP1B1 inhibition was observed when [3H]E2G was used as a substrate. Mutual inhibition studies of OATP1B1 indicated that E2G and E1S competitively inhibited each other, whereas BSP noncompetitively inhibited E2G uptake. In addition, BSP inhibited E1S in a competitive manner, but E1S caused an atypical kinetics on BSP uptake. This study showed substrate-dependent inhibition of OATP1B1 and demonstrated that E2G was the most sensitive in vitro OATP1B1 probe substrate among three substrates tested. This will give us an insight into the assessment of clinically relevant OATP1B1-mediated DDI in vitro with minimum potential of false-negative prediction. PMID- 23920220 TI - Multispecific drug transporter Slc22a8 (Oat3) regulates multiple metabolic and signaling pathways. AB - Multispecific drug transporters of the solute carrier and ATP-binding cassette families are highly conserved through evolution, but their true physiologic role remains unclear. Analyses of the organic anion transporter 3 (OAT3; encoded by Slc22a8/Oat3, originally Roct) knockout mouse have confirmed its critical role in the renal handling of common drugs (e.g., antibiotics, antivirals, diuretics) and toxins. Previous targeted metabolomics of the knockout of the closely related Oat1 have demonstrated a central metabolic role, but the same approach with Oat3 failed to reveal a similar set of endogenous substrates. Nevertheless, the Oat3 knockout is the only Oat described so far with a physiologically significant phenotype, suggesting the disturbance of metabolic or signaling pathways. Here we analyzed global gene expression in Oat3 knockout tissue, which implicated OAT3 in phase I and phase II metabolism (drug metabolizing enzymes or DMEs), as well as signaling pathways. Metabolic reconstruction with the recently developed "mouse Recon1" supported the involvement of Oat3 in the aforementioned pathways. Untargeted metabolomics were used to determine whether the predicted metabolic alterations could be confirmed. Many significant changes were observed; several metabolites were tested for direct interaction with mOAT3, whereas others were supported by published data. Oat3 thus appears critical for the handling of phase I (hydroxylation) and phase II (glucuronidation) metabolites. Oat3 also plays a role in bioenergetic pathways (e.g., the tricarboxylic acid cycle), as well as those involving vitamins (e.g., folate), steroids, prostaglandins, gut microbiome products, uremic toxins, cyclic nucleotides, amino acids, glycans, and possibly hyaluronic acid. The data seemingly consistent with the Remote Sensing and Signaling Hypothesis (Ahn and Nigam, 2009; Wu et al., 2011), also suggests that Oat3 is essential for the handling of dietary flavonoids and antioxidants. PMID- 23920222 TI - Improvement of hemodynamic and inflammatory parameters by combined hemoadsorption and hemodiafiltration in septic shock: a case report. PMID- 23920223 TI - Towards gene therapy of postoperative adhesions: fiber and transcriptional modifications enhance adenovirus targeting towards human adhesion cells. AB - Postoperative abdominal/pelvic peritoneal adhesions are a major source of morbidity (bowel obstruction, infertility, ectopic gestation as well as chronic pelvic pain) in women. In this study, we screened various transduction and transcription modifications of adenovirus (Ad) to identify those that support maximal Ad-mediated gene delivery to human adhesion fibroblasts, which in turn would enhance the efficacy of this novel treatment/preventative strategy for postoperative adhesions. We transduced primary cultures of human peritoneal adhesion fibroblasts with fiber-modified Ad vectors Ad5-RGD-luc, Ad5-Sigma-luc, Ad5/3-luc and Ad5-CAV2-luc as well as transcriptional targeting viruses Ad5 survivin-luc, Ad5-heparanase-luc, Ad5-mesothelin (MSLN)-CRAd-luc and Ad5 secretory leukoprotease inhibitor (SLPI)-luc, and compared their activity to wild type Ad5-luc. At 48 h, luciferase activity was measured and normalized to the total protein content in the cells. Among the fiber-modified Ad vectors, Ad5 Sigma-luc and among the transcriptional targeting modified Ad vectors, Ad5-MSLN CRAd-luc showed significantly increased expression levels of luciferase activity at 5, 10 and 50 plaque forming units/cell in adhesion fibroblast cells compared with wild-type Ad5-luc (p < 0.05). Specific modifications of Ad improve their gene delivery efficiency towards human peritoneal adhesion fibroblasts. Developing a safe localized method to prevent/treat postoperative adhesion formation would have a major impact on women health. PMID- 23920224 TI - Social isolation and diurnal cortisol patterns in an ageing cohort. AB - BACKGROUND: Social isolation may operate as a psychosocial stressor which disrupts functioning of the hypothalamic-pituitary-adrenocortical axis. METHODS: Using data from the MRC National Survey of Health and Development, we tested whether living alone, not being married and social network size were associated with diurnal cortisol patterns at 60-64 years. We hypothesised that recent onset compared with long-term isolation would be more strongly associated with cortisol awakening response, cortisol decline over the day and evening cortisol. Models were adjusted for sex, smoking, body mass index, alcohol intake, psychological distress and financial difficulties. RESULTS: Those widowed within the last three years had a 36% (95%CI 6%, 73%) higher night time cortisol than those who were currently married. Those newly living alone also had a higher night time cortisol and flatter diurnal slope than those living with others. CONCLUSION: Independently of multiple behavioural and psychosocial correlates, recent onset of social isolation is related to diurnal cortisol patterns that increase the risk of morbidity and mortality. PMID- 23920225 TI - Bone scintigraphy and secondary osteomalacia due to nephrotoxicity in a chronic hepatitis B patient treated with tenofovir. AB - Tenofovir is a nucleotide analogue used for the treatment of chronic hepatitis B and HIV infection. The safety of tenofovir is high but it has been described that tenofovir produces tubular toxicity and Fanconi's syndrome in some HIV-infected patients. To our knowledge this is the first documented case of bone involvement in Fanconi's syndrome in a patient treated with tenofovir for chronic hepatitis B without HIV coinfection. Bone scintigraphy has proven to be very useful for the diagnosis of secondary osteomalacia. Normalization of the bone scan after the withdrawal of the drug and the decline in alkaline phosphatase and phosphate serum levels reinforce the cause-effect relationship. PMID- 23920226 TI - Modulators of antibiotic activity from Ipomoea murucoides. AB - Reinvestigation of the CHCl3-soluble extract from the flowers of Ipomoea murucoides, through preparative-scale recycling HPLC, yielded three pentasaccharides of 11-hydroxyhexadecanoic acid, murucoidins XVII-XIX, in addition to the known murucoidin III and V, all of which were characterized by NMR spectroscopy and mass spectrometry. These compounds were found to be macrolactones of the known pentasaccharides simonic acid B and operculinic acid A. The acylating groups corresponded to acetic, (2S)-methyl-butyric, (E)-cinnamic and octanoic acids. The esterification sites were established at the C-2 of the second rhamnose and C-3 and C-4 of the third rhamnose. The aglycone lactonization was placed at C-2 or C-3 of the first rhamnose. Bioassays for modulation of antibiotic activity were performed against multidrug-resistant strains of Staphylococcus aureus, Escherichia coli Rosetta-gami, and two nosocomial pathogens: Salmonella enterica sv. Typhi and Shigella flexneri. The tested glycolipids did not act as cytotoxic (IC50>4 MUg/mL) nor as antimicrobial (MIC>128 MUg/mL) agents. However, they exerted a potentiation effect on clinically useful antibiotics against the tested bacteria by increasing their antibiotic susceptibility up to four-fold at concentrations of 25 MUg/mL. PMID- 23920227 TI - Vitamin E analyses in seeds reveal a dominant presence of tocotrienols over tocopherols in the Arecaceae family. AB - Tocopherols are thought to prevent oxidative damage during seed quiescence and dormancy in all angiosperms. However, several monocot species accumulate tocotrienols in seeds and their role remains elusive. Here, we aimed to unravel the distribution of tocopherols and tocotrienols in seeds of the Arecaceae family, to examine possible trends of vitamin E accumulation within different clades of the same family. We examined the tocopherol and tocotrienol content in seeds of 84 species. Furthermore, we evaluated the vitamin E composition of the seed coat, endosperm and embryo of seeds from 6 species, to determine possible tissue-specific functions of particular vitamin E forms. While seeds of 98.8% (83 out of 84) of the species accumulated tocotrienols, only 58.3% (49 out of 84) accumulated tocopherols. The presence of tocopherols did not follow a clear evolutionary trend, and appeared randomly in some clades only. In addition, the tissue-specific location of vitamin E in seeds revealed that the embryo contains mostly alpha-tocopherol (in seed tocopherol-accumulating species) or alpha tocotrienol (in seed tocopherol-deficient species). However, some species such as Socratea exorrhiza mostly accumulate beta-tocotrienol, and Parajubaea torallyi accumulates a mixture of tocopherols and tocotrienols in the embryo. This suggests that tocotrienols can play a similar protective role to that exerted by tocopherols in seeds, at least in some species of the Arecaceae family. We conclude that tocotrienol, rather than tocopherol, accumulation is a conserved trait in seeds of the Arecaceae family. PMID- 23920228 TI - Phytochemistry and pharmacognosy of the genus Acronychia. AB - The genus Acronychia (Rutaceae) comprise 44 species, most of which are represented by shrubs and small trees, distributed in a wide geographical area of South-Eastern Asia comprising China, India, Malaysia, Indonesia, Australia, and the islands of the western Pacific Ocean. Most of the species of the genus Acronychia have been used for centuries as natural remedies in the ethnomedical traditions of indigenous populations as anti-microbial, anti-fungal, anti spasmodic, stomachic, anti-pyretic, and anti-haemorragic agent. Moreover fruits and aerial parts are used as food in salads and condiments, while the essential oil obtained from flowers and leaves has been employed in cosmetics production. Phytochemicals isolated from Acronychia spp. include acetophenones, quinoline and acridone alkaloids, flavonoids, cinnamic acids, lignans, coumarins, steroids, and triterpenes. The reported biological activities of the above mentioned natural compounds refer to anti-plasmodial, anti-cancer, anti-oxidant, anti-inflammatory, anti-fungal, and neuroprotective effects. The aim of this review is to examine in detail from a phytochemical and pharmacologically point of view what is reported in the current literature about the properties of phytopreparations or individual active principles obtained from plants belonging to the Acronychia genus. PMID- 23920229 TI - Biocontrol of Rhizoctonia solani damping-off and promotion of tomato plant growth by endophytic actinomycetes isolated from native plants of Algerian Sahara. AB - Thirty-four endophytic actinomycetes were isolated from the roots of native plants of the Algerian Sahara. Morphological and chemical studies showed that twenty-nine isolates belonged to the Streptomyces genus and five were non Streptomyces. All isolates were screened for their in vitro antifungal activity against Rhizoctonia solani. The six that had the greatest pathogen inhibitory capacities were subsequently tested for their in vivo biocontrol potential on R. solani damping-off in sterilized and non-sterilized soils, and for their plant growth promoting activities on tomato seedlings. In both soils, coating tomato seeds with antagonistic isolates significantly reduced (P<0.05) the severity of damping-off of tomato seedlings. Among the isolates tested, the strains CA-2 and AA-2 exhibited the same disease incidence reduction as thioperoxydicarbonic diamide, tetramethylthiram (TMTD) and no significant differences (P<0.05) were observed. Furthermore, they resulted in a significant increase in the seedling fresh weight, the seedling length and the root length of the seed-treated seedlings compared to the control. The taxonomic position based on 16S rDNA sequence analysis and phylogenetic studies indicated that the strains CA-2 and AA 2 were related to Streptomyces mutabilis NBRC 12800(T) (100% of similarity) and Streptomyces cyaneofuscatus JCM 4364(T) (100% of similarity), respectively. PMID- 23920230 TI - Synergistic interaction of Rhizobium leguminosarum bv. viciae and arbuscular mycorrhizal fungi as a plant growth promoting biofertilizers for faba bean (Vicia faba L.) in alkaline soil. AB - Egyptian soils are generally characterized by slightly alkaline to alkaline pH values (7.5-8.7) which are mainly due to its dry environment. In arid and semi arid regions, salts are less concentrated and sodium dominates in carbonate and bicarbonate forms, which enhance the formation of alkaline soils. Alkaline soils have fertility problems due to poor physical properties which adversely affect the growth and the yield of crops. Therefore, this study was devoted to investigating the synergistic interaction of Rhizobium and arbuscular mycorrhizal fungi for improving growth of faba bean grown in alkaline soil. A total of 20 rhizobial isolates and 4 species of arbuscular mycorrhizal fungi (AMF) were isolated. The rhizobial isolates were investigated for their ability to grow under alkaline stress. Out of 20 isolates 3 isolates were selected as tolerant isolates. These 3 rhizobial isolates were identified on the bases of the sequences of the gene encoding 16S rRNA and designated as Rhizobium sp. Egypt 16 (HM622137), Rhizobium sp. Egypt 27 (HM622138) and Rhizobium leguminosarum bv. viciae STDF-Egypt 19 (HM587713). The best alkaline tolerant was R. leguminosarum bv. viciae STDF-Egypt 19 (HM587713). The effect of R. leguminosarum bv. viciae STDF-Egypt 19 and mixture of AMF (Acaulospora laevis, Glomus geosporum, Glomus mosseae and Scutellospora armeniaca) both individually and in combination on nodulation, nitrogen fixation and growth of Vicia faba under alkalinity stress were assessed. A significant increase over control in number and mass of nodules, nitrogenase activity, leghaemoglobin content of nodule, mycorrhizal colonization, dry mass of root and shoot was recorded in dual inoculated plants than plants with individual inoculation. The enhancement of nitrogen fixation of faba bean could be attributed to AMF facilitating the mobilization of certain elements such as P, Fe, K and other minerals that involve in synthesis of nitrogenase and leghaemoglobin. Thus it is clear that the dual inoculation with Rhizobium and AMF biofertilizer is more effective for promoting growth of faba bean grown in alkaline soils than the individual treatment, reflecting the existence of synergistic relationships among the inoculants. PMID- 23920231 TI - Human enterovirus in the gastrocnemius of patients with peripheral arterial disease. AB - BACKGROUND: Peripheral arterial disease (PAD) is characterized by myofiber degeneration and loss of function in muscles of the lower limbs. Human enterovirus (HEV) infection has been implicated in the pathogenesis of a number of muscle diseases. However, its association with PAD has not been studied. In this study, we tested the hypothesis that infectious HEV is present in skeletal muscle of patients with PAD and is associated with severity of disease. METHODS AND RESULTS: Gastrocnemius biopsies from 37 patients with PAD and 14 controls were examined for the presence of HEV RNA, viral capsid protein, viral RNA copy number, and viral infectivity. HEV RNA was detected in 54% of the biopsies from patients with PAD but was not detected in muscle biopsies from control patients. This difference in prevalence among PAD and control patients was significant at P<0.001. Viral RNA copy numbers were increased significantly at the later stages of disease; Fontaine Stage IV (10(5.50) copies/mg muscle wet weight, at P<0.005) and Stage III (10(4.87) copies/mg, at P<0.010) compared to Stage II (10(2.50) copies/mg). Viral replication was confirmed by the presence of the negative strand of viral RNA in all specimens positive for HEV RNA. Cultures of HeLa and human skeletal muscle cells treated with muscle homogenates showed HEV replication and the presence of HEV capsid protein. CONCLUSION: Our data identified infectious HEV in the gastrocnemius of PAD patients but not in controls. Viral copy number and prevalence of infection were higher in the later stages of disease. Our data point to the need for further studies to determine the contribution of HEV infection to the pathophysiology of PAD. PMID- 23920233 TI - [Multidisciplinary practice guideline 'Invasive treatment of spine related low back pain']. AB - The practice guideline 'Invasive treatment of spine related low back pain' describes the state of the art regarding the diagnosis and value of invasive treatment after failure of conservative treatment in patients with pain symptoms of facet joint pain, pain in the sacroiliac joint, coccygodynia, discogenic pain and the 'failed back surgery syndrome'. There is no consensus on definitions and a classification system for chronic low back pain symptoms. The classification in specific and nonspecific low back pain provides insufficient insight and is unable to show which therapy is effective for which disorder. The guideline working group advises a new classification system for chronic low back pain in degenerative and non-degenerative disorders. After failure of conservative treatment, several specific invasive treatments are recommended; some of these treatments should only be performed in study related settings. Some of the treatments that are currently used in daily practice are inadvisable. PMID- 23920232 TI - Variation in the use of 12-lead electrocardiography for patients with chest pain by emergency medical services in North Carolina. AB - BACKGROUND: Prehospital 12-lead electrocardiography (ECG) is critical to timely STEMI care although its use remains inconsistent. Previous studies to identify reasons for failure to obtain a prehospital ECG have generally only focused on individual emergency medical service (EMS) systems in urban areas. Our study objective was to identify patient, geographic, and EMS agency-related factors associated with failure to perform a prehospital ECG across a statewide geography. METHODS AND RESULTS: We analyzed data from the Prehospital Medical Information System (PreMIS) in North Carolina from January 2008 to November 2010 for patients >30 years of age who used EMS and had a prehospital chief complaint of chest pain. Among 3.1 million EMS encounters, 134 350 patients met study criteria. From 2008-2010, 82 311 (61%) persons with chest pain received a prehospital ECG; utilization increased from 55% in 2008 to 65% in 2010 (trend P<0.001). Utilization by health referral region ranged from 22.9% to 74.2% and was lowest in rural areas. Men were more likely than women to have an ECG performed (63.0% vs 61.3%, adjusted RR 1.02, 95% CI 1.01 to 1.04). The certification-level of the EMS provider (paramedic vsbasic/intermediate) and system-level ECG equipment availability were the strongest predictors of ECG utilization. Persons in an ambulance with a certified paramedic were significantly more likely to receive a prehospital ECG than nonparamedics (RR 2.15, 95% CI 1.55, 2.99). CONCLUSIONS: Across a large geographic area prehospital ECG use increased significantly, although important quality improvement opportunities remain. Increasing ECG availability and improving EMS certification and training levels are needed to improve overall care and reduce rural-urban treatment differences. PMID- 23920234 TI - [The 'healing environment' and the fate of autonomous art in hospitals]. AB - Attention to the role of art within healthcare is on the rise. Dutch hospitals are increasingly embracing the concept of the 'healing environment', which aims to create agreeable hospital surroundings for the well-being of employees and patients. The concept is being interpreted in diverse ways; irrespective of the specific outcome of this interpretation, the healing environment does have consequences for the healthcare facilities' policies related to art. Research at a few Dutch hospitals has revealed that the more stringently the guidelines on the healing environment are followed, the more emphasis is placed on the medical functional approach to art and the lesser attention is paid to the intrinsic value of art. Hospitals that reject the concept of the healing environment, however, also clearly demonstrate defining art in terms of making the surroundings agreeable to the patient. The healing environment therefore cannot serve as a new legitimation of autonomous artworks in existing hospital collections, but it is congruent with the recent attention given to the societal role of art. PMID- 23920235 TI - [A woman with a large mass in the breast]. AB - A 45-year-old woman presented with a palpable mass in the right breast. Ultrasound and mammography showed a cystic mass measuring 5 cm, with a solid component. The diagnosis 'intraductal papilloma' was made, based on the histological findings after biopsy. We performed lumpectomy and the diagnosis was confirmed by immunohistochemistry. Six months later, there were no signs of recurrence. PMID- 23920236 TI - [The safety culture and the quality of care: obscured by self-report]. AB - Recently, Smits M et al. investigated whether the relationship between certain medical specialties and patient safety is mediated by a 'safety culture', based on culture surveys conducted on wards in 20 Dutch hospitals (internal medicine, surgery, emergency medicine) and 1885 self-reported 'unintended' events (Journal of Clinical Nursing, 21, 3392-401). Based on the results, the authors conclude that medical specialties do not differ in 'performance' because of their safety cultures and that safety culture is not a key factor affecting patient safety. We counter that bias exists because the variables of safety culture as well as the events reported were based on self-report, mainly by nurses. Many events were minor process deviations (medication expired, delay in lab results) rather than adverse events and unlikely to be affected by a safety culture. Knowledge of a possible relationship between a particular medical specialty and adverse outcomes is important, but would also be a generalization that denies the differences in outcome between similar departments at different hospitals. PMID- 23920237 TI - [Discharge from hospital: left in limbo]. AB - An article pertaining to a large European qualitative study into the discharge of patients from hospital was published in the Dutch Journal of Medicine (Nederlands Tijdschrift voor Geneeskunde). Earlier qualitative and quantitative research in the Netherlands had resulted in the same findings: patients wish to receive more information upon discharge. Improvements have been realised, but not at every hospital or department. There is considerable variation as to how much information is desired by individual patients. Healthcare providers should take these differences into account and provide personalised information. For some patients, too much information increases their anxiety. We agree with the recommendations of the authors of the article. It is very important that nurses and doctors communicate with patients who are to be discharged. The elderly and patients who live alone need extra attention. GPs and specialists should discuss amongst themselves how to best compose a format for the specialist's report, including what type of information the GPs need to inform their patients adequately. As performance indicators, the telephone accessibility of GPs and the time it takes to receive the specialist's report could be considered as options. PMID- 23920238 TI - [New practice guideline for spine related low back pain; anesthesiologists use a different classification system than general practitioners]. AB - The practice guideline 'Invasive treatment of spine related low back pain' was recently released by the Netherlands Society of Anesthesiologists. This guideline evaluates the state of the art regarding the diagnosis and value of invasive treatment for facet joint pain, pain in the sacroiliac joint, coccygodynia, discogenic pain and the 'failed back surgery syndrome'. A new classification system for chronic low back pain was also proposed. The guideline was created in a methodologically sound manner, but the results are disappointing: the evaluated diagnoses remain disputable and the recommendations for the evaluated treatments are mostly based on expert opinion. The guideline lacks information on the scientific basis of the proposed new classification system, which makes its clinical usefulness questionable. PMID- 23920239 TI - [Does the DSM-5 have added value?]. AB - The DSM-5 was published in May of 2013. Important changes have resulted in greater harmony with the ICD and the discontinuation of the multi-axial system. Some people have criticised changes to the DSM-5 compared to the DSM-IV, arguing that it might lead to the overdiagnosis of mental disorders. One critic, Allen Frances, mentioned Binge Eating Disorder (BED) as an example; however, many studies indicate that BED is a reliable and valid diagnosis. Several arguments have been provided in support of the DSM-5 being a true improvement compared to its predecessor, the DSM-IV: the emphasis on empirical research data, the inclusion of a dimensional approach and more attention paid to a cross-cultural perspective. PMID- 23920240 TI - System of planning and evaluation of school meals. AB - OBJECTIVE: To develop a software to plan and evaluate school meals according to the main national and international standards for foods and nutrition. DESIGN: Development of software. SETTING: Public schools, Portugal. SUBJECTS: School meals for students. RESULTS: The System of Planning and Evaluation of School Meals (SPARE) is a software that allows the planning of school meals in an effective and organized way, according to the main national and international standards for food and nutrition. The regular use of this tool enables the evaluation, monitoring and verification towards continuous improvement of the quality of school meals. CONCLUSIONS: The SPARE software aims to promote healthy eating by focusing on the planning and production of safe and adequate meals in the school environment. This software can be adapted to different age groups and to different contexts, attending to specific nutritional and food standards. PMID- 23920241 TI - Caffeine and modafinil promote adult neuronal cell proliferation during 48 h of total sleep deprivation in rat dentate gyrus. AB - It has been established that sleep deprivation (SD) reduces the proliferation of neuronal precursors in the adult hippocampus. It has also been reported that psychostimulant drugs modulate adult neurogenesis. We examined the modulatory role of two psychostimulant drugs modafinil and caffeine on adult neuronal cell proliferation (NCP) during 48 h of total SD. A novel automated cage shaking stimulus was used to induce SD based on animal activity. 5-Bromo-2"-deoxyuridine (BrdU; 50mg/kg/day i.p.) was injected at the onset of the light phase for two days. Rats were successfully sleep deprived for 85-94% of total time. Stereological analysis showed that both caffeine and modafinil treatments during SD improved the number of BrdU positive cells as compared to the SD group. Caffeine treatment during SD, significantly increased early proliferative and post-mitotic stages of doublecortin (DCX) positive cells while modafinil treatment during SD, increased intermediate and post-mitotic stages of DCX positive cells compared to SD+Vehicle group. Brain-Derived Neurotrophic Factor (BDNF) expression on BrdU positive cells as well as in the dentate gyrus (DG) region was decreased significantly after sleep deprivation. Both caffeine and modafinil significantly improved BDNF expression in the DG region. Modafinil, but not caffeine, significantly decreased hippocampal adenosine level during SD in comparison to the SD+Vehicle group. It may be concluded that caffeine or modafinil treatment during 48 h of SD prevents the SD induced decline in neuronal proliferation and differentiation. Caffeine and modafinil induced alterations of NCP during SD may involve modulation of BDNF and adenosine levels. PMID- 23920242 TI - Novel angiotensin I-converting enzyme inhibitory peptides from enzymatic hydrolysates of goby (Zosterisessor ophiocephalus) muscle proteins. AB - In recent years, food protein-derived bioactive peptides have received considerable attention because of their numerous health benefits. Amongst bioactive peptides, those with antihypertensive activity are receiving special attention due to their role in cardiovascular diseases. Goby protein hydrolysates (GPHs) prepared by treatment with five different crude bacterial proteases were found to exhibit varying degrees of angiotensin I-converting enzyme (ACE) inhibitory activity. The hydrolysate generated by the crude protease from Bacillus mojavensis A21, which displayed the highest ACE inhibitory activity, was further fractionated by size exclusion chromatography on a Sephadex G-25 and reversed-phase high performance liquid chromatography (RP-HPLC). The molecular masses and amino acid sequences of five peptides, in sub-fraction F5-2, which exhibited the highest ACE inhibitory activity, were determined using ESI-MS and ESI-MS/MS, respectively. The structures of these peptides were identified as Ala Arg-Ser, Val-Val-Ala-Pro-Phe-Ala-His-Gly-Thr, Arg-Ser-Thr-Ala, Phe-Tyr-Pro-Pro, Arg-Cys-Ser-Ala-Gly-Val. Further, the sequences of fifteen peptides in the F5-4 sub-fraction, which exhibited high activity, were determined. Therefore, GPHs have a potential as hypotensive nutraceutical ingredients. BIOLOGICAL SIGNIFICANCE: Peptides find many outlets of application in the biotechnological field, amongst which are pharmaceutical applications. Progression amongst new small molecules deposited like substance medicamentous blows itself. In this context, large pharmaceutical companies invest in peptide research to open therapeutic new prospects. Even if they are used as therapeutic agents for nearly one century in their natural form, the use of peptides remains parsimonious although we experienced a significant development since a few tens of years, in particular thanks to the clarification of the methods of production, chemical in solid or biological phase such as in phage display. Peptides present many advantages compared to traditional drugs that have small molecules, Generation of bioactive peptides by proteolysis of food proteins, using exogenous proteases, is a new and interesting approach for the production and identification of new and potent specific hypotensive agents. From another side, compared with natural peptides isolated from different sources, there is more diversity in structure and mode of action of the derived bioactive peptides. In fact, proteolysis of protein substrates, having different amino acid composition and sequences, by proteases having different specificities may generate numerous specific peptide inhibitors, with different lengths and amino acid sequences. These bioactive peptides have received considerable attention for their effectiveness in both the prevention and the treatment of hypertension. PMID- 23920243 TI - Angiogenin induces modifications in the astrocyte secretome: relevance to amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting lower and upper motoneurons. Recent studies have shown that both motor neurons and non-neuronal neighbouring cells such as astrocytes and microglia contribute to disease pathology. Loss-of-function mutations in the angiogenin (ANG) gene have been identified in ALS patients. Angiogenin is enriched in motor neurons and exerts neuroprotective effects in vitro and in vivo. We have recently shown that motoneurons secrete angiogenin, and that secreted angiogenin is exclusively taken up by astrocytes, suggesting a paracrine mechanism of neuroprotection. To gain insights into astrocyte effectors of angiogenin-induced neuroprotection, we examined alterations in the astrocyte secretome induced by angiogenin treatment using quantitative proteomics based on Stable Isotope Labelling by Amino Acids in Cell Culture (SILAC). We identified 2128 proteins in conditioned media from primary cultured mouse astrocytes, including 1247 putative secreted proteins. Of these, 60 proteins showed significant regulation of secretion in response to angiogenin stimulation. Regulated proteins include chemokines and cytokines, proteases and protease inhibitors as well as proteins involved in reorganising the extracellular matrix. In conclusion, this proteomic analysis increases our knowledge of the astrocyte secretome and reveals potential molecular substrates underlying the paracrine, neuroprotective effects of angiogenin. BIOLOGICAL SIGNIFICANCE: This study provides the most extensive list of astrocyte-secreted proteins available and reveals novel potential molecular substrates of astrocyte-neuron communication. It also identifies a set of astrocyte-derived proteins that might slow down ALS disease progression. It should be relevant to a large readership of neuroscientists and clinicians, in particular those with an interest in the physiological and pathological roles of astrocytes and in the molecular and cellular mechanisms underlying neurodegenerative disorders. PMID- 23920244 TI - A profile of residents in prairie nursing homes. AB - Nursing homes have become complex care environments where residents have significant needs and most have age-related dementia. Building on research by Hirdes et al. (2011), we describe a resident profile in a representative sample of 30 urban nursing homes in the prairie provinces using Resident Assessment Instrument - Minimum Data Set 2.0 data from 5,196 resident assessments completed between 1 October 2007 and 31 December 2011. Residents were chiefly over age 85, female, and with an age-related dementia. We compared facility support and related services and resident characteristics by province, owner-operator model, and number of facility units. We observed differences in support and related services by both unit count and province. We also found that public facilities tend to care for residents with more demanding characteristics: notably cognitive impairment, aggressive behaviours, and incontinence. No clear trends associating the number of units in a facility with resident characteristics were observed. PMID- 23920245 TI - An optically stimulated luminescence dosimeter for measuring patient exposure from imaging guidance procedures. AB - There is a growing interest in patient exposure resulting from an x-ray imaging procedure used in image-guided radiation therapy. This study explores a feasibility to use a commercially available optically stimulated luminescence (OSL) dosimeter, nanoDot, for estimating imaging radiation exposure to patients. The kilovoltage x-ray sources used for kV-cone-beam CT (CBCT) imaging acquisition procedures were from a Varian on-board imager (OBI) image system. An ionization chamber was used to determine the energy response of nanoDot dosimeters. The chamber calibration factors for x-ray beam quality specified by half-value layer were obtained from an Accredited Dosimetry Calibration Laboratory. The Monte Carlo calculated dose distributions were used to validate the dose distributions measured by using the nanoDot dosimeters in phantom and in vivo. The range of the energy correction factors for the nanoDot as a function of photon energy and bow tie filters was found to be 0.88-1.13 for different kVp and bow-tie filters. Measurement uncertainties of nanoDot were approximately 2-4% after applying the energy correction factors. The tests of nanoDot placed on a RANDO phantom and on patient's skin showed consistent results. The nanoDot is suitable dosimeter for in vivo dosimetry due to its small size and manageable energy dependence. The dosimeter placed on a patient's skin has potential to serve as an experimental method to monitor and to estimate patient exposure resulting from a kilovoltage x ray imaging procedure. Due to its large variation in energy response, nanoDot is not suitable to measure radiation doses resulting from mixed beams of megavoltage therapeutic and kilovoltage imaging radiations. PMID- 23920246 TI - Design and synthesis of novel 2'-hydroxy group substituted 2-pyridone derivatives as anticancer agents. AB - We have synthesized a series of novel 2-pyridone derivatives with 1,2,3-triazole and evaluated their anti-tumor activities in vitro. The bioassays showed that the majority of the resultant compounds exerted inhibitory effects on six human cancer cell lines to various extents. In particular, compound 10k showed the best anti-tumor activities (IC50 values of A549, HeLa and SW480 cancer cell lines were 0.86 +/- 0.17 MUM, 0.54 +/- 0.23 MUM and 0.21 +/- 0.13 MUM, respectively). PMID- 23920247 TI - Fuzi-Lizhong pill compensates hypothyroid-hypothermia via ghrelin release. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi-Lizhong pill (FLZ) is a traditional Chinese medicine for treating patients with Spleen Yang deficient syndrome. Ghrelin, a peptide with 28 amino acid residues, plays multiple roles in thermogenesis. This study aims to explore FLZ regulating ghrelin to compensate hypothermia in rats with hypothyroid and indigestion. MATERIALS AND METHODS: In litter-matched rats, hypothermia was developed with both thyroidectomy at d1 and interscapular brown adipose (IBA) removal at d42, indigestion was induced with both high fat diet and fasting-feeding cycle from d56; the littermates with hypothermia and indigestion were administrated with FLZ from d70. Adaptive thermogenesis, thyroid hormones, metabolites, ghrelin dynamics were measured at d98. RESULTS: The results showed that plasma ghrelin levels were inversely correlated with the gastric ghrelin levels and adaptive thermogenesis in rats undergone both thyroidectomy and IBA removal. Fatty diet and FLZ enhanced the increase of plasma ghrelin of hypothyroid rats. These were supported by the changes of plasma thyroid related hormones, plasma metabolites, gastric ghrelin mRNA and protein, and the effects of fatty diet or FLZ. CONCLUSIONS: Our results suggest that more ghrelin release compensate chronic hypothermia in rats with both hypothyroidism and indigestion. It could explain the mechanisms of FLZ in relieving chronic hypothermia. PMID- 23920248 TI - Acute and sub-chronic toxicity of HPLC fingerprinted extract of Conyza sumatrensis (Retz.) E.H. Walker in rodents. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Conyza sumatrensis (CS) is an extensively used medicinal herb in the tropics for varied ailments related to pain, inflammation and malaria. Though in constant folkloric use, scientific validations are proving valuable. AIM OF THE STUDY: Evaluate the safety profile of methanol extract from CS in mice and rats through acute and sub-chronic toxicity studies respectively. MATERIAL AND METHODS: Acute toxicity study involved the single oral administration of CS at 1000, 2000 and 3000mg/kg in mice, while the sub chronic toxicity was carried upon in rats at doses 250, 500 and 1000mg/kg/day for 28 days. Besides body weight, general behaviour and mortality, serum biochemical parameters and liver histology were assessed after 7 and 28 days for acute and sub-chronic study respectively. The parameters were again checked on days 14 and 56 in order to assess the recovery from damage, if any. HPLC fingerprinting of the aqueous and methanol extract was performed through C18 column using water: acetonitrile as mobile phase with observations at 240nm. RESULTS: In the acute toxicity test, single oral dose of 1000, 2000 and 3000mg/kg of CS did not result in any behavioural changes or mortality, indicating non toxicity. In sub-chronic toxicity studies in rats, no mortality was observed at 250, 500 and 1000mg/kg/day when administered orally for a period of 28 days. Except Serum Glutamate Pyruvate Transaminase (SGPT) level in acute study and Alkaline Phosphatase (ALP), SGPT and Serum Glutamate Oxaloacetate Transaminase (SGOT) level in sub-chronic study, all the observational, haematological and biochemical parameters studied showed non significant changes. Histological examination of liver did not reveal any treatment-related effects in any of the studies. Moreover, haematological and biochemical changes orchestrated by CS got normalised after 14 and 56 days post treatment in acute and sub-chronic toxicity respectively. The HPLC fingerprint could resolve 11 and 28 peaks from aqueous and methanol extracts respectively. CONCLUSION: The experiments indicate the methanol extract to be safe even at high and repeated doses in pre-clinical studies even though the constituents are more than in aqueous extract. PMID- 23920249 TI - Pulmonary effects and disposition of luteolin and Artemisia afra extracts in isolated perfused lungs. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia afra (Asteraceae) is a traditional medicinal plant frequently used in steam inhalation form to treat respiratory conditions. AIM OF THE STUDY: Quantify luteolin content in Artemisia afra dried crude and aqueous extract. Evaluate the pulmonary effects of Artemisia afra steam inhalation, nebulized Artemisia afra extract and luteolin in isolated perfused lungs (IPL). Evaluate the pulmonary disposition of intravenously administered luteolin. MATERIALS AND METHODS: HPLC was used to quantify luteolin in Artemisia afra extracts. A modified version of the IPL was used to determine the effects of Artemisia afra steam inhalation, nebulized luteolin, and nebulized aqueous leaf extract on lung function, as well as the pulmonary disposition of IV luteolin. RESULTS: Artemisia afra extract contained significantly higher luteolin levels than the crude dried leaves. Inhaled Artemisia afra steam, and nebulized luteolin, and Artemisia afra extract and IV luteolin produced significant dose dependent improvements in lung function, with nebulized Artemisia afra producing the greatest improvements. Nebulisation with Artemisia afra extract yielded higher quantities of luteolin than luteolin nebulisation. CONCLUSION: Results verify the traditional use of inhalation of Artemisia afra steam, although nebulized luteolin and aqueous extract are better alternatives. Luteolin significantly contributes to the bronchodilatory effects of Artemisia afra. PMID- 23920250 TI - Ethnobotanical survey of medicinal plants used in the treatment of malaria in Ogbomoso, Southwest Nigeria. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Malaria infection is the second largest killer disease after HIV in Nigeria. Failure of the orthodox medications due to drug adulteration, high cost of procurement of antimalarial drugs and inconvenience experienced in the use of high dosage of the new antimalarial drug combination therapy has turned the attention of the people in the world towards the use of local herbs. MATERIALS AND METHODS: An ethnobotanical survey of medicinal plants used by the indigenous people of Ogbomoso for the treatment of malaria infection was conducted. Investigations were carried out on the names of plants, their parts (leaf, stem or root) used, method of preparing herbal antimalarial remedies, likely side effect and how it is administered were recorded through the use of a structured questionnaire. RESULTS: The results of the survey revealed that 40 plant species from 32 plant families were mostly used for treating malaria infection in Ogbomoso. Twenty-three different antimalarial recipes were mentioned in the survey. The Asteraceae and Anacardinceae were the most represented plant families followed by Malvaceae, Solanaceae, Annonaceae, Poaceae, Rutaceae and Meliaceae. The leaf and the stem bark have been the most frequently used plant parts while concoction and decoction were the most common method of preparation. Treatment regimens of malaria generally included drinking, bathing and steam inhalation of the aqueous herbal preparations for 5-7 days or until symptoms of malaria disappear. About 53% of the plants mentioned in the survey had side effect. CONCLUSIONS: Hence, the need for documentation of these plants for further investigation becomes necessary. PMID- 23920251 TI - Gastroprotective effects of the essential oil of Hyptis crenata Pohl ex Benth. on gastric ulcer models. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hyptis crenata Pohl ex Benth (Lamiaceae), popularly known as "hortela-brava" or "hortela do campo", is widely distributed in the northeast of Brazil. In Brazil, the leaves of this plant have been used in traditional medicine for the treatment of gastrointestinal disturbances, including gastric ulcers. In an attempt to experimentally validate this claimed antiulcerogenic activity, the gastroprotective effects of the essential oil extracted from the leaves of the Hyptis crenata Pohl ex Benth (EOHc) were evaluated in recognized gastric ulcer models in mice. MATERIALS AND METHODS: EOHc was obtained by hydrodistillation and analyzed using gas chromatography-mass spectrometry (GC-MS). Swiss male mice (25-30g) were used for the studies. The gastric ulcers were induced by oral administration of absolute ethanol or indomethacin 45min after oral pretreatment with EOHc, vehicle and positive control drugs. One hour after the ulcerative challenges, the stomachs were removed and the area of the lesions was measured. The volume, pH and total acidity of the gastric secretions were determined using the pylorus ligature model. The gastrointestinal motility was measured using gastric emptying and intestinal transit. The ethanol-induced gastric mucus depletion and lipid peroxidation were also analyzed. RESULTS: Our findings are as follows: A significant inhibition of gastric lesions induced by absolute ethanol was observed in the mice pre-treated with EOHc, at a dose of 30 and 100 and 300mg/kg (5.56+/-1.51, 2.88+/-0.82 and 1.71+/-0.54mm(2), respectively) compared to control group (118.03+/-35.4mm(2)). Also, EOHc (300mg/kg) produced a gastroprotective effect against the gastric lesions induced by indomethacin (16.07+/-4.68mm(2)) compared to control group (38.64+/-6.1mm(2)). EOHc pretreatment produced a reduction in the ethanol-induced lipid peroxidation from 3.9+/-0.22 to 2.4+/ 0.1MUmol/mg tissue (EOHc-300mg/kg and control group, respectively). We also observed that EOHc pretreatment decreased the gastric emptying, but did not alter the intestinal transit ratio, ethanol-induced depletion of the gastric wall mucus or secretion parameters (volume, pH and [H(+)]). CONCLUSION: Our data indicate that EOHc exerts a gastroprotective effect, indicated by its significant inhibition of gastric lesions in ethanol- and indomethacin-induced ulcer models, which may be associated with its accelerating effect on gastric emptying and reduction in oxidative damages. Our data suggest a potential therapeutic application for EOHc in the treatment of gastric ulcers. PMID- 23920252 TI - Guidance for methods descriptions used in preclinical imaging papers. AB - Preclinical molecular imaging is a rapidly growing field, where new imaging systems, methods, and biological findings are constantly being developed or discovered. Imaging systems and the associated software usually have multiple options for generating data, which is often overlooked but is essential when reporting the methods used to create and analyze data. Similarly, the ways in which animals are housed, handled, and treated to create physiologically based data must be well described in order that the findings be relevant, useful, and reproducible. There are frequently new developments for metabolic imaging methods. Thus, specific reporting requirements are difficult to establish; however, it remains essential to adequately report how the data have been collected, processed, and analyzed. To assist with future manuscript submissions, this article aims to provide guidelines of what details to report for several of the most common imaging modalities. Examples are provided in an attempt to give comprehensive, succinct descriptions of the essential items to report about the experimental process. PMID- 23920253 TI - Long acting beta2 agonists in adult asthma. PMID- 23920254 TI - Clinical review. Frontotemporal dementia. PMID- 23920255 TI - Article is a call to arms to defend the NHS. PMID- 23920256 TI - Formation of the "Multinational Health Service" is to blame for financial crisis in the NHS. PMID- 23920257 TI - Chief quality officers should be drawn from chartered quality professionals. PMID- 23920258 TI - Preventive care programmes keep people active and independent for longer. PMID- 23920259 TI - NICE on rehabilitation. New guidelines on rehabilitation likely to restrict practices and stifle innovation. PMID- 23920260 TI - Circle Health's sums do not add up after all. PMID- 23920261 TI - First reliable data suggest a possible increase in suicides in Greece. PMID- 23920262 TI - Unemployment and suicides during the recession in Italy. PMID- 23920263 TI - Healthcare should be excluded from EU free trade negotiations with United States and India. PMID- 23920264 TI - One third of US women travel more than 25 miles for an abortion. PMID- 23920265 TI - Flip flop policy over pioglitazone licence causes media storm in India. PMID- 23920266 TI - Streamlined stroke services in London save lives and money, study finds. PMID- 23920268 TI - Successful treatment of refractory anti-signal recognition particle myopathy using abatacept. PMID- 23920269 TI - Education level is associated with mortality in male patients undergoing maintenance hemodialysis. AB - BACKGROUND: Studies of the correlation between education levels and mortality in hemodialysis (HD) patients are rare. The aim of this multi-center study was to investigate the relationship between education levels and 3-year mortality rates in HD patients. METHODS: A total of 935 HD patients from 3 HD centers participated in this 3-year prospective observational study. Education levels were categorized as either less than senior high school and above or equal to senior high school. The causes of death and mortality rates were also analyzed for each subgroup. RESULTS: At the end of the 3-year follow-up period, 164 patients had died. In the male group, forward stepwise Cox regression analysis revealed that age, HD duration, hypertension, creatinine level, serum albumin level >=3.6 g/dl, anuria, Kt/Vurea, and high education level were significant predictive factors for 3-year mortality rates. CONCLUSION: This prospective observational study demonstrated that education level was associated with mortality in men undergoing HD. PMID- 23920270 TI - Vitamin D therapy and related metabolomics: is the calciferol dose and form the only requirements for successful clinical therapeutics? AB - A nutraceutical that has exploded onto the prescription pad in recent years is the fat soluble vitamin, vitamin D. This is due to an increasing medical interest in the utility of the vitamin in the treatment and prevention of an array of diseases and ailments. Despite the continued debate over the correct dose, form and serum levels, many clinicians fail to achieve intended therapeutic responses with their patients and deficiencies still exist. This may be due to medical professionals being less aware of the multitude of factors that can influence treatment when dosing a product. In this paper we explore the magnitude of interactions that exist between the host physiology and the vitamin and cite such points as a reason for confounding treatment end points. Aspects that are proposed to influence treatment success more critically than dose and molecular form prescribed are: organ pathology, intracellular states, the endocrine system, concomitant products, genetics, lifestyle, quality of product, and modern delivery systems. PMID- 23920271 TI - Does the treatment of normal pressure hydrocephalus put the retinal ganglion cells at risk? A brief literature review and novel hypothesis. AB - Normal pressure hydrocephalus (NPH) is a poorly understood entity as well as a source of continuous controversy in the neuroscientific community. The surgical management of this disease requires that intracranial pressure (ICP), also referred to as the cerebrospinal fluid pressure (CSFP), be lowered using a cerebrospinal fluid (CSF) diversion procedure. Numerous complications are linked with this procedure; we believe that new evidence suggests that the induction or acceleration of glaucomatous optic neuropathy are possible sequelae that warrant further investigation. We also suggest potential solutions derived from the increased understanding of the disease's pathophysiology and new advances in imaging of the optic nerve head complex. The recent inclusion of the translaminar gradient (TLG) (the difference between the intraocular pressure (IOP) and the ICP/CSFP across the thickness of the lamina cribrosa in the optic nerve head complex) in the pathogenesis of normal tension glaucoma (NTG) suggests that the disease may be a complication encountered during the treatment of NPH with CSF diversion procedures. The significant decrease in CSFP required to treat NPH increases this gradient. In addition, there have been recent observations of an increased prevalence of NTG, as well as other forms of glaucoma, among patients with NPH, thought to be due to inherently fragile neurons in these patients. This new data suggest that patients who undergo ICP lowering therapy for their NPH may be at a higher risk of developing or accelerating already present NTG. We present the clinical and theoretical basis for our hypothesis after reviewing the relevant literature linking the two entities. We also propose a possible solution, as we believe that treatment guidelines for NPH should take the TLG into account. Indeed, recent advances in the imaging of the optic nerve head complex may provide an opportunity to detect the mechanical sequelae of an increased TLG in the preclinical stage, i.e., prior to optic nerve damage. If we are able to determine safe parameters for the TLG in this population, we may be able to recommend the initiation of prophylactic glaucoma therapy for selected patients. PMID- 23920272 TI - alpha-Synuclein is a pathological link and therapeutic target for Parkinson's disease and traumatic brain injury. AB - Parkinson's disease (PD) affects more than 1% of population over 65 and it is characterized by gradual loss of nigrostriatal dopaminergic neurons and wide spread accumulation of alpha-synuclein. Collectively 30% of familial and 3-5% of sporadic form of PD are associated with genetic mutation. Compelling evidence implicates that in addition to inherited factors, acquired co-morbidities contribute to PD pathology. Here, we hypothesize that traumatic brain injury (TBI) exacerbates nigrostriatal dopaminergic degeneration by modulating PD associated genes including alpha-synuclein, DJ-1, LRRK2, among others. Thus this article will present speculative arguments of a genetic component contributing to this TBI and PD pathological overlap. PMID- 23920273 TI - An alternative explanation for the occurrence of short circuit current increases in the small intestine following challenge by bacterial enterotoxins. AB - Secretory diarrhoeal disease due to enterotoxins is thought to arise from the enhancement to pathologically high rates of normally occurring chloride ion and therefore fluid secretion from enterocytes. In support of this concept, many enterotoxins increase intestinal short-circuit current, regarded now as faithfully reflecting the increased chloride ion secretion. Contradicting this assumption, STa reduces absorption but does not cause secretion in vivo although short-circuit current is increased in vitro. There is therefore a mismatch between an assumed enterocyte mediated secretory event that should but does not cause net fluid secretion and an undoubtedly increased short-circuit current. It is proposed here that short-circuit current increases are not themselves secretory events but result from interrupted fluid absorption. A noteworthy feature of compounds that inhibit the increase in short-circuit current is that the majority are vasoactive, neuroactive or both. In general, vasodilator substances increase current. An alternative hypothesis for the origin of short circuit current increases is that these result from reflex induction of electrogenic fluid absorption. This reflex enhances a compensatory response that is also present at a cellular level. An intestinal reflex is therefore proposed by which decreases in interstitial and intravascular volume or pressure within the intestine initiate an electrogenic fluid absorption mechanism that compensates for the loss of electrically neutral fluid absorption. This hypothesis would explain the apparently complex pharmacology of short-circuit current increases since many depressor substances have receptors in common with enterocytes and enteric nerves. The proposed alternative view of the origin of short-circuit current increases assumes that these do not represent chloride secretion from the enterocytes. This view may therefore aid the successful development of anti-diarrhoeal drugs to overcome a major cause of infant mortality worldwide, if short-circuit current data are being persistently misinterpreted. The putative but testable link between interstitial volume or pressure and fluid absorption also provides support for the alternative view of secretion; namely, that enhanced capillary and epithelial cell tight junctional permeability together with increased intracapillary pressure may cause secretion and not chloride exit from the enterocytes. PMID- 23920274 TI - Sunitinib and SU11652 inhibit acid sphingomyelinase, destabilize lysosomes, and inhibit multidrug resistance. AB - Defective apoptosis signaling and multidrug resistance are major barriers for successful cancer treatment. To identify drugs capable of targeting treatment resistant cancer cells, we screened small-molecule kinase inhibitor libraries for compounds that decrease the viability of apoptosis-resistant human MCF7-Bcl-2 breast cancer cells. SU11652, a multitargeting receptor tyrosine kinase inhibitor, emerged as the most potent compound in the screen. In addition to MCF7 Bcl-2 cells, it effectively killed HeLa cervix carcinoma, U-2-OS osteosarcoma, Du145 prostate carcinoma, and WEHI-S fibrosarcoma cells at low micromolar concentration. SU11652 accumulated rapidly in lysosomes and disturbed their pH regulation and ultrastructure, eventually leading to the leakage of lysosomal proteases into the cytosol. Lysosomal destabilization was preceded by an early inhibition of acid sphingomyelinase, a lysosomal lipase that promotes lysosomal membrane stability. Accordingly, Hsp70, which supports cancer cell survival by increasing lysosomal acid sphingomyelinase activity, conferred partial protection against SU11652-induced cytotoxicity. Remarkably, SU11652 killed multidrug resistant Du145 prostate cancer cells as effectively as the drug-sensitive parental cells, and subtoxic concentrations of SU11652 effectively inhibited multidrug-resistant phenotype in Du145 prostate cancer cells. Notably, sunitinib, a structurally almost identical and widely used antiangiogenic cancer drug, exhibited similar lysosome-dependent cytotoxic activity, albeit with significantly lower efficacy. The significantly stronger lysosome-targeting activity of SU11652 suggests that it may display better efficacy in cancer treatment than sunitinib, encouraging further evaluation of its anticancer activity in vivo. Furthermore, our data provide a rationale for novel approaches to target drug-resistant cancers by combining classic chemotherapy with sunitinib or SU11652. PMID- 23920275 TI - Cetuximab reverses the Warburg effect by inhibiting HIF-1-regulated LDH-A. AB - Hypoxia-inducible factor-1 (HIF-1) plays a critical role in reprogramming cancer metabolism toward aerobic glycolysis (i.e., the Warburg effect), which is critical to supplying cancer cells with the biomass needed for proliferation. Previous studies have shown that cetuximab, an EGF receptor-blocking monoclonal antibody, downregulates the alpha subunit of HIF-1 (HIF-1alpha) through the inhibition of EGF receptor downstream cell signaling and that downregulation of HIF-1alpha is required for cetuximab-induced antiproliferative effects. However, the mechanism underlying these actions has yet to be identified. In this study, we used the Seahorse XF96 extracellular flux analyzer to assess the effect of cetuximab treatment on changes in glycolysis and mitochondrial respiration, the two major energy-producing pathways, in live cells. We found that cetuximab downregulated lactate dehydrogenase A (LDH-A) and inhibited glycolysis in cetuximab-sensitive head and neck squamous cell carcinoma (HNSCC) cells in an HIF 1alpha downregulation-dependent manner. HNSCC cells with acquired cetuximab resistance expressed a high level of HIF-1alpha and were highly glycolytic. Overexpression of a HIF-1alpha mutant (HIF-1alpha/DeltaODD) conferred resistance to cetuximab-induced G1 phase cell-cycle arrest, which could be overcome by knockdown of LDH-A expression. Inhibition of LDH-A activity with oxamate enhanced the response of cetuximab-resistant cells to cetuximab. Cetuximab had no noticeable inhibitory effect on glycolysis in nontransformed cells. These findings provide novel mechanistic insights into cetuximab-induced cell-cycle arrest from the perspective of cancer metabolism and suggest novel strategies for enhancing cetuximab response. PMID- 23920276 TI - Alpha-tomatine synergises with paclitaxel to enhance apoptosis of androgen independent human prostate cancer PC-3 cells in vitro and in vivo. AB - Alpha (alpha)-tomatine, a major saponin found in tomato has been shown to inhibit the growth of androgen-independent prostate cancer PC-3 cells. The effects of alpha-tomatine in combination with the chemotherapeutic agent paclitaxel against PC-3 cells were investigated in the present study. Combined treatment with a sub toxic dose of alpha-tomatine and paclitaxel significantly decreased cell viability with concomitant increase in the percentage of apoptotic PC-3 cells. The combined treatment, however, had no cytotoxic effect on the non-neoplastic prostate RWPE-1 cells. Apoptosis of PC-3 cells was accompanied by the inhibition of PI3K/Akt pro-survival signaling, an increase in the expression of the pro apoptotic protein BAD but a decrease in the expressions of anti-apoptotic proteins, Bcl-2 and Bcl-xL. Results from a mouse xenograft model showed the combined treatment completely suppressed subcutaneous tumor growth without significant side effects. Consistent with its in vitro anti-cancer effects, tumor materials from mice showed increased apoptosis of tumor cells with reduced protein expression of activated PI3K/Akt. These results suggest that the synergistic anti-cancer effects of paclitaxel and alpha-tomatine may be beneficial for refractory prostate cancer treatment. PMID- 23920277 TI - Synergistic interactions between the antinociceptive effect of Rhodiola rosea extract and B vitamins in the mouse formalin test. AB - AIM: In this study, the pharmacological interactions between a Rhodiola rosea ethanol extract and B-vitamins such as thiamine (B1), riboflavine (B2), pyridoxine (B6), cyanocobalamin (B12) and a mixture of vitamins B1+B6+B12 was investigated in the mouse formalin test. METHODS: Individual dose response curves of the Rhodiola rosea ethanol extract, as well as B-vitamins alone or in a mixture were evaluated in mice in which nociception was induced with 2% formalin intraplantarly. The antinociceptive mechanisms of the Rhodiola rosea were investigated by exploring the role of the opioid and serotonin receptors and the nitric oxide pathway. Isobolographic analysis was used to evaluate the pharmacological interactions between the Rhodiola rosea ethanol extract and each B-vitamin individually or the mixture of vitamins B1+B6+B12 by using the ED30 and a fixed 1:1 ratio combination. RESULTS: Administration of the Rhodiola rosea extract alone or in combination with all of the vitamins produced a significant and dose-dependent antinociceptive response. The antinociceptive effect of the Rhodiola rosea extract (ED50=81 mg/kg, p.o.) was significant and reverted in the presence of antagonists of the 5-HT1A, GABA/BDZs and opioid receptors and by blocking mediators of the nitric oxide/cGMP/K(+) channels pathway. Isobolograms demonstrate that all of the combinations investigated in this study produced a synergistic interaction experimental ED30 values were significantly smaller than those calculated theoretically. CONCLUSIONS: These results provide evidence that a Rhodiola rosea ethanol extract in combination with B-vitamins produces a significant diminution in the nociceptive response in a synergistic manner, which is controlled by various mechanisms. These findings could aid in the design of clinical studies and suggest that these combinations could be applied for pain therapy. PMID- 23920278 TI - Effects of green tea extract and (-)-epigallocatechin-3-gallate on pharmacokinetics of nadolol in rats. AB - Green tea catechins have been shown to affect the activities of drug transporters in vitro, including P-glycoprotein and organic anion transporting polypeptides. However, it remains unclear whether catechins influence the in vivo disposition of substrate drugs for these transporters. In the present study, we investigated effects of green tea extract (GTE) and (-)-epigallocatechin-3-gallate (EGCG) on pharmacokinetics of a non-selective hydrophilic beta-blocker nadolol, which is reported to be a substrate for several drug transporters and is not metabolized by cytochrome P450 enzymes. Male Sprague-Dawley rats received GTE (400 mg/kg), EGCG (150 mg/kg) or saline (control) by oral gavage, 30 min before a single intragastric administration of 10 mg/kg nadolol. Plasma and urinary concentrations of nadolol were determined using high performance liquid chromatography. Pharmacokinetic parameters were estimated by a noncompartmental analysis. Pretreatment with GTE resulted in marked reductions in the maximum concentration (Cmax) and area under the time-plasma concentration curve (AUC) of nadolol by 85% and 74%, respectively, as compared with control. In addition, EGCG alone significantly reduced Cmax and AUC of nadolol. Amounts of nadolol excreted into the urine were decreased by pretreatments with GTE and EGCG, while the terminal half-life of nadolol was not different among groups. These results suggest that the coadministration with green tea catechins, particularly EGCG, causes a significant alteration in the pharmacokinetics of nadolol, possibly through the inhibition of its intestinal absorption mediated by uptake transporters. PMID- 23920279 TI - Evaluation of molecular chaperons Hsp72 and neuropeptide Y as characteristic markers of adaptogenic activity of plant extracts. AB - We have previously demonstrated that ADAPT-232, a fixed combination of adaptogenic substances derived from Eleutherococcus senticosus root extract, Schisandra chinensis berry extract, Rhodiola rosea root extract stimulated the expression and release of neuropeptide Y (NPY) and molecular chaperone Hsp72 from isolated human neurolgia cells. Both of these mediators of stress response are known to play an important role in regulation of neuroendocrine system and immune response. We further demonstrated that ADAPT-232 induced release of Hsp70 is mediated by NPY, suggesting an existence of NPY-mediated pathway of activation of Hsp72 release into the blood circulation system. The objective of this study was to determine whether this pathway is common for adaptogens and whether NPY and/or Hsp72 can be considered as necessary specific biomarkers for adaptogenic activity. The release of NPY and Hsp72 from neuroglia cells in response to treatment with various plant extracts (n=23) including selected validated adaptogens, partly validated adaptogens, claimed but negligibly validated adaptogens and some other plant extracts affecting neuroendocrine and immune systems but never considered as adaptogens was measured using high throughput ELISA techniques. We demonstrated that adaptogens, e.g. R. rosea, S. chinensis and E. senticosus stimulate both NPY and Hsp70 release from neuroblastoma cells, while tonics and stimulants have no significant effect on NPY in this in vitro test. In the groups of partly validated adaptogens the effect of Panax ginseng and Withania somnifera was not statistically significant both on NPY and Hsp70 release, while the activating effect of Bryonia alba and Rhaponticum cartamoides was significant only on Hsp70. In contrast, all tested non-adaptogens, such as antiinflammatoty plant extracts Matricaria recutita, Pelargonium sidoides, Hedera helix and Vitis vinifera significantly inhibit Hsp70 release and have no influence on NPY release from neuroblastoma cells. These experiments were further validated using primary human neurons and confirmed that adaptogens activate the release of both NPY and Hsp70, while tested non adaptogens were inactive in NPY assay and inhibit the release of Hsp70. Taken together, our data demonstrates for the first time that neuropeptide Y and heat shock protein Hsp70 can be used as molecular biomarkers for adaptogenic activity. PMID- 23920281 TI - A rare case of pediatric colloid cysts in bilateral ventricles. AB - Colloid cysts often arise in the third ventricle. It is quite rare for colloid cysts to arise from lateral ventricles. We describe a case of a patient with colloid cysts in the bilateral ventricles. The patient eventually underwent a surgical operation to alleviate the symptoms. Colloid cysts have the potential to be misdiagnosed in the clinical practice; therefore, magnetic resonance imaging and magnetic resonance spectroscopy would be effective for differential diagnosis. PMID- 23920280 TI - Hypnotic, anticonvulsant and anxiolytic effects of 1-nitro-2-phenylethane isolated from the essential oil of Dennettia tripetala in mice. AB - This study investigated the hypnotic, anti-convulsant and anxiolytic effects of 1 nitro-2-phenylethane (BPNE) obtained from the oil of Dennettia tripetala G. Baker (Annonaceae) and established its mechanism of action. The essential oil (EO) from the leaf, fruit and seed was obtained by hydrodistillation, followed by isolation of BPNE purified to 99.2% by accelerated gradient chromatography on silica, and identified by NMR and GC-MS. The pure BPNE and EO of the dried seed (93.6%) were comparatively evaluated for hypnotic, anticonvulsant and anxiolytic effects in mice. The acute toxicity of BPNE was determined and the LD50 was 490 mg/kg, intrapritonealy. The hypnotic activities of the EO and BPNE (50-400 mg/kg, i.p.) were assessed by loss of righting reflex, while sodium pentobarbitone (PBS) and diazepam (DZM) were used as positive controls. The anticonvulsant and anxiolytic effects of the EO and BPNE were evaluated in mice. Both BPNE and EO at doses >=100 mg/kg induced spontaneous hypnosis with loss of righting reflex, significantly decreased sleep latency (SL) and also increased total sleeping time (TST) dose-dependently. They had comparable activity with NAP in TST. The BPNE exhibited higher hypnotic potency than EO at the same dose levels. The EO and BPNE offered comparable dose-related protections against PTZ- and strychnine induced convulsions. Flumazenil (2 mg/kg) blocked the hypnotic and anticonvulsant (PTZ-convulsions) effects of both EO and BPNE. The essential oil at 5-20 mg/kg dose levels significantly (p<0.05) increased the percentage time spent and number of entries into the open arms. While at the same dose range BPNE significantly (p<0.05) increased the percentage time spent and the number of entries into the open arms respectively. The study concluded that 1-nitro-2-phenylethane exhibited dose dependent significant hypnotic, anticonvulsant and anxiolytic effects and it is the compound largely responsible for the neuropharmacological effects of the oil. PMID- 23920282 TI - DASH diet score and distribution of blood pressure in middle-aged men and women. AB - BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) Trial provides critical data on the impact of a specific diet pattern (low in salt, fat, and processed foods and high in fruit and vegetables) on blood pressure (BP). The effect of compliance with a DASH-type diet on BP in a general population sample is less well defined. We studied associations between a DASH style diet and BP. METHODS: We used cross-sectional data from a study of men and women aged 47-73 years (n = 2,047). Participants completed a physical examination that included 3 standardized clinical BP recordings. A subsample (n = 1,187) had ambulatory BP measurements (ABPM) taken. Diet was assessed using a DASH dietary score constructed from a standard Food Frequency Questionnaire. Lower scores indicated less healthy diets. Hypertension was defined as clinic BP >= 140/90 mm Hg on medication or as 24-hour ABPM >= 130/80 mmHg. RESULTS: Inverse associations were evident between DASH and systolic BP (SBP). There was a difference in clinic SBP of 7.5 mm Hg and 5.1 mm Hg and a difference in ABPM SBP of 6.3mm Hg and 5.4mm Hg in men and women, respectively, between the highest and lowest DASH quintiles. In fully adjusted multivariable regression analysis, DASH score was inversely associated with SBP. Clear population differences in SBP were evident across DASH quintiles. CONCLUSIONS: The observed associations indicate that the findings are consistent with the hypothesis that adherence to DASH-equivalent diet can reduce BP at the population level. Public policy promoting a DASH-style healthy diet could have a significant impact on population health by reducing average BP in the population. PMID- 23920283 TI - The contribution of three components of nutrition knowledge to socio-economic differences in food purchasing choices. AB - OBJECTIVES: To assess socio-economic differences in three components of nutrition knowledge, i.e. knowledge of (i) the relationship between diet and disease, (ii) the nutrient content of foods and (iii) dietary guideline recommendations; furthermore, to determine if socio-economic differences in nutrition knowledge contribute to inequalities in food purchasing choices. DESIGN: The cross sectional study considered household food purchasing, nutrition knowledge, socio economic and demographic information. Household food purchasing choices were summarised by three indices, based on self-reported purchasing of sixteen groceries, nineteen fruits and twenty-one vegetables. Socio-economic position (SEP) was measured by household income and education. Associations between SEP, nutrition knowledge and food purchasing were examined using general linear models adjusted for age, gender, household type and household size. SETTING: Brisbane, Australia in 2000. SUBJECTS: Main household food shoppers (n 1003, response rate 66.4 %), located in fifty small areas (Census Collectors Districts). RESULTS: Shoppers in households of low SEP made food purchasing choices that were less consistent with dietary guideline recommendations: they were more likely to purchase grocery foods comparatively higher in salt, sugar and fat, and lower in fibre, and they purchased a narrower range of fruits and vegetables. Those of higher SEP had greater nutrition knowledge and this factor attenuated most associations between SEP and food purchasing choices. Among nutrition knowledge factors, knowledge of the relationship between diet and disease made the greatest and most consistent contribution to explaining socio-economic differences in food purchasing. CONCLUSIONS: Addressing inequalities in nutrition knowledge is likely to reduce socio-economic differences in compliance with dietary guidelines. Improving knowledge of the relationship between diet and disease appears to be a particularly relevant focus for health promotion aimed to reduce socio-economic differences in diet and related health inequalities. PMID- 23920284 TI - Zero effect of Bt rice on expression of genes coding for digestion, detoxification and immune responses and developmental performances of brown planthopper Nilaparvata lugens (Stal). AB - Transgenic Cry1Ac, Cry2Aa and Cry1Ca (Bt toxins) rice lines are well developed to manage lepidopteron pests in China. The impact of transgenic Bt rice on the non target Brown Planthopper (BPH) has become an essential part of environmental risk assessment, however, scanty evidence is found addressing on developmental and molecular responses of BPH to the ingestion of Bt protein from transgenic rice. The focus of the current study is to examine the developmental characteristics and the expression profiles of gene in relation to digestion, detoxification and immune responses were examined. Our study strongly revealed that the tested Bt rice strains have no unfavorable effect on fecundity, survival and growth of BPH. Furthermore, each of the tested genes did not exhibit distinct expression pattern responding to non Bt parental cultivar, thus, it could be concluded that Bt rice have no detrimental effects on the physiological processes of digestion, detoxification and immune responses of BPH. PMID- 23920285 TI - Temporary artery occlusion in ruptured aneurysms. PMID- 23920286 TI - Tips, tricks, subtleties, and superiority of carotid artery surgery. PMID- 23920287 TI - Reporting surgical outcomes. PMID- 23920288 TI - Lumbar disc herniation and military rank. PMID- 23920289 TI - Should we pursue superior sagittal sinus grafting in parasagittal meningiomas in 2013? PMID- 23920290 TI - Spinal hydatid disease: a multidisciplinary pathology. PMID- 23920291 TI - Venous flow rearrangement after treatment of cerebral arteriovenous malformations: a novel approach to evaluate the risks of treatment. PMID- 23920292 TI - Minimally invasive approaches in the treatment of thoracic disk herniation. PMID- 23920293 TI - Surgical strategies in interbody titanium cage fixation for cervical spondylosis and discogenic disease. PMID- 23920294 TI - Enhanced, rapid occlusion of carotid and vertebral arteries using the AMPLATZER Vascular Plug II device: the Duke Cerebrovascular Center experience in 8 patients with 22 AMPLATZER Vascular Plug II devices. AB - OBJECTIVE: Therapeutic embolization of the common carotid artery (CCA), internal carotid artery (ICA), and vertebral artery (VA) is necessary in the treatment of a subset of chronic arteriovenous fistulas (AVFs), hemorrhages, highly vascularized neoplasms before resection, and giant aneurysms. There are currently no reports of the use of the AMPLATZER Vascular Plug II (AVP II) device to occlude the CCA, ICA, or VA. The objective of this article is to present the Duke Cerebrovascular Center experience using the AVP II device in neurointerventional applications. METHODS: This case series is a retrospective review of all of the cases at Duke University Hospital in which an AVP II device was used in the CCA, ICA, or VA up to September 2012. The AVP II device was often used in conjunction with embolization coils or as multiple AVP II devices deployed in tandem. RESULTS: During 2010-2012, 8 cases meeting criteria were performed. These included 2 chronic VA to internal jugular AVFs, 1 hemorrhagic CCA to internal jugular AVF secondary to invasive head and neck squamous cell carcinoma, 1 ICA hemorrhage secondary to invasive head and neck squamous cell carcinoma, 1 ICA hemorrhage secondary to trauma, 1 ruptured ICA aneurysm, 1 giant petrous ICA aneurysm, and 1 case of cervical vertebral sarcoma requiring preoperative VA embolization. Successful occlusion of the target vessel was achieved in all 8 cases. There was 1 major complication that consisted of a watershed distribution cerebral infarct; however, this was related to emergent occlusion of the ICA in the setting of intracranial hemorrhage and was not a problem intrinsic to the AVP II device. CONCLUSIONS: The AVP II device is relatively large, self-expanding vascular occlusion device that safely allows enhanced, rapid take-down of the CCA, ICA, and VA with low risk of distal migration. PMID- 23920295 TI - Translation of computational fluid dynamics study to neurosurgery. PMID- 23920296 TI - Intratumoral hemorrhage in vestibular schwannomas. PMID- 23920297 TI - At the apex of cerebrovascular surgery--basilar tip aneurysms. PMID- 23920298 TI - Toward a better model of cerebral venous sinus thrombosis. PMID- 23920299 TI - Neurosurgery in the semisitting position in patients with a patent foramen ovale. PMID- 23920300 TI - Carotid endarterectomy: a trial by fire. PMID- 23920301 TI - Searching for the light: fluorescence guidance in glioma resection. PMID- 23920302 TI - Contralateral approach to the trigone of the lateral ventricle. PMID- 23920303 TI - Microsurgical management of basilar artery apex aneurysms. PMID- 23920304 TI - Surgical approaches to brain stem cavernous hemangiomas. PMID- 23920305 TI - Looking through a crystal ball--the question of primarily fusing to the pelvis in adult degenerative scoliosis. PMID- 23920306 TI - Plasmapore-coated titanium cages for anterior cervical discectomy and fusion. PMID- 23920307 TI - Endoscopic-assisted 5-aminolevulinic acid imaging. PMID- 23920308 TI - Role of burr hole surgery in patients with Moyamoya disease. PMID- 23920310 TI - Automated prostate segmentation in whole-body MRI scans for epidemiological studies. AB - The whole prostatic volume (PV) is an important indicator for benign prostate hyperplasia. Correlating the PV with other clinical parameters in a population based prospective cohort study (SHIP-2) requires valid prostate segmentation in a large number of whole-body MRI scans. The axial proton density fast spin echo fat saturated sequence is used for prostate screening in SHIP-2. Our automated segmentation method is based on support vector machines (SVM). We used three dimensional neighborhood information to build classification vectors from automatically generated features and randomly selected 16 MR examinations for validation. The Hausdorff distance reached a mean value of 5.048 +/- 2.413, and a mean value of 5.613 +/- 2.897 compared to manual segmentation by observers A and B. The comparison between volume measurement of SVM-based segmentation and manual segmentation of observers A and B depicts a strong correlation resulting in Spearman's rank correlation coefficients (rho) of 0.936 and 0.859, respectively. Our automated methodology based on SVM for prostate segmentation can segment the prostate in WBI scans with good segmentation quality and has considerable potential for integration in epidemiological studies. PMID- 23920309 TI - A novel extracellular drug conjugate significantly inhibits head and neck squamous cell carcinoma. AB - OBJECTIVES: Despite advances in treatment modalities, head and neck squamous cell carcinoma (HNSCC) remains a challenge to treat with poor survival and high morbidity, necessitating a therapy with greater efficacy. EDC22 is an extracellular drug conjugate of the monoclonal antibody targeting CD147 (glycoprotein highly expressed on HNSCC cells) linked with a small drug molecule inhibitor of Na, K-ATPase. In this study, EDC22's potential as a treatment modality for HNSCC was performed. MATERIALS AND METHODS: HNSCC cell lines (FADU, OSC-19, Cal27, SCC-1) were cultured in vitro and proliferation and cell viability were assessed following treatment with a range of concentrations of EDC22 (0.25 5.00MUg/mL). Mice bearing HNSCC xenografts (OSC-19, SCC-1) were treated with either EDC22 (3-10mg/kg), anti-CD147 monoclonal antibody, cisplatin (1mg/kg) or radiation therapy (2Gy/week) monotherapy or in combination. RESULTS: In vitro, treatment with minimal concentration of EDC22 (0.25MUg/mL) significantly decreased cellular proliferation and cell viability (p<0.0001). In vivo, systemic treatment with EDC22 significantly decreased primary tumor growth rate in both an orthotopic mouse model (OSC-19) and a flank tumor mouse model (SCC-1) (p<0.05). In addition, EDC22 therapy resulted in a greater reduction in tumor growth in vivo compared to radiation monotherapy (p<0.05) and a similar reduction in tumor growth compared to cisplatin monotherapy. Combination therapy provided no significant further reduction in tumor growth relative to EDC22 monotherapy. CONCLUSION: EDC22 is a potent inhibitor of HNSCC cell proliferation in vitro and in vivo, warranting further investigations of its clinical potential in the treatment of HNSCC. PMID- 23920311 TI - Coxiella burnetii seroprevalence and risk factors in sheep farmers and farm residents in The Netherlands. AB - SUMMARY: In this study, Coxiella burnetii seroprevalence was assessed for dairy and non-dairy sheep farm residents in The Netherlands for 2009-2010. Risk factors for seropositivity were identified for non-dairy sheep farm residents. Participants completed farm-based and individual questionnaires. In addition, participants were tested for IgG and IgM C. burnetii antibodies using immunofluorescent assay. Risk factors were identified by univariate, multivariate logistic regression, and multivariate multilevel analyses. In dairy and non-dairy sheep farm residents, seroprevalence was 66.7% and 51.3%, respectively. Significant risk factors were cattle contact, high goat density near the farm, sheep supplied from two provinces, high frequency of refreshing stable bedding, farm started before 1990 and presence of the Blessumer breed. Most risk factors indicate current or past goat and cattle exposure, with limited factors involving sheep. Subtyping human, cattle, goat, and sheep C. burnetii strains might elucidate their role in the infection risk of sheep farm residents. PMID- 23920312 TI - The percentage of DHA in erythrocytes can detect non-adherence to advice to increase EPA and DHA intakes. AB - Characterisation of long-term adherence to EPA and DHA intakes through biomarkers and dietary assessments has implications for interpreting the findings of long term intervention studies. Adherence to dietary advice targeting an EPA+DHA intake of 1 g/d was examined over 1 year. Men and women (n 45) received dietary advice to increase EPA and DHA intakes from seafood, nutraceutical (fish oil) or functional food sources, while a fourth group received combined advice. Blood biomarkers and dietary intakes of EPA and DHA were evaluated at baseline and post intervention at weeks 4, 8, 12, 24 and 52. Assessment by 3 d diet records indicated that EPA+DHA intakes increased relative to baseline in weeks 4-52 following the seafood, nutraceutical and combined advice (advice group * time effect, P= 0.03). The percentage of DHA in plasma and whole blood and the percentage of EPA in erythrocytes, plasma and whole blood were higher in weeks 4 52 when compared with the corresponding baseline measurement. In contrast, the percentage of DHA in erythrocytes increased to a maximum at week 12 and returned to baseline levels in weeks 24 and 52 (time effect, P< 0.01). Measurement of the percentage of DHA in erythrocytes indicates that adherence was sustained during the first 12 weeks following the dietary advice, while other blood measurements of the percentage of EPA and DHA and dietary assessment suggest short-term increases in EPA+DHA intakes immediately before weeks 24 and 52. The percentage of DHA in erythrocytes characterises adherence to EPA and DHA intakes in long term interventions. PMID- 23920313 TI - Epigenetic silencing of NAD(P)H:quinone oxidoreductase 1 by hepatitis B virus X protein increases mitochondrial injury and cellular susceptibility to oxidative stress in hepatoma cells. AB - NAD(P)H:quinone oxidoreductase 1 (NQO1) is a phase II enzyme that participates in the detoxification of dopamine-derived quinone molecules and reactive oxygen species. Our prior work using a proteomic approach found that NQO1 protein levels were significantly decreased in stable hepatitis B virus (HBV)-producing hepatoma cells relative to the empty-vector-transfected controls. However, the mechanism and biological significance of the NQO1 suppression remain elusive. In this study we demonstrate that HBV X protein (HBx) induces epigenetic silencing of NQO1 in hepatoma cells through promoter hypermethylation via recruitment of DNA methyltransferase DNMT3A to the promoter region of the NQO1 gene. In HBV-related hepatocellular carcinoma (HCC) specimens, HBx expression was correlated negatively to NQO1 transcripts but positively to NQO1 promoter hypermethylation. Downregulation of NQO1 by HBx reduced intracellular glutathione levels, impaired mitochondrial function, and increased susceptibility of hepatoma cells to oxidative stress-induced cell injury. These results suggest a novel mechanism for HBV-mediated pathogenesis of chronic liver diseases, including HCC. PMID- 23920315 TI - Levels of prenatal mercury exposure and their relationships to neonatal anthropometry in Wujiang City, China. AB - We determined the levels of prenatal Hg exposure in Wujiang City, located in the southeast of Taihu Lake in China's Jiangsu Province, and analyze the relationship between prenatal exposure to Hg and neonatal anthropometry, including birth weight, body length, and head circumference. From June 2009 to July 2010, a total of 213 mother-infant pairs were enrolled. The geometric means of Hg levels in maternal hair, fetal hair, placentas, and cord blood were 496.76 MUg/kg, 233.94 MUg/kg, 3.58 MUg/kg, and 1.54 MUg/L, respectively. The Hg levels detected in our study were significantly lower than those reported by previous studies. In addition, no significant correlations were found between Hg levels in maternal hair, fetal hair, placenta, or cord blood and neonatal anthropometrics. Together, our findings may be important for understanding the effects of prenatal exposure to Hg on newborns' development and have implications concerning the recommended dose for Hg. PMID- 23920316 TI - Biogeochemistry and community ecology in a spring-fed urban river following a major earthquake. AB - In February 2011 a MW 6.3 earthquake in Christchurch, New Zealand inundated urban waterways with sediment from liquefaction and triggered sewage spills. The impacts of, and recovery from, this natural disaster on the stream biogeochemistry and biology were assessed over six months along a longitudinal impact gradient in an urban river. The impact of liquefaction was masked by earthquake triggered sewage spills (~20,000 m(3) day(-1) entering the river for one month). Within 10 days of the earthquake dissolved oxygen in the lowest reaches was <1 mg l(-1), in-stream denitrification accelerated (attenuating 40 80% of sewage nitrogen), microbial biofilm communities changed, and several benthic invertebrate taxa disappeared. Following sewage system repairs, the river recovered in a reverse cascade, and within six months there were no differences in water chemistry, nutrient cycling, or benthic communities between severely and minimally impacted reaches. This study highlights the importance of assessing environmental impact following urban natural disasters. PMID- 23920314 TI - Interactions between alpha-tocopherol, polyunsaturated fatty acids, and lipoxygenases during embryogenesis. AB - alpha-Tocopherol is a lipid-soluble antioxidant that is specifically required for reproduction and embryogenesis. However, since its discovery, alpha-tocopherol's specific biologic functions, other than as an antioxidant, and the mechanism(s) mediating its requirement for embryogenesis remain unknown. As an antioxidant, alpha-tocopherol protects polyunsaturated fatty acids (PUFAs) from lipid peroxidation. alpha-Tocopherol is probably required during embryonic development to protect PUFAs that are crucial to development, specifically arachidonic (ARA) and docosahexaenoic (DHA) acids. Additionally, ARA and DHA are metabolized to bioactive lipid mediators via lipoxygenase enzymes, and alpha-tocopherol may directly protect, or it may mediate the production and/or actions of, these lipid mediators. In this review, we discuss how alpha-tocopherol (1) prevents the nonspecific, radical-mediated peroxidation of PUFAs, (2) functions within a greater antioxidant network to modulate the production and/or function of lipid mediators derived from 12- and 12/15-lipoxygenases, and (3) modulates 5 lipoxygenase activity. The application and implication of such interactions are discussed in the context of alpha-tocopherol requirements during embryogenesis. PMID- 23920318 TI - Validity and applications of the Montreal cognitive assessment for the assessment of vascular cognitive impairment. AB - Cognitive impairment is common among patients with stroke or other cerebrovascular disease and influences long-term outcome, including occupational functioning. Recognition and monitoring of mild cognitive impairment is thus essential to good patient care. The Montreal Cognitive Assessment (MoCA) has been suggested as a brief screening test of vascular cognitive impairment. This paper presents a critical review of the research literature evaluating the validity and utility of this test with the aim of informing future clinical and research practice. A total of 30 papers employing the MoCA in the context of cerebrovascular disease were identified. Reporting of the methods and results of such studies tended to fall short of the established reporting guidelines. Under specification of the exclusion criteria applied and their impact make it difficult to assess the potential impact of sampling bias and loss to follow-up. Nevertheless, content validity evidence suggests that the MoCA covers most of the domains that represent cognitive impairment in cerebrovascular disease, with mixed evidence for its preferential sensitivity to the type of cognitive impairment encountered in the context of vascular disease. Evidence clearly supports the need to establish norms and cut-offs for the MoCA that are culturally appropriate and that are matched to the range of cognitive impairment that is present in the population being assessed. Recent modifications of the MoCA have been developed for assessing patients with visual impairment or restricted mobility, which may reduce the impact of 'untestability' on cognitive screening in the clinic or research context. The MoCA correlates well with other measures of cognitive and functional abilities in patients with cerebrovascular disease, and may also predict future response to rehabilitation and long-term occupational outcome. Further research is needed to provide evidence for the validity of the MoCA in longitudinal studies. However, it compares favourably to the Mini Mental State Examination as a screening test that is sensitive to the milder forms of cognitive impairment that often accompany cerebrovascular disease. PMID- 23920319 TI - Papillary carcinoma arising in thyroglossal duct cyst in the lateral neck. AB - The patient presented here, a 74-year-old female, had a 3-year history of a gradually enlarging painless nodule in the right submental lateral region of the neck. A neck CT scan showed a well-demarcated cystic lesion, measuring 25mm in diameter, but without any definite evidence of neoplastic foci in the lymph nodes, thyroid gland, or lung. Clinicians first interpreted it as branchial cleft cyst, and a cystectomy was performed. Gross examination revealed a unilocular cystic lesion filled with yellowish clear fluids, containing a markedly thinned fibrous wall with smooth inner surface, partly coexisting with tiny solid and papillary-like components. On microscopic examination, the cystic tumor was lined by mono-layered ciliated columnar or metaplastic stratified squamous epithelium with underlying ectopic thyroid follicles or lymphocytic infiltrate, reminiscent of thyroglossal duct cyst (TDC), partly adjacent to the compressed lymph node tissue. Its solid parts were composed of a proliferation of atypical cuboidal to columnar epithelial cells with occasional nuclear grooves or intranuclear inclusions, arranged in a papillary growth pattern with supporting delicate fibrovascular cores. Immunohistochemically, these atypical cells were positive for thyroid transcription factor 1, thyroglobulin, and cytokeratin 19. Therefore, we finally made a diagnosis of papillary carcinoma (PC) arising in TDC in the lateral neck. Although metastatic thyroid PC of cervical lymph node was an important differential diagnosis owing to various overlapping clinicopathological features, coexistent benign lining epithelium or thyroid follicles, a histological hallmark of TDC, were present in the current case. PMID- 23920320 TI - Carcinoma showing thymus-like differentiation of the thyroid (CASTLE). AB - Carcinoma showing thymus-like differentiation (CASTLE) is a rare intrathyroidal neoplasm, probably arising from ectopic thymus or branchial pouch remnants. The tumor was first reported by Miyauchi et al. [1].The clinical and pathological features of this tumor were classified by Chan et al. [2] into 4 groups: ectopic hamartomatous thymoma, ectopic cervical thymoma, spindle ephithelial tumor with thymic-like differentiation (SETTLE), and carcinoma showing thymus-like differentiation (CASTLE). Recently, CASTLE has been designated as an independent clinicopathologic entity of thyroid tumors in the most recent edition of the World Health Organization classification of tumors of endocrine organs[3].To our knowledge, less than 100 cases of CASTLE have been reported in the literature, 45 cases of which (including one of the authors' patient) have been identified in China. We report a new case of this entity and suggest recommendations for diagnosis. PMID- 23920321 TI - Myxoid liposarcoma with cartilaginous differentiation: A case study with fish analysis and review of the literature. AB - Cartilaginous differentiation is rarely encountered in myxoid liposarcomas. To date, a small number of such cases have been described, and molecular or cytogenetic analysis was performed only in few of them. In the present study, we describe a primary myxoid liposarcoma with cartilaginous differentiation which arised in the left thigh of a 37-year-old man. Miscroscopically, the tumor consisted of areas with typical myxoid liposarcoma morphology and areas of sharply demarcated hyaline cartilage nodules. Here, we present the results of Fluorescence In Situ Hybridization (FISH) analysis that revealed the presence of FUS and DDIT3 gene rearrangements in both the liposarcomatous and cartilaginous components of the tumor. These findings confirm the neoplastic nature of the cartilage component in this rare tumor. PMID- 23920322 TI - Clinicopathologic implication of hepatic progenitor cell marker expression in hepatoblastoma. AB - Hepatic progenitor cells (HPCs) are thought to play a role in hepatoblastoma, as hepatoblastomas are characterized by an immature histology and a wide variety of cell lineages. We aimed to investigate the extent of expression of HPCs marker and its clinical implication in hepatoblastoma. We collected 61 hepatoblastomas and 9 childhood hepatocellular carcinomas (HCCs) and performed immunohistochemistry for HPC markers, including cytokeratin 19 (CK19), octamer binding transcription factor 3/4 (Oct-3/4), epithelial cell adhesion molecule (EpCAM), and delta-like 1 homolog (DLK1). Of the hepatoblastoma samples, 27/61 (44.3%), 21/61 (34.4%), 51/61 (83.6%) and 56/61 (91.8%) exhibited positivity for CK19, Oct-3/4, EpCAM and DLK-1, respectively. For HCCs, the rates of expression were 22.2% (CK19), 77.8% (EpCAM) and 77.8% (DLK-1). Oct-3/4 was not expressed in HCC cells. Hepatoblastomas with a poorly differentiated epithelial component had a higher incidence of CK19 and Oct-3/4 expression than those with a well differentiated epithelial component (p=0.005 and 0.037, respectively). Higher disease stage of hepatoblastoma was correlated with CK19 expression (p=0.043). Oct-3/4-positive hepatoblastomas were associated with short disease-free survival (p=0.035). Both hepatoblastomas and childhood HCCs, therefore, exhibit characteristics of HPCs, and the poor prognosis of patients with Oct-3/4-positive hepatoblastoma suggests that stem-like properties affect hepatoblastoma pathogenicity. PMID- 23920323 TI - Retethering in children after sectioning of the filum terminale. AB - BACKGROUND/AIM: Sectioning of the filum terminale is performed when spinal cord tethering is suspected, sometimes without clinical symptoms. Retethering can occur and require reoperation due to the presentation of either recurrent or new symptoms. The purpose of this institutional review was to identify the retethering rate in children, especially in those who were initially asymptomatic, and to discuss the role of surgery. METHODS: The medical records of all children at the Children's Hospital of Eastern Ontario (CHEO) who underwent tethered cord surgery between 1978 and 2009 for a thickened filum terminale were retrospectively reviewed, as well as those who retethered. RESULTS: A total of 146 patients with a mean age of 4.3 years underwent a low lumbar single or partial laminectomy for sectioning of the filum terminale; 44 patients (30.1%) were asymptomatic at the time of surgery, 51.4% had bladder and bowel dysfunction, 26.7% had neuroorthopedic findings, 15.8% had pain and 6.2% had progressive scoliosis; 11 children with a median age of 8.9 years had symptoms of retethering requiring reoperation (median time to retether was 4.3 years) and 4 were initially asymptomatic. Repeat surgery was successful at alleviating the new symptoms that occurred as a result of retethering. CONCLUSIONS: Of the 146 patients at CHEO who underwent surgery, 7.5% retethered, with 36% being initially asymptomatic. Those operated in the first year of life were not found to be at a higher risk. The level of the conus medullaris did not influence the rate or retethering or urological dysfunction. Children who were initially asymptomatic improved after surgery for retethering, but may not have required surgery in the first place. PMID- 23920325 TI - The emerging role of the molecular diagnostics laboratory in breast cancer personalized medicine. AB - Breast cancer is a complex disease characterized by many morphological, clinical, and molecular features. For many years, breast cancer has been classified according to traditional parameters, such as histological type, grade, tumor size, lymph node involvement and vascular invasion, and biomarkers (eg, estrogen receptor, progesterone receptor, and epidermal growth factor receptor 2), which are used in patient management. With emerging imaging techniques (ie, digital mammography, tomosynthesis, ultrasonography, magnetic resonance imaging, nuclear medicine, and genomic techniques, such as real-time RT-PCR and microarrays), breast cancer diagnostics is going through a significant evolution. Imaging technologies have improved breast cancer diagnosis, survival, and treatment by early detection of primary or metastatic lesions, differentiating benign from malignant lesions and promoting intraoperative surgical guidance and postoperative specimen evaluation. Genomic and transcriptomic technologies make the analysis of gene expression signatures and mutation status possible so that tumors may be classified more accurately with respect to diagnosis and prognosis. The -omic era has also made possible the identification of new biomarkers involved in breast cancer development, survival, and invasion that can be gradually incorporated into clinical testing. These advances in both imaging and genomics contribute to more personalized and predictive patient management. We review the progress made in breast cancer diagnosis and management using these new tools. PMID- 23920324 TI - Initial default among sputum-positive pulmonary TB patients at a referral hospital in Uttarakhand, India. AB - BACKGROUND: Initial default is a serious issue which can enhance the transmission of TB. We determined the magnitude of and the causative factors for initial default among sputum-positive pulmonary TB (PTB) patients. METHODS: In this prospective study, 2310 patients attending a referral hospital in Uttarakhand state, north India, with presumptive TB were investigated and 555 patients with sputum-positive PTB were followed-up for initiation of anti-TB treatment (ATT) during 2010-2012. The patients not confirmed as having started ATT were considered initial defaulters. RESULTS: Initial default was seen in 120 (21.6%) patients comprising 22 (18.3%) defaulters during diagnosis and 98 (81.6%) defaulters after referral for directly observed treatment, short-course (DOTS). The initial default rate was significantly higher among patients from rural areas than urban areas, illiterate patients than literate patients and smokeless tobacco-users than non-users (p<0.05 for all). The main reasons for initial default among patients referred for DOTS were limited trust in DOTS (n = 44, 44.8%), adverse effects of previous ATT (n = 41, 41.8%), dissatisfaction with health services (n = 38, 38.7%), local deaths while taking DOTS (n = 28, 28.5%), advice by others against DOTS (n = 25, 25.5%), disbelief in the diagnosis (n = 18, 18.3%) and patient death before starting treatment (n = 4, 4.0%). CONCLUSION: A high initial default rate was seen among patients with PTB. There is an urgent need to promote public awareness to lower the initial default rate. PMID- 23920327 TI - Triple-negative breast cancer and the need for new therapeutic targets. AB - Triple-negative breast cancers (TNBCs) are a diverse and heterogeneous group of tumors that by definition lack estrogen and progesterone receptors and amplification of the HER2 gene. The majority of the tumors classified as TNBCs are highly malignant, and only a subgroup responds to conventional chemotherapy with a favorable prognosis. Results from decades of research have identified important molecular characteristics that can subdivide this group of breast cancers further. High-throughput molecular analyses including sequencing, pathway analyses, and integrated analyses of alterations at the genomic and transcriptomic levels have improved our understanding of the molecular alterations involved in tumor development and progression. How this knowledge should be used for rational selection of therapy is a challenging task and the subject of numerous ongoing research programs. This review summarizes the current knowledge on the clinical characteristics and molecular alterations of TNBCs. Currently used conventional therapeutic strategies and targeted therapy studies are discussed, with references to recently published results on the molecular characterization of TNBCs. PMID- 23920326 TI - MyD88-dependent signaling prolongs survival and reduces bacterial burden during pulmonary infection with virulent Francisella tularensis. AB - Francisella tularensis is the causative agent of the debilitating febrile illness tularemia. The severe morbidity associated with F. tularensis infections is attributed to its ability to evade the host immune response. Innate immune activation is undetectable until more than 48 hours after infection. The ensuing inflammatory response is considered pathological, eliciting a septic-like state characterized by hypercytokinemia and cell death. To investigate potential pathological consequences of the innate immune response, mice deficient in a key innate immune signaling molecule, MyD88, were studied. MyD88 knockout (KO) mice were infected with the prototypical virulent F. tularensis strain, Schu S4. MyD88 KO mice succumbed to infection more rapidly than wild-type mice. The enhanced pathogenicity of Schu S4 in MyD88 KO mice was associated with greater bacterial burdens in lungs and distal organs, and the absence of IFN-gamma in the lungs, spleens, and sera. Cellular infiltrates were not observed on histological evaluation of the lungs, livers, or spleens of MyD88 KO mice, the first KO mouse described with this phenotype to our knowledge. Despite the absence of cellular infiltration, there was more cell death in the lungs of MyD88 KO mice. Thus, the host proinflammatory response is beneficial, and MyD88 signaling is required to limit bacterial burden and prolong survival during pulmonary infection by virulent F. tularensis. PMID- 23920329 TI - Reproducibility of arterial stiffness and wave reflections in chronic obstructive pulmonary disease: the contribution of lung hyperinflation and a comparison of techniques. AB - Significant cardiovascular morbidity and mortality exists in chronic obstructive pulmonary disease (COPD). Arterial stiffness is raised in COPD and may be a mechanistic link. Non-invasive assessment of arterial stiffness has the potential to be a surrogate outcome measure, although no reproducibility data exists in COPD patients. Two studies (23 and 33 COPD patients) were undertaken to 1) assess the Vicorder reproducibility of carotid-femoral pulse wave velocity and Augmentation index in COPD; 2) compare it to SphygmoCor; and 3) assess the contribution of lung hyperinflation to measurement variability. There were excellent correlations and good agreement between repeat Vicorder measurements for carotid-femoral pulse wave velocity (r = 0.96 (p < 0.001); mean difference +/ SD = -0.03 +/- 0.36 m/s (p = 0.65); co-efficient of reproducibility = 4.02%; limits of agreement = -0.68-0.75 m/s). Augmentation index significantly correlated (r = 0.736 (p < 0.001); mean difference +/-SD = 0.72 +/- 4.86% (p = 0.48), however limits of agreement were only 10.42-9.02%, with co-efficient of reproducibility of 27.93%. Comparing devices, Vicorder values were lower but there was satisfactory agreement. There were no correlation between lung hyperinflation (as measured by residual volume percent predicted, total lung capacity percent predicted or the ratio of inspiratory capacity to residual volume) and variability of measurements in either study. In COPD, measurement of carotid-femoral pulse wave velocity is highly reproducible, not affected by lung hyperinflation and suitable as a surrogate endpoint in research studies. Day-to day variation in augmentation index highlights the importance of such studies prior to the planning and undertaking of clinical COPD research. PMID- 23920328 TI - The relation of circulating YKL-40 to levels and decline of lung function in adult life. AB - BACKGROUND: YKL-40 is a chitinase-like protein that, in cross-sectional clinical studies, has been associated with severe asthma and COPD in smokers. AIM: To determine the longitudinal relation of circulating YKL-40 to levels and decline of lung function in the general population. METHODS: We used longitudinal data from up to 13 surveys from the population-based TESAOD study which was conducted in Tucson, Arizona between 1972 and 1996. In cross-sectional analyses, we also used data from 3 Spanish centers of the multicenter ECRHS study (ECRHS-Sp). Serum YKL-40 was measured at baseline in TESAOD and in survey 2 in ECRHS-Sp using ELISAs. Multivariate linear regression was used to test associations of serum YKL 40 to concomitant lung function. In TESAOD, random coefficients models were used to test associations of serum YKL-40 to subsequent decline of lung function. RESULTS: Data on YKL-40 and lung function were available from 1088 TESAOD and 854 ECRHS-Sp adult participants (59% and 51% females; respectively). In adjusted multivariate meta-analyses, being in the highest YKL-40 quartile was associated cross-sectionally with significant deficits in FEV1 and FVC %predicted. In adjusted longitudinal analyses, TESAOD participants in the top YKL-40 quartile had an FEV1 decline that was 5 ml/yr (p = 0.05) faster than subjects in the third quartile, 5 ml/yr (p = 0.02) faster than subjects in the second quartile, and 10 ml/yr (p < 0.001) faster than subjects in the lowest YKL-40 quartile. These longitudinal effects were particularly strong in smokers and absent in never smokers. After adjusting for covariates, as compared with the other three quartiles combined, the top YKL-40 quartile was associated with a 9 ml/yr (p = 0.001) faster FEV1 decline among smokers, while no significant effects were found among never smokers (2 ml/yr, p = 0.35). CONCLUSIONS: Circulating YKL-40 is associated with levels and decline of lung function in the general population and may be a biomarker of susceptibility to the long-term effects of cigarette smoking. PMID- 23920330 TI - Higher prevalence of breathlessness in elderly exposed to indoor aldehydes and VOCs in a representative sample of French dwellings. AB - The purpose of this study was to explore respiratory health effects of indoor exposures to aldehydes and volatile organic compounds (VOCs) in elderly living in a population-based representative sample of French dwellings and to compare them to the rest of the occupants of the dwellings. Twenty VOCs were objectively measured in 490 main dwellings. The respiratory conditions were assessed through a standardized questionnaire in 1012 inhabitants aged over 15 years, 144 of whom were aged over 65 years. Generalized estimating equations (GEE) were used to model the relationship between respiratory health outcomes and air pollutants concentrations using the median value of the distribution to define elevated exposure. Similar levels of indoor air pollutants were found in elderly and others. However, associations between breathlessness and living in dwellings with elevated concentrations of toluene and o-xylene respectively were statistically significant in elderly but not in the rest of the population (adjusted odds ratios (AOR(95% confidence interval) = 3.36(1.13, 9.98) and 2.85(1.06, 7.68) in elderly vs. 0.91(0.59, 1.39) and 0.79( 0.47, 1.34) in the others respectively). A more pronounced effect of n-decane on past year breathlessness was observed in case of poor ventilation in the dwellings. Our results showed a higher risk of breathlessness in elderly exposed to indoor air pollution than in the rest of the exposed population. Further investigations are needed to confirm whether this is related to frailty in elderly. PMID- 23920332 TI - Access to multiple sclerosis specialty care. AB - BACKGROUND: Health care providers recommend an annual visit to a multiple sclerosis specialty care provider. OBJECTIVE: To examine potential barriers to the implementation of this recommendation in the Veterans Health Administration. DESIGN: Observational cohort study. SETTING: Veterans Health Administration. PARTICIPANTS: Participants were drawn from the Veterans Affairs Multiple Sclerosis National Data Repository and were included if they had an outpatient visit in 2007 and were alive in 2008 (N = 14,723). MAIN OUTCOME MEASUREMENTS: Specialty care visit, receipt of medical services. RESULTS: A total of 9643 (65.5%) participants had a specialty care visit in 2007. Veterans who were service connected, had greater medical comorbidity, and who lived in urban settings were more likely to have received a specialty care visit. Veterans who were older and had to travel greater distances to a center were less likely to have a specialty care visit. CONCLUSIONS: Access to care in rural areas and areas at a greater distance from a major medical center represent notable barriers to rehabilitation and other multiple sclerosis-related care. PMID- 23920331 TI - Deletion of the beta2-adrenergic receptor prevents the development of cardiomyopathy in mice. AB - Beta adrenergic receptor (beta-AR) subtypes act through diverse signaling cascades to modulate cardiac function and remodeling. Previous in vitro studies suggest that beta1-AR signaling is cardiotoxic whereas beta2-AR signaling is cardioprotective, and may be the case during ischemia/reperfusion in vivo. The objective of this study was to assess whether beta2-ARs also play a cardioprotective role in the pathogenesis of non-ischemic forms of cardiomyopathy. To dissect the role of beta1 vs beta2-ARs in modulating MLP (Muscle LIM Protein) cardiomyopathy, we crossbred MLP-/- with beta1-/- or beta2-/ mice. Deletion of the beta2-AR improved survival, cardiac function, exercise capacity and myocyte shortening; by contrast haploinsufficency of the beta1-AR reduced survival. Pathologic changes in Ca(2+) handling were reversed in the absence of beta2-ARs: peak Ca(2+) and SR Ca(2+) were decreased in MLP-/- and beta1+/-/MLP-/- but restored in beta2-/-MLP-/-. These changes were associated with reversal of alterations in troponin I and phospholamban phosphorylation. Gi inhibition increased peak and baseline Ca(2+), recapitulating changes observed in the beta2-/-/MLP-/-. The L-type Ca(2+) blocker verapamil significantly decreased cardiac function in beta2-/-MLP-/- vs WT. We next tested if the protective effects of beta2-AR ablation were unique to the MLP model using TAC-induced heart failure. Similar to MLP, beta2-/- mice demonstrated delayed progression of heart failure with restoration of myocyte shortening and peak Ca(2+) and Ca(2+) release. Deletion of beta2-ARs prevents the development of MLP-/- cardiomyopathy via positive modulation of Ca(2+) due to removal of inhibitory Gi signaling and increased phosphorylation of troponin I and phospholamban. Similar effects were seen after TAC. Unlike previous models where beta2-ARs were found to be cardioprotective, in these two models, beta2-AR signaling appears to be deleterious, potentially through negative regulation of Ca(2+) dynamics. PMID- 23920333 TI - A new approach to assess the dependency of extant half-saturation coefficients on maximum process rates and estimate intrinsic coefficients. AB - The Monod equation is often used to describe biological treatment processes and is the foundation for many activated sludge models. The Monod equation includes a "half-saturation coefficient" to describe the effect of substrate limitations on the process rate and it is customary to consider this parameter to be a constant for a given system. The purpose of this study was to develop a methodology, and its use to show that the half-saturation coefficient for denitrification is not constant but is in fact a function of the maximum denitrification rate. A 4-step procedure is developed to investigate the dependency of half-saturation coefficients on the maximum rate and two different models are used to describe this dependency: (a) an empirical linear model and (b) a deterministic model based on Fick's law of diffusion. Both models are proved better for describing denitrification kinetics than assuming a fixed K(NO3) at low nitrate concentrations. The empirical model is more utilitarian whereas the model based on Fick's law has a fundamental basis that enables the intrinsic K(NO3) to be estimated. In this study data was analyzed from 56 denitrification rate tests and it was found that the extant K(NO3) varied between 0.07 mgN/L and 1.47 mgN/L (5th and 95th percentile respectively) with an average of 0.47 mgN/L. In contrast to this, the intrinsic K(NO3) estimated for the diffusion model was 0.01 mgN/L which indicates that the extant K(NO3) is greatly influenced by, and mostly describes, diffusion limitations. PMID- 23920334 TI - Content analysis of television food advertisements aimed at adults and children in South Africa. AB - OBJECTIVE: To determine the frequency and content of food-related television (TV) advertisements shown on South African TV. DESIGN: Four national TV channels were recorded between 15.00 and 21.00 hours (6 h each day, for seven consecutive days, over a 4-week period) to: (i) determine the number of food-related TV advertisements; and (ii) evaluate the content and approach used by advertisers to market their products. The data were viewed by two of the researchers and coded according to time slots, food categories, food products, health claims and presentation. RESULTS: Of the 1512 recorded TV advertisements, 665 (44 %) were related to food. Of these, 63 % were for food products, 21 % for alcohol, 2 % for multivitamins, 1 % for slimming products and 13 % for supermarket and pharmacy promotions. Nearly 50 % of food advertisements appeared during family viewing time. During this time the most frequent advertisements were for desserts and sweets, fast foods, hot beverages, starchy foods and sweetened drinks. The majority of the alcohol advertisements (ninety-three advertisements, 67 %) fell within the children and family viewing periods and were endorsed by celebrities. Health claims were made in 11 % of the advertisements. The most frequently used benefits claimed were 'enhances well-being', 'improves performance', 'boosts energy', 'strengthens the immune system' and 'is nutritionally balanced'. CONCLUSIONS: The majority of food advertisements shown to both children and adults do not foster good health despite the health claims made. The fact that alcohol advertisements are shown during times when children watch TV needs to be addressed. PMID- 23920335 TI - Interpersonal style moderates the effect of dating violence on symptoms of anxiety and depression. AB - Over a quarter of young women have experienced some form of violence within a dating relationship. The experience of dating violence is associated with problems in psychological functioning, including symptoms of anxiety and depression. However, not all women who experience dating violence exhibit anxious or depressive symptoms. One factor that may influence symptom expression is interpersonal style. In this study, we examined the main and moderating effects of dimensions of interpersonal style (dominance and warmth) on the association between dating violence and symptoms of anxiety and depression. Warmth exhibited a main effect on anxious and depressive symptoms over and above the effects of dating violence and other life stressors. Dominance moderated the association between dating violence and anxious and depressive symptoms. When levels of dating violence were high, women with higher levels of dominance reported fewer symptoms of anxiety and depression than women with lower dominance. These results indicated that whereas high warmth was associated with fewer symptoms of psychopathology generally, high dominance was a buffer against the effect of dating violence on symptoms more specifically. Directions for future research are discussed. PMID- 23920336 TI - Predicting commitment in young adults' physically aggressive and sexually coercive dating relationships. AB - Intimate partner violence often begins during the courtship stage of romantic relationships. Although some relationships dissolve as a result of aggression, other relationships remain intact, increasing the risk for escalated violence. The present study identified factors predictive of individual differences in emerging adults' commitment to physically aggressive or sexually coercive dating relationships. Specifically, Rusbult's Investment Model of romantic relationships (e.g., investment, satisfaction, quality of alternatives, and commitment) was applied to a longitudinal sample of 148 young adult women who reported experiencing aggression or coercion from their current partners. To further explain commitment within aggressive or coercive dating relationships, rejection sensitivity and anxious and avoidant romantic relational styles were included as predictors of the Investment Model variables. A more avoidant romantic style indirectly predicted commitment through relationship satisfaction and investment. Both commitment and rejection sensitivity significantly predicted continuing an aggressive or coercive relationship 6 months later. The present study improves our understanding of the processes involved in relationship commitment. Continuing to understand these processes will inform interventions that seek to help women who have decided to end aggressive or coercive dating relationships. PMID- 23920337 TI - The effects of adolescent intimate partner violence on women's educational attainment and earnings. AB - Intimate partner violence (IPV) is a serious, widespread problem that negatively affects women's lives, including their economic status. The current study explored whether the financial harm associated with IPV begins as early as adolescence. With longitudinal data from a sample of 498 women currently or formerly receiving welfare, we used latent growth curve modeling to examine the relationships between adolescent IPV, educational attainment, and women's earnings. We found that women who had been victimized by a partner during adolescence obtained less education compared with nonvictimized women, with victimization indirectly influencing women's earnings via educational attainment. The findings support the need for intervention strategies aimed at preventing IPV and promoting women's educational and career development over the life course. PMID- 23920338 TI - Posttraumatic stress, partner violence victimization, and harmful drinking: risk factors for relationship discord in new parents. AB - The first year of parenthood can be a stressful time, especially for high-risk couples. Symptoms of posttraumatic stress (PTS) have been associated with decreased intimacy, communication, and relationship adjustment, yet there is a lack of research on how PTS symptoms might affect couples in early parenthood. Furthermore, there is little evidence regarding the way in which PTS symptoms may affect couples above and beyond known risk factors such as intimate partner violence (IPV) and harmful alcohol use. The current study investigated how PTS symptoms were related to new parents' relationship satisfaction in the context of IPV and harmful drinking. Ninety-eight heterosexual couples filled out questionnaires 1 year after the birth of their first child. Hierarchical multiple regression analyses indicated that, for men, PTS symptoms predicted lower relationship satisfaction over and above IPV victimization and harmful drinking. However, for women, psychological IPV victimization was the only significant multivariate predictor. In addition, for men, PTS symptoms interacted with harmful drinking to predict poorer relationship satisfaction. The results suggest that women's relationship satisfaction is particularly linked to psychological IPV victimization during early parenthood, whereas men's relationship satisfaction is particularly associated with their own harmful drinking and PTS symptoms. Implications are discussed. PMID- 23920339 TI - An exploratory investigation of adolescent intimate partner violence among African American youth: a gendered analysis. AB - Extant research demonstrates that while adolescent intimate partner violence (IPV) is an ever-growing concern in the United States, most research on IPV has focused on adult victims and offenders. To fill this gap in the literature, the present research examines youth IPV by conducting focus groups with 25 male and female youth between the ages of 15 and 19 years whose race was primarily African American. Drawing on open-ended responses by adolescent participants, the present study aimed to shed light on African American youths' perceptions of IPV, their perceptions regarding such violence among their peers, the dynamics of help seeking behaviors, and what services youth perceive as most helpful in the prevention and intervention of adolescent IPV. Findings reveal that most participants only recognize physical aggression as IPV; express hesitation in disclosing violence to adults, especially nonfamily adults; and report being unaware of and/or unwilling to utilize existing prevention and intervention services traditionally targeted at adult populations. Implications for future research and policy are also presented and discussed. PMID- 23920340 TI - Fatty acids in the infant diet: size matters. PMID- 23920341 TI - Understanding the role of cleaning in the control of Salmonella Typhimurium in grower-finisher pigs: a modelling approach. AB - Salmonella Typhimurium (STM) infection in pigs represents a considerable food safety concern. This study used mathematical modelling to evaluate the effectiveness of cleaning (faeces removal) as a measure to control STM spread among grower-finisher pigs. A modified Susceptible-Infected-Recovered-Susceptible (SIRS) model of STM transmission through a contaminated environment was developed. Infected pigs were divided into three states according to the pathogen level being shed in their faeces. Infection transmission was evaluated using the basic reproduction number (R 0) and the prevalence of infectious pigs at slaughter age. Although increased frequency and efficiency of cleaning did reduce the prevalence of STM shedding at the time of slaughter, these efforts alone were not capable of eliminating the infection from the population. The level of STM faecal shedding by infectious pigs strongly influenced the infection spread and prevalence at slaughter. To control STM in pigs, cleaning should be combined with vaccination and/or isolation of high-level shedders. PMID- 23920342 TI - Nitrosyl-cobinamide (NO-Cbi), a new nitric oxide donor, improves wound healing through cGMP/cGMP-dependent protein kinase. AB - Nitric oxide (NO) donors have been shown to improve wound healing, but the mechanism is not well defined. Here we show that the novel NO donor nitrosyl cobinamide (NO-Cbi) improved in vitro wound healing in several cell types, including an established line of lung epithelial cells and primary human lung fibroblasts. On a molar basis, NO-Cbi was more effective than two other NO donors, with the effective NO-Cbi concentration ranging from 3 to 10MUM, depending on the cell type. Improved wound healing was secondary to increased cell migration and not cell proliferation. The wound healing effect of NO-Cbi was mediated by cGMP, mainly through cGMP-dependent protein kinase type I (PKGI), as determined using pharmacological inhibitors and activators, and siRNAs targeting PKG type I and II. Moreover, we found that Src and ERK were two downstream mediators of NO-Cbi's effect. We conclude that NO-Cbi is a potent inducer of cell migration and wound closure, acting via cGMP, PKG, Src, and extracellular signal regulated kinase (ERK). PMID- 23920343 TI - MR-guided breast radiotherapy: feasibility and magnetic-field impact on skin dose. AB - The UMC Utrecht MRI/linac (MRL) design provides image guidance with high soft tissue contrast, directly during radiotherapy (RT). Breast cancer patients are a potential group to benefit from better guidance in the MRL. However, due to the electron return effect, the skin dose can be increased in presence of a magnetic field. Since large skin areas are generally involved in breast RT, the purpose of this study is to investigate the effects on the skin dose, for whole-breast irradiation (WBI) and accelerated partial-breast irradiation (APBI). In ten patients with early-stage breast cancer, targets and organs at risk (OARs) were delineated on postoperative CT scans co-registered with MRI. The OARs included the skin, comprising the first 5 mm of ipsilateral-breast tissue, plus extensions. Three intensity-modulated RT techniques were considered (2* WBI, 1* APBI). Individual beam geometries were used for all patients. Specially developed MRL treatment-planning software was used. Acceptable plans were generated for 0 T, 0.35 T and 1.5 T, using a class solution. The skin dose was augmented in WBI in the presence of a magnetic field, which is a potential drawback, whereas in APBI the induced effects were negligible. This opens possibilities for developing MR-guided partial-breast treatments in the MRL. PMID- 23920344 TI - Evidence based policy decisions through a Bayesian approach: the case of a statin appraisal in The Netherlands. AB - It has often been suggested that Bayesian statistics is more congenial to the informational needs of policy makers than the standard frequentist methods. In order to illustrate this claim, we use both a Bayesian and a frequentist approach for revisiting a recommendation by the Dutch National Health Insurance Board that for all patients requiring lipid reduction, the cheapest alternative (Simvastatin) should be prescribed. We investigate whether Simvastatin and Atorvastatin, the most commonly used alternative, can be considered equivalent in terms of lipid control for patients with heterozygous familial hypercholesterolemia. Priors were elicited from GPs, cardiologists and internists. A systematic review for studies comparing Simvastatin and Atorvastatin was performed. The data from these studies were combined with the priors in a Bayesian meta-analysis. For comparability a frequentist meta-analysis was also performed. The two approaches lead to similar point estimates and 95% intervals. However, the Bayesian outcomes are easier to understand and interpret, and our Bayesian analysis leads to additional outcomes that would have more direct pertinence for policy makers, and which could help them to assess what the data have to say about the questions that are most relevant to the problems they face. PMID- 23920346 TI - Individual nodule tracking in micro-CT images of a longitudinal lung cancer mouse model. AB - We present and evaluate an automatic and quantitative method for the complex task of characterizing individual nodule volumetric progression in a longitudinal mouse model of lung cancer. Fourteen A/J mice received an intraperitoneal injection of urethane. Respiratory-gated micro-CT images of the lungs were acquired at 8, 22, and 37 weeks after injection. A radiologist identified a total of 196, 585 and 636 nodules, respectively. The three micro-CT image volumes from every animal were then registered and the nodules automatically matched with an average accuracy of 99.5%. All nodules detected at week 8 were tracked all the way to week 37, and volumetrically segmented to measure their growth and doubling rates. 92.5% of all nodules were correctly segmented, ranging from the earliest stage to advanced stage, where nodule segmentation becomes more challenging due to complex anatomy and nodule overlap. Volume segmentation was validated using a foam lung phantom with embedded polyethylene microspheres. We also correlated growth rates with nodule phenotypes based on histology, to conclude that the growth rate of malignant tumors is significantly higher than that of benign lesions. In conclusion, we present a turnkey solution that combines longitudinal imaging with nodule matching and volumetric nodule segmentation resulting in a powerful tool for preclinical research. PMID- 23920347 TI - The leptomeningeal ivy sign on fluid-attenuated inversion recovery images in moyamoya disease: positron emission tomography study. AB - BACKGROUND: The ivy sign is sometimes seen on fluid-attenuated inversion recovery (FLAIR) images in moyamoya disease (MMD). In recent studies using single-photon emission computed tomography, ivy sign proliferation correlated with decreases in cerebrovascular reserve. However, a decreased vascular reserve is not concrete. The purpose of this study was to evaluate the correlation between ivy sign proliferation and the findings of 15O gas positron emission tomography (PET). METHODS: In 19 MMD patients (12 women, age 31-69 years) with ischemic symptoms, FLAIR magnetic resonance imaging and 15O gas PET were performed. We classified the middle cerebral artery (MCA) territory into 2 regions in each hemisphere, and the degree of the ivy sign (ivy sign score) in each region was classified into 3 grades (0-2), where grade 0 indicated an absence of the ivy sign, grade 1 indicated that the ivy sign was seen on less than half of the cortical surface in each region, and grade 2 indicated that the ivy sign was seen on more than half of the cortical surface. We examined the relationship among the ivy sign score, the severity of ischemic symptoms and PET parameters in 76 MCA regions of 19 patients. RESULTS: Ivy sign scores of the regions were 0 (n = 19), 1 (n = 40), and 2 (n = 17). Total ivy sign score of a hemisphere increased as clinical symptoms became more severe. Cerebral blood flow (CBF) values were lower, cerebral blood volume (CBV) values were higher, and CBF/CBV values were lower than those of controls as symptoms became severe (p < 0.05). CBF and CBF/CBV values decreased and CBV values increased as the ivy sign score increased, and were significantly higher and lower, respectively, than control values (p < 0.05). No significant differences in cerebral metabolic rate of oxygen and oxygen extraction fraction were found between the 3 ivy sign scores. A positive correlation was found between ivy sign score and increases in CBV (p < 0.01), and a more obvious negative correlation was found between ivy sign score and decreases in CBF/CBV (p < 0.001). CONCLUSIONS: We evaluated the correlation between ivy sign proliferation and the findings of 15O gas PET. We suggested that ivy sign proliferation was associated with both dilated pial vasculature and the slow flow of developed leptomeningeal collaterals in patients with MMD. PMID- 23920348 TI - Effect of telephone health coaching (Birmingham OwnHealth) on hospital use and associated costs: cohort study with matched controls. AB - OBJECTIVES: To test the effect of a telephone health coaching service (Birmingham OwnHealth) on hospital use and associated costs. DESIGN: Analysis of person level administrative data. Difference-in-difference analysis was done relative to matched controls. SETTING: Community based intervention operating in a large English city with industry. PARTICIPANTS: 2698 patients recruited from local general practices before 2009 with heart failure, coronary heart disease, diabetes, or chronic obstructive pulmonary disease; and a history of inpatient or outpatient hospital use. These individuals were matched on a 1:1 basis to control patients from similar areas of England with respect to demographics, diagnoses of health conditions, previous hospital use, and a predictive risk score. INTERVENTION: Telephone health coaching involved a personalised care plan and a series of outbound calls usually scheduled monthly. Median length of time enrolled on the service was 25.5 months. Control participants received usual healthcare in their areas, which did not include telephone health coaching. MAIN OUTCOME MEASURES: Number of emergency hospital admissions per head over 12 months after enrolment. Secondary metrics calculated over 12 months were: hospital bed days, elective hospital admissions, outpatient attendances, and secondary care costs. RESULTS: In relation to diagnoses of health conditions and other baseline variables, matched controls and intervention patients were similar before the date of enrolment. After this point, emergency admissions increased more quickly among intervention participants than matched controls (difference 0.05 admissions per head, 95% confidence interval 0.00 to 0.09, P=0.046). Outpatient attendances also increased more quickly in the intervention group (difference 0.37 attendances per head, 0.16 to 0.58, P<0.001), as did secondary care costs (difference L175 per head, L22 to L328, P=0.025). Checks showed that we were unlikely to have missed reductions in emergency admissions because of unobserved differences between intervention and matched control groups. CONCLUSIONS: The Birmingham OwnHealth telephone health coaching intervention did not lead to the expected reductions in hospital admissions or secondary care costs over 12 months, and could have led to increases. PMID- 23920349 TI - Human to human transmission of H7N9. PMID- 23920352 TI - Multiple acquired encephaloceles: dramatic end point of chronic untreated intracranial hypertension in multi-suture craniosynostosis. PMID- 23920351 TI - Fungal lectins: structure, function and potential applications. AB - Lectins are a widespread class of proteins implicated in many essential cellular and molecular recognition processes. They recognize carbohydrates in a non catalytic, specific and reversible manner. Fungi, which include mushrooms, microfungi and yeasts, have attracted wide interest in recent years. They are indeed a promising source for novel lectins with unique specificity and potential for biomedical and biotechnological applications. Information on fungal lectins, particularly structural insight, is scarce compared to that on their plant and animal counterparts. This review therefore focuses on the structure, function, and exploitable properties of fungal lectins. PMID- 23920350 TI - Probable person to person transmission of novel avian influenza A (H7N9) virus in Eastern China, 2013: epidemiological investigation. AB - OBJECTIVE: To determine whether the novel avian influenza H7N9 virus can transmit from person to person and its efficiency. DESIGN: Epidemiological investigations conducted after a family cluster of two patients with avian H7N9 in March 2013. SETTING: Wuxi, Eastern China. PARTICIPANTS: Two patients, their close contacts, and relevant environments. Samples from the patients and environments were collected and tested by real time reverse transcriptase-polymerase chain reaction (rRT-PCR), viral culture, and haemagglutination inhibition assay. Any contacts who became ill had samples tested for avian H7N9 by rRT-PCR. Paired serum samples were obtained from contacts for serological testing by haemagglutination inhibition assays. MAIN OUTCOMES MEASURES: Clinical data, history of exposure before the onset of illnesses, and results of laboratory testing of pathogens and further analysis of sequences and phylogenetic tree to isolated strains. RESULTS: The index patient became ill five to six days after his last exposure to poultry. The second patient, his daughter aged 32, who provided unprotected bedside care in the hospital, had no known exposure to poultry. She developed symptoms six days after her last contact with her father. Two strains were isolated successfully from the two patients. Genome sequence and analyses of phylogenetic trees showed that both viruses were almost genetically identical. Forty three close contacts of both patients were identified. One had mild illness but had negative results for avian H7N9 by rRT-PCR. All 43 close contacts tested negative for haemagglutination inhibition antibodies specific for avian H7N9. CONCLUSIONS: The infection of the daughter probably resulted from contact with her father (the index patient) during unprotected exposure, suggesting that in this cluster the virus was able to transmit from person to person. The transmissibility was limited and non-sustainable. PMID- 23920353 TI - Findings from an online behavioural weight management programme provided with or without a fortified diet beverage. AB - The present multi-centre randomised weight-loss trial evaluated the efficacy of a low-intensity 12-week online behavioural modification programme, with or without a fortified diet beverage using a 2 * 2 factorial design. A total of 572 participants were randomised to: (1) an online basic lifestyle information (OBLI) intervention, consisting of one online informational class about tips for weight management; (2) an online behavioural weight management (OBWM) intervention, entailing 12 weekly online classes focused on weight-loss behaviour modification; (3) an OBLI intervention plus a fortified diet cola beverage (BEV) containing green tea extract (total catechin 167 mg), soluble fibre dextrin (10 g) and caffeine (100 mg) (OBLI+BEV); (4) OBWM+BEV. Assessments included height, weight, dual-energy X-ray absorptiometry-derived body composition, and waist circumference (WC). Attrition was 15.7 %. Intention-to-treat (ITT) models demonstrated a main effect for type of Internet programme, with those assigned to the OBWM condition losing significantly more weight (F= 7.174; P= 0.008) and fat mass (F= 4.491; P= 0.035) than those assigned to the OBLI condition. However, there was no significant main effect for the OBWM condition on body fat percentage (F= 2.906; P= 0.089) or WC (F= 3.351; P= 0.068), and no significant main effect for beverage use or significant interactions between factors in ITT models. A 12-week, low-intensity behaviourally based online programme produced a greater weight loss than a basic information website. The addition of a fortified diet beverage had no additional impact. PMID- 23920354 TI - Application of an integrated outbreak management plan for the control of leptospirosis in dairy cattle herds. AB - SUMMARY: Two outbreaks of Leptospira borgpetersenii serovar Hardjo infection in dairy cattle herds were managed through the application of enhanced biosecurity measures, whole-herd antibiotic treatment and vaccination. Micro-agglutination test antibody titres were determined in paired serum samples at 3 weeks (T1: n = 125, 97% seropositivity, median 800, range 100-12 800) and 24 weeks (T2: n = 110, 88% seropositivity, median 200, range 100-6400) after vaccination and studied in relation to cows' age, herd of origin and sampling time. From T1 to T2, vaccine elicited antibody titres decreased by 84.7% (95% CI 76.2-90.1). Consistent with increasing immunocompetence in calves (aged <12 months) and immunosenescence in adult cows (aged >36 months) associated with ageing, antibody titres correlated positively with calves' age and negatively with adult cows' age. No cow had cultivable, (histo)pathologically detectable and/or PCR-detectable leptospires in urine or kidney samples after treatment and vaccination. Vaccination together with proper biosecurity measures and chemoprophylaxis are an affordable insurance to control bovine leptospirosis. PMID- 23920355 TI - Human papillomavirus infection is associated with decreased levels of GM-CSF in cervico-vaginal fluid of infected women. AB - BACKGROUND: Although human papillomavirus (HPV) is the most common sexually transmitted infection, there are very scant data about the influence of this virus on the in vitro fertilization outcome. OBJECTIVES: To assess the presence of HPV in the cervico-vaginal fluid in relationship to the in vitro fertilization (IVF) outcome and to the concentration of selected cytokines, known to affect embryo implantation and gestation: granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF). STUDY DESIGN: Cervico-vaginal samples were collected on the day of oocyte pick-up from 82 women. Vaginas were flushed with 50 mL of sterile water and 3 mL of fluid was collected. RESULTS: Twelve women (15%) were positive for HPV. Interestingly, among HPV(+) women live birth rate was about half of the rate in HPV(-) women, although the differences were not statistically significant due to the low number of cases. Cervico-vaginal samples of a sub-group of 29 (8 HPV(+) and 21 HPV(-)) women were analyzed for GM-CSF and G-CSF by ELISA. GM-CSF but not G-CSF was significantly lower in the cervico-vaginal fluid of HPV(+) than in HPV(-) women. CONCLUSIONS: Since GM-CSF plays an important role during pregnancy, the reduced levels of GM-CSF in the cervico-vaginal fluid of HPV(+) women might contribute to explain the reduced live birth rate observed in HPV(+) women. PMID- 23920356 TI - Accumulated uremic toxins attenuate bone mechanical properties in rats with chronic kidney disease. AB - The prevalence of hip fracture is very high among patients with chronic kidney disease (CKD); however, the reason for this is unclear. We examined the effects of accumulated uremic toxins on bone chemical composition and elastic mechanical properties. Rats underwent thyroparathyroidectomy and progressive partial nephrectomy (TPTx-Nx), and were administered with vehicle or AST-120 to reduce serum indoxyl sulfate (IS) levels. Bone mechanical properties, bone mineral density (BMD), cortical bone chemical composition, and histomorphometry were determined. Storage modulus was reduced in TPTx-Nx rats compared with rats that underwent TPTx alone. BMD and histomorphometric parameters did not differ between the groups. In terms of cortical bone chemical composition, the mineral/matrix ratio and carbonate substitution was increased, whereas crystallinity was decreased in TPTx-Nx rats. The enzymatic crosslink ratio and pentosidine:matrix ratio were increased in TPTx-Nx rats. AST-120 abolished the effects of TPTx-Nx and decreased the serum IS concentration. Stepwise multiple regression analysis revealed that the pentosidine:matrix and mineral:matrix ratios were independent contributors to the storage modulus. In conclusion, the accumulated uremic toxins, including IS, seem to play an important role in deteriorating bone mechanical properties by altering the chemical composition of bone. This mechanism may account for the increased prevalence of hip fracture among patients with CKD. PMID- 23920357 TI - Perceived impact and feasibility of strategies to improve access to healthy foods in Washington State, USA. AB - OBJECTIVE: The present study measured the perceived impact and political and implementation feasibility of state-level policy strategies related to increasing access to healthy foods and limiting unhealthy foods. DESIGN: Potential state level policy strategies to improve access to healthy foods were identified through a review of evidence-based literature and policy recommendations. Respondents rated the perceived impact and political and implementation feasibility of each policy on a five-point scale using online surveys. SETTING: Washington State policy process. SUBJECTS: Forty-nine content experts (national researchers and subject experts), forty policy experts (state elected officials or their staff, gubernatorial or legislative policy analysts) and forty-five other stakeholders (state-level advocates, programme administrators, food producers). RESULTS: In aggregate, respondents rated policy impact and implementation feasibility higher than political feasibility. Policy experts rated policy strategies as less politically feasible compared with content experts (P < 0.02) or other stakeholders (P < 0.001). Eight policy strategies were rated above the median for impact and political and implementation feasibility. These included policies related to nutrition standards in schools and child-care facilities, food distribution systems, urban planning projects, water availability, joint use agreements and breast-feeding supports. CONCLUSIONS: Although they may be perceived as potentially impactful, some policies will be more difficult to enact than others. Information about the potential feasibility of policies to improve access to healthy foods can be used to focus limited policy process resources on strategies with the highest potential for enactment, implementation and impact. PMID- 23920359 TI - In vivo trp scanning of the small multidrug resistance protein EmrE confirms 3D structure models'. AB - The quaternary structure of the homodimeric small multidrug resistance protein EmrE has been studied intensely over the past decade. Structural models derived from both two- and three-dimensional crystals show EmrE as an anti-parallel homodimer. However, the resolution of the structures is rather low and their relevance for the in vivo situation has been questioned. Here, we have challenged the available structural models by a comprehensive in vivo Trp scanning of all four transmembrane helices in EmrE. The results are in close agreement with the degree of lipid exposure of individual residues predicted from coarse-grained molecular dynamics simulations of the anti-parallel dimeric structure obtained by X-ray crystallography, strongly suggesting that the X-ray structure provides a good representation of the active in vivo form of EmrE. PMID- 23920358 TI - A gene-specific method for predicting hemophilia-causing point mutations. AB - A fundamental goal of medical genetics is the accurate prediction of genotype phenotype correlations. As an approach to develop more accurate in silico tools for prediction of disease-causing mutations of structural proteins, we present a gene- and disease-specific prediction tool based on a large systematic analysis of missense mutations from hemophilia A (HA) patients. Our HA-specific prediction tool, HApredictor, showed disease prediction accuracy comparable to other publicly available prediction software. In contrast to those methods, its performance is not limited to non-synonymous mutations. Given the role of synonymous mutations in disease and drug codon optimization, we propose that utilizing a gene- and disease-specific method can be highly useful to make functional predictions possible even for synonymous mutations. Incorporating computational metrics at both nucleotide and amino acid levels along with multiple protein sequence/structure alignment significantly improved the predictive performance of our tool. HApredictor is freely available for download at http://www.ncbi.nlm.nih.gov/CBBresearch/Przytycka/HA_Predict/index.htm. PMID- 23920360 TI - Fractal structures of single-walled carbon nanotubes in biologically relevant conditions: role of chirality vs. media conditions. AB - Aggregate structure of covalently functionalized chiral specific semiconducting single-walled carbon nanotubes (SWNTs) was systematically studied employing static light scattering (SLS). Fractal dimensions (Df) of two specific chirality SWNTs-SG65 and SG76 with (6, 5) and (7, 6) chiral enrichments-were measured under four biological exposure media conditions, namely: Dulbecco's Modified Eagle Medium (DMEM), Minimum Essential Medium (MEM), Roswell Park Memorial Institute (RPMI) 1640 medium, and 0.9% saline solution. The SWNTs exhibited chiral dependence on Df with SG65 showing more fractal or loosely bound aggregate structures, i.e., lower Df values (range of 2.24+/-0.03 to 2.64+/-0.05), compared to the SG76 sample (range of 2.58+/-0.13 to 2.90+/-0.08). All the Df values reported are highly reproducible, measured from multiple SLS runs and estimated with 'random block-effects' statistical analysis that yielded all p values to be <0.001. The key mechanism for such difference in Df between the SWNT samples was identified as the difference in van der Waals (VDW) interaction energies of these samples, where higher VDW of SG76 resulted in tighter packing density. Effect of medium type showed lower sensitivity; however, presence of di-valent cations (Ca(2+)) in DMEM and MEM media resulted in relatively loose or more fractal aggregates. Moreover, presence of fetal bovine serum (FBS) and bovine serum albumin (BSA), used to mimic the in vitro cell culture condition, reduced the Df values, i.e., created more fractal structures. Steric hindrance to aggregation was identified as the key mechanism for creating the fractal structures. Also, increase in FBS concentration from 1% to 10% resulted in increasingly lower Df values. PMID- 23920361 TI - Linear and branched perfluorooctane sulfonate (PFOS) isomer patterns differ among several tissues and blood of polar bears. AB - Perfluorooctane sulfonate (PFOS) is a globally distributed persistent organic pollutant that has been found to bioaccumulate and biomagnify in aquatic food webs. Although principally in its linear isomeric configuration, 21-35% of the PFOS manufactured via electrochemical fluorination is produced as a branched structural isomer. PFOS isomer patterns were investigated in multiple tissues of polar bears (Ursus maritimus) from East Greenland. The liver (n = 9), blood (n = 19), brain (n = 16), muscle (n = 5), and adipose (n = 5) were analyzed for linear PFOS (n-PFOS), as well as multiple mono- and di-trifluoromethyl-substituted branched isomers. n-PFOS accounted for 93.0 +/- 0.5% of Sigma-PFOS isomer concentrations in the liver, whereas the proportion was significantly lower (p<0.05) in the blood (85.4 +/- 0.5%). Branched isomers were quantifiable in the liver and blood, but not in the brain, muscle, or adipose. In both the liver and blood, 6-perfluoromethylheptane sulfonate (P6MHpS) was the dominant branched isomer (2.61 +/- 0.10%, and 3.26 +/- 0.13% of Sigma-PFOS concentrations, respectively). No di-trifluoromethyl-substituted isomers were detectable in any of the tissues analyzed. These tissue-specific isomer patterns suggest isomer specific pharmacokinetics, perhaps due to differences in protein affinities, and thus differences in protein interactions, as well transport, absorption, and/or metabolism in the body. PMID- 23920362 TI - Solid state fermentation of olive mill residues by wood- and dung-dwelling Agaricomycetes: effects on peroxidase production, biomass development and phenol phytotoxicity. AB - The in vivo conversion of dry olive mill residue (DOR) by wood- and dung-dwelling fungi - Auricularia auricula-judae, Bjerkandera adusta and Coprinellus radians - increases peroxidase secretion up to 3.2-3.5-fold (~1.3, 3.5 and 7.0 Ug(-1) DOR for dye-decolorizing peroxidase, manganese peroxidase and aromatic peroxygenases, respectively). The incubation of DOR with these fungi produced a sharp decrease in total phenolic content (100% within 4 wk), a reduction in phytotoxicity as well as a certain degree of plant growth caused by the stimulating effect of fungal-treated DOR. These findings correlate with a characteristic shift in the fragmentation pattern of water-soluble aromatics (detected at 280 nm) from low (0.2, 1.5 and 2.2 kDa, respectively) to high molecular mass (35 to >200 kDa), which demonstrates the presence of a polymerization process. Phenol-rich agricultural residues are a useful tool for enzyme expression and production studies of peroxidase-producing Agaricomycetes which could make DOR a valuable organic fertilizer. PMID- 23920363 TI - Association between somatic cell count after first parturition and cumulative milk yield in dairy cows. AB - The aim was to assess the association between the somatic cell count of parity 1 cows between 5 and 30 days in milk (SCC1), and subsequent cumulative milk yield over approximately two years for cows in English and Welsh dairy herds. The dataset included records from 43,461 cows in 2111 herds, from 2004 to 2006. Cumulative milk yield was the model outcome, and a random effect was included to account for variation between herds. The model fitted the data well and was used to make predictions of cumulative milk yield, based on SCC1. A unit increase in the natural logarithm of SCC1/1000 was associated with a median decrease in cumulative milk yield of 482 kg, over a median study period of 868 days. PMID- 23920364 TI - Capturing age-related changes in functional contrast sensitivity with decreasing light levels in monocular and binocular vision. AB - PURPOSE: It is challenging to separate the effects of normal aging of the retina and visual pathways independently from optical factors, decreased retinal illuminance, and early stage disease. This study determined limits to describe the effect of light level on normal, age-related changes in monocular and binocular functional contrast sensitivity. METHODS: We recruited 95 participants aged 20 to 85 years. Contrast thresholds for correct orientation discrimination of the gap in a Landolt C optotype were measured using a 4-alternative, forced choice (4AFC) procedure at screen luminances from 34 to 0.12 cd/m(2) at the fovea and parafovea (0 degrees and +/-4 degrees ). Pupil size was measured continuously. The Health of the Retina index (HRindex) was computed to capture the loss of contrast sensitivity with decreasing light level. Participants were excluded if they exhibited performance outside the normal limits of interocular differences or HRindex values, or signs of ocular disease. RESULTS: Parafoveal contrast thresholds showed a steeper decline and higher correlation with age at the parafovea than the fovea. Of participants with clinical signs of ocular disease, 83% had HRindex values outside the normal limits. Binocular summation of contrast signals declined with age, independent of interocular differences. CONCLUSIONS: The HRindex worsens more rapidly with age at the parafovea, consistent with histologic findings of rod loss and its link to age-related degenerative disease of the retina. The HRindex and interocular differences could be used to screen for and separate the earliest stages of subclinical disease from changes caused by normal aging. PMID- 23920365 TI - Tear film images and breakup analyzed using fluorescent quenching. AB - PURPOSE: Tear evaporation should increase fluorescein concentration, causing fluorescence dimming from self-quenching for high but not low fluorescein concentration. This prediction was tested and compared to the predicted effect of "tangential flow" that fluorescence dimming should be similar for high and low concentrations. METHODS: A custom optical system was used for video recording of tear film fluorescence in 30 subjects. The subjects were asked to blink at the start of the recording and try to keep their eyes open for the rest of the 60 second recording. An initial recording was made after instillation of 1 MUL 0.1% fluorescein followed by further recordings at 5-minute intervals using 0.5% and 5% fluorescein. RESULTS: Decay of fluorescence was considerably greater for the high (5%) concentration condition than for the low (0.1%) concentration. This is shown by "ratio images" (ratio of the intensity of a fluorescence image at a later time divided by that of an earlier image), fluorescence decay curves, fluorescence decay rates, and histograms of estimated tear thickness decrease. For example, for the high concentration condition, decay rates were higher than for the low concentration for all 30 subjects (P < 0.0001, binomial test). Additionally, breakup time was significantly reduced for the high compared to the low concentration condition. CONCLUSIONS: The greater fluorescence decay and more rapid breakup for the high concentration condition are the results expected if thinning and breakup are mainly due to evaporation, hence causing self-quenching. Fluorescence decay rate for the low concentration condition was not significantly greater than zero. PMID- 23920366 TI - Lack of association between primary angle-closure glaucoma susceptibility loci and the ocular biometric parameters anterior chamber depth and axial length. AB - PURPOSE: Three susceptibility loci for primary angle-closure glaucoma (PACG) were recently identified: PLEKHA7 rs11024102, COL11A1 rs3753841, and rs1015213 located in the intergenic region between PCMTD1 and ST18. The purpose of this study was to investigate the associations of these loci with the ocular biometric parameters anterior chamber depth (ACD) and axial length (AL). METHODS: Genotype and ocular biometric data were available for four population-based studies, including three from Singapore (Singapore Chinese Eye Study, Singapore Malay Eye Study, and Singapore Indian Eye Study) and one from China (Beijing Eye Study), exceeding 7000 participants. ACD and AL were measured using the IOLMaster for the Singapore cohorts and optical low-coherence reflectometry (Lenstar 900 Optical Biometer) for the Beijing cohort. Five readings were obtained for each participant and the average was computed. Analysis excluded any eye that was pseudophakic or aphakic. RESULTS: ACD measurements and genotype data of the three loci were available for 7245, 7243, and 7239 subjects, respectively. We noted nominal evidence of association between single nucleotide polymorphism (SNP) rs1015213 (PCMTD1-ST18) and a shallower ACD when all data were meta-analyzed (beta = -0.033, P = 0.021). When multiple testing was considered, the observation was nonsignificant. There was no association between ACD and rs11024102 (PLEKHA7) or rs3753841 (COL11A1). We did not observe significant associations between AL and any of the three SNPs. CONCLUSIONS: The lack of association between the PACG susceptibility loci with ACD or AL suggests that predilection to PACG may be mediated by factors other than shallow anterior chamber or short eyeball length. PMID- 23920367 TI - Diabetes-induced impairment in visual function in mice: contributions of p38 MAPK, rage, leukocytes, and aldose reductase. AB - PURPOSE: Visual function is impaired in diabetes, but molecular causes of this dysfunction are not clear. We assessed effects of diabetes on visual psychophysics in mice, and tested the effect of therapeutic approaches reported previously to inhibit vascular lesions of the retinopathy. METHODS: We used the optokinetic test to assess contrast sensitivity and spatial frequency threshold in diabetic C57Bl/6J mice and age-matched nondiabetic controls between 2 and 10 months of diabetes. Contributions of p38 MAP kinase (MAPK), receptor for advanced glycation end products (RAGE), leukocytes, and aldose reductase (AR) to the defect in contrast sensitivity were investigated. Cataract, a potential contributor to reductions in vision, was scored. RESULTS: Diabetes of 2 months' duration impaired contrast sensitivity and spatial frequency threshold in mice. The defect in contrast sensitivity persisted for at least 10 months, and cataract did not account for this impairment. Diabetic mice deficient in AR were protected significantly from development of the diabetes-induced defects in contrast sensitivity and spatial frequency threshold. In contrast, pharmacologic inhibition of p38 MAPK or RAGE, or deletion of inducible nitrous oxide synthase (iNOS) from bone marrow-derived cells did not protect the visual function in diabetes. CONCLUSIONS: Diabetes reduces spatial frequency threshold and contrast sensitivity in mice, and the mechanism leading to development of these defects involves AR. The mechanism by which AR contributes to the diabetes-induced defect in visual function can be probed by identifying which molecular abnormalities are corrected by AR deletion, but not other therapies that do not correct the defect in visual function. PMID- 23920368 TI - Development of refractive error in individual children with regressed retinopathy of prematurity. AB - PURPOSE: We investigated longitudinally the refraction development in children with regressed retinopathy of prematurity (ROP), including those with and those without a history of peripheral retinal laser photocoagulation. METHODS: Longitudinal (0-7 years) cycloplegic refraction data were collected prospectively for two groups of preterm children: severe ROP group included those with regressed ROP following bilateral panretinal laser photocoagulation (n = 37; median gestational age [GA] = 25.2; range, 22.7-27.9 weeks) and mild/no ROP group included those with spontaneously regressed ROP or no ROP (n = 27; median GA = 27.1; range, 23.1-32.0 weeks). Analyses were based on spherical equivalent (SEQ), anisometropia, astigmatism, and age (corrected for gestation). RESULTS: The prevalence, magnitude, and rate of myopic progression all were significantly higher in the severe ROP group than in the mild/no ROP group. Longitudinal SEQ in the severe ROP group were best fit with a bilinear model. Before 1.3 years old, the rate of myopic shift was -4.7 diopters (D)/y; after 1.3 years, the rate slowed to -0.15 D/y. Longitudinal SEQ in the mild/no ROP group was best fit with a linear model, with a rate of -0.004 D/y. Anisometropia in the severe ROP group increased approximately three times faster than in the mild/no ROP group. In the severe ROP group, with-the-rule astigmatism increased significantly with age. CONCLUSIONS: The severe ROP group progressed rapidly toward myopia, particularly during the first 1.3 years; anisometropia and astigmatism also increased with age. The mild/no ROP group showed little change in refraction. Infants treated with laser photocoagulation for severe ROP should be monitored with periodic cycloplegic refractions and provided with early optical correction. PMID- 23920369 TI - Ultrasound-enhanced penetration of topical riboflavin into the corneal stroma. AB - PURPOSE: To determine whether ultrasound treatment can promote the permeation of topical riboflavin into the corneal stroma. METHODS: Fresh cadaveric rabbit eyes with intact epithelium were left for 45 minutes in riboflavin 0.1% solution and divided in the following groups: A--untreated, epithelium-on; B--ultrasound treated (1 W/cm(2) at 880 kHz for 6 minutes) with epithelium-on; and C- epithelium-off (no ultrasound). Eyes were removed from the riboflavin solution, corneas were excised, and group B was divided into B1 (with epithelium maintained) and B2 (epithelium removed for the fluorescence analysis). Confocal microscopy was performed to quantify the fluorescence intensity in the cornea according to the distance from the surface (with epithelium in groups A and B1; without epithelium in groups B2 and C). RESULTS: The average fluorescence intensity of riboflavin at a depth of 100, 150, 200, and 250 MUm was 69.97, 58.83, 49.23, and 41.72 arbitrary units (A.U.) in group A, respectively; 255.26, 206.01, 159.81, 124.20 A.U. in group B1; 218.90, 177.90, 141.43, 110.45 A.U. in group B2; and 677.64, 420.10, 250.72 and 145.07 A.U. in group C. The difference in fluorescence was statistically significant between groups A and B1 (P = 0.001) and groups B2 and C (P < 0.0001). CONCLUSIONS: Ultrasound treatment increased the entry of topical riboflavin into the corneal stroma despite the presence of a previously intact epithelial barrier. This approach may offer a means of achieving clinically useful concentrations of riboflavin within the cornea with minimum epithelial damage, thereby improving the risk profile of corneal cross linking procedures. PMID- 23920370 TI - Alarmins from corneal epithelial cells upregulate CCL11 and VCAM-1 in corneal fibroblasts. AB - PURPOSE: Severe ocular allergic diseases are characterized by pronounced conjunctival inflammation triggered by T helper 2 (Th2) cells and corneal epithelial damage induced by eosinophils. To examine the role of alarmins released by damaged corneal epithelial cells in tissue eosinophilia, we investigated the effects of a supernatant derived from necrotic human corneal epithelial (HCE) cells on expression of the chemokine CCL11 (eotaxin) and the adhesion molecule VCAM-1 in human corneal fibroblasts. METHODS: An alarmin preparation was obtained as the material released from HCE cells after three cycles of freezing and thawing. CCL11 released into culture medium and cell surface expression of VCAM-1 were measured with enzyme-linked immunosorbent assays, and the amounts of CCL11 and VCAM-1 mRNAs were quantitated by reverse transcription and real-time polymerase chain reaction analysis. Signaling by the transcription factor NF-kappaB was evaluated by immunoblot and immunofluorescence analyses. RESULTS: The combination of the necrotic HCE cell supernatant and either interleukin (IL)-4 or IL-13 induced synergistic increases in CCL11 release, VCAM-1 expression, and the abundance of CCL11 and VCAM-1 mRNAs in corneal fibroblasts. The necrotic HCE cell supernatant also induced NF-kappaB activation in corneal fibroblasts, whereas an inhibitor of NF-kappaB and IL-1 receptor antagonist each attenuated CCL11 release induced by the alarmin preparation and either IL-4 or IL-13. CONCLUSIONS: Alarmins including IL-1 released from necrotic corneal epithelial cells cooperate with Th2 cytokines to induce CCL11 production and VCAM-1 expression in corneal fibroblasts, and may thereby play an important role in tissue eosinophilia associated with ocular allergic diseases. PMID- 23920371 TI - Three-dimensional configuration of subretinal fluid in central serous chorioretinopathy. AB - PURPOSE: The purpose of this study was to characterize the 3-dimensional (3D) configuration of subretinal fluid (SRF) in idiopathic central serous chorioretinopathy (CSC) using spectral-domain optical coherence tomography (SDOCT). METHODS: The OCT images of patients with CSC were reviewed retrospectively. The 3D configurations of SRF were assessed using a modified segmentation algorithm of SDOCT. The differences of the configurations between acute and chronic CSC were compared. For the patients with acute CSC, we investigated a possible relationship between early change in 3D configuration and disease prognosis. RESULTS: We included 69 eyes of 68 patients in this study. The mean volume, the greatest basal diameter (GBD), and the area of SRF were not different between acute and chronic CSC. The mean peak height (PH) of SRF and the ratio of PH to GBD in acute CSC (298.13 +/- 92.67 MUm, 9.44 +/- 2.57%) were significantly greater than those in chronic CSC (192.97 +/- 71.05 MUm, 5.97 +/- 1.90%; P < 0.001, P < 0.001, respectively). In patients with acute CSC, the early changing pattern of 3D configurations was significantly different according to the SRF prognosis (P = 0.003). In situ decrease of SRF was observed in 94.7% of the spontaneously resolving group. However, downward elongation of SRF was observed more frequently in the persistent group (58.3%) than in the spontaneously resolving group (6.3%). CONCLUSIONS: The 3D configurations of SRF were different between acute and chronic CSC. In patients with acute onset, the early change of 3D configuration was different and varied according to the SRF prognosis. PMID- 23920372 TI - p75 neurotrophin receptor participates in the choroidal antiangiogenic and apoptotic effects of T-lymphocyte-derived microparticles. AB - PURPOSE: Choroidal neovascularization (CNV) is a major cause of vision loss in which choroidal vessels penetrate the RPE-an important source of growth factors, including nerve growth factor (NGF), whose activation via the p75NTR receptor promotes apoptosis and inhibits angiogenesis. We demonstrated previously that human T-lymphocyte-derived microparticles (LMPs) significantly inhibit angiogenesis in several models of ocular neovascularization. We investigated how LMPs modulate pro- and antiangiogenic microenvironments during choroidal angiogenesis. METHODS: Antiangiogenic effects of LMPs were investigated using a rat model of choroidal angiogenesis. The impact of LMPs on expression of major angiogenic factors was assessed by real-time quantitative PCR (qPCR). To determine whether p75NTR signalling was implicated in LMPs-induced activities, we used a specific antibody and short hairpin RNA (shRNA) targeting p75NTR. Cellular apoptosis was determined via evaluation of activated caspase-3 and annexin V binding. RESULTS: The LMPs time-dependently inhibited choroidal angiogenesis by more than 64% after 48 hours of treatment. Removal of the RPE from choroidal explants abolished the antiangiogenic effects of LMPs. The mRNA levels of pigment epithelium-derived factor (PEDF) and NGF were increased significantly following LMPs treatment of intact, but not RPE-removed choroids. Downregulation of PEDF and p75NTR significantly blocked the antiangiogenic effects of LMPs. Finally, induction of choroidal endothelial cell apoptosis by LMPs was dependent on p75NTR. CONCLUSIONS: We demonstrate for the first time to our knowledge that LMPs markedly inhibit choroidal angiogenesis via mechanisms that are dependent on the integrity of the RPE, and that are mediated largely by the PEDF and proapoptotic activities of p75NTR. PMID- 23920373 TI - In vitro and in vivo uptake study of Escherichia coli Nissle 1917 bacterial ghosts: cell-based delivery system to target ocular surface diseases. AB - PURPOSE: For the successful topical administration of drugs or vaccines to treat ocular surface diseases, efficient and well-tolerated delivery systems/carriers for conjunctival delivery are crucial in the development of new treatment strategies. The present study investigated the efficiency of internalization of bacterial ghosts (BGs) produced from probiotic Escherichia coli Nissle 1917 (EcN) by human conjunctival epithelial (HCjE) cell line, the EcN BGs cytotoxicity for HCjE cells, and in vivo uptake of EcN BGs by conjunctival guinea pig epithelial cells. METHODS: The uptake of EcN BGs by HCjE cells was analyzed by laser scanning microscopy and flow cytometry. Immunohistochemistry was used to localize the EcN BGs in the guinea pig conjunctival tissue. Cytotoxicity of EcN BGs on HCjE cells was evaluated by measurement of LDH. RESULTS: Laser scanning microscopy and flow cytometry revealed that EcN BGs internalization by HCjE cells was time- and dose dependent. No cytotoxic effect on HCjE cells was observed after EcN BGs inoculation for 30 and 120 minutes, as well as 24 hours. In addition, the uptake of EcN BGs was detected in the conjunctival cells after in vivo administration of EcN BGs into the eye of the guinea pig. CONCLUSIONS: The findings that EcN BGs are nontoxic and effectively internalized in vitro by human and in vivo by guinea pig conjunctival cells comprise an important contribution to the future use of BGs as a system for conjunctival delivery of drugs and vaccines, either to treat or prevent ocular surface diseases. PMID- 23920374 TI - Effects of Y27632 on aqueous humor outflow facility with changes in hydrodynamic pattern and morphology in human eyes. AB - PURPOSE: To determine the effect of Y27632, a Rho-kinase inhibitor on aqueous outflow facility, flow pattern, and juxtacanalicular tissue (JCT)/trabecular meshwork (TM) morphology in human eyes. METHODS: Sixteen enucleated human eyes were perfused with PBS plus glucose (GPBS) at 15 mm Hg to establish the baseline outflow facility. Six eyes were perfused for short-duration (30 minute) with either 50 MUM Y27632 or GPBS (n = 3 per group). Ten eyes were perfused for long duration (3 hours) with either 50 MUM Y27632 or GPBS (n = 5 per group). Outflow pattern was labeled using fluorescent microspheres, and effective filtration length (EFL) was measured. Morphologic changes and their relationship to EFL and facility were analyzed. RESULTS: Outflow facility significantly increased after short-duration perfusion with Y27632 compared with its own baseline (P = 0.03), but did not reach statistical significance compared with its controls (P = 0.07). Outflow facility (P = 0.01) and EFL (P < 0.05) were significantly increased after long-duration perfusion with Y27632 compared with its controls. Increases in outflow facility and EFL demonstrated a positive correlation. Morphologically, the TM and JCT of high-tracer regions were more expanded compared with low-tracer regions. A significant increase in JCT thickness was found in the long-duration Y27632 group compared with its control group (10.0 vs. 8.0 MUm, P < 0.01). CONCLUSIONS: Y27632 increases outflow facility in human eyes. This increase correlates positively with an increase in EFL, which is associated with an increased expansion in the JCT. Our data suggest that EFL could serve as a novel parameter to correlate with outflow facility. PMID- 23920375 TI - Evaluation of retinal nerve fiber layer and ganglion cell layer thickness in Alzheimer's disease using spectral-domain optical coherence tomography. AB - PURPOSE: To evaluate differences between the retinal nerve fiber layer (RNFL) thickness and RNFL + ganglion cell layer (GCL) thickness in patients affected by Alzheimer's disease (AD) and healthy patients using spectral-domain optical coherence tomography (SD-OCT). METHODS: This was a case-control prospective study. Twenty-one AD patients and 21 healthy subjects underwent neurological examination, clock-drawing test (CDT), Mini Mental State Examination (MMSE), and comprehensive ophthalmic evaluation with visual acuity. SD-OCT examination was performed using Spectralis and RTVue-100. An RNFL thickness map was obtained using the Spectralis volume protocol with 19 lines on the 30 degrees field centered on the macula. On each B-scan, the outer RNFL limit was manually set. Statistical analysis was performed to assess interoperator RNFL evaluation thickness. An RNFL+GCL thickness map was obtained using the RTVue-100 MM6 protocol. Maps were divided into the nine ETDRS subfields and each map value in every area was evaluated. A single eye from each patient was randomly chosen to perform the analysis. Differences between AD and healthy subjects were assessed. RESULTS: The two study groups were age and sex matched. MMSE results were 19.9 +/ 3.1 and 27.9 +/- 1.3, respectively (P < 0.001). There was good agreement in the manual delimitation of the RNFL layer. There was a significant difference in the thickness of both the RNFL and the RNFL+GCL in all examined fields. For example, in the inferior internal subfield, the RNFL thickness was 28.1 +/- 3.1 MUm for AD patients and 32.6 +/- 3.8 MUm for healthy subjects (P < 0.001). CONCLUSIONS: These results indicate that RNFL and RNFL+GCL thickness measurements are reduced in AD patients compared with healthy subjects. This finding may represent a useful element for the diagnosis and follow-up of this pathology. PMID- 23920376 TI - Impact of systemic lupus erythematosus on burden of illness and work productivity in the United States. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by clinical manifestations that can cause diminished activity and productivity. The objectives of this study were to: (a) longitudinally evaluate patient reported SLE disease activity, and (b) measure work productivity, missed work hours, and associated lost income among employed patients with SLE. Three cohorts (employed subjects with SLE (n = 281), nonemployed subjects with SLE (n = 265), and a control group of employed individuals without SLE (n = 300)) completed a baseline survey. Employed subjects with SLE completed follow-up surveys every two weeks during a six-month period. Measured outcomes included perceived health, disease manifestations and severity, the Lupus Impact Tracker, the Modified Systemic Lupus Activity Questionnaire, and Work Productivity and Activity Impairment Questionnaire. Higher self-reported SLE disease severity was directly associated with experiencing more frequent and more severe symptoms as well as higher levels of lost work time and lost work productivity. Though patient self assessment may differ from physician's clinical assessment, it is important to incorporate the patient perspective in clinical decision-making to optimally manage SLE patients. Given the evidence associating SLE with work disability and job loss, it may be beneficial for professionals addressing worksite modifications or compensatory strategies to be included as members of SLE medical teams. PMID- 23920378 TI - Guaranteed epsilon-optimal treatment plans with the minimum number of beams for stereotactic body radiation therapy. AB - Stereotactic body radiation therapy (SBRT) is characterized by delivering a high amount of dose in a short period of time. In SBRT the dose is delivered using open fields (e.g., beam's-eye-view) known as 'apertures'. Mathematical methods can be used for optimizing treatment planning for delivery of sufficient dose to the cancerous cells while keeping the dose to surrounding organs at risk (OARs) minimal. Two important elements of a treatment plan are quality and delivery time. Quality of a plan is measured based on the target coverage and dose to OARs. Delivery time heavily depends on the number of beams used in the plan as the setup times for different beam directions constitute a large portion of the delivery time. Therefore the ideal plan, in which all potential beams can be used, will be associated with a long impractical delivery time. We use the dose to OARs in the ideal plan to find the plan with the minimum number of beams which is guaranteed to be epsilon-optimal (i.e., a predetermined maximum deviation from the ideal plan is guaranteed). Since the treatment plan optimization is inherently a multi-criteria-optimization problem, the planner can navigate the ideal dose distribution Pareto surface and select a plan of desired target coverage versus OARs sparing, and then use the proposed technique to reduce the number of beams while guaranteeing epsilon-optimality. We use mixed integer programming (MIP) for optimization. To reduce the computation time for the resultant MIP, we use two heuristics: a beam elimination scheme and a family of heuristic cuts, known as 'neighbor cuts', based on the concept of 'adjacent beams'. We show the effectiveness of the proposed technique on two clinical cases, a liver and a lung case. Based on our technique we propose an algorithm for fast generation of epsilon-optimal plans. PMID- 23920377 TI - Reduction of Nipbl impairs cohesin loading locally and affects transcription but not cohesion-dependent functions in a mouse model of Cornelia de Lange Syndrome. AB - Cornelia de Lange Syndrome (CdLS) is a genetic disorder linked to mutations in cohesin and its regulators. To date, it is unclear which function of cohesin is more relevant to the pathology of the syndrome. A mouse heterozygous for the gene encoding the cohesin loader Nipbl recapitulates many features of CdLS. We have carefully examined Nipbl deficient cells and here report that they have robust cohesion all along the chromosome. DNA replication, DNA repair and chromosome segregation are carried out efficiently in these cells. While bulk cohesin loading is unperturbed, binding to certain promoters such as the Protocadherin genes in brain is notably affected and alters gene expression. These results provide further support for the idea that developmental defects in CdLS are caused by deregulated transcription and not by malfunction of cohesion-related processes. PMID- 23920380 TI - Carotid artery atherosclerotic profile as a predictor of the aorta atherosclerotic profile in patients with cerebrovascular events. AB - BACKGROUND: It is well known that the presence of atheroma of the thoracic aorta is a risk factor for cerebrovascular events. We sought to evaluate whether the presence and the morphology of atherosclerotic plaque in the carotid artery detected by duplex ultrasonography is associated with disease in the proximal aorta visualized by transesophageal echocardiogram in patients with a cerebrovascular event. METHODS: We carried out a cross-sectional prospective study including 147 consecutive patients with prior stroke or transient ischemic attack (TIA). Neurological evaluations were performed by an expert neurologist using clinical and tomographic diagnostic criteria including the definition of etiology and whether the patient suffered from stroke or TIA. Transthoracic and transesophageal echocardiograms and carotid artery duplex ultrasonography were performed by the same examiner. Patients with and without plaque in the carotid artery were compared using Student's t test or the chi2 test. Regression analysis was used to determine whether the presence of plaque in the carotid artery was predictive of the presence of plaque in the proximal aorta and to analyze the relationship between the echogenicity of carotid and aortic plaques. The significance level was set at p < 0.05. RESULTS: All 147 patients (95 men) were included in the analysis. Patients' ages ranged from 23 to 85 years (65 +/- 12.4 years). Most of the patients (58.5%) were Caucasian, while 41.5% were African Brazilian. Arterial hypertension, diabetes and tobacco use were more frequent among patients with atherosclerotic plaque in the aorta. A normal carotid intima media thickness halved the risk of atherosclerotic plaque in the aorta [odds ratio (OR) 0.46, 95% confidence interval (CI) 0.23-0.91; p = 0.026]. The presence of carotid plaque increased the risk of aortic plaque by 70-fold (OR 73.2, 95% CI 25.6-2,018.6; p < 0.001) in univariate analysis. The absence of atherosclerotic plaque in the carotid artery reduced the risk of plaque in the aorta to almost 0 (OR 0.014, 95% CI 0.004-0.041; p < 0.001). Considering the 86 patients with both aortic and carotid plaques, the presence of hypoechoic plaque in the carotid artery was a predictor of hypoechoic plaque in the aorta (OR 10.1, 95% CI 3.3 31.2; p < 0.001). CONCLUSIONS: The carotid artery atherosclerotic profile defined by ultrasonography is a strong predictor of the atherosclerotic profile of the proximal aorta. This should be taken into consideration before referring patients with acute cerebrovascular events for transesophageal echocardiogram. PMID- 23920379 TI - Cross-validation analysis of the prognostic significance of mucin expression in patients with resected non-small cell lung cancer treated with adjuvant chemotherapy: results from IALT, JBR.10 and ANITA. AB - INTRODUCTION: CALGB 9633 was a randomized trial of observation versus adjuvant chemotherapy for patients with stage IB non-small cell lung cancer (NSCLC). In CALGB 9633, the presence of mucin in the primary tumor was associated with shorter disease-free survival (DFS; hazard ratio (HR) = 1.9, p = 0.002) and overall survival (OS; HR = 1.9, p = 0.004). METHODS: To validate these results, mucin staining was performed on primary tumor specimens from 780 patients treated on IALT, 351 on JBR.10 and 150 on ANITA. The histochemical technique using mucicarmine was performed. The prognostic value of mucin for DFS and OS was tested in a Cox model stratified by trial and adjusted for clinical and pathological factors. A pooled analysis of all 4 trials was performed for the predictive value of mucin for benefit from adjuvant chemotherapy. RESULTS: The cross-validation group had 48% squamous, 37% adenocarcinoma and 15% other NSCLC compared with 29%, 56%, and 15%, respectively in CALGB. Among 1262 patients with assessable results, mucin was positive in IALT 24%, JBR.10 30%, ANITA 22% compared with 45% in CALGB. Histology was the only significant covariate (p < 0.0001) in multivariate analysis with mucin seen more commonly in adenocarcinoma (56%) compared with squamous (5%) and other NSCLC (15%). Mucin was a borderline negative prognostic factor for DFS (HR = 1.2 [1.0-1.5], p = 0.06) but not significantly so for OS (HR=1.1 [0.9-1.4], p = 0.25). Prognostic value did not vary according to histology: HR = 1.3 [1.0-1.6] in adenocarcinoma vs. 1.6 [1.2 2.2] for DFS in other histology (interaction p = 0.69). Mucin status was not predictive for benefit from adjuvant chemotherapy (test of interaction: DFS p = 0.27; OS p = 0.49). CONCLUSIONS: Mucin was less frequent in the cross-validation group due to its higher percentage of squamous cell carcinomas. The negative impact of mucin was confirmed for DFS but not for OS. Mucin expression was not predictive of overall survival benefit from adjuvant chemotherapy. PMID- 23920381 TI - Prenatal transport stress, postnatal maternal behavior, and offspring sex differentially affect seizure susceptibility in young rats. AB - Epilepsy is a heterogeneous and chronic neurological condition of undefined etiology in the majority of cases. Similarly, the pathogenesis of the unprovoked seizures that lead to epilepsy is not known. We are interested in the factors that modify inherent seizure susceptibility, with a particular focus on those occurring during the prenatal and early postnatal periods. Female Sprague-Dawley rats were bred in-house or transported during pregnancy at one of two gestational days (G9 or G16). The effects of transport stress, maternal behavior, and offspring sex were then examined in terms of how they were related to provoked seizure susceptibility to kainic acid (KA) or a model of febrile convulsions (FCs) on postnatal day 14 (P14). We also examined the pattern of neuronal activation in the hippocampus and amygdala as indicated by the density of FosB protein immunoreactivity (FosB-ir). Results demonstrated only a small and inconsistent effect of transport alone, suggesting that the groups differed slightly prior to experimental manipulations. However, the influence of maternal behaviors such as licking and grooming (LG), arched back nursing (ABN), and dam off time (DO) exerted a much stronger effect on the offspring. Dams designated as high LG gave birth to smaller litters, had pups that weighed less, had greater seizure susceptibility and severity, and had more FosB-ir neurons predominantly in the ventral hippocampus and the medial subnucleus of the amygdala (MeA). We also found a sex-dependent effect such that P14 males were smaller than their female littermates and had a greater seizure susceptibility and severity. Taken together, these results suggest an impact of prenatal and postnatal factors, as well as sex, on seizure susceptibility in young animals. PMID- 23920382 TI - Oncology scan--promising strategies for the treatment of locally-advanced non small cell lung cancer. PMID- 23920383 TI - In reply to Kumar et al. PMID- 23920384 TI - The four Rs of the Red Journal: a progress report from the new editorial team. PMID- 23920385 TI - Favorable anal cancer: does it include T2N0 disease? How might the electively irradiated nodal volume be reduced? PMID- 23920387 TI - Incidence, causative mechanisms, and anatomic localization of stroke in pituitary adenoma patients treated with postoperative radiation therapy versus surgery alone. AB - PURPOSE: To assess and compare the incidence of stroke and stroke subtype in pituitary adenoma patients treated with postoperative radiation therapy (RT) and surgery alone. METHODS AND MATERIALS: A cohort of 462 pituitary adenoma patients treated between 1959 and 2008 at the University Medical Center Groningen in The Netherlands was studied. Radiation therapy was administered in 236 patients. The TOAST (Trial of ORG 10172 in Acute Stroke Treatment) and the Oxfordshire Community Stroke Project classification methods were used to determine causative mechanism and anatomic localization of stroke. Stroke incidences in patients treated with RT were compared with that observed after surgery alone. Risk factors for stroke incidence were studied by log-rank test, without and with stratification for other significant risk factors. In addition, the stroke incidence was compared with the incidence rate in the general Dutch population. RESULTS: Thirteen RT patients were diagnosed with stroke, compared with 12 surgery-alone patients. The relative risk (RR) for stroke in patients treated with postoperative RT was not significantly different compared with surgery-alone patients (univariate RR 0.62, 95% confidence interval [CI] 0.28-1.35, P=.23). Stroke risk factors were coronary or peripheral artery disease (univariate and multivariate RR 10.4, 95% CI 4.7-22.8, P<.001) and hypertension (univariate RR 3.9, 95% CI 1.6-9.8, P=.002). There was no difference in TOAST and Oxfordshire classification of stroke. In this pituitary adenoma cohort 25 strokes were observed, compared with 16.91 expected (standard incidence ratio 1.48, 95% CI 1.00-1.96, P=.049). CONCLUSIONS: In pituitary adenoma patients, an increased incidence of stroke was observed compared with the general population. However, postoperative RT was not associated with an increased incidence of stroke or differences in causative mechanism or anatomic localization of stroke compared with surgery alone. The primary stroke risk factor was pre-existent coronary or peripheral artery disease. PMID- 23920388 TI - Increased bowel toxicity in patients treated with a vascular endothelial growth factor inhibitor (VEGFI) after stereotactic body radiation therapy (SBRT). AB - PURPOSE: Gastrointestinal injury occurs rarely with agents that affect the vascular endothelial growth factor receptor and with abdominal stereotactic body radiation therapy (SBRT). We explored the incidence of serious bowel injury (SBI) in patients treated with SBRT with or without vascular endothelial growth factor inhibitor (VEGFI) therapy. METHODS AND MATERIALS: Seventy-six patients with 84 primary or metastatic intra-abdominal lesions underwent SBRT (median dose, 50 Gy in 5 fractions). Of the patients, 20 (26%) received VEGFI within 2 years after SBRT (bevacizumab, n=14; sorafenib, n=4; pazopanib, n=1; sunitinib, n=1). The incidence of SBI (Common Terminology Criteria for Adverse Events, version 4.0, grade 3-5 ulceration or perforation) after SBRT was obtained, and the relationship between SBI and VEGFI was examined. RESULTS: In the combined population, 7 patients (9%) had SBI at a median of 4.6 months (range, 3-17 months) from SBRT. All 7 had received VEGFI before SBI and within 13 months of completing SBRT, and 5 received VEGFI within 3 months of SBRT. The 6-month estimate of SBI in the 26 patients receiving VEGFI within 3 months of SBRT was 38%. No SBIs were noted in the 63 patients not receiving VEGFI. The log-rank test showed a significant correlation between SBI and VEGFI within 3 months of SBRT (P=.0006) but not between SBI and radiation therapy bowel dose (P=.20). CONCLUSIONS: The combination of SBRT and VEGFI results in a higher risk of SBI than would be expected with either treatment independently. Local therapies other than SBRT may be considered if a patient is likely to receive a VEGFI in the near future. PMID- 23920389 TI - Causes of mortality after dose-escalated radiation therapy and androgen deprivation for high-risk prostate cancer. AB - PURPOSE: Men with high-risk prostate cancer have other competing causes of mortality; however, current risk stratification schema do not account for comorbidities. We aim to identify the causes of death and factors predictive for mortality in this population. METHODS AND MATERIALS: A total of 660 patients with high-risk prostate cancer were treated with definitive high-dose external beam radiation therapy (>= 74 Gy) and androgen deprivation (AD) between 1996 and 2009 at a single institution. Cox proportional hazards regression analysis was conducted to determine factors predictive of survival. RESULTS: The median radiation dose was 78 Gy, median duration of AD was 6 months, and median follow up was 74 months. The 10-year overall survival (OS) was 60.6%. Prostate cancer was the leading single cause of death, with 10-year mortality of 14.1% (95% CI 10.7-17.6), compared with other cancers (8.4%, 95% CI 5.7-11.1), cardiovascular disease (7.3%, 95% CI 4.7-9.9), and all other causes (10.4%, 95% CI 7.2-13.6). On multivariate analysis, older age (HR 1.55, P=.002) and Charlson comorbidity index score (CS) >= 1 (HR 2.20, P<.0001) were significant factors predictive of OS, whereas Gleason score, T stage, prostate-specific antigen, duration of AD, radiation dose, smoking history, and body mass index were not. Men younger than 70 years of age with CS = 0 were more likely to die of prostate cancer than any other cause, whereas older men or those with CS >= 1 more commonly suffered non prostate cancer death. The cumulative incidences of prostate cancer-specific mortality were similar regardless of age or comorbidities (P=.60). CONCLUSIONS: Men with high-risk prostate cancer are more likely to die of causes other than prostate cancer, except for the subgroup of men younger than 70 years of age without comorbidities. Only older age and presence of comorbidities significantly predicted for OS, whereas prostate cancer- and treatment-related factors did not. PMID- 23920390 TI - Long-term follow-up results of a multi-institutional phase 2 study of concurrent chemoradiation therapy for locally advanced cervical cancer in east and southeast Asia. AB - PURPOSE: To report the long-term survival and toxicity of a multi-institutional phase 2 study of concurrent chemoradiation therapy (CCRT) for locally advanced cervical cancer in east and southeast Asia. METHODS AND MATERIALS: Ten institutions from 8 Asian countries participated in the study. Between April 2003 and March 2006, 120 patients (60 with bulky stage IIB and 60 with stage IIIB) were treated with CCRT. Radiation therapy consisted of pelvic external beam radiation therapy and either high-dose-rate or low-dose-rate intracavitary brachytherapy. Five cycles of weekly cisplatin (40 mg/m(2)) were administered during the course of radiation therapy. Treatment results were evaluated by the rates of local control, overall survival, and late toxicities. RESULTS: Median follow-up was 63.7 months, and the follow-up rate at 5 years was 98%. The 5-year local control and overall survival rates for all patients were 76.8% and 55.1%, respectively. The 5-year rates of major late toxicities of the rectum and bladder were 7.9% and 0%, respectively. CONCLUSIONS: The long-term results have suggested that CCRT is safe and effective for patients with locally advanced cervical cancer in east and southeast Asia. However, further efforts are needed to improve overall survival. PMID- 23920391 TI - Classification system for identifying women at risk for altered partial breast irradiation recommendations after breast magnetic resonance imaging. AB - PURPOSE: To study the utility of preoperative breast MRI for partial breast irradiation (PBI) patient selection, using multivariable analysis of significant risk factors to create a classification rule. METHODS AND MATERIALS: Between 2002 and 2009, 712 women with newly diagnosed breast cancer underwent preoperative bilateral breast MRI at Mayo Clinic Florida. Of this cohort, 566 were retrospectively deemed eligible for PBI according to the National Surgical Adjuvant Breast and Bowel Project Protocol B-39 inclusion criteria using physical examination, mammogram, and/or ultrasound. Magnetic resonance images were then reviewed to determine their impact on patient eligibility. The patient and tumor characteristics were evaluated to determine risk factors for altered PBI eligibility after MRI and to create a classification rule. RESULTS: Of the 566 patients initially eligible for PBI, 141 (25%) were found ineligible because of pathologically proven MRI findings. Magnetic resonance imaging detected additional ipsilateral breast cancer in 118 (21%). Of these, 62 (11%) had more extensive disease than originally noted before MRI, and 64 (11%) had multicentric disease. Contralateral breast cancer was detected in 28 (5%). Four characteristics were found to be significantly associated with PBI ineligibility after MRI on multivariable analysis: premenopausal status (P=.021), detection by palpation (P<.001), first-degree relative with a history of breast cancer (P=.033), and lobular histology (P=.002). Risk factors were assigned a score of 0 2. The risk of altered PBI eligibility from MRI based on number of risk factors was 0:18%; 1:22%; 2:42%; 3:65%. CONCLUSIONS: Preoperative bilateral breast MRI altered the PBI recommendations for 25% of women. Women who may undergo PBI should be considered for breast MRI, especially those with lobular histology or with 2 or more of the following risk factors: premenopausal, detection by palpation, and first-degree relative with a history of breast cancer. PMID- 23920392 TI - Impact of the number of cautionary and/or unsuitable risk factors on outcomes after accelerated partial breast irradiation. AB - PURPOSE: To examine clinical outcomes of accelerated partial-breast irradiation (APBI) stratified by the number of American Society for Radiation Oncology consensus statement cautionary/unsuitable risk factors (RFs) present. METHODS AND MATERIALS: A total of 692 patients were treated with APBI at a single institution between April 1993 and January 2012 using interstitial (n=195), balloon (n=292), and 3-dimensional conformal radiation therapy (n=205) techniques. Clinical outcomes were evaluated by risk group and number of RFs. RESULTS: Median follow up was 5.2 years (range, 0-18.3 years). Most patients were classified as suitable (n=240, 34%) or cautionary (n=343, 50%) risk, whereas 16% (n=109) were unsuitable. In patients with increasing total RFs (1 RF, 2 RF, 3+ RF), higher rates of grade 3 histology (10% vs 18% vs 32%, P<.001), estrogen receptor negativity (0 vs 12% vs 29%, P<.001), close/positive margins (0 vs 6% vs 17%, P<.001), and use of adjuvant chemotherapy (3% vs 12% vs 33%, P<.001) were noted. When pooling cautionary and unsuitable patients, increased ipsilateral breast tumor recurrence/regional recurrence was most notable for patients with 3 or more combined RFs versus 2 or fewer combined RFs (P<.001). CONCLUSIONS: Patients with 3 or more cautionary or unsuitable RFs may be at risk for higher local, regional, and distant recurrence after breast-conserving therapy using APBI. Patients with 2 or fewer total RFs have 98% locoregional control at 5 years. Inclusion of total number of RFs in future risk stratification schemes for APBI may be warranted. PMID- 23920393 TI - Comparison of 2 common radiation therapy techniques for definitive treatment of small cell lung cancer. AB - PURPOSE: Two choices are widely used for radiation delivery, 3-dimensional conformal radiation therapy (3DCRT) and intensity modulated radiation therapy (IMRT). No randomized comparisons have been conducted in the setting of lung cancer, but theoretical concerns suggest that IMRT may negatively impact disease control. We analyzed a large cohort of limited-stage small-cell lung cancer (LS SCLC) patients treated before and after institutional conversion from 3DCRT to IMRT to compare outcomes. METHODS AND MATERIALS: Patients with LS-SCLC treated with definitive radiation at our institution between 2000 and 2009 were retrospectively reviewed. Both multivariable Cox regression and propensity score matching were used to compare oncologic outcomes of 3DCRT and IMRT in the context of other clinically relevant covariables. Acute and chronic toxicities associated with the 2 techniques were compared using Fisher exact and log-rank tests, respectively. RESULTS: A total of 223 patients were treated during the study period, with 119 receiving 3DCRT and 104 receiving IMRT. Their median age was 64 years (range, 39-90 years). Median follow-up times for 3DCRT and IMRT were 27 months (range, 2-147 months) and 22 months (range, 4-83 months), respectively. Radiation modality was not associated with differences in overall survival or disease-free survival in either multivariable or propensity score-matched analyses. IMRT patients required significantly fewer percutaneous feeding tube placements (5% vs 17%, respectively, P=.005). CONCLUSIONS: IMRT was not associated with worse oncologic outcomes than those of 3DCRT. IMRT was associated with a lower rate of esophagitis-related percutaneous feeding tube placements. PMID- 23920394 TI - Determinants of patient satisfaction during receipt of radiation therapy. AB - PURPOSE: To evaluate the correlations and relative contributions of components of a radiation oncology-specific patient satisfaction survey to their overall satisfaction scores. METHODS AND MATERIALS: From September 2006 through August 2012, we prospectively collected data from 8069 patients receiving radiation treatments with a 26-question survey. Each question was rated on a 10-point Likert scale. We analyzed the correlation between scores for each question and the overall satisfaction question. We also dichotomized the scores to reflect satisfaction versus dissatisfaction and used logistic regression to assess the relationship between items in 4 domains (the patient-provider relationship, access and environmental issues, wait times, and educational information) and overall satisfaction. RESULTS: Scores on all questions correlated with overall patient satisfaction scores (P<.0001). Satisfaction with patient-provider relationships had the greatest influence on overall satisfaction (R(2)=0.4219), followed by wait times (R(2)=0.4000), access/environment (R(2)=0.3837), and patient education (R(2)=0.3700). The specific variables with the greatest effect on patient satisfaction were the care provided by radiation therapists (odds ratio 1.91) and pain management (odds ratio 1.29). CONCLUSIONS: We found that patients' judgment of provider relationships in an outpatient radiation oncology setting were the greatest contributors to their overall satisfaction ratings. Other measures typically associated with patient satisfaction (phone access, scheduling, and ease of the check-in process) correlated less strongly with overall satisfaction. These findings may be useful for other practices preparing to assess patient ratings of quality of care. PMID- 23920395 TI - Proton arc reduces range uncertainty effects and improves conformality compared with photon volumetric modulated arc therapy in stereotactic body radiation therapy for non-small cell lung cancer. AB - PURPOSE: To describe, in a setting of non-small cell lung cancer (NSCLC), the theoretical dosimetric advantages of proton arc stereotactic body radiation therapy (SBRT) in which the beam penumbra of a rotating beam is used to reduce the impact of range uncertainties. METHODS AND MATERIALS: Thirteen patients with early-stage NSCLC treated with proton SBRT underwent repeat planning with photon volumetric modulated arc therapy (Photon-VMAT) and an in-house-developed arc planning approach for both proton passive scattering (Passive-Arc) and intensity modulated proton therapy (IMPT-Arc). An arc was mimicked with a series of beams placed at 10 degrees increments. Tumor and organ at risk doses were compared in the context of high- and low-dose regions, represented by volumes receiving >50% and <50% of the prescription dose, respectively. RESULTS: In the high-dose region, conformality index values are 2.56, 1.91, 1.31, and 1.74, and homogeneity index values are 1.29, 1.22, 1.52, and 1.18, respectively, for 3 proton passive scattered beams, Passive-Arc, IMPT-Arc, and Photon-VMAT. Therefore, proton arc leads to a 30% reduction in the 95% isodose line volume to 3-beam proton plan, sparing surrounding organs, such as lung and chest wall. For chest wall, V30 is reduced from 21 cm(3) (3 proton beams) to 11.5 cm(3), 12.9 cm(3), and 8.63 cm(3) (P=.005) for Passive-Arc, IMPT-Arc, and Photon-VMAT, respectively. In the low dose region, the mean lung dose and V20 of the ipsilateral lung are 5.01 Gy(relative biological effectiveness [RBE]), 4.38 Gy(RBE), 4.91 Gy(RBE), and 5.99 Gy(RBE) and 9.5%, 7.5%, 9.0%, and 10.0%, respectively, for 3-beam, Passive-Arc, IMPT-Arc, and Photon-VMAT, respectively. CONCLUSIONS: Stereotactic body radiation therapy with proton arc and Photon-VMAT generate significantly more conformal high-dose volumes than standard proton SBRT, without loss of coverage of the tumor and with significant sparing of nearby organs, such as chest wall. In addition, both proton arc approaches spare the healthy lung from low-dose radiation relative to photon VMAT. Our data suggest that IMPT-Arc should be developed for clinical use. PMID- 23920396 TI - Magnetic resonance imaging-based target volume delineation in radiation therapy treatment planning for brain tumors using localized region-based active contour. AB - PURPOSE: To evaluate the clinical application of a robust semiautomatic image segmentation method to determine the brain target volumes in radiation therapy treatment planning. METHODS AND MATERIALS: A local robust region-based algorithm was used on MRI brain images to study the clinical target volume (CTV) of several patients. First, 3 oncologists delineated CTVs of 10 patients manually, and the process time for each patient was calculated. The averages of the oncologists' contours were evaluated and considered as reference contours. Then, to determine the CTV through the semiautomatic method, a fourth oncologist who was blind to all manual contours selected 4-8 points around the edema and defined the initial contour. The time to obtain the final contour was calculated again for each patient. Manual and semiautomatic segmentation were compared using 3 different metric criteria: Dice coefficient, Hausdorff distance, and mean absolute distance. A comparison also was performed between volumes obtained from semiautomatic and manual methods. RESULTS: Manual delineation processing time of tumors for each patient was dependent on its size and complexity and had a mean (+/-SD) of 12.33 +/- 2.47 minutes, whereas it was 3.254 +/- 1.7507 minutes for the semiautomatic method. Means of Dice coefficient, Hausdorff distance, and mean absolute distance between manual contours were 0.84 +/- 0.02, 2.05 +/- 0.66 cm, and 0.78 +/- 0.15 cm, and they were 0.82 +/- 0.03, 1.91 +/- 0.65 cm, and 0.7 +/- 0.22 cm between manual and semiautomatic contours, respectively. Moreover, the mean volume ratio (=semiautomatic/manual) calculated for all samples was 0.87. CONCLUSIONS: Given the deformability of this method, the results showed reasonable accuracy and similarity to the results of manual contouring by the oncologists. This study shows that the localized region-based algorithms can have great ability in determining the CTV and can be appropriate alternatives for manual approaches in brain cancer. PMID- 23920397 TI - Changing patterns of disseminated gonococcal infection in France: cross-sectional data 2009-2011. AB - OBJECTIVES: Disseminated gonococcal infections (DGIs) are rare. We describe the characteristics of DGIs in France. METHODS: This is a 3-year retrospective analysis of DGI cases collected through two networks of microbiologists and infectious disease specialists in France between 2009 and 2011. DGI was defined either by the isolation of Neisseria gonorrhoeae from blood and synovial fluid or by the existence of a clinical syndrome consistent with DGI and the isolation of N gonorrhoeae from any site. We describe the epidemiological, clinical and microbiological characteristics and outcomes of DGIs. RESULTS: 21 patients (9 women, 12 men; 18-62 years old) were diagnosed with DGI. The number of DGI cases increased between 2009 and 2011. Two men who had sex with men were coinfected with HIV. We found 28 extragenital locations, including arthritis (14 cases), tenosynovitis (7), skin lesions (4), endocarditis (1), prostatitis (1) and pelvic inflammatory disease (1). Genital signs were present in five patients. The diagnosis was confirmed by cultures in 20 patients-blood (4), synovial fluid (11), genital (3), throat (1), urine (1)-and by molecular biology on a pharyngeal swab in 1 patient. Seven cases were resistant to fluoroquinolones. The patients were treated with ceftriaxone, associated with corticosteroids (two cases) and surgery (six cases). Four patients had joint sequelae. CONCLUSIONS: DGIs are increasing. Men seem to be at higher risk than women. Joint involvement was common. Microbiological diagnosis was based on culture, however molecular biology using pharyngeal swabs was helpful when cultures were negative. PMID- 23920398 TI - Prevalence of pharyngeal and rectal Chlamydia trachomatis and Neisseria gonorrhoeae infections among men who have sex with men in Germany. AB - OBJECTIVES: To determine the prevalence of pharyngeal and rectal Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections among men who have sex with men (MSM) in Germany and describe associations between these infections, sexual practices and other factors to provide an evidence base for screening recommendations. METHODS: We conducted a cross-sectional study in 22 sentinel sites of sexually transmitted infections across Germany. Pharyngeal and rectal swabs were collected and tested for CT and NG with a nucleic acid amplification test (NAAT). Information on HIV status, number of sex partners and sexual practices was collected and linked to NAAT results. RESULTS: Overall, 2247 MSM were screened for pharyngeal or rectal CT and NG infections; median age was 34 years (range 16-83). Prevalence of CT was 1.5% in pharyngeal and 8.0% in rectal specimens. Prevalence of NG was 5.5% in pharyngeal and 4.6% in rectal specimens. Local symptoms were reported in 5.1% of pharyngeal and 11.9% of rectal infections. Altogether 90.8% of rectal or pharyngeal infections would remain undetected if only symptomatic cases were tested. Rectal infection was significantly more likely in men reporting multiple partners (2-5 partners, OR=1.85; 6-10 partners, OR=2.10; >11 partners, OR=2.95), men diagnosed with HIV (OR=1.60) and men practising receptive anal intercourse without a condom (OR=1.54). Pharyngeal infection was more likely in men reporting multiple partners (6-10 partners, OR=2.88; >11 partners, OR=4.96), and men diagnosed with HIV (OR=1.78). CONCLUSIONS: Pharyngeal and rectal infections in sexually active MSM can remain undetected and thus transmissible if swabbing is not offered routinely. Screening should be offered particularly to MSM diagnosed with HIV and MSM reporting multiple partners. PMID- 23920399 TI - Cross-sectional study of hepatitis B immunity in MSM between 2002 and 2012. AB - OBJECTIVES: Incidence of hepatitis B has not been well studied recently in men who have sex with men (MSM) despite increases in sexual risk practices and other sexually transmitted infections. Our aim was to determine the incidence of hepatitis B infection among MSM and level of immunity to hepatitis B attending a sexual health service over 10 years. METHODS: A cross-sectional analysis of all MSM attending Melbourne Sexual Health Centre (MSHC) from 1 July 2002 and 30 June 2012, and a retrospective cohort study of MSM who had attended MSHC on multiple occasions who had hepatitis serology done more than once. RESULTS: Of 10 031 MSM attending the clinic, 58.4% (95% CI 57.4% to 59.4%) (5655/9677) had hepatitis B surface antibody (HepBsAb), 10.6% (95% CI 10.0% to 11.4%) (840/7888) had core antibody (HepBcAb), and 3.7% (95% CI 3.0% to 4.5%) (95/2577) had surface antigen (HepBsAg). The proportion with HepBsAb decreased from 72% to 48% (p (trend)<0.001), with HepBcAb decreased from 12% to 8% (p (trend)=0.039) and with either HepBsAb or HepBcAb, decreased from 67% to 50% (p (trend)<0.001) from 2002 to 2012, but did not change for HepBsAg (p (trend)=0.08). Seven cases of hepatitis B occurred in 3540 person-years of observation, giving an incidence of 1.98 (95% CI 0.79 to 4.07) per 1000 person-years. CONCLUSIONS: The data suggest that the current level of immunity of about 50% has been sufficient to prevent any significant hepatitis B infection in the last 10 years. Continued high levels of vaccination are important for prevention. PMID- 23920400 TI - Attribution of human Salmonella infections to animal and food sources in Italy (2002-2010): adaptations of the Dutch and modified Hald source attribution models. AB - The Dutch and modified Hald source attribution models were adapted to Italian Salmonella data to attribute human infections caused by the top 30 serotypes between 2002 and 2010 to four putative sources (Gallus gallus, turkeys, pigs, ruminants), at the points of animal reservoir (farm), exposure (food), and both combined. Attribution estimates were thus compared between different models, time periods and sampling points. All models identified pigs as the main source of human salmonellosis in Italy, accounting for 43-60% of infections, followed by G. gallus (18-34%). Attributions to turkeys and ruminants were minor. An increasing temporal trend in attributions to pigs and a decreasing one in those to G. gallus was also observed. Although the outcomes of the two models applied at farm and food levels essentially agree, they can be refined once more information becomes available, providing valuable insights about potential targets along the production chain. PMID- 23920401 TI - Genetic variants in nuclear factor-kappa B binding sites are associated with clinical outcomes in prostate cancer patients. AB - Nuclear factor-kappa B (NF-kappaB) transcription factors have been suggested to be involved in prostate cancer progression. Activated NF-kappaB translocates to the nucleus, binds to NF-kappaB binding sites and regulates target gene expression, leading to the given physiological response. It was hypothesised that the sequence variants in NF-kappaB binding sites might affect prostate cancer progression. We systematically evaluated 15 single-nucleotide polymorphisms (SNPs) within NF-kappaB binding sites those were predicted using a genome-wide database in a cohort of 1024 prostate cancer patients. Associations of these SNPs with prostate cancer characteristics and clinical outcomes after radical prostatectomy (RP) for localised disease, and after androgen-deprivation therapy (ADT) for advanced disease were assessed by Kaplan-Meier analysis and Cox regression model. We found that PSMD7 rs2387084 and MYCN rs1429409 were significantly related to earlier onset of prostate cancer and advanced clinical stage, respectively. No SNPs were significantly associated with disease recurrence after RP. Four and three SNPs were notably associated with prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM), respectively, after ADT. LSAMP rs13088089, CCL17 rs223899, PSMD7 rs2387084 and MON1B rs284924 remained the significant predictors for PCSM whilst PSMD7 rs2387084 remained a significant predictor for ACM in multivariate models including clinical predictors. Moreover, we also noted that there were strong effects of the combined genotype on PCSM and patients with a greater number of unfavourable genotypes had a shorter time to PCSM during ADT (P for trend<0.001). It was concluded that SNPs inside NF-kappaB binding sites might be useful to improve outcome prediction in prostate cancer patients. PMID- 23920402 TI - WD40 repeat-containing 62 overexpression as a novel indicator of poor prognosis for human gastric cancer. AB - AIM: WD40 repeat-containing 62 (WDR62) is a centrosome-associated gene involved in cell cycling and proliferation. However, the role of WDR62 in human malignancies remains unknown. The present study aimed to identify the role, if any, of WDR62 in the pathogenesis of human gastric cancer (GC). METHODS: WDR62 expression in 372 cases of human GC and eight GC cell lines was determined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), immunohistochemistry and Western blotting. Correlations between WDR62 expression and clinicopathological characteristics, as well as GC prognosis were determined. WDR62 regulation of GC cell proliferation, invasion, migration and cell cycle distribution were studied both in vitro and in vivo. RESULTS: WDR62 expression was significantly increased in GC tissues and cell lines and was associated with poor differentiation and prognosis of GC. WDR62 expression was elevated in GC multidrug resistant cells. Suppressing WDR62 significantly decreased cell proliferation and induced G2/M phase arrest of GC cells. Consistently, WDR62 knockdown inhibited gastric carcinogenesis in nude mice. Regulation of Akt/p38 mitogen-activated protein kinase (MAPK)/multidrug resistance gene 1 (MDR1) expression and activation by WDR62 contributed to the chemoresistance of GC cells. WDR62 overexpresses in GC and the suppression of WDR62 inhibits GC cell growth by inducing G2/M cell cycle arrest. CONCLUSION: WDR62 may be a novel prognostic marker and a potential chemotherapy target for GC. PMID- 23920403 TI - Conditions for positive and negative recencies in running memory-span recognition. AB - A positive recency effect in a running-span recognition procedure was obtained in Experiment 1 for hits and for intratrial false alarms. In running recall procedures, recency does not fit well with an active updating hypothesis. In Experiment 2, in which the beginning of the target set was marked with a cue upon presentation, the recency effects disappeared. In Experiments 3 and 4 participants were forced to maintain 2 items in memory until the last one was presented for recognition. These three items were the target set. When the last item presentation was uncertain-because of the variable length list-an unexpected negative recency effect appeared. An explanation for this change from positive to negative recency is offered based on the sharing of attentional resources put forward by others for similar procedures. PMID- 23920404 TI - Reaction time measures in deception research: comparing the effects of irrelevant and relevant stimulus-response compatibility. AB - Evidence regarding the validity of reaction time (RT) measures in deception research is mixed. One possible reason for this inconsistency is that structurally different RT paradigms have been used. The aim of this study was to experimentally investigate whether structural differences between RT tasks are related to how effective those tasks are for capturing deception. We achieved this aim by comparing the effectiveness of relevant and irrelevant stimulus response compatibility (SRC) tasks. We also investigated whether an intended but not yet completed mock crime could be assessed with both tasks. Results showed (1) a larger compatibility effect in the relevant SRC task compared to the irrelevant SRC task, (2) for both the completed and the intended crime. These results were replicated in a second experiment in which a semantic feature (instead of color) was used as critical response feature in the irrelevant SRC task. The findings support the idea that a structural analysis of deception tasks helps to identify RT measures that produce robust group effects, and that strong compatibility effects for both enacted crimes as well as merely intended crimes can be found with RT measures that are based on the manipulation of relevant SRC. PMID- 23920405 TI - Rapid visuomotor processing of phobic images in spider- and snake-fearful participants. AB - This study investigates enhanced visuomotor processing of phobic compared to fear relevant and neutral stimuli. We used a response priming design to measure rapid, automatic motor activation by natural images (spiders, snakes, mushrooms, and flowers) in spider-fearful, snake-fearful, and control participants. We found strong priming effects in all tasks and conditions; however, results showed marked differences between groups. Most importantly, in the group of spider fearful individuals, spider pictures had a strong and specific influence on even the fastest motor responses: Phobic primes entailed the largest priming effects, and phobic targets accelerated responses, both effects indicating speeded response activation by phobic images. In snake-fearful participants, this processing enhancement for phobic material was less pronounced and extended to both snake and spider images. We conclude that spider phobia leads to enhanced processing capacity for phobic images. We argue that this is enabled by long-term perceptual learning processes. PMID- 23920406 TI - Biases in evaluation of neutral words due to motor compatibility effect. AB - This study aims to demonstrate the effect of action fluency on emotional evaluation, specifically to show that neutral words can be evaluated positively or negatively depending on motor activity and evaluative setting. Right-handers naturally tend to associate positive (negative) valence to the right (left) part of space (Casasanto, 2009). We extend these associations to lateralized behaviors by studying the combined effect of motor fluency of lateral arm movements and the evaluative scale on the subjective evaluation of neutral words. Three experiments evidenced that, for right-handers, the realization of fluent rightward arm movements and the use of an evaluative scale congruent with their valence/laterality associations (left negative, right positive) led to a positive evaluation of neutral words, while non-fluent leftward movements and an incongruent scale led to a negative evaluation. This study demonstrates that emotion-action associations are experience-based, and influenced by functional and situational constraints. PMID- 23920407 TI - Effect of dietary macronutrients on postprandial incretin hormone release and satiety in obese and normal-weight women. AB - The aim of the present study was to assess the effect of dietary macronutrients on postprandial incretin responses and satiety and hunger sensation in obese and normal-weight women. A total of eleven obese and nine normal-weight women were recruited for the assessment of plasma concentrations of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and insulin and the sensation of satiety and hunger using a visual analogue scale before and during a 6 h period after administration of three different macronutrient test meals. The AUCtotal GLP-1 and AUCtotal GIP values were decreased in obese women after the consumption of a fatty meal and all the test meals, respectively. However, the AUCtotal insulin value after a carbohydrate meal was greater in the obese group. The AUCtotal satiety value was decreased only after the intake of the protein meal in obese women when compared with normal-weight women. After the consumption of the fatty meal, a significant positive correlation between maximum satiety sensation and the AUCtotal GLP-1 value in the obese group and that between minimum hunger sensation and the AUCtotal GLP-1 value in the normal-weight group were observed. In conclusion, the findings of the present study suggest that: (1) satiety sensation after consumption of carbohydrate and protein meals in the obese group is related to the postprandial insulin response, while after consumption of a fatty meal, it is related to the postprandial GLP-1 release; (2) the postprandial GIP response does not influence the sensation of satiety and hunger; (3) the reduced GLP-1 release after the intake of a fatty meal in obese individuals may explain impaired satiety sensation; (4) the impaired postprandial GIP response is not related to the consumption of macronutrients and may be the early indicator of incretin axis dysfunction in obese women. PMID- 23920408 TI - Is the elapsed time following the placement of a ventriculoperitoneal shunt catheter an individual risk factor for shunt fractures? AB - In this study, we examined whether the resistance of peritoneal catheters against the retraction force changed over time following shunt placement, and the role of this resistance in shunt fracture is discussed. We investigated peritoneal catheters removed from patients treated with a ventriculoperitoneal shunt because of hydrocephalus; previously, patients underwent shunt revision. The maximum tension, maximum elongation and elongation percentages of the peritoneal catheters were measured. The mean and maximum tension values of the revised peritoneal catheters were increased compared to the unused catheters. The maximum elongation and elongation rates were significantly decreased. The changes in the maximum elongation, elongation rate and tension values were unrelated to the time elapsed after catheter insertion. This finding indicates that the time elapsed following peritoneal catheter placement was not an individual factor based on the strength of the response of the organism to the foreign body and the mechanical trauma exposed in shunt fractures. PMID- 23920409 TI - Host immune responses of ducks infected with H5N1 highly pathogenic avian influenza viruses of different pathogenicities. AB - Our previous studies have illustrated three strains of duck-origin H5N1 highly pathogenic avian influenza viruses (HPAIVs) had varying levels of pathogenicity in ducks (Sun et al., 2011). However, the host immune response of ducks infected with those of H5N1 HPAIVs was unclear. Here, we compared viral distribution and mRNA expression of immune-related genes in ducks following infection with the two HPAIV (A/Duck/Guangdong/212/2004, DK212 and A/Duck/Guangdong/383/2008, DK383). DK383 could replicate in the tested tissue of ducks (brain, spleen, lungs, cloacal bursa, kidney, and pancreas) more rapid and efficiently than DK212 at 1 and 2 days post-inoculation. Quantitative real-time PCR analysis showed that the expression levels of TLR3, IL-6, IL-8, and MHC class II in brains were higher than those of respective genes in lungs during the early stage of post infection. Furthermore, the expression levels of IL-6 and IL-8 in the brain of ducks following infection with DK383 were remarkably higher than those of ducks infected with DK212, respectively. Our results suggest that the shift in the H5N1 HPAIVs to increased virulence in ducks may be associated with efficient and rapid replication of the virus, accompanied by early destruction of host immune responses. These data are helpful to understand the underlying mechanism of the different outcome of H5N1 HPAIVs infection in ducks. PMID- 23920410 TI - Middle Pleistocene ecology and Neanderthal subsistence: insights from stable isotope analyses in Payre (Ardeche, southeastern France). AB - The Middle Palaeolithic site of Payre in southeastern France yields abundant archaeological material associated with fossil hominid remains. With its long sequence of Middle Pleistocene deposits, Payre is a key site to study the Middle Palaeolithic chronology of this region. This study is the first to investigate carbon and oxygen isotope contents of Neanderthal tooth enamel bioapatite, together with a wide range of herbivorous and carnivorous species. The aim is to contribute to the understanding of hunting behaviour, resource partitioning, diet and habitat use of animals and Neanderthals through a palaeoecological reconstruction. Local topography had a visible influence on carbon and oxygen stable isotope values recorded in herbivore tooth enamel. This was used to investigate possible habitats of herbivores. The different herbivorous species do not show large variations of their carbon and oxygen isotope values through time, indicating niche conservatism from OIS 8-7 to OIS 6-5, i.e., independently of palaeoclimatic and palaeoenvironmental variations. Based on these new observations, we conclude that Neanderthals employed a stable subsistence strategy over time, using a variety of local resources, with resource partitioning visible between humans and carnivores, especially wolves. A comparison of the results of stable isotopic investigation with the results of tooth wear analyses previously conducted on the same teeth allowed us to demonstrate that grazing and browsing do not bind animals to a specific habitat in a C3 environment as reflected in the isotopic values. PMID- 23920412 TI - The determination of rotation axis in the rotation electron diffraction technique. AB - Methods to determine the rotation axis using the rotation electron diffraction technique are described. A combination of rotation axis tilt, beam tilt, and simulated experimental diffraction patterns with nonintegers zone axis has been used. Accurate knowledge of the crystallographic direction of the incident beam for deducing the excitation error of reflections simultaneously near Bragg positions is essential in quantitative electron diffraction. Experimental patterns from CoP3 are used as examples. PMID- 23920411 TI - Hydrogen peroxide induced impairment of endothelial progenitor cell viability is mediated through a FoxO3a dependant mechanism. AB - OBJECTIVES: Increased oxidative stress has been suggested to contribute to the functional impairment of endothelial progenitor cells (EPCs). The Forkhead box O transcription factors (FoxOs) are critical regulators involved in various cellular processes including cell apoptosis. Here, we investigated whether FoxOs are required in oxidative stress induced EPC apoptosis. METHODS AND RESULTS: EPCs were cultured from cord blood derived mononuclear cells and treated with hydrogen peroxide (H2O2) for induction of oxidative stress. Incubation with H2O2 dose dependently reduced viability and increased apoptosis in EPCs. Western blotting showed that EPCs predominantly expressed FoxO3a and the expression was markedly increased upon H2O2 treatment. Transduction with adenoviral vectors expressing either a wide-type or a non-phosphorylatable, constitutively active mutant of FoxO3a led to further increased apoptosis of EPCs after H2O2 treatment. Conversely, FoxO3a silencing rescued EPCs from these H2O2 induced deleterious effects. Overexpression of FoxO3a also increased the level of the pro-apoptotic protein Bim, whereas FoxO3a silencing downregulated H2O2 induced Bim expression. Furthermore, Matrigel assay demonstrated that FoxO3a overexpression significantly impaired the tube forming ability of EPCs, whereas its silencing completely protected EPCs from H2O2 induced decrease of capillary formation. CONCLUSIONS: These data suggest that oxidative stress induced impairment of EPC survival is mediated through a FoxO3a dependant mechanism, possibly by transcriptional regulation of Bim. Our data indicate FoxO3a as a potential therapeutic target for improvement of EPC number and function in patients with ischemic heart disease. PMID- 23920413 TI - Ehlers-Danlos syndrome: a showcase of conditions that lead to understanding matrix biology. AB - The Ehlers-Danlos syndromes (EDS) are genetically and clinically diverse disorders in which affected individuals share a number of physical characteristics, including joint hypermobility, skin extensibility, and tissue friability. Clinical investigations opened the door to identifying the biochemical and molecular etiologies of this diverse but overlapping group of disorders. In this article, we provide an overview of how these disorders inform our understanding of matrix biology, including the role of collagens (types I, III and V), proteoglycans and other proteins. PMID- 23920414 TI - Strategies of ROS regulation and antioxidant defense during transition from C3 to C4 photosynthesis in the genus Flaveria under PEG-induced osmotic stress. AB - In the present study, we aimed to elucidate how strategies of reactive oxygen species (ROS) regulation and the antioxidant defense system changed during transition from C3 to C4 photosynthesis, by using the model genus Flaveria, which contains species belonging to different steps in C4 evolution. For this reason, four Flaveria species that have different carboxylation mechanisms, Flaveria robusta (C3), Flaveria anomala (C3-C4), Flaveria brownii (C4-like) and Flaveria bidentis (C4), were used. Physiological (growth, relative water content (RWC), osmotic potential), and photosynthetical parameters (stomatal conductance (g(s)), assimilation rate (A), electron transport rate (ETR)), antioxidant defense enzymes (superoxide dismutase (SOD), catalase (CAT), peroxidase (POX), ascorbate peroxidase (APX), glutathione reductases(GR)) and their isoenzymes, non-enzymatic antioxidant contents (ascorbate, glutathione), NADPH oxidase (NOX) activity, hydrogen peroxide (H2O2) content and lipid peroxidation levels (TBARS) were measured comparatively under polyethylene glycol (PEG 6000) induced osmotic stress. Under non-stressed conditions, there was a correlation only between CAT (decreasing), APX and GR (both increasing) and the type of carboxylation pathways through C3 to C4 in Flaveria species. However, they responded differently to PEG induced osmotic stress in regards to antioxidant defense. The greatest increase in H2O2 and TBARS content was observed in C3 F. robusta, while the least substantial increase was detected in C4-like F. brownii and C4 F. bidentis, suggesting that oxidative stress is more effectively countered in C4-like and C4 species. This was achieved by a better induced enzymatic defense in F. bidentis (increased SOD, CAT, POX, and APX activity) and non-enzymatic antioxidants in F. brownii. As a response to PEG-induced oxidative stress, changes in activities of isoenzymes and also isoenzymatic patterns were observed in all Flaveria species, which might be related to ROS produced in different compartments of cells. PMID- 23920415 TI - Growing Eremanthus erythropappus in crushed laterite: A promising alternative to topsoil for bauxite-mine revegetation. AB - Topsoil is the preferred substrate for areas requiring rehabilitation after bauxite mining. However, topsoil is sometimes lacking and so there is a need to test the suitability of other, locally available substrates. In an abandoned bauxite mine in Southeastern Brazil, small patches of native vegetation spontaneously established in shallow depressions over weathered laterite, suggesting that granulometric reduction may have facilitated the establishment of plants. To test this hypothesis, blocks of laterite collected in the area were crushed to simulate texture observed in the vegetation patches. Topsoil collected in a preserved ferruginous field near to the extraction area was also used as a substrate in which Eremanthus erythropappus seedlings, a native woody species, were grown. Seedlings were cultivated without fertilizers in these two substrates and also directly over the exposed and uncrushed laterite. The species proved to be very promising for the revegetation, showing a high survival rate in all substrates. Higher annual growth rates and higher final biomass values were observed in topsoil, but the granulometric reduction of laterite doubled plant growth rate in comparison to the exposed laterite. This result was likely due to the increased availability of essential nutrients to plants and to the improvement in physical conditions for root growth and functioning. Moreover, seedling allometry was not altered by the type of substrate, suggesting that the species was highly tolerant to the new substrate conditions, a fundamental characteristic for success of revegetation of bauxite extraction degraded areas. PMID- 23920416 TI - Temporal dissolution of potentially toxic elements from silver smelting slag by synthetic environmental solutions. AB - Waste slag which is created during precious metal smelting contains high levels of potentially toxic elements (PTE) which can be mobilised from unconfined deposits into the local environment. This paper examines the extractability of selected PTE (Pb, Zn, Cd, Mn) from slag samples by synthetic solutions designed to replicate those in the environment. Extracting agents were used to replicate potential leaching scenarios which are analogous to natural chemical weathering. Slag was submersed in a rainwater simulation solution (RSS), weak citric acid solution (representing rhizosphere secretions) and control solutions (deionised water) for a one month period with solution analyses made at intervals of 1, 24, 168 and 720 h. In 1 mM citric acid, dissolution of Cd and Zn showed little change with time, although for Zn the initial dissolution was considerable. Lead in citric acid was characterized by overall poor extractability. Mn solubility increased until an equilibrium state occurred within 24 h. The solubility of studied metals in citric acid can be characterized by a short time to equilibrium. RSS proved to be an effective solvent that, unlike citric acid solution, extracted increasing concentrations of Cd, Mn and Zn with time. Solubility of Pb in RSS was again very low. When taken as a proportion of a single 2 M HNO3 extraction which was applied to slag samples, Cd was the element most readily leached into RSS and control samples. In both studied solvents, slag heterogeneity is prominent in the case of Cd and Zn solubility. Contact time with solvent appears to be an important variable for the release of PTE from slag into solution. The purpose of this study was to provide insight into the environmental chemical dissolution of PTE from slag, which causes their enrichment in surrounding soils and surface waters. PMID- 23920417 TI - Clogging evaluation of open graded friction course pavements tested under rainfall and heavy vehicle simulators. AB - In this study a new procedure is developed to obtain core samples from field sections to assess clogging mechanisms of open graded friction course (OGFC) pavements using X-ray computed tomography (CT) imaging. The approach compared X ray computed tomography (CT) images taken before and after: (1) rainfall simulations without trafficking to investigate particle-related clogging and (2) full-scale accelerated pavement rutting tests (APT) to investigate deformation related clogging of OGFC layers. Rainfall simulations were performed with runoff water of known total suspended solids (TSS) and particle size distributions (PSDs). Full-scale accelerated rutting tests were performed under controlled temperature and loads. Both investigations were performed for three different OGFC pavements with different layer thicknesses and mix types. The clogging of rutting test sections were also evaluated by comparing the surface permeability measurements performed before and after APT testing. The results of X-ray CT image processing revealed a significant reduction in air-void content of core samples after APT rutting tests. The highest air-void reduction was concentrated at the bottom of the OGFC layers. Permeability measurements also showed a 40%-90% reduction in permeability after APT trafficking. X-ray CT image processing of core samples tested under simulated rainfall showed that air void content reduction is concentrated in the lower part (2-6 mm from the bottom) of the OGFC layers as a result of particle accumulation. Small changes in air void contents were observed in the upper part of the OGFC layers (10-15 mm) while these reductions in air void contents were not significant to cause surface overflow and hence it is expected that the tested OGFC pavements will have sufficient permeability to infiltrate water during most average storm events. PMID- 23920418 TI - Clam-associated vibriosis, USA, 1988-2010. AB - Infections with Vibrio spp. have frequently been associated with consumption of bivalve molluscs, especially oysters, but illness associated with clams has also been well documented. We describe the 2312 domestically acquired foodborne Vibrio infections reported to the Cholera and Other Vibrio Illness Surveillance system from 1988 to 2010. Clams were associated with at least 4% (93 persons, 'only clams') and possibly as many as 24% (556 persons, 'any clams') of foodborne cases. Of those who consumed 'only clams', 77% of infections were caused by V. parahaemolyticus. Clam-associated illnesses were generally similar to those associated with other seafood consumption. Clams associated with these illnesses were most frequently harvested from the Atlantic coastal states and eaten raw. Our study describes the contribution of clams to the overall burden of foodborne vibriosis and indicates that a comprehensive programme to prevent foodborne vibriosis need to address the risks associated with clams. PMID- 23920419 TI - Standalone balloon dilation versus sinus surgery for chronic rhinosinusitis: a prospective, multicenter, randomized, controlled trial. AB - BACKGROUND: A prospective randomized controlled study was conducted on patients with chronic rhinosinusitis (CRS) to test the hypotheses that symptom improvement after balloon dilation was noninferior to functional endoscopic sinus surgery (FESS) and balloon dilation was superior to FESS for postoperative debridements. METHODS: Adults with uncomplicated CRS of the maxillary sinuses with or without anterior ethmoid disease who met criteria for medically necessary FESS were randomized 1:1 to office balloon dilation or FESS and followed for 6 months. A minimum of 36 patients per arm were required to test the hypotheses with 90% power. Symptom improvement using the validated 20-item Sino-Nasal Outcome Test (SNOT-20) survey, debridements, recovery outcomes, complications, and revision surgeries were compared between groups. RESULTS: Ninety-two patients (50 balloon dilation; 42 FESS) were treated. Mean SNOT-20 improvement was 1.67 +/- 1.10 and 1.60 +/- 0.96 in the balloon and FESS arms, respectively. Both groups showed clinically meaningful and statistically significant (p < 0.0001) improvement and the balloon arm was noninferior (p < 0.001) to FESS. The mean number of postprocedure debridements per patient was 0.1 +/- 0.6 in the balloon arm versus 1.2 +/- 1.0 in the FESS arm, with the balloon group showing superiority (p < 0.0001). Occurrence of postoperative nasal bleeding (p = 0.011), duration of prescription pain medication use (p < 0.001), recovery time (p = 0.002), and short-term symptom improvement (p = 0.014) were all significantly better for balloon dilation versus FESS. No complications occurred in either group and one revision surgery was reported in each arm. CONCLUSION: Balloon dilation is noninferior to FESS for symptom improvement and superior to FESS for postoperative debridements in patients with maxillary and anterior ethmoid disease. Balloon dilation is an effective treatment in patients with uncomplicated CRS who meet the criteria for medically necessary FESS. PMID- 23920420 TI - Preliminary results of the application of gonadal tissue transfer in various chicken breeds in the poultry gene conservation. AB - The aim of the study was to devise a technique to allow transfer of ovarian and testicular tissues obtained from one day old chicks to recipient animals. The following combinations of chicken breeds were used: Tetra SL/Tetra SL, Tetra SL/Harco, Tetra SL/Black Transylvanian Naked Neck, Godollo New Hampshire/Speckled Transylvanian Naked Neck (recipient/donor), respectively. Only animals less than 24h old from hatching were used as either recipient or donor. Eggs yielding recipients were treated with busulfan to hinder the development of the recipient's own gonads. Gonads were transferred surgically to the new host which was then immunosuppressed for two months. The animals were checked at 8 or 16 weeks for the existence of implanted gonads, and if found, the gonads were removed for histology examination. Tetra SL/Tetra SL pairing resulted in successfully adhered and functioning gonads in most cases. In other combinations, no gonads originating from the donors were found in the recipients. We conclude that not all breeds seem to be suitable recipients; some breeds or individuals may show incompatibility to each other and further examination is needed to find the cause of incompatibility and to establish a suitable breed combination, which can be used for gonad transfer. PMID- 23920421 TI - Wild blueberry (Vaccinium angustifolium)-enriched diet improves dyslipidaemia and modulates the expression of genes related to lipid metabolism in obese Zucker rats. AB - The present study investigated the potential of a wild blueberry (WB)-enriched diet to improve blood lipid profile and modulate the expression of genes related to lipid homeostasis in obese Zucker rats (OZR), a model of the metabolic syndrome with severe dyslipidaemia. For this purpose, twenty OZR and twenty lean Zucker rats (LZR; controls) were placed either on a control (C) or an 8 % WB diet for 8 weeks. Plasma total cholesterol (TC), HDL-cholesterol and TAG concentrations were determined. The relative expression of six genes involved in lipid metabolism was also determined in both the liver and the abdominal adipose tissue (AAT). Plasma TAG and TC concentrations were significantly lower in the OZR following WB consumption (4228 (sem 471) and 2287 (sem 125) mg/l, respectively) than in those on the C diet (5475 (sem 315) and 2631 (sem 129) mg/l, P< 0.05), while there was no change in HDL-cholesterol concentration. No significant effects were observed for plasma lipids in the LZR. Following WB consumption, the expression of the transcription factors PPARalpha and PPARgamma in the OZR was increased in the AAT, while that of sterol regulatory element binding protein 1 (SREBP-1) was decreased in the liver and AAT. The expression of fatty acid synthase was significantly decreased in both the liver and AAT and that of ATP-binding cassette transporter 1 was increased in the AAT following WB consumption. In conclusion, WB consumption appears to improve lipid profiles and modulate the expression of key enzymes and transcription factors of lipid metabolism in severely dyslipidaemic rats. PMID- 23920422 TI - Alertness and psychomotor performance effects of the histamine-3 inverse agonist MK-0249 in obstructive sleep apnea patients on continuous positive airway pressure therapy with excessive daytime sleepiness: a randomized adaptive crossover study. AB - OBJECTIVES: We aimed to evaluate the efficacy of the selective H3 receptor inverse agonist MK-0249 to treat excessive daytime sleepiness (EDS). METHODS: In this three-period, double-blind, crossover study, 125 patients (100 men, 25 women; mean age, 48.6 years) with obstructive sleep apnea receiving nasal continuous positive airway pressure therapy who had refractory EDS were randomized to 2 weeks each of daily MK-0249 (5, 8, 10, or 12 mg, adaptively assigned), modafinil 200 mg, and placebo. At baseline and after each treatment period, six maintenance of wakefulness tests (MWT) and Psychomotor Vigilance Tasks (PVT) were conducted at 2-h intervals, beginning 1h postdose (~09:00). The Epworth sleepiness scale (ESS), Clinical Global Impression of Severity (CGIS) and Digit Symbol Substitution Test (DSST) also were assessed. The primary end point was MWT sleep latency averaged over the first four time points (MWT-early). RESULTS: MWT-early mean change from baseline sleep latency at week 2 was 1.2 min for placebo, 2.1 min for MK-0249 (top two doses pooled; P>.05 vs. placebo), and 5.9 min for modafinil (P < or = .001 vs. placebo). MK-0249 showed improvements vs placebo on secondary and exploratory end points of ESS, CGIS, PVT, and DSST. Insomnia adverse events (AEs) were greater for MK-0249 (combined doses, 17.5%) than for placebo (0.9%) or modafinil (1.8%). CONCLUSION: MK-0249 did not significantly affect MWT sleep latency. However, the pattern of improvement on subjective ratings and psychomotor performance end points suggested that MK-0249 was associated with changes in aspects of cognition and performance not captured by the MWT. PMID- 23920423 TI - [Complications after conservative management of blunt liver trauma: Biliary fistula, hemobilia and biloma]. PMID- 23920424 TI - [Effectiveness of afferent loop stimulation prior to ileostomy closure]. PMID- 23920425 TI - Time-motion and physiological profile of football training sessions performed by under-15, under-17 and under-19 elite Portuguese players. AB - PURPOSE: To provide the time-motion and physiological profile of regular training sessions (TS) performed during the competitive season by under-15 (U15), under-17 (U17), and under-19 (U19) elite-level Portuguese soccer players. METHODS: One hundred fifty-one elite players of U15 (age 14.0 +/- 0.2 y, n = 56), U17 (age 15.8 +/- 0.4 y, n = 66), and U19 (age 17.8 +/- 0.6 y, n = 29) participated in the study during a 9-wk period. Time-motion and body-impact data were collected using GPS technology (15 Hz) across 38 randomly selected TS that resulted in a total of 612 samples. In addition, heart rate (HR) was continuously monitored (1 Hz) in the selected TS. RESULTS: The total distances covered (m) were higher in U17 (4648.3 +/- 831.9), followed by U19 (4212.5 +/- 935.4) and U15 (3964.5 +/- 725.4) players (F = 45.84, P < .001). Total body impacts and relative impacts were lower in U15 (total: 490.8 +/- 309.5, F = 7.3, P < .01), but no differences were identified between U17 (total: 584.0 +/- 363.5) and U19 (total: 613.1 +/- 329.4). U19 players had less high- and very-high-intensity activity (above 16 km/h; F = 11.8, P < .001) and moderate-intensity activity (10.0-15.9 km/h; F = 15.07, P < .001). HR values showed significant effects of zone (F = 575.7, P < .001) and interaction with age group (F = 9.7, P < .001), with pairwise differences between all zones (zone 1, <75%; zone 2, 75-84.9%; zone 3, 85-89.9%; zone 4, >=90%). All players spent most of their time below 75% HRmax (U15, ~50%; U17, ~42%; U19, ~50%). CONCLUSION: Results showed high variability between TS, refraining from identifying meaningful trends when measuring performance, although different demands were identified according to age group. The U15 TS were less physiologically demanding, probably because of increased focus on small-sided games to develop basic tactical principles and technical skills. The focus on game-like situations imposed higher external and internal workloads on U17 and U19 players. PMID- 23920426 TI - Long-term outcome after anticoagulation-associated intracerebral haemorrhage with or without restarting antithrombotic therapy. AB - BACKGROUND: For patients who survive intracerebral haemorrhage (ICH) during treatment with oral anticoagulation (OAC), the balance between the benefits and risks of restarting OAC is unclear. The decision to restart OAC or to start antiplatelet therapy in these patients therefore poses a dilemma for all physicians involved. We assessed the long-term outcome of patients who did or did not restart antithrombotic therapy after OAC-associated ICH. METHODS: We conducted a retrospective follow-up study of all patients discharged from our institution after OAC-associated ICH over a 10-year period. Data on the use of OAC or platelet inhibitors and the occurrence of vascular events during follow-up were assessed through questionnaires and patient files. The primary outcome was recurrent fatal or non-fatal stroke. Secondary outcomes were the occurrence of other haemorrhagic, thrombotic or thromboembolic events. With patients without antithrombotic treatment as reference, we calculated incidence ratios with corresponding 95% confidence intervals (CI) for treatment with OAC and for treatment with antiplatelet therapy. RESULTS: We included 38 patients, of whom 21 (55%) died during a mean follow-up of 3.5 years. The medication regime changed frequently during follow-up, illustrated by the fact that two thirds of the patients who had resumed OAC within 2 months of ICH terminated this at later points in time. Two recurrent strokes occurred during 35.4 patient-years without antithrombotic medication, 7 during 63.8 patient-years on antiplatelet medication (incidence ratio 1.9; 95% CI, 0.4-9.4), and 3 during 19.5 patient-years on OAC (incidence ratio 2.7; 95% CI, 0.5-16.3). There was only 1 recurrent ICH, which occurred during treatment with OAC. CONCLUSION: In this observational study, no significant difference in the primary outcome measure was found between the treatment groups, but there was a tendency towards a higher long-term risk of any stroke in patients who resumed OAC or started antiplatelet therapy. However, based on these results it is difficult to draw any concrete conclusions or make any strong recommendations. A randomized trial to assess the optimal long-term strategy after OAC-related ICH is warranted. Based on the point estimates of our study, such a trial should involve at least 300 patient-years of follow-up. PMID- 23920427 TI - Determining accurate vancomycin MIC values for methicillin-resistant Staphylococcus aureus by the microdilution method. AB - OBJECTIVES: To model the standard broth microdilution method, based on a modified Gompertz function, to obtain accurate vancomycin MIC values for methicillin resistant Staphylococcus aureus (MRSA). The effect of these MIC values on the vancomycin therapeutic target of AUC(0-24)/MIC >= 400 was evaluated. METHODS: Three clinical isolates of MRSA with different vancomycin MIC values were used in this model. The optical densities (OD) of each MIC determination were modelled by a non-linear regression method using an F-test. The OD data were adjusted to the Gompertz equation to obtain the MIC values. The mean vancomycin AUC(0-24) obtained with a 30 mg/kg/day dosing schedule was calculated using a Monte Carlo simulation over 5000 subjects, using the pharmacokinetic data obtained in vancomycin-treated patients in our hospital. RESULTS: Although the MIC values obtained with this model were lower than those of the diffusion method (Etest) in all three cases, this did not affect the AUC(0-24)/MIC ratio for the strains with MICs of 1 mg/L by Etest. However, in those strains with MIC values >1 mg/L, the confidence intervals obtained for this ratio included values <400. CONCLUSIONS: The inherent variability of the broth microdilution method could explain the differences in the clinical outcome in MRSA-infected patients treated with vancomycin, mainly in those due to strains with MIC values of 1.5-2 mg/L by Etest, because the corresponding MIC values would range from 0.84 to 1.52 mg/L by the microdilution method, which could affect the therapeutic target. PMID- 23920428 TI - Tn6168, a transposon carrying an ISAba1-activated ampC gene and conferring cephalosporin resistance in Acinetobacter baumannii. AB - OBJECTIVES: To explore the cause of third-generation cephalosporin resistance in Australian Acinetobacter baumannii isolates belonging to global clone 1 (GC1). METHODS: GC1 isolates from Australia were tested for resistance to ceftazidime and cefotaxime using disc diffusion and MICs. PCR was used to determine the context of ISAba1-ampC configurations and amplicons were sequenced. The level of transcripts was measured using quantitative real-time PCR. Multilocus sequence typing was performed. RESULTS: All ceftazidime- and cefotaxime-resistant isolates carried an appropriately oriented ISAba1 adjacent to the ampC gene and ISAba1 increased ampC transcripts 8-12-fold. In three isolates, the ampC gene next to ISAba1 was not in the normal chromosomal position. Instead, ISAba1 was 7 bp upstream of an additional copy of ampC located in a 3155 bp duplicated segment of the chromosome that differs from the resident GC1 segment by 2.3% but is almost identical to the corresponding region in several non-GC1 draft genomes. The duplicated segment is bounded by directly oriented copies of ISAba1 and flanked by a 9 bp direct duplication. This 5.5 kb transposon, named Tn6168, is in the same position in the chromosome of the three Australian isolates and the GC1 isolate AB0057. Tn6168 was also detected in an unrelated A. baumannii strain, where it was in a different location. The central part of Tn6168 was probably acquired from a sequence type ST32 (Institut Pasteur scheme) A. baumannii strain. CONCLUSIONS: The ISAba1-ampC configuration, which increases ampC expression, can be part of a composite transposon Tn6168. PMID- 23920430 TI - Normal reference ranges of antithrombin, protein C and protein S: effect of sex, age and hormonal status. AB - INTRODUCTION: Antithrombin (AT), protein C (PC) and protein S (PS) deficiencies are risk factors for venous thromboembolism. Overlapping values between heterozygous carriers and normal individuals often make a correct classification of a deficiency difficult. The aim of this study was to investigate the effect of sex, age, menopause and hormone therapy on natural anticoagulant plasma levels in a large group of healthy individuals, and to evaluate the need of separate reference ranges. MATERIALS AND METHODS: AT and PC were measured with a chromogenic assay, antigenic free PS with an ELISA test. To evaluate the effect of sex, age, oral contraception, hormonal status (and their interaction) on AT, PC and PS levels, linear regression models were used. Biological relevance and the value of the normal deviate z were chosen as rules to decide for separate reference ranges. RESULTS: The study population consisted of 1837 healthy adult individuals (741 men, 1096 women), aged 18-85 years (median age: 44 years). In men AT levels decreased after the age of 50 years. Men had higher levels of PS than women, particularly at young ages. In women, after correction for menopause, only PC levels increased with age. Menopause affected AT and PS, but not PC levels. Oral contraceptive intake was associated with a decrease of AT and PS, and an increase of PC levels. CONCLUSIONS: For AT, PC and PS, sex- and age specific normal reference ranges can be useful, in order to better discriminate true carriers of a natural anticoagulant deficiency. PMID- 23920429 TI - Plasma and whole blood clot strength measured by thrombelastography in patients treated with clopidogrel during acute coronary syndromes. AB - INTRODUCTION: Treatment with clopidogrel, a selective platelet P2Y12 receptor antagonist, reduces risk of recurrent ischemic events in patients with acute coronary syndrome (ACS), by limiting platelet aggregation and activation. Stable whole blood clot formation requires activation of platelets, generation of fibrin and final fibrin crosslinks. In this study we intended to compare plasma and whole blood thrombelastography (TEG) measurements in patients during ACS. MATERIALS AND METHODS: Whole blood and plasma samples from 32 patients with non ST segment elevation myocardial infarction (NSTEMI) were collected after administration of clopidogrel. Whole blood and plasma fibrin clot strength (MA) were determined by TEG. Platelet aggregation was determined by light transmittance aggregometry (LTA) using adenosine 5'-diphosphate (ADP), thrombin receptor activation peptide (TRAP), or collagen as agonists. Fibrinogen and C reactive protein (CRP) concentrations were measured by ELISA. RESULTS: Heightened plasma fibrin clot strength was associated with increased platelet reactivity stimulated by ADP (rho=0.536; p=0.002), TRAP (rho=0.481; p=0.007), and collagen (rho=0.538; p=0.01). In contrast to plasma fibrin MA, whole blood MA did not correlate with platelet aggregation. Platelet count was the primary contributor to the difference in thrombin induced whole blood MA and plasma fibrin MA. Increasing levels of CRP were associated with increased plasma fibrin clot strength and platelet reactivity. CONCLUSIONS: Our data suggest that inflammation is associated with increased plasma fibrin clot strength and lower platelet inhibition by clopidogrel during ACS. Platelet count is a main contributor to additional contractile force of whole blood TEG as compared to plasma TEG during treatment with clopidogrel. PMID- 23920431 TI - Considerations and pitfalls in phenotyping and reclassification of chronic obstructive pulmonary disease. AB - As the clinical and research focus of chronic obstructive pulmonary disease (COPD) evolves from regarding obstructive lung disease as a single disease entity to recognizing the complexity of disease expression, the importance of COPD phenotyping rises to the forefront. The reclassification of COPD holds both prognostic and therapeutic implications but does not come without issues that may complicate classification efforts. In this review, we discuss the significance of refining the definition of the term phenotype, consider the impact of variations in cohort severity and attribute mix, account for the contrast of longitudinal vs cross-sectional cohort analysis, recognize the differing criteria used to define disease traits along with the nuances of combining cohorts, and identify the interaction of covariates as we advance in the field of COPD phenotyping. PMID- 23920433 TI - Performance profiling in primary care: does the choice of statistical model matter? AB - BACKGROUND: Profiling is increasingly being used to generate input for improvement efforts in health care. For these efforts to be successful, profiles must reflect true provider performance, requiring an appropriate statistical model. Sophisticated models are available to account for the specific features of performance data, but they may be difficult to use and explain to providers. OBJECTIVE: To assess the influence of the statistical model on the performance profiles of primary care providers. Data Source. Administrative data (2006-2008) on 2.8 million members of a Dutch health insurer who were registered with 1 of 4396 general practitioners. METHODS: Profiles are constructed for 6 quality measures and 5 resource use measures, controlling for differences in case mix. Models include ordinary least squares, generalized linear models, and multilevel models. Separately for each model, providers are ranked on z scores and classified as outlier if belonging to the 10% with the worst or best performance. The impact of the model is evaluated using the weighted kappa for rankings overall, percentage agreement on outlier designation, and changes in rankings over time. RESULTS: Agreement among models was relatively high overall (kappa typically .0.85). Agreement on outlier designation was more variable and often below 80%, especially for high outliers. Rankings were more similar for processes than for outcomes and expenses. Agreement among annual rankings per model was low for all models. CONCLUSIONS: Differences among models were relatively small, but the choice of statistical model did affect the rankings. In addition, most measures appear to be driven largely by chance, regardless of the model that is used. Profilers should pay careful attention to the choice of both the statistical model and the performance measures. PMID- 23920432 TI - Profiling serologic biomarkers in cirrhotic patients via high-throughput Fourier transform infrared spectroscopy: toward a new diagnostic tool of hepatocellular carcinoma. AB - Identification of novel serum biomarkers of hepatocellular carcinoma (HCC) is needed for early-stage disease detection and to improve patients' survival. The aim of this study was to evaluate the potential of serum Fourier transform infrared (FTIR) spectroscopy for differentiating sera from cirrhotic patients with and without HCC. Serum samples were collected from 2 sets of patients: cirrhotic patients with HCC (n = 39) and without HCC (n = 40). The FTIR spectra (10 per sample) were acquired in the transmission mode, and data homogeneity was tested by cluster analysis to exclude outliers. After data preprocessing by extended multiplicative signal correction and principal component analysis, the Support Vector Machine (SVM) method was applied using a leave-one-out cross validation algorithm to classify the spectra into 2 classes of cirrhotic patients with and without HCC. When SVM was applied to all spectra (n = 790), the sensitivity and the specificity for the diagnosis of HCC were, respectively, 82.02% and 82.5%. When applied to the subset of spectra excluding the outliers (n = 739), SVM classification led to a sensitivity and specificity of 87.18% and 85%, respectively. Using median spectra for each patient instead of all replicates, the sensitivity and specificity were 84.62% and 82.50%, respectively. The overall accuracy rate was 82%-86%. In conclusion, this study suggests that FTIR spectroscopy combined with advanced methods of pattern analysis shows potential for differentiating sera from cirrhotic patients with and without HCC. PMID- 23920435 TI - Managing your patent assets. AB - This article includes tips to manage your patent assets effectively and efficiently. I have provided "real world" examples in the form of case studies to support my advice. My goal is to arm you with sufficient knowledge so as to enable you to devise a patent strategy that suits your company's business and scientific needs. PMID- 23920434 TI - Sequential value-of-information assessment for prospective drug safety monitoring using claims databases: the comparative safety of prasugrel v. clopidogrel. AB - BACKGROUND: Key to conducting active drug safety surveillance using longitudinal health care data is determining whether and when there is sufficient evidence to raise a safety alert. We propose to quantify the expected value of the information (VOI) to be gained through continued monitoring in terms of its potential to reduce health losses among future patients and weigh this against the health cost of exposing current patients during continued monitoring. OBJECTIVE: To apply this sequential VOI approach to monitoring the comparative safety of prasugrel v. clopidogrel on gastrointestinal (GI) bleeding. METHODS: We calculated expected health losses assuming expected mortality, nonfatal myocardial infarction (MI), and nonfatal stroke on clopidogrel were 1.27, 5.93, and 1.14 per 100 person-years, using historical data; relative rates on prasugrel were 0.95, 0.76, and 1.02 based on trial data; and MI, stroke, and GI bleed were 9%, 25%, and 0.1% as bad as death, respectively. We assigned gamma prior distributions to the rates of bleeding on clopidogrel and prasugrel to capture baseline uncertainty; in Monte Carlo simulations, prasugrel's efficacy parameters were sampled from distributions. RESULTS: Treating all patients with prasugrel minimized expected health losses, resulting in 475.3 death-equivalents over 25,000 person-years of treatment. Monitoring increased expected losses by 5, and treating all patients with clopidogrel increased losses by 46.4. In Monte Carlo simulation, monitoring on average increased expected losses by 4.6, but a reduction in losses from monitoring was supported within the bounds of uncertainty (95% confidence interval, -0.6 to 11.1). Limitations. Patient heterogeneity and the possibility of updating efficacy parameters during monitoring were not incorporated. CONCLUSION: The proposed approach integrates expected health harms and benefits of continued monitoring in the decision to raise a safety alert. PMID- 23920436 TI - Chronic effects of antidepressants on serotonin release in rat raphe slice cultures: high potency of milnacipran in the augmentation of serotonin release. AB - Most clinically-used antidepressants acutely increase monoamine levels in synaptic clefts, while their therapeutic effects often require several weeks of administration. Slow neuroadaptive changes in serotonergic neurons are considered to underlie this delayed onset of beneficial actions. Recently, we reported that sustained exposure of rat organotypic raphe slice cultures containing abundant serotonergic neurons to selective serotonin (5-HT) reuptake inhibitors (citalopram, fluoxetine and paroxetine) caused the augmentation of exocytotic serotonin release. However, the ability of other classes of antidepressants to evoke a similar outcome has not been clarified. In this study, we investigated the sustained actions of two tricyclic antidepressants (imipramine and desipramine), one tetracyclic antidepressant (mianserin), three 5-HT and noradrenaline reuptake inhibitors (milnacipran, duloxetine and venlafaxine) and one noradrenergic and specific serotonergic antidepressant (mirtazapine) on serotonin release in the slice cultures. For seven of nine antidepressants, sustained exposure to the agents at concentrations of 0.1-100 MU m augmented the level of increase in extracellular serotonin. The rank order of their potency was as follows: milnacipran>duloxetine>citalopram>venlafaxine>imipramine>fluoxetine>desipramine. Neither mirtazapine nor mianserin caused any augmentation. The highest augmentation by sustained exposure to milnacipran was partially attenuated by an alpha 1-adrenoceptor antagonist, benoxathian, while the duloxetine-, venlafaxine- and citalopram-mediated increases were not affected. These results suggest that inhibition of the 5-HT transporter is required for the enhancement of serotonin release. Furthermore, the potent augmentation by milnacipran is apparently due to the accompanied activation of the alpha 1-adrenoceptor. PMID- 23920437 TI - Identification of quinazolinyloxy biaryl urea as a new class of SUMO activating enzyme 1 inhibitors. AB - SUMO activating enzyme 1 (SUMO E1) is the first enzyme in sumoylation pathway and an important cancer drug target. However, only a few inhibitors were reported up to now that includes three natural products, semi-synthetic protein inhibitors and one AMP mimic. Here, we report the identification of quinazolinyloxy biaryl urea as a new class of SUMO E1 inhibitors. The most active compound of this class inhibited the in vitro sumoylation with an IC50 of 13.4 MUM. This compound inhibits sumoylation by blocking the formation of SUMOE1-SUMO thioester intermediate. The biological activity of the most active compound is comparable to previously reported inhibitors with properties suitable for medicinal chemistry optimization for potency and druggability. PMID- 23920438 TI - Novel cycloalkylthiophene-imine derivatives bearing benzothiazole scaffold: synthesis, characterization and antiviral activity evaluation. AB - A series of novel cycloalkylthiophene-imine derivatives containing benzothiazole unit were designed, synthesized and evaluated for their anti-viral activities. The bio-evaluation results indicated that some of the target compounds (such as 5g, 5i, 5u) exhibited good to moderate antiviral effect on CVB5, ADV7 and EV71 viruses, however, these compounds did not have inhibition activity against H1N1 virus. Especially, the compounds 4c and 4d also exhibited high antiviral activities, which provide a new and efficient approach to evolve novel multi functional antiviral agents by rational integration of active pharmacophores. PMID- 23920439 TI - Discovery of highly potent and selective D4 ligands by interactive SAR study. AB - A series of thienylmethylphenylpiperazins was synthesized and tested for affinity towards the five subtypes of dopaminergic receptors. Compound 5f showed more than 1000 folds selectivity to D4 receptors; analogue 5e showed the highest affinity to D4 receptors with Ki 3.9 nM. An interactive SAR approach was adopted and lead to compound 14a with Ki (D4) as low as 0.03 nM. Molecular docking studies showed a potential, first to report arene cation interaction between the D4 unique residue Arg-186 and the ligands' arene moiety, explaining the importance of having a strong negative electrostatic potential at this area of the compound structure. PMID- 23920440 TI - New strigolactone mimics: structure-activity relationship and mode of action as germinating stimulants for parasitic weeds. AB - Strigolactones (SLs) are new plant hormones with varies important bio-functions. This Letter deals with germination of seeds of parasitic weeds. Natural SLs have a too complex structure for synthesis. Therefore, there is an active search for SL analogues and mimics with a simpler structure with retention of activity. SL analogues all contain the D-ring connected with an enone moiety through an enol ether unit. A new mechanism for the hydrolysis SL analogues involving bidentate bound water and an alpha,beta-hydrolase with a Ser-His-Asp catalytic triad has been proposed. Newly discovered SL mimics only have the D-ring with an appropriate leaving group at C-5. A mode of action for SL mimics was proposed for which now supporting evidence is provided. As predicted an extra methyl group at C-4 of the D-ring blocks the germination of seeds of parasitic weeds. PMID- 23920441 TI - The success of endoscopic third ventriculostomy in children: analysis of prognostic factors. AB - OBJECTIVE: The treatment of hydrocephalus in children with endoscopic third ventriculostomy (ETV) has particular features and is associated with different success rates (SR). The aim of this study was to identify putative factors that could influence the outcome of ETV in children. METHODS: Clinical data of 114 consecutive patients under 18 years of age who underwent 116 consecutive ETVs from January 2000 to January 2010 were reviewed. Data were analyzed with regards to clinical and radiological SR. The actual long-term SR was compared to that predicted by the ETV Success Score (ETVSS) model. RESULTS: The study group included 49 males (43%) and 65 females (57%) with a mean age of 6.17 +/- 1.02 years (ranging from 11 days to 18 years) at surgery. Concerning the etiology of hydrocephalus, tumors and aqueductal stenosis (AS) were the most frequently observed, with each occurring in 33 cases (29%), followed by malformations in 24 (21%), cystic lesions in 6 (5%) and other etiologies in 18 patients (16%). The overall SR at the first ETV attempt was 80% (91/114), compared to 74.8% (variance 14.35, 95% CI 69.37-78.22) predicted by the ETVSS. Regarding age, SR was 58% in patients under 6 months of age, 65% in children between 6 months and 1 year, and 86% in children older than 1 year. SR for AS and hydrocephalus associated with posterior fossa tumors were 88 and 90%, respectively. Unsatisfactory results were related to previous intraventricular hemorrhage and infection. The overall complication rate in this series was 13%. CONCLUSION: ETV is safe and effective in children. In this series, the age of the patient and etiology of hydrocephalus were related to SR. Also, the ETVSS was accurate to predict outcome. In a long term follow-up, surgical experience was statistically significant in reducing complications. PMID- 23920442 TI - Obesity and nosocomial infections. AB - BACKGROUND: The prevention of healthcare-associated infections (HCAIs) is a major goal in modern healthcare. Intrinsic, patient-related factors may contribute to the risk of HCAIs. AIM: To review the association between obesity and the risk and outcome of HCAIs. METHODS: A PubMed search of relevant studies on obesity and nosocomial infections and obesity and dosing of antimicrobials. Search terms were: 'obesity', 'infection', 'nosocomial infection', 'surgical site infection', 'critical care unit', 'bacteremia', 'urinary tract infection', 'health care associated infection'. FINDINGS: Obesity has been shown to be associated with an increased risk of HCAIs in several studies. The association is most clear in cardiac, vascular, orthopaedic and gastrointestinal surgery. Body mass index (BMI) data are frequently recorded in patients undergoing surgical and invasive procedures. The recording of BMI data is not systematic in the literature and in many studies median BMI of the control group or reference group (normal weight) also indicates overweight or obesity. Thus, clear BMI cut-offs for increased infection risk cannot be determined. Obesity is frequently associated with underdosing of antimicrobials in both prophylaxis and treatment of HCAIs. Studies indicate that obesity affects the pharmacokinetics of antimicrobial drugs. However, there are no dosing recommendations for antimicrobial use in obesity. CONCLUSIONS: Obesity increases the risk of nosocomial infections and is frequently associated with underdosing of antimicrobials in both prophylaxis and treatment of HCAIs. A challenge in future hospital hygiene prevention lies in our capacity to combat obesity epidemics. PMID- 23920443 TI - Economic analysis of vancomycin-resistant enterococci at a Canadian hospital: assessing attributable cost and length of stay. AB - BACKGROUND: Competing resource demands have resulted in the de-escalation of vancomycin-resistant enterococcus (VRE) control programmes in some Canadian healthcare centres. AIM: To determine the attributable costs and length of stay (LOS) of VRE colonizations/infections in an acute care hospital in Canada. METHODS: Surveillance and financial hospital-based databases were used to conduct analyses with cases and controls from fiscal year 2008-2009 (1 April 2008 to 31 March 2009) at an acute care hospital in downtown Vancouver, Canada. A statistical analysis of attributable costs and LOS was conducted using a generalized linear model. In a secondary analysis, differences in costs and LOS were examined for VRE infections versus colonizations. FINDINGS: A total of 217 patients with VRE and a random sample of 1075 patients without VRE were examined. VRE has a positive and significant impact on patient hospitalization costs and LOS. Overall, the presence of VRE increased the estimated mean cost per patient by 61.9% (95% confidence interval: 42.3-84.3) in relative terms and $17,949 (13,949-21,464) in absolute Canadian dollars. For LOS, the attributable number of days associated with a VRE case mean was 68.0% (41.9-98.9) higher in relative terms and 13.8 days (10.0-16.9) in absolute days. In the secondary analysis comparing VRE infection and colonization costs, no statistically significant difference was found. CONCLUSIONS: Based on this analysis, the attributable cost and LOS of VRE are considerable. These factors should be considered before de escalation of a hospital VRE control programme. PMID- 23920444 TI - Better procurement can save the NHS in England L1.5bn over three years, says report. PMID- 23920445 TI - Acute trust takes over treatment centre after L53m pay off to private company. PMID- 23920446 TI - Health watchdog vows to act over marketing of products to new mothers while in hospital. PMID- 23920448 TI - Loss of caspase 7 expression is associated with poor prognosis in renal cell carcinoma clear cell subtype. AB - OBJECTIVE: To investigate the expression of CASP7 protein in renal cell carcinoma clear cell subtype (ccRCC) and its value to predict cancer-specific survival (CSS). METHODS: A tissue microarray containing 120 samples of ccRCC, 45 non ccRCC, and 66 nontumor paired samples from patients who underwent partial or radical nephrectomy was hybridized with anti-CASP7 antibody. Tissue sections were scored according to intensity and the percentage of stained cells. CASP7 immunostaining scores were used to estimate the association with clinicopathologic parameters and calculate Kaplan-Meier survival curves. RESULTS: Reduced CASP7 expression was observed in ccRCC and non-ccRCC subtypes in comparison with nontumor renal tissues (P <.0001). CASP7 immunostaining was associated (P <.05) with clinicopathologic parameters (size, incidental tumor, clinical stage, renal vein invasion, and tumor necrosis) and correlated with CSS (P = .032) and global survival (P = .046) of patients with ccRCC. In addition, CASP7 expression was able to substratify patients with ccRCC with favorable prognosis according to low clinical stage, in which negative CASP7 staining was associated with patients with lower CSS (P = .045). Finally, CASP7 staining was able to provide significant stratification according to CSS (P = .018) among patients with ccRCC with disease relapse. CONCLUSION: Our results implicate the loss of CASP7 expression in the aggressiveness of ccRCC and indicate its potential use as a clinical prognostic marker of the disease. PMID- 23920449 TI - MC4R rs489693: a clinical risk factor for second generation antipsychotic-related weight gain? AB - Weight gain is a therapy limiting and very frequent adverse effect of many second generation antipsychotic (SGA) drugs. The human melanocortin four receptor (MC4R) is a very promising candidate gene possibly influencing SGA-related weight gain. The rs489693 polymorphism near the MC4R gene was associated with SGA-related weight gain in a genome-wide association study. We tried to replicate these results in our independent naturalistic study population. From 341 Caucasian inpatients receiving at least one SGA drug (olanzapine, clozapine, risperidone, paliperidone, quetiapine or amisulpride), carriers homozygous for the rs489693 A allele (n = 35) showed a 2.2 times higher weight increase (+2.2 kg) than carriers of the CC-genotype (+1 kg) after 4 wk of treatment (analysis of covariance, p = 0.039). We revealed an even stronger effect in a subpopulation without weight gain inducing co-medication (factor 3.1, +2.8 kg, p = 0.044, (n = 16 of 169)) and in first episode patients (factor 2.7, +2.7 kg, p = 0.017, (n = 13 of 86)). Our results confirm the rs489693 A-allele as a possible risk factor for SGA-related weight gain. PMID- 23920451 TI - From intensive care monitoring to personal health monitoring to ambient intelligence. AB - The historical roots of IT-based monitoring in health care are described. Since the 1970ies monitoring has been spreading to more and more domains of health care and public health. Today one can observe monitoring of persons in many environments and regarding widely different questions. While these monitoring applications have been introduced ethical questions have been raised to balance the possible positive and negative outcomes of the approaches. Today IT technology is entering many parts of our life - IT eventually became what had been coined already in the last century by IBM as "electronic dust" which one can find in every part of our environment. As most of these "dust-particles" are able to observe something one can also understand this development as a development into ubiquitous monitoring of nearly everything at any time. The foreseen ambient intelligence worlds are also spaces of ambient monitoring. This article describes this historical development. It emphasizes why ethical and data protection questions are an absolute must in most IT activities today. PMID- 23920452 TI - The PHM-Ethics methodology: interdisciplinary technology assessment of personal health monitoring. AB - The contribution briefly introduces the PHM Ethics project and the PHM methodology. Within the PHM-Ethics project, a set of tools and modules had been developed that may assist in the evaluation and assessment of new technologies for personal health monitoring, referred to as "PHM methodology" or "PHM toolbox". An overview on this interdisciplinary methodology and its comprising modules is provided, areas of application and intended target groups are indicated. PMID- 23920454 TI - Technical literature review. AB - This review gives a comprehensive overview on the technical perspective of personal health monitoring. It is designed to build a mutual basis for the project partners of the PHM-Ethics project. A literature search was conducted to screen pertinent literature databases for relevant publications. All review papers that were retrieved were analyzed. The increasing number of publications that are published per year shows that the field of personal health monitoring is of growing interest in the research community. Most publications deal with telemonitoring, thus forming the core technology of personal health monitoring. Measured parameters, fields of application, participants and stakeholders are described. Moreover an outlook on information and communication technology that foster the integration possibilities of personal health monitoring into decision making and remote monitoring of individual people's health is provided. The removal of the technological barriers opens new perspectives in health and health care delivery using home monitoring applications. PMID- 23920455 TI - Psycho-social aspects of personal health monitoring: a descriptive literature review. AB - We aimed at providing a short review on already published studies addressing psycho-social issues of personal health monitoring (PHM). Both core questions addressed within this review are: What is the impact of PHM on intended psycho social and health-related outcomes? And which psycho-social issues affected by or related to PHM have already been investigated? This descriptive review based on a literature search using various databases (Psycinfo, Psyndex, Pubmed, SSCI). Resulting 428 abstracts were coded regarding their psycho-social content. Inspection of results was carried out along the relevance of the papers regarding psycho-social issues. Research in PHM focuses on telemonitoring and smart home applications: Tele-monitoring studies are directed to outcome-related questions, smart home studies to feasibility issues. Despite of technological matters, comparability of both systems in psycho-social issues is lacking. Tele-monitoring has been proven for impact on patient groups with chronic diseases, yet smart home still lacks evidence in health-related and psycho-social matters. Smart home applications have been investigated with respect to attitudes, perceptions and concerns of end-users, telemonitoring regarding acceptance and adherence. PMID- 23920456 TI - Legal aspects of personal health monitoring. AB - Personal health monitoring (PHM) can be defined as comprising all technical systems, processing, collecting, and storing of data linked to a person. PHM involves several legal issues that are described in this paper. This article analyses firstly the short term actions that are needed at the European level to allow personal health monitoring in respect of the interests and rights of patients such as the need to have more harmonised medical liability rules at the EU level. Introducing PHM implies also legal action at the EU level on the long run. These long-term actions are related to e.g. the way in which hospitals are organised in their relation with healthcare professionals and with other hospitals or healthcare actors. The paper analyses finally also how health monitoring projects may change the traditional (non-)relationship between patients and pharmaceutical/medical device industry. Today, the producers and distributors of medicinal products have no specific contact with patients. This situation may change when applying telemonitoring projects and may require new legal rules. PMID- 23920458 TI - Setting the scene: taxonomy of personal health monitoring. AB - In order to provide a systematic basis for communication in trans-disciplinary research projects, there is a need for taxonomies and ontologies. Our developed taxonomy of personal health monitoring (PHM) is based on a systematic literature review and an iterative adaption process with trans-disciplinary partners. The construction method of the taxonomy is an ongoing process and need regularly updates. PMID- 23920459 TI - A dependencies mapping method for personal health monitoring. AB - This chapter discusses the research undertaken in developing a comprehensive dependencies map for Personal Health Monitoring (PHM). Included is a discussion of the underlying research approach adopted and how this was operationalized. A new dependencies mapping method has been developed and this is described in detail. Illustrations of the derived tools are given using the PHM analysis undertaken. A summary of the analysis outcomes and the resulting recommendations are discussed. The chapter concludes with some suggestions of ways in which this type of data set can be used in practice to deliver fit-for-purpose PHM systems. PMID- 23920460 TI - A module for psycho-social assessment of personal health monitoring. AB - This contribution to an interdisciplinary methodology on Personal Health Monitoring (PHM) aims at developing a psycho-social module for health technology assessment on PHM applications. It covers important aspects that should be taken into account for conducting a health technology assessment from a psycho-social perspective. As it could be used in addition to other tools within the PHM-Ethics approach to health technology assessment it is considered as a module of the interdisciplinary methodology. As a prerequisite, we provide a conceptual framework on psycho-social issues of PHM applications. From that framework we delineate an integrated module for psycho-social health technology assessment for PHM applications, consisting of a map highlighting selective psycho-social issues that may appear when applying a PHM system. This psycho-social tool is at least twofold in its intention as a sole HTA tool on the one hand and as an integral part of the interdisciplinary PHM methodology on the other hand. It provides a quick overview on potential benefits and risks from the user's point of view. PMID- 23920461 TI - Ethically sound technology? Guidelines for interactive ethical assessment of personal health monitoring. AB - Novel care-technologies possess a transformational potential. Future care and support may be provided via monitoring technologies such as smart devices, sensors, actors (robots) and Information and Communication Technologies. Such technologies enable care provision outside traditional care institutions, for instance in the homes of patients. Health monitoring may become "personalized" i.e. tailored to the needs of individual care recipients' but may also alter relations between care providers and care recipents, shape and form the care environment and influence values central to health-care. Starting out from a social constructivist theory of technology, an interactive ethical assessment model is offered. The suggested model supplements a traditional analysis based on normative ethical theory (top-down approach) with interviews including relevant stakeholders (a bottom-up approach). This method has been piloted by small-scale interviews encircling stakeholder perspectives on three emerging technologies: (1) Careousel, a smart medicine-management device, (2) Robot Giraff, an interactive and mobile communication-device and (3) I-Care, a care-software that combines alarm and register system. By incorporating stakeholder perspectives into the analysis, the interactive ethical assessment model provides a richer understanding of the impact of PHM-technologies on ethical values than a traditional top-down model. If the assessment is conducted before the technology has reached the market - preferably in close interaction with developers and users - ethically sound technologies may be obtained. PMID- 23920463 TI - PHM-Ethics and ETICA: complementary approaches to ethical assessment. AB - The chapter undertakes a comparison of different approaches to the ethical assessment of novel technologies by looking at two recent research projects. ETICA was a FP7 sister project to PHM-Ethics, responsible for identification and ethical evaluation of information and communication technologies emerging in the next 10-15 years. The aims, methods, outcomes and recommendations of ETICA are compared to those of PHM-Ethics, with identification of linkages and similar findings. A relationship is identified between the two projects, in which the assessment methodologies developed in the projects are shown to operate at separate, but complementary levels. ETICA sought to reform EU ethics governance for emerging ICTs. The outcomes of PHM-Ethics are analyzed within the policy recommendations of ETICA, which demonstrate how the PHM-Ethics toolbox can contribute to ethics governance reform and context-sensitive ethical assessment of the sort called for by ETICA. PMID- 23920464 TI - Development of a personal health monitoring system--the IT-systems industry view. AB - The Development and Implementation of PHM systems require a different approach than typical application development processes. Based on a practical example it is described how ethical and legal aspects will be considered during the development process. The result is a cohesion and adoption of different methods with defined interaction points to reiterate the solution design by legal and ethical aspects. PMID- 23920465 TI - Personalized use of ICT--from telemonitoring to ambient assisted living. AB - Individual availability of information and communications technology (ICT) has enabled "Personal Health" applications like the continuous ubiquitous telemonitoring of vital signs. The concept of Ambient Assisted Living (AAL) goes beyond health and care applications utilizing home automation technology for supporting individuals with specific needs, particularly enabling elderly to live in their accustomed home as long as possible. These users usually suffer from more than one disease and need compensation of several impairments. Most current AAL projects and products however provide insulated solutions addressing only a small selection of these user needs. For comprehensive dynamic system adaptation to changing user needs an open platform supporting interoperable components is required. While the industry-driven Continua Health Alliance developed a corresponding Personal Health ecosystem, the ongoing European project universAAL aims at a universal platform for both AAL and Personal Health applications. PMID- 23920471 TI - Studies in Health Technology and Informatics. Interdisciplinary assessment of personal health monitoring. Foreword. PMID- 23920472 TI - Spinal cord injury without radiographic abnormality and the Chiari malformation: controlled observations. AB - BACKGROUND: Case reports have suggested an association between the Chiari malformation type 1 (CM1) and spinal cord injury without radiographic abnormality (SCIWORA). No controlled observations have appeared. We report a case-control study. METHODS: The Kids' Inpatient Database (KID) is a product of the Healthcare Utilization Project of the Agency for Healthcare Research and Quality. For the years 1997, 2000, 2003, 2006, and 2009, the KID includes discharge data abstracted from almost 14 million pediatric admissions. We hypothesized that CM1 predisposes children to SCIWORA in the cervicomedullary region, and we reasoned that, if this hypothesis were true, then KID admissions coded for upper cervical SCIWORA would be associated with CM1 more frequently than admissions coded for lower cervical SCIWORA. RESULTS: After exclusion of admissions with a variety of confounding diagnostic codes, we identified 754 admissions coded for upper cervical SCIWORA and 424 coded for lower cervical SCIWORA. Concurrent coding for CM1 was more prevalent among admissions coded for upper cervical SCIWORA than for lower cervical SCIWORA, but the difference did not attain statistical significance (p = 0.093; Fisher's exact test). CONCLUSIONS: These controlled observations fail to support the hypothesis that CM1 is associated with SCIWORA in childhood. If there is a real association, in the context of recent estimates of the prevalence of CM1 in the pediatric population, the magnitude of the incremental risk must be very small. PMID- 23920473 TI - Reliability of a 2-bout exercise test on a wattbike cycle ergometer. AB - PURPOSE: To determine the intraday and interday reliability of a 2 * 4-min performance test on a cycle ergometer (Wattbike) separated by 30 min of passive recovery (2 * 4MMP). METHODS: Twelve highly trained cyclists (mean +/- SD; age = 20 +/- 2 y, predicted VO2max = 59.0 +/- 3.6 mL . kg-1 . min-1) completed six 2 * 4MMP cycling tests on a Wattbike ergometer separated by 7 d. Mean power was measured to determine intraday (test 1 [T1] to test 2 [T2]) and interday reliability (weeks 1-6) over the repeated trials. RESULTS: The mean intraday reliabilities of the 2 * 4MMP test, as expressed by the typical error of measurement (TEM, W) and coefficient of variation (CV, %) over the 6 wk, were 10.0 W (95% confidence limits [CL] 8.2-11.8), and 2.6% (95%CL 2.1-3.1), respectively. The mean interday reliability TEM and CV for T1 over the 6 wk were 10.4 W (95%CL 8.7-13.3) and 2.7% (95%CL 2.3-3.5), respectively, and 11.7 W (95%CL 9.8-15.1) and 3.0% (95%CL 2.5-3.9) for T2. CONCLUSION: The testing protocol performed on a Wattbike cycle ergometer in the current study is reproducible in highly trained cyclists. The high intraday and interday reliability make it a reliable method for monitoring cycling performance and for investigating factors that affect performance in cycling events. PMID- 23920474 TI - The spectrum of olive pollen allergens. From structures to diagnosis and treatment. AB - Olive tree is one of the main allergy sources in Mediterranean countries. The identification of the allergenic repertoire from olive pollen has been essential for the development of rational strategies of standardization, diagnosis, and immunotherapy, all of them focused to increase the life quality of the patients. From its complex allergogram, twelve allergens - Ole e 1 to Ole e 12 - have been identified and characterized to date. Most of them have been cloned and produced as recombinant forms, whose availability have allowed analyzing their three dimensional structures, mapping their T-cell and B-cell epitopes, and determining the precise allergenic profile of patients for a subsequent patient-tailored immunotherapy. Protein mutant, hypoallergenic derivatives, or recombinant fragments have been also useful experimental tools to analyze the immune recognition of allergens. To test these molecules before using them for clinic purposes, a mouse model of allergic sensitizations has been used. This model has been helpful for assaying different prophylactic approaches based on tolerance induction by intranasal administration of allergens or hypoallergens, used as free or integrated in different delivery systems, and their findings suggest a promising utilization as nasal vaccines. Exosomes - nanovesicles isolated from bronchoalveolar lavage fluid of tolerogenic mice - have shown immunomodulatory properties, being able to protect mice against sensitization to Ole e 1. PMID- 23920476 TI - Health effects in the Flemish population in relation to low levels of mercury exposure: from organ to transcriptome level. AB - Due to possible health risks, quantification of mercury accumulation in humans was included in the Flemish biomonitoring programmes FLEHS I (2002-2006) and FLEHS II (2007-2011). The general objective of FLEHS I was to assess regional exposure levels in order to link possible differences in these internal exposure levels to different types of local environmental pressure. Therefore, Hg and MMHg (methylmercury) were only measured in pooled blood samples per region and per age class. In FLEHS II, mercury concentrations were measured in hair of each participant. About 200 adolescents and 250 mothers (reference group) and two times 200 adolescents (2 hotspots) were screened. The main objectives of the FLEHS II study were: (1) to determine reference levels of mercury in hair for Flanders; (2) to assess relations between mercury exposure and possible sources like fish consumption; (3) to assess dose-effect relations between mercury exposure and health effect markers. The results showed that mercury concentrations in the Flemish population were rather low compared to other studies. Mercury levels in the Flemish populations were strongly related to the age of the participants and consumption of fish. Significant negative associations were observed between mercury in hair and asthma, having received breast feeding as a newborn, age at menarche in girls, allergy for animals and free testosterone levels. Significant correlations were also observed between mercury in hair and genes JAK2, ARID4A, Hist1HA4L (boys) and HLAdrb5, PIAS2, MANN1B1, GIT and ABCA1 (girls). PMID- 23920477 TI - The novel structure of the core oligosaccharide backbone of the lipopolysaccharide from the Plesiomonas shigelloides strain CNCTC 80/89 (serotype O13). AB - The new structure of the core oligosaccharide of Plesiomonas shigelloides CNCTC 80/89 (serotype O13) lipopolysaccharide has been investigated by chemical methods, (1)H and (13)C NMR spectroscopy and matrix-assisted laser desorption/ionization time of flight (MALDI-TOF). It was concluded that the core oligosaccharide of P. shigelloides CNCTC 80/89 is a nonasaccharide with the following structure: The position of glycine was determined by MALDI-TOF MS/MS analyses. PMID- 23920475 TI - Recombinant allergen-based provocation testing. AB - Over the last 25 years, recombinant allergens from all important allergen sources have been cloned and are now available as recombinant proteins. These molecules can be produced in practically unlimited amounts without biological or batch-to batch variability. It has been shown in provocation tests that recombinant allergens have similar clinical effects as their natural counterparts. With the help of these tools it is possible to reveal the precise reactivity profiles of patients and to uncover and differentiate cross-reactivity from genuine sensitization to an allergen source. Although it has been shown some time ago that it would be possible to replace crude allergen extracts with recombinant allergens for skin prick testing, and even though the use of allergen components can improve routine diagnosis, these tools are still not available for clinical routine applications. The use of provocation tests is a crucial step in the development of new, hypoallergenic vaccines for therapy of allergic disease. Here we describe important provocation methods (skin prick test, intradermal test, atopy patch test, nasal provocation, colonoscopic provocation test) and give an overview of the clinical provocation studies which have been performed with recombinant allergens so far. PMID- 23920480 TI - Introduction to the special issue on functional neuroimaging of episodic memory. PMID- 23920479 TI - Neuronal nitric oxide synthase-derived nitric oxide is involved in gastric mucosal hyperemic response to capsaicin in rats. AB - BACKGROUND AND AIMS: Activation of transient receptor potential vanilloid type 1 (TRPV1) by capsaicin leads to gastric hyperemic response through capsaicin sensitive sensory nerves and nitric oxide (NO). The aim of the present study is to examine which isoform of nitric oxide synthase (NOS)/NO is involved in the hyperemic response to capsaicin in the rat stomach. METHODS: Gastric mucosal blood flow (GMBF) was measured by laser Doppler flowmetry in rats. The localizations of TRPV1 and neuronal NOS (nNOS) in the rat gastric mucosa were detected by immunohistochemical staining. RESULTS: The nNOS inhibitor N(5) [imino(propylamino)methyl]-L-ornithine substantially reduced GMBF during capsaicin application, whereas the endothelial NOS (eNOS) inhibitor N(5)-(1 iminomethyl)-L-ornithine did not affect the effect of capsaicin during the application. The nonselective NOS inhibitor N(G)-nitro-L-arginine methyl ester apparently inhibited the capsaicin-induced GMBF, while the inducible NOS inhibitor 1400W did not affect GMBF response to capsaicin. The immunohistochemical studies revealed nerve fibers coexpressing TRPV1 and nNOS around blood vessels in the gastric submucosa. CONCLUSION: We demonstrated for the first time that nNOS/NO is involved in gastric hyperemic responses to capsaicin. PMID- 23920478 TI - Plasma fatty acid composition and incident ischemic stroke in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: The association of individual fatty acids with ischemic stroke has not been thoroughly studied, and results have been inconsistent. Few prospective studies have systematically explored the association of biomarkers of fatty acid intake with stroke. The aim of this study was to explore which individual plasma fatty acids would be associated with higher risk of ischemic stroke among whites. METHODS: We studied 3,870 white men and women from the Minneapolis field center of the Atherosclerosis Risk in Communities (ARIC) Study, aged 45-64 years at baseline (1987-1989), who had plasma cholesterol ester (CE) and phospholipid (PL) fatty acids measured. Participants were followed through 2008 for incident ischemic stroke. Hazard ratios (HRs) with 95% confidence intervals (CIs) across quartiles of each fatty acid, measured as the percentage of total fatty acids, were calculated using the Cox proportional hazards model. RESULTS: During a maximum of 22 years of follow-up, we identified 168 cases of ischemic stroke. After adjustment for age and sex, plasma levels of saturated fatty acids were associated positively: HR (95% CI) of the highest versus the lowest quartile for CE fraction was 1.93 (1.23-3.04, p for trend = 0.01) and that for PL fraction was 1.64 (1.05-2.57, p for trend = 0.03). There was also a positive linear association with monounsaturated fatty acids, especially with palmitoleic acid: HR (95% CI) of the highest versus the lowest quartile for CE fraction was 1.86 (1.20-2.87, p for trend = 0.003) and that for PL fraction was 1.52 (0.99-2.34, p for trend = 0.005). No associations of omega-3 and omega-6 polyunsaturated fatty acids with ischemic stroke were observed, but linoleic acid was inversely and nonlinearly associated with ischemic stroke: HR (95% CI) of the highest versus the lowest quartile for CE fraction was 0.64 (0.43-0.97, p for trend = 0.13) and that for PL fraction was 0.69 (0.45-1.05, p for trend = 0.24). These associations were generally unchanged after adjustment for cardiovascular risk factors. CONCLUSIONS: In this US cohort of whites, we found significant positive associations of plasma saturated and monounsaturated fatty acids, especially of palmitoleic acid, with ischemic stroke. We also found an inverse nonlinear association between linoleic acid and ischemic stroke. PMID- 23920481 TI - Synthesis and evaluation of heteroaryl substituted diazaspirocycles as scaffolds to probe the ATP-binding site of protein kinases. AB - With the success of protein kinase inhibitors as drugs to target cancer, there is a continued need for new kinase inhibitor scaffolds. We have investigated the synthesis and kinase inhibition of new heteroaryl-substituted diazaspirocyclic compounds that mimic ATP. Versatile syntheses of substituted diazaspirocycles through ring-closing metathesis were demonstrated. Diazaspirocycles directly linked to heteroaromatic hinge binder groups provided ligand efficient inhibitors of multiple kinases, suitable as starting points for further optimization. The binding modes of representative diazaspirocyclic motifs were confirmed by protein crystallography. Selectivity profiles were influenced by the hinge binder group and the interactions of basic nitrogen atoms in the scaffold with acidic side chains of residues in the ATP pocket. The introduction of more complex substitution to the diazaspirocycles increased potency and varied the selectivity profiles of these initial hits through engagement of the P-loop and changes to the spirocycle conformation, demonstrating the potential of these core scaffolds for future application to kinase inhibitor discovery. PMID- 23920482 TI - Ascaroside activity in Caenorhabditis elegans is highly dependent on chemical structure. AB - The nematode Caenorhabditis elegans secretes ascarosides, structurally diverse derivatives of the 3,6-dideoxysugar ascarylose, and uses them in chemical communication. At high population densities, specific ascarosides, which are together known as the dauer pheromone, trigger entry into the stress-resistant dauer larval stage. In order to study the structure-activity relationships for the ascarosides, we synthesized a panel of ascarosides and tested them for dauer inducing activity. This panel includes a number of natural ascarosides that were detected in crude pheromone extract, but as yet have no assigned function, as well as many unnatural ascaroside derivatives. Most of these ascarosides, some of which have significant structural similarity to the natural dauer pheromone components, have very little dauer-inducing activity. Our results provide a primer to ascaroside structure-activity relationships and suggest that slight modifications to ascaroside structure dramatically influence binding to the relevant G protein-coupled receptors that control dauer formation. PMID- 23920483 TI - Prodrugs of N-dicarboximide derivatives of the rat selective toxicant norbormide. AB - Norbormide [5-(alpha-hydroxy-alpha-2-pyridylbenzyl)-7-(alpha-2 pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, one major drawback of NRB as a viable rodenticide relates to an evolutionary aversion developed by the rat leading to sub-lethal dosing due to either its unpleasant 'taste' or rapid onset of effects. A series of NRB-derived prodrugs were prepared in an effort to 'mask' this acute response. Their synthesis and biological evaluation (in vitro vasoconstrictory activity, in vitro hydrolytic and enzymatic stability and lethality/palatability in vivo) is described. Prodrug 2 displayed the most promising profile with respect to a delay in the onset of symptoms and was subsequently demonstrated to be significantly more palatable to rats. Moreover, prodrug 25 was found to be largely accepted by rats in a choice trial, resulting in high mortality. PMID- 23920484 TI - Metallo-beta-lactamase inhibitory activity of 3-alkyloxy and 3-amino phthalic acid derivatives and their combination effect with carbapenem. AB - 3-Alkyloxy and 3-amino phthalic acid derivatives were found to have metallo-beta lactamase inhibitory activity. Among them, 3-amino phthalic acid derivatives showed both potent activity against metallo-beta-lactamase, IMP-1 inhibitory activity and a strong combination effect with biapenem (BIPM), carbapenem antibiotic. In particular, the 4'-hydroxy-piperidine derivative showed strong IMP 1 inhibitory activity and a combination effect with various antibiotics. PMID- 23920485 TI - Synthesis of imine-pyrazolopyrimidinones and their mechanistic interventions on anticancer activity. AB - Design, synthesis and anticancer activity of a series of imine pyrazolopyrimidinones is reported for the first time. Compounds 9d, 9n and 9o in the series show encouraging in vitro anticancer activity with low micromolar IC50 values against prostate (PC3) and breast (MCF7) cancer cell lines. Some notions about structure-activity relationships and plausible mechanism of biological activity are presented. PMID- 23920487 TI - Environmentalist thinking and the question of disease causation in late Spanish Philippines. AB - The scientific understanding of disease causation was crucial to the ways in which the Spanish colonial state addressed epidemic diseases which periodically struck nineteenth-century Philippines. Scholars have often described Spanish colonial responses in terms of ineptitude and failure, and have often glossed over the multiple and competing scientific theories that preoccupied Spanish and Filipino physicians. This article examines the work and ideas of nineteenth century Spanish colonial and patriotic Filipino physicians regarding disease causation in the tropical environment of the Philippines. It will focus on two key developments-Spanish environmentalist thinking and the emerging fields of microscopy and bacteriology. Much like the British and French colonialists, Spaniards viewed tropical climates as insalubrious and conducive to disease, perceiving themselves as constitutionally at risk in hot places, ill-suited, exposed, and vulnerable to so-called native diseases. By the 1880s, however, young Filipino researchers, some of whom had trained in Spain and France, were undertaking new research on polluted water, malaria, and cells. Influenced by the revolutionary new discoveries being made in bacteriology, these researchers questioned prevailing environmentalist explanations and focused, for the first time, on the nature of pathogens and microbial pathogenesis in disease development and transmission. But germ theory remained an idea among many. This article argues that although late nineteenth-century studies in microscopy by Filipinos slowly began to challenge Spanish colonial ideas, different streams of thinking overlapped and no single scientific explanation came to predominate. PMID- 23920488 TI - A comparison of laboratory-based kayak testing protocols. AB - PURPOSE: To compare the differences in peak oxygen uptake (VO2peak) and lactate threshold (LT2) between the 7 * 4-min incremental step test (7-ST) and the maximal accumulated oxygen deficit (MAOD) test protocols in sprint kayak athletes. METHODS: Nine highly trained kayak athletes performed the 2 laboratory test protocols. The 7-ST involved six 4-min submaximal incremental stages, each separated by a 1-min recovery, before a 4-min all-out effort. The MAOD test involved four 4-min submaximal incremental stages (also with each stage separated by a 1-min recovery), followed by 20-min recovery and a 4-min all-out effort. RESULTS: No statistically significant differences in VO2peak were recorded between the 2 protocols (P > .05). However, distance covered, power output, stroke rate, and speed were almost certainly greater in the MAOD test (magnitude based inference: 99-100% positive), while blood lactate (BLa), heart rate (HR), and rating of perceived exertion (RPE) were likely lower (magnitude-based inference: 78-92% negative). The derived measures of LT2 (excluding HR) were not different between the 2 protocols. CONCLUSION: The results of this study suggest that both the 7-ST and MAOD test protocols are comparable with regard to the measurement of VO2peak and LT2 in highly trained sprint kayak athletes. However, since differences in the measures of distance traveled, power, stroke rate, HR, BLa, and RPE were reported in the maximal stage of the these 2 test protocols, their interchangeable use in a laboratory setting is not ideal if the data output is to be compared and contrasted over time. PMID- 23920490 TI - Bacterial intracellular sulfur globules: structure and function. AB - Bacteria that oxidize reduced sulfur compounds like H2S often transiently store sulfur in protein membrane-bounded intracellular sulfur globules; intracellular in this case meaning found inside the cell wall. The cultured bacteria that form these globules are primarily phylogenetically classified in the Proteobacteria and are chemotrophic or photoautotrophic. The current model organism is the purple sulfur bacterium Allochromatium vinosum. Research on this bacterium has provided the groundwork for understanding the protein membranes and the sulfur contents of globules. In addition, it has demonstrated the importance of different genes (e.g. sulfur oxidizing, sox) in their formation and in the final oxidation of sulfur in the globules to sulfate (e.g. dissimilatory sulfite reductase, dsr). Pursuing the characteristics of other intracellular sulfur globule-forming bacteria through genomics, transcriptomics and proteomics will eventually lead to a complete picture of their formation and breakdown. There will be commonality to some of the genetic, physiological and morphological characteristics involved in intracellular sulfur globules of different bacteria, but there will likely be some surprises as well. PMID- 23920491 TI - Gas vesicles across kingdoms: a comparative solid-state nuclear magnetic resonance study. AB - The buoyancy organelles of aquatic microorganisms have to meet stringent specifications: allowing gases to equilibrate freely across the proteinaceous shell, preventing the condensation of water vapor inside the hollow cavity and resisting collapse under hydrostatic pressures that vary with column depth. These properties are provided by the 7- to 8-kDa gas vesicle protein A (GvpA), repeats of which form all but small, specialized portions of the shell. Magic angle spinning nuclear magnetic resonance is uniquely capable of providing high resolution information on the fold and assembly of GvpA. Here we compare results for the gas vesicles of the haloarchaea Halobacterium salinarum with those obtained previously for the cyanobacterium Anabaena flos-aquae. The data suggest that the two organisms follow similar strategies for avoiding water condensation. On the other hand, in its relatively shallow habitat, H. salinarum is able to avoid collapse with a less costly GvpA fold than is adopted by A. flos-aquae. PMID- 23920489 TI - Microcompartments and protein machines in prokaryotes. AB - The prokaryotic cell was once thought of as a 'bag of enzymes' with little or no intracellular compartmentalization. In this view, most reactions essential for life occurred as a consequence of random molecular collisions involving substrates, cofactors and cytoplasmic enzymes. Our current conception of a prokaryote is far from this view. We now consider a bacterium or an archaeon as a highly structured, nonrandom collection of functional membrane-embedded and proteinaceous molecular machines, each of which serves a specialized function. In this article we shall present an overview of such microcompartments including (1) the bacterial cytoskeleton and the apparati allowing DNA segregation during cell division; (2) energy transduction apparati involving light-driven proton pumping and ion gradient-driven ATP synthesis; (3) prokaryotic motility and taxis machines that mediate cell movements in response to gradients of chemicals and physical forces; (4) machines of protein folding, secretion and degradation; (5) metabolosomes carrying out specific chemical reactions; (6) 24-hour clocks allowing bacteria to coordinate their metabolic activities with the daily solar cycle, and (7) proteinaceous membrane compartmentalized structures such as sulfur granules and gas vacuoles. Membrane-bound prokaryotic organelles were considered in a recent Journal of Molecular Microbiology and Biotechnology written symposium concerned with membranous compartmentalization in bacteria [J Mol Microbiol Biotechnol 2013;23:1-192]. By contrast, in this symposium, we focus on proteinaceous microcompartments. These two symposia, taken together, provide the interested reader with an objective view of the remarkable complexity of what was once thought of as a simple noncompartmentalized cell. PMID- 23920492 TI - The shells of BMC-type microcompartment organelles in bacteria. AB - Bacterial microcompartments are large proteinaceous structures that act as metabolic organelles in many bacterial cells. A shell or capsid, which is composed of a few thousand protein subunits, surrounds a series of sequentially acting enzymes and controls the diffusion of substrates and products into and out of the lumen. The carboxysome and the propanediol utilization microcompartment represent two well-studied systems among seven or more distinct types that can be delineated presently. Recent structural studies have highlighted a number of sophisticated mechanisms that underlie the function of bacterial microcompartment shell proteins. This review updates our understanding of bacterial microcompartment shells, how they are assembled, and how they carry out their functions in molecular transport and enzyme organization. PMID- 23920493 TI - Cyanobacterial carboxysomes: microcompartments that facilitate CO2 fixation. AB - Carboxysomes are extraordinarily efficient proteinaceous microcompartments that encapsulate the primary CO2-fixing enzyme (ribulose-1,5-bisphosphate carboxylase/oxygenase, RuBisCO) in cyanobacteria and some proteobacteria. These microbodies form part of a CO2-concentrating mechanism (CCM), operating together with active CO2 and HCO3(-) uptake transporters which accumulate HCO3(-) in the cytoplasm of the cell. Cyanobacteria (also known as blue-green algae) are highly productive on a global scale, especially those species from open-ocean niches, which collectively contribute nearly 30% of global net primary fixation. This productivity would not be possible without a CCM which is dependent on carboxysomes. Two evolutionarily distinct forms of carboxysome are evident that encapsulate proteobacterial RuBisCO form-1A or higher-plant RuBisCO form- 1B, respectively. Based partly on RuBisCO phylogeny, the two carboxysome types are known either as alpha-carboxysomes, found in predominantly oceanic cyanobacteria (alpha-cyanobacteria) and some proteobacteria, or as beta-carboxysomes, found mainly in freshwater/estuarine cyanobacteria (beta-cyanobacteria). Both carboxysome types are believed to have evolved in parallel as a consequence of fluctuating atmospheric CO2 levels and evolutionary pressure acting via the poor enzymatic kinetics of RuBisCO. The three-dimensional structures and protein components of each carboxysome type reflect distinct evolutionarily strategies to the same major functions: subcellular compartmentalization and RuBisCO encapsulation, oxygen exclusion, and CO2 concentration and fixation. PMID- 23920494 TI - Eut bacterial microcompartments: insights into their function, structure, and bioengineering applications. AB - Bacterial microcompartments (BMCs) are protein-based polyhedral organelles which serve to encapsulate and organize enzymes involved in key metabolic pathways. The sequestration of these pathways not only improves the overall reaction efficiency; it can also harbor toxic or volatile pathway intermediates, which would otherwise be detrimental to the cell. Genomic and phylogenetic analyses reveal the presence of these unique organelles in a diverse range of bacterial species, highlighting their evolutionary importance and the essential role that they play in bacterial cell survival. Functional and structural analyses of BMCs involved in ethanolamine utilization are developing our understanding of the self assembly and encapsulation mechanisms employed by these protein supercomplexes. This knowledge will open up exciting new avenues of research with a range of potential engineering and biotechnological applications. PMID- 23920496 TI - Control of protein function through regulated protein degradation: biotechnological and biomedical applications. AB - Targeted protein degradation is crucial for the correct function and maintenance of a cell. In bacteria, this process is largely performed by a handful of ATP dependent machines, which generally consist of two components - an unfoldase and a peptidase. In some cases, however, substrate recognition by the protease may be regulated by specialized delivery factors (known as adaptor proteins). Our detailed understanding of how these machines are regulated to prevent uncontrolled degradation within a cell has permitted the identification of novel antimicrobials that dysregulate these machines, as well as the development of tunable degradation systems that have applications in biotechnology. Here, we focus on the physiological role of the ClpP peptidase in bacteria, its role as a novel antibiotic target and the use of protein degradation as a biotechnological approach to artificially control the expression levels of a protein of interest. PMID- 23920497 TI - Focus on membrane differentiation and membrane domains in the prokaryotic cell. AB - A summary is presented of membrane differentiation in the prokaryotic cell, with an emphasis on the organization of proteins in the plasma/cell membrane. Many species belonging to the Eubacteria and Archaea have special membrane domains and/or membrane proliferation, which are vital for different cellular processes. Typical membrane domains are found in bacteria where a specific membrane protein is abundantly expressed. Lipid rafts form another example. Despite the rareness of conventional organelles as found in eukaryotes, some bacteria are known to have an intricate internal cell membrane organization. Membrane proliferation can be divided into curvature and invaginations which can lead to internal compartmentalization. This study discusses some of the clearest examples of bacteria with such domains and internal membranes. The need for membrane specialization is highest among the heterogeneous group of bacteria which harvest light energy, such as photosynthetic bacteria and halophilic archaea. Most of the highly specialized membranes and domains, such as the purple membrane, chromatophore and chlorosome, are found in these autotrophic organisms. Otherwise the need for membrane differentiation is lower and variable, except for those structures involved in cell division. Microscopy techniques have given essential insight into bacterial membrane morphology. As microscopy will further contribute to the unraveling of membrane organization in the years to come, past and present technology in electron microscopy and light microscopy is discussed. Electron microscopy was the first to unravel bacterial morphology because it can directly visualize membranes with inserted proteins, which no other technique can do. Electron microscopy techniques developed in the 1950s and perfected in the following decades involve the thin sectioning and freeze fractioning of cells. Several studies from the golden age of these techniques show amazing examples of cell membrane morphology. More recently, light microscopy in combination with the use of fluorescent dyes has become an attractive technique for protein localization with the natural membrane. However, the resolution problem in light microscopy remains and overinterpretation of observed phenomena is a pitfall. Thus, light microscopy as a stand-alone technique is not sufficient to prove, for instance, the long-range helical distribution of proteins in membrane such as MinD spirals in Bacillus subtilis. Electron tomography is an emerging electron microscopy technique that can provide three-dimensional reconstructions of small, nonchemically fixed bacteria. It will become a useful tool for studying prokaryotic membranes in more detail and is expected to collect information complementary to those of advanced light microscopy. Together, microscopy techniques can meet the challenge of the coming years: to specify membrane structures in more detail and to bring them to the level of specific protein protein interactions. PMID- 23920498 TI - Molecular motors in bacterial secretion. AB - Secretion of effectors across bacterial membranes is usually mediated by large multisubunit complexes. In most cases, the secreted effectors are virulent factors normally associated to pathogenic diseases. The biogenesis of these secretion systems and the transport of the effectors are processes that require energy. This energy could be directly obtained by using the proton motive force, but in most cases the energy associated to these processes is derived from ATP hydrolysis. Here, a description of the machineries involved in generating the energy required for system biogenesis and substrate transport by type II, III and IV secretion systems is provided, with special emphasis on highlighting the structural similarities and evolutionary relationships among the secretion ATPases. PMID- 23920495 TI - Prokaryotic proteasomes: nanocompartments of degradation. AB - Proteasomes are self-compartmentalized energy-dependent proteolytic machines found in Archaea, Actinobacteria species of bacteria and eukaryotes. Proteasomes consist of two separate protein complexes, the core particle that hydrolyzes peptide bonds and an AAA+ ATPase domain responsible for the binding, unfolding and translocation of protein substrates into the core particle for degradation. Similarly to eukaryotes, proteasomes play a central role in protein degradation and can be essential in Archaea. Core particles associate with and utilize a variety of ATPase complexes to carry out protein degradation in Archaea. In actinobacterial species, such as Mycobacterium tuberculosis, proteasome-mediated degradation is associated with pathogenesis and does not appear to be essential. Interestingly, both actinobacterial species and Archaea use small proteins to covalently modify proteins, prokaryotic ubiquitin-like proteins (Pup) in Actinobacteria and ubiquitin-like small archaeal modifier proteins (SAMP) in Archaea. These modifications may play a role in proteasome targeting similar to the ubiquitin-proteasome system in eukaryotes. PMID- 23920499 TI - Cellulosome complexes: natural biocatalysts as arming microcompartments of enzymes. AB - Cellulose, a primary component of lignocellulosic biomass, is the most abundant carbohydrate polymer in nature. Only a limited number of microorganisms are known to degrade cellulose, which is highly recalcitrant due to its crystal structure. Anaerobic bacteria efficiently degrade cellulose by producing cellulosomes, which are complexes of cellulases bound to scaffoldins. The underlying mechanisms that are responsible for the assembly and efficiency of cellulosomes are not yet fully understood. The cohesin-dockerin specificity has been extensively studied to understand cellulosome assembly. Moreover, the recent progress in proteomics has enabled integral analyses of the growth-substrate-dependent variations in cellulosomal systems. Furthermore, the proximity and targeting effects of cellulosomal synergistic actions have been investigated using designed minicellulosomes. The recent findings about cellulosome assembly, strategies for optimal cellulosome production, and beneficial features of cellulosomes as an arming microcompartment on the microbial cell surface are summarized here. PMID- 23920500 TI - Nutrient intake and peripheral artery disease in adults: key considerations in cross-sectional studies. AB - BACKGROUND & AIMS: There are limited studies of nutrient intake and peripheral artery disease (PAD). Some studies have not accounted for the functional consequences of PAD, potentially leading to biased results. To determine the associations between intakes of dietary fiber, folate, vitamins A, C, E, and B6 and PAD. METHODS: Cross-sectional analysis of 6534 adults aged 40 years and older in the U.S. National Health and Nutrition Examination Survey between 1999 and 2004, including measurement of ankle-brachial index (ABI) and nutrient intake by 24-h dietary recall. Weighted multivariable logistic regression models to determine odds ratios and 95% confidence intervals. RESULTS: The prevalence of PAD (ABI < 0.9) was 5.3% (4.7-5.9). Inverse associations between PAD and intakes of fiber, folate, and vitamins A, B6, C, and E were statistically significant when adjusting for age, sex, hypertension, diabetes and smoking. In models further adjusted for energy intake and physical activity, these odds ratios all became null (p >= 0.1). CONCLUSIONS: In this sample, dietary fiber, folate, and vitamins B6, C, and E were not associated with PAD after accounting for energy intake and activity. Adjustment for energy and physical activity are essential to avoid bias due to reverse causation in cross-sectional studies of diet and PAD. PMID- 23920501 TI - Dietary intake in children and adolescents with cystic fibrosis. AB - BACKGROUND & AIMS: The recommendation for caloric intake in CF patients is to obtain intakes between 110 and 200% of the estimated average requirement (EAR) for age groups and gender, of which 35-40 energy% should be from fat. It is questionable whether the advice is met. METHODS: 1726 Completed 3-day dietary food records of 234 CF patients (111 girls) and 2860 completed two non consecutive 24-h dietary assessments of healthy controls (1411 girls) were studied. The dietary intake in CF patients was compared with that of healthy controls by using independent sample t tests. RESULTS: Caloric intake in children with CF varied highly with age (88-127% EAR), which is below or in the lower range of the recommended 110-200% EAR. However the absolute caloric intake in CF children was significantly higher compared to controls at all ages. In addition, apart from boys aged 1-3 years, all CF children had a fat intake of 35 energy% or more. This fat intake was significantly higher than in controls, as was the consumption of saturated fat, the latter being well above 10% of the total energy intake. CONCLUSION: Although CF patients generally do not meet the EAR recommendations, they had a significantly higher caloric intake than controls. Moreover fat intake in CF patients does generally meet recommendations, but this resulted in a considerable consumption of saturated fat; a reduction of the latter seems appropriate. PMID- 23920502 TI - Entomological investigation following the resurgence of human visceral leishmaniasis in southern Algeria. AB - Visceral and cutaneous leishmaniasis are the main endemic vector born diseases in Algeria. In the Hoggar region (extreme south of the country) human visceral leishmaniasis (HVL) is known to be sporadic but during the last decade the number of cases has increased significantly. In 2010, a peak of HVL cases was registered mostly among children. Therefore an entomological survey and a retrospective study on HVL cases were carried out in order to explore the transmission of the disease. Among the sand fly caught Phlebotomus bergeroti was the most frequent species (68%) followed by Sergentomyia schwetzi (22%). In this work we describe the presence of Phlebotomus (Paraphlebotomus) kazeruni for the first time in the Hoggar region. PMID- 23920503 TI - A message from the Editorial Desk. AB - This foreword provides a welcome to all participants of MedInfo 2013 in Copenhagen. It discusses the challenges of the editorial process including issues related to the complicated format required for the submissions as well as the page limitation challenges. The new process of employing a large number of editors to tackle the enormous task of editing 188 papers and 324 posters is discussed. Gratitude is expressed to the editorial committee members Profs. Ammenwerth and Nohr as well as the assistant editors who made the process possible. PMID- 23920504 TI - A qualitative study of Swedes' opinions about shared electronic health records. AB - European countries are world-leading in the development and implementation of e Health. In Sweden, all primary healthcare centres and most hospitals use digital records. Some regions use the same software which allows for clinical information to be shared (regionally shared EHRs), but there is a movement towards making all EHRs inter-operable to allow for a National Patient Summary (NPS). The aim of this study was to explore the opinions of Swedish consumers and health professionals about shared EHRs and the NPS. Semi-structered phone interviews were conducted with consumers and health professionals. The majority of interviewed health professionals were currently using regionally shared EHRs. In their experience, having access to regionally shared EHRs facilitated a holistic patient approach, assisted in patient follow-up, and reduced inappropriate (over)prescribing. Consumers had a poor level of knowledge about shared EHRs and the NPS. Unlike health professionals, consumers perceived a NPS to be of great value. The findings indicate that there was a discrepancy between health professionals and consumers' knowledge of, and the perceived need for, a NPS. PMID- 23920505 TI - Identification of strategies to reduce computerized alerts in an electronic prescribing system using a Delphi approach. AB - OBJECTIVE: To reach consensus among prescribers of different specialties and experience on the usefulness of computerised alerts and strategies for reducing low-value alerts within a commercial electronic prescribing system. METHOD: We conducted a Delphi technique where participants were sent a 10-question survey in rounds 1 and 2 to rate the usefulness of existing alert types and to indicate if 1) therapeutic duplication alerts should be adjusted so that they fired only when both medication orders were active; 2) local messages should be changed to hyperlinks rather than alerts. Forty-seven prescribers completed round 1 and 21 round 2. RESULTS AND DISCUSSION: Prescribers varied in their views on alerts of little value but agreed allergy and intolerance alerts should be retained. Most prescribers indicated that the proposed strategies for reducing local messages and duplication alerts would not compromise patient safety. Involving users in customization of alerts proved to be a successful approach. PMID- 23920506 TI - Efficiency strategies for facilitating computerized clinical documentation in ambulatory care. AB - Most providers have experienced increased documentation demands with the use of electronic health records (EHRs). We sought to identify efficiency strategies that providers use to complete clinical documentation tasks in ambulatory care. Two observers performed ethnographic observations and interviews with 22 ambulatory care providers in a U.S. Veterans Affairs Medical Center. Observation notes and interview transcripts were coded for recurrent strategies relating to completion of the EHR progress notes. Findings included: the use of paper artifacts for handwritten notations; electronic templates for automation of certain parts of the note; use of shorthand and phrases rather than narrative writing; copying and pasting from previous EHR notes; directly entering information into the EHR note during the patient encounter; reliance on memory; and pre-populating an EHR note prior to seeing the patient. We discuss the findings in the context of distributed cognition to understand how clinical information is propagated and represented toward completion of a progress note. The study findings have important implications for improving and streamlining clinical documentation related to human factors workload management strategies. PMID- 23920507 TI - Comparing information needs of health care providers and older adults: findings from a wellness study. AB - Consumer health informatics technologies have the potential to enhance shared decision-making and communication between older adults, health care providers, and other stakeholders. The objective of this study was to characterize the information needs of these stakeholders to inform the design of informatics tools that support wellness in older adults. We conducted four focus groups with 31 older adults and three focus groups with 10 health care providers to explore information needs, goals, and preferences for information sharing. Analysis of focus group transcripts was performed to identify and compare themes for different stakeholders. We identified four themes related to information activities: perceived goals of others, perceived information needs of others, information sharing by older adults, and role of family members. Older adults, family members and health care providers differ in their information needs. We provide recommendations to facilitate design and adoption of informatics tools that connect these stakeholders. Larger studies are needed to characterize different stakeholder goals, information needs and preferences. PMID- 23920508 TI - PPADS: Physician-PArent Decision-Support for Neonatal Intensive Care. AB - Family-centered care is becoming the new standard for Neonatal Intensive Care Unit (NICU) patients. In support of this, we developed the Physician PArent Decision Support System (PPADS), which provides clinical updates and predictions of clinical outcomes for infants in the NICU to the neonatologists, and provides an aid to parents for making difficult decisions on the direction of care of their infant with the health care team. The tool may lead to earlier intervention, better allocation of resources, and reduction of the negative outcomes. The tool underwent a usability study with 8 parents whose infant survived the NICU stay and 5 neonatologists. Both parents and physicians thought the tool was easy to use, useful, and would help improve team communication. The next usability study will be with parents whose infant died while in the NICU, and then conduct a randomized prospective study with parents who have a sick infant admitted to the NICU. PMID- 23920509 TI - Ensuring clinical utility and function in a large scale national project in Australia by embedding clinical informatics into design. AB - Across the globe, healthcare delivery is being transformed by electronic sharing of health information. Such large scale health projects with a national focus are a challenge to design and implement. Delivering clinical outcomes in the context of policy, technical, and design environments represents a particular challenge. On July 1, 2012, Australia delivered the first stage of a personally controlled electronic health record - a national program for sharing a variety of health information between health professionals and between health professionals and consumers. As build of the system commenced, deficiencies of the traditional stakeholder consultation model were identified and replaced by a more structured approach, called clinical functional assurance. Utilising clinical scenarios linked to detailed design requirements, a team of clinicians certified clinical utility at implementation and release points. PMID- 23920510 TI - Enabling outsourcing XDS for imaging on the public cloud. AB - Picture Archiving and Communication System (PACS) has been the main paradigm in supporting medical imaging workflows during the last decades. Despite its consolidation, the appearance of Cross-Enterprise Document Sharing for imaging (XDS-I), within IHE initiative, constitutes a great opportunity to readapt PACS workflow for inter-institutional data exchange. XDS-I provides a centralized discovery of medical imaging and associated reports. However, the centralized XDS I actors (document registry and repository) must be deployed in a trustworthy node in order to safeguard patient privacy, data confidentiality and integrity. This paper presents XDS for Protected Imaging (XDS-p), a new approach to XDS-I that is capable of being outsourced (e.g. Cloud Computing) while maintaining privacy, confidentiality, integrity and legal concerns about patients' medical information. PMID- 23920511 TI - An information and communication technology system to detect hypoglycemia in people with type 1 diabetes. AB - Continuous glucose monitoring (CGM) is a new technology with the potential to detect hypoglycemia in people with Type 1 diabetes. However, the inaccuracy of the device in the hypoglycemic range is unfortunately too large. The aim of this study was to develop an information and communication technology system for improving hypoglycemia detection in CGM. The system was developed as an Android application with a build-in pattern classification algorithm. The algorithm processes features from CGM and typed in data from the patient, then warns the patient about incoming hypoglycemia. The system improved the detection of hypoglycemic events by 29%, with only one 1 false alert compared to CGM alone. Furthermore, the algorithm increased the average lead-time by 14 minutes. These findings indicate that it is possible to improve the hypoglycemia detection with an information and communication technology system, but that the system must be validated on a larger dataset. PMID- 23920512 TI - A semi-automatic semantic method for mapping SNOMED CT concepts to VCM Icons. AB - VCM (Visualization of Concept in Medicine) is an iconic language for representing key medical concepts by icons. However, the use of this language with reference terminologies, such as SNOMED CT, will require the mapping of its icons to the terms of these terminologies. Here, we present and evaluate a semi-automatic semantic method for the mapping of SNOMED CT concepts to VCM icons. Both SNOMED CT and VCM are compositional in nature; SNOMED CT is expressed in description logic and VCM semantics are formalized in an OWL ontology. The proposed method involves the manual mapping of a limited number of underlying concepts from the VCM ontology, followed by automatic generation of the rest of the mapping. We applied this method to the clinical findings of the SNOMED CT CORE subset, and 100 randomly-selected mappings were evaluated by three experts. The results obtained were promising, with 82 of the SNOMED CT concepts correctly linked to VCM icons according to the experts. Most of the errors were easy to fix. PMID- 23920513 TI - Assisting the translation of SNOMED CT into French. AB - The objective of this study is to evaluate to approaches assisting the translation of SNOMED CT into French. Two types of approaches were combined: a concept-based one, which relies on conceptual information of the UMLS Metathesaurus and a lexical-based one, which relieson NLP techniques. In addition to the French terminologies (whether included in UMLS or not). Using the concept based approach, a set of 156,157 (39.4%) SNOMED CT terms were translated to at least one French term from UMLS. Expanded to the French terms from UMLS terminologies translated by CISMeF, 2,548 (+0.7%) additional SNOMED CT terms were translated to at least one French term. Using the lexical-based approach, a set of 145,737 (36.8%) SNOMED CT terms were translated to at least one French term from HeTOP. The qualitative evaluation showed that 44% of the translations were rated as "relevant". Overall, the two approaches have provided the translation of 168,750 (42.6%) SNOMED CT terms into French using different bilingual terminological sources included in UMLS or in HeTOP. PMID- 23920514 TI - Taming EHR data: using semantic similarity to reduce dimensionality. AB - Medical care data is a valuable resource that can be used for many purposes including managing and planning for future health needs as well as clinical research. However, the heterogeneity and complexity of medical data can be an obstacle in applying data mining techniques. Much of the potential value of this data therefore goes untapped. In this paper we have developed a methodology that reduces the dimensionality of primary care data, in order to make it more amenable to visualisation, mining and clustering. The methodology involves employing a combination of ontology-based semantic similarity and principal component analysis (PCA) to map the data into an appropriate and informative low dimensional space. Throughout the study, we had access to anonymised patient data from primary care in Salford, UK. The results of our application of this methodology show that diagnosis codes in primary care data can be used to map patients into an informative low dimensional space, which in turn provides the opportunity to support further data exploration and medical hypothesis formulation. PMID- 23920515 TI - Smartphones : evidence-based user-interface design. AB - Smartphones have become increasingly popular among every segment of the population. Caregivers do not want to miss out on this evolution and express interest in using mobile devices to perform their everyday care. This tendency has been well understood by many software providers who have produced many medical applications for smartphones. Before going a step further and developing tools to manage Clinical Information System data on handheld devices, it is wise to ask ourselves whether these new tools are well adapted to the healthcare environment. Indeed, some studies have raised concerns regarding the efficiency of these handheld devices to input medical data, especially with the induced errors. In this paper, we look to adopt a rigorous approach to acquire evidence about these concerns through a prospective study. In order to get this evidence, the study compares several input interfaces in the context of recording vital signs on mobile devices. We would like to discover not only which interface is the most efficient, but also which one is the least prone to errors. PMID- 23920517 TI - Determining scanned body part from DICOM study description for relevant prior study matching. AB - The typical radiology reporting workflow involves the radiologist first looking at one or more relevant prior studies before interpreting the current study. To improve workflow efficiency, PACS systems can display relevant prior imaging studies, typically based on a study's anatomy as indicated in the Body Part Examined field of the DICOM header. The content of the Body Part Examined field can be very generic. For instance, an imaging study to exclude pancreatitis and another one to exclude renal stones will both have "abdomen" in their body part field, making it difficult to differentiate them. To improve prior study matching and support better study filtering, in this paper, we present a rule-based approach to determine specific body parts contained in the free-text DICOM Study Description field. Algorithms were trained using a production dataset of 1200 randomly selected unique study descriptions and validated against a test dataset of 404 study descriptions. Our validation resulted in 99.94% accuracy. The proposed technique suggests that a rule-based approach can be used for domain specific body part extraction from DICOM headers. PMID- 23920516 TI - Automated synthesis and visualization of a chemotherapy treatment regimen network. AB - Cytotoxic treatments for cancer remain highly toxic, expensive, and variably efficacious. Many chemotherapy regimens are never directly compared in randomized clinical trials (RCTs); as a result, the vast majority of guideline recommendations are ultimately derived from human expert opinion. We introduce an automated network meta-analytic approach to this clinical problem, with nodes representing regimens and edges direct comparison via RCT(s). A chemotherapy regimen network is visualized for the primary treatment of chronic myelogenous leukemia (CML). Node and edge color, size, and opacity are all utilized to provide additional information about the quality and strength of the depicted evidence. Historical versions of the network are also created. With this approach, we were able to compactly compare the results of 17 CML regimens involving RCTs of 9700 patients, representing the accumulation of 45 years of evidence. Our results closely parallel the recommendations issued by a professional guidelines organization, the National Comprehensive Cancer Network (NCCN). This approach offers a novel method for interpreting complex clinical data, with potential implications for future objective guideline development. PMID- 23920518 TI - User-directed coordination in SNOMED CT. AB - The possibility of post-coordination of SNOMED CT concepts, especially by clinical users, is both an asset and a challenge for SNOMED CT implementation. To get insight in the applicability of post-coordination, we analyzed scenarios for user-directed coordination that are described in the documentation of SNOMED CT. The analyses were based on experiences from previous and ongoing research and implementation work, including national mapping projects, and investigations on collection of data for multiple uses. These scenarios show various usability and representation problems: high number of relationships for refinement and qualification, improper options for refinement, incorrect formal definitions, and lack of support for applying editorial rules. Improved user-directed coordination in SNOMED CT in real practice requires advanced sanctioning, increased consistency of definitions of concepts in SNOMED CT, and real-time analysis of the post-coordinate expression. PMID- 23920519 TI - Consumers' online social network topologies and health behaviours. AB - Personally controlled health management systems (PCHMS) often consist of multiple design features. Yet, they currently lack empirical evidence on how consumers use and engage with a PCHMS. An online prospective study was designed to investigate how 709 consumers used a web-based PCHMS to manage their physical and emotional wellbeing over five months. The web-based PCHMS, Healthy.me, was developed at UNSW and incorporates an untethered personal health record, consumer care pathways, forums, polls, diaries, and messaging links with healthcare professionals. The two PCHMS features that consumers used most frequently, found most useful, and engaging were the social features, i.e. forum and poll. Compared to participants who did not use any PCHMS social feature, those who used either the poll or the forum were 12.3% more likely to visit a healthcare professional (P=0.001) during the study. Social network analysis of forums revealed a spectrum of social interaction patterns - from question-and-answer structures to community discussions. This study provides a basis for understanding how a PCHMS can be used as a socially-driven intervention to influence consumers' health behaviours. PMID- 23920521 TI - Segmentation of mammography by applying GrowCut for mass detection. AB - Accurately segmenting tumors in digital mammography images is a hard task. However, quality of segmentation is important to avoid misdiagnosis. In this work, the GrowCut technique, which is based on cellular automaton, was used to segment tumor regions of digitized mammograms available in the Mini-Mias database. A set of images was submitted to GrowCut technique and segmented images were compared with ground truth in terms of metrics of area, perimeter, Feret's distance, form factor, and solidity. For segmenting tumors, low user interaction is required. Results showed that GrowCut segmentation images obtained similar properties and shape of the ground-truth images, with an average estimated error close to zero, for all metrics analyzed. PMID- 23920522 TI - It is time for self-incident-reporting for patients and their families in every health care organization: a literature review. AB - The purpose of this literature review is to find out how incidents related to unintended consequences in caring processes are reported by patients or their families, and the status of patient reporting systems globally. The focus of the study is on patient self-reporting systems, and patient centrism. For that purpose, this scoping review examines studies that summarize the current position of patient self-reporting in health care. Scopus, PubMed including MEDLINE, and Cochrane retrievals, and hand search revealed in 50 articles for further analysis. The results showed that patient-reported incidents are still ifrequently researched. Patient reporting systems were implemented to some extent, but not worldwide in spite of the existence of several report systems. More research is obviously needed, especially within organizations where patient self-reporting systems are in use. PMID- 23920523 TI - Applying ontological realism to medically unexplained syndromes. AB - The past decade has witnessed an increased interest in what are called "medically unexplained syndromes" (MUS). We address the question of whether structuring the domain knowledge for MUS can be achieved by applying the principles of Ontological Realism in light of criticisms about their usefulness in areas where science has not yet led to insights univocally endorsed by the relevant communities. We analyzed whether the different perspectives held by MUS researchers can be represented without taking any particular stance and whether existing ontologies based on Ontological Realism can be further built upon. We did not find refutation of the applicability of the principles. We found the Ontology of General Medical Science and Information Artifact Ontology to provide useful frameworks for analyzing certain MUS controversies, although leaving other questions open. PMID- 23920524 TI - Developing clinical skills using a virtual patient simulator in a resource limited setting. AB - OBJECTIVE: to measure the effect of training with a virtual patient (VP) simulation system on clinical skills of healthcare professionals in Africa. METHODS: A randomized controlled intervention was carried out at Yaounde Central Hospital (Cameroon). The intervention consisted of two groups training on one of the two clinical vignettes implemented in the VP simulator. Four actors were trained to play standardized patient (SP) roles. The clinical skills (performance score) of participants were assessed on both clinical vignettes using these SPs. RESULTS: Twenty medical students from FMSB were recruited. The difference in overall score was observed between participants who received training from the VP system (higher average) and those who did not receive the training (lower average). This difference is statistically significant, especially when the focus is on participants' scores in the relevant items for proper management of the case. CONCLUSION: This study suggests that the training with a medical consultation VP simulator can develop the operational clinical skills of the user. PMID- 23920525 TI - Developing a survey to assess factors that contribute to physician involvement in clinical research. AB - BACKGROUND: Investment in research, including clinical research, has positive effects both on health of a population and economic growth of a country. Several factors have been suggested as being related to the performance of clinical research. The goal of this work was to develop and perform initial validation of a survey that measures both current research involvement of physicians, as well as previously noted factors and additional informatics factors affecting this involvement. The survey was developed in both English and Spanish with the goal of its use in Latin America. METHODS: The initial survey was developed primarily from experience with other validated surveys developed for similar purposes. It was validated in three stages with modification or elimination of questions as indicated by this testing. RESULTS: The final survey contains 33 questions in the categories of research experience, education in research, environmental factors, computer experience, and collaboration. PMID- 23920526 TI - Telephone follow-up in primary care: can interactive voice response calls work? AB - Follow-up calls after ambulatory visits are not routinely done, yet they can potentially detect and mitigate unresolved problems. Automated calls via an Interactive Voice Response System (IVRS) are an innovative way to conduct follow up, but patients' attitudes toward follow-up calls are unknown. This study assessed 1) patient perceptions about follow-up calls after visits; 2) differences in perceptions between human and IVRS calls; and 3) association between follow-up calls and patient satisfaction with care. Post-visit follow-up calls in two ambulatory care setting were done in two phases. Phase 1 used a human caller and phase 2 used IVRS. Patient satisfaction questionnaires were completed after each phase. Results showed that 88% of patients favor the idea of the calls and those receiving them found them helpful. There were no differences in attitudes between patients receiving calls from clinic staff or from an IVRS. Patients receiving calls had higher patient satisfaction scores than those not called. CONCLUSION: Patients value follow-up calls and they are associated with patient satisfaction with care. IVRS is an innovative way to conduct post-visit follow-up. PMID- 23920527 TI - Mining the changes of medical behaviors for clinical pathways. AB - In a fast-changing healthcare environment, understanding the changes of medical behaviors in clinical pathways can help hospital managers improve the pathways and make better medical strategies for patient careflow. In this study we propose an approach to detect medical behavior changes between two time periods, by providing a change pattern detection algorithm dividing the discovered change patterns into four categories (i.e., perished patterns, added patterns, unexpected changes, and emerging patterns). The proposed approach is evaluated via real-world data sets extracted from Zhejiang Huzhou Central Hospital of China with regard to the clinical pathway of bronchial lung cancer in 2007-2009 and 2011. The experiment results include three categories of change patterns from the collected data-sets, making a relatively comprehensive cover on the significant changes in clinical pathways, which might be essential from the perspectives of clinical pathway analysis and improvement. PMID- 23920528 TI - Developing a common reference model for the health informatics discipline. AB - This study reports on an examination of the IT industry's Skills Framework for the Information Age (SFIA) to determine if such a process and/or the use of this tool is suitable to be applied to the health informatics discipline. During this process, four sets of known and agreed-upon Health Informatics skill and knowledge domain statements and competencies were mapped to SFIA. The results showed that all high level SFIA skills apply to the health informatics discipline but that these need to be contextualized to suit the health industry and additional health industry specific skills and knowledge domains need to be included to truly reflect the necessary health informatics skill set from which competency statements can be developed. Adoption of an accord similar to the Seoul Accord process could be very beneficial in promoting a global understanding of the health informatics discipline. PMID- 23920529 TI - Usage and perceptions of a mobile self-management application for people with type 2 diabetes: qualitative study of a five-month trial. AB - Despite a growing number of clinical-intervention studies of mobile applications for diabetes self-management, details of participants' engagement with the intervention tools and of usability and feasibility issues are seldom reported. The Few Touch application is a mobile-phone-based self-management system for people with Type 2 diabetes mellitus (T2DM) developed by involving patient-users in design processes from an early phase to a long-term trial. An improved version was tested in a five-month trial by 11 individuals either with T2DM or at high risk of T2DM. Results showed clearer correlations between usage and perceived usefulness among these individuals compared with those involved in the design process. However, feedback on usability issues was mostly consistent between the two trials. This study therefore confirmed: 1) the value of including patient users not only in design-concept development but also in a long-term trial to identify as many factors critical to usability and usage as possible, and 2) the importance of reflecting their feedback in design iterations to minimize the number of critical factors. PMID- 23920530 TI - Human factors considerations for contraindication alerts. AB - Alert fatigue is a ubiquitous problem in clinical decision support systems. Several remedies to alert fatigue have been proposed including improving the specificity of alerts and compliance with human factors principles. Human factors principles that are relevant for drug safety alerting have been identified and operationalized for drug-drug interactions (DDIs), resulting in a previously developed and validated quantitative instrument. Such an instrument is lacking for contraindications. This study describes the operationalization of human factors principles for contraindication alerting. Thirty items associated with 10 human factors principles are included in the instrument: 4 items are new, 5 are similar, and 21 are equal to the DDI-instrument. The instrument was further operationalized to a test protocol. Three independent persons used the test protocol. Inter-rater reliability indicated moderate agreement (kappa=0.540) It is feasible to test the implementation of human factors in contraindication alert design with the newly developed instrument. PMID- 23920531 TI - Detecting effective classes of medical incident reports based on linguistic analysis for common reporting system in Japan. AB - The analysis of medical incident reports is indispensable for patient safety. Most incident reports are composed from freely written descriptions, but an analysis of such free descriptions is not sufficient in the medical field. In this study, we aim to conduct new findings using incident information, to clarify improvements that should be made to solve the root cause of an accident, and to ensure safe medical treatment through such improvements. We employed natural language processing (NLP) and network analysis to identify effective classes of medical incident reports. Network analysis can find various relationships that are not only direct but also indirect. After that, we compared the clustering results between Jichi Medical University and Osaka City University Hospital. By finding the common and different parts in medical incident report' s classes, we could show new perspectives on proposing a common reporting systems in Japan for improving patient safety. PMID- 23920532 TI - An ontological approach for the exploitation of clinical data. AB - Clinical data captured in hospital information systems may be unusable in their original format due to missing information or knowledge. The use of external resources (e.g. domain ontology) could be a way of dealing with this lack of knowledge. Our study thus aimed to develop a framework allowing a user to perform medical queries in the context of infectious diseases. By creating an interaction between a knowledge source and clinical data, using semantic and semantic web tools and methods, the users are able to perform queries on a database to obtain results about antibiotic resistance. This work has been performed in the context of the DebugIT European project that aims to control and monitor the antibioresistance growth via a semantic interoperability platform. The results obtained by the use of different semantic web tools were quantitatively evaluated by comparison of the number of results and the query execution time. We have compared our approach with classic business intelligence approaches in terms of usability and functionality. PMID- 23920533 TI - Guidelines to encourage the adoption and meaningful use of health information technologies in the South African healthcare landscape. AB - There are various benefits associated with the adoption and meaningful use of health information technologies (HITs) in the healthcare sector. Despite these benefits, the South African healthcare sector has been slow to adopt HITs such as electronic record systems. The purpose of this research project was to formulate guidelines to encourage the adoption and meaningful use of HITs in the South African healthcare landscape. A three-round Delphi study was conducted to identify factors that should be addressed to encourage the adoption and meaningful use of HITs in the South African healthcare landscape. The Delphi panel included 21 participants that were considered to be suitably knowledgeable regarding the area under consideration. Consensus was reached on 42 factors that were rated as having a direct to significant impact on the adoption and meaningful use of HITs in the South African context. These factors were further analysed to formulate 20 guidelines that indicate that there are a wide range of factors that would have to be addressed involving a multitude of stakeholders. PMID- 23920535 TI - Opportunistically discovering usability requirements for a clinical handover system. AB - Clinical Handover in hospital is a process that can cause a major risk to patients, and be inefficient and time-consuming for staff. Software designed to support such processes needs to be used in a demanding and fast-moving environment. This work formulated Usability Design Requirements for such a handover software system. The requirements have been derived from a usability evaluation at Auckland City Hospital, where the handover was observed in two different environments during a handover improvement process. The requirements were produced using a multi-method, triangulated approach and they may be able to inform the design of systems to support clinical handover. The physical environment and the protocols adopted for handover were changed during this process, with software changes waiting for a larger project. Periods of change in work practice may be particularly favourable times to perform such studies, even if major software changes are not implemented. Staff engagement with the process may also be improved during times of change. PMID- 23920534 TI - Detecting periodic limb movements with off-the-shelf accelerometers: a feasibility study. AB - Periodic limb movements are short movements of the legs that can lead to low sleep quality in the general population. Currently, the gold standard to measure periodic limb movements for diagnostic purposes is polysomnography. This is an expensive technique that requires specially fitted laboratories and specialized personnel. In this paper we explore the use of commercial, off-the-shelf accelerometers to detect periodic limb movements during sleep and compare the results to the gold standard. We recruited two subjects for one night and measured limb movements with polysomnography and Actigraph GT3X accelerometers. We developed an open source Java application for processing the data. A total of 846 events were recorded. We found a very low similarity between polysomnography and GT3X data, indicating that our accelerometer-based method is not yet feasible for medical diagnosis. Several options for further development are: the exploration of different sensor locations, sensors with higher sampling rates, as well as enhancement of data analysis methods. PMID- 23920536 TI - Evaluating predictive modeling's potential to improve teleretinal screening participation in urban safety net clinics. AB - INTRODUCTION: Screening guidelines for diabetic patients recommend yearly eye examinations to detect diabetic retinopathy and other forms of diabetic eye disease. However, annual screening rates for retinopathy in US urban safety net settings remain low. METHODS: Using data gathered from a study of teleretinal screening in six urban safety net clinics, we assessed whether predictive modeling could be of value in identifying patients at risk of developing retinopathy. We developed and examined the accuracy of two predictive modeling approaches for diabetic retinopathy in a sample of 513 diabetic individuals, using routinely available clinical variables from retrospective medical record reviews. Bayesian networks and radial basis function (neural) networks were learned using ten-fold cross-validation. RESULTS: The predictive models were modestly predictive with the best model having an AUC of 0.71. DISCUSSION: Using routinely available clinical variables to predict patients at risk of developing retinopathy and to target them for annual eye screenings may be of some usefulness to safety net clinics. PMID- 23920537 TI - Ensuring the security and availability of a hospital wireless LAN system. AB - Wireless technologies as part of the data communication infrastructure of modern hospitals are being rapidly introduced. Even though there are concerns about problems associated with wireless communication security, the demand is remarkably large. Herein we discuss security countermeasures that must be taken and issues concerning availability that must be considered to ensure safe hospital/business use of wireless LAN systems, referring to the procedures introduced at a university hospital. Security countermeasures differ according to their purpose, such as preventing illegal use or ensuring availability, both of which are discussed. The main focus of the availability discussion is on signal reach, electromagnetic noise elimination, and maintaining power supply to the network apparatus. It is our hope that this information will assist others in their efforts to ensure safe implementation of wireless LAN systems, especially in hospitals where they have the potential to greatly improve information sharing and patient safety. PMID- 23920538 TI - Simulating cloud environment for HIS backup using secret sharing. AB - In the face of a disaster hospitals are expected to be able to continue providing efficient and high-quality care to patients. It is therefore crucial for hospitals to develop business continuity plans (BCPs) that identify their vulnerabilities, and prepare procedures to overcome them. A key aspect of most hospitals' BCPs is creating the backup of the hospital information system (HIS) data at multiple remote sites. However, the need to keep the data confidential dramatically increases the costs of making such backups. Secret sharing is a method to split an original secret message so that individual pieces are meaningless, but putting sufficient number of pieces together reveals the original message. It allows creation of pseudo-redundant arrays of independent disks for privacy-sensitive data over the Internet. We developed a secret sharing environment for StarBED, a large-scale network experiment environment, and evaluated its potential and performance during disaster recovery. Simulation results showed that the entire main HIS database of Kyoto University Hospital could be retrieved within three days even if one of the distributed storage systems crashed during a disaster. PMID- 23920539 TI - Continual development of a personalized decision support system. AB - Improving the safety, quality, and efficiency of care with the help of clinical decision support tools is one of the core objectives in the meaningful use of Electronic Health Records. Successful adoption of support systems depends on the quality of delivered information, its relevance to the clinical task and individual patient, integration of the system with the entire clinical workplace, and ease of use of the system. This paper presents continuous development and evaluation, as well as lessons learned in development and maintenance of an evidence-based system that supports development of individualized patient care plans. Since its deployment in August 2009, the Evidence-Based Practice InfoBot (EBP InfoBot) system is in daily use at the NIH Clinical Center and responds to 21 requests a day, on average. PMID- 23920540 TI - Ontologies to improve chronic disease management research and quality improvement studies - a conceptual framework. AB - There is a growing burden of chronic non-communicable disease (CNCD). Managing CNCDs requires use of multiple sources of health and social care data, and information about coordination and outcomes. Many people with CNCDs have multimorbidity. Problems with data quality exacerbate challenges in measuring quality and health outcomes especially where there is multimorbidity. We have developed an ontological toolkit to support research and quality improvement studies in CNCDs using heterogeneous data, with diabetes mellitus as an exemplar. International experts held a workshop meeting, with follow up discussions and consensus building exercise. We generated conceptual statements about problems with a CNCD that ontologies might support, and a generic reference model. There were varying degrees of consensus. We propose a set of tools, and a four step method: (1) Identification and specification of data sources; (2) Conceptualisation of semantic meaning; (3) How available routine data can be used as a measure of the process or outcome of care; (4) Formalisation and validation of the final ontology. PMID- 23920541 TI - Improving heart failure information extraction by domain adaptation. AB - Adapting an information extraction application to a new domain (e.g., new categories of narrative text) typically requires re-training the application with the new narratives. But could previous training from the original domain alleviate this adaptation? After having developed an NLP-based application to extract congestive heart failure treatment performance measures from echocardiogram reports (i.e., the source domain), we adapted it to a large variety of clinical documents (i.e., the target domain). We wanted to reuse the machine learning trained models from the source domain, and experimented with several popular domain adaptation approaches such as reusing the predictions from the source model, or applying a linear interpolation. As a result, we measured higher recall and precision (92.4% and 95.3% respectively) than when training with the target domain only. PMID- 23920542 TI - An electronic dashboard to improve nursing care. AB - With the introduction of CPOE systems, nurses in a Singapore hospital were facing difficulties monitoring key patient information such as critical tasks and alerts. Issues include unfriendly user interfaces of clinical systems, information overload, and the loss of visual cues for action due to paperless workflows. The hospital decided to implement an interactive electronic dashboard on top of their CPOE system to improve visibility of vital patient data. A post implementation survey was performed to gather end-user feedback and evaluate factors that influence user satisfaction of the dashboard. Questionnaires were sent to all nurses of five pilot wards. 106 valid responses were received. User adoption was good with 86% of nurses using the dashboard every shift. Mean satisfaction score was 3.6 out of 5. User satisfaction was strongly and positively correlated to the system's perceived impact on work efficiency and care quality. From qualitative feedback, nurses generally agreed that the dashboard had improved their awareness of critical patient issues without the hassle of navigating a CPOE system. This study shows that an interactive clinical dashboard when properly integrated with a CPOE system could be a useful tool to improve daily patient care. PMID- 23920543 TI - Structured representation for core elements of common clinical decision support interventions to facilitate knowledge sharing. AB - At present, there are no widely accepted, standard approaches for representing computer-based clinical decision support (CDS) intervention types and their structural components. This study aimed to identify key requirements for the representation of five widely utilized CDS intervention types: alerts and reminders, order sets, infobuttons, documentation templates/forms, and relevant data presentation. An XML schema was proposed for representing these interventions and their core structural elements (e.g., general metadata, applicable clinical scenarios, CDS inputs, CDS outputs, and CDS logic) in a shareable manner. The schema was validated by building CDS artifacts for 22 different interventions, targeted toward guidelines and clinical conditions called for in the 2011 Meaningful Use criteria. Custom style sheets were developed to render the XML files in human-readable form. The CDS knowledge artifacts were shared via a public web portal. Our experience also identifies gaps in existing standards and informs future development of standards for CDS knowledge representation and sharing. PMID- 23920544 TI - A model-driven approach to clinical practice guidelines representation and evaluation using standards. AB - Clinical Practice Guidelines (CPGs) contain a set of schematic plans for the treatment and management of patients who have a particular clinical condition. CPGs are increasingly being used to support physician decision making. Many groups develop tools for the representation of CPGs. These differ in their approaches to addressing particular modeling challenges. Despite this strong effort, physicians still primarily rely on free-text narrative descriptions. Thus, a core challenge is to develop a formal representation of CPGs that physicians can easily read and verify, yet a machine can process, analyze and apply directly to a patient's EHR data. Our paper proposes a solution to this fundamental problem by describing an approach to CPG formalization using the Natural Rule Language (NRL), coupled with transformation to Object Constraint Language (OCL) constraints that are applied on a patient's clinical data record, in our case an HL7 Continuity of Care Document (CCD). We illustrate our approach on a simple guideline directive for Essential Hypertension. PMID- 23920545 TI - Preference-maximized nutrition planning by relative learning and ranking. AB - Effective personal dietary guidelines are essential for health management and prevention of chronic diseases. A key factor toward a successful diet planning is an individual's food preference instead of dogmatic nutrition pattern since it is unlikely that an individual would accept the meal plan merely based on the nutrition supplements. However, the extraction of personal preference is definitely not a trivial matter. The objective of this research is to achieve nutrient-balanced food recommendations for each individual, while considering individual's preferences and requirements at the same time. To reach this goal, we present the k-relative learning technique for semi-automatically extracting users' preferences in a more efficient and effective manner. Comparing to conventional methods, the proposed system can not only reveal users' opinions about foods more fairly but also save lots of labeling efforts during the training data collection stage. In addition, a smarter feedback mechanism is also proposed to enable a more pleasant experience of the user-system interaction. The resulted system is thus expected to improve users' diet habit and compliance with healthier lifestyle. PMID- 23920546 TI - Utilizing electronic health record data to determine the health of the medication process after the relocation of a children's hospital. AB - Hospital relocation is a highly complex undertaking, which has the potential to interrupt operations and poses risks for patients, staff, and providers. Little is known how hospital relocation impacts on workflow and communication. METHODS: Using existing Electronic Health Record (EHR) data we determined time from medication ordering to first dose administration as a proxy for well-being of the medication process during a five months window surrounding the relocation of a 205-bed children's hospital. RESULTS: Overall performance of the medication process has declined slightly. We identified regional (unit) differences with the pediatric intensive care unit, which had the most significant changes to its workflow, experiencing a more than doubling of the time from ordering to medication administration. Overall, there was no significant difference in time sensitive medication administration times. Evaluating the medication ordering dispensing-administration process through readily available EHR data demonstrated that the impact of a hospital' s relocation on workflow and communication can be successfully monitored. PMID- 23920547 TI - Validation of fuzzy sets in an automated detection system for intensive-care-unit acquired central-venous-catheter-related infections. AB - Central venous catheters play an important role in patient care in intensive care units (ICUs), but their use comes at the risk of catheter-related infections (CRIs). Electronic surveillance systems can detect CRIs more accurately than manual surveillance, but these systems often omit patients that do not exhibit all infection signs to their full degree, the so-called borderline group. By extending an electronic surveillance system with fuzzy constructs, the borderline group can be identified. In this study, we examined the size of the borderline group for systemic CRIs (CRI2) by calculating the frequency of fuzzy values for CRI2 and related infection parameters in patient data involving ten ICUs (75 beds) over one year. We also validated the expert-defined fuzzy constructs by comparing overall and CRI2-specific support. The study showed that more than 86% of the data contained fuzzy values, and that the borderline group for CRI2 consisted of 2% of the study group. It was also confirmed that most fuzzy constructs were good representatives of the borderline CRI2 patient group. PMID- 23920548 TI - Feasibility analysis of the privacy attributes of the personal wellness information model. AB - A feasibility analysis has been performed to study the applicability of privacy attributes with a developed wellness information model. Information privacy concerns specifically access to individually identifiable personal information and one's ability to control information about oneself. We carried out a user scenario walk-through of the privacy attributes related to the wellness components. The walk-through showed a need to relate self-regulating privacy policies to the pervasive context so that during various trust-building processes, a person is aware and can control the use, disclosure and even secondary use of his personal, private wellness information. PMID- 23920549 TI - User tests for assessing a medical image retrieval system: a pilot study. AB - Content-based image retrieval (CBIR) has often been proposed to assist medical decision making in complement to textual information search. However, applications of this novel technology have rarely reached the end users. The study presented in this paper describes the design and setup for performing pilot user tests in order to assess a medical information retrieval system that supports CBIR with the goal of having more detailed tests with an updated system. Five individuals with medical education participated in the study at the University hospitals of Geneva. They were recorded and observed while interacting with the system, and then provided feedback on the usability of the system. Participants seemed to understand the concept and practical uses of the new tools, and needed 10-15 minutes to feel confident with the system. The results of this pilot study will be used for improving the system functionalities as well as an input for designing a new iteration of larger-scale user tests among radiologists. PMID- 23920550 TI - Prediction-based threshold for medication alert. AB - This study presents a prediction-based approach to determine thresholds for a medication alert in a computerized physician order entry. Traditional static thresholds can sometimes lead to physician's alert fatigue or overlook potentially excessive medication even if the doses are belowthe configured threshold. To address this problem, we applied a random forest algorithm to develop a prediction model for medication doses, and applied a boxplot to determine the thresholds based on the prediction results. An evaluation of the eight drugs most frequently causing alerts in our hospital showed that the performances of the prediction were high, except for two drugs. It was also found that using the thresholds based on the predictions would reduce the alerts to a half of those when using the static thresholds. Notably, some cases were detected only by the prediction thresholds. The significance of the thresholds should be discussed in terms of the trade-offs between gains and losses; however, our approach, which relies on physicians' collective experiences, has practical advantages. PMID- 23920551 TI - Personal health information, privacy and surveillance: do we need a critical voice? AB - This paper argues that many expanding secondary uses of personal health information are moving beyond legitimate monitoring processes, to become surveillance practices used for purposes of controlling individuals and populations. The paper focuses on the academic discipline of health informatics as a key claim-making site for influencing understandings about uses of personal health information. Using a Foucauldian influenced analysis, it discusses the way discourses shape our attitude to expanding uses of personal health information. It argues that aspirational goals of the discipline discourage critical analyses, creating the potential for the health informatics community to support expanding use of personal information for activities that may result in discrimination, disadvantage. PMID- 23920552 TI - Steps to consider for effective decision making when selecting and prioritizing eHealth services. AB - Making the best choice for an organization when selecting IT applications or eHealth services is not always easy as there are a lot of parameters to take into account. The aim of this paper is to explore some steps to support effective decision making when selecting and prioritizing eHealth services prior to implementation and/or procurement. The steps presented in this paper were identified by interviewing nine key stakeholders at Stockholm County Council. They are supposed to work as a guide for decision making and aim to identify objectives and expected effects, technical, organizational, and economic requirements, and opportunities important to consider before decisions are taken. The steps and their respective issues and variables are concretized in a number of templates to be filled in by decision makers when selecting and prioritizing eHealth services. PMID- 23920553 TI - Early Experiences from a guideline-based computerized clinical decision support for stroke prevention in atrial fibrillation. AB - Atrial fibrillation (AF) affects 1-2% of the population. Twenty percent of all strokes are caused by AF. In this study, we represented the clinical knowledge in the European Society of Cardiology guideline using Guideline Definition Language (GDL), a format that binds openEHR archetypes, rule languages, and reference terminologies together. The computerized guidelines are applied to electronic health record (EHR) data retrospectively in order to identify possible gaps between current clinical practice and optimal care recommended by the evidence based guidelines. Treatment compliance is checked in two patient groups: one received treatment from a cardiologist who is responsible for AF treatment in the region (n=514) and the other was a much larger patient group from the whole region (n=8130). The compliance checking shows the cardiologist group has substantially higher percentage of compliant treatment compared with that of the general population group. Based on this important finding, we are now implementing at-point-of-care clinical decision support reusing the same computerized guideline knowledge in GDL format in order to increase the guideline adherence of the treatment. PMID- 23920554 TI - A web-based system to facilitate local, systematic quality improvement by multidisciplinary care teams: development and first experiences of CARDSS Online. AB - Continuous monitoring and systematic improvement of quality have become increasingly common in healthcare. To support multidisciplinary care teams in improving their clinical performance using feedback on quality indicators, we developed the CARDSS Online system. This system supports (i) monitoring of indicator-based performance, (ii) selecting aspects of care that need improvement, (iii) developing a quality improvement (QI) plan, and (iv) periodically adjusting the QI plan. During educational outreach visits, the system actively involves the team in the improvement effort, and guides them through the process of systematic QI without needing extensive knowledge of the underlying concepts. During the implementation of the system in the field of cardiac rehabilitation (CR) in the Netherlands, we have conducted the first outreach visits to four CR teams. During the visits, the teams formulated QI plans consisting of 4 to 7 improvement goals, each goal accompanied by 1 to 5 QI actions. Currently, we are evaluating the effect of CARDSS Online on the quality of CR in the Netherlands in a cluster randomized trial. PMID- 23920555 TI - User-centered design in clinical handover: exploring post-implementation outcomes for clinicians. AB - This paper examines the outcomes for clinicians from their involvement in the development of an electronic clinical hand-over tool developed using principles of user-centered design. Conventional e-health post-implementation evaluations tend to emphasize technology-related (mostly positive) outcomes. More recently, unintended (mostly negative) consequences arising from the implementation of e health technologies have also been reported. There remains limited focus on the post-implementation outcomes for users, particularly those directly involved in e health design processes. This paper presents detailed analysis and insights into the outcomes experienced post-implementation by a cohort of junior clinicians involved in developing an electronic clinical handover tool in Tasmania, Australia. The qualitative methods used included observations, semi-structured interviews and analysis of clinical handover notes. Significantly, a number of unanticipated flow-on effects were identified that mitigated some of the challenges arising during the design and implementation of the tool. The paper concludes by highlighting the importance of identifying post-implementation user outcomes beyond conventional system adoption and use and also points to the need for more comprehensive evaluative frameworks to encapsulate these broader socio technical user outcomes. PMID- 23920556 TI - Development of a semantic-based search system for immunization knowledge. AB - This study developed and implemented a children's immunization management system with English and Traditional Chinese immunization ontology for semantic-based search of immunization knowledge. Parents and guardians are able to search vaccination-related information effectively. Jena Java Application Programming Interface (API) was used to search for synonyms and associated classes in this domain and then use them for searching by Google Search API. The searching results do not only contain suggested web links but also include a basic introduction to vaccine and related preventable diseases. Compared with the Google keyword-based search, over half of the 31 trial users prefer using semantic-based search of this system. Although the search runtime on this system is not as fast as well-known search engines such as Google or Yahoo, it can accurately focus on searching for child vaccination information to provide search results that better conform to the needs of users. Furthermore, the system is also one of the few health knowledge platforms that support Traditional Chinese semantic-based search. PMID- 23920557 TI - Non-contact screening system with two microwave radars in the diagnosis of sleep apnea-hypopnea syndrome. AB - There are two key problems in applying Doppler radar to a diagnosis system for sleep apnea-hypopnea syndrome. The first is noise associated with body movement and the second is the body position in bed and the change of the sleeping posture. We propose a new automatic gain control and a real-time radar-output channel selection method which is based on a spectrum shape analysis. There are three types of sleep apnea: central sleep apnea, obstructive sleep apnea and mixed sleep apnea. In this paper we paid attention to the obstructive sleep apnea and attempted to detect the disorder of corrugated shape compared with usual breathing or the paradoxical movement of the reversed phase with chest and abdominal radar signals. A prototype of the system was set up at a sleep disorder center in a hospital and field tests were carried out with eight subjects. Despite the subjects engaging in frequent body movements while sleeping, the system was quite effective in the diagnosis of sleep apnea-hypopnea syndrome (r=0.98). PMID- 23920558 TI - Home monitoring and decision support for international liver transplant children. AB - Complications may occur after a liver transplantation, therefore proper monitoring and care in the post-operation phase plays a very important role. Sometimes, monitoring and care for patients from abroad is difficult due to a variety of reasons, e.g., different care facilities. The objective of our research for this paper is to design, implement and evaluate a home monitoring and decision support infrastructure for international children who underwent liver transplant operation. A point-of-care device and the PedsQL questionnaire were used in patients' home environment for measuring the blood parameters and assessing quality of life. By using a tablet PC and a specially developed software, the measured results were able to be transmitted to the health care providers via internet. So far, the developed infrastructure has been evaluated with four international patients/families transferring 38 records of blood test. The evaluation showed that the home monitoring and decision support infrastructure is technically feasible and is able to give timely alarm in case of abnormal situation as well as may increase parent's feeling of safety for their children. PMID- 23920559 TI - Nordic eHealth indicators: organisation of research, first results and plan for the future. AB - eHealth indicator and benchmarking activities are rapidly increasing nationally and internationally. The work is rarely based on a transparent methodology for indicator definition. This article describes first results of testing an indicator methodology for defining eHealth indicators, which was reported at the Medical Informatics Europe conference in 2012. The core elements of the methodology are illustrated, demonstrating validation of each of them in the context of Nordic eHealth Indicator work. Validation proved the importance of conducting each of the steps of the methodology, with several scientific as well as practical outcomes. The article is based on a report to be published by the Nordic Council of Ministers [4]. PMID- 23920560 TI - Mining information dependency in outpatient encounters for chronic disease care. AB - Chronic disease care, e.g., care of type 2 diabetes mellitus, is a long-term, complex process involving collaboration and coordination among multiple healthcare providers. To facilitate and accelerate the process, it is key to understand the information flow and identify the information dependency (e.g., temporal dependency of co-occurrence and sequential occurrence) during care provision, which is also the objective of this work. Since most health interventions and decisions are made in outpatient encounters for chronic patients, in this paper, we propose an approach to mine temporal information dependency in outpatient encounter records using sequential pattern mining techniques. By exploring the real data of over 10,000 type 2 diabetes patients from three hospitals, the proposed approach effectively works out sets of meaningful information dependency patterns for different patient groups. The discovered information dependency can be used to guide the information sharing between different health providers, and optimize the chronic disease care coordination. PMID- 23920561 TI - Verbal protocols for assessing the usability of clinical decision support: the retrospective sense making protocol. AB - We compare the effectiveness of two types of verbal protocol, concurrent think aloud vs. retrospective sense making, for evaluating the usability of a clinical decision support tool. Thirty-five medical and nursing students participated in a usability experiment. Participants were asked to complete seven tasks using the system under evaluation. Eighteen students were allocated to the concurrent think aloud group and the remainder followed the retrospective protocol. The retrospective protocol was significantly more sensitive than the concurrent protocol in recording unique usability problems related to users' cognitive behaviour. These problems concerned the interpretation and comprehension of statistical output, search results and system messages. These findings can be explained by the retrospective protocol's greater ability to detect compound usability problems, capturing the cognitive dimensions of users' interactions with the interface in greater depth. Evaluations of clinical decision support systems should take an evidence-based approach to selecting protocols. PMID- 23920562 TI - e-Labs and the stock of health method for simulating health policies. AB - Regional outcomes of national health policies are difficult to forecast. This is partly due to a lack of realistically complex models that can be used to appraise policy options and partly a lack of accessible and adaptable tools that can be used to simulate the consequences of policy decisions. These barriers might be overcome by exploiting the commoditization of massively parallel computing architectures, advances in machine learning, and the increased availability of large-scale linked healthcare data. This paper presents a novel modelling methodology, The Stock of Health, for harnessing emerging data and computational resources to simulate health policy, with application initially to coronary heart disease. We detail the use of multi-core graphical processing architectures to facilitate a micro-simulation approach. The simulation tools have been deployed through the IMPACT Framework. We explore how this framework can be extended to support the sharing and reuse of policy models and simulations based on the digital publishing concept of e-Lab. PMID- 23920563 TI - Supervised analysis of drug prescription sequences. AB - Hospitals have at their disposal large databases that may be considered for reuse. The objective of this work is to evaluate the impact of a drug on a specific laboratory result by analyzing these data. This analysis first involves building a record of temporal patterns, including medical context, of drug prescriptions. Changes in outcome due to these patterns of drug prescription are assessed using short phases of the inpatient stay compared to monotonous changes in the laboratory result. To illustrate this technique, we investigated potassium chloride supplementation and its impact on kalemia. This method enables us to assess the impact of a drug (in its frequent context of prescription) on a laboratory result. This kind of analysis could play a role in post-marketing studies. PMID- 23920564 TI - Functional requirements for a central research imaging data repository. AB - The current situation at many university medical centers regarding the management of biomedical research imaging data leaves much to be desired. In contrast to the recommendations of the German Research Foundation (DFG) and the German Council of Sciences and Humanities regarding the professional management of research data, there are commonly many individual data pools for research data in each institute and the management remains the responsibility of the researcher. A possible solution for this situation would be to install local central repositories for biomedical research imaging data. In this paper, we developed a scenario based on abstracted use-cases for institutional research undertakings as well as collaborative biomedical research projects and analyzed the functional requirements that a local repository would have to fulfill. We determined eight generic categories of functional requirements, which can be viewed as a basic guideline for the minimum functionality of a central repository for biomedical research imaging data. PMID- 23920565 TI - Whiteboard icons to support the blood-test process in an emergency department: an observational study of temporal patterns. AB - The competent treatment of emergency department (ED) patients requires an effective and efficient process for handling laboratory tests such as blood tests. This study investigates how ED clinicians go about the process, from ordering blood tests to acknowledging their results and, specifically, assesses the use of whiteboard icons to support this process. On the basis of observation and interviews we find that the blood-test process is intertwined with multiple other temporal patterns in ED work. The whiteboard icons, which indicate four temporally distinct steps in the blood-test process, support the nurses in maintaining the flow of patients through the ED and the physicians in assessing test results at timeouts. The main results of this study are, however, that the blood-test process is temporally and collaboratively complex, that the whiteboard icons pass by most of this complexity, that attending to the icons is yet another temporally sensitive activity to remember, and that whereas the assessment of test results is integral to patient treatment, the acknowledgement of having seen the results is a formal add-on, the responsibility for which is sometimes unclear. PMID- 23920566 TI - Routine use of the "ADE scorecards", an application for automated ADE detection in a general hospital. AB - Retrospective detection of Adverse Drug Events (ADEs) is challenging, notably because ADEs result from complex interactions between many factors. Data mining techniques have recently emerged in the field of automated retrospective ADE detection. The "ADE Scorecards" are a research application based on data-mining that has been built in the framework of the PSIP European Project, and potentially enables automated ADE retrospective detection. The objective of this paper is to evaluate the use of the ADE Scorecards in a real-life healthcare situation. For that purpose, the ADE Scorecards have been implemented in a French general hospital and have been used by the physicians and pharmacists for three years (corresponding to 73,000 inpatient stays). According to the results, 2% of the analyzed inpatient stays have a potential ADE with hyperkalemia, and 1% of them have a potential ADE with vitamin K antagonist overdose. In practice, the application, which was first designed to be a standalone web-based application for the physicians, has been used as a part of a more global quality improvement approach led by the pharmacists. PMID- 23920567 TI - Barriers to the reuse of routinely recorded clinical data: a field report. AB - Today, clinical data is routinely recorded in vast amounts, but its reuse can be challenging. A secondary use that should ideally be based on previously collected clinical data is the computation of clinical quality indicators. In the present study, we attempted to retrieve all data from our hospital that is required to compute a set of quality indicators in the domain of colorectal cancer surgery. We categorised the barriers that we encountered in the scope of this project according to an existing framework, and provide recommendations on how to prevent or surmount these barriers. Assuming that our case is not unique, these recommendations might be applicable for the design, evaluation and optimisation of Electronic Health Records. PMID- 23920568 TI - Design and implementation of an informed consent process for a standardized health information exchange solution on the example of the lower saxony bank of health. AB - OBJECTIVE: Multicenter medical treatment requires health related data to be available across institutions. Since health information exchange solutions are emergent, fulfillment of privacy needs, including patients' informed consent, is vital for successful data exchange. METHODS: We designed a software supported consent process for the recently founded Lower Saxony Bank of Health (LSBH) with regard to particularities of German law. To implement the application, web technologies and well-described interfaces to IHE XDS profile components have been used. RESULTS: A two staged process has been developed. A special consent application creates a customized form containing all orally given constraints defined by the patient. The form is printed out and signed by the patient while an electronic policy is created and registered at the LSBH. CONCLUSION: The process completely reflects a conventional informed consent procedure but increases simplicity, clarity and understandability of the consent form. Technical and legal restrictions in Germany create a media split becoming a media crack in some environments. Availability of signature cards could improve the process by making it completely electronic. PMID- 23920569 TI - Assessing the usage of a guideline-driven interactive case simulation tool for insomnia screening and treatment in an HIV clinical education program. AB - Interactive case simulation tools (ICSTs) are important vehicles to disseminate medical knowledge. We conducted a study to examine the usage of an insomnia screening and treatment case simulation tool in an HIV clinical education program. Using system usage diagrams (SUDs) as an instrument, we quantified visit frequency and length of stay for different types of system resources. Preliminary results have shown that both recommendations and interactive decision diagrams were frequently used, with the former having a longer length of stay but fewer visits. Case simulation functions seemed to be able to engage users. Future research is required to verify the generalizability of the identified usage patterns, to investigate issues in usability design, and to perform correlation analyses on system usage and context parameters. PMID- 23920570 TI - Designing for redundancy: nurses experiences with the wireless nurse call system. AB - Patients rely on the nurse call system when in need of nurses' assistance, while nurses rely on the nurse call system to coordinate work. In order to handle the highly mobile nature of nurses' work, a wireless nurse call system has been introduced at a Norwegian hospital. In light of findings from previous research that identify challenges associated with wireless nurse call systems, we have conducted qualitative and ethnographically inspired fieldwork, i.e. workshops including both ordinary and student nurses to describe nurses' present system use. We further identify challenges related to wireless nurse call system usage, in particular how nurses manage the interruptive nature of wireless nurse calls so as to ensure continuous patient support. Our analysis acknowledges that High Reliability Organization (HRO) principles are transferable to a hospital organization. Based on our data, we propose improvements for design that hopefully can help reduce disruptive interruptions, ensure quick responses to patients, and further improve quality of care and patient safety. Further, we suggest that technology should facilitate and strengthen the redundancy of function. PMID- 23920571 TI - An evaluation framework and a pilot study of a mobile platform for diabetes self management: insights from pediatric users. AB - According to WHO, pediatric diabetes is a rising global public health problem, with increasing impact on developing nations. This study summarizes a multidimensional, scalable pilot evaluation of a diabetes self-management platform combining mobile technology with social networking to capture four key metrics of Type 1 diabetes self-management, associated social interactions, and gaming features providing targeted feedback to 8 pediatric users. Based on their 2-month interaction with the application, we analyze click-stream data from social interactions, key health metrics, text comments, and usability and satisfaction surveys to evaluate engagement with the platform and effectiveness in controlling blood glucose using a product-process-program framework. Our preliminary results indicate that this framework was successful in demonstrating the potential of the mobile health platform to effectively leverage the growing use of mobile applications and social media to present a unique benefit that engaged pediatric users and provided useful insights for self-health management. PMID- 23920572 TI - Genetic testing information standardization in HL7 CDA and ISO13606. AB - Communicating genetic testing reports of a patient in a semantically interoperable way remains difficult. Most of the information is stored as non communicable documents which cannot automatically be processed. The objective of the project was to obtain semantically interoperable genetic testing reports which could be used not only for communication purposes but also for secondary uses, for example clinical trials or clinical decision support. This work describes the first part of the project, the modeling of genetic information reports using EHR standards. We used the Implementation Guide for CDA R2 Genetic Testing Report (GTR) as a basis for modeling the archetypes for both HL7 CDA and CEN/ISO 13606. This approach was validated with the information included in Usher Syndrome reports available at ISS-La Fe. The result of this work were three archetypes following ISO13606 and three archetypes following HL7 CDA model which contained all the information available in both Usher syndrome genetic testing reports and the implementation guide significant parts. PMID- 23920573 TI - Sharing ontology between ICD 11 and SNOMED CT will enable seamless re-use and semantic interoperability. AB - In order to support semantic interoperability in eHealth systems, domain terminologies need to be carefully designed. SNOMED CT and the upcoming ICD-11 represent a new generation of ontology-based terminologies and classifications. The proposed alignment of these two systems and, in consequence, the validity of their cross-utilisation requires a thorough analysis of the intended meaning of their representational units. We present the ICD11 SNOMED CT harmonization process including: a) the clarification of the interpretation of codes in both systems as representing situations rather than conditions, b) the principles proposed for aligning the two systems with the help of a common ontology, c) the high level design of this common ontology, and d) further ontology-driven issues that have arisen in the course of this work. PMID- 23920574 TI - The Austrian e-Medikation pilot evaluation: lessons learned from a national medication list. AB - The objective of this paper is to present results and recommendations from the Austrian e-Medikation pilot project. e-Medikation comprises a national medication list of all prescribed and dispensed medications as well as central medication checks. Evaluation was based on log-file analysis and survey of all participants (physicians, pharmacists, patients). During the evaluation period, 97 physicians, 58 pharmacies and more than 5.000 patients, participated. All user groups found that e-Medikation has the potential to improve patient safety, but that software quality and system architecture is not yet suitable for routine use. The evaluation resulted in 34 recommendations for further development and roll out of e-Medikation in Austria. Most of these recommendations have already been included in the recently passed law concerning the upcoming Austrian electronic health record system called "ELGA". PMID- 23920575 TI - Clinical practice guidelines and comorbid diseases: a MiniZinc representation of guideline models for mitigating adverse interactions. AB - Managing a patient with comorbid diseases according to multiple clinical practice guidelines (CPGs) may result in adverse interactions that need to be mitigated (identified and addressed) so a safe therapy can be devised. However, mitigation poses both clinical and methodological challenges. It requires extensive domain knowledge and calls for advanced CPG models and efficient algorithms to process them. We respond to the above challenges by describing our algorithm that mitigates interactions between pairs of CPGs. The algorithm creates logical models of analyzed CPGs and uses constraint logic programming (CLP) together with domain knowledge, codified as interaction and revision operators, to process them. Logical CPG models are transformed into CLP-CPG models that are solved to find a safe therapy. We represent these CLP-CPG models using MiniZinc, a standard language for CLP models. As motivation and illustration of our mitigation algorithm we use a clinical case study describing a patient managed for hypertension and deep vein thrombosis according to two individual CPGs. We apply the algorithm to this scenario and present MiniZinc representations of the constructed CLP-CPG models. PMID- 23920576 TI - Web-based peer-driven chain referrals for smoking cessation. AB - BACKGROUND: We are testing web-based respondent-driven sampling (RDS) chain referrals to recruit smokers to the Decide2Quit.org (D2Q) web-assisted tobacco intervention. METHODS: Using an online survey of smokers, we assessed the potential of recruiting 1200 smokers in 9 months using RDS chain referrals. RDS is a complex sample design, and many factors can influence its success. We conducted simulations to determine the design of optimal RDS chains. RESULTS: Smokers (n=48) were mostly female (72%) and between ages 30-60 (82%). Estimation of smokers in their network: 1-5 (40%), 6-10 (24%), and 10-20 (22%), with mean number of intimate family (2.2, SD=2.1) and close friend smokers (3.7, SD=3.8). Most smokers (82%) were willing to refer to D2Q and thought their friends (mean=5.0, SD=4.4, range=0-20) would be open to referral. Simulations suggested that with a quota of 3 and 10 seeds, 99.9% of the sample would be achieved in 107 days if the acceptance probability was 0.5. Acceptance probability of 25% would necessitate an increased quota. CONCLUSIONS: Our study suggests that it is possible to recruit smokers using RDS. PMID- 23920577 TI - Real-time multidimensional temporal analysis of complex high volume physiological data streams in the neonatal intensive care unit. AB - The intensive care of immature preterm infants is a challenging, dynamic clinical task that is complicated because these infants frequently develop a range of comorbidities as they grow and develop after their premature birth. Earliest reliable condition onset detection is a goal within this setting and high frequency physiological analysis is showing potential new pathophysiological indicators for earlier onset detection of several conditions. To realise this, a platform for multi-stream, multi-condition, multi-feature risk scoring is required. In this paper we demonstrate our multi-stream online analytics approach for condition onset detection and demonstrate a user interface approach for patient state that can be available in real-time to support condition risk scoring. PMID- 23920578 TI - Comparing approaches to measuring the adoption and usability of electronic health records: lessons learned from Canada, Denmark and Finland. AB - Internationally, the adoption of health information technology is increasing. However, a number of issues have complicated the adoption of electronic health records (EHRs). In addition to adoption issues, it is becoming increasingly recognized that healthcare providers face a variety of usability issues. In this paper, we consider approaches that have been taken to assess both adoption and usability of EHRs in Canada, Denmark and Finland. Although all three countries deploy surveys to assess adoption, the approach and focus of the surveys differs across the countries. In Denmark and Finland, these surveys are dedicated to assessing information technology (IT) usage; while in Canada, questions about IT usage are part of a larger physician survey. Regarding usability, approaches vary considerably. In Finland, the approach includes a national survey about EHR usability. In Canada, ratings of system usability are reported regionally on web sites; while in Denmark, regional study results are reported based on evaluation of commercial products. This paper highlights the need to consider different evaluation approaches internationally. PMID- 23920579 TI - International priorities for research in nursing informatics for patient care. AB - The Nursing Informatics International Research Network (NIIRN) is a group of experts who are collaborating on the development of internationally relevant research programs for nursing informatics. In this paper we outline key findings of a survey exploring international research priorities for nursing informatics. The survey was available online during May-August 2012. Respondents were asked to rate each of 20 listed research topics in terms of respondent's views of its priority for nursing informatics research. 468 completed surveys were received representing respondents from six World Health Organization regions. The two most highly ranked areas of importance for research were development of systems to provide real time feedback to nurses and assessment of the impact of HIT on nursing care and patient outcomes. The lowest ranked research topics were theory development and integrating genomic data into clinical information systems. The identification of these priorities provides a basis for future international collaborative research in the field of nursing informatics. PMID- 23920580 TI - Delivering antibiotic resistance information specifically tailored to location and time. AB - Antibiotic resistance poses a significant threat to humanity. Hundred years since the beginning of the era of antibacterial drugs, we are facing increasing numbers of infections with multi-resistant pathogens. The current approach of distributing information on antibiotic resistance in printed form in the clinics has disadvantages with respect to the actuality of the data and the regional heterogeneity of resistance patterns. We developed an application named qRe using representational state transfer as a communication standard to deliver antibiotic resistance percentage information to the end user. The data is selected specifically for his/her geographic location. The user can display the information using either the application for Android smart phones or the web application. With the presented software we show the technical feasibility of delivering antibiotic resistance information specifically tailored to location and time. A short evaluation of the software showed an overall positive response from physicians. Based on recommendations of previous investigations, we expect a measurable clinical impact. PMID- 23920581 TI - Explore and experience: mobile augmented reality for medical training. AB - In medicine, especially in basic education, it may sometimes be inappropriate to integrate real patients into classes due to ethical issues that must be avoided. Nevertheless, the quality of medical education may suffer without the use of real cases. This is especially true of medical specialties such as legal medicine: survivors of a crime are already subjected to procedures that constitute a severe emotional burden and may cause additional distress even without the added presence of students. Using augmented reality based applications may alleviate this ethical dilemma by giving students the possibility to practice the necessary skills based on virtual but nevertheless almost realistic cases. The app "mARble(r)" that is presented in this paper follows this approach. The currently available learning module for legal medicine gives users an opportunity to learn about various wound patterns by virtually overlaying them on their own skin and is applicable in different learning settings. Preliminary evaluation results covering learning efficiency and emotional components of the learning process are promising. Content modules for other medical specialtiesare currently under construction. PMID- 23920582 TI - Missed opportunities mapping: computable healthcare quality improvement. AB - INTRODUCTION: Analysing variance from care pathways in situations when adverse health outcomes have occurred may identify missed opportunities for healthcare improvement. METHODS: We developed a computational model for contrasting observed with expected care in pathway searches of coded electronic health records (EHRs). The model was applied in Salford, UK, looking at blood pressure (BP) control and cardiovascular disease (CVD) events. BP was summarised as the integral of serial measurements. RESULTS: A missed opportunities mapping (MOM) model consisting of a collection of disease Events and pathophysiologic States was used to articulate all CVD scenarios conceived. In 3718 patients suffering CVD events in Salford (2007-2012), 1186 (32%) had suboptimal BP control. This missed opportunity detection rose to 36% using the integral instead of the most recent BP record. CONCLUSIONS: MOM provides a useful, computable model for encoding care pathways and searching EHRs to detect variations from expected care. Further research is needed in other disease areas. The indications however, are that this model could be used to embed healthcare quality improvement at both patient and population levels. PMID- 23920583 TI - Patient-tailored workflow patterns from clinical practice guidelines recommendations. AB - MobiGuide is a project devoted to the development of a patient-centric decision support system based on computerized clinical guidelines for chronic illnesses including Atrial Fibrillation (AF). In this paper we describe the process of (1) identifying guideline recommendations that will require patients to take actions (e.g., take measurement, take drug), thus impacting patients' daily-life behavior, (2) eliciting from the medical experts the corresponding set of personalized operationalized advices that are not explicitly written in the guideline (patient-tailored workflow patterns) and (3) delivering this advice to patients. The analysis of the AF guideline has resulted in four types of patient tailored workflow patterns: therapy-related advisors, measurements advisors, suggestions for dealing with interventions that may require modulating patient therapy, and personalized packages for close monitoring of patients. We will show how these patterns can be generated using information stored in a patient health record that embeds clinical data and data about the patient's personal context and preferences. PMID- 23920584 TI - A comparison of approaches to providing patients access to summary care records across old and new europe: an exploration of facilitators and barriers to implementation. AB - Providing online access to their medical records should empower patients. National health services in Estonia, France, and England introduced systems to provide online access to summary health data. The Estonian patient access called "Patient Portal" shares similarities with the French system "Dossier Medical Personnel" (DMP). Both are patient-controlled records. The English system "Summary Care Record" (SCR) provided access to patients through "HealthSpace," though has now been replaced by encouraging access to GP records. Denmark and Ireland also provided access rights to patients so they could view their records. Romania, Croatia, and Greece do not have national systems. The aim of this study is to compare adoption and uptake of patient access to summary data. The Estonian record was used by 3.6% of the population, the French one by 0.5% and the English system is due for closure with only 0.01% signing up for the most comprehensive access. Few countries across Europe have adopted patient access to summary health data at a national level, and where introduced, medical records have been accessed by less than 5% of the population. PMID- 23920585 TI - Clinical simulation and workflow by use of two clinical information systems, the electronic health record and digital dictation. AB - Clinical information systems do not always support clinician workflows. An increasing number of unintended clinical incidents might be related to implementation of clinical information systems and to a new registration praxis of unintended clinical incidents. Evidence of performing clinical simulations before implementation of new clinical information systems provides the basis for use of this method. The intention has been to evaluate patient safety issues, functionality, workflow, and usefulness of a new solution before implementation in the hospitals. Use of a solution which integrates digital dictation and the EHR (electronic health record) were simulated in realistic and controlled clinical environments. Useful information dealing with workflow and patient safety were obtained. The clinical simulation demonstrated that the EHR locks during use of the integration of digital dictation, thus making it impossible to use the EHR or connected applications during digital dictation. The results of the simulations showed that the tested and evaluated solution does not support the clinical workflow. Conducting the simulations enabled us to improve the solution before implementation, but further development is necessary before implementation of the solution. PMID- 23920586 TI - Interface map as a user-driven and activity-driven interoperability standards portfolio. AB - Use of interoperability specifications such as standards and their implementation guides is currently hindered by lack of systematic directories. It is difficult for potential users of standards to locate potential specifications which could be useful for their specific development needs. We introduce a multi-directory interface map approach which supports systematic description of healthcare interoperability specifications through consistent metadata and complementary classifications. The approach is built on basic premises of standards portfolios in enterprise architectures as well as activity-driven and interoperability paradigm-based classifications. We illustrate the approach through a case project in Finland. PMID- 23920587 TI - A Unified Medical Language System (UMLS) based system for Literature-Based Discovery in medicine. AB - Literature-Based Discovery (LBD) is a technique that can be used in translational research to connect the very sparse and huge information available in scientific publications in order to extract new knowledge. This paper presents an LBD system based on the open discovery paradigm exploiting NLP techniques and UMLS medical concepts mapping, to provide a set of tools useful to discover unknown relationships. The system has been evaluated on the problem of discovering new candidate genes potentially related to dilated cardiomyopathies (DCM), and can be used in any medical context to connect different type of concepts. The validation of the system involves reproducing the discovery of genes currently associated to DCM. Validation showed that the system is able to discover many gene-disease associations by using the literature available before their first publication in a scientific article. PMID- 23920588 TI - Accuracy of an electronic problem list from primary care providers and specialists. AB - Accurate patient problem lists in Electronic Health Records (EHRs) are valuable tools for improving the quality of care, communication among professionals, facilitating research, quality measurement and the implementation of clinical decision support systems. However, problem lists are frequently inaccurate and out-of-date, and use varies widely across providers. These deficiencies limit problem list benefits. We decided to check if accuracy of problem lists-assessed at a granular level of detail-registered in EHRs depended on the specialty of the physician (primary care providers vs. specialists), and in the event that such differences did occur, whether or not accuracy had also been affected by the work environment. By using registered problems and taking the generated clinical document, we designed a cross-sectional survey following the guidelines of the Clinical Document Architecture standard. Problems registered by primary care providers have a higher level of accuracy than those registered by specialists in all settings considered (emergency unit, inpatient and outpatient). The work environment also significantly affects the accuracy level of problems registered. PMID- 23920589 TI - Clinical Computer Systems Survey (CLICS): learning about health information technology (HIT) in its context of use. AB - Successful health information technology (HIT) implementations need to be informed on the context of use and on users' attitudes. To this end, we developed the CLinical Computer Systems Survey (CLICS) instrument. CLICS reflects a socio technical view of HIT adoption, and is designed to encompass all members of the clinical team. We used the survey in a large English hospital as part of its internal evaluation of the implementation of an electronic patient record system (EPR). The survey revealed extent and type of use of the EPR; how it related to and integrated with other existing systems; and people's views on its use, usability and emergent safety issues. Significantly, participants really appreciated 'being asked'. They also reminded us of the wider range of administrative roles engaged with EPR. This observation reveals pertinent questions as to our understanding of the boundaries between administrative tasks and clinical medicine - what we propose as the field of 'administrative medicine'. PMID- 23920590 TI - Seeking evidence to support usability principles for medication-related clinical decision support (CDS) functions. AB - There is a need for evidence-based usability principles to support the design of usable medication-related computerized CDS functions and systems. Such evidence requires establishing scientific relationships between usability principles, their violation in terms of usability flaws, issuing usage problems and their consequences or outcomes in the clinical work and patient care. This kind of evidence is not currently directly available in scientific evaluation studies of medication CDS functions. A possible proxy to seek evidence is systematic review of existing scientific evaluation reports. We rely on a four-stage framework describing the chain of consequences and inferences linking usability principles to clinical outcomes to design the systematic review methodology and interpretation principles. This paper describes the four-stage framework and the resulting consequences for the systematic review design. PMID- 23920593 TI - Integrated system to automatize information collecting for the primary health care at home. AB - Data collected in a consistent manner is the basis for any decision making. This article presents a system that automates data collection by community-based health workers during their visits to the residences of users of the Brazilian Health Care System (Sistema Unico de Saude - SUS) The automated process will reduce the possibility of mistakes in the transcription of visit information and make information readily available to the Ministry of Health. Furthermore, the analysis of the information provided via this system can be useful in the implementation of health campaigns and in the control of outbreaks of epidemiological diseases. PMID- 23920591 TI - The effect of an electronic "hard-stop" alert on HIV testing rates in the emergency department. AB - Use of electronic alerts in clinical practice has had mixed effects on providers' prescribing practices. Little research has explored the use of electronic alerts for improving screening practices. New York City has one of the highest rates of HIV in the United States. Recent New York State legislation requires healthcare providers to offer an HIV test to patients aged 13-64 years during a clinical encounter. Adhering to this requirement is particularly challenging in emergency department (ED) settings, which are frequently overcrowded and under-resourced. The purpose of this study was to evaluate the effect of an electronic "hard-stop" alert on HIV testing rates in the ED. Approximately four months of data were reviewed before and after the implementation of the alert. We found that use of the electronic alert significantly increased documentation of offering an HIV test (O.R. = 267.27, p<0.001) and resulted in a significant increase in HIV testing. Findings from this study add to the current knowledge about the use of electronic alertsfor improving disease screening. PMID- 23920594 TI - Usability evaluation of family physicians' interaction with the Comorbidity Ontological Modeling and ExecuTion System (COMET). AB - OBJECTIVE: To assess how well the COMET system meets the functional goals and usability needs of family physicians (FP) for the management of patients who have comorbid chronic heart failure (CHF) and atrial fibrillation (AF). DESIGN: Nonexperimental post-interaction Think Aloud Sessions and survey involving Likert scale questionnaires. PARTICIPANTS: Licensed Family Physicians in Nova Scotia. INTERVENTION: A clinical decision support tool called "COMET - Co-morbidity Ontological Modeling & ExecuTion". COMET's main purpose is to provide evidence based recommendations for the management of patients with co-morbid CHF-AF in a family practice setting. RESULTS: Our study suggested that although the participant family physicians are potential users of the clinical decision support software like COMET, the most common usability problems encountered are related to inadequate information content, navigation, and time and effort for data entry. We recommend that a field usability testing of a CDSS using think aloud protocols in conjunction with surveys is an effective method to uncover usability problems. PMID- 23920595 TI - Clustering and summarising association rules mined from phenotype, genotype and environmental data concerning age-related hearing impairment. AB - In this study, we examine the applicability of association rules for analysing high-dimensional data concerning age-related hearing impairment (ARHI). The ARHI data of the study contain hundreds of variables concerning phenotype, genotype and environmental factors. The number of association rules produced from the data is too large for manual exploration in the raw and furthermore, the rules are overlapping. Thus, the focus of our study is to develop an approach to cluster association rules into subsets and to summarise and represent the found rule subsets for easier exploration of rules. The results show that it is possible to efficiently extract rules representing interesting environmental factor-gene or gene-gene interactions. Finding suitable parameters for the association rule mining and the possibility to post-process the mined rules is essential. The developed approach facilitates rule exploration by grouping rules with items concerning the same phenomenon to the same subset and byrevealing overlapping rules. PMID- 23920596 TI - The consequences of seniors seeking health information using the internet and other sources. AB - The internet is viewed as an important channel for patient empowerment, enabling patients to feel more knowledgeable and take action to improve their own health. Internet use among seniors in the Netherlands is increasing, but it is not known if they also use it for health information, nor if seeking information on the internet has different consequences for empowerment than seeking information from other sources. We sought to investigate seniors' use of the internet compared to other resources for health information, and the consequences in terms of both subjective responses and actions taken. Using an email invitation and a web survey, we surveyed 100 elderly internet users, of which 85% had used the internet for health information. The consequences were similar for information found via internet and other sources, and generally positive. Over half reported feeling more knowledgeable and 51% reported making lifestyle changes, but fewer reported having taken other actions (e.g. discussing the information with their doctor). Encouraging the translation of knowledge into action represents an opportunity for empowerment in this population. PMID- 23920597 TI - A system for automated general medical diagnosis using Bayesian networks. AB - In this paper we present a computer-assisted diagnostic system for general medical diagnosis developed using Bayesian network methodology and a medical data base created by experts. The system is intended for the general public as a self diagnostic tool and is available online free of charge (currently only in Polish, with an English version to be released soon). It serves as an educational self diagnostic tool intended to encourage the user to visit a doctor if the system so suggests, as is most often the case. In this paper we discuss the underlying modeling principles: assumptions behind Bayesian network architecture, solutions to scalability challenges, and computation performance. The distributed software architecture is presented, and finally, initial results based on over 97,000 diagnoses are discussed. The results suggest that the most common health problems for the young generation in Poland (typical user profile) are those resulting from stress and an unhealthy lifestyle. PMID- 23920598 TI - Design of schistosomiasis ontology (IDOSCHISTO) extending the infectious disease ontology. AB - Epidemiological monitoring of the schistosomiasis' spreading brings together many practitioners working at different levels of granularity (biology, host individual, host population), who have different perspectives (biology, clinic and epidemiology) on the same phenomenon. Biological perspective deals with pathogens (e.g. life cycle) or physiopathology while clinical perspective deals with hosts (e.g. healthy or infected host, diagnosis, treatment, etc.). In an epidemiological perspective corresponding to the host population level of granularity, the schistosomiasis disease is characterized according to the way (causes, risk factors, etc.) it spreads in this population over space and time. In this paper we provide an ontological analysis and design for the Schistosomiasis domain knowledge and spreading dynamics. IDOSCHISTO - the schistosomiasis ontology - is designed as an extension of the Infectious Disease Ontology (IDO). This ontology aims at supporting the schistosomiasis monitoring process during a spreading crisis by enabling data integration, semantic interoperability, for collaborative work on one hand and for risk analysis and decision making on the other hand. PMID- 23920599 TI - An example of an application of the semiotic inspection method in the domain of computerized patient record system. AB - Efficiently navigating through an interface and conducting work tasks in flow is what GUI designers strive for. Dental professionals, who alternate between examination and treatment of a patient and insertion of data into the Computerized Patient Record system, particularly need an interface that would facilitate the workflow. In this paper we present an inspection evaluation of an existing and widely used Computerized Patient Record system. The Semiotic Inspection Method was applied with the expectation that the method could provide evidence that task flow, navigation and wayfinding were major usability issues of the interface. Also expected was that the Semiotic Inspection would reveal the means and strategies used in the interface in order to communicate the flow. The analysis conducted using the Semiotic Inspection Method showed inconsistencies in the communication of the way forward through the interface. In addition, the profile of the users, regarding digital skills, appears to be ambiguous. Finally, the strategies used in the interface for conveying the workflow could be identified as well. PMID- 23920600 TI - Automatic de-identification of French clinical records: comparison of rule-based and machine-learning approaches. AB - In this paper, we present a comparison of two approaches to automatically de identify medical records written in French: a rule-based system and a machine learning based system using a conditional random fields (CRF) formalism. Both systems have been designed to process nine identifiers in a corpus of medical records in cardiology. We performed two evaluations: first, on 62 documents in cardiology, and on 10 documents in foetopathology - produced by optical character recognition (OCR) - to evaluate the robustness of our systems. We achieved a 0.843 (rule-based) and 0.883 (machine-learning) exact match overall F-measure in cardiology. While the rule-based system allowed us to achieve good results on nominative (first and last names) and numerical data (dates, phone numbers, and zip codes), the machine-learning approach performed best on more complex categories (postal addresses, hospital names, medical devices, and towns). On the foetopathology corpus, although our systems have not been designed for this corpus and despite OCR character recognition errors, we obtained promising results: a 0.681 (rule-based) and 0.638 (machine-learning) exact-match overall F measure. This demonstrates that existing tools can be applied to process new documents of lower quality. PMID- 23920601 TI - A method for probing disease relatedness using common clinical eligibility criteria. AB - Clinical trial eligibility criteria define fine-grained characteristics of research volunteers for various disease trials and hence are a promising data source for disease profiling. This paper explores the feasibility of using disease-specific common eligibility features (CEFs) for representing diseases and understanding their relatedness. We extracted disease-specific CEFs from eligibility criteria on ClinicalTrials.gov for three illustrative categories - cancers, mental disorders and chronic diseases - each including seven diseases. We then constructed disease-specific CEF networks to assess the degree of overlap among the diseases. Using these automatically derived networks, we observed several findings that were confirmed in medicine. For example, we highlighted connections among schizophrenia, epilepsy and depression. We also identified a link between Crohn's disease and arthritis. These observations confirm the value of using clinical trial eligibility criteria for identifying disease relatedness. We further discuss the implications of CEFs for standardizing clinical trial eligibility criteria through reuse. PMID- 23920602 TI - Epistemonikos: a free, relational, collaborative, multilingual database of health evidence. AB - Epistemonikos (www.epistemonikos.org) is a free, multilingual database of the best available health evidence. This paper describes the design, development and implementation of the Epistemonikos project. Using several web technologies to store systematic reviews, their included articles, overviews of reviews and structured summaries, Epistemonikos is able to provide a simple and powerful search tool to access health evidence for sound decision making. Currently, Epistemonikos stores more than 115,000 unique documents and more than 100,000 relationships between documents. In addition, since its database is translated into 9 different languages, Epistemonikos ensures that non-English speaking decision-makers can access the best available evidence without language barriers. PMID- 23920603 TI - Hidden Markov model for analyzing time-series health checkup data. AB - In this paper, we apply a Hidden Markov Model (HMM) to analyze time-series personal health checkup data. HMM is widely used for data having continuation and extensibility such as time-series health checkup data. Therefore, using HMM as probabilistic model to model the health checkup data is considered to be suitable, and HMM can express the process of health condition changes of a person. In this paper, a HMM with six states placed in a 2*3 matrix was prepared. We collected training features including the time-series health checkup data. Each feature consists of eight inspection parameters such as BMI, SBP, and TG. The HMM was then built using the training features. In the experiments, we built five HMMs for different gender and age conditions (e.g. male 50's) using thousands of training feature vectors, respectively. Investigating the HMMs we found that the HMMs can model three health risk levels. The models can also represent health transitions or changes, indicating the possibility of estimating the risk of lifestyle-related diseases. PMID- 23920604 TI - Building a knowledge base of severe adverse drug events based on AERS reporting data using semantic web technologies. AB - A semantically coded knowledge base of adverse drug events (ADEs) with severity information is critical for clinical decision support systems and translational research applications. However it remains challenging to measure and identify the severity information of ADEs. The objective of the study is to develop and evaluate a semantic web based approach for building a knowledge base of severe ADEs based on the FDA Adverse Event Reporting System (AERS) reporting data. We utilized a normalized AERS reporting dataset and extracted putative drug-ADE pairs and their associated outcome codes in the domain of cardiac disorders. We validated the drug-ADE associations using ADE datasets from SIDe Effect Resource (SIDER) and the UMLS. We leveraged the Common Terminology Criteria for Adverse Event (CTCAE) grading system and classified the ADEs into the CTCAE in the Web Ontology Language (OWL). We identified and validated 2,444 unique Drug-ADE pairs in the domain of cardiac disorders, of which 760 pairs are in Grade 5, 775 pairs in Grade 4 and 2,196 pairs in Grade 3. PMID- 23920605 TI - Citizens and personal health records - the case of Nelson Mandela Bay. AB - This paper explores citizen attitudes towards personal health records. The study was conducted in the Eastern Cape Province of South Africa. A cross-sectional design was used and structured questionnaires administered by data collectors. Most respondents (90%) believed it to be important to extremely important for their healthcare provider to have their complete medical records. Less than half of them (42%), however, believed that the healthcare provider did have their complete medical record available to them. Nevertheless, 69% do not keep a medical record as a way to address this concern. Most of them (84%) were not aware of the existence of electronic tools to capture a personal health record prior to participating in the survey. Concerns relating to the use of online PHRs were identified as privacy (58%), lack of time (27%) and a disinterest in computers (22%). It was found that the existence of a medical chronic condition is a strong predictor of keeping a medical record (albeit mostly in paper-based format). PMID- 23920606 TI - Early detection of hospitalized patients with previously diagnosed obstructive sleep apnea using computer decision support alerts. AB - Obstructive sleep apnea (OSA) is a worldwide problem affecting 2-14% of the general population and most patients remain undiagnosed. OSA patients are at elevated risk for hypoxemia, cardiac arrhythmias, cardiorespiratory arrest, hypoxic encephalopathy, stroke and death during hospitalization. Clinical screening questionnaires are used to identify hospitalized patients with OSA; especially before surgery. However, current screening questionnaires miss a significant number of patients and require more definitive testing before specific therapy can be started. Moreover, many patients are admitted to the hospital with a previous diagnosis of OSA that is not reported. Thus, many patients with OSA do not receive appropriate therapy during hospitalization due to the lack of information from previous inpatient and outpatient encounters. Large enterprise data warehouses provide the ability to monitor patient encounters over wide geographical areas. This study found that previously diagnosed OSA is highly prevalent and undertreated in hospitalized patients and the use of early computer alerts by respiratory therapists resulted in significantly more OSA patients receiving appropriate medical care (P < 0.002) which resulted in significantly fewer experiencing hypoxemia (P < 0.006). The impact was greater for non-surgery patients compared to surgery patients. PMID- 23920607 TI - Routinely-collected general practice data from the electronic patient record and general practitioner active electronic questioning method: a comparative study. AB - The numerous existing primary care-based research networks currently use various data collection methods. In this paper, we compared routine data extracted from general practitioners' (GPs') electronic patient records (EPRs) and GPs' answers to an electronic questionnaire. We investigated for 10,307 Belgian patients 10 healthcare conditions using clinical and biological parameters (cholesterol, blood pressure, and body mass index), diagnoses (hypertension, diabetes, and personal past cardiovascular event(s)), and drug prescriptions (antidiabetic drugs, aspirin, statins, and antihypertensive drugs). We found a relatively fair agreement (Kappa>=0.40) between the two data collection methods for 7 healthcare conditions, but no agreement for the biological parameters. When EPR data was used and compared with the questioning method, the prevalence of diagnoses and drug prescriptions was relatively lower and the prevalence of clinical and biological parameters was relatively higher (all missing data excluded) in the EPR data than in the data collected using the questioning method. Using EPR data, we calculated an acceptable proxy for the prevalence as observed using the questioning method. The comparison of the two data collection methods was a worthwhile approach, in that it could highlight potential ways to improve both care quality and information systems. PMID- 23920608 TI - Sociotechnical evaluation of the safety and effectiveness of point-of-care mobile computing devices: a case study conducted in India. AB - The potential for health information technology (IT) to enhance quality of care is limited by unanticipated problems following adoption of new systems and technologies. Proactive assessment of system vulnerabilities can help improve existing systems and ease implementation of new innovations. We applied a comprehensive socio-technical model of safe and effective health IT use to the formative evaluation of a novel tablet-based device designed to support primary care practice in rural India. Based on our conceptual model, we developed an assessment guide for the tablet system that was informed by literature review, interviews, and observations of health workers and supervisors. Our assessment revealed and addressed both technical (functionality, content, usability, user interface) and non-technical (workflow, processes and policies etc.)areas of improvement. PMID- 23920609 TI - Evaluating the impact of ICT-tools on health care delivery in sub-Saharan hospitals. AB - This research explores to what extent Information and Communication Technology (ICT)-based information management methods can help to improve efficiency and effectiveness of health services in sub-Saharan hospitals and how clinical information can be made available for secondary use enabling non-redundant reporting of health- and care performance indicators. In the course of a 6 years research effort between 2006 and 2012, it was demonstrated that patient identification, financial management and structured reporting improved dramatically after implementation of well adapted ICT-tools in a set of 19 African health facilities. Real-time financial management metrics helped hospitals to quickly identify fraudulent practices and defective invoicing procedures. Out-patient case load significantly increased compared to the national average, average length of stay has been shortened in 15 of 19 health facilities and global hospital mortality decreased. Hospital workforce-evaluated impact of hospital information system implementation on local working conditions and quality of care was very positive. It was demonstrated that local sub-Saharan health professionals strongly believe in the importance of health information systems. PMID- 23920610 TI - Exploring end users' system requirements for a handheld computer supporting both sepsis test workflow and current IT solutions. AB - Sepsis is a systemic response associated with very high mortality. Early initiation of the correct antimicrobial therapy remains a cornerstone in the treatment of sepsis. Currently, a new microbiological test is under development, which aims to detect major, prevalent pathogens in positive blood cultures within an hour. Concurrently, a tablet-based data entry and reporting system will be developed to facilitate the workflow of the test. This study investigated the system requirements for the tablet-based data entry and reporting system in order to support the clinical workflow. By observing the workflow of the blood culture analysis and through interviews with medical laboratory technicians, four main system requirements were identified. The system requirements are; the ability to receive and send data to the laboratory information system, support for the use of barcodes, the ability to access a browser based instruction system, and communication of results between medical laboratory technicians and physicians. These system requirements will be used as a basis in the future development of the tablet-based data entry and reporting system. PMID- 23920611 TI - Leveraging terminological resources for mapping between rare disease information sources. AB - BACKGROUND: Rare disease information sources are incompletely and inconsistently cross-referenced to one another, making it difficult for information seekers to navigate across them. The development of such cross-references established manually by experts is generally labor intensive and costly. OBJECTIVES: To develop an automatic mapping between two of the major rare diseases information sources, GARD and Orphanet, by leveraging terminological resources, especially the UMLS. METHODS: We map the rare disease terms from Orphanet and ORDR to the UMLS. We use the UMLS as a pivot to bridge between the rare disease terminologies. We compare our results to a mapping obtained through manually established cross-references to OMIM. RESULTS: Our mapping has a precision of 94%, a recall of 63% and an F1-score of 76%. Our automatic mapping should help facilitate the development of more complete and consistent cross-references between GARD and Orphanet, and is applicable to other rare disease information sources as well. PMID- 23920612 TI - Which patients may benefit from the use of a decision support system to improve compliance of physician decisions with clinical practice guidelines: a case study with breast cancer involving data mining. AB - OncoDoc2 is a guideline-based clinical decision support system (CDSS) for breast cancer management. It has been used as an intervention in a randomized controlled trial carried out to evaluate the impact of using a CDSS upon the compliance with clinical practice guidelines (CPGs) of multidisciplinary staff meeting decisions. Data mining was used to discover multi-criteria regularities as "emerging patterns" (EPs) associated with compliance and non-compliance with CPGs when using and not using OncoDoc2 and to assess which patients may benefit from the use of the CDSS. Decision data was collected from all participating centers. The number of EPs associated with non-compliance is smaller in the intervention arm, which suggests a practice harmonization effect of OncoDoc2. EPs associated with compliant decisions in both arms of the trial correspond to situations well identified in CPGs. EPs associated with non-compliant decisions when the system is not used are associated with compliance when the system is used except in clinical situations where evidence is lacking. PMID- 23920613 TI - An RDF/OWL knowledge base for query answering and decision support in clinical pharmacogenetics. AB - Genetic testing for personalizing pharmacotherapy is bound to become an important part of clinical routine. To address associated issues with data management and quality, we are creating a semantic knowledge base for clinical pharmacogenetics. The knowledge base is made up of three components: an expressive ontology formalized in the Web Ontology Language (OWL 2 DL), a Resource Description Framework (RDF) model for capturing detailed results of manual annotation of pharmacogenomic information in drug product labels, and an RDF conversion of relevant biomedical datasets. Our work goes beyond the state of the art in that it makes both automated reasoning as well as query answering as simple as possible, and the reasoning capabilities go beyond the capabilities of previously described ontologies. PMID- 23920614 TI - A diet management information and communication system to help chronic kidney patients cope with diet restrictions. AB - Hyperphosphatemia, hyperkalemia, and fluid overload are frequently observed and pose major physiological concerns in chronic kidney patients. The problems are closely related to inadequate diet and phosphate binder intake, which are considerable challenges for many patients. The objective of this study was to develop and test an educational decision support system to help kidney patients cope with diet restrictions and phosphate binder dosage. A prototype was designed including three main functions: 1) information and education, 2) food analyser database and diet registration, and 3) model-based decision support to phosphate binder dosage. The functions and the usability of the prototype were evaluated through user testing and qualitative interviews including five kidney patients. The decision support function was modified and tested using experimental data. In conclusion, the system was evaluated to be a relevant, and potentially beneficial tool to cope with kidney diet restrictions. Further data are necessary to validate the correct phosphate binder dosage and assess the ability of the system to decrease the incidence of fluid and electrolyte disorders in kidney patients. PMID- 23920615 TI - Concepts for a standard based cross-organisational information security management system in the context of a nationwide EHR. AB - Working with health related data necessitates appropriate levels of security and privacy. Information security, meaning ensuring confidentiality, integrity, and availability, is more organizational, than technical in nature. It includes many organizational and management measures, is based on well-defined security roles, processes, and documents, and needs permanent adaption of security policies, continuously monitoring, and measures assessment. This big challenge for any organization leads to implementation of an information security management system (ISMS). In the context of establishing a regional or national electronic health record for integrated care (ICEHR), the situation is worse. Changing the medical information exchange from on-demand peer-to-peer connections to health information networks requires all organizations participating in the EHR system to have consistent security levels and to follow the same security guidelines and rules. Also, the implementation must be monitored and audited, establishing cross organizational information security management systems (ISMS) based on international standards. This paper evaluates requirements and defines basic concepts for an ISO 27000 series-based cross-organizational ISMS in the healthcare domain and especially for the implementation of the nationwide electronic health record in Austria (ELGA). PMID- 23920616 TI - Evaluation of a computerized tool allowing retrospective detection of potential vitamin K antagonist overdoses in complex contexts. AB - Management of vitamin K antagonists (VKA) is difficult, and overdoses can have dramatic hemorrhagic consequences. These works form part of a European computerized medical data processing project, which aims to develop IT tools for describing adverse drug events (ADEs). Materials and methods A tool enabling retrospective research of potential ADE cases was developed, using complex ADE detection rules taking into account chronological parameters: the ADE scorecards. The rules were applied on 14,748 medical records from a community hospital. We evaluated the predictive positive value of the rules related to INR elevation by an expert review of the detected cases. The severity of the clinical consequences was evaluated. Results 49 cases were detected, among which 11 cases were ADEs. The predictive positive value of the rules is 22.44%, mostly related to antibiotics and amiodarone introduction. The four cases of clinical damage related to a drug were properly designated by the rules. Discussion - Conclusion Our study shows the great potential of developing complex rules for the identification of adverse drug events in large medical databases. PMID- 23920617 TI - A study of information management in the patient surgical pathway in NHSScotland. AB - We conducted a study of information management processes across the patient surgical pathway in NHSScotland. While the majority of general practitioners (GPs) consider electronic medical records systems as an essential and integral part of their work during the patient consultation, many were not fully satisfied with the functionalities of these systems. A majority of GPs considered that the national eReferral system streamlined referral processes. Almost all GPs reported marked variability in the quality of discharge information. Preoperative processes vary significantly across Scotland, with most services using paper based systems. Insufficient use is made of information provided through the patient electronic referral leading to a considerable duplication of tasks already performed in primary care. Three health-boards have implemented electronic preoperative information systems. These have transformed clinical practices and facilitated communication and information-sharing among the multi disciplinary team and within the health-boards. Substantial progress has been made towards improving information transfer and sharing within the surgical pathway in recent years. However, there remains scope for further improvements at the interface between services. PMID- 23920618 TI - Deterministic record linkage versus similarity functions: a study in health databases from Brazil. AB - The record linkage is a strategy that allows linking different databases of information from patient records. Adopting the deterministic method and similarity functions (Dice, Jaro, Jaro-Winkler and Levenshtein) for the integration of heterogeneous databases aimed at different levels of health care Brazilian (primary, secondary and tertiary). The sensitivity of deterministic method was 54.5% (95% CI: 50.4 to 58.5). The best result obtained with the dissent of only one variable (mother's name) was 80.6% (95% CI: 77.2 to 83.6) and the best result obtained using the similarity function Jaro-Winkler was 91.8% (95% CI: 89.4 to 93.9). The deterministic method has high specificity but sensitivity can be reduced by the existence of spellings and typing errors in the databases. Thus, the step-by-step approach where there was disagreement in at least one of the relationship variable can increase the sensitivity of the method and the use of similarity functions. PMID- 23920619 TI - Development of description framework of pharmacodynamics ontology and its application to possible drug-drug interaction reasoning. AB - Prediction of synergistic or antagonistic effects of drug-drug interaction (DDI) in vivo has been of considerable interest over the years. Formal representation of pharmacological knowledge such as ontology is indispensable for machine reasoning of possible DDIs. However, current pharmacology knowledge bases are not sufficient to provide formal representation of DDI information. With this background, this paper presents: (1) a description framework of pharmacodynamics ontology; and (2) a methodology to utilize pharmacodynamics ontology to detect different types of possible DDI pairs with supporting information such as underlying pharmacodynamics mechanisms. We also evaluated our methodology in the field of drugs related to noradrenaline signal transduction process and 11 different types of possible DDI pairs were detected. The main features of our methodology are the explanation capability of the reason for possible DDIs and the distinguishability of different types of DDIs. These features will not only be useful for providing supporting information to prescribers, but also for large scale monitoring of drug safety. PMID- 23920620 TI - Full-text automated detection of surgical site infections secondary to neurosurgery in Rennes, France. AB - The surveillance of Surgical Site Infections (SSI) contributes to the management of risk in French hospitals. Manual identification of infections is costly, time consuming and limits the promotion of preventive procedures by the dedicated teams. The introduction of alternative methods using automated detection strategies is promising to improve this surveillance. The present study describes an automated detection strategy for SSI in neurosurgery, based on textual analysis of medical reports stored in a clinical data warehouse. The method consists firstly, of enrichment and concept extraction from full-text reports using NOMINDEX, and secondly, text similarity measurement using a vector space model. The text detection was compared to the conventional strategy based on self declaration and to the automated detection using the diagnosis-related group database. The text-mining approach showed the best detection accuracy, with recall and precision equal to 92% and 40% respectively, and confirmed the interest of reusing full-text medical reports to perform automated detection of SSI. PMID- 23920621 TI - Use of clinical simulation for assessment in EHR-procurement: design of method. AB - In Denmark, two large regions cooperate in a public intervention process of acquiring a new eHealth-platform to support the daily clinical work of approximately 40,000 users in 14 hospitals. It is essential that the new platform, besides fulfilling comprehensive detailed specifications, supports the daily work practice consisting of numerous mixed tasks executed by many different clinical actors in various settings. Within health informatics it has proven beneficial to use human factors approaches in the design process to secure systems that are responsive to the actual field of application. While design methods are widely described, there are very limited descriptions of how to assess and compare different EHR-platforms and their support in work processes upon its procurement. This paper describes the method we have developed to undertake this task. It is discussed how the method differs and how it has been adjusted from existing assessment methods. Finally, future considerations are discussed. PMID- 23920622 TI - Machine vs. human translation of SNOMED CT terms. AB - OBJECTIVE: In the context of past and current SNOMED CT translation projects we compare three kinds of SNOMED CT translations from English to German by: (t1) professional medical translators; (t2) a free Web-based machine translation service; (t3) medical students. METHODS: 500 SNOMED CT fully specified names from the (English) International release were randomly selected. Based on this, German translations t1, t2, and t3 were generated. A German and an Austrian physician rated the translations for linguistic correctness and content fidelity. RESULTS: Kappa for inter-rater reliability was 0.4 for linguistic correctness and 0.23 for content fidelity. Average ratings of linguistic correctness did not differ significantly between human translation scenarios. Content fidelity was rated slightly better for student translators compared to professional translators. Comparing machine to human translation, the linguistic correctness differed about 0.5 scale units in favour of the human translation and about 0.25 regarding content fidelity, equally in favour of the human translation. CONCLUSION: The results demonstrate that low-cost translation solutions of medical terms may produce surprisingly good results. Although we would not recommend low-cost translation for producing standardized preferred terms, this approach can be useful for creating additional language-specific entry terms. This may serve several important use cases. We also recommend testing this method to bootstrap a crowdsourcing process, by which term translations are gathered, improved, maintained, and rated by the user community. PMID- 23920624 TI - Informatics lessons from using a novel immunization information system. AB - In the 1990s, NewYork-Presbyterian Hospital began developing a comprehensive, standards-based immunization information system. The system, known as EzVac, has been operational since 1998 and now includes information on 2 million immunizations administered to more than 260,000 individuals. The system exchanges data with multiple electronic health records, a public health immunization registry, and a standalone personal health record. EzVac modules have recently been incorporated into the OpenMRS application and are being used to enhance immunization efforts in developing nations. We report on our experience with developing and using the EzVac system for 1) clinical care, both in local and global settings, 2) public health reporting, 3) consumer engagement, and 4) clinical and informatics research. We emphasize the advantages of using health IT standards to facilitate immunization information exchange in each of these domains. PMID- 23920623 TI - Automatic platelets counter for supporting dengue case detection in primary health care in indonesia. AB - Dengue fever is a major problem in many developing countries, including Indonesia. Laboratory examination is used to diagnose dengue infection and to monitor disease progression. Hematology tests, such as platelet count, are also used for timely recognition of the development of severe dengue. In primary health care centers platelet counting is typically performed manually, which is labor intensive and requires an experienced laboratory technician. To address this challenge, we have developed an automatic platelet counter for primary health care and resource-poor settings. The technology is based on a conventional microscope equipped with a digital camera linked to a personal computer, which can capture and analyze microscope images of blood samples. To evaluate the accuracy of the technology, it was compared to platelet counts performed manual by an experienced laboratory technician. Statistical analysis shows no difference between the techniques with a kappa coefficient of 0.6. This method is judged to have great potential as a tool to help primary health centers and other facilities with limited resources to deal with the burden of dengue. PMID- 23920625 TI - Engineering natural language processing solutions for structured information from clinical text: extracting sentinel events from palliative care consult letters. AB - Despite a trend to formalize and codify medical information, natural language communications still play a prominent role in health care workflows, in particular when it comes to hand-overs between providers. Natural language processing (NLP) attempts to bridge the gap between informal, natural language information and coded, machine-interpretable data. This paper reports on a study that applies an advanced NLP method for the extraction of sentinel events in palliative care consult letters. Sentinel events are of interest to predict survival and trajectory for patients with acute palliative conditions. Our NLP method combines several novel characteristics, e.g., the consideration of topological knowledge structures sourced from an ontological terminology system (SNOMED CT). The method has been applied to the extraction of different types of sentinel events, including simple facts, temporal conditions, quantities, and degrees. A random selection of 215 anonymized consult letters was used for the study. The results of the NLP extraction were evaluated by comparison with coded sentinel event data captured independently by clinicians. The average accuracy of the automated extraction was 73.6%. PMID- 23920626 TI - Envisioning the future of home care: applications of immersive virtual reality. AB - Accelerating the design of technologies to support health in the home requires 1) better understanding of how the household context shapes consumer health behaviors and (2) the opportunity to afford engineers, designers, and health professionals the chance to systematically study the home environment. We developed the Living Environments Laboratory (LEL) with a fully immersive, six sided virtual reality CAVE to enable recreation of a broad range of household environments. We have successfully developed a virtual apartment, including a kitchen, living space, and bathroom. Over 2000 people have visited the LEL CAVE. Participants use an electronic wand to activate common household affordances such as opening a refrigerator door or lifting a cup. Challenges currently being explored include creating natural gesture to interface with virtual objects, developing robust, simple procedures to capture actual living environments and rendering them in a 3D visualization, and devising systematic stable terminologies to characterize home environments. PMID- 23920627 TI - Semantic interoperation and electronic health records: context sensitive mapping from SNOMED CT to ICD-10. AB - An important case for successful deployment of a lifetime electronic health record is reuse of clinical data from the electronic health record (EHR) for epidemiology, reimbursement, and research. We report a collaboration between the IHTSDO and the WHO to develop knowledge-based tools supporting translation of data from SNOMED CT to the ICD-10 classification. These tools have been vetted by an international community and are available for system vendors to enhance the interoperability of their products. The maps we created are also informing the development of the next generation of classifications which will employ a common ontology base between SNOMED CT and ICD-11 to promote interoperability. PMID- 23920628 TI - Experts speak: advice from key informants to small, rural hospitals on implementing the electronic health record system. AB - The US government has allocated $30 billion dollars to implement Electronic Health Records (EHRs) in hospitals and provider practices through a policy called Meaningful Use. Small, rural hospitals, particularly those designated as Critical Access Hospitals (CAHs), comprising nearly a quarter of US hospitals, had not implemented EHRs before. Little is known on implementation in this setting. We interviewed a spectrum of 31 experts in the domain. The interviews were then analyzed qualitatively to ascertain the expert recommendations. Nineteen themes emerged. The pool of experts included staff from CAHs that had recently implemented EHRs. We were able to compare their answers with those of other experts and make recommendations for stakeholders. CAH peer experts focused less on issues such as physician buy-in, communication, and the EHR team. None of them indicated concern or focus on clinical decision support systems, leadership, or governance. They were especially concerned with system selection, technology, preparatory work and a need to know more about workflow and optimization. These differences were explained by the size and nature of these small hospitals. PMID- 23920629 TI - Large scale health information exchange: implementation experiences from five states. AB - There is widespread consensus that Health Information Exchange, the electronic sharing of patients' health information between delivery settings, is critical to improving the quality and efficiency of patient care. The United States has had limited success in establishing broad-based HIE. To address these issues, the federal government funded the State Health Information Exchange Cooperative Agreement Program. An in-depth qualitative study was conducted, consisting of site visits and semi-structured discussions with 105 respondents in 5 states to understand early HIE implementation experiences. Results show the last two years have seen unprecedented growth in HIE infrastructure. Key factors such as maturity of HIE at baseline and healthcare market characteristics have shaped governance models and technical infrastructures. Early focus on stakeholder value proposition and sustainability planning is critical for long-term success. States continue to face numerous challenges in converting stakeholder support into financial commitment and real-time exchange of health information. We discuss the key issues states faced in attempting to realize broad-based HIE and offer insights that may assist other states. PMID- 23920630 TI - Establishing semantic interoperability of biomedical metadata registries using extended semantic relationships. AB - Achieving semantic interoperability is critical for biomedical data sharing between individuals, organizations and systems. The ISO/IEC 11179 MetaData Registry (MDR) standard has been recognized as one of the solutions for this purpose. The standard model, however, is limited. Representing concepts consist of two or more values, for instance, are not allowed including blood pressure with systolic and diastolic values. We addressed the structural limitations of ISO/IEC 11179 by an integrated metadata object model in our previous research. In the present study, we introduce semantic extensions for the model by defining three new types of semantic relationships; dependency, composite and variable relationships. To evaluate our extensions in a real world setting, we measured the efficiency of metadata reduction by means of mapping to existing others. We extracted metadata from the College of American Pathologist Cancer Protocols and then evaluated our extensions. With no semantic loss, one third of the extracted metadata could be successfully eliminated, suggesting better strategy for implementing clinical MDRs with improved efficiency and utility. PMID- 23920631 TI - Personalized health care and health information technology policy: an exploratory analysis. AB - Personalized healthcare (PHC) is envisioned to enhance clinical practice decision making using new genome-driven knowledge that tailors diagnosis, treatment, and prevention to the individual patient. In 2012, we conducted a focused environmental scan and informal interviews with fifteen experts to anticipate how PHC might impact health Information Technology (IT) policy in the United States. Findings indicatedthat PHC has a variable impact on current clinical practice, creates complex questions for providers, patients, and policy-makers, and will require a robust health IT infrastructure with advanced data architecture, clinical decision support, provider workflow tools, and re-use of clinical data for research. A number of health IT challenge areas were identified, along with five policy areas including: interoperable clinical decision support, standards for patient values and preferences, patient engagement, data transparency, and robust privacy and security. PMID- 23920632 TI - E-health systems for management of MDR-TB in resource-poor environments: a decade of experience and recommendations for future work. AB - INTRODUCTION: Multi-drug resistant TB (MDR-TB) is a complex infectious disease that is a growing threat to global health. It requires lengthy treatment with multiple drugs and specialized laboratory testing. To effectively scale up treatment to thousands of patients requires good information systems to support clinical care, reporting, drug forecasting, supply chain management and monitoring. METHODS: Over the last decade we have developed the PIH-EMR electronic medical record system, and subsequently OpenMRS-TB, to support the treatment of MDR-TB in Peru, Haiti, Pakistan, and other resource-poor environments. RESULTS: We describe here the experience with implementing these systems and evaluating many aspects of their performance, and review other systems for MDR-TB management. CONCLUSIONS: We recommend a new approach to information systems to address the barriers to scale up MDR-TB treatment, particularly access to the appropriate drugs and lab data. We propose moving away from fragmented, vertical systems to focus on common platforms, addressing all stages of TB care, support for open data standards and interoperability, care for a wide range of diseases including HIV, integration with mHealth applications, and ability to function in resource-poor environments. PMID- 23920633 TI - Developing a self-service query interface for re-using de-identified electronic health record data. AB - The US National Institutes of Health has developed a repository of clinical research data drawn in part from electronic health records. A new de-identified data query tool under development has been developed to support re-use of these data. We used a collection of 30 human-mediated user queries to determine whether features of the tool will be sufficient to allow users to carry out the queries themselves. The results show that the tool implemented in February 2013 will carry out a small percentage of user queries but the planned extensions will be sufficient for carrying out the majority of such queries. Future development of the tool will include extensions that correspond to the features found in human mediated queries. PMID- 23920634 TI - Automatically identifying health- and clinical-related content in wikipedia. AB - Physicians are increasingly using the Internet for finding medical information related to patient care. Wikipedia is a valuable online medical resource to be integrated into existing clinical question answering (QA) systems. On the other hand, Wikipedia contains a full spectrum of world's knowledge and therefore comprises a large partition of non-health-related content, which makes disambiguation more challenging and consequently leads to large overhead for existing systems to effectively filter irrelevant information. To overcome this, we have developed both unsupervised and supervised approaches to identify health related articles as well as clinically relevant articles. Furthermore, we explored novel features by extracting health related hierarchy from the Wikipedia category network, from which a variety of features were derived and evaluated. Our experiments show promising results and also demonstrate that employing the category hierarchy can effectively improve the system performance. PMID- 23920635 TI - Feasibility of interactive biking exercise system for telemanagement in elderly. AB - Inexpensive cycling equipment is widely available for home exercise however its use is hampered by lack of tools supporting real-time monitoring of cycling exercise in elderly and coordination with a clinical care team. To address these barriers, we developed a low-cost mobile system aimed at facilitating safe and effective home-based cycling exercise. The system used a miniature wireless 3 axis accelerometer that transmitted the cycling acceleration data to a tablet PC that was integrated with a multi-component disease management system. An exercise dashboard was presented to a patient allowing real-time graphical visualization of exercise progress. The system was programmed to alert patients when exercise intensity exceeded the levels recommended by the patient care providers and to exchange information with a central server. The feasibility of the system was assessed by testing the accuracy of cycling speed monitoring and reliability of alerts generated by the system. Our results demonstrated high validity of the system both for upper and lower extremity exercise monitoring as well as reliable data transmission between home unit and central server. PMID- 23920636 TI - Applying multiple methods to assess the readability of a large corpus of medical documents. AB - Medical documents provided to patients at the end of an episode of care, such as discharge summaries and referral letters, serve as an important vehicle to convey critical information to patients and families. Increasingly, healthcare institutions are also experimenting with granting patients direct electronic access to other types of clinical narratives that are not typically shared unless explicitly requested, such as progress notes. While these efforts have great potential to improve information transparency, their value can be severely diminished if patients are unable to read and thus unable to properly interpret the medical documents shared to them. In this study, we approached the problem by contrasting the 'readability' of two types of medical documents: referral letters vs. other genres of narrative clinician notes not explicitly intended for direct viewing by patients. To establish a baseline for comparison, we also computed readability scores of MedlinePlus articles - exemplars of fine patient education materials carefully crafted for lay audiences. We quantified document readability using four different measures. Differences in the results obtained through these measures are also discussed. PMID- 23920637 TI - Designing a mobile augmented reality tool for the locative visualisation of biomedical knowledge. AB - Mobile augmented reality (MAR) may offer new and engaging ways to support consumer participation in health. We report on design-based research into a MAR application for smartphones and tablets, intended to improve public engagement with biomedical research in a specific urban precinct. Following a review of technical capabilities and organizational and locative design considerations, we worked with staff of four research institutes to elicit their ideas about information and interaction functionalities of a shared MAR app. The results were promising, supporting the development of a prototype and initial field testing with these staff. Evidence from this project may point the way toward user centred design of MAR services that will enable more widespread adoption of the technology in other healthcare and biomedical research contexts. PMID- 23920638 TI - CONSORT-EHEALTH: implementation of a checklist for authors and editors to improve reporting of web-based and mobile randomized controlled trials. AB - BACKGROUND: Randomized trials of web-based and mobile interventions pose very specific issues and challenges. A set of best practices on how to conduct and report such trials was recently summarized in the CONSORT-EHEALTH statement (Consolidated Standards of Reporting Trials of Electronic and Mobile HEalth Applications and onLine TeleHealth), published in August 2011 as draft and in December 2011 as journal article (V1.6.1). The purpose of this presentation is to review the results of the pilot implementation at the Journal of Medical Internet Research (JMIR), a leading eHealth journal, where reporting of trials in accordance with CONSORT-EHEALTH became mandatory in late 2011. METHODS: Authors of all randomized trials submitted to JMIR were asked to complete an electronic questionnaire, which involved copying pertinent manuscript sections into a CONSORT EHEALTH database form, were asked to score the importance of CONSORT EHEALTH items, and were asked to provide narrative feedback on the value of the process. RESULTS: Between August 2011 and November 2012, 67 randomized trials were submitted, of which 61 were intended for publication in JMIR. Authors reported that it took between 1 and 16 hours to complete the checklist including making required changes to their manuscripts. 72% (48/67) of authors reported they made minor changes to the manuscript, 6% (4/67) made major changes. Most authors felt it was a useful process that improved their manuscripts: 63% (42/67) said it improved their manuscript, 13% (9/67) said it did not, 12% (8/67) indicated that it had improved a little. CONCLUSIONS: The CONSORT EHEALTH statement and checklist appeared successful in improving the quality of reporting. The checklist should be endorsed and used by authors and editors of other journals. PMID- 23920639 TI - Analyzing differences between chinese and english clinical text: a cross institution comparison of discharge summaries in two languages. AB - Worldwide adoption of Electronic Medical Records (EMRs) databases in health care have generated an unprecedented amount of clinical data available electronically. There has been an increasing trend in US and western institutions towards collaborating with China on medical research using EMR data. However, few studies have investigated characteristics of EMR data in China and their differences with the data in US hospitals. As an initial step towards differentiating EMR data in Chinese and US systems, this study attempts to understand system and cultural differences that may exist between Chinese and English clinical documents. We collected inpatient discharge summaries from one Chinese and from three US institutions and manually analyzed three major clinical components in text: medical problems, tests, and treatments. We reported comparison results at the document level and section level and discussed potential reasons for observed differences. Documenting and understanding differences in clinical reports from the US and China EMRs are important for cross-country collaborations. Our study also provided valuable insights for developing natural language processing tools for Chinese clinical text. PMID- 23920640 TI - Identifying unproven cancer treatments on the health web: addressing accuracy, generalizability and scalability. AB - Building machine learning models that identify unproven cancer treatments on the Health Web is a promising approach for dealing with the dissemination of false and dangerous information to vulnerable health consumers. Aside from the obvious requirement of accuracy, two issues are of practical importance in deploying these models in real world applications. (a) Generalizability: The models must generalize to all treatments (not just the ones used in the training of the models). (b) Scalability: The models can be applied efficiently to billions of documents on the Health Web. First, we provide methods and related empirical data demonstrating strong accuracy and generalizability. Second, by combining the MapReduce distributed architecture and high dimensionality compression via Markov Boundary feature selection, we show how to scale the application of the models to WWW-scale corpora. The present work provides evidence that (a) a very small subset of unproven cancer treatments is sufficient to build a model to identify unproven treatments on the web; (b) unproven treatments use distinct language to market their claims and this language is learnable; (c) through distributed parallelization and state of the art feature selection, it is possible to prepare the corpora and build and apply models with large scalability. PMID- 23920641 TI - Disseminating context-specific access to online knowledge resources within electronic health record systems. AB - Clinicians' patient care information needs are frequent and largely unmet. Online knowledge resources are available that can help clinicians meet these information needs. Yet, significant barriers limit the use of these resources within the clinical workflow. Infobuttons are clinical decision support tools that use the clinical context (e.g., institution, user, patient) within electronic health record (EHR) systems to anticipate clinicians' questions and provide automated links to relevant information in knowledge resources. This paper describes OpenInfobutton (www.openinfobutton.org): a standards-based, open source Web service that was designed to disseminate infobutton capabilities in multiple EHR systems and healthcare organizations. OpenInfobutton has been successfully integrated with 38 knowledge resources at 5 large healthcare organizations in the United States. We describe the OpenInfobutton architecture, knowledge resource integration, and experiences at five large healthcare organizations. PMID- 23920642 TI - Extending the NegEx lexicon for multiple languages. AB - We translated an existing English negation lexicon (NegEx) to Swedish, French, and German and compared the lexicon on corpora from each language. We observed Zipf's law for all languages, i.e., a few phrases occur a large number of times, and a large number of phrases occur fewer times. Negation triggers "no" and "not" were common for all languages; however, other triggers varied considerably. The lexicon is available in OWL and RDF format and can be extended to other languages. We discuss the challenges in translating negation triggers to other languages and issues in representing multilingual lexical knowledge. PMID- 23920643 TI - Using linked data for mining drug-drug interactions in electronic health records. AB - By nature, healthcare data is highly complex and voluminous. While on one hand, it provides unprecedented opportunities to identify hidden and unknown relationships between patients and treatment outcomes, or drugs and allergic reactions for given individuals, representing and querying large network datasets poses significant technical challenges. In this research, we study the use of Semantic Web and Linked Data technologies for identifying drug-drug interaction (DDI) information from publicly available resources, and determining if such interactions were observed using real patient data. Specifically, we apply Linked Data principles and technologies for representing patient data from electronic health records (EHRs) at Mayo Clinic as Resource Description Framework (RDF), and identify potential drug-drug interactions (PDDIs) for widely prescribed cardiovascular and gastroenterology drugs. Our results from the proof-of-concept study demonstrate the potential of applying such a methodology to study patient health outcomes as well as enabling genome-guided drug therapies and treatment interventions. PMID- 23920644 TI - My care pathways - creating open innovation in healthcare. AB - In this paper we describe initial results from the Swedish innovation project "My Care Pathways" which envisions enabling citizens to track their own health by providing them with online access to their historical, current and prospective future events. We describe an information infrastructure and its base services as well as the use of this solution as an open source platform for open innovation in healthcare. This will facilitate the development of end-user e-services for citizens. We have technically enabled the information infrastructure in close collaboration with decision makers in three Swedish health care regions, and system vendors as well as with National eHealth projects. Close collaboration between heterogeneous actors made implementation in real practice possible. However, a number of challenges, mainly related to legal and business issues, persist when implementing our results. Future work should therefore target the development of business models for sustainable provision of end-user e-services in a public health care system such as the Swedish one. Also, a legal analysis of the development of third party provider (nonhealthcare based) personal health data e-services should be done. PMID- 23920645 TI - Enabling complex queries to drug information sources through functional composition. AB - Our objective was to enable an end-user to create complex queries to drug information sources through functional composition, by creating sequences of functions from application program interfaces (API) to drug terminologies. The development of a functional composition model seeks to link functions from two distinct APIs. An ontology was developed using Protege to model the functions of the RxNorm and NDF-RT APIs by describing the semantics of their input and output. A set of rules were developed to define the interoperable conditions for functional composition. The operational definition of interoperability between function pairs is established by executing the rules on the ontology. We illustrate that the functional composition model supports common use cases, including checking interactions for RxNorm drugs and deploying allergy lists defined in reference to drug properties in NDF-RT. This model supports the RxMix application (http://mor.nlm.nih.gov/RxMix/), an application we developed for enabling complex queries to the RxNorm and NDF-RT APIs. PMID- 23920646 TI - Visualization of infectious disease outbreaks in routine practice. AB - Throughout the history of epidemiology, visualizations have been used as the interface between public-health professionals and epidemiological data. The aim of this study was to examine the impact of the level of abstraction when using visualizations on routine infectious disease control. We developed three interactive visualization prototypes at increasing levels of abstraction to communicate subsets of influenza outbreak surveillance information. The visualizations were assessed through workshops in an exploratory evaluation with infectious disease epidemiologists. The results show that despite the potential of processed, abstract, and information-dense representations, increased levels of abstraction decreased epidemiologists' understanding and confidence in visualizations. Highly abstract representations were deemed not applicable in routine practice without training. Infectious disease epidemiologists' work routines and decision-making need to be further studied in order to develop visualizations that meet both the quality requirements imposed by policy-makers and the contextual nature of work practice. PMID- 23920647 TI - Assessment of the IMIA educational accreditation process. AB - The International Medical Informatics Association (IMIA) biomedical informatics educational recommendations of 2010 provided an excellent guide for institutions across the world in updating their curricula or establishing new programs. IMIA subsequently decided to offer an accreditation process, guided by the earlier recommendations, to assess existing educational programs in the field of biomedical informatics. This paper presents an overview and SWOT analysis of the accreditation process based on a two-year trial period at three sites across continents. Because other sites are now requesting similar accreditation visits by IMIA, the lessons learned by the committee that performed the assessments during trial period will provide useful guidance for both IMIA and those educational institutions. PMID- 23920649 TI - An examination of electronic health information privacy in older adults. AB - Older adults are the quickest growing demographic group and are key consumers of health services. As the United States health system transitions to electronic health records, it is important to understand older adult perceptions of privacy and security. We performed a secondary analysis of the Health Information National Trends Survey (2012, Cycle 1), to examine differences in perceptions of electronic health information privacy between older adults and the general population. We found differences in the level of importance placed on access to electronic health information (older adults placed greater emphasis on provider as opposed to personal access) and tendency to withhold information out of concerns for privacy and security (older adults were less likely to withhold information). We provide recommendations to alleviate some of these privacy concerns. This may facilitate greater use of electronic health communication between patient and provider, while promoting shared decision making. PMID- 23920650 TI - Improving patients' electronic health record comprehension with NoteAid. AB - Allowing patients direct access to their electronic health record (EHR) notes has been shown to enhance medical understanding and may improve healthcare management and outcome. However, EHR notes contain medical terms, shortened forms, complex disease and medication names, and other domain specific jargon that make them difficult for patients to fathom. In this paper, we present a BioNLP system, NoteAid, that automatically recognizes medical concepts and links these concepts with consumer oriented, simplified definitions from external resources. We conducted a pilot evaluation for linking EHR notes through NoteAid to three external knowledge resources: MedlinePlus, the Unified Medical Language System (UMLS), and Wikipedia. Our results show that Wikipedia significantly improves EHR note readability. Preliminary analyses show that MedlinePlus and the UMLS need to improve both content readability and content coverage for consumer health information. A demonstration version of fully functional NoteAid is available at http://clinicalnotesaid.org. PMID- 23920651 TI - A guideline-derived model to facilitate the implementation of test-ordering rules within a hospital information system. AB - The culture of evidence-based practice includes also the field of laboratory medicine. Clinical laboratory expenditure is growing rapidly for various reasons including increased utilization. Delivering decision support to requesters at the point of care is one of the main incentives for implementing laboratory guidelines. Laboratory guidelines were analyzed to extract test-ordering rules. Each rule was explicated in at least one clinical situation with triggers that launch the execution of the implemented rule. The Unified Modeling Language was used to represent the categories of information elements found in the guidelines and underline the information elements that need to be structured and coded in the EHR. These information elements are related to conditions including clinical conditions, habits, family history, demographic information, medical treatments, laboratory tests, and non-laboratory test procedures. Timestamping of each event is also important for implementing laboratory prescription rules. A linkage between the conditions of this model and HL7 RIM was feasible. Use of this model facilitates the implementation of evidence-based test-ordering rules and clarifies the EHR requirements for successful implementation of guidelines. PMID- 23920652 TI - A health literacy and usability heuristic evaluation of a mobile consumer health application. AB - Usability and health literacy are two critical factors in the design and evaluation of consumer health information systems. However, methods for evaluating these two factors in conjunction remain limited. This study adapted a set of existing guidelines for the design of consumer health Web sites into evidence-based evaluation heuristics tailored specifically for mobile consumer health applications. In order to test the approach, a mobile consumer health application (app) was then evaluated using these heuristics. In addition to revealing ways to improve the usability of the system, this analysis identified opportunities to augment the content to make it more understandable by users with limited health literacy. This study successfully demonstrated the utility of converting existing design guidelines into heuristics for the evaluation of usability and health literacy. The heuristics generated could be applied for assessing and revising other existing consumer health information systems. PMID- 23920653 TI - Design of a user-centered voluntary patient safety reporting system: understanding the time and response variances by retrospective think-aloud protocols. AB - Usability is critical to the success of computerized systems, and yet it has received little attention in the field of voluntary patient safety reporting. Failures in this regard may largely account for the issues of low user acceptance and low-quality data that currently confront the system. In this study, we examined the three usability aspects of efficiency, effectiveness and user attitudes on a typical safety reporting system. The system usability was evaluated using the retrospective think-aloud testing method, which measures execution time and response consistency with think-aloud protocols. Ten end-users were recruited for the test. The descriptive statistics on users' time and response variances unveiled system features that influenced the system's reporting efficiency and effectiveness. The think-aloud protocols that reflected users' attitudes helped identify nine categories of usability problems associated with the response variances and system features. In the end, the observed semantic ambiguity, terminology complexity and carry-over effect are noted as challenges and opportunities for further usability improvements. PMID- 23920654 TI - Reducing provider cognitive workload in CPOE use: optimizing order sets. AB - Higher cognitive workload due to poor usability is a significant, unanticipated consequence of healthcare information technology (IT), resulting in new types of medical errors. An important example of this can be observed in the use of order sets, which allow safe and efficient provider order entry guided by known best practices. This paper aims to improve IT-enabled order entry by re-designing order sets using data-driven approaches to develop new order sets that match current usage and workflow, while incurring minimum cognitive workload. Applying optimization models embedded with clustering techniques, our methods identify items for constituting order sets that are relevant based on historical ordering data wherein items for a single patient are often placed together or in close temporal proximity during hospital stay. Results indicate that the new approaches dominate current solutions, significantly reducing cognitive workload, and improving order set content. Data driven methods thus offer a promising approach for designing order sets that are generalizable, evidence-based and up-to-date with current best practices. PMID- 23920655 TI - Unsupervised medical image classification by combining case-based classifiers. AB - We introduce an automated pathology classification system for medical volumetric brain image slices. Existing work often relies on handcrafted features extracted from automatic image segmentation. This is not only a challenging and time consuming process, but it may also limit the adaptability and robustness of the system. We propose a novel approach to combine sparse Gabor-feature based classifiers in an ensemble classification framework. The unsupervised nature of this non-parametric technique can significantly reduce the time and effort for system calibration. In particular, classification of medical images in this framework does not rely on segmentation, nor semantic-based or annotation-based feature selection. Our experiments show very promising results in classifying computer tomography image slices into pathological classes for traumatic brain injury patients. PMID- 23920656 TI - User experience of interRAI assessment tools in New Zealand. AB - The international residential assessment instrument (interRAI) has been adopted for phased national implementation in New Zealand. It targets people over 65 years who require needs assessment for access to long term publicly funded services. There is limited research on the barriers to adoption for interRAI electronic assessment tools, and none relating to the New Zealand health sector. This research qualitatively explored clinicians' perceptions and experience of using interRAI electronic assessment tools using semi-structured interviews guided by constructs from the Unified Theory of Acceptance and Use of Technology (UTAUT) model [9]. Analysis was conducted using thematic analysis. Three major barriers to adoption of interRAI tools emerged from the research: 1) lack of ready access to individual laptops/computers with consistent network connectivity, 2) need for ongoing training for interRAI assessors, and, 3) lack of understanding of what information is being collected and for what reasons. The growth in aging populations will see greater use of interRAI electronic assessment tools, and therefore more clinicians required to learn and use the technology. Addressing these barriers to adoption is therefore vital. PMID- 23920657 TI - Understanding waste for lean health information systems: a preliminary review. AB - Despite the rapid application of the Lean method in healthcare, its study in IT environments, particularly in Health Information Systems (HIS), is still limited primarily by a lack of waste identification. This paper aims to review the literature to provide an insight into the nature of waste in HIS from the perspective of Lean management. Eight waste frameworks within the context of healthcare and information technology were reviewed. Based on the review, it was found that all the seven waste categories from the manufacturing sector also exist in both the healthcare and IT domains. However, the nature of the waste varied depending on the processes of the domains. A number of additional waste categories were also identified. The findings reveal that the traditional waste model can be adapted to identify waste in both the healthcare and IT sectors. PMID- 23920658 TI - Navigating longitudinal clinical notes with an automated method for detecting new information. AB - Automated methods to detect new information in clinical notes may be valuable for navigating and using information in these documents for patient care. Statistical language models were evaluated as a means to quantify new information over longitudinal clinical notes for a given patient. The new information proportion (NIP) in target notes decreased logarithmically with increasing numbers of previous notes to create the language model. For a given patient, the amount of new information had cyclic patterns. Higher NIP scores correlated with notes having more new information often with clinically significant events, and lower NIP scores indicated notes with less new information. Our analysis also revealed "copying and pasting" to be widely used in generating clinical notes by copying information from the most recent historical clinical notes forward. These methods can potentially aid clinicians in finding notes with more clinically relevant new information and in reviewing notes more purposefully which may increase the efficiency of clinicians in delivering patient care. PMID- 23920659 TI - The usefulness of activity trackers in elderly with reduced mobility: a case study. AB - This study was conducted to determine the accuracy and usefulness of two current commercially available activity trackers in rollator dependent elderly with reduced mobility (RME), compared with elderly with normal mobility (NME) and healthy adults (HA). METHODS: Accuracy of pedometers placed at hip (Fitbit Ultra and Samsung GT-I9300 mobile phone) and wrist (Fitbit Ultra) were evaluated against actual steps (video) in RME (n=5), NME (n=7) and HA (n=6). Walk speed, Tinetti gait score and device percent error was calculated and analyzed in SPSS using Kruskal-Wallis, Mann-Whitney U and correlation tests. RESULTS: NME and HA walked significantly faster (p = 0.001) than RME, had significantly higher gait score (p < 0.05). Gait scores were correlated with walking speed and negatively with pedometer percent error (p < 0.01). Estimation error in RME were >60% at all device locations CONCLUSIONS: Slow walking speed and gait disorders hamper the utility of pedometers for physical activity measurement in rollator dependent elderly, with estimation errors >60%. The tested devices are better suited for use by ostensibly healthy elderly or adult populations. PMID- 23920660 TI - Health-oriented electronic oral health record for health surveillance. AB - Public health surveillance of oral health might benefit from increased access to and analysis of electronically available data including systematic collection, analysis, interpretation, and dissemination of outcome-specific data for use in public health action to improve oral health. This study aimed to develop and evaluate a new Health-oriented Electronic Oral Health Record (Health-EOHR) that integrated new oral health status graphical user interface, the health-oriented status and intervention model to facilitate oral health surveillance. We designed an experiment using focus groups and a Delphi process to develop health-oriented status and intervention model and graphical user interface. The Health-EOHR was implemented and integrated into the existing Electronic Health Record widely used in community hospitals. The study on usefulness for oral health surveillance was conducted. Overall, the dentists were significantly satisfied with the Health EOHR compared to the existing EOHR (p < 0.001). The dentists found it easy to use and were generally satisfied with the function and the impact on their work, oral health services and surveillance. PMID- 23920661 TI - Process visibility analysis in ambulatory care: a simulation study with RFID data. AB - Healthcare is primarily delivered in the ambulatory care setting worldwide. The high variability in service delivery encountered in this environment negatively impacts process efficiency and patient satisfaction. In this study, we analyze care delivery process in ambulatory care using time and location stamped data collected via Radio Frequency Identification (RFID)-enabled badges worn by patients, clinicians, and staff as they complete each clinic visit. With the objective of improving process visibility and minimizing patient waiting time, we examine this data to delineate the major components of waiting time and use simulation modeling to evaluate the impact of possible interventions. Results indicate that as a prevalent strategy, different appointment scheduling rules can only reduce patient waiting time in the waiting room. Surprisingly, waiting time in the exam room is unchanged, requiring new approaches to improve care coordination that address this delay. The results also highlight the value of RFID technology and the challenges in deploying them to improve service delivery. PMID- 23920662 TI - Identifying problematic concepts in SNOMED CT using a lexical approach. AB - SNOMED CT (SCT) has been endorsed as a premier clinical terminology by many organizations with a perceived use within electronic health records and clinical information systems. However, there are indications that, at the moment, SCT is not optimally structured for its intended use by healthcare practitioners. A study is conducted to investigate the extent of inconsistencies among the concepts in SCT. A group auditing technique to improve the quality of SCT is introduced that can help identify problematic concepts with a high probability. Positional similarity sets are defined, which are groups of concepts that are lexically similar and the position of the differing word in the fully specified name of the concepts of a set that correspond to each other. A manual auditing of a sample of such sets found 38% of the sets exhibiting one or more inconsistent concepts. Group auditing techniques such as this can thus be very helpful to assure the quality of SCT, which will help expedite its adoption as a reference terminology for clinical purposes. PMID- 23920663 TI - SocialRAD: an infrastructure for a secure, cooperative, asynchronous teleradiology system. AB - The popularity of teleradiology services has enabled a major advance in the provision of health services to areas with difficult geographical access. However, this potential has also brought with it a number of challenges: the large volume of data, characteristic of imaging tests, and security requirements designed to ensure confidentiality and integrity. Moreover, there is also a number of ethical questions involving the dominant model on the market, whereby this service is outsourced to private companies, and is not directly undertaken by professional radiologists. Therefore, the present paper proposes a cooperative model of teleradiology, where health professionals interact directly with the hospitals providing patient care. This has involved the integration of a wide range of technologies, such as the interconnection models Peer-to-Peer, Cloud Computing, Dynamic DNS, RESTful Web Services, as well as security and interoperability standards, with the aim of promoting a secure, collaborative asynchronous environment. The developed model is currently being used on an experimental basis, providing teleradiology support to cities in the north eastern hinterland of Brazil, and is fulfilling all expectations. PMID- 23920664 TI - Predicate argument structure frames for modeling information in operative notes. AB - The rich information about surgical procedures contained in operative notes is a valuable data source for improving the clinical evidence base and clinical research. In this study, we propose a set of Predicate Argument Structure (PAS) frames for surgical action verbs to assist in the creation of an information extraction (IE) system to automatically extract details about the techniques, equipment, and operative steps from operative notes. We created PropBank style PAS frames for the 30 top surgical action verbs based on examination of randomly selected sample sentences from 3,000 Laparoscopic Cholecystectomy notes. To assess completeness of the PAS frames to represent usage of same action verbs, we evaluated the PAS frames created on sample sentences from operative notes of 6 other gastrointestinal surgical procedures. Our results showed that the PAS frames created with one type of surgery can successfully denote the usage of the same verbs in operative notes of broader surgical categories. PMID- 23920665 TI - Human factors affecting the quality of routinely collected data in South Africa. AB - Evaluations that have looked at the people aspect of the health information system in South Africa have only focused on the availability of human resources and not on competence or other behavioural factors. Using the Performance of Routine Information System Management (PRISM) tool that assumes relationships between technical, behavioural and organizational determinants of the routine information processes and performance, this paper highlights some behavioural factors affecting the quality of routinely collected data in South Africa. In the context of monitoring maternal and child health programmes, data were collected from 161 health information personnel in 58 health facilities and 2 district offices from 2 conveniently sampled health districts. A self-administered questionnaire was used to assess confidence and competence levels of routine health information system (RHIS) tasks, problem solving anddata quality checking skills, and motivation. The findings suggest that 64% of the respondents have poor numerical skills and limited statistical and data quality checking skills. While the average confidence levels at performing RHIS tasks is 69%, only 22% actually displayed competence above 50%. Personnel appear to be reasonably motivated but there is considerable deficiency in their competency to interpret and use data. This may undermine the quality and utility of the RHIS. PMID- 23920666 TI - Clinical documentation as a source of information for patients - possibilities and limitations. AB - Recent legislation in many countries has given patients the right to access their own patient records. Making health-care professionals' assessments and decisions more transparent by giving patients access to their records is expected to provide patients with useful health information and reduce the power imbalance between patient and provider. We conducted both a mail survey and a face-to-face interview study, including patients who had requested a paper copy of their patient records (EPR), to explore their experiences. For many study participants, a view of their records filled in holes in the oral information they previously received. They had problems understanding parts of what they read, but rarely asked for help. Instead they searched for explanations on the Internet or attempted to understand based on the context. Patients are still afraid of seeming suspicious or displeased if they indicate that they would like to read their records. Health-care organizations should consider actively offering patients the chance to view their clinical documentation to a larger extent than what has been done so far. PMID- 23920667 TI - Santa Fe: building a virtual city to develop a family health game. AB - The current tendency of education in health is the use of new technologies like Virtual Reality. The course of UNASUS-UFCSPA specialization in family health was developed for health professionals that work in primary health care (PHC); in order to reach all Brazilian territory. Moodle is a platform where virtual activities are posted and evaluated. Santa Fe is a virtual city created in the Sketch up Pro, which aims to fit in specific clinical cases that involve matters of medicine, nursing and dentistry. The Software eAdventure was the tool used for the development of a game, offering interaction to the student with the Virtual City and the clinical cases, in the perspective of learning utilizing an entertainment method and evaluating individual performance of the students. The building of the city in the Sketch up Pro was successful and at low cost. The eAdventure was an efficient and intuitive tool, therefore, there was not necessarily a huge specific knowledge of technology or hardware with high speed processing and also speedy broad band internet for its use. PMID- 23920668 TI - Exposing public health surveillance data using existing standards. AB - With the growing use of information technologies, an increased volume of data is produced in Public Health Surveillance, enabling utilization of new data sources and analysis methods. Public health and research will benefit from the use of data standards promoting harmonization and data description through metadata. No data standard has yet been universally accepted for exchanging public health data. In this work, we implemented two existing standards eligible to expose public health data: Statistical Data and Metadata Exchange - Health Domain (SDMX HD) proposed by the World Health Organization and Open Data Protocol (OData) proposed by Microsoft Corp. SDMX-HD promotes harmonization through controlled vocabulary and predefined data structure suitable for public health but requires important investment, while OData, a generic purpose standard, proposes a simple way to expose data with minimal documentation and end-user integration tools. The two solutions were implemented and are publicly available at http://sdmx.sentiweb.fr and http://odata.sentiweb.fr. These solutions show that data sharing and interoperability are already possible in Public Health Surveillance. PMID- 23920669 TI - Finding meaning in social media: content-based social network analysis of QuitNet to identify new opportunities for health promotion. AB - Unhealthy behaviors increase individual health risks and are a socioeconomic burden. Harnessing social influence is perceived as fundamental for interventions to influence health-related behaviors. However, the mechanisms through which social influence occurs are poorly understood. Online social networks provide the opportunity to understand these mechanisms as they digitally archive communication between members. In this paper, we present a methodology for content-based social network analysis, combining qualitative coding, automated text analysis, and formal network analysis such that network structure is determined by the content of messages exchanged between members. We apply this approach to characterize the communication between members of QuitNet, an online social network for smoking cessation. Results indicate that the method identifies meaningful theme-based social sub-networks. Modeling social network data using this method can provide us with theme-specific insights such as the identities of opinion leaders and sub-community clusters. Implications for design of targeted social interventions are discussed. PMID- 23920670 TI - Information security requirements in patient-centred healthcare support systems. AB - Enabling Patient-Centred (PC) care in modern healthcare requires the flow of medical information with the patient between different healthcare providers as they follow the patient's treatment plan. However, PC care threatens the stability of the balance of information security in the support systems since legacy systems fall short of attaining a security balance when sharing their information due to compromises made between its availability, integrity, and confidentiality. Results show that the main reason for this is that information security implementation in discrete legacy systems focused mainly on information confidentiality and integrity leaving availability a challenge in collaboration. Through an empirical study using domain analysis, observations, and interviews, this paper identifies a need for six information security requirements in legacy systems to cope with this situation in order to attain the security balance in systems supporting PC care implementation in modern healthcare. PMID- 23920671 TI - Electrophysiological signal analysis and visualization using Cloudwave for epilepsy clinical research. AB - Epilepsy is the most common serious neurological disorder affecting 50-60 million persons worldwide. Electrophysiological data recordings, such as electroencephalogram (EEG), are the gold standard for diagnosis and pre-surgical evaluation in epilepsy patients. The increasing trend towards multi-center clinical studies require signal visualization and analysis tools to support real time interaction with signal data in a collaborative environment, which cannot be supported by traditional desktop-based standalone applications. As part of the Prevention and Risk Identification of SUDEP Mortality (PRISM) project, we have developed a Web-based electrophysiology data visualization and analysis platform called Cloudwave using highly scalable open source cloud computing infrastructure. Cloudwave is integrated with the PRISM patient cohort identification tool called MEDCIS (Multi-modality Epilepsy Data Capture and Integration System). The Epilepsy and Seizure Ontology (EpSO) underpins both Cloudwave and MEDCIS to support query composition and result retrieval. Cloudwave is being used by clinicians and research staff at the University Hospital - Case Medical Center (UH-CMC) Epilepsy Monitoring Unit (EMU) and will be progressively deployed at four EMUs in the United States and the United Kingdomas part of the PRISM project. PMID- 23920672 TI - An efficient pancreatic cyst identification methodology using natural language processing. AB - Pancreatic cancer is one of the deadliest cancers, mostly diagnosed at late stages. Patients with pancreatic cysts are at higher risk of developing cancer and their surveillance can help to diagnose the disease in earlier stages. In this retrospective study we collected a corpus of 1064 records from 44 patients at Indiana University Hospital from 1990 to 2012. A Natural Language Processing (NLP) system was developed and used to identify patients with pancreatic cysts. NegEx algorithm was used initially to identify the negation status of concepts that resulted in precision and recall of 98.9% and 89% respectively. Stanford Dependency parser (SDP) was then used to improve the NegEx performance resulting in precision of 98.9% and recall of 95.7%. Features related to pancreatic cysts were also extracted from patient medical records using regex and NegEx algorithm with 98.5% precision and 97.43% recall. SDP improved the NegEx algorithm by increasing the recall to 98.12%. PMID- 23920673 TI - Exploring pharmacoepidemiologic groupings of drugs from a clinical perspective. AB - OBJECTIVES: To investigate the extent to which pharmacoepidemiologic groupings are homogeneous in terms of clinical properties. METHODS: In our analysis, we classified drug subgroups from the pharmacoepidemiologic Anatomical Therapeutic Chemical (ATC) classification system based on clinical drug properties. We established mappings from ATC fifth level drug entities to drug property annotations in the National Drug File Reference Terminology (NDF-RT), including therapeutic categories, mechanisms of action, and physiologic effects. Based on the annotations for the individual drugs we computed homogeneity scores for all ATC groups and analyzed their distribution. CONCLUSIONS: We found ATC groups to be generally homogeneous, more so for mechanisms of action, and physiologic effects than for therapeutic intent. However, only half of all ATC drugs can be analyzed with this approach, in part because of missing properties in NDF-RT. PMID- 23920674 TI - CiteGraph: a citation network system for MEDLINE articles and analysis. AB - This paper details the development and implementation of CiteGraph, a system for constructing large-scale citation and co-authorship networks from full-text biomedical articles. CiteGraph represents articles and authors by uniquely identified nodes, and connects those nodes through citation and co-authorship relations. CiteGraph network encompasses over 1.65 million full-text articles and 6.35 million citations by 1.37 million unique authors from the Elsevier full-text articles. Our evaluation shows 98% 99% F1-score for mapping a citation to the corresponding article and identifying MEDLINE articles. We further analyzed the characteristics of CiteGraph and found that they are consistent with assumptions made using small-scale bibliometric analysis. We also developed several novel network-based methods for analyzing publication, citation and collaboration patterns. This is the first work to develop a completely automated system for the creation of a large-scale citation network in the biomedical domain, and also to introduce novel findings in researcher publication histories. CiteGraph can be a useful resource to both the biomedical community, and bibliometric research. PMID- 23920675 TI - On behavioral decision making and mobile health: a case study. AB - Principles and theories of behavioral decision-making (BDM) are applicable to any field, but they have special import for health care, where low-impact but repeated decisions can significantly affect quality of life. Unfortunately, limited research has focused on effective behavioral design for personal health management mobile apps. This paper addresses patient engagement approaches using the National e-Health Collaborative's "Patient Engagement Framework" and outlines specific implementations of behavioral decision theory to create an effective system for self-care. PMID- 23920676 TI - Completeness, accuracy, and presentation of information on interactions between prescription drugs and alternative medicines: an internet review. AB - BACKGROUND: As the use of the Internet continues to increase across all age groups and education levels, with usage in the US around 78%, consumers are increasingly turning to the Internet for health related information. OBJECTIVE: To assess the completeness, accuracy, and consumer friendliness of information on the Internet pertaining to drug-Complementary and Alternative Medicine (CAM) interactions with cardiac drugs. METHODS: A review of online information was performed across three search engines and ten drug-CAM pairs. RESULTS: Overall, the quality of the drug-CAM interaction information available online to consumers is fairly poor. Only one site contained an interaction checker that provided interaction information for all ten pairs, but with an accuracy rate of 50%. Reading levels ranged from 10.5-23.5, with a mean of 16.7. A value greater than 22 indicates a graduate level reading skill. CONCLUSION: Web site developers should be cautious in presenting drug-CAM interaction information unless it is comprehensive and regularly maintained. Consumers should also know how to evaluate sites before trusting the content where the consequences are potentially severe. PMID- 23920677 TI - Automatic identification of comparative effectiveness research from medline citations to support clinicians' treatment information needs. AB - Online knowledge resources such as Medline can address most clinicians' patient care information needs. Yet, significant barriers, notably lack of time, limit the use of these sources at the point of care. The most common information needs raised by clinicians are treatment-related. Comparative effectiveness studies allow clinicians to consider multiple treatment alternatives for a particular problem. Still, solutions are needed to enable efficient and effective consumption of comparative effectiveness research at the point of care. OBJECTIVE: Design and assess an algorithm for automatically identifying comparative effectiveness studies and extracting the interventions investigated in these studies. METHODS: The algorithm combines semantic natural language processing, Medline citation metadata, and machine learning techniques. We assessed the algorithm in a case study of treatment alternatives for depression. RESULTS: Both precision and recall for identifying comparative studies was 0.83. A total of 86% of the interventions extracted perfectly or partially matched the gold standard. CONCLUSION: Overall, the algorithm achieved reasonable performance. The method provides building blocks for the automatic summarization of comparative effectiveness research to inform point of care decision-making. PMID- 23920678 TI - Exploring the use of large clinical data to inform patients for shared decision making. AB - Barriers to patient participation in the shared decision making process prevent patients from fully participating in evaluating treatment options and treatment selection. Patients who use a decision aid are more informed and engaged in the shared decision making process. Patient decision aids do not use real clinical data for patient information and may not represent the data well. We designed an interface, for a shared decision making aid, that leverages clinical data to inform risk ratios and create patient stories, or vignettes, and present a visual representation of quantified treatment outcomes data. Usability testing was conducted with experts to evaluate the interface and the utility of using real clinical information that patients can explore. The experts' comments were transcribed and coded for themes. Themes were quantified and comments were interpreted for refinement and modification to the patient decision aid interface and data visualization. PMID- 23920679 TI - A formal representation for numerical data presented in published clinical trial reports. AB - Assessing the quality of and integrating clinical trial reports are necessary to practice evidence-based medicine. In particular, the numerical data is essential to understanding the strength and quality of the clinical trial study. In this paper, we present a formal representation for standardizing numerical data in published clinical trial reports, and our efforts towards developing computational tools to capture and visualize this representation. The approach includes two aspects: a process model used to precisely define experimental context behind the numerical value; and a spreadsheet, an intuitive and familiar tool used to organize numerical data. We demonstrated this representation using clinical trial reports on non-small cell lung cancer (NSCLC). We performed a preliminary evaluation to determine the usefulness of this formalism for identifying the characteristics, quality and significance of a clinical trial. Our initial results demonstrate that the representation is sufficiently expressive to capture reported numerical information in published papers. PMID- 23920680 TI - Development of a public health reporting data warehouse: lessons learned. AB - Data warehouse projects are perceived to be risky and prone to failure due to many organizational and technical challenges. However, often iterative and lengthy processes of implementation of data warehouses at an enterprise level provide an opportunity for formative evaluation of these solutions. This paper describes lessons learned from successful development and implementation of the first phase of an enterprise data warehouse to support public health surveillance at British Columbia Centre for Disease Control. Iterative and prototyping approach to development, overcoming technical challenges of extraction and integration of data from large scale clinical and ancillary systems, a novel approach to record linkage, flexible and reusable modeling of clinical data, and securing senior management support at the right time were the main factors that contributed to the success of the data warehousing project. PMID- 23920681 TI - AccessMRS: integrating OpenMRS with smart forms on Android. AB - We present a new open-source Android application, AccessMRS, for interfacing with an electronic medical record system (OpenMRS) and loading 'Smart Forms' on a mobile device. AccessMRS functions as a patient-centered interface for viewing OpenMRS data; managing patient information in reminders, task lists, and previous encounters; and launching patient-specific 'Smart Forms' for electronic data collection and dissemination of health information. We present AccessMRS in the context of related software applications we developed to serve Community Health Workers, including AccessInfo, AccessAdmin, AccessMaps, and AccessForms. The specific features and design of AccessMRS are detailed in relationship to the requirements that drove development: the workflows of the Kenyan Ministry of Health Community Health Volunteers (CHVs) supported by the AMPATH Primary Health Care Program. Specifically, AccessMRS was designed to improve the quality of community-based Maternal and Child Health services delivered by CHVs in Kosirai Division. AccessMRS is currently in use by more than 80 CHVs in Kenya and undergoing formal assessment of acceptability, effectiveness, and cost. PMID- 23920682 TI - Method to integrate clinical guidelines into the electronic health record (EHR) by applying the archetypes approach. AB - Clinical guidelines are documents that assist healthcare professionals, facilitating and standardizing diagnosis, management, and treatment in specific areas. Computerized guidelines as decision support systems (DSS) attempt to increase the performance of tasks and facilitate the use of guidelines. Most DSS are not integrated into the electronic health record (EHR), ordering some degree of rework especially related to data collection. This study's objective was to present a method for integrating clinical guidelines into the EHR. The study developed first a way to identify data and rules contained in the guidelines, and then incorporate rules into an archetype-based EHR. The proposed method tested was anemia treatment in the Chronic Kidney Disease Guideline. The phases of the method are: data and rules identification; archetypes elaboration; rules definition and inclusion in inference engine; and DSS-EHR integration and validation. The main feature of the proposed method is that it is generic and can be applied toany type of guideline. PMID- 23920684 TI - Nursing informatics and nursing ethics: addressing their disconnect through an enhanced TIGER-vision. AB - All healthcare visions, including that of The TIGER (Technology-Informatics Guiding-Educational-Reform) Initiative envisage a crucial role for nursing. However, its 7 descriptive pillars do not address the disconnect between Nursing Informatics and Nursing Ethics and their distinct communities in the clinical disciplinary landscape. Each sees itself as providing decision support by way of information inputs and ethical insights, respectively. Both have reasons - ideological, professional, institutional - for their task construction, but this simultaneously disables each from engaging fully in the point-of-(care)-decision. Increased pressure for translating 'evidence-based' research findings into 'ethically-sound', 'value-based' and 'patient-centered' practice requires rethinking the model implicit in conventional knowledge translation and informatics practice in all disciplines, including nursing. The aim is to aid 'how nurses and other health care scientists more clearly identify clinical and other relevant data that can be captured to inform future comparative effectiveness research. 'A prescriptive, theory-based discipline of '(Nursing) Decisionics' expands the Grid for Volunteer Development of TIGER's newly launched virtual learning environment (VLE). This provides an enhanced TIGER-vision for educational reform to deliver ethically coherent, person-centered care transparently. PMID- 23920685 TI - A vision for the systematic monitoring and improvement of the quality of electronic health data. AB - In parallel with the implementation of information and communications systems, health care organizations are beginning to amass large-scale repositories of clinical and administrative data. Many nations seek to leverage so-called Big Data repositories to support improvements in health outcomes, drug safety, health surveillance, and care delivery processes. An unsupported assumption is that electronic health care data are of sufficient quality to enable the varied use cases envisioned by health ministries. The reality is that many electronic health data sources are of suboptimal quality and unfit for particular uses. To more systematically define, characterize and improve electronic health data quality, we propose a novel framework for health data stewardship. The framework is adapted from prior data quality research outside of health, but it has been reshaped to apply a systems approach to data quality with an emphasis on health outcomes. The proposed framework is a beginning, not an end. We invite the biomedical informatics community to use and adapt the framework to improve health data quality and outcomes for populations in nations around the world. PMID- 23920686 TI - A continuum of sociotechnical requirements for patient-centered problem lists. AB - Specific requirements for patient-centered health information technology remain ill-defined. To create operational definitions of patient-centered problem lists, we propose a continuum of sociotechnical requirements with five stages: 1) Intradisciplinary Care Planning: Viewing and searching for problems by discipline; 2) Multi-disciplinary Care Planning: Categorizing problem states to meet discipline-specific needs; 3) Interdisciplinary Care Planning: Sharing and linking problems between disciplines; 4) Integrated and Coordinated Care Planning: Associating problems with assessments, tasks, interventions and outcomes across disciplines for coordination, knowledge development, and reporting; and 5) Patient-Centered Care Planning: Engaging patients in identification of problems and maintenance of their problem list. PMID- 23920687 TI - mHealth to revolutionize information retrieval in low and middle income countries: introduction and proposed solutions using Botswana as reference point. AB - Information retrieval (IR) practice is invaluable in health care, where the growth of medical knowledge has long surpassed human memory capabilities, and health care workers often have unmet information needs. While the information and communications technology (ICT) revolution is improving, IR in the Western world, the global digital divide has never been wider. Low and Middle Income Countries (LMICs) have the least advanced ICT infrastructure and service provision, and are also burdened with the majority of the world's health issues and severe shortages of health care workers. Initiatives utilizing mobile technology in healthcare and public health (mHealth) have shown potential at addressing these inequalities and challenges. Using Botswana as a reference point, this paper aims to broadly describe the healthcare and ICT challenges facing LMICs, the promise of mHealth as a field in health informatics, and then propose health informatics solutions that specifically address IR content and needs. One solution proposes utilizing Unstructured Supplementary Service Data (USSD) for accessing treatment guidelines, and the other solution outlines applications of smart devices for IR. PMID- 23920688 TI - Why we need a large-scale open metadata initiative in health informatics - a vision paper on open data models for clinical phenotypes. AB - Clinical phenotypes are very complex and not well described. For instance, more than 100.000 biomedical concepts are needed to describe clinical properties of patients. At present, information systems dealing with clinical phenotype data are based on secret, heterogeneous and incompatible data models. This is the root cause for the well-known grand challenge of semantic interoperability in healthcare: data exchange and analysis of medical information systems has major limitations. This problem slows down medical progressand wastes time of health care professionals. A large-scale open metadata initiative can foster exchange, discussion and consensus regarding data models for clinical phenotypes. This would be an important contribution to improve information systems in healthcare and to solve the grand challenge of semantic interoperability. PMID- 23920689 TI - Building a time-saving and adaptable tool to report adverse drug events. AB - The difficult task of detecting adverse drug events (ADEs) and the tedious process of building manual reports of ADE occurrences out of patient profiles result in a majority of adverse reactions not being reported to health regulatory authorities. The SALUS individual case safety report (ICSR) reporting tool, a component currently developed within the SALUS project, aims to support semi automatic reporting of ADEs to regulatory authorities. In this paper, we present an initial design and current state of of our ICSR reporting tool that features: (i) automatic pre-population of reporting forms through extraction of the patient data contained in an Electronic Health Record (EHR); (ii) generation and electronic submission of the completed ICSRs by the physician to regulatory authorities; and (iii) integration of the reporting process into the physician's work-flow to limit the disturbance. The objective is to increase the rates of ADE reporting and the quality of the reported data. The SALUS interoperability platform supports patient data extraction independently of the EHR data model in use and allows generation of reports using the format expected by regulatory authorities. PMID- 23920690 TI - Modeling decision support rule interactions in a clinical setting. AB - Traditionally, rule interactions are handled at implementation time through rule task properties that control the order in which rules are executed. By doing so, knowledge about the behavior and interactions of decision rules is not captured at modeling time. We argue that this is important knowledge that should be integrated in the modeling phase. In this project, we build upon current work on a conceptual schema to represent clinical knowledge for decision support in the form of if then rules. This schema currently captures provenance of the clinical content, context where such content is actionable (i.e. constraints) and the logic of the rule itself. For this project, we borrowed concepts from both the Semantic Web (i.e., Ontologies) and Complex Adaptive Systems (CAS), to explore a conceptual approach for modeling rule interactions in an enterprise-wide clinical setting. We expect that a more comprehensive modeling will facilitate knowledge authoring, editing and update; foster consistency in rules implementation and maintenance; and develop authoritative knowledge repositories to promote quality, safety and efficacy of healthcare. PMID- 23920691 TI - The WHO-ITU national eHealth strategy toolkit as an effective approach to national strategy development and implementation. AB - With few exceptions, national eHealth strategies are the pivotal tools upon which the launch or refocusing of national eHealth programmes is hinged. The process of their development obviates cross-sector ministerial commitment led by the Ministry of Health. Yet countries often grapple with the task of strategy development and best efforts frequently fail to address strategic components of eHealth key to ensure successful implementation and stakeholder engagement. This can result in strategies that are narrowly focused, with an overemphasis placed on achieving technical outcomes. Without a clear link to a broader vision of health system development and a firm commitment from partners, the ability of a strategy to shape development of a national eHealth framework will be undermined and crucial momentum for implementation will be lost. WHO and ITU have sought to address this issue through the development of the National eHealth Strategy Toolkit that provides a basis for the components and processes to be considered in a strategy development or refocusing exercise. We look at this toolkit and highlight those areas which the countries should consider in formulating their national eHealth strategy. PMID- 23920693 TI - Analysis and evaluation of clinical pathways in china. AB - To analyze and evaluate the Standard Clinical Pathways (CPs) in China and suggest improvements for future revisions, we reviewed and evaluated the Standard CPs in China based on CP evaluation framework and the standard functions for eCP. We found that Standard CPs in China can basically meet the requirements of evaluation criteria and the standard function for eCPs, but still have problems in recording, editing and statistics. Standard CPs in China are still paper-based designs, and are not applicable for the computer and network environment. Further improvement should be done in the following directions including regulating and standardizing representations of items in the cells of CP checklists, modeling and templating CP checklists, and developing variance codes. PMID- 23920694 TI - Physician satisfaction with electronic medical record in a huge hospital (China). AB - Electronic medical record (EMR) is widely used in Chinese hospitals. Yet little is known about the physician satisfaction with EMR in Chinese hospitals. The purpose of this paper is to develop an instrument to measure physician satisfaction with EMR and to survey physician satisfaction with EMR in the biggest hospital in China. We developed a questionnaire and did a cross-sectional survey on 100 physicians from July 2010 to November 2010 in the huge hospital in China. A total of 92 completed questionnaires were returned. Our results revealed that although the overall physician satisfaction with EMR was relatively high (70.7%), certain aspects of the service showed some degree of dissatisfaction (function, efficiency, quality). PMID- 23920695 TI - A manual, semi-automated and automated ROI study of fMRI hemodynamic response. AB - This study is a method comparison of three region-of-interest (ROI) tracing approaches. fMRI images acquired during an event-related frequency discrimination task were used in this study. Three [(1) manual, (2) semi-automated, (3) automated] approaches were applied to generate the ROI in the caudate nucleus and extract fMRI hemodynamic response (HR) from the ROI. Less activation with weak and delayed fMRI HR in the caudate were observed in patients than controls by the 3 approaches, but the manual and automated approaches were more sensitive in detecting such fMRI abnormalities. High correlations of the HR measures were found between the manual and semi-automated ROI approaches, suggesting that the semi-automated approach could be used as an alternative to the manual approach in detecting fMRI experimental effect. PMID- 23920696 TI - Impact of variations in anonymous record linkage on weight distribution and classification. AB - Anonymous or privacy preserving record linkage is the term for systems allowing the linkage of data from different sources while maintaining an individual's anonymity. This work displays the impact of variations in the process of generating weights in a probabilistic record linkage system on different datasets, the resulting set of weights of candidate pairs and consequently on the final classification process. Furthermore, the results give insight into general problems of current unsupervised classification methods. PMID- 23920697 TI - Overrides of clinical decision support alerts in primary care clinics. AB - Clinical Decision Support (CDS) systems can alert physicians about potential clinical risks and suggest suitable treatment alternatives at appropriate times in the health care process. We evaluated the frequency with which physicians overrode medication alerts and the override reasons provided. Data obtained from primary care practices affiliated with two Harvard teaching hospitals were downloaded. Physicians overrode more than half of CDS medication alerts, with formulary, age-based, and renal substitutions the most likely. Many drug-drug and drug-allergy interactions overridden had the potential to cause patient harm. PMID- 23920698 TI - Measurement of T2 value by using 3.0T MRI for patient with ankle arthritis. AB - This study intended to evaluate shape of ankle joint cartilage and damage to the ankle joint cartilage by measuring changes in T2 value of cartilage of healthy people without ankle arthritis and patients with ankle arthritis. The multi-echo technique was used for 20 healthy persons who had no ankle arthritis in the past or in the present clinically and 20 patients who were examined to have ankle arthritis in order to obtain T2 map image of knee joint cartilage. We divided the talotibial joint into medial position, middle position and lateral position to calculate the mean values of T2 in 18 spots that included anterior part, middle part and posterior part of cartilage of neck bone and ankle bone. Mean T2 values were measured in the healthy people group and the ankle arthritis patient group. According to the measurement results, the mean T2 value of the ankle arthritis patient group was measured to be higher than that of the healthy people group. PMID- 23920699 TI - Reducing healthcare disparities with a technology mediated solution. AB - As healthcare costs in the US continue to rise exponentially it becomes a strategic imperative to examine all areas of healthcare delivery and identify those which are currently inefficient and ineffective and identify ways to find superior solutions that support a healthcare value proposition of excellence in access quality and value. Moreover, given the current emphasis on identifying meaningful use of technology it becomes possible to develop appropriate technology solutions that not only comply with this requirement but also facilitate superior healthcare delivery to ensue. This is such the case with improving access to language services in healthcare or more specifically the development of a real time on-line technology mediated solution to support limited English proficiency patients as the following discussed. PMID- 23920700 TI - Applying predictive analytics to develop an intelligent risk detection application for healthcare contexts. AB - Healthcare is an information rich industry where successful outcomes require the processing of multi-spectral data and sound decision making. The exponential growth of data and big data issues coupled with a rapid increase of service demands in healthcare contexts today, requires a robust framework enabled by IT (information technology) solutions as well as real-time service handling in order to ensure superior decision making and successful healthcare outcomes. Such a context is appropriate for the application of real time intelligent risk detection decision support systems using predictive analytic techniques such as data mining. To illustrate the power and potential of data science technologies in healthcare decision making scenarios, the use of an intelligent risk detection (IRD) model is proffered for the context of Congenital Heart Disease (CHD) in children, an area which requires complex high risk decisions that need to be made expeditiously and accurately in order to ensure successful healthcare outcomes. PMID- 23920701 TI - Investigating the efficacy of an intelligent operation planning and support tool for acute healthcare contexts. AB - Nurses are the largest group of healthcare professionals in hospitals providing 24-hour care to patients. Hence, nurses are pivotal in coordinating and communicating patient care information in the complex network of healthcare professionals, services and other care processes. Yet, despite nurses' central role in health care delivery, intelligent systems have historically rarely been designed around nurses' operational needs. This could explain the poor integration of technologies into nursing work processes and consequent rejection by nursing professionals. The complex nature of acute care delivery in hospitals and the frequently interrupted patterns of nursing work suggest that nurses require flexible intelligent systems that can support and adapt to their variable workflow patterns. This study is designed to explore nurses' initial reactions to a new intelligent operational planning and support tool (IOPST) for acute healthcare. The following reports on the first stage of a longitudinal project to use an innovative approach involving nurses in the development of the IOPST; from conceptualization to implementation. PMID- 23920702 TI - Clinical decision support system for early detection of prostate cancer from benign hyperplasia of prostate. AB - There has been a growing research interest in the use of intelligent methods in medical informatics studies. Intelligent computer programs were implemented to aid physicians and other medical professionals in making difficult medical decisions. Prostate Neoplasia problems including benign hyperplasia and cancer of prostate are very common and cause significant delay in recovery and often require costly investigations before coming to its diagnosis. The conventional approach to build medical diagnostic system requires the formulation of rules by which the input data can be analyzed. But the formulation of such rules is very difficult with large sets of input data. Realizing the difficulty, a number of quantitative mathematical and statistical models including pattern classification technique such as Artificial neural networks (ANN), rolled based system, discriminate analysis and regression analysis has been applied as an alternative to conventional clinical and medical diagnostic. Among the mathematical and statistical modeling techniques used in medical decision support, Artificial neural networks attract many attentions in recent studies and in the last decade, the use of neural networks has become widely accepted in medical applications. This is manifested by an increasing number of medical devices currently available on the market with embedded AI algorithms, together with an accelerating pace of publication in medical journals, with over 500 academic publications year featuring Artificial Neural Networks (ANNs). PMID- 23920703 TI - Improving medication adherence for chronic disease using integrated e technologies. AB - Diabetes mellitus (DM) is a chronic disease affecting more than 285 people worldwide and the fourth leading cause of death. Increasing evidence suggests that many DM patients have poor adherence with prescribed medication therapies, impacting clinical outcomes. Patients' barriers to medication adherence and the extent to which barriers contribute to poor outcomes, however, are not routinely assessed. We designed a dashboard for an electronic health record system to integrate DM disease and medication data, including patient-reported barriers to adherence. Processes to support routine capture of data from patients are also being explored. The dashboard is being evaluated at multiple ambulatory clinics to examine whether integrated electronic tools can support patient-centered decision-making processes involving complex medication regimens for DM and other chronic diseases. PMID- 23920704 TI - Securing SSL-VPN with LR-AKE to access personal health record. AB - Using SSL-VPN requires special considerations for well-known issues such as attackers exploiting web browser vulnerabilities and phishing sites using man-in the-middle attacks. We used leakage-resilient authenticated key exchange (LR-AKE) to develop a comprehensive solution to SSL-VPN issues. Our results show that the LR-AKE should contribute to building a robust infrastructure for personal health records. PMID- 23920705 TI - Understanding responses to a renal dosing decision support system in primary care. AB - Renal dosing clinical decision support (CDS) systems have demonstrated clinical effectiveness and potential benefits for patient outcomes. However, the high override rates consistently reported are problematic and undesirable. To understand providers' use patterns of renal dosing CDS, we investigated the override reasons obtained from primary care practices affiliated with two teaching hospitals. We selected a stratified random sample of 300 alerts and reviewed electronic medical records. Appropriateness criteria and an inter-rater reliability process were used. We found that two thirds of alerts were overridden inappropriately, and this proportion was similar for frequent over-riders as compared to the remainder of physicians. These findings imply that strategies are needed to convince providers to accept more clinically appropriate suggestions, though they need to be broadly targeted. PMID- 23920706 TI - Qualities of dental chart recording and coding. AB - Chart recording and coding are the important processes in the healthcare informatics system, but there were only a few reports in the dentistry field. The objectives of this study are to study the qualities of dental chart recording and coding, as well as the achievement of lecture/workshop on this topic. The study was performed by auditing the patient's charts at the TU Dental Student Clinic from July 2011-August 2012. The chart recording mean scores ranged from 51.0 55.7%, whereas the errors in the coding process were presented in the coder part more than the doctor part. The lecture/workshop could improve the scores only in some topics. PMID- 23920707 TI - Barriers and opportunities to the widespread adoption of telemedicine: a bi country evaluation. AB - Recognizing that current practices for healthcare delivery are no longer sustainable, OECD governments are focusing more and more on how to leverage ICT to facilitate superior healthcare delivery. One such possibility is the use of Telemedicine. A major goal of telemedicine today is to develop next-generation telemedicine tools and technologies. However, key "classic" barriers continue to challenge widespread telemedicine adoption by health care organizations. These barriers include technology, financial, legal/standards, business strategy, and human resources issues. This comparative study explores the current status of barriers and opportunities to the widespread adoption of telemedicine in two different countries: Sweden, and USA. PMID- 23920708 TI - The evaluation of integrating physical restraint report and care record system. AB - Physical restraint is the nursing intervention to protect patient safety in the hospital. Nurses should monitor and charting during the physical restraint period. Physical restraint is also the measurement of Taiwan clinical performance indicator. The traditional physical restraint quality measurement depends on the nurses' report. Lacking of integrating of report and nurses' care record induces the low report rate. In 2007, we developed the integrating physical restraint report and care record system to facilitate the report process in 2300-bed medical center in northern Taiwan. We evaluated the system with two methods after system implemented for one year. The results show it significantly increased the reporting rate from before (0.77%) to after (1.5%) and had no significance difference with the average reporting rate in Taiwan (P>0.05). Most nurses felt nature to satisfy on the system usefulness (81%) and preferred to use system then use paper form record (83.1%). Almost every nurse had correct cognitions on report physical restrain event when it occurred to patients. The system seemed to be successful implemented and helpful for the quality measurement management. PMID- 23920709 TI - Evaluation of sensors for inputting data in exergames for the elderly. AB - We aim to solve which off-the-shelf motion sensor device is the most suitable for extensive usage in PC open-source exergames for the elderly. To solve this problem, we studied the specifications of the market-available sensors to reduce the initial, broad set of sensors to only two candidates: the Nintendo Wii controllers and the Microsoft(c) KinectTM camera. The capabilities of these two are tested with a demo implementation. We take into account both the accuracy in the movement-detection of the sensors, and the software-related issues. Our outcome indicates that the Microsoft(c) KinectTM camera is the option that currently provides the best solution for our purpose. This study can be helpful for researchers to choose the device that suits their project needs better, removing the sensor-choosing task time from their schedule. PMID- 23920710 TI - Personal healthcare system using cloud computing. AB - A personal healthcare system used with cloud computing has been developed. It enables a daily time-series of personal health and lifestyle data to be stored in the cloud through mobile devices. The cloud automatically extracts personally useful information, such as rules and patterns concerning lifestyle and health conditions embedded in the personal big data, by using a data mining technology. The system provides three editions (Diet, Lite, and Pro) corresponding to users' needs. PMID- 23920711 TI - Computer-aided treat to target (T2T) Approach for the Rheumatology Patient. AB - Since 2001,we had been using a document template with manual calculators to assess the disease status during each visit and based on that, formulate a proper treatment plan for our patients We had good outcomes but the process was laborious and slow. From 2007 onwards, we shifted to a rheumatology specific EMR with automatic calculators. This article compares outcomes of Rheum Aid(r) (a clinician developed EMR for rheumatology) supported "Objectified Assessment" and prescription writing on patients with rheumatic diseases versus previous use of an MS Word(r) document template and shows better turnover and patient satisfaction. PMID- 23920712 TI - Semantic prerequisites for data sharing in a biomedical research network. AB - We investigated for a research network on liver cancer semantic prerequisites for successful data sharing. To support collaboration with information technology, it is important to annotate research data with metadata. Ideally, all data handled are described ontologically to allow for automated reasoning. However, a complete ontology is hard to define. As a preliminary step we acquired a project wide common vocabulary by interviewing project partners. The vocabulary contains terms for describing the projects' processes and related data. Where the vocabulary intersects with Unified Medical Language System (UMLS) terms, the terms will be replaced by UMLS-terms. Cell line data are a subclass of the data handled in our research network. For these data we reviewed existing ontologies and developed a new ontology for cell lines. The Cell Culture Ontology (CCONT) reuses existing ontologies and enhances those with more specific cell line related properties to achieve a comprehensive description of cell lines. The results of our work can be transferred to other research networks with a similarly limited biomedical scope. PMID- 23920713 TI - Interdisciplinary care team adoption of electronic point-of-care documentation systems: an unrealized opportunity. AB - We conducted three health care evaluation studies in community and hospital settings to examine adoption of point-of-care documentation systems among interdisciplinary care team clinicians. Both community studies used a mixed methods design to assess actual system usage and clinician satisfaction. In the hospitals, scenario testing was used. Results indicated clinician adoption of the systems was universal, although not always timely with: (1) a mismatch between system functionality and workflow which was a barrier to clinician system access during patient care and reduced clinician efficiency; (2) no increase in interdisciplinary team communication; and (3) no impact on patient outcomes identified by clinicians. To facilitate adoption, clinicians should see the value of using the system as intended by receiving patient care and patient safety feedback that uses system data. PMID- 23920714 TI - A system for health promotion using tele-homecare technology in community. AB - We have developed a system for health promotion of regional inhabitants, using CATV network at Tsushima Island in Nagasaki, Japan from 2010 to 2012. This system was provided by five kinds of services such as safety confirmation system, monitoring system of vital signs, sharing system for healthcare information, supervised administration system (compliance check of medicines), and local community TV program. Based on this experience we have been challenging a new trial at Kinkai district in Nagasaki which is aimed to be sustainable and helpful servicesboth for patients and staffs. PMID- 23920715 TI - Diavideos: a diabetes health video portal. AB - Diavideos is a web platform that collects trustworthy diabetes health videos from YouTube and offers them in a easy way. YouTube is a big repository of health videos, but good content is sometimes mixed with misleading and harmful videos such as promoting anorexia [1]. Diavideos is a web portal that provides easy access to a repository of trustworthy diabetes videos. This poster describes Diavideos and explains the crawling method used to retrieve these videos from trusted channels. PMID- 23920716 TI - Future challenges of biomedical informatics for translational medicine. AB - There are many challenges for Biomedical Informatics (BMI) to meet the promises of Translational Medicine. Several of the challenges have to do with the re-use of clinical data to progress towards 4P Medicine (personalized, preventive, participatory and predictive) and using epidemiology and clinical research as well as the translation of data and knowledge obtained in the laboratory into useful information for the clinical setting. The INBIOMEDvision EU funded project tackled these challenges in a series of events with expert scientists in different related disciplines. As a result, some consensus ideas were reached about the BMI challenges in the research areas of Genotype-Phenotype integration, Translational Systems Biology and Re-use of Clinical information in the Electronic Health Records (EHR) for research and what is needed to meet them. PMID- 23920717 TI - Validation of computerized sniffer for monitoring perioperative normothermia. AB - INTRODUCTION: The World Health Organization sets a standard to maintain patient core temperature greater than 36 degrees C throughout the perioperative period. Normothermia (defined as >36 degrees C) in the Operating Room (OR) is an important factor to preventing complications in patients (MI, infection, coagulopathy). Randomized studies suggests that maintaining at higher temperatures may further reduce complications in surgery (less complications for group at 36.4 degrees C than the control group at 36.0 degrees C) [1,2]. Perioperative normothermia is an important but often unrecognized element during anesthesia. Early recognition of hypothermia would allow for appropriate interventions and prevent complications. METHODOLOGY: Manual validation of the diagnostic performance a clinical tool (alert) that would automatically measure changes in core temperature to identify patients who fail to be in range of normothermia during surgery. RESULTS: The clinical tool (alert) was found to be 97 % sensitive. PMID- 23920718 TI - A multi-agent system for monitoring patient flow. AB - Patient flow within a healthcare facility may follow different and, sometimes, complicated paths. Each path phase is associated with the documentation of the activities carried out during it and may require the consultation of clinical guidelines, medical literature and the use of specific software and decision aid systems. In this study we present the design of a Patient Flow Management System (PFMS) based on Multi Agent Systems (MAS) methodology. System requirements were identified by means of process modeling tools and a MAS consisting of six agents was designed and is under construction. Its main goal is to support both the medical staff during the health care process and the hospital managers in assuring that all the required documentation is completed and available. Moreover, such a tool can be used for the assessment and comparison of different clinical pathways, in order to identify possible improvementsand the optimum patient flow. PMID- 23920719 TI - Proposal of the patient location tracking and query (PLQ) of IHE integration profile for the better patient tracking. AB - The Patient Location Tracking Query (PLQ) is the IHE integration profile in order to find the location of patient only in a hospital, not for cross-referencing between multiple hospitals. In Japan, it is common for elderly patients to consult multiple departments in one hospital visit. To find the location of patients quickly is very important for productivity and use of resources in a hospital. We analyzed the workflow of patients and defined three actors and two transactions for PLQ integration profile. In order to collect the location of patients, multiple systems must provide the location into central management system. We proposed PLQ for the better patient care in hospitals. We believe that by using this PLQ profile hospital staffs are able to utilize the resource more efficiently. PMID- 23920720 TI - Understanding the digital divide in the clinical setting: the technology knowledge gap experienced by US safety net patients during teleretinal screening. AB - Differential access to everyday technology and healthcare amongst safety net patients is associated with low technological and health literacies, respectively. These low rates of literacy produce a complex patient "knowledge gap" that influences the effectiveness of telehealth technologies. To understand this "knowledge gap", six focus groups (2 African-American and 4 Latino) were conducted with patients who received teleretinal screenings in U.S. urban safety net settings. Findings indicate that patients' "knowledge gap" is primarily produced at three points: (1) when patients' preexisting personal barriers to care became exacerbated in the clinical setting; (2) through encounters with technology during screening; and (3) in doctor-patient follow-up. This "knowledge gap" can produce confusion and fear, potentially affecting patients' confidence in quality of care and limiting their disease management ability. In rethinking the digital divide to include the consequences of this knowledge gap faced by patients in the clinical setting, we suggest that patient education focus on both their disease and specific telehealth technologies deployed in care delivery. PMID- 23920721 TI - A framework for evaluating sequential clinical interventions with disease progression. AB - This work proposes to leverage an advanced modeling technique, namely Markov Decision Process, to evaluate sequential clinical interventions in disease management. We have demonstrated our evaluation framework on a diabetes case study over two real data sets, and discovered valuable clinical insights towards better interventions during disease progression. PMID- 23920722 TI - Possibilities and acceptance of mobile information technologies for the elderly - first results of an empirical study. AB - This paper summarizes the results of a questionnaire-study conducted for the project "Safe and mobile through accompanying assistance systems" (SIMBA) founded by the German Federal Ministry of Education and Research. The study analyzes the mobility requirements and obstacles of the 55 yearold and older seniors in three age-groups (N=210) to develop suitable health-enabling technologies. It focuses on the mobility of the elderly on foot, by public transport, by bicycle and by taxi. The usage and the acceptance of existing mobile devices are determined, to select a suitable terminal for assistance systems. The results show, that although public transport is a very important way of travelling for seniors, its role decreases with higher age. Above the age of 65 years only a small fraction of seniors uses new communication technologies. This implies that smartphones as mobility aids are only suitable for the youngest group of seniors and for future, perhaps more technology-friendly generations. PMID- 23920723 TI - A universal exchange language for healthcare. AB - We have defined a Universal Exchange Language (UEL) for healthcare that takes a green field approach to the development of a novel "XML-like" language. We consider here what given a free hand might mean: a UEL that incorporates an advanced mathematical foundation that uses Dirac's notation and algebra. For consented and public information, it allows probabilistic inference from UEL semantic web triplet tags. But also it is possible to use similar thinking to maximize the security and analytic characteristics of private health data by disaggregating or "shredding" it. Both are scalable to millions of records that could be spread across the Internet. PMID- 23920724 TI - Health informatics community priming in a small nation: the New Zealand experience. AB - New Zealand (NZ) has a rapidly expanding health information technology (IT) development industry and wide-ranging use of informatics, especially in the primary health sector. The New Zealand government through the National Health IT Board (NHITB) has promised to provide shared care health records of core information for all New Zealanders by 2014. One of the major barriers to improvement in IT use in healthcare is the dearth of trained and interested clinicians, management and technical workforce. Health Informatics New Zealand (HINZ) and the academic community in New Zealand are attempting to remedy this by raising awareness of health informatics at the grass roots level via free "primer" workshops and by developing a sustainable cross-institutional model of educational opportunities. Support from the NHITB has been forthcoming, and the workshops start in early 2013. This poster presents the process, development and preliminary findings of this work. PMID- 23920725 TI - Managing patients' wait time in specialist out-patient clinic using real-time data from existing queue management and ADT systems. AB - In major cancer centers, heavy patients load and multiple registration stations could cause significant wait time, and can be result in patient complains. Real time patient journey data and visual display are useful tools in hospital patient queue management. This paper demonstrates how we capture patient queue data without deploying any tracing devices; and how to convert data into useful patient journey information to understand where interventions are likely to be most effective. During our system development, remarkable effort has been spent on resolving data discrepancy and balancing between accuracy and system performances. A web-based dashboard to display real-time information and a framework for data analysis were also developed to facilitate our clinics' operation. Result shows our system could eliminate more than 95% of data capturing errors and has improved patient wait time data accuracy since it was deployed. PMID- 23920726 TI - Future population of atomic bomb survivors in Nagasaki. AB - The Nagasaki University Atomic Bomb Survivor Database, which was established in 1978 for elucidating the long-term health effects of the atomic bombing, has registered since 1970 about 120,000 atomic bomb survivors with a history of residence in Nagasaki city. Since the number of atomic bomb survivors has steadily been decreasing, prediction of future population is important for planning future epidemiologic studies, and we tried to predict the population of atomic bomb survivors in Nagasaki city from 2008 to 2030. In addition, we evaluated our estimated population comparing with the actual number from 2008 to 2011. PMID- 23920727 TI - Boosting standard order sets utilization through clinical decision support. AB - Well-designed standard order sets have the potential to integrate and coordinate care by communicating best practices through multiple disciplines, levels of care, and services. However, there are several challenges which certainly affected the benefits expected from standard order sets. To boost standard order sets utilization, a problem-oriented knowledge delivery solution was proposed in this study to facilitate access of standard order sets and evaluation of its treatment effect. In this solution, standard order sets were created along with diagnostic rule sets which can trigger a CDS-based reminder to help clinician quickly discovery hidden clinical problems and corresponding standard order sets during ordering. Those rule set also provide indicators for targeted evaluation of standard order sets during treatment. A prototype system was developed based on this solution and will be presented at Medinfo 2013. PMID- 23920728 TI - Ehealth education for future clinical health professionals: an integrated analysis of Australian expectations and challenges. AB - Australia is experiencing challenges in its health workforce profile to embrace reforms based on ehealth. Although there is much literature on the importance of ehealth education, our study shows that ehealth education for entry-level clinicians is not meeting the demands for a technologically savvy clinical health workforce. This poster reports on a nationally funded project Support for this project has been provided by the Australian Government Office for Learning and Teaching. The views in this project do not necessarily reflect the views of the Australian Government Office for Learning and Teaching. which examines ehealth education for the future clinical workforce in Australia. It discusses 3 key components: the current state of teaching, learning and assessment of ehealth education in health profession degrees in Australia; inclusion of ehealth competencies in accreditation guidelines of health profession degrees and ehealth skills and competencies in job descriptions for the future Australian clinical workforce. It is based on a systems view methodology that these three components are interrelated and influence the development of an ehealth capable health workforce. Results highlight that further research and development across the health workforce is needed before the education of future clinical health professionals can keep pace with the changes that ehealth is bringing to the Australian healthcare system. PMID- 23920729 TI - Analysis of the arrangement of outpatient units for patients receiving multiple consultations at a university hospital. AB - This study analyzed the arrangement (floor locations) of outpatient units for patients receiving multiple consultations. The Hospital Information System data from November 1, 2009 to September 30, 2012 of the Gunma University Hospital were used. The floor arrangements of the outpatient units were analyzed for outpatients who had received multiple consultations. A total of 168,193 outpatients who had received 1,260,307 consultations were included in the analysis. A total of 1,160,066(92.0%) outpatients had received 1 consultation, 93,763(7.4%) had received 2 consultations, and 6,478(0.6%) had received 3 or 4 consultations. Data from outpatients who had received 2 consultations were analyzed, and the data from the top 20 consultation combinations are shown. There were 12 different floor arrangements for outpatients undergoing 2 consultations. It is clear that outpatients who undergo multiple consultations must frequently move between different floors. PMID- 23920730 TI - Personalized health management services based on personal health record (PHR). AB - Currently, the concept of medical information is changed from hospital to patients as importance of self-management rises. Medical information should be able to collect and manageable by users to satisfy right-to-know of consumer. As the number of smartphones increases, services using smartphones are increasing. An application named u-CARENote was developed by Gachon University Gil Medical Center based on PHR and individual genetic information to provide personalized content and self management service to chronic disease patients. PMID- 23920731 TI - Patients prefer electronic medical records - fact or fiction? AB - Incomplete patient medical history compromises the quality of care provided to a patient while well-kept, adequate patient medical records are central to the provision of good quality of care. According to research, patients have the right to contribute to decision-making affecting their health. Hence, the researchers investigated their views regarding a paper-based system and an electronic medical record (EMR). An explorative approach was used in conducting a survey within selected general practices in the Nelson Mandela Metropole. The majority of participants thought that the use of a paper-based system had no negative impact on their health. Participants expressed concerns relating to the confidentiality of their medical records with both storage mediums. The majority of participants indicated they prefer their GP to computerise their consultation details. The main objective of the research on which this poster is based was to investigate the storage medium of preference for patients and the reasons for their preference. Overall, 48% of the 85 participants selected EMRs as their preferred storage medium and the reasons for their preference were also uncovered. PMID- 23920732 TI - Examination of improvements in "hay fever masks" based on a preference survey. AB - The long-term goal of this study is to make suggestions for improvements both in the functionality and the comfort of hygiene masks. As basic research, we conducted a survey of young A to ascertain problems with masks used for hay fever in 2009. Main questions were: (1) "Do you have HF?" (2) "What HF symptoms do you have?" (3) "Do you like, dislike or neither like nor dislike wearing a hygiene mask?" (4) "What are the reasons for that?" The ratio of symptomatic people of HF was 41% in this research. In this report, we examine the correspondence between the symptoms that people who were aware of HF had and their preference for masks, and consider functions to be given for developing masks with comfort. PMID- 23920733 TI - Hospital information system survey in qatar. AB - Healthcare can be enhanced by the effective use of information technology to improve the quality and safety of care and many healthcare providers are adopting advanced health information technology to improve their healthcare delivery process. Qatar is a relatively young Middle Eastern country with an ambitious and progressive national strategy to develop its healthcare system, including an advanced e-health infrastructure delivering the right medical information at the right time to clinicians and patients. To assess the effectiveness of such programs, it is important to have a pre-intervention baseline from which comparisons, performance against target measures and forward thinking strategic planning can be grounded. This study presents the first published campus wide survey of Hospital Information Systems in large public and private hospitals in Qatar. OBJECTIVE: To qualitatively assess and describe the current state of Hospital Information Systems in large hospitals in Qatar, and to establish a baseline or reference point for Qatar's readiness for, and adoption of Hospital Information Systems. PMID- 23920734 TI - Student perception on high-fidelity simulation during the medical clerkship. AB - The undergraduate medical students use high fidelity simulation associated with audio-visual resources in cardiology, trauma care and pediatrics during clerkship using scenarios consistent with knowledge and skills. The captured images are analyzed by all students as well as the facilitator to conduct the debriefing. Through a closed questionnaire students' perception were explored related to the use of this technology. We obtained positive results that support more investments to assure better performance to promote safety. PMID- 23920735 TI - Integrating the human phenotype ontology into HeTOP terminology-ontology server. AB - The Human Phenotype Ontology (HPO) is a controlled vocabulary which provides phenotype data related to genes or diseases. The Health Terminology/Ontology Portal (HeTOP) is a tool dedicated to both human beings and computers to access and browse biomedical terminologies or ontologies (T/O). The objective of this work was to integrate the HPO into HeTOP in order to enhance both works. This integration is a success and allows users to search and browse the HPO with a dedicated interface. Furthermore, the HPO has been enhanced with the addition of content such as new synonyms, translations, mappings. Integrating T/O such as the HPO into HeTOP is a benefit to vocabularies because it allows enrichment of them and it is also a benefit for HeTOP which provides a better service to both humans and machines. PMID- 23920736 TI - An ontology model for nursing narratives with natural language generation technology. AB - The purpose of this study was to develop an ontology model to generate nursing narratives as natural as human language from the entity-attribute-value triplets of a detailed clinical model using natural language generation technology. The model was based on the types of information and documentation time of the information along the nursing process. The typesof information are data characterizing the patient status, inferences made by the nurse from the patient data, and nursing actions selected by the nurse to change the patient status. This information was linked to the nursing process based on the time of documentation. We describe a case study illustrating the application of this model in an acute-care setting. The proposed model provides a strategy for designing an electronic nursing record system. PMID- 23920737 TI - Prospective multicenter case-control study of telemedicine for home medical care. AB - We evaluated the safety and efficacy of the combined use of remote medical services for patients with stroke, cancer, neuromuscular diseases, and other conditions, who are being cared for at home. This study was conducted as a part of a multicenter joint trial supported by the Health and Labour Sciences Research Grant for the 'Comparative Study of the home telemedicine in Japan'. PMID- 23920738 TI - ICD90CM claims data are insufficient for influenza surveillance. AB - Influenza and Influenza like illness are representative of a class of epidemic infectious diseases that have important public health implications. Early detection via Biosurveillance can speed life saving public heath responses. In the United States Biosurveillance is typically conducted using ICD9 coded visit diagnoses and uncoded chief complaint data. To determine the accuracy of ICD9 diagnoses using laboratory confirmed cases as the gold standard. We determined the sensitivity and specificity of ICD9 in detecting laboratory confirmed vs unconfirmed Influenza. ICD9-CM had a low 66.2% Positive Predictive Value (precision) for Influenza and a low 45.6% Sensitivity (recall) for Influenza. ICD9-CM proved insufficient alone for use in biosurveillance. PMID- 23920739 TI - Key factors for a successful implementation of personalized e-health services. AB - Personalized e-health services hold many promises, e.g. the improvement of health care quality or the reduction of costs. However, such services can't tap their full potential if they will not be used. That's why it is essential to understand what brings potential users to accept them. In the literature many acceptance models exist that predict the usage of innovations, but none of them specifically refers to the adoption of e-health services. Therefore we combined the Unified Theory of Acceptance and Use of Technology (UTAUT) and the e-health literacy concept and enhanced the resulting model with additional factors. MEDLINE(r) was searched; 75 studies were included for final analysis. Apart from the UTAUT variables and e-health literacy, 10 additional factors were identified: anxiety, trust, attitude toward using, computer self-efficacy, perceived system quality, search strategy, user's condition, health specific knowledge, Internet dependency and satisfaction with medical care. Future research will include the devolvement of an instrument for assessing these factors and testing the initial research model in an international context. PMID- 23920740 TI - Multi-lingual search engine to access PubMed monolingual subsets: a feasibility study. AB - PubMed contains many articles in languages other than English but it is difficult to find them using the English version of the Medical Subject Headings (MeSH) Thesaurus. The aim of this work is to propose a tool allowing access to a PubMed subset in one language, and to evaluate its performance. Translations of MeSH were enriched and gathered in the information system. PubMed subsets in main European languages were also added in our database, using a dedicated parser. The CISMeF generic semantic search engine was evaluated on the response time for simple queries. MeSH descriptors are currently available in 11 languages in the information system. All the 654,000 PubMed citations in French were integrated into CISMeF database. None of the response times exceed the threshold defined for usability (2 seconds). It is now possible to freely access biomedical literature in French using a tool in French; health professionals and lay people with a low English language may find it useful. It will be expended to several European languages: German, Spanish, Norwegian and Portuguese. PMID- 23920741 TI - High intensity, multimodality and incoherence: grand challenges in the analysis of data for health-enabling technologies. AB - When working with health-enabling technologies, researchers all over the world usually have to analyze highly intensive, multimodal and incoherent data. We explain that there is a lack of systematization within the set of methods of analysis suitable for these data. As a first step towards a methodology in this context, we present the Systematic Nomenclature for Contexts, Analysis Methods and Problems in Health-Enabling Technologies (SNOCAP-HET). PMID- 23920742 TI - Evaluation of electronic medical records for ophthalmology based on changes in staff work through introduction of electronization. AB - There have been no previous reports regarding changes in detailed staff work through electronization in ophthalmology. The efficiency of electronization in ophthalmology was investigated based on the changes in detailed staff work with the introduction of electronic medical records. Inspections and training performed by orthoptists consisted of 88 items. There were 59 items in medical examinations and treatment performed by nurses. Medical examinations and treatments performed by doctors consisted of 32 items. There were 21 items in office work performed by clerks. In total, the efficiency of staff work increased after introduction of electronic medical records for all occupational descriptions. Orthoptists and doctors showed the greatest increases in efficiency. PMID- 23920743 TI - A business process modeling experience in a complex information system re engineering. AB - This article aims to share a business process modeling experience in a re engineering project of a medical records department in a 2,965-bed hospital. It presents the modeling strategy, an extract of the results and the feedback experience. PMID- 23920744 TI - Fostering ontology alignment sharing: a general-purpose RDF mapping format. AB - RDF has established in the last years as the language for describing, publishing and sharing biomedical resources. Following this trend, a great amount of RDF based data sources, as well as ontologies, have appeared. Using a common language as RDF has provided a unified syntactic for sharing resources, but the semantics remain as the main cause of heterogeneity, hampering data integration and homogenization efforts. To overcome this issue, ontology alignment based solutions have been typically used. However, alignment information is usually codified using ad-hoc formats. In this paper, we present a general purpose ontology mapping format, totally independent from the homogenization approach to be applied. The format is accompanied with a Java API that offers mapping construction and parsing features, as well as some basic algorithms for applying it to data translation solutions. PMID- 23920745 TI - A data model based on semantically enhanced HL7 RIM for sharing patient data of breast cancer clinical trials. AB - Breast cancer clinical trial researchers have to handle heterogeneous data coming from different data sources, overloading biomedical researchers when they need to query data for retrospective analysis. This paper presents the Common Data Model (CDM) proposed within the INTEGRATE EU project to homogenize data coming from different clinical partners. This CDM is based on the Reference Information Model (RIM) from the Health Level 7 (HL7) version 3. Semantic capabilities through an SPARQL endpoint were also required to ensure the sustainability of the platform. For the SPARQL endpoint implementation, a comparison has been carried out between a Relational SQL database + D2R and a RDF database. The results show that the first option can store all clinical data received from institutions participating in the project with a better performance. It has been also evaluated by the EU Commission within a patient recruitment demonstrator. PMID- 23920746 TI - Making knowledge on healthcare technologies understandable: an ontology for lab on-a-chip systems. AB - Technology for supporting diagnosis and treatment is becoming more complex. New developments are coming up and need to be evaluated from various perspectives. Researchers from other disciplines are seldom experts in healthcare technology. The relevant terminology needs to be settled to be able to communicate interdisciplinary. In this paper, we introduce an approach on how to make complex knowledge related to technological developments in healthcare accessible and understandable for experts from other domains. In particular, we consider the field of lab-on-a-chip systems [1]. For this field, we develop an ontology that enables researchers to get insights into the domain and to study the related ethical, sociological, and legal aspects. PMID- 23920747 TI - Development of DASH Mobile: a mHealth lifestyle change intervention for the management of hypertension. AB - Several landmark studies based on the DASH diet have established the effectiveness of a lifestyle approach to blood pressure control that emphasizes a diet rich in fruits and vegetables with moderate portions of low-fat dairy and lean protein along with increased physical activity and reduced sodium intake. However, this evidence base remains underused due feasibility limitations of implementing these intense in-person interventions and poor engagement with desktop computer based versions. Mobile technologies such as smartphones and wireless sensors have the ability to deliver behavioral interventions in-the moment and with reduced user burden. DASH Mobile is a new mHealth system being developed to deliver this evidence-based lifestyle intervention to hypertensive patients. The system consists of an Android based "app" that facilitates easy tracking of DASH food portions, integrated Bluetooth blood pressure, weight and pedometer monitoring, goal setting, simple data visualizations and multimedia video clips to train patients in the basic concepts of the lifestyle change plan. At present, the system is undergoing usability testing with a pilot clinical trial planned for Spring 2013. PMID- 23920748 TI - Using data mining techniques on discovering physician practice patterns regarding to medication prescription - an exploratory study. AB - In this paper, we propose a data mining method for exploring the decision-making processes of physicians from electronic patient records and test it on the medical records of patients with type-2 diabetes mellitus. This method runs in two modes: general and partitioned. In the general mode, it mines rules from the whole medical records. In the partitioned mode, with a given partition factor, medical records are assigned into categories and a corresponding set of rules will be discovered for each category. Medication prescription predictions can be provided based on these rules. By comparing mined rules and prescription prediction accuracy under different modes, we discover that: 1) both the averaged precision and recall rate of the general mode can reach around 80%; 2) physicians tend to conform to the guideline instead of having their own preferences; 3) the medication decision can be affected by some hidden factors. These findings suggest this method show promise in discovering physician practice patterns and obtaining insights from real medical records. PMID- 23920749 TI - Quality assurance of LOINC mapping for laboratory tests - a local experience with people, process and technology. AB - In Hong Kong Hospital Authority (HA), the Electronic Patient Record (ePR) module of Clinical Management System, implemented since 2003, bring together all the information from various clinical module and hospitals into a single corporate wide, longitudinal, integrated record. Nowadays there are billions of laboratory test results stored in the web-based ePR where laboratory results being shared with the HA clinicians for patient care. In order to produce interoperable laboratory data in the ePR, the HA adopts LOINC (Logical Observation Identifiers Names and Codes) as the reference standard for laboratory tests. Every local test codes have been mapped with LOINC code where possible. Thus, the accuracy of LOINC mapping for laboratory tests in the HA is imperative. This paper describes a quality assurance program of LOINC mapping for laboratory tests conducted in 2011/12. With the use of right people, right process and right technology, we reviewed over 28,000 local test codes and there are around 2,400 distinct LOINC concepts mapped and defined in the system. PMID- 23920750 TI - The characteristics and key issues in electronic medical records (EMR) of traditional Chinese medicine TCM. AB - This poster briefly introduces the characteristics of TCM data, significances of EMR of TCM, and several key factors in the establishment of EMR of TCM. PMID- 23920751 TI - Verification system for postoperative autologous blood retransfusion. AB - Medical staff members should match blood products with patients using a barcode authentication system for blood transfusion to prevent medical accidents. However, our hospital only verifies the blood products of the Japanese Red Cross Society and the preserved autologous blood, not the autologous blood salvaged during the operation or from the oxygenator. In this study, we developed the barcode medication administration system and mobile device for verification. This system will prevent blood transfusion errors in the ward setting. PMID- 23920752 TI - Real-time surveillance of laboratory confirmed influenza based on the Danish microbiology database (MiBa). AB - The Danish microbiology database (MiBa) is a national database that automatically accumulates patient test results from all Danish Departments of Clinical Microbiology. As an example for use of MiBa, we describe the real-time surveillance of laboratory confirmed influenza established in October 2012. It functions without any extra burdens of reporting by laboratories or clinicians. This is an important improvement of the existing surveillance for influenza like illness (ILI) which includes only limited virological testing. The MiBa based surveillance adds complete national virological data which are specific for influenza, in contrast to ILI, and serves as a tool for regional and national preparedness and planning. PMID- 23920753 TI - Anonymizing patient genomic data for public sharing association studies. AB - The development of personalized medicine is tightly linked with the correct exploitation of molecular data, especially those associated with the genome sequence along with these use of genomic data there is an increasing demand to share these data for research purposes. Transition of clinical data to research is based in the anonymization of these data so the patient cannot be identified, the use of genomic data poses a great challenge because its nature of identifying data. In this work we have analyzed current methods for genome anonymization and propose a one way encryption method that may enable the process of genomic data sharing accessing only to certain regions of genomes for research purposes. PMID- 23920754 TI - Analyzing SNOMED CT and HL7 terminology binding for semantic interoperability on post-genomic clinical trials. AB - Current post-genomic clinical trials in cancer involve the collaboration of several institutions. Multi-centric retrospective analysis requires advanced methods to ensure semantic interoperability. In this scenario, the objective of the EU funded INTEGRATE project, is to provide an infrastructure to share knowledge and data in post-genomic breast cancer clinical trials. This paper presents the process carried out in this project, to bind domain terminologies in the area, such as SNOMED CT, with the HL7 v3 Reference Information Model (RIM). The proposed terminology binding follow the HL7 recommendations, but should also consider important issues such as overlapping concepts and domain terminology coverage. Although there are limitations due to the large heterogeneity of the data in the area, the proposed process has been successfully applied within the context of the INTEGRATE project. An improvement in semantic interoperability of patient data from modern breast cancer clinical trials, aims to enhance the clinical practice in oncology. PMID- 23920755 TI - Composite quality of care scores, electronic health record maturity models, and their associations; preliminary literature review results. AB - To accurately assess the association between the use of EHR systems and the quality of healthcare we need (composite) measures for quality of healthcare, and a model to measure the maturity of the EHR. This Medline-based literature study therefore focussed on three topics; (1) methods to compose a measure for quality of care based on individual quality indicators (QI), (2) models to measure EHR maturity, and (3) the association between the former two. Composite quality is most often measured using opportunity-based scores, maturity is measured in functionalities or levels. EHR maturity measures are not used extensively in biomedical literature. Most studies found a positive association between EHR use and the quality of care but almost none of them differentiate in maturity of EHR which hampers firm conclusions about this relation. PMID- 23920756 TI - Safety first! managing risks for a daisy chain of medical devices connected to the IT-network - first experiences applying IEC 80001-1. AB - The best way to ensure patient safety is to eliminate errors. To avoid errors and resulting harm from medical devices, there are rules and laws in Germany to ensure a certain quality and process [1,2]. This does not cover scenarios where devices are connected to a data network, forming a medical IT network. Arising risks need to be addressed by operating organizations, such as hospitals. International standard IEC 80001-1 offers a process for this and defines roles and responsibilities [3]. The aim of our study was to assess the application of risk management for a small initial project. We studied a daisy chain of medical devices connected to the IT network. The number of involved proprietary protocols and interface-definitions complicates the risk management, if just for the number of involved manufacturers. Identified risks could all be addressed and did not block the setup's deployment. Risk management creates an extra effort, but can reduce harm and potential financial liabilities. We can recommend starting with small projects to familiarize with the process. PMID- 23920757 TI - Extraction of the pharmacological treatment features in literature-based discovery by applying cluster analysis. AB - Literature-based discovery (LBD) facilitates the extraction of hidden relationships between a disease and chemical substances. As a methodology of LBD, we had previously proposed to apply cluster analysis to analyze the intermediate concepts between them. In this study, we compared the ranks of chemical substances predicted by our methodology to the original rank so as to validate possibilities for extraction of the heterogeneity in the relationships. As a result, we obtained two clusters. The rank for one cluster was similar to the original rank (rho=0.956), but another was different (rho=0.580). The different features from the original rank were obtained on Pharmacological Action Terms of MeSH terms. PMID- 23920758 TI - A qualitative model for physiology: apart from function and abnormality. AB - Physiological knowledge is often described in terms of mathematical models in the domain of bioinformatics, and some ontologies have been developed to integrate these models. However, such models do not explicitly describe clinicians' qualitative knowledge, which is required for clinical applications including decision support and counseling of patients to help them understand their clinical situation. This paper proposes a description framework for a qualitative and context-independent ontology of physiology, QliP, which has three features: 1) It models physiological knowledge qualitatively without mathematical knowledge; 2) The described knowledge is independent of surrounding anatomical entities and abnormality; and 3) It targets physiological components in varying degrees of granularity, from cells to organ systems. An ontology based on this proposed model enables automatic generation of a physiological state transition, starting and ending with a given state. PMID- 23920759 TI - Construction of the radiation oncology teaching files system for charged particle radiotherapy. AB - Our hospital started the charged particle therapy since 1996. New institutions for charged particle therapy are planned in the world. Our hospital are accepting many visitors from those newly planned medical institutions and having many opportunities to provide with the training to them. Based upon our experiences, we have developed the radiation oncology teaching files system for charged particle therapy. We adopted the PowerPoint of Microsoft as a basic framework of our teaching files system. By using our export function of the viewer any physician can create teaching files easily and effectively. Now our teaching file system has 33 cases for clinical and physics contents. We expect that we can improve the safety and accuracy of charged particle therapy by using our teaching files system substantially. PMID- 23920760 TI - Monitoring physicians' prescription patterns on electronic health record: the prescription pattern around clinical event (PACE) algorithm. AB - Electronic health records (EHRs) have gained attention as a valuable data source for medical research, as its adoption rate continues to rise. However, no method for the monitoring of physicians' prescription patterns has been established. Since EHR maintain all prescription data as well as clinical events that occur during the care of patients, we hypothesized that a physician's prescription pattern can be monitored from EHR. In this study, we developed a novel algorithm named PACE, Prescription pattern Around Clinical Event. This algorithm analyzes distribution of the prescription of specific drugs around the time of a clinical event. In the proof of concept study, prescription changes with regard to hyperkalemia were well represented by the algorithm, and the observed patterns well correlated with the physician's knowledge on hyperkalemia (Cohen's kappa, 0.457-0.653). We expect that this algorithm can be used to monitor the guideline adherence of physicians. PMID- 23920761 TI - CUDA implementation of histogram stretching function for improving X-ray image. AB - This paper presents a method to improve the contrast of digital X-ray image using CUDA program on a GPU. The histogram is commonly used to get the statistical distribution of the contrast in image processing. To increase the visibility of the image in real time, we use the histogram stretching function. It is difficult to implement the function on a GPU because the CUDA program is due to handle the complex process to transfer the source data and the processed results between the memory of GPU and the host system. As a result, we show to operate the histogram stretching function quickly on GPU by the CUDA program. PMID- 23920762 TI - Improving physician practice efficiency by learning lab test ordering pattern. AB - The system of electronic medical records (EMR) has been widely used in physician practice. In China, physicians have the time pressure to provide care to many patients in a short period. Improving practice efficiency is a promising direction to mitigate this predicament. During the encounter, ordering lab test is one of the most frequent actions in EMR system. In this paper, our motivation is to save physician's time by providing lab test ordering list to facilitate physician practice. To this end, we developed weight based multi-label classification framework to learn to order lab test for the current encounter according to the historical EMR. Particularly, we propose to learn the physician specific lab test ordering pattern as different physicians may have different practice behavior on the same population. Experimental results on the real data set demonstrate that physician-specific models can outperform the baseline. PMID- 23920763 TI - Impact of Thailand universal coverage scheme on the country's health information systems and health information technology. AB - Thailand achieved universal healthcare coverage with the implementation of the Universal Coverage Scheme (UCS) in 2001. This study employed qualitative method to explore the impact of the UCS on the country's health information systems (HIS) and health information technology (HIT) development. The results show that health insurance beneficiary registration system helps improve providers' service workflow and country vital statistics. Implementation of casemix financing tool, Thai Diagnosis-Related Groups, has stimulated health providers' HIS and HIT capacity building, data and medical record quality and the adoption of national administrative data standards. The system called "Disease Management Information Systems" aiming at reimbursement for select diseases increased the fragmentation of HIS and increase burden on data management to providers. The financial incentive of outpatient data quality improvement project enhance providers' HIS and HIT investment and also induce data fraudulence tendency. Implementation of UCS has largely brought favorable impact on the country HIS and HIT development. However, the unfavorable effects are also evident. PMID- 23920764 TI - An analysis of the openehr archetype semantics based on a typed lambda theory. AB - The openEHR has adopted the dual model architecture consisting of Reference Model and Archetype. The specification, however, lacks formal definitions of archetype semantics, so that its behaviors have remained ambiguous. The objective of this poster is to analyze semantics of the openEHR archetypes: its variance and mutability. We use a typed lambda calculus as an analyzing tool. As a result, we have reached the conclusion that archetypes should be 1) covariant and 2) immutable schema. PMID- 23920765 TI - A novel approach to generating CER hypotheses based on mining clinical data. AB - Comparative effectiveness research (CER) is a scientific method of investigating the effectiveness of alternative intervention methods. In a CER study, clinical researchers typically start with a CER hypothesis, and aim to evaluate it by applying a series of medical statistical methods. Traditionally, the CER hypotheses are defined manually by clinical researchers. This makes the task of hypothesis generation very time-consuming and the quality of hypothesis heavily dependent on the researchers' skills. Recently, with more electronic medical data being collected, it is highly promising to apply the computerized method for discovering CER hypotheses from clinical data sets. In this poster, we proposes a novel approach to automatically generating CER hypotheses based on mining clinical data, and presents a case study showing that the approach can facilitate clinical researchers to identify potentially valuable hypotheses and eventually define high quality CER studies. PMID- 23920766 TI - Promoting health informatics for multidisciplinary education in patient safety: a master course program in Japan. AB - Patient safety topics have been widely presented in undergraduate medical education. Some graduate programs have been developed in North America and typically focused on culture and cognitive factors. The Institute of Medicine (IOM)'s report-Health IT and Patient Safety: Building Safer Systems for Better Care addressed important issues that health IT can lead to safer care as well as introduce new risks. There is an increased need to include such topics in safety education programs. In this study, we aimed at reporting our approach regarding the promotion of health informatics as a core curriculum in a master course program. We compared our curriculum with those in recently published papers and major patient safety resources. Then, we conducted an interim survey by asking the first-year students to rate eight important patient safety topics in comparison with the AHRQ's published categories. Health Information Technology (HIT) was ranked as the most interesting topic (response rate was 100%, n=44).Our initiatives would be useful to establish a stronger link between patient safety informatics education and future HIT adoptions. PMID- 23920767 TI - Development of a system for transferring images via a network: supporting a regional liaison. AB - We developed a system that transfers images via network and started using them in our hospital's PACS (Picture Archiving and Communication Systems) in 2006. We are pleased to report that the system has been re-developed and has been running so that there will be a regional liaison in the future. It has become possible to automatically transfer images simply by selecting the destination hospital that is registered in advance at the relay server. The gateway of this system can send images to a multi-center, relay management server, which receives the images and resends them. This system has the potential to be useful for image exchange, and to serve as a regional medical liaison. PMID- 23920768 TI - An ontology design for visualizing implicit knowledge of the radiotherapy risk. AB - Knowledge sharing of radiotherapy risk contributes to keep the safety practice between the oncologists, medical physicists, and therapists. But the mechanisms of risks tend to complex because of its diversities. Recently, an ontological analysis is tried to share knowledge in the various domains. Therefore, the aim of this study is to construct Radiotherapy Risk Ontology (RRO) and clarify the implicit structures of risks towards knowledge sharing. The method of this study is below. First, the classes and relations were extracted from the risk categorization of the publications. Second, these classes and relationships were connecting and mapping by the ontology editor. Third, the total relationships of classes were verified using paired comparison chart. This paper distinguishes between publication-oriented relationships and the other relationships. And these relationships was defined the explicit and implicit relationships. RRO was constructed 789 classes and 14 types of the explicit relationships. The 22 types of the implicit relationships were clarified using paired comparison. RRO provided the conceptual mapping and the implicit knowledge. The result of this study assisted the knowledge sharing. PMID- 23920769 TI - A proposed dynamic dosing scheme to secure the target plasma drug concentrations based on the precision of the AUC estimate. AB - To reduce the number of blood samples necessary to estimate the patient's AUC (the area under the plasma drug concentration time-curve), various limited sampling strategies (LSSs) have been developed. We proposed a new LSS for busulfan, in which a curve that best approximates the measured data was searched for from a set of pre-generated theoretical plasma drug concentration time curves. We evaluated this LSS and proved that it had virtually no bias and better precision compared with conventional LSSs. However, further study revealed that the precision of our new accurate LSS was still insufficient to secure the target concentration. To solve this problem, we proposed a new dosing scheme, in which the amount of dose was adjusted dynamically according to the estimated precision of the AUC estimator. PMID- 23920770 TI - Mapping the translation challenge. AB - A map of the world of judgement and decision making seeks to locate those problems of translation that reside in the treatment of values and preferences and address the use of widely varying modes of cognition. PMID- 23920771 TI - The core clinical protocol ontology (C2PO): A realist ontology for representing the recommendations within clinical guidelines. AB - We present an initial version of the Core Clinical Protocol Ontology (C2PO). C2PO is an application ontology being developed for the semantic markup of clinical guidelines within the Evicare project. Evicare's goals are to learn more about the actual use of guidelines in the context of clinical care and develop systems to support physicians in answering their clinical questions. The initial implementation of C2PO includes definitions for clinical guideline recommendations, and the process of recommending. We followed a realist approach to ontology design. Design methodology for C2PO, including methods for class selection, is discussed. A collection of guidelines has been manually marked-up and a demonstration system developed in which specific clinical queries will retrieve relevant ranked recommendations. C2PO forms the basis for a lightweight approach to clinical decision support that uses a text-based representation. A future objective is to expand the system to support semantic search of normative medical texts including health records, order sets, and process descriptions. PMID- 23920772 TI - Primary care provider's acceptance of health information exchange utilizing IHE XDS. AB - OBJECTIVE: We assessed primary care providers' perception of a health information exchange system (HIE) based on IHE XDS in the metropolitan area of Braunschweig, Lower Saxony, Germany. DESIGN: An application enabling access to medical documents in an XDS Affinity Domain was developed. We examined usability and factors related to user acceptance. MEASUREMENTS: User perception was probed using system usability scale (SUS) and semi-structured interviews. The framework analysis was used in the review and interpretation of the interview data. RESULTS: The evaluation was performed on 7 participants. The SUS showed an above average usability with a median score of 77.5. Participants submitted suggestions for additional features and improvement of usability. Poor integration of functionality into existing workflows was most frequently criticized. CONCLUSION: We found, that, while usability was well perceived by primary care providers, challenges remain in adoption of XDS based IHE. PMID- 23920773 TI - Concept for preservation and reuse of genome and biomedical imaging research data. AB - The German Research Foundation (DFG) recommends preserving research data for at least ten years. The DFG funded project LABIMI/F establishes an infrastructure for preservation, retrieval and reuse of biomedical research data based on grid/cloud computing technology for two applications a) genome and b) imaging data. The requirements for this infrastructure were determined during workshops with relevant stakeholders. Afterwards product evaluations were conducted and the relevant products were integrated into the infrastructure concept. In this paper, we address the suitability of our solution concerning the fulfillment of the requirements. It is shown that the solution satisfies five of the eight requirement categories completely and the other three categories partly. Furthermore, in order to prove the adherence to the widely accepted Open Archival Information System (OAIS) standard, we successfully performed a mapping of our technical components to the functional entities of the OAIS. PMID- 23920774 TI - Management evaluation about introduction of electric medical record in the national hospital organization. AB - Introduction of Electronic Medical Record (EMR) into a hospital was started from 1999 in Japan. Then, most of all EMR company said that EMR improved efficacy of the management of the hospital. National Hospital Organization (NHO) has been promoting the project and introduced EMR since 2004. NHO has 143 hospitals, 51 hospitals offer acute-phase medical care services, the other 92 hospitals offer medical services mainly for chronic patients. We conducted three kinds of investigations, questionnaire survey, checking the homepage information of the hospitals and analyzing the financial statements of each NHO hospital. In this financial analysis, we applied new indicators which have been developed based on personnel costs. In 2011, there are 44 hospitals which have introduced EMR. In our result, the hospital with EMR performed more investment of equipment/capital than personnel expenses. So, there is no advantage of EMR on the financial efficacy. PMID- 23920775 TI - Storing health data in JPEG: looking at exif area capacity limits. AB - Formats for data storage in personal computers vary according to manufacturer and models for personal health-monitoring devices such as blood-pressure and body composition meters. In contrast, the data format of images from digital cameras is unified into a JPEG format with an Exif area and is already familiar to many users. We have devised a method that can contain health data as a JPEG file. Health data is stored in the Exif area in JPEG in a HL7 format. There is, however, a capacity limit of 64 KB for the Exif area. The aim of this study is to examine how much health data can actually be stored in the Exif area. We found that even with combined data from multiple devices, it was possible to store over a month of health data in a JPEG file, and using multiple JPEG files simply overcomes this limit. We believe that this method will help people to more easily handle health data regardless of the various device modelsthey use. PMID- 23920776 TI - Usability of implementing a tablet-based decision support and integrated record- keeping (DESIRE) tool in the nurse management of hypertension in rural Kenya. AB - In sub-Saharan Africa (SSA), cardiovascular disease (CVD) is the leading cause of death among individuals over the age of 30. Hypertension, a major risk factor for CVD, contributes significantly to the CVD burden in SSA. In order to address the human resource challenge of managing hypertension in low- and middle-income countries (LMICs), task-shifting hypertension care from physicians to nurses has been proposed. To support this task-shifting strategy, the Academic Partnership Providing Access to Healthcare (AMPATH) has developed an Android tablet-based electronic Decision Support and Integrated Record-Keeping (DESIRE) tool to record patient data and assist with clinical decision-making. We investigated the usability of the DESIRE tool in the setting of nurse management of hypertension in rural western Kenya through the use of "mock patient" encounters and "think aloud" exercises. Fiftyseven critical incidents were identified and twenty-three design changes were suggested. Optimization of the tool has the potential to broadly impact treatment of non-communicable diseases in LMICs by providing a model of electronic decision-support in task shifting. PMID- 23920777 TI - Mobile image upload for radiology. PMID- 23920778 TI - Design of the asthma treat smart system in a pediatric institution. AB - Asthma is one of the most common chronic pediatric conditions. Providing evidence based, guideline-appropriate care for asthma is complex. A computerized system may help providers with guideline compliance. The AsthmaTreatSmart application is a stand-alone web-based system developed in Pulmonary medicine with a multidisciplinary team based on national asthma guidelines. The application collects history and symptom information to assign a severity categorization. Medication reconciliation of asthma medications is performed with input from the patient. Severity and medication recommendation are provided for the provider. A personalized action plan and medication summary including medications, etc. is created. The system is successfully used in 6 outpatient clinics and current work is focused on integration with the electronic health record. PMID- 23920780 TI - Use of electronic dental records in Brazil. AB - This study aims to provide both a quantitative and a qualitative analysis of the usability of the most popular electronic dental records in Brazil regarding its clinical and administrative features. The softwares not only will be evaluated regarding their usage among the Brazilian dental professionals but also regarding their functionalities (present, used and desired) and the difficulties encountered by the dentists during their use. PMID- 23920779 TI - Visualizing health: a novel visualization method for personalized health summarization and guidance. AB - How to report and summarize a user's health or wellness status from the Electronic Health Records (EHR) is a important topic since a well-designed health report can provide not only a valued information source for users to exam their physical health status but also a guidance to a better health level. Existing health reports are not totally satisfying and easily bores a user by words and numeral data in them. Facial complexion is one of important indicator in the clinical diagnosis. The pathological changes of health status could often be diagnosed by inspecting the changes of facial complexion. Based on this facial complexion idea, a visualized health report, which reversely visualizes a user's health status directly on his/her outside appearance, is proposed to provide a better alternative than conventional text-based report. Due to its unique characteristic, the proposed visualized health information and guidance is expected to provide valued personalized health information and also effectively encourage users toward healthier lifestyle. PMID- 23920782 TI - A domain-based approach for retrieving trustworthy health videos from YouTube. AB - Health information retrieval and YouTube can be used as powerful tools to improve user's health knowledge. However, YouTube videos must be carefully analysed in order to avoid misleading, inaccurate, obsolete and incorrect health content. We present an approach for re-ranking health videos obtained from YouTube, called Domain-based ranking. Our system automatically identifies videos coming from trusted sources (channels), such as hospitals and health organizations, and re ranks YouTube results so that such videos are presented first in the ranking list. Video and channel metadata are used to automatically determine if a video is provided by a trusted source. The approach is tested and results show that the amount of relevant and reliable videos ranked within top-10 increase when using Domain-based ranking, compared with the original YouTube ranking. PMID- 23920781 TI - Translating MeSH concepts. AB - The concept-oriented structure of the MeSH(r) thesaurus is not yet in common use. Nevertheless, it has been shown that a concept-based querying of PubMed may be of interest. To take full advantage of the concept-oriented structure of MeSH in the information retrieval tool associated with the CISMeF catalogue, it was necessary to translate such concepts into French. PMID- 23920783 TI - SPOCS : a smarter point of care system for coordinated chronic disease management. PMID- 23920784 TI - Mobile patient applications within diabetes - from few and easy to advanced functionalities. AB - Patient diaries as apps on mobile phones are becoming increasingly common, and can be a good support tool for patients who need to organize information relevant for their disease. Self-management is important to achieving diabetes treatment goals and can be a tool for lifestyle changes for patients with Type 2 diabetes. The autoimmune disease Type 1 diabetes requires a more intensive management than Type 2 - thus more advanced functionalities is desirable for users. Both simple and easy-to-use and more advanced diaries have their respective benefits, depending on the target user group and intervention. In this poster we summarize main findings and experience from more than a decade of research and development in the diabetes area. Several versions of the mobile health research platform-the Few Touch Application (FTA) are presented to illustrate the different approaches and results. PMID- 23920785 TI - Medical concept representation: the years beyond 2000. AB - This work aims at understanding the state of the art in the broad contextual research area of "medical concept representation". Our data support the general understanding that the focus of research has moved toward medical ontologies, which we interpret as a paradigm shift. Both the opinion of socially active groups of researchers and changes in bibliometric data since 1988 support this opinion. Socially active researchers mention the OBO foundry, SNOMED CT, and the UMLS as anchor activities. PMID- 23920786 TI - Unifying acute stroke treatment guidelines for a Bayesian belief network. AB - With the large number of clinical practice guidelines available, there is an increasing need for a comprehensive unified model for acute ischemic stroke treatment to assist in clinical decision making. We present a unified treatment model derived through review of existing clinical practice guidelines, meta analyses, and clinical trials. Using logic from the treatment model, a Bayesian belief network was defined and fitted to data from our institution's observational quality improvement database for acute stroke patients. The resulting network validates known relationships between variables, treatment decisions and outcomes, and enables the exploration of new correlative relationships not defined in current guidelines. PMID- 23920787 TI - Palliative care from a medical informatics perspective in Chile, Germany, and Peru. AB - This work explores a) the use of e-health systems in the context of palliative care and b) the information needs of patients, care givers and healthcare professionals in palliative care. To achieve this we conducted a systematic literature review and interviewed health professionals in Germany, Peru, and Chile. All countries have in common that specific e-health systems are rarely used in this context and the presence of a gradient of available care between rural and urban areas. PMID- 23920788 TI - Classification of gastric cancer subtypes using ICA, MLR and Bayesian network. AB - The purpose of this study is to extract genes that could distinguish between two subtypes (diffuse and intestinal) of gastric cancer (GC) from their gene expression profile, to build a classifier based on the genes and to investigate the relationships among the selected genes, because there are big differences in the survival curve and the medical treatment between the subtypes. First, we applied Wilcoxon test, independent component analysis (ICA) and multiple logistic regression (MLR) to the profile, and conducted a classifier consisting of only three genes. We validated the classifier using test data with new 9 samples (blind test). The classifier yielded the accuracy of 100%. Finally, using the 18 genes selected by MLR and specific to each subtype, Bayesian Network was constructed, and compared with the network from GeneMANIA. Consequently, these networks were very similar each other. PMID- 23920789 TI - A study of user requests regarding the fully electronic health record system at Seoul National University Bundang Hospital. AB - Although the adoption rates for Electronic Health Records (EHRs) are growing, significant opportunities for further advances in EHR system design remain. The goal of this study was to identify issues that should be considered in the design process for the successful development of future systems by analyzing end users' service requests gathered during a recent three-year period after a comprehensive EHR system was implemented at Seoul National University's Bundang Hospital (SNUBH) in South Korea. Data on service requests from end users of the EHR system made from 2008 through 2010 were analyzed and categorized. From our study, we found that the EHR system has evolved to optimize ease of use and special functionalities for particular groups of users and particular subspecialties. PMID- 23920790 TI - Building electronic forms for elderly program: integrated care model for high risk elders in Hong Kong. AB - In Hong Kong, elderly patients discharged from hospital are at high risk of unplanned readmission. The Integrated Care Model (ICM) program is introduced to provide continuous and coordinated care for high risk elders from hospital to community to prevent unplanned readmission. A multidisciplinary working group was set up to address the requirements on developing the electronic forms for ICM program. Six (6) forms were developed. These forms can support ICM service delivery for the high risk elders, clinical documentation, statistical analysis and information sharing. PMID- 23920791 TI - The evaluation of the need to share medical data on the community medical ICT network service in Nagasaki, Japan. AB - The Community Medical ICT Network service at the Nagasaki, Japan was established in 2009. Medical information network for sharing patients data was investigated focused on the access log data from April of 2009 and October of 2010. The total number of the access to the medical information was 30,914 of 2,213 patients. And the total number of access of the image including diagnostic imaging report, medical examination, treatment and medical documents was 10,278(33.2%), 8,949(28.9%), 6,896(22.3%) and 4,791(15.5%) respectively. These results showed that these medical information had enough valued for sharing in the regional medicine. In conclusion, many types of medical information should be required for sharing in the community medical ICT network in Japan. PMID- 23920792 TI - An automated information system for families of patients in the operation room based on EMR data. AB - When children undergo surgery, the parents waiting for them outside the room feel extreme anxiety. SNUH was a full EMR hospital. But nurses had to manually operate an electronic display board which provided information regarding the progresses of the operations. The parents had to be located in front of the board. It was a unilateral and passive system. Therefore, we were about to improve the system to provide efficient information satisfying both parents and nurses. This service, which connected to the EMR system to provide real time location of patients undergoing operations, provide information through an electronic display board outside the operating room and SMS messages. We could reduce uneasiness of patients' families, increase satisfactions, and further, not only contribute to establishing the improved service of SNUH but also lessening unnecessary duties of nurses. PMID- 23920793 TI - Factors affecting the satisfaction of electronic health records (EHRs) from a physicians' perspectives in implementation. AB - The Purpose of this study is to investigate factors affecting satisfaction of the Electronic Health Records (EHRs) in Seoul National University of Korea, from a physicians' perspectives. Administration of a survey instrument containing 6 items to cover characteristics of the user's population in hospital. A sample of 327 users was selected including medical sectors for the study. The Overall response rate was 16.5%. It is mores satisfaction with EHRs that pharmacy and technician sector than physician sector after implementing the EHRs system. Of the total respondents, there was a significant association between performance 'System functionality and performance of EHRs' and 'overall satisfaction level with EHRs' (p < 0.01). In addition, physicians stated other factors that actually affected satisfaction of the EHRs systems in Hospital. Among these factors, summary note of discharge and operation factors are most correlation with satisfaction. PMID- 23920794 TI - Evaluation of an electrocardiogram on QR code. AB - An electrocardiogram (ECG) is an indispensable tool to diagnose cardiac diseases, such as ischemic heart disease, myocarditis, arrhythmia, and cardiomyopathy. Since ECG patterns vary depend on patient status, it is also used to monitor patients during treatment and comparison with ECGs with previous results is important for accurate diagnosis. However, the comparison requires connection to ECG data server in a hospital and the availability of data connection among hospitals is limited. To improve the portability and availability of ECG data regardless of server connection, we here introduce conversion of ECG data into 2D barcodes as text data and decode of the QR code for drawing ECG with Google Chart API. Fourteen cardiologists and six general physicians evaluated the system using iPhone and iPad. Overall, they were satisfied with the system in usability and accuracy of decoded ECG compared to the original ECG. This new coding system may be useful in utilizing ECG data irrespective of server connections. PMID- 23920795 TI - Usage experience with the document archiving and communication system for the storage and retrieval of medical records. AB - Standard Japanese electronic medical record (EMR) systems are associated with major shortcomings. For example, they do not assure lifelong readability of records because each document requires its own viewing software program, a system that is difficult to maintain over long periods of time. It can also be difficult for users to comprehend a patient's clinical history because different classes of documents can only be accessed from their own window. To address these problems, we developed a document-based electronic medical record that aggregates all documents for a patient in a PDF or DocuWorks format. We call this system the Document Archiving and Communication System (DACS). There are two types of viewers in the DACS: the Matrix View, which provides a time line of a patient's history, and the Tree View, which stores the documents in hierarchical document classes. We placed 2,734 document classes into 11 categories. A total of 22,3972 documents were entered per month. The frequency of use of the DACS viewer was 268,644 instances per month. The DACS viewer was used to assess a patient's clinical history. PMID- 23920796 TI - A guideline-based decision support system for headache diagnosis. AB - The ratio of correct diagnosis for primary headache has always been relatively low for general practitioners due to the unacquaintance with headache guideline in Chinese primary hospitals. This study proposed a computerized headache guideline method using SAGE module and developed a decision support system for headache diagnosis, which could be expected to help general practitioners of primary hospitals improve diagnostic accuracy. 282 previously diagnosed cases from EMR were used to evaluate the diagnostic accuracy of the system, the result is: migraine 144/153 (94.1%), tension-type headache 89/100 (89.0%), cluster headache 10/11 (90.9%) and chronic daily headache 53/57(93.0%). The proposed system is in the starting phase of the implementation at the outpatient department of Neurology in Chinese PLA general hospital. PMID- 23920797 TI - Automatic information extraction for computerized clinical guideline. AB - Clinical Guidelines (CG) are recommendations on the appropriate treatment and care of people with specific diseases and conditions. CG should be used by both physicians and patients to make the informed decision. However, the CGs are not well used due to their complexity and because they are frequently updated. The computerized CGs are proposed to make use of the computer to do the decision making. However, it needs a lot of human effort to transform the narrative CG into computerized CG. In this paper, we proposed a method to use the NLP techniques to extract the fine-grained information from the text based CG automatically. Such information could be easily converted to the computer interpretable models. PMID- 23920798 TI - Machine learning methods for clinical forms analysis in mental health. AB - In preparation for a clinical information system implementation, the Centre for Addiction and Mental Health (CAMH) Clinical Information Transformation project completed multiple preparation steps. An automated process was desired to supplement the onerous task of manual analysis of clinical forms. We used natural language processing (NLP) and machine learning (ML) methods for a series of 266 separate clinical forms. For the investigation, documents were represented by feature vectors. We used four ML algorithms for our examination of the forms: cluster analysis, k-nearest neigh-bours (kNN), decision trees and support vector machines (SVM). Parameters for each algorithm were optimized. SVM had the best performance with a precision of 64.6%. Though we did not find any method sufficiently accurate for practical use, to our knowledge this approach to forms has not been used previously in mental health. PMID- 23920799 TI - Acquisition of patient information from nurses by other health professionals under electronic medical record implementation. AB - Most electronic medical record (EMR) systems in Japan are equipped with nursing documentation functions. Electronic nursing records (ENRs) are much more accessible to doctors and paramedical staff than paper-based record systems. Face to-face communication might be used less often to acquire patient information collected by nurses if EMR systems were effectively used. We conducted a questionnaire survey to investigate the methods used by other health professionals to acquire patient information collected by nurses under EMR implementation at two university hospitals. There were 153 responses, which showed that 51% of doctors and 16% of paramedical staff still often used face-to face communication even though more than 70% of them often accessed the ENR. Only 35% of doctors and paramedical staff recognized that the EMR system helped reduce the time needed to acquire patient information; furthermore, 32% thought that using the EMR system to acquire patient information was bothersome. These results indicate that the operability of EMR systems is still insufficient for health professionals. PMID- 23920800 TI - WTP (willingness to pay) for tele-health consultation service in Hokkaido, Japan. AB - We developed a tele-health consultation system that combines a sphygmomanometer with a tele-conference system. These were placed in pharmacies and the University. We selected five pharmacies to set up a consultation room; one in a local area, two in a suburban area, and the remaining two in an urban area. Nurses with more than 5 years of clinical experience were assigned as consultants. These consultants offer health consultation but do not practice medicine. Some researchers have indicated the economic viability of at-home health management systems, but nothing has been researched on the economic viability of tele-health consultation. The objective of present study was estimated Willingness to Payment (WTP) of Tele-health consultation service. The WTP was estimated by Double-Bounded Dichotomous-Choice model. We performed logistic-regression analysis to confirm factors to affect WTP. The number of the respondent was 480. Mean WTP was calculated 495 yen and the median was 367 yen. There was significant difference for factor of "annual income", "have a willingness to use this system", and "have a child/children". PMID- 23920801 TI - Development of medical communication support system "health life passport". AB - Today, the number of foreign residents in Japan is increasingdue to globalization. However, Japan is behind other advanced countries in accepting oversea patients. Japan has to improve medical institutions' readiness to accept foreign patients, and nurture medical interpreters. To address these issues, we developed a language support application for smart phones. Anyone can download it freely. PMID- 23920802 TI - Using visual tools to improve clinical engagement and group understanding of complex IT concepts. AB - This work describes how the use of a visual patient journey modeling tool significantly improved the engagement of clinical staff and their group understanding of the complex IT concepts associated with event-driven computer simulation. Such group understanding and engagement is acknowledged as critical to the successful implementation of a wide range of quality improvement initiatives [1, 2]. The specific example described in this paper relates to the improved utilisation of chemotherapy unit resources. PMID- 23920803 TI - Display methods of electronic patient record screens: patient privacy concerns. AB - To provide adequate care, medical professionals have to collect not only medical information but also information that may be related to private aspects of the patient's life. With patients' increasing awareness of information privacy, healthcare providers have to pay attention to the patients' right of privacy. This study aimed to clarify the requirements of the display method of electronic patient record (EPR) screens in consideration of both patients' information privacy concerns and health professionals' information needs. For this purpose, semi-structured group interviews were conducted of 78 medical professionals. They pointed out that partial concealment of information to meet patients' requests for privacy could result in challenges in (1) safety in healthcare, (2) information sharing, (3) collaboration, (4) hospital management, and (5) communication. They believed that EPRs should (1) meet the requirements of the therapeutic process, (2) have restricted access, (3) provide convenient access to necessary information, and (4) facilitate interprofessional collaboration. This study provides direction for the development of display methods that balance the sharing of vital information and protection of patient privacy. PMID- 23920804 TI - Evaluation of a Context-based Prescription Alert System: A Clinical Perspective. AB - Medication alert systems have been implemented worldwide. The purpose of this study is evaluation of the medication alert systems from a clinical perspective. We surveyed physicians with regard to their reactions to the medication alerts. We collected the revised prescription information and assessed risk avoidance in all cases. The system reviewed 51,006 prescriptions and produced 16,718 physician alerts related to 13,823 prescriptions over the course of 1 month. We identified 45 prescriptions that were revised following the alert and four cases in which patient treatment may have been discontinued or adverse drug events (ADEs) may have occurred if the alerts had not been issued. We demonstrated that the system prevented these potential medication errors. This study adopted a clinical perspective and demonstrated that a real-time alert system can contribute to prevention of ADEs. PMID- 23920805 TI - Qualitative evaluation of the supporting system for diagnosis procedure combination code selection. AB - In Japan, medical staff must select a diagnosis procedure combination (DPC) code for each inpatient upon admission. We report on the development and evaluation of a supporting system for DPC code selection. This system, based on a machine learning method developed by Okamoto et al., makes DPC code suggestions that are derived from medical practice information pertaining to inpatients. The use of the suggestions helps medical staff select an appropriate DPC code for each inpatient. We asked health information management professionals to evaluate the system and to compare the suggested DPC codes with those selected by doctors. They reported that the system was generally useful and that using this system they could find some cases of hospitalized patients whose DPC codes needed correction. However, they also determined the precision of the system needs improvement. PMID- 23920806 TI - Efficiency and safety of new radiofrequency identification system in a hospital. AB - Radiofrequency identification (RFID) applications have the capability to obtain real-time information on the location and properties of tagged people or objects. The efficiency and safety of the new RFID system (UHF band, 953 MHz) were tested in our hospital. We examined whether 1 to 4 persons and medical equipment with IC tags were captured by RFID readers in a laboratory. We next tested whether electric signals produced by RFID could affect medical devices. New radio frequency tags provided extensive patient identification and helped track capital equipment within a laboratory. Electric fields produced by the new RFID did not significantly affect medical devices in our hospital. New RFID system was safe and useful for tracking people and medical equipments in a hospital. As healthcare systems today involve increasingly complex and interrelated processes, the new RFID technologies may enhance patient safety, and wellness, and reduce staff workloads in a hospital. PMID- 23920807 TI - A patient centered system for decubitus prevention based on nutrition, drinking, physical activity and sleep monitoring. AB - State-of-the-art decubitus prevention focuses mainly on special decubitus mattresses, which are indicated for extremely high risk only, while other risk factors such as nutrition or physical activity are hardly considered. Therefore, a monitoring system for decubitus prevention for persons with medium risk has been developed. The system consisted of an unobtrusive sensor system and a tablet for manual input of decubitus-relevant data concerning nutrition, drinking behavior and physical activity. The system was tested in a feasibility study. Results indicate that the system is usable and can provide useful information for decubitus prevention. Future work will include a field study, evaluating the system in a long-term study. PMID- 23920808 TI - Preliminary evaluation of a serious game for the dissemination and public awareness on preschool children's oral health. AB - This article presents the preliminary evaluation by dentists, teachers and parents of a serious game for dissemination of public awareness on preschool children's oral health. In this game, the player keeps a victory condition, while your tooth remains whole. Preliminary evaluation was performed in two parts. The first part was a questionnaire designed to evaluate the applicability of this technology and the opinions on the effectiveness of games in education and in oral health promotion. In the second part, the game is presented and an evaluation questionnaire of it is applied. This study had the participation of 115 persons. There was 80% approval which suggested that the game is an alternative for the prevention of dental awareness. Furthermore, the study perceives that teachers can work together with dentists in order to perform dental prevention. PMID- 23920809 TI - Measuring the performance of electronic health records: a case study in residential aged care in Australia. AB - Measuring the performance of electronic health records (EHR) is an important, yet un-resolved challenge. Various measurements have addressed different aspects of EHR success, yet a holistic, comprehensive measurement tool needs to be developed to capture the potential EHR success variables completely. A self-administered questionnaire survey instrument was developed based on the theoretical framework of the DeLone and McLean Information Systems Success Model. It measures nigh variables of EHR success: system quality, information quality, service quality, training, self efficacy, intention to use, use, user satisfaction and net benefits. The instrument was used to measure the performance of aged care EHR systems in three aged care organizations. The results suggest that the instrument was reliable. PMID- 23920810 TI - Development of the electronic patient record system based on problem oriented system. AB - In Japan, POS (problem oriented system) is recommended in the clinical guideline. Therefore, the records are mainly made by SOAP. We developed a system mainly with a function which enabled our staff members of all kinds of professions including doctors to enter the patients' clinical information as an identical record, regardless if they were outpatients or inpatients, and to observe the contents chronologically. This electric patient record system is called "e-kanja recording system". On this system, all staff members in the medical team can now share the same information. Moreover, the contents can be reviewed by colleagues; the quality of records has been improved as it is evaluated by the others. PMID- 23920811 TI - Personal health records are designed for people like us. AB - Current approaches to designing, implementing and evaluating personal health record systems reflect the attributes and assumptions of well-educated and well to-do users (People like Us: PLUs) rather than the needs of the most disadvantaged in society (the disempowered, disengaged and disconnected: DDDs). These electronic systems for increasing accessibility to personal health information may accentuate rather than mitigate the emerging eHealth divide. Using a PubMed review of literature on personal health record systems, we identified only seven of 73 papers, and one of 29 abstracts which made specific mention of users who were disadvantaged by low literacy levels or difficulties with access to technology. This work is part of a larger study into personal health records and disadvantage. PMID- 23920812 TI - A pilot study measuring changes in student impressions before and after clinical training using a questionnaire based on the semantic differential technique. AB - Students with a positive impression of their studies can become more motivated. This study measured the learning impact of clinical training by comparing student impressions before and after clinical training. The study included 32 students of radiological technology in their final year with the Division of Radiological Science and Technology, Department of Health Sciences, School of Medicine, Hokkaido University. To measure student impressions of x-ray examination training, we developed a questionnaire using the semantic differential technique. The resulting factor analysis identified 2 factors that accounted for 44.9% of the 10 bipolar adjective scales. Factor 1 represented a "resistance" impression of x-ray examination training, and factor 2 represented a "responsibility" impression. The differences in factor scores before and after the clinical training suggest that student impressions are affected by clinical training. PMID- 23920813 TI - Are physicians interested in the quality of life of their patients? usage of EHR integrated patient reported outcomes data. AB - In addition to clinical findings, patient reported outcomes (PRO) are a valuable source of information. However, the available time of a physician per patient is limited. Under these constraints, do physicians look into PRO data? By using an, electronic health record (EHR) integrated system for the documentation of PRO the data is directly available during treatment. To evaluate whether this information is used we analyzed access patterns for two types of PRO forms. 56% and 74% of these forms were accessed within routine care while 74% and 100% were analyzed for clinical research. PMID- 23920814 TI - A methodological approach for designing a usable ontology-based GUI in healthcare. AB - This paper presents a methodological approach to the design and evaluation of an interface for an ontology-based system used for designing care plans for monitoring patients at home. In order to define the care plans, physicians need a tool for creating instances of the ontology and configuring some rules. Our purpose is to develop an interface to allow clinicians to interact with the ontology. Although ontology-driven applications do not necessarily present the ontology in the user interface, it is our hypothesis that showing selected parts of the ontology in a "usable" way could enhance clinician's understanding and make easier the definition of the care plans. Based on prototyping and iterative testing, this methodology combines visualization techniques and usability methods. Preliminary results obtained after a formative evaluation indicate the effectiveness of suggested combination. PMID- 23920815 TI - Panel data analysis of cardiotocograph (CTG) data. AB - Panel data analysis is a statistical method, widely used in econometrics, which deals with two-dimensional panel data collected over time and over individuals. Cardiotocograph (CTG) which monitors fetal heart rate (FHR) using Doppler ultrasound and uterine contraction by strain gage is commonly used in intrapartum treatment of pregnant women. Although the relationship between FHR waveform pattern and the outcome such as umbilical blood gas data at delivery has long been analyzed, there exists no accumulated FHR patterns from large number of cases. As time-series economic fluctuations in econometrics such as consumption trend has been studied using panel data which consists of time-series and cross sectional data, we tried to apply this method to CTG data. The panel data composed of a symbolized segment of FHR pattern can be easily handled, and a perinatologist can get the whole FHR pattern view from the microscopic level of time-series FHR data. PMID- 23920816 TI - Do we have the reliable data? An exploration of data quality for AIDS information system in China. AB - A national AIDS program evaluation system has been applied to the ranking of the performance of involved public health organizations in China since 2007. The system provides quantitative performance comparison information based on automatic mining of the data stored in a unified web-based national information system, China AIDS Comprehensive Response Information Management System (the CRIMS). Hence, the quality of the AIDS program evaluation system is directly related to the data quality in the CRIMS. This study aims to evaluate the performance of the AIDS program evaluation system. The research method is qualitative interview of public health practitioners in Jiangxi Province. The public health practitioners believed that the introduction and ongoing usage of the CRIMS has significantly transformed the practice of AIDS prevention and control. They believed that the AIDS program evaluation system has brought in increased accountability of public health. They suggested that the accuracy and completeness of AIDS program evaluation needs to go beyond the data from the CRIMS. Further research will continue to identify the unknown factors that undermine the performance of AIDS programs in China. PMID- 23920817 TI - Early detection of QT interval prolongation from the ECG database system. AB - To prevent unexpected sudden cardiac patient death due to drug-induced Long QT syndrome (LQTS), we seek to build a computerized early detection and warning system of QTc interval increase tendency. We built an ECG database system that holds the digital waveform data and related information of the ECGs performed in out hospital, and developed an experimental detection system of QTc increase tendency. Despite the several problems about the accuracy of detection, we succeeded in extracting a patient who seemed to be drug-induced LQTS. A combination of such a detection system with more accuracy and drug prescription database would contribute to the early detection of drug-induced LQTS. PMID- 23920818 TI - Experience of de-identification system development for clinical research in tertiary hospital. AB - To protect patients' privacy and to improve the convenience of research, Asan Medical Center (AMC) has been developing a de-identification system for biomedical research, which mainly consists of three components: de-identification tool, search tool, and chart review tool. The de-identification tool can substitute a randomly assigned research ID for a hospital patient ID, remove the identifiers in the structured format, and mask them in the unstructured format, i.e., texts. The search tool can find the number of patients which satisfies given criteria. The chart review tool can provide de-identified patient's clinical data for review. We found that clinical data warehouse was essential for successful implementation of de-identification system, and this system should be tightly linked to an electronic institutional review board system for easy operation of honest brokers. PMID- 23920819 TI - Where to wear accelerometers to measure physical activity in people? AB - 13 volunteers walked on a treadmill at 6 different speeds while wearing different accelerometers on different body positions, a spirometry unit and heart rate devices. The goal of this experiment was to find which position on a person's body and which of the sensors is best to measure physical activity (PA) in people by means of an accelerometer. PMID- 23920820 TI - Development of electronic progress tables for multidisciplinary medical education in a university. AB - In the education of medical professionals, imitation medical records and associated documents were developed as electronic teaching materials for students in order to teach collaboration among medical professionals such as nurses, therapists and medical social workers. The roles of each medical professional and the flow of clinical practice were taught using progress tables, including medical treatment, clinical examination, and the contents of care, so that the contents of medical examination were understood based on a time series. Students' understanding of the flow of medical practice was evaluated based on the amount of description in the table before and after explanation of the important points of the clinical process concerning each medical professional. The comments of students who received the lessons suggested that this approach was useful for understanding actual clinical practice and how to utilize a progress table and to prepare information. PMID- 23920821 TI - Long-term changes of information environments and computer anxiety of nurse administrators in Japan. AB - In Japan, medical information systems, including electronic medical records, are being introduced increasingly at medical and nursing fields. Nurse administrators, who are involved in the introduction of medical information systems and who must make proper judgment, are particularly required to have at least minimal knowledge of computers and networks and the ability to think about easy-to-use medical information systems. However, few of the current generation of nurse administrators studied information science subjects in their basic education curriculum. It can be said that information education for nurse administrators has become a pressing issue. Consequently, in this study, we conducted a survey of participants taking the first level program of the education course for Japanese certified nurse administrators to ascertain the actual conditions, such as the information environments that nurse administrators are in, their anxiety attitude to computers. Comparisons over the seven years since 2004 revealed that although introduction of electronic medical records in hospitals was progressing, little change in attributes of participants taking the course was observed, such as computer anxiety. PMID- 23920822 TI - Sensor-based fall risk assessment - dagger of the mind? AB - Fall events and their severe consequences represent not only a threatening problem for the affected individual, but also cause a significant burden for health care systems. Our research work aims to elucidate some of the prospects and problems of current sensor-based fall risk assessment approaches. Selected results of a questionnaire-based survey given to experts during topical workshops at international conferences are presented. The majority of domain experts confirmed that fall risk assessment could potentially be valuable for the community and that prediction is deemed possible, though limited. We conclude with a discussion of practical issues concerning adequate outcome parameters for clinical studies and data sharing within the research community. All participants agreed that sensor-based fall risk assessment is a promising and valuable approach, but that more prospective clinical studies with clearly defined outcome measures are necessary. PMID- 23920823 TI - Towards capturing innovation effects of a CDSS (NjuRen). AB - The e-service NjuRen is a clinical decision support system used by physicians to calculate patients' renal function and provide support for selection of appropriate drug and dosage for patients with renal failure. Project NjuRen is a collaboration between Stockholm County Council and Jonkoping International Business School and aims at evaluating the socio-economic impact of implementing IT-systems in healthcare. The project consist of several steps, first the development and adaptation of a model to measure innovation effects. In the second step the development of a survey to capture factual impacts and effects. Finally, in the third step to translate the effects into socio-economic terms. The result will help decision makers to identify the achieved benefits and outcomes that the implementation of the system has brought with it. PMID- 23920824 TI - What type of innovation effects can you expect when offering e-services in the AAL domain. AB - The objective of the AAL-FOOD project (funded by the AAL Joint Programme and VINNOVA) is to develop e-services that assist elderly in their procurement, preparation and the social construct of eating food to maintain a diverse nutritional intake, and hence stay healthy longer. The project consists of members from Denmark, Italy, Netherlands, Romania and Sweden. The AAL-FOOD project has so far completed collecting user requirements from potential users in Italy, Romania and the Netherlands and identified opportunities for design solutions made available through an IT-platform under development. Service classifications have been identified as well as identification of 13 potential e services which in turn have been ranked in accordance of technical feasibility and implementation. Here we present preliminary results from on-going evaluation work conducted in the AAL-FOOD project. The evaluation aims at identifying effects of innovations through the offering of e-services directed at elderly within their homes. PMID- 23920825 TI - An affordable, usable and sustainable preventive healthcare system for unreached people in Bangladesh. PMID- 23920826 TI - Analyses of medical data models - identifying common concepts and items in a repository of medical forms. AB - One year ago the portal of Medical Data Models (http://medical-data-models.org) was presented as a resource for the scientific community. As of November 2012 there are approximately 3,300 forms with 102,000 items available in the CDISC ODM format. First descriptive analyses regarding form metadata demonstrate the capability of such a repository to identify commonly used medical concepts. Most common items are administrative attributes which indicates that more clinical information are needed to increase the secondary use of data documented within these forms. PMID- 23920827 TI - Statistical text classifier to detect specific type of medical incidents. AB - WHO Patient Safety has put focus to increase the coherence and expressiveness of patient safety classification with the foundation of International Classification for Patient Safety (ICPS). Text classification and statistical approaches has showed to be successful to identifysafety problems in the Aviation industryusing incident text information. It has been challenging to comprehend the taxonomy of medical incidents in a structured manner. Independent reporting mechanisms for patient safety incidents have been established in the UK, Canada, Australia, Japan, Hong Kong etc. This research demonstrates the potential to construct statistical text classifiers to detect specific type of medical incidents using incident text data. An illustrative example for classifying look-alike sound alike (LASA) medication incidents using structured text from 227 advisories related to medication errors from Global Patient Safety Alerts (GPSA) is shown in this poster presentation. The classifier was built using logistic regression model. ROC curve and the AUC value indicated that this is a satisfactory good model. PMID- 23920828 TI - Tutorials on basics of bioethics: an experience with post-graduate health professionals. AB - BACKGROUND: All health professionals are morally bound to recognize and address ethical issues in their daily practice. Understanding basics of bioethics can help professionals promote autonomy and protect the welfare of both patients and research participants. As part of the Fogarty International Center, NIH, USA, funded "Training Program for Psychiatric Genetics in India," NNM was trained in bioethics at University of Pittsburgh under the mentorship of Lisa S Parker, PhD. OBJECTIVES: The overall goal of this Tutorial project was to translate NNM's Ethics training for hospital-based Indian health professionals to sensitize them to the ethical issues arising in psychiatric research and practice. METHODOLOGY: After receiving official permission from the medical superintendent of PGIMER-Dr. R.M.L. Hospital, New Delhi, the program was announced. Candidates with a degree in one of the Health Care Sciences were enrolled. Five two-hour interactive sessions were held weekly on five topics. An evaluation of the effectiveness of the interactive tutorial program was conducted. RESULTS: A total of 16 participants enrolled in these tutorials. The post-program evaluation of satisfaction for all topics of the program by participants indicated high mean score. The main need identified was for continued refreshing of bioethical knowledge and skills through academic activities. PMID- 23920829 TI - Development of an early detection and monitoring system for deteriorating patients. AB - A number of methods of preventing cardiopulmonary arrest are currently in use. One such method is the alert response system developed by Seoul National University Children's Hospital, which is an early detection and monitoring system for deteriorating patients who are at risk of cardiopulmonary arrest. This system offers an effective means of detecting early warning signs and monitoring deteriorating patients, and its application can reduce rates of cardiopulmonary arrest. PMID- 23920830 TI - Evaluation of alerts for potassium-increasing drug-drug-interactions. AB - Electronic alerts for preventing hyperkalaemia during potassium-increasing drug drug-interactions (DDIs) are often overridden due to their low specificity. Treatments of 76,467 inpatients were retrospectively analysed to establish more specific alerts. Alerting concepts for identifying DDIs that induced hyperkalaemia (serum potassium >=5.5 mEq/l were compared. The positive predictive value (PPV) of alerts was 2.9% if they were triggered at onset of each potassium increasing DDI. The PPV increased to 5.1% if alerts at onset were suppressed for serum potassium levels of <4.0 mEq/l. The PPV rose to 24.2% with a novel approach, triggering alerts whenever an elevated potassium level of >4.8 mEq/l was detected at onset or during the entire DDI period. Thus, triggering DDI alerts based on periodically monitored potassium levels may improve specificity of alerts and thereby reduce alert fatigue. PMID- 23920831 TI - Using PICO to align medical evidence with MDs decision making models. AB - Modern medicine is characterized by an "explosion" in clinical research information making practical application of Evidence-Based Medicine (EBM), problematic for many clinicians. We have developed a PICO-(evidence based search strategy focusing on Patient/Population, Intervention, Comparison and Outcome) based framework for (indexing and retrieving medical evidence and we posit that the use of PICO allows for organizing evidence that is aligned with an MD's decision making model. We describe a study where medical students evaluated our PICO-based approach and results show that students are eager to apply EBM but are hindered by a lack of specialist skills. Students reported that the PICO-based framework for organizing evidence provided an intuitive way of accessing and evaluating evidence and would be useful for their clinical tasks. PMID- 23920832 TI - Empirical analysis of knowledge bases to support structured output in the Arden syntax. AB - BACKGROUND: Structured output has been suggested for the Arden Syntax to facilitate interoperability. OBJECTIVE: Tabulate the components of WRITE statements in a corpus of medical logic modules (MLMs)in order to validate requiring structured output. METHODS: WRITE statements were tabulated in 258 MLMs from 2 organizations. RESULTS: In a total of 351 WRITE statements, email destinations (226) predominated, and 39 orders and 40 coded output elements also were tabulated. Free-text strings predominated as the message data. CONCLUSIONS: Arden WRITE statements contain considerable potentially structured data now included as free text. A future, normative structured WRITE statement must address a variety of data types and destinations. PMID- 23920833 TI - Constructing mammography examination process ontology using affinity diagram and hierarchical task analysis. AB - Mammography is complex and difficult for beginner radiologic technologists (RTs) because knowledge and technical skills rely on one's experience, and it is often difficult for experienced RTs to verbally explain the process to co-workers or beginners. The purpose of this study was to construct a mammography examination process ontology for knowledge sharing among RTs and propose a new ontology construction method using an affinity diagram (AD) and hierarchical task analysis (HTA). First, tasks collected by brainstorming were clustered and connected using the AD. Subsequently, a hierarchical structure was constructed based on the clusters and relations determined in the AD. Finally, a mammography process ontology was determined based on the relations noted in the AD and HTA. As a result, the ontology contained 203 classes and 669 relations. PMID- 23920834 TI - The effects of electronic health record on the flow of information - a pilot study. AB - Papery or electrical data processing tools are used for documenting, transmitting, evaluating, recording and archiving patient data. An implementation of an electronic health record (EHR) is a complex and multi-dimensional entity. There is a need to ensure that the impact of EHR is fully evaluated. For systematic evaluation of the Hospital Information System is developed and tested a HIS-monitor (Ammenwerth et al 2007, 2011). HIS-monitor testing is one part of the evaluation study of the implementation of EHR at the Satakunta Hospital District (SHD) in Finland. With 2500 health care professionals SHD produces specialized medical care services for 226 000 residents. The aim of this study is to evaluate the effects of EHR on the flow of information. The study design is before and after of EHR system implementation. At the pilot phase the survey material was collected and the HIS-monitor questionnaire was tested. Results show that current data processing tools do not support enough the flow of information. Results were used in further development of HIS-monitor. PMID- 23920835 TI - Model medication management process in Australian nursing homes using business process modeling. AB - One of the reasons for end user avoidance or rejection to use health information systems is poor alignment of the system with healthcare workflow, likely causing by system designers' lack of thorough understanding about healthcare process. Therefore, understanding the healthcare workflow is the essential first step for the design of optimal technologies that will enable care staff to complete the intended tasks faster and better. The often use of multiple or "high risk" medicines by older people in nursing homes has the potential to increase medication error rate. To facilitate the design of information systems with most potential to improve patient safety, this study aims to understand medication management process in nursing homes using business process modeling method. The paper presents study design and preliminary findings from interviewing two registered nurses, who were team leaders in two nursing homes. Although there were subtle differences in medication management between the two homes, major medication management activities were similar. Further field observation will be conducted. Based on the data collected from observations, an as-is process model for medication management will be developed. PMID- 23920836 TI - Digital pen-based telemonitoring of elderly heart failure patients. AB - Considering that a majority of elderlies are non-users of computers and Internet we developed a telemonitoring system for elderly heart failure (HF) home care patients based on digital pen technology - a technology never used before by this patient group. We implemented the system in clinical use in a 13 months long study. Fourteen patients (mean/median age 84 years) with severe HF participated. They accepted the technology and performed daily reports of their health state using the digital pen and a Health Diary form. Via the system the clinicians detected all HF-related deteriorations at an early stage and thereby prevented hospital re-admissions for all patients during the study, implying improved symptom control and large cost savings. PMID- 23920837 TI - Nursing critical patient severity classification system predicts outcomes in patients admitted to surgical intensive care units: use of data from clinical data repository. AB - To examine the Critical Patient Severity Classification System (CPSCS) recorded by nurses to predict ICU and hospital lengths of stay and mortality, data were drawn from patients admitted to 2 surgical intensive care units (SICUs) at a university hospital in Seoul, South Korea in 2010. This retrospective study used a large data set retrieved from the Clinical Data Repository System. Among 1432 patients, the mean grade of CPSCS was 4.9 out of 6, which indicated that the subjects had generally severe conditions. The CPSCS was a statistically significant predictor of ICU and hospital LOS and mortality when patients' demographic characteristics were adjusted. In the era of emphasis on using big data, analysis of nursing assessment data should be evaluated to show importance of nursing contribution to predict patients' clinical outcomes. PMID- 23920838 TI - Construction of the integrated multicentre discharge summary database. AB - We started a multi-year project to collect discharge summaries from multiple hospitals and create a big text database to build a common document vector space, and develop various applications such as the autoselection of the disease. As the first step, we extracted discharge summary from two hospitals. Using a text mining method, we carried out a DPC selection. There was a difference in term structure and number of terms between the discharge summaries from both hospitals. Nevertheless, the selection rate of the disease is resembled closely. PMID- 23920839 TI - Are smartphones comparable to laptops for image diagnosis in teleophthalmology? AB - OBJECTIVE: To assess the reliability and accuracy of smartphones in diagnosing transmitted fundus images in comparison with a laptop. MATERIALS AND METHODS: Fundus images captured with a Topcon NW 200 camera were transferred onto a conventional laptop and a smartphone and given to ophthalmologists for diagnosis. The smartphone and the laptop diagnosis were compared with the actual face to face diagnosis statistically to assess their diagnostic accuracy. RESULTS: Fundus images of 228 eyes of 114 patients (mean age 47 years,73.6% males) were included in the study. 92.5% eyes were correctly diagnosed by both smartphones and laptop. Smartphone analysis revealed 98% sensitivity,57% specificity and kappa value of 0.62 in comparison to laptop, suggessting substantial interrater agreement. CONCLUSIONS: Smartphones are as effective as the laptop in diagnosing fundus pathologies and hold promise for teleophthalmology in future. PMID- 23920840 TI - Gamification strategy on prevention of STDs for youth. AB - Sexually transmitted diseases (STDs) and especially chlamydia is a worrying problem among North-Norwegian youngsters. Gamified web applications should be valued for sexual health education, and thus STDs prevention, for their potential to get users engaged and involved with their healthcare. Aiming to achieve that youngsters become more aware of STDs we have developed "sjekkdeg.no", a gamified web application focused on sexual health targeting North-Norwegian youngsters. Gamification techniques like avatars, achievement-based gifts and social network sharing buttons have been implemented in the site that includes educational content on sexual health and a STDs symptom checker. Preliminary results show that the game-style web app could be useful to encourage users to learn more on sexual health and STDs and thus changing their risky behaviors and preventing sexually transmitted diseases. PMID- 23920841 TI - Challenges in predicting health needs and disease patterns - a case study on the implementation of an electronic hospital separation record in Sri Lanka. AB - This paper presents analysis and insights arising from the pilot implementation of a national electronic hospital separation record system in Sri Lanka. The paper reveals that while a successful technical implementation has been achieved, numerous socio-technical challenges remain. The paper provides a tangible example of the difficulties faced by developing countries when being encouraged to rush to introduce national e-health systems. Critically, over-confidence in the accuracy, validity and inviolability of electronic data poses real challenges for local and national decision-making around prediction of disease patterns and health needs. PMID- 23920842 TI - Use of controlled vocabularies to improve biomedical information retrieval tasks. AB - The high heterogeneity of biomedical vocabulary is a major obstacle for information retrieval in large biomedical collections. Therefore, using biomedical controlled vocabularies is crucial for managing these contents. We investigate the impact of query expansion based on controlled vocabularies to improve the effectiveness of two search engines. Our strategy relies on the enrichment of users' queries with additional terms, directly derived from such vocabularies applied to infectious diseases and chemical patents. We observed that query expansion based on pathogen names resulted in improvements of the top precision of our first search engine, while the normalization of diseases degraded the top-precision. The expansion of chemical entities, which was performed on the second search engine, positively affected the mean average precision. We have shown that query expansion of some types of biomedical entities has a great potential to improve search effectiveness; therefore a fine tuning of query expansion strategies could help improving the performances of search engines. PMID- 23920843 TI - The use of a mathematical model in the adoption of an integrated EHR system. AB - The development of healthcare information systems is broadly considered a promising strategy to ensure, enhance and deliver of quality patient services, thus improving the healthcare economic sustainability [1]. However, their systematic evaluation needs to implement economic evaluation models that can help decision makers to determine a feasible and suitable analysis of the impact of an information system in the appropriate healthcare setting [2]. Aim of this paper is to define a mathematical model to provide an "ex-ante" measure of adequacy and significance in the adoption process of Electronic Healthcare Records (EHRs). In particular, the model establishes how different subjects (General Practitioners, GPs and patients) are involved in the testing process and how the resources provided can be invested to find out the most suitable intervention strategies. PMID- 23920844 TI - A maturity model to deliver a national shared medications system, options, practice, and pitfalls. AB - In July 2012 Australia launched the Personally Controlled electronic Health Record (PCEHR). This structured record allows health related information to be shared between providers as well as between providers and consumers. The next big challenge in delivering value for consumers is to use the medicines information distributed throughout the record in a way that allows better medications management at all levels. This poster points to the design and usability challenges being dealt with in that process during a national roll out and proposes a maturity model to accelerate the delivery of shared medication records. It is suggested that this model will have relevance in other jurisdictions. PMID- 23920845 TI - An efficacy driven approach for medication recommendation in type 2 diabetes treatment using data mining techniques. AB - We demonstrate how data mining techniques can help recommend effective medications when physicians need to control the glucose level of patients with type 2 diabetes. We first identify the factors that may affect physicians' medication decisions and then develop a patient-similarity based approach to automatically recommend medications for a patient with the specific condition so that his blood glucose level (measured by HbA1C value) can be well controlled. The approach is validated through experiments on real data sets and compared with the recommendations by following a clinical guideline. PMID- 23920846 TI - Model-based query language for analyzing clinical processes. AB - Nowadays large databases of clinical process data exist in hospitals. However, these data are rarely used in full scope. In order to perform queries on hospital processes, one must either choose from the predefined queries or develop queries using MS Excel-type software system, which is not always a trivial task. In this paper we propose a new query language for analyzing clinical processes that is easily perceptible also by non-IT professionals. We develop this language based on a process modeling language which is also described in this paper. Prototypes of both languages have already been verified using real examples from hospitals. PMID- 23920847 TI - Development of the regional EPR and PACS sharing system on the infrastructure of cloud computing technology controlled by patient identifier cross reference manager. AB - A Newly developed Oshidori-Net2, providing medical professionals with remote access to electronic patient record systems (EPR) and PACSs of four hospitals, of different venders, using cloud computing technology and patient identifier cross reference manager. The operation was started from April 2012. The patients moved to other hospital were applied. Objective is to show the merit and demerit of the new system. PMID- 23920848 TI - Evaluating the impact of a mobile oral telemedicine system on medical management and clinical outcomes of patients with complicated oral lesions in Botswana. AB - Mobile telemedicine, which involves the use of cellular phone telecommunications to facilitate exchange of information between parties in different locations to assist in the management of patients, has become increasingly popular, particularly in resource-limited settings. In Botswana, small studies of mobile telemedicine programs suggest access to these services positively affect patients, but these programs' impact is difficult to capture given limitations of baseline and comparative data. Our observational study uses each patient receiving mobile oral telemedicine services in Botswana as his/her own control to assess the impact of these services on his/her diagnosis and management plan. At month 5 of 12 total, preliminary analysis of eligible cases (n = 27) reveals management plan discordance between clinicians submitting cases and the specialist was 68.0% (17/25), suggesting that telemedicine can result in significant changes in management of patients. PMID- 23920849 TI - An automated routine childhood immunization approach using openEHR. AB - This project studies a working but manual immunization system in place in Pakistan, subject to concerns such as poor record-keeping, reaching targeted children and unavailability of latest census. We propose an openEHR-based solution, called Light-weight Electronic Traceable and Updatable System (LETUS), which aims at increasing childhood immunization coverage and traceability. Two key modules of the solution include: (1) a service that collects the data from the immunization workers, computes population estimates for particular regions, and creates alerts if the ratio of vaccinations over population in a region falls outside a certain range (over or under), and (2) several "thin client" modules where workers can enter their collected data and receive feedback about the current coverage in their region. The proposed software system can be integrated into existing regional immunization registry systems, and run on the servers of a local health agency to ensure timely reporting. Within each immunization registry systems, children data is sharable by applying openEHR approach. This solution will gradually replace the current record keeping process by employing smart phone applications and web services. PMID- 23920850 TI - Alumni's perception of public health informatics competencies: lessons from the Graduate Program of Public Health, Faculty of Medicine, Universitas Gadjah Mada, Indonesia. AB - Public health informatics has been defined as the systematic application of information and computer science and technology to public health practice, research, and learning [1]. Unfortunately, limited reports exist concerning to the capacity building strategies to improve public health informatics workforce in limited-resources setting. In Indonesia, only three universities, including Universitas Gadjah Mada (UGM), offer master degree program on related public health informatics discipline. UGM started a new dedicated master program on Health Management Information Systems in 2005, under the auspice of the Graduate Program of Public Health at the Faculty of Medicine. This is the first tracer study to the alumni aiming to a) identify the gaps between curriculum and the current jobs and b) describe their perception on public health informatics competencies. We distributed questionnaires to 114 alumni with 36.84 % response rate. Despite low response rate, this study provided valuable resources to set up appropriate competencies, curriculum and capacity building strategies of public health informatics workforce in Indonesia. PMID- 23920851 TI - Development and clinical study of mobile 12-lead electrocardiography based on cloud computing for cardiac emergency. AB - To improve emergency services for accurate diagnosis of cardiac emergency, we developed a low-cost new mobile electrocardiography system "Cloud Cardiology(r)" based upon cloud computing for prehospital diagnosis. This comprises a compact 12 lead ECG unit equipped with Bluetooth and Android Smartphone with an application for transmission. Cloud server enables us to share ECG simultaneously inside and outside the hospital. We evaluated the clinical effectiveness by conducting a clinical trial with historical comparison to evaluate this system in a rapid response car in the real emergency service settings. We found that this system has an ability to shorten the onset to balloon time of patients with acute myocardial infarction, resulting in better clinical outcome. Here we propose that cloud-computing based simultaneous data sharing could be powerful solution for emergency service for cardiology, along with its significant clinical outcome. PMID- 23920852 TI - Evaluating documentation of dietetic care in Swedish medical records. AB - An adequate documentation in medical records is essential for patient safety and high quality care. The aim of this study was to evaluate documentation by dietitians in Swedish medical records. A retrospective audit of147 dietetic notes in electronic medical records was performed. The audit focused at documentation of essential parts of the dietetic care, as well as other quality aspects such as lingual clarity and structure of the documentation. The nutrition intervention showed to be the most documented part of dietetic care. However, the audit showed that several important parts of nutrition care were poorly documented, for instance nearly half of the audited records had no clear nutrition problem documented, and in most of the records, the goal of nutrition intervention was missing. The study shows that Swedish dietitians need to improve documentation in medical records, as a suggestion by implementing a more structured documentation model. PMID- 23920853 TI - Mobility and health information searches - a Swedish perspective. AB - Today the first point of contact between a patient and health care is often an internet health portal - not a human. There is also a trend towards increased use of mobile devices for internet searching. We present a study of the use of mobile vs non-mobile devices when accessing the main Swedish official health portal. Our findings indicate that there is a difference in not only when people search for health information, but also the type of information searched for using different devices. We conclude that further analysis is needed to understand these differences, and consequently that the same portal solution may not suit both mobile and non-mobile health information seekers. PMID- 23920854 TI - Query engine optimization for the EHR4CR protocol feasibility scenario. AB - An essential step when recruiting patients for a Clinical Trial (CT) is to determine the number of patients that satisfy the Eligibility Criteria (ECs) for that trial. An innovative feature of the Electronic Health Records for Clinical Research (EHR4CR) platform is that when automatically determining patient counts, it also allows the user to view counts for subsets of the ECs. This is helpful because some combinations of ECs may be so restrictive that they yield very few or zero patients. If we wanted to show all possible combinations of ECs, the number of queries we would have to execute would be of 2n, where n is the total number of ECs. Assuming that an average study has between 20 and 30 ECs, the program would have to execute between 220 (1,048,576) and 230 (1,073,741,824) queries. This is not only computationally expensive but also impractical to visualise. The purpose of our research is to reduce possible combinationsto a manageable number. PMID- 23920855 TI - The development of a decision support system of vocational counseling for people with disabilities. AB - After a disability occurs, vocational rehabilitation is essential for promoting return to society and improving quality of life. To facilitate vocational rehabilitation, an effective counseling by human expert is essential. However, the number of the experts is not many. Thus, people with disabilities (PWD) have had difficulty in having proper vocational consultation service. To mitigate this problem, this study aims at developing a decision support system (DSS) to recommend appropriate jobs to PWD based on their characteristics. For doing this, the experts in disabilities, occupational research, and information systems participated in building the logic of the system. The DSS for scientific and quantitative vocational counseling enables job counselors to recommend appropriate occupations considering PWDs' characteristics. PMID- 23920856 TI - Development and maintenance of a controlled vocabulary via an electronic collaborative platform. AB - The development of electronic health records and clinical information systems has been progressing at a quickened pace in recent years. With such change, the use of standard vocabulary has aroused much interest. However, classification code sets are developed for their distinctive purposes, no single vocabulary set could satisfy the needs of all specialties; moreover, local customization would be inevitable. This poster describes how a controlled vocabulary with contribution from frontline clinicians was set up in Hong Kong Hospital Authority (HA). The adoption of an electronic maintenance portal with collaboration of representatives from all institutions would also be discussed. The use of such table has helped to maintain the interoperability of captured data between departments, specialties and institutions. PMID- 23920857 TI - Exploring barriers for health visitors' adaption of the Danish children's database. AB - Denmark has unique health informatics databases such as "The Children's Database" (CDB), which since 2009 has held data on all Danish children from birth until 17 years of age. In the current set-up a number of potential sources of error exist both technical and human - which means that the data is flawed. The objective of this paper is both to clarify errors in the database and to enlighten the underlying mechanisms causing these errors. This is done through an ethnographic study using participant observations, interviews and workshops. Errors are documented through statistical analysis. The data show redundant records. This redundancy can be explained by multiple transmissions conducted by end users or systems, or a lack of validation methods in the National CDB. In our results three types of cases are presented: from health visitors at school, from health visitors visiting families and from health visitors at central health offices. PMID- 23920858 TI - Comparison of procedure coding systems for level 1 and 2 hospitals in South Africa. AB - The ability of three procedure coding systems to reflect the procedure concepts extracted from patient records from six hospitals was compared, in order to inform decision making about a procedure coding standard for South Africa. A convenience sample of 126 procedure concepts was extracted from patient records at three level 1 hospitals and three level 2 hospitals. Each procedure concept was coded using ICPC-2, ICD-9-CM, and CCSA-2001. The extent to which each code assigned actually reflected the procedure concept was evaluated (between 'no match' and 'complete match'). For the study sample, CCSA-2001 was found to reflect the procedure concepts most completely, followed by ICD-9-CM and then ICPC-2. In practice, decision making about procedure coding standards would depend on multiple factors in addition to coding accuracy. PMID- 23920859 TI - Isosemantic rendering of clinical information using formal ontologies and RDF. AB - The generation of a semantic clinical infostructure requires linking ontologies, clinical models and terminologies [1]. Here we describe an approach that would permit data coming from different sources and represented in different standards to be queried in a homogeneous and integrated way. Our assumption is that data providers should be able to agree and share the meaning of the data they want to exchange and to exploit. We will describe how Clinical Element Model (CEM) and OpenEHR datasets can be jointly exploited in Semantic Web environments. PMID- 23920860 TI - Use of mobile devices in the emergency department. AB - Electronic health records (EHRs) are increasingly being used in health care systems, hospitals, and clinics throughout North America. Over the past several years emergency departments (ED) have increasingly become more computerized. As part of a trend towards computerization of EDs, we have seen the introduction of handheld computers, tablets, and Smartphones to provide health professionals access to patient information and decision support. In this paper we outline the current state of the research in using mobile devices in the ED. Our findings suggest there is very little research evidence that supports the use of mobile devices in the ED and more research is needed to better understand and optimize their use. PMID- 23920861 TI - Telepulmonology in the Netherlands: effect on quality and efficiency of care. AB - In telepulmonology a general practitioner (GP) digitally consults a local pulmonologist. This study assessed the effect of telepulmonology on quality and efficiency of care. Efficiency of care was measured as the percentage of prevented physical referrals. Quality of care was measured using 5 indicators. Thirty-one percent of the TelePulmonology Consultations (TPCs) were sent to prevent a physical referral, the other TPCs were sent to ask for advice of the pulmonologist. Sixty-eight percent of the TPCs sent to prevent a physical referral indeed prevented a physical referral. Eighteen percent of the TPCs sent for advice resulted in a physical referral on advice of the pulmonologist. These patients would not have been referred without telepulmonology. PMID- 23920862 TI - Toward image analysis and decision support for ultrasound technology. AB - Ultrasound is a low cost and efficient method of detecting diseases and abnormalities in the body. Yet there is a lack of precision and reliability associated with the technology, partly due to the operator dependent nature of ultrasound scanning. When scanning is performed to an agreed protocol, ultrasound has been shown to be highly reliable. This research aims to minimize these limitations that arise during ultrasound training, scanning and reporting by developing and evaluating an image analysis and decision support system that can aid the decision making process. We hypothesize that this intervention will likely increase the role of ultrasound in diagnosis when compared with other imaging technologies, particularly in low resource settings. PMID- 23920863 TI - PathGuide - model-based generation of guideline-compliant pathways for the use in different hospital information systems. AB - Clinical guidelines and clinical pathways are accepted instruments for quality assurance and process optimization. Defining a standardized patient treatment for a specific disease clinical guidelines provide evident medical knowledge for diagnostic and therapeutic issues in form of narrative recommendations. Clinical pathways offer process-like descriptions defining daily diagnostic and treatment procedures. The use of evident knowledge (in form of clinical guidelines) during pathway development is highly recommended. But the transfer of unstructured recommendations to care processes (clinical pathways) is not straightforward. This article proposes a model-based approach to support the development of guideline-compliant pathways and focuses their deployment into different target systems. Especially HIS (hospital information system) are considered as this is the critical system for managing patient care processes in the hospital. So the results of latest research provided by clinical guidelines are implemented into daily practice and therefore improve patient care. PMID- 23920864 TI - Design and implementation of a shared treatment plan in a federated health information exchange. AB - The poster presents the design and implementation of a shared treatment plan for providing unified views of medications for professionals and patients as a new added-value service on the regional healthcare network "e-toile". Strategies for integrating this service with other institutions infrastructures are also presented. PMID- 23920865 TI - Development of digital dashboard system for medical practice: maximizing efficiency of medical information retrieval and communication. AB - It is reported that digital dashboard systems in hospitals provide a user interface (UI) that can centrally manage and retrieve various information related to patients in a single screen, support the decision-making of medical professionals on a real time basis by integrating the scattered medical information systems and core work flows, enhance the competence and decision making ability of medical professionals, and reduce the probability of misdiagnosis. However, the digital dashboard systems of hospitals reported to date have some limitations when medical professionals use them to generally treat inpatients, because those were limitedly used for the work process of certain departments or developed to improve specific disease-related indicators. Seoul National University Bundang Hospital developed a new concept of EMR system to overcome such limitations. The system allows medical professionals to easily access all information on inpatients and effectively retrieve important information from any part of the hospital by displaying inpatient information in the form of digital dashboard. In this study, we would like to introduce the structure, development methodology and the usage of our new concept. PMID- 23920866 TI - Searching for document contents in an IHE-XDS EHR architecture via archetype based indexing of document types. AB - The shared EHR (electronic health record) system architecture IHE XDS is widely adopted internationally. It ensures a high level of data privacy via distributed storage of EHR documents. Its standard search capabilities, however, are limited; it only allows a retrieval of complete documents by querying a restricted set of document metadata. Existing approaches that aim to extend XDS queries to document contents typically employ a central index of document contents. Hereby they undermine XDS' basic characteristic of distributed data storage. To avoid data privacy concerns, we propose querying EHR contents in XDS by indexing document types based on Archetypes instead. We successfully tested our approach within the ISO/EN 13606 standard. PMID- 23920867 TI - On a two-level multiclassifier system with error correction applied to the control of bioprosthetic hand. AB - The paper presents an advanced method of recognition of patient's intention to move of hand prosthesis. The proposed method is based on two-level multiclassifier system (MCS) with homogeneous base classifiers dedicated to EEG, EMG and MMG biosignals and with combining mechanism using a dynamic ensemble selection (DES) scheme and probabilistic competence function. Additionally, the feedback signal derived from the prosthesis sensors is applied to the correction of classification algorithm. The performance of MCS with proposed competence function and combining procedure were experimentally compared against three benchmark MCSs using real data concerning the recognition of six types of grasping movements. The systems developed achieved the highest classification accuracies demonstrating the potential of multiple classifier systems with multimodal biosignals for the control of bioprosthetic hand. PMID- 23920868 TI - From data mining rules to medical logical modules and medical advices. AB - Using data mining in collaboration with Clinical Decision Support Systems adds new knowledge as support for medical diagnosis. The current work presents a tool which translates data mining rules supporting generation of medical advices to Arden Syntax formalism. The developed system was tested with data related to 2326 births that took place in 2010 at the Bega Obstetrics - Gynaecology Hospital, Timisoara. Based on processing these data, 14 medical rules regarding the Apgar score were generated and then translated in Arden Syntax language. PMID- 23920869 TI - User requirements for interruption management in mobile communications in hospitals. AB - In hospitals, mobile communication devices increase the occurrence of inappropriate interruptions during clinical task performance. These interruptions have been related to decreased quality of clinical care. User requirements were elicited using a scenario based approach. The results present insights into user requirements for an interruption management system for hospitals. Hospital workflow protocols were identified as a major source of interruptions. Many suggestions for managing these interruptions related to improving workflow using IT. We have shown that even though the hospital is an exceptionally demanding environment, the user requirements for interruption management concur with earlier findings in the broader fields of context aware interruption management and computer supported cooperative work. PMID- 23920871 TI - Applying UML connectors for arranging medical archetypes into a knowledge base. PMID- 23920870 TI - Health information system model for monitoring treatment and surveillance for leprosy patients in indonesia (case study in Pekalongan District, Central Java, Indonesia). AB - After India and Brazil, Indonesia has the third highest incidence/prevalence of leprosy in the world. Every year thousands of new cases and case with grade-2 disability are reported and, while the recovery rate lingers only 80-90 %. Therefore, more than 10 % of leprosy patients drop out of treatment and can be a source of new infections in the community. Our research was aimed at determining apparent difficulties in the leprosy control program as well as how a health information system (HIS) could assist the Indonesian leprosy control program. We used qualitative method with deep interview and observation of document. One of the difficulties which the Indonesian leprosy control program faces is discontinuity of patient's data due to rotating staff as well as the treatment monitoring and queries patients which should be monitored after treatment has ceased. Technology implementation is feasible through short message service (sms) reminders and web base applications. The leprosy control program urgently needs to implement continuous monitoring and recording of patients because of the particular characteristics of this contagious disease. PMID- 23920872 TI - Detecting software failures in the MAUDE database: a preliminary analysis. AB - The MAUDE (Manufacturer and User facility Device Experience) was analyzed to identify challenges in detecting software failure causing Medical Device (MD) adverse events. PMID- 23920873 TI - Enhancing research capacity of African institutions through social networking. AB - Traditionally, participation of African researchers in top Biomedical Informatics (BMI) scientific journals and conferences has been scarce. Looking beyond these numbers, an educational goal should be to improve overall research and, therefore, to increase the number of scientists/authors able to produce and publish high quality research. In such scenario, we are carrying out various efforts to expand the capacities of various institutions located at four African countries - Egypt, Ghana, Cameroon and Mali - in the framework of a European Commission-funded project, AFRICA BUILD. This project is currently carrying out activities such as e-learning, collaborative development of informatics tools, mobility of researchers, various pilot projects, and others. Our main objective is to create a self-sustained South-South network of BMI developers. PMID- 23920874 TI - Integrating population- and patient-level data for secondary use of electronic health records to study overweight and obesity. AB - We combined patient-level clinical data derived from the Electronic Health Record (EHR) with area-level environmental and socioeconomic data to study factors independently associated with overweight and obesity. Our multinomial logistic regression model showed that area-level factors such as farmers' markets, grocery stores and percent college-educated at the zip code level were significantly associated with the outcomes. However, mismatch in the granularity of community and clinical data limited us in creating a discriminatory model. While these results are promising, they reveal challenges that must be overcome in order to maximize secondary use of EHR data to further explore population health status. PMID- 23920875 TI - Standardizing drug adverse event reporting data. AB - Normalizing data in the Adverse Event Reporting System (AERS), an FDA database, would improve the mining capacity of AERS for drug safety signal detection. In this study, we aim to normalize AERS and build a publicly available normalized Adverse drug events (ADE) data source.he drug information in AERS is normalized to RxNorm, a standard terminology source for medication. Drug class information is then obtained from the National Drug File - Reference Terminology (NDF-RT). Adverse drug events (ADE) are aggregated through mapping with the PT (Preferred Term) and SOC (System Organ Class) codes of MedDRA. Our study yields an aggregated knowledge-enhanced AERS data mining set (AERS-DM). The AERS-DM could provide more perspectives to mine AERS database for drug safety signal detection and could be used by research community in the data mining field. PMID- 23920876 TI - Development of a web-based observational tool for detecting intravenous medication errors with smart infusion pumps. AB - Computerized smart infusion pumps have been widely implemented to decrease the rate of intravenous (IV) medication errors in hospitals. However, these devices have not always achieved their potential, and important IV errors still persist. Findings from a previous study [1] that assessed the frequency of IV medication errors and the impact of smart infusion pumps identified major issues related to use of smart infusion pumps in a single facility, but generalizability of these results is uncertain. Additionally, lack of standardized methodology for measuring these errors remains an issue. In this study, we developed an observational tool to capture IV medication errors through iterative participatory design with interdisciplinary experts and then tested the tool by using incident cases regarding smart pump errors. We found that the tool could capture all smart infusion pump errors and is ready for testing for use as standard data collection tool in different hospital settings. PMID- 23920877 TI - Physicians searching the web for medical question answering: a European survey and local user studies. AB - Medical professionals frequently face unmet information needs during their daily routines. We investigated the use of web search engines through a large-scale survey including 500 European physicians, as well as local user testing that observed the search behavior of physicians when facing clinical questions. We identified several differences in the search requirements and behaviors of different groups of physicians based on level of qualification and level of specialization. We also found user testing a valuable source of information about the search preferences of medical professional. The survey and user tests we conducted are among the largest and most detailed that have been conducted in this domain. PMID- 23920878 TI - Analysis of the interface and data transfer from ICU to normal wards in a German University Hospital. AB - Typically general wards and intensive care units (ICU) have very different labor organizations, structures and IT-systems in Germany. There is a need for coordination, because of the different working arrangements. Our team investigated the interface between ICU and general ward and especially the respective information transfer in the University hospital in Erlangen (Bavaria, Germany). The research team used a combination of interviews, observations and the analysis of transfer records and forms as part of a methodical triangulation. We identified 41 topics, which are discussed or presented in writing during the handover. In a second step, we investigate the requirements of data transmission in expert interviews. A data transfer concept from the perspective of the nurses and physicians was developed and we formulated recommendations for improvements of process and communication for this interface. Finally the data transfer concept was evaluated by the respondents. PMID- 23920879 TI - ICT and mobile health to improve clinical process delivery. a research project for therapy management process innovation. AB - The volume and the complexity of clinical and administrative information make Information and Communication Technologies (ICTs) essential for running and innovating healthcare. This paper tells about a project aimed to design, develop and implement a set of organizational models, acknowledged procedures and ICT tools (Mobile & Wireless solutions and Automatic Identification and Data Capture technologies) to improve actual support, safety, reliability and traceability of a specific therapy management (stem cells). The value of the project is to design a solution based on mobile and identification technology in tight collaboration with physicians and actors involved in the process to ensure usability and effectivenes in process management. PMID- 23920880 TI - Do electronic health records help undergraduate health informatics students to develop health informatics competencies? AB - The purpose of this paper is to determine the effects of hands-on exposure to an educational electronic health record (EHR) system upon undergraduate health informatics (HI) student competency development. We undertook a quasi experimental study (i.e. pre-test, post-test design), where students were given the opportunity to do hands-on work with an educational EHR over a 10 week period. HI student competencies were measured pre and post educational EHR exposure. Several HI student competencies improved significantly following hands on work with the EHR. As well, students provided more higher quality case study answerfollowing EHR use. PMID- 23920881 TI - Legal issues among doctors in the implementation of teleconsultation: a study at AIIMS, New Delhi, India. AB - Telemedicine is an essential technology for providing high-quality health care to rural people. Though India has not yet passed any legislation on telemedicine related issues, a beginning has however been made. Guidelines and Standards for Practice of Telemedicine in India have already been recommended by the Ministry of Information Technology, Govt. of India. PMID- 23920882 TI - Requirement analysis for an electronic laboratory notebook for sustainable data management in biomedical research. AB - Sustainable data management in biomedical research requires documentation of metadata for all experiments and results. Scientists usually document research data and metadata in laboratory paper notebooks. An electronic laboratory notebook (ELN) can keep metadata linked to research data resulting in a better understanding of the research results, meaning a scientific benefit [1]. Besides other challenges [2], the biggest hurdles for introducing an ELN seem to be usability, file formats, and data entry mechanisms [3] and that many ELNs are assigned to specific research fields such as biology, chemistry, or physics [4]. We aimed to identify requirements for the introduction of ELN software in a biomedical collaborative research center [5] consisting of different scientific fields and to find software fulfilling most of these requirements. PMID- 23920883 TI - Actualizing a mobile integrated system for geriatric care. AB - Population aging looms over countries all over the world. The social and economic implications of this phenomenon extend beyond the individual person and the immediate family, affecting broader society and the global community in profound ways. Aging populations increase pressure on already over-burdened public health care services and expenditures. To address this impending predicament, many health care providers and countries have turned to technological solutions. The near-ubiquity of mobile devices entails that mHealth will rapidly become a key component of technologically-enabled health care delivery services. This poster presents research and engineering challenges for a sustainable ICT solution that supports information exchange for mobile geriatric care. PMID- 23920884 TI - Social network integration of the ICD11 revision platform. AB - Classification revision and update can be defined as a social experience, with the participating community of experts behaving like a social network. ICD11 is being revised using an innovative web based process, for which we envisioned also tools for social platforms integration. The present poster preliminarily describes the Facebook tools developed for soliciting expert and participation in the ICD11 revision process. PMID- 23920885 TI - Mobile-supported life charting for bipolar patients - user requirements study. AB - It is assumed that bipolar disorder patients can benefit from monitoring their mood, sleep, medicine intake and behavior which could be both done by patients themselves and in cooperation with health care professionals. This study aims at understanding what is required from a computerized system, as seen from the view of therapists and the patients, and how the newer mobile technologies (smart phones and tablets) can be utilized to support development of such a system. The study focuses on several existing solutions available either freely or on the market. Then these solutions are evaluated by both patients and medical professionals as a part of the system requirements study to be used in a new system development that will utilize mobile technologies to support the performance and patient outcomes. PMID- 23920886 TI - Can we bridge the definition diversity in healthcare-associated infection surveillance? From IT-supported surveillance to IT-supported infection prevention and control. AB - Expectations and requirements of the surveillance of healthcare-associated infections (HAIs) trigger a growing differentiation of HAI surveillance approaches. In an attempt to bridge this diversity of definitions and to serve the needs of different user groups, we have enhanced MONI (identification, monitoring, and reporting of nosocomial infections) not only to create better reports, but also to output overviews on complex clinical matters, as well as to generate alerts and reminders for the clinicians' bedside work. PMID- 23920887 TI - Governance of extended lifecycle in large-scale eHealth initiatives: analyzing variability of enterprise architecture elements. AB - The governance of large eHealth initiatives requires traceability of many requirements and design decisions. We provide a model which we use to conceptually analyze variability of several enterprise architecture (EA) elements throughout the extended lifecycle of development goals using interrelated projects related to the national ePrescription in Finland. PMID- 23920888 TI - Clinical similarities: an innovative approach for supporting medical decisions. AB - Taking decisions in the medical domain is a very complex task. The context is strongly affected by uncertainty and the possible undesired side effects of the treatments have to be carefully considered. Currently, these decisions are based on the physician's own experience and the evidences of the published literature, according, when available, with the philosophy of Evidence Based Medicine. The main issues of this approach are that the own experience can be different, and the results in the literature are sometimes contrasting. For helping physicians while taking medical decisions, we are proposing an innovative approach based on the idea of the clinical similarity. Given a set of clinical variables, the proposed approach selects patients that are similar, presenting to the physician the respective decisions taken and the corresponding clinical effects. PMID- 23920889 TI - Behavioral support to parents through a cellular-phone website that provides the degree of urgency for medical attention of a child. AB - When a child suddenly falls ill, the child's family assesses if medical attention is required immediately. However, even in case of minor illnesses, it is not possible to approach a medical institution after consultation hours, and the burden on doctors from overtime-emergency medical examinations becomes a social problem. This study proposes the use of a cellular-phone website that provides information about the degree of urgency for medical attention to parents, who can choose the child's symptoms on the cellular-phone website regardless of the time or place. Therefore, through this study, parents experimentally evaluated the cellular-phone website; also, the effectiveness of this method as a behavioral support for parents was also evaluated. When an advice about the degree of urgency for a child's treatment was taken from the cellular-phone website, the parents felt relieved. Thus, the distress faced by pediatricians may change completely. PMID- 23920890 TI - Clinical overview: a framework for analysis. AB - In this presentation, we investigate concepts and theories for analysing how healthcare professionals achieve overview of patient cases. By 'overview' we mean the situation in which a healthcare professional with sufficient certainty and in concrete situations knows how to proceed based on available information upon a patient. Achieving overview is central for the efficient and safe use of healthcare IT systems, and for the realization of the potential improvements of healthcare that are behind investments in such systems. We focus on the theories of decision-making, sensemaking, narratives, ethnomethodology and distributed cognition. Whereas decision-making theory tend to be sequential and normative, we find the concept of 'functional deployment' in sensemaking theory, 'emplotment' in narrative theory, the focus on 'members' methods' in ethnomethodology and the inclusion of 'computational artifacts' in distributed cognition helpful. PMID- 23920891 TI - A vision for enhancing multimorbid care using clinical decision support systems. AB - There has been a substantial increase in Multimorbidity, worldwide. Extensive empirical research has found that General Practitioners (GPs) often feel overwhelmed when dealing with such patients [1]. While clinical decision support systems (CDSS) are effective at reducing clinical decision errors and improving healthcare processes across diverse settings [2], the use of CDSS within multimorbidity care is under investigated. This study employs a multi-method approach to examine how well CDSS currently support Irish GPs when dealing with multimorbid patients. The findings uncover a number of inadequacies, including: a lack of provision of integrated medical guidelines for multiple chronic diseases within current CDSS; and an inability to centralise the patient rather than the disease using such systems. This research underlines the need for further research into CDSS for multimorbidity and highlights key issues that must be addressed in order to improve how CDSS support the care of multimorbid patients. PMID- 23920892 TI - Sentiment analysis on smoking in social networks. AB - Online social networks play a vital role in daily life to share the opinions or behaviors on different topics. The data of social networks can be used to understand health-related behaviors. In this work, we used Twitter status updates to survey of smoking behaviors among the users. We introduce approach to classify the sentiment of smoke-related tweets into positive and negative tweets. The classifier is based on the Support Vector Machines (SVMs) and can achieve high accuracy up to 86%. PMID- 23920893 TI - Electronic teaching materials for inter-professional education in a college of medical professionals. AB - In order to promote the utilization of digital clinical information among medical professionals, an education program and electronic teaching materials involving fictitious model patients were developed for students in a health and welfare college. The purposes of this program were for students to learn the role of each medical professional and to understand the medical records written by each medical staff member in interdisciplinary medicine (a collaborative approach to medicine). The materials for fictitious patients, including medical records, study results, medical images and the associated documents, were stored in a database on a virtual private network. The electronic medical records were easily modified according to the specialty of the students in each class. Fictional medical records of patients with lacunar infarction, fracture of the distal radius, fracture of the femur, diabetes mellitus and breast cancer were generated and evaluated in inter-professional education classes. PMID- 23920894 TI - Information architecture considerations in designing a comprehensive tuberculosis enterprise system in Western Kenya. AB - Kenya ranks among the twenty-two countries that collectively contribute about 80% of the world's Tuberculosis cases; with a 50-200 fold increased risk of tuberculosis in HIV infected persons versus non-HIV hosts. Contemporaneously, there is an increase in mobile penetration and its use to support healthcare throughout Africa. Many are skeptical that such m-health solutions are unsustainable and not scalable. We seek to design a scalable, pervasive m-health solution for Tuberculosis care to become a use case for sustainable and scalable health IT in limited resource settings. We combine agile design principles and user-centered design to develop the architecture needed for this initiative. Furthermore, the architecture runs on multiple devices integrated to deliver functionality critical for successful Health IT implementation in limited resource settings. It is anticipated that once fully implemented, the proposed m health solution will facilitate superior monitoring and management of Tuberculosis and thereby reduce the alarming statistic regarding this disease in this region. PMID- 23920895 TI - E-record - access to all Danish public health records. AB - E-Record (in Danish: E-Journal) is at National repository of record information from all public hospitals in Denmark. It has been introduced in 2007 and today it is a backbone for interchanging EHR-information across hospitals. It is not a national EHR, but a read-only repository that supplements the local EHR information with national information. Both GP's and patients/citizens can access the information due to improved patient empowerment. Almost 50.000 different clinicians at hospitals and almost 300.000 patients/citizens have used E-Record in 2012. E-Record contains information about ICD-10 diagnosis, Pro-cedures, Notes and Discharge letters and cave information. PMID- 23920896 TI - Development and evaluation of an electronic health record configuration and customization laboratory course for clinical informatics students. AB - OBJECTIVES: There is a need for informatics educational programs to develop laboratory courses that facilitate hands-on access to an EHR, and allow students to learn and evaluate functionality and configuration options. This is particularly relevant given the diversity of backgrounds of informatics students. METHODS: We implemented an EHR laboratory course that allowed students to explore an EHR in both inpatient and outpatient clinical environments. The course focused on specific elements of the EHR including order set development, customization, clinical decision support, ancillary services, and billing and coding functionality. Students were surveyed at the end of the course for their satisfaction with the learning experience. RESULTS AND CONCLUSIONS: We detailed challenges as well as lessons learned after analyzing student evaluations of this course. Features that promote the successful offering of an online EHR course, include (1) using more than one EHR to allow students to compare functionalities, (2) ensuring appropriate course calibration, (3) countering issues specific to EHR usability, and (4) fostering a fertile environment for rich online conversations are discussed. PMID- 23920897 TI - BabySTEPS: a sugar tracking electronic portal system for gestational diabetes. AB - Gestational diabetes is a condition occurring in up to 18% [1] of pregnant women that results in an increase in blood glucose levels due to the body's inability to produce sufficient insulin given the additional needs of the baby, and/or hormonal changes that lower the body's sensitivity to insulin. If left untreated, the growing baby may become too large, increasing the risk of injury to the mother and baby during delivery. Controlling blood glucose can be a challenging task, especially for women with no previous experience and who may have unhealthy diets. An opportunity exists to further encourage compliance by providing patients electronic access to data generated during their pregnancy. Previous studies have shown the potential of portals for managing general diabetes [2], but no work has targeted glucose control in pregnant women. We present BabySTEPS (Sugar Tracking Electronic Portal System), a patient portal focused on engaging women with gestational diabetes that provides personalized feedback with the goal of reducing complications at birth and subsequent medical problems resulting from poor glucose control. PMID- 23920898 TI - Patient recruitment workflow with and without a patient recruitment system. AB - In clinical trials (CTs), the process of patient recruitment (PR) is one of the main risk factors, as almost half of all trial delays are caused by problems in PR. To our knowledge, no publication in this field describes the process of PR. Therefore, weak spots and potential benefits cannot be identified. By interviewing six domain experts and modeling the workflow in a standardized way, we describe the actors, tasks and tools within PR. We compare the current workflow with Patient Recruitment System (PRS)-supported PR. The identification of eligible participants is the most complex part, but adding a PRS simplifies it by automating repetitive tasks and taking work off the Investigators' hands. This work contributes to a common understanding of the PR process. PMID- 23920899 TI - Standardized drug and pharmacological class network construction. AB - Dozens of drug terminologies and resources capture the drug and/or drug class information, ranging from their coverage and adequacy of representation. No transformative ways are available to link them together in a standard way, which hinders data integration and data representation for drug-related clinical and translational studies. In this paper, we introduce our preliminary work for building a standardized drug and drug class network that integrates multiple drug terminological resources, using Anatomical Therapeutic Chemical (ATC) and National Drug File Reference Terminology (NDF-RT) as network backbone, and expanding with RxNorm and Structured Product Label (SPL). The network consists of 39,728 drugs and drug classes. We calculated and compared structure similarity for each drug/drug class pair from ATC and NDF-RT, and analyzed constructed drug class network from chemical structure perspective. PMID- 23920900 TI - Experience implementing electronic health records in the antenatal clinic of a teaching and referral hospital in Kenya. AB - INTRODUCTION: Electronic health records (EHRs) are receiving a lot of attention for their potential to improve care. OBJECTIVE: To develop and implement EHRs in the antenatal clinic (ANC) of a teaching and referral hospital in Western Kenya. RESULTS: A multidisciplinary team developed a phased implementation of EHRs in the ANC as part of a CDC-funded effort to develop and implement primary care EHRs in lower level and referral facilities in Kenya comprising a clinic registration system and initial- and return-visit encounter forms that captured and reported data required for reporting. This was successfully done, the EHR fully implemented in the ANC including a reminder system to enhance adherence to care guidelines. CONCLUSIONS: It is possible to implement EHRs in a referral hospital ANC. PMID- 23920901 TI - Preliminary comparison of mHealth architectures based on MU2 criteria. AB - Mobile Health (MH) is a hot topic in the health IT industry because it can make a big difference in healthcare services. Before adopting Mobile Health technology, however, we must ensure that it provides safe and reliable services to users and it should be evaluated by authoritative criteria. In US, Electronic Health Record (EHR) systems are evaluated through Meaningful Use (MU). Although MU focuses on EHR systems, it can't be thought of without MH. So in this paper we derive proper evaluation criteria for MH from MU criteria and evaluate existing MH architectures that are currently being surveyed in ISO/AWI TR 17522 - Provisions for Health Applications on Mobile/Smart Devices. PMID- 23920902 TI - Synonym-based word frequency analysis to support the development and presentation of a public health quality improvement taxonomy in an online exchange. AB - Word frequency analysis has not been fully explored as an input to public health taxonomy development. We used document analysis, expert review, and user-centered design to develop a taxonomy of public health quality improvement concepts for an online exchange of quality improvement work (www.phqix.org). Online entries were made searchable using a faceted search approach. To present the most relevant facets to users, we analyzed 334 published public health quality improvement documents using word frequency analysis to identify the most prevalent clusters of word meanings. We reviewed the highest-weighted concepts and identified their relationships to quality improvement details in our taxonomy. The meanings were mapped to items in our taxonomy, and presented in order of their weighted percentages in the data. Using this combination of methods, we developed and sorted concepts in the faceted search presentation so that relevant search criteria were accessible to users of the online exchange. Word frequency analysis may be a useful method to incorporate in other taxonomy development and presentationwhen relevant data is available. PMID- 23920903 TI - Developing an acute-physical-examination template for a Tegional EHR system aimed at improving inexperienced physician's documentation. AB - It is well-established that to increase acceptance of electronic clinical documentation tools, such as electronic health record (EHR) systems, it is important to have a strong relationship between those who document the clinical encounters and those who reaps the benefit of digitalized and more structured documentation. [1] Therefore, templates for EHR systems benefit from being closely related to clinical practice with a strong focus on primarily solving clinical problems. Clinical use as a driver for structured documentation has been the focus of the acute-physical-examination template (APET) development in the North Denmark Region. The template was developed through a participatory design where precision and clarity of documentation was prioritized as well as fast registration. The resulting template has approximately 700 easy accessible input possibilities and will be evaluated in clinical practice in the first quarter of 2013. PMID- 23920904 TI - An informatics approach to chronicling the history of IMIA. AB - With the 50th Anniversary of IMIA approaching in 2017, the IMIA Board approved the creation of a Taskforce for compiling materials and writing a history of the organization. As part of the work of the Taskforce, the authors have developed informatics tools, and begun collecting IMIA-related historical materials from its members, while soliciting participation and contributions from those involved in the early days of the organization and its predecessor IFIP-TC4. This poster describes the structure and preliminary contents of the media mining and presentation tools designed at Rutgers University for use by the IMIA History Editorial Board, being constituted to produce the 50th Anniversary publication, as well as an online archive of materials chronicling the evolution of IMIA. A major feature of the data repository is its ability to present different modalities of textual, visual and graphical (timelines, trends) summarizations for the IMIA document collection. It will be augmented with audio material, and will serve as an archival repository for historical research, including software tools for text analysis and extraction of the information entering into the 50th Anniversary volume. PMID- 23920905 TI - CICERO: an emergent conceptual model for onco-EPR systems. AB - Cancer care is one of the most complex, multi-disciplinary, and data-intensive undertakings in all of medicine, which makes it particularly well suited for the application of electronic patient record systems (EPRs) [1]. To assist with a programme of research to establish oncologists' perspectives on the requirements and benefits of EPR systems, a conceptual model for Comprehensive, Integrated, Customised Electronic Record systems for Oncology ("CICERO") is proposed. Preliminary data to refine the model were gathered using an online survey questionnaire and here we present high level emergent themes from initial analyses of the qualitative data. PMID- 23920906 TI - Evaluation of a web-based educational program for women diagnosed with breast cancer: why is the intervention effect absent? AB - To provide accurate and tailored information to women diagnosed with breast cancer a web-based educational program was developed and tested in a randomized controlled trial for impact on health self-efficacy, healthcare participation, and anxiety and depression levels. Multilevel modelling with an intention-to treat analysis revealed no treatment effect on the above-mentioned outcomes. Reasons for the non-identified effect are discussed and raise methodological questions concerning e-health supportive interventions for further research. PMID- 23920907 TI - Key-phrase based classification of public health web pages. AB - This paper describes and evaluates the public health web pages classification model based on key phrase extraction and matching. Easily extendible both in terms of new classes as well as the new language this method proves to be a good solution for text classification faced with the total lack of training data. To evaluate the proposed solution we have used a small collection of public health related web pages created by a double blind manual classification. Our experiments have shown that by choosing the adequate threshold value the desired value for either precision or recall can be achieved. PMID- 23920908 TI - 10x10 comes full circle: Spanish version back to United States in Puerto Rico. AB - The adaptation of the 10x10 certificate program in health information systems for a Puerto Rican audience is described. The 10x10 program was initially developed in the USA by the Oregon Health Sciences University (OHSU), then adapted to Latin America by Hospital Italiano de Buenos Aires. Puerto Rico is in the intersection of the United States and Latin America, in terms of government, health care system, culture and language. Therefore, it seemed reasonable to re-adapt the program back to the USA, in Spanish, taking into account these facts and the experience of the team in delivering blended learning adapted to local needs. Forty professionals from Puerto Rico are currently taking the first version of the course, supported by the Regional Extension Center for Puerto Rico and the US Virgin Islands, and endorsed by the American Medical Informatics Association (AMIA). PMID- 23920910 TI - An approach for message exchange using archetypes. AB - The application of ICT on the whole range of health sector activities, known as e health, can simplify the access to health care services and will only be acceptable for realistic scenarios if it supports efficient information exchange amongst the caregivers and their patients. The aim of this paper is present an approach for message exchange to realistic scenarios. PMID- 23920909 TI - Using a model of parallel distributed processing associated with data mining in the characterization of sexuality in a university population. AB - Using the framework for developing parallel applications Java Parallel Programming Framework were conducted performance analysis of an application for the clustering data by the method of fuzzy logic combined with Gustafson-Kessel algorithm. In addition to running in a distributed environment, for comparative purposes, were also conducted collections of processing time in environments with a single Personal Computer approach. With the results obtained by collecting time of application, there was a statistical analysis to validate the application and the algorithm as well as the use of computational clustering as a way to increase performance applications. PMID- 23920911 TI - Using ISO 25040 standard for evaluating electronic health record systems. AB - Quality of electronic health record systems (EHR-S) is one of the key points in the discussion about the safe use of this kind of system. It stimulates creation of technical standards and certifications in order to establish the minimum requirements expected for these systems. [1] In other side, EHR-S suppliers need to invest in evaluation of their products to provide systems according to these requirements. This work presents a proposal of use ISO 25040 standard, which focuses on the evaluation of software products, for define a model of evaluation of EHR-S in relation to Brazilian Certification for Electronic Health Record Systems - SBIS-CFM Certification. Proposal instantiates the process described in ISO 25040 standard using the set of requirements that is scope of the Brazilian certification. As first results, this research has produced an evaluation model and a scale for classify an EHR-S about its compliance level in relation to certification. This work in progress is part for the acquisition of the degree of master in Computer Science at the Federal University of Pernambuco. PMID- 23920912 TI - Effective healthcare process redesign through an interdisciplinary team approach. AB - Healthcare process redesign is a complex and often high risk undertaking. Typically, there is a limited understanding of the baseline process and often inadequate tools by which to assess it. This can be confounded by narrow redesign team expertise that can result in unanticipated and/or unintended redesign consequences. Interdisciplinary research teams of healthcare, biostatistics, engineering and computer science experts provide broad support for a more effective and safer approach to healthcare process redesign. We describe an interdisciplinary research team focused on medication administration process (MAP)redesign and its achievements and challenges. PMID- 23920913 TI - Inconsistencies between recorded opportunistic infections and WHO HIV staging in western Kenya. AB - Opportunistic infections (OIs) are the main cause of morbidity and mortality among patients with HIV in developing countries. It is therefore critical that accurate diagnoses are made and that they are correctly recorded and managed. We reviewed 200 randomly selected records of clinical encounters with HIV infected pregnant women attending the ante-natal care (ANC) clinic in July 2012 at the Jaramogi Oginga Odinga Teaching and Referral Hospital in Kenya. None of the clients in WHO stage 4 and 2.8% of those in WHO stage 3 had a new OI diagnosis recorded during the clinical encounter. This data suggests current under recording of OIs and the inconsistency between WHO staging and OI diagnosis. Structured methods such as SNOMED CT have the potential to improve complete and accurate recording of OIs which, in turn, enable automatedand accurate WHO staging. PMID- 23920914 TI - Changes in the cardiac rehabilitation workflow process needed for the implementation of a self-management system. AB - E-health interventions are of a growing importance for self-management of chronic conditions. This study aimed to describe the process adaptions that are needed in cardiac rehabilitation (CR) to implement a self-management system, called MyCARDSS. We created a generic workflow model based on interviews and observations at three CR clinics. Subsequently, a workflow model of the ideal situation after implementation of MyCARDSS was created. We found that the implementation will increase the complexity of existing working procedures because 1) not all patients will use MyCARDSS, 2) there is a transfer of tasks and responsibilities from professionals to patients, and 3) information in MyCARDSS needs to be synchronized with the EPR system for professionals. PMID- 23920915 TI - Computational study of the interplay of adhesion and chemotaxis in the cell seeding of tissue engineering scaffolds with incorporated chemoattractants. AB - Cell migration is important in embryogenesis, metastasis and wound healing. Often, morphogenesis involves chemotactic cell movement up or down chemical gradients. We have developed a computational model of a cell suspension in the vicinity of a porous scaffold that incorporates a chemoattractant substance. In order to study the interplay of adhesion and chemotaxis on cell seeding , we developed a computational model of the system and simulated its evolution using a Metropolis Monte Carlo algorithm. We varied the chemotactic strengths of the cells in order to identify the optimal conditions for a rapid and uniform seeding. PMID- 23920916 TI - Safety features and alerts in electronic patient medication record systems used in community pharmacy in England: an exploratory study. AB - Safety features embedded in electronic Patient Medication Record (ePMR) systems alert users about clinical hazards and errors in prescribed medicines during order entry. To date there has been little research about how these systems, their safety features and alerts are used to support practice; and how they are included in work processes in community pharmacies in England, UK. This study aimed to explore stakeholders' views and experiences regarding the safety features and alerts in ePMR systems; and how they might better support pharmacists and their team in practice. PMID- 23920917 TI - Separation of metadata and pixel data to speed DICOM tag morphing. AB - The DICOM information model combines pixel data and metadata in single DICOM object. It is not possible to access the metadata separately from the pixel data. There are use cases where only metadata is accessed. The current DICOM object format increases the running time of those use cases. Tag morphing is one of those use cases. Tag morphing includes deletion, insertion or manipulation of one or more of the metadata attributes. It is typically used for order reconciliation on study acquisition or to localize the issuer of patient ID (IPID) and the patient ID attributes when data from one domain is transferred to a different domain. In this work, we propose using Multi-Series DICOM (MSD) objects, which separate metadata from pixel data and remove duplicate attributes, to reduce the time required for Tag Morphing. The time required to update a set of study attributes in each format is compared. The results show that the MSD format significantly reduces the time required for tag morphing. PMID- 23920918 TI - Developing on-demand secure high-performance computing services for biomedical data analytics. AB - We propose a technical and process model to support biomedical researchers requiring on-demand high performance computing on potentially sensitive medical datasets. Our approach describes the use of cost-effective, secure and scalable techniques for processing medical information via protected and encrypted computing clusters within a model High Performance Computing (HPC) environment. The process model supports an investigator defined data analytics platform capable of accepting secure data migration from local clinical research data silos into a dedicated analytic environment, and secure environment cleanup upon completion. We define metrics to support the evaluation of this pilot model through performance and stability tests, and describe evaluation of its suitability towards enabling rapid deployment by individual investigators. PMID- 23920919 TI - Text mining electronic health records to identify hospital adverse events. AB - Manual reviews of health records to identify possible adverse events are time consuming. We are developing a method based on natural language processing to quickly search electronic health records for common triggers and adverse events. Our results agree fairly well with those obtained using manual reviews, and we therefore believe that it is possible to develop automatic tools for monitoring aspects of patient safety. PMID- 23920921 TI - Development of a SNOMED CT based national medication decision support system. AB - Physicians often lack the time to familiarize themselves with the details of particular allergies or other drug restrictions. Clinical Decision Support (CDS), based on a structured terminology as SNOMED CT (SCT), can help physicians get an overview, by automatically alerting allergy, interactions and other important information. The centralized CDS platform based on SCT, controls Allergy, Interactions, Risk Situation Drugs and Max Dose restrictions by the help of databases developed for these specific purposes. The CDS will respond to automatic web service requests from the hospital or GP electronic medication system (EMS) during prescription, and return alerts and information. The CDS also contains a Physicians Preference Database where the physicians individually can set which kind of alerts they want to see. The result is clinically useful information physicians can use as a base for a more effective and safer treatment, without developing alert fatigue. PMID- 23920920 TI - Piloting a national laboratory electronic programme status reporting system. AB - The NHLS performs close to 4 million CD4 tests per annum for the public sector in South Africa through a network of 60 CD4 testing laboratories. CD4 laboratory data provides an assessment of the number of patients on ART and HIV-positive patients in the pre-ART wellness programs. This study aims to develop a laboratory based Comprehensive Care, Management and Treatment of HIV and AIDS (CCMT) programme status reporting system for CD4 testing at three health facilities in the Ekurhuleni health district using a newly developed CCMT request form, the Laboratory Information System (LIMS) and Corporate Data Warehouse (CDW). The study will generate monitoring and evaluation data to assist in the management of health facilities through a national electronic corporate data warehouse. PMID- 23920922 TI - A biomedical information system for retrieval and manipulation of NHANES data. AB - The retrieval and manipulation of data from large public databases like the U.S. National Health and Nutrition Examination Survey (NHANES) may require sophisticated statistical software and significant expertise that may be unavailable in the university setting. In response, we have developed the Data Retrieval And Manipulation System (DReAMS), an automated information system to handle all processes of data extraction and cleaning and then joining different subsets to produce analysis-ready output. The system is a browser-based data warehouse application in which the input data from flat files or operational systems are aggregated in a structured way so that the desired data can be read, recoded, queried and extracted efficiently. The current pilot implementation of the system provides access to a limited amount of NHANES database. We plan to increase the amount of data available through the system in the near future and to extend the techniques to other large databases from CDU archive with a current holding of about 53 databases. PMID- 23920923 TI - Using text prediction for facilitating input and improving readability of clinical text. AB - Text prediction has the potential for facilitating and speeding up the documentation work within health care, making it possible for health personnel to allocate less time to documentation and more time to patient care. It also offers a way to produce clinical text with fewer misspellings and abbreviations, increasing readability. We have explored how text prediction can be used for input of clinical text, and how the specific challenges of text prediction in this domain can be addressed. A text prediction prototype was constructed using data from a medical journal and from medical terminologies. This prototype achieved keystroke savings of 26% when evaluated on texts mimicking authentic clinical text. The results are encouraging, indicating that there are feasible methods for text prediction in the clinical domain. PMID- 23920924 TI - An integrated risk assessment tool for team-based periodontal disease management. AB - Mounting evidence suggests a potential association of periodontal disease with systemic diseases such as diabetes, cardiovascular disease, cancer and stroke. The objective of this study is to develop an integrated risk assessment tool that displays a patients' risk for periodontal disease in the context of their systemic disease, social habits and oral health. Such a tool will be used by not just dental professionals but also by care providers who participate in the team based care for chronic disease management. Displaying relationships between risk factors and its influence on the patient's general health could be a powerful educational and disease management tool for patients and clinicians. It may also improve the coordination of care provided by the provider-members of a chronic care team. PMID- 23920926 TI - 3D visualization environment for analysis of telehealth indicators in public health. AB - With the growth of telehealth applications and the need for public health managers to have tools that facilitate visualization of indicators produced by telehealth services arose the need to have simple systems to better planning the interventions. Furthermore, Health systems are considers difficult in order to visualize the right information by many health professionals [1] because of the complexity of its Graphical User Interface (GUI) and the high cognitive load needed to handle it. To overcome this problem, we have proposed a 3D environment for the analysis of telehealth indicators in public health by managers of public health sites. Users who will use the environment are part of public health manager of family health sites that participate of Network of Telehealth Centers of Pernambuco (RedeNUTES) [2] that is part of Brazil telehealth program. This paper aims to present a 3D environment for analysis of telehealth indicators by public health manager. PMID- 23920925 TI - Architecture of a prehospital emergency patient care report system (PEPRS). AB - In recent years, prehospital emergency care adapted to the technology shift towards tablet computers and mobile computing. In particular, electronic patient care report (e-PCR) systems gained considerable attention and adoption in prehospital emergency medicine [1]. On the other hand, hospital information systems are already widely adopted. Yet, there is no universal solution for integrating prehospital emergency reports into electronic medical records of hospital information systems. Previous projects either relied on proprietary viewing workstations or examined and transferred only data for specific diseases (e.g. stroke patients[2]). Using requirements engineering and a three step software engineering approach, this project presents a generic architecture for integrating prehospital emergency care reports into hospital information systems. Aim of this project is to describe a generic architecture which can be used to implement data transfer and integration of pre hospital emergency care reports to hospital information systems. In summary, the prototype was able to integrate data in a standardized manner. The devised methods can be used design generic software for prehospital to hospital data integration. PMID- 23920927 TI - Development of best practice principles for simplifying eligibility criteria. AB - Real world data is crucial for clinical research. In hospitals this information is more and more stored in electronic health records (EHR) and could be used for clinical trial feasibility and patient recruitment. On the other side eligibility criteria within study protocols are complex and usually not written in a way that is intuitively understandable or electronically usable. As part of overcoming the gap between eligibility criteria and the data that is available in EHRs we simplified eligibility criteria and created a guideline with best practice principles. The guideline explains how understandable criteria should be formulated and illustrates with examples what 'good' and 'bad' criteria are. PMID- 23920928 TI - App-synopsis - standard reporting for medical apps. AB - The market for medical apps is rapidly expanding - both for professional use as well as for patient centered apps. There are numerous medical apps, but relevant information about their limitations and dangers is rarely available. In an exemplary evaluation of n=8 medical apps, deficits regarding data integrity, one half had security and privacy issues. Since standard users usually have neither the equipment, know-how nor time for such analyses before entrusting them with their data, ideally, manufacturers should provide information regarding the functionality and limits of their products. Mandatory information should cover data management, data protection and privacy issues. To increase transparency, a standardized reporting tool in the form of an app synopsis could be helpful for providing the necessary information. PMID- 23920929 TI - Program for validation of aggregated hospital discharge data. AB - Hospitals are major providers of health services and analysis of hospital activity data is of great interest for both policy makers and public health researchers. The WHO Regional Office for Europe disseminates the hospital discharge data from European countries through the European Hospital Morbidity Database, available on http://data.euro.who.int/hmdb. In order to ensure that reliable high quality data on hospital activities can be published in a timely manner, a program for validation of hospital discharge data has been developed using the R language for statistical computing. This program has been in use since the October 2012 version of the European Hospital Morbidity Database and its use has contributed to improved quality and comparability of data on hospital activities across Europe. PMID- 23920930 TI - In-situ eye-tracking of emergency physician result review. AB - Optimized retrieval of test results is important to patient care and patient safety. The time during which a physician is retrieving results is a vital aspect of the diagnostic process since it is when the preliminary diagnosis is confirmed or the differential is adjusted. Better characterization of the time spent while results are displayed allows for more accurate and appropriate study of this human-computer interaction and visualization in future studies. Using screen recording and eye-tracking software, this study's primary objective was to determine the time spent by physicians (1) displaying lab results on the screen, (2)looking at lab results, and (3) fixating on specific values in a live clinical setting. We performed in-situ eye tracking with retrospective glances and time on task measurement. A total of 6171 minutes of data were collected, with mean individual lab result screen display time of 34.7 seconds, mean viewing time of 13.9 seconds, and mean fixation time of 9.9 seconds. We found that time spent looking at specific data is only small fraction of time data is shown onscreen. PMID- 23920931 TI - Benefits, challenges and impact of teleconsultation - a literature review. AB - Teleconsultation involves the use of technology so that the medical professionals and patients can interact with each other bringing health to where ever it is needed. Although it has been demonstrated to be feasible and effective its sustainability remains an important question. This paper presents the results of a literature review on teleconsultation, based on the Portuguese context. Although Portugal has some successful projects, a national or international conjoint effort would be more fruitful. Technologically it gets lets costly to provide teleconsultation, as pervasive computing grows. The gap of benefits between teleconsultation and regular consultation will diminish as patients grow fonder into technology.The economic value of this type of consultation remains a difficult subject, so a small budget economic analysis, based on a break-even method, is suggested. This analysis conducted on Finland shows that teleconsultation can be cost-effective. PMID- 23920932 TI - Extracting risk modeling information from medical articles. AB - Risk modeling in healthcare is both ubiquitous and in its infancy. On the one hand, a significant proportion of medical research focuses on determining the factors that influence the incidence, severity and treatment of diseases, which is a form of risk identification. Those studies typically investigate the micro level of risk modeling, i.e., the existence of dependences between a reduced set of hypothesized (or demonstrated) risk factors and a focus disease or treatment. On the other hand, the macro-level of risk modeling, i.e., articulating how a large number of such risk factors interact to affect diseases and treatments is not widespread, though essential for medical decision support modeling. By exploiting advances in natural language processing, we believe that information contained in unstructured texts such as medical articles could be extracted to facilitate aggregation into macro-level risk models. PMID- 23920933 TI - Improve threshold segmentation using features extraction to automatic lung delimitation. AB - With the consolidation of PACS and RIS systems, the development of algorithms for tissue segmentation and diseases detection have intensely evolved in recent years. These algorithms have advanced to improve its accuracy and specificity, however, there is still some way until these algorithms achieved satisfactory error rates and reduced processing time to be used in daily diagnosis. The objective of this study is to propose a algorithm for lung segmentation in x-ray computed tomography images using features extraction, as Centroid and orientation measures, to improve the basic threshold segmentation. As result we found a accuracy of 85.5%. PMID- 23920934 TI - Visualizing sets of SNOMED CT concepts to support consistent terminology implementation and reuse of clinical data. AB - Inconsistent use of concepts is an obstacle when implementing SNOMED CT to improve comparability of information. Terminology implementation should be approached by common strategies for navigating and selecting proper concepts. This study aims to explore ways of illustrating common pathways and ancestors of particular sets of concepts, to support consistent use of SNOMED CT in EHR-system implementation processes. The prototype presented is an interactive web-based re implementation of the terminology visualization tool TermViz. The open source prototype contains terminological features that are of relevance when exploring and comparing sets of concepts in SNOMED CT. Future work should focus on evaluating the developed prototype in order to assess its applicability in EHR system-implementation contexts. PMID- 23920935 TI - PARENT joint action: increasing the added value of patient registries in a cross border setting. AB - Patient registries are poorly interoperable and as a result data exchange or aggregation across organizations, regions and countries for secondary purposes (i.e. research and public health) is difficult to perform. PARENT Joint Action aims to provide EU Member States with a set of guidelines, recommendations and tools to support setting-up, management and governance of interoperable patient registries, thus helping EU Member States to drive down cost and interoperability risks of patient registries as well as improving secondary us-age of registry data in a cross-border setting. PMID- 23920936 TI - Bone tumor resection: analysis about 3D preoperative planning and navigation method using a virtual specimen. AB - The use of three-dimensional preoperative planning and bone tumor resection guided by navigation has increased in the last ten years. However, no study to date, as far as we know, has directly provided evidence of accuracy of this method. The objective of this study was to describe a method capable of determining the accuracy of osteotomies performed for tumor resection planned and guided by navigation. We hypothesize that matching the 3D reconstructed surgical specimen is an acceptable method to determine the accuracy of virtual planning and navigation. A total of seven patients and 14 osteotomies were evaluated. After surgery, all surgical specimens were 3D reconstructed from CT images. The mean of quantitative comparisons between osteotomies planned and osteotomies obtained through the resected specimen was in a global mean of 1.56 millimeters (SD: 2.91) for all the cases. Based on our observations, a three-dimensional model obtained from the tumor surgical specimen is a useful tool to determine accuracy of 3D planning and surgical navigation. PMID- 23920937 TI - Natural language processing and inference rules as strategies for updating problem list in an electronic health record. AB - Physicians do not always keep the problem list accurate, complete and updated. OBJECTIVE: To analyze natural language processing (NLP) techniques and inference rules as strategies to maintain completeness and accuracy of the problem list in EHRs. METHODS: Non systematic literature review in PubMed, in the last 10 years. Strategies to maintain the EHRs problem list were analyzed in two ways: inputting and removing problems from the problem list. RESULTS: NLP and inference rules have acceptable performance for inputting problems into the problem list. No studies using these techniques for removing problems were published Conclusion: Both tools, NLP and inference rules have had acceptable results as tools for maintain the completeness and accuracy of the problem list. PMID- 23920938 TI - Categorial structure of acupuncture points for terminological resources. AB - Recent increase in the number of clinical reports of acupuncture requires terminological resources based on conceptual frameworks for knowledge management. For this purpose, we developed a categorial structure for acupuncture points based on ISO 17115. PMID- 23920939 TI - Impact of complementary therapies via mobile technologies on Icelandic same day surgical patients' reports of anxiety, pain and self-efficacy in healing: a randomized controlled trial in process. AB - Complementary and Alternative Therapies (CAT) are increasingly being utilized in conjunction with conventional medicine. Health Information Technology (HIT) and CAT are being scrutinized for evidence based health outcomes. The aim of this randomized controlled trial (RCT) is to determine if the use of mobile technologies delivering CAT, specifically relaxation technique (RT), medical music intervention (MMI), nature landscape applications with (NLAM) and without music (NLAWM) compared with no intervention (control group) will assist in decreasing pre- and post-surgical patients' anxiety and pain levels while increasing post-operative healing self-efficacy levels. PMID- 23920940 TI - Serious disease - serious game. AB - Teenagers with diabetes often experience their disease as a heavy burden, feeling estranged from their peers. Traditional aids to monitoring and controlling the illness are often not used by this group, because they seem to enhance this feeling. Preliminary interviews with a focus group indicate that teenagers will be motivated by competing to maintain a certain level of blood glucose, regular measurements and assessment of the glucose level in their diet as well as insulin dosing at mealtimes. By the use of serious gaming and taking a user oriented approach for the development process, the DiaApp project will develop a smartphone app that will incorporate disease monitoring and maintenance into a game, thus encouraging the teenagers to manage their disease better and educating them about it as well. PMID- 23920941 TI - Conformity between protocol eligibility criteria for electronic patient identification: a comparison of clinical trials. AB - Clinical trial eligibility criteria define the target patient population for research studies. We assessed the eligibility criteria from 40 different protocols for Type II Diabetes Mellitus and depression (20 protocols each), to determine the extent to which protocol eligibility criteria were similar at three levels (test, test-value, and test-value-time clause). This was done to determine criteria that could be standardized to aid in identification of eligible patients from electronic health records. It was found that Type II Diabetes Mellitus had 36.9% similar and depression protocols had 53.1% similar at the test-value-clause level. This study demonstrates the need for more standardization of study protocol criteria as well as the associated query definitions to be run against the electronic healthcare data. Standardizing criteria based on the similar eligibility criteria between protocols will aid in patient recruitment by being able to reuse criteria and minimizing the time and money it takes to recruit patients. PMID- 23920942 TI - Cherry: mobile application for children with cancer. AB - The Cherry project seeks to address the information needs of young cancer patients, their parents, and health care providers. It aims at helping the patients to understand various aspects of their disease and treatment, and allow them to assess and record their disease related quality of life. It uses elements of social media to offer a meeting point with the physician and peers. Information is presented in a way that is both understandable and appealing to young children in school age and adolescents. Preschool children will be studied as a separate user group to address their needs and possibilities to meet them. The Cherry system wants to utilize Internet and mobile technologies to benefit patient outcome. PMID- 23920943 TI - Developing and implementing an interoperable document-based electronic health record. AB - Health information exchange ensuring its authenticity and integrity is not a simple task. Many institutions have implemented different solutions to perform this exchange using partial or summary information, and rarely include metadata that establish the context in which they performed the primary data capture. In this setting, we proposed the creation of an alternative architecture, parallel, yet integrated with a traditional electronic health record, based on the relational data model. We used a clinical documents standard, the CDA, whose architecture allows having a scalable document-based electronic clinical data repository, plausible to be shared with the patient, other institutions, other healthcare professionals or funders, with secure and controlled access and that remains unchanged over time. Furthermore, in addition to achieving this redundant clinical data repository, it was possible to reduce printing charts thanks to the portability that this standard allows. PMID- 23920944 TI - Health management system with smart TV using zero-configuration. AB - The health services using mobile devices are available in the world. But mobile services with mobile devices still have Zero configuration problem. If the problem is solved, various services are available. Smart TV has input problem. The service using Smart TV is not yet activated. So In this Study, we propose new health management service using Smart TV using Zero-configuration. PMID- 23920945 TI - Predictive variables of the use of personal health record: the Hospital Italiano de Buenos Aires study. AB - INTRODUCTION: although trends in consumer research suggest growing interest in using electronic PHRs, actual utilization of PHRs technologies is still low. OBJECTIVE: to identify those conditions that make patients at Hospital Italiano de Buenos Aires (HIBA) use a PHR. STUDY DESIGN: Analytic Cross-sectional study. RESULTS: the average age was 55.5 years (SD 19.8), 60.5% were female (39.5%, IC95%). The rate of enrolled were almost 50% and the rate of people usage was 29.1% (95% IC 28, 87 - 29.4). The patient's characteristics that influence in PHR usage were: the presence of at least one comorbidity (disabilities or chronic conditions), look for medical assistance during the last year, female and middle age. CONCLUSION: In this study the patient's characteristics that were most likely to use our PHR were similar to what another authors published. Future research is needed to understand social, cultural and organizational issues that influences into the rate of adoption and usage. PMID- 23920946 TI - Does the low power mode of the actigraph GT3X+ accelerometer influence the device output in sleep research in healthy subjects? AB - We measured lower limb activity by means two, above each ankle vertically aligned GT3X+ accelerometers in 4 healthy adults during a single night. Triaxial raw data vector magnitude units (VMU) were recorded at 100 Hz, in order to compare two different modes of operation (i.e. low power mode (LPM)on vs. off). PMID- 23920947 TI - Finding temporal gene expression patterns for translational research. AB - Translational research of time-series of gene-expression microarray datasets makes use on gene expression profiles that have been obtained at different points in time. Our web-based multi-user program helps a researcher find temporal patterns like peaks in large pre-selected microarray data sets that include data from different but related studies in publicly available databases. If all studies use the same platform, data can be combined for a meta-analysis type approach. For combination of data from different platforms we allow only Affymetrix GeneChips, for which a method for pooling of information exists. To search for time patterns, the data are transformed into an abstract layer that is independent from the particular selection of time point in the individual studies. PMID- 23920948 TI - A hospital survey on the utilization of the master file of the standardized nursing practice terminology in Japan. AB - A common language in nursing facilitates better communication among nurses and other healthcare providers, assuring better nursing care, hence better patient outcomes. As we developed and disseminated the standardized terminology of nursing which provided nurses with a set of terms to describe nursing observations and nursing actions, we run a survey to see how much it was recognized and utilized in actual clinical settings. The result showed that approximately 60% of the respondents were cognizant of our terminology, and again 60% of them were either actually using the terminology or interested in using it in the future. For them, the main purposes of utilizing the terminology were nursing documentation and care planning. Sometimes it was used as an educational tool. This suggests that we should further develop a tool to assist nurses with their documentation and care planning alongside the revision of the terminology itself. PMID- 23920949 TI - Recommendations for collecting and processing accelerometry data in elderly people. AB - Due to the large variety of methods for collecting and analyzing accelerometer data to assess physical activity, it is difficult to compare results from different studies. Therefore, this work aims to provide recommendations for the collection and processing of such data in older people, focusing on the assessment of wearing time and intensity levels. PMID- 23920950 TI - Evaluation of algorithm for extraction of lung regions in CT exams. AB - Recently has grown the development of Computer-aided Detection Systems - CAD to improve the diagnosis of diseases identifying it at the initials stages using medical images. In this work is made a analysis of the performance of an algorithm for lung region extraction in computed tomography exams - CT. The implementation was made in MATLAB and applied to 9 CT scans of patients with lung disease (corresponding to a set of 479 images). The detection of image lung boundaries were classified by an expert radiologist as "Good" and "Poor" according the presence of errors. The results showed deficiencies which damage the algorithm performance, only 52% of the images were rated as "Good" . The problems identified were listed, and when resolved will give the needed quality to the process to be used by radiologist doctors in the patient care. PMID- 23920951 TI - Classifier-free, integrated genomic predictions of prostate cancer recurrence. AB - Genomic predictions of clinical outcome are a core promise of the Human Genome Project. Yet actionable biomarkers in clinical medicine are confounded by patient heterogeneity as patient phenotypes are rarely well characterized and often poorly understood. Furthermore, standard predictive algorithms rely on a priori knowledge of discrete phenotypes for feature selection and training. To address this limitation, we develop a classifier-free algorithm that matches individual patients to other patient outcomes based on optimized clinicopathologic feature integration and molecular pathway similarity using the K-nearest neighbor. By identifying the best matches within the collection of patient data, we are able to return the desired prediction. In prostate cancer, we demonstrate the algorithm's ability to predict cancer recurrence without the need for supervised learning techniques in independent datasets with a recall and precision of 78%. Importantly, the predictor is microarray platform independent, scalable and simple to implement. Taken together, this method provides an exciting foundation from data-driven, clinical decision-making may arise. PMID- 23920952 TI - Noninvasive diagnosis of nonalcoholic steatohepatitis disease based on clinical decision support system. AB - Non-alcoholic fatty liver disease (NAFLD) is a hepatic disease associated with metabolic syndrome. NAFLD covers a spectrum of liver disease from steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. NASH is a disease evolving under the influence of various stimuli still poorly understood. In this paper we present new clinical decision support system (CDSS) for the diagnosis of NASH and the comparison of this system with machine learning algorithms. PMID- 23920953 TI - Exploring the potential of an electronic documentation system to reduce length of stay. AB - Electronic patient records are important in patient data management. Aim of this 2-year study was to investigate the effect of an e-documentation system on the ED length of stay. The study compared three length of stay parameters with and without the use of a prototype e-documentation system. 99 of trauma patients were monitored with the use of the electronic system and 101 patients (control group) were monitored with traditional methods. Time between the admission and completion of care was significantly lower in the e-documentation group (100+/-92 minutes, control group: 149+/-29 minutes). Similar effect was also found to the total ED length of stay (127+/-93 vs. 206+/-41 minutes) and time between completion of care and ED exit (26+/-10 vs. 57+/-23 minutes). LOS was reduced with the e-documentation system. This is important for the quality of trauma patient care, since saving time during the first hours after the accident usually determines the outcome of trauma patients. PMID- 23920954 TI - The HL7 standards-based model of emergency care information. AB - Electronic medical record interoperability remains an elusive goal for the clinical informatics community. The HL7 Emergency Care Workgroup created an emergency care domain analysis model that organizes existing HL7 standards into a clinician friendly information model. The model supports the capture of domain knowledge and encoding in a sharable format. The result is a domain information model that supports interoperability of information and processes in diverse Emergency Department information systems. PMID- 23920955 TI - Workflows in cancer treatment and their influence upon clinical documentation. AB - To establish single source cancer documentation for a complete comprehensive cancer center CCC we performed a systematic analysis of diagnostic, therapeutic and documentation workflows for 13 cancer entities. Results suggest that we will need three types of clinical documentation to cover all cancer entities of the Erlangen CCC. We expect to have a workflow for solid entities with inpatient treatment, one for solid entities treated ambulatory and one for non solid cancer entities. PMID- 23920956 TI - Telehomecare technologies enhance self-management and empowerment among patients with chronic obstructive pulmonary disease (COPD) - where does health literacy fit into this equation? AB - Chronic obstructive pulmonary disease (COPD) is a chronic disease characterised by a graduate decline of pulmonary function and it constitutes a provable burden on society. Tele-homecare technology (THC) is a young field of research that has shown potential with regards to enhancing the level of self-management among COPD patients. Self-management is closely connected to health literacy. Health literacy and THC have shown great potential in terms of reducing healthcare costs and improving quality of life for COPD patients. The objective of this poster is to raise awareness regarding the potential of using THC to improve the level of health literacy. PMID- 23920957 TI - Rebuilding and the private cloud of the hospital information system by the virtualization technology. AB - In our hospital, we managed an electronic health record system and many section subsystems as a hospital information system. By the expansion of these information systems, a system becomes complicated, and maintenance and operative cost increased. Furthermore, the environment that is available to medical information is demanded anywhere anytime by expansion of the computerization. However, the expansion of the information use becomes necessary for the expansion such as the personal protection of information for security. We became rebuilding and the private cloud of the hospital information system by the virtualization technology to solve such a problem. As a result, we were able to perform a decrease in number of the servers which constituted a system, a decrease in network traffic, reduction of the operative cost. PMID- 23920958 TI - Automatic synthesis of graphical user interfaces for health information systems. AB - Model-Driven Development (MDD) techniques allow ultimately reducing software development costs by means of automatic code synthesis. Clinical data models aid in the application of MDD techniques to the domain of Health Information Systems (HISes); however, they are not so effective when used alone for the synthesis of a specific HIS since the transformation processes that MDD techniques employ usually need information about the system's overall architecture. Herein, we present a method that combines clinical data models and architecture models. We apply such method to the synthesis of graphical user interface (GUI) skeletons for HISes, illustrating its potential to reduce the amount of transformation process specifications, which is a costly MDD activity. PMID- 23920959 TI - Developing and applying a cross-disciplinary team handover information system. AB - In order to avoid medical errors, it is very important to communicate with the medical team correctly, timely and efficiently. One of main reasons for the poor outcome of multidisciplinary handover in hospital is lacking effective tools for multidisciplinary handover. The project aimed to develop a workflow-based multidisciplinary handover information system, integrated with medical record browsing, multidisciplinary handover and event tracking, to improve the correctness and effectiveness of communication among the medical team members. PMID- 23920960 TI - Traumatic brain injury rehabilitation: analysis of common data elements. AB - Physical medicine rehabilitation interventions for post-acute traumatic brain injury (TBI) are heterogeneous and subject to differences based on multi disciplinary treatment plans [1]. There is no universal knowledge representation (KR) model for TBI rehabilitation which impedes data collection, aggregation, computation, and sharing. This paper describes results of an analysis of the National Institute for Neurological Disorders and Stroke (NINDS) TBI "Common Data Elements" (CDE) clinical data standardization set. We conducted this to understand current TBI rehabilitation KR and as a foundational step toward the creation of a domain ontology. A content coverage study was performed on the "Treatment/Intervention" sub-set of CDEs. Results show that coverage of the CDEs is broad but lacks depth to represent the context of data collection in the TBI rehabilitation process. Next steps will be development of a KR model and identification and validation of domain concepts for a foundational ontology. PMID- 23920961 TI - Researchermap: a tool for visualizing author locations using Google maps. AB - We hereby present ResearcherMap, a tool to visualize locations of authors of scholarly papers. In response to a query, the system returns a map of author locations. To develop the system we first populated a database of author locations, geocoding institution locations for all available institutional affiliation data in our database. The database includes all authors of Medline papers from 1990 to 2012. We conducted a formative heuristic usability evaluation of the system and measured the system's accuracy and performance. The accuracy of finding the accurate address is 97.5% in our system. PMID- 23920962 TI - A mobile health approach to tuberculosis contact tracing in resource-limited settings. AB - Tuberculosis remains a leading cause of morbidity and mortality worldwide. In 2011, there were 8.7 million new cases and 1.4 million deaths from the disease, with >95% of these deaths taking place in low- and middle-income countries [1]. Contact tracing prevents the spread of tuberculosis by identifying and screening a case's contacts and referring symptomatic individuals to health care providers. Traditionally, contact tracing has been conducted with paper forms, which can lead to considerable inefficiencies in data collection, storage, and retrieval. These inefficiencies are problematic as tuberculosis can continue to spread if disruption of disease transmission is delayed. Mobile health approaches to tuberculosis contact tracing remain largely unaddressed and limited to management and monitoring of multidrug-resistant tuberculosis [2].To address these limitations, a mobile health application that digitizes and automates contact tracing was developed. This poster presents work currently underway to evaluate this new approach in Botswana, which has the tenth highest incidence rate of tuberculosis in the world [3]. Operational considerations for implementing a mobile health approach to contact tracing in resource-limited settings are also presented. PMID- 23920964 TI - Representing second opinion requests from primary care within the Brazilian tele health program: international classification of primary care, second edition. AB - Standardization of second opinion question-answer pairs with a classification system can be used to facilitate data sharing and reuse. The Brazilian telehealth program faces the problem of representing biomedical knowledge from the primary care second opinion demands generated by rural health care teams. The objective is to determine if one of the medical classification systems has a superior ability to standardize Portuguese-language second opinion question-answer pairs. Data from 2,638 second opinions from 2010 were randomly reduced to a 264 question answer pair data set. The semantic meaning of the question-answer pairs was manually assigned to an International Classification of Primary Care, Second edition (ICPC2) code. Eight question-answer pairs did not contain sufficient medical semantic meaning to allow for mapping to an ICPC2 code; 53 question answer pairs did contain sufficient medical semantic meaning for mapping, however an appropriate ICPC2 code did not exist; and 203 question-answer pairs did contain sufficient medical semantic meaning for mapping to an ICPC2 code. A review of the literature indicates that there is no baseline to compare the 77% success rate against. PMID- 23920963 TI - Medication extraction and guessing in Swedish, French and English. AB - Extraction of information related to the medication is an important task within the biomedical area. Our method is applied to different types of documents in three languages. The results indicate that our approach can efficiently update and enrich the existing drug vocabularies. PMID- 23920965 TI - Integrating UIMA annotators in a web-based text processing framework. AB - The Unstructured Information Management Architecture (UIMA) [1] framework is a growing platform for natural language processing (NLP) applications. However, such applications may be difficult for non-technical users deploy. This project presents a web-based framework that wraps UIMA-based annotator systems into a graphical user interface for researchers and clinicians, and a web service for developers. An annotator that extracts data elements from lung cancer radiology reports is presented to illustrate the use of the system. Annotation results from the web system can be exported to multiple formats for users to utilize in other aspects of their research and workflow. This project demonstrates the benefits of a lay-user interface for complex NLP applications. Efforts such as this can lead to increased interest and support for NLP work in the clinical domain. PMID- 23920966 TI - A model for nurses seeking information using a scholarly information map. AB - Nurses are required to obtain highly sophisticated scholarly information to contribute to the health of medical consumers through evidence-based practice (EBP). However, it is often difficult to constantly find appropriate information resources and conduct searches to obtain desired and useful information. Therefore, a system that can be used to find reliable information to satisfy the needs of clinical nurses is required. This study aimed to support nurses seeking information to aid their practice. We propose a model to support the information seeking of nurses using 2 scholarly information maps: a "Resource Map" and an "Individual Map." The Resource Map contains comprehensive information of special fields for nurses. Meanwhile, the Individual Map contains elements of case reports that help nurses to accurately specify a patient's condition. This model can help nurses develop a habit of using these maps for advancements in nursing. PMID- 23920967 TI - Text classification performance: is the sample size the only factor to be considered? AB - The use of text mining and supervised machine learning algorithms on biomedical databases has become increasingly common. However, a question remains: How much data must be annotated to create a suitable training set for a machine learning classifier? In prior research with active learning in medical text classification, we found evidence that not only sample size but also some of the intrinsic characteristics of the texts being analyzed-such as the size of the vocabulary and the length of a document-may also influence the resulting classifier's performance. This study is an attempt to create a regression model to predict performance based on sample size and other text features. While the model needs to be trained on existing datasets, we believe it is feasible to predict performance without obtaining annotations from new datasets once the model is built. PMID- 23920968 TI - Hierarchical semantic structures for medical NLP. AB - We present a framework for building a medical natural language processing (NLP) system capable of deep understanding of clinical text reports. The framework helps developers understand how various NLP-related efforts and knowledge sources can be integrated. The aspects considered include: 1) computational issues dealing with defining layers of intermediate semantic structures to reduce the dimensionality of the NLP problem; 2) algorithmic issues in which we survey the NLP literature and discuss state-of-the-art procedures used to map between various levels of the hierarchy; and 3) implementation issues to software developers with available resources. The objective of this poster is to educate readers to the various levels of semantic representation (e.g., word level concepts, ontological concepts, logical relations, logical frames, discourse structures, etc.). The poster presents an architecture for which diverse efforts and resources in medical NLP can be integrated in a principled way. PMID- 23920969 TI - Development of medical equipment alarm monitoring system. AB - In a hospital, we use a large number of medical equipment. In these use, I support the safe use by the alarm such as errors from medical equipment. There is the instrument notifying of alarm in communication, but there is the instrument by a sound and the light. For the medical safety management, confirmation of the alarm is important. We thought that stability was improved by integrating alarm from the instrument of the different type. Therefore, we thought that we integrated alarm from medical equipment. We decided to transmit an alarm signal from medical equipment by adding radio module program unit. The type of the radio used IEEE 802.15.4 (ZigBee) at a point of view of low power, International Standard, simple radio equipment. This system deals with only alarm information from medical equipment and does not handle the data. However, we understood that we were helpful very much even if it was only alarm information. We were able to in this way reduce the number of incidents. PMID- 23920970 TI - Time-dependent migration of citations through PubMed and OvidSP subsets: a study on a series of simultaneous PubMed and OvidSP searches. AB - OBJECTIVE: To quantitatively describe (1) differences between search results derived at consecutive time points with the PubMed and OvidSP literature search interfaces over a five day interval, and (2) the migration of citations through different subsets to estimate the timeliness of OvidSP. METHODS: PubMed Identifiers (PMIDs) of the following subsets were retrieved from PubMed and OvidSP simultaneously (within 8 h) at 11 days in March and April 2010 including 5 consecutive days: as supplied by publisher, in process, PubMed not MEDLINE, and OLDMEDLINE. Search results were compared for difference and intersection sets. The migration of citations on individual level was determined by comparison of corresponding sets over several days. RESULTS: The "in process" set was stable with about 446,000 - 452,000 citations; a small fraction of up to 3 % of the total subsets were in PubMed only and OvidSP only subsets. About 96 % of the ca. 10,500 citations in the OvidSP only subset migrated within 2 days out of the "in process" subset. The database of OvidSP is updated within a period of two days. PMID- 23920971 TI - The role of documentation and inter-provider information exchange in care continuity for older hip fracture patients. AB - Maintaining continuity of patient care can be difficult during transitions between care settings, when quality of care and patient safety are at risk. We sought to understand the role of inter-provider documentation and information exchange across successive care settings for complex, older patients. Data were gathered as part of a multi-site ethnographic study that followed 23 older post surgical hip fracture patients across multiple care transitions. Documentation and information exchange help build a "picture" of complex patients, but care continuity is challenged by late, missing or unnecessary information, duplicated assessments and lack of interoperability of electronic systems. This study demonstrates the importance of appropriate documentation in the transition process, but points to the need for comprehensive system-level solutions which standardize information collection and sharing along the continuum of care. PMID- 23920972 TI - Optimizing non-invasive blood pressure estimation using pulse transit time. AB - Continuous blood pressure (BP) monitoring during exercise is an important means to ensure exercise safety, particularly in seniors and individuals with various comorbidities. Use of automated BP monitors is limited during exercise. Pulse transit time (PTT) has been suggested for non-invasive BP monitoring however its implementation into clinical practice was hampered by lack of non-expensive practical solutions. The goal of this project was to introduce and to test a practical low-cost solution for using PTT to estimate BP during exercise. Our approach was based on obtaining 3 calibration points during different levels of exertion for each subject and utilizing the resulting individualized BP estimation equitation for patient-specific monitoring of BP during home-based exercise. Evaluation of the proposed approach showed that the mean difference between reference systolic BP (SBP) and estimated systolic BP was 0.0 mmHg. The optimal way to calculate PTT has been established by comparison of three main characteristic points used to derive PTT. PMID- 23920973 TI - Tracking and visualizing headache trends on a mobile or desktop website. AB - Many people suffering from chronic headaches use headache diaries to help track trends in their episodes. Studies have shown that electronic headache diaries are more effective than paper diaries for both patients and providers. We designed and implemented a full-size and mobile Web-based headache tracker and a database management system to store the data from the websites. The full-size website allows users to retrieve their data by viewing or downloading a table of the raw values they entered, or they can see a graphical visualization linking the severity of their headaches to any of several variables. Through this system's capacity to illustrate trends and track contributing factors for headaches, users, researchers and health service providers may gain better understanding of and control over chronic headaches. PMID- 23920974 TI - Exploring the possibility of modeling a genetic counseling guideline using agile methodology. AB - Increased demand of genetic counseling services heightened the necessity of a computerized genetic counseling decision support system. In order to develop an effective and efficient computerized system, modeling of genetic counseling guideline is an essential step. Throughout this pilot study, Agile methodology with United Modeling Language (UML) was utilized to model a guideline. 13 tasks and 14 associated elements were extracted. Successfully constructed conceptual class and activity diagrams revealed that Agile methodology with UML was a suitable tool to modeling a genetic counseling guideline. PMID- 23920975 TI - Proposal for a data publication and citation framework when sharing biomedical research resources. AB - Research data and biospecimen repositories are valuable resources for biomedical investigators. Sharing these resources has great potential benefits including efficient use of resources, avoiding duplicate experiments, gathering adequate sample sizes, and promoting collaboration. However, concerns from data producers about difficulties of getting proper acknowledgement for their data contributions are increasingly becoming obstacles for efficient and large-scale data sharing in reality. In this research project we analyzed the inadequacy of current policy based solution for promoting data sharing. The recommendations in this paper emphasize data publication and citation. This project aims to promote the acknowledgement of data contributors with realizable informatics tools that augment informal policy-level strategies, and do so in a way that promotes data sharing. PMID- 23920976 TI - Why do physicians have difficulty accepting clinical decision support systems? AB - Clinical decision support systems (CDSS) have not consistently demonstrated improvements in clinical care. This may partly be due to the lack of user acceptance. The purpose of this paper was to conduct a systematic literature review and task analysis to develop a model for CDSS design in order to achieve user acceptance. PMID- 23920977 TI - Effects of data transformation methods on classification of patients diagnosed with myocardial infarction. AB - Large datasets may contain redundant data. Variable selection methods that select most relevant variables in the data set, fail to consider the interaction between the variables. Data transformation methods are used to transfer the original data to a new dimension and capture the most significant information within the data set. The data set used in this study was based on 45 clinical variables collected from 697 patients diagnosed as either having myocardial infarction (MI) or not. Principal component analysis (PCA) and independent component analysis (ICA) were applied prior to classification of patients to MI or Non-MI groups using support vector machines (SVM). PMID- 23920978 TI - Preliminary evaluations of a spoken web enabled care management platform. AB - Telephones are a ubiquitous and widely accepted technology worldwide. The low ownership cost, simple user interface, intuitive voice-based access and long history contribute to the wide-spread use and success of telephones, and more recently, that of mobile phones. This study reports on our preliminary efforts to leverage this technology to bridge disparities in the access to and delivery of personalized health and wellness care by developing and evaluating a Spoken Web enabled Care Management solution. Early results with two proxy evaluations and a few visually impaired users highlight both the potential and challenges associated with this novel, voice-enabled healthcare delivery solution. PMID- 23920979 TI - Analysis of family health history based risk assessment algorithms: classification and data requirements. AB - Family Health History (FHH) is a valuable and potentially low-cost tool for risk assessment and diagnosis in patient-centered healthcare. In this study, we identified and analyzed existing FHH-based risk assessment algorithms (RAAs) for cardio-vascular disease (CVD) and colorectal cancer (CRC) to guide implementers of electronic health record (EHR) systems regarding the data requirements for computing risk using these algorithms. We found a core set of data elements that are required by most RAAs. While some of these data are available in EHR systems, the patients can be empowered to contribute the remainder. PMID- 23920980 TI - Extending VIVO ontology to represent research and educational resources in an academic biomedical informatics department. AB - The increasing need for interdisciplinary team sciences makes it vital for academic research departments to publicize their research and educational resources as part of "linked data" on the semantic web to facilitate research networking and recruitment. We extended an open-source ontology, VIVO, to represent the research and educational resources in an academic biomedical informatics department to enable ontology-based information storage and retrieval. Using participatory design methods, we surveyed representative types of visitors to the department web site to understand their information needs, and incorporated these needs into the ontology design. We added 114 classes and 186 properties to VIVO. Generalizability and scalability are the measures used in our theoretical evaluation. PMID- 23920981 TI - PHIO: a knowledge base for interpretation and calculation of public health indicators. AB - Existing population health indicators tend to be out-of-date, not fully available at local levels of geography, and not developed in a coherent/consistent manner, which hinders their use in public health. The PopHR platform aims to deliver an electronic repository that contains multiple aggregated clinical, administrative, and environmental data sources to provide a coherent view of the health status of populations in the province of Quebec, Canada. This platform is designed to provide representative information in near-real time with high geographical resolution, thereby assisting public health professionals, analysts, clinicians and the public in decision-making. This paper presents our ongoing efforts to develop an integrated population health indicator ontology (PHIO) that captures the knowledge required for calculation and interpretation of health indicators within a PopHR semantic framework. PMID- 23920982 TI - Data standard ? data quality. AB - The relationship between data quality and data standards has not been clearly articulated. While some directly state that data standards increase data quality, others claim the opposite. Depending on the type of data standard and the aspects of data quality considered, both arguments may in fact be correct. We deconstruct a typology of data standards and ap ply a dimensional definition of data quality to clearly articulate the relationship between the two, providing a framework for data quality planning. PMID- 23920983 TI - Exploring local public health work in the context of novel translation technologies. AB - Limited English proficiency (LEP) leads to disparities in health and health care. Although the LEP population in the US is growing and federal regulations require availability of translated health promotion materials, availability of these materials is lacking, partially due to the costs and time required to produce high quality translations. We conducted semi-structured interviews with employees involved in the translation process at three local health districts (LHDs) in Washington State to explore the potential for novel technologies to assist in the creation of multilingual health promotion materials. We generated a translation workflow diagram and analyzed key themes that affected the translation process. We also explored employees' opinions regarding electronic document exchange and machine translation technology (MT). Overall, public health employees were open to the incorporation of information technologies to speed the translation and dissemination of multilingual public health materials if quality could be assured. PMID- 23920984 TI - Investigating incidents of EHR failures in China: analysis of search engine reports. AB - As the healthcare industry becomes increasingly dependent on information technology (IT), the failure of computerized systems could cause catastrophic effects on patient safety. We conducted an empirical study to analyze news articles available on the internet using Baidu and Google. 116 distinct EHR outage news reports were identified. We examined characteristics, potential causes, and possible preventive strategies. Risk management strategies based are discussed. PMID- 23920985 TI - Building a common pipeline for rule-based document classification. AB - Instance-based classification of clinical text is a widely used natural language processing task employed as a step for patient classification, document retrieval, or information extraction. Rule-based approaches rely on concept identification and context analysis in order to determine the appropriate class. We propose a five-step process that enables even small research teams to develop simple but powerful rule-based NLP systems by taking advantage of a common UIMA AS based pipeline for classification. Our proposed methodology coupled with the general-purpose solution provides researchers with access to the data locked in clinical text in cases of limited human resources and compact timelines. PMID- 23920986 TI - The development of a multiplayer game for education of hospital management. AB - This paper designed and prototyped a networked hospital management serious game for education, and evaluated the prototype. A player, the president of each hospital, makes management decisions under various clinical indicators, and the decision affects condition of the other hospitals as well as of his/her own. The interaction makes the players compete, and, at the same time, exchange their findings each other. PMID- 23920987 TI - What a catch! traits that define good annotators. AB - Human annotation and chart review is an important process in biomedical informatics research, but which humans are best suited for the job? Domain expertise, such as medical or linguistic knowledge is desirable, but other factors may be equally important. The University of Utah has a group of 20+ reviewers with backgrounds in medicine and linguistics, and 10 key traits have surfaced in those best able to annotate quickly and with high quality. To identify reviewers with these key traits, we created a hiring process that includes interviewing candidates, testing their medical and linguistic knowledge, and having them complete an annotation exercise on realistic medical text. Each step is designed to assess the key traits and allow the investigator to choose the skill set required for each project. PMID- 23920988 TI - A course to teach students to learn mobile health by serving the elderly. AB - We designed a special course based on Service Learning theory to train the undergraduate students to teach the elderly people in community college to learn using smartphones for health. A 2-credit course was designed, composed of lecture & discussion and community service. 20 undergrduate stundents from university and 26 seniors from community college registered at this course. The results show very postitive impacts in both groups. The students felt doing something meaningful and learning helping the elder when the elderly felt very appreciated by being served and taught by students about the smartphones. The elderly wished us to go back in the future. PMID- 23920989 TI - Developing the nursing care plans using the "master file of standardized nursing practice terminology" in Japan. AB - A common language in nursing facilitates better communication among nurses and healthcare team, assuring better nursing care, hence better patient outcomes. As we developed and disseminated the standardized terminology of nursing which provided nurses with a set of terms to describe nursing observations and nursing actions, we developed a certain number of nursing care plans using the terms in it. The nursing care plans included those for the patients requiring medical (pharmaceutical)/surgical procedures or the patients showing some signs and symptoms. Generally, nurses found that the nursing care plans were useful and flexible enough to allow for the modification according to the needs of each individual patient. In conclusion, the nursing care plans based on the standardized terminology showed its relevance to the clinical settings. PMID- 23920990 TI - Investigating the impact of an emergency information system on patient's length of stay in the emergency department of a tertiary hospital in Saudi Arabia. AB - The emergency department has a crucial role in saving patient's lives. Efficient and reliable information through reliable information systems contribute to effective communication in these situations and ultimately shorter lengths of stay (LOS). This exploratory, cross-sectional study evaluates a current legacy emergency system in a tertiary hospital and investigates its impact on patient's length of stay (LOS) in the emergency department. A significantly shorter LOS was found between patients whose information was available and was communicated effectively in comparison to patients whose data were not available. Furthermore, longer LOS was associated with patients who required clinical services (pathology, radiology) due to the manual retrieval of results. This study has found that future implementation of a comprehensive electronic information system will facilitate effective communication workflow and timely access to patient data in the emergency department. PMID- 23920991 TI - Comparison of clinical knowledge bases for summarization of electronic health records. AB - Automated summarization tools that create condition-specific displays may improve clinician efficiency. These tools require new kinds of knowledge that is difficult to obtain. We compared five problem-medication pair knowledge bases generated using four previously described knowledge base development approaches. The number of pairs in the resulting mapped knowledge bases varied widely due to differing mapping techniques from the source terminologies, ranging from 2,873 to 63,977,738 pairs. The number of overlapping pairs across knowledge bases was low, with one knowledge base having half of the pairs overlapping with another knowledge base, and most having less than a third overlapping. Further research is necessary to better evaluate the knowledge bases independently in additional settings, and to identify methods to integrate the knowledge bases. PMID- 23920992 TI - Towards on-line ADR detection: an innovative data cube-based approach. AB - The problem of Adverse Drug Reactions (ADRs) detection is a key issue in the pharmacovigilance community. Although many related researches have been proposed in recent years, majority of them were concerned about the accuracy of the detected adverse drug reactions, very few paying attention to the performance issue of how to quickly accomplish the detection process. In this work, we propose the concept of multivalued-dimension contingency cube (MDC-cube) to facilitate multidimensional, fast and online detection of ADRs, especially those caused by drug interactions. Experiments conducted on the FDA AERS data set show that our MDC-cube based method is an order of magnitude faster than the state-of the-art ABCM-MS method. PMID- 23920993 TI - National electronic medical records integration on cloud computing system. AB - Few Healthcare providers have an advanced level of Electronic Medical Record (EMR) adoption. Others have a low level and most have no EMR at all. Cloud computing technology is a new emerging technology that has been used in other industry and showed a great success. Despite the great features of Cloud computing, they haven't been utilized fairly yet in healthcare industry. This study presents an innovative Healthcare Cloud Computing system for Integrating Electronic Health Record (EHR). The proposed Cloud system applies the Cloud Computing technology on EHR system, to present a comprehensive EHR integrated environment. PMID- 23920994 TI - Telepharmacology in clinical practice? AB - The role and collaboration of a pharmacologist with other members of the health care team is very important with his/her knowledge about prescribing, administration and pharmacodynamics of drugs as well as about using the existing drug related information systems. It seems optimal for a health care system to use telepharmacology which means a special pharmacological team (and information system) on duty available 24h to different medical specialists via remote multimedia link. PMID- 23920995 TI - A rule-based method for continuity of care identification in discharge summaries. AB - Discharge summaries are an important clinical narrative as they include the continuity of care information. Identification of data contained in their text is a difficult task due to its freeform text and lack of consensus on essential content. This research proposes a rule-based method to verify the presence of information about continuity of care in Portuguese texts, applying Natural Language Processing (NLP) techniques, and based on an annotated medical corpus. After the experiments, 4 rules were defined and applied in the text of 200 summaries to identify if they have or not the continuity of care information. This process had resulted in Precision value of 84%, Recall value of 70%, Specificity value of 97% and F-Measure value of 76% related to algorithm evaluation. PMID- 23920996 TI - Effect of EMR implementation on clinic time, patient and staff satisfaction, and chart completeness in a resource-limited antenatal clinic in Kenya. AB - Electronic Medical Records (EMR) are thought to improve healthcare through a variety of means. However, the study of EMR implementation in resource-poor settings has been minimal. Moi Teaching and Referral Hospital (MTRH) is the second largest tertiary care centre in Kenya, hosting a busy antenatal clinic serving Eldoret and surrounding regions. The recent transition from written to electronic antenatal records at MTRH permits the opportunity to study whether this change improves quality of care, in terms of: TIME: Does the patient or healthcare worker spend the same amount of time at the encounter? SATISFACTION: Is the patient or healthcare worker more or less satisfied with the encounter? COMPLETENESS: Does the antenatal record do a better job of recording key information in the antenatal history? Our Objective wasto determine the effects of EMR implementation on an antenatal clinic in a resource-limited setting. PMID- 23920997 TI - Model-based auditability of clinical trial recruitment. AB - Detailed insight into the recruitment parameters of a clinical trial is crucial to interpretation of its results, and reasons for its success or failure. Such recruitment is increasingly done through specialized software tools, sometimes linked to Electronic Health Record (EHR) systems, enabling automated capture of audit logs. However, in the absence of shared semantic models underpinning these logs, gathered data remains insular and opaque. We propose a standardized syntactical representation to capture the provenance of the recruitment task, and ground it in CRIM, a variant of the established PCROM information model for research in primary care. The method has been successfully prototyped in the EU FP7 TRANSFoRm project, where the recruitment eligibility query module has been integrated with a provenance capture infrastructure, resulting in the full reproducibility of the study design process. PMID- 23920998 TI - The NLM value set authority center. AB - The Value Set Authority Center (VSAC) at the National Library of Medicine (NLM) provides downloadable access to all official versions of vocabulary value sets contained in the Clinical Quality Measures (CQMs) used in the certification criteria for electronic health record systems ("Meaningful Use" incentive program). Each value set consists of the numerical values (codes) and human readable names (descriptions), drawn from standard vocabularies such as LOINC, RxNorm and SNOMED CT(r), that are used to define clinical data elements used in clinical quality measures (e.g., patients with diabetes, tricyclic antidepressants). The content of the VSAC will gradually expand to incorporate value sets for other use cases, as well as for new measures and updates to existing measures. PMID- 23920999 TI - Redesigned computerized prescribing system to reduce physicians' workload and improve patient safety. AB - The aim of our study was to redesign and evaluate the Computerized Prescribing System (PRS) to reduce physicians' workload and improve patient safety. The study was conducted in 2 prefectures in Japan. 186 physicians were surveyed with regard to prescription by physicians and medical office assistants. As a result, it was found that physicians demanded support from medical office assistants with regard to entry of prescription orders but for limited types of medicines. Based on our findings, we developed recommendations for a redesigned outline for PRS for the following 4 scenarios: (1) Continue prescription; (2) narcotic medicines; (3) chemotherapeutic medicines; and (4) medicines used in medical procedures. The outline was evaluated for effectiveness and safety and was confirmed to be a useful future prescription system. PMID- 23921000 TI - KidsETransplant: a platform for liver-transplanted children. AB - Since 1989, all pediatric liver transplants in Switzerland are centralized at the University Hospitals of Geneva (HUG). Approximately 125 children have received transplants since then, and their survival rate is greater than 90% - one of the highest in Europe. Maximizing the chances of success requires that patients understand and comply with follow-up treatment. The KidsETransplant project aims at helping the child - and his family - to better understand his health situation, to have access to shared resources and to be able to better communicate with healthcare professionals and other patients. PMID- 23921001 TI - Analysis of network based co-expression modules for Alzheimer's disease. AB - There has been an intensive research going on for Alzheimer's disease (AD) to understand its cause and progression through the past decade. However, the pathogenic factors that are responsible for these processes are still unclear. In this research we utilize the hippocampal gene expression data of 22 AD patients and present a framework for a comparative study to evaluate the two similarity measures, Mutual Information and Pearson Correlation Coefficient in developing gene coexpression networks. We hypothesize that Mutual Information based co expression networks can capture more biologically significant dependencies as compared to Pearson Correlation Coefficient due to its ability to capture non linear relationships. We utilize a parameter free module discovery algorithm to detect functional modules discovered by the two approaches. Further, to validate our approach, we compared the identified functional modules resulted by our experiments to the existing biological modules by computing the Jaccard index between them. Finally, we evaluated the discovered modules for their biological significance by performing biomedical literature search. We also investigated the drug interdiction pathways, which suggest potential targets for intervention. PMID- 23921068 TI - From the Scientific Program Chairs. Preface. PMID- 23921002 TI - Temporal pattern mining for multivariate clinical decision support. AB - Multivariate temporal data are collections of contiguous data values that reflect complex temporal changes over a given duration. Technological advances have resulted in significant amounts of such data in high-throughput disciplines, including EEG and iEEG data for effective and efficient healthcare informatics, and decision support. Most data analytics and data-mining algorithms are effective in capturing global trends, but fail to capture localized behavioral changes in large temporal data sets. We present a two-step algorithmic methodology to uncover temporal patterns and exploiting them for an efficient and accurate decision support system. This methodology aids the discovery of previously unknown, nontrivial, and potentially useful temporal patterns for enhanced patient-specific clinical decision support with high degrees of sensitivity and specificity. Classification results on multivariate time series iEEG data for epileptic seizure detection also demonstrate the efficacy and accuracy of the technique to uncover interesting and effective domain class specific temporal patterns. PMID- 23921069 TI - Inspiratory muscle training protocol for patients with chronic obstructive pulmonary disease (IMTCO study): a multicentre randomised controlled trial. AB - INTRODUCTION: Inspiratory muscle training (IMT) has been applied during pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD). However, it remains unclear if the addition of IMT to a general exercise training programme leads to additional clinically relevant improvements in patients with COPD. In this study, we will investigate whether the addition of IMT to a general exercise training programme improves 6 min walking distance, health-related quality of life, daily physical activity and inspiratory muscle function in patients with COPD with inspiratory muscle weakness. METHODS AND ANALYSIS: Patients with COPD (n=170) with inspiratory muscle weakness (Pi,max <60 cm H2O or <50%pred) will be recruited to a multicentre randomised placebo controlled trial of IMT and allocated into one of the two groups. Patients in both groups will follow a 3 month general exercise training programme, in combination with home based IMT. IMT will be performed with a recently developed device (POWERbreathe KH1). This device applies an inspiratory load that is provided by an electronically controlled valve (variable flow resistive load). The intervention group (n=85) will undertake an IMT programme at a high intensity (>=50% of their Pi,max), whereas the placebo group (n=85) will undertake IMT at a low training intensity (<=10% of Pi,max). Total daily IMT time for both groups will be 21 min (6 cycles of 30 breaths). Improvement in the 6 min walking distance will be the primary outcome. Inspiratory muscle function, health-related quality of life and daily physical activity will be assessed as secondary outcomes. ETHICS AND DISSEMINATION: Ethics approval has been obtained from relevant centre committees and the study has been registered in a publicly accessible clinical trial database. The results will be easily interpretable and should immediately be communicated to healthcare providers, patients and the general public. RESULTS: This can be incorporated into evidence-based treatment recommendations for clinical practice. CLINICALTRIALSGOV: NCT01397396. PMID- 23921070 TI - Maintenance hemodialysis independently increases the risk of early death after acute intracerebral hemorrhage. AB - BACKGROUND: It is unknown whether the clinical features and outcomes of intracerebral hemorrhage (ICH) patients who undergo maintenance hemodialysis (HD) at the time of ICH are similar to those of general ICH patients. METHODS: We retrospectively examined the medical records of ICH patients admitted to the Stroke Center of Kawasaki Medical School Hospital within 7 days of ICH onset between April 2004 and June 2011. Patients were classed as HD or non-HD, and clinical characteristics were compared between the two groups. ICH volume was measured on admission CT and follow-up CT scan (< 24 h after admission). Hematoma enlargement was defined as a hematoma that increased by more than 33% of its initial volume. Early death was defined as all-cause death within 14 days of ICH onset. The factors associated with early death were determined using multivariate logistic regression analysis. RESULTS: Five hundred and seven patients (320 males; 69.0 years old, interquartile range 59.0-79.0) were enrolled in the study. Thirty-six (7.2%) were receiving maintenance HD at the time of ICH and formed the HD group, and the remaining 471 patients formed the non-HD group. Use of antithrombotic agents prior to ICH was more common in the HD group than in the non-HD group (41.7 vs. 21.9%; p = 0.012). Brainstem (30.6 vs. 11.3%; p = 0.003) and lobar (19.4 vs. 6.6%; p = 0.013) hematoma locations were more common in the HD group than in the non-HD group. Enlargement of ICH volume was more common in the HD group than in the non-HD group (25.8 vs. 10.2%; p = 0.015). Early death was more common in the HD group than in the non-HD group (33.3 vs. 9.3%; p < 0.001). On the multivariate logistic regression analysis adjusted for age, sex and renal dysfunction, National Institutes of Health Stroke Scale score > 20 [odds ratio (OR) 27.40, 95% confidence interval (CI) 9.69-77.44; p < 0.001], ICH volume > 30 ml (OR 9.53, 95% CI 3.82-23.77; p < 0.001), HD (OR 6.42, 95% CI 1.39 29.76; p = 0.017), the use of antithrombotic agents (OR 3.04, 95% CI 1.22-7.56; p = 0.017) and glucose > 150 mg/dl (OR 2.51, 95% CI 1.01-6.26; p = 0.047) were independent factors associated with early death. CONCLUSION: Maintenance HD is independently associated with early death in ICH patients. PMID- 23921071 TI - Efficient soluble expression of secreted matrix metalloproteinase 26 in Brevibacillus choshinensis. AB - Matrix metalloproteinase 26 (MMP-26) is a novel member of the matrix metalloproteinase family with minimal domain constitution and unknown physiological function. The three-dimensional (3D) structure of the enzyme also remains to be deciphered. Previous studies show that MMP-26 may be expressed in Escherichia coli (E. coli) as inclusion bodies and re-natured with catalytic activity. However, the low re-naturation rate of this method limits its usage in structural studies. In this paper, we tried to clone, express and purify the pro form and catalytic form of MMP-26 (ProMMP-26 and CatMMP-26) in several widely used expression vectors and express the recombinant MMP-26 proteins in E. coli cells. These constructs resulted in insoluble expressions or soluble expressions of MMP-26 with little catalytic activity. We then used Brevibacillus choshinensis (B. choshinensis) as the host system for the soluble and active expression of MMP 26. The enzyme was secreted in soluble form in the supernatant of cell culture medium and purified via a two-step purification process that included Ni(2+) affinity chromatography followed by gel filtration. The yields of purified ProMMP 26 and CatMMP-26 were 12 and 18mg/L, respectively, with high purity and homogeneity. Both ProMMP-26 and CatMMP-26 showed gelatin zymography activity and the purified CatMMP-26 had high enzymatic activity against DQ-gelatin substrate. The large-scale soluble and active protein production for future structural studies of MMP-26 is thus feasible using the B. choshinensis host system. PMID- 23921072 TI - Large scale expression and purification of mouse melanopsin-L in the baculovirus expression system. AB - Melanopsin is the mammalian photopigment that primarily mediates non-visual photoregulated physiology. So far, this photopigment is poorly characterized with respect to structure and function. Here, we report large-scale production and purification of the intact long isoform of mouse melanopsin (melanopsin-L) using the baculovirus/insect cell expression system. Exploiting the baculoviral GP67 signal peptide, we obtained expression levels that varied between 10 30pmol/10(6)cells, equivalent to 2-5mg/L. This could be further enhanced using DMSO as a chemical chaperone. LC-MS analysis confirmed that full-length melanopsin-L was expressed and demonstrated that the majority of the expressed protein was N-glycosylated at Asn(30) and Asn(34). Other posttranslational modifications were not yet detected. Purification was achieved exploiting a C terminal deca-histag, realizing a purification factor of several hundred-fold. The final recovery of purified melanopsin-L averaged 2.5% of the starting material. This was mainly due to low extraction yields, probably since most of the protein was present as the apoprotein. The spectral data we obtained agree with an absorbance maximum in the 460-500nm wavelength region and a significant red-shift upon illumination. This is the first report on expression and purification of full length melanopsin-L at a scale that can easily be further amplified. PMID- 23921073 TI - Evaluating the utility of the body adiposity index in adolescent boys and girls. AB - OBJECTIVES: This study examines the ability of the body adiposity index to estimate percent body fat in a mixed sample of adolescents. Additionally, the sensitivity of the body adiposity index to identify adolescents with increased health risk (i.e., high waist circumference) was determined and compared to other anthropometric indicators of health (skinfolds and body mass index). DESIGN: Cross-sectional. METHODS: Anthropometric data (height, weight, waist circumference, and skinfolds) were collected on 913 adolescents (50% boys; mean age: 15.1yrs). Percent body fat estimates were determined using skinfold equations and the body adiposity index, while body mass index was calculated using weight and height (wt/ht(2)). Age- and gender-specific thresholds for waist circumference, body fat, and body mass index were utilized to create categorical values. Correlation coefficients, t-tests, and kappa statistics were used to describe the relationship between anthropometric variables. RESULTS: Correlation coefficients revealed an association between percent body fat estimates from skinfolds and body adiposity index (boys 0.77; girls 0.67); however, the body adiposity index systematically overestimated percent body fat at lower levels of adiposity, primarily in boys. Higher mean percent body fat estimates were reported using the body adiposity index compared to skinfolds in boys (25.1% vs. 17.8%), while the opposite relationship was found in girls (body adiposity index 28.5% vs. skinfolds 29.6%). Among boys and girls, correlations to waist circumference and also sensitivity values were higher for body mass index compared to either skinfolds or body adiposity index. CONCLUSIONS: No clear advantage exists in using the body adiposity index to estimate percent body fat or to identify adolescents with increased health risk. The results support the continued use of the body mass index to identify adolescents with increased health risk. PMID- 23921074 TI - Diagnosis and treatment of retroperitoneal ectopic pregnancy: review of the literature. AB - Retroperitoneal ectopic pregnancies (REP) are extremely rare, and early diagnosis and treatment is very difficult. We completed an English literature search in MEDLINE through PubMed for articles on REP. We identified 14 articles (all case reports) but selected only 12 because of unavailable data in the other 2 articles. We also report the case of an REP which was misdiagnosed as ectopic choriocarcinoma. The 33-year-old woman was admitted via the outpatient department with a history of 54 days of amenorrhea and persistent elevated serum beta-human chorionic gonadotropin (hCG) levels. The presumed diagnosis ectopic choriocarcinoma was made based on imaging findings. Single-drug chemotherapy with methotrexate (MTX; 20-mg intramuscular injection daily for 5 consecutive days) was administered. An upper abdominal mass was noticed by the patient and laparotomy was performed. A retroperitoneal pregnant lesion was found and removed successfully. The diagnosis, treatment and mechanisms of REP are discussed. We believe REP should be considered in patients with elevated serum beta-hCG levels when the uterus and adnexa appear to be normal. Systemic administration of MTX in nonruptured REP before operation may prove to be helpful. PMID- 23921076 TI - Complex level alterations of the 2f(1)-f(2) distortion product due to hypoxia. AB - OBJECTIVE: For diagnostic purposes and a better understanding of the pathophysiology of inner ear hearing disorders it would be of great interest to have parameters available that indicate inner ear hypoxia. In animal studies typical hypoxia-related alterations of the 2f1-f2 distortion product otoacoustic emissions (DPOAE) such as a reversible level decrease and destabilization could be demonstrated. The goal of this study was to investigate whether these hypoxia associated alterations can also be observed in humans because this might help develop a new diagnostic tool for patients with inner ear disorders. METHODS: In 16 volunteers DPOAE levels were continuously measured at first under normal room air conditions, during and after 8.5h of oxygen deprivation (13% O2) and during re-oxygenation. Saturation of oxygen of arterial blood (SaO2) was monitored. RESULTS: The mean SaO2 during the hypoxic interval was 78%. A significant decrease in DPOAE level under hypoxia occurred in five different test persons at one or more frequencies (f2=1, 1.5, 2, 3, and 4kHz). A destabilization of the DPOAE level with considerable fluctuations during hypoxia was observed in nine subjects at one or more frequencies. Furthermore, the so called 'post hypoxia effect' could be observed in five participants. CONCLUSION: The observations made here have been described similarly in animal studies and seem to be characteristic of metabolic disorders of the cochlea caused by hypoxia. To our knowledge, this is the first study to examine DPOAE level alterations over time in humans under conditions of normobaric hypoxia. If DPOAE destabilization is observed in a clinical setting in patients with certain inner ear hearing disorders hypoxia can be suspected as one underlying pathophysiological cause which might influence treatment decisions. PMID- 23921077 TI - G protein-coupled estrogen receptor (GPER) expression in endometrial adenocarcinoma and effect of agonist G-1 on growth of endometrial adenocarcinoma cell lines. AB - The G protein-coupled estrogen receptor (GPER, GPR30) is suggested to be involved in non-nuclear estrogen signaling and is expressed in a variety of hormone dependent cancer entities. This study was performed to further elucidate the role of this receptor in endometrial adenocarcinoma. We first analyzed GPER expression at the mRNA level in 88 endometrial cancer or normal endometrial tissue samples and compared it to those of nuclear steroid hormone receptors. GPER transcript levels were found to be about 6-fold reduced, but still present in endometrial cancer. Expression of this receptor was decreased in all grading subgroups when compared to pre- or postmenopausal endometrium. GPER mRNA expression was associated with PR mRNA levels (Spearman's rho 0.4610, p<0.001). We then tested the effect of the GPER ligand G-1 on growth of three endometrial cancer cell lines with different GPER expression. GPER protein levels were highest in RL95-2 cells, moderate in HEC-1A cells and not detectable in HEC-1B cells. The moderate expression level in HEC-1A cells was similar to average tumor tissue expression. Treatment with G-1 significantly inhibited growth of the GPER-positive cell lines RL95-2 and HEC-1A in a dose-dependent manner, whereas the GPER-negative line HEC 1B was not affected. Though GPER transcript levels were found to be reduced in endometrial cancer, our in vitro data suggest that moderate GPER expression might be sufficient to mediate growth-inhibitory effects triggered by its agonist G-1. PMID- 23921078 TI - Temporal analysis of oxidative effects on the pulmonary inflammatory response in mice exposed to cigarette smoke. AB - The most common factor related to the chronic obstructive pulmonary disease (COPD) development is the chronic smoking habit. Our study describes the temporal kinesis of pulmonary cellular influx through BALF analyses of mice acutely exposed to cigarette smoke (CS), the oxidative damage and antioxidative enzyme activities. Thirty-six mice (C57BL/6, 8weeks old, male) were divided in 6 groups: the control group (CG), exposed to ambient air, and the other 30 mice were exposed to CS. Mice exposed to CS presented, especially after the third day of exposure, different cellular subpopulations in BALF. The oxidative damage was significantly higher in CS exposed groups compared to CG. Our data showed that the evaluated inflammatory cells, observed after three days of CS exposure, indicate that this time point could be relevant to studies focusing on these cellular subpopulation activities and confirm the oxidative stress even in a short term CS exposure. PMID- 23921079 TI - Molecular identification and characterization of Type I crustin isoforms from the hemocytes of portunid crabs, Scylla tranquebarica and Portunus pelagicus. AB - Crustins are cationic antimicrobial peptides of ca. 7-14kDa with a characteristic four-disulphide core containing WAP domain, present in the hemocytes of crustaceans. The present study reports the first crustin sequences from two portunid crabs, viz. the mud crab Scylla tranquebarica (St-Crustin, JQ965930) and the blue swimmer crab Portunus pelagicus (Pp-Crustin, JQ753312). St-Crustin and Pp-Crustin represented the complete cDNA sequence of Type I crustin, with an ORF of 336bp encoding 111aa with a predicted molecular weight of 10kDa and a pI of 8. The signal sequence contained 21aa residues, which was followed by a mature peptide with a WAP domain at the C-terminus. Peptide model of St-Crustin and Pp Crustin indicated a randomly coiled structure enclosing two beta-sheets but no helices. St-Crustin and Pp-Crustin shared significant similarities with crustins of portunid crabs (68-95%) and other crabs (60-73%). Phylogenetic analysis showed that St-Crustin and Pp-Crustin possess the same ancestral origin and have a similar evolutionary status like other crustins, which has subsequently diverged at different phases of evolution. St-Crustin and Pp-Crustin were closely related to crab crustins rather than to the crustins of other crustacean groups. The wide distribution of crustins in crustaceans indicates the importance of these AMPs in the innate immunity. Discovery of novel crustins might pave way to the discovery of promising therapeutic/prophylactic agents in health management and disease control in crustacean aquaculture. PMID- 23921080 TI - Piperine ameliorates oxidative stress, inflammation and histological outcome in collagen induced arthritis. AB - OBJECTIVES: Piperine, a main component of Piper species, is a plant alkaloid with a long history of medical use in a variety of inflammatory disorders like rheumatoid arthritis. Due to side effects in current treatment modalities of rheumatoid arthritis, the interest in alternative, well tolerated anti inflammatory remedies has re-emerged. The aim of this work was to evaluate the anti-inflammatory and antiarthritic effects of piperine. METHODS: Arthritis was induced in male Wistar rats by collagen induced arthritis (CIA) method. Piperine was administered at a dose of 100mgkg(-1) and indomethacin at 1mgkg(-1) body weight once daily for 21days. The effects of treatment in the rats were assessed by biochemical (articular elastase, MPO, LPO, GSH, Catalase, SOD and NO), inflammatory mediators (IL-1beta, TNF-alpha, IL-10 and PGE2) and histological studies in joints. RESULTS: Piperine was effective in bringing significant changes on all the parameters (articular elastase, MPO, LPO, GSH, Catalase, SOD and NO) studied. Oral administration of piperine resulted in significantly reduced the levels of pro-inflammatory mediators (IL-1beta, TNF-alpha and PGE2) and increased level of IL-10. The protective effects of piperine against RA were also evident from the decrease in arthritis scoring and bone histology. CONCLUSIONS: In conclusion, the fact that piperine alter a number of factors known to be involved in RA pathogenesis indicates that piperine can be used similar to indomethacin as a safe and effective therapy for CIA and may be useful in the treatment of rheumatoid arthritis. PMID- 23921081 TI - Use of Lipiodol as a drug-delivery system for transcatheter arterial chemoembolization of hepatocellular carcinoma: a review. AB - Hepatocellular carcinoma (HCC) remains a major public health problem. Transarterial chemoembolization (TACE) is recognized as the standard of care for patients with unresectable, asymptomatic, noninvasive and multinodular HCC. This procedure is based on percutaneous administration of a cytotoxic drug emulsified with Lipiodol followed by embolization of the tumour-feeding arteries. The standard procedure involves Lipiodol, an oily contrast medium which consists of a mixture of long-chain di-iodinated ethyl esters of poppy seed fatty acids. The aim of this review is to discuss the physical properties, tumour uptake behaviour and drug delivery effects of Lipiodol, the parameters influencing tumour uptake and future prospects. Lipiodol has a unique place in TACE as it combines three specific characteristics: drug delivery, transient and plastic embolization and radiopacity properties. Substantial heterogeneity in the physicochemical characteristics of Lipiodol/cytotoxic agent emulsions might reduce the efficacy of this procedure and justifies the current interest in Lipiodol for drug delivery. PMID- 23921082 TI - Lung cancer in never smokers: disease characteristics and risk factors. AB - It is estimated that approximately 25% of all lung cancer cases are observed in never-smokers and its incidence is expected to increase due to smoking prevention programs. Risk factors for the development of lung cancer described include second-hand smoking, radon exposure, occupational exposure to carcinogens and to cooking oil fumes and indoor coal burning. Other factors reported are infections (HPV and Mycobacterium tuberculosis), hormonal and diatery factors and diabetes mellitus. Having an affected relative also increases the risk for lung cancer while recent studies have identified several single nucleotide polymorphisms associated with increased risk for lung cancer development in never smokers. Distinct clinical, pathology and molecular characteristics are observed in lung cancer in never smokers; more frequently is observed in females and adenocarcinoma is the predominant histology while it has a different pattern of molecular alterations. The purpose of this review is to summarize our current knowledge of this disease. PMID- 23921083 TI - The combined effect of survivin-targeted shRNA and emodin on the proliferation and invasion of ovarian cancer cells. AB - Survivin has been shown to be highly expressed in ovarian cancers, but not normal ovarian tissue, which makes it an attractive target for ovarian cancer treatment. Emodin is a traditional Chinese medicine that has been found to inhibit proliferation and induce apoptosis in ovarian cancer cells. Thus, in our study, we combined survivin-targeted shRNA (sur-shRNA) with emodin and tested the effects of this combination on ovarian cancer cells to identify more effective therapeutics against ovarian cancer. A sur-shRNA plasmid was constructed and transfected into the ovarian cancer cell lines SKOV3 and HO8910, and the cells were cultured for 24 h. The cells were then treated with emodin for specific time periods and assessed for viability and apoptosis using the MTT assay and flow cytometry, respectively. Cell invasion was also measured using a Matrigel invasion assay. The shRNA specific for survivin effectively reduced the expression of survivin at the mRNA and protein levels in SKOV3 and HO8910 cells. Both emodin and shRNA-mediated knockdown of survivin significantly inhibited cell proliferation, induced apoptosis, and suppressed invasion in SKOV3 and HO8910 cells (P<0.05). Moreover, the combination of the agents significantly enhanced these effects (P<0.05). We found that the combination of sur-shRNA and emodin could be effective in the treatment of ovarian cancer. PMID- 23921084 TI - Training-intensity distribution during an ironman season: relationship with competition performance. AB - PURPOSE: To describe training loads during an Ironman training program based on intensity zones and observe Training-performance relationships. METHODS: Nine triathletes completed a program with the same periodization model aiming at participation in the same Ironman event. Before and during the study, subjects performed ramp-protocol tests, running, and cycling to determine aerobic (AeT) and anaerobic thresholds (AnT) through gas-exchange analysis. For swimming, subjects performed a graded lactate test to determine AeT and AnT. Training was subsequently controlled by heart rate (HR) during each training session over 18 wk. Training and the competition were both quantified based on the cumulative time spent in 3 intensity zones: zone 1 (low intensity; AnT). RESULTS: Most of training time was spent in zone 1 (68% +/- 14%), whereas the Ironman competition was primarily performed in zone 2 (59% +/- 22%). Significant inverse correlations were found between both total training time and training time in zone 1 vs performance time in competition (r = -.69 and -.92, respectively). In contrast, there was a moderate positive correlation between total training time in zone 2 and performance time in competition (r = .53) and a strong positive correlation between percentage of total training time in zone 2 and performance time in competition (r = .94). CONCLUSIONS: While athletes perform with HR mainly in zone 2, better performances are associated with more training time spent in zone 1. A high amount of cycling training in zone 2 may contribute to poorer overall performance. PMID- 23921085 TI - The receptor AXL diversifies EGFR signaling and limits the response to EGFR targeted inhibitors in triple-negative breast cancer cells. AB - The relationship between drug resistance, changes in signaling, and emergence of an invasive phenotype is well appreciated, but the underlying mechanisms are not well understood. Using machine learning analysis applied to the Cancer Cell Line Encyclopedia database, we identified expression of AXL, the gene that encodes the epithelial-to-mesenchymal transition (EMT)-associated receptor tyrosine kinase (RTK) AXL, as exceptionally predictive of lack of response to ErbB family receptor-targeted inhibitors. Activation of EGFR (epidermal growth factor receptor) transactivated AXL, and this ligand-independent AXL activity diversified EGFR-induced signaling into additional downstream pathways beyond those triggered by EGFR alone. AXL-mediated signaling diversification was required for EGF (epidermal growth factor)-elicited motility responses in AXL positive TNBC (triple-negative breast cancer) cells. Using cross-linking coimmunoprecipitation assays, we determined that AXL associated with EGFR, other ErbB receptor family members, MET (hepatocyte growth factor receptor), and PDGFR (platelet-derived growth factor receptor) but not IGF1R (insulin-like growth factor 1 receptor) or INSR (insulin receptor). From these AXL interaction data, we predicted AXL-mediated signaling synergy for additional RTKs and validated these predictions in cells. This alternative mechanism of receptor activation limits the use of ligand-blocking therapies and indicates against therapy withdrawal after acquired resistance. Further, subadditive interaction between EGFR- and AXL-targeted inhibitors across all AXL-positive TNBC cell lines may indicate that increased abundance of EGFR is principally a means to transactivation-mediated signaling. PMID- 23921086 TI - Interference with akt signaling protects against myocardial infarction and death by limiting the consequences of oxidative stress. AB - The intricacy of multiple feedback loops in the pathways downstream of Akt allows this kinase to control multiple cellular processes in the cardiovascular system and precludes inferring consequences of its activation in specific pathological conditions. Akt1, the major Akt isoform in the heart and vasculature, has a protective role in the endothelium during atherosclerosis. However, Akt1 activation may also have detrimental consequences in the cardiovascular system. Mice lacking both the high-density lipoprotein receptor SR-BI (scavenger receptor class B type I) and ApoE (apolipoprotein E), which promotes clearance of remnant lipoproteins, are a model of severe dyslipidemia and spontaneous myocardial infarction. We found that Akt1 was activated in these mice, and this activation correlated with cardiac dysfunction, hypertrophy, and fibrosis; increased infarct area; cholesterol accumulation in macrophages and atherosclerosis; and reduced life span. Akt1 activation was associated with inflammation, oxidative stress, accumulation of oxidized lipids, and increased abundance of CD36, a major sensor of oxidative stress, and these events created a positive feedback loop that exacerbated the consequences of oxidative stress. Genetic deletion of Akt1 in this mouse model resulted in decreased mortality, alleviation of multiple complications of heart disease, and reduced occurrence of spontaneous myocardial infarction. Thus, interference with Akt1 signaling in vivo could be protective and improve survival under dyslipidemic conditions by reducing oxidative stress and responses to oxidized lipids. PMID- 23921088 TI - The ratio of osteoprotegerin to fetuin-a is independently associated with vascular stiffness in hemodialysis patients. AB - BACKGROUND: The aim of the present study was to compare levels of fetuin-A, osteoprotegerin (OPG), and heat shock protein (HSP)70 according to the stage of chronic kidney disease (CKD), as well as to evaluate the association between serum fetuin-A, OPG, and HSP70 concentrations with respect to vascular stiffness and calcification in hemodialysis (HD) patients. METHODS: We measured fetuin-A, OPG, and HSP70 in 35 healthy controls, 35 patients with stage 3 CKD, 35 patients with stage 4 CKD, and 81 HD patients. Using these data, we studied the association of fetuin-A, OPG, and HSP70 with clinical, biochemical, and vascular measures in HD patients. RESULTS: Levels of OPG and HSP70 were higher and fetuin A was lower in HD patients than in healthy controls. The cardio-ankle vascular index (CAVI) showed a positive correlation with OPG (r = 0.248, p = 0.040) and the OPG/fetuin-A ratio (r = 0.260, p = 0.031). The ankle-brachial index (ABI) showed a negative correlation with OPG (r = -0.245, p = 0.031) and the OPG/fetuin A ratio (r = -0.267, p = 0.018). Intima-media thickness (IMT) showed a positive correlation with OPG (r = 0.273, p = 0.014) and the OPG/fetuin-A ratio (r = 0.269, p = 0.015). On stepwise multiple linear regression analyses, only the logarithmic function of the OPG/fetuin-A ratio was independently associated with CAVI (beta = 13.325, SE = 6.247, p = 0.038). CONCLUSIONS: Our results demonstrate that OPG and the OPG/fetuin-A ratio are correlated with increased vascular stiffness and IMT in HD patients. In addition, the OPG/fetuin-A ratio was independently associated with vascular stiffness in HD patients. PMID- 23921089 TI - A randomized trial comparing metallic and absorbable staples for closure of a Pfannenstiel incision for cesarean delivery. AB - OBJECTIVE: The purpose of the study is to compare postoperative pain, cost, speed of closure, and patient satisfaction of Pfannenstiel skin incisions closed with traditional metallic staples vs absorbable staples after cesarean delivery. It is hypothesized that incisions closed with absorbable staples will cause less postoperative pain than traditional metallic staples. STUDY DESIGN: A randomized, controlled trial was conducted from July 2010 through May 2011. Patients undergoing a scheduled cesarean delivery via a Pfannenstiel skin incision were recruited. Patients were randomized into the control group (metallic staples) or the experimental group (absorbable staples). The postpartum nurse and patient were blinded to the type of staples. Postoperative pain was assessed using a visual analog scale on both postoperative day 1 and day of discharge, and the total dose of oral narcotics taken during the postoperative period was assessed. RESULTS: In all, 100 patients enrolled in the study: 50 in each group. Based on visual analog scale scores, there were no significant differences between the 2 groups on postoperative day 1 or day of discharge. There were no significant differences in the total dose of oral narcotics taken or in wound complication rates. The time for skin closure was significantly different: 3.5 +/- 1.7 for absorbable and 1.39 +/- 0.7 minutes for metallic staples (P < .0001). The calculated cost of each device, including placement and removal, was $285.60 for the absorbable and $150.79 for the metallic staples. CONCLUSION: Postoperative pain is comparable for both devices. The absorbable staple skin closure time, and therefore cost, is significantly greater than for metallic staples. PMID- 23921087 TI - Simultaneous profiling of 194 distinct receptor transcripts in human cells. AB - Many signal transduction cascades are initiated by transmembrane receptors with the presence or absence and abundance of receptors dictating cellular responsiveness. We provide a validated array of quantitative reverse transcription polymerase chain reaction (qRT-PCR) reagents for high-throughput profiling of the presence and relative abundance of transcripts for 194 transmembrane receptors in the human genome. We found that the qRT-PCR array had greater sensitivity and specificity for the detected receptor transcript profiles compared to conventional oligonucleotide microarrays or exon microarrays. The qRT PCR array also distinguished functional receptor presence versus absence more accurately than deep sequencing of adenylated RNA species by RNA sequencing (RNA seq). By applying qRT-PCR-based receptor transcript profiling to 40 human cell lines representing four main tissues (pancreas, skin, breast, and colon), we identified clusters of cell lines with enhanced signaling capabilities and revealed a role for receptor silencing in defining tissue lineage. Ectopic expression of the interleukin-10 (IL-10) receptor-encoding gene IL10RA in melanoma cells engaged an IL-10 autocrine loop not otherwise present in this cell type, which altered signaling, gene expression, and cellular responses to proinflammatory stimuli. Our array provides a rapid, inexpensive, and convenient means for assigning a receptor signature to any human cell or tissue type. PMID- 23921090 TI - Patient preferences for uterine preservation and hysterectomy in women with pelvic organ prolapse. AB - OBJECTIVE: The purpose of this study was to describe patient preferences for uterine preservation and hysterectomy in women with pelvic organ prolapse symptoms and to describe predictors of preference for uterine preservation. STUDY DESIGN: This multicenter, cross-sectional study evaluated patient preferences for uterine preservation vs hysterectomy in women with prolapse symptoms who were being examined for initial urogynecologic evaluation. Before meeting the physician, the women completed a questionnaire that asked them to indicate their prolapse treatment preference (uterine preservation vs hysterectomy) for scenarios in which the efficacy of treatment varied. Patient characteristics that were associated with preferences were determined, and predictors for uterine preservation preference were identified with multivariable logistic regression. RESULTS: Two hundred thirteen women participated. Assuming outcomes were equal between hysterectomy and uterine preservation, 36% of the women preferred uterine preservation; 20% of the women preferred hysterectomy, and 44% of the women had no strong preference. If uterine preservation was superior, 46% of the women preferred uterine preservation, and 11% of the women preferred hysterectomy. If hysterectomy was superior, 21% of the women still preferred uterine preservation, despite inferior efficacy. On multivariable logistic regression, women in the South had decreased odds of preferring uterine preservation compared with women in the Northeast (odds ratio [OR], 0.17; 95% CI, 0.05-0.66). Women with at least some college education (OR, 2.87; 95% CI, 1.08-7.62) and those who believed that the uterus is important for their sense of self (OR, 28.2; 95% CI, 5.00-158.7) had increased odds for preferring uterine preservation. CONCLUSION: A higher proportion of women with prolapse symptoms who were examined for urogynecologic evaluation preferred uterine preservation, compared with hysterectomy. Geographic region, education level, and belief that the uterus is important for a sense of self were predictors of preference for uterine preservation. PMID- 23921091 TI - Variations in postdelivery infection and thrombosis by hospital teaching status. AB - OBJECTIVE: Using a population-based cohort, we examined hospital-level variation overall and by teaching status in 2 maternal outcomes, postpartum infections, and thrombosis. STUDY DESIGN: Linked birth certificate and hospital admission records for mother and infant were collected on all deliveries in Pennsylvania and California from 2004 through 2005. A risk adjustment model was created using maternal and fetal comorbidities identified by International Classification of Diseases-9 codes. Hospitals were classified as teaching (TH) or nonteaching hospitals (NTH) based on the presence of obstetrics and gynecology residents. Rates of infections and thrombosis were evaluated overall and by hospital teaching status. RESULTS: A total of 939,871 patients were evaluated from 402 hospitals (369 NTH and 33 TH). The unadjusted infection and venous thromboembolic events (VTE) rates were higher in TH vs NTH (infection: 2.04% vs 1.07%, P < .001; VTE: 1.04% vs 0.08%, P < .001). There was variation in the rates of these complications across hospitals, with the adjusted observed/expected ratio rates for infection and thrombosis for each hospital, ranging from 0-5.2 and 0-8.6, respectively. CONCLUSION: There is substantial variation in infection and thrombosis rates among hospitals both overall and by teaching status, suggesting that these 2 outcomes may be useful measures of inpatient obstetric quality. PMID- 23921093 TI - Obstetrical outcome of young women with a past history of cerebral venous thrombosis. AB - BACKGROUND: This study was designed to review the obstetrical outcome of a consecutive series of cerebral venous thrombosis (CVT) affecting fertile women over a long period of time. METHODS: From a computerized database of four hospitals of a French region (Poitou-Charentes), we selected patients admitted to hospital for CVT between January 1995 and February 2012. All the case notes were re-examined by two neurologists to confirm the initial diagnosis of CVT. The criterion of inclusion in our study was the occurrence of CVT in a woman <= 40 years of age. All the patients were recontacted by telephone in September 2012 and could be seen in an outpatient clinic. The data of interest were: occurrence of subsequent pregnancies, outcome of these pregnancies, their possible complications, their management with respect to preventive medication, details on the birth and the neonate. RESULTS: Out of 190 consecutive patients hospitalized for CVT, 62 women aged <= 40 years were included (mean age 27.2 +/- 6.7 years at the time of their cerebrovascular event). The mean duration of follow-up was 89.5 +/- 60.6 months (median: 76 months). There were 45 pregnancies in 24 of the women. Among these 45 pregnancies, 1 was in progress, 24 were completed resulting in normal children, whereas 20 were terminated (5 voluntary abortions, 14 miscarriages and 1 medical abortion). During the pregnancies recorded, there was one recurrence of CVT and no extra-CVT. Various management strategies were adopted, depending on the identified cause(s) for CVT and the medical history of the patient. CONCLUSIONS: Our study confirms that the occurrence of a CVT in young women is not a contraindication for subsequent pregnancy. However, it points to a high incidence of miscarriage. Apart from this fact, there is no increase in materno-fetal complications during pregnancy and childbirth, and the neonates are healthy. The risk of recurrence of a CVT or extra-CVT during subsequent pregnancy is low but most of patients were on preventive antithrombotic medication. PMID- 23921092 TI - Uric acid excretion in rotavirus gastro-enteritis. AB - BACKGROUND: Urate urolithiasis in children has been reported in Japan in association with rotavirus (RV) gastro-enteritis (GE). AIMS: To test the hypothesis that children with RV GE have an increased risk of hyperuricosuria compared with GE presumably caused by other viruses. OBJECTIVES: Prospective analytic cohort study of urinary uric acid excretion in children presenting with GE between 1 January 2011 and 31 May 2012. METHODS: Two groups were compared: group R (RV GE) and group N (with presumed other viral causes of GE). Serum urea, creatinine (Scr), uric acid (Sur) and urinary uric acid were compared with creatinine (Uur/Ucr) ratio, fractional excretion of uric acid (FEur) and uric acid for creatinine clearance between the two groups. RESULTS: A total of 87 Emirati children were enrolled in the study. Group R included 46 children (mean age 25 months) and group N 41 children (mean age 43 months). There was no significant difference between the two groups in the blood levels of urea, creatinine, uric acid, nor in urinary pH and specific gravity. Urinary uric acid excretion measured by Uur/Ucr ratio, uric acid for creatinine clearance and FEur was not significantly different between the two groups. CONCLUSION: There was no significant difference in uric acid levels and uric acid excretion between patients with RV GE and those with other presumed viral causes of GE. Further studies with larger sample sizes including children with more severe dehydration and a prolonged course of GE are needed. PMID- 23921094 TI - Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM. AB - BACKGROUND: Indolent systemic mastocytosis (ISM) without skin lesions (ISMs(-)) shows a higher prevalence in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to bone marrow (BM) mast cells (MCs) than ISM with skin lesions (ISMs(+)). Interestingly, in almost one-half of ISMs(-) patients, MC-mediator release episodes are triggered exclusively by insects. OBJECTIVE: We aimed to determine the clinical and laboratory features of ISMs(-) associated with insect-induced anaphylaxis (insectISMs(-)) versus other patients with ISM. METHODS: A total of 335 patients presenting with MC activation syndrome, including 143 insectISMs(-), 72 ISMs(-) triggered by other factors (otherISMs(-)), 56 ISMs(+), and 64 nonclonal MC activation syndrome, were studied. RESULTS: Compared with otherISMs(-) and ISMs(+) patients, insectISMs(-) cases showed marked male predominance (78% vs 53% and 46%; P < .001), a distinct pattern of MC-related symptoms, and significantly lower median serum baseline tryptase levels (22.4 vs 28.7 and 45.8 MUg/L; P <= .009). Moreover, insectISMs(-) less frequently presented BM MC aggregates (46% vs 70% and 81%; P <= .001), and they systematically showed MC-restricted KIT mutation. CONCLUSIONS: ISMs(-) patients with anaphylaxis triggered exclusively by insects display clinical and laboratory features that are significantly different from other ISM cases, including other ISMs(-) and ISMs(+) patients, suggesting that they represent a unique subgroup of ISM with a particularly low BM MC burden in the absence of adverse prognostic factors. PMID- 23921095 TI - Structural white matter asymmetries in relation to functional asymmetries during speech perception and production. AB - Functional hemispheric asymmetries of speech production and perception are a key feature of the human language system, but their neurophysiological basis is still poorly understood. Using a combined fMRI and tract-based spatial statistics approach, we investigated the relation of microstructural asymmetries in language relevant white matter pathways and functional activation asymmetries during silent verb generation and passive listening to spoken words. Tract-based spatial statistics revealed several leftward asymmetric clusters in the arcuate fasciculus and uncinate fasciculus that were differentially related to activation asymmetries in the two functional tasks. Frontal and temporal activation asymmetries during silent verb generation were positively related to the strength of specific microstructural white matter asymmetries in the arcuate fasciculus. In contrast, microstructural uncinate fasciculus asymmetries were related to temporal activation asymmetries during passive listening. These findings suggest that white matter asymmetries may indeed be one of the factors underlying functional hemispheric asymmetries. Moreover, they also show that specific localized white matter asymmetries might be of greater relevance for functional activation asymmetries than microstructural features of whole pathways. PMID- 23921096 TI - Show me how you walk and I tell you how you feel - a functional near-infrared spectroscopy study on emotion perception based on human gait. AB - The ability to recognize and adequately interpret emotional states in others plays a fundamental role in regulating social interaction. Body language presents an essential element of nonverbal communication which is often perceived prior to mimic expression. However, the neural networks that underlie the processing of emotionally expressive body movement and body posture are poorly understood. 33 healthy subjects have been investigated using the optically based imaging method functional near-infrared spectroscopy (fNIRS) during the performance of a newly developed emotion discrimination paradigm consisting of faceless avatars expressing fearful, angry, sad, happy or neutral gait patterns. Participants were instructed to judge (a) the presented emotional state (emotion task) and (b) the observed walking speed of the respective avatar (speed task). We measured increases in cortical oxygenated haemoglobin (O2HB) in response to visual stimulation during emotion discrimination. These O2HB concentration changes were enhanced for negative emotions in contrast to neutral gait sequences in right occipito-temporal and left temporal and temporo-parietal brain regions. Moreover, fearful and angry bodies elicited higher activation increases during the emotion task compared to the speed task. Haemodynamic responses were correlated with a number of behavioural measures, whereby a positive relationship between emotion regulation strategy preference and O2HB concentration increases after sad walks was mediated by the ability to accurately categorize sad walks. Our results support the idea of a distributed brain network involved in the recognition of bodily emotion expression that comprises visual association areas as well as body/movement perception specific cortical regions that are also sensitive to emotion. This network is activated less when the emotion is not intentionally processed (i.e. during the speed task). Furthermore, activity of this perceptive network is, mediated by the ability to correctly recognize emotions, indirectly connected to active emotion regulation processes. We conclude that a full understanding of emotion perception and its neural substrate requires the investigation of dynamic representations and means of expression other than the face. PMID- 23921098 TI - Functional and structural brain differences associated with mirror-touch synaesthesia. AB - Observing touch is known to activate regions of the somatosensory cortex but the interpretation of this finding is controversial (e.g. does it reflect the simulated action of touching or the simulated reception of touch?). For most people, observing touch is not linked to reported experiences of feeling touch but in some people it is (mirror-touch synaesthetes). We conducted an fMRI study in which participants (mirror-touch synaesthetes, controls) watched movies of stimuli (face, dummy, object) being touched or approached. In addition we examined whether mirror touch synaesthesia is associated with local changes of grey and white matter volume in the brain using VBM (voxel-based morphometry). Both synaesthetes and controls activated the somatosensory system (primary and secondary somatosensory cortices, SI and SII) when viewing touch, and the same regions were activated (by a separate localiser) when feeling touch--i.e. there is a mirror system for touch. However, when comparing the two groups, we found evidence that SII seems to play a particular important role in mirror-touch synaesthesia: in synaesthetes, but not in controls, posterior SII was active for watching touch to a face (in addition to SI and posterior temporal lobe); activity in SII correlated with subjective intensity measures of mirror-touch synaesthesia (taken outside the scanner), and we observed an increase in grey matter volume within the SII of the synaesthetes' brains. In addition, the synaesthetes showed hypo-activity when watching touch to a dummy in posterior SII. We conclude that the secondary somatosensory cortex has a key role in this form of synaesthesia. PMID- 23921097 TI - Distance informed Track-Weighted Imaging (diTWI): a framework for sensitising streamline information to neuropathology. AB - Track-Weighted Imaging (TWI), where voxel intensity is based on image metrics encoded along streamline trajectories, provides a mechanism to study white matter disease. However, with generalised streamline weighting, it is difficult to localise the precise anatomical source and spread of injury or neuropathology. This limitation can be overcome by modulating the voxel weight based on the distance of the voxel from a given anatomical location along the tract, which we term diTWI: distance informed Track-Weighted Imaging. The location of known neuropathology can be delineated on any given imaging modality (e.g. MRI or PET). To demonstrate the clinical utility of this approach, we measured tumour cell infiltration along WM fibre tracts in 13 patients with newly diagnosed glioblastoma and 1 patient with Anaplastic Astrocytoma. TWI and diTWI maps were generated using information obtained from dynamic contrast enhanced MRI (area under the curve, AUC) and diffusivity maps (ADC and FA) with tumour boundaries automatically extracted using a logistic regression classifier. The accuracy of the derived tumour volumes was compared to those generated using 3,4-dihydroxy-6 [(18)F]-fluoro-l-phenylalanine (FDOPA) PET imaging. The accuracy of the tumour volumes generated from the diTWI maps was superior to volumes derived from the TWI, geometric distance or baseline AUC, FA and ADC maps. The relative overlap and relative dissimilarity rates for the diTWI generated tumour volumes after classification were found to be 82.3+/-15.3% (range 69.1-91.9) and 16.9+/-8.8% (range 7.9-37.5), respectively. These findings show that diTWI maps provide a useful framework for localising neuropathological processes occurring along WM pathways. PMID- 23921099 TI - Deep brain stimulation for enhancement of learning and memory. AB - Deep brain stimulation (DBS) has emerged as a powerful technique to treat a host of neurological and neuropsychiatric disorders from Parkinson's disease and dystonia, to depression, and obsessive compulsive disorder (Benabid et al., 1987; Lang and Lozano, 1998; Davis et al., 1997; Vidailhet et al., 2005; Mayberg et al., 2005; Nuttin et al., 1999). More recently, results suggest that DBS can enhance memory for facts and events that are dependent on the medial temporal lobe (MTL), thus raising the possibility for DBS to be used as a treatment for MTL- related neurological disorders (e.g. Alzheimer's disease, temporal lobe epilepsy, and MTL injuries). In the following review, we summarize key results that show the ability of DBS or cortical surface stimulation to enhance memory. We also discuss current knowledge regarding the temporal specificity, underlying neurophysiological mechanisms of action, and generalization of stimulation's effects on memory. Throughout our discussion, we also propose several future directions that will provide the necessary insight into if and how DBS could be used as a therapeutic treatment for memory disorders. PMID- 23921100 TI - Diffusion MRI of the developing cerebral cortical gray matter can be used to detect abnormalities in tissue microstructure associated with fetal ethanol exposure. AB - Fetal alcohol spectrum disorders (FASDs) comprise a wide range of neurological deficits that result from fetal exposure to ethanol (EtOH), and are the leading cause of environmentally related birth defects and mental retardation in the western world. One aspect of diagnostic and therapeutic intervention strategies that could substantially improve our ability to combat this significant problem would be to facilitate earlier detection of the disorders within individuals. Light microscopy-based investigations performed by several laboratories have previously shown that morphological development of neurons within the early developing cerebral cortex is abnormal within the brains of animals exposed to EtOH during fetal development. We and others have recently demonstrated that diffusion MRI can be of utility for detecting abnormal cellular morphological development in the developing cerebral cortex. We therefore assessed whether diffusion tensor imaging (DTI) could be used to distinguish the developing cerebral cortices of ex vivo rat pup brains born from dams treated with EtOH (EtOH; 4.5 g/kg, 25%) or calorie-matched quantities of maltose/dextrin (M/D) throughout gestation. Water diffusion and tissue microstructure were investigated using DTI (fractional anisotropy, FA) and histology (anisotropy index, AI), respectively. Both FA and AI decreased with age, and were higher in the EtOH than the M/D group at postnatal ages (P)0, P3, and P6. Additionally, there was a significant correlation between FA and AI measurements. These findings provide evidence that disruptions in cerebral cortical development induced by EtOH exposure can be revealed by water diffusion anisotropy patterns, and that these disruptions are directly related to cerebral cortical differentiation. PMID- 23921103 TI - Skin delivery--to Scheuplein and beyond. Preface. PMID- 23921104 TI - Skin--'that unfakeable young surface'. AB - The 20- to 25-year period from the mid-1960s to the early 1990s represents, in many ways, a 'golden era' in the understanding of skin barrier function, percutaneous penetration and (trans)dermal drug delivery. From the ground breaking mechanistic work of Scheuplein and Blank, and the 'gold standard' in vivo skin absorption experiments of Feldmann and Maibach, through the unravelling of the stratum corneum's structural and physicochemical characteristics that make it such an incredible feat of bioengineering, to the elegant biophysical and modelling studies of Potts, Francoeur and many others, the idea of administering drugs rationally to treat both local and systemic diseases was transformed from something close to the ravings of a lunatic to the reality of significant therapeutic and commercial success. This short article attempts to pick out some of the highlights along the way from the viewpoint of an interested observer and occasional participant in the 'action'. (c) 2013 S. Karger AG, Basel. PMID- 23921101 TI - Neuroimaging of the Philadelphia neurodevelopmental cohort. AB - The Philadelphia Neurodevelopmental Cohort (PNC) is a large-scale, NIMH funded initiative to understand how brain maturation mediates cognitive development and vulnerability to psychiatric illness, and understand how genetics impacts this process. As part of this study, 1445 adolescents ages 8-21 at enrollment underwent multimodal neuroimaging. Here, we highlight the conceptual basis for the effort, the study design, and the measures available in the dataset. We focus on neuroimaging measures obtained, including T1-weighted structural neuroimaging, diffusion tensor imaging, perfusion neuroimaging using arterial spin labeling, functional imaging tasks of working memory and emotion identification, and resting state imaging of functional connectivity. Furthermore, we provide characteristics regarding the final sample acquired. Finally, we describe mechanisms in place for data sharing that will allow the PNC to become a freely available public resource to advance our understanding of normal and pathological brain development. PMID- 23921105 TI - Howard I. Maibach: extraordinary leadership in integrating key concepts underpinning our understanding of percutaneous absorption and occupational dermatology. AB - The purpose of the present article is to briefly highlight some contributions of Prof. Howard I. Maibach to the field of dermatology. After a few introducing remarks regarding Howard's personal career, the article specifically reviews contributions to the understanding of percutaneous absorption and to occupational dermatology. He and his companions/coworkers established and introduced experimental prerequisites to better study and understand percutaneous absorption - both in vitro and in vivo. Not less influential was his contribution to occupational dermatology acting as a founding member of the International Contact Dermatitis Research Group and coinaugurating the North American Contact Dermatitis Group. These groups have been very active ever since. As an academic teacher, he inspired young colleagues to perform original research work and to establish their own working groups. He has done this most successfully with many fellows who worked with him over the years, and who are now leading departments or companies dedicated to dermatological research all over the world. Probably this is his most important and lasting achievement. PMID- 23921106 TI - A personal view of skin permeation (1960-2013). AB - I want to thank Mike Roberts for arranging this issue of the journal and Annette Bunge and Richard Guy for reviewing this paper. This is, first, a history of my introduction to the field of skin permeability, and then an attempt to recall (with the inaccuracies that implies) the highlights of my research (1960-1975) on skin permeation, and finally a reflection by an old-timer on more recent concepts. PMID- 23921102 TI - Distinct cortical networks activated by auditory attention and working memory load. AB - Auditory attention and working memory (WM) allow for selection and maintenance of relevant sound information in our minds, respectively, thus underlying goal directed functioning in everyday acoustic environments. It is still unclear whether these two closely coupled functions are based on a common neural circuit, or whether they involve genuinely distinct subfunctions with separate neuronal substrates. In a full factorial functional MRI (fMRI) design, we independently manipulated the levels of auditory-verbal WM load and attentional interference using modified Auditory Continuous Performance Tests. Although many frontoparietal regions were jointly activated by increases of WM load and interference, there was a double dissociation between prefrontal cortex (PFC) subareas associated selectively with either auditory attention or WM. Specifically, anterior dorsolateral PFC (DLPFC) and the right anterior insula were selectively activated by increasing WM load, whereas subregions of middle lateral PFC and inferior frontal cortex (IFC) were associated with interference only. Meanwhile, a superadditive interaction between interference and load was detected in left medial superior frontal cortex, suggesting that in this area, activations are not only overlapping, but reflect a common resource pool recruited by increased attentional and WM demands. Indices of WM-specific suppression of anterolateral non-primary auditory cortices (AC) and attention specific suppression of primary AC were also found, possibly reflecting suppression/interruption of sound-object processing of irrelevant stimuli during continuous task performance. Our results suggest a double dissociation between auditory attention and working memory in subregions of anterior DLPFC vs. middle lateral PFC/IFC in humans, respectively, in the context of substantially overlapping circuits. PMID- 23921107 TI - Current understanding of skin barrier morphology. AB - It was recently shown that the stratum corneum fat layer, i.e. the skin permeability barrier, has a unique molecular arrangement - stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety. We here give a brief historical perspective to the field of skin permeability barrier research and specifically address some selected contributions to the current understanding of skin barrier morphology. PMID- 23921108 TI - Current understanding of skin biology pertinent to skin penetration: skin biochemistry. AB - The purpose of this review is to summarize some of the biochemical or chemical findings that have contributed most significantly to our current understanding of the permeability barrier of the skin. This literature survey covers the period from the 1970s up to the present. This seems appropriate since earlier progress was comprehensively covered in a 1978 review by Bob Scheuplein entitled 'Permeability of the skin: a review of major concepts' and in the earlier review by Scheuplein and Blank entitled 'Permeability of the skin'. Both of these review articles are still being cited, and the earlier one has been cited more than 800 times. Overlap with material covered in these earlier publications will be minimized. The overall significance of findings from some of the most recent years may not yet be determined. The emphasis will be placed on the determination of the composition and structures of the epidermal lipids, especially those of the stratum corneum, key enzymes in the biosynthesis of these lipids and some of the physical chemical properties of these lipids as revealed by X-ray diffraction, infrared spectroscopy and other physical methods. PMID- 23921109 TI - Drug delivery with topically applied nanoparticles: science fiction or reality. AB - The efficacy of topically applied drugs is determined by their action mechanism and their potential capacity of passing the skin barrier. Nanoparticles are assumed to be efficient carrier systems for drug delivery through the skin barrier. For flexible nanoparticles like liposomes, this effect has been well demonstrated. The penetration properties of solid nanoparticles are currently under intensive investigation. The crucial advantage of nanoparticles over non particulate substances is their capability to penetrate deeply into the hair follicles where they can be stored for several days. There is no evidence, yet, that solid particles >=40 nm are capable of passing through the healthy skin barrier. Therefore and in spite of the long-standing research efforts in this field, commercially available solid nanoparticle-based products for drug delivery through the healthy skin are still missing. Nevertheless, the prospects for the clinical use of nanoparticles in drug delivery are tremendous. They can be designed as transport systems delivering drugs efficiently into the hair follicles in the vicinity of specific target structures. Once deposited at these structures, specific signals might trigger the release of the drugs and exert their effects on the target cells. In this article, examples of such triggered drug release are presented. PMID- 23921110 TI - Brian Barry: innovative contributions to transdermal and topical drug delivery. AB - Brian Barry published over 300 research articles across topics ranging from colloid science, vasoconstriction and the importance of thermodynamics in dermal drug delivery to exploring the structure and organisation of the stratum corneum barrier lipids and numerous strategies for improving topical and transdermal drug delivery, including penetration enhancers, supersaturation, coacervation, eutectic formation and the use of varied liposomes. As research in the area blossomed in the early 1980s, Brian wrote the book that became essential reading for both new and established dermal delivery scientists, explaining the background mathematics and principles through to formulation design. Brian also worked with numerous scientists, as collaborators and students, who have themselves taken his rigorous approach to scientific investigation into their own research groups. This paper can only describe a small fraction of the many significant contributions that Brian made to the field during his 40-year academic career. PMID- 23921111 TI - Passive and iontophoretic transport through the skin polar pathway. AB - The purpose of the present article is to briefly recount the contributions of Prof. William I. Higuchi to the area of skin transport. These contributions include developing fundamental knowledge of the barrier properties of the stratum corneum, mechanisms of skin transport, concentration gradient across skin in topical drug applications that target the viable epidermal layer, and permeation enhancement by chemical and electrical means. The complex and changeable nature of the skin barrier makes it difficult to assess and characterize the critical parameters that influence skin permeation. The systematic and mechanistic approaches taken by Dr. Higuchi in studying these parameters provided fundamental knowledge in this area and had a measured and lasting influence upon this field of study. This article specifically reviews the validation and characterization of the polar permeation pathway, the mechanistic model of skin transport, the influence of the dermis on the target skin concentration concept, and iontophoretic transport across the polar pathway of skin including the effects of electroosmosis and electropermeabilization. PMID- 23921112 TI - Analysing the skin barrier from down under. AB - Over the past 40 years the Australian contribution to the field of skin science has been led by Michael Roberts. One of his earliest papers on membrane permeation was published in Nature, setting the scene for his huge contribution to both the fundamental understanding of skin permeability and the application of that knowledge to improved clinical outcomes, new delivery technologies and minimizing toxicological risk. His work has been characterized by a mechanistic, mathematical approach to defining skin permeation. He defined the parameters important to skin permeation, established structure-penetration relationships and demonstrated the importance of maximum flux from a clinical and toxicological viewpoint. Through his systematic approach, Mike showed a parabolic relationship between maximum flux and lipophilicity, and established that this is driven mainly by variations in solubility of the solute in the stratum corneum. One of the significant strengths of Mike's work is the ability to express biological concepts in mathematical terms. He has developed mathematical models that enhance our understanding of epidermal, dermal, deep tissue permeation and follicular transport. Throughout his career Mike has been involved in pioneering new technologies both for analysing the skin barrier and influencing permeation across it. His fundamental work in the area of iontophoresis provided models that defined the parameters influencing its permeation enhancement. Mike's research has been translated into improved clinical outcomes, reduced toxicological risk and changes to the regulation of skin products. This article provides an insight into Mike Roberts and the Australian contribution to skin science. PMID- 23921113 TI - Engineering approaches to transdermal drug delivery: a tribute to contributions of prof. Robert Langer. AB - Transdermal drug delivery continues to provide an advantageous route of drug administration over injections. While the number of drugs delivered by passive transdermal patches has increased over the years, no macromolecule is currently delivered by the transdermal route. Substantial research efforts have been dedicated by a large number of researchers representing varied disciplines including biology, chemistry, pharmaceutics and engineering to understand, model and overcome the skin's barrier properties. This article focuses on engineering contributions to the field of transdermal drug delivery. The article pays tribute to Prof. Robert Langer, who pioneered the engineering approach towards transdermal drug delivery. Over a period spanning nearly 25 years since his first publication in the field of transdermal drug delivery, Bob Langer has deeply impacted the field by quantitative analysis and innovative engineering. At the same time, he has inspired several generations of engineers by collaborations and mentorship. His scientific insights, innovative technologies, translational efforts and dedicated mentorship have transformed the field. PMID- 23921114 TI - Percutaneous penetration paradigms: the contribution of Jonathan Hadgraft. AB - This paper addresses the application of physical chemistry towards understanding the processes of percutaneous penetration. Over the years, this approach has been used by the subject of this review to advance our knowledge of the skin and to interpret, model and predict dermal delivery. The basic laws of diffusion provide a framework for the comprehension of skin permeability and, as a corollary, how the barrier function can be modulated. The importance of understanding the physicochemical properties of potential skin permeants is highlighted. Rational formulation strategies for passive skin delivery are outlined. However, the overriding emphasis is that multidisciplinary approaches must be used to advance the field. This is exemplified in the work and references cited. PMID- 23921115 TI - Modelling skin penetration using the Laplace transform technique. AB - The Laplace transform is a convenient mathematical tool for solving ordinary and partial differential equations. The application of this technique to problems arising in drug penetration through the skin is reviewed in this paper. PMID- 23921116 TI - Lipid solubility and molecular weight: whose idea was that. AB - Gene Cooper was a bright theoretician, a skilled product developer, and a motivational leader who applied his talents to the skin science area early in his career. His work led to the development of finite dose skin absorption models, chemical penetration enhancer technologies and quantitative structure-penetration relationships for chemicals contacting human skin. His ideas regarding the impact of molecular weight and lipid solubility on skin transport catalyzed the later development by Potts and Guy of the first successful skin permeability model. But Gene's most important contribution to the field was as a scientific role model and an inspirational leader who launched the careers of several young scientists, including the author of this article. PMID- 23921117 TI - Richard Guy and his collaborators: 'crackling' the skin code. AB - This paper aims to summarize the contributions of Richard Guy and collaborators to the skin field. Major contributions have been areas such as the modelling of skin absorption, use of spectroscopic techniques (Fourier transform infrared spectroscopy, attenuated total reflectance Fourier transform infrared spectroscopy and impedance spectroscopy) to characterize the skin barrier and the effects of enhancing techniques on the membrane, dermatopharmacokinetics and assessment of topical bio-availability, iontophoresis and reverse iontophoresis, and use of imaging techniques to elucidate pathways of penetration and the skin disposition of nanoparticles. The field of topical and transdermal drug delivery has benefitted incalculably from the extensive work of Guy and his group: their findings about mechanisms of drug delivery and permeation enhancement, and the development of methodologies which are now accepted as gold standards by skin scientists. PMID- 23921118 TI - Annette Bunge: developing the principles in percutaneous absorption using chemical engineering principles. AB - Annette Bunge and her research group have had the central theme of mathematically modeling the dermal absorption process. Most of the research focus has been on estimating dermal absorption for the purpose of risk assessment, for exposure scenarios in the environment and in the occupational setting. Her work is the basis for the United States Environmental Protection Agency's estimations for dermal absorption from contaminated water. It is also the basis of the dermal absorption estimates used in determining if chemicals should be assigned a 'skin notation' for potential systemic toxicity following occupational skin exposure. The work is truly translational in that it started with mathematical theory, is validated with preclinical and human experiments, and then is used in guidelines to protect human health. Her valued research has also extended into the topical drug bioavailability and bioequivalence assessment field. PMID- 23921119 TI - From the structure of the skin barrier and dermal formulations to in vitro transport models for skin absorption: skin research in the Netherlands and in Germany. AB - This review presents an overview of German and Dutch research institutions and their studies in the field of skin drug delivery and adjacent topics. In the Netherlands, the involved research groups are mainly localized in Leiden, whereas in Germany the skin research institutions are spread over the whole country. The scientific studies in the Netherlands focus on the in-depth analysis of human skin composition and its individual components as well as on the development and characterization of dermal drug delivery systems ranging from liquid crystalline systems and vesicles up to microneedles with an emphasis on examining the interactions of these drug delivery systems with the human skin in vitro and in vivo. In Germany, the individual areas of research span from in-depth investigations on various drug delivery systems intended for skin application and the development of novel in vitro models for skin absorption testing up to in vivo studies focusing on the biological performance of topically applied actives. Furthermore, sophisticated analytical techniques are applied for the elucidation of skin assembly and transport processes. In addition, experimentally derived data are correlated with advanced computational modelling. Even though the individual research topics in the Netherlands and Germany are quite diverse, the exchange of knowledge and interdisciplinary collaborations between the two neighbouring countries were and are still frequently made. In this context, the review aims at highlighting crosslinks between the different institutions and individual persons to complete the picture. For each institution, the principal investigators and their studies are presented and the upcoming young scientists are introduced as an outlook for the field. This review does not claim completeness, but is rather intended to give a general overview of Dutch and German research in the field of skin drug delivery and adjacent topics. PMID- 23921120 TI - Turning theory into practice: the development of modern transdermal drug delivery systems and future trends. AB - Despite its remarkable barrier function, the skin remains an attractive site for systemic drug delivery given its easy accessibility, large surface area and the possibility to bypass the gastrointestinal tract and the liver and so modify drug absorption kinetics. The pioneering work of Scheuplein, Higuchi and others in the 1960s helped to explain the processes involved in passive percutaneous absorption and led to the development of mathematical models to describe transdermal drug delivery. The intervening years have seen these theories turned to practice and a significant number of transdermal systems are now available including some that employ active drug delivery. This review briefly discusses the evolution of transdermal therapeutic systems over the years and the potential of newer transdermal technologies to deliver hydrophilic drugs and macromolecules through the skin. PMID- 23921121 TI - The contributions of the Celtic masters and their associates. AB - This article summarizes the work of 4 researchers in the field of percutaneous absorption - Keith Brain, Mark Cronin, Dermot McCafferty and John Pugh. It summarizes their main achievements in this field and reviews their major contributions to the broader subject area. PMID- 23921122 TI - Solute-vehicle-skin interactions in percutaneous absorption: the principles and the people. AB - An appreciation of solute-vehicle-skin interactions underpins our current understanding of the processes of percutaneous absorption as well as in the prediction of the extent of absorption. This understanding has been reached through principles developed and validated over the last century through the work of a number of authors, including Dale Wurster, Takeru Higuchi, Irvin Blank, Robert Scheuplein, Gordon Flynn, Boyd Poulsen and Tom Franz, as well as by many scientists from my and younger generations. Their work has led to an appreciation of the rate-limiting steps in percutaneous penetration, the role played by the physicochemical properties of the solute, vehicle and skin and the variability that may arise from using various experimental/mathematical/pharmacokinetic models to quantify absorption as well as enabling the prediction of local and systemic efficacy and toxicity. In addition, unexpected behaviour may result from non-ideality in solute-vehicle-skin effects, including dehydration, chemical enhancement, supersaturation, metabolism, sequestration and vascular effects, including those of nanosystems on the local vasculature. In general, in vitro skin penetration profiles are predictive of in vivo profiles but a number of exceptions also exist. PMID- 23921123 TI - Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy and is characterized by recurring structural genetic alterations. Previous studies of DNA methylation suggest epigenetic alterations may also be important, but an integrated genome-wide analysis of genetic and epigenetic alterations in ALL has not been performed. We analyzed 137 B-lineage and 30 T-lineage childhood ALL cases using microarray analysis of DNA copy number alterations and gene expression, and genome-wide cytosine methylation profiling using the HpaII tiny fragment enrichment by ligation-mediated PCR (HELP) assay. We found that the different genetic subtypes of ALL are characterized by distinct DNA methylation signatures that exhibit significant correlation with gene expression profiles. We also identified an epigenetic signature common to all cases, with correlation to gene expression in 65% of these genes, suggesting that a core set of epigenetically deregulated genes is central to the initiation or maintenance of lymphoid transformation. Finally, we identified aberrant methylation in multiple genes also targeted by recurring DNA copy number alterations in ALL, suggesting that these genes are inactivated far more frequently than suggested by structural genomic analyses alone. Together, these results demonstrate subtype- and disease specific alterations in cytosine methylation in ALL that influence transcriptional activity, and are likely to exert a key role in leukemogenesis. PMID- 23921124 TI - Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. AB - The mechanisms by which deregulated nuclear factor erythroid-2-related factor 2 (NRF2) and kelch-like ECH-associated protein 1 (KEAP1) signaling promote cellular proliferation and tumorigenesis are poorly understood. Using an integrated genomics and 13C-based targeted tracer fate association (TTFA) study, we found that NRF2 regulates miR-1 and miR-206 to direct carbon flux toward the pentose phosphate pathway (PPP) and the tricarboxylic acid (TCA) cycle, reprogramming glucose metabolism. Sustained activation of NRF2 signaling in cancer cells attenuated miR-1 and miR-206 expression, leading to enhanced expression of PPP genes. Conversely, overexpression of miR-1 and miR-206 decreased the expression of metabolic genes and dramatically impaired NADPH production, ribose synthesis, and in vivo tumor growth in mice. Loss of NRF2 decreased the expression of the redox-sensitive histone deacetylase, HDAC4, resulting in increased expression of miR-1 and miR-206, and not only inhibiting PPP expression and activity but functioning as a regulatory feedback loop that repressed HDAC4 expression. In primary tumor samples, the expression of miR-1 and miR-206 was inversely correlated with PPP gene expression, and increased expression of NRF2-dependent genes was associated with poor prognosis. Our results demonstrate that microRNA dependent (miRNA-dependent) regulation of the PPP via NRF2 and HDAC4 represents a novel link between miRNA regulation, glucose metabolism, and ROS homeostasis in cancer cells. PMID- 23921125 TI - DISC1 and SLC12A2 interaction affects human hippocampal function and connectivity. AB - Hippocampal development is coordinated by both extracellular factors like GABA neurotransmission and intracellular components like DISC1. We previously reported that SLC12A2-dependent GABA depolarization and DISC1 coregulate hippocampal neuronal development, and 2 SNPs in these genes linked to mRNA expression interactively increase schizophrenia risk. Using functional MRI, we now confirm this biological interaction in vivo by showing in 2 independent samples of healthy individuals (total N = 349) that subjects homozygous for both risk alleles evince dramatically decreased hippocampal area activation (Cohen's d = 0.78)and connectivity (d = 0.57) during a recognition memory task. These data highlight the importance of epistatic models in understanding genetic association with complex brain phenotypes. PMID- 23921126 TI - Transcription factor ATF3 links host adaptive response to breast cancer metastasis. AB - Host response to cancer signals has emerged as a key factor in cancer development; however, the underlying molecular mechanism is not well understood. In this report, we demonstrate that activating transcription factor 3 (ATF3), a hub of the cellular adaptive response network, plays an important role in host cells to enhance breast cancer metastasis. Immunohistochemical analysis of patient tumor samples revealed that expression of ATF3 in stromal mononuclear cells, but not cancer epithelial cells, is correlated with worse clinical outcomes and is an independent predictor for breast cancer death. This finding was corroborated by data from mouse models showing less efficient breast cancer metastasis in Atf3-deficient mice than in WT mice. Further, mice with myeloid cell-selective KO of Atf3 showed fewer lung metastases, indicating that host ATF3 facilitates metastasis, at least in part, by its function in macrophage/myeloid cells. Gene profiling analyses of macrophages from mouse tumors identified an ATF3-regulated gene signature that could distinguish human tumor stroma from distant stroma and could predict clinical outcomes, lending credence to our mouse models. In conclusion, we identified ATF3 as a regulator in myeloid cells that enhances breast cancer metastasis and has predictive value for clinical outcomes. PMID- 23921127 TI - Type 2 alveolar cells are stem cells in adult lung. AB - Gas exchange in the lung occurs within alveoli, air-filled sacs composed of type 2 and type 1 epithelial cells (AEC2s and AEC1s), capillaries, and various resident mesenchymal cells. Here, we use a combination of in vivo clonal lineage analysis, different injury/repair systems, and in vitro culture of purified cell populations to obtain new information about the contribution of AEC2s to alveolar maintenance and repair. Genetic lineage-tracing experiments showed that surfactant protein C-positive (SFTPC-positive) AEC2s self renew and differentiate over about a year, consistent with the population containing long-term alveolar stem cells. Moreover, if many AEC2s were specifically ablated, high-resolution imaging of intact lungs showed that individual survivors undergo rapid clonal expansion and daughter cell dispersal. Individual lineage-labeled AEC2s placed into 3D culture gave rise to self-renewing "alveolospheres," which contained both AEC2s and cells expressing multiple AEC1 markers, including HOPX, a new marker for AEC1s. Growth and differentiation of the alveolospheres occurred most readily when cocultured with primary PDGFRalpha+ lung stromal cells. This population included lipofibroblasts that normally reside close to AEC2s and may therefore contribute to a stem cell niche in the murine lung. Results suggest that a similar dynamic exists between AEC2s and mesenchymal cells in the human lung. PMID- 23921128 TI - Reciprocal regulation by TLR4 and TGF-beta in tumor-initiating stem-like cells. AB - Tumor-initiating stem-like cells (TICs) are resistant to chemotherapy and associated with hepatocellular carcinoma (HCC) caused by HCV and/or alcohol related chronic liver injury. Using HCV Tg mouse models and patients with HCC, we isolated CD133(+) TICs and identified the pluripotency marker NANOG as a direct target of TLR4, which drives the tumor-initiating activity of TICs. These TLR4/NANOG-dependent TICs were defective in the TGF-beta tumor suppressor pathway. Functional oncogene screening of a TIC cDNA library identified Yap1 and Igf2bp3 as NANOG-dependent genes that inactivate TGF-beta signaling. Mechanistically, we determined that YAP1 mediates cytoplasmic retention of phosphorylated SMAD3 and suppresses SMAD3 phosphorylation/activation by the IGF2BP3/AKT/mTOR pathway. Silencing of both YAP1 and IGF2BP3 restored TGF-beta signaling, inhibited pluripotency genes and tumorigenesis, and abrogated chemoresistance of TICs. Mice with defective TGF-beta signaling (Spnb2(+/-) mice) exhibited enhanced liver TLR4 expression and developed HCC in a TLR4-dependent manner. Taken together, these results suggest that the activated TLR4/NANOG oncogenic pathway is linked to suppression of cytostatic TGF-beta signaling and could potentially serve as a therapeutic target for HCV-related HCC. PMID- 23921129 TI - FcgammaRIIb mediates amyloid-beta neurotoxicity and memory impairment in Alzheimer's disease. AB - Amyloid-beta (Abeta) induces neuronal loss and cognitive deficits and is believed to be a prominent cause of Alzheimer's disease (AD); however, the cellular pathology of the disease is not fully understood. Here, we report that IgG Fcgamma receptor II-b (FcgammaRIIb) mediates Abeta neurotoxicity and neurodegeneration. We found that FcgammaRIIb is significantly upregulated in the hippocampus of AD brains and neuronal cells exposed to synthetic Abeta. Neuronal FcgammaRIIb activated ER stress and caspase-12, and Fcgr2b KO primary neurons were resistant to synthetic Abeta-induced cell death in vitro. Fcgr2b deficiency ameliorated Abeta-induced inhibition of long-term potentiation and inhibited the reduction of synaptic density by naturally secreted Abeta. Moreover, genetic depletion of Fcgr2b rescued memory impairments in an AD mouse model. To determine the mechanism of action of FcgammaRIIb in Abeta neurotoxicity, we demonstrated that soluble Abeta oligomers interact with FcgammaRIIb in vitro and in AD brains, and that inhibition of their interaction blocks synthetic Abeta neurotoxicity. We conclude that FcgammaRIIb has an aberrant, but essential, role in Abeta-mediated neuronal dysfunction. PMID- 23921132 TI - Norton scale, hospitalization length, complications, and mortality in elderly patients admitted to internal medicine departments. AB - BACKGROUND: The Norton scale is used for assessing pressure ulcer risk. The association between admission Norton scale scores (ANSS), hospitalization length, complications, and mortality in elderly patients admitted to internal medicine departments has never been studied. OBJECTIVE: To determine if ANSS are associated with hospitalization length, complications, in-hospital mortality, and 1-year mortality in elderly patients admitted to an internal medicine department. METHODS: Medical charts of consecutive elderly (>=65 years) patients admitted to a single internal medicine department between January and March 2009 were studied for ANSS, demographics, comorbidities, hospitalization length, complications during hospitalization, in-hospital mortality, and 1-year mortality. Complications during hospitalization included acute coronary syndrome, major arrhythmias, major bleeding, stroke, systemic infections, organ failure, thromboembolism, etc. ANSS <=14 were considered low. RESULTS: The final cohort included 259 elderly patients: 54.4% were women, the mean age was 81.6 years, and the mean hospitalization length was 3.7 days. Overall, 7.3% of the patients had complications other than pressure ulcers, 3.9% died during hospitalization, and 28.6% died within 1 year. The mean ANSS was 15.4, and 37.8% of the patients had low ANSS. Patients with low ANSS had longer hospitalization (4.7 vs. 2.9 days; p = 0.002), a higher incidence of complications during hospitalization (odds ratio: 3.9; p = 0.006), and higher rates of in-hospital mortality (odds ratio: 7.0; p = 0.007) relative to patients with high ANSS. Regression analysis showed that ANSS were independently negatively associated with hospitalization length, complications during hospitalization, and in-hospital mortality (p < 0.0001, p = 0.003, and p = 0.018, respectively) regardless of age, gender, comorbidities, and pressure ulcer appearance. Rates of 1-year mortality were similar in patients with low and high ANSS. CONCLUSIONS: The Norton scale may be used for predicting hospitalization length, complications during hospitalization other than pressure ulcers, and in-hospital mortality in elderly patients admitted to an internal medicine department. PMID- 23921133 TI - Successful ablation of incessant AV reentrant tachycardia in a patient on extracorporeal membrane oxygenation. AB - We present the first described case of an accessory pathway ablation, requiring a transseptal puncture, performed on ECMO for tachycardia-induced cardiomyopathy in the context of cardiogenic shock. The performance of a transseptal puncture in such a scenario is a feasible option and should be considered if the clinical situation dictates, despite the inherent risks. After ablation of the left lateral pathway the patient was successfully weaned off ECMO and made a complete recovery. PMID- 23921131 TI - HDAC3 is essential for DNA replication in hematopoietic progenitor cells. AB - Histone deacetylase 3 (HDAC3) contributes to the regulation of gene expression, chromatin structure, and genomic stability. Because HDAC3 associates with oncoproteins that drive leukemia and lymphoma, we engineered a conditional deletion allele in mice to explore the physiological roles of Hdac3 in hematopoiesis. We used the Vav-Cre transgenic allele to trigger recombination, which yielded a dramatic loss of lymphoid cells, hypocellular bone marrow, and mild anemia. Phenotypic and functional analysis suggested that Hdac3 was required for the formation of the earliest lymphoid progenitor cells in the marrow, but that the marrow contained 3-5 times more multipotent progenitor cells. Hdac3(-/-) stem cells were severely compromised in competitive bone marrow transplantation. In vitro, Hdac3(-/-) stem and progenitor cells failed to proliferate, and most cells remained undifferentiated. Moreover, one-third of the Hdac3(-/-) stem and progenitor cells were in S phase 2 hours after BrdU labeling in vivo, suggesting that these cells were impaired in transit through the S phase. DNA fiber-labeling experiments indicated that Hdac3 was required for efficient DNA replication in hematopoietic stem and progenitor cells. Thus, Hdac3 is required for the passage of hematopoietic stem/progenitor cells through the S phase, for stem cell functions, and for lymphopoiesis. PMID- 23921134 TI - Constructing an adaptive care model for the management of disease-related symptoms throughout the course of multiple sclerosis--performance improvement CME. AB - BACKGROUND: Symptom management remains a challenging clinical aspect of MS. OBJECTIVE: To design a performance improvement continuing medical education (PI CME) activity for better clinical management of multiple sclerosis (MS)-related depression, fatigue, mobility impairment/falls, and spasticity. METHODS: Ten volunteer MS centers participated in a three-stage PI CME model: A) baseline assessment; B) practice improvement CME intervention; C) reassessment. Expert faculty developed performance measures and activity intervention tools. Designated MS center champions reviewed patient charts and entered data into an online database. Stage C data were collected eight weeks after implementation of the intervention and compared with Stage A baseline data to measure change in performance. RESULTS: Aggregate data from the 10 participating MS centers (405 patient charts) revealed performance improvements in the assessment of all four MS-related symptoms. Statistically significant improvements were found in the documented assessment of mobility impairment/falls (p=0.003) and spasticity (p<0.001). For documentation of care plans, statistically significant improvements were reported for fatigue (p=0.007) and mobility impairment/falls (p=0.040); non-significant changes were noted for depression and spasticity. CONCLUSIONS: Our PI CME interventions demonstrated performance improvement in the management of MS-related symptoms. This PI CME model (available at www.achlpicme.org/ms/toolkit) offers a new perspective on enhancing symptom management in patients with MS. PMID- 23921130 TI - Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells. AB - Metabolic reprogramming is an important driver of tumor progression; however, the metabolic regulators of tumor cell motility and metastasis are not understood. Here, we show that tumors maintain energy production under nutrient deprivation through the function of HSP90 chaperones compartmentalized in mitochondria. Using cancer cell lines, we found that mitochondrial HSP90 proteins, including tumor necrosis factor receptor-associated protein-1 (TRAP-1), dampen the activation of the nutrient-sensing AMPK and its substrate UNC-51-like kinase (ULK1), preserve cytoskeletal dynamics, and release the cell motility effector focal adhesion kinase (FAK) from inhibition by the autophagy initiator FIP200. In turn, this results in enhanced tumor cell invasion in low nutrients and metastatic dissemination to bone or liver in disease models in mice. Moreover, we found that phosphorylated ULK1 levels were correlated with shortened overall survival in patients with non-small cell lung cancer. These results demonstrate that mitochondrial HSP90 chaperones, including TRAP-1, overcome metabolic stress and promote tumor cell metastasis by limiting the activation of the nutrient sensor AMPK and preventing autophagy. PMID- 23921135 TI - Age-specific sex ratio of multiple sclerosis in the National Swedish MS Register (SMSreg). PMID- 23921136 TI - Impact of embryo number and periconceptional undernutrition on factors regulating adipogenesis, lipogenesis, and metabolism in adipose tissue in the sheep fetus. AB - Maternal undernutrition around the time of conception is associated with an increased risk of insulin resistance in adulthood. We hypothesized that maternal undernutrition during the periconceptional (PCUN: -60 to 7 days) and/or preimplantation (PIUN: 0-7 days) periods would result in a decrease in UCP1 expression and the abundance of insulin signaling molecules and an increase in the abundance of factors that regulate adipogenesis and lipogenesis in fetal perirenal adipose tissue (PAT) and that these effects would be different in singletons and twins. Maternal PCUN and PIUN resulted in a decrease in UCP1 expression in PAT, and PIUN resulted in higher circulating insulin concentrations, an increased abundance of pPKCzeta and PDK4, and a decreased abundance of Akt1, phosphorylated mTOR, and PPARgamma in PAT in singleton and twin fetuses. In singletons, there was also a decrease in the abundance of p110beta in PAT in the PCUN and PIUN groups and an increase in total AMPKalpha in PAT in the PIUN group. In twins, however, there was an increase in the abundance of mTOR in the PCUN group and an increase in PDK2 and decrease in total AMPKalpha in the PIUN group. Thus exposure to periconceptional undernutrition programs changes in the thermogenic capacity and the insulin and fatty acid oxidation signaling pathway in visceral fat, and these effects are different in singletons and twins. These findings are important, as the thermogenic capacity of brown fat and the insulin sensitivity of visceral fat are important determinants of the risk of developing obesity and an insulin resistance phenotype in later life. PMID- 23921137 TI - APPL1 transgenic mice are protected from high-fat diet-induced cardiac dysfunction. AB - APPL1 (adaptor protein containing PH domain, PTB domain, and leucine zipper motif 1) has been established as an important mediator of insulin and adiponectin signaling. Here, we investigated the influence of transgenic (Tg) APPL1 overexpression in mice on high-fat diet (HFD)-induced cardiomyopathy in mice. Wild-type (WT) mice fed an HFD for 16 wk showed cardiac dysfunction, determined by echocardiography, with decreased ejection fraction, decreased fractional shortening, and increased end diastolic volume. HFD-fed APPL1 Tg mice were significantly protected from this dysfunction. Speckle tracking echocardiography to accurately assess cardiac tissue deformation strain and wall motion also indicated dysfunction in WT mice and a similar improvement in Tg vs. WT mice on HFD. APPL1 Tg mice had less HFD-induced increase in circulating nonesteridied fatty acid levels and myocardial lipid accumulation. Lipidomic analysis using LC MS-MS showed HFD significantly increased myocardial contents of distinct ceramide, sphingomyelin, and diacylglycerol (DAG) species, of which increases in C16:0 and C18:0 ceramides plus C16:0 and C18:1 DAGs were attenuated in Tg mice. A glucose tolerance test indicated less peripheral insulin resistance in response to HFD in Tg mice, which was also apparent by measuring cardiac Akt phosphorylation and cardiomyocyte glucose uptake. In summary, APPL1 Tg mice exhibit improved peripheral metabolism, reduced cardiac lipotoxicity, and improved insulin sensitivity. These cellular effects contribute to protection from HFD-induced cardiomyopathy. PMID- 23921138 TI - Slow oscillations of KATP conductance in mouse pancreatic islets provide support for electrical bursting driven by metabolic oscillations. AB - We used the patch clamp technique in situ to test the hypothesis that slow oscillations in metabolism mediate slow electrical oscillations in mouse pancreatic islets by causing oscillations in KATP channel activity. Total conductance was measured over the course of slow bursting oscillations in surface beta-cells of islets exposed to 11.1 mM glucose by either switching from current clamp to voltage clamp at different phases of the bursting cycle or by clamping the cells to -60 mV and running two-second voltage ramps from -120 to -50 mV every 20 s. The membrane conductance, calculated from the slopes of the ramp current-voltage curves, oscillated and was larger during the silent phase than during the active phase of the burst. The ramp conductance was sensitive to diazoxide, and the oscillatory component was reduced by sulfonylureas or by lowering extracellular glucose to 2.8 mM, suggesting that the oscillatory total conductance is due to oscillatory KATP channel conductance. We demonstrate that these results are consistent with the Dual Oscillator model, in which glycolytic oscillations drive slow electrical bursting, but not with other models in which metabolic oscillations are secondary to calcium oscillations. The simulations also confirm that oscillations in membrane conductance can be well estimated from measurements of slope conductance and distinguished from gap junction conductance. Furthermore, the oscillatory conductance was blocked by tolbutamide in isolated beta-cells. The data, combined with insights from mathematical models, support a mechanism of slow (~5 min) bursting driven by oscillations in metabolism, rather than by oscillations in the intracellular free calcium concentration. PMID- 23921139 TI - Androgens influence microvascular dilation in PCOS through ET-A and ET-B receptors. AB - Hyperandrogenism and vascular dysfunction often coexist in women with polycystic ovary syndrome (PCOS). We hypothesized that testosterone compromises cutaneous microvascular dilation in women with PCOS via the endothelin-1 ET-B subtype receptor. To control and isolate testosterone's effects on microvascular dilation, we administered a gonadotropin-releasing hormone antagonist (GnRHant) for 11 days in obese, otherwise healthy women [controls, 22.0 (4) yr, 36.0 (3.2) kg/m(2)] or women with PCOS [23 (4) yr, 35.4 (1.3) kg/m(2)], adding testosterone (T; 2.5 mg/day) on days 8-11. Using laser Doppler flowmetry and cutaneous microdialysis, we measured changes in skin microcirculatory responsiveness (DeltaCVC) to local heating while perfusing ET-A (BQ-123) and ET-B (BQ-788) receptor antagonists under three experimental conditions: baseline (BL; prehormone intervention), GnRHant (day 4 of administration), and T administration. At BL, ET-A receptor inhibition enhanced heat-induced vasodilation in both groups [DeltaCVC control 2.03 (0.65), PCOS 2.10 (0.25), AU/mmHg, P < 0.05]; ET-B receptor inhibition reduced vasodilation in controls only [DeltaCVC 0.98 (0.39), 1.41 (0.45) AU/mmHg for controls, PCOS] compared with saline [DeltaCVC controls 1.27 (0.48), PCOS 1.31 (0.13) AU/mmHg]. GnRHant enhanced vasodilation in PCOS [saline DeltaCVC 1.69 (0.23) AU/mmHg vs. BL, P < 0.05] and abolished the ET-A effect in both groups, a response reasserted with T in controls. ET-B receptor inhibition reduced heat-induced vasodilation in both groups during GnRHant and T [DeltaCVC, controls: 0.95 (0.21) vs. 0.51 (13); PCOS: 1.27 (0.23) vs. 0.84 (0.27); for GnRHant vs. T, P < 0.05]. These data demonstrate that androgen suppression improves microvascular dilation in PCOS via ET-A and ET B receptors. PMID- 23921141 TI - The permissive role of prolactin as a regulator of luteinizing hormone action in the female mouse ovary and extragonadal tumorigenesis. AB - Transgenic female mice overexpressing the hCGbeta subunit (hCGbeta(+)) and producing elevated levels of luteinizing hormone (LH)/hCG bioactivity present as young adults with enhanced ovarian steroidogenesis, precocious puberty, and infertility. They subsequently develop pituitary prolactinomas, high circulating prolactin (PRL) levels, and marked mammary gland lobuloalveolar development followed by adenocarcinomas. None of these phenotypes appear in gonadectomized mice, indicating that the hCG-induced aberrations of ovarian function are responsible for the extragonadal phenotypes. PRL receptor-deficient (PRLR(-/-)) female mice are sterile, despite ovulating, due to a failure of embryo implantation, as a consequence of decreased ovarian LH receptor (Lhcgr) expression and inadequate corpus luteum formation and progesterone production. To study further the presumed permissive role of PRL in the maintenance of gonadal responsiveness to LH/hCG stimulation, we crossed the hCGbeta(+) and PRLR(-/-) mice. The double-mutant hCGbeta(+)/PRLR(-/-) females remained sterile with an ovarian phenotype similar to PRLR(-/-) mice, indicating that LH action, Lhcgr expression, and consequent luteinization are not possible without simultaneous PRL signaling. The high frequency of pituitary prolactinomas in PRLR(-/-) mice was not affected by transgenic hCGbeta expression. In contrast, none of the hCGbeta(+)/PRLR(-/-) females showed either mammary gland lobuloalveolar development or tumors, and the increased mammary gland Wnt-5b expression, possibly responsible for the tumorigenesis in hCGbeta(+) mice, was absent in double-mutant mice. Hence, high LH/hCG stimulation is unable to compensate for missing PRL signaling in the maintenance of luteal function. PRL thus appears to be a major permissive regulator of LH action in the ovary and of its secondary extragonadal effects. PMID- 23921140 TI - Diet reduction to requirements in obese/overfed ewes from early gestation prevents glucose/insulin dysregulation and returns fetal adiposity and organ development to control levels. AB - Obesity at conception and excess gestational weight gain pose significant risks for adverse health consequences in human offspring. This study evaluated the effects of reducing dietary intake of obese/overfed ewes beginning in early gestation on fetal development. Sixty days prior to conception, ewes were assigned to a control diet [CON: 100% of National Research Council (NRC) recommendations], a diet inducing maternal obesity (MO: 150% of NRC recommendations), or a maternal obesity intervention diet (MOI: 150% of NRC recommendations to day 28 of gestation, then 100% NRC) until necropsy at midgestation (day 75) or late (day 135) gestation. Fetal size and weight, as well as fetal organ weights, were greater (P < 0.05) at midgestation in MO ewes than those of CON and MOI ewes. By late gestation, whereas fetal size and weight did not differ among dietary groups, cardiac ventricular weights and wall thicknesses as well as liver and perirenal fat weights remained elevated in fetuses from MO ewes compared with those from CON and MOI ewes. MO ewes and fetuses exhibited elevated (P < 0.05) plasma concentrations of triglycerides, cholesterol, insulin, glucose, and cortisol at midgestation compared with CON and MOI ewes and fetuses. In late gestation, whereas plasma triglycerides and cholesterol, insulin, and cortisol remained elevated in MO vs. CON and MOI ewes and fetuses, glucose concentrations were elevated in both MO and MOI fetuses compared with CON fetuses, which was associated with elevated placental GLUT3 expression in both groups. These data are consistent with the concept that reducing maternal diet of obese/overfed ewes to requirements from early gestation can prevent subsequent alterations in fetal growth, adiposity, and glucose/insulin dynamics. PMID- 23921142 TI - Materno-fetal transfer of docosahexaenoic acid is impaired by gestational diabetes mellitus. AB - Better knowledge on the disturbed mechanisms implicated in materno-fetal long chain polyunsaturated fatty acid (LC-PUFA) transfer in pregnancies with gestational diabetes mellitus (GDM) may have potentially high implications for later on in effective LC-PUFA supplementation. We studied in vivo placental transfer of fatty acids (FA) using stable isotope tracers administrated to 11 control and 9 GDM pregnant women (6 treated with insulin). Subjects received orally [(13)C]palmitic, [(13)C]oleic and [(13)C]linoleic acids, and [(13)C]docosahexaenoic acid ((13)C-DHA) 12 h before elective caesarean section. Maternal blood samples were collected at -12, -3, -2, and -1 h, delivery, and +1 h. Placental tissue and venous cord blood were also collected. FA were quantified by gas chromatography (GC) and (13)C enrichments by GC-isotope ratio mass spectrometry. [(13)C]FA concentration was higher in total lipids of maternal plasma in GDM vs. controls, except for [(13)C]DHA. Moreover, [(13)C]DHA showed lower placenta/maternal plasma ratio in GDM vs. controls and significantly lower cord/maternal plasma ratio. For the other studied FA, ratios were not different between GDM and controls. Disturbed [(13)C]DHA placental uptake occurs in both GDM treated with diet or insulin, whereas the last ones also have lower [(13)C]DHA in venous cord. The tracer study pointed toward impaired placental DHA uptake as critical step, whereas the transfer of the rest of [(13)C]FA was less affected. GDM under insulin treatment could also have higher fetal fat storage, contributing to reduce [(13)C]DHA in venous cord. DHA transfer to the fetus was reduced in GDM pregnancies compared with controls, which might affect the programming of neurodevelopment in their neonates. PMID- 23921143 TI - Whole body metabolic effects of prolonged endurance training in combination with erythropoietin treatment in humans: a randomized placebo controlled trial. AB - Erythropoietin (Epo) administration improves aerobic exercise capacity and insulin sensitivity in renal patients and also increases resting energy expenditure (REE). Similar effects are observed in response to endurance training. The aim was to compare the effects of endurance training with erythropoiesis-stimulating agent (ESA) treatment in healthy humans. Thirty-six healthy untrained men were randomized to 10 wk of either: 1) placebo (n = 9), 2) ESA (n = 9), 3) endurance training (n = 10), or 4) ESA and endurance training (n = 8). In a single-blinded design, ESA/placebo was injected one time weekly. Training consisted of biking for 1 h at 65% of wattmax three times per week. Measurements performed before and after the intervention were as follows: body composition, maximal oxygen uptake, insulin sensitivity, REE, and palmitate turnover. Uncoupling protein 2 (UCP2) mRNA levels were assessed in skeletal muscle. Fat mass decreased after training (P = 0.003), whereas ESA induced a small but significant increase in intrahepatic fat (P = 0.025). Serum free fatty acid (FFA) levels and palmitate turnover decreased significantly in response to training, whereas the opposite pattern was found after ESA. REE corrected for lean body mass increased in response to ESA and training, and muscle UCP2 mRNA levels increased after ESA (P = 0.035). Insulin sensitivity increased only after training (P = 0.011). IN CONCLUSION: 1) insulin sensitivity is not improved after ESA treatment despite improved exercise capacity, 2) the calorigenic effects of ESA may be related to increased UCP2 gene expression in skeletal muscle, and 3) training and ESA exert opposite effects on lipolysis under basal conditions, increased FFA levels and liver fat fraction was observed after ESA treatment. PMID- 23921144 TI - Acid sphingomyelinase plays a key role in palmitic acid-amplified inflammatory signaling triggered by lipopolysaccharide at low concentrations in macrophages. AB - Periodontal disease is more prevalent and severe in patients with diabetes than in nondiabetic patients. In addition to diabetes, a large number of studies have demonstrated an association between obesity and chronic periodontal disease. However, the underlying mechanisms have not been well understood. Since plasma free fatty acids (FAs) are elevated in obese patients and saturated FAs such as palmitic acid (PA) have been shown to increase host inflammatory response, we sought to find out how PA interacts with lipopolysaccharide (LPS), an important pathological factor involved in periodontal disease, to enhance inflammation. We found that whereas low concentration of LPS (1 ng/ml) stimulated interleukin (IL) 6 expression in RAW 264.7 macrophages, PA further augmented it fourfold. Besides IL-6, PA amplified the stimulatory effect of LPS on a large amount of Toll-like receptor (TLR)4-mediated expression of proinflammatory signaling molecules such as IL-1 receptor-associated kinase-like 2 and proinflammatory molecules, including monocyte chemotactic protein-1 and colony-stimulating factor. We also observed that PA augmented TLR4 but not TLR2 signal, and the augmentation was mediated by nuclear factor-kappaB (NF-kappaB) pathways. To further elucidate the regulatory mechanism whereby PA amplifies LPS signal, our studies showed that PA and LPS synergistically increased hydrolysis of sphingomyelin by stimulating acid sphingomyelinase (ASMase) activity, which contributed to a marked increase in ceramide production and IL-6 upregulation. Taken together, this study has demonstrated that PA markedly augments TLR4-mediated proinflammatory signaling triggered by low concentration of LPS in macrophages, and ASMase plays a key role in the augmentation. PMID- 23921146 TI - Response to the letter to the editor by Susan Thorpe et al.: how predictive are in vitro assays for cytokine release syndrome in vivo? A comparison of methods reveals worrying differences in sensitivity and frequency of response. PMID- 23921145 TI - Long-term exposure to a high-fat diet results in the development of glucose intolerance and insulin resistance in interleukin-1 receptor I-deficient mice. AB - Emerging evidence has demonstrated that saturated fatty acids prime pro-IL-1beta production and inflammasome-mediated IL-1beta activation is critical in obesity associated insulin resistance (IR). Nonetheless, IL-1 receptor I-deficient (IL 1RI(-/-)) mice develop mature-onset obesity despite consuming a low-fat diet (LFD). With this apparent contradiction, the present study evaluated whether IL 1RI(-/-) mice were protected against long-term (6 mo) high-fat diet (HFD)-induced IR. Male wild-type and IL-1RI(-/-) mice were fed LFD or HFD for 3 or 6 mo, and glucose and insulin tolerance tests were performed. Adipose insulin sensitivity, cytokine profiles, and adipocyte morphology were assessed. The adipogenic potential of stromal vascular fraction was determined. Hepatic lipid accumulation and insulin sensitivity were characterized. IL-1RI(-/-) mice developed glucose intolerance and IR after 6 mo HFD compared with 3 mo HFD, coincident with enhanced weight gain, hyperinsulinemia, and hyperleptinemia. The aggravated IR phenotype was associated with loss of adipose functionality, switch from adipocyte hyperplasia to hypertrophy and hepatosteatosis. Induction of adipogenic genes was reduced in IL-1RI(-/-) preadipocytes after 6 mo HFD compared with 3 mo HFD. Obese LFD-IL-1RI(-/-) mice exhibited preserved metabolic health. IL-1RI(-/-) mice develop glucose intolerance and IR after 6 mo HFD intervention. While mature onset obesity is evident in LFD-IL-1RI(-/-) mice, the additional metabolic insult of HFD was required to drive adipose inflammation and systemic IR. These findings indicate an important interaction between dietary fat and IL-1, relevant to optimal metabolic health. PMID- 23921147 TI - Chemokine receptor expression on integrin-mediated stellate projections of prostate cancer cells in 3D culture. AB - The chemokine receptor CXCR7 has emerged as a regulator of prostate tumor growth and invasion, along with the well-established role of its closely related receptor, CXCR4, and their shared ligand, SDF-1alpha. Consequently, inhibition of the CXCR7/CXCR4/SDF-1alpha axis may assist in controlling prostate tumor growth and progression. To facilitate the development of potential therapeutics, further clarification of CXCR7 function is required, specifically in relation to CXCR4. In this study, we report that CXCR7 and CXCR4 were co-expressed in LNCaP, DU145 and PC3 cell lines in 2D culture. When cultured in 3D using Matrigel, a marked up regulation of both receptors was observed in PC3 cells. Interestingly, both CXCR7 and CXCR4 co-localized within radiating cellular structures, termed stellate projections, which protruded outward into the matrix. The stellate projections were rich in the expression of pro-invasive integrin beta1, beta-laminin and MMP 11 proteins. The development of the stellate projections was mediated by integrin beta1-mediated interactions with the ECM, which also regulated the expression of CXCR7 and CXCR4. Taken together, these results demonstrate that integrin-mediated cell-ECM interactions can modulate tumor cell morphology, and regulate the expression of chemokine receptors which are associated with the invasive phenotype and progression of PCa. PMID- 23921148 TI - OSU-A9 inhibits angiogenesis in human umbilical vein endothelial cells via disrupting Akt-NF-kappaB and MAPK signaling pathways. AB - Since the introduction of angiogenesis as a useful target for cancer therapy, few agents have been approved for clinical use due to the rapid development of resistance. This problem can be minimized by simultaneous targeting of multiple angiogenesis signaling pathways, a potential strategy in cancer management known as polypharmacology. The current study aimed at exploring the anti-angiogenic activity of OSU-A9, an indole-3-carbinol-derived pleotropic agent that targets mainly Akt-nuclear factor-kappa B (NF-kappaB) signaling which regulates many key players of angiogenesis such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Human umbilical vein endothelial cells (HUVECs) were used to study the in vitro anti-angiogenic effect of OSU-A9 on several key steps of angiogenesis. Results showed that OSU-A9 effectively inhibited cell proliferation and induced apoptosis and cell cycle arrest in HUVECs. Besides, OSU A9 inhibited angiogenesis as evidenced by abrogation of migration/invasion and Matrigel tube formation in HUVECs and attenuation of the in vivo neovascularization in the chicken chorioallantoic membrane assay. Mechanistically, Western blot, RT-PCR and ELISA analyses showed the ability of OSU-A9 to inhibit MMP-2 production and VEGF expression induced by hypoxia or phorbol-12-myristyl-13-acetate. Furthermore, dual inhibition of Akt-NF-kappaB and mitogen-activated protein kinase (MAPK) signaling, the key regulators of angiogenesis, was observed. Together, the current study highlights evidences for the promising anti-angiogenic activity of OSU-A9, at least in part through the inhibition of Akt-NF-kappaB and MAPK signaling and their consequent inhibition of VEGF and MMP-2. These findings support OSU-A9's clinical promise as a component of anticancer therapy. PMID- 23921149 TI - 3,5,4'-Trimethoxystilbene, a natural methoxylated analog of resveratrol, inhibits breast cancer cell invasiveness by downregulation of PI3K/Akt and Wnt/beta catenin signaling cascades and reversal of epithelial-mesenchymal transition. AB - The molecular basis of epithelial-mesenchymal transition (EMT) functions as a potential therapeutic target for breast cancer because EMT may endow breast tumor initiating cells with stem-like characteristics and enable the dissemination of breast cancer cells. We have recently verified the antitumor activity of 3,5,4' trimethoxystilbene (MR-3), a naturally methoxylated derivative of resveratrol, in colorectal cancer xenografts via an induction of apoptosis. The effect of MR-3 on EMT and the invasiveness of human MCF-7 breast adenocarcinoma cell line were also explored. We found that MR-3 significantly increased epithelial marker E-cadherin expression and triggered a cobblestone-like morphology of MCF-7 cells, while reciprocally decreasing the expression of mesenchymal markers, such as snail, slug, and vimentin. In parallel with EMT reversal, MR-3 downregulated the invasion and migration of MCF-7 cells. Exploring the action mechanism of MR-3 on the suppression of EMT and invasion indicates that MR-3 markedly reduced the expression and nuclear translocation of beta-catenin, accompanied with the downregulation of beta-catenin target genes and the increment of membrane-bound beta-catenin. These results suggest the involvement of Wnt/beta-catenin signaling in the MR-3-induced EMT reversion of MCF-7 cells. Notably, MR-3 restored glycogen synthase kinase-3beta activity by inhibiting the phosphorylation of Akt, the event required for beta-catenin destruction via a proteasome-mediated system. Overall, these findings indicate that the anti-invasive activity of MR-3 on MCF-7 cells may result from the suppression of EMT via down-regulating phosphatidylinositol 3-kinase (PI3K)/AKT signaling, and consequently, beta catenin nuclear translocation. These occurrences ultimately lead to the blockage of EMT and the invasion of breast cancer cells. PMID- 23921150 TI - Ghrelin inhibits the apoptosis of MC3T3-E1 cells through ERK and AKT signaling pathway. AB - Ghrelin is a 28-amino-acid peptide that acts as a natural endogenous ligand of the growth hormone secretagogue receptor (GHSR) and strongly stimulates the release of growth hormone from the hypothalamus-pituitary axis. Previous studies have identified the important physiological effects of ghrelin on bone metabolism, such as regulating proliferation and differentiation of osteoblasts, independent of GH/IGF-1 axis. However, research on effects and mechanisms of ghrelin on osteoblast apoptosis is still rare. In this study, we identified expression of GHSR in MC3T3-E1 cells and determined the effects of ghrelin on the apoptosis of osteoblastic MC3T3-E1 cells and the mechanism involved. Our data demonstrated that ghrelin inhibited the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, as determined by terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate nick end-labeling (TUNEL) and ELISA assays. Moreover, ghrelin upregulated Bcl-2 expression and downregulated Bax expression in a dose-dependent manner. Our study also showed decreased activated caspase-3 activity under the treatment of ghrelin. Further study suggested that ghrelin stimulated the phosphorylation of ERK and AKT. Pretreatment of cells with the ERK inhibitor PD98059, PI3K inhibitor LY294002, and GHSR-siRNA blocked the ghrelin-induced activation of ERK and AKT, respectively; however, ghrelin did not stimulate the phosphorylation of p38 or JNK. PD90859, LY294002 and GHSR-siRNA attenuated the anti-apoptosis effect of ghrelin in MC3T3-E1 cells. In conclusion, ghrelin inhibits the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, which may be mediated by activating the GHSR/ERK and GHSR/PI3K/AKT signaling pathways. PMID- 23921151 TI - Cadmium modulates adipocyte functions in metallothionein-null mice. AB - Our previous study has demonstrated that exposure to cadmium (Cd), a toxic heavy metal, causes a reduction of adipocyte size and the modulation of adipokine expression. To further investigate the significance of the Cd action, we studied the effect of Cd on the white adipose tissue (WAT) of metallothionein null (MT(-/ )) mice, which cannot form atoxic Cd-MT complexes and are used for evaluating Cd as free ions, and wild type (MT(+/+)) mice. Cd administration more significantly reduced the adipocyte size of MT(-/-) mice than that of MT(+/+) mice. Cd exposure also induced macrophage recruitment to WAT with an increase in the expression level of Ccl2 (MCP-1) in the MT(-/-) mice. The in vitro exposure of Cd to adipocytes induce triglyceride release into culture medium, decrease in the expression levels of genes involved in fatty acid synthesis and lipid hydrolysis at 24 h, and at 48 h increase in phosphorylation of the lipid-droplet-associated protein perilipin, which facilitates the degradation of stored lipids in adipocytes. Therefore, the reduction in adipocyte size by Cd may arise from an imbalance between lipid synthesis and lipolysis. In addition, the expression levels of leptin, adiponectin and resistin decreased in adipocytes. Taken together, exposure to Cd may induce unusually small adipocytes and modulate the expression of adipokines differently from the case of physiologically small adipocytes, and may accelerate the risk of developing insulin resistance and type 2 diabetes. PMID- 23921152 TI - Arsenic toxicity induced endothelial dysfunction and dementia: pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors. AB - Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate & brain GSH levels along with increase in serum & brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. PMID- 23921153 TI - Mechanisms of permanent loss of olfactory receptor neurons induced by the herbicide 2,6-dichlorobenzonitrile: effects on stem cells and noninvolvement of acute induction of the inflammatory cytokine IL-6. AB - We explored the mechanisms underlying the differential effects of two olfactory toxicants, the herbicide 2,6-dichlorobenzonitrile (DCBN) and the anti-thyroid drug methimazole (MMZ), on olfactory receptor neuron (ORN) regeneration in mouse olfactory epithelium (OE). DCBN, but not MMZ, induced inflammation-like pathological changes in OE, and DCBN increased interleukin IL-6 levels in nasal wash fluid to much greater magnitude and duration than did MMZ. At 24h after DCBN injection, the population of horizontal basal cells (HBCs; reserve, normally quiescent OE stem cells) lining the DMM became severely depleted as some of them detached from the basal lamina, and sloughed into the nasal cavity along with the globose basal cells (GBCs; heterogeneous population of stem and progenitor cells), neurons, and sustentacular cells of the neuroepithelium. In contrast, the layer of HBCs remained intact in MMZ-treated mice, as only the mature elements of the neuroepithelium were shed. Despite the respiratory metaplasia accompanying the greater severity of the DCBN lesion, residual HBCs that survived intoxication were activated by the injury and contributed to the metaplastic respiratory epithelium, as shown by tracing their descendants in a K5CreEr(T2)::fl(stop)TdTomato strain of mice in which recombination causes HBCs to express TdTomato in advance of the lesion. But, contrary to published observations with MMZ, the HBCs failed to form ORNs. A role for IL-6 in suppressing ORN regeneration in DCBN-treated mice was rejected by the failure of the anti-inflammatory drug dexamethasone to prevent the subsequent respiratory metaplasia in the DMM, suggesting that other factors lead to HBC neuro incompetence. PMID- 23921154 TI - The nitrite-oxidizing community in activated sludge from a municipal wastewater treatment plant determined by fatty acid methyl ester-stable isotope probing. AB - Metabolically-active autotrophic nitrite oxidizers from activated sludge were labeled with (13)C-bicarbonate under exposure to different temperatures and nitrite concentrations. The labeled samples were characterized by FAME-SIP (fatty acid methyl ester-stable isotope probing). The compound cis-11-palmitoleic acid, which is the major lipid of the most abundant nitrite oxidizer in activated sludge, Candidatus Nitrospira defluvii, showed (13)C-incorporation in all samples exposed to 3 mM nitrite. Subsequently, the lipid cis-7-palmitoleic acid was labeled, and it indicated the activity of a nitrite oxidizer that was different from the known Nitrospira taxa in activated sludge. The highest incorporation of cis-7-palmitoleic acid label was found after incubation with a nitrite concentration of 0.3 mM at 17 and 22 degrees C. While activity of Nitrobacter populations could not be detected by the FAME-SIP approach, an unknown nitrite oxidizer with the major lipid cis-9 isomer of palmitoleic acid exhibited (13)C incorporation at 28 degrees C with 30 mM nitrite. These results indicated flexibility of nitrite-oxidizing guilds in a complex community responding to different conditions. Labeled lipids so far not described for activated sludge associated nitrifiers indicated the presence of unknown nitrite oxidizers in this habitat. The FAME-SIP-based information can be used to define appropriate conditions for the enrichment of nitrite-oxidizing guilds from complex samples. PMID- 23921155 TI - Polymorphism of ITGB2 gene 3'-UTR+145C/A is associated with biliary atresia. AB - BACKGROUND AND STUDY AIMS: Biliary atresia (BA) is a devastating disease of infants, invariably leading to cirrhosis, end-stage liver disease, and death if untreated. The etiology of BA is unknown, although infectious, immune, and genetic causes have been suggested. This study was designed to investigate whether polymorphism of the ITGB2 (CD18) gene is associated with susceptibility to BA. METHODS: The ITGB2 gene promoter and 16 exons were genotyped following amplification and sequencing, with associations assessed using Fischer's exact test in 106 patients diagnosed with BA and 108 unrelated healthy controls. RESULTS: We found one single nucleotide polymorphism (SNP) in the ITGB2 promoter region (-680 C/T) and five SNPs in exons, including: -111 T/C in exon 1, 117 G/A in exon 3, 819 G/A in exon 7, 1101 C/A in exon 10, and 3'-UTR+145C/A in exon 16. There were no significant differences in genotype and allelic frequencies of any of the SNPs between controls and patients with BA in both the promoter and exons 1, 3, 7, and 10. 3'-UTR+145C/A showed a significant increase in the C allele frequency (OR = 2.19, 95% CI: 1.39-3.46, p = 0.0006) and a significant increase in the CC genotype (p = 0.001) in BA patients compared with healthy controls. Using a reporter gene assay, the construct that contained the risk allele (3' UTR+145 C) showed significantly higher luciferase activity than the nonrisk A allele (p = 0.007). CONCLUSION: Our study provides the first evidence of a possible role of ITGB2 3'-UTR+145C/A polymorphism in the pathogenesis of BA. PMID- 23921156 TI - Tactical considerations in the middle-distance running events at the 2012 Olympic Games: a case study. AB - PURPOSE: To identify tactical factors associated with progression from preliminary rounds in middle-distance running events at an international championship. METHODS: Results from the 2012 Olympic Games were used to access final and intermediate positions, finishing times, and season-best (SB) times for competitors in men's and women's 800-m and 1500-m events (fifteen 800-m races and ten 1500-m races). Finishing times were calculated as %SB, and Pearson product moment correlations were used to assess relationships between intermediate and finishing positions. Probability (P) of qualification to the next round was calculated for athletes in each available intermediate position. RESULTS: There were no significant differences in finishing times relative to SB between qualifiers and nonqualifiers. In the 800-m, correlation coefficients between intermediate and final positions were r = .61 and r = .84 at 400 m and 600 m, respectively, whereas in the 1500-m, correlations were r = .35, r = .43, r = .55, and r = .71 at 400 m, 800 m, 1000 m, and 1200 m, respectively. In both events, probability of qualification decreased with position at all intermediate distances. At all points, those already in qualifying positions were more likely to qualify for the next round. CONCLUSIONS: The data demonstrate that tactical positioning at intermediate points in qualifying rounds of middle-distance races is a strong determinant of qualification. In 800-m races it is important to be in a qualifying position by 400 m. In the 1500-m event, although more changes in position are apparent, position at intermediate distances is still strongly related to successful qualification. PMID- 23921157 TI - Age-related changes in insula cortical thickness and impulsivity: significance for emotional development and decision-making. AB - Insula function has been associated with emotional regulation, adjusting to changing outcomes under risk, reward and loss anticipation, discounting of future rewards, and self-rated impulsivity. The role of the insula in these processes may be fundamentally related to prospective thinking, a trait that increases with age. There is evidence that insular cortical thickness shows age related decreases that parallel age related increases in future orientation and planning. We tested the hypothesis that nonplanning decreases with age and that insula thickness is related to both age and nonplanning impulsivity. Fifty-nine male and female participants, ranging in age from 10 to 22 years old, underwent structural magnetic resonance imaging (MRI) procedures and were assessed using the Barratt Impulsiveness Scale (BIS). We observed that anterior insula thickness and nonplanning impulsivity show an inverse relationship with age and that there is a significant positive linear relationship between anterior insula thickness and nonplanning. PMID- 23921159 TI - Left lobectomy might be a risk factor for atrial fibrillation following pulmonary lobectomy. AB - OBJECTIVE: To identify risk factors for atrial fibrillation (AF) following lobectomy for a pulmonary malignant tumour. METHODS: The outcomes of patients who underwent lobectomy from February 2005 to September 2010 were analysed with respect to the development of postoperative AF. RESULTS: Among 186 patients, 20 developed AF and these had significantly higher preoperative B-type natriuretic peptide (BNP) than those without AF. A significantly high incidence of AF following pulmonary lobectomy was demonstrated in the group of patients who were male, underwent a thoracotomy, had a high preoperative value of BNP and underwent a left lobectomy. Multivariate analysis revealed that left lobectomy is the only independent risk factor. The area under the receiver-operating characteristic curve for BNP to predict postoperative AF following a left lobectomy for a pulmonary malignant tumour was 0.82 (95% confidence interval 0.70-0.93; P<0.05). A BNP level of 24.1 pg/ml had a sensitivity of 90.9% and a specificity of 56% for predicting postoperative AF following left lobectomy for a pulmonary malignant tumour. CONCLUSIONS: Left lobectomy is the only independent risk factor for postoperative AF. Elevated BNP is the risk factor for postoperative AF in patients undergoing left pulmonary lobectomy. PMID- 23921160 TI - Reply to Turtiainen and Hakala. PMID- 23921161 TI - Three-dimensional sensitivity assessment of thoracic aortic aneurysm wall stress: a probabilistic finite-element study. AB - OBJECTIVES: In clinical practice, maximum diameter is used as a criterion to estimate aneurysm-rupture risk; however, it is only a general indicator and its value becomes difficult to estimate in the thoracic segment. Improved understanding of aortic aneurysm complexity and biomechanics is needed to achieve advancements in surgical repair techniques. The objective of this study was to determine the maximum wall stress by using imaging-derived data and a specific probabilistic design integrated into finite element (FE) analysis. METHODS: Computed tomography images of thoracic aortic aneurysms from our database were analysed and the main morphological features were identified by means of a specific automatic routine. Morphological data were used to develop an idealized finite element library of thoracic aortic arch models. Sensitivity analyses were performed by using the geometrical parameters as input variables for a statistical wall stress assessment. Numerical results were compared with those obtained from deterministic analysis on patient-specific three-dimensional reconstructions. RESULTS: The results showed that in small aneurysms, wall stress values similar to those of large aneurysms can be obtained if a significant eccentricity is achieved. In small aneurysms, the peak stress is primarily affected by the eccentricity of the bulge [correlation coefficient (CC) = 0.86], while for diameters in the range of 50-60 mm, the CC is 0.43 for the eccentricity and 0.72 for the maximum diameter. CONCLUSIONS: The stress distribution in small aneurysms may contribute to the pathogenesis of aortic rupture and dissections. Our method can provide a novel and efficient procedure for generating computational models to estimate the wall stress in a comparative multivariate manner. PMID- 23921162 TI - Does the use of triclosan-coated sutures really reduce surgical site infection after open vein bypass grafting patients? PMID- 23921163 TI - A pendular prosthetic valve: severe paravalvular aortic leak. PMID- 23921164 TI - Midwives experiences of establishing partnerships: working with pregnant women who use illicit drugs. AB - OBJECTIVE: To present the interpreted experiences of midwives who choose to work with pregnant women who also use illicit drugs. DESIGN: Twelve (n=12) Australian midwives were interviewed. Each interview was audio-taped, de-identified and transcribed. The interviews were analysed using a systematic, thematic analysis approach informed by Heideggarian hermeneutic phenomenology. FINDINGS: Three themes identified from the data that encapsulate the experience were establishing partnerships, making a difference, and letting go and redefining practice. The interpretations of establishing partnerships which includes engagement, genuine regard and compassion, with a subtheme courting the system are presented in this paper. The midwives' experiences were both positive and negative, as they were rewarded and challenged by the needs of women who use illicit drugs and the systems in which they worked. CONCLUSION: The midwives in this study found that establishing partnerships was essential to their work. They appraised their experience of working with pregnant women who used illicit drugs and found strategies that attempted to meet the needs of the women, the system and themselves. The participants revealed that to support women and families who use illicit drugs in their community, partnerships must be based on deep respect and trust. Significant components engagement, genuine regard and compassion that are central to midwifery partnerships require revisiting to address the needs of this vulnerable population of women. PMID- 23921165 TI - Creation of an arteriovenous fistula is associated with significant acute local and systemic changes in microvascular function. AB - BACKGROUND: Native arteriovenous fistulae (AVF) are the vascular access of choice for haemodialysis. The consequences of AVF formation on microvascular function, locally or systemically, are unknown. METHODS: We recruited 43 predialysis patients undergoing AVF formation. Patients were studied 2 weeks prior to the planned AVF operation and 2 weeks postoperatively. Thirteen patients with failed AVF were subsequently utilised as sham controls. Laser Doppler perfusion imaging was used to measure subcutaneous microvascular blood flow. Microvascular function was assessed as an increase in perfusion in response to iontophoretic administration of vasodilatory stimuli assessing endothelial-dependent (ED) and non-endothelial-dependent (NED) vasodilatation. RESULTS: Patients with successful AVF formation had a significantly reduced ED vasodilatation in the fistula arm ( 36 +/- 46%, p < 0.001). Only NED vasodilatation was significantly reduced in the non-fistula arm (23 +/- 40%, p = 0.01). Patients who had an unsuccessful AVF operation exhibited no recordable changes. CONCLUSIONS: Formation of an AVF was associated with local and remote changes in microcirculation. Further assessments are underway to examine the contributions of local shear stress, vasoreactive substances and the autonomic responses. Although the clinical significance of these findings is not yet clear, it is intriguing that AVF formation is associated with such widespread and profound changes in microperfusion. PMID- 23921166 TI - A single strand that links multiple neuropathologies in human disease. PMID- 23921167 TI - Reply: A single strand that links multiple neuropathologies in human disease. PMID- 23921168 TI - Impact of blood collection method on first-trimester dried blood free Beta hCG and PAPP-A. AB - BACKGROUND: Analysis of dried blood specimens has been an integral part of laboratory medicine dating back to the early 1960s when they were introduced as part of neonatal screening programs. More recently, they have been used in Down syndrome screening programmes. Dried blood spot specimens can be collected either by finger-stick or by traditional venipuncture and spotted onto filter paper. We sought to evaluate whether first-trimester free Beta hCG and PAPP-A multiples of the median (MoMs) were different in dried blood specimens collected via finger stick compared to specimens collected via venipuncture. METHODS: A total of 2786 consecutive dried blood specimens were evaluated including 2144 collected using finger-stick and 644 specimens collected using venipuncture and spotted onto filter paper. Linear regression was used to assess the overall impact of collection method on dried blood free Beta hCG and PAPP-A and the impact of collection method on the trend of dried blood free Beta hCG and PAPP-A with transport time. RESULTS: For finger-stick and venipuncture, the median for free Beta hCG MoM was 0.99 and 1.04, respectively while the median PAPP-A MoM was 1.00 and 1.01, respectively. The regression formula for free Beta hCG was ln(MoM) = 0.00918 + 0.05112*Venipuncture + 0.00299*Days -0.00983*Days*Venipuncture and for PAPP-A the formula was ln(MoM) = -0.01000 + 0.04779*Venipuncture -0.00051*Days 0.02117*Days*Venipuncture. None of the coefficients were significant. CONCLUSIONS: Collection method does not impact MoM values. Thus, centres have flexibility in the collection method utilized while being able to use a single reference database for all dried blood specimens. PMID- 23921169 TI - Antimicrobial impact of cold atmospheric pressure plasma on medical critical yeasts and bacteria cultures. AB - OBJECTIVES: Plasma medicine focuses on the application of cold atmospheric pressure plasmas (CAPs) in or on the human body. So far, plasmas have been used to sterilize implant materials or other thermally unstable medical products and have been applied for chemical surface modifications. This study investigates the antimicrobial effect of physical plasmas on microorganisms which cause skin infections, such as Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans, depending on the plasma source and the kind of plasma excitation used. MATERIALS: Microorganisms were plated onto MH2 agar plates. Plasma treatment was performed using the plasma sources BLASTER MEF and kinpen 09. To investigate the antimicrobial effects, the following plasma parameters have been varied: working gas, distance from nozzle to surface, electrical power, grid spacing of treatment lines, number of treatments and work piece velocity. RESULTS: The generated plasmas had an antimicrobial effect that depended on the chosen plasma parameters, in particular on the process gas used, the plasma power and the number of treatments performed. Thus, different reactive species were observed by optical emission spectroscopy measurement in the generated plasmas. CONCLUSIONS: The study showed that CAPs exhibit profound bactericidal and fungicidal properties in vitro. However, an important factor for the antimicrobial efficacy is the composition of the 'chemical soup' supplied by the CAP system which can be regulated by the process gases used. PMID- 23921170 TI - A small-molecule-linked DNA-graphene oxide-based fluorescence-sensing system for detection of biotin. AB - In this paper, we establish a novel fluorescence-sensing system for the detection of biotin based on the interaction between DNA and graphene oxide and on protection of the terminal of the biotinylated single-stranded DNA fluorescent probe by streptavidin. In this system, streptavidin binds to the biotinylated DNA, which protects the DNA from hydrolysis by exonuclease I. The streptavidin DNA conjugate is then adsorbed to the graphene oxide resulting in the fluorescence being quenched. Upon the addition of free biotin, it competes with the labeled biotin for the binding sites of streptavidin and then the exonuclease I digests the unbound DNA probe from the 3' to the 5' terminal, releasing the fluorophore from the DNA. Because of the weak affinity between the fluorophore and graphene oxide, the fluorescence is recovered. Under optimal conditions, the fluorescence intensity is proportional to the concentration of biotin in the concentration range of 0.5-20nmol/L. The detection limit for biotin is 0.44nmol/L. The proposed fluorescence-sensing system was applied to the determination of biotin in some real samples with satisfactory reproducibility and accuracy. This work could provide a common platform for detecting small biomolecules based on protein-small molecule ligand binding. PMID- 23921171 TI - Pemetrexed use in the adjuvant setting for completely resectable non-small-cell lung cancer. AB - Supported by evidence from the LACE (Lung Adjuvant Cisplatin Evaluation) metaanalysis, cisplatin-based adjuvant chemotherapy is now recommended as the standard of care for patients with surgically resected early-stage non-small-cell lung cancer (NSCLC) per American Society of Clinical Oncology and European Society for Medical Oncology clinical practice guidelines. These standard regimens, which principally include cisplatin-etoposide and cisplatin vinorelbine, are associated with long- and short-term toxicities. Hence, cisplatin-based regimens with an improved therapeutic index and optimal safety and tolerability profile are still needed. Pemetrexed, an antifolate, is currently indicated for first-line, maintenance, and second-line therapy for advanced nonsquamous NSCLC. Pemetrexed-platinum, with or without targeted agents, has proven to be efficacious with an acceptable toxicity profile when given in the first-line metastatic setting. Therefore, it is reasonable that pemetrexed be investigated in the adjuvant setting. This review collates data from January 2000 through August 2012 on the use of pemetrexed-platinum regimens in the adjuvant setting either alone or in combination with targeted agents. To date, more than 1000 patients with early stage NSCLC have been enrolled in adjuvant therapy studies evaluating various pemetrexed-containing treatment regimens, and additional patients are being enrolled in ongoing studies. Current evidence appears to favor the combination with cisplatin over that with carboplatin. We await more robust safety and efficacy data from these ongoing adjuvant trials to define with clarity the role of pemetrexed-containing regimens in this setting. PMID- 23921172 TI - Factors related to the initial stroke severity of posterior circulation ischemic stroke. AB - BACKGROUND: Posterior circulation (PC) stroke, which was previously less well known than anterior circulation (AC) stroke, has become more identified due to the development of imaging equipment. Recently, the initial stroke severity assessed by the NIH Stroke Scale (NIHSS) was reported as a useful measure for predicting the outcome of PC as well as AC stroke. The aim of our study was to investigate the factors related to the stroke severity of PC ischemic stroke as assessed by the baseline NIHSS and the predictors of progressive neurological deficit and 3-month outcome. METHODS: All patients with first-time PC stroke (onset <= 7 days), admitted for a 5-year period and given a complete evaluation including brain MRI and angiographic studies, were enrolled. Patients were divided into two groups by the baseline NIHSS: moderate-to-severe stroke (MTSS, NIHSS > 5) and mild stroke (MS, NIHSS <= 5). Baseline characteristics, symptoms and progression, etiological subtypes, lesion characteristics from imaging, and patient 3-month outcome assessed by the modified Rankin Scale (mRS) were compared between the two groups. RESULTS: Among 604 enrolled patients with PC ischemic stroke, 143 belonged to the MTSS group and 461 to the MS group. In logistic regression analysis, MTSS was independently associated with white blood cell count (odds ratio, OR = 1.00, p = 0.001), high sensitivity C-reactive protein level (OR = 1.23, p = 0.004), dysarthria (OR = 2.59, p = 0.013), weakness (OR = 6.43, p < 0.001), dysphagia (OR = 5.77, p < 0.001) and decreased consciousness (OR = 10.54, p < 0.001). The independent predictors associated with progressive neurological deficit were MTSS (OR = 3.82, p = 0.001), the distal territory classified by lesion location (OR = 0.09, p = 0.004) and dysphagia (OR = 2.38, p = 0.010). The independent predictors associated with a 3-month mRS of 3-6 were MTSS (OR = 7.69, p < 0.001), diplopia (OR = 0.26, p = 0.023), visual field defect (OR = 4.87, p = 0.014), dysphagia (OR = 3.15, p < 0.001) and progressive neurological deficit (OR = 4.27, p < 0.001). CONCLUSIONS: The initial severity categorization of PC ischemic stroke by the NIHSS has provided several distinctions and could help with the prediction of neurological deficit progression and 3-month clinical outcome. PMID- 23921173 TI - Vented chest seals for prevention of tension pneumothorax in a communicating pneumothorax. AB - BACKGROUND: Tension pneumothorax accounts for 3%-4% of combat casualties and 10% of civilian chest trauma. Air entering a wound via a communicating pneumothorax rather than by the trachea can result in respiratory arrest and death. In such cases, the Committee on Tactical Combat Casualty Care advocates the use of unvented chest seals to prevent respiratory compromise. OBJECTIVE: A comparison of three commercially available vented chest seals was undertaken to evaluate the efficacy of tension pneumothorax prevention after seal application. METHODS: A surgical thoracostomy was created and sealed by placing a shortened 10-mL syringe barrel (with plunger in place) into the wound. Tension pneumothorax was achieved via air introduction through a Cordis to a maximum volume of 50 mL/kg. A 20% drop in mean arterial pressure or a 20% increase in heart rate confirmed hemodynamic compromise. After evacuation, one of three vented chest seals (HyFin((r)), n = 8; Sentinel((r)), n = 8, SAM((r)), n = 8) was applied. Air was injected to a maximum of 50 mL/kg twice, followed by a 10% autologous blood infusion, and finally, a third 50 mL/kg air bolus. Survivors completed all three interventions, and a 15 min recovery period. RESULTS: The introduction of 29.0 (+/-11.5) mL/kg of air resulted in tension physiology. All three seals effectively evacuated air and blood. Hemodynamic compromise failed to develop with a chest seal in place. CONCLUSIONS: HyFin((r)), SAM((r)), and Sentinel((r)) vented chest seals are equally effective in evacuating blood and air in a communicating pneumothorax model. All three prevented tension pneumothorax formation after penetrating thoracic trauma. PMID- 23921174 TI - Obesity and familial predisposition are significant determining factors of an adverse metabolic profile in young patients with congenital adrenal hyperplasia. AB - BACKGROUND/AIMS: Glucocorticoid (GC) therapy is known to predispose to an adverse metabolic profile. Therefore, we investigated the prevalence of obesity and metabolic syndrome (MetS) in young patients with congenital adrenal hyperplasia (CAH) and to correlate this prevalence with GC treatment and family history. METHODS: The study population consisted of 33 young CAH patients who received cortisone acetate during their growth periods; those who were salt wasters also received fludrocortisone. Obesity was defined by a body mass index (BMI) >95th percentile and MetS by the National Cholesterol Education Program Third Adult Treatment Panel modified criteria. Each patient's familial history of MetS components was assessed. The impact of GC therapy on the metabolic profile was analyzed by comparing CAH patients with BMI z-score-matched controls. RESULTS: MetS and obesity were observed in 12.1 and 30.3% of the CAH patients, respectively, both of which were higher than in the reference population. A positive family history of MetS was found to be more prevalent in the obese patients compared with the nonobese CAH patients, and similar findings were observed for the controls. The metabolic profile did not differ between the CAH patients and matched subjects. CONCLUSION: CAH patients presented a higher prevalence of obesity and MetS, which were not correlated with the GC treatment. This study suggests that obesity and familial predisposition are significant determining factors for an adverse metabolic profile in CAH patients. PMID- 23921176 TI - Renal carcinoma cell-derived exosomes induce human immortalized line of Jurkat T lymphocyte apoptosis in vitro. AB - OBJECTIVE: Tumor-derived exosomes usually contain some molecules that can help immune evasion by tumors. This study is aimed at investigating the potential effect of exosomes from human kidney adenocarcinoma cells on a human immortalized line of Jurkat T lymphocytes in vitro. METHODS: Exosomes were purified from human kidney adenocarcinoma ACHN cells by sequential centrifugations and ultrafiltrations, and characterized by transmission electron microscopy. The effects of exosomes on the proliferation, cytokine production and apoptosis of Jurkat T cells were determined using flow cytometry and enzyme-linked immunosorbent assay. The relative levels of pro- and anti-apoptotic molecules were determined by Western blotting. RESULTS: Exosomes were purified from ACHN cells and exhibited typical characteristics. Treatment with exosomes inhibited Jurkat T cell proliferation and induced Jurkat T cell apoptosis in a dose- and time-dependent manner. Treatment with exosomes reduced spontaneous interleukin-2 (IL-2), interferon-gamma, IL-6 and IL-10 production by Jurkat T cells. Treatment with exosomes increased the relative levels of cleaved caspase-3, -8 and -9 as well as Bax, but reduced the levels of Bcl-2 in Jurkat T cells. The purified exosomes contained Fas ligand, and treatment with soluble Fas abrogated exosome mediated Jurkat T cell apoptosis. CONCLUSIONS: Our data indicate that exosomes from kidney adenocarcinoma cells contain Fas ligand and trigger Jurkat T cell apoptosis, contributing to the immune evasion of tumors. PMID- 23921175 TI - IL-17 gene ablation does not impact Treg-mediated suppression of graft-versus host disease after bone marrow transplantation. AB - Regulatory T cell (Treg) immunotherapy is a promising strategy for the treatment of graft rejection responses and autoimmune disorders. Our and other laboratories have shown that the transfer of highly purified CD4(+)CD25(+)Foxp3(+) natural Treg can prevent lethal graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation across both major and minor histocompatibility barriers. However, recent evidence suggests that the Treg suppressive phenotype can become unstable, a phenomenon that can culminate in Treg conversion into IL 17-producing cells. We hypothesized that the intense proinflammatory signals released during an ongoing alloreaction might redirect a fraction of the transferred Treg to the Th17 cell fate, thereby losing immunosuppressive potential. We therefore sought to evaluate the impact of Il17 gene ablation on Treg stability and immunosuppressive capacity in a major MHC mismatch model. We show that although Il17 gene ablation results in a mildly enhanced Treg immunosuppressive ability in vitro, such improvement is not observed when IL-17 deficient Treg are used for GVHD suppression in vivo. Similarly, when we selectively blocked IL-1 signaling in Treg, that was shown to be necessary for Th17 conversion, we did not detect any improvement on Treg-mediated GVHD suppressive ability in vivo. Furthermore, upon ex vivo reisolation of transferred wild-type Treg, we detected little or no Treg-mediated IL-17 production upon GVHD induction. Our results indicate that blocking Th17 conversion does not affect the GVHD suppressive ability of highly purified natural Treg in vivo, suggesting that IL-17 targeting is not a valuable strategy to improve Treg immunotherapy after hematopoietic cell transplantation. PMID- 23921177 TI - Assessment of metal sorption mechanisms by aquatic macrophytes using PIXE analysis. AB - In this work, a study of the metal sorption mechanism by dead biomass has been performed. All batch metal biosorption experiments were performed using the aquatic macrophyte Egeria densa as biosorbent. Divalent cadmium and zinc solutions were used to assess the sorption mechanisms involved. Using a suitable equilibrium time of 2h and a mixture of 300 mg biosorbent and 50 mL metal solution at pH 5, monocomponent sorption experiments were performed. In order to determine the residual amounts of metals in the aqueous solutions and the concentrations of removed metals in the dry biomass, Particle Induced X-ray Emission (PIXE) measurements in thin and thick target samples were carried out. Based on the strong experimental evidence from the mass balance among the major elements participating in the sorption processes, an ion exchange process was identified as the mechanism responsible for metal removal by the dry biomass. PMID- 23921178 TI - The antifungal efficacy of nano-metals supported TiO2 and ozone on the resistant Aspergillus niger spore. AB - Recently, antimicrobial efficacy of nano-metals has been extensively investigated. However, most of the related studies focused on the bactericidal effectiveness. Molds, especially their spores, are more resistant than bacteria, and can build a high concentration in houses due to dampness. Therefore, a comprehensive evaluation of the antifungal effectiveness of nano-metals is necessary. In this study, the nano-metals (Ag, Cu and Ni) supported catalysts were successfully prepared by the incipient wetness impregnation method, while the titanium dioxide (Degussa (Evonik) P25) nanoparticle was served as the support. The antifungal experiments of Aspergillus niger spores were conducted on two surfaces (quartz and putty) in the darkness with and without ozone exposure, respectively. The critical Ag concentration to inhibit the germination and growth of A. niger spores of 5 wt% nano Ag catalyst was 65 mg/mL, lower than several cases in previous studies. The inactivation rate constants (k) of A. niger spores on nano-metals supported catalysts in the presence of ozone (k=0.475-0.966 h(-1)) were much higher than those in the absence of ozone (k=0.001-0.268 h(-1)). However, on the surface of TiO2 particles, no antifungal effect was observed until 6-h exposure to ozone. Consequently, ozone has a synergetic effect on nano metals antifungal efficacy. PMID- 23921179 TI - Fate of lead oxide during thermal treatment with tetrabromobisphenol A. AB - In this paper, the bromination reaction between lead oxide and hydrogen bromide originating from the thermal decomposition of tetrabromobisphenol A (TBBPA), under inert and oxidizing atmospheres, was investigated, using a laboratory-scale furnace. The results obtained under inert conditions indicated that bromination of PbO proceeded simultaneously with debromination of TBBPA, with an average effectiveness of 69% (max. 80%). Volatilization of the formed PbBr2 began at 315 degrees C, intensified at 750 degrees C, and reached 98% at 850 degrees C. The formed organic char served as a source of carbon for reduction of the unreacted lead oxide to metallic lead in the range 315-750 degrees C. Additional experiments conducted at selected temperatures under slightly oxidizing (5 vol% O2) and quasi-atmospheric (20 vol% O2) conditions showed no significant effects on bromination-evaporation of lead in the studied mixture. However, in isothermal treatment under quasi-atmospheric oxygen levels, complete vaporization of the formed lead bromide was obtained at a temperature of only 650 degrees C. PMID- 23921181 TI - Immobilization of heavy metals on pillared montmorillonite with a grafted chelate ligand. AB - The objective of this work was the development of an efficient adsorbent for irreversible immobilization of heavy metals in contaminated soils. The adsorbent was prepared by pillaring of montmorillonite with silica followed by grafting of a chelate ligand on its surface. Obtained adsorbent was mesoporous with high content of adsorption sites. Its structure was studied by BET adsorption of N2, dynamic light scattering, and scanning electron microscopy. The adsorption capacity of the organoclay was measured by its mixing with contaminated kaolin and soil samples and by analysis of heavy metal contents in leachate. Deionized water and 50% acetic acid were used for leaching of metals from the samples. As it was demonstrated by the experiments, the adsorbent was efficient in immobilization of heavy metals not only in neutral aqueous media but also in the presence of weak acid. As a result, the adsorbent can be used for reduction of heavy metal leaching from contaminated sites. PMID- 23921180 TI - Phenanthrene causes ocular developmental toxicity in zebrafish embryos and the possible mechanisms involved. AB - Recent studies show that polycyclic aromatic hydrocarbons (PAHs) may be a candidate cause of developmental defects of the retina, but the mechanism is still unclear. We evaluated the mechanism(s) underlying PAH-induced retinal development defects due to exposure to environmental concentrations of Phenanthrene (Phe) in zebrafish. We found that exposure to environmental concentrations of Phe caused obvious morphological changes, developmental retardation, apoptosis, and reduction of cell proliferation in the retina. Our results indicated that Phe could cause visual system developmental defects. Phe exposure up-regulated aryl hydrocarbon receptor (AhR) and microphthalmia associated transcription factor (Mtif) expression, and down-regulated zinc finger E-box binding homeobox 1 (Zeb1) and paired box 6 (Pax6). Moreover, we demonstrated that AhR was a repressor of Zeb1. We propose that Phe's ocular toxicity is mediated by up-regulating AhR, which then down-regulates Zeb1, in turn inducing Mitf expression while inhibiting Pax6 expression. PMID- 23921182 TI - An evaluation of the impact of multiwalled carbon nanotubes on soil microbial community structure and functioning. AB - This study evaluated the impacts of multiwalled carbon nanotubes (MWNTs) on microbial community composition and functioning in a sandy loam soil over 90 d. We used test concentrations in the range of lower MWNT concentrations (10mg/kg) to extremely high MWNT concentrations (10,000 mg/kg) as a worst case scenario. We observed no effects of MWNTs on soil respiration, enzymatic activities, and microbial community composition at 10, 100 and 1,000 mg/kg. However, increases in fungal fatty acid methyl ester markers were observed at the highest treatment. In addition, pyrosequencing demonstrated a decreased abundance of some bacterial genera like Derxia, Holophaga, Opitutus and Waddlia at the highest treatment while bacterial genera that are considered potential degraders of recalcitrant contaminants (such as polycyclic aromatic hydrocarbons) like Rhodococcus, Cellulomonas, Nocardioides and Pseudomonas increased. These results suggest a shift in soil microbial community composition to more tolerant microbial populations in the presence of extremely high MWNT concentrations. It is unlikely that the change observed at 10,000 mg/kg is due to metal or carbon impurities as the MWNTs used in this study were of high purity. Given the need for wide-ranging data for regulation and risk assessment of nanomaterials, this study provides valuable data. PMID- 23921183 TI - Selective sensing of Hg2+ using rhodamine-thiophene conjugate: red light emission and visual detection of intracellular Hg2+ at nanomolar level. AB - Rhodamine-thiophene conjugate (L) has been synthesized and characterized by (1)H NMR, FTIR and mass spectra. L shows a large enhancement in emission intensity in presence of Hg(2+). Moreover, naked eye color of L becomes intense red in presence of Hg(2+). The lowest detection limit for Hg(2+) is 1 * 10(-9)M in HEPES buffer (0.1M in EtOH/water, 1/1, v/v, pH 7.4). Hg(2+) induced chelation enhanced fluorescence (CHEF) is associated with spirolacram ring opening of the rhodamine unit. Trace level intracellular Hg(2+) is visualized under fluorescence microscope. PMID- 23921184 TI - Influence of caffeine pretreatment on biphasic in vitro maturation of dog oocytes. AB - Phosphodiesterase (PDE) inhibitors have been utilized for in vitro maturation (IVM) of oocytes to manipulate the meiotic resumption and progression. Premature chromatin condensation and DNA replication of the oocytes, immediately after the decrease in the cAMP level, are the difficulties in canine IVM. Caffeine, a nonselective competitive PDE inhibitor, due to its structural similarity to adenosine molecule maintains the cAMP level by occupying PDE enzymes such as PDE 3A inside the oocyte and PDE-4 and PDE-5 in the cumulus cells. In this study, the effects of 12-hour caffeine pretreatment in a biphasic IVM protocol were assessed on maturation rates of canine oocytes. Sixty hours of culture after a 12-hour of 10 mM caffeine pretreatment resulted in 16.9% +/- 2.4 of the oocytes reaching metaphase II stage (MII) and 25.9% +/- 5.2 degeneration rate compared with the control group with 2.2% +/- 2.2 MII and 37.6% +/- 4.3 degeneration rates (P < 0.05). Caffeine pretreatment induced higher mitogen-activated protein kinases (MAPK1 and MAPK3) phosphorylation and maturation-promoting factor activity at 12 hours and activated MAPK1 and maturation-promoting factor at 48 hours after culture in cumulus-oocyte complexes (COCs) compared with the control group (P < 0.05). Fresh canine COCs were also analyzed before IVM using brilliant cresyl blue (BCB) staining. Oocytes showed difference in meiotic resumption (MI-MII) (BCB+ = 16.11% +/- 5.5, BCB- = 9.86% +/- 5.0; P < 0.05) after 60 hours of culture following 12-hour caffeine pretreatment. The BCB+ canine oocytes had higher MII rate than the BCB- group under caffeine pretreatment (10.2% +/- 2.9 vs. 1.1% +/- 1.1, respectively; P < 0.05). Results indicated that 12-hour caffeine pretreatment of canine COCs improves the MII maturation rates at 72 hours and BCB+ oocytes have higher competency in vitro for nuclear maturation. PMID- 23921185 TI - Assessment of the antinociceptive effects of pregabalin alone or in combination with morphine during acetic acid-induced writhing in mice. AB - Visceral pain currently represents one of the most important pain treatment challenges in clinical practice, and investigators across the world are continuously designing and conducting numerous studies in search of new analgesics and new combination therapies. The current study assessed the analgesic effects of saline, pregabalin (2, 5, 17, 50, 100, and 200 mg/kg, i.p.) and morphine (0.25, 0.5, 1, 3 and 5 mg/kg) alone or in combination on acetic-acid induced abdominal contractions in mice. The number of writhes and the inhibitory effects (as percentages, %E) were calculated as antinociception indexes. These indexes indicated that both pregabalin (Prg) and morphine (Mrp) produced dose dependent antinociception. Pregabalin at 5 mg/kg (%E=32.5+/-4.0) or 2 mg/kg (%E=20.8+/-4.5) and morphine at 0.25 mg/kg (%E=20.2+/-7.8) and 0.5 mg/kg (%E=43.6+/-4.5) exhibited antinociceptive effects, and the combination of pregabalin and morphine produced significantly greater antinociceptive effects (%E=62.4+/-5.8 for Prg5+Mrp0.25; %E=71.7+/-4.8 for Prg5+Mrp0.5; and %E=54.1+/-4.0 for Prg2+Mrp0.25), although this enhancement was not observed when morphine was combined with 17 mg/kg pregabalin. Pre-treatment with 2 mg/kg (i.p.) naloxone did not affect increased analgesia when combined with these drugs. A dose-response curve was established for pregabalin at a fixed morphine dose and revealed that, at low doses, pregabalin dose-dependently enhanced the antinociceptive effects, while the opposite was true at high doses (17 and 25 mg/kg). In conclusion, pregabalin can produce levels of antinociception that are similar to those of morphine in acetic acid-induced viscero-somatic pain. The enhancement of antinociception produced by the co-administration of morphine and pregabalin is termed a supra-additive interaction and occurred at low doses but not at high doses. These findings militate for increased attention and caution in clinical settings. PMID- 23921186 TI - Do elite endurance athletes report their training accurately? AB - PURPOSE: The purpose of this study was to validate the accuracy of self-reported (SR) training duration and intensity distribution in elite endurance athletes. METHODS: Twenty-four elite cross-country skiers (25 +/- 4 y, 67.9 +/- 9.88 kg, 75.9 +/- 6.50 mL . min-1 . kg-1) SR all training sessions during an ~14-d altitude-training camp. Heart rate (HR) and some blood lactate measurements were collected during 466 training sessions. SR training was compared with recorded training duration from HR monitors, and SR intensity distribution was compared with expert analysis (EA) of all session data. RESULTS: SR training was nearly perfectly correlated with recorded training duration (r = .99), but SR training was 1.7% lower than recorded training duration (P < .001). SR training duration was also nearly perfectly correlated (r = .95) with recorded training duration >55% HRmax, but SR training was 11.4% higher than recorded training duration >55% HRmax (P < .001) due to SR inclusion of time <55% HRmax. No significant differences were observed in intensity distribution in zones 1-2 between SR and EA comparisons, but small discrepancies were found in zones 3-4 (P < .001). CONCLUSIONS: This study provides evidence that elite endurance athletes report their training data accurately, although some small differences were observed due to lack of a SR "gold standard." Daily SR training is a valid method of quantifying training duration and intensity distribution in elite endurance athletes. However, additional common reporting guidelines would further enhance accuracy. PMID- 23921187 TI - Expression of acetylated and dimethylated histone H3 in colorectal cancer. AB - AIM: The expression of acetylated and dimethylated histone H3 in colorectal cancer was examined by immunohistochemistry and chromatin immunoprecipitation (ChIP)/Western blot (WB) assay. The correlation between the expression of histone H3 and clinicopathological findings was analyzed. METHODS: Formalin-fixed and paraffin-embedded sections obtained from 80 operated cases of colorectal cancer were immunostained with anti-acetylated histone H3 (H3Ac) antibody and anti dimethylated histone H3 lysine 4 (H3K4) antibody. Positive immunoreactivity was evaluated using the Allred scoring system. Furthermore, the expression was confirmed by ChIP/WB assay using formalin-fixed and paraffin-embedded sections. RESULTS: There was good correlation between immunostaining and expression on ChIP/WB assay (p = 0.0005). There was a significant difference between the Allred score of H3K4 and the depth of tumor invasion (p = 0.0003) and the pathological stages (p = 0.0065). In overall survival classified by Allred scores of H3Ac (p = 0.0072) and H3K4 (p = 0.0187), the highest scores represented significantly worse prognoses than the other scores. Specifically, in stages II and III, the highest scores represented significantly worse prognoses than the other scores (p < 0.0001 and p = 0.0173, respectively). CONCLUSION: The expression of H3Ac and H3K4 may estimate patient prognosis. PMID- 23921189 TI - Urban environment: recognizing that pollution and social factors can create barriers to development of more healthy and liveable cities. PMID- 23921190 TI - Temporary filters and liver mobilization technique improve the safety and prognosis of radical nephrectomy and inferior vena cava thrombectomy in renal cell carcinoma with subdiaphragmatic thrombosis. AB - AIMS: This study aimed to investigate the safety and efficacy of preoperative temporary inferior vena cava (IVC) filter placement and intraoperative application of a liver mobilization technique. MATERIALS AND METHODS: The experiment cohort of 42 cases and the control cohort of 36 cases of renal cell carcinoma involving the IVC were analyzed retrospectively. In the experiment cohort, patients were implanted with a temporary IVC filter as routine preoperative treatment. The control cohort of 36 cases received traditional radical nephrectomy + IVC thrombectomy. RESULTS: In the experiment cohort, 42 cases did not show any symptom of tumor thrombus embolism perioperatively. The average operation time was 220 min and the average blood loss was 750 ml. Overall survival rate of improved surgery was significantly higher than traditional surgery (p = 0.0055). Moreover, tumor thrombus size and position was associated with overall survival (p = 0.0185). CONCLUSIONS: Preoperative temporary IVC filter placement and intraoperative application of a liver mobilization technique to expose the IVC can effectively prevent tumor thrombosis embolism shedding and improve surgical safety. PMID- 23921191 TI - Posterior reversible encephalopathy syndrome: a noteworthy syndrome in end-stage renal disease patients. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a clinico radiologic entity characterized by headache, visual disturbances, seizures, and the presence of edema on MRI scan, predominantly in the posterior white matter. Regarding end-stage renal disease (ESRD) and PRES, only a few cases of children on peritoneal dialysis (PD) and adults on hemodialysis have been described in the literature. CASES: We report 4 cases of adult patients on PD who presented with PRES, all of which were due to hypertension and inadequate management of fluid balance. The patients expressed typical PRES symptoms such as headache, visual disorders, and tonic/clonic seizures. The patients recovered completely and the MRI lesions disappeared after strict control of volume status. CONCLUSION: Nephrologists should be aware of the syndrome, especially when they manage hypertensive ESRD patients not compliant with the fluid and diet restrictions. MRI scan is the only diagnostic tool for defining the syndrome. Early diagnosis is important, since complete remission is achieved after appropriate treatment. PMID- 23921192 TI - Practical implementation of an existing smoking detection pipeline and reduced support vector machine training corpus requirements. AB - This study aimed to reduce reliance on large training datasets in support vector machine (SVM)-based clinical text analysis by categorizing keyword features. An enhanced Mayo smoking status detection pipeline was deployed. We used a corpus of 709 annotated patient narratives. The pipeline was optimized for local data entry practice and lexicon. SVM classifier retraining used a grouped keyword approach for better efficiency. Accuracy, precision, and F-measure of the unaltered and optimized pipelines were evaluated using k-fold cross-validation. Initial accuracy of the clinical Text Analysis and Knowledge Extraction System (cTAKES) package was 0.69. Localization and keyword grouping improved system accuracy to 0.9 and 0.92, respectively. F-measures for current and past smoker classes improved from 0.43 to 0.81 and 0.71 to 0.91, respectively. Non-smoker and unknown class F-measures were 0.96 and 0.98, respectively. Keyword grouping had no negative effect on performance, and decreased training time. Grouping keywords is a practical method to reduce training corpus size. PMID- 23921193 TI - Workshop on using natural language processing applications for enhancing clinical decision making: an executive summary. AB - In April 2012, the National Institutes of Health organized a two-day workshop entitled 'Natural Language Processing: State of the Art, Future Directions and Applications for Enhancing Clinical Decision-Making' (NLP-CDS). This report is a summary of the discussions during the second day of the workshop. Collectively, the workshop presenters and participants emphasized the need for unstructured clinical notes to be included in the decision making workflow and the need for individualized longitudinal data tracking. The workshop also discussed the need to: (1) combine evidence-based literature and patient records with machine learning and prediction models; (2) provide trusted and reproducible clinical advice; (3) prioritize evidence and test results; and (4) engage healthcare professionals, caregivers, and patients. The overall consensus of the NLP-CDS workshop was that there are promising opportunities for NLP and CDS to deliver cognitive support for healthcare professionals, caregivers, and patients. PMID- 23921194 TI - The incidence and outcomes of acute kidney injury amongst patients admitted to a level I trauma unit. AB - PURPOSE: This study aimed to identify the incidence and outcomes of patients with trauma related acute kidney injury (AKI), as defined by RIFLE criteria, at a single level I trauma centre and trauma ICU. METHODS: We performed a retrospective observational study of 666 patients admitted to a trauma ICU from a level I trauma unit from March 2008 to March 2011. We conducted multivariable logistic regression to identify independent predictors for AKI and mortality. RESULTS: The overall incidence of AKI was 15% (n=102). Median injury severity score (ISS) was 25 (inter quartile range [IQR] 16-34) and mean age was 39 (SD 16.3) in the AKI group. Thirteen patients (13%) were referred with rhabdomyolysis associated renal Failure. Overall mortality in the AKI group was 57% (n=58) but was significantly lower in the rhabdomyolysis Failure group (23% versus 64%; p=0.012). AKI was independently associated with older age, base excess (BE)<-12 (odd ratio [OR] 22.9, 95% confidence interval [CI] 1.89-276.16), IV contrast administration (OR 2.7 95% CI 1.39-5.11) and blunt trauma (OR 2.2 95% CI 1.04 4.71). AKI was an independent predictor of mortality (OR 8.5, 95% CI 4.51-15.95). Thirty-nine (38%) patients required renal replacement therapy. CONCLUSIONS: AKI in critically ill trauma patients is an independent risk factor for mortality and is independently associated with increasing age and low BE. Renal replacement therapy utilisation is high in this group and represents a significant health care cost burden. PMID- 23921195 TI - The NIHSS supplementary motor scale: a valid tool for multidisciplinary recovery trials. AB - BACKGROUND: There is a growing interest in therapies that may augment motor recovery that could be initiated in the acute stroke unit and maintained through the rehabilitation period. Homogenization of the currently fragmented stroke clinicometrics is necessary before such multidisciplinary trials can be conducted. The supplementary motor scale of the NIH Stroke Scale (SMS-NIHSS) is a simple and reliable scale for assessing proximal and distal motor function in the upper and lower extremities. We hypothesized that the currently underutilized SMS NIHSS is a valid tool for assessing motor recovery with prognosticative value. METHODS: We performed an analysis of SMS-NIHSS scores recorded in 1,281 patients enrolled in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). We plotted the probability of a favorable outcome (FO) and very favorable outcome (VFO) at 3 months based on the baseline SMS-NIHSS scores. In order to better study the relationship between SMS-NIHSS and 3-month functional outcome, we performed multivariate logistic regression analyses using both FO and VFO as outcome measures. Analyses were adjusted for potential confounders such as age, sex, side of the lesion, time from symptom onset to emergency room arrival, temperature, systolic blood pressure, blood glucose level and treatment group assignment (ORG 10172 vs. placebo). We also calculated the Spearman correlation coefficient between the SMS-NIHSS, Barthel Index (BI) and Glasgow Outcome Score (GOS) obtained at the 3-month visit. RESULTS: The mean SMS-NIHSS scores were 8.18 at baseline and 4.68 at 3 months. The SMS-NIHSS scores showed a gradual improvement during the first 3 months after stroke. There was a linear relationship between the baseline SMS-NIHSS scores and the probability of an FO or VFO at 3 months. The SMS-NIHSS baseline score was an independent predictor of FO (OR = 0.86; 95% CI 0.84-0.87; p < 0.0001) and VFO (OR = 0.85; 95% CI 0.84-0.87; p < 0.0001) at 3 months after adjusting for confounders. The degree of improvement in the SMS NIHSS scores from baseline to 3 months was also independently associated with FO and VFO (p < 0.0001). At 3 months, SMS-NIHSS scores showed a strong correlation with the BI (r = -0.70; p < 0.0001) and GOS (r = 0.73; p < 0.0001). CONCLUSIONS: The SMS-NIHSS is a valid scale for assessing motor recovery with prognosticative value, and may be sensitive to changes during recovery. Given that the SMS-NIHSS is an extension of the widely accepted NIHSS, it could be easily implemented in trials conducted in a variety of clinical research settings, including acute stroke hospitals and rehabilitation units. PMID- 23921196 TI - Serum 25-hydroxyvitamin D is associated with cognitive executive function in Dutch prefrail and frail elderly: a cross-sectional study exploring the associations of 25-hydroxyvitamin D with glucose metabolism, cognitive performance and depression. AB - OBJECTIVES: The primary objective was to explore the possible association of serum 25-hydroxyvitamin D (25[OH]D) and vitamin D intake with markers of glucose metabolism, depression, and cognitive performance. In addition, we examined to what extent the associations between vitamin D and cognitive performance were modified or mediated by fasting plasma glucose (FPG) levels. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study using data of 127 frail or prefrail Dutch elderly, aged 65 years or older. Frailty was defined according to the criteria of Fried and colleagues. A participant was classified prefrail when 1 to 2 criteria were met; frailty was classified as the presence of 3 or more criteria. MEASUREMENTS: Associations of 25(OH)D and vitamin D intake with markers of glucose metabolism and domain-specific cognitive performance were examined by multivariable regression analyses. The possible association of vitamin D with depression and global cognitive performance was explored by Poisson regression. RESULTS: No associations were observed for 25(OH)D with FPG, fasting plasma insulin (FPI), Homeostasis Model Assessment-estimated Insulin Resistance (HOMA IR), or depression. In contrast, serum 25(OH)D was positively associated with executive functioning (beta 0.007, P = .01) and tended to be associated with information-processing speed (beta 0.006, P = .06). FPG did not modify or mediate these associations. Vitamin D intake was not associated with cognitive performance, glucose metabolism, or depression. CONCLUSION: This cross-sectional study suggests an association of serum 25(OH)D with domain-specific cognitive performance, in particular executive functioning and possibly information processing speed, but not with FPG, FPI, HOMA-IR, or depression. Whether these associations are causal is yet to be demonstrated. PMID- 23921197 TI - Protective effect of resveratrol against endotoxemia-induced lung injury involves the reduction of oxidative/nitrative stress. AB - BACKGROUND: Resveratrol, a natural plant polyphenol, has received increasing attention because its varied bioactivities, including the inhibition of tumorigenesis, lipid modification and calorie-restriction. We aimed to investigate the effect of resveratrol on oxidative/nitrative stress in endotoxemia-associated acute lung injury. METHODS: Mice were injected with lipopolysaccharide (LPS, 5 mg/kg, ip). Resveratrol at a dose of 0.3 mg/kg was administered alone or immediately before injection of LPS. Twenty four hours later, lung tissues were collected for histopathologic examination, and determination of malondialdehyde (MDA), H2O2, reduced/oxidized glutathione (GSH/GSSG) ratio, total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, catalase (CAT) activity, inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) and peroxynitrite production. RESULTS: Resveratrol treatment improves histopathological changes in the lung during endotoxemia. Increased oxidative stress in endotoxemic lung was reversed by resveratrol treatment, as evidenced by the decreases of pro-oxidant biomarker (MDA and H2O2), and the increases of anti-oxidant biomarkers (GSH/GSSG ratio, T-AOC, CAT and SOD activity). Treatment with resveratrol inhibited endotoxemia-induced iNOS expression and NO production. Moreover, peroxynitrite formation in endotoxemic lung was significantly attenuated after resveratrol treatment. CONCLUSIONS: Resveratrol exerts protective effects against acute endotoxemia-associated lung injury. These beneficial effects may be due to both the anti-oxidant and anti nitrative properties of resveratrol. These findings support the potential for resveratrol as a possible pharmacological agent to reduce acute lung injury resulting from oxidative/nitrative damage. PMID- 23921198 TI - Cancer: from the partner's point of view. PMID- 23921199 TI - Open-label, phase II study of routine high-flow nasal oxygen therapy in cardiac surgical patients. AB - BACKGROUND: Respiratory complications after cardiac surgery increase morbidity, mortality, and length of stay. Studies suggest that routine delivery of positive airway pressure after extubation may be beneficial. We sought to determine whether the routine administration of nasal high-flow oxygen therapy (NHF) improves pulmonary function after cardiac surgery. METHODS: A pragmatic randomized controlled trial; participants received either NHF (45 litre min(-1)) or usual care from extubation to Day 2 after surgery. The primary outcome was number of patients with / ratio >=445 on Day 3 after surgery. The secondary outcomes included atelectasis score on chest X-ray; spirometry; intensive care and hospital length of stay; mortality on Day 28; oxygenation indices; escalation of respiratory support; and patient comfort. RESULTS: We randomized 340 patients over 14 months. The number of patients with a / ratio of >=445 on Day 3 was 78 (46.4%) in the NHF group vs 72 (42.4%) standard care [odds ratio (OR) 1.18, 95% confidence interval (CI) 0.77-1.81, P=0.45]. was reduced at both 4 h post extubation and at 9 a.m. on Day 1 in the NHF group (5.3 vs 5.4 kPa, P=0.03 and 5.1 vs 5.3 kPa, P=0.03, respectively). Escalation in respiratory support at any time in the study occurred in 47 patients (27.8%) allocated to NHF compared with 77 (45%) standard care (OR 0.47, 95% CI 0.29-0.7, P=0.001). CONCLUSIONS: Routine use of NHF did not increase / ratio on Day 3 but did reduce the requirement for escalation of respiratory support. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry www.anzctr.org.au (ACTRN12610000973011). PMID- 23921201 TI - Redundant publications. PMID- 23921202 TI - Development of reproductive organs in the ivory shell Babylonia japonica: observations from wild populations and laboratory-reared juveniles. AB - We histologically examined normal differentiation and development of genital tract and gonad in the ivory shell Babylonia japonica (Buccinidae) to determine whether the formation of male-type genitalia in imposex-exhibiting females mimics the normal development of male genitalia in prosobranch gastropods. We used a wild-caught 2-year-old specimen and laboratory-reared juveniles aged 0-24 months. Gonad differentiation was unclear before age 14 months, but progressed after 16 months. Both sexes had complete genital tract and mature gonad at 20 months. However, differentiation and development occurred earlier in females than in males. Development of genital tract preceded gonad differentiation. Vas deferens morphogenesis in males resembled that in imposex-exhibiting females. These findings help to understand the morphogenesis of genital tract and gonad in prosobranch gastropods and will contribute to more in-depth studies of the mode of action of organotin compounds such as TBT and TPhT in imposex development in female prosobranch gastropods. PMID- 23921203 TI - Metabolomic profile of the adrenal gland: from physiology to pathological conditions. AB - In this study, we i) assessed the metabolic profile of the normal adrenal cortex and medulla of adult human subjects by means of (1)H-high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR) spectroscopy; ii) compared the biochemical profile of adenoma (Ad), adrenal cortical carcinoma (ACC), and pheochromocytoma (PCC) samples with that of healthy adrenal tissue samples; and iii) investigated the metabolic differences between ACCs and Ads as well as between ACCs and PCCs. Sixty-six tissue samples (13 adrenal cortical tissue, eight medullary tissue, 13 Ad, 12 ACC, and 20 PCC samples) were analyzed. Adrenaline and noradrenaline were undetectable in cortical samples representing the metabolic signature of the tissue derived from neural crest. Similarity between the metabolic profile of Ads and that of the normal adrenal cortex was shown. Inversely, ACC samples clearly made up a detached group exhibiting the typical stigmata of neoplastic tissue such as choline-containing compounds, biochemical markers of anaerobic processes, and increased glycolysis. Significantly higher levels of lactate, acetate, and total choline-containing compounds played a major role in the differentiation of ACCs from Ads. Moreover, the high fatty acid content of ACCs contributed to the cluster identification of ACCs. Of the 14 sporadic PCC samples, 12 exhibited predominant or exclusive noradrenaline secretion. The noradrenaline:adrenaline ratio was inverted in the normal medullary tissue samples. Multiple endocrine neoplasia type 2- and NF1 related PCC samples exhibited both adrenaline and noradrenaline secretion. In the von Hippel-Lindau disease-related PCC samples, only noradrenaline secretion was detected by HRMAS NMR spectroscopy. This study is one of the first applications of metabolomics to adrenal pathophysiology and it is the largest study to report HRMAS NMR data related to the adrenal cortex and adrenal cortical tumors. PMID- 23921200 TI - Regional variation in stroke rehabilitation outcomes. AB - OBJECTIVE: To examine and describe regional variation in outcomes for persons with stroke receiving inpatient medical rehabilitation. DESIGN: Retrospective cohort design. SETTING: Inpatient rehabilitation units and facilities contributing to the Uniform Data System for Medical Rehabilitation from the United States. PARTICIPANTS: Patients (N=143,036) with stroke discharged from inpatient rehabilitation during 2006 and 2007. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Community discharge, length of stay (LOS), and discharge functional status ratings (motor, cognitive) across 10 geographic service regions defined by the Centers for Medicare and Medicaid Services (CMS). RESULTS: Approximately 71% of the sample was discharged to the community. After adjusting for covariates, the percentage discharged to the community varied from 79.1% in the Southwest (CMS region 9) to 59.4% in the Northeast (CMS region 2). Adjusted LOS varied by 2.1 days, with CMS region 1 having the longest LOS at 18.3 days and CMS regions 5 and 9 having the shortest at 16.2 days. CONCLUSIONS: Rehabilitation outcomes for persons with stroke varied across CMS regions. Substantial variation in discharge destination and LOS remained after adjusting for demographic and clinical characteristics. PMID- 23921204 TI - The management of head-and-neck paragangliomas. AB - Paragangliomas (PGLs) are tumours originating from neural crest-derived cells situated in the region of the autonomic nervous system ganglia. Head-and-neck PGLs (HNPGLs) originate from the sympathetic and parasympathetic paraganglia, most frequently from the carotid bodies and jugular, tympanic and vagal paraganglia, and are usually non-catecholamine secreting. Familial PGLs are considered to be rare, but recently genetic syndromes including multiple PGLs and/or phaeochromocytomas have been more thoroughly characterised. Nowadays, genetic screening for the genes frequently implicated in both familial and sporadic cases is routinely being recommended. HNPGLs are mostly benign, generally slow-growing tumours. Continuous growth leads to the involvement of adjacent neurovascular structures with increased morbidity rates and treatment related complications. Optimal management mostly depends on tumour location, local involvement of neurovascular structures, estimated malignancy risk, patient age and general health. Surgery is the only treatment option offering the chance of cure but with significant morbidity rates, so a more conservative approach is usually considered, especially in the more difficult cases. Radiotherapy (fractionated or stereotactic radiosurgery) leads to tumour growth arrest and symptomatic improvement in the short term in many cases, but the long-term consequences are unclear. Early detection is essential in order to increase the chance of cure with a lower morbidity rate. The constant improvement in diagnostic imaging, surgical and radiation techniques has led to a safer management of these tumours, but there are still many therapeutic challenges, and no treatment algorithm has been agreed upon until now. The management of HNPGLs requires a multidisciplinary effort addressing the genetic, surgical, radiotherapeutic, oncological, neurological and endocrinological implications. Further progress in the understanding of their pathogenesis will lead to more effective screening and earlier diagnosis, both critical to successful treatment. PMID- 23921206 TI - Positive long-term effects of Pilates exercise on the aged-related decline in balance and strength in older, community-dwelling men and women. AB - This study investigated the effect of Pilates exercise on physical fall risk factors 12 months after an initial 5-week Pilates intervention. The authors hypothesized that ongoing Pilates participation would have a positive effect on physical fall risk factors in those who continued with Pilates exercise compared with those who ceased. Thirty older ambulatory adults (M = 69 years, SD = 7) participated in Pilates classes for 5 weeks with testing preintevention (Time 1 [T1]) and postintervention (Time 2 [T2]) and 12 months later (Time 3 [T3]). Balance and leg strength were compared using a 2-way analysis of variance with repeated measures. Postural sway, dynamic balance, and function improvements evident after the initial Pilates training (T1-T2) were maintained at T3 (p < .01). Significant differences existed at T3 for dynamic balance and strength between participants who continued performing Pilates (n = 14) and those who had ceased. Balance improvements after a short Pilates intervention were maintained 1 year later in all participants, with increased benefits from ongoing participation. PMID- 23921205 TI - MicroRNAs in regulation of pluripotency and somatic cell reprogramming: small molecule with big impact. AB - MicroRNAs (miRNAs), a group of small non-coding RNAs, have emerged as significant modulators in the establishment and generation of pluripotency, a developmental process that consists of complex cell-fate arrangements. The finding of embryonic stem cell (ESC) cycle-specific miRNAs reveals an important regulation scheme of pluripotency. Subsequent studies showed the ESC-enriched or ESC-depleted miRNAs can regulate induced pluripotent stem cells(iPSC). Moreover, miRNA profiling of iPSC and ESC may distinguish them from one another and facilitate the complex of regulatory network. The accumulative effects of miRNA action enable using miRNA alone to generate iPSCs. Despite the robustness of iPSC studies, further investigations are needed since miRNA may have more impact on induced pluripotency, and the roles of miRNAs in somatic cell nuclear transfer (SCNT), another approach toward cellular reprogramming, remains unclear. This point-of view article will discuss miRNAs and their impact on the normal and induced pluripotency, as well as bring new insights on somatic cell reprogramming. PMID- 23921207 TI - Preparation of carboxymethyl chitosan-graft-beta-cyclodextrin modified silica gel and preconcentration of cadmium. AB - Carboxymethyl chitosan (CMCS) grafted with beta-cyclodextrin (CMCS-g-CD) modified silica gel as a new solid phase extraction (SPE) adsorbent for cadmium has been developed. The optimum batch experimental conditions (pH, amount of adsorbent and contact time) and column experimental conditions (concentration and volume of elution solution) were optimized, respectively. The kinetic models for Cd (II) were investigated and the results indicated that pseudo-second-order equation provided a better R(2) (R(2)>0.999) and agreement between calculated Qe value (10.6 mg/g) and the experimental Qe (exp) value (11.3 mg/g). The developed method was successfully applied to the determination of Cd(II) in lake water and tap water with recoveries ranging from 96.0% to 102.0%. PMID- 23921208 TI - Synthesis, characterization and evaluation of release retardant modified starches of Lagenaria siceraria seeds. AB - Starch isolated from under-utilized seeds of five different cultivars of Lagenaria siceraria (Mol.) standley (Cucurbitaceae) was carboxymethylated. The influence of the degree of substitution (DS) on physicochemical properties and drug release properties of starches was studied. The physicochemical profiles of the derivatives were assessed by means of FT-IR, XRD, SEM, elemental analysis, reaction efficiency, water binding capacity, swelling power, powder characteristics and visual estimation. The highest values of the DS obtained when the carboxymethylation was performed at 45 degrees C for 4h. Scanning electron microscopy (SEM) showed that after carboxymethylation, the granular appearance of the native starch was distorted. The new bands at 1576.87 cm(-1) and 1423.81 cm( 1) in Fourier transform infrared (FT-IR) indicated that the starch granules were substituted. Wide-angle X-ray diffractometry revealed that crystallinity was reduced significantly after carboxymethylation. Powder studies revealed that these starches possess potential for pharmaceutical applications. The matrix tablets were found to release the drug by Korsmeyer and Peppas kinetics. The carboxymethylated starches with high DS can be used as a drug release retardant in sustained release formulations, as the drug dissolution rate of native starches was significantly lower than the modified starches. PMID- 23921210 TI - Sex differences in attitudes toward partner infidelity. AB - Sex differences in reactions to partner infidelity have often been studied by comparing emotional reactions to scenarios of sexual versus emotional infidelity. Men, relative to women, tend to react with more distress to partner sexual infidelity than to emotional infidelity. Evolutionary theorists interpret this difference as evidence of sexually dimorphic selection pressures. In contrast, focusing only on the simple effects within each sex, social-cognitive theorists suggest that men and women do not differ in their reactions to partner infidelity. As evidenced by recent rival meta-analytic reports, these diverging perspectives remain largely unresolved and contentious. The present study was designed to take a new approach by measuring attitudes toward partner infidelity. Results were consistent with the evolutionary perspective: Men, to a significantly larger degree than women, evaluated partner sexual infidelity more negatively than emotional infidelity. PMID- 23921211 TI - Ethical review: Standardizing procedures and local shaping of ethical review practices. AB - Since ethical review practice has developed in relation to specific regulatory regimes and local contexts, it cannot be understood without paying attention to the institutional context of ethical review practices. We believe the tendency towards strong central governance and standardization in ethical review implies a lack of understanding of how specific local institutional contexts actually affect ethical review practices. Our question is: "How do local institutional contexts relate to the way REC's shape their formal mandate, and what are the implications for research governance?" To get in-depth insights in how REC's shape their formal mandates in every-day practice, we did a qualitative ethnographic-sociological study of three Dutch REC's in different contexts: an academic context, a care context and a commercial context. In analyzing these three REC's we paid attention to the procedures operative in REC practices, the cultures and everyday experiences of REC members, the scientific, social and financial resources that are available to REC's, and the evaluative perspective REC's employ. We conclude that specific local, institutional contexts offer valuable resources for ethical review. To track this, insight into the institutional configuration as a whole is necessary. Variations in the ways REC's shape their formal mandate should not be regarded problematic, but rather as fruitful opportunities for public learning. PMID- 23921212 TI - Frequency and nature of testicular and paratesticular lesions in forensic autopsies. AB - The aim of our study was to determine the frequency and nature of testicular and paratesticular lesions in forensic autopsies. A retrospective study was carried out on 495 adult male cases that underwent forensic autopsy from January 2008 to December 2011 in our Department. For each case, the following parameters were reported: age, body mass index, nature of testicular and paratesticular lesions, associated lesions in external genitalia, testicle weight, cause of death, manner of death, resuscitation attempts and prior medical history. Mean age of the studied population was 47.8 years (range 18-96). Mean body mass index was 25.3 kg/m(2) (range 15-46.2). Testicular lesions and/or paratesticular were found in 16.4% of the cases (n = 81). The most frequent lesions were, respectively, testicular atrophy (n = 38) and trauma (n = 28). In three cases showing traumatic lesions, associated traumatic lesions were found in external genitalia. Most frequent cause of death was blunt trauma (19.9% of the cases). Manner of death most frequently associated with testicular trauma was, respectively, road traffic accident (n = 11) and suicidal fall (n = 6). Mean testicular weight was, respectively, 17.9 g for the right and 20.8 g for the left (range 2-38). Atrophy was associated with testicular weight less than 10 g. A significant association between testicular atrophy and age was found, the risk of atrophy increasing quite linearly with age. No significant statistical link between prior medical history and testicular pathology was found. There was also no influence of body mass index. Resuscitation attempts were not statistically associated with testicular traumatic lesions. PMID- 23921213 TI - Neck pseudo-bruising secondary to acute aortic dissection. AB - We report a case of lethal acute aortic dissection revealed by a large ecchymotic area at the root of the neck; the subject was an 86-year-old man who died suddenly in his hospital room. His medical history included ischemic heart disease with pacemaker implantation and an aortic surgical prosthesis. Forensic autopsy showed a major subcutaneous hemorrhage in the neck and large left pleural and pericardial adhesions secondary to thoracic surgery. The cause of death was an acute aortic dissection. Large adhesions led to an extensive mediastinal hemorrhage, spreading to the subcutaneous tissues of the neck. This case report highlights the difficulties in differentiating between traumatic and pseudo bruising during a death scene investigation. The etiologies of pseudo-bruising are reviewed. PMID- 23921214 TI - The clinical management of diabetic foot in the elderly and medico-legal implications. AB - Diabetic foot is a complex and challenging pathological state, characterized by high complexity of management, morbidity and mortality. The elderly present peculiar problems which interfere on one hand with the patient's compliance and on the other with their diagnostic-therapeutic management. Difficult clinical management may result in medico-legal problems, with criminal and civil consequences. In this context, the authors present a review of the literature, analysing aspects concerning the diagnosis and treatment of diabetic foot in the elderly which may turn out to be a source of professional responsibility. Analysis of these aspects provides an opportunity to discuss elements important not only for clinicians and medical workers but also experts (judges, lawyers, medico-legal experts) who must evaluate hypotheses of professional responsibility concerning diabetic foot in the elderly. PMID- 23921215 TI - Stroke in heart failure in sinus rhythm: the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial. AB - BACKGROUND: The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial found no difference between warfarin and aspirin in patients with low ejection fraction in sinus rhythm for the primary outcome: first to occur of 84 incident ischemic strokes (IIS), 7 intracerebral hemorrhages or 531 deaths. Prespecified secondary analysis showed a 48% hazard ratio reduction (p = 0.005) for warfarin in IIS. Cardioembolism is likely the main pathogenesis of stroke in heart failure. We examined the IIS benefit for warfarin in more detail in post hoc secondary analyses. METHODS: We subtyped IIS into definite, possible and noncardioembolic using the Stroke Prevention in Atrial Fibrillation method. Statistical tests, stratified by prior ischemic stroke or transient ischemic attack, were the conditional binomial for independent Poisson variables for rates, the Cochran-Mantel-Haenszel test for stroke subtype and the van Elteren test for modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS) distributions, and an exact test for proportions. RESULTS: Twenty nine of 1,142 warfarin and 55 of 1,163 aspirin patients had IIS. The warfarin IIS rate (0.727/100 patient-years, PY) was lower than for aspirin (1.36/100 PY, p = 0.003). Definite cardioembolic IIS was less frequent on warfarin than aspirin (0.22 vs. 0.55/100 PY, p = 0.012). Possible cardioembolic IIS tended to be less frequent on warfarin than aspirin (0.37 vs. 0.67/100 PY, p = 0.063) but noncardioembolic IIS showed no difference: 5 (0.12/100 PY) versus 6 (0.15/100 PY, p = 0.768). Among patients experiencing IIS, there were no differences by treatment arm in fatal IIS, baseline mRS, mRS 90 days after IIS, and change from baseline to post-IIS mRS. The warfarin arm showed a trend to a lower proportion of severe nonfatal IIS [mRS 3-5; 3/23 (13.0%) vs. 16/48 (33.3%), p = 0.086]. There was no difference in NIHSS at the time of stroke (p = 0.825) or in post-IIS mRS (p = 0.948) between cardioembolic, possible cardioembolic and noncardioembolic stroke including both warfarin and aspirin groups. CONCLUSIONS: The observed benefits in the reduction of IIS for warfarin compared to aspirin are most significant for cardioembolic IIS among patients with low ejection fraction in sinus rhythm. This is supported by trends to lower frequencies of severe IIS and possible cardioembolic IIS in patients on warfarin compared to aspirin. PMID- 23921216 TI - Are transrectal prostate biopsies routinely indicated in patients with incidentally diagnosed prostate cancer following transurethral resection of the prostate for benign disease? AB - OBJECTIVE: To determine the indication of routine transrectal ultrasound-guided needle biopsy (TRUSBx) of the prostate gland following incidental cancer diagnosis after transurethral resection of the prostate (TURP) for benign prostatic hyperplasia. MATERIALS AND METHODS: A multi-institutional search identified 63 patients with incidental TURP-diagnosed prostate cancer from 2001 to 2010, who underwent subsequent TRUSBx or radical prostatectomy (RP). The Gleason scores from TURP were compared to those from TRUSBx or RP. Whole mount maps from RP were analysed to provide an anatomical basis for the correlation observed. To determine the clinical impact of this problem, the incidence of TURP diagnosed prostate cancer in the population was also determined. RESULTS: Of 22 patients who underwent TRUSBx, the rates of Gleason score concordance, upgrading and downgrading were 32, 14 and 54% respectively (Spearman correlation coefficient 0.20). Most cases of pathological downgrading consisted of benign cores at biopsy. Therefore, TRUSBx did not give additional Gleason score (GS) information in 86% of patients. Of 41 RP patients, the respective rates were 61, 22 and 17% (Spearman correlation coefficient 0.15). The majority of them retained a similar or lower GS between TURP and RP. Of 13 whole mount maps analysed, 6 (46%) were found with anterior/transitional zone (AZ/TZ) tumours, 6 (46%) with multifocal tumours and 1 (8%) with a large peripheral zone (PZ) tumour extending into the TZ. Regional population data show that despite a gradual reduction in the proportion of TURP-diagnosed cases over the past decade, they still account for 8.5-13% of all new cases. CONCLUSION: TURP-diagnosed prostate cancers represent predominantly AZ tumours. A TRUSBx does not give additional GS information in a majority of cases, and therefore is not routinely indicated. It may be selectively useful prior to active surveillance, but not in all pursuing radical treatment. These findings may help reduce unnecessary TRUSBx in the population. PMID- 23921217 TI - Relationship between gilt behavior and meat quality using principal component analysis. AB - Pig on-farm behavior has important repercussions on pig welfare and performance, but generally its relationship with meat quality is not well understood. We used principal component analysis to determine the relationship between meat quality traits, feeding patterns, scale activity, and number of conflict-avoidance interactions. The first principal component indicated that gilts with greater daily feed intake stayed longer in the feeder and their meat had increased intramuscular fat (IMF), was lighter in color, and, in the second principal component, had better juiciness, tenderness, chewiness, and flavor. Meat from gilts with lower scale activity scores appeared to have more IMF but greater drip losses (DL). The third principal component suggested that dominant gilts could gain priority access to the feeder, eating more and growing fatter. In conclusion, except for the slight associations with IMF and DL, gilt scale activity and conflict-avoidance behaviors were not good indicators of final meat quality attributes. PMID- 23921218 TI - Effect of aging time in vacuum on tenderness, and color and lipid stability of beef from mature cows during display in high oxygen atmosphere package. AB - The effect of aging time in vacuum on tenderness, and lipid and color stability of modified-atmosphere packaged (MAP) beef during display was evaluated in eight Friesian mature cows. Longissimus thoracis et lumborum (LTL) sections were vacuum packaged and aged for 0, 3, 6, 8, 14 and 21 days. After each aging time, the LTL sections were cut into steaks and packaged in high oxygen atmosphere (80% O2: 20% CO2). Meat shear force, and color and lipid stability were evaluated at 0, 3, 6, and 9 days of simulated retail display. Aging for 6 or 8 days improved beef tenderness with color stability, instrumental discoloration (R630-R580) and visual color evaluation in MAP similar to those of short-time aged (3 d) or un aged (0 d) beef. Longer aging times (14 and 21 d) resulted in tenderness values similar to those obtained with meat aged for 8 days but affected negatively color and lipid stability and, consequently, reduced the shelf life of beef in MAP. PMID- 23921219 TI - Religious slaughter: evaluation of current practices in selected countries. AB - As part of the project "Religious slaughter (DIALREL): improving knowledge and expertise through dialogue and debate on issues of welfare, legislation and socio economic aspects", this paper discusses an evaluation of current practices during Halal and Shechita slaughter in cattle, sheep, goats and poultry. During religious slaughter, animals are killed with and without stunning by a transverse incision across the neck that is cutting the skin, muscles (brachiocephalic, sternocephalic, sternohyoid, and sternothyroid), trachea, esophagus, carotid arteries, jugular veins and the major, superficial and deep nerves of the cervical plexus. In this report, the restraint methods, stunning, neck cutting, exsanguination, slaughter techniques and postcut handling in the abattoir were assessed for religious slaughter. Information about the procedures used during religious slaughter in Belgium, Germany, Italy, the Netherlands, Spain, the UK, Turkey and Australia was collected by means of spot visits to abattoirs. To standardize the information gathered during the spot visits three guidelines were designed, one for each species, and translated into the national languages of the countries involved. The document included questions on the handling and restraint methods (stunning, neck cutting/exsanguination/slaughter techniques and postcut handling performed under religious practices) and for pain and distress of the animal during the restraint, neck cutting and induction to death in each abattoir. Results showed differences in the time from restraining to stun and to cut in the neck cutting procedures and in the time from cut to death. PMID- 23921220 TI - Genotoxic and phytotoxic risk assessment of fresh and treated hydrochar from hydrothermal carbonization compared to biochar from pyrolysis. AB - Biochar is discussed as an option for climate change mitigation via C sequestration and may promote sustainable resource efficiency. Large-scale field trials and commercial business with char materials have already started. Therefore char materials have to be assessed for toxic compounds. We tested genotoxic effects of different hydrochars and biochars with the Tradescantia micronucleus test. For this purpose chromosomal aberrations in pollen cells of Tradescantia in the form of micronuclei were evaluated microscopically after defined exposition to extracts from char materials. Hydrochars from hydrothermal carbonization mostly exhibited significantly negative results. Additional germination experiments with hydrochar showed total germination inhibition at additions above five percent v/v in comparison to biochar. However, biological post-treatment of previously toxic hydrochar was successful and toxic effects were eliminated completely. Some post-treated hydrochars even showed growth stimulating effects. Our results clearly demonstrate the necessity of risk assessment with bioindicators. The chosen tests procedures can contribute to biochar and hydrochar characterization for safe application. PMID- 23921221 TI - Inverse mercury and selenium concentration patterns between herbivorous and piscivorous fish in the Tapajos River, Brazilian Amazon. AB - We evaluated the levels of selenium and mercury in five fish species commonly eaten by local populations of the Brazilian Amazon. Fish specimens were sampled in two lotic and three lentic areas at two different phases of the hydrological cycle. Analyses of Carbon and Nitrogen stable isotopes allowed us to confirm the trophic levels of the fish species (one herbivorous, two omnivorous and two piscivorous) and verify that these levels remained unchanged with the habitats and the season. The levels of selenium and mercury in fish varied from 50ng/g to 1006ng/g and from 17ng/g to 3502ng/g respectively. For both seasons, fish from lotic ecosystems presented higher selenium concentrations. An inverse pattern was observed between selenium and mercury concentrations within the trophic chain, and this in both seasons. Indeed, the highest mean concentrations of selenium and lowest mean concentrations of mercury were measured in the herbivorous species and the opposite in the piscivorous species. Our results unequivocally demonstrate that local riverside populations will maximize the selenium health benefits of eating fish while minimizing their risk of being chronically exposed to mercury by preferentially consuming herbivorous species and to some extent omnivorous species, while avoiding piscivorous species. PMID- 23921222 TI - Requirement of apoptosis-inducing kinase 1 for the induction of bronchial asthma following stimulation with ovalbumin. AB - BACKGROUND: Bronchial asthma is a chronic inflammatory disease of the airway. Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase kinase kinase family, is activated by environmental stress and plays a crucial role in the induction of apoptosis and inflammation. To examine whether ASK1 is involved in the induction of bronchial asthma, we investigated the role of ASK1 using a genetic approach in the production of cytokines, as well as the development of airway hyperreactivity (AHR) and antibody responses using a murine airway inflammation model. METHODS: ASK1-deficient (ASK1(-/-)) and control wild-type (WT) mice were immunized with ovalbumin (OVA) without alum intraperitoneally, followed by intranasal administration of OVA. Airway infiltration of inflammatory cells, cytokine production, AHR and antibody production were assayed. The asthmatic phenotype was assessed following intranasal administration of IL-13 or TNF-alpha. RESULTS: ASK1(-/-) mice sensitized with OVA displayed an impaired inflammatory cell infiltration into airways and a decreased AHR relative to WT mice. Moreover, the production of OVA specific IgE antibodies and proasthmatic cytokines (IL-5, IL-13 and TNF-alpha) was substantially reduced in OVA-stimulated ASK1(-/-) mice. Intranasal administration of IL-13 and OVA enhanced the accumulation of inflammatory cells in OVA-primed ASK1(-/-) mice. The OVA-induced AHR in response to methacholine was enhanced by IL-13 in WT mice but not ASK1(-/-) mice. CONCLUSIONS: The ASK1 signaling pathway regulates the OVA-induced asthmatic phenotype, specifically AHR sensitivity and cytokine production. Therefore, the ASK1 signaling pathway is a promising target for therapeutic intervention in some asthmatic patients. PMID- 23921223 TI - How robust is the 'surprise question' in predicting short-term mortality risk in haemodialysis patients? AB - BACKGROUND/AIMS: The 'surprise question' (SQ) may aid timely identification of patients with end-of-life care needs. We assessed its prognostic value and variability among clinicians caring for a cohort of haemodialysis (HD) patients. METHODS: Clinicians (29 nurses and 6 nephrologists) in each of our 3 HD units were asked to pose the SQ concerning all patients dialysing in their unit. There were 344 patients, 116 in Unit 1, 132 in Unit 2 and 96 in Unit 3. RESULTS: An adverse SQ response: 'I would not be surprised if this patient were to die in the next 12 months' was reported by individual clinicians for between 6 and 43% of patients (mean 24 +/- 9%). Nephrologists responded adversely for more patients than nurses did. Fifty-two patients died during the 12 months of follow-up. There were wide variations between clinicians in the predictive power of SQ responses. Mean odds ratios were significantly higher for nephrologists than for nurses. SQ responses of 49% of clinicians improved baseline models of 12-month mortality, more so for nephrologists (67%) than for senior nurses (50%) and nurses of lesser seniority (36%). Unit performance differed significantly. Agreements between clinicians on SQ responses improved the positive predictive value, i.e. the more clinicians agreed on an adverse response, the greater its predictive power. CONCLUSION: SQ provides a unique contribution to the prediction of short-term prognosis in HD patients, though predictive power varies with clinical discipline, seniority and clinical setting. Agreements between clinicians on adverse responses may have clinical utility. PMID- 23921224 TI - Genomics education for health educators in Texas: the Family Health History Training Program. AB - AIMS: This paper describes the development and pilot-testing of The Family Health History Training Program for Health Educators (FHHTP). Although in recent years professional organizations have urged the health promotion workforce to adopt genomics-related competencies, training opportunities designed specifically for health educators (HEs) remain scarce. Designed by a team of HEs, the FHHTP aims at preparing HEs in the state of Texas, USA, to use a family health history as a genomic health promotion tool. METHODS: In this report, we describe (a) the program's empirical and theoretical grounding, (b) its components, and (c) pilot testing of the 2 main components (Web-based and workshop trainings). The FHHTP addresses the training needs expressed by HEs and anchors itself in a theoretical model previously tested with 1,607 US-based HEs. The model draws from Social Cognitive Theory, the Theory of Planned Behavior, and Diffusion of Innovations theory. The program comprises 6 elements; the Web-based training and the training workshops are the focus of this paper. RESULTS: Pilot data indicate participants' knowledge and intention improved significantly (p < 0.05) at post-test and remained significantly higher at the 3-month follow-up. Attitudes, self-efficacy, behavior, knowledge/awareness, and intention also exhibited improvement in scores over time. CONCLUSION: We conclude, therefore, that the FHHTP can contribute significantly to the adoption of genomic competencies by Texas HEs. This report describes how the first-of-its-kind genomics training for HEs in the USA - FHHTP was developed and pilot-tested with HEs in Texas. PMID- 23921225 TI - Cortisol emphasizes the metabolic strategies employed by common carp, Cyprinus carpio at different feeding and swimming regimes. AB - The objective of this study was to investigate the interaction between feeding, exercise and cortisol on metabolic strategies of common carp over a 168h post implant period. Feeding provided readily available energy and clearly increased muscle and liver protein and glycogen stores. Swimming, feeding and cortisol all induced aerobic metabolism by increasing oxygen consumption, and stimulated protein metabolism as demonstrated by the increased ammonia and urea excretion and ammonia quotient. Hypercortisol stimulated ammonia self-detoxifying mechanisms by enhancing ammonia and urea excretion, especially during severe exercise. At high swimming level, higher branchial clearance rates in cortisol treated fish succeeded in eliminating the elevation of endogenous ammonia, resulting in reduced plasma Tamm levels compared to control and sham implanted fish. Carp easily induced anaerobic metabolism, both during routine and active swimming, with elevated lactate levels as a consequence. Both feeding and cortisol treatment increased this dependence on anaerobic metabolism. Hypercortisol induced both glycogenesis and gluconeogenesis resulting in hyperglycemia and muscle and liver glycogen deposition, most likely as a protective mechanism for prolonged stress situations and primarily fuelled by protein mobilization. PMID- 23921226 TI - Special focus: endothelial activation/dysfunction. PMID- 23921227 TI - GT3X+ accelerometer, Yamax pedometer and SC-StepMX pedometer step count accuracy in community-dwelling older adults. AB - The purpose was to compare step count accuracy of an accelerometer (ActiGraph GT3X+), a mechanical pedometer (Yamax SW200), and a piezoelectric pedometer (SC StepMX). Older adults (n = 13 with walking aids, n = 22 without; M = 81.5 years old, SD = 5.0) walked 100 m wearing the devices. Device-detected steps were compared with manually counted steps. We found no significant differences among monitors for those who walked without aids (p = .063). However, individuals who used walking aids exhibited slower gait speeds (M = 0.83 m/s, SD = 0.2) than non walking aid users (M = 1.21 m/s, SD = 0.2, p < .001), and for them the SC-StepMX demonstrated a significantly lower percentage of error (Mdn = 1.0, interquartile range [IQR] = 0.5-2.0) than the other devices (Yamax SW200, Mdn = 68.9, IQR = 35.9-89.3; left GT3X+, Mdn = 52.0, IQR = 37.1-58.9; right GT3X+, Mdn = 51.0, IQR = 32.3-66.5; p < .05). These results support using a piezoelectric pedometer for measuring steps in older adults who use walking aids and who walk slowly. PMID- 23921228 TI - Honokiol inhibits pathological retinal neovascularization in oxygen-induced retinopathy mouse model. AB - Aberrant activation of the hypoxia inducible factor (HIF) pathway is the underlying cause of retinal neovascularization, one of the most common causes of blindness worldwide. The HIF pathway also plays critical roles during tumor angiogenesis and cancer stem cell transformation. We have recently shown that honokiol is a potent inhibitor of the HIF pathway in a number of cancer and retinal pigment epithelial cell lines. Here we evaluate the safety and efficacy of honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources. Our studies show that honokiol has a better safety to efficacy profile as a HIF inhibitor than digoxin and doxorubicin. Further, we show for the first time that daily intraperitoneal injection of honokiol starting at postnatal day (P) 12 in an oxygen-induced retinopathy (OIR) mouse model significantly reduced retinal neovascularization at P17. Administration of honokiol also prevents the oxygen-induced central retinal vaso-obliteration, characteristic feature of the OIR model. Additionally, honokiol enhanced physiological revascularization of the retinal vascular plexuses. Since honokiol suppresses multiple pathways activated by HIF, in addition to the VEGF signaling, it may provide advantages over current treatments utilizing specific VEGF antagonists for ocular neovascular diseases and cancers. PMID- 23921229 TI - Design, synthesis and evaluation of a potent substrate analog inhibitor identified by scanning Ala/Phe mutagenesis, mimicking substrate co-evolution, against multidrug-resistant HIV-1 protease. AB - Multidrug-resistant (MDR) clinical isolate-769, human immunodeficiency virus type 1 (HIV-1) protease (PDB ID: 1TW7), was shown to exhibit wide-open flaps and an expanded active site cavity, causing loss of contacts with protease inhibitors. In the current study, the expanded active site cavity of MDR769 HIV-1 protease was screened with a series of peptide-inhibitors that were designed to mimic the natural substrate cleavage site, capsid/p2. Scanning Ala/Phe chemical mutagenesis approach was incorporated into the design of the peptide series to mimic the substrate co-evolution. Among the peptides synthesized and evaluated, a lead peptide (6a) with potent activity (IC50: 4.4nM) was identified against the MDR769 HIV-1 protease. Isothermal titration calorimetry data showed favorable binding profile for 6a against both wild type and MDR769 HIV-1 protease variants. Nuclear magnetic resonance spectrum of (15)N-labeled MDR769 HIV-1 protease in complex with 6a showed some major perturbations in chemical shift, supporting the peptide induced conformational changes in protease. Modeling analysis revealed multiple contacts between 6a and MDR769 HIV-1 protease. The lead peptide-inhibitor, 6a, with high potency and good binding profile can be used as the basis for developing potent small molecule inhibitors against MDR variants of HIV. PMID- 23921230 TI - Bacterial adhesion and growth reduction by novel rubber-derived oligomers. AB - In the medical field, attached bacteria can cause infections associated with catheters, incisions, burns, and medical implants especially in immunocompromised patients. The problem is exacerbated by the fact that attached bacteria are ~1000 times more resistant to antibiotics than planktonic cells. The rapid spread of antibiotic resistance in these and other organisms has led to a significant need to find new methods for preventing bacterial attachment. The goal of this research was to evaluate the effectiveness of novel polymer coatings to prevent the attachment of three medically relevant bacteria. Tests were conducted with Pseudomonas aeruginosa, Staphylococcus epidermidis, and Staphylococcus aureus for oligomers derived from modifications of natural rubber (cis 1,4-polyisoprene). The different oligomers were: PP04, with no quaternary ammonium (QA); MV067, one QA; PP06, three QA groups. In almost all experiments, cell attachment was inhibited to various extents as long as the oligomers were used. PP06 was the most effective as it decreased the planktonic cell numbers by at least 50% for all bacteria. Differences between species sensitivity were also observed. P. aeruginosa was the most resistant bacteria tested, S. aureus, the most sensitive. Further experiments are required to understand the full extent and mode of the antimicrobial properties of these surfaces. PMID- 23921232 TI - Confidence intervals for heterogeneity measures in meta-analysis. AB - Two methods of quantifying heterogeneity between studies in meta-analysis were studied. One method quantified the proportion of the total variance of the effect estimate due to variation between studies (RI), and the other calibrated the variance between studies to the size of the effect itself through a between-study coefficient of variation (CVB). Bootstrap and asymptotic confidence intervals for RI and CVB were derived and evaluated in an extensive simulation study that covered a wide range of scenarios likely to be encountered in practice. The best performance was given by asymptotic Wald confidence intervals developed for RI and CVB. The use of these heterogeneity measures together with their confidence intervals was illustrated in 5 typical meta-analyses. A new user-friendly SAS macro (SAS Institute, Inc., Cary, North Carolina) is provided to implement these methods for routine use and can be downloaded at the last author's website. PMID- 23921231 TI - Targeting the Wnt pathway in synovial sarcoma models. AB - Synovial sarcoma is an aggressive soft-tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT-SSX (SS18-SSX), drives sarcoma initiation and development. The exact mechanism of SYT SSX oncogenic function remains unknown. In an SYT-SSX2 transgenic model, we show that a constitutive Wnt/beta-catenin signal is aberrantly activated by SYT-SSX2, and inhibition of Wnt signaling through the genetic loss of beta-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1alpha activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/beta catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. These studies reveal the central role of Wnt/beta-catenin signaling in SYT-SSX2 induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents. SIGNIFICANCE: Synovial sarcoma is an aggressive soft-tissue cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT-SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans. PMID- 23921233 TI - Non-fatal opioid overdose and major depression among street-recruited young heroin users. AB - BACKGROUND/AIMS: Non-fatal opioid overdose (NFOO) and major depression (MD) are highly prevalent in heroin users. Many risk factors are known for NFOO, but studies in non-clinical samples on its relationship with MD are lacking. We aimed to examine this relationship in a street-recruited sample, controlling for potential well-known confounders. METHODS: A cross-sectional study in 452 heroin users street-recruited by chain referral methods in three Spanish cities. Eligibility criteria were: age<=30 years, heroin use at least 12 days in the last year and at least once in the last 3 months. Depression was assessed using the Composite International Diagnostic Interview. A precise definition of NFOO was used. Adjusted odds ratios (AORs) for the NFOO predictors were obtained by logistic regression. RESULTS: The prevalence of NFOO and MD in the last 12 months was 9.1 and 23.2%, respectively. After adjusting for potential confounders, NFOO and MD were significantly associated (AOR 2.2; 95% CI 1.01-4.74). Other associated factors were imprisonment (AOR 4.1; 95% CI 1.4-12.1), drug injection (AOR 6.7; 95% CI 2.4-18.4) and regular use of tranquillisers/sleeping pills (AOR 2.9; 95% CI 1.16-7). CONCLUSIONS: Drug and mental health treatment facilities should consider the relationship between MD and NFOO when contacting and treating heroin users. Imprisonment, drug injection and use of tranquillisers/sleeping pills are also risk factors for NFOO. PMID- 23921234 TI - Aortic aneurysm: an independent predictor of a looped brachiocephalic trunk in patients undergoing transradial coronary angiography. AB - BACKGROUND: A looped brachiocephalic trunk may cause transradial coronary angiography (TRA) failure with a right radial approach. The prevalences of aortic aneurysm (AA) and a looped brachiocephalic trunk are closely related to increased age. OBJECTIVE: The aim of this study was to clarify the relationship between AA and a looped brachiocephalic trunk. PATIENTS AND METHODS: A total of 1306 consecutive patients who underwent TRA through the right radial artery at Keio University Hospital between January 2007 and December 2011 were examined retrospectively. A looped brachiocephalic trunk was defined as the presence of a full 360 degrees loop in the 45 degrees left anterior oblique view requiring a change in the access site to the left radial or femoral artery. RESULTS: Of the 1306 patients who underwent TRA at Keio University Hospital between January 2007 and December 2011, 137 had AA. The patients were divided into two groups: patients with a looped brachiocephalic trunk and those without it. Patients in the looped brachiocephalic group were older and had a higher BMI. The prevalence of hypertension was higher in the looped brachiocephalic trunk group. Creatinine clearance was lower in patients with a looped brachiocephalic trunk than in those without a looped brachiocephalic trunk. Multivariate analysis showed that AA was an independent predictor of a looped brachiocephalic trunk. CONCLUSION: AA is a predictor of a looped brachiocephalic trunk that should be considered in patients undergoing TRA. PMID- 23921235 TI - Lignin-degrading peroxidases in Polyporales: an evolutionary survey based on 10 sequenced genomes. AB - The genomes of three representative Polyporales (Bjerkandera adusta, Phlebia brevispora and a member of the Ganoderma lucidum complex) were sequenced to expand our knowledge on the diversity of ligninolytic and related peroxidase genes in this Basidiomycota order that includes most wood-rotting fungi. The survey was completed by analyzing the heme-peroxidase genes in the already available genomes of seven more Polyporales species representing the antrodia, gelatoporia, core polyporoid and phlebioid clades. The study confirms the absence of ligninolytic peroxidase genes from the manganese peroxidase (MnP), lignin peroxidase (LiP) and versatile peroxidase (VP) families, in the brown-rot fungal genomes (all of them from the antrodia clade), which include only a limited number of predicted low redox-potential generic peroxidase (GP) genes. When members of the heme-thiolate peroxidase (HTP) and dye-decolorizing peroxidase (DyP) superfamilies (up to a total of 64 genes) also are considered, the newly sequenced B. adusta appears as the Polyporales species with the highest number of peroxidase genes due to the high expansion of both the ligninolytic peroxidase and DyP (super)families. The evolutionary relationships of the 111 genes for class-II peroxidases (from the GP, MnP, VP, LiP families) in the 10 Polyporales genomes is discussed including the existence of different MnP subfamilies and of a large and homogeneous LiP cluster, while different VPs mainly cluster with short MnPs. Finally, ancestral state reconstructions showed that a putative MnP gene, derived from a primitive GP that incorporated the Mn(II)-oxidation site, is the precursor of all the class-II ligninolytic peroxidases. Incorporation of an exposed tryptophan residue involved in oxidative degradation of lignin in a short MnP apparently resulted in evolution of the first VP. One of these ancient VPs might have lost the Mn(II)-oxidation site being at the origin of all the LiP enzymes, which are found only in species of the order Polyporales. PMID- 23921237 TI - Repeated loss of an anciently horizontally transferred gene cluster in Botrytis. AB - At least five of the six genes of the bikaverin secondary metabolic gene cluster were shown to have undergone horizontal transfer (HGT) from a Fusarium donor to the Botrytis lineage. Of these five, two enzyme-encoding genes are found as pseudogenes in B. cinerea whereas two regulatory genes and the transporter remain intact. To reconstruct the evolutionary events leading to decay of this gene cluster and infer a more precise timing of its transfer, we examined the genomes of nine additional broadly sampled Botrytis species. We found evidence that a Botrytis ancestor acquired the entire gene cluster through an ancient HGT that occurred before the diversification of the genus. During the subsequent evolution and diversification of the genus, four of the 10 genomes appear to have lost the gene cluster, while in the other six the cluster is in various stages of degeneration. Across the Botrytis genomes, the modes of gene decay in the cluster differed between enzyme-encoding genes, which had higher rates of transition to or retention of pseudogenes and were universally inactivated, and regulatory genes (particularly the non-pathway-specific regulator bik4), which more frequently appeared intact. Consistent with these results, the regulatory genes bik4 and bik5 showed stronger evidence of transcriptional expression than other bikaverin genes under multiple conditions in B. cinerea. These results could be explained by pleiotropy in the bikaverin regulatory genes either through rewiring or their interaction with more central pathways or by constraints on the order of gene loss driven by the intrinsic toxicity of the pathway. Our finding that most of the bikaverin pathway genes have been lost or pseudogenized in these Botrytis genomes suggests that the incidence of HGT of gene cluster-encoded metabolic pathways might be higher than what is possible to be inferred from isolated genome analyses. PMID- 23921236 TI - Description, culture and phylogenetic position of a new xerotolerant species of Physarum. AB - A new widespread myxomycete species, Physarum pseudonotabile, inhabiting the arid regions of the Eurasia, South and North America is described and illustrated. Tentatively assigned to Ph. notabile T. Macbr., a phylogeny based on the small ribosomal subunit (SSU) and elongation factor 1 alpha (EF1a) genes placed the new species in a clade far from Ph. notabile. Ph. pseudonotabile was found to be frequent in surveys based on the moist chamber culture technique with samples of litter, bark and herbivore dung collected in dry steppe and deserts of the Caspian lowland (Russia), Kazakhstan, Mongolia, China, Spain, Argentina and USA. The main morphological difference between Ph. pseudonotabile and Ph. notabile lies in spore ornamentation. Spores of the former species display irregularly distributed verrucae, whereas the latter species possesses spores with dense and regularly arranged spinulae. In addition, the ecological preferences of the two species differ. Ph. pseudonotabile inhabits the bark of living plants and ground litter in arid regions, whereas Ph. notabile is found on coarse woody debris in boreal and temperate forests. Although the new species appears to be closest to Ph. notabile morphologically, the phylogenetic analysis reveals Ph. pusillum and Ph. nivale as the closest relatives. In addition, the molecular investigations revealed a considerable amount of hidden diversity within species of Physarum with gray lime flakes. Currently we have only sufficient material to assess the morphological variation of Ph. pseudonotabile but expect that more taxa within this clade may emerge within studies combining morphological and molecular analyses. PMID- 23921238 TI - Fungal diversity of saprotrophic litter fungi in a Mediterranean maquis environment. AB - Monospecific and mixed-leaf litters from plant species of Mediterranean maquis (Quercus ilex, Phillyrea angustifolia, Pistacia lentiscus, Cistus spp.) in an undisturbed area in southern Italy were studied with respect to the structure and composition of their decomposer fungal community over an incubation period of 403 d. The data matrix structure was analyzed by means of detrended correspondence analysis (DCA), while indicator species analysis (ISA) was used to determine the preferential association of species with a substrate, a succession phase and monospecific/mixed experimental conditions. The ecological nature of the gradient expressed by the DCA axes was investigated by means of experimental and main chemical leaf-litter variables. The litter mixture had non-additive effects on the decomposition process even though the fungal species richness of the mixed litter was considerably higher than that of the monospecific litter. Our findings highlight the occurrence of shifts in the fungal community during decomposition in response to changes in the substrate, such as those related to the cellulose content and lignin/N ratio. PMID- 23921239 TI - The Epichloe endophytes associated with the woodland grass Hordelymus europaeus including four new taxa. AB - Epichloe endophytes (Clavicipitaceae, Ascomycota), including asexual forms placed in Neotyphodium, are common in cool-season grasses. Here we characterize the endophytes of the European woodland grass Hordelymus europaeus based on growth characteristics, morphology of conidiophores and conidia and phylogenetic relationships. Of the six different taxa found on H. europaeus, four are new, for which we propose the species names E. hordelymi, E. disjuncta, E. danica and subspecies E. sylvatica subsp. pollinensis. The other two are assigned to previously described E. bromicola and E. sylvatica. E. hordelymi, E. disjuncta and E. danica are asexual interspecific hybrids, while the other taxa are haploid. Only E. sylvatica subsp. pollinensis was found to reproduce sexually on H. europaeus. The high diversity of endophytes may be explained by repeated host jumps to H. europaeus with and without subsequent interspecific hybridizations. PMID- 23921240 TI - Penicillium kongii, a new terverticillate species isolated from plant leaves in China. AB - A new Penicillium species isolated from plant leaves, characterized by restricted growth, terverticillate penicilli, ovoid to ellipsoidal conidia and a red soluble pigment on yeast extract sucrose agar is reported here. Penicillium kongii sp. nov. belongs to subgenus Penicillium section Brevicompacta and is morphologically similar to P. bialowiezense and P. brevicompactum. Phylogenetic analyses based on sequence data from calmodulin gene, beta-tubulin gene and rDNA ITS1-5.8S-ITS2 show that P. kongii forms a distinctive clade. PMID- 23921241 TI - Oomycetes baited from streams in Tennessee 2010-2012. AB - Sixteen streams in middle and eastern Tennessee were surveyed for the sudden oak death pathogen Phytophthora ramorum 2010-2012. Surveys were conducted in the spring and fall using healthy Rhododendron leaves, and a total of 354 oomycete isolates were recovered. Sequence analysis of the ITS region provisionally identified 151 Phytophthora, 200 Pythium, two Halophytophthora and one Phytopythium. These include six Phytophthora species (P. cryptogea, P. hydropathica, P. irrigata, P. gonapodyides, P. lacustris, P. polonica), members of the P. citricola species complex, five unknown Phytophthora species, 11 Pythium species (P. helicoides, P. diclinum, P. litorale, P. senticosum, P. undulatum, P. vexans, P. citrinum, P. apleroticum, P. chamaihyphon, P. montanum, P. pyrilobum), three unknown Pythium species, Halophytophthora batemanensis, and one Phytopythium isolate. The biology and implications are discussed. PMID- 23921242 TI - Cellular organization in germ tube tips of Gigaspora and its phylogenetic implications. AB - Comparative morphology of the fine structure of fungal hyphal tips often is phylogenetically informative. In particular, morphology of the Spitzenkorper varies among higher taxa. To date no one has thoroughly characterized the hyphal tips of members of the phylum Glomeromycota to compare them with other fungi. This is partly due to difficulty growing and manipulating living hyphae of these obligate symbionts. We observed growing germ tubes of Gigaspora gigantea, G. margarita and G. rosea with a combination of light microscopy (LM) and transmission electron microscopy (TEM). For TEM, we used both traditional chemical fixation and cryo-fixation methods. Germ tubes of all species were extremely sensitive to manipulation. Healthy germ tubes often showed rapid bidirectional cytoplasmic streaming, whereas germ tubes that had been disturbed showed reduced or no cytoplasmic movement. Actively growing germ tubes contain a cluster of 10-20 spherical bodies approximately 3-8 MUm behind the apex. The bodies, which we hypothesize are lipid bodies, move rapidly in healthy germ tubes. These bodies disappear immediately after any cellular perturbation. Cells prepared with cryo-techniques had superior preservation compared to those that had been processed with traditional chemical protocols. For example, cryo prepared samples displayed two cell-wall layers, at least three vesicle types near the tip and three distinct cytoplasmic zones were noted. We did not detect a Spitzenkorper with either LM or TEM techniques and the tip organization of Gigaspora germ tubes appeared to be similar to hyphae in zygomycetous fungi. This observation was supported by a phylogenetic analysis of microscopic characters of hyphal tips from members of five fungal phyla. Our work emphasizes the sensitive nature of cellular organization, and the need for as little manipulation as possible to observe germ tube structure accurately. PMID- 23921243 TI - Pseudocosmospora, a new genus to accommodate Cosmospora vilior and related species. AB - Cosmospora sensu Rossman accommodated nectroid fungi with small, reddish, smooth, thin-walled perithecia but recently was found to be polyphyletic and has been segregated into multiple genera. Not all cosmospora-like fungi have been treated systematically. Some of these species include C. vilior and many specimens often labeled "Cosmospora sp." The objectives of this research were to establish the identity of C. vilior through epitypication using a recent collection that agrees with the type specimen in morphology, host and geography and to determine its phylogenetic position within Cosmospora sensu lato and the Nectriaceae. A multilocus phylogeny was constructed based on six loci (ITS, LSU, MCM7, rpb1, tef1, tub) to estimate a phylogeny. Results from the phylogenetic analyses indicated that C. vilior forms a monophyletic group with other cosmospora-like fungi that have an acremonium-like anamorph and that parasitize Eutypa and Eutypella (Ascomycota, Sordariomycetes, Xylariales, Diatrypaceae). The group is phylogenetically distinct from other previously segregated genera. A new genus, Pseudocosmospora, is described to accommodate the type species, P. eutypellae, and nine additional species in this clade. PMID- 23921244 TI - A molecular phylogenetic assessment of the genus Gyromitra in North America. AB - Gyromitra is a widespread genus of macroscopic apothecial ascomycetes whose taxa may be mycorrhizal, saprophytic or parasitic. Nuclear ribosomal 28S large subunit sequence data from 35 specimens from North America, along with sequences available in GenBank, were used in maximum-parsimony, maximum-likelihood and Bayesian analyses to reconstruct a phylogeny of Gyromitra in North America. Gyromitra sensu lato forms a monophyletic group within the Discinaceae composed of five distinct subgenera and 11 well supported clades that include Discina, Hydnotrya and Pseudorhizina. A new subgenus is proposed to accommodate G. californica and G. sphaerospora. PMID- 23921245 TI - Three new Pochonia taxa (Clavicipitaceae) from soils in Japan. AB - Fifty Pochonia strains were isolated from soil samples collected throughout Japan. Using a combination of micromorphological characters and multigene (SSU, LSU, TEF, RPB1, RPB2) phylogenics, seven taxa were identified, three of which previously were undescribed. In this paper we describe the new species, P. boninensis, and two new varieties, P. chlamydosporia var. ellipsospora and var. spinulospora. They were recovered from Chichi-jima, Aogashima and Okinawa's main island. The three new taxa are distinguished from known species and varieties by conidial morphology. We also report the first finding of P. rubescens from Japan. PMID- 23921246 TI - Fate of the contralateral limb after lower extremity amputation. AB - OBJECTIVE: Lower extremity amputation is often performed in patients where both lower extremities are at risk due to peripheral arterial disease or diabetes, yet the proportion of patients who progress to amputation of their contralateral limb is not well defined. We sought to determine the rate of subsequent amputation on both the ipsilateral and contralateral lower extremities following initial amputation. METHODS: We conducted a retrospective review of all patients undergoing lower extremity amputation (exclusive of trauma or tumor) at our institution from 1998 to 2010. We used International Classification of Diseases Ninth Revision codes to identify patients and procedures as well as comorbidities. Outcomes included the proportion of patients at 1 and 5 years undergoing contralateral and ipsilateral major and minor amputation stratified by initial major vs minor amputation. Cox proportional hazards regression analysis was performed to determine predictors of major contralateral amputation. RESULTS: We identified 1715 patients. Mean age was 67.2 years, 63% were male, 77% were diabetic, and 34% underwent an initial major amputation. After major amputation, 5.7% and 11.5% have a contralateral major amputation at 1 and 5 years, respectively. After minor amputation, 3.2% and 8.4% have a contralateral major amputation at 1 and 5 years while 10.5% and 14.2% have an ipsilateral major amputation at 1 and 5 years, respectively. Cox proportional hazards regression analysis revealed end-stage renal disease (hazard ratio [HR], 3.9; 95% confidence interval [CI], 2.3-6.5), chronic renal insufficiency (HR, 2.2; 95% CI, 1.5-3.3), atherosclerosis without diabetic neuropathy (HR, 2.9; 95% CI, 1.5-5.7), atherosclerosis with diabetic neuropathy (HR, 9.1; 95% CI, 3.7-22.5), and initial major amputation (HR, 1.8; 95% CI, 1.3-2.6) were independently predictive of subsequent contralateral major amputation. CONCLUSIONS: Rates of contralateral limb amputation are high and predicted by renal disease, atherosclerosis, and atherosclerosis with diabetic neuropathy. Physicians and patients should be alert to the high risk of subsequent amputation in the contralateral leg. All patients, but particularly those at increased risk, should undergo close surveillance and counseling to help prevent subsequent amputations in their contralateral lower extremity. PMID- 23921247 TI - A case-control study of intentional occlusion of accessory renal arteries during endovascular aortic aneurysm repair. AB - OBJECTIVE: The purpose of this study was to evaluate outcomes of patients treated by intentional coverage of accessory renal artery (ARA) during endovascular abdominal aneurysm repair (EVAR). METHODS: The clinical data of 119 patients (110 male and nine female; mean age, 75 years) from a cohort of 811 patients treated by EVAR from 1998 to 2009 was reviewed. Patients who had intentional coverage of at least one ARA (group A) were compared with two control groups, which included patients with no ARA (group B) and those who had ARA preserved during EVAR (group C). All three groups of patients were matched for age, gender, hypertension, and preoperative estimated glomerular filtration rate (eGFR). Paired pre- and postoperative computed tomography angiography was analyzed for the presence and volume of kidney infarction. End points were changes in eGFR, chronic kidney disease (CKD) stage, blood pressure measurements, presence and volume of kidney infarction, freedom from reintervention, and endoleak. RESULTS: There were 42 patients in group A, 42 in group B, and 35 in group C. Demographics, cardiovascular risk factors, and CKD classification were similar in all three groups. Among patients in group A, 44 ARAs were intentionally covered with ARAs originating from the proximal neck in 22 patients, the aneurysm sac in 20, and the iliac arteries in two. There was one (1%) early death in the entire study. Early morbidity was similar in all three groups, including four patients (9%) in group A, four (9%) in group B, and four (11%) in group C (P = .9). Six (5%) patients had >25% decrease in eGFR, including two who had ARA coverage. None of the patients required dialysis. After a mean follow-up of 37 months, there were no differences in late renal function deterioration, changes in eGFR, CKD stage, or blood pressure measurements among the three groups. Three of the 18 patients (17%) with ARA >3 mm arising from the aneurysm sac developed a type II endoleak requiring coil embolization. Kidney infarction was noted in 28 patients (67%) in group A. Freedom from reintervention at 2 years was similar in groups A (64%), B (80%), and C (96%; P = .09). CONCLUSIONS: Intentional ARA occlusion during EVAR was not associated with changes in renal function or blood pressure measurements, even when performed in patients with more advanced renal dysfunction. Type II endoleak may result from persistent outflow into large (>3 mm) ARAs that arise from the aneurysm sac. PMID- 23921248 TI - Multiple monomorphic VTs from diverticulum in RVOT. PMID- 23921249 TI - Clinical controversies in the management of critically ill patients with severe sepsis: resuscitation fluids and glucose control. AB - Severe sepsis with multiple organ dysfunction remains the most common cause of death for patients treated in intensive care units. As there is no specific treatment for severe sepsis, current management consists of antibiotics, source control and the use of supportive therapies to sustain life while waiting for the adverse effects of sepsis-induced organ dysfunction to subside. Despite the central role of supportive therapies, few have been subjected to rigorous evaluation; two exceptions are the choice of resuscitation fluid and intensity of glucose control. Current data support the use of a crystalloid fluid with the addition of albumin when needed for fluid resuscitation. Administration of hydroxyethyl starch is harmful and should be avoided. Stress hyperglycemia should be treated when blood glucose concentration exceeds 180 mg/dL (10.0 mmol/L) and when insulin therapy is needed it should be targeted to a blood glucose concentration of 144-180 mg/dL (8-10 mmol/L). PMID- 23921250 TI - Orbitofrontal and striatal circuits dynamically encode the shift between goal directed and habitual actions. AB - Shifting between goal-directed and habitual actions allows for efficient and flexible decision making. Here we demonstrate a novel, within-subject instrumental lever-pressing paradigm, in which mice shift between goal-directed and habitual actions. We identify a role for orbitofrontal cortex (OFC) in actions following outcome revaluation, and confirm that dorsal medial (DMS) and lateral striatum (DLS) mediate different action strategies. Simultaneous in vivo recordings of OFC, DMS and DLS neuronal ensembles during shifting reveal that the same neurons display different activities depending on whether presses are goal directed or habitual, with DMS and OFC becoming more and DLS less engaged during goal-directed actions. Importantly, the magnitude of neural activity changes in OFC following changes in outcome value positively correlates with the level of goal-directed behavior. Chemogenetic inhibition of OFC disrupts goal-directed actions, whereas optogenetic activation of OFC specifically increases goal directed pressing. These results also reveal a role for OFC in action revaluation, which has implications for understanding compulsive behavior. PMID- 23921251 TI - Effects of transducer mass on intramuscular temperature during ultrasound treatments. AB - CONTEXT: A potential variable that could affect rate of temperature elevation with ultrasound is the pressure (mass) that is applied to the transducer head during application. Added pressure could compress the tissue, affecting density and the transmission of ultrasound energy. Little research has been completed to determine the effects of the amount of pressure applied during therapeutic ultrasound in vivo. OBJECTIVE: To determine the effects of different applied transducer mass on intramuscular temperature during an ultrasound treatment within the left triceps surae. DESIGN: Crossover clinical trial. SETTING: Human performance research laboratory. PARTICIPANTS: Convenience sample of thirteen healthy, college-age students. INTERVENTIONS: Three separate 3-MHz, 1.0-W/cm2 ultrasound treatments were administered 1.5 cm within the triceps surae. The independent variables were the linear temperature standards (0.5 degrees C, 1.0 degrees C, 1.5 degrees C, and 2.0 degrees C above baseline) and the 3 different applied pressures measured in grams (200 g, 600 g, and 800 g). MAIN OUTCOME MEASURES: A thermocouple probe was used to measure triceps surae temperature, and time to reach the temperature standards was recorded during the ultrasound treatments. A 4 * 3 repeated-measures analysis of variance (RM-ANOVA) was used to analyze the differences for temperature points (0.5 degrees C, 1.0 degrees C, 1.5 degrees C, and 2.0 degrees C) and transducer mass (200 g, 600 g, and 800 g) and with respect to time. RESULTS: The results of the RM-ANOVA showed no temperature point and transducer-mass interaction (F6,72 = 1.69, P = .137) or main effect for mass (F2,24 = 1.23, P = .309). The time required to raise temperature 2 degrees C was 209.1 +/- 68.10 s at 200 g, 181.5 +/- 61.50 s at 600 g, and 194.9 +/- 75.54 s at 800 g. CONCLUSIONS: Under the conditions of this study, the amount of mass applied with the transducer during an ultrasound treatment does not ultimately affect the rate of tissue heating. PMID- 23921252 TI - Prevalence of sensitization to Cannabis sativa. Lipid-transfer and thaumatin-like proteins are relevant allergens. AB - BACKGROUND: Although allergy to Cannabis sativa was first reported over 40 years ago, the allergenicity has scarcely been studied. The objectives of this study were to investigate the frequency of sensitization to this plant, to analyze the clinical characteristics and allergenic profile of sensitized individuals and to identify the allergens involved. METHODS: Five hundred and forty-five individuals in Spain attending allergy clinics with respiratory or cutaneous symptoms underwent a skin-prick test (SPT) with C. sativa leaf extract. The extract was characterized by SDS-PAGE and 2-dimensional electrophoresis. Specific IgE to C. sativa was measured in positive SPT individuals. The clinical and allergenic profiles of sensitized individuals were investigated and the most-recognized allergens sequenced and characterized by liquid chromatography-mass spectrometry/mass spectrometry. RESULTS: Of this preselected population, 44 individuals had positive SPT to C. sativa (prevalence 8.1%). Prevalence was higher in individuals who were C. sativa smokers (14.6%). Two individuals reported mild symptoms with C. sativa. Twenty-one individuals from 32 available sera (65.6%) had positive specific IgE to C. sativa. Twelve sera recognized at least 6 different bands in a molecular-weight range of between 10 and 60 kDa. Six of them recognized a 10-kDa band, identified as a lipid transfer protein (LTP) and 8 recognized a 38-kDa band, identified as a thaumatin-like protein. CONCLUSIONS: There is a high prevalence of sensitization to C. sativa leaves. The clinical symptoms directly attributed to C. sativa were uncommon and mild. The sensitization profile observed suggests that C. sativa sensitization may be mediated by two mechanisms, i.e. cross-reactivity, mainly with LTP and thaumatin like protein, and exposure-related 'de novo' sensitization. PMID- 23921253 TI - Lipid metabolism in cancer. PMID- 23921254 TI - Molecular and physiological functions of sphingosine 1-phosphate transporters. AB - Sphingosine 1-phosphate (S1P) is a lipid mediator that plays important roles in diverse cellular functions such as cell proliferation, differentiation and migration. S1P is synthesized inside the cells and subsequently released to the extracellular space, where it binds to specific receptors that are located on the plasma membranes of target cells. Accumulating recent evidence suggests that S1P transporters including SPNS2 mediate S1P release from the cells and are involved in the physiological functions of S1P. In this review, we discuss recent advances in our understanding of the mechanism and physiological functions of S1P transporters. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology. PMID- 23921255 TI - S100A12 gene expression is increased in peripheral leukocytes in chronic kidney disease stage 4-5 patients with cardiovascular disease. AB - BACKGROUND/AIMS: S100A12 induces vascular inflammation contributing to the development of atherosclerosis. Serum S100A12 concentration is shown to be elevated in patients with chronic kidney disease (CKD), however the reason remains unclear. METHODS: Transcriptional levels of S100A12 and RAGE (receptor for advanced glycation end products) were measured in peripheral leukocytes by quantitative real-time RT-PCR. Subjects were 40 patients with CKD stage 4-5, 20 of whom were affected with cardiovascular disease (CVD), and 20 healthy subjects. Serum concentrations of S100A12 and soluble RAGE were measured using enzyme linked immunosorbent assay. RESULTS: The serum concentration of S100A12 was significantly higher in CKD patients than in healthy subjects (78.5 +/- 70.5 vs. 23.7 +/- 19.2 ng/ml, p = 0.0035), but that of soluble RAGE was not. The relative quantity of S100A12 mRNA was significantly greater in leukocytes from CKD patients than in those from healthy subjects [mean (95% confidence interval of the mean): 3.1 (2.2-3.9) vs. 1.2 (0.8-1.7), p = 0.0001], however that of RAGE mRNA was not. The serum concentration of S100A12 was significantly correlated with the relative quantity of S100A12 mRNA among uremic CKD patients (r(2) = 0.656, p < 0.0001). Both the serum concentration and gene expression of S100A12 were significantly higher in patients who had CVD than in those who did not. CONCLUSION: Excessive expression of the S100A12 gene in uremic leukocytes is relevant to its increased serum concentration, particularly in those affected with CVD. PMID- 23921257 TI - RNA-Seq analysis reveals genes associated with resistance to Taura syndrome virus (TSV) in the Pacific white shrimp Litopenaeus vannamei. AB - Outbreak of Taura syndrome virus (TSV) is one of the major pathogens of the Pacific white shrimp Litopenaeus vannamei. Although selective breeding for improvement of TSV resistance in L. vannamei has been successfully developed and has led to a great benefit to the shrimp farming industry worldwide. The molecular mechanisms underlying the viral resistance in shrimp remain largely unknown. In the present study, we conducted the first transcriptomic profiling of host responses in hemolymph and hemocytes in order to identify the differentially expressed genes associated with resistance to TSV in L. vannamei. High-throughput RNA-Seq was employed, obtaining 193.6 and 171.2 million high-quality Illumina reads from TSV-resistant and susceptible L. vannamei lines respectively. A total of 61,937 contigs were generated with an average length of 546.26 bp. BLASTX based gene annotation (E-value < 10(-5)) allowed the identification of 12,398 unique proteins against the NCBI non-redundant NR database. In addition, comparison of digital gene expression between resistant and susceptible strains revealed 1374 significantly differentially expressed contigs (representing 697 unigenes). Gene pathway analysis of the differentially expressed gene set highlighted several putative genes involved in the immune response activity including (1) pathogen/antigen recognition including immune regulator, adhesive protein and signal transducer; (2) coagulation; (3) proPO pathway cascade; (4) antioxidation; and (5) protease. The expression patterns of 22 differentially expressed genes involving immune response were validated by quantitative real time RT-PCR (average correlation coefficients 0.94, p-value < 0.001). Our results provide valuable information on gene functions associated with resistance to TSV in L. vannamei. PMID- 23921258 TI - Immunity to amoeba. AB - Amoebic infections in fish are most likely underestimated and sometimes overlooked due to the challenges associated with their diagnosis. Amoebic diseases reported in fish affect either gills or internal organs or may be systemic. Host response ranges from hyperplastic response in gill infections to inflammation (including granuloma formation) in internal organs. This review focuses on the immune response of Atlantic salmon to Neoparamoeba perurans, the causative agent of Amoebic Gill Disease (AGD). PMID- 23921259 TI - A sociability gene? Meta-analysis of oxytocin receptor genotype effects in humans. AB - Variation in the oxytocin receptor (OXTR) gene may partly explain individual differences in oxytocin-related social behavior. Two single nucleotide polymorphisms (SNPs) have been suggested as promising candidates: rs53576 and rs2254298, although the results of studies were not consistent. We carried out meta-analyses for these two SNPs, covering five domains of outcomes: (a) biology, (b) personality, (c) social behavior, (d) psychopathology, and (e) autism, on the basis of 82 pertinent effect sizes, 48 for OXTR rs53576 (N=17 559) and 34 for OXTR rs2254298 (N=13 547). Combined effect sizes did not differ from zero in any of the domains, nor for all domains combined. Clinical status, age, and sex did not moderate the effect sizes. Minor allele frequency was related to ethnicity, with significantly lower minor allele frequencies in samples with predominantly Caucasian participants. The domain of biological functioning seemed most promising, but comprised few studies. We conclude that so far two of the most intensively studied OXTR SNPs (rs53576 and rs2254298) failed to explain a significant part of human social behavior. PMID- 23921256 TI - Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [11C]-+-PHNO. AB - The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D2 receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D3 receptor system has recently attracted considerable clinical interest, and D3 antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioral relevance of the D3 receptor system in CD, using the positron emission tomography (PET) radiotracer [(11)C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7 240 days on scan day) and fifteen matched healthy control (HC) subjects completed two PET scans: one with [(11)C]-(+)-PHNO to assess D3 receptor binding (BPND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [(11)C]raclopride to assess D2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [(11)C]-(+)-PHNO BPND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [(11)C]raclopride BPND was lower across the striatum in CD, consistent with previous literature in ?2 week abstinence. The data suggest that in contrast to a D2 deficiency, CD individuals may have heightened D3 receptor levels, which could contribute to addiction-relevant traits. D3 upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment. PMID- 23921260 TI - Association study on the DLG4 gene and schizophrenia in the Chinese Han population. AB - BACKGROUND: Abnormal expressions of the N-methyl-D-aspartate receptor and its interacting postsynaptic density (PSD) molecules have been hypothesized to be involved in the pathophysiology of schizophrenia. Few studies have carried out association studies with DLG4 gene (coding PSD-95 protein) and sought to validate the results with Asian schizophrenia patients. PATIENTS AND METHODS: To further investigate the significance of DLG4 in Asian schizophrenic patients, we examined seven single-nucleotide polymorphisms (SNPs) within this gene in 1504 unrelated Chinese mainland individuals (893 patients and 611 controls). RESULTS: No association was found between these seven SNPs and schizophrenia within our sample. No significant differences in allele or genotype frequencies between schizophrenic paranoid patients and controls were found. CONCLUSION: Although no allelic or genotypic variances of this gene were observed, the possibility that SNPs within DLG4 represent a positive schizophrenia risk gene cannot be excluded. Our research provided a reference for further research into this gene in other populations. PMID- 23921261 TI - Stir octadecyl-modified borosilicate disk for the liquid phase microextraction of triazine herbicides from environmental waters. AB - In the present article, a novel extraction/stirring approach in the liquid phase microextraction context is presented. The new technique is based on octadecyl coated borosilicate disks which act as support of the organic extracting solvent thanks to hydrophobic interactions. The disk is integrated in a stirring element which favors the transference of the analytes to the extraction phase. The proposed extraction procedure has been characterized using the determination of nine herbicides in water samples by ultra performance liquid chromatography (UPLC) combined with ultraviolet (UV) detection as model analytical problem. All the variables involved in the extraction have been studied and optimized in depth and the optimized technique provides enrichment factors in the range from 79 to 839. The method has been analytically characterized on the basis of its linearity, sensitivity and precision. Limits of detection were in the range from 0.14MUg/L (atrazine) to 0.56MUg/L (terbumeton) with precision better than 7.3% (expressed as relative standard deviation). Relative recoveries were close to 100%, which demonstrated the applicability of the stir octadecyl-modified borosilicate disk for the proposed analytical problem. PMID- 23921262 TI - Simultaneous determination of six resorcylic acid lactones in feed using liquid chromatography-tandem mass spectrometry and multi-walled carbon nanotubes as a dispersive solid phase extraction sorbent. AB - A simple and cost-effective pre-treatment procedure was developed for six resorcylic acid lactones (RALs) in feed using dispersive solid phase extraction (dSPE) with multi-walled carbon nanotubes (MWCNTs). The sample was analysed after purification by ultra-high performance liquid chromatography-negative electrospray ionisation tandem mass spectrometry (UHPLC-ESI-MS/MS). After extraction with acetonitrile/water (80:20, v/v) and dilution with water, a dSPE procedure was carried out with MWCNTs. The pH value of the extract, the extraction time for MWCNTs, the type and amount of MWCNTs and the type of eluent were optimised to increase the sample throughput and the sensitivity. The samples were quantified using the internal standard zearalenone-D6. The absolute recoveries of the target compounds from feed samples were most efficient when using 100mg of MWCNTs with an outer diameter of less than 8nm and a length of 10 30MUm, and ethyl acetate was shown to be the most suitable solvent for desorbing the target compounds from the MWCNTs. The mean recoveries from fortified swine mixed feed samples ranged from 95.3% to 107.2% and had relative standard deviations lower than 10%; the limits of detection and quantification for RALs were in the ranges of 0.20-0.29MUg/kg and 0.54-0.78MUg/kg, respectively. PMID- 23921263 TI - Trypsin functionalization and zirconia coating of mesoporous silica nanotubes for matrix-assisted laser desorption/ionization mass spectrometry analysis of phosphoprotein. AB - Trypsin functionalized mesoporous silica nanotubes bioreactor (TEMSN) and zirconia layer coated mesoporous silica nanotubes (ZrO2-MSN) were developed to deal with the long in-solution digestion time of phosphoprotein and detection difficulty of phosphorylated peptides, respectively. Trypsin was immobilized on the mesoporous silica nanotubes via epoxy group and TEMSN were used as a bioreactor for digestion of alpha-casein within 3min. ZrO2-MSN were performed to enrich phosphopeptides selectively from in-solution digested peptide mixture of beta-casein to demonstrate that ZrO2-MSN possessed remarkable selectivity for phosphorylated peptides even at 100/1 molar ratio of BSA/beta-casein. The selective ability of ZrO2-MSN was also investigated in comparison to ZrO2 nanoparticles (ZrO2 NP). Moreover, phosphorylated peptides at the femtomole (2.5fmol) level can also be detected with high S/N (signal-to-noise) ratio. Phosphopeptides enriched from TEMSN-bioreactor digested peptide mixture of alpha casein was also performed to evaluate the cooperative performance of TEMSN and ZrO2-MSN platform. The experimental results indicated that TEMSN-bioreactor digestion changed the distribution of relative abundance of phosphopeptides and improved the relative intensity of partial phosphopeptides. This analytical strategy has also been applied to the identification of phosphopeptides isolated from non-fat bovine milk and got a comparable results compared with other materials cited from the literature. By matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS), TEMSN and ZrO2-MSN were combined together for the rapid and comprehensive analysis of phosphoprotein. PMID- 23921264 TI - A novel aqueous two phase assisted platform for efficient removal of process related impurities associated with E. coli based biotherapeutic protein products. AB - This article presents a variant of aqueous two phase system (ATPS) as a tool for selective removal of process related impurities associated with Escherichia coli, namely host cell proteins and nucleic acids. Granulocyte colony stimulating factor (GCSF) expressed in E. coli has been selected as a model protein for the study. While achieving effective removal of host cell impurities as per the regulatory requirement for recombinant therapeutics, high product recovery has been achieved by adopting a novel strategy involving resolubilization of interfacial GCSF precipitate. This has been done such that the structural and biological activity of the product is retained. Exhaustive analysis of structural as well as functional integrity of resolubilized GCSF has been carried out using advanced analytical and in vitro bioassay tools. Product recovery of 99.5% has been achieved with the concentration of host cell proteins less than 100ppm and of nucleic acids below 10ng/ml. We think that the proposed platform can enable use of ATPS as a more economical alternative to process chromatography in industrial biopharmaceutical manufacturing processes. PMID- 23921265 TI - Enantiomeric separation of volatile organics by gas chromatography for the in situ analysis of extraterrestrial materials: kinetics and thermodynamics investigation of various chiral stationary phases. AB - The performances of several commercial chiral capillary columns have been evaluated with the aim of determining the one most suitable for enantiomeric separation in a gas chromatograph onboard a space probe. We compared the GC-MS response of three capillary columns coated with different chiral stationary phases (CSP) using volatile chiral organic molecules which are potential markers of a prebiotic organic chemistry. The three different chiral capillary columns are Chirasil-Val, with an amino acid derivative CSP, ChiralDex-beta-PM, with a CSP composed of dissolved permethylated beta-cyclodextrins in polysiloxane, and Chirasil-Dex, with a CSP made of modified cyclodextrins chemically bonded to the polysiloxane backbone. Both kinetics and thermodynamics studies have been carried out to evaluate the chiral recognition potential in these different types of columns. The thermodynamic parameters also allow a better understanding of the driving forces affecting the retention and separation of the enantiomers. The Chirasil-Dex-CSP displays the best characteristics for an optimal resolution of the chiral compounds, without preliminary derivatization. This CSP had been chosen to be the only chiral column in the Sample Analysis at Mars (SAM) experiment onboard the current Mars Science Laboratory (MSL) mission, and is also part of the Mars Organic Molecules Analyzer (MOMA) gas chromatograph onboard the next Martian mission ExoMars. The use of this column could also be extended to all space missions aimed at studying chirality in space. PMID- 23921266 TI - Environment-driven reactivity of H2 on PdRu surface alloys. AB - The dissociative adsorption of molecular hydrogen on Pd(x)Ru(1-x)/Ru(0001) (0 <= x <= 1) has been investigated by means of He atom scattering, Density Functional Theory and quasi-classical trajectory calculations. Regardless of their surroundings, Pd atoms in the alloy are always less reactive than Ru ones. However, the reactivity of Ru atoms is enhanced by the presence of nearest neighbor Pd atoms. This environment-dependent reactivity of the Ru atoms in the alloy provides a sound explanation for the striking step-like dependence of the initial reactive sticking probability as a function of the Pd concentration observed in experiments. Moreover, we show that these environment-dependent effects on the reactivity of H2 on single atoms allow one to get around the usual constraint imposed by the Bronsted-Evans-Polanyi relationship between the reaction barrier and chemisorption energy. PMID- 23921267 TI - Three-dimensional CT imaging in pediatric calvarial pathologies. AB - In children with suspected cranial pathologies, three-dimensional (3D) computed tomography (CT) imaging is superior to other modalities. It can help differentiate actual pathology from normal or variant appearances. Sutures and fontanelles, synostosis, abnormalities of head shape without craniosynostosis, congenital calvarial defects, cranial fractures, bone tumors, and postoperative cranial vault can be assessed easily with 3D CT imaging. We aimed to discuss the common normal, variant, and pathological findings that 3D CT imaging can aid to diagnose as well as explain the usefulness of 3D CT imaging in the diagnosis of calvarial pathologies. PMID- 23921268 TI - MRI of diffuse liver disease: the common and uncommon etiologies. AB - Diffuse liver disease, including all causes of chronic liver disease, affects tens of millions of people worldwide. There is a growing need for diagnostic evaluation as treatments become more readily available, particularly for viral liver disease. Magnetic resonance imaging (MRI) provides unique capabilities for noninvasive characterization of liver tissue that rival or surpass the diagnostic utility of liver biopsies. There has been incremental improvement in the use of standardized MRI sequences, acquired before and after administration of contrast for the evaluation of diffuse liver disease, and this includes study of the liver parenchyma and blood supply. More recent developments have led to methods for quantifying important liver metabolites, including fat and iron, and liver fibrosis, which is the hallmark for chronic liver disease. In this study, we review the MRI techniques and diagnostic features associated with common and uncommon etiologies of diffuse liver diseases, including processes that lead to abnormal perfusion (e.g. Budd-Chiari syndrome, congestive hepatomegaly), deposition diseases (e.g. fatty liver, hemochromatosis, Wilson's disease), and abnormalities that are related to inflammation and fibrosis (e.g. primary sclerosing cholangitis, sarcoidosis). PMID- 23921269 TI - Endovascular treatment of a superficial femoral artery aneurysm using an Amplatzer Vascular Plug. PMID- 23921270 TI - Ratio of PICU versus ward cardiopulmonary resuscitation events is increasing. AB - OBJECTIVES: The aim of this study was to evaluate the relative frequency of pediatric in-hospital cardiopulmonary resuscitation events occurring in ICUs compared to general wards. We hypothesized that the proportion of pediatric cardiopulmonary resuscitation provided in ICUs versus general wards has increased over the past decade, and this shift is associated with improved resuscitation outcomes. DESIGN: Prospective and observational study. SETTING: Total of 315 hospitals in the American Heart Association's Get With The Guidelines Resuscitation database. PATIENTS: Total of 5,870 pediatric cardiopulmonary resuscitation events between January 1, 2000 and September 14, 2010. Cardiopulmonary resuscitation events were defined as external chest compressions longer than 1 minute. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was proportion of total ICU versus general ward cardiopulmonary resuscitation events over time evaluated by chi-square test for trend. Secondary outcome included return of spontaneous circulation following the cardiopulmonary resuscitation event. Among 5,870 pediatric cardiopulmonary resuscitation events, 5,477 (93.3%) occurred in ICUs compared to 393 (6.7%) in inpatient wards. Over time, significantly more of these cardiopulmonary resuscitation events occurred in the ICU compared to the wards (test for trend: p<0.01), with a prominent shift noted between 2003 and 2004 (2000-2003: 87-91% vs 2004-2010: 94-96%). In a multivariable model controlling for within center variability and other potential confounders, return of spontaneous circulation increased in 2004-2010 compared with 2000-2003 (relative risk, 1.08; 95% CI, 1.03-1.13). CONCLUSIONS: In-hospital pediatric cardiopulmonary resuscitation is much more commonly provided in ICUs than in wards, and the proportion has increased significantly over the past decade, with concomitant increases in return of spontaneous circulation. PMID- 23921271 TI - Effects of levosimendan on glomerular filtration rate, renal blood flow, and renal oxygenation after cardiac surgery with cardiopulmonary bypass: a randomized placebo-controlled study. AB - OBJECTIVES: Acute kidney injury develops in a large proportion of patients after cardiac surgery because of the low cardiac output syndrome. The inodilator levosimendan increases cardiac output after cardiac surgery with cardiopulmonary bypass, but a detailed analysis of its effects on renal perfusion, glomerular filtration, and renal oxygenation in this group of patients is lacking. We therefore evaluated the effects of levosimendan on renal blood flow, glomerular filtration rate, renal oxygen consumption, and renal oxygen demand/supply relationship, i.e., renal oxygen extraction, early after cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective, placebo-controlled, and randomized trial. SETTING: Cardiothoracic ICU of a tertiary center. PATIENTS: Postcardiac surgery patients (n=30). INTERVENTIONS: The patients were randomized to receive levosimendan, 0.1 ug/kg/min after a loading dose of 12 ug/kg (n=15), or placebo (n=15). MEASUREMENTS AND MAIN RESULTS: The experimental procedure started 4-6 hours after surgery in the ICU during propofol sedation and mechanical ventilation. Systemic hemodynamic were evaluated by a pulmonary artery thermodilution catheter. Renal blood flow and glomerular filtration rate were measured by the renal vein retrograde thermodilution technique and by renal extraction of Cr-EDTA, respectively. Central venous pressure was kept constant by colloid/crystalloid infusion. Compared to placebo, levosimendan increased cardiac index (22%), stroke volume index (15%), and heart rate (7%) and decreased systemic vascular resistance index (21%), whereas mean arterial pressure was not affected. Levosimendan induced significant increases in renal blood flow (12%, p<0.05) and glomerular filtration rate (21%, p<0.05), decreased renal vascular resistance (18%, p<0.05) but caused no significant changes in filtration fraction, renal oxygen consumption, or renal oxygen extraction, compared to placebo. CONCLUSIONS: After cardiac surgery with cardiopulmonary bypass, levosimendan induces a vasodilation, preferentially of preglomerular resistance vessels, increasing both renal blood flow and glomerular filtration rate without jeopardizing renal oxygenation. Due to its pharmacodynamic profile, levosimendan might be an interesting alternative for treatment of postoperative heart failure complicated by acute kidney injury in postcardiac surgery patients. PMID- 23921272 TI - Procalcitonin versus C-reactive protein for guiding antibiotic therapy in sepsis: a randomized trial. AB - OBJECTIVE: We sought to evaluate whether procalcitonin was superior to C-reactive protein in guiding antibiotic therapy in intensive care patients with sepsis. DESIGN: Randomized open clinical trial. SETTING: Two university hospitals in Brazil. PATIENTS: Patients with severe sepsis or septic shock. INTERVENTIONS: Patients were randomized in two groups: the procalcitonin group and the C reactive protein group. Antibiotic therapy was discontinued following a protocol based on serum levels of these markers, according to the allocation group. The procalcitonin group was considered superior if the duration of antibiotic therapy was at least 25% shorter than in the C-reactive protein group. For both groups, at least seven full-days of antibiotic therapy were ensured in patients with Sequential Organ Failure Assessment greater than 10 and/or bacteremia at inclusion, and patients with evident resolution of the infectious process had antibiotics stopped after 7 days, despite biomarkers levels. MEASUREMENTS AND MAIN RESULTS: Ninety-four patients were randomized: 49 patients to the procalcitonin group and 45 patients to the C-reactive protein group. The mean age was 59.8 (SD, 16.8) years. The median duration of antibiotic therapy for the first episode of infection was 7.0 (Q1-Q3, 6.0-8.5) days in the procalcitonin group and 6.0 (Q1-Q3, 5.0-7.0) days in the C-reactive protein group (p=0.13), with a hazard ratio of 1.206 (95% CI, 0.774-1.3; p=0.13). Overall, protocol overruling occurred in only 13 (13.8%) patients. Twenty-one patients died in each group (p=0.836). CONCLUSIONS: C-reactive protein was as useful as procalcitonin in reducing antibiotic use in a predominantly medical population of septic patients, causing no apparent harm. PMID- 23921273 TI - Impact of critical care telemedicine consultations on children in rural emergency departments. AB - OBJECTIVES: To compare the quality of care delivered to critically ill and injured children receiving telemedicine, telephone, or no consultation in rural emergency departments. DESIGN: Retrospective chart review with concurrent surveys. SETTING AND PARTICIPANTS: Three hundred twenty patients presenting in the highest triage category to five rural emergency departments with access to pediatric critical care consultations from an academic children's hospital. MEASUREMENTS AND MAIN RESULTS: Quality of care was independently rated by two pediatric emergency medicine physicians applying a previously validated 7-point implicit quality review tool to the medical records. Quality was compared using multivariable linear regression adjusting for age, severity of illness, and temporal trend. Referring physicians were surveyed to evaluate consultation related changes in their care. Parents were also surveyed to evaluate their satisfaction and perceived quality of care. In the multivariable analysis, with the no-consultation cohort as the reference, overall quality was highest among patients who received telemedicine consultations (n=58; beta=0.50 [95% CI, 0.17 0.84]), intermediate among patients receiving telephone consultation (n=63; beta=0.12 [95% CI, -0.14 to 0.39]), and lowest among patients receiving no consultation (n=199). Referring emergency department physicians reported changing their diagnosis (47.8% vs 13.3%; p<0.01) and therapeutic interventions (55.2% vs 7.1%; p<0.01) more frequently when consultations were provided using telemedicine than telephone. Parent satisfaction and perceived quality were significantly higher when telemedicine was used, compared with telephone, for six of the seven measures. CONCLUSIONS: Physician-rated quality of care was higher for patients who received consultations with telemedicine than for patients who received either telephone or no consultation. Telemedicine consultations were associated with more frequent changes in diagnostic and therapeutic interventions, and higher parent satisfaction, than telephone consultations. PMID- 23921274 TI - The impact of rapid response team on outcome of patients transferred from the ward to the ICU: a single-center study. AB - OBJECTIVES: To determine the impact of rapid response team implementation on the outcome of patients transferred from the regular hospital ward and nonward locations to the ICU. DESIGN: Retrospective before-after cohort study. SETTING: The study was performed in two ICUs, one surgical and one medical, of a tertiary medical center. PATIENTS: We included 4,890 patients transferred from the hospital ward to two ICUs and 15,855 patients admitted from nonward locations. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data on each patient were abstracted from the Acute Physiology and Chronic Health Evaluation III and the administrative hospital and rapid response team databases. The study period was divided into pre-rapid response team and rapid response team. A 24/7 critical care consult service and cardiac arrest teams were available for ward patient care during both periods. A total of 20,745 patients were admitted to the two study ICUs, of whom 4,890 were from the ward (2,466 and 2,424 during the pre rapid response team and rapid response team periods, respectively). The first ICU day severity of illness was higher for the pre-rapid response team period. A multiple logistic regression model that included predicted mortality as a covariate suggested that availability of rapid response team was associated with an increased risk of hospital death in patients transferred to the ICU from the regular ward, odds ratio (95% CI) of 1.273 (1.089-1.490). For the nonward patients, the availability of rapid response team was similarly associated with increased risk of death. The ICU length of stay was shorter during the rapid response team period both in ward transfer and in nonward transfer patients. CONCLUSIONS: Rapid response team implementation is associated with increased numbers of ICU admissions and rates, and transfer from the ward of less severely ill patients. However, rapid response team implementation did not improve the severity-of-illness-adjusted outcome of patients transferred from the ward. Implementation of rapid response team in an institution with a 24/7 ICU consult service may have unforeseen costs without obvious benefit. Our findings highlight that institutions should evaluate the impact of rapid response team on patient outcome and make modifications specific to their practices. PMID- 23921275 TI - Do intensivist staffing patterns influence hospital mortality following ICU admission? A systematic review and meta-analyses. AB - OBJECTIVE: To determine the effect of different intensivist staffing models on clinical outcomes for critically ill patients. DATA SOURCES: A sensitive search of electronic databases and hand-search of major critical care journals and conference proceedings was completed in October 2012. STUDY SELECTION: Comparative observational studies examining intensivist staffing patterns and reporting hospital or ICU mortality were included. DATA EXTRACTION: Of 16,774 citations, 52 studies met the inclusion criteria. We used random-effects meta analytic models unadjusted for case-mix or cluster effects and quantified between study heterogeneity using I. Study quality was assessed using the Newcastle Ottawa Score for cohort studies. DATA SYNTHESIS: High-intensity staffing (i.e., transfer of care to an intensivist-led team or mandatory consultation of an intensivist), compared to low-intensity staffing, was associated with lower hospital mortality (risk ratio, 0.83; 95% CI, 0.70-0.99) and ICU mortality (pooled risk ratio, 0.81; 95% CI, 0.68-0.96). Significant reductions in hospital and ICU length of stay were seen (-0.17 d, 95% CI, -0.31 to -0.03 d and -0.38 d, 95% CI, -0.55 to -0.20 d, respectively). Within high-intensity staffing models, 24-hour in-hospital intensivist coverage, compared to daytime only coverage, did not improved hospital or ICU mortality (risk ratio, 0.97; 95% CI, 0.89-1.1 and risk ratio, 0.88; 95% CI, 0.70-1.1). The benefit of high-intensity staffing was concentrated in surgical (risk ratio, 0.84; 95% CI, 0.44-1.6) and combined medical-surgical (risk ratio, 0.76; 95% CI, 0.66-0.83) ICUs, as compared to medical (risk ratio, 1.1; 95% CI, 0.83-1.5) ICUs. The effect on hospital mortality varied throughout different decades; pooled risk ratios were 0.74 (95% CI, 0.63-0.87) from 1980 to 1989, 0.96 (95% CI, 0.69-1.3) from 1990 to 1999, 0.70 (95% CI, 0.54-0.90) from 2000 to 2009, and 1.2 (95% CI, 0.84-1.8) from 2010 to 2012. These findings were similar for ICU mortality. CONCLUSIONS: High-intensity staffing is associated with reduced ICU and hospital mortality. Within a high intensity model, 24-hour in-hospital intensivist coverage did not reduce hospital, or ICU, mortality. Benefits seen in mortality were dependent on the type of ICU and decade of publication. PMID- 23921276 TI - Electrical muscle stimulation in the intensive care setting: a systematic review. AB - CONTEXT: The role of electrical muscle stimulation in intensive care has not previously been systematically reviewed. OBJECTIVES: To identify, evaluate, and synthesize the evidence examining the effectiveness and the safety of electrical muscle stimulation in the intensive care, and the optimal intervention variables. DATA SOURCES: A systematic review of articles using eight electronic databases (Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Excerpta Medica Database, Expanded Academic ASAP, MEDLINE, Physiotherapy Evidence Database, PubMed, and Scopus) personal files were searched, and cross-referencing was undertaken. ELIGIBILITY CRITERIA: Quantitative studies published in English, assessing electrical muscle stimulation in intensive care, were included. DATA EXTRACTION AND DATA SYNTHESIS: One reviewer extracted data using a standardized form, which were cross-checked by a second reviewer. Quality appraisal was undertaken by two independent reviewers using the Physiotherapy Evidence Database and Newcastle-Ottawa scales, and the National Health and Medical Research Council Hierarchy of Evidence Scale. Preferred Reporting Items for Systematic Reviews guidelines were followed. RESULTS: Nine studies on six individual patient groups of 136 participants were included. Eight were randomized controlled trials, with four studies reporting on the same cohort of participants. Electrical muscle stimulation appears to preserve muscle mass and strength in long-stay participants and in those with less acuity. No such benefits were observed when commenced prior to 7 days or in patients with high acuity. One adverse event was reported. Optimal training variables and safety of the intervention require further investigation. CONCLUSIONS: Electrical muscle stimulation is a promising intervention; however, there is conflicting evidence for its effectiveness when administered acutely. Outcomes measured are heterogeneous with small sample sizes. PMID- 23921277 TI - Interobserver agreement of Centers for Disease Control and Prevention criteria for classifying infections in critically ill patients. AB - OBJECTIVES: Correct classification of the source of infection is important in observational and interventional studies of sepsis. Centers for Disease Control and Prevention criteria are most commonly used for this purpose, but the robustness of these definitions in critically ill patients is not known. We hypothesized that in a mixed ICU population, the performance of these criteria would be generally reduced and would vary among diagnostic subgroups. DESIGN: Prospective cohort. SETTING: Data were collected as part of a cohort of 1,214 critically ill patients admitted to two hospitals in The Netherlands between January 2011 and June 2011. PATIENTS: Eight observers assessed a random sample of 168 of 554 patients who had experienced at least one infectious episode in the ICU. Each patient was assessed by two randomly selected observers who independently scored the source of infection (by affected organ system or site), the plausibility of infection (rated as none, possible, probable, or definite), and the most likely causative pathogen. Assessments were based on a post hoc review of all available clinical, radiological, and microbiological evidence. The observed diagnostic agreement for source of infection was classified as partial (i.e., matching on organ system or site) or complete (i.e., matching on specific diagnostic terms), for plausibility as partial (2-point scale) or complete (4 point scale), and for causative pathogens as an approximate or exact pathogen match. Interobserver agreement was expressed as a concordant percentage and as a kappa statistic. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 206 infectious episodes were observed. Agreement regarding the source of infection was 89% (183/206) and 69% (142/206) for a partial and complete diagnostic match, respectively. This resulted in a kappa of 0.85 (95% CI, 0.79 0.90). Agreement varied from 63% to 91% within major diagnostic categories and from 35% to 97% within specific diagnostic subgroups, with the lowest concordance observed in cases of ventilator-associated pneumonia. In the 142 episodes for which a complete match on source of infection was obtained, the interobserver agreement for plausibility of infection was 83% and 65% on a 2- and 4-point scale, respectively. For causative pathogen, agreement was 78% and 70% for an approximate and exact pathogen match, respectively. CONCLUSIONS: Interobserver agreement for classifying sources of infection using Centers for Disease Control and Prevention criteria was excellent overall. However, full concordance on all aspects of the diagnosis between independent observers was rare for some types of infection, in particular for ventilator-associated pneumonia. PMID- 23921278 TI - A randomized controlled trial of preoperative intra-aortic balloon pump in coronary patients with poor left ventricular function undergoing coronary artery bypass surgery*. AB - OBJECTIVE: Preoperative intra-aortic balloon pump use in high-risk patients undergoing surgical coronary revascularization is still a matter of debate. The objective of this study is to determine whether the preoperative use of an intra aortic balloon pump improves the outcome after coronary operations in high-risk patients. DESIGN: Single-center prospective randomized controlled trial. SETTING: Tertiary cardiac surgery center, research hospital. PATIENTS: One hundred ten subjects undergoing coronary operations, with a poor left ventricular ejection fraction (< 35%) and no hemodynamic instability. INTERVENTIONS: Patients randomized to receive preincision intra-aortic balloon pump or no intervention. MEASUREMENTS AND MAIN RESULTS: The primary outcome measurement was postoperative major morbidity rate, defined as one of prolonged mechanical ventilation, stroke, acute kidney injury, surgical revision, mediastinitis, and operative mortality. There was no difference in major morbidity rate (40% in intra-aortic balloon pump group and 31% in control group; odds ratio, 1.49 [95% CI, 0.68-3.33]). No differences were observed for cardiac index before and after the operation; at the arrival in the ICU, patients in the intra-aortic balloon pump group had a significantly (p = 0.01) lower mean systemic arterial pressure (80.1 +/- 15.1 mm Hg) versus control group patients (89.2 +/- 17.9 mm Hg). Fewer patients in the intra-aortic balloon pump group (24%) than those in the control group (44%) required dopamine infusion (p = 0.043). CONCLUSIONS: This study demonstrates that in patients undergoing nonemergent coronary operations, with a stable hemodynamic profile and a left ventricular ejection fraction less than 35%, the preincision insertion of intra-aortic balloon pump does not result in a better outcome. Given the possible complications of intra-aortic balloon pump insertion, and the additional cost of the procedure, this approach is not justified. PMID- 23921279 TI - Cancer and systemic inflammation: stage the tumour and stage the host. PMID- 23921280 TI - Association of gamma-glutamyltransferase with severity of disease at diagnosis and prognosis of ovarian cancer. AB - BACKGROUND: Gamma-glutamyltransferase (GGT) - a membrane-bound enzyme crucially involved in the cell's detoxification pathway and apoptotic balance - is involved in tumour development, progression and chemotherapy resistance. Elevated GGT serum levels are associated with increased cancer risk in women and worse prognosis in gynaecologic cancers. The present study investigated the prognostic role of GGT in ovarian cancer patients. METHODS: In this multicenter study, pre therapeutic GGT levels were ascertained in 634 consecutive patients with epithelial ovarian cancer (EOC, n=567) and borderline tumour of the ovary (BTO, n=67). Gamma-glutamyltransferase serum levels were associated with clinicopathological parameters and uni- and multivariate survival analyses were performed. Immunohistochemistry of GGT was performed in ovarian cancer tissue and correlated with GGT serum levels. RESULTS: Pre-therapeutic GGT serum levels were higher in patients with EOC (28.56 (38.24) U l(-1)) than in patients with BTO (20.01 (12.78) U l(-1), P=0.01). High GGT serum levels were associated with advanced FIGO stage (P<0.001) and with worse overall survival in univariate (P<0.001) and multivariable analysis (P=0.02, HR 1.2 (1.1-1.5)). We further investigated the association between systemic GGT serum levels and local GGT expression in EOC tumour tissue and observed an association between these two parameters (P=0.03). CONCLUSION: High pre-therapeutic GGT serum levels are associated with advanced tumour stage and serve as an independent prognostic marker for worse overall survival in patients with EOC. Gamma-glutamyltransferase expression in ovarian cancer tissue is reflected in GGT serum levels. PMID- 23921282 TI - Autism spectrum disorders and inborn errors of metabolism: an update. AB - BACKGROUND: Autism spectrum disorder is characterized by social communicative deficits with restricted interests occurring in about 1% of the population. Although its exact cause is not known, several factors have been implicated in its etiology, including inborn errors of metabolism. Although relatively uncommon, these disorders frequently occur in countries with high rates of consanguinity and are often associated with behavioral problems, such as hyperactivity and aggression. The aim of this review is to examine the association of autism with these conditions. METHOD: A computer-assisted search was performed to identify the most common inborn errors of metabolism associated with autism. RESULTS: The following disorders were identified: phenylketonuria, glucose-6-phosphatase deficiency, propionic acidemia, adenosine deaminase deficiency, Smith-Lemli-Opitz syndrome and mitochondrial disorders, and the recently described branched chain ketoacid dehydrogenase kinase deficiency. CONCLUSION: The risk of autistic features is increased in children with inborn errors of metabolism, especially in the presence of cognitive and behavioral deficits. We propose that affected children should be screened for autism. PMID- 23921281 TI - Liver fatty acid-binding protein (L-Fabp) modifies intestinal fatty acid composition and adenoma formation in ApcMin/+ mice. AB - Evidence suggests a relationship between dietary fat intake, obesity, and colorectal cancer, implying a role for fatty acid metabolism in intestinal tumorigenesis that is incompletely understood. Liver fatty acid-binding protein (L-Fabp), a dominant intestinal fatty acid-binding protein, regulates intestinal fatty acid trafficking and metabolism, and L-Fabp deletion attenuates diet induced obesity. Here, we examined whether changes in intestinal fatty acid metabolism following L-Fabp deletion modify adenoma development in Apc(Min)(/+) mice. Compound L-Fabp(-/-)Apc(Min)(/+) mice were generated and fed a 10% fat diet balanced equally between saturated, monounsaturated, and polyunsaturated fat. L Fabp(-/-)Apc(Min)(/+) mice displayed significant reductions in adenoma number and total polyp area compared with Apc(Min)(/+)controls, reflecting a significant shift in distribution toward smaller polyps. Adenomas from L-Fabp(-/ )Apc(Min)(/+) mice exhibited reductions in cellular proliferation, high-grade dysplasia, and nuclear beta-catenin translocation. Intestinal fatty acid content was increased in L-Fabp(-/-)Apc(Min)(/+) mice, and lipidomic profiling of intestinal mucosa revealed significant shifts to polyunsaturated fatty acid species with reduced saturated fatty acid species. L-Fabp(-/-)Apc(Min)(/+) mice also showed corresponding changes in mRNA expression of enzymes involved in fatty acid elongation and desaturation. Furthermore, adenomas from L-Fabp(-/ )Apc(Min)(/+) mice displayed significant reductions in mRNA abundance of nuclear hormone receptors involved in cellular proliferation and in enzymes involved in lipogenesis. These findings collectively implicate L-Fabp as an important genetic modifier of intestinal tumorigenesis, and identify fatty acid trafficking and metabolic compartmentalization as an important pathway linking dietary fat intake, obesity, and intestinal tumor formation. PMID- 23921283 TI - The impact of deflazacort on puberty in Duchenne muscular dystrophy. AB - BACKGROUND: The routine use of glucocorticoids has increased the longevity of patients with Duchenne muscular dystrophy. Long-term steroid therapy may have adverse effects on endocrine function and could influence the onset of puberty. METHODS: We assessed the pubertal development of our patients who were 14 years of age or older and had been treated with deflazacort as their only glucocorticoid. RESULTS: Half (6 of 12) of the boys who were treated with deflazacort had pubertal delay. There was no difference in the age of onset, dose, or duration of deflazacort therapy between those who did and did not have delayed puberty. CONCLUSIONS: This pilot study suggests that delayed puberty should be studied in future trials that address different doses and schedules of deflazacort therapy in Duchenne muscular dystrophy. PMID- 23921284 TI - Role of intravenous levetiracetam for acute seizure management in preterm neonates. AB - BACKGROUND: Neonatal seizures are common in the first month of life and may impair neurodevelopmental outcome. Current antiepileptic drugs used in the treatment of neonatal seizures have limited efficacy and undesirable side effects. Intravenous levetiracetam is increasingly being used in the neonatal period to treat seizures. Presently, insufficient data about the efficacy and safety of intravenous levetiracetam in preterm neonates exist. METHODS: We retrospectively analyzed data from preterm neonates who were treated with intravenous levetiracetam at our institution between January 2007 and December 2011. Data were acquired from review of our institution's electronic medical record regarding patients who were treated with intravenous levetiracetam during the neonatal period (0 to 28 days) and were born at preterm gestation (<37 weeks). RESULTS: Twelve patients received a levetiracetam load of 25 to 50 mg/kg for neonatal seizures. Nine of 11 patients (82%) reached seizure cessation within 24 hours of receiving levetiracetam. No serious side effects were evident. Seven patients (59%) were discharged on oral levetiracetam alone, four patients (33%) were discharged on no oral antiepileptic drug, and one patient (8%) was discharged on levetiracetam and phenobarbital. Eleven of 12 patients were followed up to 6 months after receiving intravenous levetiracetam. Of these, six patients (55%) had achieved seizure freedom and been completely weaned off of all antiepileptic drugs. Three patients (27%) had achieved seizure freedom while still on oral levetiracetam. CONCLUSIONS: Intravenous levetiracetam appears to be efficacious for seizure management in preterm neonates. PMID- 23921285 TI - Distinctive clinical features in arthro-myalgic patients with and without aluminum hydroxyde-induced macrophagic myofasciitis: an exploratory study. AB - Macrophagic myofasciitis (MMF) is a specific histological lesion assessing the persistence of vaccine-derived aluminum oxyhydroxide in muscle tissue, at a site of previous immunization. Long-lasting MMF is usually detected in patients with arthromyalgias, chronic fatigue, and stereotyped cognitive dysfunction. MMF diagnosis requires muscle biopsy, an invasive procedure not suitable for the routine investigation of all patients with musculoskeletal pain. To help decision making in routine practice, we designed a retrospective analysis of 130 consecutive arthro-myalgic patients, previously immunized with aluminum containing vaccines, in whom deltoid muscle biopsy was performed for diagnostic purposes. According to biopsy results, the patients were ascribed to either the MMF or the non-MMF group. MMF was diagnosed in 32.3% of the patients. MMF and non MMF groups were similar according to both the injected vaccines and the delay between vaccination and biopsy. MMF patients had less frequent fibromyalgia than non-MMF patients (>=11 fibromyalgic tender points in 16.6 vs 55.5%, p < 0.04), and more often abnormal evoked potentials suggestive of CNS demyelination (38.5 vs 5.7%, p < 0.01). Predictive bioclinical scores based on simple variables such as the number of fibromyalgic tender points, arthralgias, and spinal pain, had sensitivity ranging from 50 to 88.1% and specificity from 36.4 to 76.1%. IN CONCLUSION: (i) most aluminum-containing vaccine receivers do not have long lasting MMF in their muscle, but the prevalence of MMF among patients with arthromyalgia following immunization is substantial; (ii) patients with MMF have more CNS dysfunction and less fibromyalgic tender points than non-MMF patients; (iii) predictive scores may help to identify patients at high vs low risk of MMF. PMID- 23921286 TI - Making sense of differing overdose mortality: contributions to improved understanding of European patterns. AB - The European Monitoring Centre for Drugs and Drug Addiction, EMCDDA, publishes statistics for overdose deaths giving a European mean number, and ranking nations in a national 'league table' for overdose deaths. The interpretation of differing national levels of mortality is more problematic and more complex than is usually recognised. Different systems are used to compile mortality data and this causes problems for cross-national comparisons. Addiction behaviour can only be properly understood within its specific social and environmental ecology. Risk factors for overdose, such as the type of drug consumed, and the route of administration, are known to differ across countries. This paper describes problems associated with ranking and suggests how mortality data might be used in high-level countries aiming at reduction in the number of overdose deaths. PMID- 23921287 TI - A descriptive study of California hospice providers' perceptions of public reporting of quality data using the Family Evaluation of Hospice Care Survey. AB - The Affordable Care Act requires US hospices to report quality data to the Centers for Medicare and Medicaid Services (CMS) in 2013 with data eventually being made public. There may be some benefit to participating in a voluntary public-reporting program prior to public disclosure by CMS; therefore, we developed and conducted an electronic survey exploring California hospices' perceptions of public reporting. The majority (78.1%) of respondents reported current use of the Family Evaluation of Hospice Care tool and a willingness to consider voluntary participation in a public-reporting program outside of what is being implemented by CMS (58.6%). Tax status of responding hospices was not predictive of a willingness to participate in a statewide public-reporting program of hospice quality in our study. PMID- 23921288 TI - Providing hospice home care to the terminally ill elderly people with cancer in Taiwan: family experiences and needs. AB - We explored caregivers' experiences and needs when providing hospice home care to their terminally ill elderly patients with cancer in Taiwan for 1 year. A total of 44 caregivers were interviewed using a semistructured interview once monthly during hospice home care visits until the patients' deaths. Content analysis of the interviews revealed 5 themes, hoping for a cure, experiencing fluctuating emotions, accepting the patient's dying, regarding the patient's death as a good death, and needing emotional support and information. Caregivers in hospice home care who experienced difficulties tended to seek emotional support and information throughout the entire caregiving process. With a greater understanding of caregivers' experiences and needs, nurses can alleviate caregivers' negative emotional reactions by actively attending to their needs during this process. PMID- 23921289 TI - A matter of conscience. PMID- 23921290 TI - A physiological perspective for utility or futility of alcohol-based hand rub gel against nausea-vomiting: is it P-6 acupoint or transnasal aroma? AB - Nausea-vomiting is a common and unpleasant phenomenon with numerous underlying mechanisms and pathways that are not always well elucidated. In clinical practice, refractory nausea-vomiting is encountered in several settings. Antiemetic medications may reduce these symptoms but are not always effective in all patients. In the absence of a well-defined optimal strategy for management of nausea-vomiting, the search for better approaches to treat this distressing symptom continues. One of the alternative treatment approaches is a compounded formulation called ABHR gel that is comprised of multiple antiemetic medications and has been shown to be useful for symptomatic relief in some patients with refractory nausea-vomiting. It has been suggested that alternative mechanisms should be explored to explain the perceived efficacy of ABHR gel, because transdermal absorption leading to nil-to-minimal or subtherapeutic blood concentrations of active ingredients does not explain the role of ABHR gel in the treatment of nausea-vomiting. In the current paper, we discuss possible mechanisms that may explain ABHR transdermal gel's efficacy. Compounded ABHR transdermal gel formulation's efficacy in antagonizing nausea-vomiting that has been recently questioned may be explained by alternative mechanisms mediated through the P-6 acupoint stimulation and facial-nasal, cooling-related counterstimulation. PMID- 23921292 TI - Anterior tracheal injury during sternotomy. PMID- 23921291 TI - Immediate and late outcomes of bronchial and systemic artery embolization for palliative treatment of patients with nonsmall-cell lung cancer having hemoptysis. AB - BACKGROUND: Hemoptysis in patients with advanced lung cancer can be a life threatening. OBJECTIVES: To evaluate immediate outcomes and late outcomes of bronchial artery embolization (BAE) for palliative treatment in patients with advanced nonsmall-cell lung cancer (NSCLC) having hemoptysis. METHODS: The BAE was performed in 28 patients with NSCLC. Hemoptysis was defined as follows: massive bleeding greater than 300 mL within 24 hours (n = 8), moderate bleeding of 100 to 300 mL within 24 hours (n =12), and slight bleeding less than100 mL within 24 hours (n = 8). RESULTS: Success rate was 96%. Immediate clinical success within 24 hours after BAE was achieved in 22 of the 27 patients who underwent embolization. CONCLUSIONS: The BAE with gelatin sponge particles can provide good management of hemoptysis as a palliative treatment in patients with advanced NSCLC. PMID- 23921293 TI - Ticagrelor-associated bleeding in a patient undergoing surgery for acute type A aortic dissection. PMID- 23921294 TI - Intraoperative echocardiographic images of right ventricular outflow tract sarcoma. PMID- 23921295 TI - HIV testing policies for migrants and ethnic minorities in EU/EFTA Member States. AB - BACKGROUND: In the context of an European Centre for Disease Prevention and Control (ECDC) research project, our objective was to describe current recommendations regarding HIV testing and counselling targeting migrants and ethnic minorities in the European Union/European Economic Area/European Free Trade Association (EU/EEA/EFTA) Member States. METHODS: An on-line survey was conducted among 31 EU/EEA/EFTA Member States. The survey inquired on the existence of specific HIV testing and counselling recommendations or policies for migrants and/or ethnic minorities and the year of their publication. Additionally, we performed a review of national recommendations, guidelines or any other policy documents retrieved from an Internet search through the different countries' competent bodies. RESULTS: Twenty-nine (94%) country representatives responded the survey, and 28 documents from 27 countries were identified. National guidelines on HIV testing are heterogeneous and tailored, according to the epidemiological situation. Twenty-two countries identify migrants and four countries identify ethnic minorities as particularly vulnerable to HIV. Sixteen countries explicitly recommend offering an HIV test to migrants/ethnic minorities. Guidelines especially target people originating from HIV endemic countries, and benefits of HIV early detection are highlighted. HIV testing is not mandatory in any country, but some countries overtly facilitate this practice. CONCLUSION: Benefits of HIV testing in migrants and ethnic minorities, at both individual and community levels are recognized by many countries. In spite of this, not all countries identify the need to test these groups. PMID- 23921296 TI - Effects of different hip rotations on gluteus medius and tensor fasciae latae muscle activity during isometric side-lying hip abduction. AB - CONTEXT: Gluteus medius (Gmed) weakness is associated with some lower-extremity injuries. People with Gmed weakness might compensate by activating the tensor fasciae latae (TFL). Different hip rotations in the transverse plane may affect Gmed and TFL muscle activity during isometric side-lying hip abduction (SHA). OBJECTIVES: To compare Gmed and TFL muscle activity and the Gmed:TFL muscle activity ratio during SHA exercise with 3 different hip rotations. DESIGN: The effects of different hip rotations on Gmed, TFL, and the Gmed:TFL muscle-activity ratio during isometric SHA were analyzed with 1-way, repeated-measures analysis of variance. SETTING: University research laboratory. PARTICIPANTS: 20 healthy university students were recruited in this study. INTERVENTIONS: Participants performed isometric SHA: frontal SHA with neutral hip (frontal SHAN), frontal SHA with hip medial rotation (frontal SHA-MR), and frontal SHA with hip lateral rotation (frontal SHA-LR). MAIN OUTCOME MEASURES: Surface electromyography measured the activity of the Gmed and the TFL. A 1-way repeated-measures analysis of variance assessed the statistical significance of Gmed and TFL muscle activity. When there was a significant difference, a Bonferroni adjustment was performed. RESULTS: Frontal SHA-MR showed significantly greater Gmed muscle activation than frontal SHA-N (P = .000) or frontal SHA-LR (P = .015). Frontal SHA-LR showed significantly greater TFL muscle activation than frontal SHA-N (P = .002). Frontal SHA-MR also resulted in a significantly greater Gmed:TFL muscle activity ratio than frontal SHA-N (P = .004) or frontal SHA-LR (P = .000), and frontal SHA-N was significantly greater than frontal SHA-LR (P = .000). CONCLUSIONS: Frontal SHA-MR results in greater Gmed muscle activation and a higher Gmed:TFL muscle ratio. PMID- 23921297 TI - Comparison of predictive equations and measured resting energy expenditure among obese youth attending a pediatric healthy weight clinic: one size does not fit all. AB - BACKGROUND: The Academy of Nutrition and Dietetics recommends the use of indirect calorimetry for calculating caloric targets for weight loss in obese youth. Practitioners typically use predictive equations since indirect calorimetry is often not available. The objective of this study was to compare measured resting energy expenditure (MREE) with that estimated using published predictive equations in obese pediatric patients. MATERIAL AND METHODS: Youth aged 7 to 18 years (n = 80) who were referred to a university-based healthy weight clinic and who were greater than the 95th percentile BMI for age and gender participated. MREE was measured via a portable indirect calorimeter. Predicted energy expenditure (pEE) was estimated using published equations including those commonly used in children. pEE was compared to the MREE for each subject. Absolute mean difference between MREE and pEE, mean percentage accuracy, and mean error were determined. RESULTS: Mean percentage accuracy of pEE compared with MREE varied widely, with the Harris-Benedict, Lazzer, and Molnar equations providing the greatest accuracy (65%, 61%, and 60%, respectively). Mean differences between MREE and equation-estimated caloric targets varied from 197.9 kcal/day to 307.7 kcal/day. CONCLUSIONS: The potential to either overestimate or underestimate calorie needs in the clinical setting is significant when comparing EE derived from predictive equations with that measured using portable indirect calorimetry. While our findings suggest that the Harris-Benedict equation has improved accuracy relative to other equations in severely obese youth, the potential for error remains sufficiently great to suggest that indirect calorimetry is preferred. PMID- 23921298 TI - Evaluation of fat separation and removal methods to prepare low-fat breast milk for fat-intolerant neonates with chylothorax. AB - BACKGROUND: The purpose of this study was to compare 2 methods (syringe and spoon methods) of removing the fat from the low-fat milk portion and compare 3 methods (refrigerated centrifuge, nonrefrigerated centrifuge, and refrigeration method) of separating breast milk into the fat and low-fat milk components. METHODS: Human milk was divided into 24 aliquots using the 3 separating methods, and 2 methods (syringe, spoon) were compared to extract the low-fat milk. Thirty-one human milk samples were separated into fatty and low-fat milk layers using 3 methods: 24-hour refrigerator storage (2 degrees C), centrifuged at 3000 rpm for 15 minutes at room temperature, and spun in the refrigerated-centrifuge at 3000 rpm for 15 minutes at 2 degrees C. After 24 hours of refrigeration, a syringe was used to remove the low-fat milk. Triglycerides were analyzed before and after separation and removal methods. RESULTS: For fat removal, the syringe method (1.2 g/dl, 95% confidence interval [CI], 1.1-1.4, fat content) left 34% less residual fat compared to the spoon method (1.9 g/dl, 95% CI, 1.5-2.3); this difference did not reach statistical significance (P = .065). For fat separation, the centrifuge methods (mean: 1.0 g/dl, 95% CI, 0.8-1.1) left significantly less residual fat than the refrigerator method (3.4 g/dl, 95% CI, 3.0-3.7; P < .0001). CONCLUSION: Using the syringe vs a spoon at removing the milk from the fat, although not statistically significant, was likely of clinical importance. A centrifuge was more effective at separating the fat in human milk. PMID- 23921299 TI - Nutrition support of the postoperative cardiac surgery child. AB - There may be a correlation in critically ill children between the accuracy of estimated energy requirement and infection, mortality, and length of stay. Historically, energy needs were estimated using predictive equations with stress factor adjustments. The purpose of this review is to evaluate the evidence for indirect calorimetry, predictive equations, and other clinical indicators (ie, patient outcomes) to estimate energy requirements of the postoperative, critically ill, cardiac infant. Consistent with current guidelines, indirect calorimetry provides the best estimate of energy requirements for critically ill children. Predictive equations are unreliable, either over- or underestimate energy requirements, and do not take into account the metabolic changes that occur in the postoperative cardiac infant. To address the changing metabolic state throughout the course of illness, clinicians need to individualize recommendations by implementing frequent indirect calorimetry measurements at bedside. Actual energy delivery to the postoperative cardiac surgery child in the pediatric intensive care unit (PICU) can be further hindered by many procedural and patient barriers. The provision of appropriate caloric requirements may help clinicians correct the metabolic state and promote recovery and anabolism. Therefore, optimizing nutrition intake of the postoperative, cardiac surgical child requires a paradigm shift toward individualized nutrition prescription, in the context of a PICU-specific feeding algorithm. PMID- 23921300 TI - Renin-angiotensin system inhibitors prevent the recurrence of atrial fibrillation: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: This study was designed to assess whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could prevent the recurrence of atrial fibrillation (AF). METHODS: A systemic literature search of PubMed, EMBASE, and Cochrane Controlled Trials Register till 2012 was performed to identify randomized controlled trials involving the prevention of recurrence of AF with renin-angiotensin system blockade therapy. Subgroup analysis and meta-regression were performed. Publication bias was checked through funnel plot and Egger's test. RESULTS: Twenty-one randomized controlled trials including 13,184 patients with AF were identified. Overall, the recurrence of AF was significantly reduced in patients using ACEI/ARBs [odds ratio (OR), 0.43; 95% confidence interval (CI), 0.32-0.56; P < 0.00001], especially both in irbesartan subgroup (OR, 0.38; 95% CI, 0.21-0.68; P = 0.001) and in patients receiving antiarrhythmic drug (AAD) (OR, 0.37; 95% CI, 0.29-0.48; P < 0.00001), and there was no significant difference between ACEIs and ARBs (ACEIs: OR, 0.42; 95% CI, 0.31-0.57 and ARBs: OR, 0.42; 95% CI, 0.31-0.57). Moreover, it was found that the benefits of ACEI/ARBs revealed positive correlation to systolic blood pressure (regression coefficient: -0.0700257, P = 0.000) in no-AAD users. CONCLUSIONS: ACEI/ARBs are effective on the secondary prevention of AF, especially in patients receiving AAD and suffering from hypertension. PMID- 23921301 TI - Electrocardiographic safety of cangrelor, a new intravenous antiplatelet agent: a randomized, double-blind, placebo- and moxifloxacin-controlled thorough QT study. AB - Cangrelor is an intravenous P2Y12 inhibitor under investigation as an antiplatelet drug in the setting of acute coronary syndromes. To determine the electrophysiologic safety of parenteral cangrelor, cardiac repolarization effects were measured in 67 healthy volunteers (aged 18-45 years) in a randomized crossover design, including 4 treatment sequences of therapeutic cangrelor, supratherapeutic cangrelor, placebo, and moxifloxacin (positive control). Triplicate electrocardiogram measurements and pharmacokinetic samples were collected at baseline and 9 time points postdose on day 1. For both cangrelor and moxifloxacin, time-matched, placebo-adjusted change in QT from baseline was evaluated using an individual (QTcI) heart rate correction. After cangrelor dosing, change in QTcI was <5 ms at all times points and all corresponding upper 2-sided 90% confidence intervals (CIs) were <10 ms. Although moxifloxacin failed to show a lower CI >5 ms, expected time trends and lower CI >4.0 ms demonstrate assay sensitivity. QTcI was not affected by plasma concentrations of cangrelor metabolites, and cangrelor had no other adverse effects on electrocardiographic parameters. Clinically, cangrelor exposure was well tolerated. Thus, this thorough QT study demonstrated that therapeutic and supratherapeutic cangrelor doses do not adversely affect cardiac repolarization in normal volunteers (clinicaltrials.gov; identifier NCT00699504). PMID- 23921302 TI - Transduction of PEP-1-heme oxygenase-1 fusion protein reduces myocardial ischemia/reperfusion injury in rats. AB - Recent studies have uncovered that overexpression of heme oxygenase-1 (HO-1) by induction or gene transfer provides myocardial protection. In the present study, we investigated whether HO-1 protein mediated by cell-penetrating peptide PEP-1 could confer cardioprotection in a rat model of myocardial ischemia/reperfusion (I/R) injury. Male Sprague-Dawley rats were subjected to 30 minutes of ischemia by occluding the left anterior descending coronary artery and to 120 minutes of reperfusion to prepare the model of I/R. Animals were randomized to receive PEP-1 HO-1 fusion protein or saline 30 minutes before a 30-minute occlusion. I/R increased myocardial infarct size and levels of malondialdehyde, serum tumor necrosis factor alpha, and interleukin 6 and reduced myocardial superoxide dismutase activity. Administration of PEP-1-HO-1 reduced myocardial infarct size and levels of malondialdehyde, serum tumor necrosis factor alpha, and interleukin 6 and increased myocardial superoxide dismutase and HO-1 activities. His-probe protein was only detected in PEP-1-HO-1-transduced hearts. In addition, transduction of PEP-1-HO-1 markedly reduced elevated myocardial tissue nuclear factor-kappaB induced by I/R. The results suggested that transduction of PEP-1-HO 1 fusion protein decreased myocardial reperfusion injury, probably by attenuating the production of oxidants and proinflammatory cytokines regulated by nuclear factor-kappaB. PMID- 23921303 TI - Vascular reactivity screen of Chinese medicine danhong injection identifies Danshensu as a NO-independent but PGI2-mediated relaxation factor. AB - Danhong injection (DHI) is the most prescribed injection form of Chinese medicine for the treatment of cardiovascular diseases such as atherosclerosis, angina pectoris, and stroke in China. However, its active components and action mechanisms remain poorly defined. We hypothesized that DHI contains active components that could prevent and restore endothelial dysfunction by improving vascular relaxation activity. DHI increased vasorelaxation in vivo and ex vivo of rat aortas. Vascular reactivity screen identified that danshensu was the major relaxation factor in DHI. DHI-mediated endothelial-dependent vasorelaxation was independent on nitric oxide/endothelial nitric oxide synthase but was via prostacyclin pathway by increasing cyclooxygenase (COX)-2 gene expression and prostacyclin production. Our results revealed a previously unknown endothelium dependent vasorelaxation mechanism by danshensu and together with previously reported activity on ion channels of vascular smooth muscle cells, demonstrated that its dual actions contribute to a multicomponent Chinese herbal medicine that synergistically targets different pathways to achieve its well-documented cardiovascular protective effects. PMID- 23921304 TI - (-)-Epigallocatechin gallate inhibits TNF-alpha-induced PAI-1 production in vascular endothelial cells. AB - : (-)-Epigallocatechin gallate (EGCG), the major catechin derived from green tea, reduces the incidence of cardiovascular diseases such as atherosclerosis. Plasminogen activator inhibitor-1 (PAI-1) accelerates thrombus formation upon ruptured atherosclerotic plaques. However, it is not known whether or not EGCG inhibits PAI-1 production induced by tumor necrosis factor-alpha (TNF-alpha) in endothelial cells. This study tested the hypothesis that EGCG might have an inhibitory effect on PAI-1 production induced by TNF-alpha. Human umbilical vein endothelial cells were cultured and incubated with TNF-alpha and/or EGCG. The expression of p-extracellular regulated protein kinases (p-ERK1/2) and tumor necrosis factor receptor (TNFR1) protein was quantified by Western blotting, and PAI-1 levels were measured by enzyme-linked immunosorbent assay. The results showed that TNF-alpha increased PAI-1 production in both a dose-dependent and time-dependent manner, and EGCG prevented TNF-alpha-mediated PAI-1 production and reduced phosphorylation of ERK1/2. The ERK1/2 inhibitor, PD98059 (20 MUmol/L), downregulated TNF-alpha-induced PAI-1 expression 57.69 +/- 2.46% (P < 0.01), but had no effect in cells pretreated with EGCG. TNF-alpha stimulation resulted in a significant decrease in TNFR1, an effect that was abolished by pretreatment with EGCG. These results suggest that EGCG could provide vascular benefits in inflammatory cardiovascular diseases such as decreased thrombus formation associated with ruptured atherosclerotic plaques. PMID- 23921305 TI - Small GTPase and regulation of inflammation response in atherogenesis. AB - Small GTPases are key signal transducers from extracellular stimuli to the nucleus that regulate a variety of cellular responses, including changes in gene expression and cell adhesion and migration. Accumulating data have demonstrated that abnormal activation of these small GTPases plays a critical role in the atherosclerosis characterized by vascular abnormalities, especially endothelial dysfunction and inflammation. Here, we discuss the linkage between small GTPases, inflammation, and atherogenesis. First, small GTPases affect gene expression of inflammatory cytokines through proinflammatory signaling pathways, such as nuclear factor-kappaB, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, interlukin-8, and monocyte chemoattractant protein-1. Then, these molecules regulate the vascular inflammation through cell adhesion and migration. In turn, small GTPases are also regulated by extracellular stimuli, such as L selectin, thrombin, oxidized phospholipids, and interleukins. Thus, these inflammatory cytokines generate a vicious cycle for small GTPases and inflammatory responses in the atherogenesis. PMID- 23921306 TI - Role of small GTPase protein Rac1 in cardiovascular diseases: development of new selective pharmacological inhibitors. AB - A pathway-based genome-wide association analysis has recently identified Rac1 as one of the biologically important gene in coronary heart diseases. The role of the small GTPase Rac1 in cardiac hypertrophy and atherosclerosis has also been documented in clinical studies with the HMG-CoA reductase inhibitors and in in vitro and in vivo settings using transgenic and knockout mice. Thus, Rac1 has emerged as a new pharmacological target for the treatment of cardiovascular diseases. The activation state of Rac1 depends on the release of guanosine diphosphate and the binding of guanosine triphosphate. This cycling is regulated by the guanine nucleotide exchange factors, as activators, and by the GTPase activating proteins. Three categories of selective Rac1 inhibitors have been developed affecting different steps of this pathway: antagonists of Rac1-guanine nucleotide exchange factor interaction, allosteric inhibitors of nucleotide binding to Rac1, and antagonists of Rac1-mediated NADPH oxidase activity. These chemical compounds have shown to selectively inhibit Rac1 activation in cultured cell lines without affecting the homologous proteins RhoA and Cdc42. Moreover, pioneer studies have been conducted with Rac1 inhibitors in in vivo experimental models of cardiovascular diseases with encouraging results. The present review summarizes the current knowledge of the role of Rac1 in cardiovascular diseases and the pharmacological approaches that have been developed to selectively inhibit its function. PMID- 23921307 TI - Comparative effects of nebivolol and metoprolol on red cell distribution width and neutrophil/lymphocyte ratio in patients with newly diagnosed essential hypertension. AB - High level of circulating red cell distribution width (RDW) and neutrophil/lymphocyte (N/L) ratio may reflect ongoing vascular inflammation and play an important role in pathophysiology of hypertension. We evaluate the effects of nebivolol and metoprolol on the RDW and N/L in new essential hypertensive patients. After baseline assessment, 72 patients were randomly allocated to 5 mg/d of nebivolol (n = 37, 20 men) or 100 mg/d of metoprolol (n = 35, 18 men) and treated for 6 months. Blood pressure (BP), heart rate (HR), RDW, and N/L were measured before and after treatment. BP significantly decreased with both drugs (P < 0.001). Analog reduction was observed for resting HRs (P < 0.001), but metoprolol caused greater HR fall as compared with nebivolol (P < 0.001). After 6 months of treatment, nebivolol significantly lowered not only RDW but also the total white blood cell and N/L (P < 0.001, P = 0.023, P = 0.017, respectively). No changes were observed in metoprolol group. Percent decrease in RDW was found to be significantly higher in nebivolol than in the metoprolol group (P = 0.001) and remained also after correction for confounders (P = 0.012). Nebivolol improved RDW and N/L to a greater extent than metoprolol in patients with hypertension. These favorable effects may participate, together with the BP reduction, at the favorable properties of the drug in hypertension. PMID- 23921308 TI - The efficacy and tolerability of azilsartan in obese insulin-resistant mice with left ventricular pressure overload. AB - Angiotensin II receptor blockers (ARBs) are used widely for the treatment of heart failure. However, their use in obese and insulin-resistant patients remains controversial. To clarify their potential efficacy in these conditions, we administered azilsartan medoxomil (azilsartan), a prodrug of an angiotensin II receptor blocker to mice fed a high-fat diet (HFD) with left ventricular (LV) pressure overload (aortic banding). LV fibrosis (hydroxyproline), cardiac plasminogen activator inhibitor-1 (PAI-1; a marker of profibrosis), and creatine kinase (a marker of myocardial viability and energetics) were assessed. LV wall thickness and cardiac function were assessed echocardiographically. Mice given a HFD were obese and insulin resistant. Their LV hypertrophy was accompanied by greater LV PAI-1 and reduced LV creatine kinase compared with normal diet controls. Drug treatment reduced LV wall thickness, hypertrophy, and PAI-1 and increased cardiac output after aortic banding compared with results in HFD vehicle controls. Thus, azilsartan exerted favorable biological effects on the hearts of obese insulin-resistant mice subjected to LV pressure overload consistent with its potential utility in patients with analogous conditions. PMID- 23921310 TI - Impact of neonatal sertraline exposure on the post-myocardial infarction outcomes of adult male mice. AB - Neonatal exposure to a selective serotonin reuptake inhibitor (SSRI) leads to decreased left ventricular volumes and sympathetic activation in adult mice. We hypothesized this neonatal SSRI exposure-induced small left heart syndrome would increase post-myocardial infarction (MI) morbidity and mortality. C57BL/6 mice received saline or sertraline (5 mg/kg intraperitoneally) on postnatal days 1-14. At 5 months, male mice underwent coronary artery ligation and were monitored by radiotelemetry until death or 4 weeks after ligation. After ligation, SSRI exposed mice had increased heart rates (SSRI, 516 +/- 13 bpm; control, 470 +/- 15 bpm; P < 0.05). SSRI-exposed mice had significant reductions in left ventricular systolic volumes both before and after coronary ligation (SSRI: baseline = 20 +/- 3 MUL, post-MI = 37 +/- 10 MUL; control: baseline = 30 +/- 3 MUL, post-MI = 65 +/ 23 MUL). Post-MI echocardiography showed significantly decreased ejection fraction in control mice (baseline = 60% +/- 4%, post-MI = 41% +/- 2%, P < 0.01) but not the SSRI-exposed mice (baseline = 65% +/- 3%, post-MI = 53% +/- 7%). Neonatal SSRI exposure did not significantly alter post-MI survival. We conclude that the preexisting SSRI-induced small left heart syndrome may provide protection from post-MI ventricular dilation. PMID- 23921311 TI - Prolonged exposure to lopinavir impairs endothelium-dependent hyperpolarization mediated relaxation in rat mesenteric arteries. AB - Protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors are effective antiretroviral drugs, but their use is associated with a high incidence of cardiovascular disease. As vascular dysfunction precedes cardiovascular events, this study aimed to examine the vascular effects of clinically used PIs (indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir) and non nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine). Rat mesenteric arteries were suspended in conventional organ chambers for isometric tension recording. Efavirenz, indinavir, nelfinavir, ritonavir, and tipranavir, but not saquinavir and nevirapine, caused endothelium-independent relaxations. Lopinavir induced both endothelium-dependent and -independent relaxations; the former was inhibited by nitric oxide (NO) synthase inhibitor. Incubation with lopinavir for 24 hours reduced relaxations attributable to endothelium-derived hyperpolarization. Relaxations to the adenosine triphosphate-sensitive potassium (K(ATP)) channel opener, levcromakalim, but not those to the NO donor, sodium nitroprusside, were also inhibited. Western blotting indicated that the protein expressions of intermediate (IK(Ca)) and small (SK(Ca)) conductance calcium activated potassium channels and K(ATP) channel were reduced in mesenteric arteries incubated with lopinavir for 24 hours. In conclusion, lopinavir differs from other PIs in that it acutely induces endothelium-derived NO-mediated relaxation. However, prolonged exposure to lopinavir impairs relaxations, likely by reducing the expressions of IK(Ca), SK(Ca), and K(ATP) channels. PMID- 23921312 TI - Bilateral optic neuropathy and permanent loss of vision after treatment with amiodarone. AB - Amiodarone is a commonly prescribed and one of the most effective anti-arrhythmic drugs available. However, its use is limited by serious toxic adverse effects including optic neuropathy. Previously, amiodarone-associated optic neuropathy has been reported at an incidence of 1.3%-1.8%. Nearly, one-third of patients with amiodarone-induced toxic optic neuropathy are asymptomatic and typically visual acuity improves after drug cessation. We describe the case of a 75-year old woman who experienced severe optic neuropathy with bilateral optic disc edema and hemorrhages, irreversible loss of vision, and severe defects in visual fields after 1.5 months use of amiodarone. The optic disc edema resolved promptly after discontinuation of the drug, but the patient remained blind permanently. This is the first report of only 6.5 weeks of amiodarone treatment resulting in bilateral optic neuropathy with bilateral and irreversible loss of vision. To ideally establish a connection between amiodarone and optic neuropathy, re-exposure of the patient to the drug should reproduce the symptoms. As a limitation of the study, this was not done in the present case because it would have been unethical. The worldwide growth of the elderly population in number is expected to increase age-related conditions including cardiac diseases. The use of cardiovascular drugs, also anti-arrhythmic agents such as amiodarone, may increase. Thus, clinicians need to be aware of the possibility of drug-induced toxic optic neuropathy, especially if a patient receiving a regimen of amiodarone complains of visual problems. PMID- 23921313 TI - Balance of nitric oxide and reactive oxygen species in myocardial reperfusion injury and protection. AB - Depending on their concentrations, both nitric oxide (NO) and reactive oxygen species (ROS) take part either in myocardial ischemia reperfusion injury or in protection by ischemic and pharmacological preconditioning (Ipre) and postconditioning (Ipost). At the beginning of reperfusion, a transient release of NO is promptly scavenged by ROS to form the highly toxic peroxynitrite, which is responsible for a further increase of ROS through endothelial nitric oxide synthase uncoupling. The protective role of NO has suggested the use of NO donors to mimic Ipre and Ipost. However, NO donors have not always given the expected protection, possibly because they are responsible for the production of different amounts of ROS that depend on the amount of released NO. This review is focused on the role of the balance of NO and ROS in myocardial injury and its prevention by Ipre and Ipost and after the use of NO donors given with or without antioxidant compounds to mimic Ipre and Ipost. PMID- 23921314 TI - Nebivolol: a multifaceted antioxidant and cardioprotectant in hypertensive heart disease. AB - Cardiomyocyte necrosis with attendant microscopic scarring is a pathological feature of human hypertensive heart disease (HHD). Understanding the pathophysiological origins of necrosis is integral to its prevention. In a rat model of HHD associated with aldosterone/salt treatment (ALDOST), myocyte necrosis is attributable to oxidative stress induced by cytosolic-free [Ca]i and mitochondrial [Ca]m overloading in which the rate of reactive oxygen species generation overwhelms their rate of detoxification by endogenous Zn-based antioxidant defenses. We hypothesized that nebivolol (Neb), unlike another beta1 adrenergic receptor antagonist atenolol (Aten), would have a multifaceted antioxidant potential based on its dual property as a beta3 receptor agonist, which activates endothelial nitric oxide synthase to stimulate nitric oxide (NO) generation. NO promotes the release of cytosolic Zn sequestered inactive by its binding protein, metallothionein. Given the reciprocal regulation between these cations, increased [Zn]i reduces Ca entry and attendant rise in [Ca]i and [Ca]m. Herein, we examined the antioxidant and cardioprotectant properties of Neb and Aten in rats receiving 4 weeks ALDOST. Compared with untreated age-/sex-matched controls, ALDOST alone or ALDOST with Aten, Neb cotreatment induced endothelial nitric oxide synthase activation, NO generation and a marked increase in [Zn]i with associated decline in [Ca]i and [Ca]m. Attendant antioxidant profile at subcellular and cellular levels included attenuation of mitochondrial H2O2 production and lipid peroxidation expressed as reduced 8-isoprostane concentrations in both mitochondria and cardiac tissue. Myocyte salvage was expressed as reduced microscopic scarring and tissue collagen volume fraction. Neb is a multifaceted antioxidant with unique properties as cardioprotectant in HHD. PMID- 23921315 TI - Progress in gene therapy for heart failure. AB - Recent advances in our understanding of the pathophysiology of myocardial dysfunction in the setting of congestive heart failure have created a new opportunity in developing nonpharmacological approaches to treatment. Gene therapy has emerged as a powerful tool in targeting the molecular mechanisms of disease by preventing the ventricular remodeling and improving bioenergetics in heart failure. Refinements in vector technology, including the creation of recombinant adeno-associated viruses, have allowed for safe and efficient gene transfer. These advancements have been coupled with evolving delivery methods that include vascular, pericardial, and direct myocardial approaches. One of the most promising targets, SERCA2a, is currently being used in clinical trials. The recent success of the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease phase 2 trials using adeno-associated virus 1-SERCA2a in improving outcomes highlights the importance of gene therapy as a future tool in treating congestive heart failure. PMID- 23921316 TI - Insulin resistance and heart failure: underlying molecular mechanisms and potential pharmacological solutions. PMID- 23921309 TI - Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil. AB - Rho kinase (ROCK) is a major downstream effector of the small GTPase RhoA. ROCK family, consisting of ROCK1 and ROCK2, plays central roles in the organization of actin cytoskeleton and is involved in a wide range of fundamental cellular functions, such as contraction, adhesion, migration, proliferation, and apoptosis. Due to the discovery of effective inhibitors, such as fasudil and Y27632, the biological roles of ROCK have been extensively explored with particular attention on the cardiovascular system. In many preclinical models of cardiovascular diseases, including vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, stroke, ischemia-reperfusion injury, and heart failure, ROCK inhibitors have shown a remarkable efficacy in reducing vascular smooth muscle cell hypercontraction, endothelial dysfunction, inflammatory cell recruitment, vascular remodeling, and cardiac remodeling. Moreover, fasudil has been used in the clinical trials of several cardiovascular diseases. The continuing utilization of available pharmacological inhibitors and the development of more potent or isoform-selective inhibitors in ROCK signaling research and in treating human diseases are escalating. In this review, we discuss the recent molecular, cellular, animal, and clinical studies with a focus on the current understanding of ROCK signaling in cardiovascular physiology and diseases. We particularly note that emerging evidence suggests that selective targeting ROCK isoform based on the disease pathophysiology may represent a novel therapeutic approach for the disease treatment including cardiovascular diseases. PMID- 23921317 TI - Allergenic properties of enzymatically hydrolyzed peanut flour extracts. AB - BACKGROUND: Peanut flour is a high-protein, low-oil, powdered material prepared from roasted peanut seed. In addition to being a well-established food ingredient, peanut flour is also the active ingredient in peanut oral immunotherapy trials. Enzymatic hydrolysis was evaluated as a processing strategy to generate hydrolysates from peanut flour with reduced allergenicity. METHODS: Soluble fractions of 10% (w/v) light roasted peanut flour dispersions were hydrolyzed with the following proteases: Alcalase (pH 8.0, 60 degrees C), pepsin (pH 2.0, 37 degrees C) or Flavourzyme (pH 7.0, 50 degrees C) for 60 min. Western blotting, inhibition ELISA and basophil activation tests were used to examine IgE reactivity. RESULTS: Western blotting experiments revealed the hydrolysates retained IgE binding reactivity and these IgE-reactive peptides were primarily Ara h 2 fragments regardless of the protease tested. Inhibition ELISA assays demonstrated that each of the hydrolysates had decreased capacity to bind peanut specific IgE compared with nonhydrolyzed controls. Basophil activation tests revealed that all hydrolysates were comparable (p > 0.05) to nonhydrolyzed controls in IgE cross-linking capacity. CONCLUSIONS: These results indicate that hydrolysis of peanut flour reduced IgE binding capacity; however, IgE cross linking capacity during hydrolysis was retained, thus suggesting such hydrolysates are not hypoallergenic. PMID- 23921318 TI - Bacteremia in patients receiving TNF-alpha antagonists--a prospective multicenter study. AB - OBJECTIVE: TNF-alpha antagonists have changed the outcome of various chronic inflammatory diseases. Their use has spread widely and many patients receive those treatments for years. Previous reports found that the use of TNF-alpha antagonists may be associated with an increased risk of serious bacterial infections. We report 47 prospective bacteremia cases from the RATIO registry. METHODS: A national prospective study was conducted in France between 2004 and 2007 to collect severe bacterial infections in patients receiving TNF-alpha antagonists. All reported cases of bacteremia were validated by an expert committee. RESULTS: Forty-seven bacteremic episodes were reported. Staphylococcus aureus represented the most frequent causative pathogen (40%) and was mostly associated with bones and/or joints infections (68%) and with a worse outcome compared to that observed with other bacterial pathogens. CONCLUSIONS: Patients receiving TNF-alpha antagonists may develop bacteremia and S. aureus has to be included in the spectrum of the initial empiric antimicrobial therapy. PMID- 23921319 TI - Predictive factors for proximal junctional kyphosis in long fusions to the sacrum in adult spinal deformity. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To assess the mechanisms and the independent risk factors associated with proximal junctional kyphosis (PJK) in patients treated surgically for adult spinal deformity with long fusions to the sacrum. SUMMARY OF BACKGROUND DATA: The occurrence of PJK may be related to preoperative and postoperative sagittal parameters. The mechanisms and risk factors for PJK in adults are not well defined. METHODS: Consecutive patients who underwent long instrumented fusion surgery (>=6 vertebrae) to the sacrum with a minimum of 2 years of follow-up were retrospectively studied. Risk factors included patient factors, surgical factors, and radiographical parameters such as thoracic kyphosis (TK), lumbar lordosis (LL), sagittal vertical axis, pelvic tilt, and pelvic incidence. RESULTS: Ninety consecutive patients (mean age, 64.5 yr) met inclusion criteria. Radiographical PJK occurred in 37 of the 90 (41%) patients with a mean follow-up of 2.9 years. The most common mechanism of PJK was fracture at the upper instrumented vertebra (UIV) in 19 (51%) patients. Twelve (13%) patients with PJK were treated surgically with proximal extension of the instrumented fusion. Preoperative TK more than 30 degrees , preoperative proximal junctional angle more than 10 degrees , change in LL more than 30 degrees , and pelvic incidence more than 55 degrees were identified as predictors associated with PJK. Achievement of ideal global sagittal realignment (sagittal vertical axis <50 mm, pelvic tilt <20 degrees , and pelvic incidence-LL <+/-10 degrees ) protected against the development of PJK (19% vs. 45%). A multivariate regression analysis revealed changes in LL more than 30 degrees , and preoperative TK more than 30 degrees were the independent risk factors associated with PJK. CONCLUSION: Fracture at the UIV was the most common mechanism for PJK. Change in LL more than 30 degrees and pre-existing TK more than 30 degrees were identified as independent risk factors. Optimal postoperative alignment of the spine protects against the development of PJK. A surgical strategy to minimize PJK may include preoperative planning for reconstructions with a goal of optimal postoperative alignment. LEVEL OF EVIDENCE: 3. PMID- 23921320 TI - Magnetic resonance imaging in cadaver dogs with metallic vertebral implants at 3 Tesla: evaluation of the WARP-turbo spin echo sequence. AB - STUDY DESIGN: Laboratory investigation, ex vivo. OBJECTIVE: Postoperative complications are common after spinal implantation procedures, and magnetic resonance imaging (MRI) would be the ideal modality to image these patients. Unfortunately, the implants cause artifacts that can render MRI nondiagnostic. The WARP-turbo spin echo (TSE) sequence has been developed to mitigate artifacts caused by metal. The objective of this investigation was to evaluate the performance of the WARP-TSE sequence in canine cadaver specimens after implantation with metallic vertebral implants. SUMMARY OF BACKGROUND DATA: Magnetic field strength, implant type, and MRI acquisition technique all play a role in the severity of susceptibility artifacts. The WARP-TSE sequence uses increased bandwidth, view angle tilting, and SEMAC (slice-encoding metal artifact correction) to correct for susceptibility artifact. The WARP-TSE technique has outperformed conventional techniques in patients, after total hip arthroplasty. However, published reports of its application in subjects with vertebral column implants are lacking. METHODS: Ex vivo anterior stabilization of the atlantoaxial joint was performed on 6 adult small breed (<8 kg) cadaver dogs using stainless steel screws and polymethylmethacrylate. Axial and sagittal T2-weighted and short tau inversion recovery MRI was performed using conventional pulse sequences and WARP-TSE sequences at 3 T. Images were assessed qualitatively and quantitatively. RESULTS: Images made with the WARP-TSE sequence had smaller susceptibility artifacts and superior spinal cord margin depiction. WARP-TSE sequences reduced the length over which susceptibility artifacts caused spinal cord margin depiction interference by 24.9% to 71.5% with scan times of approximately 12 to 16 minutes. CONCLUSION: The WARP-TSE sequence is a viable option for evaluating the vertebral column after implantation with stainless steel implants. LEVEL OF EVIDENCE: N/A. PMID- 23921322 TI - Growth-sparing spinal instrumentation in skeletal dysplasia. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To report the outcomes of distraction-based, growth-sparing spinal instrumentation in patients with skeletal dysplasia. SUMMARY OF BACKGROUND DATA: Patients with skeletal dysplasia with spinal deformity often undergo early fusion, further compromising an already small chest. Nonfusion techniques may provide a safe alternative and allow for thoracic growth. METHODS: Between 2004 and 2010, 12 children with a diagnosis of various types of skeletal dysplasia underwent growth-sparing spinal instrumentation for severe spinal deformities. The mean duration of treatment with growing rods was 57 months (42-84 mo). Nine patients were treated with growing rods (8 dual, 1 single), and 3 were treated with vertical expandable prosthetic titanium rib (VEPTR; Synthes). Preoperative, initial postoperative, and final follow-up anteroposterior and lateral spine radiographs were measured for magnitude of deformity, junctional kyphosis, and implant failure. RESULTS: The major curve Cobb angle improved from a mean of 79 degrees preoperatively to a mean of 41 degrees at the last follow-up (52%). There was a decrease in mean thoracic kyphosis from 77 degrees preoperatively to 64 degrees at final follow up and an increase in mean lumbar lordosis from 58 degrees preoperatively to 63 degrees at final follow-up. The mean space available for the lungs increased by 26 mm on the concave and 24 mm on the convex side. Six patients required revision surgery for proximal junctional kyphosis. There were 4 rod failures and 6 hook and 8 screw dislodgements. One patient with vertical expandable prosthetic titanium rib had failed rib fixation that required revision. CONCLUSION: Growth sparing spinal instrumentation in patients with skeletal dysplasia and severe spinal deformity has a high complication and revision rate, and surgeons should closely monitor these patients. The complication rate is comparable with previous reports on patients with other diagnoses. However, deformities were well controlled, some trunk growth was achieved, and fusion surgery was delayed in all cases. LEVEL OF EVIDENCE: 4. PMID- 23921324 TI - Joint laxity negatively correlates with lumbar disc degeneration in young adults. AB - STUDY DESIGN: Cross-sectional study of preselected cohort of patients with neck pain. OBJECTIVE: To determine the association between joint laxity and lumbar disc degeneration in young adults. SUMMARY OF BACKGROUND DATA: Joint laxity is known to be closely related with orthopedic injuries and disease; however, studies about the relationship between spinal disorder and joint laxity are lacking. METHODS: Patients aged 30 to 40 years, seen at the outpatient clinic of our hospital for the evaluation of neck pain, who had magnetic resonance imaging of the cervical spine with routine inclusion of T2-weighted sagittal plane of the whole spine were included in the study. The Beighton and Horan criteria was used for the assessment of joint laxity. Logistic regression analysis was performed to estimate the odds ratio for lumbar disc degeneration in patients with joint laxity, and other variables including age, sex, body mass index, physical workload, neck pain (visual analogue scale score), and related disability (neck disability index score), and sagittal alignment. RESULTS: A total of 101 patients were enrolled in the study: 34 patients with joint laxity and 67 patients without joint laxity. There were no differences in age, body mass index, physical workload, neck pain (visual analogue scale score), and neck disability index score between the 2 groups, but there was a significant difference in sex ratio (P < 0.001). Patients with joint laxity showed increased lumbar lordosis (P = 0.004) and increased sacral slope (P = 0.003) but without significant difference in pelvic incidence (P = 0.084). In univariate analysis, presence of joint laxity (Beighton score >=4) as well as positive results of thumb (P = 0.016) and elbow (P = 0.047) tests were significantly associated with decreased risk for lumbar disc degeneration. Presence of joint laxity remained significant after multivariate adjustment for sex and lumbar lordosis (odds ratio = 0.373, P = 0.040). CONCLUSION: Increased joint laxity was closely associated with lower prevalence of lumbar disc degeneration in young adults, and the increased lumbar lordosis associated with joint laxity might explain the decreased risk of lumbar disc degeneration. LEVEL OF EVIDENCE: 2. PMID- 23921323 TI - Disc degeneration assessed by quantitative T2* (T2 star) correlated with functional lumbar mechanics. AB - STUDY DESIGN: Experimental correlation study design to quantify features of disc health, including signal intensity and distinction between the annulus fibrosus and nucleus pulposus, with T2* magnetic resonance imaging (MRI) and correlate with the functional mechanics in corresponding motion segments. OBJECTIVE: Establish the relationship between disc health assessed by quantitative T2* MRI and functional lumbar mechanics. SUMMARY OF BACKGROUND DATA: Degeneration leads to altered biochemistry in the disc, affecting the mechanical competence. Clinical routine MRI sequences are not adequate in detecting early changes in degeneration and fails to correlate with pain or improve patient stratification. Quantitative T2* relaxation time mapping probes biochemical features and may offer more sensitivity in assessing disc degeneration. METHODS: Cadaveric lumbar spines were imaged using quantitative T2* mapping, as well as conventional T2 weighted MRI sequences. Discs were graded by the Pfirrmann scale, and features of disc health, including signal intensity (T2* intensity area) and distinction between the annulus fibrosus and nucleus pulposus (transition zone slope), were quantified by T2*. Each motion segment was subjected to pure moment bending to determine range of motion (ROM), neutral zone (NZ), and bending stiffness. RESULTS: T2* intensity area and transition zone slope were significantly correlated with flexion ROM (P = 0.015; P = 0.002), ratio of NZ/ROM (P = 0.010; P = 0.028), and stiffness (P = 0.044; P = 0.026), as well as lateral bending NZ/ROM (P = 0.005; P = 0.010) and stiffness (P = 0.022; P = 0.029). T2* intensity area was also correlated with lateral bending ROM (P = 0.023). Pfirrmann grade was only correlated with lateral bending NZ/ROM (P = 0.001) and stiffness (P = 0.007). CONCLUSION: T2* mapping is a sensitive quantitative method capable of detecting changes associated with disc degeneration. Features of disc health quantified with T2* predicted altered functional mechanics of the lumbar spine better than traditional Pfirrmann grading. This new methodology and analysis technique may enhance the assessment of degeneration and enable greater patient stratification for therapeutic strategies. LEVEL OF EVIDENCE: N/A. PMID- 23921325 TI - Should postoperative pulmonary function be a criterion that affects upper instrumented vertebra selection in adolescent idiopathic scoliosis surgery? AB - STUDY DESIGN: A multicenter, prospective evaluation of pulmonary function testing (PFT) and radiographical measures in patients surgically treated for adolescent idiopathic scoliosis (AIS). OBJECTIVE: The objective of this study was to evaluate pulmonary function to determine whether a more proximal upper instrumented vertebra (UIV) negatively impacts pulmonary function in patients surgically treated for AIS. SUMMARY OF BACKGROUND DATA: There seems to be increasing concern that a more proximal extent of posterior thoracic spinal instrumentation and fusion reduces postoperative pulmonary function. However, there are few reports that analyze the relation between the selection of UIV and pulmonary function in AIS. METHODS: PFT and radiographical examination of 154 patients with major thoracic AIS (Lenke type 1-4) undergoing posterior thoracic spinal instrumentation and fusion without thoracoplasty were completed prospectively. Patients were divided into groups based on UIV (T1-T3 vs. T4-T5) and Lenke curve type (2 and 4 vs. 1 and 3) and analyzed respectively. Demographic, radiographical measurements, and PFT data from preoperative and 2 year time points were analyzed. RESULTS: Patients with a structural upper thoracic curve (Lenke 2 and 4) had significantly lower preoperative PFT values than those without a structural upper thoracic curve (Lenke 1 and 3). Lenke 2 and 4 patients were also more likely to be fused proximally (82%, T1-T3) than those in the Lenke 1 and 3 groups (42%, T1-T3, P< 0.05). Preoperatively, those with UIV from T1 to T3 tended to have lower PFT values than those with UIV from T4-T5; however, only percent total lung capacity was statistically different (P< 0.05). Both UIV groups showed significant increases in all absolute values (forced vital capacity, forced expiratory volume in 1s, total lung capacity) at 2-year follow up (P< 0.05) as expected with growth, and the percent predicted values (% forced vital capacity, % forced expiratory volume in 1s, % total lung capacity) remained stable. CONCLUSION: Although patients with UIV: T1-T3 showed slightly lower PFT values than UIV: T4-T5, the presence of a double thoracic curve was the primary cause of PFT reduction in these patients. Including the upper thoracic spine in the fusion had no significant effect on pulmonary function 2 years after surgical correction of AIS. LEVEL OF EVIDENCE: 3. PMID- 23921326 TI - Pedicle subtraction osteotomy in elderly patients with degenerative sagittal imbalance. AB - STUDY DESIGN: Retrospective, radiographical analysis. OBJECTIVE: To evaluate pedicle subtraction osteotomy (PSO) as a means of correcting severe degenerative sagittal imbalance in elderly patients. SUMMARY OF BACKGROUND DATA: PSO in patients with degenerative sagittal imbalance is likely to cause more complications than in patients with iatrogenic flatback deformity. METHODS: This study analyzed 34 patients who underwent fusion to the sacrum, with a minimum 2 year follow-up. Age of the patients were in the range from 58 to 73 with the mean at 65.5 years. PSO was performed at one segment in all cases, consisting of L3 (n = 26), L4 (n = 4), L2 (n = 3), and L1 (n = 1). The average number of levels fused was 8.15. Ten patients had structural interbody fusion at the lumbosacral junction. RESULTS: Applying PSO at one segment, the mean correction of the lordotic angle at the osteotomy site was 33.3 degrees , of which the loss of correction (LOC) was 4.0 degrees at the last visit. The correction of lumbar lordosis was 33.7 degrees and the LOC was 8.5 degrees . The sagittal C7 plumb was 215.9 mm before surgery, corrected to 35.1 mm after surgery, and changed to 95.9 mm by the last visit. The correction of the sagittal C7 plumb was 119.9 mm and the LOC was 60.9 mm. There was substantial LOC in lumbar lordosis and sagittal C7 plumb. In 10 patients with addition of posterior lumbar interbody fusion, the LOC of lumbar lordosis was 7.4 degrees , which was less than 9 degrees in those without it. CONCLUSION: PSO for the correction of degenerative sagittal imbalance in elderly patients resulted in correction of sagittal alignment with a significant LOC of lumbar lordosis and sagittal C7 plumb. The LOC of lumbar lordosis occurred at both the osteotomy and non-osteotomy site. The addition of anterior column support is helpful to maintain correction and reduce complications. LEVEL OF EVIDENCE: N/A. PMID- 23921327 TI - Clinical outcome of spinal reconstruction after total en bloc spondylectomy at 3 or more levels. AB - STUDY DESIGN: Retrospective clinical study. OBJECTIVE: To assess the clinical and radiological outcome of spinal reconstruction after total en bloc spondylectomy (TES) at 3 or more levels. SUMMARY OF BACKGROUND DATA: There have been few reports of multilevel spondylectomy for spinal tumor. This is the first case series on the clinical outcome for reconstructions after 3 or more levels of TES. METHODS: Twenty-six patients treated by 3 or more levels of TES at Kanazawa University Hospital were included in this analysis. Reconstruction was performed with pedicle screw fixation and a titanium mesh cage filled with autograft in all cases. To increase spinal stability in reconstruction, spinal shortening was performed. Instrument failure and radiological findings were evaluated using radiograph and computed tomographical scan with multiplanar reconstructions. The length of spinal shortening was also measured. RESULTS: Excluding 4 patients with deteriorating general condition, radiological evaluation was performed for more than 1 year in 22 patients. All 22 patients had no evidence of local recurrence at the surgical site of the spine during the follow-up period. Cage subsidence was seen in 11 patients (50%). Eight of the 11 patients showed the appearance of subsidence 1 month after the surgery. There was one instrument failure that required revision surgery 8 months after TES surgery. One other patient showed bone resorption on the contact surfaces of the cage at 24 months after the surgery. The mean length of the resection vertebrae was 84.6 mm (52-124 mm), while the length of the shortening was 10.4 mm (3-22 mm). CONCLUSION: No local recurrence was observed after TES at 3 or more levels. Cage subsidence was a common phenomenon (50%) and already observed 1 month after surgery in 8 of the 11 cases. Spinal shortening has the potential to provide good stability for multilevel TES. LEVEL OF EVIDENCE: 4. PMID- 23921328 TI - Traumatic spondyloptosis of the lumbar spine: closed reduction and internal fixation. AB - STUDY DESIGN: Case report. OBJECTIVE: To describe a novel approach to treating traumatic spondyloptosis of the lumbar spine. SUMMARY OF BACKGROUND DATA: Traumatic spondyloptosis of the lumbar spine is a relatively uncommon injury because it requires a significantly large amount of energy to occur. Reduction of these fracture dislocations in the operating room may be difficult through a solely open approach because it usually requires a significant degree of bone removal and spinal manipulation with instrumentation. METHODS: In this case report, the authors present a unique method of closed reduction followed by open fixation of a traumatic fracture dislocation of the lumbar spine. The patient in this study experienced a traumatic spondyloptosis of L3 on L4 from a high-speed motor vehicle crash in which he was ejected from the vehicle. The patient had experienced nearly complete anterior/posterior translocation of L3 on L4 and had avulsed the anterior superior aspect of the L4 vertebral body. On presentation to the trauma center, he was ASIA (American Spinal Injury Association) B; he had patchy sensory preservation in his left lower extremity. The surgical goal was to relocate his spinal fracture and rigidly fix it with a pedicle screw and rod construct. RESULTS: Under fluoroscopic guidance and with the patient under general anesthesia, we performed a closed reduction of the spinal fracture using lumbar hyperextension and full torso longitudinal traction. We were able to reduce the fracture almost completely using this technique. After open internal fixation of the patient's fracture with a rod-pedicle screw construct, we reduced the patient's fracture to a grade II spondylolisthesis, effectively. The patient went on to recover a small amount of neurological function after the procedure. CONCLUSION: The authors think that this is an effective method for reduction of these severe fractures. PMID- 23921329 TI - Gabapentin and pregabalin in the management of postoperative pain after lumbar spinal surgery: a systematic review and meta-analysis. AB - STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: To review the literature systematically and make a comprehensive understanding of the efficacy of these 2 drugs in the management of postoperative pain after lumbar spinal surgery. SUMMARY OF BACKGROUND DATA: Several trials that evaluated the efficacy of gabapentin and pregabalin in the management of postoperative pain after lumbar spinal surgery have been published. METHODS: PubMed (1980 to present), adapted for EMBASE (1980 to present), and Cochrane databases were searched for randomized placebo-controlled trials. Random effect model was used in our meta-analysis, and standard mean difference (SMD) was chosen as the pooled estimate. RESULTS: Seven trials were included in our study. All included studies could be considered to be of high quality in methodology. The pooled results from meta-analysis demonstrated that compared with placebo, both gabapentin and pregabalin could significantly reduce the postoperative narcotic consumption (SMD, -1.54, and 1.16, respectively). Oral gabapentin was efficacious in the management of postoperative pain at all time points during the first day after surgery (SMD, 1.91 at 0-6 hr, -1.30 at 6-12 hr, -1.05 at 12-24 hr, respectively). Pregabalin seemed to be also efficacious in the management of postoperative pain at 0 to 6 hours (SMD, -1.05), at 6 to 12 hours (SMD, -0.62), and at 12 to 24 hours (SMD, 0.43). Both drugs could be well tolerated in our included trials, compared with placebo. CONCLUSION: This work suggested that both gabapentin and pregabalin were efficacious in reduction of postoperative pain and narcotic requirements after lumbar spinal surgery, whereas more trials were needed to further assess the efficacy of pregabalin in the management of postoperative pain after lumbar spinal surgery. LEVEL OF EVIDENCE: 1. PMID- 23921330 TI - In vitro biomechanical study to quantify range of motion, intradiscal pressure, and facet force of 3-level dynamic stabilization constructs with decreased stiffness. AB - STUDY DESIGN: An in vitro biomechanical study. OBJECTIVE: To perform in vitro biomechanical testing on a lumbar spine using a 6-degree-of-freedom machine. To compare the range of motion (ROM), intradiscal pressure, and facet force of different 3-level dynamic stabilization constructs with traditional rigid constructs. To determine the effect of decreasing the stiffness of the dynamic construct on the various parameters. SUMMARY OF BACKGROUND DATA: Dynamic stabilization systems are a surgical option that may minimize the development of adjacent segment disease. METHODS: Seven T12-S1 specimens were tested at +/- 7.5 Nm in flexion-extension, lateral bending, and axial rotation. The testing sequence was (1) intact, (2) intact with facet sensors, (3) L3-S1 rigid (3R), (4) L3-L4 dynamic and L4-S1 rigid (1D-2R A), (5) L3-L5 dynamic and L5-S1 rigid (2D-1R A), and (6) L3-S1 dynamic (3D A). Constructs 1D-2R A, 2D-1R A, and 3D A were tested again with the specialized designs of B and C of decreased stiffness. ROM, intradiscal pressure, and facet force were measured. RESULTS: In all loading modes there was a trend of increasing motion with decreased stiffness. Significant differences were seen with more dynamic stabilization levels but no significance was seen with only decreasing the stiffness. 3R facet force at the caudal instrumented level significantly decreased compared with intact and dynamic stabilization constructs during axial rotation. CONCLUSION: Biomechanical testing resulted in a trend of increased ROM across instrumented levels as the stiffness was decreased. Dynamic stabilization increased the ROM across instrumented levels compared with rigid rods. These results suggest that decreasing the stiffness of the construct may lessen the probability of adjacent level disease. Although the specialized devices are not commercially available, clinical data would be necessary for a clearer understanding of adjacent level effects and to confirm the in vitro biomechanical findings. LEVEL OF EVIDENCE: N/A. PMID- 23921331 TI - Effect of facet joint injection versus systemic steroids in low back pain: a randomized controlled trial. AB - STUDY DESIGN: Randomized clinical trial. OBJECTIVE: To compare the effectiveness of facet joint injection versus systemic steroid in patients with a diagnosis of facet joint syndrome. SUMMARY OF BACKGROUND DATA: The term facet joint syndrome has been used to define back pain originating from the facet joints. Treatment is mainly conservative, although interventions, including intra-articular injections and medial branch nerve blocks are used to manage facet-mediated pain. Several studies have evaluated the effectiveness of these interventions. Results of facet joint injection, however, are conflicting. METHODS: Sixty subjects with a diagnosis of facet joint syndrome were enrolled in the study. They were randomized into experimental and control groups. The experimental group was administered with intra-articular injection of 6 lumbar facet joints with triamcinolone hexacetonide; the control group was administered with triamcinolone acetonide intramuscular injection of 6 lumbar paravertebral points. Visits were taken at baseline and at 1, 4, 12, and 24 weeks after interventions. Outcome measures were used: pain visual analogue scale, pain visual analogue scale during extension of the spine, Likert scale, improvement percentage scale, Roland Morris, 36-Item Short Form Health Survey, and accountability of medications taken.Homogeneity was tested using the Student t, Pearson chi, and Mann-Whitney tests. Analysis of variance was used to analyze differences in the groups over time and the Student t test to analyze differences between groups at each time evaluation. RESULTS: The groups were similar at baseline. Comparisons between the groups showed, in analysis of variance analysis, an improvement in the experimental group regarding diclofenac intake and quality of life, in the "role physical" profile, assessed by 36-Item Short Form Health Survey.In the analysis at each time point, an improvement in the experimental group was also found in the Roland-Morris questionnaire, in the improvement percentage scale and in the response to treatment, assessed by the Likert scale. CONCLUSION: Both treatments were effective, with a slight superiority of the intra-articular injection of steroids over intramuscular injection. PMID- 23921332 TI - Ti2448 pedicle screw system augmentation for posterior lumbar interbody fusion. AB - STUDY DESIGN: A finite element analysis was used. OBJECTIVE: To evaluate the feasibility of using the Ti-24Nb-4Zr-7.9Sn (Ti2448) pedicle screw system to augment single-level posterior lumbar interbody fusion (PLIF). SUMMARY OF BACKGROUND DATA: The Ti-6Al-4V pedicle screw system increases the risk of adjacent disc degeneration and stress-shielding effect due to enormous rigidity. A titanium alloy with much lower elastic modulus, Ti2448, may help to resolve the complications. METHODS: A finite element model of intact L3-S1 was established and then validated. Single-level PLIF at L4-L5 with or without a supplementary titanium-alloy pedicle screw system was simulated. A pure moment of 7.6 Nm and a 400 N preload was applied to the finite element model of PLIF, PLIF with the Ti 6Al-4V screw system, and PLIF with the Ti2448 screw system in flexion, extension, axial rotation, and lateral bending. RESULTS: The axial displacement at the fusion level decreased to 64%, 72%, 84%, and 92% of screw-free status in flexion, extension, axial rotation, and lateral bending, respectively, after augmentation of the Ti2448 screw system, which was 1% to 3% lower than the performance of the Ti-6Al-4V system. The angular displacement at the fusion level with the Ti2448 system was similar to that of the Ti-6Al-4V system, only 2% lower in flexion. Compared with the Ti-6Al-4V system, the Ti2448 system suppressed the increase of intradiscal pressures at the upper adjacent disc in all bending directions, but only in extension and axial rotation at the lower adjacent disc; the maximum stress experienced by cages and screws was higher in all bending directions when augmented with the Ti2448 system. CONCLUSION: Using the Ti2448 screw system is suggested for augmenting single-level PLIF because it induces less disc intradiscal pressure at adjacent levels and the stress-shielding effect at implant-bone surface with stabilization performance compared with the Ti-6Al-4V screw system. PMID- 23921333 TI - In focus: molecular and cell biology research in China. AB - An interactive, intellectual environment with good funding opportunities is essential for the development and success of basic research. The fast-growing economy and investment in science, together with a visionary plan, have attracted foreign scholars to work in China, motivated world-class Chinese scientists to return and strengthened the country's international collaborations. As a result, molecular and cell biology research in China has evolved rapidly over the past decade. PMID- 23921335 TI - Membrane trafficking: increasing Golgi transport options. PMID- 23921334 TI - Autophagy: Atg independence in the midgut. PMID- 23921336 TI - Amphiphilic sulfamide as a low-molecular-mass hydrogelator: A novel mode of 3-D networks formed by hydrogen-bond-directed 2-D sheet assemblies. AB - Asymmetrically substituted amphiphilic sulfamide, N-tetradecyl-N'-(6 dimethylaminohexyl)-sulfamide (3c) having a dimethylamino group at one end of the side chain, showed a strong ability to form two-dimensional (2-D) sheet-like assemblies by the 2-D hydrogen-bond networks between sulfamide moieties. Upon protonation of the amino group with acid, the cationic ammonium form of 3c induced effective hydrogelation (minimum gelation concentration: 0.5wt%) to yield a translucent, self-standing hydrogel. Infrared (IR) spectroscopy, X-ray diffraction (XRD), atomic force microscopy (AFM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) studies confirmed formation of the fibrous assemblies of the hydrogen-bond-directed 2-D nanosheets in the hydrogel. A novel mode of three-dimensional (3-D) networks was formed by branching and recombination of hydrogen-bond networks and knit-like linkages between the assemblies. The storage and loss moduli of the hydrogel (2wt%) were measured to be in the range of 10(2) and 10(3)Pa, showing relatively high mechanical stability. PMID- 23921337 TI - Sleeving nanocelluloses by admicellar polymerization. AB - This investigation reports the first application of admicellar polymerization to cellulose nanofibers in the form of bacterial cellulose, microfibrillated cellulose, and cellulose nanowhiskers using styrene and ethyl acrylate. The success of this physical sleeving was assessed by SEM, FTIR, and contact angle measurements, providing an original and simple approach to the modification of cellulose nanofibers in their pristine aqueous environment. PMID- 23921339 TI - A prospective randomized study comparing double- and single-bundle techniques for anterior cruciate ligament reconstruction. AB - BACKGROUND: The aim of the study was to compare the results after arthroscopic anterior cruciate ligament (ACL) reconstruction using either the double-bundle or single-bundle technique with hamstring tendon autografts in an unselected group of patients. HYPOTHESIS: Double-bundle ACL reconstruction will render a better outcome on the pivot-shift test. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A randomized series of 103 patients (33 women, 70 men; median age, 27 years; range, 18-52 years) with a unilateral ACL rupture underwent anatomic ACL reconstruction. The double-bundle technique was used in 53 patients, and the single-bundle technique was used in 50 patients. The ACL footprint was visualized, and the femoral tunnel was drilled through the anteromedial portal; interference screw fixation was used at both ends. The patients were examined preoperatively and at a median of 26 months (range, 22-42 months) after the reconstruction by a blinded observer. The primary variable was the pivot-shift test. RESULTS: At 2-year follow-up, 98 patients (93%) were examined. Clinical assessments at follow-up revealed no significant differences between the double bundle and single-bundle groups in terms of the pivot-shift test, KT-1000 arthrometer laxity measurements, manual Lachman test, range of motion, Lysholm knee scoring scale, Tegner activity scale, Knee Injury and Osteoarthritis and Outcome Score (KOOS), 1-legged hop test, and square hop test. A significant improvement was seen in both groups compared with the preoperative values in terms of most clinical assessments. CONCLUSION: In this prospective randomized study, the primary variable, the pivot-shift test, and other subjective and objective outcome variables revealed no significant differences between the double-bundle and single-bundle techniques at 2 years after ACL reconstruction in an unselected group of patients. PMID- 23921338 TI - Platelet-rich plasma for arthroscopic repair of large to massive rotator cuff tears: a randomized, single-blind, parallel-group trial. AB - BACKGROUND: Platelet-rich plasma (PRP) is expected to have a biological augmentation potential in the healing of various diseases and injuries, including rotator cuff tears. However, few evaluations have been performed specifically for large to massive tears. PURPOSE: To assess the efficacy of PRP augmentation in patients undergoing arthroscopic repair for large to massive rotator cuff tears. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 48 patients scheduled for arthroscopic repair of large to massive rotator cuff tears were randomly assigned to receive either PRP-augmented (PRP group) or conventional treatment (conventional group). In the PRP group, 3 PRP gels (3 * 3 mL) were applied to each patient between the torn end and the greater tuberosity. The primary outcome measure was the retear rate assessed by magnetic resonance imaging (MRI) or computed tomographic arthrography (CTA) at a minimum of 9 months after surgery. Secondary outcome measures included pain, range of motion, muscle strength, overall satisfaction, functional scores, and the change in cross sectional area (CSA) of the supraspinatus. RESULTS: The retear rate of the PRP group (20.0%) was significantly lower than that of the conventional group (55.6%) (P = .023). Clinical outcomes showed no statistical difference between the 2 groups (all P > .05) except for the overall function (P = .043). The change in 1 year postoperative and immediately postoperative CSA was significantly different between the 2 groups: -15.54 +/- 94.34 mm2 in the PRP group versus -85.62 +/- 103.57 mm2 in the conventional group (P = .047). CONCLUSION: The application of PRP for large to massive rotator cuff repairs significantly improved structural outcomes, as evidenced by a decreased retear rate and increased CSA of the supraspinatus compared with repairs without PRP augmentation. While there was no significant difference in clinical outcomes except the overall shoulder function after 1-year follow-up, better structural outcomes in the PRP group might suggest improved clinical outcomes at longer term follow-up. PMID- 23921340 TI - Are navigation systems accurate enough to predict the correction angle during high tibial osteotomy? Comparison of navigation systems with 3-dimensional computed tomography and standing radiographs. AB - BACKGROUND: Unpredicted overcorrection of the mechanical axis can occur during navigation-assisted high tibial osteotomy (HTO). It is not clear whether the erroneous overcorrection stems from the navigation system itself or from other causes. PURPOSE: To evaluate the accuracy of the navigation system in HTO by comparing the change in the femorotibial angle provided by the navigation system with the bony correction angle of the proximal tibia on 3-dimensional computed tomography (3D CT) and with the change in mechanical femorotibial alignment on standing whole-leg radiographs. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: A total of 16 knees underwent navigation-assisted HTO, and their alignment data were obtained before and after correction. For comparison, preoperative and follow-up standing whole-leg anteroposterior radiographs, lateral knee radiographs, and preoperative and postoperative 3D CT scans were taken. The medial proximal tibial angle (MPTA), posterior tibial slope, and mechanical femorotibial angle (mFTA) were measured in these images, and the 3 coronal and 3 sagittal correction angles were compared with each other. RESULTS: In the coronal plane, the mean correction angle of the navigation system was 9.3 degrees +/- 2.0 degrees valgus (range, 6 degrees -13 degrees ), and the mean MPTA on 3D CT increased 9.7 degrees +/- 2.0 degrees (range, 6.7 degrees -13.8 degrees ) after correction. The mean correction angle of the mFTA on standing radiographs was 11.9 degrees +/- 3.2 degrees valgus (range, 6.9 degrees -16.5 degrees ). There was no statistical significance between the navigation system and 3D CT (P = .187), but there was a statistically significant difference between the navigation system and standing radiographs (P = .001). The results of the correction angle in the sagittal plane were similar to those in the coronal plane. CONCLUSION: The correction of the femorotibial angle by the navigation system was not different from the bony correction angle on 3D CT. There was a discrepancy between the correction angle of the navigation system and that of the standing radiograph. CLINICAL SIGNIFICANCE: Surgeons must be cautious about the tension of soft tissue, even when using the navigation system during HTO. PMID- 23921341 TI - Isolation and analysis of tetracycline-resistant Mycoplasma agalactiae strains from an infected goat herd in Cyprus - short communication. AB - A major concern with the use of tetracycline against mycoplasmas is the development of resistance. Infections in small ruminants due to tetracyclineresistant Mycoplasma agalactiae strains are becoming a frequent problem worldwide. In the present paper the detection and analysis of three tetracycline-resistant M. agalactiae strains, isolated from infected goats in Cyprus, are reported. The three field isolates were identified as M. agalactiae by polymerase chain reaction (PCR) showing 98% identity to the M. agalactiae PG2 reference strain. Furthermore, they were found sensitive to tylosin, enrofloxacin, spiramycin and lincomycin. In contrast, they were resistant to tetracycline. None of the putative genes [tet(M), tet(O) and tet(S)] that commonly contribute to high-level resistance to tetracycline could be amplified from their genome. Contrarily, the field isolates were found to carry ISMag1, an insertion sequence related to the IS30 family of mobile elements. Although ISMag1 is widely believed to induce high-frequency chromosomal rearrangements resulting in phenotypic changes of microorganisms, its potential role in tetracycline resistance of mycoplasmas requires further studies. PMID- 23921342 TI - The effectiveness of natural and synthetic immunomodulators in the treatment of inflammatory bowel disease in dogs. AB - The aim of the study was to evaluate the usefulness of immunomodulators in the treatment of inflammatory bowel disease (IBD) in dogs. Twenty-eight dogs diagnosed with IBD took part in the study. The animals received a food containing extruded immunomodulators: beta-1,3/1,6-D-glucan, beta-hydroxy-beta-methyl butyrate (HMB) and levamisole for 42 days. Whole blood samples were analysed before and after therapy assessing changes in phagocyte activity (respiratory burst activity, RBA and potential killing activity, PKA), evaluation of proliferation response of mitogen-stimulated lymphocytes and serum gamma globulin levels, lysozyme activity, ceruloplasmin levels and interleukin activity (IL-6 and IL-10). In this experiment, beta-1,3/1,6-D-glucan delivered the highest level of treatment efficacy by producing the quickest therapeutic effect, lowering Canine Inflammatory Bowel Disease Activity Index (CIBDAI) values to below 3, improving histopathological parameters, decreasing IL-6 levels, increasing IL-10 concentrations, and producing remission periods longer than six months. HMB and levamisole were also effective in lowering CIBDAI scores, but the abatement of clinical symptoms was slower and less pronounced in comparison with beta-1,3/1,6 D-glucan. The results indicate that beta-1,3/1,6-D-glucan can be useful in the treatment of canine IBD. PMID- 23921343 TI - Ultrasonography of the lungs and pleura in healthy camels (Camelus dromedarius). AB - This study describes ultrasonography of the lungs and pleura in healthy camels (Camelus dromedarius). The different layers of the thoracic wall appeared as narrow bands of variable echogenicity. Reverberation artefacts appeared as lines of variable echogenicity that ran parallel to the pulmonary surface medial to the pleura. Because of its air content, the pulmonary parenchyma was not visualised in all camels. On the right side, the pulmonary surface was seen in the 5th through the 10th intercostal space (ICS). In addition, it was imaged in the 11th ICS in 20 camels and in the 4th ICS in three camels. The dimension of the ventral lung border was largest at the 4th ICS and smallest at the 11th ICS. The echogenic line on the surface of the lung, consisting of the costal and the parietal pleurae, was 1 to 4 mm thick. The left pulmonary surface and pleura were imaged with approximately the same frequencies as the right side. At this side, only the pulmonary surface and pleura were imaged in 15 camels in the 11th ICS. In conclusion, ultrasonography of the lungs and pleura provides information that can be used as a reference when examining camels suspected to have respiratory diseases. PMID- 23921344 TI - Equine multinodular pulmonary fibrosis (EMPF): Five case reports. AB - Equine multinodular pulmonary fibrosis (EMPF), a progressive fibrosing interstitial lung disease has been associated with gammaherpesviruses. This case series describes five horses with EMPF. Three of the horses (two in Hungary, one in the Czech Republic) were diagnosed with EMPF ante mortem. They presented with typical clinical signs of EMPF including dyspnoea and weight loss. Arterial blood gas analysis revealed hypoxaemia. Blood work showed signs of inflammation like neutrophilia and hyperfibrinogenaemia. An endoscopic examination of the respiratory tract including cytology and culture of tracheobronchial secretion and bronchoalveolar lavage were performed, revealing secondary bacterial infection in one case. A suspected diagnosis of EMPF was made on the basis of a positive EHV-5 PCR from bronchoalveolar lavage and the findings of thoracic radiographs and ultrasound examination. In one case the diagnosis was confirmed by lung biopsy. All horses died or had to be euthanised despite treatment. Two horses (from Austria) were diagnosed with EMPF post mortem. They not only had EMPF but also concurrent other diseases which seemed to be associated with immunosuppression. Three horses showed the discrete form and two horses the diffuse form of EMPF. EHV-5 DNA was identified in lung tissue of all horses by PCR. PMID- 23921345 TI - Biotransformation of trichothecenes alleviates the negative effects of T-2 toxin in pigs. AB - Between 49 and 70 days of age, three groups of growing pigs (n = 10 each) were fed diets containing 0, 0.3 and 0.5 mg/kg T-2 toxin, respectively, for 21 days. The feed of another two groups of pigs (n = 10 each) contained 0.3 or 0.5 mg/kg T 2 toxin, respectively, plus a feed additive developed for splitting up the molecular structure of Fusarium toxins, in particular trichothecenes, by deepoxidation of the molecule, at 2 kg/tonne concentration. One group (n = 10) served as positive control; their feed was free from T-2 toxin but contained the feed additive at the above concentration. Toxin concentrations at these low dietary levels impaired the feed intake and growth rate of pigs. The feed additive alleviated the negative effects and justified its potential for prevention. Data of the present study indicated a 0.2 mg/kg feed no observed effect level (NOEL) of T-2 toxin in growing pig feeds. PMID- 23921346 TI - Ultrastructural lesions and immunohistochemical analysis of Bcl-2 protein expression in the kidney of chickens with experimental ochratoxicosis. AB - A study was conducted to evaluate the nephrotoxic effect of ochratoxin A (OTA) in broiler chickens. Forty Ross 308 broilers (6 days old) were divided into two groups: one group received daily, by gavage, ochratoxin A at a daily dose of 50 MUg/kg body weight for up to 21 days, while the control group received only diluent (sunflower oil). After 21 days, the chickens were euthanised and the kidneys removed for analysis by histopathology and immunohistochemistry to detect an anti-apoptotic marker (Bcl-2), and by transmission electron microscopy. Macroscopically the kidneys were enlarged, showing degeneration and gout deposits. Histologically, glomerulonephrosis and tubulonephrosis were common lesions in all chicks. In two of the five chicks exposed to OTA for 21 days, focal tubular cell proliferation, multiple adenoma-like structures and Bcl-2 positive epithelial cells were identified in layers of the renal papilla and in convoluted tubules. Transmission electron microscopy of the proximal convoluted tubules identified abnormal forms of mitochondria. The nephrotoxic effect of ochratoxicosis in chickens is probably due to carcinogenic changes induced in the epithelial tissues. PMID- 23921347 TI - Effect of lignin supplementation of a diet contaminated with Fusarium mycotoxins on blood and intestinal lymphocyte subpopulations in chickens. AB - The objective of the study was to investigate the effects of lignin supplementation of a diet contaminated with the Fusarium mycotoxins deoxynivalenol (DON) and zearalenone (ZEA) on peripheral blood leukocytes and duodenal immunocompetent cells in broiler chickens. From day 1 after hatching, all chickens were fed an identical control diet for two weeks. Then chickens of Group 1 continued to be fed the control diet, whereas Group 2 was fed the same diet supplemented with lignin at 0.5% level. Simultaneously, Group 3 started to receive a diet contaminated with DON (2.95 mg kg-1) and ZEA (1.59 mg kg-1), while Group 4 received an identical contaminated diet supplemented with 0.5% lignin for further two weeks. Samples of blood and duodenal tissue were collected from 6 birds of each group at 4 weeks of age. Neither counts of white blood cells nor phagocytic function in the peripheral blood were significantly affected in the mycotoxin- and/or lignin-treated birds. As compared to the control, increased numbers of IgM-bearing cells were found in the peripheral blood in Group 3 fed the contaminated diet (P < 0.05) and in Group 4 given the contaminated diet supplemented with lignin (P < 0.01). While the contaminated diet led to reduced numbers of duodenal CD4+ cells, in Group 2 treated only with lignin the number of duodenal CD4+ cells was increased. Lignin enrichment of the contaminated diet did not eliminate the mycotoxin-induced reduction in the number of duodenal CD4+ cells. The results suggest that dietary supplementation of lignin as an indigestible compound to poultry feed may increase the density of some intestinal immunocompetent cells without exerting effects on that in the peripheral blood. However, when added to a diet contaminated with Fusarium mycotoxins, lignin did not prevent the mycotoxin-induced changes in the numbers of blood and intestinal immunocompetent cells. PMID- 23921348 TI - Enzootic outbreak and spontaneous regression of keratoacanthomas in a commercial layer flock. AB - This paper reports an enzootic outbreak and spontaneous regression of keratoacanthomas among adult layer hens with lesions on the skin of the legs. The observations were performed in a flock of 55,000 commercial layers (50,000 Lohmann White and 5,000 Lohmann Brown). At the age of 30 weeks, Lohmann White layers exhibited a number of growths (at an average of 60 hens per week, representing 0.1% of the flock) in the region of leg toes on a daily basis over 28 weeks that regressed during the remaining flock production period. Gross and histological investigations identified the lesions as keratoacanthomas. PCR analysis was negative for avian leukosis virus (ALV) and reticuloendotheliosis virus (REV). The present investigations have revealed an unusual case: this is the first report on an enzootic outbreak of multiple keratoacanthomas in commercial layers. The results of the aetiological investigations do not show a relation to any infectious agent or a chemical-toxic cause. The abnormal invasion of keratinocytes from the stratum corneum leading to neoplasms in this case coincides with the phase of peak laying capacity which is in fact a stress factor and might be regarded as a provocative moment. PMID- 23921349 TI - Pharmacokinetics of an immunomodulating dose of levamisole in weaned pigs. AB - Levamisole has been shown to stimulate the immune response in immunocompromised humans and animals. However, its use as an adjuvant in immunocompromised weaned pigs prone to colibacillosis has only been experimentally tested but not yet officially approved. Therefore, the aim of these studies was to study the pharmacokinetics (PK) of an immunomodulating dose of levamisole in weaned pigs. For that purpose, 20 weaned crossbred pigs were divided into two treatment groups. In this parallel-design study, a single dose of levamisole (2.5 mg/kg body weight) was administered by the intramuscular (i.m.) or oral (p.o.) route. Statistically significant differences between the i.m. and p.o. routes in terminal beta rate constant (beta), maximum plasma concentration (Cmax), area under the curve (AUC) for plasma concentration-time curve from time zero to infinity (AUC0-inf), area under the plasma concentration-time curve from time 0 to the last quantifiable time point (AUC0-t) were determined. Further research is needed to establish a relationship between the PK and the immunomodulating effect of levamisole in pigs. PMID- 23921350 TI - Effect of weak electromagnetic field on cardiac work, concentration of thyroid hormones and blood aminotransferase level in the chick embryo. AB - The aim of the study was to determine the effect of alternating electromagnetic field (EMF; 50 Hz frequency, 50 and 100 MUT induction) on cardiac work of the chick embryo. Eggs from the experimental groups were exposed to EMF throughout incubation. During the experiment, heart rate (ballistocardiographic method), thyroxine (T4) and triiodothyronine (T3) concentrations, heart weight, ventricle wall thickness, and levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. The results show, for the first time, that the exposure of chick embryos to EMF augments the heart rate, especially from 17 days of incubation. The increased heart rate in the embryos exposed to EMF was associated with considerable increases in plasma T4 and T3 concentrations, which were recorded during the final stage of embryogenesis. The significant effect of the 100-MUT field on heart weight and blood AST levels in the embryos suggests that EMF has a direct effect on the physiological function of cardiac muscle. PMID- 23921351 TI - Effect of sex ratios, spiking and extra artificial insemination on the breeding efficiency of broiler breeders. AB - Since early fertility decline is a permanent problem of broiler breeders, the aim of this study was to test the effects of various sex ratios, spiking strategies and additional artificial inseminations (AI) on their breeding efficiency. Six breeder flocks were analysed during the whole reproduction cycle. In Flock A the sex ratio was maintained at 10% during the whole cycle (control), while in Flock B the number of males was increased to a final ratio of 16%. In Flocks C (technological control), D, E and F the ratio of males was gradually decreased from 10% to 6.5% until the end of the cycle. Moreover, at the age of 44 weeks in Flocks D and E 50 and 100% of cockerels were replaced by young ones, respectively, while in Flock F additional artificial inseminations were applied in the second half of the reproduction cycle. The increase of sperm transport was successful only in Groups B (increase in male numbers) and D (50% replacement of old cockerels with young ones); however, it was not sufficient for increasing the fertility rates in either group. Nor did additional artificial inseminations (Flock F) have an effect on fertility. As a conclusion, it can be established that increasing the sperm count in the hens' oviducts in any way could not improve fertility in the last third of the production cycle. The results also suggest that the expensive and labour-intensive spiking technique used in broiler breeder management is useless. The prime factor responsible for the shortened persistence of fertility may be the reduced ability of the female oviduct to accept and store sperm. PMID- 23921352 TI - The effect of embryo presence on the expression of peroxisome proliferator activated receptor (PPAR) genes in the porcine reproductive system during periimplantation. AB - This study was undertaken to determine the effect of the presence of embryos in the uterine horn on peroxisome proliferator activated receptors (PPARs; A, D, G) gene expression in the reproductive tissues of gilts subjected to a surgical procedure. The uterus consisted of one intact horn connected to the uterine corpus and the second horn detached from the uterine corpus but connected with the contiguous ovary. The gilts were hormonally stimulated and divided into two groups: the first group, inseminated (pregnant) and the second group (cyclic), with surgical procedure but not inseminated. The animals of both groups were slaughtered on day 14 of pregnancy or on day 14 of the oestrous cycle, respectively. PPARs mRNA abundance in the endometrium and the corpus luteum (CL) was analysed by quantitative real-time PCR. During pregnancy, PPARA and PPARD MUmRNA abundance in the porcine endometrium was significantly higher in the horn containing embryos than in the contralateral horn, where embryos were absent. The endometrial PPARG1 mRNA abundance did not differ between the two horns during pregnancy and the oestrous cycle, but a higher level of the transcript was observed during pregnancy when compared to the oestrous cycle. In the CL, there were no significant differences in PPARA and PPARDMU mRNA abundance between horns in pregnant or cyclic sows. However, there was a significant increase of PPARA and PPARD transcript level in the CL from cyclic compared with pregnant sows. The results of our study suggest that PPARA and PPARD have regulatory functions in early pregnancy, and they indicate that increased levels of endometrial gene expression are correlated with the presence of embryos in the uterine horn. Higher levels of PPARA and PPARD expression in the porcine CL on day 14 of the oestrous cycle than on day 14 of pregnancy suggest that both forms are involved in the regulation of CL functions. PMID- 23921353 TI - Phylogenetic studies of H3 low pathogenic avian influenza viruses isolated from wild mallards in Poland. AB - In order to study the variation of low pathogenic avian influenza viruses (AIV) of H3 subtype in the natural reservoir, partial genetic characterisation of four AIV isolates of H3 subtype, recovered from wild mallards in Poland in 2006-2010, was performed. Phylogenetic analysis clearly confirms that there is a constant flow of AIV H3 between wild birds in Eurasia and Africa, and, to a limited degree, to North America (Alaska), with an occasional spill-over to poultry. The analysis of the PA gene of one isolate from 2010 suggests that it is closely related to several HPAI H5N1 viruses belonging to clade 2.3.2 and that, therefore, a reassortment event has occurred recently between low pathogenic and H5N1 highly pathogenic AIV. PMID- 23921355 TI - Structured cone arrays for continuous and effective collection of micron-sized oil droplets from water. AB - Environmental protection agencies and the petroleum industry require effective methods to separate micron-sized oil droplets from water. However, for most existing separation methods, phase separation occurs in the oil-water mixture. The remaining micron-scale oil droplets, which are not affected by phase separation, are difficult to handle with conventional methods on a large scale because of either a lack of separation ability or drawbacks in throughput capacity. Here we develop an oleophilic array of conical needle structures for the collection of micron-sized oil droplets, inspired by the collection of similar sized water droplets on conical cactus spines. Underwater, these structures mimic cacti and can capture micron-sized oil droplets and continuously transport them towards the base of the conical needles. Materials with this structure show obvious advantages in micron-sized oil collection with high continuity and high throughput. PMID- 23921358 TI - Theoretical characterizations of the mechanism for the dimerization of monosilicic acid in basic solution. AB - The anionic mechanisms for the elementary dimerization reaction of monosilicic acid in basic aqueous solution have been characterized comprehensively using various ab initio methods. Many new insights into the silicate oligomerization reaction, which is fundamentally important in sol-gel chemistry, zeolite synthesis, and cement hydration, are presented in this work. Conformational dependence of the dimerization reaction is proposed in view of hundreds of conformations with various inter- and intramolecular hydrogen bonding patterns along the reaction routes. An alternative water cleavage route from the five coordinated silicon intermediate is revealed. The detour involves a six-center cyclic transition state, which is more preferable energetically than the well known four-center water removal step. By including explicit water molecules, the activation barrier of the four-center water cleavage path can be reduced considerably to be even lower than the first barrier of the Si-O bond formation. In contrast, the six-center detour is less affected by the additional water molecules due to the unfavorable geometric distortion. The new understanding of the dimerization mechanism could have considerable impact on the initial stages of silica nucleation. PMID- 23921356 TI - Organ allocation in adults with congenital heart disease listed for heart transplant: impact of ventricular assist devices. AB - BACKGROUND: Adults with congenital heart disease (CHD) listed for heart transplantation are rarely supported by ventricular assist devices (VADs). This may be a disadvantage to their priority for organ allocation. We sought to determine the relationship between VAD implantation and successful transplantation among patients listed for heart transplant. METHODS: Adults with CHD patients (N = 1,250) were identified from the United Network for Organ Sharing (UNOS) database from 1985 to 2010 and compared to patients without congenital etiology for heart failure (N = 59,606). VAD use at listing, listing status, status upgrades and reasons for upgrade prior to transplant were trended at 5-year intervals and appropriate statistical comparisons were made between groups. RESULTS: Since 1985, VAD use prior to transplant has increased significantly in patients without CHD, but not in CHD patients (17% vs 3% in 2006 to 2010, p < 0.0001). CHD patients were more likely to be listed as Status 2, compared to those without (66% vs 40%, p < 0.001 for 2006 to 2010), and less likely to be upgraded to Status 1 after listing (43% vs 55%, p = 0.03). Among those upgraded to Status 1, CHD patients were less likely to have a VAD at transplant than those without (3% vs 18%, p = 0.005). VAD use was more likely to result in death in CHD patients. CONCLUSIONS: VAD use is less common in CHD patients than in patients without CHD, both at the time of listing and transplantation. Reduced VAD use appears to contribute to lower listing status and organ allocation. These differences have grown more disparate over time. Separate criteria for organ allocation for CHD patients may be justified. PMID- 23921359 TI - A bibliometric analysis of European versus USA research in the field of addiction. Research on alcohol, narcotics, prescription drug abuse, tobacco and steroids 2001-2011. AB - BACKGROUND: To compare the publication and citation rate within the areas of drug abuse and dependence research in Europe with that in the USA. METHODS: This is a bibliometric study using the Thomson Reuters Web of Knowledge as data source, 40 key words were used as search terms, but certain scientific publications not concerning the issue were excluded. Scientific publications from Denmark, England, Finland, France, Germany, Italy, the Netherlands, Norway, Spain, Sweden, and the USA were studied. The number of publications in each country and in each year in addition to the citation indices for these publications was retrieved. RESULTS: Approximately two thirds of the publications came from the USA. Both in absolute and relative figures, Europe lagged behind. The trend over the last decade was a greater gap between the amount of research performed in Europe versus the USA. There were thematic differences. Smaller European countries had a greater relative publication rate. The citations were relatively evenly distributed. CONCLUSIONS: It has been claimed that 85% of the world's research within the field of drug abuse and dependence is carried out in the USA. This study challenges this figure, but European research within this field is lagging behind. PMID- 23921361 TI - Long term outcome in subfertile couples with isolated cervical factor. AB - OBJECTIVE: A previous randomized clinical trial (RCT) compared immediate treatment with intrauterine insemination (IUI) to expectant management for six months in subfertile couples with an isolated cervical factor. That study showed higher ongoing pregnancy rates in couples receiving intrauterine insemination. The current study compared the long-term effectiveness and costs of this intervention. STUDY DESIGN: We followed all couples (N=99) who were previously included in the RCT for three years after randomization and registered pregnancies and treatments. After the initial trial period, couples in both groups were offered further treatment according to local protocol. The primary outcome was an ongoing pregnancy after three years. RESULTS: After three years, there were 36 ongoing pregnancies in the immediate IUI group (N=51 couples) and 38 ongoing pregnancies in the expectant management group (N=48 couples). The ongoing pregnancy rates were 71% and 79% respectively (RR 0.89 (95% confidence interval (CI) 0.7-1.1)). CONCLUSIONS: In couples with an isolated cervical factor, a treatment strategy including immediate treatment with IUI does not result in higher ongoing pregnancy rates on the long term. Initial expectant management is therefore justified in these couples and identifying a cervical factor by a post-coital test is unnecessary. PMID- 23921360 TI - Chemoprevention of prostate cancer by d,l-sulforaphane is augmented by pharmacological inhibition of autophagy. AB - There is a preclinical evidence that the oral administration of d,l-sulforaphane (SFN) can decrease the incidence or burden of early-stage prostate cancer [prostatic intraepithelial neoplasia (PIN)] and well-differentiated cancer (WDC) but not late-stage poorly differentiated cancer (PDC). Because SFN treatment induces cytoprotective autophagy in cultured human prostate cancer cells, the present study tested the hypothesis that chemopreventive efficacy of SFN could be augmented by the pharmacologic inhibition of autophagy using chloroquine (CQ). Incidence of PDC characterized by prostate weight of more than 1 g was significantly lower in the SFN + CQ group than in control (P = 0.004), CQ group (P = 0.026), or SFN group (P = 0.002 by Fisher exact test). Average size of the metastatic lymph node was lower by about 42% in the SFN + CQ group than in control (P = 0.043 by Wilcoxon test). On the other hand, the SFN + CQ combination was not superior to SFN alone with respect to inhibition of incidence or burden of microscopic PIN or WDC. SFN treatment caused in vivo autophagy as evidenced by transmission electron microscopy. Mechanistic studies showed that prevention of prostate cancer and metastasis by the SFN + CQ combination was associated with decreased cell proliferation, increased apoptosis, alterations in protein levels of autophagy regulators Atg5 and phospho-mTOR, and suppression of biochemical features of epithelial-mesenchymal transition. Plasma proteomics identified protein expression signature that may serve as biomarker of SFN + CQ exposure/response. This study offers a novel combination regimen for future clinical investigations for prevention of prostate cancer in humans. PMID- 23921363 TI - Erratum. PMID- 23921362 TI - Repeated ovariopexy failure in recurrent adnexal torsion: combined approach and review of the literature. AB - Adnexal torsion is a well-known but poorly recognized gynecological emergency. Most cases are in the reproductive age group and many are related to ovarian and paraovarian masses. Adnexal torsion can also occur, however, in normal-looking ovaries with elongated utero-ovarian ligaments. The authors describe the case of a young woman presenting with a sixth recurrence of right adnexal torsion with polycystic ovaries. She had had two failed ovarian fixation efforts in the third and fifth laparoscopies. A combined ovarian fixation method is described, fixing the ovary to the pelvic side wall and shortening the utero-ovarian ligament, at elective surgery one month after the detorsion operation. Ovarian fixation after adnexal torsion is not standardized and best method of fixation remains unresolved. PMID- 23921364 TI - Changing patterns and determinants of natural capital in the Yangtze River Delta of China 2000-2010. AB - Natural capital (NC) is crucial to human existence and human well-being. Evaluating ecosystem services on a regional scale has presented tremendous theoretical, methodological and policy challenges. This study addresses the challenges by developing an interdisciplinary methodology, based on expert knowledge, and by focusing on the Yangtze River Delta of China. It evaluates the stock of NC, analyzes the characteristics of, and identifies the key drivers for, spatial and temporal change in NC in the deltaic region from 2000 to 2010. A main contribution is the novel incorporation of remote sensing data that explains the dynamics of the spatio-temporal change in land use and a set of ecosystem service indicators derived from it. The study focuses on key indicators for key ecosystem services related to carbon sequestration, grain production and water supply. The indictors reflect the spatial heterogeneity of NC across diverse ecosystems in the region. Each indicator builds on land use configuration and land use composition information derived from 250 m 16-day MODIS and Landsat TM remote sensing data for 2000 and 2010, with adjustment parameters being constructed. The regional evaluation shows an overall degradation of ecosystem services, reducing total NC by 10.4% (or 8.44 billion yuan) in 2000-2010. The spatial distribution of NC exhibits a declining pattern from the south to the north of the delta. At the city level, 15 out of 16 major cities in the region have experienced dramatic loss of NC, and this pattern is significantly correlated with rapid urbanization, population growth and industrialization. Land use/land cover change and deteriorating water quality are dominant factors causing NC depletion, while increased grain productivity and environmental policies help offset the NC losses. Outcomes of this research are useful to policy makers to mitigate the declines in NC through balancing the growth between economy and population. PMID- 23921365 TI - Early-life residential exposure to soil components in rural areas and childhood respiratory health and allergy. AB - The increase in asthma and allergies has been attributed to declining exposure to environmental microorganisms. The main source of these is soil, the composition of which varies geographically and which is a major component (40-45%) of household dust. Our hypothesis-generating study aimed to investigate associations between soil components, respiratory health and allergy in a Scottish birth cohort. The cohort was recruited in utero in 1997/8, and followed up at one, two and five years for the development of wheezing, asthma and eczema. Lung function, exhaled nitric oxide and allergic sensitization were measured at age five in a subset. The Scottish Soils Database held at The James Hutton Institute was linked to the birth cohort data by the residential postcode at birth and five years. The soil database contained information on size separates, organic matter concentration, pH and a range of inorganic elements. Soil and clinical outcome data were available for 869, 790 and 727 children at one, two and five years. Three hundred and fifty nine (35%) of children had the same address at birth and five years. No associations were found between childhood outcomes and soil content in the residential area at age five. The soil silt content (2-20 MUm particle size) of the residential area at birth was associated with childhood wheeze (adjusted OR 1.20, 95% CI [1.05; 1.37]), wheeze without a cold (1.41 [1.18; 1.69]), doctor-diagnosed asthma (1.54 [1.04; 2.28]), lung function (FEV1: beta -0.025 [-0.047;-0.001]) and airway inflammation (FENO: beta 0.15 [0.03; 0.27]) at age five, but not with allergic status or eczema. Whilst residual confounding is the most likely explanation for the associations reported, the results of this study lead us to hypothesise that early life exposure to residential soil silt may adversely influence childhood respiratory health, possibly because of the organic components of silt. PMID- 23921366 TI - Airborne particulate polycyclic aromatic hydrocarbon (PAH) pollution in a background site in the North China Plain: concentration, size distribution, toxicity and sources. AB - The size-fractionated characteristics of particulate polycyclic aromatic hydrocarbons (PAHs) were studied from January 2011 to October 2011 using a Micro orifice Uniform Deposit Impactor (MOUDI) at the Yellow River Delta National Nature Reserve (YRDNNR), a background site located in the North China Plain. The average annual concentration of total PAHs in the YRDNNR (18.95 +/- 16.51 ng/m(3)) was lower than that in the urban areas of China; however, it was much higher than that in other rural or remote sites in developed countries. The dominant PAHs, which were found in each season, were fluorene (5.93%-26.80%), phenanthrene (8.17%-26.52%), fluoranthene (15.23%-27.12%) and pyrene (9.23% 16.31%). A bimodal distribution was found for 3-ring PAHs with peaks at approximately 1.0-1.8 MUm and 3.2-5.6 MUm; however, 4-6 ring PAHs followed a nearly unimodal distribution, with the highest peak in the 1.0-1.8 MUm range. The mass median diameter (MMD) values for the total PAHs averaged 1.404, 1.467, 1.218 and 0.931 MUm in spring, summer, autumn and winter, respectively. The toxicity analysis indicated that the carcinogenic potency of particulate PAHs existed primarily in the <1.8 MUm size range. Diagnostic ratios and PCA analysis indicated that the PAHs in aerosol particles were mainly derived from coal combustion. In addition, back-trajectory calculations demonstrated that atmospheric PAHs were produced primarily by local anthropogenic sources. PMID- 23921367 TI - High levels of PAH-metabolites in urine of e-waste recycling workers from Agbogbloshie, Ghana. AB - The informal recycling of electronic waste (e-waste) is an emerging source of environmental pollution in Africa. Among other toxins, polycyclic aromatic hydrocarbons (PAHs) are a major health concern for exposed individuals. In a cross-sectional study, the levels of PAH metabolites in the urine of individuals working on one of the largest e-waste recycling sites of Africa, and in controls from a suburb of Accra without direct exposure to e-waste recycling activities, were investigated. Socioeconomic data, basic health data and urine samples were collected from 72 exposed individuals and 40 controls. In the urine samples, concentrations of the hydroxylate PAH metabolites (OH-PAH) 1-hydroxyphenanthrene (1-OH-phenanthrene), the sum of 2- and 9-hydroxyphenanthrene (2-/9-OH phenanthrene), 3-hydroxyphenanthrene (3-OH-phenanthrene), 4-hydroxyphenanthrene (4-OH-phenanthrene) and 1-hydroxypyrene (1-OH-pyrene), as well as cotinine and creatinine, were determined. In the exposed group, median urinary concentrations were 0.85 MUg/g creatinine for 1-OH-phenanthrene, 0.54 MUg/g creatinine for 2-/9 OH-phenanthrene, 0.99 MUg/g creatinine for 3-OH-phenanthrene, 0.22 MUg/g creatinine for 4-OH-phenanthrene, and 1.33 MUg/g creatinine for 1-OH-pyrene, all being significantly higher compared to the control group (0.55, 0.37, 0.63, 0.11 and 0.54 MUg/g creatinine, respectively). Using a multivariate linear regression analysis including sex, cotinine and tobacco smoking as covariates, exposure to e waste recycling activities was the most important determinant for PAH exposure. On physical examination, pathological findings were rare, but about two thirds of exposed individuals complained about cough, and one quarter about chest pain. In conclusion, we observed significantly higher urinary PAH metabolite concentrations in individuals who were exposed to e-waste recycling compared to controls who were not exposed to e-waste recycling activities. The impact of e waste recycling on exposure to environmental toxins and health of individuals living in the surroundings of e-waste recycling sites warrant further investigation. PMID- 23921368 TI - Muscle activity during running with different body-weight-support mechanisms: aquatic environment versus body-weight-support treadmill. AB - BACKGROUND: Body-weight (BW) support during running can be accomplished using deep-water running (DWR; 100% BW support) and a lower-body positive-pressure (LBPP) treadmill. PURPOSE: To compare lower-extremity muscle activity during DWR and running on an LBPP treadmill at matched stride frequency. METHODS: Eight subjects (40 +/- 6.5 y, 173 +/- 7.2 cm, 66.9 +/- 11.7 kg) completed 4 running conditions all at a preferred stride frequency that was determined while running with no support. Two conditions were running on the LBPP treadmill at 60% and 80% of BW, and the other 2 conditions were different DWR styles: high knee (DWR-HK) and cross-country (DWR-CC). Average (AVG) and root-mean-square (RMS) electromyography (rectus femoris, biceps femoris, gastrocnemius, and tibialis anterior) were each compared among conditions (repeated-measures analysis of variance). RESULTS: Results for AVG and RMS variables were identical for statistical tests for each muscle. Rectus femoris electromyography during DWR-HK was lower than that of DWR-CC (P < .05) but not different than either 60% BW or 80% BW (P > .05). Biceps femoris electromyography was less during DWR-HK than DWR CC (P < .05) but greater during DWR-HK than either BW 60% or BW 80% (P < .05). Neither gastrocnemius nor tibialis anterior electromyography differed between conditions (P > .05). CONCLUSION: Neither the mechanism of BW support nor style of DWR influenced gastrocnemius or tibialis anterior muscle activity during running at the same stride frequency. However, rectus femoris and biceps femoris muscle activity were influenced by not only the mechanism of BW support but also the style of DWR. PMID- 23921371 TI - Aortic atheromas and stroke: review of literature. AB - Aortic atherosclerosis is the most common disease of the aortic arch, and patients with complicated aortic atheroma should be considered at risk of stroke. There is indeed controversy about whether and how to treat these patients. This review analyzes the literature data about the epidemiology, the association between atheroma and stroke, the classification of aortic atheroma plaques, the imaging diagnostic process, the therapeutics options, and the clinical trials performed in this clinical setting. PMID- 23921373 TI - Inhibitory effects of Diospyros kaki in a model of allergic inflammation: role of cAMP, calcium and nuclear factor-kappaB. AB - Diospyros kaki (D. kaki) has been cultivated throughout Eastern Asia for hundreds of years. D. kaki contains various biological active compounds, such as amino acids, carotenoids, flavonoids, tannins, catechins and vitamin A. Previous studies have shown that D. kaki has beneficial effects on homeostasis, constipation, hypertension, atherosclerosis and allergic dermatitis and is a good source of antioxidants, polyphenols and dietary fiber. However, the anti-allergic and anti-inflammatory effects of D. kaki have not yet been elucidated. This study aimed to investigate the protective effects of the aqueous extract of Diospyros kaki (AEDK) on mast cell-mediated allergic inflammation and to determine its possible mechanisms of action by using in vitro and in vivo mast cell-based models. The cAMP and intracellular calcium levels were measured to clarify the mechanisms by which AEDK inhibits the release of histamine from mast cells. AEDK inhibited the release of histamine and beta-hexosaminidase from mast cells by modulating cAMP and intracellular calcium levels. We also measured the expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. AEDK decreased gene expression and the secretion of the pro-inflammatory cytokines, TNF-alpha and IL-1beta by inhibiting nuclear factor kappaB. In addition, AEDK inhibited systemic and cutaneous allergic reaction. The inhibitory effects of AEDK on allergic reaction and the release of histamine were found to be similar to those of disodium cromoglycate, a known anti-allergic drug. To isolate the active component of AEDK, activity-guided fractionation was performed, based on the inhibitory effects on systemic anaphylaxis. Catechin was identified as an active compound. The present findings provide evidence that AEDK inhibits allergic inflammation and suggest the therapeutic application of AEDK in allergic inflammatory disorders. PMID- 23921375 TI - Comparison of immunoglobulin E measurements on IMMULITE and ImmunoCAP in samples consisting of allergen-specific mouse-human chimeric monoclonal antibodies towards allergen extracts and four recombinant allergens. AB - BACKGROUND: Specific immunoglobulin E (IgE) antibody in vitro tests are performed on enzyme immunoassay systems. Poor agreement among systems has been reported and comparisons have been made exclusively with allergen extracts - not with recombinant allergens. Here we compare the ImmunoCAP and the IMMULITE systems. METHODS: Ten patient samples with positive IgE toward egg white, birch pollen or cat or dog dander were compared using allergen extracts or the recombinant allergens Gal d 1, Bet v 1, Fel d 1 and Can f 1 with the two assay systems. Comparisons were also performed using four monoclonal mouse-human chimeric IgE antibodies specific for the same allergenic components. RESULTS: IMMULITE estimated a higher allergen-specific IgE concentration in sera than ImmunoCAP when testing with allergen extracts as well as recombinant allergens. The chimeric antibodies gave an equivalent response in the total IgE and specific IgE (sIgE) with an average ratio of 1.08 (range 0.9-1.3) on ImmunoCAP. In contrast, IMMULITE exhibited sIgE signals that were substantially higher than the summed level of IgE for all four chimeric antibodies (average ratio 2.96 and range 1.7 4.3). CONCLUSION: Comparison using chimeric antibodies allowed the evaluation of the true performance of the systems. ImmunoCAP measured total IgE and sIgE equally, whereas IMMULITE displayed higher sIgE signals when compared to the summed level of total IgE for all four chimeric antibodies. Results obtained with the two assay systems are not interchangeable by means of mathematical conversion. PMID- 23921376 TI - Migraine and risk of dementia: a nationwide retrospective cohort study. AB - OBJECTIVE: Migraines are one of the most common neurological disorders. Dementia is a neurodegenerative disease characterized by slow progressive memory loss and cognitive dysfunction. This retrospective cohort study investigates the association between migraines and dementia using a nationwide population-based database in Taiwan. METHODS: We retrieved the data analyzed in this study from the National Health Insurance Research database (NHIRD) in Taiwan. We used multivariate Cox proportion-hazards regression models to assess the effects of migraines on the risk of dementia after adjusting for sociodemographic characteristics and comorbidities. RESULTS: The migraine cohort had a higher prevalence of diabetes, hypertension, coronary artery disease, head injury and depression at baseline (p < 0.0001). After adjusting the covariates, migraine patients had a 1.33-fold higher risk of developing dementia [hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.22-1.46]. The sex-specific incidence rate of dementia was higher in men than in women in both cohorts, with an HR of 1.09 (95% CI 1.00-1.18) for men compared to women. Kaplan-Meier analysis shows that the cumulative incidence of dementia was 1.48% greater in the migraine cohort than in the nonmigraine cohort (log-rank test, p < 0.0001). CONCLUSIONS: This study shows that migraines are associated with a future higher risk of dementia after adjusting for comorbidities. Specifically, the association between migraine and dementia is greater in young adults than in older adults. PMID- 23921374 TI - An analysis of the structural and functional similarities of insect hemocytes and mammalian phagocytes. AB - The insect immune response demonstrates a number of structural and functional similarities to the innate immune system of mammals. As a result of these conserved features insects have become popular choices for evaluating the virulence of microbial pathogens or for assessing the efficacy of antimicrobial agents and give results which are comparable to those that can be obtained using mammals. Analysis of the cellular component of the insect and mammalian immune systems demonstrates many similarities. Insect hemocytes recognize pathogens and phagocytose material in a similar manner to neutrophils. The killing of ingested microbes is achieved in both cell types by the production of superoxide and by the release of enzymes in the process of degranulation. Insect hemocytes and mammalian neutrophils are sensitive to the same inhibitors. This review highlights the strong similarities between the phagocytic cells of both groups of animals and demonstrates the potential benefits of using selected insects as in vivo screening systems. PMID- 23921377 TI - Polymersome-mediated intracellular delivery of antibiotics to treat Porphyromonas gingivalis-infected oral epithelial cells. AB - The gram-negative anaerobe Porphyromonas gingivalis colonizes the gingival crevice and is etiologically associated with periodontal disease that can lead to alveolar bone damage and resorption, promoting tooth loss. Although susceptible to antibiotics, P. gingivalis can evade antibiotic killing by residing within gingival keratinocytes. This provides a reservoir of organisms that may recolonize the gingival crevice once antibiotic therapy is complete. Polymersomes are nanosized amphiphilic block copolymer vesicles that can encapsulate drugs. Cells internalize polymersomes by endocytosis into early endosomes, where they are disassembled by the low pH, causing intracellular release of their drug load. In this study, polymersomes were used as vehicles to deliver antibiotics in an attempt to kill intracellular P. gingivalis within monolayers of keratinocytes and organotypic oral mucosal models. Polymersome-encapsulated metronidazole or doxycycline, free metronidazole, or doxycycline, or polymersomes alone as controls, were used, and the number of surviving intracellular P. gingivalis was quantified after host cell lysis. Polymersome-encapsulated metronidazole or doxycycline significantly (P<0.05) reduced the number of intracellular P. gingivalis in both monolayer and organotypic cultures compared to free antibiotic or polymersome alone controls. Polymersomes are effective delivery vehicles for antibiotics that do not normally gain entry to host cells. This approach could be used to treat recurrent periodontitis or other diseases caused by intracellular dwelling organisms. PMID- 23921378 TI - Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission. AB - Drp1 (dynamin-related protein 1) is recruited to both mitochondrial and peroxisomal membranes to execute fission. Fis1 and Mff are Drp1 receptor/effector proteins of mitochondria and peroxisomes. Recently, MiD49 and MiD51 were also shown to recruit Drp1 to the mitochondrial surface; however, different reports have ascribed opposing roles in fission and fusion. Here, we show that MiD49 or MiD51 overexpression blocked fission by acting in a dominant-negative manner by sequestering Drp1 specifically at mitochondria, causing unopposed fusion events at mitochondria along with elongation of peroxisomes. Mitochondrial elongation caused by MiD49/51 overexpression required the action of fusion mediators mitofusins 1 and 2. Furthermore, at low level overexpression when MiD49 and MiD51 form discrete foci at mitochondria, mitochondrial fission events still occurred. Unlike Fis1 and Mff, MiD49 and MiD51 were not targeted to the peroxisomal surface, suggesting that they specifically act to facilitate Drp1-directed fission at mitochondria. Moreover, when MiD49 or MiD51 was targeted to the surface of peroxisomes or lysosomes, Drp1 was specifically recruited to these organelles. Moreover, the Drp1 recruitment activity of MiD49/51 appeared stronger than that of Mff or Fis1. We conclude that MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and suggest that they provide specificity to the division of mitochondria. PMID- 23921379 TI - Actin monomers activate inverted formin 2 by competing with its autoinhibitory interaction. AB - INF2 is an unusual formin protein in that it accelerates both actin polymerization and depolymerization, the latter through an actin filament severing activity. Similar to other formins, INF2 possesses a dimeric formin homology 2 (FH2) domain that binds filament barbed ends and is critical for polymerization and depolymerization activities. In addition, INF2 binds actin monomers through its diaphanous autoregulatory domain (DAD) that resembles a Wiskott-Aldrich syndrome protein homology 2 (WH2) sequence C-terminal to the FH2 that participates in both polymerization and depolymerization. INF2-DAD is also predicted to participate in an autoinhibitory interaction with the N-terminal diaphanous inhibitory domain (DID). In this work, we show that actin monomer binding to the DAD of INF2 competes with the DID/DAD interaction, thereby activating actin polymerization. INF2 is autoinhibited in cells because mutation of a key DID residue results in constitutive INF2 activity. In contrast, purified full-length INF2 is constitutively active in biochemical actin polymerization assays containing only INF2 and actin monomers. Addition of proteins that compete with INF2-DAD for actin binding (profilin or the WH2 from Wiskott-Aldrich syndrome protein) decrease full-length INF2 activity while not significantly decreasing activity of an INF2 construct lacking the DID sequence. Profilin mediated INF2 inhibition is relieved by an anti-N-terminal antibody for INF2 that blocks the DID/DAD interaction. These results suggest that free actin monomers can serve as INF2 activators by competing with the DID/DAD interaction. We also find that, in contrast to past results, the DID-containing N terminus of INF2 does not directly bind the Rho GTPase Cdc42. PMID- 23921380 TI - The switch-associated protein 70 (SWAP-70) bundles actin filaments and contributes to the regulation of F-actin dynamics. AB - Coordinated assembly and disassembly of actin into filaments and higher order structures such as stress fibers and lamellipodia are fundamental for cell migration and adhesion. However, the precise spatiotemporal regulation of F-actin structures is not completely understood. SWAP-70, a phosphatidylinositol 3,4,5 trisphosphate-interacting, F-actin-binding protein, participates in actin rearrangements through yet unknown mechanisms. Here, we show that SWAP-70 is an F actin-bundling protein that oligomerizes through a Gln/Glu-rich stretch within a coiled-coil region. SWAP-70 bundles filaments in parallel and anti-parallel fashion through its C-terminal F-actin binding domain and delays dilution-induced F-actin depolymerization. We further demonstrate that SWAP-70 co-localizes and directly interacts with cofilin, an F-actin severing and depolymerization factor, and contributes to the regulation of cofilin activity in vivo. In line with these activities, upon stem cell factor stimulation, murine bone marrow-derived mast cells lacking SWAP-70 display aberrant regulation of F-actin and actin free barbed ends dynamics. Moreover, proper stem cell factor-dependent cofilin activation via dephosphorylation and subcellular redistribution into a detergent resistant cytoskeletal compartment also require SWAP-70. Together, these findings reveal an important role of SWAP-70 in the dynamic spatiotemporal regulation of F actin networks. PMID- 23921381 TI - BmCREC is an endoplasmic reticulum (ER) resident protein and required for ER/Golgi morphology. AB - Silkworm posterior silkgland is a model for studying intracellular trafficking. Here, using this model, we identify several potential cargo proteins of BmKinesin 1 and focus on one candidate, BmCREC. BmCREC (also known as Bombyx mori DNA supercoiling factor, BmSCF) was previously proposed to supercoil DNA in the nucleus. However, we show here that BmCREC is localized in the ER lumen. Its C terminal tetrapeptide HDEF is recognized by the KDEL receptor, and subsequently it is retrogradely transported by coat protein I (COPI) vesicles to the ER. Lacking the HDEF tetrapeptide of BmCREC or knocking down COPI subunits results in decreased ER retention and simultaneously increased secretion of BmCREC. Furthermore, we find that BmCREC knockdown markedly disrupts the morphology of the ER and Golgi apparatus and leads to a defect of posterior silkgland tube expansion. Together, our results clarify the ER retention mechanism of BmCREC and reveal that BmCREC is indispensable for maintaining ER/Golgi morphology. PMID- 23921382 TI - Substrate recognition and hydrolysis by a family 50 exo-beta-agarase, Aga50D, from the marine bacterium Saccharophagus degradans. AB - The bacteria that metabolize agarose use multiple enzymes of complementary specificities to hydrolyze the glycosidic linkages in agarose, a linear polymer comprising the repeating disaccharide subunit of neoagarobiose (3,6-anhydro-l galactose-alpha-(1,3)-d-galactose) that are beta-(1,4)-linked. Here we present the crystal structure of a glycoside hydrolase family 50 exo-beta-agarase, Aga50D, from the marine microbe Saccharophagus degradans. This enzyme catalyzes a critical step in the metabolism of agarose by S. degradans through cleaving agarose oligomers into neoagarobiose products that can be further processed into monomers. The crystal structure of Aga50D to 1.9 A resolution reveals a (beta/alpha)8-barrel fold that is elaborated with a beta-sandwich domain and extensive loops. The structures of catalytically inactivated Aga50D in complex with non-hydrolyzed neoagarotetraose (2.05 A resolution) and neoagarooctaose (2.30 A resolution) provide views of Michaelis complexes for a beta-agarase. In these structures, the d-galactose residue in the -1 subsite is distorted into a (1)S3 skew boat conformation. The relative positioning of the putative catalytic residues are most consistent with a retaining catalytic mechanism. Additionally, the neoagarooctaose complex showed that this extended substrate made substantial interactions with the beta-sandwich domain, which resembles a carbohydrate binding module, thus creating additional plus (+) subsites and funneling the polymeric substrate through the tunnel-shaped active site. A synthesis of these results in combination with an additional neoagarobiose product complex suggests a potential exo-processive mode of action of Aga50D on the agarose double helix. PMID- 23921383 TI - Comprehensive analysis of microRNA (miRNA) targets in breast cancer cells. AB - MicroRNAs (miRNAs) regulate mRNA stability and translation through the action of the RNAi-induced silencing complex. In this study, we systematically identified endogenous miRNA target genes by using AGO2 immunoprecipitation (AGO2-IP) and microarray analyses in two breast cancer cell lines, MCF7 and MDA-MB-231, representing luminal and basal-like breast cancer, respectively. The expression levels of ~70% of the AGO2-IP mRNAs were increased by DROSHA or DICER1 knockdown. In addition, integrated analysis of miRNA expression profiles, mRNA-AGO2 interaction, and the 3'-UTR of mRNAs revealed that >60% of the AGO2-IP mRNAs were putative targets of the 50 most abundantly expressed miRNAs. Together, these results suggested that the majority of the AGO2-associated mRNAs were bona fide miRNA targets. Functional enrichment analysis uncovered that the AGO2-IP mRNAs were involved in regulation of cell cycle, apoptosis, adhesion/migration/invasion, stress responses (e.g. DNA damage and endoplasmic reticulum stress and hypoxia), and cell-cell communication (e.g. Notch and Ephrin signaling pathways). A role of miRNAs in regulating cell migration/invasion and stress response was further defined by examining the impact of DROSHA knockdown on cell behaviors. We demonstrated that DROSHA knockdown enhanced cell migration and invasion, whereas it sensitized cells to cell death induced by suspension culture, glucose depletion, and unfolding protein stress. Data from an orthotopic xenograft model showed that DROSHA knockdown resulted in reduced growth of primary tumors but enhanced lung metastasis. Taken together, these results suggest that miRNAs collectively function to promote survival of tumor cells under stress but suppress cell migration/invasion in breast cancer cells. PMID- 23921384 TI - TssK is a trimeric cytoplasmic protein interacting with components of both phage like and membrane anchoring complexes of the type VI secretion system. AB - The Type VI secretion system (T6SS) is a macromolecular machine that mediates bacteria-host or bacteria-bacteria interactions. The T6SS core apparatus assembles from 13 proteins that form two sub-assemblies: a phage-like complex and a trans-envelope complex. The Hcp, VgrG, TssE, and TssB/C subunits are structurally and functionally related to components of the tail of contractile bacteriophages. This phage-like structure is thought to be anchored to the membrane by a trans-envelope complex composed of the TssJ, TssL, and TssM proteins. However, how the two sub-complexes are connected remains unknown. Here we identify TssK, a protein that establishes contacts with the two T6SS sub complexes through direct interactions with TssL, Hcp, and TssC. TssK is a cytoplasmic protein assembling trimers that display a three-armed shape, as revealed by TEM and SAXS analyses. Fluorescence microscopy experiments further demonstrate the requirement of TssK for sheath assembly. Our results suggest a central role for TssK by linking both complexes during T6SS assembly. PMID- 23921385 TI - The Bin/amphiphysin/Rvs (BAR) domain protein endophilin B2 interacts with plectin and controls perinuclear cytoskeletal architecture. AB - Proteins of the Bin/amphiphysin/Rvs (BAR) domain superfamily are essential in controlling the shape and dynamics of intracellular membranes. Here, we present evidence for the unconventional function of a member of the endophilin family of BAR and Src homology 3 domain-containing proteins, namely endophilin B2, in the perinuclear organization of intermediate filaments. Using mass spectrometry analysis based on capturing endophilin B2 partners in in situ pre-established complexes in cells, we unravel the interaction of endophilin B2 with plectin 1, a variant of the cytoskeleton linker protein plectin as well as with vimentin. Endophilin B2 directly binds the N-terminal region of plectin 1 via Src homology 3-mediated interaction and vimentin indirectly via plectin-mediated interaction. The relevance of these interactions is strengthened by the selective and drastic reorganization of vimentin around nuclei upon overexpression of endophilin B2 and by the extensive colocalization of both proteins in a meshwork of perinuclear filamentous structures. By generating mutants of the endophilin B2 BAR domain, we show that this phenotype requires the BAR-mediated membrane binding activity of endophilin B2. Plectin 1 or endophilin B2 knockdown using RNA interference disturbed the perinuclear organization of vimentin. Altogether, these data suggest that the endophilin B2-plectin 1 complex functions as a membrane anchoring device organizing and stabilizing the perinuclear network of vimentin filaments. Finally, we present evidence for the involvement of endophilin B2 and plectin 1 in nuclear positioning in individual cells. This points to the potential importance of the endophilin B2-plectin complex in the biological functions depending on nuclear migration and positioning. PMID- 23921387 TI - Spectrin domain of eukaryotic initiation factor 3a is the docking site for formation of the a:b:i:g subcomplex. AB - eIF3a (eukaryotic translation initiation factor 3a), one of the core subunits of the eIF3 complex, has been implicated in regulating translation of different mRNAs and in tumorigenesis. A subcomplex consisting of eIF3a, eIF3b, eIF3g, and eIF3i (eIF3(a:b:i:g)) has also been identified. However, how eIF3a participates in translational regulation and in formation of the eIF3(a:b:i:g) subcomplex remain to be solved. In this study, we used the tandem affinity purification approach in combination with tandem MS/MS and identified the spectrin domain of eIF3a as the docking site for the formation of eIF3(a:b:i:g) subcomplex. Although eIF3b and eIF3i bind concurrently to the spectrin domain of eIF3a within ~10-15 amino acids apart, eIF3g binds to eIF3a indirectly via binding to the carboxyl terminal domain of eIF3b. The binding of eIF3b to the spectrin domain of eIF3a occurs in its RNA recognition motif domain where eIF3j also binds in a mutually exclusive manner. Together, we conclude that the spectrin domain of eIF3a is responsible for the formation of eIF3(a:b:i:g) subcomplex and, because of mutually exclusive nature of bindings of eIF3a and eIF3j to eIF3b, different subcomplexes of eIF3 likely exist and may perform noncanonical functions in translational regulation. PMID- 23921386 TI - ATP and AMP mutually influence their interaction with the ATP-binding cassette (ABC) adenylate kinase cystic fibrosis transmembrane conductance regulator (CFTR) at separate binding sites. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel in the ATP-binding cassette (ABC) transporter protein family. In the presence of ATP and physiologically relevant concentrations of AMP, CFTR exhibits adenylate kinase activity (ATP + AMP &lrarr2; 2 ADP). Previous studies suggested that the interaction of nucleotide triphosphate with CFTR at ATP-binding site 2 is required for this activity. Two other ABC proteins, Rad50 and a structural maintenance of chromosome protein, also have adenylate kinase activity. All three ABC adenylate kinases bind and hydrolyze ATP in the absence of other nucleotides. However, little is known about how an ABC adenylate kinase interacts with ATP and AMP when both are present. Based on data from non-ABC adenylate kinases, we hypothesized that ATP and AMP mutually influence their interaction with CFTR at separate binding sites. We further hypothesized that only one of the two CFTR ATP binding sites is involved in the adenylate kinase reaction. We found that 8 azidoadenosine 5'-triphosphate (8-N3-ATP) and 8-azidoadenosine 5'-monophosphate (8-N3-AMP) photolabeled separate sites in CFTR. Labeling of the AMP-binding site with 8-N3-AMP required the presence of ATP. Conversely, AMP enhanced photolabeling with 8-N3-ATP at ATP-binding site 2. The adenylate kinase active center probe P(1),P(5)-di(adenosine-5') pentaphosphate interacted simultaneously with an AMP-binding site and ATP-binding site 2. These results show that ATP and AMP interact with separate binding sites but mutually influence their interaction with the ABC adenylate kinase CFTR. They further indicate that the active center of the adenylate kinase comprises ATP-binding site 2. PMID- 23921388 TI - Identification and characterization of a novel human methyltransferase modulating Hsp70 protein function through lysine methylation. AB - Hsp70 proteins constitute an evolutionarily conserved protein family of ATP dependent molecular chaperones involved in a wide range of biological processes. Mammalian Hsp70 proteins are subject to various post-translational modifications, including methylation, but for most of these, a functional role has not been attributed. In this study, we identified the methyltransferase METTL21A as the enzyme responsible for trimethylation of a conserved lysine residue found in several human Hsp70 (HSPA) proteins. This enzyme, denoted by us as HSPA lysine (K) methyltransferase (HSPA-KMT), was found to catalyze trimethylation of various Hsp70 family members both in vitro and in vivo, and the reaction was stimulated by ATP. Furthermore, we show that HSPA-KMT exclusively methylates 70-kDa proteins in mammalian protein extracts, demonstrating that it is a highly specific enzyme. Finally, we show that trimethylation of HSPA8 (Hsc70) has functional consequences, as it alters the affinity of the chaperone for both the monomeric and fibrillar forms of the Parkinson disease-associated protein alpha-synuclein. PMID- 23921389 TI - Structural basis of subtilase cytotoxin SubAB assembly. AB - Pathogenic strains of Escherichia coli produce a number of toxins that belong to the AB5 toxin family, which comprise a catalytic A-subunit that induces cellular dysfunction and a B-pentamer that recognizes host glycans. Although the molecular actions of many of the individual subunits of AB5 toxins are well understood, how they self-associate and the effect of this association on cytotoxicity are poorly understood. Here we have solved the structure of the holo-SubAB toxin that, in contrast to other AB5 toxins whose molecular targets are located in the cytosol, cleaves the endoplasmic reticulum chaperone BiP. SubA interacts with SubB in a similar manner to other AB5 toxins via the A2 helix and a conserved disulfide bond that joins the A1 domain with the A2 helix. The structure revealed that the active site of SubA is not occluded by the B-pentamer, and the B-pentamer does not enhance or inhibit the activity of SubA. Structure-based sequence comparisons with other AB5 toxin family members, combined with extensive mutagenesis studies on SubB, show how the hydrophobic patch on top of the B-pentamer plays a dominant role in binding the A-subunit. The structure of SubAB and the accompanying functional characterization of various mutants of SubAB provide a framework for understanding the important role of the B-pentamer in the assembly and the intracellular trafficking of this AB5 toxin. PMID- 23921390 TI - Bacterial division proteins FtsZ and ZipA induce vesicle shrinkage and cell membrane invagination. AB - Permeable vesicles containing the proto-ring anchoring ZipA protein shrink when FtsZ, the main cell division protein, polymerizes in the presence of GTP. Shrinkage, resembling the constriction of the cytoplasmic membrane, occurs at ZipA densities higher than those found in the cell and is modulated by the dynamics of the FtsZ polymer. In vivo, an excess of ZipA generates multilayered membrane inclusions within the cytoplasm and causes the loss of the membrane function as a permeability barrier. Overproduction of ZipA at levels that block septation is accompanied by the displacement of FtsZ and two additional division proteins, FtsA and FtsN, from potential septation sites to clusters that colocalize with ZipA near the membrane. The results show that elementary constriction events mediated by defined elements involved in cell division can be evidenced both in bacteria and in vesicles. PMID- 23921392 TI - Winter cold influences the spatial and age distributions of the North American treehole mosquito Anopheles barberi. AB - We conducted experiments to assess the importance of winter cold and photoperiod as factors affecting the spatial and age distributions of overwintering larvae of the treehole mosquito Anopheles barberi. Larval dormancy in A. barberi was induced by photoperiods with 14.75 h of light or less per 24 h cycle. About 75% of the larvae entering dormancy were in the second instar regardless of photoperiod. Dormant second instar larvae survived freezing at-15 degrees C for 24 h better than dormant third instar larvae. Larvae were more likely to survive freezing at-15 degrees C in water from treeholes in which they were commonly found in nature than in water from treeholes in which they were unlikely to occur. Female oviposition was significantly higher into water from treeholes in which larvae were likely to be found than in either water from treeholes in which larvae were not commonly found or distilled water. These findings suggest that, in the northern part of its range, the distribution of A. barberi and the age structure of overwintering cohorts are influenced by extreme winter cold. The mechanisms responsible for the distribution of larvae and the overwintering age structure are, respectively, female oviposition behavior and larval photoperiodism. PMID- 23921393 TI - Parasitoid pressure and the radiation of a gallforming group (Cecidomyiidae: Asphondylia spp.) on creosote bush (Larrea tridentata). AB - We tested the Enemy Impact Hypothesis, which predicts that communities of one tropic level are organized by the tropic level above. In the case of gallforming insect communities, the hypothesis predicts that gall morphology will diverge, minimizing the number of parasitoids shared among species. We used the monophyletic group of gallforming cecidomyiids (Asphondylia spp.) on creosote bush (Larrea tridentata) to test this hypothesis, predicting that species with thicker gall walls should exclude species of parasitoids with shorter ovipositors and have lower levels of parasitism. Of 17 parasitoid species reared from Asphondylia galls on creosote bush, 9 accounted for over 98% of parasitism. Seven of these 9 species had ovipositors long enough to penetrate 10 of 13 gall morphs measured. There was no significant relationship between gall wall thickness and number of associated parasitoid species (r (2)=0.01, P>0.05, n=13). There was no relationship between gall wall thickness and types of parasitoid species colonizing galls: parasitoids with the shortest ovipositors colonized all types of gall morphs and were dominant members of the parasitoid assemblages in galls with the thickest walls. Ultimately, there were no significant differences in percent parasitism among Asphondylia species, regardless of gall wall thickness. We found no difference in numbers of associated parasitoids or percent parasitism in galls with different textures (e.g. hairy versus smooth), different locations on the plant or different phenologies. Our results suggest that enemy impact has not influenced the diversity of this gall community. Gall wall thickness, phenology, location on the plant and surface structure do not appear to influence the distribution of parasitoid species. Other explanations are offered to account for diversity in gall morphology among these species. PMID- 23921391 TI - The solution structure of heparan sulfate differs from that of heparin: implications for function. AB - The highly sulfated polysaccharides heparin and heparan sulfate (HS) play key roles in the regulation of physiological and pathophysiological processes. Despite its importance, no molecular structures of free HS have been reported up to now. By combining analytical ultracentrifugation, small angle x-ray scattering, and constrained scattering modeling recently used for heparin, we have analyzed the solution structures for eight purified HS fragments dp6-dp24 corresponding to the predominantly unsulfated GlcA-GlcNAc domains of heparan sulfate. Unlike heparin, the sedimentation coefficient s20,w of HS dp6-dp24 showed a small rotor speed dependence, where similar s20,w values of 0.82-1.26 S (absorbance optics) and 1.05-1.34 S (interference optics) were determined. The corresponding x-ray scattering measurements of HS dp6-dp24 gave radii of gyration RG values from 1.03 to 2.82 nm, cross-sectional radii of gyration RXS values from 0.31 to 0.65 nm, and maximum lengths L from 3.0 to 10.0 nm. These data showed that HS has a longer and more bent structure than heparin. Constrained scattering modeling starting from 5,000 to 12,000 conformationally randomized HS structures gave best fit dp6-dp24 molecular structures that were longer and more bent than their equivalents in heparin. Alternative fits were obtained for HS dp18 and dp24, indicating their higher bending and flexibility. We conclude that HS displays bent conformations that are significantly distinct from that for heparin. The difference is attributed to the different predominant monosaccharide sequence and reduced sulfation of HS, indicating that HS may interact differently with proteins compared with heparin. PMID- 23921394 TI - On the evolution of clutch size and nest size in passerine birds. AB - I examined the hypothesis that the clutch size of some altricial birds may be limited by over-crowding of the nestlings in the nest, by comparing data on different species of European passerines. Large-sized birds build, relative to the body, larger nests than small-sized birds, both as regards the inner and the outer nest widths and as regards edge breadth; only inner nestcup depth did not change relatively to body size. Nest size also varied in relation to nesting place. Birds with open nests built off the ground had a rather narrow nestcup, whereas those with a domed nest, or which nest in a cavity, had a wide nestcup. When only open-nesters were compared, birds nesting on, or close to, the ground tended to have a wider nestcup than birds nesting above the ground. Inner nestcup width was correlated with the amount of mosses and lichens used in building the nest; the more of such materials the narrower the nestcup. The three variables: standardised body size, nesting place, and type of nesting material used accounted for 92% of the overall variation observed in inner nestcup width. When controlling for adult body size, clutch size was positively correlated with the size of the nestcup. A multiple regression analysis showed that relative nestcup depth, nest site, and type of nesting materials used, accounted for 64% of the overall variation in clutch size. PMID- 23921395 TI - Patterns of resource use, food quality, and health status of voles (Microtus pennsylvanicus) trapped from fluctuating populations. AB - Recent studies suggest that diet quality is responsible for differential survivorship of vole cohorts (Boonstra and Boag 1987) and spacing behavior of females (Ims 1987). These phenomena have been related either to a lack of or a deterioration in the quality of the preferred food. To test this hypothesis, we compared foods habits, food quality and health status of meadow voles (Microtus pennsylvanicus) from high and low population density phases. In this study, seven plant species represented the main food items used on a regular basis and biomass values of preferred species decreased with browsing pressure. In addition, food quality of the main dietary items changed between phases forcing females to adjust their feeding strategy accordingly. Health of voles changed also opening the way to speculations on competition for high quality food resources and survivorship. PMID- 23921396 TI - Intra- and interspecific competition for mutualists: ants as a limited and limiting resource for aphids. AB - We present two years of experimental and descriptive data which support the hypothesis that fireweed aphids (Aphis varians) compete with intra-and interspecific aphid neighbors for the services of ant mutualists (Formica fusca and F. cinerea). Specifically, we have shown that ants are a Limited and Limiting resource for a tended aphid species. First, the presence of heavily aphid infested fireweed shoots significantly reduced the number of ants tending neighboring conspecific populations on fireweed. Second, the presence of ant tended aphids (Cinara sp.) on Engelmann spruce significantly reduced the number of ants tending neighboring aphid populations on fireweed. Third, the number of ants, and not just the presence of ants, had a significant effect on the fitness of fireweed aphids. Aphid populations tended by three or more F. cinerea exhibited significantly higher probabilities of persisting and growing through time than colonies tended by one or two ants. Aphid populations tended by F. fusca had a significantly higher probability of growing when tended by three or more ants only if they had declined in size during the previous week. PMID- 23921397 TI - Intraspecific variation in the water relations of Salix arctica, an arctic-alpine dwarf willow. AB - The seasonal and diurnal water relations were investigated within arctic and alpine populations of the dwarf willow Salix arctica. Marked differences that were habitat dependent (e.g. xeric vs. mesic) occured both within and between the populations. The environmental variables that most affected plant water balance and the bulk tissue water relations were soil water potential (Psisoil) and the leafto-air water vapor pressure gradient (Deltaw), however, low soil temperature (<4.0 degrees C) also had a marked effect in the wet to mesic habitats. The effects of declining Psisoil and increased ?w were most pronounced in the plants growing in xiric habitats in both populations. Stomatal response to increased ?w was two-fold greater in alpine versus arctic plants and is hypothesized to have arisen in response to more frequent exposure to the higher evaporative conditions of alpine existance. Seasonal fluctuations in the osmotic potential closely followed changes in Psisoil, suggesting that these were active rather that passive changes. Additionally, plants from xeric habiats had a lower bulk tissue elastic modulus (more elastic tissues) in both arctic and alpine populations. The osmotic and elastic properties enhanced turgor maintenance over a broad range of leaf water potentials and during periods when ?w was high. Turgor maintenance also correlated to continued transpiration despite fluctuations in soil and atmospherically induced water deficits. Arctic habitats have a shorter growing season, lower soil temperatures due to the presence of permafrost, but higher soil water potentials and lower leaf-to-air vapor pressure gradients than alpine habitats. The observed variation in patterns of stomatal conductance and in values of tissue water relations characteristics between arctic and alpine populations of S. arctica is hypothesized to have arisen in response to these different environmental regimes which represent different selective regimes that occur along the arctic-alpine environmental continuum inhabited by this wide ranging species. PMID- 23921399 TI - Spacing and kinship in the Formosan squirrel living in different habitats. AB - Spacing and kinship of the Formosan squirrel, Callosciurus erythraeus thaiwanensis, were studied in two different habitats. One, native habitat in the woods of Kenting, southern Formosa, was rich in available food throughout the year and had several species of predators. The other, a site in Kamakura, central Japan where squirrels had been introduced, had relatively scanty food and few potential predators. 1. Home ranges among males and between sexes overlapped extensively in both habitats. 2. Females occupied exclusive home ranges in Kamakura but had small overlapping home ranges in Ken-ting. 3. Most males disappeared from their natal areas at 1 year old in both habitats (86% in Kamakura and 93% in Ken-ting), but less females disappeared (36% in Kamakura and 35% in Ken-ting). 4. In Kamakura, daughters settled adjacent to the mother or inherited the home range of the mother, but never shared the mother's home range. In Ken-ting, 35% of daughters shared the home range with their mothers. 5. Tolerance among female kin in Ken-ting was probably facilitated by the richness of available food throughout the year, and functioned to reduce predation risk via alarm calling and mobbing. PMID- 23921398 TI - Patterns of water use and the tissue water relations in the dioecious shrub, Salix arctica: the physiological basis for habitat partitioning between the sexes. AB - Within the high arctic of Canada, Salix arctica, a dioecious, dwarf willow exhibits significant spatial segregation of the sexes. The overall sex ratio is female-biased and female plants are especially common in wet, higher nutrient, but lower soil temperature habitats. In contrast, male plants predominate in more xeric and lower nutrient habitats with higher soil temperatures that can be drought prone. Associated with the sex-specific habitat differences were differences in the seasonal and diurnal patterns of water use as measured by stomatal conductance to water vapor and the bulk tissue water relations of each gender. Within the wet habitats, female plants maintained higher rates of stomatal conductance (g) than males when soil and root temperatures were low (<4 degrees C). In contrast, within the xeric habitats, male plants maintained higher g and had lower leaf water potentials Psileaf at low soil water potentials and a high leaf-to-air vapor pressure gradient (Deltaw) when compared to females. Female plants had more positive carbon isotope ratios than males indicating a lower internal leaf carbon dioxide concentration and possibly higher water use efficiency relative to males. Tissue osmotic and elastic properties also differed between the sexes. Male plants demonstrated lower tissue osmotic potentials near full tissue hydration and at the turgor loss point and a lower bulk tissue elastic modulus (higher tissue elasticity) than female plants. Males also demonstrated a greater ability to osmotically adjust on a diurnal basis than females. These properties allowed male plants to maintain higher tissue turgor pressures at lower tissue water contents and Psisoil over the course of the day. The sex-specific distributional and ecophysiological characteristics were also correlated with greater total plant growth and higher fecundity of females in wet habitats, and males in xeric habitats respectively. The intersexual differences in physiology persisted in all habitats. These results and those obtained from growth chamber studies suggest that sex-specific differences have an underlying genetic basis. From these data we conjecture that selection maintaining the intersexual differences may be related to different costs associated with reproduction that can be most easily met through physiological specialization and spatial segregation of the sexes among habitats of differing conditions. PMID- 23921400 TI - Demography and competition in Hyrax : A 17 years study. AB - This study investigates the demography and interspecific interactions of 6 Heterohyrax brucei and 4 Procavia johnstoni populations, which inhabited 6 kopjes (rock outcrops) in the Serengeti National Park, Tanzania over a period of 17 years. On three kopjes (H1, O2 and PH2) both species lived sympatrically, while on the other three (H2, H3 and P1) either one or the other species occurred allopatrically. The rainfall pattern between 1971/1972 and 1981/1982 had undergone major changes. There was significantly less precipitation in the wet season and the dry season had become extremer and longer. The kopje vegetation, recorded as percentage crown cover of browse from bushes and trees, had changed also, decreasing between 1971/72 and 1982 on 5 kopjes. In three kopjes (H1, O2 and PH2), which were shared by both hyrax species, an increase in the number of P. johnstoni, a decrease (H1 and O2) and extinction (PH2) of H. brucei took place between the time periods 1971-1976 ("good browse years") and 1982-1984 ("poor browse years"). These changes are probably the result of indirect interspecific competition (exploitative competition) for browse material, which is the main food source for both species during the dry season. When the browsing resources are abundant coexistence on sympatric kopjes between both species is possible, but when browse is scarce the result is competitive exclusion of H. brucei by P. johnstoni. It is also argued, that P. johnstoni by being the larger species and by also being a grazer had several ecological advantages over H. brucei. In kopjes H2, H3 and P1 where H. brucei occurred allopatrically the population increased (H2, P1) or decreased (H3) during the same time period. Natural extinction was observed in kopje P1 in the allopatrically living P. johnstoni group through mange. Dispersal of 7 females and 7 males H. brucei as well as 1 female and 4 male P. johnstoni were recorded in kopjes H1, H2 and P1. One female H. brucei that immigrated successfully into kopje H2 reached an age of over 11 years. One H. brucei family group (H2) shifted its birth season from December January to May-August. Successful natural colonization was recorded for H. brucei in kopje P1 and for P. johnstoni in H1. Two kopjes (PH2 and H3), which had no hyrax and are located far away from other hyrax populations, were experimentally colonized in 1971 and 1972 respectively. The P. Johnstoni on PH2 and the H. brucei group on H3 had been under breeding isolation for 16 years. Under such conditions P. johnstoni males can reach an age of over 8.5 years. These long-term observations have shown that the occupancy of the kopjes by both species is a dynamic process depending on the combination of several abiotic (rainfall and availability of holes and hiding places) and biotic factors (interspecific and intraspecific competition for food, interspecific cooperation, predation and parasites) as well as the degree of inbreeding dependent on the geographic isolation of the kopje. PMID- 23921401 TI - A new technique for monitoring pollen flow in orchids. AB - The orchid Prasophyllum fimbria is pollinated by nectar-feeding native bees and wasps. The pollinia are patially separated from the viscidium by a stipe so that pollinia can be labelled with coloured histochemical stains without interfering with pollinarium removal. Pollen flow was monitored by following the movement of the coloured pollen in several populations of P. fimbria in Western Australia. Statistical analysis confirmed that pollen labelling did not interfere with pollinarium removal or subsequent pollination of the labelled flower. Fifty eight labelled pollinaria were removed by vectors from 16 test spikes, with a total of 125 flowers on 47 spikes receiving labelled pollen. An average of 2 flowers received pollen for every pollinium removed but up to 6 flowers received pollen from a single collinium. No significant differences between mean vector flights and pollen flow distances were detected. On average, geitonogamous transfers only accounted for 22% of all pollinations. This is a simple and inexpensive technique for the direct labelling of pollen with minimal disruption to the pollination system and may have applications in other plant families. PMID- 23921402 TI - Adaptive variation in structure and function of kidneys of speciating subterranean mole rats. AB - We report on kidney structure and function in subterranean mammals of four chromosomal species (2n=52, 54, 58 and 60) belonging to the Spalax ehrenbergi superspecies, in relation to their speciation and adaptive radiation from mesic (2n=52) to xeric (2n=60) environments in Israel. Structural variables measured involved: (1) Relative Medullary Thickness, (RMT); (2) Relative Kidney Weight. (RKW); and (3) Percentage of Kidney out of Body Weight (PKW). Functional variables involved: (i) Urine Solid Concentration, (USC); and (ii) Urine Osmotic Concentration (UOC). The results for chromosomal species 2n=52, 54, 58 and 60 indicated nonsignificant increase southward for RMT, but displayed significant increase along the same transect for RKW, PKW, and USC. The UOC was significantly lower in mesic 2n=52 as compared to the other three species when experimental animals were fed in the laboratory on regular carrot food. However, protein stress food (soybean) and salt stress of 0.45 mol NaCl, caused significant, three and a half fold increase of UOC in 2n=52, 54 and 58; but four and a half fold increase in 2n=60, significantly higher than in the other three species. We conclude that both structurally and functionally, the kidneys differentiated adaptively during the Pleistocene evolution of S. ehrenbergi in Israel, in accordance with aridity stress and halophyte food resources towards the desert. Nevertheless, Spalax generally shows clear upper limits in kidney structural and functional capacities, preventing it from colonizing the true desert, south of the 100 mm isohyete. PMID- 23921403 TI - Population biology of two land snails (Mesomphix spp.): variation among six southern appalachian sites with differing disturbance histories. AB - Ecological and genetic properties of two North American terrestrial gastropods (Mesomphix spp.) were characterized in paired control and previously logged watersheds in two North Carolina forests (Coweeta and the Great Smoky Mountains National Park) of the Southern Appalachian Biosphere Reserve Cluster. Shell growth was greater in the control sites, but density and mortality were largely independent of prior logging history and forest reserve. Based on starch gel electrophoresis data, both species showed their highest levels of genetic diversity in the Coweeta forest, the component of the reserve cluster which had the most extensive and variable history of logging disturbance. M. subplanus also exhibited higher levels of heterozygosity in logged than in control watersheds, and M. andrewsae showed over twice as many rare alleles in disturbed sites as in control sites. F-statistic analysis depicted both excess levels of homozygosity and moderate genetic differentiation among the populations, reflecting the effects of small population size and perhaps drift and inbreeding. Estimated gene flow was relatively low. These results correspond to the recent finding by Bryant et al. (1987) and others on the effects of bottlenecks, and to the contrasting history of habitat instability of the two major study forests. PMID- 23921404 TI - Resource partitioning by ungulates on the Isle of Rhum. AB - This paper describes the seasonal changes in vegetation community use by red deer, cattle, goats and ponies on the Isle of Rhum, Scotland. During the winter, when food resources were of low abundance and digestibility, the ungulates showed extensive resource partitioning. During the summer, when resource availability and digestibility was high, the grazing species, red deer, cattle and ponies congregated on the vegetation communities which contained high biomasses of a high quality resource, mesotrophic graminoids and forbs. Goats, with a digestive system adapted to dealing with browse, foraged primarily on the communities dominated by dwarf shrubs. The patterns of resource use in this group of ungulates are discussed in relation to competition; species had relatively exclusive esource use during periods of low food availability during tye winter and had a high degree of resource use overlap when food was abundant during the summer. This suggests that there was little competition for food during the summer and that exploitative competition for the high quality foods led to resource partitioning during the winter. Senarios are described which predict the pattern of resource use between two species (one competitively superior to the other on the preferred resource) utilizing mutually or exclusively preferred resources. A model developed by Illius and Gordon (1987), based on the allometry of metabolic requirements and bite size, is used to provide a mechanistic explanation for the observation that the red deer were able to exploit the high quality plant communities during the winter, whereas the cattle moved off to feed on poorer quality communities at this time. PMID- 23921405 TI - The relationship between foliar nitrogen content and feeding by Odontota dorsalis Thun. on Robinia pseudoacacia L. AB - The relationship between total foliar nitrogen content and feeding by Odontota dorsalis Thun. on Black Locust trees (Robinia pseudoacacia L.) was examined via experimental manipulation of foliar nitrogen levels. Trees with high concentrations of foliar nitrogen received more herbivory by adult O. dorsalis, but herbivory by larvae was independent of foliar nitrogen concentration. Late in the growing season, leaf abscission induced by herbivory tends to mask the dependence of herbivory by adults on foliar nitrogen concentration. The percentage of variation in herbivory attributable to foliar nitrogen concentration drops from 20% in June to 2% by August. These observations suggest that variation in the interaction between R. pseudoacacia and O. dorsalis is at least partially conditioned on variation in foliar nitrogen concentration. PMID- 23921406 TI - Origins of variance in seed number and mass: interaction of sex expression and herbivory in Lomatium salmoniflorum. AB - As in many plant species, Lomatium salmoniflorum (Umbelliferae) individuals produce many flowers, only a subset of which produce mature seeds that escape seed parasitism and enter the seed bank. The interrelationships between the timing and number of flowers produced, sex expression, seed set, and seed parasitism were studied for their direct and indirect effects on the numbers and masses of viable seeds produced by individual plants. In a sample population of 369 plants that produced 161 386 flowers, 76% of the plants produced some hermaphroditic flowers. The percentage of hermaphroditic flowers increased significantly with the total number of flowers produced by a plant. Seed set was 65-90% in plants producing >600 flowers, but was highly variable in plants producing fewer flowers. Hand-pollinated plants showed the same pattern of seed set, suggesting that variable seed set in small plants may result from insufficient resources for seed development. The majority of schizocarps was produced by only 12% of the plants. Parasites killed 24.5% of the seeds prior to dispersal. Another 14.5% of the seeds lacked endosperm. Hence, the initial 161 386 flowers, which included 25874 hermaphroditic flowers each capable of producing two seeds, produced 42 468 seeds of which an estimated 25906 entered the seed bank as undamaged seeds with fully developed endosperm. Path analysis indicated that the number of hermaphroditic flowers on a plant and the percentage of seeds attacked by seed parasites had the greatest direct effects on the number of viable seeds entering the seed bank. The date at which a plant began flowering and the percentage of flowers setting seed had smaller or only indirect effects on viable seed production. Mean seed mass for plants was not significantly related to any of the factors that affected seed number, but little of the variance in seed mass occurred among plants. Masses of intact seeds in the population ranged 9-fold in both 1987 and 1988. Thirty-five percent of the variance was among seeds within umbels, 46% was among umbels within plants, and only 19% was among plants. The large variation among umbels within plants resulted from a seasonal pattern in which seeds from umbels produced late in the spring had lower mean seed masses than seeds from umbels produced early in the spring. Overall, the results indicate that both direct and indirect interactions between number of flowers, the date of initiation of flowering, seed set, and seed parasitism affect the number of viable seeds entering the seed bank. These interactions strongly bias viable seed output to a small minority of plants that produce many seeds with a wide range of masses over the growing season. PMID- 23921407 TI - Trophic structure of a neotropical frugivore community: is there competition between birds and bats? AB - Dietary overlap and competition between frugivorous birds and bats in the Neotropics have been presumed to be low, but comparative data have been lacking. We determined the diets of volant frugivores in an early successional patch of Costa Rican wet forest over a one month period. Ordination of the diet matrix by Reciprocal Averaging revealed that birds and bats tend to feed on different sets of fruits and that diets differed more among bat species than among bird species. However, there was overlap between Scarlet-rumped Tanagers and three Carollia bat species on fruits of several Piper species which comprised most of the diet of these bats. Day/night exclosure experiments on P. friedrichsthalli treetlets provided evidence that birds deplete the amount of ripe fruit available to bats. These results indicate that distantly related taxa may overlap in diet and compete for fruit, despite the apparent adaptation of animal-dispersed plant species for dispersal by particular animal taxa. PMID- 23921408 TI - Competition causes regular spacing of alder in Alaskan shrub tundra. AB - Alders (Alnus crispa) in shrub tundra in northern Alaska showed significant regularity of spacing. Removal of neighboring alder shrubs stimulated nutrient accumulation and growth of remaining alders but did not stimulate nutrient accumulation or growth of any other shrub species. This demonstrates that neighboring alders competed with one another and that, when alders were removed, the resources made available were used preferentially by remaining alders rather than by the community in general. Neither patterns of seedling establishment nor patterns of frostrelated features could explain the regular distribution of alder. We suggest that regular patterns of plant distribution are restricted to sites of low-resource availability, because in these habitats (1) there is strong competition for a scarce resource, and (2) there are only one or a few dominant species to compete for these resources in a given canopy height or rooting depth. PMID- 23921409 TI - Scatter-and clump-dispersal and seedling demography: hypothesis and implications. AB - Fruit-eating animals deposit viable seeds in patterns that determine the conditions under which seeds and seedlings live or die. Many tree species are scatter-dispersed by birds, bats, or other small frugivores that regurgitate, defecate, or drop seeds singly or in pairs. These scatterdispersed plant species normally recruit as isolated individuals, and are unlikely to evolve exceptional resistance to herbivores, pathogens, or to other sources of density-dependent seed or seedling mortality. Other tree species are clump-dispersed by larger terrestrial or arboreal frugivores that defecate seeds in masses which produce bouquets of seedlings. Because their seeds invariably germinate in close proximity to other seedlings, clump-dispersed species necessarily evolve chemical or mechanical defenses against seed predators, pathogens, and herbivores that act in a densitydependent manner.Population and genetic attributes should reflect this basic dichotomy in the conditions of seedling recruitment. I predict that seedlings of scatter-dispersed species rarely survive near parents or in dense aggregations under frugivore roosts. Seed dispersal should be mandatory, often to light gaps or other special habitats. Outbred adults and juveniles are expected to exist at low densities in loose aggregations or random distributions. Seedlings of clump-dispersed trees are pre-adapted for survival in dense aggregations near parents, as well as in fecal clumps. Substantial recruitment of juveniles and young adults should occur from undispersed seeds under and near parent trees. Such species should be common, highly aggregated, and show strong genetic family structure. Because recruitment requires dispersal, scatter dispersed plant species should be especially vulnerable to loss of dispersal agents. Because offspring consistently recruit near parents, clump-dispersed plants should be less vulnerable to temporary loss of dispersal agents. PMID- 23921410 TI - Generalist caterpillar prey are more palatable than specialists for the generalist predator Iridomyrmex humilis. AB - Experiments are described which test the hypothesis that more host-specific species of caterpillars should be less aceptable to a generalist predator than polyphagous species. Caterpillars of all species were tested in paired choice tests with the Argentine ant, Iridomyrmex humilis. Experiments were replicated ten times, videotaped and later analyzed. Brightly colored specialist species (normally considered to be aposematic) were clearly the least palatable, while more cryptic specialists were also significantly less acceptable than generalists overall. Leaf-tying species were considered separately; all were highly palatable independent of host range. The results indicate that among caterpillars that do not construct leaf shelters, those with a wide post range are more acceptable than those with a narrow host range. This is consistent with the notion that generalist predators provide selection pressure favoring narrow host range in their herbivorous prey. PMID- 23921412 TI - Sensory systems: Making a choice and sticking with it. PMID- 23921415 TI - Neuronal circuits: Staying connected during growth. PMID- 23921417 TI - Safety and efficacy of skin patches containing loxoprofen sodium in diabetic patients with overt nephropathy. AB - BACKGROUND: Because oral nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects on kidney function, patients with kidney diseases are administered these drugs as transdermal patches. Little is known about the effects of NSAID patches on renal function. We therefore assessed the effects of topical loxoprofen sodium on kidney function in type 2 diabetic patients with overt nephropathy. METHODS: Twenty patients with type 2 diabetes and overt proteinuria and with knee and/or low back pain were treated with skin patches containing 100 mg loxoprofen on the knee or back for 24 h per day for 5 consecutive days. The degree of pain was assessed using a visual analogue scale (VAS). Blood and 24-h urine samples were obtained at baseline and at the end of the study. Glomerular filtration rate (GFR) was estimated from serum creatinine and cystatin C concentrations. RESULTS: The 20 patients consisted of 11 males and 9 females, of mean age 61.6 +/- 13.9 years. Loxoprofen-containing patches significantly reduced VAS pain without affecting blood pressure, GFR or urinary prostaglandin E2 concentration. Serum concentrations of loxoprofen and its active trans-OH metabolite did not correlate with GFR. CONCLUSIONS: Loxoprofen containing patches do not affect renal function in type 2 diabetic patients with overt nephropathy over a short-term period. Long-term studies are needed to clarify the safety of loxoprofen-containing patches in patients with chronic kidney diseases. PMID- 23921418 TI - Evaluation of 100 brain examinations using a 3 Tesla MR-compatible incubator safety, handling, and image quality. AB - INTRODUCTION: Several studies have revealed the importance of brain imaging in term and preterm infants. The aim of this retrospective study was to review safety, handling, and image quality of MR brain imaging using a new 3 Tesla MR compatible incubator. METHODS: Between 02/2011 and 05/2012 100 brain MRIs (84 infants, mean gestational age 32.2 +/- 4.7 weeks, mean postmenstrual age at imaging 40.6 +/- 3.4 weeks) were performed using a 3 Tesla MR-compatible incubator with dedicated, compatible head coil. Seventeen examinations (13 infants, mean gestational age 35.1 +/- 5.4 weeks, mean postmenstrual age at imaging 47.8 +/- 7.4 weeks) with a standard head coil served as a control. Image analysis was performed by a neuroradiologist and a pediatric radiologist in consensus. RESULTS: All but two patients with known apnea were transferred to the MR unit and scanned without problems. Handling was easier and faster with the incubator; relevant motion artifacts (5.9 vs. 10.8%) and the need for repetitive sedation (43.0 vs. 86.7%) were reduced. Considering only images not impaired by motion artifacts, image quality (4.8 +/- 0.4 vs. 4.3 +/- 0.8, p = 0.047) and spatial resolution (4.7 +/- 0.4 vs. 4.2 +/- 0.6, p = 0.011) of T2-weighted images were scored significantly higher in patients imaged with the incubator. SNR increased significantly (171.6 +/- 54.5 vs. 80.5 +/- 19.8, p < 0.001) with the use of the incubator. CONCLUSION: Infants can benefit from the use of a 3 Tesla MR-compatible incubator because of its safety, easier, and faster handling (compared to standard imaging) and possibility to obtain high-quality MR images even in unstable patients. PMID- 23921419 TI - Resuscitation intensity at birth is associated with changes in brain metabolic development in preterm neonates. AB - INTRODUCTION: Intensive resuscitation at birth has been linked to intraventricular haemorrhage (IVH) in the preterm neonate. However, the impact of less intensive resuscitation on more subtle alterations in brain metabolic development is largely unknown. Our objective was to determine the relationship between the intensity of neonatal resuscitation following preterm birth on brain metabolic development. METHODS: One hundred thirty-three very preterm-born neonates (median gestational age [GA] 27 +/- 2 weeks) underwent MR spectroscopic imaging early in life (median postmenstrual age 32 weeks) and again at term equivalent age (median 40 weeks). Severity of white matter injury, IVH and cerebellar haemorrhage on magnetic resonance imaging were scored. Ratios of N acetylaspartate (NAA) and lactate to choline (Cho) were calculated in eight regions of interest and were assessed in relation to intensiveness of resuscitation strategy (bag and mask, continuous positive airway pressure [CPAP], intubation, cardiopulmonary resuscitation [CPR]). RESULTS: Within the first hour of life, 14 newborns had no intervention, 3 received bag and mask, 30 had CPAP, 79 were intubated and 7 had CPR. Resuscitated infants were more likely to have IVH (p = 0.02). More intensive resuscitation was associated with decreased NAA/Cho maturation (p < 0.001, adjusting for birth GA). Metabolic development was similar in neonates requiring CPAP in comparison to those receiving no intervention. The change in lactate/Cho did not differ across resuscitation categories (p = 0.8). CONCLUSIONS: Intensity of resuscitation at birth is related to changes in metabolic brain development from early in life to term-equivalent age. Results suggest that preventing the need for intensive neonatal resuscitation may provide an opportunity to improve brain development in preterm neonates. PMID- 23921420 TI - Relapse patterns in pediatric embryonal central nervous system tumors. AB - Embryonal tumors of the central nervous system (CNS) share histological features and were therefore initially grouped as primitive neuroectodermal tumors (PNET) and treated similarly. We sought to determine the relapse patterns of specific embryonal CNS tumors. We conducted a historical cohort study of children diagnosed with CNS embryonal tumors from January 2000 to December 2011 in two pediatric neuro-oncology centers. Patients of 21 years of age or younger at time of presentation with a diagnosis of medulloblastoma, supratentorial PNET, pineoblastoma or atypical teratoid/rhabdoid tumor (ATRT) and at least one surveillance MRI were included. A total of 133 patients met inclusion criteria and 49 (37 %) patients relapsed during the observation period. The majority (79 %) of sPNET relapses were local, whereas all (100 %) PB relapses were associated with diffuse leptomeningeal disease. Relapse patterns for MB were more diverse with local recurrence in 27 %, distant recurrence in 35 % and diffuse leptomeningeal disease in 38 %. The frequency of relapses involving the spine differed (p < 0.001) between tumor types (MB 28/55 [51 %], sPNET 3/33 [9 %], ATRT 3/7 [43 %] and PB 12/12 [100 %]). No sPNET patients had isolated spinal relapse (0/14). Embryonal tumors were found to have divergent patterns of recurrence. While medulloblastoma has variable relapse presentations, sPNET relapses locally and pineoblastoma recurs with diffuse leptomeningeal disease involving the spine. These results point toward possibly new upfront treatment stratification among embryonal tumors in accordance with relapse pattern. PMID- 23921421 TI - Cardiorespiratory responses during the 6-minute walk and ramp cycle ergometer tests and their relationship to physical activity in stroke. AB - BACKGROUND AND OBJECTIVES: The 6-minute walk test (6MWT) is used to measure exercise capacity after stroke. We sought to compare cardiorespiratory responses during the 6MWT with responses to a ramp cycle ergometer test (CET) in community dwelling individuals with stroke. A secondary objective was to determine the relationship between cardiorespiratory responses during each test and daily physical activity. METHODS: Participants completed 3 evaluation sessions. The CET and 6MWT were conducted in 2 separate sessions at least 72 hours apart. Participants wore a portable gas analysis unit (Cosmed K4b2), which also measured heart rate (HR) during the 6MWT. A uniaxial accelerometer (activPAL) was used to measure time spent upright (standing and stepping) over 5 days as an estimate of daily physical activity. RESULTS: Complete CET and 6MWT data were obtained for 16 participants (14 men), a mean +/- standard deviation of 2.0 +/- 1.1 years after stroke and 71.1 +/- 9.7 years of age. Compared with the 6MWT, the CET elicited a higher VO(2peak) (P = .032), VCO(2peak) (P = .005), respiratory exchange ratio (P = .015), and self-reported perceived breathing (P < .0001) and leg heaviness (P < .0001) at test completion and a lower HR(peak) (P = .029). Except for the first minute, VO(2) during the 6MWT was, on average, 80% to 85% of VO(2peak) from the CET. Among 15 participants, average time spent upright per day was not significantly associated with 6MWT distance (r = 0.447, P = .096) or VO(2peak) from the CET (r = 0.388, P = .153). CONCLUSIONS: Exercise intensity achieved during the 6MWT appeared sufficiently high for aerobic training, assuming CET VO(2peak) accurately reflects aerobic capacity. The 6MWT may be useful for prescribing aerobic exercise poststroke. PMID- 23921422 TI - Targeted motor rehabilitation dissociates corticobulbar versus corticospinal dysfunction in an animal model of Parkinson's disease. AB - BACKGROUND: Recent evidence suggests that motor training may be beneficial for slowing the onset of motor impairments in Parkinson's disease (PD). OBJECTIVE: To examine the impact of targeted rehabilitation on limb motor and cranial motor function and the corresponding corticospinal and corticobulbar circuits in a rodent model of PD. METHODS: Baseline performance of limb (reaching) and cranial (licking) motor function were established prior to and 6 weeks following unilateral intrastriatal 6-hydroxydopamine (6-OHDA) infusions. Animals then received 6 weeks of limb motor rehabilitation (LMR) or cranial motor rehabilitation (CMR), after which motor performance was reassessed. Intracortical microstimulation (ICMS) was used to generate motor maps of corresponding corticospinal (forelimb) and corticobulbar (tongue) movement representations within the motor cortex ipsilateral to the 6-OHDA infusion. Quantitative tyrosine hydroxylase (TH) immunohistochemistry was performed to determine levels of striatal TH depletion in 6-OHDA animals using near infrared densitometry. RESULTS: (1) unilateral intrastriatal dopamine depletion impaired both reaching accuracy and lick force; (2) targeted LMR ameliorated impairments in reaching performance; however, CMR did not improve lick force impairments; (3) unilateral dopamine depletion significantly reduced forelimb but not tongue motor map topography; (4) LMR partially restored forelimb motor maps, whereas CMR did not alter tongue motor maps; and (5) significant correlations were observed between skilled reaching accuracy, forelimb motor map area, and TH depletion, but no relationships were revealed for cranial motor function, motor maps, or TH depletion. CONCLUSIONS: These data demonstrate dissociation between striatal dopamine depletion, limb versus cranial motor function, and targeted motor rehabilitation in a rodent model of PD. PMID- 23921423 TI - Partial versus radical nephrectomy: the debate regarding renal function ends while the survival controversy continues. PMID- 23921424 TI - Utilization of solid lipid nanoparticles for enhanced delivery of curcumin in cocultures of HT29-MTX and Caco-2 cells. AB - Solid lipid nanoparticles (SLN) have shown potential for encapsulation, protection and delivery of lipophilic functional components. In this study, we have investigated the capabilities of SLN to deliver a hydrophobic polyphenol compound, curcumin, in a coculture system of absorptive Caco-2 and mucus secreting HT29-MTX cells. The cells were grown on transport filters to mimic the human intestinal epithelium. Because of the hydrophobic nature of curcumin, its delivery to the basolateral compartment is expected to take place via a paracellular route. The changes in curcumin concentration in various compartments (i.e., apical, basolateral, mucus, and cell lysates) were evaluated using fluorescence spectroscopy. Two SLN systems were prepared with different emulsifying agents. The encapsulation of curcumin in SLN caused enhanced delivery compared to unencapsulated curcumin. In addition, SLN showed enhanced delivery compared to emulsion droplets containing liquid soy oil. The SLN were retained on the apical mucosal layer to a greater extent than emulsion droplets. The presence of SLN did not affect the integrity of the cellular junctions, as indicated by the TEER values, and the route of transport of the solid particles was simple diffusion, with permeability rates of about 7 * 10(-6) cm s(-1). Approximately 1% of total curcumin was delivered to the basolateral compartment, suggesting that most of the curcumin was absorbed and metabolized by the cell. PMID- 23921425 TI - RNAi gene therapy of SiHa cells via targeting human TERT induces growth inhibition and enhances radiosensitivity. AB - Telomerase activity (TA) is reactivated in more than 90% of all human malignant tumors and normal somatic cells that lack TA. Thus, human TERT (hTERT) is a promising target in malignant tumor treatment. RNA interference is a powerful tool for gene silencing. In this study, we constructed siRNA#1-4 to knock down hTERT. All siRNAs were able to downregulate hTERT differently and we chose siRNA#3 (most effectively) in the following experiments. We studied the effects on cell proliferation, cell cycle, cell apoptosis and radiosensitivity using SiHa cells. Our results showed that siRNA#3 was able to silence hTERT gene effectively. The silencing of hTERT could induce immediate growth arrest, enhance the S phase in cell cycle study and lead to early apoptosis in human cervical cancer cells (SiHa). In clonogenic assays, we used multitarget-single hit and linear-quadratic models to assess the radiosensitivity after knockdown of hTERT. All results of parameters (D0, Dq, alpha, beta) indicated that downregulation of hTERT enhanced radiosensitivity in SiHa cells. PMID- 23921426 TI - Axial-to-central chirality transfer in cyclization processes. AB - Substrates, bearing axial chirality, can cyclize intra- or inter-molecularly with concomitant transfer of axial-to-central chirality to produce at least one stereocenter. In order to satisfy a strict definition of axial-to-central chirality transfer, the initial axial chirality must be lost during the cyclization process. Highly functionalized enantiopure carbocycles and heterocycles were prepared using this strategy. The transformations of configurationally stable substrates take place with high regio- and stereo selectivity. Selected examples involving allenes, biaryls, arylamides and transient axially chiral short-lived species are discussed. Special attention is focused on the mechanistic rationale of the chirality transfer. PMID- 23921427 TI - Single-limb-balance difficulty on 4 commonly used rehabilitation devices. AB - CONTEXT: Balance training is widely used by rehabilitation professionals and has been shown to be effective at reducing risk of injury, as well as improving function after injury. However, objective evidence for the difficulty of commonly available equipment is lacking. OBJECTIVE: To assess center-of-pressure (COP) area and average sway velocity in healthy subjects while performing a single-limb stance on 4 commonly available rehabilitation devices to determine their level of difficulty. DESIGN: Single-session, randomized, repeated-measures design to assess COP area and average sway velocity while performing a single-limb stance on 4 devices positioned on a force platform. SETTING: University laboratory. SUBJECTS: A convenience sample of 57 healthy college-age subjects. INTERVENTION: Each participant balanced on the dominant limb in a nonshod single-limb stance with eyes open for 20 s during 4 conditions. The 4 conditions were randomized and included the Both Sides Up (BOSU) trainer, Airex balance pad, half-foam roller, and DynaDisc. MAIN OUTCOME MEASURE: Means and standard deviations were calculated for maximum displacement in each direction. In addition, the means and standard deviations for COP area and average sway velocity were calculated for the 4 conditions and compared using a 1-way repeated-measure ANOVA. RESULTS: Significant differences were found for both COP area and average sway velocity between the BOSU trainer and the other 3 devices. A significant difference was also found between the DynaDisc and the half-foam roller. CONCLUSIONS: Level of difficulty, as measured by COP area and average sway velocity, is different for commonly available rehabilitation equipment. Clinicians may find these results a useful guide when progressing patients through balance training. PMID- 23921428 TI - Placental programming of anxiety in adulthood revealed by Igf2-null models. AB - Imprinted, maternally silenced insulin-like growth factor-2 is expressed in both the foetus and placenta and has been shown to have roles in foetal and placental development in animal models. Here we compared mice engineered to be null for the placenta-specific P0 transcript (insulin-like growth factor-2-P0 KO) to mice with disruptions of all four insulin-like growth factor-2 transcripts, and therefore null for insulin-like growth factor-2 in both placenta and foetus (insulin-like growth factor-2-total KO). Both models lead to intrauterine growth restriction but dissociate between a situation where there is an imbalance between foetal demand and placental supply of nutrients (the insulin-like growth factor-2-P0 KO) and one where demand and supply is more balanced (the insulin-like growth factor 2-total KO). Increased reactivity to anxiety-provoking stimuli is manifested later in life only in those animals where there is a mismatch between placental supply and foetal demand for nutrients during gestation. Our findings further distinguish placental dysfunction from intrauterine growth restriction and reveal a role for the placenta in long-term programming of emotional behaviour. PMID- 23921429 TI - Physiological arousal deficits in addicted gamers differ based on preferred game genre. AB - BACKGROUND/AIMS: There has been significant discussion surrounding the psychopathology of excessive gaming and whether it constitutes an addiction. The current study investigated physiological and subjective levels of arousal in gamers of two genres and the relationship between sensation seeking and gaming addiction. METHODS: Heart rate (HR), blood pressure (BP) and skin conductance were recorded at baseline, during gaming for 15 min and after gaming in 30 massively multiplayer online role-playing game (MMORPG) and 30 first-person shooter (FPS) male gamers. Gamers were identified as addicted using the Addiction Engagement Questionnaire. Sensation seeking was measured using the Arnett Inventory of Sensation Seeking. RESULTS: Addicted MMORPG gamers (n=16) displayed significant decreases in cardiovascular activity during gaming compared to baseline and showed significant increases after gaming. Addicted FPS gamers (n=13) had significant increases in BP during gaming which decreased significantly after gaming. In comparison, non-addicted MMORPG gamers (n=14) had significant decreases in HR during gaming, whereas BP in non-addicted MMORPG and FPS gamers (n=17) increased during gaming and after gaming. There were no significant relationships between sensation seeking and addiction. CONCLUSION: There are physiological arousal deficits in addicted gamers, and these patterns differ according to the genre of game played. PMID- 23921431 TI - Towards industrially feasible treatment of potato starch processing waste by mixed cultures. AB - The present study aimed at reducing the pollution of the waste generated by the potato starch industry to the environment and transform the potato pulp and wastewater into single-cell protein (SCP) to be used as animal feed. The chemical oxygen demand of the wastewater was reduced from 26,700 to 9,100 mg/L by batch fermentation with mixed cultures in an aerated 10-L fermenter. The SCP products, with a crude protein content of 46.09 % (higher than soybean meal), were found palatable and safe for mice. During the treatment process, the microbial community was analyzed using the terminal restriction fragment length polymorphism for bacterial 16S rRNA genes. The results of the analysis suggested that Curacaobacter/Pseudoalteromonas and Paenibacillus/Bacillus were the main microorganisms in treating potato starch processing wastes. The 150-m(3)-scale fermentation demonstrated a potential for treatment in industrial applications. Fermentation of potato pulp and wastewater without adding an extra nitrogen source was a novel approach in treating the potato starch processing waste. PMID- 23921430 TI - Validation of an LC-MS/MS method to measure tacrolimus in rat kidney and liver tissue and its application to human kidney biopsies. AB - BACKGROUND: Tacrolimus (TAC) has a narrow therapeutic index and high interindividual and intraindividual pharmacokinetic variability, necessitating therapeutic drug monitoring to individualize dosage. Recent evidence suggests that intragraft TAC concentrations may better predict transplant outcomes. This study aimed to develop a method for the quantification of TAC in small biopsy sized samples of rat kidney and liver tissue, which could be applied to clinical biopsy samples from kidney transplant recipients. METHODS: Kidneys and livers were harvested from Mrp2-deficient TR- Wistar rats administered TAC (4 mg.kg.d for 14 days, n = 8) or vehicle (n = 10). Tissue samples (0.20-1.00 mg of dry weight) were solubilized enzymatically and underwent liquid-liquid extraction before analysis by liquid chromatography tandem mass spectrometry method. TAC free tissue was used in the calibrator and quality control samples. Analyte detection was accomplished using positive electrospray ionization (TAC: m/z 821.5 -> 768.6; internal standard ascomycin m/z 809.3 -> 756.4). RESULTS: Calibration curves (0.04-2.6 MUg/L) were linear (R > 0.99, n = 10), with interday and intraday calibrator coefficients of variation and bias <17% at the lower limit of quantification and <15% at all other concentrations (n = 6-10). Extraction efficiencies for TAC and ascomycin were approximately 70%, and matrix effects were minimal. Rat kidney TAC concentrations were higher (range 109-190 pg/mg tissue) than those in the liver (range 22-53 pg/mg of tissue), with median tissue/blood concentrations ratios of 72.0 and 17.6, respectively. In 2 transplant patients, kidney TAC concentrations ranged from 119 to 285 pg/mg of tissue and were approximately 20 times higher than whole blood trough TAC concentrations. CONCLUSIONS: The method displayed precision and accuracy suitable for application to TAC measurement in human kidney biopsy tissue. PMID- 23921432 TI - Neuro-ophthalmology in france. PMID- 23921433 TI - Hypertrophic olivary degeneration due to pontine hemorrhage. PMID- 23921434 TI - Human unrestricted somatic stem cell administration fails to protect nude mice from cisplatin-induced acute kidney injury. AB - BACKGROUND: Kidney failure is a debilitating disorder with limited treatment options. The kidney-protective effects of stem cells have been vastly investigated and promising results have been achieved with various sources of stem cells. However, in spite of beneficial effects on other disease models, the renoprotective potential of human cord blood-derived unrestricted somatic stem cells (USSC) has not been examined so far. METHODS: In the present study, acute kidney failure was induced in female nude mice and the effect of USSC transplantation on kidney function and structure was assessed. Furthermore, the expression of some cytokine genes was examined by real-time PCR. Homing of the transplanted cells into kidneys was assessed by flow cytometry, immunohistochemistry, and real-time PCR. RESULTS: USSC-conditioned medium did not attenuate the in vitro nephrotoxic effects of cisplatin. Transplantation of USSC to nude mice did not protect kidney function and was associated with worsened kidney structural damage. USSC transplantation was also associated with a decline in the renal expression of VEGF-A gene. In spite of these effects, the transplanted cells could not be detected in the kidneys by any of the exploited methods and they were mainly entrapped in the lungs. CONCLUSION: These data indicate that USSC are not suitable for cell therapy in the setting of acute kidney injury. Also, this study shows that these stem cells are able to affect damaged kidneys even if they are not homed there. PMID- 23921435 TI - Plasticity is the differentiated state of CD4 T cells. PMID- 23921436 TI - Dietary approaches to improving atheroprotective HDL functions. AB - High-density lipoproteins (HDL) are known to protect against cardiovascular disease (CVD). In addition to facilitating reverse cholesterol transport to remove excess lipids from the body - including atherosclerotic plaques - HDL exhibits antioxidant, anti-inflammatory, vasodilatory, and antithrombotic activities. Together, these properties contribute to the overall atheroprotective nature of HDL. However, similar to many other physiological pathways, these HDL parameters are known to become dysregulated in conditions of metabolic disease. Further, research suggests these alternative HDL properties may be regulated independently of blood HDL-cholesterol (HDL-C) levels, and must therefore be considered when designing HDL-targeted therapies. To date, a number of dietary strategies have been investigated to assess the effect of dietary components on functional properties of HDL beyond HDL-C. This review will highlight the bioactive nutrients, functional foods, and dietary programs known to modulate HDL function as a means of reducing CVD. PMID- 23921437 TI - Endovascular thrombectomy for acute ischemic stroke patients anticoagulated with dabigatran. PMID- 23921438 TI - The influence of aspirin on release of eoxin C4, leukotriene C4 and 15-HETE, in eosinophilic granulocytes isolated from patients with asthma. AB - BACKGROUND: The effect of aspirin on the release of key arachidonic acid metabolites in activated eosinophils from subjects with aspirin-intolerant asthma (AIA) has not been investigated previously, despite the characteristic eosinophilia in AIA. METHODS: Peripheral blood eosinophils were isolated from four groups of subjects: healthy volunteers (HV; n = 8), mild asthma (MA; n = 8), severe asthma (SA; n = 9) and AIA (n = 7). In the absence or presence of lysine aspirin, eosinophils were stimulated with arachidonic acid or calcium ionophore to trigger the 15-lipoxygenase-1 (15-LO) and 5-lipoxygenase (5-LO) pathways, respectively. 15(S)-hydroxy-eicosatetraenoic acid (15-HETE) and eoxin C4 (EXC4) were measured as 15-LO products and leukotriene (LT)C4 as a product of the 5-LO pathway. RESULTS: Activated eosinophils from patients with SA and AIA produced approximately five times more 15-HETE than eosinophils from HV or MA patients. In the presence of lysine-aspirin, eosinophils from AIA, MA and SA patients generated higher levels of 15-HETE than in the absence of lysine-aspirin. Furthermore, in the presence of lysine-aspirin, formation of EXC4 was also significantly increased in eosinophils from AIA patients, and LTC4 synthesis was increased both in AIA and SA patients. CONCLUSIONS: Taken together, this study shows an increased release of the recently discovered lipid mediator EXC4, as well as the main indicator of 15-LO activity, 15-HETE, in activated eosinophils from severe and aspirin-intolerant asthmatics, and also elevated EXC4 and LTC4 formation in eosinophils from AIA patients after cellular activation in the presence of lysine-aspirin. The findings support a pathophysiological role of the 15-LO pathway in SA and AIA. PMID- 23921439 TI - Impact of alcohol-related video sequences on functional MRI in abstinent alcoholics. AB - The object of this study was the identification of brain areas that were significantly more connected than other regions with a previously identified reference region, the posterior cingulate cortex, during the presentation of visual cues in alcoholics. Alcohol-related and neutral video sequences were presented to 30 alcoholics who had been abstinent for at least 4 days. Participants underwent a psychometric assessment before and after the presentation of the video sequences. Functional MRI data were acquired. Psychophysiological interaction analyses were carried out. Participants reported a significant increase in craving and arousal after the presentation of alcohol related video sequences. The simple contrast alcohol versus neutral was found not to be significantly different in the present study. The brain regions that were found to correlate significantly more with the posterior cingulate cortex under the alcohol-related condition were the inferior parietal lobe, the medial temporal lobe, the inferior frontal gyrus, the postcentral gyrus, and the precuneus. The involvement of these regions in processes of memory, self-control, and self-reflection with a particular focus on alcohol dependence and craving will be discussed. PMID- 23921440 TI - Tubular endocytosis drives remodelling of the apical surface during epithelial morphogenesis in Drosophila. AB - During morphogenesis, remodelling of cell shape requires the expansion or contraction of plasma membrane domains. Here we identify a mechanism underlying the restructuring of the apical surface during epithelial morphogenesis in Drosophila. We show that the retraction of villous protrusions and subsequent apical plasma membrane flattening is an endocytosis-driven morphogenetic process. Quantitation of endogenously tagged GFP::Rab5 dynamics reveals a massive increase in apical endocytosis that correlates with changes in apical morphology. This increase is accompanied by the formation of tubular plasma membrane invaginations that serve as platforms for the de novo generation of Rab5-positive endosomes. We identify the Rab5-effector Rabankyrin-5 as a regulator of this pathway and demonstrate that blocking dynamin activity results in the complete inhibition of tubular endocytosis, in the disappearance of Rab5 endosomes, and in the inhibition of surface flattening. These data collectively demonstrate a requirement for endocytosis in morphogenetic remodelling during epithelial development. PMID- 23921441 TI - The ENTPD5/mt-PCPH oncoprotein is a catalytically inactive member of the ectonucleoside triphosphate diphosphohydrolase family. AB - Expression of the ENTPD5/mt-PCPH onco-protein and overexpression of the normal ENTPD5/PCPH protein contribute to the malignant transformation of diverse mammalian cell types, and PCPH is mutated and/or deregulated in various human tumor types. Expression of PCPH or mt-PCPH caused similar phenotypes, yet the effects promoted by mt-PCPH expression were consistently and substantially greater. ATP depletion and increased stress-resistance are phenotypes commonly associated with PCPH and mt-PCPH expression. It was suggested that the intrinsic nucleoside triphosphate diphosphohydrolase (NTPDase) activity of PCPH and mt-PCPH may be responsible for these phenotypes, but direct supporting evidence remains to be established. Results from experiments designed to test such hypothesis demonstrate that, as expected, mt-PCPH expression in human colorectal carcinoma (CRC) cells decreased their ATP levels and conferred resistance to oxaliplatin, a colorectal cancer-relevant chemotherapeutic agent. Using a combination of site directed mutagenesis, immunoprecipitation methods, in vitro enzyme activity assays and in situ enzyme activity determinations in live cells, this report also demonstrates that the mt-PCPH oncoprotein lacks detectable NTPDase activity, indicating that direct ATP cleavage by mt-PCPH did not cause the ATP depletion observed in mt-PCPH-expressing CRC cells. These results strongly suggest that the mt-PCPH oncoprotein may regulate the cellular energy levels and subsequent chemoresistance by an NTPDase-independent mechanism. Understanding possible alternative mechanisms will be essential to devise strategies for the successful treatment of predictably therapeutically resistant tumors expressing either increased PCPH levels or, particularly, the mt-PCPH oncoprotein. PMID- 23921442 TI - The contribution of PmrAB to the virulence of a clinical isolate of Escherichia coli. AB - Previous data from our laboratory suggest a relationship between increased pmrAB expression and virulence in an Escherichia coli mouse infection model of pyelonephritis. Competitive infections with wild type and pmrAB mutants showed that disruption of pmrAB caused decreased persistence of E. coli within the mouse kidney. These results were confirmed with plasmid-mediated complementation of the pmrAB mutant. Additionally, increased expression of pmrAB from this complementing plasmid in a previously attenuated marA-rob-soxS triple mutant displayed increased bacterial persistence in the infection when compared with the triple mutant alone. These findings suggest a role for this two-component regulatory system in the virulence of E. coli in a murine pyelonephritis model. PMID- 23921443 TI - Ultrasound molecular imaging of acute cellular cardiac allograft rejection in rat with T-cell-specific nanobubbles. AB - BACKGROUND: Acute rejection (AR) is one of the main obstacles of cardiac transplantation; however, a noninvasive diagnostic method, which reflects its pathologic nature, has not been developed yet. In this study, we prepared a specific nanobubbles targeting to the activated T cells and applied it in the ultrasound molecular imaging of AR in heart transplantation by myocardial contrast echocardiography (MCE). METHODS: Nanobubbles loading anti-CD25 antibody (NB(specific)) or isotype control antibody (NB(nonspecific)) were prepared and then applied in the ultrasound molecular imaging by MCE in a rat model. MCE was performed in 24 allografts and 18 isografts that were divided into three groups, including days 2, 4, and 6 after transplantation. Confocal laser scanning microscopy was used to evaluate the binding of nanobubbles and T cells in four allografts and four isografts. RESULTS: MCE with NB(specific) in allograft showed a "delayed enhancement," and the time-intensity curve presented a second peak. The intensity and time of second peak were both positively correlated with the transplant time (P<0.01) and the pathologic grade of AR (P<0.01). Confocal laser scanning microscopy demonstrated the binding of nanobubbles and lymphocytes in myocardium post-MCE with NB(specific). CONCLUSIONS: Ultrasound molecular imaging of AR after heart transplantation can be achieved by using MCE with the nanobubbles targeted to T cells. The appearance of delayed enhancement indicates the occurrence of AR, and the intensity and time of the second peak in time intensity curve provide potential quantitative indications for diagnosis and severity of AR. PMID- 23921444 TI - Targeted antifungal prophylaxis in heart transplant recipients. AB - BACKGROUND: Antifungal prophylaxis after heart transplantation is usually targeted to high-risk recipients, but the duration is normally fixed and empirical. Our purpose was to assess the efficacy of a personalized prophylactic approach based on the duration of the risk factors. METHODS: In a prospective cohort, from 2003 to 2010, prophylaxis was only administered to patients with risk factors (13 of 133) and duration was personalized, starting with the risk factor and continued a median of 20 days after its resolution. RESULTS: Antifungal prophylaxis was prescribed only in 9.8% of the recipients and was effective in all but one patient who should have received a higher dose of caspofungin due to his obesity. Despite suffering an outbreak of invasive aspergillosis (IA) in the intensive care unit due to extremely high concentration of spores in the air (three cases with no personal risk factors), there was a reduction in the incidence of IA (8.6% vs. 2.2%; P=0.01) and Aspergillus-related mortality (5.75% vs. 1.5%; P=0.06). CONCLUSIONS: Targeted prophylaxis for IA in heart recipients provided only to patients with risk factors and maintained for a median of 20 days after their disappearance is effective and safe. A high environmental load of Aspergillus spores in the intensive care unit would also indicate the need for antifungal prophylaxis in all exposed patients. PMID- 23921445 TI - Muscle activation levels of the gluteus maximus and medius during standing hip joint strengthening exercises using elastic-tubing resistance. AB - CONTEXT: No published studies have compared muscle activation levels simultaneously for the gluteus maximus and medius muscles of stance and moving limbs during standing hip-joint strengthening while using elastic-tubing resistance. OBJECTIVE: To quantify activation levels bilaterally of the gluteus maximus and medius during resisted lower-extremity standing exercises using elastic tubing for the cross-over, reverse cross-over, front-pull, and back-pull exercise conditions. DESIGN: Repeated measures. SETTING: Laboratory. PARTICIPANTS: 26 active and healthy people, 13 men (25 +/- 3 y) and 13 women (24 +/- 1 y). INTERVENTION: Subjects completed 3 consecutive repetitions of lower extremity exercises in random order. MAIN OUTCOME MEASURES: Surface electromyographic (EMG) signals were normalized to peak activity in the maximum voluntary isometric contraction (MVIC) trial and expressed as a percentage. Magnitudes of EMG recruitment were analyzed with a 2 * 4 repeated-measures ANOVA for each muscle (alpha = .05). RESULTS: For the gluteus maximus an interaction between exercise and limb factor was significant (F3,75 = 21.5; P < .001). The moving-limb gluteus maximus was activated more than the stance limb's during the back-pull exercise (P < .001), and moving-limb gluteus maximus muscle recruitment was greater for the back-pull exercise than for the cross-over, reverse cross over, and front-pull exercises (P < .001). For the gluteus medius an interaction between exercise and limb factor was significant (F3,75 = 3.7; P < .03). Gluteus medius muscle recruitment (% MVIC) was greater in the stance limb than moving limb when performing the front-pull exercise (P < .001). Moving-limb gluteus medius muscle recruitment was greater for the reverse cross-over exercise than for the cross-over, front-pull, and back-pull exercises (P < .001). CONCLUSIONS: From a clinical standpoint there is no therapeutic benefit to selectively activate the gluteus maximus and gluteus medius muscles on the stance limb by resisting sagittal- and frontal-plane hip movements on the moving limb using resistance supplied by elastic tubing. PMID- 23921446 TI - Association of MITF and other melanosome-related proteins with chemoresistance in melanoma tumors and cell lines. AB - Previous studies in cell lines have suggested a role for melanosomes and related protein trafficking pathways in melanoma drug response. We have investigated the expression of six proteins related to melanosomes and melanogenesis (MITF, GPR143, gp100/PMEL, MLANA, TYRP1, and RAB27A) in pretreatment metastases from melanoma patients (n = 52) with different response to dacarbazine/temozolomide. Microphthalmia-associated transcription factor (MITF) and G-protein coupled receptor 143 (GPR143) showed significantly higher expression in nonresponders compared with responders. The premelanosome protein (gp100/PMEL) has been indicated previously in resistance to cisplatin in melanoma cells, but the expression levels of gp100/PMEL showed no association with response to dacarbazine/temozolomide in our clinical material. We also investigated the effects on chemosensitivity of siRNA inhibition of gp100/PMEL in the MNT-1 melanoma cell line. As expected from the study of the tumor material, no effect was detected with respect to response to temozolomide. However, knockdown of gp100/PMEL sensitized the cells to both paclitaxel and cisplatin. Overall, our results suggest that MITF, and several MITF-regulated factors, are associated with resistance to chemotherapy in melanoma and that different MITF targets can be of importance for different drugs. PMID- 23921448 TI - Dynamic flux balance analysis of batch fermentation: effect of genetic manipulations on ethanol production. AB - In silico optimization of bioethanol production from lignocellulosic biomasses is investigated by combining process systems engineering approach and systems biology approach. Lignocellulosic biomass is an attractive sustainable carbon source for fermentative production of bioethanol. For enhanced ethanol production, metabolic engineering of wild-type strains-that can metabolize both hexose and pentose sugars or microbial consortia consisting of substrate selective microbes-may be advantageous. This study presents a detailed in silico analysis of bioethanol production from glucose-xylose mixtures of various compositions by batch mono-culture and co-culture fermentation of specialized microbes. Dynamic flux balance models based on available genome-scale reconstructions of the microorganisms have been used to analyze bioethanol production, and the maximization of ethanol productivity is addressed by computing optimal aerobic-anaerobic switching times. Effects of ten metabolic engineering strategies that have been suggested in the literature for ethanol overproduction, have been evaluated for their efficiency in enhancing the ethanol productivity in the context of batch mono-culture and co-culture processes. PMID- 23921447 TI - Analysis of genome-wide association studies of Alzheimer disease and of Parkinson disease to determine if these 2 diseases share a common genetic risk. AB - IMPORTANCE: Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders. OBJECTIVE: To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD. DESIGN: Combined GWA analysis. SETTING: Data sets from the United Kingdom, Germany, France, and the United States. PARTICIPANTS: Thousands of patients with AD or PD and their controls. MAIN OUTCOMES AND MEASURES: Meta-analysis of GWA studies of AD and PD. METHODS: To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies.We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD. RESULTS: Detailed interrogation of the single nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD. CONCLUSIONS AND RELEVANCE: Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be "downstream" of the primary susceptibility genes that increase the risk of each disease. PMID- 23921449 TI - Response of constrained glassy splay-bend and twist nematic sheets to light and heat. AB - A general approach is proposed to analyze the complex photo- or thermo-response of glassy splay-bend and twist nematic sheets with boundary constraints. The governing equations are two-dimensional, as in the classical plate theory. However, the solution can generate exact three-dimensional displacement and stress distributions within the interior of the sheets, except the boundary layer whose width is of the same order of the sheet thickness. PMID- 23921450 TI - Intermediate asymptotics of the capillary-driven thin-film equation. AB - We present an analytical and numerical study of the two-dimensional capillary driven thin-film equation. In particular, we focus on the intermediate asymptotics of its solutions. Linearising the equation enables us to derive the associated Green's function and therefore obtain a complete set of solutions. Moreover, we show that the rescaled solution for any summable initial profile uniformly converges in time towards a universal self-similar attractor that is precisely the rescaled Green's function. Finally, a numerical study on compact support initial profiles enables us to conjecture the extension of our results to the nonlinear equation. PMID- 23921451 TI - Is drinking water a major route of human exposure to alkylphenol and bisphenol contaminants in France? AB - The main objective of this study was to evaluate potential exposure of a significant part of the French population to alkylphenol and bisphenol contaminants due to water consumption. The occurrence of 11 alkylphenols and bisphenols was studied in raw water and treated water samples from public water systems. One sampling campaign was performed from October 2011 to May 2012. Sampling was equally distributed across 100 French departments. In total, 291 raw water samples and 291 treated water samples were analyzed in this study, representing approximately 20 % of the national water supply flow. The occurrence of the target compounds was also determined for 29 brands of bottled water (polyethylene terephthalate [PET] bottles, polycarbonate [PC] reusable containers, and aluminum cans [ACs]) and in 5 drinking water networks where epoxy resin has been used as coating for pipes. In raw water samples, the highest individual concentration was 1,430 ng/L for bisphenol A (BPA). Of the investigated compounds, nonylphenol (NP), nonylphenol 1-carboxylic acid (NP1EC), BPA, and nonylphenol 2-ethoxylate (NP2EO) predominated (detected in 18.6, 18.6, 14.4, and 10 % of samples, respectively). Geographical variability was observed with departments crossed by major rivers or with high population densities being more affected by contamination. In treated water samples, the highest individual concentration was 505 ng/L for NP. Compared with raw water, target compounds were found in lower amounts in treated water. This difference suggests a relative effectiveness of certain water treatments for the elimination of these pollutants; however, there is also their possible transformation by reaction with chlorine. No target compounds were found in drinking water pipes coated with epoxy resin, in PET bottled water, or in water from ACs. However, levels of BPA in PC bottled water ranged from 70 to 4,210 ng/L with greater level observed in newly manufactured bottles. 4-Tert-butylphenol was only detected in recently manufactured bottles. The values observed for the monitored compounds indicate that drinking water is most likely not the main source of exposure. PMID- 23921452 TI - A self-assembled three-dimensional cloak in the visible. AB - An invisibility cloak has been designed, realized and characterized. The cloak hides free-standing sub-wavelength three-dimensional objects at the short wavelength edge of the visible spectrum. By a bottom-up approach the cloak was self-assembled around the object. Such fabrication approach constitutes a further important step towards real world applications of cloaking; leaving the realm of curiosity. The cloak and the way it was fabricated opens an avenue for many spectacular nanooptical applications such as non-disturbing sensors and photo detectors, highly efficient solar cells, or optical nanoantenna arrays with strongly suppressed cross-talk to mention only a few. Our results rely on the successful combination of concepts from various disciplines, i.e. chemistry, material science, and plasmonics. Consequently, this work will stimulate these fields by unraveling new paths for future research. PMID- 23921454 TI - Synthesis of a 3D graphite microball using a microfluidic droplet generator and its polymer composite with core-shell structure. AB - Spherical 3D graphite microballs (3D GMs) and their nanohybrids (3D GM-Fe3O4 nanoparticles) were synthesized by using a microfluidic droplet generator and a thermal evaporation-induced capillary compression method. Using the 3D GM-Fe3O4 nanoparticle as a support for polymerization, 3D GM-polypyrrole composites were produced with a unique core-shell structure. PMID- 23921456 TI - Prevalence of atopy and respiratory allergic diseases in the elderly SAPALDIA population. AB - BACKGROUND: Because of changing world demographics, the elderly population is steadily increasing. Few studies have assessed the prevalence of atopy and allergic diseases in elderly persons with objective measures. The aim of this paper is to describe the prevalence of atopy, self-reported allergic rhinitis and doctor's diagnosed asthma in persons over the age of 60 in Switzerland. METHODS: The cross-sectional examination of the Swiss Study on Air Pollution and Health in Adults (SAPALDIA 1), performed in 1991, included 9,651 adults aged 18-60 years. In 2001-2002 the same subjects were invited for a follow-up examination (SAPALDIA 2). Serum samples collected at baseline and follow-up were tested for specific IgE sensitization with the Phadiatop(r) (Phadia, Uppsala, Sweden, now Thermo Fisher Scientific) assay containing a mixture of common respiratory allergens (grass, birch, mugwort, Parietaria and olive pollen, dog, cat, horse, Cladosporium herbarum, house dust mite and flour mite). Atopy was defined as a positive result in the Phadiatop test according to guidelines by the manufacturer. The prevalence rates of atopy, self-reported allergic rhinitis and doctor's diagnosed asthma were evaluated by sex and age group (<=60 or >60 years). RESULTS: 7,667 subjects (men = 3,692/women = 3,975) participated in the follow-up by responding to a detailed questionnaire (80% of SAPALDIA 1 participants). Phadiatop results were available for 5,835 participants (men = 2,839/women = 2,996). Prevalence rates of atopy (Phadiatop positive) were 36.4% in men aged <=60 years versus 26.2% in men aged >60 years and 30.6 and 18.1% in women, respectively (both p < 0.001). Prevalence rates of self-reported allergic rhinitis in subjects >60 years old were 13.0% for men and 15.4% for women (p = 0.12), and for doctor's diagnosed asthma 6.6% versus 7.6%, respectively (p = 0.40). Both rhinitis and asthma prevalences were higher in persons <60 years. The results were not sensitive to potential bias from nonparticipation at follow-up as demonstrated by imputation of sex- and age-specific allergic rhinitis and asthma among nonparticipants. CONCLUSIONS: According to our estimates, the prevalence of allergic rhinitis among persons aged between 60 and 70 years in Switzerland in the present cohort is of the order of 13-15% and should not be underestimated, although it is lower than in age groups <=60 years. PMID- 23921457 TI - Fruit and vegetable consumption and BMI change in primary school-age children: a cohort study. AB - BACKGROUND/OBJECTIVES: Healthy eating behaviours, such as increasing fruit and vegetable consumption (FVC), are frequently used as a target or outcome measure in obesity prevention interventions. The goal of this study was to demonstrate replacement of high-caloric foods/drinks by FVC and changes in body mass index (BMI) z-score associated with FVC. SUBJECTS/METHODS: Anthropometric measurements of 1252 children (51.0% girls) were taken before school entrance (age 6 years) and repeated in the fourth grade (age 10 years). At the same time, parents were asked about their children's diet using a questionnaire. RESULTS: In longitudinal analysis, changes in FVC were not significantly correlated with changes of other nutritional habits, such as consumption of sweets and high-caloric drinks. BMI gain tended to be lower (nonsignificant) in children with increasing fruit consumption compared to those with decreasing fruit consumption. An opposite (nonsignificant) tendency was observed for vegetable consumption and BMI gain. CONCLUSIONS: Although beneficial for other health outcomes, the evidence for FVC replacing high-energy foods and thereby reducing BMI gain is weak and could not be substantiated in this study. This might be partially due to the limitation in dietary assessment. PMID- 23921453 TI - A multidimensional approach to apathy after traumatic brain injury. AB - Apathy is commonly described following traumatic brain injury (TBI) and is associated with serious consequences, notably for patients' participation in rehabilitation, family life and later social reintegration. There is strong evidence in the literature of the multidimensional nature of apathy (behavioural, cognitive and emotional), but the processes underlying each dimension are still unclear. The purpose of this article is first, to provide a critical review of the current definitions and instruments used to measure apathy in neurological and psychiatric disorders, and second, to review the prevalence, characteristics, neuroanatomical correlates, relationships with other neurobehavioural disorders and mechanisms of apathy in the TBI population. In this context, we propose a new multidimensional framework that takes into account the various mechanisms at play in the facets of apathy, including not only cognitive factors, especially executive, but also affective factors (e.g., negative mood), motivational variables (e.g., anticipatory pleasure) and aspects related to personal identity (e.g., self-esteem). Future investigations that consider these various factors will help improve the understanding of apathy. This theoretical framework opens up relevant prospects for better clinical assessment and rehabilitation of these frequently described motivational disorders in patients with brain injury. PMID- 23921458 TI - In-work tax credits for families and their impact on health status in adults. AB - BACKGROUND: By improving two social determinants of health (poverty and unemployment) in low- and middle-income families on or at risk of welfare, in work tax credit for families (IWTC) interventions could impact health status and outcomes in adults. OBJECTIVES: To assess the effects of IWTCs on health outcomes in working-age adults (18 to 64 years). SEARCH METHODS: We searched 16 electronic academic databases, including the Cochrane Public Health Group Specialised Register, Cochrane Database of Systematic Reviews (The Cochrane Library 2012, Issue 7), MEDLINE and EMBASE, as well as six grey literature databases between July and September 2012 for records published between January 1980 and July 2012. We also searched key organisational websites, handsearched reference lists of included records and relevant journals, and contacted academic experts. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials and cohort, controlled before-and-after (CBA) and interrupted time series (ITS) studies of IWTCs in working-age adults. Included primary outcomes were: self rated general health; mental health/psychological distress; mental illness; overweight/obesity; alcohol use and tobacco use. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias in included studies. We contacted study authors to obtain missing information. MAIN RESULTS: Five studies (one CBA and four ITS) comprising a total of 5,677,383 participants (all women) fulfilled the inclusion criteria and were synthesised narratively. The in-work tax credit intervention assessed in all included studies is the permanent Earned Income Tax Credit in the United States, established in 1975. This intervention distributed nearly USD 62 billion to over 27 million individuals in 2011, and its administration costs were less than one per cent of its total costs. All included studies carried a high risk of bias (especially from confounding and insufficient control for underlying time trends). Due to the small number of (observational) studies and their high risk of bias, we judged this body of evidence to have very low overall quality.One study found that IWTC had no detectable effect on self rated general health and mental health/psychological distress five years after its implementation (i.e. a considerable change in the generosity of the permanent IWTC) and on overweight/obesity eight years after implementation. One study found no effect of IWTC on tobacco use five years after implementation, one a moderate reduction in tobacco use one year after implementation (odds ratio 0.95, 95% confidence interval (CI) 0.94 to 0.96), and one differential effects, with no effect in African-Americans and a large reduction in European-Americans two years after implementation (risk difference -11.1%, 95% CI -20.9% to -1.3%). No evidence was available for the effect of IWTC on mental illness and alcohol use. No adverse effects of IWTC were identified.One study also found no detectable effect of IWTC on the number of bad physical health days and of risky biomarkers for inflammation, cardiovascular disease and metabolic conditions eight years after implementation. One study found that IWTC had a large, positive effect on income from wages or salaries one year after implementation. Two studies found no effect on employment two and five years after implementation, whereas two found a moderate increase five and eight years after implementation and one a large increase in employment due to IWTC one year after implementation.No differences in outcomes between groups with different educational status were found for self rated health and mental health/psychological distress. In one study European American women with lower levels of education were more likely to reduce tobacco use, while tobacco use did not change among African-American women with lower levels of education. However, no differences in tobacco use by educational status were observed in a second study. Two studies found that the intervention may have reduced inequity with respect to employment, where women with less education were more likely to move into employment (although one did not establish whether this difference was statistically significant), while two studies found no such difference and no studies found differences by ethnic group on employment rates. AUTHORS' CONCLUSIONS: In summary, the small and methodologically limited existing body of evidence with a high risk of bias provides no evidence for an effect of in-work tax credit for families interventions on health status (except for mixed evidence for tobacco smoking) in adults. PMID- 23921459 TI - Isolation of mesenchymal stem-like cells in meningioma specimens. AB - Cells resembling bone marrow mesenchymal stem cells (BM-MSCs) have been isolated from glioma specimens; however, little is known about the existence of mesenchymal stem-like cells (MSLCs) in meningioma. Here, we hypothesized that cells similar to BM-MSCs exist in meningioma specimens and sought to investigate whether these putative meningioma stroma MSLCs (MS-MSLCs) could be isolated. To this end, we cultured fresh meningioma specimens using the same protocols as used previously to isolate BM-MSC. Cultured cells were analyzed for surface markers associated with BM-MSCs by fluorescence-activated cell sorting (FACS) and candidate cells were exposed to mesenchymal differentiation conditions. Possible locations of MS-MSLCs were determined by immunohistochemical analysis of sections of meningioma specimens. Spindle-shaped and, adherent cells similar to BM-MSCs were isolated in 2 of 20 meningioma specimens. FACS analysis showed that the surface markers of MS-MSLCs were similar to those of BM-MSCs and the chosen cells demonstrated an ability to differentiate into osteogenic, adipogenic and chondrogenic cells. The tumorigenicity of MS-MSLCs was tested by injection of these cells into the brain of athymic nude mice; no tumors were subsequently discovered. Immunohistochemical analyses indicated that CD105+ cells were closely associated with endothelial cells and pericytes in meningioma specimens. Our results established for the first time that cells similar to BM-MSCs exist in meningioma specimens. These cells, termed MS-MSLCs, could be one component of the meningioma cellular microenvironment. PMID- 23921461 TI - Dual diagnosis screening interview to identify psychiatric comorbidity in substance users: development and validation of a brief instrument. AB - AIM: The objective of this study was to develop and validate a brief tool, the Dual Diagnosis Screening Instrument (DDSI), to screen psychiatric disorders in substance users in treatment and nontreatment-seeking samples. METHODS: A total of 827 substance users (66.5% male, mean age 28.6+/-9.9 years) recruited in treatment (in- and outpatient) and nontreatment (substance user volunteers in university research studies) settings were assessed by trained interviewers using the DDSI and the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) as the criterion standard. Both instruments were administered blind to the results of the other. Disorders obtained with the DDSI were compared to lifetime diagnoses obtained with the PRISM. Sensitivity, specificity, negative, and positive predictive values were estimated. Also test-retest reliability of the DDSI was assessed. RESULTS: The DDSI showed a high sensitivity (>=80%) for identifying lifetime depression, mania, psychosis, panic, social phobia, and specific phobia disorders. Specificity was >=82% for those diagnoses. Test-retest kappa showed excellent agreement (range 81-95%). The mean duration of the DDSI administration was 16.8+/-2.5 min. CONCLUSION: The DDSI is a valid and easy-to-administer screening tool to detect possible psychiatric comorbidity among substance users. PMID- 23921462 TI - An indicator to estimate the access to imaging services in the Costa Rican public health system. AB - The aim of this work was to develop an indicator that estimates the population's access to imaging services (IS) of health care facilities in the Costa Rican Public Health System, taking into account five aspects: (a) health care facilities infrastructure, (b) capacity of the IS according to the installed technological resources, (c) epidemiological aspects, (d) demographic aspects, and (e) location of the health facility in relation to the Capital. To achieve this, 14 variables and 7 indicators were defined. These indicators were integrated into a mathematical function which resulted in a global indicator that throws quantitative data that represents the level of access of a population to the IS in their geographic region of influence. The application of the indicator was performed in eight health facility sub-networks with defined geographical regions within the territory of Costa Rica. The level of access to the imaging service of the inhabitants of the eight sub-networks results that three of them obtained a bad access, located in east and north-central of the country; other three sub-networks obtained regular access, located in the west; and the last two who obtained a good access are located in the center of the country. The results showed that the imaging services are not equitable in each sub-network. Knowing this, it is possible to work on healthcare technology management proposals in order to strengthen the regional imaging services, contributing to decentralizing the services of the general hospitals located in the Capital. PMID- 23921460 TI - Adherence and uptake of Francisella into host cells. AB - Francisella tularensis is a highly virulent bacterial pathogen that is easily aerosolized and has a low infectious dose. As an intracellular pathogen, entry of Francisella into host cells is critical for its survival and virulence. However, the initial steps of attachment and internalization of Francisella into host cells are not well characterized, and little is known about bacterial factors that promote these processes. This review highlights our current understanding of Francisella attachment and internalization into host cells. In particular, we emphasize the host cell types Francisella has been shown to interact with, as well as specific receptors and signaling processes involved in the internalization process. This review will shed light on gaps in our current understanding and future areas of investigation. PMID- 23921463 TI - The unusual dynamics of parasite actin result from isodesmic polymerization. AB - Previous reports have indicated that parasite actins are short and inherently unstable, despite being required for motility. Here we re-examine the polymerization properties of actin in Toxoplasma gondii, unexpectedly finding that it exhibits isodesmic polymerization in contrast to the conventional nucleation-elongation process of all previously studied actins from both eukaryotes and bacteria. Polymerization kinetics of actin in T. gondii lacks both a lag phase and critical concentration, normally characteristic of actins. Unique among actins, the kinetics of assembly can be fit with a single set of rate constants for all subunit interactions, without need for separate nucleation and elongation rates. This isodesmic model accurately predicts the assembly, disassembly and the size distribution of actin filaments in T. gondii in vitro, providing a mechanistic explanation for actin dynamics in vivo. Our findings expand the repertoire of mechanisms by which actin polymerization is governed and offer clues about the evolution of self-assembling, stabilized protein polymers. PMID- 23921464 TI - Similarity of lateralized rhythmic delta activity to periodic lateralized epileptiform discharges in critically ill patients. AB - IMPORTANCE: The increasing use of continuous electroencephalography (EEG) monitoring in the intensive care unit has led to recognition of new EEG patterns that are of unclear or unknown significance. OBJECTIVE: To describe an EEG pattern, lateralized rhythmic delta activity (LRDA), encountered in critically ill subjects and determine its clinical significance in this setting. DESIGN, SETTING, AND PARTICIPANTS Retrospective review at an academic medical center of EEG recordings, medical records, and imaging studies of critically ill patients with LRDA and comparison with subjects with lateralized periodic discharges (also known as periodic lateralized epileptiform discharges), subjects with focal nonrhythmic slowing, and controls. INTERVENTION: Electroencephalography or continuous electroencephalography. MAIN OUTCOMES AND MEASURES: Cross-sectional prevalence of lateralized rhythmic delta activity; EEG characteristics; etiology, clinical, and radiological correlates; and risk of early seizures. RESULTS: We identified LRDA in 4.7%of acutely ill subjects undergoing EEG or continuous EEG monitoring. It was often associated with other focal EEG abnormalities, including lateralized periodic discharges in 44%of cases. The most common conditions associated with LRDA were intracranial hemorrhage and subarachnoid hemorrhage. Lateralized rhythmic delta activity was an independent predictor of acute seizures, with 63%of subjects having seizures during their acute illness, a proportion similar to subjects with lateralized periodic discharges (57%) and significantly higher than associated with focal nonrhythmic slowing (20%) or in control subjects (16%). Most patients (80%-90%) in the LRDA and lateralized periodic discharges groups who had seizures while undergoing continuous EEG monitoring had only nonconvulsive seizures, whereas this was the case for only 17%of patients in the other groups. Lateralized rhythmic delta activity and lateralized periodic discharges were both associated with lesions involving the cortex or juxtacortical white matter. CONCLUSIONS AND RELEVANCE: Lateralized rhythmic delta activity in critically ill patients has a similar clinical significance as lateralized periodic discharges. It reflects the presence of a focal lesion and is associated with a high risk of acute seizures, especially nonconvulsive. PMID- 23921466 TI - Successful endoscopic strategies for difficult polypectomy. AB - PURPOSE OF REVIEW: Standard endoscopic polypectomy is a powerful technique to remove most polyps found in the gastrointestinal tract. However, a small percentage of polyps can be classified as difficult, based on size, location, and/or configuration. Traditionally, these difficult polyps were referred for surgical segmental colectomy. Recently, with advancements in endoscopic techniques and accessories, a majority of these difficult polyps are now able to be completely resected using entirely endoscopic techniques. RECENT FINDINGS: Endoscopic techniques and accessories have been evolving during recent years, including increased dissemination of techniques of endoscopic submucosal dissection to the western hemisphere. In addition to refinement of endoscopic techniques, there has been increased interest in developing improved endoscopic accessories, including novel submucosal injectate with auto-dissecting properties, to improve safety and efficiency of endoscopic resection of difficult polyps. SUMMARY: This article will review currently available techniques and strategies for successful endoscopic resection for difficult polyps. PMID- 23921465 TI - Induction of antiviral genes by the tumor microenvironment confers resistance to virotherapy. AB - Oncolytic viruses obliterate tumor cells in tissue culture but not against the same tumors in vivo. We report that macrophages can induce a powerfully protective antiviral state in ovarian and breast tumors, rendering them resistant to oncolytic virotherapy. These tumors have activated JAK/STAT pathways and expression of interferon-stimulated genes (ISGs) is upregulated. Gene expression profiling (GEP) of human primary ovarian and breast tumors confirmed constitutive activation of ISGs. The tumors were heavily infiltrated with CD68+ macrophages. Exposure of OV-susceptible tumor cell lines to conditioned media from RAW264.7 or primary macrophages activated antiviral ISGs, JAK/STAT signaling and an antiviral state. Anti-IFN antibodies and shRNA knockdown studies show that this effect is mediated by an extremely low concentration of macrophage-derived IFNbeta. JAK inhibitors reversed the macrophage-induced antiviral state. This study points to a new role for tumor-associated macrophages in the induction of a constitutive antiviral state that shields tumors from viral attack. PMID- 23921467 TI - Current world literature. Endoscopy, pancreas. PMID- 23921470 TI - Diabetes prevention in postmenopausal women: lifestyle, metformin, and sex steroid intervention revisited. PMID- 23921469 TI - In silico modeling and evaluation of Gordonia alkanivorans for biodesulfurization. AB - The genus Gordonia is well known for its catabolic diversity and ability to transform several compounds including the various recalcitrant polyaromatic sulfur heterocycles (PASHs) found in the fossil fuels. In fact, some strains offer the unique ability to desulfurize even benzothiophene (BT) and other thiophenic compounds, which most of the commonly studied rhodococci strains cannot. In this work, we present the first genome scale metabolic model for G. alkanivorans, a desulfurizing strain, to enable a holistic study of its metabolism and comparison with R. erythropolis. Our model consists of 881 unique metabolites and 922 reactions associated with 568 ORFs/genes and 544 unique enzymes. It successfully predicts the growth rates from experimental studies and quantitatively elucidates the pathways for the desulfurization of the commonly studied sulfur compounds, namely dibenzothiophene (DBT) and benzothiophene (BT). Using our model, we identify the minimal media for G. alkanivorans, and show the significant effect of carbon sources on desulfurization with ethanol as the best source. Our model shows that the sulfur-containing amino acids such as cysteine and methionine decrease desulfurization activity, and G. alkanivorans prefers BT over DBT as a sulfur source. It also suggests that this preference may be driven by the lower NADH requirements for BT metabolism rather than the higher affinity of the transport system for BT. Our in silico comparison of R. erythropolis and G. alkanivorans suggests the latter to be a better desulfurizing strain due to its versatility for both BT and DBT, higher desulfurization activity, and higher growth rate. PMID- 23921471 TI - Just relax! PMID- 23921473 TI - Re: Multimorbidity and associated factors in Brazilian women aged 40 to 65 years: a population-based study. PMID- 23921472 TI - Scientific rationale for postmenopause delay in the use of conjugated equine estrogens among postmenopausal women that causes reduction in breast cancer incidence and mortality. AB - High-dose synthetic estrogens were the first successful chemical therapy used in the treatment of metastatic breast cancer in postmenopausal women, and this approach became the standard of care in postmenopausal women with metastatic breast cancer between the 1950s and the end of the 1970s. The most recent analysis of the Women's Health Initiative estrogen-alone trial in hysterectomized women revealed a persistently significant decrease in the incidence of breast cancer and breast cancer mortality. Although estrogens are known to induce the proliferation of breast cancer cells, we have shown that physiologic concentrations induce apoptosis in breast cancer cells with long-term estrogen deprivation. We have developed laboratory models that illustrate the new biology of estrogen-induced apoptosis or growth to explain the effects of estrogen therapy. The key to the success of estrogen therapy lies in a sufficient period of withdrawal of physiologic estrogens (5-10 y) and the subsequent regrowth of nascent breast tumor cells that survive under estrogen-deprived conditions. These nascent tumors are now vulnerable to estrogen-induced apoptosis. PMID- 23921474 TI - Re: Multimorbidity and associated factors in Brazilian women aged 40 to 65 years: a population-based study--reply. PMID- 23921475 TI - Re: The bone-promoting actions of formononetin in established osteopenia. PMID- 23921476 TI - Re: The bone-promoting actions of formononetin in established osteopenia--reply. PMID- 23921477 TI - Clinic of Gastroenterohepatology--overview of activities. AB - CThe Clinic of Gastroenterohepatology is a part of the Medical Faculty Skopje and University "St. Cyril and Methodius University, Skopje". It is organized as an educational, scientific and medical care institution. CThere are four diagnostic departments: an out-patients department, endoscopic department, ultrasound department and X-ray department. During Over the last several decades, the Clinic of Gastroenterohepatlogy Clinic has been intensively developed, primarily because of introducing the most recent and modern knowledge in gastroenterology, continuous medical education of the personneal as well education of the doctors and other medical personal from the other medical centrers in Macedonia and neighbouring countries. The hospital part of the Clinic is organized in three divisions, including an intensive care unit. In the department of Ultrasound are performed The most modern diagnostic and therapeutic procedures are performed in the Ultrasound department for: different various liver diseases, benign and malignant liver diseases, bilirye ducts obstructions, pancreas diseases, spleen diseases, and various abdominal and kidney diseases. PMID- 23921478 TI - University cardiology clinic. AB - In distant 1972, within framework of the Internal Clinic, a cardiologic department was organized which was soon, on 29.XII.1974, transformed into the Cardiology Clinic, later the Institute for Heart Diseases, and in 2008 was renamed the University Cardiology Clinic. The greater part of its foundation was possible owing to Prof. Dimitar Arsov and Prof. Radovan Percinkovski, who was the clinic's first director in the period from 1974 to 1984. In 1985, the Clinic moved into its own new building, and in that way was physically detached from the Internal Clinics. Until its move to the new building, the Clinic functioned in the Internal Clinics building, organized as an outpatient polyclinic and inpatient infirmary department with clinical beds, a coronary intensive care unit and a haemodynamics laboratory equipped with the most modern equipment of that time. Today the Clinic functions through two integral divisions: an inpatient infirmary department which comprises an intensive coronary care unit and fourteen wards which altogether have 139 clinical beds, and the diagnostic centre which comprises an emergency clinic and day hospital, a communal and consultative outpatients' clinic functioning on a daily basis, through which some 300-350 patients pass every day, and diagnostic laboratories with a capacity of nearly 100 non-invasive and 20-30 invasive diagnostic procedures daily. The Clinic is a teaching base, and its doctors are educators of students at the Medical, Dental and Pharmacy Faculties, and also of students at the High School for Nurses and X ray technicians, but also for those in Internal Medicine and especially Cardiology. The Clinic is also a base for scientific Masters' and post-doctoral studies, and such higher degrees are achieved not only by doctors who work here, but also by doctors from Medical Centres both in the country and abroad. Doctors working in this institution publish widely, not only a great number of books and monographs, but also original scientific papers published in indexed medical journals. PMID- 23921479 TI - Department of Nephrology at the Medical Faculty, Ss. Cyril and Methodius University, Skopje--creating nephrology protection for the citizens of the Republic of Macedonia. AB - In January 1975, de facto, the Nephrology Department was founded at the Medical Faculty in Skopje as the first institution of such a type in former Yugoslavia. The Nephrology Department was the driving force for the further development of nephrology in the Republic of Macedonia. D. Hrisoho was the first Director of the Department, and its subsequent Directors were G. Masin, M. Polenakovic, K. Zafirovska and currently A. Sikole. Prior to the establishment of the Nephrology Clinic there had been considerable experience in the diagnosis and treatment of renal patients. The first haemodialysis (HD) in the Republic of Macedonia (RM) was performed in 1959 on a patient with acute renal failure (ARF) using a Kolff Brigham rotating drum artificial kidney at the Blood Transfusion Institute in Skopje. In 1965 the Renal Unit at the Department of Medicine, Medical Faculty, Skopje obtained a new, modern "Websinger" artificial kidney with a sigma motor pump and possibilities for the use of a disposable Kolff "twin coil" dialyser. Between 1959 and 1971, HD was performed only on patients with ARF. In May 1971, a Unit for Chronic HD was founded at the Renal Unit and the programme of maintenance haemodialysis (MHD) was started with five Stuttgart Fresenius machines and 12 patients dialysed on twin coil dialysers. That was a great incentive for the development of HD in the Republic of Macedonia enforced by the great number of patients with end stage renal disease. Thus in 2007 we have 18 HD centres in the Republic of Macedonia, with 1183 patients. Treatment of the patients with MHD is the greatest success achieved in the Republic of Macedonia in nephrology concerning patients with end stage renal disease. Prior to the treatment with MHD patients were destined to die, whereas now, with this type of treatment, they have a normal life and families. Patients with kidney diseases are examined in outpatients clinics as well as treated in the wards of the Department. All types of vascular accesses, renal biopsies, bone biopsies, kidney ultrasound, plasmapheresis and other investigations are performed every day at the Nephrology Department of the Medical Faculty. On the basis of the results of renal biopsy, a classification of parenchymal renal diseases has been established, as well as appropriate immunosuppressive and other treatments. The nephrology doctrine for primary, secondary and tertiary healthcare has been prepared and has been distributed to all medical centres in the Republic of Macedonia. The first (living donor) renal transplantation was performed in July 1977. Later, living and cadaver donor transplantations were performed, so the Department of Nephrology was complete concerning dialysis and renal transplantation, and it became part of the European centres for diagnosis and therapy of kidney disease. Doctors from the Nephrology Department are among the most productive scientific workers in the Republic of Macedonia and their papers can be found on the internet Pub Med. The Department of Nephrology, together with the Nephrology Association, was the source of knowledge in the area of nephrology and the transfer of knowledge from abroad into Macedonia and vice versa. The Nephrology Association has made a great contribution in the development of nephrology in our country. The most famous European and world nephrologists have participated in the work of our association and have contributed to the development of nephrology not only in Macedonia, but on the Balkans as well. PMID- 23921480 TI - Development of the clinic of pulmonology and allergy. AB - University Pulmology and Allergy Clinic was founded in 1975 when the Depertment of Internal Medicine, directed by Prof. Dr. Dimitar Arsov, later member of the Macedonian Academy of Sciencies and Arts, was divided into eight separate and independent clinics. The first head of the Pulmonology and Allergy Clinic was Prof. Dr. Ljubomir Kotevski. He had a very difficult goal: to establish and further develop the newly formed clinic. The Clinic flourished and became one of the leading Clinics in the Clinical Centre during the directorship of Prof. dr. Dejan Dokic.. He completely rebuilt and refurbished the Clinic, which became a modern Clinic providing excellent working conditions for the employees and, most importantly, provided a first class service to the patients. During his mandate he obtained a grant from the Japanese Government worth $1,000,000 which was used to obtain a new, modern and sophisticated medical equipment. Since the establishment of the clinic, many national and international scientific projects were carried out and many scientific papers were published as well as many monographs, and chapters in scientific books. As a result of continuous education, of the total number of 24 doctors there are 16 subspecialists in respiratory medicine and 4 specialists in internal medicine. There are 9 professors in internal medicine at the University of Pulmonology and Allergy Clinic lecturing at the Medical Faculty in Skopje. The University Pulmonology and Allergy Clinic has an international reputation due to many contacts with famous European Institutions. All these international interrelations have resulted in honouring 3 professors: Prof. Dr. Gert Kunkel from Berlin, Germany, Prof. Dr. Robert Loddenkemper from Berlin, Germany and Prof. Dr. Peter Howard from Southampton, UK. PMID- 23921481 TI - Haematology in the Republic of Macedonia: present situation and brief history. AB - The development of clinical haematology in Macedonia has taken place over the past nine decades. The greatest expansion of its development took place in the second half of the 20th century. The oficial start of clinical haematology dates from 1956, when the Department of Haematology was founded within the framework of the Internal Medicine Clinic in Skopje. In the beginning, haematology represented a form of virtual sub-specialty, but its expansion was so progressive and rapid that it reached the highest peaks of Yugoslav haematology in those times. The period from 1968 to 1979 was a period of integral development of haematology and blood-transfusion science in Macedonia. Nowadays, the autonomous Public Health Institution, the University Hematology Clinic, is a unique healthcare, educational and scientific establishment in the Republic of Macedonia in its field of work. The diagnostics algorithm comprises cyto-morphologic and cyto chemical analysis, through immunologic characterization with the assistance of a flow cytometer, to sophisticated molecular analysis for detecting genetic abnormalities. The therapeutic approach is based upon modern poly haemotherapeutic protocols, application of monoclonal antibodies, immuno modulatory agents, molecular target therapy and the use of alogeneic and autologous transplantation of fresh bone-marrow and frozen haemopoietic stem cells. The current motto of the Haematology Clinic is: always help those who seek help, provide precise and early diagnostics, and apply all up-to-date therapeutic strategies, scientific research, continual education and day-to-day implementation of the latest achievements in the field of haematology in daily practice. PMID- 23921482 TI - Development of the Clinic of Endocrinology, diabetes and metabolic disorders. AB - The Clinic of Endocrinology, diabetes and metabolic disorders was founded in 1975 by Prof d-r Alexandar Plashevski. Healthcare, educational and scientific activities in the Clinic of Endocrinology are performed in its departments. The Department for hospitalized diabetic and endocrine patients consists of the metabolic and endocrine intensive care unit, the department for diagnosis and treatment of diabetics and endocrine patients, day hospital, the department for education of diabetic patients, and the national center for insulin pump therapy. The Center for Diabetes was established in 1972 by Prof d-r Dimitar Arsov. In 1975, Prof d-r Alexandar Plasheski broadened the activities of the Center for Diabetes. It was dislocated in 1980, with new accommodation outside the clinic. Since then the Center has consisted of several organized units: two specialist outpatient clinics for diabetic patients, biochemical and endocrine laboratory, sub-departments for: diabetic foot, cardiovascular diagnosis, ophthalmology, and urgent interventions. The Department of Endocrinology and Metabolic Disorders for outclinic endocrine patients was established in 1980, and it integrates the following sub-departments: thyrology, andrology, reproductive endocrinology, obesity and lipid disorders and sub-department for osteoporosis. The educational staff of the Clinic of Endocrinology organizes theoretical and practical education about Clinical Investigation and Internal Medicine with credit transfer system course of study of the Medical Faculty, Faculty of Stomatology, postgraduate studies, specializations and sub-specializations. Symposiums, 3 congresses, schools for diabetes and osteoporosis and continuous medical education were also organized. The Clinic of Endocrinology was initiator, organizer, founder and the seat of several medical associations. PMID- 23921483 TI - Effect of chromium-enriched yeast on fasting plasma glucose, glycated haemoglobin and serum lipid levels in patients with type 2 diabetes mellitus treated with insulin. AB - Chromium is required for a normal insulin function, and low levels have been linked with insulin resistance. The aim of this study was to follow the effect of chromium supplementation on fasting plasma glucose (FPG), glycated haemoglobin (HbA1c) and serum lipids in patients with type 2 diabetes mellitus (DM2) on insulin therapy. Eleven randomly selected patients with DM2 on insulin therapy were supplemented with a daily dose of 100 MUg chromium yeast for the first supplementation period of 2 weeks. In the second supplementation period, the chromium dose was doubled and continued for the next 6 weeks. The third phase was a 6-week washout period. After each period, the levels of FPG and HbA1c were compared with the corresponding values at the end of the previous period. Serum triglycerides, total HDL and LDL cholesterol values after supplementation were compared with the baseline values. FPG decreased significantly after the first period of chromium supplementation (p < 0.001), and a tendency to a further reduction was observed after the second supplementation period. Similarly, HbA1c decreased significantly in both periods (p < 0.02 and p < 0.002, respectively). Eight weeks after withdrawal of chromium supplementation, both FPG and HbA1c levels returned to their pre-intervention values. The serum lipid concentrations were not significantly influenced by chromium supplementation. Chromium supplementation could be beneficial in patients with DM2 treated with insulin, most likely due to lowered insulin resistance leading to improved glucose tolerance. This finding needs to be confirmed in a larger study. PMID- 23921484 TI - Zip1, Zip2, and Zip8 mRNA expressions were associated with growth hormone level during the growth hormone provocation test in children with short stature. AB - Short stature of children is affected by multiple factors. One of them is growth hormone (GH) deficiency. Growth hormone therapy can increase the final height of children with growth hormone deficiency. Zinc is found to induce dimerization and to enhance the bioactivity of human GH. Two gene families have been identified involved in zinc homeostasis. Previous studies in our laboratory have shown that Zip1, Zip2, Zip6, and ZnT1 mRNA were associated with zinc level in established human breast cancer in nude mice model; Zip8 was significantly lower in zinc deficient Wistar rats in kidney. In this study, five zinc transporters: Zip1, Zip2, Zip6, Zip8, and ZnT1 were chosen. We aimed to investigate the mRNA expression of zinc transporters and to explore the relationship between zinc transporters and growth hormone in short stature children. Growth hormone provocation test is used to confirm the diagnosis of growth hormone deficiency. Six short children for the test were enrolled. At the same time, 15 sex- and age matched normal children were enrolled as control. The expression levels of zinc transporters in peripheral blood mononuclear cells were determined by quantitative real-time PCR. Zip1 and Zip2 mRNA expression positively correlated with growth hormone level (r = 0.5133, P = 0.0371; r = 0.6719, P = 0.0032); Zip8 mRNA expression negatively correlated with growth hormone level (r = -0.5264, P = 0.0285) during the test in short stature children. The average expression level of Zip2 was significantly higher and Zip6, Zip8 mRNA levels were significantly lower in short stature children than in health controls at 0 min (P < 0.05, P < 0.05). PMID- 23921485 TI - Structural aspects of digestion of medium chain triglycerides studied in real time using sSAXS and Cryo-TEM. AB - PURPOSE: The purpose of this study was to investigate the colloidal structures formed on digestion of medium chain triglyceride (MCT) with a specific objective of identifying and characterizing a previously reported vesicular phase, which has been linked to supersaturation and anomalous digestion kinetics, and to evaluate the influence of lipid mass and enzyme inhibition on self assembled structure. METHODS: MCT was digested in vitro and nanostructure was monitored in real time using synchrotron small angle X-ray scattering (sSAXS), and morphology was studied using cryogenic transmission electron microscopy (cryo-TEM). RESULTS: Formation of the putative vesicular phase formed on digestion of MCT was confirmed and its structural attributes were determined. Vesicle formation was dependent on lipid mass and bile salt concentration. The use of enzyme inhibitor for offline analysis of lipolysis samples did influence structural aspects of the digestion medium when compared to real time evaluation. CONCLUSIONS: The formation of a vesicular phase was directly linked to the kinetics of lipid digestion. Vesicle formation is linked to lipid mass, or more specifically the ratio of lipid to bile salts present in the digestion mixture. Inhibition of lipase to halt digestion during sampling for offline analysis must be done with caution as structural aspects were shown to differ for the MCT digests with and without inhibitor present. PMID- 23921487 TI - Brain drug delivery systems. PMID- 23921486 TI - Mitochondrial delivery of doxorubicin by triphenylphosphonium-functionalized hyperbranched nanocarriers results in rapid and severe cytotoxicity. AB - PURPOSE: To develop a novel hyperbranched polymer-based nanocarrier for efficient drug delivery to cell mitochondria. Also to study for the first time the cytotoxic effect of doxorubicin via mitochondria-specific delivery system. METHODS: We introduced alkyltriphenylphosphonium groups (TPP) to a poly(ethylene imine) hyperbranched polymer (PEI). We harnessed the hydrophobic assembly of these alkylTPP functionalized PEI molecules into ~100 nm diameter nanoparticles (PEI-TPP) and further encapsulated the chemotherapy agent doxorubicin (DOX), to produce the mitotropic nanoparticles PEI-TPP-DOX. RESULTS: By administering PEI TPP-DOX to human prostate carcinoma cells DU145, we found that: (i) PEI-TPP-DOX specifically localized at cell mitochondria as revealed by the inherent DOX fluorescence; (ii) in contrast to the slow apoptotic cell death incurred by DOX over the period of days at micromolar concentrations, PEI-TPP-DOX triggered rapid and severe cytotoxicity within few hours of incubation and at submicromolar incubation concentrations. This cytotoxicity was mainly found to be of a necrotic nature, not precluding autophagy related death pathways to a smaller extent. CONCLUSIONS: We have elaborated a versatile mitotropic nanocarrier; furthermore, using this platform, we have developed a mitochondrial-doxorubicin formulation with exceptional cytocidal properties, even in nanomolar concentrations. PMID- 23921488 TI - Impact of release mechanism on the pharmacokinetic performance of PAUC metrics for three methylphenidate products with complex absorption. AB - PURPOSE: Investigate the performance of partial area under the drug concentration time curve (PAUC) metrics (0-3 h) and (3-24 h), for Concerta, Ritalin LA and Focalin XR (different Methylphenidate modified-release formulations). The metrics have been chosen as additional BE metrics for Ritalin LA by the FDA to establish BE for these products due to the early and late peak concentrations critical for treatment of morning and afternoon symptoms of attention deficit hyperactivity disorder (ADHD). METHODS: Two-stage analysis was performed on plasma data for the methylphenidate modified-release products. Simulations using the fitted parameters determined how changes in fast absorption rate constant k0fast, and slow absorption rate constant KAslow affected curve shape and BE determination using Cmax, AUCINF and PAUC. RESULTS: Sensitivity of the mean PAUC(test)/PAUC(reference) ratios to changes in k0fast and Kaslow were product dependent. Focalin XR mean PAUC(test)/PAUC(reference) ratios for PAUC0-3 h and PAUC3-24 h were most responsive to changes in k0Fast and Kaslow than Concerta and Ritalin LA. The PAUC(test)/PAUC(reference) ratios for (0-3 h) were not responsive to changes to Kaslow. Concerta PAUC (3-24 h) ratios were responsive to changes in Kaslow at ratios less than 1. CONCLUSIONS: Response to PAUC(0-3 h) in the formulations was greater for k0fast than was PAUC(3-24) to changes in KAslow. PMID- 23921489 TI - Folate-targeted nanoparticles based on albumin and albumin/alginate mixtures as controlled release systems of tamoxifen: synthesis and in vitro characterization. AB - PURPOSE: Preparation and in vitro characterization of tamoxifen (TMX)-loaded folate-targeted nanoparticles based on disulfide bond reduced bovine serum albumin (BSA-SH) and BSA-SH/alginate-cysteine (BSA-SH/ALG-CYS) mixtures as drug delivery systems. METHODS: Folate-nanoparticles were characterized in terms of folate content, morphology, size, zeta potential, TMX load and drug release kinetics. Additionally, cell viability and cellular uptake of nanoparticles were determined using different cancer cell lines. RESULTS: Folic acid (FOL) was successfully attached to nanoparticles (ranging between 79 and170 MUmol folate/g NP). Nanoparticles with 76-417 nm mean size were obtained and loaded with TMX (4.2-7.7 MUg/mg NP). Zeta potential and drug extraction revealed major superficial placement of the drug, especially in the case of BSA/ALG-FOL systems. Drug release studies in the presence of surfactant showed a gradual release of the drug between 4-7 h. In general, low cytotoxicity of unloaded systems was found. Internalization of the systems was achieved and mediated by folate receptor, especially in the case of BSA NP-FOL. The administration of 10 MUM TMX by TMX-FOL NP showed their efficacy as controlled TMX release systems. CONCLUSIONS: Promising anticancer action of these new TMX-loaded folate-targeted systems was demonstrated, allowing a new administration route to be studied in further in vivo studies in order to improve current TMX therapy. PMID- 23921490 TI - Understanding biorelevant drug release from a novel thermoplastic capsule by considering microstructural formulation changes during hydration. AB - PURPOSE: To study the biorelevant drug release from novel starch-based polyvinyl alcohol capsules (S-PVA-C). The effect of the shell material is studied by considering microstructural formulation changes during hydration. METHODS: Two different self-emulsifying systems containing either fenofibrate or probucol were filled in S-PVA-C, as well as capsules of gelatin (SGC) and starch (VegaGels(r)). Release analysis employed a BioDis(r) apparatus, while disintegration was studied by texture analysis. For microstructural analysis we used small angle x-ray scattering (SAXS). RESULTS: S-PVA-C opened only partially in biorelevant media compared to completely opened SGC and VegaGels(r). In case of the fenofibrate formulation, this opening mechanism caused only a short lag time, while the probucol formulation in S-PVA-C resulted in a sustained release. The latter formulation demonstrated much higher viscosity upon hydration compared to the fenofibrate system. Such a rheological effect on drug release was barely noted for SGC or VegaGels(r) and SAXS revealed differences in the hydrated microstructure. CONCLUSIONS: Even though S-PVA-C are highly attractive for encapsulation of rather hydrophilic formulations, some care is needed regarding an immediate release form. The type of formulation hydration must be considered for adequate selection of the capsule material. PMID- 23921491 TI - Direct inhibition and down-regulation by uremic plasma components of hepatic uptake transporter for SN-38, an active metabolite of irinotecan, in humans. AB - PURPOSE: Clinical study has previously revealed that plasma concentration of 7 ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan, was higher in patients with end-stage renal failure than those with normal kidney function although SN-38 is mainly eliminated in the liver. Here, we focused on inhibition by uremic toxins of hepatic SN-38 uptake and down-regulation of uptake transporter(s) by uremic plasma in humans. METHODS: We evaluated SN-38 uptake and its inhibition by uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), indoxyl sulfate (Indox), hippuric acid (HA) and indole acetate (IA), with cryopreserved human hepatocytes and HEK293 cells stably expressing hepatic uptake transporters, organic anion transporting polypeptides (OATPs). We also collected plasma samples from patients with severe renal failure to examine their effects on mRNA level of OATPs in primary cultured human hepatocytes. RESULTS: SN-38 was taken up by hepatocytes, which showed biphasic saturation patterns. The SN-38 uptake by hepatocytes was significantly inhibited by a uremic toxin mixture including clinically relevant concentrations of CMPF, Indox, HA and IA. Kinetic analyses for OATP-mediated transport revealed that the uptake of SN-38 by OATP1B1 was the highest, followed by OATP1B3. Among the uremic toxins, CMPF exhibited most potent inhibition of OATP1B1-mediated SN-38 uptake and directly inhibited the uptake of SN-38 also in hepatocytes. In addition, gene expression of OATP1B1 and OATP1B3 in hepatocytes was significantly down-regulated by the treatment with the uremic plasma. CONCLUSIONS: OATP1B1-mediated hepatic uptake of SN-38 was inhibited by uremic toxins, and gene expression of OATP1B1 was down-regulated by uremic plasma. PMID- 23921492 TI - High serum phosphorus and FGF 23 levels are associated with progression of coronary calcifications. AB - BACKGROUND: Coronary calcifications (CC) portend increased mortality in adults receiving hemodialysis (HD), however the risk factors associated with CC progression are not well known in pediatric patients. Our previous cross sectional studies demonstrated high CC prevalence (31 %) in pediatric patients, which were significantly associated with high serum phosphorus (P), fibroblast growth factor 23 (FGF) levels, dialysis vintage, and low cholesterol. The current study was undertaken to determine and elucidate CC progression in pediatric HD patients. METHODS: A 1-year prospective longitudinal study of 16 pediatric patients (ten male; mean age, 16.9 +/- 3 years; range, 10.1-20.4 years) receiving chronic HD was conducted. RESULTS: CC were observed in five of 16 (31.3 %) patients on baseline computed tomogram (CT) scan; 14/16 patients underwent 1-year CT. All patients with initial CC who completed CT at 1 year (3/5) progressed; one patient had new CC and none of the patients had resolved CC. Mean Agatston score increased from 23.4 +/- 18.06 HU (baseline) to 169 +/- 298.9 HU. Patients with CC progression had higher mean serum P (8.6 +/- 1.8 mg/dl vs. 6.3 +/- 1.1 mg/dl, p = 0.015) and FGF 23 levels (3,994 +/- 860.5 pg/ml vs. 2,327 +/- 1,206.4 pg/ml, p = 0.028). Serum P and FGF 23 levels were positively correlated with final Agatston scores (R = 0.65, p = 0.01 for serum P and R = 0.54, p = 0.045 for FGF 23) and change in Agatston scores (R = 0.65, p = 0.01 for serum P and R = 0.52, p = 0.048 for FGF 23). CONCLUSIONS: Our study shows that CC is progressive in pediatric patients receiving HD and that increased serum P and FGF 23 levels are associated with this progression. PMID- 23921493 TI - Low incidence of arrhythmias in the right ventricular infundibulum sparing approach to tetralogy of Fallot repair. AB - To improve outcomes, including arrhythmia incidence, for patients with tetralogy of Fallot (TOF), the authors' institution adopted an approach that minimizes or avoids transmural incision of the right ventricular outflow tract. When pulmonary blood flow is insufficient during the neonatal period, placement of an aortopulmonary artery shunt is preferred, followed by complete repair later in infancy. This study reviewed the perioperative and mid-term arrhythmia outcomes at the authors' institution using this approach. Patients who underwent TOF repair from 1995 to 2008 were included in the study. Patient demographics and surgical history were collected. The primary end points of the study included documented perioperative arrhythmias and arrhythmias at the 10-year follow-up assessment. Of the 298 patients who underwent TOF repair, 50 (17 %) had undergone prior placement of a systemic-to-pulmonary artery shunt. The median age at repair was 9.7 months (interquartile range, 6.3-16.2 months). Clinically significant perioperative arrhythmias were found in 12 patients (4 %) including 6 junctional tachycardias, 4 atrial tachycardias, and 1 temporary complete heart block. No patients were receiving antiarrhythmic medications more than 24 months after surgery. Of the 298 patients, 86 (29 %) had a follow-up period of 10 years or longer (median, 12.2 years). No patients experienced new arrhythmias, received antiarrhythmic therapy, experienced post-discharge ventricular tachycardia, had atrioventricular block, or required a pacemaker or defibrillator. The right ventricular infundibulum sparing approach is associated with an extremely low incidence of perioperative and midterm arrhythmias. The perioperative and mid term outcomes compare favorably with existing data from programs favoring neonatal repair. Long-term follow-up evaluation is essential to determine whether this strategy can effectively alter late pathophysiology and minimize late-term arrhythmias and associated mortality. PMID- 23921494 TI - Any role for probiotics in the therapy or prevention of autoimmune diseases? Up to-date review. AB - Probiotic use as capable preventive and therapeutic strategy in different diseases varying from allergic to autoimmune disease (AD) has been recently reported. Three interacting factors including an aberrant intestinal microbiota, a "leaky" intestinal mucosal barrier, and altered intestinal immune responsiveness have been suggested to be able to create a "perfect environment" for AD development. Regulation of intestinal microflora composition by probiotics offers the possibility to influence the development of mucosal/systemic immunity besides ADs. Moreover, with various strains of probiotics, development and/or stimulation of T helper type 2 (Th2)-mediated immune responses causing exacerbation of atopic disease have been described. Similarly, certain probiotics are known to stimulate Th1 immunity, which has been suggested as one of the mechanisms by which they can suppress Th2-mediated allergic diseases. Consequently, this presumed that excessive immunostimulation might aggravate or induce Th1-mediated immune responses and diseases such as type 1 diabetes, multiple sclerosis, and it might cause an additional safety issue. Although there is a large amount of conflicting data on the preventive/therapeutic effects of probiotics in ADs, there is fairly promising evidence to recommend as well. Thus, probiotic use cannot be generally recommended for primary prevention and therapy of ADs for now. PMID- 23921495 TI - Acquired angioedema--occurrence, clinical features and associated disorders in a Danish nationwide patient cohort. AB - BACKGROUND: The prevalence of acquired angioedema (AAE) is hitherto unknown and, to date, less than 200 patients have been reported worldwide. AAE is associated with lymphoproliferative conditions and autoantibodies against C1 inhibitor (C1INH). Rituximab (RTX) is increasingly used in the treatment of AAE patients. METHODS: A nationwide study of AAE patients was performed in Denmark. Clinical features, associated disorders, treatments and outcomes were registered. RESULTS: Eight AAE patients were identified. The diagnostic delay was on average 1 year and 8 months. Patients were treated with C1INH concentrate or icatibant on demand. Six patients were diagnosed with a clonal B-cell disorder during follow up, on average 2.5 years after the first swelling. Two patients had monoclonal B cell lymphocytosis (MBL). Two patients received RTX. CONCLUSIONS: AAE is a rare condition occurring in less than 10% of patients with C1INH deficiency in Denmark. AAE is highly associated with haematologic disorders, and we recommend yearly follow-up visits with clinical examination and blood tests including flow cytometry to diagnose B-cell conditions at an early stage. We report 2 patients with AAE and associated MBL, which is a benign expansion of clonal B lymphocytes. MBL can be the precursor of chronic lymphocytic leukaemia or is associated with non-Hodgkin's lymphoma. If angioedema is poorly controlled with standard treatment regimens, we suggest treatment of the associated haematologic disorder. Based on a review of the literature and our own data, we recommend therapy with RTX, especially in patients with anti-C1INH autoantibodies. PMID- 23921496 TI - Supracricoid partial laryngectomy in the management of t3 laryngeal cancer. AB - OBJECTIVE: To evaluate the oncologic results only in T3 glottic and supraglottic cancers regarding supracricoid partial laryngectomy (SCPL) not requiring total laryngectomy and to assess functional results by self-evaluation by the patient. Study Design Case series with medical record review. SETTING: Single tertiary care center. SUBJECTS AND METHODS: Thirty-two patients with laryngeal squamous cell carcinoma, previously untreated, who underwent SCPL with cricohyoidopexy or cricohyoidoepiglottopexy were reviewed. RESULTS: At 1, 3, and 5 years, the disease-free survival rates were 96.9%, 89.4%, and 78.2%; overall survival rates were 96.9%, 93.2%, and 87.3%; local control and locoregional control rates were 100%, 96.2%, and 96.2%; and distant metastasis-free survival rates were 100%, 100%, and 88.2%, respectively. Aspiration pneumonia was the most common complication observed. The 3 laryngeal functions (speech, swallowing, and breathing) were spared in 83.9% of patients. CONCLUSION: Supracricoid partial laryngectomy for selected glottic and supraglottic T3 tumors has excellent oncologic and functional results. PMID- 23921498 TI - Transoral carbon dioxide laser excision of an ectopic parathyroid adenoma from the hypopharynx. PMID- 23921497 TI - Standardized uptake value and resection margin involvement predict outcomes in pN0 head and neck cancer. AB - OBJECTIVE: The aim of this study was to evaluate the prognostic factors of patients with pathologically negative lymph node (pN0) head and neck cancer. Study Design Case series with chart review. SETTING: College medical center. SUBJECTS AND METHODS: The medical records of 120 patients were reviewed. Primary tumor sites included 46 larynx, 45 oral cavity, 17 oropharynx, and 12 hypopharynx. RESULTS: The recurrence rate was 14% (17/120) over a mean observation period of 33 months. Median (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) maximal standardized uptake value (SUVmax; using 8.5 as a cutoff; P = .001), positive surgical margins (P = .005), and pathologic T stage (P = .012) were found to be associated with recurrence. The 5-year disease-specific survival rate (DSSR) in our cohort was 86%. Patients with an SUVmax value higher than 8.5 and positive surgical margins had significantly decreased 5-year DSSR based on Kaplan-Meier survival curves. Multivariate Cox regression analysis confirmed the significant association between median SUVmax (using 8.5 as a cutoff; hazard ratio [HR], 6.13; 95% confidence interval [CI], 1.79-20.93; P = .004) and margin involvement (HR, 4.98; 95% CI, 1.42-17.47; P = .012). CONCLUSION: A median (18)F-FDG PET/CT SUVmax cutoff values of 8.5 or greater and positive surgical margins were associated with adverse outcomes in patients with pN0 head and neck cancer. PMID- 23921499 TI - A lactoferrin-receptor, intelectin 1, affects uptake, sub-cellular localization and release of immunochemically detectable lactoferrin by intestinal epithelial Caco-2 cells. AB - Intelectin 1 (IntL) is known as a lectin expressed in intestinal epithelia and also as a receptor for an iron-binding protein, lactoferrin (LF). Uptake of LF with bound iron by enterocytes via receptor-mediated endocytosis has been well investigated, whereas subsequent fate of endocytized LF and LF/IntL complexes remains largely unknown. In the present study, we examined contribution of IntL to the uptake, sub-cellular localization and subsequent release of LF by intestinal Caco-2 IntL-transfectants using two-site ELISA and fluorescence confocal microscopy. LF taken up by IntL-transfectants was immunochemically detected mostly as intact protein in the cell lysates, and it was a little larger in amount than that of the mock-transfectants. In the IntL-transfectants cultured on porous membrane, LF taken up from the apical side was detected immunochemically as punctate signals in the apical-side cytoplasmic region near nucleus. The LF signals were co-localized with IntL and, in a time-dependent manner, partially with early endosome antigen 1 (EEA1), but not with alkaline phosphatase. LF taken up, retained and subsequently released by the IntL transfectants was larger in amount than that of mock-transfectants. Moreover, uptake of LF altered sub-cellular localization of IntL and markedly enhanced the IntL signals within the cells. PMID- 23921500 TI - Lectin-dependent inhibition of antigen-antibody reaction: application for measuring alpha2,6-sialylated glycoforms of transferrin. AB - We developed a high-throughput Enzyme-linked immunosorbent assay (ELISA) for measuring alpha2,6-sialylated transferrin (Tf), based on inhibition of anti-Tf antibody binding to alpha2,6-sialylated Tf by a lectin, Sambucus sieboldiana Agglutinin (SSA). The inhibition was not observed with other glycoforms, such as periodate-treated, sialidase-treated and sialidase/galactosidase-treated Tf, suggesting that the assay was glycoform specific. This finding was applied to an automated latex-agglutination immunoassay, using SSA lectin as an inhibitor (SSA ALI). The concentration of alpha2,6-sialylated Tf measured by SSA-ALI in human cerebrospinal fluid was correlated with that of ELISA (r2 = 0.8554), previously developed for measuring alpha2,6-sialylated Tf. PMID- 23921501 TI - The GerW protein is essential for L-alanine-stimulated germination of Bacillus subtilis spores. AB - GerW (formerly called YtfJ) is a protein found in dormant spores of Bacillus subtilis. We have studied spore proteins in B. subtilis before, and here we report the characterization of GerW protein. Northern blot analysis revealed that gerW mRNA was transcribed by SigF-containing RNA polymerase beginning 1 h after the initiation of sporulation. Fluorescence was detected in forespores and dormant spores of B. subtilis recombinant strains expressing GerW-GFP. During germination in the presence of L-alanine or a mixture of L-asparagine, D-glucose, D-fructose and potassium ions (AGFK), normal spores of B. subtilis became darkened, stained positive with Hoechst 33342 and carboxyfluorescein diacetate succinimidyl ester (CFDA-SE), and released dipicolinic acid (DPA). In the case of gerW-deficient spores, AGFK triggered germination in a manner similar to that seen in the wild-type spores, whereas spores stimulated by L-alanine remained refractive under the phase contrast microscope, failed to stain positive with Hoechst 33342 or CFDA-SE, and released almost no DPA. These results indicate that GerW is essential for the L-alanine-induced breakdown of spore dormancy followed by core rehydration and the resumption of enzymatic activity, and suggest that GerW is involved in the early stages of germination in the presence of l-alanine. PMID- 23921502 TI - Errors of computer electrocardiography revisited: reflection on the fifth dimension of electrocardiography. PMID- 23921503 TI - Cardiotoxicity and cancer therapy. PMID- 23921504 TI - Admission hyperglycemia may be the result of counterregulatory hormones during acute coronary syndrome events. PMID- 23921505 TI - Comparison of the short-term oxidative stress response in National League basketball and soccer adolescent athletes. AB - Physical exercise is considered protective against oxidative stress-related disorders. However, there is increasing evidence that strenuous activity may induce increased oxidative stress response. This study investigated the impact of vigorous physical activity on serum oxidative stress markers in 36 soccer and 12 basketball National League adolescent athletes 40 minutes before and 15 minutes after a National League game. Serum total peroxide, fibrinogen, polymorphonuclear (PMN) elastase, and myeloperoxidase levels were determined. No significant differences in any of the measured parameters were observed before the match. Soccer players exhibited significantly lower total peroxide (P < .05) and higher PMN elastase concentrations (P < .05) than that of the basketball athletes after the game. A number of important differences between these 2 sports, such as duration or total aerobic and anaerobic demands, may affect oxidative status. These parameters need to be further examined in order to elucidate the different effects of these 2 sports on postexercise oxidative status. PMID- 23921506 TI - Relationship between neutrophil-lymphocyte ratio and isolated low high-density lipoprotein cholesterol. AB - Several studies showed that high-density lipoprotein cholesterol (HDL-C) has anti inflammatory effect. The neutrophil-lymphocyte ratio (NLR) is a new biomarker of systemic inflammation. The aim of this study was to assess the NLR in healthy participants with low HDL-C. We studied 69 patients with low HDL-C (<= 35 mg/dL) and 59 control participants (HDL-C >35 mg/dL) with similar cardiovascular risk factors. Hematological indices were measured in all patients with low HDL-C and control participants. The HDL-C was significantly lower among the patients with low HDL-C than that of the control group (31.7 +/- 2.7 vs 50.7 +/- 5.0 mg/dL, respectively; P < .001). The NLR was significantly higher among the patients with low HDL-C than that of the control group (2.6 +/- 0.8 vs 1.6 +/- 0.4, respectively; P < .001). The NLR was negatively correlated with HDL-C (P < .001, r = -.53). The NLR is significantly elevated in patients with low HDL-C when compared with control participants. PMID- 23921507 TI - The obesity paradox in patients with acute coronary syndrome: results from the Gulf RACE-2 study. AB - We investigated the association between in-hospital and peri-hospital mortality and body mass index (BMI)/waist circumference (WC) in a prospective acute coronary syndrome (ACS) registry in the Arabian Gulf. No significant associations with in-hospital mortality were found. Normal BMI had highest peri-hospital mortality, notably those with high WC. In logistic regression of mortality on obesity measures and potential confounders, the effects of obesity measures were no longer significant. In-hospital death increased by 5% with age and decreased by 42% in males. Mortality increased 3.7-fold with ST-elevation myocardial infarction (STEMI) and 3.0-fold with heart failure (HF) but decreased by 33% with dyslipidemia. Peri-hospital death increased by 4% with age and decreased by 30% in males. Mortality increased 2.8-fold with STEMI and 2.4-fold with HF. In- and peri-hospital mortality in ACS is significantly associated with age, gender, STEMI, HF, and dyslipidemia but not obesity measures. PMID- 23921508 TI - Role of interleukin-6, its receptor and soluble gp130 in chronic lung disease of prematurity. AB - BACKGROUND: Interleukin-6 (IL-6) signalling involves the interplay between IL-6, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130). IL-6 activity is modulated by the soluble receptors to produce both pro- and anti-inflammatory effects in human diseases and animal models. The expression and functional activity of these molecules in lungs of preterm ventilated infants is unknown. OBJECTIVES: We investigated this pathway in preterm infants who were at risk of developing chronic lung disease of prematurity (CLD). METHODS: Cytokines and soluble receptors were measured in bronchoalveolar lavage fluid (BALF) from ventilated preterm infants <=32 weeks of gestation who did or did not develop CLD. B9 cells, which specifically proliferate to IL-6, were used to assess BALF IL-6 functional activity. RESULTS: Inflammatory cells, IL-8 and monocyte chemotactic protein-1 were increased in BALF from the CLD group when compared to the No CLD group (p < 0.05). BALF IL-6 and sIL-6R were similar in both groups. In contrast, BALF sgp130 and sgp130/sIL-6R were greater in the CLD group when compared to the No CLD group (p = 0.01 and p = 0.02, respectively). However, the increased BALF sgp130 did not appear to modulate the BALF IL-6 functional activity. CONCLUSION: Lung inflammation was observed in the CLD group. Increased BALF sgp130 was noted in the CLD group but it did not appear to modulate the pulmonary IL-6 bioactivity. Further research is needed to investigate the potential modulatory activity of sgp130 in the preterm lung. PMID- 23921509 TI - Seeking the boundary of boundary extension. AB - Boundary extension (BE) is a remarkably consistent visual memory error in which participants remember seeing a more wide-angle image of a scene than was actually viewed (Intraub & Richardson, Journal of Experimental Psychology: Learning, Memory, and Cognition 15:179-187, 1989). Multiple stimulus factors are thought to contribute to the occurrence of BE, including object recognition, conceptual knowledge of scenes, and amodal perception at the view boundaries (Intraub, Wiley Interdisciplinary Reviews: Cognitive Science 3:117-127, 2012). In the present study, we used abstract scenes instead of images of the real world, in order to remove expectations based on semantic associations with objects and the schematic context of the view. Close-angle and wide-angle scenes were created using irregular geometric shapes rated by independent observers as lacking any easily recognizable structure. The abstract objects were tested on either a random-dot or a blank background in order to assess the influence of implied continuation of the image beyond its boundaries. The random-dot background conditions had background occlusion cues either present or absent at the image border, in order to test their influence on BE in the absence of high-level information about the scenes. The results indicate that high-level information about objects and schematic context is unnecessary for BE to occur, and that occlusion information at the image boundary also has little influence on BE. Contrary to previous studies, we also found clear BE for all conditions, despite using scenes depicting undetailed objects on a blank white background. The results highlighted the ubiquitous nature of BE and the adaptability of scene perception processes. PMID- 23921510 TI - Interobject spacing explains the attentional bias toward interacting objects. AB - Spatio-temporal interactions between simple geometrical shapes typically elicit strong impressions of intentionality. Recent research has started to explore the link between attentional processes and the detection of interacting objects. Here, we asked whether visual attention is biased toward such interactions. We investigated probe discrimination performance in algorithmically generated animations that involved two chasing objects and two randomly moving objects. In Experiment 1, we observed a pronounced attention capture effect for chasing objects. Because reduced interobject spacing is an inherent feature of interacting objects, in Experiment 2 we designed randomly moving objects that were matched to the chasing objects with respect to interobject spacing at probe onset. In this experiment, the capture effect attenuated completely. Therefore, we argue that reduced interobject spacing reflects an efficient cue to guide visual attention toward objects that interact intentionally. PMID- 23921511 TI - Follicle-stimulating hormone inhibits apoptosis in ovarian cancer cells by regulating the OCT4 stem cell signaling pathway. AB - OCT4, a stem cell marker, is overexpressed in several types of human cancer and can induce resistance to chemotherapy and inhibition of apoptosis. We previously demonstrated that human follicle stimulating hormone (FSH) can inhibit ovarian cancer cell apoptosis. However, the role of OCT4 in FSH-induced inhibition of apoptosis has not been reported in detail. Here, we profiled OCT4 protein expression in ovarian epithelial cancer (OEC) with benign cystadenoma, borderline tumor and carcinoma tissues as well as different ovarian cancer cell lines and normal ovarian epithelial cells. Furthermore, the effects of FSH on OCT4 expression and related signaling pathways were evaluated. The overexpression of OCT4 in ovarian carcinoma and OEC cell lines suggest that OCT4 plays a critical role in OEC carcinogenesis. Moreover, FSH-induced apoptosis inhibition was confirmed and FSH stimulation induced the expansion of CD44+CD117+ cells with a stem cell-like phenotype. Re-expression of OCT4 enhanced the expression of Notch, Sox2 and Nanog molecules that play critical roles in cancer stem cell proliferation and differentiation. FSH upregulated the expression of Notch, Sox2 and Nanog and these effects were abolished by knocking down OCT4, suggesting that several cancer stem cell pathways are involved in FSH regulation. We also examined OCT4 expression in surgical specimens of ovarian cancer. Immunohistostaining revealed that OCT4 expression was increased in ovarian carcinoma compared with benign cystadenomas and borderline tumors, and OCT4 expression was significantly correlated with histological grade. Staining for OCT4 was increased in serous cystadenocarcinoma, when compared with clear cell carcinoma. In summary, the OCT4 cancer stem cell signaling pathway may mediate FSH-induced inhibition of apoptosis and could provide a target for treatment of ovarian cancer. PMID- 23921512 TI - Coexistence of multiple sclerosis and ankylosing spondylitis: report of two cases. AB - BACKGROUND: Multiple sclerosis (MS) only rarely coexists with ankylosing spondylitis (AS). The optimal management of these patients represents a major challenge. METHODS: In the present study, we report 2 cases of AS with definite MS comorbidity. One of the AS-MS cases had received anti-TNFalpha treatment, which was discontinued due to exacerbation of the MS. In addition, we discuss 3 more AS cases with neurological symptoms and atypical white matter demyelinating MRI lesions after anti-TNFalpha treatment. DISCUSSION: Given the fact that anti TNFalpha drugs can potentially exacerbate a latent MS or induce atypical demyelination in the central nervous system, they should be discouraged or discontinued in relevant cases. The remaining effective therapeutic options for MS are either contradictory for AS (interferon-beta), have no definite data regarding their safety/efficacy in AS (glatiramer acetate, azathioprine, natalizumab, fingolimod), or their efficacy in MS-AS is associated with increased treatment risks (rituximab). Any of these proposed treatments may require active patient's informed consent. PMID- 23921513 TI - A novel, disruptive vaccination technology: self-adjuvanted RNActive((r)) vaccines. AB - Nucleotide based vaccines represent an enticing, novel approach to vaccination. We have developed a novel immunization technology, RNActive((r)) vaccines, that have two important characteristics: mRNA molecules are used whose protein expression capacity has been enhanced by 4 to 5 orders of magnitude by modifications of the nucleotide sequence with the naturally occurring nucleotides A (adenosine), G (guanosine), C (cytosine), U (uridine) that do not affect the primary amino acid sequence. Second, they are complexed with protamine and thus activate the immune system by involvement of toll-like receptor (TLR) 7. Essentially, this bestows self-adjuvant activity on RNActive((r)) vaccines. RNActive((r)) vaccines induce strong, balanced immune responses comprising humoral and cellular responses, effector and memory responses as well as activation of important subpopulations of immune cells, such as Th1 and Th2 cells. Pre-germinal center and germinal center B cells were detected in human patients upon vaccination. RNActive((r)) vaccines successfully protect against lethal challenges with a variety of different influenza strains in preclinical models. Anti-tumor activity was observed preclinically under therapeutic as well as prophylactic conditions. Initial clinical experiences suggest that the preclinical immunogenicity of RNActive((r)) could be successfully translated to humans. PMID- 23921515 TI - Current world literature. Hemostasis and thrombosis. PMID- 23921514 TI - Platelet ITAM signaling. AB - PURPOSE OF REVIEW: G protein-coupled receptors (GPCRs) like PAR1/4 and P2Y12 have long been known for their critical role in hemostasis. In contrast, deficiency in the immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors glycoprotein (GP)VI or C-type lectin-like receptor (CLEC)-2 is associated with only a mild bleeding diathesis in humans and mice. This review summarizes recent developments on the physiological importance of platelet ITAM signaling as well as the molecular mechanisms facilitating this signaling pathway. RECENT FINDINGS: Genetic experiments identified a critical role for platelet CLEC-2 signaling in the formation of lymphatic vessels during development. Similarly, signaling by both GPVI and CLEC-2, but not GPCRs, is required for the maintenance of vascular integrity at sites of inflammation in the adult. The molecular mechanisms underlying ITAM signaling in platelets continue to be refined. SUMMARY: Platelet ITAM signaling plays a key role for the maintenance of vascular integrity in development and the adult. This novel form of hemostasis differs from hemostasis at sites of vascular injury in that it does not depend on major platelet adhesion receptors or GPCR signaling. PMID- 23921517 TI - Observation of the Kibble-Zurek scaling law for defect formation in ion crystals. AB - Traversal of a symmetry-breaking phase transition at finite rates can lead to causally separated regions with incompatible symmetries and the formation of defects at their boundaries, which has a crucial role in quantum and statistical mechanics, cosmology and condensed matter physics. This mechanism is conjectured to follow universal scaling laws prescribed by the Kibble-Zurek mechanism. Here we determine the scaling law for defect formation in a crystal of 16 laser-cooled trapped ions, which are conducive to the precise control of structural phases and the detection of defects. The experiment reveals an exponential scaling of defect formation gamma(beta), where gamma is the rate of traversal of the critical point and beta=2.68+/-0.06. This supports the prediction of beta=8/3~2.67 for finite inhomogeneous systems. Our result demonstrates that the scaling laws also apply in the mesoscopic regime and emphasizes the potential for further tests of non equilibrium thermodynamics with ion crystals. PMID- 23921518 TI - Use of drug holidays in women taking bisphosphonates. AB - Bisphosphonates are the cornerstone of treatment for osteoporosis. These agents are generally safe and well-tolerated, but concerns have emerged about adverse effects related to long-term use, namely osteonecrosis of the jaw and atypical femur fractures. For most patients at moderate or high risk of fracture, the benefits of treatment far outweigh these serious but rare risks. Bisphosphonates accumulate in bone with some persistent protective effect after therapy is stopped, making it is reasonable to consider a "drug holiday." The duration of therapy and the length of the holiday should be based on clinical judgment. PMID- 23921519 TI - Hormone therapy: A to Z. AB - CLINICAL SCENARIO: A 65-year-old postmenopausal women comes into the office with concerns of vaginal dryness and hot flashes. She recounts numerous nights waking up drenched in sweat and days spent trying to find the coolest rooms at work. She reluctantly mentions that she and her partner have difficulty with intimacy because she has found intercourse to be painful because of vaginal dryness. She is distraught and frustrated seeking something to alleviate her menopause symptoms. As you begin a conversation about hormone therapy, she immediately becomes concerned and reluctant because she has seen many commercials indicating that this unsafe for women. PMID- 23921520 TI - What you should know about hormone therapy health risks and benefits. PMID- 23921522 TI - Expanded activity of dimer nucleases by combining ZFN and TALEN for genome editing. AB - Our ability to precisely and efficiently edit mammalian and plant genomes has been significantly improved in recent years, partially due to increasing use of designer nucleases that recognize a pre-determined DNA sequence, make a specific DNA double-strand break, and stimulate gene targeting. A pair of zinc finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs) that recognize two adjacent unique DNA sequences dimerize through the fused FokI nuclease domain and cut in the middle of target DNA sequences. We report here that increasing the length of recognition DNA sequences by TALENs or ZFNs does not necessarily translate to a higher efficiency or specificity. We also discover that one subunit of ZFNs and one subunit of TALENs can form a pair of hybrid nucleases with expanded specificity at two diverse targets, and stimulate gene targeting in multiple cell types including human induced pluripotent stem (iPS) cells with improved efficiency. PMID- 23921521 TI - Therapeutic decisions in multiple sclerosis: moving beyond efficacy. AB - Several innovative disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis have been licensed recently or are in late-stage development. The molecular targets of several of these DMTs are well defined. All affect at least 1 of 4 properties, namely (1) trafficking, (2) survival, (3) function, or (4) proliferation. In contrast to beta-interferons and glatiramer acetate, the first-generation DMTs, several newer therapies are imbued with safety issues, which may be attributed to their structure or metabolism. In addition to efficacy, understanding the relationship between the mechanism of action of the DMTs and their safety profile is pertinent for decision making and patient care. In this article, we focus primarily on the safety of DMTs in the context of understanding their pharmacological characteristics, including molecular targets, mechanism of action, chemical structure, and metabolism. While understanding mechanisms underlying DMT toxicities is incomplete, it is important to further develop this knowledge to minimize risk to patients and to ensure future therapies have the most advantageous benefit-risk profiles. Recognizing the individual classes of DMTs described here may be valuable when considering use of such agents sequentially or possibly in combination. PMID- 23921523 TI - MicroRNA-10b promotes the migration of mouse bone marrow-derived mesenchymal stem cells and downregulates the expression of E-cadherin. AB - The ability of mesenchymal stem cells (MSCs) to migrate is an important determinant of the efficiency of MSC transplant therapy. MicroRNA-10b (miR-10b) has been positively involved in the migration of a number of tumor cells lineages. To date, it remains unknown whether miR-10b affects the migration of MSCs. In the current study, the effect of miR-10b on the migration of mouse bone marrow-derived MSCs (bmMSCs) was investigated. Third-passage bmMSCs were transfected with miR-10b mimic and negative control precursor miRNA using LipofectamineTM 2000. miR-10b and E-cadherin expression and bmMSC migration were determined. The present results showed that primary bmMSCs exhibit a spindled or triangular morphology and that third-passage bmMSCs present a typical fibroblast like morphology, exhibiting CD90-positive and CD45-negative expression. Compared with the transfection of negative control miRNA, transfection of miR-10b mimic markedly upregulated miR-10b expression in bmMSCs, increased their migration and downregulated E-cadherin expression. The current observations indicate that the upregulation of miR-10b increases bmMSC migration ability, which may be involved in the downregulation of E-cadherin. PMID- 23921524 TI - An updated overview and clarification of the principle role of debridement. AB - Routine care of non-healing acute and chronic wounds often comprises either cleaning or debridement. Consequently, debridement is a basic necessity to induce the functional process of tissue repair, which makes it a central medical intervention in the management of acute and chronic, non-healing wounds. PMID- 23921526 TI - The effect of obesity on the level of fractional exhaled nitric oxide in children with asthma. AB - BACKGROUND: Several studies have demonstrated a relationship between asthma and obesity. However, the results have been conflicting with regard to the relationship between fractional exhaled nitric oxide (FeNO), used as a marker of airway inflammation in asthmatic patients, and obesity. We aimed to evaluate the association of FeNO with obesity and obesity-related metabolic complications in asthmatic and nonasthmatic children. METHODS: The study population included children aged between 6 and 17 years and consisted of 4 groups: obese asthmatics (n = 52), normal-weight asthmatics (n = 49), obese nonasthmatics (n = 51) and normal-weight nonasthmatics (n = 42). FeNO measurement and spirometry were performed for all patients. To evaluate the metabolic complications, serum lipids, glucose and insulin levels were measured. Insulin resistance (IR) was estimated by the homeostasis model assessment, HOMA-IR. All participants were evaluated for the presence of metabolic syndrome (MS). RESULTS: The mean age for the 194 subjects participating in the study was 11.6 +/- 2.5 years. The FeNO level of asthma patients with MS was not different from those without MS (14.5 +/ 8.0 and 16.7 +/- 8.7, respectively, p = 0.449). In the nonasthmatic group, subjects with MS had a higher FeNO level than subjects without MS (12.5 +/- 5.1 and 17.3 +/- 8.3, respectively, p = 0.014). Spearman's rank correlation coefficients revealed a positive correlation between FeNO and body mass index (BMI; p = 0.049, r(2): 0.204) in the nonasthmatic group and after multivariate regression analysis, BMI still persisted as an independent risk factor for FeNO. CONCLUSION: We found a positive correlation between BMI and FeNO level which suggests a link between obesity and increased airway inflammation in nonasthmatic children. PMID- 23921525 TI - Structure-based modeling of energy transfer in photosynthesis. AB - We provide a minimal model for a structure-based simulation of excitation energy transfer in pigment-protein complexes (PPCs). In our treatment, the PPC is assembled from its building blocks. The latter are defined such that electron exchange occurs only within, but not between these units. The variational principle is applied to investigate how the Coulomb interaction between building blocks changes the character of the electronic states of the PPC. In this way, the standard exciton Hamiltonian is obtained from first principles and a hierarchy of calculation schemes for the parameters of this Hamiltonian arises. Possible extensions of this approach are discussed concerning (i) the inclusion of dispersive site energy shifts and (ii) the inclusion of electron exchange between pigments. First results on electron exchange within the special pair of photosystem II of cyanobacteria and higher plants are presented and compared with earlier results on purple bacteria. In the last part of this mini-review, the coupling of electronic and nuclear degrees of freedom is considered. First, the standard exciton-vibrational Hamiltonian is parameterized with the help of a normal mode analysis of the PPC. Second, dynamical theories are discussed that exploit this Hamiltonian in the study of dissipative exciton motion. PMID- 23921527 TI - Bi and tri-substituted phenyl rings containing bisbenzimidazoles bind differentially with DNA duplexes: a biophysical and molecular simulation study. AB - Recently synthesis of programmable DNA ligands which can regulate transcription factors have increased the interest of researchers on the functional ability of DNA interacting compounds. A series of DNA interacting compounds are being designed which can differentiate between GC and AT rich DNA. In this study, we have studied the specificity of a few novel bisbenzimidazoles having different bi/tri-substituted phenyl rings, with DNA duplexes using spectroscopic methods. This study entails an integrative approach where we combine biophysical methods and molecular dynamics simulation studies to establish suitable scaffolds to target A/T DNA. We have designed a few analogues of Hoechst 33342 viz.; dimethoxy (DMA), trimethoxy (TMA), dichloro (DCA) and difluoro (DFA) functionalities and performed molecular docking of newly designed analogues with biologically relevant AT and GC rich DNA sequences. The docking studies, along with molecular dynamics (MD) simulations of d(ATATATATATATATAT)2, d(GA4T4C)2, d(GT4A4C)2 and GC rich sequence: d(GCGCGCGCGCGCGCGC)2 complexed with DMA, TMA and DFA, showed that these molecules have higher binding affinity towards AT rich DNA. None of these compounds exhibited an affinity to GC rich DNA rather we observed that these compounds destabilize GC rich DNA. The binding was characterized by strong stabilization of the polynucleotides against thermal strand separation in thermal melting experiments. New insights into the molecules binding to DNA have emerged from these studies. All the DNA binding ligands stabilized d(GA4T4C)2 and d(GT4A4C)2 more out of the five oligomers used for the study, suggesting that these ligands bind 'A4T4' and 'T4A4' strongly as compared to 'ATAT' base pairs. PMID- 23921529 TI - Is paracetamol a useful treatment for ibuprofen-resistant patent ductus arteriosus?. Concerning the article by M.Y. Oncel et al: intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants [Neonatology 2013;103:166-169]. PMID- 23921530 TI - Mincle, the receptor for mycobacterial cord factor, forms a functional receptor complex with MCL and FcepsilonRI-gamma. AB - Upon receptor activation, the myeloid C-type lectin receptor Mincle signals via the Syk-CARD9-Bcl10-MALT1 pathway. It does so by recruiting the ITAM-bearing FcepsilonRI-gamma. The related receptor macrophage C-type Lectin (MCL) has also been shown to be associated with Syk and to be dependent upon this signaling axis. We have previously shown that MCL co-precipitates with FcepsilonRI-gamma, but were unable to show a direct association, suggesting that MCL associates with FcepsilonRI-gamma via another molecule. Here, we have used rat primary cells and cell lines to investigate this missing link. A combination of flow cytometric and biochemical analysis showed that Mincle and MCL form heteromers on the cell surface. Furthermore, association with MCL and FcepsilonRI-gamma increased Mincle expression and enhanced phagocytosis of Ab-coated beads. The results presented in this paper suggest that the Mincle/MCL/FcepsilonRI-gamma complex is the functionally optimal form for these C-type lectin receptors on the surface of myeloid cells. PMID- 23921531 TI - Toxicity of upfront 131I-metaiodobenzylguanidine (131I-MIBG) therapy in newly diagnosed neuroblastoma patients: a retrospective analysis. AB - PURPOSE: In the treatment of patients with high-risk neuroblastoma, different doses of (131)I-metaiodobenzylguanidine ((131)I-MIBG) are administered at different time points during treatment. Toxicity, mainly haematological (thrombocytopenia), from (131)I-MIBG therapy is known to occur in extensively chemotherapy pretreated neuroblastoma patients. Up to now, acute toxicity from (131)I-MIBG as initial treatment has never been studied in a large cohort. The aim of this retrospective study was to document acute toxicity related to upfront (131)I-MIBG. METHODS: All neuroblastoma patients (stages 1-4 and 4S) treated upfront with (131)I-MIBG at the Emma Children's Hospital, Academic Medical Centre (1992 - 2008) were included in this retrospective analysis. The acute toxicity (during therapy) and short-term toxicity (1st month following therapy) of the first two (131)I-MIBG therapies were studied. RESULTS: Of 66 patients (34 boys, 32 girls; median age 2.2 years, range 0.1 - 9.4 years), 49 had stage 4 disease, 5 stage 4S, 6 stage 3, 1 stage 2 and 5 stage 1. The median first dose was 441 MBq/kg (range 157 - 804 MBq/kg). The median second dose was 328 MBq/kg (range 113 - 727 MBq/kg). The most frequently observed symptoms were nausea and vomiting (21 %, maximum grade II). The main toxicity was grade IV haematological, occurring only in stage 4 patients, after the first and second (131)I-MIBG therapies: anaemia (5 % and 4 %, respectively), leucocytopenia (3 % and 4 %) and thrombocytopenia (2 % and 4 %). No stem cell rescue was needed. CONCLUSION: The main acute toxicity observed was haematological followed by nausea and vomiting. One patient developed posterior reversible encephalopathy syndrome during (131)I MIBG therapy, possibly related to (131)I-MIBG. We consider (131)I-MIBG therapy to be a safe treatment modality. PMID- 23921532 TI - Return of whole-genome sequencing results in paediatric research: a statement of the P3G international paediatrics platform. PMID- 23921533 TI - Meta-analysis of SNPs involved in variance heterogeneity using Levene's test for equal variances. AB - Meta-analysis is a commonly used approach to increase the sample size for genome wide association searches when individual studies are otherwise underpowered. Here, we present a meta-analysis procedure to estimate the heterogeneity of the quantitative trait variance attributable to genetic variants using Levene's test without needing to exchange individual-level data. The meta-analysis of Levene's test offers the opportunity to combine the considerable sample size of a genome wide meta-analysis to identify the genetic basis of phenotypic variability and to prioritize single-nucleotide polymorphisms (SNPs) for gene-gene and gene environment interactions. The use of Levene's test has several advantages, including robustness to departure from the normality assumption, freedom from the influence of the main effects of SNPs, and no assumption of an additive genetic model. We conducted a meta-analysis of the log-transformed body mass index of 5892 individuals and identified a variant with a highly suggestive Levene's test P-value of 4.28E-06 near the NEGR1 locus known to be associated with extreme obesity. PMID- 23921534 TI - Consanguineous marriage and reproductive risk: attitudes and understanding of ethnic groups practising consanguinity in Western society. AB - Consanguineous couples should be adequately informed about their increased reproductive risk and possibilities for genetic counselling. Information may only be effective if it meets the needs of the target group. This study aimed to gain more insight into: (1) attitudes of people belonging to ethnic groups in Western society towards consanguinity and their understanding of risk for offspring; and (2) their attitudes regarding reproductive information targeted at consanguineous couples. Dutch Moroccans and Turks were invited to complete an online questionnaire by snowball sampling and by placing a link on two popular Dutch Moroccan/Turkish forum websites between September and October 2011. The questionnaire was completed by 201 individuals who were, on average, neither positive nor negative towards consanguinity. Respondents with a consanguineous partner were more positive, estimated the risk for the offspring lower and were less positive about the provision of risk information to consanguineous couples when compared with respondents without a consanguineous partner. Participants of Turkish origin had a more negative attitude towards consanguinity and estimated the reproductive risk higher than Moroccan participants. More than half of the respondents thought that information should be given before marriage, whereas only 10% thought it should never be provided. The general practitioner was most often mentioned (54%) as the designated professional to inform people. Information about genetic risks related to consanguinity should be offered early, preferably before marriage. The diversity of the target population requires various strategies to disseminate information and reach consanguineous couples with the offer of genetic counselling. PMID- 23921535 TI - Quantitative multiplex PCR of short fluorescent fragments for the detection of large intragenic POLG rearrangements in a large French cohort. AB - Polymerase gamma (POLG) is the gene most commonly involved in mitochondrial disorders with mitochondrial DNA instability and causes a wide range of diseases with recessive or dominant transmission. More than 170 mutations have been reported. Most of them are missense mutations, although nonsense mutations, splice-site mutations, small deletions and insertions have also been identified. However, to date, only one large-scale rearrangement has been described in a child with Alpers syndrome. Below, we report a large cohort of 160 patients with clinical, molecular and/or biochemical presentation suggestive of POLG deficiency. Using sequencing, we identified POLG variants in 22 patients (18 kindreds) including five novel pathogenic mutations. Two patients with novel mutations had unusual clinical presentation: the first exhibited an isolated ataxic neuropathy and the second was a child who presented with endocrine signs. We completed the sequencing step by quantitative multiplex PCR of short fluorescent fragments (QMPSF) analysis in 37 patients with either only one POLG heterozygous variant or a family history suggesting a dominant transmission. We identified a large intragenic deletion encompassing part of intron 21 and exon 22 of POLG in a child with refractory epilepsia partialis continua. In conclusion, we describe the first large French cohort of patients with POLG mutations, expanding the wide clinical and molecular spectrum observed in POLG disease. We confirm that large deletions in the POLG gene are rare events and we highlight the importance of QMPSF in patients with a single heterozygous POLG mutation, particularly in severe infantile phenotypes. PMID- 23921536 TI - Criteria for fairly allocating scarce health-care resources to genetic tests: which matter most? AB - The use of genetic tests is expanding rapidly. Given limited health-care budgets throughout Europe and few national coverage decisions specifically for genetic tests, decisions about allocating scarce resources to genetic tests are frequently ad hoc and left to lower-level decision makers. This study assesses substantive ethical and economic criteria to prioritize genetic services in a reasonable and fair manner. Principles for allocating health-care resources can be classified into four categories: need-based allocation; maximizing total benefits; treating people equally; and promoting and rewarding social usefulness. In the face of scarcity, the degree of an individual's need for medical intervention is an important criterion. Also, different economic concepts of efficiency are of relevance in the theory and practice of prioritizing genetic tests. Equity concerns are most likely to be relevant in terms of avoiding undesirable inequities, which may also set boundaries to the use of efficiency as a prioritization criterion. The aim of promoting and rewarding social usefulness is unlikely to be relevant to the question of what priority a genetic test should have in clinical practice. Further work is needed to select an appropriate set of criteria; operationalize them; and assign weights before some kind of standardized priority information can be added to information sources for genetic services. Besides the substantive criteria, formal considerations like those pointed out in the framework of accountability for reasonableness need to be considered in decision making. PMID- 23921538 TI - Fair allocation of health-care resources: finding a model that does not disenfranchise users of genetic services. A commentary on Rogowski et al.... PMID- 23921537 TI - Factors influencing public participation in biobanking. AB - A diversity of public participation in biobanking is a highlight for the success of biobanks. It was previously reported that only two-thirds of Jordanians expressed interest in biobanking. To promote public involvement in a biobank, it is imperative to determine the aspects that influence the decision-making to participate. On the basis of a national survey involving 3196 respondents, the influence of 13 biobanking factors was assessed, including returning research results, privacy, freedom of choice, uncertainties about research, monetary and health considerations, and personal belief. Perception toward each factor was also correlated with willingness to participate in a biobank. A considerable number of respondents indicated returning research results as influential in their decision to become biobank donors. Interestingly, whereas the positive perception of availability of general results (39%) correlated with willingness to donate for biobanking, the negative view of unavailability of individualized results (47%) did not correlate with unwillingness. Religious permission of sample donation for research had the strongest positive influence (61%) and the highest correlation to participate among positively perceived factors. Unspecified research was highly indicated as a negative factor (45%), but did not correlate with unwillingness to become a biobank donor, whereas allowed withdrawal had a positive effect (31%) and correlation to contribute to biobanking. The negative perception of accessing medical information (9.5%) and re-contact (8.5%) had the strongest correlation with unwillingness to donate to a biobank. These results may provide an insight into how to formulate strategies to promote public participation in biomedical research and biobanking. PMID- 23921539 TI - Clinical utility gene card for: hypophosphatasia - update 2013. PMID- 23921540 TI - Low temperature aqueous phase synthesis of silver/silver chloride plasmonic nanoparticles as visible light photocatalysts. AB - A one pot and environmentally benign synthetic route for plasmonic photocatalytic Ag@AgCl nanoparticles in a PVA-dissolved aqueous solution system is presented. The synthesized AgCl has a cubic-shape and its edge length can be controlled from ~57 to ~170 nm by varying the reaction temperature. In this system, PVA was used as a stabilizer for the formation of Ag@AgCl nanoparticles through interaction with Ag(+) ions. After partial reduction with l-arginine, the metallic Ag is formed on the surface of the AgCl substrates and the contents of the metallic Ag mainly affect both the visible-light absorption properties and the plasmonic photocatalytic efficiency of the Ag@AgCl nanocomposites. A plausible growth mechanism of metallic silver during the reduction process is proposed. More importantly, it is verified that the size of the AgCl substrate affected the light absorption region of the Ag@AgCl nanocomposite. PMID- 23921541 TI - The effective number of parameters in post hoc models. AB - Although a parsimonious post hoc model may involve relatively few parameters, many other potential model parameters may, in effect, be fixed at 0 after examining the data. Because these fixed parameters could have been varied if the data had come out differently, one could argue that they should be included when assessing the complexity of the model. On the other hand, intuitively, it seems that some advantage should accrue to identifying a simple and compelling description of the data, even if it is post hoc. This problem was considered here in the context of factorial designs in which a potentially parsimonious description of the results consists of a limited set of simple effects. Monte Carlo simulations were used to establish the effective numbers of parameters for various classes of such simple, but post hoc, models. PMID- 23921542 TI - Endovascular treatment of distal internal carotid artery occlusions with retrievable stents. AB - BACKGROUND: Acute stroke due to distal intracranial internal carotid artery (ICA) occlusion has a poor natural history. Outcome in patients who receive intravenous tissue plasminogen activator (tPA) is also unsatisfactory. The objective of this study is to evaluate the effectiveness and safety of endovascular treatment with retrievable stents in these patients. METHODS: Data from a prospective register of patients with acute stroke treated with an endovascular procedure in a single centre were analysed. RESULTS: A total of 20 patients with distal ICA occlusion were collected. Mean baseline National Institutes of Health Stroke Scale score was 18. Eight cases (40%) had received previous intravenous tPA. Mean time from stroke to recanalization was 393 min. Retrievable stents with proximal occlusion and aspiration were used in all cases. In 3 patients, 2 retrievable stents were used simultaneously. Complete recanalization (thrombolysis in cerebral infarction 2b/3) was accomplished in 85% of cases. A favourable clinical outcome (modified Rankin Scale score 0-2) was achieved in 13 patients (65%). Mortality occurred in 2 cases (10%). CONCLUSIONS: Endovascular treatment of patients with distal ICA occlusion seems safe and effective. Retrievable stents may be the treatment of choice, although randomized clinical trials are necessary. The use of 2 retrievable stents at the same time could be an alternative technique useful in thrombi of larger size. PMID- 23921543 TI - Proteolytic degradation of the flavonoid regulators, TRANSPARENT TESTA8 and TRANSPARENT TESTA GLABRA1, in Arabidopsis is mediated by the ubiquitin/26Sproteasome system. AB - Regulated proteolysis by the ubiquitin/26S proteasome system (UPS) has emerged as a major posttranslational control mechanism regulating transcription factor (TF) activity in plants. Anthocyanin biosynthesis in Arabidopsis is regulated by a ternary complex comprised of basic helix-loop-helix (bHLH), R2R3MYB and WD-repeat (WDR) proteins. The bHLH TF, TRAN SPAR ENT TESTA 8 (TT 8), and the WDR protein, TRAN SPAR ENT TESTA GLABRA 1 (TT G1), are essential for expression of late flavonoid biosynthesis genes. Previous studies have demonstrated that the turnover of several anthocyanin pathway regulators is controlled by the UPS. Here, we show that TT 8 and TT G1 are short-lived and targeted by the UPS for degradation. Our findings further extend our understanding of the role of the UPS in the regulation of anthocyanin biosynthesis in plants. PMID- 23921545 TI - Theoretical and functional complexity of white variegation of unripe fleshy fruits. AB - In many plant species, the bright colors of ripe fruit serve to attract frugivores to enable efficient seed dispersal. Here I show that the fleshy fruit of several dozens of species originating from Asia (southeastern, eastern and central), the Middle East, Africa, America (South, Central and North), Australia, Polynesia and Micronesia, with fruit usually larger than 1 cm, have white or light green spots while they are still unripe. In many of these species, while the spots are conspicuous, the unripe fruit is known to be poisonous, bitter or sour. I propose that this fruit syndrome may signal frugivores that the fruit is still unripe. Similarly to the succulent leaves of window-plants, these spots form windows that enable light to penetrate deeper into the photosynthetic layers in the developing fruit. This seems to be a solution to overcome the limitations of light harvest because of the high volume to surface ratio of developing fleshy fruits. The white or whitish variegation in these unripe fleshy fruits may serve at least five functions: 1) Windows for photosynthesis, 2) camouflage, 3) signaling to frugivores that they are not ripe (possibly sometimes a type of mutualism with frugivores), 4) signaling to frugivores that they are poisonous- aposematism, and 5) mimicking insect eggs to reduce egg laying. All these functions may be partly or fully simultaneous. Because these white spots appear in plants of diverse geographical and taxonomic origin, it is probably an old adaptation, and such a syndrome has appeared and been selected for many times. PMID- 23921544 TI - An efficient and rapid regeneration via multiple shoot induction from mature seed derived embryogenic and organogenic callus of Indian maize (Zea mays L.). AB - An efficient method for in vitro micro propagation and genetic transformation of plants are crucial for both basic and applied research. Maize is one of the most important cereal crops around the world. Regeneration from immature embryo is hampered due to its unavailability round the year. On the contrary mature embryo especially tropical maize is recalcitrant toward tissue culture. Here we report a highly efficient regeneration (90%) system for maize by using 2 different approaches i.e., embryogenic and organogenic callus cultures. Seeds were germinated on MS medium supplemented with 5 mg/l 2,4-D and 3 mg/l BAP. Nodal regions of 2 wks old seedlings were longitudinally split upon isolation and subsequently placed on callus initiation medium. The maximum frequency of embryogenic callus formation (90%) was obtained on MS medium supplemented with 2 mg/l 2,4-D and 1 mg/l BAP in the dark conditions. The compact granular organogenic callus formation (85% frequency) was obtained on MS medium supplemented with 2.5 mg/l 2,4-D and 1.5 mg/l BAP at light conditions. MS medium supplemented with 2 mg/l BAP, 1 mg/l Kinetin and 0.5 mg/l NAA promoted the highest frequency of shoot induction. The highest frequency of root formation was observed when shoots were grown on MS medium. The regenerated plants were successfully hardened in earthen pots after adequate acclimatization. The important advantage of this improved method is shortening of regeneration time by providing an efficient and rapid regeneration tool for obtaining more stable transformants from mature seeds of Indian tropical maize cultivar (HQPM-1). PMID- 23921546 TI - The ultrasound elastography inverse problem and the effective criteria. AB - The elastography (elasticity imaging) is one of the recent state-of-the-art methods for diagnosis of abnormalities in soft tissue. The idea is based on the computation of the tissue elasticity distribution. This leads to the inverse elasticity problem; in that, displacement field and boundary conditions are known, and elasticity distribution of the tissue is aimed for computation. We treat this problem by the Gauss-Newton method. This iterative method results in an ill-posed problem, and therefore, regularization schemes are required to deal with this issue. The impacts of the initial guess for tissue elasticity distribution, contrast ratio between elastic modulus of tumor and normal tissue, and noise level of the input data on the estimated solutions are investigated via two different regularization methods. The numerical results show that the accuracy and speed of convergence vary when different regularization methods are applied. Also, the semi-convergence behavior has been observed and discussed. At the end, we signify the necessity of a clever initial guess and intelligent stopping criteria for the iterations. The main purpose here is to highlight some technical factors that have an influence on elasticity image quality and diagnostic accuracy, and we have tried our best to make this article accessible for a broad audience. PMID- 23921547 TI - A novel heteroplasmic mitochondrial DNA mutation, A8890G, in a patient with juvenile-onset metabolic syndrome: a case report. AB - Metabolic syndrome (MS) is a complex disorder characterized by a group of metabolic abnormalities. In the present study, the case of an 18-year-old male who presented with MS characteristics with central obesity (overweight and a waist circumference of 95 cm) and dyslipidemia (high TG, low HDL levels and low apoA-I/apoB-100) was reported. The patient's family has maternally inherited diabetes and a number of the patient's maternal relatives present MS features. For the investigation of the mitochondrial DNA variants in the patient and the patient's family, genomic DNA of all the family members were extracted from peripheral blood using routine methods. Amplification of mitochondrial DNA in 24 overlapping fragments by PCR, direct sequencing and denaturing high-performance liquid chromatography was utilized for genetic analysis. Sequences were compared to the reference sequence to identify variants. Bioinformatic methods and databases were used to analyze conservation of the variants and to predict the protein secondary structure. With the exception of the patient, five relatives were diagnosed with MS. Moreover, 5 of the 8 family members had been diagnosed with diabetes, hearing loss and mild kidney impairment according to serum biochemical analysis. Further molecular genetic analysis indicated that the MS associated variant T16189C was detected in this family. Notably, a heteroplasmic mutation A8890G was detected in the patient in the mitochondrial ATP6 gene, which codes the ATP synthase subunit 6 (ATPase6). A8890G changed the highly conserved ATPase6 Lys122 into Glu122 in the mitochondrial inner membrane. However, this mutation was not detected in other family members. In conclusion, the mutation A8890G may affect the function of ATPase 6 and the production of ATP, thus contributing to juvenile-onset MS. It was not detected in other family members possibly due to the mitochondrial genetic segregation or production of a new germline mutation in the juvenile-onset patient. PMID- 23921548 TI - The TRPA1 channel and oral hypoglycemic agents: is there complicity in beta-cell exhaustion? AB - Diabetes mellitus type 2 (DM2) results from the combination of insulin unresponsiveness in target tissues and the failure of pancreatic beta cells to secrete enough insulin. (1) It is a highly prevalent chronic disease that is aggravated with time, leading to major complications, such as cardiovascular disease and peripheral and ocular neuropathies. (2) Interestingly, therapies to improve glucose homeostasis in diabetic patients usually involve the use of glibenclamide, an oral hypoglycemic drug that blocks ATP-sensitive K(+) channels (KATP), (3)(,) (4) forcing beta cells to release more insulin to overcome peripheral insulin resistance. However, sulfonylureas are ineffective for long term treatments and ultimately result in the administration of insulin to control glucose levels. (5) The mechanisms underlying beta-cell failure to respond effectively with glibenclamide after long-term treatments still needs clarification. A recent study demonstrating that this drug activates TRPA1, (6) a member of the Transient Receptor Potential (TRP) family of ion channels and a functional protein in insulin secreting cells, (7)(,) (8) has highlighted a possible role for TRPA1 as a potential mediator of sulfonylurea-induced toxicity. PMID- 23921549 TI - Definition of management zones for enhancing cultivated land conservation using combined spatial data. AB - The loss of cultivated land has increasingly become an issue of regional and national concern in China. Definition of management zones is an important measure to protect limited cultivated land resource. In this study, combined spatial data were applied to define management zones in Fuyang city, China. The yield of cultivated land was first calculated and evaluated and the spatial distribution pattern mapped; the limiting factors affecting the yield were then explored; and their maps of the spatial variability were presented using geostatistics analysis. Data were jointly analyzed for management zone definition using a combination of principal component analysis with a fuzzy clustering method, two cluster validity functions were used to determine the optimal number of cluster. Finally one-way variance analysis was performed on 3,620 soil sampling points to assess how well the defined management zones reflected the soil properties and productivity level. It was shown that there existed great potential for increasing grain production, and the amount of cultivated land played a key role in maintaining security in grain production. Organic matter, total nitrogen, available phosphorus, elevation, thickness of the plow layer, and probability of irrigation guarantee were the main limiting factors affecting the yield. The optimal number of management zones was three, and there existed significantly statistical differences between the crop yield and field parameters in each defined management zone. Management zone I presented the highest potential crop yield, fertility level, and best agricultural production condition, whereas management zone III lowest. The study showed that the procedures used may be effective in automatically defining management zones; by the development of different management zones, different strategies of cultivated land management and practice in each zone could be determined, which is of great importance to enhance cultivated land conservation, stabilize agricultural production, promote sustainable use of cultivated land and guarantee food security. PMID- 23921550 TI - MicroRNA-17~92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways. AB - MicroRNAs (miRNAs) have been broadly implicated in cancer, but their exact function and mechanism in carcinogenesis remain poorly understood. Elevated miR 17~92 expression is frequently found in human cancers, mainly due to gene amplification and Myc-mediated transcriptional upregulation. Here we show that B cell-specific miR-17~92 transgenic mice developed lymphomas with high penetrance and that, conversely, Myc-driven lymphomagenesis stringently requires two intact alleles of miR-17~92. We experimentally identified miR-17~92 target genes by PAR CLIP and validated select target genes in miR-17~92 transgenic mice. These analyses demonstrate that miR-17~92 drives lymphomagenesis by suppressing the expression of multiple negative regulators of the PI3K and NFkappaB pathways and by inhibiting the mitochondrial apoptosis pathway. Accordingly, miR-17~92-driven lymphoma cells exhibited constitutive activation of the PI3K and NFkappaB pathways and chemical inhibition of either pathway reduced tumour size and prolonged the survival of lymphoma-bearing mice. These findings establish miR 17~92 as a powerful cancer driver that coordinates the activation of multiple oncogenic pathways, and demonstrate for the first time that chemical inhibition of miRNA downstream pathways has therapeutic value in treating cancers caused by miRNA dysregulation. PMID- 23921551 TI - Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. AB - Diverse causes, including pathogenic invasion or the uptake of mineral crystals such as silica and monosodium urate (MSU), threaten cells with lysosomal rupture, which can lead to oxidative stress, inflammation, and apoptosis or necrosis. Here, we demonstrate that lysosomes are selectively sequestered by autophagy, when damaged by MSU, silica, or the lysosomotropic reagent L-Leucyl-L-leucine methyl ester (LLOMe). Autophagic machinery is recruited only on damaged lysosomes, which are then engulfed by autophagosomes. In an autophagy-dependent manner, low pH and degradation capacity of damaged lysosomes are recovered. Under conditions of lysosomal damage, loss of autophagy causes inhibition of lysosomal biogenesis in vitro and deterioration of acute kidney injury in vivo. Thus, we propose that sequestration of damaged lysosomes by autophagy is indispensable for cellular and tissue homeostasis. PMID- 23921554 TI - Give what you can and keep what you need! PMID- 23921552 TI - WHSC1 links transcription elongation to HIRA-mediated histone H3.3 deposition. AB - Actively transcribed genes are enriched with the histone variant H3.3. Although H3.3 deposition has been linked to transcription, mechanisms controlling this process remain elusive. We investigated the role of the histone methyltransferase Wolf-Hirschhorn syndrome candidate 1 (WHSC1) (NSD2/MMSET) in H3.3 deposition into interferon (IFN) response genes. IFN treatment triggered robust H3.3 incorporation into activated genes, which continued even after cessation of transcription. Likewise, UV radiation caused H3.3 deposition in UV-activated genes. However, in Whsc1(-/-) cells IFN- or UV-triggered H3.3 deposition was absent, along with a marked reduction in IFN- or UV-induced transcription. We found that WHSC1 interacted with the bromodomain protein 4 (BRD4) and the positive transcription elongation factor b (P-TEFb) and facilitated transcriptional elongation. WHSC1 also associated with HIRA, the H3.3-specific histone chaperone, independent of BRD4 and P-TEFb. WHSC1 and HIRA co-occupied IFN stimulated genes and supported prolonged H3.3 incorporation, leaving a lasting transcriptional mark. Our results reveal a previously unrecognized role of WHSC1, which links transcriptional elongation and H3.3 deposition into activated genes through two molecularly distinct pathways. PMID- 23921553 TI - NuMA phosphorylation by CDK1 couples mitotic progression with cortical dynein function. AB - Spindle positioning and spindle elongation are critical for proper cell division. In human cells, an evolutionary conserved ternary complex (NuMA/LGN/Galphai) anchors dynein at the cortex during metaphase, thus ensuring correct spindle positioning. Whether this complex contributes to anaphase spindle elongation is not known. More generally, the mechanisms coupling mitotic progression with spindle behaviour remain elusive. Here, we uncover that levels of cortical dynein markedly increase during anaphase in a NuMA-dependent manner. We demonstrate that during metaphase, CDK1-mediated phosphorylation at T2055 negatively regulates NuMA cortical localization and that this phosphorylation is counteracted by PPP2CA phosphatase activity. We establish that this tug of war is essential for proper levels of cortical dynein and thus spindle positioning during metaphase. Moreover, we find that upon CDK1 inactivation in anaphase, the rise in dephosphorylated NuMA at the cell cortex leads to cortical dynein enrichment, and thus to robust spindle elongation. Our findings uncover a mechanism whereby the status of NuMA phosphorylation coordinates mitotic progression with proper spindle function. PMID- 23921555 TI - Twisting chromatin in stem cells. PMID- 23921557 TI - Behavioral correlates of extra-pair copulation in Indri indri. AB - Active pursuit of extra-pair mating has been reported for Indri indri, the socially monogamous largest living lemur. This study, conducted in a mountain rainforest in eastern Madagascar, presents the first evidence for extra-pair mating of indri and discusses the alternative mating strategy and alteration of the social, territorial, spatial, and vocal behavior of the adult female of a group of wild indris. Further studies may investigate whether extra-pair copulation is an attempt to breed with a partner of superior quality and thus lead to extra-pair paternity. If so, it could potentially play a role in maintaining genetic variability within a population. PMID- 23921556 TI - Mfn2 modulates the UPR and mitochondrial function via repression of PERK. AB - Mitofusin 2 (Mfn2) is a key protein in mitochondrial fusion and it participates in the bridging of mitochondria to the endoplasmic reticulum (ER). Recent data indicate that Mfn2 ablation leads to ER stress. Here we report on the mechanisms by which Mfn2 modulates cellular responses to ER stress. Induction of ER stress in Mfn2-deficient cells caused massive ER expansion and excessive activation of all three Unfolded Protein Response (UPR) branches (PERK, XBP-1, and ATF6). In spite of an enhanced UPR, these cells showed reduced activation of apoptosis and autophagy during ER stress. Silencing of PERK increased the apoptosis of Mfn2 ablated cells in response to ER stress. XBP-1 loss-of-function ameliorated autophagic activity of these cells upon ER stress. Mfn2 physically interacts with PERK, and Mfn2-ablated cells showed sustained activation of this protein kinase under basal conditions. Unexpectedly, PERK silencing in these cells reduced ROS production, normalized mitochondrial calcium, and improved mitochondrial morphology. In summary, our data indicate that Mfn2 is an upstream modulator of PERK. Furthermore, Mfn2 loss-of-function reveals that PERK is a key regulator of mitochondrial morphology and function. PMID- 23921558 TI - "Re-growth etching" to large-sized porous gold nanostructures. AB - A new method, named "re-growth etching", which introduces a unique etchant "Au(I)", has been developed to fabricate large-sized porous gold nanostructures. The size of nanostructures and the number of pores can be regulated by the molar ratio of Ag and Au in the precursor. We have evaluated their performance by a model reaction of the reduction of 4-nitrophenol. The catalytic property of porous Au from Ag67.6Au32.4 (Sample 3) is higher than those of other obtained products, which are mainly attributed to its hollows-interior, porous-exterior, and the large amount of Au. The method for the large-sized porous metal nanostructures has been established for the first time and shows the potential of this route to expand the scope of fabricating porous metal nanostructures. PMID- 23921559 TI - A comparison between orthogonal and parallel plating methods for distal humerus fractures: a prospective randomized trial. AB - With the continuing improvements in implants for distal humerus fractures, it is expected that newer types of plates, which are anatomically precontoured, thinner and less irritating to soft tissue, would have comparable outcomes when used in a clinical study. The purpose of this study was to compare the clinical and radiographic outcomes in patients with distal humerus fractures who were treated with orthogonal and parallel plating methods using precontoured distal humerus plates. Sixty-seven patients with a mean age of 55.4 years (range 22-90 years) were included in this prospective study. The subjects were randomly assigned to receive 1 of 2 treatments: orthogonal or parallel plating. The following results were assessed: operating time, time to fracture union, presence of a step or gap at the articular margin, varus-valgus angulation, functional recovery, and complications. No intergroup differences were observed based on radiological and clinical results between the groups. In our practice, no significant differences were found between the orthogonal and parallel plating methods in terms of clinical outcomes, mean operation time, union time, or complication rates. There were no cases of fracture nonunion in either group; heterotrophic ossification was found 3 patients in orthogonal plating group and 2 patients in parallel plating group. In our practice, no significant differences were found between the orthogonal and parallel plating methods in terms of clinical outcomes or complication rates. However, orthogonal plating method may be preferred in cases of coronal shear fractures, where posterior to anterior fixation may provide additional stability to the intraarticular fractures. Additionally, parallel plating method may be the preferred technique used for fractures that occur at the most distal end of the humerus. PMID- 23921561 TI - Network for excellence in neuroscience clinical trials: NeuroNEXT. PMID- 23921560 TI - Direct observation of a single nanoparticle-ubiquitin corona formation. AB - The advancement of nanomedicine and the increasing applications of nanoparticles in consumer products have led to administered biological exposure and unintentional environmental accumulation of nanoparticles, causing concerns over the biocompatibility and sustainability of nanotechnology. Upon entering physiological environments, nanoparticles readily assume the form of a nanoparticle-protein corona that dictates their biological identity. Consequently, understanding the structure and dynamics of a nanoparticle-protein corona is essential for predicting the fate, transport, and toxicity of nanomaterials in living systems and for enabling the vast applications of nanomedicine. Here we combined multiscale molecular dynamics simulations and complementary experiments to characterize the silver nanoparticle-ubiquitin corona formation. Notably, ubiquitins competed with citrates for the nanoparticle surface, governed by specific electrostatic interactions. Under a high protein/nanoparticle stoichiometry, ubiquitins formed a multi-layer corona on the particle surface. The binding exhibited an unusual stretched-exponential behavior, suggesting a rich binding kinetics. Furthermore, the binding destabilized the alpha-helices while increasing the beta-sheet content of the proteins. This study revealed the atomic and molecular details of the structural and dynamic characteristics of nanoparticle-protein corona formation. PMID- 23921562 TI - HIV-related risk among female migrants working in entertainment venues in China. AB - China has experienced a surge in internal migration during the past decade, and migrant populations have been identified as a high-risk group for HIV and other sexually transmitted infections (STIs). Young female migrants often find employment in entertainment venues (bars, karaoke parlors, and massage parlors) located in metropolitan cities, and sex work transactions frequently occur in these venues. We examined factors associated with risk for HIV, other STIs, and reproductive health challenges in a cross-sectional study of 358 young female migrants, ages 18-29, working in entertainment venues in a rapidly growing urban city in China. Results indicate high levels of behavioral risk for HIV and other STIs, low rates of HIV testing, and high prevalence of problem drinking and mental health problems, including recent depression symptoms and suicidal ideation. Factors associated with increased STIs and genitourinary tract infections included commercial sex work, early sexual debut, abortion history, illicit drug use, and anxiety. Factors associated with increased HIV testing included employment in an affluent entertainment venue, education level, knowledge about where to obtain free HIV tests, condom use, and general HIV/AIDS knowledge. Findings of this study highlight the insufficient coverage of current public health services to female migrants working in entertainment venues and call for more assertive prevention interventions to mitigate risk for sexual, reproductive, behavioral, and mental health problems in this mobile population. PMID- 23921563 TI - Theory-based interventions for contraception. AB - BACKGROUND: The explicit use of theory in research helps expand the knowledge base. Theories and models have been used extensively in HIV-prevention research and in interventions for preventing sexually transmitted infections (STIs). The health behavior field uses many theories or models of change. However, educational interventions addressing contraception often have no stated theoretical base. OBJECTIVES: Review randomized controlled trials (RCTs) that tested a theoretical approach to inform contraceptive choice; encourage contraceptive use; or promote adherence to, or continuation of, a contraceptive regimen. SEARCH METHODS: Through June 2013, we searched computerized databases for trials that tested a theory-based intervention for improving contraceptive use (MEDLINE, POPLINE, CENTRAL, PsycINFO, ClinicalTrials.gov, and ICTRP). Previous searches also included EMBASE. For the initial review, we wrote to investigators to find other trials. SELECTION CRITERIA: Trials tested a theory based intervention for improving contraceptive use. We excluded trials focused on high-risk groups and preventing sexually transmitted infections or HIV. Interventions addressed the use of one or more contraceptive methods for contraception. The reports provided evidence that the intervention was based on a specific theory or model. The primary outcomes were pregnancy, contraceptive choice or use, and contraceptive adherence or continuation. DATA COLLECTION AND ANALYSIS: The primary author evaluated abstracts for eligibility. Two authors extracted data from included studies. For the dichotomous outcomes, the Mantel Haenszel odds ratio (OR) with 95% CI was calculated using a fixed-effect model. Cluster randomized trials used various methods of accounting for the clustering, such as multilevel modeling. Most reports did not provide information to calculate the effective sample size. Therefore, we presented the results as reported by the investigators. No meta-analysis was conducted due to differences in interventions and outcome measures. MAIN RESULTS: We included three new trials for a total of 17. Ten randomly assigned individuals and seven were cluster randomized. Eight trials showed some intervention effect.Two of 12 trials with pregnancy or birth data showed some effect. A theory-based group was less likely than the comparison group to have a second birth (OR 0.41; 95% CI 0.17 to 1.00) or to report a pregnancy (OR 0.24 (95% CI 0.10 to 0.56); OR 0.27 (95% CI 0.11 to 0.66)). The theoretical bases were social cognitive theory (SCT) and another social cognition model.Of 12 trials with data on contraceptive use (non-condom), six showed some effect. A theory-based group was more likely to consistently use oral contraceptives (OR 1.41; 95% CI 1.06 to 1.87), hormonal contraceptives (reported relative risk (RR) 1.30; 95% CI 1.06 to 1.58) or dual methods (reported RR 1.36; 95% CI 1.01 to 1.85); to use an effective contraceptive method (reported effect size 1.76; OR 2.04 (95% CI 1.47 to 2.83)) or use more habitual contraception (reported P < 0.05); and were less likely to use ineffective contraception (OR 0.56; 95% CI 0.31 to 0.98). Theories and models included the Health Belief Model (HBM), SCT, SCT plus another theory, other social cognition, and motivational interviewing (MI).For condom use, a theory-based group had favorable results in 5 of 11 trials. The main differences were reporting more consistent condom use (reported RR 1.57; 95% CI 1.28 to 1.94) and more condom use during last sex (reported results: risk ratio 1.47 (95% CI 1.12 to 1.93); effect size 1.68; OR 2.12 (95% CI 1.24 to 3.56); OR 1.45 (95% CI 1.03 to 2.03)). The theories were SCT, SCT plus another theory, and HBM.Nearly all trials provided multiple sessions or contacts. SCT provided the basis for seven trials focused on adolescents, of which five reported some effectiveness. Two others based on other social cognition models had favorable results with adolescents. Of six trials including adult women, five provided individual sessions. Some effect was seen in two using MI and one using the HBM. Two based on the Transtheoretical Model did not show any effect. AUTHORS' CONCLUSIONS: Eight trials provided evidence of high or moderate quality. Family planning researchers and practitioners could adapt the effective interventions, although most provided group sessions for adolescents. Three were conducted outside the USA. Clinics and low-resource settings need high-quality evidence on changing behavior. Thorough use of single theories would help in identifying what works, as would better reporting on research design and intervention implementation. PMID- 23921565 TI - Novel interventions for resistant hypertension. PMID- 23921564 TI - Topological defect formation and spontaneous symmetry breaking in ion Coulomb crystals. AB - Symmetry breaking phase transitions play an important role in nature. When a system traverses such a transition at a finite rate, its causally disconnected regions choose the new broken symmetry state independently. Where such local choices are incompatible, topological defects can form. The Kibble-Zurek mechanism predicts the defect densities to follow a power law that scales with the rate of the transition. Owing to its ubiquitous nature, this theory finds application in a wide field of systems ranging from cosmology to condensed matter. Here we present the successful creation of defects in ion Coulomb crystals by a controlled quench of the confining potential, and observe an enhanced power law scaling in accordance with numerical simulations and recent predictions. This simple system with well-defined critical exponents opens up ways to investigate the physics of non-equilibrium dynamics from the classical to the quantum regime. PMID- 23921566 TI - All systems normal: renal solute transport research in 2013. PMID- 23921567 TI - Paracetamol for ductus arteriosus closure: not always a success story. Concerning the article by M.Y. Oncel et al: intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants [Neonatology 2013;103:166-169]. PMID- 23921568 TI - A molecular diagnostic algorithm to guide pollen immunotherapy in southern Europe: towards component-resolved management of allergic diseases. AB - Correct identification of the culprit allergen is an essential part of diagnosis and treatment in immunoglobulin E (IgE)-mediated allergic diseases. In recent years, molecular biology has made important advances facilitating such identification and overcoming some of the drawbacks of natural allergen extracts, which consist of mixtures of various proteins that may be allergenic or not, specific for the allergen source or widely distributed (panallergens). New technologies offer the opportunity for a more accurate component-resolved diagnosis, of benefit especially to polysensitized allergic patients. The basic elements of molecular diagnostics with potential relevance to immunotherapy prescription are reviewed here, with a focus on Southern European sensitization patterns to pollen allergens. We propose a basic algorithm regarding component resolved diagnostic work-up for pollen allergen-specific immunotherapy candidates in Southern Europe; this and similar algorithms can form the basis of improved patient management, conceptually a 'Component-Resolved Allergy Management'. PMID- 23921569 TI - Adoptive transfer of cytomegalovirus-specific effector CD4+ T cells provides antiviral protection from murine CMV infection. AB - Cytomegalovirus (CMV) infects a majority of the human population and establishes a life-long persistence. CMV infection is usually asymptomatic but the virus carries pathogenic potential and causes severe disease in immunocompromised individuals. T-cell-mediated immunity plays an essential role in control of CMV infection and adoptive transfer of CMV-specific CD8(+) T cells restores viral immunity in immunosuppressed patients but a role for CD4(+) T cells remains elusive. Here, we analyzed in adoptive transfer studies the features and antiviral functions of virus-specific CD4(+) T cells during primary murine CMV (MCMV) infection. MCMV-specific CD4(+) T cells expanded upon MCMV infection and displayed an effector phenotype and function. Adoptive transfer of in vivo activated MCMV-specific CD4(+) T cells to immune-compromised mice was protective during pathogenic MCMV infection and IFN-gamma was a crucial mediator of this protective capacity. Moreover, co-transfer of low doses of both MCMV-specific CD4(+) T cells and CD8(+) T cells synergized in control of lytic viral replication in immune-compromised mice. Our data reveal a pivotal antiviral role for virus-specific CD4(+) T cells in protection from pathogenic CMV infection and provide evidence for their antiviral therapeutic potential. PMID- 23921570 TI - Prediction of poor outcome in cerebellar infarction by diffusion MRI. AB - OBJECTIVE: Identification of patients with posterior fossa infarction at risk for neurological deterioration remains a challenge. MRI-based assessments of MCA infarction can predict poor outcome. Similar quantitative imaging measures after cerebellar stroke have not been studied. We tested the hypothesis that MRI-based volumetric assessment of cerebellar infarcts can provide reliable information for the prediction of poor outcome. DESIGN: We retrospectively identified 44 consecutive subjects (age 55.2 +/- 13) with cerebellar stroke who underwent MRI with diffusion-weighted imaging (DWI) (median 63.7 h). Subjects were divided into poor (n = 13) and good outcomes (n = 31). Poor outcome was defined as having at least one of the following criteria: (1) mortality, (2) decompressive craniectomy, (3) ventriculostomy, and (4) decrease level of consciousness. DWI and cerebellar volume were defined on apparent diffusion coefficient maps. The ratio of the lesion volume to the whole cerebellum volume was calculated (rVolume). MEASUREMENTS AND MAIN RESULTS: Logistic regression revealed that lesion volume and rVolume were associated with increased risk of poor outcome, even after adjusting for age and NIHSS (chi(2) = 8.2230, p < 0.0042; chi(2) = 8.3992, p < 0.0038, respectively). The receiver operating characteristic curve with age, NIHSS, and volume or rVolume achieved an AUC of 0.816 (95 % CI 0.678 0.955) and 0.831 (95 % CI 0.6989-0.9636), respectively. CONCLUSIONS: Quantitative volumetric measurement predicts poor outcome of cerebellar stroke patients, even when controlling for age and NIHSS. Quantitative analysis of diffusion MRI may assist in identification of patients with cerebellar stroke at highest risk of neurological deterioration. Prospective validation is warranted. PMID- 23921571 TI - Plasma endothelin-1 as screening marker for cerebral vasospasm after subarachnoid hemorrhage. AB - BACKGROUND: Cerebral vasospasm complicating subarachnoid hemorrhage causes ischemic stroke and worsens the neurological outcome. The potential role of endothelin-1 in vasospasm pathogenesis may provide therapeutic opportunities. A recent meta-analysis however, did not support the use of endothelin antagonists. Apart from clinical assessment, transcranial Doppler and interval angiography, there are no sensitive screening markers for evolving vasospasm. We investigate the ability of serial measurement of endothelin-1 to predict the development of vasospasm following subarachnoid hemorrhage. METHODS: Endothelin-1 levels in cerebrospinal fluid and blood were measured daily in 20 patients admitted to the ICU with subarachnoid hemorrhage from days 1 to 10 following the inception bleed. In addition to clinical assessment, patients had daily transcranial Doppler. Digital subtraction angiography was performed on the suspicion of vasospasm based upon clinical or transcranial Doppler assessment. Neuron-specific enolase and SB100 were measured in blood as comparative biomarkers of neurological injury. RESULTS: Mean plasma endothelin-1 on day 5, was 4.2 mcg/L (CI 3.1-5.8) in patients with vasospasm compared to 2.5 mcg/L (CI 1.5-4.0) in those without vasospasm (P = 0.047). There were no time-related differences in cerebrospinal fluid endothelin-1, plasma NSE, or SB100 for patients with and without vasospasm. CONCLUSIONS: In patients with subarachnoid hemorrhage and vasospasm, endothelin-1 is significantly higher in plasma than in CSF on day 5. Neither NSE nor SB100 is associated with the development of vasospasm. Measurement of serial plasma endothelin-1 concentration is a potential screening marker of vasospasm. PMID- 23921572 TI - SNPs and interaction analyses of IRF6, MSX1 and PAX9 genes in patients with non syndromic cleft lip with or without palate. AB - Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common congenital deformity, often associated with missing or deformed teeth. The genes interferon regulatory factor 6 (IRF6), muscle segment homeobox 1 (MSX1) and paired box gene 9 (PAX9) are important for the development of the maxillofacial region and dentition. The aim of this study was to explore how genetic variations in IRF6, MSX1 and PAX9, as well as gene-gene interactions, are associated with NSCL/P. We investigated 9 IRF6 tag single nucleotide polymorphisms (SNPs), 2 MSX1 tag SNPs and 8 PAX9 tag SNPs selected from HapMap data from the Chinese population. The SNPs were examined for associations with NSCL/P in 204 patients and 226 controls. The results demonstrated a significant association between NSCL/P and rs2073485, rs2235371, rs2236909 and rs861020 in the IRF6 gene, and haplotype analysis supported these findings. A marginally significant difference was observed in the NSCL/P group for rs17176643 in the PAX9 gene compared to the control group. The results of gene-gene interaction analyses also indicated that the combination of rs2073485, rs2235371 or rs2236909 in IRF6 and rs17176643 in PAX9, increased the risk of NSCL/P. Thus, our study provided additional understanding of IRF6 variations in patients with NSCL/P and suggested that interactions between the IRF6 and PAX9 genes are potentially important for susceptibility to NSCL/P. PMID- 23921573 TI - Phase 1 pharmacokinetic study of MK-0646 (dalotuzumab), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in combination with cetuximab and irinotecan in Japanese patients with advanced colorectal cancer. AB - PURPOSE: The safety, tolerability, and pharmacokinetic (PK) interactions of MK 0646 in combination with cetuximab and irinotecan were investigated in Japanese patients with advanced colorectal cancer. METHODS: Twenty patients were treated in the following study arms in combination with cetuximab and irinotecan: A [MK 0646 (10 mg/kg) weekly starting on Day 22], B [MK-0646 (15 mg/kg) on Day 8, followed by 7.5 mg/kg every 2 weeks], or C [MK-0646 (10 mg/kg) on Day 1 and weekly starting on Day 22]. Dose limiting toxicities (DLTs) were evaluated during a prespecified 4-week period in arms A and B. Full PK sampling was performed to evaluate the PK interactions. RESULTS: One of the 6 evaluable patients in arm A developed a DLT (grade 3 hyperglycemia); no DLTs occurred in the 6 patients in arm B. Common treatment-related adverse events included leukopenia, neutropenia, dermatitis acneiform, paronychia, nausea, stomatitis, diarrhea, and decreased appetite. The co-administration of cetuximab and irinotecan with MK-0646 increased the MK-0646 AUC0-168h by 25 %, with MK-0646 accumulation from the previous dose contributing to the observed increase. The co-administration of MK 0646 with cetuximab and irinotecan did not affect the PK of cetuximab and irinotecan, but reduced the C max (from 16.8 to 13.0 ng/mL) and the AUC0-24h (by 13 %) of SN-38, the active metabolite of irinotecan. CONCLUSIONS: The triple combination of MK-0646, cetuximab, and irinotecan was well tolerated in Japanese patients with advanced colorectal cancer. These results indicate a minimal potential for PK interactions between MK-0646 and cetuximab and between MK-0646 and irinotecan/SN-38. PMID- 23921574 TI - Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer (CRPC). AB - PURPOSE: Recent data indicate that there is a significant cross-talk between the PI3K/Akt/mTOR and androgen receptor signaling pathways. We evaluated safety and tolerability as well as potential drug-drug interaction of ridaforolimus, a mammalian target of rapamycin (mTOR) inhibitor, when combined with the androgen receptor inhibitor bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer. PATIENTS AND METHODS: Patients were treated with the combination of ridaforolimus 30 mg/day for 5 consecutive days each week and bicalutamide 50 mg/day. Ridaforolimus pharmacokinetics was assessed with and without bicalutamide. RESULTS: Twelve patients were enrolled including 1 screen failure. Dose reductions were required in 7 patients. Three of the 11 patients experienced a dose-limited toxicity, 1 with Grade 3 hyperglycemia and 2 with Grade 2 stomatitis leading to <75 % of planned ridaforolimus dose during the first 35 days of study treatment. The pharmacokinetic results showed no differences in exposures to ridaforolimus with and without concomitant bicalutamide administration. CONCLUSIONS: Although there was no evidence of a clinically relevant pharmacological drug-drug interaction, the occurrence of dose limiting toxicities in 3 of 11 evaluable patients at a reduced dose of ridaforolimus of 30 mg/day suggests that this combination may not be well suited for asymptomatic or minimally symptomatic prostate cancer patients. PMID- 23921576 TI - A novel double-enhanced suicide gene therapy in a colon cancer cell line mediated by gef and apoptin. AB - BACKGROUND: Double-suicide gene therapy is a promising strategy for the treatment of advanced cancer. It has become an important research line in the development of gene therapy to overcome the drawbacks of single-gene therapy. OBJECTIVE: The aim of this study was to investigate the usefulness of double-suicide gene therapy with the two suicide genes, gef and apoptin, in colon carcinoma. METHODS: gef and apoptin genes were cloned into a doxycycline-regulated retrovirus mediated gene expression system. Expression of both genes in the DLD-1 cell line was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). Cell viability was determined with the sulforhodamine B colorimetric assay, and the cell cycle was studied by propidium iodide (PI) staining. Annexin V-FITC and PI assays were used to evaluate apoptosis, and the results were confirmed by electron microscopy. The mitochondrial membrane potential was measured by JC-1 assay. RESULTS: Our results showed that the combined expression of gef and apoptin genes was strikingly more effective than the expression of either gene alone. Co-expression of gef and apoptin synergistically enhanced the decrease in cell viability, increasing necrosis and inducing apoptosis in colon cancer cells via the mitochondrial pathway, which can be deficient in advanced or metastatic colon cancer. CONCLUSIONS: Double-suicide gene therapy based on gef and apoptin genes may be a candidate for the development of new colon cancer strategies, and further studies are warranted to establish the usefulness of double-suicide gene therapy in vivo. PMID- 23921575 TI - A phase II study of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy followed by surgery and adjuvant S-1 chemotherapy in potentially resectable gastric or gastroesophageal junction adenocarcinoma. AB - PURPOSE: Adjuvant chemotherapy trial of TS-1 for gastric cancer study demonstrated that postoperative S-1 chemotherapy for 1 year improved overall survival of locally advanced gastric cancer (LAGC) patients. The goals of this study were to evaluate the feasibility and efficacy of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy followed by surgery and adjuvant S-1 chemotherapy. METHODS: In this single-center, open-label, phase II study, patients with potentially resectable adenocarcinoma of the stomach or gastroesophageal junction were eligible. For neoadjuvant chemotherapy, docetaxel 50 mg/m(2) on day (D) 1, oxaliplatin 100 mg/m(2) on D1, and S-1 40 mg/m(2) bid orally on D1-14 were administrated every 3 weeks for three cycles. After DOS chemotherapy, gastrectomy was performed, and then, adjuvant S-1 40 mg/m(2) bid was given on D1-28 every 6 weeks for 1 year. The primary endpoints were the proportion of patients who did not experience grade 3 or 4 toxicities (except grade 3 neutropenia) and R0 resection rates. RESULTS: A total of 41 patients were enrolled. All patients completed three planned cycles of neoadjuvant chemotherapy without disease progression. Eighteen patients (43.9 %) did not experience any grade 3-4 toxicity (except grade 3 neutropenia) during the neoadjuvant chemotherapy. All patients underwent surgery, and R0 resection was achieved in 40 patients (97.6 %). CONCLUSION: Neoadjuvant DOS chemotherapy could be performed safely with a high R0 resection rate in LAGC patients. A phase III trial is currently underway. PMID- 23921577 TI - Risk perception of unruptured intracranial aneurysms. AB - OBJECT: Recent prospective studies have shown that the rupture rate of small unruptured intracranial aneurysms is very low. However, awareness of harboring an aneurysm often provokes anxiety and depression, which may reduce the quality of life (QOL). METHODS: This cross-sectional study enrolled 52 patients who had previously been notified of the presence of untreated unruptured aneurysms. A Markov model was constructed to simulate the natural history over time, and the age- and size-specific loss of quality-adjusted life year (QALY) caused by the aneurysms was calculated. Preference-based subjective QALY losses (PSG and PTTO) were assessed using the standard gamble (SG) and time trade-off (TTO) according to patient's own perceptions. RESULTS: Calculated theoretical QALY losses were relatively small with median values of 0.4 years (interquartile range [IQR] 0.1 1.0 years) and 1.9 % (IQR 1.1-3.7 %) of expected lifetime. The median values of PSG and PTTO were 10.0 % (IQR 5.0-14.3 %) and 19.5 % (IQR 9.0-25.0 %), respectively. Although theoretical QALY losses were smaller in the patients with small aneurysms (<5 mm) than in patients with medium ~ large aneurysms (>=5 mm), the PSG and PTTO were almost the same in both groups. The discrepancy between theoretical and subjective QALY losses was prominent in patients with small aneurysms. CONCLUSIONS: Notification of unruptured aneurysms exerts a significant psychological burden, and excessively reduces the QOL relative to the theoretical risks. The present study suggests that neurosurgeons should reconsider the method used to inform patients of small lesions with low risk of severe consequences. PMID- 23921578 TI - Safety and effectiveness of microvascular decompression for the treatment of hemifacial spasm in the elderly. AB - BACKGROUND: Hemifacial spasm (HFS) is a common disorder and has a significant impact on the quality of life. Microvascular decompression (MVD) is an effective and safe treatment option for patients with HFS, however the effectiveness and safety of MVD in elderly patients with HFS is not clear. METHODS: We enrolled 699 HFS patients who underwent MVD from February 2008 to December 2011 at the Samsung Medical Center in Seoul, Korea. Subjects were divided into two groups: an elderly group (patients who were 60 years old or older) and a younger group. We compared demographic and clinical data, surgical outcome and complications after MVD between the groups. RESULTS: The elderly group had more severe spasms and higher grade indentation than the younger group. Multiple offending vessels were more commonly detected in the elderly group. Although the improvement was similar 6 months after MVD between the groups, complications were more common in the elderly group even after controlling for possible confounding factors. In particular, ear problems including hearing loss were more common in the elderly group. CONCLUSION: MVD is an effective treatment option in elderly patients with HFS. However, surgeons should be pay attention to potential complications in elderly patients with HFS. PMID- 23921579 TI - To fundo or not to fundo? PMID- 23921580 TI - Antimicrobials and Non-healing Wounds Evidence, controversies and suggestions. AB - Non-healing wounds are a significant problem for health-care systems worldwide. In the industrialised world, almost 1-1.5% of the population will have a problem wound at any one time. Furthermore, wound management is expensive; in Europe, the average cost per episode is 6650 euros for leg ulcers and 10 000 euros for foot ulcers, and wound management accounts for 2-4% of health-care budgets. These figures are expected to rise along with an increased elderly and diabetic population.1-4. PMID- 23921581 TI - Mannosylglucosylglycerate biosynthesis in the deep-branching phylum Planctomycetes: characterization of the uncommon enzymes from Rhodopirellula baltica. AB - The biosynthetic pathway for the rare compatible solute mannosylglucosylglycerate (MGG) accumulated by Rhodopirellula baltica, a marine member of the phylum Planctomycetes, has been elucidated. Like one of the pathways used in the thermophilic bacterium Petrotoga mobilis, it has genes coding for glucosyl-3 phosphoglycerate synthase (GpgS) and mannosylglucosyl-3-phosphoglycerate (MGPG) synthase (MggA). However, unlike Ptg. mobilis, the mesophilic R. baltica uses a novel and very specific MGPG phosphatase (MggB). It also lacks a key enzyme of the alternative pathway in Ptg. mobilis - the mannosylglucosylglycerate synthase (MggS) that catalyses the condensation of glucosylglycerate with GDP-mannose to produce MGG. The R. baltica enzymes GpgS, MggA, and MggB were expressed in E. coli and characterized in terms of kinetic parameters, substrate specificity, temperature and pH dependence. This is the first characterization of genes and enzymes for the synthesis of compatible solutes in the phylum Planctomycetes and for the synthesis of MGG in a mesophile. PMID- 23921582 TI - Social support and HIV-related risk behaviors: a systematic review of the global literature. AB - Existing empirical evidence has well documented the role of social support in both physical and psychological well-being among various populations. In the context of HIV prevention, the rapid increase of studies on social support merits a systematic review to synthesize the current global literature on association between social support and HIV-related risk behaviors. The current review reveals a complex picture of this relationship across diverse populations. Existing studies indicate that higher levels of social support are related to fewer HIV related risk behaviors among female sex workers and people living with HIV/AIDS and heterosexual adults in general. However, influences of social support on HIV related risk behaviors are inconsistent within drug users, men who have sex with men and adolescents. These variations in findings may be attributed to different measurement of social support in different studies, specific context of social support for diverse population, or various characteristics of the social networks the study population obtained support from. Future studies are needed to explore the mechanism of how social support affects HIV-related risk behaviors. HIV prevention intervention efforts need to focus on the positive effect of social support for various vulnerable and at-risk populations. Future efforts also need to incorporate necessary structure change and utilize technical innovation in order to maximize the protective role of social support in HIV risk prevention or reduction. PMID- 23921583 TI - Associations between injection risk and community disadvantage among suburban injection drug users in southwestern Connecticut, USA. AB - Increases in drug abuse, injection, and opioid overdoses in suburban communities led us to study injectors residing in suburban communities in southwestern Connecticut, US. We sought to understand the influence of residence on risk and injection-associated diseases. Injectors were recruited by respondent-driven sampling and interviewed about sociodemographics, somatic and mental health, injection risk, and interactions with healthcare, harm reduction, substance abuse treatment, and criminal justice systems. HIV, hepatitis B and C (HBV and HCV) serological testing was also conducted. Our sample was consistent in geographic distribution and age to the general population and to the patterns of heroin associated overdose deaths in the suburban towns. High rates of interaction with drug abuse treatment and criminal justice systems contrasted with scant use of harm reduction services. The only factors associated with both dependent variables-residence in less disadvantaged census tracts and more injection risk were younger age and injecting in one's own residence. This contrasts with the common association among urban injectors of injection-associated risk behaviors and residence in disadvantaged communities. Poor social support and moderate/severe depression were associated with risky injection practices (but not residence in specific classes of census tracts), suggesting that a region wide dual diagnosis approach to the expansion of harm reduction services could be effective at reducing the negative consequences of injection drug use. PMID- 23921584 TI - Randomized controlled trial to test the RHANI Wives HIV intervention for women in India at risk for HIV from husbands. AB - This study involved evaluation of the short-term impact of the RHANI Wives HIV intervention among wives at risk for HIV from husbands in Mumbai, India. A two armed cluster RCT was conducted with 220 women surveyed on marital sex at baseline and 4-5 month follow-up. RHANI Wives was a multisession intervention focused on safer sex, marital communication, gender inequities and violence; control participants received basic HIV prevention education. Generalized linear mixed models were conducted to assess program impact, with cluster as a random effect and with time, treatment group, and the time by treatment interaction as fixed effects. A significant time by treatment effect on proportion of unprotected sex with husband (p = 0.01) was observed, and the rate of unprotected sex for intervention participants was lower than that of control participants at follow-up (RR = 0.83, 95 % CI = 0.75, 0.93). RHANI Wives is a promising model for women at risk for HIV from husbands. PMID- 23921585 TI - Hazardous and harmful use of alcohol and/or other drugs and health status among South African patients attending HIV clinics. AB - There is growing recognition of the influence of substance use, particularly alcohol use, on HIV disease progression. This study investigated how hazardous/harmful use of alcohol and drugs impacts the health status of 1503 patients attending HIV clinics. Of the sample, 37 % indicated hazardous/harmful drinking and 13 % indicated a drug problem. Hazardous/harmful use of alcohol and drugs was significantly related to health status, with participants using substances more likely to have TB-positive status (chi(2) = 4.30, p < 0.05), less likely to be on ARVs (chi(2) = 9.87, p < 0.05) and having lower CD4 counts (t = 4.01, p < 0.05). Structural equation modelling confirmed the centrality of hazardous/harmful use of alcohol as a direct and indirect determinant of disease progression. Based on these findings it is recommended that patients attending HIV clinics be routinely screened for problematic alcohol and/or drug use, with strong emphasis on ensuring ARV adherence in those with problematic alcohol use. PMID- 23921591 TI - Concerted interaction of TGF-beta and GDNF mediates neuronal differentiation. AB - The glial cell-line derived neurotrophic factor (GDNF) is crucial for ureteric bud morphogenesis, spermatogenesis, and development of the enteric nervous system and is a potent survival factor for various neuronal populations. However, the impact of GDNF, at least on cell survival, was found to depend strongly on the presence of transforming growth factor beta (TGF-beta). In this study, we investigate the role of TGF-beta in GDNF-induced neuronal differentiation. In a cell culture paradigm of N2aGT cells (neuroblastoma cell line), we show that TGF beta signaling localizes the GDNF ligand-binding receptor GFRa1 to the cell surface, which is a known mechanism by which TGF-beta is able to facilitate GDNF signaling. TGF-beta-mediated GDNF signaling slightly elevated the phosphorylation state of Ret, the canonical coreceptor for the GPI-linked (glycosyl phosphatidylinositol) GFRa1. On the basis of morphological as well as immunocytological data, we finally show that GDNF-mediated neuronal differentiation is intensified when GDNF and TGF-beta act in concert. PMID- 23921592 TI - Irradiated normal brain promotes invasion of glioblastoma through vascular endothelial growth and stromal cell-derived factor 1alpha. AB - The significance of irradiated normal brain volume in glioma recurrence is usually ignored by radiotherapists. The whole-brain irradiation (WBI) of 15 Gy in three fractions was delivered to C57BL/6 mice before implantation of GL261 glioma cells. The changes in vascular endothelial growth (VEGF) and stromal cell-derived factor 1alpha (SDF-1alpha) after WBI were evaluated by real-time RT-PCR and immunohistochemistry. Cell invasion assays were performed to study the effects of VEGF and SDF-1alpha. The levels of VEGF and SDF-1alpha in normal brain tissues increased after 15 Gy WBI. The WBI before tumor implantation significantly increased the invasive ability of GL261 cells. VEGF and SDF-1alpha could promote invasion of GL261 cells even after high-dose irradiation. The combination of irradiation and inhibitors such as AMD3100 may prevent irradiation-stimulated dissemination of glioma cells. PMID- 23921593 TI - Encoding of faces and objects into visual working memory: an event-related brain potential study. AB - Visual working memory (VWM) is an important prerequisite for cognitive functions, but little is known on whether the general perceptual processing advantage for faces also applies to VWM processes. The aim of the present study was (a) to test whether there is a general advantage for face stimuli in VWM and (b) to unravel whether this advantage is related to early sensory processing stages. To address these questions, we compared encoding of faces and complex nonfacial objects into VWM within a combined behavioral and event-related brain potential (ERP) study. In detail, we tested whether the N170 ERP component - which is associated with face-specific holistic processing - is affected by memory load for faces or whether it might be involved in WM encoding of any complex object. Participants performed a same-different task with either face or watch stimuli and with two different levels of memory load. Behavioral measures show an advantage for faces on the level of VWM, mirrored in higher estimated VWM capacity (i.e. Cowan's K) for faces compared with watches. In the ERP, the N170 amplitude was enhanced for faces compared with watches. However, the N170 was not modulated by working memory load either for faces or for watches. In contrast, the P3b component was affected by memory load irrespective of the stimulus category. Taken together, the results suggest that the VWM advantage for faces is not reflected at the sensory stages of stimulus processing, but rather at later higher-level processes as reflected by the P3b component. PMID- 23921594 TI - Modulation of cortical neural dynamics during thalamic deep brain stimulation in patients with essential tremor. AB - Although thalamic deep brain stimulation is an effective treatment for patients with essential tremor, little is known about its effect on cortical neural dynamics. Therefore, we investigated long-range temporal correlations and spectral power in electroencephalographic recordings of patients during OFF versus ON bilateral thalamic deep brain stimulation in comparison with healthy controls. Cortical dynamics were analyzed in the range of 6-30 Hz. We found the presence of long-range temporal correlations up to 20 s in patients and controls. Thalamic deep brain stimulation was associated with increased long-range temporal correlations in the high beta band (21-30 Hz) and decreased power in the low beta band (13-20 Hz) compared with OFF stimulation and healthy controls. Long-range temporal correlations in the 6-10 Hz range were increased with OFF stimulation compared with the controls. Importantly, deep brain stimulation-induced changes in long-range temporal correlations within 6-10 Hz and in the beta ranges (13-20, 21-30 Hz) were correlated with OFF-ON changes in the tremor severity and with the disease duration, respectively. The differential reactivity of long-range temporal correlations and spectral power to deep brain stimulation might suggest that both measures reflect distinct aspects of cortical dynamics and might represent biomarkers for stimulation-induced modulations of neural dynamics in electroencephalography. The fact that long-range temporal correlations, but not spectral power, were correlated with clinical information might suggest long range temporal correlations as a potential marker for disease severity in essential tremor. PMID- 23921595 TI - Hyperphosphorylation of CREB in human dopaminergic neurons: a kinetic study of cellular distribution of total CREB and phospho-CREB following oxidative stress. AB - The neurotoxin, 6-hydroxy dopamine (6-OHDA)-induced oxidative stress causes alterations in intracellular signalling events and activates cellular and molecular mechanisms leading to the degeneration of the dopamine-containing neurons (DCNs). The cyclic-AMP response element-binding protein (CREB) modulates the transcription of mitochondrial and nuclear genes upon phosphorylation. However, oxidative stress disrupts CREB functions and inhibits CREB signalling pathways. We have measured the activities and levels of both total CREB and its phosphorylated form (phospho-CREB) in cytosolic, mitochondrial and nuclear compartments in control (untreated) and stressed (6-OHDA-treated) DCN, differentiated from the ReNVM cell line (dDCN) at 0, 24 and 72 h time points following oxidative stress. Our results indicate that CREB phosphorylation occurs in all three subcellular locations. It further shows significant disruption of the phosphorylation process by 6-OHDA treatment and shows tridirectional trafficking of total CREB and phospho-CREB between cytosol, mitochondria and nucleus following oxidative stress induced by 6-OHDA treatment. In conclusion, our results indicate the presence of specific signalling molecules in all the compartments studied and their involvement in the signal transduction processes, where total CREB and phospho-CREB levels and activities are either upregulated or downregulated to balance each other for their roles. PMID- 23921596 TI - Use of a load cell and force-moment curves to compare transverse plane moment loads on transtibial residual limbs: A preliminary investigation. AB - BACKGROUND AND AIM: The objective of this study was to demonstrate how a load cell and force-moment curves can be used outside of a gait lab to directly measure and evaluate the transverse plane loading moment on transtibial residual limbs. TECHNIQUE: A load cell was attached distally to the socket of three transtibial amputees who walked a straight path and a circle of 3.048-m diameter with the prosthetic foot both inside and outside the curved path. DISCUSSION: Compared to straight path walking, transverse plane moment decreased when the foot was on the outside of the curved path. When the foot was on the inside, the moment did not exceed that for straight path walking for two participants; maximum transverse moment was approximately 0.15 N m/kg of body mass. Force moment curves indicated that each participant's gait was unique, but underlying similarities were observed with respect to each of the three conditions. CLINICAL RELEVANCE: A load cell in conjunction with curved and straight path walking and force-moment curves can be used outside of a gait lab to measure and examine the transverse plane loading on the residual limb. PMID- 23921597 TI - The quality of life questionnaire EQ-5D-5L: psychometric properties and normative values for the general German population. AB - PURPOSE: The health state classifier EQ-5D of the EuroQoL group has been expanded to a 5-level instrument (EQ-5D-5L), but studies on psychometric properties of this new instrument, applied to the general population, are rare. METHODS: A sample of 2,469 subjects, representatively selected from the German general population, was asked to fill in the EQ-5D-5L and several other questionnaires. Crude sum scores of the EQ-5D-5L were calculated and compared with scores derived from two sets of utilities, one from a German and one from a UK sample. RESULTS: The mean sum score (0-100 scale) was 91.5. Males reported better health states than females, and there was a nearly linear age trend. The list of the 45 most frequent health patterns (those with at least 0.2 % of the respondents) showed that almost half of the participants (47.5 %) responded being in the optimal health state, indicating a ceiling effect. Correlations between EQ-5D-5L scores and other questionnaires were very similar for all three scoring systems of the EQ-5D-5L. Finally, normative scores are given on the basis of sum scores. CONCLUSIONS: The applicability of the EQ-5D-5L in the general population is limited because of the skewness. Sum scores are useful because of their simplicity, international generalizability, and construct validity. PMID- 23921598 TI - Cordycepin-enriched Cordyceps militaris induces immunomodulation and tumor growth delay in mouse-derived breast cancer. AB - Cordyceps militaris (C. militaris) and its main functional component, cordycepin, has been shown to possess a number of pharmacological activities including immunological stimulation and antitumor effects. However, the pharmacological mechanisms of C. militaris on tumor immunity underlying its antitumor effect have yet to be elucidated. In the present study, we evaluated the antitumor and immunomodulatory effects of C. militaris on FM3A tumor-bearing C3H/He mice, comparing wild-type C. militaris and cordycepin-enriched C. militaris (JLM 0636). The concentration of cordycepin produced by crossbred JLM 0636 was 7.42 mg/g dry weight, which was 7-fold higher than that of wild-type C. militaris. Dietary administration of C. militaris revealed retardation of tumor growth as well as elongation of survival rates of tumor-bearing mice. This effect was more pronounced in JLM 0636. There was a cordycepin-dependent decrease in IL-2 and TGF beta secretion and an increase in IL-4 secretion without changes in the proliferative responses of concanavalin A-stimulated lymphocytes, which suggested that C. militaris feeding might induce changes in the subpopulations of tumor derived T lymphocytes. CD4+CD25+ cell population was significantly reduced in the total splenocytes from JLM 0636-administered mice, while CD4+ T cell population remained unchanged. FoxP3+-expressing Treg cells among CD4+CD25+ population showed a similar pattern. On the contrary, CD8+ T cells as well as the IFN-gamma expressing CD8+ T cells from tumor-bearing mice were significantly upregulated by the administration of JLM 0636. These results demonstrated the suppressive role of JLM 0636 on the function of Treg cells contributing to tumor specific IFN gamma-expressing CD8+ T cell responses in tumor-bearing mice, which explained the underlying mechanism of the antitumor immunity of cordycepin. Therefore, cordycepin-enriched C. militaris is a promising candidate for an adjuvant in cancer immunotherapy. PMID- 23921599 TI - Human dietary delta(15)N intake: representative data for principle food items. AB - Dietary analysis using delta(15)N values of human remains such as bone and hair is usually based on general principles and limited data sets. Even for modern humans, the direct ascertainment of dietary delta(15)N is difficult and laborious, due to the complexity of metabolism and nitrogen fractionation, differing dietary habits and variation of delta(15)N values of food items. The objective of this study was to summarize contemporary regional experimental and global literature data to ascertain mean representative delta(15)N values for distinct food categories. A comprehensive data set of more than 12,000 analyzed food samples was summarized from the literature. Data originated from studies dealing with (1) authenticity tracing or origin control of food items, and (2) effects of fertilization or nutrition on delta(15)N values of plants or animals. Regional German food delta(15)N values revealed no major differences compared with the mean global values derived from the literature. We found that, in contrast to other food categories, historical faunal remains of pig and poultry are significantly enriched in (15)N compared to modern samples. This difference may be due to modern industrialized breeding practices. In some food categories variations in agricultural and feeding regimens cause significant differences in delta(15)N values that may lead to misinterpretations when only limited information is available. PMID- 23921600 TI - The SafeBoosC phase II randomised clinical trial: a treatment guideline for targeted near-infrared-derived cerebral tissue oxygenation versus standard treatment in extremely preterm infants. AB - Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rStO2) reflects venous oxygen saturation. If cerebral metabolism is stable, rStO2 can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the burden of hypo and hyperoxia can be reduced by the combined use of close monitoring of the cerebral rStO2 and a treatment guideline to correct deviations in rStO2 outside a predefined target range. AIMS: To describe the rationale for and content of this treatment guideline. METHODS: Review of the literature and assessment of the quality of evidence and the grade of recommendation for each of the interventions. RESULTS AND CONCLUSIONS: A clinical intervention algorithm based on the main determinants of cerebral perfusion-oxygenation changes during the first hours after birth was generated. The treatment guideline is presented to assist neonatologists in making decisions in relation to cerebral oximetry readings in preterm infants within the SafeBoosC phase II randomised clinical trial. The evidence grades were relatively low and the guideline cannot be recommended outside a research setting. PMID- 23921601 TI - Structure-dynamics relationship in coherent transport through disordered systems. AB - Quantum transport is strongly influenced by interference with phase relations that depend on the scattering medium. As even small changes in the geometry of the medium can turn constructive interference to destructive, a clear relation between structure and fast, efficient transport is difficult to identify. Here we present a complex network analysis of quantum transport through disordered systems to elucidate the relationship between transport efficiency and structural organization. Evidence is provided for the emergence of structural classes with different geometries but similar high efficiency. Specifically, a structural motif characterized by pair sites, which are not actively participating to the dynamics, renders transport properties robust against perturbations. Our results pave the way for a systematic rationalization of the design principles behind highly efficient transport, which is of paramount importance for technological applications as well as to address transport robustness in natural-light harvesting complexes. PMID- 23921603 TI - Primary hepatic leiomyosarcoma--a rare neoplasm in an adult patient with AIDS: second case report and literature review. PMID- 23921602 TI - Reduction in superoxide dismutase expression in the epithelial mucosa of eosinophilic chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Eosinophils generate large amounts of oxidant species. The eosinophil dominant type of chronic rhinosinusitis (CRS) with nasal polyps is related to more extensive disease and a decreased likelihood of surgical success. Superoxide dismutase (SOD) is the first-line and only antioxidant enzyme that converts superoxide to hydrogen peroxide. METHODS: The patients with CRS with nasal polyps were divided into eosinophilic and noneosinophilic groups. The expression of three isoforms of SOD, intracellular copper-zinc SOD (CuZnSOD), mitochondrial manganese SOD (MnSOD) and extracellular SOD (ECSOD), were examined by enzyme activity assay, immunohistochemistry and quantitative real-time RT-PCR sampled by laser capture microdissection. RESULTS: SOD activity in the eosinophilic and noneosinophilic groups was significantly reduced compared to that of the control groups. Immunostaining of both CuZnSOD and MnSOD in the eosinophilic group was significantly decreased compared with that in the noneosinophilic and control groups. CuZnSOD mRNA of the eosinophilic group was significantly decreased compared with that of the control group, whereas MnSOD mRNA in the eosinophilic group was significantly decreased compared with that in the noneosinophilic and control groups. Neither immunoreactivity nor mRNA of ECSOD was different among the three groups. The degree of epithelial damage and disease severity were inversely correlated with CuZnSOD and MnSOD immunoreactivity. CONCLUSIONS: The reduction in SOD activity and the downregulation of the SOD message are suggested to be related to eosinophil recruitment and epithelial damage of CRS with nasal polyps. PMID- 23921604 TI - Reintroduction of imatinib in GIST. AB - PURPOSE: This review examines the clinical evidence showing that imatinib can be prescribed to treat recurrence or progression of gastrointestinal stromal tumors (GIST) in patients who interrupted first-line imatinib therapy in the adjuvant or advanced/metastatic setting. METHODOLOGY: A literature search was performed in PubMed, Web of Knowledge, and Google using the following keywords: rechallenge/reinitiation/reintroduction + gastrointestinal + imatinib and rechallenge/reinitiation/reintroduction + imatinib. RESULTS: The evidence indicates that the reintroduction of imatinib can benefit patients who experience GIST progression after interrupting treatment of advanced/metastatic disease, as well as patients who experience GIST recurrence after completing prescribed neoadjuvant and/or adjuvant therapy. Although reintroduction of imatinib may lead to suboptimal outcomes, as evidenced by higher rates of progressive disease compared to initial treatment, imatinib discontinuation does not appear to favor development of imatinib resistance, leaving dose escalation and third- or fourth line imatinib treatment as viable options for patients. CONCLUSION: Results indicate that after initial start and interruption of imatinib therapy, reintroduction of imatinib therapy is efficacious and provides continued survival benefit in patients with GIST. PMID- 23921605 TI - Predictive validity of risk assessments in juvenile offenders: Comparing the SAVRY, PCL:YV, and YLS/CMI with unstructured clinical assessments. AB - This study examined the validity and reliability of the Structured Assessment of Violence Risk in Youth (SAVRY), the Youth Level of Service/Case Management Inventory (YLS/CMI), and the Psychopathy Checklist: Youth Version (PCL:YV) in a sample of Spanish adolescents with a community sanction (N = 105). Self-reported delinquency with a follow-up period of 1 year was used as the outcome measure. The predictive validity of the three measures was compared with the unstructured judgment of the juvenile's probation officer and the self-appraisal of the juvenile. The three measures showed moderate effect sizes, ranging from area under the curve (AUC) = .75 (SAVRY) to AUC = .72 (PCL:YV), in predicting juvenile reoffending. The two unstructured judgments had no significant predictive validity whereas the SAVRY had significantly higher predictive validity compared with both unstructured judgments. Finally, SAVRY protective factor total scores and SAVRY summary risk ratings did not add incremental validity over SAVRY risk total scores. The high base rates of both violent (65.4%) and general reoffending (81.9%) underline the need for further risk assessment and management research with this population. PMID- 23921606 TI - Measurement invariance of internalizing and externalizing behavioral syndrome factors in a non-Western sample. AB - This study examined the measurement structure of Child Behavior Checklist internalizing and externalizing syndrome scales in 1,146 eleven-year-old children from a birth cohort in Mauritius. We tested for measurement invariance at configural, metric, and scalar levels by gender and religioethnicity (Creole, Hindu, Muslim). A pared-down model representing five primary factors and two secondary factors met all three forms of invariance, supporting the validity of their use for group comparisons among Mauritian children. As rated by their parents, girls were higher than boys on Somatic Complaints and lower on Aggressive Behavior, Attention Problems, and Externalizing. Creoles were higher than Muslims and Hindus on all seven factors. Hindus were higher than Muslims on Somatic Complaints and lower on Aggressive Behavior. To our knowledge, this is the first study to demonstrate strict invariance of a Child Behavior Checklist based internalizing and externalizing factor structure among subgroups within a society. PMID- 23921607 TI - Identification of TRIM22 single nucleotide polymorphisms associated with loss of inhibition of HIV-1 transcription and advanced HIV-1 disease. AB - OBJECTIVE(S): Tripartite motif-containing 22 (TRIM22) is an interferon-induced protein that inhibits HIV-1 transcription and replication in vitro. Two single nucleotide missense polymorphisms rs7935564A/G (SNP-1) and rs1063303C/G (SNP-2) characterize the coding sequence of human TRIM22 gene. We tested whether these variants affected the inhibitory effect of TRIM22 on HIV-1 replication and transcription and their potential association with HIV-1 disease. DESIGN: The allelic discrimination was determined in 182 HIV-1-negative and among HIV-1 positive individuals with advanced disease progression (advanced progressors; n = 57), normal progressors (n = 76), and long-term nonprogressors (LTNPs; n = 95). METHODS: Renilla luciferase activity was measured after infection of activated peripheral blood mononuclear cells (PBMCs) from an additional group of 61 blood donors with a recombinant HIV-1. HIV-1-long terminal repeat (LTR)-driven luciferase activity was tested in the presence of plasmid expressing TRIM22 variants in 293T cells. The SNP genotyping was determined by TaqMan assay. RESULTS: HIV-1 replication was more efficient in PBMCs from donors with SNP-1G and SNP-2G than from those with SNP-1A and SNP-2C alleles. Consistently, TRIM22 GG enhanced, whereas TRIM22-AC restricted basal HIV-1 LTR-driven transcription. In vivo, SNP-1G homozygotes and A/G heterozygotes were more frequent in advanced progressors than in LTNPs [odds ratio (OR) = 2.072, P = 0.005] or in normal progressors (OR = 1.809, P = 0.022); in contrast, SNP-2 was not associated with any state of HIV-1 disease progression. Although SNP-2 distribution was similar among the groups, TRIM22-GG haplotype was found more frequently in advanced progressors than in LTNPs (P = 0.02). CONCLUSION: TRIM22 genetic diversity affects HIV-1 replication in vitro and it is a potentially novel determinant of HIV-1 disease severity. PMID- 23921608 TI - Targeting screening and social marketing to increase detection of acute HIV infection in men who have sex with men in Vancouver, British Columbia. AB - OBJECTIVES: The contribution of acute HIV infection (AHI) to transmission is widely recognized, and increasing AHI diagnosis capacity can enhance HIV prevention through subsequent behavior change or intervention. We examined the impact of targeted pooled nucleic acid amplification testing (NAAT) and social marketing to increase AHI diagnosis among men who have sex with men (MSM) in Vancouver. DESIGN: Observational study. METHODS: We implemented pooled NAAT following negative third-generation enzyme immunoassay (EIA) testing for males above 18 years in six clinics accessed by MSM, accompanied by two social marketing campaigns developed by a community gay men's health organization. We compared test volume and diagnosis rates for pre-implementation (April 2006-March 2009) and post-implementation (April 2009-March 2012) periods. After implementation, we used linear regression to examine quarterly trends and calculated diagnostic yield. RESULTS: After implementation, the AHI diagnosis rate significantly increased from 1.03 to 1.84 per 1000 tests, as did quarterly HIV test volumes and acute to non-acute diagnosis ratio. Of the 217 new HIV diagnoses after implementation, 54 (24.9%) were AHIs (25 detected by pooled NAAT only) for an increased diagnostic yield of 11.5%. The average number of prior negative HIV tests (past 2 years) increased significantly for newly diagnosed MSM at the six study clinics compared to other newly diagnosed MSM in British Columbia, per quarter. CONCLUSION: Targeted implementation of pooled NAAT at clinics accessed by MSM is effective in increasing AHI diagnoses compared to third-generation EIA testing. Social marketing campaigns accompanying pooled NAAT implementation may contribute to increasing AHI diagnoses and frequency of HIV testing. PMID- 23921609 TI - Breastfeeding is associated with decreased pneumonia incidence among HIV-exposed, uninfected Kenyan infants. AB - OBJECTIVE: HIV-exposed uninfected (HEU) infants have higher infectious disease morbidity and mortality than unexposed infants. We determined the incidence and risk factors for pneumonia, a leading cause of infant mortality worldwide, in a cohort of HEU infants. Identifying predictors of pneumonia among HEU infants may enable early identification of those at highest risk. DESIGN: A retrospective cohort of HEU infants participating in a Kenyan perinatal HIV study, enrolled between 1999 and 2002. METHODS: Infants were followed monthly from birth to 12 months. Incidence of pneumonia diagnosed at monthly study visits, sick-child visits or by means of averbal autopsy was estimated with a 14-day window for new episodes. Cox proportional hazards regression was used to identify predictors of first pneumonia occurrence. RESULTS: Among 388 HEU infants with 328 person-years of follow-up, the incidence of pneumonia was 900/1000 child-years [95% confidence interval (CI) 800-1000]. Maternal HIV viral load at 32 weeks' gestation [hazard ratio 1.2 (1.0-1.5) per log10 difference] and being underweight (weight-for-age Z score <-2) at the previous visit [hazard ratio 1.8 (1.1-2.8)] were associated with increased risk of pneumonia. Breastfed infants had a 47% lower risk of pneumonia than those never breastfed [hazard ratio 0.53 (0.39-0.73)], independent of infant growth, maternal viral load and maternal CD4%. Breastfeeding was also associated with a 74% lower risk of pneumonia-related hospitalization [hazard ratio 0.26 (0.13-0.53)]. CONCLUSIONS: The incidence of pneumonia in this cohort of HEU infants was high. Our observations suggest that maternal viral suppression and breastfeeding may reduce the burden of pneumonia among HEU infants. PMID- 23921611 TI - Hepatitis C virus/HIV coinfection and responses to initial antiretroviral treatment. AB - OBJECTIVE: To explore the relationship between hepatitis C virus (HCV)/HIV coinfection and responses to initial antiretroviral treatment (ART). METHODS: Four AIDS Clinical Trials Group HIV treatment studies' data were combined to compare initial ART responses between HCV/HIV-coinfected and HIV-monoinfected patients as evaluated by virologic failure, CD4 cell measures, occurrence of AIDS/death and grade 3/4 safety events, using Kaplan-Meier estimates and proportional hazard, regression and mixed effects models, adjusting for baseline covariates. RESULTS: Of the 3041 included participants, 81% were men, 19% had prior history of AIDS, the median (25th, 75th percentile) baseline HIV RNA was 4.72 (4.38-5.18) log10 copies/ml, and the median (25th, 75th percentile) baseline CD4 cell count was 216.0 (76.5-327.0) cells/MUl. The 279 HCV/HIV-coinfected individuals were older (44 vs. 37 years), more likely to be black non-Hispanic (47 vs. 36%), and previous/current intravenous drug user (52 vs. 5%) than the 2762 HIV-monoinfected patients (all P values <0.001). HCV/HIV coinfection was associated with earlier virologic failure, hazard ratio (95% confidence interval): 1.43 (1.07-1.91); smaller mean CD4 cell increase and CD4% increase [ 33.8 (-52.2 to -15.4) cells/MUl and -1.16% (-1.43 to -0.89%), respectively] over a median of 132 weeks of follow-up; earlier occurrence of grade 3/4 safety event, hazard ratio 1.51 (1.26-1.81); and increased AIDS/mortality, hazard ratio 2.10 (1.31-3.37). Treatment effects comparing antiretroviral regimens were not significantly different by HCV/HIV coinfection status. CONCLUSION: HCV/HIV coinfection is associated with attenuated response to ART. Results support earlier initiation of HIV therapy and increased monitoring of those initiating ART with HCV/HIV coinfection. PMID- 23921612 TI - Food insecurity and HIV clinical outcomes in a longitudinal study of urban homeless and marginally housed HIV-infected individuals. AB - BACKGROUND: Food insecurity is common among HIV-infected individuals and has been associated with poor health. Little longitudinal research has examined the association of food insecurity with HIV clinical outcomes, or the extent to which adherence mediates these associations. DESIGN: Observational cohort study METHODS: HIV-infected homeless and marginally housed individuals in the San Francisco Research on Access to Care in the Homeless cohort completed quarterly structured interviews and blood draws. We measured food insecurity using the validated Household Food Insecurity Access Scale. Primary outcomes were: antiretroviral therapy (ART) nonadherence (<90% adherence), incomplete HIV viral load suppression more than 100 copies/ml, and CD4+ cell counts less than 200 cells/MUl. We estimated model parameters using generalized estimating equations, adjusting for sociodemographic and clinical variables. RESULTS: From May 2007 to March 2010, we followed 284 participants for a median of 22 months. At baseline 54.6% of participants were food-insecure. Food insecurity was associated with increased odds of ART nonadherence [adjusted odds ratio (AOR) = 1.48; 95% confidence interval (CI), 1.19-1.85], incomplete viral load suppression (AOR = 1.29, 95% CI 1.04-1.61), and CD4+ cell counts less than 200 cells/MUl (AOR = 1.26, 95% CI 1.01-1.56). When we included ART adherence in adjusted models for incomplete viral suppression and CD4+ cell counts less than 200 cells/MUl, the magnitude of the effect decreased slightly. CONCLUSION: Food insecurity was associated with poor HIV outcomes, including nonadherence, in a longitudinal study of US-based HIV-infected unstably housed individuals. Efforts to address food insecurity should be included in HIV-treatment programs, and may help improve health outcomes. PMID- 23921613 TI - Mortality rates in people dually infected with HIV-1/2 and those infected with either HIV-1 or HIV-2: a systematic review and meta-analysis. AB - OBJECTIVE: As compared to HIV-1 infection, HIV-2 is less transmissible, disease progression is slower, and the mortality risk is lower. It has been suggested that HIV-2 infection inhibits the progression of HIV-1 in individuals dually infected by HIV-1 and HIV-2 (HIV-D). We examined whether the mortality rates in dually infected individuals differ from those in persons infected with either HIV 1 or HIV-2. DESIGN: We conducted a systematic review and meta-analysis. METHODS: Medline and Embase databases were searched for studies that reported the number of deaths and person-years of observation (PY) for at least two of the three HIV groups (i.e. HIV-1, HIV-2, and HIV-D). Meta-analyses were then performed with random-effects models, estimating combined mortality rate ratios (MRRs). RESULTS: Of the 631 identified titles, six articles were included in the meta-analysis of HIV-D-infected individuals versus HIV-mono-infected persons, and seven were included in the analysis of HIV-1-mono-infected versus HIV-2-mono-infected individuals. The overall MRR of those infected with HIV-D versus HIV-1 was 1.11 [95% confidence interval (CI) 0.95-1.30]. The overall MRR of those infected with HIV-D versus HIV-2 was 1.81 (95% CI 1.43-2.30) and the MRR of those infected with HIV-1 versus HIV-2 was 1.86 (95% CI 1.44-2.39). CONCLUSION: HIV-2-mono-infected persons have a lower mortality rate than those mono-infected with HIV-1 and those with HIV-D. There is no evidence that HIV-2 delays progression to death in HIV-D infected individuals. PMID- 23921614 TI - Contribution of HIV infection to mortality among cancer patients in Uganda. AB - OBJECTIVE: HIV infection is associated with cancer risk. This relationship has resulted in a growing cancer burden, especially in resource-limited countries where HIV is highly prevalent. Little is known, however, about how HIV affects cancer survival in these settings. We therefore investigated the role of HIV in cancer survival in Uganda. DESIGN: Retrospective cohort (N = 802). METHODS: Eligible cancer patients were residents of Kyadondo County, at least 18 years of age at cancer diagnosis, and diagnosed between 2003 and 2010 with one of the following: breast cancer, cervical cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, or esophageal cancer. Patients were classified as HIV-infected at cancer diagnosis based on a documented positive HIV antibody test, medical history indicating HIV infection, or an HIV clinic referral letter. The primary outcome, vital status at 1 year following cancer diagnosis, was abstracted from the medical record or determined through linkage to the national hospice database. The risk of death during the year after cancer diagnosis was compared between cancer patients with and without evidence of HIV infection using Cox proportional hazards regression. RESULTS: HIV-infected cancer patients in Uganda experienced a more than two-fold increased risk of death during the year following cancer diagnosis compared to HIV-uninfected cancer patients [hazard ratio 2.28; 95% confidence interval (CI) 1.61-3.23]. This association between HIV and 1-year cancer survival was observed for both cancers with (hazard ratio 1.56; 95% CI 1.04-2.34) and without (hazard ratio 2.68; 95% CI 1.20-5.99) an infectious cause. CONCLUSION: This study demonstrates the role of HIV in cancer survival for both cancers with and without an infectious cause in a resource-limited, HIV endemic setting. PMID- 23921617 TI - Anal and penile high-risk human papillomavirus prevalence in HIV-negative and HIV infected MSM. AB - OBJECTIVE: Anal and penile high-risk human papillomavirus (HPV) infection is associated with anogenital cancer, which is especially common in HIV-infected MSM. We assessed HPV prevalence and determinants in MSM. DESIGN: Analysis of baseline data from a prospective cohort study. METHODS: MSM aged 18 years or older were recruited in Amsterdam, the Netherlands. Participants completed risk factor questionnaires. HPV DNA was analyzed in anal and penile shaft self-swabs and genotyped using a sensitive PCR and reverse line blot assay (SPF10-PCR-DEIA LiPA25-system). Multivariable logistic regression analyses were performed to assess determinants of high-risk HPV infection. RESULTS: MSM (n = 778) were recruited in 2010-2011, of whom 317 (41%) were HIV-infected. Prevalence of anal high-risk HPV infection was 45% in HIV-negative versus 65% in HIV-infected MSM (P <0.001). HPV-16 was the most frequently detected type and was more common in HIV infected MSM (13% in HIV-negative and 22% in HIV-infected MSM; P = 0.001). Prevalence of penile high-risk HPV infection was 16% in HIV-negative and 32% in HIV-infected MSM (P <0.001). In multivariable analyses, HIV infection remained associated with anal [adjusted odds ratio (aOR) 2.2; 1.8-2.7] and penile (aOR 2.0; 1.4-2.9) high-risk HPV infection. Higher number of lifetime male sex partners was significantly associated with anal and penile high-risk HPV in HIV negative, but not HIV-infected MSM. Receptive anal intercourse was associated with anal high-risk HPV in HIV-infected MSM. CONCLUSION: Anal and penile high risk HPV infections are very common in MSM. HIV infection is a strong and independent determinant for anal and penile high-risk HPV infection. Determinants for HPV infection appear to differ between HIV-negative and HIV-infected MSM. PMID- 23921616 TI - HLA B*5701 status, disease progression, and response to antiretroviral therapy. AB - OBJECTIVE: In addition to hypersensitivity reactions to abacavir, HLA B5701 has been associated with slow or nonprogression of HIV infection. We explored the effect of HLA B5701 on CD4 cell count and viral load in untreated patients and on responses to nonabacavir-containing combination antiretroviral therapy (cART) in a large UK-based cohort. DESIGN: Analysis of a cohort of HIV-infected adults. METHODS: In untreated patients, CD4 cell count and viral load at study entry were compared in HLAB5701-positive and HLAB5701-negative individuals and linear regression tested for an interaction effect of viral load and HLA B5701 on CD4 cell count. In patients starting a nonabacavir cART regimen, Cox proportional hazards models compared virological responses to cART among HLA B5701-negative, HLA B5701-positive, and those not tested. Six-month and 12-month changes in CD4 cell count were used as outcomes in linear regression to compare immunological response to cART in these groups. RESULTS: ART-naive HLA B5701-positive individuals had higher CD4 cell count (P<0.0001) and lower viral load (P<0.0001) at study entry than negatives; however, HLA B5701 status was not found to effect the association between viral load and CD4 cell count (interaction P value=0.09). HLA B5701-positive patients were more likely to achieve viral suppression than negative patients on a nonabacavir regimen [hazard ratio=1.29, 95% confidence interval, CI (1.15-1.54)] and less likely to experience viral rebound [hazard ratio=0.61, 95% CI (0.37-0.99)]. CONCLUSION: Better virological but not immunological responses to cART were seen in HLA B5701-positive patients on nonabacavir regimens. This study provides further evidence of the potentially beneficial effect of HLA B5701 on HIV progression. PMID- 23921615 TI - Bone mineral density in HIV participants randomized to raltegravir and lopinavir/ritonavir compared with standard second line therapy. AB - OBJECTIVE: To compare changes over 48 weeks in bone mineral density (BMD) between participants randomized to lopinavir/ritonavir (LPV/r) + raltegravir (RAL) or LPV/r + 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) as second line therapy. DESIGN: 48-week open-label sub-study of the Second Line trial conducted in South Africa, India, Thailand, Malaysia and Argentina. METHODS: Dual energy X-ray absorptiometry scans of proximal femur and lumbar spine were performed at baseline and week 48. Linear regression was used to compare means of differences between arms. McNemars test compared osteopenia and osteoporosis. Associations between percentage BMD changes and baseline variables were assessed by multivariate linear regression. RESULTS: Two hundred and ten participants were randomized. Analyses were adjusted for sex, BMI and smoking status. Mean (95% CI) proximal femur BMD% reduced over 48 weeks by -5.2% (-6.7 to -3.8%) in the LPV/r+2-3N(t)RTIs arm and by -2.9% (-4.3 to -1.5%) in the LPV/r+RAL arm (P = 0.0001). Lumbar spine BMD reduced by -4.2% (-5.7 to -2.7%) in the LPV/r+2-3N(t)RTIs arm and by -2.0% (-3.5 to -0.6%) in the LPV/r+RAL arm (P = 0.0006). The incidence of osteopenia (7.6%) and osteoporosis (2.0%) assessed over 48 weeks were similar between arms. Reduced BMD over 48 weeks was significantly associated with longer duration of tenofovir on study [% change (SE) -1.58 (0.38) femur, -1.65 (0.38) spine, P = 0.0001] and low baseline BMI [% change (SE) 0.5 (0.13) femur, 0.17 (0.07) spine; P < 0.01]. CONCLUSION: An N(t)RTI-sparing antiretroviral regimen of LPV/r and raltegravir as second line therapy is associated with less bone loss than a LPV/r regimen containing N(t)RTIs. PMID- 23921618 TI - Opportunities for sexual transmission of antiretroviral drug resistance among HIV infected patients in care. AB - OBJECTIVE: To assess opportunities for transmitted drug resistance (TDR), we examined sexual risk behaviours, HIV viraemia and antiretroviral resistance among patients in care. DESIGN: A retrospective, cross-sectional analysis of clinical cohort data. METHODS: For 244 UNC Center for AIDS Research HIV Clinical Cohort participants, demographic and behavioural data were obtained during in-person interviews between 2000 and 2011. Genotypic resistance tests were interpreted using WHO surveillance drug resistance mutations (SDRMs). Log-linear binomial regression was used to evaluate associations with TDR risk, defined as unprotected sex in the prior 6 months, HIV RNA at least 400 copies/ml and at least one SDRM. RESULTS: Participants included 91 (37%) women and 153 men, of whom 92 (60%) were MSM. Median age was 43 years; 70% were Black (n = 171). Most (97%) were antiretroviral-experienced; 44% had exposure to more than four regimens. Among 204 individuals on antiretrovirals, 42% reported suboptimal adherence and 29% were viraemic. Over half of participants had at least one SDRM (n = 131); 26 (11%) had triple-class resistance. Overall, 70% were sexually active, and 55% used condoms inconsistently. Thirty (12%) reported unprotected sex during periods of drug-resistant viraemia. Higher TDR risk was associated with prior homelessness [adjusted prevalence ratio (aPR) 2.20, 95% confidence interval (CI) 1.16-4.18], active substance use (aPR 3.12, 95% CI 1.47-6.62) and nonsignificantly with MSM (aPR 1.75, 95% CI 0.93-3.28). CONCLUSION: A small but significant proportion of clinic patients with drug-resistant HIV engage in sexual behaviours that place others at risk for TDR. Targeted efforts in secondary prevention could have an impact on TDR incidence, over time. PMID- 23921619 TI - Can the UNAIDS modes of transmission model be improved? A comparison of the original and revised model projections using data from a setting in west Africa. AB - OBJECTIVE: The UNAIDS modes of transmission model (MoT) is a user-friendly model, developed to predict the distribution of new HIV infections among different subgroups. The model has been used in 29 countries to guide interventions. However, there is the risk that the simplifications inherent in the MoT produce misleading findings. Using input data from Nigeria, we compare projections from the MoT with those from a revised model that incorporates additional heterogeneity. METHODS: We revised the MoT to explicitly incorporate brothel and street-based sex-work, transactional sex, and HIV-discordant couples. Both models were parameterized using behavioural and epidemiological data from Cross River State, Nigeria. Model projections were compared, and the robustness of the revised model projections to different model assumptions, was investigated. RESULTS: The original MoT predicts 21% of new infections occur in most-at-risk populations (MARPs), compared with 45% (40-75%, 95% Crl) once additional heterogeneity and updated parameterization is incorporated. Discordant couples, a subgroup previously not explicitly modelled, are predicted to contribute a third of new HIV infections. In addition, the new findings suggest that women engaging in transactional sex may be an important but previously less recognized risk group, with 16% of infections occurring in this subgroup. CONCLUSION: The MoT is an accessible model that can inform intervention priorities. However, the current model may be potentially misleading, with our comparisons in Nigeria suggesting that the model lacks resolution, making it challenging for the user to correctly interpret the nature of the epidemic. Our findings highlight the need for a formal review of the MoT. PMID- 23921620 TI - Averted HIV infections due to expanded antiretroviral treatment eligibility offsets risk of transmitted drug resistance: a modeling study. AB - BACKGROUND: Earlier antiretroviral therapy initiation can reduce the incidence of HIV-1. This benefit can be offset by increased transmitted drug resistance (TDR). We compared the preventive benefits of reducing incident infections with the potential TDR increase in East Africa. METHODS: A mathematical model was constructed to represent Kampala, Uganda, and Mombasa, Kenya. We predicted the effect of initiating treatment at different immunological thresholds (<350, <500 CD4 cells/MUl) on infections averted and mutation-specific TDR prevalence over 10 years compared to initiating treatment at CD4 cell count below 200 cells/MUl. RESULTS: When initiating treatment at CD4 cell count below 350 cells/MUl, we predict 18 [interquartile range (IQR) 11-31] and 46 (IQR 30-83) infections averted for each additional case of TDR in Kampala and Mombasa, respectively, and 22 (IQR 17-35) and 32 (IQR 21-57) infections averted when initiating at below 500. TDR is predicted to increase most strongly when initiating treatment at CD4 cell count below 500 cells/MUl, from 8.3% (IQR 7.7-9.0%) and 12.3% (IQR 11.7 13.1%) in 2012 to 19.0% (IQR 16.5-21.8%) and 19.2% (IQR 17.1-21.5%) in 10 years in Kampala and Mombasa, respectively. The TDR epidemic at all immunological thresholds was comprised mainly of resistance to non-nucleoside reverse transcriptase inhibitors. When 80-100% of individuals with virological failure are timely switched to second-line therapy, TDR is predicted to decline irrespective of treatment initiation threshold. CONCLUSION: Averted HIV infections due to the expansion of antiretroviral treatment eligibility offset the risk of transmitted drug resistance, as defined by more infections averted than TDR gained. The effectiveness of first-line non-nucleoside reverse transcriptase inhibitor-based therapy can be preserved by improving switching practices to second-line therapy. PMID- 23921621 TI - Mevalonate kinase deficiency nomenclature. PMID- 23921622 TI - Whole-genome sequencing of a green bush viper reovirus reveals a shared evolutionary history between reptilian and unusual mammalian orthoreoviruses. AB - In this study, we sequenced the whole genome of a reovirus isolated from a green bush viper (Atheris squamigera). The bush viper reovirus shared several features with other orthoreoviruses, including its genome organization. In phylogenetic analysis, this strain was monophyletic with Broome virus and baboon orthoreovirus, indicating that these viruses might have originated from a common ancestor. These new molecular data supplement previous information based mainly on biological properties of reptilian reoviruses, confirming their taxonomic position and broadening our knowledge of the evolution of members of the genus Orthoreovirus. PMID- 23921623 TI - Characterization of street rabies virus variants with an additional N-glycan at position 247 in the glycoprotein. AB - Most street rabies virus glycoproteins (G proteins) possess two N-glycosylation sites, at Asn(37) and Asn(319), whereas an additional N-glycosylation site is present in several fixed (laboratory-adapted) rabies virus strains at Asn(247), which suggests that the N-glycosylation addition may be a marker of fixed viruses. In this study, we successfully cloned two street virus strain 1088 variants, N5B#15 and N5B#10-28, in which the G proteins had an additional N glycan at position 247, and we examined whether these variants were characterized by cell culture adaptation and attenuation after intramuscular inoculation as fixed viruses. N5B#15 had four mutations, i.e., S148P and D247N in the G protein, and T137A and N2046S in the large (L) protein. N5B#10-28 had an additional mutation in the G protein, R196I. Compared with the parental 1088 virus, both variants exhibited highly efficient replication in mouse neuroblastoma-derived NA cells and reduced pathogenicity in adult mice when inoculated intramuscularly, but not intracerebrally. However, this attenuation was not attributable to the induction of strong immune responses. PMID- 23921624 TI - Treatment costs of bladder pain syndrome/interstitial cystitis in Austria: a pharmacoeconomic approach following current guidelines. AB - BACKGROUND: Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic disease with a significant impact on quality of life. A broad range of therapies are used to treat this condition, and patients are often excluded from receiving more expensive and more effective therapies because of cost issues. OBJECTIVE: The objective of this study was to assess the mid- and long-term costs (over 1, 5 and 10 years) of various therapies for BPS/IC. METHODS: Costs in an open-access health system (Austria) for three BPS/IC-specific therapies (intravesical hyaluronan, pentosanpolysulfate and amitriptyline), taken from the American Urological Association guidelines, were evaluated and compared with those of non specific symptomatic therapies. Response rates for the different therapies were taken from peer-reviewed publications and used to define the need for therapy maintenance with regard to symptom improvement. RESULTS: Despite the highest initial costs, the reduced need for further therapy in patients with long-term symptom remission after hyaluronan therapy resulted in the lowest total treatment costs at all three timepoints. Hyaluronan was cost saving against all alternatives in standard assumptions and in all sensitivity analyses. As a limitation, treatment costs in this study are specific for Austria. However, the template used for calculation of treatment costs can be transferred to all countries by inserting local prices. CONCLUSION: Disease-specific therapies with high remission rates result in significantly lower long-term costs in BPS/IC. Non specific symptomatic therapies are most expensive. Long-term cost effectiveness is crucial in the treatment of chronic diseases to limit expenses in individual healthcare systems. PMID- 23921625 TI - A case of mite-ingestion-associated exercise- induced anaphylaxis mimicking wheat dependent exercise-induced anaphylaxis. AB - We present a case of mite-ingestion-associated exercise-induced anaphylaxis mimicking wheat-dependent exercise-induced anaphylaxis (WDEIA). A 17-year-old boy was referred for an episode of anaphylaxis while jogging, 1.5 h after having eaten okonomiyaki (a Japanese pancake). Laboratory measures revealed a slightly elevated specific immunoglobulin E (IgE) antibody against omega-5 gliadin (0.41 kUA/l) and a marked elevation of specific IgE antibody against house-dust mite, Dermatophagoides farinae (142 kUA/l). A detailed interview revealed that, in spite of the referring doctor's advice to discontinue postprandial exercises, he continued his jogging routine after consuming foods containing wheat and also that his younger brother, who had mild intermittent asthma, had suffered a mild asthma attack 2 h after eating the same food. We therefore examined the okonimiyaki mix, which had been stored for several months after opening the package until this episode, under a microscope, and we found an abundant number of live mites, D. farinae. Finally, a diagnosis of mite-ingestion-associated exercise-induced anaphylaxis was made. This clinical entity should be excluded when making a diagnosis of WDEIA. PMID- 23921626 TI - A food retail-based intervention on food security and consumption. AB - The effect of the built environment on diet (and ensuing health outcomes) is less understood than the effect of diet on obesity. Natural experiments are increasingly advocated in place of cross-sectional studies unable to suggest causality. The central research question of this paper, therefore, asks whether a neighborhood-level food retail intervention will affect dietary habits or food security. The intervention did not have a significant impact on fruit and vegetable consumption, and the intervention population actually purchased prepared meals more frequently. More problematic, only 8% of respondents overall regularly consumed enough fruits and vegetables, and 34% were food insecure. Further complicating this public health issue, the new grocery store closed after 17 months of operation. Results indicate that geographic access to food is only one element of malnutrition, and that multi-pronged dietary interventions may be more effective. The economic failure of the store also suggests the importance of non-retail interventions to combat malnutrition. PMID- 23921627 TI - Effectiveness of fundoplication at the time of gastrostomy in infants with neurological impairment. AB - IMPORTANCE: Gastrostomy tube (GT) placement is the most common gastrointestinal operation performed on neonates. Concomitant fundoplication is used variably to prevent complications of gastroesophageal reflux, but its effectiveness is unproven. OBJECTIVE: To compare the effect of fundoplication at the time of GT placement vs GT placement alone on subsequent reflux-related hospitalizations in infants with neurological impairment. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, observational cohort study, defined by birth between January 1, 2005, and December 31, 2010, at 42 children's hospitals in the United States, with a 1-year follow-up period among 4163 infants with neurological impairment who underwent GT placement with or without fundoplication during their neonatal intensive care unit stay. INTERVENTION: Fundoplication and GT placement vs. GT placement alone. MAIN OUTCOMES AND MEASURES: One-year postprocedural reflux related hospitalization rates, defined as hospitalization for asthma, mechanical ventilation, gastroesophageal reflux disease, and aspiration or other types of pneumonia. Propensity to undergo concomitant fundoplication was modeled using demographics, prior procedures (tracheostomy and mechanical ventilation), and prior diagnoses (eg, pneumonia, gastroesophageal reflux disease, and other comorbidities). RESULTS: Overall, 4163 of 42,796 infants (9.7%) with neurological impairment admitted to the neonatal intensive care unit underwent GT placement alone or with fundoplication. Infants who concomitantly underwent fundoplication had more reflux-related hospitalizations during the first year than those who underwent GT placement alone (mean, 1.02; 95% CI, 0.93-1.10 vs mean, 0.92; 95% CI, 0.91-1.00). Of 1404 infants who underwent fundoplication, 1027 (73.1%) were matched based on propensity scores. The mean difference of the matched cohort for any reflux-related hospitalizations was -0.05 (95% CI, -0.20 to 0.15) per year. CONCLUSIONS AND RELEVANCE: Infants with neurological impairment who underwent fundoplication at the time of GT placement did not have a reduced rate of reflux related hospitalizations during the first year compared with those who underwent GT placement alone, despite propensity score matching. This may be due to a lack of effectiveness of fundoplication in preventing these complications or due to differences in the patient groups that were inadequately accounted for in the matching. PMID- 23921628 TI - Epigenetic modifications of prostate-derived Ets transcription factor in breast cancer cells. AB - The importance of epigenetic alterations such as DNA methylation, histone modification and nucleosome remodeling in breast cancer is well established. Epigenetic alterations are reversible, and much research has been focused on understanding these alterations with the aim of developing effective therapies. Prostate-derived Ets factor (PDEF) is a member of the Ets family of transcription factors and has long been under investigation for its key role in tumor development and progression. To date, no studies have been conducted to elucidate the epigenetic modifications of PDEF in cancer progression. Using breast and prostate cancer cells, we investigated the effect of the methylation inhibitor 5' azacytidine (AZA) on the expression of PDEF in these cells. The inhibition of methylation observed was specific to breast cancer cells as experiments with prostate cells did not exhibit any significant change. Notably, the expression of p21, a cyclin-dependent kinase (CDK) inhibitor 1 and also a target gene of PDEF, was found to be positively correlated with PDEF expression following 5'AZA treatment. Inhibition of methylation led to a decrease in the proliferation rate of MDA-MB-468 cells as revealed by MTT proliferation assay. Other epigenetic alterations such as histone modifications were not observed in these breast cancer cells following treatment with specific HDAC inhibitors. Our data suggest the possibility of epigenetic modification of PDEF due to DNA methylation and involvement of the cell cycle inhibitor p21. Future studies on the epigenetic alterations of PDEF in correlation with p21 or other targets may facilitate the development of effective therapies for the treatment of breast cancer. PMID- 23921629 TI - RNase J participates in a pentatricopeptide repeat protein-mediated 5' end maturation of chloroplast mRNAs. AB - Nucleus-encoded ribonucleases and RNA-binding proteins influence chloroplast gene expression through their roles in RNA maturation and stability. One mechanism for mRNA 5' end maturation posits that sequence-specific pentatricopeptide repeat (PPR) proteins define termini by blocking the 5'->3' exonucleolytic activity of ribonuclease J (RNase J). To test this hypothesis in vivo, virus-induced gene silencing was used to reduce the expression of three PPR proteins and RNase J, both individually and jointly, in Nicotiana benthamiana. In accordance with the stability-conferring function of the PPR proteins PPR10, HCF152 and MRL1, accumulation of the cognate RNA species atpH, petB and rbcL was reduced when the PPR-encoding genes were silenced. In contrast, RNase J reduction alone or combined with PPR deficiency resulted in reduced abundance of polycistronic precursor transcripts and mature counterparts, which were replaced by intermediately sized species with heterogeneous 5' ends. We conclude that RNase J deficiency can partially mask the absence of PPR proteins, and that RNase J is capable of processing chloroplast mRNAs up to PPR protein-binding sites. These findings support the hypothesis that RNase J is the major ribonuclease responsible for maturing chloroplast mRNA 5' termini, with RNA-binding proteins acting as barriers to its activity. PMID- 23921630 TI - RNA-dependent association with myosin IIA promotes F-actin-guided trafficking of the ELAV-like protein HuR to polysomes. AB - The role of the mRNA-binding protein human antigen R (HuR) in stabilization and translation of AU-rich elements (ARE) containing mRNAs is well established. However, the trafficking of HuR and bound mRNA cargo, which comprises a fundamental requirement for the aforementioned HuR functions is only poorly understood. By administering different cytoskeletal inhibitors, we found that the protein kinase Cdelta (PKCdelta)-triggered accumulation of cytoplasmic HuR by Angiotensin II (AngII) is an actin-myosin driven process functionally relevant for stabilization of ARE-bearing mRNAs. Furthermore, we show that the AngII induced recruitment of HuR and its bound mRNA from ribonucleoprotein particles to free and cytoskeleton bound polysomes strongly depended on an intact actomyosin cytoskeleton. In addition, HuR allocation to free and cytoskeletal bound polysomes is highly sensitive toward RNase and PPtase and structurally depends on serine 318 (S318) located within the C-terminal RNA recognition motif (RRM3). Conversely, the trafficking of the phosphomimetic HuRS318D, mimicking HuR phosphorylation at S318 by the PKCdelta remained PPtase resistant. Co immunoprecipitation experiments with truncated HuR proteins revealed that the stimulus-induced association of HuR with myosin IIA is strictly RNA dependent and mediated via the RRM3. Our data implicate a microfilament dependent transport of HuR, which is relevant for stimulus-induced targeting of ARE-bearing mRNAs from translational inactive ribonucleoprotein particles to polysomes. PMID- 23921631 TI - Quantitative set analysis for gene expression: a method to quantify gene set differential expression including gene-gene correlations. AB - Enrichment analysis of gene sets is a popular approach that provides a functional interpretation of genome-wide expression data. Existing tests are affected by inter-gene correlations, resulting in a high Type I error. The most widely used test, Gene Set Enrichment Analysis, relies on computationally intensive permutations of sample labels to generate a null distribution that preserves gene gene correlations. A more recent approach, CAMERA, attempts to correct for these correlations by estimating a variance inflation factor directly from the data. Although these methods generate P-values for detecting gene set activity, they are unable to produce confidence intervals or allow for post hoc comparisons. We have developed a new computational framework for Quantitative Set Analysis of Gene Expression (QuSAGE). QuSAGE accounts for inter-gene correlations, improves the estimation of the variance inflation factor and, rather than evaluating the deviation from a null hypothesis with a P-value, it quantifies gene-set activity with a complete probability density function. From this probability density function, P-values and confidence intervals can be extracted and post hoc analysis can be carried out while maintaining statistical traceability. Compared with Gene Set Enrichment Analysis and CAMERA, QuSAGE exhibits better sensitivity and specificity on real data profiling the response to interferon therapy (in chronic Hepatitis C virus patients) and Influenza A virus infection. QuSAGE is available as an R package, which includes the core functions for the method as well as functions to plot and visualize the results. PMID- 23921632 TI - Dissecting the interactions of SERRATE with RNA and DICER-LIKE 1 in Arabidopsis microRNA precursor processing. AB - Efficient and precise microRNA (miRNA) biogenesis in Arabidopsis is mediated by the RNaseIII-family enzyme DICER-LIKE 1 (DCL1), double-stranded RNA-binding protein HYPONASTIC LEAVES 1 and the zinc-finger (ZnF) domain-containing protein SERRATE (SE). In the present study, we examined primary miRNA precursor (pri miRNA) processing by highly purified recombinant DCL1 and SE proteins and found that SE is integral to pri-miRNA processing by DCL1. SE stimulates DCL1 cleavage of the pri-miRNA in an ionic strength-dependent manner. SE uses its N-terminal domain to bind to RNA and requires both N-terminal and ZnF domains to bind to DCL1. However, when DCL1 is bound to RNA, the interaction with the ZnF domain of SE becomes indispensible and stimulates the activity of DCL1 without requiring SE binding to RNA. Our results suggest that the interactions among SE, DCL1 and RNA are a potential point for regulating pri-miRNA processing. PMID- 23921633 TI - Detecting Alu insertions from high-throughput sequencing data. AB - High-throughput sequencing technologies have allowed for the cataloguing of variation in personal human genomes. In this manuscript, we present alu-detect, a tool that combines read-pair and split-read information to detect novel Alus and their precise breakpoints directly from either whole-genome or whole-exome sequencing data while also identifying insertions directly in the vicinity of existing Alus. To set the parameters of our method, we use simulation of a faux reference, which allows us to compute the precision and recall of various parameter settings using real sequencing data. Applying our method to 100 bp paired Illumina data from seven individuals, including two trios, we detected on average 1519 novel Alus per sample. Based on the faux-reference simulation, we estimate that our method has 97% precision and 85% recall. We identify 808 novel Alus not previously described in other studies. We also demonstrate the use of alu-detect to study the local sequence and global location preferences for novel Alu insertions. PMID- 23921634 TI - Automated and assisted RNA resonance assignment using NMR chemical shift statistics. AB - The three-dimensional structure determination of RNAs by NMR spectroscopy relies on chemical shift assignment, which still constitutes a bottleneck. In order to develop more efficient assignment strategies, we analysed relationships between sequence and (1)H and (13)C chemical shifts. Statistics of resonances from regularly Watson-Crick base-paired RNA revealed highly characteristic chemical shift clusters. We developed two approaches using these statistics for chemical shift assignment of double-stranded RNA (dsRNA): a manual approach that yields starting points for resonance assignment and simplifies decision trees and an automated approach based on the recently introduced automated resonance assignment algorithm FLYA. Both strategies require only unlabeled RNAs and three 2D spectra for assigning the H2/C2, H5/C5, H6/C6, H8/C8 and H1'/C1' chemical shifts. The manual approach proved to be efficient and robust when applied to the experimental data of RNAs with a size between 20 nt and 42 nt. The more advanced automated assignment approach was successfully applied to four stem-loop RNAs and a 42 nt siRNA, assigning 92-100% of the resonances from dsRNA regions correctly. This is the first automated approach for chemical shift assignment of non exchangeable protons of RNA and their corresponding (13)C resonances, which provides an important step toward automated structure determination of RNAs. PMID- 23921635 TI - Transcription activator like effector (TALE)-directed piggyBac transposition in human cells. AB - Insertional therapies have shown great potential for combating genetic disease and safer methods would undoubtedly broaden the variety of possible illness that can be treated. A major challenge that remains is reducing the risk of insertional mutagenesis due to random insertion by both viral and non-viral vectors. Targetable nucleases are capable of inducing double-stranded breaks to enhance homologous recombination for the introduction of transgenes at specific sequences. However, off-target DNA cleavages at unknown sites can lead to mutations that are difficult to detect. Alternatively, the piggyBac transposase is able perform all of the steps required for integration; therefore, cells confirmed to contain a single copy of a targeted transposon, for which its location is known, are likely to be devoid of aberrant genomic modifications. We aimed to retarget transposon insertions by comparing a series of novel hyperactive piggyBac constructs tethered to a custom transcription activator like effector DNA-binding domain designed to bind the first intron of the human CCR5 gene. Multiple targeting strategies were evaluated using combinations of both plasmid-DNA and transposase-protein relocalization to the target sequence. We demonstrated user-defined directed transposition to the CCR5 genomic safe harbor and isolated single-copy clones harboring targeted integrations. PMID- 23921637 TI - Environmental shaping of codon usage and functional adaptation across microbial communities. AB - Microbial communities represent the largest portion of the Earth's biomass. Metagenomics projects use high-throughput sequencing to survey these communities and shed light on genetic capabilities that enable microbes to inhabit every corner of the biosphere. Metagenome studies are generally based on (i) classifying and ranking functions of identified genes; and (ii) estimating the phyletic distribution of constituent microbial species. To understand microbial communities at the systems level, it is necessary to extend these studies beyond the species' boundaries and capture higher levels of metabolic complexity. We evaluated 11 metagenome samples and demonstrated that microbes inhabiting the same ecological niche share common preferences for synonymous codons, regardless of their phylogeny. By exploring concepts of translational optimization through codon usage adaptation, we demonstrated that community-wide bias in codon usage can be used as a prediction tool for lifestyle-specific genes across the entire microbial community, effectively considering microbial communities as meta genomes. These findings set up a 'functional metagenomics' platform for the identification of genes relevant for adaptations of entire microbial communities to environments. Our results provide valuable arguments in defining the concept of microbial species through the context of their interactions within the community. PMID- 23921636 TI - A Common Docking Domain in Progesterone Receptor-B links DUSP6 and CK2 signaling to proliferative transcriptional programs in breast cancer cells. AB - Progesterone receptors (PR) are transcription factors relevant to breast cancer biology. Herein, we describe an N-terminal common docking (CD) domain in PR-B, a motif first described in mitogen-activated protein kinases. Binding studies revealed PR-B interacts with dual-specificity phosphatase 6 (DUSP6) via the CD domain. Mutation of the PR-B CD domain (mCD) attenuated cell cycle progression and expression of PR-B target genes (including STAT5A and Wnt1); mCD PR-B failed to undergo phosphorylation on Ser81, a ck2-dependent site required for expression of these genes. PR-B Ser81 phosphorylation was dependent on binding with DUSP6 and required for recruitment of a transcriptional complex consisting of PR-B, DUSP6 and ck2 to an enhancer region upstream of the Wnt1 promoter. STAT5 was present at this site in the absence or presence of progestin. Furthermore, phospho-Ser81 PR-B was recruited to the STAT5A gene upon progestin treatment, suggestive of a feed-forward mechanism. Inhibition of JAK/STAT-signaling blocked progestin-induced STAT5A and Wnt1 expression. Our studies show that DUSP6 serves as a scaffold for ck2-dependent PR-B Ser81 phosphorylation and subsequent PR-B specific gene selection in coordination with STAT5. Coregulation of select target genes by PR-B and STAT5 is likely a global mechanism required for growth promoting programs relevant to mammary stem cell biology and cancer. PMID- 23921638 TI - Concordance of gene expression in human protein complexes reveals tissue specificity and pathology. AB - Disease-causing variants in human genes usually lead to phenotypes specific to only a few tissues. Here, we present a method for predicting tissue specificity based on quantitative deregulation of protein complexes. The underlying assumption is that the degree of coordinated expression among proteins in a complex within a given tissue may pinpoint tissues that will be affected by a mutation in the complex and coordinated expression may reveal the complex to be active in the tissue. We identified known disease genes and their protein complex partners in a high-quality human interactome. Each susceptibility gene's tissue involvement was ranked based on coordinated expression with its interaction partners in a non-disease global map of human tissue-specific expression. The approach demonstrated high overall area under the curve (0.78) and was very successfully benchmarked against a random model and an approach not using protein complexes. This was illustrated by correct tissue predictions for three case studies on leptin, insulin-like-growth-factor 2 and the inhibitor of NF-kappaB kinase subunit gamma that show high concordant expression in biologically relevant tissues. Our method identifies novel gene-phenotype associations in human diseases and predicts the tissues where associated phenotypic effects may arise. PMID- 23921639 TI - Chromatin loop organization of the junb locus in mouse dendritic cells. AB - The junb gene behaves as an immediate early gene in bacterial lipopolysaccharide (LPS)-stimulated dendritic cells (DCs), where its transient transcriptional activation is necessary for the induction of inflammatory cytokines. junb is a short gene and its transcriptional activation by LPS depends on the binding of NF kappaB to an enhancer located just downstream of its 3' UTR. Here, we have addressed the mechanisms underlying the transcriptional hyper-reactivity of junb. Using transfection and pharmacological assays to complement chromatin immunoprecipitation analyses addressing the localization of histones, polymerase II, negative elongation factor (NELF)-, DRB sensitivity-inducing factor (DSIF)- and Positive Transcription Factor b complexes, we demonstrate that junb is a RNA Pol II-paused gene where Pol II is loaded in the transcription start site domain but poorly active. Moreover, High salt-Recovered Sequence, chromosome conformation capture (3C)- and gene transfer experiments show that (i) junb is organized in a nuclear chromatin loop bringing into close spatial proximity the upstream promoter region and the downstream enhancer and (ii) this configuration permits immediate Pol II release on the junb body on binding of LPS-activated NF kappaB to the enhancer. Thus, our work unveils a novel topological framework underlying fast junb transcriptional response in DCs. Moreover, it also points to a novel layer of complexity in the modes of action of NF-kappaB. PMID- 23921640 TI - RNA polymerase III-specific general transcription factor IIIC contains a heterodimer resembling TFIIF Rap30/Rap74. AB - Transcription of tRNA-encoding genes by RNA polymerase (Pol) III requires the six subunit general transcription factor IIIC that uses subcomplexes tauA and tauB to recognize two gene-internal promoter elements named A- and B-box. The Schizosaccharomyces pombe tauA subcomplex comprises subunits Sfc1, Sfc4 and Sfc7. The crystal structure of the Sfc1/Sfc7 heterodimer reveals similar domains and overall domain architecture to the Pol II-specific general transcription factor TFIIF Rap30/Rap74. The N-terminal Sfc1/Sfc7 dimerization module consists of a triple beta-barrel similar to the N-terminal TFIIF Rap30/Rap74 dimerization module, whereas the C-terminal Sfc1 DNA-binding domain contains a winged-helix domain most similar to the TFIIF Rap30 C-terminal winged-helix domain. Sfc1 DNA binding domain recognizes single and double-stranded DNA by an unknown mechanism. Several features observed for A-box recognition by tauA resemble the recognition of promoters by bacterial RNA polymerase, where sigma factor unfolds double stranded DNA and stabilizes the non-coding DNA strand in an open conformation. Such a function has also been proposed for TFIIF, suggesting that the observed structural similarity between Sfc1/Sfc7 and TFIIF Rap30/Rap74 might also reflect similar functions. PMID- 23921641 TI - Alteration in the cavity size adjacent to the active site of RB69 DNA polymerase changes its conformational dynamics. AB - Internal cavities are a common feature of many proteins, often having profound effects on the dynamics of their interactions with substrate and binding partners. RB69 DNA polymerase (pol) has a hydrophobic cavity right below the nucleotide binding pocket at the tip of highly conserved L415 side chain. Replacement of this residue with Gly or Met in other B family pols resulted in higher mutation rates. When similar substitutions for L415 were introduced into RB69pol, only L415A and L415G had dramatic effects on pre-steady-state kinetic parameters, reducing base selectivity by several hundred fold. On the other hand, the L415M variant behaved like the wild-type. Using a novel tC(o)-tCnitro Forster Resonance Energy Transfer (FRET) assay, we were able to show that the partition of the primer terminus between pol and exonuclease (exo) domains was compromised with the L415A and L415G mutants, but not with the L415M variant. These results could be rationalized by changes in their structures as determined by high resolution X-ray crystallography. PMID- 23921642 TI - An evaluation of a novel estimator of linkage disequilibrium. AB - The analysis of systems involving many loci is important in population and quantitative genetics. An important problem is the study of linkage disequilibrium (LD), a concept relevant in genome-enabled prediction of quantitative traits and in exploration of marker-phenotype associations. This article introduces a new estimator of a LD parameter (rho(2)) that is much easier to compute than a maximum likelihood (or Bayesian) estimate of a tetra-choric correlation. We examined the conjecture that the sampling distribution of the estimator of rho(2) could be less frequency dependent than that of the estimator of r(2), a widely used metric for assessing LD. This was done via an empirical evaluation of LD in 806 Holstein-Friesian cattle using 771 single-nucleotide polymorphism (SNP) markers and of HapMap III data on 21,991 SNPs (chromosome 3) observed in 88 unrelated individuals from Tuscany. Also, 1600 haplotypes over a region of 1 Mb simulated under the coalescent were used to estimate LD using the two measures. Subsequently, a simulation study compared the new estimator with that of r(2) using several scenarios of LD and allelic frequencies. From these studies, it is concluded that rho(2) provides a useful metric for the study of LD as the distribution of its estimator is less frequency dependent than that of the standard estimator of r(2). PMID- 23921643 TI - Development of Anti-G, Anti-C and Anti-Jk(b) in a 22-Year-Old Mother during Her Fourth Pregnancy. AB - BACKGROUND: Anti-G antibodies are rarely found since anti-D, in combination with anti-C, are difficult to discriminate from anti-G antibodies in routine testing. CASE REPORT: A 22-year-old, gravida-3, para-1, woman with blood group A Rh D neg ccddee and known antibody anti-Jk(b), gave birth to her second child. While anti Jk(b) could not be detected at birth, a new anti-C was found. Antibody screening tests (IAT) were performed using gel cards and rare G positive rGr erythrocytes. Genotyping for RHD and RHCE was performed using PCR-SSP. RESULTS: The child's blood group was A Rh D neg Ccddee. Genotyping revealed Cde/cde haplotypes. The erythrocytes of the new-born showed a positive direct antiglobulin test with IgG; anti-D and anti-C could be eluted. Erythrocytes with the rare phenotype rGr were reactive with the serum of the mother. CONCLUSION: The presence of anti-D and anti-C in the eluate from then newborn's Ccddee erythrocytes proved anti-G or anti-G in combination with anti-D. When anti-C and anti-D are seen during a pregnancy, possibly anti-G is present. This observation is of relevance since women with anti-G can still develop anti-D and require rhesus prophylaxis. PMID- 23921644 TI - WIF1 causes dysfunction of heart in transgenic mice. AB - Wnt activity is a key regulator of cardiac progenitor cell self-renewal, differentiation and morphogenesis. However, Wnt inhibitory factor 1 (WIF1), a antagonists of Wnt signaling activity, its potential effects on heart development has not yet been approached by either in vivo or in vitro studies. Here, the expression of WIF1 was regulated in a different way in the dilated and hypertrophic cardiomyopathy heart from transgenic mice by mutations in cardiac troponin T, cTnT(R141W) and cTnT(R92Q). The heart tissue specific transgenic mice of WIF1 was studied using M-mode echocardiography and histologic analyses. Production levels of an array of effectors and transcription factors that impact cellular organization and tissue morphology were measured. The effects of WIF1 on beta-catenin pathway could be reversed by LiCl regarding signaling pathways and effector and respondent molecules in H9c2 cells, consistent with the expression levels of c-myc, natriuretic peptide precursor type B and skeletal muscle actin alpha1. Among the most noteworthy findings were that WIF1 impaired the function and structure of heart, and the effects on beta-catenin pathway maybe the course of the former. It is anticipated that our findings will contribute to expansion of our understanding of WIF1 biological function on heart development and possible modes of treatment of heart diseases. PMID- 23921646 TI - Stem cell transplantation for follicular lymphoma relapsed/refractory after prior rituximab: a comprehensive analysis from the NCCN lymphoma outcomes project. AB - BACKGROUND: Stem cell transplant (SCT)-related outcomes and prognostication for relapsed/refractory follicular lymphoma (FL) are not well-defined in the post rituximab era. METHODS: Through the National Comprehensive Cancer Network (NCCN) lymphoma outcomes study, 184 patients with relapsed/refractory FL who underwent autologous SCT (autoSCT) or allogenic SCT (alloSCT) following disease relapse after prior rituximab-based therapy were examined. RESULTS: Patients who underwent autoSCT (N=136) were older compared with patients who underwent alloSCT (N=48) (54 versus 51 years, respectively, P=.01) and more frequently had grade 3 FL (35% versus 8%, respectively, P=.006). Patients who underwent alloSCT received more prior therapies (4 versus 3, respectively, P<.0001) and more often had resistant disease at SCT (19% versus 6%, respectively, P=.008). Cumulative 100 day nonrelapse mortality (NRM) for autoSCT and alloSCT were 1% and 6%, respectively (P<.0001), whereas 3-year NRM rates were 3% versus 24%, respectively (P<.0001). For autoSCT and alloSCT, cumulative rates of relapse, progression, and/or transformation were 32% versus 16%, respectively (P=.03), whereas 3-year overall survival rates were 87% versus 61% (P<.0001); there were no differences in failure-free survival. AlloSCT was associated with increased risk of death on multivariate analysis (hazard ratio=2.77, 95% confidence interval=1.46-5.26, P=.002). This finding persisted on propensity scoring/matching. Multivariate analysis for autoSCT patients identified age>60 years and>3 prior therapies as adverse factors. Furthermore, a survival model was created for the autoSCT cohort based on number of factors present (0, 1, 2); 3-year failure-free survival was 72%, 47%, and 20%, respectively (P=.0003), and 3-year overall survival was 96%, 82%, and 62%, respectively (P<.0001). CONCLUSIONS: AutoSCT remains an effective therapy for patients with FL. For alloSCT, continued strategies to reduce NRM are needed. PMID- 23921647 TI - Two-stage processing in automatic detection of emotional intensity: a scalp event related potential study. AB - Scalp electrophysiological studies have supposed that emotional intensity is processed from about 170 ms. However, this is inconsistent with the rapid emotion detection of the amygdala at around 100 ms. Besides, it is unreasonable to apply this assertion to all emotional types considering emotional-specific neural networks and fast/slow emotional routes. The current paper examined whether the earliest intensity effect appeared at around 170 ms for angry expression with a fast frontal-limbic pathway. In this event-related potential study, 30 graduates completed a change detection task rather than intensity evaluation. Before N170, the earliest intensity effects (P's<0.001) were found at about 100 ms with a latency delay from the frontal area to occipitotemporal sites. Automatic detection of expressional intensity was also shown by behavioral and oral reports. These results coincided with the emotional detection function of the amygdala and the view of a re-entrant mechanism in emotion recognition. Together with previous research, we suggested a two-stage processing of emotional intensity: re-entrant modulation and fine structure encoding. Overall, these findings shed light on the time course of expressional intensity detection in the emotional-specific neural network. PMID- 23921645 TI - Analog of somatostatin vapreotide exhibits biological effects in vitro via interaction with neurokinin-1 receptor. AB - OBJECTIVES: Vapreotide, a synthetic analog of somatostatin, has analgesic activity most likely mediated through the blockade of neurokinin-1 receptor (NK1R), the substance P (SP)-preferring receptor. The ability of vapreotide to interfere with other biological effects of SP has yet to be investigated. METHODS: We studied the ability of vapreotide to antagonize NK1R in three different cell types: immortalized U373MG human astrocytoma cells, human monocyte derived macrophages (MDM) and a human embryonic kidney cell line, HEK293. Both U373MG and MDM express endogenous NK1R while HEK293 cells, which normally do not express NK1R, are stably transformed to express human NK1R (HEK293-NK1R). RESULTS: Vapreotide attenuates SP-triggered intracellular calcium increases and nuclear factor-kappaB activation in a dose-dependent manner. Vapreotide also inhibits SP-induced interleukin-8 and monocyte chemotactic protein-1 production in HEK293-NK1R and U373MG cell lines. Vapreotide inhibits HIV-1 infection of human MDM in vitro, an effect that is reversible by SP pretreatment. CONCLUSIONS: Our findings indicate that vapreotide has NK1R antagonist activity and may have a potential application as a therapeutic intervention in HIV-1 infection. PMID- 23921648 TI - Effect of increased body mass index (BMI) on time to tumour progression (TTP) in unresectable metastatic colorectal cancer (mCRC) patients treated with bevacizumab-based therapy. AB - High BMI is a well-known risk factor for the development and recurrence of several solid tumours, including CRC. Obesity is associated with increased levels of vascular endothelial growth factor (VEGF). Bevacizumab is the main targeted therapy for inhibiting tumour angiogenesis by blocking the VEGF/VEGF receptor pathway. Elevated VEGF in obese patients might provoke resistance to anti-VEGF therapy. We evaluated the efficacy of bevacizumab on TTP among mCRC patients through stratifying them according to their BMI. Patients with mCRC who had been treated with fluoropyrimidine-based combination chemotherapy with bevacizumab were included in the study. Patients were assigned according to their BMI before initiation of therapy (group A: BMI < 25 kg/m(2), group B: BMI >= 25 kg/m(2)). Multivariate analysis was performed to evaluate the risk of tumour progression. Between April 2007 and June 2011, 80 patients were treated with chemotherapy and bevacizumab as first-line therapy (n = 37 for group A, n = 43 for group B). Tumours in 56.3 % of the patients in group A (n = 21) and 76.3 % of the patients in group B (n = 33) progressed during a median 10-months (3-57 months) follow-up. The median TTP was 11.7 months in the group A and 6 months in the group B (p = 0.004). In a multivariate analysis, high BMI (>=25 kg/m(2)) was associated with significantly shorter TTP (p = 0.01; HR: 4.37). High BMI among mCRC patients treated with bevacizumab is associated with shorter TTP. Further study in larger databases is warranted for confirming the negative prognostic effect of obesity during treatment with anti-VEGF agents. PMID- 23921650 TI - Disk-cylinder and disk-sphere nanoparticles via a block copolymer blend solution construction. AB - Researchers strive to produce nanoparticles with complexity in composition and structure. Although traditional spherical, cylindrical and membranous, or planar, nanostructures are ubiquitous, scientists seek more complicated geometries for potential functionality. Here we report the simple solution construction of multigeometry nanoparticles, disk-sphere and disk-cylinder, through a straightforward, molecular-level, blending strategy with binary mixtures of block copolymers. The multigeometry nanoparticles contain disk geometry in the core with either spherical patches along the disk periphery in the case of disk-sphere particles or cylindrical edges and handles in the case of the disk-cylinder particles. The portions of different geometry in the same nanoparticles contain different core block chemistry, thus also defining multicompartments in the nanoparticles. Although the block copolymers chosen for the blends are important for the definition of the final hybrid particles, the control of the kinetic pathway of assembly is critical for successful multigeometry particle construction. PMID- 23921649 TI - Gracilibacillus xinjiangensis sp. nov., a new member of the genus Gracilibacillus isolated from Xinjiang region, China. AB - A Gram-positive, endospore-forming, rod-shaped bacterium, designated isolate J2(T) was isolated from a soil sample from Xinjiang Uyghur Autonomous Region, China. The isolate was observed to grow at 16-46 degrees C and pH 6.5-8.0. Chemotaxonomic analysis showed menaquinone-7 (MK-7) to be the major isoprenoid quinone; diphosphatidylglycerol, phosphatidylglycerol, one aminophospholipid, two phosphoglycolipids and one glycolipid as the major cellular polar lipids; and anteiso-C15:0, iso-C15:0, anteiso-C17:0 and C16:0 as the major fatty acids. Comparative analyses of the 16S rRNA gene sequence showed that strain J2(T) is most closely related to Gracilibacillus ureilyticus (with 98.8 % similarity), Gracilibacillus dipsosauri (97.2 %), Gracilibacillus quinghaiensis (97.1 %) and Gracilibacillus thailandensis (97.0 %). The DNA-DNA reassociation values between strain J2(T) and G. ureilyticus MF38(T), G. dipsosauri DD1(T), G. quinghaiensis YIM-C229(T) and G. thailandensis TP2-8(T) were 29.8 +/- 3.7, 23.0 +/- 3.5, 15.8 +/- 4.9 and 15.9 +/- 5.0 %, respectively. The genomic DNA G+C content of strain J2(T) was determined to be 36.5 mol%. Based on these data, strain J2(T) is considered as a novel species of the genus Gracilibacillus, for which the name Gracilibacillus xinjiangensis sp. nov. is proposed. The type species is J2(T) (= CGMCC 1.12449(T) = JCM 18859(T)). PMID- 23921651 TI - Inhibition by local bupivacaine-releasing microspheres of acute postoperative pain from hairy skin incision. AB - BACKGROUND: Acute postoperative pain causes physiological deficits and slows recovery. Reduction of such pain by local anesthetics that are delivered for several days postoperatively is a desirable clinical objective, which is approached by a new formulation and applied in animal studies reported here. METHODS: We subcutaneously injected a new formulation of poly-lactic-co-glycolic acid polymer microspheres, which provides steady drug release for 96+ hours into rats at the dorsal region 2 hours before surgery. A single 1.2-cm-long skin incision was followed by blunt dissection of skin away from the underlying fascia, and closed by 2 sutures, followed by 14 days of testing. Microspheres containing 5, 10, 20, and 40 mg bupivacaine were injected locally 2 hours before surgery; bupivacaine-free microspheres were the vehicle control, and bupivacaine HCl solution (0.5%), the positive control. Mechanical sensitivity was determined by the frequency of local muscle contractions to repeated pokes with nylon monofilaments (von Frey hairs) exerting 4 and 15 g forces, testing, respectively, allodynia and hyperalgesia, and by pinprick. RESULTS: Injection of bupivacaine microspheres (40 mg drug) into intact skin reduced responses to 15 g von Frey hairs for 6 hours and to pinprick for 36 hours. Respective reductions from bupivacaine HCl lasted for 3 and 2 hours. Skin incision and dissection alone caused mechanical allodynia and hyperalgesia for 14 days. Microspheres containing 20 or 40 mg bupivacaine suppressed postoperative hypersensitivity for up to 3 days, reduced integrated allodynia (area under curve of response versus time) over postoperative days 1 to 5 by 51% +/- 20% (mean +/- SE) and 78% +/- 12%, and reduced integrated hyperalgesia by 55% +/- 13% and 64% +/- 11%, for the respective doses. Five and ten milligrams bupivacaine in microspheres and the 0.5% bupivacaine solution were ineffective in reducing postoperative hypersensitivity, as were 40 mg bupivacaine microspheres injected contralateral to the incision. CONCLUSIONS: Significant suppression of postoperative pain by the slow-release bupivacaine preparation outlasts its anesthetic action on intact skin. These findings demonstrate preventive analgesia and indicate the importance of acute processes in the development of chronic postoperative pain. PMID- 23921653 TI - Case cancellation rates measured by surgical service differ whether based on the number of cases or the number of minutes cancelled. AB - BACKGROUND: Surgical cancellation rates typically are reported as the number of cancelled cases divided by the number of scheduled cases. However, the total number of cancelled minutes also has financial impact on surgeons' productivity. Cancellation rates can instead be calculated based on the number of minutes of cancelled cases. Hospitals typically benchmark cancellation rates, since not all cancellations are preventable (e.g., those due to new onset of patient symptoms requiring further workup and treatment before surgery can safely proceed). If the mean estimated duration of cancelled cases were the same as that of scheduled cases, rates would be equivalent whether calculated using the number of cancellations or the minutes of cancellations. It is unknown whether there is a difference between these 2 methods. METHODS: Data for elective, regular workday cases scheduled were obtained from 2 academic hospitals and binned into 8 sequential 13-week periods. Cancellation rates after 7:00 am or after 7:00 pm on the working day before surgery were calculated by service as (1) the numeric cancellation rate = number cancelled divided by the number scheduled and (2) the duration cancellation rate = minutes cancelled divided by the minutes scheduled. Mean differences (biases) and 95% prediction limits between the numeric and duration cancellation rates were determined. RESULTS: The hospitals' numeric cancellation rates after 7:00 am (11.6% and 10.7%) were similar to 12.2% from an academic hospital survey. Bias by individual service ranged from -1.16% +/- 1.34% to 1.93% +/- 3.01% at one hospital and -1.08% +/- 2.76% to 3.05% +/- 1.89% at the other. Mean differences between matching services at the hospitals were -0.7% +/- 0.6% to 3.3% +/- 0.3%. There was considerable variability among services for numeric cancellation rates and the prediction limits of the cancellation rate, calculated using the number of minutes cancelled. CONCLUSIONS: Calculating cancellation rates using case counts can inaccurately represent their impact on surgeon's productivity compared with using minutes of cancelled cases. Comparing numeric cancellation rates between hospitals or services without checking for bias may lead to inappropriate conclusions. We recommend that hospitals evaluate their data for potential bias to determine whether cancellation rates need to be calculated using scheduled minutes of cases rather than numbers of cancellations. PMID- 23921652 TI - The efficacy of 2 doses of epidural morphine for postcesarean delivery analgesia: a randomized noninferiority trial. AB - BACKGROUND: A single dose of epidural morphine is effective in reducing pain after cesarean delivery but is associated with adverse effects. In this study, we sought to establish whether half the traditional dose of epidural morphine, when administered as part of a multimodal analgesia regimen after cesarean delivery, was associated with noninferior analgesia and fewer adverse effects. METHODS: Ninety term parturients undergoing cesarean delivery under epidural anesthesia were enrolled in this randomized, double-blinded, noninferiority study. Patients were randomly allocated to receive either 3 mg epidural morphine or, half this dose, 1.5 mg epidural morphine. In addition, subjects received regular systemic ketorolac and acetaminophen. Rescue analgesia (oral oxycodone) was administered for breakthrough pain. The primary outcome was the difference between groups in total opioid consumption (measured in median IV morphine equivalents) within the first 24 hours. A prespecified noninferiority margin of 3.33 mg was used. Secondary outcomes included total opioid consumption from 24 to 48 hours, numerical rating scale pain scores, time to first request for analgesics, overall pain relief, maternal satisfaction, quality of recovery, and adverse effects. RESULTS: Data were analyzed for 87 participants. Noninferiority was demonstrated as the difference in median 24-hour opioid consumption between the 1.5 mg epidural morphine (EM) and 3 mg EM groups was 0 mg (1-sided 95% confidence interval [CI], 2.5 mg), which was less than the prespecified noninferiority margin of 3.33 mg. No significant differences were found between groups in the median 24- to 48-hour opioid consumption or the median total opioid consumption within 48 hours. Pain scores, overall pain relief, and satisfaction at 24 and 48 hours were not significantly different between groups. The 1.5 mg EM group had a lower incidence of moderate and severe pruritus at 6 and 12 hours (relative risk [RR] 0.44, 95% CI, 0.2-0.9 and RR 0.41, 95% CI, 0.2-0.8, respectively) and had less nausea and vomiting at 6 hours (RR 0.22, 95% CI, 0.05-0.9). There was no difference in average pain scores at 12 weeks between the 2 groups. CONCLUSION: When used as part of a multimodal analgesia regimen, 1.5 mg epidural morphine provided noninferior postcesarean analgesia and caused fewer adverse effects compared with 3 mg epidural morphine. PMID- 23921654 TI - Brief report: a comparison of clinical and research practices in measuring cerebral perfusion pressure: a literature review and practitioner survey. AB - BACKGROUND: Our objective was to determine whether there is variability in the foundational literature and across centers in how mean arterial blood pressure is measured to calculate cerebral perfusion pressure. METHODS: We reviewed foundational literature and sent an e-mail survey to members of the Neurocritical Care Society. RESULTS: Of 32 articles reporting cerebral perfusion pressure data, the reference point for mean arterial blood pressure was identified in 16: 10 heart and 6 midbrain. The overall survey response rate was 14.3%. Responses from 31 of 34 (91%) United Council for Neurologic Subspecialties fellowship-accredited Neurointensive Care Units indicated the reference point was most often the heart (74%), followed by the midbrain (16%). Conflicting answers were received from 10%. CONCLUSIONS: There is substantive heterogeneity in both research reports and clinical practice in how mean arterial blood pressure is measured to determine cerebral perfusion pressure. PMID- 23921655 TI - Stored platelet functionality is not decreased after warming with a fluid warmer. AB - BACKGROUND: Warming of IV-administered fluids and blood products is routinely performed in the operating room to help maintain normothermia. Current guidelines recommend against the warming of platelets (PLTs), although there is no evidence for this prohibition in the literature. Our goal in this pilot study was to determine whether the warming of stored PLTs had any effect on their function. METHODS: Ten units of 3-day-old, PLT-rich plasma-derived whole blood PLTs were acquired from the transfusion service. A 5-mL aliquot was taken from each unit before warming (control samples). The remainder of the unit was then passed into a blood-warming device and held there for 2 minutes. Postwarming (warmed) PLT samples were then collected from the effluent end of the warming device. PLT aggregometry assays with adenosine diphosphate, collagen, and arachidonic acid as agonists were performed on the control and warmed samples. Thromboelastography tests were also performed on the control and warmed samples from 6 of the 10 PLT units. RESULTS: The mean temperature of the control and warmed samples was 22.4 degrees C +/- 0.5 degrees C and 37.8 degrees C +/- 2.3 degrees C, respectively. There was no significant difference (all P >= 0.13) in any of the PLT aggregometry assays or in the maximum amplitude of the thromboelastography test between the control and the warmed samples. The observed mean of only 1 parameter decreased (PLT aggregometry with 5 MUM adenosine diphosphate) by 5% (95% confidence interval, -115% to 105%). The maximum change observed was PLT aggregometry with arachidonic acid as agonist, which increased by 116% (95% confidence interval, -91% to 323%). CONCLUSION: Although small in size, the results of this study do not support the prohibition against mechanical PLT warming. Studies of PLT activation after warming are also warranted. PMID- 23921657 TI - Echo rounds: incidental mass of the tricuspid valve annulus diagnosed by transesophageal echocardiography. PMID- 23921656 TI - A randomized, double-blind comparison of licorice versus sugar-water gargle for prevention of postoperative sore throat and postextubation coughing. AB - BACKGROUND: One small study suggests that gargling with licorice before induction of anesthesia reduces the risk of postoperative sore throat. Double-lumen tubes are large and thus especially likely to provoke sore throats. We therefore tested the hypothesis that preoperative gargling with licorice solution prevents postoperative sore throat and postextubation coughing in patients intubated with double-lumen tubes. METHODS: We enrolled 236 patients having elective thoracic surgery who required intubation with a double-lumen endotracheal tube. Patients were randomly assigned to gargle 5 minutes before induction of anesthesia for 1 minute with: (1) Extractum Liquiritiae Fluidum (licorice 0.5 g); or (2) Sirupus Simplex (sugar 5 g); each diluted in 30 mL water. Sore throat and postextubation coughing were evaluated 30 minutes, 90 minutes, and 4 hours after arrival in the postanesthesia care unit, and the first postoperative morning using an 11-point Likert scale by an investigator blinded to treatment. RESULTS: The incidence of postoperative sore throat was significantly reduced in patients who gargled with licorice rather than sugar-water: 19% and 36% at 30 minutes, 10% and 35% at 1.5 hours, and 21% and 45% at 4 hours, respectively. The corresponding estimated treatment effects (relative risks) were 0.54 (95% CI, 0.30-0.99, licorice versus sugar-water; P = 0.005), 0.31 (0.14-0.68) (P < 0.001), and 0.48 (0.28-0.83) (P < 0.001). CONCLUSION: Licorice gargling halved the incidence of sore throat. Preinduction gargling with licorice appears to be a simple way to prevent a common and bothersome complication. PMID- 23921658 TI - Peripheral nerve injury after local anesthetic injection. AB - BACKGROUND: A well-known complication of peripheral nerve block is peripheral nerve injury, whether from the needle or toxicity of the medication used. In this study, we sought to determine the extent of damage that results from intrafascicular injection of various commonly used local anesthetics (LAs). METHODS: Sixteen Lewis rats received an intrafascicular injection of saline (control) or 1 of 3 LAs (bupivacaine, lidocaine, or ropivacaine) into the sciatic nerve (n = 4). At a 2-week end point, the sciatic nerves were harvested for histomorphometric and electron microscopic analysis. RESULTS: Animals that received intrafascicular LA injections showed increased severity of injury as compared with control. In particular, there was a significant loss of large diameter fibers as indicated by decreased counts (P < 0.01 for all LAs) and area (P < 0.01 for all LAs) of remaining fibers in severely injured versus noninjured areas of the nerve. There was a layering of severity of injury with most severely injured areas closest to and noninjured areas furthest from the injection site. Bupivacaine caused more damage to large fibers than the other 2 LAs. In all groups, fascicular transection injury from the needle was observed. Electron microscopy confirmed nerve injury. CONCLUSIONS: Frequently used LAs at traditional concentrations are toxic to and can injure the peripheral nerve. Any combination of motor and/or sensory sequelae may result due to the varying fascicular topography of a nerve. PMID- 23921659 TI - Quantitative interaction screen of telomeric repeat-containing RNA reveals novel TERRA regulators. AB - Telomeres are actively transcribed into telomeric repeat-containing RNA (TERRA), which has been implicated in the regulation of telomere length and heterochromatin formation. Here, we applied quantitative mass spectrometry (MS) based proteomics to obtain a high-confidence interactome of TERRA. Using SILAC labeled nuclear cell lysates in an RNA pull-down experiment and two different salt conditions, we distinguished 115 proteins binding specifically to TERRA out of a large set of background binders. While TERRA binders identified in two previous studies showed little overlap, using quantitative mass spectrometry we obtained many candidates reported in these two studies. To test whether novel candidates found here are involved in TERRA regulation, we performed an esiRNA based interference analysis for 15 of them. Knockdown of 10 genes encoding candidate proteins significantly affected total cellular levels of TERRA, and RNAi of five candidates perturbed TERRA recruitment to telomeres. Notably, depletion of SRRT/ARS2, involved in miRNA processing, up-regulated both total and telomere-bound TERRA. Conversely, knockdown of MORF4L2, a component of the NuA4 histone acetyltransferase complex, reduced TERRA levels both globally and for telomere-bound TERRA. We thus identified new proteins involved in the homeostasis and telomeric abundance of TERRA, extending our knowledge of TERRA regulation. PMID- 23921660 TI - Efficient identification of Y chromosome sequences in the human and Drosophila genomes. AB - Notwithstanding their biological importance, Y chromosomes remain poorly known in most species. A major obstacle to their study is the identification of Y chromosome sequences; due to its high content of repetitive DNA, in most genome projects, the Y chromosome sequence is fragmented into a large number of small, unmapped scaffolds. Identification of Y-linked genes among these fragments has yielded important insights about the origin and evolution of Y chromosomes, but the process is labor intensive, restricting studies to a small number of species. Apart from these fragmentary assemblies, in a few mammalian species, the euchromatic sequence of the Y is essentially complete, owing to painstaking BAC mapping and sequencing. Here we use female short-read sequencing and k-mer comparison to identify Y-linked sequences in two very different genomes, Drosophila virilis and human. Using this method, essentially all D. virilis scaffolds were unambiguously classified as Y-linked or not Y-linked. We found 800 new scaffolds (totaling 8.5 Mbp), and four new genes in the Y chromosome of D. virilis, including JYalpha, a gene involved in hybrid male sterility. Our results also strongly support the preponderance of gene gains over gene losses in the evolution of the Drosophila Y. In the intensively studied human genome, used here as a positive control, we recovered all previously known genes or gene families, plus a small amount (283 kb) of new, unfinished sequence. Hence, this method works in large and complex genomes and can be applied to any species with sex chromosomes. PMID- 23921661 TI - Massively parallel synthetic promoter assays reveal the in vivo effects of binding site variants. AB - Gene promoters typically contain multiple transcription factor binding sites (TFBSs), which may vary in affinity for their cognate transcription factors (TFs). One major challenge in studying cis-regulation is to understand how TFBS variants affect gene expression. We studied the in vivo effects of TFBS variants on cis-regulation using synthetic promoters coupled with a thermodynamic model of TF binding. We measured expression driven by each promoter with RNA-seq of transcribed sequence barcodes. This allowed reporter genes to be highly multiplexed and increased our statistical power to detect the effects of TFBS variants. We analyzed the effects of TFBS variants using a thermodynamic framework that models both TF-DNA interactions and TF-TF interactions. We found that this system accurately estimates the in vivo relative affinities of TFBSs and predicts unexpected interactions between several TFBSs. Our results reveal that binding site variants can have complex effects on gene expression due to differences in TFBS affinity for cognate TFs and differences in TFBS specificity for noncognate TFs. PMID- 23921662 TI - The developmental sequence of social-communicative skills in young children with autism: a longitudinal study. AB - To explore the different developmental trajectories of social-communicative skills in children with autism and typically developing infants, two longitudinal studies were conducted. In Study 1, we examined the developmental sequence of social-communicative skills in 26 typically developing infants when they were 9 months old and reexamined them when they were 12 and 15 months old. The results indicated a reliable developmental sequence of social-communicative skills in infants with typical development. In Study 2, we explored the emergence sequence of social-communicative skills of 23 children with autism and 23 children with developmental delay between the ages of 2 and 4 years. The results demonstrated that the developmental sequence of social-communicative skills in young children with autism and children with developmental delays was different. PMID- 23921663 TI - Microbleed burden and hematoma expansion in acute intracerebral hemorrhage. AB - BACKGROUND: Intracranial amyloid and hypertensive angiopathy have been related to impaired blood vessel function and the etiology of intracerebral hemorrhage (ICH). Microbleeds (MBs) are surrogate radiological markers that are associated with these underlying angiopathies. We assessed the hypothesis that MBs are associated with hematoma expansion (HE) in patients with hyperacute ICH. METHODS: We studied patients with spontaneous supratentorial ICH within the first 6 h after onset. HE was defined as an increase>=33% in the volume of hematoma on the follow-up CT in comparison with the admission CT. The volume was calculated using the ABC/2 formula. MBs were detected by specific magnetic resonance sequences (gradient-echo). The presence, number and distribution of MBs were analyzed. RESULTS: Our study included 44 patients. Their mean age was 68.9+/-11.1 years, and 70.5% of them were men. HE was observed in 14 of the patients (31.8%). HE was more prevalent in patients with more than 10 MBs compared with patients with 1-10 MBs (60 vs 12.5%; p=0.03). CONCLUSION: A high burden of MBs is associated with an increased risk of HE in patients with ICH. This is probably a marker of a more severe underlying angiopathy. PMID- 23921671 TI - Clinical diagnosis and treatment of ectopic pregnancy. AB - BACKGROUND: Implantation of the zygote outside the uterine cavity occurs in 2% of all pregnancies. The product of conception can be removed safely by laparoscopic surgery and be submitted for histological examination. The rate of ectopic pregnancies has increased from 0.5% in 1970 to 2% today. The prevalence of ectopic pregnancy in all women presenting to an emergency department with first trimester bleeding, lower abdominal pain, or a combination of the 2 is between 6% and 16%. DESIGNATION: Workup of all localizations of ectopic pregnancies at a university department of obstetrics and gynecology. METHODS: Comparison of diagnostic and therapeutic modalities from the surgical laparoscopic approach to nonsurgical, medical options. FINDINGS: SURGICAL TREATMENT: Tubal pregnancies: (1) to preserve tubal function, salpingotomy, partial salpingectomy followed by laparoscopic anastomosis, or fimbrial milking is performed. (2) Tubectomy or salpingectomy is performed only in severely damaged or ruptured tubes or if the patient does not desire further pregnancies. Nontubal ectopic pregnancies (ovarian pregnancy, ectopic abdominal pregnancy, interstitial or cornual pregnancy/rudimentary horn, intraligamental and cervical pregnancies) all require their own specific treatment. MEDICAL TREATMENT: The predominant drug is methotrexate, but other systemic drugs, such as actinomycin D, prostaglandins, and RU 486, can also be applied. COMPLICATIONS: Tubal rupture is a complication of late diagnosed tubal pregnancy that is more difficult to treat conservatively and often indicates tubectomy or segmental resection. In 5% to 15% of treated ectopic pregnancy cases, remnant conception product parts may require a final methotrexate injection. CONCLUSIONS: This article is a review to aid clinical diagnosis of ectopic pregnancies that now can be diagnosed earlier and treated effectively by laparoscopic surgery. PMID- 23921672 TI - Oncofertility: an emerging discipline in obstetrics and gynecology. AB - Oncofertility is an exciting new interdisciplinary field that encompasses the obstetrician gynecologist, gynecologic oncologist, reproductive endocrinologist, and primary care physician in a common goal to provide fertility preservation options for cancer patients. Maintaining their fertility is of the upmost importance for many oncology patients diagnosed during their childbearing years. This review addresses the common types of cancers in reproductive-age patients and how the treatment of these cancers may impact reproductive potential. Fertility preservation treatments will also be discussed to assist health care providers in appropriately counseling patients about options after a diagnosis of cancer. The goal of oncofertility is to provide both physicians and patients with the knowledge and resources to make fertility an ongoing opportunity for all patients who desire a future with children. PMID- 23921673 TI - Contemporary uses of erythropoietin in pregnancy: a literature review. AB - OBJECTIVE: The objectives of this study were to survey the current research and provide an update on the uses and benefits of erythropoietin (EPO) in pregnancy and the postpartum period. DATA SOURCES: A review of MEDLINE (1947 to present) was performed. Search terms included "erythropoietin," "pregnan*," with subheadings of "administration & dosage," "pharmacokinetics," "therapeutic use," "fetus," "fertility." METHOD OF STUDY SELECTION: We reviewed relevant articles published from 2002 to 2012. Case reports, observational studies, case-control studies, randomized controlled trials, retrospective analyses, animal studies, and review articles were included. Articles were selected if they discussed a use of EPO in pregnancy or the immediate postpartum period, as well as use of EPO in the neonate. TABULATION, INTEGRATION, AND RESULTS: Authors independently reviewed and extracted data. Of the 65 articles reviewed, 45 were included. Erythropoietin was used in the treatment of maternal anemia. Because of the molecule's large size, recombinant EPO does not appear to cross the placenta. No fetal morbidity or mortality was noted. Therefore, this is a safe therapy that can be used in pregnancy. Use of EPO may be especially important for women who decline blood products. Neonatal uses of EPO show benefit in the treatment of anemia due to blood type incompatibility. CONCLUSIONS: Erythropoietin is gaining popularity as a therapeutic option during pregnancy and the postpartum period. Further investigation is needed to establish a standard dosage and dosing interval. New studies reviewing its use in the neonate for perinatal-hypoxic injury and anemia due to blood type incompatibility provide exciting opportunities for further therapeutic use. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians. LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to treat anemia in pregnancy, including causes and interventions; assess renal disease in pregnancy, targets of hemoglobin, precautions, and treatment considerations; and evaluate erythropoietin use in neonates and fetuses, including benefits, complications, and areas for upcoming research/uses. PMID- 23921674 TI - Self-determination theory and romantic relationship processes. AB - Self-determination theory can be viewed as a theory of optimal relationship development and functioning. We examine the concept of self that is employed in self-determination theory and explain how its unique definition allows an important and novel characterization of investing one's "self" in romantic relationships. A self-determined perspective on romantic relationships integrates several theories on romantic relationship development, but also goes beyond them by explicitly articulating the personality, developmental, and situational factors that facilitate optimal self-investment and relational functioning. Self determination promotes openness rather than defensiveness and facilitates perspective-taking, authenticity, and support of close others. The dyadic context of romantic relationships affords great opportunity for theoretical development and integration of self-determination theory with current theories of interdependence and relational well-being. PMID- 23921675 TI - The relation between intelligence and religiosity: a meta-analysis and some proposed explanations. AB - A meta-analysis of 63 studies showed a significant negative association between intelligence and religiosity. The association was stronger for college students and the general population than for participants younger than college age; it was also stronger for religious beliefs than religious behavior. For college students and the general population, means of weighted and unweighted correlations between intelligence and the strength of religious beliefs ranged from -.20 to -.25 (mean r = -.24). Three possible interpretations were discussed. First, intelligent people are less likely to conform and, thus, are more likely to resist religious dogma. Second, intelligent people tend to adopt an analytic (as opposed to intuitive) thinking style, which has been shown to undermine religious beliefs. Third, several functions of religiosity, including compensatory control, self regulation, self-enhancement, and secure attachment, are also conferred by intelligence. Intelligent people may therefore have less need for religious beliefs and practices. PMID- 23921677 TI - Capitate glandular trichomes of Helianthus annuus (Asteraceae): ultrastructure and cytological development. AB - Previous studies have shown that capitate glandular trichomes (CGT) of the common sunflower, Helianthus annuus, produce sesquiterpene lactones (STL) and flavonoids, which are sequestered and accumulated between the apical cuticle and the wall of the tip cells. To explore the cellular structures required and putatively involved in the STL biosynthesis and secretion, the present study was focused on the development of CGT and the comparison of the ultrastructure of its different cell types. Gradual maturation of flowers in the capitulum of the sunflower provided the possibility to study the simultaneous differentiation from the primordial to the secretory stage of CGT located by light microscopy (bright field, differential interference contrast and fluorescence) as well as transmission electron microscopy. It was shown that the CGT of sunflower anthers had a biseriate structure with up to 14 cell pairs. In mature trichomes, the apical cells called secretory cells were covered entirely by a large cuticle globe, which enclosed the resinous terpenoids and was specialised in thickness and structure. The secretory cells lacked chloroplasts and contained mainly smooth endoplasmic reticulum (sER). Conspicuous cell wall protuberances and an accumulation of mitochondria nearby occurred in the horizontally oriented cell walls. The cytological differences between stalk cells and secretory cells indicate a different function. The dominance of sER suggests its involvement in STL biosynthesis and cell wall protuberances enlarge the surface of the plasmamembrane of secretory cells and may be involved in the secretion processes of STL into the subcuticular space. PMID- 23921676 TI - Meiosis-I in Mesostoma ehrenbergii spermatocytes includes distance segregation and inter-polar movements of univalents, and vigorous oscillations of bivalents. AB - In this article, we describe meiosis-I in spermatocytes of the free-living freshwater flatworm Mesostoma ehrenbergii. The original observations of Oakley (1983, 1985) and Fuge (Eur J Cell Biol 44:294-298, 1987, Cell Motil Cytoskeleton 13:212-220, 1989, Protoplasma 160:39-48, 1991), the first to describe these cells, challenge our understanding of cell division, and we have expanded on these descriptions with the aim of laying the framework for further experimental work. These cells contain three bivalents and four univalent chromosomes (two pairs). Bivalent kinetochores oscillate vigorously and regularly throughout prometaphase, for up to several hours, until anaphase. Anaphase onset usually begins in the middle of the kinetochore oscillation cycle. Precocious cleavage furrows form at the start of prometaphase, ingress and then remain arrested until the end of anaphase. The four univalents do not pair, yet by anaphase there is one of each kind at each pole, an example of "distance segregation" (Hughes Schrader in Chromosoma 27:109-129, 1969). Until proper segregation is achieved, univalents move between spindle poles up to seven times in an individual cell; they move with velocities averaging 9 MUm/min, which is faster than the oscillatory motions of the bivalent kinetochores (5-6 MUm/min), and much faster than the anaphase movements of the segregating half-bivalents (1 MUm/min). Bipolar bivalents periodically reorient, most often resulting in the partner kinetochores exchanging poles. We suggest that the large numbers of inter-polar movements of univalents, and the reorientations of bivalents that lead to partners exchanging poles, might be because there is non-random segregation of chromosomes, as in some other cell types. PMID- 23921678 TI - Adolescent dosing and labeling since the Food and Drug Administration Amendments Act of 2007. AB - IMPORTANCE: During pediatric drug development, dedicated pharmacokinetic studies are generally performed in all relevant age groups to support dose selection for subsequent efficacy trials. To our knowledge, no previous assessments regarding the need for an intensive pharmacokinetic study in adolescents have been performed. OBJECTIVES: To compare U.S. Food and Drug Administration (FDA) approved adult and adolescent drug dosing and to assess the utility of allometric scaling for the prediction of drug clearance in the adolescent population. DESIGN: Adult and adolescent dosing and drug clearance data were obtained from FDA-approved drug labels and publicly available databases containing reviews of pediatric trials submitted to the FDA. Dosing information was compared for products with concordant indications for adolescent and adult patients. Adolescent drug clearance was predicted from adult pharmacokinetic data by using allometric scaling and compared with observed values. MAIN OUTCOMES AND MEASURES: Adolescent and adult dosing information and drug clearance. RESULTS: There were 126 unique products with pediatric studies submitted to the FDA since the FDA Amendments Act of 2007, of which 92 had at least 1 adolescent indication concordant with an adult indication. Of these 92 products, 87 (94.5%) have equivalent dosing for adults and adolescent patients. For 18 of these 92 products, a minimum weight or body surface area threshold is recommended for adolescents to receive adult dosing. Allometric scaling predicted adolescent drug clearance with an overall mean absolute percentage error of 17.0%. CONCLUSIONS AND RELEVANCE: Approved adult and adolescent drug dosing is equivalent for 94.5% of products with an adolescent indication studied since the FDA Amendments Act of 2007. Allometric scaling may be a useful tool to avoid unnecessary dedicated pharmacokinetic studies in the adolescent population during pediatric drug development, although each development program in adolescents requires a full discussion of drug dosing with the FDA. PMID- 23921679 TI - Development of an in-house enzyme-linked immunosorbent assay based on surface whole cell antigen for diagnosis of Helicobacter pylori infection in patients with gastroduodenal ulcer disease. AB - Helicobacter pylori (H. pylori) is a causative agent of gastritis, gastroduodenal ulcers and gastric adenocarcinoma. More than 50% world population is colonized by H. pylori, which is closely related to the chronic gastritis and gastric ulcer infection. In this study, a total of 214 gastritis patient's serum samples were screened for anti-H. pylori IgG antibody. A 96-well plate coated with 20 MUg/ml antigen and hundred-fold diluted patient's serum was allowed to react. After extensive washing with buffer, 1:2,500 diluted conjugated secondary antibody was added. Later substrate was added to observe positivity by measuring the intensity of color. Statistical analyses were performed, and p value of <0.01 was taken as significant; 84% male patients and 89% female patients, respectively, tested positive for H. pylori, while agewise distribution was 35-45 years males (40%) and 35-55 years females (52%) were found highest number of H. pylori infected patients. In-house ELISA based on surface whole cell antigen (wELISA) showed a sensitivity of 93%, specificity of 100%, accuracy 94% and kappa value 0.86 with significant correlation R-0.77020; p < 0.0001. We conclude that H. pylori local isolates surface antigen was satisfactory for diagnosis as different parameters were adjusted according to the local H. pylori isolates. Fluctuations in serum antibody titer predict the variation in an individual's response of the host against H. pylori. In-house wELISA could provide a reliable and a clinically useful method for the diagnosis of H. pylori infection in patients of Karachi, Pakistan. PMID- 23921680 TI - A genome-wide association study in Koreans identifies susceptibility loci for allergic nickel dermatitis. PMID- 23921681 TI - MicroRNA expression changes during interferon-beta treatment in the peripheral blood of multiple sclerosis patients. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules acting as post transcriptional regulators of gene expression. They are involved in many biological processes, and their dysregulation is implicated in various diseases, including multiple sclerosis (MS). Interferon-beta (IFN-beta) is widely used as a first-line immunomodulatory treatment of MS patients. Here, we present the first longitudinal study on the miRNA expression changes in response to IFN-beta therapy. Peripheral blood mononuclear cells (PBMC) were obtained before treatment initiation as well as after two days, four days, and one month, from patients with clinically isolated syndrome (CIS) and patients with relapsing-remitting MS (RRMS). We measured the expression of 651 mature miRNAs and about 19,000 mRNAs in parallel using real-time PCR arrays and Affymetrix microarrays. We observed that the up-regulation of IFN-beta-responsive genes is accompanied by a down regulation of several miRNAs, including members of the mir-29 family. These differentially expressed miRNAs were found to be associated with apoptotic processes and IFN feedback loops. A network of miRNA-mRNA target interactions was constructed by integrating the information from different databases. Our results suggest that miRNA-mediated regulation plays an important role in the mechanisms of action of IFN-beta, not only in the treatment of MS but also in normal immune responses. miRNA expression levels in the blood may serve as a biomarker of the biological effects of IFN-beta therapy that may predict individual disease activity and progression. PMID- 23921682 TI - Gender-dependent effects of enriched environment and social isolation in ischemic retinal lesion in adult rats. AB - Exposure to an enriched environment has been shown to have many positive effects on brain structure and function. Numerous studies have proven that enriched environment can reduce the lesion induced by toxic and traumatic injuries. Impoverished environment, on the other hand, can have deleterious effects on the outcome of neuronal injuries. We have previously shown that enriched conditions have protective effects in retinal injury in newborn rats. It is well-known that the efficacy of neuroprotective strategies can depend on age and gender. The aim of the present study, therefore, was to examine the effects of environmental enrichment and social isolation in retinal ischemia. We used bilateral common carotid artery occlusion to induce retinal hypoperfusion in adult Wistar rats of both genders. Groups were housed in standard, enriched or impoverished conditions. Impoverished environment was induced by social isolation. Retinas were processed for histological analysis after two weeks of survival. In the present study, we show that (1) enriched environment has protective effects in adult ischemic retinal lesion, while (2) impoverished environment further increases the degree of ischemic injury, and (3) that these environmental effects are gender-dependent: females are less responsive to the positive effects of environmental enrichment and more vulnerable to retinal ischemia in social isolation. In summary, our present study shows that the effects of both positive and negative environmental stimuli are gender-dependent in ischemic retinal lesions. PMID- 23921683 TI - Neuron biomechanics probed by atomic force microscopy. AB - Mechanical interactions play a key role in many processes associated with neuronal growth and development. Over the last few years there has been significant progress in our understanding of the role played by the substrate stiffness in neuronal growth, of the cell-substrate adhesion forces, of the generation of traction forces during axonal elongation, and of the relationships between the neuron soma elastic properties and its health. The particular capabilities of the Atomic Force Microscope (AFM), such as high spatial resolution, high degree of control over the magnitude and orientation of the applied forces, minimal sample damage, and the ability to image and interact with cells in physiologically relevant conditions make this technique particularly suitable for measuring mechanical properties of living neuronal cells. This article reviews recent advances on using the AFM for studying neuronal biomechanics, provides an overview about the state-of-the-art measurements, and suggests directions for future applications. PMID- 23921684 TI - Comparative analysis of osteogenic/chondrogenic differentiation potential in primary limb bud-derived and C3H10T1/2 cell line-based mouse micromass cultures. AB - Murine micromass models have been extensively applied to study chondrogenesis and osteogenesis to elucidate pathways of endochondral bone formation. Here we provide a detailed comparative analysis of the differentiation potential of micromass cultures established from either BMP-2 overexpressing C3H10T1/2 cells or mouse embryonic limb bud-derived chondroprogenitor cells, using micromass cultures from untransfected C3H10T1/2 cells as controls. Although the BMP-2 overexpressing C3H10T1/2 cells failed to form chondrogenic nodules, cells of both models expressed mRNA transcripts for major cartilage-specific marker genes including Sox9, Acan, Col2a1, Snorc, and Hapln1 at similar temporal sequence, while notable lubricin expression was only detected in primary cultures. Furthermore, mRNA transcripts for markers of osteogenic differentiation including Runx2, Osterix, alkaline phosphatase, osteopontin and osteocalcin were detected in both models, along with matrix calcification. Although the adipogenic lineage specific marker gene FABP4 was also expressed in micromass cultures, Oil Red O positive cells along with PPARgamma2 transcripts were only detected in C3H10T1/2 derived micromass cultures. Apart from lineage-specific marker genes, pluripotency factors (Nanog and Sox2) were also expressed in these models, reflecting on the presence of various mesenchymal lineages as well as undifferentiated cells. This cellular heterogeneity has to be taken into consideration for the interpretation of data obtained by using these models. PMID- 23921687 TI - Progression of thrombogenesis in large coronary aneurysms during anticoagulant therapy in a Buerger's disease patient. PMID- 23921685 TI - Post-transcriptional regulation by poly(ADP-ribosyl)ation of the RNA-binding proteins. AB - Gene expression is intricately regulated at the post-transcriptional level by RNA binding proteins (RBPs) via their interactions with pre-messenger RNA (pre-mRNA) and mRNA during development. However, very little is known about the mechanism regulating RBP activities in RNA metabolism. During the past few years, a large body of evidence has suggested that many RBPs, such as heterogeneous nuclear ribonucleoproteins (hnRNPs), undergo post-translational modification through poly(ADP-ribosyl)ation to modulate RNA processing, including splicing, polyadenylation, translation, miRNA biogenesis and rRNA processing. Accordingly, RBP poly(ADP-ribosyl)ation has been shown to be involved in stress responses, stem cell differentiation and retinal morphogenesis. Here, we summarize recent advances in understanding the biological roles of RBP poly(ADP-ribosyl)ation, as controlled by Poly(ADP-ribose) Polymerases (PARPs) and Poly(ADP-ribose) Glycohydrolase (PARG). In addition, we discuss the potential of PARP and PARG inhibitors for the treatment of RBP-related human diseases, including cancer and neurodegenerative disorders. PMID- 23921688 TI - Bleeding associated with acquired factor V inhibitor in a patient on warfarin treated successfully with prednisolone. AB - An 85-year-old man on warfarin for atrial fibrillation presented with skin bleeding. International normalised ratio (INR) and activated partial thromboplastin time (APTT) were elevated and did not correct even after warfarin reversal with vitamin K, prothrombin complex concentrate (PCC) and fresh frozen plasma. Mixing coagulation studies with normal plasma suggested the presence of an inhibitor rather than the multiple coagulation factor deficiencies expected with warfarin. Assays of the common-pathway coagulation factors revealed factor V concentration <2% with inhibitor level elevated to 11 Bethesda units. The bleeding resolved following a course of corticosteroids. Coagulation studies and factor V level returned to normal along with resolution of the inhibitor. We report the case of the diagnostic dilemma posed and successful therapy implemented despite the limited evidence-based data being available for the treatment of this rare condition. PMID- 23921686 TI - Contributions of microdialysis to new alternative therapeutics for hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a common complication of cirrhosis, of largely reversible impairment of brain function occurring in patients with acute or chronic liver failure or when the liver is bypassed by portosystemic shunts. The mechanisms causing this brain dysfunction are still largely unclear. The need to avoid complications caused by late diagnosis has attracted interest to understand the mechanisms underlying neuronal damage in order to find markers that will allow timely diagnosis and to propose new therapeutic alternatives to improve the care of patients. One of the experimental approaches to study HE is microdialysis; this technique allows evaluation of different chemical substances in several organs through the recollection of samples in specific places by semi permeable membranes. In this review we will discuss the contributions of microdialysis in the understanding of the physiological alterations in human hepatic encephalopathy and experimental models and the studies to find novel alternative therapies for this disease. PMID- 23921689 TI - Testicular mass with intracerebral lesions: malignancy or infection? PMID- 23921690 TI - Non-Hodgkin lymphoma mimics retroperitoneal fibrosis. AB - A 33-year-old man presented with lymphoedema and obstructive nephropathy and was first diagnosed as retroperitoneal fibrosis (RF) with consistent clinical picture and radiographic findings. Further CT-guided biopsy was performed and non-Hodgkin lymphoma was diagnosed based on pathological results. RF is usually diagnosed through clinical presentation and imaging studies. However, our case proved that biopsy should be considered to exclude malignancy, even with typical presentations of RF. Follow-up after six courses of R-CHOP (rituximab, cyclophosphamide, vindesine, epirubicin and prednisone) regimen revealed complete resolution of symptoms. PMID- 23921691 TI - Airway obstruction from accidental ingestion of a live fish. AB - We present a case of a fisherman who swallowed a live fish, which resulted in severe upper airway obstruction. The firm attachments of the fish's external fins and scales to the airway limit the removal when impacted. We outline our emergency airway management strategies and focus our discussion on the technique used to remove the impacted fish from the upper airway, which was paramount for the successful outcome of this case. PMID- 23921692 TI - Lung herniation: an uncommon presentation of Poland's syndrome in a neonate at birth. AB - A term male infant was admitted to the neonatal intensive care unit with an asymmetric chest wall and a herniating mass through the left fourth intercostal space. While crying, the left fourth intercostal space revealed a mass which herniated on expiration and receded on inspiration. On auscultation, the heart sounds were audible on the right side of the chest. Systemic examination was otherwise unremarkable. A roentgenogram of the chest revealed dextrocardia and hyperlucent left lung fields. Echocardiogram showed dextrocardia with a structurally normal heart. A clinical diagnosis of Poland's syndrome was made based on the hypoplasia of the left pectoral muscles, ribs and nipple, dextrocardia and lung herniation. He was thriving well when reviewed at 2 years of age. PMID- 23921693 TI - Acquired haemophilia A initially diagnosed as angioedema. AB - Acquired haemophilia (AH) is a bleeding diathesis caused by inhibitors to factor VIII. Patients developing AH may present with catastrophic bleeding episodes despite having no prior history of bleeding disorder. The authors report a patient with AH who presented with tongue swelling and was diagnosed with angioedema on presentation. However, the patient started bleeding spontaneously after presentation and was diagnosed with AH and the workup revealed haematoma of the tongue, which was the cause of tongue swelling. As previously reported in the literature, AH in this patient might have been precipitated secondary to exposure to an ear infection or exposure to the penicillin group of antibiotics. Laboratory examination was confirmatory for AH, which was appropriately treated with recombinant activated factor VIIa and immunosuppressive therapy with good outcomes. Understanding the pathophysiology of AH and appropriate management is important to prevent life-threatening bleeding. PMID- 23921694 TI - Purpura fulminans caused by meningococcemia in an infant. PMID- 23921695 TI - An uncommon cause of haemoptysis in a 69-year-old women. PMID- 23921696 TI - Association of possible osteopetrosis with acute myeloid leukaemia in a child. AB - Osteopetrosis is a rare disease characterised by an increase in bone mass, skeletal malformations and bone marrow failure due to defective bone resorption. We report a 3-month-old male child presented with chest infections, failure to thrive and hepatosplenomegaly and diagnosed with osteopetrosis associated with acute myeloid leukaemia M3 type (AML-M3). The patient died on day 7 of admission due to respiratory failure. To our knowledge, this is the first case where both osteopetrosis and AML is diagnosed in a patient. PMID- 23921697 TI - Appendico-cutaneous fistula 20 years after groin hernia repair with a polypropylene plug. AB - The formation of an appendico-cutaneous fistula is rare. Few case reports have been published; most describe the formation of a fistula after appendicitis. Here we describe the case of a 79-year-old woman presenting with an appendico cutaneous fistula after groin hernia repair. She was referred to our outpatient department with a painful mass in the right groin. An ultrasound showed a fluid containing mass. Incision and drainage was performed. After 9 weeks she was referred again with a persisting open wound. Fistulogram and CT scan showed a fistuleous tract involving the appendix. Wound culture showed Escherichia coli. Diagnostic laparoscopy showed an appendix stuck to the ventral wall of the abdomen without any sign of previous infection. After an appendectomy, pathological investigation revealed an appendix sana. After operation, the fistula persisted due to a polypropylene plug from the previous groin hernia correction. The (infected) plug was removed and the fistula healed. PMID- 23921698 TI - Functional characterization of recombinant bromelain of Ananas comosus expressed in a prokaryotic system. AB - Bromelain (BRM) is a defense protein present in the fruit and stem of pineapple (Ananas comosus) and it is grouped as a cysteine protease enzyme with diversified medicinal uses. Based on its therapeutic applications, bromelain has got sufficient attention in pharmaceutical industries. In the present study, the full coding gene of bromelain in pineapple stem (1,093 bp) was amplified by RT-PCR. The PCR product was cloned, sequenced, and characterized. The sequence analysis of the gene revealed the single nucleotide polymorphism and its phylogenetic relatedness. The peptide sequence deduced from the gene showed the amino acid variations, physicochemical properties and secondary and tertiary structural features of the protein. The full BRM gene was transformed to prokaryotic vector pET32b and expressed in Escherichia coli BL21 DE3pLysS host cells successfully. The identity of the recombinant bromelain (rBRM) protein was confirmed by Western blot analysis using anti-BRM-rabbit IgG antibody. The activity of recombinant bromelain compared with purified native bromelain was determined by protease assay. The inhibitory effect of rBRM compared with native BRM in the growth of Gram-positive and Gram-negative strains of Streptococcus agalactiae and Escherichia coli O111 was evident from the antibacterial sensitivity test. To the best of our knowledge, this is the first report showing the bactericidal property of rBRM expressed in a prokaryotic system. PMID- 23921699 TI - Getting ready for preschool: linking early intervention and family mental health for infants and toddlers with developmental delay. PMID- 23921700 TI - Temporal lobe arteriovenous malformations: surgical outcomes with a focus on visual field defects and epilepsy. AB - BACKGROUND: Temporal lobe arteriovenous malformations (AVMs) represent a subgroup of intracranial AVMs with particular characteristics and management issues. OBJECTIVE: To characterize the surgical outcomes of temporal lobe AVMs with emphasis on visual field deficits (VFDs) and seizures. METHODS: Between 1992 and 2008, 29 patients were operated on for temporal lobe AVMs. Patient data were retrospectively collected and analyzed. RESULTS: Twelve of 29 patients (41.4%) presented with seizures and 4 (13.7%) presented with VFDs. Postoperatively, 6 patients (24%) showed new VFDs and 2 improved, with a rate of preservation of full visual fields of 84%. Larger AVMs (> 3 cm) were significantly associated with postoperative VFD (P = .008). Epilepsy outcomes assessed by the Engel scale were as follows: 9 patients (75%) were in class I (seizure free), 1 patient (8.3%) was in class III, and 2 patients (16.6%) were in class IV (no change or worsening). Postoperative modified Rankin Scale outcomes were excellent (grade 0 1) in 18 patients, good (grade 2) in 7, and poor (grade 3-4) in 4. Older age at diagnosis correlated with a worse functional outcome (Spearman rho = 0.369; P = .049). AVMs were totally removed in 27 of 29 patients (93.1%). Complete surgical excision was confirmed with angiography. Two patients needed reoperation for AVM remnant. Three patients had persistent hemiparesis (10.3% permanent morbidity). There was no mortality. CONCLUSION: Seizure control is usually underappreciated in the surgical management of AVMs. However, in temporal lobe AVMs, good outcomes with low morbidity and good visual field preservation can be accomplished. PMID- 23921701 TI - Resolution of diminished olfactory sensation after treatment of bilateral ophthalmic segment aneurysms with flow diversion: case report. AB - BACKGROUND AND IMPORTANCE: Olfactory tract dysfunction due to an unruptured intracranial aneurysm is rare. We present a case in which a patient with impaired olfaction related to bilateral internal carotid artery aneurysms experienced subjective and quantitative objective improvement of olfactory sensation after treatment of ophthalmic segment aneurysms with flow diversion. CLINICAL PRESENTATION: A 44-year-old woman presented with hyposmia and bilateral ophthalmic segment internal carotid artery aneurysms. The symptom of hyposmia, worsening over a period of several months, was suspected to be due to mass effect from bilateral unruptured ophthalmic segment aneurysms pressing on the olfactory tracts. Each aneurysm was treated with a Pipeline embolization device (PED). Follow-up angiography at 5 months showed occlusion of both aneurysms. The patient experienced subjective improvement in olfaction and complete objective resolution of her hyposmia as measured by the validated University of Pennsylvania Smell Identification Test (UPSIT). CONCLUSION: Intracranial aneurysms causing dysfunction of olfactory sensation due to mass effect upon the olfactory tract can be successfully treated with flow diversion. Flow diversion should be considered as one of the treatment options for patients with cranial nerve dysfunction due to unruptured intracranial aneurysms. PMID- 23921702 TI - Surgical treatment of 127 anterior choroidal artery aneurysms: a cohort study of resultant ischemic complications. AB - BACKGROUND: The anterior choroidal artery (AChA) supplies important areas of the nervous system, particularly the posterior limb of the internal capsule and optic radiation. Treatment of AChA aneurysms poses particular challenges because of the complex anatomy of the aneurysm associated with the relatively small diameter of AChAs, making preservation of the parent vessel during clip ligation or endosaccular coiling challenging. OBJECTIVE: To investigate the incidence and features of ischemia in treatment of AChA aneurysms. METHODS: A prospectively maintained database of patients who underwent treatment of aneurysms from 1985 to 2011 was queried to find patients with AChA aneurysms. Age, sex, Hunt and Hess grade, treatment modality, and complications were analyzed by use of the unpaired Student t test and Fisher exact test. RESULTS: One hundred twenty-two patients harbored 127 AChA aneurysms, and 67% (82 of 122) had multiple aneurysms. Treatment included 112 microsurgical clip ligations, 8 endosaccular coil embolizations, 5 aneurysmal wrappings, and 2 surgical explorations. Complications developed in 53% (67 of 127) of AChA aneurysms. Postoperative ischemia occurred in 12% (15 of 127) of treated aneurysms. The number of temporary clip applications was most closely associated with postoperative ischemia. Glasgow Outcome Scale scores of 4 or 5 were obtained by 78% at discharge, 89% at 6 months, and 85% at 1 year. CONCLUSION: The ischemic complication rate from surgical treatment of AChA aneurysms is most closely associated with higher frequency of temporary clip applications for proximal control and may be lower than previously reported. Supplementary intraoperative tools and limitation of vessel manipulation should be used to improve outcomes. PMID- 23921703 TI - Surgical outcomes of trigeminal neuralgia in patients with multiple sclerosis. AB - BACKGROUND: Trigeminal neuralgia (TN) is relatively frequent in multiple sclerosis (MS) patients and can be extremely disabling. Surgical interventions are less effective for the treatment of MS-related TN compared with classic TN, and higher recurrence rates are observed. OBJECTIVE: To evaluate initial pain free response (IPFR), duration of pain-free intervals (PFIs), and factors predictive of outcome in different surgical modalities used to treat MS-related TN. METHODS: A total of 96 MS patients underwent 277 procedures (range, 1-11 procedures per patient) to treat TN at our institution from 1995 to 2011. Of these, 89 percutaneous retrogasserian glycerol rhizotomies, 82 balloon compressions, 52 stereotactic radiosurgeries, 28 peripheral neurectomies, 15 percutaneous radiofrequency rhizotomies, and 10 microvascular decompressions were performed as upfront or repeat treatments. RESULTS: Bilateral pain was observed in 10% of patients during the course of disease. During the follow-up period (median, 5.7 years), recurrence of symptoms was seen in 66% of patients, and 181 procedures were performed for symptom recurrence. As an initial procedure, balloon compression had the highest IPFR (95%; P = .006) and median PFI (28 months; P = .05), followed by percutaneous retrogasserian glycerol rhizotomy (IPFR, 74%, P = .04; median PFI, 9 months; P = .05). In general, repeat procedures had lower effectiveness compared with initial procedures, with no statistically significant difference seen across the various treatment modalities. CONCLUSION: Treatment failure occurs in most of the MS-related TN patients independently of the type of treatment. However, balloon compression had the highest rate of IPFR and PFI compared with other modalities in the initial treatment of MS-related TN. PMID- 23921704 TI - Inferior short-term safety profile of endoscopic third ventriculostomy compared with ventriculoperitoneal shunt placement for idiopathic normal-pressure hydrocephalus: a population-based study. AB - BACKGROUND: In small series, endoscopic third ventriculostomy (ETV) has been shown to potentially have efficacy similar to that of ventriculoperitoneal shunting (VPS) for idiopathic normal-pressure hydrocephalus (iNPH). Therefore, some clinicians have advocated for ETV to avoid the potential long-term complications associated with VPS. Complication rates for these procedures vary widely based on limited small series data. OBJECTIVE: We used a nationwide database that provides a comprehensive investigation of the perioperative safety of ETV for iNPH compared with VPS. METHODS: We identified discharges with the primary diagnosis of iNPH (International Classification of Diseases, Ninth Revision code 331.5 [ICD-9]) with ICD-9 primary procedure codes for VPS (02.34) and ETV (02.2) from 2007 to 2010. We analyzed short-term safety outcomes using univariate and hierarchical logistic regression analyses. RESULTS: There were a total of 652 discharges for ETV for iNPH and 12,845 discharges for VPS for iNPH over the study period. ETV was associated with a significantly higher mortality (3.2% vs 0.5%) and short-term complication (17.9% vs 11.8%) rates than VPS despite similar mean modified comorbidity scores. On multivariate analysis, ETV alone predicted increased mortality and increased length of stay when adjusted for other patient and hospital factors. CONCLUSION: This is the first study that robustly assesses the perioperative complications and safety outcomes of ETV for iNPH. Compared with VPS, ETV is associated with higher perioperative mortality and complication rates. This consideration is important to weigh against the potential benefit of ETV: avoiding long-term shunt dependence. Prospective, randomized studies are needed. PMID- 23921705 TI - Use of buddy wire to facilitate Y-configured stent placement in middle cerebral artery bifurcation aneurysms with daughter branches arising from the sac: a technical note. AB - BACKGROUND AND IMPORTANCE: Endovascular treatment of geometrically complex bifurcation aneurysms using a standard Y-configured stenting technique might be extremely difficult, particularly in aneurysms with daughter branches that acutely arise from the aneurysm sac itself. In those cases, deployment of the second stent through interstices of the first stent could be troublesome because of untoward angular changes in the vascular bifurcation prompted by angular changes resulting from placement of the first stent. Here, we describe a novel application of the buddy wire technique to facilitate Y-configured stenting in middle cerebral artery (MCA) bifurcation aneurysms with unfavorable anatomic configuration. CLINICAL PRESENTATION: A 60-year-old man with a left-sided MCA bifurcation aneurysm was treated using the buddy wire technique. In addition to the standard Y-configured stenting procedure, we also inserted a 0.014-inch exchange microguidewire into the superior daughter branch, which more acutely emanated from the sac, to attain a favorable bifurcation configuration before deployment of the stents in the Y configuration. The new technique was successful, and the postprocedural course of the treatment was uneventful. CONCLUSION: Use of a buddy wire in MCA bifurcation aneurysms with unfavorable anatomic configurations may be a promising method to facilitate Y-configured stent placement. PMID- 23921706 TI - The A1-A2 diameter ratio may influence formation and rupture potential of anterior communicating artery aneurysms. AB - BACKGROUND: Specific morphological factors contribute to the hemodynamics of the anterior communicating artery (AComA). No study has examined the role of the A2 segment on AComA aneurysm presence and rupture. OBJECTIVE: To examine the possibility that the ratio between A1 and A2 segments (A1-2 ratio) represents an independent risk factor for presence and rupture of AComA aneurysms (AComAAs). METHODS: A retrospective review of an institutional aneurysm database was performed; patients with ruptured and unruptured AComAAs were identified. Two control groups were selected: group A (posterior circulation aneurysms) and group B (patients without intracranial aneurysms or other vascular malformations). Measurements of A1 and A2 diameters were obtained from digital subtraction angiography (64.1% of 3-D rotational digital subtraction angiography), and the A1 2 ratio calculated. RESULTS: From January 2009 to April 2011, 156 patients were identified (52 AComAAs, 54 control group A, and 50 control group B). Mean age at the time of presentation was 56.09 years. Compared with both control groups, patients with AComAAs had greater A1 diameter (P < .01) and A1-2 ratio (P < .001) and smaller A2 diameter (P < .01). The A1-2 ratio correlated positively with the presence of AComAAs (P < .001). Ruptured AComAAs were smaller than unruptured ones (5.91 mm vs 9.25 mm, P = .02) and associated with a higher A1-2 Ratio (P = .02). The presence of a dominant A1 did not predict AComAA rupture (P = .15). The A1-2 ratio correlated positively with the presence of ruptured AComAAs (P = .04). CONCLUSION: A1-2 ratio correlates positively with the presence and rupture of AComAAs and may facilitate treatment decision in cases of small, unruptured AComAAs. PMID- 23921707 TI - Less invasive pedicled omental-cranial transposition in pediatric patients with moyamoya disease and failed prior revascularization. AB - BACKGROUND: Patients with moyamoya disease and progressive neurological deterioration despite previous revascularization pose a major treatment challenge. Many have exhausted typical sources for bypass or have ischemia in areas that are difficult to reach with an indirect pedicled flap. Omental-cranial transposition has been an effective, but sparingly used technique because of its associated morbidity. OBJECTIVE: We have refined a laparoscopic method of harvesting an omental flap that preserves its gastroepiploic arterial supply. METHODS: The pedicled omentum can be lengthened as needed by dividing it between the vascular arcades. It is transposed to the brain via skip incisions. The flap can be trimmed or stretched to cover ischemic areas of the brain. The cranial exposure is performed in parallel with pediatric surgeons. We performed this technique in 3 pediatric patients with moyamoya disease (aged 5-12 years) with previous superficial temporal artery to middle cerebral artery bypasses and progressive ischemic symptoms. In 1 patient, we transposed omentum to both hemispheres. RESULTS: Blood loss ranged from 75 to 250 mL. After surgery, patients immediately tolerated a diet and were discharged in 3 to 5 days. The ischemic symptoms of all 3 children resolved within 3 months postoperatively. Magnetic resonance imaging at 1 year showed improved perfusion and no new infarcts. Angiography showed excellent revascularization of targeted areas and patency of the donor gastroepiploic artery. CONCLUSION: Laparoscopic omental harvest for cranial-omental transposition can be performed efficiently and safely. Patients with moyamoya disease appear to tolerate this technique much better than laparotomy. With this method, we can achieve excellent angiographic revascularization and resolution of ischemic symptoms. PMID- 23921708 TI - Robotics in keyhole transcranial endoscope-assisted microsurgery: a critical review of existing systems and proposed specifications for new robotic platforms. AB - BACKGROUND: Over the past decade, advances in image guidance, endoscopy, and tube shaft instruments have allowed for the further development of keyhole transcranial endoscope-assisted microsurgery, utilizing smaller craniotomies and minimizing exposure and manipulation of unaffected brain tissue. Although such approaches offer the possibility of shorter operating times, reduced morbidity and mortality, and improved long-term outcomes, the technical skills required to perform such surgery are inevitably greater than for traditional open surgical techniques, and they have not been widely adopted by neurosurgeons. Surgical robotics, which has the ability to improve visualization and increase dexterity, therefore has the potential to enhance surgical performance. OBJECTIVE: To evaluate the role of surgical robots in keyhole transcranial endoscope-assisted microsurgery. METHODS: The technical challenges faced by surgeons utilizing keyhole craniotomies were reviewed, and a thorough appraisal of presently available robotic systems was performed. RESULTS: Surgical robotic systems have the potential to incorporate advances in augmented reality, stereoendoscopy, and jointed-wrist instruments, and therefore to significantly impact the field of keyhole neurosurgery. To date, over 30 robotic systems have been applied to neurosurgical procedures. The vast majority of these robots are best described as supervisory controlled, and are designed for stereotactic or image-guided surgery. Few telesurgical robots are suitable for keyhole neurosurgical approaches, and none are in widespread clinical use in the field. CONCLUSION: New robotic platforms in minimally invasive neurosurgery must possess clear and unambiguous advantages over conventional approaches if they are to achieve significant clinical penetration. PMID- 23921709 TI - End-to-end reanastomosis technique for fusiform aneurysms: 3-dimensional operative video. PMID- 23921710 TI - Intracranial papillary meningioma: a clinicopathologic study of 30 cases at a single institution. AB - BACKGROUND: Papillary meningioma (PM) is an uncommon meningioma subtype, and the clinical characteristics remain unclear. OBJECTIVE: To determine the clinical characteristics and prognosis of PM. METHODS: The clinical data of 30 PM patients were collected, the samples were reexamined, and the patients' prognoses were based on clinical observations and calculated according to the Kaplan-Meier method. RESULTS: The 30 patients included 16 males and 14 females (median: 34.0 years upon initial diagnosis). Of the 48 intracranial operations in the 30 patients, total removal was attained in 34 surgeries, and subtotal removal in 14 surgeries. Radiotherapy was provided in 20 patients. In 40 specimens with follow up, 29 attained the positive aggressive factors. Six tumors showed positive progestogen receptor (PR) combined with negative Bcl-2. The median follow-up period was 39.0 months. Tumor recurrence occurred in 18 patients (median: 17.0 months); the recurrence rates following total removal and subtotal removal were 57.1% and 100%, respectively. Fourteen patients died of the recurrence. In the univariate analyses, positive aggressive factors (P = .021), positive PR combined with negative Bcl-2 immunoreactivity (P = .011), the extent of resection (P = .001), and radiotherapy (P = .002) were significantly related to progression-free survival. The MIB-1 labeling index was not significantly related to progression free survival (P = .88). CONCLUSION: PM is a rare subtype of meningioma with a tendency of recurrence. The extent of resection is an important prognosis factor. The presence of positive histopathological index increases the recurrence risk. Positive PR combined with negative Bcl-2 immunoreaction might predict a good prognosis. Postoperative radiotherapy may play a vital role in prolonging the time to tumor recurrence. PMID- 23921711 TI - Intradural extramedullary spinal metastases of non-neurogenic origin: a distinct clinical entity or a subtype of leptomeningeal metastasis? A case-control study. AB - BACKGROUND: Leptomeningeal metastases from carcinoma are still poorly understood. OBJECTIVE: To better define the management of unique intradural extramedullary spinal metastases (IESM) from solid cancers of non-neurogenic origin, in particular regarding leptomeningeal metastasis (LM). METHODS: We conducted a retrospective, multicenter, case-control study including 11 patients with IESM matched with 11 patients with LM. Primary endpoint was overall survival; secondary endpoints were diagnostic criteria and prognostic factors. RESULTS: Descriptive analysis showed a clinically significant difference between IESM and LM patients regarding preexisting neurological deficit (45.5% vs 90.1%, P = .06) and malignant cells in cerebrospinal fluid (0% vs 54.5%, P = .03). The median overall survival was significantly higher for IESM patients (732 days) than for patients with LM (53 days; P < .0002). Multivariate analysis showed that preexisting neurological deficit was a negative prognostic factor for overall survival (hazard ratio: 10.2; 95% confidence interval: 1.88-102; P = .04), in contrast to functional improvement with treatment (hazard ratio: 0.01; 95% confidence interval: 0.00-0.52; P = .04). We propose the following diagnostic criteria for IESM: (1) a solid lesion located within the intradural extramedullary space, (2) the absence of other leptomeningeal lesion seen on full spine injected magnetic resonance imaging, (3) the absence of malignant cells in cerebrospinal fluid, and (4) a histological confirmation of the metastatic nature of the lesion. CONCLUSION: The significant difference in survival between IESM and LM suggests that they are 2 distinct evolutions of the metastatic disease. Distinguishing IESM also has therapeutic consequences because patients can benefit from a focal surgical treatment with functional improvement and extended survival. PMID- 23921712 TI - Reply to Aspirin is associated with lower melanoma risk among postmenopausal Caucasian women: the Women's Health Initiative. PMID- 23921713 TI - Management strategies for intraprocedural coil migration during endovascular treatment of intracranial aneurysms. AB - Migration of a coil during endovascular treatment of intracranial aneurysm occurs in 2-6% of cases. The consequences of coil migration vary significantly from minor flow alterations of the parent artery which are asymptomatic to thromboembolic occlusion of major intracranial vessels resulting in large territory infarcts. We performed a comprehensive literature review and identified 37 reported cases of migrated coil retrieval consisting of 10 case reports and six case series. Most of the aneurysms presented with rupture (65%) and were located in the anterior circulation (70%). The endovascular treatment approaches were coil embolization alone (57%), stent-assisted coiling (26%) and balloon remodeling (17%). Endovascular retrieval was performed with microwires, the Alligator Retrieval device, Merci devices, snares and stentrievers. There was a single report of microsurgical extraction following failed endovascular removal and three cases of coil fracture in which the coil fragments were secured to the vessel walls with stents. PMID- 23921714 TI - Metabolism of radiolabeled methionine in hepatocellular carcinoma. AB - PURPOSE: Radiolabeled methionine (Met) promises to be useful in the positron emission tomography (PET) imaging of hepatocellular carcinoma (HCC). However, its metabolic routes in HCC have not yet been fully understood. In this study, the metabolic pathway(s) of radiolabeled Met in HCC were investigated. PROCEDURES: To simulate the rapid blood clearance of radiolabeled Met, pulse-chase experiments were conducted. L-[methyl-(3)H]-Met or L-[1-(14)C]-Met was pulsed over control or cycloheximide-treated WCH17 cells and rat hepatocytes for 5 min and chased with cold media. The water-soluble, lipid-soluble, DNA, RNA, and protein phases were subsequently extracted and measured from the acid-precipitable and acid-soluble fractions of whole cells. The radioactive metabolites Met, S-adenosylmethionine (SAM), S-adenosylhomocysteine, Met sulfoxide, and Met sulfone were further separated by radio thin layer chromatography. RESULTS: (1) The uptake of L [methyl-(3)H]-Met in both cell types was higher than that of L-[1-(14)C]-Met. In rat hepatocytes, the uptake of L-[methyl-(3)H]-Met was significantly higher than that of L-[1-(14)C]-Met, which may contribute to its physiologic accumulation in surrounding hepatic tissues seen in PET imaging of HCC using L-[methyl-(11)C] Met. Compared to rat hepatocytes, WCH17 cells had significantly higher uptake of both radiotracers. (2) For L-[methyl-(3)H]-Met, the major intracellular uptake was found mostly in the protein phase and, to a lesser degree, in the phosphatidylethanolamine (PE) methylation pathway, which is fairly stabilized within the 55-min chase period (the main metabolites were SAM, Met, Met sulfoxide, and Met sulfone). In contrast, the uptake of Met in rat hepatocytes mainly points to phosphatidylcholine (PC) synthesis through the PE methylation pathway (the main metabolite was PC). (3) Both cell types incorporated L-[1 (14)C]-Met predominantly into protein synthesis. (4) Finally, when the protein synthesis pathway was inhibited, the incorporation of SAM derived from L-[methyl (3)H]-Met to lipid class (PC was the main metabolite) occurred at a reduced rate in WCH17 cells, suggesting that the route may be impaired in HCC. CONCLUSIONS: This study demonstrated that different metabolic pathways of radiolabeled Met exist between HCC and surrounding hepatic tissue and contribute to the patterns of increased uptake of radiolabeled Met in HCC. PMID- 23921716 TI - An analytical comparison of the principal component method and the mixed effects model for association studies in the presence of cryptic relatedness and population stratification. AB - The principal component method and the mixed effects model represent two popular approaches to controlling for population structure and cryptic relatedness in genetic association studies. There are only a handful of studies comparing their performance. These studies are typically based on simulation studies and the results are therefore limited in their applicability. In this paper, we conduct an analytical comparison of these two approaches in the presence of cryptic relatedness and population structure in terms of their validity and efficiency. In the presence of cryptic relatedness, we show that both methods are valid, but the mixed effects model is more powerful for detecting association. In the presence of population structure, however, we show that both methods can be invalid. The biases and variances of the estimates from the two methods are compared. Examples and simulation studies are provided to demonstrate the conclusions. PMID- 23921715 TI - Cell density-induced changes in lipid composition and intracellular trafficking. AB - Cell density is one of the extrinsic factors to which cells adapt their physiology when grown in culture. However, little is known about the molecular changes which occur during cell growth and how cellular responses are then modulated. In many cases, inhibitors, drugs or growth factors used for in vitro studies change the rate of cell proliferation, resulting in different cell densities in control and treated samples. Therefore, for a comprehensive data analysis, it is essential to understand the implications of cell density on the molecular level. In this study, we have investigated how lipid composition changes during cell growth, and the consequences it has for transport of Shiga toxin. By quantifying 308 individual lipid species from 17 different lipid classes, we have found that the levels and species distribution of several lipids change during cell growth, with the major changes observed for diacylglycerols, phosphatidic acids, cholesterol esters, and lysophosphatidylethanolamines. In addition, there is a reduced binding and retrograde transport of Shiga toxin in high density cells which lead to reduced intoxication by the toxin. In conclusion, our data provide novel information on how lipid composition changes during cell growth in culture, and how these changes can modulate intracellular trafficking. PMID- 23921717 TI - Levetiracetam compared with valproic acid for the prevention of postoperative seizures after supratentorial tumor surgery: a retrospective chart review. AB - INTRODUCTION: Antiepileptic drugs are commonly given for perioperative prophylaxis after brain tumor surgery, and there has been growing interest in levetiracetam, a second-generation antiepileptic drug. This retrospective study compared the seizure outcomes, side effects and durability of levetiracetam with valproic acid after a craniotomy for supratentorial brain tumors. METHODS: Between 2009 and 2012, 282 consecutive patients with a supratentorial brain tumor underwent a craniotomy at Seoul National University Bundang Hospital. Of these patients, 51 (18.1%) and 231 (81.9%) were pre-operatively administered levetiracetam and valproic acid, respectively. The postoperative seizure outcomes (within 1 month after surgery) and the long-term side effects of both drugs were evaluated. RESULTS: Of the 51 patients in the levetiracetam group, 4 (7.8%) experienced postoperative seizures after brain tumor surgery, and 15 (6.5%) of the 231 patients in the valproic acid group experienced postoperative seizures (p = 0.728). The long-term complication rate of the valproic acid group (26.8%; 62/231) was significantly higher than that of the levetiracetam group (9.8%; 5/51) [p = 0.010]. In the valproic acid group, 10 hepatotoxicities, 20 hyperammonemias and 10 hematologic abnormalities (6 thrombocytopenias, 3 pancytopenias, and 1 leucopenia) occurred. Moreover, 89 patients (38.5%) in the valproic acid group changed or added other anticonvulsants because of side effects or uncontrolled seizures, whereas only 9 patients (17.6%) in the levetiracetam group changed or added other anticonvulsants (p = 0.005). CONCLUSIONS: The postoperative seizure control rates of levetiracetam and valproic acid were not statistically significantly different; however, levetiracetam may be superior to valproic acid in terms of its safety and durability after supratentorial tumor surgery. PMID- 23921718 TI - Antioxidant phospholipid calix[4]arene mimics as micellular delivery systems. AB - Amphiphilic calix[4]arenes were designed as phospholipid mimics by incorporating PO3H2 or NMe3(+) head groups. Using PC12 cells and three stressors (H2O2, menadione and glutamate), we established safe calix[4]arene levels that are able not only to deliver antioxidant payloads of curcumin, but intriguingly also have inherent antioxidant properties. The calix[4]arenes appear to be potent synthetic antioxidants that could be used as nano-carriers for drug delivery. PMID- 23921719 TI - Is self-rated health still sensitive for changes in disease and functioning among nonagenarians? AB - OBJECTIVES: With age, there is an increasing gap between relatively stable levels of self-rated health (SRH) and actual health status. This study investigates longitudinal changes in SRH and examines its sensitivity to changes in chronic conditions and functioning among people aged 90 and older. METHODS: In the Vitality 90+ Study, questionnaires were sent to all people aged 90 years and older living in Tampere, Finland. Included were respondents who provided data on the 2001 measurement and at least one follow-up measurement in 2003, 2007, or 2010 (N = 334). Generalized Estimating Equations analyses examined longitudinal change in SRH and the predictive value of number of chronic conditions and a functioning score based on 5 activities. RESULTS: Within 2 years, most people (56.3%) had unchanged SRH, but declined SRH (22.3%) was associated with worse baseline functioning and declined functioning. Clear declines in SRH after 6 and 9 years were associated with increased chronic conditions (odds ratio [OR] = 1.23) and decreased functioning (OR = 1.28). The impact of chronic conditions and functioning was smaller among institutionalized people (chronic conditions OR = 0.90; functioning OR = 1.18) than among people living independently (chronic conditions OR = 1.30; functioning OR = 1.44). DISCUSSION: SRH among nonagenarians was sensitive to changes in the number of chronic conditions and functioning although more pronounced on the longer than on the shorter term. PMID- 23921720 TI - Role of HOXA9 and VEZF1 in endothelial biology. AB - Proper development of the vascular system as one of the earliest and most critical steps during vertebrate embryogenesis is ensured by the exact spatial and temporal control of gene expression in cells forming the vessel network. Whereas the regulation of vascular system development is well elucidated on the level of ligand-receptor signaling, the processes on the transcriptional level are much less understood. As the signaling mechanisms in embryogenesis and pathological conditions are similar, the study of embryonic blood vessel development is of great interest for the treatment of cardiovascular diseases and cancer. This review discusses two transcription factors, HOXA9 and VEZF1, which are relevant for endothelial biology but are excluded in the bulk of transcription factor references discussing endothelial biology. To our knowledge, there is no comprehensive overview of these two transcription factors available to date. Here, we summarize the current knowledge of human HOXA9 and VEZF1 biology and function, we detail their target genes and roles in endothelial biology and propose that HOXA9 and VEZF1 also deserve consideration as relevant transcriptional regulators of endothelial biology. Due to their broad role in multiple aspects of endothelial biology, they might potentially become interesting targets for therapeutic manipulation of pathological blood vessel growth. PMID- 23921722 TI - Cellular antioxidant effect of four bromophenols from the red algae, Vertebrata lanosa. AB - Three known bromophenols, 2,3-dibromo-4,5-dihydroxybenzylaldehyde (1), 2,2',3 tribromo-3',4,4',5-tetrahydroxy-6'-hydroxymethyldiphenylmethane (2) and bis(2, 3 dibromo-4,5-dihydroxylbenzyl) ether (3), and one new one, 5,5" oxybis(methylene)bis (3-bromo-4-(2',3'-dibromo-4',5'-dihydroxylbenzyl)benzene-1,2 diol) (4), were isolated from an extract of the red alga, Vertebrata lanosa. The antioxidant activity of these four bromophenols was examined using one biochemical and two cellular assays: Oxygen Radical Absorbance Capacity (ORAC), Cellular Antioxidant Activity (CAA) and Cellular Lipid Peroxidation Antioxidant Activity (CLPAA) assays. Compound 2 distinguished itself by showing potent activity, having a better antioxidant effect than luteolin in both the CAA and CLPAA assays and of quercetin in the CLPAA assay. Although several bromophenols are known to be potent antioxidants in biochemical assays, this is the first time their cellular antioxidant activity has been demonstrated. PMID- 23921721 TI - Hepatotoxic seafood poisoning (HSP) due to microcystins: a threat from the ocean? AB - Cyanobacterial blooms are a major and growing problem for freshwater ecosystems worldwide that increasingly concerns public health, with an average of 60% of blooms known to be toxic. The most studied cyanobacterial toxins belong to a family of cyclic heptapeptide hepatotoxins, called microcystins. The microcystins are stable hydrophilic cyclic heptapeptides with a potential to cause cell damage following cellular uptake via organic anion-transporting proteins (OATP). Their intracellular biologic effects presumably involve inhibition of catalytic subunits of protein phosphatases (PP1 and PP2A) and glutathione depletion. The microcystins produced by cyanobacteria pose a serious problem to human health, if they contaminate drinking water or food. These toxins are collectively responsible for human fatalities, as well as continued and widespread poisoning of wild and domestic animals. Although intoxications of aquatic organisms by microcystins have been widely documented for freshwater ecosystems, such poisonings in marine environments have only occasionally been reported. Moreover, these poisonings have been attributed to freshwater cyanobacterial species invading seas of lower salinity (e.g., the Baltic) or to the discharge of freshwater microcystins into the ocean. However, recent data suggest that microcystins are also being produced in the oceans by a number of cosmopolitan marine species, so that Hepatotoxic Seafood Poisoning (HSP) is increasingly recognized as a major health risk that follows consumption of contaminated seafood. PMID- 23921723 TI - Magnetic resonance imaging for rapid screening for the nephrotoxic and hepatotoxic effects of microcystins. AB - In vivo visualization of kidney and liver damage by Magnetic Resonance Imaging (MRI) may offer an advantage when there is a need for a simple, non-invasive and rapid method for screening of the effects of potential nephrotoxic and hepatotoxic substances in chronic experiments. Here, we used MRI for monitoring chronic intoxication with microcystins (MCs) in rat. Male adult Wistar rats were treated every other day for eight months, either with MC-LR (10 MUg/kg i.p.) or MC-YR (10 MUg/kg i.p.). Control groups were treated with vehicle solutions. T1 weighted MR-images were acquired before and at the end of the eight months experimental period. Kidney injury induced by the MCs presented with the increased intensity of T1-weighted MR-signal of the kidneys and liver as compared to these organs from the control animals treated for eight months, either with the vehicle solution or with saline. The intensification of the T1-weighted MR signal correlated with the increased volume density of heavily injured tubuli (R2 = 0.77), with heavily damaged glomeruli (R2 = 0.84) and with volume density of connective tissue (R2 = 0.72). The changes in the MR signal intensity probably reflect the presence of an abundant proteinaceous material within the dilated nephrons and proliferation of the connective tissue. T1-weighted MRI-is a valuable method for the in vivo screening of kidney and liver damage in rat models of intoxication with hepatotoxic and nephrotoxic agents, such as microcystins. PMID- 23921725 TI - Adding fat to the fire. PMID- 23921724 TI - Less is more: combination antibiotic therapy for the treatment of gram-negative bacteremia in pediatric patients. AB - IMPORTANCE: Definitive combination antibiotic therapy with a beta-lactam and an aminoglycoside for the treatment of gram-negative bacteremia is commonly prescribed in pediatric patients; however, its efficacy and toxicity relative to beta-lactam monotherapy are unknown. OBJECTIVE: To determine whether definitive combination antibiotic therapy affects mortality and nephrotoxicity in pediatric patients with gram-negative bacteremia. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study including pediatric patients (aged <=18 years) with gram-negative bacteremia hospitalized at the Johns Hopkins Children's Center between 2002 and 2011. MAIN OUTCOMES AND MEASURES: Outcomes included 30-day mortality and nephrotoxicity classified according to the pediatric RIFLE (risk for renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage renal disease) criteria. To account for nonrandom assignment of combination therapy, propensity score weighting was combined with multivariable logistic regression to estimate the effect of combination therapy on mortality and nephrotoxicity. RESULTS: Of the 879 eligible pediatric patients with bacteremia, 537 (61.1%) received combination therapy. After propensity score adjustment, baseline demographic and clinical characteristics between the groups were well balanced. There was no association between combination therapy and 30 day mortality (odds ratio, 0.98; 95% CI, 0.93-1.02; P = .27). There were 170 patients (19.3%) with evidence of acute kidney injury, including 135 (25.1%) and 35 (10.2%) in the combination therapy and monotherapy arms, respectively. Patients receiving combination therapy had approximately twice the odds of nephrotoxicity compared with those receiving monotherapy (odds ratio, 2.15; 95% CI, 2.09-2.21). CONCLUSIONS AND RELEVANCE: The use of beta-lactam monotherapy for gram-negative bacteremia in pediatric patients reduces subsequent nephrotoxicity without compromising survival. PMID- 23921726 TI - Myriad sues developers of competing breast cancer tests. PMID- 23921727 TI - US National Cancer Institute's new Ras project targets an old foe. PMID- 23921728 TI - Uncommon ventures launch to tackle uncommon diseases. PMID- 23921729 TI - Lack of small animal model hinders MERS coronavirus research. PMID- 23921730 TI - Trials challenging HIV drug doses could usher in huge cost cuts. PMID- 23921731 TI - Bacteria-killing dispute casts doubt on antibiotic development. PMID- 23921732 TI - Straight talk with...Sir John Chisholm. Interview by Elie Dolgin. PMID- 23921735 TI - A future, on ice. PMID- 23921736 TI - A little better than placebo is still better than nothing. PMID- 23921738 TI - The origin of scar-forming kidney myofibroblasts. PMID- 23921739 TI - A step toward functionally characterized prostate cancer molecular subtypes. PMID- 23921740 TI - LRH-1: orphaned, adopted and needed for pregnancy. PMID- 23921741 TI - Obesity Notches up fatty liver. PMID- 23921742 TI - Huntington's disease: easing the NMDAR traffic jam. PMID- 23921743 TI - Modulating malaria with Wolbachia. PMID- 23921744 TI - Eosinophils in the spotlight: Finding the link between obesity and asthma. PMID- 23921745 TI - Eosinophils in the spotlight: Eosinophilic airway inflammation in nonallergic asthma. PMID- 23921755 TI - Backbone and side chain NMR assignments for the ribosome assembly factor Nop6 from Saccharomyces cerevisiae. AB - The Saccharomyces cerevisiae Nop6 protein is involved in the maturation of the small ribosomal subunit. It contains a central RNA binding domain and a predicted C-terminal coiled-coil domain. Here we report the almost complete (>90%) (1)H,(13)C,(15)N backbone and side chain NMR assignment of a 15 kDa Nop6 construct comprising the RNA binding and coiled-coil domains. PMID- 23921756 TI - Advance care planning: putting an end to the agonizing perpetuation of a pointless debate. PMID- 23921754 TI - Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. AB - Human pluripotent stem cells (PSCs) are a leading candidate for cell-based therapies because of their capacity for unlimited self renewal and pluripotent differentiation. These advances have recently culminated in the first-in-human PSC clinical trials by Geron, Advanced Cell Technology and the Kobe Center for Developmental Biology for the treatment of spinal cord injury and macular degeneration. Despite their therapeutic promise, a crucial hurdle for the clinical implementation of human PSCs is their potential to form tumors in vivo. In this Perspective, we present an overview of the mechanisms underlying the tumorigenic risk of human PSC-based therapies and discuss current advances in addressing these challenges. PMID- 23921757 TI - Cancer patients and advance directives: a survey of patients in a hematology and oncology outpatient clinic. AB - BACKGROUND: In 2009, Germany enacted a new law supporting advance directives that led to heated discussions in the media and the public. 3 years after the law passed, we surveyed patients with malignant diseases with regards to their views on advance directives. PATIENTS AND METHODS: Between September 2011 and July 2012 an anonymous survey on advance directives was conducted among 617 patients at the hematology and oncology outpatient department of the University Hospital Mannheim, using a standardized questionnaire developed for this investigation. RESULTS: Of the 503 patients who returned the questionnaire, 31% (n = 157) indicated having an advance directive. Of these 157, 54% (n = 85) completed the advance directive after 2009. 56% (282 out of 503) desired more information on advance directives. Of these, 71% (201 out of 282) wanted their general physician and 45% (128 out of 282) their specialist, to provide more information about this issue. Of the 339 patients without an advance directive, 47% (n = 158) stated that they had 'not worried about that yet'. CONCLUSION: Although the percentage of patients with advance directives has increased since the legislative amendment, more information is still required by patients. It is recommended that physicians should discuss advance directives more frequently with their patients. PMID- 23921753 TI - The role of autophagy in neurodegenerative disease. AB - Autophagy is a lysosomal degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and protein aggregates. These substrates reach lysosomes by several distinct mechanisms, including delivery within endosomes as well as autophagosomes. Completion of digestion involves dynamic interactions among compartments of the autophagic and endocytic pathways. Neurons are particularly vulnerable to disruptions of these interactions, especially as the brain ages. Not surprisingly, mutations of genes regulating autophagy cause neurodegenerative diseases across the age spectrum with exceptional frequency. In late-onset disorders such as Alzheimer's disease, amyotrophic lateral sclerosis and familial Parkinson's disease, defects arise at different stages of the autophagy pathway and have different implications for pathogenesis and therapy. This Review provides an overview of the role of autophagy in neurodegenerative disease, focusing particularly on less frequently considered lysosomal clearance mechanisms and their considerable impact on disease. Various therapeutic strategies for modulating specific stages of autophagy and the current state of drug development for this purpose are also evaluated. PMID- 23921758 TI - Fatigue in the general population of Colombia - normative values for the multidimensional fatigue inventory MFI-20. AB - BACKGROUND: Fatigue is a frequent symptom in cancer patients. In Europe and Northern America fatigue questionnaires were developed and tested, but their generalizability to other cultural contexts is largely unknown. The aim of this study is to provide normative values for the Multidimensional Fatigue Inventory (MFI-20) based on a representative sample of the general population in Colombia and to test psychometric properties. METHODS: 1,500 individuals completed a questionnaire that contained the MFI-20, as well as other questionnaires, and questions on sociodemographic variables and chronic diseases. RESULTS: The mean values of the scales were marginally higher than those for 2 European samples. The mean value of the total score was 44.3 +/- 14.1. Women were affected by fatigue more than men, and there was an almost linear age trend, with higher mean scores for older subjects. People with chronic diseases were affected by fatigue more than people without chronic conditions. The best psychometric properties were obtained for the total scale (sum score) of the MFI-20. CONCLUSION: The normative values presented here can help us to assess the individual burden of fatigue in a Latin American context. Psychometric properties of the MFI-20 in Colombia are similar to those obtained in Europe. PMID- 23921759 TI - Old wine in new pipes? Treatment of advanced non-small cell lung cancer with trofosfamide. AB - BACKGROUND: The aim of this retrospective study was to examine the effect of oral trofosfamide in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with histologically or cytologically proven NSCLC, who had received at least 2 other therapies, were enrolled. The primary clinical end point was progression-free survival (PFS); secondary end points included overall survival (OS), response rate and toxicity. RESULTS: 23 patients were enrolled, 1 of whom was excluded due to non-compliance. The patients had received a median of 3 prior therapies (range 2-4). Regarding all 22 patients, median PFS was 14 weeks (95% confidence interval (CI) 9.96-18.04). The median OS was 32 weeks (95% CI 17.12-46.88). The median duration of trofosfamide therapy was 10.5 weeks (interquartile range 6.5-17.3). 20 patients (90.9%) had stable disease; 2 were not assessable. Trofosfamide therapy was stopped in 4 patients (18.2%) due to side effects. CONCLUSION: Trofosfamide is an orally applicable, well-tolerated and cost-effective drug that works in patients with advanced NSCLC, who have undergone at least 2 lines of therapy. Trofosfamide seems to be a therapeutic option in NSCLC as a further therapy line. These preliminary data need to be confirmed in a larger trial. PMID- 23921760 TI - Gemcitabine and docetaxel for metastatic soft tissue sarcoma - a single center experience. AB - BACKGROUND: Prognosis and survival for patients with metastatic soft tissue sarcoma (STS) are dismal. Standard first-line systemic chemotherapy is anthracycline-based. Gemcitabine/docetaxel (GD) is a therapeutic option in the second-line setting. Here we present the data of our single center retrospective analysis, using GD in locally advanced or metastatic disease. PATIENTS AND METHODS: Between 2005 and 2012, a total of 34 patients were identified. The majority of tumors were located in the extremities (19/34, 56%) and abdomen/retroperitoneum (10/34, 29%). Most frequent histologies included leiomyosarcoma (13/34, 38%), liposarcoma (7/34, 21%), and pleomorphic sarcoma (6/34, 18%). RESULTS: Objective response to treatment by RECIST criteria after 3 cycles was low with 6% partial responses (PR, 2/34), 65% stable disease (SD, 22/34), and 29% progressive disease (PD, 10/34). Progression-free survival at 3 and 6 months was 77 and 62%, respectively. Patients with a clinical benefit (defined as PR or SD after the 3rd treatment cycle) had a significantly prolonged median progression-free and overall survival with 8.6 months (p < 0.0001; hazard ratio (HR) 33.1) and 22.4 months (p < 0.0001; HR 12.9), respectively. Most common toxicities included hand-foot syndrome, edema, pancytopenia, febrile neutropenia, and mucositis. CONCLUSION: Overall, we conclude that GD is an active second-line regimen in metastatic STS, with manageable side effects. PMID- 23921761 TI - 5-Fluorouracil, mitomycin-c, and polysaccharide-k versus uracil-ftorafur and polysaccharide-K as adjuvant chemoimmunotherapy for patients with locally advanced gastric cancer with curative resection. AB - BACKGROUND: Despite the small but significant survival benefit of adjuvant chemotherapy in locally advanced gastric cancer (LAGC), the optimal regimen remains to be determined. We conducted a randomized trial comparing oral (PO) chemoimmunotherapy (CITX) with intravenous (IV) CITX in LAGC patients (stages IB IIIB) with curative resection (>= D2 dissection). METHODS: The patients were randomized to the IV (5-fluorouracil 500 mg/m(2) weekly for 24 weeks, mitomycin-C 8 mg/m(2) every 6 weeks * 4) or the PO (uracil-ftorafur (UFT) 400-600 mg/day for 12 months) group. Patients in both groups received PO polysaccharide-K (3 g/day for 4 months). The planned number of patients was 368 for proving the non inferiority of PO CITX compared to IV CITX for overall survival. RESULTS: The trial was closed prematurely after enrolling 82 patients (44 in the IV group, 38 in the PO group). With a median follow-up of 82 months, there were no significant differences in the 5-year disease-free survival (73% vs. 55%, p = 0.358) and overall survival (77% vs. 66%, p = 0.159) between the 2 groups. The IV group demonstrated a higher incidence of grade 2 or 3 neutropenia, thrombocytopenia, and vomiting. CONCLUSIONS: PO CITX with UFT appeared to be at least non-inferior to 5-fluorouracil and mitomycin-C CITX, with lower toxicity in the adjuvant treatment for LAGC. PMID- 23921762 TI - Primary intracranial small cell carcinoma: a case report and review of the literature. AB - BACKGROUND: Extrapulmonary small cell carcinoma is a distinct clinicopathological entity accounting for only 2.5-4% of small cell carcinomas. Here we present a case of primary intracranial small cell carcinoma. CASE REPORT: A 69-year-old woman with an isolated brain lesion presented with progressive headaches, confusion, nausea, and vomiting. A magnetic resonance imaging scan of the brain revealed a 4 * 3 * 5-cm solitary cystic tumor in the right frontoparietal lobe, accompanied by a midline shift. The mass was resected and pathologically proven to be a small cell carcinoma. The patient was given adjuvant radiotherapy but refused any chemotherapy. At the 12-month follow-up the patient was alive and well. CONCLUSION: Primary intracranial small cell carcinoma presenting as an isolated lesion is extremely rare. While there are no standard treatment guidelines for these patients, the authors believe multimodality treatment including tumorectomy and postoperative radiotherapy should be recommended. PMID- 23921763 TI - Exploration of the role of radiotherapy in the management of early glottic cancer with complete carotid artery occlusion. AB - BACKGROUND: The aim of this study was to compare intensity-modulated radiation therapy (IMRT) vs. 2D and 3D radiotherapy (RT) in the treatment of T1 glottic squamous cell carcinoma in an effort to highlight the advantages of IMRT in this particular clinical situation. CASE REPORT: We present the case of an 82-year-old female patient with T1 left true vocal cord squamous cell carcinoma and complete occlusion of the left carotid artery resulting in multiple strokes. The patient underwent definitive RT with 63 Gy (28 * 2.25 Gy). 3 plans were generated: 2D RT, 3D RT, and IMRT. The right carotid artery (Rt.CA) mean dose was 865, 2,065, and 4,268 cGy for IMRT, 3D RT, and 2D RT, respectively. The inferior pharyngeal constrictor (IPC) mean dose was 5,341, 6,456, and 6,451 cGy for IMRT, 3D RT, and 2D RT, respectively. IMRT provided the best homogeneity but at a higher cost and with prolonged treatment time. CONCLUSION: IMRT provided the finest planning target volume coverage with minimal Rt.CA and IPC doses. IMRT is recommended in certain clinical scenarios which are not manageable with other techniques. PMID- 23921764 TI - Fertility-sparing surgery in ovarian cancer: a systematic review. AB - BACKGROUND: Ovarian cancer is rarely diagnosed in women of reproductive age; however, this coincidence seems to increase due to changes in lifestyle. Available evidence on the prognostic impact of fertility-sparing surgery (FSS) is sparse, and there is an emerging need to consolidate such evidence. MATERIALS AND METHODS: Systematic review of the literature, including testing for heterogeneity and meta-analytical odds ratio (OR) calculations. RESULTS: 15 studies comprising 913 patients met the inclusion criteria for this review. Out of the 913 patients undergoing FSS, 11.4% developed recurrence during observation. Stage IB/C tumors were nearly twice as likely to recur as stage IA tumors (OR 1.72, 95% confidence interval (CI) 1.12-2.64, p < 0.05), and the risk of recurrence was 4 times higher in G2/3 compared to G1 tumors (4.26, 95% CI 2.31-7.86, p < 0.0001; and stage IC/G2/3 vs. stage IC/G1: OR 2.04, 95% CI 0.86-4.85, p > 0.05). A non-significant risk elevation was attributed to stage IC/G1 compared to stage IA/G1 (OR 1.48, 95% CI 0.66-3.16, p > 0.05). CONCLUSIONS: FSS with unilateral salpingo oophorectomy is only advisable for unilateral grade 1 tumors. Further studies employing contemporary classification criteria, such as low- versus highgrade malignancies, a strictly standardized regimen of surgical staging, and meticulous reporting of recurrence localization, may help develop more differentiated recommendations. PMID- 23921765 TI - Temozolomide-related hematologic toxicity. AB - Temozolomide (TMZ) is an oral alkylating agent used for the treatment of recurrent or newly diagnosed malignant gliomas with significant survival benefit. TMZ is generally well tolerated and safe. The most common side effects are mild to moderate, and are represented by fatigue, nausea, vomiting, thrombocytopenia, and neutropenia. However severe hematologic adverse events (HAEs), including myelodysplastic syndrome and aplastic anemia, have also been reported. In this review we present an overview of the available literature of HAEs after exposure to TMZ. PMID- 23921766 TI - microRNA-21 and its emerging role in tumor progression in systemic malignancies. PMID- 23921767 TI - Ultrasound as a diagnostic tool in detecting active Crohn's disease: a meta analysis of prospective studies. AB - OBJECTIVES: To evaluate the diagnostic accuracy of ultrasound in assessing active Crohn's disease (CD) in adults. METHODS: We systematically searched PubMed, EMBASE, Web of Science and the Cochrane Library for prospective studies in which ultrasound was performed to evaluate active CD in adults from January 1993 to April 2013. Pooled sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-) and diagnostic odds ratios (DORs) in a per-patient-based analysis were estimated. Additionally, the area under the receiver-operating characteristic (ROC) curve was calculated to measure the diagnostic accuracy of ultrasound in patients with known or suspected CD. RESULTS: Fifteen studies involving 1,558 patients were included in this meta-analysis. Overall, the pooled sensitivity (0.88) and LR- (0.14) were not heterogeneous, whereas the pooled specificity (0.97, I(2) = 72.9 %) and LR + (15.10, I(2) = 71.8 %) were. The DOR of ultrasound for assessing active CD was 121.70, with significant heterogeneity (I(2) = 63.3 %). A symmetrical summary ROC curve was plotted showing that the area under the curve was 0.94, indicating good diagnostic accuracy. Meta regression and subgroup analysis showed that the disease location may be a major cause of heterogeneity. CONCLUSIONS: This meta-analysis suggests that ultrasound has high diagnostic accuracy in detecting active CD in adults, especially for small bowel CD. KEY POINTS: * Ultrasound can detect active Crohn's disease (CD). * A meta-analysis of ultrasound for detecting active CD was carried out. * This revealed that ultrasound has high diagnostic accuracy for detecting CD. PMID- 23921769 TI - Training the approximate number system improves math proficiency. AB - Humans and nonhuman animals share an approximate number system (ANS) that permits estimation and rough calculation of quantities without symbols. Recent studies show a correlation between the acuity of the ANS and performance in symbolic math throughout development and into adulthood, which suggests that the ANS may serve as a cognitive foundation for the uniquely human capacity for symbolic math. Such a proposition leads to the untested prediction that training aimed at improving ANS performance will transfer to improvement in symbolic-math ability. In the two experiments reported here, we showed that ANS training on approximate addition and subtraction of arrays of dots selectively improved symbolic addition and subtraction. This finding strongly supports the hypothesis that complex math skills are fundamentally linked to rudimentary preverbal quantitative abilities and provides the first direct evidence that the ANS and symbolic math may be causally related. It also raises the possibility that interventions aimed at the ANS could benefit children and adults who struggle with math. PMID- 23921770 TI - Adaptive memory: the mnemonic value of animacy. AB - Distinguishing between living (animate) and nonliving (inanimate) things is essential for survival and successful reproduction. Animacy is widely recognized as a foundational dimension, appearing early in development, but its role in remembering is currently unknown. We report two studies suggesting that animacy is a critical mnemonic dimension and is one of the most important item dimensions ultimately controlling retention. Both studies show that animate words are more likely to be recalled than inanimate words, even after the stimulus classes have been equated along other mnemonically relevant dimensions (e.g., imageability and meaningfulness). Mnemonic "tunings" for animacy are easily predicted a priori by a functional-evolutionary analysis. PMID- 23921771 TI - Necrotizing fasciitis and death following an insect bite. AB - A healthy man who presented to hospital with painful swelling of the left arm following a history of insect (tick) bite developed shock and died within 48 hours. The postmortem examination revealed swelling and desquamation of skin and erythema on the left arm extending below the elbow. The subcutaneous tissue was necrotic with healthy underlying muscles. Group A beta-hemolytic streptococcus was isolated from postmortem swabs of the infected tissue. Histopathologic changes were consistent with necrotizing fasciitis.Secondary bacterial infection is an important possible complication following insect bite, and a high degree of suspicion with aggressive early treatment is required in cases of necrotizing fasciitis to prevent fatalities. Both clinicians and pathologists need to be aware of this rare, rapidly fatal condition that may follow an insect bite. PMID- 23921772 TI - Over-a-century-old death investigation system in Sri Lanka: an appraisal for reforms. AB - Although the death investigation systems in the world are divergent, the prime objective of each system is to certify the cause of death and manner of unnatural and unexplained deaths. In addition, it provides evidence for the purpose of fair administration of justice and data for health sector regulation. Many jurisdictions recently underwent considerable review and made changes to their death investigation systems in accordance with modern innovation in medicine and science. This enhanced the quality of justice in those countries. The death investigation system in Sri Lanka was originally established in 1883 and is a modified model of the British coroners system. However, the system has not undergone significant revisions since then and is confined to an informal traditional framework. The scope of this article was to review the death investigation system in Sri Lanka with a view to amend it in accordance with the current global trends. PMID- 23921773 TI - Superimposition-based personal identification using skull computed tomographic images: application to skull with mouth fixed open by residual soft tissue. AB - We previously reported that superimposition of 3-dimensional (3D) images reconstructed from computed tomographic images of skeletonized skulls on photographs of the actual skulls afforded a match of skull contours, thereby demonstrating that superimposition of 3D-reconstructed images provides results identical to those obtained with actual skulls. The current superimposition procedure requires a skeletonized skull with mouth closed and thus is not applicable to personal identification using a skull with residual soft tissue or the mouth fixed open, such as those found in mummified or burned bodies. In this study, we scanned using computed tomography the skulls of mummified and immersed body with mandibles fixed open by residual soft tissue, created 3D-reconstructed skull images, which were digitally processed by computer software to close the mandible, and superimposed the images on antemortem facial photographs. The results demonstrated morphological consistency between the 3D-reconstructed skull images and facial photographs, indicating the applicability of the method to personal identification. PMID- 23921774 TI - Sudden death and isolated right ventricular noncompaction cardiomyopathy: report of 2 autopsied adult cases. AB - A predominantly right ventricular variant of isolated noncompaction cardiomyopathy is a potentially lethal disease entity, which only recently has become recognized in the clinical and cardiac imaging literature. There are currently few established morphologic criteria for the diagnosis other than right ventricular dilation and presence of excessive regional trabeculation. To date, there have been no autopsy reports of cases following either clinical diagnosis or sudden death. We report 2 adult cases of sudden unexpected death in which unexplained right ventricular dilation and prominent apical hypertrabeculation were the principal findings. The gross and microscopic results suggest pathological similarities between, or coexistence of, right ventricular noncompaction and arrhythmogenic right ventricular cardiomyopathies. PMID- 23921775 TI - Introduction to the POWER-UP supplement. PMID- 23921776 TI - Changes in eating, physical activity and related behaviors in a primary care based weight loss intervention. AB - OBJECTIVE: To examine changes in eating behaviors and physical activity, as well as predictors of weight loss success, in obese adults who participated in a 2 year behavioral weight loss intervention conducted in a primary care setting. DESIGN: A longitudinal, randomized controlled, multisite trial. SUBJECTS: Three hundred ninety obese (body mass index, 30-50 kg m(-2)) adults, >= 21 years, in the Philadelphia region. METHODS: Participants were assigned to one of three interventions: (1) Usual Care (quarterly primary care provider (PCP) visits that included education on diet and exercise); (2) Brief Lifestyle Counseling (quarterly PCP visits plus monthly lifestyle counseling (LC) sessions about behavioral weight control); or (3) Enhanced Brief LC (the previous intervention with a choice of meal replacements or weight loss medication). RESULTS: At month 24, participants in both Brief LC and Enhanced Brief LC reported significantly greater improvements in mean (+/- s.e.) dietary restraint than those in Usual Care (4.4 +/- 0.5, 4.8 +/- 0.5 and 2.8 +/- 0.5, respectively; both P-values <= 0.016). The percentage of calories from fat, along with fruit and vegetable consumption, did not differ significantly among the three groups. At month 24, both the Brief LC and Enhanced Brief LC groups reported significantly greater increases than usual care in energy expenditure (kcal per week) from moderately vigorous activity (+593.4 +/- 175.9, +415.4 +/- 179.6 and -70.4 +/- 185.5 kcal per week, respectively; both P-values <= 0.037). The strongest predictor of weight loss at month 6 (partial R(2)=33.4%, P<0.0001) and at month 24 (partial R(2)=19.3%, P<0.001) was food records completed during the first 6 months. Participants who achieved a 5% weight loss at month 6 had 4.7 times greater odds of maintaining a >= 5% weight loss at month 24. CONCLUSIONS: A behavioral weight loss intervention delivered in a primary care setting can result in significant weight loss, with corresponding improvements in eating restraint and energy expenditure. Moreover, completion of food records, along with weight loss at month 6, is a strong predictor of long-term weight loss. PMID- 23921777 TI - Effect of lifestyle intervention on cardiometabolic risk factors: results of the POWER-UP trial. AB - OBJECTIVE: To investigate the effects of three weight loss interventions on cardiometabolic risk factors, including blood pressure, lipids, glucose and markers of insulin resistance and inflammation. We also examined whether categories of incremental weight change conferred greater improvements on these parameters. METHODS: This 2-year trial was conducted in a primary care setting and included 390 obese participants who were randomly assigned to one of three interventions: (1) Usual Care (quarterly primary care provider (PCP) visits that included education about weight management); (2) Brief Lifestyle Counseling (quarterly PCP visits plus monthly behavioral counseling provided by a trained auxiliary health-care provider); or (3) Enhanced Brief Lifestyle Counseling (the same care as described for the previous intervention, plus weight loss medications or meal replacements). The primary outcome was change in cardiometabolic risk factors among groups. RESULTS: At month 24, participants in Enhanced Brief Lifestyle Counseling lost significantly more weight than those in Usual Care (4.6 vs 1.7 kg), with no other significant differences between groups. Enhanced Brief Lifestyle Counseling produced significantly greater improvements in high-density lipoprotein (HDL) cholesterol and triglyceride levels at one or more assessments, compared with the other two interventions. Markers of insulin resistance also improved significantly more in this group throughout the 2 years. Collapsing across the three groups, greater weight loss was associated with greater improvements in triglycerides, HDL cholesterol and markers of insulin resistance and inflammation at month 24, but was not significantly associated with reductions in blood pressure, total cholesterol and low-density lipoprotein cholesterol at any time. CONCLUSIONS: Enhanced Brief Lifestyle Counseling, which produced the largest weight loss, was generally associated with the greatest improvements in cardiovascular risk factors. These findings suggest that an intensive weight loss intervention, delivered in a primary care setting, can help obese individuals improve some cardiometabolic risk factors. PMID- 23921778 TI - The impact of a primary care-based weight loss intervention on the quality of life. AB - OBJECTIVE: This study investigated changes in the quality of life of men and women who participated in a primary care-based weight loss intervention program. METHODS: Participants were enrolled in a 2-year randomized clinical trial (POWER UP) conducted at the University of Pennsylvania and in six affiliated primary care practices. Inclusion criteria included the presence of obesity (body mass index of 30-50 kg m(-2)) and at least two components of the metabolic syndrome. MAIN OUTCOME MEASURES: Quality of life was assessed by three measures: the Short Form Health Survey (SF-12); the Impact of Weight on Quality of Life-Lite; and the EuroQol-5D. RESULTS: Six months after the onset of treatment, and with a mean weight loss of 3.9 +/- 0.3 kg, participants reported significant improvements on all measures of interest with the exception of the Mental Component Score of the SF-12. These changes remained significantly improved from baseline to month 24, with the exception of the EuroQol-5D. Many of these improvements were correlated with the magnitude of weight loss and, for the most part, were consistent across gender and ethnic group. CONCLUSIONS: Individuals with obesity and components of the metabolic syndrome reported significant improvements in most domains of the quality of life with a modest weight loss of 3.7% of initial weight, which was achieved within the first 6 months of treatment. The majority of these improvements were maintained at month 24, when participants had lost 3.0% of their weight. PMID- 23921779 TI - Managing obesity in primary care practice: an overview with perspective from the POWER-UP study. AB - Primary care practitioners (PCPs) have been encouraged to screen all adults for obesity and to offer behavioral weight loss counseling to the affected individuals. However, there is limited research and guidance on how to provide such intervention in primary care settings. This led the National Heart, Lung and Blood Institute in 2005 to issue a request for applications to investigate the management of obesity in routine clinical care. Three institutions were funded under a cooperative agreement to undertake the practice-based opportunities for weight reduction (POWER) trials. The present article reviews selected randomized controlled trials, published before the initiation of POWER, and then provides a detailed overview of the rationale, methods and results of the POWER trial conducted at the University of Pennsylvania (POWER-UP). POWER-UP's findings are briefly compared with those from the two other POWER trials, conducted at Johns Hopkins University and Harvard University/Washington University. The methods of delivering behavioral weight loss counseling differed markedly across the three trials, as captured by an algorithm presented in the article. Delivery methods ranged from having medical assistants and PCPs from the practices provide counseling to using a commercially available call center, coordinated with an interactive website. Evaluation of the efficacy of primary care-based weight loss interventions must be considered in light of costs, as discussed in relation to the recent treatment model proposed by the Centers for Medicare and Medicaid Services. PMID- 23921780 TI - Cost-effectiveness of a primary care intervention to treat obesity. AB - BACKGROUND: Data on the cost-effectiveness of the behavioral treatment of obesity are not conclusive. The cost-effectiveness of treatment in primary care settings is particularly relevant. METHODS: We conducted a within-trial cost-effectiveness analysis of a primary care-based obesity intervention. Study participants were randomized to: Usual Care (UC; quarterly visits with their primary care provider); Brief Lifestyle Counseling (BLC; quarterly provider visits plus monthly weight loss counseling visits) or Enhanced Brief Lifestyle Counseling (EBLC; all above interventions, plus choice of meal replacements or weight loss medication). A health-care payer perspective was used. Intervention costs were estimated from tracking data obtained prospectively. Quality-adjusted life years (QALYs) were estimated with the EuroQol-5D. We estimated cost per kilogram-year of weight loss and cost per QALY. RESULTS: Weight losses after 2 years were 1.7, 2.9 and 4.6 kg for UC, BLC and EBLC, respectively (P=0.003 for comparison of EBLC vs UC). The incremental cost per kilogram-year lost was $292 for EBLC compared with UC (95% confidence interval (CI): $219-$437). The short-term incremental cost per QALY was $115,397, but the 95% CI were undefined. Comparison of short term cost per kg with published estimates of longer-term cost per QALY suggested that the intervention could be cost-effective over the long term (>= 10 years). CONCLUSIONS: A primary care intervention that includes monthly counseling visits and a choice of meal replacements or weight loss medication could be a cost effective treatment for obesity over the long term. However, additional studies are needed on the cost-effectiveness of behavioral treatment of obesity. PMID- 23921782 TI - Direct one-step labeling of cysteine residues on peptides with [(11)C]methyl triflate for the synthesis of PET radiopharmaceuticals. AB - Radiolabeled peptides have emerged as an attractive platform for the diagnostic and therapeutic oncology. However, the (11)C-radiolabeling of peptides for positron emission tomography (PET) has been poorly explored, owing to the relatively short half-life of carbon-11 (t 1/2 = 20.3 min) and time-consuming multi-step radiochemical reactions. Existing methods have found limited use and are not routinely encountered in the production of radiotracers. Herein, we propose a facile one-step direct (11)C-methylation of cysteine residues in peptides using [(11)C]methyl triflate under ambient temperatures (20 degrees C) and short reaction times, on the order of seconds. Good regioselectivity of this method was demonstrated by HPLC in a simple peptide (glutathione, GSH) and a more complex test decapeptide (Trp-Tyr-Trp-Ser-Arg-Cys-Lys-Trp-Thr-Gly) bearing multiple nucleophilic sites. In addition, we extend this method towards the synthesis of [(11)C]Cys(Me)-[Tyr(3)-octreotate] as a demonstration of applicability for peptides of biological interest. This octreotate derivative was obtained in non-decay-corrected radiochemical yields of 11 +/- 2 % (n = 3) with a synthesis time of approx. 30 min. PMID- 23921783 TI - Aspirin is associated with lower melanoma risk among postmenopausal Caucasian women: the Women's Health Initiative. PMID- 23921781 TI - Gender differences in the relationship between symptoms of depression and high sensitivity CRP. AB - BACKGROUND: Depression has been associated with increased risk of cardiovascular disease. The inflammatory marker C-reactive protein (CRP) has also been identified as an independent predictor of short- and long-term cardiovascular disease events. Inflammation may influence the relationship between depression and cardiovascular disease. OBJECTIVE: The objective of this study was to investigate the association between symptoms of depression and high-sensitivity CRP (hs-CRP) in an obese clinical population. We also sought to determine whether this relationship was different in men and women, given prior reports of a gender effect. METHODS: Symptoms of depression and hs-CRP were measured in 390 participants enrolled in a weight loss intervention trial that was delivered in a primary care setting. Symptoms of depression were evaluated with the Patient Health Questionnaire-8 (PHQ-8), in which a score >= 10 is consistent with major depression. RESULTS: A total of 58 (15.2%) participants reported a PHQ-8 score >= 10. The median (interquartile range) hs-CRP concentration was significantly higher in participants with symptoms consistent with major depression (7.7 (4.2 13) mg l(-1)) compared with those without depression (5.1 (3-9.7) mg l(-1); P<0.01). Symptoms consistent with major depression were significantly associated with log-transformed hs-CRP concentrations in an analysis adjusted for age, gender, obesity class and other metabolic variables (P=0.04). When interaction by gender was examined, this relationship remained significant in men (P<0.01) but not in women (P=0.32). CONCLUSIONS: Symptoms consistent with major depression were significantly associated with hs-CRP in men only, even after adjusting for age, obesity class, metabolic variables and medications known to affect inflammation. This finding suggests that there are biologic differences between men and women that may modify the relationship between hs-CRP and depression. Further studies are needed to elucidate the biologic basis for these findings. PMID- 23921784 TI - Prognostic value of metabolic tumor volume and total lesion glycolysis from 18F FDG PET/CT in patients undergoing stereotactic body radiation therapy for stage I non-small-cell lung cancer. AB - OBJECTIVES: The aim of this study was to evaluate the prognostic value of pretreatment F-fluorodeoxyglucose PET/computed tomography (CT), particularly in the assessment of metabolic tumor burden markers such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), with respect to clinical outcomes in stage I non-small-cell lung cancer (NSCLC) patients undergoing stereotactic body radiation therapy (SBRT). METHODS: This retrospective study evaluated 50 patients who underwent SBRT for stage I NSCLC from May 2007 to December 2012. The maximum standardized uptake value (SUVmax), average SUV (SUVavg), MTV, and TLG were measured from the PET/CT scan. The study population was dichotomized at the median into high and low groups. Kaplan-Meier log-rank tests were then used to compare high with low PET/CT parameter groups, and univariate Cox proportional hazards regression analysis was carried out to identify predictors of overall survival. RESULTS: The 2-year local control rate was 93.7%. After a median follow up of 25.1 months, the 2-year overall survival was 79.3%. Eight patients (16%) had disease recurrence. There were three local failures (6%), three mediastinal failures (6%), and six cases of distant metastases (12%). Both Kaplan-Meier actuarial analysis and Cox proportional hazards regression found no correlation between SUVmax, SUVavg, MTV, and TLG and overall survival. CONCLUSION: Standard PET/CT measures, such as SUVmax, as well as newer measures of metabolic tumor burden, such as MTV and TLG, were not correlated with overall survival in our study population of stage I NSCLC patients undergoing SBRT. Larger studies with longer follow-up periods are needed to confirm these results. PMID- 23921786 TI - Can serum angiogenin be used to improve the diagnostic performance in prostate cancer screening? AB - Several biomarkers have been studied to avoid unnecessary biopsies resulting from suboptimal performance of prostate-specific antigen (PSA) testing. We aimed to assess the use of serum angiogenin as a prostate cancer diagnostic tool among candidates for biopsy. We selected 252 patients referred for ultrasound-guided transrectal prostate biopsy on the basis of an abnormal digital rectal examination and/or elevated total PSA. Serum angiogenin was quantitatively analyzed by solid-phase enzyme-linked immunosorbent assay. Results of the prostatic pathology assessment (cancer vs. noncancer) were defined by biopsy. The median serum angiogenin levels were significantly higher in patients with prostate cancer (median: 487,500 vs. 414,800 pg/ml, P=0.008). Among patients with baseline tPSA of 4.0 ng/ml or less, 37.5% had serum angiogenin less than 389,000 pg/ml (sensitivity: 88.9%; specificity: 45.2%), and the probability of having prostate cancer varied from 22.5% before testing to 6.7% among those with low angiogenin levels. When further restricting the analyses to a group of patients with even lower probability of having cancer, on the basis of tPSA and f/t PSA values, the evaluation of serum angiogenin did not contribute toward a meaningful variation in the post-test probability of cancer. In conclusion, serum angiogenin levels may be useful to distinguish between cancer and noncancer patients among the candidates for prostatic biopsy in regular clinical practice. Further investigation is needed among patients with low PSA levels and to understand the relation between this biomarker and the long-term survival of prostate cancer patients. PMID- 23921785 TI - Cortical reinstatement mediates the relationship between content-specific encoding activity and subsequent recollection decisions. AB - Episodic recollection entails the conscious remembrance of event details associated with previously encountered stimuli. Recollection depends on both the establishment of cortical representations of event features during stimulus encoding and the cortical reinstatement of these representations at retrieval. Here, we used multivoxel pattern analyses of functional magnetic resonance imaging data to examine how cortical and hippocampal activity at encoding and retrieval drive recollective memory decisions. During encoding, words were associated with face or scene source contexts. At retrieval, subjects were cued to recollect the source associate of each presented word. Neurally derived estimates of encoding strength and pattern reinstatement in occipitotemporal cortex were computed for each encoding and retrieval trial, respectively. Analyses demonstrated that (1) cortical encoding strength predicted subsequent memory accuracy and reaction time, (2) encoding strength predicted encoding-phase hippocampal activity, and (3) encoding strength and retrieval-phase hippocampal activity predicted the magnitude of cortical reinstatement. Path analyses further indicated that cortical reinstatement partially mediated both the effect of cortical encoding strength and the effect of retrieval-phase hippocampal activity on subsequent source memory performance. Taken together, these results indicate that memory-guided decisions are driven in part by a pathway leading from hippocampally linked cortical encoding of event attributes to hippocampally linked cortical reinstatement at retrieval. PMID- 23921787 TI - A method for assessing the arm movement performance: probability tube. AB - Quantification of motor performance is an important component of the rehabilitation of humans with sensory-motor disability. We developed a method for assessing arm movement performance of trainees (patients) termed "probability tube" (PT). PT captures the stochastic characteristics of a desired movement when repeated by an expert (therapist). The PT is being generated automatically from data recorded during point-to-point movement executed not more than 15 repetitions by the clinician and/or other non-expert programmer in just a few minutes. We introduce the index, termed probability tube score (PTS), as a single "goodness-of-fit" value allowing quantified analysis of the recovery and effects of the therapy. This index in fact scores the difference between the movement (velocity profile) executed by the trainee and the velocity profile of the desired movement (executed by the expert). We document the goodness of the automatic method with results from studies which included healthy subjects and show the use of the PTS in healthy and post-stroke hemiplegic subjects. PMID- 23921788 TI - Improved neonatal outcomes with probiotics. PMID- 23921789 TI - [Antidotes in clinical toxicology]. AB - This overview describes antidotes, and their clinical pharmacology, that have an established significance in the currently practiced clinical toxicology because of their proven effectiveness in the treatment of serious poisonings. For the proper, efficient, and targeted use of an antidote, pharmacological knowledge is required, which is a central subject of this article. Current data from the literature are used as reference along with the accumulated experiences about possible adverse effects in order to include them in therapeutic considerations. The dosage of antidotes is the subject of several other review articles and is therefore not included in this synopsis. PMID- 23921790 TI - Cancer mortality in Europe, 2005-2009, and an overview of trends since 1980. AB - BACKGROUND: After a peak in the late 1980s, cancer mortality in Europe has declined by ~10% in both sexes up to the early 2000s. We provide an up-to-date picture of patterns and trends in mortality from major cancers in Europe. METHODS: We analyzed cancer mortality data from the World Health Organization for 25 cancer sites and 34 European countries (plus the European Union, EU) in 2005 2009. We computed age-standardized rates (per 100,000 person-years) using the world standard population and provided an overview of trends since 1980 for major European countries, using joinpoint regression. RESULTS: Cancer mortality in the EU steadily declined since the late 1980s, with reductions by 1.6% per year in 2002-2009 in men and 1% per year in 1993-2009 in women. In western Europe, rates steadily declined over the last two decades for stomach and colorectal cancer, Hodgkin lymphoma, and leukemias in both sexes, breast and (cervix) uterine cancer in women, and testicular cancer in men. In central/eastern Europe, mortality from major cancer sites has been increasing up to the late 1990s/early 2000s. In most Europe, rates have been increasing for lung cancer in women and for pancreatic cancer and soft tissue sarcomas in both sexes, while they have started to decline over recent years for multiple myeloma. In 2005-2009, there was still an over twofold difference between the highest male cancer mortality in Hungary (235.2/100,000) and the lowest one in Sweden (112.9/100,000), and a 1.7-fold one in women (from 124.4 in Denmark to 71.0/100,000 in Spain). CONCLUSIONS: With the major exceptions of female lung cancer and pancreatic cancer in both sexes, in the last quinquennium, cancer mortality has moderately but steadily declined across Europe. However, substantial differences across countries persist, requiring targeted interventions on risk factor control, early diagnosis, and improved management and pharmacological treatment for selected cancer sites. PMID- 23921791 TI - Incidence and risk of hemorrhagic events with vascular endothelial growth factor receptor tyrosine-kinase inhibitors: an up-to-date meta-analysis of 27 randomized controlled trials. AB - BACKGROUND: We aimed at determining the overall incidence and risk of hemorrhagic events associated with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). METHODS: We searched PubMed, EMBASE and Cochrane library databases for relevant prospective, randomized controlled trials (RCTs). Statistical analyses were conducted to calculate the summary incidence, relative risks (RRs) and 95% confidence intervals (CIs) by using either random-effects or fixed-effects models according to the heterogeneity of included studies. RESULTS: The overall incidence of all-grade and high-grade hemorrhagic events was 9.1% (95% CI: 6.8-12.1%) and 1.3% (95% CI 0.8% to 2.1%), respectively. And the use of VEGFR-TKIs was associated with an increased risk of hemorrhagic events, with a relative risk (RR) of 1.67 (95% CI 1.19-2.33, P = 0.003), but not for high-grade hemorrhagic events (RR 1.23, 95% CI 0.86-1.77, P = 0.25). The risk of developing all-grade hemorrhagic events varied significantly with tumor types (P < 0.001) and different VEGFR-TKIs (P < 0.001). Additionally, the most common causes of all grade hemorrhagic events were hemoptysis (48.6%) and epistaxis (20.7%), while hemoptysis (41.8%) and CNS hemorrhage (13.4%) was the most common cause of high grade hemorrhagic events. CONCLUSIONS: While the use of VEGFR-TKIs is associated with a significantly increased risk of developing hemorrhagic events in cancer patients, this is primarily for lower grade events. PMID- 23921792 TI - A note on exact conditional and unconditional tests for Hardy-Weinberg equilibrium. AB - The exact conditional approach is frequently used for testing Hardy-Weinberg equilibrium in population genetics. This approach respects the test size as compared to the traditionally used asymptotic approaches. It is a full enumeration method and very computational. Many efficient algorithms have been successfully developed to implement this exact approach. An alternative to the conditional approach is the unconditional approach, which relaxes the restriction of the fixed number of allelic counts as in the conditional approach. The first unconditional test considered in this study is the one based on maximization, which has been shown to be more powerful than the conditional test to loci with two alleles for small sample sizes. By using the p value of the conditional approach as a test statistic in the following maximization step, the second unconditional test is uniformly more powerful than the conditional approach. We compared these exact tests based on three commonly used test statistics with regards to type I error rate and power. It is recommended to use the second unconditional approach in practice due to the power gain in the case with two alleles. PMID- 23921793 TI - An azabisphosphonate-capped poly(phosphorhydrazone) dendrimer for the treatment of endotoxin-induced uveitis. AB - Over the last decade, different types of dendrimers have shown anti-inflammatory properties in their own right. In particular, we have shown that poly(phosphorhydrazone) (PPH) dendrimers are able to foster an efficient anti inflammatory response in human monocytes and can resolve the main physiopathological features of chronic arthritis in mice at 1 mg/kg. Here we afford new insights into the therapeutic potential of an azabisphosphonate-capped dendrimer (dendrimer ABP). We have challenged its anti-inflammatory and immuno modulatory properties in a robust rat model of acute uveitis induced by lipopolysaccharide (LPS). We show that dendrimer ABP at 2 ug/eye is as efficient as the "gold standard" dexamethasone at 20 ug/eye. We have demonstrated that the effect of dendrimer ABP is mediated at least through an increase of the production of the anti-inflammatory Interleukin(IL)-10 cytokine. PMID- 23921794 TI - Oligomerization of 10,16-dihydroxyhexadecanoic acid and methyl 10,16 dihydroxyhexadecanoate catalyzed by lipases. AB - The main monomer of tomato cuticle, 10,16-dihydroxyhexadecanoic acid (10,16-DHPA) and its methyl ester derivative (methyl-10,16-dihydroxyhexadecanote; methyl-10,16 DHHD), were used to study their oligomerization reactions catalyzed by five lipases: Candida antarctica lipase B (CAL-B), Rhizomucor miehei lipase (RM), Thermomyces lanuginosus lipase (TL), Pseudomonas cepacia lipase (PCL) and porcine pancreatic lipase (PPL). For 10,16-DHPA, optimum yields were obtained at 60 degrees C using toluene and 2-methyl-2-butanol (2M2B) as solvent, while for methyl-10,16-DHHD the bests yields were obtained in toluene and acetonitrile. Both reactions leaded to linear polyesters according to the NMR and FT-IR analysis, and there was no data indicating the presence of branched polymers. Using optimized conditions, poly(10,16-DHPA) and poly(methyl-10,16-DHHD) with Mw = 814 and Mn = 1,206 Da, and Mw = 982 and Mn = 860 Da, respectively, were formed according to their MALDI-TOF MS and ESI-MS data. The self-assembly of the polyesters obtained were analyzed by AFM. PMID- 23921795 TI - The potential of use basil and rosemary essential oils as effective antibacterial agents. AB - The considerable therapeutical problems of persistent infections caused by multidrug-resistant bacterial strains constitute a continuing need to find effective antimicrobial agents. The aim of this study was to demonstrate the activities of basil (Ocimum basilicum L.) and rosemary (Rosmarinus officinalis L.) essential oils against multidrug- resistant clinical strains of Escherichia coli. A detailed analysis was performed of the resistance of the drug to the strains and their sensitivity to the tested oils. The antibacterial activity of the oils was tested against standard strain Escherichia coli ATCC 25922 as well as 60 other clinical strains of Escherichia coli. The clinical strains were obtained from patients with infections of the respiratory tract, abdominal cavity, urinary tract, skin and from hospital equipment. The inhibition of microbial growth by both essential oils, presented as MIC values, were determined by agar dilution. Susceptibility testing to antibiotics was carried out using disc diffusion. The results showed that both tested essential oils are active against all of the clinical strains from Escherichia coli including extended spectrum beta-lactamase positive bacteria, but basil oil possesses a higher ability to inhibit growth. These studies may hasten the application of essential oils in the treatment and prevention of emergent resistant strains in nosocomial infections. PMID- 23921797 TI - Reactive oxygen species mediate isoalantolactone-induced apoptosis in human prostate cancer cells. AB - Isoalantolactone, a medicinal plant-derived natural compound, is known to induce apoptosis in various cancer cell lines. However, its effect on apoptosis in prostate cancer cells has not been addressed. Thus, we examined the effects of isoalantolactone on prostate cancer cells. It was found that isoalantolactone inhibits growth of both androgen-sensitive (LNCaP) as well as androgen independent (PC3 and DU-145) prostate cancer cells in a dose-dependent manner. Furthermore, our results indicate that isoalantolactone-induced apoptosis in prostate cancer PC3 cells is associated with the generation of ROS and dissipation of mitochondrial membrane potential (Deltapsim). In addition, isoalantolactone triggers apoptosis in prostate cancer cells via up-regulation of Bax, down-regulation of Bcl-2, survivin, and significant activation of caspase-3. Isoalantolactone-induced apoptosis is markedly abrogated when the cells were pretreated with N-acetylcysteine (NAC), a specific ROS inhibitor, suggesting that the apoptosis-inducing effect of isoalantolactone in prostate cancer cells is mediated by reactive oxygen species. These findings indicate that isoalantolactone induces reactive oxygen species-dependent apoptosis in prostate cancer cells via a novel mechanism involving inhibition of survivin and provide the rationale for further in vivo and preclinical investigation of isoalantolactone against human prostate cancer. PMID- 23921796 TI - Strategies for optimizing water-exchange rates of lanthanide-based contrast agents for magnetic resonance imaging. AB - This review describes recent advances in strategies for tuning the water-exchange rates of contrast agents for magnetic resonance imaging (MRI). Water-exchange rates play a critical role in determining the efficiency of contrast agents; consequently, optimization of water-exchange rates, among other parameters, is necessary to achieve high efficiencies. This need has resulted in extensive research efforts to modulate water-exchange rates by chemically altering the coordination environments of the metal complexes that function as contrast agents. The focus of this review is coordination-chemistry-based strategies used to tune the water-exchange rates of lanthanide(III)-based contrast agents for MRI. Emphasis will be given to results published in the 21st century, as well as implications of these strategies on the design of contrast agents. PMID- 23921798 TI - A prospective study of prevalence and characterization of headache following mild traumatic brain injury. AB - BACKGROUND: Headache is one of the most common and persistent symptoms following traumatic brain injury (TBI). The current study examines the prevalence and characteristics of headache following mild TBI (mTBI). METHODS: We prospectively enrolled 212 subjects within one week of mTBI who were hospitalized for observation or other system injuries in a single level 1 US trauma center and followed by telephone at three, six, and 12 months after injury for evaluation of headache. Headaches were classified according to ICHD-2 criteria as migraine, probable migraine, tension-type, cervicogenic, or unclassifiable headache. RESULTS: Subjects were 76% male and 75% white, and 58% were injured in vehicle related crashes. A follow-up rate of 90% (190/212) occurred at 12 months post injury. Eighteen percent (38/212) of subjects reported having a problem with headaches pre-injury while 54% (114/210) of subjects reported new or worse headaches compared to pre-injury immediately after injury, 62% (126/203) at three months, 69% (139/201) at six months, and 58% (109/189) at one year. Cumulative incidence was 91% (172/189) over one year. Up to 49% of headaches met criteria for migraine and probable migraine, followed by tension-type headaches (up to 40%). Age (<= 60) was found to be a risk factor, but no significant difference was found in persistence of new or worse headache compared to pre-injury between males and females. More than one-third of the subjects reported persistent headache across all three follow-up time periods. CONCLUSIONS: Headache after mTBI is very common and persistent across the first year after injury. Assertive, early treatment may be warranted to avoid chronicity and disability. Further research is needed to determine whether post-traumatic headache (PTH) responds to headache treatment used in the primary headache disorders and whether chronic PTH is preventable. PMID- 23921800 TI - [Targeted therapy: old and new possibilities]. PMID- 23921799 TI - Triptans and serious adverse vascular events: data mining of the FDA Adverse Event Reporting System database. AB - AIM: The aim of this article is to investigate the vascular safety profile of triptans through an analysis of the United States Food and Drug Administration Adverse Event Reporting System (FDA_AERS) database with a special focus on serious and unexpected adverse events. METHODS: A CASE/NON-CASE analysis was performed on the reports entered in the FDA_AERS from 2004 to 2010: CASES were reports with at least one event included in the MedDRA system organ classes 'Cardiac disorder' or 'Vascular disorders', whereas NON-CASES were all the remaining reports. Co-reported cardiovascular drugs were used as a proxy of cardiovascular risk and the adjusted reporting odds ratio (adj.ROR) with 95% confidence intervals (95% CI) was calculated. Disproportionality signals were defined as adj.ROR value >1. Adverse events were considered unexpected if not mentioned on the relevant label. RESULTS: Among 2,131,688 reports, 7808 concerned triptans. CASES were 2593 among triptans and 665,940 for all other drugs. Unexpected disproportionality signals were found in the following high-level terms of the MedDRA hierarchy: 'Cerebrovascular and spinal necrosis and vascular insufficiency' (103 triptan cases), 'Aneurysms and dissections non-site specific' (15), 'Pregnancy-associated hypertension' (10), 'Reproductive system necrosis and vascular insufficiency' (3). DISCUSSION: Our analysis revealed three main groups of unexpected associations between triptans and serious vascular events: ischaemic cerebrovascular events, aneurysms and artery dissections, and pregnancy related vascular events. A case-by-case assessment is needed to confirm or disprove their plausibility and large-scale analytical studies should be planned for risk rate estimation. In the meantime, clinicians should pay special attention to migraine diagnosis and vascular risk assessment before prescribing a triptan, also promptly reporting any unexpected event to pharmacovigilance systems. PMID- 23921801 TI - [New drugs in oncology: benefits, risks and challenges]. PMID- 23921802 TI - [(Mis) management in healthcare]. PMID- 23921803 TI - Cloning and mutagenesis of catechol 2,3-dioxygenase gene from the gram-positive Planococcus sp. strain S5. AB - In this study, the catechol 2,3-dioxygenase gene that encodes a 307- amino-acid protein was cloned from Planococcus sp. S5. The protein was identified to be a member of the superfamily I, subfamily 2A of extradiol dioxygenases. In order to study residues and regions affecting the enzyme's catalytic parameters, the c23o gene was randomly mutated by error-prone PCR. The wild-type enzyme and mutants containing substitutions within either the C-terminal or both domains were functionally produced in Escherichia coli and their activity towards catechol was characterized. The C23OB65 mutant with R296Q substitution showed significant tolerance to acidic pH with an optimum at pH 5.0. In addition, it showed activity more than 1.5 as high as that of the wild type enzyme and its Km was 2.5 times lower. It also showed altered sensitivity to substrate inhibition. The results indicate that residue at position 296 plays a role in determining pH dependence of the enzyme and its activity. Lower activity toward catechol was shown for mutants C23OB58 and C23OB81. Despite lower activity, these mutants showed higher affinity to catechol and were more sensitive to substrate concentration than nonmutated enzyme. PMID- 23921805 TI - Editor's note August, 2013. PMID- 23921804 TI - A novel approach for assessing cardiac fibrosis using label-free second harmonic generation. AB - To determine whether second harmonic generation (SHG) can be used as a novel and improved label-free technique for detection of collagen deposition in the heart. To verify whether SHG will allow accurate quantification of altered collagen deposition in diseased hearts following hypertrophic remodelling. Minimally invasive transverse aortic banding (MTAB) of mouse hearts was used to generate a reproducible model of cardiac hypertrophy. Physiological and functional assessment of hypertrophic development was performed using echocardiography and post-mortem analysis of remodelled hearts. Cardiac fibroblasts were isolated from sham-operated and hypertrophied hearts and proliferation rates compared. Multi photon laser scanning microscopy was used to capture both two-photon excited autofluorescence (TPEF) and SHG images simultaneously in two channels. TPEF images were subtracted from SHG images and the resulting signal intensities from ventricular tissue sections were calculated. Traditional picrosirius red staining was used to verify the suitability of the SHG application. MTAB surgery induced significant hypertrophic remodelling and increased cardiac fibroblast proliferation. A significant increase in the density of collagen fibres between hypertrophic and control tissues (p < 0.05) was evident using SHG. Similar increases and patterns of staining were observed using parallel traditional picrosirius red staining of collagen. Label-free SHG microscopy provides a new alternative method for quantifying collagen deposition in fibrotic hearts. PMID- 23921806 TI - Mammary analogue secretory carcinoma of the parotid gland as a secondary malignancy in a childhood survivor of atypical teratoid rhabdoid tumor. AB - We report the first case of mammary analogue secretory carcinoma (MASC) arising as a secondary malignancy in a 14 years old child with a history of atypical teratoid rhabdoid tumor (ATRT). Although MASC and ATRT are both rare malignancies, they do not share the same genetic and molecular profiles. MASC is a salivary malignancy characterized by a t(12;15)(p13;q25) translocation, resulting in an ETV6-NTRK3 fusion product encoding for a tyrosine kinase. ATRT is a highly malignant pediatric tumor characterized by a chromosome 22 mutation in the hSNF5/INI1 gene, encoding for a chromatin remodeling protein. Additionally, although mucoepidermoid carcinoma has been described as a secondary malignancy post-therapy for head and neck tumors, MASC has only been reported as a primary malignancy. Our patient was treated with a complete resection of his left sided ATRT at age 3 followed postoperatively with chemoradiotherapy. At age 14 he underwent a parotidectomy for his 1 year history of a left sided preauricular mass and was subsequently diagnosed with MASC. We not only report a case of two rare malignancies in one patient, but also the first case of MASC arising as a secondary malignancy. PMID- 23921807 TI - Person-centered dementia care and the cultural matrix of othering. AB - PURPOSE: The dominant clinical view of dementia and its treatment are through the biomedical lens-an approach to understanding the dementias that focuses on bodily and mental pathology and symptomology. Person-centered care (PCC) represents a shift in focus away from biomedical approach in elder care. The primary objective of this research was to examine how PCC was defined, shaped, and practiced by staff members within a dementia care setting. DESIGN AND METHODS: Ethnographic data were collected over an 8-month period using participant observation (400 hr) and ethnographic interviews with 20 people with dementia and 25 staff members of Cedar Winds, a dementia-specific long-term care setting that had a strong organizational support for using a person-centered approach to dementia care. RESULTS: The observed cultural matrix of othering is the focus of this article and represents the cultural processes that prevented PCC from being enacted within Cedar Winds. The three main characteristics through which the residents were othered and PCC was obstructed were (a) dementia as a master status, (b) functional dependence, and (c) aggressiveness. IMPLICATIONS: This article concludes by examining the efforts that could reduce the extent of othering and improve the person centeredness of elder care settings. PMID- 23921808 TI - The CRAPome: a contaminant repository for affinity purification-mass spectrometry data. AB - Affinity purification coupled with mass spectrometry (AP-MS) is a widely used approach for the identification of protein-protein interactions. However, for any given protein of interest, determining which of the identified polypeptides represent bona fide interactors versus those that are background contaminants (for example, proteins that interact with the solid-phase support, affinity reagent or epitope tag) is a challenging task. The standard approach is to identify nonspecific interactions using one or more negative-control purifications, but many small-scale AP-MS studies do not capture a complete, accurate background protein set when available controls are limited. Fortunately, negative controls are largely bait independent. Hence, aggregating negative controls from multiple AP-MS studies can increase coverage and improve the characterization of background associated with a given experimental protocol. Here we present the contaminant repository for affinity purification (the CRAPome) and describe its use for scoring protein-protein interactions. The repository (currently available for Homo sapiens and Saccharomyces cerevisiae) and computational tools are freely accessible at http://www.crapome.org/. PMID- 23921809 TI - Sirolimus versus tacrolimus in kidney transplant recipients receiving mycophenolate mofetil and steroids: focus on acute rejection, patient and graft survival. AB - The study aims to conduct a meta-analysis of randomized controlled trials to compare the efficacy of tacrolimus (TAC)/mycophenolate mofetil (MMF)/corticosteroids (CSs) with sirolimus (SRL)/MMF/CSs in renal transplant recipients: Research 2 databases, PubMed, and Web of Science, selecting relevant articles. Data were selected for acute rejection and patient and graft survival. Statistical value relative risk (RR) and 95% confidence intervals (CIs) were recorded. Six randomized controlled trials involving 885 patients were included. There was a significant difference in acute rejection (P = 0.001, RR = 1.69, 95% CI, 1.23-2.34). Two groups, patient survival (P = 0.96, RR = 1.02, 95% CI, 0.54 1.91) and graft survival (P = 0.09, RR = 1.56, 95% CI, 0.93-2.60), had no statistical difference. Acute rejection by those taking SRL/MMF/CSs is worse than those taking TAC/MMF/CSs. Patient and graft survival in TAC/MMF/CSs is similar to that in SRL/MMF/CSs. PMID- 23921810 TI - Totally changed, yet still the same: patients' lived experiences 5 years beyond bariatric surgery. AB - Bariatric surgery provides sustainable weight loss and increased quality of life for most, but not all patients. To increase the knowledge of this complex patient group and their needs during follow-up, we aimed to describe the essential meaning of bariatric surgery patients' long-term experiences by using a phenomenological lifeworld approach. Eight patients were interviewed between 5 and 7 years after bariatric surgery. Life after bariatric surgery was described as living with tension, ambivalence, and reinforced attention toward one's own body. The tension was related to embodied change and altered relations to the social world. The patients express an ongoing demand for control of health related habits and practices, and to not lose control over the body again. Surgical weight loss and improved physical function do not necessarily mean changed health-related habits and practices in the long term. Experiencing weight regain is connected with emotional stress, shame, and self-contempt. PMID- 23921811 TI - Influence of Mn2+ concentration on Mn2+-doped ZnS quantum dot synthesis: evaluation of the structural and photoluminescent properties. AB - The intentional introduction of transition metal impurities into semiconductor nanocrystals is an attractive approach for tuning quantum dot photoluminescence emission. Particularly, doping of ZnS quantum dots with Mn(2+) (Mn:ZnS QDs) results in a phosphorescence-type emission, attributed to the incorporation of manganese ions into the nanocrystal structure, so that delayed radiational deactivation of the energy of nanoparticles, excited through the energy levels of the metal, is enabled. However, the development of effective doping strategies can be challenging, especially if a highly efficient photoluminescent emission within a known crystalline core structure, is required (e.g. for analytical phosphorescence applications). The spectroscopic properties and the crystal structure of Mn(2+)-doped ZnS QDs are studied here to provide a better understanding on how the luminescence emission and the crystalline composition are influenced by the presence of Mn(2+) and its concentration used during the synthesis. In order to further control and optimize the synthesis of doped QDs for future bioanalytical applications, different complementary techniques including photoluminescence and X-ray powder diffraction have been employed. The information obtained has allowed standardization of the synthesis conditions of these doped QDs and the identification and quantification of the crystal phases obtained under different synthesis conditions. PMID- 23921812 TI - Improving the quality of bone marrow assessment: Impact of operator techniques and use of a specimen preparation checklist. AB - BACKGROUND: Successful bone marrow assessment is essential to the diagnosis and staging of hematologic malignancies. The objective of this study was to determine whether specific operator techniques and/or use of a specimen preparation checklist could impact the quality of bone marrow assessment by reducing the frequency of nonspicular aspirates, small cores, and nondiagnostic samples. METHODS: All bone marrow biopsies performed at the Dana-Farber Cancer Institute from April, 2012 to September, 2012 were eligible for inclusion. Six operator techniques were linked with specimen quality in a preintervention cohort. Next, a specimen preparation checklist was implemented, and outcomes were compared from the preintervention and postintervention cohorts. RESULTS: In total, 830 procedures performed by 41 operators were prospectively observed and analyzed. In the preintervention cohort (n = 413), no operator technique was associated with specimen quality in multivariable models accounting for patient characteristics and operator. Compared with the preintervention cohort, in multivariable analyses, the postintervention cohort (n = 417) had decreased odds of nondiagnostic specimens (odds ratio, 0.49; 95% confidence interval, 0.28-0.87; P = .01) and core lengths <=1 cm (odds ratio, 0.67; 95% confidence interval, 0.50 0.90; P = .009), but there was no significant difference in spicularity. CONCLUSIONS: Variation in the operator techniques studied did not have an impact on specimen quality, but implementation of a specimen preparation checklist significantly improved core length and frequency of diagnostic samples. PMID- 23921813 TI - [Difference and distance between the central and thinnest points of the cornea: impact of refractive state, age and ocular side]. AB - BACKGROUND: The aim of the study was to quantify the difference in corneal thickness between the central and thinnest points (?PachyZ-PachyD), the distance between the center of the cornea and its thinnest point (vector length PachyD) and to explore the impact of refractive state, age and ocular side. PATIENTS AND METHODS: This was a multicenter, retrospective, cross-sectional study and medical records of 16,872 eyes were reviewed. The Orbscan(r) (Bausch and Lomb) procedure was used for pachymetry and keratometry. RESULTS: The results showed that ?PachyZ PachyD and vector length PachyD were higher in hyperopic eyes (?PachyZ-PachyD: 11.99 +/- 12.08 um, vector length PachyD: 0.85 +/- 0.44 mm) compared to myopic eyes (?PachyZ-PachyD: 9.2 +/- 7.86 um, vector length PachyD: 0.7 +/- 0.37 mm; p < 0.001). Refractive state, age and ocular side demonstrated an independent, statistically significant impact on ?PachyZ-PachyD and vector length PachyD. CONCLUSIONS: As a result of the significant impact of refractive state, age and ocular side on ?PachyZ-PachyD and vector length PachyD, these variables should be considered in a normative data collection. PMID- 23921814 TI - [Correlation between microbial growth in conjunctival swabs of corneal donors and contamination of organ culture media]. AB - PURPOSE: The aim of the study was to determine the rate of contamination in conjunctival swabs from corneal donors by microbiological investigations and to correlate this with microbial contamination of the culture medium. PATIENTS AND METHODS: Contamination of conjunctival swabs and culture media was analyzed retrospectively for the years 2009, 2010 and 2011 at the LIONS corneal bank of Saar-Lor-Lux Trier/Westpfalz at the Saarland University Medical Center. The total annual number of conjunctival swabs was 316 in 2009, 341 in 2010 and 381 in 2011. Conjunctival swabs were taken prior to 1.25% povidone-iodine application. After disinfection donor corneas were harvested by in situ corneoscleral disc excision in all cases. The correlation between positive conjunctival swabs and microbial contamination of the culture medium was analyzed. RESULTS: In every year examined the contamination rate of the culture medium was significantly higher in cases of contaminated conjunctival swabs (p < 0.05 in 2009, p < 0.001 in 2010 and p = 0.004 in 2011). Of the conjunctival swabs 38.3% (2009), 53.7% (2010) and 55.6% (2011), respectively exhibited microbial growth. The principal microorganisms detected in the conjunctival swabs were coagulase negative staphylococci, gram negative rods and Staphylococcus aureus. Extending the exposure time to povidone iodine prior to removal of the corneoscleral disc from 3 min in the year 2009 to 5 min since the year 2010 resulted in a highly statistically significant (p < 0.001) reduction in contamination frequency of the medium from 10.8% (2009) to 7.0% (2010) and 4.5% (2011) was observed. In 2009, 2010 and 2011 the culture medium was contaminated in 16.5%, 11.5% and 7.6% of the donated corneas with positive conjunctival swabs and in 7.2%, 1.9% and 0.6% in donated corneas with negative conjunctival swabs, respectively. CONCLUSIONS: A positive correlation was found between contamination of the culture medium and microbial colonization of the conjunctival swabs, Nevertheless, microbial colonization of the conjunctiva was high and contamination of the culture medium was relatively low. For the microbial contamination rate of the donated corneas in the medium, conjunctival disinfection time with iodine solution before explantation of the corneoscleral disc and the addition of antibiotics to the culture medium seem to play a protective role. PMID- 23921816 TI - Turning the tide on respiratory depression. PMID- 23921815 TI - Bile acid at low pH reduces squamous differentiation and activates EGFR signaling in esophageal squamous cells in 3-D culture. AB - BACKGROUND: Barrett's esophagus is a preneoplastic metaplasia in which the normal squamous epithelium of the esophagus changes to an intestinal, columnar phenotype due to long-term gastro-esophageal reflux. The major components of this reflux are bile and stomach acid. Previous in vitro studies on the effect of bile and acid on esophageal cells have predominantly relied on transformed esophageal squamous cells or cancer cells grown in monolayer culture. DISCUSSION: In this study, we expanded our previous work using an immortalized primary esophageal squamous cell line (EPC1). We demonstrate that EPC1 cells form a multi-layer, stratified epithelium when grown on polyester transwell filters in media supplemented with calcium. When exposed to short pulses of bile and pH 5, but not either condition alone, EPC1 cells demonstrate a reduction in stratification layers and reduced expression of squamous epithelium-specific genes. Bile at pH 5 also causes activation of epidermal growth factor receptor and down-stream pathways. Blocking epidermal growth factor receptor activation partially attenuates the effects of bile acid and pH 5. These results suggest that bile at low pH, but not bile or low pH alone, promotes loss of differentiation status of stratified squamous esophageal epithelium in vitro, possibly by initiating a mucosal repair response through epidermal growth factor activation. PMID- 23921817 TI - The use of intravenous magnesium sulphate for acute migraine: meta-analysis of randomized controlled trials. AB - OBJECTIVE: The objective of this study was to assess the efficacy and tolerability of intravenous magnesium for the treatment of acute migraine in adults. SELECTION CRITERIA: Double-blind, randomized controlled trials of intravenous magnesium for acute migraine in adults. DATA SOURCES: Cochrane Central Register of Controlled Trials, Medline, EMBASE, CINAHL, National Research Register Archive, ACP Journal Club, the US Government's Clinical Trial Database, Conference Proceedings, and other sources. RESULTS: Overall, 1203 abstracts were reviewed and five randomized controlled trials totalling 295 patients were eligible for the meta-analyses. The percentage of patients who experienced relief from headache 30 min following treatment was 7% lower in the magnesium groups compared with the controls [pooled risk difference=-0.07, 95% confidence interval (CI)=-0.23 to 0.09]. The percentage of patients who experienced side-effects or adverse events was greater in the magnesium groups compared with controls by 37% (pooled risk difference=0.370, 95% CI=0.06-0.68). The percentage of patients who needed rescue analgesic medications was slightly lower in the control groups, but this was not significant (pooled risk difference=-0.021, 95% CI=-0.16 to 0.12). CONCLUSION: The meta-analyses have failed to demonstrate a beneficial effect of intravenous magnesium in terms of reduction in pain relief in acute migraine in adults, showed no benefit in terms of the need for rescue medication and in fact have shown that patients treated with magnesium were significantly more likely to report side-effects/adverse events. PMID- 23921818 TI - Calcium-channel blockers and breast cancer: a hypothesis revived. PMID- 23921819 TI - Bacterial symbionts in agricultural systems provide a strategic source for antibiotic discovery. AB - As increased antibiotic resistance erodes the efficacy of currently used drugs, the need for new candidates with therapeutic potential grows. Although the majority of antibiotics in clinical use originated from natural products, mostly from environmental actinomycetes, high rediscovery rates, among other factors, have diminished the enthusiasm for continued exploration of this historically important source. Several well-studied insect agricultural systems have bacterial symbionts that have evolved to produce small molecules that suppress environmental pathogens. These molecules represent an underexplored reservoir of potentially useful antibiotics. This report describes the multilateral symbioses common to insect agricultural systems, the general strategy used for antibiotic discovery and pertinent examples from three farming systems: fungus-farming ants, southern pine beetles (SPBs) and fungus-growing termites. PMID- 23921820 TI - Stereochemical determination of a new and cytotoxic euphane triterpenoid from the plant endophytic fungus Phomopsis chimonanthi. PMID- 23921821 TI - Identification of the incednine biosynthetic gene cluster: characterization of novel beta-glutamate-beta-decarboxylase IdnL3. AB - A biosynthetic gene cluster for the 24-membered macrolactam antibiotic incednine was identified from the producer strain, Streptomyces sp. ML694-90F3. Among the putative incednine biosynthetic enzymes, a novel pyridoxal 5'-phosphate (PLP) dependent beta-glutamate-beta-decarboxylase, IdnL3, was functionally characterized in vitro by demonstrating its (S)-3-aminobutyrate-forming activity with beta-glutamate in the presence of PLP. Because (S)-3-aminobutyrate is known for the direct precursor of incednine, this enzyme supplies the unique beta-amino acid starter unit. The identified gene cluster encodes five characteristic beta amino acid carrying enzymes, consisting of a pathway-specific ATP-dependent ligase, a discrete acyl carrier protein (ACP), beta-aminoacyl-ACP beta-amino group-protecting ATP-dependent ligase, dipeptidyl-ACP:PKS-loading ACP dipeptidyltransferase and a terminal amino acid peptidase, which are completely conserved in beta-amino acid-containing macrolactam biosynthetic gene clusters. Overall, a plausible biosynthetic pathway for incednine was proposed. PMID- 23921823 TI - Estimating sibling recurrence risk in population sample surveys. AB - BACKGROUND/AIMS: Sibling recurrence risk (SRR) is a measure of familial aggregation of a disease and is often used in family-based studies in genetic epidemiology to indicate the existence of possible genes conferring susceptibility of disease. Estimating SRR requires information about the disease status of sibships of families with two or more siblings where at least one is affected. Since family-based studies are not usually random samples, estimates of SRR derived from these studies may be biased. Network sampling used in survey research offers a way to ascertain the disease status of sibships from interviewed individuals in household survey samples, in order to obtain (approximately) unbiased estimators of SRR and its related SRR ratio (SRR divided by the prevalence of disease). METHODS: Two methods of ascertaining sibships of affected families are considered: in one method the siblings' affected status is reported by an individual, regardless of the individual's affected status, and in the other method only affected individuals can report their siblings' affected status. Network estimators of SRR and SRR ratio and estimators of their standard errors are provided. RESULTS: Reported diabetes for siblings from the 1976 National Health Interview is used to illustrate the estimation methods. The SRR ratio for diabetes among living siblings was 5.79% [relative standard error (RSE) = 5.12%], and for living or deceased siblings, it was 7.66% (RSE = 3.76%). CONCLUSIONS: Network sampling estimators can provide population estimates of SRR and SRR ratio for diseases such as diabetes. PMID- 23921824 TI - Preauricular transmandibular and transzygomatic approach for tumors of the infratemporal fossa revisited. AB - AIM: To demonstrate the surgical technique and results in patients operated on with a preauricular transmandibular transzygomatic approach. METHODS: This surgical technique was used in 21 patients with benign and malignant tumors of the infratemporal fossa (ITF), operated on between 1999 and 2011. RESULTS: Twenty one patients were enrolled in the study. There were 6 patients with benign tumors and 15 with malignant ones. No patients with benign lesions show any disease recurrence 5 years after surgery and present excellent functional and cosmetic results. Postoperatively, a reduction of pain was noted in all patients with malignant lesions. Four patients in this group, who are alive 5 years after surgery, do not demonstrate any disease progression. CONCLUSION: The described approach provides an excellent exposure of the ITF and could be the procedure of choice in the management of ITF tumors. PMID- 23921822 TI - Serum concentration of lignocaine after pertubation: an observational study. AB - OBJECTIVE: The objective of this study was to report the serum concentration of lignocaine after pertubation in patients with endometriosis. DESIGN: Prospective observational study. SETTING: The study was carried out at a gynaecological outpatient unit in Stockholm, Sweden. POPULATION: Eligible patients had endometriosis with a dysmenorrhoic pain score of >50 mm on a visual analogue scale, and patent fallopian tubes. METHODS: Patients with endometriosis (n = 25) were included in the study. The patients received pre-ovulatory pertubations with lignocaine hydrochloride 10 mg (n = 16) or ringer acetate (placebo, n = 9). The procedure comprised passing the study solution through the uterus and the fallopian tubes via an intra-cervical balloon catheter. Serum samples were collected at 0, 5, 15 and 30 min after pertubation. MAIN OUTCOME MEASURES: The serum samples were analysed for the concentration of lignocaine with an LCMS-SIM method. RESULTS: Low levels of lignocaine were detected in the serum samples following pertubation of 10 mg lignocaine hydrochloride. The highest observed concentration was seen after 30 min (mean 0.050 MUg/ml), with an individual maximum of 0.124 MUg/ml. Maximum concentration (C max) and time to C max (T max) could not be calculated, since the highest values were observed in the 30-min samples, which was the last sample obtained. Lignocaine was not detected after pertubation with placebo. CONCLUSIONS: The serum levels of lignocaine following pertubation of 10 mg lignocaine hydrochloride are detectable but low. Lignocaine pertubated through the fallopian tubes reaches the peritoneal cavity and diffuses through the peritoneum into the blood circulation. Pertubation with lignocaine is safe and has no lignocaine-related adverse events. PMID- 23921825 TI - A strain-based load identification model for beams in building structures. AB - A strain-based load identification model for beam structures subjected to multiple loads is presented. The number of sensors for the load identification model is the same as the number of load conditions acting on a beam structure. In the model, the contribution of each load to the strains measured by strain sensors is defined. In this paper, the longitudinal strains measured from multiplexed fiber Bragg grating (FBG) strain sensors are used in the load identification. To avoid the dependency on the selection of locations for FBG sensors installed on a beam structure, the measured strain is expressed by a general form of a strain sensing model defined by superimposing the distribution shapes for strains from multiple loads. Numerical simulation is conducted to verify the model. Then, the load identification model is applied to monitoring of applied loads on a 4 m-long steel beam subjected to two concentrated loads. In the experiment, seven FBG sensors and nine electrical strain gages (ESGs) were installed on the surface of the bottom flange. The experimental results indicate a good agreement between estimated loadings from the model and the loads applied by a hydraulic jack. PMID- 23921826 TI - A phenomenological model for the photocurrent transient relaxation observed in ZnO-based photodetector devices. AB - We present a phenomenological model for the photocurrent transient relaxation observed in ZnO-based metal-semiconductor-metal (MSM) planar photodetector devices based on time-resolved surface band bending. Surface band bending decreases during illumination, due to migration of photogenerated holes to the surface. Immediately after turning off illumination, conduction-band electrons must overcome a relatively low energy barrier to recombine with photogenerated holes at the surface; however, with increasing time, the adsorption of oxygen at the surface or electron trapping in the depletion region increases band bending, resulting in an increased bulk/surface energy barrier that slows the transport of photogenerated electrons. We present a complex rate equation based on thermionic transition of charge carriers to and from the surface and numerically fit this model to transient photocurrent measurements of several MSM planar ZnO photodetectors at variable temperature. Fitting parameters are found to be consistent with measured values in the literature. An understanding of the mechanism for persistent photoconductivity could lead to mitigation in future device applications. PMID- 23921827 TI - An inexpensive method for kinematic calibration of a parallel robot by using one hand-held camera as main sensor. AB - This paper presents a novel method for the calibration of a parallel robot, which allows a more accurate configuration instead of a configuration based on nominal parameters. It is used, as the main sensor with one camera installed in the robot hand that determines the relative position of the robot with respect to a spherical object fixed in the working area of the robot. The positions of the end effector are related to the incremental positions of resolvers of the robot motors. A kinematic model of the robot is used to find a new group of parameters, which minimizes errors in the kinematic equations. Additionally, properties of the spherical object and intrinsic camera parameters are utilized to model the projection of the object in the image and thereby improve spatial measurements. Finally, several working tests, static and tracking tests are executed in order to verify how the robotic system behaviour improves by using calibrated parameters against nominal parameters. In order to emphasize that, this proposed new method uses neither external nor expensive sensor. That is why new robots are useful in teaching and research activities. PMID- 23921828 TI - Sudden event recognition: a survey. AB - Event recognition is one of the most active research areas in video surveillance fields. Advancement in event recognition systems mainly aims to provide convenience, safety and an efficient lifestyle for humanity. A precise, accurate and robust approach is necessary to enable event recognition systems to respond to sudden changes in various uncontrolled environments, such as the case of an emergency, physical threat and a fire or bomb alert. The performance of sudden event recognition systems depends heavily on the accuracy of low level processing, like detection, recognition, tracking and machine learning algorithms. This survey aims to detect and characterize a sudden event, which is a subset of an abnormal event in several video surveillance applications. This paper discusses the following in detail: (1) the importance of a sudden event over a general anomalous event; (2) frameworks used in sudden event recognition; (3) the requirements and comparative studies of a sudden event recognition system and (4) various decision-making approaches for sudden event recognition. The advantages and drawbacks of using 3D images from multiple cameras for real-time application are also discussed. The paper concludes with suggestions for future research directions in sudden event recognition. PMID- 23921829 TI - Real-time N2O gas detection system for agricultural production using a 4.6-um band laser source based on a periodically poled LiNbO3 ridge waveguide. AB - This article describes a gas monitoring system for detecting nitrous oxide (N2O) gas using a compact mid-infrared laser source based on difference-frequency generation in a quasi-phase-matched LiNbO3 waveguide. We obtained a stable output power of 0.62 mW from a 4.6-MUm-band continuous-wave laser source operating at room temperature. This laser source enabled us to detect atmospheric N2O gas at a concentration as low as 35 parts per billion. Using this laser source, we constructed a new real-time in-situ monitoring system for detecting N2O gas emitted from potted plants. A few weeks of monitoring with the developed detection system revealed a strong relationship between nitrogen fertilization and N2O emission. This system is promising for the in-situ long-term monitoring of N2O in agricultural production, and it is also applicable to the detection of other greenhouse gases. PMID- 23921830 TI - An amperometric biosensor utilizing a ferrocene-mediated horseradish peroxidase reaction for the determination of capsaicin (chili hotness). AB - Chili hotness is very much dependent on the concentration of capsaicin present in the chili fruit. A new biosensor based on a horseradish peroxidase enzyme capsaicin reaction mediated by ferrocene has been successfully developed for the amperometric determination of chili hotness. The amperometric biosensor is fabricated based on a single-step immobilization of both ferrocene and horseradish peroxidase in a photocurable hydrogel membrane, poly(2-hydroxyethyl methacrylate). With mediation by ferrocene, the biosensor could measure capsaicin concentrations at a potential 0.22 V (vs. Ag/AgCl), which prevented potential interference from other electroactive species in the sample. Thus a good selectivity towards capsaicin was demonstrated. The linear response range of the biosensor towards capsaicin was from 2.5-99.0 uM with detection limit of 1.94 uM. A good relative standard deviation (RSD) for reproducibility of 6.4%-9.9% was obtained. The capsaicin biosensor demonstrated long-term stability for up to seven months. The performance of the biosensor has been validated using a standard method for the analysis of capsaicin based on HPLC. PMID- 23921831 TI - Disability for daily living is a predictor for joint replacement in patients with end-stage knee osteoarthritis. AB - The objective indicators which reflect the past results of end-stage knee osteoarthritis (OA) patients who have already received total knee arthroplasty (TKA) could be helpful for physicians to discuss with patients who are considering TKA. The aim of this prospective cohort study was to examine whether we could predict the knee OA patients who would receive TKA in advance based on baseline data, and to set cut-off points for receiving TKA. The two-hundred and forty end-stage medial-type knee OA patients were enrolled and followed up for 6 months while performing therapeutic exercises. Radiographic findings, visual analog scale for pain and a patient-oriented outcome measure, the Japanese Knee Osteoarthritis Measure (JKOM), were recorded at baseline. Relative risks (RRs) using the area under the curve (AUC) for a receiver operating characteristic (ROC) curve were calculated to evaluate several scores for receiving TKA. While 119 patients (55.3 %) did not undergo TKA, the remaining 96 patients (44.7 %) underwent TKA during this period. The AUCs of the ROC curve for the JKOM total score [0.71 (95 % CI 0.64-0.79)] were higher than those for radiographic parameters. Among the JKOM subcategories, JKOM category III, which indicates the condition in daily life, showed the highest AUC of 0.72 (0.65-0.80). The JKOM total score (65/100) and JKOM category III score (17/40) showed RRs of 2.20 (1.33 3.63) and 1.95 (1.18-3.22) for receiving TKA, respectively. The presence of disability in daily living was found to be an important factor determining whether the patient should undergo TKA. PMID- 23921833 TI - Association between depot medroxyprogesterone acetate (DMPA), physical activity and bone health. AB - Physical activity has been advocated for women in the hope of offsetting progestin-only contraceptive-related loss in bone mineral density. There is limited evidence for the beneficial effect of physical activity on bone health of hypo-oestrogenic premenopausal women. The aim of this cross-sectional study was to examine the relationship between physical activity and bone health [as measured by quantitative ultrasound (QUS)] of depot-medroxyprogesterone acetate (DMPA) users, and to investigate whether QUS measurements of DMPA users and non users differed according to physical activity. Bone health of 48 DMPA users and 48 age-matched controls (22.83 +/- 3.2 years) was assessed using calcaneal broadband ultrasound attenuation (BUA). Participants were categorised into low and high levels of physical activity based on their exposure to bone-loading exercise. Analysis of covariance was conducted to determine if QUS measurements of DMPA users and non-DMPA users differed within levels of bone-loading physical activity after controlling for body mass index. The duration of DMPA use ranged from 6 to 132 months. Participants' reference bone-loading exposure time averaged 3.3 +/- 1.8 years. Data analysis revealed that DMPA users had significantly lower BUA by 6.54 dB/MHz (t (95) = -2.411, p = 0.018) compared to non-users of DMPA. Concurrently high levels of physical activity and DMPA use led to 1.996 dB/MHz decreases in BUA. A cycle of prolonged DMPA use and concurrent engagement in high levels of physical activity appears detrimental to bone health. It is suggested that the lack of oestrogen may counteract the effects of physical activity by inhibiting bone formation in response to mechanical bone-loading. PMID- 23921832 TI - Effects of combined therapy of alendronate and low-intensity pulsed ultrasound on metaphyseal bone repair after osteotomy in the proximal tibia of aged rats. AB - Bisphosphonates and low-intensity pulsed ultrasound (LIPUS) are both known to maintain or promote callus formation during diaphyseal fracture healing. However, the effect of these treatments on the repair of metaphyseal fractures has not been elucidated. To evaluate the effects of bisphosphonates and/or LIPUS on cancellous bone healing, an osteotomy was performed on the proximal tibial metaphysis of 9-month-old Sprague-Dawley rats (n = 64). Treatment with alendronate (1 MUg/kg/day), LIPUS (20 min/day), or a combination of both was administered for 2 or 4 weeks, after which changes in bone mineral density (BMD), bone histomorphometric parameters, and the rate of cancellous bony bonding were measured. Alendronate suppressed bone resorption parameters at 2 weeks (p = 0.019) and increased bone volume and BMD at 4 weeks (p = 0.034 and p = 0.008, respectively), without affecting bony bonding. LIPUS had no significant effect on any of the histomorphometric parameters at 2 or 4 weeks, but significantly increased in BMD at 4 weeks (p = 0.026) as well as the percentage of bony bonding at both 2 and 4 weeks (p < 0.01). The combined therapy also showed significantly increased BMD compared with the control group at 4 weeks (p = 0.010) and showed a trend toward increased bony bonding. In conclusion, alendronate and LIPUS cause an additive increase in BMD at the affected metaphysis: alendronate increases the bone volume at the osteotomy site without interrupting metaphyseal repair, whereas LIPUS promotes metaphyseal bone repair, without affecting bone histomorphometric parameters. PMID- 23921834 TI - Bone mineral density in patients with destructive arthrosis of the hip joint. AB - Recent reports have shown the existence of subchondral insufficiency fracture in rapidly destructive arthrosis of the hip joint (RDA), and the findings suggest that osteopenia is related to the pathogenesis of the rapid progression of this disease. Therefore, we measured bone mineral density (BMD) in RDA patients. We measured BMD of the lumbar spine, radius, and calcaneus using dual-energy X-ray absorptiometry in 19 patients with RDA and 75 with osteoarthritis of the hip (OA) and compared BMD at different skeletal sites between RDA and OA patients. No significant differences were observed in BMD of the lumbar spine, ultradistal radius, mid-radius, and calcaneous between the RDA and OA groups. Our data suggest that RDA is not accompanied by generalized osteoporosis. Factors other than generalized bone status, for example, BMD around the affected hip joint before destruction, need to be analyzed to elucidate the pathophysiological mechanism of RDA. PMID- 23921835 TI - Enhanced NO signaling in patients with Takotsubo cardiomyopathy: short-term pain, long-term gain? AB - PURPOSE: Little information is available concerning the mechanism(s) underlying Takotsubo cardiomyopathy (TTC), other than evidence of associated catecholamine secretion. Given the known effects of catecholamines on endothelial function, we tested the hypothesis that TTC might also be associated with impairment of nitric oxide (NO) signaling. We now report an evaluation of NO signaling in TTC patients (vs. aged-matched controls) in relation to (a) severity of the acute attack and (b) rate of recovery. METHODS: In 56 patients with TTC, we utilized (1) platelet responsiveness to NO and (2) plasma levels of asymmetric dimethylarginine (ADMA) as indices of integrity of the cyclic guanosine monophosphate (cGMP) pathway. Additionally, endothelial progenitor cell (EPC) counts, which are partially NO dependent, were evaluated. These parameters were measured at the time of diagnosis and 3 months thereafter, and compared with an aging female cohort (n = 81). RESULTS: The data suggested that both NO generation and effect were accentuated in TTC patients: ADMA concentrations were lower (p = 0.003), and responsiveness to NO substantially greater (p = 0.0001) than in controls both acutely and after 3 months. Markers of severity of TTC attacks directly correlated with NO responsiveness, while extent of recovery at 3 months varied inversely with ADMA concentrations. CONCLUSION: TTC is associated with intensification of NO signaling relative to that in normal age-matched females. Our data are consistent with this intensified signal's potential contribution to the extent of initial myocardial injury, but conversely to accelerated recovery. PMID- 23921836 TI - Prediction of risk for symptomatic sialadenitis by post-therapeutic dual (131)I scintigraphy in patients with differentiated thyroid cancer. AB - OBJECTIVE: The aim of this study is to predict the risk of symptomatic sialadenitis after (131)I therapy using the early (third day post-therapy) and delayed (fifth or sixth day post-therapy) post-therapeutic (131)I scintigraphy images in patients with differentiated thyroid cancer (DTC). METHODS: Included in the study were 112 patients with DTC who underwent early and delayed (131)I scans after (131)I treatment. All patients had normal salivary gland function on salivary scintigraphy performed in the week before the (131)I treatment. Scintigraphy images were visually analyzed and the salivary gland-to-background uptake ratio (SUR) and percent change of the SUR between early and delayed scans were calculated. Calculation of effective half-life and absorbed dose in the salivary glands was performed based on the MIRD schema. RESULTS: Of 112 patients, symptomatic sialadenitis was diagnosed in 46 patients (41 %). Of these 46 patients, 83 % (38 patients) had persistent (131)I uptake in the salivary glands on both early and delayed scans. Among 55 patients with persistent (131)I uptake in the salivary glands, 69 % experienced symptomatic sialadenitis, while only 14 % of the other 57 patients experienced symptomatic sialadenitis (p < 0.0001). On the early (131)I scintigraphy, SURs of bilateral parotid glands on early scan in patients with symptomatic sialadenitis were significantly higher than in other patients (p = 0.001 for right and p = 0.004 for left). Further, patients with symptomatic sialadenitis had a higher decreasing rate of the SUR and shorter effective half-life of (131)I in bilateral parotid glands than other patients. Using visual analysis and SURs of right and left parotid glands on early (131)I scan as parameters, the sensitivities for predicting symptomatic sialadenitis were 83, 80, and 93 %, respectively. The mean values of effective half-life and absorbed dose in the parotid and submandibular glands were 20.8 +/- 6.3 h and 2.7 +/- 0.8 Gy, and 22.1 +/- 7.9 h and 2.8 +/- 1.1 Gy, respectively. CONCLUSIONS: Symptomatic sialadenitis can be predicted by post-therapeutic (131)I scintigraphy with high sensitivity. Post-therapeutic (131)I scintigraphy could provide effective information on the risk of symptomatic sialadenitis in DTC patients who underwent (131)I treatment. PMID- 23921837 TI - Evidence for the involvement of intracellular Ca(2+) ions in the elicitation mechanism of Bacillus licheniformis. AB - Treatment of Bacillus licheniformis cultures with biotic oligosaccharide elicitors is known to increase the production of the antibiotic bacitracin A. The mechanism of the elicitation is currently under investigation and in this paper we provide evidence on the modulatory role of Ca(2+) ions during this process. Addition of elicitors, mannan oligosaccharides, oligoguluronate and oligomannuronate to the liquid cultures resulted in 9.0, 5.2 and 5.0% increase in cytosolic Ca(2+) levels in B. licheniformis, while the presence of verapamil (Ca(2+) channel blocker) resulted in 74% decrease in bacitracin A levels, as compared to the control culture. We propose that Ca(2+) ions may acts as a secondary messenger in the regulation of the bacitracin A synthesis in the elicited B. licheniformis cultures. PMID- 23921838 TI - Epsilon aminocaproic acid prevents bleeding in severely thrombocytopenic patients with hematological malignancies. AB - BACKGROUND: Despite prophylactic platelet transfusions, bleeding remains a significant problem in thrombocytopenic patients. METHODS: The antifibrinolytic agent epsilon aminocaproic acid (EACA) was administered to 44 chronically (median duration, 273 days) and severely (platelet count, 8 * 10(9)/L; range, 1 * 10(9)/L 19 * 10(9)/L) thrombocytopenic patients with hematological malignancies. Prophylactic EACA at a dose of 1 g twice daily was orally administered for a median duration of 47 days (range, 7 days-209 days) until the platelet count recovered to > 30; * 10(9) /L. Platelets were only transfused if bleeding occurred. RESULTS: While receiving EACA, 59% of the patients did not bleed, 25% had 19 episodes of spontaneously resolving minor bleeding that did not require platelet transfusion, and 16% received a median of 4 platelet transfusions (range, 1 transfusion-8 transfusions) for 1 major traumatic and 9 spontaneous grade 2 to grade 3 bleeding (based on the World Health Organization classification of idiopathic thrombocytopenic purpura). No EACA toxicities were noted, and venous thromboses were not observed. CONCLUSIONS: EACA is well tolerated and is associated with a low risk of major bleeding in patients with hematological malignancies who are experiencing chronic severe thrombocytopenia. PMID- 23921839 TI - [Hirsutism and multinodular goiter in a 40-year-old female watchmaker]. AB - This article presents the case of a female patient with acromegaly caused by ectopic production of growth hormone-releasing hormone (GHRH) secretion. In the presence of typical clinical features of acromegaly but a lack of evidence for a pituitary adenoma the results of somatostatin receptor scintigraphy were indicative of a typical carcinoid of the lungs as the cause of the ectopic secretion of GHRH and the stimulation of pituitary gland growth hormone secretion resulting in acromegaly. Finally, the patient underwent curative surgical treatment. PMID- 23921840 TI - Use of antihypertensive medications and breast cancer risk among women aged 55 to 74 years. AB - IMPORTANCE: Antihypertensive agents are the most commonly prescribed class of medications in the United States. Evidence regarding the relationship between different types of antihypertensives and breast cancer risk is sparse and inconsistent, and prior studies have lacked the capacity to assess impacts of long-term use. OBJECTIVE: To evaluate associations between use of various classes of antihypertensive medications and risks of invasive ductal and invasive lobular breast cancers among postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS: Population-based case-control study in the 3-county Seattle-Puget Sound metropolitan area. Participants were women aged 55 to 74 years, 880 of them with invasive ductal breast cancer, 1027 with invasive lobular breast cancer, and 856 with no cancer serving as controls. EXPOSURES: Recency and duration of use of antihypertensive medications. MAIN OUTCOMES AND MEASURES: Risks of invasive ductal and invasive lobular breast cancers. RESULTS: Current use of calcium channel blockers for 10 or more years was associated with higher risks of ductal breast cancer (odds ratio [OR], 2.4; 95% CI, 1.2-4.9) (P= .04 for trend) and lobular breast cancer (OR, 2.6; 95% CI, 1.3-5.3) (P= .01 for trend). This relationship did not vary appreciably by type of calcium-channel blocker used (short-acting vs long-acting, dihydropyridines vs non-dihydropyridines). In contrast, use of diuretics, beta-blockers, and angiotensin II antagonists were not associated with risk. CONCLUSIONS AND RELEVANCE: While some studies have suggested a positive association between calcium-channel blocker use and breast cancer risk, this is the first study to observe that long-term current use of calcium-channel blockers in particular are associated with breast cancer risk. Additional research is needed to confirm this finding and to evaluate potential underlying biological mechanisms. PMID- 23921841 TI - Licochalcone A enhances geldanamycin-induced apoptosis through reactive oxygen species-mediated caspase activation. AB - BACKGROUND AND PURPOSE: Geldanamycin and licochalcone A induce apoptosis in cancer cells. However, whether the combination of geldanamycin and licochalcone A induced apoptosis in epithelial ovarian cancer cells is mediated by the formation of reactive oxygen species, leading to the activation of apoptotic caspase, has not been studied. EXPERIMENTAL APPROACH: Using the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3, we investigated the promoting effect of licochalcone A on geldanamycin-induced apoptosis. RESULTS: Geldanamycin induced changes in apoptosis-related protein levels, loss of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases, cleavage of PARP-1, formation of reactive oxygen species and depletion of glutathione (GSH). Licochalcone A enhanced geldanamycin-induced apoptosis-related protein activation, formation of reactive oxygen species, caspase activation and cell death. The combined effect was inhibited by the addition of oxidant scavengers. CONCLUSIONS: Licochalcone A may potentiate the apoptotic effect of geldanamycin on ovarian carcinoma cell lines by the activation of the caspase-8- and Bid-dependent pathways and the mitochondria-mediated apoptotic pathway. The apoptosis-promoting effect of licochalcone A may be mediated by its stimulatory action on the formation of reactive oxygen species and the depletion of GSH, which results in the activation of caspases. PMID- 23921844 TI - Sonographic quantification of a hepato-renal index for the assessment of hepatic steatosis in comparison with 3T proton magnetic resonance spectroscopy. AB - CONTEXT: Nonalcoholic fatty liver disease is the most frequent hepatic disorder in the developed world. Currently, liver biopsy and proton magnetic resonance spectroscopy (H-MRS) are considered the gold standard methods for the quantification of liver fat deposits. OBJECTIVE: To determine whether a Sonographic Hepato-Renal Index (SHRI) calculated using a standard workstation, without a specifically designed software, is an adequate alternative to H-MRS for the quantification of fat liver content and diagnosis of steatosis in the general population. METHODS: A total of 121 volunteers (mean age=46 years, range=21-77 years) were recruited at three medical centers in Granada (Southern Spain) from among individuals attending routine general checkups. All participants were examined by ultrasound and by H-MRS 3T, which served as a reference for the diagnosis of steatosis. The SHRI was calculated as the ratio between the echogenicity of the liver and that of the right renal parenchyma. The validity of the methodology was assessed by receiver operating characteristic curves and correlation tests. RESULTS: The quantitative SHRI showed a strong correlation (Spearman's coefficient=0.89, P<0.001) with the H-MRS 3T. The optimal SHRI cutoff points of 1.21, 1.28, and 2.15 yielded 100% sensitivity for the diagnoses of steatosis greater than 5, 25, and 50%, respectively, with a specificity greater than 70%. CONCLUSION: This study shows that the SHRI is a valid, simple, reliable, and cost-effective screening tool for the identification, assessment, and quantification of hepatic steatosis in the general population. PMID- 23921846 TI - Complete biopsy resection of diminutive polyps. AB - BACKGROUND AND STUDY AIMS: Cold biopsy forceps polypectomy (CBP) is commonly used for the removal of diminutive polyps; however, evidence for the efficacy of CBP is lacking. The aim of this study was to evaluate the adequacy of resection of diminutive polyps and to identify predictors for complete resection using CBP. PATIENTS AND METHODS: This was a prospective study from a tertiary referral hospital in Korea. A total of 196 patients were screened, and 65 patients with diminutive polyps were enrolled. CBP was used to resect diminutive polyps until no polyp was visible by chromoendoscopy using indigo carmine spray. Each polyp base was then resected using endoscopic mucosal resection (EMR) with a 1-3-mm free margin. CBP and EMR specimens were sent to the histopathology department for the evaluation of the completeness of the resection. Cross sections of the EMR specimens made at 1-mm intervals were examined by a pathologist. RESULTS: A total of 86 diminutive polyps were available for assessment. Overall, 90.7% (78/86) of the diminutive polyps were completely resected using CBP (95%CI 84.6-96.8%). The complete resection rate for all diminutive adenomas was 92.3 % (60/65; 95%CI 85.8 98.8%) and for 1-3-mm adenomas 100% (95%CI 81.5-100%). Polyp size, histology, and location, and number of biopsies were not different between the complete and incomplete resection groups. CONCLUSIONS: In this small study approximately 90 % of all diminutive polyps and 100% of 1-3-mm adenomatous polyps were completely resected using CBP and chromoendoscopy. CBP appears to be adequate for the resection of the majority of diminutive polyps, especially small sized adenomas (<= 3 mm) if no residual tissue is visible by chromoendoscopy. PMID- 23921845 TI - Smoking and smoking cessation in relation to the development of co-existing non small cell lung cancer with chronic obstructive pulmonary disease. AB - Previous studies have identified a mixed-phenotype of non-small cell lung cancer (NSCLC) with co-existing chronic obstructive pulmonary disease (COPD). Although NSCLC and COPD share a common risk factor in smoking, whether and how smoking may contribute to the coexistence of NSCLC with COPD (NSCLC-COPD) is unclear. Our study suggests that cigarette smoking is the major risk factor for the development of NSCLC-COPD, especially in females and among patients with squamous cell carcinoma subtype. PMID- 23921843 TI - Avian influenza: mixed infections and missing viruses. AB - A high prevalence and diversity of avian influenza (AI) viruses were detected in a population of wild mallards sampled during summer 2011 in California, providing an opportunity to compare results obtained before and after virus culture. We tested cloacal swab samples prior to culture by matrix real-time PCR, and by amplifying and sequencing a 640bp portion of the hemagglutinin (HA) gene. Each sample was also inoculated into embryonated chicken eggs, and full genome sequences were determined for cultured viruses. While low matrix Ct values were a good predictor of virus isolation from eggs, samples with high or undetectable Ct values also yielded isolates. Furthermore, a single passage in eggs altered the occurrence and detection of viral strains, and mixed infections (different HA subtypes) were detected less frequently after culture. There is no gold standard or perfect reference comparison for surveillance of unknown viruses, and true negatives are difficult to distinguish from false negatives. This study showed that sequencing samples prior to culture increases the detection of mixed infections and enhances the identification of viral strains and sequences that may have changed or even disappeared during culture. PMID- 23921847 TI - Assessing the impact of population stratification on association studies of rare variation. AB - AIMS: The study of rare variants, which can potentially explain a great proportion of heritability, has emerged as an important topic in human gene mapping of complex diseases. Although several statistical methods have been developed to increase the power to detect disease-related rare variants, none of these methods address an important issue that often arises in genetic studies: false positives due to population stratification. Using simulations, we investigated the impact of population stratification on false-positive rates of rare-variant association tests. METHODS: We simulated a series of case-control studies assuming various sample sizes and levels of population structure. Using such data, we examined the impact of population stratification on rare-variant collapsing and burden tests of rare variation. We further evaluated the ability of 2 existing methods (principal component analysis and genomic control) to correct for stratification in such rare-variant studies. RESULTS: We found that population stratification can have a significant influence on studies of rare variants especially when the sample size is large and the population is severely stratified. Our results showed that principal component analysis performed quite well in most situations, while genomic control often yielded conservative results. CONCLUSIONS: Our results imply that researchers need to carefully match cases and controls on ancestry in order to avoid false positives caused by population structure in studies of rare variants, particularly if genome-wide data are not available. PMID- 23921848 TI - Leaching behaviour of chlorpyriphos and cypermethrin in sandy loam soil. AB - The mobility of chlorpyriphos and cypermethrin in sandy loam soil was studied in soil columns under laboratory conditions at two application rates, 25 and 50 MUg, with simulated rainfall of 300 mm. Residues of chlorpyriphos and cypermethrin in soil and leachate were estimated by gas-liquid chromatography and confirmed by gas chromatography-mass spectrometry. Though maximum concentration of both the insecticides was found in the top 10-cm layer, chlorpyriphos was found distributed in the soil up to a depth of 35 cm and cypermethrin remained up to 15 cm. Results indicated the low mobility of both the insecticides under saturated moisture condition and hence may not contaminate ground water. No residues of any insecticide were detected in the leachate fractions. PMID- 23921849 TI - Reply to "Dural venous sinus thrombosis following head trauma: possible causes and safe imaging techniques". PMID- 23921850 TI - Correction of Chiari malformation due to closure of a concomitant thoracic meningocele. AB - INTRODUCTION: Chiari malformations are characterized by hindbrain herniation. Historically, some types have been linked to neural tube defects, but the causal relationship between the two conditions is still unclear. CASE REPORT: We report on a full-term male neonate with a prenatally diagnosed posterior thoracic meningocele, whose MRI demonstrated Chiari malformation. The meningocele was closed in the second week of life. The Chiari-related symptoms rapidly improved following surgery. Postoperative MRI at 7 months of age showed ascent of the cerebellar tonsils to a normal position. DISCUSSION: This case suggests that the traction on the cerebellum by a fixed spinal cord may play a role in the pathogenesis of the multifaceted Chiari malformations. PMID- 23921851 TI - Tissue response following papilla-sparing and sulcular incisions in oral surgery- an experimental study. AB - OBJECTIVES: The objective of this study is to compare tissue reduction following papilla-sparing and sulcular incisions in oral surgical indications. MATERIAL AND METHODS: Five beagle dogs were used. Three months after tooth extraction of P2 M1, notches were prepared at the height of the interproximal gingiva into M2 and P1. Papilla-sparing and sulcular incisions were randomly performed, full thickness flaps elevated and flaps repositioned. Three months postoperatively, tissue reduction was assessed using a digital calliper, mean values were calculated per group and analysed using a Wilcoxon matched-pair rank test. RESULTS: Papilla-sparing incisions revealed significantly less (p < 0.05) tissue reduction than sulcular incision techniques. CONCLUSION: Papilla-sparing incisions seem to induce less tissue response following flap surgery compared to sulcular incisions in oral surgical indications. Nevertheless, tissue reduction was seen in both groups. CLINICAL RELEVANCE: For surgical approaches without the necessity of direct access to the root surface (i.e., implantology, oral surgery), papilla-sparing incisions may be superior compared to sulcular incisions. PMID- 23921852 TI - Cheek rotation flap reconstruction--an anthropometric appraisal of surgical outcomes. AB - OBJECTIVES: Cheek rotation flaps are an established surgical procedure for coverage of facial skin defects especially of the cheek and infraorbital region. A comparison of pre- and postoperative anthropometric measurements may help to objectify intraoperative estimations with regards to postoperative appearance. MATERIALS AND METHODS: We present an evaluation of 31 patients undergoing periorbital reconstruction by a cheek rotation flap on standardized photographs based on reference anthropometric data. Analysis included intercanthal, binocular and eye fissure width, eye fissure, lid sulcus and upper lid height, upper and lower iris coverage, position of cornea to palpebra inferior, scleral show, ectropion, and canthal tilt. Furthermore, it was clearly differentiated whether the defect to cover included eyelid skin or not. RESULTS: Ectropion showed a significant association to surgery (p = 0.03) and time (p = 0.03). If the defect to cover included lower eyelid skin, lower iris coverage values decreased significantly (p = 0.02), meanwhile the rate of scleral show increased significantly (p < 0.01), indicating pre- to postoperative lower eyelid retraction. CONCLUSIONS: In all patients analyzed, indices were reproducible and reliable. An association between surgery and ectropion was detectable. Whenever lower eyelid skin is involved in the defect to be covered, the significantly decreased lower iris coverage and increased rate of scleral show indicate an increased risk of lower lid retraction. CLINICAL RELEVANCE: Whenever eyelid skin is involved in a defect to be covered by a cheek rotation flap, there is an increased risk of postoperative lower lid distortion. Special care has to be taken to perform techniques preventing lower lid retraction. PMID- 23921853 TI - Safe pregnancy in the world's poorest countries begins with access and ends with the obstetricians. PMID- 23921854 TI - Female health and family planning in Sierra Leone. AB - OBJECTIVE: To describe the current status of access to maternal care, family planning use, and place of delivery in Sierra Leone, one of the poorest countries in the world with one of the highest maternal mortality rates. METHODS: Data from the Surgeons OverSeas Assessment of Surgical Need, a cross-sectional two-stage cluster-based household survey conducted in Sierra Leone in 2012, were analyzed to determine access to maternal care, family planning use, and location of delivery. RESULTS: Of 3,318 females of reproductive age (12-50 years of age), 1,205 participants were interviewed in depth. Twenty percent (95% confidence interval [CI] 17.9-22.5) of respondents reported using family planning methods; injectables were the most frequently used method. Fifty-nine percent (95% CI 54.0 63.0) of the recalled deliveries took place outside of a health facility. Of the total births, 1.9% (95% CI 1.3-2.5) were reportedly delivered by cesarean and 0.4% (9/2,316) with instrumental delivery. There were 53 reported maternal deaths in the 12 months before the survey, resulting in a maternal mortality rate of 1,600 per 100,000 females per year. Of the maternal deaths, 30 females (56.6%) did not receive any type of modern health care with 53% (16/30) of families citing financial constraints. CONCLUSION: This study reaffirms a low family planning uptake and very low instrument deliveries and cesarean delivery rates in Sierra Leone. Additionally, financial barriers hinder access to health care and indicate that the free health care initiative for pregnant females is not yet fully covering the reproductive needs of the females of Sierra Leone. LEVEL OF EVIDENCE: III. PMID- 23921855 TI - Effect of child marriage on use of maternal health care services in Pakistan. AB - OBJECTIVE: To assess the association between child marriage (before 18 years of age) and maternal health care services use in Pakistan. METHODS: We limited the data from Pakistan Demographic and Health Survey, 2006-2007, to ever-married females aged 15-24 years with at least one childbirth (n=1,404) to identify differences in prenatal care provision (skilled or unskilled medical care provider), antenatal care (antenatal visits; care at home or a hospital), care at delivery (assistance by unskilled medical care provider), and place of birth by early (younger than 18 years) compared with adult (18 years or older) age at marriage. Associations between child marriage and health care services use were assessed by calculating adjusted odds ratios (OR) using logistic regression models after controlling for demographics, social equity indicators (education, wealth index, rural residence), employment status, and partners' education. RESULTS: Overall, 66.1% of ever-married respondents aged 15-24 years in Pakistan with at least one childbirth were married before the age of 18 years. More than half (61.9%) of females married as children had no formal education, and the majority (71.0%) resided in rural areas. Child marriage was significantly associated with decreased likelihood of any prenatal care (adjusted OR 0.73, 95% confidence interval [CI] 0.534-0.993) and prenatal care by skilled medical care providers (adjusted OR 0.64, 95% CI 0.476-0.871) and increased likelihood of delivery assistance by unskilled medical providers (adjusted OR 1.90, 95% CI 1.435-2.518) and delivery at home (adjusted OR 2.17, 95% CI 1.617-2.915). CONCLUSIONS: Efforts to increase the age of marriage and delay childbearing may have population-level effects on reducing disparities between females married as children and adults and improving maternal and child health in Pakistan. LEVEL OF EVIDENCE: II. PMID- 23921856 TI - Lessons learned from an obstetrics and gynecology field hospital response to natural disasters. AB - Field hospitals were deployed by the Israel Defense Forces as part of the international relief efforts after major seismic events, one in Haiti (2010) and one in Japan (2011). The teams treated a total of 44 pregnant and 24 nonpregnant women and performed 16 deliveries and three cesarean deliveries under extreme conditions. Half of all deliveries were complicated by preeclampsia and 31% were preterm (at 30-32 weeks of gestation). It is imperative that obstetrician gynecologists be included among humanitarian aid delegations sent to sites of natural disasters. The complicated cases we encountered required highly skilled obstetricians and led to a shortage of specific medications for these women. Cases that would have been considered routine under normal conditions created unanticipated ethical and practical issues in the face of very limited resources. The aim of this commentary is to share the experiences and lessons learned by our field hospital obstetrics and gynecology teams after the major earthquakes in Haiti and Japan. We present what we consider to be the 10 most important lessons learned and propose that they serve as guidelines in preparing for essential needs in other natural disaster settings. PMID- 23921857 TI - Prophylactic compared with therapeutic ibuprofen analgesia in first-trimester medical abortion: a randomized controlled trial. AB - OBJECTIVE: To compare the effectiveness of two oral analgesic regimens in first trimester medical abortion. METHODS: We randomly assigned 250 participants undergoing first-trimester abortion with mifepristone and misoprostol at three clinics to two ibuprofen regimens: therapeutic (800 mg every 4-6 hours as needed for pain) or prophylactic (800 mg starting 1 hour before the misoprostol dose, then every 4-6 hours for 48 hours regardless of pain, then as needed). We asked each participant to record her maximum pain on a scale of 0-10 daily thereafter. RESULTS: Of participants assigned to the prophylactic and therapeutic regimens, 111 of 123 (90%) and 117 of 127 (92%), respectively, provided follow-up data. More than 80% of the participants in each group complied with their assigned treatment. Participants in the prophylactic group used substantially more ibuprofen than those in the therapeutic group (median of nine and four tablets, respectively). The mean maximum pain score was 7.1 in the prophylactic group and 7.3 in the therapeutic group (standard deviations 2.5 and 2.2, respectively); the difference was not statistically significant (P=.87, adjusted for site). Duration of pain, verbal pain ratings reported at follow-up, and use of other analgesics did not differ significantly by group (all P>.05). No significant benefit of the prophylactic regimen was apparent in any population subgroup. Abortion failure and ibuprofen side effects in the two groups were similar. CONCLUSION: We found no evidence that prophylactic administration of ibuprofen reduces pain severity or duration in first-trimester medical abortion. The average pain severity experienced by participants using both regimens was high. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01457521. LEVEL OF EVIDENCE: I. PMID- 23921858 TI - Use of withdrawal and unintended pregnancy among females 15-24 years of age. AB - OBJECTIVE: To examine the prevalence of withdrawal (coitus interruptus) use among a cohort of U.S. females aged 15-24 years, to describe characteristics of withdrawal users, and to evaluate whether withdrawal users exhibit a higher risk of unintended pregnancy. METHODS: We analyzed the 2006-2008 National Survey of Family Growth, estimating with a Cox proportional hazards model the risk of an unintended pregnancy over and up to a 47-month retrospective period among females aged 15-24 years who used withdrawal relative to females who used only other methods of contraception. We also examined correlates of withdrawal use using a logit model. RESULTS: During the study period, 31.0% of females in our cohort used withdrawal. Of withdrawal users, 21.4% experienced an unintended pregnancy compared with 13.2% of females who used only other contraceptive methods (adjusted hazard ratio 1.75, 95% confidence interval [CI] 1.23-2.49). Withdrawal users were also 7.5% more likely to have used emergency contraception (adjusted odds ratio [OR] 1.57, 95% CI 1.13-2.20). Married females were 14.8% less likely than single females to use withdrawal (adjusted OR 0.58, 95% CI 0.35-0.96). CONCLUSION: Use of withdrawal as contraception is common and might place females at higher risk of unintended pregnancy. Health care providers should be aware that many patients may use withdrawal, should consider the need for emergency contraception among these females, and should encourage them to use more effective methods of contraception. LEVEL OF EVIDENCE: II. PMID- 23921859 TI - The case against cesarean delivery on maternal request in labor. AB - The ethical obligations of an obstetrician to a patient who requests a cesarean delivery without maternal or fetal indication differ depending on whether the request is made before or during labor. Informed consent is an essential dimension of respecting patient autonomy, and the process of informed consent should be extensive for a cesarean delivery in the absence of maternal or fetal indications during active labor. For this reason, physicians should rarely grant a request for cesarean delivery made during active labor. Although physicians may think that declining a request for cesarean delivery is a violation of patient autonomy, they should also be concerned about the violation of patient autonomy that results if they are unable to adequately complete the process of informed consent during labor. PMID- 23921860 TI - Lidocaine spray compared with submucosal injection for reducing pain during loop electrosurgical excision procedure: a randomized controlled trial. AB - OBJECTIVE: To examine the effectiveness of lidocaine spray compared with conventional lidocaine submucosal injection during a loop electrosurgical excision procedure (LEEP). METHODS: Women undergoing LEEP for any degrees of cervical intraepithelial neoplasia were invited to participate. The participants were randomly assigned into two groups. In group 1 (injection), the participants were anesthetized with 1.8 mL (36 mg) of 2% lidocaine with 1:100,000 epinephrine injected submucosally using a pressure syringe injector with a 27-gauge needle tip at 3, 6, 9, and 12 o'clock locations of the ectocervix. For group 2 (spray), the patients were locally anesthetized with four puffs (40 mg) of 10% lidocaine spray applied thoroughly to the ectocervix. The patients rated their pain according to a 10-cm visual analog scale at different points during the procedure including baseline, postanesthesia, excision, and 30 minutes postexcision. Primary outcomes were the excision pain score and its difference from the baseline. RESULTS: One hundred one patients (51 in the injection group and 50 in the spray group) participated in the study. The baseline pain scores, the excision pain scores, the difference between the excision and the baseline pain scores, and the postexcision pain scores were comparable between the study groups. The median postanesthesia pain score and the median difference of the postanesthesia score from baseline were significantly higher in the injection group, 3.4 compared with 0.6 and 1.9 compared with 0.0, respectively (P<.01). CONCLUSION: Lidocaine spray is an effective and practical alternative measure for reducing pain associated with electrical excision of the cervix during LEEP. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01505920. LEVEL OF EVIDENCE: I. PMID- 23921861 TI - Outcomes of subsequent pregnancies after uterine compression sutures for postpartum hemorrhage. AB - OBJECTIVE: To estimate the association between uterine compression sutures for postpartum hemorrhage and subsequent pregnancy outcomes. METHODS: We reviewed the medical records of 336 women who received uterine compression sutures to control postpartum hemorrhage during their first delivery at a single medical center between 2006 and 2011. Of these, 42 women who became pregnant again and received care through our hospital were included in this study. One hundred thirty-nine pregnant women matched for age and parity who did not receive uterine compression sutures during a previous cesarean delivery served as the control group. We compared subsequent pregnancy outcomes and operative findings during repeat cesarean delivery between the two groups. RESULTS: There were four (9.5%) miscarriages and one (2.4%) tubal pregnancy in the compression suture group compared with 14 (10.1%) miscarriages and two (1.5%) tubal pregnancies in the control group (P=.92 and P=.68, respectively). In the compression suture group, 34 (81.0%) women delivered at term and two (4.7%) women had preterm deliveries. In the control group, 114 (82.0%) women delivered at term and seven (5.0%) women had preterm deliveries (P=.88 and P=.60, respectively). The rate of pelvic adhesions on repeat cesarean delivery was significantly higher in the compression suture group than in the control group (34.3% compared with 17.5%, P=.03). CONCLUSIONS: Subsequent pregnancy outcomes were similar for women who did and those who did not receive uterine compression sutures during their prior delivery, whereas uterine adhesions at repeat cesarean delivery were more prevalent in women who received uterine compression sutures. LEVEL OF EVIDENCE: II. PMID- 23921862 TI - Effectiveness of mesh compared with nonmesh sling surgery in Medicare beneficiaries. AB - OBJECTIVE: To assess the effectiveness of mesh compared with nonmesh slings placed in different surgical settings as measured by the frequency of complications within 1 year. METHODS: We performed a retrospective cohort study of Medicare beneficiaries undergoing sling surgery from 2006 to 2008 in hospital outpatient departments and hospital-based ambulatory surgery centers. Slings were identified and categorized according to the use of mesh by Healthcare Common Procedure Coding System codes and temporary "C" Healthcare Common Procedure Coding System codes. Patients were followed for 1 year after each procedure to identify complications. Logistic models were fit to assess relationships among sling type, surgical setting, and various complications. RESULTS: We identified 6,698 Medicare beneficiaries who underwent mesh sling procedures and 445 Medicare beneficiaries who underwent nonmesh sling procedures. The overall frequency of complications was similar between the two groups at 69.8% and 72.6% in the mesh and nonmesh groups, respectively (P=.22). Infectious complications were the most common complication at 45.4% and 50.1% of the mesh and nonmesh groups, respectively (P=.06). Patients undergoing mesh procedures were less likely than patients undergoing nonmesh procedures to require management for bladder outlet obstruction (13.9% compared with 19.3%, adjusted odds ratio [OR] 0.66, 95% confidence interval [CI] 0.52-0.85) and were less likely to have a subsequent sling removal and revision or urethrolysis (2.7% compared with 4.7%, adjusted OR 0.56, 95% CI 0.35-0.89). CONCLUSION: Frequencies of most complications were similar regardless of the use of mesh except for the management of bladder outlet obstruction. These results did not differ based on the surgical setting where the sling procedure was performed. LEVEL OF EVIDENCE: II. PMID- 23921864 TI - Conflicts of interest and medical publishing. PMID- 23921863 TI - Risk factors for urinary, fecal, or dual incontinence in the Nurses' Health Study. AB - OBJECTIVE: To estimate the prevalence of urinary incontinence, fecal incontinence, and dual incontinence in a large cohort of older women and compare risk factors across the three conditions. METHODS: These cross-sectional analyses used data from the Nurses' Health Study. The 2008 questionnaire, mailed to 96,480 surviving participants aged 62-87 years, included two separate items on the prevalence of urinary and fecal incontinence. A response of leakage at least once per month defined incontinence for both urine and stool. Dual incontinence was defined by responses at this frequency for both conditions. Using a polytomous logistic regression model, we assessed each risk factor for prevalence of urinary, fecal, and dual incontinence. RESULTS: The survey was completed by 64,396 women. Thirty-eight percent had urinary incontinence alone, 4% had fecal incontinence alone, and 7% had dual incontinence. Age older than 80 years compared with age younger than 70 years was associated most strongly with dual incontinence (odds ratio [OR] 2.49, 95% confidence interval [CI] 2.28-2.73) followed by depression (OR 2.28, 95% CI 2.13-2.43), neurologic disease (OR 1.84, 95% CI 1.65-2.07), functional limitations (OR 1.86, 95% CI 1.71-2.02), multiparity (OR 1.66, 95% CI 1.41-1.94), and heavier fetal birth weight (OR 1.24, 95% CI 1.10-1.41). Obesity was associated only with urinary incontinence (OR 1.99, 95% CI 1.90-2.08) and type 2 diabetes mellitus was a stronger risk factor for fecal than urinary incontinence (OR 1.43, 95% CI 1.28-1.59). Black race was associated with a reduced risk of all types of incontinence, especially dual incontinence (OR 0.30, 95% CI 0.21-0.44). CONCLUSION: In this large cohort, dual incontinence was primarily associated with advanced age, decompensating medical conditions, depression, and multiparity. LEVEL OF EVIDENCE: II. PMID- 23921865 TI - Selma's gamble. PMID- 23921866 TI - Costs and clinical outcomes of noninvasive fetal RhD typing for targeted prophylaxis. AB - OBJECTIVE: To examine the cost and clinical outcomes of noninvasive RhD typing with cell-free fetal DNA to selectively deliver antenatal and postnatal prophylaxis with anti-D immune globulin for prevention of alloimmunization in RhD negative women. METHODS: We developed a decision tree to compare the costs and clinical outcomes of three strategies in an RhD-negative nonalloimmunized population as follows: 1) routine antenatal anti-D immune globulin prophylaxis and postpartum prophylaxis guided by cord blood typing (the current approach in most of the United States); 2) noninvasive fetal RhD typing with prophylaxis guided by test results; and 3) no screening or prophylaxis. Costs were estimated for testing and treatment algorithms using hospital billing records and information from the manufacturer of the fetal RhD genotyping test. Probability estimates were derived from published literature. The decision tree and sensitivity analyses were constructed and performed with Microsoft Excel. RESULTS: We estimated the cost of the current approach to prevention of alloimmunization to be $351 per pregnancy, and we estimated the cost of noninvasive determination of fetal RhD status to be $682. Assuming essentially perfect test performance, threshold analysis found the cost must decrease to $119 to break even. The gap widened in favor of routine prophylaxis in most other circumstances (increased false-negative test rate and decreasing prevalence of RhD negativity). CONCLUSION: Unless the cost of noninvasive fetal RhD typing is reduced substantially, routine antenatal anti-D immune globulin prophylaxis with postpartum prophylaxis guided by cord blood typing is less costly than noninvasive determination of fetal RhD status. PMID- 23921867 TI - Simple, validated vaginal birth after cesarean delivery prediction model for use at the time of admission. AB - OBJECTIVE: To create a simple tool for predicting the likelihood of successful trial of labor after cesarean delivery (TOLAC) during the pregnancy after a primary cesarean delivery using variables available at the time of admission. METHODS: Data for all deliveries at 14 regional hospitals over an 8-year period were reviewed. Women with one cesarean delivery and one subsequent delivery were included. Variables associated with successful VBAC were identified using multivariable logistic regression. Points were assigned to these characteristics, with weighting based on the coefficients in the regression model to calculate an integer VBAC score. The VBAC score was correlated with TOLAC success rate and was externally validated in an independent cohort using a logistic regression model. RESULTS: A total of 5,445 women met inclusion criteria. Of those women, 1,170 (21.5%) underwent TOLAC. Of the women who underwent trial of labor, 938 (80%) had a successful VBAC. A VBAC score was generated based on the Bishop score (cervical examination) at the time of admission, with points added for history of vaginal birth, age younger than 35 years, absence of recurrent indication, and body mass index less than 30. Women with a VBAC score less than 10 had a likelihood of TOLAC success less than 50%. Women with a VBAC score more than 16 had a TOLAC success rate more than 85%. The model performed well in an independent cohort with an area under the curve of 0.80 (95% confidence interval 0.76-0.84). CONCLUSIONS: Prediction of TOLAC success at the time of admission is highly dependent on the initial cervical examination. This simple VBAC score can be utilized when counseling women considering TOLAC. LEVEL OF EVIDENCE: II. PMID- 23921868 TI - Efficacy of a regional network for ovarian cancer care. AB - OBJECTIVE: To study the influence of a regional collaboration in epithelial ovarian cancer care on staging procedures, debulking results, and survival. METHODS: In an effort to optimize epithelial ovarian cancer treatment, a regional collaboration was introduced in the Netherlands in 2000. Gynecologic oncologists from the university center conducted surgery in community hospitals when ovarian cancer was considered based on the risk of malignancy index or clinical suspicion. The National Cancer Registry registered 1,554 patients with epithelial ovarian cancer diagnosed in 11 participating Dutch hospitals between 1996 and 2010. Surgical procedures were compared during three periods (1996-1999, 2000 2004, and 2005-2009). Log-rank tests compared Kaplan-Meier survival curves of progression-free and overall survival before (1996-2000) and during the start of the collaboration (2001-2005). RESULTS: Staging was adequate for 139 patients (23.0%) before collaboration, and this proportion increased during the study periods to 32.1% and 62.1% (P<.01), when gynecologic oncologists more often staged cancer in patients (36.7% compared with 54.7% and 80.6%; P<.01). For 1,197 patients with advanced stage disease (stage IIb or greater), the proportion of debulking procedures with an optimal (residual volume less than1 cm) as well as a complete result (no residuals) increased during the 14-year study period from 57.4% to 76.5% (P<.01) and from 24.1% to 43.4% (P<.01), respectively. Survival rates were similar before and during the start of the collaboration. In multivariable analysis, the treatment variables completeness of debulking, chemotherapy, and gynecologic oncologist attendance were independent prognostic factors for overall survival, as were age, stage, and tumor grade. CONCLUSIONS: After regional collaboration, gynecologic oncologists attended more surgeries and surgical outcomes improved, but progress in survival could not be demonstrated. Regional collaboration improved care for ovarian cancer patients. LEVEL OF EVIDENCE: II. PMID- 23921869 TI - Incidence of pregnancy-associated cancer in Denmark, 1977-2006. AB - OBJECTIVE: To estimate the incidence of pregnancy-associated cancer during a 30 year period in Denmark on the basis of both births and abortions with and without age adjustment and age standardization. METHODS: Using data from the nationwide Danish registries, we investigated the occurrence of pregnancy-associated cancer (defined as cancer diagnosed during pregnancy and up to 1 year after pregnancy has ended) in pregnancies resulting in a birth (live birth or stillbirth) or an abortion. We included patients with primary cancer diagnosed at ages 15-44 years during 1977-2006 according to the Danish Cancer Registry. The patients were linked to the Medical Birth Registry, the Registry for Induced Abortions, and the National Patient Registry to obtain information on pregnancies. RESULTS: We identified 2,426 patients with pregnancy-associated cancer. The three most frequent types were melanoma, cervical cancer, and breast cancer. We found an increase in the total numbers of all pregnancy-associated cancers from 572 cases during 1977-1986 to 1,052 cases during 1997-2006. The proportions of all pregnancy-associated cancers among all cancers increased from 5.4% to 8.3% during the same periods. The overall crude incidence rate of all pregnancy-associated cancer was 89.6 out of 100,000 pregnancies. The crude incidence increased over time, with an average annual percentage change of 2.9% (95% confidence interval [CI] 2.4-3.3). After age adjustment, the increase was still statistically significant (1.6%, 95% CI 1.1-2.1). CONCLUSION: We found a statistically significant increase in pregnancy-associated cancer during the 30-year study period. The tendency to postpone childbirth only partly explains the increase in incidence rates. LEVEL OF EVIDENCE: III. PMID- 23921870 TI - Maternal morbidity and risk of death at delivery hospitalization. AB - OBJECTIVE: To examine the effect of underlying maternal morbidities on the odds of maternal death during delivery hospitalization. METHODS: We used data that linked birth certificates to hospital discharge diagnoses from singleton live births at 22 weeks of gestation or later during 1995-2003 in New York City. Maternal morbidities examined included prepregnancy weight more than 114 kilograms (250 pounds), chronic hypertension, pregestational or gestational diabetes mellitus, chronic cardiovascular disease, pulmonary hypertension, chronic lung disease, human immunodeficiency virus (HIV), and preeclampsia or eclampsia. Associations with maternal mortality were estimated using multivariate logistic regression. RESULTS: During the specified time period, 1,084,862 live singleton births and 132 maternal deaths occurred. Patients with increasing maternal age, non-Hispanic black ethnicity, self-pay or Medicaid, primary cesarean delivery, and premature delivery had higher rates of maternal mortality during delivery hospitalization. From the entire study population, 4.1% had preeclampsia or eclampsia (n=44,004), 1.8% had chronic hypertension (n=19,647), 1.1% of patients were classified as obese (n=11,936), 0.7% had pregestational diabetes (n=7,474), 0.4% had HIV (n=4,665), and 0.01% had pulmonary hypertension (n=166). Preeclampsia or eclampsia (adjusted odds ratio [OR], 8.1; 95% confidence interval [CI], 5.5-12.1), chronic hypertension (adjusted OR, 7.7; 95% CI 4.7 12.5), underlying maternal obesity (adjusted OR, 2.9; 95% CI 1.1-8.1), pregestational diabetes (adjusted OR, 3.3; 95% CI 1.3-8.1), HIV (adjusted OR, 7.7; 95% CI 3.4-17.8), and pulmonary hypertension (adjusted OR, 65.1; 95% CI 15.8 269.3) were associated with an increased risk of death during the delivery hospitalization. CONCLUSION: The presence of maternal disease significantly increases the odds of maternal mortality at the time of delivery hospitalization. LEVEL OF EVIDENCE: II. PMID- 23921871 TI - Glycosylated fibronectin as a first-trimester biomarker for prediction of gestational diabetes. AB - OBJECTIVE: To evaluate the potential clinical utility of serum biomarkers for first-trimester prediction of gestational diabetes mellitus (GDM). METHODS: Maternal serum concentrations of glycosylated (Sambucus nigra lectin-reactive) fibronectin, adiponectin, sex hormone-binding globulin, placental lactogen, and high-sensitivity C-reactive protein (CRP) were measured at 5-13 weeks of gestation in a case-control study of 90 pregnant women with subsequent development of GDM and in 92 control group participants. Ability to detect GDM was assessed using logistic regression modeling and receiver operating characteristic (ROC) curves. Classification performance and positive and negative predictive values were reported at specific thresholds. Glycosylated fibronectin variation across trimesters was evaluated using a serial-measures analysis of 35 nondiabetic control group participants. RESULTS: First-trimester serum concentrations of glycosylated fibronectin, adiponectin, high-sensitivity CRP, and placental lactogen were significantly associated (P<.001) with GDM. After adjustment for maternal factors and other biomarkers, glycosylated fibronectin demonstrated an independent association with GDM (P<.001). Adiponectin, high sensitivity CRP, and placental lactogen demonstrated modest classification performance compared with glycosylated fibronectin (respectively: area under the curve [AUC] 0.63; 95% confidence interval [CI] 0.53-0.71; AUC 0.68; 95% CI 0.60 0.76; and AUC 0.67, 95% CI 0.59-0.75; compared with AUC 0.91; 95% CI 0.87-0.96). Glycosylated fibronectin levels above a threshold of 120 mg/L correctly identified 57 GDM case group participants with a positive predictive value of 63% (95% CI 53-72%) and a negative predictive value of 95% (95% CI 94-95%) at a population prevalence of 12%. There was no association between sex hormone binding globulin and GDM. CONCLUSION: First-trimester glycosylated fibronectin is a potential pregnancy-specific biomarker for early identification of women at risk for GDM. LEVEL OF EVIDENCE: II. PMID- 23921872 TI - Obesity epidemic: truth or consequences. PMID- 23921874 TI - Effect of smoking cessation on gestational and postpartum weight gain and neonatal birth weight. AB - OBJECTIVE: To examine the association among smoking cessation, gestational and postpartum weight gain, and neonatal birth weight. METHODS: We analyzed prospectively collected data from 1,774 women with term singleton pregnancies. Smoking status during pregnancy was categorized as nonsmokers, smokers, and quitters; and smoking status 1 year postpartum as nonsmokers, smokers, relapsed quitters, and sustained quitters. The association between smoking status and gestational weight gain, weight gain 1 year postpartum, and neonatal birth weight was tested by linear regression analysis, and the association between smoking status and neonatal birth weight less than the 10th percentile for gestational age and sex was tested by multivariable logistic regression analysis. RESULTS: Gestational weight gain at 16 weeks of gestation was comparable for nonsmokers, smokers, and quitters. The adjusted mean gestational weight gain at 37 weeks of gestation was 2.0 kg (95% confidence interval [CI] 1.5-2.6) higher in quitters compared with nonsmokers. The rate of neonatal birth weight less than the 10th percentile was 21.7% among smokers, 8.0% among quitters, and 7.4% among nonsmokers. The adjusted odds ratio (OR) for birth weight less than 10th percentile was 3.6 (95% CI 2.5-5.2) in neonates born to smokers; the risk was similar for quitters (OR 1.0, 95% CI 0.6-1.6). One year after delivery, sustained quitters had a 2.4-kg (95% CI 1.6-3.1) higher adjusted postpartum weight gain than nonsmokers. CONCLUSION: Smoking cessation is associated with gestational as well as postpartum weight gain. However, smoking cessation is associated with a substantially lower rate of neonatal birth weight less than the 10th percentile. LEVEL OF EVIDENCE: II. PMID- 23921873 TI - Antiphospholipid antibodies in stillbirth. AB - OBJECTIVE: To compare antiphospholipid antibodies in deliveries with and without stillbirth using a multicenter, population-based case-control study of stillbirths and live births. METHODS: Maternal sera were assayed for immunoglobulin (Ig)G and IgM anticardiolipin and anti-beta2-glycoprotein-I antibodies. Assays were performed in 582 stillbirth deliveries and 1,547 live birth deliveries. RESULTS: Elevated levels of IgG anticardiolipin and IgG anti beta2-glycoprotein-I antibodies were associated with an approximate threefold increased odds of stillbirth (crude odds ratio [OR] 3.43, 95% confidence interval [CI] 1.79-6.60, 3.8% compared with 1.1% and OR 3.17, 95% CI 1.30-7.72, (1.9% compared with 0.6%, respectively) when all deliveries with stillbirth were compared with all deliveries with live birth. When the subset of stillbirths not associated with fetal anomalies or obstetric complications was compared with term live births, elevated IgG anticardiolipin antibodies were associated with stillbirth (5.0% compared with 1.0%; OR 5.30, 95% CI, 2.39-11.76; IgG anti-beta2 glycoprotein-I antibodies (1.9% compared with 0.6%) had an OR of 3.00 (95% CI 1.01-8.90) and IgM anticardiolipin antibodies (6.0% compared with 3.0%) had an OR of 2.03 (95% CI 1.09-3.76). Elevated levels of anticardiolipin and anti-beta2 glycoprotein-I antibodies were associated with a threefold to fivefold increased odds of stillbirth. CONCLUSIONS: Our data support consideration of testing for antiphospholipid antibodies in cases of otherwise unexplained stillbirth. LEVEL OF EVIDENCE: II. PMID- 23921875 TI - Manual rotation to decrease operative delivery in posterior or transverse positions. AB - OBJECTIVE: To assess the effect of a policy of manual rotation on the mode of delivery of fetuses in posterior or transverse positions at full dilatation. METHODS: This was a prospective study to compare two policies of management for posterior and transverse positions in two different hospitals (Hospital 1: no manual rotation and Hospital 2: manual rotation). We used univariable and multivariable analyses to study the association between the management policy for posterior and transverse positions at full dilatation in these hospitals and maternal and neonatal outcomes. The principal end point was operative delivery (ie, cesarean or instrumental vaginal delivery). All factors associated with the risk of operative delivery in the univariable analysis (P<.1) were included in the logistic regression models. We then specifically studied whether manual rotation was independently associated with a reduction in operative deliveries. RESULTS: The rate of posterior or transverse positions at full dilatation was 15.9% (n=111) in Hospital 1 and 15.3% (n=220) in Hospital 2 (P=.75). Of the 172 attempts of manual rotation in Hospital 2, 155 (90.1%) were successful. The rate of operative delivery was significantly lower in Hospital 2, which performed manual rotations (23.2% compared with 38.7% in Hospital 1, adjusted odds ratio [OR] 0.52, 95% confidence interval [CI] 0.28-0.95). After multivariable analysis, manual rotation remained significantly associated with a reduction in the risk of operative delivery (adjusted OR 0.45, 95% CI 0.25-0.85). Five-minute Apgar score and arterial pH at birth were similar in the two hospitals. CONCLUSION: For fetuses in posterior or transverse positions at full dilatation, a strategy of manual rotation is associated with a reduction in the rate of operative delivery. LEVEL OF EVIDENCE: III. PMID- 23921876 TI - Inactivated influenza vaccine during pregnancy and risks for adverse obstetric events. AB - OBJECTIVE: To compare risks for adverse obstetric events between females who did and did not receive trivalent inactivated influenza vaccine during pregnancy. METHOD: This retrospective, observational cohort study was conducted at seven Vaccine Safety Datalink sites. Pregnancies were identified from administrative and claims data using a validated algorithm. Females vaccinated while pregnant from 2002 to 2009 were matched one-to-two with replacement to unvaccinated pregnant females. Using a generalized estimating equation method with a Poisson distribution and log link, we evaluated the association of trivalent inactivated influenza vaccine with 13 outcomes. Given our large sample size and multiple comparisons (19 contrasts), a cutoff for significance of P<.005 was selected a priori. RESULTS: Our cohort included 74,292 vaccinated females matched on age, site, and pregnancy start date with 144,597 unvaccinated females. We did not observe increased risks within 42 days of vaccination for hyperemesis, chronic hypertension, gestational hypertension, gestational diabetes, proteinuria, or urinary tract infection. Using a risk window from vaccination through pregnancy end, we did not observe increased risks after vaccination for proteinuria, urinary tract infection, gestational hypertension, preeclampsia or eclampsia, chorioamnionitis, puerperal infection, venous complications, pulmonary embolism, or peripartum cardiomyopathy. A reduced risk for gestational diabetes after vaccination was detected (adjusted hazard rate ratio 0.88, 95% confidence interval 0.83-0.93), likely as a result of healthy vaccine bias or earlier detection among vaccinees. CONCLUSION: In this large cohort, influenza vaccination during pregnancy was not associated with increased risks for medically attended adverse obstetric events. LEVEL OF EVIDENCE: II. PMID- 23921877 TI - Laboring through informed consent. PMID- 23921878 TI - Norethindrone acetate 1.0 milligram and ethinyl estradiol 10 micrograms as an ultra low-dose oral contraceptive. AB - OBJECTIVE: To assess the efficacy, safety, and tolerability of an extended duration, combined hormonal oral contraceptive pill (OCP) that reduces the estrogen exposure by almost half compared with other OCPs. METHODS: This open label, uncontrolled, multicenter study used an ultra low-dose OCP (1.0 mg norethindrone acetate and 10 micrograms ethinyl E2). The OCP was administered in a regimen of 24 days of a 28-day cycle followed by 10 micrograms ethinyl E2 for 2 days and an inactive tablet for 2 days. The study included healthy, heterosexually active women aged 18-45 years who were at risk of pregnancy. RESULTS: The discontinuation rate was 41.7% (692/1,660 patients). Twenty-six pregnancies occurred in 1,555 participants during 15,596 at-risk cycles, resulting in a Pearl Index of 2.2 and a cumulative pregnancy rate of 2.1 for the overall population. Participants experienced an average of 2.6 days of intracyclic (unscheduled) bleeding or spotting per cycle over treatment cycles 213. Intracyclic bleeding was more common in users new to OCPs than in users switching from another OCP and in women aged 18-35 years compared with those aged 36 years or older. The frequency of bleeding episodes decreased after cycle 2 and throughout treatment in all subpopulations. CONCLUSION: The findings of this study demonstrate that this ultra low-dose OCP regimen is effective in preventing pregnancy with a safety and tolerability profile that is comparable with that reported for other low-dose OCPs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00391807. LEVEL OF EVIDENCE: III. PMID- 23921879 TI - Endometrial stromal sarcoma: a systematic review. AB - OBJECTIVE: To summarize available studies with respect to evaluation and management of patients with endometrial stromal sarcoma and undifferentiated endometrial sarcoma. DATA SOURCES: We conducted an electronic search of research articles published in English between January 1, 1981, and January 1, 2013, using MEDLINE, PubMed, and ClinicalTrials.gov (www.clinicaltrials.gov) databases. METHODS OF STUDY SELECTION: Of the 115 studies initially identified, 86 were chosen after limiting the review to those articles focusing on endometrial stromal sarcoma and crossreferencing to eliminate duplication. Review articles were excluded. Of the 86 studies meeting eligibility criteria, 84 were retrospective, one was a prospective phase II trial, and one was a phase III randomized study. Data were extracted systematically. Each of the reviewers assessed the quality of each study independently. TABULATION, INTEGRATION, AND RESULTS: Data were abstracted using standard abstraction templates to summarize study findings. Given the rarity of this tumor, we report available data with respect to epidemiology, pathogenesis, prognostic factors, and treatment. Endometrial stromal sarcoma and undifferentiated endometrial sarcoma comprise an estimated 1% of all uterine cancers and less than 10% of all uterine mesenchymal neoplasms. Hysterectomy and bilateral salpingo-oophorectomy is the cornerstone of treatment for early-stage (I or II) disease. Surgical resection when feasible may also be appropriate for patients presenting with advanced-stage tumors. The value of adjuvant therapy for early-stage disease remains unproven. Hormone therapy continues to be the most efficacious treatment modality for patients with advanced-stage or recurrent disease. CONCLUSION: Endometrial stromal sarcoma and undifferentiated endometrial sarcoma are rare tumors. Surgical resection is appropriate for patients with early-stage (I or II) disease and those with resectable, advanced-stage (III or IV) tumors. Hormone therapy may be appropriate in treating advanced and recurrent disease. PMID- 23921880 TI - What is new in postpartum hemorrhage? Best articles from the past year. AB - This month, we focus on current research in postpartum hemorrhage. Dr. Rouse discusses five recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 23921882 TI - A systematic review and meta-regression of temporal trends in adult CD4(+) cell count at presentation to HIV care, 1992-2011. AB - BACKGROUND: The clinical status of human immunodeficiency virus (HIV)-positive persons at the time of presentation to medical care has important individual- and population-level implications. METHODS: We synthesized the literature on clinical status of adults newly presenting to care for HIV infection in developed countries to generate an estimate of the time trend for CD4 cell count at the initiation of HIV care. We systematically searched PubMed for studies published between January 2000 and November 2011 to identify those that reported CD4 cell count for patients newly presenting to HIV care according to standardized inclusion criteria. We abstracted the mean or median CD4 cell count or reconstructed the mean CD4 cell count from the presented data describing the number or proportion of patients in CD4 cell count categories. We estimated the change in CD4 cell count over time by modeling it as a weighted linear function of calendar year. RESULTS: Based on a meta-regression of 197 point estimates encompassing CD4 cell count measurements from 169 007 patients in 44 studies, mean CD4 cell count at presentation increased minimally by 1.5 cells/MUL per year (95% CI, -6.1 to 5.5 cells/MUL per year), from 307 cells/MUL in 1992 to 336 cells/MUL in 2011. CONCLUSIONS: In developed countries, patients' CD4 cell counts at first presentation to medical care have not increased meaningfully over the past 20 years. New and innovative strategies are imperative to identify persons earlier in the course of their infection and link them promptly with medical care. PMID- 23921883 TI - Editorial commentary: Under the spell of the red queen. PMID- 23921881 TI - The incidence of AIDS-defining illnesses at a current CD4 count >= 200 cells/MUL in the post-combination antiretroviral therapy era. AB - BACKGROUND: Few studies consider the incidence of individual AIDS-defining illnesses (ADIs) at higher CD4 counts, relevant on a population level for monitoring and resource allocation. METHODS: Individuals from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) aged >=14 years with >=1 CD4 count of >=200 uL between 1998 and 2010 were included. Incidence rates (per 1000 person-years of follow-up [PYFU]) were calculated for each ADI within different CD4 strata; Poisson regression, using generalized estimating equations and robust standard errors, was used to model rates of ADIs with current CD4 >=500/uL. RESULTS: A total of 12 135 ADIs occurred at a CD4 count of >=200 cells/uL among 207 539 persons with 1 154 803 PYFU. Incidence rates declined from 20.5 per 1000 PYFU (95% confidence interval [CI], 20.0-21.1 per 1000 PYFU) with current CD4 200-349 cells/uL to 4.1 per 1000 PYFU (95% CI, 3.6 4.6 per 1000 PYFU) with current CD4 >= 1000 cells/uL. Persons with a current CD4 of 500-749 cells/uL had a significantly higher rate of ADIs (adjusted incidence rate ratio [aIRR], 1.20; 95% CI, 1.10-1.32), whereas those with a current CD4 of >=1000 cells/uL had a similar rate (aIRR, 0.92; 95% CI, .79-1.07), compared to a current CD4 of 750-999 cells/uL. Results were consistent in persons with high or low viral load. Findings were stronger for malignant ADIs (aIRR, 1.52; 95% CI, 1.25-1.86) than for nonmalignant ADIs (aIRR, 1.12; 95% CI, 1.01-1.25), comparing persons with a current CD4 of 500-749 cells/uL to 750-999 cells/uL. DISCUSSION: The incidence of ADIs was higher in individuals with a current CD4 count of 500 749 cells/uL compared to those with a CD4 count of 750-999 cells/uL, but did not decrease further at higher CD4 counts. Results were similar in patients virologically suppressed on combination antiretroviral therapy, suggesting that immune reconstitution is not complete until the CD4 increases to >750 cells/uL. PMID- 23921884 TI - Physical activity is related to the structural integrity of cerebral white matter. AB - OBJECTIVE: To investigate the relation between physical exercise and the microstructural integrity of cerebral white matter. METHODS: Four hundred forty individuals with cerebral small-vessel disease, aged between 50 and 85 years, without dementia, were included and underwent MRI scanning. Physical exercise was assessed with a structured questionnaire. The cross-sectional relation between physical exercise and the microstructural integrity of the white matter was assessed by applying Tract-Based Spatial Statistics to diffusion tensor imaging parameters. RESULTS: Being more physically active was negatively related to the mean, axial, and radial diffusivity in numerous regions of the white matter, indicative of higher white matter integrity. CONCLUSIONS: These data indicate an association between physical activity and the integrity of the cerebral white matter's microstructure. Prospective studies are required to investigate a possible causal association between physical activity and cognitive decline. PMID- 23921885 TI - Diagnostic challenge and therapeutic dilemma in necrotizing myopathy. PMID- 23921887 TI - Hunting for autoantibodies in multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS. Many findings support the assumption that the immune system plays a key role in the pathogenesis of MS, at least during the relapsing-remitting phase of disease.(1,2) Both arms of the adapted immune response seem to be crucial for the induction and maintenance of the autoimmune response as suggested by the success of therapies targeting T cells, B cells, or both. While genes and pathways involved in the pathogenesis of MS have emerged from recent studies, the molecular targets of the autoimmune response in MS are still largely uncertain. The identification of these targets, to better understand the pathogenesis and develop specific immune therapies, has been the focus of MS research during the last decades. PMID- 23921886 TI - Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. AB - OBJECTIVE: To profile the reactivity of CSF-derived immunoglobulin from patients with multiple sclerosis (MS) against a large panel of antigens, to identify disease-specific reactivities. METHODS: CSF from subjects with MS with elevated immunoglobulin G and CSF from control subjects presenting with other inflammatory neurologic disease were screened against a protein array consisting of 9,393 proteins. Reactivity to a candidate protein identified using these arrays was confirmed with ELISA and immunocytochemistry. RESULTS: Autoantibodies against one protein on the array, recombination signal binding protein for immunoglobulin kappa J region (RBPJ), discriminated between patients with MS and controls (p = 0.0052). Using a large validation cohort, we found a higher prevalence of autoantibodies against RBPJ in the CSF of patients with MS (12.5%) compared with the CSF of patients with other neurologic diseases (1.6%; p = 0.02) by ELISA. This difference in reactivity was restricted to the CSF as serum reactivity against RBPJ did not differ between patients and controls. The presence of CSF autoantibodies against RBPJ was further confirmed by immunocytochemistry. CONCLUSIONS: These data indicate that RBPJ, a ubiquitous protein of the Notch signaling pathway that plays an important role in Epstein-Barr virus infection, is a novel MS autoantigen candidate that is recognized by CSF-derived immunoglobulin G in a subset of patients with MS. PMID- 23921888 TI - Analysis of clinicopathological features and prognostic factors of desmoplastic small round cell tumor. AB - Desmoplastic small round cell tumor (DSRCT) is a relatively uncommon and highly aggressive malignancy in young males. It is associated with a poor outcome, due in part to missed diagnosis. To characterize the clinical pathological features of DSRCT in Chinese patients and to find out the characteristics of treatment and prognostic factors, the authors collected and analyzed the clinical information of 48 cases. A total of 48 cases of DSRCT between March 1995 and March 2012 were retrospectively reviewed and analyzed. The clinical information, histological results and survival data of the patients were collected. Median age was 26.96 +/ 14.09 years with a range of 6-66 years. Thirty-three patients (68.75%) were seen before 30 years old, and 15 patients (31.25%) were diagnosed after 30 years old. The male-to-female ratio is 3.36 :1. Among them, 37 cases presented with tumors in the abdominal or pelvic cavity; the other 11 cases had extra-abdominal tumors. The most common symptoms were abdominal pain (19/48, 39.58%) and palpable mass (12/48, 25.00%). The percentage of patients received surgery, complete surgery, and chemotherapy was 79.17%, 37.50%, and 52.08%, respectively. Median follow-up duration was 2.67 years. Median overall survival for all patients was 24.33 months (95% CI: 9.74-38.92 months) and median event-free survival for all patients was 8.00 months (95% CI: 5.13-10.89 months). Univariate analysis revealed that surgery, effective debulking surgery, chemotherapy and any two or more combined therapeutics were significant prognostic factors for longer overall survival (p < 0.05). Cox regression analysis showed complete surgery was an independent prognostic factor. Standard therapy for DSRCT consists of combination of surgical resection and postoperative chemotherapy. Complete surgery is an independent prognostic factor and should be further investigated. PMID- 23921889 TI - Correctness is mandatory in science: response to 'Correct determination of critical flicker frequency is mandatory when comparisons to other tests are made'. PMID- 23921890 TI - Treatment of patients with dual hepatitis B and C: a step in the right direction. PMID- 23921891 TI - Effect of prophylactic cranial irradiation on survival in elderly patients with limited-stage small cell lung cancer. AB - BACKGROUND: Prophylactic cranial irradiation (PCI) improves survival in patients with limited-stage small cell lung cancer (SCLC) who have a complete response to chemotherapy and radiotherapy, yet to the best of the authors' knowledge, data specific to the elderly population are lacking. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, the authors identified 1926 patients aged >= 70 years who were diagnosed with limited-stage SCLC between 1988 and 1997. Overall survival (OS) for patients who received PCI versus those who did not were estimated using the Kaplan-Meier method and compared with the log rank test. A Cox proportional hazards model was further fitted to estimate the effect of PCI on OS after adjusting for age, race, sex, tumor size, lymph node status, stage of disease, and receipt of thoracic radiotherapy and surgery. RESULTS: The median age of the patients was 75 years (range, 70 years-94 years) and 138 patients (7.2 %) received PCI. The 2-year and 5-year OS rates were 33.3% (95% confidence interval [95% CI], 25.6%-41.2%) and 11.6% (95% CI, 6.9%-17.6%), respectively, among patients who received PCI versus 23.1% (95% CI, 21.2%-25.1%) and 8.6% (95% CI, 7.3%-9.9%), respectively, among patients who did not receive PCI (P = .028). On multivariable analysis, PCI was found to be an independent predictor of OS (hazards ratio, 0.72; 95% CI, 0.54-0.97 [P = .032]). On subgroup analysis, PCI remained an independent predictor of OS among patients aged >= 75 years, but not among patients aged >= 80 years. CONCLUSIONS: The receipt of PCI is associated with improved OS in patients aged >= 70 years with SCLC, suggesting that the benefit of PCI is maintained in the elderly population. PMID- 23921892 TI - Evolution to twice daily bolus intravenous tacrolimus: optimizing efficacy and safety of calcineurin inhibitor delivery early post lung transplant. AB - BACKGROUND: Achieving therapeutic levels of cyclosporine (CSA) or Tacrolimus (TAC) early post lung transplantation (LTx) is challenging. Gut dysmotility, renal dysfunction and seizure risk are variably present and problematic. This study reports a single center. MATERIAL AND METHODS: All adult LTx recipients from Aug 06-Aug 11 were divided into 4 cohorts: A) intravenous (IV) CSA twice daily (BD) 6 hr bolus then oral CSA, n=63; B) sub-lingual (SL) TAC BD then oral TAC, n=90; C) oral TAC BD, n=18; and D) IV TAC BD 4hr bolus then oral TAC, n=62. CSA/TAC trough levels were measured at days 1-7, 14 and 28 aiming for target trough levels >250 ng/ml and >8ng/ml respectively. RESULTS: There were no differences in demographics, ICU and total length of stay between groups. Target trough levels were achieved in 13%*#, 26%*, 17% and 37%# of patients for Groups A D respectively, (*#p<0.05) by day 7, increasing to 65%, 74%, 88% and 72% by day 14 (p=ns). Acute rejection at day 14 was seen in 3%*, 6%, 17%* and 5% respectively (*p<0.05) Acute rejection <90days was noted in 15%, 17%, 22% and 11% respectively (p=ns). No significant difference in neurotoxicity or acute nephrotoxicity was apparent across the groups. CONCLUSIONS: Early post LTx, SL and oral routes of immunosuppressive administration are less efficacious than intravenous. BD bolus IV TAC achieved significantly higher target levels earlier, with correspondingly lower acute rejection rates and acceptable safety of administration. PMID- 23921893 TI - Single-walled carbon nanotubes for high-performance electronics. AB - Single-walled carbon nanotubes (SWNT) could replace silicon in high-performance electronics with their exceptional electrical properties and intrinsic ultra-thin body. During the past five years, the major focus of this field is gradually shifting from proof-of-concept prototyping in academia to technology development in industry with emphasis on manufacturability and integration issues. This article reviews recent advances, starting with experimental and modeling works that evaluate the potential of adopting SWNTs in ultimately scaled transistors. Techniques to separate nanotubes according to their electronic types and assemble them into aligned arrays are then discussed, followed by a description of the engineering aspects in their implementation in integrated circuits and systems. A concluding discussion provides some perspectives on future challenges and research opportunities. PMID- 23921894 TI - The role of PARL and HtrA2 in striatal neuronal injury after transient global cerebral ischemia. AB - The presenilin-associated rhomboid-like (PARL) protein and high temperature requirement factor A2 (HtrA2) are key regulators of mitochondrial integrity and play pivotal roles in apoptosis. However, their roles after cerebral ischemia have not been thoroughly elucidated. To clarify these roles, mice were subjected to transient global cerebral ischemia, and striatal neuronal injury was assessed. Western blot and coimmunoprecipitation analyses revealed that PARL and processed HtrA2 localized to mitochondria, and that PARL was bound to HtrA2 in sham animals. Expression of PARL and processed HtrA2 in mitochondria significantly decreased 6 to 72 hours after ischemia, and the binding of PARL to HtrA2 disappeared after ischemia. In contrast, expression of processed HtrA2 increased 24 hours after ischemia in the cytosol, where HtrA2 was bound to X chromosome linked inhibitor-of-apoptosis protein (XIAP). Administration of PARL small interfering RNA inhibited HtrA2 processing and worsened ischemic neuronal injury. Our results show that downregulation of PARL after ischemia is a key step in ischemic neuronal injury, and that it decreases HtrA2 processing and increases neuronal vulnerability. In addition, processed HtrA2 released into the cytosol after ischemia contributes to neuronal injury via inhibition of XIAP. PMID- 23921895 TI - Cerebral blood flow quantification using vessel-encoded arterial spin labeling. AB - Arterial spin labeling (ASL) techniques are gaining popularity for visualizing and quantifying cerebral blood flow (CBF) in a range of patient groups. However, most ASL methods lack vessel-selective information, which is important for the assessment of collateral flow and the arterial supply to lesions. In this study, we explored the use of vessel-encoded pseudocontinuous ASL (VEPCASL) with multiple postlabeling delays to obtain individual quantitative CBF and bolus arrival time maps for each of the four main brain-feeding arteries and compared the results against those obtained with conventional pseudocontinuous ASL (PCASL) using matched scan time. Simulations showed that PCASL systematically underestimated CBF by up to 37% in voxels supplied by two arteries, whereas VEPCASL maintained CBF accuracy since each vascular component is treated separately. Experimental results in healthy volunteers showed that there is no systematic bias in the CBF estimates produced by VEPCASL and that the signal-to noise ratio of the two techniques is comparable. Although more complex acquisition and image processing is required and the potential for motion sensitivity is increased, VEPCASL provides comparable data to PCASL but with the added benefit of vessel-selective information. This could lead to more accurate CBF estimates in patients with a significant collateral flow. PMID- 23921896 TI - Comparison of CO2 in air versus carbogen for the measurement of cerebrovascular reactivity with magnetic resonance imaging. AB - Measurement of cerebrovascular reactivity (CVR) can give valuable information about existing pathology and the risk of adverse events, such as stroke. A common method of obtaining regional CVR values is by measuring the blood flow response to carbon dioxide (CO2)-enriched air using arterial spin labeling (ASL) or blood oxygen level-dependent (BOLD) imaging. Recently, several studies have used carbogen gas (containing only CO2 and oxygen) as an alternative stimulus. A direct comparison was performed between CVR values acquired by ASL and BOLD imaging using stimuli of (1) 5% CO2 in air and (2) 5% CO2 in oxygen (carbogen-5). Although BOLD and ASL CVR values are shown to be correlated for CO2 in air (mean response 0.11+/-0.03% BOLD, 4.46+/-1.80% ASL, n=16 hemispheres), this correlation disappears during a carbogen stimulus (0.36+/-0.06% BOLD, 4.97+/-1.30% ASL). It is concluded that BOLD imaging should generally not be used in conjunction with a carbogen stimulus when measuring CVR, and that care must be taken when interpreting CVR as measured by ASL, as values obtained from different stimuli (CO2 in air versus carbogen) are not directly comparable. PMID- 23921897 TI - Why does brain metabolism not favor burning of fatty acids to provide energy? Reflections on disadvantages of the use of free fatty acids as fuel for brain. AB - It is puzzling that hydrogen-rich fatty acids are used only poorly as fuel in the brain. The long-standing belief that a slow passage of fatty acids across the blood-brain barrier might be the reason. However, this has been corrected by experimental results. Otherwise, accumulated nonesterified fatty acids or their activated derivatives could exert detrimental activities on mitochondria, which might trigger the mitochondrial route of apoptosis. Here, we draw attention to three particular problems: (1) ATP generation linked to beta-oxidation of fatty acids demands more oxygen than glucose, thereby enhancing the risk for neurons to become hypoxic; (2) beta-oxidation of fatty acids generates superoxide, which, taken together with the poor anti-oxidative defense in neurons, causes severe oxidative stress; (3) the rate of ATP generation based on adipose tissue-derived fatty acids is slower than that using blood glucose as fuel. Thus, in periods of extended continuous and rapid neuronal firing, fatty acid oxidation cannot guarantee rapid ATP generation in neurons. We conjecture that the disadvantages connected with using fatty acids as fuel have created evolutionary pressure on lowering the expression of the beta-oxidation enzyme equipment in brain mitochondria to avoid extensive fatty acid oxidation and to favor glucose oxidation in brain. PMID- 23921898 TI - Tracer kinetic modeling of [(11)C]AFM, a new PET imaging agent for the serotonin transporter. AB - [(11)C]AFM, or [(11)C]2-[2-(dimethylaminomethyl)phenylthio]-5 fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [(11)C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time-activity curves were well described by MA1. The rank order of [(11)C]AFM binding potential (BPND) matched well with the known regional SERT densities. For routine use of [(11)C]AFM, several noninvasive methods for quantification of regional binding were evaluated, including simplified reference tissue models (SRTM and SRTM2), and multilinear reference tissue models (MRTM and MRTM2). The best methods for region of interest (ROI) analysis were MA1, MRTM2, and SRTM2, with fixed population kinetic values ( or b') for the reference methods. The MA1 and MRTM2 methods were best for parametric imaging. These results showed that [(11)C]AFM is a suitable PET radioligand to image and quantify SERT in humans. PMID- 23921900 TI - Reference region automatic extraction in dynamic [(11)C]PIB. AB - The positron emission tomography (PET) radiotracer [(11)C]Pittsburgh Compound B (PIB) is a marker of amyloid plaque deposition in brain, and binding potential is usually quantified using the cerebellum as a reference where the specific binding is negligible. The use of the cerebellum as a reference, however, has been questioned by the reported cerebellar [(11)C]PIB retention in familial Alzheimer's disease (AD) subjects. In this work, we developed a supervised clustering procedure for the automatic extraction of a reference region in [(11)C]PIB studies. Supervised clustering models each gray matter voxel as the linear combination of three predefined kinetic classes, normal and lesion gray matter, and blood pool, and extract reference voxels in which the contribution of the normal gray matter class is high. In the validation with idiopathic AD subjects, supervised clustering extracted reference voxels mostly in the cerebellum that indicated little specific [(11)C]PIB binding, and total distribution volumes of the extracted region were lower than those of the cerebellum. Next, the methodology was applied to the familial AD cohort where the cerebellar amyloid load had been demonstrated previously, resulting in higher binding potential compared with that obtained with the cerebellar reference. The supervised clustering method is a useful tool for the accurate quantification of [(11)C]PIB studies. PMID- 23921901 TI - A computational model of oxygen transport in the cerebrocapillary levels for normal and pathologic brain function. AB - The oxygen exchange and correlation between the cerebral blood flow (CBF) and cerebral metabolic rate of oxygen consumption (CMRO2) in the cortical capillary levels for normal and pathologic brain functions remain the subject of debate. A 3D realistic mesoscale model of the cortical capillary network (non-tree like) is constructed using a random Voronoi tessellation in which each edge represents a capillary segment. The hemodynamics and oxygen transport are numerically simulated in the model, which involves rheological laws in the capillaries, oxygen diffusion, and non-linear binding of oxygen to hemoglobin, respectively. The findings show that the cerebral hypoxia due to a significant decreased perfusion (as can occur in stroke) can be avoided by a moderate reduction in oxygen demand. Oxygen extraction fraction (OEF) can be an important indicator for the brain oxygen metabolism under normal perfusion and misery-perfusion syndrome (leading to ischemia). The results demonstrated that a disproportionately large increase in blood supply is required for a small increase in the oxygen demand, which, in turn, is strongly dependent on the resting OEF. The predicted flow metabolism coupling in the model supports the experimental studies of spatiotemporal stimulations in humans by positron emission tomography and functional magnetic resonance imaging. PMID- 23921902 TI - Adenosine A2A receptor deficiency alleviates blast-induced cognitive dysfunction. AB - Traumatic brain injury (TBI), particularly explosive blast-induced TBI (bTBI), has become the most prevalent injury among military personnel. The disruption of cognitive function is one of the most serious consequences of bTBI because its long-lasting effects prevent survivors fulfilling their active duty and resuming normal civilian life. However, the mechanisms are poorly understood and there is no treatment available. This study investigated the effects of adenosine A2A receptor (A2AR) on bTBI-induced cognitive deficit, and explored the underlying mechanisms. After being subjected to moderate whole-body blast injury, mice lacking the A2AR (A2AR knockout (KO)) showed less severity and shorter duration of impaired spatial reference memory and working memory than wild-type mice did. In addition, bTBI-induced cortical and hippocampal lesions, as well as proinflammatory cytokine expression, glutamate release, edema, cell loss, and gliosis in both early and prolonged phases of the injury, were significantly attenuated in A2AR KO mice. The results suggest that early injury and chronic neuropathological damages are important mechanisms of bTBI-induced cognitive impairment, and that the impairment can be attenuated by preventing A2AR activation. These findings suggest that A2AR antagonism is a potential therapeutic strategy for mild-to-moderate bTBI and consequent cognitive impairment. PMID- 23921899 TI - Blood-brain barrier dysfunction as a cause and consequence of Alzheimer's disease. AB - The blood-brain barrier (BBB) plays critical roles in the maintenance of central nervous system (CNS) homeostasis. Dysfunction of the BBB occurs in a number of CNS diseases, including Alzheimer's disease (AD). A prevailing hypothesis in the AD field is the amyloid cascade hypothesis that states that amyloid-beta (Abeta) deposition in the CNS initiates a cascade of molecular events that cause neurodegeneration, leading to AD onset and progression. In this review, the participation of the BBB in the amyloid cascade and in other mechanisms of AD neurodegeneration will be discussed. We will specifically focus on three aspects of BBB dysfunction: disruption, perturbation of transporters, and secretion of neurotoxic substances by the BBB. We will also discuss the interaction of the BBB with components of the neurovascular unit in relation to AD and the potential contribution of AD risk factors to aspects of BBB dysfunction. From the results discussed herein, we conclude that BBB dysfunction contributes to AD through a number of mechanisms that could be initiated in the presence or absence of Abeta pathology. PMID- 23921904 TI - PARL and HtrA2: another intricate ischemic neuronal apoptotic process starting within mitochondria. PMID- 23921903 TI - Regulation of optic nerve head blood flow during combined changes in intraocular pressure and arterial blood pressure. AB - In the choroid, there is evidence that blood flow does not only depend on ocular perfusion pressure (OPP), but also on absolute mean arterial pressure (MAP) and intraocular pressure (IOP). The present study included 40 healthy subjects to investigate whether such behavior is also found in the optic nerve head (ONH). The ONH blood flow (ONHBF) was studied using laser Doppler flowmetry during a separate increase in IOP and MAP as well as during a combined elevation. Mean arterial pressure was increased by isometric exercise and IOP by the suction method. During both, the change in ONHBF was less pronounced than the change in OPP indicating autoregulation. Correlation analysis was performed for the combined experiments after pooling all data according to IOP and MAP values. A correlation between ONHBF and MAP was found at IOPs ?25 mm Hg (P<0.001), but not at IOPs>25 mm Hg (P=0.79). Optic nerve head blood flow and IOP were significantly correlated (P<0.001), and ONHBF was only slightly dependent on MAP. The data of the present study indicate a complex regulation of ONHBF during combined changes in MAP and IOP. Our results may be compatible with myogenic mechanisms underlying autoregulation, and indicate better ONHBF regulation during an increase in MAP than during an increase in IOP. PMID- 23921905 TI - Differential shell strength of Cepaea nemoralis colour morphs--implications for their anti-predator defence. AB - One of the most spectacular evolutionary forces is predation, evidenced to stimulate polymorphism in many prey species. Shell colour polymorphism of the land snail Cepaea nemoralis is a well-known model in evolutionary research. Nevertheless, the knowledge on the ecological causes driving its evolution remains incomplete and proximal factors shaping predatory pressure on C. nemoralis morphs are unknown. We evaluated shell crushing resistance and thickness, constituting crucial snail anti-predator defences in two shell areas (the apex and labium) of eight C. nemoralis morphotypes differing in shell colour and banding pattern. A GLM showed a significant effect of shell colour, banding pattern and shell thickness on shell strength. Pink shells were stronger than yellow ones, and banded forms had stronger shells than unbanded snails. The labium (usually attacked by mice) was generally thicker and more resistant than the apex (usually crushed by birds). Thicker shells were more resistant to crushing, and the rate of shell strength increase per unit of shell thickness was greater in pink and banded individuals compared to yellow and unbanded ones. Yellow and unbanded morphs have been found to be preferred by mice in the previous studies, which suggests that shell strength may be an important trait used in prey selection by these shell-crushing predators. The differences in potential anti-predator defences among snail morphs, found in the present study, justify future research on direct effect of C. nemoralis morphs shell strength on predator selectivity. PMID- 23921906 TI - Comparative effectiveness of fecal immunochemical test outreach, colonoscopy outreach, and usual care for boosting colorectal cancer screening among the underserved: a randomized clinical trial. AB - IMPORTANCE: Colorectal cancer (CRC) screening saves lives, but participation rates are low among underserved populations. Knowledge on effective approaches for screening the underserved, including best test type to offer, is limited. OBJECTIVE: To determine (1) if organized mailed outreach boosts CRC screening compared with usual care and (2) if FIT is superior to colonoscopy outreach for CRC screening participation in an underserved population. DESIGN, SETTING, AND PARTICIPANTS: We identified uninsured patients, not up to date with CRC screening, age 54 to 64 years, served by the John Peter Smith Health Network, Fort Worth and Tarrant County, Texas, a safety net health system. INTERVENTIONS: Patients were assigned randomly to 1 of 3 groups. One group was assigned to fecal immunochemical test (FIT) outreach, consisting of mailed invitation to use and return an enclosed no-cost FIT (n = 1593). A second was assigned to colonoscopy outreach, consisting of mailed invitation to schedule a no-cost colonoscopy (n = 479). The third group was assigned to usual care, consisting of opportunistic primary care visit-based screening (n = 3898). In addition, FIT and colonoscopy outreach groups received telephone follow-up to promote test completion. MAIN OUTCOME MEASURES: Screening participation in any CRC test within 1 year after randomization. RESULTS: Mean patient age was 59 years; 64% of patients were women. The sample was 41% white, 24% black, 29% Hispanic, and 7% other race/ethnicity. Screening participation was significantly higher for both FIT (40.7%) and colonoscopy outreach (24.6%) than for usual care (12.1%) (P < .001 for both comparisons with usual care). Screening was significantly higher for FIT than for colonoscopy outreach (P < .001). In stratified analyses, screening was higher for FIT and colonoscopy outreach than for usual care, and higher for FIT than for colonoscopy outreach among whites, blacks, and Hispanics (P < .005 for all comparisons). Rates of CRC identification and advanced adenoma detection were 0.4% and 0.8% for FIT outreach, 0.4% and 1.3% for colonoscopy outreach, and 0.2% and 0.4% for usual care, respectively (P < .05 for colonoscopy vs usual care advanced adenoma comparison; P > .05 for all other comparisons). Eleven of 60 patients with abnormal FIT results did not complete colonoscopy. CONCLUSIONS AND REVELANCE: Among underserved patients whose CRC screening was not up to date, mailed outreach invitations resulted in markedly higher CRC screening compared with usual care. Outreach was more effective with FIT than with colonoscopy invitation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01191411. PMID- 23921908 TI - A comment on 'Changes in bone mineral density in women following 1-year gastric bypass surgery' published by Casagrande DS et al. PMID- 23921909 TI - Changes in bone mineral density in women following 1-year gastric bypass surgery, published by Casagrande DS et al.--reply. PMID- 23921907 TI - Genetic variants in fas signaling pathway genes and risk of gastric cancer. AB - Populations in north central China are at high risk for gastric cancers (GC), and altered FAS-mediated cell signaling and/or apoptosis may contribute to this risk. We examined the association of 554 single nucleotide polymorphisms (SNPs) in 53 Fas signaling-related genes using a pathway-based approach in 1758 GC cases (1126 gastric cardia adenocarcinomas (GCA) and 632 gastric noncardia adenocarcinomas (GNCA)), and 2111 controls from a genome-wide association study (GWAS) of GC in ethnic Chinese. SNP associations with risk of overall GC, GCA and GNCA were evaluated using unconditional logistic regressions controlling for age, sex and study. Gene- and pathway-based associations were tested using the adaptive rank truncated product (ARTP) method. Statistical significance was evaluated empirically by permutation. Significant pathway-based associations were observed for Fas signaling with risk of overall GC (p = 5.5E-04) and GCA (p = 6.3E-03), but not GNCA (p= 8.1E-02). Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2 and IKBKB were associated with risk of GC (nominal p < 0.05), and FAF1 and MAPK8 were significantly associated with risk of both GCA and GNCA (nominal p< 0.05). Our examination of genetic variation in the Fas signaling pathway is consistent with an association of altered Fas signaling and/or apoptosis with risk of GC. As one of the first attempts to investigate a pathway-level association, our results suggest that these genes and the Fas signaling pathway warrant further evaluation in relation to GC risk in other populations. PMID- 23921911 TI - Layer-by-layer thinning of MoS2 by thermal annealing. AB - By thermal annealing, few-layer MoS2 flakes can be thinned down. In one hour, the upper layer is peeled off due to sublimation. Eventually, monolayer MoS2 is achieved. We have characterized the process by optical contrast, Raman spectroscopy and atomic force microscopy (AFM), and observed a mixture of surfaces of N and N- 1 layers. PMID- 23921910 TI - A controllable susceptibility marker for passive device tracking. AB - PURPOSE: To design and demonstrate a new susceptibility-based tracking device with an artifact that can be mechanically turned on and off, thus permitting tracking and imaging at the device tip with limited artifact. METHODS: The magnetic susceptibilities of readily obtainable grades of titanium and graphite were measured. Using numerical optimization, layer thicknesses for three concentric cylinders were found where the field from the graphite layer maximally cancelled the fields from titanium layers. The tracking elements were fabricated for an outer diameter of 3 mm and attached to a catheter to show feasibility of detection in phantoms and in vivo. RESULTS: The device was successfully integrated into a 9F catheter, and its use with conventional guidewires under fluoroscopy was demonstrated by guiding the catheter through the bifurcation into the carotid artery. MR images including the catheter tip were acquired with the device in both the "on" and "off" positions. CONCLUSION: A new passive tracking device with a susceptibility effect that can be enabled and disabled by sliding one of the components was designed, fabricated, and demonstrated in phantoms and in vivo. The device may also be integrated into many different interventional MR devices such as needles, ultrasound transducers for prostate biopsy, or any catheter-based devices. PMID- 23921912 TI - Hypothyroidism and oxidative stress: differential effect on the heart of virgin and pregnant rats. AB - The present study investigates the effects of hypothyroidism on both the redox state and the thyroid hormone receptors expression in the heart ventricle of virgin and pregnant rats.Hypothyroid state was induced by 6-n-propyl-2-thiouracil in drinking water given to Wistar rats starting 8 days before mating until day 21 of pregnancy or for 30 days in virgin rats. Serum paraoxonase-1 (PON-1) activity, serum and heart nitrites, and thiobarbituric acid-reactive substances (TBARS) were analyzed. Heart protein oxidation, as carbonyls, and copper-zinc superoxide dismutase (CuZnSOD), glutathione peroxidase (GPx), and catalase (CAT) activities, were determined. In addition, heart expressions of NADPH oxidase (NOX-2), CAT, SOD, GPx, and thyroid receptors (TRalpha and TRbeta) mRNA were assessed by RT PCR. Inducible and endothelial Nitric Oxide Synthase (iNOS and eNOS) were determined by Western blot. Hypothyroidism in the heart of virgin rats decreased TRalpha and TRbeta expressions, and induced oxidative stress, leading to a decrease of nitrites and an increase of carbonyls, NOX-2 mRNA, and GPx activity. A decreased PON-1 activity suggested low protection against oxidative stress in blood circulation. Pregnancy reduced TRalpha and TRbeta mRNA expressions and induced oxidative stress by increasing nitrite and TBARS levels, SOD and CAT activities and NOX-2, eNOS and iNOS expressions, while hypothyroidism, emphasized the decreases of TRalpha mRNA levels and did not alter the redox state in the heart. TR expressions and redox balance of rat hearts depend on the physiological state. Pregnancy per se seems to protect the heart against oxidative stress induced by hypothyroidism. Supporting Information for this article is available online at http://www.thieme-connect.de/ejournals/toc/hmr. PMID- 23921913 TI - Genomic analysis of sexual dimorphism of gene expression in the mouse adrenal gland. AB - A relevant gender difference exists in adrenal physiology and propensity to disease. In mice, a remarkable sexual dimorphism is present in several components of the hypothalamic-pituitary-adrenal axis, with females displaying higher adrenal weight, plasma ACTH, corticosterone, and aldosterone levels than males. The molecular bases of this sexual dimorphism are little known. We have compared global gene expression profiles in males vs. female mouse adrenal glands and also studied the effect that testosterone treatment and castration have on adrenal gene expression in female vs. male mice, respectively. Our study evidenced a set of 71 genes that are coordinately modulated according to sex and hormonal treatments and represent the core sexually dimorphic expression program in the mouse adrenal gland. Moreover, we show that some genes involved in steroid metabolism have a remarkable sexual dimorphic expression and identify new potential markers for the adrenal X-zone, a transitory cellular layer in the inner adrenal cortex, which spontaneously regresses at puberty in males and during the first pregnancy in females and has an uncertain physiological role. Finally, sexually dimorphic expression of the transcriptional regulators Nr5a1 and Nr0b1 may explain at least in part the differences in adrenal steroidogenesis between sexes. PMID- 23921916 TI - Mastoid cholesterol granuloma with posterior cranial fossa compression. PMID- 23921915 TI - ACE2 and FZD1 are prognosis markers in squamous cell/adenosquamous carcinoma and adenocarcinoma of gallbladder. AB - The clinicopathological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder have not been well documented, and no prognosis marker has been identified because of the rare occurrence of this gallbladder cancer subtype. In this study, we examined ACE2 and FZD1 expression in 46 SC/ASCs and 80 adenocarcinomas using immunohistochemistry and further analyzed their correlations with clinicopathological characteristics. We demonstrated that positive FZD1 and negative ACE2 expression were significantly associated with large tumor size, high TNM stage, lymph node metastasis and invasion of SC/ASC and AC. Univariate Kaplan-Meier analysis showed that positive FZD1 and negative ACE2 expression as well as differentiation, tumor size, TNM stage, lymph node metastasis, invasion, and surgical curability were closely associated with decreased overall survival in both SC/ASC (p < 0.001) and AC (p < 0.001) patients. The average survival time in SC/ASC and AC patients with FZD1(-)ACE2(+) expression was significantly longer than that in patients with FZD1(+)ACE2(-) or FZD1(+)ACE2(+) (p < 0.01). Multivariate Cox regression analysis showed that positive FZD1 and negative ACE2 expression are independent poor-prognostic factors for both SC/ASC and AC patients. In addition, FZD1 expression positively, but ACE2 expression negatively correlated with the expression of CA19-9 in SC/ASC and AC. Our study suggested that positive FZD1 and negative ACE2 expression are closely related to the expression of CA19-9; clinical, pathological, and biological behaviors; as well as poor-prognosis of gallbladder cancer. PMID- 23921917 TI - Endolymphatic hydrops in Meniere's disease: cause, consequence, or epiphenomenon? AB - OBJECTIVE: To determine the relationship of endolymphatic hydrops to Meniere's disease. DATA SOURCES: Comprehensive review of articles from 1938 through 2012 via Medline and Index Medicus. STUDY SELECTION: Articles discussing Meniere's disease and/or endolymphatic hydrops that include temporal bone autopsy data. DATA EXTRACTION: Fifty-three case reports and series were studied containing examination of 541 hydropic temporal bones and including 276 patients with Meniere's disease. These were divided into those meeting the 1995 American Academy of Otolaryngology-Head and Neck Surgery criteria for Meniere's disease and those that failed to meet these criteria. CONCLUSION: An individual meeting the 1995 criteria for Meniere's disease has a near certain probability of having endolymphatic hydrops in at least 1 ear. Autopsy data do not support the view that the association of MD and EH is an epiphenomenon or that MD causes EH; this leaves us with the probability that EH causes MD. If it is causative, hydrops alone is insufficient to cause Meniere's disease, indicating that there must be one or more additional cofactors that cause asymptomatic hydrops to become symptomatic Meniere's disease. Vascular risk factors should be studied as possible cofactors. PMID- 23921918 TI - Converted and upgraded maps programmed in the newer speech processor for the first generation of multichannel cochlear implant. AB - OBJECTIVE: To identify the technological contributions of the newer version of speech processor to the first generation of multichannel cochlear implant and the satisfaction of users of the new technology. Among the new features available, we focused on the effect of the frequency allocation table, the T-SPL and C-SPL, and the preprocessing gain adjustments (adaptive dynamic range optimization). STUDY DESIGN: Prospective exploratory study. SETTING: Cochlear implant center at hospital. PATIENTS: Cochlear implant users of the Spectra processor with speech recognition in closed set. Seventeen patients were selected between the ages of 15 and 82 and deployed for more than 8 years. INTERVENTIONS: The technology update of the speech processor for the Nucleus 22. MAIN OUTCOME MEASURES: To determine Freedom's contribution, thresholds and speech perception tests were performed with the last map used with the Spectra and the maps created for Freedom. To identify the effect of the frequency allocation table, both upgraded and converted maps were programmed. One map was programmed with 25 dB T-SPL and 65 dB C-SPL and the other map with adaptive dynamic range optimization. To assess satisfaction, SADL and APHAB were used. RESULTS: All speech perception tests and all sound field thresholds were statistically better with the new speech processor; 64.7% of patients preferred maintaining the same frequency table that was suggested for the older processor. The sound field threshold was statistically significant at 500, 1,000, 1,500, and 2,000 Hz with 25 dB T-SPL/65 dB C-SPL. Regarding patient's satisfaction, there was a statistically significant improvement, only in the subscale of speech in noise abilities and phone use. CONCLUSION: The new technology improved the performance of patients with the first generation of multichannel cochlear implant. PMID- 23921919 TI - Acoustic hearing implants for mixed hearing loss: a systematic review. AB - OBJECTIVE: A systematic review of literature to determine the clinical outcome and safety of the range of acoustic hearing implants (AHIs) in adults with mixed hearing loss (MHL). DATA SOURCES: Databases MEDLINE, Embase, and Cochrane were searched with no language restrictions between 1950, or the start date of each database, up to March 1, 2013. STUDY SELECTION: Initial search found 1,794 studies, of which, 19 met the inclusion criteria of AHI for adults with MHL where safety, coupling strategies to the inner ear, hearing outcome, and patient reported outcome measures (PROMs) were analyzed, preferably compared with a conventional hearing aid or a bone-conduction implant. DATA EXTRACTION: A study quality assessment based on different parameters was included: specification of eligibility criteria, prospective study, ethical approval gained, appropriate controls, power calculation, outcome measures, and analysis performed. DATA SYNTHESIS: Comparisons between studies were made based on structured review as meta-analysis was not feasible because of the heterogeneity of outcome measures and reports. CONCLUSION: The current systematic review shows that AHI and their different coupling strategies in the treatment of MHL were beneficial in terms of speech in quiet, PROM, and safety regarding residual hearing. Overall, the level of evidence and the quality of the included studies were judged to be moderate to low. More comprehensive data on coupling to the inner ear and the comparison with conventional hearing aids or alternatives for speech in noise is mandatory. Long term follow-up data are also needed. PMID- 23921920 TI - Effects of acoustic stimuli used for vestibular evoked myogenic potential studies on the cochlear function. AB - OBJECTIVE: To study if acoustic stimuli used for vestibular evoked myogenic potential (VEMP) studies can damage the cochlea. STUDY DESIGN: Prospective diagnostic study. SETTING: Academic tertiary referral center. METHODS: In 30 young healthy adults aged between 20 and 35 years without any audiovestibular disorders, cVEMP studies were performed in a standard setting (tone burst, 500 Hz, 133 dB SPL, stimuli rate 200). Before and after acoustic stimulation for the cVEMP examination, the cochlear function was measured using pure tone audiometry and distortion product otoacoustic emissions (DPOAE). Additionally, the subjects were asked about ear symptoms. RESULTS: In all subjects, cVEMP could be recorded. Eight (27%) of them reported subjective hearing symptoms direct after the VEMP examination. All were again free of complaints on the next day. Hearing thresholds did not deteriorate in pure tone audiometry. DPOAE levels decreased on the exposed side in the high-frequency range (4,000-6,000 Hz). The subjects with subjective ear symptoms had a stronger level decrease. In a follow-up measurement 24 hours later, the DPOAE levels showed recovery. CONCLUSION: Acoustic stimuli used to elicit VEMP were found to have an adverse effect on the cochlear function. A clinically relevant hearing loss was not found in our study in healthy adults. Subjective auditory symptoms were reversible within 24 hours. Nevertheless, the stimulus levels and the number of repetitions should be kept as low as possible. PMID- 23921921 TI - Do we really need a Coupler for the round window application of an AMEI? AB - OBJECTIVE: Implanting active middle ear implants (AMEI) at the round window has become a standard procedure to restore hearing for patients with moderate inner ear or mixed hearing loss. The round window (RW)-Coupler was developed as an alternative coupling aid to fit smaller RW diameters and require less drilling in the RW niche. The question arises whether using the RW-Coupler is useful and a safe procedure compared with the nonuse of the RW-Coupler MATERIALS AND METHODS: Forty-nine German-speaking patients were implanted with either a RW-Coupler attached to an AMEI floating mass transducer (FMT) or without coupler. They were evaluated preoperatively and postoperatively for bone and air conduction thresholds with and without the implant, as well as speech perception tests. RESULTS: Bone conduction thresholds remained stable preoperatively and postoperatively. The patient's functional gain was slightly better with the RW Coupler. Focusing on the average speech perception performances, both groups presented an improvement of speech perception above 80% at 65 dB HL. CONCLUSION: RW-Coupler-Vibroplasty was found to be a safe procedure, which produced good results in this group of patients with mixed hearing loss. PMID- 23921922 TI - Response to letter to the editor by Dr. Tamas Karosi Re: "Correlation of computed tomography with histopathology in otosclerosis", Quesnel et al. Otol Neurotol 2013; 34(1):22-28. PMID- 23921923 TI - Mid-term results after a newly designed nitinol stapes prosthesis use in 46 patients. AB - OBJECTIVE: Analysis of 12-month midterm clinical and audiometric data of patients with otosclerosis who underwent stapedotomy using a newly designed prosthesis made of nitinol, a shape memory alloy. PATIENTS: Fifty-five ears of 50 consecutive patients who underwent stapetotomy between March 2010 and July 2011 were included. They met the inclusion criteria of primary procedures, a clinical follow-up and absence of nickel allergy. INTERVENTION: Stapedotomy and insertion of a newly designed stapes prosthesis. MAIN OUTCOME MEASURES: Preoperative and postoperative (3 and 12 mo) air and bone conduction thresholds were recorded. Pure tone average and air bone gap (difference of air and bone conduction thresholds) were calculated for 500, 1,000, 2,000, and 3,000 Hz. The occurrence of complications was assessed. RESULTS: Air conduction thresholds, pure tone average, and air-bone gap improved significantly 3 and 12 months postoperatively. Bone conduction threshold improved significantly at 2,000 Hz 3 months postoperatively and at 1,000 and 2,000 Hz 12 months postoperatively. A PTA of less than 20 dB was achieved in 96% of ears. No sensorineural hearing loss or other prosthesis-related adverse effects were observed. CONCLUSION: Postoperative hearing results are comparable to the results obtained with other self-crimping prostheses. No complications or failures related to the prosthesis occurred. A longer follow-up is necessary to prove long-term stability of hearing results and safety of the new prosthesis. PMID- 23921924 TI - Endolymphatic hydrops revealed by magnetic resonance imaging in patients with acute low-tone sensorineural hearing loss. AB - OBJECTIVE: Acute low-tone sensorineural hearing loss (ALHL) has been reported to be associated with endolymphatic hydrops (EHs). However, evaluation of the size of the endolymphatic space has not been reported. We attempted to visualize EH in ALHL using magnetic resonance imaging (MRI). STUDY DESIGN: Prospective diagnostic study. SETTING: University hospital. METHODS: We evaluated 25 ears of 25 unilateral ALHL patients. Three-tesla MRI was obtained 24 hours after intratympanic injection of gadolinium (Gd) (n = 5) or 4 hours after intravenous injection of Gd (n = 20). A radiologist blinded to the patients' clinical data classified the degree of EH in the vestibule and cochlea into 3 groups: none, mild, and significant. RESULTS: On the affected sides, cochlear EH was recognized in 23 ears (92%) and was classified as significant EH (n = 15) or mild EH (n = 8); vestibular EH was detected in 22 ears (88%), classified as significant EH (n = 16) or mild EH (n = 6). Cochlear EH was more frequently observed in the affected ear than in the contralateral ear (90% versus 40%, p < 0.05). CONCLUSION: In ALHL, EH was observed not only in the cochlea but also in the vestibule as in Meniere's disease. PMID- 23921925 TI - Recurrent contralateral hearing loss after 2 craniotomies for vestibular schwannoma: etiologic implications. AB - OBJECTIVE: To describe recurrent sudden sensorineural hearing loss after contralateral vestibular schwannoma resection and re-resection. STUDY DESIGN: Clinical capsule report. SETTING: Tertiary academic referral hospital. PATIENT: A patient who underwent 2 craniotomies for vestibular schwannoma. RESULTS: In 2003, a patient experienced contralateral low-frequency sensorineural hearing loss after undergoing translabyrinthine resection of a vestibular schwannoma. This resolved after a course of oral steroids. Seven years later, in 2010, the patient developed tumor recurrence. After retrosigmoid resection, the patient experienced a similar episode of transient, contralateral, low-frequency predominant sensorineural hearing loss. CONCLUSION: The recurrence of contralateral hearing loss after craniotomies years apart suggests that patient specific anatomic risk factors predispose an individual to hearing loss after contralateral cerebellopontine angle surgery. Patients with previous history of contralateral hearing loss should be counseled that they may be at increased risk for recurrent loss in the setting of re-resection. PMID- 23921926 TI - The role of imaging in the diagnosis and management of otosclerosis. AB - OBJECTIVE: To examine the evidence for the role of radiologic imaging in the diagnosis and management of otosclerosis. DATA SOURCES: A review of contemporary (1990 to present) English medical literature via MedLine using the terms imaging, otosclerosis, otospongiosis, stapes surgery, computed tomography, magnetic resonance, CT, and MRI was performed. STUDY SELECTION: Abstracts were reviewed independently by 2 authors and relevant articles were then evaluated. Exclusion criteria included editorials, non-English language, comments, and letters. DATA EXTRACTION: Level of evidence was assigned in accordance with the Oxford Centre for Evidence-based Medicine guidance (Levels I-V). RESULTS: Thirty-seven articles met the inclusion criteria, of which, 11 were of Level III, 22 of Level IV, and 4 of level V evidence. High-resolution computed tomography (CT) of the temporal bones is the imaging technique of choice in the diagnosis of otosclerosis with newer multidetector scanners demonstrating a sensitivity and specificity in excess of 90%. There is Level III evidence that CT densitometry and extent of disease on CT correlates with hearing thresholds. Extensive and multifocal disease on CT has a poorer prognosis (Level III/IV). The potential use of CT in staging classifications, surgical planning, predicting surgical outcomes and risk of complications has also been described and evaluated. CONCLUSION: This systematic review indicates that imaging has a useful role in both the diagnosis and management of otosclerosis, supported principally by Level III/IV evidence. PMID- 23921927 TI - NF2 genetic alterations in sporadic vestibular schwannomas: clinical implications. AB - HYPOTHESIS: NF2 gene alterations may have a clinical impact in non-NF2 vestibular schwannomas (VSs). BACKGROUND: It has been suggested that NF2 mutations might correlate with clinical expression of VS in NF2 patients. The aim of this study was to analyze the impact of genetic alterations in the NF2 gene on epidemiologic, clinical, and radiologic features of patients with sporadic VS. The association between cigarette consumption and the molecular genetic findings was also studied. METHODS: The study group consisted of 51 patients who underwent surgery for removal of vestibular schwannoma in our institution between January 2006 and December 2010. Five highly polymorphic microsatellite DNA markers were used to observe the frequency of loss of heterozygosity (LOH) in chromosome 22. The NF2 gene mutations were detected using polymerase chain reaction amplification and denaturing high-performance liquid chromatography analysis (PCR/dHPLC), and direct sequencing of NF2. Multiplex ligation-dependent probe amplification (MLPA) of the NF2 gene was also performed. RESULTS: An NF2 mutation was identified in 49%, 22q LOH in 57%, and MLPA alterations in 13.7% of the cases. One mutational hit was present in 27%, and 2 hits were present in 45% of the tumors. No association was found between the type of NF2 mutation and relevant clinical parameters. The presence of NF2 mutations detected by PCR/dHPLC was associated with no complaint of hearing loss at the time of diagnosis (p = 0.023), with subjective aural fullness (p = 0.022) and with an absence of tumor involvement of the internal auditory canal (p = 0.029). Patients with NF2 mutations had lower mean corrected PTA thresholds compared with those with no NF2 mutation (p = 0.037). Inactivation of the NF2 gene by mutation, MLPA, or LOH was more frequent in smokers when compared with never smokers (p = 0.048). CONCLUSION: NF2 mutations may play a role in the pathophysiology of hearing loss as well as in the pattern of growth of VS. Cigarette smoking in patients with VS seems to play a role in both the risk of developing the tumor and also in its genetic profile. More studies are needed to corroborate these results and, more broadly, to establish links between molecular and clinical data. PMID- 23921928 TI - Detection of receiver location and migration after cochlear implantation using 3D rendering of computed tomography. AB - OBJECTIVES: The purpose of this study was to objectively evaluate the position and migration of the cochlear implant receiver and ball electrode using 3 dimensional (3D) rendering of computed tomography. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Thirty-one patients were treated for profound sensorineural hearing loss with cochlear implant. The operative methods were divided into 2 groups: an inverted J-shaped incision with bony tie-down suture, and a minimally invasive incision without tie-down suture. INTERVENTION(S): When the receiver and ball electrode were detected in 3D imaging, the zygomatic process-receiver angle (ZRA), ear canal to receiver distance (ERD), and ear canal to ball electrode distance (EBD) were measured. MAIN OUTCOME MEASURE(S): Comparison and statistical analysis of postoperative angle and distances. RESULTS: The mean ZRA, EBD, and ERD values were 139.1 degrees, 20.7 mm, and 36.0 mm, respectively. The mean ZRA in patients with an inverted J-shaped incision was significantly wider than for those with a minimally invasive incision (151.2 versus 136.9, p = 0.002). In 10 patients who received postoperative computed tomography 2 times, ZRA increased from 138.6 to 144.4 degrees (p < 0.001) and ERD decreased from 37.0 to 34.9 mm (p = 0.001). CONCLUSION: 3D computed tomography is a useful tool for localization and migration of the receiver and ball electrode. Micro downward movements of the receiver were found in both bony tie-down and non-tie-down suture groups. PMID- 23921929 TI - Cochlear implant electrode failure secondary to silicone touch-up during device manufacturing. AB - STUDY DESIGN: Retrospective case report. SETTING: Tertiary referral cochlear implant center. PATIENT: A 21-year-old woman was implanted with Advanced Bionics HiFocus Clarion device without complication. Five years later, the patient presented with dizziness, fluctuating implant performance, and facial pain. INTERVENTION: Surgical exploration revealed a torn electrode silicon casing in conjunction with scar contraction bending the electrode against bony facial nerve canal at the facial recess. Suspension of the electrode such that the damaged portion was not in contact with mastoid cavity led to temporary resolution of symptoms. Explantation and reimplantation procedures were carried out 2 months later. RESULTS: Postexplantation device analysis by the manufacturer demonstrated silicone touch-up at the site of failure. Six years since reimplantation, the patient has remained symptom-free. It is very likely that the touch-up silicon weakened the electrode and, in conjunction with chronic scar contraction, led to the tear on the silicon casing. CONCLUSION: Isolated cochlear implant electrode failure is a rare but possible long-term complication in older generation devices. The author reports 1 case of implant device failure partly because of silicon touch-up that was applied at the location of electrode failure during its manufacturing process. PMID- 23921930 TI - Multicenter study with a direct acoustic cochlear implant. AB - OBJECTIVE: To confirm the clinical efficacy and safety of a direct acoustic cochlear implant. STUDY DESIGN: Prospective multicenter study. SETTING: The study was performed at 3 university hospitals in Europe (Germany, The Netherlands, and Switzerland). PATIENTS: Fifteen patients with severe-to-profound mixed hearing loss because of otosclerosis or previous failed stapes surgery. INTERVENTION: Implantation with a Codacs direct acoustic cochlear implant investigational device (ID) combined with a stapedotomy with a conventional stapes prosthesis MAIN OUTCOME MEASURES: Preoperative and postoperative (3 months after activation of the investigational direct acoustic cochlear implant) audiometric evaluation measuring conventional pure tone and speech audiometry, tympanometry, aided thresholds in sound field and hearing difficulty by the Abbreviated Profile of Hearing Aid Benefit questionnaire. RESULTS: The preoperative and postoperative air and bone conduction thresholds did not change significantly by the implantation with the investigational Direct Acoustic Cochlear Implant. The mean sound field thresholds (0.25-8 kHz) improved significantly by 48 dB. The word recognition scores (WRS) at 50, 65, and 80 dB SPL improved significantly by 30.4%, 75%, and 78.2%, respectively, after implantation with the investigational direct acoustic cochlear implant compared with the preoperative unaided condition. The difficulty in hearing, measured by the Abbreviated Profile of Hearing Aid Benefit, decreased by 27% after implantation with the investigational direct acoustic cochlear implant. CONCLUSION: Patients with moderate-to-severe mixed hearing loss because of otosclerosis can benefit substantially using the Codacs investigational device. PMID- 23921931 TI - Lessons learned in otologic surgery: 30 years of malpractice cases in the United States. AB - OBJECTIVE: To analyze malpractice litigation trends to better understand the causes and outcomes of suits involving otologic surgeries to prevent future litigation and improve physician awareness. METHODS: Court records of legal trials from 1983 to 2012 were obtained from 2 major computerized databases WESTLAW and LexisNexis. Data were compiled on the demographics of the defendant, plaintiff, use of otolaryngologists/otologists as expert witnesses, nature of injury, type of surgery, legal allegations, verdicts, and judgments. RESULTS: Fifty-eight unique cases met inclusion criteria and were selected for review. The most common surgeries that went to trial were mastoidectomy (48%), ossiculoplasty (21%), and tympanoplasty (16%). Eleven (19%) of the cases were resolved through a settlement before a verdict was reached. Verdicts in favor of the plaintiffs (31%) were awarded an average of $1,131,189. The most common alleged injuries were hearing loss (45%) and facial nerve injury (38%). Of the cases found in favor of the plaintiff, the most common reasons cited were improper performance of the surgery (50%), failure to properly diagnose and treat (33%), and inadequate informed consent and delay in diagnosis (22% each). Case outcomes involving pediatric patients were not significantly different than those of adults (p = 0.34); however, adults received higher financial awards on average ($1 million versus $232,000; p < 0.0003). CONCLUSION: Obtaining an appropriate diagnosis, thoroughly discussing all options and potential risks, presenting realistic expectations, and executing the surgery correctly are crucial to patient care. Understanding the reasons surgeons go to trial may assist in mitigating risk for potential lawsuits. PMID- 23921932 TI - Cortical deafness: a case report and review of the literature. AB - OBJECTIVE: To review the literature regarding cortical hearing loss and document a case of cortical hearing loss including its presentation, diagnosis, and evolution over 32 months of follow-up. PATIENT: A 56-year-old woman with profound bilateral sensorineural hearing loss secondary to sequential hemorrhagic, temporal lobe infarctions separated in time by 8 months. INTERVENTION: Diagnostic. RESULTS: Sequential infarctions affecting the patient's auditory radiations and primary auditory cortices bilaterally combined to cause cortical hearing loss. At presentation, audiogram revealed a bilateral profound sensorineural hearing loss with no reliable responses to pure-tone or speech audiometry. She has subsequently recovered the ability to distinguish environmental sounds. At her 32-month follow-up, she had a pure-tone average (PTA) of 62 dB on the right and 70 dB on the left but continued to display a poor word recognition score (0%). A literature review was performed from the year 1891 until the present. CONCLUSION: Cortical deafness is an exceedingly rare entity. Presentation and recovery of hearing are dependent on the extent of the initial lesions. The majority of patients can expect improvements in pure-tone auditory thresholds over time; however patients should be counseled that recovery of the ability to understand speech is unlikely. PMID- 23921933 TI - Cochlear implants to treat deafness caused by vestibular schwannomas. AB - OBJECTIVE: Rehabilitation of hearing is complicated in patients with profound bilateral hearing loss in the presence of sporadic vestibular schwannoma (VS) or neurofibromatosis 2 (NF2), especially if the tumor does not need to be removed. We present the outcome of patients who have had a cochlear implant in the tumor affected ear without removal of the primary tumor. DESIGN: This is a retrospective multicentre study investigating outcomes of cochlear implantation in profoundly deaf patients with vestibular schwannoma in the implanted ear. MATERIALS AND METHODS: Out of 11 implanted patients, 5 required no treatment for their tumor, whereas 6 had previously undergone radiotherapy. Nine patients experienced NF2, and 2 had unilateral VS in the only hearing ear. Postoperative hearing was assessed with open and closed set speech discrimination, including City University of New York (CUNY) in noise and Bamford, Kowal and Bench (BKB) sentence scores. RESULTS: Patients with untreated lesions experienced marked improvement in their BKB and CUNY scores in the implanted ear and were daily cochlear implant users. The improvement was less consistent in the patients who had radiotherapy where only 1 patient attained open set speech discrimination. CONCLUSION: Patients with unilateral VS (sporadic or those affected with NF2) whose tumor status was stable, benefited from cochlear implantation in their tumor-affected ear. Patients who had radiotherapy also benefited from CI, but their outcomes were variable. PMID- 23921934 TI - In vitro accuracy evaluation of image-guided robot system for direct cochlear access. AB - HYPOTHESIS: A previously developed image-guided robot system can safely drill a tunnel from the lateral mastoid surface, through the facial recess, to the middle ear, as a viable alternative to conventional mastoidectomy for cochlear electrode insertion. BACKGROUND: Direct cochlear access (DCA) provides a minimally invasive tunnel from the lateral surface of the mastoid through the facial recess to the middle ear for cochlear electrode insertion. A safe and effective tunnel drilled through the narrow facial recess requires a highly accurate image-guided surgical system. Previous attempts have relied on patient-specific templates and robotic systems to guide drilling tools. In this study, we report on improvements made to an image-guided surgical robot system developed specifically for this purpose and the resulting accuracy achieved in vitro. MATERIALS AND METHODS: The proposed image-guided robotic DCA procedure was carried out bilaterally on 4 whole head cadaver specimens. Specimens were implanted with titanium fiducial markers and imaged with cone-beam CT. A preoperative plan was created using a custom software package wherein relevant anatomical structures of the facial recess were segmented, and a drill trajectory targeting the round window was defined. Patient to-image registration was performed with the custom robot system to reference the preoperative plan, and the DCA tunnel was drilled in 3 stages with progressively longer drill bits. The position of the drilled tunnel was defined as a line fitted to a point cloud of the segmented tunnel using principle component analysis (PCA function in MatLab). The accuracy of the DCA was then assessed by coregistering preoperative and postoperative image data and measuring the deviation of the drilled tunnel from the plan. The final step of electrode insertion was also performed through the DCA tunnel after manual removal of the promontory through the external auditory canal. RESULTS: Drilling error was defined as the lateral deviation of the tool in the plane perpendicular to the drill axis (excluding depth error). Errors of 0.08 +/- 0.05 mm and 0.15 +/- 0.08 mm were measured on the lateral mastoid surface and at the target on the round window, respectively (n =8). Full electrode insertion was possible for 7 cases. In 1 case, the electrode was partially inserted with 1 contact pair external to the cochlea. CONCLUSION: The purpose-built robot system was able to perform a safe and reliable DCA for cochlear implantation. The workflow implemented in this study mimics the envisioned clinical procedure showing the feasibility of future clinical implementation. PMID- 23921935 TI - Readability assessment of Internet-based patient education materials related to acoustic neuromas. AB - OBJECTIVE: The objectives of this study were to assess the readability of Internet-based patient education materials related to acoustic neuromas (AN IPEMs) by 4 widely validated readability indices, to evaluate scores against the existing sixth grade recommended reading level, and to compare the readability scores of patient education materials (PEMs) produced by professional organizations, clinical practices, hospitals, and miscellaneous sources. MATERIALS AND METHODS: AN-IPEMs from 67 web sites (6 professional societies, 33 clinical practices, 19 hospitals, and 9 miscellaneous) were assessed using Flesch Reading Ease Score (FRES), Flesch-Kincaid Grade Level (FKGL), Simple Measure of Gobbledygook (SMOG), and Gunning Frequency of Gobbledygook (Gunning FOG). Scores were then evaluated against national recommendations by 1-tailed t tests and against each other using 1-way ANOVAs. RESULTS: The average FKGL, SMOG, and Gunning FOG scores were all significantly higher than the recommended sixth grade reading level suggested by the USDHHS (p < 0.0001, single sample 1-tailed t test). Zero articles, by all indices, had a reading level equal to or below the sixth grade reading level. The FKGLs also varied between the various sources at a significant level (p = 0.01 one-way ANOVA independent samples). The average FKGLs of clinical practice and professional society AN-IPEMs were significantly higher than the average FKGLs of hospital AN-IPEMs (both p <= 0.05 one-tailed t-tests assuming unequal variances). CONCLUSION: AN-IPEMs are written at a level significantly higher than that suggested by national recommendations. Current AN IPEMs may need to be revised in order to enhance patient comprehension. PMID- 23921936 TI - Comparison of eardrum mobility in acute otitis media and otitis media with effusion models. AB - OBJECTIVE: To investigate the eardrum mobility difference between acute otitis media (AOM) and experimental otitis media with effusion (OME). ANIMAL MODELS: Thirty-three Hartley guinea pigs were included in this study. The AOM and OME were created by transbullar injection of Streptococcus pneumoniae and lipopolysaccharide into the middle ear, respectively. MAIN OUTCOME MEASURES: Three days after inoculation, the morphologic changes of the middle ear were assessed with otoscopy and histologic sections. Vibrations of the tympanic membrane (TM) at umbo in response to pure tone sound were measured using laser Doppler vibrometry. RESULTS: The purulent effusion, ossicular adhesion, and thickened TM and middle ear mucosa were observed in the AOM ears, and the OME ears had serous effusion and less thickened TM and mucosa in the middle ear. The displacement of TM in AOM was lower than that in OME ears, especially at 0.2 to 4 kHz. CONCLUSION: The TM mobility difference between the AOM and OME ears were mainly caused by the middle ear ossicular structure changes during the bacterial infection in AOM. PMID- 23921937 TI - Cochlear implantation feasibility in rhesus macaque monkey: anatomic and radiologic results. AB - BACKGROUND: Large animal models of implantable hearing devices are needed to assess innovative technologies before using them in humans. The rhesus macaque has cognitive abilities close to humans and has been used in the past but with noncommercial implants or no detailed radiologic descriptions of the surgical procedures. The aim of this study was to evaluate the feasibility of cochlear implantation in this animal model. METHODS: We present detailed radiologic data (CT scan and Cone beam computed tomography) from 7 heads of rhesus macaque monkeys coming from autopsy materials. Several comparative measurements were performed with 10 human temporal bones to emphasize similarities and differences between the macaque and the human inner ear. The radiologic analyses helped planning the surgical approach for cochlear implant insertion in the macaque. RESULTS: We managed to perform one full (720 degrees) and 3 partial insertions (190-330 degrees) of cochlear implants in 4 rhesus macaque cochleae, documented by cone beam computed tomography reconstructions. We confirm that the procedure is facilitated in this animal because the cochlea dimensions are close to humans. However, marked differences in the orientation of the external auditory canal and the basal turn must be taken into account. We suggest that the removal of the inferior wall of tympanal bone provides the optimal axis for electrode array insertion. CONCLUSION: The rhesus macaque monkey is a valid and close-to-human animal model for cochlear implants insertion. Because this species is widely used in both behavioral and physiologic studies, we expect that functional implants can be coupled with electrophysiologic recordings to study the mechanisms of auditory compensation. PMID- 23921938 TI - Microbial flora of cochlear implants by gene pyrosequencing. AB - OBJECTIVE: To describe the microbial flora associated with cochlear implants (CIs) removed for infectious and noninfectious indications. STUDY DESIGN: Prospective, controlled. SETTING: Academic, tertiary medical center. PATIENTS: All patients undergoing CI removal. INTERVENTION: CIs were removed with aseptic technique and processed for microbial identification. MAIN OUTCOME MEASURE: CI microbes were identified with routine culture and speciation and 16s deoxyribonucleic acid 454-pyrosequencing. RESULTS: All CIs had evidence of microbes. Propionibacterium acnes and Acidovorax facilis were more common on noninfected CIs (p = 0.005, 0.031). Staphylococcus aureus was more common on infected CIs (p = 0.003). The microbial profiles associated with CI infection were different from, but overlapped with those of noninfected CIs. Microbial culture with selective media identified pathogens not identified on pyrosequencing. CONCLUSION: Bacteria are present on all CIs, both with and without evidence of clinical infection, but species differ with clinical status. Empiric therapy for CI infections should include coverage for S. aureus. Gene pyrosequencing and selective culture techniques may yield complementary results that may impact the management of CI infections. PMID- 23921939 TI - Cost of cholesteatoma care at a tertiary medical center. AB - OBJECTIVE: Estimate the available direct cost of cholesteatoma care in a university practice. STUDY DESIGN: Retrospective review of both physician and hospital financial data during a recent 3-year period. SETTING: University-based tertiary referral medical system. PATIENTS: Adults (>= 18 yr old) with cholesteatoma. INTERVENTION(S): Financial information associated with both physician and hospital encounters were analyzed in a deidentified manner. MAIN OUTCOME MEASURE(S): Frequency and type of encounter, charges, collections, and payers were tabulated. RESULTS: Approximately 949 physician encounters (817 clinic, 130 surgical, and 2 inpatient) among 344 patients resulted in greater than $700, 000 in charges and greater than $211,000 in receipts (~ 30% rate of collection). The average physician charge per patient per year was approximately $1,600. About 259 hospital encounters among 171 patients resulted in greater than $1.8 million in charges and greater than $520,000 in receipts (~ 28% collection rate). The average hospital charge per patient per year was ~$10,000. For physician encounters, managed care (37%) and Medicare (25%) were the most common payers, whereas 17% were uninsured. For hospital encounters, managed care (28%) and Medicare (14%) were the most common payers, whereas 24% were uninsured. CONCLUSION: The direct cost of care for patients with cholesteatoma is significant. The current treatment paradigm for this chronic disorder results in repeated health care system access and associated direct (and unmeasured indirect) expenses. Future treatment paradigms should be designed to improve disease-specific quality of life while mitigating this financial impact. PMID- 23921940 TI - Face validity study of an artificial temporal bone for simulation surgery. AB - HYPOTHESIS: Using the rapid prototype (RP) technology, a physical construct of a human temporal bone was developed based on cadaveric tissue to permit simulated surgical training. The objective of the study was to test the face validity of the model. BACKGROUND: The cost and access to human cadaveric temporal bones is becoming increasingly challenging, particularly if there are religious and regulatory restrictions. There is a need to develop alternative strategies to improve accessibility. METHODS: Ultra high-resolution computed tomography (CT) images (0.15-mm resolution) were obtained from a cadaver temporal bone. Manual segmentation and conversion into a stereolithography file format permitted printing on a RP stereolithography printer. A 3-dimensional physical model was hardened to achieve the desired consistency. Eight practicing otologists were recruited to evaluate this model. Respondents were asked to drill the artificial bone and complete a rating survey upon completion. RESULTS: In using a Likert scale between 1 and 5, results for anatomic accuracy were favorable, with the best scores for overall morphology (4.63) and for lateral structures within the bone (4.5). The poorest scores were for the semicircular canals (3.75) and chorda tympani (3.25). Scores for haptic realism were good as well. The average score for the question "overall, how valuable is the model as a surgical simulator" was 4.1. The experts felt that junior residents (PGY 1-3) would benefit most from this surgical education model. CONCLUSION: The outer structures of the RP artificial temporal bone can be considered to have face validity. Improvements will continue to be made to address some of the deficiencies in the anatomic and haptic realism of this model. PMID- 23921941 TI - Clinical outcome after cochlear implantation in patients with unilateral hearing loss due to labyrinthitis ossificans. AB - OBJECTIVES: Cochlear implantation (CI) is the treatment of choice in bilateral labyrinthitis ossificans (LO). The aim of this clinical case study was to evaluate audiologic and subjective outcomes after CI treatment for unilateral hearing loss (UHL) because of LO and to identify optimal timing for treatment. PATIENTS: Three subjects (age 40, 54, and 68 yr) with UHL because of LO were enrolled. Duration of deafness was 1.5, 12, and 120 months. INTERVENTION: After extensive consultation, testing with conventional contralateral routing of signal hearing aid and bone-anchored hearing instrument, CI candidacy was confirmed and CI surgery performed. MAIN OUTCOME MEASURES: Test of open-set speech recognition in background noise and sound localization were performed preoperatively, in unaided and aided conditions, and in the CI-aided condition, at 6 and 12 months postoperatively. Subjective assessment via the Speech, Spatial and Qualities scale (SSQ) and the Tinnitus Visual Analogue Scale was performed at preimplant and 12 months postimplant. CONCLUSION: The data show moderate-to-high hearing benefit after CI in 2 cases and no benefit for the third. SSQ and tinnitus scales show benefit from CI use in both cases. CI treatment should be performed as early as possible, ideally before signs of obliteration are evident. Counseling on all rehabilitation options is important. PMID- 23921942 TI - Cochlear implantation in older adults: long-term analysis of complications and device survival in a consecutive series. AB - OBJECTIVES: To analyze the postoperative complications associated with cochlear implant (CI) surgery in a large consecutive case series of older adults (>= 60 yr). STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Approximately 445 individuals aged 60 years and older who received a first CI between 1999 and 2011. INTERVENTIONS: Cochlear implantation. MAIN OUTCOME MEASURE(S): Postoperative complications classified as major (meningitis, immediate postoperative facial weakness, device failure, flap dehiscence, and surgical removal) and minor (surgical site infection, balance problems, delayed postoperative facial weakness, and facial nerve stimulation). RESULTS: The mean age at implantation was 72.7 years (60-94.9 yr), and the median duration of follow-up was 4.8 years (0.1-12.5 yr). There were 42 minor complications in 41 patients (9.2%) and 36 major complications in 21 patients (4.7%). Seventeen patients (3.8%) required surgical device removal, 15 of whom underwent reimplantation. A Kaplan-Meier analysis of rates of device explantation demonstrated that at 5 and 10 years after CI, respectively, 95.4% and 93.1% of patients retained their original CI. When comparing complications between patients aged 60 to 74 years and those aged 75 years and older, there was a higher prevalence of balance problems lasting more than 1 month in the older group (9.5% versus 4.9%, p = 0.05). CONCLUSION: Our results indicate that the safety profile of cochlear implantation in an older population is comparable to that of younger adults and children. We suggest that concerns for increased postoperative complications in patients of advanced age do not need to be a primary consideration when determining CI candidacy. PMID- 23921943 TI - Experimental assessment of polyphonic tones with cochlear implants. AB - HYPOTHESIS: We hypothesized that cochlear implant (CI) users are able to discriminate tones consisting of 1 and 2 modulation frequencies when the stimuli are applied through direct electrical stimulation. BACKGROUND: Music perception is a very challenging task for CI users. In music, multiple tones often occur simultaneously, an essential feature of harmony. Proper encoding of simultaneous tones is crucial to musical perception and appreciation. With current implant processing strategies, CI users are severely impaired in the perception of pitch and polyphony. METHODS: The ability of CI users to identify the number of simultaneous tones was assessed. Stimuli were applied with direct electrical stimulation. Stimuli with 1 modulation frequency were applied on a basal, a middle, and an apical electrode to determine if there was an effect of cochlear region. Stimuli with 2 modulation frequencies were applied on combinations of an apical electrode together with a basal or a middle electrode. Additionally, 2 modulations frequencies were presented at the same time on an apical electrode only. RESULTS: Results demonstrate that subjects were generally able to identify the number of modulation frequencies in the presented stimuli. Performance for 1 modulation frequency stimuli was significantly above chance level on all 3 electrodes tested. Performance was best on the apical and the middle electrode, followed by the basal electrode. Subjects were also able to identify 2 modulation frequencies significantly above chance level on all 3 combinations tested. Performance was best on combination apical-basal followed by apical-middle. Performance was worst when 2 modulation frequencies were applied on an apical electrode only, but it was still significantly above chance level. CONCLUSION: If sound processing strategies were to use concurrent modulation frequencies on multiple or single electrodes, then possibly polyphonic tones would be better perceived by CI users yielding better music and language perception. PMID- 23921944 TI - Multiple myeloma with isolated plasmacytoma in temporal bone. PMID- 23921945 TI - Efficacy and safety profile of long-term exposure to lenalidomide in patients with recurrent multiple myeloma. AB - BACKGROUND: Lenalidomide in combination with dexamethasone (Len/Dex) is indicated for patients with recurrent/refractory multiple myeloma (RRMM) who were treated with 1 prior therapy until evidence of disease progression. The objective of the current study was to determine the efficacy and safety profile of long-term exposure to Len/Dex. METHODS: A total of 50 patients with RRMM who were treated with long-term Len for >= 2 years from 2 Intergroupe Francophone du Myelome (IFM) centers (Lille and Nancy) were included in the current study. RESULTS: The median age of the patients was 58 years, with 30% of the patients aged >65 years, 49% having an International Staging System stage of 2 and 3, 12% having severe renal insufficiency, and 8% demonstrating an adverse result on fluorescence in situ hybridization. Approximately 56% of the patients received treatment with Len/Dex for >= 3 years. The median duration of treatment with Len/Dex was 3 years (range, 2 years-7 years). The response rates for partial response or better and very good partial response or better for the overall cohort were 96% and 74%, respectively, which is similar to patients exposed to Len for >= 3 years. With a median follow up of 4 years, 19 (38%) patients had stopped treatment with Len/Dex. The time to disease progression rate at 37 months was 78% and 91%, respectively, in patients exposed to Len for 2 years to <3 years and for >= 3 years (P=025). The safety profile was manageable, similar to that of Len when administered for a shorter period of time; 16% of patients had grade 3 to 4 neutropenia, 6% had thrombopenia, 6% had anemia, and 20% experienced thromboembolic events, all of venous type. The annual incidence rate of second primary malignancy was 1.96% in the current series. CONCLUSIONS: The results of the current study confirmed that the Len/Dex combination is feasible for long-term use in patients with RRMM, with a significant benefit noted in terms of time to disease progression for prolonged treatment with Len/Dex. PMID- 23921947 TI - To treat or not to treat? and How to treat? Two questions whose answers are far removed from evidence informed practice in child psychiatry. PMID- 23921948 TI - [Septic monarthritis caused by Sphingomonas paucimobilis]. AB - Sphingomonas paucimobilis, formerly known as Pseudomonas paucimobilis, is a rare cause of septic arthritis and is therefore regarded as being of minor clinical interest in rheumatological diagnostics. In this connection the yellow pigmented, aerobic, glucose non-fermenting, Gram negative bacillus is usually associated with immunocompromised patients. A case of septic arthritis in a 70-year-old man with chronic obstructive pulmonary disease (COPD) initially presenting with right knee pain, swelling and redness is reported. After diagnosis of septic gonarthritis due to Sphingomonas paucimobilis, the infection was successfully treated by oral antibiotic therapy with ofloxacine based on the patient's antibiotic susceptibility profile, combined with analgesic and anti-inflammatory local physical therapy several times a day leading to a considerable improvement in the symptoms so that operative interventions could therefore be avoided. PMID- 23921946 TI - T helper cell polarization in healthy people: implications for cardiovascular disease. AB - Atherosclerosis is a chronic inflammatory disease characterized by T lymphocyte infiltration into the atherosclerotic plaque. Assessments of T cell subtypes have demonstrated a predominance of CD4(+) T helper (Th) cells, implicated Th1 and Th17 immunity in both human and mouse atherogenesis, and provided some evidence suggesting protective roles of Th2 and T regulatory cells. Observations that certain inbred mouse strains have an inherent T helper bias suggest a genetic predisposition toward developing a particular T helper phenotype. This review summarizes our current understanding of mechanisms of antigen processing for major histocompatibility complex molecules, describes the different T helper cell subsets and their roles in atherosclerosis, and discusses mechanisms of genetic predisposition toward Th1/Th2 bias in mice. We also present data from our laboratory demonstrating inherent Th1/Th2 phenotypes in apparently healthy human volunteers that are stable over time and discuss the potential implications for cardiovascular disease. PMID- 23921949 TI - Heterogeneity of response to biologic treatment: perspective for psoriasis. AB - Psoriasis treatment responses are affected by patient characteristics. However, the literature does not contain reviews of factors that affect the response to biologic therapies. We therefore performed a comprehensive literature search to identify papers describing demographic, lifestyle, and clinical factors associated with response to biologic drug therapy in psoriatic patients. We found that age, gender, ethnicity, alcohol consumption, smoking, geographic location, age at diagnosis, duration and severity of psoriasis, and baseline C-reactive protein levels did not consistently affect response to biologic psoriasis therapy. However, increased body mass index (BMI) appears to adversely affect responses. It might therefore be valuable to include BMI as a stratification variable in future studies of psoriasis therapies and to consider a patient's weight or BMI when selecting a systemic psoriasis treatment. PMID- 23921950 TI - Highly rapid and efficient conversion of human fibroblasts to keratinocyte-like cells. AB - Cell fate commitment during development is achieved through the expression of lineage-specific transcription factors. Recent studies have suggested that the expression of combinations of these lineage-specific transcription factors can convert adult somatic cells from one type to another. Here we report that the combination of p63, a master regulator of epidermal development and differentiation, and KLF4, a regulator of epidermal differentiation, is sufficient to convert dermal fibroblasts to a keratinocyte phenotype. Induced keratinocytes (KCs) expressed KC-specific proteins and had a transcriptome similar to KCs. Reprogramming to a KC phenotype was rapid and efficient with a vast majority of cells morphologically resembling and expressing KC-specific genes within a week of p63 and KLF4 transduction. Furthermore, p63 and KLF4 are capable of inducing a KC phenotype even in a cancerous cell line, highlighting their importance for epidermal specification. The robustness of the conversion process also allows the use of this as a model system to study the mechanisms of reprogramming. PMID- 23921951 TI - Oncogenic activation of MEK/ERK primes melanoma cells for adaptation to endoplasmic reticulum stress. AB - Cancer cells commonly undergo chronic endoplasmic reticulum (ER) stress, to which the cells have to adapt for survival and proliferation. We report here that in melanoma cells intrinsic activation of the ER stress response/unfolded protein response (UPR) is, at least in part, caused by increased outputs of protein synthesis driven by oncogenic activation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) and promotes proliferation and protects against apoptosis induced by acute ER stress. Inhibition of oncogenic BRAF(V600E) or MEK-attenuated activation of inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) signaling of the UPR in melanoma cells. This was associated with decreased phosphorylation of eukaryotic initiation factor 4E (eIF4E) and nascent protein synthesis and was recapitulated by knockdown of eIF4E. In line with this, introduction of BRAF(V600E) into melanocytes led to increases in eIF4E phosphorylation and protein production and triggered activation of the UPR. Similar to knockdown of glucose-regulated protein 78 (GRP78), inhibition of XBP1 decelerated melanoma cell proliferation and enhanced apoptosis induced by the pharmacological ER stress inducers tunicamycin and thapasigargin. Collectively, these results reveal that potentiation of adaptation to chronic ER stress is another mechanism by which oncogenic activation of the MEK/ERK pathway promotes the pathogenesis of melanoma. PMID- 23921952 TI - TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds. AB - Proper activation of macrophages (Mphi) in the inflammatory phase of acute wound healing is essential for physiological tissue repair. However, there is a strong indication that robust Mphi inflammatory responses may be causal for the fibrotic response always accompanying adult wound healing. Using a complementary approach of in vitro and in vivo studies, we here addressed the question of whether mesenchymal stem cells (MSCs)-due to their anti-inflammatory properties-would control Mphi activation and tissue fibrosis in a murine model of full-thickness skin wounds. We have shown that the tumor necrosis factor-alpha (TNF-alpha) stimulated protein 6 (TSG-6) released from MSCs in co-culture with activated Mphi or following injection into wound margins suppressed the release of TNF-alpha from activated Mphi and concomitantly induced a switch from a high to an anti fibrotic low transforming growth factor-beta1 (TGF-beta1)/TGF-beta3 ratio. This study provides insight into what we believe to be a previously undescribed multifaceted role of MSC-released TSG-6 in wound healing. MSC-released TSG-6 was identified to improve wound healing by limiting Mphi activation, inflammation, and fibrosis. TSG-6 and MSC-based therapies may thus qualify as promising strategies to enhance tissue repair and to prevent excessive tissue fibrosis. PMID- 23921953 TI - The speed of cocaine delivery determines the subsequent motivation to self administer the drug. AB - The rapid delivery of drugs of abuse to the brain is associated with an increased likelihood and severity of addiction. Here we evaluated the hypothesis that rapidly delivered cocaine facilitates the addiction process by promoting the development of enhanced motivation for the drug. Rats lever-pressed for cocaine delivered intravenously over 5 or 90 s under fixed ratio (FR) during 6-h sessions. The motivation for cocaine was subsequently assessed using a progressive ratio (PR) schedule, where each successive drug injection cost an exponentially greater number of lever presses, until the cessation of responding. Throughout all self-administration sessions, all rats could only take one injection every 90 s. The 5-s groups self-administered more drug than the 90-s groups across the FR sessions. Under PR, animals that had chronically self administered rapidly delivered cocaine took more cocaine across a range of doses and regardless of whether the drug was delivered over 5 or 90 s during PR testing. The speed of delivery also determined the long-term neurobiological impact of cocaine. Fourteen days following cocaine withdrawal, caudate-putamen D2 levels were decreased only in the 90-s rats, and quinpirole-mediated Galpha(i/o) protein activation was increased to a greater extent in the 90- vs 5-s rats. Thus, rapid delivery promotes the pursuit of cocaine in the face of rising costs and alters cocaine-induced changes in striatal D2 receptor number and function. As such, rapidly delivered cocaine might facilitate addiction because it more readily alters brain motivation circuits in ways that contribute to the compulsive pursuit of the drug. PMID- 23921954 TI - Kappa opioid receptors on dopaminergic neurons are necessary for kappa-mediated place aversion. AB - Kappa-opioid receptor (KOR) agonists have dysphoric properties in humans and are aversive in rodents. This has been attributed to the activation of KORs within the mesolimbic dopamine (DA) system. However, the role of DA in KOR-mediated aversion and stress remains divisive as recent studies have suggested that activation of KORs on serotonergic neurons may be sufficient to mediate aversive behaviors. To address this question, we used conditional knock-out (KO) mice with KORs deleted on DA neurons (DAT(Cre/wt)/KOR(loxp/loxp), or DATCre-KOR KO). In agreement with previous findings, control mice (DAT(Cre/wt)/KOR(wt/wt) or WT) showed conditioned place aversion (CPA) to the systemically administered KOR agonist U69,593. In contrast, DATCre-KOR KO mice did not exhibit CPA with this same agonist. In addition, in vivo microdialysis showed that systemic U69,593 decreased overflow of DA in the nucleus accumbens (NAc) in WT mice, but had no effect in DATCre-KOR KO mice. Intra- ventral tegmental area (VTA) delivery of KORs using an adeno-associated viral gene construct, resulted in phenotypic rescue of the KOR-mediated NAc DA response and aversive behavior in DATCre-KOR KO animals. These results provide evidence that KORs on VTA DA neurons are necessary to mediate KOR-mediated aversive behavior. Therefore, our data, along with recent findings, suggest that the neuronal mechanisms of KOR-mediated aversive behavior may include both dopaminergic and serotonergic components. PMID- 23921955 TI - Fine mapping of the Ph-3 gene conferring resistance to late blight (Phytophthora infestans) in tomato. AB - Late blight, caused by the oomycete pathogen Phytophthora infestans (Mont.) de Bary, is a devastating disease for tomato and potato crops. In the past decades, many late blight resistance (R) genes have been characterized in potato. In contrast, less work has been conducted on tomato. The Ph-3 gene from Solanum pimpinellifolium was introgressed into cultivated tomatoes and conferred broad spectrum resistance to P. infestans. It was previously assigned to the long arm of chromosome 9. In this study, a high-resolution genetic map covering the Ph-3 locus was constructed using an F2 population of a cross between Solanum lycopersicum CLN2037B (containing Ph-3) and S. lycopersicum LA4084. Ph-3 was mapped in a 0.5 cM interval between two markers, Indel_3 and P55. Eight putative genes were found in the corresponding 74 kb region of the tomato Heinz1706 reference genome. Four of these genes are resistance gene analogs (RGAs) with a typical nucleotide-binding adaptor shared by APAF-1, R proteins, and CED-4 domain. Each RGA showed high homology to the late blight R gene Rpi-vnt1.1 from Solanum venturii. Transient gene silencing indicated that a member of this RGA family is required for Ph-3-mediated resistance to late blight in tomato. Furthermore, this RGA family was also found in the potato genome, but the number of the RGAs was higher than in tomato. PMID- 23921956 TI - Out of America: tracing the genetic footprints of the global diffusion of maize. AB - Maize was first domesticated in a restricted valley in south-central Mexico. It was diffused throughout the Americas over thousands of years, and following the discovery of the New World by Columbus, was introduced into Europe. Trade and colonization introduced it further into all parts of the world to which it could adapt. Repeated introductions, local selection and adaptation, a highly diverse gene pool and outcrossing nature, and global trade in maize led to difficulty understanding exactly where the diversity of many of the local maize landraces originated. This is particularly true in Africa and Asia, where historical accounts are scarce or contradictory. Knowledge of post-domestication movements of maize around the world would assist in germplasm conservation and plant breeding efforts. To this end, we used SSR markers to genotype multiple individuals from hundreds of representative landraces from around the world. Applying a multidisciplinary approach combining genetic, linguistic, and historical data, we reconstructed possible patterns of maize diffusion throughout the world from American "contribution" centers, which we propose reflect the origins of maize worldwide. These results shed new light on introductions of maize into Africa and Asia. By providing a first globally comprehensive genetic characterization of landraces using markers appropriate to this evolutionary time frame, we explore the post-domestication evolutionary history of maize and highlight original diversity sources that may be tapped for plant improvement in different regions of the world. PMID- 23921957 TI - Genetic mapping of QTL for resistance to Fusarium head blight spread (type 2 resistance) in a Triticum dicoccoides * Triticum durum backcross-derived population. AB - Improvement of resistance to Fusarium head blight (FHB) is a continuous challenge for durum wheat breeders, particularly due to the limited genetic variation within this crop species. We accordingly generated a backcross-derived mapping population using the type 2 FHB resistant Triticum dicoccoides line Mt. Gerizim #36 as donor and the modern Austrian T. durum cultivar Helidur as recipient; 103 BC1F6:7 lines were phenotyped for type 2 FHB resistance using single-spikelet inoculations and genotyped with 421 DNA markers (SSR and AFLP). QTL mapping revealed two highly significant QTL, mapping to chromosomes 3A and 6B, respectively. For both QTL the T. dicoccoides allele improved type 2 FHB resistance. Recombinant lines with both favorable alleles fixed conferred high resistance to FHB similar to that observed in the T. dicoccoides parent. The results appear directly applicable for durum wheat resistance breeding. PMID- 23921959 TI - Managing chronic disease in hospitalized patients. PMID- 23921958 TI - Multifunctional antitumor molecule 5'-triphosphate siRNA combining glutaminase silencing and RIG-I activation. AB - Resisting cell death, reprogrammed metabolism and immune escape are fundamental traits of hard-to-treat cancers. Therapeutic improvement can be expected by designing drugs targeting all three aspects. 5'-Triphosphate RNA (ppp-RNA), a specific ligand of the pattern recognition receptor retinoic acid-inducible gene I (RIG-I), has been shown to trigger intrinsic apoptosis of malignant cells and to activate antitumor immune responses via type I interferons (IFNs). In our study, we designed a ppp-modified siRNA specifically silencing glutaminase (ppp GLS), a key enzyme of glutaminolysis that is indispensable for many cancer types. Bifunctional ppp-GLS induced more prominent antitumor responses than RNA molecules that contained either the RIG-I ligand motif or GLS silencing capability alone. The cytopathic effect was constrained to tumor cells as nonmalignant cells were not affected. We then analyzed the mechanisms leading to the profound antitumor efficacy. First, ppp-GLS effectively induced intrinsic proapoptotic signaling. In addition, GLS silencing sensitized malignant cells to RIG-I-induced apoptosis. Moreover, disturbed glutaminolysis by GLS silencing contributed to enhanced cytotoxicity. Finally, RIG-I activation blocked autophagic degradation leading to dysfunctional mitochondria and reactive oxygen species (ROS) generation, whereas GLS silencing severely impaired ROS scavenging systems, leading to a vicious circle of ROS-mediated cytotoxicity. Taken together, ppp-GLS combines cell death induction, immune activation and glutaminase inhibition in a single molecule and has high therapeutic efficacy against cancer cells. PMID- 23921960 TI - Quantification of pancreatic function using a clinically feasible short endoscopic secretin test. AB - OBJECTIVES: Clinical and morphological criteria are not precise enough to diagnose early chronic pancreatitis (CP). We investigated if short endoscopic pancreas function testing as a part of routine upper endoscopy could improve clinical diagnostics. METHODS: Patients with suspected CP underwent modified secretin-stimulated upper endoscopy (short endoscopic secretin test, or EST). Duodenal juice was collected during 15 minutes starting 30 minutes after stimulation. A modified scoring system for CP after Layer with bicarbonate and fecal elastase 1 (FE1) was used. We tested with receiver operating characteristic curves the diagnostic accuracy of bicarbonate and FE1 and with analysis of variance how precise the 2 parameters can discriminate the groups. RESULTS: Fifty two patients aged 19 to 67 years and 25 healthy controls aged 19 to 64 years were included. Twenty-four patients fulfilled the modified Layer Score for CP or non CP. The overall accuracy of the EST versus FE1 test was 85%/71%, with positive and negative predictive values of 100%/79% and 80%/69%, respectively. CONCLUSIONS: Short EST is rapid and easy to perform and can be incorporated in daily routines. We demonstrate that EST is superior to FE1 in the assessment of pancreatic insufficiency and may prove to be useful in diagnosing early or mild CP. PMID- 23921961 TI - Proteinase-activated receptors differentially modulate in vitro invasion of human pancreatic adenocarcinoma PANC-1 cells in correlation with changes in the expression of CDC42 protein. AB - OBJECTIVES: Proteinase-activated receptor-1 (PAR-1) and PAR-2 have been associated with increased invasiveness and metastasis in human malignancies. The role of PAR-3 has been less investigated. We examined the role of PARs in a human pancreatic adenocarcinoma PANC-1 cell line phenotype in vitro. METHODS: We knocked down PAR-1, PAR-2, or PAR-3, whereas empty vector-infected cells served as controls. Specific peptide agonists of PARs were used to stimulate the receptors. In vitro assays of colony formation, migration, and invasion were used to characterize the phenotypes, and Western analysis was used to follow cell division control protein 42 homolog (CDC42) expression. RESULTS: PAR-1 and PAR-2 knockdowns (KDs) were markedly less, whereas PAR-3 KDs were robustly more migratory and invasive than the controls. Stimulation of PAR-1 or PAR-2 by their peptide agonists increased, whereas PAR-3 agonist reduced the invasion of the control cells. Knockdowns of all three PARs exhibited changes in the expression of CDC42, which correlated with the changes in their invasion. Conversely, stimulation of vector-control cells with PAR-1 or PAR-2 agonists enhanced, whereas PAR-3 agonist reduced the expression of CDC42. In the respective KD cells, the effects of the agonists were abrogated. CONCLUSION: The expression and/or activation of PARs is linked to the invasiveness of PANC-1 cells in vitro, probably via modulation of the expression of CDC42. PMID- 23921962 TI - Cell surface sialic acid modulates extracellular matrix adhesion and migration in pancreatic adenocarcinoma cells. AB - OBJECTIVES: Tumor cells modulate their extracellular matrix (ECM) adhesion and migration to become more metastatic. Moreover, they show an increase in sialic acid, which could have an effect on their ECM adhesion and migration. This work describes the influence of pancreatic adenocarcinoma cell surface alpha2,3- and alpha2,6-sialic acid determinants on the aforementioned processes. METHODS: We have characterized the cell surface alpha2,3- and alpha2,6-sialic acids, and sialyl-Lewis x levels and the integrin levels of 2 pancreatic adenocarcinoma cell lines, Capan-1 and MDAPanc-28, grown at different cell densities, and also of the ST3Gal III overexpressing Capan-1 cells, C31. We have measured their adhesion to several ECM proteins and their migration through collagen with and without blocking their sialic acid determinants. RESULTS: Adhesion to ECM proteins of Capan-1 and MDAPanc-28 grown at different cell densities, and of C31, depended on their cell surface sialic acid determinants repertoire, correlating the higher alpha2,6-sialic acid levels with their increased ECM adhesion. Cell migration also depended on their sialic acid determinants expression; and in this case, higher alpha2,3-sialic acid levels correlated with a more migratory phenotype. CONCLUSION: This study shows how the intrinsic heterogeneity of cell membrane sialylation regulates the adhesive and migratory potential of pancreatic adenocarcinoma cells. PMID- 23921964 TI - Cerulein-induced acute pancreatitis is associated with c-Jun NH(2)-terminal kinase 1-dependent ferritin degradation and iron-dependent free radicals formation. AB - OBJECTIVES: The main goal of this work was to get insight into the mechanism of cerulein-induced reactive oxygen species (ROS) formation and impact of c-Jun NH(2)-terminal kinase (JNK) on this process. METHODS: The study was performed on Wistar rats and on a cellular model of acute pancreatitis (AP) using AR42J cell line. RESULTS: First of all, we observed that during AP, the iron storage protein ferritin in the rat pancreas undergoes degradation accompanied by an increased formation of protein carbonyls. Pancreatic acinar AR42J cells stimulated by cerulein showed increased labile iron pool that was accompanied by a decrease in the cellular ferritin-L level and an increase in the ROS formation. The changes in the ferritin-L level were inversely correlated with the ROS formation. The cells expressing inactive JNK1 mutant were completely resistant to cerulein induced ferritin degradation. CONCLUSIONS: Our data showed that cerulein-induced AP in rats and on cellular model is accompanied by JNK1-dependent ferritin degradation, increases labile iron pool and ROS formation. PMID- 23921963 TI - Expression of MUC4 mucin is observed mainly in the intestinal type of intraductal papillary mucinous neoplasm of the pancreas. AB - OBJECTIVES: This study aimed to examine expression profile of MUC4 in intraductal papillary mucinous neoplasm of the pancreas (IPMN). METHODS: We performed immunohistochemistry (IHC) of MUC4 in 142 IPMNs, with evaluation of the specificity of 2 anti-MUC4 monoclonal antibodies, 8G7 and 1G8, in cancer cell lines. RESULTS: Monoclonal antibody 8G7 showed a clear immunoreactivity, whereas MAb 1G8 did not show any immunoreactivity, in the Western blotting and IHC for human pancreatic carcinoma cell lines expressing MUC4 messenger RNA. However, IHC signals detected by both monoclonal antibodies were observed in the tissue specimens. The expression rates of MUC4/8G7 detected by MAb 8G7 and MUC4/1G8 detected by MAb 1G8 in the intestinal-type IPMNs were significantly higher than those in the gastric-type IPMNs. In the intestinal-type IPMNs, MUC4/8G7 was expressed mainly in the cytoplasm of the neoplastic cells, whereas MUC4/1G8 was expressed mainly at the cell apexes. Even in the gastric-type IPMNs with rare MUC4 expression in the low-grade dysplasia, both MUC4 expression rates increased when dysplasia advanced. CONCLUSIONS: A significantly higher expression of MUC4 in intestinal-type IPMNs than in gastric-type IPMNs will be one of the biomarkers to discriminate between the intestinal-type IPMNs with high malignancy potential from gastric-type IPMNs with low malignancy potential. PMID- 23921965 TI - Chylothorax after coronary artery bypass grafting using the right internal thoracic artery. AB - Chylothorax is a rare but serious complication of coronary artery bypass grafting (CABG) that results from disruption of the thoracic duct while harvesting the internal thoracic artery (ITA). A 78-year-old woman developed a large-volume milky pleural effusion 3 days after CABG. Biochemical analysis of the fluid resulted in a diagnosis of chylothorax. After failure of conservative medical treatment, including stopping her oral intake and starting total parenteral nutrition, surgical repair was performed via repeat median sternotomy. Intraoperative exploration revealed disruption of the thoracic duct or one of its tributaries close to the proximal portion of the right ITA, which was closed with interrupted sutures. In the majority of previous reports of chylothorax after CABG, the left ITA was used. However, harvesting of either the left or right ITA risks disruption of the thoracic duct and its tributaries, because of the high degree of anatomic variability of the thoracic duct system. PMID- 23921966 TI - A case of hemothorax following seat-belt injury with a bulla in the apex of the lung: a subtype of spontaneous hemopneumothorax. AB - We experienced a case of a subtype of spontaneous hemopneumothorax caused by external forces associated with a seat-belt injury. A female aged 39 years sustained a minor collision with an oncoming car while she was driving. Although pneumothorax was not detected, hemothorax and bleeding from the area surrounding the subclavian artery were observed on contrast-enhanced chest computed tomography (CT). After confirming continuous bleeding into the thoracic cavity after superselective arterial embolization, we performed emergency open surgery. We found a bulla in the apex of the lung, and the thoracic stump of the bulla was considered the source of bleeding. In this case, the direct cause of hemothorax was considered to be the external force associated with the seat-belt injury. When a bulla in the apex of the lung and continuous bleeding are both observed on CT, spontaneous hemopneumothorax should be suspected, necessitating open chest surgery in cases where pneumothorax is not observed. PMID- 23921967 TI - Cost effectiveness of alternative strategies for incorporating bevacizumab into the primary treatment of ovarian cancer. AB - BACKGROUND: The objective of this study was to evaluate the comparative effectiveness of strategies that incorporated bevacizumab into the primary platinum-based treatment of ovarian cancer: 1) no bevacizumab; 2) concurrent and maintenance bevacizumab for all; 3) bevacizumab for suboptimally debulked stage III and stage IV disease (high-risk cohort); and the evaluation of an alternative exploratory strategy of 4) directed bevacizumab therapy based on a predictive test for bevacizumab responsiveness. METHODS: A modified Markov state transition model with a 3-year time horizon that simulated publically available International Collaboration on Ovarian Neoplasms (ICON7) trial outcomes was used to evaluate the cost effectiveness of each strategy. Costs and adverse events were incorporated. An alternative strategy was used to model the impact on overall survival of a genetic-based predictive test. A Monte Carlo simulation simultaneously accounted for uncertainty in key parameters. RESULTS: The incorporation of bevacizumab for high-risk patients had an incremental cost effectiveness ratio of $168,000 per quality-adjusted life-year (QALY) saved compared with chemotherapy alone and dominated a strategy of giving bevacizumab to all patients with ovarian cancer. Monte Carlo simulation acceptability curves indicated that, at a willingness-to-pay threshold of $200,000 per QALY, the treatment of high-risk women with bevacizumab was the strategy of choice in 84% of simulations. A predictive test had an incremental cost-effectiveness ratio of $129,000 per QALY compared with chemotherapy alone and dominated other bevacizumab treatment strategies. CONCLUSIONS: The selective treatment of women with suboptimal and/or stage IV ovarian cancer was a more cost-effective use of bevacizumab than universal treatment but still did not fall within the limits of common willingness-to-pay thresholds. Continued investigation of potentially cost effective strategies, such as a predictive test, is necessary to optimize the use of this expensive treatment. PMID- 23921968 TI - Towards [NiFe]-hydrogenase biomimetic models that couple H2 binding with functionally relevant intramolecular electron transfers: a quantum chemical study. AB - [FeFe]- and [NiFe]-hydrogenases are dihydrogen-evolving metalloenzymes that share striking structural and functional similarities, despite being phylogenetically unrelated. Most notably, they are able to combine substrate binding and redox functionalities, which has important bearings on their efficiency. Model complexes of [FeFe]-hydrogenases that are able to couple H2 binding with a substrate-dependent intramolecular electron transfer promoting dihydrogen activation were recently shown to reproduce the complex redox chemistry of the all-iron enzyme. Notably, coupling of H2 binding and intramolecular redox events was proposed to have a key role also in [NiFe]-hydrogenases, but this feature is not reproduced in currently available nickel-iron biomimetic compounds. In the present study, we exploit dedicated density functional theory approaches to show that H2 binding and activation on a NiFe core can be favored by the installment of conveniently substituted isocyanoferrocenes, thanks to their ability to undergo intramolecular reduction upon substrate binding. Our results support the concept that a unified view on hydrogenase chemistry is a key element to direct future efforts in the modeling of microbial H2 metabolism. PMID- 23921969 TI - Neuropsychological profile of children after an episode of neuroborreliosis. AB - BACKGROUND: In the majority of patients with Lyme neuroborreliosis (LNB), neurological symptoms are transient. The extent of neuropsychological and neuropsychiatric problems in children is not well researched. OBJECTIVES: The study aimed to investigate cognitive functions and behavioral problems in children after LNB. PATIENTS AND METHODS: A total of 20 children between 6 and 16 years of age with an episode of LNB at least 4 month before neuropsychological testing were enrolled in the study and compared with 20 healthy controls. Children with LNB had cranial nerve palsies or meningoencephalitis, immunoglobulin G and immunoglobulin M antibodies for Borrelia burgdorferi in the peripheral blood, pleocytosis in the cerebrospinal fluid (leukocytes > 10 cells/MUL) and/or an intrathecal synthesis of antibodies for B. burgdorferi.Neuropsychological tests assessing intellectual skills, memory, and executive functions were used. Two parental questionnaires assessing behavior, psychiatric problems, and executive functions were administered. RESULTS: Intellectual skills, memory, and executive functions of children after an episode of LNB were within the normal range. In the subcategory of working memory, children after an episode of LNB performed worse than controls. The questionnaires did not reveal behavior or psychiatric problems, although there was a tendency that children after an episode of LNB had more physical complaints. CONCLUSION: Neuropsychological deficits resulting from LNB in childhood are rare. Most children had a good cognitive, emotional, and behavioral outcome. PMID- 23921970 TI - 13C NMR spectroscopy of copoly(arylenephthalide) derivatives with diphenyloxide and terphenyl fragments in the main chain. AB - (1) H and (13) S NMR spectral assignments have been provided for low-molecular reference monomers, poly(diphenyleneoxidephthalide) and periodic copoly(arylenephthalide) derivatives such as AB, ABB, and ABBB (where A = terphenylenephthalide and B = diphenyleneoxidephthalide) using (1) H-(1) H COSY, (1) H-(13) C HSQC and HMBC NMR techniques. Distinctive (13) C NMR chemical shifts of a main chain have been observed containing fragments of similar structures and lateral phthalate groups being part of various diads. PMID- 23921971 TI - Advances in diagnosis and treatment of hilar cholangiocarcinoma -- a review. AB - Hilar cholangiocarcinoma (HC) is a rare tumor that causes devastating disease. In the late stages, this carcinoma primarily invades the portal vein and metastasizes to the hepatic lobes; it is associated with a poor prognosis. HC is diagnosed by its clinical manifestation and results of imaging techniques such as ultrasound, computed tomography, magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiography, and percutaneous transhepatic cholangiography. Preoperative hepatic bile drainage can improve symptoms associated with insufficient liver and kidney function, coagulopathy, and jaundice. Surgical margin-negative (R0) resection, including major liver resection, is the most effective and potentially curative treatment for HC. If the tumor is not resected, then liver transplantation with adjuvant management can improve survival. We conducted a systematic review of developments in imaging studies and major surgical hepatectomy for HC with positive outcomes regarding quality of life. PMID- 23921972 TI - Brief report: broad autism phenotype in adults is associated with performance on an eye-tracking measure of joint attention. AB - The current study takes advantage of modern eye-tracking technology and evaluates how individuals allocate their attention when viewing social videos that display an adult model who is gazing at a series of targets that appear and disappear in the four corners of the screen (congruent condition), or gazing elsewhere (incongruent condition). Data demonstrated the feasibility of administrating this experimental paradigm to a diverse sample of healthy adult college students (N = 44). Results revealed that individual differences in gaze allocation were significantly related to a self-report measure evaluating features of the broad autism phenotype, suggesting that individual variation in the broad autism phenotype is related to individual differences in gaze allocation. PMID- 23921973 TI - Brief report: MECP2 mutations in people without Rett syndrome. AB - Mutations in Methyl-CpG-Binding protein 2 (MECP2) are commonly associated with the neurodevelopmental disorder Rett syndrome (RTT). However, some people with RTT do not have mutations in MECP2, and interestingly there have been people identified with MECP2 mutations that do not have the clinical features of RTT. In this report we present four people with neurodevelopmental abnormalities and clear RTT-disease causing MECP2 mutation but lacking the characteristic clinical features of RTT. One patient's symptoms suggest an extension of the known spectrum of MECP2 associated phenotypes to include global developmental delay with obsessive compulsive disorder and attention deficit hyperactivity disorder. These results reemphasize that RTT should remain a clinical diagnosis, based on the recent consensus criteria. PMID- 23921974 TI - Analysis of protein interactions in situ by proximity ligation assays. AB - The fate of the cell is governed by interactions among proteins, nucleic acids, and other biomolecules. It is vital to look at these interactions in a cellular environment if we want to increase our understanding of cellular processes. Herein we will describe how the in situ proximity ligation assay (in situ PLA) can be used to visualize protein interactions in fixed cells and tissues. In situ PLA is a novel technique that uses DNA, together with DNA modifying processes such as ligation, cleavage, and polymerization, as tools to create surrogate markers for protein interactions of interest. Different in situ PLA designs make it possible not only to detect protein-protein interactions but also post translational modifications and interactions of proteins with nucleic acids. Flexibility in DNA probe design and the multitude of different DNA modifying enzymes provide the basis for modifications of the method to make it suitable to use in many applications. Furthermore, examples of how in situ PLA can be combined with other methods for a comprehensive view of the cellular activity status are discussed. PMID- 23921975 TI - Lack of association between body weight and mortality in patients on veno-venous extracorporeal membrane oxygenation. AB - PURPOSE: To analyse the association of body weight with hospital mortality of adult patients supported with veno-venous extracorporeal membrane oxygenation (VV ECMO). METHODS: Retrospective analysis of the international Extracorporeal Life Support Organization (ELSO) registry. Univariate and multivariable logistic regression analyses were used to estimate the odds ratio (OR) of hospital death for each body weight quartile. Adjustment was made for demographic, physiologic and ECMO-related characteristics. We undertook a similar analysis for the subgroup of patients with confirmed H1N1 infection on VV ECMO. RESULTS: The study group consisted of 1,334 adult patients supported with VV ECMO between 2005 and 2011 with a median (Q1, Q3) body weight of 80 kg (69, 101 kg). Univariate analysis identified increased body weight to be associated with a reduced risk of death. In multivariable analysis, only age greater than 53 years, primary diagnosis other than pneumonia and intubation time longer than 3 days prior to initiation of ECMO were independent risk factors for mortality, whereas the association between high body weight and adjusted risk of death (OR 0.73, 95% CI 0.52-1.04, P = 0.08) was no longer statistically significant. The body weight of the 196 patients with confirmed H1N1 infection was significantly higher than that of the remaining study group. Body weight was not significantly associated with risk of death for these patients either (univariate OR for Q4 vs. Q1: 0.75, 95% CI 0.33-1.72, P = 0.49). CONCLUSIONS: Increased body weight was not a risk factor for hospital mortality in adult patients who required support with VV ECMO. High body weight should therefore not be regarded as a contraindication to initiation of VV ECMO in adult patients. Data collection and reporting that include patient height in addition to body weight would facilitate future research into the association of obesity with outcome of ECMO patients. PMID- 23921976 TI - Effect of sedation level on the prevalence of delirium when assessed with CAM-ICU and ICDSC. AB - PURPOSE: We hypothesized that reduced arousability (Richmond Agitation Sedation Scale, RASS, scores -2 to -3) for any reason during delirium assessment increases the apparent prevalence of delirium in intensive care patients. To test this hypothesis, we assessed delirium using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and Intensive Care Delirium Screening Checklist (ICDSC) in intensive care patients during sedation stops, and related the findings to the level of sedation, as assessed with RASS score. METHODS: We assessed delirium in 80 patients with ICU stay longer than 48 h using CAM-ICU and ICDSC during daily sedation stops. Sedation was assessed using RASS. The effect of including patients with a RASS of -2 and -3 during sedation stop ("light to moderate sedation", eye contact less than 10 s or not at all, respectively) on prevalence of delirium was analyzed. RESULTS: A total of 467 patient days were assessed. The proportion of CAM-ICU-positive evaluations decreased from 53 to 31 % (p < 0.001) if assessments from patients at RASS -2/-3 (22 % of all assessments) were excluded. Similarly, the number of positive ICDSC results decreased from 51 to 29 % (p < 0.001). CONCLUSIONS: Sedation per se can result in positive items of both CAM-ICU and ICDSC, and therefore in a diagnosis of delirium. Consequently, apparent prevalence of delirium is dependent on how a depressed level of consciousness after sedation stop is interpreted (delirium vs persisting sedation). We suggest that any reports on delirium using these assessment tools should be stratified for a sedation score during the assessment. PMID- 23921977 TI - Noninvasive ventilation at the end of life: and now? PMID- 23921978 TI - Prediction of long-term mortality in ICU patients: model validation and assessing the effect of using in-hospital versus long-term mortality on benchmarking. AB - PURPOSE: To analyze the influence of using mortality 1, 3, and 6 months after intensive care unit (ICU) admission instead of in-hospital mortality on the quality indicator standardized mortality ratio (SMR). METHODS: A cohort study of 77,616 patients admitted to 44 Dutch mixed ICUs between 1 January 2008 and 1 July 2011. Four Acute Physiology and Chronic Health Evaluation (APACHE) IV models were customized to predict in-hospital mortality and mortality 1, 3, and 6 months after ICU admission. Models' performance, the SMR and associated SMR rank position of the ICUs were assessed by bootstrapping. RESULTS: The customized APACHE IV models can be used for prediction of in-hospital mortality as well as for mortality 1, 3, and 6 months after ICU admission. When SMR based on mortality 1, 3 or 6 months after ICU admission was used instead of in-hospital SMR, 23, 36, and 30% of the ICUs, respectively, received a significantly different SMR. The percentages of patients discharged from ICU to another medical facility outside the hospital or to home had a significant influence on the difference in SMR rank position if mortality 1 month after ICU admission was used instead of in-hospital mortality. CONCLUSIONS: The SMR and SMR rank position of ICUs were significantly influenced by the chosen endpoint of follow-up. Case-mix-adjusted in-hospital mortality is still influenced by discharge policies, therefore SMR based on mortality at a fixed time point after ICU admission should preferably be used as a quality indicator for benchmarking purposes. PMID- 23921979 TI - Impact of improvement in preoperative oral health on nosocomial pneumonia in a group of cardiac surgery patients: a single arm prospective intervention study. AB - PURPOSE: To evaluate the effects of an oral health protocol on the incidence of postoperative pneumonia in patients submitted to coronary artery bypass grafting and to valve surgery. METHODS: All patients admitted to a public cardiac surgery hospital were examined by a dentist and had a thorough dentistry anamnesis and an intraoral exam focusing on teeth, gums, and tongue. Patients were taught how to brush their teeth and tongue and how to clean their jugal and palatal membranes. Chlorhexidine gluconate (CXG) 0.12% oral rinse twice a day was used until surgery. Data on age, sex, comorbidities, oral evaluation, type of surgery, and development of pneumonia were obtained. Statistical analysis was done on these variables to evaluate the impact of the study protocol. RESULTS: A total of 226 patients were enrolled, 136 male (60.2%). The median age was 59 years. There were 123 (54.4%) patients with coronary artery disease and 103 (45.6%) with valve disease. There were 18/226 (8%) postoperative pneumonias (PP), nine in each group. Ten occurred in dentate patients and eight in edentulous ones. Oral health optimization was achieved in 208/226 (92%) of patients in the preoperative period. The presence of tongue plaque (OR 17, P < 0.001) and of poor hygiene of the total superior dentures (OR 25, P < 0.001) in the preoperative period significantly increased the chance of PP. The use of CXG 0.12% in the preoperative period (OR 0.06, P < 0.001) and on the day of surgery (OR 0.002, P < 0.001) was protective against PP. Mortality in patients without pneumonia was 9/208 (4.32%) vs. 6/19 (33.3%) in those with pneumonia. The presence of pneumonia increased the chances of death by 11 times (P < 0.001). The mean pneumonia rate in ICU in the 6 months before the study protocol was 32 per 1,000 ventilator days, 24 during the 6-month intervention period, and 10 during the next 6 months following the study. CONCLUSIONS: PP rates were reduced using a simple and efficient protocol of dental care that improved oral hygiene in the preoperative period of cardiac surgery patients. PMID- 23921980 TI - Ultrasound pupillary assessment in the critical patient. PMID- 23921981 TI - Extracorporeal membrane oxygenation instead of invasive mechanical ventilation in patients with acute respiratory distress syndrome. PMID- 23921983 TI - [Renal diseases in rheumatology]. AB - Renal involvement and renal function disorders are commonplace in patients with rheumatic diseases and are often decisive for the prognosis. Typical nephrological complications in rheumatology are renal manifestations or delayed sequelae of the underlying disease in addition to drug-induced renal failure, e.g. by nonsteroidal anti-inflammatory drugs (NSAIDs). The differentiation from other common causes of disturbed renal function (e.g. diabetes and hypertension) is important and often difficult in individual cases. Renal involvement can be clinically manifested in many different ways. The spectrum ranges from slight functional disorders with, for example discrete erythrocyturia/proteinuria and normal renal function up to rapidly progressive renal failure. The probability of renal damage also varies greatly between different underlying diseases. For example, renal involvement in rheumatoid arthritis is a rarity but in contrast relatively normal in systemic lupus erythematosus. In the course of the differential diagnostics urine sediment, protein values and sonography are still the most important factors and the indications for kidney biopsy should be generously applied. Early initiation of immunosuppression can substantially improve the renal prognosis of inflammatory systemic diseases. PMID- 23921985 TI - [The UN Disability Rights Convention and its implementation in Germany]. PMID- 23921986 TI - [Interpreting change scores of the Behavioural Rating Scale for Geriatric Inpatients (GIP)]. AB - The Behavioural Rating Scale for Geriatric Inpatients (GIP) consists of fourteen, Rasch modelled subscales, each measuring different aspects of behavioural, cognitive and affective disturbances in elderly patients. Four additional measures are derived from the GIP: care dependency, apathy, cognition and affect. The objective of the study was to determine the reproducibility of the 18 measures. A convenience sample of 56 patients in psychogeriatric day care was assessed twice by the same observer (a professional caregiver). The median time interval between rating occasions was 45 days (interquartile range 34-58 days). Reproducibility was determined by calculating intraclass correlation coefficients (ICC agreement) for test-retest reliability. The minimal detectable difference (MDD) was calculated based on the standard error of measurement (SEM agreement). Test-retest reliability expressed by the ICCs varied from 0.57 (incoherent behaviour) to 0.93 (anxious behaviour). Standard errors of measurement varied from 0.28 (anxious behaviour) to 1.63 (care dependency). The results show how the GIP can be applied when interpreting individual change in psychogeriatric day care participants. PMID- 23921987 TI - Health impact of external funding for HIV, tuberculosis and malaria: systematic review. AB - BACKGROUND: Since 2002, development assistance for health has substantially increased, especially investments for HIV, tuberculosis (TB) and malaria control. We undertook a systematic review to assess and synthesize the existing evidence in the scientific literature on the health impacts of these investments. METHODS AND FINDINGS: We systematically searched databases for peer-reviewed and grey literature, using tailored search strategies. We screened studies for study design and relevance, using predefined inclusion criteria, and selected those that enabled us to link health outcomes or impact to increased external funding. For all included studies, we recorded dataset and study characteristics, health outcomes and impacts. We analysed the data using a causal-chain framework to develop a narrative summary of the published evidence. Thirteen articles, representing 11 individual studies set in Africa and Asia reporting impacts on HIV, tuberculosis and malaria, met the inclusion criteria. Only two of these studies documented the entire causal-chain spanning from funding to programme scale-up, to outputs, outcomes and impacts. Nonetheless, overall we find a positive correlation between consecutive steps in the causal chain, suggesting that external funds for HIV, tuberculosis and malaria programmes contributed to improved health outcomes and impact. CONCLUSIONS: Despite the large number of supported programmes worldwide and despite an abundance of published studies on HIV, TB and malaria control, we identified very few eligible studies that adequately demonstrated the full process by which external funding has been translated to health impact. Most of these studies did not move beyond demonstrating statistical association, as opposed to contribution or causation. We thus recommend that funding organizations and researchers increase the emphasis on ensuring data capture along the causal pathway to demonstrate effect and contribution of external financing. The findings of these comprehensive and rigorously conducted impact evaluations should also be made publicly accessible. PMID- 23921988 TI - Achieving effective universal health coverage with equity: evidence from Chile. AB - Chile's 'health guarantees' approach to providing universal and equitable coverage for quality healthcare in a dual public-private health system has generated global interest. The programme, called AUGE, defines legally enforceable rights to explicit healthcare benefits for priority health conditions, which incrementally covered 56 problems representing 75% of the disease burden between 2005 and 2009. It was accompanied by other health reform measures to increase public financing and public sector planning to secure the guarantees nationwide, as well as the state's stewardship role. We analysed data from household surveys conducted before and after the AUGE reform to estimate changes in levels of unmet health need, defined as the lack of a healthcare visit for a health problem occurring in the last 30 days, by age, sex, income, education, health insurance, residence and ethnicity; fitting logistic regression models and using predictive margins. The overall prevalence of unmet health need was much lower in 2009 (17.6%, 95% CI: 16.5%, 18.6%) than in 2000 (30.0%, 95% CI: 28.3%, 31.7%). Differences by income and education extremes and rural-urban residence disappeared. In 2009, people who had been in treatment for a condition covered by AUGE in the past year had a lower adjusted prevalence of unmet need for their recent problem (11.7%, 95% CI: 10.5%, 13.2%) than who had not (21.0%, 95% CI: 19.6%, 22.4%). Despite limitations including cross-sectional and self reported data, our findings suggest that the Chilean health system has become more equitable and responsive to need. While these changes cannot be directly attributed to AUGE, they were coincident with the AUGE reforms. However, healthcare equity concerns are still present, relating to quality of care, health system barriers and differential access for health conditions that are not covered by AUGE. PMID- 23921989 TI - Presence of disseminated tumor cells in bone marrow correlates with tumor stage and nodal involvement in cervical cancer patients. AB - Detection of disseminated tumor cells (DTCs) in the bone marrow (BM) of breast cancer patients is associated with poor outcome. The aim of our study was to evaluate the impact of BM status on survival in a large cohort of cervical cancer patients. Three hundred twenty-five patients with cervical cancer were included into this prospective two-center study (University Hospitals Tuebingen, Munich, Germany). BM was collected preoperatively. DTCs were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3. DTCs were detected in 22% of all BM aspirates. The number of CK-positive cells ranged from 1 to 93 per 2 * 10(6) mononuclear cells. Eighteen percent of patients with T1 stage presented with DTCs in BM compared to 30% in T2 and 45% in T3/4 patients. Among nodal negative patients, 18% had tumor cells in BM compared to 32% of nodal positive patients. Positive DTC status was associated with tumor size (p = 0.007) and nodal status (p = 0.009) but not with grading (p = 0.426). DTC status did not correlate with overall or disease-free survival. In the univariate analysis, tumor stage, nodal status, resection status and grading correlated with OS and DFS. In the multivariate analysis, only tumor stage and nodal status were independent predictors of OS and tumor stage, nodal status and grading of DFS. Tumor cell dissemination into BM is thus a common phenomenon in cervical cancer and correlates with higher tumor load but lacks prognostic relevance. Alternative detection methods may be needed to establish prognostic potential. PMID- 23921991 TI - Projections of cancer prevalence by phase of care: a potential tool for planning future health service needs. AB - PURPOSE: The objective of this study is to describe a method for estimating the number of cancer survivors requiring different types of cancer care in the future. METHODS: Colon cancer data (1972-2007) from the New South Wales (NSW) Central Cancer Registry were used to estimate prevalence in 2008-2017, which was then divided into five phases of care (initial, post-treatment monitoring, treatment for recurrence and second colon cancer, long-term survivors and last year of life). Patterns of care study data were used to calculate the type and number of treatments required by patients in initial care. RESULTS: There were 17,375 patients living in NSW who had a past diagnosis of first primary colon cancer in 2007. Our statistical model suggests that by 2017, this number will have increased to 22,671. At least 2,430 patients are expected to require initial surgery for colon cancer in 2017, and of these, 753 will also require adjuvant chemotherapy. Furthermore, an additional 538 cases will require therapy due to cancer recurrence (307) or a second primary colon cancer (231). CONCLUSION: Our proposed method provides more complete estimates of future cancer care needs. With some modifications, this method can be used to estimate the future prevalence of many major cancer types in many other jurisdictions. IMPLICATIONS FOR CANCER SURVIVORS: Our proposed method can be a useful tool for planning future cancer care with the goal of improving the cancer survivorship experience for survivors, their caregivers and their families. PMID- 23921992 TI - Identification of Arabidopsis BAK1-associating receptor-like kinase 1 (BARK1) and characterization of its gene expression and brassinosteroid-regulated root phenotypes. AB - Brassinosteroids (BRs) activate the BRI1 and BAK1/SERK3 membrane receptor complex, which leads to a wide range of changes in gene expression, plant growth and development. As an initial step to elucidate additional roles of BAK1, we cloned a BAK1-binding protein, BAK1-Associating Receptor-Like Kinase 1 (BARK1), and characterized its gene expression and root phenotypes. BARK1 is a putative membrane LRR-RLK (leucine-rich repeat receptor-like kinase) protein that specifically binds to BAK1 and its homologs. Careful examination of BARK1 expression using transgenic plants expressing a green fluorescent protein (GFP) reporter under the control of the native BARK1 promoter (BARK1p::GFP) revealed that this gene is ubiquitously expressed in most plant tissues, and shows especially strong expression in the xylem vasculature of primary and lateral roots as well as in mature pollen. Interestingly, the expression of the BARK1 gene was increased in the BR biosynthetic loss-of-function mutant, det2, and a loss-of-function mutant of BR signaling, bak1-3. In contrast, this gene was down regulated in the bzr1-1D plant, which is a BR signal gain-of-function mutant. BARK1-overexpressing transgenic plants clearly enhanced primary root growth in a dose-dependent manner, and their roots were hypersensitive to BR-induced root growth inhibition. In addition, both the number and density of lateral roots were dramatically increased in the BARK1 transgenic plants in a dose-dependent manner. Together with observations that ARF (AUXIN RESPONSE FACTOR) genes are up regulated in the BARK1 overexpressor, we suggest that the BARK1 overexpressor phenotype with more lateral roots is partly due to the increased expression of ARF genes in this genetic background. In conclusion, BAK1-interacting BARK1 protein may be involved in BR-mediated plant growth and development such as in lateral roots via auxin regulation. PMID- 23921993 TI - The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a Mendelian randomisation study. AB - OBJECTIVE: Variation in the fat mass and obesity-associated (FTO) gene influences susceptibility to obesity. A variant in the FTO gene has been implicated in genetic risk to osteoarthritis (OA). We examined the role of the FTO polymorphism rs8044769 in risk of knee and hip OA in cases and controls incorporating body mass index (BMI) information. METHODS: 5409 knee OA patients, 4355 hip OA patients and up to 5362 healthy controls from 7 independent cohorts from the UK and Australia were genotyped for rs8044769. The association of the FTO variant with OA was investigated in case/control analyses with and without BMI adjustment and in analyses matched for BMI category. A mendelian randomisation approach was employed using the FTO variant as the instrumental variable to evaluate the role of overweight on OA. RESULTS: In the meta-analysis of all overweight (BMI>=25) samples versus normal-weight controls irrespective of OA status the association of rs8044769 with overweight is highly significant (OR[CIs] for allele G=1.14 [01.08 to 1.19], p=7.5*10(-7)). A significant association with knee OA is present in the analysis without BMI adjustment (OR[CIs]=1.08[1.02 to 1.14], p=0.009) but the signal fully attenuates after BMI adjustment (OR[CIs]=0.99[0.93 to 1.05], p=0.666). We observe no evidence for association in the BMI-matched meta analyses. Using mendelian randomisation approaches we confirm the causal role of overweight on OA. CONCLUSIONS: Our data highlight the contribution of genetic risk to overweight in defining risk to OA but the association is exclusively mediated by the effect on BMI. This is consistent with what is known of the biology of the FTO gene and supports the causative role of high BMI in OA. PMID- 23921994 TI - Development of patient-centred standards of care for rheumatoid arthritis in Europe: the eumusc.net project. AB - OBJECTIVE: The eumusc.net project is a European Union (EU) commission and European League Against Rheumatism (EULAR)funded project that aims to facilitate equal standards for musculoskeletal health in all EU countries. One work-package was to develop evidence-based and patient-centred standards of care (SOC), for rheumatoid arthritis (RA) understandable for patients and professionals across Europe. METHOD: A review of documents covering clinical practice 'guidelines' and SOC for RA was conducted. The obtained documents were evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) criteria, and all recommended methods to treat RA were extracted. Based on this information, a three-round Delphi exercise was performed including a consensus group meeting of 21 researchers and patient representatives. RESULTS: 16 patient-centred SOC were formulated including a lay version in the format of a checklist. An example is SOC 3: 'People with RA should receive a treatment plan developed individually between them and their clinician at each visit.' The corresponding checklist question reads: 'Have I received a treatment plan which includes an explanation of my management, expected goals and outcomes and important contact details?' CONCLUSIONS: The SOC for RA will be available in all 23 official European languages and contribute to more unified treatment approaches in Europe. PMID- 23921995 TI - Hepatitis C virus-induced vasculitis: therapeutic options. AB - Hepatitis C virus (HCV) is now well recognised as the main etiologic agent of mixed cryoglobulinaemia vasculitis (cryovas). New opportunities and problems in developing therapy have therefore emerged. Antiviral therapy with pegylated interferon-alpha and ribavirin (plus protease inhibitor in the case of HCV genotype 1 infection) should be considered as induction therapy for HCV-cryovas with mild to moderate disease severity and activity. An early virologic response to antiviral therapy is correlated with a complete clinical response of HCV cryovas. In patients presenting with more severe disease (ie, worsening of renal function, mononeuritis multiplex, extensive skin disease including ulcers and distal necrosis), an immunosuppression induction phase is often necessary while awaiting the generally slow response to antiviral treatments. Combination therapy with rituximab plus an optimal antiviral agent is recommended, as it may target the downstream B cell arm of autoimmunity and the viral trigger. Careful monitoring for adverse effects is mandatory, since some manifestations of HCV cryovas, such as peripheral neuropathy or skin ulcers, may worsen with interferon based therapy. Clinicians should be aware of the possibility of malignant lymphoma when patients develop a relapse of cryovas without virological relapse. Room for other treatment strategies is very limited. Low-dose corticosteroids may help to control minor intermittent inflammatory signs such arthralgia but do not succeed in case of major organ involvement. Other immunosuppressants should be given only in case of refractory forms of HCV-cryovas, which are frequently associated with an underlying B cell lymphoma. PMID- 23921996 TI - Validation of the educational needs assessment tool as a generic instrument for rheumatic diseases in seven European countries. AB - OBJECTIVES: To validate the educational needs assessment tool (ENAT) as a generic tool for assessing the educational needs of patients with rheumatic diseases in European Countries. METHODS: A convenience sample of patients from seven European countries was included comprising the following diagnostic groups: ankylosing spondylitis, psoriatic arthritis, systemic sclerosis, systemic lupus erythematosus, osteoarthritis (OA) and fibromyalgia syndrome. Translated versions of the ENAT were completed through surveys in each country. Rasch analysis was used to assess the construct validity of the adapted ENATs including differential item functioning by culture (cross-cultural DIF). Initially, the data from each country and diagnostic group were fitted to the Rasch model separately, and then the pooled data from each diagnostic group. RESULTS: The sample comprised 3015 patients; the majority, 1996 (66.2%), were women. Patient characteristics (stratified by diagnostic group) were comparable across countries except the educational background, which was variable. In most occasions, the 39-item ENAT deviated significantly from the Rasch model expectations (item-trait interaction chi(2) p<0.05). After correction for local dependency (grouping the items into seven domains and analysing them as 'testlets'), fit to the model was satisfied (item-trait interaction chi(2) p>0.18) in all pooled disease group datasets except OA (chi(2)=99.91; p=0.002). The internal consistency in each group was high (Person Separation Index above 0.90). There was no significant DIF by person characteristics. Cross-cultural DIF was found in some items, which required adjustments. Subsequently, interval-level scales were calibrated to enable transformation of ENAT scores when required. CONCLUSIONS: The adapted ENAT is a valid tool with high internal consistency providing accurate estimation of the educational needs of people with rheumatic diseases. Cross-cultural comparison of educational needs is now possible. PMID- 23921997 TI - Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. AB - OBJECTIVES: Spondyloarthritides (SpA) are characterised by both peripheral and axial arthritis. The hallmarks of peripheral SpA are the development of enthesitis, most typically of the Achilles tendon and plantar fascia, and new bone formation. This study was undertaken to unravel the mechanisms leading towards enthesitis and new bone formation in preclinical models of SpA. RESULTS: First, we demonstrated that TNF(DeltaARE) mice show typical inflammatory features highly reminiscent of SpA. The first signs of inflammation were found at the entheses. Importantly, enthesitis occurred equally in the presence or absence of mature T and B cells, underscoring the importance of stromal cells. Hind limb unloading in TNF(DeltaARE) mice significantly suppressed inflammation of the Achilles tendon compared with weight bearing controls. Erk1/2 signalling plays a crucial role in mechanotransduction-associated inflammation. Furthermore, new bone formation is strongly promoted at entheseal sites by biomechanical stress and correlates with the degree of inflammation. CONCLUSIONS: These findings provide a formal proof of the concept that mechanical strain drives both entheseal inflammation and new bone formation in SpA. PMID- 23922000 TI - Who is now responsible for discovering and warning about adverse effects of generic drugs? PMID- 23922001 TI - Synthesis of homogeneous MUC1 oligomers via a bi-directional ligation strategy. AB - The efficient synthesis of homogeneous MUC1 peptide oligomers using sequential ligation reactions in the N-to-C and C-to-N directions is reported. The bi directional ligation strategy makes use of thioester formation via N -> S acyl shift chemistry in combination with peptide ligation reactions and was used to prepare a library of peptide oligomers ranging in molecular mass from 3.8-9.4 kDa, comprised of between 2 and 5 repeats of the MUC1 variable number tandem repeat sequence. PMID- 23922002 TI - Impact of internet-based cancer survivorship care plans on health care and lifestyle behaviors. AB - BACKGROUND: Survivorship care plans (SCP) are currently recommended by the Institute of Medicine, and will soon be required for accreditation by the American College of Surgeons Commission on Cancer. To the best of the authors' knowledge, the impact of SCPs on cancer survivors has not been previously reported. METHODS: In 2007, the authors created an Internet tool for the creation of SCPs that provides customized guidelines for survivorship care. Users are sent a voluntary follow-up survey 1 month after initial use. RESULTS: From May 2010 through January 2013, 8690 cancer survivors used the SCP tool. The most common diagnoses were breast (45%), hematologic (12%), and gastrointestinal (11%) cancers; the median age of the survivors was 51 years. Of these, 875 (10%) respondents provided information for future electronic contact and 298 responded to a 1-month follow-up survey. They reported that the information provided was "good" to "excellent" in 93% of cases, and new in 65% of cases. With regard to the emotional impact of the SCP, 62% of responding survivors believed that it provided "just enough" information, 72% felt "more informed," and 94% believed they would recommend it to others. The majority of respondents (63%) thought that the SCP changed their health care participation, and 80% shared/planned to share it with their health care team. Of those survivors who had done so, 80% reported that it improved communication with their health care providers. Greater than one half of survey users (54%) reported that they had made or planned to make a lifestyle change in response to the SCP, most commonly dietary modification and increased exercise. CONCLUSIONS: Survivorship care plans are useful vehicles with which to promote lifestyle and behavioral changes, and to assist survivors with communication with health care providers. These findings support recommendations from the Institute of Medicine and the American College of Surgeons Commission on Cancer. PMID- 23922003 TI - Features of coronary plaque in patients with metabolic syndrome and diabetes mellitus assessed by 3-vessel optical coherence tomography. AB - BACKGROUND: The pathophysiological basis for the association between metabolic syndrome (MetS) and coronary artery disease is not well understood. We sought to characterize coronary plaques in patients with MetS by using optical coherence tomography. METHODS AND RESULTS: We identified 451 coronary plaques from 171 subjects who underwent optical coherence tomographic imaging in 3 coronary arteries. Subjects were divided into 3 groups: diabetes mellitus (DM, n=77), MetS (n=35), and a control group (C group, n=59) without DM or MetS. Optical coherence tomographic analysis included the presence of lipid-rich plaque, maximum lipid arc, lipid-core length, lipid index (LI), fibrous cap thickness, and thin-cap fibroatheroma. We defined LI as mean lipid arc multiplied by lipid-core length. Lipid-core length and LI were significantly greater in DM and MetS than in C group (lipid-core length: 7.7 +/- 4.0 and 7.0 +/- 3.8 versus 5.5 +/- 2.4 mm; P<0.001 and P=0.012, and LI: 1164 +/- 716 and 1086 +/- 693 versus 796 +/- 417 mm; P<0.001 and P=0.008). Maximum lipid arc was significantly greater in DM than in C group, whereas no significant difference was observed between MetS and C group (196 +/- 45 degrees , 187 +/- 42 degrees versus 176 +/- 52 degrees ; P=0.002 and P=0.182). Fibrous cap thickness and thin-cap fibroatheroma showed no significant difference among the 3 groups. In multivariate analysis, DM and MetS were independently associated with LI, whereas only acute coronary syndrome was the independent predictor for thin-cap fibroatheroma. CONCLUSIONS: Compared with control subjects, coronary plaques in MetS contain larger lipid. However, the MetS criteria used in this study could not distinguish the vulnerable features such as thin-cap fibroatheroma, suggesting the necessity of complementary information to identify patients at high risk for cardiovascular events. PMID- 23922004 TI - T1 mapping with cardiovascular MRI is highly sensitive for Fabry disease independent of hypertrophy and sex. AB - BACKGROUND: Fabry disease (FD) is an X-linked disorder of lysosomal metabolism affecting multiple organs with cardiac disease being the leading cause of death. Current imaging evaluations of the heart are suboptimal. The goals of the current study are to evaluate the potential of quantitative T1 mapping with cardiovascular MRI as a disease-specific imaging biomarker. METHODS AND RESULTS: A total of 31 patients with FD, 23 healthy controls, and 21 subjects with concentric remodeling or hypertrophy underwent cardiovascular MRI to measure left ventricular (LV) morphology, function, delayed enhancement, as well as myocardial T1 values, and derived parameters (extracellular volume). All subjects had LV ejection fraction >50% and similar volumes. FD and concentric remodeling or hypertrophy had similarly increased mass, wall thickness, and mass/volume as compared with controls. A total of 16 of 31 FD subjects and 10 of 21 concentric remodeling or hypertrophy subjects had LV hypertrophy. Noncontrast myocardial T1 values were substantially lower in FD as compared with controls and concentric remodeling or hypertrophy (1070 +/- 50, 1177 +/- 27, and 1207 +/- 33 ms, respectively; P<0.001), but extracellular volume was similar in all groups (21.7 +/- 2.4%, 22.2 +/- 3.1%, and 21.8 +/- 3.9%, respectively). Single-voxel NMR spectroscopy in 4 FD and 4 healthy control subjects showed a significant negative linear relationship between lipid content and noncontrast T1 values (r=-0.9; P=0.002). Female subjects had lower LV mass and wall thickness, longer myocardial T1 values and larger extracellular volume suggesting a key sex difference in cardiac remodeling. CONCLUSIONS: Reduced noncontrast myocardial T1 values are the most sensitive and specific cardiovascular MRI parameter in patients with FD irrespective of sex and LV morphology and function. PMID- 23922005 TI - Longitudinal determinants of left ventricular mass and geometry: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - BACKGROUND: The purpose of this study was to identify determinants of 20-year change in left ventricular (LV) mass (LVM) and LV geometry in black and white young adults in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. METHODS AND RESULTS: We studied 2426 black and white men and women (54.7% white) aged 43 to 55 years with cardiovascular risk factor data and echocardiograms from CARDIA year 5 and 25 examinations. In regression models, year 25 LVM or relative wall thickness was the dependent variable and with year 5 echo values, age, sex, race, body mass index, change in body mass index, mean arterial blood pressure, change in mean blood pressure, heart rate, change in heart rate, tobacco use, presence of diabetes mellitus, alcohol use, and physical activity score as independent variables. LVM and relative wall thickness increased, whereas prevalence of normal geometry declined from 84.2% to 69.7%. Significant determinants of year 25 LVM/m(2.7) were year 5 LVM, year 5 and change in body mass index, year 5 and change in mean arterial pressure, year 5 and change in heart rate, baseline diabetes mellitus, and year 5 tobacco and alcohol use (overall r(2)=0.40). Significant determinants of year 25 relative LV wall thickness were year 5 value, black race, change in body mass index, year 5 and change in mean arterial pressure, starting smoking, and year 5 diabetes mellitus (overall r(2)=0.11). CONCLUSIONS: Prevalence of abnormal LV hypertrophy and geometry increased from young adulthood to middle age. Both young adult cardiovascular risk traits and change in these traits predicted change in LV mass/geometry. PMID- 23922007 TI - Impact of the CYP2C19*17 polymorphism on the clinical outcome of clopidogrel therapy in Asian patients undergoing percutaneous coronary intervention. AB - The impact of the CYP2C19*17 polymorphism on the clinical outcome in Asians undergoing percutaneous coronary intervention (PCI) is unknown. We sought to assess the long-term impact of CYP2C19*17 on the risk for adverse clinical events in 2188 Korean patients taking clopidogrel after PCI. The prevalence of the CYP2C19*17 allele [*wt/*17: 2.4% (n = 53), *17/*17: 0%] was very low. The 2-year cumulative event rates for bleeding [*wt/*17 vs. *wt/*wt: 2 vs. 2.3%; adjusted hazard ratio (HR), 1.23; 95% confidence interval (CI), 0.16-9.45], stent thrombosis (2 vs. 1.1%; HR, 3.98; 95% CI, 0.49-31.6) or composite of any death, and myocardial infarction or stroke (5.4 vs. 7.1%; HR, 1.37; 95% CI, 0.32-5.73) did not differ on the basis of the presence of CYP2C19*17. In conclusion, in our study population of Asian patients, the CYP2C19*17 polymorphism was not associated with adverse clinical outcomes after PCI because of its low prevalence, the rarity of homozygotes, and the relatively low rate of adverse clinical events. PMID- 23922008 TI - What do we know and not know about mirabegron, a novel beta3 agonist, in the treatment of overactive bladder? AB - INTRODUCTION AND HYPOTHESIS: Mirabegron is a novel beta3-adrenoceptor agonist recently approved by Japanese, American, and European authorities for overactive bladder (OAB) therapy. Here we review existing knowledge on this new class of medication, analyze existing literature on the topic, and make recommendations regarding its administration and necessary future studies. METHODS: We reviewed the current literature and analyzed mirabegron efficacy, safety, and suitability for treating OAB symptoms. We performed a systematic search of Medline/PubMed, and Embase. Studies exploring mechanisms involved in the effects of mirabegron were included. Searches were limited to the English language. RESULTS: Two phase II and two large-scale phase III multinational randomized controlled trials have supported mirabegron efficacy and tolerability with up to 12 weeks of therapy in OAB patients. The reported frequency and severity of treatment-emergent and serious adverse events were similar to antimuscarinics but with more than threefold lower incidence of dry mouth than with tolterodine. However, effects on the cardiovascular system, cognitive functions, pharmacokinetic interactions with other drugs, and long-term adverse events have not yet been fully investigated. CONCLUSION: Anticholinergic drugs should remain the first-line pharmacologic treatment for OAB until head-to-head comparative study eventually shows that mirabegron has equivalent or superior efficacy. However, it seems logical to use mirabegron as second-line treatment of OAB in patients who are poor responders or intolerant to anticholinergics. PMID- 23922009 TI - The relationship between uterine leiomyomata and pelvic floor symptoms. AB - INTRODUCTION AND HYPOTHESIS: To compare pelvic floor symptoms in women with a leiomyomatous uterus <=12 weeks and those >12 weeks in size and to evaluate the resolution of these symptoms after surgical intervention. METHODS: The PFDI-20, PFIQ-7 and 3-day voiding diaries were administered prospectively to all subjects. Demographics and questionnaire responses were compared using a t test, Chi squared test or Mann-Whitney U test as indicated. RESULTS: One hundred and forty five women completed the questionnaires and were included for analysis. There were 58 women with uterine size <=12 weeks (group I) and 87 women with size >12 weeks (group II). Participants in group I reported more straining to defecate (p = 0.042), while group II reported increased feeling of incomplete bladder emptying (p = 0.007) and difficulty emptying their bladder (p = 0.008). Review of ultrasound images revealed no difference in pelvic floor symptoms when stratified by leiomyoma location. At 1-year follow-up, 69 women (48 %) responded, and 40 (58 %) had undergone surgical intervention. Surgery was shown to improve symptoms for all questions reviewed at 1-year follow-up. CONCLUSIONS: A leiomyomatous uterus >12 weeks is associated with the symptom of incomplete bladder emptying, but does not appear to have an effect on other pelvic floor symptoms compared with women with a smaller leiomyomatous uterus. Surgical intervention for leiomyomata improves pelvic floor symptoms. PMID- 23922006 TI - PharmGKB summary: cyclosporine and tacrolimus pathways. PMID- 23922010 TI - Dietary fat differentially influences the lipids storage on the adipose tissue in metabolic syndrome patients. AB - PURPOSE: Adipose tissue is now recognized as a highly active metabolic and endocrine organ. Our aim was to investigate the effect of the dietary fat on the two main adipose tissue functions, endocrine and lipid store, by analyzing the adipose tissue gene expression from metabolic syndrome patients. METHODS: A randomized, controlled trial conducted within the LIPGENE study assigned 39 metabolic syndrome patients to 1 of 4 isoenergetic diets: (1) high-saturated fatty acid (HSFA), (2) high-monounsaturated fatty acid (HMUFA), (3) low-fat, high complex carbohydrate diet supplemented with long-chain n-3 fatty acids (LFHCC n 3), and (4) low-fat, high-complex carbohydrate diet supplemented with placebo (LFHCC), for 12 weeks each. A fat challenge reflecting the fatty acid composition as the original diets was conducted post-intervention. RESULTS: The long-term consumption of HSFA, LFHCC, and LFHCC n-3 diets, but not HMUFA diet, decreased the perilipin fasting mRNA levels. LFHCC diet consumption increased fasting FABP4 expression, while it was reduced by the consumption of LFHCC n-3 diet. LFHCC meal reduced, while LFHCC n-3 meal intake increased postprandial CAV1 expression. CONCLUSION: The quantity and quality of dietary fat induce differential lipid storage and processing related gene expression, which may interact with the expression of adipokines through common regulatory mechanisms. PMID- 23922011 TI - Needle subcision: a conservative treatment for facial dimpling after elimination of odontogenic infection source: a technical note. AB - AIM: Extraoral skin fistula after resolution of odontogenic infection often resolves spontaneously, but in some cases, facial dimpling occur which needs revision surgery. This article evaluates the result of needle subcision for treatment of this condition, with or without dermal filler injection. METHODS: Five patients with facial dimpling that was remained after elimination of odontogenic infection origin were evaluated. Subcision alone was used in four patients, and needle subcision followed by dermal filler was done in a patient. RESULTS: Facial dimpling in the chin (a case), mandibular lower border (two cases) as well as cheek skin (two cases) were treated by this method. All patients were satisfied with the cosmetic results. Six month after surgery, treatment outcomes were stable. CONCLUSION: Needle subcision is a simple and conservative method for correction of facial dimpling after elimination of odontogenic infection source. PMID- 23922012 TI - Therapeutic immunization and local low-dose tumor irradiation, a reinforcing combination. AB - Therapeutic cancer vaccines show promise in preclinical studies, yet their clinical efficacy is limited. Increased recruitment of immune cells into tumors and suppression of the immune suppressive tumor environment are critical components toward effective cancer immunotherapies. Here, we report how local low dose irradiation, alone or with a therapeutic immunization based on Semliki Forest virus (SFV) against human papillomavirus (HPV)-related cancer, influences these immune mechanisms. We first demonstrated that immunization with SFVeE6,7 or SFVeOVA, replicon particles expressing either HPV16 E6/E7 or ovalbumin, resulted in an antigen-specific migration of CD8+ T cells into HPV- and OVA-specific tumors. Local low-dose tumor irradiation alone resulted in a 2-fold increase of intratumoral CD8+ T cells. When 14 Gy irradiation was combined with immunization, intratumoral numbers of CD8+ T cells increased 10-fold and the number of CD8+ T cells specific for the E7- epitope increased more than 20-fold. Irradiation alone however also increased the number of intratumoral myeloid-derived suppressor cells (MDSCs) 3.5-fold. Importantly, this number did not further increase when combined with immunization. As a result, the ratio of antigen-specific CD8+ T cells and MDSCs in tumors increased up to 85-fold compared to the control. We furthermore demonstrated that following irradiation CCR2 and CCL2, CXCR6 and CCL16, chemokines and ligands involved in tumor homing of immune cells, were significantly up regulated. This study demonstrates that local low-dose tumor irradiation influences the intratumoral immune population induced by SFVeE6,7 immunization by a strong increase in the ratio of antitumoral to immune suppressive cells, thus changing the intratumoral immune balance in favor of antitumor activity. PMID- 23922013 TI - Notch signaling pathway in cumulus cells can be a novel marker to identify poor and normal responder IVF patients. AB - PURPOSE: To identify expression of Notch signaling proteins and its ligands in human cumulus cells which were obtained by follicle aspiration and to compare the differences of this protein expression between the normal and poor responder patients. METHODS: 47 patients who applied to the assisted reproductive treatments with various infertility problems were included to the study. Controlled ovarian hyperstimulation was performed by using GnRH agonist and gonadotropins. Serum hormon levels were measured by using Chemilluminescent Microparticle Immunoassay method for each patient. After ultrasonographic ovarian follicle screening, oocytes were retrievaled. Cumulus cells obtained from the follicles were cultured for 72 h and immunuhistochemistry were performed for Notch1, Notch2, Notch3, Notch4, Jagged1 and Jagged2 proteins. Histological score (HSCORE) were applied to all of the samples. The association between Notch and its ligands protein expressions and the oocyte-embryo quality and fertilization rates were investigated. RESULTS: Significant differences were observed between the mean values of age, AMH and FSH in the 2 groups, respectively (p < 0.05). However, the mean female infertility duration and total gonadotropin dose did not differ significantly between normal and poor responder groups. All the patients cumulus cells expressed Notch1, Notch2, Notch3, Notch4, Jagged1 and Jagged2. There was a significant difference (p < 0.05) only for Notch2 between the 2 groups and a positive correlation between Notch2 and Notch3 (r = 547, p = 0.00) expressions were noted. Furthermore, no correlations were observed between the following: Notch1, Notch2, Notch3, Notch4, Jagged1, and Jagged2 expression; mature oocyte number; fertilization rates, and embryo quality percentage in both of the groups. CONCLUSION: Notch signalling proteins can be an indicator for understanding the ovarian response in ovulation induction. PMID- 23922014 TI - Engineering of bacteria for the visualization of targeted delivery of a cytolytic anticancer agent. AB - A number of recent reports have demonstrated that attenuated Salmonella typhimurium are capable of targeting both primary and metastatic tumors. The use of bacteria as a vehicle for the delivery of anticancer drugs requires a mechanism that precisely regulates and visualizes gene expression to ensure the appropriate timing and location of drug production. To integrate these functions into bacteria, we used a repressor-regulated tetracycline efflux system, in which the expression of a therapeutic gene and an imaging reporter gene were controlled by divergent promoters (tetAP and tetRP) in response to extracellular tetracycline. Attenuated S. typhimurium was transformed with the expression plasmids encoding cytolysin A, a therapeutic gene, and renilla luciferase variant 8, an imaging reporter gene, and administered intravenously to tumor-bearing mice. The engineered Salmonella successfully localized to tumor tissue and gene expression was dependent on the concentration of inducer, indicating the feasibility of peripheral control of bacterial gene expression. The bioluminescence signal permitted the localization of gene expression from the bacteria. The engineered bacteria significantly suppressed both primary and metastatic tumors and prolonged survival in mice. Therefore, engineered bacteria that carry a therapeutic and an imaging reporter gene for targeted anticancer therapy can be designed as a theranostic agent. PMID- 23922017 TI - On the Poisson's ratio of the nucleus pulposus. AB - Existing experimental data on the Poisson's ratio of nucleus pulposus (NP) tissue is limited. This study aims to determine whether the Poisson's ratio of NP tissue is strain-dependent, strain-rate-dependent, or varies with axial location in the disk. Thirty-two cylindrical plugs of bovine tail NP tissue were subjected to ramphold unconfined compression to 20% axial strain in 5% increments, at either 30 lm/s or 0.3 lm/s ramp speeds and the radial displacement determined using biaxial video extensometry. Following radial recoil, the true Poisson's ratio of the solid phase of NP tissue increased linearly with increasing strain and demonstrated strain-rate dependency. The latter finding suggests that the solid matrix undergoes stress relaxation during the test. For small strains, we suggest a Poisson's ratio of 0.125 to be used in biphasic models of the intervertebral disk PMID- 23922015 TI - Silencing PP2A inhibitor by lenti-shRNA interference ameliorates neuropathologies and memory deficits in tg2576 mice. AB - Deficits of protein phosphatase-2A (PP2A) play a crucial role in tau hyperphosphorylation, amyloid overproduction, and synaptic suppression of Alzheimer's disease (AD), in which PP2A is inactivated by the endogenously increased inhibitory protein, namely inhibitor-2 of PP2A (I2(PP2A)). Therefore, in vivo silencing I2(PP2A) may rescue PP2A and mitigate AD neurodegeneration. By infusion of lentivirus-shRNA targeting I2(PP2A) (LV-siI2(PP2A)) into hippocampus and frontal cortex of 11-month-old tg2576 mice, we demonstrated that expression of LV-siI2(PP2A) decreased remarkably the elevated I2(PP2A) in both mRNA and protein levels. Simultaneously, the PP2A activity was restored with the mechanisms involving reduction of the inhibitory binding of I2(PP2A) to PP2A catalytic subunit (PP2AC), repression of the inhibitory Leu309-demethylation and elevation of PP2AC. Silencing I2(PP2A) induced a long-lasting attenuation of amyloidogenesis in tg2576 mice with inhibition of amyloid precursor protein hyperphosphorylation and beta-secretase activity, whereas simultaneous inhibition of PP2A abolished the antiamyloidogenic effects of I2(PP2A) silencing. Finally, silencing I2(PP2A) could improve learning and memory of tg2576 mice with preservation of several memory-associated components. Our data reveal that targeting I2(PP2A) can efficiently rescue Abeta toxicities and improve the memory deficits in tg2576 mice, suggesting that I2(PP2A) could be a promising target for potential AD therapies. PMID- 23922018 TI - Interdepartmental communication. PMID- 23922019 TI - Takotsubo cardiomyopathy complicated by cardiac tamponade. AB - We describe a 76-year-old patient with takotsubo cardiomyopathy complicated by cardiac tamponade. Pericardial effusion in takotsubo cardiomyopthy is common but a cardiac tamponade is very rare. The use of anticoagulants may increase the risk of pericardial effusion and should be considered with care. PMID- 23922020 TI - Optimisation of cardiac resynchronisation therapy during exercise. PMID- 23922021 TI - A supraventricular tachycardia showing alternation of the QRS interval. PMID- 23922022 TI - Volumetric tumor growth in advanced non-small cell lung cancer patients with EGFR mutations during EGFR-tyrosine kinase inhibitor therapy: developing criteria to continue therapy beyond RECIST progression. AB - BACKGROUND: The objective of this study was to define the volumetric tumor growth rate in patients who had advanced nonsmall cell lung cancer (NSCLC) with sensitizing epidermal growth factor receptor (EGFR) mutations and had initially received treatment with EGFR-tyrosine kinase inhibitor (TKI) therapy beyond progression. METHODS: The study included 58 patients with advanced NSCLC who had sensitizing EGFR mutations treated with first-line gefitinib or erlotinib, had baseline computed tomography (CT) scans available that revealed a measurable lung lesion, had at least 2 follow-up CT scans during TKI therapy, and had experienced volumetric tumor growth. The tumor volume (in mm3) of the dominant lung lesion was measured on baseline and follow-up CT scans during therapy. In total, 405 volume measurements were analyzed in a linear mixed-effects model, fitting time as a random effect, to define the growth rate of the logarithm of tumor volume (log(e)V). RESULTS: A linear mixed-effects model was fitted to predict the growth of log(e)V, adjusting for time in months from baseline. Log(e)V was estimated as a function of time in months among patients whose tumors started growing after the nadir: log(e)V = 0.12*time + 7.68. In this formula, the regression coefficient for time, 0.12/month, represents the growth rate of log(e)V (standard error, 0.015/month; P < .001). When adjusted for baseline volume, log(e)V0, the growth rate was also 0.12/month (standard error, 0.015/month; P < .001; log(e)V = 0.12*months + 0.72 log(e)V0 + 0.61). CONCLUSIONS: Tumor volume models defined volumetric tumor growth after the nadir in patients with EGFR-mutant, advanced NSCLC who were receiving TKI, providing a reference value for the tumor growth rate in patients who progress after the nadir on TKI therapy. The results can be studied further in additional cohorts to develop practical criteria to help identify patients who are slowly progressing and can safely remain on EGFR-TKIs. PMID- 23922024 TI - Functional balance assessment with pediatric balance scale in girls with visual impairment. AB - PURPOSE: To examine functional balance abilities in girls with visual impairment (VI) and to investigate the correlation between stabilography and clinical balance assessment using the Pediatric Balance Scale (PBS) in girls with VI. METHODS: The PBS and stabilography were administered to 26 girls with VI aged 10 to 15 years. The association between PBS scores and sway parameters was examined using the Spearman correlation coefficient. RESULTS: The range of PBS scores was 47 to 56. Balance difficulties appeared in single-leg stance, tandem stance, and reaching forward. The PBS scores correlated with all but 2 sway parameters, with r values ranging from -0.18 to -0.58. CONCLUSIONS: Girls with VI present difficulties in upright stance when the size of the base of support is narrowed and in situations where the center of gravity approaches the edge of the base of support. There is a need to provide interventions to improve balance abilities in girls with VI. PMID- 23922023 TI - Medial prefrontal cortex Transient Receptor Potential Vanilloid Type 1 (TRPV1) in the expression of contextual fear conditioning in Wistar rats. AB - RATIONALE: Contextual fear is evoked by re-exposing an animal to an environment that has been previously paired with an aversive or unpleasant stimulus. It can be assessed by freezing and cardiovascular changes such as increase in mean arterial pressure and heart rate. A marked increase in neuronal activity is associated with contextual fear conditioning, especially in limbic structures involved with defense reactions, such as the ventral portion of medial prefrontal cortex. OBJECTIVE: Given the fact that transient receptor potential vanilloid type 1 (TRPV1) receptors could be involved in the expression of defensive behavior, the present work tested the hypothesis that TRPV1 manipulation in the ventromedial prefrontal cortex (vMPFC) modulates the expression of contextual conditioned fear. METHODS: Male Wistar rats received bilateral microinjections into the vMPFC of the TRPV1 receptor antagonists capsazepine (1, 10, and 60 nmol/200 nL) or 6-iodonordihydrocapsaicin (3 nmol/200 nL), and the TRPV1 agonist capsaicin (1 nmol/200 nL) preceded by vehicle or 6-iodonordihydrocapsaicin before re-exposure to the experimental chamber for 10 min, 48 h after conditioning in two different protocols distinct by their aversiveness. RESULTS: Both antagonists reduced the freezing and cardiovascular responses in the high aversive protocol. Capsaicin caused an increase in fear-associated responses that could be blocked by 6-iodonordihydrocapsaicin. CONCLUSIONS: Our results indicate that TRPV1 receptors located in the vMPFC have a tonic involvement in the modulation of the expression of contextual fear conditioning. PMID- 23922025 TI - Commentary on "Functional balance assessment with pediatric balance scale in girls with visual impairment". PMID- 23922026 TI - Diagnosis dialog for pediatric physical therapists: hypotonia, developmental coordination disorder, and pediatric obesity as examples. AB - PURPOSE: To clarify what diagnosis means for pediatric physical therapists, to provide several examples of human movement dysfunction syndromes, and to offer guidance for how pediatric physical therapists may continue this work in any clinical setting. KEY POINTS: The importance of diagnosis in pediatric physical therapy is presented along with examples of 3 different processes used to develop diagnostic labels. These processes included surveys to identify consensus opinion of clinicians, a literature review, and a combination of these 2. Hypotonia, developmental coordination disorder, and pediatric obesity are presented as examples. SUMMARY: The 3 diagnoses serve as a basis for ongoing dialogue, discussion, and development of diagnostic labels for human movement syndromes identified by pediatric physical therapists. PMID- 23922027 TI - Halogen effect on structure and 13C NMR chemical shift of 3,6-disubstituted-N alkyl carbazoles. AB - Structures of selected 3,6-dihalogeno-N-alkyl carbazole derivatives were calculated at the B3LYP/6-311++G(3df,2pd) level of theory, and their (13) C nuclear magnetic resonance (NMR) isotropic shieldings were predicted using density functional theory (DFT). The model compounds contained 9H, N-methyl and N ethyl derivatives. The relativistic effect of Br and I atoms on nuclear shieldings was modeled using the spin-orbit zeroth-order regular approximation (ZORA) method. Significant heavy atom shielding effects for the carbon atom directly bonded with Br and I were observed (~-10 and ~-30 ppm while the other carbon shifts were practically unaffected). The decreasing electronegativity of the halogen substituent (F, Cl, Br, and I) was reflected in both nonrelativistic and relativistic NMR results as decreased values of chemical shifts of carbon atoms attached to halogen (C3 and C6) leading to a strong sensitivity to halogen atom type at 3 and 6 positions of the carbazole ring. The predicted NMR data correctly reproduce the available experimental data for unsubstituted N alkylcarbazoles. PMID- 23922028 TI - Azobenzene-functionalized N-heterocyclic carbenes as photochromic ligands in silver(i) and gold(i) complexes. AB - The reaction of meta- and para-bromomethylene-azobenzenes with 1-methyl-imidazole yields the respective meta-/para-functionalized azobenzenes tagged with an imidazolium group. Similar reactions of ortho- and para-bromo-azobenzene with imidazole and successive quaternation with benzylbromide give the analogues, with an imidazolium group in ortho/para substituted azobenzenes. With the exception of the ortho derivative, all imidazolium salts could be transformed into their respective silver(i) complexes by reaction with Ag2O. Transmetallation of these silver(i) complexes with (Me2S)AuCl gives the azobenzene-containing complexes (NHC)AuCl. Two of these formed crystals suitable for X-ray diffraction, which revealed the typical linear coordination geometry of the NHC-Au-Cl moiety. All gold complexes feature E->Z photo-isomerisation upon irradiation with UV light. The thermal back reaction to the E-isomers is relatively slow and comparable to that of other azobenzene compounds. PMID- 23922029 TI - Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs. AB - MGH2.1 is a herpes simplex virus type 1 (HSV1) oncolytic virus that expresses two prodrug-activating transgenes: the cyclophosphamide (CPA)-activating cytochrome P4502B1 (CYP2B1) and the CPT11-activating secreted human intestinal carboxylesterase (shiCE). Toxicology and biodistribution of MGH2.1 in the presence/absence of prodrugs was evaluated in mice. MGH2.1 +/- prodrugs was cytotoxic to human glioma cells, but not to normal cells. Pharmacokinetically, intracranial MGH2.1 did not significantly alter the metabolism of intraperitoneally (i.p.) administered prodrugs in mouse plasma, brain, or liver. MGH2.1 did not induce an acute inflammatory reaction. MGH2.1 DNA was detected in brains of mice inoculated with 10(8) pfus for up to 60 days. However, only one animal showed evidence of viral gene expression at this time. Expression of virally encoded genes was restricted to brain. Intracranial inoculation of MGH2.1 did not induce lethality at 10(8) pfus in the absence of prodrugs and at 10(6) pfus in the presence of prodrugs. This study provides safety and toxicology data justifying a possible clinical trial of intratumoral injection of MGH2.1 with peripheral administration of CPA and/or CPT11 prodrugs in humans with malignant gliomas.Molecular Therapy-Nucleic Acids (2013) 2, e113; doi:10.1038/mtna.2013.38; published online 6 August 2013. PMID- 23922030 TI - Progressive amnestic dementia, hippocampal sclerosis, and mutation in C9ORF72. AB - The most common cause of familial frontotemporal lobar degeneration with TAR DNA binding protein-43 pathology (FTLD-TDP) has been found to be an expansion of a hexanucleotide repeat (GGGGCC) in a noncoding region of the gene C9ORF72. Hippocampal sclerosis (HpScl) is a common finding in FTLD-TDP. Our objective was to screen for the presence of C9ORF72 hexanucleotide repeat expansions in a pathologically confirmed cohort of "pure" hippocampal sclerosis cases (n = 33), outside the setting of FTLD-TDP and Alzheimer's disease (AD). Using a recently described repeat-associated non-ATG (RAN) translation (C9RANT) antibody that was found to be highly specific for c9FTD/ALS, we identified a single "pure" HpScl autopsy case with a repeat expansion in C9ORF72 (c9HpScl). Mutation screening was also performed with repeat-primed polymerase chain reaction and further confirmed with Southern blotting. The c9HpScl patient had a 14-year history of a slowly progressive amnestic syndrome and a clinical diagnosis of probable AD. Neuropsychological testing revealed memory impairment, but no deficits in other cognitive domains. Autopsy showed hippocampal sclerosis with TDP-43 immunoreactive neuronal inclusions relatively limited to limbic lobe structures. Neuritic pathology immunoreactive for p62 was more frequent than TDP-43 in amygdala and hippocampus. Frequent p62-positive neuronal inclusions were present in cerebellar granule neurons as is typical of C9ORF72 mutation carriers. There was no significant FTLD or motor neuron disease. C9RANT was found to be sensitive and specific in this autopsy-confirmed series of HpScl cases. The findings in this patient suggest that the clinical and pathologic spectrum of C9ORF72 repeat expansion is wider than frontotemporal dementia and motor neuron disease, including cases of progressive amnestic dementia with restricted TDP-43 pathology associated with HpScl. PMID- 23922031 TI - Prospective study of Merkel cell polyomavirus and risk of Merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is a rare type of skin cancer that has a characteristically increased incidence among immunosuppressed subjects. The DNA of Merkel cell polyomavirus (MCV) is regularly found in most MCC tumors. We investigated whether Merkel cell polyomavirus (MCV) infection increases the risk for future MCC. Two large biobank cohorts (Southern Sweden Microbiology Biobank and the Janus Biobank), containing samples from 856,000 healthy donors, were linked to the Cancer Registries in Sweden and Norway to identify cases of MCC occurring up to 30 years after donation of a serum sample. For each of the 22 cases (nine males and 13 females), four matched controls were included. The serum samples were analyzed with an MCV neutralization assay and for IgG antibodies to MCV pseudovirions, using JC polyomavirus and cutaneous human papillomaviruses as control antigens. An increased risk for future MCC was associated both with high levels of MCV antibodies [OR 4.4, 95% CI 1.3-17.4] and with MCV neutralizing activity (OR 5.3, 95% CI 1.3-32.3). In males, MCV seropositivity was not associated to MCC risk, whereas the risk was strongly increased in females, both for high levels of MCV antibodies (OR 7.0, 95% CI 1.6-42.8) and for MCV neutralizing activity (OR 14.3, 95% CI 1.7-677). In conclusion, we found prospective evidence that MCV infection is associated with an increased risk for future MCC, in particular among females. PMID- 23922033 TI - 4,4'-Bis(trifluoromethyl)-2,2'-bipyridine--a multipurpose ligand scaffold for lanthanoid-based luminescence/19F NMR probes. AB - The tetradentate ligand 4,4'-bis(trifluoromethyl)-2,2'-bipyridine-6,6' dicarboxylic acid (H(2)1) and three corresponding anionic rare earth complexes [RE(1)2](-) (RE = Y, Tb, Dy) were synthesized. The terbium and dysprosium complexes show lanthanoid-centered luminescence in aqueous solution, as well as paramagnetically enhanced longitudinal magnetic relaxation of the (19)F nuclei. PMID- 23922034 TI - Detection of tautomer proportions of dimedone in solution: a new approach based on theoretical and FT-IR viewpoint. AB - Molecular structures of stable tautomers of dimedone [5,5-dimethyl-cyclohexane 1,3-dione and 3-hydroxy-5,5-dimethylcyclohex-2-enone] were optimized and vibrational frequencies were calculated in five different organic solvents (dimethylsulfoxide, methanol, acetonitrile, dichloromethane and chloroform). Geometry optimizations and harmonic vibrational frequency calculations were performed at DFT 6-31+G(d,p), DFT 6-311++G(2d,2p), MP2 6-311++G (2d,2p) and MP2 aug-cc-pVDZ levels for both stable forms of dimedone. Experimental FT-IR spectra of dimedone have also been recorded in the same solvents. A new approach was developed in order to determine tautomers' ratio using both experimental and theoretical data in Lambert-Beer equation. Obtained results were compared with experimental results published in literature. It has been concluded that while DFT 6-31+G(d,p) method provides accurate enol ratio in DMSO, MeOH, and DCM, in order to obtain accurate results for the other solvents the MP2 aug-cc-pVDZ level calculations should be used for CH3CN and CHCl3 solutions. PMID- 23922035 TI - Kinky circumflex grafts: the left appendage flip maneuver. AB - The "too-long," or redundant, circumflex graft is notorious for its tendency to form a kink. The acute angle (the kink) typically occurs over the front of the pulmonary trunk. Described herein are (1) the left appendage flip maneuver, a simple solution to correct graft kink, and (2) analysis and explanation of vein graft kink. PMID- 23922036 TI - 4,5-dianilinophtalimide protects neuroendocrine cells against serum deprivation induced stress and apoptosis. AB - OBJECTIVE: The aim of this study was to reveal the effects of 4,5 dianilinophthalimide (DAPH), which inhibits amyloid beta fibrillization, against serum deprivation (SD)-induced apoptosis and the possible mechanisms in differentiated PC12 neuron cells. METHODS: Firstly, we evaluated whether DAPH protects cell viability exposed to SD by MTT assay. Next, we examined the changes of phospho-p38 MAPK (Thr180/Tyr182), phospho-HSP27 (Ser82), phospho-c-JUN (Ser73) and cleaved-CASP3 (Asp175) profiles by immunoblotting, in PC12 cells exposed to SD. Intracellular reactive oxygen species (ROS) level was also measured. RESULTS: SD induced apoptosis accompanied by up-regulation of phospho-p38 MAPK (Thr180/Tyr182), phospho-HSP27 (Ser82), phospho-c-JUN (Ser73), cleaved-CASP3 (Asp175) and intracellular ROS content. Co-treatment with non-toxic doses of DAPH prevented apoptosis by the attenuation of activated proteins and reduction of ROS level. These results suggest that serum deprivation-induced apoptosis inhibited by DAPH administration. CONCLUSION: We have provided for the first evidence that DAPH has a neuroprotective effect on SD-caused stress, probably via contributing the re-establishment of redox homeostasis. PMID- 23922037 TI - Brain aging and testosterone-induced neuroprotection: studies on cultured sheep cortical neurons. AB - OBJECTIVE: This research reports the expression of topoisomerase betaII in fetal sheep neuronal cells. The beta isoform of DNA topoisomerase II plays a role in DNA repair process in non proliferating cells as neurons and its expression tends to be downregulated with senescence. METHODS: Cortical neurons from 60-day-old sheep embryos underwent two protocols: the former based on rising time of culture (10, 20 and 30 days); the latter based on the 72hrs exposure to 3-nitro-L tyrosine (oxidative/nitrosative stressor) and/or testosterone. RESULTS: Our results showed an increase in beta-galactosidase activity and, in contrast, a reduction in topoisomerase betaII expression with time (first protocol). The exposure of sheep primary neurons to 3-nitro-L-tyrosine led to an upregulation of betaII topoisomerase expression to be likely seen as a reaction to nitrosative stress. Testosterone addition to 3-nitro-L-tyrosine-exposed cells results in topoisomerase betaII decrease possibly due to the neuroprotective properties of testosterone (second protocol). No significant variations in the marker of aging beta-galactosidase were observed in the cells exposed to 3-nitro-L-tyrosine and testosterone. CONCLUSION: The protocol based on time could be of some interest as a model of neuronal senescence in vitro. Topoisomerase betaII decrease with aging likely indicates a reduced ability to repair DNA during neuronal senescence. In contrast, the second protocol may not be seen as a reliable model of aging since 3-nitro-L-tyrosine does not lead to a topoisomerase betaII decrease. Testosterone was able to cope with oxidative/nitrosative damage, allowing cells to reduce their needs in DNA repair which in turn leads to a downregulation of topoisomerase IIbeta expression. PMID- 23922038 TI - Chronic exposure to benzyl butyl phthalate (BBP) alters social interaction and fear conditioning in male adult rats: alterations in amygdalar MeCP2, ERK1/2 and ERalpha. AB - OBJECTIVES: Benzyl Butyl Phthalate (BBP) is an industrial plasticizer that has an unknown action in the central nervous system. Phthalates have recently been associated with behavioral actions that are linked to their endocrine disrupting properties. The purpose of this study was to investigate the behavioral and molecular effects of BBP treatment in male rats. DESIGN: Male rats were chronically exposed to BBP in the drinking water (5.0 ppm and 10.0 ppm) throughout adolescence and into the adult phase of life. Their behavior was then assessed in a learning and memory task (fear conditioning), open field exploration and a test of sociability. RESULTS: BBP treated rats showed decreased freezing in fear conditioning, no changes in open field exploration, and increased aberrant social behavior. Rats were sacrificed at post natal day 140 and blood and brains were harvested and processed. We found increased hormonally active estrogen, 17-beta estradiol, in the serum of BBP treated rats. BBP treatment also induced changes in amygdalar proteins related to synaptic plasticity including decreased MeCP2 levels that correlated with tests of sociability with no changes in stress related proteins such as nuclear factor kappa B (NFkB). We also found alterations in physiological responses as measured by body weight without changes in food consumption suggesting disruption of metabolism and body homeostasis. CONCLUSIONS: We suggest that BBP administration disrupts normal learning and social behavior, and that these effects could be related to alterations of amygdala function. PMID- 23922039 TI - Contralateral delayed hematoma secondary to anticoagulant treatment-related intracerebral hemorrhage. AB - The incidence of anticoagulant treatment (AT)-related intracerebral hemorrhage (AT-ICH) is increasing in consequence of the increased incidence of ischemic stroke due to an aging population. AT-ICH is associated with a risk of ongoing bleeding, death, or disability. Cerebral amyloid angiopathy (CAA), a common pathological finding among the elderly that is associated with macro- and microscopic hematoma development, might increase the risk of ICH. We report a rare case of contralateral delayed hematoma in the context of CAA secondary to acute ICH after AT for intracerebral ischemic stroke. PMID- 23922040 TI - Development of the internet based psychoeducation for patients with bipolar affective disorder. AB - OBJECTIVE: Despite pharmacological treatment of bipolar affective disorder has many advantages; only drug treatment remains insufficiently beneficial to many patients. The combination of pharmacotherapy and internet psychoeducation seems to be the effective way how to improve remission. Internet-based therapy programs offer an exclusive chance for large underserved parts of the population to make evidence-based treatment without the need of full-time therapist. Our goal was to create a psychoeducational program for patients suffering from bipolar disorder that can be used in Czech Republic. METHODS: There were identified studies through Web of Science, PUBMED, and Scopus databases as well as existing reviews were used in development of comprehensive internet psychoeducational program for patients with bipolar disorder. The search terms included "bipolar disorder", "psychoeducation", and "internet psychoeducation". The search was performed with no language or time restrictions. RESULTS: The internet psychoeducational program was developed in accordance to the data from the literature review. The aim of the Internet psychoeducational program of the Department of Psychiatry University Hospital in Olomouc is to familiarize patients with the fundamental nature of bipolar affective disorder, the character and principles of pharmacotherapy, the recognition of the warning signs of relapse, inappropriate and stressful stereotypes in communication within families, and finally the practice of social skills. CONCLUSION: Information from studies can help to prepare comprehensive psychoeducational program for bipolar patients. PMID- 23922041 TI - Effects of melatonin hormone on hippocampus in pinealectomized rats: an immunohistochemical and biochemical study. AB - OBJECTIVE: The effects of melatonin on antioxidant status were examined in pinealectomized rats using enzymatic, histological and immunohistochemical techniques. The aim of this study is to investigate the effects of melatonin on hippocampal apoptosis. MATERIALS AND METHODS: Male Wistar rats (n=21) were divided into 3 groups: Group I and group II were designated as control (sham pinealectomy) and pinealectomized rats, respectively. Rats in group III were pinealectomized and injected daily with melatonin (1 mg/kg) for 3 months beginning at day 7 after surgery. At the end of experimental period, all rats were killed by decapitation. The brains of the rats were removed and the hippocampus tissue was obtained from all brain specimens. The right hippocampal specimens of all rats were used for determination of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) levels. The left hippocampus tissue specimens of all animals were used for immunohistochemical and histological evaluation. RESULTS: The levels of SOD and GSH-Px were significantly decreased, and MDA levels were significantly increased in pinealectomized rats compared to the controls. In the histological and immunohistochemical evaluation of this group, increase of pyknotic cells, vacuolar degeneration and apoptosis were observed. However, increased SOD and GSH-Px enzyme activities, and decreased MDA levels were detected in the rats administered melatonin after pinealectomy. Furthermore, histological and apoptotic changes in hippocampus caused by pinealectomy were lost in the rats treated with melatonin. CONCLUSIONS: The results of our study revealed that pinealectomy-induced oxidative damage and morphological changes in the hippocampal tissue were suppressed by melatonin. PMID- 23922042 TI - Granular cell tumor of the neurohypophysis: case report and review of the literature. AB - A 54-year-old woman presented with a stalk mass that was discovered incidentally with mild visual fields defect. The mass was operated surgically by the fronto temporal approach, and histology met the diagnosis of neurohypophesial granular cell tumor (GCT). After surgery, the patient suffered from an irreversible severe bi-temporal visual deficit and an irreversible hypopituitarism. We review the literature and discuss the clinical nature of GCTs, treatment options and outcome. In an effort to avoid the severe complications that may result from surgical removal of neurohypophesial GCT, we discuss also the possibility of choosing the conservative approach with close follow-up. The tumor's firm consistency, tendency to hemorrhage, involving the pituitary stalk and lack of dissection plane from basal brain structure render surgery difficult, and maximal resection often requires sacrificing the stalk. Moreover, small asymptomatic neurohypophysial GCTs are common findings, most probably benign tumors with slow growing nature. Hence, for a neurohypophesial tumor which is suspected to be a GCT, we offer to consider the alternative approach, with close clinical, visual field and radiological study follow up. PMID- 23922044 TI - Nitrosative-induced posttranslational alpha-tubulin changes on high-glucose exposed Schwannoma cell line. AB - OBJECTIVE: One of the major complications during prolonged hyperglycemic condition is the onset of the so-called diabetic neuropathy, that can affect the peripheral nervous system. Evidence has reported that glucose-induced oxidative stress could be a key mediator in this process, impairing the cytoskeletal structures, such as microtubules. In general, much attention is paid to the possible nitrosative-induced changes of neurons during hyperglycemic conditions, while little is known of the Schwann cells. METHODS: Using morphological examination, immunofluorescence staining and western blot analysis, the possible hyperglycemic oxidative-induced microtubular changes in the RT4 Schwannoma cell line was investigated. RESULTS: After 72 hrs of 180 mM d-glucose exposure, a decrease of total, tyrosinated and detyrosinated alpha-tubulins was found, whereas a significant increase of the acetylated alpha-tubulin isotype and 3 nitro-l-tyrosine was present, both through western blot and immunofluorescence staining. Moreover a downregulation of catalase and deacetylase Sirt2 enzymes was detected. CONCLUSION: Our data underline the importance of nitrosative-induced microtubular alterations in the PNS, during hyperglycemic conditions, highlighting that Schwann cells may be directly involved in the pathogenesis of diabetic neuropathy, through the impairment of their microtubular network. PMID- 23922043 TI - Lack of association between CD226 genetic variants and inflammatory demyelinating diseases in Korean population. AB - OBJECTIVE: This study was conducted to find the possible association between CD226 polymorphisms and inflammatory demyelinating diseases in Korean population. METHODS: A total of 14 CD226 SNPs were selected based on their linkage disequilibrium, minor allele frequency, and location. Then, the SNPs were genotyped in 178 IDD patients and 237 healthy controls. Subsequently, we conducted logistic analysis to find possible associations RESULTS: Statistical analyses revealed only a marginal signal for a common SNP rs1788229 with inflammatory demyelinating disease (p=0.05), while other SNPs failed to show associations with any diseases. However, the significance of rs1788229 disappeared after a multiple testing correction of the data (p>0.05). Interestingly, rs763361, which showed significant associations with multiple sclerosis in several previous studies, did not show any association at all. CONCLUSIONS: While prior studies have found CD226 polymorphisms to be significantly associated with inflammatory demyelinating diseases, our results indicate the CD226 polymorphisms to be not associated with the diseases in Korean population. However, our results suggest that the causal genes for inflammatory demyelinating diseases may vary depending on the population. PMID- 23922045 TI - Prevalence and impact of restless legs syndrome in pregnancy. AB - BACKGROUND: Restless legs syndrome (RLS) is a frequent neurological disorder which predominantly affects women. Pregnancy is one of the most common conditions leading to secondary RLS. Severe symptoms of RLS may lead to complications of pregnancy and/or labor. The aim of this study was to determine the prevalence and characteristics of RLS in pregnant women. METHODS: Women in the third trimester of gravidity filled out a simple questionnaire based on the official diagnostic criteria for RLS. Positive responders were interviewed in order to further characterize their symptoms. Afterwards information on changes in frequency and/or intensity of the symptoms after delivery was obtained by a telephone follow-up. All data were statistically analysed. RESULTS: A total of 300 questionnaires were completed. All 94 RLS-positives met the four diagnostic criteria (31.33%). There was no difference in age, body mass index, or the number of previous pregnancies between RLS-positives and RLS-negatives, but weight gain during pregnancy was significantly higher in RLS-positives. More than 30% of positives had clinically significant symptoms, and 50% reported sleep disturbances. Almost 75% of the cases of RLS were secondary, i.e., symptoms occurred only during pregnancy (with a peak in the third trimester). More complications of pregnancy or labor occurred in women with RLS, but this was only marginally significant. CONCLUSIONS: Our study confirmed the relatively high prevalence of RLS in pregnant women compared with the general population. Although almost three-fourths of the symptoms were only transient throughout pregnancy, the impact of the severe symptoms and sleep deprivation on the course of pregnancy and delivery was not negligible. Early detection and adequate treatment of severe RLS are necessary to prevent maternal discomfort and possible health risks. The questionnaire method is a simple, reliable diagnostic tool. PMID- 23922046 TI - Serum and urinary leptin and ghrelin in children with nephrotic syndrome. AB - OBJECTIVE: The aim of the present study was to evaluate the serum and urinary levels of leptin and ghrelin in children with primary idiopathic nephrotic syndrome (NS), to compare these results between patients during the relapse and remission phase and to evaluate the possible role of leptin and ghrelin in the pathogenesis of NS. PATIENTS AND METHODS: Forty-nine children with primary idiopathic NS (25 children with relapse and 24 children in remission), who were followed up at the Pediatric Nephrology Unit, enrolled. Twenty-eight age- and sex matched healthy children served as controls. Serum and urinary leptin levels were determined by immunoenzymatic ELISA, and serum and urinary ghrelin levels were determined by the RIA method. RESULTS: The serum leptin levels were significantly lower in the children with NS during the relapse phase than in the children with NS during remission or in the controls (1.42+/-0.34 ng/dl and 3.60+/-0.70 ng/ml; p<0.01, 1.42+/-0.34 ng/ml and 5.27+/-4.67 ng/ml; p<0.001, respectively). The urinary leptin excretion levels were significantly higher in the relapse group than in the controls (0.40+/-0.11 ng/ml and 0.12+/-0.06 ng/ml, p<0.01, respectively). The serum ghrelin levels were similar between the study groups (p>0.05). The urinary ghrelin excretion levels were significantly higher in the relapse group than in the remission group and the controls (965.0 pg/ml [93-3711] and 679.7 pg/ml [93-3783], p<0.05; 965.0 pg/ml [93-3711] and 387.7 pg/ml [114 1214], p<0.001, respectively). The urinary ghrelin levels were also significantly higher in the remission group than in the controls (679.7 pg/ml [93-3783] and 387.7 pg/ml [114-1214]), p<0.01, respectively). The serum leptin levels were positively correlated with the serum albumin levels (r=0.440, p<0.05) and were negatively correlated with the serum triglyceride levels during the relapse phase. The urinary leptin and ghrelin levels were positively correlated with proteinuria in the relapse group. CONCLUSIONS: We propose that leptin plays a role in the pathophysiology of NS and is associated with proteinuria, hypoproteinemia and hyperlipidemia. The significant urinary excretion of ghrelin in children with NS is possibly due to underlying pathophysiological changes, and normal serum ghrelin levels might be associated with an unknown compensatory mechanism. PMID- 23922047 TI - Spontaneous remission of acromegaly after infarctive apoplexy with a possible relation to MRI and diabetes mellitus. AB - OBJECTIVES: Pituitary apoplexy is a rare clinical syndrome associated with rapid enlargement of a pituitary mass. We report the initial presentation, subsequent course and outcome of an acromegalic patient who developed spontaneous remission following pituitary apoplexy with pathologic findings of tumor infarction. CLINICAL PRESENTATION: A 38 year-old man with typical acromegalic features was referred to our hospital. He had been diabetic and hypertensive. His basal GH and IGF-1 levels were high (80 ug/L and 747 ng/mL respectively). Sella MRI showed a macroadenoma about 19*20 mm in size. He admitted to emergency department with complains of severe frontal headache accompanied by nausea and vomiting two days after MRI was taken. His neurological examination and visual field test were normal. Emergent MRI of the sella disclosed an enhancing intrasellar mass of 24*23 mm compressing the optic chiasm. The patient underwent transsphenoidal decompression of the lesion. Histological examination revealed an adenomatous tissue showing nonhemorrhagic coagulation necrosis. Before surgery, his GH levels declined to 2.72 ug/L spontaneously and after surgery he was in remission even leading to a state of growth hormone deficiency. CONCLUSION: When apoplexy occurs in functioning adenomas, it may cause spontaneous remission. However pituitary apoplexy due to tumor infarction is very rare. Various precipitating factors have been reported in 25-30% of pituitary apoplexy patients. Diabetes mellitus and diabetic ketoacidosis are one of these. The presence of contrast media induced endothelial swelling with the result of hypoperfusion and diabetes mellitus associated vasculopathy might be a precipitating factor in this patient. PMID- 23922048 TI - The response of the autonomic nervous system to the cholinesterase inhibitor, donepezil. AB - OBJECTIVE: Donepezil, a cholinesterase inhibitor (ChEI) that is widely used to treat Alzheimer's disease, is thought to act by increasing extracellular acethylcholine (ACh) in the central nervous system. The effects of the administration of ChEIs on the autonomic nervous system, however, are complex and controversial. METHODS: In this study we observed the effects of donepezil at a dose of 3 mg/kg intraperitoneally (i.p.) on the autonomic nervous system for two weeks using heart rate variability (HRV). In HRV, the high frequency (HF) band is influenced by cardiac parasympathetic tone, and the low frequency (LF) band is influenced by both sympathetic and parasympathetic activity. The ratio of LF and HF (LF/HF) is used for the assessment of the sympathetic nervous system. RESULTS: In the current study the LF/HF was found to be significantly increased by day 1, but the magnitude of the response gradually decreased. The absolute power of HF increased after an i.p of donepezil of 3 mg daily in groups treated for 1 week and for 2 weeks compared to the single-dose groups. CONCLUSION: Our results suggested that ChEI administration induced sympathetic nervous activation acutely, but chronic administration induced parasympathetic activation. PMID- 23922049 TI - The thyrotropin-releasing hormone test may predict recurrence of clinical depression within ten years after discharge. AB - OBJECTIVES: The underlying pathogenic mechanisms and predictors of recurrence in major depressive disorder are still largely unknown. Hypothalamic-pituitary thyroid (HPT) axis and hypothalamus-pituitary-adrenocortical (HPA) axis dysregulation are thought to be related to the development and course of depression. DESIGN AND SETTING: Over a ten-year period, we investigated whether the results of thyrotropin-releasing hormone (TRH) testing and combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) testing could be correlated with the recurrence of depression in 25 outpatients with clinically remitted major depression for at least 10 years. MATERIALS AND METHODS: Twenty five patients (16 women and 9 men, 48.1 years of age, SD=11.4, range 22-84) with major depressive disorder were available for evaluation during hospitalization. TRH and DEX/CRH tests were administered at admission. RESULTS: Patients who recurred within ten years after remission exhibited significantly higher thyroid stimulating hormone (TSH) responses to TRH at the time of admission compared to those who did not recur. There was no significant correlation between recurrence and DEX/CRH levels after controlling for age, sex, and body mass index. CONCLUSION: The findings of this study suggest that the TRH test may predict future recurrence in patients with depression. PMID- 23922050 TI - Working memory impairment as a common component in recurrent depressive disorder and certain somatic diseases. AB - OBJECTIVES: Deterioration of the working memory is regarded as one of the most important deficits in a number of somatic diseases. The purpose of the present study was to compare the effectiveness of working memory in 4 groups of patients: 1) diagnosed with recurrent depressive disorder (rDD), 2) with diabetes type 1 (DM1), 3) with diabetes type 2 (DM2), 4) with arterial hypertension (HA) and in healthy controls (HC). METHODS: The study comprised 300 subjects: rDD (n=99), DM1 (n=31), DM2 (n=31), HA (n=30) and HC (n=109).Cognitive function assessment was based on Trail Making Test (TMT) and the Stroop test. RESULTS: Analysis of variance (ANOVA) indicated statistically significant differences of the mean values among particular groups for each of the analysed results of the Stroop Test and TMT (p<0.0001). Patients with DM1 performed better in both TMT and Stroop tests, when compared to those diagnosed with HA. Patients with HA obtained better results than patients with DM2. Patients with rDD performed significantly worse than those with DM1 in both parts of TMT (A/time: p=0.022, B/time: p<0.001) and in the Stroop test (RCNb/time: p<0.001; NCWd/time: p=0.001; NCWd/errors: p=0.443). They also obtained worse results than patients with DM2 and HA, however, the differences were not statistically significant. CONCLUSIONS: 1) Our study has confirmed previous results showing association between depressive disorder and cognitive impairment. 2) Patients with rDD had worse performance on working memory tasks than the patients with DM type 1, DM type 2 and HA. 3) Further investigation is needed to clarify the role of inflammatory and oxidative and nitrosative stress (O&NS) processes in neurocognitive dysfunctions occurring in recurrent depression and somatic disease. PMID- 23922052 TI - From ynamides to highly substituted benzo[b]furans: gold(I)-catalyzed 5-endo-dig cyclization/rearrangement of alkylic oxonium intermediates. AB - A series of arylynamides with alkyloxy groups at the ortho position of the aryl group was prepared through a short alkylation/cross-coupling/amidation sequence. The gold-catalyzed conversion of these substrates combined both C-O and C-C formation steps, thus providing benzofurans with amine functionalities at the 2 position and alkyl groups at the 3-position. Cross-over experiments showed that the alkyl-migration step was an intermolecular process. X-ray crystal-structure analysis of two of the products supported our structural assignment. In some cases, the corresponding benzofurans without the alkyl group at the 3-position were obtained as side-products, which were formed through a competing protodeauration process. PMID- 23922051 TI - Giant pseudocyst of the anterior abdominal wall after incisional hernia mesh repair: a rare case report. PMID- 23922053 TI - Meta-analysis of the association between cigarette smoking and peripheral arterial disease. AB - CONTEXT: Smoking is an important risk factor for peripheral arterial disease (PAD). OBJECTIVE: To undertake a meta-analysis of the association between cigarette smoking and PAD. DATA SOURCES: Medline, Embase, PubMed and Web of Science databases. STUDY SELECTION: Relevant studies published up to 30 April 2012 were identified. DATA EXTRACTION: Performed by two researchers. Overall and stratified random effects meta-analyses, cumulative meta-analyses and metaregression analyses were conducted. Heterogeneity was tested using the I(2) test, and publication and small study bias using funnel plots and Egger's test. RESULTS: Fifty-five eligible studies were identified: 43 cross-sectional, 10 cohort and 2 case-control. Of the 68 results for current smokers, 59 (86.8%) were statistically significant and the pooled OR was 2.71 (95% CI 2.28 to 3.21). There was a high level of heterogeneity (I(2) 94.9%, p<0.001) and Egger's test was significant (p=0.023). The association with smoking was significant among both general (OR 3.08, 95% CI 2.56 to 3.69) and disease populations (OR 1.54, 95% CI 1.31 to 1.83). Of the 40 results for ex-smokers, 29 (72.5%) were statistically significant and the pooled OR was 1.67 (95% CI 1.54 to 1.81). There was moderate heterogeneity (I(2) 54.7%, p<0.001) and Egger's test was significant (p<0.001). CONCLUSIONS: There is now substantial evidence of an association between active smoking and PAD. The magnitude of the association is greater than that reported for coronary heart disease. The risk is lower among ex-smokers but, nonetheless, significantly increased compared with never smokers. The results highlight the need for interventions both to encourage quitting among existing smokers and discourage commencement among never smokers. PMID- 23922054 TI - Population pharmacokinetic analysis from phase I and phase II studies of the humanized monovalent antibody, onartuzumab (MetMAb), in patients with advanced solid tumors. AB - Onartuzumab is a unique, humanized, monovalent (one-armed) monoclonal antibody (mAb) against the MET receptor. The intravenous (IV) pharmacokinetics (PK) of onartuzumab were investigated in a phase I study and a phase II study in recurrent non-small cell lung cancer (NSCLC) patients. The potential for drug drug interaction (DDI) was assessed during co-administration of IV onartuzumab with oral erlotinib, by measuring the PK of both drugs. The concentration-time profiles of onartuzumab were adequately described using a two-compartment model with linear clearance (CL) at doses between 4 and 30 mg/kg. The estimates for CL, central compartment volume (V1 ), and median terminal half-life were 0.439 L/day, 2.77 L, and 13.4 days, respectively. Statistically significant covariates included creatinine clearance (CrCL) on clearance, weight and gender on V1 , and weight on peripheral compartment volume (V2 ), but the clinical relevance of these covariates needs to be further evaluated. The current analysis did not indicate obvious DDI between onartuzumab and erlotinib. MET diagnostic status did not impact the exposure of either agent. Despite the slightly faster clearance compared with typical bivalent mAbs, the PK of onartuzumab support dosing regimens of 15 mg/kg every 3 weeks or doses equivalent to achieve the target minimum tumoristatic concentration in patients. PMID- 23922055 TI - Multiclass method for antimicrobial analysis in animal feeds by liquid chromatography-tandem mass spectrometry. AB - A rapid multiclass method that covers 50 antimicrobials from 13 different families in animal feeds was developed. Samples were extracted using a mixture of methanol, acetonitrile and a McIlvaine buffer combined with sonication. Feed extracts were simply diluted prior to injection, since the clean-up strategies that were tested, based on either solid-phase extraction or dispersive solid phase extraction, were ineffective at minimizing matrix-related signal suppression/enhancement. Analysis was carried out by liquid chromatography coupled to tandem mass spectrometry using an electrospray ionization source operating in positive and negative modes. For the quantification, matrix fortified standard calibration curves were used to compensate for matrix effects and losses in sample preparation. The method was validated in-house in pig, poultry and cattle feed matrices and showed satisfactory performance characteristics. Thus, the proposed approach was suitable for application in a routine high-throughput laboratory for the official control of feeds. PMID- 23922056 TI - A feasibility study into the production of a freeze-dried oyster reference material for paralytic shellfish poisoning toxins. AB - Matrix reference materials are an essential component for the validation and quality control of analytical methodologies for the quantitation of marine biotoxins in shellfish. Given the potential advantages of reference materials in powder form, a study was conducted to assess the feasibility for the production of a freeze-dried oyster tissue reference material containing a range of important paralytic shellfish poisoning toxins. One bulk sample of a wet oyster tissue homogenate was generated following mass culturing of toxic Alexandrium and oyster feeding experiments. The bulk tissue was used to prepare untreated wet frozen aliquots with the remainder being freeze-dried and processed into appropriately-sized powder samples. A pre-column oxidation LC-FLD analysis was used to confirm the absence of any chromatographic artefacts resulting from the processing and to confirm acceptable homogeneity of the tissues. Excellent stability over both the short-term (1 month) and long-term (1 year) of the freeze dried material was demonstrated as compared with the stability of the untreated wet tissue. A post-column oxidation LC-FLD method was used to confirm the absence of toxin epimerisation in freeze-dried tissues which were observed in the wet tissues. Overall the work showed the feasibility of an approach to produce a homogenous freeze-dried oyster matrix material with enhanced stability in comparison to the untreated wet tissue. The potential for use of the process for preparation of large scale production batches of a freeze-dried CRM for paralytic shellfish poisoning toxins has therefore been demonstrated. PMID- 23922057 TI - Patterns of accidental craniocerebral injury occurring in early childhood. AB - OBJECTIVE: To describe the range of intracranial injuries encountered in 0-2-year olds in cases of accidental head injury where the mechanism of trauma was well characterised and to assess the clinical consequences. DESIGN: A retrospective review of imaging and clinical data. SETTING: Two tertiary paediatric referral centres. PATIENTS: All children aged 0-2 undergoing cranial CT as indicated by National Institute for Health and Clinical Excellence guidance for head injury from 2006 to 2011. After exclusion criteria, 149 patients were included. MAIN OUTCOME MEASURES: Rates of skull fracture, intracranial haemorrhage, parenchymal injuries and ischaemic change per type of mechanism of injury. Rates of neurological sequelae on follow-up. RESULTS: Skull fractures were demonstrated in 54 (36%) patients of whom 17 (11%) had thin underlying subdural haemorrhage (SDH). Extradural haemorrhage complicated one fracture and two cases of isolated subdural haematomas were seen without skull fracture. Radiologically evident brain parenchymal injuries were present in three patients, all with mechanisms of injury involving high levels of force; severe neurological sequelae were only seen in one patient, who had diffuse hypoxic-ischaemic damage at presentation and whose (accidental) mechanism of injury involved extensive acceleration/deceleration/translational forces. CONCLUSIONS: Skull fractures and focal SDH are relatively common following minor trauma in this age group but in the vast majority of cases there are no long-term neurological sequelae. Conversely, diffuse brain injury with severe subsequent neurological impairment was only seen in patients with a correspondingly severe mechanism of injury. PMID- 23922058 TI - Physical illness in looked-after children: a cross-sectional study. AB - OBJECTIVE: To compare the reported point prevalence of chronic physical illness among children looked after by local authorities with those living in their own homes. DESIGN: Cross-sectional study, using questionnaire data from a national survey. SETTING: The UK. PARTICIPANTS: Random samples of children aged 5-15 years. Children looked after were selected from Department of Health databases, stratified according to placement type. The child benefit register was the sampling frame for children in their own homes, weighted to match the child population demographic and compensate for response variability. MAIN OUTCOME: Carer-reported prevalence of 10 physical illnesses. RESULTS: Data were collected on 1253 looked-after children and 10 438 children in their own homes. There were lower rates of asthma, eczema and hay fever reported among looked-after children compared with children at home (ORs, adjusted for age, gender and ethnicity, were 0.63, 0.61 and 0.36, respectively). Epilepsy, cystic fibrosis and cerebral palsy were more commonly reported in looked-after children (adjusted ORs 4.13, 4.2 and 7.26, respectively). There was no difference in the proportions of children in the two groups reporting glue ear, diabetes mellitus, spina bifida or cancer. CONCLUSIONS: Looked-after children have an increased prevalence of some physical illnesses. The results also suggest that there may be significant unmet need, with health professionals and carers failing to identify other illnesses. The lower reported prevalence of atopic conditions may reflect a truly lower occurrence of such diseases in looked-after children; this requires further work to explore. PMID- 23922059 TI - Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL). AB - BACKGROUND: Although rituximab-based chemoimmunotherapy (CIT) has substantially improved clinical outcomes in chronic lymphocytic leukemia (CLL), only 40% to 50% of patients achieve a complete remission (CR). There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a fully human anti-CD20 monoclonal antibody with greater apparent single-agent activity than rituximab in CLL patients. METHODS: Previously untreated CLL patients in need of therapy received 6 cycles of CIT induction with pentostatin, cyclophosphamide, and ofatumumab (PCO) followed by response assessment. RESULTS: Of the 48 patients enrolled, 77% completed PCO induction. Adverse events during induction included grade 3+ hematologic toxicity (27%) and grade 3+ nonhematologic toxicity (23%). Median CD4 count after induction and 6 months later were 186 * 10(6)/L and 272 * 10(6) /L. The overall response rate was 96% (46 of 48 patients), and the CR rate was 46% (22 of 48 patients). Among the 38 patients who underwent minimal residual disease evaluation, 7 (18%) were negative for minimal residual disease. After median follow-up of 24 months, 10 (21%) patients have progressed and 8 (17%) have required retreatment. The efficacy and toxicity of ofatumumab-based CIT compare favorably to our historical trials of rituximab-based CIT using an identical chemotherapy backbone (n = 64). Time to retreatment also appeared longer for ofatumumab-based CIT (free of retreatment at 24 months: 86% [95% confidence interval = 75-99] versus 68% [95% confidence interval = 56-81] for rituximab-based CIT). CONCLUSIONS: Ofatumumab-based CIT is well tolerated in patients with previously untreated CLL. The efficacy of ofatumumab-based CIT compares favorably to historical trials of rituximab-based CIT, suggesting randomized trials comparing ofatumumab-based CIT and rituximab based CIT should be considered. PMID- 23922060 TI - Transplantation of xenogeneic islets: are we there yet? AB - Beta cell replacement therapy has been proposed as a novel therapy for the treatment of type 1 diabetes. The proof of concept has been demonstrated with successful islet allotransplantation. Islet xenotransplantation has been proposed as an alternative, more reliable, and infinite source of beta cells. The advantages of islet xenotransplantation are the ability to transplant a well differentiated cell that is responsive to glucose and the potential for genetic modification which focuses the treatment on the donor rather than the recipient. The major hurdle remains overcoming the severe cellular rejection that affects xenografts. This review will focus on the major advances that have occurred with genetic modification and the successful therapeutic strategies that have been demonstrated in nonhuman primates. Novel approaches to overcome cell-mediated rejection including biological agents that target selectively costimulation molecules, the development of local immunosuppression through genetic manipulation, and encapsulation will be discussed. Overall, there has been considerable progress in all these areas, which eventually should lead to clinical trials. PMID- 23922061 TI - Personalized estimates of benefit from preventive care guidelines: a proof of concept. AB - BACKGROUND: The U.S. Preventive Services Task Force (USPSTF) makes recommendations for 60 distinct clinical services, but clinicians rarely have time to fully evaluate and implement the recommendations. OBJECTIVE: To complete a proof of concept for prioritization and personalization of USPSTF recommendations, using patient-specific clinical characteristics. DESIGN: Mathematical model. DATA SOURCES: USPSTF recommendations and supporting evidence and National Vital Statistics Reports. TARGET POPULATION: Nonpregnant adults. TIME HORIZON: Lifetime. PERSPECTIVE: Individual. INTERVENTION: USPSTF grade A and B recommendations. OUTCOME MEASURES: Personalized gain in life expectancy associated each recommendation. RESULTS OF BASE-CASE ANALYSIS: Increases in life expectancy varied more than 100-fold across USPSTF recommendations, and the rank order of benefits varied considerably among patients. For an obese man aged 62 years who smoked and had hypercholesterolemia, hypertension, and a family history of colorectal cancer, the model's top 3 recommendations (from most to least gain in life expectancy) were tobacco cessation (adding 2.8 life-years), weight loss (adding 1.6 life-years), and blood pressure control (adding 0.8 life-year). Lower ranked recommendations were a healthier diet, aspirin use, cholesterol reduction, colonoscopy, screening for abdominal aortic aneurysm, and HIV testing (each adding 0.1 to 0.3 life-years). For a person with the same characteristics plus uncontrolled type 2 diabetes mellitus, the model's top 3 recommendations were diabetes control, tobacco cessation, and weight loss (each adding 1.4 to 1.8 life years). RESULTS OF SENSITIVITY ANALYSIS: Robust to variation of model inputs and satisfied face validity criteria. LIMITATION: Expected adherence rates and quality of life were not considered. CONCLUSION: Models of personalized preventive care may illustrate how magnitude and rank order of benefit associated with preventive guidelines vary across recommendations and patients. These predictions may help clinicians to prioritize USPSTF recommendations at the patient level. PMID- 23922062 TI - Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. AB - BACKGROUND: Celiac disease (CD) is associated with an increased risk for lymphoproliferative malignancy (LPM). Whether this risk is affected by the results of follow-up intestinal biopsy, performed to document mucosal healing, is unknown. OBJECTIVE: To examine the association between mucosal healing in CD and subsequent LPM. DESIGN: Population-based cohort study. SETTING: 28 pathology departments in Sweden. PATIENTS: 7625 patients with CD who had follow-up biopsy after initial diagnosis. MEASUREMENTS: The risk for LPM was compared with that of the general population by using expected rates. The rate of LPM in patients with persistent villous atrophy was compared with that of those with mucosal healing by using Cox regression. RESULTS: Among 7625 patients with CD and follow-up biopsy, 3308 (43%) had persistent villous atrophy. The overall risk for LPM was higher than that in the general population (standardized incidence ratio [SIR], 2.81 [95% CI, 2.10 to 3.67]) and was greater among patients with persistent villous atrophy (SIR, 3.78 [CI, 2.71 to 5.12]) than among those with mucosal healing (SIR, 1.50 [CI, 0.77 to 2.62]). Persistent villous atrophy compared with mucosal healing was associated with an increased risk for LPM (hazard ratio [HR], 2.26 [CI, 1.18 to 4.34]). The risk for T-cell lymphoma was increased (HR, 3.51 [CI, 0.75 to 16.34]) but not for B-cell lymphoma (HR, 0.97 [CI, 0.21 to 4.49]). LIMITATION: No data on dietary adherence. CONCLUSION: Increased risk for LPM in CD is associated with the follow-up biopsy results, with a higher risk among patients with persistent villous atrophy. Follow-up biopsy may effectively stratify patients with CD by risk for subsequent LPM. PMID- 23922063 TI - Improving chronic disease care by adding laypersons to the primary care team: a parallel randomized trial. AB - BACKGROUND: Improving the quality and efficiency of chronic disease care is an important goal. OBJECTIVE: To test whether patients with chronic disease working with lay "care guides" would achieve more evidence-based goals than those receiving usual care. DESIGN: Parallel-group randomized trial, stratified by clinic and conducted from July 2010 to April 2012. Patients were assigned in a 2:1 ratio to a care guide or usual care. Patients, providers, and persons assessing outcomes were not blinded to treatment assignment. (ClinicalTrials.gov: NCT01156974). SETTING: 6 primary care clinics in Minnesota. PATIENTS: Adults with hypertension, diabetes, or heart failure. INTERVENTION: 2135 patients were given disease-specific information about standard care goals and asked to work toward goals for 1 year, with or without the help of a care guide. Care guides were 12 laypersons who received brief training about these diseases and behavior change. MEASUREMENTS: The primary end point for each patient was change in percentage of goals met 1 year after enrollment. RESULTS: The percentage of goals met increased in both the care guide and usual care groups (changes from baseline, 10.0% and 3.9%, respectively). Patients with care guides achieved more goals than usual care patients (82.6% vs. 79.1%; odds ratio, 1.31 [95% CI, 1.16 to 1.47]; P < 0.001); reduced unmet goals by 30.1% compared with 12.6% for usual care patients; and improved more than usual care patients in meeting several individual goals, including not using tobacco. Estimated cost was $286 per patient per year. LIMITATIONS: Providers' usual care may have been influenced by contact with care guides. Last available data in the electronic health record were used to assess end points. CONCLUSION: Adding care guides to the primary care team can improve care for some patients with chronic disease at low cost. PMID- 23922065 TI - Evaluating diagnostic accuracy in the face of multiple reference standards. AB - A universal challenge in studies that quantify the accuracy of diagnostic tests is establishing whether each participant has the disease of interest. Ideally, the same preferred reference standard would be used for all participants; however, for practical or ethical reasons, alternative reference standards that are often less accurate are frequently used instead. The use of different reference standards across participants in a single study is known as differential verification.Differential verification can cause severely biased accuracy estimates of the test or model being studied. Many variations of differential verification exist, but not all introduce the same risk of bias. A risk-of-bias assessment requires detailed information about which participants receive which reference standards and an estimate of the accuracy of the alternative reference standard. This article classifies types of differential verification and explores how they can lead to bias. It also provides guidance on how to report results and assess the risk of bias when differential verification occurs and highlights potential ways to correct for the bias. PMID- 23922064 TI - Self-measured blood pressure monitoring in the management of hypertension: a systematic review and meta-analysis. AB - BACKGROUND: Clinical guidelines recommend that adults with hypertension self monitor their blood pressure (BP). PURPOSE: To summarize evidence about the effectiveness of self-measured blood pressure (SMBP) monitoring in adults with hypertension. DATA SOURCES: MEDLINE (inception to 8 February 2013) and Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter 2012). STUDY SELECTION: 52 prospective comparative studies of SMBP monitoring with or without additional support versus usual care or an alternative SMBP monitoring intervention in persons with hypertension. DATA EXTRACTION: Data on population, interventions, BP, other outcomes, and study method were extracted. Random-effects model meta-analyses were done. DATA SYNTHESIS: For SMBP monitoring alone versus usual care (26 comparisons), moderate strength evidence supports a lower BP with SMBP monitoring at 6 months (summary net difference, -3.9 mm Hg and -2.4 mm Hg for systolic BP and diastolic BP) but not at 12 months. For SMBP monitoring plus additional support versus usual care (25 comparisons), high-strength evidence supports a lower BP with use of SMBP monitoring, ranging from -3.4 to -8.9 mm Hg for systolic BP and from -1.9 to -4.4 mm Hg for diastolic BP, at 12 months in good-quality studies. For SMBP monitoring plus additional support versus SMBP monitoring alone or with less intense additional support (13 comparisons), low-strength evidence fails to support a difference. Across all comparisons, evidence for clinical outcomes is insufficient. For other surrogate or intermediate outcomes, low-strength evidence fails to show differences. LIMITATION: Clinical heterogeneity in protocols for SMBP monitoring, additional support, BP targets, and management; follow-up of 1 year or less in most studies, with sparse clinical outcome data. CONCLUSION: Self measured BP monitoring with or without additional support lowers BP compared with usual care, but the BP effect beyond 12 months and long-term benefits remain uncertain. Additional support enhances the BP-lowering effect. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 23922066 TI - Prioritizing guideline-recommended interventions. PMID- 23922067 TI - Knowledge and ignorance in the care of chronic disease. PMID- 23922068 TI - The racist patient. PMID- 23922069 TI - The racist patient. PMID- 23922070 TI - The racist patient. PMID- 23922071 TI - The racist patient. PMID- 23922072 TI - The racist patient. Author reply. PMID- 23922073 TI - The racist patient. PMID- 23922074 TI - Benjamin Babington and the quadricuspid aortic valve. PMID- 23922077 TI - Summaries for Patients. Personalized estimates of benefit from preventive care guidelines. PMID- 23922078 TI - Summaries for patients. Risk for lymphoma and the results of follow-up gut biopsies in patients with celiac disease. PMID- 23922079 TI - Summaries for Patients. Does adding laypersons to primary care teams improve care for chronic diseases? PMID- 23922080 TI - Acute gastrointestinal bleeding. PMID- 23922081 TI - A chiral-based magnetic memory device without a permanent magnet. AB - Several technologies are currently in use for computer memory devices. However, there is a need for a universal memory device that has high density, high speed and low power requirements. To this end, various types of magnetic-based technologies with a permanent magnet have been proposed. Recent charge-transfer studies indicate that chiral molecules act as an efficient spin filter. Here we utilize this effect to achieve a proof of concept for a new type of chiral-based magnetic-based Si-compatible universal memory device without a permanent magnet. More specifically, we use spin-selective charge transfer through a self-assembled monolayer of polyalanine to magnetize a Ni layer. This magnitude of magnetization corresponds to applying an external magnetic field of 0.4 T to the Ni layer. The readout is achieved using low currents. The presented technology has the potential to overcome the limitations of other magnetic-based memory technologies to allow fabricating inexpensive, high-density universal memory-on-chip devices. PMID- 23922082 TI - Associations of breastfeeding with bulimic behaviors and eating disorders among adolescents. AB - PURPOSE: To use the lifecourse framework to examine the association between duration of breastfeeding and risk of developing bulimic behaviors or a diagnosed eating disorder. METHOD: Questionnaires were sent every 12-24 months between 1996 and 2005 to 6,436 females and 5,756 males in the Growing Up Today Study, who were 9-14 years at baseline. Duration of breastfeeding was reported by the participants' mothers in 1997. We used generalized estimating equations to estimate the association of breastfeeding with purging, binge eating, engaging in bulimic behaviors, and having a diagnosed eating disorder. RESULTS: Compared to girls who were breastfed for more than 9 months, those who were breastfed for less than 4 months did not have a significantly different prevalence of purging, binge eating, bulimic behaviors, and self-reported history of diagnosed eating disorders. Adjusting for gestational age/birthweight, age, age at menarche, maternal history of an eating disorder, and maternal body mass index, short duration of breastfeeding was not associated with any outcome among the girls [adjusted odds ratios (AOR) ranged from 0.8 to 1.1]. Among the boys, the results showed no significant associations between duration of breastfeeding and purging, binge eating, and self-reported history of diagnosed eating disorder. However, there was a suggestion that boys who had been breastfed for less than 4 months were at a higher risk of engaging in bulimic behaviors [AOR: 1.5, 95% confidence interval (CI), 1.0-2.3]. DISCUSSION: No association was found between duration of breastfeeding and risk of developing bulimic behaviors or a diagnosed eating disorder among girls or boys with the one exception of longer duration of breastfeeding associated with fewer bulimic behaviors in boys. Although there are many benefits to breastfeeding, our data suggest that breastfeeding does not offer any protection against binge eating or purging, nor does it present harmful effects. PMID- 23922084 TI - [The aesthetic character of caring knowledge]. AB - The identity of nursing is founded on caring knowledge, which is derived from our understanding of its experience-revealed essence. This purposive knowledge differs from scientific knowledge because validity guides the latter and ethics guides the former. Therefore, justifying the objectivity of caring knowledge should be based on the aesthetic character of this knowledge rather than on a general social-science explanation. PMID- 23922083 TI - Expression of Foxp3, TGF-beta and IL-10 in American cutaneous leishmaniasis lesions. AB - Regulatory T cells (Tregs) are a unique population of CD25+CD4+ T cells that regulate innate and adaptive immune responses and have the ability to control the excessive or misdirected effects of the immune system. This modulation involves different mechanisms, such as the suppression of T cell proliferation and cytokine production, the secretion of suppressive cytokines (IL-10 and TGF-beta) and the induction of effector T cell apoptosis in humans with infectious diseases such as Leishmania infections. The aim of this study was to evaluate the expression of Foxp3, IL-10 and TGF-beta through immunohistochemistry in 22 skin biopsies of patients with localized cutaneous leishmaniasis (LCL) caused by Leishmania (Viannia) spp. from an endemic area in pre-Amazonian area of Maranhao State, Brazil. The density of these markers was also analyzed according to the species of parasite and the progression of the disease. The cellular density was 234 cells/mm(2) for Foxp3+ cells, 357 cells/mm(2) for TGF-beta+ cells and 648 cells/mm(2) for IL-10+ cells in the studied skin lesions. The analysis of the cellular density of these immunological markers in relation to the species of Leishmania demonstrated that lesions caused by L. (V.) braziliensis had a lower density of Foxp3+ cells than lesions caused by L. (Viannia) spp. The expression of IL-10 was also lower in lesions caused by L. (V.) braziliensis. There were no significant differences in TGF-beta expression between the two groups. The evaluation of these markers according to the progression of the disease did not reveal any significant differences. These findings suggest that Treg Foxp3+ cells, IL-10, and TGF-beta play important roles in the immunopathogenesis of LCL and that these roles differ depending on the causal Leishmania species. PMID- 23922085 TI - [The aesthetic practice of care ethics]. AB - Situated between the doctor and the patient, nurses play a central role in the doctor-patient relationship. Nurses attend to patients' exhaustion and take responsibility for the "Other," in Levinas' sense of the word. In discussions of the doctor-patient relationship, the patient is often regarded as the "Other". This perspective seeks to challenge the traditional contention that the doctor plays the dominant role. In the structure of this relationship, the doctor, responsible for providing diagnoses, is the subject and the patient is the object. The latter constantly feels frustrated and helpless and requires the comfort of the nurse. In this sense, the nurse, having the direct contact with the patient, constantly sees the faces of the patients. In the care relationship, the patient's frustration and helplessness will sometimes be expressed to the nurse if the patient cannot be affectively affirmed. In this type of situation, the nurse bears not simply his / her routine work, but also affective devotion and endurance. On the one hand, the nurse must practice professional medical care in the face of patients' affective feelings and emotions and, on the other hand, he / she must treat the patient as a relative and suppress inner feelings and emotions. How does a nurse situate herself into the doctor-patient relationship? As the nurse is asked to treat the patient as a relative, how does he / she face inner emotions? This paper reflects on the possibility of the aesthetic practice of care ethics. PMID- 23922086 TI - [Helping people is beautiful: an inquiry into the aesthetic consciousness of the helping profession]. AB - This article addresses the helping profession as an art. The author uses an art philosophy perspective to review the phenomenon and meaning of the helping profession as "art" and addresses several questions. These questions include: What category or categories of art best define the helping profession? Can the process and / or results of helping be appreciated as works of art? What is the value of treating the helping profession as an art form? The purpose of this article is to expand knowledge regarding the aesthetic nature of the helping profession. PMID- 23922087 TI - [Reflections on physical spaces and mental spaces]. AB - This article analyzes certain reciprocal impacts from physical spaces to mental spaces. If the epistemological construction and the spatial imagination from the subject of cogito or the social collectivities are able to influence the construction and creation of the physical spaces of that subject, then the context of that physical space may also affect the cognitive or social subject's mental cognition. This article applies the methodology of iconology from art history (E. Panofsky) and sociology (P. Bourdieu) to explore correlations between the creation of imaginative and physical spaces from the collective consciousness and mental cognition. The author uses Gilles Deleuses's opinion regarding the 17th-century Baroque style and contemporary social collective symptoms as an explanation. From these theoretical studies, the author analyzes the differences of spatial epistemology generated by Taiwan's special geological text. Finally, the author applies Michel Foucault's studies on spatial context to assess the possible application of this thesis of reciprocal impacts from mental spaces to physical spaces in a nursing context. PMID- 23922088 TI - [Exploration of nursing art and aesthetic experiences: cross-disciplinary links and dialogues]. AB - Interdisciplinary understanding is crucial for readers today. This article integrates the ideas of four care-aesthetics-column writers in order to illustrate and discuss nursing art and aesthetic care experiences in a cross disciplinary conversation. This article reflects critically on the art, culture, and nature of nursing in the five themes of: 1) the shape of nursing knowledge, "science" or "art"?; 2) the caring arts: passively regulative or consciously creative labor?; 3) busy hospital workers: a landscape of persons and objects or the creators of the scenery?; 4) nursing skills, arts, and the Tao; and 5) art liberation: is the nursing profession in need of a revolution or fundamental reform? This article utilizes diverse and occasionally contradictory points of view together with practical examples in order to encourage readers to interlink their disparate professional nursing skills and draw aesthetic knowledge from multiple sources and experiences. PMID- 23922089 TI - [Effectiveness evaluation of healthy lifestyle interventions in childhood obesity prevention: a systematic review]. AB - BACKGROUND: There is significant reporting on evidence-based research in the literature regarding lifestyle modification programs. There is a need to review and synthesize results in order to develop childhood obesity prevention and intervention strategy recommendations. PURPOSE: Main purposes of the present review were to update the systematic review and critical appraisal of recent evidence in this area and assess the efficacy and quality of published research studies. METHODS: Studies included in this review incorporated the following inclusion criteria: obese children participants 5 to 14 years of age; a face-to face randomized-controlled study with a 4-week intervention period; and anthropometry, physical activity, sedentary behavior evaluated as primary outcomes after > 6 months. Eleven studies met the 3 inclusion criteria. All were found using the following key word string: RCT or CCT interventional study researches, childhood obesity, overweight, preventive intervention, healthy lifestyle". RESULTS: Evidence from these studies showed that all interventions varied in terms of approach and settings. Most provided a healthy lifestyle program duration of more than 15 minutes per week. Those that included culturally sensitive diet education and 30-60 minutes of moderate-intensity exercise everyday significantly enhanced childhood obesity prevention in terms of both anthropometry and dietary habits and decreased sedentary behavior. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Results suggest that effective healthy lifestyle programs for childhood obesity prevention in Taiwan should provide dietary guidance sensitive to Taiwanese dietary habits, encourage daily physical activities, and decrease sedentary behavior. PMID- 23922090 TI - [Testing the reliability and validity of a parenting scale for Indonesia mothers in transnational marriages]. AB - BACKGROUND: In Taiwan, transnational-marriage families face more challenges to childrearing success than their domestic marriage counterparts. The parenting approaches and behaviors of transnational-marriage mothers have yet to be adequately studied, and few quantitative studies have been done. PURPOSE: The present study verifies the reliability and validity of the Modified Child Rearing Practice Report (M-CRPR) parenting scale for Indonesian mothers in transnational marriage families in Taiwan. METHODS: Purposive sampling was used to recruit Indonesian mothers in the Kaohsiung and Pingtung. Women who were the primary caregiver of one or more children aged between 3 and 12 years were asked to participate. In-depth interviews were first conducted to determine whether participant experiences fit the M-CRPR concept. A total of 201 qualified women agreed to participate and were asked to respond to the Indonesian-version M-CRPR, produced using a double-translation approach. M-CRPR reliability and validity were subsequently evaluated. RESULTS: Factor analysis identified three factor clusters: nurturance (15 items), restrictiveness (14 items), and protection (5 items). The factor loading of each item was between 0.32 and 0.69 and these 3 factors explained 28.13% of total variance. The internal consistency of the Indonesia-version M-CRPR was 0.84 and the ICC was 0.88. CONCLUSIONS: The reliability and validity of the Indonesian M-CRPR were both acceptable. This instrument may be used to investigate parenting issues faced by Indonesia mothers in transnational-marriage. PMID- 23922091 TI - [Self-directed learning in nursing students with different background factors]. AB - BACKGROUND: Fostering self-directed learning skills in nursing students may provide a foundation for improving the specialty knowledge of these nurses. PURPOSE: This study examines the current status of nursing student self-directed learning behavior and explores how different background factors impact self directed learning. METHODS: This research design used a cross-sectional survey and convenience sampling. A total of 550 questionnaires were distributed to participants in enrolled in nursing programs at a 2-year nursing program at an institute of technology in northern Taiwan and a 4-year nursing program at an institute of technology in southern Taiwan. A convenience sampling was used to collect data, with 537 valid questionnaires used in data analysis. RESULTS: Results indicated that the self-directed learning and self-management of nursing students between 20-21 years old was significantly higher than those of students between 18-19 years old. Self-directed learning, desire of learning and self control in 2-year nursing students were significantly higher than in 4-year and extension education department nursing student participants. Two-year nursing students had the highest self-management scores, followed by extension education department participants and 4-year nursing students. Finally, participants who associated highly with the nursing profession earned the highest self-directed total score, followed by those participants who associated generally and those who associated mildly. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The results recommend that teachers at nursing institutes help students develop self-directed learning. Results also recommend teachers increase their students' association with the nursing specialty through understanding the impact of different background factors on self-directed learning. PMID- 23922092 TI - [A comparison of the efficacy of different wound dressing management techniques in preventing pressure ulcers]. AB - BACKGROUND: Although high-technology wound dressings are widely used in clinical care worldwide, no evidence or discussions have been published regarding the efficacy of these dressings in preventing pressure ulcers. PURPOSE: This study presents a repositioning of routine management combined with hydrocolloid dressing or foam dressing for pressure ulcer prevention. METHODS: We used a quasi experimental design and recruited a convenience sample of 90 from a surgical intensive care unit (SICU) at a medical center in Hualien County, Taiwan. Participants were allocated randomly to one of three groups: repositioning of routine management, hydrocolloid dressing, and foam dressing. Study instruments included a pressure ulcer risk table (Braden scale) and the pressure ulcer classification system of the European Pressure Ulcer Advisory Panel. An independent sample t-test, ANOVA, and Mann-Whitney U test were used to verify research hypotheses. RESULTS: The repositioning of routine management group had the highest pressure ulcer incidence rate, followed by the hydrocolloid-dressing group. The foam-dressing group recorded no pressure ulcers. Pressure ulcer occurrence grades were primarily level 1 and 2. There was no significance difference in pressure ulcer occurrence time between the repositioning of routine management group and the hydrocolloid-dressing group. Finally, there were significant differences (p < .05) among gender, hypertension history, and BMI regardless of pressure ulcer incidences. CONCLUSIONS: It is recommended that patients in high-risk groups in clinical settings adopt strategies including repositioning and regular visual skin examinations. Also, hydrocolloid or foam dressings may be used as appropriate to prevent sacral pressure ulcers. PMID- 23922093 TI - [A case study on duty of care in professional nursing]. AB - BACKGROUND: Nurses are expected to discharge their duty of care effectively and professionally to prevent medical negligence. Only three articles have previously focused on medical negligence. Duty of care and medical negligence in nursing are topics that have been neglected in Taiwan. PURPOSE: (1) Classify the duty of care of professional nurses; (2) Investigate the facts and disputes in the current case; (3) Clarify the legal issues involved with regard to duty-of-care violations in the current case; (4) Explore the causal relationships in a legal context between nurses' duty-of-care violations and patient harm / injury. METHODS: Literature analysis and a case study are used to analyze Supreme Court Verdict No.5550 (2010). RESULTS: Duty of care for nursing professionals may be classified into seven broad categories. Each category has its distinct correlatives. In nursing practice, every nursing behavior has a corresponding duty. In this case, the case study nurse did not discharge her obstetric professional duty and failed to inform the doctor in a timely manner. Negligence resulted in prenatal death and the case study nurse was found guilty. CONCLUSIONS: In order to prevent committing a crime, nurses should gain a better understanding of their duty of care and adequately discharge these duties in daily practice. PMID- 23922094 TI - [Conceptual model of teasing and bullying in adolescents]. AB - Teasing and bullying incident levels have increased markedly in recent years according to international news reports. School and community-level action to stop and prevent bullying is a key focus of government education policy worldwide. Teasing is a usual facet of social interaction among youth and is related to bullying behavior. Although teasing and bullying are significant concerns, references for relevant concept analysis are lacking in the nursing field. To facilitate early screening to identify high-risk bullies and help victims effectively stop bullying events, concept analysis is needed to clarify and distinguish between the two concepts of teasing and bullying. The aim of this study is to integrate relevant published literature to determine the reasons for and relationships between teasing and bullying. We chose obesity as an example to construct a teasing and bullying conceptual model for adolescents and used this model to explore the related factors and health impacts of obesity. We found that both teaser intent and recipient perceptions correlated with bullying behavior. Duration and severity may induce teasing to become bullying. Because weight-based teasing is common among adolescents, we chose obesity as an example issue to demonstrate our adolescents teasing and bullying concept model. We then integrated the antecedent and consequential factors of teasing and bullying for obese adolescents. Weight-control strategies can stop school bullying if early interventions are performed in high-risk populations. PMID- 23922095 TI - [Spontaneous fracture: a potential clinical concern]. AB - Spontaneous fracture is an issue of increasing concern in clinical care. However, this topic has received only limited attention in nursing research. Gaps in understanding related to spontaneous fractures may increase medical-legal risks faced by frontline care nurses, exacerbate nursing pressures, and serve as a disincentive to remain in the already understaffed nursing profession. This article reviews previous research on spontaneous fractures to determine the epidemiological causes of clinical spontaneous fracture and identify effective prevention strategies. We hope this paper may increase clinical practitioner and expert awareness of spontaneous fractures; help establish a screening mechanism to identify high risk spontaneous fracture patients; and help nurses develop and implement proactive prevention / treatment strategies to strengthen awareness of this topic among patients and their families. PMID- 23922096 TI - [Case management: a concept analysis]. AB - While the case management approach has been increasingly applied to healthcare worldwide in recent years, significant differences in application exist among discrete medical systems. This paper applies a methodology outlined by Walker and Avant to analyze the case management concept. This methodology is designed to assist medical staff to understand a concept in order to better achieve concept goals. The case management approach works to leverage organizational strategies to resolve case-specific circumstances and issues in order to accomplish organizational goals. Defining attributes of case management include: (1) highly complex cases; (2) the use of multidisciplinary professional teams to resolve case problems in the most cost-effective manner; (3) the use of case managers to manage the effective integration and operation of the multidisciplinary team; and (4) helping cases improve and make effective use of medical system resources. PMID- 23922097 TI - [Using logotherapy to relieve death anxiety in a patient with recurrent cancer: a nursing experience]. AB - We used logotherapy concepts to manage the mental impact of recurrent cancer on a patient. The patient had received radiotherapy for nasopharyngeal carcinoma approximately one year prior to the March 9th - April 21st, 2011 nursing care period. The authors interacted with the patient during the care period via personal observation and telephone interview. Patient data was also collected from medical staff. Integral nursing assessment disclosed that the patient faced several major nursing issues, including death anxiety, pain, and sleep disturbance. This report describes how logotherapy was utilized to enable the patient better understand his condition and ultimately allow him to identify and pursue renewed meaning and happiness in life. Logotherapy helped alleviate the death anxiety caused by recurrent cancer and helped the patient self-reconfirm the meaning of life. PMID- 23922098 TI - A novel role of the tumor suppressor GNMT in cellular defense against DNA damage. AB - Glycine N-methyltransferase (GNMT) is a folate binding protein commonly diminished in human hepatoma yet its role in tumor development remains to be established. GNMT binds to methylfolate but is also inhibited by it; how such interactions affect human carcinogenesis is unclear. We postulated that GNMT plays a role in folate-dependent methyl group homeostasis and helps maintain genome integrity by promoting nucleotide biosynthesis and DNA repair. To test the hypothesis, GNMT was over-expressed in GNMT-null cell lines cultured in conditions of folate abundance or restriction. The partitioning of folate dependent 1-carbon groups was investigated using stable isotopic tracers and GC/MS. DNA damage was assessed as uracil content in cell models, as well as in Gnmt wildtype (Gnmt(+/+)), heterozygote (Gnmt(+/-)) and knockout (Gnmt(-/-)) mice under folate deplete, replete, or supplementation conditions. Our study demonstrated that GMMT 1) supports methylene-folate dependent pyrimidine synthesis; 2) supports formylfolate dependent purine syntheses; 3) minimizes uracil incorporation into DNA when cells and animals were exposed to folate depletion; 4) translocates into nuclei during prolonged folate depletion. In conclusion, loss of GNMT impairs nucleotide biosynthesis. Over-expression of GNMT enhances nucleotide biosynthesis and improves DNA integrity by reducing uracil misincorporation in DNA both in vitro and in vivo. To our best knowledge, the role of GNMT in folate dependent 1-carbon transfer in nucleotide biosynthesis has never been investigated. The present study gives new insights into the underlying mechanism by which GNMT can participate in tumor prevention/suppression in humans. PMID- 23922103 TI - The tumour suppressor miR-34c targets MET in prostate cancer cells. AB - BACKGROUND: The microRNA, miR-34c, is a well-established regulator of tumour suppression. It is downregulated in most forms of cancers and inhibits malignant growth by repressing genes involved in processes such as proliferation, anti apoptosis, stemness, and migration. We have previously reported downregulation and tumour suppressive properties for miR-34c in prostate cancer (PCa). METHODS: In this study, we set out to further characterize the mechanisms by which miR-34c deregulation contributes to PCa progression. The genes regulated by miR-34c in the PCa cell line PC3 were identified by microarray analyses and were found to be enriched in cell death, cell cycle, cellular growth, and cellular movement pathways. One of the identified targets was MET, a receptor tyrosine kinase activated by hepatocyte growth factor, that is crucial for metastatic progression. RESULTS: We confirmed the inhibitory effect of miR-34c on both MET transcript and protein levels. The binding of miR-34c to two binding sites in the 3'-UTR of MET was validated using luciferase reporter assays and target site blockers. The effect of this regulation on the miR-34c inhibition of the migratory phenotype was also confirmed. In addition, a significant inverse correlation between miR-34c expression levels and MET immunostaining was found in PCa patients. CONCLUSION: These findings provide a novel molecular mechanism of MET regulation in PCa and contribute to the increasing evidence that miR-34c has a key tumour suppressive role in PCa. PMID- 23922104 TI - Src kinases in chondrosarcoma chemoresistance and migration: dasatinib sensitises to doxorubicin in TP53 mutant cells. AB - BACKGROUND: Chondrosarcomas are malignant cartilage-forming tumours of bone. Because of their resistance to conventional chemotherapy and radiotherapy, currently no treatment strategies exist for unresectable and metastatic chondrosarcoma. Previously, PI3K/AKT/GSK3beta and Src kinase pathways were shown to be activated in chondrosarcoma cell lines. Our aim was to investigate the role of these kinases in chemoresistance and migration in chondrosarcoma in relation to TP53 mutation status. METHODS: We used five conventional and three dedifferentiated chondrosarcoma cell lines and investigated the effect of PI3K/AKT/GSK3beta pathway inhibition (enzastaurin) and Src pathway inhibition (dasatinib) in chemoresistance using WST assay and live cell imaging with AnnexinV staining. Immunohistochemistry on tissue microarrays (TMAs) containing 157 cartilaginous tumours was performed for Src family members. Migration assays were performed with the RTCA xCelligence System. RESULTS: Src inhibition was found to overcome chemoresistance, to induce apoptosis and to inhibit migration. Cell lines with TP53 mutations responded better to combination therapy than wild type cell lines (P=0.002). Tissue microarray immunohistochemistry confirmed active Src (pSrc) signalling, with Fyn being most abundantly expressed (76.1%). CONCLUSION: These results strongly indicate Src family kinases, in particular Fyn, as a potential target for the treatment of inoperable and metastatic chondrosarcomas, and to sensitise for doxorubicin especially in the presence of TP53 mutations. PMID- 23922106 TI - Proline-rich tyrosine kinase 2 and its phosphorylated form pY881 are novel prognostic markers for non-small-cell lung cancer progression and patients' overall survival. AB - BACKGROUND: Our previous study revealed that proline-rich tyrosine kinase 2 (Pyk2) is implicated in both anchorage-independent growth and anoikis resistance in lung cancer cells. This study aims to explore the expression and clinical significance of Pyk2 and its phosphorylated forms in non-small-cell lung cancer (NSCLC). METHODS: The mRNA and protein levels of Pyk2 or cancer stem cell markers (ALDH1a1, ABCG2 and Bmi-1) were either examined by reverse transcription-PCR or western blotting. An immunohistochemistry (IHC) assay was conducted to analyse the expression of Pyk2 and its phosphorylated forms in 128 NSCLC cases. RESULTS: The levels of Pyk2 mRNA, total protein, and its phosphorylated form pY881 were higher in lung cancer lesions than in the paired noncancerous tissues. The IHC analysis showed the levels of the Pyk2 and Pyk2[pY881] proteins were highly expressed in 70 (54.7%) and 77 (60.2%) cases, respectively. Both Pyk2 and Pyk2[pY881] were independent prognostic factors for NSCLC patients. The gain and loss study of Pyk2 function revealed that Pyk2 could upregulate the expression of ALDH1a1, ABCG2 and Bmi-1 and enhance the ability of colony formation in soft agar assay in A549 and H460 cells. CONCLUSION: Both Pyk2 and phosphorylated Pyk2[pY881] are potential prognostic factors and therapeutic targets for NSCLC. PMID- 23922107 TI - Tubal ligation in relation to menopausal symptoms and breast cancer risk. AB - BACKGROUND: Local inflammation after tubal ligation may affect ovarian function and breast cancer risk. METHODS: We analysed tubal ligation, menopausal characteristics, and breast cancer risk in the Sister Study cohort (N=50,884 women). RESULTS: Tubal ligation was associated with hot flashes (hazard ratio (HR) 1.09; 95% confidence interval (CI): 1.06-1.12) but not menopausal age (HR 0.99; 95% CI: 0.96-1.02). Tubal ligation did not have an impact on breast cancer overall (HR 0.95; 95% CI: 0.85-1.06), but had a suggested inverse relation with oestrogen receptor+/progesterone receptor+ invasive tumours (HR 0.84; 95% CI: 0.70-1.01), possibly because of subsequent hysterectomy/bilateral oophorectomy. CONCLUSION: Tubal ligation does not influence overall breast cancer risk. PMID- 23922105 TI - Proanthocyanidins and other flavonoids in relation to endometrial cancer risk: a case-control study in Italy. AB - BACKGROUND: Because of their antioxidant and antimutagenic properties, flavonoids may reduce cancer risk. Some flavonoids have antiestrogenic effects that can inhibit the growth and proliferation of endometrial cancer cells. METHODS: In order to examine the relation between dietary flavonoids and endometrial cancer, we analysed data from an Italian case-control study including 454 incident, histologically confirmed endometrial cancers and 908 hospital-based controls. Information was collected through a validated food-frequency questionnaire. We applied data on food and beverage composition to estimate the intake of flavanols, flavanones, flavonols, anthocyanidins, flavones, isoflavones, and proanthocyanidins. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from multiple logistic regression models conditioned on age and study centre and adjusted for major confounding factors. RESULTS: Women in the highest quartile category of proanthocyanidins with >=3 mers vs the first three quartile categories had an OR for endometrial cancer of 0.66 (95% CI=0.48-0.89). For no other class of flavonoids, a significant overall association was found. There was a suggestion of an inverse association for flavanones and isoflavones among women with body mass index <25 kg m(-2), and, for flavanones, among parous or non-users of hormone-replacement therapy women. CONCLUSION: High consumption of selected proanthocyanidins may reduce endometrial cancer risk. PMID- 23922108 TI - Changes in tumour vessel density upon treatment with anti-angiogenic agents: relationship with response and resistance to therapy. AB - BACKGROUND: We examine how changes in a surrogate marker of tumour vessel density correlate with response and resistance to anti-angiogenic therapy. METHODS: In metastatic renal cancer patients treated with anti-angiogenic tyrosine kinase inhibitors, arterial phase contrast-enhanced computed tomography was used to simultaneously measure changes in: (a) tumour size, and (b) tumour enhancement (a surrogate marker of tumour vessel density) within individual lesions. RESULTS: No correlation between baseline tumour enhancement and lesion shrinkage was observed, but a reduction in tumour enhancement on treatment was strongly correlated with reduction in lesion size (r=0.654, P<0.0001). However, close examination of individual metastases revealed different types of response: (1) good vascular response with significant tumour shrinkage, (2) good vascular response with stabilisation of disease, (3) poor vascular response with stabilisation of disease and (4) poor vascular response with progression. Moreover, contrasting responses between different lesions within the same patient were observed. We also assessed rebound vascularisation in tumours that acquired resistance to treatment. The amplitude of rebound vascularisation was greater in lesions that had a better initial response to therapy (P=0.008). INTERPRETATION: Changes in a surrogate marker of tumour vessel density correlate with response and resistance to anti-angiogenic therapy. The data provide insight into the mechanisms that underlie response and resistance to this class of agent. PMID- 23922109 TI - High plasma fibrinogen level represents an independent negative prognostic factor regarding cancer-specific, metastasis-free, as well as overall survival in a European cohort of non-metastatic renal cell carcinoma patients. AB - BACKGROUND: In recent years, plasma fibrinogen has been ascribed an important role in the pathophysiology of tumour cell invasion and metastases. A relatively small-scale study has indicated that plasma fibrinogen levels may serve as a prognostic factor for predicting clinical outcomes in non-metastatic renal cell carcinoma (RCC) patients. METHODS: Data from 994 consecutive non-metastatic RCC patients, operated between 2000 and 2010 at a single, tertiary academic centre, were evaluated. Analyses of plasma fibrinogen levels were performed one day before the surgical interventions. Patients were categorised using a cut-off value of 466 mg dl-1 according to a calculation by receiver-operating curve analysis. Cancer-specific (CSS), metastasis-free (MFS), as well as overall survival (OS) were assessed using the Kaplan-Meier method. To evaluate the independent prognostic impact of plasma fibrinogen level, a multivariable Cox regression model was performed for all three different endpoints. RESULTS: High plasma fibrinogen levels were associated with various well-established prognostic factors, including age, advanced tumour stage, tumour grade and histologic tumour necrosis (all P<0.05). Furthermore, in multivariable analysis, a high plasma fibrinogen level was statistically significantly associated with a poor outcome for patients' CSS (hazard ratio (HR): 2.47, 95% confidence interval (CI): 1.49 4.11, P<0.001), MFS (HR: 2.15, 95% CI: 1.44-3.22, P<0.001) and OS (HR: 2.48, 95% CI: 1.80-3.40, P<0.001). CONCLUSION: A high plasma fibrinogen level seems to represent a strong and independent negative prognostic factor regarding CSS, MFS and OS in non-metastatic RCC patients. Thus, this easily determinable laboratory value should be considered as an additional prognostic factor for RCC patients' individual risk assessment. PMID- 23922110 TI - Evolutionary game theory of growth factor production: implications for tumour heterogeneity and resistance to therapies. AB - BACKGROUND: Tumour heterogeneity is documented for many characters, including the production of growth factors, one of the hallmarks of cancer. What maintains heterogeneity remains an open question that has implications for diagnosis and treatment, as drugs that target growth factors are susceptible to the evolution of resistance. METHODS: I use evolutionary game theory to model collective interactions between cancer cells, to analyse the dynamics of the production of growth factors and the effect of therapies that reduce their amount. RESULTS: Five types of dynamics are possible, including the coexistence of producer and non-producer cells, depending on the production cost of the growth factor, on its diffusion range and on the degree of synergy of the benefit it confers to the cells. Perturbations of the equilibrium mimicking therapies that target growth factors are effective in reducing the amount of growth factor in the long term only if the reduction is extremely efficient and immediate. CONCLUSION: Collective interactions within the tumour can maintain heterogeneity for the production of growth factors and explain why therapies like anti-angiogenic drugs and RNA interference that reduce the amount of available growth factors are effective in the short term but often lead to relapse. Alternative strategies for evolutionarily stable treatments are discussed. PMID- 23922111 TI - MicroRNA-126 and epidermal growth factor-like domain 7-an angiogenic couple of importance in metastatic colorectal cancer. Results from the Nordic ACT trial. AB - BACKGROUND: This study investigated the clinical importance of linked angiogenetic biomarkers to chemotherapy, combined with the anti-vascular endothelial growth factor A (anti-VEGF-A), as a first-line treatment in patients with metastatic colorectal cancer (mCRC). METHODS: A total of 230 patients from a randomised phase III study were included. The primary microRNA-126 (pri-miRNA 126) A24G single-nucleotide polymorphism and the mature miRNA-126 were analysed by PCR using genomic DNA (full blood) and formalin-fixed paraffin-embedded tissue sections, respectively. The epidermal growth factor-like domain 7 (EGFL7) protein was visualised and quantified using immunohistochemistry. RESULTS: High tumour expression of miRNA-126 was significantly related to a longer progression-free survival. The independent prognostic value of miRNA-126 was confirmed using a Cox regression analysis (hazard ratio=0.49, 95% confidence interval=0.29-0.84, P=0.009). Although not significant, a relationship between EGFL7 expression and response rates is suggested, with EGFL7 expression at the invasive front being lower in responding patients than in the non-responders (P=0.063). CONCLUSION: The results validate the previous findings on the prognostic value of miRNA-126 in mCRC and may suggest a relationship between treatment efficacy and EGFL7 expression. As miRNA-126 may target VEGF-A as well as EGFL7, the results may provide predictive information in relation to next-generation anti-angiogenetics. PMID- 23922112 TI - Clinical and genetic predictors of weight gain in patients diagnosed with breast cancer. AB - BACKGROUND: Post-diagnosis weight gain in breast cancer patients has been associated with increased cancer recurrence and mortality. Our study was designed to identify risk factors for this weight gain and create a predictive model to identify a high-risk population for targeted interventions. METHODS: Chart review was conducted on 459 breast cancer patients from Northwestern Robert H. Lurie Cancer Centre to obtain weights and body mass indices (BMIs) over an 18-month period from diagnosis. We also recorded tumour characteristics, demographics, clinical factors, and treatment regimens. Blood samples were genotyped for 14 single-nucleotide polymorphisms (SNPs) in fat mass and obesity-associated protein (FTO) and adiponectin pathway genes (ADIPOQ and ADIPOR1). RESULTS: In all, 56% of patients had >0.5 kg m(-2) increase in BMI from diagnosis to 18 months, with average BMI and weight gain of 1.9 kg m(-2) and 5.1 kg, respectively. Our best predictive model was a primarily SNP-based model incorporating all 14 FTO and adiponectin pathway SNPs studied, their epistatic interactions, and age and BMI at diagnosis, with area under receiver operating characteristic curve of 0.85 for 18-month weight gain. CONCLUSION: We created a powerful risk prediction model that can identify breast cancer patients at high risk for weight gain. PMID- 23922113 TI - High CC chemokine receptor 7 expression improves postoperative prognosis of lung adenocarcinoma patients. AB - BACKGROUND: Chemokines and chemokine receptors not only have significant roles in cancer metastasis and tumorigenesis but also act as antitumour agents. The interaction between the Crk-like adaptor protein (CrkL), which is encoded by the CRKL gene, and non-receptor tyrosine kinase c-ABL is reported to transform many cells into malignant cells. We examined the effects of CC chemokine receptor 7 (CCR7), CCR7 ligands and CrkL and c-ABL in lung adenocarcinoma. METHODS: One hundred and twenty patients with lung adenocarcinoma were included in this historical cohort analysis. We examined CCR7 and CCR7 ligands and CrkL and c-ABL mRNA expressions in surgically resected lung adenocarcinoma specimens and evaluated their contribution to prognosis, and the relationship with epidermal growth factor receptor (EGFR) and TP53 mutations. RESULTS: High CCR7 mRNA expressions indicated better prognoses than those of the groups with low CCR7 mRNA expressions (P=0.007, HR=2.00, 95% CI of ratio: 1.22 -3.31). In lung adenocarcinoma, CrkL and c-ABL mRNAs were related to CCR7 mRNA expression (P<0.0001). CrkL and c-ABL mRNA expressions were influenced by EGFR mutations. A high expression of CCL19 was a good prognostic factor of lung adenocarcinoma. CONCLUSION: We propose that CCR7 and CCL19 are clinically good prognostic factors and that CCR7 is strongly related to CrkL and c-ABL kinase mRNA expression in lung adenocarcinoma. PMID- 23922114 TI - A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group. AB - BACKGROUND: Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS. METHODS: We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate. RESULTS: Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21-79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10-35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months. CONCLUSION: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD. PMID- 23922116 TI - Donor-acceptor (D-A)-substituted polyyne chromophores: modulation of their optoelectronic properties by varying the length of the acetylene spacer. AB - A series of donor-acceptor-substituted alkynes, 2 a-f, was synthesized in which the length of the pi-conjugated polyyne spacer between the N,N-diisopropylanilino donor and the 1,1,4,4-tetracyanobuta-1,3-diene (TCBD) acceptor was systematically changed. The effect of this structural change on the optoelectronic properties of the molecules and, ultimately, their third-order optical nonlinearity was comprehensively investigated. The branched N,N-diisopropyl groups on the anilino donor moieties combined with the nonplanar geometry of 2 a-f imparted exceptionally high solubility to these chromophores. This important property allowed for performing INADEQUATE NMR measurements without (13) C labeling, which, in turn, resulted in a complete assignment of the carbon skeleton in chromophores 2 a-f and the determination of the (13) C-(13) C coupling constants. This body of data provided unprecedented insight into characteristic (13) C chemical shift patterns in push-pull-substituted polyynes. Electrochemical and UV/Vis spectroscopic studies showed that the HOMO-LUMO energy gap decreases with increasing length of the polyyne spacer, while this effect levels off for spacers with more than four acetylene units. The third-order optical nonlinearity of this series of molecules was determined by measuring the rotational averages of the third-order polarizabilities (gammarot ) by degenerate four-wave mixing (DFWM). These latter studies revealed high third-order optical nonlinearities for the new chromophores; most importantly, they provided fundamental insight into the effect of the conjugated spacer length in D-A polyynes, that can be exploited in the future design of suitable charge-transfer chromophores for applications in optoelectronic devices. PMID- 23922115 TI - Chemotherapy for testicular cancer induces acute alterations in diastolic heart function. AB - BACKGROUND: After treatment with cisplatin-based chemotherapy for testicular cancer (TC), patients have higher prevalence of cardiovascular complications after long-term follow up. Little is known about acute cardiovascular effects of cisplatin-based chemotherapy. The aim of this study was to explore acute effects of chemotherapy on cardiac function in patients treated for TC. METHODS: Fourteen TC patients (age 34.6 +/- 12.3 years) were studied before and 3 months after start with cisplatin-based chemotherapy. Cardiac function was assessed with magnetic resonance imaging. Fasting glucose and insulin levels were measured and insulin sensitivity, reflected by the quantitative insulin sensitivity index (Quicki index), was calculated. RESULTS: Left ventricular (LV) end-diastolic volume and LV stroke volume (SV) significantly decreased from 192 +/- 27 to 175 +/- 26 ml (P<0.05) and 109 +/- 18 to 95 +/- 16 ml (P<0.05), respectively. The ratio of early and atrial filling velocities across the mitral valve, a parameter of diastolic heart function, decreased after chemotherapy from 1.87 +/- 0.43 to 1.64 +/- 0.45 (P<0.01). Metabolic parameters were unfavourably changed, reflected by a decreased Quicki index, which reduced from 0.39 +/- 0.05 to 0.36 +/- 0.05 (P<0.05). CONCLUSION: Chemotherapy for TC induces acute alterations in diastolic heart function, paralleled by unfavourable metabolic changes. Therefore, early after chemotherapy, metabolic treatment may be indicated to possibly reduce long term cardiovascular complications. PMID- 23922118 TI - Egg incubation effects generate positive correlations between size, speed and learning ability in young lizards. AB - Previous studies have suggested that body size and locomotor performance are targets of Darwinian selection in reptiles. However, much of the variation in these traits may derive from phenotypically plastic responses to incubation temperature, rather than from underlying genetic variation. Intriguingly, incubation temperature may also influence cognitive traits such as learning ability. Therefore, we might expect correlations between a reptile's size, locomotor speed and learning ability either due to selection on all of these traits or due to environmental effects during egg incubation. In the present study, we incubated lizard eggs (Scincidae: Bassiana duperreyi) under 'hot' and 'cold' thermal regimes and then assessed differences in hatchling body size, running speed and learning ability. We measured learning ability using a Y-maze and a food reward. We found high correlations between size, speed and learning ability, using two different metrics to quantify learning (time to solution, and directness of route), and showed that environmental effects (incubation temperature) cause these correlations. If widespread, such correlations challenge any simple interpretation of fitness advantages due to body size or speed within a population; for example, survivors may be larger and faster than nonsurvivors because of differences in learning ability, not because of their size or speed. PMID- 23922117 TI - In vitro antimicrobial properties of silver-polysaccharide coatings on porous fiber-reinforced composites for bone implants. AB - Biostable fiber-reinforced composite (FRC) implants prepared from bisphenol-A dimethacrylate and triethyleneglycoldimethacrylate resin reinforced with E-glass fibers have been successfully used in cranial reconstructions in 15 patients. Recently, porous FRC structures were suggested as potential implant materials. Compared with smooth surface, porous surface allows implant incorporation via bone ingrowth, but is also a subject to bacterial attachment. Non-cytotoxic silver-polysaccharide nanocomposite coatings may provide a way to decrease the risk of bacterial contamination of porous FRC structures. This study is focused on the in vitro characterization of the effect porosity on the antimicrobial efficiency of the coatings against Staphylococcus aureus and Pseudomonas aeruginosa by a series of microbiological tests (initial adhesion, antimicrobial efficacy, and biofilm formation). Characterization included confocal laser scanning microscopy and scanning electron microscopy. The effect of porosity on the initial attachment of S. aureus was pronounced, but in the case of P. aeruginosa the effect was negligible. There were no significant effects of the coatings on the initial bacterial attachment. In the antimicrobial efficacy test, the coatings were potent against both strains regardless of the sample morphology. In the biofilm tests, there were no clear effects either of morphology or of the coating. Further coating development is foreseen to achieve a longer-term antimicrobial effect to inhibiting bacterial implant colonization. PMID- 23922119 TI - Radiofrequency ablation versus open hepatic resection for elderly patients (> 65 years) with very early or early hepatocellular carcinoma. AB - BACKGROUND: This study retrospectively compared the safety and efficacy of percutaneous radiofrequency ablation (RFA) with open hepatic resection (HR) in elderly patients (age > 65 years) with very early or early hepatocellular carcinoma (HCC). METHODS: Elderly patients (n = 180) with very early or early HCC were studied. This study was approved by the Ethics Committee of the Cancer Center of Sun Yat-Sen University, Guangzhou, China. Written informed consent was obtained from each patient before treatment. As an initial treatment, 89 patients were treated by RFA and 91 patients by HR. The survival curves were constructed by the Kaplan-Meier method and compared by log-rank test. RESULTS: The 1-, 3-, and 5-year overall survivals were 93.2%, 71.1%, and 55.2% for the RFA group and 88.8%, 62.8%, and 51.9% for the HR group, respectively (P = .305). The corresponding recurrence-free survivals for these 2 groups were 84.1%, 62.7%, and 35.5% and 76.7%, 39.3%, and 33.1%, respectively (P = .035). On subgroup analysis for tumor <= 3 cm, the 1-, 3-, and 5-year overall survivals were 94.2%, 82.6%, and 67.5% for the RFA group and 90.1%, 65.0%, and 55.1% for the HR group, respectively (P = .038). The corresponding recurrence-free survivals for the 2 groups were 85.5%, 69.1%, and 40.7%, and 82.2%, 40.1%, and 31.8%, respectively (P = .049). For tumor > 3 cm, there was no significant difference between these 2 groups for overall survivals and recurrence-free survivals (P = .543, P = .356, respectively). A multivariate regression analysis showed that treatment type was the only significant prognostic factor for recurrence-free survival (P = .039). CONCLUSIONS: There was no difference between the HR and RFA groups for overall survival, but RFA had better efficacy than HR for elderly patients with HCC <= 3 cm. PMID- 23922120 TI - Psychological distress and comorbid physical conditions: disease or disability? AB - BACKGROUND: The relationship between comorbidity and psychological distress is well documented, however the mechanism of this association is unclear. We aim to assess the extent to which the association between common chronic conditions and high scores on the Kessler Psychological Distress Scale (K10) measure of psychological distress vary according to comorbid conditions, disability, and sociodemographic circumstances. METHODS: Analysis of self-reported cross sectional data from the New South Wales 45 and Up Study, Australia, for 236,508 participants aged 45 years and over, using logistic regression modeling. RESULTS: Self-reported heart attack/angina, other heart disease, stroke, and diabetes were all significantly associated with higher risk of high/very high K10 scores. These associations were attenuated, but remained statistically significant, when comorbidity, disability, and sociodemographic factors were added to the model. Men reporting needing help for daily tasks were nine times as likely to report high/very high K10 scores as those without this need, and women reporting needing help were seven times more likely to have high/very high K10 scores. CONCLUSIONS: Heart attack/angina, other heart disease, stroke, and diabetes are all significantly associated with psychological distress. However, these effects are partly explained by other comorbid conditions, limitations on physical functioning, and sociodemographic factors. These findings highlight the importance of developing public health policies that encompass psychological, physiological, and social domains, and provide crucial insights for clinicians in identifying and supporting those people at risk of psychological distress. PMID- 23922121 TI - The impact of sleep deprivation on food desire in the human brain. AB - Epidemiological evidence supports a link between sleep loss and obesity. However, the detrimental impact of sleep deprivation on central brain mechanisms governing appetitive food desire remains unknown. Here we report that sleep deprivation significantly decreases activity in appetitive evaluation regions within the human frontal cortex and insular cortex during food desirability choices, combined with a converse amplification of activity within the amygdala. Moreover, this bi-directional change in the profile of brain activity is further associated with a significant increase in the desire for weight-gain promoting high-calorie foods following sleep deprivation, the extent of which is predicted by the subjective severity of sleep loss across participants. These findings provide an explanatory brain mechanism by which insufficient sleep may lead to the development/maintenance of obesity through diminished activity in higher-order cortical evaluation regions, combined with excess subcortical limbic responsivity, resulting in the selection of foods most capable of triggering weight-gain. PMID- 23922122 TI - Combined two-photon microscopy and angiographic optical coherence tomography. AB - A combined two-photon microscopy (TPM) and angiographic optical coherence tomography (OCT) is developed, which can provide molecular, cellular, structural, and vascular information of tissue specimens in vivo. This combined system is implemented by adding an OCT vasculature visualization method to the previous combined TPM and OCT, and then is applied to in vivo tissue imaging. Two animal models, a mouse brain cranial window model and a mouse ear cancer model, are used. Both molecular, cellular information at local regions of tissues, and structural, vascular information at relatively larger regions are visualized in the same sections. In vivo tissue microenvironments are better elucidated by the combined TPM and angiographic OCT. PMID- 23922123 TI - Role of Mandelbaum-like effect in the differentiation of hyperopes and myopes using a hologram. AB - Recently, we tested the vision of spectacle corrected subjects using a special hologram (http://dx.doi.org/10.1364/BOE.3.001173). A subject viewing through this hologram sees the images of various numbers at different distances from the eye. Each of these images subtends an angle of 50' at the eye. Each image corresponds to a different amount of divergence or convergence at the eye. The limit of convergence (positive blur) with which a subject can recognize the numbers was measured. Hyperopes could recognize numbers with 0.9 D more of positive blur in comparison with myopes. This difference was not obtained with a standard test chart under white light illumination using positive lenses to provide the blur. The observed difference with the hologram is then attributed to the multivergence nature of the target in the hologram and/or the monochromaticity of the illumination used. Using a hologram of a logMAR chart at a single distance of infinity we have now found that the observed difference is induced by the multivergence target and is due to an effect that is similar to the Mandelbaum effect. We present the details of this experiment and compare the results obtained with our earlier experiment. PMID- 23922125 TI - Accurate in situ measurement of complex refractive index and particle size in intralipid emulsions. AB - A first accurate measurement of the complex refractive index in an intralipid emulsion is demonstrated, and thereby the average scatterer particle size using standard Mie scattering calculations is extracted. Our method is based on measurement and modeling of the reflectance of a divergent laser beam from the sample surface. In the absence of any definitive reference data for the complex refractive index or particle size in highly turbid intralipid emulsions, we base our claim of accuracy on the fact that our work offers several critically important advantages over previously reported attempts. First, our measurements are in situ in the sense that they do not require any sample dilution, thus eliminating dilution errors. Second, our theoretical model does not employ any fitting parameters other than the two quantities we seek to determine, i.e., the real and imaginary parts of the refractive index, thus eliminating ambiguities arising from multiple extraneous fitting parameters. Third, we fit the entire reflectance-versus-incident-angle data curve instead of focusing on only the critical angle region, which is just a small subset of the data. Finally, despite our use of highly scattering opaque samples, our experiment uniquely satisfies a key assumption behind the Mie scattering formalism, namely, no multiple scattering occurs. Further proof of our method's validity is given by the fact that our measured particle size finds good agreement with the value obtained by dynamic light scattering. PMID- 23922124 TI - Label-free optical lymphangiography: development of an automatic segmentation method applied to optical coherence tomography to visualize lymphatic vessels using Hessian filters. AB - Lymphatic vessels are a part of the circulatory system that collect plasma and other substances that have leaked from the capillaries into interstitial fluid (lymph) and transport lymph back to the circulatory system. Since lymph is transparent, lymphatic vessels appear as dark hallow vessel-like regions in optical coherence tomography (OCT) cross sectional images. We propose an automatic method to segment lymphatic vessel lumen from OCT structural cross sections using eigenvalues of Hessian filters. Compared to the existing method based on intensity threshold, Hessian filters are more selective on vessel shape and less sensitive to intensity variations and noise. Using this segmentation technique along with optical micro-angiography allows label-free noninvasive simultaneous visualization of blood and lymphatic vessels in vivo. Lymphatic vessels play an important role in cancer, immune system response, inflammatory disease, wound healing and tissue regeneration. Development of imaging techniques and visualization tools for lymphatic vessels is valuable in understanding the mechanisms and studying therapeutic methods in related disease and tissue response. PMID- 23922126 TI - Relationship between obesity phenotypes and genetic determinants in a mouse model for juvenile obesity. AB - Obesity, a state of imbalance between lean mass and fat mass, is important for the etiology of diseases affected by the interplay of multiple genetic and environmental factors. Although genome-wide association studies have repeatedly associated genes with obesity and body weight, the mechanisms underlying the interaction between the muscle and adipose tissues remain unknown. Using 351 mice (at 10 wk of age) of an intercross population between Berlin Fat Mouse Inbred (BFMI) and C57BL/6NCrl (B6N) mice, we examined the causal relationships between genetic variations and multiple traits: body lean mass and fat mass, adipokines, and bone mineral density. Furthermore, evidence from structural equation modeling suggests causality among these traits. In the BFMI model, juvenile obesity affects lean mass and impairs bone mineral density via adipokines secreted from the white adipose tissues. While previous studies have indicated that lean mass has a causative effect on adiposity, in the Berlin Fat Mouse model that has been selected for juvenile obesity (at 9 wk of age) for >90 generations, however, the causality is switched from fat mass to lean mass. In addition, linkage studies and statistical modeling have indicated that quantitative trait loci on chromosomes 5 and 6 affect both lean mass and fat mass. These lines of evidence indicate that the muscle and adipose tissues interact with one another and the interaction is modulated by genetic variations that are shaped by selections. Experimental examinations are necessary to verify the biological role of the inferred causalities. PMID- 23922127 TI - Gene expression profiling of articular cartilage reveals functional pathways and networks of candidate genes for osteochondrosis in pigs. AB - Osteochondrosis (OC) is a joint disorder that frequently causes leg weakness in growing pigs, resulting in welfare problems and economic losses. We aimed to detect molecular pathways relevant to the emergence of the disease and to identify candidate genes for the liability to the disorder. Therefore, we compared microarray-based expression patterns of articular cartilage with (n=11) and without (n=11) histologically diagnosed OC lesions obtained from discordant sib-pairs. A total of 1,564 genes were found with different transcript abundance [differentially expressed (DE) genes] at q<=0.05. To further identify candidate genes, we integrated data from quantitative trait loci (QTL) and genome-wide association (GWA) studies with the expression analysis. We detected 317 DE genes within the QTL confidence intervals, of which 26 DE genes also overlapped GWA regions. Ingenuity Pathway Analysis suggests a pathogenic role of immune response, angiogenesis, and synthesis of extracellular matrix pathways for OC. These processes could facilitate the emergence of defects. But they may also promote the degradation of articular cartilage and the worsening of the disease. A functional network was derived that comprised genes with functional and positional clues of their role in bone and cartilage metabolisms and development, including extracellular matrix genes (e.g., LOX, OGN, and ASPN), angiogenesis genes (e.g., ANGPTL4 and PDGFA), and immune response genes (e.g., ICAM1, AZGP1, C1QB, C1QC, PDE4B, and CDA). The study identified molecular processes linked to OC and several genes with positional, genetic-statistical, and functional evidence for their role in the emergence of articular cartilage lesions and the liability to OC. PMID- 23922129 TI - Cell cycle arrest in a model of colistin nephrotoxicity. AB - Colistin (polymixin E) is an antibiotic prescribed with resurging frequency for multidrug resistant gram negative bacterial infections. It is associated with nephrotoxicity in humans in up to 55% of cases. Little is known regarding genes involved in colistin nephrotoxicity. A murine model of colistin-mediated kidney injury was developed. C57/BL6 mice were administered saline or colistin at a dose of 16 mg/kg/day in 2 divided intraperitoneal doses and killed after either 3 or 15 days of colistin. After 15 days, mice exposed to colistin had elevated blood urea nitrogen (BUN), creatinine, and pathologic evidence of acute tubular necrosis and apoptosis. After 3 days, mice had neither BUN elevation nor substantial pathologic injury; however, urinary neutrophil gelatinase-associated lipocalin was elevated (P = 0.017). An Illumina gene expression array was performed on kidney RNA harvested 72 h after first colistin dose to identify differentially expressed genes early in drug treatment. Array data revealed 21 differentially expressed genes (false discovery rate < 0.1) between control and colistin-exposed mice, including LGALS3 and CCNB1. The gene signature was significantly enriched for genes involved in cell cycle proliferation. RT-PCR, immunoblot, and immunostaining validated the relevance of key genes and proteins. This murine model offers insights into the potential mechanism of colistin mediated nephrotoxicity. Further studies will determine whether the identified genes play a causative or protective role in colistin-induced nephrotoxicity. PMID- 23922130 TI - The Addenbrooke's Cognitive Examination-Revised accurately detects cognitive decline in Huntington's disease. AB - Cognitive features, which begin before manifestation of the motor features, are an integral part of Huntington's disease and profoundly affect quality of life. A number of neuropsychological batteries have been used to assess this aspect of the condition, many of which are difficult to administer and time consuming, especially in advanced disease. We, therefore, investigated a simple and practical way to monitor cognition using the Addenbrooke's Cognitive Examination Revised (ACE-R) in 126 manifest Huntington's disease patients, 28 premanifest gene carriers and 21 controls. Using this test, we demonstrated a selective decrease in phonemic, but not semantic, fluency in premanifest participants Cognitive decline in manifest Huntington's disease varied according to disease severity with extensive cognitive decline observed in early-stage Huntington's disease patients, indicating that this would be an optimal stage for interventions designed to halt cognitive decline, and lesser changes in the advanced cases. We next examined cognitive performance in patients prescribed antidopaminergic drugs as these drugs are known to decrease cognition when administered to healthy volunteers. We paradoxically found that these drugs may be beneficial, as early-stage Huntington's disease participants in receipt of them had improved attention and Mini-Mental State Examination scores. In conclusion, this is the first study to test the usefulness of the ACE-R in a Huntington's disease population and demonstrates that this is a brief, inexpensive and practical way to measure global cognitive performance in clinical practice with potential use in clinical trials. PMID- 23922128 TI - Identification and comparative analyses of myocardial miRNAs involved in the fetal response to maternal obesity. AB - Human and animal studies show that suboptimal intrauterine environments lead to fetal programming, predisposing offspring to disease in later life. Maternal obesity has been shown to program offspring for cardiovascular disease (CVD), diabetes, and obesity. MicroRNAs (miRNAs) are small, noncoding RNA molecules that act as key regulators of numerous cellular processes. Compelling evidence links miRNAs to the control of cardiac development and etiology of cardiac pathology; however, little is known about their role in the fetal cardiac response to maternal obesity. Our aim was to sequence and profile the cardiac miRNAs that are dysregulated in the hearts of baboon fetuses born to high fat/high fructose-diet (HFD) fed mothers for comparison with fetal hearts from mothers eating a regular diet. Eighty miRNAs were differentially expressed. Of those, 55 miRNAs were upregulated and 25 downregulated with HFD. Twenty-two miRNAs were mapped to human; 14 of these miRNAs were previously reported to be dysregulated in experimental or human CVD. We used an Ingenuity Pathway Analysis to integrate miRNA profiling and bioinformatics predictions to determine miRNA-regulated processes and genes potentially involved in fetal programming. We found a correlation between miRNA expression and putative gene targets involved in developmental disorders and CVD. Cellular death, growth, and proliferation were the most affected cellular functions in response to maternal obesity. Thus, the current study reveals significant alterations in cardiac miRNA expression in the fetus of obese baboons. The epigenetic modifications caused by adverse prenatal environment may represent one of the mechanisms underlying fetal programming of CVD. PMID- 23922132 TI - Epigenetic mechanisms and developmental choice hierarchies in T-lymphocyte development. AB - Three interlocking problems in gene regulation are: how to explain genome-wide targeting of transcription factors in different cell types, how prior transcription factor action can establish an 'epigenetic state' that changes the options for future transcription factor action, and how directly a sequence of developmental decisions can be memorialized in a hierarchy of repression structures applied to key genes of the 'paths not taken'. This review uses the finely staged process of T-cell lineage commitment as a test case in which to examine how changes in developmental status are reflected in changes in transcription factor expression, transcription factor binding distribution across genomic sites, and chromatin modification. These are evaluated in a framework of reciprocal effects of previous chromatin structure features on transcription factor access and of transcription factor binding on other factors and on future chromatin structure. PMID- 23922133 TI - Picking or nibbling: frequency and associated clinical features in bulimia nervosa, anorexia nervosa, and binge eating disorder. AB - OBJECTIVE: Picking or ribbling (P&N) is a newly studied eating behavior characterized by eating in an unplanned and repetitious manner in between meals and snacks. This behavior seems to be related to poorer weight loss outcomes after bariatric surgery for weight loss in severely obese patients, but clarification is still required regarding its value in other clinical samples. The purpose of this study was to investigate the frequency of P&N across different eating disorder samples, as well as to examine its association with psychopathological eating disorder features. METHOD: Our sample included treatment-seeking adult participants, recruited for five different clinical trials: 259 binge eating disorder (BED); 264 bulimia nervosa (BN), and 137 anorexia nervosa (AN). Participants were assessed using the Eating Disorders Examination interview before entering the clinical trials. RESULTS: P&N was reported by 44% of the BED; 57.6% of the BN; and 34.3% of the AN participants. No association was found between P&N and BMI, the presence of compensatory behaviors, binge eating, or any of the eating disorder examination subscales. DISCUSSION: This study suggests that P&N behavior is highly prevalent across eating disorder diagnoses, but it is not associated with psychopathology symptoms or other eating disordered behaviors. PMID- 23922134 TI - Management of OAB in those over age 65. AB - The International Continence Society (ICS) defines overactive bladder (OAB) as an association of symptoms including "urgency, with or without urge incontinence, usually with increased frequency and nocturia". This conditon has been associated with a decrease in quality of life and a higher related risk of overall health condition decrease, and is rising since its prevalence increases with age and the forecast for the world population estimates an increase of those over 65 years old. Aging alone can be considered a major risk factor for developing OAB symptoms that are considered multifactorial and due to body tissue and anatomic changes, lifestyle-associated factors, comorbidities and personal characteristics. The high prevalence of this condition and multiple etiology factors makes of its treatment a challenge-especially in the older population. A major concern over OAB treatment of elderly patients is the risk of cognitive side effects due to the pharmacologic treatment with anticholinergic drugs. First line treatment for OAB symptoms are the use of pharmacologic therapy with antimuscarinic drugs, which has been proved to be effective in controlling urgency, urge incontinence episodes, incontinence episodes, and nocturia. The impact caused by this condition is significant regarding the economic and human costs associated bringing into attention the need of studying and reviewing this specific population. Conservative Management and Lifestyle Modifications: Behavioral therapy's aims are to reduce urinary frequency and urgency to an accepted level and to increase bladder outlet volume. It consists of actions to teach patients to improve and learn bladder control. Lifestyle modifications are a conjunct of daily activities that can be managed to have the lowest interference on the functioning of the urinary tract. Pharmacologic Therapy: There are various medications with antimuscarinic properties available for the treatment of OAB symptoms. The most commonly used are oxybutinin, tolterodine, solifenacin, darifenacin, fesosterodine and trospium. Second-line Therapy: OAB treatment accounts for some refractory to conventional treatment patients who will require alternative therapies to achieve improvement of symptoms as the use of intradetrusor injection of botulinum A toxin by binding to receptors on the membrane of cholinergic nerves causing temporary chemodenervation and consequent muscle relaxation. Neuromodulation is also an effective therapy that aims to achieve inhibition of detrusor activity by continuous neural stimulation through peripheral nerves as the use of the tibial nerve or central as it is performed by direct spine stimulation on sacral roots through the implantation of an automated generator. In conclusion, evidence from the literature has shown that antimuscarinic treatment of OAB in the elderly population is safe and effective in improving symptoms and patient's quality of life. Managing OAB symptoms in this population is a great challenge. An optimal therapeutic approach to treat should involve medical treatment with drug and behavioral therapy in addition to lifestyle advice. PMID- 23922143 TI - Antianginal therapy before percutaneous coronary intervention. AB - BACKGROUND: The regional variability of percutaneous coronary intervention (PCI) rates may be explained by variations in the medical treatment of stable coronary artery disease. We sought to determine whether greater regional use of antianginal medications in PCI patients is associated with lower regional rates of PCI. METHODS AND RESULTS: Using CathPCI Registry and Dartmouth Atlas data, we examined patients undergoing elective PCI for stable coronary artery disease from January 1, 2009, through March 31, 2011, and calculated rates of providing >= 2 antianginal medicines before PCI. We regressed the hospital referral region rates of PCI per 1000 Medicare enrollees in 2007 on the regions' rates of providing >= 2 antianginal medications before PCI. Among 300772 PCI procedures, 32.8%, 48.3%, 16.1%, and 2.8% of patients were on 0, 1, 2, or >= 3 antianginal medications, respectively. The median rate of providing >= 2 antianginal medications before PCI was 18.9%. Although substantial variability existed across hospital referral regions in providing >= 2 antianginal medications and in rates of PCI from the Dartmouth Atlas, there was no association between the rates of PCI in each hospital referral region and the rates of >= 2 antianginal medications before PCI (Spearman rho, 0.0277; P=0.64). CONCLUSIONS: We found no association between the intensity of antianginal therapy and the use of PCI across hospital referral regions, despite the variability of both. Opportunities likely exist in many regions to increase the use of antianginal therapy before proceeding to elective PCI, and more research is needed to explain observed variations in care. PMID- 23922144 TI - Comparison of bivalirudin and radial access across a spectrum of preprocedural risk of bleeding in percutaneous coronary intervention: analysis from the national cardiovascular data registry. AB - BACKGROUND: Bleeding is a common, noncardiac, preventable complication of percutaneous coronary intervention. We compared the relative safety of radial access and bivalirudin in percutaneous coronary intervention. METHODS AND RESULTS: From CathPCI Registry, we determined the association between the site of arterial access, bivalirudin, and periprocedural bleeding rates in 501 017 patients. Radial access patients receiving heparin (radial group) were compared with those receiving bivalirudin (radial combination group). Femoral access patients who had bivalirudin and a vascular closure device served as a reference group (femoral group). An inverse probability weighting analysis incorporating propensity scores was used to compare groups. The overall rate of bleeding was 2.59%. It was 2.71% in the femoral group, 2.5% in the radial group, and 1.82% in the radial combination groups (P<0.001). When compared with femoral group, the adjusted odds ratio for bleeding was significantly lower for patients with radial combination group (odds ratio, 0.79; 95% confidence interval, 0.72-0.86), but not for radial group (odds ratio, 0.96; 95% confidence interval, 0.88-1.05), unless patients treated with IIb/IIIa were excluded (radial group-IIb/IIIa odds ratio, 0.84; 95% confidence interval, 0.75-0.94).The number needed to treat to prevent 1 bleeding event with radial combination group was 138, whereas the number needed to treat to prevent 1 bleeding event in high-bleeding risk patients was 68. CONCLUSIONS: In this observational analysis, the combination of bivalirudin and radial access was associated with reduced bleeding event rate. This benefit was present across the entire spectrum of preprocedural risk of bleeding, with or without exposure to IIb/IIIa inhibitors. These data support an adequately powered randomized trial comparing bleeding avoidance strategies. PMID- 23922145 TI - Outcomes with various drug-eluting or bare metal stents in patients with ST segment-elevation myocardial infarction: a mixed treatment comparison analysis of trial level data from 34 068 patient-years of follow-up from randomized trials. AB - BACKGROUND: The efficacy and safety of drug-eluting stents (DES) in patients with ST-segment-elevation myocardial infarction (STEMI) is controversial. Consequently, DES implantation has a class IIa indication in the American College of Cardiology/American Heart Association and the European Society of Cardiology STEMI guidelines. METHODS AND RESULTS: PUBMED, EMBASE, and CENTRAL were searched for randomized clinical trials, until March 2013, comparing any of the 5 Food and Drug Administration-approved durable stent and polymer DES (sirolimus eluting stent, paclitaxel eluting stent, everolimus-eluting stent [EES], zotarolimus eluting stent, and zotarolimus-eluting stent resolute), against each other or bare metal stents (BMS), and enrolling >= 50 patients with STEMI. Efficacy (target vessel revascularization) and safety (death, myocardial infarction, and stent thrombosis) outcomes at the longest reported follow-up times were evaluated. Twenty-eight randomized clinical trials with 34 068 patient-years of follow-up on subjects with STEMI fulfilled the inclusion criteria. When compared with BMS (reference rate ratio [RR] of 1), sirolimus eluting stent (RR, 0.46; 95% credibility interval [CrI], 0.36-0.56), paclitaxel eluting stent (RR, 0.69; 95% CrI, 0.53-0.87), and EES (RR, 0.42; 95% CrI, 0.26-0.62) were associated with a statistically significant reduction in rate of target vessel revascularization, with the point estimate for zotarolimus-eluting stent resolute trending in a similar direction. There was no increase in the risk of death, myocardial infarction, or stent thrombosis with any DES compared with BMS. Moreover, EES was associated with a statistically significant reduction in the rate of stent thrombosis when compared with sirolimus eluting stent (RR, 0.38; 95% CrI, 0.21 0.74), paclitaxel eluting stent (RR, 0.39; 95% CrI, 0.21-0.73), and even BMS (RR, 0.42; 95% CrI, 0.23-0.76). There was a 74% probability that EES had the lowest rate of any stent thrombosis when compared with all other stent types (no data on zotarolimus-eluting stent resolute). There was no increase in very late stent thrombosis with EES versus BMS (RR, 0.89; 95% CrI, 0.09-8.67). CONCLUSIONS: In patients with STEMI, DES versus BMS was associated with substantial decrease in the risk of target vessel revascularization without compromising safety. EES had the added advantage of substantial reduction in the risk of stent thrombosis when compared with first-generation DES and BMS with no increase in very late stent thrombosis. PMID- 23922146 TI - Endovascular repair of type B aortic dissection: long-term results of the randomized investigation of stent grafts in aortic dissection trial. AB - BACKGROUND: Thoracic endovascular aortic repair (TEVAR) represents a therapeutic concept for type B aortic dissection. Long-term outcomes and morphology after TEVAR for uncomplicated dissection are unknown. METHODS AND RESULTS: A total of 140 patients with stable type B aortic dissection previously randomized to optimal medical treatment and TEVAR (n=72) versus optimal medical treatment alone (n=68) were analyzed retrospectively for aorta-specific, all-cause outcomes, and disease progression using landmark statistical analysis of years 2 to 5 after index procedure. Cox regression was used to compare outcomes between groups; all analyses are based on intention to treat. The risk of all-cause mortality (11.1% versus 19.3%; P=0.13), aorta-specific mortality (6.9% versus 19.3%; P=0.04), and progression (27.0% versus 46.1%; P=0.04) after 5 years was lower with TEVAR than with optimal medical treatment alone. Landmark analysis suggested a benefit of TEVAR for all end points between 2 and 5 years; for example, for all-cause mortality (0% versus 16.9%; P=0.0003), aorta-specific mortality (0% versus 16.9%; P=0.0005), and for progression (4.1% versus 28.1%; P=0.004); Landmarking at 1 year and 1 month revealed consistent findings. Both improved survival and less progression of disease at 5 years after elective TEVAR were associated with stent graft induced false lumen thrombosis in 90.6% of cases (P<0.0001). CONCLUSIONS: In this study of survivors of type B aortic dissection, TEVAR in addition to optimal medical treatment is associated with improved 5-year aorta-specific survival and delayed disease progression. In stable type B dissection with suitable anatomy, preemptive TEVAR should be considered to improve late outcome. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01415804. PMID- 23922147 TI - Effects of endothelial dysfunction on residual platelet aggregability after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease. AB - BACKGROUND: Dual antiplatelet therapy with aspirin and clopidogrel is widely used in patients with coronary stents. High residual platelet reactivity (high RPR) after dual antiplatelet therapy is associated with increased cardiovascular events. Endothelial function could affect platelet reactivity in vivo. We hypothesized that endothelial dysfunction could be associated with high RPR after dual antiplatelet therapy in patients with stable coronary artery disease. METHODS AND RESULTS: We screened patients with stable coronary artery disease for cytochrome P450 (CYP) 2C19 genotypes and enrolled 103 patients who lacked CYP2C19*2 or *3 loss-of-function allele to minimize the effect of this gene on high RPR. All patients received aspirin (100 mg/d) and clopidogrel (75 mg/d for long-term treatment or a loading dose of 300 mg) before the following tests. Platelet aggregability was assessed as P2Y12 reaction unit using the VerifyNow System. High RPR was defined as P2Y12 reaction unit >= 230. Peripheral endothelial function was expressed as reactive hyperemia index using reactive hyperemia peripheral arterial tonometry. Fifty-three patients exhibited high RPR. High RPR patients were significantly older, had higher levels of B-type natriuretic peptide, and were predominantly hypertensive compared with non-high RPR patients. Reactive hyperemia index was significantly lower in high RPR patients (0.46 +/- 0.15) compared with non-high RPR patients (0.61 +/- 0.18; P<0.001). Linear regression analysis demonstrated significant negative correlation between reactive hyperemia index and P2Y12 reaction unit (r=-0.32; P=0.001). Multivariable logistic regression analysis identified reactive hyperemia index as an independent and significant determinant of high RPR (odds ratio, 0.55; 95% confidence interval, 0.39-0.78; P=0.001). CONCLUSIONS: In patients with stable coronary artery disease, endothelial function was significantly impaired in high RPR patients. Endothelial dysfunction is independently correlated with high RPR after dual antiplatelet therapy. CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp/ctr. Unique identifier: UMIN000008239. PMID- 23922149 TI - (19) F NMR spectroscopy as a probe of cytoplasmic viscosity and weak protein interactions in living cells. AB - Protein mobility in living cells is vital for cell function. Both cytosolic viscosity and weak protein-protein interactions affect mobility, but examining viscosity and weak interaction effects is challenging. Herein, we demonstrate the use of (19) F NMR spectroscopy to measure cytoplasmic viscosity and to characterize nonspecific protein-protein interactions in living Escherichia coli cells. The origins of resonance broadening in Escherichia coli cells were also investigated. We found that sample inhomogeneity has a negligible effect on resonance broadening, the cytoplasmic viscosity is only about 2-3 times that of water, and ubiquitous transient weak protein-protein interactions in the cytosol play a significant role in governing the detection of proteins by using in-cell NMR spectroscopy. PMID- 23922150 TI - ICY 2012 highlights. PMID- 23922151 TI - Vascular proteomics--the forgotten blood vessels. PMID- 23922148 TI - Evaluating comparative effectiveness with observational data: endoscopic ultrasound and survival in pancreatic cancer. AB - BACKGROUND: A previous observational study reported that endoscopic ultrasound (EUS) is associated with improved survival in older patients with pancreatic cancer. The objective of this study was to reevaluate this association using different statistical methods to control for confounding and selection bias. METHODS: Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data (1992-2007) was used to identify patients with locoregional pancreatic cancer. Two-year survival in patients who did and did not receive EUS was compared by using standard Cox proportional hazards models, propensity score methodology, and instrumental variable analysis. RESULTS: EUS was associated with improved survival in both unadjusted (hazard ratio [HR] = 0.67, 95% confidence interval [CI] = 0.63-0.72) and standard regression analyses (HR = 0.78, 95% CI = 0.73 0.84) which controlled for age, sex, race, marital status, tumor stage, SEER region, Charlson comorbidity, year of diagnosis, education, preoperative biliary stenting, chemotherapy, radiation, and pancreatic resection. Propensity score adjustment, matching, and stratification did not attenuate this survival benefit. In an instrumental variable analysis, the survival benefit was no longer observed (HR = 1.00, 95% CI = 0.73-1.36). CONCLUSIONS: These results demonstrate the need to exercise caution in using administrative data to infer causal mortality benefits with diagnostic and/or treatment interventions in cancer research. PMID- 23922156 TI - Spontaneous sequential compartment syndrome of the lower limbs. AB - Spontaneous compartment syndrome is a rare condition and requires urgent surgical treatment to achieve favorable outcome. Several cases have been reported in the literature, and it has been associated with patients with diabetes. We present a case of acute spontaneous sequential compartment syndrome of the lower limbs in a patient with poorly controlled type 1 diabetes. PMID- 23922157 TI - Endovascular treatment of a malpositioned screw in the thoracic aorta after anterior spinal instrumentation: the screwed aorta. AB - An interesting case report detailing the management of an aorta that was inadvertently screwed during spinal fixation. The management and imaging encompass the use of computer tomography and intravascular ultrasound to determine the trajectory of the screw and the successful management of the patient. PMID- 23922158 TI - Treatment of primary infected juxtarenal aortic aneurysm with the multilayer stent. AB - PURPOSE: To report the use of multilayer uncovered stent to treat primary infected juxtarenal aortic aneurysm. CASE REPORT: A 50-year-old man was admitted to hospital for rapid onset of intractable abdominal pain and high fever. Computed tomographic scan showed 2 juxtarenal saccular aneurysms of abdominal aorta with morphologic and clinical changes compatible with infectious etiology. Patient was treated with multilayer flow-modulating stent. Follow-up imaging showed persistent aneurysm exclusion and continuous aneurysm shrinkage of the sac until complete regression to a normal aortic configuration was seen at 1 year. During follow-up (24 months), patient continued to do well, and there was no recurrence of infection. CONCLUSION: Multilayer stent appeared to be an acceptable treatment option for primary infected juxtarenal aortic aneurysms. Aneurysmal sac completely disappeared and visceral branches remained patent at 2 year follow-up. However, longer follow-up is necessary to evaluate the long-term patency of involved visceral arteries. PMID- 23922159 TI - Assessing needs and resources for the home visiting system in Alabama: a mixed methods approach. AB - The purpose of this article is to describe the initial assessment for the development of a home visiting (HV) system in a state with no existing system. We outline a mixed methods process where the quantitative component was used to identify the communities that possess "at-risk" profiles, and the qualitative component explored the resources and gaps in existing HV services. We employed a mixed methods approach, using six categories of indicators from quantitative secondary data sources to identify "at-risk" profiles for Alabama's 67 counties. A weighted score for each indicator was calculated and counties were ranked. Surveys and focus groups were conducted to further define resources and gaps of existing HV programs. The composite indicator scores identified 13 counties as having the highest level of risk. Five of these 13 communities had no HV home visitation services. Areas of focus for future HV system development include trust, communication, availability, cost, and timeliness. In this assessment related to the Alabama HV system, we used quantitative data to apply criteria to the indicators being measured and qualitative data to supplement the quantitative findings. We examined resources, gaps, program quality, and capacity of the existing HV programs in order to assist in the future development of the HV system and early childhood system. The methods presented in this paper have potential applications beyond HV programs and systems, including broader examinations of complex systems for service provision to the maternal and child health populations. PMID- 23922160 TI - Does additional prenatal care in the home improve birth outcomes for women with a prior preterm delivery? A randomized clinical trial. AB - Women with a history of a prior preterm birth (PTB) have a high probability of a recurrent preterm birth. Some risk factors and health behaviors that contribute to PTB may be amenable to intervention. Home visitation is a promising method to deliver evidence based interventions. We evaluated a system of care designed to reduce preterm births and hospital length of stay in a sample of pregnant women with a history of a PTB. Single site randomized clinical trial. Eligibility: >18 years with prior live birth >=20-<37 weeks gestation; <24 weeks gestation at enrollment; spoke and read English; received care at regional medical center. All participants (N = 211) received standard prenatal care. Intervention participants (N = 109) also received home visits by certified nurse-midwives guided by protocols for specific risk factors (e.g., depressive symptoms, abuse, smoking). Data was collected via multiple methods and sources including intervention fidelity assessments. Average age 27.8 years; mean gestational age at enrollment was 15 weeks. Racial breakdown mirrored local demographics. Most had a partner, high school education, and 62% had Medicaid. No statistically significant group differences were found in gestational age at birth. Intervention participants had a shorter intrapartum length of stay. Enhanced prenatal care by nurse-midwife home visits may limit some risk factors and shorten intrapartum length of stay for women with a prior PTB. This study contributes to knowledge about evidence based home visit interventions directed at risk factors associated with PTB. PMID- 23922161 TI - Family aggregation and risk factors of obsessive-compulsive disorders in a nationwide three-generation study. AB - BACKGROUND: This nationwide register-based study investigates how often obsessive compulsive disorders (OCD) with different age at diagnosis occur in affected families compared to control families. Furthermore, the study addresses the impact of certain risk factors, that is, sex, degree of urbanization, year of birth, and maternal and paternal age at birth. METHODS: A total of N = 2,057 child and adolescent psychiatric subjects born between 1952 and 2000 and registered in the Danish Psychiatric Central Research Register developed OCD before the age of 18. In addition, N = 6,055 controls without any psychiatric diagnosis before age 18 and matched for age, sex, and residential region were included. Psychiatric diagnoses were also obtained for the first-degree relatives as a part of the Danish Three-Generation Study. A family load component was obtained by using various mixed regression models. RESULTS: OCD occurred significantly more often in case than in control families. Having a mother, father, sibling, or an offspring with the disorder was proven to be a risk factor. Maternal age above 35 years, male sex by tendency, and ascending year of birth were associated with having OCD. Furthermore, case relatives did not develop OCD earlier than control relatives. The risk of OCD in the case probands was significantly increased when first-degree family members had either OCD, or tic disorders, or affective disorders, or anxiety disorders. CONCLUSIONS: These findings based on a very large and representative dataset provide further and very solid evidence for the high family aggregation of OCD. PMID- 23922162 TI - Accuracy of inhaler use in patients with chronic obstructive pulmonary disease. AB - Inaccurate use of medication inhalers can reduce effectiveness, patient adherence, and disease stability. Therefore, the accurate use of inhalers in patients with chronic obstructive pulmonary disease (COPD) is crucial. This cross sectional study evaluated 196 Korean patients with COPD for step-by-step accuracy of inhaler use with four different types of inhalers (metered-dose inhaler [MDI], Turbuhaler, Diskus, and HandiHaler); differences in accuracy levels by sociodemographic or clinical characteristics were evaluated. Descriptive statistics and t tests were used for data analysis. The proportion of patients with completely accurate inhaler use was low, ranging from 21.9% (Turbuhaler) to 46.2% (MDI). Errors with all types of inhalers were most commonly seen in the "breathing out" steps, before and after medication inhalation. Personalized nursing educational programs, correcting errors individually for each patient, could dramatically increase the accuracy of inhaler use and the effectiveness of the inhaled medications in patients with COPD. PMID- 23922165 TI - Contributions of Pauli repulsions to the energetics and physical properties computed in QM/MM methods. AB - Conventional combined quantum mechanical/molecular mechanical (QM/MM) methods lack explicit treatment of Pauli repulsions between the quantum-mechanical and molecular-mechanical subsystems. Instead, classical Lennard-Jones (LJ) potentials between QM and MM nuclei are used to model electronic Pauli repulsion and long range London dispersion, despite the fact that the latter two are inherently of quantum nature. Use of the simple LJ potential in QM/MM methods can reproduce minimal geometries and energies of many molecular clusters reasonably well, as compared to full QM calculations. However, we show here that the LJ potential cannot correctly describe subtle details of the electron density of the QM subsystem because of the neglect of Pauli repulsions between the QM and MM subsystems. The inaccurate electron density subsequently affects the calculation of electronic and magnetic properties of the QM subsystem. To explicitly consider Pauli interactions with QM/MM methods, we propose a method to use empirical effective potentials on the MM atoms. The test case of the binding energy and magnetic properties of a water dimer shows promising results for the general application of effective potentials to mimic Pauli repulsions in QM/MM calculations. PMID- 23922164 TI - Resveratrol mitigates isoflurane-induced neuroapoptosis by inhibiting the activation of the Akt-regulated mitochondrial apoptotic signaling pathway. AB - The inhalation anesthetic, isoflurane, induces learning and memory impairment. Mitochondrial dysfunction and oxidative stress are thought to play important roles in isoflurane-induced neuroapoptosis. In this study, we treated neuronal cells with isoflurane for 6 h. We found that isoflurane induced the opening of mitochondrial permeability transition pores, increased the levels of reactive oxygen species and the activation of caspase-3, and decreased the mitochondrial membrane potential and the intracellular calcium ion concentration. Resveratrol (RESV; trans-3,5,4'-trihydroxystilbene), a naturally occurring phytoalexin, is found at high concentrations in the skin of red grapes and red wine and has been demonstrated to have anti-infective, antioxidant and cardioprotective functions. Our findings demonstrated that the neuroprotective effects of RESV were independent on its direct radical scavenging properties. Following treatment of the cells with various concentrations of RESV, we found that RESV induced the expression of mitochondrial superoxide dismutase and catalase activity, and reduced mitochondrial oxidative stress and damage. The data from the present study demonstrate that RESV effectively protects neuronal cells from isoflurane induced cytotoxicity by activating the Akt signaling pathway. PMID- 23922166 TI - Molecular basis of the clinical features of Al-Awadi-Raas-Rothschild (limb/pelvis/uterus-hypoplasia/aplasia) syndrome (AARRS) and Fuhrmann syndrome. AB - This paper reviews the molecular basis of the clinical features of Al-Awadi-Raas Rothschild (limb/pelvis/uterus-hypoplasia-aplasia) (AARRS) syndrome and Fuhrmann syndrome. Human WNT7A mutations are also reviewed. Based on this review, these mutations will be classified into two main groups of phenotypes: Fuhrmann and AARRS phenotypes in which there is partial and complete loss of WNT7A functions, respectively. PMID- 23922167 TI - Hydrocolloid dressings for healing diabetic foot ulcers. AB - BACKGROUND: Foot ulcers in people with diabetes are a prevalent and serious global health issue. Wound dressings are regarded as important components of ulcer treatment, with clinicians and patients having many different types to choose from including hydrocolloid dressings. There is a range of different hydrocolloids available including fibrous-hydrocolloid and hydrocolloid (matrix) dressings. A clear and current overview of current evidence is required to facilitate decision-making regarding dressing use. OBJECTIVES: To compare the effects of hydrocolloid wound dressings with no dressing or alternative dressings on the healing of foot ulcers in people with diabetes. SEARCH METHODS: For this first update, in April 2013, we searched the following databases the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. There were no restrictions based on language or date of publication. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) that have compared the effects on ulcer healing of hydrocolloid with alternative wound treatments in the treatment of foot ulcers in people with diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: We included five studies (535 participants) in the review: these compared hydrocolloids with basic wound contact dressings, foam dressings, alginate dressings and a topical treatment. Meta-analysis of two studies indicated no statistically significant difference in ulcer healing between fibrous-hydrocolloids and basic wound contact dressings: risk ratio 1.01 (95% CI 0.74 to 1.38). One of these studies found that a basic wound contact dressing was more cost-effective than a fibrous-hydrocolloid dressing. One study compared a hydrocolloid-matrix dressing with a foam dressing and found no statistically significant difference in the number of ulcers healed. There was no statistically significant difference in healing between an antimicrobial (silver) fibrous-hydrocolloid dressing and standard alginate dressing; an antimicrobial dressing (iodine-impregnated) and a standard fibrous hydrocolloid dressing or a standard fibrous hydrocolloid dressing and a topical cream containing plant extracts. AUTHORS' CONCLUSIONS: Currently there is no research evidence to suggest that any type of hydrocolloid wound dressing is more effective in healing diabetic foot ulcers than other types of dressing or a topical cream containing plant extracts. Decision makers may wish to consider aspects such as dressing cost and the wound management properties offered by each dressing type e.g. exudate management. PMID- 23922168 TI - Assessment of myocardial damage by cardiac MRI in patients with anorexia nervosa. AB - OBJECTIVE: Cardiac damage is a major complication of anorexia nervosa (AN). The present study evaluated the prevalence of myocardial damage in patients with AN by cardiac magnetic resonance imaging (CMR). METHOD: This study was cross sectional and observational. Forty consecutive female patients with a diagnosis of AN and 28 healthy female subjects were evaluated from January 2007 to 2011 at the Department of Psychiatry (University of Istanbul, Istanbul, Turkey). Following enrollment in the study, participants underwent a cardiac evaluation, a physical examination, a standard electrocardiogram (ECG), an echocardiography and a CMR. RESULTS: Body weight, body mass index and heart rate values were lower in patients with AN than in the control group. When compared with control groups, patients with AN showed reduced left ventricular mass with normal systolic function. Compared to control subjects, patients with AN had higher prevalence of pericardial effusion (30% in the AN group, 4% in the control group, p = .005) and mitral valve prolapses (23% in the AN group, 4% in the control group, p = .03). Myocardial fibrosis (detected as late gadolinium enhancement on CMR) was found in 23% of patients with AN. Myocardial fibrosis was not detected in any control subject (p = .007). CONCLUSION: A strong association was found between myocardial fibrosis and AN. Cardiac damage of myocardial fibrosis in asymptomatic patients with AN can be found by CMR examination. PMID- 23922169 TI - Epidemiology of MRSA in southern Sweden: strong relation to foreign country of origin, health care abroad and foreign travel. AB - All notified MRSA cases in Skane County have been followed since 2000. We have investigated the MRSA epidemiology over time, method of acquisition, whether some spa types are more prone to spread, and/or cause more infections, and the connection between spa type and country of acquisition/origin. All cases between 2000 and 2010 were included. Infection or colonization and the presence of PVL genes were noted. The spa types of the index cases were correlated with community or healthcare acquisition, proportion of MRSA-positive household contacts, country of origin of families and country of acquisition of MRSA. The number of cases increased from 31 in 2000 to 315 in 2010. Most cases were community acquired and the median age was 30 years. Thirty-two per cent of the MRSA cases were found because of a clinical infection. Of the household contacts 35 % were MRSA-positive. Only 24 % of the MRSA cases were both of Swedish origin and had contracted MRSA in Sweden. An association between spa type and certain regions of acquisition/origin was noted. Spa types t044, t002 and t008 were the most predominant strains. PVL-positive spa types t008, t019 and t044 caused more skin infections than the other spa types. Our results support screening for MRSA in patients with health care contacts abroad, culturing of patients with skin infections contracted outside Sweden and performing contact tracing among household members. Knowledge of spa type might give guidance in the process of contact tracing. Eradication treatment of MRSA spa types causing more skin infections may be warranted. PMID- 23922170 TI - Pain sensitivity is normalized after a repeated bout of eccentric exercise. AB - PURPOSE: The purpose of this study was to investigate the effect of repeated bouts of eccentric exercise on the nociceptive withdrawal reflex (NWR) threshold, a measure of sensitivity in the spinal nociceptive system. METHODS: Sixteen healthy students (age 25.7 +/- 0.6 years, BMI 24.8 +/- 1 kg m(-2)) participated in this randomized, controlled, crossover study. Two identical bouts of high intensity eccentric exercises were performed on the tibialis anterior muscle 7 days apart. Control sessions involving no exercise were performed 4 weeks apart the exercise sessions. Pressure pain thresholds (PPT) and the NWR threshold were recorded before, immediately after, and 1 day after both bouts of exercise. RESULTS: Pressure pain thresholds decreased significantly at two of the muscle belly sites on the day after initial bout compared with baseline. NWR threshold decreased by 25 +/- 4 % immediately after initial bout and by 30 +/- 5 % the next day (p < 0.05) as an indication of generalized pain hypersensitivity. On the contrary, no changes were found in both pain thresholds after second bout of eccentric exercise indicating that both localized and generalized pain sensitivity were normalized. CONCLUSION: In conclusion, this study for the first time documented that an initial bout of unaccustomed high-intensity eccentric exercise, which results in muscle soreness can induce central sensitization. A repeated bout of exercise, however, facilitates inherent protective spinal mechanisms against the development of muscle soreness. PMID- 23922171 TI - Effects of feeding schedule changes on the circadian phase of the cardiac autonomic nervous system and serum lipid levels. AB - PURPOSE: The purpose of this study was to investigate whether scheduling meals earlier in the day affects the circadian phase of the cardiac autonomic nervous system as assessed by heart rate variability (HRV) and serum lipid levels. METHODS: Healthy men aged 21.4 +/- 0.5 years (n = 14) with a habit of regularly skipping breakfast participated in this parallel trial involving altered feeding schedules. Participants in the early mealtime group (EM group, n = 8) were asked to eat three meals at 8:00, 13:00, and 18:00, and the control group (n = 6) ate at 13:00, 18:00, and 23:00 for 2 weeks. On the measurement day before and after intervention, fasting blood samples and 24-h electrocardiograph recordings were collected. Spectral analysis was used for approximate 10-min HRV segments. Low frequency (LF) power, high frequency (HF) power, and the ratio of HF to total power (%HF) were calculated to assess sympathovagal balance. Acrophases of the circadian rhythm of HRV variables were obtained by nonlinear least squares regression. RESULTS: Triglyceride and total and LDL cholesterol levels were significantly decreased in the EM group when compared with the control group (p = 0.035, 0.008, and 0.004, respectively). Acrophases for HRV variables were advanced in the EM group and their difference between before and after the intervention in LF power (-3.2 +/- 1.2 h) and %HF (-1.2 +/- 0.5 h) reached significant level, respectively (p < 0.05). CONCLUSIONS: Timing of meals was a key factor in regulating circadian phases of the cardiac autonomic nervous system and lipid metabolism. PMID- 23922172 TI - Influence of CMV/EBV serostatus on respiratory infection incidence during 4 months of winter training in a student cohort of endurance athletes. AB - AIM: The purpose of this study was to examine the influence of previous infection with cytomegalovirus (CMV) or Epstein Barr virus (EBV) on the incidence, severity and duration of upper respiratory tract infections (URTIs) in endurance athletes during a 4-month winter training period. METHODS: Blood samples were obtained from 236 subjects (166 males and 70 females, aged 18-35 years) at the start of the study period. Plasma samples were analysed for CMV and EBV serostatus. Weekly training and daily illness logs were kept for the next 16 weeks. RESULTS: With regard to CMV/EBV serostatus, the results indicated that athletes with previous CMV infection (n = 58, 25 % of cohort) had significantly fewer URTI symptom days (median 2 vs. 4 days, p = 0.033) during the study period than those with no previous infection (n = 178, 75 %), whereas positive EBV serostatus (n = 197, 84 %) had no influence on URTI episode incidence, severity or duration. Moreover, we found that athletes with prior infection of both CMV and EBV (n = 50, 21 %) had 50 % fewer URTI episodes (p = 0.04) and symptom days (median 2 vs 8 days, p = 0.01) than athletes who were seronegative for both CMV and EBV (n = 31, 13 %). CONCLUSIONS: Previous coinfection with CMV and EBV might promote protective immune surveillance to lower the risk of URTI. Further research is required to clarify why previous CMV and EBV infection reduces the incidence of URTI. PMID- 23922173 TI - Lenalidomide performance in the real world: patterns of use and effectiveness in a Medicare population with myelodysplastic syndromes. AB - BACKGROUND: Lenalidomide is approved for the treatment of anemia with transfusion dependence (TD) in patients with lower-risk myelodysplastic syndrome (MDS) with 5q deletion (del5q-MDS), but its "real-life" use and effect on transfusion needs are unclear. In the current study, the authors examined its use in the Medicare population. METHODS: Patients with MDS who were enrolled in Medicare Parts A, B, and D were identified using International Classification of Diseases 9-Clinical Modification (ICD-9) codes from 100% Medicare claims from 2006 through 2008. Patients were followed until the end of the study or death. Claims were used to determine time to initiation of lenalidomide, daily dose, duration, and other MDS therapies. Transfusion status was defined each week based on transfusion use in rolling 8-week period: TD, required transfusions during 2 weeks, separated by >= 3 weeks; transfusion user (TU), 1 transfusion; and transfusion independence (TI), no transfusions. RESULTS: A total of 753 of 23,855 patients (3.2%) received lenalidomide, including 31% of 470 patients with del5q-MDS. At the time of lenalidomide initiation, 33% of patients were TD, 31% were TU, and 36% were TI. The median time to lenalidomide initiation was shorter for patients with del5q MDS than for other lower-risk patients (8 weeks vs 20 weeks; P < .01). The percentage of patients with del5q-MDS receiving lenalidomide increased over time. Lenalidomide initiation was found to be negatively associated with older age and baseline diabetes, stroke, and renal disease. During the observation period, 44% of TU/TD patients (53% of the patients with del5q-MDS) achieved reductions in transfusion use; among TD patients receiving >= 3 cycles, 77% reduced their transfusion use and 40% achieved TI. CONCLUSIONS: To the authors' knowledge, the current study is the first report of lenalidomide use in a large Medicare enrolled population with MDS. Reductions in transfusion rates were overall consistent with data from clinical trials. Response rates were higher when >= 3 lenalidomide cycles were received. PMID- 23922174 TI - Antitumor activity of a polysaccharide fraction from Laminaria japonica on U14 cervical carcinoma-bearing mice. AB - In the present study, we investigated the in vitro and in vivo antitumor effects of a sulfated polysaccharide fraction from the brown alga Laminaria japonica (LJSP) on cervical carcinoma. In vitro, the results showed that LJSP exhibited the highest cell growth inhibitory effect on cervical carcinoma U14 cells among five tumor cell lines. In vivo, the results showed that LJSP could not only inhibit the growth of the tumor but also enhance the spleen and thymus indexes, as well as the body weight of U14 tumor-bearing mice. Moreover, the white blood cell count of H22 tumor-bearing mice showed no change in the LJSP-treated groups and little toxicological effects were observed on hepatic function and renal function in LJSP-treated mice bearing U14 tumor cells. Besides, LJSP induced apoptosis of transplanted tumor tissues by increasing the ratio of Bax/Bcl-2. These data showed that LJSP exhibited prominent antitumor activities and low toxic effects; thus, it could be developed to a safe and effective anticancer agent. PMID- 23922176 TI - On time-frequency techniques in biomedical signal analysis. PMID- 23922175 TI - Glucose-regulated protein 78 mediates hormone-independent prostate cancer progression and metastasis through maspin and COX-2 expression. AB - Glucose-regulated protein 78 (GRP78) plays an essential role in embryonic development and in the progression and therapeutic resistance of many cancers. However, little is known about the function of GRP78 in hormone-independent prostate cancer. Here, we found that the expression levels of GRP78 were higher in PC-3 cells than in DU-145 cells. When the expression of GRP78 was silenced using a GRP78-specific small interfering RNA in PC-3 cells, the growth rate and adhesive ability were reduced. Cell migration was dramatically decreased in GRP78 depleted cells. Dissection of the involved signal pathways revealed that maspin expression was upregulated after silencing GRP78 expression. The upregulation of maspin and downregulation of COX-2 may cause the decrease in cell proliferation and migration observed after silencing GRP78 expression. Silencing GRP78 expression may suppress the proliferation, adhesion, and migration of prostate cancer cells via maspin and COX-2 regulation. PMID- 23922177 TI - Discussion of "time-frequency techniques in biomedical signal analysis: a tutorial review of similarities and differences". PMID- 23922178 TI - GMDS 2012 - medical informatics, medicine and neighboring disciplines. PMID- 23922179 TI - Effects of alcohol on attentional mechanisms involved in figure reversals. AB - OBJECTIVE: The impairing effects of alcohol on attention are well documented and are thought to involve inhibitory mechanisms. We used ambiguous figures (Face Vase and Necker cube) to test whether the intentional control mechanism is more vulnerable to the effects of alcohol than the automatic mechanism. METHOD: Participants were assigned to an alcohol (Study 1, N = 15; Study 2, N = 18), placebo (Study 1, N = 15; Study 2, N = 20) or control (Study 1 only, N = 10) group. The doses of alcohol were 0.8 g/kg for men and 0.75 g/kg for women. Participants were shown the Face-Vase and Necker cube figures and two variants of each, which were biased in varying degrees towards one interpretation. Study 1 assessed the automatic control mechanism by asking participants to report spontaneous reversals. Study 2 assessed the intentional control mechanism by asking participants to increase reversal rate. RESULTS: In Study 1, reversal rate was similar for all groups, whereas in Study 2, the alcohol group reported more reversals than the control group, although this was true only for the biased versions of the Face-Vase illusion. CONCLUSIONS: The effect of alcohol on reversal rate is observed only during intentional reversals of semantically meaningful stimuli and only when the stimulus is biased. PMID- 23922180 TI - Pharmaceutical enhancement and medical professionals. AB - Emerging data indicates the prevalence and increased use of pharmaceutical enhancements by young medical professionals. As pharmaceutical enhancements advance and become more readily available, it is imperative to consider their impact on medical professionals. If pharmaceutical enhancements augment a person's neurological capacities to higher functioning levels, and in some situations having higher functioning levels of focus and concentration could improve patient care, then might medical professionals have a responsibility to enhance? In this paper, I suggest medical professionals may have a responsibility to use pharmaceutical enhancements. In some situations, having higher functioning levels of focus and concentration is conducive to providing the best possible care to a patient. In these circumstances medical professionals should use pharmaceutical cognitive enhancements. I conclude by examining the limitations and implications of this responsibility in the practice of medicine and areas for future research. PMID- 23922181 TI - Control of Exchange Interactions in pi Dimers of 6-Oxophenalenoxyl Neutral pi Radicals: Spin-Density Distributions and Multicentered-Two-Electron Bonding Governed by Topological Symmetry and Substitution at the 8-Position. AB - The tri-tert-butylphenalenyl (TBPLY) radical exists as a pi dimer in the crystal form with perfect overlapping of the singly occupied molecular orbitals (SOMOs) causing strong antiferromagnetic exchange interactions. 2,5-Di-tert-butyl-6 oxophenalenoxyl (6OPO) is a phenalenyl-based air-stable neutral pi radical with extensive spin delocalization and is a counter analogue of phenalenyl in terms of the topological symmetry of the spin density distribution. X-ray crystal structure analyses showed that 8-tert-butyl- and 8-(p-XC6H4)-6OPOs (X=I, Br) also form pi dimers in the crystalline state. The pi-dimeric structure of 8-tert-butyl 6OPO is seemingly similar to that of TBPLY even though its SOMO-SOMO overlap is small compared with that of TBPLY. The 8-(p-XC6H4) derivatives form slipped stacking pi dimers in which the SOMO-SOMO overlaps are greater than in 8-tert butyl-6OPO, but still smaller than in TBPLY. The solid-state electronic spectra of the 6OPO derivatives show much weaker intradimer charge-transfer bands, and SQUID measurements for 8-(p-BrC6H4)-6OPO show a weak antiferromagnetic exchange interaction in the pi dimer. These results demonstrate that the control of the spin distribution patterns of the phenalenyl skeleton switches the mode of exchange interaction within the phenalenyl-based pi dimer. The formation of the relevant multicenter-two-electron bonds is discussed. PMID- 23922182 TI - Higher persistence in newly diagnosed nonvalvular atrial fibrillation patients treated with dabigatran versus warfarin. AB - BACKGROUND: Oral anticoagulation therapy is the primary tool in reducing stroke risk in patients with nonvalvular atrial fibrillation but is underused. Patients nonpersistent with therapy contribute to this underuse. The objective of this study was to compare persistence rates in newly diagnosed nonvalvular atrial fibrillation patients treated with warfarin versus dabigatran as their oral anticoagulation. METHODS AND RESULTS: US Department of Defense administrative claims were used to identify patients receiving warfarin or dabigatran between October 28, 2010, and June 30, 2012. Patient records were examined for a minimum of 12 months before index date to restrict the analyses to those newly diagnosed with nonvalvular atrial fibrillation and naive-to-treatment, identifying 1775 on warfarin and 3370 on dabigatran. Propensity score matching was used to identify 1745 matched pairs. Persistence was defined as time on therapy to discontinuation. Kaplan-Meier curves were used to depict persistence over time. Cox proportional hazards model was used to determine the factors significantly associated with persistence. Using a 60-day permissible medication gap, the persistence rates were higher for dabigatran than for warfarin at both 6 months (72% versus 53%) and 1 year (63% versus 39%). Patients on dabigatran with a low to-moderate risk of stroke (CHADS2<2) or with a higher bleed risk (HEMORR2HAGES>3) had a higher likelihood of nonpersistence (hazard ratios, 1.37; 95% confidence interval, 1.17-1.60; P<0.001; and hazard ratios, 1.24; 95% confidence interval, 1.04-1.47; P=0.016). CONCLUSIONS: Patients who initiated dabigatran treatment were more persistent than patients who began warfarin treatment. Within each cohort, patients with lower stroke risk were more likely to discontinue therapy. PMID- 23922183 TI - Immunoelectron microscopic observation of connexin43 in rat odontoblasts. AB - Gap junctions play an important role in differentiation of odontoblasts. Gap junction protein, connexin 43 is expressed in odontoblast. However, the detailed localization in odontoblasts has yet to be fully investigated. We investigated the localization of connexin43 in rat odontoblasts immuno-electron microscopically. The rats were transcardially fixed with 1% paraformaldehyde in 0.1M phosphate buffer, and mandibles were decalcified with 10% ethylenediamine tetraacetic acid. Pre-embedding method was carried out for immuno-electron microscopic analysis. Microscopically, gap junctions were localized between bodies of odontoblasts, and between bodies and processes of odontoblasts. The gap junctions were labeled with gold particles that indicated connexin43. These results suggest that gap junctions between odontoblasts are definitely composed of connexin43 in rats, and our methods used in this study is useful to investigate localization of connexin43 immuno-electron microscopically. PMID- 23922184 TI - Combined treatment for facial rejuvenation using an optimized pulsed light source followed by a fractional non-ablative laser. AB - BACKGROUND: Combination laser treatments can potentially increase the effectiveness of treatment without the additional downtime associated with another procedure. OBJECTIVE: To assess the effectiveness and safety of combining non-ablative fractional treatments with optimized intense pulsed light. METHODS AND MATERIALS: Ten subjects (Group A) received full face treatments with a non ablative fractional either followed or preceded by an optimized intense pulsed light source. Twenty-six subjects (Group B) received only full face treatments with the same non-ablative, fractional laser device. RESULTS: For Group A, the overall average Fitzpatrick Wrinkle Scale for all patients improved from 6.3 +/- 1.1 at baseline to 5.9 +/- 0.8 one month following one treatment for an average improvement of 0.4 +/- 0.6 (P < 0.10 paired t-test n = 9). The average pigment improvement score was 1.8 +/- 0.9 on a 4-point scale. In Group B, the average Fitzpatrick Wrinkle Scale improved from 6.0 +/- 1.6 at baseline to 5.2 +/- 1.4 at 3 months for an average improvement of 0.8 +/- 0.7 (P < 0.001, n = 26 paired t test). The average pigment improvement score was 1.4 +/- 1.0 (P < 0.001, t-test, n = 26). Adverse events were similar in the two groups. CONCLUSION: The combination of an optimized intense pulsed light source with a non-ablative fractional laser during the same treatment session is safe and effective. PMID- 23922185 TI - Present features and future vision of laparoscopy-assisted total gastrectomy (LATG). PMID- 23922186 TI - Nitrates for acute heart failure syndromes. AB - BACKGROUND: Current drug therapy for acute heart failure syndromes (AHFS) consists mainly of diuretics supplemented by vasodilators or inotropes. Nitrates have been used as vasodilators in AHFS for many years and have been shown to improve some aspects of AHFS in some small studies. The aim of this review was to determine the clinical efficacy and safety of nitrate vasodilators in AHFS. OBJECTIVES: To quantify the effect of different nitrate preparations (isosorbide dinitrate and nitroglycerin) and the effect of route of administration of nitrates on clinical outcome, and to evaluate the safety and tolerability of nitrates in the management of AHFS. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (1950 to July week 2 2011) and EMBASE (1980 to week 28 2011). We searched the Current Controlled Trials MetaRegister of Clinical Trials (compiled by Current Science) (July 2011). We checked the reference lists of trials and contacted trial authors. We imposed no language restriction. SELECTION CRITERIA: Randomised controlled trials comparing nitrates (isosorbide dinitrate and nitroglycerin) with alternative interventions (frusemide and morphine, frusemide alone, hydralazine, prenalterol, intravenous nesiritide and placebo) in the management of AHFS in adults aged 18 and over. DATA COLLECTION AND ANALYSIS: Two authors independently performed data extraction. Two authors performed trial quality assessment. We used mean difference (MD), odds ratio (OR) and 95% confidence intervals (CI) to measure effect sizes. Two authors independently assessed and rated the methodological quality of each trial using the Cochrane Collaboration tool for assessing risk of bias. MAIN RESULTS: Four studies (634 participants) met the inclusion criteria. Two of the included studies included only patients with AHFS following acute myocardial infarction (AMI); one study excluded patients with overt AMI; and one study included participants with AHFS with and without acute coronary syndromes.Based on a single study, there was no significant difference in the rapidity of symptom relief between intravenous nitroglycerin/N-acetylcysteine and intravenous frusemide/morphine after 30 minutes (fixed-effect MD -0.30, 95% CI -0.65 to 0.05), 60 minutes (fixed-effect MD -0.20, 95% CI -0.65 to 0.25), three hours (fixed-effect MD 0.20, 95% CI -0.27 to 0.67) and 24 hours (fixed-effect MD 0.00, 95% CI -0.31 to 0.31). There is no evidence to support a difference in AHFS patients receiving intravenous nitrate vasodilator therapy or alternative interventions with regard to the following outcome measures: requirement for mechanical ventilation, systolic blood pressure (SBP) change after three hours and 24 hours, diastolic blood pressure (DBP) change after 30, 60 and 90 minutes, heart rate change at 30 minutes, 60 minutes, three hours and 24 hours, pulmonary artery occlusion pressure (PAOP) change after three hours and 18 hours, cardiac output (CO) change at 90 minutes and three hours and progression to myocardial infarction. There is a significantly higher incidence of adverse events after three hours with nitroglycerin compared with placebo (odds ratio 2.29, 95% CI 1.26 to 4.16) based on a single study. There was no consistent evidence to support a difference in AHFS patients receiving intravenous nitrate vasodilator therapy or alternative interventions with regard to the following secondary outcome measures: SBP change after 30 and 60 minutes, heart rate change after 90 minutes, and PAOP change after 90 minutes. None of the included studies reported healthcare costs as an outcome measure. There were no data reported by any of the studies relating to the acceptability of the treatment to the patients (patient satisfaction scores).Overall there was a paucity of relevant quality data in the included studies. Assessment of overall risk of bias in these studies was limited as three of the studies did not give sufficient detail to allow assessment of potential risk of bias. AUTHORS' CONCLUSIONS: There appears to be no significant difference between nitrate vasodilator therapy and alternative interventions in the treatment of AHFS, with regard to symptom relief and haemodynamic variables. Nitrates may be associated with a lower incidence of adverse effects after three hours compared with placebo. However, there is a lack of data to draw any firm conclusions concerning the use of nitrates in AHFS because current evidence is based on few low-quality studies. PMID- 23922188 TI - MRT letter: high resolution SEM imaging of nano-architecture of cured urea formaldehyde resin using plasma coating of osmium. AB - Nanoarchitecture of cured urea-formaldehyde (UF) resins was examined with a field emission scanning electron microscope (FE-SEM) after coating samples with osmium, which is considered to produce particles of considerably smaller size compared to other metal coatings used in SEM studies. This method enabled comparison of the nanoarchitecture of UF resins of low (1.0) and high (1.6) formaldehyde/urea (F/U) mole ratios to be made, based on imaging of extremely small size particles as part of UF resin architecture, not described before. Imaging revealed presence of relatively large globular particles (148.084-703.983 nm size range) as well as smaller substructures (28.004-39.604 nm size range) as part of the architecture of 1.0-mole UF resin. Globular particles were also present in 1.6 mole UF resin, but of considerably smaller size (14.760-50.269 nm). The work presented demonstrates usefulness of osmium coating in unraveling the intricacies of the nanostructural organization of cured UF resins, prompting wider application of this immensely useful but grossly underutilized metal coating type in high resolution SEM examination of biological and materials samples. PMID- 23922187 TI - A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701. AB - BACKGROUND: Rituximab combined with chemotherapy has improved the survival of previously untreated patients with follicular lymphoma (FL). Nevertheless, many patients neither want nor can tolerate chemotherapy, leading to interest in biological approaches. Epratuzumab is a humanized anti-CD22 monoclonal antibody with efficacy in relapsed FL. Because both rituximab and epratuzumab have single agent activity in FL, the antibody combination was evaluated as initial treatment of patients with FL. METHODS: Fifty-nine untreated patients with FL received epratuzumab 360 mg/m2 with rituximab 375 mg/m2 weekly for 4 induction doses. This combination was continued as extended induction in weeks 12, 20, 28, and 36. Response assessed by computed tomography was correlated with clinical risk factors, [18F]fluorodeoxyglucose positron emission tomography findings at week 3, Fcgamma polymorphisms, immunohistochemical markers, and statin use. RESULTS: Therapy was well-tolerated, with toxicities similar to expected with rituximab monotherapy. Fifty-two (88.2%) evaluable patients responded, including 25 complete responses (42.4%) and 27 partial responses (45.8%). At 3 years follow up, 60% of patients remain in remission. Follicular Lymphoma International Prognostic Index (FLIPI) risk strongly predicted progression-free survival (P = .022). CONCLUSIONS: The high response rate and prolonged time to progression observed with this antibody combination are comparable to those observed after standard chemoimmunotherapies and further support the development of biologic, nonchemotherapeutic approaches for these patients. PMID- 23922189 TI - What is normal femoral head/neck anatomy? An analysis of radial CT reconstructions in adolescents. AB - BACKGROUND: Cam morphology in femoroacetabular impingement has been implicated in the development of osteoarthritis. The alpha angle and femoral head/neck offset are widely used to determine femoral head asphericity. To our knowledge, no study has evaluated the alpha angle circumferentially using three-dimensional imaging in a population of healthy individuals of adolescent age. QUESTIONS/PURPOSES: We sought to (1) determine normal values for the alpha angle in adolescents, (2) define the location along the neck with the highest alpha angle, and (3) determine normal femoral head and neck radii and femoral head/neck offset. METHODS: Fifty CT scans from a database of scans obtained for reasons not related to hip pain were studied. The average age of the subjects was 15 years (range, 14 16 years). Alpha angle and femoral head/neck offset were measured circumferentially. RESULTS: The alpha angle averaged 40.66 +/- 4.46 mm for males and 37.77 +/- 5.65 mm for females. The alpha angle generally was highest between the 11:40 and 12:40 o'clock and between the 6:00 and 7:40 o'clock positions. The femoral head radius was 24.53 +/- 1.74 mm for males and 21.94 +/- 1.13 mm for females, and the femoral neck radius was 16.14 +/- 2.32 mm for males and 13.82 +/ 2.38 mm for females. The mean femoral head/neck offset was 8.39 +/- 1.97 mm for males and 8.13 +/- 2.27 mm for females. CONCLUSIONS: In this healthy population of 14- to 16-year-old subjects, the highest alpha angle was at the superior and inferior aspects of the heads rather than at the anterosuperior aspect. This information will provide benchmark values for distinction between normal and abnormal morphologic features of the femoral head. PMID- 23922190 TI - The interaction of synesthetic and print color and its relation to visual imagery. AB - Synesthetic color induced by graphemes is well understood to be an automatic perceptual phenomenon paralleling print color in some ways, but also differing in others. We addressed this juxtaposition by asking how synesthetes are affected by synesthetic and print colors that are the same. We tested two groups of grapheme color synesthetes using a basic color-priming method in which a grapheme prime was presented, followed by a color patch (probe), the color of which was to be named as quickly and accurately as possible. The primes induced either no color, print color only, synesthetic color only, or both forms of color (e.g., a letter "A" printed in red that also triggered synesthetic red). As expected, responses to name the probe color were faster if it was congruent with the prime color than if it was incongruent. The new finding (Exp. 1) was that a prime that induced the same print and synesthetic colors led to substantially larger priming effects than did either type of color individually, an effect that could not be attributed to semantic priming (Exp. 2). In addition, the synesthesia effects correlated with a standard measure of visual imagery. These findings are discussed as being consistent with the hypothesis that print and synesthetic color converge on similar color mechanisms. PMID- 23922191 TI - Synchronous telehealth technologies in psychotherapy for depression: a meta analysis. AB - BACKGROUND: Many patients suffering from depression lack immediate access to care. The use of synchronous telehealth modalities to deliver psychotherapy is one solution to this problem. This meta-analysis examined differences in treatment efficacy for psychotherapy administered via synchronous telehealth as compared to standard nontelehealth approaches. METHOD: We located 14 articles that met inclusion criteria of the use of a synchronous telehealth modality for treatment compared to a standard nontelehealth modality comparison group. RESULTS: Overall, a statistically significant systematic difference between modes of delivery was not identified (g = 0.14, SE = 0.08, 95% CI = [-0.03, 0.30], P = .098, I(2) = 49.74%). Stratification methods and metaregression were used to analyze the contributions of type of comparison group, intervention modality, and targeted mental health outcome to moderation of effect size (ES) estimates and heterogeneity. Type of comparison group (face-to-face versus care-as-usual) had the strongest influence on observed heterogeneity and moderated the summary ES. The only detectable difference in efficacy was restricted to studies that used care-as-usual as the comparison group (g = 0.29, SE = 0.06, 95% CI = [0.16, 0.41], P < .001, I(2) = 5.14%). CONCLUSIONS: Overall, we found no evidence to suggest that the delivery of psychotherapy via synchronous telehealth modalities is less effective than nontelehealth means in reducing depression symptoms. PMID- 23922192 TI - Safety and efficacy of transdermal buprenorphine for the relief of cancer pain. AB - PURPOSE: This study aimed to synthesize the available evidence on the efficacy and safety of transdermal (TD) buprenorphine. METHODS: We searched studies in electronic databases. Randomized controlled trials (RCTs) assessing the efficacy of TD buprenorphine comparing with placebo or other comparator drug in relieving cancer pain were included. The primary end points are patient-reported pain intensity and pain relief. For dichotomous data, the summary relative risk (RR) and its 95 % confidence interval (CI) were derived using random-effect model in view of heterogeneity testing. RESULTS: Eight clinical trials (n = 909) were included in the analysis. Only a few studies reported the same outcome in similar way, which created difficulty in the pooling of outcome data. Two studies (n = 288) assessed 'responders' and showed a significant difference between TD buprenorphine and placebo in all three doses of TD buprenorphine, 35.5, 52.5, or 70 MUg/h (RR 1.74, 95 % CI 1.31-2.32; I (2) 0 %); the numbers-needed-to-treat was 5.8 (3.9-11). Two studies (n = 331) showed a comparable requirement for rescue SL buprenorphine between TD buprenorphine and placebo (RR 1.25, 95 % CI 0.84-1.88; I (2) 0 %). The preferred outcome measure '50 % pain relief' was not reported in any included studies. On the basis of summary quality, further research is likely to have an important impact on our confidence in the estimate. CONCLUSION: Transdermal buprenorphine has an increasing role for the relief of cancer pain. Further research in this field is needed. Multicentre studies in this field using a common protocol and strict supervision will be more practicable. PMID- 23922195 TI - CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis. AB - The aim of this study was to summarize results on the association of cytotoxic T lymphocyte antigen-4 (CTLA-4) promoter exon-1 +49 and 1722T/C polymorphism with systemic lupus erythematosus (SLE) susceptibility by using the meta-analysis. We searched all the publications about the association between CTLA-4) promoter exon 1 +49 and 1722T/C polymorphism and SLE from PubMed, Elsevier Science Direct, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), and Wanfang (Chinese). Previous CTLA-4 association studies with SLE, however, have produced inconsistent results. We have performed a meta analysis to better assess the purported associations. A total of 17 independent studies (to June 2012) testing association between one or more CTLA-4 polymorphisms and SLE were used in this analysis. We have compared allele and genotype frequencies at two polymorphic sites found in exon-1 (at +49) and the promoter region (at -1722). The data demonstrate that the exon-1 +49 polymorphism is associated with SLE susceptibility in Asian population. The overall risk, measured by odds ratio (OR), stratification by ethnicity indicates the exon-1 +49 GG+GA genotype is associated with SLE, at least in Asians (OR = 0.85, 95 % CI = 0.73-0.99, P = 0.04 for GG+GA vs. AA; OR = 0.85, 95 % CI = 0.72-1.00, P = 0.05 for AG vs. AA). Similar trends are found in allele-specific risk estimates and disease association. Overall, there was significant association between the 1722T/C polymorphism and overall SLE risks (OR = 0.78, 95 % CI = 0.63-0.97, P = 0.04 for GG+GA vs. AA, OR = 0.87, 95 % CI = 0.76-0.99, P = 0.04 for G vs. A) in Asian population.In summary, this meta-analysis demonstrates that the CTLA-4 promoter +49A/G and promoter -1722C/T polymorphism may confer susceptibility to SLE, especially in Asian-derived population. PMID- 23922197 TI - Structural chromosomal abnormalities detected during CVS analysis and their role in the prenatal ascertainment of cryptic subtelomeric rearrangements. AB - Mosaic structural chromosomal abnormalities observed along the trophoblast mesenchyme-fetal axis, although rare, pose a difficult problem for their prognostic interpretation in prenatal diagnosis. Additional issues are raised by the presence of mosaic imbalances of the same chromosome showing different sizes in the different tissues, that is, deletions and duplications in the cytotrophoblast and mesenchyme of chorionic villi (CV). Some of these cytogenetic rearrangements originate from the post-zygotic breakage of a dicentric chromosome or of the product of its first anaphasic breakage. Selection of the most viable cell line may result in confined placental mosaicism of the most severe imbalance, favoring the presence of the cell lines with the mildest duplications or deletions in the fetal tissues. We document three cases of ambiguous results in CV analysis due to the presence of different cell lines involving structural rearrangements of the same chromosome which were represented differently in the trophoblast and the mesenchyme. Observation by conventional karyotype of a grossly rearranged chromosome in one of the CV preparations (direct or culture) was crucial to call attention to the involved chromosomal region in other tissues (villi or amniotic fluid), allowing the prenatal diagnosis through molecular cytogenetic methods of subtelomeric rearrangements [del(7)(q36qter); del(11)(q25qter); del(20)(p13pter)]. This would have surely been undiagnosed with the routine banding technique. In conclusion, the possibility to diagnose complex abnormalities leading to cryptic subtelomeric rearrangements, together with a better knowledge of the initial/intermediate products leading to the final abnormal cryptic deletion should be added to the advantages of the CV sampling technique. PMID- 23922196 TI - Association of NADPH oxidase p22phox gene C242T, A640G and -930A/G polymorphisms with primary knee osteoarthritis in the Greek population. AB - Osteoarthritis (OA) is the most common form of arthritis with still unknown pathogenic etiology and considerable contribution of genetic factors. Recently, a new emerging role of oxidative stress in the pathology of OA has been reported, lacking however elucidation of the underlying mechanism. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase being a complex enzyme produced by chondrocytes, presents the major source of reactive oxygen species and main contributor of increased oxidative stress. The present study aims to evaluate the association of NADPH oxidase p22phox gene C242T, A640G and -A930G polymorphisms with primary knee OA in the Greek population. One hundred fifty five patients with primary symptomatic knee OA participated in the study along with 139 matched controls. Genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism technique. Allelic and genotypic frequencies were compared between both study groups. NADPH p22phox -A930G polymorphism was significantly associated with knee OA in the crude analysis (P = 0.018). No significant difference was detected for C242T and A640G polymorphisms (P > 0.05). The association between -A930G polymorphism and knee OA disappeared when the results were adjusted for obesity (P = 0.078, odds ratio 0.54, 95 % CI 0.272-1.071). The interaction between all three polymorphisms was not significant. The present study shows that NADPH oxidase p22phox gene C242T, A640G and -A930G polymorphisms are not risk factors for knee OA susceptibility in the Greek population. Further studies are needed to give a global view of the importance of this polymorphism in the pathogenesis of OA. PMID- 23922198 TI - The Triological Society and its research legacy. PMID- 23922199 TI - Introduction to the special issue on reliability and replication in cognitive and affective neuroscience research. PMID- 23922200 TI - Cyclisation versus 1,1-Carboboration: Reactions of B(C6F5)3 with Propargyl Amides. AB - A series of propargyl amides were prepared and their reactions with the Lewis acidic compound B(C6F5)3 were investigated. These reactions were shown to afford novel heterocycles under mild conditions. The reaction of a variety of N substituted propargyl amides with B(C6F5)3 led to an intramolecular oxo-boration cyclisation reaction, which afforded the 5-alkylidene-4,5-dihydrooxazolium borate species. Secondary propargyl amides gave oxazoles in B(C6F5)3 mediated (catalytic) cyclisation reactions. In the special case of disubstitution adjacent to the nitrogen atom, 1,1-carboboration is favoured as a result of the increased steric hindrance (1,3-allylic strain) in the 5-alkylidene-4,5-dihydrooxazolium borate species. PMID- 23922201 TI - Next generation sequencing and rare genetic variants: from human population studies to medical genetics. AB - The allelic frequency spectrum emerging from several Next Generation Sequencing (NGS) projects is revealing important details about evolutionary and demographic forces that shaped the human genome. Herein, we discuss some of the achievements of the use of low-frequency and rare variants from NGS studies. The majority of variants that affect protein-coding regions are recent and rare. Often, the novel rare variants are enriched for deleterious alleles and are population-specific, making them suitable for the study of disease susceptibility. To investigate this kind of variation and its effects in association studies, very large sample sizes will be necessary to achieve sufficient statistical power. Moreover, as these variants are typically population-specific, the replication of disease associations across populations could be very difficult due to population stratification. Therefore, the design of experiments focusing on the identification of rare variants and their effects should be carefully planned. Although several successes have already been achieved through NGS for genetic epidemiology, pharmacogenetic and clinical purposes, with improvements of the sequencing technology and decreased costs, further advances are expected in the near future. PMID- 23922202 TI - Early light reduction for preventing retinopathy of prematurity in very low birth weight infants. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a complex condition of the developing retinal blood vessels and is one of the leading causes of preventable childhood blindness. Several risk factors for ROP have been studied over the past 50 years. Among them, general immaturity (low birth weight and low gestational age) and prolonged oxygen therapy have been consistently related to disease onset. However, it is understood that the progression of the disease is multifactorial and may be associated with others risk factors, such as multiple gestation, apnoea, intracranial haemorrhage, anaemia, sepsis, prolonged mechanical ventilation, multiple transfusions and light exposure. Furthermore, the precise role of these individual factors in the development of the disease has not yet been well established. OBJECTIVES: To determine whether the reduction of early environmental light exposure reduces the incidence of retinopathy of prematurity (ROP) or poor ROP outcomes among very low birth weight infants. SEARCH METHODS: We searched the following databases: the Cochrane Neonatal Group Specialised Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, CINAHL, HealthSTAR, Science Citation Index Database, CANCERLIT, the Oxford Database of Perinatal Trials and www.clinicaltrials.gov. We also searched previous reviews including cross-references, abstracts, conference and symposia proceedings, and contacted expert informants. This search was updated in October 2012. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that reduced light exposure to premature infants within the first seven days following birth were considered for this review. We also considered cluster-randomised controlled trials. DATA COLLECTION AND ANALYSIS: Data on clinical outcomes including any acute ROP and poor ROP outcome were extracted by both review authors independently and consensus reached. We conducted data analysis according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Data from four randomised trials with a total of 897 participants failed to show any reduction in acute ROP or poor ROP outcome with the reduction of ambient light to premature infants' retinas. The overall methodological quality of the included studies was about evenly split between those in which the classification was unclear and those in which the studies were categorised as low risk of bias. There was no report on the secondary outcomes considered in this review: quality of life measures; and time of exposure to oxygen. AUTHORS' CONCLUSIONS: The evidence shows that bright light is not the cause of retinopathy of prematurity and that the reduction of exposure of the retinas of premature infants to light has no effect on the incidence of the disease. PMID- 23922203 TI - Naegleria fowleri glycoconjugates with residues of alpha-D-mannose are involved in adherence of trophozoites to mouse nasal mucosa. AB - We analyzed the possible role of glycoconjugates containing alpha-D-mannose and alpha-D-glucose residues in adherence of trophozoites to mouse nasal epithelium. Trophozoites incubated with 20 MUg of one of three different lectins which preferentially recognized these residues were inoculated intranasally in Balb/c mice. Mouse survival was 40% with Pisum sativum and Canavalia ensiformis and 20% with Galanthus nivalis amebic pretreatment, compared with 0% survival for control animals administered trophozoites without pretreatment. Possibly some of the glycoproteins found in Naegleria fowleri represent an adherence factor. Differences in the saccharide sequences of the Naegleria species, even on the same glycoconjugate structure, could explain the different results corresponding to the distinct pretreatments (C. ensiformis, G. nivalis, and P. sativum). We found a higher expression of glycoconjugates recognized by P. sativum in Naegleria lovaniensis than N. fowleri, probably due to the higher number of oligosaccharides containing an alpha-1,6-linked fucose moiety expressed on the former species. PMID- 23922204 TI - Antiplasmodial activity of ethanolic extracts of some selected medicinal plants from the northwest of Iran. AB - The effectiveness of antimalarial drugs is declining at an ever accelerating rate, with consequent increase in malaria-related morbidity and mortality. The newest antiplasmodial drug from plants is needed to overcome this problem. The aim of this study was to assess antimalarial activity of the ethanolic extracts of 10 different medicinal plants from eight families against Plasmodium falciparum chloroquine-sensitive 3D7 strain. The selection of the hereby studied plants was based on the existing information on their local ethnobotanic history. Plants were dried, powdered, and macerated in a hydroalcoholic solution. Resulting extracts have been assessed for in vitro and in vivo antimalarial and brine shrimp toxicity activities. Of 10 plant species tested, four plants: Althea officinalis L. (Malvaceae), Myrtus communis Linn (Myrtaceae), Plantago major (Plantaginaceae), and Glycyrrhiza glabra L. (Papilionaceae) displayed promising antimalarial activity in vitro (50% inhibitory concentration values of 62.77, 42.18, 40.00, and 13.56 MUg/mL, respectively) with no toxicity against brine shrimp larvae. The crude extracts of three active plants, G. glabra, M. communis, and A. officinalis, also significantly reduced parasitemia in vivo in female Swiss albino mice at a dose of 400 mg/kg compared to no treatment. Antiplasmodial activities of extracts of A. officinalis and M. communis are reported for the first time. PMID- 23922205 TI - Clinical characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma. AB - BACKGROUND: Hotspot mutations in BRAF and NRAS are the most common somatic events in patients with melanoma. These mutations occur at highly conserved residues, but include several different substitutions. To determine whether specific mutations are clinically important to differentiate, tumor characteristics and clinical outcomes were compared among patients with advanced melanoma with 1) BRAF V600E versus V600K mutations and 2) NRAS exon 1 versus exon 2 mutations. METHODS: Retrospective clinical and pathologic data were collected for patients with advanced melanoma with BRAF or NRAS mutations. The demographics, tumor characteristics, and clinical outcomes of the patients were compared to identify significant mutation-specific associations. RESULTS: Among 302 patients with activating BRAF mutations, 76% had BRAF V600E and 24% had V600K substitutions. Compared with V600E, the presence of a V600K mutation was significantly associated with older age (median, 60.0 years vs 44.7 years; P < .001), male sex (80% vs 59%; P = .001), head/neck primary tumor location (30% vs 15%; P = .0026), shorter interval to stage IV disease (0.98 years vs 2.8 years; P = .015), and a shorter overall survival from the time of diagnosis of stage IV disease (median, 2.44 years vs 1.25 years; hazards ratio, 1.68 [P = .014]). Comparison of 136 patients with NRAS exon 1 (18%) and exon 2 (82%) mutations found an association with primary tumor histology (P = .0096) only. CONCLUSIONS: The presence of different substitutions at BRAF V600 correlates with patient demographics, tumor characteristics, and prognosis. These findings demonstrate the presence of mutation-specific clinical differences between different BRAF genotypes in patients with melanoma, and support the incorporation of this information in patient evaluation and clinical trial design. PMID- 23922206 TI - Chloroplast small heat shock protein HSP21 interacts with plastid nucleoid protein pTAC5 and is essential for chloroplast development in Arabidopsis under heat stress. AB - Compared with small heat shock proteins (sHSPs) in other organisms, those in plants are the most abundant and diverse. However, the molecular mechanisms by which sHSPs are involved in cell protection remain unknown. Here, we characterized the role of HSP21, a plastid nucleoid-localized sHSP, in chloroplast development under heat stress. We show that an Arabidopsis thaliana knockout mutant of HSP21 had an ivory phenotype under heat stress. Quantitative real-time RT-PCR, run-on transcription, RNA gel blot, and polysome association analyses demonstrated that HSP21 is involved in plastid-encoded RNA polymerase (PEP)-dependent transcription. We found that the plastid nucleoid protein pTAC5 was an HSP21 target. pTAC5 has a C4-type zinc finger similar to that of Escherichia coli DnaJ and zinc-dependent disulfide isomerase activity. Reduction of pTAC5 expression by RNA interference led to similar phenotypic effects as observed in hsp21. HSP21 and pTAC5 formed a complex that was associated mainly with the PEP complex. HSP21 and pTAC5 were associated with the PEP complex not only during transcription initiation, but also during elongation and termination. Our results suggest that HSP21 and pTAC5 are required for chloroplast development under heat stress by maintaining PEP function. PMID- 23922207 TI - Epigenetic and genetic influences on DNA methylation variation in maize populations. AB - DNA methylation is a chromatin modification that is frequently associated with epigenetic regulation in plants and mammals. However, genetic changes such as transposon insertions can also lead to changes in DNA methylation. Genome-wide profiles of DNA methylation for 20 maize (Zea mays) inbred lines were used to discover differentially methylated regions (DMRs). The methylation level for each of these DMRs was also assayed in 31 additional maize or teosinte genotypes, resulting in the discovery of 1966 common DMRs and 1754 rare DMRs. Analysis of recombinant inbred lines provides evidence that the majority of DMRs are heritable. A local association scan found that nearly half of the DMRs with common variation are significantly associated with single nucleotide polymorphisms found within or near the DMR. Many of the DMRs that are significantly associated with local genetic variation are found near transposable elements that may contribute to the variation in DNA methylation. Analysis of gene expression in the same samples used for DNA methylation profiling identified over 300 genes with expression patterns that are significantly associated with DNA methylation variation. Collectively, our results suggest that DNA methylation variation is influenced by genetic and epigenetic changes that are often stably inherited and can influence the expression of nearby genes. PMID- 23922209 TI - Yoga for depression: a systematic review and meta-analysis. AB - BACKGROUND: Mind-body medical interventions are commonly used to cope with depression and yoga is one of the most commonly used mind-body interventions. The aim of this review was to systematically assess and meta-analyze the effectiveness of yoga for depression. METHODS: Medline/PubMed, Scopus, the Cochrane Library, PsycINFO, and IndMED were searched through January 2013. Randomized controlled trials (RCTs) of yoga for patients with depressive disorders and individuals with elevated levels of depression were included. Main outcomes were severity of depression and remission rates, secondary outcomes were anxiety, quality of life, and safety. RESULTS: Twelve RCTs with 619 participants were included. Three RCTs had low risk of bias. Regarding severity of depression, there was moderate evidence for short-term effects of yoga compared to usual care (standardized mean difference (SMD) = -0.69; 95% confidence interval (CI) -0.99, 0.39; P < .001), and limited evidence compared to relaxation (SMD = -0.62; 95%CI 1.03, -0.22; P = .003), and aerobic exercise (SMD = -0.59; 95% CI -0.99, -0.18; P = .004). Limited evidence was found for short-term effects of yoga on anxiety compared to relaxation (SMD = -0.79; 95% CI -1.3, -0.26; P = .004). Subgroup analyses revealed evidence for effects in patients with depressive disorders and in individuals with elevated levels of depression. Due to the paucity and heterogeneity of the RCTs, no meta-analyses on long-term effects were possible. No RCT reported safety data. CONCLUSIONS: Despite methodological drawbacks of the included studies, yoga could be considered an ancillary treatment option for patients with depressive disorders and individuals with elevated levels of depression. PMID- 23922208 TI - WRKY6 transcription factor restricts arsenate uptake and transposon activation in Arabidopsis. AB - Stress constantly challenges plant adaptation to the environment. Of all stress types, arsenic was a major threat during the early evolution of plants. The most prevalent chemical form of arsenic is arsenate, whose similarity to phosphate renders it easily incorporated into cells via the phosphate transporters. Here, we found that arsenate stress provokes a notable transposon burst in plants, in coordination with arsenate/phosphate transporter repression, which immediately restricts arsenate uptake. This repression was accompanied by delocalization of the phosphate transporter from the plasma membrane. When arsenate was removed, the system rapidly restored transcriptional expression and membrane localization of the transporter. We identify WRKY6 as an arsenate-responsive transcription factor that mediates arsenate/phosphate transporter gene expression and restricts arsenate-induced transposon activation. Plants therefore have a dual WRKY dependent signaling mechanism that modulates arsenate uptake and transposon expression, providing a coordinated strategy for arsenate tolerance and transposon gene silencing. PMID- 23922210 TI - Nanoscale elemental sensitivity study of Nd2Fe14B using absorption correlation tomography. AB - Transmission X-ray microscopy (TXM) is a rapidly developing technique with the capability of nanoscale three dimensional (3D) real-space imaging. Combined with the wide range in energy tunability from synchrotron sources, TXM enables the retrieval of 3D microstructural information with elemental/chemical sensitivity that would otherwise be inaccessible. The differential absorption contrast above and below absorption edges has been used to reconstruct the distributions of different elements, assuming the absorption edges of the interested elements are fairly well separated. Here we present an "Absorption Correlation Tomography" (ACT) method based on the correlation of the material absorption across multiple edges. ACT overcomes the significant limitation caused by overlapping absorption edges, significantly expands the capabilities of TXM, and makes it possible for fully quantitative nano-scale 3D structural investigation with chemical/elemental sensitivity. The capability and robustness of this new methodology is demonstrated in a case study of an important type of rare earth magnet (Nd2Fe14B). PMID- 23922211 TI - A pilot study on the effect of a symbiotic mixture in irritable bowel syndrome: an open-label, partially controlled, 6-month extension of a previously published trial. AB - BACKGROUND: In recent years, the efficacy of probiotics has received considerable attention in the treatment for irritable bowel syndrome (IBS). In this regard, a symbiotic mixture (Probinul((r))) has shown beneficial effects. The aim of this study was to extend the previously published 4-week randomized, double-blinded, placebo-controlled study of this symbiotic mixture. METHODS: This is an open label prospective, partially controlled, 6-month extension period pilot study in which patients continued to receive the symbiotic mixture (Group 1) or were switched from placebo to symbiotic mixture (Group 2) using cyclic administration (last 2 weeks/month). The primary endpoints were the overall satisfactory relief of bloating and flatulence (assessed as proportions of responders). The secondary endpoints were evaluation of the symptom severity scores (bloating, flatulence, pain and urgency) and bowel function scores (frequency, consistency and incomplete evacuation). RESULTS: Twenty-six IBS patients completed the 6-month extension period (13 patients in Group 1 and 13 patients in Group 2). In the per protocol analysis, the proportions of responders across time were not significantly different in the groups but in Group 2, there was an increased percentage of responders for flatulence (p = 0.07). In addition, the score of flatulence was reduced significantly during the 6-month treatment period in Group 2 (p < 0.05), while no other significant differences were detected. CONCLUSIONS: Treatment with this symbiotic mixture was associated with persistence of relief from flatulence or new reduction in flatulence in the present 6-month long extension study. These results need to be more comprehensively assessed in large, long-term, randomized, placebo-controlled studies. PMID- 23922212 TI - Adipose tissue-derived products for complex fistula treatment. PMID- 23922213 TI - Testing gene-environment interactions in family-based association studies using trait-based ascertained samples. AB - The study of gene-environment interactions is an increasingly important aspect of genetic epidemiological investigation. Historically, it has been difficult to study gene-environment interactions using a family-based design for quantitative traits or when parent-offspring trios were incomplete. The QBAT-I provides researchers a tool to estimate and test for a gene-environment interaction in families of arbitrary structure that are sampled without regard to the phenotype of interest, but is vulnerable to inflated type I error if families are ascertained on the basis of the phenotype. In this study, we verified the potential for type I error of the QBAT-I when applied to samples ascertained on a trait of interest. The magnitude of the inflation increases as the main genetic effect increases and as the ascertainment becomes more extreme. We propose an ascertainment-corrected score test that allows the use of the QBAT-I to test for gene-environment interactions in ascertained samples. Our results indicate that the score test and an ad hoc method we propose can often restore the nominal type I error rate, and in cases where complete restoration is not possible, dramatically reduce the inflation of the type I error rate in ascertained samples. PMID- 23922214 TI - Laquinimod for multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system, and it causes major socioeconomic burden for the individual patient and for society. An inflammatory pathology occurs during the early relapsing stage of MS and a neurodegenerative pathology dominates the later progressive stage of the disease. Not all MS patients respond adequately to currently available disease-modifying drugs (DMDs). Alternative MS treatments with new modes of action are required to expand the current options for disease-modifying therapies (DMTs) and to aim for freedom from relapses, inflammatory lesions, disability progression and neurodegeneration. Laquinimod has dual properties of immunomodulation and neuroprotection and is a potentially promising new oral DMD in the treatment of relapsing MS. OBJECTIVES: To assess the effectiveness and safety profile of laquinimod as monotherapy or combination therapy versus placebo or approved DMDs (interferon-beta, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate) for modifying the disease course in patients with MS. SEARCH METHODS: The Review Group Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register which, among other sources, contains trials from CENTRAL (The Cochrane Library 2013, Issue 2), MEDLINE, EMBASE, CINAHL, LILACS, PEDro and Clinical trials registries (29 April 2013). We checked references in identified trials and manually searched the reports (2004 to March 2013) from neurological associations and MS societies. We also communicated with researchers participating in trials on laquinimod and contacted Teva Pharmaceutical Industries. SELECTION CRITERIA: All randomised, double-blind, controlled, parallel group clinical trials (RCTs) with a length of follow-up of at least one year evaluating laquinimod, as monotherapy or combination therapy, versus placebo or approved DMDs for patients with MS. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. Disagreements were discussed and resolved by consensus among review authors. Principal investigators of included studies were contacted for additional data or confirmation of information. MAIN RESULTS: Only one study met our inclusion criteria, involving 1106 adult patients with relapsing-remitting MS (RRMS) and an entry Expanded Disability Status Scale (EDSS) score of <= 5.5 and an entry disease duration of >= 6 months. Five hundred and fifty patients treated with laquinimod at a dose of 0.6 mg orally administered once daily in a capsule were compared with 556 patients treated with a matching placebo capsule. The study had a high risk for attrition bias (21.9%). Laquinimod had potential benefits in reducing relapse rates and was safe for most patients with RRMS in the short term. The most common adverse events included headache, back pain, arthralgia, diarrhoea, cough, urinary tract infection, elevated alanine aminotransferase, insomnia, nausea, abdominal pain and sinusitis. One ongoing trial was identified. AUTHORS' CONCLUSIONS: We found low-level evidence for the use of laquinimod as a disease-modifying therapy for MS because only one study with limited quality (high risk of attrition bias) was included. The published study suggests that laquinimod at a dose of 0.6 mg orally administered once daily may be safe and have potential benefits for most patients with RRMS in the short term. We are waiting for the publication of ongoing trials. PMID- 23922215 TI - Sigma-2 receptor ligands and their perspectives in cancer diagnosis and therapy. AB - The sigma-2 receptor is highly expressed in various rapidly proliferating cancer cells and regarded as a cancer cell biomarker. Selective sigma-2 ligands have been shown to specifically label the tumor sites, induce cancer cells to undergo apoptosis, and inhibit tumor growth. Sigma-2 ligands are potentially useful as cancer diagnostics, anticancer therapeutics, or adjuvant anticancer treatment agents. However, both the cloning of this receptor and the identification of its endogenous ligand have not been successful, and the lack of structural information has severely hindered the understanding of its physiological roles, its signaling pathways, and the development of more selective sigma-2 ligands. Recent data have implicated that sigma-2 binding sites are within the lipid rafts and that PGRMC1 (progesterone receptor membrane component 1) complex and sigma-2 receptor may be coupled with EGFR (epidermal growth factor receptor), mTOR (mammalian target of rapamycin), caspases, and ion channels. Due to its promising applications in cancer management, there are rapidly increasing research efforts that are being directed into this field. This review article updates the current understanding of sigma-2 receptor and its potential physiological roles, applications, interaction with other effectors, with special focuses on the development of sigma-2 ligands, their chemical structures, pharmacological profiles, applications in imaging and anticancer therapy. PMID- 23922216 TI - Chronic alcohol consumption promotes alterations on salivary gland regeneration process. AB - The aim of this study is to investigate the histological effect of alcohol ingestion on the regeneration of the submandibular gland (SMG) in rats. Twelve 60 day-old male Wistar rats were randomized into two experimental groups. Test group (TG) animals ingested 40 degrees GL of alcohol for 45 days before surgery, being its concentration gradually increased 10 degrees GL/week for 4 weeks to achieve the final concentration of 40 degrees GL. The control group (CG) received water during the whole experimental period. One-third of the left SMG lobe was removed. Three and seven days after, the whole gland was excised and analyzed. In the TG, the inflammatory process was pronounced when comparing the CG on day 3. The inverse aspect was observed on day 7, associated with an advanced parenchyma development. Changes in laminin expression and glycoproteins production were observed in the TG, causing advanced morphogenesis and delay in cytodifferentiation during the salivary gland regeneration, probably due to alcohol effects. Animals who received ethanol showed alterations in the pattern of glandular regeneration. PMID- 23922217 TI - Sca-1 expression defines developmental stages of mouse pDCs that show functional heterogeneity in the endosomal but not lysosomal TLR9 response. AB - Plasmacytoid dendritic cells (pDCs) play an important role in innate and adaptive immunity and were shown to be identical to previously described natural interferon (IFN)-alpha-producing cells. Here, we describe two functionally distinct pDC subpopulations that are characterized by the differential expression of stem cell antigen-1 (Sca-1; Ly-6A/E). Sca-1(-) pDCs are mainly found in the BM, appear first during development, show a higher proliferative activity, and represent the more precursor phenotype. Sca-1(+) pDCs are mostly located in secondary lymphoid organs and represent a later developmental stage. Sca-1(-) pDCs give rise to an Sca-1(+) subset upon activation or in response to endogenous type I IFN. Interestingly, in contrast to Sca-1(-) pDCs, Sca-1(+) pDCs are defective in IFN-alpha production upon endosomal TLR9 stimulation, whereas lysosomal signaling via TLR9 is functional in both subsets. Gene expression analysis revealed that osteopontin is strongly upregulated in Sca-1(-) pDCs. These data provide evidence for the molecular basis of the observed functional heterogeneity, as the intracellular isoform of osteopontin couples TLR9 signaling to IFN-alpha expression. Taken together, our results indicate that Sca-1(-) pDCs are an early developmental stage of pDCs with distinct innate functions representing the true murine natural IFN-alpha-producing cells. PMID- 23922218 TI - Flow cytometry-based enumeration and functional characterization of CD8 T regulatory cells in patients with multiple myeloma before and after lenalidomide plus dexamethasone treatment. AB - BACKGROUND: Multiple myeloma (MM) is a malignancy of plasma cells frequently associated with immune abnormalities. Several studies have confirmed that in MM immune deregulation can be mediated by increased numbers of CD4 T regulatory (Treg) cells, and these cells were also associated with poor outcome. In this study, we aimed to study CD8 Treg cells before and after lenalidomide plus dexamethasone (len-dex) treatment in MM patients. METHODS: Using flow cytometry, we enumerated and assessed suppressive function of CD8 Treg cells in 16 MM patients before and after len-dex treatment. RESULTS: Numbers of CD8 Treg cells (CD8+CD25hi+FoxP3+) (P < 0.01) were significantly increased in MM patients (before treatment) compared to healthy donors. However, no significant changes were observed in CD4 and CD8 T cells. A significant increase in CD8 Treg cells was observed after len-dex treatment compared to pre-treatment but no significant difference was observed in CD4 and CD8 T cells. Proliferation assay data showed that CD8 Treg cells inhibited proliferation of CD4 T cells and IFN-gamma secretion in a concentration dependent manner. Suppressive activity of CD8 Treg cells did not differ significantly between healthy donors, untreated and len-dex treated MM patients. A significant abnormal level of IL-10 was observed from proliferation assays of untreated and len-dex treated MM patients compared to healthy donors (P <= 0.03). CONCLUSIONS: Using flow cytometry, we have shown that suppressive CD8 Treg cells are increased in MM patients and len-dex treatment is unable to control these suppressive CD8 Treg cells. PMID- 23922219 TI - Role of CNPase in the oligodendrocytic extracellular 2',3'-cAMP-adenosine pathway. AB - Extracellular adenosine 3',5'-cyclic monophosphate (3',5'-cAMP) is an endogenous source of localized adenosine production in many organs. Recent studies suggest that extracellular 2',3'-cAMP (positional isomer of 3',5'-cAMP) is also a source of adenosine, particularly in the brain in vivo post-injury. Moreover, in vitro studies show that both microglia and astrocytes can convert extracellular 2',3' cAMP to adenosine. Here, we examined the ability of primary mouse oligodendrocytes and neurons to metabolize extracellular 2',3'-cAMP and their respective adenosine monophosphates (2'-AMP and 3'-AMP). Cells were also isolated from mice deficient in 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase). Oligodendrocytes metabolized 2',3'-cAMP to 2'-AMP with 10-fold greater efficiency than did neurons (and also more than previously examined microglia and astrocytes); whereas, the production of 3'-AMP was minimal in both oligodendrocytes and neurons. The production of 2'-AMP from 2',3'-cAMP was reduced by 65% in CNPase -/- versus CNPase +/+ oligodendrocytes. Oligodendrocytes also converted 2'-AMP to adenosine, and this was also attenuated in CNPase -/- oligodendrocytes. Inhibition of classic 3',5'-cAMP-3'-phosphodiesterases with 3 isobutyl-1-methylxanthine did not block metabolism of 2',3'-cAMP to 2'-AMP and inhibition of classic ecto-5'-nucleotidase (CD73) with alpha,beta-methylene adenosine-5'-diphosphate did not attenuate the conversion of 2'-AMP to adenosine. These studies demonstrate that oligodendrocytes express the extracellular 2',3' cAMP-adenosine pathway (2',3'-cAMP -> 2'-AMP -> adenosine). This pathway is more robustly expressed in oligodendrocytes than in all other CNS cell types because CNPase is the predominant enzyme that metabolizes 2',3'-cAMP to 2-AMP in CNS cells. By reducing levels of 2',3'-cAMP (a mitochondrial toxin) and increasing levels of adenosine (a neuroprotectant), oligodendrocytes may protect axons from injury. PMID- 23922220 TI - Imipramine-induced c-Fos expression in the medial prefrontal cortex is decreased in the ACTH-treated rats. AB - Previous studies have shown that the antidepressive-like effect of tricyclic antidepressants is blocked by repeated treatments with adrenocorticotropic hormone (ACTH). However, little is known about the neuroanatomy underlying the mechanism of the imipramine treatment-resistant depression model. In the present study, first experimental evidence showed no significant difference of the serum imipramine concentrations between the saline and ACTH-treated rats. In further study, imipramine produced significant increases in the c-Fos expression in the medial prefrontal cortex (mPFC), the dentate gyrus of the hippocampus (DGH), and the central nucleus of the amygdala (CeA), in rats repeatedly treated with saline. The imipramine-increased c-Fos immunoreactivity was suppressed in the mPFC of rats repeatedly treated with ACTH. However, there was no significant difference in c-Fos expression in the DGH and CeA between ACTH- and saline treated rats. These results suggest that the mPFC is maybe involved in effects of the imipramine in the ACTH-treated rats. PMID- 23922222 TI - Copper-mediated deoxygenative trifluoromethylation of benzylic xanthates: generation of a C-CF(3) bond from an O-based electrophile. AB - The conversion of an alcohol-based functional group, into a trifluoromethyl analogue is a desirable transformation. However, few methods are capable of converting O-based electrophiles into trifluoromethanes. The copper-mediated trifluoromethylation of benzylic xanthates using Umemoto's reagent as the source of CF3 to form C-CF3 bonds is described. The method is compatible with an array of benzylic xanthates bearing useful functional groups. A preliminary mechanistic investigation suggests that the C-CF3 bond forms by reaction of the substrate with in situ generated CuCF3 and CuOTf. Further evidence suggests that the reaction could proceed via a radical cation intermediate. PMID- 23922224 TI - Qualitative interaction trees: a tool to identify qualitative treatment-subgroup interactions. AB - When two alternative treatments (A and B) are available, some subgroup of patients may display a better outcome with treatment A than with B, whereas for another subgroup, the reverse may be true. If this is the case, a qualitative (i.e., disordinal) treatment-subgroup interaction is present. Such interactions imply that some subgroups of patients should be treated differently and are therefore most relevant for personalized medicine. In case of data from randomized clinical trials with many patient characteristics that could interact with treatment in a complex way, a suitable statistical approach to detect qualitative treatment-subgroup interactions is not yet available. As a way out, in the present paper, we propose a new method for this purpose, called QUalitative INteraction Trees (QUINT). QUINT results in a binary tree that subdivides the patients into terminal nodes on the basis of patient characteristics; these nodes are further assigned to one of three classes: a first for which A is better than B, a second for which B is better than A, and an optional third for which type of treatment makes no difference. Results of QUINT on simulated data showed satisfactory performance, with regard to optimization and recovery. Results of an application to real data suggested that, compared with other approaches, QUINT provided a more pronounced picture of the qualitative interactions that are present in the data. PMID- 23922221 TI - CpG oligodeoxynucleotide as immune adjuvant enhances photodynamic therapy response in murine metastatic breast cancer. AB - Breast cancer is the most common cause of cancer death in women. The side effects and complications following current breast cancer therapy can be devastating. Moreover, the prognosis in late stages of the diseases is usually poor. Photodynamic therapy (PDT) is a promising cancer treatment modality that is capable of both local tumor destruction and immune stimulation. However, treatment with PDT alone is often non-curative due to tumor-induced immune cell dysfunction and immune suppression. This phenomenon has motivated a new approach by combining immunostimulants with PDT to enhance anti-tumor immunity. In the present study, we investigated PDT mediated by verteporfin and 690 nm light delivered 15 min later, in combination with an immunomodulation approach using CpG oligodeoxynucleotide for the treatment of 4T1 metastatic breast cancer in a BALB/c immunocompetent mouse model. In vitro, CpG primed immature dendritic cells (DC) via toll like receptor 9 to phagocytose PDT killed tumor cells leading to DC maturation and activation. Peritumoral injection of CpG after PDT in mice gave improved local tumor control and a survival advantage compared to either treatment alone (p < 0.05). CpG may be a valuable dendritic cell targeted immunoadjuvant to combine with PDT. PMID- 23922223 TI - RhoGDIalpha downregulates androgen receptor signaling in prostate cancer cells. AB - INTRODUCTION: Treatment of primary prostate cancer (CaP) is the withdrawal of androgens. However, CaP eventually progresses to grow in a castration-resistant state due to aberrant activation of androgen receptor (AR). Understanding the mechanisms leading to the aberrant activation of AR is critical to develop effective therapy. We have previously identified Rho GDP Dissociation Inhibitor alpha (GDIalpha) as a novel suppressor in prostate cancer. In this study, we examine the effect of GDIalpha on AR signaling in prostate cancer cells. METHODS: GDIalpha was transiently or stably transfected into several prostate cancer cell lines including LNCaP, C4-2, CWR22Rv1, and DU145. The regulation of AR expression by GDIalpha was analyzed by qRT-PCR and Western blot. AR activity was measured by luciferase reporter assays and electrophoretic mobility shift analysis (EMSA). Immunofluorescence assay was performed to study AR nuclear translocation. The interaction between GDIalpha and AR was examined by co-immunoprecipitation assays. RESULTS: In this study, we have identified GDIalpha as a negative regulator of AR signaling pathway. Overexpression of GDIalpha downregulates AR expression at both mRNA and protein levels. Overexpression of GDIalpha is able to prevent AR nuclear translocation and inhibit transactivation of AR target genes. Co-immunoprecipitation assays showed that GDIalpha physically interacts with the N-terminal domain of AR. CONCLUSIONS: GDIalpha suppresses AR signaling through inhibition of AR expression, nuclear translocation, and recruitment to androgen responsive genes. GDIalpha regulatory pathway may play a critical role in regulating AR signaling and prostate cancer growth and progression. PMID- 23922225 TI - beta-amyloid and ATP-induced diffusional trapping of astrocyte and neuronal metabotropic glutamate type-5 receptors. AB - beta-Amyloid (Abeta) oligomers initiate synaptotoxicity following their interaction with the plasma membrane. Several proteins including metabotropic glutamate type 5 receptors (mGluR5s) contribute to this process. We observed an overexpression of mGluR5s in reactive astrocytes surrounding Abeta plaques in brain sections from an Alzheimer's disease mouse model. In a simplified cell culture system, using immunocytochemistry and single molecule imaging, we demonstrated a rapid binding of Abeta oligomers on the plasma membrane of astrocytes. The resulting aggregates of Abeta oligomers led to the diffusional trapping and clustering of mGluR5s. Further, Abeta oligomers induced an increase in ATP release following activation of astroglial mGluR5s by its agonist. ATP slowed mGluR5s diffusion in astrocytes as well as in neurons co-cultured with astrocytes. This effect, which is purinergic receptor-dependent, was not observed in pure neuronal cultures. Thus, Abeta oligomer- and mGluR5-dependent ATP release by astrocytes may contribute to the overall deleterious effect of mGluR5s in Alzheimer's disease. GLIA 2013;61:1673-1686. PMID- 23922226 TI - Use of CD157 in FLAER-based assays for high-sensitivity PNH granulocyte and PNH monocyte detection. AB - BACKGROUND: Recent Flow Cytometric guidelines to detect Paroxysmal Nocturnal Hemoglobinuria (PNH) in white blood cells recommend using FLAER-based assays to detect granulocytes and monocytes lacking expression of GPI-linked structures. However national proficiency testing results continue to suggest a need for improved testing algorithms, including the need to optimize diagnostic analytes in PNH. METHODS: CD157 is another GPI-linked structure expressed on both granulocytes and monocytes and here we assess its ability to replace CD24 and CD14 in predicate 4-color granulocyte and monocyte assays respectively. We also assess a single tube, 5-color combination of FLAER, CD157, CD64, CD15, and CD45 to simultaneously detect PNH clones in granulocyte and monocyte lineages. RESULTS: Delineation of PNH from normal phenotypes with 4- or 5-color CD157-based assays compared favorably with 4-color predicate methods and PNH clone size data were similar and highly correlated (R(2) >0.99) with predicate values over a range (0.06%-99.8%) of samples. Both CD157-based assays exhibited similar high levels of sensitivity and low background levels in normal samples. CONCLUSIONS: While CD157-based 4- and 5-color assays generated closely similar results to the predicate assays on a range of PNH and normal samples, the 5-color assay has significant advantages. Only a single 5-color WBC reagent cocktail is required to detect both PNH granulocytes and monocytes. Additionally, sample preparation and analysis time is reduced yielding significant efficiencies in technical resources and reagent costs. All 4- and 5-color reagent sets stained stabilized whole blood PNH preparations, used in external quality assurance programs. PMID- 23922227 TI - Cost-effectiveness of hematopoietic stem cell mobilization strategies including plerixafor in multiple myeloma and lymphoma patients. AB - Peripheral blood stem cells (PBSCs) are preferred source of hematopoietic stem cells for autologous transplantation. Mobilization of PBSCs using chemotherapy and/or granulocyte colony-stimulating factor (G-CSF) however fails in around 20%. Combining G-CSF with plerixafor increases the mobilizations success. We compared cost-effectiveness of following schemes: the use of plerixafor "on demand" (POD) during the first mobilization in all patients with inadequate response, the remobilization with plerixafor following failure of the first standard mobilization (SSP), and the standard (re)mobilization scheme without plerixafor (SSNP). Decision tree models populated with data from a first-of-a-kind patient registry in six Czech centers (n = 93) were built to compare clinical benefits and direct costs from the payer's perspective. The success rates and costs for POD, SSP and SSNP mobilizations were; 94.9%, $7,197; 94.7%, $8,049; 84.7%, $5,991, respectively. The direct cost per successfully treated patient was $7,586, $8,501, and $7,077, respectively. The cost of re-mobilization of a poor mobilizer was $5,808 with G-CSF only and $16,755 if plerixafor was added. The total cost of plerixafor "on-demand" in the sub-cohort of poor mobilizers was $17,120. Generally, plerixafor improves the mobilization success by 10% and allows an additional patient to be successfully mobilized for incremental $11,803. Plerixafor is better and cheaper if used "on demand" than within a subsequent remobilization. PMID- 23922228 TI - Underlying the mechanism of vancomycin and human serum albumin interaction: a biophysical study. AB - In the present study, the binding mechanism of vancomycin with human serum albumin (HSA) was determined. Upon addition of vancomycin to HSA, the fluorescence emission was quenched and the binding constant of vancomycin with HSA was found to be 6.05 * 10(3) M(-1) at 295 K, which corresponds to -2.16 * 10(4) J.mol(-1) of free energy. The conformation of HSA was altered upon binding of vancomycin with a decrease in alpha helix and an increase in beta sheets and random coils, suggesting partial unfolding of the secondary structure. Molecular docking experiments found that vancomycin binds strongly with HSA at the hydrophobic pocket through hydrogen bonding and van der Waals interactions. An average binding distance of 4.71 nm has been determined on the basis of the Forster resonance energy theory. It was demonstrated that vancomycin binding to HSA causes protein structural changes. PMID- 23922230 TI - The molecular pathogenesis of migraine: new developments and opportunities. AB - Migraine is a prevalent, debilitating and costly disorder with an ongoing unmet medical need. Human genetic studies have provided considerable insights into the molecular underpinnings of this complex brain disorder. Classical linkage studies have revealed the causes of familial hemiplegic migraine, while more recently genome-wide association studies have identified several susceptibility loci for typical migraine. New ways of accessing neurons and other cells directly from patients with migraine through the use of induced pluripotent stem cells offer exciting opportunities to understand the molecular pathogenesis. In conjunction with next generation omics, there are unprecedented opportunities to reveal key molecular players in the disease process and discover new drug targets. PMID- 23922229 TI - Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome. AB - Dravet syndrome is a severe epileptic encephalopathy mainly caused by heterozygous mutations in the SCN1A gene encoding a voltage-gated sodium channel Nav1.1. We previously reported dense localization of Nav1.1 in parvalbumin (PV) positive inhibitory interneurons in mice and abnormal firing of those neurons in Nav1.1-deficient mice. In the present study, we investigated the physiologic consequence of selective Nav1.1 deletion in mouse global inhibitory neurons, forebrain excitatory neurons or PV cells, using vesicular GABA transporter (VGAT) Cre, empty spiracles homolog 1 (Emx1)-Cre or PV-Cre recombinase drivers. We show that selective Nav1.1 deletion using VGAT-Cre causes epileptic seizures and premature death that are unexpectedly more severe than those observed in constitutive Nav1.1-deficient mice. Nav1.1 deletion using Emx1-Cre does not cause any noticeable abnormalities in mice; however, the severe lethality observed with VGAT-Cre-driven Nav1.1 deletion is rescued by additional Nav1.1 deletion using Emx1-Cre. In addition to predominant expression in PV interneurons, we detected Nav1.1 in subpopulations of excitatory neurons, including entorhino-hippocampal projection neurons, a subpopulation of neocortical layer V excitatory neurons, and thalamo-cortical projection neurons. We further show that even minimal selective Nav1.1 deletion, using PV-Cre, is sufficient to cause spontaneous epileptic seizures and ataxia in mice. Overall, our results indicate that functional impairment of PV inhibitory neurons with Nav1.1 haploinsufficiency contributes to the epileptic pathology of Dravet syndrome, and show for the first time that Nav1.1 haploinsufficiency in excitatory neurons has an ameliorating effect on the pathology. PMID- 23922231 TI - A defective Krab-domain zinc-finger transcription factor contributes to altered myogenesis in myotonic dystrophy type 1. AB - Myotonic dystrophy type 1 (DM1) is an RNA-mediated disorder caused by a non coding CTG repeat expansion that, in particular, provokes functional alteration of CUG-binding proteins. As a consequence, several genes with misregulated alternative splicing have been linked to clinical symptoms. In our search for additional molecular mechanisms that would trigger functional defects in DM1, we took advantage of mutant gene-carrying human embryonic stem cell lines to identify differentially expressed genes. Among the different genes found to be misregulated by DM1 mutation, one strongly downregulated gene encodes a transcription factor, ZNF37A. In this paper, we show that this defect in expression, which derives from a loss of RNA stability, is controlled by the RNA binding protein, CUGBP1, and is associated with impaired myogenesis-a functional defect reminiscent of that observed in DM1. Loss of the ZNF37A protein results in changes in the expression of the subunit alpha1 of the receptor for the interleukin 13. This suggests that the pathological molecular mechanisms linking ZNF37A and myogenesis may involve the signaling pathway that is known to promote myoblast recruitment during development and regeneration. PMID- 23922232 TI - In search of low-frequency and rare variants affecting complex traits. AB - The allelic architecture of complex traits is likely to be underpinned by a combination of multiple common frequency and rare variants. Targeted genotyping arrays and next-generation sequencing technologies at the whole-genome sequencing (WGS) and whole-exome scales (WES) are increasingly employed to access sequence variation across the full minor allele frequency (MAF) spectrum. Different study design strategies that make use of diverse technologies, imputation and sample selection approaches are an active target of development and evaluation efforts. Initial insights into the contribution of rare variants in common diseases and medically relevant quantitative traits point to low-frequency and rare alleles acting either independently or in aggregate and in several cases alongside common variants. Studies conducted in population isolates have been successful in detecting rare variant associations with complex phenotypes. Statistical methodologies that enable the joint analysis of rare variants across regions of the genome continue to evolve with current efforts focusing on incorporating information such as functional annotation, and on the meta-analysis of these burden tests. In addition, population stratification, defining genome-wide statistical significance thresholds and the design of appropriate replication experiments constitute important considerations for the powerful analysis and interpretation of rare variant association studies. Progress in addressing these emerging challenges and the accrual of sufficiently large data sets are poised to help the field of complex trait genetics enter a promising era of discovery. PMID- 23922233 TI - The applications of single-cell genomics. AB - We all start out as a single totipotent cell that is programmed to produce a multicellular organism. How do individual cells make those complex developmental switches? How do single cells within a tissue or organ differ, how do they coordinate their actions or go astray in a disease process? These are long standing and fundamental questions in biology that are now becoming tractable because of advances in microfluidics, DNA amplification and DNA sequencing. Methods for studying single-cell transcriptomes (or at least the polyadenylated mRNA fraction of it) are by far the furthest ahead and reveal remarkable heterogeneity between morphologically identical cells. The analysis of genomic DNA variation is not far behind. The other 'omics' of single cells pose greater technological obstacles, but they are progressing and promise to yield highly integrated large data sets in the near future. PMID- 23922234 TI - Conversion of levulinate into succinate through catalytic oxidative carbon-carbon bond cleavage with dioxygen. AB - Grand Cleft Oxo: Levulinate, available from biomass, is oxidized into succinate through manganese(III)-catalyzed selective cleavage of C?C bonds with molecular oxygen. In addition to levulinate, a wide range of aliphatic methyl ketones also undergo oxidative C?C bond cleavage at the carbonyl group. This procedure offers a route to valuable dicarboxylic acids from biomass resources by nonfermentive approaches. PMID- 23922235 TI - Are curcuminoids effective C-reactive protein-lowering agents in clinical practice? Evidence from a meta-analysis. AB - BACKGROUND: Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and cardiovascular disease (CVD). In this context, C-reactive protein (CRP) has been identified as a strong predictor and independent risk factor of CVD. Curcuminoids are multifunctional natural product with promising cardioprotective and anti-inflammatory properties. Curcuminoids have been suggested to lower circulating levels of CRP, but clinical findings have not been consistent. OBJECTIVES: To pool the published results of clinical trials on the impact of supplementation with curcuminoids on circulating levels of CRP. METHODS: PubMed/MEDLINE and SCOPUS databases were searched for clinical trials reporting circulating CRP changes in individuals receiving curcuminoids. Effect sizes with 95% confidence intervals (CI) were calculated using a random-effects model. Inter-study heterogeneity was assessed using Cochran's Q and I(2) tests. Sensitivity analyses were conducted using leave-one-out method. RESULTS: Six trials comprising 172 subjects in the curcuminoids group and 170 subjects in the placebo group fulfilled the eligibility criteria and included in the meta analysis. Compared with placebo, supplementation with curcuminoids was associated with a significant reduction in circulating CRP levels (weighed mean difference: 6.44 mg/L; 95% CI: -10.77 - -2.11; p = 0.004). This significant effect was maintained in subgroups of trials that used bioavailability-improved preparations of curcuminoids and had supplementation duration of >=4 weeks, but not in the subgroups without these characteristics. CONCLUSIONS: Supplementation with curcuminoids may reduce circulating CRP levels. This effect appears to depend on the bioavailability of curcuminoids preparations and also duration of supplementation. Future well-designed and long-term trials are warranted to verify this effect of curcuminoids. PMID- 23922236 TI - Multiple imputation for an incomplete covariate that is a ratio. AB - We are concerned with multiple imputation of the ratio of two variables, which is to be used as a covariate in a regression analysis. If the numerator and denominator are not missing simultaneously, it seems sensible to make use of the observed variable in the imputation model. One such strategy is to impute missing values for the numerator and denominator, or the log-transformed numerator and denominator, and then calculate the ratio of interest; we call this 'passive' imputation. Alternatively, missing ratio values might be imputed directly, with or without the numerator and/or the denominator in the imputation model; we call this 'active' imputation. In two motivating datasets, one involving body mass index as a covariate and the other involving the ratio of total to high-density lipoprotein cholesterol, we assess the sensitivity of results to the choice of imputation model and, as an alternative, explore fully Bayesian joint models for the outcome and incomplete ratio. Fully Bayesian approaches using Winbugs were unusable in both datasets because of computational problems. In our first dataset, multiple imputation results are similar regardless of the imputation model; in the second, results are sensitive to the choice of imputation model. Sensitivity depends strongly on the coefficient of variation of the ratio's denominator. A simulation study demonstrates that passive imputation without transformation is risky because it can lead to downward bias when the coefficient of variation of the ratio's denominator is larger than about 0.1. Active imputation or passive imputation after log-transformation is preferable. PMID- 23922237 TI - Successful treatment of drug-induced acute liver failure with high-volume plasma exchange. AB - We report two patients with drug-induced liver injury (DILI)-related acute liver failure (ALF) who were successfully treated with high-volume plasma exchange without liver transplantation. The first patient was a 66-year-old man admitted because of a perforated duodenal ulcer complicated with peritonitis and septic shock. After treatment with multiple antibiotics, the patient developed DILI and ALF. Grade 3 hepatic encephalopathy and profound jaundice were present. Symptoms and signs of ALF improved dramatically after initiation of plasma exchange. The patient was discharged uneventfully. The second patient was a 94-year-old man admitted for treatment of newly diagnosed pulmonary tuberculosis. DILI and ALF developed 5 days after initiation of anti-tuberculosis treatment. Grade 4 hepatic encephalopathy was present. After plasma exchange, the patient's level of consciousness improved dramatically, and he recovered from ALF. These 2 cases show the potential of plasma exchange in the treatment of DILI despite occurrence acute liver failure. PMID- 23922238 TI - Prevention of urinary tract infections with vaccinium products. AB - Cranberries exert a dose-dependent inhibition of the adherence of E. coli fimbriae to uroepithelial cells. This was demonstrated in vitro but also ex vivo in vitro with urine from cranberry consumers. The active principle has not been identified in detail but type-A proanthocyanidins (PAC) play an important role in the mechanism of action. Since the three species, American cranberry (Vaccinium macrocarpon), European cranberry (Vaccinium oxycoccus) and/or lingonberry (Vaccinium vitis-idaea), have different patterns of type-A PACs, results from one species cannot be transferred to the others. It seems likely that most of the studies with monopreparations from V. macrocarpon were underdosed. Whereas photometric PAC quantification may overestimate the true content on co-active compounds, reversed phase high-performance liquid chromatograpy may underestimate them. Recent studies with PAC doses in the upper range (DMAC method) or declared type-A PAC content in the daily dose reveal a dose-dependent trend of clinical effectiveness, however, with a possible ceiling effect. In order to clarify this, future three-arm studies should investigate Vaccinium preparations with higher type-A PAC doses than previously used. We analysed two popular European vitis idaea products, a mother juice and a proprietary extract. Both preparations may be appropriate to confirm the Vaccinium urinary tract infection-preventive effect beyond doubt. PMID- 23922239 TI - Efficient beta-cell regeneration by a combination of neogenesis and replication following beta-cell ablation and reversal of pancreatic duct ligation. AB - Achieving efficient beta-cell regeneration is a major goal of diabetes research. Previously, we found that a combination of beta-cell ablation and pancreatic duct ligation led to beta-cell regeneration by direct conversion from alpha-cells. Here, we studied the effect of surgical reversal of the duct ligation, finding that there was a wave of beta-cell replication following reversal. The combination of beta-cell neogenesis prior to reversal of the duct ligation and beta-cell replication following reversal resulted in efficient beta-cell regeneration and eventual recovery of function. This provides an important proof of principle that efficient beta-cell regeneration is possible, even from a starting point of profound beta-cell ablation. This has important implications for efforts to promote beta-cell regeneration. PMID- 23922240 TI - Puma, but not noxa is essential for oligodendroglial cell death. AB - The mechanisms involved in oligodendroglial cell death in human demyelinating diseases are only partly understood. Here, we demonstrate that the BH3 only protein Puma, but not Noxa, is essential for oligodendroglial cell death in toxic demyelination induced by the copper chelator cuprizone. Primary oligodendrocytes derived from Noxa- or Puma-deficient mice showed comparable differentiation to wild-type cells, but Puma-deficient oligodendrocytes were less susceptible to spontaneous, staurosporine, or nitric oxide-induced cell death. Furthermore, Puma was expressed in oligodendrocytes in multiple sclerosis (MS) lesions and Puma mRNA levels were upregulated in primary human oligodendrocytes upon cell death induction by staurosporine. Our data demonstrate that Puma is pivotal for oligodendroglial cell death induced by different cell death stimuli and might play a role in oligodendroglial cell death in MS. PMID- 23922241 TI - Hemophagocytic lymphohistiocytosis after allogeneic bone marrow transplantation during chronic norovirus infection. AB - Hemophagocytic lymphohistiocytosis (HLH) is a macrophage activating syndrome that is known to develop in patients with autoimmune disease, malignancies or infection, for example with Epstein-Barr virus, cytomegalovirus or varicella zoster virus. We describe a 24-month old boy with acute myelogenous leukaemia relapse and allogeneic bone marrow transplantation, who developed HLH on day +40 during chronic infection with norovirus. Here, we report for the first time the development of HLH in combination with chronic norovirus infection after allogeneic bone marrow transplantation in a hematopoietic malignancy. PMID- 23922242 TI - Peptides that bind specifically to an antibody from a chronic lymphocytic leukemia clone expressing unmutated immunoglobulin variable region genes. AB - Chronic lymphocytic leukemia (CLL) is a clonal disease of a subset of human B lymphocytes. Although the cause of the disease is unknown, its development and evolution appear to be promoted by signals delivered when B-cell receptors (BCRs) engage (auto)antigens. Here, using a peptide phage display library of enhanced size and diverse composition, we examined the binding specificity of a recombinant monoclonal antibody (mAb) constructed with the heavy chain and light chain variable domains of a CLL BCR that does not exhibit somatic mutations. As determined by testing the peptides identified in the selected peptide phage pool, this CLL-associated unmutated mAb bound a diverse set of sequences, some of which clustered in families based on amino acid sequence. Synthesis of these peptides and characterization of binding with the CLL-associated mAb revealed that mAb peptide interactions were generally specific. Moreover, the mAb-peptide interactions were of lower affinities (micromolar KD), as measured by surface plasmon resonance, than those observed with a CLL mAb containing somatic mutations (nanomolar KD) and with immunoglobulin heavy chain variable (IGHV) mutated antibodies selected by environmental antigens. This information may be of value in identifying and targeting B lymphocytes expressing specific BCRs in CLL patients and healthy subjects with monoclonal B lymphocytosis. PMID- 23922243 TI - Immunomodulatory and antibacterial effects of cystatin 9 against Francisella tularensis. AB - Cystatin 9 (CST9) is a member of the type 2 cysteine protease inhibitor family, which has been shown to have immunomodulatory effects that restrain inflammation, but its functions against bacterial infections are unknown. Here, we report that purified human recombinant (r)CST9 protects against the deadly bacterium Francisella tularensis (Ft) in vitro and in vivo. Macrophages infected with the Ft human pathogen Schu 4 (S4), then given 50 pg of rCST9 exhibited significantly decreased intracellular bacterial replication and increased killing via preventing the escape of S4 from the phagosome. Further, rCST9 induced autophagy in macrophages via the regulation of the mammalian target of rapamycin (mTOR) signaling pathways. rCST9 promoted the upregulation of macrophage proteins involved in antiinflammation and antiapoptosis, while restraining proinflammatory associated proteins. Interestingly, the viability and virulence of S4 also was decreased directly by rCST9. In a mouse model of Ft inhalation, rCST9 significantly decreased organ bacterial burden and improved survival, which was not accompanied by excessive cytokine secretion or subsequent immune cell migration. The current report is the first to show the immunomodulatory and antimicrobial functions of rCST9 against Ft. We hypothesize that the attenuation of inflammation by rCST9 may be exploited for therapeutic purposes during infection. PMID- 23922244 TI - Temporal dynamics of clonal evolution in chronic lymphocytic leukemia with stereotyped IGHV4-34/IGKV2-30 antigen receptors: longitudinal immunogenetic evidence. AB - Chronic lymphocytic leukemia (CLL) patients assigned to stereotyped subset 4 possess distinctive patterns of intraclonal diversification (ID) within their immunoglobulin (IG) genes. Although highly indicative of an ongoing response to antigen(s), the critical question concerning the precise timing of antigen involvement is unresolved. Hence, we conducted a large-scale longitudinal study of eight subset 4 cases totaling 511 and 398 subcloned IG heavy and kappa sequences. Importantly, we could establish a hierarchical pattern of subclonal evolution, thus revealing which somatic hypermutations were negatively or positively selected. In addition, distinct clusters of subcloned sequences with cluster-specific mutational profiles were observed initially; however, at later time points, the minor cluster had often disappeared and hence not been selected. Despite the high intensity of ID, it was remarkable that certain residues remained essentially unaltered. These novel findings strongly support a role for persistent antigen stimulation in the clonal evolution of CLL subset 4. PMID- 23922245 TI - Towards high conductivity in anion-exchange membranes for alkaline fuel cells. PMID- 23922246 TI - Length of human pregnancy and contributors to its natural variation. AB - STUDY QUESTION: How variable is the length of human pregnancy, and are early hormonal events related to gestational length? SUMMARY ANSWER: Among natural conceptions where the date of conception (ovulation) is known, the variation in pregnancy length spanned 37 days, even after excluding women with complications or preterm births. WHAT IS KNOWN ALREADY: Previous studies of length of gestation have either estimated gestational age by last menstrual period (LMP) or ultrasound (both imperfect measures) or included pregnancies conceived through assisted reproductive technology. STUDY DESIGN, SIZE, DURATION: The Early Pregnancy Study was a prospective cohort study (1982-85) that followed 130 singleton pregnancies from unassisted conception to birth, with detailed hormonal measurements through the conception cycle; 125 of these pregnancies were included in this analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: We calculated the length of gestation beginning at conception (ovulation) in 125 naturally conceived, singleton live births. Ovulation, implantation and corpus luteum (CL) rescue pattern were identified with urinary hormone measurements. We accounted for events that artificially shorten the natural length of gestation (Cesarean delivery or labor induction, i.e. 'censoring') using Kaplan-Meier curves and proportional hazards models. We examined hormonal and other factors in relation to length of gestation. We did not have ultrasound information to compare with our gold standard measure. MAIN RESULTS AND THE ROLE OF CHANCE: The median time from ovulation to birth was 268 days (38 weeks, 2 days). Even after excluding six preterm births, the gestational length range was 37 days. The coefficient of variation was higher when measured by LMP (4.9%) than by ovulation (3.7%), reflecting the variability of time of ovulation. Conceptions that took longer to implant also took longer from implantation to delivery (P = 0.02). CL rescue pattern (reflecting ovarian response to implantation) was predictive (P = 0.006): pregnancies with a rapid progesterone rise were longer than those with delayed rise (a 12-day difference in the median gestational length). Mothers with longer gestations were older (P = 0.02), had longer pregnancies in other births (P < 0.0001) and were heavier at birth (P = 0.01). We did not see an association between the length of gestation and several factors that have been associated with gestational length in previous studies: body mass index, alcohol intake, parity or offspring sex. LIMITATIONS, REASONS FOR CAUTION: The sample size was small and some exposures were rare, reducing power to detect weak associations. WIDER IMPLICATIONS OF THE FINDINGS: Human gestational length varies considerably even when measured exactly (from ovulation). An individual woman's deliveries tend to occur at similar gestational ages. Events in the first 2 weeks after conception are predictive of subsequent pregnancy length, and may suggest pathways underlying the timing of delivery. STUDY FUNDING/COMPETING INTEREST: This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. None of the authors has any conflict of interest to declare. PMID- 23922247 TI - Comments on: Advice for Families Traveling to Developing Countries With Young Children. doi:10.1177/0009922813491313. PMID- 23922248 TI - Polyarthritis in a 19-year-old female with systemic lupus erythematosus. PMID- 23922249 TI - Current practices regarding codeine administration among pediatricians and pediatric subspecialists. AB - Pharmacogenomic studies have revealed a wide variation in the metabolism of codeine to its active metabolite, morphine. A particular subset of patients, known as ultrarapid metabolizers, possesses multiple copies of the CYP2D6 gene responsible for codeine metabolism. This has been linked to serious morbidity and mortality in pediatric patients leading to considerable debate regarding the use of codeine for analgesia in the pediatric population. The current study surveyed the current practice of codeine prescription in pediatric health care providers from a single tertiary care pediatric hospital. Of the 298 responders, 43.3% (129 of 298) continue to prescribe codeine for pain management in children. The vast majority of codeine prescribers were primary health care providers (89.1%). Most of the primary care practitioners were in office-based (42.6%) or hospital-based (45.7%) group practices. There was no significant difference in codeine use based on years of experience. Given the risks associated with this practice, increased education targeting this group appears warranted. PMID- 23922250 TI - Penile and scrotal swelling mimicking child abuse. PMID- 23922251 TI - Excess screen time in US children: association with family rules and alternative activities. AB - We describe the association of screen time in excess of American Academy of Pediatrics recommendations (<=2 h/d) with family television-use policies and regular nonscreen activities among US school-aged children. Data from the 2007 National Survey of Children's Health were used. The sum of minutes spent on television, videos, video games, and recreational computer use was calculated for children 6 to 17 years old. Bivariate and multivariate logistic regression models were used to calculate relative odds of exceeding American Academy of Pediatrics guidelines and of heavy screen use (>4 h/d) for varying family media-use policies and frequency of alternative activities (physical activity and family meals). In all, 49% of school-aged children had screen time >2 h/d and 16% had screen time >4 h/d. Lower frequency of family meals, presence of TV in the bedroom, absence of rules about TV viewing, and less physical activity were associated with both >2 and >4 hours per day of screen time. PMID- 23922252 TI - Re: Dannaway J, Ng H, Deshpande AV. Adherence to ICCS nomenclature guidelines in subsequent literature: a bibliometric study. Neurourol Urodyn 2013;32;952-956. PMID- 23922253 TI - The AWOL tool: derivation and validation of a delirium prediction rule. AB - BACKGROUND: Risk factors for delirium are well-described, yet there is no widely used tool to predict the development of delirium upon admission in hospitalized medical patients. OBJECTIVE: To develop and validate a tool to predict the likelihood of developing delirium during hospitalization. DESIGN: Prospective cohort study with derivation (May 2010-November 2010) and validation (October 2011-March 2012) cohorts. SETTING: Two academic medical centers and 1 Veterans Affairs medical center. PATIENTS: Consecutive medical inpatients (209 in the derivation and 165 in the validation cohort) over age 50 years without delirium at the time of admission. MEASUREMENTS: Delirium assessed daily for up to 6 days using the Confusion Assessment Method. RESULTS: The AWOL prediction rule was derived by assigning 1 point to each of 4 items assessed upon enrollment that were independently associated with the development of delirium (Age >= 80 years, failure to spell "World" backward, disOrientation to place, and higher nurse rated iLlness severity). Higher scores were associated with higher rates of delirium in the derivation and validation cohorts (P for trend < 0.001 and 0.025, respectively). Rates of delirium according to score in the combined population were: 0(1/50, 2%), 1(5/141, 4%), 2(15/107, 14%), 3(10/50, 20%), and 4(7/11, 64%) (P for trend < 0.001). Area under the receiver operating characteristic curve for the derivation and validation cohorts was 0.81 (0.73-0.90) and 0.69 (0.54-0.83) respectively. CONCLUSIONS: The AWOL prediction rule characterizes medical patients' risk for delirium at the time of hospital admission and could be used for clinical stratification and in trials of delirium prevention. PMID- 23922254 TI - Phytochemical study of the alkaloidal fractions of Unonopsis duckei R. E. Fr. guided by electrospray ionisation ion-trap tandem mass spectrometry. AB - INTRODUCTION: The Unonopsis genus is a promising source of aporphinoid alkaloids, substances with great biological potential. These alkaloids have a well-defined mass spectrometry fragmentation pattern that, together with previous phytochemical knowledge, can guide the isolation of alkaloids not yet described for the genus. OBJECTIVE: Isolate substances not yet described in the Unonopsis genus, guided by alkaloidal profile analyses of stem barks, twigs and leaves of Unonopsis duckei using electrospray ionisation ion-trap tandem mass spectrometry (ESI-IT/MS(n) ). METHODS: Methanolic extracts from stem barks, twigs and leaves were submitted to a liquid-liquid, acid-base partitioning treatment to obtain the alkaloidal fractions. These fractions were analysed by direct infusion into an ESI-IT/MS(n) system. The major alkaloids observed for each fraction were submitted to fragmentation analysis. RESULTS: The MS fragmentation patterns revealed the presence of alkaloids previously reported for Annonaceae, including nornuciferine, anonaine, asimilobine, liriodenine and lysicamine, known for the Unonopsis genus, as well as others that were not yet described for this genus. In this way, the proaporphine alkaloid glaziovine was isolated, as well as a mixture of the aporphine alkaloids glaucine and norglaucine, all described for the first time in the Unonopsis genus. CONCLUSION: Mass spectrometry monitoring was fundamental to prioritise the isolation of substances not yet identified for the Unonopsis genus, dismissing known compounds and simplifying the phytochemical study. PMID- 23922256 TI - Message from the editor. PMID- 23922255 TI - Rapid, isothermal DNA self-replication induced by a destabilizing lesion. AB - You spin me round: Using a destabilizing abasic site and high concentration of ligase, rapid DNA self-replication in an isothermal ligase chain reaction (LCR) was produced. Both destabilization and rapid ligation are essential for proper LCR replication. This method also provides insight into prebiotic nucleotide replication and is a potential amplification method for biodiagnostics. PMID- 23922257 TI - AQP5 is differentially regulated in astrocytes during metabolic and traumatic injuries. AB - Water movement plays vital roles in both physiological and pathological conditions in the brain. Astrocytes are responsible for regulating this water movement and are the major contributors to brain edema in pathological conditions. Aquaporins (AQPs) in astrocytes play critical roles in the regulation of water movement in the brain. AQP1, 3, 4, 5, 8, and 9 have been reported in the brain. Compared with AQP1, 4, and 9, AQP3, 5, and 8 are less studied. Among the lesser known AQPs, AQP5, which has multiple functions identified outside the central nervous system, is also indicated to be involved in hypoxia injury in astrocytes. In our study, AQP5 expression could be detected both in primary cultures of astrocytes and neurons, and AQP5 expression in astrocytes was confirmed in 1- to 4-week old primary cultures of astrocytes. AQP5 was localized on the cytoplasmic membrane and in the cytoplasm of astrocytes. AQP5 expression was downregulated during ischemia treatment and upregulated after scratch-wound injury, which was also confirmed in a middle cerebral artery occlusion model and a stab-wound injury model in vivo. The AQP5 increased after scratch injury was polarized to the migrating processes and cytoplasmic membrane of astrocytes in the leading edge of the scratch-wound, and AQP5 over-expression facilitated astrocyte process elongation after scratch injury. Taken together, these results indicate that AQP5 might be an important water channel in astrocytes that is differentially expressed during various brain injuries. PMID- 23922258 TI - Effects of vibration therapy on hormone response and stress in severely disabled patients: a double-blind randomized placebo-controlled clinical trial. AB - PURPOSE: To assess the effects of vibration therapy (VT) on quality of life and hormone response in severely disabled patients compared with placebo. DESIGN: A longitudinal prospective, double-blind, randomized placebo-controlled trial, with pre and postintervention assessments. METHODS: A total of 20 severely disabled individuals were recruited from a National Reference Centre in Spain: 13 (65%) men and 7 (35%) women, 45.5 +/- 9.32 years of age (range 41: 22-63). We evaluated their physical stress and state anxiety. RESULTS: No statistically significant changes were found in the socio-psychological variables studied, while in the experimental group state anxiety decreased significantly with p < 0.01 (Z = 2.38; one-tailed p = .009) and, among the biological variables, the level of cortisol fell (p = 0.03). CONCLUSION: Short periods of exposure to low-frequency and low amplitude local vibration are a safe and effective mechanical stimulus that can have a positive effect in terms of hormone response. CLINICAL RELEVANCE: VT can be considered to have an anti-stress effect. PMID- 23922259 TI - Burst-swimming performance predicts the outcome of cannibalistic interactions in green poison frog larvae (Dendrobates auratus). AB - Whole-animal performance (e.g., swimming speed, bite force) functions as a fundamental link between organism and environment and, as such, performance characteristics are important in determining the outcomes of agonistic interactions, both interspecific and intraspecific. Cannibalism is an intraspecific agonistic interaction for which winners may be expected to exhibit superior performance in characteristics relevant to cannibalistic behavior. The larvae of the Green Poison Frog (Dendrobates auratus) exhibit cannibalistic behavior in which "fast-starts" (i.e., high velocity and acceleration from a resting position) are used in attempts to bite and avoid being bitten by conspecifics. We tested the hypothesis that superior fast-start swimming performance is positively associated with winning cannibalistic interactions between similarly sized individuals. Fast-starts by larvae were imaged with a high-speed camera, and pairs of size-matched individuals then underwent interaction trials to determine whether swimming performance is associated with winning a cannibalistic interaction. Linear acceleration of the snout tip, approximating the position of the mouthparts used to attack an opponent, was significantly greater in winners than losers. At the estimated center of mass, generally representing a target for an attacking opponent, linear velocity and acceleration were significantly greater in winners than losers. Understanding the role of performance in intraspecific interactions can help elucidate how they contribute to population dynamics, and thus how such interactions ultimately drive morphological and behavioral evolution. PMID- 23922260 TI - Concise review: combining human leukocyte antigen G and mesenchymal stem cells for immunosuppressant biotherapy. AB - Both human leukocyte antigen G (HLA-G) and multipotential mesenchymal stem/stromal cells (MSCs) exhibit immunomodulatory functions. In allogeneic tranplantation, the risks of acute and chronic rejection are still high despite improvement in immunosuppressive treatments, and the induction of a state of tolerance to alloantigens is not achieved. Immunomodulatory properties of MSCs and HLA-G in human allogeneic tranplantation to induce tolerance appears attractive and promising. Interestingly, we and others have demonstrated that MSCs can express HLA-G. In this review, we focus on the expression of HLA-G by MSCs and discuss how to ensure and improve the immunomodulatory properties of MSCs by selectively targeting MSCs expressing HLA-G (MSCs(HLA-G+)). We also discuss the possible uses of MSCs(HLA-G+) for therapeutic purposes, notably, to overcome acute and chronic immune rejection in solid-organ allogeneic transplantation in humans. Since MSCs are phenotypically and functionally heterogeneous, it is of primary interest to have specific markers ensuring that they have strong immunosuppressive potential and HLA-G may be a valuable candidate. PMID- 23922263 TI - Tripaddled anterolateral thigh flap for simultaneous reconstruction of bilateral buccal defects after buccal cancer ablation and severe oral submucous fibrosis release: a case report. AB - For buccal squamous cell carcinoma (SCC) patients accompanied with severe oral submucous fibrosis (OSF), it is a challenge to simultaneously reconstruct bilateral buccal defects created from cancer resection and contralateral OSF release to improve postoperative mouth opening. Herein, we present a case of reconstruction of bilateral buccal defects in a 46-year-old patient who had left buccal SCC accompanied with severe OSF. Extensive ablation involved the left full thickness cheek as well as part of mandible and a release of right OSF tissue were performed. A tripaddled anterolateral thigh (ALT) flap with three independent sets of perforators was harvested for reconstruction. The flap survived in its entirety. No donor or recipient site complication occurred. The preoperative inter-incisor distance (IID) was 1 mm, while the postoperative IID was 23 mm. This is the first report on the use of one tripaddled ALT flap for reconstruction of bilateral buccal defects created from cancer ablation and severe contralateral OSF release. PMID- 23922264 TI - Synthesis of small combinatorial libraries of natural products: identification and quantification of new long-chain 3-methyl-2-alkanones from the root essential oil of Inula helenium L. (Asteraceae). AB - INTRODUCTION: Recently, a potent anti-staphylococcal activity of Inula helenium L. (Asteraceae) root essential oil was reported. Also, bioassay guided fractionation of the oil pointed to eudesmane sesquiterpene lactones and a series of unidentified constituents as the main carriers of the observed activity. OBJECTIVE: To identify nine new constituents (long-chain 3-methyl-2-alkanones) from a fraction of this root essential oil with a low minimum inhibitory concentration value (0.8 ug/mL) by employing a synthetic methodology that leads to the formation of a small combinatorial library of these compounds. METHODS: The identity of these constituents was inferred from mass spectral fragmentation patterns and GC retention data. A library of 3-methyl-2-alkanones (C11 -C19 homologous series) was synthesised in three steps starting from methyl acetoacetate and the corresponding alkyl halides. The synthetic library was also screened for in vitro anti-microbial activity. RESULTS: Gas chromatographic analyses of I. helenium essential oil samples with spiked compounds from the synthesised library corroborated the tentative identifications of the long-chain 3-methyl-2-alkanones. The availability of these anti-microbial compounds from this library made it possible to construct GC/FID calibration curves and determine their content in the plant material: 0.08 - 24.2 mg/100 g of dry roots. CONCLUSION: The small combinatorial library approach enabled the first unequivocal identification of long-chain 3-methyl-2-alkanones as plant secondary metabolites, and, also, allowed determination of not only a single compound and biological properties, but those of a group of structurally related compounds. PMID- 23922265 TI - The effect of altering a single component of a rehabilitation programme on the functional recovery of stroke patients: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the effect of altering a single component of a rehabilitation programme (e.g. adding bilateral practice alone) on functional recovery after stroke, defined using a measure of activity. DATA SOURCES: A search was conducted of Medline/Pubmed, CINAHL and Web of Science. REVIEW METHODS: Two reviewers independently assessed eligibility. Randomized controlled trials were included if all participants received the same base intervention, and the experimental group experienced alteration of a single component of the training programme. This could be manipulation of an intrinsic component of training (e.g. intensity) or the addition of a discretionary component (e.g. augmented feedback). One reviewer extracted the data and another independently checked a subsample (20%). Quality was appraised according to the PEDro scale. RESULTS: Thirty-six studies (n = 1724 participants) were included. These evaluated nine training components: mechanical degrees of freedom, intensity of practice, load, practice schedule, augmented feedback, bilateral movements, constraint of the unimpaired limb, mental practice and mirrored-visual feedback. Manipulation of the mechanical degrees of freedom of the trunk during reaching and the addition of mental practice during upper limb training were the only single components found to independently enhance recovery of function after stroke. CONCLUSION: This review provides limited evidence to support the supposition that altering a single component of a rehabilitation programme realises greater functional recovery for stroke survivors. Further investigations are required to determine the most effective single components of rehabilitation programmes, and the combinations that may enhance functional recovery. PMID- 23922266 TI - In vivo confocal microscopy and histopathology of the conjunctiva in trachomatous scarring and normal tissue: a systematic comparison. AB - AIM: To compare in vivo confocal microscopy (IVCM) with the histopathological examination of tissue and cellular changes in normal and diseased conjunctiva. METHODS: Participants underwent clinical examination and IVCM of the tarsal conjunctiva. A biopsy of the upper tarsal conjunctiva was collected and stained with tinctorial stains and by immunohistochemical staining for CD45 and CD83. Connective tissue scarring, inflammatory cell density and the presence of dendritiform cells were quantitatively assessed in a masked manner by both IVCM and histological assessments for comparative analysis. RESULTS: Thirty-four participants with severe trachomatous conjunctival scarring and 33 participants with healthy conjunctiva were recruited. The IVCM connective tissue scarring score was strongly associated with the histological grading of scarring (p<0.001). There was limited evidence of an association between the IVCM inflammatory cell infiltrate and the histological inflammatory cell grade (p=0.05). We did not find any evidence to support the hypothesis that dendritiform cells seen with IVCM are mature, conventional dendritic cells. CONCLUSIONS: The results show that IVCM can be used to robustly quantitate connective tissue scarring and also has a role in measuring the inflammatory cell infiltrate. The discordance between IVCM dendritiform cells and immunohistochemical dendritic cells may be a result of study limitations or may be because these dendritiform structures represent another cell type, such as fibroblasts, rather than dendritic cells. PMID- 23922267 TI - The single-stranded DNA-binding protein WHIRLY1 represses WRKY53 expression and delays leaf senescence in a developmental stage-dependent manner in Arabidopsis. AB - Leaf senescence in plants involves both positive and negative transcriptional regulation. In this work, we show evidence for the single-stranded DNA-binding protein WHIRLY1 (WHY1) that functions as an upstream suppressor of WRKY53 in a developmental stage-dependent manner during leaf senescence in Arabidopsis (Arabidopsis thaliana). The why1 mutant displayed an early-senescence phenotype. In this background, the expression levels of both WRKY53 and the senescence associated protease gene SAG12 increased. WHY1 bound to the sequence region that contains an elicitor response element motif-like sequence, GNNNAAATT, plus an AT rich telomeric repeat-like sequence in the WRKY53 promoter in in vivo and in vitro mutagenesis assays as well as in a chromatin immunoprecipitation assay. This binding to the promoter of WRKY53 was regulated in a developmental stage dependent manner, as verified by chromatin immunoprecipitation-polymerase chain reaction assay. This direct interaction was further determined by a transient expression assay in which WHY1 repressed beta-GLUCURONIDASE gene expression driven by the WRKY53 promoter. Genetic analysis of double mutant transgenic plants revealed that WHY1 overexpression in the wrky53 mutant (oeWHY1wrky53) had no effect on the stay-green phenotype of the wrky53 mutant, while a WHY1 knockout mutant in the wrky53 mutant background (why1wrky53) generated subtle change in the leaf yellow/green phenotype. These results suggest that WHY1 was an upstream regulator of WRKY53 during leaf senescence. PMID- 23922269 TI - ROOT HAIR DEFECTIVE3 family of dynamin-like GTPases mediates homotypic endoplasmic reticulum fusion and is essential for Arabidopsis development. AB - In all eukaryotic cells, the endoplasmic reticulum (ER) forms a tubular network whose generation requires the fusion of ER membranes. In Arabidopsis (Arabidopsis thaliana), the membrane-bound GTPase ROOT HAIR DEFECTIVE3 (RHD3) is a potential candidate to mediate ER fusion. In addition, Arabidopsis has two tissue-specific isoforms of RHD3, namely RHD3-like (RL) proteins, and their function is not clear. Here, we show that a null allele of RHD3, rhd3-8, causes growth defects and shortened root hairs. A point mutant, rhd3-1, exhibits a more severe growth phenotype than the null mutant, likely because it exerts a dominant-negative effect on the RL proteins. Genetic analysis reveals that the double deletion of RHD3 and RL1 is lethal and that the rhd3 rl2 plants produce no viable pollen, suggesting that the RL proteins are redundant to RHD3. RHD3 family proteins can replace Sey1p, the homolog of RHD3 in yeast (Saccharomyces cerevisiae), in the maintenance of ER morphology, and they are able to fuse membranes both in vivo and in vitro. Our results suggest that RHD3 proteins mediate ER fusion and are essential for plant development and that the formation of the tubular ER network is of general physiological significance. PMID- 23922268 TI - Thylakoid membrane maturation and PSII activation are linked in greening Synechocystis sp. PCC 6803 cells. AB - Thylakoid membranes are typical and essential features of both chloroplasts and cyanobacteria. While they are crucial for phototrophic growth of cyanobacterial cells, biogenesis of thylakoid membranes is not well understood yet. Dark-grown Synechocystis sp. PCC 6803 cells contain only rudimentary thylakoid membranes but still a relatively high amount of phycobilisomes, inactive photosystem II and active photosystem I centers. After shifting dark-grown Synechocystis sp. PCC 6803 cells into the light, "greening" of Synechocystis sp. PCC 6803 cells, i.e. thylakoid membrane formation and recovery of photosynthetic electron transport reactions, was monitored. Complete restoration of a typical thylakoid membrane system was observed within 24 hours after an initial lag phase of 6 to 8 hours. Furthermore, activation of photosystem II complexes and restoration of a functional photosynthetic electron transport chain appears to be linked to the biogenesis of organized thylakoid membrane pairs. PMID- 23922270 TI - ROSMETER: a bioinformatic tool for the identification of transcriptomic imprints related to reactive oxygen species type and origin provides new insights into stress responses. AB - The chemical identity of the reactive oxygen species (ROS) and its subcellular origin will leave a specific imprint on the transcriptome response. In order to facilitate the appreciation of ROS signaling, we developed a tool that is tuned to qualify this imprint. Transcriptome data from experiments in Arabidopsis (Arabidopsis thaliana) for which the ROS type and organelle origin are known were compiled into indices and made accessible by a Web-based interface called ROSMETER. The ROSMETER algorithm uses a vector-based algorithm to portray the ROS signature for a given transcriptome. The ROSMETER platform was applied to identify the ROS signatures profiles in transcriptomes of senescing plants and of those exposed to abiotic and biotic stresses. An unexpected highly significant ROS transcriptome signature of mitochondrial stress was detected during the early presymptomatic stages of leaf senescence, which was accompanied by the specific oxidation of mitochondria-targeted redox-sensitive green fluorescent protein probe. The ROSMETER analysis of diverse stresses revealed both commonalties and prominent differences between various abiotic stress conditions, such as salt, cold, ultraviolet light, drought, heat, and pathogens. Interestingly, early responses to the various abiotic stresses clustered together, independent of later responses, and exhibited negative correlations to several ROS indices. In general, the ROS transcriptome signature of abiotic stresses showed limited correlation to a few indices, while biotic stresses showed broad correlation with multiple indices. The ROSMETER platform can assist in formulating hypotheses to delineate the role of ROS in plant acclimation to environmental stress conditions and to elucidate the molecular mechanisms of the oxidative stress response in plants. PMID- 23922272 TI - A lyotropic chiral smectic C liquid crystal with polar electrooptic switching. PMID- 23922271 TI - Calcium-dependent protein kinase CPK6 positively functions in induction by yeast elicitor of stomatal closure and inhibition by yeast elicitor of light-induced stomatal opening in Arabidopsis. AB - Yeast elicitor (YEL) induces stomatal closure that is mediated by a Ca(2+) dependent signaling pathway. A Ca(2+)-dependent protein kinase, CPK6, positively regulates activation of ion channels in abscisic acid and methyl jasmonate signaling, leading to stomatal closure in Arabidopsis (Arabidopsis thaliana). YEL also inhibits light-induced stomatal opening. However, it remains unknown whether CPK6 is involved in induction by YEL of stomatal closure or in inhibition by YEL of light-induced stomatal opening. In this study, we investigated the roles of CPK6 in induction by YEL of stomatal closure and inhibition by YEL of light induced stomatal opening in Arabidopsis. Disruption of CPK6 gene impaired induction by YEL of stomatal closure and inhibition by YEL of light-induced stomatal opening. Activation by YEL of nonselective Ca(2+)-permeable cation channels was impaired in cpk6-2 guard cells, and transient elevations elicited by YEL in cytosolic-free Ca(2+) concentration were suppressed in cpk6-2 and cpk6-1 guard cells. YEL activated slow anion channels in wild-type guard cells but not in cpk6-2 or cpk6-1 and inhibited inward-rectifying K(+) channels in wild-type guard cells but not in cpk6-2 or cpk6-1. The cpk6-2 and cpk6-1 mutations inhibited YEL-induced hydrogen peroxide accumulation in guard cells and apoplast of rosette leaves but did not affect YEL-induced hydrogen peroxide production in the apoplast of rosette leaves. These results suggest that CPK6 positively functions in induction by YEL of stomatal closure and inhibition by YEL of light induced stomatal opening in Arabidopsis and is a convergent point of signaling pathways for stomatal closure in response to abiotic and biotic stress. PMID- 23922273 TI - Turbidity and salinity affect feeding performance and physiological stress in the endangered delta smelt. AB - Coastal estuaries are among the most heavily impacted ecosystems worldwide with many keystone fauna critically endangered. The delta smelt (Hypomesus transpacificus) is an endangered pelagic fish species endemic to the Sacramento San Joaquin Estuary in northern California, and is considered as an indicator species for ecosystem health. This ecosystem is characterized by tidal and seasonal gradients in water parameters (e.g., salinity, temperature, and turbidity), but is also subject to altered water-flow regimes due to water extraction. In this study, we evaluated the effects of turbidity and salinity on feeding performance and the stress response of delta smelt because both of these parameters are influenced by water flows through the San Francisco Bay Delta (SFBD) and are known to be of critical importance to the completion of the delta smelt's life cycle. Juvenile delta smelt were exposed to a matrix of turbidities and salinities ranging from 5 to 250 nephelometric turbidity units (NTUs) and 0.2 to 15 parts per thousand (ppt), respectively, for 2 h. Best statistical models using Akaike's Information Criterion supported that increasing turbidities resulted in reduced feeding rates, especially at 250 NTU. In contrast, best explanatory models for gene transcription of sodium-potassium-ATPase (Na/K ATPase)-an indicator of osmoregulatory stress, hypothalamic pro-opiomelanocortin a precursor protein to adrenocorticotropic hormone (expressed in response to biological stress), and whole-body cortisol were affected by salinity alone. Only transcription of glutathione-S-transferase, a phase II detoxification enzyme that protects cells against reactive oxygen species, was affected by both salinity and turbidity. Taken together, these data suggest that turbidity is an important determinant of feeding, whereas salinity is an important abiotic factor influencing the cellular stress response in delta smelt. Our data support habitat association studies that have shown greater delta smelt abundances in the low salinity zone (0.5-6.0 ppt) of San Francisco Bay, a zone that is also understood to have optimal turbidities. By determining the responses of juvenile delta smelt to key abiotic factors, we hope to aid resource managers in making informed decisions in support of delta smelt conservation. PMID- 23922274 TI - Environmental conditions experienced during the tadpole stage alter post metamorphic glucocorticoid response to stress in an amphibian. AB - Exposure to adverse environmental conditions during early development can shape life-history traits and have lasting effects on physiological function in later life. Although findings within the biomedical literature have shown that environmentally induced elevations in glucocorticoids (GCs) during critical developmental windows can cause persistent carry-over effects (i.e., developmental programming), little is known about whether such effects of GCs can be generalized to wildlife species. Using wood frogs as a study species, we conducted an experiment with a split-plot design to assess the short-term and the long-term physiological consequences of availability of food, hydroperiod length (i.e., pond drying), and the interaction between these two environmental conditions. In outdoor experimental ponds, we reared tadpoles in chronically high or low-food conditions, and tadpoles from each pond experienced either high water until metamorphosis or a reduction in water volume during late developmental stages (after Gosner stage 38). After metamorphosis, animals were housed individually and fed ad libitum for 10 weeks, and growth rate, fat content, and resting and acute stress-induced GC levels were measured. We found that tadpoles experiencing low availability of food and reduced water volume had elevated GC levels, reduced mass, and body condition as they approached metamorphosis. At 10 weeks after metamorphosis, we found that these two conditions also had persistent interactive effects on post-metamorphic allocation of resources to growth, energy storage, and responsiveness of GCs to a novel stressor. Of individuals that experienced reduced water volume, only those that experienced high food as tadpoles were able to catch up to individuals that did not experience reduced water volume in terms of body mass, femur length, and body condition, and they allocated more resources to fat storage. By contrast, 10-week old frogs with low food and that experienced low water volume and low-food levels as tadpoles allocated fewer resources to mass-specific growth, stored less fat, and exhibited blunted GC response to a novel stressor relative to those that did not experience water-reduction. Our findings demonstrate that environmental conditions experienced prior to and during important developmental transitions shape resource allocation and the ability to physiologically respond to future stressors in juvenile and potentially adult animals. These results suggest that chronic and acute environmental stressors experienced during early life stages can have cumulative and interactive effects that need to be considered when modeling the ecological and evolutionary consequences of environmental change on populations. PMID- 23922275 TI - Ultra-sensitive graphene-plasmonic hybrid platform for label-free detection. AB - A graphene-Au nano-pyramid hybrid system that enables label-free single molecule detection is demonstrated. The bio-compatible graphene-based SERS platform boosts a high density of hot spots with local SERS enhancement factor over 10(10) . We demonstrate that graphene can play a key role in quantitative study of SERS mechanisms, and can also serve as a promising building block in SERS active structures especially for biosensor applications. PMID- 23922276 TI - Investigation of the optimal timing for chondrogenic priming of MSCs to enhance osteogenic differentiation in vitro as a bone tissue engineering strategy. AB - Recent in vitro tissue engineering approaches have shown that chondrogenic priming of human bone marrow mesenchymal stem cells (MSCs) can have a positive effect on osteogenesis in vivo. However, whether chondrogenic priming is an effective in vitro bone regeneration strategy is not yet known. In particular, the appropriate timing for chondrogenic priming in vitro is unknown albeit that in vivo cartilage formation persists for a specific period before bone formation. The objective of this study is to determine the optimum time for chondrogenic priming of MSCs to enhance osteogenic differentiation by MSCs in vitro. Pellets derived from murine and human MSCs were cultured in six different media groups: two control groups (chondrogenic and osteogenic) and four chondrogenic priming groups (10, 14, 21 and 28 days priming). Biochemical analyses (Hoechst, sulfate glycosaminoglycan (sGAG), Alkaline Phosphate (ALP), calcium), histology (Alcian Blue, Alizarin Red) and immunohistochemistry (collagen types I, II and X) were performed on the samples at specific times. Our results show that after 49 days the highest amount of sGAG production occurred in MSCs chondrogenically primed for 21 days and 28 days. Moreover we found that chondrogenic priming of MSCs in vitro for specific amounts of time (14 days, 21 days) can have optimum influence on their mineralization capacity and can produce a construct that is mineralized throughout the core. Determining the optimum time for chondrogenic priming to enhance osteogenic differentiation in vitro provides information that might lead to a novel regenerative treatment for large bone defects, as well as addressing the major limitation of core degradation and construct failure. PMID- 23922278 TI - Diel rhythms of sexual behavior and pheromone titers in Isoceras sibirica Alpheraky (Lepidoptera, Cossidae). AB - The adult behavior and sex pheromone titers of Isoceras sibirica Alpheraky (Lepidoptera, Cossidae) were investigated to determine the diel periodicity of pheromone production during one scotophase and the effect of age on pheromone production. The results showed that females began to call on the first night after eclosion and called mainly during the second half of scotophase. The percentage of females calling was highest in 1- to 3-day-old females and lowest in 4- to 5-day-old females. The onset of scotophase calling occurred earlier as females aged. The responses to the pheromone source of males aged 1-5 days were monitored in a wind tunnel. Peak activity was observed in 3-day-old males, 4 h after the onset of the scotophase. The mating of all 1- to 3-day-old moths began after 6 h in scotophase and some 4- to 5-day-old moths began during the fourth hour. The average duration of copulation was 34.2 +/- 18.2 min (N = 45) and ranged from 17.0 to 56.3 min. Gas chromatography-mass spectrometry (GC-MS) analysis of hexane extracts of pheromone glands revealed that the titers of the three sex pheromone components, (Z)-9-tetradecenyl acetate (Z9-14:Ac), (Z)-7 tetradecenyl acetate, and (Z)-9-hexadecadecenyl acetate were very low on the first night after eclosion, increased and peaked on the second night, then decreased with age. During the first 4 h of the scotophase, titers remained invariant, whereas from 4 to 6 h, pheromone titers increased sharply and peaked, with the greatest peak observed in the primary component, Z9-14:Ac. After the peak, all recorded titers declined until they reached a minimum between the ninth and tenth hours of the dark cycle. In field tests, most of the males were captured in traps during 00:00-02:00 h (13 +/- 0.48), and females aged 2 days attracted more males than females of other ages. We infer that the I. sibirica mating system is organized around circadian control of mate calling and mating. PMID- 23922277 TI - Noninvasive pulsed focused ultrasound allows spatiotemporal control of targeted homing for multiple stem cell types in murine skeletal muscle and the magnitude of cell homing can be increased through repeated applications. AB - Stem cells are promising therapeutics for cardiovascular diseases, and i.v. injection is the most desirable route of administration clinically. Subsequent homing of exogenous stem cells to pathological loci is frequently required for therapeutic efficacy and is mediated by chemoattractants (cell adhesion molecules, cytokines, and growth factors). Homing processes are inefficient and depend on short-lived pathological inflammation that limits the window of opportunity for cell injections. Noninvasive pulsed focused ultrasound (pFUS), which emphasizes mechanical ultrasound-tissue interactions, can be precisely targeted in the body and is a promising approach to target and maximize stem cell delivery by stimulating chemoattractant expression in pFUS-treated tissue prior to cell infusions. We demonstrate that pFUS is nondestructive to murine skeletal muscle tissue (no necrosis, hemorrhage, or muscle stem cell activation) and initiates a largely M2-type macrophage response. We also demonstrate that local upregulation of chemoattractants in pFUS-treated skeletal muscle leads to enhance homing, permeability, and retention of human mesenchymal stem cells (MSC) and human endothelial precursor cells (EPC). Furthermore, the magnitude of MSC or EPC homing was increased when pFUS treatments and cell infusions were repeated daily. This study demonstrates that pFUS defines transient "molecular zip codes" of elevated chemoattractants in targeted muscle tissue, which effectively provides spatiotemporal control and tunability of the homing process for multiple stem cell types. pFUS is a clinically translatable modality that may ultimately improve homing efficiency and flexibility of cell therapies for cardiovascular diseases. PMID- 23922279 TI - Atomic-layer-deposition-assisted formation of carbon nanoflakes on metal oxides and energy storage application. AB - Nanostructured carbon is widely used in energy storage devices (e.g., Li-ion and Li-air batteries and supercapacitors). A new method is developed for the generation of carbon nanoflakes on various metal oxide nanostructures by combining atomic layer deposition (ALD) and glucose carbonization. Various metal oxide@nanoflake carbon (MO@f-C) core-branch nanostructures are obtained. For the mechanism, it is proposed that the ALD Al2 O3 and glucose form a composite layer. Upon thermal annealing, the composite layer becomes fragmented and moves outward, accompanied by carbon deposition on the alumina skeleton. When tested as electrochemical supercapacitor electrode, the hierarchical MO@f-C nanostructures exhibit better properties compared with the pristine metal oxides or the carbon coating without ALD. The enhancement can be ascribed to increased specific surface areas and electric conductivity due to the carbon flake coating. This peculiar carbon coating method with the unique hierarchical nanostructure may provide a new insight into the preparation of 'oxides + carbon' hybrid electrode materials for energy storage applications. PMID- 23922280 TI - Mobility and quality of life after discharge from a clinical geriatric setting focused on gender and age. AB - PURPOSE: The purpose of this study was to assess the long-term functional status and quality of life of older individuals with functional mobility impairment. DESIGN: A prospective longitudinal study was conducted. METHODS: The study sample consisted of elderly patients who had been admitted to a rehabilitation facility in Hamburg, Germany. Data were collected from February 2008 to August 2009 in the rehabilitation center and the living environment of the participants after discharge. Quality of life was assessed using the WHO Quality of Life-BREF; activities of daily living were measured using the Barthel-Index (BI). FINDINGS: Functional status and overall quality of life increased from admission (BI = 73.33) to 6 months postadmission (BI = 89.29) but decreased at 12 months postadmission (BI = 85.71). Quality of life significantly increased in the psychological domain from admission (57.85) to 6 months follow-up (67.85) (p = .010). Men showed a better functional status over time (p = .010) than women. Higher quality of life scores were associated with higher MMSE (p = .031) and self-efficacy scores (p = .019) at admission. CONCLUSION: The findings of this study suggest a need for interventions to improve functional status and quality of life in this population, especially following 6 months after discharge. CLINICAL RELEVANCE: Special interventions should address physical quality of life and physical functioning. Gender differences should be considered in planning and implementing programs. PMID- 23922281 TI - Wet-chemical preparation of copper foam monoliths with tunable densities and complex macroscopic shapes. AB - Macroscopic monoliths of copper foams have been prepared by a template-assisted wet-chemical process. The method offers subtle control over the pore size and size distribution, density and macroscopic size and shape of the metal foam. Uniaxial compression tests revealed different deformation behavior depending on the relative density. Non-vacuum-based and low-temperature routes are attractive for the cost-effective production of metal foams. PMID- 23922282 TI - Evaluation of the effectiveness of anterior cruciate ligament injury prevention programme training components: a systematic review and meta-analysis. AB - BACKGROUND: Anterior cruciate ligament (ACL) injury prevention programmes have shown mixed results, which may be due to differing emphasis on training components. The purpose of this study was to (1) quantify the overall and relative duration of each training component encompassed within these programmes and (2) examine the effect of these durations on ACL injury rates. METHODS: A systematic review was completed and meta-analyses performed on eligible studies to produce a pooled OR estimate of the effectiveness of these programmes. Meta regression was used to detect any relationship that programme duration and the duration of individual training components had on ACL injury rates. RESULTS: 13 studies were included for review. Results of the meta-analyses revealed a significant reduction of injuries after preventative training programmes for all ACL injuries (pooled OR estimate of 0.612, 95% CI 0.44 to 0.85; p=0.004) and for non-contact ACL injuries (OR 0.351, 95% CI 0.23 to 0.54; p<0.001). Results of meta-regression analysis revealed that a greater duration of balance training was associated with a higher injury risk for ACL injury (p=0.04), while greater durations of static stretching was associated with a lower injury risk for non contact ACL injuries (p=0.04). CONCLUSIONS: While ACL prevention programmes are successful in reducing the risk of ACL injury, the ideal combination and emphasis of training components within these programmes remains unclear. Evidence indicates that greater emphases on balance training and static stretching may be associated with an increase and decrease in injury risk, respectively. PMID- 23922283 TI - Induction of beta-cell replication by a synthetic HNF4alpha antagonist. AB - Increasing the number of beta cells is critical to a definitive therapy for diabetes. Previously, we discovered potent synthetic small molecule antagonists of the nuclear receptor transcription factor HNF4alpha. The natural ligands of HNF4alpha are thought to be fatty acids. Because obesity, in which there are high circulating levels of free fatty acids, is one of the few conditions leading to beta-cell hyperplasia, we tested the hypothesis that a potent HNF4alpha antagonist might stimulate beta-cell replication. A bioavailable HNF4alpha antagonist was injected into normal mice and rabbits and beta-cell ablated mice and the effect on beta-cell replication was measured. In normal mice and rabbits, the compound induced beta-cell replication and repressed the expression of multiple cyclin-dependent kinase inhibitors, including p16 that plays a critical role in suppressing beta-cell replication. Interestingly, in beta-cell ablated mice, the compound induced alpha- and delta-cell, in addition to beta-cell replication, and beta-cell number was substantially increased. Overall, the data presented here are consistent with a model in which the well-known effects of obesity and high fat diet on beta-cell replication occur by inhibition of HNF4alpha. The availability of a potent synthetic HNF4alpha antagonist raises the possibility that this effect might be a viable route to promote significant increases in beta-cell replication in diseases with reduced beta-cell mass, including type I and type II diabetes. PMID- 23922284 TI - Cloning and characterization of two EcR isoforms from Japanese pine sawyer, Monochamus alternates. AB - The ecdysone receptor (EcR) is the hormonal receptor of ecdysteroids, which regulates insect growth and development. In this study, we cloned and characterized two isoforms of EcR in Monochamus alternates named MaEcR A and MaEcR B. The cDNAs of MaEcR A and MaEcR B have open repeating frames of 1,695 and 1,392 bp, respectively. The deduced proteins have the same C-terminal sequence and varied in N-terminal, and are consistent with reports on other insect species, particularly with the receptor of another coleopteran, Tribolium castaneum. The isoform-specific developmental expression profile of EcR in the epidermis and the midgut were analyzed with quantitative real-time reverse transcriptase polymerase chain reaction in the pupal stage. RNA interference (RNAi) with common or isoform-specific regions induced developmental stagnation. When treated in the later larval stage, RNAi with either the common sequence or an EcR A specific sequence caused more severe effects and most larvae died prior to adulthood. The EcR B specific sequence caused less severe effects and about half of the treated larvae became adults, but some showed developmental defects. RNAi with both isoforms at early pupal stage attenuated the expression of 20E regulated genes E74, E75, and HR3. The study demonstrates the role of EcR in the transduction of ecdysteroid response in Monochamus alternatus. PMID- 23922285 TI - Using micro to manipulate nano. AB - A "Micro to nano" dewetting strategy is presented to generate multi-direction controlled, precise-positioning 1D assemblies of conductive silver (Ag) NPs based on a superhydrophobicity-directed assembly strategy. Electrons can transport along linear NP assemblies and their behavior is sustained by coating a coaxial protecting layer outside the nanostructures. This new concept might open new routes for NP-based nanoelectronic circuit fabrication. PMID- 23922286 TI - Correlation between participation in a cardiac rehabilitation program and quality of life of patients with coronary artery disease. AB - PURPOSE: To examine the correlation between participation in a cardiac rehabilitation (CR) program and quality of life (QoL). DESIGN: A prospective study of patients with coronary artery disease (CAD). METHODS: Participants completed questionnaires before and after a 3-month CR program. Patients were surveyed using a cardiac history evaluation and the MacNew Heart Disease Health Related QoL questionnaire. FINDINGS: Of those eligible, only 14% of the participants were women and 7% were of Arab ethnicity. Patients' QoL significantly improved following participation. Higher level of education was associated with improved QoL. Conversely, cardiac risk factor burden was associated with a decline in QoL. No association was found between cardiac risk stratification, age or religiosity and QoL. CONCLUSIONS: Improved QoL after CR program participation should raise awareness of the significant benefits of CR among healthcare professionals. CLINICAL RELEVANCE: CR for those patients with CAD should be implemented, with a focus on women and minorities. PMID- 23922287 TI - Preparation of anchovy (Engraulis japonicus) protein hydrolysates with high free radical-scavenging activity using endogenous and commercial enzymes. AB - Anchovy protein hydrolysates with high free radical-scavenging activity were prepared by endogenous and commercial enzymes. Various hydrolytic factors (commercial protease composition, protease concentration, temperature, and reaction time) were optimized. Using a single-factor experiment, three commercial proteases (Protamex, Flavourzyme 500 MG, and Alcalase 2.4 L) were selected for further optimization using a simplex lattice design. The optimum composition of Protamex:Flavourzyme 500 MG:Alcalase 2.4 L was found to be 1.1:1.0:0.9. The hydrolytic conditions (commercial protease concentration, temperature, and reaction time) for the optimum protease composition were optimized using a Box Behnken design. The optimum hydrolytic conditions were as follows: total commercial protease concentration of 3.27%, pH of 7.5, temperature of 55.4C, and reaction time of 2.7 h. Under these conditions, hydrolysate with a 1, 1-diphenyl 2-picryhydrazyl scavenging activity of 84.7% was obtained. Meanwhile, a degree of hydrolysis of 33.2% and high protein nitrogen recovery of 87.5% were achieved. The amino acid composition of the hydrolysates demonstrated that they have high nutritional value, thereby suggesting that the hydrolysates have potential to be used as raw material for functional food. PMID- 23922288 TI - Influence of maltodextrin and environmental stresses on stability of whey protein concentrate/kappa-carrageenan stabilized sesame oil-in-water emulsions. AB - The influence of maltodextrin with different concentrations (0-30%) and dextrose equivalent (dextrose equivalent 10 and dextrose equivalent 15) under different environmental stresses (pH 3-8, NaCl 0-500 mM, and sucrose 0-20%) on the stability of whey protein concentrate/kappa-carrageenan stabilized sesame oil-in water emulsions was investigated by mean particle diameter, particle size distribution, zeta-potential, microstructure, and viscosity. Sesame oil-in-water emulsions containing anionic droplets stabilized by interfacial membranes comprising whey protein concentrate/kappa-carrageenan/maltodextrin (15% sesame oil, 0.5% whey protein concentrate, 0.2% kappa-carrageenan, 0.02% sodium azide and 0-30% maltodextrin with dextrose equivalent of 10 and 15, 5 mM phosphate buffer, pH 7) were produced using a homogenizer. The primary emulsion (1 degrees ) containing whey protein concentrate-coated droplets was prepared by homogenizing. The secondary emulsion (2 degrees ) containing whey protein concentrate-kappa-carrageenan in the absence or presence of maltodextrin was produced by mixing the 1 degrees emulsion with an aqueous kappa-carrageenan in the absence or presence of maltodextrin solution. There were no significant changes in mean droplet diameter and zeta-potential of droplets at any maltodextrin concentration (0-30%) or dextrose equivalent (10 and 15) after 24 h storage. The apparent viscosity of emulsions increased when the maltodextrin concentration increased. The 2 degrees emulsion containing 15% maltodextrin with dextrose equivalent of 10 had the stability to aggregation at pH 6-8, NaCl <= 300 mM, and sucrose 0-20%. The addition of maltodextrin to emulsion can be used to form emulsions with different physicochemical properties for various applications in food processing (for example, encapsulation). PMID- 23922289 TI - Tunable electroluminescence in planar graphene/SiO(2) memristors. AB - Electroluminescence and resistive switching are first realized simultaneously in graphene/SiO2 memristor devices. The electroluminescence peaks can be tuned between 550 nm and 770 nm reliably via setting the device to different resistance states by applying different voltages. The combination of resistive switching and electroluminescence may bring new functionalities for these memristor devices which are fully compatible with silicon-based electronics. PMID- 23922290 TI - Effects of a 6-month nurse-led self-management program on comprehensive pulmonary rehabilitation for patients with COPD receiving home oxygen therapy. AB - PURPOSE: This study was to examine the effectiveness of a nurse-led 6-month comprehensive pulmonary rehabilitation program for stage IV chronic obstructive pulmonary disease patients receiving home oxygen therapy. DESIGN: A controlled clinical study was performed. METHODS: Face-to-face and telephone interviews were conducted with the intervention group, whereas conventional education was given to the control group. FINDINGS: Fifteen participants were analyzed in each group. There were no improvements in physiological outcomes; however, the severity of dyspnea, social activity, and walking distance significantly improved in the intervention group, and consequently quality of life was improved. Three patients in the intervention group received treatment for cold-like-symptoms but did not require hospitalization. However, five patients in the control group received treatment for cold-like-symptoms and two required hospitalization. CONCLUSIONS: The findings demonstrate that our program contributes to patients' learning of self-management skills and significantly improves dyspnea, social activity level, walking distance, and overall quality of life. PMID- 23922291 TI - Ancillary techniques on direct-smear aspirate slides: a significant evolution for cytopathology techniques. PMID- 23922292 TI - Reprogramming of two somatic nuclei in the same ooplasm leads to pluripotent embryonic stem cells. AB - The conversion of the nuclear program of a somatic cell from a differentiated to an undifferentiated state can be accomplished by transplanting its nucleus to an enucleated oocyte (somatic cell nuclear transfer [SCNT]) in a process termed "reprogramming." This process achieves pluripotency and occasionally also totipotency. Exploiting the obstacle of tetraploidy to full development in mammals, we show that mouse ooplasts transplanted with two somatic nuclei simultaneously (double SCNT) support preimplantation development and derivation of novel tetraploid SCNT embryonic stem cells (tNT-ESCs). Although the double SCNT embryos do not recapitulate the expression pattern of the pluripotency associated gene Oct4 in fertilized embryos, derivative tNT-ESCs have characteristics of genuine pluripotency: in vitro they differentiate into neurons, cardiomyocytes, and endodermal cells; in vivo, tNT-ESCs form teratomas, albeit at reduced rates compared to diploid counterparts. Global transcriptome analysis revealed only few specific alterations, for example, in the quantitative expression of gastrulation-associated genes. In conclusion, we have shown that the oocyte's reprogramming capacity is in excess of a single nucleus and that double nucleus-transplanted embryos and derivative ESCs are very similar to their diploid counterparts. These results have key implications for reprogramming studies based on pluripotency: while reprogramming in the tetraploid state was known from fusion-mediated reprogramming and from fetal and adult hepatocyte derived induced pluripotent stem cells, we have now accomplished it with enucleated oocytes. PMID- 23922293 TI - Use of primary cultures of Kenyon cells from bumblebee brains to assess pesticide side effects. AB - Bumblebees are important pollinators in natural and agricultural ecosystems. The latter results in the frequent exposure of bumblebees to pesticides. We report here on a new bioassay that uses primary cultures of neurons derived from adult bumblebee workers to evaluate possible side-effects of the neonicotinoid pesticide imidacloprid. Mushroom bodies (MBs) from the brains of bumblebee workers were dissected and dissociated to produce cultures of Kenyon cells (KCs). Cultured KCs typically extend branched, dendrite-like processes called neurites, with substantial growth evident 24-48 h after culture initiation. Exposure of cultured KCs obtained from newly eclosed adult workers to 2.5 parts per billion (ppb) imidacloprid, an environmentally relevant concentration of pesticide, did not have a detectable effect on neurite outgrowth. By contrast, in cultures prepared from newly eclosed adult bumblebees, inhibitory effects of imidacloprid were evident when the medium contained 25 ppb imidacloprid, and no growth was observed at 2,500 ppb. The KCs of older workers (13-day-old nurses and foragers) appeared to be more sensitive to imidacloprid than newly eclosed adults, as strong effects on KCs obtained from older nurses and foragers were also evident at 2.5 ppb imidacloprid. In conclusion, primary cultures using KCs of bumblebee worker brains offer a tool to assess sublethal effects of neurotoxic pesticides in vitro. Such studies also have the potential to contribute to the understanding of mechanisms of plasticity in the adult bumblebee brain. PMID- 23922294 TI - Electrochemically "writing" graphene from graphene oxide. AB - A novel approach of patterning graphene on conductive surfaces based on local electrochemical reduction of graphene oxide is reported. Graphene is "written" from typical graphene oxide dispersion by applying negative potential on conductive surfaces vs. a micrometer-sized counter electrode "pen" with scanning electrochemical microscopy (SECM). Micrometer scaled patterns are successfully generated on gold and stainless steel surfaces. PMID- 23922295 TI - Multifunctional hybrid nanocomposites with magnetically controlled reversible shape-memory effect. AB - Magneto-sensitivity and a thermo-sensitive reversible shape-memory effect have been successfully integrated into a hybrid nanocomposite, resulting in a magnetically controlled actuator. The complex requirements for gaining this multifunctionality are fulfilled by combining netpoints on the molecular and nano level in a polyesterurethane network prepared from hydroxyl group decorated magnetic nanoparticles, crystallizable star-shaped poly(omega-pentadecalactone) precursors, and a diisocyanate. PMID- 23922296 TI - Are computed tomography scans of cadavers perceived as a useful educational adjunct in a surgical anatomy course? PMID- 23922297 TI - Apodemes associated with limbs support serial homology of claws and jaws in Onychophora (velvet worms). AB - Although the onychophoran jaw blades are believed to be derivatives of foot claws, serial homology of these structures has not been demonstrated. To shed light on the evolutionary origin of the onychophoran jaws, we searched for morphological landmarks and compared the internal and external anatomy of jaws and distal leg portions in representatives of the two major onychophoran subgroups, the Peripatidae and Peripatopsidae. Our data revealed hitherto unknown structures associated with the onychophoran limbs, such as a soft diastemal membrane separating the anterior and posterior portions of the inner jaw blade (present only in Peripatidae), apodemes associated with feet, an eversible dorsal sac at the basis of each foot claw, and a specific arrangement of musculature associated with the sclerotised claws, jaws and their apodemes. Specific correspondences in structure and position of apodemes support serial homology of claws and jaws, suggesting that the onychophoran jaw evolved from the distal portion rather than the entire limb in the last common ancestor of Onychophora. PMID- 23922298 TI - Quantitative analysis of the efficacy of gradient table correction on improving the accuracy of fiber tractography. AB - PURPOSE: Several groups suggested that the gradient table of a DTI data set should be reoriented to compensate for head motion. Although the effects of this correction were demonstrated qualitatively, its efficacy was not demonstrated quantitatively to date. The main goal of this study was to investigate the efficacy of gradient table correction on improving the accuracy of fiber tractography. METHODS: First, the effects of gradient table correction on the estimation of fractional anisotropy (FA) maps and the primary diffusion direction were quantified and compared with the inherent uncertainty in the estimation process. Then, the effects of gradient table correction on tractography were quantified. RESULTS: The corrections in FA values were only a fraction of the typical values seen in major fasciculi and inter-subject variance. The corrections to the primary diffusion direction were also much smaller than the uncertainty inherent in the estimation of its direction. However, the directional estimates were biased due to head motion and deviated fiber tracking. CONCLUSIONS: Corrections to FA values were negligible and are not expected to affect group comparisons. However, a small but consistent bias was introduced to the estimates of primary diffusion direction, which might affect brain connectivity analyses based on fiber tracking. PMID- 23922299 TI - Merkel polyomavirus-specific T cells fluctuate with merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers. AB - PURPOSE: The persistent expression of Merkel cell polyomavirus (MCPyV) oncoproteins in Merkel cell carcinoma (MCC) provides a unique opportunity to characterize immune evasion mechanisms in human cancer. We isolated MCPyV specific T cells and determined their frequency and functional status. EXPERIMENTAL DESIGN: Multiparameter flow cytometry panels and HLA/peptide tetramers were used to identify and characterize T cells from tumors (n = 7) and blood (n = 18) of patients with MCC and control subjects (n = 10). PD-1 ligand (PD-L1) and CD8 expression within tumors were determined using mRNA profiling (n = 35) and immunohistochemistry (n = 13). RESULTS: MCPyV-specific CD8 T cells were detected directly ex vivo from the blood samples of 7 out of 11 (64%) patients with MCPyV-positive tumors. In contrast, 0 of 10 control subjects had detectable levels of these cells in their blood (P < 0.01). MCPyV-specific T cells in serial blood specimens increased with MCC disease progression and decreased with effective therapy. MCPyV-specific CD8 T cells and MCC-infiltrating lymphocytes expressed higher levels of therapeutically targetable PD-1 and Tim-3 inhibitory receptors compared with T cells specific to other human viruses (P < 0.01). PD-L1 was present in 9 of 13 (69%) MCCs and its expression was correlated with CD8 lymphocyte infiltration. CONCLUSIONS: MCC-targeting T cells expand with tumor burden and express high levels of immune checkpoint receptors PD-1 and Tim-3. Reversal of these inhibitory pathways is therefore a promising therapeutic approach for this virus-driven cancer. PMID- 23922300 TI - Characterization of CD45-/CD31+/CD105+ circulating cells in the peripheral blood of patients with gynecologic malignancies. AB - PURPOSE: Circulating endothelial cells (CEC) have been widely used as a prognostic biomarker and regarded as a promising strategy for monitoring the response to treatment in several cancers. However, the presence and biologic roles of CECs have remained controversial for decades because technical standards for the identification and quantification of CECs have not been established. Here, we hypothesized that CECs detected by flow cytometry might be monocytes rather than endothelial cells. EXPERIMENTAL DESIGN: The frequency of representative CEC subsets (i.e., CD45(-)/CD31(+), CD45(-)/CD31(+)/CD146(+), CD45(-)/CD31(+)/CD105(+)) was analyzed in the peripheral blood of patients with gynecologic cancer (n = 56) and healthy volunteers (n = 44). CD45(-)/CD31(+) cells, which are components of CECs, were isolated and the expression of various markers (CD146, CD105, vWF, and CD144 for endothelial cells; CD68 and CD14 for monocytes) was examined by immunocytochemistry. RESULTS: CD45(-)/CD31(+)/CD105(+) cells were significantly increased in the peripheral blood of patients with cancer, whereas evaluation of CD45(-)/CD31(+)/CD146(+) cells was not possible both in patients with cancer and healthy controls due to the limited resolution of the flow cytometry. Immunocytochemistry analyses showed that these CD45( )/CD31(+)/CD105(+) cells did not express vWF and CD146 but rather CD144. Furthermore, CD45(-)/CD31(+)/CD105(+) cells uniformly expressed the monocyte specific markers CD14 and CD68. These results suggest that CD45( )/CD31(+)/CD105(+) cells carry the characteristics of monocytes rather than endothelial cells. CONCLUSIONS: Our data indicate that CD45(-)/CD31(+)/CD105(+) circulating cells, which are significantly increased in the peripheral blood of patients with gynecologic cancer, are monocytes rather than endothelial cells. Further investigation is required to determine the biologic significance of their presence and function in relation with angiogenesis. PMID- 23922301 TI - Adoptive T-cell therapy for cancer: boutique therapy or treatment modality? AB - Adoptive cellular therapy, involving the ex vivo enrichment and expansion of antigen-specific immune cells for adoptive transfer, has emerged as an increasingly effective modality for the treatment of patients with advanced cancer refractory to conventional therapy. PMID- 23922302 TI - Efficacy of chemotherapy in BRCA1/2 mutation carrier ovarian cancer in the setting of PARP inhibitor resistance: a multi-institutional study. AB - PURPOSE: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated. EXPERIMENTAL DESIGN: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at >=200 mg twice daily for one month or more. Tumor samples were obtained in the post olaparib setting where feasible and analyzed by massively parallel sequencing. RESULTS: Data were collected from 89 patients who received a median of 3 (range 1 11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13-21] and 34 weeks (95% CI, 26-42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15-29) and OS of 45 weeks (95% CI, 15-75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0 0.375)]. CONCLUSIONS: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. PMID- 23922303 TI - Acute infection induces a metastatic niche: a double menace for cancer patients. AB - Tumor-derived factors can induce a premetastatic niche, yet little is known about how metastatic microenvironments are influenced by external insults, such as acute infections commonly seen in patients with cancer. New findings reveal increased metastasis to the lung after acute bacterial infection via the CXCR4/ubiquitin axis, suggesting new targets for antimetastasis therapeutics. PMID- 23922304 TI - Brg1 is required for stem cell maintenance in the murine intestinal epithelium in a tissue-specific manner. AB - Brg1 is a chromatin remodeling factor involved in mediation of a plethora of signaling pathways leading to its participation in various physiological processes both during development and in adult tissues. Among other signaling pathways, the Wnt pathway has been proposed to require Brg1 for transactivation of its target genes. Given the pivotal role of the Wnt pathway in the maintenance of normal intestinal homeostasis, we aimed to investigate the effects of Brg1 loss on the intestinal physiology. To this end, we deleted Brg1 in the murine small and large intestinal epithelia using a range of transgenic approaches. Pan epithelial loss of Brg1 in the small intestine resulted in crypt ablation, while partial Brg1 deficiency led to gradual repopulation of the intestinal mucosa with wild-type cells. In contrast, Brg1 loss in the large intestinal epithelium was compensated by upregulation of Brm. We propose that while Brg1 is dispensable for the survival and function of the progenitor and differentiated cells in the murine intestinal epithelium, it is essential for the maintenance of the stem cell population in a tissue-specific manner. PMID- 23922305 TI - Multitasking water-soluble synthetic G-quartets: from preferential RNA-quadruplex interaction to biocatalytic activity. AB - Natural G-quartets, a cyclic and coplanar array of four guanine residues held together through a Watson-Crick/Hoogsteen hydrogen-bond network, have received recently much attention due to their involvement in G-quadruplex DNA, an alternative higher-order DNA structure strongly suspected to play important roles in key cellular events. Besides this, synthetic G-quartets (SQ), which artificially mimic native G-quartets, have also been widely studied for their involvement in nanotechnological applications (i.e., nanowires, artificial ion channels, etc.). In contrast, intramolecular synthetic G-quartets (iSQ), also named template-assembled synthetic G-quartets (TASQ), have been more sparingly investigated, despite a technological potential just as interesting. Herein, we report on a particular iSQ named (PNA) DOTASQ, which demonstrates very interesting properties in terms of DNA and RNA interaction (notably its selective recognition of quadruplexes according to a bioinspired process) and catalytic activities, through its ability to perform peroxidase-like hemin-mediated oxidations either in an autonomous fashion (i.e., as pre-catalyst for TASQzyme reactions) or in conjunction with quadruplex DNA (i.e., as enhancing agents for DNAzyme processes). These results provide a solid scientific basis for TASQ to be used as multitasking tools for bionanotechnological applications. PMID- 23922306 TI - Clinical correlates in an experimental model of repetitive mild brain injury. AB - OBJECTIVE: Although there is growing awareness of the long-term cognitive effects of repetitive mild traumatic brain injury (rmTBI; eg, sports concussions), whether repeated concussions cause long-term cognitive deficits remains controversial. Moreover, whether cognitive deficits depend on increased amyloid beta deposition and tau phosphorylation or are worsened by the apolipoprotein E4 allele remains unknown. Here, we use an experimental model of rmTBI to address these clinical controversies. METHODS: A weight drop rmTBI model was used that results in cognitive deficits without loss of consciousness, seizures, or gross or microscopic evidence of brain damage. Cognitive function was assessed using a Morris water maze (MWM) paradigm. Immunostaining and enzyme-linked immunosorbent assay (ELISA) were used to assess amyloid beta deposition and tau hyperphosphorylation. Brain volume and white matter integrity were assessed by magnetic resonance imaging (MRI). RESULTS: Mice subjected to rmTBI daily or weekly but not biweekly or monthly had persistent cognitive deficits as long as 1 year after injuries. Long-term cognitive deficits were associated with increased astrocytosis but not tau phosphorylation or amyloid beta (by ELISA); plaques or tangles (by immunohistochemistry); or brain volume loss or changes in white matter integrity (by MRI). APOE4 was not associated with worse MWM performance after rmTBI. INTERPRETATION: Within the vulnerable time period between injuries, rmTBI produces long-term cognitive deficits independent of increased amyloid beta or tau phosphorylation. In this model, cognitive outcome is not influenced by APOE4 status. The data have implications for the long-term mental health of athletes who suffer multiple concussions. PMID- 23922307 TI - Determination of clinically relevant content for a musculoskeletal anatomy curriculum for physical medicine and rehabilitation residents. AB - To address the need for more clinical anatomy training in residency education, many postgraduate programs have implemented structured anatomy courses into their curriculum. Consensus often does not exist on specific content and level of detail of the content that should be included in such curricula. This article describes the use of the Delphi method to identify clinically relevant content to incorporate in a musculoskeletal anatomy curriculum for Physical Medicine and Rehabilitation (PM&R) residents. A two round modified Delphi involving PM&R experts was used to establish the curricular content. The anatomical structures and clinical conditions presented to the expert group were compiled using multiple sources: clinical musculoskeletal anatomy cases from the PM&R residency program at the University of Toronto; consultation with PM&R experts; and textbooks. In each round, experts rated the importance of each curricular item to PM&R residency education using a five-point Likert scale. Internal consistency (Cronbach's alpha) was used to determine consensus at the end of each round and agreement scores were used as an outcome measure to determine the content to include in the curriculum. The overall internal consistency in both rounds was 0.99. A total of 37 physiatrists from across Canada participated and the overall response rate over two rounds was 97%. The initial curricular list consisted of 361 items. After the second iteration, the list was reduced by 44%. By using a national consensus method we were able to objectively determine the relevant anatomical structures and clinical musculoskeletal conditions important in daily PM&R practice. PMID- 23922308 TI - Beat-to-beat variation in pulse wave velocity during breathing maneuvers. AB - PURPOSE: Thoracic pulse wave velocity (PWV) variation due to modulated trans mural pressure (TMP) may indicate mechanical properties of the aorta. Our aim was to measure beat-to-beat thoracic PWV and TMP to observe its normal variation during respiratory maneuvers. METHODS: We validated PWV measurements from a real time velocity projection MRI scan in a pulsatile phantom. A volunteer study showed inter-scan repeatability of steady-state PWV, and observed PWV variation when performing Mueller and Valsalva maneuvers. Synchronized to the real-time projection velocity data, TMP was measured using a mouth piece and pressure sensor arrangement monitoring the intra-thoracic pressure and a single arterial pressure measurement. RESULTS: In the phantom, beat-to-beat PWV derived from real time projection (5.33 +/- 0.32 m s(-1) ) agreed well with experimentally derived PWV using ultrasound probes (5.72 +/- 0.50 m s(-1) ). The within-subject PWV variation between scans was 0.28 m s(-1) . Volunteers' PWVs increased during Mueller maneuver (TMP increase of 14.67 +/- 10.69 mmHg) by 32% (P < 0.001), and during Valsalva maneuver (TMP decrease of TMP = 17.01 +/- 12.91 mmHg), PWV response were inconsistent with an average increase of 14% (P < 0.05). CONCLUSION: Gating TMP to beat-to-beat PWV allows insight into how aortic stiffness varies with strain. However, quantifying nonlinear arterial stiffness requires real-time arterial pressure measurement. PMID- 23922309 TI - Current update on the status of totally percutaneous aneurysm repair. AB - The evolution of minimally invasive procedures to treat aortic aneurysms has expanded to include access interventions as well. Traditionally, groin exposures have been the standard approach for common femoral artery exposure with open cutdown; however, inherent and related complications to that approach have paved the road to the percutaneous approach. Current available evidence from the literature supports the feasibility and the safety of percutaneous endovascular aneurysm repair (PEVAR); however, predictors of success are not well defined. We should examine all available studies (both prospective and retrospective) in order to draw a conclusion and evidence-based outcome for selecting patients who would benefit the most from PEVAR. PMID- 23922310 TI - Supramolecular Polymers Based on Efficient Pillar[5]arene-Neutral Guest Motifs. AB - Neutral and efficient: A neutral guest with a cyano site and a triazole site, which can be easily prepared and modified, is demonstrated to strongly bind with pillar[5]arene. Based on this new recognition motif, two neutral supramolecular polymers in organic media, which are currently unfeasible by means of host-guest interactions of crown ethers and calixarenes, were fabricated. One is AA/BB-type, and the other is A2/B3-type. PMID- 23922311 TI - Transient stress-based and strain-based hemolysis estimation in a simplified blood pump. AB - We compare two approaches to numerical estimation of mechanical hemolysis in a simplified blood pump model. The stress-based model relies on the instantaneous shear stress in the blood flow, whereas the strain-based model uses an additional tensor equation to relate distortion of red blood cells to a shear stress measure. We use the newly proposed least-squares finite element method (LSFEM) to prevent negative concentration fields and show a stable and volume preserving LSFEM for the tensor equation. Application of both models to a simplified centrifugal blood pump at three different operating conditions shows that the stress-based model overestimates the rate of hemolysis. The strain-based model is found to deliver lower hemolysis rates because it incorporates a more detailed description of biophysical phenomena into the simulation process. PMID- 23922312 TI - Dynamic compaction of human mesenchymal stem/precursor cells into spheres self activates caspase-dependent IL1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1). AB - Human mesenchymal stem/precursor cells (MSC) are similar to some other stem/progenitor cells in that they compact into spheres when cultured in hanging drops or on nonadherent surfaces. Assembly of MSC into spheres alters many of their properties, including enhanced secretion of factors that mediate inflammatory and immune responses. Here we demonstrated that MSC spontaneously aggregated into sphere-like structures after injection into a subcutaneous air pouch or the peritoneum of mice. The structures were similar to MSC spheres formed in cultures demonstrated by the increased expression of genes for inflammation-modulating factors TSG6, STC1, and COX2, a key enzyme in production of PGE2. To identify the signaling pathways involved, hanging drop cultures were used to follow the time-dependent changes in the cells as they compacted into spheres. Among the genes upregulated were genes for the stress-activated signaling pathway for IL1alpha/beta, and the contact-dependent signaling pathway for Notch. An inhibitor of caspases reduced the upregulation of IL1A/B expression, and inhibitors of IL1 signaling decreased production of PGE2, TSG6, and STC1. Also, inhibition of IL1A/B expression and secretion of PGE2 negated the anti-inflammatory effects of MSC spheres on stimulated macrophages. Experiments with gamma-secretase inhibitors suggested that Notch signaling was also required for production of PGE2 but not TSG6 or STC1. The results indicated that assembly of MSC into spheres triggers caspase-dependent IL1 signaling and the secretion of modulators of inflammation and immunity. Similar aggregation in vivo may account for some of the effects observed with administration of the cells in animal models. PMID- 23922313 TI - Robust inference from multiple test statistics via permutations: a better alternative to the single test statistic approach for randomized trials. AB - Formal inference in randomized clinical trials is based on controlling the type I error rate associated with a single pre-specified statistic. The deficiency of using just one method of analysis is that it depends on assumptions that may not be met. For robust inference, we propose pre-specifying multiple test statistics and relying on the minimum p-value for testing the null hypothesis of no treatment effect. The null hypothesis associated with the various test statistics is that the treatment groups are indistinguishable. The critical value for hypothesis testing comes from permutation distributions. Rejection of the null hypothesis when the smallest p-value is less than the critical value controls the type I error rate at its designated value. Even if one of the candidate test statistics has low power, the adverse effect on the power of the minimum p-value statistic is not much. Its use is illustrated with examples. We conclude that it is better to rely on the minimum p-value rather than a single statistic particularly when that single statistic is the logrank test, because of the cost and complexity of many survival trials. PMID- 23922314 TI - Red-light-induced cationic photopolymerization: perylene derivatives as efficient photoinitiators. AB - Nine different perylene derivatives are prepared and their ability to initiate, when combined with an iodonium salt (and optionally N-vinylcarbazole), a ring opening cationic photopolymerization of epoxides under very soft halogen lamp irradiation is investigated. One of them is particularly efficient under a red laser diode exposure at 635 nm and belongs now to the very few systems available at this wavelength. The photochemical mechanisms are studied by steady-state photolysis, electron spin resonance spin trapping, fluorescence, cyclic voltammetry, and laser flash photolysis techniques. PMID- 23922315 TI - Highly efficient construction of bisspirooxindoles containing vicinal spirocenters through an organocatalytic modified Feist-Benary reaction. AB - We have developed an organocatalytic modified Feist-Benary reaction of cyclic dicarbonyl compounds, isatins and cyclic alpha-bromo dicarbonyl compounds. This method affords bisspirooxindole-fused dihydrofurans containing two vicinal spiro centers. To the best of our knowledge, employing cyclic alpha-halo dicarbonyl compounds for the synthesis of bisspirooxindole-fused dihydrofurans has not been previously reported. PMID- 23922316 TI - Finite element analysis on longitudinal and radial functionally graded femoral prosthesis. AB - This study focused on developing a 3D finite element model of functionally graded femoral prostheses to decrease stress shielding and to improve total hip replacement performance. The mechanical properties of the modeled functionally graded femoral prostheses were adjusted in the sagittal and transverse planes by changing the volume fraction gradient exponent. Prostheses with material changes in the sagittal and transverse planes were considered longitudinal and radial prostheses, respectively. The effects of cemented and noncemented implantation methods were also considered in this study. Strain energy and von Mises stresses were determined at the femoral proximal metaphysis and interfaces of the implanted femur components, respectively. Results demonstrated that the strain energy increased proportionally with increasing volume fraction gradient exponent, whereas the interface stresses decreased on the prostheses surfaces. A limited increase was also observed at the surfaces of the bone and cement. The periprosthetic femur with a noncemented prosthesis exhibited higher strain energy than with a cemented prosthesis. Radial prostheses implantation displayed more strain energy than longitudinal prostheses implantation in the femoral proximal part. Functionally graded materials also increased strain energy and exhibited promising potentials as substitutes of conventional materials to decrease stress shielding and to enhance total hip replacement lifespan. PMID- 23922317 TI - Polydiacetylene-peptide 1D nanomaterials. AB - Polydiacetylenes have received intense attention on account of their well established chromic alterations that are detectable often by the naked eye, making them ideal for a variety of applications such as biosensory materials. These polymers have been fabricated in a variety of materials platforms including 3D crystals, 2D monolayers, and 0D spherical vesicles; however, 1D morphologies that might be useful for directional energy migration are less common. This article describes the development and current research efforts of protein-based 1D nanowire-like supramolecular assemblies with embedded polydiacetylenes. PMID- 23922318 TI - Molecular functions of the LIM-homeobox transcription factor Lhx2 in hematopoietic progenitor cells derived from mouse embryonic stem cells. AB - We previously demonstrated that hematopoietic stem cell (HSC)-like cells are robustly expanded from mouse embryonic stem cells (ESCs) by enforced expression of Lhx2, a LIM-homeobox domain (LIM-HD) transcription factor. In this study, we analyzed the functions of Lhx2 in that process using an ESC line harboring an inducible Lhx2 gene cassette. When ESCs are cultured on OP9 stromal cells, hematopoietic progenitor cells (HPCs) are differentiated and these HPCs are prone to undergo rapid differentiation into mature hematopoietic cells. Lhx2 inhibited differentiation of HPCs into mature hematopoietic cells and this effect would lead to accumulation of HSC-like cells. LIM-HD factors interact with LIM domain binding (Ldb) protein and this interaction abrogates binding of LIM-only (Lmo) protein to Ldb. We found that one of Lmo protein, Lmo2, was unstable due to dissociation of Lmo2 from Ldb1 in the presence of Lhx2. This effect of Lhx2 on the amount of Lmo2 contributed into accumulation of HSC-like cells, since enforced expression of Lmo2 into HSC-like cells inhibited their self-renewal. Expression of Gata3 and Tal1/Scl was increased in HSC-like cells and enforced expression of Lmo2 reduced expression of Gata3 but not Tal1/Scl. Enforced expression of Gata3 into HPCs inhibited mature hematopoietic cell differentiation, whereas Gata3-knockdown abrogated the Lhx2-mediated expansion of HPCs. We propose that multiple transcription factors/cofactors are involved in the Lhx2-mediated expansion of HSC-like cells from ESCs. Lhx2 appears to fine tune the balance between self-renewal and differentiation of HSC-like cells. PMID- 23922319 TI - A combined experimental and computational study of linear ruthenium(II) coordination oligomers with end-capping organic redox sites: insight into the light absorption and charge delocalization. AB - Two series of linear ruthenium coordination oligomers, [(Ntpy)Ru(n)(tppz)(n 1)(tpy)](2n+) (mono-Ntpy series, n = 1-3) and [(Ntpy)2Ru(n)(tppz)(n-1)](2n+) (bis Ntpy series, n = 1-3) have been prepared, where Ntpy is the capping ligand 4'-di p-anisylamino-2,2':6',2''-terpyridine, tppz is tetra-2-pyridylpyrazine, and tpy is 2,2':6',2''-terpyridine. The electrochemical measurements evidence oxidation events from both the amine segments and the metal centers and reduction waves from tppz and the capping ligands. Both series complexes display much enhanced light absorption with respect to model complexes without terminal amine units. Density functional theory (DFT) calculations have been performed on both series and time-dependent DFT (TD-DFT) calculations have been performed on the bis-Ntpy series compounds (n = 1-4) to characterize their electronic structures and excited states and predict the electronic properties of long-chain polymers. Upon one-electron oxidation, the mono-Ntpy-series monoruthenium and diruthenium complexes display N(+)-localized transitions and metal-to-nitrogen charge transfer (MNCT) transitions in the near-infrared (NIR) region. DFT and TD-DFT computations on the one-electron-oxidized forms of the mono-Ntpy-series compounds (n = 1-4) provide insight into the nature of the MNCT transitions and the degree of charge delocalization. PMID- 23922320 TI - A mutation in the promoter region of zipA, a component of the divisome, suppresses the shape defect of RodZ-deficient cells. AB - RodZ is important for maintaining the rod shape of Escherichia coli. Loss of RodZ causes conversion of the rod shape to a round shape and a growth rate slower than that of wild-type cells. Suppressor mutations that simultaneously restore both the growth rates and the rod shape were isolated. Most of the suppressor mutations are found in mreB, mrdA, or mrdB. One of the mutations was in the promoter region of zipA, which encodes a crucial component of the cell division machinery. In this study, we investigated the mechanism of the suppression by this mutation. ZipA was slightly but significantly increased in the suppressor cells and led to a delay in cell division. While round-shaped mreB and mrdA mutants lose cell bipolarity, we found that round-shaped rodZ mutants retained cell bipolarity. Therefore, we concluded that a delay in the completion of septation provides extra time to elongate the cell laterally so that the zipA suppressor mutant is able to recover its ovoid or rod shape. The suppression by zipA demonstrates that the regulation of timing of septation potentially contributes to the conversion of morphology in bacterial cells. PMID- 23922321 TI - Early outgrowth cells release soluble endocrine antifibrotic factors that reduce progressive organ fibrosis. AB - Adult bone marrow-derived cells can improve organ function in chronic disease models, ostensibly by the release of paracrine factors. It has, however, been difficult to reconcile this prevailing paradigm with the lack of cell retention within injured organs and their rapid migration to the reticuloendothelial system. Here, we provide evidence that the salutary antifibrotic effects of bone marrow-derived early outgrowth cells (EOCs) are more consistent with an endocrine mode of action, demonstrating not only the presence of antifibrotic factors in the plasma of EOC-treated rats but also that EOC conditioned medium (EOC-CM) potently attenuates both TGF-beta- and angiotensin II-induced fibroblast collagen production in vitro. To examine the therapeutic relevance of these findings in vivo, 5/6 subtotally nephrectomized rats, a model of chronic kidney and heart failure characterized by progressive fibrosis of both organs, were randomized to receive i.v. injections of EOC-CM, unconditioned medium, or 10(6) EOCs. Rats that received unconditioned medium developed severe kidney injury with cardiac diastolic dysfunction. In comparison, EOC-CM-treated rats demonstrated substantially improved renal and cardiac function and structure, mimicking the changes found in EOC-treated animals. Mass spectrometric analysis of EOC-CM identified proteins that regulate cellular functions implicated in fibrosis. These results indicate that EOCs secrete soluble factor(s) with highly potent antifibrotic activity, that when injected intravenously replicate the salutary effects of the cells themselves. Together, these findings suggest that an endocrine mode of action may underlie the effectiveness of cell therapy in certain settings and portend the possibility for systemic delivery of cell-free therapy. PMID- 23922322 TI - Re-using Mini-Sentinel data following rapid assessments of potential safety signals via modular analytic programs. AB - The U.S. Food and Drug Administration (FDA)'s Mini-Sentinel pilot has created a distributed data system with over 125 million lives and nearly 350 million person years of observation time. The pilot allows the FDA to use modular analytic programs to assess suspected safety signals quickly. The FDA convened a committee to assess the implications of such rapid assessments on subsequent analyses of the same product-outcome pair using the same data. The committee offers several non-binding recommendations based on the strength of the knowledge of the suspected association before running the analysis: signal generation (an analysis with no prior), signal refinement (an analysis with a weak or moderate prior), and signal evaluation (an analysis with a strong prior). The committee believes that modular programs (MPs) are most useful for signal refinement. If MPs are used for analyses with no or weak/moderate priors, the committee members generally agree that the data may be re-used if certain conditions are met. When there is a strong prior, the committee recommends that a protocol-based assessment be used; Mini-Sentinel data may be analyzed by MPs and re-used only under very uncommon circumstances. The committee agrees that any subsequent assessment of the same product-outcome pair that follows an MP analysis should not be interpreted as independent confirmation of the association, such as would be established via replication of the same product-outcome association in two different populations. Instead, the follow-up assessment should be interpreted as an analysis that has reduced insofar as possible systematic errors that may have been present or residual in the original MP analysis. The committee also discussed how this general framework may apply to two completed rapid assessments of dabigatran and bleeding risk and of olmesartan and celiac disease risk. PMID- 23922323 TI - Ultra high performance liquid chromatography with ion-trap TOF-MS for the fast characterization of flavonoids in Citrus bergamia juice. AB - We have developed a fast ultra HPLC with ion-trap TOF-MS method for the analysis of flavonoids in Citrus bergamia juice. With respect to the typical methods for the analysis of these matrices based on conventional HPLC techniques, a tenfold faster separation was attained. The use of a core-shell particle column ensured high resolution within the fast analysis time of only 5 min. Unambiguous determination of flavonoid identity was obtained by the employment of a hybrid ion-trap TOF mass spectrometer with high mass accuracy (average error 1.69 ppm). The system showed good retention time and peak area repeatability, with maximum RSD% values of 0.36 and 3.86, respectively, as well as good linearity (R(2) >= 0.99). Our results show that ultra HPLC can be a useful tool for ultra fast qualitative/quantitative analysis of flavonoid compounds in citrus fruit juices. PMID- 23922324 TI - Is obesity a risk factor for impaired cognition in young adults with low birth weight? AB - BACKGROUND: Overweight and obesity are risk factors for cardiovascular disease. There is also an association between body mass index (BMI) and cognitive ability. Since low birth weight is associated with adult metabolic disease, particularly in obese subjects, the question emerges whether obesity has an additional negative effect on cognitive function in subjects with low birth weight. OBJECTIVES: The aim was to analyse whether overweight or obesity influence intellectual performance in young adults with particular focus on those with a low birth weight. METHODS: Data were collected from the Swedish Medical Birth Register on 620,834 males born between 1973 and 1988 and matched to results on intellectual performance and BMI at conscription. RESULTS: The risk for low intellectual performance was higher for those with high BMI compared to those with normal. The highest risk was found among subjects with low birth weight and overweight or obesity in young adulthood (odds ratios, 1.98 [1.73-2.22] and 2.59 [2.00-3.34], respectively). However, subjects with further high birth weight and a high BMI at conscription had no further increased risk. CONCLUSIONS: Overweight and obesity are associated with an increased risk of subnormal intellectual performance in young adult males. Subjects with low birth weight and adolescent overweight/obesity are at particular risk of subnormal performance. A high birth weight increases the risk for obesity, but a high adult BMI does not further increase the risk for subnormal performance. PMID- 23922325 TI - Contribute to the selection of the American College of Toxicology. PMID- 23922326 TI - Using immunotoxicity information to improve cancer risk assessment for polycyclic aromatic hydrocarbon mixtures. AB - Estimating cancer risk from environmental mixtures containing polycyclic aromatic hydrocarbons (PAHs) is challenging. Ideally, each mixture would undergo toxicity testing to derive a cancer slope factor (CSF) for use in site-specific cancer risk assessments. However, this whole mixture approach is extremely costly in terms of finances, time, and animal usage. Alternatively, if an untested mixture is "sufficiently similar" to a well-characterized mixture with a CSF, the "surrogate" CSF can be used in risk assessments. We propose that similarity between 2 mixtures could be established using an in vitro battery of genotoxic and nongenotoxic tests. An observed association between carcinogenicity and immunosuppression of PAHs suggests that the addition of immune suppression assays may improve this battery. First, using published studies of benzo[a]pyrene (BaP) and other PAHs, we demonstrated a correlation between the derived immune suppression relative potency factors (RPFs) for 9 PAHs and their respective cancer RPFs, confirming observations published previously. Second, we constructed an integrated knowledge map for immune suppression by BaP based on the available mechanistic information. The map illustrates the mechanistic complexities involved in BaP immunosuppression, suggesting that multiple in vitro tests of immune suppression involving different processes, cell types, and tissues will have greater predictive value for immune suppression in vivo than a single test. Based on these observations, research strategies are recommended to validate a battery of in vitro immune suppression tests that, along with tests for genotoxic and other nongenotoxic modes of cancer action, could be used to establish "sufficient similarity" of 2 mixtures for site-specific cancer risk assessments. PMID- 23922327 TI - The random card sort method and respondent certainty in contingent valuation: an exploratory investigation of range bias. AB - Willingness to pay (WTP) values derived from contingent valuation surveys are prone to a number of biases. Range bias occurs when the range of money values presented to respondents in a payment card affects their stated WTP values. This paper reports the results of an exploratory study whose aim was to investigate whether the effects of range bias can be reduced through the use of an alternative to the standard payment card method, namely, a random card sort method. The results suggest that the random card sort method is prone to range bias but that this bias may be mitigated by restricting the analysis to the WTP values of those respondents who indicate they are 'definitely sure' they would pay their stated WTP. PMID- 23922328 TI - Oncogene-induced cellular senescence elicits an anti-Warburg effect. AB - Oncogene-induced senescence is now recognized as being an important mechanism in protecting against cancer. The phenotypic consequences, i.e., the inhibition of cell proliferation, are well described in model systems and specific events/key players defined. However, there is still the need to understand, at a more global level, the network of events involved both in terms of cause and consequence. This paper shows the power of systematic proteomic analyses, both targeted and global, in addressing such biological questions, highlighting the widespread nature of histone acetylation changes, and the opposite metabolic changes to those seen in the Warburg effect. PMID- 23922329 TI - Charged surfactants induce a non-fibrillar aggregation pathway of amyloid-beta peptide. AB - The amyloid beta-peptide with a sequence of 42 amino acids is the major constituent of extracellular amyloid deposits in Alzheimer's disease plaques. The control of the peptide self-assembly is difficult to achieve because the process is fast and is affected by many variables. In this paper, we describe the effect of different charged and non-charged surfactants on Abeta(1-42) fibrillation to define common alternate aggregation pathways. The characterization of the peptide surfactant interactions by ultra-structural analysis, thioflavin T assay and secondary structure analysis, suggested that charged surfactants interact with Abeta(1-42) through electrostatic interactions. Charged micelles slow down the aggregation process and stabilize the peptide in the oligomeric state, whereas non-charged surfactants promote the Abeta(1-42) fibril formation. PMID- 23922330 TI - PET-guided biopsy with needle navigation facilitates diagnosis of angiosarcoma in neurofibromatosis type 1. AB - Malignant degeneration frequently arises from preexisting plexiform neurofibroma in patients with neurofibromatosis type 1 (NF1). Image guided biopsy for diagnostic purposes, such as with CT guidance, can be technically challenging in these patients, as CT cannot distinguish malignant from benign areas within the same tumor. Navigation with multi-modality (PET, CT, and ultrasound) image fusion facilitated the successful biopsy and diagnosis of angiosarcoma arising from a pelvic neurofibroma in a patient with NF1. Successful targeting assisted treatment selection in this case. This novel navigation technique may facilitate the otherwise difficult diagnosis of malignancy in patients with NF1. PMID- 23922331 TI - STIM1 and STIM2-mediated Ca(2+) influx regulates antitumour immunity by CD8(+) T cells. AB - Store-operated calcium entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels regulates the function of many immune cells. Patients with loss of-function mutations in the CRAC channel genes ORAI1 or STIM1 are immunodeficient and are prone to develop virus-associated tumours. This and the reported role of Ca(2+) signals in cytotoxic lymphocyte function suggest that SOCE may be critical for tumour immune surveillance. Using conditional knock out mice lacking STIM1 and its homologue STIM2, we find that SOCE in CD8(+) T cells is required to prevent the engraftment of melanoma and colon carcinoma cells and to control tumour growth. SOCE is essential for the cytotoxic function of CTLs both in vivo and in vitro by regulating the degranulation of CTLs, their expression of Fas ligand and production of TNF-alpha and IFN-gamma. Our results emphasize an important role of SOCE in antitumour immunity, which is significant given recent reports arguing in favour of CRAC channel inhibition for cancer therapy. PMID- 23922332 TI - Health care utilization among homebound elders: does caregiver burden play a role? AB - OBJECTIVE: To describe informal caregiver and patient characteristics associated with high caregiver burden in homebound elders and to examine associations between high caregiver burden and patient health care utilization at the practice level. METHOD: We used a cross-sectional and prospective cohort design to study 214 caregiver-patient dyads in a home-based primary care program. RESULTS: Informal caregivers with the highest burden were more likely to help with more activities of daily living and instrumental activities of daily living and spend >40 hr/week in caregiving. Patients whose caregivers experienced the highest burden were more likely to be non-White males without 24-hr paid homecare. There were no significant independent associations between high burden and high calls, high visits, or social work involvement. DISCUSSION: In this medically complex and highly dependent population, further study of how families and other caregivers impact health care utilization is needed. PMID- 23922333 TI - Diketopyrrolopyrrole-thiophene-based acceptor-donor-acceptor conjugated materials for high-performance field-effect transistors. AB - We report the synthesis, morphology, and field-effect-transistor (FET) characteristics of new acceptor-donor-acceptor conjugated materials that consist of diketopyrrolopyrrole (DPP) acceptor groups and one of four different thiophene moieties, that is, dithiophene (2T), thieno[3,2-b]-thiophene (TT), dithieno[3,2 b:2',3'-d]-thiophene (DTT), and 5,5'''-di-(2-ethylhexyl) [2,3';5',2'';4'',2''']quaterthiophene (4T). The optical band gaps of the as prepared materials are smaller than 1.7 eV, which is attributed to the strong intramolecular charge transfer and the backbone coplanarity of the thiophene moieties. The order of both crystallinity and FET mobility (*10(-2)-*10(-4) cm(2) V(-1) s(-1)) is >>>DTT2DP, which differ in the structure of the pi-conjugated cores and core symmetry. Well-ordered intermolecular chain packing was confirmed by the GIXD and AFM results. In particular, the FET hole mobility of was further improved to 0.1 cm(2) V(-1) s(-1), which was attributed to the well interconnected structure through solution-shearing. These experimental results suggest the potential applications of the new DPP-thiophene-DPP conjugated materials for organic electronic devices. PMID- 23922334 TI - Effect of high porosity on biodegradation of poly (4-hydroxybutyrate) in vivo. AB - Poly-4-hydroxybutyrate, P(4HB), is a biosynthetic thermoplastic polymer that has been studied as a bio-absorbable medical material. In order to explore the in vivo biodegradation behaviour of porous P(4HB) membranes with specified apertures (89-150 um), membranes with different porosities were implanted subcutaneously into the backs of 27 eight-week-old Sprague Dawley(r) rats. The implanted specimens were examined with Masson and hematoxylin and eosin staining. Masson staining indicated that the P(4HB) membranes were encased in fibrous cysts and that more collagen fibers were present within the sections of the hyper-porosity group. Hematoxylin and eosin staining showed that the residual area of the P(4HB) membranes in the hyper-porosity group decreased sharply compared to the hypo porosity group, which implied that the P(4HB) membranes with higher porosity degraded faster than those with lower porosity. A slow degradation phase persisted for approximately 14 weeks during the degradation process. After the 16th week, the P(4HB) scaffolds fell into a fast degradation phase. The residual areas of the hyper-porosity P(4HB) membranes at the 32nd week were reduced by 39.76% compared with the second week after implantation. We concluded that P(4HB) membranes manifest a special biodegradation behavior in vivo and that the increased porosity of these membranes is an important factor favoring their biodegradation rates. PMID- 23922335 TI - alpha-Arylation, alpha-arylative esterification, or acylation: a stoichiometry dependent trichotomy in the Pd-catalyzed cross-coupling between aldehydes and aryl bromides. PMID- 23922336 TI - Heart rate variability and experimentally induced pain in healthy adults: a systematic review. AB - BACKGROUND: Reactivity of the autonomic nervous system to experimental pain stimuli has been extensively studied using measures of heart rate and blood pressure. Heart rate variability (HRV) attempts to tease out the relative contributions of sympathetic and parasympathetic activity in the autonomic control of the heart and may therefore be more appropriate to investigate autonomic response to short-term nociceptive stimulation in detail. The current evidence on HRV and experimentally induced pain has not yet been synthesized within a systematic review. METHOD: English articles indexed in PubMed, EMBASE, Psyndex, PsycINFO, CINAHL and the Cochrane Library were reviewed for eligibility under pre-specified inclusion criteria. Studies were included when they reported empirical work on autonomic response (specifically, HRV) to experimentally induced pain in healthy adults. The method of pain induction, the methodological features of HRV analysis (time domain and frequency domain measures), as well as pain and HRV-related findings were derived from the studies. RESULTS: The search revealed a total of 20 publications eligible for inclusion. Key results demonstrate an increase in sympathetic-baroreflex activity and a decrease in vagal-parasympathetic activity as reflected by changes in frequency domain measures of HRV. CONCLUSION: HRV has several advantages compared to other measures of autonomic reactivity in studies investigating physiological response to nociceptive stimulation. Future studies should focus on comparisons between different methods of pain induction, interindividual variability in pain sensitivity by baseline autonomic activity, and the implications of both on the use of HRV within routine clinical evaluations. PMID- 23922337 TI - Ottawa needs to address social determinants of health, Canadians tell CMA. PMID- 23922338 TI - A chat with Cabinet Minister Dr. Kellie Leitch. Interview by Roger Collier. PMID- 23922339 TI - A discussion with digital health pioneer Dr. Eric Topol. Interview by Paul Webster. PMID- 23922341 TI - New health minister doesn't mean new regime, say experts. PMID- 23922342 TI - Persistent dry cough: an unusual presentation of renal cell carcinoma. PMID- 23922343 TI - Federal government should take a bigger role in health care, leaders say. PMID- 23922344 TI - Iron deficiency in early childhood. PMID- 23922345 TI - Poor diet takes toll on health of US population. PMID- 23922346 TI - Relation between place of residence and postpartum depression. AB - BACKGROUND: The relation between place of residence and risk of postpartum depression is uncertain. We evaluated the relation between place of residence and risk of postpartum depression in a population-based sample of Canadian women. METHODS: Female postpartum respondents to the 2006 Canadian Maternity Experiences Survey (n=6126) were classified as living in rural (<1000 inhabitants or population density<400/km2), semirural (nonrural but <30,000 inhabitants), semiurban (30 000-499 999 inhabitants) or urban (>=500,000 inhabitants) areas. We further subdivided women living in rural areas based on the social and occupational connectivity of their community to larger urban centres. We compared the prevalence of postpartum depression (score of >=13 on the Edinburgh Postnatal Depression Scale) across these groups and adjusted for the effect of known risk factors for postpartum depression. RESULTS: The prevalence of postpartum depression was higher among women living in urban areas than among those living in rural, semirural or semiurban areas. The difference between semiurban and urban areas could not be fully explained by other measured risk factors for postpartum depression (adjusted odds ratio 0.60, 95% confidence interval 0.42 0.84). In rural areas, there was a nonsignificant gradient of risk: women with less connection to larger urban centres were at greater risk of postpartum depression than women in areas with greater connection. INTERPRETATION: There are systematic differences in the distribution of risk factors for postpartum depression across geographic areas, resulting in an increased risk of depression among women living in large urban areas. Prevention programs directed at modifiable risk factors (e.g., social support) could specifically target women living in these areas to reduce the rates of postpartum depression. PMID- 23922347 TI - Approach to follow-up of the patient with differentiated thyroid cancer and positive anti-thyroglobulin antibodies. AB - Anti-thyroglobulin antibodies are commonly identified in patients with differentiated follicular cell-derived thyroid cancer. When present, they interfere with the measurement of thyroglobulin (Tg), which is the primary biochemical marker used for disease surveillance, creating challenges in monitoring patients for residual or recurrent disease. Moreover, there is variability in measuring anti-Tg antibodies according to the different assays, such that not all patients with anti-Tg antibodies are identifiable on a single assay system. The persistence of anti-Tg antibodies, especially if levels are rising, may indicate persistent, recurrent, or progressive thyroid cancer. In contrast, declining anti-Tg antibody levels may indicate reduced tumor burden or the absence of disease. In this review, we will explore in a case-based manner the data supporting monitoring and treatment paradigms for patients with anti-Tg antibodies and will stress areas where more evidence is needed to better inform clinicians regarding the management of patients with this challenging situation. PMID- 23922354 TI - Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. AB - CONTEXT: Public health authorities around the world recommend widely variable supplementation strategies for adults, whereas several professional organizations, including The Endocrine Society, recommend higher supplementation. METHODS: We analyzed published randomized controlled clinical trials to define the optimal intake or vitamin D status for bone and extraskeletal health. CONCLUSIONS: The extraskeletal effects of vitamin D are plausible as based on preclinical data and observational studies. However, apart from the beneficial effects of 800 IU/d of vitamin D3 for reduction of falls in the elderly, causality remains yet unproven in randomized controlled trials (RCTs). The greatest risk for cancer, infections, cardiovascular and metabolic diseases is associated with 25-hydroxyvitamin D (25OHD) levels below 20 ng/mL. There is ample evidence from RCTs that calcium and bone homeostasis, estimated from serum 1,25 dihydroxyvitamin D and PTH, calcium absorption, or bone mass, can be normalized by 25OHD levels above 20 ng/mL. Moreover, vitamin D supplementation (800 IU/d) in combination with calcium can reduce fracture incidence by about 20%. Such a dose will bring serum levels of 25OHD above 20 ng/mL in nearly all postmenopausal women. Based on calculations of the metabolic clearance of 25OHD, a daily intake of 500-700 IU of vitamin D3 is sufficient to maintain serum 25OHD levels of 20 ng/mL. Therefore, the recommendations for a daily intake of 1500-2000 IU/d or serum 25OHD levels of 30 ng or higher for all adults or elderly subjects, as suggested by The Endocrine Society Task Force, are premature. Fortunately, ongoing RCTs will help to guide us to solve this important public health question. PMID- 23922355 TI - One cancer destroys another: short report of a myeloid sarcoma causing ischaemic necrosis of an adenocarcinoma. AB - We present a highly unusual case and histological images of a patient who underwent complete resection of a perforated caecal adenocarcinoma caused by angiodestruction of the proximal vasculature by a distinct acute myeloid infiltrate. Both tumours were removed in their entirety at one visit to theatre and the patient remains well and in remission 18 months later. PMID- 23922356 TI - Prognostic implications of anaplastic lymphoma kinase gene aberrations in rhabdomyosarcoma; an immunohistochemical and fluorescence in situ hybridisation study. AB - BACKGROUND: We investigated the diagnostic and prognostic usefulness of anaplastic lymphoma kinase (ALK) expression in Asian rhabdomyosarcoma (RMS) patients. PATIENTS AND METHODS: A total of 38 RMS tissue samples were collected over a 14-year period (1998-2012). ALK protein expression and gene copy number were analysed by immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH). RESULTS: Ten of the 38 RMS patients (26.3%) showed positive ALK protein expression. ALK protein expression was predominantly positive in alveolar RMS (ARMS) compared with embryonal RMS (ERMS) (80% vs 20%, p=0.03). ALK protein expression was statistically associated with ARMS histology, metastatic disease at diagnosis, and primary trunk site. In FISH analysis, no translocations were detected and ALK gene copy number gain was observed more frequently in ARMS than in ERMS (40% vs 17%). The ALK-positive group showed inferior overall survival (OS) compared with ALK-negative group (p=0.014) for both alveolar and embryonal RMS patients. In multivariate analysis, positive ALK expression was an independent prognostic factor for OS (p=0.02; HR, 3.1; 95% CI 1.2 to 8.3). There was a significant strong positive correlation between ALK gene copy number and protein expression (Spearman's r<0.001, r=0.77). CONCLUSIONS: We demonstrated that ALK protein expression is statistically associated with ARMS histology, metastatic disease at diagnosis and primary trunk site. Additionally, ALK expression was an independent prognostic factor for worse survival. There was a strong correlation between IHC and FISH. Further studies are needed to evaluate the potential diagnostic and therapeutic role of ALK expression in RMS. PMID- 23922357 TI - Columnar cell-like changes in the male breast. AB - AIMS: Columnar cell lesions are known as a link between normal breast and low grade neoplastic lesions in female, but have not been established in the male breast. This study evaluated the presence of ducts showing columnar cell-like features in the male breast. METHODS: Seventy-one consecutive surgical resections from men (6 invasive breast carcinoma of grade 3, 1 atypical ductal hyperplasia and 64 other lesions) were reviewed to identify foci of dilated ducts with columnar epithelial cells, and their morphological features including apical snouts, intraluminal secretions and calcifications were assessed. The expression of CK5/6 and estrogen receptor (ER) was evaluated immunohistochemically. Clinicopathological features including patients' age, histological diagnosis and gynaecomastoid hyperplasia were documented. RESULTS: Ducts showing columnar cell like features were identified in 39 cases, morphologically as distended ducts with round or undulating outline. There was an outer layer of myoepithelial cells and an inner layer of columnar luminal cells showing apical snouts, but without intraluminal secretions or calcifications. Immunohistochemically, these columnar epithelial cells were negative for CK5/6 in 38/39 cases and all were ER heterogeneously positive. These changes were associated with older age, but their incidence did not differ whether they were associated with invasive breast carcinoma, atypical ductal hyperplasia and other lesions. CONCLUSIONS: In the male breast, there is an entity sharing morphological features and immunohistochemical profile of columnar cell lesions. PMID- 23922358 TI - Metabolomics in plant environmental physiology. AB - Changes in plant metabolism are at the heart of plant developmental processes, underpinning many of the ways in which plants respond to the environment. As such, the comprehensive study of plant metabolism, or metabolomics, is highly valuable in identifying phenotypic effects of abiotic and biotic stresses on plants. When study is in reference to analysing samples that are relevant to environmental or ecologically based hypotheses, it is termed 'environmental metabolomics'. The emergence of environmental metabolomics as one of the latest of the omics technologies has been one of the most critically important recent developments in plant physiology. Its applications broach the entire landscape of plant ecology, from the understanding of plant plasticity and adaptation through to community composition and even genetic modification in crops. The multitude of novel studies published utilizing metabolomics methods employ a variety of techniques, from the initial stages of tissue sampling, through to sample preservation, transportation, and analysis. This review introduces the concept and applications of plant environmental metabolomics as an ecologically important investigative tool. It examines the main techniques used in situ within field sites, with particular reference to sampling and processing, and those more appropriate for use in laboratory-based settings with emphasis on secondary metabolite analysis. PMID- 23922359 TI - Mandatory vaccination. PMID- 23922360 TI - Mandatory vaccination. PMID- 23922361 TI - Mandatory vaccination. PMID- 23922362 TI - JHPPL workshop on Medicaid fiscal and governance issues: objectives and themes. AB - At a November 2012 workshop, state health policy officials, other Medicaid and insurance exchange practitioners, and health policy researchers discussed issues surrounding the implementation and sustainability of Medicaid expansion and insurance exchange coordination under the Patient Protection and Affordable Care Act (PPACA). Foremost were concerns about (1) intergovernmental relations (states experiencing uncertain information, lack of coordination among federal agencies, and limited resources to take on new responsibilities under the PPACA), and (2) policy design (new issues such as Medicaid exchange coordination on top of preexisting Medicaid challenges). JHPPL has proposed the creation of a research network to develop policy options and share strategies and best practices. PMID- 23922363 TI - Ordered accumulation of mutations conferring resistance to sulfadoxine pyrimethamine in the Plasmodium falciparum parasite. AB - BACKGROUND: Monitoring the prevalence of drug resistant Plasmodium falciparum is essential for effective malaria control. Resistance to pyrimethamine and sulfadoxine increases as mutations accumulate in the parasite genes encoding dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps), respectively. Although parasites are exposed to these antifolate drugs simultaneously, it remains virtually unknown whether dhfr and dhps mutations accumulate along interrelated paths. METHODS: We investigated the order of step-wise accumulation in dhfr and dhps by cumulative analyses using binomial tests in 575 P. falciparum isolates obtained from 7 countries in Asia and Melanesia. RESULTS: An initial step in the accumulation of mutations preferentially occurred in dhfr (2 mutations), followed by 1 mutation in dhps. In a subsequent step, mutations were estimated separately for 5 dhfr/dhps-resistant lineages identified using 12 microsatellites flanking dhfr and dhps. Among these lineages, we found 3 major mutational paths, each of which follows a unique stepwise trajectory to produce the most highly resistant form with 4 mutations in dhfr and 3 in dhps. CONCLUSIONS: The ordered accumulation of mutations in dhfr and dhps elucidated here will assist in predicting the status and progression of antifolate resistance in malaria-endemic regions where antifolate drugs are used for intermittent preventive treatment. PMID- 23922364 TI - Procollagen III N-terminal propeptide and desmosine are released by matrix destruction in pulmonary tuberculosis. AB - BACKGROUND: Tuberculosis is transmitted by patients with pulmonary disease. Matrix metalloproteinases (MMPs) drive lung destruction in tuberculosis but the resulting matrix degradation products (MDPs) have not been studied. We investigate the hypothesis that MMP activity generates matrix turnover products as correlates of lung pathology. METHODS: Induced sputum and plasma were collected prospectively from human immunodeficiency virus (HIV) positive and negative patients with pulmonary tuberculosis and controls. Concentrations of MDPs and MMPs were analyzed by ELISA and Luminex array in 2 patient cohorts. RESULTS: Procollagen III N-terminal propeptide (PIIINP) was 3.8-fold higher in induced sputum of HIV-uninfected tuberculosis patients compared to controls and desmosine, released during elastin degradation, was 2.4-fold higher. PIIINP was elevated in plasma of tuberculosis patients. Plasma PIIINP correlated with induced sputum MMP-1 concentrations and radiological scores, demonstrating that circulating MDPs reflect lung destruction. In a second patient cohort of mixed HIV seroprevalence, plasma PIIINP concentration was increased 3.0-fold above controls (P < .001). Plasma matrix metalloproteinase-8 concentrations were also higher in tuberculosis patients (P = .001). Receiver operating characteristic analysis utilizing these 2 variables demonstrated an area under the curve of 0.832 (P < .001). CONCLUSIONS: In pulmonary tuberculosis, MMP-driven immunopathology generates matrix degradation products. PMID- 23922365 TI - Targeting of the purine biosynthesis host cell pathway enhances the activity of tenofovir against sensitive and drug-resistant HIV-1. AB - BACKGROUND: Targeting host-cell pathways to increase the potency of nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs) is an important strategy for clinical investigation. Resveratrol is a natural product that inhibits cellular ribonucleotide reductase, prolonging the S phase of the cell cycle and preferentially lowering dATP levels. METHODS: We performed in vitro evaluation of resveratrol on the antiviral activity of adenosine analog tenofovir (TFV) against sensitive and drug-resistant human immunodeficiency virus type 1 (HIV-1), from subtypes B and C, in primary cells. RESULTS: Resveratrol enhanced the antiviral activity of TFV by up to 10-fold and restored susceptibility of TFV-resistant viruses. Resveratrol prevented wild-type HIV-1 from developing phenotypic resistance to TFV. Notably, resveratrol enhanced TFV activity against sensitive and resistant HIV-1 from both subtypes B and C. CONCLUSIONS: Prolonged wide-scale use of thymidine analogs in the setting of viral failure has limited the efficacy of second-line NRTI-based regimens in Africa. Moreover, the extensive use of ddI and d4T has led to high frequencies of the K65R mutation, further compromising TFV efficacy. In light of increasing resistance to commonly used NRTIs in global HIV treatment programs, targeting nucleoside biosynthesis with resveratrol, or derivatives with improved bioavailabilities, is a potential strategy to maintain, enhance, and restore susceptibility of commonly used NRTIs. PMID- 23922366 TI - Natural killer cell-mediated innate sieve effect on HIV-1: the impact of KIR/HLA polymorphism on HIV-1 subtype-specific acquisition in east Africa. AB - Here we explore the association between killer cell immunoglobulin-like receptor (KIR)/HLA and human immunodeficiency virus type 1 (HIV-1) acquisition with different viral subtypes circulating in East Africa. In the prospective Cohort Development (CODE) cohort (Mbeya, Tanzania), carriers of KIR3DS1 and its putative ligand (HLA-A or HLA-B Bw4-80Ile alleles) showed increased HIV-1 acquisition risk (odds ratio [OR] = 3.46; 95% confidence interval [CI], 1.12-10.63; P = .04) and a trend for enrichment for subtype A and A-containing recombinants (78% vs. 46%; OR = 4.05; 95% CI, .91-28.30; P = .09) at the expense of subtype C (11% vs. 43%; OR = 0.17; 95% CI, .01-.97; P = .08). In vitro, only natural killer cells from KIR3DS1(+)/HLA-Bw4-80Ile(+) healthy donors showed a 2-fold increased capacity to inhibit replication of subtype C vs subtype A viruses (P = .01). These findings suggest the presence of an innate sieve effect and may inform HIV-1 vaccine development. PMID- 23922367 TI - Clinical impact of human coronaviruses 229E and OC43 infection in diverse adult populations. AB - BACKGROUND: The incidence and clinical impact of coronavirus (CoV) infection in elderly persons and those with underlying cardiopulmonary disease over a long duration is not well described. We determined the incidence and clinical impact of 229E and OC43 CoV in this population during 4 consecutive winters, and compared illnesses to influenza A, respiratory syncytial virus, and human metapneumovirus. METHODS: CoV 229E and OC43 were detected by reverse transcription polymerase chain reaction and serology in 4 adult populations under surveillance for acute respiratory illness during the winters of 1999-2003. Cohorts included healthy young adults, healthy elderly adults, high-risk adults with underlying cardiopulmonary disease, and a hospitalized group. RESULTS: Three hundred ninety-eight CoV infections were identified, with annual infection rates ranging from 2.8% to 26% in prospective cohorts, and prevalence ranging from 3.3% to 11.1% in the hospitalized cohort. The incidence of infections with each strain was similar, although asymptomatic infection and viral coinfection was significantly more common with 229E than OC43 infection. Although the incidence and clinical manifestations were similar for each strain, OC43-infected subjects tended to seek more medical care, as OC43 was twice as common as 229E among the hospitalized cohort. CONCLUSIONS: CoV infections in the elderly are frequent, likely causing substantial medical disease burden. PMID- 23922368 TI - Torque Teno virus in children who underwent orthotopic liver transplantation: new insights about a common pathogen. AB - BACKGROUND: Torque Teno virus (TTV) is a ubiquitous infectious agent. Transplant recipients are at risk of hepatitis E virus (HEV) infection and could be vulnerable to TTV-associated adverse effects. The aim of this study was to evaluate the influence of immunosuppression and HEV infection on TTV replication and liver injury in pediatric patients after orthotopic liver transplantation (OLT). METHODS: Pediatric recipients of liver transplants were classified into the following 2 groups: (1) those with normal serum aminotransferases levels and (2) those with persistently increased serum aminotransferases levels and histological features of chronic hepatitis of unknown etiology. The TTV load was assessed in 342 serum samples by use of TaqMan real-time polymerase chain reaction, along with TTV genogroups and coinfection with HEV. RESULTS: TTV DNA was detected in 96% of tested serum samples. Viral load was significantly lower in patients with features of chronic hepatitis, of whom 78% had liver fibrosis scores of >=2. Viral load decreased during posttransplantation follow-up. Viral load and genogroups were influenced by immunosuppression. Lower viral load was observed in patients coinfected with HEV. CONCLUSIONS: TTV infection is widespread, and its replication is closely related to immune status and viral coinfection. High TTV viremia is not associated with hepatitis after OLT, but, conversely, liver inflammatory activity impairs TTV replication. PMID- 23922369 TI - CD8 T cell exhaustion in human visceral leishmaniasis. AB - Little is known about CD8 T cells in human visceral leishmaniasis (VL) and it is unclear if these cells have a protective, pathological and/or suppressive function. In experimental VL CD8 T cells have been shown to contribute to parasite control and play an important role in vaccine-generated immunity. To better understand the role of CD8 T cells in human VL, we examined molecules associated with anergy and cytotoxic T lymphocytes (CTL) in peripheral blood mononuclear cells (PBMC) and splenic aspirates (SA), and in CD8 cells derived from these tissues. Gene and surface marker expression suggest that splenic CD8 cell predominantly display an anergic phenotype, whereas CD8-PBMC have features of both anergic cells and CTLs. CD8 cells contribute to the baseline IFNgamma levels in whole blood (WB) and SA cultures, but not to the Leishmania induced IFNgamma release that is revealed using WB cultures. Blockade of CTLA-4 or PD1 had no effect on IFNgamma production or parasite survival in SA cultures. Following cure, CD8 T cells contribute to the Leishmania induced IFNgamma production observed in Leishmania stimulated cell cultures. We suggest CD8 T cells are driven to anergy/exhaustion in human VL, which affect their ability to contribute to protective immune responses. PMID- 23922370 TI - HIV and influenza virus infections are associated with increased blood pneumococcal load: a prospective, hospital-based observational study in South Africa, 2009-2011. AB - BACKGROUND: Increased pneumococcal loads are associated with severe outcomes. We determined the prevalence of pneumococcal DNA in blood specimens from patients hospitalized with acute lower respiratory tract infection and identified factors associated with invasive pneumococcal pneumonia, bacterial loads, and death. METHODS: A total of 8523 patients were enrolled as part of prospective hospital based surveillance. Blood was collected for quantitative pneumococcal (lytA) detection, and nasopharyngeal specimens were collected for detection of influenza virus and other respiratory viruses by real-time polymerase chain reaction. RESULTS: Of 6396 cases (75%) with lytA results, 422 (7%) were positive for pneumococcal DNA. The prevalences of human immunodeficiency virus (HIV) and influenza virus were 51% (2965/5855) and 8% (485/6358), respectively. On multivariable analysis, HIV infection (adjusted odds ratio [aOR], 2.4; 95% confidence interval [CI], 1.6-3.6), influenza virus coinfection (aOR, 1.4; 95% CI, 1.2-2.1), oxygen therapy during admission (aOR, 1.6; 95% CI, 1.1-2.3) and in hospital death (aOR, 2.1; 95% CI, 1.1-4.0) were significantly associated with increased pneumococcal load. Among lytA-positive patients, after adjustment for length of hospitalization, duration of symptoms, and oxygen therapy during admission, pneumococcal loads >=10,000 DNA copies/mL (aOR, 3.6; 95% CI, 1.8-7.2) were associated with increased risk of death. CONCLUSIONS: HIV and influenza virus infections were associated with elevated pneumococcal loads, which, in turn, were associated with increased risk of death. PMID- 23922371 TI - Immunomodulatory effects of vitamin D on innate and adaptive immune responses to Streptococcus pneumoniae. AB - BACKGROUND: Streptococcus pneumoniae forms part of the normal nasopharyngeal flora but can also cause a broad spectrum of inflammatory diseases. Vitamin D has potent effects on human immunity, including induction of antimicrobial peptides and suppression of T-cell proliferation, but its ability to modulate the immune response to pneumococci is unknown. METHODS: Monocyte-derived dendritic cells (DCs) were stimulated with pneumococcal peptidoglycan (PGN) in the presence or absence of vitamin D. Expression of maturation markers, cytokines, pattern recognition receptors, and antimicrobial peptides were measured with flow cytometry, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. Stimulated DCs were cocultured with autologous T-helper cells, and concentrations of T-helper (Th) 1-, Th17-, and regulatory T-cell-related cytokines were measured with enzyme-linked immunosorbent assay. RESULTS: Vitamin D enhanced DC maturation and expression of the migration marker C-C chemokine receptor type 7 (CCR7) in PGN-stimulated cells. It also enhanced expression of key pattern recognition receptors (Toll-like receptor 2, Nucleotide-binding oligomerization domain-containing protein 2 [Nod2]) and induced a synergistic up regulation of the inflammatory mediator IL-1beta and the beta-defensin Human Beta Defensin 3 (hBD-3). Furthermore, vitamin D skewed the DC-mediated T-helper response to PGN from an inflammatory Th1/Th17 phenotype toward a regulatory T cell phenotype. CONCLUSION: Vitamin D modulates key elements of innate immunity while dampening adaptive immune responses in DCs after pneumococcal challenge, which may have implications for prevention and treatment of pneumococcus-induced inflammation. PMID- 23922373 TI - HIV type 1 polymerase gene polymorphisms are associated with phenotypic differences in replication capacity and disease progression. AB - BACKGROUND: Determinants of intersubtype differences in human immunodeficiency virus type 1 (HIV-1) clinical disease progression remain unknown. METHODS: HIV-1 subtype was independently determined for 5 separate genomic regions in 396 HIV-1 seroconverters from Rakai, Uganda, using a multiregion hybridization assay. Replication capacities (RC) in samples from a subset of 145 of these subjects were determined. HIV-1 genomic regions and pol RC were examined for association with disease progression. Amino acid polymorphisms were examined for association with pol RC. RESULTS: In multivariate analyses, the hazard for progression to the composite end point (defined as a CD4(+) T-cell count <250 cells/mm(3), antiretroviral therapy initiation, or death) among patients with subtype D pol infection was 2.4 times the hazard for those infected with subtype A pol infection (P = .001). Compared with subtype A pol (the reference group), the hazard for progression to the composite end point for subtype D pol infection with a pol RC >67% (ie, the median pol RC) was significantly greater (HR, 4.6; 95% confidence interval [CI], 1.9-11.0; P = .001), whereas the hazard for progression to the composite end point for subtype D pol infection with a pol RC <=67% was not significantly different (HR, 2.2; 95% CI, 1.0-4.9; P = .051). Amino acid substitutions at protease positions 62 and 64 and at reverse transcriptase position 272 were associated with significant differences in pol RC. CONCLUSIONS: HIV-1 pol gene intersubtype and RC differences are associated with disease progression and may be influenced by amino acid polymorphisms. PMID- 23922372 TI - Inflammatory monocytes mediate early and organ-specific innate defense during systemic candidiasis. AB - Candida albicans is a commensal fungus that can cause systemic disease in patients with breaches in mucosal integrity, indwelling catheters, and defects in phagocyte function. Although circulating human and murine monocytes bind C. albicans and promote inflammation, it remains unclear whether C-C chemokine receptor 2 (CCR2)- and Ly6C-expressing inflammatory monocytes exert a protective or a deleterious function during systemic infection. During murine systemic candidiasis, interruption of CCR2-dependent inflammatory monocyte trafficking into infected kidneys impaired fungal clearance and decreased murine survival. Depletion of CCR2-expressing cells led to uncontrolled fungal growth in the kidneys and brain and demonstrated an essential antifungal role for inflammatory monocytes and their tissue-resident derivatives in the first 48 hours postinfection. Adoptive transfer of purified inflammatory monocytes in depleted hosts reversed the defect in fungal clearance to a substantial extent, indicating a compartmentally and temporally restricted protective function that can be transferred to enhance systemic innate antifungal immunity. PMID- 23922374 TI - Combination antiretroviral therapy with raltegravir leads to rapid immunologic reconstitution in treatment-naive patients with chronic HIV infection. AB - BACKGROUND: In treatment-naive, human immunodeficiency virus (HIV)-infected persons, combination antiretroviral therapy (cART) incorporating raltegravir (RAL) is highly effective for virologic suppression, but characteristics of immunologic recovery have not been described. METHODS: We performed a 48-week substudy of 15 patients, median age 40 years, within a phase 2 randomized trial of RAL-cART in treatment-naive patients with chronic HIV infection. RESULTS: Plasma viral load decreased from 5.2 +/- 5.3 log10 HIV RNA copies/mL to 2.2 +/- 2.4 log10 copies/mL at week 4, reaching <50 copies/mL at week 8 in 13 of 15 patients. Total CD4 T cells increased at week 4, as did central memory CD4 T cells in association with reduction of the immune activation markers HLA-DR and CD38 and immune exhaustion marker PD1 in CD4 and CD8 T cells. Naive CD4 T cells increased at week 24 with appearance of HIV gag-specific interleukin 2, interferon-gamma, and CD107a responses in CD4 and CD8 T cells at week 48. Plasma lipopolysaccharide and soluble CD14 decreased, but at week 48 were elevated as compared to healthy volunteers. Altogether, the week 48 immune profile was more favorable in patients taking RAL-cART than in patients treated with non-RAL-cART. CONCLUSIONS: RAL in first-line treatment regimens results in rapid immune reconstitution with residual low-level microbial translocation. PMID- 23922376 TI - Incidence and clinical characteristics of herpes zoster among children in the varicella vaccine era, 2005-2009. AB - BACKGROUND: Vaccine-strain herpes zoster (HZ) can occur after varicella vaccination. This study determined the number and proportion of HZ cases caused by vaccine-strain varicella zoster virus (VZV), assessed the positive predictive value of provider diagnosis of HZ, and computed HZ incidence rates in vaccinated and unvaccinated children. METHODS: We used electronic medical records to identify all office visits with an HZ diagnosis for children aged <18 years in a managed care plan. Providers collected skin specimens and completed a questionnaire. Specimens were tested by polymerase chain reaction to identify wild-type or vaccine-strain VZV. RESULTS: From May 2005 to September 2009, we enrolled 322 subjects. VZV was detected in 82% of specimens (84% wild-type, 15% vaccine-strain, 1% possible vaccine-wild-type recombinant). Among the 118 vaccinated subjects, VZV was detected in 70% (52% wild-type). The positive predictive value for provider diagnosis of "definite HZ" was 93% for unvaccinated and 79% for vaccinated children. The incidence of laboratory-confirmed HZ was 48 per 100,000 person-years in vaccinated children (both wild-type and vaccine strain) and 230 per 100,000 person-years in unvaccinated children (wild-type only). CONCLUSIONS: HZ incidence in vaccinated children was 79% lower than in unvaccinated children. Among vaccinated children, half of HZ cases were due to wild-type VZV. PMID- 23922377 TI - Immunogenicity, safety, and immune persistence of a novel inactivated human enterovirus 71 vaccine: a phase II, Randomized, double-blind, placebo-controlled Trial. AB - BACKGROUND: Vaccination is considered a top priority for the control of human enterovirus 71 (EV71) infection outbreaks. METHODS: On the basis of phase I trial results, we conducted a double-blind, randomized, controlled trial to evaluate the optimal dose, immunogenicity, safety and immune persistence of the vaccine. A total of 480 healthy infants were randomly assigned to receive 2 injections of 100 U of vaccine, 200 U of vaccine, 400 U of vaccine, or placebo. Solicited adverse events (AEs) within 7 days and unsolicited AEs within 28 days after each vaccination were collected for safety evaluation. Blood samples were collected for neutralizing antibody assay. RESULTS: EV71 vaccine was well tolerated, and no dose-related safety concerns were observed. Two doses of the vaccine yielded seropositivity frequencies of 92.3%, 95.9%, and 99.0% (with titers >=1:8) in the 100 U, 200 U, and 400 U groups, respectively. Geometric mean titers measured by neutralizing antibody assay increased to 60.2 (95% confidence interval [CI], 41.9 86.4), 72.8 (95% CI, 50.8-104.3), and 252.1 (95% CI, 180.8-351.6) for the 100 U, 200 U, and 400 U groups, respectively. The dose-response relationship, with the 400 U dose showing higher immunogenicity than the 100 U and 200 U doses, remained until 13 months after the second vaccination, despite waning antibody levels. CONCLUSIONS: The 400 U dose was recommended as the optimal dose for the phase III trial because of its good safety profile and higher immunogenicity. PMID- 23922375 TI - Staphylococcal Enterotoxin B-specific monoclonal antibody 20B1 successfully treats diverse Staphylococcus aureus infections. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has become a major health threat in the United States. Staphylococcal enterotoxin B (SEB) is a potent superantigen that contributes to its virulence. High mortality and frequent failure of therapy despite available antibiotics have stimulated research efforts to develop adjunctive therapies. METHODS: Treatment benefits of SEB-specific monoclonal antibody (mAb) 20B1 were investigated in mice in sepsis, superficial skin, and deep-tissue infection models. RESULTS: Mice challenged with a SEB-producing MRSA strain developed fatal sepsis, extensive tissue skin infection, and abscess-forming deep-seeded thigh muscle infection. Animals preimmunized against SEB or treated passively with mAb 20B1 exhibited enhanced survival in the sepsis model, whereas decrease of bacterial burden was observed in the superficial skin and deep-tissue models. mAb 20B1 bound to SEB in the infected tissue and decreased abscess formation and proinflammatory cytokine levels, lymphocyte proliferation, and neutrophil recruitment. CONCLUSIONS: mAb 20B1, an SEB-neutralizing mAb, is effective against MRSA infection. mAb 20B1 protects against lethal sepsis and reduces skin tissue invasion and deep-abscess formation. The mAb penetrates well into the abscess and binds to SEB. It affects the outcome of S. aureus infection by modulating the host's proinflammatory immune response. PMID- 23922378 TI - Plasmodium products contribute to severe malarial anemia by inhibiting erythropoietin-induced proliferation of erythroid precursors. AB - Low reticulocytosis, indicating reduced red blood cell (RBC) output, is an important feature of severe malarial anemia. Evidence supports a role for Plasmodium products, especially hemozoin (Hz), in suppressed erythropoiesis during malaria, but the mechanism(s) involved remains unclear. Here, we demonstrated that low reticulocytosis and suppressed erythropoietin (Epo)-induced erythropoiesis are features of malarial anemia in Plasmodium yoelii- and Plasmodium berghei ANKA-infected mice, similar to our previous observations in Plasmodium chabaudi AS-infected mice. The magnitude of decreases in RBC was a reflection of parasitemia level, but low reticulocytosis was evident despite differences in parasitemia, clinical manifestation, and infection outcome. Schizont extracts and Hz from P. falciparum and P. yoelii and synthetic Hz suppressed Epo-induced proliferation of erythroid precursors in vitro but did not inhibit RBC maturation. To determine whether Hz contributes to malarial anemia, P. yoelii-derived or synthetic Hz was administered to naive mice, and the development of anemia, reticulocytosis, and RBC turnover was determined. Parasite derived Hz induced significant decreases in RBC and increased RBC turnover with compensatory reticulocytosis, but anemia was not as severe as that in infected mice. Our findings suggest that parasite factors, including Hz, contribute to severe malarial anemia by suppressing Epo-induced proliferation of erythroid precursors. PMID- 23922379 TI - Adenosine augments IL-10-induced STAT3 signaling in M2c macrophages. AB - The alternatively activated macrophage phenotype induced by IL-10 is called M2c. Adenosine is an endogenous purine nucleoside that accumulates in the extracellular space in response to metabolic disturbances, hypoxia, inflammation, physical damage, or apoptosis. As adenosine is known to regulate classically activated M1 and IL4- and IL-13-activated M2a macrophages, the goal of the present study was to explore its effects on M2c macrophages. We found that adenosine augmented the IL-10-induced expression of TIMP-1 and arginase-1 by the mouse macrophage cell line RAW 264.7 and by mouse BMDMs. The effects of AR stimulation on IL-10-induced TIMP-1 or arginase-1 expression were lacking in A2BAR KO macrophages. The role of A2BAR on TIMP-1 production of RAW 264.7 cells was confirmed with specific agonist BAY606583 and antagonist PSB0788. AR stimulation augmented IL-10-induced STAT3 phosphorylation in macrophages, and pharmacological inhibition or silencing of STAT3 using siRNA reduced the stimulatory effect of AR stimulation on TIMP-1 production. In contrast to its stimulatory effect on IL-10-induced STAT3 activation, adenosine inhibited IL-6 induced STAT3 phosphorylation and SAA3 expression. In conclusion, adenosine enhances IL-10-induced STAT3 signaling and M2c macrophage activation. PMID- 23922381 TI - Coordinated induction of cyclooxygenase-2/prostaglandin E2 and hepatocyte growth factor by apoptotic cells prevents lung fibrosis. AB - Apoptotic cell instillation after bleomycin induces persistent HGF production and protects from pulmonary fibrosis, but the underlying mechanism remains unclear. We investigated immediate and prolonged effects of in vivo instillation of apoptotic cells into bleomycin-stimulated mouse lungs (2 days old) on COX-2 expression in lung tissue and alveolar macrophages and PGE2 production in BALF. Furthermore, functional interaction between these molecules and HGF, following apoptotic cell instillation in a bleomycin-induced lung fibrosis model, was assessed. Apoptotic cell instillation results in enhanced immediate and prolonged expression of COX-2 and PGE2 when compared with those from bleomycin-only-treated mice. Coadministration of the COX-2-selective inhibitor NS398 or the selective PGE2R EP2 inhibitor AH6809 inhibited the increase in HGF production. Inhibition of HGF signaling using PHA-665752 inhibited increases in COX-2 and PGE2. Long term inhibition of COX-2, PGE2, or HGF reversed the reduction of TGF-beta, apoptotic and MPO activities, protein levels, and hydroxyproline contents. Up regulation of COX-2/PGE2 and HGF through a positive-feedback loop may be an important mechanism whereby apoptotic cell instillation exerts the net results of anti-inflammatory, antiapoptotic, and antifibrotic action. PMID- 23922380 TI - RelB: an outlier in leukocyte biology. AB - RelB is one of the more unusual members of the NF-kappaB family. This family, arguably the best known group of transcription regulators, regulates an astonishing array of cell types and biological processes. This includes regulation of cell growth, differentiation and death by apoptosis, and the development and function of the innate and adaptive-immune system. RelB is best known for its roles in lymphoid development, DC biology, and noncanonical signaling. Within the last few years, however, surprising functions of RelB have emerged. The N-terminal leucine zipper motif of RelB, a motif unique among the NF kappaB family, may associate with more diverse DNA sequences than other NF-kappaB members. RelB is capable of direct binding to the AhR that supports the xenobiotic-detoxifying pathway. RelB can regulate the circadian rhythm by directly binding to the BMAL partner of CLOCK. Finally, RelB also couples with bioenergy NAD(+) sensor SIRT1 to integrate acute inflammation with changes in metabolism and mitochondrial bioenergetics. In this review, we will explore these unique aspects of RelB, specifically with regard to its role in immunity. PMID- 23922382 TI - Increased levels of invariant natural killer T lymphocytes worsen metabolic abnormalities and atherosclerosis in obese mice. AB - Obesity is a chronic inflammatory state characterized by infiltration of adipose tissue by immune cell populations, including T lymphocytes. Natural killer T (NKT) cells, a specialized lymphocyte subset recognizing lipid antigens, can be pro- or anti-inflammatory. Their role in adipose inflammation continues to be inconclusive and contradictory. In obesity, the infiltration of tissues by invariant NKT (iNKT) cells is decreased. We therefore hypothesized that an excess iNKT cell complement might improve metabolic abnormalities in obesity. Valpha14 transgenic (Valpha14tg) mice, with increased iNKT cell numbers, on a LDL receptor deficient (Ldlr(-/-)) background and control Ldlr(-/-) mice were placed on an obesogenic diet for 16 weeks. Valpha14tg.Ldlr(-/-) mice gained 25% more weight and had increased adiposity than littermate controls. Transgenic mice also developed greater dyslipidemia, hyperinsulinemia, insulin resistance, and hepatic triglyceride accumulation. Increased macrophage Mac2 immunostaining and proinflammatory macrophage gene expression suggested worsened adipose inflammation. Concurrently, these mice had increased atherosclerotic lesion area and aortic inflammation. Thus, increasing the complement of iNKT cells surprisingly exacerbated the metabolic, inflammatory, and atherosclerotic features of obesity. These findings suggest that the reduction of iNKT cells normally observed in obesity may represent a physiological attempt to compensate for this inflammatory condition. PMID- 23922383 TI - Chylomicron metabolism in rats: kinetic modeling indicates that the particles remain at endothelial sites for minutes. AB - Chylomicrons labeled in vivo with (14)C-oleic acid (primarily in triglycerides, providing a tracer for lipolysis) and (3)H-retinol (primarily in ester form, providing a tracer for the core lipids) were injected into rats. Radioactivity in tissues was followed at a series of times up to 40 min and the data were analyzed by compartmental modeling. For heart-like tissues it was necessary to allow the chylomicrons to enter into a compartment where lipolysis is rapid and then transfer to a second compartment where lipolysis is slower. The particles remained in these compartments for minutes and when they returned to blood they had reduced affinity for binding in the tissue. In contrast, the data for liver could readily be fitted with a single compartment for native and lipolyzed chylomicrons in blood, and there was no need for a pathway back to blood. A composite model was built from the individual tissue models. This whole-body model could simultaneously fit all data for both fed and fasted rats and allowed estimation of fluxes and residence times in the four compartments; native and lipolyzed chylomicrons ("remnants") in blood, and particles in the tissue compartments where lipolysis is rapid and slow, respectively. PMID- 23922384 TI - Alternative splicing modifies the effect of mutations in COL11A1 and results in recessive type 2 Stickler syndrome with profound hearing loss. AB - BACKGROUND: Stickler syndromes types 1, 2 and 3 are usually dominant disorders caused by mutations in the genes COL2A1, COL11A1 and COL11A2 that encode the fibrillar collagens types II and XI present in cartilage and vitreous. Rare recessive forms of Stickler syndrome exist that are due to mutations in genes encoding type IX collagen (COL9A1 type 4 Stickler syndrome and COL9A2 type 5 Stickler syndrome). Recently, recessive mutations in the COL11A1 gene have been demonstrated to result in fibrochondrogenesis, a much more severe skeletal dysplasia, which is often lethal. Here we demonstrate that some mutations in COL11A1 are recessive, modified by alternative splicing and result in type 2 Stickler syndrome rather than fibrochondrogenesis. METHODS: Patients referred to the national Stickler syndrome diagnostic service for England, UK were assessed clinically and subsequently sequenced for mutations in COL11A1. Additional in silico and functional studies to assess the effect of sequence variants on pre mRNA processing and collagen structure were performed. RESULTS: In three different families, heterozygous COL11A1 biallelic null, null/missense or silent/missense mutations, were found. They resulted in a recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss and are clinically distinct from the recessive types 4 and 5 variants of Stickler syndrome. One mutant allele in each family is capable of synthesising a normal alpha1(XI) procollagen molecule, via variable pre-mRNA processing. CONCLUSION: This new variant has important implications for molecular diagnosis and counselling families with type 2 Stickler syndrome. PMID- 23922385 TI - A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance. AB - Screening for Fabry disease (FD) reveals a high prevalence of individuals with alpha-galactosidase A (GLA) genetic variants of unknown significance (GVUS). These individuals often do not express characteristic features of FD. A systematic review on FD screening studies was performed to interpret the significance of GLA gene variants and to calculate the prevalence of definite classical and uncertain cases. We searched PubMed and Embase for screening studies on FD. We collected data on screening methods, clinical, biochemical and genetic assessments. The pooled prevalence of identified subjects and those with a definite diagnosis of classical FD were calculated. As criteria for a definite diagnosis, we used the presence of a GLA variant, absent or near-absent leukocyte enzyme activity and characteristic features of FD. Fifty-one studies were selected, 45 in high-risk and 6 in newborn populations. The most often used screening method was an enzyme activity assay. Cut-off values comprised 10-55% of the mean reference value for men and up to 80% for women. Prevalence of GLA variants in newborns was 0.04%. In high-risk populations the overall prevalence of individuals with GLA variants was 0.62%, while the prevalence of a definite diagnosis of FD was 0.12%. The majority of identified individuals in high-risk and newborn populations harbour GVUS or neutral variants in the GLA gene. To determine the pathogenicity of a GVUS in an individual, improved diagnostic criteria are needed. We propose a diagnostic algorithm to approach the individual with an uncertain diagnosis. PMID- 23922387 TI - Does surgery accelerate progression of amyotrophic lateral sclerosis? AB - BACKGROUND: Surgery is not a recognised potential amyotrophic lateral sclerosis (ALS) risk factor that might modify the onset or course of ALS. METHODS: We studied our database of ALS patients, which includes questions concerning surgical procedures. We defined surgery as an operative procedure requiring general or regional anaesthesia, but not local anaesthesia. Patients were classified as G1-no surgery; G2-surgery performed >=3 months before disease onset; G3-surgery <3 months before disease onset; and G4-surgery after disease onset. The ALS-FRS score was evaluated every 3 months from presentation. The maximal ALS-FRS score was ascribed to disease onset, itself defined as symptom onset. RESULTS: 657 patients with ALS were studied. In G3 there was a positive correlation between onset-region and surgery-region (p=0.032). In G4, 35 (57.6%) patients had surgery, probably due to initial misdiagnosis. The rate of functional change (%) in G4 was significantly greater in the 3-month period immediately after surgery as compared with the 3-month period before (1.46%+/ 1.35 vs. 6.30%+/-8.10, p=0.005) and the following 3 months (3.30%+/-3.10, p=0.006). CONCLUSIONS: The site of surgery before ALS onset correlates with the region of onset of ALS. Patients with slower disease progression are at an increased risk of undergoing surgery, probably as part of initial difficulty in diagnosis. We noted accelerated disease progression during the 3-month period after surgery. Definite diagnosis is important to avoid unnecessary surgical trauma and subsequent more rapid deterioration. PMID- 23922388 TI - Unique insights into the intestinal absorption, transit, and subsequent biodistribution of polymer-derived microspheres. AB - Polymeric microspheres (MSs) have received attention for their potential to improve the delivery of drugs with poor oral bioavailability. Although MSs can be absorbed into the absorptive epithelium of the small intestine, little is known about the physiologic mechanisms that are responsible for their cellular trafficking. In these experiments, nonbiodegradable polystyrene MSs (diameter range: 500 nm to 5 um) were delivered locally to the jejunum or ileum or by oral administration to young male rats. Following administration, MSs were taken up rapidly (<= 5 min) by the small intestine and were detected by transmission electron microscopy and confocal laser scanning microscopy. Gel permeation chromatography confirmed that polymer was present in all tissue samples, including the brain. These results confirm that MSs (diameter range: 500 nm to 5 um) were absorbed by the small intestine and distributed throughout the rat. After delivering MSs to the jejunum or ileum, high concentrations of polystyrene were detected in the liver, kidneys, and lungs. The pharmacologic inhibitors chlorpromazine, phorbol 12-myristate 13-acetate, and cytochalasin D caused a reduction in the total number of MSs absorbed in the jejunum and ileum, demonstrating that nonphagocytic processes (including endocytosis) direct the uptake of MSs in the small intestine. These results challenge the convention that phagocytic cells such as the microfold cells solely facilitate MS absorption in the small intestine. PMID- 23922389 TI - Structural basis of the C1q/C1s interaction and its central role in assembly of the C1 complex of complement activation. AB - Complement component C1, the complex that initiates the classical pathway of complement activation, is a 790-kDa assembly formed from the target-recognition subcomponent C1q and the modular proteases C1r and C1s. The proteases are elongated tetramers that become more compact when they bind to the collagen-like domains of C1q. Here, we describe a series of structures that reveal how the subcomponents associate to form C1. A complex between C1s and a collagen-like peptide containing the C1r/C1s-binding motif of C1q shows that the collagen binds to a shallow groove via a critical lysine side chain that contacts Ca(2+) coordinating residues. The data explain the Ca(2+)-dependent binding mechanism, which is conserved in C1r and also in mannan-binding lectin-associated serine proteases, the serine proteases of the lectin pathway activation complexes. In an accompanying structure, C1s forms a compact ring-shaped tetramer featuring a unique head-to-tail interaction at its center that replicates the likely arrangement of C1r/C1s polypeptides in the C1 complex. Additional structures reveal how C1s polypeptides are positioned to enable activation by C1r and interaction with the substrate C4 inside the cage-like assembly formed by the collagenous stems of C1q. Together with previously determined structures of C1r fragments, the results reported here provide a structural basis for understanding the early steps of complement activation via the classical pathway. PMID- 23922390 TI - Conformational states and recognition of amyloidogenic peptides of human insulin degrading enzyme. AB - Insulin-degrading enzyme (IDE) selectively degrades the monomer of amyloidogenic peptides and contributes to clearance of amyloid beta (Abeta). Thus, IDE retards the progression of Alzheimer's disease. IDE possesses an enclosed catalytic chamber that engulfs and degrades its peptide substrates; however, the molecular mechanism of IDE function, including substrate access to the chamber and recognition, remains elusive. Here, we captured a unique IDE conformation by using a synthetic antibody fragment as a crystallization chaperone. An unexpected displacement of a door subdomain creates an ~18-A opening to the chamber. This swinging-door mechanism permits the entry of short peptides into the catalytic chamber and disrupts the catalytic site within IDE door subdomain. Given the propensity of amyloidogenic peptides to convert into beta-strands for their polymerization into amyloid fibrils, they also use such beta-strands to stabilize the disrupted catalytic site resided at IDE door subdomain for their degradation by IDE. Thus, action of the swinging door allows IDE to recognize amyloidogenicity by substrate-induced stabilization of the IDE catalytic cleft. Small angle X-ray scattering (SAXS) analysis revealed that IDE exists as a mixture of closed and open states. These open states, which are distinct from the swinging door state, permit entry of larger substrates (e.g., Abeta, insulin) to the chamber and are preferred in solution. Mutational studies confirmed the critical roles of the door subdomain and hinge loop joining the N- and C-terminal halves of IDE for catalysis. Together, our data provide insights into the conformational changes of IDE that govern the selective destruction of amyloidogenic peptides. PMID- 23922391 TI - Elucidation of the anaerobic pathway for the corrin component of cobalamin (vitamin B12). AB - It has been known for the past 20 years that two pathways exist in nature for the de novo biosynthesis of the coenzyme form of vitamin B12, adenosylcobalamin, representing aerobic and anaerobic routes. In contrast to the aerobic pathway, the anaerobic route has remained enigmatic because many of its intermediates have proven technically challenging to isolate, because of their inherent instability. However, by studying the anaerobic cobalamin biosynthetic pathway in Bacillus megaterium and using homologously overproduced enzymes, it has been possible to isolate all of the intermediates between uroporphyrinogen III and cobyrinic acid. Consequently, it has been possible to detail the activities of purified cobinamide biosynthesis (Cbi) proteins CbiF, CbiG, CbiD, CbiJ, CbiET, and CbiC, as well as show the direct in vitro conversion of 5-aminolevulinic acid into cobyrinic acid using a mixture of 14 purified enzymes. This approach has resulted in the isolation of the long sought intermediates, cobalt-precorrin-6A and -6B and cobalt-precorrin-8. EPR, in particular, has proven an effective technique in following these transformations with the cobalt(II) paramagnetic electron in the dyz orbital, rather than the typical dz2. This result has allowed us to speculate that the metal ion plays an unexpected role in assisting the interconversion of pathway intermediates. By determining a function for all of the pathway enzymes, we complete the tool set for cobalamin biosynthesis and pave the way for not only enhancing cobalamin production, but also design of cobalamin derivatives through their combinatorial use and modification. PMID- 23922392 TI - SAD-A kinase controls islet beta-cell size and function as a mediator of mTORC1 signaling. AB - The mammalian target of rapamycin (mTOR) plays an important role in controlling islet beta-cell function. However, the underlying molecular mechanisms remain poorly elucidated. Synapses of amphids defective kinase-A (SAD-A) is a 5' adenosine monophosphate-activated protein kinase-related protein kinase that is exclusively expressed in pancreas and brain. In this study, we investigated a role of the kinase in regulating pancreatic beta-cell morphology and function as a mediator of mTOR complex 1 (mTORC1) signaling. We show that global SAD-A deletion leads to defective glucose-stimulated insulin secretion and petite islets, which are reminiscent of the defects in mice with global deletion of ribosomal protein S6 kinase 1, a downstream target of mTORC1. Consistent with these findings, selective deletion of SAD-A in pancreas decreased islet beta-cell size, whereas SAD-A overexpression significantly increased the size of mouse insulinomas cell lines beta-cells. In direct support of SAD-A as a unique mediator of mTORC1 signaling in islet beta-cells, we demonstrate that glucose dramatically stimulated SAD-A protein translation in isolated mouse islets, which was potently inhibited by rapamycin, an inhibitor of mTORC1. Moreover, the 5' untranslated region of SAD-A mRNA is highly structured and requires mTORC1 signaling for its translation initiation. Together, these findings identified SAD A as a unique pancreas-specific effector protein of mTORC1 signaling. PMID- 23922393 TI - Sea surface height evidence for long-term warming effects of tropical cyclones on the ocean. AB - Tropical cyclones have been hypothesized to influence climate by pumping heat into the ocean, but a direct measure of this warming effect is still lacking. We quantified cyclone-induced ocean warming by directly monitoring the thermal expansion of water in the wake of cyclones, using satellite-based sea surface height data that provide a unique way of tracking the changes in ocean heat content on seasonal and longer timescales. We find that the long-term effect of cyclones is to warm the ocean at a rate of 0.32 +/- 0.15 PW between 1993 and 2009, i.e., ~23 times more efficiently per unit area than the background equatorial warming, making cyclones potentially important modulators of the climate by affecting heat transport in the ocean-atmosphere system. Furthermore, our analysis reveals that the rate of warming increases with cyclone intensity. This, together with a predicted shift in the distribution of cyclones toward higher intensities as climate warms, suggests the ocean will get even warmer, possibly leading to a positive feedback. PMID- 23922394 TI - A combination of directing groups and chiral anion phase-transfer catalysis for enantioselective fluorination of alkenes. AB - We report a catalytic enantioselective electrophilic fluorination of alkenes to form tertiary and quaternary C(sp3)-F bonds and generate beta-amino- and beta aryl-allylic fluorides. The reaction takes advantage of the ability of chiral phosphate anions to serve as solid-liquid phase transfer catalysts and hydrogen bond with directing groups on the substrate. A variety of heterocyclic, carbocyclic, and acyclic alkenes react with good to excellent yields and high enantioselectivities. Further, we demonstrate a one-pot, tandem dihalogenation cyclization reaction, using the same catalytic system twice in series, with an analogous electrophilic brominating reagent in the second step. PMID- 23922395 TI - Structure of the processive rubber oxygenase RoxA from Xanthomonas sp. AB - Rubber oxygenase A (RoxA) is one of only two known enzymes able to catalyze the oxidative cleavage of latex for biodegradation. RoxA acts as a processive dioxygenase to yield the predominant product 12-oxo-4,8-dimethyl-trideca-4,8 diene-1-al (ODTD), a tri-isoprene unit. Here we present a structural analysis of RoxA from Xanthomonas sp. strain 35Y at a resolution of 1.8 A. The enzyme is a 75 kDa diheme c-type cytochrome with an unusually low degree of secondary structure. Analysis of the heme group arrangement and peptide chain topology of RoxA confirmed a distant kinship with diheme peroxidases of the CcpA family, but the proteins are functionally distinct, and the extracellular RoxA has evolved to have twice the molecular mass by successively accumulating extensions of peripheral loops. RoxA incorporates both oxygen atoms of its cosubstrate dioxygen into the rubber cleavage product ODTD, and we show that RoxA is isolated with O2 stably bound to the active site heme iron. Activation and cleavage of O2 require binding of polyisoprene, and thus the substrate needs to use hydrophobic access channels to reach the deeply buried active site of RoxA. The location and nature of these channels support a processive mechanism of latex cleavage. PMID- 23922397 TI - Patient whiteboards to improve patient-centred care in the hospital. AB - BACKGROUND: Patient whiteboards facilitate communication between patients and hospital providers, but little is known about their impact on patient satisfaction and awareness. Our objectives were to: measure the impact in improving patients' understanding of and satisfaction with care; understand barriers for their use by physicians and how these could be overcome; and explore their impact on staff and patients' families. METHODS: In 2012, we conducted a 3 week pilot of multidisciplinary whiteboard use with 104 inpatients on the general medicine service at Stanford University Medical Center. A brief, inperson survey was conducted with two groups: (1) 56 patients on two inpatient units with whiteboards and (2) 48 patients on two inpatient units without whiteboards. Questions included understanding of: physician name, goals of care, discharge date and satisfaction with care. We surveyed 25 internal medicine residents regarding challenges of whiteboard use, along with physical therapists, occupational therapists, case managers, consulting physicians and patients' family members (n=40). RESULTS: The use of whiteboards significantly increased the proportion of patients who knew: their physician (p<==0.0001), goals for admission (p<==0.0016), their estimated discharge date (p<==0.049) and improved satisfaction with the hospital stay overall (p<==0.0242). Physicians, ancillary staff and patient families all found the whiteboards to be helpful. In response, residents were also more likely to integrate whiteboard use into their daily work flow. CONCLUSIONS: Inpatient whiteboards help physicians and ancillary staff with communication, improve patients' awareness of their care team, admission plans and duration of admission, and significantly improve patient overall satisfaction. PMID- 23922396 TI - T-box transcription factor T-bet, a key player in a unique type of B-cell activation essential for effective viral clearance. AB - IgG2a is known to be the most efficient antibody isotype for viral clearance. Here, we demonstrate a unique pathway of B-cell activation, leading to IgG2a production, and involving synergistic stimulation via B-cell antigen receptors, toll-like receptor 7 (TLR7), and IFNgamma receptors on B cells. This synergistic stimulation leads to induction of T-box transcription factor T-bet expression in B cells, which, in turn, drives expression of CD11b and CD11c on B cells. T bet/CD11b/CD11c positive B cells appear during antiviral responses and produce high titers of antiviral IgG2a antibodies that are critical for efficient viral clearance. The results thus demonstrate a previously unknown role for T-bet expression in B cells during viral infections. Moreover, the appearance of T bet(+) B cells during antiviral responses and during autoimmunity suggests a possible link between these two processes. PMID- 23922398 TI - Predictors of mortality of extremely low birthweight babies in a tertiary care centre of a developing country. AB - INTRODUCTION: Perinatal care has changed dramatically over last decade contributing to improved survival of extremely low birthweight (ELBW) babies. OBJECTIVE: We conducted the present study with the objective to identify immediate obstetric causes of preterm delivery; analyse the maternal risk factors and to evaluate the morbidity and mortality of ELBW babies delivered in our hospital. The results were compared with those of 10 years ago from the same hospital to determine whether there has been any significant change in the predictors of mortality METHODS: A retrospective analysis of case records of 283 ELBW babies delivered in our hospital over a period of 24 months from 1 April 2010 to 31 March 2012 was conducted. RESULTS: The total neonatal mortality rate was 38.7%. 85 babies (30%) were small for gestational age. Mean gestational age and mean birth weight was 28.5 weeks and 883.4 g, respectively. Using multivariate logistic regression analysis, significant risk factors for neonatal mortality in mothers were anaemia (p=0.00001, OR 3.13, CI 1.756 to 5.56), inadequate antenatal care (p=0.00001, OR 4.74, CI 2.59 to 8.69) premature rupture of membrane with antenatal antibiotic usage (p=0.003, OR 3.375, CI 1.512 to 7.53. Risk factors for mortality in babies were male sex (p=0.08, OR 3.48 CI 1.4 to 8.8), lower birth weight (p=0.000005), lower gestational age (p=0.00001) use of respiratory support in the form of continuous positive airway pressure (p=0.03), or mechanical ventilation (p=0.00001) and pulmonary or intraventricular haemorrhage (p=0.0001). CONCLUSIONS: Babies with lower gestational age lower birth weight and those babies whose mothers had not received adequate antenatal care or antenatal steroids had worse prognosis. PMID- 23922399 TI - Chronic fatigue self-management in primary care: a randomized trial. AB - OBJECTIVE: To assess the efficacy of brief fatigue self-management (FSM) for medically unexplained chronic fatigue (UCF) and chronic fatigue syndrome (CFS) in primary care. METHODS: A randomized controlled design was used wherein 111 patients with UCF or CFS were randomly assigned to two sessions of FSM, two sessions of symptom monitoring support (attention control; AC), or a usual care control condition (UC). Participants were assessed at baseline and at 3 and 12 months after treatment. The primary outcome, the Fatigue Severity Scale, measured fatigue impact on functioning. Analysis was by intention to treat (multiple imputation) and also by per protocol. RESULTS: A group * time interaction across the 15-month trial showed significantly greater reductions in fatigue impact in the FSM group in comparison with the AC group (p < .023) and the UC group (p < .013). Medium effect sizes for reduced fatigue impact in the FSM group were found in comparison with the AC group (d = 0.46) and the UC group (d = 0.40). The per protocol analysis revealed large effect sizes for the same comparisons. Clinically significant decreases in fatigue impact were found for 53% of participants in the FSM condition, 14% in the AC condition, and 17% in the UC condition. Dropout rates at the 12-month follow-up were high (42%-53%), perhaps attributable to the burden of monthly telephone calls to assess health care use. CONCLUSION: A brief self-management intervention for patients with UCF or CFS seemed to be clinically effective for reducing the impact of fatigue on functioning. Trial Registration clinicaltrials.gov Identifier: NCT00997451. PMID- 23922400 TI - A life-style physical activity intervention and the antibody response to pneumococcal vaccination in women. AB - OBJECTIVE: To assess whether a life-style physical activity intervention improved antibody response to a pneumococcal vaccination in sedentary middle-aged women. METHODS: Eighty-nine sedentary women completed a 16-week exercise (physical activity consultation, pedometer, telephone/e-mail prompts; n = 44) or control (advisory leaflet; n = 45) intervention. Pneumococcal vaccination was administered at 12 weeks, and antibody titers (11 of the 23 contained in the pneumococcal vaccine) were determined before vaccination and 4 weeks and 6 months later. Physical activity, aerobic fitness, body composition, and psychological factors were measured before and after the intervention. RESULTS: The intervention group displayed a greater increase in walking behavior (from mean [standard deviation] = 82.16 [90.90] to 251.87 [202.13]) compared with the control condition (111.67 [94.64] to 165.16 [117.22]; time by group interaction: F(1,68) = 11.25, p = .001, eta(2) = 0.14). Quality of life also improved in the intervention group (from 19.37 [3.22] to 16.70 [4.29]) compared with the control condition (19.97 [4.22] to 19.48 [5.37]; time by group interaction: F(1,66) = 4.44, p = .039, eta(2) = 0.06). However, no significant effects of the intervention on antibody response were found (time by group eta(2) for each of the 11 pneumococcal strains ranged from 0.001 to 0.018; p values all >.264). CONCLUSIONS: Participation in a life-style physical activity intervention increased subjective and objective physical activity levels and quality of life but did not affect antibody response to pneumococcal vaccination. PMID- 23922401 TI - The impact of emotion-related autonomic nervous system responsiveness on pain sensitivity in female patients with fibromyalgia. AB - OBJECTIVE: Patients with fibromyalgia have shown hyporeactive autonomic nervous system (ANS) responses to physical stressors, augmented pain to ANS changes, and heightened negative emotions, which can increase pain. This study examined ANS reactivity to negative emotions and its association with pain in fibromyalgia and control participants. METHODS: Sixty-two women with fibromyalgia and 59 women in a control group recalled neutral, and anger- and sadness-eliciting experiences while ANS activity was monitored. Clinical and experimental pain were assessed in response to each emotion. RESULTS: Compared with neutral recall, heart rate (p = .050), mean arterial pressure (p < .001), and high-frequency heart rate variability (p = .012) increased in response to sadness, whereas heart rate decreased (p = .002) and mean arterial pressure increased (p < .001) in response to anger; however, ANS responses did not differ between patients and control participants (all p > .29). Among patients only, decreased preejection period (anger-pain threshold: r = 0.31, p = .018) and total peripheral resistance in response to negative emotions (anger-pain tolerance: r = 0.35, p = .025; sadness pain threshold: r = 0.51, p < .001; sadness-pain tolerance: r = 0.61, p < .001) correlated with more pain. CONCLUSIONS: These data suggest that the ANS is not hyporesponsive to elicited emotions in fibromyalgia; however, patients with a larger pain response showed an ANS response pattern reflecting heightened beta adrenergic and reduced alpha-adrenergic reactivity. Future research should test whether a specific ANS response pattern to emotions is a consequence of increased pain or whether it amplifies pain. PMID- 23922402 TI - Comparison of depressive symptoms in type 2 diabetes using a two-stage survey design. AB - OBJECTIVE: To test the validity of the Patient Health Questionnaire-9 (PHQ-9) in adults with newly diagnosed Type 2 diabetes mellitus (T2DM) and compare the distribution of PHQ-9 items in those with and without Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) depression. METHODS: A two stage survey design was used in primary care centers (n = 96). In Stage 1, participants were administered the PHQ-9 and biopsychosocial measures. In Stage 2, PHQ-9 positives (score >= 10) and randomly selected PHQ-9 negatives (score <10) had a diagnostic interview, Schedule for Clinical Assessment in Neuropsychiatry 2.1. The sensitivity, specificity and receiver operating characteristics of the PHQ-9 were calculated. The means of PHQ-9 items were compared. RESULTS: Stage 1: Prevalence of PHQ-9 positives (completing Stage 2) was 12.1% (n = 182). PHQ-9 positives were younger (mean [standard deviation] age = 52.8 [9.47] versus 56.2 [11.50] years, p < .001) and had higher body mass index (32.7 [7.08] versus 31.6 [6.25] kg/m(2), p = .028) than PHQ-9 negatives (n = 1278). Stage 2: Prevalence of DSM-IV depression was 5.6% (n = 84). The optimal cutoff was >= 12 (sensitivity = 86.9%, specificity = 80.3%). PHQ-9 true positives scored significantly higher than PHQ-9 false positives on all items, excluding sleep (mean [standard deviation] score = 2.4 [0.98] versus 2.2 [1.06]), fatigue (2.5 [0.80] versus 2.3 [0.86]), and appetite (1.6 [1.23] versus 1.5 [1.26]). CONCLUSIONS: Over-identification of depression by PHQ-9 in T2DM may be driven by presence of symptoms in keeping with an organic origin. PMID- 23922404 TI - Hospital performance based on treatment delays: comparison of ranking methods. AB - BACKGROUND: Reducing time-to-care is crucial in many acute and chronic diseases. Quality indicators based on target delays derived from guidelines are used to compare hospital performance but there is no accepted methodology for comparing performance when no target delay has been established. AIM: To explore by different statistical methods the uncertainty in hospital comparisons that are based on delay indicators, when no target delay is available. METHODS: Data for hospital door-to-needle time were extracted from a 2010 study of 1699 patients in 57 hospitals with ST-elevated myocardial infarction. We determined whether the times in each hospital were statistically different from the overall mean time or the median time for all hospitals by (i) one-way analysis of variance (ANOVA), (ii) non-parametric ANOVA with Nelson-Hsu adjustment (ANOVA R) and (iii) the proportional hazard model (PHM). We also tested for the assumptions underlying the methods: normal distribution for ANOVA, homogeneity of variances (homoscedasticity) for ANOVA and ANOVA R, and proportionality for PHM. RESULTS: Door-to-needle times were available for 889 patients in 44 hospitals. Data distribution was not Gaussian. Test assumptions were verified for ANOVA R (homoscedasticity) for one data subset (>48-h times (48H) excluded) and for PHM (proportionality) for two data subsets (48H or >95th percentile (P95) times excluded). The same five significantly better performers were identified in each case (although ANOVA R missed one). ANOVA R (48H) identified two significantly poorer performers, PHM (48H) identified three and PHM (P95) just one. Poorer performers differed according to method. CONCLUSIONS: The tested statistical methods yielded broadly similar results but no method was truly satisfactory. A transparency statement should therefore always specify the ranking method used to compare hospital performance. PMID- 23922403 TI - Surgical checklists: a systematic review of impacts and implementation. AB - BACKGROUND: Surgical complications represent a significant cause of morbidity and mortality with the rate of major complications after inpatient surgery estimated at 3-17% in industrialised countries. The purpose of this review was to summarise experience with surgical checklist use and efficacy for improving patient safety. METHODS: A search of four databases (MEDLINE, CINAHL, EMBASE and the Cochrane Database of Controlled Trials) was conducted from 1 January 2000 to 26 October 2012. Articles describing actual use of the WHO checklist, the Surgical Patient Safety System (SURPASS) checklist, a wrong-site surgery checklist or an anaesthesia equipment checklist were eligible for inclusion (this manuscript summarises all but the anaesthesia equipment checklists, which are described in the Agency for Healthcare Research and Quality publication). RESULTS: We included a total of 33 studies. We report a variety of outcomes including avoidance of adverse events, facilitators and barriers to implementation. Checklists have been adopted in a wide variety of settings and represent a promising strategy for improving the culture of patient safety and perioperative care in a wide variety of settings. Surgical checklists were associated with increased detection of potential safety hazards, decreased surgical complications and improved communication among operating staff. Strategies for successful checklist implementation included enlisting institutional leaders as local champions, incorporating staff feedback for checklist adaptation and avoiding redundancies with existing systems for collecting information. CONCLUSIONS: Surgical checklists represent a relatively simple and promising strategy for addressing surgical patient safety worldwide. Further studies are needed to evaluate to what degree checklists improve clinical outcomes and whether improvements may be more pronounced in particular settings. PMID- 23922405 TI - Prescribing errors on admission to hospital and their potential impact: a mixed methods study. AB - BACKGROUND: Medication errors are an important cause of morbidity and mortality and adversely affect clinical outcomes. Prescribing errors constitute one type of medication error and occur particularly on admission to hospital; little is known about how they arise. AIM: This study investigated how doctors obtain the information necessary to prescribe on admission to hospital, and the number and potential impact of any errors. SETTING: English teaching hospital-acute medical unit. METHODS: Ethics approval was granted. Data were collected over four 1-week periods; November 2009, January 2010, April 2010 and April 2011. The patient admission process was directly observed, field notes were recorded using a standard form. Doctors participated in a structured interview; case notes of all patients admitted during study periods were reviewed. RESULTS: There were differences between perceived practice stated in interviews and actual practice observed. All 19 doctors interviewed indicated that they would sometimes or always use more than one source of information for a medication history; a single source was used in 31/68 observed cases. 7/12 doctors both observed and interviewed indicated that they would confirm medication with patients; observations showed they did so for only 2/12 patients. In 66/68 cases, the patient/carer was able to discuss medication, 14 were asked no medication-related questions. Of 688 medication charts reviewed, 318 (46.2%) had errors. A total of 851 errors were identified; 737/851 (86.6%) involved omission of a medicine; 94/737 (12.8%) of these were potentially significant. CONCLUSIONS: Although doctors know the importance of obtaining an accurate medication history and checking prescriptions with patients, they often fail to put this into practice, resulting in prescribing errors. PMID- 23922444 TI - Modeling a space-variant cortical representation for apparent motion. AB - Receptive field sizes of neurons in early primate visual areas increase with eccentricity, as does temporal processing speed. The fovea is evidently specialized for slow, fine movements while the periphery is suited for fast, coarse movements. In either the fovea or periphery discrete flashes can produce motion percepts. Grossberg and Rudd (1989) used traveling Gaussian activity profiles to model long-range apparent motion percepts. We propose a neural model constrained by physiological data to explain how signals from retinal ganglion cells to V1 affect the perception of motion as a function of eccentricity. Our model incorporates cortical magnification, receptive field overlap and scatter, and spatial and temporal response characteristics of retinal ganglion cells for cortical processing of motion. Consistent with the finding of Baker and Braddick (1985), in our model the maximum flash distance that is perceived as an apparent motion (Dmax) increases linearly as a function of eccentricity. Baker and Braddick (1985) made qualitative predictions about the functional significance of both stimulus and visual system parameters that constrain motion perception, such as an increase in the range of detectable motions as a function of eccentricity and the likely role of higher visual processes in determining Dmax. We generate corresponding quantitative predictions for those functional dependencies for individual aspects of motion processing. Simulation results indicate that the early visual pathway can explain the qualitative linear increase of Dmax data without reliance on extrastriate areas, but that those higher visual areas may serve as a modulatory influence on the exact Dmax increase. PMID- 23922445 TI - Scanners and drillers: characterizing expert visual search through volumetric images. AB - Modern imaging methods like computed tomography (CT) generate 3-D volumes of image data. How do radiologists search through such images? Are certain strategies more efficient? Although there is a large literature devoted to understanding search in 2-D, relatively little is known about search in volumetric space. In recent years, with the ever-increasing popularity of volumetric medical imaging, this question has taken on increased importance as we try to understand, and ultimately reduce, errors in diagnostic radiology. In the current study, we asked 24 radiologists to search chest CTs for lung nodules that could indicate lung cancer. To search, radiologists scrolled up and down through a "stack" of 2-D chest CT "slices." At each moment, we tracked eye movements in the 2-D image plane and coregistered eye position with the current slice. We used these data to create a 3-D representation of the eye movements through the image volume. Radiologists tended to follow one of two dominant search strategies: "drilling" and "scanning." Drillers restrict eye movements to a small region of the lung while quickly scrolling through depth. Scanners move more slowly through depth and search an entire level of the lung before moving on to the next level in depth. Driller performance was superior to the scanners on a variety of metrics, including lung nodule detection rate, percentage of the lung covered, and the percentage of search errors where a nodule was never fixated. PMID- 23922446 TI - The functional effects of color perception and color imagery. AB - Functional imaging research and studies of brain-damaged patients suggest the mechanisms of color perception and color imagery have some degree of overlap. Previous research into color imagery has focused on compound images consisting of both color and form, e.g., whole objects. Little is known regarding the characteristics of pure color imagery-color without form structure. Binocular rivalry has proven to be a successful method for assessing mental imagery indirectly, quantitatively, and reliably. Here, we utilized this technique to access pure color imagery. Experiment 1 consisted of three conditions, in which participants were instructed to either imagine pure colors according to a letter cue, imagine pure colors in the presence of background luminance, or passively view weak perceptual color patches. Subsequently, a brief rivalry display was presented. Results indicated that perceptual dominance during rivalry was significantly biased by the participants' prior color imagery and perception. However, for imagery, the addition of background luminance attenuated this priming effect. In Experiment 2, we tested whether color imagery was location specific in retinotopic space. Color imagery was only found to prime subsequent rivalry when the imagery and rivalry stimuli occurred at the same retinotopic location. These results demonstrate that imagery of pure colors without form structure can influence subsequent color perception and can be localized in retinotopic space. These results are consistent with previous studies examining mental imagery of compound visual stimuli and demonstrate the potential of investigations into mental imagery of individual visual features. PMID- 23922447 TI - Hepatocyte nuclear factor 1 regulates the expression of the organic cation transporter 1 via binding to an evolutionary conserved region in intron 1 of the OCT1 gene. AB - The organic cation transporter 1 (OCT1), also known as solute carrier family 22 member 1, is strongly and specifically expressed in the human liver. Here we show that the hepatocyte nuclear factor 1 (HNF1) regulates OCT1 transcription and contributes to the strong, liver-specific expression of OCT1. Bioinformatic analyses revealed strong conservation of HNF1 binding motifs in an evolutionary conserved region (ECR) in intron 1 of the OCT1 gene. Electrophoretic mobility shift and chromatin immunoprecipitation assays confirmed the specific binding of HNF1 to the intron 1 ECR. In reporter gene assays performed in HepG2 cells, the intron 1 ECR increased SV40 promoter activity by 22-fold and OCT1 promoter activity by 13-fold. The increase was reversed when the HNF1 binding sites in the intron 1 ECR were mutated or the endogenous HNF1alpha expression was downregulated with small interfering RNA. Following HNF1alpha overexpression in Huh7 cells, the intron 1 ECR increased SV40 promoter activity by 11-fold and OCT1 promoter activity by 6-fold. Without HNF1alpha overexpression, the increases were only 3- and 2-fold, respectively. Finally, in human liver samples, high HNF1 expression was significantly correlated with high OCT1 expression (r = 0.48, P = 0.002, n = 40). In conclusion, HNF1 is a strong regulator of OCT1 expression. It remains to be determined whether genetic variants, disease conditions, or drugs that affect HNF1 activity may affect the pharmacokinetics and efficacy of OCT1 transported drugs such as morphine, tropisetron, ondansetron, tramadol, and metformin. Beyond OCT1, this study demonstrates the validity and usefulness of interspecies comparisons in the discovery of functionally relevant genomic sequences. PMID- 23922449 TI - Linear electro-optic properties of relaxor-based ferroelectric 0.24Pb(In1/2Nb1/2)O3-(0.76 - x)Pb(Mg1/3Nb2/3)O3-xPbTiO3 single crystals. AB - Linear electro-optic properties of 0.24Pb(In1/2Nb1/2)O3-(0.76 - x)Pb(Mg1/3Nb2/3)O3-xPbTiO3 single crystals, with compositions in the rhombohedral, morphotropic phase boundary (MPB) and tetragonal phases, have been investigated. Very large effective electro-optic coefficient [Formula: see text] (204 pm/V) was observed in a crystal with the MPB composition when it is poled along [001]. The rhombohedral phase (x = 0.27 and 0.30) single crystals poled along [111] direction and tetragonal phase (x = 0.39) single crystal poled along [001] direction are in single domain, and their electro-optic coefficients ([Formula: see text] = 76, 94, and 43 pm/V for the crystals with x = 0.27, 0.30, and 0.39, respectively) were found to be much higher than that of traditional electro-optic single crystal LiNbO3 ([Formula: see text] = 19.9 pm/V). The electro-optic coefficients of the single crystal in the rhombohedral phase have excellent temperature stability in the experimental temperature range of 10-40 degrees C. The half-wave voltage [Formula: see text] was calculated to be much lower (less than 1000 V) than that of LiNbO3 single crystal (2800 V). These superior properties make the ternary relaxor-PT single crystals very promising for electro-optic modulation applications. PMID- 23922448 TI - Enhancement of Ca(2+) influx and ciliary beating by membrane hyperpolarization due to ATP-sensitive K(+) channel opening in mouse airway epithelial cells. AB - Among the several types of cells composing the airway epithelium, the ciliary cells are responsible for one of the most important defense mechanisms of the airway epithelium: the transport of inhaled particles back up into the throat by coordinated ciliary movement. Changes in the cytoplasmic Ca(2+) concentration ([Ca(2+)]i) are the main driving force controlling the ciliary activity. In mouse ciliary cells, membrane hyperpolarization from -20 to -60 mV under whole-cell voltage-clamp induced a slow but significant [Ca(2+)]i rise in a reversible manner. This rise was completely inhibited by the removal of Ca(2+) from the extracellular solution. Application of diazoxide, an ATP-dependent K(+) channel opener, dose-dependently induced a membrane hyperpolarization (EC50 = 2.3 MUM), which was prevented by the addition of 5 MUM glibenclamide. An inwardly rectifying current was elicited by the application of 10 MUM diazoxide and suppressed by subsequent addition of 5 MUM glibenclamide. Moreover, the application of 10 MUM diazoxide induced a significant [Ca(2+)]i rise and facilitated ciliary movement. Multi-cell reverse-transcription polymerase chain reaction analyses and immunocytochemical staining suggested that the subunit combination of Kir6.2/SUR2B and possibly also Kir6.1/SUR2B is expressed in ciliary cells. The confocal Ca(2+) imaging analyses suggested that the [Ca(2+)]i rise induced by diazoxide occurred preferentially in the apical submembrane region. In conclusion, the application of a KATP channel opener to airway ciliary cells induces membrane hyperpolarization and thereby induces a [Ca(2+)]i rise via the facilitation of Ca(2+) influx through the non-voltage-dependent Ca(2+) permeable channels. Therefore, a KATP opener may be beneficial in facilitating ciliary movement. PMID- 23922450 TI - Exploring scientifically proven herbal aphrodisiacs. AB - Procreation was an important moral and religious issue and aphrodisiacs were sought to ensure both male and female potency. Sexual dysfunction is an inability to achieve a normal sexual intercourse, including premature ejaculation, retrograded, retarded or inhibited ejaculation, erectile dysfunction, arousal difficulties (reduced libido), compulsive sexual behavior, orgasmic disorder, and failure of detumescence. The introduction of the first pharmacologically approved remedy for impotence, Viagra (sildenafil) in 1990s caused a wave of public attention, propelled in part by heavy advertising. The search for such substances dates back millennia. An aphrodisiac is an agent (food or drug) that arouses sexual desire. The hunt for natural supplement from medicinal plants is being intensified mainly because of its fewer side effects. In this review, we have mentioned the pharmacologically tested (either in man or animal or in both) aphrodisiac plants, which have claimed for its uses. PMID- 23922451 TI - Endophytic bacteria as a source of novel antibiotics: An overview. AB - World human population is increasing with an alarming rate; and a variety of new types of health issues are popping up. For instance, increase in number of drug resistant bacteria is a cause of concern. Research on antibiotics and other microbial natural products is pivotal in the global fight against the growing problem of antibiotic resistance. It is necessary to find new antibiotics to tackle this problem. The use of therapeutic plant species in traditional medicine is as old as mankind; and currently, it is strongly believed that all types of plant species across the plant kingdom do harbour endophytic bacteria (EB). The natural therapeutic compounds produced by EB do have several potential applications in pharmaceutical industry. The EB derived natural products such as Ecomycins, Pseudomycins, Munumbicins and Xiamycins are antibacterial, antimycotic and antiplasmodial. Some of these natural products have been reported to possess even antiviral (including Human Immunodeficiency Virus (HIV)) properties. Therefore, to deal with increasing number of drug-resistant pathogens EB could serve as a potential source of novel antibiotics. PMID- 23922452 TI - Types of headache and those remedies in traditional persian medicine. AB - The history of headache, as a common neurological complication, goes back to almost 9000 years ago. Many ancient civilizations present references to headaches and the coherent treatment strategies. Accordingly, several documents comprising headache complications embodying precise medical information stem from Traditional Persian Medicine (TPM) that can provide useful opportunities for more comprehensive treatment. We conducted a survey on headache through original important pharmacopeias and other important medical manuscripts of TPM which were written during 9(th) to 19(th) centuries and have derived all headache categories and herbal remedies. An extensive search of scientific data banks, such as Medline and Scopus, has also been exercised to find results relating to the anti inflammatory, anti-nociceptive, and analgesic effects of denoted medicinal herbs. The concept of headache and treatments in TPM covers over 20 various types of headache and more than 160 different medicinal plants administered for oral, topical, and nasal application according to 1000 years of the subject documents. Nearly, 60% of remarked medicinal herbs have related anti-inflammatory or analgesic effects and some current headache types have similarities and conformities to those of traditional types. Beside historical approaches, there are many possible and available strategies that can lead to development of new and effective headache treatment from medicinal plants so that this study can provide beneficial information on clinical remedies based on centuries of experience in the field of headache which can stand as a new candidate for further investigations. PMID- 23922453 TI - In vitro production of alkaloids: Factors, approaches, challenges and prospects. AB - The wide diversity of plant secondary metabolites is largely used for the production of various pharmaceutical compounds. In vitro cell tissue or organ culture has been employed as a possible alternative to produce such industrial compounds. Tissue culture techniques provide continuous, reliable, and renewable source of valuable plant pharmaceuticals and might be used for the large-scale culture of the plant cells from which these secondary metabolites can be extracted. Alkaloids are one of the most important secondary metabolites known to play a vital role in various pharmaceutical applications leading to an increased commercial importance in recent years. The tissue culture techniques may be utilized to improve their production of alkaloids via somaclonal variations and genetic transformations. The focus of this review is toward the application of different tissue culture methods/techniques employed for the in vitro production of alkaloids with a systematic approach to improve their production. PMID- 23922454 TI - Plants with anti-Leishmania activity: Integrative review from 2000 to 2011. AB - The search for more effective new drugs to treat Leishmaniasis is undoubtedly relevant. Our objective in this study was to investigate research publications addressing plants with anti-Leishmaniasis activity. An integrative review of the literature from 2000 to 2011 was carried out in the databases such as Latin American and Caribbean Health Sciences (LILACS), Scientific Electronic Library Online (SciELO), and Medical Literature Analysis and Retrieval System Online (MEDLINE). In the initial search, 150 articles were found, with 25 based in LILACS, 68 in SciELO, and 46 in MEDLINE. From these data, after reading the abstracts that were available online, we excluded 12 from LILACS, 39 from SciELO, and 28 from MEDLINE for presenting article duplications. This left 61 articles to be read; however, only 18 of them answered the research questions and determined the final sample of this review. The results showed that research involving the search for new drugs against Leishmaniasis should be intensified, especially for the amastigote form, and studies with in vivo tests could become a great strategy for successfully finding new treatments for Leishmaniasis. It is believed that it is extremely important and urgent to conduct more trials in search of new effective drugs against Leishmaniasis that possess minimal adverse effects and that are easily accessible to the public. PMID- 23922455 TI - Turmeric (curcumin) remedies gastroprotective action. AB - The purpose of this review is to summarize the pertinent literature published in the present era regarding the antiulcerogenic property of curcumin against the pathological changes in response to ulcer effectors (Helicobacter pylori infection, chronic ingestion of non-steroidal anti-inflammatory drugs, and exogenous substances). The gastrointestinal problems caused by different etiologies was observed to be associated with the alterations of various physiologic parameters such as reactive oxygen species, nitric oxide synthase, lipid peroxidation, and secretion of excessive gastric acid. Gastrointestinal ulcer results probably due to imbalance between the aggressive and the defensive factors. In 80% of the cases, gastric ulcer is caused primarily due to the use of non-steroidal anti-inflammatory category of drug, 10% by H. pylori, and about 8 10% by the intake of very spicy and fast food. Although a number of antiulcer drugs and cytoprotectants are available, all these drugs have side effects and limitations. In the recent years a widespread search has been launched to identify new antiulcer drugs from synthetic and natural resources. An Indian dietary derivative (curcumin), a yellow pigment found in the rhizome of Curcuma longa, has been widely used for the treatment of several diseases. Epidemiologically, it was suggested that curcumin might reduce the risk of inflammatory disorders, such as cancer and ulcer. These biological effects are attributed to its anti-inflammatory and antioxidant activities. It can, therefore, be reported from the literature that curcumin PRevents gastrointestinal-induced ulcer and can be recommended as a novel drug for ulcer treatment. PMID- 23922456 TI - Biosynthesis pathways of ginkgolides. AB - The ginkgolides, acting as anti-platelet-activating factors, have been studied for many years. The biosynthetic pathway of ginkgolides is still far away from unveiling at the level of molecular genetics and biochemistry. There are at least 11 kinds of enzymes having been cloned from Ginkgo biloba L., which catalyze the formation of ginkgolides via a series of reactions. Some researchers have indicated that the addition of precursors and elicitors can influence the accumulation of ginkgolides in the suspension cell cultures of G. biloba. There are also other factors that can influence the production of ginkgolides. This review focuses on the aforementioned aspects to discuss the biosynthetic pathways of the ginkgolides. PMID- 23922457 TI - Search for antisickling agents from plants. AB - The sickle cell disease is fatal in nature. Thousands of children are dying off due to this health problem throughout the globe. Due to the rapid development of diagnosis and clinical managements such patients are living up to a respectable age. But as there is no permanent cure the patients are suffering from bone and joint pain, jaundice, hepato-splenomegaly, chronic infections etc. The main physiological complicacy is due to the polymerization of sickle hemoglobin (HbS), (sickling process) inside the red blood cell (RBC) of these patients during deoxygenating state. The change of RBC from spherical to sickle shape is due to the polymerization of mutant hemoglobin (HbS) inside the RBC and membrane distortion during anoxic condition. The mechanism and the process of sickling are very complex and multifactor in nature. To get rid from such complicacies it is necessary to suitably and accurately stop the sickling of RBC of the patients. The potential anti-sickling agents either from natural sources and/or synthetic molecules may be helpful for reducing the clinical morbidity of the patients. A lot of natural compounds from plant extracts have been tried by several workers in recent past. Most of the studies are based on in vitro red cell sickling studies and their mode of action has not been properly understood. Although, few studies have been in vivo in nature pertaining to transgenic sickle animal model, there is paucity of data on the human studies. The result of such studies although has shown some degree of success, a promising anti-sickling agent is yet to be established. PMID- 23922458 TI - An overview on saffron, phytochemicals, and medicinal properties. AB - Saffron is the most valuable medicinal food product because of its importance in Iran's agricultural economy. The dried stigmas of the plant Crocus sativus (Iridaceae) are processing to produce saffron as a well-known spice which has some other importance in pharmaceutics, cosmetics, perfumery, and textile dye producing industries. Recently, reports about the pharmacological activity of this plant increase its importance in the world. The world's annual saffron production is estimated around 300 tons per year (Iran produces 76% of total) and also saffron is considered to be the most expensive spice in the world; hence, there are efforts for its artificial production or defraud. Therefore, the quality conservation of saffron needs to certify in the international trade market following international ISO or the Food and Drug Administration (FDA) criteria and standards. In this paper, the recent (or sometimes less documented) reports on phytochemistry, pharmacology, and standard methods for quality evaluation of saffron, as a medicinal food spice, from field cultivation to market are reviewed. PMID- 23922459 TI - Trema orientalis Linn. Blume: A potential for prospecting for drugs for various uses. AB - Medicinal plants are used by traditional practitioners to treat several ailments. Ethnomedicinal studies on Trema orientalis Linn. Blume (Ulmaceae) have shown that it is used in the treatment of diabetes mellitus, respiratory diseases, oliguria, and malaria. This article is aimed at providing comprehensive information on the medicinal uses, biology, phytochemical constituents, and pharmacological data available on T. orientalis. This has been done to explore its therapeutic potential for future research opportunities. This review was compiled with information obtained from databases such as Medline, Elsevier, Springer, Science Direct, Pubmed, Google Scholar, and a library search for articles published in peer-reviewed journals. Compounds present in the plant include tannins, saponins, flavanoids, triterpenes, phytosterols, and several constituents of xanthones. Some pharmacological research done on the plant has focused on, hypoglycemic activity, analgesic, anti-inflammatory activities, anti-plasmodial activity, diuretic activity, laxativity effect, anti-convulsant activity, anti-helmintic activity, anti-sickling effect, anti-oxidant, and anti-bacterial activity. This compilation strongly supports the view that T. orientalis has beneficial therapeutic properties, and indicates its potential as an effective herbal remedy for several diseases. The promising results from several research works could be further substantiated by clinical trials. PMID- 23922460 TI - Phytochemistry and medicinal properties of Phaleria macrocarpa (Scheff.) Boerl. extracts. AB - Phaleria macrocarpa, commonly known as Mahkota dewa is a medicinal plant that is indigenous to Indonesia and Malaysia. Extracts of P. macrocarpa have been used since years in traditional medicine that are evaluated scientifically as well. The extracts are reported for a number of valuable medicinal properties such as anti-cancer, anti-diabetic, anti-hyperlipidemic, anti-inflammatory, anti bacterial, anti-fungal, anti-oxidant and vasorelaxant effect. The constituents isolated from different parts of P. macrocarpa include Phalerin, gallic acid, Icaricide C, magniferin, mahkoside A, dodecanoic acid, palmitic acid, des acetylflavicordin-A, flavicordin-A, flavicordin-D, flavicordin-A glucoside, ethyl stearate, lignans, alkaloids andsaponins. The present review is an up-to-date summary of occurrence, botanical description, ethnopharmacology, bioactivity and toxicological studies related to P. macrocarpa. PMID- 23922461 TI - Stool therapy may become a preferred treatment of recurrent Clostridium difficile? AB - Fecal enemas were first reported to successfully treat life threatening enterocolitis in 1958, but fecal therapy to treat Clostridium difficile (C. difficile) infection has remained esoteric and not well investigated until recently. In the past few years, systematic reviews of case series and case reports of fecal microbiota transplant for recurrent C. difficile infection have become available and validate use of fecal transplant for C. difficile enterocolitis. Methods of fecal transplant reported in the literature include: nasogastric tube, gastroscope, duodenal tube, colonoscopy, rectal tube, and fecal enemas administered at home; no method has been shown to be superior. A recent randomized study published in New England Journal of Medicine found fecal transplant to be superior to oral vancomycin alone in treatment of recurrent C. difficile enterocolitis. The significance of this trial cannot be underestimated as it lends credibility to the idea of intentionally using microbes to combat disease, providing an alternative to the older paradigm of disease eradication through use of antimicrobials. PMID- 23922462 TI - Strategies to rescue steatotic livers before transplantation in clinical and experimental studies. AB - The shortage of donor livers has led to an increased use of organs from expanded criteria donors. Included are livers with steatosis, a metabolic abnormality that increases the likelihood of graft complications post-transplantation. After a brief introduction on the etiology, pathophysiology, categories and experimental models of hepatic steatosis, we herein review the methods to rescue steatotic donor livers before transplantation applied in clinical and experimental studies. The methods span the spectrum of encouraging donor weight loss, employing drug therapy, heat shock preconditioning, ischemia preconditioning and selective anesthesia on donors, and the treatment on isolated grafts during preservation. These methods work at different stages of transplantation process, although share similar molecular mechanisms including lipid metabolism stimulation through enzymes or nuclear receptor e.g., peroxisomal proliferator-activated receptor, or anti-inflammation through suppressing cytokines e.g., tumor necrosis factor alpha, or antioxidant therapies to alleviate oxidative stress. This similarity of molecular mechanisms implies possible future attempts to reinforce each approach by repeating the same treatment approach at several stages of procurement and preservation, as well as utilizing these alternative approaches in tandem. PMID- 23922463 TI - Clinical utility of anti-p53 auto-antibody: systematic review and focus on colorectal cancer. AB - Mutation of the p53 gene is a key event in the carcinogenesis of many different types of tumours. These can occur throughout the length of the p53 gene. Anti-p53 auto-antibodies are commonly produced in response to these p53 mutations. This review firstly describes the various mechanisms of p53 dysfunction and their association with subsequent carcinogenesis. Following this, the mechanisms of induction of anti-p53 auto-antibody production are shown, with various hypotheses for the discrepancies between the presence of p53 mutation and the presence/absence of anti-p53 auto-antibodies. A systematic review was performed with a descriptive summary of key findings of each anti-p53 auto-antibody study in all cancers published in the last 30 years. Using this, the cumulative frequency of anti-p53 auto-antibody in each cancer type is calculated and then compared with the incidence of p53 mutation in each cancer to provide the largest sample calculation and correlation between mutation and anti-p53 auto-antibody published to date. Finally, the review focuses on the data of anti-p53 auto antibody in colorectal cancer studies, and discusses future strategies including the potentially promising role using anti-p53 auto-antibody presence in screening and surveillance. PMID- 23922465 TI - Hepatic arterial infusion chemotherapy in hepatocellular carcinoma with portal vein tumor thrombosis. AB - AIM: To evaluate the prognostic factors and efficacy of hepatic arterial infusion chemotherapy in hepatocellular carcinoma with portal vein tumor thrombosis. METHODS: Fifty hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) were treated using hepatic arterial infusion chemotherapy (HAIC) via a subcutaneously implanted port. The epirubicin-cisplatin-5 fluorouracil (ECF) chemotherapeutic regimen consisted of 35 mg/m(2) epirubicin on day 1, 60 mg/m(2) cisplatin for 2 h on day 2, and 500 mg/m(2) 5-fluorouracil for 5 h on days 1-3. The treatments were repeated every 3 or 4 wk. RESULTS: Three (6%) of the 50 patients achieved a complete response (CR), 13 (26%) showed partial responses (PR), and 22 (44%) had stable disease (SD). The median survival and time to progression were 7 and 2 mo, respectively. After 2 cycles of HAIC, CR was achieved in 1 patient (2%), PR in 10 patients (20%) and SD in 26 patients (52%). Significant pre-treatment prognostic factors were a tumor volume of < 400 cm(3) (P = 0.01) and normal levels of protein induced by vitamin K absence or antagonist (PIVKA)-II (P = 0.022). After 2 cycles of treatment, disease control (CR + PR + SD) (P = 0.001), PVTT response (P = 0.003) and alpha-fetoprotein reduction of over 50% (P = 0.02) were independent factors for survival. Objective response (CR + PR), disease control, PVTT response, and combination therapy during the HAIC were also significant prognostic factors. Adverse events were tolerable and successfully managed. CONCLUSION: HAIC may be an effective treatment modality for advanced HCC with PVTT in patients with tumors < 400 cm(3) and good prognostic factors. PMID- 23922464 TI - Update on small intestinal stem cells. AB - Among somatic stem cells, those residing in the intestine represent a fascinating and poorly explored research field. Particularly, somatic stem cells reside in the small intestine at the level of the crypt base, in a constant balance between self-renewal and differentiation. Aim of the present review is to delve into the mechanisms that regulate the delicate equilibrium through which intestinal stem cells orchestrate intestinal architecture. To this aim, special focus will be addressed to identify the integrating signals from the surrounding niche, supporting a model whereby distinct cell populations facilitate homeostatic vs injury-induced regeneration. PMID- 23922466 TI - Garcinia Cambogia attenuates diet-induced adiposity but exacerbates hepatic collagen accumulation and inflammation. AB - AIM: To investigate long-term effects of Garcinia Cambogia (GC), weight-loss supplement, on adiposity and non-alcoholic fatty liver disease in obese mice. METHODS: Obesity-prone C57BL/6J mice were fed a high-fat diet (HFD, 45 kcal% fat) with or without GC (1%, w/w) for 16 wk. The HFD contained 45 kcal% fat, 20 kcal% protein and 35 kcal% carbohydrate. They were given free access to food and distilled water, and food consumption and body weight were measured daily and weekly, respectively. Data were expressed as the mean +/- SE. Statistical analyses were performed using the statistical package for the social science software program. Student's t test was used to assess the differences between the groups. Statistical significance was considered at P < 0.05. RESULTS: There were no significant changes in body weight and food intake between the groups. However, the supplementation of GC significantly lowered visceral fat accumulation and adipocyte size via inhibition of fatty acid synthase activity and its mRNA expression in visceral adipose tissue, along with enhanced enzymatic activity and gene expression involved in adipose fatty acid beta-oxidation. Moreover, GC supplementation resulted in significant reductions in glucose intolerance and the plasma resistin level in the HFD-fed mice. However, we first demonstrated that it increased hepatic collagen accumulation, lipid peroxidation and mRNA levels of genes related to oxidative stress (superoxide dismutase and glutathione peroxidase) and inflammatory responses (tumor necrosis factor-alpha and monocyte chemoattractant protein-1) as well as plasma alanine transaminase and aspartate transaminase levels, although HFD-induced hepatic steatosis was not altered. CONCLUSION: GC protects against HFD-induced obesity by modulating adipose fatty acid synthesis and beta-oxidation but induces hepatic fibrosis, inflammation and oxidative stress. PMID- 23922467 TI - Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses. AB - AIM: To investigate the potential therapeutic effects of mesenchymal stem cells (MSCs) in inflammatory bowel disease (IBD), we transplanted MSCs into an experimental model of IBD. METHODS: A rectal enema of trinitrobenzene sulfonic acid (TNBS) (100 mg/kg body weight) was administered to female BALB/c mice. Bone marrow mesenchymal stem cells (BMSCs) were derived from male green fluorescent protein (GFP) transgenic mice and were transplanted intravenously into the experimental animals after disease onset. Clinical activity scores and histological changes were evaluated. GFP and Sex determining region Y gene (SRY) expression were used for cell tracking. Ki67 positive cells and Lgr5-expressing cells were determined to measure proliferative activity. Inflammatory response was determined by measuring the levels of different inflammatory mediators in the colon and serum. The inflammatory cytokines included tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-6, IL-17, IL 4, IL-10, and transforming growth factor (TGF-beta). Master regulators of Th1 cells (T-box expressed in T cells, T-bet), Th17 cells (retinoid related orphan receptor gamma(t), RORgammat), Th2 cells (GATA family of transcription factors 3, GATA3) and regulatory T cells (forkhead box P3, Foxp3) were also determined. RESULTS: Systemic infusion of GFP-BMSCs ameliorated the clinical and histopathologic severity of colitis, including body weight loss, diarrhea and inflammation, and increased survival (P < 0.05). The cell tracking study showed that MSCs homed to the injured colon. MSCs promoted proliferation of intestinal epithelial cells and differentiation of intestinal stem cells (P < 0.01). This therapeutic effect was mainly mediated by down-regulation of both Th1-Th17-driven autoimmune and inflammatory responses (IL-2, TNF-alpha, IFN-gamma, T-bet; IL-6, IL-17, RORgammat), and by up-regulation of Th2 activities (IL-4, IL-10, GATA-3) (P < 0.05). MSCs also induced activated CD4(+)CD25(+)Foxp3(+) regulatory T cells (TGF-beta, IL-10, Foxp3) with a suppressive capacity on Th1-Th17 effecter responses and promoted Th2 differentiation in vivo (P < 0.05). CONCLUSION: MSCs are key regulators of immune and inflammatory responses and may be an attractive candidate for cell-based therapy of IBD. PMID- 23922468 TI - Probiotic supplementation decreases intestinal transit time: meta-analysis of randomized controlled trials. AB - AIM: To determine the efficacy of probiotic supplementation on intestinal transit time (ITT) and to identify factors that influence these outcomes. METHODS: A systematic review of randomized controlled trials (RCTs) of probiotic supplementation that measured ITT in adults was conducted by searching MEDLINE and EMBASE using relevant key word combinations. Main search limits included RCTs of probiotic supplementation in healthy or constipated adults that measured ITT. Study quality was assessed using the Jadad scale. A random effects meta-analysis was performed with standardized mean difference (SMD) of ITT between probiotic and control groups as the primary outcome. Meta-regression and subgroup analyses were conducted to examine the impact of moderator variables on ITT SMD. RESULTS: A total of 11 clinical trials with 13 treatment effects representing 464 subjects were included in this analysis. Probiotic supplementation was associated with decreased ITT in relation to controls, with an SMD of 0.40 (95%CI: 0.20-0.59, P < 0.001). Constipation (r (2) = 39%, P = 0.01), higher mean age (r (2) = 27%, P = 0.03), and higher percentage of female subjects (r (2) = 23%, P < 0.05) were predictive of decreased ITT with probiotics in meta-regression. Subgroup analyses demonstrated statistically greater reductions in ITT with probiotics in subjects with vs without constipation and in older vs younger subjects [both SMD: 0.59 (95%CI: 0.39-0.79) vs 0.17 (95%CI: -0.08-0.42), P = 0.01]. Medium to large treatment effects were identified with Bifidobacterium Lactis (B. lactis) HN019 (SMD: 0.72, 95%CI: 0.27-1.18, P < 0.01) and B. lactis DN-173 010 (SMD: 0.54, 95%CI: 0.15-0.94, P < 0.01) while other single strains and combination products yielded small treatment effects. CONCLUSION: Overall, short-term probiotic supplementation decreases ITT with consistently greater treatment effects identified in constipated or older adults and with certain probiotic strains. PMID- 23922469 TI - Comparison of double balloon enteroscopy in adults and children. AB - AIM: To compare results of double balloon enteroscopy (DBE) procedures in pediatric and adult patients. METHODS: The medical files of patients who underwent DBE at Gazi University School of Medicine, Ankara, Turkey between 2009 and 2011 were examined retrospectively. Adult and pediatric patients were compared according to DBE indications, procedure duration, final diagnosis, and complications. DBE procedures were performed in an operating room under general anesthesia by two endoscopists. An oral or anal approach was preferred according to estimated lesion sites. Overnight fasting of at least 6 h prior to the start of the procedure was adequate for preprocedural preparation of oral DBE procedures. Bowel cleansing was performed by oral administration of sennosides A and B solution, 2 mL/kg, and anal saline laxative enema. The patients were followed up for 2 h after the procedure in terms of possible complications. RESULTS: DBE was performed in 35 patients (5 pediatric and 30 adult). DBE procedures were performed for abdominal pain, chronic diarrhea, bleeding, chronic vomiting, anemia, and postoperative evaluation of anastomosis. Final diagnosis was diffuse gastric angiodysplasia (n = 1); diffuse jejunal angiodysplasia (n = 1); ulceration in the bulbus (n = 1); celiac disease (n = 1); low differentiated metastatic carcinoma (n = 1); Peutz-Jeghers syndrome (n = 1); adenomatous polyp (n = 1) and stricture formation in anastomosis line (n = 1). During postprocedural follow-up, abdominal pain and elevated amylase levels were noted in three patients and one patient developed abdominal perforation. CONCLUSION: With the help of technological improvements, we may use enteroscopy as a safe modality more frequently in younger and smaller children. PMID- 23922470 TI - Utility of single and double balloon endoscopy in patients with difficult colonoscopy: a randomized controlled trial. AB - AIM: To compare the utility of single-balloon colonoscopy (SBC) or double-balloon colonoscopy (DBC) for difficult colonoscopies. METHODS: Between August 2008 and June 2010, patients in whom total colonoscopy failed within 30 min of insertion were assigned randomly to undergo either SBC or DBC. No sedatives were used. After the endoscopy, all patients were asked to evaluate pain during the procedure on a 10-point analog scale (1 = no pain; 10 = worst imaginable pain) with a questionnaire. The study outcomes were the cecal intubation rate and time, endoscopic findings, complications, and pain score. RESULTS: The SBC and DBC groups included 11 and 10 patients, respectively. All but one SBC patient achieved total colonoscopy successfully. The cecal intubation times were 18 min (range: 10-85 min) and 12.8 min (range: 9.5-42 min) in the SBC and DBC groups, respectively (P = 0.17). No difference was observed in the prevalence of colon polyps between the SBC and DBC groups (45% vs 30%, P = 0.66). SBC showed advanced colon cancer in the ascending colon, which was inaccessible using conventional colonoscopy. The respective pain scores were 5 (1-10) [median (range)] and 5 (1 6) in the SBC and DBC groups (P = 0.64). No complications were noted in any patient. CONCLUSION: The utility of single- and double-balloon endoscopy for colonoscopy seems comparable in patients with incomplete colonoscopy using a conventional colonoscope. PMID- 23922471 TI - Clinical outcome in patients with hepatocellular carcinoma after living-donor liver transplantation. AB - AIM: To investigate risk factors for hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT) and efficacy of various criteria. METHODS: From October 2000 to November 2011, 233 adult patients underwent LDLT for HCC at our institution. After excluding nine postoperative mortality cases, we analyzed retrospectively 224 patients. To identify risk factors for recurrence, we evaluated recurrence, disease-free survival (DFS) rate, survival rate, and various other factors which are based on the characteristics of both the patient and tumor. Additionally, we developed our own criteria based on our data. Next, we compared our selection criteria with various tumor-grading scales, such as the Milan criteria, University of California, San Francisco (UCSF) criteria, TNM stage, Barcelona Clinic Liver Cancer (BCLC) stage and Cancer of the Liver Italian Program (CLIP) scoring system. The median follow up was 68 (6-139) mo. RESULTS: In 224 patients who received LDLT for HCC, 37 (16.5%) experienced tumor recurrence during the follow-up period. The 5-year DFS and overall survival rates after LDLT in all patients with HCC were 80.9% and 76.4%, respectively. On multivariate analysis, the tumor diameter {5 cm; P < 0.001; exponentiation of the B coefficient [Exp(B)], 11.89; 95%CI: 3.784-37.368} and alpha fetoprotein level [AFP, 100 ng/mL; P = 0.021; Exp(B), 2.892; 95%CI: 1.172-7.132] had significant influences on HCC recurrence after LDLT. Therefore, these two factors were included in our criteria. Based on these data, we set our selection criteria as a tumor diameter <= 5 cm and AFP <= 100 ng/mL. Within our new criteria (140/214, 65.4%), the 5-year DFS and overall survival rates were 88.6% and 81.8%, respectively. Our criteria (P = 0.001), Milan criteria (P = 0.009), and UCSF criteria (P = 0.001) showed a significant difference in DFS rate. And our criteria (P = 0.006) and UCSF criteria (P = 0.009) showed a significant difference in overall survival rate. But Milan criteria did not show significant difference in overall survival rate (P = 0.137). Among stages 0, A, B and C of BCLC, stage C had a significantly higher recurrence rate (P = 0.001), lower DFS (P = 0.001), and overall survival rate (P = 0.005) compared with the other stages. Using the CLIP scoring system, the group with a score of 4 to 5 showed a high recurrence rate (P = 0.023) and lower DFS (P = 0.011); however, the overall survival rate did not differ from that of the lower scoring group. The TNM system showed a trend of increased recurrence rate, decreased DFS, or survival rate according to T stage, albeit without statistical significance. CONCLUSION: LDLT is considered the preferred therapeutic option in patients with an AFP level less than 100 ng/mL and a tumor diameter of less than 5 cm. PMID- 23922472 TI - Risk of sedation for diagnostic esophagogastroduodenoscopy in obstructive sleep apnea patients. AB - AIM: To investigate whether patients with obstructive sleep apnea (OSA) are at risk of sedation-related complications during diagnostic esophagogastroduodenoscopy (EGD). METHODS: A prospective study was performed in consecutive patients with OSA, who were confirmed with full-night polysomnography between July 2010 and April 2011. The occurrence of cardiopulmonary complications related to sedation during diagnostic EGD was compared between OSA and control groups. RESULTS: During the study period, 31 patients with OSA and 65 controls were enrolled. Compared with the control group, a higher dosage of midazolam was administered (P = 0.000) and a higher proportion of deep sedation was performed (P = 0.024) in the OSA group. However, all adverse events, including sedation failure, paradoxical responses, snoring or apnea, hypoxia, hypotension, oxygen or flumazenil administration, and other adverse events were not different between the two groups (all P > 0.1). Patients with OSA were not predisposed to hypoxia with multivariate logistic regression analysis (P = 0.068). CONCLUSION: In patients with OSA, this limited sized study did not disclose an increased risk of cardiopulmonary complications during diagnostic EGD under sedation. PMID- 23922473 TI - A feasible modified biopsy method for tissue diagnosis of gastric subepithelial tumors. AB - AIM: To evaluate the diagnostic yield and safety of a modified technique for the histological diagnosis of subepithelial tumors (SETs). METHODS: A retrospective review of patients who underwent a modified technique for the histological diagnosis of gastric SETs, consisting of a mucosal incision with a fixed flexible snare (MIF) and deep-tissue biopsy under conventional endoscopic view, from January 2012 to January 2013 was performed. Eleven patients with gastric SETs 10 30 mm in diameter and originating from the third or fourth layer on endoscopic ultrasonography were included. RESULTS: The mean age was 59.8 (range, 45-76) years, and 5 patients were male. The mean size of the SETs was 21.8 (range, 11 30) mm. The number of biopsy specimens was 6.3 (range 5-8). The mean procedure time was 9.0 min (range, 4-17 min). The diagnostic yield of MIF biopsies was 90.9% (10/11). The histological diagnoses were leiomyoma (4/11, 36.4%), aberrant pancreas (3/11, 27.3%), gastrointestinal stromal tumors (2/11, 18.2%), an inflammatory fibrinoid tumor (1/11, 9.1%); one result was non-diagnostic (1/11, 9.1%). There were six mesenchymal tumors; the specimens obtained in each case were sufficient for an immunohistochemical diagnosis. There was no major bleeding, but one perforation occurred that was successfully controlled by endoscopic clipping. CONCLUSION: The MIF biopsy was simple to perform, safe, and required a shorter procedure time, with a high diagnostic yield for small SETs. PMID- 23922474 TI - A novel technique for endoscopic ultrasound-guided biliary drainage. AB - AIM: To describe a successful endoscopic ultrasound (EUS)-guided biliary drainage technique with high success and low complication rates. METHODS: The recorded data of consecutive patients who presented to Siriraj Gastrointestinal Endoscopy Center, Siriraj Hospital in Bangkok, Thailand for treatment of malignant obstructive jaundice but failed endoscopic retrograde cholangiopancreatography and underwent subsequent EUS-guided biliary drainage were retrospectively reviewed. The patients' baseline characteristics, clinical manifestations, procedure details, and post-procedure follow-up data were recorded and analyzed. Clinical outcomes were assessed by physical exam and standard laboratory tests. Technical success of the procedure was defined as completion of the stent insertion. Clinical success was defined as improvement of the patient's overall clinical manifestations, in terms of general well-being evidenced by physical examination, restoration of normal appetite, and adequate biliary drainage. Overall median survival time was calculated as the time from the procedure until the time of death, and survival analysis was performed by the Kaplan-Meier method. The Student's t-test and the chi(2) test were used to assess the significance of inter-group differences. RESULTS: A total of 21 cases were enrolled, a single endoscopist performed all the procedures. The mean age was 62.8 years (range: 46-84 years). The sex distribution was almost equal, including 11 women and 10 men. Patients with failed papillary cannulation (33.3%), duodenal obstruction (42.9%), failed selective cannulation (19.0%), and surgical altered anatomy (4.8%) were considered candidates for EUS-guided biliary drainage. Six patients underwent EUS-guided choledochoduodenostomy and 15 underwent EUS-guided hepaticogastrostomy. The technique using non-cauterization and no balloon dilation was performed for all cases, employing the in-house manufactured tapered tip Teflon catheter to achieve the dilation. The technical success and clinical success rates of this technique were 95.2% and 90.5%, respectively. Complications included bile leakage and pneumoperitoneum, occurred at a rate of 9.5%. None of the patients died from the procedure. One patient presented with a biloma, a major complication that was successfully treated by another endoscopic procedure. CONCLUSION: We present a highly effective EUS-guided biliary drainage technique that does not require cauterization or balloon dilation. PMID- 23922475 TI - Quality of life after laparoscopic vs open sphincter-preserving resection for rectal cancer. AB - AIM: To compare quality of life (QoL) outcomes in Chinese patients after curative laparoscopic vs open surgery for rectal cancer. METHODS: Eligible Chinese patients with rectal cancer undergoing curative laparoscopic or open sphincter preserving resection between July 2006 and July 2008 were enrolled in this prospective study. The QoL outcomes were assessed longitudinally using the validated Chinese versions of the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires before surgery and at 4, 8, and 12 mo after surgery. The QoL scores at the different time points were compared between the laparoscopic and open groups. A higher score on a functional scale indicated better functioning, whereas a higher score on a symptom scale indicated a higher degree of symptoms. RESULTS: Seventy-four patients (49 laparoscopic and 25 open) were enrolled. The two groups of patients were comparable in terms of sociodemographic data, types of surgery, tumor staging, and baseline mean QoL scores. There was no significant decrease from baseline in global QoL for the laparoscopic group at different time points, whereas the global QoL was worse compared to baseline beginning at 4 mo but returned to baseline by 12 mo for the open group (P = 0.019, Friedman test). Compared to the open group, the laparoscopic group had significantly better physical (89.9 +/- 1.4 vs 79.2 +/- 3.7, P = 0.016), role (85.0 +/- 3.4 vs 63.3 +/- 6.9, P = 0.005), and cognitive (73.5 +/- 3.4 vs 50.7 +/- 6.2, P = 0.002) functioning at 8 mo, fewer micturition problems at 4-8 mo (4 mo: 32.3 +/- 4.7 vs 54.7 +/- 7.1, P = 0.011; 8 mo: 22.8 +/- 4.0 vs 40.7 +/- 6.9, P = 0.020), and fewer male sexual problems from 8 mo onward (20.0 +/- 8.5 vs 76.7 +/- 14.5, P = 0.013). At 12 mo after surgery, no significant differences were observed in any functional or symptom scale between the two groups, with the exception of male sexual problems, which remained worse in the open group (29.2 +/- 11.3 vs 80.0 +/- 9.7, P = 0.026). CONCLUSION: Laparoscopic sphincter-preserving resection for rectal cancer is associated with better preservation of QoL and fewer male sexual problems when compared with open surgery in Chinese patients. These findings, however, should be interpreted with caution because of the small sample size of the study. PMID- 23922476 TI - Sonographic evaluation of proximal gastric accommodation in patients with functional dyspepsia. AB - AIM: To assess the value of ultrasonography (US) in evaluation of proximal gastric accommodation disorder in patients with functional dyspepsia (FD). METHODS: Between April 2011 and March 2012, 45 patients with FD and 27 healthy volunteers were enrolled in this study. Two-dimensional ultrasound (2DUS) and 3 dimensional ultrasound (3DUS) were performed sequentially to measure proximal gastric area (PGA), maximal proximal gastric diameter (MPGD), and proximal gastric volume (PGV). These values were measured separately in the two groups every other 5 min for a duration of 25 min after the beginning of ingestion of a test meal. Air pocket grading was done separately for images of 2DUS and blocks of 3DUS obtained at five scanning time points. RESULTS: Both PGA and PGV of patients were significantly smaller than healthy controls (P = 0.000 and 0.002, respectively). Comparing the two parameters between the groups at each time point, the differences were also statistically significant (P = 0.000-0.013), except at 10 min for the PGV (P = 0.077). However, no overall difference was found between the groups in the MPGD measurements (P = 0.114), though it was statistically significant at a 20-minute examination point (P = 0.026). A total of 360 sets or blocks of images were obtained for both 2DUS and 3DUS. For the images analyzed by 2DUS, none were excluded because of gastric gas, and 50 (13.9%) and 310 (86.1%) sets were determined as air pockets grades 1 and 2, respectively. For the images analyzed by 3DUS, 23 (6.4%) blocks were excluded from the measurement due to presence of a large fundus air pocket (grade 3); fifty (13.9%) and 287 (79.7%) blocks were also graded as 1 and 2, respectively. CONCLUSION: Measurement of both PGA and PGV by 2DUS and 3DUS could be useful for assessment of the proximal gastric accommodation. PMID- 23922477 TI - Influence of endoscopic submucosal dissection on esophageal motility. AB - AIM: To assess esophageal motility after esophageal endoscopic submucosal dissection (ESD). METHODS: Twelve patients (6 men and 6 women) aged 53-64 years (mean age, 58 years) who underwent regular examination 3-12 mo after esophageal ESD for neoplasms of the esophageal body were included in this study. The ESD procedure was performed under deep sedation using a combination of propofol and fentanyl, and involved a submucosal injection to lift the lesion and use of a dual-knife and an insulated-tip knife to create a circumferential incision around the lesion extending into the submucosa. Esophageal motility was examined using a high-resolution manometry system. Dysphagia was graded using a five-point scale according to the Mellow and Pinkas scoring system. Patient symptoms and the results of esophageal manometry were then analyzed. RESULTS: Of the 12 patients enrolled, 1 patient had grade 2 dysphagia, 1 patient had grade 1 dysphagia, and 3 patients complained of sporadic dysphagia. Ineffective esophageal motility was observed in 5 of 6 patients with above semi-circumference of resection extension. Of these 5 patients, 1 patient complained of grade 2 dysphagia (with esophageal stricture), one patient complained of grade 1 dysphagia, and 3 patients complained of sporadic dysphagia. Normal esophageal body manometry was observed in all 6 patients with below semi-circumference of resection extension. The 6 patients with normal esophageal motility did not complain of dysphagia. CONCLUSION: Extensive esophageal ESD may cause esophageal dysmotility in some patients, and might also have an influence on dysphagia although without esophageal stricture. PMID- 23922478 TI - Learning curve of transumbilical suture-suspension single-incision laparoscopic cholecystectomy. AB - AIM: To investigate the learning curve of transumbilical suture-suspension single incision laparoscopic cholecystectomy (SILC). METHODS: The clinical data of 180 consecutive transumbilical suture-suspension SILCs performed by a team in our department during the period from August 2009 to March 2011 were retrospectively analyzed. Patients were divided into nine groups according to operation dates, and each group included 20 patients operated on consecutively in each time period. The surgical outcome was assessed by comparing operation time, blood loss during operation, and complications between groups in order to evaluate the improvement in technique. RESULTS: A total of 180 SILCs were successfully performed by five doctors. The average operation time was 53.58 +/- 30.08 min (range: 20.00-160.00 min) and average blood loss was 12.70 +/- 11.60 mL (range: 0.00-100.00 mL). None of the patients were converted to laparotomy or multi-port laparoscopic cholecystectomy. There were no major complications such as hemorrhage or biliary system injury during surgery. Eight postoperative complications occurred mainly in the first three groups (n = 6), and included ecchymosis around the umbilical incision (n = 7) which resolved without special treatment, and one case of delayed bile leakage in group 8, which was treated by ultrasound-guided puncture and drainage. There were no differences in intraoperative blood loss, postoperative complications and length of postoperative hospital stay among the groups. Bonferroni's test showed that the operation time in group 1 was significantly longer than that in the other groups (F = 7.257, P = 0.000). The majority of patients in each group were discharged within 2 d, with an average postoperative hospital stay of 1.9 +/- 1.2 d. CONCLUSION: Following scientific principles and standard procedures, a team experienced in multi-port laparoscopic cholecystectomy can master the technique of SILC after 20 cases. PMID- 23922479 TI - Stepwise sedation for elderly patients with mild/moderate COPD during upper gastrointestinal endoscopy. AB - AIM: To investigate stepwise sedation for elderly patients with mild/moderate chronic obstructive pulmonary disease (COPD) during upper gastrointestinal (GI) endoscopy. METHODS: Eighty-six elderly patients with mild/moderate COPD and 82 elderly patients without COPD scheduled for upper GI endoscopy were randomly assigned to receive one of the following two sedation methods: stepwise sedation involving three-stage administration of propofol combined with midazolam [COPD with stepwise sedation (group Cs), and non-COPD with stepwise sedation (group Ns)] or continuous sedation involving continuous administration of propofol combined with midazolam [COPD with continuous sedation (group Cc), and non-COPD with continuous sedation (group Nc)]. Saturation of peripheral oxygen (SpO2), blood pressure, and pulse rate were monitored, and patient discomfort, adverse events, drugs dosage, and recovery time were recorded. RESULTS: All endoscopies were completed successfully. The occurrences of hypoxemia in groups Cs, Cc, Ns, and Nc were 4 (9.3%), 12 (27.9%), 3 (7.3%), and 5 (12.2%), respectively. The occurrence of hypoxemia in group Cs was significantly lower than that in group Cc (P < 0.05). The average decreases in value of SpO2, systolic blood pressure, and diastolic blood pressure in group Cs were significantly lower than those in group Cc. Additionally, propofol dosage and overall rate of adverse events in group Cs were lower than those in group Cc. Finally, the recovery time in group Cs was significantly shorter than that in group Cc, and that in group Ns was significantly shorter than that in group Nc (P < 0.001). CONCLUSION: The stepwise sedation method is effective and safer than the continuous sedation method for elderly patients with mild/moderate COPD during upper GI endoscopy. PMID- 23922480 TI - Meta-analysis of stapled hemorrhoidopexy vs LigaSure hemorrhoidectomy. AB - AIM: To compare outcome of stapled hemorrhoidopexy (SH) vs LigaSure hemorrhoidectomy (LH) by a meta-analysis of available randomized controlled trials (RCTs). METHODS: Databases, including PubMed, EMBASE, the Cochrane Library, and the Science Citation Index updated to December 2012, were searched. The main outcomes measured were operating time, early postoperative pain, postoperative urinary retention and bleeding, wound problems, gas or fecal incontinence, anal stenosis, length of hospital stay, residual skin tags, prolapse, and recurrence. The meta-analysis was performed using the free software Review Manager. Differences observed between the two groups were expressed as the odds ratio (OR) with 95%CI. A fixed-effects model was used to pool data when statistical heterogeneity was not present. If statistical heterogeneity was present (P < 0.05), a random-effects model was used. RESULTS: The initial search identified 10 publications. After screening, five RCTs published as full articles were included in this meta-analysis. Among the five studies, all described a comparison of the patient baseline characteristics and showed that there was no statistically significant difference between the two groups. Although most of the analyzed outcomes were similar between the two operative techniques, the operating time for SH was significantly longer than for LH (P < 0.00001; OR= 6.39, 95%CI: -7.68 - -5.10). The incidence of residual skin tags and prolapse was significantly lower in the LH group than in the SH group [2/111 (1.8%) vs 16/105 (15.2%); P = 0.0004; OR= 0.17, 95%CI: 0.06-0.45). The incidence of recurrence after the procedures was significantly lower in the LH group than in the SH group [2/173 (1.2%) vs 13/174 (7.5%); P = 0.003; OR= 0.21, 95%CI: 0.07-0.59]. CONCLUSION: Both SH and LH are probably equally valuable techniques in modern hemorrhoid surgery. However, LigaSure might have slightly favorable immediate postoperative results and technical advantages. PMID- 23922482 TI - Intrahepatic endometriosis as differential diagnosis: case report and literature review. AB - Intrahepatic endometriosis is one of the rarest forms of atypical endometriosis; only eighteen cases have been reported in the English literature. We describe the case of a 32-year-old woman, who presented with persistent, non-cyclical upper right quadrant abdominal pain, a central liver cyst, and no history of endometriosis. Three years previous, she was diagnosed with an intrahepatic cyst. The lesion progressed and two laparoscopic deroofing-operations were performed, yet the diagnosis of intrahepatic endometriosis was never reached. She presented in our clinic with further progress of the cyst as well as obstruction of the intrahepatic biliary system. The magnetic resonance imaging showed a 9.5 cm * 12 cm, lobulated intrahepatic cyst. We performed an ultrasonic pericystectomy. Immunostaining confirmed intrahepatic endometriosis. Only one of the previously described eighteen patients with intrahepatic endometriosis presented with cyclical pain in the upper right abdominal quadrant accompanying menstruation. This lack of a "typical" clinic makes it challenging to diagnose extragonadal endometriosis without histopathology. A previous history of endometriosis was described in only twelve cases, thus the diagnosis of this condition should not be limited to patients with a known history of endometriosis. Six of 18 patients were postmenopausal, demonstrating this condition is not limited to women of reproductive age. A preoperative diagnosis was only reached in seven of the previously described cases, highlighting the importance of preoperative biopsies. Yet due to the potential adverse effects, a transhepatic biopsy must be discussed individually. Although rare, intrahepatic endometriosis should always be considered as a differential diagnosis in women with recurrent hepatic cysts, regardless of age or previous medical history. In such cases, histology is essential and a pericystectomy should be performed as standard of care. PMID- 23922483 TI - Bleeding Dieulafoy's-like lesions of the gut identified by capsule endoscopy. AB - Dieulafoy's-like lesions (DLs-like) represent a cause of obscure gastrointestinal bleeding, enteroscopy being the main diagnostic and therapeutic procedure. Frequently, more than one enteroscopy is needed to identify the bleeding vessel. In our practice, video capsule endoscopy (VCE) identified and guided therapy in four cases of DLs-like; three of them were localized on the small bowel. We report, for the first time, a diagnosis of colonic DL-like performed by colon capsule endoscopy. Two patients presented with severe cardiovascular disorders, being hemodynamically unstable during VCE examination. Based on the VCE findings, only one invasive therapeutic procedure per patient was necessary to achieve hemostasis. VCE and enteroscopy may be regarded as complementary procedures in patients with gut DLs-like. PMID- 23922481 TI - FDG-PET in diagnosis, staging and prognosis of pancreatic carcinoma: a meta analysis. AB - AIM: To investigate the potential role of positron emission tomography (PET) in the diagnosis, staging and prognosis predicting of pancreatic carcinoma (PC). METHODS: A systematic review of relevant literatures in PubMed, Embase and Cochrane Library was performed. The sensitivity and specificity of diagnostic and staging studies, and HRs for prognosis predicting studies were pooled. The bivariate model was used for diagnostic studies and the random-effect model for prognostic studies. Heterogeneity between included studies was tested using chi(2) test, and subgroup analysis was performed to explain the heterogeneities. All of the calculations were performed using Stata version 11.0. RESULTS: A total of 39 studies were included. The pooled sensitivity of PET in diagnosing PC (30 studies, 1582 patients), evaluating N stating (4 studies, 101 patients) and liver metastasis (7 studies, 316 patients) were 0.91 (95%CI: 0.88-0.93), 0.64 (95%CI: 0.50-0.76), and 0.67 (95%CI: 0.52-0.79), respectively; and the corresponding specificity was 0.81 (95%CI: 0.75-0.85), 0.81 (95%CI: 0.25-0.85), and 0.96 (95%CI: 0.89-0.98), respectively. In prognosis analysis (6 studies, 198 patients), significant difference of overall survival was observed between high and low standardized uptake value groups (HR = 2.39, 95%CI: 1.57-3.63). Subgroup analysis showed that PET/CT was more sensitive than PET alone in evaluating liver metastasis of PC, 0.82 (95%CI: 0.48-0.98) and 0.67 (95%CI: 0.52-0.79), respectively. CONCLUSION: PET can be used as a valuable diagnostic and predictive tool for PC, but its effect in the staging of PC remains indeterminate. PMID- 23922484 TI - Endoscopic appearance of AIDS-related gastrointestinal lymphoma with c-MYC rearrangements: case report and literature review. AB - Acquired immune deficiency syndrome (AIDS)-related lymphoma (ARL) remains the main cause of AIDS-related deaths in the highly active anti-retroviral therapy (HAART) era. Recently, rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma. Here, we report a rare case of gastrointestinal (GI)-ARL with MYC rearrangements and coinfected with Epstein Barr virus (EBV) infection presenting with various endoscopic findings. A 38-year old homosexual man who presented with anemia and was diagnosed with an human immunodeficiency virus infection for the first time. GI endoscopy revealed multiple dish-like lesions, ulcerations, bloody spots, nodular masses with active bleeding in the stomach, erythematous flat lesions in the duodenum, and multiple nodular masses in the colon and rectum. Magnified endoscopy with narrow band imaging showed a honeycomb-like pattern without irregular microvessels in the dish-like lesions of the stomach. Biopsy specimens from the stomach, duodenum, colon, and rectum revealed diffuse large B-cell lymphoma concomitant with EBV infection that was detected by high tissue EBV-polymerase chain reaction levels and Epstein-Barr virus small RNAs in situ hybridization. Fluorescence in situ hybridization analysis revealed a fusion between the immunoglobulin heavy chain (IgH) and c-MYC genes, but not between the IgH and BCL2 loci. After 1-mo of treatment with HAART and R-CHOP, endoscopic appearance improved remarkably, and the histological features of the biopsy specimens revealed no evidence of lymphoma. However, he died from multiple organ failure on the 139(th) day after diagnosis. The cause of his poor outcome may be related to MYC rearrangement. The GI tract involvement in ARL is rarely reported, and its endoscopic findings are various and may be different from those in non-AIDS GI lymphoma; thus, we also conducted a literature review of GI-ARL cases. PMID- 23922485 TI - Laparoscopic cholecystectomy in patients with anesthetic problems. AB - Laparoscopic cholecystectomy is a standard operation for benign gallbladder disease. As experience with laparoscopic cholecystectomy has increased, the procedure has become possible in patients with anesthetic problems. Patients with ankylosing spondylitis or severe kyphosis represent a challenging group to anesthesiologists and laparoscopic surgeons since these diseases are associated with difficult intubation, restrictive ventilatory defects, and cardiac problems. The relatively new approach of awake fiberoptic intubation is considered to be the safest option for patients with anticipated airway difficulties. Laparoscopic cholecystectomy is usually performed under general anesthesia but considerable difficulties in anesthetic management are encountered during laparoscopic surgery; for example, hemodynamic instability may develop in patients with cardiopulmonary dysfunction due to pneumoperitoneum and position changes during the operation. Nonetheless, regional anesthesia can be considered as a valid option for patients with gallbladder disease who are poor candidates for general anesthesia due to cardiopulmonary problems. We report three cases of laparoscopic cholecystectomy successfully performed in patients with anesthetic problems that included cardiopulmonary disease, severe kyphosis, and ankylosing spondylitis. PMID- 23922486 TI - Idiopathic chronic ulcerative enteritis with perforation and recurrent bleeding: a case report. AB - Idiopathic chronic ulcerative enteritis (ICUE) is a distinct entity without a defined etiology and is rarely seen in the clinic. Patients with ICUE mainly present with insidious abdominal symptoms such as chronic abdominal pain and intermittent gastrointestinal hemorrhage and symptoms of malnourishment in the early stages of the disease. ICUE is always difficult to diagnose. However, as the disease progresses, patients have a variety of acute abdominal complications such as hemorrhage, perforation, or ileus. Surgical intervention is always needed, and the condition can recur and require repeat laparotomy. When diffuse ulceration of the small bowel is present in the absence of recognizable causes, it is classified as nonspecific or idiopathic. The histological examination always demonstrates an acute, chronic inflammatory infiltration without giant cells, granulomas, or villous atrophy. The etiology of ICUE has not been identified, and its pathogenesis is poorly understood; therefore, radical surgical resection is considered the best available treatment. Here, we report a case of ICUE characterized by nonspecific, multiple, small intestinal ulcers resulting in perforation and recurrent bleeding. The differential diagnosis and the treatment are also discussed. PMID- 23922487 TI - Hydrogen saline prevents selenite-induced cataract in rats. AB - PURPOSE: The aim of this study was to investigate the potential antioxidative effect and mechanism for the protective effects of hydrogen saline on selenite induced cataract in rats. METHODS: Sprague-Dawley rat pups were divided into the following groups: control (Group A), selenite induced (Group B), and selenite plus hydrogen saline treated (Group C). Rat pups in Groups B and C received a single subcutaneous injection of sodium selenite (25 MUmol/kg bodyweight) on postnatal day 12. Group C also received an intraperitoneal injection of H2 saline (5 ml/kg bodyweight) daily from postnatal day 8 to postnatal day 17. The development of cataract was assessed weekly by slit-lamp examination for 2 weeks. After sacrifice, extricated lenses were analyzed for activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase, levels of malondialdehyde, reduced glutathione (GSH), and total sulfhydryl contents. RESULTS: The magnitude of lens opacification in Group B was significantly higher than in Group A (p<0.05), while Group C had less opacification than Group B (p<0.05). Compared with Group B, the mean activities of the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase, levels of GSH, and total sulfhydryl contents were higher, whereas the level of malondialdehyde was lower following treatment with hydrogen saline(p<0.05). CONCLUSIONS: This is an initial report showing that hydrogen saline can prevent selenite-induced cataract in rats. It acts via maintaining antioxidant enzymes and GSH, protecting the sulfhydryl group, and inhibiting lipid peroxidation. PMID- 23922488 TI - Mutation analysis of the SLC4A11 gene in Indian families with congenital hereditary endothelial dystrophy 2 and a review of the literature. AB - PURPOSE: Congenital hereditary endothelial dystrophy 2 (CHED2) is an autosomal recessive disorder caused by mutations in the solute carrier family 4, sodium borate transporter, member 11 (SLC4A11) gene. The purpose of this study was to identify the genetic cause of CHED2 in six Indian families and catalog all known mutations in the SLC4A11 gene. METHODS: Peripheral blood samples were collected from individuals of the families with CHED2 and used in genomic DNA isolation. PCR primers were used to amplify the entire coding region including intron-exon junctions of SLC4A11. Amplicons were subsequently sequenced to identify the mutations. RESULTS: DNA sequence analysis of the six families identified four novel (viz., p.Thr262Ile, p.Gly417Arg, p.Cys611Arg, and p.His724Asp) mutations and one known p.Arg869His homozygous mutation in the SLC4A11 gene. The mutation p.Gly417Arg was identified in two families. CONCLUSIONS: This study increases the mutation spectrum of the SLC4A11 gene. A review of the literature showed that the total number of mutations in the SLC4A11 gene described to date is 78. Most of the mutations are missense, followed by insertions-deletions. The present study will be helpful in genetic diagnosis of the families reported here. PMID- 23922489 TI - Survey of familial glaucoma shows a high incidence of cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) mutations in non-consanguineous congenital forms in a Spanish population. AB - PURPOSE: To identify myocilin (MYOC) and cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) mutations in a Spanish population with different clinical forms of familial glaucoma or ocular hypertension (OHT). METHODS: Index patients from 226 families participated in this study. Patients were diagnosed with familial glaucoma or OHT by complete ophthalmologic examination. Screening for MYOC mutations was performed in 207 index patients: 96 with adult-onset primary open-angle glaucoma (POAG), 21 with primary congenital glaucoma (PCG), 18 with juvenile-onset open-angle glaucoma (JOAG), five with Axenfeld-Rieger syndrome (ARS), and 67 with other types of glaucoma. One hundred two of the families (including all those in whom a MYOC mutation was detected) were also screened for CYP1B1 mutations: 45 POAG, 25 PCG, 21 JOAG, four ARS, and seven others. RESULTS: We examined 292 individuals (patients and relatives) with a positive family history of glaucoma or OHT. We identified two novel MYOC variants, p.Lys39Arg and p.Glu218Lys, in two families with POAG, and six previously reported MYOC mutations in seven families with POAG (four), JOAG (one), PCG (one), and normotensive glaucoma (one). CYP1B1 mutations were found in 16 index patients with PCG (nine), POAG (three), JOAG (two), and ARS (two). CONCLUSIONS: The high percentage (9/25=36%) of mutations in CYP1B1 found in non-consanguineous patients with congenital glaucoma mandates genetic testing. However, the percentage of mutations (9/207=4.4%) in MYOC associated with glaucoma is relatively low in our population. The variable phenotype expression of glaucoma, even in families, cannot be explained with a digenic mechanism between MYOC and CYP1B1. PMID- 23922490 TI - LDLR-/-ApoB100/100 mice with insulin-like growth factor II overexpression reveal a novel form of retinopathy with photoreceptor atrophy and altered morphology of the retina. AB - PURPOSE: The aim of this study was to characterize the ocular morphology of low density lipoprotein receptor-deficient apolipoprotein B-100-only mice, where overexpression of insulin-like growth factor II (IGF-II) has been shown to induce glucose intolerance and increase atherosclerotic lesion progression and calcification. METHODS: Fifteen-month-old mice were examined on a normal chow diet and after 3 months of a high-fat Western diet. IGF-II-negative LDLR(-/ )ApoB(100/100) littermates and C57Bl/6J mice served as controls. In vivo color images of the fundi were obtained, and eyes were processed either for retinal flat mounts for assessment of neovascularization or for paraffin-embedded samples for immunohistochemical analyses. RESULTS: IGF-II overexpression and the resulting prediabetic phenotype did not induce microvascular damage when assessed in fundus photographs and retinal whole mounts, and the number of capillaries in IGF-II/LDLR(-/-)ApoB(100/100) mice was not significantly different from LDLR(-/ )ApoB(100/100) mice. However, morphology of the inner nuclear, outer plexiform, and outer nuclear layers was altered in the IGF-II/LDLR(-/-)ApoB(100/100) mice. Moreover, photoreceptor atrophy and thinning of the outer nuclear layer were present. Caspase-3 staining was positive in the photoreceptor inner segment. In addition, retinas of the IGF-II/LDLR(-/-)ApoB(100/100) mice displayed reduced rhodopsin positivity, consistent with the decreased number of photoreceptor cells. CONCLUSIONS: This study reports a novel form of retinopathy with photoreceptor atrophy and abundant changes in retinal morphology in a mouse model of prediabetes and atherosclerosis. PMID- 23922491 TI - Study of 27 aqueous humor cytokines in patients with type 2 diabetes with or without retinopathy. AB - PURPOSE: To compare the changes in the levels of 27 aqueous humor cytokines between nondiabetic controls and patients with type 2 diabetes and to ascertain the association of these cytokines with diabetic retinopathy (DR). METHODS: Undiluted aqueous humor samples were obtained from 102 nondiabetic patients (102 eyes) and 136 consecutive diabetic patients (136 eyes) who were divided into nine groups according to the Early Treatment of Diabetic Retinopathy Study severity scale. The concentrations of 27 cytokines in the aqueous humor samples were measured using a multiplex bead immunoassay. RESULTS: Compared with the nondiabetic controls, the diabetic patients had significantly higher concentrations of interleukin-1beta (IL-1beta; p<0.001), IL-6 (p<0.001), IL-8 (p<0.001), monocyte chemoattractant protein-1 (p<0.001), interferon gamma-induced protein-10 (p<0.001), and vascular endothelial growth factor (p<0.001) in the aqueous humor. However, the IL-10 (p=0.002) and IL-12 (p=0.013) concentrations were significantly lower for the diabetic patients. There were no significant differences in the concentrations of other cytokines between the diabetic patients and the controls. The IL-1beta, IL-6, IL-8, monocyte chemoattractant protein-1, and interferon gamma-induced protein-10 levels in the aqueous humor increased as the severity of DR increased. The correlation was significant. However, the vascular endothelial growth factor concentration was not correlated with the severity of DR. In addition, the IL-10 and IL-12 levels in the aqueous humor decreased as the severity of DR increased, and this negative correlation was significant. CONCLUSIONS: Various cytokines associated with inflammation and angiogenesis may contribute to the pathogenesis of DR, and chemokines may be more closely related to the development of this disease. PMID- 23922492 TI - Microglial ramification and redistribution concomitant with the attenuation of choroidal neovascularization by neuroprotectin D1. AB - PURPOSE: Neuroprotectin D1 (NPD1) attenuates laser-induced choroidal neovascularization (CNV) when administered intraperitoneally. Due to its lipophilicity and low molecular weight, NPD1 is well suited for topical delivery; thus, we investigated the efficacy of topically applied NPD1 in attenuating CNV. We also examined the effect of NPD1 on the recruitment and activation of microglia surrounding CNV lesions. METHODS: Mice were given laser-induced CNV and treated with NPD1 eye drops. CNV was evaluated by fluorescein leakage using a novel image analysis method and by isolectin B4 immunofluorescence of neovasculature. Microglia; recruitment was assessed by quantification. Using form factor, solidity, convexity, and fractal dimension, microglial activation was quantitatively assessed by two-dimensional, and for the first time, three dimensional morphology. An ImageJ plugin, 3D Shape, was developed to enable this analysis. RESULTS: NPD1 attenuated leakage and neovascularization. The proximity of microglia to CNV lesions was significantly closer with NPD1. Consistent with the cellular ramification, microglia in NPD1-treated eyes were larger and exhibited a lower form factor and higher fractal dimension. CONCLUSIONS: Our data show that NPD1 signaling induces a ramified, non-injury-inducing microglial phenotype coincident with attenuation of CNV. Since microglia are crucial participants in neurodegenerative diseases, the discovery that microglia are potential targets of NPD1 signaling warrants further investigation. PMID- 23922493 TI - Status of serum VEGF and ICAM-1 and its association with external limiting membrane and inner segment-outer segment junction disruption in type 2 diabetes mellitus. AB - PURPOSE: To correlate the serum levels of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) with the severity of retinopathy and disruption of the external limiting membrane (ELM) and inner segment-outer segment (IS-OS) junction in type 2 diabetes mellitus (DM). METHODS: Study subjects included patients with type 2 DM [diabetes mellitus with no retinopathy (No DR; n=19); non-proliferative diabetic retinopathy (NPDR; n=19); proliferative diabetic retinopathy (PDR; n=20)] and healthy controls (n=19) between the ages of 40 and 65 years. Disruption of the ELM and the IS-OS junction was graded by spectral domain optical coherence tomography as follows: grade 0-no disruption of ELM and IS-OS junction; grade 1-ELM disrupted, inner segment-outer segment (IS-OS) junction intact; grade 2-both ELM and IS-OS junction disrupted. The serum levels of VEGF and ICAM-1were analyzed using the standard protocol. RESULTS: A significant difference was found between the serum levels of VEGF and ICAM-1 and the various study groups (p<0.001). A positive correlation was found between the grade of disruption and the levels of VEGF (r=0.45, p<0.0001) and ICAM-1 (r=0.40, p=0.0003). A significant positive correlation was found between logMAR visual acuity and grade of disruption (r=0.85, p<0.0001). CONCLUSIONS: An increase in serum VEGF and ICAM-1 levels is associated with an increase in the severity of diabetic retinopathy and the grade of ELM and IS-OS junction disruption. PMID- 23922495 TI - A Hybrid Interval-Robust Optimization Model for Water Quality Management. AB - In water quality management problems, uncertainties may exist in many system components and pollution-related processes (i.e., random nature of hydrodynamic conditions, variability in physicochemical processes, dynamic interactions between pollutant loading and receiving water bodies, and indeterminacy of available water and treated wastewater). These complexities lead to difficulties in formulating and solving the resulting nonlinear optimization problems. In this study, a hybrid interval-robust optimization (HIRO) method was developed through coupling stochastic robust optimization and interval linear programming. HIRO can effectively reflect the complex system features under uncertainty, where implications of water quality/quantity restrictions for achieving regional economic development objectives are studied. By delimiting the uncertain decision space through dimensional enlargement of the original chemical oxygen demand (COD) discharge constraints, HIRO enhances the robustness of the optimization processes and resulting solutions. This method was applied to planning of industry development in association with river-water pollution concern in New Binhai District of Tianjin, China. Results demonstrated that the proposed optimization model can effectively communicate uncertainties into the optimization process and generate a spectrum of potential inexact solutions supporting local decision makers in managing benefit-effective water quality management schemes. HIRO is helpful for analysis of policy scenarios related to different levels of economic penalties, while also providing insight into the tradeoff between system benefits and environmental requirements. PMID- 23922494 TI - Expression of adiponectin and its receptors in type 1 diabetes mellitus in human and mouse retinas. AB - PURPOSE: Recent studies have suggested that adiponectin (APN) is associated with several retinal diseases. We studied the expression of APN and its receptors (AdipoRs) in the human retina and in a mouse model of type 1 diabetes mellitus (T1DM). METHODS: Human eyeball specimens were obtained from the Chongqing Eye Bank. eNOS-knockout (eNOS-/-) mice were randomly divided into a T1DM group and a control group. The T1DM model was induced with an intraperitoneal injection of streptozotocin. To locate the AdipoRs in the retina, immunofluorescence was performed. Total APN protein and RNA were extracted from the neural retina and the retinal pigment epithelium (RPE)-choroid complex, and the APN protein was detected with enzyme-linked immunosorbent assay (ELISA). The mRNA and the protein of AdipoRs in the retina were detected with qRT-PCR and western blotting, respectively. The unpaired Student t test was used to assess the significance between the T1DM and the control groups, with p<0.05 regarded as statistically significant. RESULTS: APN, AdipoR1, and AdipoR2 were identified in the neural retina and in the RPE-choroid of humans and mice. AdipoR1 was found in the internal limiting membrane and in the outer segments of the photoreceptors in human and mouse retinas, whereas no noticeable AdipoR2 expression was seen in the retinal frozen sections of human and mouse eyes. Compared to the control group, APN and AdipoR1 expression in the retina was elevated in the T1DM group, but AdipoR2 expression remained unchanged. CONCLUSIONS: We demonstrated that APN, AdipoR1, and AdipoR2 exist in human and mouse retinas and that retinal APN and AdipoR1 protein levels are elevated in T1DM mice, implying that the APN-AdipoR1 axis may be activated in the diabetic retina. In contrast, AdipoR2 appears to play a minor role in this pathological process. PMID- 23922496 TI - Indacaterol: a comprehensive review. AB - At present there is no cure for chronic obstructive pulmonary disease (COPD). However, some nonpharmacologic treatments, such as rehabilitation and lung volume reduction surgery, as well as pharmacologic intervention, can relieve some of the patient's symptoms and improve quality of life, while also reducing the rate of exacerbations and hospitalizations. There needs to be a paradigm shift away from the unjustified nihilistic approach to COPD towards considering it a preventable and treatable disease. After patients quit smoking and start to lead healthier lifestyles, long-acting bronchodilators, such as long-acting beta-adrenergic agents (LABA) and long-acting antimuscarinic agents (LAMA), are recommended as the cornerstone of treatment for COPD, either as monotherapy or in combination. COPD is characterized by a reduced maximum expiratory flow and slow forced emptying of the lungs, which progress over time and are not completely reversible. In this condition, gas gets trapped in the lungs and pulmonary hyperinflation occurs. LABA and LAMA improve airway patency and deflate the lungs. Indacaterol is the first once-daily LABA approved for treatment of COPD, and is administered by inhalation through the Breezhaler(r) device. The speed of bronchodilation is similar to that with salbutamol (ie, about five minutes) and longer (ie, 24 hours) than that with traditional LABA, with the same 12-hour effect as salmeterol and formoterol, both of which require twice-daily administration. This is why indacaterol has been called the "ultra-LABA". On the one hand, the fast onset of action provides immediate relief of symptoms, and on the other, its constant 24-hour bronchodilation provides "pharmacologic stenting" which facilitates lung emptying, thereby decreasing trapped gas and pulmonary hyperinflation. Once-daily administration of a fast and long-acting bronchodilator can improve patient adherence with therapy, which is known to be a major problem for many medical treatments. Dose-finding trials have shown that 75 MUg is the minimum dose needed to achieve clinically important improvement. However, indacaterol 150 MUg and 300 MUg achieve an even greater improvement in lung function and patient-oriented outcomes. Further, these two doses of indacaterol significantly reduce pulmonary hyperinflation, thereby improving exercise tolerance and ability to perform day-to-day activities. It is more effective on lung volumes at the 300 MUg dose than formoterol, and better than salmeterol and tiotropium at the 150 MUg dose, at least in the acute setting. It is noteworthy that few studies document these results in patients with COPD and moderate airflow obstruction. These are exactly the kind of patients our research should be concentrating on, in view of the accelerated decay in forced expiratory volume in one second at this stage of the disease. Finally, all the relevant studies show that indacaterol is consistently well tolerated by patients with COPD at every stage, and that it has a high safety profile. PMID- 23922497 TI - ISTRY 2013 Special Issue. PMID- 23922498 TI - Nutritional aspect of tryptophan metabolism. AB - Mammals, including humans, can synthesize the vitamin nicotinamide from tryptophan in the liver. The resultant nicotinamide is distributed to non-hepatic tissues. We have studied the effects of changes in tryptophan-nicotinamide metabolism on niacin nutritional status. The liver plays a critical role in nicotinamide supply. Animal studies showed that the tryptophan-nicotinamide pathway is affected by physiological conditions, the presence of disease, nutrients, hormones, and chemicals. Human studies have shown that 1 mg of nicotinamide is produced from 67 mg of tryptophan intake, and that the conversion ratio of tryptophan to nicotinamide is enhanced from mid to late pregnancy. These findings have contributed to the determination of dietary reference intakes for niacin recommended in the Dietary Reference Intakes for Japanese 2010. Our findings suggest that the conversion of nicotinamide from tryptophan is important in maintaining niacin nutrition. PMID- 23922499 TI - Determination of l-tryptophan and l-kynurenine in Human Serum by using LC-MS after Derivatization with (R)-DBD-PyNCS. AB - Concentrations of l-tryptophan (l-Trp) and its metabolite, l-kynurenine (l-KYN), in sera of 19 normal subjects (age: 23.6 +/- 3.5 y, male: 8, female: 11) were determined by high-performance liquid chromatography with mass-spectrometric detection, following their derivatization with (R)-(-)-4-(N, N dimethylaminosulfonyl)-7-(3-isothiocyanatopyrrolidin-1-yl)-2,1,3-benzoxadiazole (DBD-PyNCS). A significant positive correlation between l-Trp and l-KYN concentrations was observed (r = 0.532, P < 0.05). Serum l-Trp concentration in male subjects (95.65 +/- 4.27 MUM) was significantly higher than that in female subjects (79.20 +/- 3.34 MUM; P < 0.05), while no significant differences in l KYN concentration or the l-KYN:l-Trp ratio were observed between male and female subjects. PMID- 23922501 TI - Kynurenine Pathway Pathologies: do Nicotinamide and Other Pathway Co-Factors have a Therapeutic Role in Reduction of Symptom Severity, Including Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM). AB - The definition of dual tryptophan pathways has increased the understanding of the mind-body, body-mind dichotomy. The serotonergic pathway highlights the primary (endogenous) psychiatric disorders. The up-regulation of the kynurenine pathway by physical illnesses can cause neuropathic and immunological disorders1 associated with secondary neuropsychiatric symptoms. Tryptophan and nicotinamide deficiencies fall within the protein energy malnutrition (PEM) spectrum. They can arise if the kynurenine pathway is stressed by primary or secondary inflammatory conditions and the consequent imbalance of available catabolic/anabolic substrates may adversely influence convalescent phase efficiency. The replacement of depleted or reduced NAD+ levels and other cofactors can perhaps improve the clinical management of these disorders. Chronic fatigue syndrome (CFS) and fibromyalgia (FM) appear to meet the criteria of a tryptophan-kynurenine pathway disorder with potential neuroimmunological sequelae. Aspects of some of the putative precipitating factors have been previously outlined.2,3 An analysis of the areas of metabolic dysfunction will focus on future directions for research and management. PMID- 23922502 TI - Species and cell types difference in tryptophan metabolism. AB - L-Tryptophan (L-TRP) is a nutritionally essential amino acid and the kynurenine (KYN) pathway is the major route of L-TRP catabolism. Besides being synthesized for proteins, L-TRP and its metabolites have critical roles for the functions of nervous and immune systems. Many researches show that optimal amounts of L-TRP in diets depend on species, developmental stages, environmental factors and health status. We have shown that KYN pathway-related enzyme activities vary among species, tissue and cell types in physiological conditions. Furthermore, the response of these enzyme activities to systemic and/or central nervous system immune activation and inflammation depends on species and cell types. Thus, it is very important to choose appropriate animal species and cell types in which to evaluate the physiologic and pathologic effects of increased KYN pathway metabolism. We believe that understanding L-TRP metabolism among species and cell types provides a better idea for analysis of human pathological condition. PMID- 23922500 TI - Role of NAD(+), Oxidative Stress, and Tryptophan Metabolism in Autism Spectrum Disorders. AB - Autism spectrum disorder (ASD) is a pervasive neuro-developmental disorder characterized by impaired social interaction, reduced/absent verbal and non verbal communication, and repetitive behavior during early childhood. The etiology of this developmental disorder is poorly understood, and no biomarkers have been identified. Identification of novel biochemical markers related to autism would be advantageous for earlier clinical diagnosis and intervention. Studies suggest that oxidative stress-induced mechanisms and reduced antioxidant defense, mitochondrial dysfunction, and impaired energy metabolism (NAD(+), NADH, ATP, pyruvate, and lactate), are major causes of ASD. This review provides renewed insight regarding current autism research related to oxidative stress, mitochondrial dysfunction, and altered tryptophan metabolism in ASD. PMID- 23922503 TI - Tryptophan-restriction diets help to maintain L-tryptophan homeostasis in tryptophan 2,3-dioxygenase knockout mice. AB - We hypothesized that the requirements of essential nutrients are dependent upon catabolic abilities. Mice lacking L-tryptophan 2,3-dioxygenase (TDO) are available. The body concentration of L-tryptophan (L-Trp) has been reported to be higher in TDO-deficient mice than in wild-type (WT) mice. We examined the requirement of an appropriate L-Trp level for TDO-deficient mice using several biomarkers. TDO-deficient mice were fed a 10% amino-acid mixture diet containing 0.06%, 0.08%, and 0.17% L-Trp. WT mice fed a 0.17% Trp diet (standard diet) were used as control mice. The concentrations of L-Trp and its metabolites via serotonin were higher in TDO-deficient mice fed the 0.17% L-Trp diet than in WT mice fed the standard diet, but the concentrations were almost identical between TDO-deficient mice fed the 0.06% L-Trp diet and WT mice fed the standard diet. Therefore, as hypothesized, requirements of essential nutrients are dependent on catabolic abilities. PMID- 23922504 TI - Exploitation of the IDO Pathway in the Therapy of Rheumatoid Arthritis. AB - Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting step along the kynurenine pathway and is thought to play a key role in immune homeostasis through depletion of tryptophan and accumulation of kynurenines. In this review we summarize recent research into the possibility of harnessing the IDO pathway for the therapy of rheumatoid arthritis. Inhibition of IDO activity, or knockout of the gene encoding IDO, was shown to cause an increase in the severity of collagen-induced arthritis, an animal model of rheumatoid arthritis. The increased severity of disease was associated with elevated numbers of pathogenic Th1 and Th17 cells in the joints and draining lymph nodes. In another study, analysis of the kinetics of expression of downstream kynurenine pathway enzymes during the course of arthritis revealed a potential role for tryptophan metabolites in resolution of arthritis. Furthermore, the therapeutic administration of L-kynurenine or [3,4-dimethoxycinnamonyl]-anthranilic acid (a synthetic derivative of 3-hydroxy-anthranilic acid) significantly reduced both clinical and histological progression of experimental arthritis. These findings raise the possibility of exploiting the IDO pathway for the therapy of autoimmune disease. PMID- 23922505 TI - Long-term efficacy and safety of ramosetron in the treatment of diarrhea predominant irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a functional disease with persisting gastrointestinal symptoms that has been classified into four subtypes. Serotonin (5-hydroxytryptamine [5-HT]) plays important physiological roles in the contraction and relaxation of smooth muscle. Intraluminal distension of the intestine is known to stimulate the release of endogenous 5-HT from enterochromaffin cells, activating 5-HT3 receptors located on primary afferent neurons and leading to increases in intestinal secretions and peristaltic activity. Ramosetron, a potent and selective 5-HT3-receptor antagonist, has been in development for use in patients suffering from diarrhea-predominant IBS. In a double-blind, placebo-controlled, parallel-group study of 418 patients with diarrhea-predominant IBS-D, once-daily 5 MUg and 10 MUg doses of ramosetron increased the monthly responder rates of IBS symptoms compared to placebo. In a 12-week randomized controlled trial of 539 patients, a positive response to treatment was reported by 47% of a once-daily 5 MUg dose of ramosetron-treated individuals compared to 27% of patients receiving placebo (P<0.001). Furthermore, the responder rate was increased in the oral administration of 5 MUg of ramosetron for at least 28 weeks (up to 52 weeks), and long-term efficacy for overall improvement of IBS symptoms was also demonstrated. The rate was further increased subsequently. Adverse events were reported by 7% in ramosetron treatment. No serious adverse events, eg, severe constipation or ischemic colitis, were reported for long-term treatment with ramosetron. In conclusion, further studies to evaluate the long-term efficacy and safety of ramosetron are warranted in the form of randomized controlled trials. PMID- 23922506 TI - A clinical review of recent findings in the epidemiology of inflammatory bowel disease. AB - Inflammatory bowel diseases (IBD), including both Crohn's disease and ulcerative colitis, are disorders of chronic inflammation of the gastrointestinal tract marked by episodes of relapse and remission. Over the past several decades, advances have been made in understanding the epidemiology of IBD. The incidence and prevalence of both Crohn's disease and ulcerative colitis have been increasing worldwide across pediatric and adult populations. As IBD is thought to be related to a combination of individual genetic susceptibility, environmental triggers, and alterations in the gut microbiome that stimulate an inflammatory response, understanding the potentially modifiable environmental risk factors associated with the development or the course of IBD could impact disease rates or management in the future. Current hypotheses as to the development of IBD are reviewed, as are a host of environmental cofactors that have been investigated as both protective and inciting factors for IBD onset. Such environmental factors include breast feeding, gastrointestinal infections, urban versus rural lifestyle, medication exposures, stress, smoking, and diet. The role of these factors in disease course is also reviewed. Looking forward, there is still much to be learned about the etiology of IBD and how specific environmental exposures intimately impact the development of disease and also the potential for relapse. PMID- 23922507 TI - Almanac 2011: Heart Failure. The National Society Journals Present Selected Research that has Driven Recent Advances in Clinical Cardiology. PMID- 23922508 TI - Almanac 2011: Cardiac Arrhythmias and Pacing. The National Society Journals Present Selected Research that has Driven Recent Advances in Clinical Cardiology. PMID- 23922511 TI - A stent thrombosis 1465 days after implantation. AB - Stent thrombosis is a fatal complication in patients after percutaneous coronary intervention. We report drug eluting stent thrombosis occurred over four years after implantation. PMID- 23922510 TI - Socio-medical Characteristics of Coronary Disease in Bosnia and Herzegovina and the World. AB - INTRODUCTION: Coronary heart disease and its etiology are complex socio-medical and clinical problem in this century. World Health Organization defined coronary artery disease as acute and chronic heart ailments due to disruption of flow and myocardial blood supply. Diseases of the cardiovascular system in spite of preventable risk factors are responsible for approximately 50% of all deaths in the developed world, and this ratio is higher in developing countries. RISK FACTORS: CORONARY HEART DISEASE RISK FACTORS CAN BE DIVIDED IN THOSE WHICH ARE NOT PREVENTABLE SUCH AS: personal and family history of cardiovascular diseases, age and gender and preventable risk factors including: high blood pressure, elevated blood cholesterol, smoking, reduced physical activity, elevated blood sugar, increased body weight, alcohol use, psychosocial factors and nutrition. There are also newly emerging risk factors which includes increased homocysteine, thrombogenic and inflammatory factors. Prevention of coronary heart disease risk factors: The concept of risk assessment factors, their reduction, initially begun in the Framingham Heart Study and refined in other models. Primary prevention relates to changing lifestyle and influencing preventable risk factors. Numerous studies and meta-analysis showed that lifestyle modification, risk reduction factors, particularly by changing diet, stopping smoking, increasing physical activity, blood pressure control can be effective in the prevention and reduction of coronary heart disease. Primary health care physicians i.e. family physicians need to take an active role in assessment of risk factors for coronary heart disease. CONCLUSION: The data in this paper, based on the findings from other studies, suggest the importance of using a modified algorithm in order to estimates the overall risk of coronary disease in high-risk groups among the patients in the primary health care settings. PMID- 23922509 TI - Almanac 2011: Acute Coronary Syndromes. The National Society Journals Present Selected Research that has Driven Recent Advances in Clinical Cardiology. AB - This overview highlights some recent advances in the epidemiology, diagnosis, risk stratification and treatment of acute coronary syndromes. The sheer volume of new studies reflects the robust state of global cardiovascular research but the focus here is on findings that are of most interest to the practising cardiologist. Incidence and mortality rates for myocardial infarction are in decline, probably owing to a combination of lifestyle changes, particularly smoking cessation, and improved pharmacological and interventional treatment. Troponins remain central for diagnosis and new high-sensitivity assays are further lowering detection thresholds and improving outcomes. The incremental diagnostic value of other circulating biomarkers remains unclear and for risk stratification simple clinical algorithms such as the GRACE score have proved more useful. Primary PCI with minimal treatment delay is the most effective reperfusion strategy in ST elevation myocardial infarction (STEMI). Radial access is associated with less bleeding than with the femoral approach, but outcomes appear similar. Manual thrombectomy limits distal embolisation and infarct size while drug-eluting stents reduce the need for further revascularisation procedures. Non-culprit disease is best dealt with electively as a staged procedure after primary PCI has been completed. The development of antithrombotic and antiplatelet regimens for primary PCI continues to evolve, with new indications for fondaparinux and bivalirudin as well as small-molecule glycoprotein (GP)IIb/IIIa inhibitors. If timely primary PCI is unavailable, fibrinolytic treatment remains an option but a strategy of early angiographic assessment is recommended for all patients. Non-ST segment elevation myocardial infarction (NSTEMI) is now the dominant phenotype and outcomes after the acute phase are significantly worse than for STEMI. Many patients with NSTEMI remain undertreated and there is a large body of recent work seeking to define the most effective antithrombotic and antiplatelet regimens for this group of patients. The benefits of early invasive treatment for most patients are not in dispute but optimal timing remains unresolved. Cardiac rehabilitation is recommended for all patients with acute myocardial infarction but take-up rates are disappointing. Home-based programmes are effective and may be more acceptable for many patients. Evidence for the benefits of lifestyle modification and pharmacotherapy for secondary prevention continues to accumulate but the argument for omega-3 fatty acid supplements is now hard to sustain following recent negative trials. Implantable cardioverter-defibrillators for patients with severe myocardial infarction protect against sudden death but for primary prevention should be based on left ventricular ejection fraction measurements late (around 40 days) after presentation, earlier deployment showing no mortality benefit. PMID- 23922512 TI - Conflicts in Rights of Disclosure of HIV Status in South Western Nigeria: the Health Care Provider's Perspective. AB - INTRODUCTION: Close interaction between clients and health care workers as regards disclosure, refusal of treatment and right to know status has been a subject of debate in legal and medical quarters. The objective of this study was to assess perceived rights of health care workers towards disclosure of HIV status in Lagos State in Southwestern Nigeria. METHODS: This was a descriptive cross sectional study carried out among 260 health care workers using multistage sampling technique. Research instruments were semi structured self administered and pre tested questionnaires. Data was analyzed using the SPSS softwares. RESULTS: Mean age of respondents was 39.3(+3.7) years. One hundred and eight four (70.8%) of the health workers studied said that it is the right of health care workers to know the HIV status of clients before commencement of treatments, and 36 (13.8%) agreed that health care workers have the right to refuse to treat or carry out procedure on known HIV positive clients. Twenty (7.7%) said that HIV positive health care workers should not be allowed to handle clients clinically, 72 (27.7%) believed that it is the right of HIV positive clients to know the HIV status of health care workers before attending to them, 36 (13.8%) of respondents has ever disclosed their HIV status to clients before carrying out procedures on them. Fifty six (21.5%) of respondents were willing to show their result results to a HIV positive clients who insist on knowing his or her HIV status, 84 (32.3%) believed that clients has the right to refuse a known HIV positive health care workers to treat or carry out some procedures. DISCUSSION: There was no statistically significant association between readiness to disclose HIV status and believing that health care workers have the right to know the status of clients before given them treatment ({P< 0.05). CONCLUSION: The need to balance out perceived rights of health care workers and clients would assist in provision of quality services to HIV positive clients. PMID- 23922513 TI - Hypertension and Related Morbidity among Geriatric Population of Eastern India. AB - OBJECTIVES: To assess the prevalence of hypertension among geriatric population and to find out its association with socio demographic parameters, non communicable diseases and level of daily activities. METHODOLOGY: Community based cross sectional study was conducted among geriatric population of Tarakeswar town, India. 402 persons were selected from total 2258 elderly persons by systematic random sampling and data was collected using pretested questionnaire followed by physical examination. Data was analyzed using SPSS Version 16.0. RESULTS: 53.5% respondents were hypertensive. Prevalence of hypertension was significantly more among higher age group (p=0.031). Hypertension was also associated with Diabetes mellitus (p<0.001), cardiovascular diseases (p<0.001), cerebrovascular accidents (p<0.001) and obesity (p<0.001). 38.46% hypertensives were not under medication. Practice of taking antihypertensive medicines was significantly lower in lower income group (30.8% versus 80.6%; p<0.001) and illiterates (34.0% versus 74.8%; p<0.001). Activities of daily living for self maintenance and level of satisfaction over life were significantly lower among hypertensives. CONCLUSION: More than half of the elderly are suffering from hypertension. Most of the hypertensives are suffering also from other diseases, resulting in significant reduction of daily activities and compromised satisfaction over life. Hypertension, being a treatable ailment, leaves a space for intervention to reduce these geriatric morbidities. PMID- 23922514 TI - Body satisfaction and management in Iranian students. AB - PURPOSE: Despite the importance of body satisfaction on self concept and well being, there is little study about it or its consequences in Iranian populations, a part of Asian culture. The aim of this study was the assessment of body satisfaction and body management strategies in Iranian university students. WORK METHOD: This survey was performed based on a self-administrated questionnaire in 535 university and post graduate students. WORK RESULTS: About 2/3rd of the students had moderate to severe body dissatisfaction and 40% of the students were using body management methods. Rhinoplasty and heavy exercise were the most frequent body management methods in women and men, respectively. CONCLUSION: Widespread research on body satisfaction prevalence and its management behaviors in the general population can be effective in reducing the negative health, social and economic consequences of harmful behaviors. PMID- 23922516 TI - Social networks in improvement of health care. AB - Social network is a social structure made of individuals or organizations associated with one or more types of interdependence (friendship, common interests, work, knowledge, prestige, etc.) which are the "nodes" of the network. Networks can be organized to exchange information, knowledge or financial assistance under the various interest groups in universities, workplaces and associations of citizens. Today the most popular and widely used networks are based on application of the Internet as the main ICT. Depending on the method of connection, their field of activity and expertise of those who participate in certain networks, the network can be classified into the following groups: a) Social Networks with personal physical connectivity (the citizens' associations, transplant networks, etc.), b) Global social internet network (Facebook, Twitter, Skype), c) specific health internet social network (forums, Health Care Forums, Healthcare Industry Forum), d) The health community internet network of non professionals (DailyStrength, CaringBridge, CarePages, MyFamilyHealth), e) Scientific social internet network (BiomedExperts, ResearchGate, iMedExchange), f) Social internet network which supported professionals (HealthBoards, Spas and Hope Association of Disabled and diabetic Enurgi), g) Scientific medical internet network databases in the system of scientific and technical information (CC, Pubmed/Medline, Excerpta Medica/EMBASE, ISI Web Knowledge, EBSCO, Index Copernicus, Social Science Index, etc.). The information in the network are exchanged in real time and in a way that has until recently been impossible in real life of people in the community. Networks allow tens of thousands of specific groups of people performing a series of social, professional and educational activities in the place of living and housing, place of work or other locations where individuals are. Network provides access to information related to education, health, nutrition, drugs, procedures, etc., which gives a special emphasis on public health aspects of information, especially in the field of medicine and health care. The authors of this paper discuss the role and practical importance of social networks in improving the health and solving of health problems without the physical entrance into the health care system. Social networks have their advantages and disadvantages, benefits and costs, especially when it comes to information which within the network set unprofessional people from unreliable sources, without an adequate selection. The ethical aspect of the norms in this segment is still not adequately regulated, so any sanctions for the unauthorized and malicious use of social networks in private and other purposes in order to obtain personal gain at the expense of individuals or groups (sick or healthy, owners of certain businesses and companies, health organizations and pharmaceutical manufacturers, etc.), for which there is still no global or European codes and standards of conduct. Cyber crime is now one of the mostly present types of crime in modern times, as evidenced by numerous scandals that are happening both globally and locally. PMID- 23922515 TI - The impact of periodontitis in the preterm birth and body size of newborns. AB - BACKGROUND: Increasing evidence suggests that maternal gingivitis and periodontitis may be a risk factor for preterm birth and other adverse pregnancy outcomes. OBJECTIVE: To assess the relationship between periodotitis and preterm birth. METHODS: A retrospective study which included 230 pregnant women, and the delivery follow up to determine the correlation between periodontitis and preterm birth. RESULTS: The study indicates that periodontal infection can lead to placental-fetal exposure and, when coupled with a fetal inflammatory response, can lead to preterm delivery. Periodontitis is correlated with preterm birth, so early diagnosis and a careful treatment are very important issues. RESULTS: In 2009 at the Neurology Clinic CCUS have treated 34 patients who passed the committee for recommendation to interferon therapy (25 women and 9 men). The diagnosis of multiple sclerosis is safe based on the criteria of international panel in 2000. EDSS Average score for men was 1.8, 1.9 for women, the total EDSS score was 1.8. The gender ratio is 3:1 in women than in men. Sixteen patients received interferon by the Commission for multiple sclerosis, the Federal Ministry of Health and their therapy was initiated at the clinic. CONCLUSION: Periodontitis is one of the main causes of preterm-premature rupture of membranes and a proper treatment is the best solution for this pathology. PMID- 23922517 TI - Importance of sideropenic anemia in the diagnosis of gastrointestinal tract tumors. AB - INTRODUCTION: Sideropenic anemia is a hypochromic, microcytic anemia caused by insufficient iron level in the body. This is the most common anemia. In a large percentage it is the symptom of gastrointestinal tract cancer. Anemia was defined by hemoglobin level <119 g/dl, hematocrit <0.356 for women or hemoglobin level <138 g/dL and hematocrit <0415 for men. Gastric cancer after lung cancer is the second most common malignant tumor in the world. Frequent localization is the antrum, and less frequently in the cardia and fundus. Definite factors in the development of gastric cancer are chronic atrophic gastritis, H. pylori, intestinal metaplasia, and epithelial dysplasia as a precancerous lesion. Strong link between sideropenic anemia and gastrointestinal tract cancers recommend that patients with sideropenic anemia without a clear indication underwent same gastroscopic and colonoscopy examination. The goals were to prove sideropenic anemia, diagnose and histologically confirm tumors, tumors location and correlates anemia with tumor anemia or show the dependence of anemia on tumor. RESULTS: The study included 100 subjects (50 from counseling center for hematology that came due to sideropenic anemia and 50 patients from the Clinic for Gastroenterology who had gastrointestinal tract cancer). Respondents had regular laboratory tests and endoscopic examinations, ultrasound of the abdomen, CT of the abdomen and tumor markers. In the group of patients from Counseling center for hematology with sideropenic anemia was found 11 cancerous processes, mostly in form of gastric and colon cancer. In the group of patients hospitalized at the Clinic for Gastroenterology most cancer process were localized in the stomach and colorectum. CONCLUSION: Tumors of the gastrointestinal tract are the most common cause of sideropenic anemia, due to which the patients often first contact Counseling center for hematology. Sideropenic anemia is more common in men as also the number of digestive tract cancers in men. Sideropenic anemia has a significant place in the diagnosis of gastrointestinal tract tumors. Sideropenic anemia is most common in men after 50 years of age. The most common tumors of the gastrointestinal tube were gastric and colon cancer. PMID- 23922519 TI - Management knowledge and skills required in the health care system of the Federation bosnia and herzegovina. AB - Extremely complex health care organizations, by their structure and organization, operate in a constantly changing business environment, and such situation implies and requires complex and demanding health management. Therefore, in order to manage health organizations in a competent manner, health managers must possess various managerial skills and be familiar with problems in health care. Research, identification, analysis, and assessment of health management education and training needs are basic preconditions for the development and implementation of adequate programs to meet those needs. Along with other specific activities, this research helped to determine the nature, profile, and level of top-priority needs for education. The need for knowledge of certain areas in health management, as well as the need for mastering concrete managerial competencies has been recognized as top-priorities requiring additional improvement and upgrading. PMID- 23922518 TI - Admission rate of patients with most common psychiatric disorders in relation to seasons and climatic factors during 2010/2011. AB - INTRODUCTION: Climate and its impact on human health and mental illness have been in the focus of the research since years in the field. AIM: The aim of the research is to study the admissions rate to the psychiatric clinic in correlation to seasons and climate. MATERIAL AND METHOD: The research was conducted in a Psychiatric clinic of the Clinical Center in Sarajevo. Randomly selected subjects (aged 5-89 years, 1316 males and 1039 females) N=2355, were interviewed by the Structural Clinical Interview (SCID) which generated DSM-IV. In this retrospective-prospective, clinicalepidemiological study subjects were divided into groups according to type of disorders. Correlation between the impact of seasons and the rate of admissions to a Psychiatric clinic was analyzed. Certain data were taken from Federal Hydrometeorological Institute in Sarajevo of the climatic situation for period of the study. RESULTS AND CONCLUSIONS: Of the total number of subjects who were admitted to the clinic in the period of 2010/2011 the most common diagnoses were F10-F19, F20-F29, F30-F39, F40-F48, and the suicide attempts as the separate entity. It was found correlation between certain seasons and the effects of the certain weather parameters at an increased admission rate of subjects with the certain diseases. PMID- 23922520 TI - Common Health Risks, Required Precautions of Travelers and their Customs Towards the Use of Travel Medicine Services. AB - INTRODUCTION: There is an increasing number of people who travel around the world. Every traveler is exposed to nearly all infectious risks which may occur during his travel time. Some of the main risk factors can be water quality, temperature and high humidity and the exposure to multi-resistant microorganisms. To tackle the upcoming problem there is an imperative need to develop a new branch of medicine with the name of travel medicine. REVIEW RESULTS: A consultation prior to departure for an upcoming trip is required, focusing to a personalized healthcare plan, based on international scientific protocols and epidemiological studies.Travelers must acquire essential information about the prevailing hygiene conditions and climatic differentiations that occur in the region. Additionally there are several health risks upon the arrival at destination. A scheduled visit to a health professional is necessary, especially in the case of travelers suffering from chronic diseases or those taking medication, while vaccination is considered essential for specific destination countries. Healthcare professionals should be able to inform travelers and evaluate their needs. According to research studies on notion and attitudes travelers' specific risks, only few of them are well-informed during a trip. While most studies indicate that travelers have some kind of pre travel medical consultation, not all of them proceed to the required vaccinations and medications. CONCLUSION: Travelling for business or leisure around the world may be unhealthy. The importance of proper preparation prior to the travel requires to be adequately informed by specialized healthcare professionals, and to receive appropriate vaccinations and medications, when required. The results of the review of notions and attitudes of travelers during the trip indicate not only the need for further development of the branch of travel medicine but especially the need for the expansion and the availability of health services. PMID- 23922521 TI - Stress as provoking factor for the first and repeated multiple sclerosis seizures. AB - INTRODUCTION: Multiple sclerosis is an inflammatory, autoimmune, disease of the white mass of the brain, which sometimes may involve the gray matter (subcortical and ones in the anterior horns of the spinal cord) with the chronic nature and generally with progressive course. As a possible cause of this disease state are listed genetic predisposition, early viral infections and environmental factors, with special effects of stress as a provoking factor in first episode of the disease and relapses because stress leads to modulation of the immune system and immune response to various causes. GOAL: To determine the existence of intense stressful events as a factor in the development of the first episode of illness and worsening of the seizures. MATERIAL AND METHODS: We analyzed all newly discovered cases of multiple sclerosis over a two year period (January 2010 - December 2011) during the first or second hospitalization, and worsening of seizures for previously diagnosed patients in this period. In order to confirm the MS diagnosis are taken history, neurological examination, MRI of the brain, VEP, CSF examination and for those with repeated hospitalization only follow-up of EDSS scores trough neurological examination. RESULTS: During the two year period there were 109 newly diagnosed cases of MS from which 80 F and 29 M (ratio 2.7:1), aged 17-59 years, mean age 32.93+/-9.69 years and 41 patients (29 F and 12M with seizures worsening in previously diagnosed disease. Disease duration was from 6 months to 17 years. 72.94% had relapsing-remitting course of the disease (RRMS) and 27.1% had secondary progressive type (SPMS). Stress as a provoking factor preceded in 47.44% the first episode of the disease, infections (respiratory) in 18.3%, and the pregnancy with postpartum period in 8.77% women, whereas in the group of patients with previously diagnosed illness relapse (n=41) showed that the infection is most common precipitating factor which preceded relapse in 58.54% of patients, stress in 29.02%) and the pregnancy with postpartum period in 12.5% of patients. CONCLUSION: An intensive stressor is certainly one of the triggers for the development of Multiple Sclerosis, as the first episode and worsening of previously established disease. PMID- 23922522 TI - Chlamydia pneumoniae and helicobacter pylori serology - importance in patients with coronary heart disease. AB - BACKGROUND: Chronic infections in CHD are due to one or both of the organisms Chlamydia pneumoniae and Helicobacter pylori. AIM: To examine the association between serum markers of Chlamydia pneumoniae and Helicobacter pylori infection and markers of myocardial damage. in patients with acute coronary syndrome (ACS), with chronic coronary artery disease (CAD) and in-control group. MATERIAL AND METHODS: Sera were taken from a total of 153 subjects. Subjects were divided in three groups: 64 patients with ACS; 53 patients with CAD and a group of 35 conditionally healthy individuals. Analysis of patients' sera for IgG antibodies to H. pylori and markers for myocardial damage was done on the Immulite system. The presence of specific IgG and IgA antibodies to C. pneumoniae was determined with MIF, Sero FIA (Savyon Diagnostics, Israel). Statistical analysis of data was done using the statistical program SPSS (Statistical Package for Social Sciences), version 13. RESULTS AND DISCUSSION: There was a high significant difference in troponin levels between the three groups of subjects (p=0.0000). Levels of creatine kinase isoenzyme (CK-MB) were highest in the ACS group (500.0 ng/mL). There was a statistically significant difference between CG subjects and ACS patients due to more frequent detection of antichlamydial IgA antibodies in patients with acute coronary syndrome. Positive serum immune response for Helicobacter pylori was 17 (53.1%) and 29 (80.6%), respectively. CONCLUSION: Increased IgA antibody titers for C. Pneumoniae, increased CRP values as well as classic markers of myocardial damage are risk factors for coronary events. PMID- 23922523 TI - Validation of the child perceptions questionnaire 8-10 in bosnia and herzegovina. AB - BACKGROUND: Paediatric oral disorders are numerous and it can be assumed that those have negative effect on the life quality in children. From 2002 to 2006 were developed the life quality measures for children aged 8-10 and 11-14 years, Child Perceptions Questionnaires, CPQs. Those are the components of the Child Oral Health Quality of Life Questionnaire (COHQOL). AIM: The aim of this study was to translate the CPQ for children 8 to 10 years into the one of the languages in Bosnia and Herzegovina, to cross-culturaly adapt the instrument, and to evaluate its comprehensibility among Bosnian language speaking children. METHODS: Instrument was translated from English into the Bosnian language according to the recommended translation procedure. After the cultural adaptation, questionnaire was tested among 8-10 years old children (N=18). RESULTS: During the cultural adaptation of the instrument, changes were made on three questions. One question had to be changed due to understanding difficulties. CONCLUSION: CPQ8-10 was translated and culturaly adapted. Testing among children showed that the Bosnia Herzegovina version of the CPQ8-10 is comprehensive and it can be used for measuring oral health-related quality of life in children this age. PMID- 23922524 TI - Social networks in medical education in bosnia and herzegovina. AB - INTRODUCTION: Beginning with the late twentieth and early twenty-first century, the Internet was a significant additional tool in the education of teenagers. Later, it takes more and more significant role in educating students and professionals. GOAL: The aim of this paper is to investigate, to what extent and how effectively the Internet is used today by students of biomedical faculties in Bosnia and Herzegovina. In addition, more specifically, this paper will research the implications of the well-known social networks in education of students and health professionals in Bosnia and Herzegovina. We compared the ratio of using Social networks by students for spreading medical information as basics for health education at medical faculties at 3 universities in Bosnia and Herzegovina (B&H). RESULTS AND DISCUSSION: The results showed that only 11.6% of professors use Facebook type of social network, 49.3% of them have a profile on BiomedExperts scientific social network and 79% have available articles in the largest biomedical literature database MEDLINE. Students are also frequent users of general social networks and educational clips from You Tube, which they prefer to utilize considerably more than the other types of professionals. Students rarely use the facilities of professional social networks, because they contain mainly data and information needed for further, postgraduate professional education. CONCLUSION: In B&H there are decent conditions for the use of online social networks in the education of health professionals. While students enthusiastically embraced these opportunities, this is not so much a case with health care professionals in practice; while scientific health care workers have not shown greater interest in the use of social networks, both for purposes of scientific research and in terms of self-education and training of students. PMID- 23922525 TI - Changes of arterial blood gases after different ranges of surgical lung resection. AB - INTRODUCTION: In recent years there has been increase in the number of patients who need thoracic surgery - first of all different types of pulmonary resection because of primary bronchial cancer, and very often among patients whose lung function is impaired due to different degree of bronchial obstruction so it is necessary to assess functional status before and after lung surgery to avoid the development of respiratory insufficiency. OBJECTIVE: To show the changes in the level of arterial blood gases after various ranges of lung resection. MATERIAL AND METHODS: The study was done on 71 patients surgically treated at the Clinic for Thoracic Surgery KCU Sarajevo, who were previously treated at the Clinic for Pulmonary Diseases "Podhrastovi" in the period from 01. 06. 2009. to 01. 09. 2011. Different types of lung resection were made. Patients whose percentage of ppoFEV1 was (prognosed postoperative FEV1) was less than 30% of normal values of FEV1 for that patients were not given a permission for lung resection. We monitored the changes in levels-partial pressures of blood gases (PaO2, PaCO2 and SaO2) one and two months after resection and compared them to preoperative values. As there were no significant differences between the values obtained one and two months after surgery, in the results we showed arterial blood gas analysis obtained two months after surgical resection. Results were statistically analyzed by SPSS and Microsoft Office Excel. Statistical significance was determined at an interval of 95%. RESULTS: In 59 patients (83%) there was an increase, and in 12 patients (17%) there was a decrease of PaO2, compared to preoperative values. In 58 patients (82%) there was a decrease, and in 13 patients (18%) there was an increase in PaCO2, compared to preoperative values. For all subjects (group as whole): The value of the PaO2 was significantly increased after lung surgery compared to preoperative values (p <0.05) so is the value of the SaO2%. The value of the PaCO2 was significantly decreased after lung surgery compared to preoperative values (p <0.05). Respiratory insufficiency was developed in none of patients. CONCLUSION: If the % ppoFEV1 (% prognosed postoperative FEV1) is bigger than 30% of normal values of FEV1 (according to sex, weight, height, age) in patient planned for lung resection surgery there is no development of respiratory insufficiency after resection. PMID- 23922526 TI - Quality of life factor as breast cancer risks. AB - BACKGROUND: Numerous studies have observed risk factors for breast cancer. We investigated the association between quality life factors as breast cancer risks in a case-control study in industrial Zenica- Doboj Canton in Bosnia and Herzegovina. METHODS: The case-control study was included 200 women, 100 without (control subjects) and 100 women with diagnosed breast cancer. We used questionnaires about breast cancer risks" as study tool. Logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CI) and a full assessment of confounding was included in analysis. RESULTS: Breast cancer was positive associated with increasing age of life (from 45 years and more; OR= 1.25); further relative breast cancer history (OR= 4.42; 95%CI, 0.483-4.043); exposure to CT (OR=2.02; 95%CI, 1,254-3.261); never birth child (OR= 1.394; 95%CI, 0.808-2,407); used replacement hormonal therapy (OR= 1.826; 95%CI, 1.637 10.590); arrival time of menstruation (OR=2.651; 95%CI, 1.303-1.571); length of smoking status (OR=1.534; 95%CI, 0.756-3.098), alcohol consumption (OR=1.728; 95% CI, 0.396-7.533); exposure to CT per year (p=0.009), routine physical inactivity (p=0.009) and replacement hormones treatment (p=0.036). CONCLUSION: Inverse associations of breast cancer and poverty, arival time of menopause were observed. The link between breast cancer and a distant-cousin- degree family history of breast cancer was inverse association with breast cancer too. These results provide further evidence that, for most women, physical activity may reduce the risk of invasive breast cancer. PMID- 23922527 TI - Role of enteropathogenic Escherichia coli in paediatric diarrhoeas in South India. AB - BACKGROUND: Enteropathogenic Escherichia coli(EPEC) is a major cause of diarrhoea in children below 5 years of age. Serotyping is classical method for identification of EPEC strains. But serotypic markers are rarely sufficient to reliably identify the strains as Escherichia coli. Introduction of PCR methodology which depends on detection of virulence factors has provided a practical and rapid way of detecting diarrhoeagenic Esch.coli. Multiantibiotic resistant EPEC strains are a common phenomenon with world wide extension. Moreover for the selection of appropriate therapy of dirrhoeas, knowledge of local antimicrobial therapy pattern plays an important role. OBJECTIVES: To study the role of EPEC in Paediatric diarrhoea by both Serogrouping and Molecular characterisation by PCR and to analyse the antibiotic susceptabililty patterns of EPEC strains in our area. MATERIALS AND METHODS: Prospective study of stool samples collected from children with diarrhoea and without diarrhoea who were below 5 years of age was conducted from May to November 2011. Escherichia.coli isolates were identified by Microscopy, Culture and Biochemical reactions. Among the Escherichia coli isolates, EPEC isolates were identified by Serogrouping. Escherichia coli isolates were also subjected to Molecular characterisation by Multiplex PCR assay and those isolates which showed pathogenic genes were futher serotyped. Antibiotic susceptibility pattern of EPEC isolates was determined by CLSI guidelines. RESULTS: Among the Escherichia coli isolates 36.8% in the diarrhoeal group and none of them from the nondiarrhoeal group were identified as EPEC by serogrouping. 73.3% of the EPEC isolates were below 2 years of age and no much difference in the sex distribution was observed. Mild to moderate dehydration and feccal leuckocytes were seen in 59.9% and 56.6% of isolates respectively. High resistance to Nalidixic acid, Ampicillin, Cotrimoxazole, Ciprofloxacin and Norfloxacin was observed in the diarrhoeal group and resistance to only ampicillin was seen in the nondiarrhoeal group. In the diarrhoeal group 38.8% of Escherichia coli were EAEC and no other diarrhoeagenic Escherichia coli group was found by molecular characterisation. In the nondiarrhoeal Escherichia coli strains, 46.6% showed EAEC genes. EAEC strains in the diarrhoeal group belonged to multiple serotypes, the most common serotype being ONT and in the nondiarrhoeal group, 85.7% were of a single serotype, the most common isolate being O153. Among the Escherichia coli isolates which agglutinated with EPEC polyvalent antisera, 33.3% were positive for Enteroaggregative genes. (Table 1). CONCLUSION: EPEC is still an important pathogen in paediatric diarrhoeas. O serogrouping can still be relied upon for detection of EPEC. Dehydration is one of the clinical features of EPEC diarrhoea. Fluoroquinolones should only be prescribed in children as second line antibiotics. EAEC are present in classical ' O ' serogroups. Serotype O 153 has an increasing potential for asymptomatic carrier state in children below 5 years of age in our area. PMID- 23922528 TI - Prevalence of neurotic, somatoform and stress induced disorders in relation to the seasons and climatic factors during the 2010/2011. AB - INTRODUCTION: Psychiatric disorders have been considered to have seasonal variation for a long time. GOAL: The goal of this research is to study the admissions rate of neurotic and somatoform disorders, as well as stress induced disorder in relation to season and climatic factors during 2010/2011. MATERIAL AND METHOD: The research was conducted at the Psychiatric Clinic, Clinical Center of University in Sarajevo. Randomly selected subjects (aged 5-89 years, 1316 males and 1039 females) N=2355, were interviewed by the Structural Clinical Interview (SCID) which generated DSM-IV diagnoses. In this retrospective prospective, clinical-epidemiological study subjects were divided into groups according to type of disorders. Correlation between the impact of seasons and the rate of admissions to a Psychiatric clinic was analyzed. Certain data were taken from Federal Hydrometeorological Institute in Sarajevo about the climatic situation for period of the study. RESULTS AND CONCLUSIONS: From the total number of subjects who were admitted to the clinic in the period of 2010/2011 the most common diagnoses were F10-F19, F20-F29, F30-F39, F40-F48, and the suicide attempts as the separate entity. It was found the correlation between certain seasons and the effects of the certain weather parameters at an increased admission rate of subjects with the neurotic, somatoform and stress induced disorders. PMID- 23922529 TI - Unusual side effects of interferon Beta-1a in patient with multiple sclerosis. AB - This is a descriptive case report of a 30-year-old man with massive epistaxis, echymosis on arms, abnormal CBC and increased plasma urea and creatinine level (i.e. above normal range). Probably, these are as side effects of interferon beta 1a injection. This is the first report according to our literature search (Pub Med, Google scholar, ISI web of knowledge, ProQuest, MD consult, Science Direct, and SCOPUS) about interferon beta-1a related abnormal kidney function tests hereafter. Abnormal kidney function tests (i.e. increased plasma urea and creatinie level) is not a known as side effect of interferon beta-1a. This case indicates, likely potential for development of these side effects with this medication. PMID- 23922530 TI - Cross-cultural Adaptation of a Questionnaire on Self-perceived Level of Skills, Abilities and Competencies of Family Physicians in Albania. AB - OBJECTIVE: Our aim was to validate an international instrument measuring self perceived competency level of family physicians in Albania. METHODS: A representative sample of 57 family physicians operating in primary health care services was interviewed twice in March-April 2012 in Tirana (26 men and 31 women; median age: 46 years, inter-quartile range: 38-56 years). A structured questionnaire was administered [and subsequently re-administered after two weeks (test-retest)] to all family physicians aiming to self-assess physicians' level of abilities, skills and competencies regarding different domains of quality of health care. The questionnaire included 37 items organized into 6 subscales/domains. Answers for each item of the tool ranged from 1 ("novice" physicians) to 5 ("expert" physicians). An overall summary score (range: 37-185) and a subscale summary score for each domain were calculated for the test and retest procedures. Cronbach's alpha was used to assess the internal consistency for both the test and the retest procedures, whereas Spearman's rho was employed to assess the stability over time (test-retest reliability) of the instrument. RESULTS: Cronbach's alpha was 0.87 for the test and 0.86 for the retest procedure. Overall, Spearman's rho was 0.84 (P<0.001). The overall summary score for the 37 items of the instrument was 96.3+/-10.0 for the test and 97.3+/-10.1 for the retest. All the subscale summary scores were very similar for the test and the retest procedure. CONCLUSION: This study provides evidence on cross cultural adaptation of an international instrument taping self-perceived level of competencies of family physicians in Albania. The questionnaire displayed a satisfactory internal consistency for both test and retest procedures in this sample of family physicians in Albania. Furthermore, the high test-retest reliability (stability over time) of the instrument suggests a good potential for wide scale application to nationally representative samples of family physicians in Albanian populations. PMID- 23922531 TI - The most common detected risk and etiologic factors of pulmonary thromboembolism. AB - INTRODUCTION: Pulmonary thromboembolism (PTE) is the most serious manifestation of thromboembolic disease. OBJECTIVE: To determine the most common risk and etiologic factors of pulmonary tromboembolism in patients treated in Intensive care unit of Clinic for Pulmonary Diseases and TB "Podhrastovi" in three-year- period from 2008. to 2010. MATERIAL AND METHODS: We retrospectively analysed patients with PTE treated in Intensive care unit of Clinic for Pulmonary Diseases and TB "Podhrastovi" in three-year period from 2008. to 2010. PTE was diagnosed by high resolute computed tomography, in most of them ventilatory /perfusion scintigraphy (V/P SPECT) was made, with proper laboratory analyses (D-dimmer, platelets , fibrinogen, and if it was needed protein C, S and AT III factor were examined). In all of them echosonography of abdomen and pelvis was done, also the examination by angiologist, and in patients with indications echosonography of the heart and Color Doppler of leg veins was made. We analysed risk and etiologic factors for PTE in each patient. RESULTS: In 222 treated patients with PTE risk factors were found in 124 or 55.86% patients, etiologic factors were found in 31 or 13.96%, and both risk and etiologic factors in one patient were found in 18 or 8.11% patients. CONCLUSION: PTE is very serious disease that very often has fatal prognosis, and can develop with previously entirely healthy people, and as soon as we become suspicious of its presence we have to made appropriate diagnostic procedures and include appropriate therapy. We can after look for risk and etiologic factors and try to influence them. PMID- 23922532 TI - The Syndrome of Sleep Apnea in the Elderly Suffering from COPD and Live in the County of Attica, Greece. AB - INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) and obstructive sleep apnea syndrome are two diseases, which often coexist in one person. The sleep apnea is often caused by an interruption to breath when sleeping, due to an obstruction of the upper airway during inhalation, causing chronic snoring, morning headaches, increased body weight, blood pressure and sleepiness during the day. AIM: The purpose of this study is to investigate the extend of this problem among a large group of elderly people living in the Attica Basin. MATERIAL AND METHODS: Material of the study was 500 people aged 70 and above years old, including 274 men and 226 women. Data collection was facilitated with the use of an anonymous questionnaire with the purpose to identify patients with apnea, after a personal interview with the researcher. Data analysis was performed with the use of the statistical package SPSS 17. RESULTS: Based on their responses to the questionnaires, it was found that 98.0% of the participants have abnormal sleepiness during the day. The 35.4% of them show no apnea, while 36.0% of the sample suffer from mild sleep apnea. It is important though, the fact that about one out of three seniors, 28.6%, shows sleep apnea in a high risk level. CONCLUSIONS: COPD is a complex disease that occurs in a large proportion of the elderly. Emphasis should be given on early diagnosis and treatment of sleep apnea syndrome, in order to improve the quality of the elderly life. PMID- 23922533 TI - Correlation of barometer pressure and incidence of cerebrovascular insult. AB - INTRODUCTION: The intention of this work is to research whether the link between the barometer pressure and the cerebrovascular insult (CVI) exists. The stroke is the first cause of non-traumatic disability and third illness by mortality in the majority of available relevant literature. GOALS: Goal of the sudy was to research all the cases of the patients who suffered from the acute stroke in the Canton of Sarajevo and those who were treated in the pre-hospital phase by Emergency Medical Institute staff and their working diagnosis was established as CVI ac. MATERIAL AND METHODS: The criteria in the research were established for inclusion and exclusion of cases. The days with and without CVI cases were compared with the meteorological data obtained from the Hydro-meteorological Institute of Federation of Bosnia and Herzegovina . Since the approval was requested and obtained from the Hydro-meteorological Institute, all the meteorological data could be compared. The meteorological data comprise the barometer pressure measuring every day at 7 h, 14 h and 21 h. RESULTS AND DISCUSSION: In the retrospective study, there will be followed, during three years (2004, 2005 and 2006), the cases of the patients who suffered from the stroke, and, the emergency medical care was offered to them by the side of the Emergency Medical Institute of Canton of Sarajevo staff. All the cases in the Canton of Sarajevo were followed regardless of the place of incidence: whether the help was offered in Institute's outpatient departments, patient's flat or at public place. Due to the extensiveness of data (in the analysis comprising three years, there was the total of 1930 cases), the test of normal distribution was used. Since it was about the pre-hospital research, the acute stroke was looked at generally without division by types. The certain diagnostics by types can only be established in the hospital. CONCLUSION: The results in the research indicate that the extreme values of barometer pressure, regardless of their being increased ones or decreased ones, influence the increase of CVI incidence, while by comparing the average values in the days with CVI and without CVI, they did not have any influence on the CVI incidence. PMID- 23922534 TI - A conceptual framework for quality of care. AB - Despite extensive research on defining and measuring health care quality, little attention has been given to different stakeholders' perspectives of high-quality health care services. The main purpose of this study was to explore the attributes of quality healthcare in the Iranian context. Exploratory in-depth individual and focus group interviews were conducted with key healthcare stakeholders including clients, providers, managers, policy makers, payers, suppliers and accreditation panel members to identify the healthcare service quality attributes and dimensions. Data analysis was carried out by content analysis, with the constant comparative method. Over 100 attributes of quality healthcare service were elicited and grouped into five categories. The dimensions were: efficacy, effectiveness, efficiency, empathy, and environment. Consequently, a comprehensive model of service quality was developed for health care context. The findings of the current study led to a conceptual framework of healthcare quality. This model leads to a better understanding of the different aspects of quality in health care and provides a better basis for defining, measuring and controlling quality of health care services. PMID- 23922535 TI - Smallest organism; highest threat. AB - Ever since the discovery of virus in beginning of 20th century, infections caused by these organisms have captured attention of researchers. The evolution of viruses is still a controversy, even same for their categorization in either living or non-living. It is clear that besides many controversies virus remains challenging to treat as well as to control in some extent. Though vaccines are available as prophylactic tool and antiviral drugs for treatment, still virus exist in host cells if they successfully invade biological machinery. Now it remains as challenge to treat these smallest organisms with high degree of efficacy and safety. To answer the demand of the present world there is urgent need of more potent and novel drugs for treatment and vaccines to prevent infection. Answer to this problem will definitely reduce casualties occurring worldwide. This review presents few of the pandemics, their causative agents, current status of treatment and future prospective. PMID- 23922536 TI - 20th Anniversary of the European Public Health Association (EUPHA) and 5th European Public Health Conference, Portomaso, St. Julian's, Malta, November 08 10th 2012. PMID- 23922539 TI - The Art of Compromise in Transfusion/Transplantation Medicine (and Some Parallels in Classical Literature). PMID- 23922540 TI - Evidence-Based Policy and Practice Leads to Changes in the Criteria for MSM to Donate Blood. AB - SUMMARY: On November 7, 2011, the permanent deferral from blood donation of men who have sex with men (MSM) changed in England, Scotland and Wales, to a 12-month deferral since last relevant sexual contact. This change was made following an evidence-based policy review by the Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO). The review concluded that the available evidence supported the introduction of a 12-month fixed period deferral and that the risks associated with a 12-month deferral of MSM were equivalent to a permanent deferral. The permanent deferral for MSM was introduced in 1985 in response to the spread of acquired immunodeficiency syndrome (AIDS) caused by HIV. The change was supported by new data on the level of compliance with the permanent deferral, advances in the testing and processing of donated blood, changes in the epidemiology of sexually transmitted infections (STIs) and improved scientific knowledge. This review discusses how the decision to change the deferral period was reached and highlights some of the remaining issues relating to this contentious matter. PMID- 23922541 TI - Platelet transfusion - the art and science of compromise. AB - SUMMARY: Many modern therapies depend on platelet (PLT) transfusion support. PLTs have a 4- to 7-day shelf life and are frequently in short supply. In order to optimize the inventory PLTs are often transfused to adults without regard for ABO compatibility. Hemolytic reactions are infrequent despite the presence of 'high titer' anti-A and anti-B antibodies in some of the units. Despite the low risk for hemolysis, some centers provide only ABO identical PLTs to their recipients; this practice might have other beneficial outcomes that remain to be proven. Strategies to mitigate the risk of hemolysis and the clinical and laboratory outcomes following ABO-matched and mismatched transfusions will be discussed. Although the PLTs themselves do not carry the D antigen, a small number of RBCs are also transfused with every PLT dose. The quantity of RBCs varies by the type of PLT preparation, and even a small quantity of D+ RBCs can alloimmunize a susceptible D- host. Thus PLT units are labeled as D+/-, and most transfusion services try to prevent the transfusion of D+ PLTs to D- females of childbearing age. A similar policy for patients with hematological diseases is controversial, and the elements and mechanisms of anti-D alloimmunization will be discussed. PMID- 23922542 TI - RHD PCR of D-Negative Blood Donors. AB - SUMMARY: RHD PCR of blood donors may be used to reveal weak D, partial D, DEL and chimeric D+/D- donors among presumed D-negative blood donors. Units donated by such donors pose a definite yet low risk for anti-D immunization of transfusion recipients. The frequency of DEL donors among D-negative donors is 1:350 to 1:2,000 in Europe and up to 1:5 in Asian countries. Different strategies for RHD PCR of blood donors have been used. Probably, the most cost-efficient implementation is replacement of sensitive D antigen testing with the indirect antiglobulin test by RHD PCR in pools which might even reduce total testing cost. PMID- 23922543 TI - Luminex((r)) and its applications for solid organ transplantation, hematopoietic stem cell transplantation, and transfusion. AB - SUMMARY: The detection of antibodies against the human leukocyte antigen (HLA) complex has become indispensable in every clinical practice. The development of solid-phase assays like the Luminex allows the standardized measurement of anti HLA antibodies (HLAab) with high sensitivity, albeit the relevance for some clinical settings remains a matter of debate. In this review we aim to describe the principle of Luminex-based antibody detection, including two modifications that allow identifying solely complement-activating antibodies. We then describe three applications for Luminex: i) detection of HLAab preceding solid-organ transplantation and monitoring of donor-specific antibodies posttransplant as a risk factor for antibody-mediated rejection; ii) presence of HLAab in recipients as a risk for graft failure in hematopoietic stem cell transplantation, especially in haploidentical or mismatched transplantations; iii) role of HLAab in blood transfusion including refractory thrombocytopenia and selection of suitable platelet donors, transfusion-related lung injury after plasma transfusion, and immunization against HLA after red blood cell transfusion despite leukodepletion. Although the Luminex platform constitutes a potent technology for HLA antibody detection, some drawbacks require the well-educated analysis and interpretation of data in critical cases. In addition, Luminex has become an important tool to identify clinically relevant antibodies. PMID- 23922544 TI - Role and Value of Luminex((r))-Detected HLA Antibodies before and after Kidney Transplantation. AB - SUMMARY: The complement-dependent lymphocytotoxicity (CDC) method has been the classical technique to detect human leukocyte antigen (HLA) antibodies in sera of patients who are listed for kidney transplantation. Because of the drawbacks of CDC, such as low sensitivity and low resolution in characterizing antibody specificities, the more specific ELISA technology was introduced in the 1990s which utilizes solubilized HLA molecules instead of lymphocytes. During the last 10 years, the introduction of the Luminex-based single antigen bead (L-SAB) technology, which uses recombinant single HLA molecules, allows detection and characterization of HLA antibodies at greater sensitivity than CDC and ELISA. A drawback associated with this technique is that the interpretation of results is demanding and requires comprehensive experience in HLA antibody diagnostics. Herein we discuss the current role and value of L-SAB technology in the clinical management of sensitized kidney transplant recipients. PMID- 23922545 TI - Diagnostic applications of next generation sequencing in immunogenetics and molecular oncology. AB - SUMMARY: With the introduction of the next generation sequencing (NGS) technologies, remarkable new diagnostic applications have been established in daily routine. Implementation of NGS is challenging in clinical diagnostics, but definite advantages and new diagnostic possibilities make the switch to the technology inevitable. In addition to the higher sequencing capacity, clonal sequencing of single molecules, multiplexing of samples, higher diagnostic sensitivity, workflow miniaturization, and cost benefits are some of the valuable features of the technology. After the recent advances, NGS emerged as a proven alternative for classical Sanger sequencing in the typing of human leukocyte antigens (HLA). By virtue of the clonal amplification of single DNA molecules ambiguous typing results can be avoided. Simultaneously, a higher sample throughput can be achieved by tagging of DNA molecules with multiplex identifiers and pooling of PCR products before sequencing. In our experience, up to 380 samples can be typed for HLA-A, -B, and -DRB1 in high-resolution during every sequencing run. In molecular oncology, NGS shows a markedly increased sensitivity in comparison to the conventional Sanger sequencing and is developing to the standard diagnostic tool in detection of somatic mutations in cancer cells with great impact on personalized treatment of patients. PMID- 23922546 TI - Emerging infectious threats to the blood supply: seroepidemiological studies in iran - a review. AB - SUMMARY: The risk of transfusion-transmitted infections has been greatly reduced by improvements in donor screening and testing. However, newly recognized blood borne infectious agents can be threats to blood safety. In order to evaluate the prevalence some of these agents in blood donors, a systematic review was conducted. Data were obtained from published papers related to HGV, Torque Teno virus (TTV), HTLV, West Nile virus (WNV) and SEN virus (SEN-V). Based on these studies, the prevalence of HGV varied from 1 to 8.6% for anti-E2 and from 0 to 4.8% for HGV RNA. The prevalence of TTV DNA and HTLV-I varied from 2.7 to 79.5% and from 0.013 to 2.3%, respectively. The WNV-specific IgM antibody and WNV RNA are negative in blood donors. Prevalence rates of SEN-V in Iranian blood donors range from 23 to 90.8%. Consequences of these infectious agents for blood safety are different. Thus, the need to perform laboratory screening as well as effectiveness and efficiency of laboratory tests depend on pathogenicity level and epidemiological conditions of emerging infections. However, being prepared based on the current level of risk and interventions to reduce the risk can be effective in reducing the potential threat for blood supply. PMID- 23922547 TI - Expressional analysis of the astrocytic Kir4.1 channel in a pilocarpine-induced temporal lobe epilepsy model. AB - The inwardly rectifying potassium (Kir) channel Kir4.1 in brain astrocytes mediates spatial K(+) buffering and regulates neural activities. Recent studies have shown that loss-of-function mutations in the human gene KCNJ10 encoding Kir4.1 cause epileptic seizures, suggesting a close relationship between the Kir4.1 channel function and epileptogenesis. Here, we performed expressional analysis of Kir4.1 in a pilocarpine-induced rat model of temporal lobe epilepsy (TLE) to explore the role of Kir4.1 channels in modifying TLE epileptogenesis. Treatment of rats with pilocarpine (350 mg/kg, i.p.) induced acute status epilepticus, which subsequently caused spontaneous seizures 7-8 weeks after the pilocarpine treatment. Western blot analysis revealed that TLE rats (interictal condition) showed significantly higher levels of Kir4.1 than the control animals in the cerebral cortex, striatum, and hypothalamus. However, the expression of other Kir subunits, Kir5.1 and Kir2.1, remained unaltered. Immunohistochemical analysis illustrated that Kir4.1-immunoreactivity-positive astrocytes in the pilocarpine-induced TLE model were markedly increased in most of the brain regions examined, concomitant with an increase in the number of glial fibrillary acidic protein (GFAP)-positive astrocytes. In addition, Kir4.1 expression ratios relative to the number of astrocytes (Kir4.1-positive cells/GFAP-positive cells) were region-specifically elevated in the amygdala (i.e., medial and cortical amygdaloid nuclei) and sensory cortex. The present study demonstrated for the first time that the expression of astrocytic Kir4.1 channels was elevated in a pilocarpine-induced TLE model, especially in the amygdala, suggesting that astrocytic Kir4.1 channels play a role in modifying TLE epileptogenesis, possibly by acting as an inhibitory compensatory mechanism. PMID- 23922548 TI - Diagnosis of Arterial Media Calcification in Chronic Kidney Disease. AB - PURPOSE: Arterial media calcification (AMC) is often the only vascular calcification (VC) present in young patients with chronic renal failure and its presence is associated with higher mortality rates. Currently, X-ray imaging (as a standard approach) is able to show AMC in areas without diffuse overlapping arterial intimal calcification (AIC), but X-ray imaging only allows us to identify this lesion when the vessel is widely calcified. The aim of this study was to evaluate the possibility of using ultrasonography as opposed to X-rays to visualize AMC in patients with chronic renal failure. Patients and Methods: In this cross-sectional study, we examined 105 patients (chronic kidney disease stage IV: 19 patients, hemodialysis: 48 patients, renal transplant: 26 patients; mean age: 54 +/- 14 years; 65 males and 40 females); B-mode ultrasonography was performed to detect AMC or AIC on the superficial femoral artery (SFA). As a control, plain radiography of the thigh was performed in all patients. RESULTS: Upon ultrasonography investigation, 12 subjects were excluded due to diffuse VC on the SFA that did not permit a distinction between AMC and AIC. In the remaining 93 patients, AMC was detected on the SFA in 43 patients using ultrasonography and in 20 patients using the standard approach. The sensitivity and specificity of the standard approach for the detection of AMC on the SFA were 47 and 100%, respectively. The positive and negative predictive values of the standard approach were 1 and 0.68, respectively. CONCLUSION: Ultrasonography is able to detect AMC better than the X-ray approach, focusing on individuals at higher risk. PMID- 23922549 TI - Pulmonary Hypertension and Right Heart Failure in Chronic Kidney Disease: New Challenge for 21st-Century Cardionephrologists. AB - Pulmonary hypertension is defined as an increased systolic pulmonary pressure of >30 mm Hg, and it shows a 40% prevalence in hemodialysis patients due to vascular access (both central venous catheter and arteriovenous fistula). Secondary pulmonary hypertension in chronic kidney disease patients is strictly related to pulmonary circulation impairment together with chronic volume overload and increased levels of cytokines and growth factors, such as FGF, PDGF, and TGF beta, leading to fibrosis. Endothelial dysfunction, together with lower activation of NOS, increased levels of serum endothelin and fibrin storages, involves an extensive growth of endothelial cells leading to complete obliteration of pulmonary vessels. Pulmonary hypertension has no pathognomonic and distinctive symptoms and signs; standard transthoracic echocardiography allows easy assessment of compliance of the right heart chambers. The therapeutic approach is based on traditional drugs such as digitalis-derived drugs, vasodilatory agents (calcium channel blockers), and oral anticoagulants. New pharmacological agents are under investigation, such as prostaglandin analogues, endothelin receptor blockers, and phosphodiesterase-5 inhibitors. PMID- 23922550 TI - Comparison and Reproducibility of Techniques for Fluid Status Assessment in Chronic Hemodialysis Patients. AB - BACKGROUND: Several methods have been developed to assess the hydration status in chronic hemodialysis (HD) patients. The aim of this study was to compare body bioimpedance spectroscopy (BIS) with ultrasound (US) lung comet score (ULCs), B type natriuretic peptide (BNP) and inferior vena cava diameter (IVCD) by US for the estimation of dry weight before and after HD and to analyze all methods in terms of fluid status variations induced by HD. An additional aim of this study was to establish the interoperator reproducibility of these methods. METHODS: Two nephrologists evaluated BIS, ULCs, IVCD during inspiration (min) and expiration (max), the inferior vena cava collapsibility index (IVCCI) as well as BNP before and after HD in 30 patients. The same operators measured BIS, ULCs and IVCD in 28 HD patients in a blinded fashion. RESULTS: There was a significant reduction in BIS, ULCs, IVCD and BNP after HD (p < 0.001), but a less significant reduction in IVCCI (p = 0.13). There was a significant correlation between BIS and ULCs, BNP and indexed IVCD (IVCDi)min (p < 0.05) before and after HD, and between BIS and IVCDimax only before HD. CONCLUSION: All methods were able to describe hyperhydration before and after HD, except for IVCCI after HD. All techniques correlated with BIS before HD. After HD, ULCs correlated better with BIS than IVCD in terms of evaluation of fluid status. It could be expected that the ULCs can give a real-time evaluation of interstitial water. The reproducibility of the measurement of BIS, IVCD and ULCs between the two operators was high. PMID- 23922551 TI - A Common APOE Polymorphism Is an Independent Risk Factor for Reduced Glomerular Filtration Rate in the Spanish RENASTUR Cohort. AB - OBJECTIVE: APOE gene variants may contribute to the risk of chronic kidney disease. Our aim was to determine whether the common APOE epsilon2/epsilon3/epsilon4 polymorphism is associated with a reduced estimated glomerular filtration rate (eGFR) in the RENASTUR population, a cohort of elderly individuals from the region Asturias (northern Spain). METHODS: A total of 743 Spanish Caucasians aged 55-85 years were genotyped for the APOE epsilon2/epsilon3/epsilon4 polymorphism. Individuals with a previous diagnosis of renal disease were not eligible for the study. Participants with a documented history of type 2 diabetes mellitus (T2DM) or hypertension or who were receiving antidiabetic or antihypertensive drugs were classified as diabetics and hypertensives. The eGFR was calculated using the Modification of Diet in Renal Disease formula, and those with an eGFR <60 ml/min/1.73 m2 (n = 91) were considered as having impaired renal function. The effect of alleles and genotypes on clinical (hypertension, T2DM) and analytical findings was statistically determined. RESULTS: In addition to age and T2DM, APOE-epsilon2 was significantly associated with an eGFR <60 ml/min/1.73 m2 (p = 0.002; OR = 2.30). This association remained statistically significant after correction for multiple variables. Although the effect of the APOE-epsilon2 allele on the eGFR was observed both among diabetics and nondiabetics, the significance was stronger in the T2DM group. CONCLUSION: The APOE-epsilon2 allele is a genetic risk factor for impaired renal function among healthy elderly Spanish individuals. PMID- 23922552 TI - The Association between Parathyroid Hormone Levels and Hemoglobin in Diabetic and Nondiabetic Participants in the National Kidney Foundation's Kidney Early Evaluation Program. AB - BACKGROUND: Both anemia and secondary hyperparathyroidism are reflections of hormonal failure in chronic kidney disease (CKD). While the association of elevated levels of parathyroid hormone (PTH) and anemia has been studied among those with advanced CKD, less is known about this association in mild-to-moderate CKD. METHODS: In a cross-sectional analysis, the relationship between PTH and hemoglobin levels was investigated in 10,750 participants in the National Kidney Foundation's Kidney Early Evaluation Program with an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. RESULTS: In the unadjusted analysis, higher PTH levels were associated with lower hemoglobin levels. However, after multivariable adjustment for age, race, gender, smoking status, education, cardiovascular disease, diabetes, hypertension, cancer, albuminuria, BMI, baseline eGFR, calcium, and phosphorus, the direction of association changed. As compared to the first PTH quintile, hemoglobin levels were 0.09 g/dl (95% CI: 0.01-0.18), 0.15 g/dl (95% CI: 0.07-0.24), 0.18 g/dl (95% CI: 0.09-0.26), and 0.13 g/dl (95% CI: 0.07-0.25) higher for the second, third, fourth, and fifth quintiles, respectively. Similarly, each standard deviation increase in natural log transformed PTH was associated with a 0.06 g/dl (95% CI: 0.03-0.09, p = 0.0003) increase in hemoglobin. However, a significant effect modification was seen for diabetes (p = 0.0003). Each standard deviation increase in natural log transformed PTH was associated with a 0.10 g/dl (95% CI: 0.054-0.138, p < 0.0001) increase in hemoglobin, while no association was seen among those without diabetes mellitus. CONCLUSION: After multivariable adjustment, there was a small positive association between PTH and hemoglobin among diabetics but not among nondiabetics. PMID- 23922553 TI - Incidence and Main Determinants of Contrast-Induced Nephropathy following Coronary Angiography or Subsequent Balloon Angioplasty. AB - BACKGROUND/AIMS: Patient assessment by imaging studies using contrast media is currently replacing open procedures, especially in high-risk patients. However, the use of such contrast media might result in acute events and injuries after the procedure. In the present study, we first determined the incidence of contrast-induced nephropathy (CIN) in a sample of Iranian patients who candidated for coronary angiography and/or angioplasty, and then assessed major risk factors predicting the appearance of CIN following these procedures. METHODS: Two hundred and fifty consecutive, eligible patients scheduled for coronary angiography and/or angioplasty at the Afshar Hospital in Yazd between January 2009 and August 2010 were considered for enrollment. Renal function was measured at baseline and 48 h after the intervention, and CIN was defined by an increase in creatinine of >0.5 mg/dl or 25% of the initial value. The predictive role of potential risk factors was determined in a multivariate model adjusted for comorbidities, preexisting renal impairment, and angiographic data. RESULTS: CIN following coronary angiography or angioplasty appeared in 12.8% of the cases. A myocardial infarction before the procedure (OR = 2.121, p = 0.036) and a prior history of hypertension (OR = 2.789, p = 0.025) predicted the appearance of acute renal failure following angiography or subsequent angioplasty. A low estimated glomerular filtration rate at baseline slightly predicted CIN after these interventions. CONCLUSION: Transient acute renal dysfunction occurred in 12.8% of the patients within 48 h after angiography or subsequent angioplasty and could be predicted by a myocardial infarction before the procedure or by a prior history of systolic hypertension. PMID- 23922554 TI - What Is the Meaning of Increased Myocardial Injury Enzymes during Hemodialysis? A Tissue Doppler Imaging Study. AB - BACKGROUND: Cardiovascular death is decreasing in the general population; however, it appears in still higher rates and even increases gradually in hemodialysis (HD) patients. This situation has led to a debate about cardiovascular adverse effects of HD which lead to significant changes in cardiac and hemodynamic events. It is known that troponins are often elevated in HD patients, and high levels of troponin are associated with increased mortality. Therefore, it is difficult to interpret the value of elevations in chronic kidney disease patients. METHODS: Echocardiographic and biochemical parameters of 41 patients treated with HD were evaluated before and after a HD session. RESULTS: HD led to an increased heart rate, and tissue Doppler imaging parameters such as early diastolic mitral peak velocity (E)/early diastolic myocardial peak velocity (e) and septal e decreased significantly after HD. HD caused an increase in troponin I, myoglobin and cardiac creatine kinase (CK MB) levels (p = 0.019, p < 0.001 and p = 0.018, respectively). A decrease in the left ventricular peak systolic myocardial (LV S') velocity (p = 0.011) was detected in patients with increased levels of cardiac damage markers (group 2) compared to those without increased levels of cardiac damage markers (group 1) in HD. CONCLUSION: A decrease in LV S' velocity was found to be an independent predictor of an increase of myocardial injury enzymes in HD (odds ratio = 1.099; p = 0.039). We concluded that HD may lead to significant acute stress upon the myocardium. PMID- 23922555 TI - The Novel Angiotensin II Receptor Blocker Azilsartan Medoxomil Ameliorates Insulin Resistance Induced by Chronic Angiotensin II Treatment in Rat Skeletal Muscle. AB - Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin angiotensin-aldosterone system. The effectiveness of azilsartan medoxomil (AZIL M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. Male Sprague-Dawley rats were treated for 8 weeks with or without Ang II (200 ng/kg/min) combined with either vehicle or AZIL-M (1 mg/kg/day). Ang II induced significant (p < 0.05) increases in blood pressure, which were completely prevented by AZIL-M. Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL M co-treatment increased this parameter. Moreover, AZIL-M treatment of Ang II infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser473 (81%) and Thr308 (23%)] and AS160 Thr642 (42%), in red gastrocnemius muscle frozen in situ. Absolute AMPKalpha (Thr172) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr389 phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPKalpha and suppressed p70 S6K1 activation. PMID- 23922556 TI - The Effect of Peginterferon Alpha-2a vs. Peginterferon Alpha-2b in Treatment of Naive Chronic HCV Genotype-4 Patients: A Single Centre Egyptian Study. AB - BACKGROUND: Egypt has one of the highest (16-8%) prevalence rates of HCV infection in the world. Approximately 90% of Egyptian HCV isolates belong to a single subtype (4a), which responds less successfully to interferon therapy than other subtypes. Studies comparing the efficacy and safety of PEGIFN alfa-2a and PEGIFN alfa-2b in treatment-naive HCV-infected patients have shown conflicting results. OBJECTIVES: Assessing the effects of Peginterferon alpha-2a versus Peginterferon alpha-2b on the sustained virological response in naive chronic HCV genotype-4 Egyptian patients. PATIENTS AND METHODS: This retrospective study cohort consists of 3718 chronic HCV patients admitted to a large, Egyptian medical center. 1985 patients had been treated with PEG-IFN alfa-2a plus RBV and 1733 patients with PEG-IFN alfa-2b plus RBV between years 2007-2011. Efficacy outcomes were sustained virologic response (SVR) and treatment discontinuation rates due to serious adverse effects. RESULTS: The ETR & SVR in patients treated with PEGIFN alfa-2a was 64.1% and 59.6% as compared to treatment with PEGIFN alfa 2b where these parameters were 58.2% and 53.9% respectively (P < 0.05). Treatment discontinuation rates, were similar in the two types of PEGIFN [0.66 (0.37-1.16); P = 0.15]. Significant dose reduction was evident with peginterferon alfa-2b (35.3%) than peginterferon alpha-2a (27.3 %) (P < 0.01). Patients with lower base line AFP and ALT were most likely to achieve SVR using INF alpha 2-a. CONCLUSIONS: Peginterferon alpha-2a has a higher efficacy regarding ETR and SVR as compared to Peginterferon alfa-2b in treatment of naive chronic HCV genotype-4 patients. PMID- 23922557 TI - Development and Application of an In-house Line Probe Assay for Hepatitis C Virus Genotyping. AB - BACKGROUND: Hepatitis C virus (HCV) is the major cause of chronic liver disease. HCV is a single stranded positive sense RNA of approximately 9.6 Kb. Because of high conservativeness of 5?untranslated region of HCV genome, it is widely used for virus genotyping. Different methods are used for the virus genotyping, but all involve some difficulties. OBJECTIVES: The aim of the present study was to develop an in-house reverse hybridization method as a line probe assay, for HCV genotyping. MATERIALS AND METHODS: Sixty serum samples were collected with newly diagnosis of HCV infection. Genotyping process had already been performed for the samples using RT-PCR RFLP method. After total RNA extraction from the samples and cDNA synthesis, nested PCR method was applied for amplification of the target sequence on the 5?UTR. In the nested PCR, biotinylated oligonucleotides were used as inner primers. Optimized concentrations of the biotinylated inner primers (as positive control), two universal and seven specific probes were spotted onto nylon membrane stripes in a defined pattern. Hybridization process was conducted between the probes and the denaturized biotin labeled PCR products. Finally, the stripes were developed by using streptavidin conjugated alkaline phosphate as a signal generating agent. To determine the diagnostic sensitivity and specificity of the home made LiPA, a panel containing 60 confirmed sera with positive results for HCV (and PCR-RFLP genotyped) was subjected to evaluate. RESULTS: Agarose gel electrophoresis of the nested PCR products using the outer and inner primers showed 305 and 234 bp fragments respectively. After performing hybridization and detection processes on the prepared strips, the colored bands were formed for the positive control, universal probes and the corresponding genotypes. HCV genotype results were found to be in 100% concordance through studying 60 sera that were successfully typed by the two methods. P-value of 0.045 conveys that the two methods were the same and had no significant difference. CONCLUSIONS: The most common genotyping method in Iran is RT-PCR RFLP. Given the results and advantages of this homemade technique, such as high specificity and sensitivity, ability for detection of most genotypes, it provides possibility of evaluating much of the isolates without needing electrophoresis stage. PMID- 23922558 TI - Clinical characteristics of patients with hepatocellular carcinoma in a middle eastern population. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of death in Saudi male patients. Local clinical and demographic data of this disease are scarce. OBJECTIVES: We sought to describe the clinical characteristics and outcomes of patients from two tertiary care centers in Saudi Arabia. PATIENTS AND METHODS: Data were collected for all patients diagnosed to have hepatocellular carcinoma between June 2003 and July 2008 who had been registered in a special research database (the Saudi Observatory Liver Disease Registry (SOLID)). Data were extracted from SOLID for clinical, biochemical, radiologic parameters and outcome. RESULTS: Data was available for 363 patients, the mean age of diagnosis was 66 years, 74% of patients were males, and Hepatitis C was the underlying cause of liver disease in 48%, while Hepatitis B in 29%. Most of the patients were diagnosed at an advanced stage, 53 % of patients had a CLIP score of 4 to 6 (advanced stage), 55% had large multi-nodular tumors and 16% had vascular invasion or extra-hepatic spread at the time of diagnosis. Most of the patients had decompensated cirrhosis; with child-pogh score B in 44% and C in 26% with presence of portal hypertension in 55%. Forty eight percent died during the study period. Predictors of poor survival in the univariate analysis were; presence of portal vein thrombosis (P = 0.03), portal hypertension (P < 0.0001), presence of ascites (P = 0.022), hepatic encephalopathy (P < 0.0001), advanced child-pough score (P < 0.0001), bilirubin > 22 (P < 0.0001) and INR > 1.2 (P = 0.02). On multivariate analysis, only the presence of portal hypertension, bilirubin > 22 and severe hepatic encephalopathy were significant with adjusted hazard ratio of 1.6 (95% CI; 1.04-2.47), 1.76 (95% CI; 1.12-2.8), and 3.18 (95% CI; 1.42-7.14) respectively. CONCLUSIONS: The data from this cohort indicates that most of patients diagnosed with HCC present at late tumor and liver disease stages, when prognosis is usually dismal. Regular cancer surveillance in cirrhotic patients might change the outcomes. Further studies with results of treatment outcomes in this community are needed. PMID- 23922560 TI - Autoimmune Hepatitis or Wilson's Disease, a Clinical Dilemma. PMID- 23922559 TI - Lower intrafamilial transmission rate of hepatitis B in patients with hepatitis d coinfection: a data-mining approach. AB - BACKGROUND: The presence of an infected family member significantly increases the risk of HBV transmission, but many socio-demographic and viral characteristics of family members affect the transmission rate. OBJECTIVES: In this study, we have used data mining techniques to investigate the impact of different variables in intrafamilial transmission of HBV infection. PATIENTS AND METHODS: demographic information, viral markers, and medical history of 330 patients with chronic hepatitis B and their offspring attending a referral center in Tehran were collected. Data-mining techniques were administered to detect patterns. RESULTS: The overall transmission rate was 15.7% (5.4% and 27.3% for male and female index cases respectively). In female patients, HBe Ag positively affected the transmission rate (49% vs. 23.4%). There was a dominant change in transmission rate of female patients with negative results for Hbe Ag with HDV coinfection, where the transmission rate changed from 25% in patients with negative results for HDV Ab to 5% in those with positive results. In Hbe Ag negative male index cases, the transmission rate was 1.3% in cases with positive results for HDV Ab compared to 7% in those with negative findings. The overall transmission rate was statistically different between patients with positive and negative results for HDV Ab (P = 0.016). CONCLUSIONS: There is a minor but consistent pattern change in the presence of HDV infection which reduces familial transmission of HBV, especially in female patients with negative results for HBe Ag. PMID- 23922561 TI - Prevalence and factors associated with hepatitis B virus infection among senior citizens in a southern brazilian city. AB - BACKGROUND: Given the long term exposure to risk factors, it is likely that older adults exhibit the highest proportions of HBV serological markers. Nevertheless, there are few methodologically adequate studies in Brazil evaluating the prevalence and risk factors for HBV infection in individuals aged 60 years or more. OBJECTIVES: To estimate the prevalence and factors associated with HBV infection in elderly residents in the city of Tubarao/SC. PATIENTS AND METHODS: This cross-sectional study included 820 individuals (>= 60 years) selected by simple random sampling. The variables were compared by chi-square test or Fisher's exact test and those with P < 0.200 were included in the regression model. RESULTS: The mean age of patients was 68.6 +/- 7.0 years, 39% were men and 92% Caucasian. Five subjects (0.6%) presented with positive HBsAg and 124 (15.1%) were anti-HBc reactive. Bivariate analysis showed that the presence of anti-HBc was associated with age >= 67 years, <= 4 years of schooling, acupuncture therapy and lower proportion of subjects exposed to invasive procedures. In multivariate analysis, the following variables remained independently associated with HBV infection: male gender, marital status, <= 4 years of schooling and acupuncture. CONCLUSIONS: The prevalence of anti-HBc among the elderly in the city of Tubarao was higher than in previous studies evaluating blood donors in the same region. Despite the association of previous HBV infection and factors indirectly related to sexual risk behaviors, the results suggest the involvement of invasive therapeutic procedures in the HBV transmission chain. PMID- 23922562 TI - Sequence and structural analysis of 3' untranslated region of hepatitis C virus, genotype 3a, from pakistani isolates. AB - BACKGROUND: Hepatitis C virus (HCV) is the cause of high morbidity and mortality worldwide, inflicting around one million people in Pakistan alone. The HCV genomic RNA harbors conserved structural elements that are indispensable for its replication. The 3' untranslated region (UTR) contains several of these elements essentially involved in regulating the major steps of the viral life cycle. OBJECTIVES: Differences in regulatory elements of HCV may contribute towards differential infectivity of local isolates. The present study explicates sequence analysis and secondary structure prediction of HCV 3'UTR region of subtype 3a from Pakistan to characterize this particular region. PATIENTS AND METHODS: HCV 3'UTR region was amplified, cloned and sequenced from five different patients. Sequence and structural analysis was performed and phylogenetic analysis was carried out using the 3'UTR sequence reported in NCBI nucleotide data base (http://www.ncbi.nlm.nih.gov/nuccore) by other studies. RESULTS: Sequence analysis of the amplified fragment from five patients indicated that the 3'UTR is composed of 214-235 nts. Its sequence contains a type-specific variable region followed by a poly U/UC region and a highly conserved X-tail of 98 nts. The variable region reported here has 26 nts and one stem loop at the secondary structure that differentiate it from HCV genotype 1a ( GT1a) 3'UTR which contains additional 14 nts and two stem loops. The poly U/UC region varied in length (100 79 nts) and nucleotide sequence within the Pakistani isolates, and among different genotypes. Some substitutions found in the X-tail do not affect secondary structure of this element suggesting that this region might play an important role in replication, stabilization and packaging of HCV genome. Additionally, U residues are not present at the end of the X-tail in Pakistani 3a isolates as otherwise reported for the variants of genotype 1b. CONCLUSIONS: Sequence and structural diversity of the 3'UTR variable region and Poly U/UC region found in the local isolates indicate specificity in the regulating elements of 3'UTR that might be associated with differential replication efficacy of the HCV Pakistani isolates. The study necessitates functional characterization of these regulating elements to elucidate variable viral efficiency and pathogenicity associated with inter-geographical isolates. PMID- 23922563 TI - No correlation between interleukin-10 gene promoter polymorphisms and hepatitis B virus infection outcome. AB - BACKGROUND: Single nucleotide polymorphisms (SNP) in the promoter region of the interleukin (IL)-10 genes have a role in determining hepatitis B virus (HBV) outcome. OBJECTIVES: This study evaluates the correlation between HBV infection and SNP in IL-10 gene promoter. PATIENTS AND METHODS: Ninety-six HBV-infected patients (32 chronic hepatitis B infection patients, 34 healthy carriers, 30 spontaneously recovered cases) and 31 healthy controls were enrolled. Three biallelic (-819,-592,-1082) regions in the IL-10 gene promoter were sequenced for all patients. RESULTS: Genotypes and haplotypes of IL-10 gene promoter region at position -1082, -819 and -592 were not significantly different among controls, HBV recovered cases, carriers and chronic HBV patients. Nevertheless, A/A genotype at position -592 and T/T genotype at position -819 were more frequently seen in the HBV clearance group, while frequency of G/G genotype at position 1082 was more prevalent in the persistence group. GCC/GCC and GCC/ACC haplotypes were significantly observed in anti-HBe positive individuals. CONCLUSIONS: Our findings showed that IL-10 promoter polymorphisms were not correlated with HBV infection prognosis. Nevertheless, individuals carrying high and intermediate producer of IL-10 haplotypes had a better ability to develop anti-HBe than low producer carriers. PMID- 23922564 TI - Non alcoholic fatty liver disease in southern Iran: a population based study. AB - BACKGROUND: Population based studies on prevalence and risk factors of NAFLD in Iranian population are few. The prevalence of NAFLD and non alcoholic steatohepatitis (NASH) in Iranians varies from 2.9% to 7.1% in general population and 55.8% in patients with type 2 diabetes mellitus. OBJECTIVES: To determine the prevalence and determinants of non alcoholic fatty liver disease (NAFLD) in a sample of adult Iranian general population. PATIENTS AND METHODS: This was a cross-sectional study being performed in Shiraz, southern Iran during a 10-month period from November 2010 to September 2011 through cluster random sampling of Iranian general population in Shiraz region. All individuals undergone anthropometric, blood pressure measurements, thorough medical history and physical examinations. Laboratory measurements included fasting blood glucose (FBS), lipid profile, complete blood count (CBC) and liver function tests. NAFLD was diagnosed by transabdominal ultrasonography. RESULTS: 819 subjects were included in this study among which were 340 males (41.5%) and 479 females (58.5%) with the mean age of 43.1 +/- 14.1 years. NAFLD was diagnosed in 176 (21.5%) subjects. Patients with NAFLD were significantly older (P < 0.001), had higher proportion of male gender (P = 0.004) and had higher BMI (P < 0.001). They also had higher prevalence of hypertension (P < 0.001), high FBS (P < 0.001), high cholesterol (P = 0.026), high triglyceride (P < 0.001) and high waist circumference (P < 0.001). Taking all these together, patients with NAFLD had significantly higher prevalence of metabolic syndrome when compared to healthy subjects (P < 0.001). CONCLUSION: The prevalence of NAFLD in this group of Iranian adult general population is 21.5%. NAFLD in Iranian population is associated with male gender, old age, obesity, and features of metabolic syndrome. PMID- 23922565 TI - Association of Adiponectin rs1501299 and rs266729 Gene Polymorphisms With Nonalcoholic Fatty Liver Disease. AB - BACKGROUND: Genetic and environmental factors are important for the development of nonalcoholic fatty liver disease (NAFLD). Adiponectin is a white and brown adipose tissue hormone, and have been found to play essential roles in the regulation of energy homoeostasis. Recent reports have identified a possible role of adiponectin in NAFLD via PPARgamma pathway. OBJECTIVES: The present study was designed to find out the impact of adiponectin rs1501299 (276G/T) and rs266729 ( 11377C/G) gene polymorphisms in NAFLD. PATIENTS AND METHODS: Eighty-three patients with diagnosis of NAFLD, and 93 healthy subjects were included in the study. Tetra ARMS-PCR was designed to detect single nucleotide polymorphisms. RESULTS: A significant difference was found between NAFLD and control group regarding the rs266729 polymorphism (chi2 = 7.35, P = 0.025). The rs266729 polymorphism increased the risk of NAFLD in codominant (CC vs. CG: OR = 2.18, 95% CI = 1.16 - 4.12, P = 0.016) and dominant (CC vs. CG/GG: OR = 2.31, 95% CI = 1.25 - 4.27; P = 0.008) inheritance tested models. The G allele increased the risk of NAFLD (OR = 1.63, 95% CI = 1.03 - 2.57, P = 0.037) in comparison with C allele. No significant difference was found between the groups concerning adiponectin rs1501299 gene polymorphism (chi2 = 0.70, P = 0.697). CONCLUSIONS: adiponectin rs266729 polymorphism might be a candidate gene, which determines the susceptibility to NAFLD. Larger studies are necessary to confirm these findings in various populations. PMID- 23922566 TI - A Prospective Clinical Study on Blood Mercury Levels Following Endodontic Root end Surgery with Amalgam. AB - INTRODUCTION: The purpose of this clinical study was to compare the blood mercury levels before and after endodontic surgery using amalgam as a root-end filling material. MATERIALS AND METHODS: Fourteen patients requiring periradicular surgery participated in this prospective clinical study. A zinc-free amalgam was employed as root-end filling material. Blood samples were collected at three intervals: immediately before, immediately after and one week postoperatively. Mercury content of the blood was determined using gold amalgamation cold-vapor atomic absorption spectrometry. Obtained data were analyzed using analysis of variance for repeated measures and paired t-test. RESULTS: The mean (SD) of blood mercury levels was 2.20 (0.24) ng/mL immediately before surgery, 2.24 (0.28) ng/mL immediately after surgery and 2.44 (0.17) ng/mL one week after the periradicular surgery. The blood mercury level one week post-operative was significantly higher than both blood mercury levels immediately before (P<0.001) and immediately after (P=0.005) the surgery. CONCLUSION: Placement of an amalgam retroseal during endodontic surgery can increase blood mercury levels after one week. The mercury levels however, are still lower than the toxic mercury levels. We suggest using more suitable and biocompatible root-end filling materials. PMID- 23922567 TI - Evaluation of the quality of four root canal obturation techniques using micro computed tomography. AB - INTRODUCTION: One of the key factors in successful endodontic therapy is to adequately fill the root canals. The aim of this in vitro study was to compare the quality of four different root canal obturation techniques: cold lateral condensation (CLC), warm vertical condensation (WVC), Obtura II (OII) and Gutta Flow (GF) by using micro-computed tomography (micro CT). MATERIALS AND METHODS: A total of 20 extracted maxillary first molars prepared with ProTaper files, were randomly divided into four groups. Micro CT was used to measure the internal volume of root canals. Following application of AH26 sealer to canal obturation, new micro-CT images were taken and the volume percentage (VP) of voids, gutta percha and sealer at different levels were calculated with CT software. Data was statistically analyzed using Kruskal-Wallis and Mann-Whitney U tests. RESULTS: The highest percentage of filling material was observed in GF group followed by OII with no statistically significant difference (P>0.05). These two groups had a significantly more acceptable filling than WVC and CLC groups (P<0.05). Voids were detected in all samples. There was a significant difference between the highest and the lowest percentage of voids in CLC (19.6%) and GF groups (6.7%), respectively. In the apical third, CLC and OII showed the highest and the lowest percentage of voids (5.5% and 2.6%) and the lowest and highest percentage of gutta-percha (76.52% and 94.26%), respectively. These differences were statistically significant (P<0.05). CONCLUSION: None of the root canal filled teeth were gap-free. GF and CLC techniques showed the highest and lowest VP of obturation materials, respectively. PMID- 23922568 TI - Residual dentin thickness of bifurcated maxillary premolars following two post space preparation methods. AB - INTRODUCTION: The aim of this in vitro study was to compare the effect of Gates Glidden and Peeso reamer drills on residual dentin thickness during post space preparation in order to discover which method has minimum root structure damage. MATERIALS AND METHODS: Thirty extracted human maxillary premolars with bifurcations at root middle were horizontally cut 15 mm coronal to the apical end after root canal treatment. The samples were scannedby Cone Beam Computed Tomography (CBCT) before and after preparing the post space. Residual dentin thicknesses were measured at 4-, 6-, and 8-mm levels from the apex. Data were analyzed using repeated measured ANOVA. RESULTS: Endodontic therapy and post space preparations removed more dentin within the bifurcation of both roots compared to outer dentin. The difference in residual dentin thickness was highly significant regarding stage (before and after post space preparation) in all levels and stage * device in coronal and middle levels (P<.05). This in vitro study emphasizes the minimal dentin width in the buccal root of maxillary premolars, especially near the bifurcation. CONCLUSION: Lack of adequate residual dentin thickness after post space preparation implies that the use of posts in maxillary first premolars should be limited. When mandatory, it is recommended that post space be prepared with Gates-Glidden drill in the palatal root of maxillary first premolars and use of Peeso reamer be avoided. PMID- 23922569 TI - The prevalence of bilateral three-rooted mandibular first molar in Indian population. AB - INTRODUCTION: The purpose of the present study was to evaluate the prevalence of bilateral three-rooted mandibular first and second molars in Indian population. MATERIALS AND METHODS: A total of 215 patients were screened bilaterally for mandibular first and second molar and 430 samples of periapical radiographs were obtained. The gender, symmetry, and prevalence of three-rooted mandibular first and second molars were recorded. The correlation between left and right side occurrences and distribution were recorded and analysed using Z-test. RESULTS: The results showed that 33 teeth had three-rooted mandibular first molars, 16 male and 17 female (P=0.442). Overall, 21 teeth of right jaw and 12 teeth of left jaw (P=0.103) showed presence of an extra-root. The prevalence of three-rooted mandibular first molars was 7.67% and second molar was 0.23%. The bilateral frequency distribution was 3.72% for the first molar. There was no statistically significant difference between right side and left side mandibular molars. Also, gender did not show a significant relationship with this variant. CONCLUSION: The endodontic treatments of first mandibular molars require a careful clinical approach in Indian population as a high racial prevalence of 7.67% three-rooted molars was found. However, in the same population, 0.23% mandibular second molars had three roots. PMID- 23922570 TI - A New Classification for the Relationship between Periodontal, Periapical, and Peri-implant Complications. AB - INTRODUCTION: There are numerous studies supporting the high success rate of dental implants used for reconstruction of missing teeth. However, complications like mucositis and peri-implantitis are increasingly reported. Placement of dental implants in partially edentulous patients is associated with the risk of peri-implant diseases, especially when an old or a new inflammatory lesion is present adjacent to the implant site. Although no consensus has been reached on the difference in prevalence of peri-implant mucositis and peri-implantitis between fully and partially edentulous patients, available data clearly show that the combination of periodontal lesion and peri-implantitis is a possible risk factor for further complications. Several classification systems have been suggested for determination of the severity of disease around dental implants. However, no classification has been proposed for combined biological complications around teeth and implants. This study reviews the possible pathologic communication routes between natural dentition and the implants installed adjacent to them. Furthermore, we introduce a new classification system for the peri-implant disease in association with natural teeth called "PIST". This system was designed based on the origin of the defects in order to clarify the different pathological situations which can be detected around dental implant. Using this classification system can help improve diagnosis, comparison and subsequent selection of the best treatment option. PMID- 23922572 TI - An In Vitro Comparison of Propex II Apex Locator to Standard Radiographic Method. AB - INTRODUCTION: The aim of this in vitro study was to compare the accuracy of radiography in assessing working length to Propex II apex locator. MATERIALS AND METHODS: Thirty single canal extracted human teeth with patent apical foramen were selected. Access cavities were prepared. Anatomic length (AL) was determined by inserting a K-file into the root canal until the file tip was just visible at the most coronal aspect of the apical foramen; subsequently 0.5 mm was deducted from this measured length. Working length by radiographic method (RL) was determined using Ingle's method. Propex II apex locator was used to determine the electronic working length (EL). From these calculated lengths, AL was deducted to obtain D-value. D-value in the range of +/-0.5 mm was considered to be acceptable. RESULTS: The percentage accuracy of RL and Propex II apex locator was 76.6% and 86.6%, respectively. Paired t-test revealed significant difference between the RL and Propex II apex locator (P<0.05). CONCLUSION: Under these in vitro conditions, Propex II apex locator has determined working length more accurately than radiographic method. PMID- 23922571 TI - Sealing Ability of Orthograde MTA and CEM Cement in Apically Resected Roots Using Bacterial Leakage Method. AB - INTRODUCTION: The aim of this in vitro study was to determine the sealing ability of orthograde ProRoot mineral trioxide aggregate (MTA) and calcium enriched mixture (CEM) cement as root-end filling materials. MATERIALS AND METHODS: Fifty four extracted single-rooted human teeth were used. The samples were randomly divided into 3 experimental groups. In group A and B, 4 mm of WMTA and CEM cement were placed in an orthograde manner and 3 mm of apices were resected after 24 hours. In group C the apical 3 mm of each root was resected and the root-end prepared with ultrasonic tips to a depth of 3 mm and subsequently, then filled with MTA. The apical sealing ability was performed with bacterial leakage method. Statistical analysis was carried out with Chi-square test. RESULTS: There were no significant differences in the extent of bacterial leakage between the three experimental groups (P>0.05). CONCLUSION: Based on the limitations of this in vitro study, we concluded that MTA and CEM cement can be placed in an orthograde manner when there is a potential need for root-end surgery. PMID- 23922573 TI - The effect of deproteinized bovine bone mineral on saos-2 cell proliferation. AB - INTRODUCTION: Deproteinized bovine bone mineral (Bio-Oss) is a xenogenic bone substitute, widely used in maxillofacial bone regeneration. The aim of this in vitro study was to investigate its influence on the growth behavior of human osteosarcoma cell line, Saos-2 culture, and compare it with the physiologic dose of Dexamethasone, an inductive factor for osteoblasts. MATERIALS AND METHODS: Human osteosarcoma cells, Saos-2, were cultured on Bio-Oss and their growth rate was compared to Saos-2 cultures treated with Dexamethasone 10(-7) M in contrast to cells cultivated in PBS, in the control group. Assessment of proliferation was performed after 24, 36, and 48 hours by counting cells using trypan blue exclusion method. Alkaline phosphatase was measured spectrophotometrically at 405 nm with paranitrophenol buffer. RESULTS: After 48 hours, the number of Saos-2 cells increased significantly when subcultured with Bio-Oss. Bio-Oss was more effective on the enhancement of proliferation of Saos-2 cells when compared to the physiologic dose of Dexamethasone (P<0.05). Alkaline phosphatase activity increased in cells grown on Bio-Oss and dexamethasone 10(-7) M in contrast to cells cultivated in PBS control group. The greatest level of activity was observed in the group containing Bio-Oss after 48 hour. CONCLUSION: The significant increase of cell proliferation and alkaline phosphatase activity in cells cultured on Bio-Oss, compared to Dexamethasone-treated cells, suggests the important role of this bone substitute in promoting bone regeneration. PMID- 23922574 TI - Prevalence of toothache and associated factors: a population-based study in southeast iran. AB - INTRODUCTION: This study was carried out to estimate toothache prevalence among adult residents in Kerman. MATERIALS AND METHODS: This cross-sectional, population-based study was conducted among individuals aged over 18 years (n=1800). The relevant data on the prevalence of toothache and associated factors were collected by interviewing the individuals in their homes and filling out a questionnaire designed by the examiners. Prevalence of toothache and associated factors that patients recalled previous to their interview were analyzed by chi square test and multivariate logistic regression analysis. RESULTS: Nine hundred ninety-one individuals (55.1%) reported toothache during the 6 months before the interview. The participants who flossed daily, had regular dental visits, and had higher education showed a significantly lower prevalence of toothache (P<0.05), whereas regular tooth brushing and economic level of residency had no significant effect on the prevalence of toothache. Individuals between the ages of 26 and 45 [odds ratio (OR)=2.0], with a family size of more than 4 (OR=1.5), not using dental floss (OR=1.5), or having a mental or psychological illness (OR=1.5) were more likely to have a history of toothache. CONCLUSION: High prevalence of toothache (more than half) among residents of Kerman shows a serious and major public health problem. Toothache prevalence in middle aged adults, lower education, bigger family size, lower dental hygiene habit and/or those having mental or psychological illness were more common in the city of Kerman. PMID- 23922575 TI - The Prophylactic Effects of Zintoma and Ibuprofen on Post-endodontic Pain of Molars with Irreversible Pulpitis: A Randomized Clinical Trial. AB - INTRODUCTION: Post endodontic pain is often linked to the inflammatory process as well as additional central mechanisms. The purpose of the present double-blind randomized clinical trial study was to compare the prophylactic effects of a derivative of Zingiber Officinale, Zintoma, and Ibuprofen on post endodontic pain of molars with irreversible pulpitis. MATERIALS AND METHODS: The post endodontic pain of 72 enrolled patients suffering from irreversible pulpitis was assessed after prophylactic use of 400 mg Ibuprofen, 2 gr Zintoma and placebo. Using the Heft-Parker Visual Analogue Scale, the patients recorded their perceived pain before taking the medicament (baseline), immediately after and also at 4, 8, 12, 24, 48, and 72 h post one-visit endodontic treatment. The statistical analysis was done using Kruskal-Wallis, Mann-Whitney, and Freedman tests (P<0.05). RESULTS: At all times, there was significant difference between the Ibuprofen and Zintoma (P<0.05) and also between the Ibuprofen and placebo (P<0.05). However, there was no significant difference between Zintoma and the placebo in any of time intervals (P>0.05). No side effects were observed. CONCLUSION: The obtained results of the trial revealed that prophylactic use of 2 gr Zintoma is not an effective pain relieving agent. PMID- 23922576 TI - Fracture Resistance of Root Canals Obturated with Gutta-Percha versus Resilon with Two Different Techniques. AB - INTRODUCTION: Dentin removal during root canal instrumentation creates a weaker root structure and increases its potential to fracture. The aim of this in vitro experimental study was to compare fracture resistance of teeth filled with gutta percha, and Resilon using two different techniques. MATERIALS AND METHODS: This study was performed on 105 single-canal extracted maxillary incisors. Samples were divided into seven groups of 15 each. Three groups were prepared with K files; three groups with Race rotary files and in one group no preparation was carried out. Of all samples prepared either manually or with rotary instruments, 15 teeth were obturated using gutta-percha and AH26 sealer, 15 teeth were filled with Resilon and 15 teeth remained unfilled. Loading force to fracture was measured and ANOVA and Tukey tests were used for statistical analysis. RESULTS: No statistically significant differences were observed between different preparation techniques. The intact roots showed significantly greater fracture resistance compared to both instrumented groups (P<0.01). Resilon Group showed significantly higher resistance than gutta-percha Group (P<0.01); however the difference between Resilon and intact teeth was not statistically significant. CONCLUSION: Accoding to the results of this in vitro study, root canal filling using Resilon may increase the fracture resistance of treated teeth. PMID- 23922577 TI - Periradicular surgery of human permanent teeth with calcium-enriched mixture cement. AB - INTRODUCTION: Root-end preparation and restoration with an endodontic material are required when nonsurgical endodontic retreatment has failed or is impossible. The present clinical study reports the treatment outcomes of periradicular surgery using calcium-enriched mixture (CEM) cement. MATERIALS AND METHODS: A prospective outcome study of periradicular surgery using CEM was conducted on 14 permanent teeth with persistent apical periodontitis. Using a standardized surgical protocol, 2-3 mm of the root apex was resected; approximately 3 mm deep root-end cavities were ultrasonically prepared and filled with CEM cement. All patients were available for recall. RESULTS: Clinical and radiographic examination revealed complete healing of periradicular lesions, i.e. regeneration of periodontal ligament and lamina dura in 13 teeth (93% success) during a mean time of 18 months; moreover, the teeth were functional and asymptomatic. CONCLUSION: Favorable treatment outcomes in this prospective clinical study suggested that CEM cement may be a suitable root-end filling biomaterial. PMID- 23922578 TI - Vital pulp therapy with three different pulpotomy agents in immature molars: a case report. AB - INTRODUCTION: This case report describes apexogenesis treatment of three molar teeth of an 8-year-old boy using three different pulpotomy agents. METHODS: Pulpotomy was performed on decayed immature molar teeth with established irreversible pulpitis and the remaining pulp was capped with either zinc oxide eugenol, ProRoot mineral trioxide aggregate or calcium-enriched mixture (CEM) cement. Teeth were restored with stainless steel crowns. RESULTS: Eighteen months clinical and radiographic follow-up revealed successful preservation of pulpal vitality with continued root development in all treated teeth. CONCLUSION: Based on this case report, CEM cement may be an alternative option for pulpotomy treatment of immature permanent molars. PMID- 23922579 TI - Stressors in clinical nursing education in Iran: A systematic review. AB - BACKGROUND: Clinical education is a critical and complex component of nursing education that is influenced by many variables. One of them is stress, which may disturb students' learning, too. Stressors may differ according to the learning situation and environment, and recognizing them, seems to be essential for corrective interventions. The present work was performed to identify stressors in clinical nursing education in Iran, according to the published research reports. MATERIALS AND METHODS: In this systematic review, all published research reports available in Iranian and International web-based data bases and search engines were searched. Also, the archives of peer reviewed Iranian nursing and medical education journals (published between 1989 and 2009) were hand searched. Out of 1104 retrieved records (by a more general terms of clinical education AND Nursing), after stepwise screening, 15 original research articles were selected for content analysis. Coded data were classified and their frequency was represented in Tables. RESULTS: THE FOLLOWING THEMES WERE OBTAINED TO CLASSIFY MAIN AREAS OF IMPORTANCE FOR FACTORS RELATED TO STRESS IN CLINICAL NURSING EDUCATION: a) clinical competence and ability to play one's roles, b) care load, or stress due to care, c) main area of education, d) interpersonal relationships and interactions, e) clinical environment (facilities and equipments, space, learning opportunities, etc,...). Subthemes were also identified in each theme. CONCLUSION: Published studies in Iran provide appropriate background evidences for planning and evaluating interventional programs to reduce stress among nursing students and instructors. Each identified theme in this study could be considered as a subject for planned interventions. Among them, it seems that interpersonal relationships and interactions is of the highest priority. PMID- 23922580 TI - The effect of a care program on pain intensity of cancer patients who underwent surgery and hospitalized in Sayyed-Al-Shohada Hospital of Isfahan University of Medical Sciences in 2011. AB - INTRODUCTION: One of the most frequent issues nurses encounter with after or during cancer-related surgeries is pain. For postoperative pain relief, different nonpharmacologic interventions, such as nurse-patient communication, mental support, preoperative education, and consultation can be used. Doing such interventions may decrease postoperative pain. However, the research results regarding the effect of such measurements on pain intensity is contradictory. So in this research study the effect of a pain management plan on pain intensity after cancer surgery was assessed. MATERIALS AND METHODS: The present study is a pre- and posttest case and control clinical trial, which was conducted in Sayyed Al-Shohada Hospital of Isfahan University of Medical Sciences in 2011. Care program consisted of pain education, communication with the patient, and pain measurement. Seventy patients were sampled based on the inclusion criteria and randomly assigned in 2 groups. Data were collected using American Pain Society patient outcome questionnaire, which measured pain intensity. RESULTS: In the experimental group, the mean score of pain intensity before surgery and in the first 12-24 h after surgery was less than the control group. Also comparing pain intensity mean differences before and in the first 12 h, before and in the first 24 h indicated that the experimental group had lower scores than the control group, but these differences were not statistically significant. In both the groups, in the first 24 h following surgery the mean score of pain intensity decreased significantly. DISCUSSION: Results of the present research study suggested that a nursing pain management program consisting consultation, education, and pain assessment may have a clinical effect on cancer patient pain intensity following surgery. However, these results were not statistically significant. This might be due to the limited sample size as well as conducting the program in a short period of time. It is recommended that effects of such a program on the pain intensity will be examined further with a larger sample and in a longer period of time. PMID- 23922581 TI - Quality of sleep and its related risk factors in hospitalized older patients in Kashan's Hospitals, Iran 2009. AB - CONTEXT: Sleep is an effective factor in the process recovery from diseases. Many variables affect the sleep quality of hospitalized older patients. AIM: This study was conducted to evaluate the quality of sleep and its related risk factors in hospitalized older patients in Kashan's hospitals, Iran 2009. SETTINGS AND DESIGN: a cross-sectional study was carried out on a sample of 400 hospitalized older adults in the hospital of Kashan, Iran. MATERIALS AND METHODS: The Farsi Pittsburgh Sleep Quality Index (FPSQI) was used for gathering data. A global sum of 6 or greater indicates a poor quality of sleep. STATISTICAL ANALYSIS USED: data were analyzed using the Chi-square test, t-test, ANOVA, and binary logistic regression at the multivariate model. RESULTS: The overall quality of sleep of the patients in this study was poor. In the final regression model, sex (OR = 0.342), level of education (OR = 0.470), type of ward (OR = 0.592), previous hospitalization experience (OR = 2.336), and use of hypnotics in hospital (OR = 3.633) were the most important predictors of sleep quality. The most prevalent sleep disturbing factors were worries and anxiety, environmental noises and pain. However, the most negative effects on the PSQI mean score were reported to be from dyspnea, environmental lights, and changes in the sleep habits. Quality of sleep also had significant relationship with sleep latency (P = 0.001) and having a respiratory disorder. CONCLUSIONS: The knowledge of sleep disturbing factors in hospitalized older adults might help in planning preventive strategies to improve quality of sleep. PMID- 23922582 TI - The effect of yoga on coping strategies among intensive care unit nurses. AB - INTRODUCTION: Nowadays, it has been known that individuals handle coping strategies when faced with stressful events. These strategies play an important role in individuals. Nurses are exposed to high stress, which directly affects their job satisfaction and the quality of their services. Therefore, the present study tried to investigate the effect of Yoga on stress coping strategies among nurses working in intensive care units (ICUs). MATERIALS AND METHODS: In this quasi-experimental study, 34 female nurses working in ICU who were qualified to enter the study were selected. Yoga exercises were administrated two sessions a week for 8 weeks in the study group. CS-R questionnaire was filled before and after intervention. The data were analyzed by descriptive and inferential (t test) statistical tests. RESULTS: The results of statistical tests showed that the highest application of stress coping strategies was for inconsistent stress coping strategy. There was a significant difference in the mean scores of coping strategies of stress focus, emotion focus, and ineffectiveness after Yoga exercises compared with those before the yoga sessions. DISCUSSION: With regard to the findings, 8 weeks exercises of Yoga can be considered as a complementary treatment to amend stress coping strategies. Further studies in this field are suggested. PMID- 23922583 TI - The effect of psycho-educational intervention on the life quality of major depressive patients referred to hospitals affiliated to Shiraz University of Medical Sciences in Shiraz-Iran. AB - BACKGROUND: Depression is the world's fourth most prevalent health problem which is associated with substantial mortality, direct medical cost, diminished life quality, and significant physical and psychosocial impairment. This study aimed to investigate the effect of psycho-educational intervention on the life quality of major depressive patients. MATERIALS AND METHODS: Sixty patients who were willing and had met the required criteria for participation were selected from hospitals in Shiraz city, Iran. So 30 of the patients were assigned to the experimental group and 30 others to the control group. For data collection, a two part questionnaire was developed, the first part consists of 13 items related to general characteristics and the second part with 36 items on life quality were used. The experimental group was divided into five subgroups of 6 patients. For each group, six intervention sessions were scheduled. The control group did not receive the intervention. The questionnaires were completed for all subjects in the experimental and control groups before and 1 month after the end of psycho educational intervention. Tabulated data were analyzed using chi-square, independent and pair T-test. RESULTS: The results of the study indicated that psycho-educational intervention in comparison with other available treatments proved to be more effective on eight domains of life quality in the experimental group. A significant difference was observed for all the domains (P < 0.001). CONCLUSION: Psycho-educational intervention can be used as an auxiliary treatment in improving life quality and decreasing depression in patients suffering from major depressive disorder. PMID- 23922584 TI - Satisfaction levels about hospital wards' environment among adolescents hospitalized in adult wards vs. pediatric ones. AB - BACKGROUND: Adolescents admitted to hospital are either surrounded by children or adults. However, age-appropriate facilities are often not provided to meet the needs of adolescents, which should be incorporated in the wards. This study compares the satisfaction level about physical environment of the wards among adolescents who have been admitted to pediatric and adult wards. MATERIALS AND METHODS: In a cross-sectional study, 200 adolescents aged 10-19 were selected from adult and pediatric wards and studied for their level of satisfaction about physical environments of selected wards in Isfahan city. RESULTS: Among the adolescents surveyed in adult and pediatric wards, 44% and 54% reported high satisfaction levels with physical aspects of the ward environment and its facilities, respectively. The average satisfaction level among adolescents in pediatric wards was higher than among adolescents in adult wards (P = 0.04). However, no significant difference was found between age, number, and length of hospital admissions, insurance, and satisfaction levels with physical aspects of the ward environment and facilities. CONCLUSIONS: Adolescents reported better satisfaction with the pediatric wards' environment compared to adults' ward. They require specialized wards to meet their needs according to their developmental period. If not available, facilities should be provided in pediatric wards where adolescents have reported better satisfaction with the wards' environment. PMID- 23922585 TI - Impact of exercise on affective responses in female adolescents with type I diabetes. AB - BACKGROUND: Adolescent is a time of profound biologic, intellectual, psychological, and socioeconomic change that they will face a crisis. Therefore, compatibility may be exposed to many hazards, such as depression, anxiety, and other emotional problems. Nevertheless, a planned regular exercise enhances physical and mental health of adolescent female with diabetes. The aim of this study was to determine the effect of exercise on emotional reactions of female adolescents with type I diabetes. MATERIALS AND METHODS: This study was a quasi experimental research conducted in Endocrine and Metabolism Research Centre. A total of 72 patients were randomly allocated in the two groups. The intervention group did aerobic exercise for 45 minutes, while the control group did not aerobic exercise. Data were collected using a Symptom Checklist (SCL)-90 questionnaire. Data were analyzed and using descriptive and inferential statistics methods and SPSS software. RESULTS: The results showed that the mean score for physical symptoms, depression, obsession-compulsion, interpersonal sensitivity, aggression, phobia, paranoid ideation, psychosis, and anxiety in the test group significantly decreased after intervention than before intervention. The average score in the control group did not differ. The average total score of emotional reactions in the test group after the intervention decreased before the intervention significantly (P = 0.001). However, in the control group, the mean scores did not differ (P = 0.97). CONCLUSION: The findings showed that regular exercise is effective on affective responses of adolescent females with type I diabetes. PMID- 23922586 TI - Survey of critical thinking and clinical decision making in nursing student of Kerman University. AB - CONTEXT: The ability to think critically is an essential element in nursing education and more specifically in nurses' clinical decision making (CDM). AIMS: Critical thinking (CT) and CDM ability as well as their relationship were examined among nursing students of Kerman University. SETTINGS AND DESIGN: STUDY WAS DESIGNED IN FOUR TOWNS: Kerman, Bam, Jiroft, and Zarand, settled in Kerman province. MATERIALS AND METHODS: This research was a cross-sectional descriptive correlation study. 300 nursing students with different level of education were asked to fill two questionnaires including: (1) California Critical Thinking Skills Test (CCTST) and (2) Lauri and Salantera (2002) CDM instrument. STATISTICAL ANALYSIS USED: Data were analyzed with SPSS12 and descriptive and inferential statistics. RESULTS: Nursing students yielded a low score (mean = 5/40 from 20) of CT and a mild score (mean = 12.8 from 20) of CDM. We found positively correlation between male and CT and CDM score with mean score of the nursing student. Also CDM score in male was more than female but not significant, and Jirofts CDM nursing student was significantly better than other city. CONCLUSIONS: Although students that answers evaluation question in CCTST better can gave better CDM score but there isn't relationship between CT and CDM of nursing student. The finding showed that mean score of nursing student CT was low. Reason can be either due to the defects of nursing education program, teaching, and learning strategies. PMID- 23922587 TI - Function of nurses and other staff to minimize hospital waste in selected hospitals in Isfahan. AB - CONTEXT: Medical waste (MW) is all waste materials generated at health care facilities. MW naturally is hazardous for environment and subsequently for human. Waste minimization (WM) is the latest alternative for risk reduction. All hospital staff generally and nurses specially can play an active role through education and the implementation of measures to reduce medical wastage and their environmental effects. AIMS: This study is aimed to compare nurses and other staff functions in selected hospitals in Isfahan about waste minimization strategies. SETTINGS AND DESIGN: This is a descriptive analytical study. The study tool was a researcher -designed questionnaire in five area of waste minimization based on WHO recommendation. MATERIALS AND METHODS: There were 90 nurses and other staff from randomized selected public and private hospitals of Isfahan as the sample of this research. This study was done in 2009. STATISTICAL ANALYSIS USED: Data were analyzed by t-test using SPSS16. RESULTS: Nurses mean score of WM performance was 58.16 (12), and others was 58.56 (12.18) (of max 100). There was no significant difference between nurses and others mean score of WM performance according to t-test. There was not significant difference between WM performances of two studied groups in public and private hospitals based on t test. Comparing between two studied groups mean scores by waste minimization areas indicated that nurses have done significantly better in source reduction area and other staffs have acted better in waste segregation (P < 0.05). CONCLUSIONS: All of hospital staff specially, nurses have an important role in qualified waste management practice of hospitals. Totally mean score of WM performance in hospitals (nurses and other) was average. With regard to other countries activities, this result is disappointing. So, it is necessary to plan educational programs for hospital staff, especially nurses. PMID- 23922588 TI - The relationship between organizational trust and nurse administrators' productivity in hospitals. AB - CONTEXT: Management of health care organizations based on employee's mutual trust will increase the improvement in functions and tasks. AIMS: The present study was performed to investigate the relationship between organizational trust and the nurse administrators' productivity in educational health centers of in Health Education Centers of Isfahan University of Medical Sciences. SETTINGS AND DESIGN: This research was a descriptive and correlational study. MATERIALS AND METHODS: The population included all nurse administrators. In this research, 165 nurses were selected through random sampling method. Data collection instruments were organizational trust questionnaire based on Robbins's model and productivity questionnaire based on Hersy and Blanchard's model. Validity of these questionnaires was determined through content validity and their reliability was calculated through Cranach's alpha. Statistical analysis was used: The data analysis was done using the SPSS (18) statistical software. RESULTS: The indicators of organizational trust such as loyalty, competence, honesty, and stability were more than average level but explicitness indicator was at average level. The components of productivity such as ability, job knowledge, environmental compatibility, performance feedback, and validity were more than average level but motivation factor was at average level and organizational support was less than average level. There were a significant multiple correlations between organizational trust and productivity. Beta coefficients among organizational trust and productivity were significant and no autocorrelation existed and regression model was significant. CONCLUSIONS: Committed employees, timely performing the tasks and developing the sense of responsibility among employees can enhance production and productivity in the health care organizations. PMID- 23922589 TI - A study of relationship between the organizational justice and organizational citizenship behavior among nurses in selected hospitals of Isfahan University of Medical Sciences. AB - CONTEXT: Numerous researches have been carried out to indicate that organizational justice (OJ) is a variable that anticipates many other variables in organizations, especially in hospitals. Organizational behavior (OCB) is one of the most important variables. AIMS: We aimed to study the relationship between OJ and OCB of nurses in selected hospitals in Isfahan. MATERIALS AND METHODS: This was a descriptive correlational study. The research was conducted among nurses of selected hospitals in Isfahan. STATISTICAL ANALYSIS USED: Data were gathered using two questionnaires of OJ, and OCB. The t-test, chi-square, and Pearson correlation test were used to analyze the data through SPSS version 13. RESULTS: In general, the mean score (SD) of OJ among nurses was 41.2 (16.2) and the mean score of OCB was 57.7 (18). Finally, there was no significant relationship between OJ, civil virtue, and sportsmanship. There was a significant relationship between OJ, OCB, courtesy, and conscientiousness. CONCLUSION: As the scores of OCB and OJ among nurses were average in selected hospitals, the managers of the hospitals should improve the perception of justice among nurses. Today, organizations need efficient and expert workers to achieve their goals, and to grow and improve in all aspects. In fact, the efficiency and effectiveness of organizations depend on the staffs, especially in hospitals. PMID- 23922590 TI - Association of the folic acid consumption and its serum levels with preeclampsia in pregnant women. AB - BACKGROUND AND OBJECTIVES: Preeclampsia is one of the main causes of maternal and fetal mortality. Despite numerous studies, its etiology is unknown. Recently there has been attention towards Folic acid. This study examined the association of Folic acid consumption and its serum levels with Preeclampsia. MATERIALS AND METHODS: A case-control study conducted in Tabriz- Alzahra hospital. 52 preeclamptic women in 34-42 weeks and 52 normotensive pregnant women were studied from Jun to Nov 2009. Data was gathered through interview with the women and review of their medical records. Folic acid serum levels were measured by electrochemiluminescence method on Elecsys-2010 system using the Roche brand kit. Data were analyzed by t-test, chi-square, exact fisher and logistic regression. RESULTS: 46% of women in the case group and 71% in the control group regularly consumed Folic acid supplements before and during the first trimester of pregnancy. Frequency of correct pattern of Folic acid consumption in the case group were significantly lower than control group (P = 0.02). Findings about frequency of main food groups' consumption containing folic acid indicated that the only mean difference between two groups was in relation to fruits (P = 0.002). The mean of Folic Acid serum levels in preeclamptic group was significantly lower than non- preeclamptic group [10.9 (3.9) vs. 13.6 (4.0) ng/ml, P = 0.001]. CONCLUSION: it is recommended all health care providers educate clients especially high risk women about regular and timely consumption of supplements as well as food groups containing Folic acid specially fruits and its possible role in prevention of preeclampsia. PMID- 23922591 TI - Perceptions and practices of fasting in Ramadan during pregnancy in Pakistan. AB - BACKGROUND: Islam clearly exempts fasting in Ramadan during sickness, pregnancy, and breastfeeding. Yet, some women prefer to fast despite realizing their increase in nutritional demand during pregnancy. Nurses and other healthcare providers face a difficult task of providing appropriate medical advice to Muslim women regarding the safety and impact of their fasting. The present study was conducted to examine the concepts and practices of maternal fasting during pregnancy in Pakistani Muslim women. MATERIALS AND METHODS: A cross-sectional study was done in 2008 on 353 females from gynecology departments of hospitals in major cities of two provinces of Pakistan. Non-probability convenient sampling technique was used and a questionnaire was used to collect data from females who had experienced pregnancy during Ramadan at least once in life. Questions related to perceptions and practices of fasting in pregnancy along with demographic data were asked. Analysis was done on SPSS version 16. Chi-square test was used to assess associations and P < 0.05 was considered statistically significant. All ethical considerations were taken into account for the respondents. RESULTS: Out of the total, 309 (87.5%) fasted during their pregnancies while 43 (12.5%) did not fast at all. Among those who fasted, 42.5% (n = 150) fasted for the whole month, 23.8% (n = 84) fasted on alternate days, 10.5% (n = 37) fasted only on weekends/holidays, and 10.8% (n = 38) fasted on particular special days. The majority perceived no harm and risk caused by fasting to them or to fetus during pregnancy. Although adverse effects during fasting were frequently reported, only 24% break their fast. A significant association was found between gravida and education with fasting (P w< 0.05). A total of 88% of women believed that fasting during pregnancy (in good health) is "obligatory" while 12% thought otherwise. CONCLUSION: Pakistani Muslim women showed a strong compassion for fasting in pregnancy despite overall decrease in maternal health indicators. There is a need for nurses and other healthcare providers in all Muslim countries and especially in non-Muslim countries with cultural diversity to be fully aware of the effects of fasting in pregnancy so that they can act promptly ensuring safe and healthy delivery. PMID- 23922593 TI - Factors influencing attendance at structured self-management education programs for diabetes. AB - AIMS: There are several structured self-management education programs which are available nationally for patients with diabetes in the UK. This study was aimed to determine the factors influencing participation of patients with diabetes in the programs. PATIENTS AND METHODS: A cross-sectional survey through semi structured questionnaire distributed to 550 patients attending primary or secondary care diabetes services, as well to those in community venues, was conducted. The inclusion criteria were people >=18 years with diabetes diagnosed for 1 year or longer. RESULTS: There was a lack of awareness of the programs among the respondents. There were statistically significant differences between tendency to attend the programs with demographic variables, qualification, and self-efficacy. The results also indicated that an individual will be more likely to participate in the structured self-management education programs if she/he feels at risk of complications, that diabetes complications are serious, and believes that the programs may help to avoid these risks. CONCLUSIONS: This study indicated the nature of multidimensionality of the factors influencing participation in the programs. PMID- 23922592 TI - Concept analysis of professional commitment in Iranian nurses. AB - AIM: Professional commitment has been widely discussed during the last decade. There is no comprehensive definition about "professional commitment in Iranian nurses." Hence, this study was conducted with the aim of analyzing the concept of professional commitment in Iranian nurses. MATERIALS AND METHODS: Hybrid model was used in three phases. Firstly, in the theoretical phase, data were retrieved from the CINHAl, MEDLINE, PubMed, OVID, Google scholar, and SID databases. The literature search used the keywords "professional commitment" and "nursing." The final sample included 27 papers published in English between 2001 and 2011.Secondly, in the fieldwork phase, deep interviews with five clinical nurses were carried out, and thirdly, in the final analytical phase, the obtained data from theoretical and fieldwork phases were combined and a comprehensive analysis was conducted. RESULTS: Loyalty and tendency to remain in the profession and responsibility to the professional issues were extracted in theoretical phase. Commitment to promote caring abilities, satisfying of being a nurse, and belonging to the nursing profession were obtained in fieldwork phase. Finally, two main themes including "commitment to offering the best nursing care" and "commitment to promotion of the nursing profession" were extracted. CONCLUSION: Nursing is a humanistic profession; it has some particular characteristics due to the profession's nature. In this paper, a definition composed of two main dimensions of professional commitment in nursing has been introduced. PMID- 23922594 TI - Semantic divergence in clinical education: Student-centered or student democracy. AB - AIMS: Although several studies have confirmed the validity and the strength of the student-centered approach and most training centeres have put it as the heading of their agenda, there are still problems in the method of implementation, increasing the need for further research to review the mode of implementation. In this regard, the present study has been conducted to investigate students' and educators' perception in terms of interaction manner in clinical education process. SETTINGS AND DESIGN: This study was performed in a qualitative approach and by the conventional content analysis method. MATERIALS AND METHODS: Data were collected until saturation through use of individual semi structured interviews. Twenty-one subjects including undergraduate nursing students (8 cases), faculty member educators (9 cases), head nurses (3 cases), and educational supervisor (1 case) participated in the study, and the data were analyzed using MAXQDA3 software. RESULTS: "tudent democrac" was extracted through data analysis as the main theme of the study. Participants' experience in terms of the five sub-themes included instructor's loss of dignity, negligence in the evaluation of the students, poor discipline, lack of compliance with the educator, and lack of motivation. CONCLUSIONS: Instructor's weaknesses in planning, guiding, and evaluating the students led to student's interference in these affairs and a challenge in effective student-centered approach. Although excessive emphasis on students' opinion for educational evaluation is apparently a sign of tribute to the students, it ultimately contributes to ignoring the process of learning to attract students' interest, occupational devaluation, and a decrease in students' motivation. PMID- 23922596 TI - The association between following transportation standards of the burned patients referred to Imam Mosakazem Hospital and the caused early complications in 2011. AB - BACKGROUND AND GOAL: Burn is an irreparable event, which results in numerous physical, psychological, social, and economic complications. The burned patients should be merely treated in a professional burn center due to vast clinical range of these patients. Since, a percentage of mortality in burned patients is for the patients' transportation from other centers; this study has aimed to investigate the manner of their transportation to Imam Mosa Kazem Hospital. MATERIALS AND METHODS: This is a descriptive cross-sectional study on 98 subjects selected through sequential sampling from thermally burned patients being referred to Isfahan burn emergency center by ambulance from August 2011 to November 2011. The data including demographic information and event details, burned surface, burning grade and the province of origin were collected by a questionnaire, as well as a checklist related to caring team standards, transportation team, transportation equipment, and outcomes. The data were analyzed by descriptive statistical tests. RESULTS: Based on the findings, the longest transportation time was 6.35 (4.30) hours. There was no significant association between patients' O2intake and hypoxemia. There was no association between patients' hypothermia and cooling the burn in the patients at the event location. There was a significant association between intake of fluid within transportation and urine output and hypovolemia (P = 0.00). Most of the defects of treatment were related to the equipments and infection control devices. DISCUSSION: The findings showed that burned patients' transportation is so far from standards in Iran, and the authorities' should pay specific attention to that in form of vast national investigations. PMID- 23922595 TI - Iranian undergraduate nursing student perceptions of informal learning: A qualitative research. AB - BACKGROUND: Nursing education is both formal and informal. Formal education represents only a small part of all the learning involved; and many students learn more effectively through informal processes. There is little information about nursing student informal education and how it affects their character and practice. MATERIALS AND METHODS: This qualitative study explores undergraduate nursing student perceptions of informal learning during nursing studies. Data were gathered through semi-structured interviews with a sample of undergraduate nursing students (n = 14). Strauss and Corbin's constant comparison analysis approach was used for data analysis. RESULTS: The categories that emerged included personal maturity and emotional development, social development, closeness to God, alterations in value systems, and ethical and professional commitment. CONCLUSION: Findings reveal that nursing education could take advantage of informal learning opportunities to develop students' nontechnical skills and produce more competent students. Implications for nursing education are discussed. PMID- 23922597 TI - Nursing faculties' knowledge and attitude on evidence-based practice. AB - BACKGROUND: Evidence-based practice (EBP) is one of the main professional competencies for health care professionals and a priority for medicine and nursing curriculum as well. EBP leads to improve effective and efficient care and patient outcomes. Nurse educators have responsibility to teach the future nurses, and an opportunity to promote patient outcomes. Therefore, the aim of this study was to describe nurse educators' knowledge and attitude on EBP. MATERIALS AND METHODS: This was a descriptive study conducted in nursing faculties of two major universities of medical sciences affiliated to Ministry of Health and Medical Sciences in Tehran, Iran. Data were gathered using a three-section questionnaire. Content and face validity was further enhanced by submitting it to nursing research and education experts. Statistical analysis was carried out using SPSS 11 software. RESULTS: According the results, nursing faculties' knowledge of EBP was mainly moderate (47.1%). Significant statistical relationship was found between the level of knowledge with education and teaching experience in different nursing programs. Nurses generally held positive attitudes toward EBP (88.6%) and there was no statistical significant relationship with demographic variables. CONCLUSION: Nursing educators are in a position to influence nursing research in clinical practice in the future. Therefore, it is critical to achieve implementation of EBP and be a change agent for a paradigm shift toward EBP. PMID- 23922598 TI - Sleep quality among residents of an old folk's home in Malaysia. AB - BACKGROUND: Sleep is an essential part of life. Lack of sleep has been linked with increased morbidity and mortality. The objective of this study was to determine the sleep quality of older adults residing in a private elderly care institution in Malaysia. MATERIALS AND METHODS: This cross sectional study was conducted among consenting residents of a 200-bed non-governmental charity old folks home in Penang, Malaysia. The sleep quality of the respondents was measured using the Pittsburgh Sleep Quality Index (PSQI). Quality of life (WHOQOL-BREF), their attitude to ageing (AAQ), Barthel index (Activities of Daily Living) and body mass index were also measured. Data was analysed using PASW. RESULTS: The PSQI score ranged from 0 to 16 with a mean score of 7.1 (SD 3.4) and 76.8% (116) had scores >= 5. The differences in the mean score for chronic illness (t = 0.14/P = 0.04), the people that could be counted on for help (t = 4.09/P = 0.02) and the feasibility of getting practical help from fellow residents (t = 4.41/P = 0.01) were statistically significant. There was a negative correlation between the PSQI score and the WHOQOL-BREF score (-0.318/0.00) and AAQ score ( 0.332/0.00). CONCLUSIONS: Staff working in an elderly care institution should understand the important relationship of illnesses, social support and sleep hygiene in the wellbeing of the residents. PMID- 23922599 TI - Application of Burn's wean assessment program on the duration of mechanical ventilation among patients in intensive care units: A clinical trial. AB - BACKGROUND: Weaning decision for the patients on a mechanical ventilation (MV) device is often made based on personal judgments and experiences, which results in longer MV length of stay and higher costs. Therefore, the present study aimed to the effect of application of Burn's wean assessment program on MV length of stay among the patients hospitalized in intensive care units (ICUs). MATERIALS AND METHODS: This is a clinical trial in which 50 patients connected to mechanical ventilators for more than 48 h were selected through convenient sampling and were randomly divided into two groups of 25 subjects. Burn's wean assessment program was employed in study group, while weaning was assessed by a physician in control group. The findings were analyzed by descriptive (frequency distribution, mean and SD) and inferential (independent t-test, Chi-square, Fisher's exact test, and Mann Whitney) statistical tests. RESULTS: The findings showed that length of MV was 134.2 (20.5) h which was significantly less than the control (P = 0.03). CONCLUSION: The results showed that application of Burn's wean assessment by the nurses to assess patients' readiness for weaning from the ventilator is a safe method in day time and shortens the length of MV in ICUs compared to the routine methods. PMID- 23922600 TI - Prevalence of professional burnout and its related factors among nurses in Tabriz in 2010. AB - INTRODUCTION: Burnout is a syndrome containing three dimensions of emotional exhaustion, depersonalization, and reduction of personal accomplishment. Nurses are exposed to professional burnout (PB) due to their exposure to physical, mental, and emotional stressors, which can lead to numerous complications in their personal, social, and organizational life. This study aimed to define the prevalence of PB amongst nurses working in hospitals in Tabriz and to detect its related effective factors in 2010. MATERIALS AND METHODS: This is a cross sectional analytical study conducted on all selected nurses working in hospitals in Tabriz. The questionnaires were filled and returned by 712 subjects after taking their consent. The data were collected by a questionnaire including questions on demographic characteristics and Maslach Burnout Inventory (MBI). Independent t-test was employed to compare mean quantitative variables in two groups of individuals with and without PB. Chi-square test was also adopted to compare the prevalence of PB in levels of qualitative variables. Logistic regression test was employed for multiple analyses of PB related factors. In this analysis, variables in level of 0.2 which had an association with PB as a single variable were entered to the model. RESULTS: Among the nurses taking part in the study, 156 (21.9%, CI 95%: 19.0-25.1) suffered from PB based on its definition. The risk of burnout is increased by 1.12-folds for each overwork night shift. Higher education increases professional burnout by 3.17-folds. CONCLUSION: The prevalence of burnout among nurses in Tabriz was revealed. Night shift and education level were shown to have an association with professional burnout. PMID- 23922601 TI - A comparison between the effects of simple and traction splints on pain intensity in patients with femur fractures. AB - BACKGROUND: Fractures of femur are among the most important causes of mortality in musculoskeletal injuries. Owning to lack of adequate research to compare various techniques of fracture stabilization, there has not yet been an agreement over a protocol to utilize a specific type of splint for femoral fracture immobilization. This study was thus conducted to compare the effects of simple and traction splints on pain intensityimmediately after and at the 1(st), 6(th), and 12(th)h after splinting among patients with femur fracture in the centers affiliated to Isfahan University of Medical Sciences (Isfahan, Iran). MATERIALS AND METHODS: This quasi-experimental study was performed on 32 patients with femur fractures. Prehospital emergency ambulances were divided into two groups of simple and traction splints using a table of random numbers. Continuous convenient sampling was employed in each group to use either a simple or a traction splint for the patients with femur fractures. Pain intensity of the patients was then measured by a visual analogue scale (VAS) immediately, 1 h, 6 h, and 12 h after splinting. The effects of the two techniques were finally compared. RESULTS: After splinting, pain intensity decreased significantly in both groups (P = 0.0001 in both groups). The reductions were significantly more in the traction splint group at the 1(st), 6(th)(P = 0.0001), and 12(th)h after splinting (P = 0.02) compared with the simple splint group. There was no significant difference in pain intensity immediately after splintingbetween the two groups (P = 0.441). CONCLUSION: The significant difference in pain reduction between the simple and traction splint groups at the 1(st), 6(th), and 12(th)h after splinting emphasizes the superiority of traction splints. PMID- 23922602 TI - Mental illness stigma among nurses in psychiatric wards of teaching hospitals in the north-west of Iran. AB - BACKGROUND: Stigma is one of the obstacles in the treatment and regaining the mental health of people with mental illness. The aim was determination of mental illness stigma among nurses in psychiatric wards. This study was conducted in psychiatric wards of teaching hospitals in Tabriz, Urmia, and Ardabil in the north-west of Iran. MATERIALS AND METHODS: This research is a descriptive analysis study in which 80 nurses participated. A researcher-made questionnaire was used, which measured demographic characteristics and mental illness stigma in the three components of cognitive, emotional, and behavioral. All data were analyzed using SPSS13 software and descriptive and analytical statistics. RESULTS: Majority of nurses (72.5%) had medium level of stigma toward people with mental illness. About half of them (48.8%) had great inclination toward the social isolation of patients. The majority of them (62.5%) had positive emotional responses and 27.5% had stereotypical views. There was a significant correlation between experience of living with and kinship of nurses to person with mental illness, with prejudice toward and discrimination of patients. There was also a significant correlation between interest in the continuation of work in the psychiatric ward and prejudice, and also between educational degree and stereotypical views. CONCLUSIONS: The data suggest there is a close correlation between the personal experience of nurses and existence of mental illness stigma among them. Therefore, the implementation of constant educational programs on mental illness for nurses and opportunities for them to have direct contact with treated patients is suggested. PMID- 23922605 TI - Efficacy of life skills training on general health in students. AB - BACKGROUND: With regard to the importance of life skills, the present study deals with the effect of life skills training on general health of the students. MATERIALS AND METHODS: This was a one-group, pre-test, post-test, quasi experimental research. Forty students were selected through purposive sampling method. The data collection tool was Goldberg General Health Questionnaire. RESULTS: Paired t-test showed a 22 score significant decrease in general health after education compared to before education (P < 0.01). CONCLUSION: This study showed that life skills education increases general health level of the students. PMID- 23922604 TI - Effect of phase III cardiac rehabilitation and relaxation on the quality of life in patients with cardiac syndrome X. AB - BACKGROUND: Cardiac syndrome X is a relatively common disorder, and still not much is known about the causative factors or its pathophysiology, which makes it difficult to cure. Due to its chronic nature and debilitating symptoms, many patients have significantly reduced quality of life (QOL).The purpose of this study was to assess the impact of phase III cardiac rehabilitation (CR) and relaxation on the QOL of patients. MATERIALS AND METHODS: This research is a randomized clinical trial study. Forty eligible and consenting women (age 30-65 years) were randomly assigned to four groups. In the first group (n = 11), progressive muscle relaxation (PMR); in the second group (n = 11), phase III CR; and in the third group (n = 11), PMR along with phase III CR were performed for 8 weeks at home. The fourth group (n = 7) was used as the control group. Short form of QOL questionnaire (SF-36) was used for data gathering. Data analysis was performed using chi(2), Kruskal-Wallis, and rank sum difference tests. RESULTS: After phase III CR, relaxation, and combination of CR and relaxation, patients demonstrated improved QOL (P < 0.001). The results of post-test multiple comparisons showed that there were statistically significant differences between control and all intervention groups (P < 0.05). There was also statistically significant difference between relaxation and combination of phase III CR and relaxation groups (P < 0.5). CONCLUSIONS: An 8-week phase III CR program together with relaxation improved QOL of patients with cardiac syndrome X. We suggest phase III CR program together with relaxation as an effective treatment in these patients. PMID- 23922603 TI - Female adolescents' experiences and perceptions regarding sexual health education in Iranian schools: A qualitative content analysis. AB - BACKGROUND: Despite so many unmet sexual health education (SHE) needs of adolescents, socio-cultural challenges have caused this issue to be ignored in different scoieties. This study investigated Iranian female adolescents' experiences and perceptions with respect to SHE that they received at schools, and what they really needed, expected, and preferred. MATERIALS AND METHODS: In this qualitative study, seven focus group discussions (44 adolescents) and 13 individual in-depth interviews were conducted among female adolescents aged 14-18 in Mashhad and Ahvaz, Iran, to explore adolescents' experiences and perceptions towards SHE in Iranian schools. Data were analyzed using qualitative content analysis. RESULTS: Analyzing adolescents' perspectives and experiences revealed their great dissatisfaction with SHE in schools. Emerged categories included: lack of obligation and priority for SHE, sexual reticence and evading, making adolescents frightened of sexual issues, inconsistency of SHE with adolescents' needs, unqualified educators, and lack of appropriate educational materials. CONCLUSION: This study found some similarities between expectations of Iranian adolescents and those of adolescents from other cultures about an SHE program. Adolescents showed great abilities to appraise health services delivered for them, and so any program for sexual health promotion in adolescents ought to address adolescents' needs, demands, and aspirations. Their contribution can provide insights for tailoring SHE programs for adolescents. PMID- 23922606 TI - The philosophy of evidence-based clinical practice: Is evidence enough? PMID- 23922608 TI - Role of gender in the survival of surgical patients with nonsmall cell lung cancer. AB - PURPOSE: There are reports of greater survival rates in nonsmall cell lung cancer (NSCLC) patients of female gender. The objective of this study was to evaluate the role of gender in survival of NSCLC patients treated surgically with curative intent (stage I/II). METHODS: In a retrospective cohort design, we screened 498 NSCLC patients submitted to thoracotomies at the hospital Sgammao Lucas, in Porto Alegre, Brazil from 1990 to 2009. After exclusion of patients that did not fit to all the inclusion criteria, we analyzed survival rates of 385 subjects. Survival was analyzed using the Kaplan-Meier method. The Cox regression model was used to evaluate potential confounding factors. RESULTS: Survival rates at 5 and 10 years were 65.3% and 49.5% for women and 46.5% and 33.2% for men, respectively (P = 0.006). Considering only stage I patients, the survival rates at 5 and 10 years were 76.2% and 55.1% for women and 50.7% and 35.4% for men, respectively (P = 0.011). No significant differences in survival rates were found among stage II patients. CONCLUSIONS: Our results show female gender as a possible protective factor for better survival of stage I NSCLC patients, but not among stage II patients. This study adds data to the knowledge that combined both genders survival rates for NSCLC is not an adequate prognosis. PMID- 23922607 TI - Extracorporeal life support for acute respiratory distress syndromes. AB - The morbidity and mortality of acute respiratory distress syndrome remain to be high. Over the last 50 years, the clinical management of these patients has undergone vast changes. Significant improvement in the care of these patients involves the development of mechanical ventilation strategies, but the benefits of these strategies remain controversial. With a growing trend of extracorporeal support for critically ill patients, we provide a historical review of extracorporeal membrane oxygenation (ECMO) including its failures and successes as well as discussing extracorporeal devices now available or nearly accessible while examining current clinical indications and trends of ECMO in respiratory failure. PMID- 23922609 TI - Tuberculosis incidence trends in Saudi Arabia over 20 years: 1991-2010. AB - OBJECTIVE: To evaluate tuberculosis (TB) incidence rates and trends over a period of 20 years (1991-2010) and assess the impact of the National TB Control Program (NTP) on incidence trends. METHODS: This is a retrospective study of TB surveillance data reported by the Ministry of Health. We evaluated TB incidence data by nationality, age, and region of the country and assessed incidence trends over 20 years of study. Chi-squared test was used to assess trend change and its significance. RESULTS: There were a total of 64,345 reported TB cases over the study period. Of these 48% were Non-Saudis. TB annual incidence rate ranged between 14 and 17/100,000. For Saudis, the rate ranged between 8.6 and 12.2/100,000. Non-Saudis had 2-3 times higher incidence. Disease trend was rising over the first 10 years of the study period then it started to fall slightly. The incidence increased with age, but only people older than 45 years showed a declining trend. Regional variations were observed. Makkah and Jazan regions had the highest incidence rates. Disease trends were rising over the last 10 years in Makkah and Central regions. CONCLUSION: TB control seems to be facing some challenges in several regions of the Kingdom. NTP needs to evaluate and improve TB control strategies in order to reduce disease incidence to elimination levels. PMID- 23922610 TI - Association of bronchoalveolar lavage yield with chest computed tomography findings and symptoms in immunocompromised patients. AB - INTRODUCTION: Fiber-optic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) is a common procedure performed in immunocompromised patients with undiagnosed pulmonary pathology. Identifying patients with the highest potential diagnostic yield may help to avoid morbidity in patients unlikely to benefit from the procedure. We sought to determine which patient factors, specifically chest computed tomography (CT) findings, affected diagnostic yield of BAL. METHODS: Retrospective chart review of immunocompromised patients who underwent FOB with BAL from 01/01/2010 to 12/31/2011 at an academic medical center was performed. The lung lobe lavaged, characteristics of pulmonary infiltrate on radiograph, patient symptoms, and diagnostic yield were collected. A positive diagnostic yield was defined as a positive microbiological culture, finding on cytopathologic staining, diffuse alveolar hemorrhage, alveolar eosinophilia or a positive immunologic or nucleic acid assay. RESULTS: The overall diagnostic yield was 52.6%. Infiltrates that were predominantly reticular or nodular by CT had a lower diagnostic yield than predominantly consolidated, ground-glass, or tree-in bud infiltrates (36.5% vs. 61.2%, P = 0.0058). The diagnostic yield was significantly improved in patients with both fever and chest symptoms compared to patients without symptoms (61.3% vs. 29.6%, P = 0.0066). CONCLUSION: CT findings of reticular and nodular infiltrates portend a worse diagnostic yield from BAL than those that are alveolar in nature. Symptomatic patients are more likely to have diagnostic FOB with BAL than asymptomatic patients. PMID- 23922611 TI - Surgical approach and outcomes for treatment of pulmonary metastases. AB - AIMS: To investigate the surgical approach and outcomes, as well as prognostic factors for pulmonary metastasectomy. METHODS: Clinical data of 201 patients treated by pulmonary metastasectomy between January 1990 and December 2009 were retrospectively reviewed. One hundred thirty three patients were received an approach of thoracotomy while 68 with video-assisted thoracoscopic surgery (VATS). There were 54 lobectomies, 139 wedge resections and 8 pneumonectomies. Hilar or mediastinal lymph nodes dissection or sampling was carried out in 38 patients with lobectomy. The Kaplan-Meier method was used for the survival analysis. Cox proportional hazards model was used for multivariate analysis. RESULTS: The 5 years survival rate of patients after metastasectomy was 50.5%, and the median survival time was 65.9 months. The median survival time of patients with hilar or mediastinal lymph nodes metastasis was 23 months. By univariate analysis, significant prognostic factors included disease-free interval (DFI), number of metastases, number of affected lobe, surgical approach (open vs. VATS) and pathology types. DFI, number of metastases, and pathology types were revealed by Cox multivariate analysis as independent prognostic factors. CONCLUSION: Surgical resection of pulmonary metastases is safe and effective. Palpation of the lung is still seen as necessary to detect the occult nodule. More accurate and sensitive pre-operative mediastinal staging are required. PMID- 23922612 TI - Knowledge of thromboprophylaxis guidelines pre- and post-didactic lectures during a venous thromboembolism awareness day at a tertiary-care hospital. AB - BACKGROUND: Didactic lectures are frequently used to improve compliance with practice guidelines. This study assessed the knowledge of health-care providers (HCPs) at a tertiary-care hospital of its evidence-based thromboprophylaxis guidelines and the impact of didactic lectures on their knowledge. METHODS: The hospital launched a multifaceted approach to improve thromboprophylaxis practices, which included posters, a pocket-size guidelines summary and didactic lectures during the annual thromboprophylaxis awareness days. A self-administered questionnaire was distributed to HCPs before and after lectures on thromboprophylaxis guidelines (June 2010). The questionnaire, formulated and validated by two physicians, two nurses and a clinical pharmacist, covered various subjects such as risk stratification, anticoagulant dosing and the choice of anticoagulants in specific clinical situations. RESULTS: Seventy-two and 63 HCPs submitted the pre- and post-test, respectively (62% physicians, 28% nurses, from different clinical disciplines). The mean scores were 7.8 +/- 2.1 (median = 8.0, range = 2-12, maximum possible score = 15) for the pre-test and 8.4 +/- 1.8 for the post-test, P = 0.053. There was no significant difference in the pre-test scores of nurses and physicians (7.9 +/- 1.7 and 8.2 +/- 2.4, respectively, P = 0.67). For the 35 HCPs who completed the pre- and post-tests, their scores were 7.7 +/- 1.7 and 8.8 +/- 1.6, respectively, P = 0.003. Knowledge of appropriate anticoagulant administration in specific clinical situations was frequently inadequate, with approximately two-thirds of participants failing to adjust low molecular-weight heparin doses in patients with renal failure. CONCLUSIONS: Education via didactic lectures resulted in a modest improvement of HCPs' knowledge of thromboprophylaxis guidelines. This supports the need for a multifaceted approach to improve the awareness and implementation of thromboprophylaxis guidelines. PMID- 23922614 TI - Pneumothorax, music and balloons: A case series. AB - We describe two cases of spontaneous pneumothorax in young healthy adults with no underlying structural lung disease. The onset of pneumothorax was following physical activity including playing musical instruments and blowing of balloons. There is sparse data evaluating the pathophysiology of primary spontaneous pneumothorax in relation to increased mouth pressures. These cases highlight the possible physical effect of valsalva manoeuvre on transpulmonary pressures, and the potential risk of developing pneumothorax in otherwise healthy individuals. This aspect of pneumothorax development is worthy of further exploration, to better elucidate the mechanism and enhance our understanding of this common respiratory presentation. PMID- 23922613 TI - Feasibility and long-term efficacy of video-assisted thoracic surgery for unexpected pathologic N2 disease in non-small cell lung cancer. AB - OBJECTIVES: This study compares early and late outcomes for treatment by video assisted thoracic surgery (VATS) versus treatment by thoracotomy for clinical N0, but post-operatively unexpected, pathologic N2 disease (cN0-pN2). METHODS: Clinical records of patients with unexpected N2 non-small cell lung cancer (NSCLC) who underwent VATS were retrospectively reviewed, and their early and late outcomes were compared to those of patients undergoing conventional thoracotomy during the same period. RESULTS: VATS lobectomy took a longer time than thoracotomy (P < 0.001), but removal of thoracic drainage and patient discharge were earlier for patients in the VATS group (P < 0.001). There was no difference in lymph node dissection, mortality and morbidity between the two groups (P > 0.05). The median follow-up time for 287 patients (89.7%) was 37.0 months (range: 7.0-69.0). The VATS group had a longer survival time than for the thoracotomy group (median 49.0 months vs. 31.7 months, P < 0.001). The increased survival time of the VATS group was due to patients with a single station of N2 metastasis (P = 0.001), rather than to patients with multiple stations of N2 metastasis (P = 0.225). CONCLUSIONS: It is both feasible and safe to perform VATS lobectomy on patients with unexpected N2 NSCLC. VATS provides better survival rates for those patients with just one station of metastatic mediastinal lymph nodes. PMID- 23922615 TI - Gastrobronchial fistula a rare complication post laparoscopic sleeve gastrectomy. AB - Gastrobronchial fistula is a rare but serious complication of laparoscopic sleeve gastrectomy with significant morbidity and mortality. We present the case of a 30 year-old man who underwent laparoscopic sleeve gastrectomy for morbid obesity and presented later with a history of chronic productive cough. Upper gastrointestinal series showed the presence of a communicating fistula between the stomach and the left lung bronchial tree. PMID- 23922616 TI - Measuring the quality of life of people with dementia in nursing homes in Germany - the study protocol for the Qol-Dem Project. AB - BACKGROUND: QUALIDEM is a standardized dementia-specific quality of life (Qol) measurement, which was developed and validated in the Netherlands. A German version has been available since 2008. This study protocol describes the design and methodology for the quality of life of people with dementia (Qol-Dem) project. OBJECTIVE: This project aims to evaluate the reliability and validity of the German version of the QUALIDEM. METHOD: Due to the lack of both a universal definition of Qol and of standards to verify the validity of Qol measurements, this study is divided into three phases. The aim of the first theoretical phase is the development of a dementia-specific Qol model as a result of a meta synthesis of qualitative studies. The second empirical phase consists of the three following steps: (a) an investigation of the scalability and internal consistency of the measure, (b) an evaluation of the interrater and intrarater reliability, and (c) an extensive evaluation of the validity of the QUALIDEM. The resulting Qol model (phase 1) will be used for the selection of appropriate comparators for validity testing. In the third phase, the QUALIDEM will be adapted, if necessary, based on the knowledge generated in the first two phases. CONCLUSION: The findings of the Qol-Dem project should deliver an accurate assessment of the psychometric properties of the German version of the QUALIDEM. The results will contribute to the further development of the instrument. Furthermore, the results will contribute to the theoretical development of the concept of Qol among people with dementia. PMID- 23922617 TI - The German Pain Catastrophizing Scale for Children (PCS-C) - psychometric analysis and evaluation of the construct. AB - OBJECTIVE: The Pain Catastrophizing Scale, adapted for children (PCS-C) by Crombez et al. (2003), was translated into German (SKS-D) and evaluated regarding its factorial structure, its reliability and validity. The association of catastrophizing with various pain characteristics and disability measures was examined as well as its association to neighboring constructs. METHOD: The paper and-pencil version of the SKS-D was used in two different samples of children and adolescents. Analyses were conducted on a subgroup of participants from an epidemiological sample [n=898; age: M=12.9 (SD=1.4)] who had experienced monthly headaches in the 6-months period before and a clinical sample [n=60; age: M=12.6 (SD=0.8)] seeking treatment for recurrent headaches. RESULTS: Exploratory factor analysis (PCA) suggested a one-factor model in contrast to the 3-factor model suggested by Crombez et al. (2003). The unidimensional scale showed distinct homogeneity and satisfying reliability. The clinical sample showed significantly higher scores than the epidemiological group. Also girls scored higher than boys. The catastrophizing explained a considerable amount of variance in pain and disability parameters in both samples thus underlining its validity. The psychological variables internalising, anxiety sensitivity and somatosensory amplification showed significant small to moderate associations with pain catastrophizing and also with pain and disability. After controlling for the above mentioned psychological variables, catastrophizing still yielded an independent contribution to the explanation of variance in pain and disability parameters. CONCLUSIONS: The PCS-C in its German form is a valid and reliable instrument for assessing catastrophizing in children with recurrent pain, in particular headache, in the age of 10-16 years. Pain catastrophizing is suggested to be assessed especially in pediatric pain patients as it is a significant moderator of pain and disability. In children with a distinct tendency to catastrophize cognitive restructuring should become a target of pediatric pain therapy, as a reduction of catastrophizing cognitions may indirectly help to ameliorate pain and disability. PMID- 23922633 TI - Cytolethal distending toxin in isolates of Aggregatibacter actinomycetemcomitans from Ghanaian adolescents and association with serotype and disease progression. AB - BACKGROUND AND OBJECTIVES: The cytolethal distending toxin (Cdt) is a highly conserved exotoxin that are produced by a number of Gram negative bacteria, including Aggregatibacter actinomycetemcomitans, and affects mammalian cells by inhibiting cell division and causing apoptosis. A complete cdt-operon is present in the majority of A. actinomycetemcomitans, but the proportion of isolates that lack cdt-encoding genes (A, B and C) varies according to the population studied. The objectives of this study were to examine serotype, Cdt-genotype, and Cdt activity in isolates of A. actinomycetemcomitans collected from an adolescent West African population and to examine the association between the carrier status of A. actinomycetemcomitans and the progression of attachment loss (AL). MATERIALS AND METHODS: A total of 249 A. actinomycetemcomitans isolates from 200 Ghanaian adolescents were examined for serotype and cdt-genotype by PCR. The activity of the Cdt-toxin was examined by DNA-staining of exposed cultured cells and documented with flow cytometry. The periodontal status of the participants was examined at baseline and at a two-year follow-up. RESULTS: Presence of all three cdt-encoding genes was detected in 79% of the examined A. actinomycetemcomitans isolates. All these isolates showed a substantial Cdt activity. The two different cdt-genotypes (with and without presence of all three cdt-encoding genes) showed a serotype-dependent distribution pattern. Presence of A. actinomycetemcomitans was significantly associated with progression of AL (OR = 5.126; 95% CI = [2.994-8.779], p<0.001). CONCLUSION: A. actinomycetemcomitans isolated from the Ghanaian adolescents showed a distribution of serotype and cdt genotype in line with results based on other previously studied populations. Presence of A. actinomycetemcomitans was significantly associated with disease progression, in particular the b serotype, whereas the association with disease progression was not particularly related to cdt-genotype, and Cdt-activity. PMID- 23922634 TI - An RGD-modified MRI-visible polymeric vector for targeted siRNA delivery to hepatocellular carcinoma in nude mice. AB - RNA interference (RNAi) has significant therapeutic promise for the genetic treatment of hepatocellular carcinoma (HCC). Targeted vectors are able to deliver small interfering RNA (siRNA) into HCC cells with high transfection efficiency and stability. The tripeptide arginine glycine aspartic acid (RGD)-modified non viral vector, polyethylene glycol-grafted polyethylenimine functionalized with superparamagnetic iron oxide nanoparticles (RGD-PEG-g-PEI-SPION), was constructed as a magnetic resonance imaging (MRI)-visible nanocarrier for the delivery of Survivin siRNA targeting the human HCC cell line Bel-7402. The biophysical characterization of the RGD-PEG-g-PEI-SPION was performed. The RGD-modified complexes exhibited a higher transfection efficiency in transferring Survivin siRNA into Bel-7402 cells compared with a non-targeted delivery system, which resulted in more significant gene suppression at both the Survivin mRNA and protein expression levels. Then, the level of caspase-3 activation was significantly elevated, and a remarkable level of tumor cell apoptosis was induced. As a result, the tumor growth in the nude mice Bel-7402 hepatoma model was significantly inhibited. The targeting ability of the RGD-PEG-g-PEI-SPION was successfully imaged by MRI scans performed in vitro and in vivo. Our results strongly indicated that the RGD-PEG-g-PEI-SPION can potentially be used as a targeted non-viral vector for altering gene expression in the treatment of hepatocellular carcinoma and for detecting the tumor in vivo as an effective MRI probe. PMID- 23922635 TI - Context-dependent competition in a model gut bacterial community. AB - Understanding the ecological processes that generate complex community structures may provide insight into the establishment and maintenance of a normal microbial community in the human gastrointestinal tract, yet very little is known about how biotic interactions influence community dynamics in this system. Here, we use natural strains of Escherichia coli and a simplified model microbiota to demonstrate that the colonization process on the strain level can be context dependent, in the sense that the outcome of intra-specific competition may be determined by the composition of the background community. These results are consistent with previous models for competition between organisms where one competitor has adapted to low resource environments whereas the other is optimized for rapid reproduction when resources are abundant. The genomic profiles of E. coli strains representing these differing ecological strategies provide clues for deciphering the genetic underpinnings of niche adaptation within a single species. Our findings extend the role of ecological theory in understanding microbial systems and the conceptual toolbox for describing microbial community dynamics. There are few, if any, concrete examples of context dependent competition on a single trophic level. However, this phenomenon can have potentially dramatic effects on which bacteria will successfully establish and persist in the gastrointestinal system, and the principle should be equally applicable to other microbial ecosystems. PMID- 23922636 TI - Study on citrus response to huanglongbing highlights a down-regulation of defense related proteins in lemon plants upon 'Ca. Liberibacter asiaticus' infection. AB - Citrus huanglongbing (HLB) is a highly destructive disease of citrus presumably caused by 'Candidatus Liberibacterasiaticus' (Las), a gram-negative, insect transmitted, phloem-limited alpha-proteobacterium. Although almost all citrus plants are susceptible to HLB, reports have shown reduced susceptibility to Las infection in lemon (Citrus limon) plants. The aim of this study is to identify intra-species specific molecular mechanisms associated with Las-induced responses in lemon plants. To achieve this, comparative 2-DE and mass spectrometry, in addition to Inductively Coupled Plasma Spectroscopy (ICPS) analyses, were applied to investigate differences in protein accumulation and the concentrations of cationic elements in leaves of healthy and Las-infected lemon plants. Results showed a differential accumulation of 27 proteins, including an increase in accumulation of starch synthase but decrease in the production of photosynthesis related proteins in Las-infected lemon plants compared to healthy plants. Furthermore, there was a 6% increase (P > 0.05) in K concentration in leaves of lemon plants upon Las infection, which support results from previous studies and might represent a common response pattern of citrus plants to Las infection. Interestingly, contrary to reports from prior studies, this study showed a general reduction in the production of defense-related pathogen-response proteins but a 128% increase in Zn concentration in lemon plants in response to Las infection. Taken together, this study sheds light on general and intra-species specific responses associated with the response of citrus plants to Las. PMID- 23922637 TI - Abnormal contextual modulation of visual contour detection in patients with schizophrenia. AB - Schizophrenia patients demonstrate perceptual deficits consistent with broad dysfunction in visual context processing. These include poor integration of segments forming visual contours, and reduced visual contrast effects (e.g. weaker orientation-dependent surround suppression, ODSS). Background image context can influence contour perception, as stimuli near the contour affect detection accuracy. Because of ODSS, this contextual modulation depends on the relative orientation between the contour and flanking elements, with parallel flankers impairing contour perception. However in schizophrenia, the impact of abnormal ODSS during contour perception is not clear. It is also unknown whether deficient contour perception marks genetic liability for schizophrenia, or is strictly associated with clinical expression of this disorder. We examined contour detection in 25 adults with schizophrenia, 13 unaffected first-degree biological relatives of schizophrenia patients, and 28 healthy controls. Subjects performed a psychophysics experiment designed to quantify the effect of flanker orientation during contour detection. Overall, patients with schizophrenia showed poorer contour detection performance than relatives or controls. Parallel flankers suppressed and orthogonal flankers enhanced contour detection performance for all groups, but parallel suppression was relatively weaker for schizophrenia patients than healthy controls. Relatives of patients showed equivalent performance with controls. Computational modeling suggested that abnormal contextual modulation in schizophrenia may be explained by suppression that is more broadly tuned for orientation. Abnormal flanker suppression in schizophrenia is consistent with weaker ODSS and/or broader orientation tuning. This work provides the first evidence that such perceptual abnormalities may not be associated with a genetic liability for schizophrenia. PMID- 23922638 TI - The caudate signals bad reputation during trust decisions. AB - The ability to initiate and sustain trust is critical to health and well-being. Willingness to trust is in part determined by the reputation of the putative trustee, gained via direct interactions or indirectly through word of mouth. Few studies have examined how the reputation of others is instantiated in the brain during trust decisions. Here we use an event-related functional MRI (fMRI) design to examine what neural signals correspond to experimentally manipulated reputations acquired in direct interactions during trust decisions. We hypothesized that the caudate (dorsal striatum) and putamen (ventral striatum) and amygdala would signal differential reputations during decision-making. Twenty nine healthy adults underwent fMRI scanning while completing an iterated Trust Game as trusters with three fictive trustee partners who had different tendencies to reciprocate (i.e., likelihood of rewarding the truster), which were learned over multiple exchanges with real-time feedback. We show that the caudate (both left and right) signals reputation during trust decisions, such that caudate is more active to partners with two types of "bad" reputations, either indifferent partners (who reciprocate 50% of the time) or unfair partners (who reciprocate 25% of the time), than to those with "good" reputations (who reciprocate 75% of the time). Further, individual differences in caudate activity related to biases in trusting behavior in the most uncertain situation, i.e. when facing an indifferent partner. We also report on other areas that were activated by reputation at p < 0.05 whole brain corrected. Our findings suggest that the caudate is involved in signaling and integrating reputations gained through experience into trust decisions, demonstrating a neural basis for this key social process. PMID- 23922644 TI - Cortisol patterns are associated with T cell activation in HIV. AB - OBJECTIVE: The level of T cell activation in untreated HIV disease is strongly and independently associated with risk of immunologic and clinical progression. The factors that influence the level of activation, however, are not fully defined. Since endogenous glucocorticoids are important in regulating inflammation, we sought to determine whether less optimal diurnal cortisol patterns are associated with greater T cell activation. METHODS: We studied 128 HIV-infected adults who were not on treatment and had a CD4(+) T cell count above 250 cells/ul. We assessed T cell activation by CD38 expression using flow cytometry, and diurnal cortisol was assessed with salivary measurements. RESULTS: Lower waking cortisol levels correlated with greater T cell immune activation, measured by CD38 mean fluorescent intensity, on CD4(+) T cells (r = -0.26, p = 0.006). Participants with lower waking cortisol also showed a trend toward greater activation on CD8(+) T cells (r = -0.17, p = 0.08). A greater diurnal decline in cortisol, usually considered a healthy pattern, correlated with less CD4(+) (r = 0.24, p = 0.018) and CD8(+) (r = 0.24, p = 0.017) activation. CONCLUSIONS: These data suggest that the hypothalamic-pituitary-adrenal (HPA) axis contributes to the regulation of T cell activation in HIV. This may represent an important pathway through which psychological states and the HPA axis influence progression of HIV. PMID- 23922645 TI - New methods for assessing the fascinating nature of nature experiences. AB - In recent years, numerous environmental psychology studies have demonstrated that contact with nature as opposed to urban settings can improve an individual's mood, can lead to increased levels of vitality, and can offer an opportunity to recover from stress. According to Attention Restoration Theory (ART) the restorative potential of natural environments is situated in the fact that nature can replenish depleted attentional resources. This replenishment takes place, in part, because nature is deemed to be a source of fascination, with fascination being described as having an "attentional", an "affective" and an "effort" dimension. However, the claim that fascination with nature involves these three dimensions is to a large extent based on intuition or derived from introspection based measurement methods, such as self-reports. In three studies, we aimed to more objectively assess whether these three dimensions indeed applied to experiences related to natural environments, before any (attentional) depletion has taken place. The instruments that were used were: (a) the affect misattribution procedure (Study 1), (b) the dot probe paradigm (Study 2) and (c) a cognitively effortful task (Study 3). These instrument were respectively aimed at verifying the affective, attentional and effort dimension of fascination. Overall, the results provide objective evidence for the claims made within the ART framework, that natural as opposed to urban settings are affectively positive (cfr., affective dimension) and that people have an attentional bias to natural (rather than urban) environments (cfr., attentional dimension). The results regarding the effort dimension are less straightforward, and suggest that this dimension only becomes important in sufficiently difficult cognitive tasks. PMID- 23922646 TI - Peripheral reduction of FGFR4 with antisense oligonucleotides increases metabolic rate and lowers adiposity in diet-induced obese mice. AB - Obesity is a primary risk factor for multiple metabolic disorders. Many drugs for the treatment of obesity, which mainly act through CNS as appetite suppressants, have failed during development or been removed from the market due to unacceptable adverse effects. Thus, there are very few efficacious drugs available and remains a great unmet medical need for anti-obesity drugs that increase energy expenditure by acting on peripheral tissues without severe side effects. Here, we report a novel approach involving antisense inhibition of fibroblast growth factor receptor 4 (FGFR4) in peripheral tissues. Treatment of diet-induce obese (DIO) mice with FGFR4 antisense oligonucleotides (ASO) specifically reduced liver FGFR4 expression that not only resulted in decrease in body weight (BW) and adiposity in free-feeding conditions, but also lowered BW and adiposity under caloric restriction. In addition, combination treatment with FGFR4 ASO and rimonabant showed additive reduction in BW and adiposity. FGFR4 ASO treatment increased basal metabolic rate during free-feeding conditions and, more importantly, prevented adaptive decreases of metabolic rate induced by caloric restriction. The treatment increased fatty acid oxidation while decreased lipogenesis in both liver and fat. Mechanistic studies indicated that anti obesity effect of FGFR4 ASO was mediated at least in part through an induction of plasma FGF15 level resulted from reduction of hepatic FGFR4 expression. The anti obesity effect was accompanied by improvement in plasma glycemia, whole body insulin sensitivity, plasma lipid levels and liver steatosis. Therefore, FGFR4 could be a potential novel target and antisense reduction of hepatic FGFR4 expression could be an efficacious therapy as an adjunct to diet restriction or to an appetite suppressant for the treatment of obesity and related metabolic disorders. PMID- 23922647 TI - Optimizing nasal potential difference analysis for CFTR modulator development: assessment of ivacaftor in CF subjects with the G551D-CFTR mutation. AB - Nasal potential difference (NPD) is used as a biomarker of the cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) activity. We evaluated methods to detect changes in chloride and sodium transport by NPD based on a secondary analysis of a Phase II CFTR-modulator study. Thirty nine subjects with CF who also had the G551D-CFTR mutation were randomized to receive ivacaftor (KalydecoTM; also known as VX-770) in four doses or placebo twice daily for at least 14 days. All data were analyzed by a single investigator who was blinded to treatment assignment. We compared three analysis methods to determine the best approach to quantify changes in chloride and sodium transport: (1) the average of both nostrils; (2) the most-polarized nostril at each visit; and (3) the most-polarized nostril at screening carried forward. Parameters of ion transport included the PD change with zero chloride plus isoproterenol (CFTR activity), the basal PD, Ringer's PD, and change in PD with amiloride (measurements of ENaC activity), and the delta NPD (measuring CFTR and ENaC activity). The average and most-polarized nostril at each visit were most sensitive to changes in chloride and sodium transport, whereas the most-polarized nostril at screening carried forward was less discriminatory. Based on our findings, NPD studies should assess both nostrils rather than a single nostril. We also found that changes in CFTR activity were more readily detected than changes in ENaC activity, and that rigorous standardization was associated with relatively good within-subject reproducibility in placebo-treated subjects (+/- 2.8 mV). Therefore, we have confirmed an assay of reasonable reproducibility for detecting chloride-transport improvements in response to CFTR modulation. PMID- 23922648 TI - Comparison of different cells of Haematococcus pluvialis reveals an extensive acclimation mechanism during its aging process: from a perspective of photosynthesis. AB - Both biomass dominated green vegetative cells (GV) and astaxanthin-dominated orange resting cells (OR) affect the final astaxanthin yield in industry. Examination of Haematococcus pluvialis revealed that the OR cells greatly varied from the GV cells at both cellular and subcellular levels. In particular, the thylakoid membranes in the OR were disassembled and fragmented. Furthermore, the OR conserved most of the photosynthetic pigments, with elevated concentrations of violaxanthin, antheraxanthin, and neoxanthin. Notably, moderate photosynthesis was detected in OR, even though most of the thylakoid membranes were disassembled, when compared with those in the GV. However, the energy distribution pattern between photosystem I and II (PSI and PSII) in the OR favored PSI, which was also confirmed by 77-K fluorescence. As zeaxanthin was not detected in the OR, we attribute the acclimation role to astaxanthin, instead of xanthophyll cycle. Additionally, proteomic-scale comparison analysis of thylakoids of the OR and GV indicated no photosynthetically remarkable variations. However, an extensive acclimation mechanism of H. pluvialis was proposed, in which proteins in thylakoid of GV were noted to be involved in biomass accumulation and those in OR were involved in stress response. Conclusions of the comparative analysis might provide some physiological background of OR for astaxanthin production by using H. pluvialis. PMID- 23922649 TI - Patient factors influencing the prescribing of lipid lowering drugs for primary prevention of cardiovascular disease in UK general practice: a national retrospective cohort study. AB - BACKGROUND: Guidelines indicate eligibility for lipid lowering drugs, but it is not known to what extent GPs' follow guidelines in routine clinical practice or whether additional clinical factors systematically influence their prescribing decisions. METHODS: A retrospective cohort analysis was undertaken using electronic primary care records from 421 UK general practices. At baseline (May 2008) patients were aged 30 to 74 years, free from cardiovascular disease and not taking lipid lowering drugs. The outcome was prescription of a lipid lowering drug within the next two years. The proportions of eligible and ineligible patients prescribed lipid lowering drugs were reported and multivariable logistic regression models were used to investigate associations between age, sex, cardiovascular risk factors and prescribing. RESULTS: Of 365,718 patients with complete data, 13.8% (50,558) were prescribed lipid lowering drugs: 28.5% (21,101/74,137) of those eligible and 10.1% (29,457/291,581) of those ineligible. Only 41.7% (21,101/50,558) of those prescribed lipid lowering drugs were eligible. In multivariable analysis prescribing was most strongly associated with increasing age (OR for age >= 65 years 4.21; 95% CI 4.05-4.39); diabetes (OR 4.49; 95% CI 4.35-4.64); total cholesterol level >= 7 mmol/L (OR 2.20; 95% CI 2.12-2.29); and >= 4 blood pressure measurements in the past year (OR 4.24; 95% CI 4.06-4.42). The predictors were similar in eligible and ineligible patients. CONCLUSIONS: Most lipid lowering drugs for primary prevention are prescribed to ineligible patients. There is underuse of lipid lowering drugs in eligible patients. PMID- 23922650 TI - Association study of 167 candidate genes for schizophrenia selected by a multi domain evidence-based prioritization algorithm and neurodevelopmental hypothesis. AB - Integrating evidence from multiple domains is useful in prioritizing disease candidate genes for subsequent testing. We ranked all known human genes (n=3819) under linkage peaks in the Irish Study of High-Density Schizophrenia Families using three different evidence domains: 1) a meta-analysis of microarray gene expression results using the Stanley Brain collection, 2) a schizophrenia protein protein interaction network, and 3) a systematic literature search. Each gene was assigned a domain-specific p-value and ranked after evaluating the evidence within each domain. For comparison to this ranking process, a large-scale candidate gene hypothesis was also tested by including genes with Gene Ontology terms related to neurodevelopment. Subsequently, genotypes of 3725 SNPs in 167 genes from a custom Illumina iSelect array were used to evaluate the top ranked vs. hypothesis selected genes. Seventy-three genes were both highly ranked and involved in neurodevelopment (category 1) while 42 and 52 genes were exclusive to neurodevelopment (category 2) or highly ranked (category 3), respectively. The most significant associations were observed in genes PRKG1, PRKCE, and CNTN4 but no individual SNPs were significant after correction for multiple testing. Comparison of the approaches showed an excess of significant tests using the hypothesis-driven neurodevelopment category. Random selection of similar sized genes from two independent genome-wide association studies (GWAS) of schizophrenia showed the excess was unlikely by chance. In a further meta analysis of three GWAS datasets, four candidate SNPs reached nominal significance. Although gene ranking using integrated sources of prior information did not enrich for significant results in the current experiment, gene selection using an a priori hypothesis (neurodevelopment) was superior to random selection. As such, further development of gene ranking strategies using more carefully selected sources of information is warranted. PMID- 23922651 TI - Selective hepatitis B virus vaccination has reduced hepatitis B virus transmission in the Netherlands. AB - BACKGROUND & AIMS: In the Netherlands, a selective hepatitis B virus (HBV) vaccination programme started in 2002 for men having sex with men, drug users, commercial sex workers and heterosexuals with frequent partner changes. We assessed the programme's effectiveness to guide policy on HBV prevention. METHODS: We analysed reports of acute HBV infection in the Netherlands between 2004 and 2010 requesting serum from patients for HBV-genome S- and C-region sequencing. We used coalescence analyses to assess genetic diversity of nonimported genotype-A cases over time. RESULTS: 1687 patients with acute HBV infection were reported between 2004 and 2010. The incidence of reported acute HBV infection decreased from 1.8 to 1.2 per 100,000 inhabitants, mostly due to a reduction in the number of cases in men who have sex with men. Men were overrepresented among cases with an unknown route of transmission, especially among genotype A2 cases mainly associated with transmission through male homosexual contact. The genetic diversity of nonimported genotype-A strains obtained from men who have sex with men decreased from 2006 onwards, suggesting HBV incidence in this group decreased. CONCLUSIONS: The selective HBV-vaccination programme for behavioural high-risk groups very likely reduced the incidence of HBV infection in the Netherlands mainly by preventing HBV infections in men who have sex with men. A considerable proportion of cases in men who did not report risk behaviour was probably acquired through homosexual contact. Our findings support continuation of the programme, and adopting similar approaches in other countries where HBV transmission is focused in high-risk adults. PMID- 23922652 TI - MRSA in Africa: filling the global map of antimicrobial resistance. AB - We sought to assess the prevalence of methicillin-resistance among Staphylococcus aureus isolates in Africa. We included articles published in 2005 or later reporting for the prevalence of MRSA among S. aureus clinical isolates. Thirty two studies were included. In Tunisia, the prevalence of MRSA increased from 16% to 41% between 2002-2007, while in Libya it was 31% in 2007. In South Africa, the prevalence decreased from 36% in 2006 to 24% during 2007-2011. In Botswana, the prevalence varied from 23-44% between 2000-2007. In Algeria and Egypt, the prevalence was 45% and 52% between 2003-2005, respectively. In Nigeria, the prevalence was greater in the northern than the southern part. In Ethiopia and the Ivory Coast, the prevalence was 55% and 39%, respectively. The prevalence of MRSA was lower than 50% in most of the African countries, although it appears to have risen since 2000 in many African countries, except for South Africa. PMID- 23922653 TI - Computational study on the different ligands induced conformation change of beta2 adrenergic receptor-Gs protein complex. AB - beta2 adrenergic receptor (beta2AR) regulated many key physiological processes by activation of a heterotrimeric GTP binding protein (Gs protein). This process could be modulated by different types of ligands. But the details about this modulation process were still not depicted. Here, we performed molecular dynamics (MD) simulations on the structures of beta2AR-Gs protein in complex with different types of ligands. The simulation results demonstrated that the agonist BI-167107 could form hydrogen bonds with Ser203(5.42), Ser207(5.46) and Asn293(6.55) more than the inverse agonist ICI 118,551. The different binding modes of ligands further affected the conformation of beta2AR. The energy landscape profiled the energy contour map of the stable and dissociated conformation of Galphas and Gbetagamma when different types of ligands bound to beta2AR. It also showed the minimum energy pathway about the conformational change of Galphas and Gbetagamma along the reaction coordinates. By using interactive essential dynamics analysis, we found that Galphas and Gbetagamma domain of Gs protein had the tendency to separate when the inverse agonist ICI 118,551 bound to beta2AR. The alpha5-helix had a relatively quick movement with respect to transmembrane segments of beta2AR when the inverse agonist ICI 118,551 bound to beta2AR. Besides, the analysis of the centroid distance of Galphas and Gbetagamma showed that the Galphas was separated from Gbetagamma during the MD simulations. Our results not only could provide details about the different types of ligands that induced conformational change of beta2AR and Gs protein, but also supplied more information for different efficacies of drug design of beta2AR. PMID- 23922654 TI - Expression of the domain cassette 8 Plasmodium falciparum erythrocyte membrane protein 1 is associated with cerebral malaria in Benin. AB - BACKGROUND: Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) is a highly polymorphic adherence receptor expressed on the surface of infected erythrocytes. Based on sequence homology PfEMP-1 variants have been grouped into three major groups A-C, the highly conserved VAR2CSA variants, and semi-conserved types defined by tandem runs of specific domains ("domain cassettes" (DC)). The PfEMP-1 type expressed determines the adherence phenotype, and is associated with clinical outcome of infection. METHODS: Parasite isolates from Beninese children or women presenting with, respectively, CM or PAM were collected along with samples from patients with uncomplicated malaria (UM). We assessed the transcript level of var genes by RT-qPCR and the expression of PfEMP-1 proteins by LC-MS/MS. RESULTS: Var genes encoding DC8 and Group A PfEMP-1 were transcribed more often and at higher levels in cerebral malaria vs. uncomplicated malaria patients. LC MS/MS identified peptides from group A, DC8 PfEMP-1 more frequently in cerebral malaria than in uncomplicated malaria and pregnancy-associated malaria samples. CONCLUSION: This is the first study to show association between PfEMP-1 subtype and disease outcome by direct analysis of parasites proteome. The results corroborate that group A and specifically the PfEMP-1 types DC8 are universally associated with cerebral malaria. This is a crucial observation for promoting studies on malaria pathogenesis. PMID- 23922655 TI - Defensive aggregation (huddling) in Rattus norvegicus toward predator odor: individual differences, social buffering effects and neural correlates. AB - Aggregation is a defensive strategy employed by many prey species in response to predatory threat. Our group has characterized defensive aggregation (huddling) in Rattus norvegicus in response to a ball of cat fur. In this situation some rats huddle less, and approach the threatening cue more than others (active vs. passive responders). The present study explored whether active responding is a stable phenotype associated with behaviors outside direct predatory encounters. The neural substrates of active and passive responding under predatory threat were explored using c-Fos immunohistochemistry. Finally, we examined whether the presence of conspecifics during predatory threat biases behavior towards active responding. Active and passive responding styles were found to be stable in individual rats across consecutive group exposures to cat fur, and were predicted by anxiety-like behavior in an open-field emergence test. Active responders displayed less conditioned fear in an environment associated with predatory threat, and had higher post-exposure intake of a weak sucrose solution (a test of "anhedonia"). Active responding was associated with: greater cat fur-induced activation of the accessory olfactory bulb, reflecting greater olfactory stimulation in rats actively approaching the fur; lowered activation of somatosensory cortex, reflecting reduced huddling with conspecifics; and reduced activation in the lateral septum. Social exposure to cat fur promoted active responding relative to individual exposure, and lowered c-Fos expression in the dorsomedial periaqueductal grey, medial caudate putamen and lateral habenula. We conclude that individual differences in anti-predator behavior appear stable traits with active responders having a more resilient phenotype. Social exposure to predatory threat has an acute buffering effect, subtly changing the neural and behavioral response towards threat and encouraging active responding. An association between active responding and lower c-Fos expression in the lateral septum is consistent with previous studies that highlight this region as an important neurobiological substrate of defensive aggregation. PMID- 23922656 TI - Rifaximin-mediated changes to the epithelial cell proteome: 2-D gel analysis. AB - Rifaximin is a semi-synthetic rifamycin derivative that is used to treat different conditions including bacterial diarrhea and hepatic encephalopathy. Rifaximin is of particular interest because it is poorly adsorbed in the intestines and has minimal effect on colonic microflora. We previously demonstrated that rifaximin affected epithelial cell physiology by altering infectivity by enteric pathogens and baseline inflammation suggesting that rifaximin conferred cytoprotection against colonization and infection. Effects of rifaximin on epithelial cells were further examined by comparing the protein expression profile of cells pretreated with rifaximin, rifampin (control antibiotic), or media (untreated). Two-dimensional (2-D) gel electrophoresis identified 36 protein spots that were up- or down-regulated by over 1.7-fold in rifaximin treated cells compared to controls. 15 of these spots were down regulated, including annexin A5, intestinal-type alkaline phosphatase, histone H4, and histone-binding protein RbbP4. 21 spots were up-regulated, including heat shock protein (HSP) 90alpha and fascin. Many of the identified proteins are associated with cell structure and cytoskeleton, transcription and translation, and cellular metabolism. These data suggested that in addition to its antimicrobial properties, rifaximin may alter host cell physiology that provides cytoprotective effects against bacterial pathogens. PMID- 23922657 TI - Identification of a potent endothelium-derived angiogenic factor. AB - The secretion of angiogenic factors by vascular endothelial cells is one of the key mechanisms of angiogenesis. Here we report on the isolation of a new potent angiogenic factor, diuridine tetraphosphate (Up4U) from the secretome of human endothelial cells. The angiogenic effect of the endothelial secretome was partially reduced after incubation with alkaline phosphatase and abolished in the presence of suramin. In one fraction, purified to homogeneity by reversed phase and affinity chromatography, Up4U was identified by MALDI-LIFT-fragment-mass spectrometry, enzymatic cleavage analysis and retention-time comparison. Beside a strong angiogenic effect on the yolk sac membrane and the developing rat embryo itself, Up4U increased the proliferation rate of endothelial cells and, in the presence of PDGF, of vascular smooth muscle cells. Up4U stimulated the migration rate of endothelial cells via P2Y2-receptors, increased the ability of endothelial cells to form capillary-like tubes and acts as a potent inducer of sprouting angiogenesis originating from gel-embedded EC spheroids. Endothelial cells released Up4U after stimulation with shear stress. Mean total plasma Up4U concentrations of healthy subjects (N=6) were sufficient to induce angiogenic and proliferative effects (1.34 +/- 0.26 nmol L(-1)). In conclusion, Up4U is a novel strong human endothelium-derived angiogenic factor. PMID- 23922659 TI - Behaviour of non-donor specific antibodies during rapid re-synthesis of donor specific HLA antibodies after antibody incompatible renal transplantation. AB - BACKGROUND: HLA directed antibodies play an important role in acute and chronic allograft rejection. During viral infection of a patient with HLA antibodies, the HLA antibody levels may rise even though there is no new immunization with antigen. However it is not known whether the converse occurs, and whether changes on non-donor specific antibodies are associated with any outcomes following HLA antibody incompatible renal transplantation. METHODS: 55 patients, 31 women and 24 men, who underwent HLAi renal transplant in our center from September 2005 to September 2010 were included in the studies. We analysed the data using two different approaches, based on; i) DSA levels and ii) rejection episode post transplant. HLA antibody levels were measured during the early post transplant period and corresponding CMV, VZV and Anti-HBs IgG antibody levels and blood group IgG, IgM and IgA antibodies were quantified. RESULTS: Despite a significant DSA antibody rise no significant non-donor specific HLA antibody, viral or blood group antibody rise was found. In rejection episode analyses, multiple logistic regression modelling showed that change in the DSA was significantly associated with rejection (p = 0.002), even when adjusted for other antibody levels. No other antibody levels were predictive of rejection. Increase in DSA from pre treatment to a post transplant peak of 1000 was equivalent to an increased chance of rejection with an odds ratio of 1.47 (1.08, 2.00). CONCLUSION: In spite of increases or decreases in the DSA levels, there were no changes in the viral or the blood group antibodies in these patients. Thus the DSA rise is specific in contrast to the viral, blood group or third party antibodies post transplantation. Increases in the DSA post transplant in comparison to pre treatment are strongly associated with occurrence of rejection. PMID- 23922658 TI - Altered resting state brain dynamics in temporal lobe epilepsy can be observed in spectral power, functional connectivity and graph theory metrics. AB - Despite a wealth of EEG epilepsy data that accumulated for over half a century, our ability to understand brain dynamics associated with epilepsy remains limited. Using EEG data from 15 controls and 9 left temporal lobe epilepsy (LTLE) patients, in this study we characterize how the dynamics of the healthy brain differ from the "dynamically balanced" state of the brain of epilepsy patients treated with anti-epileptic drugs in the context of resting state. We show that such differences can be observed in band power, synchronization and network measures, as well as deviations from the small world network (SWN) architecture of the healthy brain. The theta (4-7 Hz) and high alpha (10-13 Hz) bands showed the biggest deviations from healthy controls across various measures. In particular, patients demonstrated significantly higher power and synchronization than controls in the theta band, but lower synchronization and power in the high alpha band. Furthermore, differences between controls and patients in graph theory metrics revealed deviations from a SWN architecture. In the theta band epilepsy patients showed deviations toward an orderly network, while in the high alpha band they deviated toward a random network. These findings show that, despite the focal nature of LTLE, the epileptic brain differs in its global network characteristics from the healthy brain. To our knowledge, this is the only study to encompass power, connectivity and graph theory metrics to investigate the reorganization of resting state functional networks in LTLE patients. PMID- 23922660 TI - Effect of sequence and stereochemistry reversal on p53 peptide mimicry. AB - Peptidomimetics effective in modulating protein-protein interactions and resistant to proteolysis have potential in therapeutic applications. An appealing yet underperforming peptidomimetic strategy is to employ D-amino acids and reversed sequences to mimic a lead peptide conformation, either separately or as the combined retro-inverso peptide. In this work, we examine the conformations of inverse, reverse and retro-inverso peptides of p53(15-29) using implicit solvent molecular dynamics simulation and circular dichroism spectroscopy. In order to obtain converged ensembles for the peptides, we find enhanced sampling is required via the replica exchange molecular dynamics method. From these replica exchange simulations, the D-peptide analogues of p53(15-29) result in a predominantly left-handed helical conformation. When the parent sequence is reversed sequence as either the L-peptide and D-peptide, these peptides display a greater helical propensity, feature reflected by NMR and CD studies in TFE/water solvent. The simulations also indicate that, while approximately similar orientations of the side-chains are possible by the peptide analogues, their ability to mimic the parent peptide is severely compromised by backbone orientation (for D-amino acids) and side-chain orientation (for reversed sequences). A retro-inverso peptide is disadvantaged as a mimic in both aspects, and further chemical modification is required to enable this concept to be used fruitfully in peptidomimetic design. The replica exchange molecular simulation approach adopted here, with its ability to provide detailed conformational insights into modified peptides, has potential as a tool to guide structure-based design of new improved peptidomimetics. PMID- 23922662 TI - MicroRNA-224 targets SMAD family member 4 to promote cell proliferation and negatively influence patient survival. AB - MicroRNA-224 (miR-224) is frequently over-expressed in liver and colorectal cancers. We and others have previously described the role of miR-224 over expression in cell proliferation in vitro but we have yet to identify the relevant miR-224 direct target. In this study, we further demonstrated that miR 224 up-regulation promotes cell proliferation using both in vitro assays and in vivo tumor growth models. We systematically screened for high confidence miR-224 targets by overlapping in silico predicted targets from multiple algorithms and significantly down-regulated genes in miR-224-expressing cells from whole genome expression microarrays. A total of 72 high confidence miR-224 targets were identified and found to be enriched in various cancer-related processes. SMAD family member 4 (SMAD4) is experimentally validated as the direct cellular target through which miR-224 promotes cell proliferation. The clinical relevance of our experimental observations was supported by a statistically significant inverse correlation between miR-224 and SMAD4 transcript expression in tumor versus paired adjacent non-tumorous tissues from HCC patients (p<0.001, r= -0.45, R(2) =0.122). Furthermore, miR-224 up-regulation and SMAD4 down-regulation is significantly associated with poorer patient survival (p<0.05). In summary, miR 224/SMAD4 pathway is a clinically relevant pathway to provide new insights in understanding HCC. (191 words). PMID- 23922661 TI - Genome-wide identification of molecular pathways and biomarkers in response to arsenic exposure in zebrafish liver. AB - Inorganic arsenic is a worldwide metalloid pollutant in environment. Although extensive studies on arsenic-induced toxicity have been conducted using in vivo and in vitro models, the exact molecular mechanism of arsenate toxicity remains elusive. Here, the RNA-SAGE (serial analysis of gene expression) sequencing technology was used to analyse hepatic response to arsenic exposure at the transcriptome level. Based on more than 12 million SAGE tags mapped to zebrafish genes, 1,444 differentially expressed genes (750 up-regulated and 694 down regulated) were identified from a relatively abundant transcripts (>10 TPM [transcripts per million]) based on minimal two-fold change. By gene ontology analyses, these differentially expressed genes were significantly enriched in several major biological processes including oxidation reduction, translation, iron ion transport, cell redox, homeostasis, etc. Accordingly, the main pathways disturbed include metabolic pathways, proteasome, oxidative phosphorylation, cancer, etc. Ingenity Pathway Analysis further revealed a network with four important upstream factors or hub genes, including Jun, Kras, APoE and Nr2f2. The network indicated apparent molecular events involved in oxidative stress, carcinogenesis, and metabolism. In order to identify potential biomarker genes for arsenic exposure, 27 out of 29 up-regulated transcripts were validated by RT qPCR analysis in pooled RNA samples. Among these, 14 transcripts were further confirmed for up-regulation by a lower dosage of arsenic in majority of individual zebrafish. Finally, at least four of these genes, frh3 (ferrintin H3), mgst1 (microsomal glutathione S-transferase-like), cmbl (carboxymethylenebutenolidase homolog) and slc40a1 (solute carrier family 40 [iron-regulated transporter], member 1) could be confirmed in individual medaka fish similarly treated by arsenic; thus, these four genes might be robust arsenic biomarkers across species. Thus, our work represents the first comprehensive investigation of molecular mechanism of asenic toxicity and genome-wide search for potential biomarkers for arsenic exposure. PMID- 23922663 TI - QTL analysis of dietary obesity in C57BL/6byj X 129P3/J F2 mice: diet- and sex dependent effects. AB - Obesity is a heritable trait caused by complex interactions between genes and environment, including diet. Gene-by-diet interactions are difficult to study in humans because the human diet is hard to control. Here, we used mice to study dietary obesity genes, by four methods. First, we bred 213 F2 mice from strains that are susceptible [C57BL/6ByJ (B6)] or resistant [129P3/J (129)] to dietary obesity. Percent body fat was assessed after mice ate low-energy diet and again after the same mice ate high-energy diet for 8 weeks. Linkage analyses identified QTLs associated with dietary obesity. Three methods were used to filter candidate genes within the QTL regions: (a) association mapping was conducted using >40 strains; (b) differential gene expression and (c) comparison of genomic DNA sequence, using two strains closely related to the progenitor strains from Experiment 1. The QTL effects depended on whether the mice were male or female or which diet they were recently fed. After feeding a low-energy diet, percent body fat was linked to chr 7 (LOD=3.42). After feeding a high-energy diet, percent body fat was linked to chr 9 (Obq5; LOD=3.88), chr 12 (Obq34; LOD=3.88), and chr 17 (LOD=4.56). The Chr 7 and 12 QTLs were sex dependent and all QTL were diet dependent. The combination of filtering methods highlighted seven candidate genes within the QTL locus boundaries: Crx, Dmpk, Ahr, Mrpl28, Glo1, Tubb5, and Mut. However, these filtering methods have limitations so gene identification will require alternative strategies, such as the construction of congenics with very small donor regions. PMID- 23922664 TI - High prevalence of anemia in children and adult women in an urban population in southern Brazil. AB - This population-based study was designed to detect the prevalence of anemia in a healthy population of children (18 months to 7 years) and women (14 to 30 years) tested in 2006-2007 in the state of Rio Grande do Sul, Brazil as part of an effort to tackle this massive problem that still affects so many people in the XXI century. Anemia was defined according to the WHO. Capillary blood was measured and socioeconomic status was determined according to the Brazilian Association of Market Research Agencies. The median prevalence of anemia in 2198 children was 45.4% and in 1999 women 36.4%. Anemia decreased with age during childhood; although significantly more prevalent in lower classes individuals, it was also high in the upper classes. There are indirect evidences that the lack of iron supplementation and/or iron fortified food may play a role in it. Professionals and society wise measures of education have to be implemented in order to address possible biologic factors involved in childhood psychosocial development in southern Brazil. PMID- 23922665 TI - Using a body-fixed sensor to identify subclinical gait difficulties in older adults with IADL disability: maximizing the output of the timed up and go. AB - OBJECTIVE: The identification and documentation of subclinical gait impairments in older adults may facilitate the appropriate use of interventions for preventing or delaying mobility disability. We tested whether measures derived from a single body-fixed sensor worn during traditional Timed Up and Go (TUG) testing could identify subclinical gait impairments in community dwelling older adults without mobility disability. METHODS: We used data from 432 older adults without dementia (mean age 83.30 +/- 7.04 yrs, 76.62% female) participating in the Rush Memory and Aging Project. The traditional TUG was conducted while subjects wore a body-fixed sensor. We derived measures of overall TUG performance and different subtasks including transitions (sit-to-stand, stand-to-sit), walking, and turning. Multivariate analysis was used to compare persons with and without mobility disability and to compare individuals with and without Instrumental Activities of Daily Living disability (IADL-disability), all of whom did not have mobility disability. RESULTS: As expected, individuals with mobility disability performed worse on all TUG subtasks (p<0.03), compared to those who had no mobility disability. Individuals without mobility disability but with IADL disability had difficulties with turns, had lower yaw amplitude (p<0.004) during turns, were slower (p<0.001), and had less consistent gait (p<0.02). CONCLUSIONS: A single body-worn sensor can be employed in the community-setting to complement conventional gait testing. It provides a wide range of quantitative gait measures that appear to help to identify subclinical gait impairments in older adults. PMID- 23922666 TI - Wrinkled1, a ubiquitous regulator in oil accumulating tissues from Arabidopsis embryos to oil palm mesocarp. AB - Wrinkled1 (AtWRI1) is a key transcription factor in the regulation of plant oil synthesis in seed and non-seed tissues. The structural features of WRI1 important for its function are not well understood. Comparison of WRI1 orthologs across many diverse plant species revealed a conserved 9 bp exon encoding the amino acids "VYL". Site-directed mutagenesis of amino acids within the 'VYL' exon of AtWRI1 failed to restore the full oil content of wri1-1 seeds, providing direct evidence for an essential role of this small exon in AtWRI1 function. Arabidopsis WRI1 is predicted to have three alternative splice forms. To understand expression of these splice forms we performed RNASeq of Arabidopsis developing seeds and queried other EST and RNASeq databases from several tissues and plant species. In all cases, only one splice form was detected and VYL was observed in transcripts of all WRI1 orthologs investigated. We also characterized a phylogenetically distant WRI1 ortholog (EgWRI1) as an example of a non-seed isoform that is highly expressed in the mesocarp tissue of oil palm. The C terminal region of EgWRI1 is over 90 amino acids shorter than AtWRI1 and has surprisingly low sequence conservation. Nevertheless, the EgWRI1 protein can restore multiple phenotypes of the Arabidopsis wri1-1 loss-of-function mutant, including reduced seed oil, the "wrinkled" seed coat, reduced seed germination, and impaired seedling establishment. Taken together, this study provides an example of combining phylogenetic analysis with mutagenesis, deep-sequencing technology and computational analysis to examine key elements of the structure and function of the WRI1 plant transcription factor. PMID- 23922667 TI - DNA methyltransferase candidate polymorphisms, imprinting methylation, and birth outcome. AB - BACKGROUND: Birth weight and prematurity are important obstetric outcomes linked to lifelong health. We studied a large birth cohort to look for evidence of epigenetic involvement in birth outcomes. METHODS: We investigated the association between birth weight, length, placental weight and duration of gestation and four candidate variants in 1,236 mothers and 1,073 newborns; DNMT1 (rs2162560), DNMT3A (rs734693), DNMT3B (rs2424913) and DNMT3L (rs7354779). We measured methylation of LINE1 and the imprinted genes, PEG3, SNRPN, and IGF2, in cord blood. RESULTS: The minor DNMT3L allele in the baby was associated with higher birth weight (+54 95% CI 10,99 g; p = 0.016), birth length (+0.23 95% CI 0.04,0.42 cm; p = 0.017), placental weight, (+18 95% CI 3,33 g; p = 0.017), and reduced risk of being in the lowest birth weight decile (p = 0.018) or requiring neonatal care (p = 0.039). The DNMT3B minor allele in the mother was associated with an increased risk of prematurity (p = 0.001). Placental size was related to PEG3 (p<0.001) and IGF2 (p<0.001) methylation. Birth weight was related to LINE1 and IGF2 methylation but only at p = 0.052. The risk of requiring neonatal treatment was related to LINE1 (p = 0.010) and SNRPN (p = 0.001) methylation. PEG3 methylation was influenced by baby DNMT3A genotype (p = 0.012) and LINE1 by baby 3B genotype (p = 0.044). Maternal DNMT3L genotype was related to IGF2 methylation in the cord blood but this effect was only seen in carriers of the minor frequency allele (p = 0.050). CONCLUSIONS: The results here suggest that epigenetic processes are linked birth outcome and health in early life. Our emerging understanding of the role of epigenetics in health and biological function across the lifecourse suggests that these early epigenetic events could have longer term implications. PMID- 23922668 TI - Methadone maintenance treatment participant retention and behavioural effectiveness in China: a systematic review and meta-analysis. AB - BACKGROUND: Methadone maintenance treatment (MMT) has been scaled up by the Chinese government alongside persistent compulsory drug user detention, but the extent to which detention interferes with MMT is unknown. The study systematically reviews Chinese MMT retention rates, reasons for drop out, and behavioural changes. METHOD: Chinese and English databases of literature are searched for studies reporting retention rates, drug use and sexual behaviours among MMT participants in China between 2004 and 2013. The estimates are summarized through a systematic review and meta-analysis. RESULTS: A total of 74 studies representing 43,263 individuals are included in this analysis. About a third of MMT participants drop out during the first three months of treatment (retention rate 69.0% (95% CI 57.7-78.4%)). Police arrest and detention in compulsory rehabilitation was the most common cause of drop out, accounting for 22.2% of all those not retained. Among retained participants, changing unsafe drug use behaviours was more effective than changing unsafe sexual behaviours. At 12 months following MMT initiation, 24.6% (15.7-33.5%) of MMT participants had a positive urine test, 9.3% (4.7-17.8%) injected drugs and only 1.1% (0.4-3.0%) sold sex for drugs. These correspond to 0.002 (<0.001-0.011), 0.045 (0.004-0.114) and 0.209 (0.076-0.580) times lower odds than baseline. However, MMT participants did not have substantial changes in condom use rates. CONCLUSION: MMT is effective in drug users in China but participant retention is poor, substantially related to compulsory detention. Reforming the compulsory drug user detention system may improve MMT retention and effectiveness. PMID- 23922670 TI - Blood viscosity and the expression of inflammatory and adhesion markers in homozygous sickle cell disease subjects with chronic leg ulcers. AB - OBJECTIVE: To determine differences in TNF-alpha, IL-1beta, IL-10, sICAM-1 concentrations, leg hypoxia and whole blood viscosity (WBV) at shear rates of 46 sec(-1) and 230 sec(-1) in persons with homozygous S sickle cell disease (SCD) with and without chronic leg ulceration and in AA genotype controls. DESIGN: & METHODS: fifty-five age-matched participants were recruited into the study: 31 SS subjects without leg ulcers (SSn), 24 SS subjects with leg ulcers (SSu) and 18 AA controls. Haematological indices were measured using an AC.Tron Coulter Counter. Quantification of inflammatory, anti-inflammatory and adhesion molecules was performed by ELISA. Measurement of whole blood viscosity was done using a Wells Brookfield cone-plate viscometer. Quantification of microvascular tissue oxygenation was done by Visible Lightguide spectrophotometry. RESULTS: TNF-alpha and whole blood viscosity at 46 sec(-1) and 230 sec(-1) (1.75, 2.02 vs. 0.83, 1.26, p<0.05) were significantly greater in sickle cell disease subjects than in controls. There were no differences in plasma concentration of sICAM-1, IL-1beta and IL-10 between SCD subjects and controls. IL-1beta (median, IQR: 0.96, 1.7 vs. 0, 0.87; p<0.01) and sICAM-1 (226.5, 156.48 vs. 107.63, 121.5, p<0.005) were significantly greater in SSu group compared with SSn. However there were no differences in TNF-alpha (2, 3.98 vs. 0, 2.66) and IL-10 (13.34, 5.95 vs. 11.92, 2.99) concentrations between SSu and SSn. WBV in the SSu group at 46 sec(-1) and at 230 Sec 1 were 1.9 (95%CI; 1.2, 3.1) and 2.3 (1.2, 4.4) times greater than in the SSn group. There were no differences in the degree of tissue hypoxia as determined by lightguide spectrophotometry. CONCLUSION: Inflammatory, adhesion markers and WBV may be associated with leg ulceration in sickle cell disease by way of inflammation-mediated vasoocclusion/vasoconstriction. Impaired skin oxygenation does not appear to be associated with chronic ulcers in these subjects with sickle cell disease. PMID- 23922669 TI - Cancer-associated fibroblasts promote proliferation of endometrial cancer cells. AB - Endometrial cancer is the most commonly diagnosed gynecologic malignancy worldwide; yet the tumor microenvironment, especially the fibroblast cells surrounding the cancer cells, is poorly understood. We established four primary cultures of fibroblasts from human endometrial cancer tissues (cancer-associated fibroblasts, CAFs) using antibody-conjugated magnetic bead isolation. These relatively homogenous fibroblast cultures expressed fibroblast markers (CD90, vimentin and alpha-smooth muscle actin) and hormonal (estrogen and progesterone) receptors. Conditioned media collected from CAFs induced a dose-dependent proliferation of both primary cultures and cell lines of endometrial cancer in vitro (175%) when compared to non-treated cells, in contrast to those from normal endometrial fibroblast cell line (51%) (P<0.0001). These effects were not observed in fibroblast culture derived from benign endometrial hyperplasia tissues, indicating the specificity of CAFs in affecting endometrial cancer cell proliferation. To determine the mechanism underlying the differential fibroblast effects, we compared the activation of PI3K/Akt and MAPK/Erk pathways in endometrial cancer cells following treatment with normal fibroblasts- and CAFs conditioned media. Western blot analysis showed that the expression of both phosphorylated forms of Akt and Erk were significantly down-regulated in normal fibroblasts-treated cells, but were up-regulated/maintained in CAFs-treated cells. Treatment with specific inhibitors LY294002 and U0126 reversed the CAFs mediated cell proliferation (P<0.0001), suggesting for a role of these pathways in modulating endometrial cancer cell proliferation. Rapamycin, which targets a downstream molecule in PI3K pathway (mTOR), also suppressed CAFs-induced cell proliferation by inducing apoptosis. Cytokine profiling analysis revealed that CAFs secrete higher levels of macrophage chemoattractant protein (MCP)-1, interleukin (IL)-6, IL-8, RANTES and vascular endothelial growth factor (VEGF) than normal fibroblasts. Our data suggests that in contrast to normal fibroblasts, CAFs may exhibit a pro-tumorigenic effect in the progression of endometrial cancer, and PI3K/Akt and MAPK/Erk signaling may represent critical regulators in how endometrial cancer cells respond to their microenvironment. PMID- 23922671 TI - Psychosocial characteristics and social networks of suicidal prisoners: towards a model of suicidal behaviour in detention. AB - Prisoners are at increased risk of suicide. Investigation of both individual and environmental risk factors may assist in developing suicide prevention policies for prisoners and other high-risk populations. We conducted a matched case control interview study with 60 male prisoners who had made near-lethal suicide attempts in prison (cases) and 60 male prisoners who had not (controls). We compared levels of depression, hopelessness, self-esteem, impulsivity, aggression, hostility, childhood abuse, life events (including events occurring in prison), social support, and social networks in univariate and multivariate models. A range of psychosocial factors was associated with near-lethal self-harm in prisoners. Compared with controls, cases reported higher levels of depression, hopelessness, impulsivity, and aggression, and lower levels of self-esteem and social support (all p values <0.001). Adverse life events and criminal history factors were also associated with near-lethal self-harm, especially having a prior prison spell and having been bullied in prison, both of which remained significant in multivariate analyses. The findings support a model of suicidal behaviour in prisoners that incorporates imported vulnerability factors, clinical factors, and prison experiences, and underscores their interaction. Strategies to reduce self-harm and suicide in prisoners should include attention to such factors. PMID- 23922672 TI - The flavonoid pathway in tomato seedlings: transcript abundance and the modeling of metabolite dynamics. AB - Flavonoids are secondary metabolites present in all terrestrial plants. The flavonoid pathway has been extensively studied, and many of the involved genes and metabolites have been described in the literature. Despite this extensive knowledge, the functioning of the pathway in vivo is still poorly understood. Here, we study the flavonoid pathway using both experiments and mathematical models. We measured flavonoid metabolite dynamics in two tissues, hypocotyls and cotyledons, during tomato seedling development. Interestingly, the same backbone of interactions leads to very different accumulation patterns in the different tissues. Initially, we developed a mathematical model with constant enzyme concentrations that described the metabolic networks separately in both tissues. This model was unable to fit the measured flavonoid dynamics in the hypocotyls, even if we allowed unrealistic parameter values. This suggested us to investigate the effect of transcript abundance on flavonoid accumulation. We found that the expression of candidate flavonoid genes varies considerably with time. Variation in transcript abundance results in enzymatic variation, which could have a large effect on metabolite accumulation. Candidate transcript abundance was included in the mathematical model as representative for enzyme concentration. We fitted the resulting model to the flavonoid dynamics in the cotyledons, and tested it by applying it to the data from hypocotyls. When transcript abundance is included, we are indeed able to explain flavonoid dynamics in both tissues. Importantly, this is possible under the biologically relevant restriction that the enzymatic properties estimated by the model are conserved between the tissues. PMID- 23922673 TI - LDL cholesterolemia as a novel risk factor for radiographic progression of rheumatoid arthritis: a single-center prospective study. AB - Dyslipidemia has been implicated in various musculoskeletal diseases, including rheumatoid arthritis (RA). Evidence is emerging that there might be a pathogenic interaction among inflammation, dyslipidemia, and adipokines. We prospectively investigated the association of cumulative lipid levels with radiographic progression of RA. RA patients (n=242) underwent plasma cholesterol assessment at four visits. Disease activity parameters and X-rays of the hands and feet were also serially monitored in these patients. The cumulative inflammatory burden and lipid levels were estimated by time-integrated values. Serum leptin and adiponectin concentrations were determined by ELISA. When patients were divided into three groups according to time-integrated lipid levels, as expected, patients with LDL cholesterol and/or triglyceride levels in the third tertile had persistently higher ESR and CRP levels. In parallel, a more rapid radiographic progression over two years was observed in patients with higher LDL cholesterol and/or triglyceride levels. In multivariate analysis, time-integrated LDL cholesterol was independently associated with radiographic progression. Particularly, the risk of radiographic progression was 5.6-fold in a subgroup with both LDL cholesterol and triglyceride levels in the third tertile. Moreover, LDL cholesterol synergistically increased the adjusted probability of radiographic progression in patients with high serum leptin levels but not in those without. These results demonstrate that LDL cholesterolemia is a novel serum marker that can be used to predict radiographic progression of RA, which seems to be related to circulatory leptin levels. We suggest that personalized and more aggressive anti-rheumatic therapy is required for dyslipidemic subgroups in RA patients. PMID- 23922674 TI - Morphoproteomic profiling of the mammalian target of rapamycin (mTOR) signaling pathway in desmoplastic small round cell tumor (EWS/WT1), Ewing's sarcoma (EWS/FLI1) and Wilms' tumor(WT1). AB - BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma in adolescents and young adults. The hallmark of this disease is a EWS-WT1 translocation resulting from apposition of the Ewing's sarcoma (EWS) gene with the Wilms' tumor (WT1) gene. We performed morphoproteomic profiling of DSRCT (EWS WT1), Ewing's sarcoma (EWS-FLI1) and Wilms' tumor (WT1) to better understand the signaling pathways for selecting future targeted therapies. METHODOLOGY: This pilot study assessed patients with DSRCT, Wilms' tumor and Ewing's sarcoma. Morphoproteomics and immunohistochemical probes were applied to detect: p-mTOR (Ser2448); p-Akt (Ser473); p-ERK1/2 (Thr202/Tyr204); p-STAT3 (Tyr 705); and cell cycle-related analytes along with their negative controls. PRINCIPAL FINDINGS: In DSRCT the PI3K/Akt/mTOR pathway is constitutively activated by p-Akt (Ser 473) expression in the nuclear compartment of the tumor cells and p-mTOR phosphorylated on Ser 2448, suggesting mTORC2 (rictor+mTOR) as the dominant form. Ewing's sarcoma had upregulated p-Akt and p-mTOR, predominantly mTORC2. In Wilm's tumor, the mTOR pathway is also activated with most tumor cells moderately expressing p-mTOR (Ser 2448) in plasmalemmal and cytoplasmic compartments. This coincides with the constitutive activation of one of the downstream effectors of the mTORC1 signaling pathway, namely p-p70S6K (Thr 389). There was constitutive activation of the Ras/Raf/ERK pathway p-ERK 1/2 (Thr202/Tyr204) expression in the Wilms tumor and metastatic Ewing's sarcoma, but not in the DSRCT. CONCLUSION: MORPHOPROTEOMIC TUMOR ANALYSES REVEALED CONSTITUTIVE ACTIVATION OF THE MTOR PATHWAY AS EVIDENCED BY: (a) expression of phosphorylated (p)-mTOR, p-p70S6K; (b) mTORC 2 in EWS and DSRCT; (c) ERK signaling was seen in the advanced setting indicating these as resistance pathways to IGF1R related therapies. This is the first morphoproteomic study of such pathways in these rare malignancies and may have potential therapeutic implications. Further study using morphoproteomic assessments of these tumors are warranted. PMID- 23922675 TI - Boolean network model for cancer pathways: predicting carcinogenesis and targeted therapy outcomes. AB - A Boolean dynamical system integrating the main signaling pathways involved in cancer is constructed based on the currently known protein-protein interaction network. This system exhibits stationary protein activation patterns--attractors- dependent on the cell's microenvironment. These dynamical attractors were determined through simulations and their stabilities against mutations were tested. In a higher hierarchical level, it was possible to group the network attractors into distinct cell phenotypes and determine driver mutations that promote phenotypic transitions. We find that driver nodes are not necessarily central in the network topology, but at least they are direct regulators of central components towards which converge or through which crosstalk distinct cancer signaling pathways. The predicted drivers are in agreement with those pointed out by diverse census of cancer genes recently performed for several human cancers. Furthermore, our results demonstrate that cell phenotypes can evolve towards full malignancy through distinct sequences of accumulated mutations. In particular, the network model supports routes of carcinogenesis known for some tumor types. Finally, the Boolean network model is employed to evaluate the outcome of molecularly targeted cancer therapies. The major find is that monotherapies were additive in their effects and that the association of targeted drugs is necessary for cancer eradication. PMID- 23922676 TI - Deoxynivalenol impairs hepatic and intestinal gene expression of selected oxidative stress, tight junction and inflammation proteins in broiler chickens, but addition of an adsorbing agent shifts the effects to the distal parts of the small intestine. AB - Broiler chickens are rather resistant to deoxynivalenol and thus, clinical signs are rarely seen. However, effects of subclinical concentrations of deoxynivalenol on both the intestine and the liver are less frequently studied at the molecular level. During our study, we investigated the effects of three weeks of feeding deoxynivalenol on the gut wall morphology, intestinal barrier function and inflammation in broiler chickens. In addition, oxidative stress was evaluated in both the liver and intestine. Besides, the effect of a clay-based mycotoxin adsorbing agent on these different aspects was also studied. Our results show that feeding deoxynivalenol affects the gut wall morphology both in duodenum and jejenum of broiler chickens. A qRT-PCR analysis revealed that deoxynivalenol acts in a very specific way on the intestinal barrier, since only an up-regulation in mRNA expression of claudin 5 in jejunum was observed, while no effects were seen on claudin 1, zona occludens 1 and 2. Addition of an adsorbing agent resulted in an up-regulation of all the investigated genes coding for the intestinal barrier in the ileum. Up-regulation of Toll-like receptor 4 and two markers of oxidative stress (heme-oxigenase or HMOX and xanthine oxidoreductase or XOR) were mainly seen in the jejunum and to a lesser extent in the ileum in response to deoxynivalenol, while in combination with an adsorbing agent main effect was seen in the ileum. These results suggest that an adsorbing agent may lead to higher concentrations of deoxynivalenol in the more distal parts of the small intestine. In the liver, XOR was up-regulated due to DON exposure. HMOX and HIF-1alpha (hypoxia-inducible factor 1alpha) were down-regulated due to feeding DON but also due to feeding the adsorbing agent alone or in combination with DON. PMID- 23922677 TI - ALK-rearranged lung cancer in Chinese: a comprehensive assessment of clinicopathology, IHC, FISH and RT-PCR. AB - Approximately 3-7% of non-small cell lung cancers harbor an anaplastic lymphoma kinase (ALK) gene fusion, constituting a new molecular subtype of lung cancer that responds to crizotinib, an ALK inhibitor. Although previous studies have evaluated ALK-rearranged lung cancers, the comprehensive analysis of lung cancer in Chinese has not well assessed. Herein, we identified 44 cases of ALK rearranged samples by fluorescent in-situ hybridization (FISH), immunohistochemistry (IHC), and reverse transcription polymerase chain reaction (RT-PCR) in a large number of surgically resected lung cancers. All 44 ALK rearranged lung cancers were adenocarcinomas, with 2 cases having additional focal squamous components. The goal was to analyse the clinicopathological features of ALK-rearranged lung adenocarcinomas. Our data showed that a cribriform structure, prominent extracellular mucus and any type of mucous cell pattern may be either sensitive or specific to predict an ALK rearrangement. We used FISH as the standard detection method. We compared the ALK rearrangement accuracy of FISH, RT-PCR and IHC. RT-PCR could define both the ALK fusion partner and the fusion variant, but seemed unable to detect all translocations involving the ALK gene. It is noteworthy that IHC using the D5F3 antibody (Cell Signaling Technology) showed higher sensitivity and specificity than the ALK1 antibody (Dako). Therefore, we conclude that IHC remains a cost-effective and efficient technique for diagnosing ALK rearrangements and that D5F3 can be the optimal screening antibody in clinical practice. PMID- 23922678 TI - A simple and fast non-radioactive bridging immunoassay for insulin autoantibodies. AB - Type 1 diabetes (T1D) is an autoimmune disease which results from the destruction of pancreatic beta cells. Autoantibodies directed against islet antigens are valuable diagnostic tools. Insulin autoantibodies (IAAs) are usually the first to appear and also the most difficult to detect amongst the four major islet autoantibodies. A non-radioactive IAA bridging ELISA was developed to this end. In this assay, one site of the IAAs from serum samples is bound to a hapten labeled insulin (GC300-insulin), which is subsequently captured on anti-GC300 antibody-coated 96-well plates. The other site of the IAAs is bound to biotinylated insulin, allowing the complex to be detected by an enzyme streptavidin conjugate. In the present study, 50 serum samples from patients with newly diagnosed T1D and 100 control sera from non-diabetic individuals were analyzed with our new assay and the results were correlated with an IAA radioimmunoassay (RIA). Using IAA bridging ELISA, IAAs were detected in 32 out of 50 T1D children, whereas with IAA RIA, 41 out of 50 children with newly diagnosed T1D were scored as positive. In conclusion, the IAA bridging ELISA could serve as an attractive approach for rapid and automated detection of IAAs in T1D patients for diagnostic purposes. PMID- 23922679 TI - Circulating endothelial cells and procoagulant microparticles in patients with glioblastoma: prognostic value. AB - AIM: Circulating endothelial cells and microparticles are prognostic factors in cancer. However, their prognostic and predictive value in patients with glioblastoma is unclear. The objective of this study was to investigate the potential prognostic value of circulating endothelial cells and microparticles in patients with newly diagnosed glioblastoma treated with standard radiotherapy and concomitant temozolomide. In addition, we have analyzed the methylation status of the MGMT promoter. METHODS: Peripheral blood samples were obtained before and at the end of the concomitant treatment. Blood samples from healthy volunteers were also obtained as controls. Endothelial cells were measured by an immunomagnetic technique and immunofluorescence microscopy. Microparticles were quantified by flow cytometry. Microparticle-mediated procoagulant activity was measured by endogen thrombin generation and by phospholipid-dependent clotting time. Methylation status of MGMT promoter was determined by multiplex ligation dependent probe amplification. RESULTS: Pretreatment levels of circulating endothelial cells and microparticles were higher in patients than in controls (p<0.001). After treatment, levels of microparticles and thrombin generation decreased, and phospholipid-dependent clotting time increased significantly. A high pretreatment endothelial cell count, corresponding to the 99(th) percentile in controls, was associated with poor overall survival. MGMT promoter methylation was present in 27% of tumor samples and was associated to a higher overall survival (66 weeks vs 30 weeks, p<0.004). CONCLUSION: Levels of circulating endothelial cells may have prognostic value in patients with glioblastoma. PMID- 23922681 TI - The apgar score and infant mortality. AB - OBJECTIVE: To evaluate if the Apgar score remains pertinent in contemporary practice after more than 50 years of wide use, and to assess the value of the Apgar score in predicting infant survival, expanding from the neonatal to the post-neonatal period. METHODS: The U.S. linked live birth and infant death dataset was used, which included 25,168,052 singleton births and 768,305 twin births. The outcome of interest was infant death within 1 year after birth. Cox proportional hazard-model was used to estimate risk ratio of infant mortality with different Apgar scores. RESULTS: Among births with a very low Apgar score at five minutes (1-3), the neonatal and post-neonatal mortality rates remained high until term (>= 37 weeks). On the other hand, among births with a high Apgar score (>=7), neonatal and post-neonatal mortality rate decreased progressively with gestational age. Non-Hispanic White had a consistently higher neonatal mortality than non-Hispanic Black in both preterm and term births. However, for post neonatal mortality, Black had significantly higher rate than White. The pattern of changes in neonatal and post-neonatal mortality by Apgar score in twin births is essentially the same as that in singleton births. CONCLUSIONS: The Apgar score system has continuing value for predicting neonatal and post-neonatal adverse outcomes in term as well as preterm infants, and is applicable to twins and in various race/ethnic groups. PMID- 23922680 TI - Comparison of apparent diffusion coefficient and T2 relaxation time variation patterns in assessment of age and disc level related intervertebral disc changes. AB - PURPOSE: To compare the variation patterns of ADC and T2 values in different age and intervertebral disc (IVD) levels, thus to identify their sensitivities in assessing age and disc level related IVDs changes. MATERIALS AND METHODS: The T2 and ADC values were recorded from 345 IVDs of 69 volunteers. Kendall's correlation analysis was used to identify the relationship between age and T2/ADC mean values respectively. The one-way analysis of variance (ANOVA) with post hoc analysis was then applied to test the differences of T2 and ADC values among different IVD levels and age groups, followed by linear regression analysis between age (<45 and >45 years) and T2/ADC mean values. This study was approved by the Ethics Committee of the Chinese Academy of Medical Sciences and the Peking Union Medical College Hospital. RESULTS: Significant negative correlation was observed between age and T2/ADC mean values. The T2 and ADC values showed significant differences among IVD levels and among age groups except for T2 values in age group 1 (25-34 years) and group 2 (35-44 years), and for ADC values at L1-2 level. Both T2 and ADC values showed significant differences between young (age<45 years) and elderly group (age>45 years) at each IVD level. A linear relationship was observed between age and T2/ADC mean values in the elderly group as well as in the young group for the ADC mean values, while no such tendency was identified in the young group for the T2 mean values. CONCLUSIONS: ADC values may be a more sensitive parameter than T2 in assessing age and disc level related intervertebral disc changes. PMID- 23922682 TI - Loss of NAC1 expression is associated with defective bony patterning in the murine vertebral axis. AB - NAC1 encoded by NACC1 is a member of the BTB/POZ family of proteins and participates in several pathobiological processes. However, its function during tissue development has not been elucidated. In this study, we compared homozygous null mutant Nacc1(-/-) and wild type Nacc1(+/+) mice to determine the consequences of diminished NAC1 expression. The most remarkable change in Nacc1( /-) mice was a vertebral patterning defect in which most knockout animals exhibited a morphological transformation of the sixth lumbar vertebra (L6) into a sacral identity; thus, the total number of pre-sacral vertebrae was decreased by one (to 25) in Nacc1(-/-) mice. Heterozygous Nacc1(+/-) mice had an increased tendency to adopt an intermediate phenotype in which L6 underwent partial sacralization. Nacc1(-/-) mice also exhibited non-closure of the dorsal aspects of thoracic vertebrae T10-T12. Chondrocytes from Nacc1(+/+) mice expressed abundant NAC1 while Nacc1(-/-) chondrocytes had undetectable levels. Loss of NAC1 in Nacc1(-/-) mice was associated with significantly reduced chondrocyte migratory potential as well as decreased expression of matrilin-3 and matrilin-4, two cartilage-associated extracellular matrix proteins with roles in the development and homeostasis of cartilage and bone. These data suggest that NAC1 participates in the motility and differentiation of developing chondrocytes and cartilaginous tissues, and its expression is necessary to maintain normal axial patterning of murine skeleton. PMID- 23922683 TI - Targeting the giant cell tumor stromal cell: functional characterization and a novel therapeutic strategy. AB - Giant cell tumor of bone (GCTB) is a benign, locally destructive neoplasm, with tumors comprised of mesenchymal fibroblast-like stromal cells; monocytic, mononuclear cells of myeloid lineage; and the characteristic osteoclast-like, multinucleated giant cells. Hampering the study of the complex interaction of its constituent cell types is the propensity of longstanding, repeatedly passaged cell cultures to undergo phenotypic alteration and loss of osteoclast-inducing capacities. In this study, we employed a novel, single-step technique to purify freshly harvested stromal cells using a CD14-negative selection column. Using 9 freshly harvested GCTB specimens and the purified stromal cell component, we performed analyses for markers of osteoblast lineage and analyzed the capacity of the stromal cells to undergo osteoblastic differentiation and induce osteoclastogenesis in co-cultures with monocytic cells. Successful purification of the CD14-negative stromal cells was confirmed via flow cytometric analysis and immunocytochemistry. Osteogenic media upregulated the expression of osteocalcin, suggesting an osteoblastic lineage of the GCTB stromal cells. The effects of the Wnt pathway agonist, SB415286, and recombinant human bone morphogenetic protein (BMP)-2 on osteoblastogenesis varied among samples. Notably, osteogenic media and SB415286 reversed the receptor activator of NF-kappaB ligand (RANKL)/osteoprotegerin (OPG) expression ratio resulting in diminished osteoclastogenic capacity. Recombinant human BMP2 had the opposite effect, resulting in enhanced and sustained support of osteoclastogenesis. Targeting the giant cell tumor stromal cell may be an effective adjunct to existing anti resorptive strategies. PMID- 23922684 TI - Propyl-2-(8-(3,4-difluorobenzyl)-2',5'-dioxo-8-azaspiro[bicyclo[3.2.1] octane 3,4'-imidazolidine]-1'-yl) acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest. AB - BACKGROUND: Due to the functional defects in apoptosis signaling molecules or deficient activation of apoptosis pathways, leukemia has become an aggressive disease with poor prognosis. Although the majority of leukemia patients initially respond to chemotherapy, relapse is still the leading cause of death. Hence targeting apoptosis pathway would be a promising strategy for the improved treatment of leukemia. Hydantoin derivatives possess a wide range of important biological and pharmacological properties including anticancer properties. Here we investigated the antileukemic activity and mechanism of action of one of the potent azaspiro hydantoin derivative, (ASHD). MATERIALS AND METHODS: To investigate the antileukemic efficacy of ASHD, we have used MTT assay, cell cycle analysis by FACS, tritiated thymidine incorporation assay, Annexin V staining, JC1 staining and western blot analysis. RESULTS: Results showed that ASHD was approximately 3-fold more potent than the parent compounds in inducing cytotoxicity. Tritiated thymidine assay in conjunction with cell cycle analysis suggests that ASHD inhibited the growth of leukemic cells. The limited effect of ASHD on cell viability of normal cells indicated that it may be specifically directed to cancer cells. Translocation of phosphatidyl serine, activation of caspase 3, caspase 9, PARP, alteration in the ratio of BCL2/BAD protein expression as well as the loss of mitochondrial membrane potential suggests activation of the intrinsic pathway of apoptosis. CONCLUSION: These results could facilitate the future development of novel hydantoin derivatives as chemotherapeutic agents for leukemia. PMID- 23922685 TI - Cinnamic acid increases lignin production and inhibits soybean root growth. AB - Cinnamic acid is a known allelochemical that affects seed germination and plant root growth and therefore influences several metabolic processes. In the present work, we evaluated its effects on growth, indole-3-acetic acid (IAA) oxidase and cinnamate 4-hydroxylase (C4H) activities and lignin monomer composition in soybean (Glycine max) roots. The results revealed that exogenously applied cinnamic acid inhibited root growth and increased IAA oxidase and C4H activities. The allelochemical increased the total lignin content, thus altering the sum and ratios of the p-hydroxyphenyl (H), guaiacyl (G), and syringyl (S) lignin monomers. When applied alone or with cinnamic acid, piperonylic acid (PIP, a quasi-irreversible inhibitor of C4H) reduced C4H activity, lignin and the H, G, S monomer content compared to the cinnamic acid treatment. Taken together, these results indicate that exogenously applied cinnamic acid can be channeled into the phenylpropanoid pathway via the C4H reaction, resulting in an increase in H lignin. In conjunction with enhanced IAA oxidase activity, these metabolic responses lead to the stiffening of the cell wall and are followed by a reduction in soybean root growth. PMID- 23922686 TI - Protection of radiation-induced damage to the hematopoietic system, small intestine and salivary glands in rats by JNJ7777120 compound, a histamine H4 ligand. AB - Based on previous data on the histamine radioprotective effect on highly radiosensitive tissues, in the present work we aimed at investigating the radioprotective potential of the H4R ligand, JNJ7777120, on ionizing radiation induced injury and genotoxic damage in small intestine, salivary glands and hematopoietic tissue. For that purpose, rats were divided into 4 groups. JNJ7777120 and JNJ7777120-irradiated groups received a daily subcutaneous JNJ7777120 injection (10 mg/kg) starting 24 h before irradiation. Irradiated groups received a single dose of 5 Gy on whole-body using Cesium-137 source and were sacrificed 3 or 30 days after irradiation. Tissues were removed, fixed, stained with hematoxylin and eosin or PAS staining and histological characteristics were evaluated. Proliferative and apoptotic markers were studied by immunohistochemistry, while micronucleus assay was performed to evaluate DNA damage. Submandibular gland (SMG) function was evaluated by methacholine-induced salivation. Results indicate that JNJ7777120 treatment diminished mucosal atrophy and preserved villi and the number of crypts after radiation exposure (240+/-8 vs. 165+/-10, P<0.01). This effect was associated to a reduced apoptosis and DNA damage in intestinal crypts. JNJ7777120 reduced radiation-induced aplasia, preserving medullar components and reducing formation of micronucleus and also it accelerated bone marrow repopulation. Furthermore, it reduced micronucleus frequency in peripheral blood (27+/-8 vs. 149+/-22, in 1,000 erythrocytes, P<0.01). JNJ7777120 completely reversed radiation-induced reduced salivation, conserving glandular mass with normal histological appearance and reducing apoptosis and atrophy of SMG. JNJ7777120 exhibits radioprotective effects against radiation-induced cytotoxic and genotoxic damages in small intestine, SMG and hematopoietic tissues and, thus, could be of clinical value for patients undergoing radiotherapy. PMID- 23922687 TI - Association between interleukin-4 receptor alpha chain (IL4RA) I50V and Q551R polymorphisms and asthma risk: an update meta-analysis. AB - BACKGROUND: The associations between the interleukin-4 receptor alpha chain (IL4RA) I50V and Q551R polymorphisms and asthma risk remained controversial. METHODS: We searched the Pubmed, Embase, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases for studies published before February 2013. The strengths of the associations were calculated using odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A total of 50 studies were included in this meta-analysis. There was a significant association between the IL4RA I50V polymorphism and asthma risk in a dominant genetic model (OR = 1.13, 95% CI 1.04 1.23, P = 0.005). The IL4RA Q551R polymorphism was associated with a significantly elevated asthma risk in a recessive genetic model (OR = 1.46, 95% CI 1.22-1.75, P<0.0001). Subgroup analyses found that the IL4RA I50V polymorphism was significantly associated with asthma risk in Asians (OR = 1.72, 95% CI 1.31 2.25, P<0.0001), pediatric asthma risk (OR = 1.50, 95% CI 1.13-1.99, P = 0.005), and atopic asthma risk (OR = 1.88, 95% CI 1.27-2.79, P = 0.002). CONCLUSIONS: The results of this meta-analysis suggested that the IL4RA I50V and Q551R polymorphisms may be risk factors for developing asthma. PMID- 23922688 TI - A scallop nitric oxide synthase (NOS) with structure similar to neuronal NOS and its involvement in the immune defense. AB - BACKGROUND: Nitric oxide synthase (NOS) is responsible for synthesizing nitric oxide (NO) from L-arginine, and involved in multiple physiological functions. However, its immunological role in mollusc was seldom reported. METHODOLOGY: In the present study, an NOS (CfNOS) gene was identified from the scallop Chlamys farreri encoding a polypeptide of 1486 amino acids. Its amino acid sequence shared 50.0~54.7, 40.7~47.0 and 42.5~44.5% similarities with vertebrate neuronal (n), endothelial (e) and inducible (i) NOSs, respectively. CfNOS contained PDZ, oxygenase and reductase domains, which resembled those in nNOS. The CfNOS mRNA transcripts expressed in all embryos and larvae after the 2-cell embryo stage, and were detectable in all tested tissues with the highest level in the gonad, and with the immune tissues hepatopancreas and haemocytes included. Moreover, the immunoreactive area of CfNOS distributed over the haemocyte cytoplasm and cell membrane. After LPS, beta-glucan and PGN stimulation, the expression level of CfNOS mRNA in haemocytes increased significantly at 3 h (4.0-, 4.8- and 2.7-fold, respectively, P < 0.01), and reached the peak at 12 h (15.3- and 27.6-fold for LPS and beta-glucan respectively, P < 0.01) and 24 h (17.3-fold for PGN, P < 0.01). In addition, TNF-alpha also induced the expression of CfNOS, which started to increase at 1 h (5.2-fold, P < 0.05) and peaked at 6 h (19.9-fold, P < 0.01). The catalytic activity of the native CfNOS protein was 30.3 +/- 0.3 U mgprot(-1), and it decreased significantly after the addition of the selective inhibitors of nNOS and iNOS (26.9 +/- 0.4 and 29.3 +/- 0.1 U mgprot(-1), respectively, P < 0.01). CONCLUSIONS: These results suggested that CfNOS, with identical structure with nNOS and similar enzymatic characteristics to nNOS and iNOS, played the immunological role of iNOS to be involved in the scallop immune defense against PAMPs and TNF-alpha. PMID- 23922689 TI - hESC expansion and stemness are independent of connexin forty-three-mediated intercellular communication between hESCs and hASC feeder cells. AB - BACKGROUND: Human embryonic stem cells (hESCs) are a promising and powerful source of cells for applications in regenerative medicine, tissue engineering, cell-based therapies, and drug discovery. Many researchers have employed conventional culture techniques using feeder cells to expand hESCs in significant numbers, although feeder-free culture techniques have recently been developed. In regard to stem cell expansion, gap junctional intercellular communication (GJIC) is thought to play an important role in hESC survival and differentiation. Indeed, it has been reported that hESC-hESC communication through connexin 43 (Cx43, one of the major gap junctional proteins) is crucial for the maintenance of hESC stemness during expansion. However, the role of GJIC between hESCs and feeder cells is unclear and has not yet been reported. METHODOLOGY/PRINCIPAL FINDINGS: This study therefore examined whether a direct Cx43-mediated interaction between hESCs and human adipose-derived stem cells (hASCs) influences the maintenance of hESC stemness. Over 10 passages, hESCs cultured on a layer of Cx43-downregulated hASC feeder cells showed normal morphology, proliferation (colony growth), and stemness, as assessed by alkaline phosphatase (AP), OCT4 (POU5F1-Human gene Nomenclature Database), SOX2, and NANOG expression. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that Cx43-mediated GJIC between hESCs and hASC feeder cells is not an important factor for the conservation of hESC stemness and expansion. PMID- 23922690 TI - Regulatory CD4+Foxp3+ T cells control the severity of anaphylaxis. AB - OBJECTIVE: Anaphylaxis is a life-threatening outcome of immediate-type hypersensitivity to allergen, consecutive to mast cell degranulation by allergen specific IgE. Regulatory T cells (Treg) can control allergic sensitization and mast cell degranulation, yet their clinical benefit on anaphylactic symptoms is poorly documented. Here we investigated whether Treg action during the effector arm of the allergic response alleviates anaphylaxis. METHODS: We used a validated model of IgE-mediated passive systemic anaphylaxis, induced by intravenous challenge with DNP-HSA in mice passively sensitized with DNP-specific IgE. Anaphylaxis was monitored by the drop in body temperature as well as plasma histamine and serum mMCP1 levels. The role of Treg was analyzed using MHC class II-deficient (Abeta( degrees / degrees )) mice, treatment with anti-CD25 or anti CD4 mAbs and conditional ablation of Foxp3(+) Treg in DEREG mice. Therapeutic efficacy of Treg was also evaluated by transfer experiments using FoxP3-eGFP knock-in mice. RESULTS: Anaphylaxis did not occur in mast cell-deficient W/W(v) mutant mice and was only moderate and transient in mice deficient for histamine receptor-1. Defects in constitutive Treg, either genetic or induced by antibody or toxin treatment resulted in a more severe and/or sustained hypothermia, associated with a rise in serum mMCP1, but not histamine. Adoptive transfer of Foxp3(+) Treg from either naive or DNP-sensitized donors similarly alleviated body temperature loss in Treg-deficient DEREG mice. CONCLUSION: Constitutive Foxp3(+) Treg can control the symptomatic phase of mast cell and IgE-dependent anaphylaxis in mice. This might open up new therapeutic avenues using constitutive rather than Ag-specific Treg for inducing tolerance in allergic patients. PMID- 23922691 TI - Genomic treasure troves: complete genome sequencing of herbarium and insect museum specimens. AB - Unlocking the vast genomic diversity stored in natural history collections would create unprecedented opportunities for genome-scale evolutionary, phylogenetic, domestication and population genomic studies. Many researchers have been discouraged from using historical specimens in molecular studies because of both generally limited success of DNA extraction and the challenges associated with PCR-amplifying highly degraded DNA. In today's next-generation sequencing (NGS) world, opportunities and prospects for historical DNA have changed dramatically, as most NGS methods are actually designed for taking short fragmented DNA molecules as templates. Here we show that using a standard multiplex and paired end Illumina sequencing approach, genome-scale sequence data can be generated reliably from dry-preserved plant, fungal and insect specimens collected up to 115 years ago, and with minimal destructive sampling. Using a reference-based assembly approach, we were able to produce the entire nuclear genome of a 43-year old Arabidopsis thaliana (Brassicaceae) herbarium specimen with high and uniform sequence coverage. Nuclear genome sequences of three fungal specimens of 22-82 years of age (Agaricus bisporus, Laccaria bicolor, Pleurotus ostreatus) were generated with 81.4-97.9% exome coverage. Complete organellar genome sequences were assembled for all specimens. Using de novo assembly we retrieved between 16.2-71.0% of coding sequence regions, and hence remain somewhat cautious about prospects for de novo genome assembly from historical specimens. Non-target sequence contaminations were observed in 2 of our insect museum specimens. We anticipate that future museum genomics projects will perhaps not generate entire genome sequences in all cases (our specimens contained relatively small and low complexity genomes), but at least generating vital comparative genomic data for testing (phylo)genetic, demographic and genetic hypotheses, that become increasingly more horizontal. Furthermore, NGS of historical DNA enables recovering crucial genetic information from old type specimens that to date have remained mostly unutilized and, thus, opens up a new frontier for taxonomic research as well. PMID- 23922692 TI - Tracking Nile Delta vulnerability to Holocene change. AB - Understanding deltaic resilience in the face of Holocene climate change and human impacts is an important challenge for the earth sciences in characterizing the full range of present and future wetland responses to global warming. Here, we report an 8000-year mass balance record from the Nile Delta to reconstruct when and how this sedimentary basin has responded to past hydrological shifts. In a global Holocene context, the long-term decrease in Nile Delta accretion rates is consistent with insolation-driven changes in the 'monsoon pacemaker', attested throughout the mid-latitude tropics. Following the early to mid-Holocene growth of the Nile's deltaic plain, sediment losses and pronounced erosion are first recorded after ~4000 years ago, the corollaries of falling sediment supply and an intensification of anthropogenic impacts from the Pharaonic period onwards. Against the backcloth of the Saharan 'depeopling', reduced river flow underpinned by a weakening of monsoonal precipitation appears to have been particularly conducive to the expansion of human activities on the delta by exposing productive floodplain lands for occupation and irrigation agriculture. The reconstruction suggests that the Nile Delta has a particularly long history of vulnerability to extreme events (e.g. floods and storms) and sea-level rise, although the present sediment-starved system does not have a direct Holocene analogue. This study highlights the importance of the world's deltas as sensitive archives to investigate Holocene geosystem responses to climate change, risks and hazards, and societal interaction. PMID- 23922693 TI - Olfaction and environment: Tsimane' of Bolivian rainforest have lower threshold of odor detection than industrialized German people. AB - Olfactory sensitivity varies between individuals. However, data regarding cross cultural and inter-group differences are scarce. We compared the thresholds of odor detection of the traditional society of Tsimane' (native Amazonians of the Bolivian rainforest; n = 151) and people living in Dresden (Germany; n = 286) using "Sniffin' Sticks" threshold subtest. Tsimane' detected n-butanol at significantly lower concentrations than the German subjects. The distribution of thresholds of the Tsimane' was very specific, with 25% of Tsimane' obtaining better results in the olfactory test than any member of the German group. These data suggest that differences in olfactory sensitivity seem to be especially salient between industrialized and non-industrialized populations inhabiting different environmental conditions. We hypothesize that the possible sources of such differences are: (i) the impact of pollution which impairs the olfactory abilities of people from industrialized countries; (ii) better training of olfaction because of the higher importance of smell in traditional populations; (iii) environmental pressures shaping olfactory abilities in these populations. PMID- 23922694 TI - The poplar MYB master switches bind to the SMRE site and activate the secondary wall biosynthetic program during wood formation. AB - Wood is mainly composed of secondary walls, which constitute the most abundant stored carbon produced by vascular plants. Understanding the molecular mechanisms controlling secondary wall deposition during wood formation is not only an important issue in plant biology but also critical for providing molecular tools to custom-design wood composition suited for diverse end uses. Past molecular and genetic studies have revealed a transcriptional network encompassing a group of wood-associated NAC and MYB transcription factors that are involved in the regulation of the secondary wall biosynthetic program during wood formation in poplar trees. Here, we report the functional characterization of poplar orthologs of MYB46 and MYB83 that are known to be master switches of secondary wall biosynthesis in Arabidopsis. In addition to the two previously-described PtrMYB3 and PtrMYB20, two other MYBs, PtrMYB2 and PtrMYB21, were shown to be MYB46/MYB83 orthologs by complementation and overexpression studies in Arabidopsis. The functional roles of these PtrMYBs in regulating secondary wall biosynthesis were further demonstrated in transgenic poplar plants showing an ectopic deposition of secondary walls in PtrMYB overexpressors and a reduction of secondary wall thickening in their dominant repressors. Furthermore, PtrMYB2/3/20/21 together with two other tree MYBs, the Eucalyptus EgMYB2 and the pine PtMYB4, were shown to differentially bind to and activate the eight variants of the 7-bp SMRE consensus sequence, composed of ACC(A/T)A(A/C)(T/C). Together, our results indicate that the tree MYBs, PtrMYB2/3/20/21, EgMYB2 and PtMYB4, are master transcriptional switches that activate the SMRE sites in the promoters of target genes and thereby regulate secondary wall biosynthesis during wood formation. PMID- 23922695 TI - Bioenergetics of the calf muscle in Friedreich ataxia patients measured by 31P MRS before and after treatment with recombinant human erythropoietin. AB - Friedreich ataxia (FRDA) is caused by a GAA repeat expansion in the FXN gene leading to reduced expression of the mitochondrial protein frataxin. Recombinant human erythropoietin (rhuEPO) is suggested to increase frataxin levels, alter mitochondrial function and improve clinical scores in FRDA patients. Aim of the present pilot study was to investigate mitochondrial metabolism of skeletal muscle tissue in FRDA patients and examine effects of rhuEPO administration by phosphorus 31 magnetic resonance spectroscopy (31P MRS). Seven genetically confirmed FRDA patients underwent 31P MRS of the calf muscles using a rest exercise-recovery protocol before and after receiving 3000 IU of rhuEPO for eight weeks. FRDA patients showed more rapid phosphocreatine (PCr) depletion and increased accumulation of inorganic phosphate (Pi) during incremental exercise as compared to controls. After maximal exhaustive exercise prolonged regeneration of PCR and slowed decline in Pi can be seen in FRDA. PCr regeneration as hallmark of mitochondrial ATP production revealed correlation to activity of complex II/III of the respiratory chain and to demographic values. PCr and Pi kinetics were not influenced by rhuEPO administration. Our results confirm mitochondrial dysfunction and exercise intolerance due to impaired oxidative phosphorylation in skeletal muscle tissue of FRDA patients. MRS did not show improved mitochondrial bioenergetics after eight weeks of rhuEPO exposition in skeletal muscle tissue of FRDA patients. TRIAL REGISTRATION: EU Clinical Trials Register2008-000040-13. PMID- 23922696 TI - tRNA binding to antitumor drug doxorubicin and its analogue. AB - The binding sites of antitumor drug doxorubicin (DOX) and its analogue N (trifluoroacetyl) doxorubicin (FDOX) with tRNA were located, using FTIR, CD, fluorescence spectroscopic methods and molecular modeling. Different binding sites are involved in drug-tRNA adducts with DOX located in the vicinity of A-29, A-31, A-38, C-25, C-27, C-28, G-30 and U-41, while FDOX bindings involved A-23, A 44, C-25, C-27, G-24, G-42, G-53, G-45 and U-41 with similar free binding energy (-4.44 for DOX and -4.41 kcal/mol for FDOX adducts). Spectroscopic results showed that both hydrophilic and hydrophobic contacts are involved in drug-tRNA complexation and FDOX forms more stable complexes than DOX with K DOX-tRNA=4.7 (+/- 0.5)* 10(4) M(-1) and K FDOX-tRNA=6.3 (+/- 0.7)* 10(4) M(-1). The number of drug molecules bound per tRNA (n) was 0.6 for DOX and 0.4 for FDOX. No major alterations of tRNA structure were observed and tRNA remained in A-family conformation, while biopolymer aggregation and particle formation occurred at high drug concentrations. PMID- 23922697 TI - Mutations in planar cell polarity gene SCRIB are associated with spina bifida. AB - Neural tube defects (NTDs) (OMIM #182940) including anencephaly, spina bifida and craniorachischisis, are severe congenital malformations that affect 0.5-1 in 1,000 live births in the United States, with varying prevalence around the world. Mutations in planar cell polarity (PCP) genes are believed to cause a variety of NTDs in both mice and humans. SCRIB is a PCP-associated gene. Mice that are homozygous for the Scrib p.I285K and circletail (Crc) mutations, present with the most severe form of NTDs, namely craniorachischisis. A recent study reported that mutations in SCRIB were associated with craniorachischisis in humans, but whether SCRIB mutations contribute to increased spina bifida risk is still unknown. We sequenced the SCRIB gene in 192 infants with spina bifida and 190 healthy controls. Among the spina bifida patients, we identified five novel missense mutations that were predicted-to-be-deleterious by the PolyPhen software. Of these five mutations, three of them (p.P1043L, p.P1332L, p.L1520R) significantly affected the subcellular localization of SCRIB. In addition, we demonstrated that the craniorachischisis mouse line-90 mutation I285K, also affected SCRIB subcellular localization. In contrast, only one novel missense mutation (p.A1257T) was detected in control samples, and it was predicted to be benign. This study demonstrated that rare deleterious mutations of SCRIB may contribute to the multifactorial risk for human spina bifida. PMID- 23922698 TI - Mechanisms of HIV entry into the CNS: increased sensitivity of HIV infected CD14+CD16+ monocytes to CCL2 and key roles of CCR2, JAM-A, and ALCAM in diapedesis. AB - As HIV infected individuals live longer, the prevalence of HIV associated neurocognitive disorders is increasing, despite successful antiretroviral therapy. CD14(+)CD16(+) monocytes are critical to the neuropathogenesis of HIV as they promote viral seeding of the brain and establish neuroinflammation. The mechanisms by which HIV infected and uninfected monocytes cross the blood brain barrier and enter the central nervous system are not fully understood. We determined that HIV infection of CD14(+)CD16(+) monocytes resulted in their highly increased transmigration across the blood brain barrier in response to CCL2 as compared to uninfected cells, which did not occur in the absence of the chemokine. This exuberant transmigration of HIV infected monocytes was due, at least in part, to increased CCR2 and significantly heightened sensitivity to CCL2. The entry of HIV infected and uninfected CD14(+)CD16(+) monocytes into the brain was facilitated by significantly increased surface JAM-A, ALCAM, CD99, and PECAM-1, as compared to CD14(+) cells that are CD16 negative. Upon HIV infection, there was an additional increase in surface JAM-A and ALCAM on CD14(+)CD16(+) monocytes isolated from some individuals. Antibodies to ALCAM and JAM-A inhibited the transmigration of both HIV infected and uninfected CD14(+)CD16(+) monocytes across the BBB, demonstrating their importance in facilitating monocyte transmigration and entry into the brain parenchyma. Targeting CCR2, JAM-A, and ALCAM present on CD14(+)CD16(+) monocytes that preferentially infiltrate the CNS represents a therapeutic strategy to reduce viral seeding of the brain as well as the ongoing neuroinflammation that occurs during HIV pathogenesis. PMID- 23922699 TI - The histidine-phosphocarrier protein of the phosphoenolpyruvate: sugar phosphotransferase system of Bacillus sphaericus self-associates. AB - The phosphotransferase system (PTS) is involved in the use of carbon sources in bacteria. Bacillus sphaericus, a bacterium with the ability to produce insecticidal proteins, is unable to use hexoses and pentoses as the sole carbon source, but it has ptsHI genes encoding the two general proteins of the PTS: enzyme I (EI) and the histidine phosphocarrier (HPr). In this work, we describe the biophysical and structural properties of HPr from B. sphaericus, HPr(bs), and its affinity towards EI of other species to find out whether there is inter species binding. Conversely to what happens to other members of the HPr family, HPr(bs) forms several self-associated species. The conformational stability of the protein is low, and it unfolds irreversibly during heating. The protein binds to the N-terminal domain of EI from Streptomyces coelicolor, EIN(sc), with a higher affinity than that of the natural partner of EIN(sc), HPr(sc). Modelling of the complex between EIN(sc) and HPr(bs) suggests that binding occurs similarly to that observed in other HPr species. We discuss the functional implications of the oligomeric states of HPr(bs) for the glycolytic activity of B. sphaericus, as well as a strategy to inhibit binding between HPr(sc) and EIN(sc). PMID- 23922700 TI - Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. AB - BACKGROUND: Increased intra-hepatic resistance to portal blood flow is the primary factor leading to portal hypertension in cirrhosis. Up-regulated expression of cyclooxygenase-2 (COX-2) in the cirrhotic liver might be a potential target to ameliorate portal hypertension. OBJECTIVE: To verify the effect of celecoxib, a selective inhibitor of COX-2, on portal hypertension and the mechanisms behind it. METHODS: Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA). 36 rats were randomly assigned to control, TAA and TAA+celecoxib groups. Portal pressures were measured by introduction of catheters into portal vein. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and mRNAs for collagen III and alpha-SMA. The neovasculature was determined by hepatic vascular areas, vascular casts and CD31 expression. Expressions of COX-2, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2) and related signal molecules were quantitated. RESULTS: Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8%, p<0.01. Celecoxib treatment greatly reduced the tortuous hepatic portal venules. The data of fibrotic areas, CD31expression, mRNA levels of alpha-SMA and collagen III in TAA+celecoxib group were much lower than those in TAA group, p<0.01. Furthermore, the up-regulation of hepatic mRNA and protein levels of VEGF, VEGFR-2 and COX-2 induced by TAA was significantly inhibited after celecoxib treatment. The expressions of prostaglandin E2 (PGE2), phosphorylated extracellular signal-regulated kinase (p-ERK), hypoxia-inducible factor-1alpha (HIF-1alpha), and c-fos were also down-regulated after celecoxib treatment. CONCLUSIONS: Long term administration of celecoxib can efficiently ameliorate portal hypertension in TAA rat model by its dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. The anti-angiogenesis effect afforded by celecoxib may attribute to its modulation on VEGF/VEGFR-2 through the down regulation of integrated signal pathways involving PGE2- HIF-1alpha- VEGF and p ERK- c-fos- VEGFR-2. PMID- 23922701 TI - Overexpressed DNA polymerase iota regulated by JNK/c-Jun contributes to hypermutagenesis in bladder cancer. AB - Human DNA polymerase iota (pol iota) possesses high error-prone DNA replication features and performs translesion DNA synthesis. It may be specialized and strictly regulated in normal mammalian cells. Dysregulation of pol iota may contribute to the acquisition of a mutator phenotype. However, there are few reports describing the transcription regulatory mechanism of pol iota, and there is controversy regarding its role in carcinogenesis. In this study, we performed the deletion and point-mutation experiment, EMSA, ChIP, RNA interference and western blot assay to prove that c-Jun activated by c-Jun N-terminal kinase (JNK) regulates the transcription of pol iota in normal and cancer cells. Xeroderma pigmentosum group C protein (XPC) and ataxia-telangiectasia mutated related protein (ATR) promote early JNK activation in response to DNA damage and consequently enhance the expression of pol iota, indicating that the novel role of JNK signal pathway is involved in DNA damage response. Furthermore, associated with elevated c-Jun activity, the overexpression of pol iota is positively correlated with the clinical tumor grade in 97 bladder cancer samples and may contribute to the hypermutagenesis. The overexpressed pol iota-involved mutagenesis is dependent on JNK/c-Jun pathway in bladder cancer cells identifying by the special mutation spectra. Our results support the conclusion that dysregulation of pol iota by JNK/c-Jun is involved in carcinogenesis and offer a novel understanding of the role of pol iota or c-Jun in mutagenesis. PMID- 23922703 TI - Porous allograft bone scaffolds: doping with strontium. AB - Strontium (Sr) can promote the process of bone formation. To improve bioactivity, porous allograft bone scaffolds (ABS) were doped with Sr and the mechanical strength and bioactivity of the scaffolds were evaluated. Sr-doped ABS were prepared using the ion exchange method. The density and distribution of Sr in bone scaffolds were investigated by inductively coupled plasma optical emission spectrometry (ICP-OES), X-ray photoelectron spectroscopy (XPS), and energy dispersive X-ray spectroscopy (EDS). Controlled release of strontium ions was measured and mechanical strength was evaluated by a compressive strength test. The bioactivity of Sr-doped ABS was investigated by a simulated body fluid (SBF) assay, cytotoxicity testing, and an in vivo implantation experiment. The Sr molar concentration [Sr/(Sr+Ca)] in ABS surpassed 5% and Sr was distributed nearly evenly. XPS analyses suggest that Sr combined with oxygen and carbonate radicals. Released Sr ions were detected in the immersion solution at higher concentration than calcium ions until day 30. The compressive strength of the Sr-doped ABS did not change significantly. The bioactivity of Sr-doped material, as measured by the in vitro SBF immersion method, was superior to that of the Sr-free freeze dried bone and the Sr-doped material did not show cytotoxicity compared with Sr free culture medium. The rate of bone mineral deposition for Sr-doped ABS was faster than that of the control at 4 weeks (3.28 +/- 0.23 um/day vs. 2.60 +/- 0.20 um/day; p<0.05). Sr can be evenly doped into porous ABS at relevant concentrations to create highly active bone substitutes. PMID- 23922702 TI - The role of heat shock protein 70 in the protective effect of YC-1 on beta amyloid-induced toxicity in differentiated PC12 cells. AB - Neurodegenerative brain disorders such as Alzheimer's disease (AD) have been well investigated. However, significant methods for the treatment of the progression of AD are unavailable currently. Heat shock protein 70 (Hsp70) plays important roles in neural protection from stress by assisting cellular protein folding. In this study, we investigated the effect and the molecular mechanism of YC-1, an activator of guanylyl cyclase (GC), on Abeta25-35-induced cytotoxicity in differentiated PC12 cells. The results of this study showed that Abeta25-35 (10 uM) significantly increased p25 protein production in a pattern that was consistent with the increase in MU-calpain expression. Moreover, Abeta25-35 significantly increased tau hyperphosphorylation and induced differentiated PC12 cell death. YC-1 (0.5-10 uM) prevented the cell death induced by Abeta25-35. In addition, YC-1 (1, 10 uM) significantly blocked Abeta25-35-induced MU-calpain expression and decreased the formation of p25 and tau hyperphosphorylation. Moreover, YC-1 (5-20 uM) alone or combined with Abeta25-35 (10 uM) significantly increased the expression of Hsp70 in differentiated PC12 cells. The neuroprotective effect of YC-1 was significantly attenuated by an Hsp70 inhibitor (quercetin, 50 uM) or in PC12 cells transfected with an Hsp70 small interfering RNA. However, pretreatment of cells with the GC inhibitor ODQ (10 uM) did not affect the neuroprotective effect of YC-1 against Abeta25-35 in differentiated PC12 cells. These results suggest that the neuroprotective effect of YC-1 against Abeta25-35-induced toxicity is mainly mediated by the induction of Hsp70. Thus, YC-1 is a potential agent against AD. PMID- 23922704 TI - Comprehensive mapping of common immunodominant epitopes in the eastern equine encephalitis virus E2 protein recognized by avian antibody responses. AB - Eastern equine encephalitis virus (EEEV) is a mosquito-borne virus that can cause both human and equine encephalitis with high case fatality rates. EEEV can also be widespread among birds, including pheasants, ostriches, emu, turkeys, whooping cranes and chickens. The E2 protein of EEEV and other Alphaviruses is an important immunogenic protein that elicits antibodies of diagnostic value. While many therapeutic and diagnostic applications of E2 protein-specific antibodies have been reported, the specific epitopes on E2 protein recognized by the antibody responses of different susceptible hosts, including avian species, remain poorly defined. In the present study, the avian E2-reactive polyclonal antibody (PAb) response was mapped to linear peptide epitopes using PAbs elicited in chickens and ducks following immunization with recombinant EEEV E2 protein and a series of 42 partially overlapping peptides covering the entire EEEV E2 protein. We identified 12 and 13 peptides recognized by the chicken and duck PAb response, respectively. Six of these linear peptides were commonly recognized by PAbs elicited in both avian species. Among them five epitopes recognized by both avian, the epitopes located at amino acids 211-226 and 331-352 were conserved among the EEEV antigenic complex, but not other associated alphaviruses, whereas the epitopes at amino acids 11-26, 30-45 and 151-166 were specific to EEEV subtype I. The five common peptide epitopes were not recognized by avian PAbs against Avian Influenza Virus (AIV) and Duck Plague Virus (DPV). The identification and characterization of EEEV E2 antibody epitopes may be aid the development of diagnostic tools and facilitate the design of epitope-based vaccines for EEEV. These results also offer information with which to study the structure of EEEV E2 protein. PMID- 23922705 TI - Piriformospora indica root colonization triggers local and systemic root responses and inhibits secondary colonization of distal roots. AB - Piriformosporaindica is a basidiomycete fungus colonizing roots of a wide range of higher plants, including crop plants and the model plant Arabidopsis thaliana. Previous studies have shown that P. indica improves growth, and enhances systemic pathogen resistance in leaves of host plants. To investigate systemic effects within the root system, we established a hydroponic split-root cultivation system for Arabidopsis. Using quantitative real-time PCR, we show that initial P. indica colonization triggers a local, transient response of several defense-related transcripts, of which some were also induced in shoots and in distal, non colonized roots of the same plant. Systemic effects on distal roots included the inhibition of secondary P. indica colonization. Faster and stronger induction of defense-related transcripts during secondary inoculation revealed that a P. indica pretreatment triggers root-wide priming of defense responses, which could cause the observed reduction of secondary colonization levels. Secondary P. indica colonization also induced defense responses in distant, already colonized parts of the root. Endophytic fungi therefore trigger a spatially specific response in directly colonized and in systemic root tissues of host plants. PMID- 23922706 TI - Simple system for isothermal DNA amplification coupled to lateral flow detection. AB - Infectious disease diagnosis in point-of-care settings can be greatly improved through integrated, automated nucleic acid testing devices. We have developed an early prototype for a low-cost system which executes isothermal DNA amplification coupled to nucleic acid lateral flow (NALF) detection in a mesofluidic cartridge attached to a portable instrument. Fluid handling inside the cartridge is facilitated through one-way passive valves, flexible pouches, and electrolysis driven pumps, which promotes a compact and inexpensive instrument design. The closed-system disposable prevents workspace amplicon contamination. The cartridge design is based on standard scalable manufacturing techniques such as injection molding. Nucleic acid amplification occurs in a two-layer pouch that enables efficient heat transfer. We have demonstrated as proof of principle the amplification and detection of Mycobacterium tuberculosis (M.tb) genomic DNA in the cartridge, using either Loop Mediated Amplification (LAMP) or the Exponential Amplification Reaction (EXPAR), both coupled to NALF detection. We envision that a refined version of this cartridge, including upstream sample preparation coupled to amplification and detection, will enable fully-automated sample-in to answer-out infectious disease diagnosis in primary care settings of low-resource countries with high disease burden. PMID- 23922707 TI - Seasonality in polyps of a tropical cubozoan: A latina nr mordens. AB - A latina nr mordens have been located in large predictable spawning aggregations near Osprey Reef in the Coral Sea eight to ten days after a full moon; however, polyps have never been located in-situ. The polyp stage contributes to the abundance of medusae through asexual reproduction and metamorphosis, and may influence the periodicity of medusae by metamorphosis of the polyp. To elucidate the relationship between medusae periodicity and polyp ecology, polyps were exposed to thermal and osmotic treatments in order to determine the theoretical environmental limits to their distribution. Maximum fecundity occurred in thermal treatments of 21 to 25oC and the theoretical minimum thermal requirement for population stability was approximately 17oC. Polyps were also exposed to five feeding regimes and fecundity was found to be positively correlated with feeding frequency. Thermal and osmotic variations did not induce metamorphosis in this species, however, reduced food did. The implications of asexual reproduction and cues for metamorphosis in relation to population dynamics of this species are discussed. PMID- 23922708 TI - Contribution of distinct homeodomain DNA binding specificities to Drosophila embryonic mesodermal cell-specific gene expression programs. AB - Homeodomain (HD) proteins are a large family of evolutionarily conserved transcription factors (TFs) having diverse developmental functions, often acting within the same cell types, yet many members of this family paradoxically recognize similar DNA sequences. Thus, with multiple family members having the potential to recognize the same DNA sequences in cis-regulatory elements, it is difficult to ascertain the role of an individual HD or a subclass of HDs in mediating a particular developmental function. To investigate this problem, we focused our studies on the Drosophila embryonic mesoderm where HD TFs are required to establish not only segmental identities (such as the Hox TFs), but also tissue and cell fate specification and differentiation (such as the NK-2 HDs, Six HDs and identity HDs (I-HDs)). Here we utilized the complete spectrum of DNA binding specificities determined by protein binding microarrays (PBMs) for a diverse collection of HDs to modify the nucleotide sequences of numerous mesodermal enhancers to be recognized by either no or a single subclass of HDs, and subsequently assayed the consequences of these changes on enhancer function in transgenic reporter assays. These studies show that individual mesodermal enhancers receive separate transcriptional input from both I-HD and Hox subclasses of HDs. In addition, we demonstrate that enhancers regulating upstream components of the mesodermal regulatory network are targeted by the Six class of HDs. Finally, we establish the necessity of NK-2 HD binding sequences to activate gene expression in multiple mesodermal tissues, supporting a potential role for the NK-2 HD TF Tinman (Tin) as a pioneer factor that cooperates with other factors to regulate cell-specific gene expression programs. Collectively, these results underscore the critical role played by HDs of multiple subclasses in inducing the unique genetic programs of individual mesodermal cells, and in coordinating the gene regulatory networks directing mesoderm development. PMID- 23922710 TI - Volatile exchange between undamaged plants - a new mechanism affecting insect orientation in intercropping. AB - Changes in plant volatile emission can be induced by exposure to volatiles from neighbouring insect-attacked plants. However, plants are also exposed to volatiles from unattacked neighbours, and the consequences of this have not been explored. We investigated whether volatile exchange between undamaged plants affects volatile emission and plant-insect interaction. Consistently greater quantities of two terpenoids were found in the headspace of potato previously exposed to volatiles from undamaged onion plants identified by mass spectrometry. Using live plants and synthetic blends mimicking exposed and unexposed potato, we tested the olfactory response of winged aphids, Myzus persicae. The altered potato volatile profile deterred aphids in laboratory experiments. Further, we show that growing potato together with onion in the field reduces the abundance of winged, host-seeking aphids. Our study broadens the ecological significance of the phenomenon; volatiles carry not only information on whether or not neighbouring plants are under attack, but also information on the emitter plants themselves. In this way responding plants could obtain information on whether the neighbouring plant is a competitive threat and can accordingly adjust their growth towards it. We interpret this as a response in the process of adaptation towards neighbouring plants. Furthermore, these physiological changes in the responding plants have significant ecological impact, as behaviour of aphids was affected. Since herbivore host plants are potentially under constant exposure to these volatiles, our study has major implications for the understanding of how mechanisms within plant communities affect insects. This knowledge could be used to improve plant protection and increase scientific understanding of communication between plants and its impact on other organisms. PMID- 23922709 TI - A characterization of the Manduca sexta serotonin receptors in the context of olfactory neuromodulation. AB - Neuromodulation, the alteration of individual neuron response properties, has dramatic consequences for neural network function and is a phenomenon observed across all brain regions and taxa. However, the mechanisms underlying neuromodulation are made complex by the diversity of neuromodulatory receptors expressed within a neural network. In this study we begin to examine the receptor basis for serotonergic neuromodulation in the antennal lobe of Manduca sexta. To this end we cloned all four known insect serotonin receptor types from Manduca (the Ms5HTRs). We used phylogenetic analyses to classify the Ms5HTRs and to establish their relationships to other insect serotonin receptors, other insect amine receptors and the vertebrate serotonin receptors. Pharmacological assays demonstrated that each Ms5HTR was selective for serotonin over other endogenous amines and that serotonin had a similar potency at all four Ms5HTRs. The pharmacological assays also identified several agonists and antagonists of the different Ms5HTRs. Finally, we found that the Ms5HT1A receptor was expressed in a subpopulation of GABAergic local interneurons suggesting that the Ms5HTRs are likely expressed heterogeneously within the antennal lobe based on functional neuronal subtype. PMID- 23922711 TI - Outcomes and impact of HIV prevention, ART and TB programs in Swaziland--early evidence from public health triangulation. AB - INTRODUCTION: Swaziland's severe HIV epidemic inspired an early national response since the late 1980s, and regular reporting of program outcomes since the onset of a national antiretroviral treatment (ART) program in 2004. We assessed effectiveness outcomes and mortality trends in relation to ART, HIV testing and counseling (HTC), tuberculosis (TB) and prevention of mother to child transmission (PMTCT). METHODS: Data triangulated include intervention coverage and outcomes according to program registries (2001-2010), hospital admissions and deaths disaggregated by age and sex (2001-2010) and population mortality estimates from the 1997 and 2007 censuses and the 2007 demographic and health survey. RESULTS: By 2010, ART reached 70% of the estimated number of people living with HIV/AIDS with CD4<350/mm(3), with progressively improving patient retention and survival. As of 2010, 88% of health facilities providing antenatal care offered comprehensive PMTCT services. The HTC program recorded a halving in the proportion of adults tested who were HIV-infected; similarly HIV infection rates among HIV-exposed babies halved from 2007 to 2010. Case fatality rates among hospital patients diagnosed with HIV/AIDS started to decrease from 2005-6 in adults and especially in children, contrasting with stable case fatality for other causes including TB. All-cause child in-patient case fatality rates started to decrease from 2005-6. TB case notifications as well as rates of HIV/TB co infection among notified TB patients continued a steady increase through 2010, while coverage of HIV testing and CPT for co-infected patients increased to above 80%. CONCLUSION: Against a background of high, but stable HIV prevalence and decreasing HIV incidence, we documented early evidence of a mortality decline associated with the expanded national HIV response since 2004. Attribution of impact to specific interventions (versus natural epidemic dynamics) will require additional data from future household surveys, and improved routine (program, surveillance, and hospital) data at district level. PMID- 23922712 TI - Identification of parasite-host habitats in Anxiang county, Hunan Province, China based on multi-temporal China-Brazil earth resources satellite (CBERS) images. AB - Remote sensing is a promising technique for monitoring the distribution and dynamics of various vector-borne diseases. In this study, we used the multi temporal CBERS images, obtained free of charge, to predict the habitats of the snail Oncomelania hupensis, the sole intermediate host of schistosomiasis japonica, a snail-borne parasitic disease of considerable public health in China. Areas of suitable snail habitats were identified based on the normalized difference vegetation index (NDVI) and the normalized difference water index (NDWI), and the predictive model was tested against sites (snails present or absent) that were surveyed directly for O. hupensis. The model performed well (sensitivity and specificity were 63.64% and 78.09%, respectively), and with further development, we may provide an accurate, inexpensive tool for the broad scale monitoring and control of schistosomiasis, and other similar vector-borne diseases. PMID- 23922713 TI - Dynamics of HIV-containing compartments in macrophages reveal sequestration of virions and transient surface connections. AB - During HIV pathogenesis, infected macrophages behave as "viral reservoirs" that accumulate and retain virions within dedicated internal Virus-Containing Compartments (VCCs). The nature of VCCs remains ill characterized and controversial. Using wild-type HIV-1 and a replication-competent HIV-1 carrying GFP internal to the Gag precursor, we analyzed the biogenesis and evolution of VCCs in primary human macrophages. VCCs appear roughly 14 hours after viral protein synthesis is detected, initially contain few motile viral particles, and then mature to fill up with virions that become packed and immobile. The amount of intracellular Gag, the proportion of dense VCCs, and the density of viral particles in their lumen increased with time post-infection. In contrast, the secretion of virions, their infectivity and their transmission to T cells decreased overtime, suggesting that HIV-infected macrophages tend to pack and retain newly formed virions into dense compartments. A minor proportion of VCCs remains connected to the plasma membrane overtime. Surprisingly, live cell imaging combined with correlative light and electron microscopy revealed that such connections can be transient, highlighting their dynamic nature. Together, our results shed light on the late phases of the HIV-1 cycle and reveal some of its macrophage specific features. PMID- 23922714 TI - Lung surfactant levels are regulated by Ig-Hepta/GPR116 by monitoring surfactant protein D. AB - Lung surfactant is a complex mixture of lipids and proteins, which is secreted from the alveolar type II epithelial cell and coats the surface of alveoli as a thin layer. It plays a crucial role in the prevention of alveolar collapse through its ability to reduce surface tension. Under normal conditions, surfactant homeostasis is maintained by balancing its release and the uptake by the type II cell for recycling and the internalization by alveolar macrophages for degradation. Little is known about how the surfactant pool is monitored and regulated. Here we show, by an analysis of gene-targeted mice exhibiting massive accumulation of surfactant, that Ig-Hepta/GPR116, an orphan receptor, is expressed on the type II cell and sensing the amount of surfactant by monitoring one of its protein components, surfactant protein D, and its deletion results in a pulmonary alveolar proteinosis and emphysema-like pathology. By a coexpression experiment with Sp-D and the extracellular region of Ig-Hepta/GPR116 followed by immunoprecipitation, we identified Sp-D as the ligand of Ig-Hepta/GPR116. Analyses of surfactant metabolism in Ig-Hepta(+/+) and Ig-Hepta(-/-) mice by using radioactive tracers indicated that the Ig-Hepta/GPR116 signaling system exerts attenuating effects on (i) balanced synthesis of surfactant lipids and proteins and (ii) surfactant secretion, and (iii) a stimulating effect on recycling (uptake) in response to elevated levels of Sp-D in alveolar space. PMID- 23922715 TI - Development of a nuclear morphometric signature for prostate cancer risk in negative biopsies. AB - BACKGROUND: Our objective was to develop and validate a multi-feature nuclear score based on image analysis of direct DNA staining, and to test its association with field effects and subsequent detection of prostate cancer (PCa) in benign biopsies. METHODS: Tissue sections from 39 prostatectomies were Feulgen-stained and digitally scanned (400*), providing maps of DNA content per pixel. PCa and benign epithelial nuclei were randomly selected for measurement of 52 basic morphometric features. Logistic regression models discriminating benign from PCa nuclei, and benign from malignant nuclear populations, were built and cross validated by AUC analysis. Nuclear populations were randomly collected <1 mm or >5 mm from cancer foci, and from cancer-free prostates, HGPIN, and PCa Gleason grade 3-5. Nuclei also were collected from negative biopsy subjects who had a subsequent diagnosis of PCa and age-matched cancer-free controls (20 pairs). RESULTS: A multi-feature nuclear score discriminated cancer from benign cell populations with AUCs of 0.91 and 0.79, respectively, in training and validation sets of patients. In prostatectomy samples, both nuclear- and population-level models revealed cancer-like features in benign nuclei adjacent to PCa, compared to nuclei that were more distant or from PCa-free glands. In negative biopsies, a validated model with 5 variance features yielded significantly higher scores in cases than controls (P = 0.026). CONCLUSIONS: A multifeature nuclear morphometric score, obtained by automated digital analysis, was validated for discrimination of benign from cancer nuclei. This score demonstrated field effects in benign epithelial nuclei at varying distance from PCa lesions, and was associated with subsequent PCa detection in negative biopsies. IMPACT: This nuclear score shows promise as a risk predictor among men with negative biopsies and as an intermediate biomarker in Phase II chemoprevention trials. The results also suggest that subvisual disturbances in nuclear structure precede the development of pre-neoplastic lesions. PMID- 23922716 TI - An impact study of the design of exergaming parameters on body intensity from objective and gameplay-based player experience perspectives, based on balance training exergame. AB - Kinect-based exergames allow players to undertake physical exercise in an interactive manner with visual stimulation. Previous studies focused on investigating physical fitness based on calories or heart rate to ascertain the effectiveness of exergames. However, designing an exergame for specific training purposes, with intensity levels suited to the needs and skills of the players, requires the investigation of motion performance to study player experience. This study investigates how parameters of a Kinect-based exergame, combined with balance training exercises, influence the balance control ability and intensity level the player can tolerate, by analyzing both objective and gameplay-based player experience, and taking enjoyment and difficulty levels into account. The exergame tested required participants to maintain their balance standing on one leg within a posture frame (PF) while a force plate evaluated the player's balance control ability in both static and dynamic gaming modes. The number of collisions with the PF depended on the frame's travel time for static PFs, and the leg-raising rate and angle for dynamic PFs. In terms of center of pressure (COP) metrics, significant impacts were caused by the frame's travel time on MDIST-AP for static PFs, and the leg-raising rate on MDIST-ML and TOTEX for dynamic PFs. The best static PF balance control performance was observed with a larger frame offset by a travel time of 2 seconds, and the worst performance with a smaller frame and a travel time of 1 second. The best dynamic PF performance was with a leg-raising rate of 1 second at a 45-degree angle, while the worst performance was with a rate of 2 seconds at a 90-degree angle. The results demonstrated that different evaluation methods for player experience could result in different findings, making it harder to study the design of those exergames with training purposes based on player experience. PMID- 23922717 TI - Physical activity in deprived communities in London: examining individual and neighbourhood-level factors. AB - INTRODUCTION: The objectives of this study were to examine relationships between neighbourhood-level and individual-level characteristics and physical activity in deprived London neighbourhoods. METHODS: In 40 of the most deprived neighbourhoods in London (ranked in top 11% in London by Index of Multiple Deprivation) a cross-sectional survey (n = 4107 adults aged > = 16 years), neighbourhood audit tool, GIS measures and routine data measured neighbourhood and individual-level characteristics. The binary outcome was meeting the minimum recommended (CMO, UK) 5 * 30 mins moderate physical activity per week. Multilevel modelling was used to examine associations between physical activity and individual and neighbourhood-level characteristics. RESULTS: Respondents living more than 300 m away from accessible greenspace had lower odds of achieving recommended physical activity levels than those who lived within 300 m; from 301 600 m (OR = 0.7; 95% CI 0.5-0.9) and from 601-900 m (OR = 0.6; 95% CI 0.4-0.8). There was substantial residual between-neighbourhood variance in physical activity (median odds ratio = 1.7). Other objectively measured neighbourhood level characteristics were not associated with physical activity levels. CONCLUSIONS: Distance to nearest greenspace is associated with meeting recommended physical activity levels in deprived London neighbourhoods. Despite residual variance in physical activity levels between neighbourhoods, we found little evidence for the influence of other measured neighbourhood-level characteristics. PMID- 23922719 TI - Black tea high-molecular-weight polyphenol stimulates exercise training-induced improvement of endurance capacity in mouse via the link between AMPK and GLUT4. AB - Aerobic exercise can promote "fast-to-slow transition" in skeletal muscles, i.e. an increase in oxidative fibers, mitochondria, and myoglobin and improvement in glucose and lipid metabolism. Here, we found that mice administered Mitochondria Activation Factor (MAF) combined with exercise training could run longer distances and for a longer time compared with the exercise only group; MAF is a high-molecular-weight polyphenol purified from black tea. Furthermore, MAF intake combined with exercise training increased phosphorylation of AMPK and mRNA level of glucose transporter 4 (GLUT4). Thus, our data demonstrate for the first time that MAF activates exercise training-induced intracellular signaling pathways that involve AMPK, and improves endurance capacity. PMID- 23922718 TI - Modeling the minimal newborn's intersubjective mind: the visuotopic-somatotopic alignment hypothesis in the superior colliculus. AB - The question whether newborns possess inborn social skills is a long debate in developmental psychology. Fetal behavioral and anatomical observations show evidences for the control of eye movements and facial behaviors during the third trimester of pregnancy whereas specific sub-cortical areas, like the superior colliculus (SC) and the striatum appear to be functionally mature to support these behaviors. These observations suggest that the newborn is potentially mature for developing minimal social skills. In this manuscript, we propose that the mechanism of sensory alignment observed in SC is particularly important for enabling the social skills observed at birth such as facial preference and facial mimicry. In a computational simulation of the maturing superior colliculus connected to a simulated facial tissue of a fetus, we model how the incoming tactile information is used to direct visual attention toward faces. We suggest that the unisensory superficial visual layer (eye-centered) and the deep somatopic layer (face-centered) in SC are combined into an intermediate layer for visuo-tactile integration and that multimodal alignment in this third layer allows newborns to have a sensitivity to configuration of eyes and mouth. We show that the visual and tactile maps align through a Hebbian learning stage and and strengthen their synaptic links from each other into the intermediate layer. It results that the global network produces some emergent properties such as sensitivity toward the spatial configuration of face-like patterns and the detection of eyes and mouth movement. PMID- 23922720 TI - Childhood chronic physical aggression associates with adult cytokine levels in plasma. AB - BACKGROUND: An increasing number of animal and human studies are indicating that inflammation is associated with behavioral disorders including aggression. This study investigates the association between chronic physical aggression during childhood and plasma cytokine levels in early adulthood. METHODOLOGY/PRINCIPAL FINDINGS: Two longitudinal studies were used to select males on a chronic physical aggression trajectory from childhood to adolescence (n = 7) and a control group from the same background (n = 25). Physical aggression was assessed yearly by teachers from childhood to adolescence and plasma levels of 10 inflammatory cytokines were assessed at age 26 and 28 years. Compared to the control group, males on a chronic physical aggression trajectory from childhood to adolescence had consistently lower plasma levels of five cytokines: lower pro inflammatory interleukins IL-1alpha (T(28.7) = 3.48, P = 0.002) and IL-6 (T(26.9) = 3.76, P = 0.001), lower anti-inflammatory interleukin IL-4 (T(27.1) = 4.91, P = 0.00004) and IL-10 (T(29.8) = 2.84, P = 0.008) and lower chemokine IL-8 (T(26) = 3.69, P = 0.001). The plasma levels of four cytokines accurately predicted aggressive and control group membership for all subjects. CONCLUSIONS/SIGNIFICANCE: Physical aggression of boys during childhood is a strong predictor of reduced plasma levels of cytokines in early adulthood. The causal and physiological relations underlying this association should be further investigated since animal data suggest that some cytokines such as IL-6 and IL 1beta play a causal role in aggression. PMID- 23922721 TI - Mitochondrial dysfunction promotes breast cancer cell migration and invasion through HIF1alpha accumulation via increased production of reactive oxygen species. AB - Although mitochondrial dysfunction has been observed in various types of human cancer cells, the molecular mechanism underlying mitochondrial dysfunction mediated tumorigenesis remains largely elusive. To further explore the function of mitochondria and their involvement in the pathogenic mechanisms of cancer development, mitochondrial dysfunction clones of breast cancer cells were generated by rotenone treatment, a specific inhibitor of mitochondrial electron transport complex I. These clones were verified by mitochondrial respiratory defect measurement. Moreover, those clones exhibited increased reactive oxygen species (ROS), and showed higher migration and invasive behaviors compared with their parental cells. Furthermore, antioxidant N-acetyl cysteine, PEG-catalase, and mito-TEMPO effectively inhibited cell migration and invasion in these clones. Notably, ROS regulated malignant cellular behavior was in part mediated through upregulation of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor. Our results suggest that mitochondrial dysfunction promotes cancer cell motility partly through HIF1alpha accumulation mediated via increased production of reactive oxygen species. PMID- 23922723 TI - Land suitability assessment on a watershed of Loess Plateau using the analytic hierarchy process. AB - In order to reduce soil erosion and desertification, the Sloping Land Conversion Program has been conducted in China for more than 15 years, and large areas of farmland have been converted to forest and grassland. However, this large-scale vegetation-restoration project has faced some key problems (e.g. soil drying) that have limited the successful development of the current ecological-recovery policy. Therefore, it is necessary to know about the land use, vegetation, and soil, and their inter-relationships in order to identify the suitability of vegetation restoration. This study was conducted at the watershed level in the ecologically vulnerable region of the Loess Plateau, to evaluate the land suitability using the analytic hierarchy process (AHP). The results showed that (1) the area unsuitable for crops accounted for 73.3% of the watershed, and the main factors restricting cropland development were soil physical properties and soil nutrients; (2) the area suitable for grassland was about 86.7% of the watershed, with the remaining 13.3% being unsuitable; (3) an area of 3.95 km(2), accounting for 66.7% of the watershed, was unsuitable for forest. Overall, the grassland was found to be the most suitable land-use to support the aims of the Sloping Land Conversion Program in the Liudaogou watershed. Under the constraints of soil water shortage and nutrient deficits, crops and forests were considered to be inappropriate land uses in the study area, especially on sloping land. When selecting species for re-vegetation, non-native grass species with high water requirements should be avoided so as to guarantee the sustainable development of grassland and effective ecological functioning. Our study provides local land managers and farmers with valuable information about the inappropriateness of growing trees in the study area along with some information on species selection for planting in the semi-arid area of the Loess Plateau. PMID- 23922722 TI - MiR-376c down-regulation accelerates EGF-dependent migration by targeting GRB2 in the HuCCT1 human intrahepatic cholangiocarcinoma cell line. AB - MicroRNA miR-376c was expressed in normal intrahepatic biliary epithelial cells (HIBEpiC), but was significantly suppressed in the HuCCT1 intrahepatic cholangiocarcinoma (ICC) cell line. The biological significance of the down regulation of miR-376c in HuCCT1 cells is unknown. We hypothesized that miR-376c could function as a tumor suppressor in these cells. To test this hypothesis, we sought the targets of miR-376c, and characterized the effect of its down regulation on HuCCT1 cells. We performed proteomic analysis of miR-376c overexpressing HuCCT1 cells to identify candidate targets of miR-376c, and validated these targets by 3'-UTR reporter assay. Transwell migration assays were performed to study the migratory response of HuCCT1 cells to miR-376c overexpression. Furthermore, microarrays were used to identify the signaling that were potentially involved in the miR-376c-modulated migration of HuCCT1. Finally, we assessed epigenetic changes within the potential promoter region of the miR 376c gene in these cells. Proteomic analysis and subsequent validation assays showed that growth factor receptor-bound protein 2 (GRB2) was a direct target of miR-376c. The transwell migration assay revealed that miR-376c significantly reduced epidermal growth factor (EGF)-dependent cell migration in HuCCT1 cells. DNA microarray and subsequent pathway analysis showed that interleukin 1 beta and matrix metallopeptidase 9 were possible participants in EGF-dependent migration of HuCCT1 cells. Bisulfite sequencing showed higher methylation levels of CpG sites upstream of the miR-376c gene in HuCCT1 relative to HIBEpiC cells. Combined treatment with the DNA-demethylating agent 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor trichostatin A significantly upregulated the expression of miR-376c in HuCCT1 cells. We revealed that epigenetic repression of miR-376c accelerated EGF-dependent cell migration through its target GRB2 in HuCCT1 cells. These findings suggest that miR-376c functions as a tumor suppressor. Since metastasis is the major cause of death in ICC, microRNA manipulation could lead to the development of novel anti-cancer therapy strategies for ICC. PMID- 23922724 TI - Temporal but not spatial variability during gait is reduced after selective dorsal rhizotomy in children with cerebral palsy. AB - INTRODUCTION: Variability in task output is a ubiquitous characteristic that results from non-continuous motor neuron firing during muscular force generation. However, variability can also be attributed to errors in control and coordination of the motor neurons themselves in diseases such as cerebral palsy (CP). Selective dorsal rhizotomy (SDR), a neurosurgical approach to sever sensory nerve roots, is thought to decrease redundant or excessive afferent signalling to intramedullary neurons. In addition to its demonstrated ability to reduce muscular spasticity, we hypothesised that SDR is able to decrease variability during gait, the most frequent functional motor activity of daily living. METHODS: Twelve CP children (aged 6.1 +/- 1.3 yrs), who underwent SDR and performed gait analysis pre- and 12 months postoperatively, were compared to a control group of eleven typically developing (TD) children. Coefficients of variability as well as mean values were analysed for: temporal variables of gait, spatial parameters and velocity. RESULTS: Gait parameters of cadence (p = 0.006) and foot progression angle at mid-stance (p = 0.041) changed significantly from pre- to post-SDR. The variability of every temporal parameter was significantly reduced after SDR (p = 0.003-0.049), while it remained generally unchanged for the spatial parameters. Only a small change in gait velocity was observed, but variability in cadence was significantly reduced after SDR (p = 0.015). Almost all parameters changed with a tendency towards normal, but differences between TD and CP children remained in all parameters. DISCUSSION: The results confirm that SDR improves functional gait performance in children with CP. However, almost exclusively, parameters of temporal variability were significantly improved, leading to the conjecture that temporal variability and spatial variability may be governed independently by the motor cortex. As a result, temporal parameters of task performance may be more vulnerable to disruption, but also more responsive to treatment success of interventions such as SDR. PMID- 23922725 TI - Effects of dietary arginine and glutamine on alleviating the impairment induced by deoxynivalenol stress and immune relevant cytokines in growing pigs. AB - Deoxynivalenol (DON) is a mycotoxin that reduces feed intake and animal performance, especially in swine. Arginine and glutamine play important roles in swine nutrition. The objective of this study was to determine the effects of dietary supplementation with arginine and glutamine on both the impairment induced by DON stress and immune relevant cytokines in growing pigs. A total of forty 60-d-old healthy growing pigs with a mean body weight of 16.28+/-1.54 kg were randomly divided into 5 groups, and assigned to 3 amino acid treatments fed 1.0% arginine (Arg), 1.0% glutamine (Gln) and 0.5% Arg+0.5% Gln, respectively, plus a toxin control and a non-toxin control. Pigs in the 3 amino acid treatments were fed the corresponding amino acids, and those in non-toxin control and toxin control were fed commercial diet with 1.64% Alanine as isonitrogenous control for 7 days. The toxin control and amino acid treatments were then challenged by feeding DON-contaminated diet with a final DON concentration of 6 mg/kg of diet for 21 days. No significant differences were observed between toxin control and the amino acid groups with regard to the average daily gain (ADG), although the values for average daily feed intake (ADFI) in the amino acid groups were significantly higher than that in toxin control (P<0.01). The relative liver weight in toxin control was significantly greater than those in non-toxin control, arginine and Arg+Glu groups (P<0.01), but there were no significant differences in other organs. With regard to serum biochemistry, the values of BUN, ALP, ALT and AST in the amino acid groups were lower than those in toxin control. IGF1, GH and SOD in the amino acid groups were significantly higher than those in toxin control (P<0.01). The IL-2 and TNFalpha values in the amino acid groups were similar to those in non-toxin control, and significantly lower than those in toxin control (P<0.01). These results showed the effects of dietary supplementation with arginine and glutamine on alleviating the impairment induced by DON stress and immune relevant cytokines in growing pigs. PMID- 23922726 TI - Optimizing information in Next-Generation-Sequencing (NGS) reads for improving de novo genome assembly. AB - Next-Generation-Sequencing is advantageous because of its much higher data throughput and much lower cost compared with the traditional Sanger method. However, NGS reads are shorter than Sanger reads, making de novo genome assembly very challenging. Because genome assembly is essential for all downstream biological studies, great efforts have been made to enhance the completeness of genome assembly, which requires the presence of long reads or long distance information. To improve de novo genome assembly, we develop a computational program, ARF-PE, to increase the length of Illumina reads. ARF-PE takes as input Illumina paired-end (PE) reads and recovers the original DNA fragments from which two ends the paired reads are obtained. On the PE data of four bacteria, ARF-PE recovered >87% of the DNA fragments and achieved >98% of perfect DNA fragment recovery. Using Velvet, SOAPdenovo, Newbler, and CABOG, we evaluated the benefits of recovered DNA fragments to genome assembly. For all four bacteria, the recovered DNA fragments increased the assembly contiguity. For example, the N50 lengths of the P. brasiliensis contigs assembled by SOAPdenovo and Newbler increased from 80,524 bp to 166,573 bp and from 80,655 bp to 193,388 bp, respectively. ARF-PE also increased assembly accuracy in many cases. On the PE data of two fungi and a human chromosome, ARF-PE doubled and tripled the N50 length. However, the assembly accuracies dropped, but still remained >91%. In general, ARF-PE can increase both assembly contiguity and accuracy for bacterial genomes. For complex eukaryotic genomes, ARF-PE is promising because it raises assembly contiguity. But future error correction is needed for ARF-PE to also increase the assembly accuracy. ARF-PE is freely available at http://140.116.235.124/~tliu/arf-pe/. PMID- 23922727 TI - MKK3 was involved in larval settlement of the barnacle Amphibalanus amphitrite through activating the kinase activity of p38MAPK. AB - The p38 mitogen-activated protein kinase (p38MAPK) plays a key role in larval settlement of the barnacle Amphibalanus amphitrite. To study the signaling pathway associated with p38MAPK during larval settlement, we sought to identify the upstream kinase of p38MAPK. Three MKKs (MKK3, MKK4 and MKK7) and three MAPKs (p38MAPK, ERK and JNK) in A. amphitrite were cloned and recombinantly expressed in E. coli. Through kinase assays, we found that MKK3, but not MKK4 or MKK7, phosphorylated p38MAPK. Furthermore, MKK3 activity was specific to p38MAPK, as it did not phosphorylate ERK or JNK. To further investigate the functional relationship between MKK3 and p38MAPK in vivo, we studied the localization of phospho-MKK3 (pMKK3) and MKK3 by immunostaining. Consistent with the patterns of p38MAPK and phospho-p38MAPK (pp38MAPK), pMKK3 and MKK3 mainly localized to the antennules of the cyprids. Western blot analysis revealed that pMKK3 levels, like pp38MAPK levels, were elevated at cyprid stage, compared to nauplii and juvenile stages. Moreover, pMKK3 levels increased after treatment with adult barnacle crude extracts, suggesting that MKK3 might mediate the stimulatory effects of adult barnacle extracts on the p38MAPK pathway. PMID- 23922728 TI - Association of major depressive episode with negative outcomes of tuberculosis treatment. AB - BACKGROUND: Pulmonary tuberculosis (TB) persists an important contributor to the burden of diseases in developing countries. TB control success is based on the patient's compliance to the treatment. Depressive disorders have been negatively associated with compliance of therapeutic schemes for chronic diseases. This study aimed to estimate the significance and magnitude of major depressive episode as a hazard factor for negative outcomes (NO), including abandon or death in patients receiving TB treatment. METHODOLOGY/PRINCIPAL FINDINGS: A longitudinal study was conducted to evaluate the association of major depressive episode (MDE), as measured by a 5-item version of the Center for Epidemiological Studies Depression Scale (CES-D) with NO to TB treatment. Patients with confirmed TB were enrolled before the start of TB treatment. Baseline measurements included socio-demographic variables as well as the CES-D, which was also applied every month until the end of the treatment. Death and treatment default were assessed monthly. Survivor function (SF) for NO according to MDE status (CES-D>=6) at baseline (MDEb) was estimated. Cox's Regression was performed for bivariate analyses as well as for the multivariate model. A total of 325 patients accepted to participate in the study, of which 34 where excluded for diagnosis of MDR-TB. NO was observed in 24 patients (8.2%); 109 (37%) presented MDEb. Statistically significant difference was found on the SF of patients with and without MDEb (0.85 vs. 0.96, p-value = 0.002). The hazard ratio for NO, controlled for age, sex, marital status and instruction level was 3.54 (95%CI 1.43-8.75; p-value = 0.006). CONCLUSION: The presence of MDE at baseline is associated to NO of TB treatment. Targeting detection and treatment of MDE may improve TB treatment outcomes. PMID- 23922729 TI - Dimerization of the glucan phosphatase laforin requires the participation of cysteine 329. AB - Laforin, encoded by a gene that is mutated in Lafora Disease (LD, OMIM 254780), is a modular protein composed of a carbohydrate-binding module and a dual specificity phosphatase domain. Laforin is the founding member of the glucan phosphatase family and regulates the levels of phosphate present in glycogen. Multiple reports have described the capability of laforin to form dimers, although the function of these dimers and their relationship with LD remains unclear. Recent evidence suggests that laforin dimerization depends on redox conditions, suggesting that disulfide bonds are involved in laforin dimerization. Using site-directed mutagenesis we constructed laforin mutants in which individual cysteine residues were replaced by serine and then tested the ability of each protein to dimerize using recombinant protein as well as a mammalian cell culture assay. Laforin-Cys329Ser was the only Cys/Ser mutant unable to form dimers in both assays. We also generated a laforin truncation lacking the last three amino acids, laforin-Cys329X, and this truncation also failed to dimerize. Interestingly, laforin-Cys329Ser and laforin-Cys329X were able to bind glucans, and maintained wild type phosphatase activity against both exogenous and biologically relevant substrates. Furthermore, laforin-Cys329Ser was fully capable of participating in the ubiquitination process driven by a laforin-malin complex. These results suggest that dimerization is not required for laforin phosphatase activity, glucan binding, or for the formation of a functional laforin-malin complex. Cumulatively, these results suggest that cysteine 329 is specifically involved in the dimerization process of laforin. Therefore, the C329S mutant constitutes a valuable tool to analyze the physiological implications of laforin's oligomerization. PMID- 23922730 TI - The neuroanatomical organization of projection neurons associated with different olfactory bulb pathways in the sea lamprey, Petromyzon marinus. AB - Although there is abundant evidence for segregated processing in the olfactory system across vertebrate taxa, the spatial relationship between the second order projection neurons (PNs) of olfactory subsystems connecting sensory input to higher brain structures is less clear. In the sea lamprey, there is tight coupling between olfaction and locomotion via PNs extending to the posterior tuberculum from the medial region of the olfactory bulb. This medial region receives peripheral input predominantly from the accessory olfactory organ. However, the axons from olfactory sensory neurons residing in the main olfactory epithelium extend to non-medial regions of the olfactory bulb, and the non-medial bulbar PNs extend their axons to the lateral pallium. It is not known if the receptive fields of the PNs in the two output pathways overlap; nor has the morphology of these PNs been investigated. In this study, retrograde labelling was utilized to investigate the PNs belonging to medial and non-medial projections. The dendrites and somata of the medial PNs were confined to medial glomerular neuropil, and dendrites of non-medial PNs did not enter this territory. The cell bodies and dendrites of the non-medial PNs were predominantly located below the glomeruli (frequently deeper in the olfactory bulb). While PNs in both locations contained single or multiple primary dendrites, the somal size was greater for medial than for non-medial PNs. When considered with the evidence to-date, this study shows different neuroanatomical organization for medial olfactory bulb PNs extending to locomotor control centers and non-medial PNs extending to the lateral pallium in this vertebrate. PMID- 23922731 TI - Telomere length and physical performance at older ages: an individual participant meta-analysis. AB - BACKGROUND: Telomeres are involved in cellular ageing and shorten with increasing age. If telomere length is a valuable biomarker of ageing, then telomere shortening should be associated with worse physical performance, an ageing trait, but evidence for such an association is lacking. The purpose of this study was to examine whether change in telomere length is associated with physical performance. METHODS: Using data from four UK adult cohorts (ages 53-80 years at baseline), we undertook cross-sectional and longitudinal analyses. We analysed each study separately and then used meta-analytic methods to pool the results. Physical performance was measured using walking and chair rise speed, standing balance time and grip strength. Telomere length was measured by quantitative real time polymerase chain reaction (PCR) in whole blood at baseline and follow-up (time 1, time 2). RESULTS: Total sample sizes in meta-analyses ranged from 1,217 to 3,707. There was little evidence that telomere length was associated with walking speed, balance or grip strength, though weak associations were seen with chair rise speed and grip strength at baseline (p = 0.02 and 0.01 respectively). Faster chair rise speed at follow-up, was associated with a smaller decline in telomere length between time 1 and time 2 (standardised coefficient per SD increase 0.061, 95% CI 0.006, 0.115, p = 0.03) but this was consistent with chance (p =0.08) after further adjustment. CONCLUSIONS: Whereas shortening of leukocyte telomeres might be an important measure of cellular ageing, there is little evidence that it is a strong biomarker for physical performance. PMID- 23922732 TI - What is the primary cause of individual differences in contrast sensitivity? AB - One of the primary objectives of early visual processing is the detection of luminance variations, often termed image contrast. Normal observers can differ in this ability by at least a factor of 4, yet this variation is typically overlooked, and has never been convincingly explained. This study uses two techniques to investigate the main source of individual variations in contrast sensitivity. First, a noise masking experiment assessed whether differences were due to the observer's internal noise, or the efficiency with which they extracted information from the stimulus. Second, contrast discrimination functions from 18 previous studies were compared (pairwise, within studies) using a computational model to determine whether differences were due to internal noise or the low level gain properties of contrast transduction. Taken together, the evidence points to differences in contrast gain as being responsible for the majority of individual variation across the normal population. This result is compared with related findings in attention and amblyopia. PMID- 23922734 TI - The fusarium mycotoxin deoxynivalenol can inhibit plant apoptosis-like programmed cell death. AB - The Fusarium genus of fungi is responsible for commercially devastating crop diseases and the contamination of cereals with harmful mycotoxins. Fusarium mycotoxins aid infection, establishment, and spread of the fungus within the host plant. We investigated the effects of the Fusarium mycotoxin deoxynivalenol (DON) on the viability of Arabidopsis cells. Although it is known to trigger apoptosis in animal cells, DON treatment at low concentrations surprisingly did not kill these cells. On the contrary, we found that DON inhibited apoptosis-like programmed cell death (PCD) in Arabidopsis cells subjected to abiotic stress treatment in a manner independent of mitochondrial cytochrome c release. This suggested that Fusarium may utilise mycotoxins to suppress plant apoptosis-like PCD. To test this, we infected Arabidopsis cells with a wild type and a DON-minus mutant strain of F. graminearum and found that only the DON producing strain could inhibit death induced by heat treatment. These results indicate that mycotoxins may be capable of disarming plant apoptosis-like PCD and thereby suggest a novel way that some fungi can influence plant cell fate. PMID- 23922733 TI - Epidemiology and management of cysticercosis and Taenia solium taeniasis in Europe, systematic review 1990-2011. AB - BACKGROUND: Cysticercosis is caused by the invasion of human or pig tissues by the metacestode larval stage of Taenia solium. In Europe, the disease was endemic in the past but the autochthonous natural life cycle of the parasite is currently completed very rarely. Recently, imported cases have increased in parallel to the increased number of migrations and international travels. The lack of specific surveillance systems for cysticercosis leads to underestimation of the epidemiological and clinical impacts. OBJECTIVES: To review the available data on epidemiology and management of cysticercosis in Europe. METHODS: A review of literature on human cysticercosis and T. solium taeniasis in Europe published between 1990-2011 was conducted. RESULTS: Out of 846 cysticercosis cases described in the literature, 522 cases were autochthonous and 324 cases were imported. The majority (70.1%) of the autochthonous cases were diagnosed in Portugal from 1983 and 1994. Imported cases of which 242 (74.7%) diagnosed in migrants and 57 (17.6%) in European travellers, showed an increasing trend. Most of imported cases were acquired in Latin America (69.8% of migrants and 44.0% of travellers). The majority of imported cases were diagnosed in Spain (47.5%), France (16.7%) and Italy (8.3%). One third of neurosurgical procedures were performed because the suspected diagnosis was cerebral neoplasm. Sixty eight autochthonous and 5 imported T. solium taeniasis cases were reported. CONCLUSIONS: Cysticercosis remains a challenge for European care providers, since they are often poorly aware of this infection and have little familiarity in managing this disease. Cysticercosis should be included among mandatory reportable diseases, in order to improve the accuracy of epidemiological information. European health care providers might benefit from a transfer of knowledge from colleagues working in endemic areas and the development of shared diagnostic and therapeutic processes would have impact on the quality of the European health systems. PMID- 23922737 TI - An estrogen receptor dependent mechanism of Oroxylin A in the repression of inflammatory response. AB - Oroxylin A, a natural flavonoid, is one of the main bioactive compounds that underlie the anti-inflammatory effect of the medicinal herb Scutellaria baicalensis Georgi widely used in southeastern Asia; however, the molecular mechanisms for the therapeutic benefits remain largely unclear. In this study, we found that Oroxylin A induces estrogen-responsive gene expression and promoter activity. In macrophages, Oroxylin A treatment significantly attenuates lipopolysaccharide (LPS)-induced but not basal inflammatory response, including nitric oxide (NO) production and the expression of inflammatory mediators (i.e., iNOS and COX-2) and cytokines (i.e., TNF-alpha, IL-1beta, and IL-6), in an estrogen receptor (ER)-dependent manner. Oroxylin A treatment also dramatically decreases LPS-induced secretion of pro-inflammatory cytokines. Furthermore, the downregulation of all these inflammatory parameters by Oroxylin A was abolished when cells were pretreated with specific ER antagonist. Thus, Oroxylin A is a novel phytoestrogen and exhibits anti-inflammatory effects that are mediated by ER activity. PMID- 23922735 TI - Crucial role of TRPC1 and TRPC4 in cystitis-induced neuronal sprouting and bladder overactivity. AB - PURPOSE: During cystitis, increased innervation of the bladder by sensory nerves may contribute to bladder overactivity and pain. The mechanisms whereby cystitis leads to hyperinnervation of the bladder are, however, poorly understood. Since TRP channels have been implicated in the guidance of growth cones and survival of neurons, we investigated their involvement in the increases in bladder innervation and bladder activity in rodent models of cystitis. MATERIALS AND METHODS: To induce bladder hyperactivity, we chronically injected cyclophosphamide in rats and mice. All experiments were performed a week later. We used quantitative transcriptional analysis and immunohistochemistry to determine TRP channel expression on retrolabelled bladder sensory neurons. To assess bladder function and referred hyperalgesia, urodynamic analysis, detrusor strip contractility and Von Frey filament experiments were done in wild type and knock-out mice. RESULTS: Repeated cyclophosphamide injections induce a specific increase in the expression of TRPC1 and TRPC4 in bladder-innervating sensory neurons and the sprouting of sensory fibers in the bladder mucosa. Interestingly, cyclophosphamide-treated Trpc1/c4(-/-) mice no longer exhibited increased bladder innervations, and, concomitantly, the development of bladder overactivity was diminished in these mice. We did not observe a difference neither in bladder contraction features of double knock-out animals nor in cyclophosphamide-induced referred pain behavior. CONCLUSIONS: Collectively, our data suggest that TRPC1 and TRPC4 are involved in the sprouting of sensory neurons following bladder cystitis, which leads to overactive bladder disease. PMID- 23922736 TI - Choroid sprouting assay: an ex vivo model of microvascular angiogenesis. AB - Angiogenesis of the microvasculature is central to the etiology of many diseases including proliferative retinopathy, age-related macular degeneration and cancer. A mouse model of microvascular angiogenesis would be very valuable and enable access to a wide range of genetically manipulated tissues that closely approximate small blood vessel growth in vivo. Vascular endothelial cells cultured in vitro are widely used, however, isolating pure vascular murine endothelial cells is technically challenging. A microvascular mouse explant model that is robust, quantitative and can be reproduced without difficulty would overcome these limitations. Here we characterized and optimized for reproducibility an organotypic microvascular angiogenesis mouse and rat model from the choroid, a microvascular bed in the posterior of eye. The choroidal tissues from C57BL/6J and 129S6/SvEvTac mice and Sprague Dawley rats were isolated and incubated in Matrigel. Vascular sprouting was comparable between choroid samples obtained from different animals of the same genetic background. The sprouting area, normalized to controls, was highly reproducible between independent experiments. We developed a semi-automated macro in ImageJ software to allow for more efficient quantification of sprouting area. Isolated choroid explants responded to manipulation of the external environment while maintaining the local interactions of endothelial cells with neighboring cells, including pericytes and macrophages as evidenced by immunohistochemistry and fluorescence activated cell sorting (FACS) analysis. This reproducible ex vivo angiogenesis assay can be used to evaluate angiogenic potential of pharmacologic compounds on microvessels and can take advantage of genetically manipulated mouse tissue for microvascular disease research. PMID- 23922738 TI - Antitumor activity of hierridin B, a cyanobacterial secondary metabolite found in both filamentous and unicellular marine strains. AB - Cyanobacteria are widely recognized as a valuable source of bioactive metabolites. The majority of such compounds have been isolated from so-called complex cyanobacteria, such as filamentous or colonial forms, which usually display a larger number of biosynthetic gene clusters in their genomes, when compared to free-living unicellular forms. Nevertheless, picocyanobacteria are also known to have potential to produce bioactive natural products. Here, we report the isolation of hierridin B from the marine picocyanobacterium Cyanobium sp. LEGE 06113. This compound had previously been isolated from the filamentous epiphytic cyanobacterium Phormidium ectocarpi SAG 60.90, and had been shown to possess antiplasmodial activity. A phylogenetic analysis of the 16S rRNA gene from both strains confirmed that these cyanobacteria derive from different evolutionary lineages. We further investigated the biological activity of hierridin B, and tested its cytotoxicity towards a panel of human cancer cell lines; it showed selective cytotoxicity towards HT-29 colon adenocarcinoma cells. PMID- 23922740 TI - Smoothness without smoothing: why Gaussian naive Bayes is not naive for multi subject searchlight studies. AB - Spatial smoothness is helpful when averaging fMRI signals across multiple subjects, as it allows different subjects' corresponding brain areas to be pooled together even if they are slightly misaligned. However, smoothing is usually not applied when performing multivoxel pattern-based analyses (MVPA), as it runs the risk of blurring away the information that fine-grained spatial patterns contain. It would therefore be desirable, if possible, to carry out pattern-based analyses which take unsmoothed data as their input but which produce smooth images as output. We show here that the Gaussian Naive Bayes (GNB) classifier does precisely this, when it is used in "searchlight" pattern-based analyses. We explain why this occurs, and illustrate the effect in real fMRI data. Moreover, we show that analyses using GNBs produce results at the multi-subject level which are statistically robust, neurally plausible, and which replicate across two independent data sets. By contrast, SVM classifiers applied to the same data do not generate a replication, even if the SVM-derived searchlight maps have smoothing applied to them. An additional advantage of GNB classifiers for searchlight analyses is that they are orders of magnitude faster to compute than more complex alternatives such as SVMs. Collectively, these results suggest that Gaussian Naive Bayes classifiers may be a highly non-naive choice for multi subject pattern-based fMRI studies. PMID- 23922739 TI - Autophagy activation clears ELAVL1/HuR-mediated accumulation of SQSTM1/p62 during proteasomal inhibition in human retinal pigment epithelial cells. AB - Age-related macular degeneration (AMD) is the most common reason of visual impairment in the elderly in the Western countries. The degeneration of retinal pigment epithelial cells (RPE) causes secondarily adverse effects on neural retina leading to visual loss. The aging characteristics of the RPE involve lysosomal accumulation of lipofuscin and extracellular protein aggregates called "drusen". Molecular mechanisms behind protein aggregations are weakly understood. There is intriguing evidence suggesting that protein SQSTM1/p62, together with autophagy, has a role in the pathology of different degenerative diseases. It appears that SQSTM1/p62 is a connecting link between autophagy and proteasome mediated proteolysis, and expressed strongly under the exposure to various oxidative stimuli and proteasomal inhibition. ELAVL1/HuR protein is a post transcriptional factor, which acts mainly as a positive regulator of gene expression by binding to specific mRNAs whose corresponding proteins are fundamental for key cellular functions. We here show that, under proteasomal inhibitor MG-132, ELAVL1/HuR is up-regulated at both mRNA and protein levels, and that this protein binds and post-transcriptionally regulates SQSTM1/p62 mRNA in ARPE-19 cell line. Furthermore, we observed that proteasomal inhibition caused accumulation of SQSTM1/p62 bound irreversibly to perinuclear protein aggregates. The addition of the AMPK activator AICAR was pro-survival and promoted cleansing by autophagy of the former complex, but not of the ELAVL1/HuR accumulation, indeed suggesting that SQSTM1/p62 is decreased through autophagy-mediated degradation, while ELAVL1/HuR through the proteasomal pathway. Interestingly, when compared to human controls, AMD donor samples show strong SQSTM1/p62 rather than ELAVL1/HuR accumulation in the drusen rich macular area suggesting impaired autophagy in the pathology of AMD. PMID- 23922741 TI - Ventilatory chemosensory drive is blunted in the mdx mouse model of Duchenne Muscular Dystrophy (DMD). AB - Duchenne Muscular Dystrophy (DMD) is caused by mutations in the DMD gene resulting in an absence of dystrophin in neurons and muscle. Respiratory failure is the most common cause of mortality and previous studies have largely concentrated on diaphragmatic muscle necrosis and respiratory failure component. Here, we investigated the integrity of respiratory control mechanisms in the mdx mouse model of DMD. Whole body plethysmograph in parallel with phrenic nerve activity recordings revealed a lower respiratory rate and minute ventilation during normoxia and a blunting of the hypoxic ventilatory reflex in response to mild levels of hypoxia together with a poor performance on a hypoxic stress test in mdx mice. Arterial blood gas analysis revealed low PaO2 and pH and high PaCO2 in mdx mice. To investigate chemosensory respiratory drive, we analyzed the carotid body by molecular and functional means. Dystrophin mRNA and protein was expressed in normal mice carotid bodies however, they are absent in mdx mice. Functional analysis revealed abnormalities in Dejours test and the early component of the hypercapnic ventilatory reflex in mdx mice. Together, these results demonstrate a malfunction in the peripheral chemosensory drive that would be predicted to contribute to the respiratory failure in mdx mice. These data suggest that investigating and monitoring peripheral chemosensory drive function may be useful for improving the management of DMD patients with respiratory failure. PMID- 23922742 TI - The human neutrophil subsets defined by the presence or absence of OLFM4 both transmigrate into tissue in vivo and give rise to distinct NETs in vitro. AB - Neutrophil heterogeneity was described decades ago, but it could not be elucidated at the time whether the existence of different neutrophil subsets had any biological relevance. It has been corroborated in recent years that neutrophil subsets, defined by differential expression of various markers, are indeed present in human blood, calling for renewed attention to this question. The expression of the granule protein olfactomedin 4 (OLFM4) has been suggested to define two such neutrophil subsets. We confirm the simultaneous presence of one OLFM4-positive and one OLFM4-negative neutrophil subpopulation as well as the localization of the protein to specific granules. In vitro, these neutrophil subsets displayed equal tendency to undergo apoptosis and phagocytose bacteria. In addition, the subpopulations were recruited equally to inflammatory sites in vivo, and this was true both in an experimental model of acute inflammation and in naturally occurring pathological joint inflammation. In line with its subcellular localization, only limited OLFM4 release was seen upon in vivo transmigration, and release through conventional degranulation required strong secretagogues. However, extracellular release of OLFM4 could be achieved upon formation of neutrophil extracellular traps (NETs) where it was detected only in a subset of the NETs. Although we were unable to demonstrate any functional differences between the OLFM4-defined subsets, our data show that different neutrophil subsets are present in inflamed tissue in vivo. Furthermore, we demonstrate NETs characterized by different markers for the first time, and our results open up for functions of OLFM4 itself in the extracellular space through exposure in NETs. PMID- 23922743 TI - Exploring the host parasitism of the migratory plant-parasitic nematode Ditylenchus destuctor by expressed sequence tags analysis. AB - The potato rot nematode, Ditylenchus destructor, is a very destructive nematode pest on many agriculturally important crops worldwide, but the molecular characterization of its parasitism of plant has been limited. The effectors involved in nematode parasitism of plant for several sedentary endo-parasitic nematodes such as Heterodera glycines, Globodera rostochiensis and Meloidogyne incognita have been identified and extensively studied over the past two decades. Ditylenchus destructor, as a migratory plant parasitic nematode, has different feeding behavior, life cycle and host response. Comparing the transcriptome and parasitome among different types of plant-parasitic nematodes is the way to understand more fully the parasitic mechanism of plant nematodes. We undertook the approach of sequencing expressed sequence tags (ESTs) derived from a mixed stage cDNA library of D. destructor. This is the first study of D. destructor ESTs. A total of 9800 ESTs were grouped into 5008 clusters including 3606 singletons and 1402 multi-member contigs, representing a catalog of D. destructor genes. Implementing a bioinformatics' workflow, we found 1391 clusters have no match in the available gene database; 31 clusters only have similarities to genes identified from D. africanus, the most closely related species to D. destructor; 1991 clusters were annotated using Gene Ontology (GO); 1550 clusters were assigned enzyme commission (EC) numbers; and 1211 clusters were mapped to 181 KEGG biochemical pathways. 22 ESTs had similarities to reported nematode effectors. Interestedly, most of the effectors identified in this study are involved in host cell wall degradation or modification, such as 1,4-beta glucanse, 1,3-beta-glucanse, pectate lyase, chitinases and expansin, or host defense suppression such as calreticulin, annexin and venom allergen-like protein. This result implies that the migratory plant-parasitic nematode D. destructor secrets similar effectors to those of sedentary plant nematodes. Finally we further characterized the two D. destructor expansin proteins. PMID- 23922744 TI - PrP(ST), a soluble, protease resistant and truncated PrP form features in the pathogenesis of a genetic prion disease. AB - While the conversion of PrP(C) into PrP(Sc) in the transmissible form of prion disease requires a preexisting PrP(Sc) seed, in genetic prion disease accumulation of disease related PrP could be associated with biochemical and metabolic modifications resulting from the designated PrP mutation. To investigate this possibility, we looked into the time related changes of PrP proteins in the brains of TgMHu2ME199K/wt mice, a line modeling for heterozygous genetic prion disease linked to the E200K PrP mutation. We found that while oligomeric entities of mutant E199KPrP exist at all ages, aggregates of wt PrP in the same brains presented only in advanced disease, indicating a late onset conversion process. We also show that most PK resistant PrP in TgMHu2ME199K mice is soluble and truncated (PrP(ST)), a pathogenic form never before associated with prion disease. We next looked into brain samples from E200K patients and found that both PK resistant PrPs, PrP(ST) as in TgMHu2ME199K mice, and "classical" PrP(Sc) as in infectious prion diseases, coincide in the patient's post mortem brains. We hypothesize that aberrant metabolism of mutant PrPs may result in the formation of previously unknown forms of the prion protein and that these may be central for the fatal outcome of the genetic prion condition. PMID- 23922746 TI - A randomized pilot study of L-arginine infusion in severe falciparum malaria: preliminary safety, efficacy and pharmacokinetics. AB - BACKGROUND: Decreased nitric oxide (NO) and hypoargininemia are associated with severe falciparum malaria and may contribute to severe disease. Intravenous L arginine increases endothelial NO in moderately-severe malaria (MSM) without adverse effects. The safety, efficacy and pharmacokinetics of L-arginine or other agents to improve NO bioavailability in severe malaria have not been assessed. METHODS: In an open-label pilot study of L-arginine in adults with severe malaria (ARGISM-1 Study), patients were randomized to 12 g L-arginine hydrochloride or saline over 8 hours together with intravenous artesunate. Vital signs, selected biochemical measures (including blood lactate and L-arginine) and endothelial NO bioavailability (using reactive hyperemia peripheral arterial tonometry [RH-PAT]) were assessed serially. Pharmacokinetic analyses of L-arginine concentrations were performed using NONMEM. RESULTS: Six patients received L-arginine and two saline infusions. There were no deaths in either group. There were no changes in mean systolic (SBP) and diastolic blood pressure (DBP) or other vital signs with L-arginine, although a transient but clinically unimportant mean maximal decrease in SBP of 14 mmHg was noted. No significant changes in mean potassium, glucose, bicarbonate, or pH were seen, with transient mean maximal increases in plasma potassium of 0.3 mmol/L, and mean maximal decreases in blood glucose of 0.8 mmol/L and bicarbonate of 2.3 mEq/L following L-arginine administration. There was no effect on lactate clearance or RH-PAT index. Pharmacokinetic modelling (n = 4) showed L-arginine concentrations 40% lower than predicted from models developed in MSM. CONCLUSION: In the first clinical trial of an adjunctive treatment aimed at increasing NO bioavailability in severe malaria, L-arginine infused at 12 g over 8 hours was safe, but did not improve lactate clearance or endothelial NO bioavailability. Future studies may require increased doses of L arginine. TRIAL REGISTRATION: ClinicalTrials.gov NCT00616304. PMID- 23922745 TI - Induction of an inflammatory loop by interleukin-1beta and tumor necrosis factor alpha involves NF-kB and STAT-1 in differentiated human neuroprogenitor cells. AB - Proinflammatory cytokines secreted from microglia are known to induce a secondary immune response in astrocytes leading to an inflammatory loop. Cytokines also interfere with neurogenesis during aging and in neurodegenerative diseases. The present study examined the mechanism of induction of inflammatory mediators at the transcriptional level in human differentiated neuroprogenitor cells (NPCs). Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) induced the expression of cytokines and chemokines in differentiated human NPCs as shown by an immune pathway-specific array. Network motif (NM) analysis of these genes revealed 118 three-node NMs, suggesting complex interactions between inflammatory mediators and transcription factors. Immunofluorescent staining showed increases in the levels of IL-8 and CXCL10 proteins in neurons and glial cells. Findings from Taqman low density array suggested the synergistic actions of IL-1beta and TNF-alpha in the induction of a majority of inflammatory genes by a mechanism involving NF-kB and STAT-1. Nuclear localization of these transcription factors in differentiated NPCs was observed following exposure to IL-1alpha and TNF alpha. Further studies on CXCL10, a chemokine known to be elevated in the Alzheimer's brain, showed that TNF-alpha is a stronger inducer of CXCL10 promoter when compared to IL-1beta. The synergy between these cytokines was lost when ISRE or kB elements in CXCL10 promoter were mutated. Our findings suggest that the activation of inflammatory pathways in neurons and astrocytes through transcription factors including NF-kB and STAT-1 play important roles in neuroglial interactions and in sustaining the vicious cycle of inflammatory response. PMID- 23922747 TI - A simple method to extract DNA from hair shafts using enzymatic laundry powder. AB - A simple method to extract DNA from hair shafts was developed by using enzymatic laundry powder at the first step of the process. The whole extraction can be finished in less than 2 hours. The simple extraction reagent proposed here contains only two cheap components: ordinary enzymatic laundry powder and PCR buffer. After extraction, an ultra sensitive fluorescent nucleic acid stain, PicoGreen, was used for quantifying trace amount of double-stranded DNA in the solution extracted. For further validation of DNA extraction, four primers were employed to amplify DNA microsatellite loci. Both fluorescence spectroscopy and PCR results suggested that this method can extract DNA from hair shafts with good efficiency and repeatability. The study will greatly facilitate the use of hair shafts in future for DNA analyses on genome-wide scale. PMID- 23922748 TI - Effect of trans fatty acid intake on LC-MS and NMR plasma profiles. AB - BACKGROUND: The consumption of high levels of industrial trans fatty acids (TFA) has been related to cardiovascular disease, diabetes and sudden cardiac death but the causal mechanisms are not well known. In this study, NMR and LC-MS untargeted metabolomics has been used as an approach to explore the impact of TFA intake on plasma metabolites. METHODOLOGY/PRINCIPAL FINDINGS: In a double-blinded randomized controlled parallel-group study, 52 overweight postmenopausal women received either partially hydrogenated soybean oil, providing 15.7 g/day of TFA (trans18:1) or control oil with mainly oleic acid for 16 weeks. Subsequent to the intervention period, the subjects participated in a 12-week dietary weight loss program. Before and after the TFA intervention and after the weight loss programme, volunteers participated in an oral glucose tolerance test. PLSDA revealed elevated lipid profiles with TFA intake. NMR indicated up-regulated LDL cholesterol levels and unsaturation. LC-MS profiles demonstrated elevated levels of specific polyunsaturated (PUFA) long-chain phosphatidylcholines (PCs) and a sphingomyelin (SM) which were confirmed with a lipidomics based method. Plasma levels of these markers of TFA intake declined to their low baseline levels after the weight loss program for the TFA group and did not fluctuate for the control group. The marker levels were unaffected by OGTT. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that intake of TFA affects phospholipid metabolism. The preferential integration of trans18:1 into the sn-1 position of PCs, all containing PUFA in the sn-2 position, could be explained by a general up regulation in the formation of long-chain PUFAs after TFA intake and/or by specific mobilisation of these fats into PCs. NMR supported these findings by revealing increased unsaturation of plasma lipids in the TFA group. These specific changes in membrane lipid species may be related to the mechanisms of TFA-induced disease but need further validation as risk markers. TRIAL REGISTRATION: Registered at clinicaltrials.gov as NCT00655902. PMID- 23922749 TI - Low concentrations of hydrogen peroxide or nitrite induced of Paracoccidioides brasiliensis cell proliferation in a Ras-dependent manner. AB - Paracoccidioides brasiliensis, a causative agent of paracoccidioidomycosis (PCM), should be able to adapt to dramatic environmental changes inside the infected host after inhalation of air-borne conidia and transition to pathogenic yeasts. Proteins with antioxidant functions may protect fungal cells against reactive oxygen (ROS) and nitrogen (RNS) species generated by phagocytic cells, thus acting as potential virulence factors. Ras GTPases are involved in stress responses, cell morphology, and differentiation in a range of organisms. Ras, in its activated form, interacts with effector proteins and can initiate a kinase cascade. In lower eukaryotes, Byr2 kinase represents a Ras target. The present study investigated the role of Ras in P. brasiliensis after in vitro stimulus with ROS or RNS. We have demonstrated that low concentrations of H2O2 (0.1 mM) or NO2 (0.1-0.25 uM) stimulated P. brasiliensis yeast cell proliferation and that was not observed when yeast cells were pre-incubated with farnesyltransferase inhibitor. We constructed an expression plasmid containing the Byr2 Ras-binding domain (RBD) fused with GST (RBD-Byr2-GST) to detect the Ras active form. After stimulation with low concentrations of H2O2 or NO2, the Ras active form was observed in fungal extracts. Besides, NO2 induced a rapid increase in S nitrosylated Ras levels. This alternative posttranslational modification of Ras, probably in residue Cys123, would lead to an exchange of GDP for GTP and consequent GTPase activation in P. brasiliensis. In conclusion, low concentrations of H2O2 or NO2 stimulated P. brasiliensis proliferation through Ras activation. PMID- 23922750 TI - Automatic quantitative MRI texture analysis in small-for-gestational-age fetuses discriminates abnormal neonatal neurobehavior. AB - BACKGROUND: We tested the hypothesis whether texture analysis (TA) from MR images could identify patterns associated with an abnormal neurobehavior in small for gestational age (SGA) neonates. METHODS: Ultrasound and MRI were performed on 91 SGA fetuses at 37 weeks of GA. Frontal lobe, basal ganglia, mesencephalon and cerebellum were delineated from fetal MRIs. SGA neonates underwent NBAS test and were classified as abnormal if >= 1 area was <5(th) centile and as normal if all areas were >5(th) centile. Textural features associated with neurodevelopment were selected and machine learning was used to model a predictive algorithm. RESULTS: Of the 91 SGA neonates, 49 were classified as normal and 42 as abnormal. The accuracies to predict an abnormal neurobehavior based on TA were 95.12% for frontal lobe, 95.56% for basal ganglia, 93.18% for mesencephalon and 83.33% for cerebellum. CONCLUSIONS: Fetal brain MRI textural patterns were associated with neonatal neurodevelopment. Brain MRI TA could be a useful tool to predict abnormal neurodevelopment in SGA. PMID- 23922751 TI - Analysis of radiocarbon, stable isotopes and DNA in teeth to facilitate identification of unknown decedents. AB - The characterization of unidentified bodies or suspected human remains is a frequent and important task for forensic investigators. However, any identification method requires clues to the person's identity to allow for comparisons with missing persons. If such clues are lacking, information about the year of birth, sex and geographic origin of the victim, is particularly helpful to aid in the identification casework and limit the search for possible matches. We present here results of stable isotope analysis of (13)C and (18)O, and bomb-pulse (14)C analyses that can help in the casework. The (14)C analysis of enamel provided information of the year of birth with an average absolute error of 1.8+/-1.3 years. We also found that analysis of enamel and root from the same tooth can be used to determine if the (14)C values match the rising or falling part of the bomb-curve. Enamel laydown times can be used to estimate the date of birth of individuals, but here we show that this detour is unnecessary when using a large set of crude (14)C data of tooth enamel as a reference. The levels of (13)C in tooth enamel were higher in North America than in teeth from Europe and Asia, and Mexican teeth showed even higher levels than those from USA. DNA analysis was performed on 28 teeth, and provided individual-specific profiles in most cases and sex determination in all cases. In conclusion, these analyses can dramatically limit the number of possible matches and hence facilitate person identification work. PMID- 23922752 TI - Prostaglandin E2-EP3 axis in fine-tuning excessive skin inflammation by restricting dendritic cell functions. AB - Prostaglandin E2 (PGE2) is produced in the skin and is suggested to play a role in the regulation of cutaneous immune homeostasis and responses. However, the multifaceted functions of PGE2 continue to elude our understanding, especially because of the multiplicity of PGE2 receptors--EP1, EP2, EP3, and EP4. While cAMP elevating EP4 is known to activate the functions of cutaneous dendritic cells (DCs), including Langerhans cells (LCs) and dermal DCs, the role of cAMP suppressing EP3 in this process remains unknown. Here we demonstrated that an EP3 receptor selective agonist, ONO-AE-248, inhibited chemotaxis and co-stimulatory molecule expressions of DCs in vitro. A suboptimal dose of antigen was sufficient to induce contact hypersensitivity in EP3-deficient mice. Intriguingly, EP3 deficiency did not impair skin inflammation at all when the antigen dose was sufficiently high. EP3 limited the functions of cutaneous DCs only when the antigen dose was low. In contrast to EP4, the observed unappreciated function of EP3 may stabilize the cutaneous DCs to halt the impetuous response to a suboptimal dose of antigen. Taken together, PGE2-EP3 signaling is essential for fine-tuning excessive skin inflammation by restricting DC functions. PMID- 23922753 TI - Implementation of mental health service has an impact on retention in HIV care: a nested case-control study in a japanese HIV care facility. AB - BACKGROUND: Poor retention in the care of patients with human immunodeficiency virus (HIV) is associated with adverse patient outcomes such as antiretroviral therapy failure and death. Therefore, appropriate case management is required for better patient retention; however, which intervention in case management is important has not been fully investigated. Meanwhile, in Japan, each local government is required to organize mental health services for patients with HIV so that a case manager at an HIV care facility can utilize them, but little is known about the association between implementation of the services and loss to follow-up. Therefore, we investigated that by a nested case-control study. METHODS: The target population consisted of all patients with HIV who visited Osaka National Hospital, the largest HIV care facility in western Japan, between 2000 and 2010. Loss to follow-up was defined as not returning for follow-up care more than 1 year after the last visit. Independent variables included patient demographics, characteristics of the disease and treatment, and whether the patients have received mental health services. For each case, three controls were randomly selected and matched. RESULTS: Of the 1620 eligible patients, 88 loss to follow-up cases were identified and 264 controls were matched. Multivariate adjusted conditional logistic regression revealed that loss to follow-up was less frequent among patients who had received mental health services implemented by their case managers (adjusted odds ratio [95% confidence interval] 0.35 [0.16 0.76]). Loss to follow-up also occurred more frequently in patients who did not receive antiretroviral therapy (adjusted odds ratio [95% confidence interval], 7.51 [3.34-16.9]), who were under 30 years old (2.74 [1.36-5.50]), or who were without jobs (3.38 [1.58-7.23]). CONCLUSION: Mental health service implementation by case managers has a significant impact on patient retention. PMID- 23922754 TI - Validation of next generation sequencing technologies in comparison to current diagnostic gold standards for BRAF, EGFR and KRAS mutational analysis. AB - Next Generation Sequencing (NGS) has the potential of becoming an important tool in clinical diagnosis and therapeutic decision-making in oncology owing to its enhanced sensitivity in DNA mutation detection, fast-turnaround of samples in comparison to current gold standard methods and the potential to sequence a large number of cancer-driving genes at the one time. We aim to test the diagnostic accuracy of current NGS technology in the analysis of mutations that represent current standard-of-care, and its reliability to generate concomitant information on other key genes in human oncogenesis. Thirteen clinical samples (8 lung adenocarcinomas, 3 colon carcinomas and 2 malignant melanomas) already genotyped for EGFR, KRAS and BRAF mutations by current standard-of-care methods (Sanger Sequencing and q-PCR), were analysed for detection of mutations in the same three genes using two NGS platforms and an additional 43 genes with one of these platforms. The results were analysed using closed platform-specific proprietary bioinformatics software as well as open third party applications. Our results indicate that the existing format of the NGS technology performed well in detecting the clinically relevant mutations stated above but may not be reliable for a broader unsupervised analysis of the wider genome in its current design. Our study represents a diagnostically lead validation of the major strengths and weaknesses of this technology before consideration for diagnostic use. PMID- 23922755 TI - The effect of criticism on functional brain connectivity and associations with neuroticism. AB - Neuroticism is a robust personality trait that constitutes a risk factor for psychopathology, especially anxiety disorders and depression. High neurotic individuals tend to be more self-critical and are overly sensitive to criticism by others. Hence, we used a novel resting-state paradigm to investigate the effect of criticism on functional brain connectivity and associations with neuroticism. Forty-eight participants completed the NEO Personality Inventory Revised (NEO-PI-R) to assess neuroticism. Next, we recorded resting state functional magnetic resonance imaging (rsfMRI) during two sessions. We manipulated the second session before scanning by presenting three standardized critical remarks through headphones, in which the subject was urged to please lie still in the scanner. A seed-based functional connectivity method and subsequent clustering were used to analyse the resting state data. Based on the reviewed literature related to criticism, we selected brain regions associated with self reflective processing and stress-regulation as regions of interest. The findings showed enhanced functional connectivity between the clustered seed regions and brain areas involved in emotion processing and social cognition during the processing of criticism. Concurrently, functional connectivity was reduced between these clusters and brain structures related to the default mode network and higher-order cognitive control. Furthermore, individuals scoring higher on neuroticism showed altered functional connectivity between the clustered seed regions and brain areas involved in the appraisal, expression and regulation of negative emotions. These results may suggest that the criticized person is attempting to understand the beliefs, perceptions and feelings of the critic in order to facilitate flexible and adaptive social behavior. Furthermore, multiple aspects of emotion processing were found to be affected in individuals scoring higher on neuroticism during the processing of criticism, which may increase their sensitivity to negative social-evaluation. PMID- 23922756 TI - Spatial relationships between GABAergic and glutamatergic synapses on the dendrites of distinct types of mouse retinal ganglion cells across development. AB - Neuronal output requires a concerted balance between excitatory and inhibitory (I/E) input. Like other circuits, inhibitory synaptogenesis in the retina precedes excitatory synaptogenesis. How then do neurons attain their mature balance of I/E ratios despite temporal offset in synaptogenesis? To directly compare the development of glutamatergic and GABAergic synapses onto the same cell, we biolistically transfected retinal ganglion cells (RGCs) with PSD95CFP, a marker of glutamatergic postsynaptic sites, in transgenic Thy1-YFPgamma2 mice in which GABAA receptors are fluorescently tagged. We mapped YFPgamma2 and PSD95CFP puncta distributions on three RGC types at postnatal day P12, shortly before eye opening, and at P21 when robust light responses in RGCs are present. The mature IGABA/E ratios varied among ON-Sustained (S) A-type, OFF-S A-type, and bistratified direction selective (DS) RGCs. These ratios were attained at different rates, before eye-opening for ON-S and OFF-S A-type, and after eye opening for DS RGCs. At both ages examined, the IGABA/E ratio was uniform across the arbors of the three RGC types. Furthermore, measurements of the distances between neighboring PSD95CFP and YFPgamma2 puncta on RGC dendrites indicate that their local relationship is established early in development, and cannot be predicted by random organization. These close spatial associations between glutamatergic and GABAergic postsynaptic sites appear to represent local synaptic arrangements revealed by correlative light and EM reconstructions of a single RGC's dendrites. Thus, although RGC types have different IGABA/E ratios and establish these ratios at separate rates, the local relationship between excitatory and inhibitory inputs appear similarly constrained across the RGC types studied. PMID- 23922757 TI - Comparison between internalizing anti-HER2 mAbs and non-internalizing anti-CEA mAbs in alpha-radioimmunotherapy of small volume peritoneal carcinomatosis using 212Pb. AB - BACKGROUND AND PURPOSE: We assessed the contribution of antibody internalization in the efficacy and toxicity of intraperitoneal alpha-radioimmunotherapy (RIT) of small volume carcinomatosis using (212)Pb-labeled monoclonal antibodies (mAbs) that target HER2 (internalizing) or CEA (non-internalizing) receptors. MATERIALS AND METHODS: Athymic nude mice bearing 2-3 mm intraperitoneal tumor xenografts were intraperitoneally injected with similar activities (370, 740 and 1480 kBq; 37 MBq/mg) of (212)Pb-labeled 35A7 (anti-CEA), trastuzumab (anti-HER2) or PX (non specific) mAbs, or with equivalent amounts of unlabeled mAbs, or with NaCl. Tumor volume was monitored by bioluminescence and survival was reported. Hematologic toxicity and body weight were assessed. Biodistribution of (212)Pb-labeled mAbs and absorbed dose-effect relationships using MIRD formalism were established. RESULTS: Transient hematological toxicity, as revealed by white blood cells and platelets numbering, was reported in mice treated with the highest activities of (212)Pb-labeled mAbs. The median survival (MS) was significantly higher in mice injected with 1.48 MBq of (212)Pb-35A7 (non-internalizing mAbs) (MS = 94 days) than in animals treated with the same activity of (212)Pb-PX mAbs or with NaCl (MS = 18 days). MS was even not reached after 130 days when follow-up was discontinued in mice treated with 1.48 MBq of (212)Pb-trastuzumab. The later efficacy was unexpected since final absorbed dose resulting from injection of 1.48 MBq, was higher for (212)Pb-35A7 (35.5 Gy) than for (212)Pb-trastuzumab (27.6 Gy). These results also highlight the lack of absorbed dose-effect relationship when mean absorbed dose was calculated using MIRD formalism and the requirement to perform small-scale dosimetry. CONCLUSIONS: These data indicate that it might be an advantage of using internalizing anti-HER2 compared with non internalizing anti-CEA (212)Pb-labeled mAbs in the therapy of small volume xenograft tumors. They support clinical investigations of (212)Pb-mAbs RIT as an adjuvant treatment after cytoreductive surgery in patients with peritoneal carcinomatosis. PMID- 23922758 TI - Low immunogenicity of neural progenitor cells differentiated from induced pluripotent stem cells derived from less immunogenic somatic cells. AB - The groundbreaking discovery of induced pluripotent stem cells (iPS cells) provides a new source for cell therapy. However, whether the iPS derived functional lineages from different cell origins have different immunogenicity remains unknown. It had been known that the cells isolated from extra-embryonic tissues, such as umbilical cord mesenchymal cells (UMCs), are less immunogenic than other adult lineages such as skin fibroblasts (SFs). In this report, we differentiated iPS cells from human UMCs and SFs into neural progenitor cells (NPCs) and analyzed their immunogenicity. Through co-culture with allologous peripheral blood mononuclear cells (PBMCs), we showed that UMCs were indeed less immunogenic than skin cells to simulate proliferation of PBMCs. Surprisingly, we found that the NPCs differentiated from UMC-iPS cells retained low immunogenicity as the parental UMCs based on the PBMC proliferation assay. In cytotoxic expression assay, reactions in most kinds of immune effector cells showed more perforin and granzyme B expression with SF-NPCs stimulation than that with UMC NPCs stimulation in PBMC co-culture system, in T cell co-culture system as well. Furthermore, through whole genome expression microarray analysis, we showed that over 70 immune genes, including all members of HLA-I, were expressed at lower levels in NPCs derived from UMC-iPS cells than that from SF-iPS cells. Our results demonstrated a phenomenon that the low immunogenicity of the less immunogenic cells could be retained after cell reprogramming and further differentiation, thus provide a new concept to generate functional lineages with lower immunogenicity for regenerative medicine. PMID- 23922759 TI - Genetic variation in the NOC gene is associated with body mass index in Chinese subjects. AB - Circadian clock genes are critical regulators of energy homeostasis and metabolism. However, whether variation in the circadian genes is associated with metabolic phenotypes in humans remains to be explored. In this study, we systemically genotyped 20 tag single nucleotide polymorphisms (SNPs) in 8 candidate genes involved in circadian clock, including CLOCK, BMAL1(ARNTL), PER1, PER2, CRY1, CRY2, CSNK1E,, and NOC(CCRN4L) in 1,510 non-diabetic Chinese subjects in Taipei and Yunlin populations in Taiwan. Their associations with metabolic phenotypes were analyzed. We found that genetic variation in the NOC gene, rs9684900 was associated with body mass index (BMI) (P = 0.0016, Bonferroni corrected P = 0.032). Another variant, rs135764 in the CSNK1E gene was associated with fasting glucose (P = 0.0023, Bonferroni corrected P = 0.046). These associations were consistent in both Taipei and Yunlin populations. Significant epistatic and joint effects between SNPs on BMI and related phenotypes were observed. Furthermore, NOC mRNA levels in human abdominal adipose tissue were significantly increased in obese subjects compared to non-obese controls. CONCLUSION: Genetic variation in the NOC gene is associated with BMI in Chinese subjects. PMID- 23922760 TI - Transcriptomic analysis of insulin-sensitive tissues from anti-diabetic drug treated ZDF rats, a T2DM animal model. AB - Gene expression changes have been associated with type 2 diabetes mellitus (T2DM); however, the alterations are not fully understood. We investigated the effects of anti-diabetic drugs on gene expression in Zucker diabetic fatty (ZDF) rats using oligonucleotide microarray technology to identify gene expression changes occurring in T2DM. Global gene expression in the pancreas, adipose tissue, skeletal muscle, and liver was profiled from Zucker lean control (ZLC) and anti-diabetic drug treated ZDF rats compared with those in ZDF rats. We showed that anti-diabetic drugs regulate the expression of a large number of genes. We provided a more integrated view of the diabetic changes by examining the gene expression networks. The resulting sub-networks allowed us to identify several biological processes that were significantly enriched by the anti diabetic drug treatment, including oxidative phosphorylation (OXPHOS), systemic lupus erythematous, and the chemokine signaling pathway. Among them, we found that white adipose tissue from ZDF rats showed decreased expression of a set of OXPHOS genes that were normalized by rosiglitazone treatment accompanied by rescued blood glucose levels. In conclusion, we suggest that alterations in OXPHOS gene expression in white adipose tissue may play a role in the pathogenesis and drug mediated recovery of T2DM through a comprehensive gene expression network study after multi-drug treatment of ZDF rats. PMID- 23922761 TI - Majority rules with random tie-breaking in Boolean gene regulatory networks. AB - We consider threshold boolean gene regulatory networks, where the update function of each gene is described as a majority rule evaluated among the regulators of that gene: it is turned ON when the sum of its regulator contributions is positive (activators contribute positively whereas repressors contribute negatively) and turned OFF when this sum is negative. In case of a tie (when contributions cancel each other out), it is often assumed that the gene keeps it current state. This framework has been successfully used to model cell cycle control in yeast. Moreover, several studies consider stochastic extensions to assess the robustness of such a model. Here, we introduce a novel, natural stochastic extension of the majority rule. It consists in randomly choosing the next value of a gene only in case of a tie. Hence, the resulting model includes deterministic and probabilistic updates. We present variants of the majority rule, including alternate treatments of the tie situation. Impact of these variants on the corresponding dynamical behaviours is discussed. After a thorough study of a class of two-node networks, we illustrate the interest of our stochastic extension using a published cell cycle model. In particular, we demonstrate that steady state analysis can be rigorously performed and can lead to effective predictions; these relate for example to the identification of interactions whose addition would ensure that a specific state is absorbing. PMID- 23922762 TI - Assessing gibberellins oxidase activity by anion exchange/hydrophobic polymer monolithic capillary liquid chromatography-mass spectrometry. AB - Bioactive gibberellins (GAs) play a key regulatory role in plant growth and development. In the biosynthesis of GAs, GA3-oxidase catalyzes the final step to produce bioactive GAs. Thus, the evaluation of GA3-oxidase activity is critical for elucidating the regulation mechanism of plant growth controlled by GAs. However, assessing catalytic activity of endogenous GA3-oxidase remains challenging. In the current study, we developed a capillary liquid chromatography -mass spectrometry (cLC-MS) method for the sensitive assay of in-vitro recombinant or endogenous GA3-oxidase by analyzing the catalytic substrates and products of GA3-oxidase (GA1, GA4, GA9, GA20). An anion exchange/hydrophobic poly([2-(methacryloyloxy)ethyl]trimethylammonium-co-divinylbenzene-co-ethylene glycol dimethacrylate)(META-co-DVB-co-EDMA) monolithic column was successfully prepared for the separation of all target GAs. The limits of detection (LODs, Signal/Noise = 3) of GAs were in the range of 0.62-0.90 fmol. We determined the kinetic parameters (K m) of recombinant GA3-oxidase in Escherichia coli (E. coli) cell lysates, which is consistent with previous reports. Furthermore, by using isotope labeled substrates, we successfully evaluated the activity of endogenous GA3-oxidase that converts GA9 to GA4 in four types of plant samples, which is, to the best of our knowledge, the first report for the quantification of the activity of endogenous GA3-oxidase in plant. Taken together, the method developed here provides a good solution for the evaluation of endogenous GA3-oxidase activity in plant, which may promote the in-depth study of the growth regulation mechanism governed by GAs in plant physiology. PMID- 23922763 TI - Myeloid-derived suppressor cells modulate immune responses independently of NADPH oxidase in the ovarian tumor microenvironment in mice. AB - The phagocyte NADPH oxidase generates superoxide anion and downstream reactive oxidant intermediates in response to infectious threat, and is a critical mediator of antimicrobial host defense and inflammatory responses. Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are recruited by cancer cells, accumulate locally and systemically in advanced cancer, and can abrogate anti-tumor immunity. Prior studies have implicated the phagocyte NADPH oxidase as being an important component promoting MDSC accumulation and immunosuppression in cancer. We therefore used engineered NADPH oxidase-deficient (p47 (phox-/-)) mice to delineate the role of this enzyme complex in MDSC accumulation and function in a syngeneic mouse model of epithelial ovarian cancer. We found that the presence of NADPH oxidase did not affect tumor progression. The accumulation of MDSCs locally and systemically was similar in tumor-bearing wild-type (WT) and p47 (phox-/-) mice. Although MDSCs from tumor-bearing WT mice had functional NADPH oxidase, the suppressive effect of MDSCs on ex vivo stimulated T cell proliferation was NADPH oxidase-independent. In contrast to other tumor-bearing mouse models, our results show that MDSC accumulation and immunosuppression in syngeneic epithelial ovarian cancer is NADPH oxidase-independent. We speculate that factors inherent to the tumor, tumor microenvironment, or both determine the specific requirement for NADPH oxidase in MDSC accumulation and function. PMID- 23922764 TI - Bayesian detection of causal rare variants under posterior consistency. AB - Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature. PMID- 23922765 TI - The epidemiological modelling of major depressive disorder: application for the Global Burden of Disease Study 2010. AB - BACKGROUND: Although the detrimental impact of major depressive disorder (MDD) at the individual level has been described, its global epidemiology remains unclear given limitations in the data. Here we present the modelled epidemiological profile of MDD dealing with heterogeneity in the data, enforcing internal consistency between epidemiological parameters and making estimates for world regions with no empirical data. These estimates were used to quantify the burden of MDD for the Global Burden of Disease Study 2010 (GBD 2010). METHOD: Analyses drew on data from our existing literature review of the epidemiology of MDD. DisMod-MR, the latest version of the generic disease modelling system redesigned as a Bayesian meta-regression tool, derived prevalence by age, year and sex for 21 regions. Prior epidemiological knowledge, study- and country-level covariates adjusted sub-optimal raw data. RESULTS: There were over 298 million cases of MDD globally at any point in time in 2010, with the highest proportion of cases occurring between 25 and 34 years. Global point prevalence was very similar across time (4.4% (95% uncertainty: 4.2-4.7%) in 1990, 4.4% (4.1-4.7%) in 2005 and 2010), but higher in females (5.5% (5.0-6.0%) compared to males (3.2% (3.0 3.6%) in 2010. Regions in conflict had higher prevalence than those with no conflict. The annual incidence of an episode of MDD followed a similar age and regional pattern to prevalence but was about one and a half times higher, consistent with an average duration of 37.7 weeks. CONCLUSION: We were able to integrate available data, including those from high quality surveys and sub optimal studies, into a model adjusting for known methodological sources of heterogeneity. We were also able to estimate the epidemiology of MDD in regions with no available data. This informed GBD 2010 and the public health field, with a clearer understanding of the global distribution of MDD. PMID- 23922766 TI - Alternative immunomodulatory strategies for xenotransplantation: CD80/CD86-CTLA4 pathway-modified immature dendritic cells promote xenograft survival. AB - BACKGROUND: Xenotransplantation is a promising approach to circumventing the current organ shortage. However, T-cell-dependent anti-xenoresponses are a major challenge to successful xenografts. Given the advantages of the use of CTLA4-Ig in the survival of allografts, the purpose of the study was to investigate the therapeutic potential of CTLA4-IgG4 modified immature dendritic cells (imDCs) in the prevention of islets xenograft rejection. METHODS: CTLA4-IgG4 was constructed by the fusion of the extracellular regions of porcine CTLA4 to human the hIgG4 Fc region. The imDCs were induced and cultured from porcine peripheral blood mononuclear cells (PBMC). The CTLA4-IgG4 modified imDCs were delivered via the portal vein to the liver of diabetic mice (insulin-dependent diabetes mellitus) before islet xenografting, and mCTLA4-Ig was administered intravenously after xenotransplantation. RESULTS: The xenograft survival of mice receiving unmodified imDCs was approximately 30 days. However, following administration of CTLA4-IgG4 modified imDCs before grafting and mCTLA4-Ig after grafting, xenografts survived for more than 100 days. Flow cytometric analysis showed that the CD4(+)CD25(+)Foxp3(+) Treg population was increased in spleens. The efficacy of donor CTLA4-IgG4 modified imDCs correlated partially with the amplification of Tregs. CONCLUSIONS: These results confirm that selective inhibition of the direct and indirect pathways of T-cell activation by donor CTLA4-IgG4 modified imDCs and receptor CTLA4-Ig is a highly effective strategy to promote survival of xenografts. PMID- 23922767 TI - Shifts in the distribution of mass densities is a signature of caloric restriction in Caenorhabditis elegans. AB - Although the starvation response of the model multicellular organism Caenorhabditis elegans is a subject of much research, there is no convenient phenotypic readout of caloric restriction that can be applicable to large numbers of worms. This paper describes the distribution of mass densities of populations of C. elegans, from larval stages up to day one of adulthood, using isopycnic centrifugation, and finds that density is a convenient, if complex, phenotypic readout in C. elegans. The density of worms in synchronized populations of wildtype N2 C. elegans grown under standard solid-phase culture conditions was normally distributed, with distributions peaked sharply at a mean of 1.091 g/cm(3) for L1, L2 and L3 larvae, 1.087 g/cm(3) for L4 larvae, 1.081 g/cm(3) for newly molted adults, and 1.074 g/cm(3) at 24 hours of adulthood. The density of adult worms under starvation stress fell well outside this range, falling to a mean value of 1.054 g/cm(3) after eight hours of starvation. This decrease in density correlated with the consumption of stored glycogen in the food-deprived worms. The density of the worms increased when deprived of food for longer durations, corresponding to a shift in the response of the worms: worms sacrifice their bodies by retaining larvae, which consume the adults from within. Density based screens with the drug Ivermectin on worms cultured on single plates resulted in a clear bimodal (double-peaked) distribution of densities corresponding to drug exposed and non-exposed worms. Thus, measurements of changes in density could be used to conduct screens on the effects of drugs on several populations of worms cultured on single plates. PMID- 23922769 TI - Track-a-worm, an open-source system for quantitative assessment of C. elegans locomotory and bending behavior. AB - A major challenge of neuroscience is to understand the circuit and gene bases of behavior. C. elegans is commonly used as a model system to investigate how various gene products function at specific tissue, cellular, and synaptic foci to produce complicated locomotory and bending behavior. The investigation generally requires quantitative behavioral analyses using an automated single-worm tracker, which constantly records and analyzes the position and body shape of a freely moving worm at a high magnification. Many single-worm trackers have been developed to meet lab-specific needs, but none has been widely implemented for various reasons, such as hardware difficult to assemble, and software lacking sufficient functionality, having closed source code, or using a programming language that is not broadly accessible. The lack of a versatile system convenient for wide implementation makes data comparisons difficult and compels other labs to develop new worm trackers. Here we describe Track-A-Worm, a system rich in functionality, open in source code, and easy to use. The system includes plug-and-play hardware (a stereomicroscope, a digital camera and a motorized stage), custom software written to run with Matlab in Windows 7, and a detailed user manual. Grayscale images are automatically converted to binary images followed by head identification and placement of 13 markers along a deduced spline. The software can extract and quantify a variety of parameters, including distance traveled, average speed, distance/time/speed of forward and backward locomotion, frequency and amplitude of dominant bends, overall bending activities measured as root mean square, and sum of all bends. It also plots worm travel path, bend trace, and bend frequency spectrum. All functionality is performed through graphical user interfaces and data is exported to clearly-annotated and documented Excel files. These features make Track-A-Worm a good candidate for implementation in other labs. PMID- 23922768 TI - Macromolecular crowding as a suppressor of human IAPP fibril formation and cytotoxicity. AB - The biological cell is known to exhibit a highly crowded milieu, which significantly influences protein aggregation and association processes. As several cell degenerative diseases are related to the self-association and fibrillation of amyloidogenic peptides, understanding of the impact of macromolecular crowding on these processes is of high biomedical importance. It is further of particular relevance as most in vitro studies on amyloid aggregation have been performed in diluted solution which does not reflect the complexity of their cellular surrounding. The study presented here focuses on the self-association of the type-2 diabetes mellitus related human islet amyloid polypeptide (hIAPP) in various crowded environments including network-forming macromolecular crowding reagents and protein crowders. It was possible to identify two competing processes: a crowder concentration and type dependent stabilization of globular off-pathway species and a--consequently--retarded or even inhibited hIAPP fibrillation reaction. The cause of these crowding effects was revealed to be mainly excluded volume in the polymeric crowders, whereas non specific interactions seem to be most dominant in protein crowded environments. Specific hIAPP cytotoxicity assays on pancreatic beta-cells reveal non-toxicity for the stabilized globular species, in contrast to the high cytotoxicity imposed by the normal fibrillation pathway. From these findings it can be concluded that cellular crowding is able to effectively stabilize the monomeric conformation of hIAPP, hence enabling the conduction of its normal physiological function and prevent this highly amyloidogenic peptide from cytotoxic aggregation and fibrillation. PMID- 23922770 TI - The potential impact of improving appropriate treatment for fever on malaria and non-malarial febrile illness management in under-5s: a decision-tree modelling approach. AB - BACKGROUND: As international funding for malaria programmes plateaus, limited resources must be rationally managed for malaria and non-malarial febrile illnesses (NMFI). Given widespread unnecessary treatment of NMFI with first-line antimalarial Artemisinin Combination Therapies (ACTs), our aim was to estimate the effect of health-systems factors on rates of appropriate treatment for fever and on use of ACTs. METHODS: A decision-tree tool was developed to investigate the impact of improving aspects of the fever care-pathway and also evaluate the impact in Tanzania of the revised WHO malaria guidelines advocating diagnostic led management. RESULTS: Model outputs using baseline parameters suggest 49% malaria cases attending a clinic would receive ACTs (95% Uncertainty Interval:40.6-59.2%) but that 44% (95% UI:35-54.8%) NMFI cases would also receive ACTs. Provision of 100% ACT stock predicted a 28.9% increase in malaria cases treated with ACT, but also an increase in overtreatment of NMFI, with 70% NMFI cases (95% UI:56.4-79.2%) projected to receive ACTs, and thus an overall 13% reduction (95% UI:5-21.6%) in correct management of febrile cases. Modelling increased availability or use of diagnostics had little effect on malaria management outputs, but may significantly reduce NMFI overtreatment. The model predicts the early rollout of revised WHO guidelines in Tanzania may have led to a 35% decrease (95% UI:31.2-39.8%) in NMFI overtreatment, but also a 19.5% reduction (95% UI:11-27.2%), in malaria cases receiving ACTs, due to a potential fourfold decrease in cases that were untested or tested false-negative (42.5% vs.8.9%) and so untreated. DISCUSSION: Modelling multi-pronged intervention strategies proved most effective to improve malaria treatment without increasing NMFI overtreatment. As malaria transmission declines, health system interventions must be guided by whether the management priority is an increase in malaria cases receiving ACTs (reducing the treatment gap), reducing ACT waste through unnecessary treatment of NMFI or expanding appropriate treatment of all febrile illness. PMID- 23922771 TI - Reorganization of the intact somatosensory cortex immediately after spinal cord injury. AB - Sensory deafferentation produces extensive reorganization of the corresponding deafferented cortex. Little is known, however, about the role of the adjacent intact cortex in this reorganization. Here we show that a complete thoracic transection of the spinal cord immediately increases the responses of the intact forepaw cortex to forepaw stimuli (above the level of the lesion) in anesthetized rats. These increased forepaw responses were independent of the global changes in cortical state induced by the spinal cord transection described in our previous work (Aguilar et al., J Neurosci 2010), as the responses increased both when the cortex was in a silent state (down-state) or in an active state (up-state). The increased responses in the intact forepaw cortex correlated with increased responses in the deafferented hindpaw cortex, suggesting that they could represent different points of view of the same immediate state-independent functional reorganization of the primary somatosensory cortex after spinal cord injury. Collectively, the results of the present study and of our previous study suggest that both state-dependent and state-independent mechanisms can jointly contribute to cortical reorganization immediately after spinal cord injury. PMID- 23922772 TI - Four jointed box 1 promotes angiogenesis and is associated with poor patient survival in colorectal carcinoma. AB - Angiogenesis, the recruitment and re-configuration of pre-existing vasculature, is essential for tumor growth and metastasis. Increased tumor vascularization often correlates with poor patient outcomes in a broad spectrum of carcinomas. We identified four jointed box 1 (FJX1) as a candidate regulator of tumor angiogenesis in colorectal cancer. FJX1 mRNA and protein are upregulated in human colorectal tumor epithelium as compared with normal epithelium and colorectal adenomas, and high expression of FJX1 is associated with poor patient prognosis. FJX1 mRNA expression in colorectal cancer tissues is significantly correlated with changes in known angiogenesis genes. Augmented expression of FJX1 in colon cancer cells promotes growth of xenografts in athymic mice and is associated with increased tumor cell proliferation and vascularization. Furthermore, FJX1 null mice develop significantly fewer colonic polyps than wild-type littermates after combined dextran sodium sulfate (DSS) and azoxymethane (AOM) treatment. In vitro, conditioned media from FJX1 expressing cells promoted endothelial cell capillary tube formation in a HIF1-alpha dependent manner. Taken together our results support the conclusion that FJX1 is a novel regulator of tumor progression, due in part, to its effect on tumor vascularization. PMID- 23922773 TI - A robotics-based behavioral paradigm to measure anxiety-related responses in zebrafish. AB - Zebrafish are gaining momentum as a laboratory animal species for the study of anxiety-related disorders in translational research, whereby they serve a fundamental complement to laboratory rodents. Several anxiety-related behavioral paradigms, which rest upon the presentation of live predatorial stimuli, may yield inconsistent results due to fatigue, habituation, or idiosyncratic responses exhibited by the stimulus itself. To overcome these limitations, we designed and manufactured a fully controllable robot inspired by a natural aquatic predator (Indian leaf fish, Nandus nandus) of zebrafish. We report that this robot elicits aversive antipredatorial reactions in a preference test and that data obtained therein correlate with data observed in traditional anxiety- and fear-related tests (light/dark preference and shelter-seeking). Finally, ethanol administration (0.25; 0.50; 1.00%) exerts anxiolytic effects, thus supporting the view that robotic stimuli can be used in the analysis of anxiety related behaviors in zebrafish. PMID- 23922774 TI - Modulation of the Akt pathway reveals a novel link with PERK/eIF2alpha, which is relevant during hypoxia. AB - The unfolded protein response (UPR) and the Akt signaling pathway share several regulatory functions and have the capacity to determine cell outcome under specific conditions. However, both pathways have largely been studied independently. Here, we asked whether the Akt pathway regulates the UPR. To this end, we used a series of chemical compounds that modulate PI3K/Akt pathway and monitored the activity of the three UPR branches: PERK, IRE1 and ATF6. The antiproliferative and antiviral drug Akt-IV strongly and persistently activated all three branches of the UPR. We present evidence that activation of PERK/eIF2alpha requires Akt and that PERK is a direct Akt target. Chemical activation of this novel Akt/PERK pathway by Akt-IV leads to cell death, which was largely dependent on the presence of PERK and IRE1. Finally, we show that hypoxia-induced activation of eIF2alpha requires Akt, providing a physiologically relevant condition for the interaction between Akt and the PERK branch of the UPR. These data suggest the UPR and the Akt pathway signal to one another as a means of controlling cell fate. PMID- 23922775 TI - Undernutrition affects cell survival, oxidative stress, Ca2+ handling and signaling pathways in vas deferens, crippling reproductive capacity. AB - BACKGROUND: The aim of this work was to investigate the mechanisms by which chronic malnutrition (CM) affects vas deferens function, leading to compromised reproductive capacity. Previous studies have shown that maternal malnutrition affects the reproductive tracts of adult male offspring. However, little is known about the effects of CM, a widespread life-long condition that persists from conception throughout growth to adult life. METHODOLOGY/PRINCIPAL FINDINGS: Young adult male rats, which were chronically malnourished from weaning, presented decreased total and haploid cells in the vas deferens, hypertrophy of the muscle layer in the epididymal portion of the vas deferens and intense atrophy of the muscular coat in its prostatic portion. At a molecular level, the vas deferens tissue of CM rats exhibited a huge rise in lipid peroxidation and protein carbonylation, evidence of an accentuated increase in local reactive oxygen species levels. The kinetics of plasma membrane Ca(2+)-ATPase activity and its kinase-mediated phosphorylation by PKA and PKC in the vas deferens revealed malnutrition-induced modifications in velocity, Ca(2+) affinity and regulation of Ca(2+) handling proteins. The severely crippled content of the 12-kDa FK506 binding protein, which controls passive Ca(2+) release from the sarco(endo) plasmic reticulum, revealed another target of malnutrition related to intracellular Ca(2+) handling, with a potential effect on forward propulsion of sperm cells. As a possible compensatory response, malnutrition led to enhanced sarco(endo) plasmic reticulum Ca(2+)-ATPase activity, possibly caused by stimulatory PKA-mediated phosphorylation. CONCLUSIONS/SIGNIFICANCE: The functional correlates of these cellular and molecular hallmarks of chronic malnutrition on the vas deferens were an accentuated reduction in fertility and fecundity. PMID- 23922776 TI - Impact of the Ku complex on HIV-1 expression and latency. AB - Ku, a cellular complex required for human cell survival and involved in double strand break DNA repair and multiple other cellular processes, may modulate retroviral multiplication, although the precise mechanism through which it acts is still controversial. Recently, Ku was identified as a possible anti-human immunodeficiency virus type 1 (HIV-1) target in human cells, in two global approaches. Here we investigated the role of Ku on the HIV-1 replication cycle by analyzing the expression level of a panel of non-replicative lentiviral vectors expressing the green fluorescent protein in human colorectal carcinoma HCT 116 cells, stably or transiently depleted of Ku. We found that in this cellular model the depletion of Ku did not affect the efficiency of (pre-)integrative steps but decreased the early HIV-1 expression by acting at the transcriptional level. This negative effect was specific of the HIV-1 promoter, required the obligatory step of viral DNA integration and was reversed by transient depletion of p53. We also provided evidence on a direct binding of Ku to HIV-1 LTR in transduced cells. Ku not only promotes the early transcription from the HIV-1 promoter, but also limits the constitution of viral latency. Moreover, in the presence of a normal level of Ku, HIV-1 expression was gradually lost over time, likely due to the counter-selection of HIV-1-expressing cells. On the contrary, the reactivation of transgene expression from HIV-1 by means of trichostatin A- or tumor necrosis factor alpha-administration was enhanced under condition of Ku haplodepletion, suggesting a phenomenon of provirus latency. These observations plead in favor of the hypothesis that Ku has an impact on HIV-1 expression and latency at early- and mid-time after integration. PMID- 23922777 TI - A strong anti-inflammatory signature revealed by liver transcription profiling of Tmprss6-/- mice. AB - Control of systemic iron homeostasis is interconnected with the inflammatory response through the key iron regulator, the antimicrobial peptide hepcidin. We have previously shown that mice with iron deficiency anemia (IDA)-low hepcidin show a pro-inflammatory response that is blunted in iron deficient-high hepcidin Tmprss6 KO mice. The transcriptional response associated with chronic hepcidin overexpression due to genetic inactivation of Tmprss6 is unknown. By using whole genome transcription profiling of the liver and analysis of spleen immune-related genes we identified several functional pathways differentially expressed in Tmprss6 KO mice, compared to IDA animals and thus irrespective of the iron status. In the effort of defining genes potentially targets of Tmprss6 we analyzed liver gene expression changes according to the genotype and independently of treatment. Tmprss6 inactivation causes down-regulation of liver pathways connected to immune and inflammatory response as well as spleen genes related to macrophage activation and inflammatory cytokines production. The anti inflammatory status of Tmprss6 KO animals was confirmed by the down-regulation of pathways related to immunity, stress response and intracellular signaling in both liver and spleen after LPS treatment. Opposite to Tmprss6 KO mice, Hfe(-/-) mice are characterized by iron overload with inappropriately low hepcidin levels. Liver expression profiling of Hfe(-/-) deficient versus iron loaded mice show the opposite expression of some of the genes modulated by the loss of Tmprss6. Altogether our results confirm the anti-inflammatory status of Tmprss6 KO mice and identify new potential target pathways/genes of Tmprss6. PMID- 23922779 TI - Spatial and temporal biogeography of soil microbial communities in arid and semiarid regions. AB - Microbial communities in soils may change in accordance with distance, season, climate, soil texture and other environmental parameters. Microbial diversity patterns have been extensively surveyed in temperate regions, but few such studies attempted to address them with respect to spatial and temporal scales and their correlations to environmental factors, especially in arid ecosystems. In order to fill this gap on a regional scale, the molecular fingerprints and abundance of three taxonomic groups--Bacteria, alpha-Proteobacteria and Actinobacteria--were sampled from soils 0.5-100 km apart in arid, semi-arid, dry Mediterranean and shoreline Mediterranean regions in Israel. Additionally, on a local scale, the molecular fingerprints of three taxonomic groups--Bacteria, Archaea and Fungi--were sampled from soils 1 cm-500 m apart in the semi-arid region, in both summer and winter. Fingerprints of the Bacteria differentiated between all regions (P<0.02), while those of the alpha-Proteobacteria differentiated between some of the regions (0.010.05). Locally, fingerprints of archaea and fungi did not display distance-decay relationships (P>0.13), that is, the dissimilarity between communities did not increase with geographic distance. Neither was this phenomenon evident in bacterial samples in summer (P>0.24); in winter, however, differences between bacterial communities significantly increased as the geographic distances between them grew (P<0.01). Microbial community structures, as well as microbial abundance, were both significantly correlated to precipitation and soil characteristics: texture, organic matter and water content (R(2)>0.60, P<0.01). We conclude that on the whole, microbial biogeography in arid and semi-arid soils in Israel is determined more by specific environmental factors than geographic distances and spatial distribution patterns. PMID- 23922778 TI - Deep sequencing analysis of HCV NS3 resistance-associated variants and mutation linkage in liver transplant recipients. AB - Viral variants with decreased susceptibility to HCV protease inhibitors (PIs) occur naturally and preexist at low levels within HCV populations. In patients failing PI monotherapy, single and double mutants conferring intermediate to high level resistance to PIs have been selected in vivo. The abundance, temporal dynamics and linkage of naturally occurring resistance-associated variants (RAVs), however, have not been characterized in detail. Here, using high-density pyrosequencing, we analyzed HCV NS3 gene segments from 20 subjects with chronic HCV infection, including 12 subjects before and after liver transplantation. Bioinformatics analysis revealed that Q80 substitution was a dominant variant in 40% of the subjects, whereas other RAVs circulate at low levels within quasispecies populations. Low frequency mutation linkage was detectable by Illumina paired-end sequencing in as low as 0.5% of the mock populations constructed from in vitro RNA transcripts but were uncommon in vivo. We show that naturally occurring RAVs are common and can persist long term following liver transplant at low levels not readily detectable by conventional sequencing. Our results indicate that mutation linkage at low levels could be identified using the Illumina paired-end approach. The methods described here should facilitate the analysis of low frequency HCV drug resistance, mutation linkage and evolution, which may inform future therapeutic strategies in patients undergoing direct acting antiviral therapies. PMID- 23922780 TI - Increments and duplication events of enzymes and transcription factors influence metabolic and regulatory diversity in prokaryotes. AB - In this work, the content of enzymes and DNA-binding transcription factors (TFs) in 794 non-redundant prokaryotic genomes was evaluated. The identification of enzymes was based on annotations deposited in the KEGG database as well as in databases of functional domains (COG and PFAM) and structural domains (Superfamily). For identifications of the TFs, hidden Markov profiles were constructed based on well-known transcriptional regulatory families. From these analyses, we obtained diverse and interesting results, such as the negative rate of incremental changes in the number of detected enzymes with respect to the genome size. On the contrary, for TFs the rate incremented as the complexity of genome increased. This inverse related performance shapes the diversity of metabolic and regulatory networks and impacts the availability of enzymes and TFs. Furthermore, the intersection of the derivatives between enzymes and TFs was identified at 9,659 genes, after this point, the regulatory complexity grows faster than metabolic complexity. In addition, TFs have a low number of duplications, in contrast to the apparent high number of duplications associated with enzymes. Despite the greater number of duplicated enzymes versus TFs, the increment by which duplicates appear is higher in TFs. A lower proportion of enzymes among archaeal genomes (22%) than in the bacterial ones (27%) was also found. This low proportion might be compensated by the interconnection between the metabolic pathways in Archaea. A similar proportion was also found for the archaeal TFs, for which the formation of regulatory complexes has been proposed. Finally, an enrichment of multifunctional enzymes in Bacteria, as a mechanism of ecological adaptation, was detected. PMID- 23922781 TI - Antenatal depression in Anuradhapura, Sri Lanka and the factor structure of the Sinhalese version of Edinburgh post partum depression scale among pregnant women. AB - BACKGROUND: Mental health problems among women of reproductive age group contribute to 7% of Global Burden of Diseases of women of all ages. Purpose of this study was to determine the prevalence and correlates of antenatal depression among pregnant women in Anuradhapura, Sri Lanka, and to explore the factor structure of EPDS. METHODS: Pregnant women with gestational age of 24-36 weeks and residing in Anuradhapura district, Sri Lanka were recruited to the study using a two stage cluster sampling procedure. Sinhalese version of Edinburgh Post Partum Depression Scale (EPDS) and an interviewer administered questionnaire was use to collect data. A cut off value of 9 was used for the Sinhalese version of EPDS. RESULTS: A total of 376 pregnant women were studied. Median EPDS score among pregnant women was 5 (IQR 2-8). Prevalence of antenatal depression in this study sample was 16.2% (n = 61). Thought of self harming (item number 10) was reported by 26 pregnant women (6.9%). None of the socio-demographic factors were associated with depression in this study sample. Having heart burn was significantly associated with depressive symptoms (p = 0.041). Sri Lankan version of EPDS showed a two factor solution. Anxiety was not emerged as a separate factor in this analysis. CONCLUSIONS: Prevalence of antenatal depression in Anuradhapura, Sri Lanka was relatively low. Anxiety was not emerged as a separate factor in the Sinhalese version of the EPDS. PMID- 23922783 TI - Anurans from the Lower Cretaceous Jehol Group of western Liaoning, China. AB - BACKGROUND: To date, the Lower Cretaceous Jehol Group of western Liaoning, China has yielded five monotypic genera of anurans, including Liaobatrachus grabaui, Callobatrachus sanyanensis, Mesophryne beipiaoensis, Dalianbatrachus mengi, and Yizhoubatrachus macilentus. However, the validity and distinctness of these taxa have been questioned. METHODOLOGY/PRINCIPAL FINDING: We provide a comprehensive analysis of the Jehol frogs that includes a re-examination of the published taxa as well as an examination of a number of new specimens that have been collected over the past 10 years. The results show that the five previously named taxa can be referred to three species of one genus-Liaobatrachus grabaui, L. beipiaoensis comb. nov. and L. macilentus comb. nov.. The diagnosis of Liaobatrachus is revised, and a new diagnosis is provided for each species of this genus. We also establish Liaobatrachus zhaoi sp. nov., on the basis of a dozen well-preserved specimens from a new locality. This taxon is distinguished by a unique combination of characteristics, including relatively long hind limbs, a rounded rather than triangular acetabulum, and a gradually-tapering cultriform process of the parasphenoid. In addition, an unnamed frog from a higher horizon, which has narrow sacral diapophyses and particularly long legs, is different from Liaobatrachus and represents another form of anuran in the Jehol Biota. CONCLUSION/SIGNIFICANCE: Comparisons with other Mesozoic and extant anurans and the primary phylogenetic analysis both suggest that Liaobatrachus is a member of the anuran crown-group and forms a polytomy with leiopelmatids (Ascaphus and Leiopelma) and the remaining crown-group anurans (Lalagobatrachia). PMID- 23922782 TI - Transcription coactivators p300 and CBP are necessary for photoreceptor-specific chromatin organization and gene expression. AB - Rod and cone photoreceptor neurons in the mammalian retina possess specialized cellular architecture and functional features for converting light to a neuronal signal. Establishing and maintaining these characteristics requires appropriate expression of a specific set of genes, which is tightly regulated by a network of photoreceptor transcription factors centered on the cone-rod homeobox protein CRX. CRX recruits transcription coactivators p300 and CBP to acetylate promoter bound histones and activate transcription of target genes. To further elucidate the role of these two coactivators, we conditionally knocked out Ep300 and/or CrebBP in differentiating rods or cones, using opsin-driven Cre recombinase. Knockout of either factor alone exerted minimal effects, but loss of both factors severely disrupted target cell morphology and function: the unique nuclear chromatin organization seen in mouse rods was reversed, accompanied by redistribution of nuclear territories associated with repressive and active histone marks. Transcription of many genes including CRX targets was severely impaired, correlating with reduced histone H3/H4 acetylation (the products of p300/CBP) on target gene promoters. Interestingly, the presence of a single wild type allele of either coactivator prevented many of these defects, with Ep300 more effective than Cbp. These results suggest that p300 and CBP play essential roles in maintaining photoreceptor-specific structure, function and gene expression. PMID- 23922784 TI - Incidence and prevalence of tuberculosis among household contacts of pulmonary tuberculosis patients in a peri-urban population of South Delhi, India. AB - BACKGROUND: Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the leading causes of mortality and morbidity across all age groups throughout the world, especially in developing countries. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have included 432 open index cases with their 1608 household contacts in a prospective cohort study conducted from May 2007 to March 2009. The follow-up period was 2 years. All Index cases were diagnosed on the basis of suggestive signs and symptoms and sputum being AFB positive. Among the 432 index patients, 250 (57.9%) were males and 182 (42.1%) females; with mean age of 34 +/- 14.4 yr and 26 +/- 11.1 yr, respectively. Out of 1608 household contacts, 866 (53.9%) were males and 742 (46.1%) females; with mean age of 26.5 +/- 15.8 and 26.5 +/- 16.0 yr, respectively. Of the total 432 households, 304 (70.4%) had <= 4 members and 128 (29.6%) had >= 5 members. The median size of the family was four. Of the 1608 contacts, 1206 were able to provide sputum samples, of whom 83 (6.9%) were found MTB culture positive. Household contacts belonging to adult age group were predominantly (74, 89.2%) infected as compared to the children (9, 10.8%). On screening the contact relationship status with index patients, 52 (62.7%) were first-degree relatives, 18 (34.6%) second-degree relatives and 12 (14.5%) spouses who got infected from their respective index patients. Co-prevalent and incident tuberculosis was found in 52 (4.3%) and 31 (2.6%) contacts, respectively. In incident cases, the diagnosis could be made between 4 to 24 months of follow-up, after their baseline evaluation. CONCLUSION: Active household contact investigation is a powerful tool to detect and treat tuberculosis at early stages and the only method to control TB in high-TB-burden countries. PMID- 23922785 TI - The endoplasmic reticulum-resident chaperone heat shock protein 47 protects the Golgi apparatus from the effects of O-glycosylation inhibition. AB - The Golgi apparatus is important for the transport of secretory cargo. Glycosylation is a major post-translational event. Recognition of O-glycans on proteins is necessary for glycoprotein trafficking. In this study, specific inhibition of O-glycosylation (Golgi stress) induced the expression of endoplasmic reticulum (ER)-resident heat shock protein (HSP) 47 in NIH3T3 cells, although cell death was not induced by Golgi stress alone. When HSP47 expression was downregulated by siRNA, inhibition of O-glycosylation caused cell death. Three days after the induction of Golgi stress, the Golgi apparatus was disassembled, many vacuoles appeared near the Golgi apparatus and extended into the cytoplasm, the nuclei had split, and cell death assay-positive cells appeared. Six hours after the induction of Golgi stress, HSP47-knockdown cells exhibited increased cleavage of Golgi-resident caspase-2. Furthermore, activation of mitochondrial caspase-9 and ER-resident unfolded protein response (UPR) related molecules and efflux of cytochrome c from the mitochondria to the cytoplasm was observed in HSP47-knockdown cells 24 h after the induction of Golgi stress. These findings indicate that (i) the ER-resident chaperon HSP47 protected cells from Golgi stress, and (ii) Golgi stress-induced cell death caused by the inhibition of HSP47 expression resulted from caspase-2 activation in the Golgi apparatus, extending to the ER and mitochondria. PMID- 23922786 TI - Human papillomavirus in the lesions of the oral mucosa according to topography. AB - BACKGROUND: The association between human papillomavirus (HPV) types and oral lesions has been shown in many studies. Considering the significance that HPV has in the development of malignant and potentially malignant disorders of the oral mucosa, the purpose of this study was to investigate the prevalence of HPV DNA in different oral lesions. In addition, we wanted to elucidate whether the HPV infection is associated predominantly with either the lesion or a particular anatomic site of the oral cavity. METHODOLOGY/PRINCIPAL FINDINGS: The study included 246 subjects with different oral lesions, and 73 subjects with apparently healthy oral mucosa (controls). The oral lesions were classified according to their surface morphology and clinical diagnosis. The epithelial cells were collected with a cytobrush from different topographic sites in the oral cavity of the oral lesions and controls. The presence of HPV DNA was evaluated by consensus and type-specific primer-directed polymerase chain reaction. The HPV positivity was detected in 17.7% of oral lesions, significantly more than in apparently healthy mucosa (6.8%), with a higher presence in benign proliferative mucosal lesions (18.6%). High-risk HPV types were predominantly found in potentially malignant oral disorders (HPV16 in 4.3% and HPV31 in 3.4%), while benign proliferative lesions as well as healthy oral mucosa contained mainly undetermined HPV type (13.6 and 6.8%, respectively). CONCLUSIONS/SIGNIFICANCE: The distribution of positive HPV findings on the oral mucosa seems to be more associated with a particular anatomical site than the diagnosis itself. Samples taken from the vermilion border, labial commissures, and hard palate were most often HPV positive. Thus, topography plays a role in HPV prevalence findings in oral lesions. Because of the higher prevalence of the high-risk HPV types in potentially malignant oral disorders, these lesions need to be continuously controlled and treated. PMID- 23922787 TI - HIV risk-reduction counseling and testing on behavior change of MSM. AB - HIV and AIDS incidence in China is high among men who have sex with men (MSM) and ours was one of few studies in China to evaluate the role of HIV risk reduction counseling and testing. Respondent-driven sampling (RDS) was used to recruit 430 MSM. Participants were followed up at 6, 12 and 18 months to evaluate behavioral changes after counseling to reduce risk behaviors. At baseline, HIV prevalence was 4.7%, whereas HIV incidence was 5.2 per 100 person-years. The incidence was 3.8 during six to 12 months, and 1.1 during 12 to 18 months. During the study period, the reported unprotected anal intercourse (UAI) significantly decreased from 60.9% to 42.9%. The proportion of participants who had one or no partner significantly increased from 40.9% to 48.0%. The study also found that some risk behaviors decreased between baseline and 12 months, followed by a slight increase between 12 and 18 months. Reductions in UAI can be achieved through counseling and testing, but may wane over time. Future programs should consider HIV risk reduction counseling and testing for interventions in MSM in China. PMID- 23922788 TI - Functional analysis of PGRP-LA in Drosophila immunity. AB - PeptidoGlycan Recognition Proteins (PGRPs) are key regulators of the insect innate antibacterial response. Even if they have been intensively studied, some of them have yet unknown functions. Here, we present a functional analysis of PGRP-LA, an as yet uncharacterized Drosophila PGRP. The PGRP-LA gene is located in cluster with PGRP-LC and PGRP-LF, which encode a receptor and a negative regulator of the Imd pathway, respectively. Structure predictions indicate that PGRP-LA would not bind to peptidoglycan, pointing to a regulatory role of this PGRP. PGRP-LA expression was enriched in barrier epithelia, but low in the fat body. Use of a newly generated PGRP-LA deficient mutant indicates that PGRP-LA is not required for the production of antimicrobial peptides by the fat body in response to a systemic infection. Focusing on the respiratory tract, where PGRP LA is strongly expressed, we conducted a genome-wide microarray analysis of the tracheal immune response of wild-type, Relish, and PGRP-LA mutant larvae. Comparing our data to previous microarray studies, we report that a majority of genes regulated in the trachea upon infection differ from those induced in the gut or the fat body. Importantly, antimicrobial peptide gene expression was reduced in the tracheae of larvae and in the adult gut of PGRP-LA-deficient Drosophila upon oral bacterial infection. Together, our results suggest that PGRP LA positively regulates the Imd pathway in barrier epithelia. PMID- 23922789 TI - Genome-wide analysis of small RNA and novel microRNA discovery during fiber and seed initial development in Gossypium hirsutum. L. AB - Cotton is the source of the most important, renewable natural textile fiber and oil in the world. MicroRNAs (miRNAs) are endogenous, non-coding, approximately 18 24 nucleotides long RNAs and function in the negative regulation of their target genes. Two mostly overlapping libraries of small RNA molecules were constructed and sequenced, and served as repetition sets of data to identify miRNAs involved in fiber initiation and seed development. The D genome sequence of Gossypium raimondii was used in conjunction with EST sequences to predict miRNA precursors. Overall, 93 new miRNA precursors were identified, of which 28 belonged to 10 known families and the other 65 were considered to be novel miRNAs. Seven hundred EST sequences were proposed to be candidate target genes which involved in the regulation of a diverse group of genes with diverse functions and transcription factors. Some of the novel miRNAs and candidate target genes were validated by the Northern blot and rapid amplification of 5' cDNA ends (5' RACE). PMID- 23922790 TI - Synthesis, structure and antibacterial activity of potent DNA gyrase inhibitors: N'-benzoyl-3-(4-bromophenyl)-1H-pyrazole-5-carbohydrazide derivatives. AB - A total of 19 novel (3a-3s) N'-benzoyl-3-(4-bromophenyl)-1H-pyrazole-5 carbohydrazide analogs were designed, synthesized, and evaluated for biological activities as potential DNA gyrase inhibitors. The results showed that compound 3k can strongly inhibit Staphylococcus aureus DNA gyrase and Bacillus subtilis DNA gyrase (with IC50 of 0.15 ug/mL and 0.25 ug/mL, respectively). Structure activity relationships were also discussed base on the biological and docking simulation results. PMID- 23922791 TI - Genetic aberrations in imatinib-resistant dermatofibrosarcoma protuberans revealed by whole genome sequencing. AB - Dermatofibrosarcoma protuberans (DFSP) is a very rare soft tissue sarcoma. DFSP often reveals a specific chromosome translocation, t(17;22)(q22;q13), which results in the fusion of collagen 1 alpha 1 (COL1A1) gene and platelet-derived growth factor-B (PDGFB) gene. The COL1A1-PDGFB fusion protein activates the PDGFB receptor and resultant constitutive activation of PDGFR receptor is essential in the pathogenesis of DFSP. Thus, blocking PDGFR receptor activation with imatinib has shown promising activity in the treatment of advanced and metastatic DFSP. Despite the success with targeted agents in cancers, acquired drug resistance eventually occurs. Here, we tried to identify potential drug resistance mechanisms against imatinib in a 46-year old female with DFSP who initially responded well to imatinib but suffered rapid disease progression. We performed whole-genome sequencing of both pre-treatment and post-treatment tumor tissue to identify the mutational events associated with imatinib resistance. No significant copy number alterations, insertion, and deletions were identified during imatinib treatment. Of note, we identified newly emerged 8 non-synonymous somatic mutations of the genes (ACAP2, CARD10, KIAA0556, PAAQR7, PPP1R39, SAFB2, STARD9, and ZFYVE9) in the imatinib-resistant tumor tissue. This study revealed diverse possible candidate mechanisms by which imatinib resistance to PDGFRB inhibition may arise in DFSP, and highlights the usefulness of whole-genome sequencing in identifying drug resistance mechanisms and in pursuing genome directed, personalized anti-cancer therapy. PMID- 23922792 TI - Reverse differentiation as a gene filtering tool in genome expression profiling of adipogenesis for fat marker gene selection and their analysis. AB - BACKGROUND: During mesenchymal stem cell (MSC) conversion into adipocytes, the adipogenic cocktail consisting of insulin, dexamethasone, indomethacin and 3 isobutyl-1-methylxanthine not only induces adipogenic-specific but also genes for non-adipogenic processes. Therefore, not all significantly expressed genes represent adipogenic-specific marker genes. So, our aim was to filter only adipogenic-specific out of all expressed genes. We hypothesize that exclusively adipogenic-specific genes change their expression during adipogenesis, and reverse during dedifferentiation. Thus, MSC were adipogenic differentiated and dedifferentiated. RESULTS: Adipogenesis and reverse adipogenesis was verified by Oil Red O staining and expression of PPARG and FABP4. Based on GeneChips, 991 genes were differentially expressed during adipogenesis and grouped in 4 clusters. According to bioinformatic analysis the relevance of genes with adipogenic-linked biological annotations, expression sites, molecular functions, signaling pathways and transcription factor binding sites was high in cluster 1, including all prominent adipogenic genes like ADIPOQ, C/EBPA, LPL, PPARG and FABP4, moderate in clusters 2-3, and negligible in cluster 4. During reversed adipogenesis, only 782 expressed genes (clusters 1-3) were reverted, including 597 genes not reported for adipogenesis before. We identified APCDD1, CHI3L1, RARRES1 and SEMA3G as potential adipogenic-specific genes. CONCLUSION: The model system of adipogenesis linked to reverse adipogenesis allowed the filtration of 782 adipogenic-specific genes out of total 991 significantly expressed genes. Database analysis of adipogenic-specific biological annotations, transcription factors and signaling pathways further validated and valued our concept, because most of the filtered 782 genes showed affiliation to adipogenesis. Based on this approach, the selected and filtered genes would be potentially important for characterization of adipogenesis and monitoring of clinical translation for soft tissue regeneration. Moreover, we report 4 new marker genes. PMID- 23922793 TI - Resuscitation of ischemic donor livers with normothermic machine perfusion: a metabolic flux analysis of treatment in rats. AB - Normothermic machine perfusion has previously been demonstrated to restore damaged warm ischemic livers to transplantable condition in animal models. However, the mechanisms of recovery are unclear, preventing rational optimization of perfusion systems and slowing clinical translation of machine perfusion. In this study, organ recovery time and major perfusate shortcomings were evaluated using a comprehensive metabolic analysis of organ function in perfusion prior to successful transplantation. Two groups, Fresh livers and livers subjected to 1 hr of warm ischemia (WI) received perfusion for a total preservation time of 6 hrs, followed by successful transplantation. 24 metabolic fluxes were directly measured and 38 stoichiometrically-related fluxes were estimated via a mass balance model of the major pathways of energy metabolism. This analysis revealed stable metabolism in Fresh livers throughout perfusion while identifying two distinct metabolic states in WI livers, separated at t = 2 hrs, coinciding with recovery of oxygen uptake rates to Fresh liver values. This finding strongly suggests successful organ resuscitation within 2 hrs of perfusion. Overall perfused livers regulated metabolism of perfusate substrates according to their metabolic needs, despite supraphysiological levels of some metabolites. This study establishes the first integrative metabolic basis for the dynamics of recovery during perfusion treatment of marginal livers. Our initial findings support enhanced oxygen delivery for both timely recovery and long-term sustenance. These results are expected to lead the optimization of the treatment protocols and perfusion media from a metabolic perspective, facilitating translation to clinical use. PMID- 23922794 TI - 15-Deoxy-Delta12,14-prostaglandin J2 inhibits macrophage colonization by Salmonella enterica serovar Typhimurium. AB - 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) is an anti-inflammatory downstream product of the cyclooxygenase enzymes. It has been implicated to play a protective role in a variety of inflammatory mediated diseases, including rheumatoid arthritis, neural damage, and myocardial infarctions. Here we show that 15d-PGJ2 also plays a role in Salmonella infection. Salmonella enterica Typhimurium is a Gram-negative facultative intracellular pathogen that is able to survive and replicate inside phagocytic immune cells, allowing for bacterial dissemination to systemic sites. Salmonella species cause a wide range of morbidity and mortality due to gastroenteritis and typhoid fever. Previously we have shown that in mouse models of typhoid fever, Salmonella infection causes a major perturbation in the prostaglandin pathway. Specifically, we saw that 15d PGJ2 production was significantly increased in both liver and feces. In this work we show that 15d-PGJ2 production is also significantly increased in macrophages infected with Salmonella. Furthermore, we show that the addition of 15d-PGJ2 to Salmonella infected RAW264.7, J774, and bone marrow derived macrophages is sufficient to significantly reduce bacterial colonization. We also show evidence that 15d-PGJ2 is reducing bacterial uptake by macrophages. 15d-PGJ2 reduces the inflammatory response of these infected macrophages, as evidenced by a reduction in the production of cytokines and reactive nitrogen species. The inflammatory response of the macrophage is important for full Salmonella virulence, as it can give the bacteria cues for virulence. The reduction in bacterial colonization is independent of the expression of Salmonella virulence genes SPI1 and SPI2, and is independent of the 15d-PGJ2 ligand PPAR-gamma. 15d-PGJ2 also causes an increase in ERK1/2 phosphorylation in infected macrophages. In conclusion, we show here that 15d-PGJ2 mediates the outcome of bacterial infection, a previously unidentified role for this prostaglandin. PMID- 23922795 TI - Hinged plakin domains provide specialized degrees of articulation in envoplakin, periplakin and desmoplakin. AB - Envoplakin, periplakin and desmoplakin are cytoskeletal proteins that provide structural integrity within the skin and heart by resisting shear forces. Here we reveal the nature of unique hinges within their plakin domains that provides divergent degrees of flexibility between rigid long and short arms composed of spectrin repeats. The range of mobility of the two arms about the hinge is revealed by applying the ensemble optimization method to small-angle X-ray scattering data. Envoplakin and periplakin adopt 'L' shaped conformations exhibiting a 'helicopter propeller'-like mobility about the hinge. By contrast desmoplakin exhibits essentially unrestricted mobility by 'jack-knifing' about the hinge. Thus the diversity of molecular jointing that can occur about plakin hinges includes 'L' shaped bends, 'U' turns and fully extended 'I' orientations between rigid blocks of spectrin repeats. This establishes specialised hinges in plakin domains as a key source of flexibility that may allow sweeping of cellular spaces during assembly of cellular structures and could impart adaptability, so preventing irreversible damage to desmosomes and the cell cytoskeleton upon exposure to mechanical stress. PMID- 23922796 TI - Genome-wide association analysis of aluminum tolerance in cultivated and Tibetan wild barley. AB - Tibetan wild barley (Hordeum vulgare L. ssp. spontaneum), originated and grown in harsh enviroNment in Tibet, is well-known for its rich germpalsm with high tolerance to abiotic stresses. However, the genetic variation and genes involved in Al tolerance are not totally known for the wild barley. In this study, a genome-wide association analysis (GWAS) was performed by using four root parameters related with Al tolerance and 469 DArT markers on 7 chromosomes within or across 110 Tibetan wild accessions and 56 cultivated cultivars. Population structure and cluster analysis revealed that a wide genetic diversity was present in Tibetan wild barley. Linkage disequilibrium (LD) decayed more rapidly in Tibetan wild barley (9.30 cM) than cultivated barley (11.52 cM), indicating that GWAS may provide higher resolution in the Tibetan group. Two novel Tibetan group specific loci, bpb-9458 and bpb-8524 were identified, which were associated with relative longest root growth (RLRG), located at 2H and 7H on barely genome, and could explain 12.9% and 9.7% of the phenotypic variation, respectively. Moreover, a common locus bpb-6949, localized 0.8 cM away from a candidate gene HvMATE, was detected in both wild and cultivated barleys, and showed significant association with total root growth (TRG). The present study highlights that Tibetan wild barley could provide elite germplasm novel genes for barley Al-tolerant improvement. PMID- 23922797 TI - Diagnostic ultrasound induced inertial cavitation to non-invasively restore coronary and microvascular flow in acute myocardial infarction. AB - Ultrasound induced cavitation has been explored as a method of dissolving intravascular and microvascular thrombi in acute myocardial infarction. The purpose of this study was to determine the type of cavitation required for success, and whether longer pulse duration therapeutic impulses (sustaining the duration of cavitation) could restore both microvascular and epicardial flow with this technique. Accordingly, in 36 hyperlipidemic atherosclerotic pigs, thrombotic occlusions were induced in the mid-left anterior descending artery. Pigs were then randomized to either a) 1/2 dose tissue plasminogen activator (0.5 mg/kg) alone; or same dose plasminogen activator and an intravenous microbubble infusion with either b) guided high mechanical index short pulse (2.0 MI; 5 usec) therapeutic ultrasound impulses; or c) guided 1.0 mechanical index long pulse (20 usec) impulses. Passive cavitation detectors indicated the high mechanical index impulses (both long and short pulse duration) induced inertial cavitation within the microvasculature. Epicardial recanalization rates following randomized treatments were highest in pigs treated with the long pulse duration therapeutic impulses (83% versus 59% for short pulse, and 49% for tissue plasminogen activator alone; p<0.05). Even without epicardial recanalization, however, early microvascular recovery occurred with both short and long pulse therapeutic impulses (p<0.005 compared to tissue plasminogen activator alone), and wall thickening improved within the risk area only in pigs treated with ultrasound and microbubbles. We conclude that although short pulse duration guided therapeutic impulses from a diagnostic transducer transiently improve microvascular flow, long pulse duration therapeutic impulses produce sustained epicardial and microvascular re-flow in acute myocardial infarction. PMID- 23922798 TI - Histone demethylase retinoblastoma binding protein 2 is overexpressed in hepatocellular carcinoma and negatively regulated by hsa-miR-212. AB - BACKGROUND: The H3K4 demethylase retinoblastoma binding protein 2 (RBP2) is involved in the pathogenesis of gastric cancer, but its role and regulation in hepatocellular carcinoma (HCC) is unknown. We determined the function of RBP2 and its regulation in HCC in vitro and in human tissues. METHODS: We analyzed gene expression in 20 specimens each of human HCC and normal liver tissue by quantitative real-time PCR and immunohistochemistry. Proliferation was analyzed by foci formation and senescence by beta-galactosidase staining. Promoter activity was detected by luciferase reporter assay. RESULTS: The expression of RBP2 was stronger in cancerous than non-cancerous tissues, but that of its binding microRNA, Homo sapiens miR-212 (hsa-miR-212), showed an opposite pattern. SiRNA knockdown of RBP2 significantly upregulated cyclin-dependent kinase inhibitors (CDKIs), with suppression of HCC cell proliferation and induction of senescence. Overexpression of hsa-miR-212 suppressed RBP2 expression, with inhibited cell proliferation and induced cellular senescence, which coincided with upregulated CDKIs; with low hsa-miR-212 expression, CDKIs were downregulated in HCC tissue. Inhibition of hsa-miR-212 expression upregulated RBP2 expression. Luciferase reporter assay detected the direct binding of hsa-miR-212 to the RBP2 3' UTR. CONCLUSIONS: RBP2 is overexpressed in HCC and negatively regulated by hsa miR-212. The hsa-miR-212-RBP2-CDKI pathway may be important in the pathogenesis of HCC. PMID- 23922799 TI - Low temperature mitigates cardia bifida in zebrafish embryos. AB - The coordinated migration of bilateral cardiomyocytes and the formation of the cardiac cone are essential for heart tube formation. We investigated gene regulatory mechanisms involved in myocardial migration, and regulation of the timing of cardiac cone formation in zebrafish embryos. Through screening of zebrafish treated with ethylnitrosourea, we isolated a mutant with a hypomorphic allele of mil (s1pr2)/edg5, called s1pr2(as10) (as10). Mutant embryos with this allele expressed less mil/edg5 mRNA and exhibited cardia bifida prior to 28 hours post-fertilization. Although the bilateral hearts of the mutants gradually fused together, the resulting formation of two atria and one tightly-packed ventricle failed to support normal blood circulation. Interestingly, cardia bifida of s1pr2(as10) embryos could be rescued and normal circulation could be restored by incubating the embryos at low temperature (22.5 degrees C). Rescue was also observed in gata5 and bon cardia bifida morphants raised at 22.5 degrees C. The use of DNA microarrays, digital gene expression analyses, loss-of-function, as well as mRNA and protein rescue experiments, revealed that low temperature mitigates cardia bifida by regulating the expression of genes encoding components of the extracellular matrix (fibronectin 1, tenascin-c, tenascin-w). Furthermore, the addition of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, significantly decreased the effect of low temperature on mitigating cardia bifida in s1pr2(as10) embryos. Our study reveals that temperature coordinates the development of the heart tube and somitogenesis, and that extracellular matrix genes (fibronectin 1, tenascin-c and tenascin-w) are involved. PMID- 23922801 TI - The mental health consequences of the recession: economic hardship and employment of people with mental health problems in 27 European countries. AB - OBJECTIVES: A period of economic recession may be particularly difficult for people with mental health problems as they may be at higher risk of losing their jobs, and more competitive labour markets can also make it more difficult to find a new job. This study assesses unemployment rates among individuals with mental health problems before and during the current economic recession. METHODS: Using individual and aggregate level data collected from 27 EU countries in the Eurobarometer surveys of 2006 and 2010, we examined changes in unemployment rates over this period among individuals with and without mental health problems. RESULTS: Following the onset of the recession, the gap in unemployment rates between individuals with and without mental health problems significantly widened (odds ratio: 1.12, 95% confidence interval: 1.03, 1.34). This disparity became even greater for males, and individuals with low levels of education. Individuals with mental health problems living in countries with higher levels of stigmatizing attitudes regarding dangerousness of people with mental illness were more vulnerable to unemployment in 2010, but not 2006. Greater agreement that people with mental health problems have themselves to blame, was associated with lower likelihood of unemployment for individuals with and without mental health problems. CONCLUSION: These findings study suggest that times of economic hardship may intensify social exclusion of people with mental health problems, especially males and individuals with lower education. Interventions to combat economic exclusion and to promote social participation of individuals with mental health problems are even more important during times of economic crisis, and these efforts should target support to the most vulnerable groups. PMID- 23922800 TI - Identification of novel adhesins of M. tuberculosis H37Rv using integrated approach of multiple computational algorithms and experimental analysis. AB - Pathogenic bacteria interacting with eukaryotic host express adhesins on their surface. These adhesins aid in bacterial attachment to the host cell receptors during colonization. A few adhesins such as Heparin binding hemagglutinin adhesin (HBHA), Apa, Malate Synthase of M. tuberculosis have been identified using specific experimental interaction models based on the biological knowledge of the pathogen. In the present work, we carried out computational screening for adhesins of M. tuberculosis. We used an integrated computational approach using SPAAN for predicting adhesins, PSORTb, SubLoc and LocTree for extracellular localization, and BLAST for verifying non-similarity to human proteins. These steps are among the first of reverse vaccinology. Multiple claims and attacks from different algorithms were processed through argumentative approach. Additional filtration criteria included selection for proteins with low molecular weights and absence of literature reports. We examined binding potential of the selected proteins using an image based ELISA. The protein Rv2599 (membrane protein) binds to human fibronectin, laminin and collagen. Rv3717 (N acetylmuramoyl-L-alanine amidase) and Rv0309 (L,D-transpeptidase) bind to fibronectin and laminin. We report Rv2599 (membrane protein), Rv0309 and Rv3717 as novel adhesins of M. tuberculosis H37Rv. Our results expand the number of known adhesins of M. tuberculosis and suggest their regulated expression in different stages. PMID- 23922803 TI - Connectivity between migrating and landlocked populations of a diadromous fish species investigated using otolith microchemistry. AB - Smelt Osmerus eperlanus has two different life history strategies in The Netherlands. The migrating population inhabits the Wadden Sea and spawns in freshwater areas. After the closure of the Afsluitdijk in 1932, part of the smelt population became landlocked. The fresh water smelt population has been in severe decline since 1990, and has strongly negatively impacted the numbers of piscivorous water birds relying on smelt as their main prey. The lakes that were formed after the dike closure, IJsselmeer and Markermeer have been assigned as Natura 2000 sites, based on their importance for (among others) piscivorous water birds. Because of the declining fresh water smelt population, the question arose whether this population is still supported by the diadromous population. Opportunities for exchange between fresh water and the sea are however limited to discharge sluices. The relationship between the diadromous and landlocked smelt population was analysed by means of otolith microchemistry. Our interpretation of otolith strontium ((88)Sr) patterns from smelt specimens collected in the fresh water area of Lake IJsselmeer and Markermeer, compared to those collected in the nearby marine environment, is that there is currently no evidence for a substantial contribution from the diadromous population to the spawning stock of the landlocked population. PMID- 23922802 TI - Effects of murine and human bone marrow-derived mesenchymal stem cells on cuprizone induced demyelination. AB - For the treatment of patients with multiple sclerosis there are no regenerative approaches to enhance remyelination. Mesenchymal stem cells (MSC) have been proposed to exert such regenerative functions. Intravenous administration of human MSC reduced the clinical severity of experimental autoimmune encephalomyelitis (EAE), an animal model mimicking some aspects of multiple sclerosis. However, it is not clear if this effect was achieved by systemic immunomodulation or if there is an active neuroregeneration in the central nervous system (CNS). In order to investigate remyelination and regeneration in the CNS we analysed the effects of intravenously and intranasally applied murine and human bone marrow-derived MSC on cuprizone induced demyelination, a toxic animal model which allows analysis of remyelination without the influence of the peripheral immune system. In contrast to EAE no effects of MSC on de- and remyelination and glial cell reactions were found. In addition, neither murine nor human MSC entered the lesions in the CNS in this toxic model. In conclusion, MSC are not directed into CNS lesions in the cuprizone model where the blood brain-barrier is intact and thus cannot provide support for regenerative processes. PMID- 23922804 TI - Pathological neural attractor dynamics in slowly growing gliomas supports an optimal time frame for white matter plasticity. AB - Neurological function in patients with slowly growing brain tumors can be preserved even after extensive tumor resection. However, the global process of cortical reshaping and cerebral redistribution cannot be understood without taking into account the white matter tracts. The aim of this study was to predict the functional consequences of tumor-induced white matter damage by computer simulation. A computational model was proposed, incorporating two cortical patches and the white matter connections of the uncinate fasciculus. Tumor induced structural changes were modeled such that different aspects of the connectivity were altered, mimicking the biological heterogeneity of gliomas. The network performance was quantified by comparing memory pattern recall and the plastic compensatory capacity of the network was analyzed. The model predicts an optimal level of synaptic conductance boost that compensates for tumor-induced connectivity loss. Tumor density appears to change the optimal plasticity regime, but tumor size does not. Compensatory conductance values that are too high lead to performance loss in the network and eventually to epileptic activity. Tumors of different configurations show differences in memory recall performance with slightly lower plasticity values for dense tumors compared to more diffuse tumors. Simulation results also suggest an optimal noise level that is capable of increasing the recall performance in tumor-induced white matter damage. In conclusion, the model presented here is able to capture the influence of different tumor-related parameters on memory pattern recall decline and provides a new way to study the functional consequences of white matter invasion by slowly growing brain tumors. PMID- 23922805 TI - Plant trait assembly affects superiority of grazer's foraging strategies in species-rich grasslands. AB - BACKGROUND: Current plant--herbivore interaction models and experiments with mammalian herbivores grazing plant monocultures show the superiority of a maximizing forage quality strategy (MFQ) over a maximizing intake strategy (MI). However, there is a lack of evidence whether grazers comply with the model predictions under field conditions. METHODOLOGY/FINDINGS: We assessed diet selection of sheep (Ovis aries) using plant functional traits in productive mesic vs. low-productivity dry species-rich grasslands dominated by resource exploitative vs. resource-conservative species respectively. Each grassland type was studied in two replicates for two years. We investigated the first grazing cycle in a set of 288 plots with a diameter of 30 cm, i.e. the size of sheep feeding station. In mesic grasslands, high plot defoliation was associated with community weighted means of leaf traits referring to high forage quality, i.e. low leaf dry matter content (LDMC) and high specific leaf area (SLA), with a high proportion of legumes and the most with high community weighted mean of forage indicator value. In contrast in dry grasslands, high community weighted mean of canopy height, an estimate of forage quantity, was the best predictor of plot defoliation. Similar differences in selection on forage quality vs. quantity were detected within plots. Sheep selected plants with higher forage indicator values than the plot specific community weighted mean of forage indicator value in mesic grasslands whereas taller plants were selected in dry grasslands. However, at this scale sheep avoided legumes and plants with higher SLA, preferred plants with higher LDMC while grazing plants with higher forage indicator values in mesic grasslands. CONCLUSIONS: Our findings indicate that MFQ appears superior over MI only in habitats with a predominance of resource-exploitative species. Furthermore, plant functional traits (LDMC, SLA, nitrogen fixer) seem to be helpful correlates of forage quality only at the community level. PMID- 23922806 TI - An apparent lack of epidemiologic association between hepatitis C virus knowledge and the prevalence of hepatitis C infection in a national survey in Egypt. AB - BACKGROUND: Egypt has by far the largest hepatitis C virus (HCV) prevalence in the world with 14.7% of the population being antibody positive for HCV. The aim of this study was to examine the association between knowledge of HCV and HCV antibody positivity among the Egyptian population. METHODS: We characterized different measures of HCV knowledge and examined their associations with HCV prevalence, by analyzing a nationally representative database using standard epidemiologic methods. The database, the 2008 Egyptian Demographic and Health Survey, included demographic, health, and HCV biomarker information for a sample of over 12,000 individuals. RESULTS: Basic knowledge of HCV was found to be high, but multiple gaps were identified in the specific knowledge of HCV and its modes of transmission. There was no statistically significant difference in HCV prevalence between those who have heard of HCV infection and those who have not (14.4% vs. 15.9%, p>.05). Similar results were found for the other HCV knowledge measures including those specific to HCV modes of transmission and to the sources of information for HCV awareness. Logistic regression analyses did not demonstrate an association between HCV knowledge and HCV prevalence. CONCLUSIONS: Our results do not provide support for an effect of awareness on reducing the risk of HCV infection in Egypt. Public health messages directed at the lay public may not provide sufficient empowerment for individuals to avoid HCV infection, and should be complemented with prevention programs to promote and strengthen infection control in the settings of exposure, particularly in health care facilities. PMID- 23922807 TI - Circulating miRNA biomarkers for Alzheimer's disease. AB - A minimally invasive diagnostic assay for early detection of Alzheimer's disease (AD) is required to select optimal patient groups in clinical trials, monitor disease progression and response to treatment, and to better plan patient clinical care. Blood is an attractive source for biomarkers due to minimal discomfort to the patient, encouraging greater compliance in clinical trials and frequent testing. MiRNAs belong to the class of non-coding regulatory RNA molecules of ~22 nt length and are now recognized to regulate ~60% of all known genes through post-transcriptional gene silencing (RNAi). They have potential as useful biomarkers for clinical use because of their stability and ease of detection in many tissues, especially blood. Circulating profiles of miRNAs have been shown to discriminate different tumor types, indicate staging and progression of the disease and to be useful as prognostic markers. Recently their role in neurodegenerative diseases, both as diagnostic biomarkers as well as explaining basic disease etiology has come into focus. Here we report the discovery and validation of a unique circulating 7-miRNA signature (hsa-let-7d 5p, hsa-let-7g-5p, hsa-miR-15b-5p, hsa-miR-142-3p, hsa-miR-191-5p, hsa-miR-301a 3p and hsa-miR-545-3p) in plasma, which could distinguish AD patients from normal controls (NC) with >95% accuracy (AUC of 0.953). There was a >2 fold difference for all signature miRNAs between the AD and NC samples, with p-values<0.05. Pathway analysis, taking into account enriched target mRNAs for these signature miRNAs was also carried out, suggesting that the disturbance of multiple enzymatic pathways including lipid metabolism could play a role in AD etiology. PMID- 23922808 TI - Differentiated neuroprogenitor cells incubated with human or canine adenovirus, or lentiviral vectors have distinct transcriptome profiles. AB - Several studies have demonstrated the potential for vector-mediated gene transfer to the brain. Helper-dependent (HD) human (HAd) and canine (CAV-2) adenovirus, and VSV-G-pseudotyped self-inactivating HIV-1 vectors (LV) effectively transduce human brain cells and their toxicity has been partly analysed. However, their effect on the brain homeostasis is far from fully defined, especially because of the complexity of the central nervous system (CNS). With the goal of dissecting the toxicogenomic signatures of the three vectors for human neurons, we transduced a bona fide human neuronal system with HD-HAd, HD-CAV-2 and LV. We analysed the transcriptional response of more than 47,000 transcripts using gene chips. Chip data showed that HD-CAV-2 and LV vectors activated the innate arm of the immune response, including Toll-like receptors and hyaluronan circuits. LV vector also induced an IFN response. Moreover, HD-CAV-2 and LV vectors affected DNA damage pathways--but in opposite directions--suggesting a differential response of the p53 and ATM pathways to the vector genomes. As a general response to the vectors, human neurons activated pro-survival genes and neuron morphogenesis, presumably with the goal of re-establishing homeostasis. These data are complementary to in vivo studies on brain vector toxicity and allow a better understanding of the impact of viral vectors on human neurons, and mechanistic approaches to improve the therapeutic impact of brain-directed gene transfer. PMID- 23922810 TI - On the evolutionary and biogeographic history of Saxifraga sect. Trachyphyllum (Gaud.) Koch (Saxifragaceae Juss.). AB - Arctic-alpine plants in the genus Saxifraga L. (Saxifragaceae Juss.) provide an excellent system for investigating the process of diversification in northern regions. Yet, sect. Trachyphyllum (Gaud.) Koch, which is comprised of about 8 to 26 species, has still not been explored by molecular systematists even though taxonomists concur that the section needs to be thoroughly re-examined. Our goals were to use chloroplast trnL-F and nuclear ITS DNA sequence data to circumscribe the section phylogenetically, test models of geographically-based population divergence, and assess the utility of morphological characters in estimating evolutionary relationships. To do so, we sequenced both genetic markers for 19 taxa within the section. The phylogenetic inferences of sect. Trachyphyllum using maximum likelihood and Bayesian analyses showed that the section is polyphyletic, with S. aspera L. and S bryoides L. falling outside the main clade. In addition, the analyses supported several taxonomic re-classifications to prior names. We used two approaches to test biogeographic hypotheses: i) a coalescent approach in Mesquite to test the fit of our reconstructed gene trees to geographically-based models of population divergence and ii) a maximum likelihood inference in Lagrange. These tests uncovered strong support for an origin of the clade in the Southern Rocky Mountains of North America followed by dispersal and divergence episodes across refugia. Finally we adopted a stochastic character mapping approach in SIMMAP to investigate the utility of morphological characters in estimating evolutionary relationships among taxa. We found that few morphological characters were phylogenetically informative and many were misleading. Our molecular analyses provide a foundation for the diversity and evolutionary relationships within sect. Trachyphyllum and hypotheses for better understanding the patterns and processes of divergence in this section, other saxifrages, and plants inhabiting the North Pacific Rim. PMID- 23922809 TI - Antidepressant and neurocognitive effects of isoflurane anesthesia versus electroconvulsive therapy in refractory depression. AB - BACKGROUND: Many patients have serious depression that is nonresponsive to medications, but refuse electroconvulsive therapy (ECT). Early research suggested that isoflurane anesthesia may be an effective alternative to ECT. Subsequent studies altered drug, dose or number of treatments, and failed to replicate this success, halting research on isoflurane's antidepressant effects for a decade. Our aim was to re-examine whether isoflurane has antidepressant effects comparable to ECT, with less adverse effects on cognition. METHOD: Patients with medication-refractory depression received an average of 10 treatments of bifrontal ECT (n = 20) or isoflurane (n = 8) over 3 weeks. Depression severity (Hamilton Rating Scale for Depression-24) and neurocognitive responses (anterograde and retrograde memory, processing speed and verbal fluency) were assessed at Pretreatment, Post all treatments and 4-week Follow-up. RESULTS: Both treatments produced significant reductions in depression scores at Post-treatment and 4-week Follow-up; however, ECT had modestly better antidepressant effect at follow-up in severity-matched patients. Immediately Post-treatment, ECT (but not isoflurane) patients showed declines in memory, fluency, and processing speed. At Follow-up, only autobiographical memory remained below Pretreatment level for ECT patients, but isoflurane patients had greater test-retest neurocognitive score improvement. CONCLUSIONS: Our data reconfirm that isoflurane has an antidepressant effect approaching ECT with less adverse neurocognitive effects, and reinforce the need for a larger clinical trial. PMID- 23922811 TI - Differential programming of B cells in AID deficient mice. AB - The Aicda locus encodes the activation induced cytidine deaminase (AID) and is highly expressed in germinal center (GC) B cells to initiate somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin (Ig) genes. Besides these Ig specific activities in B cells, AID has been implicated in active DNA demethylation in non-B cell systems. We here determined a potential role of AID as an epigenetic eraser and transcriptional regulator in B cells. RNA Seq on different B cell subsets revealed that Aicda(-/-) B cells are developmentally affected. However as shown by RNA-Seq, MethylCap-Seq, and SNP analysis these transcriptome alterations may not relate to AID, but alternatively to a CBA mouse strain derived region around the targeted Aicda locus. These unexpected confounding parameters provide alternative, AID-independent interpretations on genotype-phenotype correlations previously reported in numerous studies on AID using the Aicda(-/-) mouse strain. PMID- 23922812 TI - Chronic administration of proanthocyanidins or docosahexaenoic acid reverses the increase of miR-33a and miR-122 in dyslipidemic obese rats. AB - miR-33 and miR-122 are major regulators of lipid metabolism in the liver, and their deregulation has been linked to the development of metabolic diseases such as obesity and metabolic syndrome. However, the biological importance of these miRNAs has been defined using genetic models. The aim of this study was to evaluate whether the levels of miR-122 and miR-33a in rat liver correlate with lipemia in nutritional models. For this purpose, we analyzed the levels of miRNA 33a and miR-122 in the livers of dyslipidemic cafeteria diet-fed rats and of cafeteria diet-fed rats supplemented with proanthocyanidins and/or omega-3 PUFAs because these two dietary components are well-known to counteract dyslipidemia. The results showed that the dyslipidemia induced in rats that were fed a cafeteria diet resulted in the upregulation of miR-33a and miR-122 in the liver, whereas the presence of proanthocyanidins and/or omega-3 PUFAs counteracted the increase of these two miRNAs. However, srebp2, the host gene of miR-33a, was significantly repressed by omega-3 PUFAs but not by proanthocyanidins. Liver mRNA levels of the miR-122 and miR-33a target genes, fas and pparbeta/delta, cpt1a and abca1, respectively, were consistent with the expression of these two miRNAs under each condition. Moreover, the miR-33a and abca1 levels were also analyzed in PBMCs. Interestingly, the miR-33a levels evaluated in PBMCs under each condition were similar to the liver levels but enhanced. This demonstrates that miR-33a is expressed in PBMCs and that these cells can be used as a non-invasive way to reflect the expression of this miRNA in the liver. These findings cast new light on the regulation of miR-33a and miR-122 in a dyslipidemic model of obese rats and the way these miRNAs are modulated by dietary components in the liver and in PBMCs. PMID- 23922813 TI - Presence and significant determinants of cognitive impairment in a large sample of patients with multiple sclerosis. AB - OBJECTIVES: To investigate the presence and the nature of cognitive impairment in a large sample of patients with Multiple Sclerosis (MS), and to identify clinical and demographic determinants of cognitive impairment in MS. METHODS: 303 patients with MS and 279 healthy controls were administered the Brief Repeatable Battery of Neuropsychological tests (BRB-N); measures of pre-morbid verbal competence and neuropsychiatric measures were also administered. RESULTS: Patients and healthy controls were matched for age, gender, education and pre-morbid verbal Intelligence Quotient. Patients presenting with cognitive impairment were 108/303 (35.6%). In the overall group of participants, the significant predictors of the most sensitive BRB-N scores were: presence of MS, age, education, and Vocabulary. The significant predictors when considering MS patients only were: course of MS, age, education, vocabulary, and depression. Using logistic regression analyses, significant determinants of the presence of cognitive impairment in relapsing remitting MS patients were: duration of illness (OR = 1.053, 95% CI = 1.010 1.097, p = 0.015), Expanded Disability Status Scale score (OR = 1.247, 95% CI = 1.024-1.517, p = 0.028), and vocabulary (OR = 0.960, 95% CI = 0.936-0.984, p = 0.001), while in the smaller group of progressive MS patients these predictors did not play a significant role in determining the cognitive outcome. CONCLUSIONS: Our results corroborate the evidence about the presence and the nature of cognitive impairment in a large sample of patients with MS. Furthermore, our findings identify significant clinical and demographic determinants of cognitive impairment in a large sample of MS patients for the first time. Implications for further research and clinical practice were discussed. PMID- 23922814 TI - An activating mutation reveals a second binding mode of the integrin alpha2 I domain to the GFOGER motif in collagens. AB - The GFOGER motif in collagens (O denotes hydroxyproline) represents a high affinity binding site for all collagen-binding integrins. Other GxOGER motifs require integrin activation for maximal binding. The E318W mutant of the integrin alpha2beta1 I domain displays a relaxed collagen specificity, typical of an active state. E318W binds more strongly than the wild-type alpha2 I domain to GMOGER, and forms a 2:1 complex with a homotrimeric, collagen-like, GFOGER peptide. Crystal structure analysis of this complex reveals two E318W I domains, A and B, bound to a single triple helix. The E318W I domains are virtually identical to the collagen-bound wild-type I domain, suggesting that the E318W mutation activates the I domain by destabilising the unligated conformation. E318W I domain A interacts with two collagen chains similarly to wild-type I domain (high-affinity mode). E318W I domain B makes favourable interactions with only one collagen chain (low-affinity mode). This observation suggests that single GxOGER motifs in the heterotrimeric collagens V and IX may support binding of activated integrins. PMID- 23922815 TI - Diversity, relationships, and biogeography of the lambeosaurine dinosaurs from the European Archipelago, with description of the New Aralosaurin Canardia garonnensis. AB - We provide a thorough re-evaluation of the taxonomic diversity, phylogenetic relationships, and historical biogeography of the lambeosaurine hadrosaurids from the European Archipelago. Previously published occurrences of European Lambeosaurinae are reviewed and new specimens collected from upper Maastrichtian strata of the south-central Pyrenees are described. No support is found for the recognition of European saurolophines in the available hadrosaurid materials recovered so far from this area. A new genus and species of basal lambeosaurine, Canardia garonnensis, is described on the basis of cranial and appendicular elements collected from upper Maastrichtian strata of southern France. C. garonnensis differs from all other hadrosaurids, except Aralosaurus tuberiferus, in having maxilla with prominent subrectangular rostrodorsal flange; it differs from A. tuberiferus in a few maxillary and prefrontal characters. Together with A. tuberiferus, C. garonnensis integrates the newly recognized tribe Aralosaurini. Inference of lambeosaurine interrelationships via maximum parsimony analysis indicates that the other three known European lambeosaurines are representatives of two additional subclades (tribes) of these hadrosaurids: Tsintaosaurini (Pararhabdodon isonensis) and Lambeosaurini (the Arenysaurus ardevoli-Blasisaurus canudoi clade). The tribes Aralosaurini, Tsintaosaurini, Lambeosaurini, and Parasaurolophini are formally defined and diagnosed for the first time. Three event-based quantitative methods of ancestral range reconstruction were implemented to infer the historical biogeography of European lambeosaurines: Dispersal-Vicariance Analysis, Bayesian Binary MCMC, and Dispersal-Extinction-Cladogenesis. The results of these analyses, coupled with the absence of pre-Maastrichtian lambeosaurines in the Mesozoic vertebrate fossil record of Europe, favor the hypothesis that aralosaurins and tsintaosaurins were Asian immigrants that reached the Ibero-Armorican island via dispersal events sometime during the Maastrichtian. Less conclusive is the biogeographical history of European lambeosaurins; several scenarios, occurring sometime during the Maastrichtian, are possible, from vicariance leading to the splitting of Asian or North American from European ranges to a dispersal event from North America to the European Archipelago. PMID- 23922816 TI - Visuospatial working memory in toddlers with a history of periventricular Leukomalacia: an EEG narrow-band power analysis. AB - BACKGROUND: Periventricular Leukomalacia (PVL) affects white matter, but grey matter injuries have also been reported, particularly in the dorsomedial nucleus and the cortex. Both structures have been related to working memory (WM) processes. The aim of this study was to compare behavioral performances and EEG power spectra during a visuospatial working memory task (VSWMT) of toddlers with a history of PVL and healthy toddlers. METHODOLOGY/PRINCIPAL FINDINGS: A prospective, comparative study of WM was conducted in toddlers with a history of PVL and healthy toddlers. The task responses and the EEG narrow-band power spectra during a VSWMT were compared in both groups. The EEG absolute power was analyzed during the following three conditions: baseline, attention and WM retention. The number of correct responses was higher in the healthy group (20.5 +/- 5.0) compared to the PVL group (16.1 +/- 3.9) (p = 0.04). The healthy group had absolute power EEG increases (p <= 0.05) during WM compared to the attention condition in the bilateral frontal and right temporal, parietal and occipital regions in frequencies ranging from 1.17 to 2.34 Hz and in the right temporal, parietal and occipital regions in frequencies ranging from 14.06 to 15.23 Hz. In contrast, the PVL group had absolute power increases (p <= 0.05) in the bilateral fronto-parietal, left central and occipital regions in frequencies that ranged from 1.17 to 3.52 Hz and in the bilateral frontal and right temporal regions in frequencies ranging from 9.37 to 19.14 Hz. CONCLUSIONS/SIGNIFICANCE: This study provides evidence that PVL toddlers have visuospatial WM deficits and a very different pattern of absolute power increases compared to a healthy group of toddlers, with greater absolute power in the low frequency range and widespread neuronal networks in the WM retention phase. PMID- 23922817 TI - Sperm recovery and IVF after testicular sperm extraction (TESE): effect of male diagnosis and use of off-site surgical centers on sperm recovery and IVF. AB - OBJECTIVE: Determine whether testicular sperm extractions and pregnancy outcomes are influenced by male and female infertility diagnoses, location of surgical center and time to cryopreservation. PATIENTS: One hundred and thirty men undergoing testicular sperm extraction and 76 couples undergoing 123 in vitro fertilization cycles with testicular sperm. OUTCOME MEASURES: Successful sperm recovery defined as 1-2 sperm/0.5 mL by diagnosis including obstructive azoospermia (n = 60), non-obstructive azoospermia (n = 39), cancer (n = 14), paralysis (n = 7) and other (n = 10). Obstructive azoospermia was analyzed as congenital absence of the vas deferens (n = 22), vasectomy or failed vasectomy reversal (n = 37) and "other"(n = 1). Sperm recovery was also evaluated by surgical site including infertility clinic (n = 54), hospital operating room (n = 67) and physician's office (n = 11). Treatment cycles were evaluated for number of oocytes, fertilization, embryo quality, implantation rate and clinical/ongoing pregnancies as related to male diagnosis, female diagnosis, and use of fresh or cryopreserved testicular sperm. RESULTS: Testicular sperm recovery from azoospermic males with all diagnoses was high (70 to 100%) except non-obstructive azoospermia (31%) and was not influenced by distance from surgical center to laboratory. Following in vitro fertilization, rate of fertilization was significantly lower with non-obstructive azoospermia (43%, p = <0.0001) compared to other male diagnoses (66%, p = <0.0001, 59% p = 0.015). No differences were noted in clinical pregnancy rate by male diagnosis; however, the delivery rate per cycle was significantly higher with obstructive azoospermia (38% p = 0.0371) compared to diagnoses of cancer, paralysis or other (16.7%). Women diagnosed with diminished ovarian reserve had a reduced clinical pregnancy rate (7.4% p = 0.007) compared to those with other diagnoses (44%). CONCLUSION: Testicular sperm extraction is a safe and effective option regardless of the etiology of the azoospermia. The type of surgical center and/or its distance from the laboratory was not related to success. Men with non-obstructive azoospermia have a lower chance of successful sperm retrieval and fertilization. PMID- 23922818 TI - Lesional accumulation of CD163-expressing cells in the gut of patients with inflammatory bowel disease. AB - Monocytes/macrophages displaying different markers of activation/differentiation infiltrate the inflamed gut of patients with inflammatory bowel diseases (IBD), but the role that each monocyte/macrophage subpopulation plays in the pathogenesis of IBD is not fully understood. The hemoglobin scavenger receptor CD163, a specific marker of monocytes/macrophages, has been associated with either anti-inflammatory or inflammatory functions of macrophages in several pathologies. In this study we examined the tissue distribution and function of CD163-expressing monocytes/macrophages in IBD. CD163 RNA and protein expression was more pronounced in IBD in comparison to normal controls, with no significant difference between Crohn's disease and Ulcerative colitis. In IBD, over expression of CD163 was restricted to areas with active inflammation and not influenced by current therapy. Immunohistochemical analysis confirmed the accumulation of CD163-expressing cells in IBD, mostly around and inside blood vessels, thus suggesting that these cells are partly recruited from the systemic circulation. Indeed, FACS analysis of circulating mononuclear cells showed that the fractions of CD163-positive monocytes were increased in IBD patients as compared to controls. Functionally, interleukin-6 up-regulated CD163 expression in lamina propria mononuclear cells and mucosal explants of normal subjects. In IBD blood and mucosal cell cultures, cross-linking of CD163 with a specific monoclonal anti-CD163 antibody enhanced tumor necrosis factor-alpha synthesis. These findings indicate that IBD mucosa is abundantly infiltrated with CD163 positive cells, which could contribute to amplify the inflammatory cytokine response. PMID- 23922819 TI - The effect of orexin-A on cardiac dysfunction mediated by NADPH oxidase-derived superoxide anion in ventrolateral medulla. AB - Hypocretin/orexin-producing neurons, located in the perifornical region of the lateral hypothalamus area (LHA) and projecting to the brain sites of rostral ventrolateral medulla (RVLM), involve in the increase of sympathetic activity, thereby regulating cardiovascular function. The current study was designed to test the hypothesis that the central orexin-A (OXA) could be involved in the cardiovascular dysfunction of acute myocardial infarction (AMI) by releasing NAD(P)H oxidase-derived superoxide anion (O2 (-)) generation in RVLM, AMI rat model established by ligating the left anterior descending (LAD) coronary artery to induce manifestation of cardiac dysfunction, monitored by the indicators as heart rate (HR), heart rate variability (HRV), mean arterial pressure (MAP) and left intraventricular pressure. The results showed that the expressions of OXA in LHA and orexin 1 receptor (OX1R) increased in RVLM of AMI rats. The double immunofluorescent staining indicated that OX1R positive cells and NAD(P)H oxidative subunit gp91phox or p47phox-immunoreactive (IR) cells were co-localized in RVLM. Microinjection of OXA into the cerebral ventricle significantly increased O2 (-) production and mRNA expression of NAD(P)H oxidase subunits when compared with aCSF-treated ones. Exogenous OXA administration in RVLM produced pressor and tachycardiac effects. Furthermore, the antagonist of OX1R and OX2R (SB-408124 and TCS OX2 29, respectively) or apocynin (APO), an inhibitor of NAD(P)H oxidase, partly abolished those cardiovascular responses of OXA. HRV power spectral analysis showed that exogenous OXA led to decreased HF component of HRV and increased LF/HF ratio in comparison with aCSF, which suggested that OXA might be related to sympathovagal imbalance. As indicated by the results, OXA might participate in the central regulation of cardiovascular activities by disturbing the sympathovagal balance in AMI, which could be explained by the possibility that OXR and NAD(P)H-derived O2 (-) in RVLM mediates OXA-induced cardiovascular responses. PMID- 23922820 TI - Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s). AB - Clostridium difficile infection (CDI) is the leading cause of hospital and community-acquired antibiotic-associated diarrhoea and currently represents a significant health burden. Although the role and contribution of C. difficile toxins to disease pathogenesis is being increasingly understood, at present other facets of C. difficile-host interactions, in particular, bacterial-driven effects on host immunity remain less studied. Using an ex-vivo model of infection, we report that the human gastrointestinal mucosa elicits a rapid and significant cytokine response to C. difficile. Marked increase in IFN-gamma with modest increase in IL-22 and IL-17A was noted. Significant increase in IL-8 suggested potential for neutrophil influx while presence of IL-12, IL-23, IL-1beta and IL-6 was indicative of a cytokine milieu that may modulate subsequent T cell immunity. Majority of C. difficile-driven effects on murine bone-marrow-derived dendritic cell (BMDC) activation were toxin-independent; the toxins were however responsible for BMDC inflammasome activation. In contrast, human monocyte-derived DCs (mDCs) released IL-1beta even in the absence of toxins suggesting host specific mediation. Infected DC-T cell crosstalk revealed the ability of R20291 and 630 WT strains to elicit a differential DC IL-12 family cytokine milieu which culminated in significantly greater Th1 immunity in response to R20291. Interestingly, both strains induced a similar Th17 response. Elicitation of mucosal IFN-gamma/IL-17A and Th1/Th17 immunity to C. difficile indicates a central role for this dual cytokine axis in establishing antimicrobial immunity to CDI. PMID- 23922821 TI - Gene expression profiles deciphering leaf senescence variation between early- and late-senescence cotton lines. AB - Leaf senescence varies greatly among genotypes of cotton (Gossypium hirsutium L), possibly due to the different expression of senescence-related genes. To determine genes involved in leaf senescence, we performed genome-wide transcriptional profiling of the main-stem leaves of an early- (K1) and a late senescence (K2) cotton line at 110 day after planting (DAP) using the Solexa technology. The profiling analysis indicated that 1132 genes were up-regulated and 455 genes down-regulated in K1 compared with K2 at 110 DAP. The Solexa data were highly consistent with, and thus were validated by those from real-time quantitative PCR (RT-PCR). Most of the genes related to photosynthesis, anabolism of carbohydrates and other biomolecules were down-regulated, but those for catabolism of proteins, nucleic acids, lipids and nutrient recycling were mostly up-regulated in K1 compared with K2. Fifty-one differently expressed hormone related genes were identified, of which 5 ethylene, 3 brassinosteroid (BR), 5 JA, 18 auxin, 8 GA and 1 ABA related genes were up-regulated in K1 compared with K2, indicating that these hormone-related genes might play crucial roles in early senescence of K1 leaves. Many differently expressed transcription factor (TF) genes were identified and 11 NAC and 8 WRKY TF genes were up-regulated in K1 compared with K2, suggesting that TF genes, especially NAC and WRKY genes were involved in early senescence of K1 leaves. Genotypic variation in leaf senescence was attributed to differently expressed genes, particularly hormone-related and TF genes. PMID- 23922822 TI - Metabotropic glutamate receptor 1 expression and its polymorphic variants associate with breast cancer phenotypes. AB - Several epidemiological studies have suggested a link between melanoma and breast cancer. Metabotropic glutamate receptor 1 (GRM1), which is involved in many cellular processes including proliferation and differentiation, has been implicated in melanomagenesis, with ectopic expression of GRM1 causing malignant transformation of melanocytes. This study was undertaken to evaluate GRM1 expression and polymorphic variants in GRM1 for associations with breast cancer phenotypes. Three single nucleotide polymorphisms (SNPs) in GRM1 were evaluated for associations with breast cancer clinicopathologic variables. GRM1 expression was evaluated in human normal and cancerous breast tissue and for in vitro response to hormonal manipulation. Genotyping was performed on genomic DNA from over 1,000 breast cancer patients. Rs6923492 and rs362962 genotypes associated with age at diagnosis that was highly dependent upon the breast cancer molecular phenotype. The rs362962 TT genotype also associated with risk of estrogen receptor or progesterone receptor positive breast cancer. In vitro analysis showed increased GRM1 expression in breast cancer cells treated with estrogen or the combination of estrogen and progesterone, but reduced GRM1 expression with tamoxifen treatment. Evaluation of GRM1 expression in human breast tumor specimens demonstrated significant correlations between GRM1 staining with tissue type and molecular features. Furthermore, analysis of gene expression data from primary breast tumors showed that high GRM1 expression correlated with a shorter distant metastasis-free survival as compared to low GRM1 expression in tamoxifen treated patients. Additionally, induced knockdown of GRM1 in an estrogen receptor positive breast cancer cell line correlated with reduced cell proliferation. Taken together, these findings suggest a functional role for GRM1 in breast cancer. PMID- 23922823 TI - De novo assembly and characterization of two transcriptomes reveal multiple light mediated functions in the scallop eye (Bivalvia: Pectinidae). AB - BACKGROUND: The eye has evolved across 13 separate lineages of molluscs. Yet, there have been very few studies examining the molecular machinary underlying eye function of this group, which is due, in part, to a lack of genomic resources. The scallop (Bivalvia: Pectinidae) represents a compeling molluscan model to study photoreception due to its morphologically novel and separately evolved mirror-type eye. We sequenced the adult eye transcriptome of two scallop species to: 1) identify the phototransduction pathway components; 2) identify any additional light detection functions; and 3) test the hypothesis that molluscs possess genes not found in other animal lineages. RESULTS: A total of 3,039 contigs from the bay scallop, Argopecten irradians and 26,395 contigs from the sea scallop, Placopecten magellanicus were produced by 454 sequencing. Targeted BLAST searches and functional annotation using Gene Ontology (GO) terms and KEGG pathways identified transcripts from three light detection systems: two phototransduction pathways and the circadian clock, a previously unrecognized function of the scallop eye. By comparing the scallop transcriptomes to molluscan and non-molluscan genomes, we discovered that a large proportion of the transcripts (7,776 sequences) may be specific to the scallop lineage. Nearly one third of these contain transmembrane protein domains, suggesting these unannotated transcripts may be sensory receptors. CONCLUSIONS: Our data provide the most comprehensive transcriptomic resource currently available from a single molluscan eye type. Candidate genes potentially involved in sensory reception were identified, and are worthy of further investigation. This resource, combined with recent phylogenetic and genomic data, provides a strong foundation for future investigations of the function and evolution of molluscan photosensory systems in this morphologically and taxonomically diverse phylum. PMID- 23922824 TI - Chromatin accessibility data sets show bias due to sequence specificity of the DNase I enzyme. AB - BACKGROUND: DNase I is an enzyme which cuts duplex DNA at a rate that depends strongly upon its chromatin environment. In combination with high-throughput sequencing (HTS) technology, it can be used to infer genome-wide landscapes of open chromatin regions. Using this technology, systematic identification of hundreds of thousands of DNase I hypersensitive sites (DHS) per cell type has been possible, and this in turn has helped to precisely delineate genomic regulatory compartments. However, to date there has been relatively little investigation into possible biases affecting this data. RESULTS: We report a significant degree of sequence preference spanning sites cut by DNase I in a number of published data sets. The two major protocols in current use each show a different pattern, but for a given protocol the pattern of sequence specificity seems to be quite consistent. The patterns are substantially different from biases seen in other types of HTS data sets, and in some cases the most constrained position lies outside the sequenced fragment, implying that this constraint must relate to the digestion process rather than events occurring during library preparation or sequencing. CONCLUSIONS: DNase I is a sequence specific enzyme, with a specificity that may depend on experimental conditions. This sequence specificity is not taken into account by existing pipelines for identifying open chromatin regions. Care must be taken when interpreting DNase I results, especially when looking at the precise locations of the reads. Future studies may be able to improve the sensitivity and precision of chromatin state measurement by compensating for sequence bias. PMID- 23922825 TI - Use of anti-granulocyte scintigraphy with 99mTc-labeled monoclonal antibodies for the diagnosis of periprosthetic infection in patients after total joint arthroplasty: a diagnostic meta-analysis. AB - The accurate diagnosis of periprosthetic joint infections (PJI) is crucial for therapy and the prevention of complications. No diagnostic test of PJI is 100% accurate. The aim of this study was to assess the use of anti-granulocyte scintigraphy using 99 mTc-labeled monoclonal antibodies to diagnose PJI after total joint arthroplasty. A systematic search of all relevant studies published through January 2013 was conducted using the MEDLINE, EMBASE, OVID, and ScienceDirect databases. Observational studies that assessed the accuracy of the anti-granulocyte scintigraphy with monoclonal antibodies or antibody fragments labeled with technetium 99 m in diagnosis for PJI and provided data on specificity and sensitivity were identified. Standard methods recommended for meta-analysis of diagnostic accuracy were used. Nineteen studies were eligible for inclusion. The results demonstrated that the area under the summary receiver operator curve was 0.88, and the diagnostic accuracy (Q*) was 0.81. Additionally, the diagnostic odds ratio (DOR) was 18.76 with a corresponding 95% confidence interval of 10.45-33.68. The pooled sensitivity and specificity of the diagnostic method for the diagnosis of PJI were 83% and 79%, respectively, while the pooled positive likelihood ratio (PLR) was 3.56, and the negative likelihood ratio (NLR) was 0.26. Anti-granulocyte scintigraphy using 99 mTc-labeled monoclonal antibodies has a reasonable role in the diagnosis of PJI after total joint arthroplasty. Due to the limitations of the present meta-analysis, additional high-quality original studies are required to confirm the predictive value. PMID- 23922826 TI - Persistent low level of osterix accelerates interleukin-6 production and impairs regeneration after tissue injury. AB - Osterix (Osx) is an essential transcription factor for osteoblast differentiation and bone formation. Osx knockout show a complete absence of bone formation, whereas Osx conditional knockout in osteoblasts produce an osteopenic phenotype after birth. Here, we questioned whether Osx has a potential role in regulating physiological homeostasis. In Osx heterozygotes expressing low levels of Osx in bones, the expression levels of pro-inflammatory cytokines were significantly elevated, indicating that reduced Osx expression may reflect an inflammatory prone state. In particular, the expression of interleukin-6, a key mediator of chronic inflammation, was increased in Osx heterozygotes and decreased in Osx overexpressing osteoblasts, and transcriptionally down-regulated by Osx. Although no significant differences were revealed in renal morphology and function between Osx heterozygotes and wild-type under normoxic conditions, recovery of kidneys after ischemic damage was remarkably delayed in Osx heterozygotes, as indicated by elevated blood urea nitrogen and creatinine levels, and by morphological alterations consistent with acute tubular necrosis. Eventually, protracted low Osx expression level caused an inflammatory-prone state in the body, resulting in the enhanced susceptibility to renal injury and the delayed renal repair after ischemia/reperfusion. This study suggests that the maintenance of Osx expression in bone is important in terms of preventing the onset of an inflammatory-prone state. PMID- 23922827 TI - Aging 2.0: health information about dementia on Twitter. AB - Online social media is widespread, easily accessible and attracts a global audience with a widening demographic. As a large proportion of adults now seek health information online and through social media applications, communication about health has become increasingly interactive and dynamic. Online health information has the potential to significantly impact public health, especially as the population gets older and the prevalence of dementia increases. However, little is known about how information pertaining to age-associated diseases is disseminated on popular social media platforms. To fill this knowledge gap, we examined empirically: (i) who is using social media to share information about dementia, (ii) what sources of information about dementia are promoted, and (iii) which dementia themes dominate the discussion. We data-mined the microblogging platform Twitter for content containing dementia-related keywords for a period of 24 hours and retrieved over 9,200 tweets. A coding guide was developed and content analysis conducted on a random sample (10%), and on a subsample from top users' tweets to assess impact. We found that a majority of tweets contained a link to a third party site rather than personal information, and these links redirected mainly to news sites and health information sites. As well, a large number of tweets discussed recent research findings related to the prediction and risk management of Alzheimer's disease. The results highlight the need for the dementia research community to harness the reach of this medium and its potential as a tool for multidirectional engagement. PMID- 23922828 TI - Activity-dependent modulation of odorant receptor gene expression in the mouse olfactory epithelium. AB - Activity plays critical roles in development and maintenance of the olfactory system, which undergoes considerable neurogenesis throughout life. In the mouse olfactory epithelium, each olfactory sensory neuron (OSN) stably expresses a single odorant receptor (OR) type out of a repertoire of ~1200 and the OSNs with the same OR identity are distributed within one of the few broadly-defined zones. However, it remains elusive whether and how activity modulates such OR expression patterns. Here we addressed this question by investigating OR gene expression via in situ hybridization when sensory experience or neuronal excitability is manipulated. We first examined the expression patterns of fifteen OR genes in mice which underwent neonatal, unilateral naris closure. After four-week occlusion, the cell density in the closed (sensory-deprived) side was significantly lower (for four ORs), similar (for three ORs), or significantly higher (for eight ORs) as compared to that in the open (over-stimulated) side, suggesting that sensory inputs have differential effects on OSNs expressing different OR genes. We next examined the expression patterns of seven OR genes in transgenic mice in which mature OSNs had reduced neuronal excitability. Neuronal silencing led to a significant reduction in the cell density for most OR genes tested and thinner olfactory epithelium with an increased density of apoptotic cells. These results suggest that sensory experience plays important roles in shaping OR gene expression patterns and the neuronal activity is critical for survival of OSNs. PMID- 23922829 TI - Dynamic stability of coral reefs on the west Australian coast. AB - Monitoring changes in coral cover and composition through space and time can provide insights to reef health and assist the focus of management and conservation efforts. We used a meta-analytical approach to assess coral cover data across latitudes 10-35 degrees S along the west Australian coast, including 25 years of data from the Ningaloo region. Current estimates of coral cover ranged between 3 and 44% in coral habitats. Coral communities in the northern regions were dominated by corals from the families Acroporidae and Poritidae, which became less common at higher latitudes. At Ningaloo Reef coral cover has remained relatively stable through time (~28%), although north-eastern and southern areas have experienced significant declines in overall cover. These declines are likely related to periodic disturbances such as cyclones and thermal anomalies, which were particularly noticeable around 1998/1999 and 2010/2011. Linear mixed effects models (LME) suggest latitude explains 10% of the deviance in coral cover through time at Ningaloo. Acroporidae has decreased in abundance relative to other common families at Ningaloo in the south, which might be related to persistence of more thermally and mechanically tolerant families. We identify regions where quantitative time-series data on coral cover and composition are lacking, particularly in north-western Australia. Standardising routine monitoring methods used by management and research agencies at these, and other locations, would allow a more robust assessment of coral condition and a better basis for conservation of coral reefs. PMID- 23922830 TI - The pathological phenotypes of human TDP-43 transgenic mouse models are independent of downregulation of mouse Tdp-43. AB - Tar DNA binding protein 43 (TDP-43) is the major component of pathological deposits in frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and in amyotrophic lateral sclerosis (ALS). It has been reported that TDP-43 transgenic mouse models expressing human TDP-43 wild-type or ALS-associated mutations recapitulate certain ALS and FTLD pathological phenotypes. Of note, expression of human TDP-43 (hTDP-43) reduces the levels of mouse Tdp-43 (mTdp 43). However, it remained unclear whether the mechanisms through which TDP-43 induces ALS or FTLD-like pathologies resulted from a reduction in mTdp-43, an increase in hTDP-43, or a combination of both. In elucidating the role of mTdp-43 and hTDP-43 in hTDP-43 transgenic mice, we observed that reduction of mTdp-43 in non-transgenic mice by intraventricular brain injection of AAV1-shTardbp leads to a dramatic increase in the levels of splicing variants of mouse sortilin 1 and translin. However, the levels of these two abnormal splicing variants are not increased in hTDP-43 transgenic mice despite significant downregulation of mTdp 43 in these mice. Moreover, further downregulation of mTdp-43 in hTDP-43 hemizygous mice, which are asymptomatic, to the levels equivalent to that of mTdp 43 in hTDP-43 homozygous mice does not induce the pathological phenotypes observed in the homozygous mice. Lastly, the number of dendritic spines and the RNA levels of TDP-43 RNA targets critical for synapse formation and function are significantly decreased in symptomatic homozygous mice. Together, our findings indicate that mTdp-43 downregulation does not lead to a loss of function mechanism or account for the pathological phenotypes observed in hTDP-43 homozygous mice because hTDP-43 compensates for the reduction, and associated functions of mTdp-43. Rather, expression of hTDP-43 beyond a certain threshold leads to abnormal metabolism of TDP-43 RNA targets critical for neuronal structure and function, which might be responsible for the ALS or FTLD-like pathologies observed in homozygous hTDP-43 transgenic mice. PMID- 23922831 TI - Implementation fidelity of the national malaria control program in Burkina Faso. AB - BACKGROUND: Every year 40,000 people die of malaria in Burkina Faso. In 2010, the Burkinabe authorities implemented a national malaria control program that provides for the distribution of mosquito nets and the home-based treatment of children with fever by community health workers. The objective of this study was to measure the implementation fidelity of this program. METHODS: We conducted a case study in two comparable districts (Kaya and Zorgho). Data were collected one year after the program's implementation through field observations (10 weeks), documentary analysis, and individual interviews with stakeholders (n = 48) working at different levels of the program. The analysis framework looked at the fidelity of (i) the intervention's content, (ii) its coverage, and (iii) its schedule. RESULTS: The program's implementation was relatively faithful to what was originally planned and was comparable in the two districts. It encountered certain obstacles in terms of the provision of supplies. Coverage fidelity was better in Kaya than in Zorgho, where many community health workers (CHW) experienced problems with the restocking of artemisinin-based combination therapy and with remuneration for periods of training. In both districts, the community was rarely involved in the process of selecting CHWs. The components affected by scheduling all experienced successive implementation delays that pushed nets distribution and the initial provision of artemisinin-based combination therapies to the CHWs past the 2010 malaria season. CONCLUSIONS: The activities intended by the program were mostly implemented with good fidelity. However, the implementation was plagued by delays that probably postponed the expected beneficial effects. PMID- 23922832 TI - Ocular hypertension after pediatric cataract surgery: baseline characteristics and first-year report. AB - Monitoring intraocular pressure (IOP) is essential for pediatric cataract treatment but always difficult due to lack of cooperation in young children. We present the baseline characteristics and the first-year results of a long-term prospective cohort study, which are aimed to determine the relationship of the incidence of ocular hypertension (OH) in children after cataract surgery during the first-year period and the risk of developing late-onset glaucoma. Children were included with the following criteria: they were <=10 years old and scheduled to undergo cataract surgery with/without intraocular lens implantation; they were compliant with our follow-up protocol, which included monitoring IOP using a Tono Pen under sedation or anesthesia. Incidence of OH, peak OH value, OH onset time and OH duration within a 12-month period following surgery were measured. In brief, 206 patients (379 eyes) were included and OH developed in 66 of 379 (17.4%) eyes. The mean follow-up period was 14.0+/-3.2 months (median, 12 months; range, 10-16 months). Moreover, 33 of 196 (16.8%) aphakic eyes and 33 of 183 (18.0%) IOL eyes were diagnosed with OH. The peak OH onset times were at 1-week (34/66, 51.5%) and 1-month (14/66, 21.2%) appointments postsurgery. The peak IOP value in the OH eyes was 29.9+/-7.5 mmHg (median, 29 mmHg; range, 21-48 mmHg). The duration of OH was 30.9+/-31.2 days (median, 30 days; range, 3-150 days). OH recurred in 13 eyes with a history of OH diagnosed within 1 month postsurgery (13/54, 24.1%), which needed temporary or long term use of antiglaucoma medications. In conclusion, the incidence of OH in children after cataract surgery was 17.4% during the first-year period. Children who have suffered elevated IOP in the first year after cataract surgery should be followed closely to determine if there is an increased risk of developing late-onset glaucoma. PMID- 23922833 TI - Electroconvulsive therapy induces neurogenesis in frontal rat brain areas. AB - Electroconvulsive therapy (ECT) is an effective therapy for several psychiatric disorders, including severe major depression, mania and certain forms of schizophrenia. It had been proposed that ECT acts by modulating local plasticity via the stimulation of neurogenesis. In fact, among antidepressant therapies, ECT is the most robust enhancer of neurogenesis in the hippocampus of rodents and non human primates. The existence of ECT-triggered neurogenesis in other brain areas, particularly in those adjacent to the other main locus of neurogenesis, the subventricular zone (SVZ), had so far remained unknown. Here we show that ECT also strongly enhances neurogenesis in frontal brain areas, especially in the rostro-medial striatum, generating specific, small-size calretinin-positive interneurons. We provide here the first evidence that ECT stimulates neurogenesis in areas outside the hippocampus. Our data may open research possibilities that focus on the plastic changes induced by ECT in frontal limbic circuitry. PMID- 23922834 TI - Effect of angle on flow-induced vibrations of pinniped vibrissae. AB - Two types of vibrissal surface structures, undulated and smooth, exist among pinnipeds. Most Phocidae have vibrissae with undulated surfaces, while Otariidae, Odobenidae, and a few phocid species possess vibrissae with smooth surfaces. Variations in cross-sectional profile and orientation of the vibrissae also exist between pinniped species. These factors may influence the way that the vibrissae behave when exposed to water flow. This study investigated the effect that vibrissal surface structure and orientation have on flow-induced vibrations of pinniped vibrissae. Laser vibrometry was used to record vibrations along the whisker shaft from the undulated vibrissae of harbor seals (Phoca vitulina) and northern elephant seals (Mirounga angustirostris) and the smooth vibrissae of California sea lions (Zalophus californianus). Vibrations along the whisker shaft were measured in a flume tank, at three orientations (0 degrees , 45 degrees , 90 degrees ) to the water flow. The results show that vibration frequency and velocity ranges were similar for both undulated and smooth vibrissae. Angle of orientation, rather than surface structure, had the greatest effect on flow induced vibrations. Vibration velocity was up to 60 times higher when the wide, flat aspect of the whisker faced into the flow (90 degrees ), compared to when the thin edge faced into the flow (0 degrees ). Vibration frequency was also dependent on angle of orientation. Peak frequencies were measured up to 270 Hz and were highest at the 0 degrees orientation for all whiskers. Furthermore, CT scanning was used to quantify the three-dimensional structure of pinniped vibrissae that may influence flow interactions. The CT data provide evidence that all vibrissae are flattened in cross-section to some extent and that differences exist in the orientation of this profile with respect to the major curvature of the hair shaft. These data support the hypothesis that a compressed cross sectional profile may play a key role in reducing self-noise of the vibrissae. PMID- 23922835 TI - Finding evidence for local transmission of contagious disease in molecular epidemiological datasets. AB - Surveillance systems of contagious diseases record information on cases to monitor incidence of disease and to evaluate effectiveness of interventions. These systems focus on a well-defined population; a key question is whether observed cases are infected through local transmission within the population or whether cases are the result of importation of infection into the population. Local spread of infection calls for different intervention measures than importation of infection. Besides standardized information on time of symptom onset and location of cases, pathogen genotyping or sequencing offers essential information to address this question. Here we introduce a method that takes full advantage of both the genetic and epidemiological data to distinguish local transmission from importation of infection, by comparing inter-case distances in temporal, spatial and genetic data. Cases that are part of a local transmission chain will have shorter distances between their geographical locations, shorter durations between their times of symptom onset and shorter genetic distances between their pathogen sequences as compared to cases that are due to importation. In contrast to generic clustering algorithms, the proposed method explicitly accounts for the fact that during local transmission of a contagious disease the cases are caused by other cases. No pathogen-specific assumptions are needed due to the use of ordinal distances, which allow for direct comparison between the disparate data types. Using simulations, we test the performance of the method in identifying local transmission of disease in large datasets, and assess how sensitivity and specificity change with varying size of local transmission chains and varying overall disease incidence. PMID- 23922836 TI - Gastrointestinal symptoms are still prevalent and negatively impact health related quality of life: a large cross-sectional population based study in The Netherlands. AB - BACKGROUND: Over the last decades important risk factors for gastrointestinal symptoms have shifted, which may have changed its population prevalence. The aim of this study was to assess the current prevalence of gastrointestinal symptoms, appraise associated factors and assess health-related quality of life in the general population. METHODS: A total of 51,869 questionnaires were sent to a representative sample of the Dutch adult general population in December 2008. Demographic characteristics, gastrointestinal symptoms, health-related quality of life, medication use and co-morbidity were reported. We used multivariable logistic regression analysis to determine factors associated with gastrointestinal symptoms. RESULTS: A total of 18,317 questionnaires were returned, and 16,758 were eligible for analysis. Prevalence of gastrointestinal symptoms was 26%. Most frequent symptoms were bloating (63%), borborygmi (60%) and flatulence (71%). Female gender (adjusted OR (aOR) 1.59, 95% CI 1.43-1.77), asthma/COPD (aOR 1.47, 95% CI 1.21-1.79), use of paracetamol (aOR 1.33, 95% CI 1.20-1.47), antidepressants (aOR 1.56, 95% CI 1.22-2.00) and acid-suppressive medication were independently associated with presence of gastrointestinal symptoms. Age over 65 years (aOR 0.75, 95% CI 0.65-0.87), and use of statins (aOR 0.75, 95% CI 0.61-0.93) were associated with a lower prevalence of gastrointestinal symptoms. Respondents with gastrointestinal symptoms had a lower mean health-related quality of life of 0.81 (SD = 0.21) compared to 0.92 (SD = 0.14) for persons without gastrointestinal symptoms (P<0.01). CONCLUSIONS: Prevalence of gastrointestinal symptoms in the Dutch community is high and associated with decreased health-related quality of life. PMID- 23922837 TI - Amino acid usage is asymmetrically biased in AT- and GC-rich microbial genomes. AB - INTRODUCTION: Genomic base composition ranges from less than 25% AT to more than 85% AT in prokaryotes. Since only a small fraction of prokaryotic genomes is not protein coding even a minor change in genomic base composition will induce profound protein changes. We examined how amino acid and codon frequencies were distributed in over 2000 microbial genomes and how these distributions were affected by base compositional changes. In addition, we wanted to know how genome wide amino acid usage was biased in the different genomes and how changes to base composition and mutations affected this bias. To carry this out, we used a Generalized Additive Mixed-effects Model (GAMM) to explore non-linear associations and strong data dependences in closely related microbes; principal component analysis (PCA) was used to examine genomic amino acid- and codon frequencies, while the concept of relative entropy was used to analyze genomic mutation rates. RESULTS: We found that genomic amino acid frequencies carried a stronger phylogenetic signal than codon frequencies, but that this signal was weak compared to that of genomic %AT. Further, in contrast to codon usage bias (CUB), amino acid usage bias (AAUB) was differently distributed in AT- and GC rich genomes in the sense that AT-rich genomes did not prefer specific amino acids over others to the same extent as GC-rich genomes. AAUB was also associated with relative entropy; genomes with low AAUB contained more random mutations as a consequence of relaxed purifying selection than genomes with higher AAUB. CONCLUSION: Genomic base composition has a substantial effect on both amino acid- and codon frequencies in bacterial genomes. While phylogeny influenced amino acid usage more in GC-rich genomes, AT-content was driving amino acid usage in AT-rich genomes. We found the GAMM model to be an excellent tool to analyze the genomic data used in this study. PMID- 23922838 TI - TaCIPK29, a CBL-interacting protein kinase gene from wheat, confers salt stress tolerance in transgenic tobacco. AB - Calcineurin B-like protein-interacting protein kinases (CIPKs) have been found to be responsive to abiotic stress. However, their precise functions and the related molecular mechanisms in abiotic stress tolerance are not completely understood, especially in wheat. In the present study, TaCIPK29 was identified as a new member of CIPK gene family in wheat. TaCIPK29 transcript increased after NaCl, cold, methyl viologen (MV), abscisic acid (ABA) and ethylene treatments. Over expression of TaCIPK29 in tobacco resulted in increased salt tolerance, which was demonstrated by higher germination rates, longer root lengths and better growth status of transgenic tobacco plants compared to controls when both were treated with salt stress. Physiological measurements indicated that transgenic tobacco seedlings retained high K(+)/Na(+) ratios and Ca(2+) content by up-regulating some transporter genes expression and also possessed lower H2O2 levels and reduced membrane injury by increasing the expression and activities of catalase (CAT) and peroxidase (POD) under salt stress. Moreover, transgenic lines conferred tolerance to oxidative stress by increasing the activity and expression of CAT. Finally, TaCIPK29 was located throughout cells and it preferentially interacted with TaCBL2, TaCBL3, NtCBL2, NtCBL3 and NtCAT1. Taken together, our results showed that TaCIPK29 functions as a positive factor under salt stress and is involved in regulating cations and reactive oxygen species (ROS) homeostasis. PMID- 23922839 TI - Schiff base switch II precedes the retinal thermal isomerization in the photocycle of bacteriorhodopsin. AB - In bacteriorhodopsin, the order of molecular events that control the cytoplasmic or extracellular accessibility of the Schiff bases (SB) are not well understood. We use molecular dynamics simulations to study a process involved in the second accessibility switch of SB that occurs after its reprotonation in the N intermediate of the photocycle. We find that once protonated, the SB C15 = NZ bond switches from a cytoplasmic facing (13-cis, 15-anti) configuration to an extracellular facing (13-cis, 15-syn) configuration on the pico to nanosecond timescale. Significantly, rotation about the retinal's C13 = C14 double bond is not observed. The dynamics of the isomeric state transitions of the protonated SB are strongly influenced by the surrounding charges and dielectric effects of other buried ions, particularly D96 and D212. Our simulations indicate that the thermal isomerization of retinal from 13-cis back to all-trans likely occurs independently from and after the SB C15 = NZ rotation in the N-to-O transition. PMID- 23922841 TI - GenGIS 2: geospatial analysis of traditional and genetic biodiversity, with new gradient algorithms and an extensible plugin framework. AB - GenGIS is free and open source software designed to integrate biodiversity data with a digital map and information about geography and habitat. While originally developed with microbial community analyses and phylogeography in mind, GenGIS has been applied to a wide range of datasets. A key feature of GenGIS is the ability to test geographic axes that can correspond to routes of migration or gradients that influence community similarity. Here we introduce GenGIS version 2, which extends the linear gradient tests introduced in the first version to allow comprehensive testing of all possible linear geographic axes. GenGIS v2 also includes a new plugin framework that supports the development and use of graphically driven analysis packages: initial plugins include implementations of linear regression and the Mantel test, calculations of alpha-diversity (e.g., Shannon Index) for all samples, and geographic visualizations of dissimilarity matrices. We have also implemented a recently published method for biomonitoring reference condition analysis (RCA), which compares observed species richness and diversity to predicted values to determine whether a given site has been impacted. The newest version of GenGIS supports vector data in addition to raster files. We demonstrate the new features of GenGIS by performing a full gradient analysis of an Australian kangaroo apple data set, by using plugins and embedded statistical commands to analyze human microbiome sample data, and by applying RCA to a set of samples from Atlantic Canada. GenGIS release versions, tutorials and documentation are freely available at http://kiwi.cs.dal.ca/GenGIS, and source code is available at https://github.com/beiko-lab/gengis. PMID- 23922840 TI - GABA transporter-1 deficiency confers schizophrenia-like behavioral phenotypes. AB - The mechanism underlying the pathogenesis of schizophrenia remains poorly understood. The hyper-dopamine and hypo-NMDA receptor hypotheses have been the most enduring ideas. Recently, emerging evidence implicates alterations of the major inhibitory system, GABAergic neurotransmission in the schizophrenic patients. However, the pathophysiological role of GABAergic system in schizophrenia still remains dubious. In this study, we took advantage of GABA transporter 1 (GAT1) knockout (KO) mouse, a unique animal model with elevated ambient GABA, to study the schizophrenia-related behavioral abnormalities. We found that GAT1 KO mice displayed multiple behavioral abnormalities related to schizophrenic positive, negative and cognitive symptoms. Moreover, GAT1 deficiency did not change the striatal dopamine levels, but significantly enhanced the tonic GABA currents in prefrontal cortex. The GABA(A) receptor antagonist picrotoxin could effectively ameliorate several behavioral defects of GAT1 KO mice. These results identified a novel function of GAT1, and indicated that the elevated ambient GABA contributed critically to the pathogenesis of schizophrenia. Furthermore, several commonly used antipsychotic drugs were effective in treating the locomotor hyperactivity in GAT1 KO mice, suggesting the utility of GAT1 KO mice as an alternative animal model for studying schizophrenia pathogenesis and developing new antipsychotic drugs. PMID- 23922842 TI - Biochemical characterization of a polysialyltransferase from Mannheimia haemolytica A2 and comparison to other bacterial polysialyltransferases. AB - Polysialic acids are bioactive carbohydrates found in eukaryotes and some bacterial pathogens. The bacterial polysialyltransferases (PSTs), which catalyze the synthesis of polysialic acid capsules, have previously been identified in select strains of Escherichia coli and Neisseria meningitidis and are classified in the Carbohydrate-Active enZYmes Database as glycosyltransferase family GT-38. In this study using DNA sequence analysis and functional characterization we have identified a novel polysialyltransferase from the bovine/ovine pathogen Mannheimia haemolytica A2 (PSTMh). The enzyme was expressed in recombinant form as a soluble maltose-binding-protein fusion in parallel with the related PSTs from E. coli K1 and N. meningitidis group B in order to perform a side-by-side comparison. Biochemical properties including solubility, acceptor preference, reaction pH optima, thermostability, kinetics, and product chain length for the enzymes were compared using a synthetic fluorescent acceptor molecule. PSTMh exhibited biochemical properties that make it an attractive candidate for chemi enzymatic synthesis applications of polysialic acid. The activity of PSTMh was examined on a model glycoprotein and the surface of a neuroprogenitor cell line where the results supported its development for use in applications to therapeutic protein modification and cell surface glycan remodelling to enable cell migration at implantation sites to promote wound healing. The three PSTs examined here demonstrated different properties that would each be useful to therapeutic applications. PMID- 23922843 TI - Evaluation of genome sequencing quality in selected plant species using expressed sequence tags. AB - BACKGROUND: With the completion of genome sequencing projects for more than 30 plant species, large volumes of genome sequences have been produced and stored in online databases. Advancements in sequencing technologies have reduced the cost and time of whole genome sequencing enabling more and more plants to be subjected to genome sequencing. Despite this, genome sequence qualities of multiple plants have not been evaluated. METHODOLOGY/PRINCIPAL FINDING: Integrity and accuracy were calculated to evaluate the genome sequence quality of 32 plants. The integrity of a genome sequence is presented by the ratio of chromosome size and genome size (or between scaffold size and genome size), which ranged from 55.31% to nearly 100%. The accuracy of genome sequence was presented by the ratio between matched EST and selected ESTs where 52.93% ~ 98.28% and 89.02% ~ 98.85% of the randomly selected clean ESTs could be mapped to chromosome and scaffold sequences, respectively. According to the integrity, accuracy and other analysis of each plant species, thirteen plant species were divided into four levels. Arabidopsis thaliana, Oryza sativa and Zea mays had the highest quality, followed by Brachypodium distachyon, Populus trichocarpa, Vitis vinifera and Glycine max, Sorghum bicolor, Solanum lycopersicum and Fragaria vesca, and Lotus japonicus, Medicago truncatula and Malus * domestica in that order. Assembling the scaffold sequences into chromosome sequences should be the primary task for the remaining nineteen species. Low GC content and repeat DNA influences genome sequence assembly. CONCLUSION: The quality of plant genome sequences was found to be lower than envisaged and thus the rapid development of genome sequencing projects as well as research on bioinformatics tools and the algorithms of genome sequence assembly should provide increased processing and correction of genome sequences that have already been published. PMID- 23922844 TI - Background factors of reflux esophagitis and non-erosive reflux disease: a cross sectional study of 10,837 subjects in Japan. AB - BACKGROUND: Despite the high prevalence of gastroesophageal reflux disease (GERD), its risk factors are still a subject of controversy. This is probably due to inadequate distinction between reflux esophagitis (RE) and non-erosive reflux disease (NERD), and is also due to inadequate evaluation of adjacent stomach. Our aim is therefore to define background factors of RE and NERD independently, based on the evaluation of Helicobacter pylori infection and gastric atrophy. METHODS: We analyzed 10,837 healthy Japanese subjects (6,332 men and 4,505 women, aged 20 87 years) who underwent upper gastrointestinal endoscopy. RE was diagnosed as the presence of mucosal break, and NERD was diagnosed as the presence of heartburn and/or acid regurgitation in RE-free subjects. Using GERD-free subjects as control, background factors for RE and NERD were separately analyzed using logistic regression to evaluate standardized coefficients (SC), odds ratio (OR), and p-value. RESULTS: Of the 10,837 study subjects, we diagnosed 733 (6.8%) as RE and 1,722 (15.9%) as NERD. For RE, male gender (SC = 0.557, OR = 1.75), HP non infection (SC = 0.552, OR = 1.74), higher pepsinogen I/II ratio (SC = 0.496, OR = 1.64), higher BMI (SC = 0.464, OR = 1.60), alcohol drinking (SC = 0.161, OR = 1.17), older age (SC = 0.148, OR = 1.16), and smoking (SC = 0.129, OR = 1.14) are positively correlated factors. For NERD, HP infection (SC = 0.106, OR = 1.11), female gender (SC = 0.099, OR = 1.10), younger age (SC = 0.099, OR = 1.10), higher pepsinogen I/II ratio (SC = 0.099, OR = 1.10), smoking (SC = 0.080, OR = 1.08), higher BMI (SC = 0.078, OR = 1.08), and alcohol drinking (SC = 0.076, OR = 1.08) are positively correlated factors. Prevalence of RE in subjects with chronic HP infection and successful HP eradication denotes significant difference (2.3% and 8.8%; p<0.0001), whereas that of NERD shows no difference (18.2% and 20.8%; p = 0.064). CONCLUSIONS: Significantly associated factors of NERD are considerably different from those of RE, indicating that these two disorders are pathophysiologically distinct. Eradication of Helicobacter pylori may have disadvantageous effects on RE but not on NERD. PMID- 23922846 TI - Genetic and antigenic characterization of enterovirus 71 in Ho Chi Minh City, Vietnam, 2011. AB - Enterovirus 71 (EV71) frequently causes fatal infections in young children in Asia. In 2011, EV71 epidemics occurred in southern Vietnam. We conducted genetic and antigenic analysis of the EV71 isolates and found that 94% of them were genotype C4a related to two lineages circulating in China and 6% were genotype C5 which have circulated in Vietnam since 2003. Antigenic variants were not detected. EV71 vaccines are being developed. Longitudinal enterovirus surveillance data are critical to formulate vaccination policy in Vietnam. PMID- 23922845 TI - Identification and quantification of DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in human cells by liquid chromatography/isotope-dilution tandem mass spectrometry. AB - Unless repaired, DNA damage can drive mutagenesis or cell death. DNA repair proteins may therefore be used as biomarkers in disease etiology or therapeutic response prediction. Thus, the accurate determination of DNA repair protein expression and genotype is of fundamental importance. Among DNA repair proteins involved in base excision repair, apurinic/apyrimidinic endonuclease 1 (APE1) is the major endonuclease in mammals and plays important roles in transcriptional regulation and modulating stress responses. Here, we present a novel approach involving LC-MS/MS with isotope-dilution to positively identify and accurately quantify APE1 in human cells and mouse tissue. A completely (15)N-labeled full length human APE1 was produced and used as an internal standard. Fourteen tryptic peptides of both human APE1 (hAPE1) and (15)N-labeled hAPE1 were identified following trypsin digestion. These peptides matched the theoretical peptides expected from trypsin digestion and provided a statistically significant protein score that would unequivocally identify hAPE1. Using the developed methodology, APE1 was positively identified and quantified in nuclear and cytoplasmic extracts of multiple human cell lines and mouse liver using selected-reaction monitoring of typical mass transitions of the tryptic peptides. We also show that the methodology can be applied to the identification of hAPE1 variants found in the human population. The results describe a novel approach for the accurate measurement of wild-type and variant forms of hAPE1 in vivo, and ultimately for defining the role of this protein in disease development and treatment responses. PMID- 23922847 TI - Outer membrane permeabilization is an essential step in the killing of gram negative bacteria by the lectin RegIIIbeta. AB - The C-type lectin RegIIIbeta can kill certain Gram-positive and Gram-negative bacteria. The susceptibility of S. Typhimurium depends on the bacterial growth phase, i.e., bacteria from the logarithmic growth phase do bind RegIIIbeta and are subsequently killed. Lipid A is one of the bacterial targets for RegIIIbeta. However, at the molecular level, it is not understood how RegIIIbeta interacts with and kills Gram-negative bacteria. Here, we show that RegIIIbeta interacts with Gram-negative bacteria in two distinct steps. Initially, it binds to surface exposed lipid A. The lipid A can be shielded by the O-antigen of lipopolysaccharide (LPS), as indicated by the exquisite susceptibility of wbaP mutants to RegIIIbeta-mediated killing. Increased cell viability after incubation with an anti-lipid A antibody also supports this conclusion. This RegIIIbeta binding permeabilizes the outer membrane to hydrophobic dyes like Ethidium bromide or to bulky bacteriolytic enzymes like lysozyme. Conversely, compromising the outer membrane integrity by the mild detergent Triton X-100 enhances the antibacterial effect of RegIIIbeta. Based on our observations, we conclude that RegIIIbeta interacts with Gram-negative bacteria in two subsequent steps. Initially, it binds to the outer membrane thus leading to outer membrane permeabilization. This initial step is necessary for RegIIIbeta to reach a second, still not well understood target site (presumably localized in the periplasm or the cytoplasmic membrane), thereby triggering bacterial death. This provides novel insights into the outer membrane-step of the bactericidal mechanism of RegIIIbeta. PMID- 23922848 TI - Clinically relevant dimer interface mutants of STAT1 transcription factor exhibit differential gene expression. AB - A transition from a parallel to an antiparallel dimer configuration of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for interferon (IFN)-mediated signal transduction. However, the precise molecular mechanisms linking conformational changes to target gene activation by STAT1 are still largely unknown. In the present study, we have characterized, in more detail than before, two disease-associated point mutants with amino acid substitutions at both sites of the dimer interface (F172W and T385A). First, we confirmed that IFNgamma-stimulation of transfected cells led to enhanced tyrosine phosphorylation of mutant STAT1 as compared to the wild-type protein, which consequently resulted in its prolonged nuclear accumulation. Using an in vitro dephosphorylation assay, we demonstrated that, in contrast to wild type STAT1 and similar to the F172W mutant, also T385A resisted enzymatic inactivation by the nuclear phosphatase Tc45. Transcriptional activation of IFNgamma-driven endogenous target genes differed between wild-type and mutant STAT1. While expression of genes containing a single classical gamma-activated site (GAS), such as irf1, gpb1, and mig1, was virtually unaffected by the presence of either of two amino acid exchanges, induction of the cxcl10 and mcp1 gene was significantly enhanced. The latter two genes both contain an additional TTC/GAA binding motif separated by 10 bp from the palindromic GAS sequence. The transcriptional superiority of the mutants on these genes was reflected by their increased binding affinity to DNA fragments containing the identified "one-and-a half-GAS" motif. In summary, our data demonstrate that two clinically relevant interface mutants of STAT1 exhibit gene-specific effects and point to the rather complex role of the assumed conformational shift between two different dimer configurations for efficient transcriptional regulation. PMID- 23922849 TI - 3D texture analysis reveals imperceptible MRI textural alterations in the thalamus and putamen in progressive myoclonic epilepsy type 1, EPM1. AB - Progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessively inherited neurodegenerative disorder characterized by young onset age, myoclonus and tonic-clonic epileptic seizures. At the time of diagnosis, the visual assessment of the brain MRI is usually normal, with no major changes found later. Therefore, we utilized texture analysis (TA) to characterize and classify the underlying properties of the affected brain tissue by means of 3D texture features. Sixteen genetically verified patients with EPM1 and 16 healthy controls were included in the study. TA was performed upon 3D volumes of interest that were placed bilaterally in the thalamus, amygdala, hippocampus, caudate nucleus and putamen. Compared to the healthy controls, EPM1 patients had significant textural differences especially in the thalamus and right putamen. The most significantly differing texture features included parameters that measure the complexity and heterogeneity of the tissue, such as the co-occurrence matrix based entropy and angular second moment, and also the run-length matrix-based parameters of gray-level non-uniformity, short run emphasis and long run emphasis. This study demonstrates the usability of 3D TA for extracting additional information from MR images. Textural alterations which suggest complex, coarse and heterogeneous appearance were found bilaterally in the thalamus, supporting the previous literature on thalamic pathology in EPM1. The observed putamenal involvement is a novel finding. Our results encourage further studies on the clinical applications, feasibility, reproducibility and reliability of 3D TA. PMID- 23922850 TI - Optical spectral surveillance of breast tissue landscapes for detection of residual disease in breast tumor margins. AB - We demonstrate a strategy to "sense" the micro-morphology of a breast tumor margin over a wide field of view by creating quantitative hyperspectral maps of the tissue optical properties (absorption and scattering), where each voxel can be deconstructed to provide information on the underlying histology. Information about the underlying tissue histology is encoded in the quantitative spectral information (in the visible wavelength range), and residual carcinoma is detected as a shift in the histological landscape to one with less fat and higher glandular content. To demonstrate this strategy, fully intact, fresh lumpectomy specimens (n = 88) from 70 patients were imaged intra-operatively. The ability of spectral imaging to sense changes in histology over large imaging areas was determined using inter-patient mammographic breast density (MBD) variation in cancer-free tissues as a model system. We discovered that increased MBD was associated with higher baseline beta-carotene concentrations (p = 0.066) and higher scattering coefficients (p = 0.007) as measured by spectral imaging, and a trend toward decreased adipocyte size and increased adipocyte density as measured by histological examination in BMI-matched patients. The ability of spectral imaging to detect cancer intra-operatively was demonstrated when MBD-specific breast characteristics were considered. Specifically, the ratio of beta-carotene concentration to the light scattering coefficient can report on the relative amount of fat to glandular density at the tissue surface to determine positive margin status, when baseline differences in these parameters between patients with low and high MBD are taken into account by the appropriate selection of threshold values. When MBD was included as a variable a priori, the device was estimated to have a sensitivity of 74% and a specificity of 86% in detecting close or positive margins, regardless of tumor type. Superior performance was demonstrated in high MBD tissue, a population that typically has a higher percentage of involved margins. PMID- 23922851 TI - Analysis of the interaction interfaces of the N-terminal domain from Pseudomonas aeruginosa MutL. AB - Mismatch Repair System corrects mutations arising from DNA replication that escape from DNA polymerase proofreading activity. This system consists of three main proteins, MutS-L-H, responsible for lesion recognition and repair. MutL is a member of GHKL ATPase family and its ATPase cycle has been proposed to modulate MutL activity during the repair process. Pseudomonas aeruginosa MutL (PaMutL) contains an N-terminal (NTD) ATPase domain connected by a linker to a C-terminal (CTD) dimerization domain that possesses metal ion-dependent endonuclease activity. With the aim to identify characteristics that allow the PaMutL NTD allosteric control of CTD endonuclease activity, we used an in silico and experimental approach to determine the interaction surfaces of P. aeruginosa NTD (PaNTD), and compared it with the well characterized Escherichia coli MutL NTD (EcNTD). Molecular dynamics simulations of PaNTD and EcNTD bound to or free of adenosine nucleotides showed that a significant difference exists between the behavior of the EcNTD and PaNTD dimerization interface, particularly in the ATP lid. Structure based simulations of MutL homologues with endonuclease activity were performed that allowed an insight of the dimerization interface behavior in this family of proteins. Our experimental results show that, unlike EcNTD, PaNTD is dimeric in presence of ADP. Simulations in mixed solvent allowed us to identify the PaNTD putative DNA binding patch and a putative interaction patch located opposite to the dimerization face. Structure based simulations of PaNTD dimer in presence of ADP or ATP suggest that nucleotide binding could differentially modulate PaNTD protein-protein interactions. Far western assays performed in presence of ADP or ATP are in agreement with our in silico analysis. PMID- 23922852 TI - The Lewis histo-blood group system: molecular analysis of the 59T>G, 508G>A, and 1067T>A polymorphisms in an Amazonian population. AB - BACKGROUND: The Lewis (FUT3) gene is responsible for the expression of the Le(a) and Le(b) blood group antigens. The individuals, who not synthesize these antigens have the phenotype Lewis negative, due to the presence of some single nucleotide polymorphisms (SNPs), such as 59T>G, 508G>A and 1067T>A, whose distribution is different in various ethnic groups. Our aim was to verify the frequencies of these SNPs in an admixed population of Belem-Para-Brazil. MATERIALS AND METHODS: Polymerase chain reaction/restriction enzyme method were used to detect these SNPs in the FUT3 gene, whereas Lewis phenotypes were defined by the direct hemagglutination and in saliva by Dot-Elisa assay in a random sample of 150 individuals from admixed population of Belem in the northeast Brazilian Amazon region. RESULTS: The frequency of these SNPs was detected as 47.6% (59T>G), 17.3% (508G>A) and 5.3% (1067T>A).The discrepancies between blood and salivary Lewis phenotypes are related to the relatively high frequencies of 59T>G and the null allele 508G>A. Whereas 38.6% of the individuals were Lewis negative based on blood, only 17.24% also tested negative when their saliva were analyzed. CONCLUSION: We have found a marked consistency between the phenotypes and genotypes of the Lewis blood group system. Furthermore, our obtained FST values reveal distinct frequencies of the FUT3 SNPs between the present sample and its representative ancestral populations. These observations will help to evaluate the Lewis antigens impact as susceptibility markers, in genetic association studies to certain diseases. PMID- 23922853 TI - AMPK-regulated and Akt-dependent enhancement of glucose uptake is essential in ischemic preconditioning-alleviated reperfusion injury. AB - AIMS: Ischemic preconditioning (IPC) is a potent form of endogenous protection. However, IPC-induced cardioprotective effect is significantly blunted in insulin resistance-related diseases and the underlying mechanism is unclear. This study aimed to determine the role of glucose metabolism in IPC-reduced reperfusion injury. METHODS: Normal or streptozotocin (STZ)-treated diabetic rats subjected to 2 cycles of 5 min ischemia/5 min reperfusion prior to myocardial ischemia (30 min)/reperfusion (3 h). Myocardial glucose uptake was determined by (18)F fluorodeoxyglucose-positron emission tomography (PET) scan and gamma-counter biodistribution assay. RESULTS: IPC exerted significant cardioprotection and markedly improved myocardial glucose uptake 1 h after reperfusion (P<0.01) as evidenced by PET images and gamma-counter biodistribution assay in ischemia/reperfused rats. Meanwhile, myocardial translocation of glucose transporter 4 (GLUT4) to plasma membrane together with myocardial Akt and AMPK phosphorylation were significantly enhanced in preconditioned hearts. Intramyocardial injection of GLUT4 siRNA markedly decreased GLUT4 expression and blocked the cardioprotection of IPC as evidence by increased myocardial infarct size. Moreover, the PI3K inhibitor wortmannin significantly inhibited activation of Akt and AMPK, reduced GLUT4 translocation, glucose uptake and ultimately, depressed IPC-induced cardioprotection. Furthermore, IPC-afforded antiapoptotic effect was markedly blunted in STZ-treated diabetic rats. Exogenous insulin supplementation significantly improved glucose uptake via co-activation of myocardial AMPK and Akt and alleviated ischemia/reperfusion injury as evidenced by reduced myocardial apoptosis and infarction size in STZ-treated rats (P<0.05). CONCLUSIONS: The present study firstly examined the role of myocardial glucose metabolism during reperfusion in IPC using direct genetic modulation in vivo. Augmented glucose uptake via co-activation of myocardial AMPK and Akt in reperfused myocardium is essential to IPC-alleviated reperfusion injury. This intrinsic metabolic modulation and cardioprotective capacity are present in STZ treated hearts and can be triggered by insulin. PMID- 23922854 TI - The natural pesticide dihydrorotenone induces human plasma cell apoptosis by triggering endoplasmic reticulum stress and activating p38 signaling pathway. AB - Dihydrorotenone (DHR) is a natural pesticide widely used in farming industry, such as organic produces. DHR is a potent mitochondrial inhibitor and probably induces Parkinsonian syndrome, however, it is not known whether DHR is toxic to other systems. In the present study, we evaluated the cytotoxicity of DHR on human plasma cells. As predicted, DHR impaired mitochondrial function by decreasing mitochondrial membrane potential in plasma cells. Because mito dysfunction leads to unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, we examined the signature proteins in ER stress, including GRP78, ATF4, and CHOP. After DHR treatment, these proteins were significantly upregulated. It is reported that activation of the mitogen-activated protein kinases p38 and JNK are involved in endoplasmic reticulum stress. However, in the subsequent study, DHR was found to activate p38 but not the JNK signaling. When pre-treated with p38 inhibitor SB203580, activation of p38 and cell apoptosis induced by DHR was partially blocked. Thus, we found that DHR induced human plasma cell death by activating the p38 but not the JNK signaling pathway. Because plasma cells are very important in the immune system, this study provided a new insight in the safety evaluation of DHR application. PMID- 23922855 TI - Suppression of cytochrome p450 reductase enhances long-term hematopoietic stem cell repopulation efficiency in mice. AB - BACKGROUND: Bone marrow microenvironment (niche) plays essential roles in the fate of hematopoietic stem cells (HSCs). Intracellular and extracellular redox metabolic microenvironment is one of the critical factors for the maintenance of the niche. Cytochrome P450 reductase (CPR) is an obligate electron donor to all microsomal cytochrome P450 enzymes (P450 or CYP), and contributes to the redox metabolic process. However, its role in maintaining HSCs is unknown. OBJECTIVE: To examine the effects of low CPR expression on HSCs function using a mouse model of globally suppressed Cpr gene expression (Cpr Low, CL mice). METHODS: Hematopoietic cell subpopulations in bone marrow (BM) and peripheral blood (PB) from WT and CL mice were examined for their repopulation and differentiation ability upon BM competitive transplantation and enriched HSC (LKS(+)) transplantation. Effects of low CPR expression on hematopoiesis were examined by transplanting normal BM cells into CL recipients. Reactive oxygen species (ROS), cell cycle, and apoptosis in CL mice were analyzed by flow cytometry for DCF-DA fluorescence intensity, Ki67 protein, and Annexin-V, respectively. RESULTS: The levels of ROS in BM cells, HPCs and HSCs were comparable between CL and WT mice. In comparison to WT mice, the number of LT-HSCs or ST-HSCs was lower in CL mice while CMPs, GMPs and MEPs in CL mice were higher than that in WT control. Competitive transplantation assay revealed enhanced repopulation capacity of HSCs with low CPR expression, but no difference in differentiation potential upon in vitro experiments. Furthermore, lymphoid differentiation of donor cells decreased while their myeloid differentiation increased under CL microenvironment although the overall level of donor hematopoietic repopulation was not significantly altered. CONCLUSIONS: Our studies demonstrate that suppressing CPR expression enhances the repopulation efficiency of HSCs and a low CPR expression microenvironment favors the differentiation of myeloid over lymphoid lineage cells. PMID- 23922856 TI - Passive smoking and risk of type 2 diabetes: a meta-analysis of prospective cohort studies. AB - BACKGROUNDS/OBJECTIVE: The prevalence of diabetes is increasing rapidly all over the world. However, studies on passive smoking and type 2 diabetes have not been systematically assessed. Therefore, we conducted a meta-analysis to explore whether an association exists between passive smoking and risk of type 2 diabetes. METHODS: We searched PubMed, EMBASE, Cochrane library and Web of Science up to April 9(th), 2013, to identify prospective cohort studies that assessed passive smoking and risk of type 2 diabetes. The fixed-effect model was used to calculate the overall relative risk (RR). RESULT: 4 prospective cohort studies were included for analysis, with a total of 112,351 participants involved. The pooled RR was 1.28 (95% confidence interval (CI) 1.14 to 1.44) comparing those who were exposed to passive smoking with those who were not. Subgroup, sensitivity analysis and publication bias test suggested the overall result of this analysis was robust. CONCLUSIONS: Passive smoking is associated with a significantly increased risk of type 2 diabetes. Further well-designed studies are warranted to confirm this association. PMID- 23922857 TI - Early and later life stress alter brain activity and sleep in rats. AB - Exposure to early life stress may profoundly influence the developing brain in lasting ways. Neuropsychiatric disorders associated with early life adversity may involve neural changes reflected in EEG power as a measure of brain activity and disturbed sleep. The main aim of the present study was for the first time to characterize possible changes in adult EEG power after postnatal maternal separation in rats. Furthermore, in the same animals, we investigated how EEG power and sleep architecture were affected after exposure to a chronic mild stress protocol. During postnatal day 2-14 male rats were exposed to either long maternal separation (180 min) or brief maternal separation (10 min). Long maternally separated offspring showed a sleep-wake nonspecific reduction in adult EEG power at the frontal EEG derivation compared to the brief maternally separated group. The quality of slow wave sleep differed as the long maternally separated group showed lower delta power in the frontal-frontal EEG and a slower reduction of the sleep pressure. Exposure to chronic mild stress led to a lower EEG power in both groups. Chronic exposure to mild stressors affected sleep differently in the two groups of maternal separation. Long maternally separated offspring showed more total sleep time, more episodes of rapid eye movement sleep and higher percentage of non-rapid eye movement episodes ending in rapid eye movement sleep compared to brief maternal separation. Chronic stress affected similarly other sleep parameters and flattened the sleep homeostasis curves in all offspring. The results confirm that early environmental conditions modulate the brain functioning in a long-lasting way. PMID- 23922858 TI - Semen abnormalities, sperm DNA damage and global hypermethylation in health workers occupationally exposed to ionizing radiation. AB - BACKGROUND: Cytogenetic studies have demonstrated that low levels of chronic radiation exposure can potentially increase the frequency of chromosomal aberrations and aneuploidy in somatic cells. Epidemiological studies have shown that health workers occupationally exposed to ionizing radiation bear an increased risk of hematological malignancies. OBJECTIVES: To find the influence of occupational radiation exposure on semen characteristics, including genetic and epigenetic integrity of spermatozoa in a chronically exposed population. METHODS: This cross sectional study included 134 male volunteers of which 83 were occupationally exposed to ionizing radiation and 51 were non-exposed control subjects. Semen characteristics, sperm DNA fragmentation, aneuploidy and incidence of global hypermethylation in the spermatozoa were determined and compared between the non-exposed and the exposed group. RESULTS: Direct comparison of the semen characteristics between the non-exposed and the exposed population revealed significant differences in motility characteristics, viability, and morphological abnormalities (P<0.05-0.0001). Although, the level of sperm DNA fragmentation was significantly higher in the exposed group as compared to the non-exposed group (P<0.05-0.0001), the incidence of sperm aneuploidy was not statistically different between the two groups. However, a significant number of hypermethylated spermatozoa were observed in the exposed group in comparison to non-exposed group (P<0.05). CONCLUSIONS: We provide the first evidence on the detrimental effects of occupational radiation exposure on functional, genetic and epigenetic integrity of sperm in health workers. However, further studies are required to confirm the potential detrimental effects of ionizing radiation in these subjects. PMID- 23922859 TI - Reappraisal of the therapeutic role of celecoxib in cholangiocarcinoma. AB - Cholangiocarcinoma (CCA), a lethal disease, affects many thousands worldwide yearly. Surgical resection provides the best chance for a cure; however, only one third of CCA patients present with a resectable tumour at the time of diagnosis. Currently, no effective chemotherapy is available for advanced CCA. Cyclooxygenase-2 (COX-2) is a potential oncogene expressing in human CCA tissues and represents a candidate target for treatment; however, COX-2 inhibitors increase the risk of negative cardiovascular events as application for chemoprevention aim. Here, we re-evaluated the effectiveness and safety of celecoxib, one widely used COX-2 inhibitor, in treating CCA. We demonstrated that celecoxib exhibited an anti-proliferative effect on CGCCA cells via cell cycle arrest at G2 phase and apoptosis induction. Treatment for 5 weeks high dose celecoxib (160 mg/kg) significantly repressed thioacetamide-induced CCA tumour growth in rats as monitored by animal positron emission tomography through apoptosis induction. No obviously observable side effects were noted during the therapeutic period. As retrospectively reviewing 78 intrahepatic mass-forming CCA patients, their survival was strongly and negatively associated with a positive resection margin and high COX-2 expression. Based on our result, we concluded that short-term high dose celecoxib may be a promising therapeutic regimen for CCA. Yet its clinical application still needs more studies to prove its safety. PMID- 23922860 TI - A re-analysis of the Cochrane Library data: the dangers of unobserved heterogeneity in meta-analyses. AB - BACKGROUND: Heterogeneity has a key role in meta-analysis methods and can greatly affect conclusions. However, true levels of heterogeneity are unknown and often researchers assume homogeneity. We aim to: a) investigate the prevalence of unobserved heterogeneity and the validity of the assumption of homogeneity; b) assess the performance of various meta-analysis methods; c) apply the findings to published meta-analyses. METHODS AND FINDINGS: We accessed 57,397 meta-analyses, available in the Cochrane Library in August 2012. Using simulated data we assessed the performance of various meta-analysis methods in different scenarios. The prevalence of a zero heterogeneity estimate in the simulated scenarios was compared with that in the Cochrane data, to estimate the degree of unobserved heterogeneity in the latter. We re-analysed all meta-analyses using all methods and assessed the sensitivity of the statistical conclusions. Levels of unobserved heterogeneity in the Cochrane data appeared to be high, especially for small meta analyses. A bootstrapped version of the DerSimonian-Laird approach performed best in both detecting heterogeneity and in returning more accurate overall effect estimates. Re-analysing all meta-analyses with this new method we found that in cases where heterogeneity had originally been detected but ignored, 17-20% of the statistical conclusions changed. Rates were much lower where the original analysis did not detect heterogeneity or took it into account, between 1% and 3%. CONCLUSIONS: When evidence for heterogeneity is lacking, standard practice is to assume homogeneity and apply a simpler fixed-effect meta-analysis. We find that assuming homogeneity often results in a misleading analysis, since heterogeneity is very likely present but undetected. Our new method represents a small improvement but the problem largely remains, especially for very small meta analyses. One solution is to test the sensitivity of the meta-analysis conclusions to assumed moderate and large degrees of heterogeneity. Equally, whenever heterogeneity is detected, it should not be ignored. PMID- 23922861 TI - Role of minor groove width and hydration pattern on amsacrine interaction with DNA. AB - Amsacrine is an anilinoacridine derivative anticancer drug, used to treat a wide variety of malignancies. In cells, amsacrine poisons topoisomerase 2 by stabilizing DNA-drug-enzyme ternary complex. Presence of amsacrine increases the steady-state concentration of these ternary complexes which in turn hampers DNA replication and results in subsequent cell death. Due to reversible binding and rapid slip-out of amsacrine from DNA duplex, structural data is not available on amsacrine-DNA complexes. In the present work, we designed five oligonucleotide duplexes, differing in their minor groove widths and hydration pattern, and examined their binding with amsacrine using attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. Complexes of amsacrine with calf thymus DNA were also evaluated for a comparison. Our results demonstrate for the first time that amsacrine is not a simple intercalator; rather mixed type of DNA binding (intercalation and minor groove) takes place between amsacrine and DNA. Further, this binding is highly sensitive towards the geometries and hydration patterns of different minor grooves present in the DNA. This study shows that ligand binding to DNA could be very sensitive to DNA base composition and DNA groove structures. Results demonstrated here could have implication for understanding cytotoxic mechanism of aminoacridine based anticancer drugs and provide directions to modify these drugs for better efficacy and few side effects. PMID- 23922862 TI - Maternal deprivation enhances behavioral vulnerability to stress associated with miR-504 expression in nucleus accumbens of rats. AB - OBJECTIVE: In this study, the effect of maternal deprivation (MD) and chronic unpredictable stress (CUS) in inducing depressive behaviors and associated molecular mechanism were investigated in rats. METHODS: Maternal deprivation was established by separating pups from their mothers for 6 hours daily from postnatal day 1 to day 14. Chronic unpredictable stress was established by water deprivation, elevated open platform, food deprivation, restraint stress and electric foot shock. The depressive behaviors were determined by use of sucrose preference test and forced swim test. RESULTS: Rats in MD/CUS group exhibited lower sucrose preference rate, longer immobility time, and lighter body weights than rats in other groups (MD/control, non-MD/CUS and non-MD/control group). Meanwhile, higher miR-504 expression and lower dopamine receptor D1 (DRD1) and D2 (DRD2) expression were observed in the nucleus accumbens of rats in the MD/CUS group than in the other three groups. MiR-504 expression correlated negatively with DRD1 gene expression and sucrose preference rate in the sucrose preference test, but correlated positively with immobility time in forced swim test. Both DRD2 mRNA and protein expression correlated negatively with immobility time in forced swim test. CONCLUSION: These results suggest that MD enhances behavioral vulnerability to stress during adulthood, which is associated with the upregulation of miR-504 and downregulation of DRD2 expression in the nucleus accumbens. PMID- 23922863 TI - Drawing to remember: external support of older adults' eyewitness performance. AB - Although healthy aging is accompanied by a general decline in memory functioning, environmental support at retrieval can improve older adults' (+65 years) episodic remembering. Despite those over the age of 65 years representing a growing proportion of the population, few environmental retrieval support methods have been empirically evaluated for use with older witnesses and victims of crime. Here, the efficacy of a novel retrieval technique, the Sketch Mental Reinstatement of Context, is compared with a standard Mental Reinstatement of Context and a no support control (Control). Fifty-one participants witnessed an unexpected live event, and 48 hours later were interviewed using one of three aforementioned techniques. In line with predictions emanating from cognitive theories of aging and the environmental support hypothesis, participants in the Sketch Mental Reinstatement of Context condition recalled significantly more correct information and fewer inaccurate items. The Sketch Mental Reinstatement of Context technique appears to scaffold memory retrieval in an age-appropriate manner during a post-event interview, possibly by encouraging more effortful retrieval and reducing dual-task load. As such, this procedure offers an effective alternative to current approaches, adding to the toolbox of techniques available to forensic and other interviewers. PMID- 23922864 TI - Intracellular adhesion molecule-1 K469E gene polymorphism and risk of diabetic microvascular complications: a meta-analysis. AB - BACKGROUND: A number of studies evaluated the association of intracellular adhesion molecule-1 (ICAM-1) K469E (rs5498, A/G) gene polymorphism with diabetic microvascular complications (DMI) including diabetic nephropathy (DN) and diabetic retinopathy (DR) in different populations. However, the results of individual studies remain conflicting. METHODS: A comprehensive search was conducted to identify all eligible studies of the above-mentioned associations. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were assessed using the fixed or random effect model. RESULTS: Seven studies involving 3411 subjects were included. Overall, the meta-analysis showed a significant association of the A allele with increased risk of DMI susceptibility in a recessive model (OR = 1.37, 95% CI 1.04-1.80, P = 0.02). In the subgroup analysis stratified by ethnicity, significant association was found in Asians but not in Caucasians (OR = 1.78, 95% CI 1.13-2.81, P = 0.01; OR = 1.10, 95% CI 0.79-1.54, P = 0.58, respectively). Moreover, it showed a significant association between the A allele and risk of DN in a recessive model (OR = 1.25, 95% CI 1.02-1.55, P = 0.04). CONCLUSIONS: This meta-analysis suggested that the K469E polymorphism in ICAM-1 gene might affect individual susceptibility to DMI and showed a discrepancy in different ethnicities. Further investigations are needed to validate the association. PMID- 23922865 TI - Connectivity, not frequency, determines the fate of a morpheme. AB - Morphemes are the smallest meaningful parts of words and therefore represent a natural unit to study the evolution of words. To analyze the influence of language change on morphemes, we performed a large scale analysis of German and English vocabulary covering the last 200 years. Using a network approach from bioinformatics, we examined the historical dynamics of morphemes, the fixation of new morphemes and the emergence of words containing existing morphemes. We found that these processes are driven mainly by the number of different direct neighbors of a morpheme in words (connectivity, an equivalent to family size or type frequency) and not its frequency of usage (equivalent to token frequency). This contrasts words, whose survival is determined by their frequency of usage. We therefore identified features of morphemes which are not dictated by the statistical properties of words. As morphemes are also relevant for the mental representation of words, this result might enable establishing a link between an individual's perception of language and historical language change. PMID- 23922866 TI - Evaluation of bladder diary parameters based on correlation with the volume at strong desire to void in filling cystometry. AB - Accurate assessment of patient bladder capacity is important in determining the proper initial treatment for lower urinary tract dysfunctions and as well as for monitoring therapeutic outcomes. However, urodynamic study is an invasive procedure. Thus, it is important to find a surrogate for invasive urodynamic study, and the aim of this study is to identify the parameter from patient recorded bladder diary that is best correlated to the volume at strong desire to void (VSD) derived from urodynamic studies. A total of 900 women who underwent urodynamic studies at a university hospital between January 2009 and December 2011. Correlation between bladder diary parameters and VSD was investigated by Spearman rank-correlation coefficient. Days 1 to 3 average maximum daytime voided volumes excluding the first morning void (DVVmaxavg) (mean 263 ml) had the highest correlation with VSD (mean 261 ml; rho = 0.51, p<0.001). The predictive value of VSD was 146+0.44 * DVVmaxavg. The days 1, 2, and 3 daytime maximum voided volumes excluding the first morning void (DVVmax) were all significantly associated with VSD and had similar mean volumes (rho = 0.43-0.46, all p<0.001). DVVmaxavg had the highest area under the receiver operating characteristic curve (0.75; 95% confidence interval = 0.72-0.78) for predicting bladder oversensitivity. The threshold of DVVmaxavg <250 ml had good predictive value for detecting bladder oversensitivity (sensitivity 70.9%; specificity 65.8%), and day 1 DVVmax <250 ml had similar sensitivity (70.6%) and specificity (59.1%). Besides, the correlation coefficients (rho) between day 1, day 2 and day 3 DVVmax and DVVmaxavg were good with a range of 0.70-0.89. In conclusion, DVVmaxavg was the bladder diary parameter best correlated with VSD. DVVmaxavg and day 1 DVVmax may be useful in screening for bladder oversensitivity. PMID- 23922867 TI - Tryptase activation of immortalized human urothelial cell mitogen-activated protein kinase. AB - The pathogenesis of interstitial cystitis/painful bladder syndrome (IC/PBS) is multifactorial, but likely involves urothelial cell dysfunction and mast cell accumulation in the bladder wall. Activated mast cells in the bladder wall release several inflammatory mediators, including histamine and tryptase. We determined whether mitogen-activated protein (MAP) kinases are activated in response to tryptase stimulation of urothelial cells derived from human normal and IC/PBS bladders. Tryptase stimulation of normal urothelial cells resulted in a 2.5-fold increase in extracellular signal regulated kinase 1/2 (ERK 1/2). A 5.5 fold increase in ERK 1/2 activity was observed in urothelial cells isolated from IC/PBS bladders. No significant change in p38 MAP kinase was observed in tryptase stimulated normal urothelial cells but a 2.5-fold increase was observed in cells isolated from IC/PBS bladders. Inhibition of ERK 1/2 with PD98059 or inhibition of p38 MAP kinase with SB203580 did not block tryptase-stimulated iPLA2 activation. Incubation with the membrane phospholipid-derived PLA2 hydrolysis product lysoplasmenylcholine increased ERK 1/2 activity, suggesting the iPLA2 activation is upstream of ERK 1/2. Real time measurements of impedance to evaluate wound healing of cell cultures indicated increased healing rates in normal and IC/PBS urothelial cells in the presence of tryptase, with inhibition of ERK 1/2 significantly decreasing the wound healing rate of IC/PBS urothelium. We conclude that activation of ERK 1/2 in response to tryptase stimulation may facilitate wound healing or cell motility in areas of inflammation in the bladder associated with IC/PBS. PMID- 23922868 TI - Effects of sildenafil on the gastrocnemius and cardiac muscles of rats in a model of prolonged moderate exercise training. AB - Moderate exercise training improves energetic metabolism, tissue perfusion and induces cardiac and skeletal muscle remodeling. Sildenafil, a potent phosphodiesterase-5 inhibitor used to treat erectile dysfunction, reduces infarct size and increases tissue oxygenation in experimental models of cardiovascular disease. We have evaluated the effects of prolonged moderate exercise training and a repeat administration of sildenafil on the rat gastrocnemius and cardiac muscles. Animals were divided into two groups: sedentary and trained. Each group was subdivided into animals treated with vehicle or with two doses of sildenafil (10 or 15 mg/kg/day) during the last week of training. Physical exercise did not induce cardiac hypertrophy, whereas it increased mRNA levels of the PGC-1alpha, HIF-1alpha and VEGF genes, which are involved in mitochondrial biogenesis and angiogenesis, and reduced mRNA levels of FoxO3a, MuRF-1 and Atrogin-1. Sildenafil dose-dependently promoted both angiogenesis, as shown by increased capillary density, and muscle atrophy, as shown by muscle fibre size. These effects were more pronounced in trained animals. Our data confirm the beneficial effects of a moderate and prolonged training on cardiovascular and skeletal systems and document the positive and negative effects of sildenafil on these tissues at doses higher than those used in clinical practice. This report may impact on the use of sildenafil as a substance able to influence sports performance. PMID- 23922870 TI - Trade-based estimation of bluefin tuna catches in the Eastern Atlantic and Mediterranean, 2005-2011. AB - The Eastern Atlantic and Mediterranean stock of Bluefin tuna Thunnus thynnus (BFTE) has long been considered overfished and at risk of collapse. Although ICCAT quotas for this stock have decreased considerably over the past years, uncertainty exists about the degree of catch beyond this quota. The extent of such catch is an important piece of information in stock assessment models as well as being an indicator of the effectiveness of fisheries management. We present a model using Bluefin tuna trade data to infer actual catches. Basing our calculations on 25 countries involved in BFTE trade, we estimate that between 2005 and 2011, allowable quotas were exceeded by 44 percent. This gap between catch and quotas has slightly increased over past years, leading to estimated excess catches of 57 percent for the period between 2008 and 2011. To improve assessments, preparation and design of BFTE management, we suggest that the estimated total removals reported in this paper be included in stock assessment models for BFTE. An implication of our findings is that ICCAT member states should take stronger measures to monitor and enforce compliance with quotas. PMID- 23922869 TI - Adaptive and specialised transcriptional responses to xenobiotic stress in Caenorhabditis elegans are regulated by nuclear hormone receptors. AB - Characterisation of the pathways by which xenobiotics are metabolised and excreted in both target and non-target organisms is crucial for the rational design of effective and specific novel bioactive molecules. Consequently, we have investigated the induced responses of the model nematode Caenorhabditis elegans to a variety of xenobiotics which represent a range of putative modes of action. The majority of genes that were specifically induced in preliminary microarray analyses encoded enzymes from Phase I and II metabolism, including cytochrome P450s, short chain dehydrogenases, UDP-glucuronosyl transferases and glutathione transferases. Changes in gene expression were confirmed by quantitative PCR and GFP induction in reporter strains driven by promoters for transcription of twelve induced enzymes was investigated. The particular complement of metabolic genes induced was found to be highly contingent on the xenobiotic applied. The known regulators of responses to applied chemicals ahr-1, hif-1, mdt-15 and nhr-8 were not required for any of these inducible responses and skn-1 regulated GFP expression from only two of the promoters. Reporter strains were used in conjunction with systematic RNAi screens to identify transcription factors which drive expression of these genes under xenobiotic exposure. These transcription factors appeared to regulate specific xenobiotic responses and have no reported phenotypes under standard conditions. Focussing on nhr-176 we demonstrate the role of this transcription factor in mediating the resistance to thiabendazole. PMID- 23922871 TI - Enhanced growth of endothelial precursor cells on PCG-matrix facilitates accelerated, fibrosis-free, wound healing: a diabetic mouse model. AB - Diabetes mellitus (DM)-induced endothelial progenitor cell (EPC) dysfunction causes impaired wound healing, which can be rescued by delivery of large numbers of 'normal' EPCs onto such wounds. The principal challenges herein are (a) the high number of EPCs required and (b) their sustained delivery onto the wounds. Most of the currently available scaffolds either serve as passive devices for cellular delivery or allow adherence and proliferation, but not both. This clearly indicates that matrices possessing both attributes are 'the need of the day' for efficient healing of diabetic wounds. Therefore, we developed a system that not only allows selective enrichment and expansion of EPCs, but also efficiently delivers them onto the wounds. Murine bone marrow-derived mononuclear cells (MNCs) were seeded onto a PolyCaprolactone-Gelatin (PCG) nano-fiber matrix that offers a combined advantage of strength, biocompatibility wettability; and cultured them in EGM2 to allow EPC growth. The efficacy of the PCG matrix in supporting the EPC growth and delivery was assessed by various in vitro parameters. Its efficacy in diabetic wound healing was assessed by a topical application of the PCG-EPCs onto diabetic wounds. The PCG matrix promoted a high level attachment of EPCs and enhanced their growth, colony formation, and proliferation without compromising their viability as compared to Poly L-lactic acid (PLLA) and Vitronectin (VN), the matrix and non-matrix controls respectively. The PCG-matrix also allowed a sustained chemotactic migration of EPCs in vitro. The matrix-effected sustained delivery of EPCs onto the diabetic wounds resulted in an enhanced fibrosis-free wound healing as compared to the controls. Our data, thus, highlight the novel therapeutic potential of PCG-EPCs as a combined 'growth and delivery system' to achieve an accelerated fibrosis free healing of dermal lesions, including diabetic wounds. PMID- 23922872 TI - Emersion induces nitrogen release and alteration of nitrogen metabolism in the intertidal genus Porphyra. AB - We investigated emersion-induced nitrogen (N) release from Porphyra umbilicalis Kutz. Thallus N concentration decreased during 4 h of emersion. Tissue N and soluble protein contents of P. umbilicalis were positively correlated and decreased during emersion. Growth of P. umbilicalis did not simply dilute the pre emersion tissue N concentration. Rather, N was lost from tissues during emersion. We hypothesize that emersion-induced N release occurs when proteins are catabolized. While the delta(15)N value of tissues exposed to emersion was higher than that of continuously submerged tissues, further discrimination of stable N isotopes did not occur during the 4 h emersion. We conclude that N release from Porphyra during emersion did not result from bacterial denitrification, but possibly as a consequence of photorespiration. The release of N by P. umbilicalis into the environment during emersion suggests a novel role of intertidal seaweeds in the global N cycle. Emersion also altered the physiological function (nitrate uptake, nitrate reductase and glutamine synthetase activity, growth rate) of P. umbilicalis and the co-occurring upper intertidal species P. linearis Grev., though in a seasonally influenced manner. Individuals of the year round perennial species P. umbilicalis were more tolerant of emersion than ephemeral, cold temperate P. linearis in early winter. However, the mid-winter populations of both P. linearis and P. umbilicalis, had similar temporal physiological patterns during emersion. PMID- 23922873 TI - Recursive N-way partial least squares for brain-computer interface. AB - In the article tensor-input/tensor-output blockwise Recursive N-way Partial Least Squares (RNPLS) regression is considered. It combines the multi-way tensors decomposition with a consecutive calculation scheme and allows blockwise treatment of tensor data arrays with huge dimensions, as well as the adaptive modeling of time-dependent processes with tensor variables. In the article the numerical study of the algorithm is undertaken. The RNPLS algorithm demonstrates fast and stable convergence of regression coefficients. Applied to Brain Computer Interface system calibration, the algorithm provides an efficient adjustment of the decoding model. Combining the online adaptation with easy interpretation of results, the method can be effectively applied in a variety of multi-modal neural activity flow modeling tasks. PMID- 23922874 TI - Nicotinamide phosphoribosyl transferase (Nampt) is a target of microRNA-26b in colorectal cancer cells. AB - A number of cancers show increased expression of Nicotinamide phosphoribosyl transferase (Nampt). However, the mechanism through which Nampt is upregulated is unclear. In our study, we found that the Nampt-specific chemical inhibitor FK866 significantly inhibited cell survival and reduced nicotinamide adenine dinucleotide (NAD) levels in LoVo and SW480 cell lines. Bioinformatics analyses suggested that miR-26b targets Nampt mRNA. We identified Nampt as a new target of miR-26b and demonstrated that miR-26b inhibits Nampt expression at the protein and mRNA levels by binding to the Nampt 3'-UTR. Moreover, we found that miR-26b was down regulated in cancer tissues relative to that in adjacent normal tissues in 18 colorectal cancer patients. A statistically significant inverse correlation between miR-26b and Nampt expression was observed in samples from colorectal cancer patients and in 5 colorectal cell lines (HT-29, SW480, SW1116, LoVo, and HCT116). In addition, over expression of miR-26b strongly inhibited LoVo cell survival and invasion, an effect partially abrogated by the addition of NAD. In conclusion, this study demonstrated that the NAD-salvaging biosynthesis pathway involving Nampt might play a role in colorectal cancer cell survival. MiR-26b may serve as a tumor suppressor by targeting Nampt. PMID- 23922876 TI - Notch1 signaling regulates the proliferation and self-renewal of human dental follicle cells by modulating the G1/S phase transition and telomerase activity. AB - Multipotent human dental follicle cells (HDFCs) have been intensively studied in periodontal regeneration research, yet the role of Notch1 in HDFCs has not been fully understood. The aim of the current study is to explore the role of Notch1 signaling in HDFCs self-renewal and proliferation. HDFCs were obtained from the extracted wisdom teeth from adolescent patients. Regulation of Notch1 signaling in the HDFCs was achieved by overexpressing the exogenous intracellular domain of Notch1 (ICN1) or silencing Notch1 by shRNA. The regulatory effects of Notch1 on HDFC proliferation, cell cycle distribution and the expression of cell cycle regulators were investigated through various molecular technologies, including plasmid construction, retrovirus preparation and infection, qRT-PCR, western blot, RBP-Jk luciferase reporter and cell proliferation assay. Our data clearly show that constitutively activation of Notch1 stimulates the HDFCs proliferation while inhibition of the Notch1 suppresses their proliferation in vitro. In addition, the HDFCs proliferation is associated with the increased expression of cell cycle regulators, e.g. cyclin D1, cyclin D2, cyclin D3, cyclin E1, CDK2, CDK4, CDK6, and SKP2 and the decreased expression of p27 (kip1). Moreover, our data show that the G1/S phase transition (indicating proliferation) and telomerase activity (indicating self-renewal) can be enhanced by overexpression of ICN1 but halted by inhibition of Notch1. Together, the current study provides evidence for the first time that Notch1 signaling regulates the proliferation and self-renewal capacity of HDFCs through modulation of the G1/S phase transition and the telomerase activity. PMID- 23922877 TI - The formation of the patterns of desert shrub communities on the Western Ordos Plateau, China: the roles of seed dispersal and sand burial. AB - The western Ordos Plateau is a key area of shrub diversity and a National Nature Reserve of endangered shrub species in north-west China. Desert expansion is becoming the most important threat to these endangered species. However, little is known about the effects of sand burial on the dynamics of the shrub community. This study aims to investigate how the shrubs as a community and as different individual shrubs respond to the disturbances caused by the desert expansion. The approach used by this study is to separate the seed-dispersal strategy from the sand-burial forces that are involved in structuring the shrub communities at different disturbance stages. Four communities for different disturbance stages were surveyed by using 50*50 m plots. The individual shrubs were classified into coloniser and successor groups at the seed-dispersal stage and strong and weak sand-burial tolerance groups at the sand-expansion stage. We employed spatial point pattern analysis with null models for each community to examine the seed dispersal strategy and sand-burial forces affecting community distribution patterns. At the seed-dispersal stage, the interactions between the colonisers and the successors showed significant positive correlation at a scale of 0-1 m and significant negative correlation at a scale of 2 m; significant negative correlations between the groups with strong and weak sand-burial tolerance in the early stage of sand expansion at scales of 3-6 m, and significant positive correlation in the later stage of sand expansion at a scale of 13 m, were found. Seed-dispersal strategy is a reasonable mechanism to explain the shrub community pattern formation in the earlier stages, whereas sand burial is the primary reason for the disappearance of shrubs with weak sand-burial tolerance, this irreversible disturbance causes homogenisation of the community structure and produces aging populations of shrub species. This has an important influence on the succession direction of desert shrub communities. PMID- 23922875 TI - SAHA enhances synaptic function and plasticity in vitro but has limited brain availability in vivo and does not impact cognition. AB - Suberoylanilide hydroxamic acid (SAHA) is an inhibitor of histone deacetylases (HDACs) used for the treatment of cutaneous T cell lymphoma (CTCL) and under consideration for other indications. In vivo studies suggest reducing HDAC function can enhance synaptic function and memory, raising the possibility that SAHA treatment could have neurological benefits. We first examined the impacts of SAHA on synaptic function in vitro using rat organotypic hippocampal brain slices. Following several days of SAHA treatment, basal excitatory but not inhibitory synaptic function was enhanced. Presynaptic release probability and intrinsic neuronal excitability were unaffected suggesting SAHA treatment selectively enhanced postsynaptic excitatory function. In addition, long-term potentiation (LTP) of excitatory synapses was augmented, while long-term depression (LTD) was impaired in SAHA treated slices. Despite the in vitro synaptic enhancements, in vivo SAHA treatment did not rescue memory deficits in the Tg2576 mouse model of Alzheimer's disease (AD). Along with the lack of behavioral impact, pharmacokinetic analysis indicated poor brain availability of SAHA. Broader assessment of in vivo SAHA treatment using high-content phenotypic characterization of C57Bl6 mice failed to demonstrate significant behavioral effects of up to 150 mg/kg SAHA following either acute or chronic injections. Potentially explaining the low brain exposure and lack of behavioral impacts, SAHA was found to be a substrate of the blood brain barrier (BBB) efflux transporters Pgp and Bcrp1. Thus while our in vitro data show that HDAC inhibition can enhance excitatory synaptic strength and potentiation, our in vivo data suggests limited brain availability may contribute to the lack of behavioral impact of SAHA following peripheral delivery. These results do not predict CNS effects of SAHA during clinical use and also emphasize the importance of analyzing brain drug levels when interpreting preclinical behavioral pharmacology. PMID- 23922878 TI - Biliverdin protects against liver ischemia reperfusion injury in swine. AB - Ischemia reperfusion injury (IRI) in organ transplantation remains a serious and unsolved problem. Organs that undergo significant damage during IRI, function less well immediately after reperfusion and tend to have more problems at later times when rejection can occur. Biliverdin has emerged as an agent that potently suppress IRI in rodent models. Since the use of biliverdin is being developed as a potential therapeutic modality for humans, we tested the efficacy for its effects on IRI of the liver in swine, an accepted and relevant pre-clinical animal model. Administration of biliverdin resulted in rapid appearance of bilirubin in the serum and significantly suppressed IRI-induced liver dysfunction as measured by multiple parameters including urea and ammonia clearance, neutrophil infiltration and tissue histopathology including hepatocyte cell death. Taken together, our findings, in a large animal model, provide strong support for the continued evaluation of biliverdin as a potential therapeutic in the clinical setting of transplantation of the liver and perhaps other organs. PMID- 23922879 TI - Threonine affects intestinal function, protein synthesis and gene expression of TOR in Jian carp (Cyprinus carpio var. Jian). AB - This study aimed to investigate the effects of threonine (Thr) on the digestive and absorptive ability, proliferation and differentiation of enterocytes, and gene expression of juvenile Jian carp (Cyprinus carpio var. Jian). First, seven isonitrogenous diets containing graded levels of Thr (7.4-25.2 g/kg diet) were fed to the fishes for 60 days. Second, enterocyte proliferation and differentiation were assayed by culturing enterocytes with graded levels of Thr (0-275 mg/l) in vitro. Finally, enterocytes were cultured with 0 and 205 mg/l Thr to determine protein synthesis. The percent weight gain (PWG), specific growth rate, feed intake, feed efficiency, protein retention value, activities of trypsin, lipase and amylase, weights and protein contents of hepatopancreas and intestine, folds heights, activities of alkaline phosphatase (AKP), gamma- glutamyl transpeptidase and Na(+)/K(+)-ATPase in all intestinal segments, glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) activities in hepatopancreas, and 4E-BP2 gene expression in muscle, hepatopancreas and intestinal segments were significantly enhanced by Thr (p<0.05). However, the plasma ammonia concentration and TOR gene expression decreased (p<0.05). In vitro, Thr supplement significantly increased cell numbers, protein content, the activities of GOT, GPT, AKP and Na(+)/K(+)-ATPase, and protein synthesis rate of enterocytes, and decreased LDH activity and ammonia content in cell medium (p<0.05). In conclusion, Thr improved growth, digestive and absorptive capacity, enterocyte proliferation and differentiation, and protein synthesis and regulated TOR and 4E-BP2 gene expression in juvenile Jian carp. The dietary Thr requirement of juvenile Jian carp was 16.25 g/kg diet (51.3 g/kg protein) based on quadratic regression analysis of PWG. PMID- 23922880 TI - Acetyl-l-carnitine and oxfenicine on cardiac pumping mechanics in streptozotocin induced diabetes in male Wistar rats. AB - INTRODUCTION: In the treatment of patients with diabetes, one objective is an improvement of cardiac metabolism to alleviate the left ventricular (LV) function. For this study, we compared the effects of acetyl-l-carnitine (one of the carnitine derivatives) and of oxfenicine (a carnitine palmitoyltransferase-1 inhibitor) on cardiac pumping mechanics in streptozotocin-induced diabetes in male Wistar rats, with a particular focus on the pressure-flow-volume relationship. METHODS: Diabetes was induced by a single tail vein injection of 55 mg kg(-1) streptozotocin. The diabetic animals were treated on a daily basis with either acetyl-L-carnitine (1 g L(-1) in drinking water) or oxfenicine (150 mg kg( 1) by oral gavage) for 8 wk. They were also compared with untreated age-matched diabetic controls. LV pressure and ascending aortic flow signals were recorded to calculate the maximal systolic elastance (E max) and the theoretical maximum flow (Q max). Physically, E max reflects the contractility of the myocardium as an intact heart, whereas Q max has an inverse relationship with the LV internal resistance. RESULTS: When comparing the diabetic rats with their age-matched controls, the cardiodynamic condition was characterized by a decline in E max associated with the unaltered Q max. Acetyl-l-carnitine (but not oxfenicine) had reduced cardiac levels of malondialdehyde in these insulin-deficient animals. However, treating with acetyl-l-carnitine or oxfenicine resulted in an increase in E max, which suggests that these 2 drugs may protect the contractile status from deteriorating in the diabetic heart. By contrast, Q max showed a significant fall after administration of oxfenicine, but not with acetyl-L-carnitine. The decrease in Q max corresponded to an increase in total vascular resistance when treated with oxfenicine. CONCLUSIONS: Acetyl-l-carnitine, but not oxfencine, optimizes the integrative nature of cardiac pumping mechanics by preventing the diabetes-induced deterioration in myocardial intrinsic contractility associated with unaltered LV internal resistance. PMID- 23922881 TI - PIMT prevents the apoptosis of endothelial cells in response to glycated low density lipoproteins and protective effects of grape seed procyanidin B2. AB - BACKGROUND: The development of diabetic angiopathy is associated with profound vascular endothelial cells (VEC) dysfunction and apoptosis. Glycated low density lipoproteins (gly-LDL) continuously produced in the setting of diabetic patients play an important role in causing VEC dysfunction and apoptosis. However, the underlying molecular mechanism remains largely elusive. Protein L-isoaspartyl methyltransferase (PIMT) is a widely expressed protein repair enzyme by multiple cell types of arterial wall including VEC. Our previous proteomic studies showed that the expression of PIMT was significantly decreased in the aorta of diabetic rats as compared with control rats and treatment with grape seed procyanidin extracts significantly increased the PIMT expression in diabetic rats. We hypothesized that PIMT plays a critical role in gly-LDL induced VEC apoptosis; grape seed procyanidin B2 (GSPB2) protect against gly-LDL induced VEC apoptosis through PIMT regulation. METHODS AND RESULTS: HUVEC transfected negative control and PIMT siRNA were treated with or without GSPB2 (10 umol/L) for 48 h. Moreover, HUVEC of PIMT overexpression were stimulated by gly-LDL (50 ug/ml) in the presence or absence of GSPB2 (10 umol/L) for 48 h. Our results showed that gly LDL downregulated PIMT expression and PIMT overexpression or GSPB2 significantly attenuated gly-LDL induced VEC apoptosis. PIMT siRNA increased VEC apoptosis with up-regulation of p53, cytochrome c release, caspase-9 and caspase-3 activation. Mechanistically, overexpression of PIMT or GSPB2 increased the phosphorylation of ERK1/2 and GSK3beta in the gly-LDL induced VEC. CONCLUSION: In summary, our study identified PIMT as a key player responsible for gly-LDL induced VEC apoptosis and GSPB2 protect against gly-LDL induced VEC apoptosis by PIMT up-regulation. Targeting PIMT including use of GSPB2 could be turned into clinical application in the fighting against diabetic vascular complications. PMID- 23922882 TI - Astrocyte atrophy and immune dysfunction in self-harming macaques. AB - BACKGROUND: Self-injurious behavior (SIB) is a complex condition that exhibits a spectrum of abnormal neuropsychological and locomotor behaviors. Mechanisms for neuropathogenesis could include irregular immune activation, host soluble factors, and astrocyte dysfunction. METHODS: We examined the role of astrocytes as modulators of immune function in macaques with SIB. We measured changes in astrocyte morphology and function. Paraffin sections of frontal cortices from rhesus macaques identified with SIB were stained for glial fibrillary acidic protein (GFAP) and Toll-like receptor 2 (TLR2). Morphologic features of astrocytes were determined using computer-assisted camera lucida. RESULTS: There was atrophy of white matter astrocyte cell bodies, decreased arbor length in both white and gray matter astrocytes, and decreased bifurcations and tips on astrocytes in animals with SIB. This was combined with a five-fold increase in the proportion of astrocytes immunopositive for TLR2. CONCLUSIONS: These results provide direct evidence that SIB induces immune activation of astrocytes concomitant with quantifiably different morphology. PMID- 23922883 TI - Integration host factor of Mycobacterium tuberculosis, mIHF, compacts DNA by a bending mechanism. AB - The bacterial chromosomal DNA is folded into a compact structure called as 'nucleoid' so that the bacterial genome can be accommodated inside the cell. The shape and size of the nucleoid are determined by several factors including DNA supercoiling, macromolecular crowding and nucleoid associated proteins (NAPs). NAPs bind to different sites of the genome in sequence specific or non-sequence specific manner and play an important role in DNA compaction as well as regulation. Until recently, few NAPs have been discovered in mycobacteria owing to poor sequence similarities with other histone-like proteins of eubacteria. Several putative NAPs have now been identified in Mycobacteria on the basis of enriched basic residues or histone-like "PAKK" motifs. Here, we investigate mycobacterial Integration Host Factor (mIHF) for its architectural roles as a NAP using atomic force microscopy and DNA compaction experiments. We demonstrate that mIHF binds DNA in a non-sequence specific manner and compacts it by a DNA bending mechanism. AFM experiments also indicate a dual architectural role for mIHF in DNA compaction as well as relaxation. These results suggest a convergent evolution in the mechanism of E. coli and mycobacterial IHF in DNA compaction. PMID- 23922884 TI - Validity and reliability of enzyme immunoassays using Leishmania major or L. infantum antigens for the diagnosis of canine visceral leishmaniasis in Brazil. AB - BACKGROUND: American visceral leishmaniasis is caused by the protozoan Leishmania infantum. Dogs are the main reservoirs in the domestic transmission cycle. The limited accuracy of diagnostic tests for canine leishmaniasis may contribute to the lack of impact of control measures recommended by the Brazilian Ministry of Health. The objective of this study was to estimate the accuracy of two enzyme linked immunosorbent assays employing L. major or L. infantum antigens and their reliability between three laboratories of different levels of complexity. METHODS: A validation study of ELISA techniques using L. major or L. infantum antigens was conducted. Direct visualization of the parasite in hematoxylin/eosin stained histopathological sections, immunohistochemistry, and isolation of the parasite in culture.were used as gold standard. An animal that was positive in at least one of the tests was defined as infected with L. infantum. Serum samples collected from 1,425 dogs were analyzed. Samples were separated in three aliquots and tested in three different laboratories. Sensitivity, specificity and the area under de ROC curve were calculated and the reliability was evaluated between the participant laboratories. RESULTS: The sensitivity was 91.8% and 89.8% for the L. major and L. infantum assays, respectively. The specificity was 83.75% and 82.7% for the L. major and L. infantum assays, respectively. The area under de ROC curve was 0.920 and 0.898 for L. major and L. infantum, respectively. The mean intraclass correlation coefficients between laboratories ranged from 0.890 to 0.948 when L. major was used as antigen, and from 0.818 to 0.879 when L. infantum was used. INTERPRETATION: ELISA tests using L. major or L. infantum antigens have similar accuracy and reliability. Our results do not support the substitution of the L. major antigen of the ELISA test currently used for the diagnosis of canine visceral leishmaniasis in Brazil. PMID- 23922885 TI - Bisphenol A impairs hepatic glucose sensing in C57BL/6 male mice. AB - AIMS/HYPOTHESIS: Glucose sensing (eg. glucokinase activity) becomes impaired in the development of type 2 diabetes, the etiology of which is unclear. Estrogen can stimulate glucokinase activity, whereas the pervasive environmental pollutant bisphenol A (BPA) can inhibit estrogen action, hence we aimed to determine the effect of BPA on glucokinase activity directly. METHODS: To evaluate a potential acute effect on hepatic glucokinase activity, BPA in water (n = 5) vs. water alone (n = 5) was administered at the EPA's purported "safe dose" (50 ug/kg) by gavage to lean 6-month old male C57BL/6 mice. Two hours later, animals were euthanized and hepatic glucokinase activity measured over glucose levels from 1 20 mmol/l in liver homogenate. To determine the effect of chronic BPA exposure on hepatic glucokinase activity, lean 6-month old male C57BL/6 mice were provided with water (n = 15) or water with 1.75 mM BPA (~50 ug/kg/day; n = 14) for 2 weeks. Following the 2-week exposure, animals were euthanized and glucokinase activity measured as above. RESULTS: Hepatic glucokinase activity was signficantly suppressed after 2 hours in animals given an oral BPA bolus compared to those who received only water (p = 0.002-0.029 at glucose 5-20 mmol/l; overall treatment effect p<0.001). Exposure to BPA over 2 weeks also suppressed hepatic glucokinase activity in exposed vs. unexposed mice (overall treatment effect, p = 0.003). In both experiments, the Hill coefficient was higher and Vmax lower in mice treated with BPA. CONCLUSIONS/INTERPRETATION: Both acute and chronic exposure to BPA significantly impair hepatic glucokinase activity and function. These findings identify a potential mechanism for how BPA may increase risk for diabetes. PMID- 23922886 TI - Ron knockdown and Ron monoclonal antibody IMC-RON8 sensitize pancreatic cancer to histone deacetylase inhibitors (HDACi). AB - Recepteur d'origine nantais (Ron) is overexpressed in a panel of pancreatic cancer cells and tissue samples from pancreatic cancer patients. Ron can be activated by its ligand macrophage stimulating protein (MSP), thereby activating oncogenic signaling pathways. Crosstalk between Ron and EGFR, c-Met, or IGF-1R may provide a mechanism underlying drug resistance. Thus, targeting Ron may represent a novel therapeutic strategy. IMC-RON8 is the first Ron monoclonal antibody (mAb) entering clinical trial for targeting Ron overexpression. Our studies show IMC-RON8 downmodulated Ron expression in pancreatic cancer cells and significantly blocked MSP-stimulated Ron activation, downstream Akt and ERK phosphorylation, and survivin mRNA expression. IMC-RON8 hindered MSP-induced cell migration and reduced cell transformation. Histone deacetylase inhibitors (HDACi) are reported to target expression of various genes through modification of nucleosome histones and non-histone proteins. Our work shows HDACi TSA and Panobinostat (PS) decreased Ron mRNA and protein expression in pancreatic cancer cells. PS also reduced downstream signaling of pAkt, survivin, and XIAP, as well as enhanced cell apoptosis. Interestingly, PS reduced colony formation in Ron knockdown cells to a greater extent than Ron scramble control cells in colony formation and soft agarose assays. IMC-RON8 could also sensitize pancreatic cancer cells to PS, as reflected by reduced colony numbers and size in combination treatment with IMC-RON8 and PS compared to single treatment alone. The co-treatment further reduced Ron expression and pAkt, and increased PARP cleavage compared to either treatment alone. This study suggests the potential for a novel combination approach which may ultimately be of value in treatment of pancreatic cancer. PMID- 23922887 TI - TNF-alpha decreases VEGF secretion in highly polarized RPE cells but increases it in non-polarized RPE cells related to crosstalk between JNK and NF-kappaB pathways. AB - Asymmetrical secretion of vascular endothelial growth factor (VEGF) by retinal pigment epithelial (RPE) cells in situ is critical for maintaining the homeostasis of the retina and choroid. VEGF is also involved in the development and progression of age-related macular degeneration (AMD). We studied the effect of tumor necrosis factor-alpha (TNF-alpha) on the secretion of VEGF in polarized and non-polarized RPE cells (P-RPE cells and N-RPE cells, respectively) in culture and in situ in rats. A subretinal injection of TNF-alpha caused a decrease in VEGF expression and choroidal atrophy. Porcine RPE cells were seeded on TranswellTM filters, and their maturation and polarization were confirmed by the asymmetrical VEGF secretion and trans electrical resistance. Exposure to TNF alpha decreased the VEGF secretion in P-RPE cells but increased it in N-RPE cells in culture. TNF-alpha inactivated JNK in P-RPE cells but activated it in N-RPE cells, and TNF-alpha activated NF-kappaB in P-RPE cells but not in N-RPE cells. Inhibition of NF-kappaB activated JNK in both types of RPE cells indicating crosstalk between JNK and NF-kappaB. TNF-alpha induced the inhibitory effects of NF-kappaB on JNK in P-RPE cells because NF-kappaB is continuously inactivated. In N-RPE cells, however, it was not evident because NF-kappaB was already activated. The basic activation pattern of JNK and NF-kappaB and their crosstalk led to opposing responses of RPE cells to TNF-alpha. These results suggest that VEGF secretion under inflammatory conditions depends on cellular polarization, and the TNF-alpha-induced VEGF down-regulation may result in choroidal atrophy in polarized physiological RPE cells. TNF-alpha-induced VEGF up-regulation may cause neovascularization by non-polarized or non-physiological RPE cells. PMID- 23922888 TI - Metformin, a diabetes drug, eliminates tumor-initiating hepatocellular carcinoma cells. AB - Metformin has been widely used as an oral drug for diabetes mellitus for approximately 60 years. Interestingly, recent reports showed that metformin exhibited an anti-tumor action in a wide range of malignancies including hepatocellular carcinoma (HCC). In the present study, we investigated its impact on tumor-initiating HCC cells. Metformin suppressed cell growth and induced apoptosis in a dose-dependent manner. Flow cytometric analysis showed that metformin treatment markedly reduced the number of tumor-initiating epithelial cell adhesion molecule (EpCAM)(+) HCC cells. Non-adherent sphere formation assays of EpCAM(+) cells showed that metformin impaired not only their sphere-forming ability, but also their self-renewal capability. Consistent with this, immunostaining of spheres revealed that metformin significantly decreased the number of component cells positive for hepatic stem cell markers such as EpCAM and alpha-fetoprotein. In a xenograft transplantation model using non-obese diabetic/severe combined immunodeficient mice, metformin and/or sorafenib treatment suppressed the growth of tumors derived from transplanted HCC cells. Notably, the administration of metformin but not sorafenib decreased the number of EpCAM(+) cells and impaired their self-renewal capability. As reported, metformin activated AMP-activated protein kinase (AMPK) through phosphorylation; however its inhibitory effect on the mammalian target of rapamycin (mTOR) pathway did not necessarily correlate with its anti-tumor activity toward EpCAM(+) tumor initiating HCC cells. These results indicate that metformin is a promising therapeutic agent for the elimination of tumor-initiating HCC cells and suggest as-yet-unknown functions other than its inhibitory effect on the AMPK/mTOR pathway. PMID- 23922889 TI - Galectin-3 induces clustering of CD147 and integrin-beta1 transmembrane glycoprotein receptors on the RPE cell surface. AB - Proliferative vitreoretinopathy (PVR) is a blinding disease frequently occurring after retinal detachment surgery. Adhesion, migration and matrix remodeling of dedifferentiated retinal pigment epithelial (RPE) cells characterize the onset of the disease. Treatment options are still restrained and identification of factors responsible for the abnormal behavior of the RPE cells will facilitate the development of novel therapeutics. Galectin-3, a carbohydrate-binding protein, was previously found to inhibit attachment and spreading of retinal pigment epithelial cells, and thus bares the potential to counteract PVR-associated cellular events. However, the identities of the corresponding cell surface glycoprotein receptor proteins on RPE cells are not known. Here we characterize RPE-specific Gal-3 containing glycoprotein complexes using a proteomic approach. Integrin-beta1, integrin-alpha3 and CD147/EMMPRIN, a transmembrane glycoprotein implicated in regulating matrix metalloproteinase induction, were identified as potential Gal-3 interactors on RPE cell surfaces. In reciprocal immunoprecipitation experiments we confirmed that Gal-3 associated with CD147 and integrin-beta1, but not with integrin-alpha3. Additionally, association of Gal-3 with CD147 and integrin-beta1 was observed in co-localization analyses, while integrin-alpha3 only partially co-localized with Gal-3. Blocking of CD147 and integrin-beta1 on RPE cell surfaces inhibited binding of Gal-3, whereas blocking of integrin-alpha3 failed to do so, suggesting that integrin-alpha3 is rather an indirect interactor. Importantly, Gal-3 binding promoted pronounced clustering and co-localization of CD147 and integrin-beta1, with only partial association of integrin-alpha3. Finally, we show that RPE derived CD147 and integrin-beta1, but not integrin-alpha3, carry predominantly beta-1,6-N-actyl-D-glucosamine-branched glycans, which are high-affinity ligands for Gal-3. We conclude from these data that extracellular Gal-3 triggers clustering of CD147 and integrin-beta1 via interaction with beta1,6-branched N-glycans on RPE cells and hypothesize that Gal 3 acts as a positive regulator for CD147/integrin-beta1 clustering and therefore modifies RPE cell behavior contributing to the pathogenesis of PVR. Further investigations at this pathway may aid in the development of specific therapies for PVR. PMID- 23922890 TI - Chronic alterations in monoaminergic cells in the locus coeruleus in orexin neuron-ablated narcoleptic mice. AB - Narcolepsy patients often suffer from insomnia in addition to excessive daytime sleepiness. Narcoleptic animals also show behavioral instability characterized by frequent transitions between all vigilance states, exhibiting very short bouts of NREM sleep as well as wakefulness. The instability of wakefulness states in narcolepsy is thought to be due to deficiency of orexins, neuropeptides produced in the lateral hypothalamic neurons, which play a highly important role in maintaining wakefulness. However, the mechanism responsible for sleep instability in this disorder remains to be elucidated. Because firing of orexin neurons ceases during sleep in healthy animals, deficiency of orexins does not explain the abnormality of sleep. We hypothesized that chronic compensatory changes in the neurophysiologica activity of the locus coeruleus (LC) and dorsal raphe (DR) nucleus in response to the progressive loss of endogenous orexin tone underlie the pathological regulation of sleep/wake states. To evaluate this hypothesis, we examined firing patterns of serotonergic (5-HT) neurons and noradrenergic (NA) neurons in the brain stem, two important neuronal populations in the regulation of sleep/wakefulness states. We recorded single-unit activities of 5-HT neurons and NA neurons in the DR nucleus and LC of orexin neuron-ablated narcoleptic mice. We found that while the firing pattern of 5-HT neurons in narcoleptic mice was similar to that in wildtype mice, that of NA neurons was significantly different from that in wildtype mice. In narcoleptic mice, NA neurons showed a higher firing frequency during both wakefulness and NREM sleep as compared with wildtype mice. In vitro patch-clamp study of NA neurons of narcoleptic mice suggested a functional decrease of GABAergic input to these neurons. These alterations might play roles in the sleep abnormality in narcolepsy. PMID- 23922891 TI - Development and biotechnological application of a novel endoxylanase family GH10 identified from sugarcane soil metagenome. AB - Metagenomics has been widely employed for discovery of new enzymes and pathways to conversion of lignocellulosic biomass to fuels and chemicals. In this context, the present study reports the isolation, recombinant expression, biochemical and structural characterization of a novel endoxylanase family GH10 (SCXyl) identified from sugarcane soil metagenome. The recombinant SCXyl was highly active against xylan from beechwood and showed optimal enzyme activity at pH 6,0 and 45 degrees C. The crystal structure was solved at 2.75 A resolution, revealing the classical (beta/alpha)8-barrel fold with a conserved active-site pocket and an inherent flexibility of the Trp281-Arg291 loop that can adopt distinct conformational states depending on substrate binding. The capillary electrophoresis analysis of degradation products evidenced that the enzyme displays unusual capacity to degrade small xylooligosaccharides, such as xylotriose, which is consistent to the hydrophobic contacts at the +1 subsite and low-binding energies of subsites that are distant from the site of hydrolysis. The main reaction products from xylan polymers and phosphoric acid-pretreated sugarcane bagasse (PASB) were xylooligosaccharides, but, after a longer incubation time, xylobiose and xylose were also formed. Moreover, the use of SCXyl as pre-treatment step of PASB, prior to the addition of commercial cellulolytic cocktail, significantly enhanced the saccharification process. All these characteristics demonstrate the advantageous application of this enzyme in several biotechnological processes in food and feed industry and also in the enzymatic pretreatment of biomass for feedstock and ethanol production. PMID- 23922892 TI - Prognostic value of radiological response to chemotherapy in patients with osteosarcoma. AB - BACKGROUND: Chemotherapy is essential to improve the prognosis of the patients with osteosarcoma, and the response to chemotherapy is an important prognostic factor. In this study, the impact of various radiological examinations on overall survival (OS) and event-free survival (EFS) was evaluated. METHOD: Eighty-two patients with high-grade osteosarcoma were included in this study, and we evaluated the following factors for prognostic significance: age (>=40 years), gender (male), tumor location (truncal site), metastatic disease, histological response to chemotherapy, radiological response to chemotherapy assessed using X ray, angiography, CT, MRI, (201)Tl scintigraphy, and (99m)Tc-MIBI scintigraphy ((99m)Tc-MIBI), and combined radiological score (CRS). RESULTS: Univariate analyses revealed that metastatic disease, histological response, (99m)Tc-MIBI, and CRS were significantly correlated with OS. Multivariate analyses showed that metastatic disease (OS: HR 35.9, P<0.001; EFS: HR 17.32, P<0.001) was an independent predictor of OS and EFS. Tumor location (HR 36.1, P = 0.003), histological response (HR 31.1, P = 0.036), and (99m)Tc-MIBI (HR 18.4, P = 0.038) were significant prognostic factors for OS. Moreover, CRS was a marginally significant predictor of OS and EFS. CONCLUSION: The chemotherapeutic effects evaluated by (99m)Tc-MIBI and CRS could be considered as prognostic factors in osteosarcoma. PMID- 23922893 TI - Survival of patients with hepatocellular carcinoma (HCC) treated by percutaneous radio-frequency ablation (RFA) is affected by complete radiological response. AB - BACKGROUND: Radio-frequency ablation (RFA) has been employed in the treatment of Barcelona Clinic Liver Cancer (BCLC) early stage hepatocellular carcinoma (HCC) as curative treatments. AIM: To assess the effectiveness and the safety of RFA in patients with early HCC and compensated cirrhosis. METHODS: A cohort of 151 consecutive patients with early stage HCC (122 Child-Pugh class A and 29 class B patients) treated with RFA were enrolled. Clinical, laboratory and radiological follow-up data were collected from the time of first RFA. A single lesion was observed in 113/151 (74.8%), two lesions in 32/151 (21.2%), and three lesions in 6/151 (4%) of patients. RESULTS: The overall survival rates were 94%, 80%, 64%, 49%, and 41% at 12, 24, 36, 48 and 60 months, respectively. Complete response (CR) at 1 month (p<0.0001) and serum albumin levels (p = 0.0004) were the only variables indipendently linked to survival by multivariate Cox model. By multivariate analysis, tumor size (p = 0.01) is the only variable associated with an increased likehood of CR. The proportion of major complications after treatment was 4%. CONCLUSIONS: RFA is safe and effective for managing HCC with cirrhosis, especially for patients with HCC <=3 cm and higher baseline albumin levels. Complete response after RFA significantly increases survival. PMID- 23922894 TI - Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy. AB - Von Hippel-Lindau tumor suppressor (VHL) is lost in the majority of clear cell renal cell carcinomas (ccRCC). Folliculin (FLCN) is a tumor suppressor whose function is lost in Birt-Hogg-Dube syndrome (BHD), a disorder characterized by renal cancer of multiple histological types including clear cell carcinoma, cutaneous fibrofolliculoma, and pneumothorax. Here we explored whether there is connection between VHL and FLCN in clear cell renal carcinoma cell lines and tumors. We demonstrate that VHL regulates expression of FLCN at the mRNA and protein levels in RCC cell lines, and that FLCN protein expression is decreased in human ccRCC tumors with VHL loss, as compared with matched normal kidney tissue. Knockdown of FLCN results in increased formation of tumors by RCC cells with wild-type VHL in orthotopic xenografts in nude mice, an indication that FLCN plays a role in the tumor-suppressing activity of VHL. Interestingly, FLCN, similarly to VHL, is necessary for the activity of LC3C-mediated autophagic program that we have previously characterized as contributing to the tumor suppressing activity of VHL. The results show the existence of functional crosstalk between two major tumor suppressors in renal cancer, VHL and FLCN, converging on regulation of autophagy. PMID- 23922896 TI - Genetic polymorphism of NOS3 with susceptibility to deep vein thrombosis after orthopedic surgery: a case-control study in Chinese Han population. AB - Deep vein thrombosis is one of the common complications of orthopedic surgery. Studies indicated that genetic factors played a considerable role in the pathogenesis of deep vein thrombosis. Endothelial nitric oxide synthase which encoded by nitric oxide synthase 3 (NOS3), can generate nitric oxide in endothelial cells. As a predominant regulator for vascular homeostasis, nitric oxide might be involved in the pathogenesis of thrombosis. It had been proved that the NOS3 polymorphism (rs1799983) was associated with the development of cardiovascular diseases. Our objective was to evaluate the association between the NOS3 polymorphism (rs1799983) and deep vein thrombosis after orthopedic surgery in Chinese Han population. The polymorphism was genotyped in 224 subjects with deep vein thrombosis after orthopedic surgery and 580 controls. Allele and genotype frequencies were compared between subjects with deep vein thrombosis and control subjects. The allele and genotype frequencies of the NOS3 polymorphism (rs1799983) were significantly different between subjects with deep vein thrombosis and control subjects. There were also significant differences when the subjects were stratified by gender, surgery type and hypertension status. These findings suggested that the NOS3 polymorphism (rs1799983) was associated with susceptibility to the deep vein thrombosis after orthopedic surgery in Chinese Han population, and NOS3 might play a role in the development of deep vein thrombosis after orthopedic surgery. PMID- 23922895 TI - Structural basis for the regulation of maternal embryonic leucine zipper kinase. AB - MELK (maternal embryonic leucine zipper kinase), which is a member of the AMPK (AMP-activated protein kinase)-related kinase family, plays important roles in diverse cellular processes and has become a promising drug target for certain cancers. However, the regulatory mechanism of MELK remains elusive. Here, we report the crystal structure of a fragment of human MELK that contains the kinase domain and ubiquitin-associated (UBA) domain. The UBA domain tightly binds to the back of the kinase domain, which may contribute to the proper conformation and activity of the kinase domain. Interestingly, the activation segment in the kinase domain displays a unique conformation that contains an intramolecular disulfide bond. The structural and biochemical analyses unravel the molecular mechanisms for the autophosphorylation/activation of MELK and the dependence of its catalytic activity on reducing agents. Thus, our results may provide the basis for designing specific MELK inhibitors for cancer treatment. PMID- 23922897 TI - Acetaldehyde-derived advanced glycation end-products promote alcoholic liver disease. AB - BACKGROUND: Chronic ingestion of ethanol increases acetaldehyde and leads to the production of acetaldehyde-derived advanced glycation end-products (AA-AGE). We evaluated the toxicity of AA-AGE on hepatocytes and studied the role of AA-AGE in the pathogenesis of alcoholic liver disease (ALD). METHODS: Rat hepatocyte cultures were treated with N-ethyllysine (NEL) or AA-AGE and the cell viability was evaluated using MTT assay. Male Wistar rats were fed with liquid diet containing 5% ethanol for 8 weeks following normal diet for another 12 weeks. A group of animals was sacrificed at 4th, 6th, and 8th week and the remaining animals at 12th, 14th, 16th, 18th, and 20th week. The liver sections were stained for AA-AGE and 4-hydroxy-2-nonenal (4-HNE). Liver biopsy obtained from ALD patients was also stained for AA-AGE and 4-HNE. RESULTS: Hepatocyte viability was significantly reduced in cultures treated with AA-AGE compared to NEL treated or control cultures. Severe fatty degeneration was observed during chronic administration of ethanol increasing from 4-8 weeks. The staining of AA-AGE and 4 HNE was correlated with the degree of ALD in both rat and human. In rats, hepatic fatty degeneration was completely disappeared and the staining for both AA-AGE and 4-HNE returned to normal at 12th week of abstinence. Staining for AA-AGE and 4-HNE was completely absent in normal human liver. CONCLUSIONS: The data demonstrated that AA-AGE is toxic to hepatocytes, but not NEL. Chronic ethanol ingestion produces AA-AGE and reactive oxygen species that contribute to the pathogenesis of ALD. Abstinence of alcohol results in complete disappearance of both AA-AGE and 4-HNE along with fatty degeneration suggesting that AA-AGE plays a significant role in the pathogenesis of ALD. PMID- 23922898 TI - Gene duplication and fragment recombination drive functional diversification of a superfamily of cytoplasmic effectors in Phytophthora sojae. AB - Phytophthora and other oomycetes secrete a large number of putative host cytoplasmic effectors with conserved FLAK motifs following signal peptides, termed crinkling and necrosis inducing proteins (CRN), or Crinkler. Here, we first investigated the evolutionary patterns and mechanisms of CRN effectors in Phytophthora sojae and compared them to two other Phytophthora species. The genes encoding CRN effectors could be divided into 45 orthologous gene groups (OGG), and most OGGs unequally distributed in the three species, in which each underwent large number of gene gains or losses, indicating that the CRN genes expanded after species evolution in Phytophthora and evolved through pathoadaptation. The 134 expanded genes in P. sojae encoded family proteins including 82 functional genes and expressed at higher levels while the other 68 genes encoding orphan proteins were less expressed and contained 50 pseudogenes. Furthermore, we demonstrated that most expanded genes underwent gene duplication or/and fragment recombination. Three different mechanisms that drove gene duplication or recombination were identified. Finally, the expanded CRN effectors exhibited varying pathogenic functions, including induction of programmed cell death (PCD) and suppression of PCD through PAMP-triggered immunity or/and effector-triggered immunity. Overall, these results suggest that gene duplication and fragment recombination may be two mechanisms that drive the expansion and neofunctionalization of the CRN family in P. sojae, which aids in understanding the roles of CRN effectors within each oomycete pathogen. PMID- 23922900 TI - Nutritional status of orphaned and separated children and adolescents living in community and institutional environments in uasin gishu county, kenya. AB - OBJECTIVE: To describe the nutritional status of orphaned and separated children and adolescents (OSCA) living in households in the community (HH), on the street, and those in institutional environments in western Kenya. METHODS: The study enrolled OSCA from 300 randomly selected households (HH), 19 Charitable Children's Institutions (CCIs), and 100 street-involved children. Measures of malnutrition were standardized with Z-scores using World Health Organization criteria; Z-scores <=-2 standard deviations (sd) were moderate-severe malnutrition. Data were analyzed using multivariable logistic regression adjusting for child age, sex, HIV status, whether the child had been hospitalized in the previous year, time living with current guardian, and intra-household clustering for adequacy of diet and moderate-severe malnutrition. RESULTS: Included are data from 2862 participants (1337 in CCI's, 1425 in HH's, and 100 street youth). The population was 46% female with median age at enrolment of 11.1 years. Only 4.4% of households and institutions reported household food security; 93% of children in HH reported an adequate diet vs. 95% in CCI's and 99% among street youth. After adjustment, OSCA in HH were less likely to have an adequate diet compared to those in CCI's (AOR 0.4, 95% CI 0.2-1.0). After adjustment, there were no differences between the categories of children on weight-for-age, weight-for-height, or BMI-for-age. Children living in HH (AOR 2.6, 95% CI: 2.0 3.4) and street youth (AOR: 5.9, 95% CI: 3.6-9.5) were more likely than children in CCI's to be low height-for-age. CONCLUSION: OSCA in HH are less likely to have an adequate diet compared to children in CCI's. They and street children are more likely to be moderately-severely low height-for-age compared to children in CCI's, suggesting chronic malnutrition among them. PMID- 23922899 TI - Full transcriptome analysis of early dorsoventral patterning in zebrafish. AB - Understanding the molecular interactions that lead to the establishment of the major body axes during embryogenesis is one of the main goals of developmental biology. Although the past two decades have revolutionized our knowledge about the genetic basis of these patterning processes, the list of genes involved in axis formation is unlikely to be complete. In order to identify new genes involved in the establishment of the dorsoventral (DV) axis during early stages of zebrafish embryonic development, we employed next generation sequencing for full transcriptome analysis of normal embryos and embryos lacking overt DV pattern. A combination of different statistical approaches yielded 41 differentially expressed candidate genes and we confirmed by in situ hybridization the early dorsal expression of 32 genes that are transcribed shortly after the onset of zygotic transcription. Although promoter analysis of the validated genes suggests no general enrichment for the binding sites of early acting transcription factors, most of these genes carry "bivalent" epigenetic histone modifications at the time when zygotic transcription is initiated, suggesting a "poised" transcriptional status. Our results reveal some new candidates of the dorsal gene regulatory network and suggest that a plurality of the earliest upregulated genes on the dorsal side have a role in the modulation of the canonical Wnt pathway. PMID- 23922901 TI - Spatiotemporal expression of matrix metalloproteinases (MMPs) is regulated by the Ca2+-signal transducer S100A4 in the pathogenesis of thoracic aortic aneurysm. AB - AIMS: This study investigated whether S100A4 plays a potential role in the formation of thoracic aortic aneurysm (TAA). METHODS AND RESULTS: The thoracic aortas of male Sprague-Dawley rats were exposed to 0.5 M CaCl2 or normal saline (NaCl). Animals were euthanized at specified time-points (2, 4, and 10 weeks post TAA induction). The treated aortic segments were harvested, and mRNA levels, protein expressions and immunohistochemistry of MMP-2, MMP-9 and S100A4 were analyzed. The A7r5 cell lines were used for an in vitro study. Experiments were also performed using human TAA samples for comparison. Localized aneurysmal dilation was observed in the CaCl2-treated segments. The transcription levels of S100A4 and MMPs were elevated in CaCl2-treated segments versus controls, and a significant correlation between S100A4 and expression of MMPs was observed across all time-points. Immunohistochemical studies revealed similar expression pattern of S100A4 and MMP proteins, as well as co-localization of S100A4 with the cell lineage markers (alphaSMA and CD68) and inflammatory markers (MMPs and NF-kappaB P65 subunit). The proliferative ability of A7r5 cells after transfection with S100A4 siRNA was suppressed, and down-regulation of S100A4 inhibited MMP-2 and MMP-9 expression in vitro. Increased expression of S100A4 was observed in all layers of the aorta wall in human TAA specimens. Serum concentrations of S100A4 determined by ELISA were found to be significantly increased in TAA patients. CONCLUSIONS: This study established the important roles of S100A4 and MMPs in the development of TAA. PMID- 23922902 TI - Predictive accuracy of 29-comorbidity index for in-hospital deaths in US adult hospitalizations with a diagnosis of venous thromboembolism. AB - BACKGROUND: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant source of mortality and morbidity worldwide. By analyzing data of the 2010 Nationwide Inpatient Sample from the Agency for Healthcare Research and Quality (AHRQ), we evaluated the predictive accuracy of the AHRQ's 29-comorbidity index with in-hospital death among US adult hospitalizations with a diagnosis of VTE. METHODS: We assessed the case-fatality and prevalence of comorbidities among a sample of 153,518 adult hospitalizations with a diagnosis of VTE that comprised 87,605 DVTs and 65,913 PEs (with and without DVT). We estimated adjusted odds ratios and 95% confidence intervals with multivariable logistic regression models by using comorbidities as predictors and status of in-hospital death as an outcome variable. We assessed the c-statistics for the predictive accuracy of the logistic regression models. RESULTS: In 2010, approximately 41,944 in-hospital deaths (20,212 with DVT and 21,732 with PE) occurred among 770,137 hospitalizations with a diagnosis of VTE. When compared separately to hospitalizations with VTE, DVT, or PE that had no corresponding comorbidities, congestive heart failure, chronic pulmonary disease, coagulopathy, liver disease, lymphoma, fluid and electrolyte disorders, metastatic cancer, other neurological disorders, peripheral vascular disorders, pulmonary circulation disorders, renal failure, solid tumor without metastasis, and weight loss were positively and independently associated with 10%-125% increased likelihoods of in-hospital death. The c-statistic values ranged from 0.776 to 0.802. CONCLUSION: The results of this study indicated that comorbidity was associated independently with risk of death among hospitalizations with VTE and among hospitalizations with DVT or PE. The AHRQ 29-comorbidity index provides acceptable to excellent predictive accuracy for in-hospital deaths among adult hospitalizations with VTE and among those with DVT or PE. PMID- 23922903 TI - Modulation of NKG2D expression in human CD8(+) T cells corresponding with tuberculosis drug cure. AB - BACKGROUND: Biomarkers predicting tuberculosis treatment response and cure would facilitate drug development. This study investigated expression patterns of the co-stimulation molecule NKG2D in human tuberculosis and treatment to determine its potential usefulness as a host biomarker of tuberculosis drug efficacy. METHODS: Tuberculosis patients (n = 26) were recruited in Lahore, Pakistan, at diagnosis and followed up during treatment. Household contacts (n = 24) were also recruited. NKG2D expression was measured by qRT-PCR in RNA samples both ex vivo and following overnight mycobacterial stimulation in vitro. Protein expression of NKG2D and granzyme B was measured by flow cytometry. RESULTS: NKG2D expression in newly diagnosed tuberculosis patients was similar to household contacts in ex vivo RNA, but was higher following in vitro stimulation. The NKG2D expression was dramatically reduced by intensive phase chemotherapy, in both ex vivo blood RNA and CD8(+) T cell protein expression, but then reverted to higher levels after the continuation phase in successfully treated patients. CONCLUSION: The changes in NKG2D expression through successful treatment reflect modulation of the peripheral cytotoxic T cell response. This likely reflects firstly in vivo stimulation by live Mycobacterium tuberculosis, followed by the response to dead bacilli, antigen-release and finally immunopathology resolution. Such changes in host peripheral gene expression, alongside clinical and microbiological indices, could be developed into a biosignature of tuberculosis drug-induced cure to be used in future clinical trials. PMID- 23922904 TI - Patterns of treatment interruption among patients with multidrug-resistant TB (MDR TB) and association with interim and final treatment outcomes. AB - BACKGROUND: The reasons that patients with multidrug-resistant tuberculosis (MDR TB) miss treatment are multi-factorial and complex. Identifying patterns of treatment interruption that predict poor outcomes can be used to target program activities aiming to improve treatment adherence. OBJECTIVE: To characterize patterns of treatment interruption among MDR TB patients and determine the association between patterns and treatment outcomes. METHODS: Retrospective analysis of MDR TB patients. A treatment interruption was defined as any time that a patient missed a prescribed dose of treatment for at least 1 day but for a period of less than 2 consecutive months. Patients were characterized by the number, length and variability of interruptions, variability of time between interruptions, and percent of missed doses. Final treatment outcome was dichotomized as a successful (cured or completed) or poor outcome (defaulted, failed, or died). Risk ratios were calculated to determine the association between characteristics of treatment interruption and treatment outcomes. All analyses were conducted in 6 month treatment intervals. RESULTS: Only 7.0% of 583 patients completed treatment without interruption. Of the remaining 542 patients, the median time to the first interruption was 2 1/2 months (70 days). In multivariate analysis, patients who had longer interruptions with sporadic variability during the 6-12 month or the 12-18 month treatment period had a significantly increased risk for poor outcomes compared to patients who had short, regular interruptions (RR(adj) 4.37, 95% CI 1.2-15.8; = 0.03 and RR(adj) 3.38, 95% CI 1.6-7.1; p = 0.001, respectively). In addition, missing 10% or more of the prescribed doses during any 6 month period in the initial 18 months of therapy significantly increased the risk for poor outcomes (RR(adj) range 1.55 2.35; p-value range 0.01-0.005). CONCLUSION: Patients that miss more consecutive days of treatment with sporadic interruption patterns or a greater proportion of treatment are at an increased risk for poor treatment outcomes. PMID- 23922905 TI - Candidate transcriptomic sources of inbreeding depression in Drosophila melanogaster. AB - The genomic causes of inbreeding depression are poorly known. Several studies have found widespread transcriptomic alterations in inbred organisms, but it remains unclear which of these alterations are causes of the depression and which are mere responses to the ensuing physiological stress induced by increased homozygosity due to inbreeding. Attempting to differentiate causes from responses, we made a c-DNA microarray analysis of inbreeding depression in Drosophila melanogaster. The rationale of the experiment was that, while depression is a general phenomenon involving reductions in fitness in different inbred lines, its first genetic causes would be different for each inbred line, as they are expected to be caused by the fixation of rare deleterious genes. We took four sets of inbred sublines, each set descending from a different founding pair obtained from a large outbred stock, and compared the expression of the three most depressed sublines and the three least depressed sublines from each set. Many changes in expression were common to all sets, but fourteen genes, grouped in four expression clusters, showed strong set-specific changes, and were therefore possible candidates to be sources of the inbreeding depression observed. PMID- 23922906 TI - Imperfect implementation of an early warning scoring system in a Danish teaching hospital: a cross-sectional study. AB - BACKGROUND: In 2007, the initiation of a patient safety campaign led to the introduction of Ward Observational Charts (WOC) and Medical Early Warning Score (MEWS) at Naestved Regional Hospital. This included systematic measuring of vital signs of all patients in order to prevent patient deterioration and assure timely and correct initiation of treatment. The aim of this study was to assess to what degree WOC guidelines being followed by ward staff. DESIGN AND SETTING: A 7-day prospective, observational, randomised, cross-sectional, point prevalence study of WOC guideline compliance in hospitalised patients on twelve wards at Naestved Hospital. RESULTS: The study included 132 patients. Of these, 58% had been observed and managed correctly according to WOC guidelines. 77% had all MEWS elements recorded by staff. One patient had no MEWS elements recorded. Only 38% of patients with abnormal MEWS were correctly escalated by nursing staff. Staff was aware of the abnormal MEWS observed by investigator in 60% of the patients. Each element of WOC was on average recorded by staff in 90% of the patients. CONCLUSION: At the time of our study, the long-term implementation of WOC guidelines has not been completed satisfactorily. The lacking component in the implementation of MEWS and WOC is the documentation of action taken upon finding an abnormal value. Unsuccessful implementation could result in incorrect results from evaluation of an early warning system. We suggest a redesign of the training programme to educate staff in recognising and caring for critically ill patients at Naestved Hospital. PMID- 23922908 TI - Chromosome painting in three species of buteoninae: a cytogenetic signature reinforces the monophyly of South American species. AB - Buteoninae (Falconiformes, Accipitridae) consist of the widely distributed genus Buteo, and several closely related species in a group called "sub-buteonine hawks", such as Buteogallus, Parabuteo, Asturina, Leucopternis and Busarellus, with unsolved phylogenetic relationships. Diploid number ranges between 2n = 66 and 2n = 68. Only one species, L. albicollis had its karyotype analyzed by molecular cytogenetics. The aim of this study was to present chromosomal analysis of three species of Buteoninae: Rupornis magnirostris, Asturina nitida and Buteogallus meridionallis using fluorescence in situ hybridization (FISH) experiments with telomeric and rDNA probes, as well as whole chromosome probes derived from Gallus gallus and Leucopternis albicollis. The three species analyzed herein showed similar karyotypes, with 2n = 68. Telomeric probes showed some interstitial telomeric sequences, which could be resulted by fusion processes occurred in the chromosomal evolution of the group, including the one found in the tassociation GGA1p/GGA6. In fact, this association was observed in all the three species analyzed in this paper, and also in L. albicollis, suggesting that it represents a cytogenetic signature which reinforces the monophyly of Neotropical buteoninae species. PMID- 23922907 TI - Role of the Arabidopsis PIN6 auxin transporter in auxin homeostasis and auxin mediated development. AB - Plant-specific PIN-formed (PIN) efflux transporters for the plant hormone auxin are required for tissue-specific directional auxin transport and cellular auxin homeostasis. The Arabidopsis PIN protein family has been shown to play important roles in developmental processes such as embryogenesis, organogenesis, vascular tissue differentiation, root meristem patterning and tropic growth. Here we analyzed roles of the less characterised Arabidopsis PIN6 auxin transporter. PIN6 is auxin-inducible and is expressed during multiple auxin-regulated developmental processes. Loss of pin6 function interfered with primary root growth and lateral root development. Misexpression of PIN6 affected auxin transport and interfered with auxin homeostasis in other growth processes such as shoot apical dominance, lateral root primordia development, adventitious root formation, root hair outgrowth and root waving. These changes in auxin-regulated growth correlated with a reduction in total auxin transport as well as with an altered activity of DR5-GUS auxin response reporter. Overall, the data indicate that PIN6 regulates auxin homeostasis during plant development. PMID- 23922909 TI - Evaluation of nanoparticle uptake in co-culture cancer models. AB - Co-culture models are currently bridging the gap between classical cultures and in vivo animal models. Exploring this novel approach unlocks the possibility to mimic the tumor microenvironment in vitro, through the establishment of cancer stroma synergistic interactions. Notably, these organotypic models offer a perfect platform for the development and pre-clinical evaluation of candidate nanocarriers loaded with anti-tumoral drugs in a high throughput screening mode, with lower costs and absence of ethical issues. However, this evaluation was until now limited to co-culture systems established with precise cell ratios, not addressing the natural cell heterogeneity commonly found in different tumors. Therefore, herein the multifunctional nanocarriers efficiency was characterized in various fibroblast-MCF-7 co-culture systems containing different cell ratios, in order to unravel key design parameters that influence nanocarrier performance and the therapeutic outcome. The successful establishment of the co-culture models was confirmed by the tissue-like distribution of the different cells in culture. Nanoparticles incubation in the various co-culture systems reveals that these nanocarriers possess targeting specificity for cancer cells, indicating their suitability for being used in this illness therapy. Additionally, by using different co-culture ratios, different nanoparticle uptake profiles were obtained. These findings are of crucial importance for the future design and optimization of new drug delivery systems, since their real targeting capacity must be addressed in heterogenous cell populations, such as those found in tumors. PMID- 23922910 TI - A clinical tool for reducing central nervous system depression among neonates exposed to codeine through breast milk. AB - BACKGROUND: Neonates are commonly exposed to maternal codeine through breast milk. Central Nervous System (CNS) depression has been reported in up to 24% of nurslings following codeine exposure. In 2009, we developed guidelines to improve the safety of codeine use during breastfeeding based on previously established pharmacogenetic and clinical risk factors. The primary objective of this study was to prospectively evaluate the effectiveness of these guidelines in ensuring neonatal safety. METHODS AND FINDINGS: Women taking codeine for pain following caesarean section were given safety guidelines, including advice to use the lowest codeine dose for no longer than four days and to switch to a non-opioid when possible. Mothers provided a saliva sample for analysis of genes involved in opioid disposition, metabolism and response. A total of 238 consenting women participated. Neonatal sedation was reported in 2.1% (5/238) of breastfeeding women taking codeine according to our safety guidelines. This rate was eight fold lower than that reported in previous prospective studies. Women reporting sedated infants were taking codeine for a significantly longer period of time (4.80+/ 2.59 days vs. 2.52+/-1.58 days, p = 0.0018). While following the codeine safety guidelines, mothers were less likely to supplement with formula, reported lower rates of sedation in themselves and breastfed more frequently throughout the day when compared to previously reported rates. Genotyping analysis of cytochrome p450 2D6 (CYP2D6), uridine-diphosphate glucuronosyltransferase (UGT) 2B7, p glycoprotein (ABCB1), the mu-opioid receptor (OPRM1) and catechol-o demethyltransferase (COMT) did not predict codeine response in breastfeeding mother/infant pairs when following the safety guidelines. CONCLUSIONS: The only cases of CNS depression occurred when the length of codeine use exceeded the guideline recommendations. Neonatal safety of codeine can be improved using evidence-based guidelines, even in those deemed by genetics to be at high risk for toxicity. PMID- 23922912 TI - Low C-reactive protein levels in a traditional West-African population living in a malaria endemic area. AB - BACKGROUND: C-reactive protein (CRP) levels are reported to be elevated in populations of African descent living in affluent environments compared to populations of European ancestry. However, the natural history of CRP levels in populations of African descent living under adverse environments remains largely unknown. METHODS: CRP levels were measured with a high sensitivity assay in 624 apparently healthy individuals who contributed blood as part of a study on innate immune responsiveness in a traditional Ghanaian population living under adverse environmental conditions in a malaria endemic area. As a comparison, we included CRP measurements from 2931 apparently healthy individuals from the Dutch population that were included in the same batch of CRP analyses. Associations between CRP and body mass index (BMI), immune responsiveness, and P. falciparum parasitaemia were investigated. RESULTS: In an age- and sex-adjusted model, CRP levels were 0.54 mg/L lower in the Ghanaian compared to the Dutch cohort (1.52 vs. 0.98 mg/L, p<0.001). When accounting for the substantially higher average BMI in the Dutch compared to the Ghanaians (25.6 vs. 18.4 kg/m(2)) the difference in CRP levels disappeared. BMI associated positively with CRP in the Dutch but not in the Ghanaians. In individuals with an acute phase response, CRP levels were higher in the Ghanaian compared to the Dutch cohort (24.6 vs. 17.3 mg/L, p = 0.04). Levels of CRP were positively related to immune responsiveness and P. falciparum parasitaemia (all p<0.001) among Ghanaians. CONCLUSIONS: Our study demonstrates that West-Africans do not exhibit an inherently high inflammatory state. The role of genes, environment and gene-environment interaction in explaining reports of elevated CRP levels in populations of African ancestry when compared to other ethnicities living in affluent environments thus merits further investigation. PMID- 23922911 TI - Sequence analysis of the genome of piscine orthoreovirus (PRV) associated with heart and skeletal muscle inflammation (HSMI) in Atlantic salmon (Salmo salar). AB - Piscine orthoreovirus (PRV) is associated with heart- and skeletal muscle inflammation (HSMI) of farmed Atlantic salmon (Salmo salar). We have performed detailed sequence analysis of the PRV genome with focus on putative encoded proteins, compared with prototype strains from mammalian (MRV T3D)- and avian orthoreoviruses (ARV-138), and aquareovirus (GCRV-873). Amino acid identities were low for most gene segments but detailed sequence analysis showed that many protein motifs or key amino acid residues known to be central to protein function are conserved for most PRV proteins. For M-class proteins this included a proline residue in MU2 which, for MRV, has been shown to play a key role in both the formation and structural organization of virus inclusion bodies, and affect interferon-beta signaling and induction of myocarditis. Predicted structural similarities in the inner core-forming proteins lambda1 and sigma2 suggest a conserved core structure. In contrast, low amino acid identities in the predicted PRV surface proteins MU1, sigma1 and sigma3 suggested differences regarding cellular interactions between the reovirus genera. However, for sigma1, amino acid residues central for MRV binding to sialic acids, and cleavage- and myristoylation sites in MU1 required for endosomal membrane penetration during infection are partially or wholly conserved in the homologous PRV proteins. In PRV sigma3 the only conserved element found was a zinc finger motif. We provide evidence that the S1 segment encoding sigma3 also encodes a 124 aa (p13) protein, which appears to be localized to intracellular Golgi-like structures. The S2 and L2 gene segments are also potentially polycistronic, predicted to encode a 71 aa- (p8) and a 98 aa (p11) protein, respectively. It is concluded that PRV has more properties in common with orthoreoviruses than with aquareoviruses. PMID- 23922914 TI - Cytokinin-induced parthenocarpic fruit development in tomato is partly dependent on enhanced gibberellin and auxin biosynthesis. AB - Fruit set of plants largely depends on the biosynthesis and crosstalk of phytohormones. To date the role of cytokinins (CKs) in the fruit development is less understood. Here, we showed that parthenocarpic fruit could be induced by 1 (2-chloro-4-pyridyl)-3-phenylurea (CPPU, an active CK) in tomato (Solanumlycopersicum cv. Micro-Tom). The fresh weight of CPPU-induced parthenocarpic fruits was comparable with that induced by GA3. Importantly, CPPU induced parthenocarpy was found to be compromised by simultaneous application of paclobutrazol (a GA biosynthesis inhibitor), and this effect could be restored by exogenous GA3. Like pollination, CPPU-induced fruit showed enhanced accumulation of GA1+3 and indole-3-acetic (IAA), which were accompanied by elevated expression of GA biosynthesis genes like SlGPS, SlGA20ox1, SlGA20ox2 and SlGA3ox1, and IAA biosynthesis gene ToFZY. Elevated GAs level in CPPU-induced fruits was also associated with down-regulation of GA inactivation genes, namely SlGA2ox1,2,3,4,5 in comparison with untreated control. These results suggested that CKs may induce parthenocarpy in tomato partially through modulation of GA and IAA metabolisms. PMID- 23922913 TI - Lysine-specific demethylase 1 (LSD1/KDM1A) contributes to colorectal tumorigenesis via activation of the Wnt/beta-catenin pathway by down-regulating Dickkopf-1 (DKK1) [corrected]. AB - We collected paired samples of tumor and adjacent normal colorectal tissues from 22 patients with colorectal carcinoma to compare the differences in the expression of lysine specific demethylase 1 (LSD1) in these two tissues. The results showed that in 19 paired samples (86.4%), LSD1 is more highly expressed in tumor tissue than in normal tissue. To explore the role of LSD1 in colorectal tumorigenesis, we used somatic cell gene targeting to generate an LSD1 knockout (KO) HCT 116 human colorectal cancer cell line as a research model. The analysis of phenotypic changes showed that LSD1 KO colorectal cancer cells are less tumorigenic, both in vivo and in vitro. The differential expression analysis of the cells by mRNA sequencing (RNA-Seq) yielded 2,663 differentially expressed genes, and 28 of these genes had highly significant differences (Q <0.01). We then selected the 4 colorectal cancer-related genes ADM, DKK1, HAS3 and SMURF2 for quantitative real-time PCR verification. The results showed that the differences in the expression of ADM, DKK1 and HAS3 were consistent with those measured using the RNA-Seq data. As DKK1 was the gene with the most significant differential expression, we analyzed the key proteins of the DKK1-related Wnt/beta-catenin signaling pathway and found that, after knocking out LSD1, the amount of free beta-catenin translocated to the nucleus was significantly reduced and that the transcription of the signaling pathway target gene c-Myc was down regulated. Our studies show that LSD1 activates the Wnt/beta-catenin signaling pathway by down-regulating the pathway antagonist DKK1, which may be one of the mechanisms leading to colorectal tumorigenesis. PMID- 23922915 TI - Elimination of aberrant DRG circuitries in Sema3A mutant mice leads to extensive neuronal deficits. AB - Axon guidance molecules determine the pattern of neuronal circuits. Accuracy of the process is ensured by unknown mechanisms that correct early guidance errors. Since the time frame of error correction in Sema3A null mice partly overlaps with the period of naturally occurring cell death in dorsal root ganglia (DRG) development, we tested the hypothesis that apoptosis of misguided neurons enables error correction. We crossed BAX null mice, in which DRG apoptosis is blocked, with Sema3A null mice to induce errors. Analyses of these double-null mouse embryos showed that the elimination of abnormal projections is not blocked in the absence of BAX. Surprisingly however, there are fewer surviving neurons in Sema3A null or Sema3A/BAX double-null newborn mice than in wild-type mice. These results suggest that guidance errors are corrected by a BAX-independent cell death mechanism. Thus, aberrant axonal guidance may lead to reductions in neuronal numbers to suboptimal levels, perhaps increasing the likelihood of neuropathological consequences later in life. PMID- 23922916 TI - Structural and functional characterization of the recombinant death domain from death-associated protein kinase. AB - Death-associated protein kinase (DAPk) is a calcium/calmodulin-regulated Ser/Thr protein kinase that functions at an important point of integration for cell death signaling pathways. DAPk has a structurally unique multi-domain architecture, including a C-terminally positioned death domain (DD) that is a positive regulator of DAPk activity. In this study, recombinant DAPk-DD was observed to aggregate readily and could not be prepared in sufficient yield for structural analysis. However, DAPk-DD could be obtained as a soluble protein in the form of a translational fusion protein with the B1 domain of streptococcal protein G. In contrast to other DDs that adopt the canonical six amphipathic alpha-helices arranged in a compact fold, the DAPk-DD was found to possess surprisingly low regular secondary structure content and an absence of a stable globular fold, as determined by circular dichroism (CD), NMR spectroscopy and a temperature dependent fluorescence assay. Furthermore, we measured the in vitro interaction between extracellular-regulated kinase-2 (ERK2) and various recombinant DAPk-DD constructs. Despite the low level of structural order, the recombinant DAPk-DD retained the ability to interact with ERK2 in a 1?1 ratio with a K d in the low micromolar range. Only the full-length DAPk-DD could bind ERK2, indicating that the apparent 'D-motif' located in the putative sixth helix of DAPk-DD is not sufficient for ERK2 recognition. CD analysis revealed that binding of DAPk-DD to ERK2 is not accompanied by a significant change in secondary structure. Taken together our data argue that the DAPk-DD, when expressed in isolation, does not adopt a classical DD fold, yet in this state retains the capacity to interact with at least one of its binding partners. The lack of a stable globular structure for the DAPk-DD may reflect either that its folding would be supported by interactions absent in our experimental set-up, or a limitation in the structural bioinformatics assignment of the three-dimensional structure. PMID- 23922917 TI - SIRT1 is a direct coactivator of thyroid hormone receptor beta1 with gene specific actions. AB - Sirtuin 1 (SIRT1) NAD(+)-dependent deacetylase regulates energy metabolism by modulating expression of genes involved in gluconeogenesis and other liver fasting responses. While many effects of SIRT1 on gene expression are mediated by deacetylation and activation of peroxisome proliferator activated receptor coactivator alpha (PGC-1alpha), SIRT1 also binds directly to DNA bound transcription factors, including nuclear receptors (NRs), to modulate their activity. Since thyroid hormone receptor beta1 (TRbeta1) regulates several SIRT1 target genes in liver and interacts with PGC-1alpha, we hypothesized that SIRT1 may influence TRbeta1. Here, we confirm that SIRT1 cooperates with PGC-1alpha to enhance response to triiodothyronine, T3. We also find, however, that SIRT1 stimulates TRbeta1 activity in a manner that is independent of PGC-1alpha but requires SIRT1 deacetylase activity. SIRT1 interacts with TRbeta1 in vitro, promotes TRbeta1 deacetylation in the presence of T3 and enhances ubiquitin dependent TRbeta1 turnover; a common response of NRs to activating ligands. More surprisingly, SIRT1 knockdown only strongly inhibits T3 response of a subset of TRbeta1 target genes, including glucose 6 phosphatase (G-6-Pc), and this is associated with blockade of TRbeta1 binding to the G-6-Pc promoter. Drugs that target the SIRT1 pathway, resveratrol and nicotinamide, modulate T3 response at dual TRbeta1/SIRT1 target genes. We propose that SIRT1 is a gene-specific TRbeta1 co-regulator and TRbeta1/SIRT1 interactions could play important roles in regulation of liver metabolic response. Our results open possibilities for modulation of subsets of TR target genes with drugs that influence the SIRT1 pathway. PMID- 23922918 TI - Isolation and characterization of a conserved domain in the eremophyte H+-PPase family. AB - H(+)-translocating inorganic pyrophosphatases (H(+)-PPase) were recognized as the original energy donors in the development of plants. A large number of researchers have shown that H(+)-PPase could be an early-originated protein that participated in many important biochemical and physiological processes. In this study we cloned 14 novel sequences from 7 eremophytes: Sophora alopecuroid (Sa), Glycyrrhiza uralensis (Gu), Glycyrrhiza inflata (Gi), Suaeda salsa (Ss), Suaeda rigida (Sr), Halostachys caspica (Hc), and Karelinia caspia (Kc). These novel sequences included 6 ORFs and 8 fragments, and they were identified as H(+) PPases based on the typical conserved domains. Besides the identified domains, sequence alignment showed that there still were two novel conserved motifs. A phylogenetic tree was constructed, including the 14 novel H(+)-PPase amino acid sequences and the other 34 identified H(+)-PPase protein sequences representing plants, algae, protozoans and bacteria. It was shown that these 48 H(+)-PPases were classified into two groups: type I and type II H(+)-PPase. The novel 14 eremophyte H(+)-PPases were classified into the type I H(+)-PPase. The 3D structures of these H(+)-PPase proteins were predicted, which suggested that all type I H(+)-PPases from higher plants and algae were homodimers, while other type I H(+)-PPases from bacteria and protozoans and all type II H(+)-PPases were monomers. The 3D structures of these novel H(+)-PPases were homodimers except for SaVP3, which was a monomer. This regular structure could provide important evidence for the evolutionary origin and study of the relationship between the structure and function among members of the H(+)-PPase family. PMID- 23922919 TI - Yeast one-hybrid ggamma recruitment system for identification of protein lipidation motifs. AB - Fatty acids and isoprenoids can be covalently attached to a variety of proteins. These lipid modifications regulate protein structure, localization and function. Here, we describe a yeast one-hybrid approach based on the Ggamma recruitment system that is useful for identifying sequence motifs those influence lipid modification to recruit proteins to the plasma membrane. Our approach facilitates the isolation of yeast cells expressing lipid-modified proteins via a simple and easy growth selection assay utilizing G-protein signaling that induces diploid formation. In the current study, we selected the N-terminal sequence of Galpha subunits as a model case to investigate dual lipid modification, i.e., myristoylation and palmitoylation, a modification that is widely conserved from yeast to higher eukaryotes. Our results suggest that both lipid modifications are required for restoration of G-protein signaling. Although we could not differentiate between myristoylation and palmitoylation, N-terminal position 7 and 8 play some critical role. Moreover, we tested the preference for specific amino-acid residues at position 7 and 8 using library-based screening. This new approach will be useful to explore protein-lipid associations and to determine the corresponding sequence motifs. PMID- 23922920 TI - The microbial community in the feces of the white rhinoceros (Ceratotherium simum) as determined by barcoded pyrosequencing analysis. AB - As a non-ruminant herbivore, the white rhinoceros has the ability to utilize fibrous plant matter through microbial fermentation in the hindgut. So far, there has been no report using molecular techniques to study the gut microbiota of the white rhinoceros. We used barcoded pyrosequencing to characterize 105,651 sequences of 16S rRNA genes obtained from fecal samples from five white rhinoceroses. Results showed that Firmicutes and Bacteroidetes were the predominant phyla in the samples, which were comprised largely of unclassified bacteria. The microbiota of one animal treated with drug therapy differed from those in other healthy animals, and was dominated by Aerococcus -related bacteria. The core microbiota in the healthy rhinoceros were dominated by phyla Firmicutes and Bacteroidetes, represented by the Ruminococcaceae, Lachnospiraceae, Rikenellaceae and Prevotellaceae families. The present work provides a phylogenetic framework for understanding the complex microbial community of the rhinoceros; however, further studies are required to link the distinctive microbiota with their digestive role in the hindgut of the white rhinoceros. PMID- 23922921 TI - Ningaloo reef: shallow marine habitats mapped using a hyperspectral sensor. AB - Research, monitoring and management of large marine protected areas require detailed and up-to-date habitat maps. Ningaloo Marine Park (including the Muiron Islands) in north-western Australia (stretching across three degrees of latitude) was mapped to 20 m depth using HyMap airborne hyperspectral imagery (125 bands) at 3.5 m resolution across the 762 km(2) of reef environment between the shoreline and reef slope. The imagery was corrected for atmospheric, air-water interface and water column influences to retrieve bottom reflectance and bathymetry using the physics-based Modular Inversion and Processing System. Using field-validated, image-derived spectra from a representative range of cover types, the classification combined a semi-automated, pixel-based approach with fuzzy logic and derivative techniques. Five thematic classification levels for benthic cover (with probability maps) were generated with varying degrees of detail, ranging from a basic one with three classes (biotic, abiotic and mixed) to the most detailed with 46 classes. The latter consisted of all abiotic and biotic seabed components and hard coral growth forms in dominant or mixed states. The overall accuracy of mapping for the most detailed maps was 70% for the highest classification level. Macro-algal communities formed most of the benthic cover, while hard and soft corals represented only about 7% of the mapped area (58.6 km(2)). Dense tabulate coral was the largest coral mosaic type (37% of all corals) and the rest of the corals were a mix of tabulate, digitate, massive and soft corals. Our results show that for this shallow, fringing reef environment situated in the arid tropics, hyperspectral remote sensing techniques can offer an efficient and cost-effective approach to mapping and monitoring reef habitats over large, remote and inaccessible areas. PMID- 23922922 TI - Elevated CO2 levels do not affect the shell structure of the bivalve Arctica islandica from the Western Baltic. AB - Shells of the bivalve Arctica islandica are used to reconstruct paleo environmental conditions (e.g. temperature) via biogeochemical proxies, i.e. biogenic components that are related closely to environmental parameters at the time of shell formation. Several studies have shown that proxies like element and isotope-ratios can be affected by shell growth and microstructure. Thus it is essential to evaluate the impact of changing environmental parameters such as high pCO2 and consequent changes in carbonate chemistry on shell properties to validate these biogeochemical proxies for a wider range of environmental conditions. Growth experiments with Arctica islandica from the Western Baltic Sea kept under different pCO2 levels (from 380 to 1120 uatm) indicate no affect of elevated pCO2 on shell growth or crystal microstructure, indicating that A. islandica shows an adaptation to a wider range of pCO2 levels than reported for other species. Accordingly, proxy information derived from A. islandica shells of this region contains no pCO2 related bias. PMID- 23922923 TI - In vitro efficient transfection by CM18-Tat11 hybrid peptide: a new tool for gene delivery applications. AB - Cell penetrating peptides (CPPs) are actively researched as non-viral molecular carriers for the controlled delivery of nucleic acids into cells, but widespread application is severely hampered by their trapping into endosomes. Here we show that the recently introduced endosomolytic CM18-Tat11 hybrid peptide (KWKLFKKIGAVLKVLTTG-YGRKKRRQRRR, residues 1-7 of Cecropin-A, 2-12 of Melittin, and 47-57 of HIV-1 Tat protein) can be exploited to obtain a self-assembled peptide-DNA vector which maintains the CM18-Tat11 ability to enter cells and destabilize vesicular membranes, concomitantly yielding high DNA transfection efficiency with no detectable cytotoxic effects. Different peptide-DNA stoichiometric ratios were tested to optimize vector size, charge, and stability characteristics. The transfection efficiency of selected candidates is quantitatively investigated by the luciferase-reporter assay. Vector intracellular trafficking is monitored in real time and in live cells by confocal microscopy. In particular, fluorescence resonant energy transfer (FRET) between suitably-labeled peptide and DNA modules was exploited to monitor complex disassembly during endocytosis, and this process is correlated to transfection timing and efficiency. We argue that these results can open the way to the rational design and application of CM18-Tat11-based systems for gene-delivery purposes. PMID- 23922924 TI - Aliskiren and amlodipine in the management of essential hypertension: meta analysis of randomized controlled trials. AB - BACKGROUND: Aliskiren is a novel renin-angiotensin aldosterone system (RAAS) inhibitor, the combination therapy of aliskiren and amlodipine for blood pressure control have been reported recently. The primary objective of this analysis is to review recently reported randomized controlled trials (RCTs) to compare antihypertensive effects and adverse events between mono (amlodipine or aliskiren alone) and combination therapy of both medicines. METHODS: Databases for the search included Pubmed, Embase and the Cochrane Central Register of Controlled Trials. Revman v5.0 statistical program was used to analyze the data. Weighted mean differences (WMD) with a 95% confidence interval (CI) were used for the calculation of continuous data, and relative risk (RR) with a 95% CI was used for dichotomous data. RESULTS: We analyzed the data from 7 RCTs for a total of 6074 participants in this meta-analysis. We found that the aliskiren/amlodipine combination therapy had a stronger effect in lowering blood pressure as compared with the monotherapy using aliskiren (SBP: WMD = -10.42, 95% CI -13.03~-7.82, P<0.00001; DBP: WMD = -6.60, 95% CI -7.22~-5.97, P<0.00001) or amlodipine (SBP: WMD = -4.85, 95% CI -6.88~-2.81, P<0.00001; DBP: WMD = -2.91, 95% CI -3.85~-1.97, P<0.00001). No differences were found in terms of adverse events between combination therapy and monotherapy, except for the rates of peripheral edema and hypokalaemia which were significantly lower in the combination therapy than in the amlodipine monotherapy (RR = 0.78, 0.66~0.92, P = 0.004; RR = 0.51, 0.27~0.97, P = 0.04). Similar antihypertensive effects were found in both obese (body mass index > = 30 kg/m(2)) hypertensive and non-obese (body mass index <30 kg/m(2)) hypertensive patients. Moreover, there was no difference with the blood pressure lowering or adverse effects with regards to the combination therapy in both subgroups. CONCLUSION: We found that aliskiren/amlodipine combination therapy provided a more effective blood pressure reduction than monotherapy with either drug without increase in the occurrence of adverse events. PMID- 23922925 TI - Reproductive effects of two neonicotinoid insecticides on mouse sperm function and early embryonic development in vitro. AB - Acetamiprid (ACE) and imidacloprid (IMI) are two major members in the family of neonicotinoid pesticides, which are synthesized with a higher selectivity to insects. The present study determined and compared in vitro effects of ACE, IMI and nicotine on mammalian reproduction by using an integrated testing strategy for reproductive toxicology, which covered sperm quality, sperm penetration into oocytes and preimplantation embryonic development. Direct chemical exposure (500 uM or 5 mM) on spermatozoa during capacitation was performed, and in vitro fertilization (IVF) process, zygotes and 2-cell embryos were respectively incubated with chemical-supplemented medium until blastocyst formation to evaluate the reproductive toxicity of these chemicals and monitor the stages mainly affected. Generally, treatment of 500 uM or 5 mM chemicals for 30 min did not change sperm motility and DNA integrity significantly but the fertilization ability in in vitro fertilization (IVF) process, indicating that IVF process could detect and distinguish subtle effect of spermatozoa exposed to different chemicals. Culture experiment in the presence of chemicals in medium showed that fertilization process and zygotes are adversely affected by direct exposure of chemicals (P<0.05), in an order of nicotine>IMI>ACE, whereas developmental progression of 2-cell stage embryos was similar to controls (P>0.05). These findings unveiled the hazardous effects of neonicotinoid pesticides exposure on mammalian sperm fertilization ability as well as embryonic development, raising the concerns that neonicotinoid pesticides may pose reproductive risks on human reproductive health, especially in professional populations. PMID- 23922926 TI - Association between physician specialty and risk of prescribing inappropriate pill splitting. AB - BACKGROUND: Prescription errors that occur due to the process of pill splitting are a common medication problem; however, available prescription information involving inappropriate pill splitting and its associated factors is lacking. METHODS: We retrospectively evaluated a cohort of ambulatory prescriptions involving extended-release or enteric-coated formulations in a Taiwan medical center during a 5-month period in 2010. For this study, those pill splitting prescriptions involving special oral formulations were defined as inappropriate prescriptions. Information obtained included patient demographics, prescriber specialty and prescription details, which were assessed to identify factors associated with inappropriate pill splitting. RESULTS: There were 1,252 inappropriate prescriptions identified in this cohort study, representing a prescription frequency for inappropriate pill splitting of 1.0% among 124,300 prescriptions with special oral formulations. Among 35 drugs with special oral formulations in our study, 20 different drugs (57.1%, 20/35) had ever been prescribed to split. Anti-diabetic agents, cardiovascular agents and central nervous system agents were the most common drug classes involved in inappropriate splitting. The rate of inappropriate pill splitting was higher in older (over 65 years of age) patients (1.1%, 832/75,387). Eighty-seven percent (1089/1252) of inappropriate prescriptions were prescribed by internists. The rate of inappropriate pill splitting was highest from endocrinologists (3.4%, 429/12,477), nephrologists (1.3%, 81/6,028) and cardiologists (1.3%, 297/23,531). Multivariate logistic regression analysis revealed that the strongest factor associated with individual specific drug of inappropriate splitting was particular physician specialties. CONCLUSION: This study provides important insights into the inappropriate prescription of special oral formulation related to pill splitting, and helps to aggregate information that can assist medical professionals in creating processes for reducing inappropriate pill splitting in the future. PMID- 23922927 TI - Recognition of higher order patterns in proteins: immunologic kernels. AB - By applying analysis of the principal components of amino acid physical properties we predicted cathepsin cleavage sites, MHC binding affinity, and probability of B-cell epitope binding of peptides in tetanus toxin and in ten diverse additional proteins. Cross-correlation of these metrics, for peptides of all possible amino acid index positions, each evaluated in the context of a +/-25 amino acid flanking region, indicated that there is a strongly repetitive pattern of short peptides of approximately thirty amino acids each bounded by cathepsin cleavage sites and each comprising B-cell linear epitopes, MHC-I and MHC-II binding peptides. Such "immunologic kernel" peptides comprise all signals necessary for adaptive immunologic cognition, response and recall. The patterns described indicate a higher order spatial integration that forms a symbolic logic coordinating the adaptive immune system. PMID- 23922928 TI - Ectopic Runx1 expression rescues Tal-1-deficiency in the generation of primitive and definitive hematopoiesis. AB - The transcription factors SCL/Tal-1 and AML1/Runx1 control the generation of pluripotent hematopoietic stem cells (pHSC) and, thereby, primitive and definitive hematopoiesis, during embryonic development of the mouse from mesoderm. Thus, Runx1-deficient mice generate primitive, but not definitive hematopoiesis, while Tal-1-deficient mice are completely defective. Primitive as well as definitive hematopoiesis can be developed "in vitro" from embryonic stem cells (ESC). We show that wild type, as well as Tal-1(-/-) and Runx1(-/-) ESCs, induced to differentiation, all expand within 5 days to comparable numbers of Flk1(+) mesodermal cells. While wild type ESCs further differentiate to primitive and definitive erythrocytes, to c-fms(+)Gr1(+)Mac1(+) myeloid cells, and to B220(+)CD19(+) B- and CD4(+)/CD8(+) T-lymphoid cells, Runx1(-/-) ESCs, as expected, only develop primitive erythrocytes, and Tal-1(-/-) ESCs do not generate any hematopoietic cells. Retroviral transduction with Runx1 of Runx1(-/ ) ESCs, differentiated for 4 days to mesoderm, rescues definitive erythropoiesis, myelopoiesis and lymphopoiesis, though only with 1-10% of the efficiencies of wild type ESC hematopoiesis. Surprisingly, Tal-1(-/-) ESCs can also be rescued at comparably low efficiencies to primitive and definitive erythropoiesis, and to myelopoiesis and lymphopoiesis by retroviral transduction with Runx1. These results suggest that Tal-1 expression is needed to express Runx1 in mesoderm, and that ectopic expression of Runx1 in mesoderm is sufficient to induce primitive as well as definitive hematopoiesis in the absence of Tal-1. Retroviral transduction of "in vitro" differentiating Tal-1(-/-) and Runx1(-/-) ESCs should be a useful experimental tool to probe selected genes for activities in the generation of hematopoietic progenitors "in vitro", and to assess the potential transforming activities in hematopoiesis of mutant forms of Tal-1 and Runx1 from acute myeloid leukemia and related tumors. PMID- 23922929 TI - Cisplatin and doxorubicin induce distinct mechanisms of ovarian follicle loss; imatinib provides selective protection only against cisplatin. AB - PURPOSE: Chemotherapy treatment in premenopausal women has been linked to ovarian follicle loss and premature ovarian failure; the exact mechanism by which this occurs is uncertain. Here, two commonly used chemotherapeutic agents (cisplatin and doxorubicin) were added to a mouse ovary culture system, to compare the sequence of events that leads to germ cell loss. The ability of imatinib mesylate to protect the ovary against cisplatin or doxorubicin-induced ovarian damage was also examined. EXPERIMENTAL DESIGN: Newborn mouse ovaries were cultured for a total of six days, exposed to a chemotherapeutic agent on the second day: this allowed for the examination of the earliest stages of follicle development. Cleaved PARP and TUNEL were used to assess apoptosis following drug treatment. Imatinib was added to cultures with cisplatin and doxorubicin to determine any protective effect. RESULTS: Histological analysis of ovaries treated with cisplatin showed oocyte-specific damage; in comparison doxorubicin preferentially caused damage to the granulosa cells. Cleaved PARP expression significantly increased for cisplatin (16 fold, p<0.001) and doxorubicin (3 fold, p<0.01). TUNEL staining gave little evidence of primordial follicle damage with either drug. Imatinib had a significant protective effect against cisplatin-induced follicle damage (p<0.01) but not against doxorubicin treatment. CONCLUSION: Cisplatin and doxorubicin both induced ovarian damage, but in a markedly different pattern, with imatinib protecting the ovary against damage by cisplatin but not doxorubicin. Any treatment designed to block the effects of chemotherapeutic agents on the ovary may need to be specific to the drug(s) the patient is exposed to. PMID- 23922930 TI - Larger body size at metamorphosis enhances survival, growth and performance of young cane toads (Rhinella marina). AB - Body size at metamorphosis is a key trait in species (such as many anurans) with biphasic life-histories. Experimental studies have shown that metamorph size is highly plastic, depending upon larval density and environmental conditions (e.g. temperature, food supply, water quality, chemical cues from conspecifics, predators and competitors). To test the hypothesis that this developmental plasticity is adaptive, or to determine if inducing plasticity can be used to control an invasive species, we need to know whether or not a metamorphosing anuran's body size influences its subsequent viability. For logistical reasons, there are few data on this topic under field conditions. We studied cane toads (Rhinella marina) within their invasive Australian range. Metamorph body size is highly plastic in this species, and our laboratory studies showed that larger metamorphs had better locomotor performance (both on land and in the water), and were more adept at catching and consuming prey. In mark-recapture trials in outdoor enclosures, larger body size enhanced metamorph survival and growth rate under some seasonal conditions. Larger metamorphs maintained their size advantage over smaller siblings for at least a month. Our data support the critical but rarely-tested assumption that all else being equal, larger body size at metamorphosis is likely to enhance an individual's long term viability. Thus, manipulations to reduce body size at metamorphosis in cane toads may help to reduce the ecological impact of this invasive species. PMID- 23922931 TI - Analysis of unannotated equine transcripts identified by mRNA sequencing. AB - Sequencing of equine mRNA (RNA-seq) identified 428 putative transcripts which do not map to any previously annotated or predicted horse genes. Most of these encode the equine homologs of known protein-coding genes described in other species, yet the potential exists to identify novel and perhaps equine-specific gene structures. A set of 36 transcripts were prioritized for further study by filtering for levels of expression (depth of RNA-seq read coverage), distance from annotated features in the equine genome, the number of putative exons, and patterns of gene expression between tissues. From these, four were selected for further investigation based on predicted open reading frames of greater than or equal to 50 amino acids and lack of detectable homology to known genes across species. Sanger sequencing of RT-PCR amplicons from additional equine samples confirmed expression and structural annotation of each transcript. Functional predictions were made by conserved domain searches. A single transcript, expressed in the cerebellum, contains a putative kruppel-associated box (KRAB) domain, suggesting a potential function associated with zinc finger proteins and transcriptional regulation. Overall levels of conserved synteny and sequence conservation across a 1MB region surrounding each transcript were approximately 73% compared to the human, canine, and bovine genomes; however, the four loci display some areas of low conservation and sequence inversion in regions that immediately flank these previously unannotated equine transcripts. Taken together, the evidence suggests that these four transcripts are likely to be equine-specific. PMID- 23922932 TI - The aqueous extract of Ficus religiosa induces cell cycle arrest in human cervical cancer cell lines SiHa (HPV-16 Positive) and apoptosis in HeLa (HPV-18 positive). AB - Natural products are being extensively explored for their potential to prevent as well as treat cancer due to their ability to target multiple molecular pathways. Ficus religiosa has been shown to exert diverse biological activities including apoptosis in breast cancer cell lines. In the present study, we report the anti neoplastic potential of aqueous extract of F. religiosa (FRaq) bark in human cervical cancer cell lines, SiHa and HeLa. FRaq altered the growth kinetics of SiHa (HPV-16 positive) and HeLa (HPV-18 positive) cells in a dose-dependent manner. It blocked the cell cycle progression at G1/S phase in SiHa that was characterized by an increase in the expression of p53, p21 and pRb proteins with a simultaneous decrease in the expression of phospho Rb (ppRb) protein. On the other hand, in HeLa, FRaq induced apoptosis through an increase in intracellular Ca(2+) leading to loss of mitochondrial membrane potential, release of cytochrome c and increase in the expression of caspase-3. Moreover, FRaq reduced the migration as well as invasion capability of both the cervical cancer cell lines accompanied with downregulation of MMP-2 and Her-2 expression. Interestingly, FRaq reduced the expression of viral oncoproteins E6 and E7 in both the cervical cancer cell lines. All these data suggest that F. religiosa could be explored for its chemopreventive potential in cervical cancer. PMID- 23922933 TI - Crosstalk between Shh and TGF-beta signaling in cyclosporine-enhanced cell proliferation in human gingival fibroblasts. AB - BACKGROUND: Immunosuppressant cyclosporine-A induces gingival hyperplasia, which is characterized by increased fibroblast proliferation and overproduction of extracellular matrix components and regulated by transforming growth factor-beta (TGF-beta). The TGF-beta and Sonic hedgehog (Shh) pathways both mediate cell proliferation. Crosstalk between these pathways in cancer has recently been proposed, but the hierarchical pattern of this crosstalk remains unclear. In normal fibroblasts, a TGF-beta-stimulating Shh pattern was observed in induced fibrosis. However, Shh pathway involvement in cyclosporine-enhanced gingival proliferation and the existence of crosstalk with the TGF-beta pathway remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: Cyclosporine enhanced mRNA and protein levels of TGF-beta and Shh in human gingival fibroblasts (RT-PCR and western blotting). A TGF-beta pathway inhibitor mitigated cyclosporine-enhanced cell proliferation and an Shh pathway inhibitor attenuated cyclosporine-enhanced proliferation in fibroblasts (MTS assay and/or RT-PCR of PCNA). Exogenous TGF beta increased Shh expression; however, exogenous Shh did not alter TGF-beta expression. The TGF-beta pathway inhibitor mitigated cyclosporine-upregulated Shh expression, but the Shh pathway inhibitor did not alter cyclosporine-upregulated TGF-beta expression. CONCLUSIONS/SIGNIFICANCE: The TGF-beta and Shh pathways mediate cyclosporine-enhanced gingival fibroblast proliferation. Exogenous TGF beta increased Shh expression, and inhibition of TGF-beta signaling abrogated the cyclosporine-induced upregulation of Shh expression; however, TGF-beta expression appeared unchanged by enhanced or inhibited Shh signaling. This is the first study demonstrating the role of Shh in cyclosporine-enhanced gingival cell proliferation; moreover, it defines a hierarchical crosstalk pattern in which TGF beta regulates Shh in gingival fibroblasts. Understanding the regulation of cyclosporine-related Shh and TGF-beta signaling and crosstalk in gingival overgrowth will clarify the mechanism of cyclosporine-induced gingival enlargement and help develop targeted therapeutics for blocking these pathways, which can be applied in pre-clinical and clinical settings. PMID- 23922934 TI - Progression of kidney disease in non-diabetic patients with coronary artery disease: predictive role of circulating matrix metalloproteinase-2, -3, and -9. AB - BACKGROUND: Circulating matrix metalloproteinase (MMP)-2, -3 and -9 are well recognized in predicting cardiovascular outcome in coronary artery disease (CAD), but their risks for chronic kidney disease (CKD) are lacking. Therefore, the present study aimed to investigate whether circulating MMP levels could independently predict future kidney disease progression in non-diabetic CAD patients. METHODS: The prospective study enrolled 251 non-diabetic subjects referred for coronary angiography, containing normal coronary artery (n = 30) and CAD with insignificant (n = 95) and significant (n = 126) stenosis. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula. eGFR decline rate was calculated and the primary endpoint was a decline in eGFR over 25% from baseline. RESULTS: The eGFR decline rate (ml/min/1.73 m(2) per year) in patients with CAD (1.22 [-1.27, 1.05]) was greater than that in those with normal coronary artery (0.21 [-2.63, 0.47], P<0.01). The circulating MMP-2, -3 and -9 were independently associated with faster eGFR decline among CAD patients. The mean follow-up period was 8.5+/-2.4 years, and 39 patients reached the primary endpoint. In multivariate Cox regression model, the adjusted hazard ratios of MMP 2 >=861 ng/mL, MMP-3 >=227 ng/mL and MMP-9 >=49 ng/mL for predicting CKD progression were 2.47 (95% CI, 1.21 to 5.07), 2.15 (1.12 to 4.18), and 4.71 (2.14 to 10.4), respectively. While added to a model of conventional risk factors and baseline eGFR, MMP-2, -3 and -9 further significantly improved the model predictability for CKD progression (c statistic, 0.817). In the sensitivity analyses, the results were similar no matter if we changed the endpoints of a decline of >20% in eGFR from baseline or final eGFR < 60 mL/min/1.73 m(2). CONCLUSION: Circulating MMP-2, -3 and -9 are independently associated with kidney disease progression in non-diabetic CAD patients and add incremental predictive power to conventional risk factors. PMID- 23922935 TI - Ursolic acid inhibits adipogenesis in 3T3-L1 adipocytes through LKB1/AMPK pathway. AB - BACKGROUND: Ursolic acid (UA) is a triterpenoid compound with multiple biological functions. This compound has recently been reported to possess an anti-obesity effect; however, the mechanisms are less understood. OBJECTIVE: As adipogenesis plays a critical role in obesity, the present study was conducted to investigate the effect of UA on adipogenesis and mechanisms of action in 3T3-L1 preadipocytes. METHODS AND RESULTS: The 3T3-L1 preadipocytes were induced to differentiate in the presence or absence of UA for 6 days. The cells were determined for proliferation, differentiation, fat accumulation as well as the protein expressions of molecular targets that regulate or are involved in fatty acid synthesis and oxidation. The results demonstrated that ursolic acid at concentrations ranging from 2.5 uM to 10 uM dose-dependently attenuated adipogenesis, accompanied by reduced protein expression of CCAAT element binding protein beta (C/EBPbeta), peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT element binding protein alpha (C/EBPalpha) and sterol regulatory element binding protein 1c (SREBP-1c), respectively. Ursolic acid increased the phosphorylation of acetyl-CoA carboxylase (ACC) and protein expression of carnitine palmitoyltransferase 1 (CPT1), but decreased protein expression of fatty acid synthase (FAS) and fatty acid-binding protein 4 (FABP4). Ursolic acid increased the phosphorylation of AMP-activated protein kinase (AMPK) and protein expression of (silent mating type information regulation 2, homolog) 1 (Sirt1). Further studies demonstrated that the anti-adipogenic effect of UA was reversed by the AMPK siRNA, but not by the Sirt1 inhibitor nicotinamide. Liver kinase B1 (LKB1), the upstream kinase of AMPK, was upregulated by UA. When LKB1 was silenced with siRNA or the inhibitor radicicol, the effect of UA on AMPK activation was diminished. CONCLUSIONS: Ursolic acid inhibited 3T3-L1 preadipocyte differentiation and adipogenesis through the LKB1/AMPK pathway. There is potential to develop UA into a therapeutic agent for the prevention or treatment of obesity. PMID- 23922936 TI - Sequencing and characterisation of an extensive Atlantic salmon (Salmo salar L.) microRNA repertoire. AB - Atlantic salmon (Salmo salar L.), a member of the family Salmonidae, is a totemic species of ecological and cultural significance that is also economically important in terms of both sports fisheries and aquaculture. These factors have promoted the continuous development of genomic resources for this species, furthering both fundamental and applied research. MicroRNAs (miRNA) are small endogenous non-coding RNA molecules that control spatial and temporal expression of targeted genes through post-transcriptional regulation. While miRNA have been characterised in detail for many other species, this is not yet the case for Atlantic salmon. To identify miRNAs from Atlantic salmon, we constructed whole fish miRNA libraries for 18 individual juveniles (fry, four months post hatch) and characterised them by Illumina high-throughput sequencing (total of 354,505,167 paired-ended reads). We report an extensive and partly novel repertoire of miRNA sequences, comprising 888 miRNA genes (547 unique mature miRNA sequences), quantify their expression levels in basal conditions, examine their homology to miRNAs from other species and identify their predicted target genes. We also identify the location and putative copy number of the miRNA genes in the draft Atlantic salmon reference genome sequence. The Atlantic salmon miRNAs experimentally identified in this study provide a robust large-scale resource for functional genome research in salmonids. There is an opportunity to explore the evolution of salmonid miRNAs following the relatively recent whole genome duplication event in salmonid species and to investigate the role of miRNAs in the regulation of gene expression in particular their contribution to variation in economically and ecologically important traits. PMID- 23922937 TI - Applying reversible mutations of nodulation and nitrogen-fixation genes to study social cheating in Rhizobium etli-legume interaction. AB - Mutualisms are common in nature, though these symbioses can be quite permeable to cheaters in situations where one individual parasitizes the other by discontinuing cooperation yet still exploits the benefits of the partnership. In the Rhizobium-legume system, there are two separate contexts, namely nodulation and nitrogen fixation processes, by which resident Rhizobium individuals can benefit by cheating. Here, we constructed reversible and irreversible mutations in key nodulation and nitrogen-fixation pathways of Rhizobium etli and compared their interaction with plant hosts Phaseolus vulgaris to that of wild type. We show that R. etli reversible mutants deficient in nodulation factor production are capable of intra-specific cheating, wherein mutants exploit other Rhizobium individuals capable of producing these factors. Similarly, we show that R. etli mutants are also capable of cheating inter-specifically, colonizing the host legume yet contributing nothing to the partnership in terms of nitrogen fixation. Our findings indicate that cheating is possible in both of these frameworks, seemingly without damaging the stability of the mutualism itself. These results may potentially help explain observations suggesting that legume plants are commonly infected by multiple bacterial lineages during the nodulation process. PMID- 23922938 TI - E- and p-selectins are essential for repopulation of chronic myelogenous and chronic eosinophilic leukemias in a scid mouse xenograft model. AB - In chronic myelogenous (CML) and chronic eosinophilic leukemia (CEL), neoplastic cells spread via the circulation into various extramedullary organs. As E- and P selectin constitute the starting point for the leucocyte adhesion/invasion cascade, and CEL and CML cells share many properties with normal granulocytes, we investigated the role of these selectins in CEL and CML cell expansion and organ invasion in a xenotransplantation model using scid mice. Using two human leukemic cell lines (EOL-1 and K562), we were able to show that E- and P-selectins mediate leukemia cell tethering and adherence in a laminar flow assay. While E-selectin binding depended on sialylated carbohydrate moieties, P-selectin binding was completely (K562) or partially (EOL-1) independent of these carbohydrates indicating the involvement of non-canonical selectin ligands. In a xenograft model in scid mice, both cell lines invaded the bone marrow and other organs, formed chloromas, and ultimately produced an overt leukemia. In contrast, in E- and P-selectin knockout scid mice, the cells failed to show engraftment in 8 out of 10 animals and even if they did engraft, they produced only little organ invasion and chloroma formation. Together, these data suggest that E- and P selectins play an important role in leukemic dissemination in CML and CEL. PMID- 23922939 TI - Beyond cytoarchitectonics: the internal and external connectivity structure of the caudate nucleus. AB - While there is ample evidence on the functional and connectional differentiation of the caudate nucleus (CN), less is known about its potential microstructural subdivisions. However, this latter aspect is critical to the local information processing capabilities of the tissue. We applied diffusion MRI, a non-invasive in vivo method that has great potential for the exploration of the brain structure-behavior relationship, in order to characterize the local fiber structure in gray matter of the CN. We report novel evidence of a functionally meaningful structural tri-partition along the anterior-posterior axis of this region. The connectivity of the CN subregions is in line with connectivity evidence from earlier invasive studies in animal models. In addition, histological validation using polarized light imaging (PLI) confirms these results, corroborating the notion that cortico-subcortico-cortical loops involve microstructurally differentiated regions in the caudate nucleus. Methodologically speaking, the comparison with advanced analysis of diffusion MRI shows that diffusion tensor imaging (DTI) yields a simplified view of the CN fiber architecture which is refined by advanced high angular resolution imaging methods. PMID- 23922940 TI - Cardiac complications associated with short-term mortality in schizophrenia patients hospitalized for pneumonia: a nationwide case-control study. AB - BACKGROUND: Pneumonia is one of most prevalent infectious diseases worldwide and is associated with considerable mortality. In comparison to general population, schizophrenia patients hospitalized for pneumonia have poorer outcomes. We explored the risk factors of short-term mortality in this population because the information is lacking in the literature. METHODS: In a nationwide schizophrenia cohort, derived from the National Health Insurance Research Database in Taiwan, that was hospitalized for pneumonia between 2000 and 2008 (n = 1,741), we identified 141 subjects who died during their hospitalizations or shortly after their discharges. Based on risk-set sampling in a 1?4 ratio, 468 matched controls were selected from the study cohort (i.e., schizophrenia cohort with pneumonia). Physical illnesses were categorized as pre-existing and incident illnesses that developed after pneumonia respectively. Exposures to medications were categorized by type, duration, and defined daily dose. We used stepwise conditional logistic regression to explore the risk factors for short-term mortality. RESULTS: Pre existing arrhythmia was associated with short-term mortality (adjusted risk ratio [RR] = 4.99, p<0.01). Several variables during hospitalization were associated with increased mortality risk, including incident arrhythmia (RR = 7.44, p<0.01), incident heart failure (RR = 5.49, p = 0.0183) and the use of hypoglycemic drugs (RR = 2.32, p<0.01). Furthermore, individual antipsychotic drugs (such as clozapine) known to induce pneumonia were not significantly associated with the risk. CONCLUSIONS: Incident cardiac complications following pneumonia are associated with increased short-term mortality. These findings have broad implications for clinical intervention and future studies are needed to clarify the mechanisms of the risk factors. PMID- 23922941 TI - Coordinate based meta-analysis of functional neuroimaging data; false discovery control and diagnostics. AB - Coordinate based meta-analysis (CBMA) is widely used to find regions of consistent activation across fMRI studies that have been selected for their functional relevance to a given hypothesis. Only reported coordinates (foci), and a model of their spatial uncertainty, are used in the analysis. Results are clusters of foci where multiple studies have reported in the same spatial region, indicating functional relevance. There are several published methods that perform the analysis in a voxel-wise manner, resulting in around 10(5) statistical tests, and considerable emphasis placed on controlling the risk of type 1 statistical error. Here we address this issue by dramatically reducing the number of tests, and by introducing a new false discovery rate control: the false cluster discovery rate (FCDR). FCDR is particularly interpretable and relevant to the results of CBMA, controlling the type 1 error by limiting the proportion of clusters that are expected under the null hypothesis. We also introduce a data diagnostic scheme to help ensure quality of the analysis, and demonstrate its use in the example studies. We show that we control the false clusters better than the widely used ALE method by performing numerical experiments, and that our clustering scheme results in more complete reporting of structures relevant to the functional task. PMID- 23922942 TI - Type IV pilus proteins form an integrated structure extending from the cytoplasm to the outer membrane. AB - The bacterial type IV pilus (T4P) is the strongest biological motor known to date as its retraction can generate forces well over 100 pN. Myxococcus xanthus, a delta-proteobacterium, provides a good model for T4P investigations because its social (S) gliding motility is powered by T4P. In this study, the interactions among M. xanthus T4P proteins were investigated using genetics and the yeast two hybrid (Y2H) system. Our genetic analysis suggests that there is an integrated T4P structure that crosses the inner membrane (IM), periplasm and the outer membrane (OM). Moreover, this structure exists in the absence of the pilus filament. A systematic Y2H survey provided evidence for direct interactions among IM and OM proteins exposed to the periplasm. For example, the IM lipoprotein PilP interacted with its cognate OM protein PilQ. In addition, interactions among T4P proteins from the thermophile Thermus thermophilus were investigated by Y2H. The results indicated similar protein-protein interactions in the T4P system of this non-proteobacterium despite significant sequence divergence between T4P proteins in T. thermophilus and M. xanthus. The observations here support the model of an integrated T4P structure in the absence of a pilus in diverse bacterial species. PMID- 23922943 TI - Overexpression of AtSHN1/WIN1 provokes unique defense responses. AB - The plant cell cuticle serves as the first barrier protecting plants from mechanical injury and invading pathogens. The cuticle can be breached by cutinase producing pathogens and the degradation products may activate pathogenesis signals in the invading pathogens. Cuticle degradation products may also trigger the plant's defense responses. Botrytis cinerea is an important plant pathogen, capable of attacking and causing disease in a wide range of plant species. Arabidopsis thaliana shn1-1D is a gain-of-function mutant, which has a modified cuticular lipid composition. We used this mutant to examine the effect of altering the whole-cuticle metabolic pathway on plant responses to B. cinerea attack. Following infection with B. cinerea, the shn1-1D mutant discolored more quickly, accumulated more H2O2, and showed accelerated cell death relative to wild-type (WT) plants. Whole transcriptome analysis of B. cinerea-inoculated shn1 1D vs. WT plants revealed marked upregulation of genes associated with senescence, oxidative stress and defense responses on the one hand, and genes involved in the magnitude of defense-response control on the other. We propose that altered cutin monomer content and composition of shn1-1D plants triggers excessive reactive oxygen species accumulation and release which leads to a strong, unique and uncontrollable defense response, resulting in plant sensitivity and death. PMID- 23922944 TI - Environmental maternal effects mediate the resistance of maritime pine to biotic stress. AB - The resistance to abiotic stress is increasingly recognised as being impacted by maternal effects, given that environmental conditions experienced by parent (mother) trees affect stress tolerance in offspring. We hypothesised that abiotic environmental maternal effects may also mediate the resistance of trees to biotic stress. The influence of maternal environment and maternal genotype and the interaction of these two factors on early resistance of Pinus pinaster half-sibs to the Fusarium circinatum pathogen was studied using 10 mother genotypes clonally replicated in two contrasting environments. Necrosis length of infected seedlings was 16% shorter in seedlings grown from favourable maternal environment seeds than in seedlings grown from unfavourable maternal environment seeds. Damage caused by F. circinatum was mediated by maternal environment and maternal genotype, but not by seed mass. Mechanisms unrelated to seed provisioning, perhaps of epigenetic nature, were probably involved in the transgenerational plasticity of P. pinaster, mediating its resistance to biotic stress. Our findings suggest that the transgenerational resistance of pines due to an abiotic stress may interact with the defensive response of pines to a biotic stress. PMID- 23922945 TI - A shift towards pro-inflammatory CD16+ monocyte subsets with preserved cytokine production potential after kidney transplantation. AB - BACKGROUND: The presence of monocyte-macrophage lineage cells in rejecting kidney transplants is associated with worse graft outcome. At present, it is still unclear how the monocyte-macrophage related responses develop after transplantation. Here, we studied the dynamics, phenotypic and functional characteristics of circulating monocytes during the first 6 months after transplantation and aimed to establish the differences between kidney transplant recipients and healthy individuals. METHODS: Phenotype, activation status and cytokine production capacity of classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++), monocytes were determined by flow cytometry in a cohort of 33 healthy individuals, 30 renal transplant recipients at transplantation, 19 recipients at 3 months and 16 recipients at 6 months after transplantation using a cross-sectional approach. RESULTS: The percentage of both CD16+ monocyte subsets was significantly increased in transplant recipients compared to healthy individuals, indicative of triggered innate immunity (p<=0.039). Enhanced production capacity of tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta was observed by monocytes at transplantation compared to healthy individuals. Remarkably, three months post transplant, in presence of potent immunosuppressive drugs and despite improved kidney function, interferon-gamma, tumor necrosis factor-alpha and interleukin-10 production capacity still remained significantly increased. CONCLUSION: Our data demonstrate a skewed balance towards pro-inflammatory CD16+ monocytes that is present at the time of transplantation and retained for at least 6 months after transplantation. This shift could be one of the important drivers of early post transplant cellular immunity. PMID- 23922946 TI - RFMirTarget: predicting human microRNA target genes with a random forest classifier. AB - MicroRNAs are key regulators of eukaryotic gene expression whose fundamental role has already been identified in many cell pathways. The correct identification of miRNAs targets is still a major challenge in bioinformatics and has motivated the development of several computational methods to overcome inherent limitations of experimental analysis. Indeed, the best results reported so far in terms of specificity and sensitivity are associated to machine learning-based methods for microRNA-target prediction. Following this trend, in the current paper we discuss and explore a microRNA-target prediction method based on a random forest classifier, namely RFMirTarget. Despite its well-known robustness regarding general classifying tasks, to the best of our knowledge, random forest have not been deeply explored for the specific context of predicting microRNAs targets. Our framework first analyzes alignments between candidate microRNA-target pairs and extracts a set of structural, thermodynamics, alignment, seed and position based features, upon which classification is performed. Experiments have shown that RFMirTarget outperforms several well-known classifiers with statistical significance, and that its performance is not impaired by the class imbalance problem or features correlation. Moreover, comparing it against other algorithms for microRNA target prediction using independent test data sets from TarBase and starBase, we observe a very promising performance, with higher sensitivity in relation to other methods. Finally, tests performed with RFMirTarget show the benefits of feature selection even for a classifier with embedded feature importance analysis, and the consistency between relevant features identified and important biological properties for effective microRNA-target gene alignment. PMID- 23922947 TI - Complete genome sequence of the first Chinese virulent infectious laryngotracheitis virus. AB - Infectious laryngotracheitis (ILT) is an acute respiratory disease caused by infectious laryngotracheitis virus (ILTV). The complete genome sequences of five attenuated ILTV vaccine strains and six virulent ILTV strains as well as two Australian ILTV field strains have been published in Australia and the USA so far. To provide the complete genome sequence information of ILTVs from different geographic regions, the whole genome of ILTV LJS09 isolated in China was sequenced. The genome of ILTV LJS09 was 153,201 bp in length, and contained 79 ORFs. Most of the ORFs had high sequence identity with homologous ORFs of reference strains. There was a large fragment deletion within the noncoding region of unique long region (UL) of ILTV LJS09 compared with SA2 and A20 strains. Though the origin binding protein of ILTV LJS09 existed, there was no AT rich region in strain LJS09. Alignments of the amino acid sequences revealed seven mutations at amino acids 71 (Arg -> Lys), 116 (Ala -> Val), 207 (Thr -> Ile) and 644 (Thr -> Ile) on glycoprotein B, 155 (Phe -> Ser) and 376 (Arg -> His) on glycoprotein D and 8 (Gln->Pro) on glycoprotein L of ILTV LJS09 compared to those of virulent strain (USDA) as ILTV LJS09 did not grow on chicken embryo fibroblasts, suggesting the role of the key seven amino acids in determination of the cell tropism of ILTV LJS09. This is the first complete genome sequence of the virulent strain of ILTV in Asia using the conventional PCR method, which will help to facilitate the future molecular biological research of ILTVs. PMID- 23922948 TI - Are the effects of response inhibition on gambling long-lasting? AB - A recent study has shown that short-term training in response inhibition can make people more cautious for up to two hours when making decisions. However, the longevity of such training effects is unclear. In this study we tested whether training in the stop-signal paradigm reduces risky gambling when the training and gambling task are separated by 24 hours. Two independent experiments revealed that the aftereffects of stop-signal training are negligible after 24 hours. This was supported by Bayes factors that provided strong support for the null hypothesis. These findings indicate the need to better optimise the parameters of inhibition training to achieve clinical efficacy, potentially by strengthening automatic associations between specific stimuli and stopping. PMID- 23922949 TI - MicroRNA-1 downregulation increases connexin 43 displacement and induces ventricular tachyarrhythmias in rodent hypertrophic hearts. AB - Downregulation of the muscle-specific microRNA-1 (miR-1) mediates the induction of pathologic cardiac hypertrophy. Dysfunction of the gap junction protein connexin 43 (Cx43), an established miR-1 target, during cardiac hypertrophy leads to ventricular tachyarrhythmias (VT). However, it is still unknown whether miR-1 and Cx43 are interconnected in the pro-arrhythmic context of hypertrophy. Thus, in this study we investigated whether a reduction in the extent of cardiac hypertrophy could limit the pathological electrical remodeling of Cx43 and the onset of VT by modulating miR-1 levels. Wistar male rats underwent mechanical constriction of the ascending aorta to induce pathologic left ventricular hypertrophy (LVH) and afterwards were randomly assigned to receive 10mg/kg valsartan, VAL (LVH+VAL) delivered in the drinking water or placebo (LVH) for 12 weeks. Sham surgery was performed for control groups. Programmed ventricular stimulation reproducibly induced VT in LVH compared to LVH+VAL group. When compared to sham controls, rats from LVH group showed a significant decrease of miR-1 and an increase of Cx43 expression and its ERK1/2-dependent phosphorylation, which displaces Cx43 from the gap junction. Interestingly, VAL administration to rats with aortic banding significantly reduced cardiac hypertrophy and prevented miR-1 down-regulation and Cx43 up-regulation and phosphorylation. Gain- and loss-of-function experiments in neonatal cardiomyocytes (NCMs) in vitro confirmed that Cx43 is a direct target of miR-1. Accordingly, in vitro angiotensin II stimulation reduced miR-1 levels and increased Cx43 expression and phosphorylation compared to un-stimulated NCMs. Finally, in vivo miR-1 cardiac overexpression by an adenoviral vector intra myocardial injection reduced Cx43 expression and phosphorylation in mice with isoproterenol-induced LVH. In conclusion, miR-1 regulates Cx43 expression and activity in hypertrophic cardiomyocytes in vitro and in vivo. Treatment of pressure overload-induced myocyte hypertrophy reduces the risk of life threatening VT by normalizing miR-1 expression levels with the consequent stabilization of Cx43 expression and activity within the gap junction. PMID- 23922951 TI - Interannual variability of fisheries economic returns and energy ratios is mostly explained by gear type. AB - According to portfolio theory applied to fisheries management, economic returns are stabilised by harvesting in a portfolio stocks of species whose returns are negatively correlated and for which the portfolio economic return variance is smaller than the sum of stock specific return variances. Also, variability is expected to decrease with portfolio width. Using a range of indicators, these predictions were tested for the French fishing fleets in the Bay of Biscay (Northeast Atlantic) during the period 2001-2009. For this, vessels were grouped into eight fishing fleets based on the gears used and exploited species were grouped into five functional groups. The portfolio width of fleets ranged from 1 3 functional groups, or 4-19 species. Economic fleet returns (sale revenues minus fishing costs) varied strongly between years; the interannual variability was independent of portfolio width (species or functional groups). Energy ratio expressed by the ratio between fuel energy used for fishing and energy contained in landings varied from 0.3 for purse seines to 9.7 for trawlers using bottom trawls alone or in combination with pelagic trawls independent of portfolio width. Interannual variability in total sale revenues was larger than the sum of species specific sales revenue variability, except for fleets using hooks and pelagic trawlers; it increased with the number of species exploited. In conclusion, the interannual variability of economic returns or energy ratios of French fisheries in the Bay of Biscay did not decrease with the number of species or functional groups exploited, though it varied between fleets. PMID- 23922950 TI - Mechanisms of Nrf2 protection in astrocytes as identified by quantitative proteomics and siRNA screening. AB - The Nrf2 (NF-E2 related factor 2)-ARE (antioxidant response element) pathway controls a powerful array of endogenous cellular antioxidant systems and is an important pathway in the detoxification of reactive oxygen species (ROS) in the brain. Using a combination of quantitative proteomics and siRNA screening, we have identified novel protective mechanisms of the Nrf2-ARE pathway against oxidative stress in astrocytes. Studies from our lab and others have shown Nrf2 overexpression protects astrocytes from oxidative stress. However, the exact mechanisms by which Nrf2 elicits these effects are unknown. In this study, we show that induction of Nrf2 reduces levels of reactive oxygen species (ROS) produced by various oxidative stressors and results in robust cytoprotection. To identify the enzymes responsible for these effects, we used stable isotope labeling by amino acids in cell culture (SILAC) and quantitative shotgun proteomics to identify 72 Nrf2-regulated proteins in astrocytes. We hypothesized a subset of these proteins might play a critical role in Nrf2 protection. In order to identify these critical proteins, we used bioinformatics to narrow our target list of proteins and then systematically screened each candidate with siRNA to assess the role of each in Nrf2 protection. We screened each target against H2O2, tert-butyl hydroperoxide, and 4-hydroxynonenal and subsequently identified three enzymes-catalase, prostaglandin reductase-1, and peroxiredoxin-6 that are critical for Nrf2-mediated protection in astrocytes. PMID- 23922952 TI - The anaphase-promoting complex protein 5 (AnapC5) associates with A20 and inhibits IL-17-mediated signal transduction. AB - IL-17 is the founding member of a family of cytokines and receptors with unique structures and signaling properties. IL-17 is the signature cytokine of Th17 cells, a relatively new T cell population that promotes inflammation in settings of infection and autoimmunity. Despite advances in understanding Th17 cells, mechanisms of IL-17-mediated signal transduction are less well defined. IL-17 signaling requires contributions from two receptor subunits, IL-17RA and IL-17RC. Mutants of IL-17RC lacking the cytoplasmic domain are nonfunctional, indicating that IL-17RC provides essential but poorly understood signaling contributions to IL-17-mediated signaling. To better understand the role of IL-17RC in signaling, we performed a yeast 2-hybrid screen to identify novel proteins associated with the IL-17RC cytoplasmic tail. One of the most frequent candidates was the anaphase promoting complex protein 7 (APC7 or AnapC7), which interacted with both IL-17RC and IL-17RA. Knockdown of AnapC7 by siRNA silencing exerted no detectable impact on IL-17 signaling. However, AnapC5, which associates with AnapC7, was also able to bind IL-17RA and IL-17RC. Moreover, AnapC5 silencing enhanced IL-17 induced gene expression, suggesting an inhibitory activity. Strikingly, AnapC5 also associated with A20 (TNFAIP3), a recently-identified negative feedback regulator of IL-17 signal transduction. IL-17 signaling was not impacted by knockdown of Itch or TAXBP1, scaffolding proteins that mediate A20 inhibition in the TNFalpha and IL-1 signaling pathways. These data suggest a model in which AnapC5, rather than TAX1BP1 and Itch, is a novel adaptor and negative regulator of IL-17 signaling pathways. PMID- 23922953 TI - Mesenchymal stem cell therapy stimulates endogenous host progenitor cells to improve colonic epithelial regeneration. AB - Patients who undergo pelvic radiotherapy may develop severe and chronic complications resulting from gastrointestinal alterations. The lack of curative treatment highlights the importance of novel and effective therapeutic strategies. We thus tested the therapeutic benefit of mesenchymal stem cells (MSC) treatment and proposed molecular mechanisms of action. MSC efficacy was tested in an experimental model of radiation-induced severe colonic ulceration histologically similar to that observed in patients. In this model, MSC from bone marrow were administered intravenously, immediately or three weeks (established lesions) after irradiation. MSC therapy reduces radiation-induced colonic ulceration and increases animal survival. MSC treatment induces therapeutic efficacy whatever the time of cell infusion. Infused-MSC engraft in the colon but also increase endogenous MSC mobilization in blood that have lasting benefits over time. In vitro analysis demonstrates that the MSC effect is mediated by paracrine mechanisms through the non-canonical WNT (Wingless integration site) pathway. In irradiated rat colons, MSC treatment increases the expression of the non-canonical WNT4 ligand by epithelial cells. The epithelial regenerative process is improved after MSC injection by stimulation of colonic epithelial cells positive for SOX9 (SRY-box containing gene 9) progenitor/stem cell markers. This study demonstrates that MSC treatment induces stimulation of endogenous host progenitor cells to improve the regenerative process and constitutes an initial approach to arguing in favor of the use of MSC to limit/reduce colorectal damage induced by radiation. PMID- 23922954 TI - Relationship between genotypes Sult1a2 and Cyp2d6 and tamoxifen metabolism in breast cancer patients. AB - Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche AmpliChip(r) CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N oxide were isolated and quantified using a high-pressure liquid chromatography tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001). No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A2*2 and SULT1A2*3 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p = 0.025 and p = 0.006, respectively), as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen. PMID- 23922955 TI - Ribonucleotide reductase large subunit M1 predicts poor survival due to modulation of proliferative and invasive ability of gastric cancer. AB - OBJECTIVES: We aimed to investigate the prognostic value of RRM1 in GC patients. METHODS: A total of assessable 389 GC patients with clinicopathological and survival information were enrolled from City of Hope (COH, n = 67) and Zhejiang University (ZJU, n = 322). RRM1 protein expression was determined by immunohistochemistry on FFPE tissue samples. Kaplan-Meier and Cox analyses were used to measure survival. Ras/Raf activity and invasion assays were used to evaluate the role of RRM1 in GC cell lines. RESULTS: In vitro experiments demonstrated RRM1 activated Ras/Raf/MAPK signal transduction and promoted GC cell proliferation. Meanwhile, RRM1 expression was significantly associated with lymph node involvement, tumor size, Ki67 expression, histological subtype and histological grade in the GC tissue samples (p<0.05). Kaplan-Meier analysis illustrated that high RRM1 expression predicted poor survival in GC patients in the COH and ZJU cohorts (log-rank p<0.01). In multivariate Cox analysis, the hazard ratios of RRM1 for overall survival were 2.55 (95% CI 1.27-5.15) and 1.51 (95% CI 1.07-2.13) in the COH and ZJU sets, respectively. In particular, RRM1 specifically predicted the outcome of advanced GCs with poor differentiation and high proliferative ability. Furthermore, inhibition of RRM1 by siRNA significantly reduced the dNTP pool, Ras/Raf and MMP-9 activities and the levels of p-MEK, p-ERK and NF-kappaB, resulting in growth retardation and reduced invasion in AGS and NCI-N87 cells. CONCLUSIONS: RRM1 overexpression predicts poor survival in GC patients with advanced TNM stage. RRM1 could potentially serve as prognostic biomarker and therapeutic target for GCs. PMID- 23922956 TI - Association between CFH Y402H polymorphism and age related macular degeneration in North Indian cohort. AB - The purpose of the study was to determine serum complement factor H (CFH) levels in patients of age related macular degeneration (AMD) and examine its association with CFH Y402H polymorphism. 115 AMD patients and 61 normal controls were recruited in this study. The single nucleotide polymorphism was assayed by real time PCR and serum CFH levels were measured by ELISA and standardized to total serum protein. Chi-square test was applied to polymorphism analysis while Mann Whitney U-statistic for CFH-levels. Mendelian randomization approach was used for determining causal relationship. The genotype frequency differed between the AMD patients (TT- 18.3%, TC-41.3% and CC-40.4%) and controls (TT-76.3%, TC-13.6%, and CC-10.1%) (p = 0001). The frequency of alleles was also significantly different when AMD (T-39% and C-61%) was compared to controls (T-83% and C-17%) (p = 0.0001). Level of serum CFH was significantly lower in AMD patients as compared to normal controls (p = 0.001). Our data showed that the CFH Y402H polymorphism is a risk factor for AMD in the North Indian population. Mendelian randomization approach revealed that CFH Y402H polymorphism affects AMD risk through the modification of CFH serum levels. PMID- 23922957 TI - Virological efficacy in cerebrospinal fluid and neurocognitive status in patients with long-term monotherapy based on lopinavir/ritonavir: an exploratory study. AB - BACKGROUND: Data on suppression of HIV replication in the CNS and on the subsequent risk of neurocognitive impairment using monotherapy with boosted protease inhibitors are limited. METHODS: Ours was an exploratory cross-sectional study in patients on lopinavir/ritonavir-based monotherapy (LPV/r-MT) or standard triple therapy (LPV/r-ART) for at least 96 weeks who maintained a plasma viral load <50 copies/mL. HIV-1 RNA in CSF was determined by HIV-1 SuperLow assay (lower limit of detection, 1 copy/mL). Neurocognitive functioning was assessed using a recommended battery of neuropsychological tests covering 7 areas. Neurocognitive impairment (NCI) was determined and also a global deficit score (GDS) for study comparisons. RESULTS: Seventeen patients on LPV/r-MT and 17 on LPV/r-ART were included. Fourteen (82.4%) patients on LPV/r-MT and 16 (94.1%) on LPV/r-ART had HIV-1 RNA <1 copy/mL in CSF (p = 0.601). NCI was observed in 7 patients on LPV/r-MT and in 10 on LPV/r-ART (41% vs 59%; p = 0.494). Mean (SD) GDS was 0.22 (0.20) in patients on LPV/r-MT and 0.47 (0.34) in those on LPV/r-ART (p = 0.012). CONCLUSIONS: Suppression of HIV in CSF is similar in individuals with durable plasma HIV-1 RNA suppression who are receiving LPV/r-MT or LPV/r-ART for at least 96 weeks. Findings for HIV-1 replication in CSF and neurocognitive status indicate that this strategy seems to be safe for CNS functioning. PMID- 23922958 TI - Automatic nuclei segmentation in H&E stained breast cancer histopathology images. AB - The introduction of fast digital slide scanners that provide whole slide images has led to a revival of interest in image analysis applications in pathology. Segmentation of cells and nuclei is an important first step towards automatic analysis of digitized microscopy images. We therefore developed an automated nuclei segmentation method that works with hematoxylin and eosin (H&E) stained breast cancer histopathology images, which represent regions of whole digital slides. The procedure can be divided into four main steps: 1) pre-processing with color unmixing and morphological operators, 2) marker-controlled watershed segmentation at multiple scales and with different markers, 3) post-processing for rejection of false regions and 4) merging of the results from multiple scales. The procedure was developed on a set of 21 breast cancer cases (subset A) and tested on a separate validation set of 18 cases (subset B). The evaluation was done in terms of both detection accuracy (sensitivity and positive predictive value) and segmentation accuracy (Dice coefficient). The mean estimated sensitivity for subset A was 0.875 (+/-0.092) and for subset B 0.853 (+/-0.077). The mean estimated positive predictive value was 0.904 (+/-0.075) and 0.886 (+/ 0.069) for subsets A and B, respectively. For both subsets, the distribution of the Dice coefficients had a high peak around 0.9, with the vast majority of segmentations having values larger than 0.8. PMID- 23922959 TI - Nucleotidyl cyclase activity of particulate guanylyl cyclase A: comparison with particulate guanylyl cyclases E and F, soluble guanylyl cyclase and bacterial adenylyl cyclases CyaA and edema factor. AB - Guanylyl cyclases (GCs) regulate many physiological processes by catalyzing the synthesis of the second messenger cGMP. The GC family consists of seven particulate GCs (pGCs) and a nitric oxide-activated soluble GC (sGC). Rat sGC alpha1beta1 possesses much broader substrate specificity than previously assumed. Moreover, the exotoxins CyaA from Bordetella pertussis and edema factor (EF) from Bacillus anthracis possess nucleotidyl cyclase (NC) activity. pGC-A is a natriuretic peptide-activated homodimer with two catalytic sites that act cooperatively. Here, we studied the NC activity of rat pGC-A in membranes of stably transfected HEK293 cells using a highly sensitive and specific HPLC-MS/MS technique. GTP and ITP were effective, and ATP and XTP were only poor, pGC-A substrates. In contrast to sGC, pGC-A did not use CTP and UTP as substrates. pGC E and pGC-F expressed in bovine rod outer segment membranes used only GTP as substrate. In intact HEK293 cells, pGC-A generated only cGMP. In contrast to pGCs, EF and CyaA showed very broad substrate-specificity. In conclusion, NCs exhibit different substrate-specificities, arguing against substrate-leakiness of enzymes and pointing to distinct physiological functions of cyclic purine and pyrimidine nucleotides. PMID- 23922961 TI - Psychometric validation study of the liebowitz social anxiety scale - self reported version for Brazilian Portuguese. AB - Social Anxiety Disorder (SAD) is prevalent and rarely diagnosed due to the difficulty in recognizing its symptoms as belonging to a disorder. Therefore, the evaluation/screening scales are of great importance for its detection, with the most used being the Liebowitz Social Anxiety Scale (LSAS). Thus, this study proposed to evaluate the psychometric properties of internal consistency and convergent validity, as well as the confirmatory factorial analysis and reliability of the self-reported version of the LSAS (LSAS-SR), translated into Brazilian Portuguese, in a sample of the general population (N = 413) and in a SAD clinical sample (N = 252). The convergent validity with specific scales for the evaluation of SAD and a general anxiety scale presented correlations ranging from 0.21 to 0.84. The confirmatory factorial analysis did not replicate the previously indicated findings of the literature, with the difficulty being in obtaining a consensus factorial structure common to the diverse cultures in which the instrument was studied. The LSAS-SR presented excellent internal consistency (alpha = 0.90-0.96) and test-retest reliability (Intraclass Correlation Coefficient = 0.81; Pearson's = 0.82). The present findings support those of international studies that attest to the excellent psychometric properties of the LSAS-SR, endorsing its status as the gold standard. PMID- 23922960 TI - Contamination of bananas with beauvericin and fusaric acid produced by Fusarium oxysporum f. sp. cubense. AB - BACKGROUND: Fusarium wilt, caused by the fungal pathogen Fusarium oxysporum f. sp. cubense (Foc), is one of the most destructive diseases of banana. Toxins produced by Foc have been proposed to play an important role during the pathogenic process. The objectives of this study were to investigate the contamination of banana with toxins produced by Foc, and to elucidate their role in pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Twenty isolates of Foc representing races 1 and 4 were isolated from diseased bananas in five Chinese provinces. Two toxins were consistently associated with Foc, fusaric acid (FA) and beauvericin (BEA). Cytotoxicity of the two toxins on banana protoplast was determined using the Alamar Blue assay. The virulence of 20 Foc isolates was further tested by inoculating tissue culture banana plantlets, and the contents of toxins determined in banana roots, pseudostems and leaves. Virulence of Foc isolates correlated well with toxin deposition in the host plant. To determine the natural occurrence of the two toxins in banana plants with Fusarium wilt symptoms, samples were collected before harvest from the pseudostems, fruit and leaves from 10 Pisang Awak 'Guangfen #1' and 10 Cavendish 'Brazilian' plants. Fusaric acid and BEA were detected in all the tissues, including the fruits. CONCLUSIONS/SIGNFICANCE: The current study provides the first investigation of toxins produced by Foc in banana. The toxins produced by Foc, and their levels of contamination of banana fruits, however, were too low to be of concern to human and animal health. Rather, these toxins appear to contribute to the pathogenicity of the fungus during infection of banana plants. PMID- 23922963 TI - Multi-scale, direct and indirect effects of the urban stream syndrome on amphibian communities in streams. AB - Urbanization affects streams by modifying hydrology, increasing pollution and disrupting in-stream and riparian conditions, leading to negative responses by biotic communities. Given the global trend of increasing urbanization, improved understanding of its direct and indirect effects at multiple scales is needed to assist management. The theory of stream ecology suggests that the riverscape and the surrounding landscape are inextricably linked, and watershed-scale processes will also affect in-stream conditions and communities. This is particularly true for species with semi-aquatic life cycles, such as amphibians, which transfer energy between streams and surrounding terrestrial areas. We related measures of urbanization at different scales to frog communities in streams along an urbanization gradient in Melbourne, Australia. We used boosted regression trees to determine the importance of predictors and the shape of species responses. We then used structural equation models to investigate possible indirect effects of watershed imperviousness on in-stream parameters. The proportion of riparian vegetation and road density surrounding the site at the reach scale (500-m radius) had positive and negative effects, respectively, on species richness and on the occurrence of the two most common species in the area (Criniasignifera and Limnodynastesdumerilii). Road density and local aquatic vegetation interacted in influencing species richness, suggesting that isolation of a site can prevent colonization, in spite of apparently good local habitat. Attenuated imperviousness at the catchment scale had a negative effect on local aquatic vegetation, indicating possible indirect effects on frog species not revealed by single-level models. Processes at the landscape scale, particularly related to individual ranging distances, can affect frog species directly and indirectly. Catchment imperviousness might not affect adult frogs directly, but by modifying hydrology it can disrupt local vegetation and prove indirectly detrimental. Integrating multiple-scale management actions may help to meet conservation targets for streams in the face of urbanization. PMID- 23922962 TI - Cognitive reactivity, implicit associations, and the incidence of depression: a two-year prospective study. AB - BACKGROUND: Cognitive reactivity to sad mood is a vulnerability marker of depression. Implicit self-depressed associations are related to depression status and reduced remission probability. It is unknown whether these cognitive vulnerabilities precede the first onset of depression. AIM: To test the predictive value of cognitive reactivity and implicit self-depressed associations for the incidence of depressive disorders. METHODS: Prospective cohort study of 834 never-depressed individuals, followed over a two-year period. The predictive value of cognitive reactivity and implicit self-depressed associations for the onset of depressive disorders was assessed using binomial logistic regression. The multivariate model corrected for baseline levels of subclinical depressive symptoms, neuroticism, for the presence of a history of anxiety disorders, for family history of depressive or anxiety disorders, and for the incidence of negative life events. RESULTS: As single predictors, both cognitive reactivity and implicit self-depressed associations were significantly associated with depression incidence. In the multivariate model, cognitive reactivity was significantly associated with depression incidence, together with baseline depressive symptoms and the number of negative life events, whereas implicit self depressed associations were not. CONCLUSION: Cognitive reactivity to sad mood is associated with the incidence of depressive disorders, also when various other depression-related variables are controlled for. Implicit self-depressed associations predicted depression incidence in a bivariate test, but not when controlling for other predictors. PMID- 23922964 TI - The linker pivot in Ci-VSP: the key to unlock catalysis. AB - In the voltage-sensitive phosphatase Ci-VSP, conformational changes in the transmembrane voltage sensor domain (VSD) are transduced to the intracellular catalytic domain (CD) leading to its dephosphorylation activity against membrane embedded phosphoinositides. The linker between both domains is proposed to be crucial for the VSD-CD coupling. With a combined approach of electrophysiological measurements on Xenopus oocytes and molecular dynamics simulations of a Ci-VSP model embedded in a lipid bilayer, we analyzed how conformational changes in the linker mediate the interaction between the CD and the activated VSD. In this way, we identified specific residues in the linker that interact with well-defined amino acids in one of the three loops forming the active site of the protein, named TI loop. With our results, we shed light into the early steps of the coupling process between the VSD and the CD, which are based on fine-tuned electrostatic and hydrophobic interactions between the linker, the membrane and the CD. PMID- 23922965 TI - Mechanistic insights into the neutralization of cytotoxic abrin by the monoclonal antibody D6F10. AB - Abrin, an A/B toxin obtained from the Abrus precatorius plant is extremely toxic and a potential bio-warfare agent. Till date there is no antidote or vaccine available against this toxin. The only known neutralizing monoclonal antibody against abrin, namely D6F10, has been shown to rescue the toxicity of abrin in cells as well as in mice. The present study focuses on mapping the epitopic region to understand the mechanism of neutralization of abrin by the antibody D6F10. Truncation and mutational analysis of abrin A chain revealed that the amino acids 74-123 of abrin A chain contain the core epitope and the residues Thr112, Gly114 and Arg118 are crucial for binding of the antibody. In silico analysis of the position of the mapped epitope indicated that it is present close to the active site cleft of abrin A chain. Thus, binding of the antibody near the active site blocks the enzymatic activity of abrin A chain, thereby rescuing inhibition of protein synthesis by the toxin in vitro. At 1?10 molar concentration of abrin:antibody, the antibody D6F10 rescued cells from abrin mediated inhibition of protein synthesis but did not prevent cell attachment of abrin. Further, internalization of the antibody bound to abrin was observed in cells by confocal microscopy. This is a novel finding which suggests that the antibody might function intracellularly and possibly explains the rescue of abrin's toxicity by the antibody in whole cells and animals. To our knowledge, this study is the first report on a neutralizing epitope for abrin and provides mechanistic insights into the poorly understood mode of action of anti-A chain antibodies against several toxins including ricin. PMID- 23922967 TI - Free-ranging male koalas use size-related variation in formant frequencies to assess rival males. AB - Although the use of formant frequencies in nonhuman animal vocal communication systems has received considerable recent interest, only a few studies have examined the importance of these acoustic cues to body size during intra-sexual competition between males. Here we used playback experiments to present free ranging male koalas with re-synthesised bellow vocalisations in which the formants were shifted to simulate either a large or a small adult male. We found that male looking responses did not differ according to the size variant condition played back. In contrast, male koalas produced longer bellows and spent more time bellowing when they were presented with playbacks simulating larger rivals. In addition, males were significantly slower to respond to this class of playback stimuli than they were to bellows simulating small males. Our results indicate that male koalas invest more effort into their vocal responses when they are presented with bellows that have lower formants indicative of larger rivals, but also show that males are slower to engage in vocal exchanges with larger males that represent more dangerous rivals. By demonstrating that male koalas use formants to assess rivals during the breeding season we have provided evidence that male-male competition constitutes an important selection pressure for broadcasting and attending to size-related formant information in this species. Further empirical studies should investigate the extent to which the use of formants during intra-sexual competition is widespread throughout mammals. PMID- 23922966 TI - Persistent posttetanic depression at cerebellar parallel fiber to Purkinje cell synapses. AB - Plasticity at the cerebellar parallel fiber to Purkinje cell synapse may underlie information processing and motor learning. In vivo, parallel fibers appear to fire in short high frequency bursts likely to activate sparsely distributed synapses over the Purkinje cell dendritic tree. Here, we report that short parallel fiber tetanic stimulation evokes a ~7-15% depression which develops over 2 min and lasts for at least 20 min. In contrast to the concomitantly evoked short-term endocannabinoid-mediated depression, this persistent posttetanic depression (PTD) does not exhibit a dependency on the spatial pattern of synapse activation and is not caused by any detectable change in presynaptic calcium signaling. This persistent PTD is however associated with increased paired-pulse facilitation and coefficient of variation of synaptic responses, suggesting that its expression is presynaptic. The chelation of postsynaptic calcium prevents its induction, suggesting that post- to presynaptic (retrograde) signaling is required. We rule out endocannabinoid signaling since the inhibition of type 1 cannabinoid receptors, monoacylglycerol lipase or vanilloid receptor 1, or incubation with anandamide had no detectable effect. The persistent PTD is maximal in pre-adolescent mice, abolished by adrenergic and dopaminergic receptors block, but unaffected by adrenergic and dopaminergic agonists. Our data unveils a novel form of plasticity at parallel fiber synapses: a persistent PTD induced by physiologically relevant input patterns, age-dependent, and strongly modulated by the monoaminergic system. We further provide evidence supporting that the plasticity mechanism involves retrograde signaling and presynaptic diacylglycerol. PMID- 23922968 TI - Construction of a phylogenetic tree of photosynthetic prokaryotes based on average similarities of whole genome sequences. AB - Phylogenetic trees have been constructed for a wide range of organisms using gene sequence information, especially through the identification of orthologous genes that have been vertically inherited. The number of available complete genome sequences is rapidly increasing, and many tools for construction of genome trees based on whole genome sequences have been proposed. However, development of a reasonable method of using complete genome sequences for construction of phylogenetic trees has not been established. We have developed a method for construction of phylogenetic trees based on the average sequence similarities of whole genome sequences. We used this method to examine the phylogeny of 115 photosynthetic prokaryotes, i.e., cyanobacteria, Chlorobi, proteobacteria, Chloroflexi, Firmicutes and nonphotosynthetic organisms including Archaea. Although the bootstrap values for the branching order of phyla were low, probably due to lateral gene transfer and saturated mutation, the obtained tree was largely consistent with the previously reported phylogenetic trees, indicating that this method is a robust alternative to traditional phylogenetic methods. PMID- 23922969 TI - Metabolic rate and climatic fluctuations shape continental wide pattern of genetic divergence and biodiversity in fishes. AB - Taxonomically exhaustive and continent wide patterns of genetic divergence within and between species have rarely been described and the underlying evolutionary causes shaping biodiversity distribution remain contentious. Here, we show that geographic patterns of intraspecific and interspecific genetic divergence among nearly all of the North American freshwater fish species (>750 species) support a dual role involving both the late Pliocene-Pleistocene climatic fluctuations and metabolic rate in determining latitudinal gradients of genetic divergence and very likely influencing speciation rates. Results indicate that the recurrent glacial cycles caused global reduction in intraspecific diversity, interspecific genetic divergence, and species richness at higher latitudes. At the opposite, longer geographic isolation, higher metabolic rate increasing substitution rate and possibly the rapid accumulation of genetic incompatibilities, led to an increasing biodiversity towards lower latitudes. This indicates that both intrinsic and extrinsic factors similarly affect micro and macro evolutionary processes shaping global patterns of biodiversity distribution. These results also indicate that factors favouring allopatric speciation are the main drivers underlying the diversification of North American freshwater fishes. PMID- 23922970 TI - Mutation of GDP-mannose-4,6-dehydratase in colorectal cancer metastasis. AB - Fucosylation is a crucial oligosaccharide modification in cancer. The known function of fucosylation in cancer is to mediate metastasis through selectin ligand-dependent processes. Previously, we found complete loss of fucosylation in the colon cancer cell line HCT116 due to a mutation in the GDP-fucose synthetic enzyme, GDP-mannose-4,6-dehydratase (GMDS). Loss of fucosylation led to escape of cancer cells from tumor immune surveillance followed by tumor progression and metastasis, suggesting a novel function of fucosylation in tumor progression pathway. In the present study, we investigated the frequency of GMDS mutation in a number of clinical colorectal cancer tissue samples: 81 samples of primary colorectal cancer tissue and 39 samples of metastatic lesion including liver and lymph node. Four types of deletion mutation in GMDS were identified in original cancer tissues as well as metastatic lesions. The frequency of GMDS mutation was slightly higher in metastatic lesions (12.8%, 5/39 samples) than in original cancer tissues (8.6%, 7/81 samples). No mutation of the GMDS gene was observed in normal colon tissues surrounding cancer tissues, suggesting that the mutation is somatic rather than in the germline. Immunohistochemical analysis revealed complete loss of fucosylation in three cases of cancer tissue. All three cases had GMDS mutation. In one of three cases, loss of fucosylation was observed in only metastatic lesion, but not its original colon cancer tissue. These data demonstrate involvement of GMDS mutation in the progression of colorectal cancer. PMID- 23922971 TI - Genetic associations with diabetes: meta-analyses of 10 candidate polymorphisms. AB - AIMS: The goal of our study is to investigate the combined contribution of 10 genetic variants to diabetes susceptibility. METHODS: Bibliographic databases were searched from 1970 to Dec 2012 for studies that reported on genetic association study of diabetes. After a comprehensive filtering procedure, 10 candidate gene variants with informative genotype information were collected for the current meta-anlayses. Using the REVMAN software, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the combined contribution of the selected genetic variants to diabetes. RESULTS: A total of 37 articles among 37,033 cases and 54,716 controls were involved in the present meta-analyses of 10 genetic variants. Three variants were found to be significantly associated with type 1 diabetes (T1D): NLRP1 rs12150220 (OR = 0.71, 95% CI = 0.55-0.92, P = 0.01), IL2RA rs11594656 (OR = 0.86, 95% CI = 0.82-0.91, P<0.00001), and CLEC16A rs725613 (OR = 0.71, 95% CI = 0.55-0.92, P = 0.01). APOA5 -1131T/C polymorphism was shown to be significantly associated with of type 2 diabetes (T2D, OR = 1.27, 95% CI = 1.03-1.57, P = 0.03). No association with diabetes was showed in the meta-analyses of other six genetic variants, including SLC2A10 rs2335491, ATF6 rs2070150, KLF11 rs35927125, CASQ1 rs2275703, GNB3 C825T, and IL12B 1188A/C. CONCLUSION: Our results demonstrated that IL2RA rs11594656 and CLEC16A rs725613 are protective factors of T1D, while NLRP1 rs12150220 and APOA5 -1131T/C are risky factors of T1D and T2D, respectively. PMID- 23922972 TI - Gene silencing of porcine MUC13 and ITGB5: candidate genes towards Escherichia coli F4ac adhesion. AB - BACKGROUND: Integrin beta-5 (ITGB5) and mucin 13 (MUC13) genes are highly expressed on the apical surface of intestinal epithelia and are thought to be candidate genes for controlling the expression of the receptor for enterotoxigenic Escherichia coli (ETEC) F4ac. Human MUC13 protein has an expected role in protecting intestinal mucosal surfaces and porcine ITGB5 is a newly identified potential receptor for ETEC F4ac. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that ITGB5 and MUC13 both play key roles in protection of the intestinal mucosa against pathogenic bacterium, porcine intestinal epithelial cells (IPEC-J2) were transfected with ITGB5-targeting, MUC13-targeting or negative control small interfering RNA (siRNA), respectively. Firstly, we measured mRNA expression levels of mucin genes (MUC4, MUC20), pro-inflammatory genes (IL8, IL1A, IL6, CXCL2), anti-inflammatory mediator SLPI, and PLAU after RNAi treatments with and without ETEC infection. Secondly, we compared the adhesions of ETEC to the pre- and post-knockdown IPEC-J2 cells of ITGB5 and MUC13, respectively. We found that ITGB5 and MUC13 knockdown both had small but significant effects in attenuating the inflammation induced by ETEC infection, and both increased bacterial adhesion in response to F4ac ETEC exposure. CONCLUSIONS/SIGNIFICANCE: Our current study first reported that ITGB5 and MUC13 are important adhesion molecules of mucosal epithelial signaling in response to Escherichia coli in pigs. These data suggest that both ITGB5 and MUC13 play key roles in defending the attachment and adhesion of ETEC to porcine jejunal cells and in maintaining epithelial barrier and immunity function. PMID- 23922974 TI - HSV-2 regulates monocyte inflammatory response via the Fas/FasL pathway. AB - Monocytic cells represent important cellular elements of the innate and adaptive immune responses in viral infections. We assessed the role of Fas/FasL in promoting monocyte apoptosis during HSV-2 infection by using an in vitro model based on the murine RAW 264.7 monocytic cell line and an in vivo murine model of HSV-2 infection applied to C57BL6, MRL-Fas(lpr)/J (Fas-/-) and C3-Fasl(gld)/J (FasL-/-) mice. HSV-2 infection of the monocytic cell line led to early induction of apoptosis, with no protective expression of anti-apoptotic Bcl-2. HSV-2 infected monocytes up-regulated Fas and FasL expression early during in vitro infection but were susceptible to Fas induced apoptosis. The vaginal monocytes in the HSV-2 murine model of infection up-regulated FasL expression and were susceptible to Fas induced apoptosis. HSV-2 infection of Fas and FasL- deficient mice led to decreased apoptosis of monocytes and impaired recruitment of NK, CD4+ and CD8+ T cells within the infection sites. The vaginal lavages of HSV-2 infected Fas and FasL- deficient showed decreased production of CXCL9, CXCL10 and TNF-alpha in comparison to HSV-2 infected wild-type mice strain. The decreased recruitment of immune competent cells was accompanied by delayed virus clearance from the infected tissue. Triggering of the Fas receptor on HSV-2 infected monocytes in vitro up-regulated the expression of CXCL9 chemokines and the cytokine TNF-alpha. Our study provides novel insights on the role of Fas/FasL pathway not only in apoptosis of monocytes but also in regulating local immune response by monocytes during HSV-2 infection. PMID- 23922973 TI - Cortical endogenic neural regeneration of adult rat after traumatic brain injury. AB - Focal and diffuse neuronal loss happened after traumatic brain injury (TBI). With little in the way of effective repair, recent interest has focused on endogenic neural progenitor cells (NPCs) as a potential method for regeneration. Whether endogenic neural regeneration happened in the cortex of adult rat after TBI remains to be determined. In this study, rats were divided into a sham group and a TBI group, and the rat model of medium TBI was induced by controlled cortical impact. Rats were injected with BrdU at 1 to 7 days post-injury (dpi) to allow identification of differentiated cells and sacrificed at 1, 3, 7, 14 and 28 dpi for immunofluorescence. Results showed nestin(+)/sox-2(+) NPCs and GFAP(+)/sox 2(+) radial glial (RG)-like cells emerged in peri-injured cortex at 1, 3, 7, 14 dpi and peaked at 3 dpi. The number of GFAP(+)/sox-2(+) cells was less than that of nestin(+)/sox-2(+) cells. Nestin(+)/sox-2(+) cells from posterior periventricle (pPV) immigrated into peri-injured cortex through corpus callosum (CC) were found. DCX(+)/BrdU(+) newborn immature neurons in peri-injured cortex were found only at 3, 7, 14 dpi. A few MAP-2(+)/BrdU(+) newborn neurons in peri injured cortex were found only at 7 and 14 dpi. NeuN(+)/BrdU(+) mature neurons were not found in peri-injured cortex at 1, 3, 7, 14 and 28 dpi. While GFAP(+)/BrdU(+) astrocytes emerged in peri-injured cortex at 1, 3, 7, 14, 28 dpi and peaked at 7 dpi then kept in a stable state. In the corresponding time point, the percentage of GFAP(+)/BrdU(+) astrocytes in BrdU(+) cells was more than that of NPCs or newborn neurons. No CNP(+)/BrdU(+) oligodendrocytes were found in peri injured cortex. These findings suggest that NPCs from pPV and reactive RG-like cells emerge in peri-injured cortex of adult rats after TBI. It can differentiate into immature neurons and astrocytes, but the former fail to grow up to mature neurons. PMID- 23922975 TI - The incidence of first venous thromboembolism in and around pregnancy using linked primary and secondary care data: a population based cohort study from England and comparative meta-analysis. AB - BACKGROUND: Recent linkage between primary and secondary care data has provided valuable information for studying heath outcomes that may initially present in different health care settings. The aim of this study was therefore, twofold: to use linked primary and secondary care data to determine an optimum definition for estimating the incidence of first VTE in and around pregnancy; and secondly to conduct a systematic literature review of studies on perinatal VTE incidence with the purpose of comparing our estimates. METHODS: We used primary care data from the Clinical Practice Research Datalink (CPRD), which incorporates linkages to secondary care contained within Hospital Episode Statistics (HES) between 1997 and 2010 to estimate the incidence rate of VTE in the antepartum and postpartum period. We systematically searched the literature on the incidence of VTE during antepartum and postpartum periods and performed a meta-analysis to provide comparison. FINDINGS: Using combined CPRD and HES data and a restrictive VTE definition, the absolute rate during the antepartum period and first six weeks postpartum (early postpartum) were 99 (95%CI 85-116) and 468 (95%CI 391-561) per 100,000 person-years respectively. These were comparable to the pooled estimates from our meta-analysis (using studies after 2005) during the antepartum period (118/100,000 person-years) and early postpartum (424/100,000 person-years). When we used only secondary care data to identify VTE events, incidence was lower during the early postpartum period (308/100,000 person-years), whereas relying only on primary care data lead to lower incidence during the time around delivery, but higher rates during the postpartum period (558/100,000 person years). CONCLUSION: Using combined CPRD and HES data gives estimates of the risk of VTE in and around pregnancy that are comparable to the existing literature. It also provides more accurate estimation of the date of VTE diagnosis which will allow risk stratification during specific pregnancy and postpartum periods. PMID- 23922976 TI - The expression of TMPRSS4 and Erk1 correlates with metastasis and poor prognosis in Chinese patients with gastric cancer. AB - PURPOSE: The present study investigated the clinical significance of transmembrane protease, serine 4(TMPRSS4) and extracellular signal-regulated kinases 1 (Erk1) in the development, progression and metastasis of gastric cancer. METHODS: Immunohistochemistry was employed to analyze TMPRSS4 and Erk1 expression in 436 gastric cancer cases and 92 non-cancerous human gastric tissues. RESULTS: Protein levels of TMPRSS4 and Erk1 were up-regulated in gastric cancer lesions compared with adjacent noncancerous tissues. High expression of TMPRSS4 correlated with age, size, Lauren's classification, depth of invasion, lymph node and distant metastases, regional lymph node stage and TNM stage, and also with expression of Erk1. In stages I, II and III, the 5-year survival rate of patients with high TMPRSS4 expression was significantly lower than in patients with low expression. Further multivariate analysis suggests that up-regulation of TMPRSS4 and Erk1 were independent prognostic indicators for the disease, along with depth of invasion, lymph node and distant metastasis and TNM stage. CONCLUSIONS: Expression of TMPRSS4 in gastric cancer is significantly associated with lymph node and distant metastasis, high Erk1 expression, and poor prognosis. TMPRSS4 and Erk1 proteins could be useful markers to predict tumor progression and prognosis of gastric cancer. PMID- 23922977 TI - Comparative study of two box H/ACA ribonucleoprotein pseudouridine-synthases: relation between conformational dynamics of the guide RNA, enzyme assembly and activity. AB - Multiple RNA-guided pseudouridine synthases, H/ACA ribonucleoprotein particles (RNPs) which contain a guide RNA and four proteins, catalyze site-specific post transcriptional isomerization of uridines into pseudouridines in substrate RNAs. In archaeal particles, the guide small RNA (sRNA) is anchored by the pseudouridine synthase aCBF5 and the ribosomal protein L7Ae. Protein aNOP10 interacts with both aCBF5 and L7Ae. The fourth protein, aGAR1, interacts with aCBF5 and enhances catalytic efficiency. Here, we compared the features of two H/ACA sRNAs, Pab21 and Pab91, from Pyrococcus abyssi. We found that aCBF5 binds much more weakly to Pab91 than to Pab21. Surprisingly, the Pab91 sRNP exhibits a higher catalytic efficiency than the Pab21 sRNP. We thus investigated the molecular basis of the differential efficiencies observed for the assembly and catalytic activity of the two enzymes. For this, we compared profiles of the extent of lead-induced cleavages in these sRNAs during a stepwise reconstitution of the sRNPs, and analyzed the impact of the absence of the aNOP10-L7Ae interaction. Such probing experiments indicated that the sRNAs undergo a series of conformational changes upon RNP assembly. These changes were also evaluated directly by circular dichroism (CD) spectroscopy, a tool highly adapted to analyzing RNA conformational dynamics. In addition, our results reveal that the conformation of helix P1 formed at the base of the H/ACA sRNAs is optimized in Pab21 for efficient aCBF5 binding and RNP assembly. Moreover, P1 swapping improved the assembly of the Pab91 sRNP. Nonetheless, efficient aCBF5 binding probably also relies on the pseudouridylation pocket which is not optimized for high activity in the case of Pab21. PMID- 23922978 TI - Diverse honeydew-consuming fungal communities associated with scale insects. AB - Sooty mould fungi are ubiquitous, abundant consumers of insect-honeydew that have been little-studied. They form a complex of unrelated fungi that coexist and compete for honeydew, which is a chemically complex resource. In this study, we used scanning electron microscopy in combination with T-RFLP community profiling and ITS-based tag-pyrosequencing to extensively describe the sooty mould community associated with the honeydews of two ecologically important New Zealand coelostomidiid scale insects, Coelostomidia wairoensis and Ultracoelostoma brittini. We tested the influence of host plant on the community composition of associated sooty moulds, and undertook limited analyses to examine the influence of scale insect species and geographic location. We report here a previously unknown degree of fungal diversity present in this complex, with pyrosequencing detecting on average 243 operational taxonomic units across the different sooty mould samples. In contrast, T-RFLP detected only a total of 24 different "species" (unique peaks). Nevertheless, both techniques identified similar patterns of diversity suggesting that either method is appropriate for community profiling. The composition of the microbial community associated with individual scale insect species varied although the differences may in part reflect variation in host preference and site. Scanning electron microscopy visualised an intertwined mass of fungal hyphae and fruiting bodies in near-intact physical condition, but was unable to distinguish between the different fungal communities on a morphological level, highlighting the need for molecular research. The substantial diversity revealed for the first time by pyrosequencing and our inability to identify two-thirds of the diversity to further than the fungal division highlights the significant gap in our knowledge of these fungal groups. This study provides a first extensive look at the community diversity of the fungal community closely associated with the keystone insect-honeydew systems of New Zealand's native forests and suggests there is much to learn about sooty mould communities. PMID- 23922979 TI - Partial restoration of macrophage alteration from diet-induced obesity in response to Porphyromonas gingivalis infection. AB - Obesity is a chronic inflammatory disease that weakens macrophage innate immune response to infections. Since M1 polarization is crucial during acute infectious diseases, we hypothesized that diet-induced obesity inhibits M1 polarization of macrophages in the response to bacterial infections. Bone marrow macrophages (BMMPhi) from lean and obese mice were exposed to live Porphyromonas gingivalis (P. gingivalis) for three incubation times (1 h, 4 h and 24 h). Flow cytometry analysis revealed that the M1 polarization was inhibited after P. gingivalis exposure in BMMPhi from obese mice when compared with BMMPhi from lean counterparts. Using a computational approach in conjunction with microarray data, we identified switching genes that may differentially control the behavior of response pathways in macrophages from lean and obese mice. The two most prominent switching genes were thrombospondin 1 and arginase 1. Protein expression levels of both genes were higher in obese BMMPhi than in lean BMMPhi after exposure to P. gingivalis. Inhibition of either thrombospondin 1 or arginase 1 by specific inhibitors recovered the M1 polarization of BMMPhi from obese mice after P. gingivalis exposure. These data indicate that thrombospondin 1 and arginase 1 are important bacterial response genes, whose regulation is altered in macrophages from obese mice. PMID- 23922981 TI - Overexpression of CTHRC1 in hepatocellular carcinoma promotes tumor invasion and predicts poor prognosis. AB - Collagen triple helix repeat containing-1 (CTHRC1) is a secreted glycoprotein that activates the planar cell polarity pathway of Wnt signaling. Using microarray analysis, we found that the CTHRC1 gene is overexpressed in hepatocellular carcinoma (HCC). The level of CTHRC1 mRNA was measured in 201 surgically resected HCCs using real time reverse transcription-polymerase chain reaction. Overexpression of CTHRC1 in HCC was associated with large tumor size and advanced tumor stage. Furthermore, expression of CTHRC1 as was identified as an independent prognostic factors in the multivariate analysis. Suppression of CTHRC1 expression inhibited tumor migration and invasion whereas overexpression of CTHRC1 promoted tumor invasion. Activation of RhoA, but not Rac1 or Cdc42, was found to play a crucial role in CTHRC1-induced cell migration. CTHRC1 promoted adhesion of cancer cells to extracellular matrix through induction of integrin beta1 expression and activation of focal adhesion kinase. These results suggest CTHRC1 promotes tumor invasion and metastasis by enhancing the adhesion and migratory abilities of tumor cells. It is also a promising biomarker for predicting the prognosis of patients with HCC. PMID- 23922980 TI - Gene expression analysis of rice seedling under potassium deprivation reveals major changes in metabolism and signaling components. AB - Plant nutrition is one of the important areas for improving the yield and quality in crops as well as non-crop plants. Potassium is an essential plant nutrient and is required in abundance for their proper growth and development. Potassium deficiency directly affects the plant growth and hence crop yield and production. Recently, potassium-dependent transcriptomic analysis has been performed in the model plant Arabidopsis, however in cereals and crop plants; such a transcriptome analysis has not been undertaken till date. In rice, the molecular mechanism for the regulation of potassium starvation responses has not been investigated in detail. Here, we present a combined physiological and whole genome transcriptomic study of rice seedlings exposed to a brief period of potassium deficiency then replenished with potassium. Our results reveal that the expressions of a diverse set of genes annotated with many distinct functions were altered under potassium deprivation. Our findings highlight altered expression patterns of potassium responsive genes majorly involved in metabolic processes, stress responses, signaling pathways, transcriptional regulation, and transport of multiple molecules including K(+). Interestingly, several genes responsive to low potassium conditions show a reversal in expression upon resupply of potassium. The results of this study indicate that potassium deprivation leads to activation of multiple genes and gene networks, which may be acting in concert to sense the external potassium and mediate uptake, distribution and ultimately adaptation to low potassium conditions. The interplay of both upregulated and downregulated genes globally in response to potassium deprivation determines how plants cope with the stress of nutrient deficiency at different physiological as well as developmental stages of plants. PMID- 23922982 TI - Diversity in the major polysaccharide antigen of Acinetobacter baumannii assessed by DNA sequencing, and development of a molecular serotyping scheme. AB - We have sequenced the gene clusters for type strains of the Acinetobacter baumannii serotyping scheme developed in the 1990s, and used the sequences to better understand diversity in surface polysaccharides of the genus. We obtained genome sequences for 27 available serovar type strains, and identified 25 polysaccharide gene cluster sequences. There are structures for 12 of these polysaccharides, and in general the genes present are appropriate to the structure where known. This greatly facilitates interpretation. We also find 53 different glycosyltransferase genes, and for 7 strains can provisionally allocate specific genes to all linkages. We identified primers that will distinguish the 25 sequence forms by PCR or microarray, or alternatively the genes can be used to determine serotype by "molecular serology". We applied the latter to 190 Acinetobacter genome-derived gene-clusters, and found 76 that have one of the 25 gene-cluster forms. We also found novel gene clusters and added 52 new gene cluster sequence forms with different wzy genes and different gene contents. Altogether, the strains that have one of the original 25 sequence forms include 98 A. baumannii (24 from our strains) and 5 A. nosocomialis (3 from our strains), whereas 32 genomes from 12 species other than A. baumannii or A. nosocomialis, all have new sequence forms. One of the 25 serovar type sequences is found to be in European clone I (EC I), 2 are in EC II but none in EC III. The public genome strains add an additional 52 new sequence forms, and also bring the number found in EC I to 5, in EC II to 9 and in EC III to 2. PMID- 23922983 TI - Targeting cancer-related inflammation: Chinese herbal medicine inhibits epithelial-to-mesenchymal transition in pancreatic cancer. AB - Pancreatic cancer is an almost universally fatal disease resulting from early invasion of adjacent structures and metastasis and the lack of an effective treatment modality. Our previous studies have shown that Qingyihuaji Formula (QYHJ), a seven-herb Chinese medicine formula, had significant anti-cancer effects in pancreatic cancer. Here, we examined the effects of QYHJ on pancreatic cancer cell invasion and metastasis and the potential associated mechanism(s). We found that QYHJ inhibited both tumor growth and metastasis in nude mice with human pancreatic cancer cell xenografts. Further study indicated that QYHJ inhibited epithelial-to-mesenchymal transition (EMT), which is characterized by increased E-cadherin expression and decreased vimentin, N-cadherin and Slug expression. Interleukin 6 (IL-6), a pro-inflammatory cytokine produced mainly by macrophages, could promote cancer cell EMT and invasion. In contrast, treatment with QYHJ inhibited cancer-related inflammation in tumors by decreasing infiltration of tumor-associated macrophages and IL-6 production, thus preventing cell invasion and metastasis. These results suggested that the Chinese herbal medicine QYHJ could inhibit pancreatic cancer cell invasion and metastasis in part by reversing tumor-supporting inflammation. PMID- 23922984 TI - Common and rare EGFR and KRAS mutations in a Dutch non-small-cell lung cancer population and their clinical outcome. AB - INTRODUCTION: In randomly assigned studies with EGFR TKI only a minor proportion of patients with NSCLC have genetically profiled biopsies. Guidelines provide evidence to perform EGFR and KRAS mutation analysis in non-squamous NSCLC. We explored tumor biopsy quality offered for mutation testing, different mutations distribution, and outcome with EGFR TKI. PATIENT AND METHODS: Clinical data from 8 regional hospitals were studied for patient and tumor characteristics, treatment and overall survival. Biopsies sent to the central laboratory were evaluated for DNA quality and subsequently analyzed for mutations in exons 18-21 of EGFR and exon 2 of KRAS by bidirectional sequence analysis. RESULTS: Tumors from 442 subsequent patients were analyzed. For 74 patients (17%) tumors were unsuitable for mutation analysis. Thirty-eight patients (10.9%) had EGFR mutations with 79% known activating mutations. One hundred eight patients (30%) had functional KRAS mutations. The mutation spectrum was comparable to the Cosmic database. Following treatment in the first or second line with EGFR TKI median overall survival for patients with EGFR (n = 14), KRAS (n = 14) mutations and wild type EGFR/KRAS (n = 31) was not reached, 20 and 9 months, respectively. CONCLUSION: One out of every 6 tumor samples was inadequate for mutation analysis. Patients with EGFR activating mutations treated with EGFR-TKI have the longest survival. PMID- 23922985 TI - Plasma L-ergothioneine measurement by high-performance liquid chromatography and capillary electrophoresis after a pre-column derivatization with 5 iodoacetamidofluorescein (5-IAF) and fluorescence detection. AB - Two sensitive and reproducible capillary electrophoresis and high-performance liquid chromatography-fluorescence procedures were established for quantitative determination of L-egothioneine in plasma. After derivatization of L ergothioneine with 5-iodoacetamidofluorescein, the separation was carried out by HPLC on an ODS-2 C-18 sperisorb column by using a linear gradient elution and by HPCE on an uncoated fused silica capillary, 50 um id, and 60 cm length. The methods were validated and found to be linear in the range of 0.3 to 10 umol/l. The limit of quantification was 0.27 umol/l for HPCE and 0.15 umol/l for HPLC. The variations for intra- and inter-assay precision were around 6 RSD%, and the mean recovery accuracy close to 100% (96.11%). PMID- 23922986 TI - Natural windbreaks sustain bird diversity in a tea-dominated landscape. AB - Windbreaks often form networks of forest habitats that improve connectivity and thus conserve biodiversity, but little is known of such effects in the tropics. We determined bird species richness and community composition in windbreaks composed of remnant native vegetation amongst tea plantations (natural windbreaks), and compared it with the surrounding primary forests. Fifty-one, ten minute point counts were conducted in each habitat type over three days. Despite the limited sampling period, our bird inventories in both natural windbreaks and primary forests were nearly complete, as indicated by bootstrap true richness estimator. Bird species richness and abundance between primary forests and windbreaks were similar, however a difference in bird community composition was observed. Abundances of important functional groups such as frugivores and insectivores did not vary between habitat types but nectarivores were more abundant in windbreaks, potentially as a result of the use of windbreaks as traveling routes, foraging and nesting sites. This preliminary study suggests that natural windbreaks may be important habitats for the persistence of bird species in a production landscape. However, a better understanding of the required physical and compositional characteristics for windbreaks to sustain bird communities is needed for effective conservation management. PMID- 23922987 TI - The retinoid-related orphan receptor RORalpha promotes keratinocyte differentiation via FOXN1. AB - RORalpha is a retinoid-related orphan nuclear receptor that regulates inflammation, lipid metabolism, and cellular differentiation of several non epithelial tissues. In spite of its high expression in skin epithelium, its functions in this tissue remain unclear. Using gain- and loss-of-function approaches to alter RORalpha gene expression in human keratinocytes (HKCs), we have found that this transcription factor functions as a regulator of epidermal differentiation. Among the 4 RORalpha isoforms, RORalpha4 is prominently expressed by keratinocytes in a manner that increases with differentiation. In contrast, RORalpha levels are significantly lower in skin squamous cell carcinoma tumors (SCCs) and cell lines. Increasing the levels of RORalpha4 in HKCs enhanced the expression of structural proteins associated with early and late differentiation, as well as genes involved in lipid barrier formation. Gene silencing of RORalpha impaired the ability of keratinocytes to differentiate in an in vivo epidermal cyst model. The pro-differentiation function of RORalpha is mediated at least in part by FOXN1, a well-known pro-differentiation transcription factor that we establish as a novel direct target of RORalpha in keratinocytes. Our results point to RORalpha as a novel node in the keratinocyte differentiation network and further suggest that the identification of RORalpha ligands may prove useful for treating skin disorders that are associated with abnormal keratinocyte differentiation, including cancer. PMID- 23922988 TI - Trivalent combination vaccine induces broad heterologous immune responses to norovirus and rotavirus in mice. AB - Rotavirus (RV) and norovirus (NoV) are the two major causes of viral gastroenteritis (GE) in children worldwide. We have developed an injectable vaccine design to prevent infection or GE induced with these enteric viruses. The trivalent combination vaccine consists of NoV capsid (VP1) derived virus-like particles (VLPs) of GI-3 and GII-4 representing the two major NoV genogroups and tubular RV recombinant VP6 (rVP6), the most conserved and abundant RV protein. Each component was produced in insect cells by a recombinant baculovirus expression system and combined in vitro. The vaccine components were administered intramuscularly to BALB/c mice either separately or in the trivalent combination. High levels of NoV and RV type specific serum IgGs with high avidity (>50%) as well as intestinal IgGs were detected in the immunized mice. Cross-reactive IgG antibodies were also elicited against heterologous NoV VLPs not used for immunization (GII-4 NO, GII-12 and GI-1 VLPs) and to different RVs from cell cultures. NoV-specific serum antibodies blocked binding of homologous and heterologous VLPs to the putative receptors, histo-blood group antigens, suggesting broad NoV neutralizing activity of the sera. Mucosal antibodies of mice immunized with the trivalent combination vaccine inhibited RV infection in vitro. In addition, cross-reactive T cell immune responses to NoV and RV-specific antigens were detected. All the responses were sustained for up to six months. No mutual inhibition of the components in the trivalent vaccine combination was observed. In conclusion, the NoV GI and GII VLPs combination induced broader cross-reactive and potentially neutralizing immune responses than either of the VLPs alone. Therefore, trivalent vaccine might induce protective immune responses to the vast majority of circulating NoV and RV genotypes. PMID- 23922989 TI - Correlates of HIV acquisition in a cohort of Black men who have sex with men in the United States: HIV prevention trials network (HPTN) 061. AB - BACKGROUND: Black men who have sex with men (MSM) in the United States (US) are affected by HIV at disproportionate rates compared to MSM of other race/ethnicities. Current HIV incidence estimates in this group are needed to appropriately target prevention efforts. METHODS: From July 2009 to October 2010, Black MSM reporting unprotected anal intercourse with a man in the past six months were enrolled and followed for one year in six US cities for a feasibility study of a multi-component intervention to reduce HIV infection. HIV incidence based on HIV seroconversion was calculated as number of events/100 person-years. Multivariate proportional hazards modeling with time-dependent covariates was used to identify correlates of HIV acquisition. RESULTS: Of 1,553 Black MSM enrolled, 1,164 were HIV-uninfected at baseline and included in follow-up. Overall annual HIV incidence was 3.0% (95% confidence interval (CI): 2.0, 4.4%) and 5.9% among men <=30 years old (95% CI: 3.6, 9.1%). Men <=30 years old reported significantly higher levels of sexual risk and were more likely to have a sexually transmitted infection diagnosed during follow-up. Younger men also were more likely to not have a usual place for health care, not have visited a health care provider recently, and to have unmet health care needs. In multivariate analysis, age <=30 years (hazard ratio (HR): 3.4; 95% CI: 1.4, 8.3) and unprotected receptive anal intercourse with HIV-positive or unknown status partners (HR: 4.1; 95% CI: 1.9, 9.1) were significantly associated with HIV acquisition. CONCLUSION: In the largest cohort of prospectively-followed Black MSM in the US, HIV incidence was high, particularly among young men. Targeted, tailored and culturally appropriate HIV prevention strategies incorporating behavioral, social and biomedical based interventions are urgently needed to lower these rates. PMID- 23922990 TI - Telomerase contributes to fludarabine resistance in primary human leukemic lymphocytes. AB - We report that Imetelstat, a telomerase inhibitor that binds to the RNA component of telomerase (hTR), can sensitize primary CLL lymphocytes to fludarabine in vitro. This effect was observed in lymphocytes from clinically resistant cases and with cytogenetic abnormalities associated with bad prognosis. Imetelstat mediated-sensitization to fludarabine was not associated with telomerase activity, but with the basal expression of Ku80. Since both Imetelstat and Ku80 bind hTR, we assessed 1) if Ku80 and Imetelstat alter each other's binding to hTR in vitro and 2) the effect of an oligonucleotide complementary to the Ku binding site in hTR (Ku oligo) on the survival of primary CLL lymphocytes exposed to fludarabine. We show that Imetelstat interferes with the binding of Ku70/80 (Ku) to hTR and that the Ku oligo can sensitize CLL lymphocytes to FLU. Our results suggest that Ku binding to hTR may contribute to fludarabine resistance in CLL lmphocytes. This is the first report highlighting the potentially broad effectiveness of Imetelstat in CLL, and the potential biological and clinical implications of a functional interaction between Ku and hTR in primary human cancer cells. PMID- 23922991 TI - The LDL receptor-related protein 1 (LRP1) regulates the PDGF signaling pathway by binding the protein phosphatase SHP-2 and modulating SHP-2- mediated PDGF signaling events. AB - BACKGROUND: The PDGF signaling pathway plays a major role in several biological systems, including vascular remodeling that occurs following percutaneous transluminal coronary angioplasty. Recent studies have shown that the LDL receptor-related protein 1 (LRP1) is a physiological regulator of the PDGF signaling pathway. The underlying mechanistic details of how this regulation occurs have yet to be resolved. Activation of the PDGF receptor beta (PDGFRbeta) leads to tyrosine phosphorylation of the LRP1 cytoplasmic domain within endosomes and generates an LRP1 molecule with increased affinity for adaptor proteins such as SHP-2 that are involved in signaling pathways. SHP-2 is a protein tyrosine phosphatase that positively regulates the PDGFRbeta pathway, and is required for PDGF-mediated chemotaxis. We investigated the possibility that LRP1 may regulate the PDGFRbeta signaling pathway by binding SHP-2 and competing with the PDGFRbeta for this molecule. METHODOLOGY/PRINCIPAL FINDINGS: To quantify the interaction between SHP-2 and phosphorylated forms of the LRP1 intracellular domain, we utilized an ELISA with purified recombinant proteins. These studies revealed high affinity binding of SHP-2 to phosphorylated forms of both LRP1 intracellular domain and the PDGFRbeta kinase domain. By employing the well characterized dynamin inhibitor, dynasore, we established that PDGF-induced SHP-2 phosphorylation primarily occurs within endosomal compartments, the same compartments in which LRP1 is tyrosine phosphorylated by activated PDGFRbeta. Immunofluorescence studies revealed colocalization of LRP1 and phospho-SHP-2 following PDGF stimulation of fibroblasts. To define the contribution of LRP1 to SHP-2-mediated PDGF chemotaxis, we employed fibroblasts expressing LRP1 and deficient in LRP1 and a specific SHP-2 inhibitor, NSC-87877. Our results reveal that LRP1 modulates SHP-2-mediated PDGF-mediated chemotaxis. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that phosphorylated forms of LRP1 and PDGFRbeta compete for SHP-2 binding, and that expression of LRP1 attenuates SHP-2-mediated PDGF signaling events. PMID- 23922992 TI - Changes in bleaching susceptibility among corals subject to ocean warming and recurrent bleaching in Moorea, French Polynesia. AB - BACKGROUND: Climate-induced coral bleaching poses a major threat to coral reef ecosystems, mostly because of the sensitivities of key habitat-forming corals to increasing temperature. However, susceptibility to bleaching varies greatly among coral genera and there are likely to be major changes in the relative abundance of different corals, even if the wholesale loss of corals does not occur for several decades. Here we document variation in bleaching susceptibility among key genera of reef-building corals in Moorea, French Polynesia, and compare bleaching incidence during mass-bleaching events documented in 1991, 1994, 2002 and 2007. METHODOLOGY/PRINCIPAL FINDINGS: This study compared the proportion of colonies that bleached for four major genera of reef-building corals (Acropora, Montipora, Pocillopora and Porites), during each of four well-documented bleaching events from 1991 to 2007. Acropora and Montipora consistently bleached in far greater proportions (up to 98%) than Pocillopora and Porites. However, there was an apparent and sustained decline in the proportion of colonies that bleached during successive bleaching events, especially for Acropora and Montipora. In 2007, only 77% of Acropora colonies bleached compared with 98% in 1991. Temporal variation in the proportion of coral colonies bleached may be attributable to differences in environmental conditions among years. Alternately, the sustained declines in bleaching incidence among highly susceptible corals may be indicative of acclimation or adaptation. CONCLUSIONS/SIGNIFICANCE: Coral genera that are highly susceptible to coral bleaching, and especially Acropora and Montipora, exhibit temporal declines in their susceptibility to thermal anomalies at Moorea, French Polynesia. One possible explanation for these findings is that gradual removal of highly susceptible genotypes (through selective mortality of individuals, populations, and/or species) is producing a coral assemblage that is more resistant to sustained and ongoing ocean warming. PMID- 23922994 TI - Woodland dynamics at the northern range periphery: a challenge for protected area management in a changing world. AB - Managers of protected natural areas increasingly are confronted with novel ecological conditions and conflicting objectives to preserve the past while fostering resilience for an uncertain future. This dilemma may be pronounced at range peripheries where rates of change are accelerated and ongoing invasions often are perceived as threats to local ecosystems. We provide an example from City of Rocks National Reserve (CIRO) in southern Idaho, positioned at the northern range periphery of pinyon-juniper (P-J) woodland. Reserve managers are concerned about P-J woodland encroachment into adjacent sagebrush steppe, but the rates and biophysical variability of encroachment are not well documented and management options are not well understood. We quantified the rate and extent of woodland change between 1950 and 2009 based on a random sample of aerial photo interpretation plots distributed across biophysical gradients. Our study revealed that woodland cover remained at approximately 20% of the study area over the 59 year period. In the absence of disturbance, P-J woodlands exhibited the highest rate of increase among vegetation types at 0.37% yr(-1). Overall, late successional P-J stands increased in area by over 100% through the process of densification (infilling). However, wildfires during the period resulted in a net decrease of woody evergreen vegetation, particularly among early and mid successional P-J stands. Elevated wildfire risk associated with expanding novel annual grasslands and drought is likely to continue to be a fundamental driver of change in CIRO woodlands. Because P-J woodlands contribute to regional biodiversity and may contract at trailing edges with global warming, CIRO may become important to P-J woodland conservation in the future. Our study provides a widely applicable toolset for assessing woodland ecotone dynamics that can help managers reconcile the competing demands to maintain historical fidelity and contribute meaningfully to the U.S. protected area network in a future with novel, no-analog ecosystems. PMID- 23922993 TI - Amiodarone inhibits apamin-sensitive potassium currents. AB - BACKGROUND: Apamin sensitive potassium current (I KAS), carried by the type 2 small conductance Ca(2+)-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles. OBJECTIVE: To test the hypothesis that amiodarone inhibits I KAS in human embryonic kidney 293 (HEK-293) cells. METHODS: We used the patch-clamp technique to study I KAS in HEK 293 cells transiently expressing human SK2 before and after amiodarone administration. RESULTS: Amiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67 +/- 0.25 uM with 1 uM intrapipette Ca(2+)). Maximal inhibition was observed with 50 uM amiodarone which inhibited 85.6 +/- 3.1% of IKAS induced with 1 uM intrapipette Ca(2+) (n = 3). IKAS inhibition by amiodarone was not voltage dependent, but was Ca(2+)-dependent: 30 uM amiodarone inhibited 81.5+/-1.9% of I KAS induced with 1 uM Ca(2+) (n = 4), and 16.4+/-4.9% with 250 nM Ca(2+) (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage independent but Ca(2+) dependent inhibition of I KAS. CONCLUSION: Both amiodarone and desethylamiodarone inhibit I KAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca(2+) concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles. PMID- 23922995 TI - Molecular phylogeny and biogeography of Petaurista inferred from the cytochrome b gene, with implications for the taxonomic status of P. caniceps, P. marica and P. sybilla. AB - The polymorphic genus Petaurista includes a group of diverse species and subspecies that are adapted for gliding and arboreal life. This morphological diversity has resulted in taxonomic discrepancies, and molecular phylogenetic studies have been limited by taxon sampling. To clarify this controversial taxonomy, we used the cytochrome b gene to reconstruct the phylogeny to obtain a more accurate picture of the evolutionary relationships, species differentiation and divergence pattern of Petaurista. The results revealed a significant inconsistency between taxonomic designations, phylogeny and genetic distances. When 6 recognized species were included, species delimitation revealed 15 putative species, a finding that warrants a comprehensive morphological diagnosis and a re-assessment of the species status. The validity of P. caniceps and P. marica was discussed. An estimation of the molecular divergence time demonstrated that the diversification and speciation of Petaurista began during the later Miocene and may have been affected by the uplifting of the Qinghai-Tibet plateau and subsequent climate change. PMID- 23922996 TI - Plasmodium falciparum var gene expression homogeneity as a marker of the host parasite relationship under different levels of naturally acquired immunity to malaria. AB - Acquired immunity to Plasmodium falciparum infection causes a change from frequent, sometimes life-threatening, malaria in young children to asymptomatic, chronic infections in older children and adults. Little is known about how this transition occurs but antibodies to the extremely diverse PfEMP1 parasite antigens are thought to play a role. PfEMP1 is encoded by a family of 60 var genes that undergo clonal antigenic variation, potentially creating an antigenically heterogeneous infecting population of parasites within the host. Previous theoretical work suggests that antibodies to PfEMP1 may play a role in "orchestrating" their expression within infections leading to sequential, homogeneous expression of var genes, and prolonged infection chronicity. Here, using a cloning and sequencing approach we compare the var expression homogeneity (VEH) between isolates from children with asymptomatic and clinical infections. We show that asymptomatic infections have higher VEH than clinical infections and a broader host antibody response. We discuss this in relation to the potential role of host antibodies in promoting chronicity of infection and parasite survival through the low transmission season. PMID- 23922997 TI - Expression analysis of combinatorial genes using a bi-cistronic T2A expression system in porcine fibroblasts. AB - In pig-to-primate xenotransplantation, multiple transgenic pigs are required to overcome a series of transplant rejections. The generation of multiple transgenic pigs either by breeding or the introduction of several mono-cistronic vectors has been hampered by the differential expression patterns of the target genes. To achieve simultaneous expression of multiple genes, a poly-cistronic expression system using the 2A peptide derived from the Thosea asigna virus (T2A) can be considered an alternative choice. Before applying T2A expression system to pig generation, the expression patterns of multiple genes in this system should be precisely evaluated. In this study, we constructed several bi-cistronic T2A expression vectors, which combine target genes that are frequently used in the xenotransplantation field, and introduced them into porcine fibroblasts. The proteins targeted to the same or different subcellular regions were efficiently expressed without affecting the localization or expression levels of the other protein. However, when a gene with low expression efficiency was inserted into the upstream region of the T2A sequences, the expression level of the downstream gene was significantly decreased compared with the expression efficiency without the insertion. A small interfering RNA targeting one gene in this system resulted in the significant downregulation of both the target gene and the other gene, indicating that multiple genes combined into a T2A expression vector can be considered as a single gene in terms of transcription and translation. In summary, the efficient expression of a downstream gene can be achieved if the expression of the upstream gene is efficient. PMID- 23922998 TI - Epigenetics and sex-specific fitness: an experimental test using male-limited evolution in Drosophila melanogaster. AB - When males and females have different fitness optima for the same trait but share loci, intralocus sexual conflict is likely to occur. Epigenetic mechanisms such as genomic imprinting (in which expression is altered according to parent-of origin) and sex-specific maternal effects have been suggested as ways by which this conflict can be resolved. However these ideas have not yet been empirically tested. We designed an experimental evolution protocol in Drosophila melanogaster that enabled us to look for epigenetic effects on the X-chromosome-a hotspot for sexually antagonistic loci. We used special compound-X females to enforce father to-son transmission of the X-chromosome for many generations, and compared fitness and gene expression levels between Control males, males with a Control X chromosome that had undergone one generation of father-son transmission, and males with an X-chromosome that had undergone many generations of father-son transmission. Fitness differences were dramatic, with experimentally-evolved males approximately 20% greater than controls, and with males inheriting a non evolved X from their father about 20% lower than controls. These data are consistent with both strong intralocus sexual conflict and misimprinting of the X chromosome under paternal inheritance. However, expression differences suggested that reduced fitness under paternal X inheritance was largely due to deleterious maternal effects. Our data confirm the sexually-antagonistic nature of Drosophila's X-chromosome and suggest that the response to male-limited X chromosome evolution entails compensatory evolution for maternal effects, and perhaps modification of other epigenetic effects via coevolution of the sex chromosomes. PMID- 23922999 TI - Relationship between the magnitude of intraocular pressure during an episode of acute elevation and retinal damage four weeks later in rats. AB - PURPOSE: To determine relationship between the magnitude of intraocular pressure (IOP) during a fixed-duration episode of acute elevation and the loss of retinal function and structure 4 weeks later in rats. METHODS: Unilateral elevation of IOP (105 minutes) was achieved manometrically in adult Brown Norway rats (9 groups; n = 4 to 8 each, 10-100 mm Hg and sham control). Full-field ERGs were recorded simultaneously from treated and control eyes 4 weeks after IOP elevation. Scotopic ERG stimuli were white flashes (-6.04 to 2.72 log cd.s.m( 2)). Photopic ERGs were recorded (1.22 to 2.72 log cd.s.m(-2)) after 15 min of light adaptation (150 cd/m(2)). Relative amplitude (treated/control, %) of ERG components versus IOP was described with a cummulative normal function. Retinal ganglion cell (RGC) layer density was determined post mortem by histology. RESULTS: All ERG components failed to recover completely normal amplitudes by 4 weeks after the insult if IOP was 70 mmHg or greater during the episode. There was no ERG recovery at all if IOP was 100 mmHg. Outer retinal (photoreceptor) function demonstrated the least sensitivity to prior acute IOP elevation. ERG components reflecting inner retinal function were correlated with post mortem RGC layer density. CONCLUSIONS: Retinal function recovers after IOP normalization, such that it requires a level of acute IOP elevation approximately 10 mmHg higher to cause a pattern of permanent dysfunction similar to that observed during the acute event. There is a 'threshold' for permanent retinal functional loss in the rat at an IOP between 60 and 70 mmHg if sustained for 105 minutes or more. PMID- 23923000 TI - Secreted acid phosphatase (SapM) of Mycobacterium tuberculosis is indispensable for arresting phagosomal maturation and growth of the pathogen in guinea pig tissues. AB - Tuberculosis (TB) is responsible for nearly 1.4 million deaths globally every year and continues to remain a serious threat to human health. The problem is further complicated by the growing incidence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), emphasizing the need for the development of new drugs against this disease. Phagosomal maturation arrest is an important strategy employed by Mycobacterium tuberculosis to evade the host immune system. Secretory acid phosphatase (SapM) of M.tuberculosis is known to dephosphorylate phosphotidylinositol 3-phosphate (PI3P) present on phagosomes. However, there have been divergent reports on the involvement of SapM in phagosomal maturation arrest in mycobacteria. This study was aimed at reascertaining the involvement of SapM in phagosomal maturation arrest in M.tuberculosis. Further, for the first time, we have also studied whether SapM is essential for the pathogenesis of M.tuberculosis. By deleting the sapM gene of M.tuberculosis, we demonstrate that MtbDeltasapM is defective in the arrest of phagosomal maturation as well as for growth in human THP-1 macrophages. We further show that MtbDeltasapM is severely attenuated for growth in the lungs and spleen of guinea pigs and has a significantly reduced ability to cause pathological damage in the host when compared with the parental strain. Also, the guinea pigs infected with MtbDeltasapM exhibited a significantly enhanced survival when compared with M.tuberculosis infected animals. The importance of SapM in phagosomal maturation arrest as well as in the pathogenesis of M.tuberculosis establishes it as an attractive target for the development of new therapeutic molecules against tuberculosis. PMID- 23923001 TI - Fast and inexpensive detection of total and extractable element concentrations in aquatic sediments using near-infrared reflectance spectroscopy (NIRS). AB - Adequate biogeochemical characterization and monitoring of aquatic ecosystems, both for scientific purposes and for water management, pose high demands on spatial and temporal replication of chemical analyses. Near-infrared reflectance spectroscopy (NIRS) may offer a rapid, low-cost and reproducible alternative to standard analytical sample processing (digestion or extraction) and measuring techniques used for the chemical characterization of aquatic sediments. We analyzed a total of 191 sediment samples for total and NaCl-extractable concentrations of Al, Ca, Fe, K, Mg, Mn, N, Na, P, S, Si, and Zn as well as oxalate- extractable concentrations of Al, Fe, Mn and P. Based on the NIR spectral data and the reference values, calibration models for the prediction of element concentrations in unknown samples were developed and tested with an external validation procedure. Except Mn, all prediction models of total element concentrations were found to be acceptable to excellent (ratio of performance deviation: RPD 1.8-3.1). For extractable element fractions, viable model precision could be achieved for NaCl-extractable Ca, K, Mg, NH4 (+)-N, S and Si (RPD 1.7-2.2) and oxalate-extractable Al, Fe and P (RPD 1.9-2.3). For those elements that showed maximum total values below 3 g kg(-1) prediction models were found to become increasingly critical (RPD <2.0). Low concentrations also limited the performance of NIRS calibrations for extracted elements, with critical concentration thresholds <0.1 g kg(-1) and 3.3 g kg(-1) for NaCl and oxalate extractions, respectively. Thus, reliable NIRS measurements of trace metals are restricted to sediments with high metal content. Nevertheless, we demonstrated the suitability of NIRS measurements to determine a large array of chemical properties of aquatic sediments. The results indicate great potential of this fast technique as an analytical tool to better understand the large spatial and temporal variation of sediment characteristics in an economically viable way. PMID- 23923002 TI - Haplotypes of NOS3 gene polymorphisms in dilated cardiomyopathy. AB - Dilated Cardiomyopathy (DCM) is characterized by systolic dysfunction, followed by heart failure necessitating cardiac transplantation. The genetic basis is well established by the identification of mutations in sarcomere and cytoskeleton gene/s. Modifier genes and environmental factors are also considered to play a significant role in the variable expression of the disease, hence various mechanisms are implicated and one such mechanism is oxidative stress. Nitric Oxide (NO), a primary physiological transmitter derived from endothelium seems to play a composite role with diverse anti-atherogenic effects as vasodilator. Three functional polymorphisms of endothelial nitric oxide synthase (NOS3) gene viz., T 786C of the 5' flanking region, 27bp VNTR in intron4 and G894T of exon 7 were genotyped to identify their role in DCM. A total of 115 DCM samples and 454 controls were included. Genotyping was carried out by PCR -RFLP method. Allelic and genotypic frequencies were computed in both control & patient groups and appropriate statistical tests were employed. A significant association of TC genotype (T-786C) with an odds ratio of 1.74, (95% CI 1.14 - 2.67, p = 0.01) was observed in DCM. Likewise the GT genotypic frequency of G894T polymorphism was found to be statistically significant (OR 2.10, 95% CI 1.34-3.27, p = 0.0011), with the recessive allele T being significantly associated with DCM (OR 1.64, 95% CI 1.18 - 2.30, p = 0.003). The haplotype carrying the recessive alleles of G894T and T-786C, C4bT was found to exhibit 7 folds increased risk for DCM compared to the controls. Hence C4bT haplotype could be the risk haplotype for DCM. Our findings suggest the possible implication of NOS3 gene in the disease phenotype, wherein NOS3 may be synergistically functioning in DCM associated heart failure via the excessive production of NO in cardiomyocytes resulting in decreased myocardial contractility and systolic dysfunction, a common feature of DCM phenotype. PMID- 23923003 TI - Regulation of coronaviral poly(A) tail length during infection. AB - The positive-strand coronavirus genome of ~30 kilobase in length and subgenomic (sg) mRNAs of shorter lengths, are 5' and 3'-co-terminal by virtue of a common 5' capped leader and a common 3'-polyadenylated untranslated region. Here, by ligating head-to-tail viral RNAs from bovine coronavirus-infected cells and sequencing across the ligated junctions, it was learned that at the time of peak viral RNA synthesis [6 hours postinfection (hpi)] the 3' poly(A) tail on genomic and sgmRNAs is ~65 nucleotides (nt) in length. Surprisingly, this length was found to vary throughout infection from ~45 nt immediately after virus entry (at 0 to 4 hpi) to ~65 nt later on (at 6 h to 9 hpi) and from ~65 nt (at 6 h to 9 hpi) to ~30 nt (at 120-144 hpi). With the same method, poly(U) sequences of the same lengths were simultaneously found on the ligated viral negative-strand RNAs. Functional analyses of poly(A) tail length on specific viral RNA species, furthermore, revealed that translation, in vivo, of RNAs with the longer poly(A) tail was enhanced over those with the shorter poly(A). Although the mechanisms by which the tail lengths vary is unknown, experimental results together suggest that the length of the poly(A) and poly(U) tails is regulated. One potential function of regulated poly(A) tail length might be that for the coronavirus genome a longer poly(A) favors translation. The regulation of coronavirus translation by poly(A) tail length resembles that during embryonal development suggesting there may be mechanistic parallels. PMID- 23923004 TI - A computational exploration of the interactions of the green tea polyphenol (-) Epigallocatechin 3-Gallate with cardiac muscle troponin C. AB - Thanks to its polyphenols and phytochemicals, green tea is believed to have a number of health benefits, including protecting from heart disease, but its mechanism of action at the molecular level is still not understood. Here we explore, by means of atomistic simulations, how the most abundant of the green tea polyphenols, (-)-Epigallocatechin 3-Gallate (EGCg), interacts with the structural C terminal domain of cardiac muscle troponin C (cCTnC), a calcium binding protein that plays an important role in heart contractions. We find that EGCg favourably binds to the hydrophobic cleft of cCTnC consistently with solution NMR experiments. It also binds to cCTnC in the presence of the anchoring region of troponin I (cTnI(34-71)) at the interface between the E and H helices. This appears to affect the strength of the interaction between cCTnC and cTnI(34 71) and also counter-acts the effects of the Gly159Asp mutation, related to dilated cardiomyopathy. Our simulations support the picture that EGCg interacting with the C terminal domain of troponin C may help in regulating the calcium signalling either through competitive binding with the anchoring domain of cTnI or by affecting the interaction between cCTnC and cTnI(34-71). PMID- 23923006 TI - Inorganic nitrogen derived from foraging honey bees could have adaptive benefits for the plants they visit. AB - In most terrestrial ecosystems, nitrogen (N) is the most limiting nutrient for plant growth. Honey bees may help alleviate this limitation because their feces (frass) have high concentration of organic nitrogen that may decompose in soil and provide inorganic N to plants. However, information on soil N processes associated with bee frass is not available. The objectives of this work were to 1) estimate the amount of bee frass produced by a honey bee colony and 2) evaluate nitrogen mineralization and ammonia volatilization from bee frass when surface applied or incorporated into soil. Two cage studies were conducted to estimate the amount of frass produced by a 5000-bee colony, and three laboratory studies were carried out in which bee frass, surface-applied or incorporated into soil, was incubated at 25(o)C for 15 to 45 days. The average rate of bee frass production by a 5,000-bee colony was estimated at 2.27 to 2.69 g N month(-1). Nitrogen mineralization from bee frass during 30 days released 20% of the organic N when bee frass was surface applied and 34% when frass was incorporated into the soil. Volatilized NH3 corresponded to 1% or less of total N. The potential amount of inorganic N released to the soil by a typical colony of 20,000 bees foraging in an area similar to that of the experimental cages (3.24 m(2)) was estimated at 0.62 to 0.74 g N m(-2) month(-1) which may be significant at a community scale in terms of soil microbial activity and plant growth. Thus, the deposition of available N by foraging bees could have adaptive benefits for the plants they visit, a collateral benefit deriving from the primary activity of pollination. PMID- 23923005 TI - Molecular biomarkers of vascular dysfunction in obstructive sleep apnea. AB - Untreated and long-lasting obstructive sleep apnea (OSA) may lead to important vascular abnormalities, including endothelial cell (EC) dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (micro)vasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation), and human dermal microvascular (HMVEC) and coronary artery endothelial cells (HCAEC) cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20), hypoxia-inducible factor 1 alpha (HIF-1alpha?? and vascular endothelial growth factor (VEGF) expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO2]<75%) compared to mildly hypoxemic OSA patients (SaO2 75%-90%) and a significant upregulation of vascular cell adhesion molecule 1 (VCAM-1) expression compared to control subjects. Gene expression profile in aortas of mice exposed to IH demonstrated a significant upregulation of eNOS and VEGF. In an in vitro model of OSA, IH increased expression of A20 and decreased eNOS and HIF-1alpha expression in HMVEC, while increased A20, VCAM-1 and HIF-1alphaexpression in HCAEC, indicating that EC in culture originating from distinct vascular beds respond differently to IH stress. We conclude that gene expression profiles in skin of OSA patients may correlate with disease severity and, if validated by further studies, could possibly predict vascular risk in OSA patients. PMID- 23923007 TI - Nuclear T-STAR protein expression correlates with HER2 status, hormone receptor negativity and prolonged recurrence free survival in primary breast cancer and decreased cancer cell growth in vitro. AB - T-STAR (testis-signal transduction and activation of RNA) is an RNA binding protein, containing an SH3-binding domain and thus potentially playing a role in integration of cell signaling and RNA metabolism. The specific function of T-STAR is unknown and its implication in cancer is poorly characterized. Expression of T STAR has been reported in human testis, muscle and brain tissues, and is associated with a growth-inhibitory role in immortalized fibroblasts. The aim of this paper was to investigate the functional role of T-STAR through (i) survival analysis of patients with primary invasive breast cancer and (ii) experimental evaluation of the effect of T-STAR on breast cancer cell growth. T-STAR protein expression was analysed by immunohistochemistry (IHC) in tissue microarrays with tumors from 289 patients with primary invasive breast cancer, and correlations to clinicopathological characteristics, recurrence-free and overall survival (RFS and OS) and established tumor markers such as HER2 and ER status were evaluated. In addition, the function of T-STAR was investigated using siRNA-mediated knock down and overexpression of the gene in six breast cancer cell lines. Of the tumors analysed, 86% showed nuclear T-STAR expression, which was significantly associated with an improved RFS and strongly associated with positive HER2 status and negative hormone receptor status. Furthermore, experimental data showed that overexpression of T-STAR decreased cellular growth while knock-down increased it, as shown both by thymidine incorporation and metabolic activity. In summary, we demonstrate that T-STAR protein expression correlates with an improved RFS in primary breast cancer. This is supported by functional data, indicating that T STAR regulation is of importance both for breast cancer biology and clinical outcome but future studies are needed to determine a potential role in patient stratification. PMID- 23923009 TI - A unique mitochondrial transcription factor B protein in Dictyostelium discoideum. AB - Unlike their bacteriophage homologs, mitochondrial RNA polymerases require the assistance of transcription factors in order to transcribe mitochondrial DNA efficiently. The transcription factor A family has been shown to be important for transcription of the human mitochondrial DNA, with some of its regulatory activity located in its extended C-terminal tail. The mitochondrial transcription factor B family often has functions not only in transcription, but also in mitochondrial rRNA modification, a hallmark of its alpha-proteobacterial origin. We have identified and characterised a mitochondrial transcription factor B homolog in the soil dwelling cellular slime mould Dictyostelium discoideum, an organism widely established as a model for studying eukaryotic cell biology. Using in bacterio functional assays, we demonstrate that the mitochondrial transcription factor B homolog not only functions as a mitochondrial transcription factor, but that it also has a role in rRNA methylation. Additionally, we show that the transcriptional activation properties of the D. discoideum protein are located in its extended C-terminal tail, a feature not seen before in the mitochondrial transcription factor B family, but reminiscent of the human mitochondrial transcription factor A. This report contributes to our current understanding of the complexities of mitochondrial transcription, and its evolution in eukaryotes. PMID- 23923010 TI - Prognostic significance of ESR1 gene amplification, mRNA/protein expression and functional profiles in high-risk early breast cancer: a translational study of the Hellenic Cooperative Oncology Group (HeCOG). AB - BACKGROUND: Discrepant data have been published on the incidence and prognostic significance of ESR1 gene amplification in early breast cancer. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tumor blocks were collected from women with early breast cancer participating in two HeCOG adjuvant trials. Messenger RNA was studied by quantitative PCR, ER protein expression was centrally assessed using immunohistochemistry (IHC) and ESR1 gene copy number by dual fluorescent in situ hybridization probes. RESULTS: In a total of 1010 women with resected node positive early breast adenocarcinoma, the tumoral ESR1/CEP6 gene ratio was suggestive of deletion in 159 (15.7%), gene gain in 551 (54.6%) and amplification in 42 cases (4.2%), with only 30 tumors (3%) harboring five or more ESR1 copies. Gene copy number ratio showed a significant, though weak correlation to mRNA and protein expression (Spearman's Rho <0.23, p = 0.01). ESR1 clusters were observed in 9.5% (57 gain, 38 amplification) of cases. In contrast to mRNA and protein expression, which were favorable prognosticators, gene copy number changes did not obtain prognostic significance. When ESR1/CEP6 gene ratio was combined with function (as defined by ER protein and mRNA expression) in a molecular classifier, the Gene Functional profile, it was functional status that impacted on prognosis. In univariate analysis, patients with functional tumors (positive ER protein expression and gene ratio normal or gain/amplification) fared better than those with non-functional tumors with ESR1 gain (HR for relapse or death 0.49-0.64, p = 0.003). Significant interactions were observed between gene gain/amplification and paclitaxel therapy (trend for DFS benefit from paclitaxel only in patients with ESR1 gain/amplification, p = 0.066) and Gene Functional profile with HER2 amplification (Gene Functional profile prognostic only in HER2 normal cases, p = 0.029). CONCLUSIONS: ESR1 gene deletion and amplification do not constitute per se prognostic markers, instead they can be classified to distinct prognostic groups according to their protein-mediated functional status. PMID- 23923008 TI - HIV-1 infected lymphoid organs upregulate expression and release of the cleaved form of uPAR that modulates chemotaxis and virus expression. AB - Cell-associated receptor for urokinase plasminogen activator (uPAR) is released as both full-length soluble uPAR (suPAR) and cleaved (c-suPAR) form that maintain ability to bind to integrins and other receptors, thus triggering and modulating cell signaling responses. Concerning HIV-1 infection, plasma levels of suPAR have been correlated with the severity of disease, levels of immune activation and ineffective immune recovery also in individuals receiving combination anti retroviral therapy (cART). However, it is unknown whether and which suPAR forms might contribute to HIV-1 induced pathogenesis and to the related state of immune activation. In this regard, lymphoid organs represent an import site of chronic immune activation and virus persistence even in individuals receiving cART. Lymphoid organs of HIV-1(+) individuals showed an enhanced number of follicular dendritic cells, macrophages and endothelial cells expressing the cell-associated uPAR in comparison to those of uninfected individuals. In order to investigate the potential role of suPAR forms in HIV-1 infection of secondary lymphoid organs, tonsil histocultures were established from HIV-1 seronegative individuals and infected ex vivo with CCR5- and CXCR4-dependent HIV-1 strains. The levels of suPAR and c-suPAR were significantly increased in HIV-infected tonsil histocultures supernatants in comparison to autologous uninfected histocultures. Supernatants from infected and uninfected cultures before and after immunodepletion of suPAR forms were incubated with the chronically infected promonocytic U1 cell line characterized by a state of proviral latency in unstimulated conditions. In the contest of HIV-conditioned supernatants we established that c-suPAR, but not suPAR, inhibited chemotaxis and induced virus expression in U1 cells. In conclusion, lymphoid organs are an important site of production and release of both suPAR and c-suPAR, this latter form being endowed with the capacity of inhibiting chemotaxis and inducing HIV-1 expression. PMID- 23923011 TI - Distinct functional interactions between actin isoforms and nonsarcomeric myosins. AB - Despite their near sequence identity, actin isoforms cannot completely replace each other in vivo and show marked differences in their tissue-specific and subcellular localization. Little is known about isoform-specific differences in their interactions with myosin motors and other actin-binding proteins. Mammalian cytoplasmic beta- and gamma-actin interact with nonsarcomeric conventional myosins such as the members of the nonmuscle myosin-2 family and myosin-7A. These interactions support a wide range of cellular processes including cytokinesis, maintenance of cell polarity, cell adhesion, migration, and mechano-electrical transduction. To elucidate differences in the ability of isoactins to bind and stimulate the enzymatic activity of individual myosin isoforms, we characterized the interactions of human skeletal muscle alpha-actin, cytoplasmic beta-actin, and cytoplasmic gamma-actin with human myosin-7A and nonmuscle myosins-2A, -2B and -2C1. In the case of nonmuscle myosins-2A and -2B, the interaction with either cytoplasmic actin isoform results in 4-fold greater stimulation of myosin ATPase activity than was observed in the presence of alpha-skeletal muscle actin. Nonmuscle myosin-2C1 is most potently activated by beta-actin and myosin-7A by gamma-actin. Our results indicate that beta- and gamma-actin isoforms contribute to the modulation of nonmuscle myosin-2 and myosin-7A activity and thereby to the spatial and temporal regulation of cytoskeletal dynamics. FRET-based analyses show efficient copolymerization abilities for the actin isoforms in vitro. Experiments with hybrid actin filaments show that the extent of actomyosin coupling efficiency can be regulated by the isoform composition of actin filaments. PMID- 23923012 TI - ParallelStructure: a R package to distribute parallel runs of the population genetics program STRUCTURE on multi-core computers. AB - This software package provides an R-based framework to make use of multi-core computers when running analyses in the population genetics program STRUCTURE. It is especially addressed to those users of STRUCTURE dealing with numerous and repeated data analyses, and who could take advantage of an efficient script to automatically distribute STRUCTURE jobs among multiple processors. It also consists of additional functions to divide analyses among combinations of populations within a single data set without the need to manually produce multiple projects, as it is currently the case in STRUCTURE. The package consists of two main functions: MPI_structure() and parallel_structure() as well as an example data file. We compared the performance in computing time for this example data on two computer architectures and showed that the use of the present functions can result in several-fold improvements in terms of computation time. ParallelStructure is freely available at https://r-forge.r project.org/projects/parallstructure/. PMID- 23923013 TI - Myosin II-mediated focal adhesion maturation is tension insensitive. AB - Myosin II motors drive changes in focal adhesion morphology and composition in a "maturation process" that is crucial for regulating adhesion dynamics and signaling guiding cell adhesion, migration and fate. The underlying mechanisms of maturation, however, have been obscured by the intermingled effects of myosin II on lamellar actin architecture, dynamics and force transmission. Here, we show that focal adhesion growth rate stays constant even when cellular tension is reduced by 75%. Focal adhesion growth halts only when myosin stresses are sufficiently low to impair actin retrograde flow. Focal adhesion lifetime is reduced at low levels of cellular tension, but adhesion stability can be rescued at low levels of force by over-expression of alpha-actinin or constitutively active Dia1. Our work identifies a minimal myosin activity threshold that is necessary to drive lamellar actin retrograde flow is sufficient to permit focal adhesion elongation. Above this nominal threshold, myosin-mediated actin organization and dynamics regulate focal adhesion growth and stability in a force insensitive fashion. PMID- 23923014 TI - High content screening as high quality assay for biological evaluation of photosensitizers in vitro. AB - A novel single step assay approach to screen a library of photdynamic therapy (PDT) compounds was developed. Utilizing high content analysis (HCA) technologies several robust cellular parameters were identified, which can be used to determine the phototoxic effects of porphyrin compounds which have been developed as potential anticancer agents directed against esophageal carcinoma. To demonstrate the proof of principle of this approach a small detailed study on five porphyrin based compounds was performed utilizing two relevant esophageal cancer cell lines (OE21 and SKGT-4). The measurable outputs from these early studies were then evaluated by performing a pilot screen using a set of 22 compounds. These data were evaluated and validated by performing comparative studies using a traditional colorimetric assay (MTT). The studies demonstrated that the HCS assay offers significant advantages over and above the currently used methods (directly related to the intracellular presence of the compounds by analysis of their integrated intensity and area within the cells). A high correlation was found between the high content screening (HCS) and MTT data. However, the HCS approach provides additional information that allows a better understanding of the behavior of these compounds when interacting at the cellular level. This is the first step towards an automated high-throughput screening of photosensitizer drug candidates and the beginnings of an integrated and comprehensive quantitative structure action relationship (QSAR) study for photosensitizer libraries. PMID- 23923015 TI - An analysis of the role of the indigenous microbiota in cholesterol gallstone pathogenesis. AB - BACKGROUND AND AIMS: Cholesterol gallstone disease is a complex process involving both genetic and environmental variables. No information exists regarding what role if any the indigenous gastrointestinal microbiota may play in cholesterol gallstone pathogenesis and whether variations in the microbiota can alter cholesterol gallstone prevalence rates. METHODS: Genetically related substrains (BALB/cJ and BALB/cJBomTac) and (BALB/AnNTac and BALB/cByJ) of mice obtained from different vendors were compared for cholesterol gallstone prevalence after being fed a lithogenic diet for 8 weeks. The indigenous microbiome was altered in these substrains by oral gavage of fecal slurries as adults, by cross-fostering to mice with divergent flora at <1 day of age or by rederiving into a germ-free state. RESULTS: Alterations in the indigenous microbiome altered significantly the accumulation of mucin gel and normalized gallbladder weight but did not alter cholesterol gallstone susceptibility in conventionally housed SPF mice. Germ-free rederivation rendered mice more susceptible to cholesterol gallstone formation. This susceptibility appeared to be largely due to alterations in gallbladder size and gallbladder wall inflammation. Colonization of germ-free mice with members of altered Schaedler flora normalized the gallstone phenotype to a level similar to conventionally housed mice. CONCLUSIONS: These data demonstrate that alterations in the gastrointestinal microbiome may alter aspects of cholesterol gallstone pathogenesis and that in the appropriate circumstances these changes may impact cholesterol cholelithogenesis. PMID- 23923016 TI - Multiphoton laser tomography and fluorescence lifetime imaging of melanoma: morphologic features and quantitative data for sensitive and specific non invasive diagnostics. AB - Multiphoton laser tomography (MPT) combined with fluorescence lifetime imaging (FLIM) is a non-invasive imaging technique, based on the study of fluorescence decay times of naturally occurring fluorescent molecules, enabling a non-invasive investigation of the skin with subcellular resolution. The aim of this retrospective observational ex vivo study, was to characterize melanoma both from a morphologic and a quantitative point of view, attaining an improvement in the diagnostic accuracy with respect to dermoscopy. In the training phase, thirty parameters, comprising both cytological descriptors and architectural aspects, were identified. The training set included 6 melanomas with a mean Breslow thickness+/-S.D. of 0.89+/-0.48 mm. In the test phase, these parameters were blindly evaluated on a test data set consisting of 25 melanomas, 50 nevi and 50 basal cell carcinomas. Melanomas in the test phase comprised 8 in situ lesions and had a mean thickness+/-S.D. of 0.77+/-1.2 mm. Moreover, quantitative FLIM data were calculated for special areas of interest. Melanoma was characterized by the presence of atypical short lifetime cells and architectural disorder, in contrast to nevi presenting typical cells and a regular histoarchitecture. Sensitivity and specificity values for melanoma diagnosis were 100% and 98%, respectively, whereas dermoscopy achieved the same sensitivity, but a lower specificity (82%). Mean fluorescence lifetime values of melanocytic cells did not vary between melanomas and nevi, but significantly differed from those referring to basal cell carcinoma enabling a differential diagnosis based on quantitative data. Data from prospective preoperative trials are needed to confirm if MPT/FLIM could increase diagnostic specificity and thus reduce unnecessary surgical excisions. PMID- 23923017 TI - Histone deacetylase inhibitor upregulates peroxisomal fatty acid oxidation and inhibits apoptotic cell death in abcd1-deficient glial cells. AB - In X-ALD, mutation/deletion of ALD gene (ABCD1) and the resultant very long chain fatty acid (VLCFA) derangement has dramatically opposing effects in astrocytes and oligodendrocytes. While loss of Abcd1 in astrocytes produces a robust inflammatory response, the oligodendrocytes undergo cell death leading to demyelination in X-linked adrenoleukodystrophy (X-ALD). The mechanisms of these distinct pathways in the two cell types are not well understood. Here, we investigated the effects of Abcd1-knockdown and the subsequent alteration in VLCFA metabolism in human U87 astrocytes and rat B12 oligodendrocytes. Loss of Abcd1 inhibited peroxisomal beta-oxidation activity and increased expression of VLCFA synthesizing enzymes, elongase of very long chain fatty acids (ELOVLs) (1 and 3) in both cell types. However, higher induction of ELOVL's in Abcd1 deficient B12 oligodendrocytes than astrocytes suggests that ELOVL pathway may play a prominent role in oligodendrocytes in X-ALD. While astrocytes are able to maintain the cellular homeostasis of anti-apoptotic proteins, Abcd1-deletion in B12 oligodendrocytes downregulated the anti-apototic (Bcl-2 and Bcl-xL) and cell survival (phospho-Erk1/2) proteins, and upregulated the pro-apoptotic proteins (Bad, Bim, Bax and Bid) leading to cell loss. These observations provide insights into different cellular signaling mechanisms in response to Abcd1-deletion in two different cell types of CNS. The apoptotic responses were accompanied by activation of caspase-3 and caspase-9 suggesting the involvement of mitochondrial caspase-9-dependent mechanism in Abcd1-deficient oligodendrocytes. Treatment with histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) corrected the VLCFA derangement both in vitro and in vivo, and inhibited the oligodendrocytes loss. These observations provide a proof-of principle that HDAC inhibitor SAHA may have a therapeutic potential for X-ALD. PMID- 23923018 TI - Do price subsidies on artemisinin combination therapy for malaria increase household use? Evidence from a repeated cross-sectional study in remote regions of Tanzania. AB - BACKGROUND: The Affordable Medicines Facility-malaria (AMFm) is a pilot program that uses price subsidies to increase access to Artemisinin Combination Therapies (ACTs), currently the most effective malaria treatment. Recent evidence suggests that availability and affordability of ACTs in retail sector drug shops (where many people treat malaria) has increased under the AMFm, but it is unclear whether household level ACT use has increased. METHODS AND FINDINGS: household surveys were conducted in two remote regions of Tanzania (Mtwara and Rukwa) in three waves: March 2011, December 2011 and March 2012, corresponding to 3, 13 and 16 months into the AMFm implementation respectively. Information about suspected malaria episodes including treatment location and medications taken was collected. Respondents were also asked about antimalarial preferences and perceptions about the availability of these medications. Significant increases in ACT use, preference and perceived availability were found between Rounds 1 and 3 though not for all measures between Rounds 1 and 2. ACT use among suspected malaria episodes was 51.1% in March 2011 and increased by 10.9 percentage points by Round 3 (p = .017). The greatest increase was among retail sector patients, where ACT use increased from 31% in Round 1 to 49% in Round 2 (p = .037) and to 61% (p<.0001) by Round 3. The fraction of suspected malaria episodes treated in the retail sector increased from 30.2% in Round 1 to 46.7% in Round 3 (p = .0009), mostly due to a decrease in patients who sought no treatment at all. No significant changes in public sector treatment seeking were found. CONCLUSIONS: The AMFm has led to significant increases in ACT use for suspected malaria, especially in the retail sector. No evidence is found supporting the concerns that the AMFm would crowd out public sector treatment or neglect patients in remote areas and from low SES groups. PMID- 23923019 TI - Loss of function in Mlo orthologs reduces susceptibility of pepper and tomato to powdery mildew disease caused by Leveillula taurica. AB - Powdery mildew disease caused by Leveillula taurica is a serious fungal threat to greenhouse tomato and pepper production. In contrast to most powdery mildew species which are epiphytic, L. taurica is an endophytic fungus colonizing the mesophyll tissues of the leaf. In barley, Arabidopsis, tomato and pea, the correct functioning of specific homologues of the plant Mlo gene family has been found to be required for pathogenesis of epiphytic powdery mildew fungi. The aim of this study was to investigate the involvement of the Mlo genes in susceptibility to the endophytic fungus L. taurica. In tomato (Solanum lycopersicum), a loss-of-function mutation in the SlMlo1 gene results in resistance to powdery mildew disease caused by Oidium neolycopersici. When the tomato Slmlo1 mutant was inoculated with L. taurica in this study, it proved to be less susceptible compared to the control, S. lycopersicum cv. Moneymaker. Further, overexpression of SlMlo1 in the tomato Slmlo1 mutant enhanced susceptibility to L. taurica. In pepper, the CaMlo2 gene was isolated by applying a homology-based cloning approach. Compared to the previously identified CaMlo1 gene, the CaMlo2 gene is more similar to SlMlo1 as shown by phylogenetic analysis, and the expression of CaMlo2 is up-regulated at an earlier time point upon L. taurica infection. However, results of virus-induced gene silencing suggest that both CaMlo1 and CaMlo2 may be involved in the susceptibility of pepper to L. taurica. The fact that overexpression of CaMlo2 restored the susceptibility of the tomato Slmlo1 mutant to O. neolycopersici and increased its susceptibility to L. taurica confirmed the role of CaMlo2 acting as a susceptibility factor to different powdery mildews, though the role of CaMlo1 as a co-factor for susceptibility cannot be excluded. PMID- 23923020 TI - Nowhere to invade: Rumex crispus and Typha latifolia projected to disappear under future climate scenarios. AB - Future climate change has been predicted to affect the potential distribution of plant species. However, only few studies have addressed how invasive species may respond to future climate change despite the known effects of plant species invasion on nutrient cycles, ecosystem functions, and agricultural yields. In this study, we predicted the potential distributions of two invasive species, Rumex crispus and Typha latifolia, under current and future (2050) climatic conditions. Future climate scenarios considered in our study include A1B, A2, A2A, B1, and B2A. We found that these two species will lose their habitat under the A1B, A2, A2A, and B1 scenarios. Their distributions will be maintained under future climatic conditions related to B2A scenarios, but the total area will be less than 10% of that under the current climatic condition. We also investigated variations of the most influential climatic variables that are likely to cause habitat loss of the two species. Our results demonstrate that rising mean annual temperature, variations of the coldest quarter, and precipitation of the coldest quarter are the main factors contributing to habitat loss of R. crispus. For T. latifolia, the main factors are rising mean annual temperature, variations in temperature of the coldest quarter, mean annual precipitation, and precipitation of the coldest quarter. These results demonstrate that the warmer and wetter climatic conditions of the coldest season (or month) will be mainly responsible for habitat loss of R. crispus and T. latifolia in the future. We also discuss uncertainties related to our study (and similar studies) and suggest that particular attention should be directed toward the manner in which invasive species cope with rapid climate changes because evolutionary change can be rapid for species that invade new areas. PMID- 23923021 TI - From interaction to co-association --a Fisher r-to-z transformation-based simple statistic for real world genome-wide association study. AB - Currently, the genetic variants identified by genome wide association study (GWAS) generally only account for a small proportion of the total heritability for complex disease. One crucial reason is the underutilization of gene-gene joint effects commonly encountered in GWAS, which includes their main effects and co-association. However, gene-gene co-association is often customarily put into the framework of gene-gene interaction vaguely. From the causal graph perspective, we elucidate in detail the concept and rationality of gene-gene co association as well as its relationship with traditional gene-gene interaction, and propose two Fisher r-to-z transformation-based simple statistics to detect it. Three series of simulations further highlight that gene-gene co-association refers to the extent to which the joint effects of two genes differs from the main effects, not only due to the traditional interaction under the nearly independent condition but the correlation between two genes. The proposed statistics are more powerful than logistic regression under various situations, cannot be affected by linkage disequilibrium and can have acceptable false positive rate as long as strictly following the reasonable GWAS data analysis roadmap. Furthermore, an application to gene pathway analysis associated with leprosy confirms in practice that our proposed gene-gene co-association concepts as well as the correspondingly proposed statistics are strongly in line with reality. PMID- 23923022 TI - De novo transcriptome assembly for the tropical grass Panicum maximum Jacq. AB - Guinea grass (Panicum maximum Jacq.) is a tropical African grass often used to feed beef cattle, which is an important economic activity in Brazil. Brazil is the leader in global meat exportation because of its exclusively pasture-raised bovine herds. Guinea grass also has potential uses in bioenergy production due to its elevated biomass generation through the C4 photosynthesis pathway. We generated approximately 13 Gb of data from Illumina sequencing of P. maximum leaves. Four different genotypes were sequenced, and the combined reads were assembled de novo into 38,192 unigenes and annotated; approximately 63% of the unigenes had homology to other proteins in the NCBI non-redundant protein database. Functional classification through COG (Clusters of Orthologous Groups), GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses showed that the unigenes from Guinea grass leaves are involved in a wide range of biological processes and metabolic pathways, including C4 photosynthesis and lignocellulose generation, which are important for cattle grazing and bioenergy production. The most abundant transcripts were involved in carbon fixation, photosynthesis, RNA translation and heavy metal cellular homeostasis. Finally, we identified a number of potential molecular markers, including 5,035 microsatellites (SSRs) and 346,456 single nucleotide polymorphisms (SNPs). To the best of our knowledge, this is the first study to characterize the complete leaf transcriptome of P. maximum using high-throughput sequencing. The biological information provided here will aid in gene expression studies and marker-assisted selection-based breeding research in tropical grasses. PMID- 23923023 TI - Brain signature characterizing the body-brain-mind axis of transsexuals. AB - Individuals with gender identity disorder (GID), who are commonly referred to as transsexuals (TXs), are afflicted by negative psychosocial stressors. Central to the psychological complex of TXs is the conviction of belonging to the opposite sex. Neuroanatomical and functional brain imaging studies have demonstrated that the GID is associated with brain alterations. In this study, we found that TXs identify, when viewing male-female couples in erotic or non-erotic ("neutral") interactions, with the couple member of the desired gender in both situations. By means of functional magnetic resonance imaging, we found that the TXs, as opposed to controls (CONs), displayed an increased functional connectivity between the ventral tegmental area, which is associated with dimorphic genital representation, and anterior cingulate cortex subregions, which play a key role in social exclusion, conflict monitoring and punishment adjustment. The neural connectivity pattern suggests a brain signature of the psychosocial distress for the gender-sex incongruity of TXs. PMID- 23923024 TI - Circadian adaptation to night shift work influences sleep, performance, mood and the autonomic modulation of the heart. AB - Our aim was to investigate how circadian adaptation to night shift work affects psychomotor performance, sleep, subjective alertness and mood, melatonin levels, and heart rate variability (HRV). Fifteen healthy police officers on patrol working rotating shifts participated to a bright light intervention study with 2 participants studied under two conditions. The participants entered the laboratory for 48 h before and after a series of 7 consecutive night shifts in the field. The nighttime and daytime sleep periods were scheduled during the first and second laboratory visit, respectively. The subjects were considered "adapted" to night shifts if their peak salivary melatonin occurred during their daytime sleep period during the second visit. The sleep duration and quality were comparable between laboratory visits in the adapted group, whereas they were reduced during visit 2 in the non-adapted group. Reaction speed was higher at the end of the waking period during the second laboratory visit in the adapted compared to the non-adapted group. Sleep onset latency (SOL) and subjective mood levels were significantly reduced and the LF?HF ratio during daytime sleep was significantly increased in the non-adapted group compared to the adapted group. Circadian adaptation to night shift work led to better performance, alertness and mood levels, longer daytime sleep, and lower sympathetic dominance during daytime sleep. These results suggest that the degree of circadian adaptation to night shift work is associated to different health indices. Longitudinal studies are required to investigate long-term clinical implications of circadian misalignment to atypical work schedules. PMID- 23923025 TI - Serum oxidized albumin and cardiovascular mortality in normoalbuminemic hemodialysis patients: a cohort study. AB - BACKGROUND: Substantial evidence suggests that increased oxidative stress in hemodialysis (HD) patients may contribute to cardiovascular complications. Oxidative modifications of human serum albumin (HSA), the largest thiol pool in plasma, alter its biological properties and may affect its antioxidant potential in HD patients. METHODS: We conducted a long-term follow-up study in a cohort of normoalbuminemic HD patients to examine the impact of redox state of serum albumin on patients' survival by measuring the human nonmercaptoalbumin (HNA) fraction of HSA. RESULTS: After adjusting for potential demographic, anthropometric, and clinical confounders, a positive association of HNA level with the risk of death from cardiovascular disease (CVD) and all-cause mortality was observed in normoalbuminemic HD patients. Using stratified analysis, we found a stronger association between HNA level and the risk of death from CVD and all cause mortality in patients with pre-existing CVD. CONCLUSIONS: Serum HNA level is a positive predictor of mortality in normoalbuminemic HD patients, especially among those with pre-existing CVD. Increased oxidative stress resulting from biological changes in serum albumin levels could contribute to accelerated atherosclerosis and the development of cardiovascular disease in HD patients. PMID- 23923026 TI - Profiling of circulating microRNAs after a bout of acute resistance exercise in humans. AB - Recent studies have revealed a new aspect of physiological regulation in which microRNAs (miRNAs) play fundamental roles in diverse biological and pathological processes. Furthermore, it was recently discovered that miRNAs are stably secreted into blood and that circulating miRNAs may play important roles in cell cell communication. Here, we examined whether the circulating miRNA profile is affected by acute resistance exercise. Twelve males performed a resistance exercise session (bench press and leg press), consisting of five sets of 10 repetitions at 70% of maximum strength, with a 1 min rest between sets. Blood samples were taken before exercise, and at 0 and 60 min, 1 day, and 3 days after exercise. The circulating miRNA profile was determined by microarray analysis. Quantitative real-time PCR confirmed that the miR-149* level increased three days after resistance exercise. In contrast, the miR-146a and miR-221 levels decreased three days after resistance exercise. Our findings suggest that circulating miRNA levels change in response to acute resistance exercise, and miRNAs may play important roles in resistance-exercise-induced adaptation. PMID- 23923028 TI - Epitope mapping of conformational V2-specific anti-HIV human monoclonal antibodies reveals an immunodominant site in V2. AB - In the case-control study of the RV144 vaccine trial, the levels of antibodies to the V1V2 region of the gp120 envelope glycoprotein were found to correlate inversely with risk of HIV infection. This recent demonstration of the potential role of V1V2 as a vaccine target has catapulted this region into the focus of HIV 1 research. We previously described seven human monoclonal antibodies (mAbs) derived from HIV-infected individuals that are directed against conformational epitopes in the V1V2 domain. In this study, using lysates of SF162 pseudoviruses carrying V1V2 mutations, we mapped the epitopes of these seven mAbs. All tested mAbs demonstrated a similar binding pattern in which three mutations (F176A, Y177T, and D180L) abrogated binding of at least six of the seven mAbs to <=15% of SF162 wildtype binding. Binding of six or all of the mAbs was reduced to <=50% of wildtype by single substitutions at seven positions (168, 180, 181, 183, 184, 191, and 193), while one change, V181I, increased the binding of all mAbs. When mapped onto a model of V2, our results suggest that the epitope of the conformational V2 mAbs is located mostly in the disordered region of the available crystal structure of V1V2, overlapping and surrounding the alpha4beta7 binding site on V2. PMID- 23923027 TI - Downregulated E-cadherin expression indicates worse prognosis in Asian patients with colorectal cancer: evidence from meta-analysis. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) plays a crucial role in the progression and aggressiveness of colorectal carcinoma. E-cadherin is the best characterized molecular marker of EMT, but its prognostic significance for patients with CRC remains inconclusive. METHODOLOGY: Eligible studies were searched from the PubMed, Embase and Web of Science databases. Correlation between E-cadherin expression and clinicopathological features and prognosis was analyzed. Subgroup analysis was also performed according to study location, number of patients, quality score of studies and cut-off value. PRINCIPAL FINDINGS: A total of 27 studies comprising 4244 cases met the inclusion criteria. Meta-analysis suggested that downregulated E-cadherin expression had an unfavorable impact on overall survival (OS) of CRC (n = 2730 in 14 studies; HR = 2.27, 95%CI: 1.63-3.17; Z = 4.83; P = 0.000). Subgroup analysis indicated that low E-cadherin expression was significantly associated with worse OS in Asian patients (n = 1054 in 9 studies; HR = 2.86, 95%CI: 2.13-3.7, Z = 7.11; P = 0.000) but not in European patients (n = 1552 in 4 studies; HR = 1.14, 95%CI: 0.95-1.35, Z = 1.39; P = 0.165). In addition, reduced E-cadherin expression indicated an unfavorable OS only when the cut off value of low E-cadherin expression was >50% (n = 512 in 4 studies; HR = 2.08, 95%CI 1.45-2.94, Z = 4.05; P = 0.000). Downregulated E-cadherin expression was greatly related with differentiation grade, Dukes' stages, lymphnode status and metastasis. The pooled OR was 0.36(95%CI: 0.19-0.7, Z = 3.03, P = 0.002), 0.34(95%CI: 0.21-0.55, Z = 6.61, P = 0.000), 0.49(95%CI: 0.32-0.74, Z = 3.02, P = 0.002) and 0.45(95%CI: 0.22-0.91, Z = 3.43, P = 0.001), respectively. CONCLUSIONS: This study showed that low or absent E-cadherin expression detected by immunohistochemistry served as a valuable prognostic factor of CRC. However, downregulated E-cadherin expression seemed to be associated with worse prognosis in Asian CRC patients but not in European CRC patients. Additionally, this meta-analysis suggested that the negative threshold of E-cadherin should be >50% when we detected its expression in the immunohistochemistry stain. PMID- 23923029 TI - Abundant intracellular IgG in enterocytes and endoderm lacking FcRn. AB - FcRn, a non-classical MHCI molecule, transports IgG from mother to young and regulates the rate of IgG degradation throughout life. Brambell proposed a mechanism that unified these two functions, saying that IgG was pinocytosed nonspecifically by the cell into an FcRn-expressing endosome, where, at low pH, it bound to FcRn and was exocytosed. This theory was immediately challenged by claims that FcRn specificity for ligand could be conferred at the cell surface in neonatal jejunum. Assessing Brambell's hypothesis we found abundant nonspecifically endocytosed IgG present in the cytoplasm of FcRn(-/-) enterocytes. Further, IgG was present in the intercellular clefts and the cores of FcRn(+/+) but not FcRn(-/-) jejunum. FcRn specificity for ligand could be determined within the cell. PMID- 23923030 TI - Enriched environment at work and the incidence of dementia: results of the Leipzig longitudinal study of the aged (LEILA 75+). AB - BACKGROUND: The high incidence of cognitive impairments in the aging population together with the challenges it imposes on health systems raise the question of what effect working life has on cognitive abilities. Animal models have demonstrated that so called enriched environments protect against neurodegenerative diseases, such as dementia. The aim was to investigate the impact of enriched environment at work on the incidence of dementia. METHODS: The Leipzig Longitudinal Study of the Aged (LEILA 75+) is an ongoing representative population cohort study that examines cognitive functioning and dementia in individuals aged 75 years and older. The participants' occupational information was matched to O*NET SOC codes and the relevant job descriptors were used to create occupational context indices describing enriched environment at work. RESULTS: Results of logistic regression modeling suggest that a higher level of the index Executive was associated with a lower risk of incident dementia (odds ratio = 0.61, 95% confidence interval = 0.47-0.79, p<0.001). Adjustment for various confounders did not alter the association. The cognitive stimulation indices were only significant in univariate analysis. The Novelty-index remained non-significant. CONCLUSIONS: The results suggest that occupational contexts enriched with independent planning/performance of work tasks might decrease the risk of developing dementia. A protective effect of enriched environment at work in general, namely high cognitive stimulation or confrontation with new tasks, could not be confirmed by the results. PMID- 23923031 TI - BAFF controls neural cell survival through BAFF receptor. AB - Various neuroprotective factors have been shown to help prevention of neuronal cell death, which is responsible for the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, most of these therapeutic potentials have been tested by administration of recombinant proteins, transgenic expression or virus vector-mediated gene transfer. Therefore, it remains to be clarified whether any endogenous factors has advantage for neuroprotection in a pathological nervous system. Here we show the role of BAFF-R signaling pathway in the control of neural cell survival. Both B cell-activating factor (BAFF) and its receptor (BAFF-R) are expressed in mouse neurons and BAFF-R deficiency reduces the survival of primary cultured neurons. Although many studies have so far addressed the functional role of BAFF-R on the differentiation of B cells, impaired BAFF-R signaling resulted in accelerated disease progression in an animal model of inherited ALS. We further demonstrate that BAFF-R deficient bone marrow cells or genetic depletion of B cells does not affect the disease progression, indicating that BAFF-mediated signals on neurons, not on B cells, support neural cell survival. These findings suggest opportunities to improve therapeutic outcome for patients with neurodegenerative diseases by synthesized BAFF treatment. PMID- 23923032 TI - A metabolically-stabilized phosphonate analog of lysophosphatidic acid attenuates collagen-induced arthritis. AB - Rheumatoid arthritis (RA) is a destructive arthropathy with systemic manifestations, characterized by chronic synovial inflammation. Under the influence of the pro-inflammatory milieu synovial fibroblasts (SFs), the main effector cells in disease pathogenesis become activated and hyperplastic while releasing a number of signals that include pro-inflammatory factors and tissue remodeling enzymes. Activated RA SFs in mouse or human arthritic joints express significant quantities of autotaxin (ATX), a lysophospholipase D responsible for the majority of lysophosphatidic acid (LPA) production in the serum and inflamed sites. Conditional genetic ablation of ATX from SFs resulted in attenuation of disease symptoms in animal models, an effect attributed to diminished LPA signaling in the synovium, shown to activate SF effector functions. Here we show that administration of 1-bromo-3(S)-hydroxy-4-(palmitoyloxy)butyl-phosphonate (BrP-LPA), a metabolically stabilized analog of LPA and a dual function inhibitor of ATX and pan-antagonist of LPA receptors, attenuates collagen induced arthritis (CIA) development, thus validating the ATX/LPA axis as a novel therapeutic target in RA. PMID- 23923033 TI - The association between plasma 25-hydroxyvitamin D and subgroups in age-related macular degeneration: a cross-sectional study. AB - OBJECTIVES: To evaluate potential differences in plasma 25-hydroxyvitamin in subtypes of age-related macular degeneration (AMD), and in patients in Clinical Age-Related Maculopathy Staging (CARMS) group 5 with or without subretinal fibrosis. METHODS: This single-center cross-sectional study included 178 participants during a period of 20 months. Ninety-five patients belonged to CARMS 5; twelve belonged to CARMS 4; twenty-two belonged to CARMS 2 or 3; and 49 individuals did not have AMD (CARMS 1). Following a structured interview, a detailed bilateral retinal examination was performed and participants were allocated to their respective subgroups in accordance with the Clinical Age Related Maculopathy Staging system. Plasma 25-hydroxyvitamin D2 and D3 were analyzed using liquid chromatography-tandem mass spectrometry. Genomic DNA was extracted from leukocytes and genotyped for single nucleotide polymorphisms (SNPs) in the vitamin D metabolism. Differences in plasma 25-hydroxyvitamin D were determined in the subgroups as well as between patients in CARMS 5 with or without subretinal fibrosis. RESULTS: Plasma 25-hydroxyvitamin D was comparable in patients across CARMS groups 1 to 5 (p = 0.83). In CARMS 5, the presence of subretinal fibrosis was associated with significantly lower concentrations of 25 hydroxyvitamin D as compared to the absence of subretinal fibrosis (47.2 versus 75.6 nmol/L, p<0.001). Patients in CARMS 5 with subretinal fibrosis were more likely to have insufficient levels of 25-hydroxyvitamin D compared to patients without subretinal fibrosis (p = 0.006). No association was found between the SNPs rs10877012, rs2228570, rs4588, or rs7041 and AMD subgroups or plasma 25 hydroxyvitamin levels. CONCLUSIONS: This study suggests that the presence of subretinal fibrosis in patients belonging to CARMS 5 may be associated with a poor vitamin D status. Our observations warrant further investigation into the role of vitamin D in the development of subretinal fibrosis. PMID- 23923034 TI - Neural correlates of central inhibition during physical fatigue. AB - Central inhibition plays a pivotal role in determining physical performance during physical fatigue. Classical conditioning of central inhibition is believed to be associated with the pathophysiology of chronic fatigue. We tried to determine whether classical conditioning of central inhibition can really occur and to clarify the neural mechanisms of central inhibition related to classical conditioning during physical fatigue using magnetoencephalography (MEG). Eight right-handed volunteers participated in this study. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. Participants underwent MEG recording during imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The next day, neural activities during imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of fatigue sensation and sympathetic nerve activity on the second day were significantly higher relative to those of the first day. Equivalent current dipoles (ECDs) in the posterior cingulated cortex (PCC), with latencies of approximately 460 ms, were observed in all the participants on the second day, although ECDs were not identified in any of the participants on the first day. We demonstrated that classical conditioning of central inhibition can occur and that the PCC is involved in the neural substrates of central inhibition related to classical conditioning during physical fatigue. PMID- 23923035 TI - Rapid fabricating technique for multi-layered human hepatic cell sheets by forceful contraction of the fibroblast monolayer. AB - Cell sheet engineering is attracting attention from investigators in various fields, from basic research scientists to clinicians focused on regenerative medicine. However, hepatocytes have a limited proliferation potential in vitro, and it generally takes a several days to form a sheet morphology and multi layered sheets. We herein report our rapid and efficient technique for generating multi-layered human hepatic cell (HepaRG(r) cell) sheets using pre-cultured fibroblast monolayers derived from human skin (TIG-118 cells) as a feeder layer on a temperature-responsive culture dish. Multi-layered TIG-118/HepaRG cell sheets with a thick morphology were harvested on day 4 of culturing HepaRG cells by forceful contraction of the TIG-118 cells, and the resulting sheet could be easily handled. In addition, the human albumin and alpha 1-antitrypsin synthesis activities of TIG-118/HepaRG cells were approximately 1.2 and 1.3 times higher than those of HepaRG cells, respectively. Therefore, this technique is considered to be a promising modality for rapidly fabricating multi-layered human hepatocyte sheets from cells with limited proliferation potential, and the engineered cell sheet could be used for cell transplantation with highly specific functions. PMID- 23923036 TI - Optic radiation fiber tractography in glioma patients based on high angular resolution diffusion imaging with compressed sensing compared with diffusion tensor imaging - initial experience. AB - OBJECTIVE: Up to now, fiber tractography in the clinical routine is mostly based on diffusion tensor imaging (DTI). However, there are known drawbacks in the resolution of crossing or kissing fibers and in the vicinity of a tumor or edema. These restrictions can be overcome by tractography based on High Angular Resolution Diffusion Imaging (HARDI) which in turn requires larger numbers of gradients resulting in longer acquisition times. Using compressed sensing (CS) techniques, HARDI signals can be obtained by using less non-collinear diffusion gradients, thus enabling the use of HARDI-based fiber tractography in the clinical routine. METHODS: Eight patients with gliomas in the temporal lobe, in proximity to the optic radiation (OR), underwent 3T MRI including a diffusion weighted dataset with 30 gradient directions. Fiber tractography of the OR using a deterministic streamline algorithm based on DTI was compared to tractography based on reconstructed diffusion signals using HARDI+CS. RESULTS: HARDI+CS based tractography displayed the OR more conclusively compared to the DTI-based results in all eight cases. In particular, the potential of HARDI+CS-based tractography was observed for cases of high grade gliomas with significant peritumoral edema, larger tumor size or closer proximity of tumor and reconstructed fiber tract. CONCLUSIONS: Overcoming the problem of long acquisition times, HARDI+CS seems to be a promising basis for fiber tractography of the OR in regions of disturbed diffusion, areas of high interest in glioma surgery. PMID- 23923037 TI - Mutations of residues 249 and 256 in VP2 are involved in the replication and virulence of infectious Bursal disease virus. AB - Infectious bursal disease virus (IBDV) is a pathogen of worldwide significance to the poultry industry. Although the PDE and PFG domains of the capsid protein VP2 contribute significantly to virulence and fitness, the detailed molecular basis for the pathogenicity of IBDV is still not fully understood. Because residues 253 and 284 of VP2 are not the sole determinants of virulence, we hypothesized that other residues involved in virulence and fitness might exist in the PDE and PFG domains of VP2. To test this, five amino acid changes selected by sequence comparison of the PDE and PFG domains of VP2 were introduced individually using a reverse genetics system into the virulent strain (rGx-F9VP2). Then reverse mutations of the selected residues 249 and 256 were introduced individually into the attenuated strain (rGt). Seven modified viruses were generated and evaluated in vitro (CEF cells) and in vivo (SPF chicken). For residue 249, Q249R could elevate in vitro and reduce in vivo the replication of rGx-F9VP2 while R249Q could reduce in vitro and elevate in vivo the replication of rGt; meanwhile Q249R reduced the virulence of rGx-F9VP2 while R249Q increased the virulence of rGt, which indicated that residue 249 significantly contributed to the replication and virulence of IBDV. For residue 256, I256V could elevate in vitro and reduce in vivo the replication of rGx-F9VP2 while V256I could reduce in vitro but didn't change in vivo the replication of rGt; although V256I didn't increase the virulence of rGt, I256V obviously reduced the virulence of virulent IBDV. The present results demonstrate for the first time, to different extent, residues 249 and 256 of VP2 are involved in the replication efficiency and virulence of IBDV; this is not only beneficial to further understanding of pathogenic mechanism but also to the design of newly tailored vaccines against IBDV. PMID- 23923038 TI - Klotho sensitivity of the neuronal excitatory amino acid transporters EAAT3 and EAAT4. AB - Klotho, a transmembrane protein, which can be cleaved off as beta-glucuronidase and hormone, is released in both, kidney and choroid plexus and encountered in blood and cerebrospinal fluid. Klotho deficiency leads to early appearance of age related disorders and premature death. Klotho may modify transport by inhibiting 1,25(OH)2D3 formation or by directly affecting channel and carrier proteins. The present study explored whether Klotho influences the activity of the Na(+) coupled excitatory amino acid transporters EAAT3 and EAAT4, which are expressed in kidney (EAAT3), intestine (EAAT3) and brain (EAAT3 and EAAT4). To this end, cRNA encoding EAAT3 or EAAT4 was injected into Xenopus oocytes with and without additional injection of cRNA encoding Klotho. EAAT expressing Xenopus oocytes were further treated with recombinant human beta-Klotho protein with or without beta-glucuronidase inhibitor D-saccharic acid 1,4-lactone monohydrate (DSAL). Electrogenic excitatory amino acid transport was determined as L-glutamate induced current (Iglu) in two electrode voltage clamp experiments. EAAT3 and EAAT4 protein abundance in the Xenopus oocyte cell membrane was visualized by confocal microscopy and quantified utilizing chemiluminescence. As a result, coexpression of Klotho cRNA significantly increased Iglu in both, EAAT3 or EAAT4 expressing Xenopus oocytes. Klotho cRNA coexpression significantly increased the maximal current and cell membrane protein abundance of both EAAT3 and EAAT4. The effect of Klotho coexpression on EAAT3 and EAAT4 activity was mimicked by treating EAAT3 or EAAT4-expressing Xenopus oocytes with recombinant human beta Klotho protein. The effects of Klotho coexpression and of treatment with recombinant human beta-Klotho protein were both abrogated in the presence of DSAL (10 uM). In conclusion, Klotho is a novel, powerful regulator of the excitatory amino acid transporters EAAT3 and EAAT4. PMID- 23923039 TI - Generation of live piglets for the first time using sperm retrieved from immature testicular tissue cryopreserved and grafted into nude mice. AB - Cryopreservation of immature testicular tissues is essential for increasing the possibilities of offspring generation by testicular xenografting for agricultural or medical purposes. However, successful production of offspring from the sperm involved has never been reported previously. In the present study, therefore, using intracytoplasmic sperm injection (ICSI), we examined whether xenogeneic sperm obtained from immature pig testicular tissue after cryopreservation would have the capacity to produce live piglets. Testicular fragments from 9- to 11-day old piglets were vitrified after 10- or 20-min immersion in vitrification solution containing ethylene glycol (EG), polyvinyl pyrrolidone (PVP) and trehalose as cryoprotectants, and then stored in liquid nitrogen for more than 140 days. Thirty nude mice were assigned to each immersion-time group. Testicular fragments were transplanted under the back skin of castrated mice immediately after warming and removal of the cryoprotectants. Blood and testicular grafts were then recovered from the recipient mice on days 60, 120, 180 and 230-350 (day 0 = grafting). Histological assessment of the testicular grafts and analyses of inhibin and testosterone production revealed no significant differences between the two immersion-time groups, indicating equal growth activity of the cryopreserved tissues. A single sperm obtained from a mouse in each group on day 230-350 was injected into an in vitro-matured porcine oocyte, and then the ICSI oocytes were transferred to the oviducts of estrus-synchronized recipient gilts. One out of 4 gilts that had received oocytes fertilized using sperm from the 10 min immersion group delivered 2 live piglets, and one of another 4 gilts from the 20-min group delivered 4 live piglets. Thus, we have successfully generated porcine offspring utilizing sperm from immature testicular tissues after cryopreservation and transplantation into nude mice. The present model using pigs will be applicable to many large animals, since pigs are phylogenetically distant from the murine recipients. PMID- 23923040 TI - In vivo administration of a JAK3 inhibitor to chronically siv infected rhesus macaques leads to NK cell depletion associated with transient modest increase in viral loads. AB - Innate immune responses are reasoned to play an important role during both acute and chronic SIV infection and play a deterministic role during the acute stages on the rate of infection and disease progression. NK cells are an integral part of the innate immune system but their role in influencing the course of SIV infection has been a subject of debate. As a means to delineate the effect of NK cells on SIV infection, use was made of a Janus kinase 3 (JAK3) inhibitor that has previously been shown to be effective in the depletion of NK cells in vivo in nonhuman primates (NHP). Extensive safety and in vitro/in vivo PK studies were conducted and an optimal dose that depletes NK cells and NK cell function in vivo identified. Six chronically SIV infected rhesus macaques, 3 with undetectable/low plasma viral loads and 3 with high plasma viral loads were administered a daily oral dose of 10 mg/kg for 35 days. Data obtained showed that, at the dose tested, the major cell lineage affected both in the blood and the GI tissues were the NK cells. Such depletion appeared to be associated with a transient increase in plasma and GI tissue viral loads. Whereas the number of NK cells returned to baseline values in the blood, the GI tissues remained depleted of NK cells for a prolonged period of time. Recent findings show that the JAK3 inhibitor utilized in the studies reported herein has a broader activity than previously reported with dose dependent effects on both JAK2 and JAK1 suggests that it is likely that multiple pathways are affected with the administration of this drug that needs to be taken into account. The findings reported herein are the first studies on the use of a JAK3 inhibitor in lentivirus infected NHP. PMID- 23923041 TI - The innate immunity adaptor SARM translocates to the nucleus to stabilize lamins and prevent DNA fragmentation in response to pro-apoptotic signaling. AB - Sterile alpha and armadillo-motif containing protein (SARM), a highly conserved and structurally unique member of the MyD88 family of Toll-like receptor adaptors, plays an important role in innate immunity signaling and apoptosis. Its exact mechanism of intracellular action remains unclear. Apoptosis is an ancient and ubiquitous process of programmed cell death that results in disruption of the nuclear lamina and, ultimately, dismantling of the nucleus. In addition to supporting the nuclear membrane, lamins serve important roles in chromatin organization, epigenetic regulation, transcription, nuclear transport, and mitosis. Mutations and other damage that destabilize nuclear lamins (laminopathies) underlie a number of intractable human diseases. Here, we report that SARM translocates to the nucleus of human embryonic kidney cells by using its amino-terminal Armadillo repeat region. Within the nucleus, SARM forms a previously unreported lattice akin to the nuclear lamina scaffold. Moreover, we show that SARM protects lamins from apoptotic degradation and reduces internucleosomal DNA fragmentation in response to signaling induced by the proinflammatory cytokine Tumor Necrosis Factor alpha. These findings indicate an important link between the innate immunity adaptor SARM and stabilization of nuclear lamins during inflammation-driven apoptosis in human cells. PMID- 23923042 TI - Migraine with aura is associated with an incomplete circle of willis: results of a prospective observational study. AB - OBJECTIVE: To compare the prevalence of an incomplete circle of Willis in patients with migraine with aura, migraine without aura, and control subjects, and correlate circle of Willis variations with alterations in cerebral perfusion. METHODS: Migraine with aura, migraine without aura, and control subjects were prospectively enrolled in a 1?1?1 ratio. Magnetic resonance angiography was performed to examine circle of Willis anatomy and arterial spin labeled perfusion magnetic resonance imaging to measure cerebral blood flow. A standardized template rating system was used to categorize circle of Willis variants. The primary pre-specified outcome measure was the frequency of an incomplete circle of Willis. The association between circle of Willis variations and cerebral blood flow was also analyzed. RESULTS: 170 subjects were enrolled (56 migraine with aura, 61 migraine without aura, 53 controls). An incomplete circle of Willis was significantly more common in the migraine with aura compared to control group (73% vs. 51%, p = 0.02), with a similar trend for the migraine without aura group (67% vs. 51%, p = 0.08). Using a quantitative score of the burden of circle of Willis variants, migraine with aura subjects had a higher burden of variants than controls (p = 0.02). Compared to those with a complete circle, subjects with an incomplete circle had greater asymmetry in hemispheric cerebral blood flow (p = 0.05). Specific posterior cerebral artery variants were associated with greater asymmetries of blood flow in the posterior cerebral artery territory. CONCLUSIONS: An incomplete circle of Willis is more common in migraine with aura subjects than controls, and is associated with alterations in cerebral blood flow. PMID- 23923043 TI - beta-blocker timolol prevents arrhythmogenic Ca2+ release and normalizes Ca2+ and Zn2+ dyshomeostasis in hyperglycemic rat heart. AB - Defective cardiac mechanical activity in diabetes results from alterations in intracellular Ca(2+) handling, in part, due to increased oxidative stress. Beta blockers demonstrate marked beneficial effects in heart dysfunction with scavenging free radicals and/or acting as an antioxidant. The aim of this study was to address how beta-blocker timolol-treatment of diabetic rats exerts cardioprotection. Timolol-treatment (12-week), one-week following diabetes induction, prevented diabetes-induced depressed left ventricular basal contractile activity, prolonged cellular electrical activity, and attenuated the increase in isolated-cardiomyocyte size without hyperglycemic effect. Both in vivo and in vitro timolol-treatment of diabetic cardiomyocytes prevented the altered kinetic parameters of Ca(2+) transients and reduced Ca(2+) loading of sarcoplasmic reticulum (SR), basal intracellular free Ca(2+) and Zn(2+) ([Ca(2+)]i and [Zn(2+)]i), and spatio-temporal properties of the Ca(2+) sparks, significantly. Timolol also antagonized hyperphosphorylation of cardiac ryanodine receptor (RyR2), and significantly restored depleted protein levels of both RyR2 and calstabin2. Western blot analysis demonstrated that timolol-treatment also significantly normalized depressed levels of some [Ca(2+)]i-handling regulators, such as Na(+)/Ca(2+) exchanger (NCX) and phospho-phospholamban (pPLN) to PLN ratio. Incubation of diabetic cardiomyocytes with 4-mM glutathione exerted similar beneficial effects on RyR2-macromolecular complex and basal levels of both [Ca(2+)]i and [Zn(2+)]i, increased intracellular Zn(2+) hyperphosphorylated RyR2 in a concentration-dependent manner. Timolol also led to a balanced oxidant/antioxidant level in both heart and circulation and prevented altered cellular redox state of the heart. We thus report, for the first time, that the preventing effect of timolol, directly targeting heart, seems to be associated with a normalization of macromolecular complex of RyR2 and some Ca(2+) handling regulators, and prevention of Ca(2+) leak, and thereby normalization of both [Ca(2+)]i and [Zn(2+)]i homeostasis in diabetic rat heart, at least in part by controlling the cellular redox status of hyperglycemic cardiomyocytes. PMID- 23923045 TI - Development and validation of a multiplex, real-time RT PCR assay for the simultaneous detection of classical and African swine fever viruses. AB - A single-step, multiplex, real-time polymerase chain reaction (RT-PCR) was developed for the simultaneous and differential laboratory diagnosis of Classical swine fever virus (CSFV) and African swine fever virus (ASFV) alongside an exogenous internal control RNA (IC-RNA). Combining a single extraction methodology and primer and probe sets for detection of the three target nucleic acids CSFV, ASFV and IC-RNA, had no effect on the analytical sensitivity of the assay and the new triplex RT-PCR was comparable to standard PCR techniques for CSFV and ASFV diagnosis. After optimisation the assay had a detection limit of 5 CSFV genome copies and 22 ASFV genome copies. Analytical specificity of the triplex assay was validated using a panel of viruses representing 9 of the 11 CSFV subgenotypes, at least 8 of the 22 ASFV genotypes as well as non-CSFV pestiviruses. Positive and negative clinical samples from animals infected experimentally, due to field exposure or collected from the UK which is free from both swine diseases, were used to evaluate the diagnostic sensitivity and specificity for detection of both viruses. The diagnostic sensitivity was 100% for both viruses whilst diagnostic specificity estimates were 100% for CSFV detection and 97.3% for ASFV detection. The inclusion of a heterologous internal control allowed identification of false negative results, which occurred at a higher level than expected. The triplex assay described here offers a valuable new tool for the differential detection of the causative viruses of two clinically indistinguishable porcine diseases, whose geographical occurrence is increasingly overlapping. PMID- 23923044 TI - Aggregation of lipid-anchored full-length H-Ras in lipid bilayers: simulations with the MARTINI force field. AB - Lipid-anchored Ras oncoproteins assemble into transient, nano-sized substructures on the plasma membrane. These substructures, called nanoclusters, were proposed to be crucial for high-fidelity signal transmission in cells. However, the molecular basis of Ras nanoclustering is poorly understood. In this work, we used coarse-grained (CG) molecular dynamics simulations to investigate the molecular mechanism by which full-length H-ras proteins form nanoclusters in a model membrane. We chose two different conformations of H-ras that were proposed to represent the active and inactive state of the protein, and a domain-forming model bilayer made up of di16:0-PC (DPPC), di18:2-PC (DLiPC) and cholesterol. We found that, irrespective of the initial conformation, Ras molecules assembled into a single large aggregate. However, the two binding modes, which are characterized by the different orientation of the G-domain with respect to the membrane, differ in dynamics and organization during and after aggregation. Some of these differences involve regions of Ras that are important for effector/modulator binding, which may partly explain observed differences in the ability of active and inactive H-ras nanoclusters to recruit effectors. The simulations also revealed some limitations in the CG force field to study protein assembly in solution, which we discuss in the context of proposed potential avenues of improvement. PMID- 23923046 TI - Ontogenetic scaling of fore- and hind limb posture in wild chacma baboons (Papio hamadryas ursinus). AB - Large-scale interspecific studies of mammals ranging between 0.04-280 kg have shown that larger animals walk with more extended limb joints. Within a taxon or clade, however, the relationship between body size and joint posture is less straightforward. Factors that may affect the lack of congruence between broad and narrow phylogenetic analyses of limb kinematics include limited sampling of (1) ranges of body size, and/or (2) numbers of individuals. Unfortunately, both issues are inherent in laboratory-based or zoo locomotion research. In this study, we examined the relationship between body mass and elbow and knee joint angles (our proxies of fore- and hind limb posture, respectively) in a cross sectional ontogenetic sample of wild chacma baboons (Papio hamadryas ursinus) habituated in the De Hoop Nature Reserve, South Africa. Videos were obtained from 33 individuals of known age (12 to >= 108 months) and body mass (2-29.5 kg) during walking trials. Results show that older, heavier baboons walk with significantly more extended knee joints but not elbow joints. This pattern is consistent when examining only males, but not within the female sample. Heavier, older baboons also display significantly less variation in their hind limb posture compared to lighter, young animals. Thus, within this ontogenetic sample of a single primate species spanning an order of magnitude in body mass, hind limb posture exhibited a postural scaling phenomenon while the forelimbs did not. These findings may further help explain 1) why younger mammals (including baboons) tend to have relatively stronger bones than adults, and 2) why humeri appear relatively weaker than femora (in at least baboons). Finally, this study demonstrates how field-acquired kinematics can help answer fundamental biomechanical questions usually addressed only in animal gait laboratories. PMID- 23923047 TI - STAT3 signaling induces the differentiation of human ICOS(+) CD4 T cells helping B lymphocytes. AB - The generation of high-affinity antibodies and the development of B cell memory are dependent on the help provided by CD4 T cells. Mouse studies indicate that STAT3 signaling in CD4 T cells promotes the acquisition of the B cell help function. However, the role of STAT3 in humans has been controversial. In this study, we show that IL-6 and other STAT3 activating cytokines (IL-21 and IL-27) induce the differentiation of CD4 T cells promoting antibody production by B cells. The acquisition of B cell stimulating properties by naive cord blood CD4 T cells required the STAT3-dependent expression of ICOS and IL-21. Gene reporter and ChIP experiments unambiguously demonstrated that upon IL-6 stimulation, STAT3 induces the transcription of the ICOS gene through direct recruitment to the proximal promoter region indicating that STAT3 acts in part through the direct activation of the ICOS gene. PMID- 23923048 TI - Tyrosine 416 is phosphorylated in the closed, repressed conformation of c-Src. AB - c-Src kinase activity is regulated by phosphorylation of Y527 and Y416. Y527 phosphorylation stabilizes a closed conformation, which suppresses kinase activity towards substrates, whereas phosphorylation at Y416 promotes an elevated kinase activity by stabilizing the activation loop in a manner permissive for substrate binding. Here we investigated the correlation of Y416 phosphorylation with c-Src activity when c-Src was locked into the open and closed conformations (by mutations Y527F and Q528E, P529E, G530I respectively). Consistent with prior findings, we found Y416 to be more greatly phosphorylated when c-Src was in an open, active conformation. However, we also observed an appreciable amount of Y416 was phosphorylated when c-Src was in a closed, repressed conformation under conditions by which c-Src was unable to phosphorylate substrate STAT3. The phosphorylation of Y416 in the closed conformation arose by autophosphorylation, since abolishing kinase activity by mutating the ATP binding site (K295M) prevented phosphorylation. Basal Y416 phosphorylation correlated positively with cellular levels of c-Src suggesting autophosphorylation depended on self association. Using sedimentation velocity analysis on cell lysate with fluorescence detection optics, we confirmed that c-Src forms monomers and dimers, with the open conformation also forming a minor population of larger mass complexes. Collectively, our studies suggest a model by which dimerization of c Src primes c-Src via Y416 phosphorylation to enable rapid potentiation of activity when Src adopts an open conformation. Once in the open conformation, c Src can amplify the response by recruiting and phosphorylating substrates such as STAT3 and increasing the extent of autophosphorylation. PMID- 23923049 TI - Primary vitamin D target genes allow a categorization of possible benefits of vitamin D3 supplementation. AB - Vitamin D deficiency has been associated with an increased risk of developing a number of diseases. Here we investigated samples from 71 pre-diabetic individuals of the VitDmet study, a 5-month high dose vitamin D3 intervention trial during Finnish winter, for their changes in serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations and the expression of primary vitamin D target genes in peripheral blood mononuclear cells and adipose tissue. A negative correlation between serum concentrations of parathyroid hormone and 25(OH)D3 suggested an overall normal physiological vitamin D response among the participants. The genes CD14 and thrombomodulin (THBD) are up-regulated primary vitamin D targets and showed to be suitable gene expression markers for vitamin D signaling in both primary tissues. However, in a ranking of the samples concerning their expected response to vitamin D only the top half showed a positive correlation between the changes of CD14 or THBD mRNA and serum 25(OH)D3 concentrations. Interestingly, this categorization allows unmasking a negative correlation between changes in serum concentrations of 25(OH)D3 and the inflammation marker interleukin 6. We propose the genes CD14 and THBD as transcriptomic biomarkers, from which the effects of a vitamin D3 supplementation can be evaluated. These biomarkers allow the classification of subjects into those, who might benefit from a vitamin D3 supplementation, and others who do not. PMID- 23923050 TI - An integrated peptide-antigen microarray on plasmonic gold films for sensitive human antibody profiling. AB - High-throughput screening for interactions of peptides with a variety of antibody targets could greatly facilitate proteomic analysis for epitope mapping, enzyme profiling, drug discovery and biomarker identification. Peptide microarrays are suited for such undertaking because of their high-throughput capability. However, existing peptide microarrays lack the sensitivity needed for detecting low abundance proteins or low affinity peptide-protein interactions. This work presents a new peptide microarray platform constructed on nanostructured plasmonic gold substrates capable of metal enhanced NIR fluorescence enhancement (NIR-FE) by hundreds of folds for screening peptide-antibody interactions with ultrahigh sensitivity. Further, an integrated histone peptide and whole antigen array is developed on the same plasmonic gold chip for profiling human antibodies in the sera of systemic lupus erythematosus (SLE) patients, revealing that collectively a panel of biomarkers against unmodified and post-translationally modified histone peptides and several whole antigens allow more accurate differentiation of SLE patients from healthy individuals than profiling biomarkers against peptides or whole antigens alone. PMID- 23923051 TI - Transcriptome analysis of duck liver and identification of differentially expressed transcripts in response to duck hepatitis A virus genotype C infection. AB - BACKGROUND: Duck is an economically important poultry and animal model for human viral hepatitis B. However, the molecular mechanisms underlying host-virus interaction remain unclear because of limited information on the duck genome. This study aims to characterize the duck normal liver transcriptome and to identify the differentially expressed transcripts at 24 h after duck hepatitis A virus genotype C (DHAV-C) infection using Illumina-Solexa sequencing. RESULTS: After removal of low-quality sequences and assembly, a total of 52,757 unigenes was obtained from the normal liver group. Further blast analysis showed that 18,918 unigenes successfully matched the known genes in the database. GO analysis revealed that 25,116 unigenes took part in 61 categories of biological processes, cellular components, and molecular functions. Among the 25 clusters of orthologous group categories (COG), the cluster for "General function prediction only" represented the largest group, followed by "Transcription" and "Replication, recombination, and repair." KEGG analysis showed that 17,628 unigenes were involved in 301 pathways. Through comparison of normal and infected transcriptome data, we identified 20 significantly differentially expressed unigenes, which were further confirmed by real-time polymerase chain reaction. Of the 20 unigenes, nine matched the known genes in the database, including three up regulated genes (virus replicase polyprotein, LRRC3B, and PCK1) and six down regulated genes (CRP, AICL-like 2, L1CAM, CYB26A1, CHAC1, and ADAM32). The remaining 11 novel unigenes that did not match any known genes in the database may provide a basis for the discovery of new transcripts associated with infection. CONCLUSION: This study provided a gene expression pattern for normal duck liver and for the previously unrecognized changes in gene transcription that are altered during DHAV-C infection. Our data revealed useful information for future studies on the duck genome and provided new insights into the molecular mechanism of host-DHAV-C interaction. PMID- 23923052 TI - Aberrant default mode functional connectivity in early onset schizophrenia. AB - BACKGROUND: The default mode network (DMN) has been linked to a number of mental disorders including schizophrenia. However, the abnormal connectivity of DMN in early onset schizophrenia (EOS) has been rarely reported. METHODS: Independent component analysis (ICA) was used to investigate functional connectivity (FC) of the DMN in 32 first-episode adolescents with EOS and 32 age and gender-matched healthy controls. RESULTS: Compared to healthy controls, patients with EOS showed increased FC between the medial frontal gyrus and other areas of the DMN. Partial correlation analyses showed that the FC of medial frontal gyrus significantly correlated with PANSS-positive symptoms (partial correlation coefficient = 0.538, Bonferoni corrected P = 0.018). LIMITATIONS: Although the sample size of participants was comparable with most fMRI studies to date, it was still relatively small. Pediatric brains were registered to the MNI adult brain template. However, possible age-specific differences in spatial normalization that arise from registering pediatric brains to the MNI adult brain template may have little effect on fMRI results. CONCLUSION: This study provides evidence for functional abnormalities of DMN in first-episode EOS. These abnormalities could be a source of abnormal introspectively-oriented mental actives. PMID- 23923053 TI - Tuberculosis epidemiology in islands: insularity, hosts and trade. AB - Because of their relative simplicity and the barriers to gene flow, islands are ideal systems to study the distribution of biodiversity. However, the knowledge that can be extracted from this peculiar ecosystem regarding epidemiology of economically relevant diseases has not been widely addressed. We used information available in the scientific literature for 10 old world islands or archipelagos and original data on Sicily to gain new insights into the epidemiology of the Mycobacterium tuberculosis complex (MTC). We explored three nonexclusive working hypotheses on the processes modulating bovine tuberculosis (bTB) herd prevalence in cattle and MTC strain diversity: insularity, hosts and trade. Results suggest that bTB herd prevalence was positively correlated with island size, the presence of wild hosts, and the number of imported cattle, but neither with isolation nor with cattle density. MTC strain diversity was positively related with cattle bTB prevalence, presence of wild hosts and the number of imported cattle, but not with island size, isolation, and cattle density. The three most common spoligotype patterns coincided between Sicily and mainland Italy. However in Sicily, these common patterns showed a clearer dominance than on the Italian mainland, and seven of 19 patterns (37%) found in Sicily had not been reported from continental Italy. Strain patterns were not spatially clustered in Sicily. We were able to infer several aspects of MTC epidemiology and control in islands and thus in fragmented host and pathogen populations. Our results point out the relevance of the intensity of the cattle commercial networks in the epidemiology of MTC, and suggest that eradication will prove more difficult with increasing size of the island and its environmental complexity, mainly in terms of the diversity of suitable domestic and wild MTC hosts. PMID- 23923054 TI - Retinal vascular caliber is associated with cardiovascular biomarkers of oxidative stress and inflammation: the POLA study. AB - PURPOSE: Retinal vascular caliber has been linked with increased cardiovascular risk and is predictive of cardiovascular pathology, including stroke and coronary heart disease. Oxidative stress, as well as inflammatory mechanisms, plays a major role in the pathogenesis and progression of atherosclerosis, plaque rupture and vascular thrombotic propensity. The purpose of this study is to explore the relationship between retinal vascular calibers and biomarkers of oxidative stress and inflammation, in subjects free of cardiovascular pathology. PATIENTS AND METHODS: Cross-sectional analysis from a community-dwelling cohort comprising 1224 individuals aged 60 years and over, without a history of coronary or peripheral artery disease or stroke. Retinal vascular caliber was measured from fundus photographs using semi-automated standardized imaging software. Oxidative stress was evaluated using plasma superoxide dismutase 2 and glutathione peroxidase (GPx-3) activities, and inflammatory state was assessed using plasma high sensitivity C-reactive protein (hsCRP) and orosomucoid. RESULTS: In a multivariate model controlling for cardiovascular risk factors, larger retinal arteriolar caliber was independently related to higher level of GPx-3 activity (p = 0.003) whereas larger venular caliber was associated with higher levels of hsCRP (p = 0.0001) and orosomucoid (p = 0.01). CONCLUSION: In the present study, biomarkers of oxidative stress regulation and inflammation were independently associated with retinal vascular calibers. This suggests that an assessment of retinal vessels may offer early and non-invasive detection of subclinical vascular pathology. PMID- 23923055 TI - Genome-wide survey and comparative analysis of LTR retrotransposons and their captured genes in rice and sorghum. AB - Long terminal repeat (LTR) retrotransposons are the major class I mobile elements in plants. They play crucial roles in gene expansion, diversification and evolution. However, their captured genes are yet to be genome-widely identified and characterized in most of plants although many genomes have been completely sequenced. In this study, we have identified 7,043 and 23,915 full-length LTR retrotransposons in the rice and sorghum genomes, respectively. High percentages of rice full-length LTR retrotransposons were distributed near centromeric region in each of the chromosomes. In contrast, sorghum full-length LTR retrotransposons were not enriched in centromere regions. This dissimilarity could be due to the discrepant retrotransposition during and after divergence from their common ancestor thus might be contributing to species divergence. A total of 672 and 1,343 genes have been captured by these elements in rice and sorghum, respectively. Gene Ontology (GO) and gene set enrichment analysis (GSEA) showed that no over-represented GO term was identified in LTR captured rice genes. For LTR captured sorghum genes, GO terms with functions in DNA/RNA metabolism and chromatin organization were over-represented. Only 36% of LTR captured rice genes were expressed and expression divergence was estimated as 11.9%. Higher percentage of LTR captured rice genes have evolved into pseudogenes under neutral selection. On the contrary, higher percentage of LTR captured sorghum genes were under purifying selection and 72.4% of them were expressed. Thus, higher percentage of LTR captured sorghum genes was functional. Small RNA analysis suggested that some of LTR captured genes in rice and sorghum might have been involved in negative regulation. On the other hand, positive selection has been observed in both rice and sorghum LTR captured genes and some of them were still expressed and functional. The data suggest that some of these LTR captured genes might have evolved into new gene functions. PMID- 23923056 TI - Physicians infrequently adhere to hepatitis vaccination guidelines for chronic liver disease. AB - BACKGROUND AND GOALS: Hepatitis A (HAV) and hepatitis B (HBV) vaccination in patients with chronic liver disease is an accepted standard of care. We determined HAV and HBV vaccination rates in a tertiary care referral hepatology clinic and the impact of electronic health record (EHR)-based reminders on adherence to vaccination guidelines. METHODS: We reviewed the records of 705 patients with chronic liver disease referred to our liver clinic in 2008 with at least two follow-up visits during the subsequent year. Demographics, referral source, etiology, and hepatitis serology were recorded. We determined whether eligible patients were offered vaccination and whether patients received vaccination. Barriers to vaccination were determined by a follow-up telephone interview. RESULTS: HAV and HBV serologic testing prior to referral and at the liver clinic were performed in 14.5% and 17.7%; and 76.7% and 74% patients, respectively. Hepatologists recommended vaccination for HAV in 63% and for HBV in 59.7% of eligible patients. Patient demographics or disease etiology did not influence recommendation rates. Significant variability was observed in vaccination recommendation amongst individual providers (30-98.6%), which did not correlate with the number of patients seen by each physician. Vaccination recommendation rates were not different for Medicare patients with hepatitis C infection for whom a vaccination reminder was automatically generated by the EHR. Most patients who failed to get vaccination after recommendation offered no specific reason for noncompliance; insurance was a barrier in a minority. CONCLUSIONS: Hepatitis vaccination rates were suboptimal even in an academic, sub speciality setting, with wide-variability in provider adherence to vaccination guidelines. PMID- 23923057 TI - Learning of multi-modal stimuli in hawkmoths. AB - The hawkmoth, Manduca sexta, uses both colour and odour to find flowers when foraging for nectar. In the present study we investigated how vision and olfaction interact during learning. Manduca sexta were equally attracted to a scented blue coloured feeding target (multimodal stimulus) as to one that does not carry any scent (unimodal stimulus; visual) or to an invisible scented target (unimodal stimulus; odour). This naive attraction to multimodal as well as to unimodal stimuli could be manipulated through training. Moths trained to feed from a blue, scented multimodal feeding target will, when tested in a set-up containing all three feeding targets, select the multimodal target as well as the scented, unimodal target, but ignore the visual target. Interestingly, moths trained to feed from a blue, unimodal visual feeding target will select the visual target as well as the scented, multimodal target, but ignore the unimodal odour target. Our results indicate that a multimodal target is perceived as two separate modalities, colour and odour, rather than as a unique fused target. These findings differ from earlier studies of desert ants that perceive combined visual and odour signals as a unique fused stimulus following learning trials. PMID- 23923058 TI - TcTASV-C, a protein family in Trypanosoma cruzi that is predominantly trypomastigote-stage specific and secreted to the medium. AB - Among the several multigene families codified by the genome of T. cruzi, the TcTASV family was the latest discovered. The TcTASV (Trypomastigote, Alanine, Serine, Valine) family is composed of ~40 members, with conserved carboxi- and amino-termini but with a variable central core. According to the length and sequence of the central region the family is split into 3 subfamilies. The TcTASV family is conserved in the genomes of - at least - lineages TcI and TcVI and has no orthologues in other trypanosomatids. In the present work we focus on the study of the TcTASV-C subfamily, composed by 16 genes in the CL Brener strain. We determined that TcTASV-C is preferentially expressed in trypomastigotes, but it is not a major component of the parasite. Both immunoflourescence and flow cytometry experiments indicated that TcTASV-C has a clonal expression, i.e. it is not expressed by all the parasites of a certain population at the same time. We also determined that TcTASV-C is phosphorylated and glycosylated. TASV-C is attached to the parasite surface by a GPI anchor and is shed spontaneously into the medium. About 30% of sera from infected hosts reacted with TcTASV-C, confirming its exposition to the immune system. Its superficial localization and secretory nature suggest a possible role in host-parasite interactions. PMID- 23923059 TI - Bacterial cyclic AMP-phosphodiesterase activity coordinates biofilm formation. AB - Biofilm-related infections are a major contributor to human disease, and the capacity for surface attachment and biofilm formation are key attributes for the pathogenesis of microbes. Serratia marcescens type I fimbriae-dependent biofilms are coordinated by the adenylate cyclase, CyaA, and the cyclic 3',5'-adenosine monophosphate (cAMP)-cAMP receptor protein (CRP) complex. This study uses S. marcescens as a model system to test the role of cAMP-phosphodiesterase activity in controlling biofilm formation. Herein we describe the characterization of a putative S. marcescens cAMP-phosphodiesterase gene (SMA3506), designated as cpdS, and demonstrated to be a functional cAMP-phosphodiesterase both in vitro and in vivo. Deletion of cpdS resulted in defective biofilm formation and reduced type I fimbriae production, whereas multicopy expression of cpdS conferred a type I fimbriae-dependent hyper-biofilm. Together, these results support a model in which bacterial cAMP-phosphodiesterase activity modulates biofilm formation. PMID- 23923060 TI - Altered islet morphology but normal islet secretory function in vitro in a mouse model with microvascular alterations in the pancreas. AB - BACKGROUND: Our previous studies have shown that signal transducer and activator of transcription 3 (STAT3) signaling is important for the development of pancreatic microvasculature via its regulation of vascular endothelial growth factor-A (VEGF-A). Pancreas-specific STAT3-KO mice exhibit glucose intolerance and impaired insulin secretion in vivo, along with microvascular alterations in the pancreas. However, the specific role of STAT3 signaling in the regulation of pancreatic islet development and function is not entirely understood. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the role of STAT3 signaling in the formation and maintenance of pancreatic islets, we studied pancreas-specific STAT3-KO mice. Histological analysis showed that STAT3 deficiency affected pancreatic islet morphology. We found an increased proportion of small-sized islets and a reduced fraction of medium-sized islets, indicating abnormal islet development in STAT3-KO mice. Interestingly, the islet area relative to the whole pancreas area in transgenic and control mice was not significantly different. Immunohistochemical analysis on pancreatic cryosections revealed abnormalities in islet architecture in STAT3-KO mice: the pattern of peripheral distribution of glucagon-positive alpha-cells was altered. At the same time, islets belonging to different size categories isolated from STAT3-KO mice exhibited normal glucose stimulated insulin secretion in perifusion experiments in vitro when compared to control mice. CONCLUSIONS: Our data demonstrate that STAT3 signaling in the pancreas is required for normal islet formation and/or maintenance. Altered islet size distribution in the KO mice does not result in an impaired islet secretory function in vitro. Therefore, our current study supports that the glucose intolerance and in vivo insulin secretion defect in pancreas-specific STAT3-KO mice is due to altered microvasculature in the pancreas, and not intrinsic beta cell function. PMID- 23923061 TI - Modulating the actin cytoskeleton affects mechanically induced signal transduction and differentiation in mesenchymal stem cells. AB - Mechanical interactions of mesenchymal stem cells (MSC) with the environment play a significant role in controlling the diverse biological functions of these cells. Mechanical forces are transduced by integrins to the actin cytoskeleton that functions as a scaffold to switch mechanical signals into biochemical pathways. To explore the significance of cytoskeletal mechanisms in human MSC we modulated the actin cytoskeleton using the depolymerising drugs cytochalasin D (CytD) and latrunculin A (LatA), as well as the stabilizing drug jasplakinolide (Jasp) and examined the activation of the signalling molecules ERK and AKT during mechanical loading. All three drugs provoked significant changes in cell morphology and organisation of the cytoskeleton. Application of mechanical forces to beta1-integrin receptors using magnetic beads without deformation of the cell shape induced a phosphorylation of ERK and AKT. Of the two drugs that inhibited the cytoskeletal polymerization, LatA completely blocked the activation of ERK and AKT due to mechanical forces, whereas CytD inhibited the activation of AKT but not of ERK. Activation of both signalling molecules by integrin loading was not affected due to cell treatment with the cytoskeleton stabilizing drug Jasp. To correlate the effects of the drugs on mechanically induced activation of AKT and ERK with parameters of MSC differentiation, we studied ALP activity as a marker for osteogenic differentiation and examined the uptake of fat droplets as marker for adipogenic differentiation in the presence of the drugs. All three drugs inhibited ALP activity of MSC in osteogenic differentiation medium. Adipogenic differentiation was enhanced by CytD and Jasp, but not by LatA. The results indicate that modulation of the cytoskeleton using perturbing drugs can differentially modify both mechanically induced signal transduction and MSC differentiation. In addition to activation of the signalling molecules ERK and AKT, other cytoskeletal mechanisms are involved in MSC differentiation. PMID- 23923062 TI - Dependence of the firearm-related homicide rate on gun availability: a mathematical analysis. AB - In the USA, the relationship between the legal availability of guns and the firearm-related homicide rate has been debated. It has been argued that unrestricted gun availability promotes the occurrence of firearm-induced homicides. It has also been pointed out that gun possession can protect potential victims when attacked. This paper provides a first mathematical analysis of this tradeoff, with the goal to steer the debate towards arguing about assumptions, statistics, and scientific methods. The model is based on a set of clearly defined assumptions, which are supported by available statistical data, and is formulated axiomatically such that results do not depend on arbitrary mathematical expressions. According to this framework, two alternative scenarios can minimize the gun-related homicide rate: a ban of private firearms possession, or a policy allowing the general population to carry guns. Importantly, the model identifies the crucial parameters that determine which policy minimizes the death rate, and thus serves as a guide for the design of future epidemiological studies. The parameters that need to be measured include the fraction of offenders that illegally possess a gun, the degree of protection provided by gun ownership, and the fraction of the population who take up their right to own a gun and carry it when attacked. Limited data available in the literature were used to demonstrate how the model can be parameterized, and this preliminary analysis suggests that a ban of private firearm possession, or possibly a partial reduction in gun availability, might lower the rate of firearm-induced homicides. This, however, should not be seen as a policy recommendation, due to the limited data available to inform and parameterize the model. However, the model clearly defines what needs to be measured, and provides a basis for a scientific discussion about assumptions and data. PMID- 23923064 TI - Urothelial eddies in papillary urothelial neoplasms: a distinct morphologic pattern with low risk for progression. AB - We encountered an undescribed histologic feature of papillary urothelial neoplasms: "urothelial eddy", which was histologically reminiscent of squamous eddy of irritated follicular keratosis of the skin. A review of 756 patients with transurethral resection of bladder tumor revealed 10 patients (1.3%) of papillary urothelial neoplasms with urothelial eddies. All cases were male with a median age of 65 years. Urothelial eddies were characterized by small ovoid nests of ovoid to spindle cells arranged in an onion-skin pattern with fine cytoplasmic processes within wide intercellular space. The cytoplasmic processes mimicked intercellular bridges but ultrastructurally were cytoplasmic microvillous projections. They were of papillary urothelial neoplasm of low malignant potential in seven patients and low-grade urothelial carcinoma in three patients. Nine patients presented as non-invasive tumor and one patient showed microinvasion within papillary stalks. Six patients showed an inverted growth pattern. Their immunoprofile was more similar to that of conventional urothelial carcinoma rather than squamous cell carcinoma: high expressions of GATA3, S100P, uroplakin III, and cytokeratin 7; and low expressions of high molecular weight cytokeratin and p53. The Ki-67 labeling index was low (mean and median values, 2% each). During the follow-up period (mean, 88.7 months), four patients, including the microinvasive patient, showed recurrence with the same grade and stage but neither progressed into muscle-invasive tumor nor caused death. Our results suggest that urothelial eddy is a rare aberrant histology of papillary urothelial neoplasms with indolent behavior and should be discriminated from squamous differentiation of urothelial carcinoma, which has a poor prognosis. PMID- 23923065 TI - Histopathological and functional effects of antimony on the renal cortex of growing albino rat. AB - Contamination of the environment with antimony compounds may affect human health through the persistent exposure to small doses over a long period. Sixty growing male albino rats, weighing 43-57 grams, utilized in this study. The animals were divided into 3 groups; each of 20 rats: animals of group I served as control, animals of group II received 6 mg/kg body weight antimony trisulfide daily for 8 weeks with drinking water, and those of group III received the same dose by the same route for 12 weeks. The Malpighian renal corpuscles showed distortion, destruction and congestion of glomerular tuft, vacuoles in the glomeruli, peritubular haemorrhage, obliteration of Bowman's space, and thickening with irregularity of Bowman's membrane. The proximal convoluted tubules demonstrated patchy loss of their brush border, thickening of the basement membrane with loss of its basal infoldings, disarrangement of the mitochondria, pleomorphic vacuoles in the cytoplasm, apical destruction of the cells, apical migration of the nuclei, and absence of microvilli. On the other hand, peri-tubular hemorrhage, apical vacuolation, small atrophic nuclei, swelling of mitochondria, obliteration of the lumina, destruction of cells, and presence of tissue debris in the lumina, were observed in the distal convoluted tubules. The present work demonstrated the hazardous effect of antimony on the renal function as evidenced by the significant increase of the level of blood urea, serum creatinine, and serum sodium and potassium. In conclusion, this study proposed that continuous oral administration of antimony for 8 and 12 weeks has hazardous toxic effect on the structure and function of the kidney in growing albino rat. Based on the results of the present study, it is recommended to avoid the use of any drinking water contaminated with antimony compounds and forbidden its use in infants and children foods. PMID- 23923066 TI - IL4 and IL-17A provide a Th2/Th17-polarized inflammatory milieu in favor of TGF beta1 to induce bronchial epithelial-mesenchymal transition (EMT). AB - Severe asthma is a chronic airway disease characterized by the Th2/Th17-polarized inflammation along with permanent airway remodeling. Despite past extensive studies, the exact role for Th2 and Th17 cytokines in asthmatic pathoetiology, particularly in the pathogenesis of bronchial epithelial-mesenchymal transition (EMT), is yet to be fully addressed. We herein conducted studies in 16-HBE cells and demonstrated that Th2-derived IL-4 and Th17-derived IL-17A provide a chronic inflammatory milieu that favors TGF-beta1 to induce bronchial EMT. A synergic action was noted between TGF-beta1, IL-4 and IL-17A in terms of induction of EMT. IL-4 and IL-17A synergized with TGF-beta1 to induce epithelial cells re-entering cell cycle, and to promote epithelial to mesenchymal morphological transistion, and by which they enhanced the capacity of TGF-beta1 to suppress E-cadherin expression, and to induce a-SMA expression in epithelial cells. Mechanistic studies revealed that this synergic action is coordinated by the regulation of ERK1/2 activity. Our results not only provide a novel insight into the understanding of the mechanisms underlying airway remodeling in asthmatic condition, but also have the potential for developing more effective therapeutic strategies against severe asthmatics in clinical settings. PMID- 23923067 TI - RAF1-MEK1-ERK/AKT axis may confer NSCLC cell lines resistance to erlotinib. AB - The fact that advanced NSCLC patients with wild type (wt) EGFR can benefit from erlotinib therapy makes it critical to find out biomarkers for effective selection of patients and improving the therapy effects. In present study, 3 NSCLC cell lines (U1752, Calu-6 and NCI-H292) with wt EGFR and different sensitivities to erlotinib were used for microarray analysis. The differential basal gene expression between 2 NSCLC cell lines was analyzed, about 353 genes were expression-altered with higher than 2-fold changes between Calu-6 and U1752. And Ingenuity Pathway Analysis (IPA) showed that these genes were mainly enriched in regulation of epithelial-mesenchymal transition (EMT) pathway, Wnt-beta catenin signaling, Tec kinase signaling and some types of cancer-related signaling. More interestingly, RAF1 (c-raf), MAP2K1 (MEK1), SNAI and downstream signaling molecules ERK and AKT were predicted to be activated in erlotinib resistant cell line by IPA. Subsequent immunoblotting experiments showed that the phosphorylation of ERK and AKT were exactly increased stepwise from erlotinib sensitive cell line to erlotinib resistant cell lines. Collectively, activation of RAF1-MEK1-ERK/AKT axis may determine the resistance of NSCLC cell lines bearing wt EGFR to erlotinib. Our work provides potential biomarkers and therapeutic targets for NSCLC patients harboring wt EGFR. PMID- 23923068 TI - Effect of intra-cisternal application of kainic acid on the spinal cord and locomotor activity in rats. AB - Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease of idiopathic etiology. Glutamate excitotoxicity is one of the proposed hypotheses causing progressive death of motor neurons. We aimed to develop an experimental animal model of this disease to enhance the knowledge of pathophysiological mechanism of ALS. Male Wistar rats were infused with Kainic acid (KA) intra-cisternally for 5 days at the dosage of 50 fmol/day and 150 fmol/day. Locomotor activity, sensory function and histological changes in cervical and lumbar sections of spinal cord were evaluated. Glial Fibrillary Acidic Protein (GFAP) and Neurofilament Protein (NFP) were used as immunohistochemical marker for reactive astrogliosis and neuronal damage respectively. Specific Superoxide Dismutase (SOD) activity of spinal cord was estimated. The locomotor activity in the parameter of observed mean action time remained reduced on 14(th) day after administration of KA. Spinal motor neurons under Nissl stain showed pyknosis of nucleus and vacuolation of neuropil. GFAP expression increased significantly in the lumbar section of the spinal cord with high dose of KA treatment (p<0.05). NFP was expressed in axonal fibres around the neurons in KA-treated rats. A significant increase in specific SOD activity in both cervical and lumbar sections of the spinal cord was found with low dose of KA treatment (p<0.05). This study concludes that spinal cord damage with some features similar to ALS can be produced by low dose intra cisternal administration of KA. PMID- 23923069 TI - Inhibition of GAP-43 by propentofylline in a rat model of neuropathic pain. AB - Neural plasticity within the spinal nociceptive network may be fundamental to the chronic nature of neuropathic pain. The relation of growth-associated protein-43 (GAP-43), a protein involved in the nerve fiber growth and sprouting, to pain hypersensitivity has been investigated. Glial activation and inflammatory cytokines released by microglia and astrocytes are considered to be involved in the neural sprouting and plasticity. In the present study, the anti-nociception effect of propentofylline, a glial modulating agent, was investigated in a rat chronic constriction injury (CCI) model aiming to explore the role of GAP-43 expression. Our results demonstrated that propentofylline could attenuate the CCI induced mechanical allodynia and thermal hyperalgesia and inhibit the astrocyte activation and production of IL-1beta. GAP-43 expression was also down-regulated by intrathecal propentofylline. These findings suggest that astrocyte activation is involved in the regulation of GAP-43 expression and propentofylline might be used in the treatment of neuropathic pain. PMID- 23923070 TI - Tea polyphenols prevent lung from preneoplastic lesions and effect p53 and bcl-2 gene expression in rat lung tissues. AB - Lung cancer is one of the cancers that have the highest incidence and the highest mortality rate, and it is of great interest to identify ways to prevent its occurrence. We had established an animal model by using 3,4-benzopyrene intra pulmonary injection in our previous study, and had observed that the rats lung carcinoma incidence and multiplicity were significantly reduced by green tea administration. This study further investigated the effect of tea polyphenols on rat lung preneoplastic lesions using the lung carcinoma model established by 3,4 benzopyrene intra-pulmonary injection. Sprague-Dawley rats of the same age were randomly divided into 10 groups and treated with 3,4-benzopyrene by intra pulmonary injection. Five groups were given 0.3% solution of tea polyphenols (equivalent to 1.2% of green tea) in drinking water, while the other 5 groups were given pure drinking water. The rats were sacrificed at 0, 1, 4, 8 and 16 weeks after carcinogen treatment. In the control groups of rats, local bronchial inflammation were observed at 1 week after 3,4-benzopyrene treatment. From 4 weeks to 16 weeks after carcinogen treatment, hyperplasia, cell hyperproliferation, heterogeneity were observed in the bronchial epithelium. Meanwhile, the expression of p53 mRNA and protein, as well as the level of bcl-2, increased in the bronchial epithelial lesion. Tea polyphenols treatment significantly alleviated the bronchial epithelial lesions. At the same time, tea polyphenols treatment enhanced p53 expression, but reduced bcl-2 expression. These results indicated that tea polyphenols may have preventive effect against lung preneoplasm lesions, possibly through regulating the expression of some critical genes such as p53 and bcl-2. PMID- 23923071 TI - Histometric analyses of cancellous and cortical interface in autogenous bone grafting. AB - Surgical procedures involving the rehabilitation of the maxillofacial region frequently require bone grafts; the aim of this research was to evaluate the interface between recipient and graft with cortical or cancellous contact. 6 adult beagle dogs with 15 kg weight were included in the study. Under general anesthesia, an 8 mm diameter block was obtained from parietal bone of each animal and was put on the frontal bone with a 12 mm 1.5 screws. Was used the lag screw technique from better contact between the recipient and graft. 3-week and 6-week euthanized period were chosen for histometric evaluation. Hematoxylin-eosin was used in a histologic routine technique and histomorphometry was realized with IMAGEJ software. T test was used for data analyses with p<0.05 for statistical significance. The result show some differences in descriptive histology but non statistical differences in the interface between cortical or cancellous bone at 3 or 6 week; as natural, after 6 week of surgery, bone integration was better and statistically superior to 3-week analyses. We conclude that integration of cortical or cancellous bone can be usefully without differences. PMID- 23923072 TI - DNA microarray reveals different pathways responding to paclitaxel and docetaxel in non-small cell lung cancer cell line. AB - The wide use of paclitaxel and docetaxel in NSCLC clinical treatment makes it necessary to find biomarkers for identifying patients who can benefit from paclitaxel or docetaxel. In present study, NCI-H460, a NSCLC cell line with different sensitivity to paclitaxel and docetaxel, was applied to DNA microarray expression profiling analysis at different time points of lower dose treatment with paclitaxel or docetaxel. And the complex signaling pathways regulating the drug response were identified, and several novel sensitivity-realted markers were biocomputated.The dynamic changes of responding genes showed that paclitaxel effect is acute but that of docetaxel is durable at least for 48 hours in NCI H460 cells. Functional annotation of the genes with altered expression showed that genes/pathways responding to these two drugs were dramatically different. Gene expression changes induced by paclitaxel treatment were mainly enriched in actin cytoskeleton (ACTC1, MYL2 and MYH2), tyrosine-protein kinases (ERRB4, KIT and TIE1) and focal adhesion pathway (MYL2, IGF1 and FLT1), while the expression alterations responding to docetaxel were highly co-related to cell surface receptor linked signal transduction (SHH, DRD5 and ADM2), cytokine-cytokine receptor interaction (IL1A and IL6) and cell cycle regulation (CCNB1, CCNE2 and PCNA). Moreover, we also confirmed some different expression patterns with real time PCR. Our study will provide the potential biomarkers for paclitaxel and docetaxel-selection therapy in clinical application. PMID- 23923073 TI - Combined detection of p16(INK4a) and IMP3 increase the concordance rate between cervical cytologic and histologic diagnosis. AB - Currently, there are discrepancies in the interpretation between cervical liquid based cytology (LBC) and histologic diagnoses. The aim of our study was to evaluate the utility of p16(INK4a) (p16) and IMP3 staining of LBC specimens to increase the concordance rate. A total of 98 cell blocks with biopsy results, including 37 low-grade squamous intraepithelial lesions (LSIL), 36 high-grade squamous intraepithelial lesions (HSIL), and 25 squamous cell carcinomas (SCC), were selected for the immunocytochemical analysis of p16 and IMP3. The LBC diagnoses corresponded with histological diagnoses for 59.5% (22/37), 63.9% (23/36), and 88.0% (22/25) of LSIL, HSIL, and SCC lesions, respectively. We found a high frequency of p16 positivity in HSIL (72.2%) and SCC (100%), but not LSIL (29.7%). IMP3 was frequently expressed in SCC (84.0%), but rarely in LSIL (8.1%) and HSIL (25.0%). Cervical intraepithelial neoplasia 1 (CIN1) was negative for both p16 and IMP3, CIN2/3 tended to be positive for p16 and negative for IMP3, and SCC was positive for both p16 and IMP3. The combination of p16 and IMP3 immunostaining had a higher sensitivity and specificity for detecting CIN1 and CIN2/3 than cytology. For detecting SCC, p16/IMP3 had a higher sensitivity than cytology, but a lower specificity. IMP3 is a useful diagnostic immunomarker that can be used to identify SCC and the combination of p16/IMP3 expression was found to improve the discrepant results between cytologic and histologic diagnoses. PMID- 23923074 TI - Expression of Snail transcription factor in prostatic adenocarcinoma in Egypt: correlation with Maspin protein expression and clinicopathologic variables. AB - BACKGROUND: Snail transcription factor and Maspin tumor suppressor serpin are involved in the regulation of progression, invasion and metastasis of many human malignancies. However, there is very limited data in the literature about their role in prostatic adenocarcinoma. The present study was designed to investigate Snail and Maspin expression, their interrelationship and their relationship to different clinicopathologic variables in clinically detectable prostatic adenocarcinoma. MATERIAL AND METHODS: Tissue sections from 110 resected prostatic lesions distributed as 80 cases of prostatic adenocarcinoma and 30 cases of benign prostatic hyperplasia (BPH) were evaluated for Snail and Maspin proteins expression by immunohistochemistry. RESULTS: Snail protein expression was detected in 53.8% of prostatic adenocarcinomas versus none of BPH cases (p = < 0.001). A significant positive correlation of Snail expression to cancer grade (p = 0.015), lymph node metastasis (p = 0.026) and pTNM stage (p = 0.036). Maspin expression was detected in 36.6% of prostatic adenocarcinomas versus 93.3% of BPH cases (p = < 0.001). A significant negative correlation of Maspin expression to cancer grade (p = 0.007) and lymphovascular invasion (p = 0.017). Also detected was a significant negative relationship between Snail and Maspin expression in cancer cases under investigation (p = 0.002). CONCLUSION: Snail immunohistochemical expression can be promising as a potential prognostic biomarker in prostatic adenocarcinoma since it was significantly associated with clinicopathologic variables of progressive disease. A potential role for Snail in regulating Maspin expression is suggested based on the finding of negative association between Snail and Maspin expression in prostatic adenocarcinoma. PMID- 23923075 TI - Expression of soluble Fas and soluble FasL in human nucleus pulposus cells. AB - The study aimed for addressing the expression of soluble Fas (sFas) and soluble Fas Ligand (sFasL) in human nucleus pulposus (NP) and its attendant relationship with disc degeneration. Human NP samples were collected from patients with disc degeneration and cadavers as degenerate and normal groups, respectively. Subsequently, NP cells were cultured in monolayer. ELISA was performed to identify the expression levels of sFas and sFasL in the supernatant of NP cell cultures in vitro. Quantitative real-time PCR was used to detect the expression of sFas and sFasL in human NP cells in mRNA solution. The study comprised 12 degenerate and 8 normal cadaveric NP samples. The concentration value of sFas in the supernatant was significantly higher from degenerate NP than that from normal NP at each time point. In contrast, sFasL was significantly lower at each time point. Moreover, the expression of sFas and sFasL reached the peak at various early stages of cell cultures and decreased thereafter. Furthermore, the mRNA level of Fas in degenerate NP cells was significantly higher than that in normal cells; whereas FasL showed an opposite pattern. The study is the first addressing the expression of sFas and sFasL in human NP cell cultures. Moreover, the expression of sFas and sFasL varies with culture time in vitro with different levels in degenerate and normal settings. These findings indicate that sFas and sFasL might play a role in intervertebral disc degeneration. PMID- 23923076 TI - Butyrate alleviates metabolic impairments and protects pancreatic beta cell function in pregnant mice with obesity. AB - The relative or absolute deficiency of pancreatic beta-cell mass function underlies the pathogenesis of diabetes. It is necessary to alleviate the metabolic stress and reduce the demand for insulin to decrease the effects of mutations affecting beta-cell expansion. Butyrate is a natural nutrient existed in food and can also be produced physiologically through the intestinal fermentation of fiber. Pregnancy and obesity model would be helpful for understanding how beta-cell adapt to insulin resistance and how butyrate alleviate the metabolic impairment and protect pancreatic beta cell function in pregnant mice with obesity. C57BL/6J female mice were divided into three groups and fed with high fat food (HF group, 40% energy from fat), high fat with sodium butyrate food (HSF group, 95% HF with 5% butyrate), or control food (CF group, 14% energy from fat), respectively. The feeding would last for 14 weeks before mating and throughout the gestation period. A subset of dams were sacrificed at gestational day (GD) 14.5 to evaluate the changes of metabolism and beta-cell function, mass, proliferation and apoptosis, inflammatory reaction of islet from different diet. Pancreases were double immuno-labeled to assess the islet morphology, insulin expression, expression of proliferation gene PCNA and anti apoptosis gene bcl-2. Moreover, we detected the expression of NF-kappaB, phosphorylated NF-kappaB (pNF-kappaB) to evaluate the islet inflammatory response with immunohistochemistry. Mice fed with HSF showed obviously changes including the decreased values of weight gain, glucose, insulin, triglyceride and total cholesterol level of blood compared with high fat diet group, and the reduced circulating maternal pro-inflammation factors at GD14.5. Mice fed with HF displayed beta-cell hyperplasia with a greater beta-cell size and beta-cell area in pancreas. Furthermore, the higher ratio of apoptosis and inflammatory response were found in HF group compared with HSF and CF group, while the proliferation rates of beta-cell increased in HF group, but not in HSF or CF. Butyrate shows an obvious function of anti-obesity, and can alleviate the metabolic stress, maintain the beta-cell function and protect them from inflammatory response in pregnant obese mouse without obvious fetus toxicity. PMID- 23923077 TI - Effect of chronic psychosocial stress on nonalcoholic steatohepatitis in mice. AB - Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which may progress towards inflammation (nonalcoholic steatohepatitis (NASH)). NAFLD is regarded as a consequence of a sedentary, food abundant lifestyle which, in the modern world, often coincides with chronically high levels of perceived psychosocial stress. Here, we aimed to characterize the effect of chronic psychosocial stress on the development of NAFLD/NASH in male mice either fed with standard chow or NASH-inducing high fat diet. Chronic psychosocial stress was induced by chronic subordinate colony housing (CSC), a pre-clinically validated paradigm relevant for human affective and somatic disorders. Single housed (SHC) mice served as controls. Under standard chow conditions CSC mice revealed lower hepatic triglyceride levels but higher hepatic TNFalpha, MCP-1 and HMOX mRNA expression, while serum transaminase levels did not significantly differ from SHC mice. Under the NASH-inducing high-fat diet CSC and SHC mice showed similar body weight-gain and serum levels of glucose and adiponectin. Moreover, liver histology as well as TNFalpha, MCP-1 and HMOX expression were similar in CSC and SHC mice fed with HFD. Surprisingly, CSC showed even significantly lower transaminase levels than SHC mice fed with the same NASH-inducing diet. Together, these data indicate that under normal dietary conditions the CSC model induces noticeable hepatic oxidative stress and inflammation without causing manifest hepatocellular injury. In contrast, CSC exhibited a protective effect on hepatocellular injury in a dietary NASH-model. Identification of the underlying mechanisms of this phenomenon may lead to novel therapeutic strategies to prevent progression of NAFLD. PMID- 23923079 TI - Sperm protein 17, MAGE-C1 and NY-ESO-1 in hepatocellular carcinoma: expression frequency and their correlation with clinical parameters. AB - This study is dedicated to investigate the expression patterns of sperm protein 17 (Sp17), melanoma-specific antigen (MAGE)-C1 and New York esophageal squamous cell carcinoma-1 (NY-ESO-1), to explore the correlation between these cancer testis antigens and clinical parameters, and to evaluate their values in diagnosis and differentiation of hepatocellular carcinoma. METHODS: Immunohistochemical staining was performed in 45 paraffin-embedded hepatocellular carcinoma specimens. 45 normal peripheral hepatic tissues collected from adjacent non-cancerous areas were used as controls. RESULTS: Positive results of immunohistostaining were obtained in 16 (35.6%), 7 (15.6%) and 36 (80.0%) samples using MAGE-C1, NY-ESO-1 and Sp17 antibodies, respectively. The immunoreactivity of Sp17 was also found in 7 (14.0%) control samples. A statistical correlation between the frequency of Sp17 expression and tumor differentiation grade in hepatocellular carcinoma was confirmed. CONCLUSIONS: Sp17 is highly expressed in hepatocellular carcinoma cells. The frequency of Sp17 expression is closely related to the pathologic differentiation in hepatocellular carcinoma. PMID- 23923078 TI - The cervical malignant cells display a down regulation of ER-alpha but retain the ER-beta expression. AB - The human cervix is a tissue target of sex steroid hormones as estradiol (E2) which exerts its action through of the estrogen receptors alpha and beta (ER alpha and ER-beta). In this study we investigated the expression of ER-alpha and ER-beta in human invasive cervical carcinomas using immunohistochemistry and RT PCR analyses and compared with that observed in the corresponding normal tissue. The results show nuclear expression of ER-alpha mainly in the first third of normal cervical epithelium, however, decreased or absent expression were present in invasive cervical carcinoma, indicating that expression of ER-alpha is lost in cervical cancer. Nevertheless, by RT-PCR we were able to demonstrate mRNA expression of ER-alpha in invasive cervical tissues. These results suggest that loss of ER-alpha could be due to a mechanism of post-transcriptional and/or post translational regulation of its gene during the progression to invasive carcinoma. On the other hand, ER-beta was expressed in normal cervix with an expression pattern similar to ER-alpha. In addition to its nuclear localization, cytoplasmic immunoreaction of ER-beta was present in the epithelium of invasive cervical carcinomas, suggesting an association between cytoplasmic ER-beta expression and invasive phenotype in the cervical tumors. In summary, the results show that the cervical malignant cells tend to loss the ER-alpha but maintain the ER-beta actively expressed. Loss of expression of ER-alpha in neoplastic tissue suggests that the estrogenic effects could be conducted through the ER-beta in human neoplastic cervical tissue. More detailed studies are needed to confirm this suggestion and to determine the role of ER-beta in cervical cancer. PMID- 23923080 TI - Association of the brain-derived neurotrophic factor gene G196A rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia. AB - This study aimed to explore the association between BDNF G196A gene rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia. METHODS: BDNF G196A rs6265 genotype and allele frequency were measured using Polymerase Chain Reaction (PCR) methods in 224 drug-free patients with schizophrenia and 220 controls. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and cognitive functioning was assessed using the Wisconsin Card Sorting Test (WCST) and the Trail Making Test (TMT). In the patient group, differences in severity of symptoms across the three genotypes (i.e., G/G, G/A and A/A) of G196A were assessed using one-way analysis of variance. RESULTS: G/A genotype had higher frequencies than GG or AA genotype in both patients and controls. There was no significant difference in G/G, G/A, A/A genotype frequency between patients and controls (P > 0.05). The allele G had higher frequencies than allele A in both patients and controls. There was no significant difference in G or A allele frequency between patients and controls (P > 0.05). There was significant difference in A/A genotype frequency between positive group patients and negative group patients. There was no significant difference in cognitive performance between patients with G/G, G/A and A/A genotype (all P > 0.05). CONCLUSION: BDNF G196A gene rs6265 polymorphism is not associated with the cognitive function but with the clinical symptoms of schizophrenia. PMID- 23923081 TI - Adult Hirschsprung's disease: report of four cases. AB - Adult Hirschsprung's disease (HD) is a rare motor disorder of the gut that is frequently misdiagnosed as refractory constipation. The primary pathogenic defect in adult HD is identical to that seen in infancy or childhood, and is characterized by the total absence of intramural ganglion cells of the submucosal (Meissner) and myenteric (Auerbach) neural plexuses in the affected segment of the bowel. Ninety-four percent of HD cases are diagnosed before the patient reaches 5 years of age, however, on rare occasion, mild cases of HD may go undiagnosed until he or she reaches adulthood. In this study, we describe four cases of adult HD with a history of longstanding recurrent constipation, relieved by laxatives, and presenting to the Department of Gastrointestinal Surgery with progressive abdominal distention, colicky pain or acute intestinal obstruction. Barium enema or computed tomography revealed a grossly distended proximal large colon with fecal retention. Intraoperative frozen section biopsy was performed in all cases and showed aganglionosis of the stenotic segment and a normal distal rectum. In all cases, patient symptoms were completely resolved and there were no complications arising immediately post-surgery or at one-year follow-up. Adult HD should be considered in the differential diagnosis of cases where adult patients present with chronic constipation or even acute intestinal obstruction. The modified one-stage Martin-Duhamel or Rehbein's procedure is a feasible surgical option for treating cases of adult HD involving a segment or the entire bowel. PMID- 23923082 TI - Breast implant-associated ALK-negative anaplastic large cell lymphoma: a case report and discussion of possible pathogenesis. AB - Breast implant associated anaplastic large cell lymphoma (BIA-ALCL) is a recently recognized clinical entity, with only 39 well-documented cases reported worldwide, including 3 fatalities. Because of its rarity, the clinical and pathologic features of this malignancy have yet to be fully defined. Moreover, the pathogenesis of ALCL in association with textured silicone gel breast implants is poorly understood. Here we report a case of BIA-ALCL arising in a 67 year-old woman with a mastectomy due to breast cancer followed by implantation of textured silicone gel breast prosthesis. The patient presented with breast enlargement and tenderness 8 years following reconstructive surgery. MRI revealed a fluid collection surrounding the affected breast implant. Pathologic examination confirmed the presence of malignant ALCL T cells that were CD30+, CD8+, CD15+, HLA-DR+, CD25+ ALK- and p53. A diagnosis of indolent BIA-ALCL was made since tumor cells were not found outside of the capsule. Interestingly, an extensive mixed lymphocytic infiltrate and ectopic lymphoid tissue (lymphoid neogenesis) adjacent to the fibrous implant capsule were present. The patient was treated with capsulectomy and implantation of new breast prostheses. Six months later, the patient was found to have BIA-ALCL involvement of an axillary lymph node with cytogenetic evolution of the tumor. To our knowledge, this is the sixth reported case of aggressive BIA-ALCL. Unique features of this case include the association with lymphoid neogenesis and the in vivo cytogenetic progression of the tumor. This case provides insight into the potential role of chronic inflammation and genetic instability in the pathogenesis of BIA-ALCL. PMID- 23923083 TI - Primary anaplastic large cell lymphoma in the dura of the brain: case report and prediction of a favorable prognosis. AB - Anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma composed of CD30 positive lymphoid cells. ALCL arising in the dura matter of the brain is even more infrequent, in which only one case has been reported worldwide so far. We report a case of a 30-year-old immunocompetent male with a dura-based mass, radiographically consistent with meningioma. However, the excised mass via a left parieto-occipital craniotomy was composed of large, pleomorphic lymphoid cells to be immunopositive for CD3, CD30, anaplastic lymphoma kinase protein-1 (ALK-1) and epithelial membrane antigen (EMA), and immunonegative for CD20, CD15 and CD68. Multiple ALK gene fusion signals in the ALK locus were detected by fluorescence in situ hybridization (FISH) analysis. The patient was treated with CHOP chemotherapy and intrathecal methotrexate along with brain radiation therapy, which resulted in a complete remission. In an analysis of 25 previously reported primary CNS ALCLs, ALK-1 positivity was shown to be prevalent in younger age, as ALCL occurs outside the brain. Patient less than 23 years, ALK-1 positivity and unifocal tumor may be associated with a better prognosis. However, sex, dural or leptomeningeal involvement, immune status, and tumor necrosis do not appear to have any influence on survival. PMID- 23923084 TI - Dedifferentiated endometrial cancer: an atypical case diagnosed from cerebellar and adrenal metastasis: case presentation and review of literature. AB - Dedifferentiated endometrial cancer (DEC) is microscopically characterized by the presence of high-grade areas emerging from low-grade tumour. DEC is an aggressive tumour even when the dedifferentiated component represents only 20% of the entire neoplasm. A proper histological diagnosis is essential to define the most appropriate therapeutic approach for these tumors, since they are characterized by a particularly aggressive trend and by an extremely poor prognosis. We report a single case of DEC associated with dedifferentiated and adrenal metastasis, for which the patient underwent both abdominal-pelvic and cerebellar surgery. Dedifferentiated carcinoma of the endometrium is a poorly recognized neoplasm since they have not been clearly defined the histological features discriminating this neoplasm from high-grade endometrioid adenocarcinoma. Revising existing literature we found 79 described cases of central nervous system secondary involvement and 13 cases where the onset of the disease was characterized by neurological signs and symptoms. We could only find two reported cases of adrenal metastases originating from endometrial neoplasia but in no case of dedifferentiated endometrial carcinoma previously described has been reported the concomitant adrenal-cerebellar involvement. PMID- 23923085 TI - Micropthalmia transcription factor (MITF) as a diagnostic marker for metastatic melanomas negative for other melanoma markers. AB - Metastatic malignant melanoma has a wide spectrum of histopathologic patterns and often lacks melanin pigment. Without a known primary tumor, the diagnosis of metastatic malignant melanoma relies on a combination of morphology and immunohistochemical profile. Infrequently, commonly used markers for melanoma (S100, HMB45, Melan-A and Tyrosinase A) are negative. These cases pose critical diagnostic challenges. Recent studies show that Microphthalmia Transcription Factor (MITF) has high sensitivity (88-100%) and specificity for metastatic melanoma. We are reporting here three cases of high grade tumors that were studied by a comprehensive immunohistochemical panel including cytokeratins, S100, HMB-45, Melan A, Tyrosinase, and MITF. All three tumors were also analyzed for the presence of BRAF mutations. All three metastatic tumors were negative for S100, Melan A, HMB-45 and Tyrosinase but positive for MITF. Subsequent to the diagnoses, previously existing or concurrent primary melanomas were identified in 2 of the 3 cases. Interestingly, S100, Melan A, and HMB-45 were positive in the primary tumors. No BRAF (V600E) mutations were identified in the three metastatic melanomas and CD 117 (c-kit) was positive in one of the cases. In summary, our experience shows that MITF can be a valuable adjunct in the diagnosis of metastatic tumors that are suspicious for melanoma but negative for other melanoma markers. PMID- 23923086 TI - Urethral adenocarcinoma associated with intestinal-type metaplasia, case report and literature review. AB - The presence of glandular epithelium in urinary tract biopsies poses a diagnostic challenge. Intestinal metaplasia of the urethra may be seen in many congenital, iatrogenic, and reactive conditions, as well as in association with malignant conditions such as urethral adenocarcinoma. We present a case of a 61 year-old woman presenting with microscopic hematuria. Successive biopsies showed glandular epithelium with focal atypia in close association with inflammation, but no overt malignancy. Only on surgical resection was the associated high grade adenocarcinoma revealed. When intestinal-type mucosa is present within a urinary tract biopsy, associated malignancy may be present only focally. Thorough sampling and consideration of the differential diagnosis is imperative. PMID- 23923087 TI - Sarcomatoid carcinoma with small cell carcinoma component of the urinary bladder: a case report with review of the literature. AB - Sarcomatoid carcinoma of the urinary bladder is an uncommon neoplasm characterized histopathologically by the presence of malignant spindle cell and epithelial components. Albeit extremely rare, sarcomatoid carcinoma with small cell carcinoma has been reported. Herein, we describe an additional case of sarcomatoid carcinoma with small cell carcinoma and squamous cell carcinoma of the urinary bladder and review the clinicopathological features of this type of tumor. An 82-year-old Japanese male presented with hematuria. Computed tomography demonstrated a large tumor in the urinary bladder. Histopathological study of the resected urinary bladder tumor showed that approximately 80% of the tumor was comprised of small cell carcinoma, and the remaining components were spindle cell proliferation (approximately 15%) and squamous cell carcinoma (5%). Both the spindle cell and squamous cell carcinoma components were intermingled with nests of the small cell carcinoma. This is the fifth documented case of sarcomatoid carcinoma with small cell carcinoma of the urinary bladder. Our review of the clinicopathological features of this type of tumor revealed that: i) elderly males are mainly affected, ii) the most common chief complaint is hematuria, iii) the epithelial component may include urothelial carcinoma, adenocarcinoma, and/or squamous cell carcinoma, and iv) the sarcomatous component is composed of spindle cell proliferation. The histogenesis of this type of tumor remains a matter of controversy. However, recent molecular analyses demonstrated a monoclonal origin of both components. This theory can account for the various types of carcinomatous components in this tumor as seen in the present case. PMID- 23923088 TI - Prominent gelatinous bone marrow transformation presenting prior to myelodysplastic syndrome: a case report with review of the literature. AB - Gelatinous bone marrow transformation (GMT) is a rare disorder characterized by the presence of fat cell atrophy, loss of hematopoietic cells, and deposition of extracellular gelatinous materials. GMT is not a specific disease, but is strongly associated with malnutrition and drugs. Albeit extremely rare, GMT has been reported in patients with myeloproliferative disorders. Herein, we report the second documented case of hypoplastic myelodysplastic syndrome (MDS) accompanying GMT. A 73-year-old Japanese male with excellent nutrition status and no history of alcohol or drug intake was detected with pancytopenia. The initial bone marrow aspirate specimen reveled hypocellular marrow without dysplastic signs in the myeloid cells. Bone marrow biopsy demonstrated hypocellular bone marrow with prominent GMT. He received blood transfusions, however, pancytopenia continued to progress. The second bone marrow aspirate specimen showed dysplastic changes, such as pseudo-Pelger-Huet cells, hypogranular or agranular granulocytes, and megakaryocytes with multiple small nuclei. Cytogenetic study demonstrated deletion of chromosome 7. Therefore, an ultimate diagnosis of hypoplastic MDS accompanying GMT was made. Only a limited number of cases of myeloproliferative disorders with GMT have been reported. Our analysis of these cases revealed that chromosome 7 abnormality is frequently observed in this condition. Moreover, findings from the current case suggested that myeloproliferative disorders including MDS must be included in the differential diagnostic considerations of GMT patients, who have no history of malnutrition or drugs, and careful examination of the bone marrow smear specimen and cytogenetic analysis are necessary for early detection of underlying myeloproliferative disorders. PMID- 23923089 TI - Flame figures associated with eosinophilic dermatosis of hematologic malignancy: is it possible to distinguish the condition from eosinophilic cellulitis in patients with hematoproliferative disease? AB - Eosinophilic dermatosis of hematologic malignancy is a multifaceted dermatosis with a wide morphological spectrum, presenting as pruritic, erythematous, papular and occasionally vesicular, urticarial, nodular eruptions. Histopathologically eosinophil infiltration in the super and deep dermis was found. We reported a case of eosinophilic dermatosis of hematologic malignancy presented as urticarial and vesicular lesions in a patient with chronic lymphocytic leukemia. A skin biopsy revealed a prominent subepidermal blister and a diffuse infiltrate of eosinophils with flame figures in the dermis and subcutaneous tissue. Although flame figures associated with eosinophilic dermatosis of hematologic malignancy is rarely reported, we believe that it would not seem unusual to find them in this skin disease. Eosinophilic cellulitis, which share clinical and histological features with eosinophilic dermatosis of hematologic malignancy, has also been described as showing an association with hematoproliferative diseases. In order to clearly describe eosinophilic dermatosis in patients with hematologic malignancies, the terminology eosinophilic dermatosis of hematologic malignancy, instead of eosinophilic cellulitis, would be a more suitable term in patients with eosinophilic dermatosis. PMID- 23923090 TI - Ovarian mucinous cystic tumor with sarcoma-like mural nodules and multifocal anaplastic carcinoma: a case report. AB - A 48-year-old woman presented with left abdominal pain and fullness. Computed tomography scan revealed a multicystic mass with multifocal mural nodules. Histologic examination showed a mucinous cystic tumor with cystadenoma, borderline malignant cystadenoma and cystadenocarcinoma, which were associated with sarcoma-like mural nodules (SLMNs) and multifocal anaplastic carcinoma. Mural nodules showed a positive reaction for CD56 and vimentin, but were negative for cytokeratin 7 and SMA. She underwent postoperative chemotherapy and is currently under follow-up; no recurrence or metastases were found in the first year of follow-up. Ovarian mucinous cystic tumor with SLMNs and foci of anaplastic carcinoma is extremely rare. To our knowledge, this case reports the most complex neoplastic and reactive components. Our findings shed some light on the pathogenesis of this rather rare carcinoma. We think that the formation of SLMNs may be the result of the reactive proliferation of undifferentiated mesenchymal cells, while the anaplastic carcinoma may be derived from mucinous epithelium. Moreover, because of difficulties encountered in their differential diagnosis, we think that the existence of foci of anaplastic carcinoma along with SLMNs necessitates careful histologic and immunohistochemical analysis of mural nodules for the determination of treatment and prognosis. PMID- 23923091 TI - Streptococcus agalactiae vaginitis: nonhemolytic variant on the Liofilchem(r) Chromatic StreptoB. AB - Streptococcus agalactiae (group B Streptococcus, GBS) vaginal pathogenicity is not uniformly acknowledged throughout the literature; accordingly, in women, genital itching and burning, along with leukorrhea are commonly and almost exclusively referred to bacterial vaginosis, candidiasis and trichomoniasis. Conversely, GBS virulence for vagina was recognized in the past, as the organism has been observed to potentially cause local inflammation and discharge, as well as lactobacilli rarefaction. We depict here a case where a nonhemolytic (gamma hemolytic) GBS strain was found to be the etiologic agent of vaginal infection. Such uncommon S. agalactiae phenotypes are hard to be recognized and may be therefore responsible for misdiagnosing and underestimation of GBS vaginitis prevalence; here, we had the support of the Liofilchem((r)) Chromatic StreptoB medium, that successfully detected such an atypical variant. PMID- 23923092 TI - Clinical analysis of 16 patients with acute pancreatitis in the third trimester of pregnancy. AB - AIM: Acute pancreatitis (AP), in particular, severe acute pancreatitis (SAP), is a rare but challenging complication during pregnancy in terms of diagnosis and management. The objective of this paper is to investigate the causes and therapeutic strategies of AP in patients during the third trimester of pregnancy. METHODS: We performed a retrospective analysis of the clinical features, laboratory data, and outcomes in 16 patients with acute pancreatitis during the third trimester of pregnancy. RESULTS: Information was collected on admission, management, and outcome. A total 16 patients were diagnosed with acute pancreatitis during pregnancy. In 7 of 9 patients with mild AP, pregnancy was terminated by cesarean section and all 9 cases were cured. In 4 out of 7 patients with SAP, pregnancy was terminated by cesarean section in conjunction with peritoneal irrigation and drainage, and the mothers and infants survived. In the remaining 3 patients with SAP, there was one case of intrauterine death in which Induced labor was performed and 2 patients died of multiple organ failure. CONCLUSION: A high-fat diet and cholelithiasis are the triggers of AP in pregnancy. Conservative treatment is the preferred therapeutic method; in particular, for mild AP. Endoscopic surgery and peritoneal drainage are effective for acute biliary pancreatitis. Patients with hyperlipidemic pancreatitis should undergo lipid-lowering therapy, and hemofiltration should be done as soon as it becomes necessary. For patients with SAP, termination of pregnancy should be carried out as early as possible. PMID- 23923094 TI - Determining Community Health Status Priorities in an Online Analytic Processing (OLAP) Environment. AB - INTRODUCTION: The determination of priorities is an essential component of community health status assessment. Yet, there is an acknowledged need for a systematic method which will utilize data in standardized comparisons to yield priorities based on objective analyses. METHOD: We have deployed a web-based system with: a flexible online analytic processing (OLAP) interface; multiple sources of event-level data conformed to common definitions in a data warehouse structure; and, centralized technical infrastructure with distributed analytical capabilities. The PRIORITIZATION TOOL integrated into the system takes full advantage of the granularity of multidimensional sources of data to: apply a series of defined objective criteria; vary the weight of those criteria and detect the reordering of the rankings in real-time; and, apply the prioritization algorithm to different categories of health status outcomes. RESULTS: In our example, mortality outcomes for Miami-Dade County, Florida, were considered with three different weighting combinations of the four primary ranking criteria. The resultant analyses return markedly different mortality priority rankings based upon the selection and weighting of the criteria. CONCLUSION: Rankings of community health outcomes based on a static set of criteria with fixed weighting factors may not provide sufficient information necessary for priority setting and may, in fact, be misleading. PMID- 23923093 TI - A focus area maturity model for a statewide master person index. AB - OBJECTIVE: The sharing of personally identifiable information across organizational boundaries to facilitate patient identification in Utah presents significant policy challenges. Our objective was to create a focus area maturity model to describe and evaluate our progress in developing a policy framework to support a statewide master person index (sMPI) for healthcare and public health operations and research in Utah. MATERIALS AND METHODS: We used various artifacts, including minutes from policy guidance committee meetings over a span of 18 months, a report from Utah's Digital Health Services Commission, and a draft technical requirements document to retrospectively analyze our work and create a focus area maturity model describing the domain of policy needed to support the sMPI. We then used our model to assess our progress and future goals. CONCLUSIONS: The focus area maturity model provides an orderly path that can guide the complex process of developing a functional statewide master person index among diverse, autonomous partners. While this paper focuses on our experience in Utah, we believe that the arguments for using a focus area maturity model to guide the development of state or regional MPIs is of general interest. PMID- 23923095 TI - Steps to a sustainable public health surveillance enterprise?a commentary from the international society for disease surveillance. AB - More than a decade into the 21(st) century, the ability to effectively monitor community health status, as well as forecast, detect, and respond to disease outbreaks and other events of public health significance, remains a major challenge. As an issue that affects population health, economic stability, and global security, the public health surveillance enterprise warrants the attention of decision makers at all levels. Public health practitioners responsible for surveillance functions are best positioned to identify the key elements needed for creating and maintaining effective and sustainable surveillance systems. This paper presents the recommendations of the Sustainable Surveillance Workgroup convened by the International Society for Disease Surveillance (ISDS) to identify strategies for building, strengthening, and maintaining surveillance systems that are equipped to provide data continuity and to handle both established and new data sources and public health surveillance practices. PMID- 23923096 TI - Immunization registries in the EMR Era. AB - BACKGROUND: The CDC established a national objective to create population-based tracking of immunizations through regional and statewide registries nearly 2 decades ago, and these registries have increased coverage rates and reduced duplicate immunizations. With increased adoption of commercial electronic medical records (EMR), some institutions have used unidirectional links to send immunization data to designated registries. However, access to these registries within a vendor EMR has not been previously reported. PURPOSE: To develop a visually integrated interface between an EMR and a statewide immunization registry at a previously non-reporting hospital, and to assess subsequent changes in provider use and satisfaction. METHODS: A group of healthcare providers were surveyed before and after implementation of the new interface. The surveys addressed access of the California Immunization Registry (CAIR), and satisfaction with the availability of immunization information. Information Technology (IT) teams developed a "smart-link" within the electronic patient chart that provides a single-click interface for visual integration of data within the CAIR database. RESULTS: Use of the tool has increased in the months since its initiation, and over 20,000 new immunizations have been exported successfully to CAIR since the hospital began sharing data with the registry. Survey data suggest that providers find this tool improves workflow and overall satisfaction with availability of immunization data. (p=0.009). CONCLUSIONS: Visual integration of external registries into a vendor EMR system is feasible and improves provider satisfaction and registry reporting. PMID- 23923097 TI - Development of a Web GIS Application for Visualizing and Analyzing Community Out of Hospital Cardiac Arrest Patterns. AB - Improving survival rates at the neighborhood level is increasingly seen as a priority for reducing overall rates of out-of-hospital cardiac arrest (OHCA) in the United States. Since wide disparities exist in OHCA rates at the neighborhood level, it is important for public health officials and residents to be able to quickly locate neighborhoods where people are at elevated risk for cardiac arrest and to target these areas for educational outreach and other mitigation strategies. This paper describes an OHCA web mapping application that was developed to provide users with interactive maps and data for them to quickly visualize and analyze the geographic pattern of cardiac arrest rates, bystander CPR rates, and survival rates at the neighborhood level in different U.S. cities. The data comes from the CARES Registry and is provided over a period spanning several years so users can visualize trends in neighborhood out-of-hospital cardiac arrest patterns. Users can also visualize areas that are statistical hot and cold spots for cardiac arrest and compare OHCA and bystander CPR rates in the hot and cold spots. Although not designed as a public participation GIS (PPGIS), this application seeks to provide a forum around which data and maps about local patterns of OHCA can be shared, analyzed and discussed with a view of empowering local communities to take action to address the high rates of OHCA in their vicinity. PMID- 23923098 TI - Social and Institutional issues in the Adoption of School-based Technology-aided Sexual Health Education Program. AB - OBJECTIVE: School-based sexual health education interventions can reach young people of diverse backgrounds and equip them with knowledge and skills for protecting themselves against HIV/AIDS, unwanted pregnancies, and live healthy and responsible lives. However, given that school-based sexual health education intervention are health projects implemented in educational settings, variety of social and institutional issues can present challenges. This study aimed to obtain rich insights into the facilitating or inhibiting mediators for the implementation of a school-based sexual health education intervention in Uganda. METHOD: This study conducted 16 qualitative interviews to investigate the mediators for the implementation of the school-based sexual health education intervention based on experiences of two Ugandan schools: the school which successfully completed the implementation of the intervention, and the school which abandoned the intervention half-way the implementation. RESULTS: Rather than the technological aspects, results indicate that the implementation was strongly influenced by interplay of social and institutional mediators, which were more favourable in the "successful" school than in the "failure school". These mediators were: perceived students' vulnerability to HIV and unwanted pregnancies; teachers' skills and willingness to deliver the intervention, management support; match with routine workflow, social-cultural and religious compatibility, and stakeholder involvement. CONCLUSION: Rather than focusing exclusively on technological aspects, experiences from this evaluation suggest the urgent need to also create social, institutional, and religious climate which are supportive of school-based computer-assisted sexual health education. Evidence-based recommendations are provided, which can guide potential replications, improvements, and policy formulation in subsequent school-based sexual health education interventions. PMID- 23923099 TI - Google Scholar is not enough to be used alone for systematic reviews. AB - BACKGROUND: Google Scholar (GS) has been noted for its ability to search broadly for important references in the literature. Gehanno et al. recently examined GS in their study: 'Is Google scholar enough to be used alone for systematic reviews?' In this paper, we revisit this important question, and some of Gehanno et al.'s other findings in evaluating the academic search engine. METHODS: The authors searched for a recent systematic review (SR) of comparable size to run search tests similar to those in Gehanno et al. We selected Chou et al. (2013) contacting the authors for a list of publications they found in their SR on social media in health. We queried GS for each of those 506 titles (in quotes ""), one by one. When GS failed to retrieve a paper, or produced too many results, we used the allintitle: command to find papers with the same title. RESULTS: Google Scholar produced records for ~95% of the papers cited by Chou et al. (n=476/506). A few of the 30 papers that were not in GS were later retrieved via PubMed and even regular Google Search. But due to its different structure, we could not run searches in GS that were originally performed by Chou et al. in PubMed, Web of Science, Scopus and PsycINFO(r). Identifying 506 papers in GS was an inefficient process, especially for papers using similar search terms. CONCLUSIONS: Has Google Scholar improved enough to be used alone in searching for systematic reviews? No. GS' constantly-changing content, algorithms and database structure make it a poor choice for systematic reviews. Looking for papers when you know their titles is a far different issue from discovering them initially. Further research is needed to determine when and how (and for what purposes) GS can be used alone. Google should provide details about GS' database coverage and improve its interface (e.g., with semantic search filters, stored searching, etc.). Perhaps then it will be an appropriate choice for systematic reviews. PMID- 23923100 TI - PTT Advisor: A CDC-supported initiative to develop a mobile clinical laboratory decision support application for the iOS platform. AB - OBJECTIVES: This manuscript describes the development of PTT (Partial Thromboplastin Time) Advisor, one of the first of a handful of iOS-based mobile applications to be released by the US Centers for Disease Control and Prevention (CDC). PTT Advisor has been a collaboration between two groups at CDC (Informatics R&D and Laboratory Science), and one partner team (Clinical Laboratory Integration into Healthcare Collaborative - CLIHC). The application offers clinicians a resource to quickly select the appropriate follow-up tests to evaluate patients with a prolonged PTT and a normal Prothrombin Time (PT) laboratory result. METHODS: The application was designed leveraging an agile methodology, and best practices in user experience (UX) design and mobile application development. RESULTS: As it is an open-source project, the code to PTT Advisor was made available to the public under the Apache Software License. On July 6, 2012, the free app was approved by Apple, and was published to their App Store. CONCLUSIONS: Regardless of the complexity of the mobile application, the level of effort required in the development process should not be underestimated. There are several issues that make designing the UI for a mobile phone challenging (not just small screen size): the touchscreen, users' mobile mindset (tasks need to be quick and focused), and the fact that mobile UI conventions/expectations are still being defined and refined (due to the maturity level of the field of mobile application development). PMID- 23923101 TI - Effective sharing of health records, maintaining privacy: a practical schema. AB - A principal goal of computerisation of medical records is to join up care services for patients, so that their records can follow them wherever they go and thereby reduce delays, duplications, risks and errors, and costs. Healthcare records are increasingly being stored electronically, which has created the necessary conditions for them to be readily sharable. However simply driving the implementation of electronic medical records is not sufficient, as recent developments have demonstrated (1): there remain significant obstacles. The three main obstacles relate to (a) record accessibility (knowing where event records are and being able to access them), (b) maintaining privacy (ensuring that only those authorised by the patient can access and extract meaning from the records) and (c) assuring the functionality of the shared information (ensuring that the records can be shared non-proprietorially across platforms without loss of meaning, and that their authenticity and trustworthiness are demonstrable). These constitute a set of issues that need new thinking, since existing systems are struggling to deliver them. The solution to this puzzle lies in three main parts. Clearly there is only one environment suited to such widespread sharing, which is the World Wide Web, so this is the communications basis. Part one requires that a sharable synoptic record is created for each care event and stored in standard web-format and in readily accessible locations, on 'the web' or in 'the cloud'. To maintain privacy these publicly-accessible records must be suitably protected either stripped of identifiers (names, addresses, dates, places etc.) and/or encrypted: either way the record must be tagged with a tag that means nothing to anyone, but serves to identify and authenticate a specific record when retrieved. For ease of retrieval patients must hold an index of care events, records and web locations (plus any associated information for each such as encryption keys, context etc.). For added security, as well as for trustworthiness, a method of verifying authenticity, integrity and authorship is required, which can be provided using a public key infrastructure (PKI) for cryptography (2). The second part of the solution is to give control over record access and sharing to the patient (or their identified representative), enabling them to authorise access by providing the index and access keys to their records. This can be done using a token (fe.g. smart card) or a secure online index which holds these details: this serves to relieve the formal record keeper of responsibility for external access control and privacy (internal access control and privacy can remain an institutional responsibility). The third part of the solution is to process the content of the stored records such that there is a 'plain English' copy, as well as an electronic copy which is coded and marked up using XML tags for each data element to signify 'type' (e.g. administrative, financial, operational, clinical etc.) and sub-types (e.g. diagnosis, medication, procedure, investigation result etc.). This ensures that the recipient can always read the data using a basic browser, but can readily manipulate and re-arrange the data for display and storage if they have a more sophisticated installation. PMID- 23923102 TI - Visualizing Central Line -Associated Blood Stream Infection (CLABSI) Outcome Data for Decision Making by Health Care Consumers and Practitioners-An Evaluation Study. AB - The purpose of this study was to evaluate information visualization of publicly reported central line-associated blood stream infection (CLABSI) outcome data for decision making by diverse target audiences - health care consumers and practitioners. We describe the challenges in publicly reporting of healthcare associated infections (HAIs) data and the interpretation of an evaluation metric. Several options for visualization of CLABSI data were designed and evaluated employing exploratory working group, two confirmatory focus groups' observations, and experts' committee validation of the final designs. Survey-data collection and evaluation criteria results, collected from the two focus groups, are presented and are used to develop the final recommendations for how to visualize publicly-reported CLABSI data from Maryland acute care hospitals. Both health care consumer and practitioner's perspectives are highlighted and categorized based on the visualizations' dimensions framework. Finally, a recommended format for visualizing CLABSI outcome data based on the evaluation study is summarized. PMID- 23923103 TI - Can internet access growth help reduce the global burden of noncommunicable diseases? AB - Noncommunicable diseases, such as cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes, are currently the leading causes of death in several regions of the world. The continuing fast increase in the global burden of noncommunicable diseases is accompanied by a speedy worldwide internet access growth. The worldwide number of internet users has doubled over the past five years. As the internet can make the access to information on a healthy lifestyle and disease prevention activities easier, internet access growth may help to promote good health. Against this background, I discuss the roles the internet and access to information can play in health promotion. I also present an open access web portal on local prevention and health promotion activities. It was initiated by two German states to link health information from disparate sources and to organize this information in a user-friendly way. The web portal focuses on reducing preventable lifestyle-related risk factors associated with noncommunicable diseases, including physical inactivity, unhealthy diet, tobacco use, and the harmful use of alcohol. This local initiative has the potential for scaling up and can serve as a blueprint for other areas that have or will acquire internet access. PMID- 23923104 TI - A Decision Support Tool for Using an ICD-10 Anatomographer to Address Admission Coding Inaccuracies: A Commentary. PMID- 23923105 TI - Crystal structure of a putative aspartic proteinase domain of the Mycobacterium tuberculosis cell surface antigen PE_PGRS16. AB - We report the crystal structure of the first prokaryotic aspartic proteinase-like domain identified in the genome of Mycobacterium tuberculosis. A search in the genomes of Mycobacterium species showed that the C-terminal domains of some of the PE family proteins contain two classic DT/SG motifs of aspartic proteinases with a low overall sequence similarity to HIV proteinase. The three-dimensional structure of one of them, Rv0977 (PE_PGRS16) of M. tuberculosis revealed the characteristic pepsin-fold and catalytic site architecture. However, the active site was completely blocked by the N-terminal His-tag. Surprisingly, the enzyme was found to be inactive even after the removal of the N-terminal His-tag. A comparison of the structure with pepsins showed significant differences in the critical substrate binding residues and in the flap tyrosine conformation that could contribute to the lack of proteolytic activity of Rv0977. PMID- 23923106 TI - Fecal transplantation for the treatment of recurrent clostridium difficile infection. AB - Clostridium difficile infection (CDI) is currently a leading cause of antibiotic and health care-related diarrhea. The incidence and the severity of CDI-related diarrhea have increased dramatically in the USA and Europe in the past few decades. The emergence of multidrug-resistant hypervirulent strains of C. difficile has led to an increase in mortality. Fecal microbiota transplantation (FMT) (also known as fecal bacteriotherapy) has been utilized sporadically since the 1950s; and currently, the interest in using FMT has grown again in the past few years for the treatment of CDI and other chronic gastrointestinal diseases. FMT has shown to be effective, cheap, and has very few side effects. It is believed to manipulate and restore the gut microbiota, and therefore enhances the growth of "healthy" bacteria that break the cycle of recurrent CDI. This article focus on the recent case reports on FMT, and general approach to patients undergoing this therapy. Data were obtained through a literature search via PubMed and Google. PMID- 23923107 TI - Antibiotic resistance in sepsis patients: evaluation and recommendation of antibiotic use. AB - BACKGROUND: The appropriate selection of empirical antibiotics based on the pattern of local antibiotic resistance can reduce the mortality rate and increase the rational use of antibiotics. AIMS: We analyze the pattern of antibiotic use and the sensitivity patterns of antibiotics to support the rational use of antibiotics in patients with sepsis. MATERIALS AND METHODS: A retrospective observational study was conducted in adult sepsis patient at one of Indonesian hospital during January-December 2011. Data were collected from the hospital medical record department. Descriptive analysis was used in the processing and interpretation of data. RESULTS: A total of 76 patients were included as research subjects. Lung infection was the highest source of infection. In the 66.3% of clinical specimens that were culture positive for microbes, Klebsiella pneumoniae, Escherichia coli, Staphylococcus hominis were detected with the highest frequency. The six most frequently used antibiotics, levofloxacin, ceftazidime, ciprofloxacin, cefotaxime, ceftriaxone, and erythromycin, showed an average resistance above 50%. CONCLUSIONS: The high use of antibiotic with a high level resistance requires a policy to support its rational use. Local microbial pattern based on site infection and pattern of antibiotics sensitivity test can be used as supporting data to optimize appropriateness of empirical antibiotics therapy in sepsis patients. PMID- 23923108 TI - Cyst of the canal of nuck in pediatric patients. AB - BACKGROUND: Cyst of the canal of Nuck is a rare cause of inguinal swelling in female infants and children. AIM: The purpose of this study is to discuss the clinical, radiological, and histopathological findings, differential diagnosis, and surgical treatment of this disease in the light of our experience. MATERIALS AND METHODS: This study was conducted in six children who were operated on with cyst of the canal of Nuck at the pediatric surgery clinic in July 1998-March 2013. All information was collected from patient's files and computer records retrospectively. RESULTS: Patients were between the ages of 1 and 12 years. Size of the cysts has varied between 23 mm and 55.2 mm. In all cases, cyst was on the right side. In physical examination while five cases had palpable, well circumscribed, mobile and painless mass, in one case the mass was immobile. In one patient, the mass was reducible; in the other 5 patients the mass was non reducible. First patient was operated immediately with the early diagnosis of incarcerated inguinal hernia, the second one was operated under elective conditions with early diagnosis of inguinal hernia and it was diagnosed during operation, and in the last 4 patients pre-operative true diagnosis was possible. CONCLUSIONS: As clinical findings of the cyst of the canal of Nuck are variable, pre-operative true diagnosis can only be related to increasing experience. PMID- 23923109 TI - Pars inter-articularis and laminar morphology of the terminal lumbar vertebra in lumbosacral transitional variations. AB - BACKGROUND: Lumbo-sacral transitional variations are common in the general population. Structural inadequacies of the terminal lumbar vertebral pars interarticularis (PI) and lamina have often been implicated as important factors for lumbo-sacral instability. AIMS: Quantifying dimensions of PI and laminae in terminal lumbar vertebrae associated with lumbosacral transitions and compare them with their normal counterparts. MATERIALS AND METHODS: Fourth lumbar vertebrae in spines involved with complete sacralization of the fifth lumbar (L5) vertebrae and L5 vertebrae associated with lumbosacral accessory articulation were measured for the height, width and thickness of the PI and the laminae on both sides and compared to normal vertebrae. RESULTS: Dimensions in sacralization associated terminal vertebrae were smaller than the normal. The height of the PI and the widths of laminae were observed to be significantly smaller in terminal lumbar segment in sacralized specimen. Lumbo-sacral accessory articulations demonstrated smaller overall dimensions of several parameters. Lamiane in the last lumbar segment associated with lumbo-sacral transitions demonstrate smaller dimensions compared to the normal ones. Sacralization results in maximum diminution of these parameters. CONCLUSIONS: Smaller PI may predispose spondylolysis and spondylolisthesis at lumbo-sacral junctions associated with transitional variations, and warrant special attention to avoid iatrogenic injuries. PMID- 23923110 TI - Association of Obstructive Sleep Apnea Severity with Exercise Capacity and Health related Quality of Life. AB - BACKGROUND: Current research is inconclusive as to whether obstructive sleep apnea severity directly limits exercise capacity and lowers health-related quality of life (HRQoL). AIMS: The aim of this study was to evaluate the association of obstructive sleep apnea severity with determinants of exercise capacity and HRQoL. SUBJECTS AND METHODS: Subjects were evaluated by home somnography and classified as no obstructive sleep apnea (n = 43) or as having mild (n = 27), moderate or severe obstructive sleep apnea (n = 21). Exercise capacity was assessed by a ramping cycle ergometer test, and HRQoL was assessed with the SF-36 questionnaire. RESULTS: Greater obstructive sleep apnea severity was associated with older age, higher body weight, higher body mass index, lower peak aerobic capacity, a higher percentage of peak aerobic capacity at a submaximal exercise intensity of 55 watts, and lower physical component summary score from the SF-36. None of these variables were statistically different among obstructive sleep apnea severity groups after controlling for age and body weight. Obstructive sleep apnea severity was not associated with any cardiorespiratory fitness or HRQoL parameter. CONCLUSIONS: Obstructive sleep apnea severity has no independent association with exercise capacity or HRQoL. PMID- 23923111 TI - Prevalence of Pulmonary Tuberculosis Among HIV Positive Patients Attending Antiretroviral Therapy Clinic. AB - BACKGROUND: Tuberculosis (TB) is the most common serious opportunistic infection in HIV positive patients and is the manifestation of AIDS in more than 50% of cases in developing countries. TB can occur at any time during the course of HIV infection. AIM: To describe the socio-demographic profile and prevalence of pulmonary tuberculosis (HIV/TB co-infection) among HIV positive patients been attended at the antiretroviral therapy clinic (ART) clinic at tertiary care teaching hospital of western Maharashtra, India. MATERIALS AND METHODS: A cross sectional study was carried out at the ART clinic of Pravara Rural Hospital, Loni, from June 2011 to May 2012. A total of 1012 HIV positive patients, who attended ART clinic, receiving ART treatment during the study period, were included in the analysis. The statistical analysis was performed using SPSS software (Version 17.0). RESULTS: This study showed 1012/172 (17%) prevalence of pulmonary tuberculosis among HIV positive patients, of which 87 (50.58%) were males and 85 (48.42%) were females. Low CD4 count (< 50/MUl) had statistically significant association with HIV/TB co-infection as compared to HIV infection only (P < 0.0001). CONCLUSION: The study showed that 17% of HIV infected persons had tuberculosis co-infection. More strategic preventive measures that enhance body immunity among HIV patients are highly needed as early as possible before they develop active tuberculosis. PMID- 23923112 TI - Association of carotid plaque echogenicity with recurrence of ischemic stroke. AB - BACKGROUND: Atherosclerosis is related to various cardiovascular and cerebrovascular events like cerebral infarction. Recurrence of ischemic stroke is specifically related to atherosclerotic load as determined by the presence of carotid atheromatous plaques and its echogenicity. AIM: This study was to evaluate the association of recurrence of stroke with echogenic characteristics of carotid plaque in ischemic stroke patients. MATERIALS AND METHODS: Carotid sonography using high-resolution 7.5 MHz along with gray-scale technique was done in each ischemic stroke patient to find the occurrence of plaque and its echogenicity according to Mannheim Carotid Intima-Media Thickness Consensus (2004 2006). Followup of patient done to know the recurrence of stroke during 6-month duration and its association with plaque echogenicity. RESULTS: A significant association found between the presence of plaque and known cerebrovascular risk factors. Also significant association found between recurrence of stroke and echolucent character of carotid plaque in bivariate analysis (P = 0.0028). CONCLUSIONS: Recurrence of stroke is related to advanced stage of atherosclerosis that is specified by carotid plaque and its characteristics. It will help us to identify groups of patients at different risk for stroke and planning better strategies to prevent such events. PMID- 23923113 TI - Micronutrient intake and the presence of the metabolic syndrome. AB - BACKGROUND: Dietary micronutrients have been proposed to protect against oxidative damage and related clinical complications. AIMS: We aimed to compare the micronutrient intake between individuals with and without metabolic syndrome (MS). MATERIALS AND METHODS: This cross-sectional study included 3800 men and women who were aged between 35 and 65 years. The diagnosis of the MS was based on International Diabetes Federation criteria. Dietary intake of participants was assessed using a questionnaire for 24 h dietary recall. Student's t-test and Mann Whitney U-tests were used for comparing the micronutrient intake of subjects with or without the MS and the odds ratio for the presence of the MS was calculated for each micronutrient by control for total energy intake adjusted by the residue method. RESULTS: The mean age of MS subjects and the control group was 48.8 +/- 7.9 years and 47.6 +/- 7.6 years, respectively. Energy-adjusted intake of vitamin E (P < 0.05), B2 (P < 0.01), and B12 (P < 0.05) was higher in normal women compared with women with MS. Energy-adjusted intake of vitamin B1 was significantly higher in women with MS. After logistic regression analysis, no significant association between micronutrient intake and MS was shown. CONCLUSION: We found no significant association between micronutrient intake and MS. PMID- 23923114 TI - Langerhans Cell Sarcoma Arising from Chronic Lymphocytic Lymphoma/Small Lymphocytic Leukemia: Lineage Analysis and BRAF V600E Mutation Study. AB - BACKGROUND: the phenomenon that histiocytic/dendritic cell sarcomas may be transformed from lymphoproliferative diseases is dubbed 'transdifferentiation'. Langerhans cell sarcoma (LCS) transdifferentiated from chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL) is extremely rare. The underlying mechanisms of LCS tumorogenesis and its transdifferentiation from CLL/SLL are largely unknown. AIMS: the authors strive to further characterize LCS, to understand the potential molecular changes in LCS and the underlying mechanisms of CLL/SLL transformation to LCS. MATERIALS AND METHODS: a progressively enlarging right inguinal lymph node from a 68-year-old female patient with a history of CLL was biopsied and submitted for flow cytometry analysis, routine hematoxylin, and eosin (H and E) stain and immunohistochemical study. Furthermore, clonality study (fluorescent in situ hybridization (FISH) analysis with a CLL panel probes) and BRAF V600E mutation study (pyrosequencing and immunostain) were performed. RESULTS: two different neoplasms, LCS and CLL/SLL, were discovered to occur simultaneously in the same lymph node. These two entities were shown to be clonally related. More importantly, for the first time, BRAF V600E mutation was detected in LCS. CONCLUSIONS: LCS can be transdifferentiated from CLL/SLL and BRAF V600E mutation may provide the foundation for alternative therapy of LCS. PMID- 23923115 TI - Ligation is Not Enough to Secure the Aortic End of the Anomalous Systemic Artery. PMID- 23923116 TI - Neurological stigma. PMID- 23923117 TI - A cautious head count of our neighbors. PMID- 23923118 TI - Are the Institute of Medicine's trustworthiness guidelines trustworthy? AB - The Institute of Medicine (IOM) has published a set of eight standards for guideline development groups (GDGs) to derive trustworthy clinical practice guidelines (CPGs). We investigated the adherence of these IOM guidelines to its own standards. The IOM document passed two of its own standards ("GDG-Systematic Review Team Interaction" and "GDG Composition"), only partially passed two others ("Articulation of Recommendation" and "External Review") and failed to pass four ("Establishing Transparency," "Management of Conflict of Interest," "Establishing Evidence Foundations" and "Updating"). The IOM standards for the development of CPGs do not meet their own criteria of trustworthiness. Further study is needed to determine the best methodology to evaluate CPGs. PMID- 23923119 TI - Defining the elusive 'medical practice'. PMID- 23923120 TI - A virtual cataract surgery course for ophthalmologists-in-training. AB - Virtual reality (VR) surgery simulation is an emerging teaching tool to train residents in cataract surgery. The widespread adoption of virtual surgery has been limited, however, by high costs and the absence of standardized curricula and evidence demonstrating the impact of VR training on resident surgical outcomes. We outline a resident virtual cataract surgery course--freely accessible online--that we hope will contribute to the development of a standardized VR cataract surgery curriculum. PMID- 23923121 TI - Methadone-induced Torsades de pointes. AB - Torsades de pointes is a polymorphic ventricular tachycardia that can quickly evolve into ventricular fibrillation and sudden death. This arrhythmia often occurs secondary to medication- induced cardiac repolarization dysfunction with resultant prolonged QTc interval on ECG. Numerous medications can predispose patients to this deadly tachycardia. We report a case of methadone-induced Torsades de pointes complicated by ventricular fibrillation and cardiac arrest. Through rapid taper of methadone, the patient's ECG normalized, allowing for safe discharge. This clinical vignette highlights the importance of close monitoring of patient medications. Performing periodic ECGs with prompt removal of offending agent when repolarization abnormalities are appreciated is ideal. Most importantly, as the vast array of medications continues to grow, it is imperative that clinicians are cognizant of side effects and tailor treatment accordingly. PMID- 23923122 TI - Impact of preventive medications in migraine patients at Rhode Island Hospital. AB - OBJECTIVE: Determine healthcare resource utilization in migraine patients prescribed preventive medications in the resident neurology clinic at Rhode Island Hospital. BACKGROUND: Similar institutions have demonstrated that treatment with preventive migraine medications results in significant decreases in outpatient and ED visits, CT/ MRI scans and abortive medication usage. METHODS: Retrospective chart review identified 166 patients based on icd-9 code. Resource utilization was defined as documented emergency room visits, MRI/CT, hospitalizations, outpatient visits and abortive medication usage. RESULTS: There was no difference in resource utilization in those patients taking or not taking a preventive medication. Only 53% were on a level A recommended medication and of those 35.5% were treated with recommended doses. CONCLUSION: UNLIKE similar institutions, there was no difference in resource utilization in patients taking preventive medications. A possible explanation for this discrepancy may be that patients are sub-optimally treated with less effective medications and doses. Employment of appropriate preventive medications may result in a decrease in the utilization of healthcare resources. PMID- 23923123 TI - 'The sandwich sign': mesenteric lymphoma. PMID- 23923124 TI - Mathematical model and dynamic computer simulation on free flow zone electrophoresis. AB - In this paper, a mathematical model was proposed for calculating physico-chemical parameters and simulating the separation process of solutes in free-flow zone electrophoresis (FFZE). Computer software was developed and implemented in a Delphi XE2 environment based on the model, which comprises zone electrophoresis, electrolyte solution, hydrodynamics and diffusion as well as conversion equations. The simulation results reveal that (i) the software is capable of simulating a dynamic process of FFZE properly; (ii) the software can simulate operation parameters (e.g., electric field, flow rate and pH value) for experimental optimization; (iii) the simulator is able to display the final electropherogram of numerous analytes in FFZE; and (iv) the electropherogram of FFZE can be automatically converted to that of capillary zone electrophoresis. In order to verify the rationality and reliability of this software, the relevant experiments were conducted and further compared with the simulations. The comparisons demonstrated the high agreement between the simulations and the experiments as well as those cited from the relevant references. In addition, effective mobility, diffusion coefficient and concentration of solutes can be conveniently gained via the software. The developed mathematical model and designed software have evident significance for the optimization of experimental conditions and basic physico-chemical parameters in FFZE. PMID- 23923125 TI - Isotope-dilution UPLC-MS/MS determination of cell-secreted bioactive lipids. AB - Secreted bioactive lipids play critical roles in cell-to-cell communication and have been implicated in inflammatory immune responses such as anaphylaxis, vasodilation, and bronchoconstriction. Analysis of secreted bioactive lipids can be challenging due to their relatively short lifetimes and structural diversity. Herein, a method has been developed using ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to quantify five cell-secreted, structurally and functionally diverse bioactive lipids (PGD2, LTC4, LTD4, LTE4, PAF) that play roles in inflammation. Sample analysis time is 5 min, and isotopically labeled internal standards are used for quantification. This method was applied to an immortal secretory cell line (RBL-2H3), a heterogeneous primary cell culture containing peritoneal mast cells, and murine platelets. In RBL cell supernatant samples, intrasample precisions ranged from 7.32-21.6%, averaging 17.0%, and spike recoveries in cell supernatant matrices ranged from 88.0-107%, averaging 97.0%. Calibration curves were linear from 10 ng mL(-1) to 250 ng mL( 1), and limits of detection ranged from 0.0348 ng mL(-1) to 0.803 ng mL(-1). This method was applied to the determination of lipid secretion from mast cells and platelets, demonstrating broad applicability for lipid measurement in primary culture biological systems. PMID- 23923127 TI - Desorption electro-flow focusing ionization of explosives and narcotics for ambient pressure mass spectrometry. AB - Desorption electro-flow focusing ionization (DEFFI), a desorption-based ambient ion source, was developed, characterized, and evaluated as a possible source for field deployable ambient pressure mass spectrometry (APMS). DEFFI, based on an electro-flow focusing system, provides a unique configuration for the generation of highly charged energetic droplets for sample analysis and ionization. A concentrically flowing carrier gas focuses the liquid emanating from a capillary through a small orifice, generating a steady fluid jet. An electric field is applied across this jet formation region, producing high velocity charged droplets that impinge on an analyte laden surface. This configuration separates the jet charging region from the external environment, eliminating detrimental effects from droplet space charge or target surface charging. The sample desorption and ionization processes operate similar to desorption electrospray ionization (DESI). DEFFI demonstrated strong signal intensities and improved signal-to-noise ratios in both positive and negative mode mass spectrometry for narcotics, i.e., cocaine, and explosives, i.e., cyclotrimethylenetrinitramine (RDX), respectively. A characterization of DEFFI ionization mechanisms identified operation regimes of both electrospray and corona discharge based analyte ionization, as well as limitations in overall signal. In addition, the DEFFI response was directly compared to DESI-MS under similar operating conditions. This comparison established a wider and more stable optimal operating range, while requiring an order of magnitude lower applied gas pressure and applied potential for DEFFI than DESI. These reductions are due to the physical mode of jet formation and geometric configuration differences between DEFFI and DESI, pointing to a potential benefit of DEFFI-MS for field implementation. PMID- 23923126 TI - Sensitive and reusable electrochemiluminescent aptasensor achieved with diblock oligonucleotides immobilized solely through preferential adenine-Au interaction. AB - Strong Au-S chemistry to self-assemble thiolated oligonucleotides at gold electrode is an efficient strategy to construct electrochemiluminescent (ECL) aptasensor. However, it remains challenging to precisely control the orientation and conformation of surface-tethered oligonucleotides and to reuse ECL aptasensor because of the narrow electrochemical window of thiolated DNA film on Au surface (below ~0.80 V versus Ag/AgCl). Here, we demonstrate adenine/thymine diblock oligonucleotides (d(Am-Tn)) to substitute DNA-SH in DNA immobilization for constructing ECL aptasensor. As a proof-of-principle, thrombin was used to present the properties of the proposed sensor. The as-formed ECL aptasensor had a wide electrochemical window and good stability (decreased 5.38% after 200 cyclic potential cycles, 0-1.2 V versus Ag/AgCl). Moreover, the aptasensor exhibited an extremely low detection limit (0.017 pM) and offered good selectivity toward thrombin. This detection limit was at least one order of magnitude lower than those of previous methods for thrombin. Additionally, the ECL aptasensor was reusable (n = 3) and showed good reproducibility (relative standard derivation, 4.7% (n = 6)). We believe that the strategy demonstrated here provides a good platform for DNA immobilization in constructing ECL even electrochemical aptasensor for the detection of targets in clinical analysis conveniently. PMID- 23923128 TI - A ferrofluid-based homogeneous assay for highly sensitive and selective detection of single-nucleotide polymorphisms. AB - A simple and low-cost colorimetric assay utilizing ferrofluidic nanoparticulate probes (FNPs) and a ligase for single-nucleotide polymorphism genotyping is described. Excellent sensitivity and selectivity were accomplished through the engagement of the FNPs and a ligase chain reaction. PMID- 23923129 TI - QM/MM surface-hopping dynamics of a bridged azobenzene derivative. AB - Ethylene-bridged azobenzene (diazocine) has been shown to have superior photochemical properties. So far, however, experimental and theoretical quantum yields did not match, not even qualitatively. Here, a large-scale QM/MM surface hopping study of this molecule is presented. For both photo-isomerization directions, surprisingly prominent solvent effects are found and analyzed by detailed comparisons against gas phase dynamics and experimental data. By taking explicit n-hexane solvent into account, the quantum yields change markedly and approach the experimental values, where the same solvent was used. PMID- 23923130 TI - Introduction: how dysregulation of mental processes and behaviors lead to pathology. PMID- 23923131 TI - [Clinical pharmacy frees up time for diagnosis and treatment]. PMID- 23923132 TI - [It should be studied better]. PMID- 23923133 TI - [Uncertainty about the duration of HPV vaccine immunogenicity in boys]. PMID- 23923135 TI - [Psychiatry--what could be done differently?]. PMID- 23923136 TI - [Psychiatry--what could be done differently? Reply]. PMID- 23923137 TI - [The emergency medicine specialist can be in front--now!]. PMID- 23923138 TI - Change in terminology: "mental retardation" to "intellectual disability." Final rule. AB - This final rule adopts, without change, the notice of proposed rulemaking (NPRM) we published in the Federal Register on January 28, 2013. We are replacing the term "mental retardation'' with "intellectual disability'' in our Listing of Impairments (listings) that we use to evaluate claims involving mental disorders in adults and children under titles II and XVI of the Social Security Act (Act) and in other appropriate sections of our rules. This change reflects the widespread adoption of the term "intellectual disability'' by Congress, government agencies, and various public and private organizations. PMID- 23923139 TI - Food labeling: gluten-free labeling of foods. Final rule. AB - The Food and Drug Administration (FDA or we) is issuing a final rule to define the term "gluten-free'' for voluntary use in the labeling of foods. The final rule defines the term "gluten-free'' to mean that the food bearing the claim does not contain an ingredient that is a gluten-containing grain (e.g., spelt wheat); an ingredient that is derived from a gluten-containing grain and that has not been processed to remove gluten (e.g., wheat flour); or an ingredient that is derived from a gluten-containing grain and that has been processed to remove gluten (e.g., wheat starch), if the use of that ingredient results in the presence of 20 parts per million (ppm) or more gluten in the food (i.e., 20 milligrams (mg) or more gluten per kilogram (kg) of food); or inherently does not contain gluten; and that any unavoidable presence of gluten in the food is below 20 ppm gluten (i.e., below 20 mg gluten per kg of food). A food that bears the claim "no gluten,'' "free of gluten,'' or "without gluten'' in its labeling and fails to meet the requirements for a "gluten-free'' claim will be deemed to be misbranded. In addition, a food whose labeling includes the term "wheat'' in the ingredient list or in a separate "Contains wheat'' statement as required by a section of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) and also bears the claim "gluten-free'' will be deemed to be misbranded unless its labeling also bears additional language clarifying that the wheat has been processed to allow the food to meet FDA requirements for a "gluten-free'' claim. Establishing a definition of the term "gluten-free'' and uniform conditions for its use in food labeling will help ensure that individuals with celiac disease are not misled and are provided with truthful and accurate information with respect to foods so labeled. We are issuing the final rule under the Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA). PMID- 23923140 TI - Basic Program Elements for Federal employee Occupational Safety and Health Programs and related matters; Subpart I for Recordkeeping and Reporting Requirements. Final rule. AB - OSHA is issuing a final rule amending the Basic Program Elements to require Federal agencies to submit their occupational injury and illness recordkeeping information to the Bureau of Labor Statistics (BLS) and OSHA on an annual basis. The information, which is already required to be created and maintained by Federal agencies, will be used by BLS to aggregate injury and illness information throughout the Federal government. OSHA will use the information to identify Federal establishments with high incidence rates for targeted inspection, and assist in determining the most effective safety and health training for Federal employees. The final rule also interprets several existing basic program elements in our regulations to clarify requirements applicable to Federal agencies, amends the date when Federal agencies must submit to the Secretary of Labor their annual report on occupational safety and health programs, amends the date when the Secretary of Labor must submit to the President the annual report on Federal agency safety and health, and clarifies that Federal agencies must include uncompensated volunteers when reporting and recording occupational injuries and illnesses. PMID- 23923141 TI - [The application of psychotherapy has always been consubstantial]. PMID- 23923142 TI - [Anthropology and psychiatry]. PMID- 23923143 TI - [Interview with Miguel Mihanovich. Interview by Santiago A. Levin]. PMID- 23923145 TI - [The deficit of nursing staff]. PMID- 23923144 TI - Medicare program; inpatient rehabilitation facility prospective payment system for federal fiscal year 2014. Final rule. AB - This final rule updates the prospective payment rates for inpatient rehabilitation facilities (IRFs) for federal fiscal year (FY) 2014 (for discharges occurring on or after October 1, 2013 and on or before September 30, 2014) as required by the statute. This final rule also revised the list of diagnosis codes that may be counted toward an IRF's "60 percent rule'' compliance calculation to determine "presumptive compliance,'' update the IRF facility-level adjustment factors using an enhanced estimation methodology, revise sections of the Inpatient Rehabilitation Facility-Patient Assessment Instrument, revise requirements for acute care hospitals that have IRF units, clarify the IRF regulation text regarding limitation of review, update references to previously changed sections in the regulations text, and revise and update quality measures and reporting requirements under the IRF quality reporting program. PMID- 23923146 TI - Medicare program; prospective payment system and consolidated billing for skilled nursing facilities for FY 2014. Final rule. AB - This final rule updates the payment rates used under the prospective payment system for skilled nursing facilities (SNFs) for fiscal year (FY) 2014. In addition, it revises and rebases the SNF market basket, revises and updates the labor related share, and makes certain technical and conforming revisions in the regulations text. This final rule also includes a policy for reporting the SNF market basket forecast error in certain limited circumstances and adds a new item to the Minimum Data Set (MDS), Version 3.0 for reporting the number of distinct therapy days. Finally, this final rule adopts a change to the diagnosis code used to determine which residents will receive the AIDS add-on payment, effective for services provided on or after the October 1, 2014 implementation date for conversion to ICD-10-CM. PMID- 23923147 TI - [Out of focus: pharmacotherapy of underdiagnosed clinical forms]. PMID- 23923148 TI - Effect of garlic extract on blood glucose level and lipid profile in normal and alloxan diabetic rabbits. PMID- 23923149 TI - Teething signs and symptoms: persisting misconceptions among health professionals in New Zealand. AB - OBJECTIVES: To investigate current beliefs and treatment recommendations for teething symptoms among health professionals in New Zealand. DESIGN: Cross sectional survey of seven groups of health professionals. METHOD: A written questionnaire was mailed in March 2011 to 336 health professionals practising in Wellington City, Hutt Valley and Kapiti Coast, in New Zealand. The self administered questionnaire sought information on how many children are perceived to experience teething symptoms, what symptoms are attributed to teething, suggested treatments for teething symptoms, and how distressing teething is to children and parents. RESULTS: The response rate to the single-wave survey was 41%. Although the beliefs varied widely across the groups, almost half (48%) of health professionals believed that some children have teething-associated problems, and 32% believed that most children do. Just over one-third of participants incorrectly attributed fever to teething. Health professionals also incorrectly chose nappy rash (31%), loose stools (27%), runny nose (19%) and mouth ulcers (15%) as teething signs or symptoms. Most participants (65%) suggested paracetamol as a treatment for teething; 60% chose teething gels and 48% suggested teething toys or rings. Most respondents believed that teething is moderately distressing to both the child and parent. CONCLUSIONS: The findings show that misconceptions about the symptoms of teething are held by some health professionals. Many believe that teething causes a variety of serious and systemic symptoms. The study has also shown that teething beliefs vary greatly across the different health professions. PMID- 23923150 TI - Orthodontic tooth movement of traumatised or root-canal-treated teeth: a clinical review. PMID- 23923151 TI - Exercise intervention for a musculoskeletal disorder in an oral health student: a case report. AB - OBJECTIVES: to describe and evaluate the effect of an exercise self-management programme for an oral health student who was suffering from a musculoskeletal disorder which had developed in the clinical environment during the course of training. DESIGN: Single participant case report. SETTING: The University of Otago Faculty of Dentistry and School of Physiotherapy. METHODS: The participant was a 21-year-old female student, enrolled in the University of Otago Bachelor of Oral Health (BOH) course, who was suffering back and neck pain which had developed during her training. A series of chairside stretches, regular home based stretches, aerobic conditioning and postural strengthening exercises was prescribed. Pain and function was assessed using standardised questionnaires at the commencement of the exercise programme, and again at 6 weeks and 13 weeks. RESULTS: The participant demonstrated an improvement in her outcome questionnaires exceeding the MCID scores after 13 weeks. CONCLUSIONS: This case report provides a basis for highlighting the importance of measuring and monitoring MSD in a student learning oral health skills; it supports the findings of previous studies showing that an exercise intervention has some benefit for MSD in oral health students. PMID- 23923152 TI - Impact of malocclusion on quality of life among New Zealand adolescents. AB - OBJECTIVES: To determine whether malocclusion is associated with oral-health related quality of life (OHRQoL) in New Zealand adolescents. METHODS: Data from two cross-sectional epidemiological studies of adolescents in Taranaki and Otago were used. Each participant completed a self-administered questionnaire and underwent a clinical examination. Information collected included sociodemographic characteristics (sex, ethnicity and household deprivation), and clinical measures (caries and malocclusion, the latter measured with the Dental Aesthetic Index, or DAI). OHRQoL was measured using the validated 16-item impact short-form Child Perceptions Questionnaire (CPQ11-14). Linear regression was used to model the CPQ11-14 score. RESULTS: 783 adolescents (52.6% male) took part. One-fifth had a handicapping malocclusion and one-third had a minor malocclusion or none. The overall mean DMFS was 2.3 (SD, 3.8), with slightly more than 50% being caries free. With the exception of the oral symptoms domain, females presented with higher mean CPQ11-14 and domain scores, while Maori had lower scores. There was a distinct gradient in mean CPQ11-14 and domain scores across the categories of malocclusion severity, whereby those in the 'handicapping' category of the DAI had the highest CPQ11-14 score. Linear regression modeling of the CPQ11-14 score showed that, after controlling for DMFS and socio-demographic characteristics, malocclusion category and being female were positively associated with higher CPQ11-14 scores. CONCLUSION: A severe malocclusion appears to have a negative impact on the OHRQoL of New Zealand adolescents. PMID- 23923153 TI - A decade of a dental student community engagement in Rotorua. PMID- 23923154 TI - Review on dental implants by Ng et al. PMID- 23923155 TI - Nurse directors need to be equipped for the job. PMID- 23923156 TI - Holding directors to account for abuse could hinder recruitment. PMID- 23923157 TI - Boom in nurse researchers brings more patients into clinical trials. PMID- 23923158 TI - Promise of 1,200 jobs in Abu Dhabi rouses interest in working overseas. PMID- 23923159 TI - National NHS strategy seeks to accelerate number of organ donors. PMID- 23923161 TI - Finding a better way to support mentors. AB - Students need high-quality mentoring to develop into safe, competent and compassionate nurses. NMC standards for mentors recognise the importance of the role and more support is being offered in difficult areas, such as failing unsatisfactory students. PMID- 23923160 TI - Watchdog re-focuses attention on NMC's fitness to practise cases. PMID- 23923162 TI - Rewarding journey. AB - A hospital passport scheme being rolled out in Scotland helps children feel in control when in hospital, as well as reducing stress for those staff caring for them. The passport records children's preferences during procedures, offers advice on coping strategies, and provides a place for collecting reward stickers. PMID- 23923163 TI - Online road to self-recovery. AB - People living in the community with mental health problems often have difficulty accessing psychological therapies. Nurse consultant Steve Cottrell has designed an online interactive treatment that has helped thousands of people with stress, anxiety and panic disorders to develop their own self-recovery skills. PMID- 23923164 TI - Peri-operative hypothermia: implications for practice. AB - This article explores whether there are adverse surgical outcomes for patients who experience hypothermia in the peri-operative period. Findings of this literature review highlight the need to establish a standard definition of hypothermia. Furthermore, the literature supports the full implementation of the National Institute for Health and Care Excellence guidance on The Management of Lnadvertent Perioperative Hypothermia in Adults. A total of 18 studies were critically appraised to determine their rigour, reliability and validity. A discussion of the findings from the studies has taken into account the inferences drawn from the appraisal. Evaluation of the quality of the evidence has been used to evaluate which findings could apply to clinical practice. While there were variations in study quality, the evidence supports developing an effective strategy for preventing hypothermia in the peri-operative period. PMID- 23923165 TI - Assessment and management of paracetamol poisoning in adults. AB - Paracetamol is a low cost, effective analgesic that is widely available in the UK. Paracetamol is the drug most commonly taken in overdose and can lead to acute liver failure, which can be fatal. This article focuses on the assessment and management of paracetamol poisoning in adults. It includes current UK guidelines on paracetamol poisoning, which changed in September 2012 following a review by the Commission on Human Medicines. It also discusses strategies to reduce incidence and severity of paracetamol poisoning, and outlines the metabolism of paracetamol at therapeutic doses and in overdose. PMID- 23923166 TI - Vulnerability. PMID- 23923167 TI - Reviewing the evidence for advanced dressings. AB - The principles of moist wound healing have become widely accepted since the seminal work of George Winter in the 1960s. In the subsequent 50 years, many publications have extolled the clinical value of modern or advanced wound dressings. This article reviews the findings of two studies arguing that the benefits of advanced wound care products, which are based largely on th principles of moist wound healing, cannot be justified in terms of healing outcomes or cost effectiveness. These studies have the potential to affect clinical practice and decision making, and the article highlights the importance of analysing and interpreting the findings of such studies cautiously. PMID- 23923168 TI - Management of burns in intensive and acute care. AB - Patients with major burns require specialist care in burn centres, taking into account the complex systemic response to a burn injury, avoidance of complications, specialist wound care and supportive multidisciplinary management. Occasionally, these patients may be managed in other settings, such as emergency departments or general intensive care units and ward areas, for example after an explosion or major disaster. Therefore, general nurses require an understanding of patients' complex needs, and should be aware of the latest developments in burn care and up-to-date evidence to ensure best practice. PMID- 23923169 TI - Brokers for education. PMID- 23923171 TI - Honing vital skills in practice. PMID- 23923170 TI - Expertise from the continent. PMID- 23923172 TI - Making the argument for change. PMID- 23923174 TI - Supervisory status will give senior nurses front line role. PMID- 23923173 TI - Managers admit to making poor use of complaints data. PMID- 23923175 TI - Health chiefs reject need for extra sanctions to address poor standards. PMID- 23923176 TI - Promoting public interest in clinical research. PMID- 23923177 TI - Giving the silent majority a voice. PMID- 23923178 TI - How Schwartz rounds can be used to combat compassion fatigue. AB - Hospice nurses were the first to have some of their experiences described as 'compassion fatigue' but this term can now be applied to all nursing staff in clinical environments. Compassion fatigue can suddenly render nurses unable to distinguish between their own emotions and those of their patients. This fatigue can result in staff becoming emotionally drained and therefore unable to provide high quality care. While nurses have to regain public trust in the wake of the Mid Staffordshire NHS Foundation Trust inquiry, this article considers whether or not Schwartz rounds, an initiative introduced from the US, can help maintain the wellbeing of staff and so protect the quality of patient care. PMID- 23923180 TI - Understanding nursing 'nous' in the context of service improvements. AB - Nurse managers face the challenges of how best to improve healthcare services in ways that can be evaluated readily by patients and that engage nurses. They also need to demonstrate how staff resource has been successfully deployed. This article ventures that a better understanding of 'nous' - the organisational ability of nurses to combine skills to clear purpose and patient benefit - may assist nurse managers to achieve these aims. It explores what staff nous consists of and examines critically more traditional modes of thinking about staff as intellectual capital. The reader is shown how staff nous might feature in new patient evaluations of care, nursing staff appraisals and the design of care initiatives. PMID- 23923179 TI - Visible leadership: going back to the front line. AB - The report into care at Mid Staffordshire NHS Foundation Trust called for strong leadership in nursing and the government's response acknowledged the importance of senior managers gaining front line experience of the NHS. This article discusses the background to the need for visible leadership and the advantages and disadvantages of different approaches to engaging with the front line. Lessons from other industries are considered and a spectrum of engagement activities relevant to health care suggested. Senior leaders' visits to the front line have brought identified benefits for staff but there is little proof of patient benefits, so more research needs to be commissioned to generate evidence of effectiveness. PMID- 23923181 TI - Winning combination. PMID- 23923182 TI - TNAI ushers in new era in 2013. PMID- 23923183 TI - Letter from the SNA advisor. PMID- 23923184 TI - Effect of antenatal exercises on labour outcome among primigravid mothers. AB - Exercise is a natural part of life. Physical exercises increase mood-elevating chemicals in the brain and thereby reduce pregnancy-related blues. As the women need to exercise during pregnancy, the present study was conducted to determine the effect of antenatal exercises on labour process among primigravid mothers at selected Urban Health Centres in Coimbatore (Tamilnadu). The practise of antenatal exercises revealed a significant difference in duration of labour, nature of delivery, behaviour manifestations, and level of pain in mother and presence of asphyxia and birth injuries in new born. PMID- 23923185 TI - Assessment of computer-related health problems among post-graduate nursing students. AB - The study was conducted to assess computer-related health problems among post graduate nursing students and to develop a Self Instructional Module for prevention of computer-related health problems in a selected university situated in Delhi. A descriptive survey with co-relational design was adopted. A total of 97 samples were selected from different faculties of Jamia Hamdard by multi stage sampling with systematic random sampling technique. Among post-graduate students, majority of sample subjects had average compliance with computer-related ergonomics principles. As regards computer related health problems, majority of post graduate students had moderate computer-related health problems, Self Instructional Module developed for prevention of computer-related health problems was found to be acceptable by the post-graduate students. PMID- 23923186 TI - Vestibular rehabilitation: rehabilitation options for patients with dizziness and imbalance. PMID- 23923187 TI - XXIV TNAI Biennial (73rd) Conference, Bhopal (MP), 27-28 November 2012. PMID- 23923188 TI - XXIV TNAI Biennial (73rd) Conference, Bhopal (MP), 27-28 November 2012. PMID- 23923189 TI - XXIV TNAI Biennial (73rd) Conference, Bhopal (MP), 27-28 November 2012. Unfolding the conference theme--quality clinical practice: nurses' concern. PMID- 23923190 TI - Logotherapy. PMID- 23923191 TI - Effect of computer assisted instructions on central venous catheter care in knowledge and practice of staff nurses in a selected hospital in Uttar Pradesh. AB - The aim of this study was to evaluate the effectiveness of Computer Assisted Instructions (CAI) on Central Venous Catheter (CVC) Care in terms of knowledge and practice of staff nurses working in intensive care units of a selected hospital in Uttar Pradesh. Using quantitative research approach, 30 staff nurses were included in the study based on purposive sampling technique and (a) a structured knowledge questionnaire was administered, and (b) an observation checklist was administered. It was found that the computer-assisted instructions on central venous catheter care was effective in increasing the knowledge and practice of staff nurses and there was a significant positive relationship between the post-test knowledge scores and post-test practice scores indicating that an increase in knowledge would result in better practice among staff nurses regarding central venous catheter care. PMID- 23923192 TI - Are consumer rights only in books? PMID- 23923194 TI - Solitary is cruel and unusual. Isolating inmates inflicts permanent mental harm. The practice must be curbed. PMID- 23923195 TI - Beyond the God particle. The death of particle physics in the U.S. has been greatly exaggerated. PMID- 23923193 TI - Case management insider. Back to basics: a day in the life of a hospital case manager--Part 1. AB - In this month's Case Management Insider we have begun to review the case management process. The process has a total of eight steps, and we have completed our review of six of them. Next month we will continue with the final two steps in the case management process and also discuss best practices for doing an admission assessment. We will also review a case study which should help you in applying the steps we have been reviewing! PMID- 23923196 TI - Hidden and dangerous. Polio could soon be wiped out--but only if scientists can track down the last carriers. PMID- 23923197 TI - The art of distraction. An undersea sculpture garden in waters around Cancun is saving a reef from tourist traffic. PMID- 23923198 TI - Computing superstorm Sandy. The mathematics of predicting a hurricane's path. PMID- 23923200 TI - Phantom planets. Why hyperactive stars are planet hunters' biggest headache. PMID- 23923199 TI - Bug vs. superbug. Hungry microbes can hunt down drug-resistant superbugs. PMID- 23923201 TI - A microbial mystery PMID- 23923202 TI - Rethinking rabies. Some rabies infections may not be lethal, but be especially wary of dog bites. PMID- 23923203 TI - The last thing you'll memorize. Have smartphones in every pocket made memorization obsolete? PMID- 23923204 TI - Perchance to prune. During sleep, the brain weakens the connections among nerve cells, apparently conserving energy and, paradoxically, aiding memory. PMID- 23923205 TI - What is real? PMID- 23923206 TI - Big data goes to school. PMID- 23923207 TI - Hype and hope. PMID- 23923208 TI - Machine learning. PMID- 23923209 TI - Why we need high-speed schools. PMID- 23923210 TI - "I was pleasantly surprised". PMID- 23923211 TI - Why exercise works magic. PMID- 23923212 TI - Raising the wreck. PMID- 23923213 TI - The surprising origins of life's complexity. PMID- 23923214 TI - How to swim in molasses. PMID- 23923215 TI - Five myths of terrorism. Wht terror doesn't work. PMID- 23923216 TI - Living in harm's way. Damage from storms will rise sharply, even without climate change. PMID- 23923217 TI - CARDIAC program in West Kentucky: a retrospective data analysis. AB - Obesity is a leading contributing factor resulting in a multitude of health problems for adults and children throughout the United States. Kentucky statistics reveal 37.1% of children aged 10-17 as being classified as overweight and obese. Obesity in children increases the risk for cardiovascular and other health conditions such as high blood pressure, hyperlipidemia, and diabetes. In order to better understand obesity and cardiovascular risks of children in Western Kentucky, several community organizations formed a partnership to assess the risks of fourth grade children. This partnership consisted of collaboration between multiple health care organizations to assess body mass index, fitness scores, capillary glucose and cholesterol, and blood pressure. This article explains the findings from a retrospective data analysis related to this implementation program. PMID- 23923218 TI - Measurement of critical thinking for the RN to BSN student. PMID- 23923219 TI - Contracts: avoiding the wrong regrets. PMID- 23923220 TI - Blazing a trail in convenient care. PMID- 23923221 TI - Gut reaction: the role of probiotics in GI health. PMID- 23923222 TI - Depression in diabetes patients. An overview of screening tools for use in primary care settings. PMID- 23923223 TI - Infant formulas. Partnering with parents for rational decision making. PMID- 23923224 TI - Current trends in aesthetics. Patients want less invasive options and total-body attention. PMID- 23923225 TI - Cover picture: an English Heritage blue plaque for Lilian Lindsay. PMID- 23923226 TI - Lilian Lindsay (1871-1960): the quest for an English Heritage blue plaque. PMID- 23923227 TI - Lilian's ladies: a global perspective. Part 2. PMID- 23923229 TI - The first identification of forensic odontology endorsed by the American justice system. PMID- 23923230 TI - Professor Aylwin Drakeford Hitchin (1907-1996). PMID- 23923231 TI - The Harvey-Fletcher Medal and Prize. PMID- 23923232 TI - Oral surgery at Queen Mary's Hospital Roehampton. PMID- 23923233 TI - Francis Robert Lloyd and the celebrated traveller: a British Raj murder mystery. AB - In 1854 the Schlagintweit brothers, scientist-explorers from Vienna were invited by the East India company to make a geological survey of the northern parts of the sub-continent. Adolphe Schlagintweit had wanted to cross into Central Asia from India. He had proceeded as far as Kashgar when he was allegedly murdered by a chief of one of the wandering tribes. His decapitated head became a source of intrigue. The paper describes the incident and the subsequent role of Dr F R Lloyd, a dentist from India, in the police investigation that followed. This is the first documented case from India of a legal case making use of forensic odontology. PMID- 23923234 TI - One compassionate man and his military service (1946-1986). PMID- 23923235 TI - Doris Rosemary Ridley: orthodontist (1930-2013). PMID- 23923236 TI - The Royal Dental Hospital's London School of Dental Surgery and its deans. Part 1: the 1st to 4th deans. PMID- 23923237 TI - Sir John Tomes, his grave and the Hunterian Museum Bicentenary. PMID- 23923238 TI - Remembering Donna Diers: A true trailblazer. PMID- 23923239 TI - Understanding nursing units with data and theory. AB - Nursing units are social systems whose function depends on many variables. Available nursing data, combined with a theory of organizational diagnosis, can be used to understand nursing unit performance. One troubled unit served as a case study in organizational diagnosis and treatment using modern methods of data mining and performance improvement. Systems theory did not prescribe how to fix an underbounded system. The theory did suggest, however, that addressing the characteristics of overbounded and underbounded systems can provide some order and structure and identify helpful resources. In this instance, the data analysis served to help define the unit's problems in conjunction with information gained from talking with the nurses and touring the unit, but it was the theory that gave hints for direction for change. PMID- 23923240 TI - Demystifiying state health insurance marketplaces. AB - The state health insurance exchanges, mandated under the Patient Protection and Affordable Care Act, will impact how health care is delivered and reimbursed, and will touch the lives of nurses in all professional roles. The dynamics of how each model will operate within each state is currently a work in progress. Nurses have a tradition of providing voice and leadership in the health care reform arena from the unique position as both consumers and health care professionals. The time is right to contact state legislators and advocate for nurses to sit on the governing boards of the state health care exchanges. Communication between nurses in all states should be an ongoing dialogue through specialty and state nursing organizations to ensure nursing is aware of both issues and best practices nationwide. PMID- 23923241 TI - Internal migration of nurses in the United States: migratory prompts and difference in job satisfaction between migrants and non-migrants. AB - In the United States, nurses are highly mobile due to a nursing shortage and the transferability of their skills. Despite the importance of internal migration (inter-state movement) of nurses in the distribution of the supply nurses, little is known about such migration. Researchers used data from the 2004 and 2008 National Sample Survey of Registered Nurses to examine the factors associated with nurses' internal migration as well as the difference in job satisfaction for migrant and non-migrant nurses. Factors associated with a higher likelihood of internal migration were: a change in employer, higher earnings, not foreign educated, less nursing experience, a younger age, being male, being single, having no children, the Nursing Licensure Compact, and not being employed in the state where the first RN license was obtained. Migrant nurses had lower job satisfaction than non-migrant nurses; higher job satisfaction is noted with higher earnings levels. The development of policies such as relocation and social support to help migrant nurses cope and adjust to a new working environment are proposed. PMID- 23923242 TI - Economic aspects of nursing in inpatient naturopathy: vidence from Germany. AB - The costs of nursing in Germany are defined in terms of "nursing-relevant secondary diagnoses." However, the further development of the German-DRG system reveals nursing diagnoses play a constantly declining role with regard to increasing severity and revenue assurance. In particular, additional therapeutic nursing services performed, for example, by specially trained, certified nurses in acute hospitals focusing on naturopathy are not adequately defined. In this study, researchers analyzed naturopathic care, especially the nursing costs for inpatient care of multi-morbid cardiac patients, with a particular focus on a holistic, comprehensive treatment. Results indicated the nursing costs in an inpatient acute hospital with a naturopathic focus are significantly higher than nursing costs in hospitals operating exclusively according to conventional medicine. Questions about adequate determination of the costs of DRGs for professional groups such as the nursing service need to be addressed. PMID- 23923243 TI - A legacy of data use by Donna Diers. AB - Donna Diers, PhD, RN, FAAN, is renowned for her work as a visionary, scholar, thought leader, scientist, and writer in areas of advanced practice, nursing, and public policy. She envisioned a relationship between diagnosis-related groups, the work of nurses in resource consumption, and patient outcomes. Dr. Diers helped blaze the path for creating a hospital-based service dedicated to answering operational questions from clinicians through analysis of clinical and financial data sets. She recognized the value of nurses' access to data experts to contemplate and analyze the critical patient care questions and their impact on clinical quality and cost. Dr. Diers was the master of using local data for change at the unit level. Her lifetime contributions and dedication profoundly affected the uses of data for future generations of nurses. PMID- 23923244 TI - Are you tired? Overcoming leadership styles that create leader fatigue. AB - Part of the culture of nursing is convincing everyone you are perpetually overworked and overwhelmed. The leadership style the leader chooses will determine whether he or she will be energized or overwhelmed. When the leader is unable and unwilling to surround him or herself with people who are more knowledgeable and astute, the level of stress and worry becomes unbearable. Relationships thrive when a structure is present. Your staff will be energized and empowered, and will reach incredible levels of productivity and the highest level of achievement possible. Doing "nothing" allows your staff to grow as people and as a team, and you will be free to do the work of the leader, and not be tired. PMID- 23923245 TI - Demonstrating the value in nursing: an interview with Linda McGillis Hall. Interview by Christine T. Kovner. PMID- 23923246 TI - Health insurance exchanges: A call for nursing action. AB - State health insurance exchanges will provide the opportunity for consumers to have options regarding health insurance coverage. Nurses have a vital role to play in the implementation of exchanges. Knowing the basic facts about how these exchanges will work, what the benefits will be, and access to reliable information sources will enable nurses to provide trusted guidance. The development of this new insurance marketplace is also an opportunity to address the long-standing barriers to advance practice registered nurses (APRN) practice. PMID- 23923247 TI - End freeze on gun violence research. PMID- 23923248 TI - Assessment of postarrival tuberculosis examinations among immigrants and refugees screened overseas. AB - BACKGROUND: Immigrants and refugees screened overseas and found to have Mycobacterium tuberculosis infection (TB arrivers) are either treated fortuberculosis (TB) or, if disease is not found these arrivers are given a TB classification of latent TB infection (LTBI) and are referred for reexamination after arriving in the United States. METHODS: A retrospective cohort analysis was performed of TB arrivers in Connecticut to determine the proportion of TB arrivers documentedwith their postarrival domestic medical examination and to determine the proportion of TB arriverswho started and completed LTBI treatment. RESULTS: Of 184TB arrivers, 109 (59%) were evaluated for TB after arrival and four (4%) were diagnosed withTB. Of 105 personswith LTBI,49 (47%) started treatment, and of those 15(30%) completedtreatment. CONCLUSION: The majority of TB cases in Connecticut are among foreign-born individuals. Improving TB control overseas is a crucial step in the reduction of TB in the United States. Improvements are still needed to ensure timely, postarrival medical examinations that ensure treatment for high-risk persons with LTBI to reduce TB in Connecticut's foreign-born populations. PMID- 23923249 TI - Legionella pneumonia complicated by myocarditis and torsades de pointes: A case report and review of literature. AB - Legionella infection most commonly manifests as pneumonia. Extrapulmonarylegionellosis is rare, but the clinical manifestations are often dramatic. Myocardialinvolvementis the most common extrapulmonary manifestation of legionellosis and can result in left ventricular dysfunction. We report a case of Legionellapneumopbila-induced myocarditis and acute left ventricular dysfunction with subsequent development of torsades de pointes (TdP) in a young adult with no other risk factors. Early recognition of this complication is paramount as timely initiation of appropriate antibiotics is crucial to ensure full recovery from this form of reversible carditis. PMID- 23923250 TI - A case of Creutzfeldt-Jakob disease following cataract surgery: sporadic versus iatrogenic cause. AB - Creutzfeldt-Jakob Disease (CJD) is a fatal neurologic disorder caused by an infectious agent called a human prion protein. CJD can be classified as sporadic CJD, familial CJD, variant CJD, and iatrogenic CJD. We report a 64-year-old man diagnosed with CJD three months after cataract surgery. Although sporadic CJD is the most common type, the patient's cataract surgery elicited the possibility of an iatrogenic transmission. It is important to consider whether visual symptoms are a manifestation of sporadic CJD, rather than cataract surgery resulting in iatrogenic CJD. Preceding cataract surgeries have been reported with CJD, but there is no proven causality. This case highlights consideration of sporadic versus iatrogenic cause when seen in association with cataract surgery. PMID- 23923251 TI - Colonic schistosomiasis and associated cecal neuroma. AB - Schistosomiasis remains a major health threat in many resource-poor countries and is being seen with increasing frequency in developed countries among immigrants and tourists who have a history of freshwater exposure in endemic areas. We report a case ofa 56-year-old male with no significant past medical history, who presented for a routine screening colonoscopy, which revealed two polyps in the cecum, and multiple petechiae in the rectum. Histologic evaluation showed presence of Schistosoma mansoni eggs. One of the polyps, where eggs were also present, was diagnosed as neuroma/ Schwann cell hamartoma. This is the first reported casewhere colonic schistosomiasis is associatedwith cecal neuroma. PMID- 23923252 TI - A 78-year-old man with rapidly-progressing sarcomatoid renal cell carcinoma. AB - We report a case of metastatic sarcomatoid renal cell carcinoma (SRCC), which presented as nephrotic syndrome with diffuse peripheral edema. At the time of diagnosis, the metastatic disease involved bone, with peritoneal lymphadenopathy. The nephrotic syndrome did not improve after nephrectomy. Systemic disease progressed quickly postoperatively. The sarcomatoid renal cell carcinoma in this case had an aggressive clinical course. CNS metastasis quickly developed, and the patient passed away soon after. PMID- 23923253 TI - Mild therapeutic hypothermia and anoxia due to hanging: case series and review of the literature. PMID- 23923254 TI - Smoking-induced monoclonal B-lymphocytosis in two female smokers: what are the odds? AB - Persistentpolyclonal B-cell lympho-cytosis (PPBL) is awell-known entity, characterized by a persistent lymphocytosis with circulating atypical lymphocytes. Affecting mainly younger females, this condition has been linked with chronic tobacco use. Reports have shown atypical lymphocytes in smoking related B-lymphocytosis to display some genetic and molecular features normally seen only in hematologic malignancies. In addition, a large study has associated chronic lymphocytic leukemia (CLL) with chronic smoking. We describe herein two unique patients with chronic smoking history, persistent neutrophilia and incidentally discovered monoclonal B-lymphocytosis (MBL). The MBL inthe firstpatient was preceded by a PPBL. Clinical scenarios in our patients suggest that the MBL might have been caused by chronic cigarette smoking. We further postulate that tobacco-induced B-lymphocytic proliferation may become neoplastic. PMID- 23923255 TI - Effect of zoledronic acid on bone density and markers of bone turnover in a community clinic. AB - OBJECTIVE: This study aims to document the efficacy of zoledronic acid by comparing bone densities and markers of bone turnover, in patients with osteoporosis. METHODS: Bone mineral density (BMD) and urinary N-telopeptide, a marker of bone turnover, were compared before and after treatment with intravenous zoledronic acid. RESULTS: 52 participants had atleast two doses of zoledronic acid over 36 months. Significant increases in BMD were found in the spine (t=4.38, P<0.01) and decrease in bone turnover marker N-telopeptide (t=3.30, P=0.002). Small but significant correlations were determined between prior steroid use and change in BMD in the spine (r=0.35, P<0.05), and family history of osteoporosis and change in BMD in the right femur (r=0.38, P<0.05). CONCLUSION: Annual infusions of zoledronic acid for at least two years, revealed a significant increase in bone density at the spine and a decrease in urinary N telopeptide in patients treated at our center. PMID- 23923256 TI - Lessons from Benjamin Rush. PMID- 23923257 TI - Clinical medicine: The serotonin story, how science grows. 1963. PMID- 23923258 TI - Beyond the tipping point. PMID- 23923259 TI - Hunting and gathering information. PMID- 23923260 TI - Nuts and bolts. PMID- 23923261 TI - Summer rash. PMID- 23923262 TI - "Pay attack will sink morale and add to staffing crisis". PMID- 23923263 TI - Fresh attack on contract by 2016. PMID- 23923264 TI - Lessons from Francis can reach beyond hospitals, says DH nurse. PMID- 23923265 TI - "Peer support in mental health needs a welcome, not wariness". PMID- 23923266 TI - "It is dangerous to think that ending dehydration is simple". PMID- 23923267 TI - Hydration--the missing part of nutritional care. AB - Dehydration contributes to poor patient outcomes and can lead to avoidable harm. This article analyses incident reports from National Reporting and Learning System (NRLS) relating to hydration and shows that this area of care continues to be frequently neglected. Reasons for this are suggested with recommendations for changing practice to reduce the negative impact this has on patient outcomes. PMID- 23923268 TI - Maintaining hydration in enteral tube feeding. AB - Although recognition of the importance of hydration is increasing, there is little research relating to hydration in enterally fed patients. An online survey found a lack of evidence-based guidance and a need for a greater understanding of this area. PMID- 23923269 TI - Improving the accuracy of BP measurement. PMID- 23923270 TI - A guide for HCAs on safe patient transfers. AB - This article is written predominantly for healthcare assistants. It may also be useful for anyone less familiar with transferring patients or who delegates to HCAs. It offers a definition of patient transfer and addresses considerations for patient safety and the role of HCAs throughout the three distinct phases of transfer, which are: preparation to transfer (before); considerations of transfer (during); and at the point of final handover (actual transfer) in a hospital. It also addresses the role of escorting patients, and highlights the difference between transferring and escorting. Finally, a framework for best practice is suggested, which could be applied in clinical areas where high proportions of patients are transferred, such as emergency departments, discharge lounges and admissions or assessment units. This framework is adaptable and can help in the development of local hospital policies for the safe transfer of patients. The key message of this article is that patient transfer is a process that requires adequate preparation and occurs in distinct phases, each of which must be carried out with proper care and attention if patients are to be transferred safely. PMID- 23923271 TI - Improving recovery with critical care rehabilitation. AB - It is well documented that, following a period of critical illness, patients can suffer complex physical and non-physical complications. This has considerable effects on patients and their families in all aspects of life. This article discusses a service improvement project that led to the development of a critical care rehabilitation pathway, its implementation at Gateshead Healthcare Foundation Trust, and how it is being use to improve patient care, experiences and quality of life. Implementation of the pathway has resulted in 52% reduction in length of hospital stay during ward care. PMID- 23923272 TI - Seamus O'Brien. Interview. PMID- 23923273 TI - New homes for neurology. PMID- 23923274 TI - Leading with compassion. PMID- 23923275 TI - Proceed with caution. I.T. security concerns, a host of other issues have kept mental health data in the shadows. PMID- 23923276 TI - ACO profiles: evolution in motion. Getting all the underpinnings of accountable care to work together is proving to be a multi-faceted challenge. PMID- 23923277 TI - Finding the right consultant. Growing regulatory and HIT pressures have spurred changes in why health care organizations engage consultants. PMID- 23923278 TI - Psyched for change. Interview by Elizabeth Gardner. PMID- 23923279 TI - Building the right skills for the healthcare workforce of the future. PMID- 23923280 TI - Do patients on statins also need niacin? AB - Niacin has been used for years to treat hypercholesterolemia, but may not be as beneficial as thought for patients at high risk of cardiovascular disease. Until further research is done, niacin should be used only in patients who do not tolerate or respond to statin therapy, and never in patients who have achieved goal LDL cholesterol on a statin. PMID- 23923281 TI - A toddler's fever and rash. PMID- 23923282 TI - Lipoprotein abnormalities in patients with type 2 diabetes and metabolic syndrome. AB - Cardiovascular disease remains the leading cause of death in men and women in the United States. Aggressive treatment of insulin resistance and its associated lipid abnormalities remains a top priority for preventing cardiovascular morbidity and mortality. PMID- 23923283 TI - Evaluating the adult with new-onset pleural effusion. AB - PAs play an essential role in recognizing new-onset pleural effusion in adults. This article reviews risk factors, patient assessment, diagnostic testing, initial management, and treatment. PMID- 23923284 TI - Pneumomediastinum from a severe asthma attack. AB - Spontaneous pneumomediastinum is a rare complication of an asthma exacerbation characterized by chest pain, dyspnea, neck swelling, and subcutaneous emphysema. Although the condition is usually benign and treatment is primarily supportive, surgical intervention may be needed if the patient develops hemodynamic or respiratory failure. PMID- 23923285 TI - How to recognize and treat childhood leukemia. AB - Acute leukemia may be difficult to diagnose in children because of the lack of specific findings. The key is to recognize unexplained symptoms and consider leukemia as a differential. Prompt treatment improves outcomes. PMID- 23923286 TI - Seizure disorder. PMID- 23923287 TI - GnRH receptor antagonists for prostate cancer. AB - GnRH receptor antagonists can reduce testosterone levels without the adverse reactions caused by other drugs used to treat prostate cancer. These drugs also offer hope for prolonged control of metastasis. PMID- 23923288 TI - A slow-growing, painful hand mass. PMID- 23923289 TI - Benign rhythm disturbance or ominous marker? PMID- 23923290 TI - Acute rhinosinusitis: new guidelines for diagnosis and treatment. AB - New treatment guidelines for acute rhinosinusitis outline when antibiotic therapy is appropriate, as well as describe evidence-based treatment to relieve symptoms, prevent complications, and prevent chronic disease. PMID- 23923291 TI - Fathoming the unfathomable. PMID- 23923293 TI - [Meat free diet increases longevity in men]. PMID- 23923292 TI - [Is it caused by the medication? Sweet syndrome]. PMID- 23923294 TI - [Does the person grow with his responsibilities, and if yes, where?]. PMID- 23923295 TI - [General practice charges: now there will be four fateful quarters]. PMID- 23923296 TI - [Calculating service charges for foreign patients]. PMID- 23923297 TI - [Rapid decision in special situations]. PMID- 23923298 TI - [How children of divorce suffer - and what strengthens them (interview by Dr. Elke Oberhofer)]. PMID- 23923299 TI - [How to discontinue steroid medication]. PMID- 23923300 TI - [Naturopathy consultation. Can nature help when the ears are ringing?]. PMID- 23923301 TI - [However, the sparrow moulted into a hummingbird]. PMID- 23923302 TI - [Pain free at the end of life]. PMID- 23923303 TI - [Can they be prevented?]. PMID- 23923304 TI - [Caffeine protects against accidents during long automobile trips]. PMID- 23923305 TI - [Low sexual transmission of HCV]. PMID- 23923306 TI - [How well do Z-substances help in insomnia?]. PMID- 23923307 TI - [HP eradication prevents recurrent hemorrhages caused by acetylsalicylic acid]. PMID- 23923308 TI - [Non-resorbable antibiotic improves prognosis in liver cirrhosis]. PMID- 23923309 TI - [Problematic: analgesics before the marathon]. PMID- 23923310 TI - [A singular live show]. PMID- 23923311 TI - [Compass in a sea of diagnostic uncertainty]. PMID- 23923312 TI - [Chest pain in general practice]. PMID- 23923313 TI - ["Since antibiotic therapy I suffer from chronic diarrhea"]. PMID- 23923314 TI - ["I sleep enough but I am still tired"]. PMID- 23923315 TI - [Heartburn and belching]. PMID- 23923316 TI - [Sexual problems in men]. PMID- 23923317 TI - [Diverticulitis: stage-dependent therapy]. PMID- 23923318 TI - [Stage adjusted therapy of burn injuries]. PMID- 23923319 TI - [Labile hypertension, borderline hypertension--a reappraisal]. PMID- 23923320 TI - [Non-selective NSAIDs and coxibs: what are myths, what are facts?]. PMID- 23923321 TI - [Thyroid diseases with perspectives]. PMID- 23923322 TI - May you live in interesting times. PMID- 23923323 TI - Annotated checklist of the mosquitoes of the Republic of Moldova. AB - The mosquito fauna of the Republic of Moldova is poorly known. In an effort to understand the Culicidae fauna better, mosquito collections have been conducted between early April and middle November from 2008 to 2012. A total of 10,923 larval specimens and 8,246 adults were collected from 20 regions of Moldova. Altogether 36 species have been recorded during the recent study, bringing the total Moldovan mosquito fauna to 40 species in 9 genera and 11 subgenera. New state records include the following 7 species: Anopheles pseudopictus, An. melanoon, Aedes geminus, Culex torrentium, Culiseta longiareolata, Coquillettidia buxtoni, and Uranotaenia unguiculata. PMID- 23923324 TI - Evaluation of methods for collecting blood-engorged mosquitoes from habitats within a wildlife refuge. AB - Mortality of American white pelican (Pelecanus erythrorhynchos) chicks attributed to West Nile virus (WNV) prompted field studies on the bionomics of mosquitoes on a wildlife refuge in northern Montana. One component of these studies was to identify blood meal sources for Culex tarsalis, the primary vector of WNV in the region, and the potential bridge vectors Aedes vexans and Culiseta inornata. To accomplish this, 3 methods were evaluated to collect bloodfed mosquitoes: a gasoline powered aspirator, CO2-baited light traps, and fiber pots in shelterbelts consisting of stands of deciduous trees and shrubs and marshes along the lake edge. Fiber pots were also deployed in open fields of prairie grasses. Overall, fiber pots were the most efficient method for collecting engorged Cx. tarsalis and Cs. inornata, largely due to shorter sampling and processing times. Aedes vexans was not collected in fiber pots but was more abundant in aspiration samples than the other 2 species. The optimal location for collecting Cx. tarsalis was dependent on trapping method. Aspirations and fiber pot placements collected more Cx. tarsalis in shelterbelts, while CO2-baited light traps collected more Cx. tarsalis in the marsh habitat. Sixteen avian and 4 mammalian hosts were identified from bloodfed Cx. tarsalis with 46 blood meals derived from birds and 49 from mammals. Aedes vexans and Cs. inornata fed predominantly on white-tailed deer (Odocoileus virginianus) and cattle (Bos taurus), respectively. Humans were identified as hosts in 33% of engorged Cx. tarsalis, 4% of engorged Ae. vexans, and 18% of engorged Cs. inornata. PMID- 23923325 TI - West Nile virus infection rates and avian serology in east-central Illinois. AB - Understanding the geographic role of different species of mosquito vectors and vertebrate hosts in West Nile virus (WNV) transmission cycles can facilitate the development and implementation of targeted surveillance and control measures. This study examined the relationship between WNV-antibody rates in birds and mosquito infection rates and bloodfeeding patterns in east-central Illinois. The earliest detection of WNV-RNA by reverse transcription-polymerase chain reaction TaqMan was from Culex restuans; however, amplification typically coincided with an increase in abundance of Cx. pipiens. Trap type influenced annual estimates of infection rates in Culex species, as well as estimation of blood meal source. Bird species with the highest WNV-antibody rates (i.e., Mourning Doves [Zenaida macroura], Northern Cardinals [Cardinalis cardinalis], American Robins [Turdus migratorius], and House Sparrows [Passer domesticus]) were also the common species found in Culex blood meals. Although antibody rates were not directly proportional to estimated avian abundance, the apparent availability of mammal species did influence proportion of mammal to bird blood meals. Antibody prevalence in the American Robin was lower than expected based on the strong attraction of Culex to American Robins for blood meals. Age-related differences in serology were evident, antibody rates increased in older groups of robins and sparrows, whereas 1st-year hatch and older adults of Mourning Doves and Northern Cardinals had equally high rates of antibody-positive serum samples. The vector and host interactions observed in east-central Illinois (Champaign County), an urban area surrounded by agriculture, are compared to studies in the densely population areas of southern Cook County. PMID- 23923326 TI - West Nile virus outbreak in Phoenix, Arizona--2010: entomological observations and epidemiological correlations. AB - In 2010, Arizona experienced an unusually early and severe outbreak of West Nile virus (WNV) centered in the southeast section of Maricopa County. Entomological data were collected before and during the outbreak, from May 25 through July 31, 2010, using the CO2-baited light trap monitoring system maintained by Maricopa County Vector Control. In the outbreak area, the most abundant species in the Town of Gilbert and in the area covered by the Roosevelt Water Conservation District was Culex quinquefasciatus, constituting 75.1% and 71.8% of the total number of mosquitoes collected, respectively. Vector index (VI) profiles showed that the abundance of infected Cx. quinquefasciatus peaked prior to human cases, suggesting that this species was involved in the initiation of the outbreak. In contrast, the VI profiles for Cx. tarsalis were consistently low, suggesting limited involvement in initiating and sustaining transmission. Taken together, the higher abundance and the VI profiles strongly suggest that Cx. quinquefasciatus was the primary vector for this outbreak. The VI profiles consistently showed that the abundance of infected mosquitoes peaked 1 to 2 wk before the peaks of human cases, suggesting that VI could have successfully been utilized to predict the WNV outbreak in Maricopa County, AZ, in 2010. PMID- 23923327 TI - Potential for populations of Aedes j. japonicus to transmit Rift Valley fever virus in the USA. AB - Aedes japonicus japonicus was introduced into the northeastern USA in 1998 and has since spread to more than 25 states. Because this species has been shown to be a competent laboratory vector of several viruses, readily feeds on large mammals, and has become a pest in several areas, there is concern that it might serve as a vector of Rift Valley fever virus (RVFV) should that virus be introduced into North America. Infection with RVFV causes mortality in > 90% of young domestic ungulates (e.g., calves, kids, and lambs), as well as causing a febrile illness and occasional deaths in humans. Therefore, we evaluated Ae. j. japonicus captured in North Carolina and in Maryland for their ability to serve as potential vectors for RVFV. After feeding on infected adult hamsters, these mosquitoes were tested for infection, dissemination, and the ability to transmit RVFV after incubation at 26 degrees C for 7-28 days. Both the Maryland and North Carolina populations of Ae. j. japonicus were highly efficient laboratory vectors of RVFV, with infection rates > 90% and dissemination rates > 84% for those mosquitoes that fed on hamsters with viremias > or = 10(8.5) plaque-forming units/ml. Thus, Ae. j. japonicus should be targeted for immediate control should RVFV be introduced into an area where this mosquito is now present. PMID- 23923328 TI - Comparison between diflubenzuron and a Bacillus thuringiensis israelensis- and Lysinibacillus sphaericus-based formulation for the control of mosquito larvae in urban catch basins in Switzerland. AB - A field test was conducted to evaluate a commercial biolarvicide based on Bacillus thuringiensis var. israelensis and Lysinibacillus sphaericus to control mosquitoes breeding in catch basins in southern Switzerland. The efficacy and residual activity of the microbial mosquito larvicide applied at the recommended rate of 10 g per catch basin was compared to the currently used larvicide diflubenzuron. Both products provided a very good control activity (> 97% of reduction) of late instars (3rd and 4th instars) and pupae for 4 wk. However, only the microbial formulation controlled immature stages during the whole period of the trial, with > 98% of larval reduction. A single application of the microbial larvicide applied at 10 g per catch basin significantly reduced the number of immature mosquitoes for at least 70 days. The quantity of rainfall in the 48-h period before each sampling and the water temperature did not influence the efficacy of the treatments. Under the environmental conditions encountered in southern Switzerland, the larvicide tested may be a valid alternative to diflubenzuron to control mosquitoes in urban catch basins. The long-lasting control by the microbial larvicide further reduces the number of treatments required to keep the population of mosquitoes at low levels. PMID- 23923329 TI - Evaluation of mosquito responses to pyrethroid insecticides topically applied to sheep. AB - A rise in the incidence of mosquito-transmitted Cache Valley virus (CVV) in lambs in 2011 prompted a study to evaluate on-animal pyrethroid insecticides to reduce mosquito attacks on sheep. Using enclosure traps for 1 night per wk for 6 wk, we compared engorgement rates of mosquitoes given the opportunity to feed on untreated sheep and sheep treated with 1 Python insecticide ear tag (containing 10% zeta-cypermethrin and 20% piperonyl butoxide) per animal or 2 synergized permethrin body spray treatments (containing 2.5% permethrin and 2.5% piperonyl butoxide). During the 6-wk study, 18,920 mosquitoes were collected in the animal baited enclosure traps. Thirteen species were identified from these collections with the floodwater species Aedes increpitus and Ae. idahoensis making up 68% of the total. Potential CVV vector species, making up 25% of the samples, included Ae. vexans, Ae. dorsalis, Culex tarsalis, and Culiseta inornata. Traps baited with untreated sheep collected 9,701 mosquitoes with 65% of these engorged. Traps baited with sheep treated with Python ear tags or permethrin spray collected 4,034 and 4,555, respectively, with engorgement rates of 23% and 35%. Blood feeding on ear-tagged sheep was significantly reduced by as much as 90% compared to the untreated sheep, and protection lasted 4 wk or longer. Permethrin spray treatments were most effective within 24 h after application and provided better protection against Ae. dorsalis than the Python tag. Effectiveness of the permethrin spray diminished 1 wk after the 2nd application was made. The effect of these treatments appeared to be repellency because negligible mosquito mortality was observed at the time of collection. Further evaluation of these insecticides under conditions of natural exposure to a mosquito-borne pathogen is warranted. PMID- 23923330 TI - History of Aedes mosquitoes in Hawaii. AB - As a geographically isolated island chain with no native mosquitoes, Hawaii is a model for examining the mechanisms behind insect vector invasions and their subsequent interactions with each other and with human populations. The yellow fever mosquito, Aedes aegypti, and the Asian tiger mosquito, Ae. albopictus, have been responsible for epidemics of dengue in Hawaii. As one of the world's earliest locations to be invaded by both species, Hawaii's history is particularly relevant because both species are currently invading new areas worldwide and are implicated in outbreaks of emergent or reemergent pathogens such as dengue, chikungunya, and yellow fever. Here we analyze the historical records of mosquito introductions in order to understand the factors that have led to the current distribution of these 2 mosquitoes in the Hawaiian Islands. PMID- 23923331 TI - An assessment of the importance of subsurface catch basins for Aedes aegypti adult production during the dry season in a neighborhood of Merida, Mexico. AB - We compared the number of adult Aedes aegypti emerging from subsurface catch basins located in the streets against the number of pupae (as a proxy of adults emerging) from the entire container larval habitats found at residential premises within 1 ha of a neighborhood in the Mexican city of Merida during 8 days in the dry season of 2012. Aedes aegypti adults were collected from 60% of the subsurface catch basins. They produced 12 adults/day/ha (95% confidence interval [CI], 6.4 to 17.9), 5 females (95% CI, 2.1 to 7.7), and 7 males (95% CI, 3.8 to 10.7). In contrast, only 7 containers holding water were identified in 30 premises inspected, 1 bucket was positive for Ae. aegypti larvae, but no pupae positive containers were found. No other mosquito species were found. This study revealed the importance of this type of nonresidential and subterranean aquatic habitat for Ae. aegypti adult production in this neighborhood of Merida during the dry season. PMID- 23923332 TI - Predatory efficacy of Culex (Lutzia) fuscanus on mosquito vectors of human diseases in Sri Lanka. AB - Larvae of Culex (Lutzia) Fuscanus were collected from ovitraps in a natural breeding site. Collected larvae were used to establish a self-mating colony, and larval progeny were then used to determine their predatory efficacy on larvae of 3 vector mosquito species, Aedes aegypti, Anopheles subpictus, and Cx. tritaeniorhynchus. Statistical analysis revealed that Cx. fuscanus showed greater feeding efficacy for Ae. aegypti than for Cx. tritaeniorhynchus and An. subpictus. The natural predatory role of this species can potentially be exploited for biological control of mosquito vectors in Sri Lanka. PMID- 23923333 TI - An evaluation of the larvicidal effects of ORIGIN 3-6-9. AB - The effect of ORIGIN 3-6-9, a combination of fatty acids and amino acids derived from castor beans, was evaluated against Aedes albopictus larvae in water containing varying concentrations of this compound. At rates above 50 ppm, it caused 100% mortality, whereas at 5 ppm or less, larval mortality was not significantly different from that of the control. Tests repeated at 7, 14, and 28 days posttreatment demonstrated no reduction in effectiveness against the test species. PMID- 23923334 TI - Droplet sampling of an oil-based and two water-based antievaporant ultra-low volume insecticide formulations using Teflon- and magnesium oxide-coated slides. AB - We estimated the diameters below which 50% and 90% of the volume of droplets exist (Dv50 and Dv90, respectively) of 1 oil-based (Permanone 30-30) and 2 water based (AquaReslin, Aqua-K-Othrine) antievaporant aerosols (with the Film Forming Aqueous Spray Technology [FFAST]) using Teflon- and magnesium oxide (MgO)-coated slides and determined whether the aging of the droplets on the slides (up to 60 min) exhibited any significant effect on Dv50 and Dv90 calculations. There were no significant differences in either Dv50 or Dv90 estimates on MgO-coated slides at 0 min and 60 min for all 3 products tested. On Teflon-coated slides, the only product that showed significant difference between 0 min and 60 min in both Dv50 and Dv90 estimates was Aqua-K-Othrine, perhaps due to a difference in formulation components. Specifically, both values corresponding to Dv50 and Dv90 at 60 min decreased by approximately 50% when compared to the values at 0 min. For the other 2 products, AquaReslin and Permanone, aging of droplets on Teflon up to 60 min did not have any significant effect on Dv50 and Dv90 values. To further investigate the behavior of Aqua-K-Othrine droplets on Teflon-coated slides we observed the droplets immediately after spraying and at 10-min intervals under different conditions of temperature and humidity. The majority of the shrinkage occurred within the 1st 10 min after impaction on the slides under all conditions tested. So in most field situations where slides are read several hours or days after collection, this shrinkage would not be observed. The MgO-coated slides should be the preferred field method for sampling droplets of Aqua-K-Othirne with the FFAST antievaporant technology. PMID- 23923335 TI - Experiences with the large-scale operation of the Biogents Sentinel trap. AB - We obtained 160 Biogents Sentinel traps (BGS-traps) to monitor adult mosquito populations for the Area-wide Pest Management Program for the Asian tiger mosquito (Aedes albopictus) in New Jersey. We deployed between 90 and 110 BGS traps weekly from May through October of 2008, 2009, 2010. and 2011. Here we detail our experience: challenges with acquisition, defects in construction, as well as actions taken to correct problems we found and preempt them in the future. Further, we describe the impact of these problems on our research and provide a cost analysis of repairs. PMID- 23923336 TI - 2013 AMCA Memorial Lecture honoree: Thomas Desmond Mulhern 1908-1993 Tommy Mulhern and the lost crusade. PMID- 23923337 TI - [The properties of simple medicines according to Avicenna (980-1037): analysis of some sections of the Canon]. AB - Avicenna spoke on pharmacology in several works, and this article considers his discussions in the Canon, a vast synthesis of the greco-arabian medicine of his time. More precisely, it focuses on book II, which treats simple medicines. This text makes evident that the Persian physician's central preoccupation was the efficacy of the treatment, since it concentrates on the properties of medicines. In this context, the article examines their different classifications and related topics, such as the notion of temperament, central to Avicenna's thought, and the concrete effects medicines have on the body. Yet, these theoretical notions only have sense in practical application. For Avicenna, medicine is both a theoretical and a practical science. For this reason, the second book of the Canon ends with an imposing pharmacopoeia, where the properties described theoretically at the beginning of the book appear in the list of simple medicines, so that the physician can select them according to the intended treatment's goals. The article analyzes a plant from this pharmacopoeia as an example of this practical application, making evident the logic Avicenna uses in detailing the different properties of each simple medicine. PMID- 23923338 TI - [Priest-doctors in Russia]. AB - Jean Pierre Frank offers in the early nineteenth century a revolution in medical Russian Empire. Indeed, Russia is in an emergency situation where the lack of practitioners is obvious. The imperial project is inspired by past practices in some European countries. Frank fits these transfers and implements a unique model where the priest-doctor stands out as the solution to overcome the lack of medicalization of the Empire. Even if the attempt was a failure, it remains that the proposals were part of Frank in both an ancient tradition that priests and physicians providing care for souls and bodies, but also showed that called his wishes the advent of "public health" in this country disinherited. PMID- 23923339 TI - [Health and salvation: the Mazdaznan-movement in the context of its beginnings]. AB - There are diverse religious groups which have developed special forms of "methodical lifestyle" (Max Weber). Projects of life reform and new religious movements around 1900 brought up specific ways of living and influenced one another in respect to ideas and practices. Using the example of the Mazdaznan Movement some forms of interdependencies will be demonstrated. Since the group formed in the U.S.A. at the turn of the 20th century I will try to contextualize its central practices such as vegetarianism, intestinal care and breathing exercises within the specific context of American cultural and religious history. PMID- 23923340 TI - [From South Tyrol to Wurttemberg: the "resettlement" of South Tyrolean psychiatric patients within the Germano-Italian Option Agreement of 1939]. AB - Object of this article is the procedure of the transport of South Tyrol patients to the South Wuerttemberg asylums Zwiefalten und Schussenried as well as to some extent to the former asylum of Weissenau near Ravensburg in 1940 and 1942. Attention is focused on the pioneering state pre-negotiations, the so-called option treaties between the German Reich and Fascist Italy as part of the general aspect of National Socialist bio-Politics.The treatment of these South Tyrol patients in the asylums themselves, as well as their fate will be put into the context of the resettlement actions at the margins of the "Third Reich", which started in 1939 and widely affected the European continent. By presenting the abuse of medical patients in the aim to solve the political problems having occurred after bio-political goals had been set into practice, this study offers new material to the history of National Socialist psychiatry, as well as to National Socialist Foreign Policy in the case of Italy. PMID- 23923342 TI - How a nurse experienced being nursed in a day treatment center. PMID- 23923341 TI - [The "shoeleather epidemiology" or the reinvention of medical survey. Alice Hamilton and industrial medicine in early 20th century America]. AB - Dr. Alice Hamilton (1869-1970) was a pioneer in industrial medicine, a new discipline that emerged with a new interest in working conditions and occupational hazards within an era of unprecedented industrial growth. From various sources, including her reports after she visited Arizona copper belt in 1919, my paper emphasizes the innovation of Hamilton's approach,"shoeleather epidemiology". She went to the source of information in workshops, plants and construction sites, observed the very concrete part of industrial work, interviewed many stakeholders in and around the workplace, making a methodological toolbox for industrial surveys. Her method combined an old medical practice (the medical inquiry) and a new clinical field (the plant) and placed the worker as a patient in the core of the issue of occupational health and safety. PMID- 23923343 TI - Fitting square theories into round projects. PMID- 23923344 TI - The development and testing of the nurses' cardiac triage instrument. AB - Rapid recognition and treatment of myocardial infarction (MI) reduces morbidity and mortality. Although emergency department (ED) nurses are often the first provider to evaluate individuals and are in a prime position to initiate MI guideline recommendations, no valid and reliable instrument was found to quantify their decision-making processes. The purpose of this study was to develop and test the psychometric properties of a new theoretically driven, empirically based instrument for measuring nurses' cardiac triage decisions. Using a descriptive research design, data were collected using a mailed survey. There were 158 ED nurses who completed a mailed questionnaire. Factor analysis revealed three factors (patient presentation, unbiased nurse reasoning process, and nurse action) with good internal consistency (Cronbach's alpha = .903, .809, .718) and sample adequacy (KMO = .758) of the 30-item instrument. The newly developed instrument has the potential to improve patient outcomes surrounding early MI identification and treatment. PMID- 23923345 TI - Nursing staff's understanding expressions of people with advanced dementia disease. AB - People with advanced dementia disease (ADD) are known to have communication difficulties and thus it presents a challenge in understanding the expressions of these people. Because successful communication presupposes cooperation at least between 2 individuals, both individual's actions must be acknowledged. The aim of this study is to describe nursing staff's ways of understanding the expressions of people with ADD when communicating with them. Interviews from 8 nursing staff were analyzed using qualitative content analysis. Two themes were constructed: "Being in communication" and "Doing communication." Being in communication means that nursing staff perceive people with ADD as being capable of communication. Doing communication means that nursing staff attempt different individualized strategies to understand what people with ADD communicate. Good care of people with ADD presupposes nursing staff that are willing and able to relate to other people and to maintain good care for people with ADD continuous education and supervision are needed. PMID- 23923346 TI - Postpartum weight self-management: a concept analysis. AB - AIM: The aim of this concept analysis is to create a clear definition and framework to guide weight self-management research and promotion of healthy weight self-management during the postpartum period. BACKGROUND: A woman's ability to manage her weight through the postpartum transition has lifelong implications for her weight status. METHODS: This concept analysis was guided by Walker and Avant (2005). A broad search of sources was performed, yielding 56 articles in which postpartum weight self-management was the main focus. RESULTS: From consideration of the attributes of postpartum weight self-management, a descriptive, situation-specific theory emerged: Postpartum weight self-management is a process by which the transition to motherhood is viewed by the woman as an opportunity to intentionally engage in healthy weight self-management behaviors by minimizing the salient inhibitors and maximizing the salient facilitators to action. CONCLUSION: This analysis provides a clarification of the process concept of postpartum weight self-management and its consequences, giving direction for measurement, clinical application, and further research. Future nursing interventions and research should be aimed at helping women to view the postpartum period as a normative transition in which they have the opportunity to take charge of their own health and the health of their family. PMID- 23923347 TI - Physical activity interventions among older adults: a literature review. AB - Physical activity (PA) is important in the management of chronic illness among older adults worldwide. Researchers have conducted several intervention studies to increase PA behavior in this population. This review of the past 12 years of relevant PA intervention research among adults aged 60 years and older systematically summarized research findings, identified characteristics of successful interventions, and proposed areas of future research. There were 20 studies reviewed for this article, most employing a combination of cognitive behavioral intervention design. Cognitive-based only and combination interventions were more successful in changing PA behavior; however, behavioral based interventions demonstrated more long-term changes in PA behavior. Among theory-based interventions, self-efficacy was the most commonly operationalized construct. Findings from this review may inform future primary research to promote PA behavior among older adults, as well as gerontological clinical practice. PMID- 23923348 TI - Is diarrhea-predominant irritable bowel syndrome a low-grade gut inflammatory disorder? PMID- 23923349 TI - Occult hepatitis B: the Egyptian situation. AB - Occult hepatitis B infection is defined as the presence of HBV DNA in serum and/or the liver tissue without detectable HBsAg with or without anti-HBc or anti HBs antibodies. In Egypt many studies on occult hepatitis B have been conducted and this infection is well established in various patients groups. This short review sheds light on the occurrence of occult hepatitis B infection among different disease states in Egypt. The coexistence of occult hepatitis B with hepatitis C infection is of particular importance because of its added co morbidity of liver enzymes elevation, increased severity of liver disease and increased risk of hepatocellular carcinoma. Patients on regular hemodialysis and those exposed to blood transfusion are at high risk of acquiring this form of infection. The highest prevalence of occult hepatitis B virus in Egypt was reported among patients with hepatocellular carcinoma and similar to the scenario for classic hepatitis B infection, genotype D is the most prevalent genotype. PMID- 23923350 TI - Pro-inflammatory and anti-inflammatory cytokine response in diarrhoea-predominant irritable bowel syndrome patients. AB - BACKGROUND AND AIM: Irritable bowel syndrome (IBS) is referred to as a functional bowel disorder which is diagnosed by a number of characteristic symptoms (Rome II criteria) in the absence of detectable structural abnormalities. Low-grade inflammation of the intestine may be one of the reasons for development of diarrhoea-predominant IBS (IBS-D). We undertook this study to estimate the serum levels of pro-inflammatory (IL-6, TNF-alpha) and anti-inflammatory (IL-10) cytokines in IBS-D patients. METHODS: A total of 108 diarrhoea patients were screened. Out of these only 63 adult IBS-D patients were enrolled. Age and sex matched 62 apparently healthy controls with no GI symptoms were also recruited. Out of 63 IBS-D patients, 37 were males while there were 32 males among the controls. The patients with IBS-D were diagnosed according to the Rome II criteria. Levels of serum IL-6, TNF-alpha and IL-10 were measured in all subjects using ELISA. RESULTS: Mean (+/- SD) age of IBS-D patients (42.6 +/- 19.5 years) was comparable (p = 0.64) to that of controls (43.5 +/- 18.7 years). The mean (+/ SD) levels of IL-6 in IBS-D patients (32.2 +/- 12.01 pg/ml) was significantly higher (p < 0.001) than in controls (7.48 +/- 2.55 pg/ml). The levels of TNF alpha in IBS-D patients (16.3 +/- 5.2 pg/ml) were also significantly higher (p < 0.05) than in controls (7.94 +/- 2.19 pg/ml). There was no significant difference in the serum levels of IL-10 (p = 0.23) between IBS-D patients (5.75 +/- 2.1 pg/ml) and controls (5.84 +/- 1.9 pg/ml). CONCLUSION: Our results indicate that mild inflammation is involved in IBS-D patients as proinflammatory cytokines were increased although no difference in anti-inflammatory cytokine was observed. PMID- 23923351 TI - Nutritional status and prognosis in cirrhotic patients. AB - BACKGROUND AND AIMS: Malnutrition is commonly associated with chronic liver disease. The presence of protein-calorie malnutrition has been shown to be associated with increased short- and long-term mortality in patients with acute and chronic liver disease. We undertook this study to assess the prognostic value of nutritional status in predicting survival in cirrhotic patients. The aim of our study was to determine whether assessment of nutritional status using the RFH SGA score adds significantly to CP (Child-Pugh) and MELD scores in predicting patient prognosis and survival in cirrhotic patients. METHODS: Diagnosed cases of cirrhosis were enrolled and their nutritional assessment was done using the RFH SGA score. All patients were followed up for a period of 6 months. The mortality rates in the various groups were compared with respect to their nutritional status. Multivariate analysis was used to determine the factors associated with mortality. RESULTS: A total of 73 cirrhotic patients were taken up for this study. Of these, 23 patients (31.5%) were well nourished, 21 (28.8%) had mild to moderate malnourishment and 29 (39.7%) were severely malnourished. Multivariate analyses of various parameters identified poor nutritional status, increased CP grade, increased creatinine, lower sodium levels and longer prothrombin time as being independently associated with poorer survival. CONCLUSIONS: RFH-SGA is a simple and inexpensive tool for assessing the nutritional status in cirrhotic patients and can reliably predict their disease prognosis and survival. PMID- 23923352 TI - Role of histopathological examination in nontraumatic perforation of colon. AB - AIM: Nontraumatic perforation of colon is an uncommon cause of peritonitis requiring early surgical intervention. This study was carried out to determine the prevalence patterns of the different etiologies of nontraumatic perforation of colon. METHODS AND RESULTS: A total of 35 patients with segments of colon or perforation margins removed for perforation were included. Most of the perforations occurred in the caecum, of which two were seen at the ileocaecal junction. The commonest cause was infection (amoebiasis: 13 cases and tuberculosis: 5 cases) followed by ulcers of non specific ulcers (12 cases). There were three cases of adenocarcinoma causing secondary perforation and one case of idiopathic intestinal gangrene and volvulus each. CONCLUSION: In tropics, non traumatic perforations of colon most often involves caecal and ileocaecal segment and the most common etiology is amoebiasis. PMID- 23923353 TI - Evaluation of previous abdominal pain episodes in women with biliary pancreatitis: possible higher incidence of recurrent attacks. AB - BACKGROUND AND AIM: Recurrent biliary pancreatitis is described as episodes of new abdominal pain after diagnosis of pancreatitis. Few studies have analyzed the abdominal pain before the diagnosis of acute pancreatitis. Our study aimed to analyze factors associated with previous abdominal pain episodes in patients with biliary pancreatitis, and elucidate its possible pancreatic origin. METHODS: Data from direct interrogation and medical records was analyzed from 48 hospitalized female patients with diagnosis of acute biliary pancreatitis. RESULTS: Mean age of our patients was 31.6 years (SD +/- 13.9). Forty one (85.4%) patients gave history of at least one previous abdominal pain episode. During the episode 37 (90.2%) patients received H2 receptor antagonist or proton pump inhibitors as treatment; 26 (63.4%) had epigastric pain; 23(56.1%) gave association with cholecystokinetic food; 21 (51.2%) complained of nausea and/or vomiting; 23 (56.1%) had jaundice, acholia and/or dark urine; and 20 (48.9%) patients had microlithiasis and/or biliary sludge. CONCLUSIONS: Previous abdominal pain episodes had similar characteristics to a pancreatic episode in a high percentage of our patients. These characteristics suggest that these episodes are often undiagnosed pancreatic attacks. PMID- 23923354 TI - Community acquired secondary bacterial peritonitis in a tertiary hospital of South India: an audit with special reference to peritoneal fluid culture. AB - BACKGROUND: This study was conducted to elucidate the spectrum of community acquired acute bacterial peritonitis, the role of microbiological culture in its management and other factors affecting its outcome. METHODS: This was a prospective study wherein we examined cases of secondary bacterial peritonitis admitted and operated at our institution from January 2005 to May 2006. The peritoneal fluid was sent for bacterial culture and sensitivity testing. Patients were followed up with relevant progress details till discharge or death. RESULTS: We enrolled 352 patients. The mean age of the study population was 42.4 years with a male:female ratio of 7:1. Gastroduodenal perforations formed the major site of perforation (51%), followed by small bowel (29%) and appendicular perforations (17%). Culture positivity rate was 64%. Escherichia coli and Klebsiella species were the predominant isolates from peritoneal fluid. These main isolates were predominantly sensitive to ceftazidime, amikacin and chloramphenicol. Ampicillin with gentamicin and metronidazole was the first line of treatment used preoperatively in 67% of the patients, given its low cost and easier availability. The overall morbidity and mortality rates were 52% and 16.5% respectively. 78% of patients received inadequate antibiotics preoperatively. Only 26% had appropriate change of antibiotics postoperatively. CONCLUSIONS: There was no significant benefit of postoperative change of antibiotics based on culture results. Analysis of factors influencing mortality shows dominance of host related factors over the type and source of infection with high risk population identified by age > 60 years, delayed presentations > 3 days and APACHE II score > 15. PMID- 23923355 TI - Uneventful passage of long pointed foreign body after accidental ingestion: report of two unusual cases. PMID- 23923356 TI - Congenital short pancreas. PMID- 23923357 TI - Multiple gastrointestinal and extragastrointestinal stromal tumors in a male infant--an extreme rarity. PMID- 23923358 TI - Spleen preserving distal pancreatectomy for a large papillary cystic and solid tumor of the pancreas. PMID- 23923360 TI - Congenital esophagobronchial fistula in an adult. PMID- 23923359 TI - Asymptomatic heterotopic pancreas in the mesentery. PMID- 23923361 TI - Invasive pulmonary aspergillosis in a young man with Crohn's disease. PMID- 23923362 TI - Endoscopic diagnosis of a case of malignant melanoma. PMID- 23923363 TI - Inflammatory myofibroblastic tumor of gall bladder. PMID- 23923364 TI - Carpet villous adenoma of the rectum in an incarcerated rectal prolapse. PMID- 23923365 TI - Chemical cauterisation of bleeding spiders. PMID- 23923366 TI - Insulin resistance and "lipotoxic liver diseases". PMID- 23923367 TI - Upper GI bleeding - has mortality changed with advancements in therapy? PMID- 23923368 TI - Difficult to treat spontaneous bacterial peritonitis. AB - Spontaneous bacterial peritonitis (SBP) is the most frequent infection in patients with cirrhosis. It is associated with high mortality at admission and its occurrence alters the natural course with a high 1 year mortality. Presence of > 250 polymorphonuclear cell (PMN)/mm3 in the India ascitic fluid is diagnostic of SBP. SBP is usually treated with IV antibiotics using third generation cephalosporins and fluoroquinolones. However, despite effective initial treatment subsequent recurrence of SBP with its accompanying mortality has resulted in use of long term antibiotic prophylaxis and such patients are recommended for liver transplant. An increased frequency of multidrug resistant bacterial SBP has recently been recognised with use of prophylaxis and is associated with enhanced mortality. Further, cirrhotics get repeated hospitalisation and ICU care leading to nosocomial infection causing SBP. Therefore, frequency of multidrug resistant bacteria induced SBP among the above settings has increased and the relative risk (RR) of mortality with bacterial resistance has been estimated to be 4 times higher than in patients with SBP without bacterial resistance. Therapeutic approach in such patients at present is a clinical challenge and they are difficult to treat patients. Therefore, SBP can be categorized into community acquired and nosocomial! multidrug resistant SBP. PMID- 23923369 TI - Spectrum of upper gastrointestinal hemorrhage in coastal Odisha. AB - INTRODUCTION: Upper gastrointestinal bleeding (UGIB) is one of the commonest gastrointestinal emergencies encountered by physicians and surgeons. The spectrum of upper gastrointestinal bleeding varies from region to region and depends on the status of the center in healthcare hierarchy. AIM: To determine the etiology of UGIB at a gastroenterology clinic in coastal Orissa and to compare it with other regions of India. METHODS: Six hundred and eight consecutive patients with UGIB reporting to a gastroenterology outpatient clinic were subjected to upper gastrointestinal endoscopy (UGIE) to find out the etiology. The clinical profile and endoscopic findings were analyzed and compared with the data on UGIB from other regions of the country. RESULTS: The mean age of patients was 42+/-18.2 years. Majority of them were males (85.53%) and male: female ratio was 6:1. The commonest cause of UGIB was duodenal ulcer (DU) which accounted for 57.57% cases. Portal hypertension was responsible for bleed in only 12.83%. Benign prepyloric ulcer accounted for 6.41% cases and concomitant duodenal ulcer and benign pyloric ulcer were seen in 3.61%. Gastric ulcer was responsible for 1.8% only. Neoplasm accounted for 7.73% of cases. Other less common causes were erosive gastritis (1.8%), Mallory Weiss tear (1.8%), and retch gastropathy (1.1%). Non steroidal anti inflammatory (NSAID) ingestion was reported in 7.56% of cases. Melena was the commonest mode of presentation. Surprisingly, over two third cases of DU bleeds were not associated with abdominal pain. CONCLUSIONS: Bleeding duodenal ulcer was the commonest cause of UGIB in coastal Odisha. This is in contrast to reports from other parts of India, where variceal bleeding is the predominant etiology. The differences could be due to the reason that the studies which have portrayed variceal bleeding as the commonest cause of UGIB reflect the etiology of bleed of only severe cases which were referred to these centers - all of whom needed urgent hospitalization. The figures from our study are true reflection of the real etiological spectrum of UGIB in this region. PMID- 23923370 TI - Insulin resistance and metabolic syndrome in nonobese Indian patients with non alcoholic fatty liver disease. AB - BACKGROUND: Insulin resistance has been recognized as a major factor in the development of non-alcoholic fatty liver disease (NAFLD). The association between insulin resistance and NAFLD, as a risk factor independent of obesity has been less well established. This study aims to determine presence of insulin resistance and components of metabolic syndrome in non-obese patients with NAFLD. METHODS: 150 patients (mean age 42.25 _ 10.50 y; 115 (76%) male, 35 (24%) female) diagnosed with NAFLD participated in the study. We measured body mass index (BMI), waist circumference (WC), waist hip ratio (WHR), fasting lipid profile, fasting glucose, fasting insulin, and liver function. Insulin resistance was calculated using the homeostasis model of assessment (HOMA) formula. Insulin resistance was arbitrarily considered altered when it was >1.64. RESULTS: 120 (80%) of the 150 patients were pbese (BMI >23) according to the Asia Pacific criteria. 40 (30%) had metabolic syndrome. 97.5% (117/120) had insulin resistance with mean HOMA-insulin resistance (IR) of 10.9+/-5.3. Thirty (20%) were non obese; of these, 7 had central obesity (WC > 90 cm for men, > 80 cm for women). Twenty-three (15.3%) patients were lean NAFLD with BMI 21.6+/-1.5, WC 82.9+/-4.7 (BMI< 23, WC <90 cm in men and < 80 cm in women) 80% of these 23 (18/23) had insulin resistance with mean HOMA-IR of 3.4+/-1.9. Only 4 (17%) did not have any component of metabolic syndrome. CONCLUSION: Insulin resistance often associated with metabolic syndrome is common and plays a key role amongst lean Indian patients with non-alcoholic fatty liver disease. PMID- 23923371 TI - The role of image guided percutaneous drainage in multidisciplinary management of necrotizing pancreatitis. AB - BACKGROUND: Percutaneous catheter drainage (PCD) has become popular as a minimally invasive technique in the treatment armamentarium of patients with necrotizing pancreatitis requiring intervention. It obviates surgery and its attendant morbidity in a considerable number of patients in this setting. AIM: The aim of the study was to examine whether PCD upfront avoids surgery in a cohort of patients with necrotizing pancreatitis requiring intervention, and to identify factors predicting its failure. METHODS: We retrospectively reviewed demographic, clinical, and perioperative details of patients with severe acute pancreatitis from January 2009 to December 2011. Of 40 patients with necrotizing pancreatitis admitted to the surgical gastroenterology unit at our institute, 23 patients requiring PCD or surgical intervention were included in this study. Patients with successful and failed PCD were compared to identify factors predictive of failure of PCD. We also compared patients undergoing open necroseotomy with those undergoing PCD upfront, and open necrosectomy in terms of major complications including death. RESULTS: . Surgery was avoided in 7/23 (30%) patients with necrotizing pancreatitis who underwent PCD upfront. Higher APACHE II score (p=0.003) and extent of intrapancreatic necrosis (> 50%, p=0.03) were statistically significant predictors of failure of PCD. Although the complications were not different in patients undergoing PCD upfront followed by surgery, they had lower APACHE II and SOFA scores after PCD and had resolution of organ failures. CONCLUSIONS: PCD obviates surgery or acts as a temporizing measure in a significant number of patients with necrotizing pancreatitis. APACHE II scores and extent of intrapancreatic necrosis are principle factors determining success of PCD. PMID- 23923372 TI - Fibrosis in non-alcoholic fatty liver disease: correlation with simple blood indices and association with tumor necrosis factor-alpha polymorphisms. AB - AIM: The study was conducted with an aim to evaluate the clinico-pathological profile, the correlation of AST: ALT ratio and APRI with histological fibrosis, and the frequency of two specific polymorphisms (-238, -308) in the TNF alpha promoter region in patients with NAFLD. METHODS: The present study compared aspartate transaminase/alanine transaminase (AST/ALT) ratio and AST-to-platelet ratio index (APRI) with fibrosis score in 29 patients who underwent liver biopsy for NAFLD. Single nucleotide polymorphisms (SNP) in the tumor necrosis factor alpha (TNF-alpha) promoter region at positions -308 and -238 were examined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: AST/ALT ratio correlated better than the APRI with liver fibrosis in patients with NAFLD (AUROC of 0.9 compared to 0.68). TNF-alpha promoter region SNPs were present in only a minority of patients, and did not correlate with fibrosis severity. CONCLUSIONS: AST/ALT ratio correlated well with liver fibrosis in Indian patients with NAFLD. The SNPs studied had no role in development of fibrosis in Indian patients with NAFLD. PMID- 23923373 TI - Asymptomatic portal hypertension incidentally detected during upper gastrointestinal endoscopy. AB - Esophageal or gastric varices may be incidentally seen during endoscopy for dyspeptic or reflux symptoms. However, the frequency of their occurrence in these patients is unknown. Our center follows the scope and treat strategy for adult patients with dyspeptic or reflux symptoms and this provided us an opportunity to study this. Apart from providing an idea on the etiological spectrum, our data suggests that patients with incidentally detected varices have well preserved liver function which may provide a window for better management. PMID- 23923375 TI - Chronic pancreatitis causing thrombotic occlusion of IVC and renal veins. PMID- 23923374 TI - Recurrent acute hepatitis caused by albendazole. PMID- 23923376 TI - Synchronous colorectal cancer with aplastic anemia. PMID- 23923377 TI - Intrabiliary rupture of hepatic hydatid cyst with impacted hydatid membranes at ampulla of Vater presenting as acute pancreatitis. PMID- 23923378 TI - Development of huge pancreatic pseudocyst following organophosphorus poisoning - a case report and review of literature. PMID- 23923379 TI - PET positive lesions with increased SUV in post-surgical patients: where do we stand? PMID- 23923380 TI - Synchronous adenocarcinoma of the gall bladder and pancreas in a young woman. PMID- 23923381 TI - An unusual case of urinary ascites presenting as postoperative acute oliguric renal failure. PMID- 23923382 TI - Clinical aspects of fungal infections in diabetes. AB - Diabetes mellitus is one of the main risk factors of fungal infections of oral cavity, lower part of gastrointestinal tract, skin, foot, urogenital system and blood. Mycosis is a serious diagnostic and therapeutic problem and cause of mortality in diabetes. Fungal infections are also an important problem among hemodialysis patients with diabetes or diabetic patients after pancreas or kidney transplantation This work briefly describes the etiology, symptoms, diagnosis and ways of prophylaxis and treatment of mycosis in diabetic population. There is also emphasized the great connection between effective treatment of mycosis and glycemic control. PMID- 23923383 TI - Albumin as a drug delivery and diagnostic tool and its market approved products. AB - Albumin is one of the most extensively studied endogenous proteins which are used in the fabrication of drug delivery and diagnostic technologies during last 10 years. This review provides a summary of products involving the use of albumin as a drug delivery tool for getting better the pharmacokinetics of a drug by developing the targetted drug delivery systems and diagnosing the pathologies. Using albumin, following market approved products have been developed: Levemir and Victoza (antidiabetic product), Abraxane (antimetastatic breast cancer product), and Nanocoll and Albures (for lymphoscintigraphy and diagnosis of cancer and rheumatoid arthritis). PMID- 23923384 TI - Molecularly imprinted polymers as the future drug delivery devices. AB - In recent years, the investigations of new drug delivery systems have been directed on the development of some "intelligent" drug delivery devices that are able to directly respond to the patient's individual needs. New drug delivery systems should maximize the efficiency of administrated therapeutic agents and improve the patient's quality of life. Introduction of the new drug delivery devices is an important scientific goal, which could be achieved by combining new technologies and intelligent biomaterials. Molecular imprinting technology has a high potential for the preparation of optimized drug delivery forms. Here, molecularly imprinted polymers (MIPs) are promising new materials for such purposes, but their application in this field is nowadays at a developing stage. In this review, the principles of molecular imprinting and the recognition release mechanisms of polymeric matrices are discussed. The potential application of molecularly imprinted materials as the future drug delivery systems with various administering routes (transdermal, ocular or oral) are presented, and some future prospects for the imprinted polymers are outlined. PMID- 23923385 TI - Application of TLC method with video scanning in estimation of daily dietary intake of specific flavonoids--preliminary studies. AB - Flavonoids, substances present in foods of plant origin, play an important role in many metabolic processes. Numerous properties of these substances were described, including their anti-allergic, antitumor and antioxidant properties. Therefore, an increased intake of these nutrients may play a beneficial role in human health. The aim of the presented study was to estimate the daily intake of specific flavonoid compounds using thin layer chromatography (TLC) combined with densitometric qualitative and quantitative analysis. Performed investigations revealed the presence of two flavonoids in the extracts from daily food rations- naringenin and hesperidin. Naringenin content in the daily food ration of women was calculated to be 179-537 mg, whereas in the group of men it ranged around 181 550 mg, depending on the conducted method of extraction and solvent system used. Daily dietary intake of hesperidin was calculated to be 193-534 mg in the group of women and 194-562 mg in the group of men. The highest degree of extraction of these flavonoids was obtained for the mixture of acetone and water (7 : 3, v/v) by means of accelerated solvent extraction (ASE). PMID- 23923386 TI - Spectroscopic investigations of fluoroquinolones metal ion complexes. AB - The complex formation reaction, between fluoroquinolones (FQ): ciprofloxacin (CPX), enoxacin (ENX), enrofloxacin (ENRX), lomefloxacin (LOMX), levofloxacin (LEVX), ofloxacin (OFX), norfloxacin (NFX), sparfloxacin (SPRX) and aluminum(III), iron(III), copper(II) and zinc(II) ions were investigated. The spectrophotometic titration method in a wide range of pH was utilized for estimation of complex formation equilibrium. The application of Bjerrum method allowed to estimate the complex equilibrium of analyzed species in the reaction mixture. The overall stability constants (logbeta(pqr)) of fluoroquinolones complexes with metal ions were calculated using HYPRERQUAD program. The most stable complexes FQ were created with iron(III) and aluminum(III) and than copper(II) and zinc(II) ions, respectively. The highest values of calculated logbeta(pqr) were obtained for the Me(FQ)3H3 species and the lowest for the Me(FQ)2OH forms. Furthermore, an additional studies have been performed. The effect of the polyvalent metal ions on the complex structure has been investigated. The IR and 1H, 13C and 19F NMR spectroscopy methods were used for the confirmation of the structure of the FQ-Me complex formations. The most significant shifts of signals of 1H NMR spectra of the fluoroquinolones and their complexes were found for the protons substituted in the positions 2, 5 and 8, whereas the 13C NMR spectra showed up the shifts changes for carbon atoms in positions 2, 3, 3a and 4. PMID- 23923387 TI - Determination of linezolid in human serum by reversed-phase high-performance liquid chromatography with ultraviolet and diode array detection. AB - A high-performance liquid chromatographic (HPLC) method with UV and DAD detection for the quantitative determination of linezolid in human serum was developed in present work. Chromatography was carried out by reversed-phase technique on a RP 18 column with a mobile phase composed of 50 mM phosphate buffer and acetonitrile (76 : 26, v/v), adjusted to pH 3.5 with orthophosphoric acid. Serum samples were deproteinized with methanol centrifuged and then, the supernatant was analyzed using HPLC procedure. No interference was observed at the retention times of linezolid from blank serum or ten commonly used antibiotics. A concentration range from 0.50 to 30.0 g/mL was utilized to construct calibration curves. The lower limit of detection was determined to be 0.1 microg/mL of serum for both detectors. The lower limit of quantification of 0.25 microg/mL (CV = 2.6%) was established for determination using HPLC-UV and 0.5 microg/mL (CV = 5.42%) for HPLC-DAD. The recovery of linezolid was approximately 100%. Intra-day accuracy ranged from 0.97 to 12.63% and 0.74 to 10.85% for HPLC-UV and HPLC-DAD method, respectively. Intra-day precision was less than 4.69% for HPLC-UV and less than 5.42% for HPLC-DAD method. Tests confirmed the stability of linezolid in serum during three freeze-thaw cycles and during long-term storage of frozen serum for up to 6 weeks; in extracts it was stable in the HPLC autosampler over 24 h. Statistical analysis by Student's t-test showed no significant difference between the results obtained by these two methods. In summary, these methods will be used and adapted for infected patients in intensive care unit, to determine linezolid serum concentrations in order to know the pharmacokinetic profiles of linezolid. PMID- 23923388 TI - Development and validation of stability-indicating TLC-densitometric method for determination of betaxolol with LC-ESI/MS analysis of degradation product. AB - The purpose of this work was to develop a sensitive stability indicating TLC densitometric method for the determination of betaxolol (Bx) in pharmaceutical preparations and to study the stability of Bx in acidic solutions. The method was developed on TLC aluminium plates precoated with silica gel F254using the mobile phase chloroform-methanol-ammonia 25% (18 : 4: 0.2, v/v/v) which gives compact spots for Bx (R(f) approximately equal to 0.64) and its degradation product (R(f) approximately equal to 0.39). Densitometric analysis was carried out in UV at 280 nm. The developed method is highly sensitive (LOD = 66.6 ng/spot, LOQ = 200 ng/spot), precise (RSD = 2.73%) and accurate (mean recovery = 100.28% at 100% level). Bx was subjected to acidic and alkaline hydrolysis but degradation was observed only in acidic solutions. The degradation process was described with kinetic and thermodynamic parameters. Based on LC-ESI/MS analysis, it was found that Bx decomposes in acidic solution to produce ethoxyphenoxy-3-[(1 methylethyl)amino]propan-2-ol. PMID- 23923389 TI - Studies on esterification and sulfonation of riboflavin via semi-empirical methods. AB - The article presents extended computer investigations of various sulfate derivatives of riboflavin. A number of physicochemical parameters such as total energy, binding energy and formation heat were calculated via semi-empirical methods AM1 and PM3 for the different derivatives of riboflavin. Their analysis made it possible to determine the sequence of formation of sulfate derivatives- esterification is the easiest at hydroxyl groups at the farthest positions from the ring. This methodology may be used to study biologically active compounds. PMID- 23923390 TI - Endohedral complexes of fullerene C60 with small convalent molecules (H2O, NH3, H2, 2H2, 3H2, 4H2, O2, O3) in the context of potential drug transporter system. AB - The fullerene C60 has chemical properties which seem to predestinate it to be effective transporter of drugs in biological system. To prove this, the DFT/B3LYP (6-31G*) calculations were performed especially in order to determine the structures and energies of the inclusion complexes of C60 with small molecules. It was found that the small molecule is more compact when it is located in the centre of the C60 cage than as isolated molecule. The calculated inclusion energies in case of: H2O, NH3, O2, O3, H2, 2H2, 3H2, 4H2 are: 1.84, 3.81, 3.75, 21.07, 1.97, 20.10, 47.78 and 77.54 kcal/mol, respectively. The charge transfer and the influence of the complexed small molecules on the electrostatic potential distribution inside and outside of the C60 cavity are discussed. PMID- 23923391 TI - A concise synthesis and antimicrobial activity of a novel series of naphthylpyridine-3-carbonitrile compounds. AB - A novel series of acyclic nucleosides 2-5 and 13a-c were synthesized by utilizing 4-phenyl-6(naphthalen-2-yl)-2-oxo-1,2-dihydropridine-3-carbonitrile (1) as a key starting material. Chlorination of 1 yielded the chloro analogue 6 that was allowed to react with urea, thiourea, thiosemicarbazide and alicyclic secondary amines to produce the corresponding derivatives 7a-c and 11a-c. Further condensation of 6 with various amino acids provided the compounds 8-10, whereas hydrazinolysis of 6 yielded the hydrazinyl analogue 12 which was condensed with different isothiocyanates and acid anhydrides to afford derivatives 18-20, respectively. Upon treatment of 12 with sodium nitrite, the azide derivative 14 was obtained which was subjected to reaction with various active methylene compounds to obtain the corresponding triazolo derivatives 15-17. The structure assignment of the new compounds is based on chemicaland spectroscopic evidence. Antimicrobial evaluation of the newly synthesized derivatives was performed using ciprofloxacin and fluconazole as reference antibacterial and antifungal drugs. The most effective compounds against the tested bacterial and fungal isolates were the benzothiohydrazide compound 18b followed by the hydrazone and the phthalic anhydride derivatives 13c and 20, respectively. PMID- 23923392 TI - Synthesis and research of benzylamides of some isocyclic and heterocyclic acids as potential anticonvulsants. AB - A series of benzylamides of isocyclic and heterocyclic acids was synthesized and tested in Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Near all synthesized derivatives of heterocyclic acids showed activity. All obtained derivatives of mono- and bicyclic isocyclic acids were inactive. The power of action of heterocyclic acids derivatives seems does not depend upon kind of heteroatom (N, O or S). One of the compounds (2-furoic acid benzylamide (4)) appeared most promising. It showed in minimal clonic seizure (6Hz) test (ASP) in rats after i. p. administration: MES ED50 = 36.5 mg/kg, TOX TD50 = 269.75 mg/kg, and PI = 7.39. PMID- 23923393 TI - A novel class of substituted spiro [quinazoline-2,1'-cyclohexane] derivatives as effective PPAR-1 inhibitors: molecular modeling, synthesis, cytotoxic and enzyme assay evaluation. AB - Molecular docking simulation study was carried out to design a novel series of spiro [(2H, 3H)quinazoline-2,1'-cyclohexan]-4(1H)-one derivatives as a new class of effective PARP-1 inhibitors. Spiro [2H-3,1-benzoxazine-2,1'-cyclohexan]-4(1H) one (5) was the starting compound to synthesize the target proposed analogues. The derivatives that showed the top scores and had the best fitting in the binding sites of the target protein were selected to evaluate their in vitro anti proliferative activity against the cultured human breast carcinoma cell line (MCF 7) using doxorubicin as a standard drug. Additionally, the compounds that exhibited the highest cytotoxic efficiency were further subjected to PARP-1 enzyme assay taking 3-aminobenzamide as the reference drug. The structures of the novel derivatives were confirmed on the bases of microanalytical and spectral data. PMID- 23923394 TI - In vitro anti-oxidative activities and GC-MS analysis of various solvent extracts of Cassia singueana parts. AB - The present study was conducted to investigate the anti-oxidative activities of different solvent extracts of Cassia singueana parts. Our results indicate that all the extracts have reducing power (Fe3+ --> Fe2+) and DPPH radical scavenging abilities. However, the ethyl acetate extract of the stem bark has the highest total reducing power whilst the ethanol extract of the stem bark has more potent free radical scavenging activity than all the other extracts. The ethyl acetate extract of the stem bark exhibited more powerful hydroxyl radical scavenging activity than other extracts whilst the aqueous extract of the leaves displayed more potent nitric oxide inhibition activity than other extracts. The GC-MS analysis of the ethyl acetate extract of the stem bark and the ethanol extract of the root and leaves indicated that several aromatic compounds, including phenolics, fatty acids, amino acids and triterpenoids were present in these extracts. Data from this study suggest that the parts of C. singueana possessed anti-oxidative activities and can be used as a potential alternative medicine for oxidative stress related non-communicable chronic diseases. Further experimental and clinical studies in this regard are warranted. PMID- 23923395 TI - Effect of water soluble carrier on dissolution profiles of diclofenac sodium. AB - Pharmaceutical aviailability of diclofenac sodium from solid dispersions of PEG 6000 have been studied in comparison to those of the corresponding physical mixtures and pure diclofenac sodium. The diclofenac sodium is poorly water soluble drug. The properties of diclofenac sodium-PEG 6000 solid dispersions have been determined by the methods of differential scanning calorimetry (DSC), X-ray diffraction and scanning electron microscopy (SEM). The effect of PEG 6000 on the solubility of selected diclofenac sodium dispersions has been studied. The solubility of diclofenac sodium from its solid dispersion has been found to increase in the presence of PEG 6000. PMID- 23923396 TI - New formula herbal pellets demonstrate a uniform and stable release of the active ingredients in vitro. AB - The aim of this study was to evaluate the effect of different capsule filling manufacturing techniques and storage conditions on the release of the active ingredients from herbal capsules during the dissolution test in vitro. Different techniques for the preparation of the original mixture of dry extracts were applied, and subsequently capsules with six different fillings were prepared. The stability of the capsules was evaluated in different long-term storage conditions, registering changes in the water content (loss of drying), capsule disintegration time, and phenolic compounds dissolution test in vitro. The baseline of phenolic compounds release in the control capsules (filled with the mixture of the powder of dry herbal extracts) was the highest, compared to other capsule groups, yet during long-term storage, these capsules accumulated too much moisture, which impeded capsule disintegration time and phenolic compounds release. The study showed that moisture and temperature changes occurring during the storage of the preparation had a negative effect on the release of phenolic compounds from herbal capsules. Capsules filled with pellets demonstrated a uniform and stable release of the active ingredients in different long-term storage conditions, which indicates that the manufacturing technology of dry herbal extracts affects the stability of the active ingredients. PMID- 23923397 TI - Kinetics of degradation of imidapril hydrochloride in finished dosage formulations. AB - This study investigates the impact of relative air humidity and temperature on the stability of imidapril hydrochloride (IMD) tablets. For this purpose the forced degradation test was used and the following environmental conditions were employed: RH = 76.4% and the temperature range of 313 - 333 K. For the determination of IMD content in the analyzed samples a reversed-phase high performance liquid chromatography (RP-HPLC) technique was used. Three series of tablets were prepared: whole-blistered tablets, whole-bare tablets and halved bare tablets, in order to analyze the influence of different in-home storage habits on IMD tablets' quality. In the course of the study, the degradation of IMD was observed in each series of tablets. The kinetic mechanisms and the thermodynamic parameters of these reactions were established. It was evidenced that halved IMD tablets stored without immediate packaging retain their quality only for 12 days while tablets stored according to label recommendations are stable for 513 days. PMID- 23923398 TI - Development of in vitro-in vivo correlation for encapsulated metoprolol tartrate. AB - This study was aimed to develop level A, B and C in vitro-in vivo correlation (IVIVC) for encapsulated metoprolol tartrate (T1, T2 and T3 having metoprolol tartrate/polymer ratio of 1: 1, 1: 1.5 and 1: 2,w/w). The in vitro data were correlated with in vivo data. For level A IVIVC, drug absorption data were calculated using Wagner-Nelson method. In addition, convolution approach was used to approximate plasma drug levels from in vitro dissolution data. The coefficient of determination (R2) for level A IVIVC was 0.720, 0.905, 0.928 and 0.878 for Mepressor, T1, T2 andT3 formulations, respectively, with acceptable percent error (< 15%). The value of R2 for level B and C IVIVC was 0.231and 0.714, respectively. It is also concluded that level A IVIVC is a proficient mathematical model for biowaiver studies involving study parameters as those implemented for T1S (T1formulation tested for dissolution in the presence of sodium lauryl sulfate) revealing that IVIVC level A is dosage form specific, rather than to be drug specific. PMID- 23923399 TI - Effect of two hydrophobic polymers on the release of gliclazide from their matrix tablets. AB - Gliclazide is an oral hypoglycemic agent, indicated in non insulin dependent diabetes mellitus and in patients with diabetic retinopathy. It has good tolerability and is a short acting sulfonyl urea that requires large dose to maintain the blood glucose level. So development of a sustained release formulation of gliclazide (GLZ) is required for better patient compliance. This study was conducted to assess the effects of different drug polymer ratios on the release profile of gliclazide from the matrix. Oral matrix tablets of gliclazide were prepared by hot melt method, using pure and blended mixture of glyceryl monostearate (GMS) and stearic acid (SA) in different ratios. In vitro release pattern was studied for 8 h in phosphate buffer media (pH 7.4). Different kinetic models including zero order, first order, Higuchi and Peppas were applied to evaluate drug release behavior. Drug excipient compatibility was evaluated by scanning with DSC and FTIR. Higuchi model was found the most appropriate model for describing the release profile of GLZ and non-Fickian release was found predominant mechanism of drug release. The release of drug from the matrix was greatly controlled by GMS while SA appeared to facilitate the release of drug from matrix tablets. FTIR results showed no chemical interaction between drug and the polymers, and DSC results indicated amorphous state of GLZ and polymers without significant complex formation. The results indicate that matrix tablets of gliclazide using glyceryl monostearate and stearic acid showed marked sustained release properties. PMID- 23923400 TI - Compounded preparations with nystatin for oral and oromucosal administration. AB - Therapy of oral, esophageal and gastrointestinal candidiasis is still a common problem that can be solved by an administration of antimycotics. Major disadvantage of registered commercial antifungal medicinal products is their price, so the health care system and its payers may profit from extemporaneous compounding. An appropriate drug therapy for candidiasis (trush) is nystatin, which is a substance available in the Czech Republic for the magistral preparation relatively recently, since 2010. Making formulas for extemporaneous compounding is quite simple and preparations particularly useful for dentists, pediatricians, otolaryngologists, oncologists and gastroenterologists. The authors formulated composition of viscous oromucosal suspension, oral/oromucosal hydrogel and oromucosal gelatine globule which may be present as compounded products containing nystatin for oromucosal and/or oral administration. The preparation is practically verified and magistral products have been already used in clinical practice. PMID- 23923401 TI - Drug coverage insurance as a novel element of private health insurance in Poland. AB - In recent years, there have been observed increased costs of health care in Poland. The patient's out of pocket expenses on drug have grown too. To the above, the insurance companies have offered patients drug coverage insurance policies since recently. Drug insurance policy covers the cost of purchasing pharmaceutical products not reimbursed by the National Health Fund is a modern product on the Polish health insurance market. The aim of the article is to characterize drug coverage insurance policies on the health insurance market in Poland. The Polish insurance market and entities offered these types of insurance are also presented. PMID- 23923402 TI - Restrictions on the conduct of advertising of medicinal products in Poland and their violations. AB - Similarly to other European countries, the Polish pharmaceutical market is in the phase of maturity characterized by limited speed of increase in sales. In connection with escalation of the competitive struggle, being the result of globalization and development of enterprises producing generic medications, the most important aim for pharmaceutical companies has been to maintain profitability on the right level. To perform this task, companies producing medications have to carry out proper marketing actions. The marketing elements include, apart from the product, the price and the distribution, also promotion which is inextricably linked with advertising. It is a special type of information message that aims at evoking a specific consumer's attitude and belief. Advertising of medicinal products is subject to detailed legislative and non-legislative regulations. The aim of the article is to present legal regulations within the scope of advertising of medicinal products and violations of these regulations based on example decisions of the Main Pharmaceutical Inspector issued in the years 2008-2010. Abundant rulings of the Main Pharmaceutical Inspector prove that both advertisements addressed to public attention and those addressed to specialists often diverge from the criteria determined by the Pharmaceutical Law. In the face of still increasing violations of the provisions of the Pharmaceutical Law act, it seems that introducing a ban on advertising or any possible financial sanctions is not a sufficient punishment for advertisers. Thus, an introduction of other, more rigorous legal regulations as a deterrent for those involved in illegal advertising of medicinal products ought to be considered. PMID- 23923403 TI - Correlation between intracerebral hemorrhage score and surgical outcome of spontaneous intracerebral hemorrhage. AB - Spontaneous intracerebral hemorrhage (ICH) comprises 10-15% of all strokes and has a higher risk of morbidity and mortality (40-45%). A simple and widely valid clinical grading scale, the Intracerebral Hemorrhage Score (ICH score) was developed to predict to outcome of spontaneous ICH. The aim of the present study was to assess the relation between the ICH score and the surgical outcome of ICH by Glasgow Outcome Scale (GOS) at the 30th post ictus day in our perspective. This prospective study was done during the period of April 2009 to October 2010 in Department of Neurosurgery, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka. Forty three cases were enrolled by set inclusion and exclusion criteria. Intracerebral Hemorrhage Score was calculated during admission and the surgical outcome of ICH was determined by GOS by face to face or telephone interview using structured questionnaire on their 30th post ictus day. Correlation between the ICH score and the surgical outcome of ICH was done by Pearson's correlation coefficient test. Value of r was found to be -0.635 which was statistically highly significant (p = .001) and the relation was found to be negative. Higher ICH score had unfavorable outcome As correlation between the ICH score and the surgical outcome of ICH was found statistically highly significant, it can be used widely as a grading scale in preoperative counseling. The use of ICH score could improve standardization of clinical treatment protocols and clinical research studies in ICH. PMID- 23923404 TI - Comparative study of the effect of ethanolic extract of Swietenia mahagoni seeds with rosiglitazone on experimentally induced diabetes mellitus in rats. AB - The study was performed to compare the blood glucose lowering effect of Swietenia mahagoni seeds with an oral antidiabetic drug, rosiglitazone in experimentally induced diabetic rats. Twentyfour healthy Long Evans Norwegian strain of rats were included in the study and divided into four groups (A, B, C and D) comprising 6 rats each. Group A (control group) received standard rat food for 14 days. Diabetes was induced by a single intraperitoneal administration of alloxan 120 mg/kg body weight in Group B, C and D. Group B was given standard food for 10 days and considered as diabetic control. Group C and D were treated with ethanolic extract of Swietenia mahagoni seeds 1000 mg/kg and rosiglitazone 10 mg/kg orally respectively. Administration of ethanolic extract of Swietenia mahagoni seeds in group C and rosiglitazone in group D produced a significant reduction in blood glucose level as compared to diabetic control (group B). Histological examination of pancreas showed destruction of beta cells in Islets of pancreas in group B whereas retaining of islets and few degranulations of beta cells of pancreas found in group C and group D. The observations and results of the present study provide information that ethanolic extract of Swietenia mahagoni seeds has hypoglycaemic effect in experimentally induced diabetic rats which requires further investigation. PMID- 23923405 TI - Sustained virological response after treatment in patients with chronic hepatitis C infection--a five year follow up. AB - Peginterferon alpha-2a and ribavirin combination therapy achieves a sustained virological response (SVR) in patients with chronic hepatitis C. Little is know about long-term durability of hepatitis C virus--Ribonucleic acid (HCV-RNA) negativity in patient treated with pegylated interferon and ribavirin therapy. Aim of this study was to evaluate the durability of virologic response in patients with SVR to anti-viral therapy treated at our centre. A total of 52 patients with chronic hepatitis C virus infection who had obtained SVR after Peginterferon alpha-2a and ribavirin combination therapy were followed up to 5 years with annual HCV-RNA testing. During this follow up period, 4 of 52 patients with initial SVR developed late relapse of hepatitis C virus infection. Relapse was more common in patients who has cirrhosis (3/6 [50%]) vs (1/46 [2.17%]) without cirrhosis. In conclusion, SVR is durable in most patients, but some patients do have late relapse; long-term follow up may be particularly important in a subset of patients with hepatitis C virus infection who have liver cirrhosis. PMID- 23923406 TI - Ultrasound guided fine needle aspiration cytology: a sensitive diagnostic tool for diagnosis of intra-abdominal lesions. AB - Ultrasound guided fine needle aspiration cytology is widely accepted as a safe diagnostic procedure in various neoplastic and non-plastic disorders. This study was conducted to determine the usefulness and diagnostic accuracy of ultrasound guided fine needle aspiration cytology in the diagnosis of intraabdominal lesions. This cross sectional study was conducted in the Department of Radiology and Imaging, Sylhet MAG Osmani Medical College Hospital, Sylhet, Bangladesh during the period of June 2007 to June 2009. A total 78 patients with intra abdominal lesions were included in this study. Fifty nine (75.6%) were males and 19 (24.4%) were females. Out of total aspirates 29 (37.2%) were categorized as benign, 41 (52.6%) were malignant and 8 (10.3%) were non-representative, as it contained only blood. Most of the benign lesions were liver abscess 19 (24.4%). A diagnosis of primary malignancy was established in 26 (33.3%) and that of secondary in 15 (19.2%). The results showed a sensitivity of 89.7%. Ultrasound guided fine needle aspiration cytology is a sensitive diagnostic tool in a wide spectrum of intra-abdominal neoplastic and non-neoplastic disorders. It is a simple, safe, rapidand inexpensive technique. PMID- 23923407 TI - Leptin to adiponectin ratio in preeclampsia. AB - The aim of the present study was to assess leptin/adiponectin ratio in preeclamptic patients compared with normal pregnant women. A cross-sectional study was designed. The study population consisted of 30 preeclamptic patients and 30 healthy pregnant women. Serum levels of total leptin and adiponectin were assessed using commercially available enzyme-linked immunosorbent assay methods. The one-way ANOVA and Student's t tests and Pearson's correlation analysis were used for statistical calculations. Levels of leptin and adiponectin were also adjusted for BMI. A p-value < 0.05 was considered statistically significant. The leptin/adiponectin ratio was increased significantly in preeclamptic patients. The leptin/adiponectin ratio was significantly higher in severe preeclamptic patient than in mild preeclampsia. Adjusted leptin/adiponectin ratio was also significantly increased in preeclamptic patients than in normal pregnant women. The findings of the present study suggest that the leptin/adiponectin ratio was increased in preeclamsia and imbalance between the adipocytokines could be involved in the pathogenesis of preeclampsia. PMID- 23923408 TI - Adverse outcome of methotrexate and mini pulse betamethasone in the treatment of lichen planus. AB - The objectives of this study were to compare the adverse outcome of methotrexate and mini pulse betamethasone therapy in the treatment of lichen planus. It was a clinical trial conducted in the department of Dermatology and Venereology, Bangabandhu Sheikh Mujib Medical University, Dhaka, from January 2009 to December 2010. Forty four patients of lichen planus were included in the study. Patients in Group-A, (n = 23) were treated with methotrexate (10 mg) single morning dose and group-B (n = 21) were treated with mini pulse betamethasone (5 mg) single morning dose on 2 consecutive days during the period of 12 weeks. Adverse outcomes were measured by clinical examination and laboratory investigations during follow up visits. Anemia 3 (14.2%) and edema 12 (57.1%) developed in group B but none in group-A. In group-B, dyspepsia 15 (71.4%), acne 10 (47.6%), mooning face 8 (38.1%), striae 8 (38.1%) and hypertrichosis 4 (19.0%) developed but none in group-A. Intermittent diarrhoea, headache, nausea and fatigue complained in both groups of patients but the percentage of complaints was higher among group-B compared to group-A. Menstrual abnormality developed in group-B 5(71.4%) but none in group-A. Laboratory investigations showed abnormality in platelet count and SGPT in group-A but none in group-B. The adverse effects of methotrexate on haematological parameter and liver functions were mild and could be prevented by reducing the dose but the adverse effects of betamethasone were unavoidable. The overall adverse effects were less in group-A than group-B. Therefore, methotrexate can be used as an alternative safer option for the treatment of lichen planus. PMID- 23923409 TI - Factors responsible for increased percent recirculation in arterio-venous fistula among the haemodialysis patients. AB - Recirculation is an important issue in haemodialysis (HD) patients as increased percent recirculation causes decreased dialysis delivery of the patients. The purpose of the study was to determine the amount and factors of recirculation in those patients. The study was a cross sectional one carried in the Department of Nephrology, Dhaka Medical College and Hospital during October 2010 to September 2011. A total of 118 end stage renal disease patients with arterio-venous fistula who were on HD for more than 3 months were purposively selected. The degree of recirculation was measured with urea based two needle technique method. For each patient distances between arterial and venous and distances of needles from fistula and its directions were recorded. Echocardiography and A-V fistula Colour Doppler Ultrasound were also performed. The mean A-V fistula recirculation was 8.1 +/- 5.5% with a range 0-66%. The most common factors were close proximity and improper arterial and venous needles placement. No difference was observed between diabetic and non diabetic also between hypertensive and normotensive. A-V fistula recirculation is common occurrence in HD patients and the most common factors of recirculation are misplacement and close proximity of needles therefore emphasis should be given on education and training of HD staffs. PMID- 23923410 TI - Risk factors of multi-drug-resistant tuberculosis in Bangladeshi population: a case control study. AB - Despite success in tuberculosis control, multi-drug resistant tuberculosis in Bangladesh is increasing and currently multi-drug-resistant tuberculosis rate is 3.6% in new cases and 19% in re-treatment cases. This study focused on determination of multi-drug-resistant tuberculosis which is warranted for effective prevention strategy. An unmatched case control study was conducted in 2010. Purposively recruited 136 culture-proved multi-drug-resistant- tuberculosis cases and 152 cured tuberculosis patients were interviewed. Associations between exposure and outcome variables were initially tested by chi2-test, t-test. A result was considered significant at p value < 0.05. Effects of exposure variables were also assessed after adjusting for other variables by binary logistic regression models. Crude and adjusted Odds Ratio with 95% Confidence Interval was computed. Younger age (p = 0.008) and, peri-urban locality (p = 0.002) were associated with multi-drug-resistant tuberculosis. History of contact (p < 0.001) and tuberculosis in the past (p < 0.001) were four and eight times, respectively, more likely to influence multi-drug-resistant tuberculosis. Regularity [Odds Ratio 0.05; 95% Confidence Interval (0.01 to 0.39)] and always observation of treatment [Odds Ratio 0.25; 95% Confidence Interval (0.10 to 0.61)], sputum conversion [Odds Ratio 0.02; 95% Confidence Interval (0.01 to 0.08)] negatively associated with multi-drug-resistant tuberculosis. Gender and socio-economic status did not show any influence. Treatment course and sputum conversion was the best predictors. Like other developing countries adequacy of treatment is the most important exposure variable. Strengthening of control activities might contribute in preventing development of resistance in tuberculosis patients. PMID- 23923411 TI - Normal value of pulsatility index of umbilical artery in second and third trimester of pregnancy. AB - This cross sectional study was carried out on 60 pregnant Bangladeshi women in the department of Radiology and Imaging, BIRDEM for measurement of Pulsatility Index (PI) of umbilical artery of their fetuses by duplex colour Doppler sonography during 2nd and 3rd trimester of pregnancies. Considering total 2nd and 3rd trimesters the mean PI value of umbilical artery was 1.24 (SD +/- 0.27). While considering the gestational in separate trimesters, study showed that the value of PI in 2nd trimester was 1.33 (SD +/- 0.29) and in 3rd trimester PI was 1.18 (SD +/- 0.25). Paired t test shows there was a highly significant (t = 35.79, df = 59, Level of significance = 0.001) difference between mean values of PI in different gestational ages. It was observed that there was gradual decrease of PI value with increase of gestational age (r = -0.207) but this decrease of PI was not statistically significant (p = 0.113). Regression analysis between dependent PI value and independent gestational age showed linear negative relationship but this was not statistically significant (p = 0.11). This study revealed that the Pulsatility index of umbilical artery was decreased with increase of gestational age from 2nd to 3rd trimester. PMID- 23923412 TI - Microsurgical excision of olfactory groove meningioma's: a brief study of outcome of different surgical approaches. PMID- 23923413 TI - Applicable models for multi-component adsorption of dyes: a review. AB - Adsorption is one of the several techniques that has been successfully used for dyes removal. Since most industrial colored effluents contain several components including dyes, having a strong knowledge about the scope of competitive adsorption process is a powerful key to design an appropriate system. This is mainly because of the complexity brought about by the increasing number of parameters needed for process description which complicates not only the process modeling but also the experimental data collection. A multicomponent adsorption model should be based on fundamental soundness, speed, and simplicity of calculation. For such systems, competition will change the adsorbent-adsorbate attractions. Thus, there is major concern to develop an accurate and reliable method to predict dye adsorption behavior in multi-component systems. This article covers topics such as the theory of dyes adsorption in multi-component systems along with applicable models according to the consistent theories presented by researchers. PMID- 23923414 TI - Effects of sludge dredging on the prevention and control of algae-caused black bloom in Taihu Lake, China. AB - Algae-caused black bloom (also known as black water agglomerate) has recently become a critical problem in some Chinese lakes. It has been suggested that the occurrence of algae-caused black bloom was caused by the cooperation of nutrient rich sediment with dead algae, and sludge dredging was adopted to control black bloom in some lakes of China. In this article, based on the simulation of black bloom using a Y-shape apparatus for modeling natural conditions, both un-dredged and dredged sites in three areas of Taihu-Lake, China were studied to estimate the effects of dredging on the prevention and control of black bloom. During the experiment, drained algae were added to all six sites as an additional organic load; subsequently, the dissolved oxygen decreased rapidly, dropping to 0 mg/L at the sediment-water interface. Black bloom did not occur in the dredged sites of Moon Bay and Nan Quan, whereas all three un-dredged sites at Fudu Port, Moon Bay and Nan Quan experienced black bloom. Black bloom also occurred at the dredged site of Fudu Port one day later than at the other sites, and the odor and color were lighter than at the other locations. The color and odor of the black water mainly result from the presence of sulfides such as metal sulfides and hydrogen sulfide, among other chemicals, under reductive conditions. The color and odor of the water, together with the high concentrations of nutrients, were mainly caused by the decomposition of the algae and the presence of nutrient-rich sediment. Overall, the removal of the nutrient-rich sediment by dredging can prevent the occurrence and control the degree of algae-caused black bloom in Taihu Lake. PMID- 23923415 TI - Distribution characteristics and source identification of polychlorinated dibenzo p-dioxin and dibenzofurans, and dioxin-like polychlorinated biphenyls in the waters from River Kanzaki, running through Osaka urban area, Japan. AB - This is the first to elucidate the distribution and sources of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/PCDFs), and dioxin-like polychlorinated biphenyls in the waters from Kanzaki River, which is one of the most heavily polluted rivers in Japan. The World Health Organization (WHO)-toxic equivalent quantities (TEQs) in waters from the mainstream exceeded the Japanese environmental standard (1.0 pg-TEQ/L). The PCDD/PCDFs were dominated by highly chlorinated DFs, which predominantly contributed to the WHO-TEQs, suggesting that the main causes would be the incineration-related wastes. To find the sources, the dioxin congener concentrations in water and sediment samples from its tributary small waterways were determined. Abnormally high WHO-TEQs were detected in a water (50 pg-TEQ/L) and a sediment sample (41,000 ng-TEQ/kg dry weight) near the industrial solid waste incinerators (ISWIs). The PCDD/PCDF characteristics agreed well with those of the incinerator-related wastes as seen in the mainstream. These facts indicate that the dioxin pollution in the mainstream could be largely related to the industrial wastes from the ISWIs. Here, a TEQ apportionment method was used to understand the contribution of the pyrogenic sources to the WHO-TEQs. The average contribution ratios of the pyrogenic sources to WHO-TEQs were more than 80% for river waters from the mainstream, indicating that the elevated WHO-TEQs in the mainstream had been largely caused by the ISWIs. PMID- 23923416 TI - Pre-oxidation with KMnO4 changes extra-cellular organic matter's secretion characteristics to improve algal removal by coagulation with a low dosage of polyaluminium chloride. AB - Microcystis aeruginosa was used to study the effect of KMnO4 pre-oxidation on algal removal through coagulation with polyaluminium chloride (PAC). KMnO4 pre oxidation improved the coagulation efficiency of algal at a low dosage of PAC. The optimal KMnO4 feeding period was in the stationary growth phase of Microcystis aeruginosa. KMnO4 traumatized the algal cells and stimulated cellular release of organic matter, contributing to the pool of extra-cellular organic matter (EOM). KMnO4 also decomposed EOM, especially small molecular weight EOM. Lower concentrations of KMnO4, such as 2 mg/L, induced algae cells to produce moderate amounts of new EOM with molecular weights of 11, 280, and 1500 kDa. These relatively large molecules combined easily with PAC, promoting coagulation and removal of algae. High concentrations of KMnO4 lysed algae cells and produced much high-molecular-weight EOM that did not enhance flocculation by PAC at lower dosages. PMID- 23923417 TI - Identification of causative compounds and microorganisms for musty odor occurrence in the Huangpu River, China. AB - There are regular problems of musty odor in the Huangpu River, a major source of drinking water for Shanghai, China. In this study, the musty odor and its main causative compounds in the Huangpu River source water were confirmed through a yearly investigation using flavor profile analysis combined with HSPME-GC-MS analysis. The investigation showed that 2-methylisoborneol (2-MIB) with a concentration level between 28.6 and 71.0 ng/L was responsible for the musty odor in summer from July to September. Microscopic observation confirmed with the cloning results showed that Phormidium spp., which accounted for 80%-95% of the algal cell density, was the microorganisms responsible for the production of 2 MIB and the estimated 2-MIB yield was 0.022 pg/cell. Results from a wide-area sampling campaign in the Huangpu River watershed showed that, other than the large tributaries receiving water from Tai Lake, several small creeks close to the intake may have contributed most of the 2-MIB and the Phormidium spp. to the Huangpu River source water. This study provides methodology for the investigation of odor causing compounds and microorganisms in river-type source water, and the result will be useful for water quality control in both source water and drinking water. PMID- 23923418 TI - Influences of perfluorooctanoic acid on the aggregation of multi-walled carbon nanotubes. AB - The aggregation of multi-walled carbon nanotubes (MWCNTs) in the aqueous phase not only inhibits their extensive utilization in various aspects but also dominates their environmental fate and transport. The role of surfactants at low concentration in the aggregation of MWCNTs has been studied, however the effect of perfluorinated surfactants at low concentration is uncertain. To understand this interfacial phenomenon, the influences of perfluorooctanoic acid (PFOA), and sodium dodecyl sulfate (SDS) as a control, on MWCNT aggregation in the aqueous phase were examined by the UV absorbency method. Influences of pH and cationic species on the critical coagulation concentration (CCC) value were evaluated. The CCC values were dependent on the concentration of PFOA, however a pronounced effect of SDS concentration on the CCC values was not observed. The CCC values of the MWCNTs were 51.6 mmol/L in NaCl and 0.28 mmol/L in CaCl2 solutions, which suggested pronounced differences in the effects of Na+ and Ca2+ ions on the aggregation of the MWCNTs. The presence of both PFOA and SDS significantly decreased the CCC values of the MWCNTs in NaCl solution. The aggregation of the MWCNTs took place under acidic conditions and was not notably altered under neutral and alkaline conditions due to the electrostatic repulsion of deprotonated functional groups on the surface of the MWCNTs. PMID- 23923419 TI - Rapid degradation of hexachlorobenzene by micron Ag/Fe bimetal particles. AB - The feasibility of the rapid degradation of hexachlorobenzene (HCB) by micron size silver (Ag)/iron (Fe) particles was investigated. Ag/Fe particles with different ratios (0, 0.05%, 0.09%, 0.20%, and 0.45%) were prepared by electroless silver plating on 300 mesh Fe powder, and were used to degrade HCB at different pH values and temperatures. The dechlorination ability of Fe greatly increased with small Ag addition, whereas too much added Ag would cover the Fe surface and reduce the effective reaction surface, thereby decreasing the extent of dechlorination. The optimal Ag/Fe ratio was 0.09%. Tafel polarization curves showed that HCB was rapidly degraded at neutral or acidic pH, whereas low pH levels severely intensified H2 production, which consumed the reducing electrons needed for the HCB degradation. HCB degradation was more sensitive to temperature than pH. The rate constant of HCB dechlorination was 0.452 min- at 85 degrees C, 50 times higher than that at 31 degrees C. HCB was degraded in a successive dechlorination pathway, yielding the main products 1,2,4,5-tetrachlorobenzene and 1,2,4-trichlorobenzene within 2 hr. PMID- 23923420 TI - Removal of Pb(II) from aqueous solution by hydrous manganese dioxide: adsorption behavior and mechanism. AB - Hydrous manganese dioxide (HMO) synthesized by redox of potassium permanganate and hydrogen peroxide was used as an adsorbent for Pb(II) removal. The specific surface area, pore volume and BJH pore diameter of the HMO were 79.31 m2/g, 0.07 cm3/g and 3.38 nm, respectively. The adsorption equilibrium at 298 K could be well described by the Langmuir isotherm equation with qmax value of 352.55 mg/g. The negative values of deltaG and the positive values of deltaH and deltaS indicated the adsorption process was spontaneous and endothermic. The pseudo second-order equation could best fit the adsorption data. The value of the calculated activation energy for Pb(II) adsorption onto the HMO was 38.23 kJ/mol. The uptake of Pb(II) by HMO was correlated with increasing surface hydroxyl group content and the main adsorbed speciation was PbOH+. The final chemical state of Pb(II) on the surface of HMO was similar to PbO. HMO was a promising candidate for Pb(II) removal from aqueous solution. PMID- 23923421 TI - Cr(VI) reduction capability of humic acid extracted from the organic component of municipal solid waste. AB - The capacity of humic acid extracted from organic waste (HAw) to reduce Cr(VI) was tested at pH 2.5, 4 and 6 and compared with coal-derived humic acid (HAc). HAw was more effective than HAc in reducing Cr(VI). The kinetics of Cr(VI) reductions depended strongly on pH. The calculation of the apparent rate coefficients indicated that HAw was more efficient at reducing Cr(VI) than HAc, but was also more efficient than HAs from soil and peat. The reduction capability of HAs depends on the type of functional groups (i.e., thiols and phenols) present, rather than the free radicals. HAw was more efficient at reducing Cr(VI) than HAc because more reactive phenols were present, i.e., methoxy- and methyl phenols. PMID- 23923422 TI - Off-flavor compounds from decaying cyanobacterial blooms of Lake Taihu. AB - The effect of cyanobacterial bloom decay on water quality and the complete degradation of cyanobacterial blooms in a short period were examined by an enclosure experiment in Gonghu Bay of Lake Taihu, China. Water quality parameters as well as taste and odor compounds during the breakdown of cyanobacterial blooms were measured. Results showed that the decay of cyanobacterial blooms caused anoxic water conditions, decreased pH, and increased nutrient loading to the lake water. The highest concentrations of dimethyl sulfide (DMS), dimethyl trisulfide (DMTS), and beta-cyclocitral were observed in the anoxic water, at 62331.8, 12413.3, and 1374.9 ng/L, respectively. 2-Methylisoborneol was dominant during the live growth phase of cyanobacterial blooms, whereas DMS and DMTS were dominant during the decomposition phase. Dissolved oxygen, pH, and chlorophyll a were negatively correlated with DMS, DMTS, and beta-cyclocitral, whereas total phosphorus, total nitrogen, and ammonium (NH(4+)-N) were positively correlated with DMS, DMTS, beta3-cyclocitral, and beta-ionone. The experimental results suggested that preventing the anaerobic decomposition of cyanobacterial blooms is an important strategy against the recurrence of a malodor crisis in Lake Taihu. PMID- 23923423 TI - Pollutant concentrations and pollution loads in stormwater runoff from different land uses in Chongqing. AB - To investigate the distribution of pollutant concentrations and pollution loads in stormwater runoff in Chongqing, six typical land use types were selected and studied from August 2009 to September 2011. Statistical analysis on the distribution of pollutant concentrations in all water samples shows that pollutant concentrations fluctuate greatly in rainfall-runoff, and the concentrations of the same pollutant also vary greatly in different rainfall events. In addition, it indicates that the event mean concentrations (EMCs) of total suspended solids (TSS) and chemical oxygen demand (COD) from urban traffic roads (UTR) are significantly higher than those from residential roads (RR), commercial areas (CA), concrete roofs (CR), tile roofs (TRoof), and campus catchment areas (CCA); and the EMCs of total phosphorus (TP) and NH3-N from UTR and CA are 2.35-5 and 3 times of the class-II standard values specified in the Environmental Quality Standards for Surface Water (GB 3838-2002). The EMCs of Fe, Pb and Cd are also much higher than the class-III standard values. The analysis of pollution load producing coefficients (PLPC) reveals that the main pollution source of TSS, COD and TP is UTR. The analysis of correlations between rainfall factors and EMCs/PLPC indicates that rainfall duration is correlated with EMCs/PLPC of TSS for TRoof and TP for UTR, while rainfall intensity is correlated with EMCs/PLPC of TP for both CR and CCA. The results of this study provide a reference for better management of non-point source pollution in urban regions. PMID- 23923425 TI - Synergistic impacts of anthropogenic and biogenic emissions on summer surface O3 in East Asia. AB - A factor separation technique and an improved regional air quality model (RAQM) were applied to calculate synergistic contributions of anthropogenic volatile organic compounds (AVOCs), biogenic volatile organic compounds (BVOCs) and nitrogen oxides (NOx) to daily maximum surface 03 (O3DM) concentrations in East Asia in summer (June to August 2000). The summer averaged synergistic impacts of AVOCs and NOx are dominant in most areas of North China, with a maximum of 60 ppbv, while those of BVOCs and NOx are notable only in some limited areas with high BVOC emissions in South China, with a maximum of 25 ppbv. This result implies that BVOCs contribute much less to summer averaged O3DM concentrations than AVOCs in most areas of East Asia at a coarse spatial resolution (1 degree x 1 degree) although global emissions of BVOCs are much greater than those of AVOCs. Daily maximum total contributions of BVOCs can approach 20 ppbv in North China, but they can reach 40 ppbv in South China, approaching or exceeding those in some developed countries in Europe and North America. BVOC emissions in such special areas should be considered when 03 control measures are taken. Synergistic contributions among AVOCs, BVOCs and NOx significantly enhance O3 concentrations in the Beijing-Tianjin-Tangshan region and decrease them in some areas in South China. Thus, the total contributions of BVOCs to O3DM vary significantly from day to day and from location to location. This result suggests that 03 control measures obtained from episodic studies could be limited for long term applications. PMID- 23923426 TI - Effect of central ventilation and air conditioner system on the concentration and health risk from airborne polycyclic aromatic hydrocarbons. AB - Central ventilation and air conditioner systems are widely utilized nowadays in public places for air exchange and temperature control, which significantly influences the transfer of pollutants between indoors and outdoors. To study the effect of central ventilation and air conditioner systems on the concentration and health risk from airborne pollutants, a spatial and temporal survey was carried out using polycyclic aromatic hydrocarbons (PAHs) as agent pollutants. During the period when the central ventilation system operated without air conditioning (AC-off period), concentrations of 2-4 ring PAHs in the model supermarket were dominated by outdoor levels, due to the good linearity between indoor air and outdoor air (r(p) > 0.769, p < 0.05), and the slopes (1.2-4.54) indicated that ventilating like the model supermarket increased the potential health risks from low molecular weight PAHs. During the period when the central ventilation and air conditioner systems were working simultaneously (AC-on period), although the total levels of PAHs were increased, the concentrations and percentage of the particulate PAHs indoors declined significantly. The BaP equivalency (BaPeq) concentration indicated that utilization of air conditioning reduced the health risks from PAHs in the model supermarket. PMID- 23923424 TI - Influence of fuel mass load, oxygen supply and burning rate on emission factor and size distribution of carbonaceous particulate matter from indoor corn straw burning. AB - The uncertainty in emission estimation is strongly associated with the variation in emission factor (EF), which could be influenced by a variety of factors such as fuel properties, stove type, fire management and even methods used in measurements. The impacts of these factors are complicated and often interact with each other. Controlled burning experiments were conducted to investigate the influences of fuel mass load, air supply and burning rate on the emissions and size distributions of carbonaceous particulate matter (PM) from indoor corn straw burning in a cooking stove. The results showed that the EFs of PM (EF(PM)), organic carbon (EFoc) and elemental carbon (EF(EC)) were independent of the fuel mass load. The differences among them under different burning rates or air supply amounts were also found to be insignificant (p > 0.05) in the tested circumstances. PM from the indoor corn straw burning was dominated by fine PM with diameter less than 2.1 microm, contributing 86.4% +/- 3.9% of the total. The size distribution of PM was influenced by the burning rate and air supply conditions. On average, EF(PM), EF(OC) and EF(EC) for corn straw burned in a residential cooking stove were (3.84 +/- 1.02), (0.846 +/- 0.895) and (0.391 +/- 0.350) g/kg, respectively. EF(PM), EF(OC) and EF(EC) were found to be positively correlated with each other (p < 0.05), but they were not significantly correlated with the EF of co-emitted CO, suggesting that special attention should be paid to the use of CO as a surrogate for other incomplete combustion pollutants. PMID- 23923427 TI - Emission inventory evaluation using observations of regional atmospheric background stations of China. AB - Any accurate simulation of regional air quality by numerical models entails accurate and up-to-date emissions data for that region. The INTEX-B2006 (I06), one of the newest emission inventories recently popularly used in China and East Asia, has been assessed using the Community Multiscale Air Quality model and observations from regional atmospheric background stations of China. Comparisons of the model results with the observations for the species SO2, NO2, O3 and CO from the three regional atmospheric background stations of Shangdianzi, Longfengshan and Linan show that the model can basically capture the temporal characteristics of observations such as the monthly, seasonal and diurnal variance trends. Compared to the other three species, the simulated CO values were grossly underestimated by about two-third or one-half of the observed values, related to the uncertainty in CO emissions. Compared to the other two stations, Shangdianzi had poorer simulations, especially for SO2 and CO, which partly resulted from the site location close to local emission sources from the Beijing area; and the regional inventory used was not capable of capturing the influencing factors of strong regional sources on stations. Generally, the fact that summer gave poor simulation, especially for SO2 and O3, might partly relate to poor simulations of meteorological fields such as temperature and wind. PMID- 23923428 TI - An improved GC-ECD method for measuring atmospheric N2O. AB - Gas chromatography equipped with an electron capture detector (GC-ECD) has been widely used for measuring atmospheric N2O, but nonlinear response and the influence of atmospheric CO2 have been recognized as defects for quantification. An original GC-ECD method using N2 as carrier gas was improved by introducing a small flow rate of CO2 makeup gas into the ECD, which could well remedy the above defects. The N2O signal of the improved method was 4-fold higher than that of the original method and the relative standard deviation was reduced from > 1% to 0.31%. N2O concentrations with different CO2 concentrations (172.2 x 10(-6)-1722 x 10(-6) mol/mol) measured by the improved GC-ECD method were in line with the actual N2O concentrations. However, the N2O concentrations detected by the original method were largely biased with a variation range of -4.5%-7%. The N2O fluxes between an agricultural field and the atmosphere measured by the original method were greatly overestimated in comparison with those measured by the improved method. Good linear correlation (R2 = 0.9996) between the response of the improved ECD and N2O concentrations (93 x 10(-9)-1966 x 10(-9) mol/mol) indicated that atmospheric N2O could be accurately quantified via a single standard gas. Atmospheric N20 concentrations comparatively measured by the improved method and a high precision GC-ECD method were in good agreement. PMID- 23923429 TI - Adsorption of carbon dioxide on amine-modified TiO2 nanotubes. AB - TiO2 nanotubes (TiNT) were prepared by a hydrothermal treatment and modified by three kinds of amines, namely ethylenediamine, polyetherimide and tetraethylenepentamine (TEPA), to study their CO2 adsorption properties from gas streams. The resultant samples were characterized by X-ray diffraction, transmission electron microscopy, and infrared spectroscopy, as well as low temperature N2 adsorption. CO2 capture was investigated in a dynamic packed column at 30 degrees C. TEPA-modified TiO2 nanotubes showed the highest adsorption capacity of 167.64 mg/g because it had the highest amino-group content among the three amines. CO2 fixation on TiNT impregnated by TEPA was investigated at 30, 50, and 70 degrees C, and the adsorption capacity increased slightly with temperature. Following the adsorption step, the sorbents were regenerated by temperature programmed desorption, and the TiNT-TEPA sample, as CO2 sorbent, was found to be readily regenerated and energy-efficient. The cycle test also revealed that the TiNT-TEPA adsorbent is fairly stable, with only a 5% drop in the adsorption capacity after 10 adsorption/desorption cycles. In addition, the CO2 adsorption behavior was investigated with the deactivation model, and which showed an excellent prediction for the TiNT-TEPA breakthrough curves. PMID- 23923430 TI - Factors influencing the contents of metals and as in soils around the watershed of Guanting Reservoir, China. AB - Topsoil samples from 61 sites around the Guanting Reservoir, China, were measured for Cu, Zn, Cr, Ni, Cd, Pb and As concentrations. The mean concentrations of Cu, Zn, Cr, Ni, Cd, Pb and As were 16.8, 59.4, 37.8, 18.3, 0.32, 20.1 and 8.67 mg/kg dry weight, respectively. Factors that influence the dynamics of these metals in soils around the watersheds of Beijing reservoirs were examined. The influence of atmospheric deposition, land use, soil texture, soil type and soil chemical parameters on metal contents in soils was investigated. Atmospheric deposition, land use and soil texture were the important factors affecting heavy metal residues. Soil type and soil chemical parameters were also involved in heavy metal retention in soils. The data provided in this study are considered crucial for reservoir remediation, especially since the Guanting Reservoir will serve as one of the main drinking water sources for Beijing in the foreseeable future. PMID- 23923431 TI - Photolysis of polycyclic aromatic hydrocarbons on soil surfaces under UV irradiation. AB - Photolysis of some polycyclic aromatic hydrocarbons (PAHs) on soil surfaces may play an important role in the fate of PAHs in the environment. Photolysis of PAHs on soil surfaces under UV irradiation was investigated. The effects of oxygen, irradiation intensity and soil moisture on the degradation of the three PAHs were observed. The results showed that oxygen, soil moisture and irradiation intensity enhanced the photolysis of the three PAHs on soil surfaces. The degradation of the three PAHs on soil surfaces is related to their absorption spectra and the oxidation-half-wave potential. The photolysis of PAHs on soil surfaces in the presence of oxygen followed pseudo first-order kinetics. The photolysis half lives ranged from 37.87 days for benzo[a]pyrene to 58.73 days for phenanthrene. The results indicate that photolysis is a successful way to remediate PAHs contaminated soils. PMID- 23923432 TI - Sorption and transport studies of cetyl trimethylammonium bromide (CTAB) and Triton X-100 in clayey soil. AB - Surfactants are soil washing agents and facilitators for subsurface remediation of hydrocarbon spills. It is important to understand the sorption and transport behavior of surfactants for enhanced soil remediation. The adsorption and desorption isotherms of cetyl trimethylammonium bromide (CTAB) and Triton X-100 with sand and kaolinite have been quantified. Kaolinite clay had the highest sorption capacity compared to blasting sand. Transport parameters such as diffusion coefficient (D) and retardation factor (R) of the above mentioned surfactant solutions were determined in clayey soils (82.5% sand and 17.5% kaolinite mixture) with near zero and 0.1 g/L ionic strength. NaCl was used as the electrolyte solution. Convection-Diffusion equation was used to model the breakthrough curves of the surfactants. Bromide ion was chosen as the tracer material in order to characterize the column. CTAB and Triton X-100 were used to flush the perchloroethylene (PCE) contaminated soil. The effectiveness of CTAB and Triton X-100 in flushing the PCE from the contaminated soil was quantified. PMID- 23923433 TI - Effects of soil water and nitrogen availability on photosynthesis and water use efficiency of Robinia pseudoacacia seedlings. AB - The efficient use of water and nitrogen (N) to promote growth and increase yield of fruit trees and crops is well studied. However, little is known about their effects on woody plants growing in arid and semiarid areas with limited water and N availability. To examine the effects of water and N supply on early growth and water use efficiency (WUE) of trees on dry soils, one-year-old seedlings of Robinia pseudoacacia were exposed to three soil water contents (non-limiting, medium drought, and severe drought) as well as to low and high N levels, for four months. Photosynthetic parameters, leaf instantaneous WUE (WUEi) and whole tree WUE (WUEb) were determined. Results showed that, independent of N levels, increasing soil water content enhanced the tree transpiration rate (Tr), stomatal conductance (Gs), intercellular CO2 concentration (Ci), maximum net assimilation rate (Amax), apparent quantum yield (AQY), the range of photosynthetically active radiation (PAR) due to both reduced light compensation point and enhanced light saturation point, and dark respiration rate (Rd), resulting in a higher net photosynthetic rate (Pn) and a significantly increased whole tree biomass. Consequently, WUEi and WUEb were reduced at low N, whereas WUEi was enhanced at high N levels. Irrespective of soil water availability, N supply enhanced Pn in association with an increase of Gs and Ci and a decrease of the stomatal limitation value (Ls), while Tr remained unchanged. Biomass and WUEi increased under non-limiting water conditions and medium drought, as well as WUEb under all water conditions; but under severe drought, WUEi and biomass were not affected by N application. In conclusion, increasing soil water availability improves photosynthetic capacity and biomass accumulation under low and high N levels, but its effects on WUE vary with soil N levels. N supply increased Pn and WUE, but under severe drought, N supply did not enhance WUEi and biomass. PMID- 23923434 TI - Phytoremediation potential of charophytes: bioaccumulation and toxicity studies of cadmium, lead and zinc. AB - The ability for usage of common freshwater charophytes, Chara aculeolata and Nitella opaca in removal of cadmium (Cd), lead (Pb) and zinc (Zn) from wastewater was examined. C. aculeolata and N. opaca were exposed to various concentrations of Cd (0.25 and 0.5 mg/L), Pb (5 and 10 mg/L) and Zn (5 and 10 mg/L) solutions under hydroponic conditions for 6 days. C. aculeolata was more tolerant of Cd and Pb than N. opaca. The relative growth rate of N. opaca was drastically reduced at high concentrations of Cd and Pb although both were tolerant of Zn. Both macroalgae showed a reduction in chloroplast, chlorophyll and carotenoid content after Cd and Pb exposure, while Zn exposure had little effects. The bioaccumulation of both Cd and Pb was higher in N. opaca (1544.3 microg/g at 0.5 mg/L Cd, 21657.0 microg/g at 10 mg/L Pb) whereas higher Zn accumulation was observed in C. aculeolata (6703.5 microg/g at 10 mg/L Zn). In addition, high bioconcentration factor values (> 1000) for Cd and Pb were observed in both species. C. aculeolata showed higher percentage of Cd and Pb removal (> 95%) than N. opaca and seemed to be a better choice for Cd and Pb removal from wastewater due to its tolerance to these metals. PMID- 23923435 TI - Sulfur speciation and bioaccumulation in camphor tree leaves as atmospheric sulfur indicator analyzed by synchrotron radiation XRF and XANES. AB - Analyzing and understanding the effects of ambient pollution on plants is getting more and more attention as a topic of environmental biology. A method based on synchrotron radiation X-ray fluorescence and X-ray absorption near edge structure spectroscopy was established to analyze the sulfur concentration and speciation in mature camphor tree leaves (CTLs), which were sampled from 5 local fields in Shanghai, China. Annual SO2 concentration, SO4(2-) concentration in atmospheric particulate, SO4(2-) and sulfur concentration in soil were also analyzed to explore the relationship between ambient sulfur sources and the sulfur nutrient cycling in CTLs. Total sulfur concentration in mature camphor tree leaves was 766 1704 mg/kg. The mainly detected sulfur states and their corresponding compounds were +6 (sulfate, include inorganic sulfate and organic sulfate), +5.2 (sulfonate), +2.2 (suloxides), +0.6 (thiols and thiothers), +0.2 (organic sulfides). Total sulfur concentration was strongly correlated with sulfate proportion with a linear correlation coefficient up to 0.977, which suggested that sulfur accumulated in CTLs as sulfate form. Reduced sulfur compounds (organic sulfides, thiols, thioethers, sulfoxide and sulfonate) assimilation was sufficed to meet the nutrient requirement for growth at a balanced level around 526 mg/kg. The sulfate accumulation mainly caused by atmospheric sulfur pollution such as SO2 and airborne sulfate particulate instead of soil contamination. From urban to suburb place, sulfate in mature CTLs decreased as the atmospheric sulfur pollution reduced, but a dramatic increase presented near the seashore, where the marine sulfate emission and maritime activity pollution were significant. The sulfur concentration and speciation in mature CTLs effectively represented the long-term biological accumulation of atmospheric sulfur pollution in local environment. PMID- 23923436 TI - Hydrocarbon biodegradation and dynamic laser speckle for detecting chemotactic responses at low bacterial concentration. AB - We report on the biodegradation of pure hydrocarbons and chemotaxis towards these compounds by an isolated chlorophenol degrader, Pseudomonas strain H. The biochemical and phylogenetic analysis of the 16S rDNA sequence identified Pseudomonas strain H as having 99.56% similarity with P. aeruginosa PA01. This strain was able to degrade n-hexadecane, 1-undecene, 1-nonene, 1-decene, 1 dodecene and kerosene. It grew in the presence of 1-octene, while this hydrocarbons is toxic to other hydrocarbons degraders. Pseudomonas strain H was also chemotactic towards n-hexadecane, kerosene, 1-undecene and 1-dodecene. These results show that this Pseudomonas strain H is an attractive candidate for hydrocarbon-containing wastewater bioremediation in controlled environments. Since the classical standard techniques for detecting chemotaxis are not efficient at low bacterial concentrations, we demonstrate the use of the dynamic speckle laser method, which is simple and inexpensive, to confirm bacterial chemotaxis at low cell concentrations (less than 10(5) colony-forming unit per millilitre (CFU/mL)) when hydrocarbons are the attractants. PMID- 23923437 TI - Biogeochemical reductive release of soil embedded arsenate around a crater area (Guandu) in northern Taiwan using X-ray absorption near-edge spectroscopy. AB - This study investigates biogeochemical reductive release of arsenate from beudantite into solution in a crater area in northern Taiwan, using a combination of X-ray absorption near-edge structure (XANES) and atomic absorption spectrometry. Total arsenic (As) concentrations in the soil were more than 200 mg/kg. Over four months of laboratory experiments, less than 0.8% As was released into solution after reduction experiments. The 71% to 83% As was chemically reduced into arsenite (As(III)) and partially weathering into the soluble phase. The kinetic dissolution and re-precipitation of As, Fe, Pb and sulfate in this area of paddy soils merits further study. PMID- 23923438 TI - [Problems in your practice]. PMID- 23923439 TI - [Wasp and bee stings]. AB - Occasionally a dentist is confronted with a painful, red facial swelling which has suddenly appeared, with no signs of a dental cause. In addition to the other possible causes, one should consider the possibility of an insect bite, especially in the summer months. The consequences of an insect bite or sting are often underestimated. Hymenopterae (wasps and honeybees) stings are not generally serious in nature, but can result in severe systemic medical complications, such as an allergic reaction. Dentists who are confronted with a patient with an insect bite or sting must provide the patient with adequate information and if necessary take measures in order to prevent further complications. PMID- 23923440 TI - [Modified polyurethane foam as a local hemostatic agent after dental extractions]. AB - In this split mouth experiment, the feasibility ofpolyurethane foam as a local hemostatic agent after dental extractions was studied. Ten healthy patients underwent 2 extractions ofa dental element in 1 treatment session. The 10 patients were subsequently randomly divided in a gelatin group and a collagen group. In the gelatin group, a polyurethane foam (PU) was applied in 1 extraction socket, while in the other socket a commercially available gelatin foam was applied. In the collagen group, a PU was applied in 1 socket, and a collagen wadding in the other. All hemostats were removed after 2 minutes, after which the degree of coagulation was measured using a thrombin/antithrombin test and a fibrinogen test. This study suggests that polyurethane foam has hemostatic capacity. Large scale clinical research is needed to confirm this finding, and should indicate whether this hemostatic capacity is clinically relevant. PMID- 23923441 TI - [Oral medicine 8. Leukoplakia of the oral mucosa]. AB - Leukoplakia of the oral mucosa is a potentially malignant disorder, which means that there is an elevated risk oftransformation into a squamous cell carcinoma. The term oral leukoplakia is a clinical diagnosis for a predominantly white lesion which is not immediately recognizable as another well definable lesion which is white in appearance. Oral leukoplakia is generally an asymptomatic disorder of the mucosa with a prevalence of less than 2 per cent in the adult population. Tobacco usage is considered to be the most important etiological factor. Malignant transformation into a squamous cell carcinoma occurs in about I per cent per year. A patient with oral leukoplakia is generally referred to an oral and maxillofacial surgeon, who takes a biopsy for a definitive histopathological diagnosis. The outcome of the histopathological study, which may vary from hyperkeratosis to invasive squamous cell carcinoma, will determine the treatment. It is preferable that every leukoplakia is removed to reduce the risk of malignant transformation. Long term follow-up is indicated. Follow-up may in some cases be performed by the general dental practitioner. PMID- 23923442 TI - [Dental and health law 4. The treatment of minors and of adults who are unable to give informed consent]. AB - When minors are treated, a complex triangular relationship can emerge among dentist, patient and the individual legally responsible for the patient. Generally speaking, both parents are those legally responsible for a child. This might not be the case if the parents are not married to each other or have divorced, or when there is a question of a child protection ruling. The governing rule is that dentists are required to honour the obligations to the legal representatives thatfollow from the patients' rights concerning the treatment of children under the age of 12. In the case of patients between the ages of 12 and 16, dentists are required to act in accordance with their obligations to both those legally responsible and to the patients. Finally, in the case ofpatients who are 16 and older, dentists are required to act only in accordance with their obligations to the patients. There are, however, various exceptions to this governing rule. One of the most common examples is the patient who is a minor of 16 or older who is unable to determine what is in his own best interest. That criterium is also used in determining the capability to give informed consent in adults. PMID- 23923443 TI - [The conventional and the digital impression method for single-unit and multi unit fixed dental prostheses]. AB - To manufacture single-unit and multi-unit fixed dental prostheses, an accurate cast is required. Casts can be obtained either by the conventional or the digital impression method. For both methods, dry tooth surfaces and a well exposed finish line of the tooth preparation are required. The conventional impression method requires an elastic impression material. Elastomers have a high detail accuracy, which can produce, in combination with a good fitting and rigid impression tray, an impression with reliable dimensional stability. Based on the number of different impression material consistencies used and the number ofphases of the impression procedure, several options of the conventional impression method can be distinguished. For the digital impression method, teeth or implants are scanned to produce a digital cast which can be used directly with the help of computer technology to produce single-unit or multi-unit fixed dental prostheses. The digital impression method has a number of advantages when compared to the conventional impression method, but is not applicable for all prosthetic cases. PMID- 23923445 TI - [In a crisis situation, let's innovate!]. PMID- 23923446 TI - [What will be the role of the nurse with vaccination programs?]. PMID- 23923444 TI - [Aftercare for durability and profitability of single-unit and multi-unit fixed dental prostheses]. AB - An important aim ofa treatment with single-unit and multi-unit fixed dental prostheses is a durable and profitable treatment outcome. That requires aftercare, too. First, the frequency of routine oral examinations should be assessed, using an individual risk profile. The objectives of the routine oral examinations are the prevention and, when necessary, the treatment of pathological conditions and complications. With regard to prevention, attention should be paid to information and instruction, oral biofilm and calculus, non functional activities, hard tooth tissues, periodontal and peri-implant tissues, and saliva. Subsequently, it can be determined whether the intended durability and profitability have been achieved or can still be achieved, whether or not through indicated adjustments. Special attention should be paid to endodontically treated teeth. Restorative, repair or replacement treatments may be indicated in case ofcomplications, such as loose single- or multi-unitfixed dental prosthesis, fracture of a fixed dental prosthesis unit, lost tooth pulp vitality, tooth root fracture, and implant or implant abutment problems. PMID- 23923447 TI - [Perinatal health in France, mixed results]. PMID- 23923448 TI - [Bronchiolitis does not aggravate the neurodevelopmental prognosis of extremely premature infants]. PMID- 23923449 TI - [Eating disorders. Using the body to indicate suffering]. PMID- 23923450 TI - [Anorexia, a broken connection]. PMID- 23923451 TI - [Therapeutic bonds for the treatment of eating disorders]. AB - Anorexia is the most common eating disorder. Aside from the weight loss and its effects on the body, this disease is characterised by relationship difficulties within the family. Institutional treatment aims to enable the teenager and her family to meet different professionals and, gradually, to create diverse bonds. The young patient thereby experiences difference and uncertainty in the relationship with others, while retaining the reassurance of an empathetic bond. PMID- 23923452 TI - [Family therapy in the treatment of eating disorders]. AB - With eating disorders, family therapies are concerned with how the family relationships work. The aim is to develop sufficient relational flexibility in order that each family member can find his or her place and develop their autonomy, without threatening the family balance. PMID- 23923453 TI - [Anorexia in adolescents, the experience of caregivers and team supervision]. AB - The hospital treatment of anorexic adolescents is complex, multidisciplinary and often long.The psychopathological functioning of these young patients places the caregivers in a difficult position. The team of the adolescent crisis and hospitalisation unit at Caen general hospital benefits from the support of a psychologist from outside the unit. PMID- 23923454 TI - [Anorexia and corporal mediations]. AB - The body, the central point of expression of the anorexic symptom, is an important therapeutic lever.The young anorexic girl protects herself through corporal hypertonicity. This tension is consistent with her fears of seeing her body becoming that of an adult and to feel emotions and sensations with too much force. Corporal mediation consists in helping the young girls get to grips with this body. PMID- 23923455 TI - [Treatment study hospitalizations and eating disorders]. AB - Treatment-study hospitalisations are indicated in the case of severe eating disorders. This original programme for long term hospitalisation enables young patients to follow an individualised treatment at the same time as receiving support in their studies, adapted to the clinical condition. PMID- 23923456 TI - [Home monitoring of infants suffering from infantile anorexia]. AB - The construction of parenthood comes under pressure when an infant suffers from anorexia nervosa. Support at home for the family can be provided by the child health nurse using Esther Bick's infant observation method. Over the course of the visits, the intrafamily relationships are appeased to create an atmosphere which is favourable to the harmonious development of the child. PMID- 23923457 TI - [A network approach for the treatment of adolescents]. AB - The treatment of eating disorders is long and complex. It requires the involvement of professionals from the medical, allied health and social fields to work with the wide diversity of patients and families. There are a variety of different centres and ways of working. A care network constitutes a resource for professionals as well as for patients and their families, favouring the coordination of all players involved in their care. PMID- 23923459 TI - [Bibliography. Eating disorders]. PMID- 23923458 TI - [The fight against eating disorders]. PMID- 23923460 TI - [Remaining a parent despite a child's cancer]. AB - The experience of cancer in a child is traumatic for the child and the family Despite the medical advances which have been made, it is a serious pathology marked by uncertainty as regards the future of the young patient. The parents, shaken, often underestimate the importance of maintaining their educational role with their child. Child health nurses, in collaboration with the multidisciplinary team, have an important role to play in supporting parenthood. PMID- 23923461 TI - Case of the month. Pyogenic granuloma. PMID- 23923462 TI - Oral cancer: what to do? PMID- 23923463 TI - The limitations of the clinical oral examination in detecting dysplastic oral lesions and oral squamous cell carcinoma. AB - BACKGROUND: The clinical oral examination (COE) is the criterion standard for the initial detection of oral lesions that harbor dysplasia or oral squamous cell carcinoma (OSCC) at an early stage when they are most treatable. The authors conducted a systematic review to assess the effectiveness of the COE in predicting histologic diagnosis of dysplasia or OSCC. METHODS: The authors conducted automated searches of PubMed, Web of Knowledge, and the Cochrane Library from 1966 through 2010 for randomized controlled trials and observational studies that included the terms "oral mucosal lesion screening" and "oral lesions." They determined the quality (sensitivity, specificity, positive predictive value, negative predictive value and diagnostic odds ratio) of selected studies by using the Quality Assessment of Diagnostic Accuracy Studies tool. RESULTS: The overall diagnostic odds ratio was 6.1 (95% confidence interval, 2.1-17.6); therefore, the COE was considered to have poor overall performance as a diagnostic method for predicting dysplasia and OSCC. CLINICAL IMPLICATIONS: On the basis of the available literature, the authors determined that a COE of mucosal lesions generally is not predictive of histologic diagnosis. The fact that OSCCs often are diagnosed at an advanced stage of disease indicates the need for improving the COE and for developing adjuncts to help detect and diagnose oral mucosal lesions. PMID- 23923464 TI - It's not just an "oral cancer" exam. AB - The early identification and treatment of cancer of the head and neck, including oropharyngeal cancer (OPC), is associated with an improved survival rate. Specific efforts to promote screening to improve the early detection of OPC have come under scrutiny, largely due to the low prevalence of the disease. However, screening the patient for OPC does not occur as an isolated event in contemporary practice, but as an integral component of the hard and soft tissue examination to determine the totality of the patient's oral health. Three patient vignettes are presented to demonstrate that, regardless the outcome of the debate over OPC screening, the oral health care professional who performs a thorough examination of the head and neck is often in the best position to discover early cancer affecting the head and neck. PMID- 23923465 TI - Penicillin not effective for preoperative irreversible pulpitis pain (UT CAT #2244). PMID- 23923466 TI - Oral cancer: FAQ. AB - The efficacy of clinical examination in detecting intraoral malignances has recently been called into question, as it does not accurately predict the histological diagnosis. A brief reexamination of one study provides some insights into what this means to the clinician. Making a diagnosis on the basis of a clinical examination may result in a false-positive finding and unnecessary treatment. However, a more significant concern would be a false-negative finding, in which disease is present but not detected and therefore not treated. The most effective preventive strategy is to help patients reduce or eliminate dangerous habits, and to remain alert for signs of potentially malignant or early-stage lesions, and perform routine visual and tactile examinations of all patients. A working knowledge of the clinical epidemiology of oral cancer, familiarity with the risk factors, signs and symptoms, together with continued vigilance in the form of regular, systematic and thorough clinical examination remains the most basic means of ensuring early detection of oral cancer and providing the best care possible. PMID- 23923467 TI - E-cigarettes: What's known, what's unknown. AB - Use and awareness of the e-cigarette, also referred to in the literature as an Electronic Nicotine Delivery Device, has dramatically increased since its introduction to the U.S. market in 2007. The regulatory power of the Food and Drug Administration over these devices is restricted to their classification as a tobacco product, as the manufacturers do not claim a therapeutic effect, as is the case with nicotine replacement therapy. The use, safety, chemical content and efficacy of the device for smoking cessation is the subject of considerable debate in the scientific community and poses a challenge to clinicians whose patients have elected to use e-cigarettes as a replacement for (or in addition to) cigarettes, to reduce the number of cigarettes they smoke, or for smoking cessation. PMID- 23923468 TI - The unanswered question? PMID- 23923469 TI - Physicians' conceptualization of "closure" as a benefit of physician-parent follow-up meetings after a child's death in the pediatric intensive care unit. AB - We examined physicians' conceptualization of closure as a benefit of follow-up meetings with bereaved parents. The frequency of use and the meaning of the word "closure" were analyzed in transcripts of interviews with 67 critical care physicians affiliated with the Collaborative Pediatric Critical Care Research Network. In all, 38 physicians (57 percent) used the word "closure" at least once (median: 2; range: 1 to 7), for a total of 86 times. Physicians indicated that closure is a process or trajectory rather than an achievable goal. They also indicated that parents and physicians can move toward closure by gaining a better understanding of the causes and circumstances of the death and by reconnecting with, or resolving relationships between, parents and health professionals. Physicians suggested that a primary reason to conduct follow-up meetings is that such meetings offer parents and physicians an opportunity to move toward closure. Future research should attempt to determine whether followup meetings reduce the negative effects of bereavement for parents and physicians. PMID- 23923470 TI - Living fully in the shadow of mortal time: psychosocial assets in advanced cancer. AB - OBJECTIVE: This study aimed to characterize the strategies and psychosocial conditions that influence how resilient people live in the face of advanced cancer. METHODS: Grounded theory interviews and a survey of 10 resilient people with advanced cancer were collected and analyzed. FINDINGS: Personal assets - including positive relationships, purpose in life, faith, and mastery- contributed to living fully in mortal time. Strategies included embracing paradox, reframing time, deepening connections, and aligning actions with priorities. Open-ended interviews yielded rich illness and life stories; many participants requested a copy of the transcript. CONCLUSION: Resilient people use a range of strategies to thrive in the face of advanced cancer. PMID- 23923471 TI - Evaluation of the role and cost-effectiveness of end-of-life orthopaedic interventions in cancer patients with skeletal metastases to the hip. AB - This study aimed to evaluate the effect of hip reconstruction on patients with skeletal metastases to the hip. We investigated the effect of hip reconstruction on quality of life and ambulatory status, as well as cost-effectiveness of hip reconstruction in this group of patients. PMID- 23923472 TI - Determinants of family satisfaction with inpatient palliative care in Korea. AB - OBJECTIVE: We aimed to identify which structures and processes of care are key determinants of overall satisfaction with palliative care. METHODS: A nationwide, multicentre, cross-sectional questionnaire survey was conducted with 501 bereaved family members of terminal cancer patients (effective response rate: 20.9 percent). Structures and processes were evaluated using the Care Evaluation Scale (CES). RESULTS: In univariate analyses, all domains of the CES were significantly associated with overall satisfaction with care. In multivariate analyses, the domains of physical care by physician, physical care by nurse, environment, and coordination positively influenced overall satisfaction. After case-mix adjustment, physical care by nurse, age of patient, and lower education level of bereaved family member remained as significant determinants. CONCLUSION: Our finding that nursing is the most critical determinant of overall satisfaction within many structure and process domains has an important implication for clinical quality improvement and resource allocation. PMID- 23923473 TI - Development of advance care planning research priorities: a call to action. AB - The objective of this study was to develop a national, prioritized research agenda for advance care planning (ACP). We first identified a list of comprehensive ACP research topics and determined priority criteria through focus groups. We next conducted a survey wherein importance weights were assigned to priority criteria and each ACP topic was rated. We combined weights and ratings into overall scores. A total of 17 ACP topics were developed and placed into four categories: patients and family members, the general public, professionals, and the healthcare system. Four main priority criteria were created: feasibility, consistency with ethical and societal values, economic considerations, and impact. Of the 100 individuals we invited to participate in the survey, 62 accepted. Prioritized topics centred largely on the impact of ACP on health resource utilization, communicating advance care planning across settings, and the preferred manner of engaging patients in ACP. PMID- 23923474 TI - Learning palliative care in India: two personal perspectives. PMID- 23923475 TI - Predictors of home death in palliative care patients: a critical literature review. PMID- 23923476 TI - Methadone as an additional opioid for a cancer patient with severe neuropathic and bone pain not responsive to other opioids and adjuvant analgesics. PMID- 23923477 TI - Anniversary. PMID- 23923478 TI - Conscientious objector: Edna St. Vincent Millay, mortality, and the role of palliative care. PMID- 23923479 TI - Successional changes in functional composition contrast for dry and wet tropical forest. AB - We tested whether and how functional composition changes with succession in dry deciduous and wet evergreen forests of Mexico. We hypothesized that compositional changes during succession in dry forest were mainly determined by increasing water availability leading to community functional changes from conservative to acquisitive strategies, and in wet forest by decreasing light availability leading to changes from acquisitive to conservative strategies. Research was carried out in 15 dry secondary forest plots (5-63 years after abandonment) and 17 wet secondary forest plots (< 1-25 years after abandonment). Community-level functional traits were represented by community-weighted means based on 11 functional traits measured on 132 species. Successional changes in functional composition are more marked in dry forest than in wet forest and largely characterized by different traits. During dry forest succession, conservative traits related to drought tolerance and drought avoidance decreased, as predicted. Unexpectedly acquisitive leaf traits also decreased, whereas seed size and dependence on biotic dispersal increased. In wet forest succession, functional composition changed from acquisitive to conservative leaf traits, suggesting light availability as the main driver of changes. Distinct suites of traits shape functional composition changes in dry and wet forest succession, responding to different environmental filters. PMID- 23923480 TI - Emergent fungal entomopathogen does not alter density dependence in a viral competitor. AB - Population cycles in forest Lepidoptera often result from recurring density dependent epizootics of entomopathogens. While these systems are typically dominated by a single pathogen species, insects are often infected by multiple pathogens, yet little is known how pathogens interact to affect host dynamics. The apparent invasion of northeastern North America by the fungal entomopathogen Entomophaga maimaiga some time prior to 1989 provides a unique opportunity to evaluate such interactions. Prior to the arrival of E. maimaga, the oscillatory dynamics of host gypsy moth, Lymantria dispar, populations were apparently driven by epizootics of a nucleopolyhedrovirus. Subsequent to its emergence, E. maimaiga has caused extensive mortality in host populations, but little is known about how it has altered multigenerational dynamics of the gypsy moth and its virus. Here we compared demographic data collected in gypsy moth populations prior to vs. after E. maimaiga's invasion. We found that the recently invading fungal pathogen virtually always causes greater levels of mortality in hosts than does the virus, but fungal mortality is largely density independent. Moreover, the presence of the fungus has apparently not altered the gypsy moth-virus density-dependent interactions that were shown to drive periodic oscillations in hosts before the arrival of the fungus. PMID- 23923481 TI - Native congeners provide biotic resistance to invasive Potentilla through soil biota. AB - Soil biota can facilitate exotic plant invasions and these effects can be influenced by specific phylogenetic relationships among plant taxa. We measured the effects of sterilizing soils from different native plant monocultures on the growth of Potentilla recta, an exotic invasive forb in North America, and conducted plant-soil feedback experiments with P. recta, two native congeners, a close confamilial, and Festuca idahoensis, a native grass species. We also reanalyzed data comparing the ability of P. recta to invade experimentally constructed congeneric monocultures vs. monocultures of a broad suite of non congeners. We found that monocultures as a group, other than those of the native P. arguta, were highly invasible by P. recta. In contrast, this was not the case for monocultures of P. arguta. In our first experiment, the biomass of P. recta was 50% greater when grown in soil from F. idahoensis monocultures compared to when it was grown in soils from P. arguta or P. recta monocultures. Sterilizing soil from F. idahoensis rhizospheres had no effect on the biomass of P. recta, but sterilizing soil from P. arguta and P. recta rhizospheres increased the biomass of P. recta by 108% and 90%, respectively. In a second experiment, soil trained by F. idahoensis resulted in a positive feedback for P. recta. In contrast, soils trained independently by each of the two native Potentilla species, or the closely related Dasiphora (formerly Potentilla) resulted in decreases in the total biomass of the invasive P. recta indicating strong negative feedbacks. Soil trained by P. recta also resulted in intraspecific negative feedbacks. Our results demonstrate substantial negative feedbacks for an invader in its nonnative range under certain conditions, and that native congeners can mount strong biotic resistance to an invader through the accumulation of deleterious soil biota. PMID- 23923482 TI - Carry-over effects from breeding modulate the annual cycle of a long-distance migrant: an experimental demonstration. AB - Carry-over effects relate to events or processes that influence individual performance in a subsequent season, but their occurrence in the annual cycle of migratory avian taxa is seldom studied. We investigated if different levels of resource allocation to reproduction may result in carry-over effects that change the timing and destination of long-distance migration. We reduced the parental investment of Cory's Shearwaters Calonectris diomedea by removing their chick at an early stage. When compared to individuals with greater parental investment (controls that raised chicks to close to fledging), manipulated birds started most stages of migration sooner and returned to the colony earlier at the start of the following breeding season. Late arrival in the subsequent nesting season increased the probability of skipping a breeding year. Manipulated males were less likely to engage in long-distance migration, which supports the idea that partial migration is condition dependent. Our study demonstrates experimentally that energetic or time-dependent costs of reproduction may have an enduring impact on migration schedule and on nonbreeding geographical distribution of long distance migrants, which may also influence the ability to breed in the following season. PMID- 23923483 TI - Vegetation context influences the strength and targets of pollinator-mediated selection in a deceptive orchid. AB - Clarifying the relationship between environmental context and the adaptive significance of floral traits is fundamental for an understanding of spatial and temporal variation in pollinator-mediated selection. We manipulated vegetation height and pollination regime of the orchid Dactylorhiza lapponica in a factorial design to test whether pollinator-mediated selection on floral traits is stronger in tall than in short vegetation, and whether this difference is larger for visual traits affecting pollinator attraction than for traits affecting pollination efficiency. In tall vegetation, pollinators mediated strong selection for taller plants (change in selection gradient for pollination, deltabeta(poll) = 0.33), more flowers (deltabeta(poll) = 0.34), and longer spurs (deltabeta(poll) = 0.42). In short vegetation, there was no significant selection on plant height, and pollinator-mediated selection on number of flowers and spur length was reduced by 52% and 25%, respectively. The results demonstrate experimentally that vegetation context can markedly influence the strength of pollinator-mediated selection on visual display traits, and indicate that this effect is weaker for traits affecting pollination efficiency. The study illustrates how crossed manipulations of environmental factors can reveal the causal links between ecological context and selection on floral traits. PMID- 23923484 TI - Human-induced reversal of fortunes for migratory ungulates? PMID- 23923485 TI - Animal migration amid shifting patterns of phenology and predation: lessons from a Yellowstone elk herd. AB - Migration is a striking behavioral strategy by which many animals enhance resource acquisition while reducing predation risk. Historically, the demographic benefits of such movements made migration common, but in many taxa the phenomenon is considered globally threatened. Here we describe a long-term decline in the productivity of elk (Cervus elaphus) that migrate through intact wilderness areas to protected summer ranges inside Yellowstone National Park, USA. We attribute this decline to a long-term reduction in the demographic benefits that ungulates typically gain from migration. Among migratory elk, we observed a 21-year, 70% reduction in recruitment and a 4-year, 19% depression in their pregnancy rate largely caused by infrequent reproduction of females that were young or lactating. In contrast, among resident elk, we have recently observed increasing recruitment and a high rate of pregnancy. Landscape-level changes in habitat quality and predation appear to be responsible for the declining productivity of Yellowstone migrants. From 1989 to 2009, migratory elk experienced an increasing rate and shorter duration of green-up coincident with warmer spring-summer temperatures and reduced spring precipitation, also consistent with observations of an unusually severe drought in the region. Migrants are also now exposed to four times as many grizzly bears (Ursus arctos) and wolves (Canis lupus) as resident elk. Both of these restored predators consume migratory elk calves at high rates in the Yellowstone wilderness but are maintained at low densities via lethal management and human disturbance in the year-round habitats of resident elk. Our findings suggest that large-carnivore recovery and drought, operating simultaneously along an elevation gradient, have disproportionately influenced the demography of migratory elk. Many migratory animals travel large geographic distances between their seasonal ranges. Changes in land use and climate that disparately influence such seasonal ranges may alter the ecological basis of migratory behavior, representing an important challenge for, and a powerful lens into, the ecology and conservation of migratory taxa. PMID- 23923486 TI - Ungulate migration, plant phenology, and large carnivores: the times they are a changin'. PMID- 23923487 TI - Assessing fitness consequences of migratory tactics requires long-term individually based monitoring. PMID- 23923488 TI - Do irrigation and predator control reduce the productivity of migratory ungulate herds? PMID- 23923489 TI - Will central Wyoming elk stop migrating to Yellowstone, and should we care? PMID- 23923490 TI - Environmental change and the evolution of migration. PMID- 23923492 TI - Fitness consequences of dispersal: is leaving home the best of a bad lot? AB - Using 20 years of demographic and genetic data from four populations of banner tailed kangaroo rats (Dipodomys spectabilis), we asked whether dispersing individuals gain benefits during adulthood that might compensate for the substantial survival costs they experience as juveniles. Compared to philopatric animals, within- and between-population dispersers gained no measureable advantages in adult survival, fecundity, or probability of recruiting offspring to adulthood. Restricting analyses to members of two central populations living more than 15 times the median dispersal distance from the study site edge, and using peripheral populations only to detect dispersal or offspring recruitment "offsite," did not change this result. Population density during year of birth had small negative effects on adult survival and fecundity, but there were no interactions with dispersal phenotype. We found no evidence that dispersers gained access to superior habitat or that their offspring suffered less inbreeding depression. Our results are consistent with fitness advantages being indirect; by leaving, dispersers release their kin from competition. Our results are also consistent with the possibility that dispersal is the "best of a bad lot." If dispersal is a conditional strategy, then the benefits may be obscured in observational data that compare dispersing individuals to philopatric individuals rather than to individuals whose dispersal phenotype is experimentally manipulated. PMID- 23923491 TI - Rejoinder: challenge and opportunity in the study of ungulate migration amid environmental change. PMID- 23923493 TI - Constant properties of plant-frugivore networks despite fluctuations in fruit and bird communities in space and time. AB - Human-induced changes in anthropogenic landscapes are a predominant threat to biodiversity and have been documented to affect mutualistic interactions between plants and animals, such as avian seed dispersal. Interactions between fleshy fruited plants and frugivorous birds are highly seasonal in temperate ecosystems. Nevertheless, combined effects of landscape modification and seasonal variation on plant-frugivore interactions have never been assessed from a network perspective. Here, we present the first study that simultaneously investigates effects of landscape modification and seasonal variation on plant-frugivore interactions and on functional and interaction diversity of plant-frugivore networks. We recorded visitation rates of 39 frugivorous bird species to 28 fruiting-plant species in Central Germany from early summer to late autumn in hedgerows within three landscape types arranged along a gradient of decreasing anthropogenic modification and increasing structural diversity (i.e., farmland, orchard, forest edge). We analyzed how species richness, abundance, and community composition, as well as functional and interaction diversity of fruiting plants and frugivorous birds changed with landscape type, fruit availability, and season. We found that visitation rates of frugivorous birds were lower in farmland, but only in summer. In autumn, visitation rates were similar in all landscape types and strongly increased with increasing local fruit availability. The functional diversity of fruits and frugivorous birds and their interaction diversity remained surprisingly constant in all landscape types. Due to seasonal changes in communities of fruiting plants and frugivorous birds, functional dispersion of fruiting plants was lower in autumn than in summer, whereas functional richness and dispersion of frugivorous birds was higher in autumn than in summer. Our results indicate that seasonal changes in fruit availability influence the abundance of frugivorous birds along gradients of structural diversity at the landscape scale. Although seasonal fluctuations influenced the functional diversity of avian frugivore communities, we found constant interaction diversity of plant-frugivore networks in space and time, probably due to the functional redundancy of frugivorous birds. These findings indicate a high robustness of avian frugivory to moderate levels of human-induced landscape modification in temperate ecosystems and call for studies testing the generality of these findings for ultimate avian seed dispersal functions. PMID- 23923494 TI - Landscape-scale eco-evolutionary dynamics: selection by seed predators and fire determine a major reproductive strategy. AB - Recent work in model systems has demonstrated significant effects of rapid evolutionary change on ecological processes (eco-evolutionary dynamics). Fewer studies have addressed whether eco-evolutionary dynamics structure natural ecosystems. We investigated variation in the frequency of serotiny in lodgepole pine (Pinus contorta), a widespread species in which postfire seedling density and ecosystem structure are largely determined by serotiny. Serotiny, the retention of mature seeds in cones in a canopy seed bank, is thought to be an adaptation for stand-replacing fire, but less attention has been paid to the potential selective effects of seed predation on serotiny. We hypothesized that spatial variation in percentage serotiny in lodgepole pine forests results from an eco-evolutionary dynamic where the local level of serotiny depends on the relative strengths of conflicting directional selection from fire (favoring serotiny) and seed predation (favoring cones that open at maturity). We measured percentage serotiny, the abundance of American red squirrels (Tamiasciurus hudsonicus; the primary pre-dispersal seed predator of lodgepole pine), and several measures of forest structure in Yellowstone National Park, USA. Fire frequency strongly predicted the frequency of serotiny, a pattern that is well supported in the literature. At sites with high fire frequency (return intervals of -135-185 years) where fire favors increased serotiny, squirrel abundance was negatively associated with serotiny, suggesting that selection from predation can overwhelm selection from fire when squirrels are abundant. At sites with low fire frequency (return intervals of -280-310 years), serotiny was nearly universally uncommon (< 10%). Finally, forest structure strongly predicted squirrel density independently of serotiny, and serotiny provided no additional explanatory power, suggesting that the correlation is caused by selection against serotiny exerted by squirrels, rather than squirrels responding to variation in percentage serotiny. PMID- 23923495 TI - Broadening the ecological context of ungulate-ecosystem interactions: the importance of space, seasonality, and nitrogen. AB - Spatial heterogeneity of soil resources, particularly nitrogen availability, affects herbaceous-layer cover and diversity in temperate forest ecosystems. Current hypotheses predict that ungulate herbivores influence nitrogen availability at the stand scale, but how ungulates affect nitrogen availability at finer spatial scales that are relevant to the herb layer is less understood. We tested the hypothesis that ungulate exclusion reduces the spatial complexity of nitrogen availability at neighborhood scales (1-26 m) apart from mean stand scale effects. This outcome was expected due to a lack of ungulate nitrogenous waste deposition within exclosures and seasonally variable ungulate habitat use. To test this hypothesis we examined spatial patterning of ammonium and nitrate availability, herb-layer cover and diversity, and under-canopy solar radiation using geostatistical models. Our study sites included six stands of eastern hemlock (Tsuga canadensis) forest: three where white-tailed deer (Odocoileus virginianus) were excluded and three that were accessible to deer. Where deer were present, patch sizes of ammonium availability, cover, and diversity were smaller compared to deer exclosures, whereas mean site-level effects were not significant. Within deer exclosures cover and solar radiation were more similar in patch size than were cover and nitrogen availability. Our results suggest that browsing ungulates affect spatial patterns of herb-layer cover and diversity through the excretion of nitrogenous wastes in small, discrete patches. Ungulate excreted nitrogen deposition and herbivory were concentrated in the dormant season, allowing herb-layer plants a greater opportunity to benefit from nitrogen additions. Therefore, the impact of ungulates on nitrogen cycling in forest ecosystems varies with spatial scale and the seasonal timing of ungulate impacts. In this way, ungulates may function as a seasonally dependent link between fine scale and landscape-level ecological processes. PMID- 23923496 TI - Day length, reproductive effort, and the avian latitudinal clutch size gradient. AB - Explaining latitudinal patterns in life history traits remains a challenge for ecologists and evolutionary biologists. One such prominent pattern is the latitudinal gradient in clutch size in birds: the number of eggs laid in a reproductive bout increases with latitude in many species. One intuitive hypothesis proposes that the longer days at high latitudes during the breeding season allow parents to spend more time foraging each day, which results in greater total food delivery to the brood each day, and hence more offspring produced. This day length hypothesis is virtually untested, although it was proposed nearly 100 years ago. We developed a conceptual framework for distinguishing between the day length hypothesis and the widely accepted alternative hypothesis that attributes the latitudinal gradient in clutch size to increased per capita food resources at higher latitudes. Using this framework to contrast components of reproductive effort and life history patterns in a mid- and high-latitude Tree Swallow (Tachycineta bicolor) population provided clear evidence for the day length hypothesis, but little evidence for the alternative. Our findings suggest that the length of an animal's workday may be an important, but unappreciated, component of reproductive effort. PMID- 23923497 TI - Brood parasitism correlates with the strength of spatial autocorrelation of life history and defensive traits in Magpies. AB - Environmental characteristics of neighboring locations are generally more similar than those of distant locations. Selection pressures due to parasitism and other environmental conditions shape life history traits of hosts; thus, the probability of parasitism should be associated with the strength of spatial autocorrelation in life history and defensive traits of their hosts. Here we test this hypothesis in three different subpopulations of Magpie (Pica pica) parasitized by the Great Spotted Cuckoo (Clamator glandarius) during three breeding seasons. In some of the years and study plots, we found evidence of positive spatial autocorrelations for clutch size and parasitism rate, but not for laying date. As predicted, brood parasitism was associated with the strength of these spatial autocorrelations. Magpies that bred close to each other in areas of high risk of parasitism responded similarly to experimental parasitic eggs. Moreover, an elevated risk of parasitism eliminated the spatial autocorrelation for clutch size, which became randomly distributed. We discuss possible mechanisms explaining these associations, which may have important consequences for estimating evolutionary responses of hosts to parasitic infections and, therefore, for epidemiological, ecological, and evolutionary studies of host parasite relationships. PMID- 23923498 TI - Consumer diversity interacts with prey defenses to drive ecosystem function. AB - Prey traits linking consumer diversity to ecosystem function remain poorly understood. On tropical coral reefs, herbivores promote coral dominance by suppressing competing macroalgae, but the roles of herbivore identity and diversity, macroalgal defenses, and their interactions in affecting reef resilience and function are unclear. We studied adjacent pairs of no-take marine reserves and fished areas on reefs in Fiji and found that protected reefs supported 7-17x greater biomass, 2-3x higher species richness of herbivorous fishes, and 3-11x more live coral cover than did fished reefs. In contrast, macroalgae were 27-61x more abundant and 3-4x more species-rich on fished reefs. When we transplanted seven common macroalgae from fished reefs into reserves they were rapidly consumed, suggesting that rates of herbivory (ecosystem functioning) differed inside vs. outside reserves. We then video-recorded feeding activity on the same seven macroalgae when transplanted into reserves, and assessed the functional redundancy vs. complementarity of herbivorous fishes consuming these macroalgae. Of 29 species of larger herbivorous fishes on these reefs, only four species accounted for 97% of macroalgal consumption. Two unicornfish consumed a range of brown macroalgae, a parrotfish consumed multiple red algae, and a rabbitfish consumed a green alga, with almost no diet overlap among these groups. The two most chemically rich, allelopathic algae were each consumed by a single, but different, fish species. This striking complementarity resulted from herbivore species differing in their tolerances to macroalgal chemical and structural defenses. A model of assemblage diet breadth based on our feeding observations predicted that high browser diversity would be required for effective control of macroalgae on Fijian reefs. In support of this model, we observed strong negative relationships between herbivore diversity and macroalgal abundance and diversity across the six study reefs. Our findings indicate that the total diet breadth of the herbivore community and the probability of all macroalgae being removed from reefs by herbivores increases with increasing herbivore diversity, but that a few critical species drive this relationship. Therefore, interactions between algal defenses and herbivore tolerances create an essential role for consumer diversity in the functioning and resilience of coral reefs. PMID- 23923499 TI - Aggregated filter-feeding consumers alter nutrient limitation: consequences for ecosystem and community dynamics. AB - Nutrient cycling is a key process linking organisms in ecosystems. This is especially apparent in stream environments in which nutrients are taken up readily and cycled through the system in a downstream trajectory. Ecological stoichiometry predicts that biogeochemical cycles of different elements are interdependent because the organisms that drive these cycles require fixed ratios of nutrients. There is growing recognition that animals play an important role in biogeochemical cycling across ecosystems. In particular, dense aggregations of consumers can create biogeochemical hotspots in aquatic ecosystems via nutrient translocation. We predicted that filter-feeding freshwater mussels, which occur as speciose, high-biomass aggregates, would create biogeochemical hotspots in streams by altering nutrient limitation and algal dynamics. In a field study, we manipulated nitrogen and phosphorus using nutrient-diffusing substrates in areas with high and low mussel abundance, recorded algal growth and community composition, and determined in situ mussel excretion stoichiometry at 18 sites in three rivers (Kiamichi, Little, and Mountain Fork Rivers, south-central United States). Our results indicate that mussels greatly influence ecosystem processes by modifying the nutrients that limit primary productivity. Sites without mussels were N-limited with -26% higher relative abundances of N-fixing blue-green algae, while sites with high mussel densities were co-limited (N and P) and dominated by diatoms. These results corroborated the results of our excretion experiments; our path analysis indicated that mussel excretion has a strong influence on stream water column N:P. Due to the high N:P of mussel excretion, strict N-limitation was alleviated, and the system switched to being co-limited by both N and P. This shows that translocation of nutrients by mussel aggregations is important to nutrient dynamics and algal species composition in these rivers. Our study highlights the importance of consumers and this imperiled faunal group on nutrient cycling and community dynamics in aquatic ecosystems. PMID- 23923500 TI - Stronger biotic resistance in tropics relative to temperate zone: effects of predation on marine invasion dynamics. AB - Latitudinal patterns of nonnative species richness suggest fewer successful invasions in the tropics, relative to temperate regions. One main hypothesis for this pattern is that biotic resistance to invasion is stronger in the tropics than at higher latitudes. Biotic resistance can limit the distribution and abundance of nonnative species and, in extreme cases, can prevent establishment. We provide the first experimental test of this hypothesis, comparing the strength of biotic resistance in a tropical and a temperate marine ecosystem. Predation is one mechanism of biotic resistance, and since predation can be stronger at lower latitudes, we predicted that predation will serve to increase biotic resistance more in the tropics than at higher latitude. We conducted predator-exclusion experiments on marine epifaunal communities, a heavily invaded system, focusing on nonnative tunicates as a model fauna. The effect of predation on species richness of nonnative tunicates was more than three times greater at sites in tropical Panama than in temperate Connecticut, consistent with the prediction of stronger biotic resistance in the tropics. In Connecticut, predation reduced the abundance of one nonnative tunicate but did not affect the abundances of any other nonnative tunicate species, and no species were excluded from communities. In contrast, predation resulted in striking reductions in abundance and often exclusion of nonnative tunicates from experimental communities in Panama. If proved to be general, latitudinal differences in the biotic resistance of communities to nonnative species establishment may help explain emerging patterns of global invasions. PMID- 23923501 TI - Variation in stochastic demography between and within central and peripheral regions in a widespread short-lived herb. AB - Analyzing intraspecific variation in population dynamics in relation to environmental factors is crucial to understand the current and future distributions of plant species. Across ranges, peripheral populations are often expected to show lower and more temporally variable vital rates than central populations, although it remains unclear how much any differences in vital rates actually contribute to differences in population growth rates. Moreover, few demographic studies accounting for environmental stochasticity have been carried out both at continental and regional scales. In this study we calculated stochastic growth rates in five central and six northern peripheral populations of the widespread shortlived herb Plantago coronopus along the Atlantic Coast in Europe. To evaluate at two spatial scales how mean values and variability of vital rates (i.e., fecundity, recruitment, survival, growth, and shrinkage) contributed to the differences in stochastic growth rates, we performed Stochastic Life Table Response Experiment (SLTRE) analyses between and within central and peripheral regions. Additionally, we searched for correlations between vital rate contributions and local environmental conditions. Lower mean values and greater variability for some vital rates in peripheral than in central populations had an overall negative but nonsignificant effect on the stochastic growth rates in the periphery. Different life cycle components accounted for differences in population growth depending on spatial scale, although recruitment was the vital rate with the highest influence both between and within regions. Interestingly, the same pattern of differentiation among populations was found within central and peripheral areas: in both regions, one group of populations displayed positive contributions of growth and shrinkage and negative contributions of recruitment and survival; the opposite pattern was found in the remaining populations. These differences in vital rate contributions among populations within regions were correlated with precipitation regime, whereas at the continental scale, differences in contribution patterns were related to temperature. Altogether, our results show how populations of P. coronopus exhibit life cycle differences that may enable the species to persist in locations with widely varying environmental conditions. This demographic flexibility may help to explain the success of widespread plants across large and heterogeneous ranges. PMID- 23923502 TI - Mycorrhizas in the Central European flora: relationships with plant life history traits and ecology. AB - Plant traits have been widely used to characterize different aspects of the ecology of plant species. Despite its wide distribution and its proven significance at the level of individuals, communities, and populations, the ability to form mycorrhizal associations has been largely neglected in these studies so far. Analyzing plant traits associated with the occurrence of mycorrhizas in plants can therefore enhance our understanding of plant strategies and distributions. Using a comparative approach, we tested for associations between mycorrhizal status and habitat characteristics, life history traits, and plant distribution patterns in 1752 species of the German flora (a major part of the Central European flora). Data were analyzed using log-linear models or generalized linear models, both accounting for phylogenetic relationships. Obligatorily mycorrhizal (OM) species tended to be positively associated with higher temperature, drier habitats, and higher pH; and negatively associated with moist, acidic, and fertile soils. Competitive species were more frequently OM, and stress tolerators were non-mycorrhizal (NM), while ruderal species did not show any preference. Facultatively mycorrhizal (FM) species showed the widest geographic and ecological amplitude. Indigenous species were more frequently FM and neophytes (recent aliens) more frequently OM than expected. FM species differed markedly from OM and NM species in almost all analyzed traits. Specifically, they showed a wider geographic distribution and ecological niche. Our study of the relationships between mycorrhizal status and other plant traits provides a comprehensive test of existing hypotheses and reveals novel patterns. The clear distinction between FM and OM + NM species in terms of their ecology opens up a new field of research in plant-mycorrhizal ecology. PMID- 23923503 TI - High population variability and source-sink dynamics in a solitary bee species. AB - Although solitary bees are considered to play key roles in ecosystem functions, surprisingly few studies have explored their population dynamics. We investigated the population dynamics of a rare, declining, solitary bee (Andrena humilis) in a landscape of 80 km2 in southern Sweden from 2003 to 2011. Only one population was persistent throughout all years studied; most likely this population supplied the surrounding landscape with 11 smaller, temporary local populations. Despite stable pollen availability, the size of the persistent population fluctuated dramatically in a two-year cycle over the nine years, with 490-1230 nests in odd numbered years and 21-48 nests in even-numbered years. These fluctuations were not significantly related to climatic variables or pollen availability. Nineteen colonization and 14 extinction events were recorded. Occupancy decreased with distance from the persistent population and increased with increasing resource (pollen) availability. There were significant positive correlations between the size of the persistent population and patch occupancy and colonization. Colonizations were generally more common in patches closer to the persistent population, whereas extinctions were independent of distance from the persistent population. Our results highlight the complex population dynamics that exist for this solitary bee species, which could be due to source-sink dynamics, a prolonged diapause, or can represent a bet-hedging strategy to avoid natural enemies and survive in small habitat patches. If large fluctuations in solitary bee populations prove to be widespread, it will have important implications for interpreting ecological relationships, bee conservation, and pollination. PMID- 23923504 TI - On estimating probability of presence from use-availability or presence background data. AB - A fundamental ecological modeling task is to estimate the probability that a species is present in (or uses) a site, conditional on environmental variables. For many species, available data consist of "presence" data (locations where the species [or evidence of it] has been observed), together with "background" data, a random sample of available environmental conditions. Recently published papers disagree on whether probability of presence is identifiable from such presence background data alone. This paper aims to resolve the disagreement, demonstrating that additional information is required. We defined seven simulated species representing various simple shapes of response to environmental variables (constant, linear, convex, unimodal, S-shaped) and ran five logistic model fitting methods using 1000 presence samples and 10 000 background samples; the simulations were repeated 100 times. The experiment revealed a stark contrast between two groups of methods: those based on a strong assumption that species' true probability of presence exactly matches a given parametric form had highly variable predictions and much larger RMS error than methods that take population prevalence (the fraction of sites in which the species is present) as an additional parameter. For six species, the former group grossly under- or overestimated probability of presence. The cause was not model structure or choice of link function, because all methods were logistic with linear and, where necessary, quadratic terms. Rather, the experiment demonstrates that an estimate of prevalence is not just helpful, but is necessary (except in special cases) for identifying probability of presence. We therefore advise against use of methods that rely on the strong assumption, due to Lele and Keim (recently advocated by Royle et al.) and Lancaster and Imbens. The methods are fragile, and their strong assumption is unlikely to be true in practice. We emphasize, however, that we are not arguing against standard statistical methods such as logistic regression, generalized linear models, and so forth, none of which requires the strong assumption. If probability of presence is required for a given application, there is no panacea for lack of data. Presence-background data must be augmented with an additional datum, e.g., species' prevalence, to reliably estimate absolute (rather than relative) probability of presence. PMID- 23923505 TI - Are wolves saving Yellowstone's aspen? A landscape-level test of a behaviorally mediated trophic cascade: comment. PMID- 23923506 TI - Are wolves saving Yellowstone's aspen? A landscape-level test of a behaviorally mediated trophic cascade: reply. PMID- 23923507 TI - Collision of chronic lymphocytic leukemia/small lymphocytic lymphoma and melanoma. PMID- 23923508 TI - In memoriam: Hilary Koprowski: a Renaissance scientist. PMID- 23923509 TI - It's microbiology, citizens. PMID- 23923510 TI - [Comment on "Physical activity levels, ownership of goods promoting sedentary behaviour and risk of myocardial infarction: results of the INTERHEART study"]. PMID- 23923511 TI - Institutional ethics committees and stem cell research. PMID- 23923512 TI - An insight into the medical humanities. PMID- 23923513 TI - [Volume 100, number 6 of our journal, Bulletin du Cancer]. PMID- 23923514 TI - [Editorial by the Minister of Social and Health Concerns]. PMID- 23923515 TI - [An integrated approach to the service of the campaign against cancer]. PMID- 23923516 TI - [One Hundred years for a promising future]. PMID- 23923517 TI - [The CRA Foundation: The ambition of curing 2 cancers out of 3]. PMID- 23923518 TI - [The eponyms of CAC]. PMID- 23923519 TI - [Cancer French Hospital Federation: Public hospitals at the service of cancer patients]. PMID- 23923520 TI - New tool aims to standardize handoffs in the ED, boosting safety and preventing communication failures. AB - To address identified patient safety risks in the handoff process, a group of emergency providers developed Safer Sign Out, a paper-based template that prompts clinicians to jointly review issues of concern on patients who are being passed from one clinician to another at the end of a shift. Already in practice at 12 hospitals in the Mid-Atlantic region, the approach is now being disseminated nationwide with the help of the non-profit Emergency Medicine Patient Safety Foundation. Advocates of the new tool say very few EDs have a clear, agreed-upon process for how to conduct handoffs. Safer Sign Out seeks to prevent communications failures by putting structure into the handoff process. In addition to prompting incoming and outgoing physicians to discuss each patient being handed off, the approach involves having both physicians round at the bedside of these patients so that patients fully understand when their care is being transitioned to a new provider. PMID- 23923521 TI - Rapid-response process reduces mortality, facilitates speedy treatment for patients with sepsis. AB - To reduce mortality and improve the care of patients with sepsis, Wake Forest Baptist Medical Center in Winston-Salem, NC, created a new rapid-response protocol aimed at facilitating earlier diagnosis and treatment. In this approach, clinicians who suspect a patient may have sepsis can call a Code Sepsis, which will fast-track the series of tests and evaluations that are needed to confirm the diagnosis and get appropriate patients on IV antibiotics quickly. Administrators say the approach fits in with the culture of the ED, and it has quickly slashed time-to-treatment in this environment. In just one year, the hospital has been able to reduce its risk-adjusted mortality index from 1.8 to less than 1.25. In the ED, where a modified version of the approach has been in place since April 1 of this year, the percentage of patients with sepsis receiving antibiotics within one hour of diagnosis has increased from 25% to 85%. Key to the success of the approach are specially trained rapid-response nurses who are called in on a case whenever a diagnosis of sepsis is suspected and a series of policy changes designed to facilitate needed diagnostic tests to confirm a diagnosis. A mandated online education module helped to bring all clinicians and staff up to speed on the new process quickly. PMID- 23923522 TI - San Diego ED leverages telemedicine in a bid to ease crowding, long wait times. AB - In a study dubbed Emergency Department Telemedicine Initiative to Rapidly Accommodate in Times of Emergency (EDTITRATE), investigators at the University of California San Diego Health System are gauging whether remote physicians can be quickly and cost-effectively mobilized to evaluate patients when the ED is busy. While there have been administrative hurdles involved with implementing the approach, investigators say the strategy could offer big savings in terms of time and efficiency. Onsite nurses facilitate telemedicine encounters, utilizing technology that enables remote physicians to evaluate patients. While both patients and providers give the telemedicine encounters high marks, managing the workflow is challenging. Investigators say the approach could produce significant gains in efficiency, including the possibility that a single on-call physician could remotely treat patients from multiple ED sites. PMID- 23923523 TI - IMs gain importance as CMS focuses on discharge planning. PMID- 23923524 TI - IMs, HINNs: more than just a chore. AB - The Important Message from Medicare (IM), advising patients of their right to appeal their discharge, should be issued correctly or your hospital could be fined or lose the ability to receive reimbursement from Medicare. IMs should be given as close as possible to admission but no later than two days after admission. If patients remain in the hospital for two additional days, they must receive a second copy. Use the IM as an opportunity to discuss the discharge process with patients and families and to alert them to the expected discharge date. When patients appeal, drill down and determine the reason they appealed and use your finding to improve your discharge process. PMID- 23923525 TI - Know your HINNs and when to deliver them. AB - Hospital-Issued Notices of Noncoverage (HINN) inform patients that they will be responsible for the bill if they choose to stay in the hospital when the care they are receiving or about to receive will not be covered by Medicare. If hospitals don't give a HINN when services aren't covered by Medicare, they can't bill patients for services later on. CMS gives hospitals the option of using Condition Code 44 to change a patient's status from inpatient to outpatient to correct an unnecessary admission, then collect payment from Medicare for Medicare Part B services. All HINNs must be signed by the patient and a copy included in their file. If the patient refuses to sign, a copy should be placed in the file with a notation of the refusal to sign. PMID- 23923526 TI - Hospital trains CMs on IMs, HINNs. AB - Scottsdale (AZ) Healthcare System provides training for case managers on delivery of the Important Message from Medicare (IM) and has developed a system to ensure that delivery of the IMs doesn't fall through the cracks. Case managers spend an average of 15 minutes discussing the IM with patients using a prepared script and give patients who may be confused a Medicare publication that explains the IM. To ensure that no one falls through the cracks on weekends when there is a smaller case management staff, the Friday case managers concentrate on delivering the IMs to patients who are expected to go home over the weekend. Appeals are rare and most of the time are made because the family expected the patient stay to be longer so they'd have more time to get ready at home. PMID- 23923527 TI - CMS updates discharge planning guidelines. AB - The need for timely and comprehensive discharge planning takes on new importance as the Centers for Medicare & Medicaid Services (CMS) issues revised Discharge Planning Interpretive Guidelines for surveyors to use to assess a hospital's compliance with the Medicare Conditions of Participation. Surveyors will use the guidelines as they review medical records to determine if hospitals are following CMS criteria for evaluating patients, creating a discharge plan, and communicating with the next level of care. The guidelines provide detailed information on how patients should be evaluated to determine the need for discharge planning, how a discharge plan should be developed, and how hospitals should ensure a smooth transition as patients move from one setting to another. For the first time, CMS has included "blue boxes," which give suggestions that hospitals can use to improve discharge planning and transition and urges hospitals to voluntarily adopt them, although they will not be considered in determining compliance. PMID- 23923528 TI - ICD-10 means better documentation is a must. AB - The U.S. Department of Health and Human Services has set Oct. 1, 2014, as the firm date for implementation of ICD-10. There is no grace period for implementation. All claims to any payer must use ICD-10 codes for medical diagnosis and inpatient procedures or they may be rejected and providers will have to resubmit them. The ICD-10 code set has more fields than ICD-9 and requires a more detailed level of documentation. Case managers need to understand what the new coding set means and how it will affect their work. PMID- 23923529 TI - Caring for caregivers after Boston bombing. PMID- 23923530 TI - Kidney disease education: A niche for PAs and NPs. AB - OBJECTIVE: This study evaluated the number of Stage 4 chronic kidney disease (CKD) education classes taught by physician assistants (PAs) and NPs. METHODS: Descriptive analysis of data from the CMS Public Use File were calculated for 2010-2011 kidney disease education classes with particular focus on PAs and NPs. RESULTS: In 2010, 4,580 individual and 1,612 group classes were held; one-third of individual classes and two-thirds of group classes were taught by PAs and NPs. In 2011, with a 32% increase in classes, the percentages of PA and NP instructors stayed the same. PAs and NPs predominantly teach home classes, group classes, and outpatient hospital classes. CONCLUSIONS: Less than 7% of eligible patients were offered education classes in 2010-2011. An examination of Medicare billing data shows PAs and NPs are underused in patient education, an area in which they are uniquely qualified. PMID- 23923531 TI - Case study. Futility on the border. Commentary. PMID- 23923532 TI - Case Study. Futility on the border. Commentary. PMID- 23923533 TI - Reply: To PMID 23233464. PMID- 23923534 TI - CDC27 protein is involved in radiation response in squamous cell cervix carcinoma. AB - In the present study, an attempt was made to identify genes involved in radiation response in cervix carcinoma. Differential display technique was used to study the expression profiles of tumour biopsy samples obtained from patients, responding and not responding to treatment. The samples were obtained prior to radiotherapy and subsequent to treatment with Tele-radiation at 10 Gray (Gy). One of the differentially expressed cDNAs, when sequenced was identified to be CDC27. Immuno-histochemical analysis of pre- and post-treated tumour samples from fifteen patients showed the downregulation of expression of CDC27 protein in seven patients. Down-regulation was associated with poorer response to radiotherapy. Cervical cancer cell lines SiHa and C33A were irradiated and their nuclei were stained for expression of CDC27 and analyzed using fluorescent activated cell sorting (FACS). Down-regulation of CDC27 protein in the irradiated SiHa cell line was associated with greater survival fraction, compared to the irradiated C33A cell line, which had only slight fall in the level of CDC27 protein. This is the first study to suggest a role for CDC27 in radiation response. However, a larger cohort is needed to further confirm the value of CDC27 protein as a predictive marker, for radiation response in cervix cancer. PMID- 23923536 TI - Purification and characterization of alpha-amylase from Bacillus amyloliquefaciens NCIM 2829. AB - Alpha-Amylase (EC 3.2.1.1) was purified to homogeneity (specific activity 58,000 micromole min(-1) mg protein(-1)) from the culture filtrate of Bacillus amyloliquefaciens NCIM 2829. Its molecular mass was found to be 67.5 kDa. The activity of the enzyme increased by almost 50% in the presence of Co+2 ion. Hg2+ and Cu2+ acted as strong inhibitors of the enzyme. The tryptophan moities of the enzyme were fairly protected from the aqueous environment. However, the globular interior of the protein was somewhat loosely packed. The protein had nearly an equal amount of alpha-helical and beta-sheet structure in dilute solution. In concentrated solution, its secondary structure had a higher proportion of beta sheet at the expense of some random coil structure. The protein showed a molten globule state at a low concentration of chaotropic agent. The denaturation profile of the protein showed no cooperativity. Co2+ enhanced the structural stability of the enzyme. PMID- 23923535 TI - Crystal structure of a novel phospholipase A2 from crude venom of Indian cobra sub-species Naja naja sagittifera at 1.48 angstoms resolution. AB - Secretory phospholipase A2s (PLA2s), the structurally-homologous enzymes share a common qualitative catalytic site, but differ greatly in their pharmacological properties and toxicities. There has been a recognizable pattern of mutations in the primary sequence of PLA2s that alter their catalytic properties significantly. In the present study, the amino acid sequence and the three dimensional structure of a new isoform of PLA2 from crude venom of Indian cobra sub-species Naja naja sagittifera (N.n.s.) has been determined by X-ray crystallography. The crystal structure has revealed several novel features of PLA2 folding and function. It contains 913 protein atoms and one each of Ca2+, phosphate and acetate ions with 142 solvent water molecules. A Ca2+ ion is present in the calcium-binding loop and forms a seven-fold coordination with a distorted pentagonal bipyramidal geometry. One of the coordination linkages is with the acetate ion, instead of the conserved water molecule. The presence of Lys at position 31 has a stabilizing effect on the loop Tyr 25-Cys 29 by interacting with carbonyl oxygen atoms of Tyr 25, Gly 26 and Cys 29. In turn, it lends stability to the Ca(2+)-binding loop as well. Another unique feature of the PLA2 structure is the formation of an intrastrand hydrogen bond, involving Ogamma of Thr 73 and Oepsilon2 of Glu 71, thus helping the beta-wing to act as a sharp arrow for insertion into other molecules. Yet another important feature of this PLA2 pertains to the conformation of its C-terminal segment, which is stabilized by a unique hydrogen bond through carbonyl oxygen of Lys 116 and Ndelta2 of Asn 120. This structural feature may be useful in the molecular recognition of the PLA2 through C-terminal segment. PMID- 23923537 TI - Effect of exogenous sucrose on the enzymes of starch degradation and sucrose metabolism in cowpea (Vigna unguiculata L.) seedlings. AB - Addition of exogenous sucrose and mannitol in the growth medium decreased the germination and growth of cowpea (Vigna unguiculata L. cv C-88) seedlings. The reduced seedling growth appeared to be due to the decreased acid invertase activity in growing parts of the seedlings. An exogenous supply of sucrose upregulated the sucrose phosphate synthase (SPS) activity in different parts of seedlings. Decreased amylase activity in cotyledons and the mobilization of starch from cotyledons to the growing axis was observed in the presence of exogenous sucrose and mannitol. High sucrose content observed in different tissues in the presence of exogenous sucrose and mannitol was possibly due to high SPS and low acid invertase activities and reduced conversion of sucrose to starch. It appears that exogenous sucrose acts mainly as an osmoticum, rather than a source of carbon for the growing seedlings. PMID- 23923538 TI - A study of thermal denaturation/renaturation in DNA using laser light scattering: a new approach. AB - The thermal denaturation/renaturation processes in E. coli and eukaryotic DNAs have been studied using the laser light scattering (LS) technique. The differential scattering intensity curve has been utilized to determine the transition temperature T(m). The effect of solution pH on DNA thermal denaturation has been examined. It has been shown clearly that LS is an extremely sensitive method (more than the UV absorption method) and reveals even the subtler effects such as the pre-transition fluctuations, and that the DNA denaturation is prominently affected by pH. The dependence of melting temperature (T(m)) on composition of DNA, number of base pairs and base sequences has also been investigated. It has been observed that depending upon its base sequence, the T(m) decreases in the case of renatured DNAs. The results have been compared with the UV absorption studies. PMID- 23923539 TI - Analysis of solid-phase allele-specific primer extension characteristics on biochip in combination with modified primers and PicoGreen staining method. AB - DNA microarray technology offers potential for future high-throughput variation genotyping. Allele-specific primer extension procedure on microarray has been considered as an efficient method for single nucleotide polymorphism(SNP) genotyping. However, the high cost of the fluorescent-labeled dNTP used for signal detection in this method limits its application. In the present study, we evaluated the characteristics of solid-phase allele-specific primer extension, in terms of specificity and efficiency and demonstrated that compared to liquid phase reaction, it requires lower annealing temperature, and higher template and Mg2+ concentrations. The extension efficiency and specificity were though linked, behave diametric during the gradient change of template and Mg2+ concentrations or annealing temperature. To obtain both optimal signal intensity and specificity, we introduced an artificial mismatched base at the third position from the primer 3'end, which enhanced the specificity significantly. The PicoGreen staining method, which could decrease the cost greatly, was then introduced to replace the fluorescent-labeled dNTP for signal detection. PMID- 23923540 TI - QSAR analysis of 2,4-diaminopyrido[2,3-d]pyrimidines and 2,4-diaminopyrrolo[2,3 d]pyrimidines as dihydrofolate reductase inhibitors. AB - Dihydrofolate reductase (DHFR) plays a ubiquitous role in the biosynthesis of DNA, RNA and essential amino acid methionine, and exhibits potential application in the treatment and prophylaxis of AIDS-associated opportunistic microbial infections. In this study, a series of DHFR analogs of 2,4-diaminopyrido[2,3 d]pyrimidines and 2,4-diaminopyrrolo[2,3-d]pyrimidines were subjected to quantitative structure-activity relationship (QSAR) analysis. The results showed that the electronic properties, energy of lowest unoccupied molecular orbital (LUMO) and Z-component of dipole moment (DPL3) of the molecule could be explored to design the potent DHFR inhibitors. LUMO is indicative of pi-bonding interaction of species crucial for the electrophilicity of the molecules. This suggests that molecules are able to interact with electron-rich area at the receptor site. DPL3 is related to the molecular charge distribution in Z component. These electronic parameters can be altered through the incorporation of electronegative groups. The QSAR study provides important structural insights for designing the potent DHFR inhibitors. PMID- 23923541 TI - Evaluation of hepatoprotective potential of propolis extract in carbon tetrachloride induced liver injury in rats. AB - Propolis (bee glue), a resinous wax-like beehive product has been used since ancient times for its pharmaceutical properties. In the present study, the ethanolic extract of propolis (50, 100, 200 and 400 mg/kg, p.o.) was studied for its hepatoprotective activity against carbon tetrachloride (CCl4, 1.5 ml/kg, i.p.) induced liver damage in rats. Administration of CCl4 caused a sharp elevation in the activity of serum transaminases, serum alkaline phosphatase, acid phosphatase and hepatic lipid peroxidation (LPO) levels, and a significant decrease in the ATPase, alkaline phosphatase and succinic dehydrogenase activities in the liver and kidney and hepatic GSH level. The treatment with propolis extract at the doses of 200 and 400 mg/kg significantly reversed the various biochemical alterations in blood, liver and kidney induced by CCl4 intoxication. The hepatoprotective property of propolis may be due to its antioxidant activity. PMID- 23923542 TI - Thermodynamic study of magnesium ion binding to alpha-amylase. AB - The interaction of alpha-amylase (from Bacillus amyloliquefaciens) with Mg2+ ion was studied using UV spectrophotometric and isothermal titration calorimetric (ITC) methods at 27 degrees C in 30 mM Tris buffer solution at pH = 7.0. The binding isotherm for metal-protein interaction was easily obtained by carrying out ITC experiment at two different concentrations (2 microM and 50 microM) of the protein. Alpha-Amylase had eight identical and independent binding sites for Mg2+ ion, which showed non-cooperativity in the binding process. The binding of Mg2+ ion was exothermic (deltaH= -17.3 kJ mol(-1)) with association binding constant of 2.08 mM(-1). The binding slightly destabilized the enzyme against thermal denaturation, as evident from absorption studies. PMID- 23923543 TI - Studies on surfactant-biopolymer interaction. II. Interaction of cetyl trimethyl ammonium-, cetyl ethanolyl dimethyl ammonium-, cetyl diethanolyl methyl ammonium- and cetyl triphenyl phosphonium bromides and cetyl pyridinium chloride with calf thymus DNA. AB - The interaction of the surfactants cetyl trimethyl ammonium-, cetyl ethanolyl dimethyl ammonium-, cetyl diethanolyl methyl ammonium-, and cetyl triphenyl phosphonium bromides and cetyl pyridinium chloride with calf thymus DNA was studied at 303 K in phosphate buffer (pH 7.0) at 10 mM NaCl using spectrophotometric, viscometric, tensiometric, dynamic light scattering, circular dichroism, fluorescence microscopic and microcalorimetric techniques. All the surfactants interacted fairly with DNA, making the biopolymer condensed, even to the aggregated globular configuration at higher [surfactant]/[DNA] mole ratio (R), with direct evidence from fluorescence microscopy. Melting temperature and light scattering intensity of the DNA increased, whereas viscosity decreased in the presence of the surfactants. Tensiometry evidenced effective interaction at [surfactant] as low as 7.6 microM. Isothermal titration calorimetric measurements supported low enthalpy of binding, induced aggregation of the surfactants, increased critical micellar concentration and association of aggregates with the biopolymer at higher R, evidencing distinctions in thermal behaviour. PMID- 23923544 TI - Oxidative stress in tumour-bearing fore-stomach and distant normal organs of Swiss albino mice. AB - Antioxidant status in the tumour-bearing fore-stomach and distant normal organs (liver, spleen, kidney and heart) was investigated in Swiss albino mice. In addition, the cytochrome P450 (cyt P450) system was also examined in the liver. Benzo(a)pyrene [B(a)P] (8 doses of 1 mg/0.1 ml) was administered twice a week for 4 weeks to develop fore-stomach tumour. The animals were sacrificed at the end of 140 days. The specific activities of catalase (CAT), DT-diaphorase (DTD) and glutathione-S-transferase (GST) were found decreased, and the level of reduced glutathione (GSH) and the specific activity of lactate dehydrogenase (LDH) increased in the tumour-bearing fore-stomach; however, no change was observed in superoxide dismutase (SOD) activity. The specific activities of antioxidant enzymes, and levels of GSH were also altered in the normal organs, depending upon the type of tissue. In addition, the contents of cyt P450 and cyt b5, and the activity of NADPH cyt P450 reductase were significantly decreased in the liver. The results suggest increased oxidative stress in the tumour, and disturbance in the cooperative antioxidant functions in the distant normal organs. Inhibition of cyt P450 system reflected the possible adverse effect on drug metabolism function of the liver. Since, the antioxidant potential and the drug metabolism function were altered, the findings may have relevance to the radiation and chemotherapy of cancer. PMID- 23923545 TI - Induction of apoptosis in pheochromocytoma (PC12) cells exposed to eicosapentaenoic acid in vitro. AB - The effect of different concentrations of eicosapentaenoic acid (EPA), on rat pheochromocytoma PC12 cells were evaluated using cell viability, lactate dehydrogenase (LDH) activity, flow cytometric DNA analysis and electronic microscopy. A time- and dose-dependent decrease in the cell viability was observed in the cultures of PC12 cells, supplemented with EPA. The incubation with 200 microM EPA for 48 and 72 hr induced a decrease in the cell viability by 53.40 and 53.43%, respectively. Treatment of PC12 cells with EPA induced apoptosis in a concentration-dependent manner, as evidenced by flow cytometry analysis. The highest percentage of apoptotic cells accumulated to 30.32%, following treatment with 200 microM EPA. The LDH levels increased significantly on treatment with 100 and 200 microM EPA, by 144.4 and 197.3%, respectively, compared with the untreated control. In addition, the cell morphology change was also observed by electron microscopy. The results suggest that EPA mediates its effect on the PC12 cells, at least in part, via the induction by apoptosis. PMID- 23923546 TI - Molecular and biochemical markers associated with leaffolder (Cnaphalocrocis medinalis G.) resistance in rice (Oryza sativa L.). AB - Association of molecular markers namely isozymes and simple sequence repeats (SSRs) and various biochemical markers to leaffolder (Cnaphalocrocis medinalis G., a predominant insect pest of rice) resistance were studied in rice (Oryza sativa L.). Recombinant inbred lines (RILs) of F8 generation obtained by crossing IR36 (susceptible parent) and TNAULFR831311 (moderately resistant parent) were used in this study. Soluble protein content, protein profile, and peroxidase and phenylalanine ammonia lyase (PAL) activities were the various biochemical markers studied. Decrease in soluble leaf protein content was observed in all lines, due to insect infestation. Protein profiling revealed an enhanced expression of a high molecular mass (> 97 kDa) protein in all the infested lines. Besides, there was an increased induction of a 38 kDa protein in infested resistant parent and resistant RILs. A significant increase in peroxidase and PAL activities was observed after infestation. In peroxidase isozyme analysis, carried out after infestation, "isoform 1" was found to be more prominent in the susceptible lines and "isoform 2" in the resistant lines. Bulk segregant analysis (BSA) with twenty five rice microsatellites (RM) resulted in identification of three polymorphic markers between bulks RM11 and RM432 located on chromosome 7 and RM271 on chromosome 10 of rice. These markers may be associated with leaffolder resistance in rice and can be used in marker-assisted selection for leaffolder resistance in rice. PMID- 23923547 TI - Methods for inhibition of residual lipase activity in colorimetric assay: a comparative study. AB - A comparative study of various treatments for inhibition of the residual activity of a lipase (obtained from Bacillus coagulans MTCC-6375) in a colorimetric assay using p-nitrophenyl palmitate (pNPP) was made. Direct chilling of contents of reaction mixture or addition of chilled mixture of ethanol : acetone (1:1) decreased the residual lipase activity by 94.0 and 95.0% respectively, as compared to lipase incubated at 45 degrees C for 20 min (control). Amongst various ionic and non-ionic detergents, Triton X-100 (0.07%, v/v) and sodium lauryl sarcosine or SLS (0.25%, w/v) partially, and SDS (0.05%, w/v) completely blocked the residual lipase activity of B. coagulans lipase in colorimetric assay. Addition of a serine protease inhibitor, PMSF (15 mM) or EDTA (200 mM) inhibited residual lipase activity by 99.5 and 100%, respectively. However, addition of reducing agents viz., 2-mercaptoethanol and dithiothreitol caused decomposition of chromogenic substrate (pNPP) thus rendering the colorimetric method unfit for lipase assay. EDTA (200 mM) and SDS (0.05%, w/v) were also highly effective in inhibiting the residual activities of lipases of Pseudomonas aeruginosa MTCC-4713, P. cepacia and commercial grade lipolytic preparations such as lipozyme, lipolase and porcine pancreatic lipase. However, PMSF (15 mM) completely inhibited the residual activity of lipase of P. aeruginosa. PMID- 23923548 TI - TRNomics: a comparative analysis of Picrophilus torridus with other archaeal thermoacidophiles. AB - In the euryarchaeal thermoacidophile Picrophilus torridus DSM 9790, we identified a copy of rare tRNA(Ile)(TAT) gene, along with the other 47 tDNAs with the help of our in-house program. Further, tRNAs of P. torridus were also compared with other archaeal thermoacidophiles Thermoplasma acidophilum, T. volcanium, Sulfolobus solfataricus and S. tokodaii. PMID- 23923549 TI - Occurrence of trypsin-like protease in cardamom (Elettaria cardamomum Maton). AB - Occurrence of trypsin-like protease in fresh cardamom (Elettaria cardamomum Maton) seeds, as evidenced by the benzoyl-arg-p-nitroanilide (BApNA) hydrolyzing ability of the seed enzyme preparation under alkaline condition is reported for the first time. The enzyme has a pH and temperature optima as 8 and 45 degrees C, respectively. It is inhibited by aprotinin and phenylmethyl sulfonyl fluoride (PMSF) in a dose-dependent manner, suggesting the presence of serine residues at the active site. The enzyme had a V(max) of 98.01 nmoles p-nitroaniline released per min per mg protein and K(m) of 0.0684 mM with BApNA as substrate. Addition of aprotinin (75.75 microM) increased K(m) value by three-folds, whereas the V(max) was reduced by 23%. PMID- 23923550 TI - Antioxidant activity of ethanolic extract of Terminalia chebula fruit against isoproterenol-induced oxidative stress in rats. AB - Antioxidant activity of ethanolic extract of fruits of Terminalia chebula (500 mg/kg body wt, orally for 30 days) against isoproterenol-induced oxidative stress was investigated in rats. The levels of serum lipid peroxides, iron, ascorbic acid, vitamin E, plasma iron-binding capacity, and the activities of ceruloplasmin and glutathione were assayed, in addition to the activities of the antioxidant enzymes--glutathione peroxidase, glutathione reductase, glutathione-S transferase, superoxide dismutase and catalase in the heart tissue. Administration of isoproterenol increased the levels of lipid peroxides and iron, with corresponding decrease in the activities of the enzymic and non-enzymic antioxidants. The pre-treatment with ethanolic extract of fruits significantly prevented the alterations induced by isoproterenol, and maintained a near normal antioxidant status. Results suggest that the cardioprotective effect of T. chebula fruit may partly be attributed to its antioxidant properties. PMID- 23923551 TI - Biochemical changes in erythrocyte membrane in uncontrolled type 2 diabetes mellitus. AB - The levels of lipid peroxidation and alterations in lipid composition and ATPase activities were determined in erythrocyte plasma membrane of uncontrolled type 2 diabetes mellitus (DM) patients. The study groups consisted of 30 patients (16 males, 14 females) attending the Out Patients' Department of Lokmanya Tilak Municipal General Hospital, Mumbai, and 23 age- and sex-matched control subjects (15 males, 8 females). Glycated haemoglobin (an index of long-term glycaemic control), erythrocyte membrane cholesterol, phospholipid and cholesterol to phospholipid molar ratio, lipid peroxidation products in the form of thiobarbituric acid-reactive substances (TBARS), and Na(+)-K(+)-ATPase activity were found to be significantly increased, and Mg(2+)-ATPase activity significantly decreased, in the diabetic subjects, as compared to controls. The study suggests that biochemical changes in the erythrocyte membrane may be involved in the pathophysiology of type 2 DM. PMID- 23923552 TI - Effect of phenobarbitone on cytochrome P450 activity and chlorpyrifos and 3,5,6 trichloropyridinol levels in liver and serum in rat. AB - Chlorpyrifos [O,O'-diethyl-O-(3,5,6-trichloro-2-pyridyl) phosphorothionate, CPF] undergoes oxidative desulfuration or dearylation by hepatic microsomal cytochrome P450 (CYP)-mediated monooxygenase reaction to CPF oxon or desethyl CPF, which are further metabolized to 3,5,6-trichloropyridinol (TCP). The present study showed that CPF exposure caused induction of hepatic CYP levels in rats. Phenobarbitone (PB) treatment elevated CYP activity by about 2.2-folds in controls, while CPF exposure to PB-treated rats did not cause further elevation in CYP levels. The levels of CPF in liver tissue and serum of rats given 50 and 100 mg CPF/kg body wt for 3 weeks were 17.15 ng and 29.39 ng/g and 33.71 ng and 56.34 ng/ml, respectively. The levels of TCP in these rats were 123.58 ng and 215.26 ng/g in liver tissue and 391.73 ng and 599.32 ng/ml in serum respectively. On PB treatment, CPF levels were decreased by 46% and 38% in liver and 23% and 20% in serum of rats receiving 50 mg and 100 mg CPF/kg body wt for 3 days, while TCP levels were increased by 6% and 22% in liver and 22% and 44% serum, respectively. Results of this study clearly show that CYP2B, the PB-inducible form can biotransform CPF faster into TCP. PMID- 23923553 TI - Yolk protein profiles of three prawn (Macrobrachium) species during reproductive cycle. AB - Ovarian yolk protein (vitellin) of adult freshwater prawns Macrobrachium malcolmsonii, M. rosenbergii and M. lamarreii was characterized, and relationship between the gonadosomatic index (GSI) and the appearance of specific polypeptides in their ovary during different stages (early-mature, mature and spent) of reproductive cycle was studied. Mature ovaries of all the three species showed increased GSI values, compared to the respective early-mature ovaries. Protein profiles at the three stages of ovarian maturation were analysed by SDS-PAGE. Polypeptides of low molecular mass (20 to 70 kDa) were prominent in the early mature ovary, whereas in mature ovary, 89 and 100 kDa polypeptides were predominant. Immunodiffusion studies, using antiserum raised against purified vitellin from mature ovary of M. malcolmsonii indicated antigenic similarities of vitellins among the three species. PMID- 23923554 TI - Fractal studies on the protein secondary structure elements. AB - The fractal dimensions of the protein secondary structure elements based on the positional distributions were calculated. The seven secondary structure elements could be grouped into two distinct classes based on their fractal dimensions. A negative correlation was observed between the dimensional values of the secondary structures and their abundances. Markov model was applied, to check the persistence of transitions of the secondary structure elements, in the protein sequences. The results suggest the presence of long-range correlations in the protein sequences that may be useful in prediction algorithms. PMID- 23923555 TI - Stage-specific cytosolic protein kinase C-like activity in human malarial parasite Plasmodium falciparum. AB - Protein kinase C (PKC)-like activity was characterized in malarial parasite Plasmodium falciparum and its involvement in growth, maturation and differentiation functions, during the asexual stages (ring, trophozoite and schizont) of development was studied. PKC-like activity was found distributed in all the stages of the parasite maturation. The activity was predominantly cytosolic, however it was also present in the membrane fraction. The activation of cytosolic PKC required Ca2+, phosphatidyl serine (PS), and either diacylglycerol or phorbol myristate acetate (PMA). The 9-fold increase in the activity was observed in the presence of the co-factors (Ca2+, PS and PMA) in the late trophozoite stage, as compared to the ring stage. The activation of trophozoites with PMA resulted in redistribution of PKC-like activity from cytosol to membrane fractions. An antimalarial drug, chloroquine (CQ) inhibited directly the PKC-like activity in a dose-dependent manner (IC50 of 45 nM) in trophozoites of chloroquine-sensitive CQ(S) strains, however, the activity remained unaltered in the chloroquine-resistant CQ(R) strains. Kinetic studies showed that the inhibition of cytosolic PKC-like activity by CQ was non competitive with respect to ATP, histone and PS. The results suggest that the PKC like activity is developmentally expressed during the parasitic survival and development. PMID- 23923557 TI - Purification and partial characterization of alpha-D-mannosidase from Erythrina indica seeds. AB - Alpha-D-Mannosidase (EC: 3.2.1.24), a glycoprotein with 8.6% carbohydrate was purified (26 fold purification) to homogeneity from Erythrina indica seeds, by gel filtration on Bio-Gel P-100 and affinity chromatography on Con-A CL Seralose. The enzyme had the molecular mass of 124 kDa and 127 kDa by gel filtration and SDS-PAGE, respectively. The optimum pH and temperature for enzyme activity were found to be 4.6 and 50 degrees C, respectively. The K(m) value for the enzyme was 2.1 mM for p-nitrophenyl-alpha-D-mannopyranoside. The enzyme activity was found to depend on the presence of Zn2+. Chemical modification studies revealed the involvement of tryptophan, serine and cysteine for enzyme activity. PMID- 23923556 TI - RNase and DNase activities of antiviral proteins from leaves of Bougainvillea xbuttiana. AB - Antiviral proteins (AVPs) purified from the leaves of Bougainvillea xbuttiana cv Mahara exhibited RNase activity against viral RNA of the tobamoviruses, Tobacco mosaic virus (TMV) and Sunnhemp rosette virus (SRV). They caused complete degradation of viral RNAs in a concentration-dependent manner. RNase activity gel assay ruled out the possibility of the presence of contaminating nucleases. AVPs also showed DNase activity, as indicated by conversion of supercoiled form of plasmid DNA into relaxed and linear forms. The implications of these activities in controlling plant viruses are discussed. PMID- 23923558 TI - Embryo is not required for initiation of alpha-amylase activity in germinating cowpea (Vigna unguiculata L.) seeds. AB - When embryonated and de-embryonated cotyledons of cowpea (Vigna unguiculata L.) were kept for germination, only embryonated cotyledons (EC) developed into seedlings. alpha-Amylase activity appeared late in de-embryonated cotyledons (DEC), but increased and matched with that of EC on 4th day, and thereafter started declining. A higher content of reducing sugars may be one of the factors in down regulating the activity in DEC after 4th day, in comparison to EC, where it continued increasing. Addition of GA3 to DEC did not increase the activity significantly, suggesting that GA3 was not a limiting factor for amylase initiation. Addition of 1 mM chlorocholine chloride (CCC) to DEC decreased activity by about 50%, suggesting that GA3 might partly be synthesized in the DEC and hence the activity could be initiated independent of embryo. However, for mobilization of starch, amylase activity has to be sustained for a longer period, for which sink strength in the form of shoot and root is essential. Unlike cereals, where embryo is required for induction of amylase, the process of amylase induction in germinating cowpea seeds appear to be different. Purification of alpha-amylase from EC and DEC by DEAE-cellulose and Sephadex G 150 column chromatography revealed three peaks in EC, and only one in DEC, indicating that gibberellin present in DEC could induce only one form of amylase. Amylase from DEC had higher K(m) value (0.33 mg ml(-1) of starch), as compared to the corresponding K(m) value in EC (0.11 to 0.16). PMID- 23923559 TI - Beta-Aminobutyric acid-mediated enhancement of resistance in tobacco against TMV and consideration of its capability in wounded tobacco plants. AB - Systemic acquired resistance (SAR) is an important component of disease resistance arsenal of plants, and is associated with enhanced potency of activating local and systemic defense-related responses upon pathogen attack. In this report, we demonstrated that pre-treatment with beta-aminobutyric acid (BABA), a new elicitor of SAR in the plants, enhanced resistance against tobacco mosaic virus (TMV) in a temperately-sensitive tobacco (Nicotiana tabacum L.) cultivar Yunyan 85. The resistance is based on the elicitation of defense-related responses induced by BABA that brings the TMV-susceptible tobacco plants to a defense-ready state, even before exposure to the pathogen. The induced resistance was strongly associated with potentiated activation of defense-related enzymes [phenylalanine ammonia lyase (PAL) and polyphenol oxidase (PPO)] activities, proportional to the concentration of the BABA sprayed. Interestingly, simultaneous clipping, an important agricultural practice in tobacco production, attenuated BABA-mediated enhancement of TMV resistance in tobacco. The changes in the defense-related enzymes activities indicated that the interaction between BABA and wounding was reciprocally antagonistic. Moreover, such a negative interaction regulated the expression of defense-related enzymes. depending on the time of induction. PMID- 23923560 TI - Phytomitogen induced changes in levels of inositol phosphates in the bovine lymphocytes. AB - The changes in levels of inositol phosphates and phosphoinositides were studied in the bovine lymphocytes, in response to phytomitogens (lectins)-concanavalin A (con A) and phytohaemagglutinin (PHA). Addition of con A and PHA resulted in a rapid increase in the cpm of total inositol phosphates (from 8599 +/- 100 cpm/2 x 10(6) cells to 11228 +/- 126 cpm/2 x 10(6) and 9758 +/- 100 cpm/2 x10(6) cells, respectively) at 1 min after mitogen stimulation. There was a concomitant decrease in the phosphatidylinositol levels at 1 min, which continued up to 5 min. At 1 min of stimulation, inositol diphosphate fraction exhibited maximum increase, as compared to inositol mono- and triphosphates, suggesting that it contributed the most towards the overall increase in the total inositol phosphates levels. Results suggest that bovine lymphocytes respond to phytomitogens with a rapid turnover of phosphoinositides. PMID- 23923561 TI - Extracellular enzyme production by environmental strains of Serratia spp. isolated from river Narmada. AB - Serratia a gram-negative enteric bacterium is generally recovered from clinical samples as an opportunistic human pathogen and rarely from water and soil. The extracellular enzymes produced by pathogen add to its virulence. In the present study, the extracellular enzymes secretion by 26 environmental strains of Serratia spp., isolated from different stations of river Narmada was investigated. Majority of isolates were capable of producing extracellular enzymes i.e., amylase, protease, lipase and chitinase, suggesting that they can be exploited as biocontrol and biodegrading agents. All the isolates, except S. fonticola were found to be potent protease producers, while only five isolates of S. marcescens produced chitinase. PMID- 23923562 TI - Characterization and purification of alkaline phosphatase from Elephas trogontherii (Steppe elephant) bone. AB - Four isozymes of alkaline phosphatase (AP) were purified from Elephas trogontherii (Steppe elephant) from different locations in the bone (outer and inner peripheral, cytosolic, and integral) using Sephadex G-200 gel filtration and TEAE-cellulose anion-exchange chromatography. The specimen was obtained from Erzurum Museum and its age was approx. 0.3-0.5 million years old. No fungi or bacteria were present in the bone sample. The enzyme activity was determined by using p-nitrophenylphosphate as a substrate. SDS-PAGE of all the isozymes gave a single band at the same location. The molecular mass of the four isozymes as determined by using gel filtration was about 60 kDa. Optimum pHs for the four isozymes were between 8-8.5. The optimum temperatures of the isozymes were: outer peripheral, 37.5 degrees C, cytosolic, 37.5 degrees C, inner peripheral, 35 degrees C and integral, 40 degrees C. The values of V(max) and K(m), as well different optimum temperatures indicated that isozymes were structurally different. PMID- 23923563 TI - Determination of serum lactate with alkylamine glass bound lactate oxidase. AB - Commercial lactate oxidase (Lactate:O2; oxidoreductase EC 1.1.3.2) from Pediococcus species was immobilized on to alkylamine glass beads (pore diameter 55 nm) through glutaraldehyde coupling with a conjugation yield of 3.2 mg/g support and 105% retention of initial activity. Immobilized enzyme showed maximum activity at pH 6.5, when incubated at 40 degrees C for 12 min and was used for determination of lactic acid in serum. The H2O2 generated from serum lactate by immobilized enzyme was measured colorimetrically at 565 nm by its oxidative coupling with 4-aminoantipyrine and N,N'-dimethyaniline catalyzed by horseradish peroxidase. A linear relationship was observed between A565 and lactic acid concentration ranging from 0.075 mM to 10 mM. The minimum detection limit of the method was 0.075 mM, which was better than that of enzymic colorimetric method employing free enzyme (0.2 mM). Within day and between day coefficient of variations were < 8.0% and < 19%, respectively. Serum lactic acid values determined by the present method were in good correlation (r = 0.99) with the currently used enzymic colorimetric method. The cost of lactate determination for 100 serum samples was less, as compared with Sigma kit method. PMID- 23923564 TI - Oxidative stress in relation to lipid profiles in different stages of breast cancer. AB - The changes in the levels of MDA, nitrite, vit. E, lipids (total cholesterol and triglycerides) and lipoproteins (HDL and LDL cholesterol) were estimated among breast cancer patients, in relation to different clinical stages (stage I to IV). MDA and nitrite levels were increased in breast cancer patients, irrespective of clinical stage, as compared to controls (p < 0.01). Their levels were also significantly elevated from stage III to stage IV (p < 0.05). In contrast, vit. E levels were decreased in all stages, as compared to control group (p < 0.05), the decrease was more pronounced in stage II and IV. Compared to controls, serum triglycerides were elevated in all patient groups (p < 0.05); the maximum increase was in stage IV. HDL-cholesterol decreased in all stages, when compared with control group (p < 0.05). These findings support the hypothesis that reactive oxygen and nitrogen species are increased in breast cancer, especially metastases and may cause consumption of vit. E. PMID- 23923565 TI - Apolipoproteins and their role in different clinical conditions: an overview. AB - Apolipoproteins or apoproteins are a group of proteins associated with lipoproteins in different proportions and play significant roles in several diseases. Different types of apolipoproteins, including apolipoproteins A, B, C, D, E, H and J and their subclasses have been reported, in addition to a few more apolipoproteins reported recently. These proteins have varied, but definite roles in normal physiology in our body. Moreover, their blood levels have strong association with clinical conditions during different diseases and are used as diagnostic and prognostic markers and to compute index of risk for some serious disease entities. Present article gives an overview of the structural features, physiological significance and diagnostic and clinical implications of apolipoproteins. PMID- 23923566 TI - Variant of mitochondrial ribosomal protein s28 (mrps28) gene is differentially expressed in response to radiation in a cervical carcinoma derived cell line. AB - Gene expression before and after radiation treatment (10 Gy) in a cervical carcinoma derived cell line SiHa was studied. Differential display performed on non-irradiated and irradiated cells (10 Gy) using a combination of 3 anchor primers and 16 arbitrary primers yielded 20 differentially expressed fragments. Differential expression of one of the fragments differentially expressed in the irradiated sample was also confirmed in Northern blots. Cloning and sequencing of the fragment revealed it to be similar to a splice variant of the MRPS28 gene. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed using primers designed to amplify the splice variant and confirmed the expression. In conclusion, the study shows that the splice variant kDec03 of the MRPS28 gene is differentially expressed in response to radiation in SiHa cells. PMID- 23923567 TI - Temporal expression patterns of timeless in vg and cry(b) mutants of Drosophila melanogaster. AB - The temporal expression patterns of timeless (tim) in Drosophila melanogaster at various time points were studied in intestine and salivary gland of wild type (WT), vestigial (vg) and cryptochrome-absent (cry(b)) mutants under 12 hr:12 hr white light:darkness (LD) and 12 hr:12 hr blue light (450 nm):darkness (BD) conditions. At ZT 06 and ZT 10, tim expression was almost nil and at ZT 18 and ZT 22, the expression was most pronounced in WT and mutants, when compared to other time points. As vg flies have greatly reduced wings, their gross locomotor activity was poorer and levels of tim expression were also least than WT flies. The weaker expression of tim in cry(b) flies suggested the significant role of blue light photoreceptor cryptochrome for a stronger synchronization of circadian clock. The expression patterns of tim in the salivary gland of larvae further suggested the presence of peripheral oscillators during the developmental stages. PMID- 23923568 TI - Phospholipase C from two bacterial strains acts differently on pure phospholipids and membrane bound glycosylphosphatidylinositol (GPI) anchors. AB - Phospholipase C (PLC) was purified to homogeneity from the culture filtrate of Bacillus cereus (65-fold, 540 U/mg protein) and B. thuringiensis (76-fold, 306 U/mg protein) by conventional techniques of enzyme purification. The purified enzymes have the molecular mass of 34 kDa and 38 kDa respectively, as determined by SDS-PAGE. Both the PLCs exhibited identical sensitivity to pH, temperature, cations, anions and inhibitors like glutathione and p-chloromercuribenzoate. PLC Bc showed a preference for phosphatidylinositol, while PLC-Bt favoured phosphatidylcholine as the substrate. Although both the enzymes were able to hydrolyze pure phosphatidylinositol, distinct differences were observed in their activity on phosphatidylinositol-anchored membrane proteins. PLC-Bc cleaved and released alkaline phosphatase, a GPI-anchored marker enzyme from microsomal membranes to a greater extent, than PLC-Bt. Experiments with sperm membranes, followed by SDS-PAGE revealed that the pattern of proteins released from their GPI-anchors by PLC-Bc and PLC-Bt were dissimilar. Although some proteins were cleaved in common by both PLCs, some others including a prominent 57 kDa protein were resistant to PLC-Bt, but sensitive to cleavage by PLC-Bc. The type of modification in the GPI anchor, special environment on membranes, and relative charge of host plasma membrane to the charge of PLC may be the factors that are responsible for the differential action of two enzymes. PMID- 23923569 TI - Effects of metal ions and an inhibitor on the fluorescence and activity of acutolysin A from Agkistrodon acutus venom. AB - Acutolysin A, a protein isolated from the venom of Chinese Five-pace snake (Agkistrodon acutus) has shown marked hemorrhagic and proteolytic activities. In the present study, the effects of metal ions and an inhibitor EDTA on the fluorescence and function of autolysin A have been studied, by following fluorescence and activity measurements. Acutolysin A contains a Ca(2+)-binding site, which provides it with important structural stability, and a Zn(2+)-binding site, which is essential for its enzymatic activities. The removal of metal ions in acutolysin A by incubation with EDTA results in irreversible inhibition and complete denaturation, and a marked decrease in its fluorescence intensity. The fluorescence intensity of acutolysin A is also decreased in the presence of Cu2+, Co2+, Mn2+ or Mg2+, but does not change in the presence of Ca2+, Cd2+, or Tb3+. Caseinolytic activity of acutolysin A is enhanced by Co2+, Ca2+ and Mg2+, but is partly inhibited by Cu2+, Mn2+ and Tb3+, and completely inhibited by Cd2+. Both Zn2+ and Co2+ recover the loss of activity of the protein caused by Cd2+. PMID- 23923570 TI - Exploring selectivity requirements for COX-2 versus COX-1 binding of 2-(5-phenyl pyrazol-1-yl)-5-methanesulfonylpyridines using topological and physico-chemical parameters. AB - Considering the current need for development of selective cyclooxygenase-2 (COX 2) inhibitors, an attempt has been made to explore physico-chemical requirements of 2-(5-phenyl-pyrazol-1-yl)-5-methanesulfonylpyridines for binding with COX-1 and COX-2 enzyme subtypes and also to explore the selectivity requirements. In this study, E-states of different common atoms of the molecules (calculated according to Kier & Hall), first order valence connectivity and physicochemical parameters (hydrophobicity pi, Hammett sigma and molar refractivity MR of different ring substituents) were used as independent variables along with suitable dummy parameters in the stepwise regression method. The best equation describing COX-1 binding affinity [n = 25, Q2 = 0.606, R(a)2 = 0.702, R2 = 0.752, R = 0.867, s = 0.447, F = 15.2 (df 4, 20)] suggests that the COX-1 binding affinity increases in the presence of a halogen substituent at R1 position and a p-alkoxy or p-methylthio substituent at R2 position. Furthermore, a difluoromethyl group is preferred over a trifluoromethyl group at R position for the COX-1 binding. The best equation describing COX-2 binding affinity [n = 32, Q2 = 0.622, R(a)2= 0.692, R2 = 0.732, R = 0.856, s = 0.265, F = 18.4 (df 4, 27)] shows that the COX-2 binding affinity increases with the presence of a halogen substituent at R1 position and increase of size of R2 substituents. However, it decreases in case of simultaneous presence of 3-chloro and 4-methoxy groups on the phenyl nucleus and in the presence of highly lipophilic R2 substituents. The best selectivity relation [n = 25, Q2 = 0.455, R(a)2 = 0.605, R2 = 0.670, R = 0.819, s = 0.423, F = 10.2 (df 4, 20)] suggests that the COX-2 selectivity decreases in the presence of p-alkoxy group and electron-withdrawing para substituents at R2 position. Again, a trifluoro group is conductive for the selectivity instead of a difluoromethyl group at R position. Furthermore, branching may also play significant role in determining the selectivity as evidenced from the connectivity parameter. PMID- 23923571 TI - Role of a protein inhibitor isolated from human renal stone matrix in urolithiasis. AB - The role of biomolecule(s) from renal stone matrix in urolithiasis was investigated. The ability of a particular fraction (> 10 kDa fraction) isolated from the EDTA extract of powdered human renal stones to influence calcium oxalate monohydrate (COM) crystal growth was studied. The most potent inhibitor of COM crystal growth obtained from > 10 kDa fraction was purified by various chromatographic techniques and SDS-PAGE, etc. and was found to have a molecular mass of 36 kDa. The urine and serum samples obtained from normal persons were found to be more potent in inhibiting the growth of COM crystals as compared to the kidney-stone patients. Polyclonal antibodies were raised against this inhibitor and were employed to determine the concentration of 36 kDa inhibitor in urine and serum samples of normal persons and kidney-stone patients. PMID- 23923572 TI - Modulation of spontaneous electrical activity of freshly isolated 3-day embryonic chick ventricle by cAMP and cGMP. AB - Effects of cyclic nucleotides 8-Bromo-cAMP and 8-Bromo-cGMP (membrane permeable analogs of cAMP and cGMP) were examined on action potential (AP) configuration and rate of spontaneous firing of the freshly isolated 3-day embryonic chick ventricle (ECV) to assess the role of L-type slow Ca2+ channels in upstroke of AP and spontaneous electrical activity (pacemaker potential). The 3-day ECV exhibited prominent automaticity and spontaneous APs characterized by maximum upstroke velocity (+V(max)), maximum diastolic potential (MDP), overshoot (E(ov)), AP duration at -20 mV (APD20) and cycle length (CL) of 33.09 +/- 3.18 V/sec, -63.77 +/- 1.17 mV, 17.40 +/- 0.91 mV, 51.20 +/- 3.05 m sec and 795 +/- 150 m sec, respectively (n = 10 preparations). 8-Br-cAMP (1 mM) caused significant increase in E(ov) and APD20 (37% and 56%, respectively, p < 0.01), but failed to produce any stimulatory effect on +V(max) and MDP. Surprisingly, 8 Br-cAMP produced negative chronotropic effect on spontaneous firing (automaticity) and enhanced the CL significantly by 43% (p < 0.05). 8-Br-cGMP, however, had no effect on AP configuration and the rate of spontaneous firing. The present findings with 8-Br-cAMP suggest that L-type slow Ca2+ channels do not contribute to upstroke of AP and pacemaker potential of spontaneously firing freshly isolated 3-day ECV. The negative chronotropic effect of 8-Br-cAMP suggests that the ionic mechanism underlying pacemaker potential is [Ca]i dependent. However, the lack of any effect of 8-Br-cGMP on spontaneous electrical activity of freshly isolated 3-day ECV indicates that cGMP does not modulate the basal Ca2+ channel activity in young embryonic myocardium. PMID- 23923573 TI - Proton NMR transverse relaxation time and membrane stability in wheat leaves exposed to high temperature shock. AB - Electrolyte leakage from leaves and NMR transverse relaxation time (T2) of leaf water were used to differentiate between heat-tolerant (NIAW 845) and susceptible (HD 2428) wheat (Triticum aestivum L.) cultivars. The leaves were exposed to high temperature shock in the range 30 to 55 degrees C and the damage caused, when evaluated by the two approaches was in close agreement. The critical temperature of injury leading to loss of membrane integrity was lower (39.1 degrees C) for susceptible cultivar, compared to tolerant cultivar (44.2 degrees C). Component analyses of NMR data revealed the existence of two fractions of cellular water in leaf tissues, namely, bound and free bulk water with distinct relaxation times. A dramatic reduction in the proportion of free water and a corresponding increase in bound water was observed in response to increase in temperature. This change in proportion occurred around 38 degrees C and 43 degrees C in HD 2428 and NIAW 845 respectively. The high temperature induced irreversible damage to cellular membrane integrity led to loss of compartmentation of cellular water fractions. The tolerant cultivar maintained its membrane integrity and cell water compartmentation until a temperature of 43 degrees C and susceptible could maintain it only until 38 degrees C. PMID- 23923574 TI - Age-related changes in the elemental constituents and molecular behaviour of bone. AB - Age-related changes in bone composition within the age groups of 30, 60, 120 and 180 days in rats have been studied using thermogravimetery, elemental analysis and energy dispersive Xray (ED X-ray). The structural changes in rats the bone samples were monitored by IR spectroscopy. The main constituents of hydroxyapatite, namely Ca, P and their oxides were analyzed. Organic changes, such as C and N contents in the matrix were found to have a predominant role in the initial development of the bone. An incremental increase in the mineral content of bone with advancing age was also observed. Elemental composition (C and N contents) was observed to be independent of age at the initial stages. The amount of Ca and its oxide content was found to increase, and the P and its oxides showed a decreasing trend, with the advancing age. IR spectra revealed that the mineral phase comprised both amorphous and crystalline hydroxyapatite, even at maturity; the amorphous content being higher at the earlier stages (14.09%, at 30 days), but was gradually replaced by crystalline component with advancing age (63.09% at 180 days). The present data may be useful in explaining the ageing phenomenon and helpful in understanding the bone growth and remodeling. PMID- 23923575 TI - Binding of heme to human serum albumin: steady-state fluorescence, circular dichroism and optical difference spectroscopic studies. AB - The binding of monomeric heme to human serum albumin (HSA) was investigated using steady-state fluorescence, circular dichroism (CD) and optical difference spectroscopic (ODS) techniques. The existence of one strong binding site for heme on HSA was confirmed by titrating heme with HSA and following the quenching of tryptophan (Trp214) fluorescence emission intensity that occurred due to energy transfer. Up to around 1:1 stoichiometric ratio of HSA/heme, the quenching was observed to be very strong, however at higher ratios the quenching progressed very weakly. Similarly, the negative CD band centered at -397 nm, which appeared on adding heme to HSA, increased in intensity on sequential addition of heme up to [heme]/[HSA] = 1. Titration of HSA with heme was followed by ODS and the dissociation constant K(D) = (4.0 +/- 1.0) x 10(-5) M was deduced. Results have been explained on the basis of Michaelis-Menton type of mechanism for the heme binding, in which heme first binds reversibly to His146 at the surface of the protein to form an intermediate complex, followed by irreversible binding to Tyr161 in the interior of the protein. PMID- 23923576 TI - Amino acids differentially regulate insulin receptor tyrosine kinase and phosphatidyl inositol-3-OH-kinase activities in human monocytes exposed to high glucose concentration. AB - Chronic hyperglycemia and insulin resistance are the common factors involved in the development of vascular complications in diabetes mellitus (DM) patients. Since insulin signaling pathway has been shown to be regulated by nutritional supplements, in the present study, we investigated the possible effects of free amino acids, such as lysine, arginine and alanine and their mixture in modulating the insulin receptor tyrosine kinase (IRTK) and phosphatidyl inositol-3-OH-kinase (PI3K) activities and on the changes in actin dynamics in monocytes (MC), exposed to high glucose concentration (25 mM). IRTK and PI3K activities were markedly decreased in MC, incubated with 25 mM glucose. However, on treatment with amino acids, only lysine was effective in augmenting IRTK and PI3K activities in a dose dependent manner. Arginine had marginal effect in promoting these activities. Equimolar mixture of amino acids showed marginal effect of augmenting only IRTK activity. Alanine had no effect. The F-actin filaments showed grossly diminished organization in the cells treated with 25 mM glucose alone, as assessed by specific binding to phalloidin-FITC, when compared with cells treated with 5 mM glucose. On the other hand, a significant improvement in the F-actin organization was observed in the cells co-incubated with 25 mM glucose and lysine. A possible molecular mechanism is the antiglycating effect of amino acids. The signal transduction starts with binding of ATP to lysine at position 1030 in the beta sub unit of the receptor. This lysine (1030) may be protected by the added lysine or to some extent arginine from glycation and loss of function. In summary, our findings suggest that the amino acids apart from their antiglycating property can also modulate/influence the activities of pivotal enzymes that are upstream in the insulin-mediated signal transduction pathway and bring down glucose. PMID- 23923577 TI - Role of MMP-2 in oxidant-mediated regulation of Ca2+ uptake in microsomes of bovine pulmonary artery smooth muscle. AB - Treatment of bovine pulmonary artery smooth muscle microsomes with tert butylhydroperoxide (t-buOOH) (300 microM) markedly stimulated matrix metalloproteinase-2 (MMP-2) activity and enhanced Ca(2+)-ATPase activity and ATP dependent Ca2+ uptake. Pre-treatment with vit. E (1 mM) and tissue inhibitor of metalloproteinase-2 (TIMP-2) (50 microg/ml) prevented t-buOOH-induced stimulation of MMP-2 activity, Ca(2+)-ATPase activity and ATP-dependent Ca2+ uptake. In contrast, Na(+)-dependent Ca2+ uptake was inhibited by t-buOOH and the inhibition was reversed by vit. E (1 mM) and TIMP-2 (50 microg/ml). However, t-buOOH triggered changes in MMP-2 activity, and ATP- and Na(+)-dependent Ca2+ uptake were not reversed upon pre-treatment of the microsomes with a low concentration of 5 microg/ml of TIMP-2, which on the contrary reversed MMP-2 (1 microg/ml) mediated alteration on these parameters. The inhibition of Na(+)-dependent Ca2+ uptake by MMP-2 under t-buOOH treatment overpowered the stimulation of ATP dependent Ca2+ uptake in the microsomes. Combined treatment of the microsomes with low doses of MMP-2 (0.5 microg/ml) and t-buOOH (100 microM) augmented Ca(2+) ATPase activity and ATP-dependent Ca2+ uptake, but inhibited Na(+)-dependent Ca2+ uptake, compared to that elicited by either MMP-2 (0.5 microg/ml) or t-buOOH (100 microM). Pre-treatment with TIMP-2 (50 microg/ml) reversed the effects of MMP-2 (0.5 microg/ml) and/or t-buOOH (100 microM). Although pre-treatment with 5 microg/ml of TIMP-2 reversed the effects produced by MMP-2 (0.5 microg/ml), but it did not inhibit the responses elicited by t-buOOH (300 microM) or t-buOOH (100 microM) plus MMP-2 (0.5 microg/ml) in the microsomes. Treatment with TIMP-2 (5 microg/ml) inhibited MMP-2 (1 microg/ml) activity (assessed by [14C]-gelatin degradation), whereas treatment of t-buOOH (300 microM) with TIMP-2 (5 microg/ml) abolished the inhibitory effect of TIMP-2 (5 microg/ml) on MMP-2 (1 microg/ml) activity (assessed by [14C]-gelatin degradation). Overall, these results suggested that t-buOOH inactivated TIMP-2, the ambient inhibitor of MMP-2, leading to activation of the ambient proteinase, MMP-2 which subsequently stimulated Ca(2+)-ATPase activity and ATP-dependent Ca2+ uptake, but inhibited Na(+)-dependent Ca2+ uptake, resulting in a marked decrease in Ca2+ uptake in the microsomes. PMID- 23923578 TI - Effect of iron concentration on the expression and activity of catalase peroxidases in mycobacteria. AB - Mycobacterial catalases are known to exist in different isoforms. We studied the influence of iron concentration on the expression and activity of the different isoforms in Mycobacterium bovis BCG, M. smegmatis, M. fortuitum, M. kansasii and M. vaccae by growing them under iron-sufficient (4 microg Fe/mL) and iron deficient (0.02 microg Fe/ml) conditions. Upon iron deprivation, significant differences were observed in the catalase/peroxidase activities in both quantitative spectrophotometric assays and in the activity staining in native gels. Notable feature was that the peroxidase activity showed a significant decrease upon iron deprivation in all the mycobacteria, except M. vaccae. Peroxidase activity in all the mycobacteria, irrespective of the iron status was susceptible to heat inactivation. However, the isoforms of catalase showed differences in their heat stability, indicating possible structural differences in these proteins. For example, M. bovis BCG expressed a heat labile catalase under iron-sufficient conditions, while a heat stable catalase band of similar mobility was expressed under iron-deprivation conditions. The study clearly indicates that iron plays an important role in the regulation of expression of the different isoforms of the catalase-peroxidases. PMID- 23923579 TI - Isolation and characterization of two N-acetyl-D-lactosamine specific lectins from tubers of Arisaema intermedium Blume and A. wallichianum Hook f. AB - Two new lectins were purified from the tubers of Arisaema intermedium Blume and A. wallichianum Hook. f. (family: Araceae) by affinity chromatography on asialofetuin-linked amino activated silica beads. The bound lectins were eluted with 0.1 M glycine-HCl, pH 2.5. They gave a single band corresponding to subunit M(r) 13.4 kDa in SDS-PAGE, pH 8.3. On gel filtration chromatography, the lectins showed a M(r) of 51.2 kDa, suggesting a homotetrameric structure. Both the lectins gave a single peak on size exclusion HPLC and cation-exchange columns and a single band on PAGE, pH 4.5. However, like other monocot lectins, they gave multiple bands in isoelectric focusing and at PAGE 8.3. The lectins were inhibited by N-acetyl-D-lactosamine (LacNAc), a disaccharide and asialofetuin, a complex desialylated serum glycoprotein. They had no requirement for divalent metal ions i.e., Ca2+ and Mn2+ for their activity and were found to be mitogenic towards human lymphocytes. A. intermedium showed antiproliferative effect against various human cancer cell lines in vitro. PMID- 23923580 TI - An improved method for isolation of photosystem II from marine alga Porphyra yezoensis Udea. AB - An improved method for isolation and characterization of photosystem (PS)II particles from thylakoid membranes of gametophytes of a marine alga Porphyra yezoensis Udea is reported. Thylakoid membranes were isolated using ultracentrifugation and differential speeds centrifugation and were further purified by the first sucrose density gradient centrifugation (SDGC). PSII particles with high 2, 6-dichloroindophenol (DCIP) photo-reduction activity were isolated by the second SDGC from the thylakoid membranes. Absorption and fluorescence spectra of the thylakoid membranes and PSII particles were recorded and their polypeptides composition was studied. Thylakoid membranes obtained by the above two methods showed similar spectral properties and polypeptides composition. PSII particles, in addition to common extrinsic proteins found in PSII of other plants, contained cyt c-550, a 20 kDa protein, along with two new proteins (14 kDa and 16 kDa). PMID- 23923581 TI - A simplified fluorimetric method for corticosterone estimation in rat serum, tissues and mitochondria. AB - A simplified procedure has been developed for the extraction and estimation of corticosterone from rat serum, tissues and mitochondria. The suitably diluted samples were treated with freshly prepared chloroform: methanol mixture (2:1, v/v) and then extracted directly with the chloroform. Almost quantitative recoveries (90% and above) were obtained with the present method, compared to poor recoveries (65-81%) and variable results obtained by earlier procedure. Quantification of corticosterone content in tissues, such as liver, brain and heart, and in the mitochondria indicated significant concentration of corticosterone in tissues and mitochondria, as compared to the serum. The presence of corticosterone in the mitochondria suggests that the hormone may play a role in regulation of mitochondrial gene expression and/or their turnover. PMID- 23923582 TI - Chlorpyrifos-induced alterations in rat brain acetylcholinesterase, lipid peroxidation and ATPases. AB - The effect of chlorpyrifos (O, O'-diethyl-3, 5, 6-trichloro-2-pyridyl phosphorothionate, CPF) exposure on acetylcholinesterase (AChE) activity, lipid peroxidation and different ATPases activities was studied in rats. CPF caused significant inhibition of synaptosomal AChE activity in different regions of brain (fore, mid and hind) and inhibition ranged from 36 to 82% in rats receiving 20-100 mg CPF/kg body wt for 3 days. It also produced oxidative stress, resulting in marked increase in peroxidative damage of membrane lipids in a dose-dependent manner. The levels of malondialdehyde (MDA) and 4-hydroxy-2-nonanal (4-HNE), two major end products of lipid peroxidation were significantly increased in all the regions of brain. Increase in MDA levels was 66%, 117% and 172% in fore brain, 70%, 108% and 170% in mid brain and 40%, 110% and 169% in hind brain of rats given 20, 50 and 100 mg CPF/kg body wt for 3 days. The maximum increase in 4-HNE levels in all the three regions of brain was observed in the animals receiving CPF 100 mg/kg body wt. Na+/K+, Mg2+ and Ca(2+)-ATPases were inhibited to different extents in fore-, mid- and hind brain regions of rats given 20, 50 and 100 mg/kg body wt CPF for 3 days. Highest inhibition in the activity of Na+/K(+) ATPase observed more than 90% in mid and hind-brain. Mg(2+)-ATPase in hind brain showed inhibition up to 97%. Inhibition in Ca(2+)-ATPase activity was also ranged from 22-94% in synaptosomes at different doses of CPF. PMID- 23923583 TI - Oxidative stress in paracetamol-induced pathogenesis: (I). Renal damage. AB - The effect of administration of paracetamol (1 g/kg body wt) on oxidative damage to proteins and lipids in the kidney was studied at various time intervals in adult male Wistar rats. Iindicators of oxidative stress, such as protein thiol, protein carbonyl content and lipid peroxide levels were assayed along with thiol dependent enzyme activities, glutamine synthase and glyceraldehyde-3-phosphate dehydrogenase. Paracetamol-induced renal damage after 4 hr of administration was evidenced by elevation in plasma creatinine levels and the presence of acute tubular necrosis on histological examination of the kidney. No significant change in any other parameters was observed, except for decreased glutathione level. An increase in lipid peroxide level was observed at 24 hr after treatment. The results suggest that oxidative stress may not play a causative role, but contribute to the pathogenesis of paracetamol-induced renal damage. PMID- 23923584 TI - [Critical issues in megatrials on new oral anticoagulants. Rocket AF: applying results to low risk patients]. PMID- 23923585 TI - [Management strategies and choice of antithrombotic treatment in patients admitted with acute coronary syndrome--executive summary for clinical practice. Consensus Document of the Regional Chapters of the Italian National Association of Hospital Cardiologists (ANMCO) and of the Italian Society of Emergency Medicine (SIMEU)]. AB - This document has been developed by the Lazio regional chapters of two scientific associations, the Italian National Association of Hospital Cardiologists (ANMCO) and the Italian Society of Emergency Medicine (SIMEU), whose members are actively involved in the everyday management of Acute Coronary Syndromes (ACS). The document is aimed at providing a specific, practical, evidence-based guideline for the effective management of antithrombotic treatment (antiplatelet and anticoagulant) in the complex and ever changing scenario of ACS. The document employs a synthetic approach which considers two main issues: the actual operative context of treatment delivery and the general management strategy. PMID- 23923586 TI - Health-promoting properties of artichoke in preventing cardiovascular disease by its lipidic and glycemic-reducing action. AB - The artichoke, Cynara scolymus, is one of the most ancient plants grown in the world, and its extracts, obtained from different parts of the plant (leaves, fruits and roots), have been used as medicaments from time immemorial. The pharmacological and therapeutic effects of the artichoke on the liver had already been well known in the 17th century. Modern studies started in the last century confirmed the stimulating properties of artichoke extracts on the liver and gallbladder. The ensuing wave of research was initially focused on the patent liver-stimulating, diuretic and choleretic effects exerted by artichoke preparations on both animals and man, then discovering such other therapeutic properties as the hypolipemizing activity, antioxidant activity and hypoglycemizing activity. This review enumerates the most significant studies that have highlighted these therapeutic properties. Complementary medicine information needs to be incorporated into clinical practice and patient and professional education, in addition to adequate education about proper nutrition. Awareness of the widespread use of complementary and alternative medicine by people with metabolic disorders is crucial for healthcare professionals in order to prevent cardiovascular disease. PMID- 23923587 TI - [New perspectives in cardiovascular risk reduction: focus on HDL]. AB - Cardiovascular diseases represent the leading cause of morbidity and mortality worldwide, mostly contributing to hospitalizations and health care costs. Dyslipidemias represent one of the major cardiovascular risk factor and its management, throughout life-style modifications and pharmacological interventions, has shown to reduce cardiac events. The risk of adverse cardiovascular events is related not only to elevated LDL blood levels, but also to decreased HDL concentrations, that exhibit protective effects in the development of atherosclerotic process. Aim of this review is to summarize current evidences about defensing effects of such lipoproteins and to show the most recent pharmacological strategies to reduce cardiovascular risk through the increase of their circulating levels. PMID- 23923588 TI - [Ten year cardio-cerebro-vascular mortality and morbidity in a Southern Italy cohort: the VIP Project data]. AB - RATIONALE: In Italy the mortality data were obtained almost exclusively from the data RENCAM (Name Causes of Death Register), while there are few prospective surveys. In order to assess whether there are particular epidemiological conditions in the geographical area of Mercato S. Severino, in Southern Italy, we have studied, and reassessed at ten years (1998/99 - 2008/09), a cohort of adult general population in a project of cardiovascular epidemiology and prevention. MATERIALS AND METHODS: We calculated the rates of mortality and morbidity from cardiovascular events covering the period 1998/99 - 2008/09, in a cohort of 1200 persons (600 men and 600 women) aged 25 to 74 years. Data were standardized using the European standard population. RESULTS: Mortality from cardiovascular causes was 46.5% in men and 48.7% in women; it was mainly concentrated in the age group 65-74 years where it occurred on 62.9% of deaths in men and 66.7% in women. Regarding morbidity, the incidence of events to ten years of non-fatal myocardial infarction was 2.2% in men and of 1.8% in women. PTCA interventions to ten year have been 3.3% in men and 3.4% in women, the interventions of aorto-coronary bypass have been 2.4% and 0.5% for men and women respectively. While all major cardiovascular events have been more frequent in men, in women there was a higher incidence of stroke (1.6% vs 0.9%). CONCLUSIONS: Although by comparison with other European countries Italy is among the countries considered at low-risk of coronary heart disease, in Campania cardiovascular diseases reach higher rates than the rest of the country. Our results are in line with the literature data and confirm that cardiovascular diseases are a major public health problem. Local analysis to propose means to provide useful information for planning prevention interventions targeted to their own territory. PMID- 23923590 TI - [Tamoxifen treatment and pulmunary embolism: a case report and literature review]. AB - Breast carcinoma is becoming a spread disease that needs a specif teraphy. Tamoxifen is the first line treatment in patients with positivity of expression of estrogen receptors. The risk of thromboembolism is high in patients treated with tamoxifene indipendent from the neoplastic disease. This work focuses the attention on tamoxifen mechanism of thrombosis. PMID- 23923589 TI - Psychological needs and mental health in women aged > or = 65 years after cardiac surgery: an exploratory study. AB - BACKGROUND: Recent developments in cardiac care have led to an increase survival even among elderly cardiac patients. Previous studies showed that women have worse health related outcomes compared with men. The main aims of this study are to assess psychological needs and factors promoting mental health among women aged > or = 65 years following heart surgery. METHODS: 74 consecutive women aged > or = 65 years and referred to a cardiac rehabilitation unit in Northern Italy after heart surgery were enrolled in this exploratory study. Psychological questionnaires exploring cognitive functioning, psychological needs, anxiety, depression, physical and mental health status, self-esteem were administered by a psychologist to each patient using a face-to-face interview. RESULTS: The main areas of psychological needs reported by patients were relational and emotional support, assistance and treatment, information about diagnosis and future conditions and information concerning economic-insurance issues. Multivariate linear regression analysis showed that factors significantly associated with patients' mental health were anxiety (p = 0.01) and locus of control (p = 0.01). CONCLUSIONS: In order to improve older cardiac women's mental health after cardiac surgery is important to offer tailored rehabilitative interventions able to meet their specific needs such as the management of anxiety symptoms and loss of control, the need to regain the family role, the need of more information concerning the diagnosis and prognosis and emotional support. PMID- 23923591 TI - A drastic complex atheromatous aorta. A case report. AB - Aortic atherosclerosis is the most common disease of the aorta. More than 50% of the plaques thicker than 4 mm are located along the descending aorta. The complex morphology of the plaque, such as ulceration or the presence of thrombi, is associated with increased embolic risk. The increasing use of transesophageal echocardiogram has enhanced the recognition of aortic atheromas. We describe a case of a male patient with complex atherosclerotic disease involving the coronary vessels and descending aortic tract with some embolic complications. PMID- 23923592 TI - Reality checks: A comparative analysis of future benefits from private-sector, voluntary-enrollment 401(k) plans vs. stylized, final-average-pay defined benefit and cash balance plans. PMID- 23923593 TI - One goal is the starting point to another... PMID- 23923594 TI - Alzheimer's disease: an update. PMID- 23923595 TI - Practical aspects of viva-voce examinations in nursing: the ground realities. PMID- 23923596 TI - Assessing the prevalence of obesity and measures to control it among females. AB - The present exploratory study design was considered appropriate for the study to assess the prevalence of obesity. An interview schedule was prepared to collect the data. Health promotion model was the base for the conceptual frame work. Data was collected from 150 females between the age of 26-50 years from the Ahata Mohammed Tahir near Christian Medical College and Hospital, Ludhiana, Punjab. Data was collected using purposive sampling technique. Analysis and interpretation was done according to the objective of the study. The data was analysed by calculating percentage, mean and standard deviation. PMID- 23923597 TI - Efficacy of nursing interventions in reducing social and occupational disabilities among patients with neurosis. AB - Individuals suffering from neurosis suffer from social and occupational disabilities similar to that of psychoses. Though understanding of disabilities in neurosis is essential in management of the clients, the relevant interventional studies are very limited. The present study attempted to evaluate the effect of nursing interventions in reducing social and occupational disabilities in neurotic patients. Sixty neurotic patients diagnosed as per ICD 9 criteria were randomly assigned to experimental and control groups followed by pre-assessment by Groningen social disability schedule. Of the 10 sessions of nursing intervention, 3 were individual sessions with clients, 5 with clients and family members and 2 with small group of clients with similar problems; nursing intervention group and non-nursing intervention group received the routine drug treatment at rural community mental health centre, NIMHANS, Bengaluru. The post assessment was carried out first, second, and the third month followed by the nursing intervention. The findings revealed statistically significant reduction in social and occupational disabilities. A community-based psychosocial intervention led by community health nurses catering to the needs of neurotic patients is indicated by the results. PMID- 23923598 TI - Effect of stress management interventions on job stress among nurses working in critical care units. AB - Stress in nurses affects their health and increases absenteeism, attrition rate, injury claims, infection rates and errors in treating patients. This in turn significantly increases the cost of employment in healthcare units. Proper management of stress ensures greater efficiency at work place and improved wellbeing of the employee. Therefore, a pre-experimental study was conducted among 30 Critical Care Unit nurses working inMedical College Hospital, Thiruvananthapuram, (Kerala) to assess the effect of stress management interventions such as Job Stress Awareness, Assertiveness Training, Time Management, andProgressive Muscle Relaxation on job stress. The results showed that caring for patients, general job requirements and workload were the major sources of stress for the nurses. The level of severe stress was reduced from 60 percent to 20 percent during post-test. The Stress Management Interventions were statistically effective in reducing the stress of nurses at p<0.001 level. PMID- 23923599 TI - Effectiveness of semi sitting position during 2nd stage of labour on maternal and neonatal outcomes among primigravida. AB - This post-test experimental study was conducted among 50 primigravida mothers - 25 each in experimental and control groups in a maternity centre of Coimbatore (TN) with a view to assess the effect of semi-sitting position during second stage of labour on maternal and neonatal outcomes. It was found that semi sitting position is beneficial in enhancing thrust and directing the uterine contraction force on foetus that lead to fewer late decelerations and increased APGAR score. PMID- 23923600 TI - Knowledge and attitude of nursing personnel regarding patient safety and rights in hospitals of Delhi. AB - Nursing ethics apart, the increased awareness towards the treatment procedures being adopted and the standards of hygiene in the hospital setting necessitates proper knowledge and attitude of the personnel attending the patients. The present study, conducted in government and private hospitals of Delhi covered 200 samples (100 each from government and private), using Structured Knowledge Questionnaire. It was revealed that majority of nursing staff working in private hospitals had greater knowledge about patient safety and rights; they also had better patient-friendly attitude. It is suggested that nurses should practice with relevant guidelines in mind. PMID- 23923601 TI - Body's response to heat - pathophysiology of burns. PMID- 23923602 TI - Effect of oral care solutions in reducing ventilator-associated pneumonia: review of current evidence. PMID- 23923603 TI - Pluripotent lineage of CD133 stem cells isolated from human skin samples. AB - Skin stem cells are very important in cosmetics, pharmacological and regenerative medicine and burn cases. Foreskin samples surgically removed after circumcision from boys below 7 years were collected and primary epidermal cells were prepared by enzymatic and mechanical tituration method. Selecting CD133 (prominin-1) multipotent stem cell marker, enriched stem cells were analyzed by MACS using CD133 antibodies conjugated with magnetic beads. CD133 positive and negative cells with specific skin stem cells markers like - CD34 (Universal stem cells marker), CD29 (integrin beta-1) and CD49f (integrin alpha-6) immunophenotypes were screened and sorted in flowcytometer. Further the expression of four embryonic genes or transcription factors of pluripotent stem cells were analyzed for pluripotent character of sorted cells. It was found that skin stem cell markers associated with CD133 cells, differentially expressed CD34, CD29 and CD49f immunophenotyes on both positive and negative CD133 cells in FACS analysis. The embryonic stem cell markers (induced pluripotent stem cell markers) like Oct4, SOX2, Notch-2 and K19 genes were expressed in CD133 positive epidermal cells. It is therefore evident that foreskin derived epidermal stem cells showed pluripotent or multipotent nature. This finding opens up avenues for new uses of these stem cells for direct cell seeding in wound healing, surgical suturing and drug screening. PMID- 23923604 TI - Cloning and expression analysis of multiple proteins encoding P gene of Newcastle disease virus. AB - Viral gene oncotherapy is emerging as a biotherapeutic cancer treatment modality based on targeted killing of cancer cells by viral genes. Newcastle disease virus (NDV) has the property to cause selective oncolysis of tumor cells sparing normal cells. NDV has a single stranded negative sense RNA genome, which is 15,186 nucleotide long and consists of six genes, which codes for eight proteins. NDV like other paramyxoviruses has the ability to generate multiple proteins from the P gene. P protein is encoded by an unedited transcript of the P gene, whereas the V and W protein are the results of RNA editing event in which one and two G residues are inserted at a conserved editing site within the P gene mRNA resulting in V and W transcripts, respectively. Although NDV is known to cause oncolysis by triggering apoptosis, the role of different viral proteins in selective oncolysis is still unclear. P gene edited products are known for its anti-apoptotic property in homologous host. In the present study, NDV P gene and its RNA edited products were amplified, cloned, sequenced and in vitro expression was done in HeLa cells. Further constructs were assayed for their apoptosis inducing ability in HeLa cells. Preliminary study suggested that P, V and W proteins are not apoptotic to HeLa cells. PMID- 23923605 TI - Development of a peptide based latex agglutination assay for serotype identification of foot and mouth disease virus. AB - Out of 200 serum samples collected from cattle (142) and buffaloes (58) of various ages and sexand subjected to latex agglutination test (LAT) using serotype specific peptides (O, A, Asia 1) and also with peptide for non structural protein 2B (NSP-2B), 114 (70%) samples were positive against FMDV type 'O', 102 (51%) against serotype 'A' and 104 (52%) against serotype 'Asia 1'. With NSP-2B peptide a total of 71 (35.5%) samples were positive. The results suggest that LAT could be used for the diagnosis of foot and mouth disease virus as it is easy, cheap and effective test. PMID- 23923606 TI - Glycyrrhizin ameliorates insulin resistance, hyperglycemia, dyslipidemia and oxidative stress in fructose-induced metabolic syndrome-X in rat model. AB - This study investigates if glycyrrhizin, a constituent of licorice (Glycyrrhiza glabra) root, is able to treat the complications (insulin resistance, hyperglycemia, dyslipidemia and oxidative stress) of metabolic syndrome. Metabolic syndrome was induced in rats by feeding a fructose-enriched (60%) diet for six weeks, after which single dose of glycyrrhizin (50 mg/kg body weight) was administered intraperitoneally. Different biochemical parameters from blood were estimated during three weeks after treatment. Then the rats were sacrificed to collect skeletal muscle tissue. Glycyrrhizin reduced the enhanced levels of blood glucose, insulin and lipids in metabolic syndrome group. Increased advanced glycation end products of hemoglobin, glycohemoglobin, hemoglobin-mediated iron release and iron-mediated free radical reactions (arachidonic acid and deoxyribose degradation) in metabolic syndrome were inhibited by glycyrrhizin treatment. Reduced activities of enzymatic antioxidants (superoxide dismutase and catalase) and elevated oxidative stress markers (malonaldehyde, fructosamine, hemoglobin carbonyl content and DNA damage) in metabolic syndrome were reversed to almost normal levels by glycyrrhizin. The decreased levels of peroxisome proliferator activated receptor gamma (PPARgamma) and glucose transporter 4 (GLUT4) proteins in skeletal muscle of metabolic syndrome group were elevated by glycyrrhizin, indicating improved fatty acid oxidation and glucose homeostasis. PMID- 23923607 TI - Aqueous extract of Allium sativum L bulbs offer nephroprotection by attenuating vascular endothelial growth factor and extracellular signal-regulated kinase-1 expression in diabetic rats. AB - To investigate the nephroprotective effect of garlic and elucidate the mechanism by which it prevents the progression of diabetic nephropathy in diabetic rats, diabetes was induced by a single ip injection of streptozotocin (45 mg/kg body weight). Garlic extract (500 mg/kg body weight) and aminoguanidine (1 g/L) were supplemented in the treatment groups. Histopathological examination using H&E, PAS staining and the immunohistochemical analysis of vascular endothelial growth factor (VEGF) and extracellular signal-regulated kinase-1 (ERK-1) expression were performed on kidney sections at the end of 12 weeks. Significant change in both, the urine and serum biochemistry confirmed kidney damage in diabetic animals which was further confirmed by the histological changes such as mesangial expansion, glomerular basement membrane thickening, glycosuria and proteinuria. However, the diabetic animals treated with garlic extract showed a significant change in urine and serum biochemical parameters such as albumin, urea nitrogen and creatinine compared to that of diabetic rats. Further, the garlic supplemented diabetic rats showed a significant decrease in the expression of VEGF and ERK-1 compared to diabetic rats, attenuating mesangial expansion and glomerulosclerosis. Thus, garlic extract rendered nephroprotection in diabetic rats. PMID- 23923608 TI - Ameliorative effect of Luffa acutangula Roxb. on doxorubicin induced cardiac and nephrotoxicity in mice. AB - The present study reports protective effect of hydro-alcoholic extract of Luffa acutangula (HAELA) on doxorubicin (DXR) induced cardio and nephrotoxicity in mice by studying various serum biomarkers, antioxidants in target organs and histoarchitecture alterations. Pretreatment with HAELA reversed significantly the elevated serum biomarkers, alanine amino transferase, lactate dehydrogenase and creatinine phosphokinase in heart and kidney in DXR treated mice. In addition, HAELA treatment inhibited elevated malondialdehyde formation and restored the depleted glutathione, catalase, superoxide dismutase in heart and kidney tissue. The altered histoarchitecture of heart and kidney tissue due to DXR treatment were also improved with HAELA. The protective activity observed with HAELA on DXR induced cardio and nephrotoxicity in mice was found to be related to its antioxidant property which finally results in membrane stabilization. PMID- 23923609 TI - Healing effects of Aegle marmelos (L.) Correa fruit extract on experimental colitis. AB - Graded doses of 50% ethanolic extract of dried fruit pulp of Aegle marmelos (AME) (100, 200 and 400 mg/kg) daily for 14 days in acetic acid (AA)-induced colitis in rats showed 200 mg/kg of AME as an optimal effective dose against AA-induced colonic damage score and weight. This dose (200 mg/kg; po) was further studied in AA-induced colitis for its effects on various physical (mucous/blood in stool, food and water intake and body weight changes), histology, antibacterial activity and biochemical parameters like free radicals (nitric oxide and lipid peroxidation), antioxidants (superoxide dismutase, catalase and reduced glutathione) and myeloperoxidase (acute-inflammatory marker) activities in rat colonic tissue. AME decreased colonic mucosal damage and inflammation (macroscopic and microscopic), mucous/bloody diarrhea, fecal frequency and increased body weight affected in AA-induced colitis. AME showed significant antibacterial activity and enhanced the antioxidants but decreased free radicals and myeloperoxidase activities thereby decreasing tissue damage and inflammation and thus, affording ulcer healing. The above effects of A. marmelos authenticated its use in indigenous system of Medicine. PMID- 23923610 TI - Anti-oxidative protection against iron overload-induced liver damage in mice by Cajanus cajan (L.) Millsp. leaf extract. AB - In view of the contribution of iron deposition in the oxidative pathologic process of liver disease, the potential of 70% methanolic extract of C. cajan leaf (CLME) towards antioxidative protection against iron-overload-induced liver damage in mice has been investigated. DPPH radical scavenging and protection of Fenton reaction induced DNA damage was conducted in vitro. Post oral administration of CLME to iron overloaded mice, the levels of antioxidant and serum enzymes, hepatic iron, serum ferritin, lipid peroxidation, and protein carbonyl and hydroxyproline contents were measured, in comparison to deferasirox treated mice. Oral treatment of the plant extract effectively lowered the elevated levels of liver iron, lipid peroxidation, protein carbonyl and hydroxyproline. There was notable increment in the dropped levels of hepatic antioxidants. The dosage of the plant extract not only made the levels of serum enzymes approach normal value, but also counteracted the overwhelmed serum ferritin level. The in vitro studies indicated potential antioxidant activity of CLME. The histopathological observations also substantiated the ameliorative function of the plant extract. Accordingly, it is suggested that Cajanus cajan leaf can be a useful herbal remedy to suppress oxidative damage caused by iron overload. PMID- 23923611 TI - Effect of newly isolated Lactobacillus ingluviei ADK10, from chicken intestinal tract on acetaminophen induced oxidative stress in Wistar rats. AB - The total antioxidative activity of L. ingluviei ADK10 isolated from chicken intestine intact cells and cell free culture supernatant (CFCS) was 54- 67.95%. The ability to scavenge a,a-Diphenyl-b-Picrylhydrazyl free radical ranged from 71 and 64% in intact cells and CFCS respectively. Total reducing activity of bacteria was equivalent to 290 microM/L of cysteine. Reducing glutathione activity was equivalent to 93.95 microg/mL. Oral administration of the strain at a dose of 10(9) cfu/kg body weight to acetaminophen induced oxidative stress in rats increased catalase, glutathione and superoxide dismutase activity in the blood, liver and kidney and lowered malondialdehyde level. The results indicate that L. ingluviei ADK10 has potential free radical scavenging activity for the treatment of oxidative stress related disease. PMID- 23923612 TI - A new C-glucosylflavone from Sorindeia juglandifolia. AB - Phytochemical investigation of the leaves of Sorindeia juglandifolia A. Rich. led to the isolation and identification of a new C-glucosylflavone, 2",6"-di-O-acetyl 7-O-methyl vitexin (1), together with seven known compounds, 2"-O-acetyl-7-O methyl vitexin (2), mearnsitrin (3), robustaflavone (4), 3-O-galloyl catechin (5), tachioside (2-methoxy-benzene-1,4-diol-1-O-beta-glucopyranoside) (6), 3beta O-D-glucopyranosyl-beta-stigmasterol (7), and methyl gallate (8). The structures of 1 and the known compounds were established by IR, UV, MS, 1D, and 2D NMR spectra and by comparison with those of related compounds. PMID- 23923613 TI - New guaianolide-type sesquiterpene lactones from Inula verbascifolia. AB - The aerial parts of Inula verbascifolia afforded two new guaianolide-type sesquiterpene lactones. Their structures were determined by spectroscopic methods (IR, MS, 1H NMR, 13C NMR, DEPT, 1H-1H COSY, HMQC, and HMBC). PMID- 23923614 TI - Cardiovascular effects induced by linalool in normotensive and hypertensive rats. AB - Linalool is a monoterpene alcohol and constituent of several Brazilian aromatic medicinal plants, popularly used against hypertension. Cardiovascular effects induced by linalool were evaluated. In normotensive rats, (+/-)-linalool [1, 5, 10, and 20 mg/kg body weight (BW); intravenous (i.v.)]-induced hypotension was associated with tachycardia, which was attenuated by atropine (2 mg/kg BW) and N(G)-nitro-L-arginine methyl ester (20 mg/kg BW), but was not modified after indomethacin (5 mg/kg BW) administration. In hypertensive rats, linalool [200 mg/kg BW; oral (v.o.)] reduced blood pressure without changing the heart rate. In intact rings of rat mesenteric artery precontracted with 10 microM phenylephrine, linalool (from 6.4 x 10(-6) to 6.4 x 10(-3) M) induced relaxations in a concentration-dependent manner [E(max) = (115 +/- 13)%] that were not changed after atropine administration [E(max) = (105 +/- 2)%], and were not different from those obtained in endothelium-denuded rings precontracted with phenylephrine [E(max) = (108 +/- 7)%] or 80 mM KCl [E(max) = (113 +/- 7)%] or tetraethylammonium incubation [E(max) = (105 +/- 12)%]. Linalool (1.9 x 10(-3) M) antagonized the contractions induced by CaCl2 (3 x 10(-6)-10(-2) M) (maximal inhibition, 81%). Furthermore, linalool inhibited the contractions induced by 10 microM phenylephrine or 20 mM caffeine. In conclusion, these results demonstrate that linalool reduces blood pressure probably due to a direct effect on the vascular smooth muscle leading to vasodilation. PMID- 23923615 TI - Screening of antimicrobial activity and cytotoxic effects of two Cladonia species. AB - The present study explores the antimicrobial activity and cytotoxic effects in culture assays of two fruticose soil lichens, Cladonia rangiformis Hoffm. and Cladonia convoluta (Lamkey) Cout., to contribute to possible pharmacological uses of lichens. In vitro antimicrobial activities of methanol and chloroform extracts against two Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), two Gram-positive bacteria (Enterococcus faecalis and Staphylococcus aureus), and the yeast Candida albicans were examined using the paper disc method and through determination of minimal inhibitory concentrations (MICs). The data showed the presence of antibiotic substances in the chloroform and the methanol extracts of the lichen species. The chloroform extracts exhibited more significant antimicrobial activity than the methanol extracts. However, a higher antifungal activity was noted in the methanol extract of C. rangiformis. The maximum antimicrobial activity was recorded for the chloroform extract of C. convoluta against E. coli. The cytotoxic effects of the lichen extracts on human breast cancer MCF-7 cells were evaluated by the trypan blue assay yielding IC50 values of ca. 173 and 167 microg/ml for the extracts from C. rangiformis and C. convoluta, respectively. PMID- 23923616 TI - Medicinal plants of Chile: evaluation of their anti-Trypanosoma cruzi activity. AB - The extracts of several plants of Central Chile exhibited anti-Trypanosoma cruzi trypomastigotes activity. Most active extracts were those obtained from Podanthus ovatifolius, Berberis microphylla, Kageneckia oblonga, and Drimys winteri. The active extract of Drimys winteri (IC50 51.2 microg/mL) was purified and three drimane sesquiterpenes were obtained: polygodial, drimenol, and isodrimenin. Isodrimenin and drimenol were found to be active against the trypomastigote form of T. cruzi with IC50 values of 27.9 and 25.1 microM, respectively. PMID- 23923617 TI - Inhibition of cholinergic contractions of rat ileum by tkopane-type alkaloids present in Schizanthus hookeri. AB - The relative lack of specificity of atropine as a competitive antagonist of muscarinic receptors is a frequent cause of undesirable parasympathetic side effects. Consequently, new tropane alkaloids with potentially greater selectivity are usually seen with real interest. The cholinergic antagonistic effects of a purified mixture of tropane alkaloids extracted from Schizanthus hookeri were evaluated in rat ileum. For this purpose, ileal segments were obtained from randomly selected male Sprague-Dawley rats, and the effect of 1 x 10(-4), 1 x 10( 3), and 1 x 10(-2) mg/mL of the purified mixture of alkaloids on the contractile response of the ileum induced with increasing doses of carbachol (5 x 10(-8) - 10(-4) M) was determined. The results were compared with those obtained in the presence of 3.46 x 10(-7), 3.46 x 10(-6), and 3.46 x 10(-5) mg/mL atropine as an agonist. Tropane alkaloids extracted from Schizanthus hookeri competitively antagonized acetylcholine muscarinic receptors. PMID- 23923618 TI - GC-MS and MALDI-TOF MS profiling of sucrose esters from Nicotiana tabacum and N. rustica. AB - Matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) has been applied for the first time to the analysis of the sucrose esters from the surface of Nicotiana L. leaves. The profiles obtained for the model plant N. tabacum were similar to those from the gas chromatography-flame ionization detector (GC-FID) analysis. The most reproducible results were obtained using a dihydroxybenzoic acid (DHB) matrix. The main advantage of this method is that crude plant extracts can be analysed without sample clean-up. GC MS analysis of Aztec tobacco (N. rustica) extracts revealed the presence of three types of sucrose esters. All identified compounds had three C4-C8 acyl chains substituting the glucose moiety, while the fructose part of the molecule was substituted with 0, 1, or 2 acetyl groups. MALDI-TOF MS analysis of the sucrose ester fraction revealed the presence of compounds not eluting from a GC column. Combining the data from both GC-MS and MALDI-TOF MS experiments, we obtained a full sucrose ester profile, which is based on the molecular weight of the compounds and on the number of acyl chains in the molecule. PMID- 23923619 TI - Optimization of enniatin production by solid-phase fermentation of Fusarium tricinctum. AB - Enniatins are cyclic depsipeptides produced by fungi of the genus Fusarium that are of interest due to their pronounced biological activities; especially enniatins A, A1, B, and B1 possess anticarcinogenic and anti-HIV properties. In the present study, F. tricinctum was grown on seven solid media and in one liquid growth medium with or without addition of peptone or of amino acid precursors in order to identify favourable media with simple cultivation conditions for maximum enniatin production. Additionally, the optimal duration of growth was investigated for the highest yields of enniatins. From the different media analysed, white beans (Phaseolus vulgaris, solid medium) induced the highest accumulation of enniatins A, A1, B, and B1, that reached a maximum of 1,365 mg total enniatins in 1 L growth medium after 18 days of fermentation. Fermentation of F. tricinctum on white beans gave the highest yield of enniatins compared to all other media analysed in this study. PMID- 23923620 TI - Microbial sulfation of 8-prenylnaringenin. AB - Out of 24 fungal strains tested for their ability to transform 8 prenylnaringenin, Syncephalastrum racemosum was found to convert this phytoestrogen to a sulfate derivative. The conjugation with sulfuric acid observed in this study is paralleled in mammals indicating that microbes can be used to mimic mammalian metabolism. PMID- 23923621 TI - Field screening of known pheromone components of longhorned beetles in the subfamily Cerambycinae (Coleoptera: Cerambycidae) in Hungary. AB - Five compounds known to be pheromone components of longhorned beetles (Coleoptera: Cerambycidae) in the subfamily Cerambycinae were field-tested as attractants and possible pheromones for the cerambycid fauna of Hungary. Nine cerambycid species were caught in baited traps. Large numbers of both sexes of the cerambycine species Molorchus umbellatarum Schreb. were caught in traps baited with (2R*,3S*)-octanediol, while the diastereomeric (2R*,3R*)-octanediol was to some extent attractive as well. This is the first report on an aggregation attractant and a likely pheromone for a species in the cerambycine tribe Molorchini. The results of our study support the hypothesis that the diol/hydroxyketone pheromone motif is characteristic of and highly conserved within the subfamily Cerambycinae. Intraspecific chemical communication is summarized for the subfamily Cerambycinae, and possible links between taxonomy, insect behaviour, and pheromone structures are described. PMID- 23923622 TI - Development of semiochemical attractants for monitoring and controlling Chlorophorus caragana. AB - Chlorophorus caragana is an important wood-boring pest that infests Caragana korshinskii. The larvae bore into the stems to the point of hollowing them out, causing the whole tree to wither and even die. To control these infestations, volatile compounds were collected from C. korshinskii and used in electroantennography to ascertain which plant semiochemicals could be used to trap adult C. caragana in the field. Isophorone, cis-3-hexen-1-ol, 3-pentanone, dibutyl phthalate, and diisobutyl phthalate were the main volatile compounds produced by C. korshinskii. These compounds induced dose-dependent electrophysiological responses in the antennae of adult C. caragana to some degree. Accordingly, 58 different compound mixtures were tested in field trapping experiments over two consecutive years. Isophorone was most attractive to adult insects. In the field, the best traps were funnel-shaped ones hanging at a height of 1 m. The trapping efficiency was 63.8%. Adult beetles appear between mid June and late August, with an eclosion peak in mid July. The prototype trapping system developed could be used as a tool to monitor and control C. caragana adults. PMID- 23923623 TI - Chemical compounds from the preanal gland secretions of the male tree agama (Acanthocercus atricollis) (fam. Agamidae). AB - Chemical signals have an important role in the reproductive behaviour of many lizards. However, the compounds secreted by their femoral or preanal glands, which may be used as sexual signals, are mainly known for lizard species within the Scleroglossa clade, whereas compounds in secretions of lizards within the Iguania clade are much less studied. Based on mass spectra, obtained by GC-MS, we found 60 lipophilic compounds in preanal gland secretions of the male tree agama (Acanthocercus atricollis) (fam. Agamidae), including steroids (mainly cholesterol, cholest-3-ene, and some of their derivatives), fatty acids ranging between n-C12 and n-C18 (mainly hexadecanoic and octadecenoic acids), ketones from n-C17 to n-C25, and other minor compounds, such as tocopherol, squalene, waxy esters, and furanones. We compare the compounds found with those present in other lizard species and discuss their potential function in social behaviour. PMID- 23923624 TI - Selfish DNA: a pharmaceutical perspective. AB - Almost 25 years ago, Theo Dingermann published the discovery of a new mobile genetic element in the unicellular microbe Dictyostelium discoideum in the journal Science. An interesting property of this new molecular parasite, the Dictyostelium Repetitive Element (DRE), was that all integrations were found approximately 50 base pairs (bp) upstream of transfer RNA (tRNA) genes in the D. discoideum genome, thus implying an active targeting mechanism to avoid the disruption of host cell genes by the retrotransposition process. Since then, the facultative multicellular "social amoeba" D. discoideum has become a popular model for analyzing complex cellular functions such as cell movement, chemotaxis, phagocytosis, and cell differentiation, important areas of biomedical research that are often hard to investigate in cells from "higher organisms" including humans. Therefore, progress in the development of methods to study Dictyostelium biology has also provoked research on transposable elements in this organism. Early work on the DRE element suggested that studying its molecular mechanism of site-specific integration might promote human gene therapy technology through the design of integrating gene transfer vectors with low intrinsic genotoxic potential. In this review article, I will briefly review the original research performed on the DRE transposable element in the Dingermann lab and report on how the emergence of genomics technologies and the development of tools to analyze de novo retrotransposition events in D. discoideum cells will expand our knowledge of DRE biology in the future. PMID- 23923625 TI - Dictyostelium genomics: how it developed and what we have learned from it. AB - Dictyostelium discoideum is the most prominent member of the social amoebae. It has been used as an experimental system since more than 50 years and a large number of scientists worldwide work on different aspects such as chemotaxis, cytoskeleton, differentiation and development. Dictyostelium shares more features with animals than fungi although it diverged much earlier in evolution. Many of the results obtained with D. discoideum can therefore be transferred to animals making D. discoideum a valuable model organism. Targeted gene inactivation using homologous recombination is easy and mutant phenotypes can be readily isolated due to the haploid nature of its genome. Furthermore, a variety of techniques and tools are available that facilitate the experimental work; its genome and that of several Dictyostelidae has been sequenced and most recently a high-resolution genome wide nucleosome map for D. discoideum has been generated. PMID- 23923626 TI - A new perspective on old drugs: non-mitotic actions of tubulin-binding drugs play a major role in cancer treatment. AB - Microtubule-targeting agents (MTAs) are the most frequently used anti-cancer drugs. They can be divided into tubulin stabilizing and destabilizing agents. Their mode of action has been ascribed to their ability to interfere with the spindle apparatus and, thus, to block mitosis leading to tumor cell death. However, this view has been challenged in the last years and it became increasingly evident that non-mitotic actions of MTAs, i.e. their ability to affect the dynamics of interphase microtubules, are the most relevant mechanism underlying their efficacy. In this review we are presenting a distinct selection of examples of studies describing biological effects of MTAs in three areas: (i) mitosis-independent cell death and metastasis, (ii) tumor angiogenesis, and (iii) vascular-disrupting activity. PMID- 23923627 TI - Advances in personalized medicine - medicinal chemistry and pharmacology of vemurafenib and ivacaftor. AB - Pharmacogenomics offers an entrance in the field of personalized medicine. This form of adapted therapy is going to be the future concerning the reduction of side effects and efficacy of the treatment of severe diseases. Vemurafenib and Ivacaftor are the first FDA approved drugs specially addressing mutated proteins. Both substances showed promising results in all clinical trials combined with relatively mild side effects by vemurafenib and placebo-like side effects by ivacaftor. The efficacy in addressing the specific mutation of each compound was confirmed in preclinical and clinical development. PMID- 23923628 TI - Plasma pharmacy - physical plasma in pharmaceutical applications. AB - During the last years the use of physical plasma for medical applications has grown rapidly. A multitude of findings about plasma-cell and plasma-tissue interactions and its possible use in therapy have been provided. One of the key findings of plasma medical basic research is that several biological effects do not result from direct plasma-cell or plasma-tissue interaction but are mediated by liquids. Above all, it was demonstrated that simple liquids like water or physiological saline, are antimicrobially active after treatment by atmospheric pressure plasma and that these effects are attributable to the generation of different low-molecular reactive species. Besides, it could be shown that plasma treatment leads to the stimulation of specific aspects of cell metabolism and to a transient and reversible increase of diffusion properties of biological barriers. All these results gave rise to think about another new and innovative field of medical plasma application. In contrast to plasma medicine, which means the direct use of plasmas on or in the living organism for direct therapeutic purposes, this field - as a specific field of medical plasma application - is called plasma pharmacy. Based on the present state of knowledge, most promising application fields of plasma pharmacy might be: plasma-based generation of biologically active liquids; plasma-based preparation, optimization, or stabilization of - mainly liquid - pharmaceutical preparations; support of drug transport across biological barriers; plasma-based stimulation of biotechnological processes. PMID- 23923629 TI - Fungal endophytes - secret producers of bioactive plant metabolites. AB - The potential of endophytic fungi as promising sources of bioactive natural products continues to attract broad attention. Endophytic fungi are defined as fungi that live asymptomatically within the tissues of higher plants. This overview will highlight the uniqueness of endophytic fungi as alternative sources of pharmaceutically valuable compounds originally isolated from higher plants, e.g. paclitaxel, camptothecin and podophyllotoxin. In addition, it will shed light on the fungal biosynthesis of plant associated metabolites as well as new approaches developed to improve the production of commercially important plant derived compounds with the involvement of endophytic fungi. PMID- 23923630 TI - [On freedom of scientific research]. AB - Debates about science and, more specifically, about scientific research quickly bring up the question about its freedom. Science is readily blamed for technological disasters or criticized for nursing fantasies of omnipotence and commercial gain. This prompts the call for a restriction of its freedom. At the same time, society's demands on science are enormous, to the effect that science and technology have acquired the status of a deus-ex-machina: they are expected to furnish short-term, affordable, and convenient solutions to a wide range of problems, including issues of health, transportation, food and, more generally, a comfortable life. What kind of freedom is required to meet these expectations? Who is in a position to grant it? What does freedom for science mean and how is it linked to responsibility? The paper examines the current situation of freedom in scientific research and of its restrictions, many of which are mentally or economically conditioned. It calls for the involvement of an informed, self confident bourgeoisie in research decisions and for the educational measures this necessitates. Finally, it demands a greater appreciation of education (rather than training) as the basis of social trust, and the recognition of continuous education as a productive investment of time and a crucial element in the employment of social goods. PMID- 23923631 TI - Piperazine modification in 2,4,6-triaminopyrimidine derivatives as histamine H4 receptor ligands. AB - The human histamine H4 receptor (hH4R) is a promising new target in the therapy of inflammatory and immunomodulatory diseases. The 2,4,6-triaminopyrimidine structure has been established as a potent hH4R affinity scaffold. By using the inverse agonist ST-1012 as reference ligand, piperazine modifications were performed to get larger structural variations. Therefore, different spacers were introduced into the lead structure and the influence on affinity of this basic element was evaluated. While a short distance between aminopyrimidine and basic moiety is beneficial, a lipophilic group in the eastern part is necessary to maintain hH4R affinity. PMID- 23923633 TI - Determination of acarbose by capillary zone electrophoresis. AB - Acarbose (Glucobay, Bayer AG) acts as a potent alpha-glucosidase-inhibitor, which delays the intestinal starch digestion resulting in a reduction of postprandial blood glucose and insulin levels. Acarbose is a pseudo-tetrasaccharide, with two D-glucose units linked via an alpha 1-->4 glycosidic bond to acarviosin, which is a N-glycoside composed of an unsaturated cyclitol and 4-amino-4,6-dideoxy-alpha-D glucopyranose. Several methods for the determination of acarbose by capillary electrophoresis can be found in literature. They are based either on the derivatisation with 7-aminonaphthalene-1,3-disulfonic acid (ANDS) or on the detection of the unsaturated cyclitol at wavelengths below 200 nm. The aim of our work was the determination of acarbose making use of a previously developed method based on reductive amination with S-phenylethylamine. The aminoalditols generated in the reaction formed differently charged borate-complexes depending on the configuration of the sugar. After successful method optimisation we were able to separate two potential impurities of acarbose, D-maltose und D-glucose. For the quantitation of acarbose in Glucobay tablets an additional borate-buffer system was established, reducing the total time of analysis to less than 10 min. PMID- 23923632 TI - Possibilities and limitations of capillary electropherosis in pharmaceutical analysis. AB - Capillary electropherosis (CE) has been proved to be an important alternative to high-performance liquid chromatography (HPLC) in pharmaceutical analysis. However, when it comes to the analysis of compounds, e.g. impurities or metabolites, of very different polarity and water solubility CE and the related techniques come to its limits. This is demonstrated for the antipsychotic drug quetiapine and its impurities. A nonaqueous capillary electrophoresis (NACE) method was developed using a background electrolyte (BGE) composed of ammonium acetate dissolved in a mixture of acetonitrile and methanol including acetic acid to protonate the substances. The NACE method gave an excellent separation of all components. Since the conductivity of the BGE used in the NACE method is quite low and problems with current occurred, an additional aqueous capillary zone electrophoresis (CZE) method was developed for quetiapine and the two water soluble derivatives, using phosphate buffer as BGE. The method was validated with regard to repeatability and limit of detection. PMID- 23923634 TI - Stachydrine in Leonurus cardiaca, Leonurus japonicus, Leonotis leonurus: detection and quantification by instrumental HPTLC and 1H-qNMR analyses. AB - Stachydrine ((2S)-1,1-dimethylpyrrolidinium-2-carboxylic acid) may be regarded as an essential active principle of the aerial parts of Leonurus japonicus Houtt. (Leonuri herba, yimucao; Chin.Ph., DAB) which are used in TCM and Kampo for the treatment of various gynaecological and cardiovascular disorders. Medically and botanically closely related Lamioideae drugs are the fruits of L. japonicus (Leonuri fructus, chongweizi; Chin.Ph.), the aerial parts of European Leonurus cardiaca L. (Leonuri cardiacae herba; Ph.Eur.) as well as the aerial parts of their South African relative Leonotis leonurus (L.) R.Br. (Leonotis leonuri herba). Regarding L. cardiaca, stachydrine might be an exceptionally interesting constituent as Dragendorff-positive substances like stachydrine were found to be enriched in an antiarrhythmic L. cardiaca refined extract, which was most recently developed via bioassay guided fractionation. The few pharmacological publications on this betaine do indeed describe cardiovascular, hypotensive, and tissue protective effects. However, its pharmacopeial analytics poses a severe difficulty, as it does not contain any chromophoric group suitable for customary HPLC-UV detection. For quality control of yimucao according to Chin.Ph. the entirety of its N-containing compounds is photometrically quantified after Reinecke's complexation. Unfortunately, this method suffers from a relatively low reproducibility. Since no reliable quantification method for stachydrine is available up to now, a highly reproducible instrumental HPTLC method was newly developed, using postchromatographic derivatization by Vagujfalvi reagent, thus changing non absorbing stachydrine into a detectable derivative at 517 nm, and an automatic HPTLC system with scanner and analysis software (winCATS). This method was shown to be precise with respect to concentration and yielded highly reproducible data over numerous inter-day repetitions. Not only did the independent evaluation of the scanned HPTLC sheets for stachydrine peak area and height result in almost identical values for all samples, but also the results of a parallel-developed direct quantitative 1H-NMR procedure using its N-CH3 singlet delta 3.03 ppm in comparison with the singlet of the two vinylic protons of the internal standard maleic acid at delta 6.18 ppm were always within the standard deviation of the HPTLC data. These measurements of 12 drug samples revealed stachydrine contents (w/w) of 0.2 to 1.0% for the L. japonicus aerial parts, 0.6 to 1.5 % for the L. cardiaca aerial parts, 6.7% for the antiarrhythmic refined extract of L. cardiaca, and 0.3% for the aerial parts of Leonotis leonurus, while both L. japonicus and L. cardiaca fruits contained, on average, 0.2 %. Furthermore, stachydrine was found for the first time as a constituent of L. japonicus and L. cardiaca fruits as well as Leonotis leonurus. Methodically, instrumental HPTLC may be a powerful tool for quality assurance for stachydrine containing plants and herbal drugs, especially for industrial routine protocols. PMID- 23923635 TI - An improved assay for the detection of alterations in bacterial DNA supercoiling in vivo. AB - Due to the increasing prevalence of antibiotic resistance and the yet low output of the genomics-based drug discovery approach novel strategies are urgently needed to detect new antibiotics. One such strategy uses known ubiquitous targets like DNA topoisomerases. However, to detect inhibitors of these enzymes by an in vitro assay time-consuming isolation of enzymes and DNA followed by electrophoretic separation of topoisomers are required. Instead, this study aimed at developing an in vivo assay for the detection of alterations in DNA supercoiling indicative of topoisomerase inhibition by a reporter gene assay. A pair of plasmids was developed which carry the reporter gene luc for firefly luciferase under control of either promoter ptopA (pPHB90) or pgyrA (pPHB91), whose activities are reciprocally affected by alterations of the supercoiling degree. Each plasmid is individually transferred into E. coli cells. The quotient of the luciferase activities determined using cells with either plasmid was taken as relative measure of the global supercoiling degree Qsc (quotient of supercoiling). Using isogenic reference strains with known alterations of the global DNA supercoiling degree due to mutations in either gyrB or topA, the reporter gene system was able to detect both a decrease and an increase of the negative supercoiling degree compared to the isogenic parent strain. Treating cells with known inhibitors of DNA gyrase, like fluoroquinolones, novobiocin as well as simocyclinone D8 from Streptomyces antibioticus which has been identified as an inhibitor of DNA gyrase in vitro, also caused decreases of the Qsc value in vivo. The suitability of this reporter gene system to screen for anti topoisomerase I and II compounds from various natural sources like plant extracts by sensing alterations of the DNA supercoiling was demonstrated and offers a new application to identify novel compounds active against bacterial topoisomerases I and gyrase. PMID- 23923636 TI - Development of nanoparticle-bound arylsulfatase B for enzyme replacement therapy of mucopolysaccharidosis VI. AB - Lysosomal storage disorders like mucopolysaccharidosis (MPS) VI are rare diseases with a lack of well-suited treatments. Even though an enzyme replacement therapy (ERT) of recombinant arylsulfatase B (ASB) is available for MPS VI, the administration cannot positively affect the neurologic manifestations such as spinal cord compression. Since nanoparticles (NP) have shown to be effective drug carriers, the feasibility of arylsulfatase B adsorption onto poly(butyl cyanoacrylate) (PBCA) nanoparticles was investigated in this study. In order to advance the ERT of ASB, the adsorption of the latter on the surface of PBCA NP as well as in vitro release in serum was investigated. With alteration of parameters like temperature, incubation time, pH, and enzyme amount, the adsorption process revealed to be stable with a maximum capacity of 67 microg/mg NP at a pH of 6.3. In vitro release experiments demonstrated that the adsorption is stable for at least 60 minutes in human blood serum, indicating that the ASB-loaded PBCA nanoparticles represent a promising candidate for ERT of MPS VI. PMID- 23923637 TI - Salt screening and characterization for poorly soluble, weak basic compounds: case study albendazole. AB - In preclinical development, salt forms are often screened to assess their ability to improve drug candidate properties. In this study albendazole was used as a model for poorly soluble, weak basic compounds typical of current drug discovery programs. Four salts, the hydrochloride, mesylate, sulfate und tosylate, were prepared and characterized with respect to their physicochemical properties. Identity was confirmed by 1H NMR spectroscopy, ion chromatography and vibrational spectroscopy. The solid state forms of the albendazole salts were examined by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), laser diffraction measurement of particle size distribution (PSD), B.E.T. measurement of the specific surface area and 13C solid state NMR spectroscopy. Thermal behaviour and hygroscopicity were assessed by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), Karl Fischer titration (KFT) and by variable temperature XRPD. Additionally, solubility and dissolution experiments were carried out in water and buffers. The different salt forms show pronounced differences in their physicochemical behaviour, especially with respect to hygroscopicity (sulfate > hydrochloride > tosylate > mesylate) and dissolution (rank order is pH dependent, all better than the free base). A salt form with highly improved physicochemical properties, the mesylate, was identified. The results demonstrate that extensive physicochemical characterization is needed to select the salt form most appropriate for further pharmaceutical development. PMID- 23923638 TI - Influence of different test parameters on in vitro drug release from topical diclofenac formulations in a vertical diffusion cell setup. AB - In the past decades, the vertical diffusion cell has emerged as a useful device for testing drug release of topical dosage forms. However, to date neither a general USP method nor formulation-related monographs have been published in international pharmacopoeia. The purpose of the present work was to examine the influence of different test parameters in a vertical diffusion cell setup on in vitro drug release from semi-solid preparations for cutaneous application. Diclofenac was selected as the model compound. Release experiments were performed in a 7 ml Microett vertical diffusion cell system. Various test parameters, including the media composition and pH, degassing, membrane material and pore size, stirring speed and stirrer type, were varied. Results obtained with different test parameter settings clearly indicate that both drug properties and instrumental details can have a huge impact on the outcome of in vitro diffusion/drug release studies with the vertical diffusion cell. Thus, the selection of adequate test parameters is crucial for the success of the release experiments and, as shown in the present study, optimal test parameters/conditions need to be established and validated on a case by case study. PMID- 23923639 TI - Evaluation of the mechanism of gelation of an oleogel based on a triterpene extract from the outer bark of birch. AB - Oleogels are known for their high physical, chemical, and mechanical stability and good in vivo efficacy, which make them appropriate vehicles for dermal drug delivery and skin care for very dry skin. Modern formulation research focusses on well tolerated and sustainable formulation concepts. This paper deals with an innovative oleogel, which is based on a triterpene dry extract from the outer bark of birch (TE). In this formulation TE does not only act as an excipient but provides interesting pharmacological properties at the same time. The oleogel was formulated using solely Simmondsia Chinensis seed oil (jojoba oil) and TE. Fluorescence microscopy and confocal Raman microscopy showed that suspended TE particles arrange in a three-dimensional gel network. Infrared spectroscopy revealed that the formation of hydrogen bonds between TE particles is responsible for the self-assembly of TE in oil. Moreover, the influence of TE concentration and morphology of the TE particles on the viscoelasticity of the resulting oleogels was analyzed. Gel strength increased with TE concentration and was critical to the specific surface area of the TE particles. PMID- 23923640 TI - Upregulation of the 5-lipoxygenase pathway in human monocytes by growth and differentiation factors. AB - 5-Lipoxygenase (5-LO) is the key enzyme in leukotriene biosynthesis. Leukotrienes are key mediators of inflammation, allergic and innate immune reactions. 5-LO expression is mainly restricted to a variety of immune competent cells including B-lymphocytes, granulocytes and monocytes/macrophages. Here, we studied the effects of the growth or differentiation factors TGFbeta, 1,25(OH)2D3, GM-CSF and TNFalpha on 5-LO mRNA and protein expression and on 5-LO activity in human monocytes. We found that cultivation of monocytes under standard culture conditions downregulates 5-LO mRNA expression which could be prevented by addition of the four factors. Monocyte 5-LO activity was serum-dependent and cultivation of the cells in serum-free medium strongly downregulated cellular 5 LO activity which could be prevented by TGFbeta, 1,25(OH)2D3, GM-CSF and TNFalpha to different extents. The protein kinase A activator dibutyryl-cAMP blocked the effects of the four factors. The data suggest that 5-LO expression and activity in monocytes is strongly regulated by pro- and anti-inflammatory growth or differentiation factors. PMID- 23923641 TI - Neuroprotection by bilobalide in ischemia: improvement of mitochondrial function. AB - Bilobalide, an active constituent of Ginkgo biloba, is known to have neuroprotective properties, but its mode of action remains unclear. In this study, bilobalide significantly reduced brain damage in mice (indicated by TTC staining) when given before transient middle cerebral artery occlusion (tMCAO). As measured by microdialysis in the ischemic striatum, local perfusion with bilobalide (10 microM) reduced ischemia-induced glutamate release by 70% while glucose levels were not affected. Mitochondria isolated from ischemic brain showed a decrease of respiration compared to non-ischemic controls. Treatment with bilobalide (10 mg/kg) before tMCAO improved respiratory capacity of complex I significantly when measured ex vivo. In addition, mitochondrial swelling induced ex vivo by calcium was used to estimate opening of the mitochondrial permeability transition pore. In this assay, the changes induced by tMCAO were completely reversed when mice had received pretreatment with bilobalide. We conclude that neuroprotection by bilobalide involves a mechanism in which the drug reverses ischemia-induced changes in mitochondria, leading to a reduction of glutamate release. PMID- 23923642 TI - Simvastatin alters membrane cholesterol distribution and beta-amyloid levels in brains of female APP751SL mice. AB - Statins (HMG-CoA reductase or CSE-inhibitors) strongly reduce the cellular amyloid-beta protein production by modulating the processing of amyloid precursor protein (APP) in vitro. Several in vivo studies have addressed this important issue in transgenic mouse models with inconsistent results. Recently, we showed that simvastatin alters cholesterol distribution in synaptosomal membranes (SPM) in vivo. In the present study, we tested whether these changes in cholesterol membrane distribution affect APP-processing in vivo. Female APP751SL mice were force-fed with simvastatin (50 mg/kg b.wt.) by oral gavage over a time period of 3 weeks. Our data show that chronic simvastatin treatment decreased cholesterol levels in the brain and affected cholesterol distribution within SPM. Simvastatin significantly increased the levels of insoluble Abeta1-40 and Abeta1-42 but reduced levels of soluble Abeta1-40 in the brain. The reduction of soluble Abeta1 40 levels in the brain was associated with an increase of plasma-levels of AP31.40 in simvastatin-treated animals that may indicate enhanced Abeta1-40 clearance from the brain. Although the observed alteration in transbilayer cholesterol is likely to be involved in changes of APP processing by alpha-, beta and gamma-secretase, we cannot exclude other potential mechanisms of statins such as lipid and non-lipid related, pleiotropic effects. Our data were evaluated in reference to published studies and a possible gender effect was identified. PMID- 23923643 TI - Chromatin organisation of transgenes in Dictyostelium. AB - The introduction of transgenes in Dictyostelium discoideum typically results in the integration of the transformation vector into the genome at one or a few insertion sites as tandem arrays of approximately 100 copies. Exceptions are extrachromosomal vectors, which do not integrate into chromosomes, and vectors containing resistance markers such as blasticidin, which integrate as single copies at one or a few sites. Here we report that low copy number vector inserts display typical euchromatic features while high copy number insertions are enriched for modifications associate with heterochromatin. Interestingly, high copy number insertions also colocalise with heterochromatin, are enriched for the centromeric histone CenH3 and display centromere-like behaviour during mitosis. We also found that the chromatin organisation on extrachromosmal transgenes is different from those integrated into the chromosomes. PMID- 23923644 TI - An alternative splice process renders the MLL protein either into a transcriptional activator or repressor. AB - The biological process of differentiation - from a fertilized egg to a human being - is a consecutive mechanism that leads to the establishment of tissue specific gene expression, but also to a coordinated shut-down of all those genes that are not necessary for a given cell type. This process is accompanied by posttranslational modifications of the chromatin (DNA methylation and covalent histone modifications), also termed the "epigenetic layer". All epigenetic processes are mediated by protein complexes that either mediate specific DNA methylation patterns, or modify nucleosomal proteins in a covalent fashion (acetylation, methylation, phosphorylation and ubiquitinylation). One important player involved in epigenetics is the MLL protein which represents a histone H3 methyltransferase. The MLL gene gained much attention because of its frequent genetic rearrangements, thereby creating oncogenic MLL fusion genes that cause acute leukemia in pediatric and adult patients. This article is summarizing certain functional aspects about MLL, but is mainly emphasizing on an alternative splice event within the PHD domain. This changes the biological properties of the MLL protein, thereby influencing its ability of being either a transcriptional activator or repressor. PMID- 23923645 TI - Molecular determinants of cancer cell sensitivity and resistance towards the sesquiterpene farnesol. AB - Farnesol is a non-cyclic sesquiterpene (isoprenoid) found in the essential oils of many plants. In cancer biology, farnesylation of mutated Ras oncoproteins allows the proteins to dock to the membrane and be functionalized. Therefore, farnesyltransferase is a target for drug development to inhibit Ras. Farnesol exhibits cytotoxic activity against tumor cells in vitro and in vivo, implying that novel treatment strategies may be devised independent of Ras farnesylation. Tumors frequently develop resistance towards standard chemotherapies, and thus novel agents are urgently required that bypass the cross-resistance evoked by established anticancer drugs. We investigated whether classical mechanisms of drug resistance such as ATP-binding cassette transporters (P-glycoprotein/MDR1, MRP1, BCRP), the tumor suppressor gene TP53, and the oncogene EGFR play a role in the response of tumor cells to farnesol. Remarkably, none of these genes conferred resistance to farnesol, indicating that this compound may be useful for the treatment of otherwise drug-resistant and refractory tumors expressing these mechanisms of resistance. Furthermore, we applied a pharmacogenomic approach to explore molecular determinants of sensitivity and resistance to farnesol. Among the candidates were genes involved in apoptosis (STAB2, NUMBL), regulation of transcription (CDYL, FOXA2) and diverse other functional groups (INE1, CTRL, MRS2, NEB, LMO7, C9orf3, EHBP1). The fact that these genes are not associated with resistance to traditional anticancer drugs suggests farnesol may possess a novel mechanism of action, and consequently might bypass drug resistance to established chemotherapeutics. PMID- 23923646 TI - Clindamycin binding to ribosomes revisited: foot printing and computational detection of two binding sites within the peptidyl transferase center. AB - Clindamycin is a semi-synthetic lincosamide, active against most Gram-positive bacteria and some protozoa. It binds to the 50S ribosomal subunit and inhibits early peptide chain elongation. By kinetic analysis it has been shown that clindamycin (I) competitively interacts with the A-site of translating ribosomes (C) to form the encounter complex CI, which then slowly isomerizes to a tighter complex, termed C*I. As the final complex is capable of synthesizing peptide bonds with decreased velocity, it was assumed that in C*I complex the drug is fixed near the P-site of the ribosome. In the present study, two series of chemical foot printing experiments were carried out. In the first series, clindamycin and ribosomal complex C were incubated for 1 s and then DMS or kethoxal was added (CI probing). In the second series, complex C was preincubated with clindamycin for 1 min before the addition of DMS or kethoxal (C*I probing). It was found that clindamycin in CI complex protects A2451 and A2602 from chemical probing, both located within the A-site of the catalytic center. In contrast, it strongly protects G2505 in C*I complex, which is a discrete foot print of peptidyl-tRNA bound to the P-site. In both CI and C*I complexes, clindamycin also protects nucleotides A2058 and A2059, located next to the entrance of the exit-tunnel where the nascent peptide leaves the ribosome. Polyamines negatively affect the protection of G2505, but favor the protection of A2451 and A2602 nucleotides. Structure modeling confirms the kinetic and chemical foot printing results and suggests that clindamycin mode of action is more complex than a simple competitive inhibition of peptide bond formation. PMID- 23923647 TI - Defining the role of MRP-mediated efflux and glutathione in detoxification of oxaliplatin. AB - Albeit platinum complexes are widely used in cancer chemotherapy, their cellular processing has not been completely elucidated so far. In this study the effects of modulating multidrug resistance-associated protein (MRP)-mediated efflux and glutathione (GSH) depletion on the cytotoxicity of oxaliplatin were assessed in a human ileocecal colorectal adenocarcinoma cell line and its oxaliplatin-resistant variant. Upon oxaliplatin exposure, DNA platination was elevated by co-incubation with Gu83, a MRP1 and MRP2 inhibitor, but cytotoxicity was not increased. Addition of oxaliplatin did not alter the cellular GSH content. Following GSH depletion, platinum accumulation was unchanged but cytotoxicity was increased in oxaliplatin-sensitive cells. In conclusion, modulation of MRP-mediated efflux did not affect oxaliplatin cytotoxicity in the investigated cell lines. Intracellular GSH depletion seems to sensitize the cells but does not overcome resistance. PMID- 23923648 TI - Antibacterial activity of the recombinant antimicrobial peptide Ib-AMP4 from Impatiens balsamina and its synergy with other antimicrobial agents against drug resistant bacteria. AB - Ib-AMP4 is an antimicrobial peptide of Impatiens balsamina (Balsaminaceae). Ib AMP4 was produced as a recombinant peptide and in this study its antimicrobial activity against human bacterial pathogens was investigated. Ib-AMP4 was bactericidal against both Gram positive and Gram negative bacteria with MIC values between 0.49 and 3.5 microM in sensitive species. A genuine synergistic effect was achieved when IB-AMP4 was employed in combination with the plant monoterpene thymol against drug-resistant Klebsiella pneumoniae (KPC) ATCC700603, or with the antibiotics vancomycin or oxacillin against Enterococcus faecalis (VRE) ATCC51299. PMID- 23923649 TI - Characterization of a Yariv precipitated arabinogalactan-protein from fruits of rye (Secale cereale L.). AB - An arabinogalactan-protein (AGP) with a molecular mass of 110 kDa was isolated from whole grain of rye (Secale cereale L.) by double precipitation with (beta-D Glc)3-Yariv-phenylglycoside (3GlcY) and its structure was analyzed. The AGP consists of a hydroxyproline-rich protein backbone of about 7 % and an arabinogalactan moiety of about 93%. By alkaline hydrolysis, hydroxyproline was identified as the main amino acid responsible for the binding between the protein and the carbohydrate subunits via an O-glycosidic linkage. The arabinogalactan moieties are highly branched consisting of 1,3-linked Galp residues, some of them linked in position 6 to 1,6-Galp side chains, terminating in Araf residues. With regard to its structure, the rye AGP is comparable to other cereal AGPs like those from oat or wheat grain. PMID- 23923650 TI - Toxic pyrrolizidinalkaloids as undesired contaminants in food and feed: degradation of the PAs from Senecio jacobaea in silage. AB - Pyrrolizidine alkaloids (PAs) can show a hazardous potential for men and animals. They can act as cancerogenic, mutagenic, teratogenic and fetotoxic agents. One pathway of a human intoxication is its occurence as contaminants in food and feed. Here, the contamination of cereals already led to severe and fatal intoxication episodes. Besides this, milk is of special concern as it is the main food for children which show a very high susceptibility for a PA intoxication. Milk can contain PAs in case the milk producing animals have access to contaminated feed. In this context it is of special interest whether the PA content of contaminated silage remains stable during the ensiling procedure or show a more or less high level of decomposition. We could show that ensiling will not lead to PA-free silage. PMID- 23923651 TI - Gniditrin is the main diterpenoid constituent in the bark of Daphne mezereum L. AB - The bark of Daphne mezereum L. is known as toxic drug due to the presence of diterpene esters. The phytochemical analysis of the bark used for preparation of homeopathic mother tinctures showed that gniditrin was the main diterpene constituent, only in the fruits of D. mezereum mezerein could be detected. The complete NMR data of gniditrin are published for the first time. PMID- 23923652 TI - Tripterygium wilfordii Hook. f. - how a traditional Taiwanese medicinal plant found its way to the West. AB - Tripterygium wilfordii is regarded as a promising traditional medicinal plant showing several, mainly antiinflammatory and cytotoxic activities. It contains unusal natural products currently under investigation as lead compounds. The species has been well known in Traditional Chinese Medicine but was recognized in Western science as an insecticide not before the 1930's and as a promising medicinal plant in the 1960's. The name refers to Charles Wilford, employed as a botanical collector at Kew Botanical Gardens, London from 1857-1860. He collected the plant on the island of Taiwan, formerly called Formosa, in June 1858, unfortunately without reporting its medicinal use in the country of origin. The plant was named according to the Linnaean system before 1862 what initially concealed its medicinal properties which had to be re-discovered in the second half of the 20th century. PMID- 23923653 TI - ['One health' also for pets]. PMID- 23923654 TI - [Current value of the dog]. PMID- 23923655 TI - [Surveillance]. PMID- 23923656 TI - Improvement of technical results following use of Ingelvac CircoFLEX in a Dutch organic breeding and fattening farm: a case report. AB - Porcine Circovirus type 2 (PCV2) is a ubiquitous infection and major cause of production loss for the pig industry. The aim of this study was to evaluate the effect of vaccination against PCV2 on technical results of pigs on an organic breeding and fattening farm, focussing on growth and mortality of weaned piglets and fattening pigs. The study was based on retrospective data between January 2009 and May 2011. During the study period, three subsequent vaccination strategies were used: 1. Stellamune One, 2. Stellamune One+CircoFLEX, 3. MycoFLEX+CircoFLEX. From these three periods, the corresponding management- and slaughterhouse data were analysed by an ANOVA-test. Due to few data in period 2 and an outbreak of Actinobacillus pleuropneumoniae during periods 2 and 3, these two periods were combined in one period and analysed by a two-sample t-test. Mortality of weaned piglets decreased with 3.6% (0.6 - 6.6%) (P0.023) in comparison to period 1 and average daily weight gain improved by 21 gram (7 - 34 gram) (P0.004) in periods 2 and 3. Mortality of fattening pigs was 2.3% (1.2 - 3.5%) (P0.001) less than in period 1 and corrected energy conversion rate improved 0.27 (0.05 - 0.49) (P0.017). There was no significant effect on slaughterhouse parameters. In conclusion, vaccination against PCV2 improved technical results of weaned and fattening pigs on this farm. The advantage of vaccination with MycoFLEX+CircoFLEX instead of Stellamune One+CircoFLEX is that the two FLEX-vaccines can be mixed and administered as a one shot vaccine, reducing work load and animal stressors. PMID- 23923657 TI - [The history of rabies in animals in the Netherlands]. PMID- 23923658 TI - [Almost all chicks positive for ESBL's]. PMID- 23923659 TI - [Intravenous cytostatic agent applicable to veterinary medicine]. PMID- 23923660 TI - [Watch out with travel to Spain]. PMID- 23923661 TI - [Professor Arie Brand, vision and development. Interview by Andries van Foreest and Ko Minderhoud]. PMID- 23923662 TI - [Don't sit on the farmer's lap]. PMID- 23923663 TI - Activated charcoal adsorption of volatile anesthetic agents for anesthesia machine preparation of malignant hyperthermia susceptible patients. PMID- 23923664 TI - 3-in-1 block: are we still using this misnomer? PMID- 23923665 TI - Response. PMID- 23923666 TI - AANA introduces an evidence-based infection control guide. AB - The American Association of Nurse Anesthetists Infection Control Task Force applied a rigorous evidence-based process to the revision of the Infection Control Guide for Certified Registered Nurse Anesthetists. This article details the necessity of a current Professional Practice infection control document, including an expansion of infection control and prevention literature since the last revision of this document; a multitude of infectious outbreaks; and an overwhelming lack of adherence to principles of effective hand hygiene, asepsis, and safe injection practices. Specific areas discussed include preventive measures used by Certified Registered Nurse Anesthetists during patient care activities; infection control measures aimed at procedures involving the anesthesia delivery system; and infection control practices for cleaning, disinfecting, and terminal cleaning of the environment. PMID- 23923667 TI - The national practitioner data bank and CRNA anesthesia-related malpractice payments. AB - A retrospective analysis of the National Practitioner Data Bank (NPDB) Public Use Data File was performed on anesthesia-related malpractice payments from 2004 to 2010. Anesthesia-related allegations, malpractice act or omission codes, severity of injury, and cost were assessed. The NPDB captured 369 anesthesia-related malpractice payments associated with Certified Registered Nurse Anesthetists (CRNAs), of which the 3 most frequently coded injury classifications for severity were death, minor permanent injury, and grave permanent injury. In general, the most costly payments based on median cost were major permanent injury, followed by grave permanent injury and death. When reviewing specific allegations of malpractice act or omission among the total number of CRNA malpractice payments, the most common allegations were improper performance,, failure to monitor, and problem with intubation. Patients between the ages of 40 and 59 years, inpatients, and female gender were independently more prevalent among CRNA malpractice claims leading to payment than other patient demographics. PMID- 23923668 TI - Predicting success in nurse anesthesia programs: an evidence-based review of admission criteria. AB - Nurse anesthesia programs strive to minimize attrition due to academic reasons and maximize student success. The authors examined the evidence for evaluating applicants to nurse anesthesia programs that may help predict success in the program and on the National Certification Examination for Nurse Anesthetists. A search strategy guided gathering of evidence from peer-reviewed journals. Evidence from non-anesthesia graduate nursing programs was included because of the suspected lack of evidence specifically examining nurse anesthesia programs. Eight sources involved solely graduate nurse anesthesia programs, 9 involved graduate nursing programs without stu-graduate nursing programs with student registered Nurdent registered nurse anesthetists, and 2 pertained to nurse anesthetists. Most of the evidence sources were descriptive studies. The evidence overall supports current commonly used admissions criteria such as undergraduate grade point averages. The requirement for applicants to take the Graduate Record Examination should be examined closely. Programs should also consider the length of time the applicant has been out of a formal educational setting. Based on these findings, programs may cautiously explore revising the admission policy. Further investigations are proposed to explore the predictive value of various admission criteria. PMID- 23923669 TI - Investigation of the anxiolytic effects of xanthohumol, a component of humulus lupulus (Hops), in the male Sprague-Dawley rat. AB - The purpose of this study was to investigate the anxiolytic effects of xanthohumol, a component of Humulus lupulus (hops), and its potential interaction with the benzodiazepine binding site on the y-aminobutyric acid (GABAA) receptor in the male Sprague-Dawley rat. This was a prospective, randomized, between subjects experimental study. Fifty-five rats were assigned to 1 Sof 5 groups with 11 rats per group: control (vehicle), xanthohumol, midazolam, midazolam with xanthohumol, and flumazenil with xanthohumol. In this study the elevated plus maze measured the behavioral components of anxiety and motor movements. A 2 tailed multivariate analysis of variance and least significant difference post hoc test was used to determine if a significant difference existed. Our data suggest that xanthohumol does not produce anxiolysis by modulation of the GABAA receptor; however, there may be a possible interaction between xanthohumol and midazolam, or xanthohumol may influence the modulation of another neurotransmitter site in the central nervous system. Alone, xanthohumol does not show significant modulation of the benzodiazepine receptor. Additional research should investigate if xanthohumol acts as a benzodiazepine GABAA partial agonist or antagonist or if it modulates another neurotransmitter system in the central nervous system. PMID- 23923670 TI - Posttraumatic stress disorder and anesthesia emergence. AB - Emergence agitation or delirium is a known phenomenon in the postanesthesia period. The underlying cause is not definitively understood. In a U.S. Army hospital's postanesthesia care unit, combat-related posttraumatic stress disorder (PTSD) can complicate interventions. Scant evidence-based research exists on the issue. By presenting case studies of 2 patients who underwent different surgical procedures, the authors argue that traditional modalities to reorient and calm patients experiencing emergence agitation who have PTSD are not shown to be effective. The first procedure demonstrates outcomes in a situation handled through traditional interventions. The second procedure demonstrates outcomes after incorporation of evidence-driven interventions. The authors conclude that best practice includes a proper identification of patients at risk of emergence agitation, a minimally stimulating environment, intraoperative sympatholytic therapy, and patient and staff education. Although the case studies presented support these principles, research is needed to provide stronger evidence. Military medical and research personnel can take the lead on this issue and be a source for improved outcomes and high-quality patient care. PMID- 23923671 TI - Absorption atelectasis: incidence and clinical implications. AB - General anesthesia is known to cause pulmonary atelectasis; in turn, atelectasis increases shunt, decreases compliance, and may lead to perioperative hypoxemia. One mechanism for the formation of atelectasis intraoperatively is ventilation with 100% oxygen. The goal of this review is to determine if research suggests that intraoperative ventilation with 100% oxygen leads to clinically significant pulmonary side effects. An initial literature search included electronic databases (Cumulative Index to Nursing & Allied Health Literature [CINAHL], PubMed, MEDLINE, Embase, and The GeneraCochrane Library) using the following search terms: oxygen (administration and dosage), atelectasis, pulmonary complications, and anesthesia. Results were limited to research studies, human subjects, and English-language publications between 1965 and 2011. From this body of research, it appears that absorption atelectasis does occur in healthy anesthetized adults breathing 100% oxygen. Data reviewed suggest that absorption atelectasis does not have significant clinical implications in healthy adults. However, further research is warranted in populations at increased risk of postoperative hypoxemia, including obese or elderly patients and those with preexisting cardiopulmonary disease. PMID- 23923672 TI - Preoperative chlorhexidine anaphylaxis in a patient scheduled for coronary artery bypass graft: a case report. AB - Chlorhexidine is a synthetic antiseptic and disinfectant that has been widely used in the healthcare setting and in everyday household products. In addition to oral rinses and skin preparations, manufacturers have incorporated chlorhexidine coatings into medical devices such as urinary catheters, endotracheal tubes, and central venous catheters in an effort to reduce infection rates. Despite the ubiquitous use of chlorhexidine, severe reactions, such as anaphylaxis, are relatively rare. This case report describes a 65-year-old patient scheduled for coronary artery bypass graft surgery who preoperatively experienced anaphylaxis to chlorhexidine delivered through multiple routes of administration. To our knowledge, this is the first reported perioperative anaphylactic reaction to chlorhexidine in the United States. A review of the anaphylaxis cascade, the prevalence of hospital-acquired infections, and the risks of using chlorhexidine are thoroughly discussed. It must be appreciated that life-threatening reactions to this commonly used agent are more than just a theoretical possibility. PMID- 23923673 TI - Methylene blue encephalopathy: a case report and review of published cases. AB - Methylene blue is a cationic thiazine dye useful in staining parathyroid glands during surgical resection. There have been a number of reports of altered neurologic status postoperatively in patients who are taking antidepressant medications when they received methylene blue for their surgery. We present a case report and review 30 additional cases that have been reported in the literature. It has been suggested that in susceptible individuals an interaction occurs between methylene blue and serotonergic agents that precipitates serotonin syndrome. Because people with hyperparathyroidism commonly experience depression as part of their illness, anesthesia practitioners should exercise increased vigilance when administering methylene blue to these patients. PMID- 23923674 TI - Elective laparoscopic fetal laser photocoagulation in twin-twin transfusion syndrome: a case report. AB - Twin-twin transfusion syndrome (TTTS) is a complication of multiple gestation in which arteriovenous vascular communications occur in a shared placenta. Due to these communications, there is an imbalance of blood flow between the developing fetuses. This results in 1 twin becoming the donor and the other becoming the recipient. In severe cases, the recipient may experience polycythemia, polyhydramnios, and hydrops fetalis, while in the donor oligohydramnios and severe anemia may develop. It has been reported that fetal mortality can reach as high as 60% to 80% if TTTS develops before 26 weeks' gestation and goes untreated. Therapeutic options available include decompression amniocentesis, amniotic septostomy, interruption of the placental vessel communications, and selective fetal reduction. Selective fetoscopic laser photocoagulation of abnormal vascular communications has shown to result in increasing survival rates and has become a definitive treatment option for severe TTTS. The case report presented involves a 32-year-old, gravida 5, para 2 patient at 19 weeks' estimated gestational age with a monochorionic diamniotic twin gestation with TTS diagnosed using ultrasonography presenting for an elective laparoscopic fetal laser photocoagulation. PMID- 23923675 TI - Examining transfer of care processes in nurse anesthesia practice: introducing the PATIENT protocol. AB - Human factors, such as inadequate situation awareness, have been associated with preventable accidents in anesthesia practice. Integral to developing situation awareness in the operating room environment is the safe and efficient exchange of essential information when the care of a patient is transferred from one anesthesia provider to another for circumstances such as breaks, meals, and the end of a scheduled work shift. An effective transfer involves the communication of critical information in an effort to preserve the quality and continuity of care. HumaThis article describes a 2-phase, nonexperimental exploratory study with a purpose to (1) examine current transfer of care practices of Certified Registered Nurse Anesthetists during the intraoperative period and (2) develop, implement, and evaluate a communication checklist tool designed to improve situation awareness. Findings from this study have the potential to contribute to the understanding of current transfer of care practices, promote situation awareness in a swift and organized manner, and minimize variation in transfer of care processes that exist in practice today. PMID- 23923676 TI - Unilateral hypoglossal neurapraxia following endotracheal intubation for total shoulder arthroplasty. AB - A case is described of postoperative right hypoglossal neurapraxia after general anesthesia and interscalene block with endotracheal intubation for left total shoulder arthroplasty. Postoperative hypoglossal neurapraxia has been reported in cases, yet it remains a rare complication of anesthesia-related interventions. In this case report, postulated causes of hypoglossal neurapraxia are presented. A review of the literature pertaining to anesthesia-related causes of hypoglossal nerve injury is included. Anesthesia providers should be aware of the course of cranial nerve XII as it relates to the position of the head and neck and use of airway instrumentation. In suspected cases of hypoglossal neurapraxia, conservative therapeutic interventions may be warranted. PMID- 23923677 TI - Mitochondrial diseases and anesthesia: a literature review of current opinions. AB - This course explores the considerations that the anesthesia provider has to be aware of, when caring for a patient with a mitochondrial myopathy. Even though these disorders are rare, these patients may also need surgical care, requiring that the anesthesia provider be informed of the best anesthesia options to consider. A narrative review of documented cases and their outcomes is used to generate a resource of current opinions in the anesthetic care of this patient population. PMID- 23923678 TI - Preventing preterm birth. PMID- 23923679 TI - Usual clinical presentation of bizarre parosteal osteochondromatous proliferation (BPOP) with unusual histology. AB - Bizarre parosteal osteochondromatous proliferation (BPOP) or Nora's lesion is a unique, bony lesion that most often arises in the small bones of the hands and feet. The lesion was first described by Nora et al. in 1983, and documented cases have now shown the lesion to arise in the long bones, skull, maxilla and mandible. Radiographically, the bony lesion typically lacks a connection with the adjacent medullary cavity which is commonly seen with osteochondroma, the main differential diagnosis for Nora's lesion. Reported is the case of a 35-year-old male who presented to the orthopedic clinic after a non-painful mass arising on the right index finger was identified on routine physical examination. The lesion was surgically removed and sent for pathologic evaluation. Microscopic examination of the lesion revealed a disordered spindle cell proliferation and trabecular bone with no cartilaginous cap. The findings were believed to represent an osteocartilaginous neoplasm with radiographs and magnetic resonance imaging (MRI) suggestive of Nora's lesion. Thus, it was felt that the lesion fell within the overall spectrum of BPOP. The lesion is a unique entity that requires a complete history and physical exam along with radiographic and histologic analysis for proper identification. The lesion is benign but may be locally aggressive. Complete excision is the treatment of choice, and recurrence is common. PMID- 23923680 TI - Doxycycline-induced pancreatitis: a rare finding. AB - BACKGROUND: Drug-induced pancreatitis (DIP) is a rare problem in medicine. A retrospective study from 45 German centers of gastroenterology concluded that only 22 of 1613 (1.4 percent) cases of acute pancreatitis in 1993 were DIP. Though DIP is a rare etiology of acute pancreatitis compared to other common etiologies like alcohol, gallstones, hypercalcemia, hypertriglyceridemia, infection, trauma or medical procedures like endoscopic retrograde cholangiopancreatography (ERCP), its incidence continues to rise. We report a case of a 21-year-old female with DIP following doxycycline treatment for an upper respiratory infection. CASE: A 21-year-old, otherwise healthy female presented with severe abdominal discomfort associated with nausea and vomiting. She was hemodynamically stable with normal vital signs. Physical exam revealed a soft but tender to palpation epigastric area. Peritoneal signs were negative. Urinalysis was negative for acute infection. Urine human chorionic gonadotrophin was negative for pregnancy. Laboratory findings revealed a mildly elevated lipase level at 128 U/L (normal 13-60) but was otherwise normal. A computed tomography of abdomen and pelvis revealed evidence of fat stranding consistent with acute pancreatitis. A right upper quadrant ultrasound ruled out gallstones. A serum triglyceride was within normal limit at 80mg/dl. She denied any alcohol use. On further questioning, the patient admitted to previously being diagnosed with an upper respiratory infection two weeks earlier. She had consequently finished a 10 day course of doxycycline therapy, with her last dose five days before presentation. After a literature review of drugs implicated in DIP and ruling out other causes of acute pancreatitis, we concluded that our patient had doxycycline induced pancreatitis. Follow-up visit three weeks post discharge revealed complete resolution of previous symptoms. CONCLUSION: In our vastly evolving pharmacotherapy world, DIP should be entertained as a possible etiology of idiopathic pancreatitis, especially after other common causes have been ruled out. PMID- 23923681 TI - Student interest and knowledge concerning global health electives: a USD Sanford School of Medicine study. AB - Due to society's globalization, medical students increasingly pursue electives in global health. Such international experiences hold several inherent benefits for both the student traveler and the sponsoring institution. In order to enhance global health education at the Sanford School of Medicine (SSOM) of the University of South Dakota (USD), the medical student body was surveyed regarding prior international travel experiences, interest in serving globally, prohibitive factors toward embarking on a global health experience, and objective knowledge concerning medical service in an international context. In total, almost 95 percent of students indicated they were either very interested or somewhat interested in serving internationally during medical school or later during their career. The most prohibitive factors were funding concerns, lack of information and travel preparation demands. The survey responses indicate there is a great interest in the development of a cohesive global health curriculum for the SSOM. PMID- 23923682 TI - 2013 American Diabetes Association update: treatment of hypertension in patients with diabetes. PMID- 23923683 TI - Disability insurance: sick or hurt doesn't have to mean broke. PMID- 23923684 TI - Patient education: when to take away pain. PMID- 23923685 TI - Extenuating circumstances: clinical decisions and revisions. PMID- 23923687 TI - Quality focus: president's page. PMID- 23923686 TI - DAKOTACARE update: how PhRMA is changing their approach to key generic launches, observations in the marketplace. PMID- 23923688 TI - Video self-modeling in children with autism: a pilot study validating prerequisite skills and extending the utilization of VSM across skill sets. AB - Given the recent interest in the use of video self-modeling (VSM) to provide instruction within iPod apps and other pieces of handheld mobile assistive technologies, investigating appropriate prerequisite skills for effective use of this intervention is particularly timely and relevant. To provide additional information regarding the efficacy of VSM for students with autism and to provide insights into any possible prerequisite skills students may require for such efficacy, the authors investigated the use of VSM in increasing the instances of effective initiations of interpersonal greetings for three students with autism that exhibited different pre-intervention abilities. Results showed that only one of the three participants showed an increase in self-initiated greetings following the viewing of videos edited to show each participant self-modeling a greeting when entering his or her classroom. Due to the differences in initial skill sets between the three children, this finding supports anecdotally observed student prerequisite abilities mentioned in previous studies that may be required to effectively utilize video based teaching methods. PMID- 23923689 TI - Engaging older adults with dementia in creative occupations using artificially intelligent assistive technology. AB - Engagement in creative occupations has been shown to promote well-being for older adults with dementia. Providing access to such occupations is often difficult, as successful participation requires face-time with a person who is knowledgeable in facilitating engagement as well as access to any required resources, such as an arts studio. In response, a computer-based device, the Engaging Platform for Art Development (ePAD), was created to with the aim of enabling more independent access to art creation, ePAD is a an artificially intelligent touch-screen device that estimates a client's level of engagement and provides prompts to encourage engagement if the client becomes disengaged. ePAD is customizable such that an art therapist can choose themes and tools that they feel reflect their client's needs and preferences. This article presents a mixed-methods study that evaluated ePAD's usability by six older adult (with mild-to-moderate dementia) and art therapist dyads. Usability measures suggest that all participants found ePAD engaging but did not find prompts effective. Future development of ePAD includes improving the prompts, implementing the recommendations made by participants in this research, and long-term testing in more naturalistic art therapy contexts. PMID- 23923690 TI - Enhancing mobile phones for people with visual impairments through haptic icons: the effect of learning processes. AB - We report the results of a study on the learnability ofhaptic icons used in a system for incoming-call identification in mobile phones. The aim was to explore the feasibility of using haptic icons to create new assistive technologies for people with visual impairments. We compared the performance and satisfaction of users with different visual capacities (visually impaired vs. sighted) and using different learning processes (unimodal vs. multimodal). A better recognition rate and user experience were observed for the visually impaired than for sighted users and for multimodal rather than unimodal learning processes. PMID- 23923691 TI - Evaluation of distinct input methods of an intelligent wheelchair in simulated and real environments: a performance and usability study. AB - This article focuses on evaluating the usability of an intelligent wheelchair (IW) in both real and simulated environments. The wheelchair is controlled at a high-level by a flexible multimodal interface, using voice commands, facial expressions, head movements and joystick as its main inputs. A quasi-experimental design was applied including a deterministic sample with a questionnaire that enabled to apply the system usability scale. The subjects were divided in two independent samples: 46 individuals performing the experiment with an IW in a simulated environment (28 using different commands in a sequential way and 18 with the liberty to choose the command); 12 individuals performing the experiment with a real IW The main conclusion achieved by this study is that the usability of the IW in a real environment is higher than in the simulated environment. However, there were not statistical evidences to affirm that there are differences between the real and simulated wheelchairs in terms of safety and control. Also, most of users considered the multimodal way of driving the wheelchair very practical and satisfactory. Thus, it may be concluded that the multimodal interfaces enables very easy and safe control of the IW both in simulated and real environments. PMID- 23923692 TI - A review of EEG-based brain-computer interfaces as access pathways for individuals with severe disabilities. AB - Electroencephalography (EEG) is a non-invasive method for measuring brain activity and is a strong candidate for brain-computer interface (BCI) development. While BCIs can be used as a means of communication for individuals with severe disabilities, the majority of existing studies have reported BCI evaluations by able-bodied individuals. Considering the many differences in body functions and usage scenarios between individuals with disabilities and able bodied individuals, involvement of the target population in BCI evaluation is necessary. In this review, 39 studies reporting EEG-oriented BCI assessment by individuals with disabilities were identified in the past decade. With respect to participant populations, a need for assessing BCI performance for the pediatric population with severe disabilities was identified as an important future direction. Acquiring a reliable communication pathway during early stages of development is crucial in avoiding learned helplessness in pediatric-onset disabilities. With respect to evaluation, augmenting traditional measures of system performance with those relating to contextual factors was recommended for realizing user-centered designs appropriate for integration in real-life. Considering indicators of user state and developing more effective training paradigms are recommended for future studies of BCI involving individuals with disabilities. PMID- 23923693 TI - Mechanical efficiency of walking with spring-loaded axillary crutches. AB - The objective of this study was to investigate the effect of using spring-loaded crutches on mechanical efficiency in comparison to the use of standard crutches. Seven healthy male participants were recruited for this experiment. They were instructed to walk around a track on two types of crutches for five minutes under four controlled conditions. Ground reaction force and motion trajectories were recorded, which were used to calculate mechanical energy expenditure. Simultaneously, portable gas analysis machinery was used to collect the metabolic parameters of participants, in order to determine mechanical efficiency, the ratio of mechanical energy expenditure to metabolic energy expenditure. It was found that the mechanical efficiency was significantly higher when participants walked with spring-loaded crutches than when they walked with standard crutches. There were no significant differences in metabolic energy expenditure between the spring-loaded crutch conditions and standard crutch conditions. PMID- 23923694 TI - A model of job activity description for workplace accommodation assessment. AB - Workplace accommodations to enable employees with disabilities to perform essential job tasks are an important strategy ways for increasing the presence of people with disabilities in the labor market. However, assessments, which are crucial to identifying necessary accommodations, are typically conducted using a variety of methods that lack consistent procedures and comprehensiveness of information. This can lead to the rediscovery of the same solutions over and over, inability to replicate assessments and a failure to effectively meet all of an individual's accommodation needs. To address standardize assessment tools and processes, a taxonomy of demand-producing activity factors is needed to complement the taxonomies of demand-producing person and environment factors already available in the International Classification of Functioning, Disability and Health (ICF). The purpose of this article is to propose a hierarchical model of accommodation assessment based on level of specificity of job activity. While the proposed model is neither a taxonomy nor an assessment process, the seven level hierarchical model provides a conceptual framework of job activity that is the first step toward such a taxonomy as well as providing a common language that can bridge the many approaches to assessment. The model was designed and refined through testing against various job examples. Different levels of activity are defined to be easily linked to different accommodation strategies. Finally, the levels can be cross-walked to the ICF, which enhances its acceptability, utility and universality. PMID- 23923695 TI - A tradition of caring. PMID- 23923696 TI - Delaware's Home for a Healthy Tomorrow: capital campaign annual report. PMID- 23923698 TI - States delay CMS dual eligible demonstration projects. PMID- 23923697 TI - Evaluation of educational interventions for three lesser-known illnesses. AB - BACKGROUND: Lesser known illnesses (LKI) such as hemochromatosis, celiac disease, and Lyme disease are likely to be under-diagnosed due to the often varied and sometimes vague symptoms and lack of familiarity with testing. Insufficient testing and diagnoses of these LKI could result in poor outcomes for patients and unnecessary costs. OBJECTIVES: The objective of this research was to evaluate the effectiveness of educational campaigns designed to inform physicians about the symptoms of LKIs and the basis to test patients for the diseases. METHODS: A multi-level educational intervention was designed and conducted. The prevalence rate of testing, diagnosis, and the ratio of diagnoses to testing (D/T ratio) for hemochromatosis, celiac disease, and Lyme disease were determined for pre intervention, intervention, and post-intervention time periods. Using the prevalence rates, ANOVA regression analysis was used to estimate the effect of the educational intervention on clients in Medicare Professional System, Medicare Institutional System, and Christiana Care outpatient data. RESULTS: The educational intervention appeared effective at increasing the rate of testing, diagnosis, and the ratio of diagnoses to tests, within the Medicare Institutional System. Generally low rates of the LKI were observed, with large monthly volatility in testing and diagnosis rates. CONCLUSION: The low yields of diagnosis, represented by small D/T ratios, indicate that considerable financial resources have been employed for testing without increased detection of cases above those that would have otherwise been identified. PMID- 23923699 TI - Maps show distribution of home patients. PMID- 23923700 TI - It's not a job, it's a...profession. PMID- 23923701 TI - SGoing with the flow: the basics of water treatment. PMID- 23923702 TI - If you want to advance on the career ladder, certifications can help. PMID- 23923703 TI - Home dialyzors cleared for takeoff. PMID- 23923704 TI - Student engages patients with drama therapy. PMID- 23923705 TI - We know about physician burnout; what about physician happiness? PMID- 23923706 TI - Physician well-being: A powerful way to improve the patient experience. PMID- 23923707 TI - Cognitive assessment in the practice of medicine--dealing with the aging physician. PMID- 23923708 TI - Is digital medicine coming soon? PMID- 23923709 TI - Quality improvement and patient safety in the age of reform: preconditions for success. PMID- 23923710 TI - Physician assistants--making my life and your life easier. PMID- 23923711 TI - Transforming pediatric care in a community hospital. PMID- 23923712 TI - Computer simulation for re-engineering medical supply distribution in hospitals. PMID- 23923713 TI - Practical lean for physician leaders. PMID- 23923714 TI - Finding and communicating value when you're the expert at the meeting. PMID- 23923715 TI - Electronic health records: where we are and where we're going. PMID- 23923716 TI - ACOs offer realistic hope of economic fix for health care. PMID- 23923717 TI - Preparing for your first physician executive role. PMID- 23923718 TI - Generational attitudes affect adoption of social media by physician leaders. PMID- 23923720 TI - Broadening the dialogue: a challenge for us all. PMID- 23923719 TI - PCORI, comparative effectiveness and the ACA: improving patient outcomes or cookbook medicine? PMID- 23923721 TI - Conceptual and idea/ logical colonization: ideational practices in the world of journal editing. PMID- 23923722 TI - Being "ec/centric" in a world of increasing diversity. PMID- 23923723 TI - Working on the "jagged edge": reflections on Thorne and Chinn. PMID- 23923724 TI - Reflections from the South. PMID- 23923725 TI - The Balancing Act: mission, readers, and other voices. PMID- 23923726 TI - Melq'ilwiye: coming together--intersections of identity, culture, and health for urban Aboriginal youth. AB - The goal of this exploratory community-based participatory action research project was twofold: to determine how urban Aboriginal youth identify their health needs within a culturally centred model of health and wellness, and to create new knowledge and research capacity by and with urban Aboriginal youth and urban Aboriginal health-care providers. A mixed-method approach was employed to examine these experiences using talking circles and a survey. The study contributes to anticolonial research in that it resists narratives of dis(ease) put forth through neocolonial research paradigms.A key focus was the development of strategies that address the aspirations of urban Aboriginal youth, laying foundations upon which their potential in health and wellness can be nurtured, supported, and realized. The study contributes to a new narrative of the health of urban Aboriginal youth within a culturally centred and culturally safe framework that acknowledges their strong connection to their Indigenous lands, languages, and traditions while also recognizing the spaces between which they move. PMID- 23923727 TI - Breastfeeding and Aboriginal women: validation of the Breastfeeding Self-Efficacy Scale-Short Form. AB - The purpose of this methodological investigation, part of a prospective cohort study, was to test the reliability and validity of the Breastfeeding Self Efficacy Scale-Short Form (BSES-SF) among Aboriginal women.The sample comprised 130 breastfeeding Aboriginal women from the postpartum ward of an urban tertiary care hospital or a rural community hospital.The women provided baseline information while in hospital and were telephoned at 4 and 8 weeks postpartum for assessment of their method of infant feeding. The BSES-SF was found to be a valid and reliable tool for assessing breastfeeding self-efficacy among Aboriginal women. Significant differences were found in BSES-SF in-hospital scores among women who at 4 weeks postpartum were exclusively breastfeeding, combination feeding, or solely feeding formula (F(2) = 7.31, p = 0.001).The authors conclude that Aboriginal women with low breastfeeding self-efficacy in the early postpartum period may be at risk for early cessation and could benefit from additional breastfeeding support. PMID- 23923728 TI - Maternal-infant health outcomes and nursing practice in a remote First Nations community in northern Canada. AB - This article reports those findings related to maternal-infant health outcomes of an ethnographic study that explored nursing practice, continuity of care, and health outcomes in one remote First Nations community in northern Canada. Use of multiple data sources within an ethnographic design ensured that quantitative health outcomes data were interpreted within a contextualized understanding of the remote First Nations community.The sample comprised the charts of 65 mothers and 63 infants randomly selected for retrospective chart review. The findings suggest suboptimal maternal-infant health outcomes on several of the health indicator criteria identified for the purposes of this study. The authors discuss long-term sequelae of prenatal and infant health in terms of diabetes and other chronic health conditions in First Nations populations.They explore the implications of these findings in relation to nurses' preparation to offer prenatal and infant primary care in remote First Nations communities. PMID- 23923729 TI - Summation of the frequency, severity, and primary causative factors associated with injuries and fatalities involving confined spaces in agriculture. AB - A project was undertaken to estimate the frequency, severity, and primary causative factors associated with injuries and fatalities involving confined spaces in agriculture, including grain bins, silos, and manure storage and handling facilities. A total of 1255 cases from 41 states were analyzed. These cases were included in the Purdue Agriculture Confined Space Database and occurred during the period 1964-2010. During the period 2001-2010, an average of 51 cases were documented annually. Approximately 71% of all documented cases involved grain, and over 16% of all cases involved children under the age of 16. This article presents a summary of the identified incidents and offers conclusions drawn from the study's findings. PMID- 23923730 TI - Task-based noise exposures for farmers involved in grain production. AB - Few studies have been done examining noise exposures associated with agricultural tasks. This study was conducted to address that research gap by calculating the noise exposures for tasks and equipment associated with grain production and assessing the variability in those exposures. An additional aim of this study was to identify tasks and equipment that could be targeted for intervention strategies as a means toward reducing the total noise exposures of farmers and farm workers. Through the use of personal noise dosimetry and direct observation, over 30,000 one-minute noise exposure measurements and corresponding task and equipment data were collected on 18 farms and compiled into a task-based noise exposure database. Mean noise exposures were calculated for 23 tasks and 18 pieces of equipment. The noise exposures for the tasks and equipment ranged from 78.6 to 99.9 dBA and from 80.8 to 96.2 dBA, respectively, with most of the noise exposures having a large standard deviation and maximum noise exposure level. Most of the variability in the task and equipment noise exposures was attributable to within-farm variations (e.g., work practices, distance from noise sources). Comparisons of the mean noise exposures for the agricultural tasks and equipment revealed that most were not statistically different. Grain production tasks and equipment with high mean noise exposures were identified. However the substantial variability in the noise exposures and the occurrence of intense noise measurements for nearly every task and piece of equipment indicate that targeting a few specific tasks or equipment for intervention strategies would reduce lifetime noise exposure but would not completely eliminate exposure to hazardous noise levels. PMID- 23923731 TI - Increases in ROPS pricing from 2006-2012 and the impact on ROPS demand. AB - In 2006, a social marketing campaign was developed to increase the installation of rollover protective structures (ROPS) on unprotected New York tractors. Using data gathered from the program's hotline, the impact of price increases on farmers' interest in ROPS is examined. Pricing data were obtained for all rigid ROPS kits commercially available in the U.S. since 2006. These data were stratified into two groups of ROPS suppliers: (1) tractor manufacturers that sell ROPS for their own tractors, referred to in this study as original equipment manufacturers (OEMs), and (2) aftermarket (AM) ROPS suppliers. The trend in price increases was contrasted with the change in the consumer price index (CPI), the probability of retrofitting within quintiles of cost was estimated, and the increase in ROPS prices over time was plotted The average price increase for a ROPS kit (excluding shipping and installation) over the six years of the study was 23.3% for OEM versus 60.5% for AM (p < 0.0001). Out-of-pocket expenses held steady for OEM versus a six-year increase of $203 for AM (p = 0.098). The probability of a farmer retrofitting dropped monotonically from 66.9% in the lowest ROPS cost quintile to 23% in the highest. If these trends continue, the proportion of inquiries resulting in a ROPS retrofit will fall below 20% by 2020 for AM ROPS. Based on other trends identified in the literature, it is reasonable to assume that decreases in ROPS installation are likely to affect the tractor owners who are most likely to need these safety devices. PMID- 23923732 TI - Measurement of worker perceptions of trust and safety climate in managers and supervisors at commercial grain elevators. AB - The safety climate of an agricultural workplace may be affected by several things, including the level of trust that workers have in their work group supervisor and organizational management. Safety climate has been used by previous safety researchers as a measure of worker perceptions of the relative importance of safety as compared with other operational goals. Trust has been linked to several positive safety outcomes, particularly in hazardous work environments, but has not been examined relative to safety climate in the perennially hazardous work environment of a commercial grain elevator. In this study, 177 workers at three Midwest grain elevator companies completed online surveys measuring their perceptions of trust and safety at two administrative levels: organizational management and work group supervisors. Positive and significant relationships were noted between trust and safety climate perceptions for organizational managers and for work group supervisors. Results from this research suggest that worker trust in organizational management and work group supervisors has a positive influence on the employees' perceptions of safety climate at the organizational and work group levels in an agricultural workplace. PMID- 23923733 TI - [Live from Melbourne, the 25th four-year meeting of the International Council of Nurses: equity and access to health care]. PMID- 23923734 TI - [The beginnings of the nursing profession : the complementary relationship between secular caregivers and hospital nuns in France in the 17th and 18th centuries]. AB - The words used for designating the caregivers are ambiguous. Little by little, the word "nurse" becomes widely used, mainly in the feminine form due to the need of specialized staff. Health care structures are developing in the 17th and 18 centuries, the remains of which you can find in today hospitals (Salpetriere hospital, Hotel-Dieu hospital in Paris). The government of Louis XIV cares for the poor sick people, the vagabonds and the beggars. It opens new general hospitals as it will be the case later in all Europe. In the 17th century, the staff of the general hospital in Paris is entirely secular. The Paris general hospital is headed by the magistrates of Paris Parliament. The healthcare institutions employ both secular and religious staff for example the Hotel Dieu in Paris and the one in Marseilles. In the 17th century, there are 2000 secular caregivers in France. The order of the "Filles de la Charite" (grey sisters) is not submitted to the rule of enclosure. They renew their vows every year. For their founders Vincent de Paul and Louise de Marcillac, their monastery should be the cells of the sick, their cloister should be the rooms of the hospitals or the streets of the town. The secular or religious caregivers are excellent in the apothecary and they open a network of small dispensaries. It improves the health of the French population and allows fighting against the epidemics. This activity allowed some women to have a rewarding activity and a social status of which they were apparently satisfied. PMID- 23923735 TI - [Positive deviance: concept analysis using the evolutionary approach of Rodgers]. AB - Positive deviance is a relatively new concept in healthcare. Since 2006, it has been applied to infection control in order to increase the awareness to good hand hygiene practices. This article focus on presenting analytical results of this concept using the evolutionary approach of Rodgers based on the philosophical postulate that concepts are dynamical and changing with time. For doing so, a census of the writings in nursing, medicine and psychology was carried out. By going through the CINAHL, Medline and PsyclNFO databases using positive deviance as a keyword for the time period: 1975 to May 2012, and in accordance with the method of Rodgers, ninety articles were retained (30 per discipline). The analysis enables one to notice that positive deviance described as an individual characteristic at first, is now used as a behavioral changing approach in nursing and medicine as well. At the end of the analysis and apart from this article, positive deviance will be used in order to study the practice of nurses that adheres to hand hygiene despite limiting constraints within hospital. We will then be able to continue the development of this concept in order to bring it, as Rodgers recommends, beyond the analysis. It would then be an important contribution to good nursing practices in the field of infection control and prevention. PMID- 23923736 TI - [Developmental care principle-based concept analysis]. AB - INTRODUCTION: Developmental care is a combination of interventions that focused on the adaptation of the neonatal environment to support the development of preterm infants. BACKGROUND: Although the concept of developmental care emerges from psychology, its application is integrated into the nursing care of premature infants hospitalized in the neonatal unit. OBJECTIVES: Analysis of developmental care concept has been carried out in order to establish the theoretical foundations and propose a conceptualization according to a nursing perspective. METHOD: This article presents the results of the principle based analysis of the developmental care concept. RESULTS: A conceptualization of developmental care in a nursing perspective is suggested according to the results of the principles analysis of developmental care. DISCUSSION: The identification of the theoretical basis of the concept of developmental care is the first step towards the theoretical integration of this concept that emerge from psychology in the nursing discipline. CONCLUSION: The results of this concept analysis and the proposed conceptualization contribute to the development of nursing knowledge. They can guide the practice of nurses working in the neonatal unit and who provide daily care for premature infant. They can also guide teaching and research on developmental care in nursing. PMID- 23923737 TI - [The contribution of nursing science to interprofessional knowledge development]. AB - Health professionals have to work together to ensure quality patient care.There are many studies exploring interprofessional education and practice. However, interprofessional knowledge is related to teamwork and organizational context. Some frameworks include "patient-centered" concepts to highlight the contribution of the patient but descriptions of the patient's contribution to the interprofessional practice are limited. Nursing professionals develop extensive expertise as a patient-centered professional practice and their experience can inspire new collaborative approaches.This article aims to summarize the state of knowledge regarding interprofessional practice and patient-centered nursing expertise.We also highlight the contribution of nursing in developing this approach and the ways in which nursing contributes to the development of interprofessional knowledge that is consistent with its values. PMID- 23923738 TI - [Sick leave during pregnancy: an analysis of French hospitals from 2005 until 2008 demonstrates the major importance for jobs with physical demands]. AB - INTRODUCTION: sick-leave in the course of pregnancy play a role under estimated according to several studies.They bring to light the existence of risk factors concerning the physical load for contractions, sick-leave, hospitalizations and prematurity.The data obtained on the totality of the wage earners of the AP-HP allow to avoid all the possible bias and to determine the potential impact of a policy of reduction of the physical load METHOD: The data of four years could be analyzed.The used database is PILOT RH, intranet application restoring information extracted from GIPSIE who was until 2008 the institutional software of management of the careers of all the workers of the AP-HP. RESULTS: In 2008,3 937 women having had a maternity leave (ML) accumulated 132 360 days of ordinary sick-leave (OL) (that is 33,6 days on average) without inclusion of the 15 days accepted for "pathological pregnancy" (PP) and "post pregnancy leave". Ordinary sick-leave of all the 53 132 women amounts to 11.5 days by agent. But, the set apart of the women having had a ML reduces the number of days of sick-leave to 9,7 days This difference weighs for 15.6 % of the total of the absenteeism OL. The results are similar on the four years. The analysis by occupational category, for 2008, shows that the average number of days of sick-leave, after exclusion of women having had a ML, decreases with the physical load of the posts estimated by the study PRESST-NEXT :ancillary staff 19.9 days, nursing aids 13.7 days, registered nurses 8.2 days, specialized nurses 7.7 days, medico - technical workers 5.7 days and head nurses 5.1 days. For the women having had a ML, the average number of days of ordinary sick-leave, is the most raised for nursing aids (41.9 days) followed by the ancillary staff (36 days) and the registered nurses (36 days) and slightly less for the specialized nurses (28.3 days). On the other hand, in the professions having least physical load the women have less than 25 days of ordinary sick-leave the year of their pregnancy :medico-technical workers 21.3 days, head nurses 23.1 days and administration staff 23.7 days.The results are similar on the four years. For the nurses, it is 25.5% of total ordinary sick-leave that are attributable to the women having had a pregnancy, and 34.4 % if we add OL and 15 days of official "pathological pregnancy". DISCUSSION: An intervention to reduce the physical load in test hospitals could be led.The reduction of sick-leave in the course of pregnancy can be a fast indicator of evaluation of the efficiency of the investments. The improvements will benefit to all the agents, in the medium term, with a reduction of the risks of musculoskeletal disorders. Such an action also allows to maintain the employability of the older employees and to integrate) persons into situation of handicap in a work which has for them a strong sense and which they do not want to give up. PMID- 23923739 TI - [Patient record based ward rounds as an example of coordination between doctors and nurses "courses of action"]. AB - Working in the hospital field is characterized by collective work that requires collaboration and coordination. Characterizing the way, in which individual activities contribute to the construction of a collective activity, is an important issue to better understand teamwork. A phenomenological research approach was applied to analyze the situated activity of nurses and physicians during patient record based ward rounds, according to the theoretical and methodological frame of "course of action" Our findings revealed ward rounds comprising not only an information exchange but a privileged space and moment of construction of knowledge and coordination. Two processes were derived from the actors' commitments and concerns, and from their articulation: "seeking to contribute to a shared interpretation of the situation" and "seeking to develop a precise working knowledge of the situation". These processes contribute to characterize the coordination between the professionals involved in hospital care. Future educational activities for health care professionals should consider the importance of the perception of and meanings for the involved professionals and consider training actions to foster reflecting on and during action. PMID- 23923740 TI - [State of knowledge: couples' experiences of hospitalization due to high-risk pregnancy]. AB - Taking charge of women with high-risk pregnancy is emerging. In some cases, hospitalization of the pregnant woman might be needed. In nursing sciences, few is known on the couples' experience of the hospitalization, because this event has mostly been explored using a maternal perspective. Some authors however suggest that using a systemic perspective would enhance the comprehension of this phenomenon and guide nursing cares development. In order to clarify the actual understanding of the phenomenon, a literature review has been made. The aim of this article is to present the state of knowledge regarding couples' experience of the women's hospitalization due to high-risk pregnancy. This is compared with the actual nursing practice in the context of practice of the first author of this article. The main themes emerging of this literature review include: giving sense to the antenatal hospitalization, organizing themselves to face danger, taking charge of stress and anxiety through hospitalization and needing each other support. This is followed by a consideration of possible research and nursing practice recommendations, while adopting a systemic constructivist perspective. It takes into account relations between partners and the hospitalization context. Finally, a model presenting the actual nursing practice is discussed. PMID- 23923741 TI - [Functions of nurses in hematopoietic stem cell transplantation units]. AB - INTRODUCTION: nurses working at the hematopoietic stem cells transplantation (HSCT) unit execute very specialized activities since transplantation is more than just being complex but involves a set of procedural techniques. OBJECTIVE: describe activities completed by nurses working at HSCT units and classify them according to the frame of reference of a Brazilian HSTC unit. METHOD: A qualitative descriptive research was carried out in May 2011 with 12 nurses using systematic observation techniques of their daily activities for a total of 77 hours. RESULTS: staff nurses principally carry out caregiving activities and education whereas those related to cooperation, coordination and supervision are mainly executed by the nurse manager and visiting nurses. CONCLUSION: nurses carry out all functions. They take charge of all transplant patients treatments and services. In some way, nurses exceed the scope of the profession. PMID- 23923742 TI - [Nursing in prison: inmates as patients]. AB - There are very few studies investigating the work nurses do in prisons. Based on data stemming from a research in Psychodynamics of Work and a literature review, this paper describes nursing practices in a Canadian penitentiary institution. Three male nurses and two female nurses participated in three two-hour long focus group sessions. Central sources of pleasure that emerged from the focus groups were the scope of nursing care practice ; the autonomy and collaboration with physicians; nursing care practices devoid of moral value judgments, the humanitarian approach, caring and the wish to make a difference in the lives of the inmates ; the pride connected to this unusual professional context, and the recognition by peers and inmates. The main sources of suffering on the other hand were the feeling that rehabilitation was more an ideal than reality ; the paradox of providing both care and safety ; the scary characteristics of working alone ; the fear of lawsuits, and the feeling of being observed continuously. The resulting data we discuss show the issues of a certain dissociation that exists between the patient and the inmate, the fear of contamination of a healthcare nursing identity by the place of practice, but also the feeling of plenitude and sublimation. The conclusion stresses the tension that exists between security and caring, distance and proximity. PMID- 23923743 TI - [Cigars, burgundy and small frogs]. PMID- 23923744 TI - [What do the new guidelines on the treatment of diabetes?]. PMID- 23923745 TI - [Porokeratosis of Mibelli]. PMID- 23923746 TI - [What intentions in the new program of the DFASM?]. PMID- 23923747 TI - [Cervico-facial necrotizing fasciitis]. AB - Cervical fasciitis is a life-threatening condition often due to a benign pharyngeal or dental infection, leading to extensive necrosis, spreading along the fascia of the neck and possibly to the mediastinum. It represents one of the most severe ENT emergencies which requires immediate treatment by a multidisciplinary team. Facing any banal infection of the head and neck, great attention should be paid to any functional or general symptoms and signs of severe sepsis. Patient should be urgently referred to a tertiary center where a CT scan should immediately be done, followed by surgical drainage of the any cervical or thoracic abscesses. Intensive medical care is then needed to treat the frequently encountered cardio-hemodynamic failures or secondary pulmonary or mediastinal infections. The extreme severity of the condition is attested by a mortality rate averaging 5-10%, pneumopathy developing in 1/3 of the patients, hemodynamic failure or mediastinitis in half of the patients, mean duration of mechanical ventilation of 10 days, intubation of 13 days, tracheostomy of 31 days, intensive care unit of 17 days and hospitalization of 26 days. Functional and esthetic sequellae were observed in half of the patients. No predisposing factors could be identified except possibly inadequate initial medical treatment and self-medication by non steroidal antiinflammatory drugs. PMID- 23923748 TI - [Diabetes, obesity and heart complications]. AB - Although epidemiologic analyses suggest a correlation between higher rates of cardiovascular disease and chronic hyperglycemia, to date, no randomized clinical trial has convincingly demonstrated a beneficial effect of intensive therapy on macrovascular outcomes in individuals with long-standing type 2 diabetes. In contrast, intensive initial control in individuals with newly diagnosed diabetes has long-term benefit in decreasing the risk of myocardial infarction, diabetes related death, and overall death. There is strong, consistent evidence that the relationship between blood glucose levels and cardiovascular risk extends into the no diabetic range and obesity. Therefore, multifactorial risk reduction should be a top priority for prevention of macrovascular complications. We should keep in mind that obesity and diabetes also increase the risk of heart failure independent of coronary heart disease and hypertension and may cause a cardiomyopathy, a frequent, forgotten, and often fatal complication. This multifactorial disease should be treated by a multidisciplinary team. PMID- 23923749 TI - [Pyothorax-associated lymphoma]. PMID- 23923750 TI - [PBworks, the "educational" wiki]. PMID- 23923751 TI - [Chronic pains. A very high prevalence, but it is possible to relieve the vast majority of patients]. PMID- 23923752 TI - [Pathophysiology of chronic pain. Classification of three subtypes of pain]. AB - Pain is a physiological sensation which aim is to alert for an upcoming danger that may threaten the individual. This system includes peripheral nociceptors that initiate the nociceptive message. Then, the information is conveyed to the brain through the spinothalamic tract that projects to the thalamus, insula, SII and other areas. In clinical situations, a dysfunction of this nociceptive system explains chronic pain that can be simply classified into 3 subtypes according to pathophysiological mechanisms. Case 1: the nociceptive system is functioning normally, and provides (appropriately) a pain message that informs the brain of a local inflammation, or cancer, or infection... This is the situation of chronic pain because of an excess of nociception. Case 2: there is a (past or present) lesion of the nervous system that induces a dysfunction in the pain system. This is the neuropathic pain. Case 3: between the two former cases, there is no evidence for a lesion in the nociceptive system, and there are no evidences for lesion at the peripheral level, but there are evidences of dysregulation(s). These are the cases of dysfunctional pain. PMID- 23923753 TI - [Evaluation of chronic pain]. AB - In 2007, the Plan for the improvement of the quality of life of people with chronic diseases stressed that support for pain was the first expectations of patient associations. And pain support is primarily the field of competence of the treating physician. It is in this context, that (HAS) recommendations were developed to promote the implementation of care tailored for people expressing a chronic pain. They advocate the support procedure: the identification and evaluation of the chronic pain in ambulatory (history, etiologic assessment, tests), the establishment of treatment or application with a specialized structure, diagnostic or therapeutic advice. PMID- 23923754 TI - [Treatment of nociceptive pain in primary care setting]. AB - The pharmacological treatment of chronic pains induced by an excess of nociception is mainly based on analgesics which are classified according to their pharmacological nature (not opioid/opioid) and to their power according to the three World Health Organization steps. Their use is founded on a strategy which differs from the nature of pain (cancer pain vs no cancer pain), in particular with regard to the use of the strong opioids. PMID- 23923755 TI - [Pharmacological treatment of neuropathic pain in primary care]. AB - Neuropathic pain is difficult to treat. First line treatment includes tricyclic antidepressants (notably amitriptyline), mixed serotonin and norepinephrine reuptake inhibitors (duloxetine for diabetic peripheral neuropathic pain), antiepileptics (gabapentin and pregabalin) and topical agents (lidocaine plasters for postherpetic neuralgia). These drugs can be subsequently associated in case of partial response to monotherapy. Opioids and tramadol are only considered second/third line, alone or in combination with first line drugs. PMID- 23923756 TI - [Treatment of dysfunctional pain in primary care]. PMID- 23923757 TI - [Neurosurgical treatment of chronic pain]. AB - Neurosurgical treatment of pain is based on 3 concepts: 1) lesional techniques interrupt the transmission of nociceptive neural input by lesionning the nociceptive pathways (cordotomy, radicotomy...), they are indicated to treat morphine-resistant cancer pain; 2) neuromodulation techniques try to decrease pain by reinforcing inhibitory mechanisms, using chronic electrical stimulation of the nervous system (peripheral nerve stimulation, spinal cord stimulation, motor cortex stimulation...) to treat chronic neuropathic pain; 3) intrathecal infusion of analgesics (morphine, ziconotide), using implantable pumps, allows to increase their efficacy and to reduce their side effects. These techniques can improve, sometimes dramatically, patients with severe and chronic pain, refractory to all other treatments. PMID- 23923758 TI - [Role of chronic pain management structures]. AB - The chronic pain management structures were identified by the French health authorities regarding two levels: consultation (with a pluri-professional organization and proximity missions) and the center (with a multidisciplinary organization and expertise). Access to these structures is facilitated by guidelines published in 2008 by the Haute Autorite de sante. PMID- 23923759 TI - [Management of chronic pain in the future]. AB - The major development of experimental and clinical pain research over the last two decades should result in the development of new treatment strategies. In the future, the management of chronic pain should rely both on new molecules targetting specific pathophysiological mechanisms and new non pharmacological approaches, such as non invasive transcranial magnetic stimulation, acting on endogenous pain modulatory systems. The variety of new treatment options should allow a more efficacious management of chronic pain, taylored to each patient's profile. PMID- 23923760 TI - [Colonic diverticulosis: natural history and therapeutic indications]. AB - Colonic diverticulosis defined by the presence of mucosal hernia passing through the colic muscularis is symptomatic due to complications in 10-20% of cases. It affects less than 10% of patients before 40 years old and reaches 80% at 80 years old. Primary prevention is a diet of 25g of dietary fiber per day. We are witnessing a decrease of the number of the resections during the last ten years. The diagnosis requires CT proofs. The most serious complications are often inaugural, and severity of acute accesses decreases then. Emergency cares are often minimally invasive therapies as imaging guided and laparoscopic drainage. Resection is reserved for peritonitis, chronic stenosis, fistula, or persistent diseases despite medical management, in patients with more than 3 outbreaks and patients with specific medical risk or immunocompromised. PMID- 23923761 TI - [Medical treatment of sigmoid diverticulitis]. AB - Acute diverticulitis is defined by diverticular and peridiverticular inflammation and infection and is efficiently treated medically in most of the cases. For most patients, outpatient treatment is possible and hospitalization is only indicated if the patient is unable to eat, suffers from an acute attack, has diverticulitis related complications or if symptoms fail to improve despite adequate outpatient therapy The treatment of acute uncomplicated diverticulitis usually consists of broad-spectrum antibiotics covering both aerobic and anaerobic bacteria. Antibiotic therapy is usually administrated for 7 to 10 days but its duration can be longer if any complications occur. If there is no clinical improvement within 2 or 3 days, repeat CT imaging is needed, as this may reveal an abscess, phlegmon or fistula, which may require percutaneous drainage or surgery. The published literature does not support the recommendation of any prophylactic diet or medical treatment for reducing the risk of first or recurrent diverticulitis in patients with diverticulosis. PMID- 23923762 TI - [Radiological treatment of sigmoid diverticulitis]. PMID- 23923763 TI - [Surgical treatment of sigmoid diverticulitis]. AB - Surgery for diverticulitis is usually discussed in two situations: in emergency to treat a diverticulitis related complication or electively to prevent the risk of diverticulitis recurrence (prophylactic colonic resection). Surgical treatment of complicated diverticulitis has gone to changes during the last decade thanks to advances in laparoscopic surgery and interventional radiology (drainage, embolization). Emergency surgery for diverticulitis is mainly indicated (90%) for infectious related complications and more rarely for bleeding or stenosis. Surgery is the standard treatment of peritonitis complicating diverticulitis (Hinchey 3 or 4) and is recommended in Hinchey 1 or 2 diverticulitis after failure of a well conducted medical treatment with or without radiological drainage (for abscesses >or= 5cm). Indications for prophylactic surgery after an episode of uncomplicated diverticulitis is not systematic and should be discussed case by case according to the baseline characteristics of patients. Prophylactic surgery consists in sigmoid resection including the sigmoido-rectal junction with colorectal anastomosis and should be performed under laparoscopy. PMID- 23923764 TI - [Follow-up and dietary advice after sigmoid diverticulitis]. AB - Currently published data do not demonstrate the benefit of any medical treatment in the prevention of the onset or the recurrence of colonic diverticular disease. No specific diet can be recommended to patients with colonic diverticula for the prevention of diverticular disease. Non steroidal anti-inflammatory drugs as well as corticosteroids should be used cautiously in patients with diverticular disease since they induce a higher rate of complications, especially diverticular haemorrhage and severe sigmoid diverticulitis. In patients over 50 years old, or if a sigmoidectomy is needed, physicians should perform a colonoscopy in order to rule out colonic polyps or neoplasm. PMID- 23923765 TI - [Too many physicians?]. PMID- 23923766 TI - [Breast tumours]. PMID- 23923767 TI - [Multiple sclerosis]. PMID- 23923768 TI - [Sport and health. Sport attitude in children and adults. Nutritional needs in sportsmen]. PMID- 23923769 TI - [Risk factors, prevention and cancers]. PMID- 23923770 TI - [History of absinthe]. PMID- 23923771 TI - Speciation of organic phosphorus in a sediment profile of Lake Taihu. I: Chemical forms and their transformation. AB - Organic phosphorus (nonreactive P, NRP) is a major component of P in sediments, but information about its chemical forms and dynamic transformation is limited. The chemical forms and dynamic behaviors of NRP in a sediment profile from Lake Taihu, a freshwater and eutrophic lake in China, were investigated. Five forms of NRP in the sediments were extracted based on a chemical fractionation technique, including easily labile NRP (NaHCO3-NRP), reactive metal oxide-bound NRP (HCl NRP), humic acid-associated NRP (NaOH-NRP(HA)), fulvic acid-associated NRP (NaOH NRP(FA)) and residual NRP (Res-TP). There were notable transformations with increasing sediment depth from the labile NaHCO3-NRP and NaOH-NRP pools to the recalcitrant HCl-NRP and Res-TP pools, which caused the NRP to become increasingly recalcitrant as the early diagenetic processes proceeded. Further analyses showed that the relative changes in contents of organic matter and reactive Fe oxides in the sediment profile triggered a competition for binding NRP fractions and led to the transformation of NRP. The results highlighted the importance of abiotic processes in regulating the diagenesis of organic P and its stability in sediments. PMID- 23923772 TI - Flow field and dissolved oxygen distributions in the outer channel of the Orbal oxidation ditch by monitor and CFD simulation. AB - In the Orbal oxidation ditch, denitrification is primarily accomplished in the outer channel. However, the detailed characteristics of the flow field and dissolved oxygen (DO) distribution in the outer channel are not well understood. Therefore, in this study, the flow velocity and DO concentration in the outer channel of an Orbal oxidation ditch system in a wastewater treatment plant in Beijing (China) were monitored under actual operation conditions. The flow field and DO concentration distributions were analyzed by computed fluid dynamic modeling. In situ monitoring and modeling both showed that the flow velocity was heterogeneous in the outer channel. As a result, the DO was also heterogeneously distributed in the outer channel, with concentration gradients occurring along the flow direction as well as in the cross-section. This heterogeneous DO distribution created many anoxic and aerobic zones, which may have facilitated simultaneous nitrification-denitrification in the channel. These findings may provide supporting information for rational optimization of the performance of the Orbal oxidation ditch. PMID- 23923773 TI - Removal of Cu(II) from acidic electroplating effluent by biochars generated from crop straws. AB - The removal efficiency of copper (Cu(II)) from an actual acidic electroplating effluent by biochars generated from canola, rice, soybean and peanut straws was investigated. The biochars simultaneously removed Cu(II) from the effluent, mainly through the mechanisms of adsorption and precipitation, and neutralized its acidity. The removal efficiency of Cu(II) by the biochars followed the order: peanut straw char > soybean straw char > canola straw char > rice straw char >> a commercial activated carbonaceous material, which is consistent with the alkalinity of the biochars. The pH of the effluent was a key factor determining the removal efficiency of Cu(II) by biochars. Raising the initial pH of the effluent enhanced the removal of Cu(II) from it. The optimum pyrolysis temperature was 400 degrees C for producing biochar from crop straws for acidic wastewater treatment, and the optimum reaction time was 8 hr. PMID- 23923774 TI - Optimisation of chemical purification conditions for direct application of solid metal salt coagulants: treatment of peatland-derived diffuse runoff. AB - The drainage of peatland areas for peat extraction, agriculture or bioenergy requires affordable, simple and reliable treatment methods that can purify waters rich in particulates and dissolved organic carbon. This work focused on the optimisation of chemical purification process for the direct dosage of solid metal salt coagulants. It investigated process requirements of solid coagulants and the influence of water quality, temperature and process parameters on their performance. This is the first attempt to provide information on specific process requirements of solid coagulants. Three solid inorganic coagulants were evaluated: aluminium sulphate, ferric sulphate and ferric aluminium sulphate. Pre dissolved aluminium and ferric sulphate were also tested with the objective of identifying the effects of in-line coagulant dissolution on purification performance. It was determined that the pre-dissolution of the coagulants had a significant effect on coagulant performance and process requirements. Highest purification levels achieved by solid coagulants, even at 30% higher dosages, were generally lower (5%-30%) than those achieved by pre-dissolved coagulants. Furthermore, the mixing requirements of coagulants pre-dissolved prior to addition differed substantially from those of solid coagulants. The pH of the water samples being purified had a major influence on coagulant dosage and purification efficiency. Ferric sulphate (70 mg/L) was found to be the best performing solid coagulant achieving the following load removals: suspended solids (59%-88%), total organic carbon (56%-62%), total phosphorus (87%-90%), phosphate phosphorus (85%-92%) and total nitrogen (33%-44%). The results show that the use of solid coagulants is a viable option for the treatment of peatland derived runoff water if solid coagulant-specific process requirements, such as mixing and settling time, are considered. PMID- 23923775 TI - Removal of nitrogen from wastewater with perennial ryegrass/artificial aquatic mats biofilm combined system. AB - To develop a cost-effective combined phytoremediation and biological process, a combined perennial ryegrass/artificial aquatic mat biofilm reactor was used to treat synthetic wastewater. Influent ammonium loading, reflux ratio, hydraulic retention time (HRT) and temperature all had significant effects on the treatment efficiency. The results indicated that the effluent concentration of ammonium increased with increasing influent ammonium loading. The reactor temperature played an important role in the nitrification process. The ammonium removal efficiency significantly decreased from 80% to 30%-50% when the reactor temperature dropped to below 10 degrees C. In addition, the optimal nitrogen removal condition was a reflux ratio of 2. The nitrate and ammonium concentration of the effluent were consistent with the HRT of the combined system. The chemical oxygen demand (COD) removal efficiency was at a high level during the whole experiment, being almost 80% after the start-up, and then mostly above 90%. The direct uptake of N by the perennial ryegrass accounted for 18.17% of the total N removal by the whole system. The perennial ryegrass absorption was a significant contributor to nitrogen removal in the combined system. The result illustrated that the combined perennial ryegrass/artificial aquatic mat biofilm reactor demonstrated good performance in ammonium, total N and COD removal. PMID- 23923776 TI - Microbial community characterization, activity analysis and purifying efficiency in a biofilter process. AB - The growth and metabolism of microbial communities on biologically activated carbon (BAC) play a crucial role in the purification of drinking water. To gain insight into the growth and metabolic characteristics of microbial communities and the efficiency of drinking water treatment in a BAC filter, we analyzed the heterotrophic plate count (HPC), phospholipid, dehydrogenase, metabolic function and water quality parameters during start-up and steady-state periods. In the start-up process of the filter with natural biofilm colonization, the variation in heterotrophic plate count levels was S-curved. The total phospholipid level was very low during the first 5 days and reached a maximum value after 40 days in the filter. The activity of dehydrogenase gradually increased during the first 30 days and then reached a plateau. The functional diversity of the microbial community in the filter increased, and then reached a relatively stable level by day 40. After an initial decrease, which was followed by an increase, the removal rate of NH4(+)-N and COD(Mn) became stable and was 80% and 28%, respectively, by day 40. The consumption rate of dissolved oxygen reached a steady level after 29 days, and remained at 18%. At the steady operation state, the levels of HPC, phospholipid, dehydrogenase activity and carbon source utilization had no significant differences after 6 months compared to levels measured on day 40. The filter was shown to be effective in removing NH4(+)-N, NO2(-)-N, COD(Mn), UV254, biodegradable dissolved organic carbon and trace organic pollutants from the influent. Our results suggest that understanding changes in the growth and metabolism of microorganisms in BAC filter could help to improve the efficiency of biological treatment of drinking water. PMID- 23923777 TI - Performance of a completely autotrophic nitrogen removal over nitrite process for treating wastewater with different substrates at ambient temperature. AB - The stability and parameters of a bio-ceramic filter for completely autotrophic nitrogen removal were investigated. The completely autotrophic nitrogen removal over nitrite (CANON) reactor was fed with different concentrations of ammonia (400, 300, and 200 mg N/L) but constant influent ammonia load. The results showed that the CANON system can achieve good treatment performance at ambient temperature (15-23 degrees C). The average removal rate and removal loading of NH4(+)-N and TN was 83.90%, 1.26 kg N/(m3 x day), and 70.14%, 1.09 kg N/(m3 x day), respectively. Among the influencing factors like pH, dissolved oxygen and alkalinity, it was indicated that the pH was the key parameter of the performance of the CANON system. Observing the variation of pH would contribute to better control of the CANON system in an intuitive and fast way. Denaturing gradient gel electrophoresis analysis of microorganisms further revealed that there were some significant changes in the community structure of ammonium oxidizing bacteria, which had low diversity in different stages, while the species of anaerobic ammonium oxidizing (anammox) bacteria were fewer and the community composition was relatively stable. These observations showed that anaerobic ammonia oxidation was more stable than the aerobic ammonia oxidation, which could explain that why the CANON system maintained a good removal efficiency under the changing substrate conditions. PMID- 23923778 TI - Performance study and kinetic modeling of hybrid bioreactor for treatment of bi substrate mixture of phenol-m-cresol in wastewater: process optimization with response surface methodology. AB - Performance of a hybrid reactor comprising of trickling filter (TF) and aeration tank (AT) unit was studied for biological treatment of wastewater containing mixture of phenol and m-cresol, using mixed microbial culture. The reactor was operated with hydraulic loading rates (HLR) and phenolics loading rates (PLR) between 0.222-1.078 m3/(m2 x day) and 0.900-3.456 kg/(m3 x day), respectively. The efficiency of substrate removal varied between 71%-100% for the range of HLR and PLR studied. The fixed film unit showed better substrate removal efficiency than the aeration tank and was more resistant to substrate inhibition. The kinetic parameters related to both units of the reactor were evaluated and their variation with HLR and PLR were monitored. It revealed the presence of substrate inhibition at high PLR both in TF and AT unit. The biofilm model established the substrate concentration profile within the film by solving differential equation of substrate mass transfer using boundary problem solver tool 'bvp4c' of MATLAB 7.1 software. Response surface methodology was used to design and optimize the biodegradation process using Design Expert 8 software, where phenol and m-cresol concentrations, residence time were chosen as input variables and percentage of removal was the response. The design of experiment showed that a quadratic model could be fitted best for the present experimental study. Significant interaction of the residence time with the substrate concentrations was observed. The optimized condition for operating the reactor as predicted by the model was 230 mg/L of phenol, 190 mg/L of m-cresol with residence time of 24.82 hr to achieve 99.92% substrate removal. PMID- 23923779 TI - Analysis of aerobic granular sludge formation based on grey system theory. AB - Based on grey entropy analysis, the relational grade of operational parameters with aerobic granular sludge's granulation indicators was studied. The former consisted of settling time (ST), aeration time (AT), superficial gas velocity (SGV), height/diameter (H/D) ratio and organic loading rates (OLR), the latter included sludge volume index (SVI) and set-up time. The calculated result showed that for SVI and set-up time, the influence orders and the corresponding grey entropy relational grades (GERG) were: SGV (0.9935) > AT (0.9921) > OLR (0.9894) > ST (0.9876) > H/D (0.9857) and SGV (0.9928) > H/D (0.9914) > AT (0.9909) > OLR (0.9897) > ST (0.9878). The chosen parameters were all key impact factors as each GERG was larger than 0.98. SGV played an important role in improving SVI transformation and facilitating the set-up process. The influence of ST on SVI and set-up time was relatively low due to its dual functions. SVI transformation and rapid set-up demanded different optimal H/D ratio scopes (10-20 and 16-20). Meanwhile, different functions could be obtained through adjusting certain factors' scope. PMID- 23923780 TI - Ethyl thiosemicarbazide intercalated organophilic calcined hydrotalcite as a potential sorbent for the removal of uranium(VI) and thorium(IV) ions from aqueous solutions. AB - This work was conducted to determine the practicability of using a new adsorbent 4-ethyl thiosemicarbazide intercalated, organophilic calcined hydrotalcite (ETSC OHTC) for the removal of uranium (U(VI)), and thorium (Th(IV)) from water and wastewater. The FTIR analysis helped in realizing the involvement of nitrogen and sulphur atoms of ETSC in binding the metal ions through complex formation. Parameters like adsorbent dosage, solution pH, initial metal ions concentration, contact time and ionic strength, that influence adsorption phenomenon, were studied. The optimum pH for maximum adsorption of U(VI) and Th(IV) was found to be in the range 4.0-6.0. The contact time required for reaching equilibrium was 4 hr. The pseudo second-order kinetic model was the best fit to represent the kinetic data. Analysis of the equilibrium adsorption data using Langmuir, Freundlich and Sips models showed that the Freundlich model was well suited to describe the metal ions adsorption. The K(F) values were 25.43 and 29.11 mg/g for U(VI) and Th(IV), respectively, at 30 degrees C. The adsorbent can be regenerated effectively from U(VI) and Th(IV) loaded ones using 0.01 mol/L HCl. The new adsorbent was quite stable for many cycles, without much reduction in its adsorption capacity towards the metals. PMID- 23923781 TI - Observed levels and trends of gaseous SO2 and HNO3 at Mt. Waliguan, China: results from 1997 to 2009. AB - Long-term measurements of SO2 and HNO3, particularly those from the background sites, are rarely reported. We present for the first time the long-term measurements of SO2 and HNO3 at Waliguan (WLG), the only global baseline station in the back-land of the Eurasian Continent. The concentrations of SO2 and HNO3 were observed at WLG from 1997 to 2009. The observed annual mean concentrations of SO2 and HNO3 at WLG were 1.28 +/- 0.41 and 0.22 +/- 0.19 microg/m3, respectively. The HNO3 concentrations were much higher in warmer seasons than in colder seasons, while the SO2 concentrations showed a nearly reversed seasonal pattern. In most months, the concentration of HNO3 was significantly correlated with that of SO2, suggesting that some common factors influence the variations of both gases and the precursors of HNO3 may partially be from the SO2-emitting sources. The SO2 concentration had a very significant (P < 0.0001) decreasing trend (-0.2 microg/(m3 x yr)) in 1997-2002, but a significant (P < 0.05) increasing trend (+0.06 microg/(m3 x yr)) in 2003-2009. The HNO3 concentration showed no statistically significant trend during 1997-2009. While the decrease of SO2 in 1997-2002 agrees with the trend of global SO2 emissions, the increase in 2003-2009 is not consistent with the decreasing trends in many other regions over the world. Trajectory analysis suggests that the airmasses from the northern Qinghai-Tibetan Plateau and the Takla Makan Desert regions contributed significantly to the increasing trends of SO2 and HNO3 at WLG in 2003-2009, with a rate of +0.13 microg/(m3 x yr) and +0.007 microg/(m3 x yr), respectively. PMID- 23923782 TI - Influence of SO2 in incineration flue gas on the sequestration of CO2 by municipal solid waste incinerator fly ash. AB - The influence of CO2 content and presence of SO2 on the sequestration of CO2 by municipal solid waste incinerator (MSWI) fly ash was studied by investigating the carbonation reaction of MSWI fly ash with different combinations of simulated flue gas. The reaction between fly ash and 100% CO2 was relatively fast; the uptake of CO2 reached 87 g CO2/kg ash, and the sequestered CO2 could be entirely released at high temperatures. When CO2 content was reduced to 12%, the reaction rate decreased; the uptake fell to 41 g CO2/kg ash, and 70.7% of the sequestered CO2 could be released. With 12% CO2 in the presence of SO2, the reaction rate significantly decreased; the uptake was just 17 g CO2/kg ash, and only 52.9% of the sequestered CO2 could be released. SO2 in the simulated gas restricted the ability of fly ash to sequester CO2 because it blocked the pores of the ash. PMID- 23923783 TI - Seasonal variation and source apportionment of organic and inorganic compounds in PM2.5 and PM10 particulates in Beijing, China. AB - The distribution and source of the solvent-extractable organic and inorganic components in PM2.5 (aerodynamics equivalent diameter below 2.5 microns), and PM10 (aerodynamics equivalent diameter below 10 microns) fractions of airborne particles were studied weekly from September 2006 to August 2007 in Beijing. The extracted organic and inorganic compounds identified in both particle size ranges consisted of n-alkanes, PAHs (polycyclic aromatic hydrocarbons), fatty acids and water soluble ions. The potential emission sources of these organic compounds were reconciled by combining the values of n-alkane carbon preference index (CPI), %waxC(n), selected diagnostic ratios of PAHs and principal component analysis in both size ranges. The mean cumulative concentrations of n-alkanes reached 1128.65 ng/m3 in Beijing, 74% of which (i.e., 831.7 ng/m3) was in the PM2.5 fraction, PAHs reached 136.45 ng/m3 (113.44 ng/m3 or 83% in PM2.5), and fatty acids reached 436.99 ng/m3 (324.41 ng/m3 or 74% in PM2.5), which resulted in overall enrichment in the fine particles. The average concentrations of SO4(2 ), NO3(-), and NH4(+) were 21.3 +/- 15.2, 6.1 +/- 1.8, 12.5 +/- 6.1 microg/m3 in PM2.5, and 25.8 +/- 15.5, 8.9 +/- 2.6, 16.9 +/- 9.5 microg/m3 in PM10, respectively. These three secondary ions primarily existed as ammonium sulfate ((NH4)2SO4), ammonium bisulfate (NH4HSO4) and ammonium nitrate (NH4NO3). The characteristic ratios of PAHs revealed that the primary sources of PAHs were coal combustion, followed by gasoline combustion. The ratios of stearic/palmitic acid indicated the major contribution of vehicle emissions to fatty acids in airborne particles. The major alkane sources were biogenic sources and fossil fuel combustion. The major sources of PAHs were vehicular emission and coal combustion. PMID- 23923785 TI - Ground-high altitude joint detection of ozone and nitrogen oxides in urban areas of Beijing. AB - Based on observational data of ozone (O3) and nitrogen oxide (NO(x)) mixing ratios on the ground and at high altitude in urban areas of Beijing during a period of six days in November 2011, the temporal and spatial characteristics of mixing ratios were analyzed. The major findings include: urban O3 mixing ratios are low and NO(x) mixing ratios are always high near the road in November. Vertical variations of the gases are significantly different in and above the planetary boundary layer. The mixing ratio of O3 is negatively correlated with that of NO(x) and they are positively correlated with air temperature, which is the main factor directly causing vertical variation of O3 and NO(x) mixing ratios at 600-2100 m altitude. The NO(x) mixing ratios elevated during the heating period, while the O3 mixing ratios decreased: these phenomena are more significant at high altitudes compared to lower altitudes. During November, air masses in the urban areas of Beijing are brought by northwesterly winds, which transport O3 and NO(x) at low mixing ratios. Due to Beijing's natural geographical location, northwest air currents are beneficial to the dilution and dispersion of pollutants, which can result in lower O3 and NO(x) background values in the Beijing urban area. PMID- 23923784 TI - Emissions of particulate matter and associated polycyclic aromatic hydrocarbons from agricultural diesel engine fueled with degummed, deacidified mixed crude palm oil blends. AB - Mixed crude palm oil (MCPO), the mixture of palm fiber oil and palm kernel oil, has become of great interest as a renewable energy source. It can be easily extracted from whole dried palm fruits. In the present work, the degummed, deacidified MCPO was blended in petroleum diesel at portions of 30% and 40% by volume and then tested in agricultural diesel engines for long-term usage. The particulates from the exhaust of the engines were collected every 500 hr using a four-stage cascade air sampler. The 50% cut-off aerodynamic diameters for the first three stages were 10, 2.5 and 1 microm, while the last stage collected all particles smaller than 1 microm. Sixteen particle bounded polycyclic aromatic hydrocarbons (PAHs) were analyzed using a high performance liquid chromatography. The results indicated that the size distribution of particulate matter was in the accumulation mode and the pattern of total PAHs associated with fine-particles (< 1 microm) showed a dominance of larger molecular weight PAHs (4-6 aromatic rings), especially pyrene. The mass median diameter, PM and total PAH concentrations decreased when increasing the palm oil content, but increased when the running hours of the engine were increased. In addition, Commercial petroleum diesel (PB0) gave the highest value of carcinogenic potency equivalent (BaP(eq)) for all particle size ranges. As the palm oil was increased, the BaP(eq) decreased gradually. Therefore the degummed-deacidified MCPO blends are recommended for diesel substitute. PMID- 23923786 TI - Characterization of Methylocystis strain JTA1 isolated from aged refuse and its tolerance to chloroform. AB - To accelerate the efficiency of methane biodegradation in landfills, a Gram negative, rod-shaped, non-motile, non-spore-forming bacterium, JTA1, which can utilize methane as well as acetate, was isolated from the Laogang MSW landfills, Shanghai, China. Strain JTA1 was a member of genus Methylocystis on the basis of 16S rRNA and pmoA gene sequence similarity. The maximum specific cell growth rates (micro(max) = 0.042 hr(-1), R2 = 0.995) was derived through Boltzmann simulation, and the apparent half-saturation constants (K(m(app)) = 7.08 mmol/L, R2 = 0.982) was calculated according to Michaelis-Menton hyperbolic model, indicating that Methylocystis strain JTA1 had higher-affinity potential for methane oxidation than other reported methanotrophs. By way of adding the strain JTA1 culture, the methane consumption of aged refuse reached 115 mL, almost two times of control experiment. In addition, high tolerance of Methylocystis strain JTA1 to chloroform could facilitate the methane oxidation of aged refuse bio covers. At the chloroform concentration of 50 mg/L, the methane-oxidation rate of bio-cover reached 0.114 mL/(day x g), much higher than the highest rate, 0.0135 mL/(day x g), of reported bio-covers. In conclusion, strain JTA1 opens up a new possibility for environmental biotechnology, such as soil or landfills bioremediation and wastewater decontamination. PMID- 23923787 TI - Allelopathic effects of gallic acid from Aegiceras corniculatum on Cyclotella caspia. AB - High abundance of algae and eutrophication were observed in mangrove wetlands and these were estimated to be associated with root exudates of some specific mangrove plants to a certain extent. Root exudates form allelopathic effects from mangroves. The main secondary metabolites of Aegiceras corniculatum had been detected to be organic phenolic acids. Gallic acid had been isolated and identified from A. corniculatum. The half-maximal inhibitory concentration of gallic acid on alge Cyclotella caspia was tested as 15.46 mg/L. The effects on algal cell morphology were mainly shown as elongated cells, with no apparent cell inclusions, such as oil droplets, chloroplast. At a dose of 2 mg/L, gallic acid had a stimulative effect on the specific growth rate of algae on day 3. The contents of malondialdehyde, superoxide dismutase, soluble carbohydrates and chlorophyll a in algal cells showed an overall "low promotion and high suppression". Our results could provide preliminary and valuable reference on the complex influences of mangroves on microecology and microbial communities in the rhizosphere system. PMID- 23923788 TI - Toxicity detection of sodium nitrite, borax and aluminum potassium sulfate using electrochemical method. AB - Based on the inhibition effect on the respiratory chain activity of microorganisms by toxicants, an electrochemical method has been developed to measure the current variation of a mediator in the presence of microorganisms contacted with a toxicant. Microelectrode arrays were adopted in this study, which can accelerate the mass transfer rate of an analyte to the electrode and also increase the total current signal, resulting in an improvement in detection sensitivity. We selected Escherichia coli as the testee and the standard glucose glutamic acid as an exogenous material. Under oxygen restriction, the experiments in the presence of toxicant were performed at optimum conditions (solution pH 7.0, 37 degrees C and reaction for 3 hr). The resulting solution was then separated from the suspended microorganisms and was measured by an electrochemical method, using ferricyanide as a mediator. The current signal obtained represents the reoxidation of ferrocyanide, which was transformed to inhibiting efficiency, IC50, as a quantitative measure of toxicity. The IC50 values measured were 410, 570 and 830 mg/L for sodium nitrite, borax and aluminum potassium sulfate, respectively. The results show that the toxicity sequence for these three food additives is consistent with the value reported by other methods. Furthermore, the order of damage degree to the microorganism was also observed to be: sodium nitrite > borax > aluminum potassium sulfate > blank, according to the atomic force microscopy images of E. coli after being incubated for 3 hr with the toxic compound in buffer solutions. The electrochemical method is expected to be a sensitive and simple alternative to toxicity screening for chemical food additives. PMID- 23923789 TI - A comparative study of Mn/CeO2, Mn/ZrO2 and Mn/Ce-ZrO2 for low temperature selective catalytic reduction of NO with NH3 in the presence of SO2 and H2O. AB - Ce-ZrO2 is a widely used three-way catalyst support. Because of the large surface area and excellent redox quality, Ce-ZrO2 may have potential application in selective catalytic reduction (SCR) systems. In the present work, Ce-ZrO2 was introduced into a low-temperature SCR system and CeO2 and ZrO2 supports were also introduced to make a contrastive study. Mn/CeO2, Mn/ZrO2 and Mn/Ce-ZrO2 were prepared by impregnating these supports with Mn(NO3)2 solution, and have been characterized by N2-BET, XRD, TPR, TPD, XPS, FT-IR and TG. The activity and resistance to SO2 and H2O of the catalysts were investigated. Mn/Ce-ZrO2 and Mn/CeO2 were proved to have better low-temperature activities than Mn/ZrO2, and yielded 98.6% and 96.8% NO conversion at 180 degrees C, respectively. This is mainly because Mn/Ce-ZrO2 and Mn/CeO2 had higher dispersion of manganese oxides, better redox properties and more weakly adsorbed oxygen species than Mn/ZrO2. In addition, Mn/Ce-ZrO2 showed a good resistance to SO2 and H2O and presented 87.1% NO conversion, even under SO2 and H2O treatment for 6 hours, and the activity of Mn/Ce-ZrO2 was almost restored to its original level after cutting off the injection of SO2 and H2O. This was due to the weak water absorption and weak sulfation process on the surface of the catalyst. PMID- 23923790 TI - Removal of benzotriazole by heterogeneous photoelectro-Fenton like process using ZnFe2O4 nanoparticles as catalyst. AB - ZnFe2O4 nanoparticles (ZFNPs) were developed as catalyst for the degradation of benzotriazole (BTA) by heterogeneous photoelectro-Fenton (PE-Fenton) like process. ZFNPs were prepared by a co-precipitation process and then characterized with transmission electron microscopy (TEM), X-ray fluorescence (XRF), X-ray diffraction (XRD) and BET surface area. Using such ZFNPs as catalyst, the degradation of BTA was investigated. Due to the high catalytic activity of ZFNPs, PE-Fenton like process showed efficient degradation of BTA. The influencing factors such as pH, dosage of ZFNPs, applied potential and initial concentration of BTA were systematically investigated. Under the optimum conditions, 91.2% of BTA was removed after 180 min treatment. PMID- 23923791 TI - Metal loaded zeolite adsorbents for hydrogen cyanide removal. AB - Metal (Cu, Co, or Zn) loaded ZSM-5 and Y zeolite adsorbents were prepared for the adsorption of hydrogen cyanide (HCN) toxic gas. The results showed that the HCN breakthrough capacity was enhanced significantly when zeolites were loaded with Cu. The physical and chemical properties of the adsorbents that influence the HCN adsorption capacity were analyzed. The maximal HCN breakthrough capacities were about the same for both zeolites at 2.2 mol of HCN/mol of Cu. The Cu2p XPS spectra showed that the possible species present were Cu2O and CuO. The N1s XPS data and FT-IR spectra indicated that CN(-) would be formed in the presence of Cu+/Cu2+ and oxygen gas, and the reaction product could be adsorbed onto Cu/ZSM-5 zeolite more easily than HCN. PMID- 23923792 TI - Preparation and evaluation of Zr-beta-FeOOH for efficient arsenic removal. AB - A Zr-beta-FeOOH adsorbent for both As(V) and As(III) removal was prepared by a chemical co-precipitation method. Compared with beta-FeOOH, the addition of Zr enhanced the adsorption capacities for As(V) and As(III), especially As(III). The maximum adsorption capacities for As(III) and As(V) were 120 and 60 mg/g respectively at pH 7.0, much higher than for many reported adsorbents. The adsorption data accorded with Freundlich isotherms. At neutral pH, for As(V), adsorption equilibrium was approached after 3 hr, while for As(III), adsorption equilibrium was approached after 5 hr. Kinetic data fitted well to the pseudo second-order reaction model. As(V) elimination was favored at acidic pH, whereas the adsorption of As(III) by Zr-beta-FeOOH was found to be effective over a wide pH range of 4-10. Competitive anions hindered the adsorption according to the sequence: phosphate > silicate > bicarbonate > sulfate > nitrate, while Ca2+ and Mg2+ increased the removal of As(III) and As(V) slightly. The high adsorption capability and good performance in other aspects make Zr-beta-FeOOH a potentially attractive adsorbent for the removal of both As(III) and As(V) from water. PMID- 23923793 TI - Application of red mud as a basic catalyst for biodiesel production. AB - Red mud was investigated in triglyceride transesterification with a view to determine its viability as a basic catalyst for use in biodiesel synthesis. The effect of calcination temperature on the structure and activity of red mud catalysts was investigated. It was found that highly active catalyst was obtained by simply drying red mud at 200 degrees C. Utilization of red mud as a catalyst for biodiesel production not only provides a cost-effective and environmentally friendly way of recycling this solid red mud waste, significantly reducing its environmental effects, but also reduces the price of biodiesel to make biodiesel competitive with petroleum diesel. PMID- 23923794 TI - Amino-functionalized core-shell magnetic mesoporous composite microspheres for Pb(II) and Cd(II) removal. AB - Amino-functionalized Fe3O4@mesoporous SiO2 core-shell composite microspheres NH2 MS in created in multiple synthesis steps have been investigated for Pb(II) and Cd(II) adsorption. The microspheres were characterized by transmission electron microscope (TEM), scanning electron microscope (SEM), N2 adsorption-desorption, zeta potential measurements and vibrating sample magnetometer. Batch adsorption tests indicated that NH2-MS exhibited higher adsorption affinity toward Pb(II) and Cd(II) than MS did. The Langmuir model could fit the adsorption isotherm very well with maximum adsorption capacity of 128.21 and 51.81 mg/g for Pb(II) and Cd(II), respectively, implying that adsorption processes involved monolayer adsorption. Pb(II) and Cd(II) adsorption could be well described by the pseudo second-order kinetics model, and was found to be strongly dependent on pH and humic acid. The Pb(II)- and Cd(II)-loaded microspheres were effectively desorbed using 0.01 mol/L HCl or EDTA solution. NH2-MS have promise for use as adsorbents in the removal of Pb(II) and Cd(II) in wastewater treatment processes. PMID- 23923795 TI - Electrochemical detection and degradation of ibuprofen from water on multi-walled carbon nanotubes-epoxy composite electrode. AB - This work describes the electrochemical behaviour of ibuprofen on two types of multi-walled carbon nanotubes based composite electrodes, i.e., multi-walled carbon nanotubes-epoxy (MWCNT) and silver-modified zeolite-multi-walled carbon nanotubes-epoxy (AgZMWCNT) composites electrodes. The composite electrodes were obtained using two-roll mill procedure. SEM images of surfaces of the composites revealed a homogeneous distribution of the composite components within the epoxy matrix. AgZMWCNT composite electrode exhibited the better electrical conductivity and larger electroactive surface area. The electrochemical determination of ibuprofen (IBP) was achieved using AgZMWCNT by cyclic voltammetry, differential pulsed voltammetry, square-wave voltammetry and chronoamperometry. The IBP degradation occurred on both composite electrodes under controlled electrolysis at 1.2 and 1.75 V vs. Ag/AgCl, and IBP concentration was determined comparatively by differential-pulsed voltammetry, under optimized conditions using AgZMWCNT electrode and UV-Vis spectrophotometry methods to determine the IBP degradation performance for each electrode. AgZMWCNT electrode exhibited a dual character allowing a double application in IBP degradation process and its control. PMID- 23923796 TI - Striving for excellence. PMID- 23923797 TI - Take action: certification. PMID- 23923798 TI - We can do better: with certification. PMID- 23923799 TI - Certification 101: the pathway to excellence. AB - Certification in a nursing specialty validates that patient care providers have attained the knowledge and skills necessary for competent practice in the particular specialty, achieving a higher degree of professional competence than the minimal requirement for licensure. Certification yields benefits to the individual nurse, the profession, and the public, including improved patient safety and a commitment to lifelong learning. PMID- 23923800 TI - The public's perception of certification. AB - For individual patients as well as the general public, what is the laymen's perception and understanding of certification? And how does the public's awareness of the value of certification enhance health care? This article discusses the public's understanding of certification and offers some best practices to increase this understanding. PMID- 23923801 TI - Advanced practice registered nurse certification. AB - Advanced practice registered nurses (APRNs) in nephrology began to be certified through the Nephrology Nursing Certification Commission (NNCC) in 2006. Since that time, the APRN Consensus Model has been developed, which addresses licensure, accreditation, certification, and education and which strongly recommends specialty certification for advanced practice nurses. This article discusses NNCC certification for advanced practice in nephrology nursing and describes the major components of the APRN Consensus Model. PMID- 23923802 TI - Job analysis and role delineation: LPN/LVNs and hemodialysis technicians. AB - To provide safe and quality care to patients on hemodialysis, nephrology registered nurses must fully understand the roles of the healthcare providers to whom they delegate patient care. A job analysis survey of hemodialysis technicians and licensed practical nurses/licensed vocational nurses (LPNs/LVNs) was conducted by the Nephrology Nursing Certification Commission (NNCC) in 2011 to 1) revalidate the Certified Clinical Hemodialysis Technician (CCHT) test blueprint, 2) delineate differences in practice between entry-level technicians and experienced/advanced technicians, and 3) delineate differences in practice between hemodialysis technicians and LPNs/LVNs in hemodialysis settings. Significant differences in practice were identified among the three groups, which led to the development by NNCC of two additional certification examinations: the Certified Clinical Hemodialysis Technician-Advanced (CCHT-A) examination and the Certified Dialysis LPN/LVN (CD-LPN/LVN) examination. PMID- 23923803 TI - Nephrology certification: what is it? AB - Professional certification is a term heard frequently in the nephrology setting; however, other terms, such as licensure and competency, are often confused with certification. This article provides a basic discussion of each of these terms, and then explores the options for certification currently available that are specific to nephrology caregivers. PMID- 23923804 TI - Certification--good for business. AB - Since the pay-for-performance reimbursement by Medicare and commercial health plans was enacted and continues to expand over time, financial penalties have been placed on healthcare facilities providing dialysis services that demonstrate poor outcomes. It is advantageous for institutions to seek consistent, solid and positive outcomes to ensure that patients will be well cared for and reimbursement will not be negatively impacted. This article explores how certified nurses can be good for business and the bottom line. PMID- 23923805 TI - Fifteen-minute versus thirty-minute blood pressure evaluation during chronic hemodialysis. AB - Based on a literature review, the physiology of blood pressure control and hemodynamic changes that occur during a hemodialysis treatment, blood pressure evaluations at 15-minute intervals as opposed to 30-minute intervals may enable nephrology nurses and other care providers to recognize and prevent dramatic drops in blood pressure. Through maintenance of blood pressure stability and prevention of intradialytic hypotension, patient morbidity and mortality may be decreased. Blood pressure monitoring is one component for ensuring quality care, decreasing morbidity, and decreasing mortality. Integration of assessment data, estimated dry weight evaluation, and patient adherence are fundamental to the promotion of good health outcomes. PMID- 23923806 TI - Nursing risk assessment: fall prevention strategies in the outpatient hemodialysis setting. PMID- 23923807 TI - Why careproviders may conclude that treating a patient is futile. AB - I shall examine one way that careproviders may come to judgments of "futility" in cases that are less than clearcut, in the hope that, if such judgment is unwarranted, it may be avoided. PMID- 23923808 TI - Repetitive foreign body ingestion: ethical considerations. AB - The treatment of persons who frequently present to the healthcare system following repetitive foreign body ingestion has been addressed in the psychiatric literature. However, there has been little exploration of the ethical considerations regarding the treatment of these patients. The complexity of their medical and psychiatric presentation raises fundamental ethical questions regarding the duty to treat, patient autonomy, justice, and futility. Careful ethical analysis is particularly important in this context, since the frustration that medical professionals may feel in response may lead to false assumptions that can negatively impact patient care. A careful exploration of these questions can increase awareness and understanding, which in turn can lead to improved treatment of patients who repetitively ingest foreign bodies. Care for patients who inflict self-harm, particularly by repetitive foreign body ingestion, is not futile. The patients have a right to treatment and are entitled to resources. Efforts should be made to provide a more comprehensive treatment approach to these patients. PMID- 23923809 TI - The intensity and frequency of moral distress among different healthcare disciplines. AB - INTRODUCTION: The objectives of this study are to assess and compare differences in the intensity, frequency, and overall severity of moral distress among a diverse group of healthcare professionals. METHODS: Participants from within Baylor Health Care System completed an online seven-point Likert scale (range, 0 to 6) moral distress survey containing nine core clinical scenarios and additional scenarios specific to each participant's discipline. Higher scores reflected greater intensity and/or frequency of moral distress. RESULTS: More than 2,700 healthcare professionals responded to the survey (response rate 18.14 percent); survey respondents represented multiple healthcare disciplines across a variety of settings in a single healthcare system. Intensity of moral distress was high in all disciplines, although the causes of highest intensity varied by discipline. Mean moral distress intensity for the nine core scenarios was higher among physicians than nurses, but the mean moral distress frequency was higher among nurses. Taking into account both intensity and frequency, the difference in mean moral distress score was statistically significant among the various disciplines. Using post hoc analysis, differences were greatest between nurses and therapists. CONCLUSIONS: Moral distress has previously been described as a phenomenon predominantly among nursing professionals.This first-of-its-kind multidisciplinary study of moral distress suggests the phenomenon is significant across multiple professional healthcare disciplines. Healthcare professionals should be sensitive to situations that create moral distress for colleagues from other disciplines. Policy makers and administrators should explore options to lessen moral distress and professional burnout that frequently accompanies it. PMID- 23923810 TI - "He got his last wishes": ways of knowing a loved one's end-of-life preferences and whether those preferences were honored. AB - As a patient approaches death, family members often are asked about their loved one's preferences regarding treatment at the end of life. Advance care directives may provide information for families and surrogate decision makers; however, less than one-third of Americans have completed such documents. As the U.S. population continues to age, many surrogate decision makers likely will rely on other means to discern or interpret a loved one's preferences. While many surrogates indicate that they have some knowledge of their loved one's preferences, how surrogates obtain such knowledge is not well understood. Additionally, although research indicates that the emotional burden of end-of-life decision making is diminished when surrogates have knowledge that a loved one's preferences are honored, it remains unclear how surrogates come to know these preferences were carried out. The current study examined the ways that next of kin knew veterans' end-of-life preferences, and their ways of knowing whether those preferences were honored in Veteran Affairs Medical Center (VAMC) inpatient settings. PMID- 23923812 TI - The threshold moment: ethical tensions surrounding decision making on tracheostomy for patients in the intensive care unit. AB - With the aging of the general population and the ability of intensivists to support patients using ventilator support, tracheostomy has become a vital tool in the medical management of critically ill patients. While much of the medical literature on tracheostomy has focused on the optimal timing of and indications for performing this procedure, little is written on the ethical tensions that can revolve around decisions by patients, surrogates, and physicians on its use.This article will elucidate the ethical dilemmas that can arise surrounding the use of tracheostomy in critically ill patients and how ethics consultants and committees can approach these cases to allow resolution. PMID- 23923813 TI - A response to Dubler's commentary on "surmounting elusive barriers: the case for bioethics mediation". AB - Dubler's commentary focuses on knowledge of clinical medicine and "institutional savvy" as pieces of the skill set required of bioethics mediators. Here, I describe why, as a practical matter, such requirements are unlikely to be achieved by a meaningful number of aspirants. Simultaneously, I examine the reasons why Dubler's criteria are inherently risk-laden and would be better addressed as a dialogue among experienced practitioners regarding the merits of alternative stylistic approaches, rather than as universal threshold criteria for the practice of bioethics mediation. PMID- 23923811 TI - Making decisions for hospitalized older adults: ethical factors considered by family surrogates. AB - BACKGROUND: Hospitalized older adults frequently have impaired cognition and must rely on surrogates to make major medical decisions. Ethical standards for surrogate decision making are well delineated, but little is known about what factors surrogates actually consider when making decisions. OBJECTIVES: To determine factors surrogate decision makers consider when making major medical decisions for hospitalized older adults, and whether or not they adhere to established ethical standards. DESIGN: Semi-structured interview study of the experience and process of decision making. SETTING: A public safety-net hospital and a tertiary referral hospital in a large city in the Midwest United States. PARTICIPANTS: The study included 35 surrogates with a recent decision-making experience for an inpatient aged 65 or older. MEASUREMENTS: The key factors that surrogates considered when making decisions. Interview transcripts were coded and analyzed using the grounded theory method of qualitative analysis. RESULTS: Surrogates considered patient-centered factors and surrogate-centered factors. Patient-centered factors included: (1) respecting the patient's input, (2) using past knowledge of the patient to infer the patient's wishes, and (3) considering what is in the patient's best interests. Some surrogates expressed a desire for more information about the patient's prior wishes. Surrogate-centered factors included: (1) surrogate's wishes as a guide, (2) surrogate's religious beliefs and/or spirituality, (3) surrogate's interests, and (4) family consensus. CONCLUSION: Our study indicates that surrogate decision making is more complex than the standard ethical models, which are limited to considerations of the patient's autonomy and beneficence. Because surrogates also imagine what they would want under the circumstances and consider their own needs and preferences, models of surrogate decision making must account for these additional considerations. Surrogates' desire for more information about patients' preferences suggests a need for greater advance care planning. PMID- 23923814 TI - The art of the chart note in clinical ethics consultation and bioethics mediation: conveying information that can be understood and evaluated. AB - Unlike bioethics mediators who are employed by healthcare organizations as outside consultants, mediators who are embedded in an institution must be authorized to chronicle a clinical ethics consultation (CEC) or a mediation in a patient's medical chart. This is an important privilege, as the chart is a legal document. In this article I discuss this important part of a bioethics mediator's tool kit in my presentation of a case illustrating how bioethics mediation may proceed, and what this approach using both bioethics and mediation may add. PMID- 23923815 TI - Legal briefing: the new Patient Self-Determination Act. AB - This issue's "legal briefing" column covers recent legal developments involving the Patient Self-Determination Act (PSDA). Enacted in the wake of the U.S. Supreme Court's Cruzan decision in 1990, the PSDA remains a seminal event in the development of U.S. bioethics public policy, but the PSDA has long been criticized as inadequate and ineffective. Finally, recent legislative and regulatory changes promise to revitalize and rejuvenate it. The PSDA has been the subject of recent articles in The Journal of clinical ethics.' I categorize new legal developments concerning the PSDA into the following eight sections: (1) Background and history (2) Rules and requirements (3) Criticism and challenges (4) Failed efforts to amend the PSDA (5) Personalize your Care Act of 2013 (6) New regulations (7) New regulatory guidance (8) Expanded enforcement. PMID- 23923816 TI - Design of a photoswitchable cadherin. AB - There is a growing interest in engineering proteins whose function can be controlled with the spatial and temporal precision of light. Here, we present a novel example of a functional light-triggered switch in the Ca-dependent cell cell adhesion protein E-cadherin, created using a mechanism-based design strategy. We report an 18-fold change in apparent Ca(2+) binding affinity upon illumination. Our results include a detailed examination of functional switching via linked changes in Ca(2+) binding and cadherin dimerization. This design opens avenues toward controllable tools that could be applied to many long-standing questions about cadherin's biological function in cell-cell adhesion and downstream signaling. PMID- 23923818 TI - Clinicians' perceptions of factors contributing to complexity and intensity of care of outpatients with traumatic brain injury. AB - PRIMARY OBJECTIVE: This study investigated clinicians' perceptions on factors linked to patient complexity in traumatic brain injury (TBI) outpatient rehabilitation. METHOD: Twelve clinicians from various disciplines, working in TBI outpatient programmes from three rehabilitation institutions in Montreal, Quebec, were recruited using convenience and snowball sampling. Data was collected through focus groups and individual interviews and thematic analysis was used to identify themes. MAIN OUTCOMES AND RESULTS: Participants identified complexity factors falling under the following themes: sequelae of TBI (cognitive/behavioural/psychological impacts), personal factors (personality traits, pre-medical state, lifestyle and age), patients' environment (architectural, social, language, cultural and financial) and therapeutic relationship (mismatch, misunderstanding and personality clashes). Clinicians also reported facilitators to optimal treatment delivery such as quality of services and working in an interdisciplinary team. Limited time, training and resources were identified as barriers to treatment. CONCLUSION: A substantial proportion of patients in outpatient TBI programmes seem to follow an atypical evolution and exhibit added complexity. In order to optimize quality of care, clinicians recommended increased community awareness about TBI, increased resources for rehabilitation clinicians and specialized services post-discharge. These findings are insightful for stakeholders; providing a basis for discussions on policy changes that can better meet this population's needs. PMID- 23923817 TI - Juliprosopine and juliprosine from prosopis juliflora leaves induce mitochondrial damage and cytoplasmic vacuolation on cocultured glial cells and neurons. AB - Prosopis juliflora is a shrub largely used for animal and human consumption. However, ingestion has been shown to induce intoxication in animals, which is characterized by neuromuscular alterations induced by mechanisms that are not yet well understood. In this study, we investigated the cytotoxicity of a total alkaloid extract (TAE) and one alkaloid fraction (F32) obtained from P. juliflora leaves to rat cortical neurons and glial cells. Nuclear magnetic resonance characterization of F32 showed that this fraction is composed of a mixture of two piperidine alkaloids, juliprosopine (majority constituent) and juliprosine. TAE and F32 at concentrations between 0.3 and 45 MUg/mL were tested for 24 h on neuron/glial cell primary cocultures. The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide test revealed that TAE and F32 were cytotoxic to cocultures, and their IC50 values were 31.07 and 7.362 MUg/mL, respectively. Exposure to a subtoxic concentration of TAE or F32 (0.3-3 MUg/mL) induced vacuolation and disruption of the astrocyte monolayer and neurite network, ultrastructural changes, characterized by formation of double-membrane vacuoles, and mitochondrial damage, associated with changes in beta-tubulin III and glial fibrillary acidic protein expression. Microglial proliferation was also observed in cultures exposed to TAE or F32, with increasing levels of OX-42-positive cells. Considering that F32 was more cytotoxic than TAE and that F32 reproduced in vitro the main morphologic and ultrastructural changes of "cara torta" disease, we can also suggest that piperidine alkaloids juliprosopine and juliprosine are primarily responsible for the neurotoxic damage observed in animals after they have consumed the plant. PMID- 23923819 TI - Biobased polymer composites derived from corn stover and feather meals as double coating materials for controlled-release and water-retention urea fertilizers. AB - In this paper, we synthesized a biobased polyurethane using liquefied corn stover, isocyanate, and diethylenetriamine. The synthesized polyurethane was used as a coating material to control nitrogen (N) release from polymer-coated urea. A novel superabsorbent composite was also formulated from chicken feather protein (CFP), acrylic acid, and N,N'-methylenebisacrylamide and used as an outer coating material for water retention. We studied the N release characteristics and water retention capability of the double-layer polymer-coated urea (DPCU) applied in both water and soils. The ear yields, dry matter accumulation, total N use efficiency and N leaching from a sweet corn soil-plant system under two different irrigation regimes were also investigated. Comparison of DPCU treatments with conventional urea fertilizer revealed that DPCU treatments reduced the N release rate and improved water retention capability. Evaluation of soil and plant characteristics within the soil-plant system revealed that DPCU application effectively reduced N leaching loss, improved total N use efficiency, and increased soil water retention capability. PMID- 23923820 TI - Crossing the junction in the gap of melanoma brain metastasis. PMID- 23923821 TI - How the leopard gets its spots: a transmembrane peptidase specifies feline pigmentation patterns. PMID- 23923822 TI - The Spanish Riding School and the Haute Ecole of complex trait genetics. PMID- 23923823 TI - Study of the atmospheric chemistry of 2-formylcinnamaldehyde. AB - 2-Formylcinnamaldehyde is a significant product of the reaction of naphthalene with OH radicals, and its photolysis and gas-phase reactions with O3, NO3 radicals, and OH radicals have been investigated in this work. 2 Formylcinnamaldehyde was observed to undergo photolysis by black lamps, with a photolysis rate of 0.14 * J(NO2), where J(NO2) is the NO2 photolysis rate. The measured rate constants for the reactions of 2-formylcinnamaldehyde with O3, NO3 radicals, and OH radicals (in units of cm(3) molecule(-1) s(-1)) were 1.8 * 10( 18), 4.3 * 10(-14), and 2.1 * 10(-11), respectively, with those for the O3 and NO3 reactions being for the E-isomer. 2-Formylcinnamaldehyde was observed to undergo significant adsorption and desorption from the reaction chamber Teflon film walls, and the photolysis rate and rate constants are subject to significant uncertainties. In the atmosphere, the dominant chemical loss processes for 2 formylcinnamaldehyde will be photolysis during daylight hours and reaction with NO3 radicals during nighttime. Phthaldialdehyde and glyoxal were observed as products of the OH radical and O3 reactions, and photolysis of E-2 formylcinnamaldehyde led to formation of Z-2-formylcinnamaldehyde plus two other molecular weight 160 isomers. The present results are compared with previous literature data, and reaction mechanisms are discussed. PMID- 23923824 TI - Research in biomechanics gathers engineers, clinicians, biologists and materials specialists. PMID- 23923825 TI - Divided media-based simulations of tissue morphogenesis. PMID- 23923826 TI - Off-plane motion of an oblate capsule in a simple shear flow. PMID- 23923827 TI - Hydrodynamic interactions among large populations of swimming micro-organisms. PMID- 23923828 TI - Towards numerical prediction of red blood cells dynamics within a cytometer. PMID- 23923829 TI - Collective motility of sperm in confined cells. PMID- 23923830 TI - A mechanical model for cell motility and tissue morphogenesis. PMID- 23923831 TI - Microrheology of complex systems and living cells using AFM. PMID- 23923832 TI - Treatment of a stenosed arteriovenous fistula by balloon angioplasty with or without stenting: comparison of effects on haemodynamics. PMID- 23923833 TI - Coupled fluid flow and ion transport through intact skin. PMID- 23923834 TI - Micromechanical modelling of the arterial wall: influence of mechanical heterogeneities on the wall stress distribution and the peak wall stress. PMID- 23923835 TI - Effect of viscoelasticity of arterial wall on pulse wave: a comparative study on ovine. PMID- 23923836 TI - Wall shear stress and endothelial cells dysfunction in the context of abdominal aortic aneurysms. PMID- 23923837 TI - Mitral bileaflet mechanical heart valves dysfunction and patient/prosthesis mismatch: in vitro investigation of differential diagnosis. PMID- 23923838 TI - Flow of concentrated red blood cell suspensions at micro-bifurcations: an in vitro experimental study. PMID- 23923839 TI - Numerical simulation of the migration phenomena and type 1a endoleak of thoracic aneurysm endograft. PMID- 23923840 TI - Strength balance and low back pain. PMID- 23923841 TI - Hand orientation while steering. PMID- 23923842 TI - When motor simulation of disequilibrium increases postural stability. PMID- 23923843 TI - Age-related effects of temporal pressure on the postural organisation of rapid leg flexion. PMID- 23923844 TI - Preliminary study of rider back biomechanics. PMID- 23923845 TI - Numerical simulation of breast deformation under static conditions. PMID- 23923846 TI - Vibration transmissibility in different body positions with various vibration frequencies in a vertical vibration platform. PMID- 23923847 TI - Determination of human body segment inertial parameters using a fringe projection method. PMID- 23923848 TI - A new ilio-femoro-tibial range of motion (IFT-ROM) test: reproducibility and effect of a passive stretching programme. PMID- 23923849 TI - A numerical approach to assess the soft tissue artefact during human movement analysis. PMID- 23923850 TI - Global sensitivity analysis of the kinematics obtained with a multi-body optimisation using a parallel mechanism of the shoulder. PMID- 23923851 TI - An SVD approach to reaching tasks based on Cartesian geodesics. PMID- 23923852 TI - Is there a predominant influence between heel height, upper height and sole stiffness on young children gait dynamics? PMID- 23923853 TI - Accelerometric signal during gait: cut-off frequency as a function of movement speed and sensor location. PMID- 23923854 TI - Rotation axes in overarm throwing. PMID- 23923855 TI - Contact force computation based on BSIPs. PMID- 23923856 TI - Joint intra-individual variability simulation based on UCM hypothesis. PMID- 23923857 TI - What about running on Mars? Dynamical response to unweighing of the running pattern. PMID- 23923858 TI - Multifactorial gait analysis of children with flat foot and hind foot valgus deformity. PMID- 23923859 TI - Eccentric rate of force development determines jumping performance. PMID- 23923860 TI - Validity of an accelerometric system for measuring force-time-based data during jumping tasks. PMID- 23923861 TI - Mechanical equivalent model of vibration transmission in cycling. PMID- 23923862 TI - Experimental protocol for the risk assessment in cycling. PMID- 23923863 TI - Biomechanical analysis of the strike motion in ice-climbing activity. PMID- 23923864 TI - Fatigue evaluation on pilots during a 24-hour karting race using a postural force platform. PMID- 23923865 TI - How to reconstruct athlete movement during outdoor rowing? A pilot study. PMID- 23923866 TI - The effect of shoe drop on running pattern. PMID- 23923867 TI - Influence of racket polar moment on joint loads during tennis forehand drive. PMID- 23923868 TI - Influence of hand-held racket on scapulothoracic kinematics during humeral elevation in the scapular plane in young tennis players: a preliminary study. PMID- 23923869 TI - Effect of time during a running session with minimal footwear. PMID- 23923870 TI - Muscle force strategies in relation to saddle setback management in cycling. PMID- 23923871 TI - Finite helical axis versus symmetrical axis of rotation approach for the human knee joint: squats, rowing and cycling. PMID- 23923872 TI - Is handgrip force changed following a 45-min kart driving session in competition? PMID- 23923873 TI - Relationship between the gross efficiency and muscular skin temperature of lower limb in cycling: a preliminary study. PMID- 23923874 TI - Evaluation of wheelchair user's upper limb kinematics during throwing activities: a preliminary study. PMID- 23923875 TI - Comparison of steering forces of healthy versus disabled drivers under simulation condition. PMID- 23923876 TI - Chronology of postural and focal component of muscular activity during manual wheelchair propulsion initiation: effect of different trajectories and velocities. PMID- 23923877 TI - Handrim mechanical power during wheelchair propulsion on level and cross-slope surfaces: a preliminary study. PMID- 23923878 TI - Vaulting quantification for transfemoral amputees in different gait situations. PMID- 23923879 TI - A brain and gaze-controlled wheelchair. PMID- 23923880 TI - Proposal of an index for evaluating pitch instability during actual locomotion with a manual wheelchair. PMID- 23923881 TI - Impact of the subject and wheelchair properties during slope ascent in manual wheelchair: a theoretical study. PMID- 23923883 TI - 3D accelerometric gait analysis in dogs using smartphone. PMID- 23923882 TI - Mechanical energy expenditure of subject with multiple sclerosis engaged in daily activities: a case study. PMID- 23923884 TI - Estimation of longitudinal hoof slip displacement at the canter on two different track surfaces using accelerometric and kinematic methods: a preliminary comparative study with one horse. PMID- 23923885 TI - Comparison of the moment at the distal interphalangeal joint on asphalt and on sand in horses at trot. PMID- 23923886 TI - External loads on the leading and trailing forelimbs of a jumping horse at landing measured with a dynamometric horseshoe. PMID- 23923887 TI - Multi-modal framework for subject-specific finite element model generation aimed at pressure ulcer prevention. PMID- 23923888 TI - Dynamic biomechanical modelling for foot ulcer prevention. PMID- 23923889 TI - EMG-based validation of musculo-skeletal models for gait analysis. PMID- 23923890 TI - Musculoskeletal modelling of cerebral palsy children: sensitivity analysis of musculoskeletal model parameter's values for gait analysis. PMID- 23923891 TI - Gastrocnemius medialis fascicle and Achilles' tendon behaviour during a quick release movement. PMID- 23923892 TI - Relationships between hip muscles and trunk flexor and extensor muscles in chronic low back pain patients: a preliminary study. PMID- 23923893 TI - Effect of the muscle activation level distribution on normal stress field: a numerical study. PMID- 23923894 TI - Validation of optimisation model that estimates the musculotendinous forces during an isometric extension of knee. PMID- 23923895 TI - Evaluation of neck muscles activation patterns during simple isometric tasks. PMID- 23923896 TI - Comparison between model-based and measured force polytopes: towards isometric force capacity evaluation. PMID- 23923897 TI - Using the humanoid robotics framework for testing different plausible control architectures of human reaching movements. PMID- 23923898 TI - An advanced robotics motion generation framework for inferring the organisation of human movements. PMID- 23923899 TI - Using a motion capture system to identify pertinent design parameters of a bio inspired mechanical hand. PMID- 23923900 TI - The PROMIS model to highlight the importance of the foetus to the validation of a pregnant woman model. PMID- 23923901 TI - Analysis of train driver protection in rail collisions. PMID- 23923902 TI - Evaluation of wrist guard effectiveness for snowboarders. PMID- 23923903 TI - Influence of loading speed on the mechanical properties of the colon. PMID- 23923904 TI - Relationship between human rib mechanical properties and cortical bone density measured by high-resolution quantitative computed tomography. PMID- 23923905 TI - Parametric finite element modelling of the human lower cervical spinal cord. PMID- 23923906 TI - Hip joint centre location from anatomical landmarks for automotive seated posture reconstruction. PMID- 23923907 TI - Finite element head model simulation and head injury prediction. PMID- 23923908 TI - Internal kidney's behaviour during compressive loading using ultrafast echography. PMID- 23923909 TI - A new method to assess the deformations of internal organs of the abdomen during impact. PMID- 23923910 TI - Kinematic and dynamic responses of the scrum. PMID- 23923911 TI - Anisotropy and strain rate effects on bovine cortical bone: combination of high resolution imaging and dynamic loading. PMID- 23923912 TI - Original experimental ballistic set-up for mechanical behaviour characterisation of the cranial bone. PMID- 23923913 TI - Multiscale modelling of the mechanical behaviour of human humerus under impact. PMID- 23923914 TI - 3D freehand ultrasound to estimate the glenohumeral rotation centre. PMID- 23923916 TI - Biomechanical analysis and modelling of lumbar belt: preliminary study. PMID- 23923915 TI - Structural and tribological study of healthy and biomimetic SF. PMID- 23923917 TI - The effect of nucleotomy on facet joint loading in the porcine lumbar spine. PMID- 23923918 TI - Necessary precision levels for the subchondral mineralised zone thickness of the facet joint to optimise finite-element model. PMID- 23923919 TI - In vitro characterisation of the biomechanical properties of the subchondral mineralised zone of lumbosacral facet joints. PMID- 23923920 TI - Reliable femoral frame construction on MRI images. PMID- 23923922 TI - Dissecan osteochondritis of the elbow: a possible explanation with a numerical study. PMID- 23923921 TI - Method to determine bones' relative displacement using a CT scan: application to the scaphoid and lunate bones. PMID- 23923923 TI - 3D dynamic numerical simulations of intervertebral disc: bending and twisting. PMID- 23923924 TI - Numerical modelling of a new flexible spinal implant to control scoliosis aggravation. First set-up of a parametric study. PMID- 23923925 TI - Evaluation of a primary TMJ implant fixation using screws: a numerical study. PMID- 23923926 TI - Experimental analysis of biomechanical behaviour of stabilised occipitocervical junctions. PMID- 23923927 TI - Biomechanical analysis of pedicle screw pullout strength. PMID- 23923928 TI - Development and validation of a numerical model for tibial component analysis in total ankle replacement. PMID- 23923929 TI - Simulation of bone ingrowth in non-resorbable substitutes. PMID- 23923930 TI - Silk nerve: bioactive implant for peripheral nerve regeneration. PMID- 23923931 TI - Effects of thermal ageing on the static and cyclic mechanical properties of carbon fibres/PDMS composites for use in medicine. PMID- 23923932 TI - The importance of the geometry of the screws in TMJ implant fixation. PMID- 23923933 TI - Second-gradient models accounting for some effects of microstructure on remodelling of bones reconstructed with bioresorbable materials. PMID- 23923934 TI - Comparison between constitutive models for the solid phase of biphasic agarose/chondrocytes constructs for knee cartilage engineering. PMID- 23923935 TI - Effect of ions on the interactions of glass nanoparticles with monolayer lung surfactant: applications for the study of inhaled airborne wear particles. PMID- 23923936 TI - Diffusion-reaction model to describe osteogenesis within a titanium scaffold. PMID- 23923937 TI - A simple model for the perfusion of porous hydrogel scaffolds under culture in a sustentation like bioreactor. PMID- 23923938 TI - Subject-specific finite element modelling of canine long bones up to fracture. PMID- 23923939 TI - A three-scale identification of orthotropic properties of trabecular bone. PMID- 23923940 TI - Intervertebral disc characterisation by elastography: a preliminary study. PMID- 23923941 TI - Biomechanical breast modelling to improve patient positioning during breast cancer radiotherapy. PMID- 23923942 TI - Mechanical behaviour of annulus fibrosus tissue: identification of a poro-hyper elastic model from experimental measurements. PMID- 23923943 TI - Imaging of the human Glisson's capsule by two-photon excitation microscopy and mechanical characterisation by uniaxial tensile tests. PMID- 23923944 TI - Experimental protocol to characterise damage of appendicular bone. PMID- 23923945 TI - Mechanical properties of deep-sea molluscan shell. PMID- 23923946 TI - Nanoindentation mapping reveals gradients in the mechanical properties of dental enamel in rat incisors. PMID- 23923947 TI - Crystallographic texture determines mechanical properties of molluscan nacre. PMID- 23923948 TI - Space and phase normalisations in motion correction for magnetic resonance elastography. PMID- 23923949 TI - Asymmetric kinematics and dynamics of the temporomandibular joint without pain: a case report. PMID- 23923951 TI - A method of scar evaluation using non-contact 3D scanner. PMID- 23923950 TI - Finite element analysis of temporomandibular joints during opening-closing motion: asynchronous case report. PMID- 23923952 TI - Advanced modelling of the mechanical behaviour of biological tissues: application to 3D breast deformation. PMID- 23923953 TI - Numerical assessment of the effects of the axial variations of porosity and mineralisation on the elastic properties in the human femoral neck. PMID- 23923954 TI - Experimental measures of human intracranial arteries wall properties. PMID- 23923955 TI - Shell finite element model for interactive foetal head deformation during childbirth. PMID- 23923956 TI - Comparison between the mechanical behaviour of the human healthy AA and commercial prostheses under various mechanical loadings. PMID- 23923957 TI - Preservation of tangent modulus of pericardial tissue during cold storage. PMID- 23923958 TI - Using a 3D needle-tissue force distribution basis to optimise the design of an instrumented needle. PMID- 23923959 TI - Anatomic sampling site and perfusate osmolarity effects on periosteum intrinsic permeability. PMID- 23923960 TI - Prediction of bone anisotropic mechanical properties in osteoporotic human vertebral body from microstructural parameters. PMID- 23923961 TI - Evaluation of the elastic modulus of cortical bone: adaptation of experimental protocols to small samples. PMID- 23923962 TI - Mechanical and physicochemical responses for hyaline cartilage: role of protein beta1 integrin in mechanotransduction. PMID- 23923963 TI - Patient-specific modelling of the calf muscle under elastic compression using magnetic resonance imaging and ultrasound elastography. PMID- 23923964 TI - Stochastic multiscale modelling of elastic properties of bone ultrastructure. PMID- 23923965 TI - Determination of mechanical properties of cortical bone using AFM under dry and immersed conditions. PMID- 23923966 TI - Creep simulation and comparison of micro-CT-based FE model of porcine and human cancellous bone. PMID- 23923968 TI - Impact of locoregional therapy and alpha-fetoprotein on outcomes in transplantation for liver cancer: a UNOS Region 6 pooled analysis--conclusion about locoregional therapy. PMID- 23923967 TI - Myocardial scaffold-based cardiac tissue engineering: application of coordinated mechanical and electrical stimulations. AB - Recently, we developed an optimal decellularization protocol to generate 3D porcine myocardial scaffolds, which preserve the natural extracellular matrix structure, mechanical anisotropy, and vasculature templates and also show good cell recellularization and differentiation potential. In this study, a multistimulation bioreactor was built to provide coordinated mechanical and electrical stimulation for facilitating stem cell differentiation and cardiac construct development. The acellular myocardial scaffolds were seeded with mesenchymal stem cells (10(6) cells/mL) by needle injection and subjected to 5 azacytidine treatment (3 MUmol/L, 24 h) and various bioreactor conditioning protocols. We found that after 2 days of culturing with mechanical (20% strain) and electrical stimulation (5 V, 1 Hz), high cell density and good cell viability were observed in the reseeded scaffold. Immunofluorescence staining demonstrated that the differentiated cells showed a cardiomyocyte-like phenotype by expressing sarcomeric alpha-actinin, myosin heavy chain, cardiac troponin T, connexin-43, and N-cadherin. Biaxial mechanical testing demonstrated that positive tissue remodeling took place after 2 days of bioreactor conditioning (20% strain + 5 V, 1 Hz); passive mechanical properties of the 2 day and 4 day tissue constructs were comparable to those of the tissue constructs produced by stirring reseeding followed by 2 weeks of static culturing, implying the effectiveness and efficiency of the coordinated simulations in promoting tissue remodeling. In short, the synergistic stimulations might be beneficial not only for the quality of cardiac construct development but also for patients by reducing the waiting time in future clinical scenarios. PMID- 23923969 TI - Successful conversion to belatacept after thrombotic microangiopathy in kidney transplant patients. AB - Thrombotic microangiopathy (TMA) is a severe complication of kidney transplantation. TMA may occur de novo or as recurrent disease post-transplant. De novo disease is usually associated with immunosuppressive drugs or can be seen as a part of endothelial damage that accompanies antibody-mediated rejection. Treatment for de novo TMA is limited to plasma exchange and change in immunosuppression. We report two cases of de novo TMA post-transplant that were successfully treated by converting to belatacept for maintenance immunosuppression. PMID- 23923970 TI - Short-term evaluation of autologous transplantation of bone marrow-derived mesenchymal stem cells in patients with cirrhosis: Egyptian study. AB - BACKGROUND: Stem cell-based therapy has received attention as a possible alternative to organ transplantation. The aim of this study was to assess the safety and efficacy of autologous transplantation of bone marrow (BM)-derived stromal cells in post-HCV liver cirrhosis patients. METHODOLOGY: 10 * 10(6) of isolated human bone marrow (HBM)-stromal cells in 10 mL normal saline were injected in the spleen of 20 patients with end-stage liver cirrhosis guided by the ultrasonography, and then patients were followed up on monthly basis for six months. RESULTS: A statistically significant decrease was detected in the total bilirubin, aspartate transaminase (AST), alanine transaminase (ALT) (p value<0.01), prothrombin time (PT), and international normalized ratio (INR) levels (p-value<0.05), while a statistically significant increase in the albumin and PC (p-value<0.05) after follow-up. CONCLUSION: This study suggested the safety, feasibility, and efficacy of the intrasplenic injection of autologous BM stromal cells in improving liver function in Egyptian patients with cirrhosis. PMID- 23923971 TI - Inactivity on the kidney transplant wait-list is associated with inferior pre- and post-transplant outcomes. AB - BACKGROUND: The majority of kidney transplant (KT) candidates spend some time on the transplant wait-list (WL) prior to kidney transplantation. We examined the impact of WL inactivity on clinical outcomes. METHODS: All adult KT candidates first actively wait-listed between January 1, 1996, and December 31, 2005, in the United States were grouped by frequency of inactivity on the WL. Transplantation rate, pre- and post-transplant patient survival and death-censored kidney graft survival were compared. RESULTS: Of 159,774 candidates who were placed on the WL, 48,598 (30.4%) experienced one or more periods of inactivity. Candidates with inactivity once or more on the WL had 42% and 27% less likelihood of KT, respectively (HR 0.58, 95% CI 0.57, 0.59 and HR 0.73, 95% CI 0.71, 0.75). WL inactivity once or more was associated with a higher likelihood of death (HR 1.94, 95% CI 1.88, 2.00 and HR 2.13, 95% CI 2.02, 2.24). Among KT recipients, inactivity more than once on the WL was associated with a higher risk of death (HR 1.14, 95% CI 1.05, 1.23). CONCLUSIONS: Periods of inactivity on the WL predict increased mortality pre- and post-transplantation. A better understanding of the reasons for WL inactivity is essential to improve WL management and post transplant outcomes. PMID- 23923973 TI - A critical analysis of early death after adult liver transplants. AB - INTRODUCTION: The 15% mortality rate of liver transplant recipients at one yr may be viewed as a feat in comparison with the waiting list mortality, yet it nonetheless leaves room for much improvement. Our aim was to critically examine the mortality rates to identify high-risk periods and to incorporate cause of death into the analysis of post-transplant survival. METHODS: We performed a retrospective analysis on United Network for Organ Sharing data for all adult recipients of liver transplants from January 1, 2002 to October 31, 2011. Our analysis included multivariate logistic regression where the primary outcome measure was patient death of 49,288 recipients. RESULTS: The highest mortality rate by day post-transplant was on day 0 (0.9%). The most significant risk factors were as follows: for one-d mortality from technical failure, intensive care unit admission odds ratio (OR 3.2); for one-d mortality from graft failure, warm ischemia >75 min (OR 5.6); for one-month mortality from infection, a previous transplant (OR 3.3); and for one-month mortality from graft failure, a previous transplant (OR 3.7). CONCLUSION: We found that the highest mortality rate after liver transplantation is within the first day and the first month post transplant. Those two high-risk periods have common, as well as different, risk factors for mortality. PMID- 23923972 TI - Pretransplant coronary artery disease associated with worse clinical outcomes in pancreas transplantation. AB - BACKGROUND: Coronary artery disease (CAD) is common in patients with type I diabetes and may be associated with worse outcomes in patients undergoing pancreas transplantation (PT). This study evaluates PT patients to determine the pre transplant prevalence of CAD and assesses the post-transplant outcomes including complications and survival. METHODS: This study is a retrospective review of PTs from 2003 to 2011. Diagnosis of CAD required cardiac catheterization. Outcomes included: myocardial infarction (MI), stroke, and survival. RESULTS: There were 405 transplants in 389 patients with median follow up of 56 months. Pre transplant prevalence of CAD was 19% (n = 74). There was no increased risk of perioperative, 90-d or one-yr mortality for patients with CAD. The CAD group did have increased risk of MI (11% vs. 1%, p < 0.001) and stroke (8% vs. 3%, p = 0.02). Controlling for patient and donor age, and history of CAD, the CAD group had decreased patient survival at five yr (82% vs. 90%, p = 0.09, HR 1.77) by Cox regression. CONCLUSIONS: Patients with type I diabetes and CAD have increased risk of MI and stroke post-pancreas transplant, with decreased five-yr survival. Patients without CAD and a negative pre transplant cardiac evaluation carry a low risk of post-transplant MI. PMID- 23923974 TI - The utilization of sirolimus and the impact on wound-healing complications in obese kidney transplant recipients. AB - BACKGROUND: Wound healing is a known complication associated with sirolimus therapy. Previous studies have demonstrated that obesity is a risk factor for wound-healing complications (WHC) in patients receiving sirolimus therapy; however, the incidence has not been defined. METHODS: This is a single-center, retrospective cohort study of de novo kidney transplant recipients (KTR) transplanted with a body mass index (BMI) of >= 30 kg/m(2) between January 2002 and April 2011 receiving sirolimus vs. sirolimus-free maintenance immunosuppression. RESULTS: A total of 317 KTR, 71 sirolimus-free patients and 246 sirolimus patients, were eligible for inclusion. There was no difference in the primary outcome of WHC within six months of transplant (sirolimus 32.1% vs. sirolimus-free 29.6%, p = 0.107). Sirolimus exposure was not found to influence WHC (OR 2.906, 95% CI 0.922-9.160); however, BMI Class II (OR 1.830, 95% CI 1.051 3.186) and Class III (OR 3.154, 95% CI 1.484-6.705) were significant predictors of WHC. There was no difference in WHC between the sirolimus group and sirolimus free group among patients in obesity Class I (27.3% vs. 15.1%, p = 0.064), Class II (36.6% vs. 34.8%, p = 0.195), or Class III (48.0% vs. 53.3%, p = 0.243). CONCLUSION: In our experience, sirolimus does not increase WHC in obese KTR and can be safely used as maintenance immunosuppression immediately following transplant. PMID- 23923975 TI - Liver transplantation after severe hepatic trauma: a sustainable practice. A single-center experience and review of the literature. AB - Severe hepatic trauma is a rare indication for liver transplantation (LT). We report our single-center experience of LT for hepatic trauma. Four new cases are discussed in light of a literature review in order to depict the pathways leading from hepatic trauma to LT and to assess the outcomes of this practice. LT is generally indicated in case of uncontrollable hemorrhage, acute liver failure, or post-traumatic late sequelae. Hepatic vessels thrombosis, sepsis, major hepatic resections, and a late referral are factors associated with the progression toward irreversible liver failure. Considering all reported cases, early patient and graft survival reached 68% and 62%, respectively, but in the last decade both have improved to 84%. LT after severe hepatic trauma is a sustainable practice considering the current good outcomes and the ineluctable death of these patients without LT. PMID- 23923976 TI - Asthma control test via text messaging: could it be a tool for evaluating asthma control? AB - INTRODUCTION: Originally, the Asthma Control Test (ACT) was designed for English speaking patients using a paper-and-pencil format. The Turkish version of the ACT was recently validated. This article compares the paper-and-pencil and web-based texting formats of the Turkish version of the ACT and evaluates the compatibility of these ACT scores with GINA-based physician assessments of asthma control. METHODS: This multicentre prospective study included 431 asthma patients from outpatient clinics in Turkey. The patients were randomized into a paper-and pencil group (n = 220) and a text messaging group (n = 211). Patients completed the ACT at Visit 1, after 10 +/- 2 days, and at 5 +/- 1 week to demonstrate the reliability and responsiveness of the test. At each visit, physicians assessed patients' asthma control levels. RESULTS: The ACT administered via texting showed an internal consistency of 0.82. For the texting group, we found a significant correlation between the ACT and physician assessments at Visit 1 (r = 0.60, p < 0.001). The AUC was 0.87, with a sensitivity of 78.0% and a specificity of 77.5% for a score of <=19 for screening "uncontrolled" asthma in the texting group. CONCLUSION: When the Turkish version of the ACT was administered via either the paper-and-pencil or text messaging test, scores were closely associated with physician assessments of asthma control. PMID- 23923977 TI - Exposure and impact of a mass media campaign targeting sexual health amongst Scottish men who have sex with men: an outcome evaluation. AB - BACKGROUND: This paper explores the exposure and impact of a Scottish mass media campaign: Make Your Position Clear. It ran from October 2009 to July 2010, targeted gay men and other men who have sex with men (MSM), and had two key aims: to promote regular sexual health and HIV testing every 6 months, and to promote the use of appropriate condoms and water-based lubricant with each episode of anal intercourse. METHODS: A cross-sectional survey (anonymous and self-report) was conducted 10 months after the campaign was launched (July 2010). Men were recruited from commercial venues. Outcome measures included use of lubricant, testing for sexually transmitted infections and HIV, and intentions to seek HIV testing within the following six months. Linear-by-linear chi-square analysis and binary logistic regressions were conducted to explore the associations between the outcome measures and campaign exposure. RESULTS: The total sample was 822 men (62.6% response rate). Men self-identifying as HIV positive were excluded from the analysis (n=38). Binary logistic analysis indicated that those with mid or high campaign exposure were more likely to have been tested for HIV in the previous six months when adjusted for age, area of residence and use of the "gay scene" (AOR=1.96, 95% CI=1.26 to 3.06, p=.003), but were not more likely to be tested for STIs (AOR=1.37, 95% CI=0.88 to 2.16, p=.167). When adjusted for previous HIV testing, those with mid or high campaign exposure were not more likely to indicate intention to be tested for HIV in the following six months (AOR=1.30, 95% CI=0.73 to 2.32, p=.367). Those with no campaign exposure were less likely than those with low exposure to have used appropriate lubricant with anal sex partners in the previous year (AOR=0.42, 95% CI=0.23 to 0.77, p=.005). CONCLUSIONS: The campaign had demonstrable reach. The analysis showed partial support for the role of mass media campaigns in improving sexual health outcomes. This suggests that a role for mass media campaigns remains within combination HIV prevention. PMID- 23923979 TI - Rescheduling nursing shifts: scoping the challenge and examining the potential of mathematical model based tools. AB - AIM: To review research in the literature on nursing shift scheduling / rescheduling, and to report key issues identified in a consultation exercise with managers in four English National Health Service trusts to inform the development of mathematical tools for rescheduling decision-making. BACKGROUND: Shift rescheduling is unrecognised as an everyday time-consuming management task with different imperatives from scheduling. Poor rescheduling decisions can have quality, cost and morale implications. EVALUATION: A systematic critical literature review identified rescheduling issues and existing mathematic modelling tools. A consultation exercise with nursing managers examined the complex challenges associated with rescheduling. KEY ISSUES: Minimal research exists on rescheduling compared with scheduling. Poor rescheduling can result in greater disruption to planned nursing shifts and may impact negatively on the quality and cost of patient care, and nurse morale and retention. Very little research examines management challenges or mathematical modelling for rescheduling. CONCLUSION: Shift rescheduling is a complex and frequent management activity that is more challenging than scheduling. Mathematical modelling may have potential as a tool to support managers to minimise rescheduling disruption. IMPLICATIONS FOR NURSING MANAGEMENT: The lack of specific methodological support for rescheduling that takes into account its complexity, increases the likelihood of harm for patients and stress for nursing staff and managers. PMID- 23923978 TI - Highly conserved cysteines are involved in the oligomerization of occludin-redox dependency of the second extracellular loop. AB - The tight junction (TJ) marker occludin is a 4-transmembrane domain (TMD) protein with unclear physiological and pathological functions, interacting with other TJ proteins. It oligomerizes and is redox sensitive. However, oligomerization sites and mechanisms are unknown. AIMS: To identify hypoxia-sensitive binding sites, we investigated the consequences of amino-acid substitutions of highly conserved cysteines in human occludin, under normal and hypoxic incubations. RESULTS: (i) The extracellular loop 2 (ECL2) showed homophilic trans- and cis-association between opposing cells and along the cell membrane, respectively, caused by a loop properly folded via an intraloop disulfide bridge between the shielded C216 and C237. Hypoxia and reductants prevented the associations. (ii) C82 in TMD1 directly cis-associated without disulfide formation. (iii) C76 in TMD1 and C148 in TMD2 limited the trans-interaction; C76 also limited occludin-related paracellular tightness and changed the strand morphology of claudin-1. (iv) The diminished binding strength found after substituting C82, C216, or C237 was accompanied by increased occludin mobility in the cell membrane. INNOVATION: The data enable the first experimentally proven structural model of occludin and its homophilic interaction sites, in which the ECL2, via intraloop disulfide formation, has a central role in occludin's hypoxia-sensitive oligomerization and to regulate the structure of TJs. CONCLUSION: Our findings support the new concept that occludin acts as a hypoxiasensor and contributes toward regulating the TJ assembly redox dependently. This is of pathogenic relevance for tissue barrier injury with reducing conditions. The ECL2 disulfide might be a model for four TMD proteins in TJs with two conserved cysteines in an ECL. PMID- 23923980 TI - Tactical proficiency among table tennis players with and without intellectual disabilities. AB - The effect of intellectual impairment on sports performance has received limited attention by researchers. As a contribution to closing this gap, the purpose of the present investigation was to examine the differences in tactical proficiency between table tennis players with and without intellectual disabilities (ID). These groups were matched for training-volume and experience and consisted of 41 male (age = 27+/-8) and 30 female (age= 28+/-8) elite players with ID and a reference group of 12 male (age= 24+/-12) and 5 female (age= 20+/-9) players without ID. In two different test settings - one a World Championship and the other a training camp - the players in each group performed 60 semi-standardised rallies against the same opponent. Players were told that 12 sets of five identical services would be delivered, and their goal was to return the service with the intention of 'winning the point'. The test results were validated for this study, to compute tactical proficiency scores (maximal score of eight points) for each player. A two-way Analysis of Variance (ANOVA) revealed significantly lower proficiency scores for players with ID than for those without ID. Repeated-measures ANOVA revealed that within each series of five rallies, starting with identical services, all participants were able to significantly improve their tactical proficiency gradually, but players without ID scored 4.3+/ 0.5 from the first ball on, and while athletes with ID only 3.3+/-0.7 after five balls. The results of this study indicate that ID is associated with decreased tactical proficiency in table tennis. PMID- 23923981 TI - ATP6V1B1 mutations in distal renal tubular acidosis and sensorineural hearing loss: clinical and genetic spectrum of five families. AB - Distal renal tubular acidosis (DRTA) is characterized by tubular defects in urinary acidification and hyperchloremic metabolic acidosis, hypokalemia, hypercalciuria, hypocitraturia, nephrocalcinosis and nephrolithiasis. Mutations in ATP6V1B1 cause DRTA associated with sensorineural hearing loss. The objective of this multicenter study is to screen DRTA patients with sensorineural hearing loss for ATP6V1B1 gene mutations and present genotype/phenotype correlation. Clinical data in five unrelated consanguineous families with DRTA and hearing loss were obtained in Turkey. For mutation screening, all coding exons of ATP6V1B1 were PCR-amplified and sequenced from genomic DNA. In our cohort of five families, there were four different homozygous ATP6V1B1 mutations in affected individuals: c.91C>T (p.R31X), c.232G>A (p.G78R), c.497delC (p.T166RfsX9) and c.1155dupC (p.I386HfsX56). Our study shows that rare and family-specific variants in ATP6V1B1 are responsible for DRTA and sensorineural hearing loss syndrome in Turkey. While firm genotype-phenotype correlations are not available, detailed clinical and molecular analyses provide data to be used in genetic counseling. PMID- 23923982 TI - Enantioselective catalytic transannular ketone-ene reactions. AB - Highly enantio- and diastereoselective transannular ketone-ene reactions are catalyzed by a new chromium(III) triflate tridentate Schiff base complex. Electronically unactivated keto-olefins undergo heteroene reactions at ambient temperature to afford enantioenriched bicyclic alcohols, common structural motifs in natural products. The kinetic resolution of a configurationally stable planar chiral cyclodecenone is also described. PMID- 23923983 TI - Multimetallic complexes featuring a bridging N-heterocyclic phosphido/phosphenium ligand: synthesis, structure, and theoretical investigation. AB - By incorporating an N-heterocyclic phosphenium/phosphide (NHP) ligand into a chelating pincer ligand framework (PPP(+)/PPP(-)), we have elucidated several different and unprecedented binding modes of NHP ligands in homobimetallic, heterobimetallic, and trimetallic metal complexes. One-electron reduction of the previously reported (PPP)(-)/M(II) complexes (PPP)M-Cl (M = Pd (1), Pt (2)) results in clean formation of the symmetric homobimetallic M(I)/M(I) complexes [(MU-PPP)Pd]2 (5) and [(MU-PPP)Pt]2 (6). The tridentate NHP ligand has also been utilized as a bridging linker in the M/Co heterobimetallic compounds (OC)3Co(u PPP)M(CO) (M = Pd (7), Pt (8)), synthesized via salt elimination from mixtures of 1 and 2 and Na[Co(CO)4]. Furthermore, an NHP-bridged trimetallic complex (PPP)2Pd3Cl2 (9) can be synthesized in a manner similar to precursor 1 (Pd(PPh3)4 + (PPP)Cl) via careful adjustment of reaction stoichiometry. Examination of the interatomic distances and angles in complexes 5-9, in tandem with density functional theory calculations have been used to evaluate and characterize the bonding interactions in these complexes. PMID- 23923984 TI - Vertical CNT-Si photodiode array. AB - A photodiode consisting of nanopillars of thin-film silicon p-i-n on an array of vertically aligned carbon nanotubes (CNTs) with a noncontinuous cathode electrode is demonstrated. The structure exploits the intrinsic enhancement of the CNTs' electric field, which leads to reduction in the photodiode's operating voltage and response time and enhancement of optical coupling due to better light trapping, as compared with the conventional planar photodiode. These improvements translate to higher resolution and higher frame rate flat-panel imaging systems for a broad range of applications, including computed tomography and particle detection. PMID- 23923985 TI - High conjugated linoleic acid enriched ghee (clarified butter) increases the antioxidant and antiatherogenic potency in female Wistar rats. AB - BACKGROUND: Hypercholesterolemia and oxidative stress are the main stimulating factors responsible for coronary artery disease and progression of atherosclerosis. Dairy food products are rich in conjugated linoleic acid (CLA) which is considered as an important component due to its potential health benefits such as anticarcinogenic, antiatherogenic, antidiabetic and antiadipogenic properties. In the present study, the effect of CLA enriched ghee on the antioxidant enzyme system and antiatherogenic properties in Wistar rats has been studied. METHODS: Female Wistar rats of 21 days were taken for the study and fed with soybean diet (Control diet), low CLA diet and high CLA ghee diet (treatments) for thirty five days for studying antioxidative enzymes and sixteen weeks in case of antiatherogenic studies. RESULTS: Feeding of high CLA enhanced ghee during pubescent period in rats lead to an increase in catalase (CAT) and superoxide dismutase (SOD) enzyme activities in blood and increased CAT, SOD and glutathione transferase (GST) enzymes activities in liver by 27, 130 and 168 percent, respectively. Plasma nitrate concentration and Haemoglobin levels remained the same in all the treatments. Feeding of high CLA ghee resulted in lower (P < 0.01) plasma cholesterol & triglyceride level (52.17 and 30.27%), and higher high density lipoproteins (33.26%) than feeding of soybean oil (control group) and thus manifested in decreased (P < 0.05) atherogenic index (from 0.472 to 0.244). Lesser cholesterol and triglyceride levels were observed in the liver and aorta of high CLA fed rats than in those of the other groups. Histopathological studies of liver showed normal hepatic cords with portal triad in the high CLA ghee fed rats whereas fatty degeneration of hepatocytes containing fat vacuoles was observed in the liver of the other groups. CONCLUSION: This paper is the first report of the antioxidant and antiatherogenic properties of the high CLA enriched ghee suggesting that high CLA ghee can be used as a potential food for decreasing the risk of cardiovascular diseases, particularly in India, where, ghee is widely used for culinary and medicinal purposes. PMID- 23923986 TI - Oxidative stress and hepatitis C virus. AB - The disproportionate imbalance between the systemic manifestation of reactive oxygen species and body's ability to detoxify the reactive intermediates is referred to as oxidative stress. Several biological processes as well as infectious agents, physiological or environmental stress, and perturbed antioxidant response can promote oxidative stress. Oxidative stress usually happens when cells are exposed to more electrically charged reactive oxygen species (ROS) such as H2O2 or O2-. The cells' ability to handle such pro-oxidant species is impeded by viral infections particularly within liver that plays an important role in metabolism and detoxification of harmful substances. During liver diseases (such as hepatocellular or cholestatic problems), the produced ROS are involved in transcriptional activation of a large number of cytokines and growth factors, and continued production of ROS and Reactive Nitrogen Species (RNS) feed into the vicious cycle. Many human viruses like HCV are evolved to manipulate this delicate pro- and antioxidant balance; thus generating the sustainable oxidative stress that not only causes hepatic damage but also stimulates the processes to reduce treatment of damage. In this review article, the oxidant and antioxidant pathways that are perturbed by HCV genes are discussed. In the first line of risk, the pathways of lipid metabolism present a clear danger in accumulation of viral induced ROS. Viral infection leads to decrease in cellular concentrations of glutathione (GSH) resulting in oxidation of important components of cells such as proteins, DNA and lipids as well as double strand breakage of DNA. These disorders have the tendency to lead the cells toward cirrhosis and hepatocellular carcinoma in adults due to constant insult. We have highlighted the importance of such pathways and revealed differences in the extent of oxidative stress caused by HCV infection. PMID- 23923987 TI - General practice variation in spirometry testing among patients receiving first time prescriptions for medication targeting obstructive lung disease in Denmark: a population-based observational study. AB - BACKGROUND: Spirometry testing is essential to confirm an obstructive lung disease, but studies have reported that a large proportion of patients diagnosed with COPD or asthma have no history of spirometry testing. Also, it has been shown that many patients are prescribed medication for obstructive lung disease without a relevant diagnosis or spirometry test registered. General practice characteristics have been reported to influence diagnosis and management of several chronic diseases. However, these findings are inconsistent, and it is uncertain whether practice characteristics influence spirometry testing among patients receiving medication for obstructive lung disease. The aim of this study was therefore to examine if practice characteristics are associated with spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease. METHODS: A national register-based cohort study was performed. All patients over 18 years receiving first-time prescriptions for medication targeting obstructive lung disease in 2008 were identified and detailed patient-specific data on sociodemographic status and spirometry tests were extracted. Information on practice characteristics like number of doctors, number of patients per doctor, training practice status, as well as age and gender of the general practitioners was linked to each medication user. RESULTS: Partnership practices had a higher odds ratio (OR) of performing spirometry compared with single-handed practices (OR 1.24, CI 1.09-1.40). We found a significant association between increasing general practitioner age and decreasing spirometry testing. This tendency was most pronounced among partnership practices, where doctors over 65 years had the lowest odds of spirometry testing (OR 0.25, CI 0.10-0.61). Training practice status was significantly associated with spirometry testing among single-handed practices (OR 1.40, CI 1.10-1.79). CONCLUSION: Some of the variation in spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease was associated with practice characteristics. This variation in performance may indicate a potential for quality improvement. PMID- 23923989 TI - Serratus plane block: a novel ultrasound-guided thoracic wall nerve block. AB - We present a novel ultrasound-guided regional anaesthetic technique that may achieve complete paraesthesia of the hemithorax. This technique may be a viable alternative to current regional anaesthetic techniques such as thoracic paravertebral and central neuraxial blockade, which can be technically more challenging and have a higher potential side-effect profile. We performed the serratus block at two different levels in the midaxillary line on four female volunteers. We recorded the degree of paraesthesia obtained and performed fat suppression magnetic resonance imaging and three-dimensional reconstructions of the spread of local anaesthetic in the serratus plane. All volunteers reported an effective block that provided long-lasting paraesthesia (750-840 min). There were no side-effects noted in this initial descriptive study. While these are preliminary findings, and must be confirmed in a clinical trial, they highlight the potential for the serratus plane block to provide analgesia following surgery on the thoracic wall. We suggest that this novel approach appears to be safe, effective, and easy to perform, and is associated with a low risk of side effects. PMID- 23923990 TI - On access and accountability--two Supreme Court rulings on generic drugs. PMID- 23923991 TI - Zolpidem and driving impairment--identifying persons at risk. PMID- 23923992 TI - Middle East respiratory syndrome coronavirus infections in health care workers. PMID- 23923993 TI - Particle size distribution of brown and white rice during gastric digestion measured by image analysis. AB - The particle size distribution of foods during gastric digestion indicates the amount of physical breakdown that occurred due to the peristaltic movement of the stomach walls in addition to the breakdown that initially occurred during oral processing. The objective of this study was to present an image analysis technique that was rapid, simple, and could distinguish between food components (that is, rice kernel and bran layer in brown rice). The technique was used to quantify particle breakdown of brown and white rice during gastric digestion in growing pigs (used as a model for an adult human) over 480 min of digestion. The particle area distributions were fit to a Rosin-Rammler distribution function. Brown and white rice exhibited considerable breakdown as the number of particles per image decreased over time. The median particle area (x(50)) increased during digestion, suggesting a gastric sieving phenomenon, where small particles were emptied and larger particles were retained for additional breakdown. Brown rice breakdown was further quantified by an examination of the bran layer fragments and rice grain pieces. The percentage of total particle area composed of bran layer fragments was greater in the distal stomach than the proximal stomach in the first 120 min of digestion. The results of this study showed that image analysis may be used to quantify particle breakdown of a soft food product during gastric digestion, discriminate between different food components, and help to clarify the role of food structure and processing in food breakdown during gastric digestion. PMID- 23923995 TI - Glucocorticoid-resistant asthma: more than meets the eye. AB - INTRODUCTION: For decades glucocorticoids have been considered as the gold standard for the treatment of asthma. We present a case report of typical glucocorticoid-resistant asthma and current consensus in definitions of "severe refractory", "difficult" and "glucocorticoid-resistant" asthma. METHODS: Full text papers and abstracts were identified on the basis of a comprehensive literature search primarily in MEDLINE (1966 to June 2012) but also in the Cochrane Central Register of Controlled Trials database. RESULTS: Glucocorticoid resistant asthmatics are a small subset of patients who pose noteworthy diagnostic challenges while contributing disproportionately to health care costs. Recognition of various asthma phenotypes has aided in characterizing groups with severe asthma and given a better understanding of its pathophysiological process. The molecular mechanism of glucocorticoid action is complicated and several pathways have been identified to explain drug resistance, which in turn is crucial for drug development. Tobacco smoking appears to be the single most important contributor of glucocorticoid resistance. We present the emerging and promising concepts in the management of glucocorticoid-resistant asthma, which mainly include drugs targeting specific molecules, receptors, inflammatory cells or immune processes. CONCLUSION: The challenges in making a diagnosis of glucocorticoid-resistant asthma may contribute to underestimating its prevalence and impact on patient care. Considerable progress has been made in identifying distinct phenotypes and mechanisms of glucocorticoid resistance; therefore the future of new drug development in management of asthma is promising. PMID- 23923994 TI - Sleep duration, asthma and obesity. AB - BACKGROUND: Obesity is more prevalent in asthmatics. Sleep duration is a novel risk factor for obesity in general populations. OBJECTIVE: We tested the association of sleep duration and asthma characteristics with obesity. METHODS: Adults at tertiary clinics were surveyed on asthma symptoms and habitual sleep duration. Medical records were used to assess asthma severity step (1-4), extract height and weight, current medications and diagnosed comorbid conditions. BMI >=30 kg/m(2) defined obesity. Habitual sleep was categorized as <6 (very short), 6 to <7 h (short), 7-8 h (normal), >8 to <=9 h (long) and >9 h (very long). Inhaled corticosteroid doses were categorized as low, moderate and high. RESULTS: Among 611 participants (mean BMI 30 +/- 8), 249 (41%) were obese. After adjustment for covariates, obesity was associated with short and very long sleep: as compared to normal sleepers, the odds of being obese were on an average 66% higher ([95% CI: 1.07-2.57], p = 0.02) among short and 124% higher ([1.08-1.65], p = 0.03) among very long sleepers, and the association with very short sleep approached significance (1.74 [0.96-3.14], p = 0.06). Obesity was also significantly related to highest asthma step (1.87 [1.09-3.21], p = 0.02) and psychopathology (1.64 [1.08-2.48], p = 0.02), and a trend was seen with high-dose inhaled corticosteroids (1.82 [0.93-3.56], p = 0.08). CONCLUSIONS: Obesity in asthmatics is associated with shorter and very long sleep duration, worse asthma severity, psychopathology and high-dose inhaled corticosteroids. Although this cross-sectional study cannot prove causality, we speculate that further investigation of sleep may provide new opportunities to reduce the rising prevalence of obesity among asthmatics. PMID- 23923996 TI - Possible brain injury events and symptoms in elementary school children. AB - PRIMARY OBJECTIVE: The purpose of this study was to determine the prevalence of potential mild brain injury incidents accompanied by behavioural changes in a non clinical population of elementary school-aged children. The researchers also examined data regarding the occurrence of possible brain injuries among regular vs special education students. RESEARCH DESIGN: Survey study. METHODS AND PROCEDURES: The researchers distributed questionnaires through which parents or guardians of 692 first-to-fifth grade students provided information about possible brain injury incidents and associated behavioural changes. MAIN OUTCOMES AND RESULTS: Findings suggest that as many as one-third of children experience one or more incidents potentially resulting in brain injury before completing elementary school. Despite this, only 7.66% of the sample received positive screen results because of behavioural changes associated with a potential incident. None of the 53 children with positive screens were receiving special education services through the traumatic brain injury category of IDEA at the time of the screening. Positive screens were more common among students verified for special education than those enrolled in regular education. Specifically, 25.40% of positive screen results were for children identified with a disability warranting special education services; in contrast, only 5.90% of regular education students received positive screen results. PMID- 23923998 TI - Hypothyroidism presenting as reversible renal impairment: an interesting case report. AB - We describe an interesting case of reversible renal impairment secondary to hypothyroidism. A 57-years-old man was referred from peripheral institution for evaluation of elevated serum creatinine. He had vague complaints of weakness, lethargy and muscle ache but no urinary symptoms. He was found to have hypothyroidism, and thyroid hormone replacement therapy (THRT) was started which resulted in reversal of the renal dysfunction. There was marked improvement in estimated glomerular filtration rate. 99mTc DTPA renal scans done before and after THRT suggested hypothyroidism responsible for this reversible renal impairment. Several studies have described the pathophysiology of diminished renal function in hypothyroidism. Few studies or case reports have shown total amelioration of renal impairment as seen in our patient. The etiology is presumed to be multifactorial, in which hemodynamic effects and a direct effect of thyroid hormone on the kidney play an important role. We suggest that patients with renal impairment of unknown cause have thyroid function tests undertaken as part of routine investigation. PMID- 23923999 TI - Comparing colour discrimination and proofreading performance under compact fluorescent and halogen lamp lighting. AB - Legislation in many countries has banned inefficient household lighting. Consequently, classic incandescent lamps have to be replaced by more efficient alternatives such as halogen and compact fluorescent lamps (CFL). Alternatives differ in their spectral power distributions, implying colour-rendering differences. Participants performed a colour discrimination task - the Farnsworth Munsell 100 Hue Test--and a proofreading task under CFL or halogen lighting of comparable correlated colour temperatures at low (70 lx) or high (800 lx) illuminance. Illuminance positively affected colour discrimination and proofreading performance, whereas the light source was only relevant for colour discrimination. Discrimination was impaired with CFL lighting. There were no differences between light sources in terms of self-reported physical discomfort and mood state, but the majority of the participants correctly judged halogen lighting to be more appropriate for discriminating colours. The findings hint at the colour-rendering deficiencies associated with energy-efficient CFLs. PRACTITIONER SUMMARY: In order to compare performance under energy-efficient alternatives of classic incandescent lighting, colour discrimination and proofreading performance was compared under CFL and halogen lighting. Colour discrimination was impaired under CFLs, which hints at the practical drawbacks associated with the reduced colour-rendering properties of energy-efficient CFLs. PMID- 23924000 TI - Payer agnosticism. PMID- 23924001 TI - Experiments in continuity--rethinking residency training in ambulatory care. PMID- 23924002 TI - Sequence-based discovery of Bradyrhizobium enterica in cord colitis syndrome. AB - BACKGROUND: Immunosuppression is associated with a variety of idiopathic clinical syndromes that may have infectious causes. It has been hypothesized that the cord colitis syndrome, a complication of umbilical-cord hematopoietic stem-cell transplantation, is infectious in origin. METHODS: We performed shotgun DNA sequencing on four archived, paraffin-embedded endoscopic colon-biopsy specimens obtained from two patients with cord colitis. Computational subtraction of human and known microbial sequences and assembly of residual sequences into a bacterial draft genome were performed. We used polymerase-chain-reaction (PCR) assays and fluorescence in situ hybridization to determine whether the corresponding bacterium was present in additional patients and controls. RESULTS: DNA sequencing of the biopsy specimens revealed more than 2.5 million sequencing reads that did not match known organisms. These sequences were computationally assembled into a 7.65-Mb draft genome showing a high degree of homology with genomes of bacteria in the bradyrhizobium genus. The corresponding newly discovered bacterium was provisionally named Bradyrhizobium enterica. PCR identified B. enterica nucleotide sequences in biopsy specimens from all three additional patients with cord colitis whose samples were tested, whereas B. enterica sequences were absent in samples obtained from healthy controls and patients with colon cancer or graft-versus-host disease. CONCLUSIONS: We assembled a novel bacterial draft genome from the direct sequencing of tissue specimens from patients with cord colitis. Association of these sequences with cord colitis suggests that B. enterica may be an opportunistic human pathogen. (Funded by the National Cancer Institute and others.) PMID- 23924003 TI - ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. AB - BACKGROUND: No plasma biomarkers are associated with the response of acute graft versus-host disease (GVHD) to therapy after allogeneic hematopoietic stem-cell transplantation. METHODS: We compared 12 biomarkers in plasma obtained a median of 16 days after therapy initiation from 10 patients with a complete response by day 28 after therapy initiation and in plasma obtained from 10 patients with progressive GVHD during therapy. The lead biomarker, suppression of tumorigenicity 2 (ST2), was measured at the beginning of treatment for GVHD in plasma from 381 patients and during the first month after transplantation in three independent sets totaling 673 patients to determine the association of this biomarker with treatment-resistant GVHD and 6-month mortality after treatment or transplantation. RESULTS: Of the 12 markers, ST2 had the most significant association with resistance to GVHD therapy and subsequent death without relapse. As compared with patients with low ST2 values at therapy initiation, patients with high ST2 values were 2.3 times as likely to have treatment-resistant GVHD (95% confidence interval [CI], 1.5 to 3.6) and 3.7 times as likely to die within 6 months after therapy (95% CI, 2.3 to 5.9). Patients with low ST2 values had lower mortality without relapse than patients with high ST2 values, regardless of the GVHD grade (11% vs. 31% among patients with grade I or II GVHD and 14% vs. 67% among patients with grade III or IV GVHD, P<0.001 for both comparisons). Plasma ST2 values at day 14 after transplantation were associated with 6-month mortality without relapse, regardless of the intensity of the conditioning regimen. CONCLUSIONS: ST2 levels measured at the initiation of therapy for GVHD and during the first month after transplantation improved risk stratification for treatment-resistant GVHD and death without relapse after transplantation. (Funded by the National Institutes of Health.) PMID- 23924005 TI - Clinical Practice. Mild asthma. PMID- 23924006 TI - Images in clinical medicine. Rubella rash. PMID- 23924004 TI - Glucose levels and risk of dementia. AB - BACKGROUND: Diabetes is a risk factor for dementia. It is unknown whether higher glucose levels increase the risk of dementia in people without diabetes. METHODS: We used 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2067 participants without dementia to examine the relationship between glucose levels and the risk of dementia. Participants were from the Adult Changes in Thought study and included 839 men and 1228 women whose mean age at baseline was 76 years; 232 participants had diabetes, and 1835 did not. We fit Cox regression models, stratified according to diabetes status and adjusted for age, sex, study cohort, educational level, level of exercise, blood pressure, and status with respect to coronary and cerebrovascular diseases, atrial fibrillation, smoking, and treatment for hypertension. RESULTS: During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia (P=0.01); with a glucose level of 115 mg per deciliter (6.4 mmol per liter) as compared with 100 mg per deciliter (5.5 mmol per liter), the adjusted hazard ratio for dementia was 1.18 (95% confidence interval [CI], 1.04 to 1.33). Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia (P=0.002); with a glucose level of 190 mg per deciliter (10.5 mmol per liter) as compared with 160 mg per deciliter (8.9 mmol per liter), the adjusted hazard ratio was 1.40 (95% CI, 1.12 to 1.76). CONCLUSIONS: Our results suggest that higher glucose levels may be a risk factor for dementia, even among persons without diabetes. (Funded by the National Institutes of Health.) PMID- 23924007 TI - Case records of the Massachusetts General Hospital. Case 24-2013. A 53-year-old woman with erythroderma, pruritus, and lymphadenopathy. PMID- 23924009 TI - Cuffed and exposed--perp-walking bradyrhizobium. PMID- 23924008 TI - Toward new treatments for mantle-cell lymphoma? PMID- 23924010 TI - Cardiac aging and rejuvenation--a sense of humors? PMID- 23924011 TI - Prophylactic platelet transfusion. PMID- 23924012 TI - Prophylactic platelet transfusion. PMID- 23924013 TI - Biventricular pacing for atrioventricular block and systolic dysfunction. PMID- 23924014 TI - Biventricular pacing for atrioventricular block and systolic dysfunction. PMID- 23924015 TI - Biventricular pacing for atrioventricular block and systolic dysfunction. PMID- 23924016 TI - Cardiovascular risks with azithromycin. PMID- 23924017 TI - Cardiovascular risks with azithromycin. PMID- 23924018 TI - Cardiovascular risks with azithromycin. PMID- 23924019 TI - Effects of medicaid on clinical outcomes. PMID- 23924020 TI - Effects of medicaid on clinical outcomes. PMID- 23924021 TI - Effects of medicaid on clinical outcomes. PMID- 23924022 TI - Effects of medicaid on clinical outcomes. PMID- 23924023 TI - Case 12-2013: a woman with pulmonary infiltrates and respiratory failure. PMID- 23924024 TI - Case 12-2013: a woman with pulmonary infiltrates and respiratory failure. PMID- 23924025 TI - Reversal of Cushing's syndrome by vandetanib in medullary thyroid carcinoma. PMID- 23924027 TI - Images in clinical medicine. Pellets in the appendix. PMID- 23924029 TI - A survey of attitudes of local citizens of a residential area toward urban stray cats in Japan. AB - This study surveyed the attitudes of local residents living in an urban area in Japan toward stray cats. An anonymous questionnaire asked local residents (359 houses) about their attitudes toward stray cats. Responses were received from126 houses (35%). Answers about nuisance, respondents' actions, and actions to be taken with regard to stray cats did not differ by place or type of residence of respondents. More than one third (36.7 +/- 16.6%) of the respondents answered that the "bad smell of the feces and urine" was a nuisance. Respondents who lived in detached houses tended to like cats compared with those who lived in condominiums. Respondents who liked cats took care of cats more frequently, whereas those who disliked cats chased cats away and prevented their intrusion into their houses and land. However, it is noteworthy that one third or more (minimum value: 37.8%) of respondents of all kinds answered that neutering is one effective way to suppress the population of stray cats. PMID- 23924030 TI - Factor structure of the Depression Anxiety Stress Scales in individuals with traumatic brain injury. AB - PRIMARY OBJECTIVE: The Depression Anxiety Stress Scales (DASS) and its shorter version, the DASS21, demonstrate a consistent factor structure. However, when these scales are used with people with traumatic brain injury (TBI), it is possible that TBI symptoms that overlap with anxiety and depression (e.g., irritability, inertia, emotional lability) result in changes to the underlying structure. This study aimed to establish whether the factor structure of the DASS and DASS21 when used with individuals with TBI is consistent with the three scales designated in the manual. METHODS AND PROCEDURES: One hundred and twenty three participants with mild-to-severe TBI completed the DASS. MAIN OUTCOMES AND RESULTS: The factor structure of the DASS was found to be consistent with the designated scales, with the exception of four items that cross-loaded weakly on multiple factors. However, the factor structure of the DASS21 did not correspond as closely to the designated depression, anxiety and stress scales, which appeared to be due to the fact that many of the highest loading items on the DASS were not included items in the DASS21. CONCLUSIONS: These results indicate that it may be preferable to use the full DASS, rather than the DASS21, with individuals with TBI. PMID- 23924028 TI - miR-205 hinders the malignant interplay between prostate cancer cells and associated fibroblasts. AB - AIMS: Tumor microenvironment is a strong determinant for the acquisition of metastatic potential of cancer cells. We have recently demonstrated that cancer associated fibroblasts (CAFs) elicit a redox-dependent epithelial-mesenchymal transition (EMT) in prostate cancer (PCa) cells, driven by cycloxygenase 2/hypoxia-inducible factor-1 (HIF-1)/nuclear factor-kappaB pathway and enhancing tumor aggressiveness. Here, we investigated the involvement of microRNAs (miRNAs) in tumor-stroma interplay to identify possible tools to counteract oxidative stress and metastasis dissemination. RESULTS: We found that miR-205 is the most downmodulated miRNA in PCa cells upon CAF stimulation, due to direct transcriptional repression by HIF-1, a known redox-sensitive transcription factor. Rescue experiments demonstrated that ectopic miR-205 overexpression in PCa cells counteracts CAF-induced EMT, thus impairing enhancement of cell invasion, acquisition of stem cell traits, tumorigenicity, and metastatic dissemination. In addition, miR-205 blocks tumor-driven activation of surrounding fibroblasts by reducing pro-inflammatory cytokine secretion. INNOVATION: Overall, such findings suggest miR-205 as a brake against PCa metastasis by blocking both the afferent and efferent arms of the circuit between tumor cells and associated fibroblasts, thus interrupting the pro-oxidant and pro-inflammatory circuitries engaged by reactive stroma. CONCLUSION: The evidence that miR-205 replacement in PCa cells is able not only to prevent but also to revert the oxidative/pro inflammatory axis leading to EMT induced by CAFs sets the rationale for developing miRNA-based approaches to prevent and treat metastatic disease. PMID- 23924031 TI - The use of low-level light therapy in the treatment of androgenetic alopecia and female pattern hair loss. AB - Androgenetic alopecia (AGA) or female pattern hair loss (FPHL) is the most common form of hair loss in men and women. Despite its common occurrence, our understanding of the etiology of AGA and FPHL remains incomplete. As such, traditional therapies demonstrate modest efficacies and new therapies continue to be sought. Low-level light therapy (LLLT) is a relatively new technique used to promote hair growth in both men and women with AGA and FPHL. Currently, there exist several LLLT devices marketed for the treatment of alopecia, which claim to stimulate hair growth; yet marketing these devices only requires that safety, not efficacy, be established. A handful of studies have since investigated the efficacy of LLLT for alopecia with mixed results. These studies suffered from power, confounding and analysis issues which resulted in a high risk of bias in LLLT studies. Due to the paucity of well-conducted randomized controlled trials, the efficacy of LLLT devices remains unclear. Randomized controlled trials of LLLT conducted and reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement would greatly increase the credibility of the evidence and clarify the ambiguity of the effectiveness of LLLT in the treatment of AGA and FPHL. PMID- 23924033 TI - Alveolar nerve repositioning with rescue implants for management of previous treatment. A clinical report. AB - The goal of modern implant dentistry is to return patients to oral health in a rapid and predictable fashion, following a diagnostically driven treatment plan. If only a limited number of implants can be placed, or some fail and the prosthetic phase of implant dentistry is chosen to complete the patient's treatment, the final outcome may result in partial patient satisfaction and is commonly referred to as a "compromise." Previous All-on-4 implant treatment for the patient presented here resulted in a compromise, with an inadequate support system for the mandibular prosthesis and a maxillary complete denture with poor esthetics. The patient was unable to function adequately and also was disappointed with the resulting appearance. Correction of the compromised treatment consisted of bilateral inferior alveolar nerve elevation and repositioning without bone removal for lateral transposition, to gain room for rescue implants for a totally implant-supported and stabilized prosthesis. Treatment time to return the patient to satisfactory comfort, function, facial esthetics, and speech was approximately 2 weeks. The definitive mandibular prosthesis was designed for total implant support and stability with patient retrievability. Adequate space between the mandibular bar system and the soft tissue created a high water bridge effect for self-cleansing. Following a short interim mandibular healing period, the maxillary sinuses were bilaterally grafted to compensate for bone inadequacies and deficiencies for future maxillary implant reconstruction. PMID- 23924032 TI - A multi-stakeholder perspective on the use of alternative test strategies for nanomaterial safety assessment. AB - There has been a conceptual shift in toxicological studies from describing what happens to explaining how the adverse outcome occurs, thereby enabling a deeper and improved understanding of how biomolecular and mechanistic profiling can inform hazard identification and improve risk assessment. Compared to traditional toxicology methods, which have a heavy reliance on animals, new approaches to generate toxicological data are becoming available for the safety assessment of chemicals, including high-throughput and high-content screening (HTS, HCS). With the emergence of nanotechnology, the exponential increase in the total number of engineered nanomaterials (ENMs) in research, development, and commercialization requires a robust scientific approach to screen ENM safety in humans and the environment rapidly and efficiently. Spurred by the developments in chemical testing, a promising new toxicological paradigm for ENMs is to use alternative test strategies (ATS), which reduce reliance on animal testing through the use of in vitro and in silico methods such as HTS, HCS, and computational modeling. Furthermore, this allows for the comparative analysis of large numbers of ENMs simultaneously and for hazard assessment at various stages of the product development process and overall life cycle. Using carbon nanotubes as a case study, a workshop bringing together national and international leaders from government, industry, and academia was convened at the University of California, Los Angeles, to discuss the utility of ATS for decision-making analyses of ENMs. After lively discussions, a short list of generally shared viewpoints on this topic was generated, including a general view that ATS approaches for ENMs can significantly benefit chemical safety analysis. PMID- 23924034 TI - Rapidly progressive glomerulonephritis in a patient with familial Mediterranean fever and renal amyloidosis. PMID- 23924035 TI - Breast ductal carcinoma in situ presenting as recurrent non-puerperal mastitis: case report and literature review. AB - Breast ductal carcinoma in situ (DCIS) is a preinvasive form of breast cancer. It typically presents as microcalcifications which are picked up on screening mammogram. We report an atypical case of breast DCIS presenting with recurrent non-puerperal mastitis with a normal mammogram and perform a literature review. PMID- 23924036 TI - Two novel mitoviruses from a Canadian isolate of the Dutch elm pathogen Ophiostoma novo-ulmi (93-1224). AB - BACKGROUND: Ophiostoma novo-ulmi is the causative agent of Dutch elm disease (DED). It is an ascomycetous filamentous fungus that ranks as the third most devastating fungal pathogen in Canada. The disease front has spread eastward and westward from the epicentre in Ontario and Quebec and is threatening elm populations across the country. Numerous mitigation strategies have been tried to eradicate this pathogen, but success has thus far been limited. An alternative approach might utilize double-stranded RNA (dsRNA) mycoviruses which have been reported to induce hypovirulence in other fungi. METHODS: Using a modified single primer amplification technique (SPAT) in combination with chromosomal walking, we have determined the genome sequence of two RdRp encoding dsRNA viruses from an O. novo-ulmi isolate (93-1224) collected from the disease front in Winnipeg. RESULTS: We propose that these viruses, which we have named OnuMV1c and OnuMV7 based on sequence similarity to other Ophiostoma mitoviruses, are two new members of the genus Mitovirus in the family Narnaviridae. CONCLUSIONS: The discovery of such dsRNA elements raises the potential for engineering these viruses to include other genetic elements, such as anti-sense or interfering RNAs, to create novel and highly specific biological controls. Naive fungal hosts could be infected with both the engineered molecule and a helper mitovirus encoding an RdRp which would provide replication capacity for both molecules. PMID- 23924038 TI - Certainty and uncertainty: NICE guidance on 'depth of anaesthesia' monitoring. PMID- 23924037 TI - Site-specific antibody-polymer conjugates for siRNA delivery. AB - We describe here the development of site-specific antibody-polymer conjugates (APCs) for the selective delivery of small interference RNAs (siRNAs) to target cells. APCs were synthesized in good yields by conjugating an aminooxy derivatized cationic block copolymer to an anti-HER2 Fab or full-length IgG by means of genetically encoded p-acetyl phenylalanine (pAcF). The APCs all showed binding affinity comparable to that of HER2 as their native counterparts and no significant cellular cytotoxicity. Mutant S202-pAcF Fab and Q389-pAcF IgG polymer conjugates specifically delivered siRNAs to HER2(+) cells and mediated potent gene silencing at both the mRNA and protein levels. However, a mutant A121-pAcF IgG polymer conjugate, despite its high binding affinity to HER2 antigen, did not induce a significant RNA interference response in HER2(+) cells, presumably due to steric interference with antigen binding and internalization. These results highlight the importance of conjugation site on the activity of antibody-polymer based therapeutics and suggest that such chemically defined APCs may afford a useful targeted delivery platform for siRNAs or other nucleic acid-based therapies. PMID- 23924039 TI - Evidence-based guidelines for the informal use of computers by children to promote the development of academic, cognitive and social skills. AB - The use of computers in the home has become very common among young children. This paper reviews research on the effects of informal computer use and identifies potential pathways through which computers may impact children's development. Based on the evidence reviewed, we present the following guidelines to arrange informal computer experiences that will promote the development of children's academic, cognitive and social skills: (1) children should be encouraged to use computers for moderate amounts of time (2-3 days a week for an hour or two per day) and (2) children's use of computers should (a) include non violent action-based computer games as well as educational games, (b) not displace social activities but should instead be arranged to provide opportunities for social engagement with peers and family members and (c) involve content with pro-social and non-violent themes. We conclude the paper with questions that must be addressed in future research. PRACTITIONER SUMMARY: This paper reviews research on the effects of informal computer use on children's academic, cognitive and social skills. Based on the evidence presented, we have presented guidelines to enable parents, teachers and other adults to arrange informal computer experiences so as to maximise their potential benefit for children's development. PMID- 23924040 TI - "Moving forward: a cross sectional baseline study of staff and student attitudes towards a totally smoke free university campus". AB - BACKGROUND: Baseline data were collected to inform the adoption, implementation and institutionalisation phases of a completely smoke free campus policy at a large Western Australian university with a diverse student and staff community. METHODS: An online survey was randomly emailed to staff and students to measure the attitudes towards and the acceptability and enforcement of the policy prior to implementation. In total, 969 respondents completed the survey. RESULTS: General attitudes towards smoking were negative. While smokers, ex-smokers and non-smokers were supportive of smoke free policy on campus, 65.7% of respondents felt the campus should be completely smoke free. Respondents indicated a smoke free policy should be stringently enforced. The majority of respondents reported that they had been exposed to second-hand smoke on campus (n = 768; 79.5%). CONCLUSION: Theory of Organisational Change provides a useful framework to support the implementation of the completely smoke free policy in the University setting. The implementation process needs to consider the broad range of issues associated with implementing a completely smoke free policy and address issues such as safety of smokers, ensuring smokers are not marginalised and ensuring a comprehensive program is implemented. These baseline findings can be used to advocate for the implementation of a comprehensive range of strategies that recognise the addictive nature of tobacco smoking and address attitude and behaviour change, environmental adaptations and effective implementation of the policy. Administration should consider smokers and non-smokers when policy is implemented. PMID- 23924041 TI - Steric hindrance of photoswitching in self-assembled monolayers of azobenzene and alkane thiols. AB - Surface-bound azobenzenes exhibit reversible photoswitching via trans-cis photoisomerization and have been proposed for a variety of applications such as photowritable optical media, liquid crystal displays, molecular electronics, and smart wetting surfaces. We report a novel synthetic route using simple protection chemistry to form azobenzene-functionalized SAMs on gold and present a mechanistic study of the molecular order, orientation, and conformation in these self-assembled monolayers (SAMs). We use vibrational sum-frequency generation (VSFG) to characterize their vibrational modes, molecular orientation, and photoisomerization kinetics. Trans-cis conformational change of azobenzene leads to the change in the orientation of the nitrile marker group detected by VSFG. Mixed SAMs of azobenzene and alkane thiols are used to investigate the steric hindrance effects. While 100% azobenzene SAMs do not exhibit photoisomerization due to tight packing, we observe reversible switching (>10 cycles) in mixed SAMs with only 34% and 50% of alkane thiol spacers. PMID- 23924044 TI - Association of biomarkers of inflammation and cell adhesion with lung function in the elderly: a population-based study. AB - BACKGROUND: Low lung function is associated with increased morbidity and mortality. It is therefore of interest to identify biomarkers that are associated with impaired lung function. The aim of the study was to analyse associations of biomarkers and combinations of biomarkers with lung function in an elderly general population. METHODS: Lung function (FEV1 and FVC) and a panel of 15 inflammatory markers from blood samples were analysed in 888 subjects aged 70 years. Biomarkers included cytokines, chemokines, adhesion molecules, C-reactive protein (CRP) and leukocyte count. RESULTS: Leukocyte count and CRP were independently associated with FEV1 after adjustments for other inflammatory markers, sex, BMI, current smoking and pack-years of smoking. In a similar model, leukocyte count and vascular cell adhesion protein 1 (VCAM-1) were the biomarkers that were significantly associated with FVC. Subjects that had both leukocyte count and CRP in the lowest tertile had a FEV1 that was 9% of predicted higher than subjects with leukocyte count and CRP in the highest tertile (103+/-16 vs. 94+/-21% of predicted, p=0.0002) (mean+/-SD). A difference of 8% of predicted in FVC was found between subjects with leukocyte count and VCAM-1 in the lowest and highest tertiles, respectively (106+/-18 vs. 98+/-19% of predicted, p=0.002). CONCLUSION: Leucocyte count, CRP and VCAM-1 were found to relate to poorer lung function. A dose related association was found for the combination leukocyte count and CRP towards FEV1 and leukocyte and VCAM-1 towards FVC. This indicates that combination of two biomarkers yielded more information than assessing them one by one when analysing the association between systemic inflammation and lung function. PMID- 23924043 TI - Extracellular matrix determinants and the regulation of cancer cell invasion stratagems. AB - During development, wound repair and disease-related processes, such as cancer, normal, or neoplastic cell types traffic through the extracellular matrix (ECM), the complex composite of collagens, elastin, glycoproteins, proteoglycans, and glycosaminoglycans that dictate tissue architecture. Current evidence suggests that tissue-invasive processes may proceed by protease-dependent or protease independent strategies whose selection is not only governed by the characteristics of the motile cell population, but also by the structural properties of the intervening ECM. Herein, we review the mechanisms by which ECM dimensionality, elasticity, crosslinking, and pore size impact patterns of cell invasion. This summary should prove useful when designing new experimental approaches for interrogating invasion programs as well as identifying potential cellular targets for next-generation therapeutics. PMID- 23924045 TI - Metabolic assessment prior to total pancreatectomy and islet autotransplant: utility, limitations and potential. AB - Islet autotransplant (IAT) may ameliorate postsurgical diabetes following total pancreatectomy (TP), but outcomes are dependent upon islet mass, which is unknown prior to pancreatectomy. We evaluated whether preoperative metabolic testing could predict islet isolation outcomes and thus improve assessment of TPIAT candidates. We examined the relationship between measures from frequent sample IV glucose tolerance tests (FSIVGTT) and mixed meal tolerance tests (MMTT) and islet mass in 60 adult patients, with multivariate logistic regression modeling to identify predictors of islet mass >=2500 IEQ/kg. The acute C-peptide response to glucose (ACRglu) and disposition index from FSIVGTT correlated modestly with the islet equivalents per kilogram body weight (IEQ/kg). Fasting and MMTT glucose levels and HbA1c correlated inversely with IEQ/kg (r values -0.33 to -0.40, p <= 0.05). In multivariate logistic regression modeling, normal fasting glucose (<100 mg/dL) and stimulated C-peptide on MMTT >=4 ng/mL were associated with greater odds of receiving an islet mass >=2500 IEQ/kg (OR 0.93 for fasting glucose, CI 0.87-1.0; OR 7.9 for C-peptide, CI 1.75-35.6). In conclusion, parameters obtained from FSIVGTT correlate modestly with islet isolation outcomes. Stimulated C peptide >=4 ng/mL on MMTT conveyed eight times the odds of receiving >=2500 IEQ/kg, a threshold associated with reasonable metabolic control postoperatively. PMID- 23924047 TI - Toward the understanding of radical reactions: experimental and computational studies of titanium(III) diamine bis(phenolate) complexes. AB - Radical reactions of titanium(III) [Ti((tBu2)O2NN')Cl(S)] (S = THF, 1; S = py, 2; (tBu2)O2NN' = Me2N(CH2)2N(CH2-2-O-3,5-(t)Bu2C6H2)2) are described. Reactions with neutral electron acceptors led to metal oxidation to Ti(IV), [Ti((tBu2)O2NN')Cl(TEMPO)] (4) being formed with the TEMPO radical and [Ti((tBu2)O2NN')Cl2] (9) with PhN?NPh. [Ti((tBu2)O2NN')Cl2] was also formed when [Ti((tBu2)O2NN')Cl(S)] was oxidized by [Cp2Fe][BPh4], but the [Cp2Fe][PF6] analogue yielded [Ti((tBu2)O2NN')ClF] (8). The reactions of [Ti((tBu2)O2NN')Cl(S)] with O2 gave [Ti((tBu2)O2NN')Cl]2(MU-O) (3). The DFT calculated Gibbs energy for the above reaction showed it to be exergonic (DeltaG298 = -123.6 kcal.mol(-1)). [Ti((tBu2)O2NN')(CH2Ph)(S)] (S = THF, 5; py, 6) are not stable in solution for long periods and in diethyl ether gave 1:1 cocrystals of [Ti((tBu2)O2NN')(CH2Ph)2] (7) and [Ti((tBu2)O2NN')Cl]2(MU-O) (3), most probably resulting from a disproportionation process of titanium(III) followed by oxygen abstraction by the resulting Ti(II) species. The oxidation of [Ti((tBu2)O2NN')(kappa(2)-{CH2-2-(NMe2)-C6H4})] (10), which is a Ti(III) benzyl stabilized by the intramolecular coordination of the NMe2 moiety, led to a complex mixture. Recrystallization of this mixture under air led to a 1:1 cocrystal of two coordination isomers of the titanium oxo dimer (3). In one of these isomers, one metal is pentacoordinate and the dimethylamine moiety of the diamine bis(phenolate) ligand is not bonded to the metal, displaying a coordination mode of the ligand never observed before. The other titanium center is distorted octahedral with two cis-phenolate moieties. In the second unit, the coordination of the two ancillary ligands to the titanium centers reveals mutually cis-phenolate groups in one-half of the molecule and trans-coordinated in the other titanium center, keeping a distorted octahedral environment around each titanium. PMID- 23924046 TI - Technology-enhanced program for child disruptive behavior disorders: development and pilot randomized control trial. AB - Early onset disruptive behavior disorders are overrepresented in low-income families; yet these families are less likely to engage in behavioral parent training (BPT) than other groups. This project aimed to develop and pilot test a technology-enhanced version of one evidence-based BPT program, Helping the Noncompliant Child (HNC). The aim was to increase engagement of low-income families and, in turn, child behavior outcomes, with potential cost-savings associated with greater treatment efficiency. Low-income families of 3- to 8-year old children with clinically significant disruptive behaviors were randomized to and completed standard HNC (n = 8) or Technology-Enhanced HNC (TE-HNC; n = 7). On average, caregivers were 37 years old; 87% were female, and 80% worked at least part-time. More than half (53%) of the youth were boys; the average age of the sample was 5.67 years. All families received the standard HNC program; however, TE-HNC also included the following smartphone enhancements: (a) skills video series, (b) brief daily surveys, (c) text message reminders, (d) video recording home practice, and (e) midweek video calls. TE-HNC yielded larger effect sizes than HNC for all engagement outcomes. Both groups yielded clinically significant improvements in disruptive behavior; however, findings suggest that the greater program engagement associated with TE-HNC boosted child treatment outcome. Further evidence for the boost afforded by the technology is revealed in family responses to postassessment interviews. Finally, cost analysis suggests that TE HNC families also required fewer sessions than HNC families to complete the program, an efficiency that did not compromise family satisfaction. TE-HNC shows promise as an innovative approach to engaging low-income families in BPT with potential cost-savings and, therefore, merits further investigation on a larger scale. PMID- 23924048 TI - The impact of mean first-year heart rate on outcomes after heart transplantation: does it make a difference? AB - BACKGROUND: Cardiac denervation following transplantation has a variable effect on heart rate (HR), and the consequence of this is not known. We examined the impact of first-year HR on five-yr outcomes after heart transplant. METHODS: We evaluated 544 heart transplant recipients from 1994 to 2008. Patients were divided into groups by mean first-year HR: group 1, HR < 90 (mean 85.0 +/- 4.3); group 2, 90 <= HR < 110 (mean 97.8 +/- 4.9); group 3, HR >= 110 (mean 111.5 +/- 1.8). Endpoints included one-yr freedom from treated rejection, five-yr survival, five-yr freedom from cardiac allograft vasculopathy (CAV), and five-yr freedom from non-fatal major adverse cardiac events (NF-MACE). RESULTS: One-yr freedom from treated rejection, five-yr survival and freedom from CAV were not significantly different between groups. Five-yr freedom from NF-MACE was significantly lower in group 3 compared with group 2, 69% vs. 91%, p < 0.01, mainly due to higher prevalence of congestive heart failure (CHF) in group 3 over five yr. CONCLUSIONS: Mean first-year HR does not provide prognostic significance for one-yr freedom from treated rejection, five-yr survival or development of CAV five yr after heart transplant. These results suggest that HR post-heart transplantation does not affect long-term outcomes, but high first-year HRs may be associated with new-onset CHF. PMID- 23924049 TI - Effect of different ripening conditions on pigments of pepper for paprika production at green stage of maturity. AB - The content and composition of pigments and CIELab color properties in fruits ripened in the field were compared with those obtained in ground paprika produced from green pepper fruits after postharvest ripening for 15 days in a greenhouse under different conditions. Obtained data for pigment content, composition, and esterification rate have shown that the processes of pigment biosynthesis in fruits ripened under greenhouse conditions are different from those occurring in fruits naturally matured in the field: the red/yellow pigment ratio (3:1) in greenhouse-ripened fruits is much higher than in naturally ripened pepper in breaker (1:1) and also in faint red (2:1) ripening stages from the field. Additionally, during the postharvest ripening of green pepper in the greenhouse esterification processes are less expressed than during the ripening of the fruits in the field. Postharvest ripening under natural daylight resulted in higher content of red pigments, followed by higher ASTA value. PMID- 23924050 TI - A 24-week, randomized, controlled trial of rivastigmine patch 13.3 mg/24 h versus 4.6 mg/24 h in severe Alzheimer's dementia. AB - AIMS: The 24-week, prospective, randomized, double-blind ACTION study investigated the efficacy, safety, and tolerability of 13.3 versus 4.6 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease (AD). METHODS: Patients had probable AD and Mini-Mental State Examination scores >=3-<=12. Primary outcome measures were as follows: Severe Impairment Battery (SIB) and AD Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV). Secondary outcomes were as follows: ADCS-Clinical Global Impression of Change (ADCS-CGIC), 12-item Neuropsychiatric Inventory (NPI-12), and safety/tolerability. RESULTS: Of 1014 patients screened, 716 were randomized to 13.3 mg/24 h (N = 356) or 4.6 mg/24 h (N = 360) patch. Baseline characteristics/demographics were comparable. Completion rates were as follows: 64.3% (N = 229) with 13.3 mg/24 h and 65.0% (N = 234) with 4.6 mg/24 h patch. The 13.3 mg/24 h patch was significantly superior to 4.6 mg/24 h patch on cognition (SIB) and function (ADCS-ADL-SIV) at Week 16 (P < 0.0001 and P = 0.049, respectively) and 24 (primary endpoint; P < 0.0001 and P = 0.025). Significant between-group differences (Week 24) were observed on the ADCS-CGIC (P = 0.0023), not NPI-12 (P = 0.1437). A similar proportion of the 13.3 mg/24 h and 4.6 mg/24 h patch groups reported adverse events (AEs; 74.6% and 73.3%, respectively) and serious AEs (14.9% and 13.6%). CONCLUSIONS: The 13.3 mg/24 h patch demonstrated superior efficacy to 4.6 mg/24 h patch on SIB and ADCS-ADL-SIV, without marked increase in AEs, suggesting higher-dose patch has a favorable benefit-to-risk profile in severe AD. PMID- 23924051 TI - In vivo implanted bone marrow-derived mesenchymal stem cells trigger a cascade of cellular events leading to the formation of an ectopic bone regenerative niche. AB - We recently reported that mouse bone marrow stromal cells, also known as bone marrow (BM)-derived mesenchymal stem cells (MSCs), seeded onto a scaffold and implanted in vivo, led to an ectopic bone deposition by host cells. This MSCs capacity was critically dependent on their commitment level, being present only in MSCs cultured in presence of fibroblast growth factor-2. Taking advantage of a chimeric mouse model, in this study we show that seeded MSCs trigger a cascade of events resulting in the mobilization of macrophages, the induction of their functional switch from a proinflammatory to a proresolving phenotype, and the subsequent formation of a bone regenerative niche through the recruitment, within the first 2 weeks of implantation, of endothelial progenitors and of cells with an osteogenic potential (CD146+CD105+), both of them derived from the BM. Moreover, we demonstrated that, in an inflammatory environment, MSCs secrete a large amount of prostaglandin E2 playing a key role in the macrophage phenotype switch. PMID- 23924052 TI - Substance P as a mediator of neurogenic inflammation after balloon compression induced spinal cord injury. AB - Although clinical spinal cord injury (SCI) occurs within a closed environment, most experimental models of SCI create an open injury. Such an open environment precludes the measurement of intrathecal pressure (ITP), whose increase after SCI has been linked to the development of greater tissue damage and functional deficits. Raised ITP may be potentiated by edema, which we have recently shown to be associated with substance P (SP) induced neurogenic inflammation in both traumatic brain injury and stroke. The present study investigates whether SP plays a similar role as a mediator of neurogenic inflammation after SCI. A closed balloon compression injury was induced at T10 in New Zealand white rabbits. Animals were thereafter assessed for blood spinal cord barrier (BSCB) permeability, edema, ITP, histological outcome, and functional outcome from 5 h to 2 weeks post-SCI. The balloon compression model produced significant increases in BSCB permeability, edema, and ITP along with significant functional deficits that persisted for 2 weeks. Histological assessment demonstrated decreased SP immunoreactivity in the injured spinal cord while NK1 receptor immunoreactivity initially increased before returning to sham levels. In addition, aquaporin 4 immunoreactivity increased early post-SCI, implicating this water channel in the development of edema after SCI. The changes described in the present study support a role for SP as a mediator of neurogenic inflammation after SCI. PMID- 23924054 TI - Immunogenic assessment of plant-produced human papillomavirus type 16 L1/L2 chimaeras. AB - Cervical cancer is caused by infection with human papillomaviruses (HPV) and is a global concern, particularly in developing countries, which have ~80% of the burden. HPV L1 virus-like particle (VLP) type-restricted vaccines prevent new infections and associated disease. However, their high cost has limited their application, and cytological screening programmes are still required to detect malignant lesions associated with the nonvaccine types. Thus, there is an urgent need for cheap second-generation HPV vaccines that protect against multiple types. The objective of this study was to express novel HPV-16 L1-based chimaeras, containing cross-protective epitopes from the L2 minor capsid protein, in tobacco plants. These L1/L2 chimaeras contained epitope sequences derived from HPV-16 L2 amino acid 108-120, 56-81 or 17-36 substituted into the C-terminal helix 4 (h4) region of L1 from amino acid 414. All chimaeras were expressed in Nicotiana benthamiana via an Agrobacterium-mediated transient system and targeted to chloroplasts. The chimaeras were highly expressed with yields of ~1.2 g/kg plant tissue; however, they assembled differently, indicating that the length and nature of the L2 epitope affect VLP assembly. The chimaera containing L2 amino acids 108-120 was the most successful candidate vaccine. It assembled into small VLPs and elicited anti-L1 and anti-L2 responses in mice, and antisera neutralized homologous HPV-16 and heterologous HPV-52 pseudovirions. The other chimaeras predominantly assembled into capsomeres and other aggregates and elicited weaker humoral immune responses, demonstrating the importance of VLP assembly for the immunogenicity of candidate vaccines. PMID- 23924056 TI - Recreational-related head injuries in Qatar. AB - BACKGROUND: The incidence of recreation related-injuries (RRI) among the physically active population is increasing. This study aimed to analyse frequency and characteristics of RRI in Qatar. METHODS: A retrospective chart review was conducted for all patients with head injuries who sustained a RRI and were admitted to the trauma unit between 2008-2011. Patients' demographics, injuries, complications and mortality were analysed. RESULTS: Of 1665 cases of head injury, 107 (6.4%) had RRI. The majority of cases were males with mean age of 27 +/- 12, injury severity score of 14 +/- 8 and head abbreviated injury score of 3.2 +/- 0.9. Mechanisms of injury included All-Terrain Vehicle, Jet-skiing, football and water-boat. Patients sustained RRI mainly had contusion followed by subarachnoid haemorrhage, subdural and epidural haematoma. Upper extremities and the chest were the most frequently associated injuries. Severe head injuries were observed in 18% of patients with Glasgow Coma Score <8. Median length of stay was 4 (1-67) days. The incidence of RRI was highest amongst Asians (66%) and nationals (23%). The overall mortality among patients with RRI was 7%. CONCLUSION: RRI causes significant morbidity and mortality. An urgent need is recommended for legislative amendment and public awareness for safety regulations during recreational activities involving potential risk of trauma. PMID- 23924055 TI - Diffused and sustained inhibitory effects of intestinal electrical stimulation on intestinal motility mediated via sympathetic pathway. AB - OBJECTIVE: The aims were to investigate the energy-dose response effect of intestinal electrical stimulation (IES) on small bowel motility, to compare the effect of forward and backward IES, and to explore the possibility of using intermittent IES and mechanism of IES on intestinal motility. MATERIALS AND METHODS: Five dogs implanted with a duodenal cannula and one pair of intestinal serosal electrodes were studied in five sessions: 1) energy-dose response study; 2) forward IES; 3) backward IES; 4) intermittent IES vs. continuous IES; 5) administration of guanethidine. The contractile activity and tonic pressure of the small intestine were recorded. The duration of sustained effect after turning off IES was manually calculated. RESULTS: 1) IES with long pulse energy dose dependently inhibited contractile activity and tonic pressure of the small intestine (p < 0.001). 2) The duration of sustained inhibitory effect of IES on the small intestine depended on the energy of IES delivered (p < 0.001). 3) The potency of the inhibitory effect was the same between forward and backward IES. 4) The efficacy of intermittent IES was the same as continuous IES in inhibiting motility of the small intestine. 5) Guanethidine blocked the inhibitory effect of IES on intestinal motility. CONCLUSIONS: IES with long pulses inhibits small intestinal motility; the effect is energy-dose dependent, diffused, and sustained. Intermittent IES has the same efficacy as the continuous IES in inhibiting small intestinal motility. Forward and backward IES have similar inhibitory effects on small bowel motility. This IES-induced inhibitory effect is mediated via the sympathetic pathway. PMID- 23924057 TI - Comparisons of liquid and gaseous microdrops deposited on surfaces via a retreating tip. AB - The rupture of a liquid bridge has many applications while the rupture of a gaseous bridge is gaining importance in the use of bubbles to affect the speed of liquid flow over surfaces. Here, comparative experiments were conducted for liquid and gaseous bridges dispensed at fixed volumes of 6 MUL on silicone (hydrophobic) and silane coated glass (hydrophilic) surfaces and with the dispensing tip retracted at different speeds. With the liquid bridge, increasing the retracting speed left behind lower volumes on the substrate. The pinch off position and the contact line radius were factors that determined the volume. The bridge first entered into a receding state before being able to restore toward equilibrium in a relaxation process closer to rupture. On silicone the contact angle was able to undergo higher degrees of hysteresis with faster tip retraction speeds due to the lower free surface energy. With gaseous bridges, only a very small volume was left behind on the silane coated glass while the volume deposited on silicone could be tuned from almost none at low retraction speeds to virtually the entire gaseous volume bridge at high retraction speeds. The tip and neck distances from the substrate increased with tip speed until 0.5 mm/s on the silicone surface, but, beyond that, the position remained invariant until rupture. With the progress toward rupture for the gaseous bridge, the contact angle advanced rather than receded and there was no relaxation stage that brought the contact angle back toward equilibrium before rupture. Overall the gaseous bridges responded very differently to tip retraction than the liquid bridges. PMID- 23924053 TI - Differential metabolic actions of specific statins: clinical and therapeutic considerations. AB - SIGNIFICANCE: Statins, the most widely prescribed drugs in clinical practice, mainly act by reducing the plasma level of low-density lipoprotein (LDL) cholesterol. A shift in redox homeostasis to an imbalance between reactive oxygen species generation and endogenous antioxidant mechanisms results in oxidative stress that has been implicated in the pathogenesis of various diseases, including those of the cardiovascular system. Beyond their efficacy in lowering LDL cholesterol, statins modulate redox systems that are implicated in the development of atherosclerosis, cardiovascular morbidity, and mortality. RECENT ADVANCES: Differences in specific statins or their dosages result in differential metabolic actions arising from off-target or unknown mechanisms of action that can have important implications for overall patient morbidity and mortality. CRITICAL ISSUES: A recent meta-analysis and a combined analysis have suggested that high doses of statins increase the risk of developing type 2 diabetes mellitus, but reduce the risk of cardiovascular events. Thus, it is important to consider the cardiovascular and metabolic context and natural history of diseases when choosing a specific statin therapy for optimal individual patient health over the long term. FUTURE DIRECTIONS: More information is needed regarding the metabolism of statins, and the off-target or unknown actions of statins in affecting insulin resistance and metabolic homeostasis. The differential metabolic effects of specific statins should be considered in formulating optimal therapeutic strategies to reduce not just cardiovascular-related but also overall patient morbidity and mortality. PMID- 23924058 TI - Accessibility, reactivity, and selectivity of side chains within a channel of de novo peptide assembly. AB - Ab initio design of enzymes requires precise and predictable positioning of reactive functional groups within accessible and controlled environments of de novo protein scaffolds. Here we show that multiple thiol moieties can be placed within a central channel, with approximate dimensions 6 * 42 A, of a de novo, six helix peptide assembly (CC-Hex). Layers of six cysteine residues are introduced at two different sites ~6 (the "L24C" mutant) and ~17 A (L17C) from the C terminal opening of the channel. X-ray crystal structures confirm the mutant structures as hexamers with internal free thiol, rather than disulfide-linked cysteine residues. Both mutants are hexa-alkylated upon addition of iodoacetamide, demonstrating accessibility and full reactivity of the thiol groups. Comparison of the alkylation and unfolding rates of the hexamers indicates that access is directly through the channel and not via dissociation and unfolding of the assembly. Moreover, neither mutant reacts with iodoacetic acid, demonstrating selectivity of the largely hydrophobic channel. These studies show that it is possible to engineer reactive side chains with both precision and control into a de novo scaffold to produce protein-like structures with chemoselective reactivity. PMID- 23924059 TI - NaV1.7: stress-induced changes in immunoreactivity within magnocellular neurosecretory neurons of the supraoptic nucleus. AB - BACKGROUND: NaV1.7 is preferentially expressed, at relatively high levels, in peripheral neurons, and is often referred to as a "peripheral" sodium channel, and NaV1.7-specific blockers are under study as potential pain therapeutics which might be expected to have minimal CNS side effects. However, occasional reports of patients with NaV1.7 gain-of-function mutations and apparent hypothalamic dysfunction have appeared. The two sodium channels previously studied within the rat hypothalamic supraoptic nucleus, NaV1.2 and NaV1.6, display up-regulated expression in response to osmotic stress. RESULTS: Here we show that NaV1.7 is present within vasopressin-producing neurons and oxytocin-producing neurons within the rat hypothalamus, and demonstrate that the level of Nav1.7 immunoreactivity is increased in these cells in response to osmotic stress. CONCLUSIONS: NaV1.7 is present within neurosecretory neurons of rat supraoptic nucleus, where the level of immunoreactivity is dynamic, increasing in response to osmotic stress. Whether NaV1.7 levels are up-regulated within the human hypothalamus in response to environmental factors or stress, and whether NaV1.7 plays a functional role in human hypothalamus, is not yet known. Until these questions are resolved, the present findings suggest the need for careful assessment of hypothalamic function in patients with NaV1.7 mutations, especially when subjected to stress, and for monitoring of hypothalamic function as NaV1.7 blocking agents are studied. PMID- 23924061 TI - Similarities and differences of emotions in human-machine and human-human interactions: what kind of emotions are relevant for future companion systems? AB - Cognitive-technical intelligence is envisioned to be constantly available and capable of adapting to the user's emotions. However, the question is: what specific emotions should be reliably recognised by intelligent systems? Hence, in this study, we have attempted to identify similarities and differences of emotions between human-human (HHI) and human-machine interactions (HMI). We focused on what emotions in the experienced scenarios of HMI are retroactively reflected as compared with HHI. The sample consisted of N = 145 participants, who were divided into two groups. Positive and negative scenario descriptions of HMI and HHI were given by the first and second groups, respectively. Subsequently, the participants evaluated their respective scenarios with the help of 94 adjectives relating to emotions. The correlations between the occurrences of emotions in the HMI versus HHI were very high. The results do not support the statement that only a few emotions in HMI are relevant. PMID- 23924060 TI - Delta III reverse shoulder arthroplasty in the treatment of complex 3- and 4-part fractures of the proximal humerus: 6 to 42 months of follow up. AB - BACKGROUND: There is a growing tendency for complex proximal humerus fractures (PHF) in osteoporotic patients to be treated with reverse shoulder arthroplasty (RSA). It has been proposed that RSA has more benefits than other treatment options. The aim of our study was to investigate preoperative characteristics as well as clinical and radiological outcomes in patients with complex 3- or 4-part PHF who had undergone primary RSA. METHODS: Patients with a minimum follow-up of 6 months who had undergone a primary RSA after 3- or 4-part PHF in the period between 2008 and 2011 were eligible for the study. Clinical records, X-rays and CT-scans were investigated and a clinical examination was performed. Disabilities of the Arm, Shoulder and Hand (DASH) score and Constant-Murley score (CMS) were calculated. Sixteen patients were examined as part of the study. The mean follow up was 20 months (range 6-42 months). According to Codman-Hertel classification we encountered 15 Hertel "12" and 1 Hertel "8" type fractures. RESULTS: Thirty two patients (27 female - 84.4%) with a mean age of 72 years underwent operations to treat complex 3- and 4-part fractures of the proximal humerus. Sixteen patients were reexamined. In 14 cases the dominant upper extremity was on the right, in 2 cases it was on the left, in 6 cases the right side was affected and in 10 cases the left side was affected. The mean CMS was 54.8 (range 18-95) and the mean DASH was 37.5 (range 2.9-81). A trend was established between the CMS and dominance of the affected shoulder. The CMS was better if the affected shoulder was on the non-dominant side (p-value 0.051). No statistical difference was noted between age and clinical outcome. CONCLUSIONS: Our mid-term follow-up shows satisfying results in terms of the treatment of severe displaced fractures in elderly patients with RSA. RSA can provide immediate relief and good shoulder function in elderly patients. Nevertheless, the question of longevity of these implants remains to be observed. PMID- 23924063 TI - Imaging features of primary sarcomas of the great vessels in CT, MRI and PET/CT: a single-center experience. AB - BACKGROUND: To investigate the imaging features of primary sarcomas of the great vessels in CT, MRI and (18)F-FDG PET/CT. METHODS: Thirteen patients with a primary sarcoma of the great vessels were retrospectively evaluated. All available images studies including F-18 FDG PET(/CT) (n = 4), MDCT (n = 12) and MRI (n = 6) were evaluated and indicative image features of this rare tumor entity were identified. RESULTS: The median interval between the first imaging study and the final diagnosis was 11 weeks (0-12 weeks). The most frequently observed imaging findings suggestive of malignant disease in patients with sarcomas of the pulmonary arteries were a large filling defect with vascular distension, unilaterality and a lack of improvement despite effective anticoagulation. In patients with aortic sarcomas we most frequently observed a pedunculated appearance and an atypical location of the filling defect. The F-18 FDG PET(/CT) examinations demonstrated an unequivocal hypermetabolism of the lesion in all cases (4/4). MRI proved lesion vascularization in 5/6 cases. CONCLUSION: Intravascular unilateral or atypically located filling defects of the great vessels with vascular distension, a pedunculated shape and lack of improvement despite effective anticoagulation are suspicious for primary sarcoma on MDCT or MRI. MR perfusion techniques can add information on the nature of the lesion but the findings may be subtle and equivocal. F-18 FDG PET/CT may have a potential role in these patients and may be considered as part of the imaging workup. PMID- 23924064 TI - Prognostic factors affecting the clinical outcome of carcinoma ex pleomorphic adenoma in the major salivary gland. AB - BACKGROUND: Carcinoma ex pleomorphic adenoma (CXPA) is an uncommon malignant tumor with highly aggressive biological behavior. Our goal was to investigate the prognosis of CXPA in the major salivary glands and factors influencing it. METHODS: We retrospectively reviewed 51 patients diagnosed with CXPA of the major salivary glands between 1999 and 2006, comprising 36 males and 15 females, aged from 23 to 86 years. All patients underwent surgery with curative intention, and 21 received postoperative radiation therapy. RESULTS: Of the 51 patients, 39.2% developed locoregional recurrence and 27.5% developed distant metastases. Median follow-up was 54 months. At the time of analysis, 29 (56.9%) patients were deceased. Overall survival was 62.7% at 3 years and 50.3% at 5 years. Tumor specific survival was 64.4% at 3 years and 53.5% at 5 years. Using chi-squared tests, invasiveness, T stage, lymph node involvement and clinical stage were found to be significantly associated with locoregional recurrence. Histological grade, invasiveness, lymph node involvement and perineural invasion were associated with distant metastases (P < 0.05). Cox analysis showed that T stage, lymph node involvement, histological grade and perineural invasion were independent prognostic factors for overall survival. CONCLUSION: T stage, lymph node involvement, histological grade, perineural invasion and extent of invasion are important prognostic factors of CXPA in the major salivary glands. Surgery is the primary treatment modality for CXPA and postoperative radiation therapy may be used in patients with factors for poor prognosis. PMID- 23924066 TI - Alemtuzumab induction in simultaneous pancreas and kidney transplantation. AB - BACKGROUND: Alemtuzumab (AZ) is a monoclonal anti-CD52 antibody used as an induction agent in organ transplantation. Few studies have analyzed this agent in the context of simultaneous kidney-pancreas transplantation (SPKT). METHODS: We examined US registry data of SPKT recipient outcomes from January 2002 to October 2009 stratified by induction agent including AZ, other T-cell-depleting agents combined (T cell), IL2 receptor blockade (IL-2RAb), and no induction (none). RESULTS: Of 6860 SPKT recipients, induction therapy was AZ in 10%, T cell in 49%, IL-2RAb in 18%, and none in 22%. On multivariate analysis, there were no significant differences in overall patient survival, pancreas or renal allograft survival, or delayed renal graft function for the three induction groups compared with no induction. Rehospitalization within six months of transplantation occurred more often with AZ (51%) T cell (52%), and IL-2RAB (45%) compared with none (41%; p < 0.0001). On multivariate analysis, there was a significant higher odds of six-month rehospitalization with AZ (aOR 1.40, 95%CI 1.14-1.71), IL-2RAb (aOR 1.20, 95%CI 1.01-1.42-1.20), and other T-cell-depleting agents (aOR 1.50, 95%CI 1.31-1.73) compared with none. Median length of stay was significantly shorter in the AZ (8 d) compared with the IL-2RAb (9 d), T cell (10 d), and none (10 d) groups (p < 0.0001). CONCLUSIONS: There are no differences in patient, pancreas or renal allograft survival using AZ induction. AZ may confer an advantage in the perioperative period as evidenced by a decreased hospital length of stay. However, this benefit may be lost due to more frequent rehospitalizations. PMID- 23924067 TI - Dissociative photodetachment of the ethoxide anion and stability of the ethoxy radical CH3CH2O*. AB - The ethoxy radical is an important species in combustion chemistry; however, considerable debate regarding the fragmentation pathways exists. In order to examine the stability and dissociation dynamics of the ethoxy radical in the two lowest electronic states, dissociative photodetachment experiments at 3.20 eV were carried out on the ethoxide anion, CH3CH2O(-), and its per-deuterated isotopologue. Production of excited radicals by photodetachment of the alkoxide anion was found to lead to only CH3 + H2CO products, with no indication of the energetically allowed H-loss channel, H + CH3CHO. Ab initio calculations for the anionic and neutral surfaces, including relevant isomerization and dissociation barriers, were carried out using the CBS-QB3 method to aid in interpretation of the data. The energetics observed in the photoelectron-photofragment coincidence spectra indicate that the calculated barrier (0.70 eV) for the process CH3CH2O -> CH3 + H2CO and the stability of the CH3CH2O radical relative to those products are upper limits. PMID- 23924065 TI - Preventive intervention for living donor psychosocial outcomes: feasibility and efficacy in a randomized controlled trial. AB - There are no evidence-based interventions to prevent adverse psychosocial consequences after living donation. We conducted a single-site randomized controlled trial to examine the postdonation impact of a preventive intervention utilizing motivational interviewing (MI) to target a major risk factor for poor psychosocial outcomes, residual ambivalence (i.e. lingering hesitation and uncertainty) about donating. Of 184 prospective kidney or liver donors, 131 screened positive for ambivalence; 113 were randomized to (a) the MI intervention, (b) an active comparison condition (health education) or (c) standard care only before donation. Ambivalence was reassessed postintervention (before donation). Primary trial outcomes-psychosocial variables in somatic, psychological and family interpersonal relationship domains-were assessed at 6 weeks and 3 months postdonation. MI subjects showed the greatest decline in ambivalence (p = 0.050). On somatic outcomes, by 3 months postdonation MI subjects reported fewer physical symptoms (p = 0.038), lower rates of fatigue (p = 0.021) and pain (p = 0.016), shorter recovery times (p = 0.041) and fewer unexpected medical problems (p = 0.023). Among psychological and interpersonal outcomes, they had a lower rate of anxiety symptoms (p = 0.046) and fewer unexpected family-related problems (p = 0.045). They did not differ on depression, feelings about donation or family relationship quality. The findings suggest that the intervention merits testing in a larger, multisite trial. PMID- 23924068 TI - Lentivirus-activated T regulatory cells suppress T helper cell interleukin-2 production by inhibiting nuclear factor of activated T cells 2 binding to the interleukin-2 promoter. AB - Using the feline immunodeficiency virus (FIV) model for AIDS lentivirus infection, we previously demonstrated that Treg cells from FIV-infected cats up regulate membrane-associated tumor growth factor beta (mTGF-beta) during the course of infection and that activated T lymphocytes up-regulate TGF-beta receptor II (TGF-betaRII) during the course of infection. Furthermore, we have demonstrated that autologous coculture of Tregs with Th cells from FIV-infected cats leads to suppression of interleukin (IL)-2 production and loss of proliferation in a TGF-beta-dependent fashion. Nuclear factor of activated T cells (NFAT) 2 has been identified as integral to effector Th cell maturation and function by promoting IL-2 transcription. Therefore, we questioned whether NFAT2 expression might be altered by TGF-beta signaling. Feline NFAT2 exon sequences were identified based upon sequence homology to human and murine NFAT2. Following stimulation, IL-2 and NFAT2 mRNA levels were similarly increased in both FIV(-) and FIV(+) cats. Activated CD4(+)CD25(-) cells from both FIV(-) and FIV(+) cats cocultured with autologous CD4(+)CD25(+) cells or treated with TGF-beta demonstrated decreased IL-2 production; however, NFAT2 mRNA levels were unaffected. Although NFAT2 mRNA levels were unaffected, chromatin immunoprecipitation (ChIP) for NFAT2 indicated decreased NFAT2 binding at the IL 2 promoter in suppressed Th cells. These data suggest that TGF-beta-mediated Treg cell suppression of IL-2 transcription is modulated through alterations in NFAT2 binding to the IL-2 promoter. PMID- 23924070 TI - Comparison of 10% potassium hydroxide solution versus cryotherapy in the treatment of molluscum contagiosum: an open randomized clinical trial. AB - INTRODUCTION: Molluscum contagiosum (MC) is a common cutaneous viral infection. Potassium hydroxide (KOH), as a strong alkali, and cryotherapy have been used for its treatment. The objective of this study was to compare these two treatment modalities. METHODS: 30 patients, aged between 1 and 24 years of age, were randomly divided into 2 groups: 15 were treated with KOH 10% solution and 15 were treated with cryotherapy. KOH 10 % was applied by the patient or their parent(s) two times a day until the lesions disappeared completely. Cryotherapy was performed with liquid nitrogen spray, repeated weekly for 4 weeks. The assessment of response and side effects were performed weekly for 4 weeks. RESULTS: In the KOH group, 86.6% had complete response, 6.7% had partial response and 6.7% had no response after 4 weeks. In the cryotherapy group, 93.3% had complete response and 6.7% had partial response. There was no statistically significant difference between the two groups (p > 0.05). Postinflammatory hyperpigmentation, as a side effect, was mostly noted with cryotherapy. CONCLUSION: Both treatment modalities were equally effective. Since KOH is inexpensive and confers better cosmetic results compared to cryotherapy, it can be used as a suitable treatment modality for MC. PMID- 23924069 TI - The impact of previous traumatic brain injury on health and functioning: a TRACK TBI study. AB - The idea that multiple traumatic brain injury (TBI) can have a cumulative detrimental effect on functioning is widely accepted. Most research supporting this idea comes from athlete samples, and it is not known whether remote history of previous TBI affects functioning after subsequent TBI in community-based samples. This study investigates whether a previous history of TBI with loss of consciousness (LOC) is associated with worse health and functioning in a sample of individuals who require emergency department care for current TBI. Twenty three percent of the 586 individuals with current TBI in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study reported having sustained a previous TBI with LOC. Individuals with previous TBI were more likely to be unemployed (chi(2)=17.86; p=0.000), report a variety of chronic medical and psychiatric conditions (4.75<=chi(2)>=24.16; p<0.05), and report substance use (16.35<=chi(2)>=27.57; p<0.01) before the acute injury, compared to those with no previous TBI history. Those with a previous TBI had less-severe acute injuries, but experienced worse outcomes at 6-month follow-up. Results of a series of regression analyses controlling for demographics and acute injury severity indicated that individuals with previous TBI reported more mood symptoms, more postconcussive symptoms, lower life satisfaction, and had slower processing speed and poorer verbal learning, compared to those with no previous TBI history. These findings suggest that history of TBI with LOC may have important implications for health and psychological functioning after TBI in community-based samples. PMID- 23924071 TI - Bone morphogenetic protein-2/-4 upregulation promoted by endothelial cells in coculture enhances mouse embryoid body differentiation. AB - Endothelial cells (ECs) provide inductive signals for cell differentiation in vivo. However, it is unknown if these cells promote such differentiation in vitro and the signals involved. We investigated whether ECs are able to enhance the differentiation of the three germ layers and the underlying mechanisms. We established a coculture system of mouse embryoid bodies (EBs) and ECs. Then, we analyzed the expression of markers representative of the three germ layers, such as PDX-1, proinsulin, insulin1 (endoderm), nestin, neurofilament light (ectoderm), CD31, cardiotin, and cardiac troponin I (mesoderm) in EBs cultured alone (controls) or with ECs. A significant increase of these markers was observed in EBs cocultured with ECs compared to controls. The cocultured EBs also exhibited more robust vascular networks similar to those EBs treated with bone morphogenetic protein-2 or -4 (BMP-2 or -4). Therefore, the role of these peptides in the differentiation was investigated. We found a significant upregulation of BMP-2/-4 and BMP receptor 1A in EBs treated with EC conditioned medium (EC-CM) at early or middle stages of EB development. Recombinant human BMP 2 and BMP-4 exerted similar effects than EC-CM in the expression of BMPs or in the upregulation of the three germ layer specific markers. BMP-2/-4 antagonists, such as noggin and chordin-like-1, respectively inhibited the EC-CM inductive effects. These results demonstrate that ECs enhance the differentiation in vitro of cells that derived from the three germ layers and that BMP-2/-4 play a central role in this process. PMID- 23924072 TI - Synthesis and structural characterization of base-stabilized oligomeric heterovinylidenes. AB - Metalation of the (iminophosphoranyl)phosphine PPh2CH2(PPh2?NSiMe3) (1) with an equimolar amount of n-BuLi afforded the monolithium salt [Li{CH(PPh2)(PPh2?NSiMe3)}(THF)2] (2). The reaction of 2 with GeCl2.1,4-dioxane has led to the formation of a germavinylene moiety, which trimerized to form a new heterocyclic cage compound, [{(PPh2?NSiMe3)(PPh2)C?Ge:}{(PPh2?NSiMe3)(PPh2)C}2Ge->Ge:] (3). A similar reaction of the lithium methanide complex 2 with SnCl2 afforded the stannavinylidene moiety, which underwent a "head-to-tail" cycloaddition to form a stable 1,3-distannacyclobutane, 4. A trapping reaction of 4 with diiron nonacarbonyl gave the novel iron stannavinylidene complex 5. The solid-state structure analysis of 5 reveals that it contains two stannavinylidene moieties bonded in a Sn-P "head-to-tail" fashion, with one of the tin(II) centers coordinating to a Fe(CO)4 moiety. The X-ray structures of 2-5 have been determined by X-ray crystallography. In addition, the dynamic behavior of 5 has been studied by means of variable-temperature (31)P and (119)Sn NMR spectroscopy. PMID- 23924073 TI - Merely misunderstood? Receptive, expressive, and pragmatic language in young children with disruptive behavior disorders. AB - Children with disruptive behavior disorders (DBDs) often seem to have poorer language skills compared to same-age peers; however, language as an early risk factor for DBD has received little empirical attention. The present study provides an empirical examination of associations between normal language variation and DBD by investigating receptive, expressive, and pragmatic language skills and preschool DBD symptoms. The sample consisted of 109 preschoolers ages 3 to 6 (M = 4.77 years, SD = 1.10, 59% boys; 73% with DBD, including oppositional defiant disorder [ODD] and attention-deficit/hyperactivity disorder [ADHD]) along with their primary caregivers, who completed a clinician-administered interview, symptom questionnaires, and a questionnaire measure of pragmatic language, and teacher and/or daycare providers completed symptom questionnaires. Children completed objective tests of receptive and expressive vocabulary. Preschoolers with DBD showed poorer receptive, expressive, and pragmatic skills compared to preschoolers without DBD. Preschoolers with ADHD-only or ADHD+ODD exhibited poorer language skills, compared to ODD and non-DBD groups. Specificity analyses suggested that parent-rated hyperactivity-impulsivity were particularly associated with poorer language skills. Thus, preschoolers with DBD exhibited poorer language skills compared to preschoolers without DBD, and preschoolers with increased hyperactivity-impulsivity exhibited particular problems with language skills. This work suggests the need for early assessment of language in preschoolers, particularly those with ADHD, as well as the possible utility of tailored interventions focused on improving language skills, particularly for those with high hyperactivity-impulsivity. PMID- 23924074 TI - Identification and characterization of OsEBS, a gene involved in enhanced plant biomass and spikelet number in rice. AB - Common wild rice (Oryza rufipogon Griff.) is an important genetic reservoir for rice improvement. We investigated a quantitative trait locus (QTL), qGP5-1, which is related to plant height, leaf size and panicle architecture, using a set of introgression lines of O. rufipogon in the background of the Indica cultivar Guichao2 (Oryza sativa L.). We cloned and characterized qGP5-1 and confirmed that the newly identified gene OsEBS (enhancing biomass and spikelet number) increased plant height, leaf size and spikelet number per panicle, leading to an increase in total grain yield per plant. Our results showed that the increased size of vegetative organs in OsEBS-expressed plants was enormously caused by increasing cell number. Sequence alignment showed that OsEBS protein contains a region with high similarity to the N-terminal conserved ATPase domain of Hsp70, but it lacks the C-terminal regions of the peptide-binding domain and the C-terminal lid. More results indicated that OsEBS gene did not have typical characteristics of Hsp70 in this study. Furthermore, Arabidopsis (Arabidopsis thaliana) transformed with OsEBS showed a similar phenotype to OsEBS-transgenic rice, indicating a conserved function of OsEBS among plant species. Together, we report the cloning and characterization of OsEBS, a new QTL that controls rice biomass and spikelet number, through map-based cloning, and it may have utility in improving grain yield in rice. PMID- 23924075 TI - Reversible nerve conduction block using kilohertz frequency alternating current. AB - OBJECTIVES: The features and clinical applications of balanced-charge kilohertz frequency alternating currents (KHFAC) are reviewed. Preclinical studies of KHFAC block have demonstrated that it can produce an extremely rapid and reversible block of nerve conduction. Recent systematic analysis and experimentation utilizing KHFAC block have resulted in a significant increase in interest in KHFAC block, both scientifically and clinically. MATERIALS AND METHODS: We review the history and characteristics of KHFAC block, the methods used to investigate this type of block, the experimental evaluation of block, and the electrical parameters and electrode designs needed to achieve successful block. We then analyze the existing clinical applications of high-frequency currents, comparing the early results with the known features of KHFAC block. RESULTS: Although many features of KHFAC block have been characterized, there is still much that is unknown regarding the response of neural structures to rapidly fluctuating electrical fields. The clinical reports to date do not provide sufficient information to properly evaluate the mechanisms that result in successful or unsuccessful treatment. CONCLUSIONS: KHFAC nerve block has significant potential as a means of controlling nerve activity for the purpose of treating disease. However, early clinical studies in the use of high-frequency currents for the treatment of pain have not been designed to elucidate mechanisms or allow direct comparisons to preclinical data. We strongly encourage the careful reporting of the parameters utilized in these clinical studies, as well as the development of outcome measures that could illuminate the mechanisms of this modality. PMID- 23924077 TI - Low-density lipoprotein-cholesterol-induced endothelial dysfunction and oxidative stress: the role of statins. AB - SIGNIFICANCE: Cardiovascular diseases (CVD) represent a major public health burden. High low-density lipoprotein (LDL)-cholesterol is a recognized pathogenic factor for atherosclerosis, and its complications and statins represent the most potent and widely used therapeutic approach to prevent and control these disorders. RECENT ADVANCES: A number of clinical and experimental studies concur to identify endothelial dysfunction as a primary step in the development of atherosclerosis, as well as a risk factor for subsequent clinical events. Oxidant stress resulting from chronic elevation of plasma LDL-cholesterol (LDL-chol) is a major contributor to both endothelial dysfunction and its complications, for example, through alterations of endothelial nitric oxide signaling. CRITICAL ISSUES: Statin treatment reduces morbidity and mortality of CVD, but increasing evidence questions that this is exclusively through reduction of plasma LDL-chol. The identification of ancillary effects on (cardio)vascular biology, for example, through their modulation of oxidative stress, will not only increase our understanding of their mechanisms of action, with a potential broadening of their indication(s), but also lead to the identification of new molecular targets for future therapeutic developments in CVD. FUTURE DIRECTIONS: Further characterization of molecular pathways targeted by statins, for example, not directly mediated by changes in plasma lipid concentrations, should enable a more comprehensive approach to the pathogenesis of (cardio)vascular disease, including, for example, epigenetic regulation and fine tuning of cell metabolism. PMID- 23924078 TI - Double-gate light-emitting electrochemical transistor: confining the organic p-n junction. AB - In conventional light-emitting electrochemical cells (LECs), an off-centered p-n junction is one of the major drawbacks, as it leads to exciton quenching at one of the charge-injecting electrodes and results in performance instability. To combat this problem, we have developed a new device configuration, the double gate light-emitting electrochemical transistor (DG-LECT), in which the location of the light-emitting p-n junction can be precisely defined via the position of the two gate terminals. Based on a planar LEC structure, two gate electrodes made from an electrochemically active conducting polymer are employed to predefine the p- and n-doped area of the light-emitting polymer. Thus, a p-n junction is formed in between the p-doped and n-doped regions. We demonstrate a homogeneous and centered p-n junction as well as other predefined junction patterns in these DG LECT devices. Additionally, we report an electrical model that explains the operation of the DG-LECTs. The DG-LECT device provides a new tool to study the fundamental physics of LECs, as it dissects the key working process of LEC into decoupled p-doping, n-doping, and electroluminescence. PMID- 23924076 TI - Acute and chronic phases of complex regional pain syndrome in mice are accompanied by distinct transcriptional changes in the spinal cord. AB - BACKGROUND: CRPS is a painful, debilitating, and often-chronic condition characterized by various sensory, motor, and vascular disturbances. Despite many years of study, current treatments are limited by our understanding of the underlying mechanisms. Little is known on the molecular level concerning changes in gene expression supporting the nociceptive sensitization commonly observed in CRPS limbs, or how those changes might evolve over time. RESULTS: We used a well characterized mouse tibial fracture/cast immobilization model of CRPS to study molecular, vascular and nociceptive changes. We observed that the acute (3 weeks after fracture) and chronic (7 weeks after fracture) phases of CRPS-like changes in our model were accompanied by unique alterations in spinal gene expression corresponding to distinct canonical pathways. For the acute phase, top regulated pathways were: chemokine signaling, glycogen degradation, and cAMP-mediated signaling; while for the chronic phase, the associated pathways were: coagulation system, granzyme A signaling, and aryl hydrocarbon receptor signaling. We then focused on the role of CcL2, a chemokine that we showed to be upregulated at the mRNA and protein levels in spinal cord tissue in our model. We confirmed its association with the nociceptive sensitization displayed in this model by demonstrating that the spinal but not peripheral administration of a CCR2 antagonist (RS504393) in CRPS animals could decrease mechanical allodynia. The spinal administration of CcL2 itself resulted in mechanical allodynia in control mice. CONCLUSIONS: Our data provide a global look at the transcriptional changes in the spinal cord that accompany the acute and chronic phases of CRPS as modeled in mice. Furthermore, it follows up on one of the top-regulated genes coding for CcL2 and validates its role in regulating nociception in the fracture/cast model of CRPS. PMID- 23924079 TI - Developing cohesive and strategic communication research. PMID- 23924080 TI - Children with cerebral palsy are just like everyone else: what you train is what you get. PMID- 23924081 TI - How the imaging investigation of EAST syndrome points towards the future of radiological multi-parametric phenotyping of a genetic disease. PMID- 23924082 TI - One side or two? PMID- 23924083 TI - Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome. AB - AIM: Recently, we reported a previously unrecognized symptom constellation comprising epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) associated with recessive mutations in the KCNJ10 gene. Here, we provide a detailed characterization of the clinical features of the syndrome to aid patient management with respect to diagnosis, prognostic counselling, and identification of best treatment modalities. METHOD: We conducted a retrospective review of the detailed neurological and neuroradiological features of nine children (four females, five males; age range at last examination 6-20y) with genetically proven EAST syndrome. RESULTS: All children presented with tonic clonic seizures in infancy. Later, non-progressive, cerebellar ataxia and hearing loss were noted. Whilst seizures mostly responded well to treatment, ataxia proved to be the most debilitating feature, with three patients non-ambulant. All available magnetic resonance imaging (MRI) revealed subtle symmetrical signal changes in the cerebellar dentate nuclei. Moreover, four patients had a small corpus callosum and brainstem hypoplasia, and three had a small spinal cord. Regional quantitative volumetric analysis of the images confirmed the corpus callosum and brainstem hypoplasia and showed further patterns of variation from the norm. INTERPRETATION: The neurological features of EAST syndrome appear to be non-progressive, which is important for prognostic counselling. The spectrum of EAST syndrome includes consistent abnormalities on brain MRI, which may aid diagnosis. Further longitudinal documentation is required to determine the true natural history of the disorder. PMID- 23924084 TI - Cross-parent reliability in rating ASD markers in infants. AB - OBJECTIVE: To investigate the congruence and discrepancies between mother and father reports of early autism spectrum disorders (ASD) markers. METHODS: Mothers (n = 80) and fathers (n = 78) of 12-month-old infants (55% boys) completed the first year inventory (FYI), an ASD norm-referenced screening questionnaire. Mothers also completed the Infant Toddler Social Emotional Assessment (ITSEA). RESULTS: There were significant and moderate intra-class correlations between mother and father reports for most FYI factors. Fathers' median FYI social communication domain score was almost twice that of mothers. Mann-Whitney tests indicated that fathers rated their child significantly higher than mothers on the four FYI social-communication factors and on the sensory processing factor. Linear weighted kappa analyses indicated poor agreement on gaze-related and reactivity FYI items. FYI social-communication and sensory-regulatory factors showed significant correlations with corresponding ITSEA scores. CONCLUSIONS: Social-communication markers pose a greater challenge for consistent report across parents than sensory-regulatory markers. PMID- 23924086 TI - Levothyroxine and lung cancer in females: the importance of oxidative stress. AB - BACKGROUND: Levothyroxine (LT4) treatment can lead to iatrogenic hyperthyroidism and oxidative stress that can cause patient discomfort. Oxidative stress is also recognized as one of the causes of chronic diseases and cancer. METHODS: The prevalence of breast, colorectal, gastric and lung cancer in 18 Italian Regions during 2010 was correlated with the sales of LT4 in 2009. The cancer prevalence was analyzed in women aged 30-84. This age range corresponds to more than 80% of the consumers of the drug and to about 99% of all malignant cancers. The correlation between sales of LT4 and cancers was determined with the technique of Density Ellipses. The age and smoking contribution for lung cancer was determined with the Sequential test. RESULTS: No significant correlation was seen between LT4 sales and breast, colorectal and gastric cancers. A significant correlation was instead found for lung cancer (p<0.05) corrected for smoking and age. CONCLUSIONS: LT4 consumption in Italy is about 0.7 boxes/women/year. There is a correlation between lung cancer and LT4 treatment and oxidative stress caused by LT4 supplementation can be one of the causes. Although we cannot exclude that dysthyroidism needing LT4 supplementation might be the ground for lung cancer itself and measuring oxidative stress could be helpful in avoiding excessive use of the drug. PMID- 23924085 TI - Brain-derived neurotrophic factor (Val66Met) polymorphism and olfactory ability in young adults. AB - BACKGROUND: Brain- derived neurotrophic factor (BDNF) is linked to neurodegenerative diseases (e.g. Alzheimer disease and Parkinson disease) which are often characterized by olfactory impairment. A specific single nucleotide polymorphism of the BDNF gene, the Val66Met, modulates intracellular trafficking and activity-dependent secretion of BDNF protein. The aim of this study was to investigate a possible association between brain- derived neurotrophic factor Val66Met polymorphism and olfactory function, a well-known biomarker for neurodegeneration, in healthy young adults. A total of 101 subjects (45 males, age 38.7 +/- 9.4 years) were assessed using the Sniffin' Sticks Extended Test, a highly reliable commercial olfactory test composed of three sub-parts, calculating olfactory threshold (sensitivity), odor discrimination and odor identification. The Val66Met polymorphism was determined by polymerase chain reaction -restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: An impaired function in Met carriers was found, especially when compared to subjects with Val/Val genotype, in the threshold (5.5 +/- 2.0 vs 6.5 +/- 1.8, p = 0.009), discrimination (10.3+/- 2.5 vs 11.9 +/- 2.2, p = 0.002), and identification task (13.3 +/- 1.6 vs 14.1 +/- 1.3, p = 0.007), as well as in the overall TDI Score (29.1 +/- 4.5 vs 32.6 +/- 3.9, p < 0.001). CONCLUSIONS: These findings appear to have implications for the evaluation of olfactory function and the relation of its impairment to cognitive decline and neurodegenerative disease. PMID- 23924103 TI - Squeeze on social care budgets leaves nurses to fill in the gaps. PMID- 23924087 TI - Avoid the vital issue of funding at your peril. PMID- 23924110 TI - 'It is a privilege to be recognised'. PMID- 23924111 TI - More than just a listening ear. PMID- 23924127 TI - ICN withdrawal does not mean an end to the RCN's global work. PMID- 23924126 TI - How could we honour the memory of nurse Jacintha? PMID- 23924128 TI - Our avalanche helped to expose health secretary's unlawful act. PMID- 23924129 TI - Lewisham ruling is a great triumph for the community. PMID- 23924133 TI - Don't overlook psychological care in paracetamol overdose. PMID- 23924135 TI - Causes and consequences of sleep deprivation in hospitalised patients. AB - Sleep is a fundamental component of good health, however its promotion in acute hospital settings does not appear to be a priority. This literature review, which considered qualitative and quantitative research methodology, aimed to determine the factors that affect the quality of sleep experienced by patients in hospital, and the effects of sleep deprivation on the health and wellbeing of these individuals. Causes of sleep disruption are varied and include environmental and bio-cognitive factors, including pain, bright light, noise, anxiety and stress. The environmental and bio-cognitive consequences of sleep deprivation on the health and recovery of hospital inpatients are outlined. PMID- 23924136 TI - Informed consent in clinical research. AB - Since increasing numbers of patients are asked to take part in clinical trials, nurses need to be aware of the principles of valid, informed consent. This article explores consent, which aims to protect the rights, safety and wellbeing of patients. In particular, the history of consent in research and the elements involved in obtaining informed consent from potential participants in research studies are discussed. PMID- 23924137 TI - Diagnosis and management of patients with bronchiectasis. AB - Diagnosis of bronchiectasis should be considered in individuals presenting with respiratory symptoms similar to asthma and chronic obstructive pulmonary disease that have not responded to usual treatment. This article provides an overview of the prevalence, diagnosis and management of bronchiectasis to inform nursing care and improve patient outcomes. PMID- 23924138 TI - Nutrition and hydration. PMID- 23924139 TI - Midwife on a mission. PMID- 23924141 TI - Use your influence for good. PMID- 23924143 TI - Student life - try this for an experience. PMID- 23924145 TI - Ultrasensitive molecular detection using thermal conductance of a hydrophobic gold-water interface. AB - The thermal conductance from a hydrophobic gold aqueous interface is measured with increasing solute concentration. A small amount of aqueous solute molecules (1 solute molecule in 550 water molecules) dramatically increases the heat dissipation into the surrounding liquid. This result is consistent with a thermal conductance that is limited by an interface interaction where minority aqueous components significantly alter the surface properties and heat transport through the interface. The increase in heat dissipation can be used to make an extremely sensitive molecular detector that can be scaled to give single molecule detection without amplification or utilizing fluorescence labels. PMID- 23924144 TI - Effects of neuromuscular training (NEMEX-TJR) on patient-reported outcomes and physical function in severe primary hip or knee osteoarthritis: a controlled before-and-after study. AB - BACKGROUND: The benefits of exercise in mild and moderate knee or hip osteoarthritis (OA) are apparent, but the evidence in severe OA is less clear. We recently reported that neuromuscular training was well tolerated and feasible in patients with severe primary hip or knee OA. The aims of this controlled before and-after study were to compare baseline status to an age-matched population based reference group and to examine the effects of neuromuscular training on patient-reported outcomes and physical function in patients with severe primary OA of the hip or knee. METHODS: 87 patients (60-77 years) with severe primary OA of the hip (n = 38, 55% women) or knee (n = 49, 59% women) awaiting total joint replacement (TJR) had supervised, neuromuscular training (NEMEX-TJR) in groups with individualized level and progression of training. A reference group (n = 43, 53% women) was included for comparison with patients' data. Assessments included self-reported outcomes (HOOS/KOOS) and measures of physical function (chair stands, number of knee bends/30 sec, knee extensor strength, 20-meter walk test) at baseline and at follow-up before TJR. Analysis of covariance (ANCOVA) was used for comparing patients and references and elucidating influence of demographic factors on change. The paired t-test was used for comparisons within groups. RESULTS: At baseline, patients reported worse scores than the references in all HOOS/KOOS subscales (hip 27-47%, knee 14-52%, of reference scores, respectively) and had functional limitations (hip 72-85%, knee 42-85%, of references scores, respectively). NEMEX-TJR (mean 12 weeks (SD 5.6) of training) improved self reported outcomes (hip 9-29%, knee 7-20%) and physical function (hip 3-18%, knee 5-19%) (p < 0.005). Between 42% and 62% of hip OA patients, and 39% and 61% of knee OA patients, displayed a clinically meaningful improvement (>=15%) in HOOS/KOOS subscales by training. The improvement in HOOS/KOOS subscale ADL was greater for patients with knee OA than hip OA, while the improvement in subscale Sport/Rec was greater for patients with hip OA than knee OA. CONCLUSIONS: Both self-reported outcomes and physical function were clearly worse compared with the reference group. Neuromuscular training with an individualized approach and gradual progression showed promise for improving patient-reported outcomes and physical function even in older patients with severe primary OA of the hip or knee. PMID- 23924146 TI - Delayed allograft inflammation following alemtuzumab induction for kidney transplantation. AB - BACKGROUND: In a recent clinical trial in kidney transplant recipients, induction with alemtuzumab and rabbit-antithymocyte globulin (r-ATG) was equally effective in preventing rejection during the first post-transplant year; however, this study did not include protocol biopsies. METHODS: The aim of this study was to analyze the impact of alemtuzumab induction on rejection and subclinical inflammation during the first post-transplant year compared with a historic control group receiving induction with r-ATG. All patients received tacrolimus and mycophenolate mofetil (MMF). RESULTS: There were 361 in the alemtuzumab group and 478 in the r-ATG groups. Rejection (excluding Banff borderline), during the first year, occurred in 14% of the alemtuzumab group and 9% of the r-ATG group (p = 0.03). Estimated glomerular filtration rate (GFR) (chronic kidney disease (CKD) EPI formula) at one yr and graft survival at three yr were similar. On the protocol biopsies, interstitial inflammation (Banff i scores) and tubulitis (Banff t scores) were more likely in the r-ATG group at one month, but at four and 12 months, both inflammation and tubulitis were more likely in the alemtuzumab group. CONCLUSIONS: We conclude that alemtuzumab induction is associated with delayed inflammation at four and 12 months, but this inflammation did not appear to negatively impact the GFR or graft survival. PMID- 23924147 TI - Angiotensin II Type 1 receptor antibodies: great expectations? PMID- 23924148 TI - Scaling normal adhesion force capacity with a generalized parameter. AB - The adhesive response of a rigid flat cylindrical indenter in contact with a compliant elastic layer of varying confinement is investigated experimentally and described analytically. Using a soft elastic gel with substrate thickness, t, and indenter radius, a, 28 unique combinations of the confinement parameter, a/t, are examined over a range of 0.016 < a/t < 7.2. Continuous force capacity predictions as a function of a/t and material properties are provided through a scaling theory and are found to agree well with the experimental data. We further collapse all of the data over orders of magnitude in adhesive force capacity onto a single line described by a generalized reversible adhesion scaling parameter, A/C, where A is the contact area and C is the compliance. As the scaling analysis does not assume a specific separation mechanism the adhesive force capacity is well described during both axisymmetric edge separation and during interfacial fingering and cavitation instabilities. We discuss how the geometry of the contact, specifically increasing the degree of confinement, allows reversible adhesive materials to be designed that are not "sticky" or "tacky", yet can be very strong and provide high performance. PMID- 23924149 TI - Thyrotropin signaling confers more aggressive features with higher genomic instability on BRAF(V600E)-induced thyroid tumors in a mouse model. AB - BACKGROUND: The BRAF(V600E) mutation is the most common genetic alteration in papillary thyroid carcinomas (PTCs). Transgenic mice overexpressing BRAF(V600E) in their thyroids under control of the thyroglobulin promoter (Tg-BRAF2 mice) developed invasive PTCs with high penetrance. However, these mice showed elevated thyrotropin (TSH) levels, which also stimulate the proliferation of thyrocytes and tumorigenesis. The purpose of the present study was to investigate how TSH signaling cooperates with BRAF(V600E) in the process of thyroid carcinogenesis. METHODS: We crossed Tg-BRAF2 mice with TSH receptor knockout (TshR(-/-)) mice. Four genetically distinct mice groups-Braf(wt)/TshR(+/-) (group 1), Braf(wt)/TshR(-/-) (group 2), Tg-BRAF2/TshR(+/-) (group 3), and Tg-BRAF2/TshR(-/ ) (group 4)--were sacrificed at 12 and 24 weeks of age. We performed histopathological analysis. Genomic instability was evaluated by immunofluorescence for p53-binding protein 1 (53BP1) and gammaH2AX. Invasiveness and genomic instability were also evaluated using thyroid PCCL3 cells expressing BRAF(V600E). RESULTS: Groups 3 and 4 developed distinct neoplasias comparable to human PTCs. Group 3 developed typically larger, more aggressive, invasive tumors compared to group 4. The frequency of 53BP1 and gammaH2AX foci-indicators of genomic instability--in group 3 was higher than that in group 4. TSH also enhanced invasiveness and genomic instability in PCCL3 cells with BRAF(V600E) expression. CONCLUSIONS: These data demonstrate that the TSH signaling confers more aggressive features in BRAF(V600E)-induced thyroid tumors in mice. This might be due, in part, to accelerated genomic instability. PMID- 23924150 TI - Correlated diffusion imaging. AB - BACKGROUND: Prostate cancer is one of the leading causes of cancer death in the male population. Fortunately, the prognosis is excellent if detected at an early stage. Hence, the detection and localization of prostate cancer is crucial for diagnosis, as well as treatment via targeted focal therapy. New imaging techniques can potentially be invaluable tools for improving prostate cancer detection and localization. METHODS: In this study, we introduce a new form of diffusion magnetic resonance imaging called correlated diffusion imaging, where the tissue being imaged is characterized by the joint correlation of diffusion signal attenuation across multiple gradient pulse strengths and timings. By taking into account signal attenuation at different water diffusion motion sensitivities, correlated diffusion imaging can provide improved delineation between cancerous tissue and healthy tissue when compared to existing diffusion imaging modalities. RESULTS: Quantitative evaluation using receiver operating characteristic (ROC) curve analysis, tissue class separability analysis, and visual assessment by an expert radiologist were performed to study correlated diffusion imaging for the task of prostate cancer diagnosis. These results are compared with that obtained using T2-weighted imaging and standard diffusion imaging (via the apparent diffusion coefficient (ADC)). Experimental results suggest that correlated diffusion imaging provide improved delineation between healthy and cancerous tissue and may have potential as a diagnostic tool for cancer detection and localization in the prostate gland. CONCLUSIONS: A new form of diffusion magnetic resonance imaging called correlated diffusion imaging (CDI) was developed for the purpose of aiding radiologists in cancer detection and localization in the prostate gland. Preliminary results show CDI shows considerable promise as a diagnostic aid for radiologists in the detection and localization of prostate cancer. PMID- 23924151 TI - Cl...Cl interactions in molecular crystals: insights from the theoretical charge density analysis. AB - The structure, IR harmonic frequencies and intensities of normal vibrations of 20 molecular crystals with the X-Cl...Cl-X contacts of different types, where X = C, Cl, and F and the Cl...Cl distance varying from ~3.0 to ~4.0 A, are computed using the solid-state DFT method. The obtained crystalline wave functions have been further used to define and describe quantitatively the Cl...Cl interactions via the electron-density features at the Cl...Cl bond critical points. We found that the electron-density at the bond critical point is almost independent of the particular type of the contact or hybridization of the ipso carbon atom. The energy of Cl...Cl interactions, E(int), is evaluated from the linking E(int) and local electronic kinetic energy density at the Cl...Cl bond critical points. E(int) varies from 2 to 12 kJ/mol. The applicability of the geometrical criterion for the detection of the Cl...Cl interactions in crystals with two or more intermolecular Cl...Cl contacts for the unique chlorine atom is not straightforward. The detection of these interactions in such crystals may be done by the quantum-topological analysis of the periodic electron density. PMID- 23924152 TI - Increased population use of medications for male lower urinary tract symptoms/benign prostatic hyperplasia correlates with changes in indications for transurethral resection of the prostate. AB - OBJECTIVE: The aim of this study was to determine whether there are correlations between medication use for lower urinary tract symptoms/benign prostate hypertrophy (LUTS/BPH) and alteration in incidence and indications for transurethral resection of the prostate (TURP). MATERIAL AND METHODS: The number of TURP patients between 1984 and 2008 in Iceland was obtained from hospital registries. The number of defined daily doses (DDDs) of 5-alpha-reductase inhibitors (5aRIs) and alpha-blockers (ABs) sold was obtained from the Icelandic Medicines Control Agency. Charts of all surgical BPH patients in Iceland from 1998 to 2008 were retrospectively reviewed. The main outcomes measures were: DDDs sold of 5aRIs and ABs, total numbers of TURP, indications for TURP and complications. RESULTS: After the introduction of ABs and 5aRIs, sales increased annually at a near linear rate. TURP rates peaked in 1992, then declined. In 2008, 81 and 3.4 of 1000 men over the age of 50 used LUTS/BPH medications or underwent TURP, respectively. There was an inverse correlation between LUTS/BPH medication use and (i) overall TURP (R(2) = 0.85), (ii) TURP done for absolute indications (R(2) = 0.91), and (iii) LUTS with (R(2) = 0.77) and (iv) without previous medical therapy (R(2) = 0.75). As medication use rose, fewer TURPs were performed for previous history of urinary retention, and more for recurrent urinary tract infections. CONCLUSION: Increased use of ABs and 5aRIs in the Icelandic population correlated with decreasing incidences of TURP procedures for both LUTS and absolute indications. The sequelae of BPH and indications for TURP are changing as medication use increases, although a clear causative link is hard to establish. PMID- 23924153 TI - Fabrication of multifunctional Gd2O3/Au hybrid nanoprobe via a one-step approach for near-infrared fluorescence and magnetic resonance multimodal imaging in vivo. AB - Facile fabrication of multimodal imaging probes is highly desired for bioimaging application due to their integrated advantages of several imaging modalities. Here, we report a simple and one-step mild strategy to fabricate a multifunctional Gd2O3/Au hybrid nanoprobe. Bovine serum albumin (BSA) was used as the template in the biomineralization synthesis. The fabricated BSA-Gd2O3/Au nanoprobe showed excellent chemical stability, intense near-infrared (NIR) fluorescence, and good magnetic resonance imaging (MRI) ability. The multimodal imaging potential of the prepared multifunctional nanoprobe was demonstrated by successful NIR fluorescent and magnetic resonance blood pool imaging. Further modification of BSA-Gd2O3/Au with arginine-glycine-aspartic acid peptide c(RGDyK) (RGD) enabled the nanoprobe for targeted tumor imaging in vivo. PMID- 23924155 TI - Spinal cord stimulators: socioeconomic disparities in four US states. AB - OBJECTIVES: Spinal cord stimulators (SCS) are increasingly placed in the United States in both the inpatient and outpatient setting. Although these interventions appear to be safe, the characteristics of the patients selected for ambulatory procedures have not been investigated. MATERIALS AND METHODS: We performed a retrospective cohort study involving 4843 patients who underwent outpatient and 4197 who underwent inpatient SCS placements and were registered in State Ambulatory Surgery Databases and State Inpatient Databases, respectively, for New York, California, Florida, and North Carolina from 2005 to 2008. RESULTS: In a multivariate analysis, male gender (odds ratio (OR) 1.22, 95% confidence interval (CI), 1.12, 1.33), high volume hospitals (OR 2.16, 95% CI, 1.94, 2.41), and Caucasian race (OR 1.25, 95% CI, 1.10, 1.41) were significantly associated with outpatient procedures. Higher Charlson Comorbidity Index (OR 0.36, 95% CI, 0.24, 0.54) and Medicare/Medicaid insurance (OR 0.75, 95% CI, 0.67, 0.83) were associated with a decreased chance of outpatient procedures. The rate of 30-day postoperative readmissions was higher among inpatients. Institutional charges were significantly lower for outpatient lumbar discectomies. The median total charge for inpatient hospitalization after SCS placement was $60,624 as compared with $22,288 for the outpatient setting (p < 0.0001). CONCLUSIONS: Access to ambulatory SCS placement appears to be more common for Caucasians, male patients, with private insurance, and fewer comorbidities, in the setting of higher volume hospitals. Further investigation is needed in the direction of mapping these disparities for appropriate resource utilization. PMID- 23924154 TI - HIV type 1 infection of plasmacytoid and myeloid dendritic cells is restricted by high levels of SAMHD1 and cannot be counteracted by Vpx. AB - Dendritic cells are professional antigen-presenting cells of the immune system and are major producers of type-I interferon. Their role in HIV-1 infection is not well understood. They express CD4 and CCR5 yet appear to be resistant to infection. In culture, infection of the cells with HIV-1 is inhibited by the host cell restriction factor SAMHD1. Lentiviruses such as HIV-2/SIVmac counteract the restriction by encoding Vpx, a virion-packaged accessory protein that induces the proteasomal degradation of SAMHD1. In this study we investigated SAMHD1-mediated restriction in the two major dendritic cell subsets: plasmacytoid dendritic cells (pDC) and myeloid dendritic cells (mDC). The cells were highly resistant to HIV-1 and expressed high levels of SAMHD1. SAMHD1 amino acid residue T592, a target of CDK1 phosphorylation, was unphosphorylated, corresponding to the antiviral form of the enzyme. The resistance to infection was not counteracted by Vpx and SAMHD1 was not degraded in these cells. Treatment of pDCs with a cocktail of antibodies that blocked type-I interferon signaling partially restored the ability of Vpx to induce SAMHD1 degradation and caused the cells to become partially permissive to infection. pDCs and mDCs responded to HIV-1 virions by inducing an innate immune response but did not appear to sense newly produced Gag protein. The findings suggest that in vivo, dendritic cells serve as sentinels to alert the immune system to the virus but do not themselves become infected by virtue of high levels of SAMHD1. PMID- 23924156 TI - Detecting feigned ADHD in later adolescence: an examination of three PAI-A negative distortion indicators. AB - The validity of various indicators of response distortion on the Personality Assessment Inventory-Adolescent (PAI-A; Morey, 2007a) and its potential usefulness to detect malingering were evaluated by having 17- and 18-year-old students complete the PAI-A attempting to simulate Attention Deficit/Hyperactivity Disorder (ADHD) under coached or noncoached conditions. Scores for these respondents on the Negative Impression and Positive Impression scales, the Malingering Index, and the Rogers Discriminant Function (RDF) were compared to those of 17- and 18-year-old patients receiving clinical diagnoses of ADHD. Simulating respondents also completed the Conners Adult ADHD Rating Scale (CAARS) to determine if they could successfully simulate self-reported symptoms of ADHD. A total of 45% of simulating participants obtained CAARS scores reflecting clinically significant symptoms of ADHD. All indicators demonstrated the ability to distinguish between actual patients and feigned responses of successful simulators, with the RDF demonstrating the greatest accuracy in distinguishing these groups. PMID- 23924157 TI - Superoxide dismutases: you've come a long way, baby. PMID- 23924159 TI - Applications of biotechnology and genomics in potato improvement. AB - Potato is the third most important global food crop and the most widely grown noncereal crop. As a species highly amenable to cell culture, it has a long history of biotechnology applications for crop improvement. This review begins with a historical perspective on potato improvement using biotechnology encompassing pathogen elimination, wide hybridization, ploidy manipulation and applications of cell culture. We describe the past developments and new approaches for gene transfer to potato. Transformation is highly effective for adding single genes to existing elite potato clones with no, or minimal, disturbances to their genetic background and represents the only effective way to produce isogenic lines of specific genotypes/cultivars. This is virtually impossible via traditional breeding as, due to the high heterozygosity in the tetraploid potato genome, the genetic integrity of potato clones is lost upon sexual reproduction as a result of allele segregation. These genetic attributes have also provided challenges for the development of genetic maps and applications of molecular markers and genomics in potato breeding. Various molecular approaches used to characterize loci, (candidate) genes and alleles in potato, and associating phenotype with genotype are also described. The recent determination of the potato genome sequence has presented new opportunities for genomewide assays to provide tools for gene discovery and enabling the development of robustly unique marker haplotypes spanning QTL regions. The latter will be useful in introgression breeding and whole-genome approaches such as genomic selection to improve the efficiency of selecting elite clones and enhancing genetic gain over time. PMID- 23924158 TI - Candidate serum biomarkers for early intestinal cancer using 15N metabolic labeling and quantitative proteomics in the ApcMin/+ mouse. AB - Current screening procedures for colorectal cancer are imperfect and highly invasive and result in increased mortality rates due to low compliance. The goal of the experiments reported herein is to identify potential blood-based biomarkers indicative of early stage intestinal cancers using the ApcMin/+ mouse model of intestinal cancer as an experimental system. Serum proteins from tumor bearing ApcMin/+ mice were quantitatively compared to tumor-free Apc+/+ wild-type mice via in anima metabolic labeling with 14N/15N-labeled Spirulina algae and an LTQ Orbitrap mass spectrometer. Out of 1116 total serum proteins quantified, this study identified 40 that were differentially expressed and correlated with the increase in intestinal neoplasms. A subset of these differentially expressed proteins underwent a secondary quantitative screen using selected reaction monitoring-mass spectrometry with stable isotope-labeled peptides. Using both quantitative techniques, we identified MGAM and COL1A1 as downregulated and ITIH3 and F5 as upregulated in serum. All but COL1A1 were similarly differentially expressed in the mRNA of neoplastic colonic tissues of ApcMin/+ mice compared to normal wild-type tissue. These differentially expressed proteins identified in the ApcMin/+ mouse model have provided a set of candidate biomarkers for future validation screens in humans. PMID- 23924160 TI - High-resolution cellular MRI: gadolinium and iron oxide nanoparticles for in depth dual-cell imaging of engineered tissue constructs. AB - Recent advances in cell therapy and tissue engineering opened new windows for regenerative medicine, but still necessitate innovative noninvasive imaging technologies. We demonstrate that high-resolution magnetic resonance imaging (MRI) allows combining cellular-scale resolution with the ability to detect two cell types simultaneously at any tissue depth. Two contrast agents, based on iron oxide and gadolinium oxide rigid nanoplatforms, were used to "tattoo" endothelial cells and stem cells, respectively, with no impact on cell functions, including their capacity for differentiation. The labeled cells' contrast properties were optimized for simultaneous MRI detection: endothelial cells and stem cells seeded together in a polysaccharide-based scaffold material for tissue engineering appeared respectively in black and white and could be tracked, at the cellular level, both in vitro and in vivo. In addition, endothelial cells labeled with iron oxide nanoparticles could be remotely manipulated by applying a magnetic field, allowing the creation of vessel substitutes with in-depth detection of individual cellular components. PMID- 23924161 TI - A genetically encoded fluorescent probe in mammalian cells. AB - Fluorescent reporters are useful in vitro and in vivo probes of protein structure, function, and localization. Here we report that the fluorescent amino acid, 3-(6-acetylnaphthalen-2-ylamino)-2-aminopropanoic acid (Anap), can be site specifically incorporated into proteins in mammalian cells in response to the TAG codon with high efficiency using an orthogonal amber suppressor tRNA/aminoacyl tRNA synthetase (aaRS) pair. We further demonstrate that Anap can be used to image the subcellular localization of proteins in live mammalian cells. The small size of Anap, its environment-sensitive fluorescence, and the ability to introduce Anap at specific sites in the proteome by simple mutagenesis make it a unique and valuable tool in eukaryotic cell biology. PMID- 23924162 TI - Embedding health policy and systems research into decision-making processes in low- and middle-income countries. AB - Attention is increasingly directed to bridging the gap between the production of knowledge and its use for health decision-making in low- and middle-income countries (LMICs). An important and underdeveloped area of health policy and systems research (HPSR) is the organization of this process. Drawing from an interdisciplinary conception of embeddedness, a literature review was conducted to identify examples of embedded HPSR used to inform decision-making in LMICs. The results of the literature review were organized according to the World Health Organization's Building Blocks Framework. Next, a conceptual model was created to illustrate the arrangement of organizations that produce embedded HPSR and the characteristics that facilitate its uptake into the arena of decision-making. We found that multiple forces converge to create context-specific pathways through which evidence enters into decision-making. Depending on the decision under consideration, the literature indicates that decision-makers may call upon an intricate combination of actors for sourcing HPSR. While proximity to decision making does have advantages, it is not the position of the organization within the network, but rather the qualities the organization possesses, that enable it to be embedded. Our findings suggest that four qualities influence embeddedness: reputation, capacity, quality of connections to decision-makers, and quantity of connections to decision-makers and others. In addition to this, the policy environment (e.g. the presence of legislation governing the use of HPSR, presence of strong civil society, etc.) strongly influences uptake. Through this conceptual model, we can understand which conditions are likely to enhance uptake of HPSR in LMIC health systems. This raises several important considerations for decision-makers and researchers about the arrangement and interaction of evidence generating organizations in health systems. PMID- 23924163 TI - MatrixCatch--a novel tool for the recognition of composite regulatory elements in promoters. AB - BACKGROUND: Accurate recognition of regulatory elements in promoters is an essential prerequisite for understanding the mechanisms of gene regulation at the level of transcription. Composite regulatory elements represent a particular type of such transcriptional regulatory elements consisting of pairs of individual DNA motifs. In contrast to the present approach, most available recognition techniques are based purely on statistical evaluation of the occurrence of single motifs. Such methods are limited in application, since the accuracy of recognition is greatly dependent on the size and quality of the sequence dataset. Methods that exploit available knowledge and have broad applicability are evidently needed. RESULTS: We developed a novel method to identify composite regulatory elements in promoters using a library of known examples. In depth investigation of regularities encoded in known composite elements allowed us to introduce a new characteristic measure and to improve the specificity compared with other methods. Tests on an established benchmark and real genomic data show that our method outperforms other available methods based either on known examples or statistical evaluations. In addition to better recognition, a practical advantage of this method is first the ability to detect a high number of different types of composite elements, and second direct biological interpretation of the identified results. The program is available at http://gnaweb.helmholtz-hzi.de/cgi-bin/MCatch/MatrixCatch.pl and includes an option to extend the provided library by user supplied data. CONCLUSIONS: The novel algorithm for the identification of composite regulatory elements presented in this paper was proved to be superior to existing methods. Its application to tissue specific promoters identified several highly specific composite elements with relevance to their biological function. This approach together with other methods will further advance the understanding of transcriptional regulation of genes. PMID- 23924164 TI - Children's voices--Differentiating a child perspective from a child's perspective. AB - OBJECTIVE: The aim of this paper was to discuss differences between having a child perspective and taking the child's perspective based on the problem being investigated. METHODS: Conceptual paper based on narrative review. RESULTS: The child's perspective in research concerning children that need additional support are important. The difference between having a child perspective and taking the child's perspective in conjunction with the need to know children's opinions has been discussed in the literature. From an ideological perspective the difference between the two perspectives seems self-evident, but the perspectives might be better seen as different ends on a continuum solely from an adult's view of children to solely the perspective of children themselves. Depending on the research question, the design of the study may benefit from taking either perspective. In this article, we discuss the difference between the perspectives based on the problem being investigated, children's capacity to express opinions, environmental adaptations and the degree of interpretation needed to understand children's opinions. CONCLUSION: The examples provided indicate that children's opinions can be regarded in most research, although to different degrees. PMID- 23924165 TI - Optimal treatment for spinal cord injury associated with cervical canal stenosis (OSCIS): a study protocol for a randomized controlled trial comparing early versus delayed surgery. AB - BACKGROUND: The optimal management of acute cervical spinal cord injury (SCI) associated with preexisting canal stenosis remains to be established. The objective of this study is to examine whether early surgical decompression (within 24 hours after admission) would result in greater improvement in motor function compared with delayed surgery (later than two weeks) in cervical SCI patients presenting with canal stenosis, but without bony injury. METHODS/DESIGN: OSCIS is a randomized, controlled, parallel-group, assessor-blinded, multicenter trial. We will recruit 100 cervical SCI patients who are admitted within 48 hours of injury (aged 20 to 79 years; without fractures or dislocations; American Spinal Injury Association (ASIA) grade C; preexisting spinal canal stenosis). Patients will be enrolled from 36 participating hospitals across Japan and randomly allocated in a 1:1 ratio to either early surgical decompression (within 24 hours after admission) or delayed surgery following at least two weeks of conservative treatment. The primary outcomes include: 1) the change from baseline to one year in the ASIA motor score; 2) the total score of the Spinal Cord Independence Measure and 3) the proportion of patients who are able to walk without human assistance. The secondary outcomes are: 1) the health-related quality of life as measured by the Medical Outcomes Study Short Form 36 and the EuroQol 5 Dimension; 2) the Neuropathic Pain Symptom Inventory and 3) the walking status as evaluated with the Walking Index for Spinal Cord Injury II. The analysis will be on an intention-to-treat basis. The primary analysis will be a comparison of the primary and secondary outcomes one year after the injury. DISCUSSION: The results of this study will provide evidence of the potential benefit of early surgical decompression compared to the current 'watch and wait' strategy. PMID- 23924166 TI - Preterm infant care. PMID- 23924167 TI - Patient experiences with interventions to reduce surgery cancellations: a qualitative study. AB - BACKGROUND: The cancellation of planned surgery harms patients, increases waiting times and wastes scarce health resources. Previous studies have evaluated interventions to reduce cancellations from medical and management perspectives; these have focused on cost, length of stay, improved efficiency, and reduced post operative complications. In our case a hospital had experienced high cancellation rates and therefore redesigned their pathway for elective surgery to reduce cancelations. We studied how patients experienced interventions to reduce cancellations. METHODS: We conducted a comparative, qualitative case study by interviewing 8 patients who had experienced the redesigned pathway, and 8 patients who had experienced the original pathway. We performed a content analysis of the interviews using a theory-based coding scheme. Through a process of coding and condensing, we identified themes of patient experience. RESULTS: We identified three common themes summarizing patients' positive experiences with the effects of the interventions: the importance of being involved in scheduling time for surgery, individualized preparation before the hospital admission, and relationships with few clinicians during their hospital stay. CONCLUSIONS: Patients appreciated the effects of interventions to reduce cancellations, because they increased their autonomy. Unanticipated consequences were that the telephone reminder created a personalized dialogue and centralization of surgical preparation and discharge processes improved continuity of care. Thus apart from improving surgical logistics, the pathway became more patient-centered. PMID- 23924169 TI - An update to managing renal transplant ischemia reperfusion injury: novel therapies in the pipeline. PMID- 23924168 TI - Biological implications of extracellular adenosine in hepatic ischemia and reperfusion injury. AB - The purine nucleoside adenosine is clinically employed in the treatment of supraventricular tachycardia. In addition, it has direct coronary vasodilatory effects, and may influence platelet aggregation. Experimental observations mechanistically link extracellular adenosine to cellular adaptation to hypoxia. Adenosine generation has been implicated in several pathophysiologic processes including angiogenesis, tumor defenses and neurodegeneration. In solid organ transplantation, prolonged tissue ischemia and subsequent reperfusion injury may lead to profound graft dysfunction. Importantly, conditions of limited oxygen availability are associated with increased production of extracellular adenosine and subsequent tissue protection. Within the rapidly expanding field of adenosine biology, several enzymatic steps in adenosine production have been characterized and multiple receptor subtypes have been identified. In this review, we briefly examine the biologic steps involved in adenosine generation and chronicle the current state of adenosine signaling in hepatic ischemia and reperfusion injury. PMID- 23924170 TI - Stabilizing nanostructured solid oxide fuel cell cathode with atomic layer deposition. AB - We demonstrate that the highly active but unstable nanostructured intermediate temperature solid oxide fuel cell cathode, La0.6Sr0.4CoO3-delta (LSCo), can retain its high oxygen reduction reaction (ORR) activity with exceptional stability for 4000 h at 700 degrees C by overcoating its surfaces with a conformal layer of nanoscale ZrO2 films through atomic layer deposition (ALD). The benefits from the presence of the nanoscale ALD-ZrO2 overcoats are remarkable: a factor of 19 and 18 reduction in polarization area-specific resistance and degradation rate over the pristine sample, respectively. The unique multifunctionality of the ALD-derived nanoscaled ZrO2 overcoats, that is, possessing porosity for O2 access to LSCo, conducting both electrons and oxide ions, confining thermal growth of LSCo nanoparticles, and suppressing surface Sr segregation is deemed the key enabler for the observed stable and active nanostructured cathode. PMID- 23924171 TI - Combined sulfur K-edge XANES-EXAFS study of the effect of protonation on the sulfate tetrahedron in solids and solutions. AB - Sulfur K-edge X-ray absorption spectroscopy (XAS) has been used to distinguish between aqueous and solid sulfates and to investigate changes in their speciation. Data have been collected for tetrahedrally coordinated S in K2SO4 and KHSO4 solids and aqueous solutions. With a first qualitative analysis of the X ray absorption near-edge structure (XANES) spectra, it has been observed that those for solids are much more structured and distinguishable from those of aqueous solutions. The protonation state has a strong effect on the white line of sulfates and has been assigned to the different charge delocalization in the samples, the effect of the solvating water molecules and multiple scattering effects. In the extended X-ray absorption fine structure (EXAFS) spectra, the backscattering from the first O shell dominated the EXAFS fine structure function, chi(k), but the nonlinear multiple scattering contributions occurring in the first coordination shell are significant and must be considered in the EXAFS analysis. The intensity of these contributions strongly depend on the symmetry of the system. For a distorted tetrahedron, the intensity of the multiple scattering contributions is less than that found in a regular tetrahedron. The FEFF code has been used to model the contributions of the multiple-scattering processes. The observed experimental evidence in the XAS data can be used to distinguish between sulfates in solids and liquids. This is applicable to many chemical, geochemical, and biological systems. PMID- 23924172 TI - Meditation and neurodegenerative diseases. AB - Neurodegenerative diseases pose a significant problem for the healthcare system, doctors, and patients. With an aging population, more and more individuals are developing neurodegenerative diseases and there are few treatment options at the present time. Meditation techniques present an interesting potential adjuvant treatment for patients with neurodegenerative diseases and have the advantage of being inexpensive, and easy to teach and perform. There is increasing research evidence to support the application of meditation techniques to help improve cognition and memory in patients with neurodegenerative diseases. This review discusses the current data on meditation, memory, and attention, and the potential applications of meditation techniques in patients with neurodegenerative diseases. PMID- 23924174 TI - The cognitive impact of sexual abuse and PTSD in children: a neuropsychological study. AB - Sexual abuse is known to have an impact on both child and adult mental health, but the neuropsychological basis of this effect is still largely unknown. This study compared neuropsychological test results from a group of 76 children, 13 of them sexual abuse victims with symptoms of post-traumatic stress disorder, 26 victims of sexual abuse who showed no symptoms post-traumatic stress disorder, and 37 controls. The groups were matched by age, sex, socioeconomic status, and educational level. Child sexual abuse was associated with reduced ability to inhibit automatic responses measured by the Stroop test regardless of post traumatic stress disorder status. These findings indicate possible attentional inhibition difficulties in child victims of sexual abuse, which may help explain psychopathology associated with the experience. PMID- 23924173 TI - Heterozygous p.Asp50Asn mutation in the GJB2 gene in two Cameroonian patients with keratitis-ichthyosis-deafness (KID) syndrome. AB - BACKGROUND: Keratitis-Ichthyosis-Deafness (KID) syndrome (OMIM 148210) is a congenital ectodermal defect that consists of an atypical ichthyosiform erythroderma associated with congenital sensorineural deafness. KID appears to be genetically heterogeneous and most cases are caused by GJB2 mutations. Mutations in African patients have been rarely described. CASE PRESENTATION: We report on two unrelated Cameroonian individuals affected with sporadic KID, presenting with the classic phenotypic triad. The two patients were heterozygous for the most frequent p.Asp50Asn mutation. This first report in patients from sub-Saharan African origin supports the hypothesis that the occurrence of KID due to p.Asp50Asn mutation in GJB2 seems not to be population specific. CONCLUSIONS: Our finding has implication in medical genetic practice, specifically in the molecular diagnosis of KID in Africans. These cases also reveal and emphasize the urgent need to develop appropriate policies to care for patients with rare/orphan diseases in Sub-Saharan Africa, as many of these cases become more and more recognizable. PMID- 23924175 TI - Exploring mental health adjustment of children post sexual assault in South Africa. AB - Large numbers of children are affected by child sexual abuse in South Africa. This study aimed to assess psychological adjustment of children post sexual assault. In-depth, semistructured interviews were conducted with caretakers, and structured interviews using mental health assessment screening tools were given to children at three intervals over a five-month period after presentation at a sexual assault center. Almost half of the children met clinical criteria for anxiety, and two-thirds met criteria for full symptom post-traumatic stress disorder two to four weeks post disclosure. With standard care, we observed some recovery; 43.3% of children still met full symptom post-traumatic stress disorder nearly six months post disclosure. Our findings indicate that current practice in South Africa does not promote adequate recovery for children. PMID- 23924176 TI - Family environment, personality, and psychological symptoms in adults sexually abused as children. AB - The current study examined the relationships between family environment characteristics, personality traits, and current psychological symptoms in adults with a history of child sexual abuse. Family environment characteristics, personality traits, and psychological symptoms in 18 abused and 18 nonabused college students were examined using ANOVAs and MANOVAs. Pearson product moment correlations were also performed. Results indicated significantly more dysfunctional family environment characteristics (inflexibility, poor cohesion, family dissatisfaction, and poor family communication) in the abused versus the nonabused group. There were significantly higher levels in the personality traits of neuroticism and openness to experience in the abused group; however, there were no significant differences in psychological symptoms when comparing the two groups. The implications of the results and areas of future research are discussed. PMID- 23924177 TI - A study of shame from sexual abuse within the context of a Norwegian incest center. AB - Working with those who have experienced sexual abuse is a complicated matter because such abuse not only involves the violation of the victim's body, but it often generates shame in those involved. This article is based on empirical data from 26 hours of videotaped focus group interviews with 19 adult men and women in a Norwegian incest center who spoke openly of the shame they experienced from sexual abuse as children, parents, and employees. Findings from this study show that shame from sexual abuse can be grouped into seven major categories: (a) family, (b) emotions, (c) body, (d) food, (e) self-image, (f) sex, and (g) therapy. PMID- 23924178 TI - Sister-sister incest: data from an anonymous computerized survey. AB - Retrospective data were entered anonymously by 1,521 adult women using a computer assisted self-interview. Thirty-one participants were victims of sister-sister incest, 40 were victims of brother-sister incest, 19 were victims of father daughter incest, 8 were victims of sexual abuse by an adult female (including one mother), and 232 were victims of sexual abuse by an adult male other than their father before reaching 18 years of age. The rest (1,203) served as controls. The victims of sister-sister incest had significantly more problematic outcomes than controls on many measures as adults. Victims of sister-sister incest were more depressed and more likely than controls to be distant from the perpetrator-sister and to have traded sex for money, experienced an unplanned pregnancy, engaged in four different types of masturbation, and engaged in 13 different same-sex behaviors. Our findings were consistent with other reports of early eroticization and persistent hypereroticization of incest victims. PMID- 23924179 TI - Treatment implications arising from a qualitative analysis of letters written by the nonoffending partners of men who have perpetrated child sexual abuse. AB - There is a dearth of current empirical research exploring the experiences of nonoffending partners, or women whose partners have perpetrated child sexual abuse. Existing literature is dated and focuses disproportionately on intrafamilial abuse. This research explores how nonoffending partners construct and understand their experiences using thematic analysis within a social constructionist framework. Findings indicate that discovery of a partner's sexual offending is a profoundly distressing experience. It can inhibit a woman's ability to process the broader implications of her partner's behavior, including issues of risk, the impact on the victim, and the additional protective responsibilities she must adopt in the future. Implications for future research and clinical practice are discussed. PMID- 23924180 TI - Prevention of child sexual abuse: analysis and discussion of the field. AB - Prevention of child sexual abuse is complicated, challenging, and highly necessary as sexual abuse of children and youth represents an extensive problem across the world. This article reviews the existing preventive interventions targeting children, parents, and professionals. An alternative way of organizing the child sexual abuse prevention research literature is offered and applied with emphasis on three areas: (a) child sexual abuse prevention interventions, (b) meta-analyses of child sexual abuse prevention interventions, and (c) general theoretical models about prevention and the child. Based on an analysis of these areas, it was found that there was a lack of connection between theoretical models and concrete preventive interventions. An overview of current challenges and future possibilities in this area is provided. PMID- 23924181 TI - Health care and female survivors of childhood sexual abuse: health professionals' perspectives. AB - The present study explored health professionals' experiences with adult survivors of child sexual abuse in New Zealand. Face-to-face, semistructured interviews of up to an hour took place with 13 health professionals. The participants were asked about training, screening practices, their response to disclosures, and advice to other health professionals. A model-transition to ethical practice emerged from the data, where delivering more sensitive health care to child sexual abuse survivors sits on a continuum from lack of awareness of child sexual abuse to delivery of care where all patients are comfortable. We recommend making sensitive care for all as the standard care of practice and providing training for health professionals on how to deal with disclosures. PMID- 23924182 TI - The influence of knowing someone with HIV/AIDS on preventive behaviors in Italy. AB - The influence of knowing someone with HIV/AIDS on HIV preventive behaviors has become increasingly relevant in the literature, with controversial findings. The aim of this study was to investigate the relationship between knowing someone with HIV/AIDS and preventive behaviors in a representative sample of the Italian adult population. Drawing on two sociocognitive models, perceived threat and HIV/AIDS knowledge were proposed as mediators of this relationship. Results from 1969 telephone interviews were analyzed. Questions included sociodemographic information, knowing someone with HIV/AIDS, past sexual behaviors, HIV/AIDS knowledge, HIV/AIDS perceived threat (susceptibility and severity), and preventive behaviors (HIV testing and condom use). The results of mediation models showed that knowing someone with HIV/AIDS had an indirect effect on condom use through HIV-perceived susceptibility. Knowing someone with HIV/AIDS showed a direct and an indirect effect through HIV/AIDS knowledge on HIV testing. PMID- 23924183 TI - Dynamic regulation of P-glycoprotein in human brain capillaries. AB - Considering its role as a major blood-brain barrier gatekeeper, the dynamic regulation of the efflux transporter P-glycoprotein is of considerable functional relevance. In particular, disease-associated alterations in transport function might affect central nervous system drug efficacy. Thus, targeting regulatory signaling cascades might render a basis for novel therapeutic approaches. Using capillaries freshly prepared from patient tissue resected during epilepsy surgery, we demonstrate dynamic regulation of P-glycoprotein in human brain capillaries. Glutamate proved to up-regulate P-glycoprotein efflux transport in a significant manner via endothelial NMDA receptors. Both inhibition of cyclooxygenase-2 and antagonism at the glycine-binding site of the NMDA receptor prevented the glutamate-mediated induction of P-glycoprotein transport function in human capillaries. In conclusion, the data argue against species differences in the signaling factors increasing endothelial P-glycoprotein transport function in response to glutamate exposure. Targeting of cyclooxygenase-2 and of the NMDA receptor glycine-binding site was confirmed as an efficacious approach to control P-glycoprotein function. The findings might render a basis for translational development of add-on approaches to improve brain penetration and efficacy of drugs. PMID- 23924184 TI - Assessing interpersonal profiles associated with varying levels of effortful control. AB - Research has linked individual differences in effortful control (EC) with variations in interpersonal functioning in children and adolescents. Using the Inventory of Interpersonal Problems-Short Circumplex (Hopwood, Pincus, DeMoor, & Koonce, 2008), this study investigated interpersonal problem profiles associated with EC in 763 nonclinical young adults. We found that individuals with low EC reported intrusive interpersonal problems and high levels of interpersonal distress, whereas individuals with high EC reported cold interpersonal problems but low levels of interpersonal distress. Results suggest that EC might play an important role in shaping interpersonal functioning. PMID- 23924185 TI - The influence of pauses on the fatigue of upper limb muscles during the task of ironing. AB - The aim of this study was to analyze the influence of position and pauses on muscle activity and fatigue during the task of ironing. Ten female participants performed the task of ironing in two different positions (standing and sitting) for 10 min each with a 1-min pause at the end of each task. Muscle activity and fatigue from the upper trapezium, anterior deltoid, and pectoralis major were analyzed using surface electromyography. The results showed that the positions had no significant influence on muscle activity; nevertheless, they had significant influence on muscular fatigue. In addition, the pauses were possibly beneficial in decreasing the muscle fatigue, but the results were not conclusive. PMID- 23924186 TI - Electric stress-induced threshold voltage instability of multilayer MoS2 field effect transistors. AB - We investigated the gate bias stress effects of multilayered MoS2 field effect transistors (FETs) with a back-gated configuration. The electrical stability of the MoS2 FETs can be significantly influenced by the electrical stress type, relative sweep rate, and stress time in an ambient environment. Specifically, when a positive gate bias stress was applied to the MoS2 FET, the current of the device decreased and its threshold shifted in the positive gate bias direction. In contrast, with a negative gate bias stress, the current of the device increased and the threshold shifted in the negative gate bias direction. The gate bias stress effects were enhanced when a gate bias was applied for a longer time or when a slower sweep rate was used. These phenomena can be explained by the charge trapping due to the adsorption or desorption of oxygen and/or water on the MoS2 surface with a positive or negative gate bias, respectively, under an ambient environment. This study will be helpful in understanding the electrical stress-induced instability of the MoS2-based electronic devices and will also give insight into the design of desirable devices for electronics applications. PMID- 23924187 TI - Computational design of an unnatural amino acid dependent metalloprotein with atomic level accuracy. AB - Genetically encoded unnatural amino acids could facilitate the design of proteins and enzymes of novel function, but correctly specifying sites of incorporation and the identities and orientations of surrounding residues represents a formidable challenge. Computational design methods have been used to identify optimal locations for functional sites in proteins and design the surrounding residues but have not incorporated unnatural amino acids in this process. We extended the Rosetta design methodology to design metalloproteins in which the amino acid (2,2'-bipyridin-5yl)alanine (Bpy-Ala) is a primary ligand of a bound metal ion. Following initial results that indicated the importance of buttressing the Bpy-Ala amino acid, we designed a buried metal binding site with octahedral coordination geometry consisting of Bpy-Ala, two protein-based metal ligands, and two metal-bound water molecules. Experimental characterization revealed a Bpy-Ala mediated metalloprotein with the ability to bind divalent cations including Co(2+), Zn(2+), Fe(2+), and Ni(2+), with a Kd for Zn(2+) of ~40 pM. X-ray crystal structures of the designed protein bound to Co(2+) and Ni(2+) have RMSDs to the design model of 0.9 and 1.0 A respectively over all atoms in the binding site. PMID- 23924188 TI - Short communication: Late refills during the first year of antiretroviral therapy predict mortality and program failure among HIV-infected adults in urban Zambia. AB - We evaluated the association of the number of late antiretroviral therapy (ART) refills with patient outcomes in a large public-sector human immunodeficiency virus treatment program in Lusaka, Zambia. Using pharmacy data routinely collected during 2004-2010, we calculated the number of late refills during the initial year of ART. We used multivariable Cox proportional hazard regression to examine the association between the number of late refills and death or program failure (i.e., death, loss to follow-up, or program withdrawal) >12 months after ART initiation, with and without stratification by the medication possession ratio (MPR) during the initial year of ART. Of 53,015 adults who received ART for >=12 months (median follow-up duration, 86.1 months; interquartile range, 53.2 128.2 months), 26,847 (50.6%) had 0 late refills, 16,762 (31.6%) had 1, 6,505 (12.3%) had 2, and 2,901 (5.5%) had >=3. Kaplan-Meier analysis revealed that >=3 late refills was associated with a greater mortality risk than 1 and 2 late refills (p<0.001, by the log-rank test). The mortality risk was greater for patients with 2 late refills [adjusted hazard ratio (HR), 1.17; 95% confidence interval (CI), 0.99-1.38] or >=3 late refills (adjusted HR, 1.51; 95% CI, 1.23 1.87), compared with that for patients with 0-1 late refills. Program failure was associated with >=2 late refills. An MPR of <80% was associated with similar increases in mortality risk across late-refill strata. Monitoring late refills during the initial period of ART may help resource- and time-constrained clinics identify patients at risk for program failure. PMID- 23924189 TI - Body mass index affects proliferation and osteogenic differentiation of human subcutaneous adipose tissue-derived stem cells. AB - BACKGROUND: Obesity is associated with a higher risk of developing cancer and co morbidities that are part of the metabolic syndrome. Adipose tissue is recognized as an endocrine organ, as it affects a number of physiological functions, and contains adipose tissue-derived stem cells (ASCs). ASCs can differentiate into cells of multiple lineages, and as such are applicable to tissue engineering and regenerative medicine. Yet the question of whether ASC functionality is affected by the donor's body mass index (BMI) still exists. RESULTS: ASCs were isolated from patients having different BMIs (BMI-ASCs), within the ranges of 18.5-32.8. It was hypothesized that overweight BMI-ASCs would be more compromised in early adipogenic and osteogenic potential, and ability to form colonies in vitro. BMI was inversely correlated with ASC proliferation and colony forming potential as assessed by CyQUANT proliferation assay (fluorescence- based measurement of cellular DNA content), and colony forming assays. BMI was positively correlated with early time point (day 7) but not later time point (day 15) intracytoplasmic lipid accumulation as assessed by Oil-Red-O staining. Alizarin red staining and RT-PCR for alkaline phosphatase demonstrated that elevated BMI resulted in compromised ASC mineralization of extracellular matrix and decreased alkaline phosphatase mRNA expression. CONCLUSIONS: These data demonstrate that elevated BMI resulted in reduced ASC proliferation, and potentially compromised osteogenic capacity in vitro; thus BMI is an important criterion to consider in selecting ASC donors for clinical applications. PMID- 23924191 TI - Molecular threading and tunable molecular recognition on DNA origami nanostructures. AB - The DNA origami technology holds great promise for the assembly of nanoscopic technological devices and studies of biochemical reactions at the single-molecule level. For these, it is essential to establish well controlled attachment of functional materials to predefined sites on the DNA origami nanostructures for reliable measurements and versatile applications. However, the two-sided nature of the origami scaffold has shown limitations in this regard. We hypothesized that holes of the commonly used two-dimensional DNA origami designs are large enough for the passage of single-stranded (ss)-DNA. Sufficiently long ssDNA initially located on one side of the origami should thus be able to "thread" to the other side through the holes in the origami sheet. By using an origami sheet attached with patterned biotinylated ssDNA spacers and monitoring streptavidin binding with atomic force microscopic (AFM) imaging, we provide unambiguous evidence that the biotin ligands positioned on one side have indeed threaded through to the other side. Our finding reveals a previously overlooked critical design feature that should provide new interpretations to previous experiments and new opportunities for the construction of origami structures with new functional capabilities. PMID- 23924192 TI - Time to viral load suppression in antiretroviral-naive and -experienced HIV infected pregnant women on highly active antiretroviral therapy: implications for pregnant women presenting late in gestation. AB - OBJECTIVE: To compare time to achieve viral load <400 copies/ml and <1000 copies/ml in HIV-infected antiretroviral (ARV) -naive versus ARV-experienced pregnant women on highly active antiretroviral therapy (HAART). DESIGN: Retrospective cohort study. SETTING: Three university medical centers, USA. POPULATION: HIV-infected pregnant women initiated or restarted on HAART during pregnancy. METHODS: We calculated time to viral load <400 copies/ml and <1000 copies/ml in HIV-infected pregnant women on HAART who reported at least 50% adherence, stratifying based on previous ARV exposure history. MAIN OUTCOME MEASURES: Time to HIV viral load <400 copies/ml and <1000 copies/ml. RESULTS: We evaluated 138 HIV-infected pregnant women, comprising 76 ARV-naive and 62 ARV experienced. Ninety-three percent of ARV-naive women achieved a viral load < 400 copies/ml during pregnancy compared with 92% of ARV-experienced women (P = 0.82). The median number of days to achieve a viral load < 400 copies/ml in the ARV naive cohort was 25.0 (range 3.5-133; interquartile range 16-34) days compared with 27.0 (range 8-162.5; interquartile range 18.5-54.3) days in the ARV experienced cohort (P = 0.02). In a multiple predictor analysis, women with higher adherence (adjusted relative hazard [aRH] per 10% increase in adherence 1.29, 95% confidence interval [CI] 1.08-1.54, P = 0.01) and receiving a non nucleotide reverse transcriptase inhibitor (NNRTI) -based regimen (aRH 2.48, 95% CI 1.33-4.63, P = 0.01) were more likely to achieve viral load <400 copies/ml earlier. Increased baseline HIV log10 viral load was associated with a later time of achieving viral load <400 copies/ml (aRH 0.60, 95% CI 0.39-0.92, P = 0.02). In a corresponding model of time to achieve viral load <1000 copies/ml, adherence (aRH per 10% increase in adherence 1.79, 95% CI 1.34-2.39, P < 0.001), receipt of NNRTI (aRH 2.95, 95% CI 1.23-7.06, P = 0.02), and CD4 cell count (aRH per 50 count increase in CD4 1.12, 95% CI 1.03-1.22, P = 0.01) were associated with an earlier time to achieve viral load below this threshold. Increasing baseline HIV log10 viral load was associated with a longer time of achieving viral load <1000 copies/ml (aRH 0.54, 95% CI 0.34-0.86, P = 0.01). In multiple predictor models, previous ARV exposure was not significantly associated with time to achieve viral load below thresholds of <400 copies/ml and <1000 copies/ml. CONCLUSIONS: Pregnant women with >=50% adherence, whether ARV-naive or ARV-experienced, on average achieve a viral load <400 copies/ml within a median of 26 days and a viral load of <1000 copies/ml within a median of 14 days of HAART initiation. Increased adherence, receipt of NNRTI-based regimen and lower baseline HIV log10 viral load were all statistically significant predictors of earlier time to achieve viral load <400 copies/ml and <1000 copies/ml. Increased CD4 count was statistically significant as a predictor of earlier time to achieve viral load <1000 copies/ml. PMID- 23924193 TI - Hypogammaglobulinemia: time to reevaluate? PMID- 23924194 TI - Effect of concurrent cognitive tasks on temporo-spatial parameters of gait among children with cerebral palsy and typically developed controls. AB - OBJECTIVE: To assess the influence of different concurrent cognitive tasks on gait characteristics in children with cerebral palsy (CP) and typically developed (TD) controls. METHODS: Eleven children with CP and eleven TD controls walked under three conditions: at a self-selected speed, at a self-selected speed while memorizing and recalling a series of three random numbers, at a self-selected speed while listening and identifying commonly experienced sounds. Gait parameters were measured with the GAITRite((r)) system. RESULTS: Children with CP walked slower in both assignments as compared to baseline walking; TD controls reduce walking velocity only during the sounds assignment. Step length was constantly reduced and step time and length variability were constantly increased among children with CP as compared to TD controls, throughout assignments. CONCLUSION: It might be advisable for clinicians when assessing walking performance in children with CP, to assess it during both single and dual-task conditions. PMID- 23924195 TI - Exploring age-related brain degeneration in meditation practitioners. AB - A growing body of research suggests that meditation practices are associated with substantial psychological as well as physiological benefits. In searching for the biological mechanisms underlying the beneficial impact of meditation, studies have revealed practice-induced alterations of neurotransmitters, brain activity, and cognitive abilities, just to name a few. These findings not only imply a close link between meditation and brain structure, but also suggest possible modulating effects of meditation on age-related brain atrophy. Given that normal aging is associated with significant loss of brain tissue, meditation-induced growth and/or preservation might manifest as a seemingly reduced brain age in meditators (i.e., cerebral measures characteristic of younger brains). Surprisingly, there are only three published studies that have addressed the question of whether meditation diminishes age-related brain degeneration. This paper reviews these three studies with respect to the brain attributes studied, the analytical strategies applied, and the findings revealed. The review concludes with an elaborate discussion on the significance of existing studies, implications and directions for future studies, as well as the overall relevance of this field of research. PMID- 23924190 TI - Targeting inflammation and oxidative stress in atrial fibrillation: role of 3 hydroxy-3-methylglutaryl-coenzyme a reductase inhibition with statins. AB - SIGNIFICANCE: Atrial fibrillation (AF) is a burgeoning health-care problem, and the currently available therapeutic armamentarium is barely efficient. Experimental and clinical evidence implicates inflammation and myocardial oxidative stress in the pathogenesis of AF. RECENT ADVANCES: Local and systemic inflammation has been found to both precede and follow the new onset of AF, and NOX2-dependent generation of reactive oxygen species in human right atrial samples has been independently associated with the occurrence of AF in the postoperative period in patients undergoing cardiac surgery. Anti-inflammatory and antioxidant agents can prevent atrial electrical remodeling in animal models of atrial tachypacing and the new onset of AF after cardiac surgery, suggesting a causal relationship between inflammation/oxidative stress and the atrial substrate that supports AF. CRITICAL ISSUES: Statin therapy, by redressing the myocardial nitroso-redox balance and reducing inflammation, has emerged as a potentially effective strategy for the prevention of AF. Evidence indicates that statins prevent AF-induced electrical remodeling in animal models of atrial tachypacing and may reduce the new onset of AF after cardiac surgery. However, whether statins have antiarrhythmic properties in humans has yet to be conclusively demonstrated, as data from randomized controlled trials specifically addressing the relevance of statin therapy for the primary and secondary prevention of AF remain scanty. FUTURE DIRECTIONS: A better understanding of the mechanisms underpinning the putative antiarrhythmic effects of statins may afford tailoring AF treatment to specific clinical settings and patient's subgroups. Large-scale randomized clinical trials are needed to support the indication of statin therapy solely on the basis of AF prevention. PMID- 23924196 TI - The impact of education and globalization on sexual and reproductive health: retrospective evidence from eastern and southern Africa. AB - The objective of this study is to qualify the relationship between sexual and reproductive health (SRH) and educational attainment in eastern and southern Africa (ESA). We hypothesize that the regional level of globalization is a moderating factor in the relationship between SRH and educational attainment. Using retrospective data from Kenya, Malawi, Tanzania, and Zambia, the associations between SRH (eight indicators), educational attainment, and globalization were examined using multilevel logistic regression analysis. It was found that the model fit for every SRH outcome indicator increased significantly after including the interaction between globalization and educational attainment, supporting the hypothesis. Depending on the level of globalization, three types of relationships between education and SRH were found: (1) for the indicators "more than four children," "intercourse before 17 years," "first child before 20 years," and "one or more child died" education is risk-decreasing, and the reduction is stronger in more globalized regions; (2) for the indicators "condom use at last intercourse" and "current contraceptive use" education is risk decreasing, and the reduction is stronger in less globalized regions; (3) for the indicators "HIV positive" and "more than four lifetime sexual partners" education is risk increasing, but only in less globalized regions. In conclusion, these effects are related to three types of access: (1) access to services, (2) access to information, and (3) access to sexual networks. The findings highlight the relevance of globalization when analyzing the association between SRH and education, and the importance of structural factors in the development of effective SRH promotion interventions. PMID- 23924202 TI - Modeling of dielectric properties of aqueous salt solutions with an equation of state. AB - The static permittivity is the most important physical property for thermodynamic models that account for the electrostatic interactions between ions. The measured static permittivity in mixtures containing electrolytes is reduced due to kinetic depolarization and reorientation of the dipoles in the electrical field surrounding ions. Kinetic depolarization may explain 25-75% of the observed decrease in the permittivity of solutions containing salts, but since this is a dynamic property, this effect should not be included in the thermodynamic modeling of electrolytes. Kinetic depolarization has, however, been ignored in relation to thermodynamic modeling, and authors have either neglected the effect of salts on permittivity or used empirical correlations fitted to the measured static permittivity, leading to an overestimation of the reduction in the thermodynamic static permittivity. We present a new methodology for obtaining the static permittivity over wide ranges of temperatures, pressures, and compositions for use within an equation of state for mixed solvents containing salts. The static permittivity is calculated from a new extension of the framework developed by Onsager, Kirkwood, and Frohlich to associating mixtures. Wertheim's association model as formulated in the statistical associating fluid theory is used to account for hydrogen-bonding molecules and ion-solvent association. Finally, we compare the Debye-Huckel Helmholtz energy obtained using an empirical model with the new physical model and show that the empirical models may introduce unphysical behavior in the equation of state. PMID- 23924198 TI - Treatment of the humeral shaft fractures--minimally invasive osteosynthesis with bridge plate versus conservative treatment with functional brace: study protocol for a randomised controlled trial. AB - BACKGROUND: Humeral shaft fractures account for 1 to 3% of all fractures in adults and for 20% of all humeral fractures. Non-operative treatment is still the standard treatment of isolated humeral shaft fractures, although this method can present unsatisfactory results. Surgical treatment is reserved for specific conditions. Modern concepts of internal fixation of long bone shaft fractures advocate relative stabilisation techniques with no harm to fracture zone. Recently described, minimally invasive bridge plate osteosynthesis has been shown to be a secure technique with good results for treating humeral shaft fractures. There is no good quality evidence advocating which method is more effective. This randomised controlled trial will be performed to investigate the effectiveness of surgical treatment of humeral shaft fractures with bridge plating in comparison with conservative treatment with functional brace. METHODS/DESIGN: This randomised clinical trial aims to include 110 patients with humeral shaft fractures who will be allocated after randomisation to one of the two groups: bridge plate or functional brace. Surgical treatment will be performed according to technique described by Livani and Belangero using a narrow DCP plate. Non operative management will consist of a functional brace for 6 weeks or until fracture consolidation. All patients will be included in the same rehabilitation program and will be followed up for 1 year after intervention. The primary outcome will be the DASH score after 6 months of intervention. As secondary outcomes, we will assess SF-36 questionnaire, treatment complications, Constant score, pain (Visual Analogue Scale) and radiographs. DISCUSSION: According to current evidence shown in a recent systematic review, this study is one of the first randomised controlled trials designed to compare two methods to treat humeral shaft fractures (functional brace and bridge plate surgery). PMID- 23924203 TI - Surface-confined crystalline two-dimensional covalent organic frameworks via on surface Schiff-base coupling. AB - We performed a co-condensation reaction between aromatic aldehyde and aromatic diamine monomers on a highly oriented pyrolytic graphite surface either at a solid/liquid interface at room temperature or in low vacuum with moderate heating. With this simple and moderate methodology, we have obtained surface confined 2D covalent organic frameworks (COFs) with few defects and almost entire surface coverage. The single crystalline domain can extend to more than 1 MUm(2). By varying the backbone length of aromatic diamines the pore size of 2D surface COFs is tunable from ~1.7 to 3.5 nm. In addition, the nature of the surface COF can be modified by introducing functional groups into the aromatic amine precursor, which has been demonstrated by introducing methyl groups to the backbone of the diamine. Formation of small portions of bilayers was observed by both scanning tunneling microscopy (STM) and AFM, which clearly reveals an eclipsed stacking manner. PMID- 23924204 TI - Tuning the electronic structure of titanium oxide support to enhance the electrochemical activity of platinum nanoparticles. AB - Two times higher activity and three times higher stability in methanol oxidation reaction, a 0.12 V negative shift of the CO oxidation peak potential, and a 0.07 V positive shift of the oxygen reaction potential compared to Pt nanoparticles on pristine TiO2 support were achieved by tuning the electronic structure of the titanium oxide support of Pt nanoparticle catalysts. This was accomplished by adding oxygen vacancies or doping with fluorine. Experimental trends are interpreted in the context of an electronic structure model, showing an improvement in electrochemical activity when the Fermi level of the support material in Pt/TiOx systems is close to the Pt Fermi level and the redox potential of the reaction. The present approach provides guidance for the selection of the support material of Pt/TiOx systems and may be applied to other metal-oxide support materials, thus having direct implications in the design and optimization of fuel cell catalyst supports. PMID- 23924205 TI - Incision length for kidney transplantation does not influence short- or long-term outcome: a prospective randomized controlled trial. AB - BACKGROUND: While previous studies suggest advantages of minimally invasive surgery in living donor nephrectomy, similar data are lacking for kidney transplant recipients. Our aim was to prospectively evaluate short- and long-term outcome for kidney transplant recipients, comparing a short transverse (ST) to a classical hockey-stick (HS) incision. METHODS: Sixty-six patients were randomized into two groups: ST vs. HS from January 2008 to May 2010. ST was defined as incision length <=9 cm and HS as >14 cm. Perioperative data were collected, with evaluation of intra- and postoperative complications and quality of recovery (QoR) score. RESULTS: There were no significant differences in patient demographics, early or long-term postoperative pain. There were no significant differences in QoR scores between the ST and HS group. Predictive for a worse QoR was persisting incisional pain at the 30-month follow-up. Thirty-days mortality, morbidity, and long-term kidney function did not differ between the two groups (p = 1.00, p = 0.62 and p = 0.66, respectively). CONCLUSIONS: Patient satisfaction as well as graft function and patient mortality was not influenced by incision length. With patient and graft safety being paramount, especially in times of organ shortage, incision length should reflect the requirement for a successful transplantation and not be a measure of feasibility. PMID- 23924206 TI - Adaptation of the pituitary-adrenal axis to daily repeated forced swim exposure in rats is dependent on the temperature of water. AB - Comparison of exposure to certain predominantly emotional stressors reveals a qualitatively similar neuroendocrine response profile as well as a reduction of physiological responses after daily repeated exposure (adaptation). However, particular physical components of the stressor may interfere with adaptation. As defective adaptation to stress can enhance the probability to develop pathologies, we studied in adult male rats (n = 10/group) swimming behavior (struggling, immobility and mild swim) and physiological responses (ACTH, corticosterone and rectal temperature) to daily repeated exposure to forced swim (20 min, 13 d) at 25 or 36 degrees C (swim25 or swim36). Rats were repeatedly blood-sampled by tail-nick and hormones measured by radioimmunoassay. Some differences were observed between the two swim temperature groups after the first exposure to forced swim: (a) active behaviors were greater in swim25 than swim36 groups; (b) swim25 but not swim36 caused hypothermia; and (c) swim36 elicited the same ACTH response as swim25, but plasma corticosterone concentration was lower for swim36 at 30 min post-swim. After daily repeated exposure, adaptation in ACTH secretion was observed with swim36 already on day 4, whereas with swim25 adaptation was not observed until day 13 and was of lower magnitude. Nevertheless, after repeated exposure to swim25 a partial protection from hypothermia was observed and the two swim conditions resulted in progressive reduction of active behaviors. Thus, daily repeated swim at 25 degrees C impairs adaptation of the hypothalamic-pituitary-adrenal axis as compared to swim at 36 degrees C, supporting the hypothesis that certain physical components of predominantly emotional stressors can interfere with the process of adaptation. PMID- 23924207 TI - IMAC fractionation in combination with LC-MS reveals H2B and NIF-1 peptides as potential bladder cancer biomarkers. AB - Improvement in bladder cancer (BC) management requires more effective diagnosis and prognosis of disease recurrence and progression. Urinary biomarkers attract special interest because of the noninvasive means of urine collection. Proteomic analysis of urine entails the adoption of a fractionation methodology to reduce sample complexity. In this study, we applied immobilized metal affinity chromatography in combination with high-resolution LC-MS/MS for the discovery of native urinary peptides potentially associated with BC aggressiveness. This approach was employed toward urine samples from patients with invasive BC, noninvasive BC, and benign urogenital diseases. A total of 1845 peptides were identified, corresponding to a total of 638 precursor proteins. Specific enrichment for proteins involved in nucleosome assembly and for zinc-finger transcription factors was observed. The differential expression of two candidate biomarkers, histone H2B and NIF-1 (zinc finger 335) in BC, was verified in independent sets of urine samples by ELISA and by immunohistochemical analysis of BC tissue. The results collectively support changes in the expression of both of these proteins with tumor progression, suggesting their potential role as markers for discriminating BC stages. In addition, the data indicate a possible involvement of NIF-1 in BC progression, likely as a suppressor and through interactions with Sox9 and HoxA1. PMID- 23924208 TI - Derangements of lacrimal drainage-associated lymphoid tissue (LDALT) in human chronic dacryocystitis. AB - AIMS: To study the changes in the lacrimal drainage-associated lymphoid tissue of the lacrimal sac in human chronic dacryocystitis and its possible implications in understanding the immune defense mechanisms and etiopathogenesis of primary acquired nasolacrimal duct obstruction. METHODS: Retrospective interventional study involving 200 lacrimal sacs of 164 consecutive patients seen between July 2009 and July 2012. Data collected include demographics, clinical presentation, laterality, age at presentation, duration of symptoms, diagnostic irrigation, indications for a dacyrocystectomy, pattern and severity of lymphoid infiltrate, types of lymphoid follicles and their locations, plasma cells, and other cellular infiltrates. The associated epithelial, stromal, and luminal changes with an emphasis on acini, mucosal glands, blood vessels, lymphatics, and goblet cells were also noted. Immunohistochemistry using CD3, CD20, CD138, and immunoglobulin A were used to substantiate the lymphoid tissues of the lacrimal sac. RESULTS: A total of 200 lacrimal sacs were obtained from dacryocystectomy of 164 patients. The patients included 60.5% (99/164) females and 39.6% (65/164) males, with a mean age of 58.4 years at presentation. Laterality showed a predominance of left lacrimal sacs (55%, 110/200) as compared to the right lacrimal sacs (45%, 90/200). Symptoms of epiphora and discharge of more than 6 months duration were considered to be chronic. Lymphoid infiltrate pattern was diffuse in majority of the sacs (81%, 162/200), with subepithelial and intraepithelial together being the commonest location (46.5%, 93/200). Distinct lymphoid follicles were seen in 28% (56/200). Most of the sacs showed mild plasma cell infiltration (66.5%, 133/200). IgA-rich secretions were noted in the lumen and the lining epithelium in 34.5% (69/200). Other common changes noted include increase in the goblet cells (82%, 164/200), dilated lymphatics (94%, 188/200), proliferating blood vessels (99%, 198/200), thickened epithelium (54.5%, 109/200), and stromal fibrosis (88%, 176/200). CONCLUSION: This study presents the largest series to date (n = 200 lacrimal sacs) exclusively on changes in lacrimal drainage associated lymphoid tissue in human chronic dacryocystitis. This study could be the starting point for further exploration into the molecular biology, immunological implications, and possible implications of LDALT derangements on etiopathogenesis of primary acquired nasolacrimal duct obstruction. PMID- 23924209 TI - Physical activity and mortality in a prospective cohort of middle-aged and elderly men - a time perspective. AB - BACKGROUND: Higher physical activity (PA) levels are known to be associated with lower risk of death. Less attention, however, has been paid to directly evaluate the effect of PA on the time by which a certain fraction of the population has died. METHODS: A population-based cohort of 29,362 men 45 to 79 years of age was followed from January 1998 to December 2010. A total of 4,570 men died. PA was assessed through a self-administrated questionnaire. Adjusted differences in the number of months by which 10% (10th percentile) of the cohort has died, according to levels of total PA (TPA) and different domains of PA were estimated using Laplace regression. RESULTS: Overall, the 10th survival percentile was 9.6 years, that is, 90% of the cohort lived longer than 9.6 years. We found a strong evidence of non-linearity between TPA and the 10th survival percentile (P-value < 0.001). Compared to men with the lowest TPA (29 metabolic equivalents (MET) hrs/day), men with a median TPA (41 MET-hrs/day) had 30 months longer survival (95% CI: 25-35). Below the median TPA, every increment of 4 MET-hrs/day, approximately a 30 minutes brisk pace daily walk, was associated with a longer survival of 11 months (95% CI: 8-15). Above the median TPA additional activity was not significantly associated with better survival. CONCLUSIONS: We found that a physically active lifestyle is associated with a substantial improvement in survival time, up to 2.5 years over 13 years of follow-up. PMID- 23924211 TI - Exploring trait assessment of samples, persons, and cultures. AB - I present a very broad overview of what I have learned about personality trait assessment at different levels and offer some views on future directions for research and clinical practice. I review some basic principles of scale development and argue that internal consistency has been overemphasized; more attention to retest reliability is needed. Because protocol validity is crucial for individual assessment and because validity scales have limited utility, I urge combining assessments from multiple informants, and I present some statistical tools for that purpose. As culture-level traits, I discuss ethos, national character stereotypes, and aggregated personality traits, and summarize evidence for the validity of the latter. Our understanding of trait profiles of cultures is limited, but it can guide future exploration. PMID- 23924210 TI - Asymmetric catalysis at a distance: catalytic, site-selective phosphorylation of teicoplanin. AB - We report three distinct, peptide-based catalysts that enable site-selective phosphorylation of three distinct hydroxyl groups within the complex glycopeptide antibiotic teicoplanin A2-2. Two of the catalysts are based on a design that capitalizes on a catalyst-substrate interaction that mimics the biological mechanism of action for teicoplanin. These catalysts are based on a DXaa-DXaa peptide motif that is known to target the teicoplanin structure in a specific manner. The third was identified through evaluation of a set of catalysts that had been developed for historically distinct projects. Each catalyst contains additional functionality designed to dispose a catalytic moiety (a nucleophilic alkylimidazole) at a different region of the glycopeptide structure. A combination of mass spectrometry and 2D-NMR spectroscopy allowed structural assignment of the distinct phosphorylated teicoplanin derivatives. Mechanistic studies are also reported that support the hypotheses that led to the discovery of the catalysts. In this manner, small molecule catalysts have been achieved that allow rational, catalytic control over reactions at sites that are separated by 11.6, 16.5, and nearly 17.7 A, based on the X-ray crystal structure of teicoplanin A2-2. Finally, we report the biological activity of the new phosphorylated teicoplanin analogs and compare the results to the natural product itself. PMID- 23924212 TI - Synthesis and biological evaluation of radio and dye labeled amino functionalized dendritic polyglycerol sulfates as multivalent anti-inflammatory compounds. AB - Herein we describe a platform technology for the synthesis and characterization of partially aminated, (35)S-labeled, dendritic polyglycerol sulfate (dPG(35)S amine) and fluorescent dPGS indocarbocyanine (ICC) dye conjugates. These polymer conjugates, based on a biocompatible dendritic polyglycerol scaffold, exhibit a high affinity to inflamed tissue in vivo and represent promising candidates for therapeutic and diagnostic applications. By utilizing a one-step sequential copolymerization approach, dendritic polyglycerol (Mn ~ 4.5 kDa) containing 9.4% N-phthalimide protected amine functionalities was prepared on a large scale. Sulfation and simultaneous radio labeling with (35)SO3 pyridine complex, followed by cleavage of the N-phthalimide protecting groups, yielded dPG(35)S amine as a beta emitting, inflammation specific probe with free amino functionalities for conjugation. Furthermore, efficient labeling procedures with ICC via iminothiolane modification and subsequent "Michael" addition of the maleimide functionalized ICC dye, as well as by amide formation via NHS derivatized ICC on a dPGS amine scaffold, are described. The dPGS-ICC conjugates were investigated with respect to their photophysical properties, and both the radiolabeled and fluorescent compounds were comparatively visualized in histological tissue sections (radio detection and fluorescence microscopy) of animals treated with dPGS. Furthermore, cellular uptake of dPGS-ICC was found in endothelial cord blood (HUVEC) and the epithelial lung cells (A549). The presented synthetic routes allow a reproducible, controlled synthesis of dPGS amine on kilogram scale applying a one-pot batch reaction process. dPGS amine can be used for analysis via radioactivity or fluorescence, thereby creating a new platform for inflammation specific, multimodal imaging purposes using other attachable probes or contrast agents. PMID- 23924213 TI - Persistence of acetonitrile bilayers at the interface of acetonitrile/water mixtures with silica. AB - Previous experiments and simulations have shown that acetonitrile organizes into a lipid-like bilayer at the liquid/silica interface. Recent simulations have further suggested that this bilayer structure persists in mixtures of acetonitrile with water, even at low acetonitrile concentrations. This behavior is indicative of microscopic phase separation of these liquids near silica interfaces and may have important ramifications for the use of acetonitrile in chromatography and heterogeneous catalysis. To explore this phenomenon, we have used vibrational sum-frequency-generation spectroscopy to probe acetonitrile/water mixtures at a silica interface. Our spectra provide evidence that acetonitrile partitions to the hydrated silica interface even when the mole fraction of acetonitrile is as low as 10%. A blue shift is observed in the spectrum of the methyl symmetric stretch upon increasing water mole fraction, in agreement with vibrational spectra of bulk mixtures. Line shape analysis suggests that acetonitrile may exist in the form of bilayer patches at high water mole fractions. PMID- 23924214 TI - A core/satellite multifunctional nanotheranostic for in vivo imaging and tumor eradication by radiation/photothermal synergistic therapy. AB - To integrate photothermal ablation (PTA) with radiotherapy (RT) for improved cancer therapy, we constructed a novel multifunctional core/satellite nanotheranostic (CSNT) by decorating ultrasmall CuS nanoparticles onto the surface of a silica-coated rare earth upconversion nanoparticle. These CSNTs could not only convert near-infrared light into heat for effective thermal ablation but also induce a highly localized radiation dose boost to trigger substantially enhanced radiation damage both in vitro and in vivo. With the synergistic interaction between PTA and the enhanced RT, the tumor could be eradicated without visible recurrence in 120 days. Notably, hematological analysis and histological examination unambiguously revealed their negligible toxicity to the mice within a month. Moreover, the novel CSNTs facilitate excellent upconversion luminescence/magnetic resonance/computer tomography trimodal imagings. This multifunctional nanocomposite is believed to be capable of playing a vital role in future oncotherapy by the synergistic effects between enhanced RT and PTA under the potential trimodal imaging guidance. PMID- 23924215 TI - Prevalence, correlates and pattern of Hepatitis B among antenatal clinic attenders in Yaounde-Cameroon: is perinatal transmission of HBV neglected in Cameroon? AB - BACKGROUND: Few studies have evaluated the prevalence of HBV in the general Cameroonian population or among antenatal attendants. The aim of this study was to determine the prevalence, correlates and patterns of Hepatitis B surface antigen among pregnant women attending antenatal care in Yaounde-Cameroon. METHODS: This was a cross-sectional multicenter study carried out in a referral hospital and two secondary hospitals in Yaounde, the capital of Cameroon. The study lasted 15 months (March 2011 to June 2012), and recruited 959 pregnant women. Patient recruitment was consecutive. The HBsAg was tested using the Monalisa HBsAg Ultra ELISA kit. Other hepatitis B markers were equally tested. RESULTS: The prevalence of hepatitis B infection (HBsAg) among antenatal clinic attenders in our setting was 7.7%. Amongst these women, just 5.4% were previously aware of their HBsAg status. The rate of HBV infectivity was high, with 28% of HBsAg positive women having evidence of HBeAg in their plasma, and up to 45.8% of these women lacking antibodies against hepatitis B e antigen (anti-HBe). About 41% of the pregnant women had had previous contact with HBV as evidenced by the positive status for anti-HBc. CONCLUSION: The prevalence of hepatitis B among pregnant women in Cameroon is high, and the pattern tends towards high infectivity and therefore increased risk of perinatal HBV transmission. These highlight the need to step up preventive efforts against hepatitis B infection and perinatal HBV transmission in our community. PMID- 23924217 TI - Maternal and perinatal outcomes among nulliparous adolescents in low- and middle income countries: a multi-country study. AB - OBJECTIVE: To investigate the risk of adverse pregnancy outcomes and caesarean section among adolescents in low- and middle-income countries. DESIGN: Secondary analysis using facility-based cross-sectional data from the World Health Organization (WHO) Global Survey on Maternal and Perinatal Health. SETTING: Twenty-three countries in Africa, Latin America, and Asia. POPULATION: Women admitted for delivery in 363 health facilities during 2-3 months between 2004 and 2008. METHODS: We constructed multilevel logistic regression models to estimate the effect of young maternal age on risks of adverse pregnancy outcomes. MAIN OUTCOME MEASURES: Risk of adverse pregnancy outcomes among young mothers. RESULTS: A total of 78 646 nulliparous mothers aged <=24 years and their singleton infants were included in the analysis. Compared with mothers aged 20-24 years, adolescents aged 16-19 years had a significantly lower risk of caesarean section (adjusted OR 0.75, 95% CI 0.71-0.79). When the analysis was restricted to caesarean section indicated for presumed cephalopelvic disproportion, the risk of caesarean section was significantly higher among mothers aged <=15 years (aOR 1.27, 95% CI 1.07-1.49) than among those aged 20-24 years. Higher risks of low birthweight and preterm birth were found among adolescents aged 16-19 years (aOR 1.10, 95% CI 1.03-1.17; aOR 1.16, 95% CI 1.09-1.23, respectively) and <=15 years (aOR 1.33, 95% CI 1.14-1.54; aOR 1.56, 95% CI 1.35-1.80, respectively). CONCLUSIONS: Adolescent girls experiencing pregnancy at a very young age (i.e. <16 years) have an increased risk of adverse pregnancy outcomes. PMID- 23924216 TI - RNA replicon delivery via lipid-complexed PRINT protein particles. AB - Herein we report the development of a nonviral lipid-complexed PRINT (particle replication in nonwetting templates) protein particle system (LPP particle) for RNA replicon delivery with a view toward RNA replicon-based vaccination. Cylindrical bovine serum albumin (BSA) particles (diameter (d) 1 MUm, height (h) 1 MUm) loaded with RNA replicon and stabilized with a fully reversible disulfide cross-linker were fabricated using PRINT technology. Highly efficient delivery of the particles to Vero cells was achieved by complexing particles with a mixture of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine (DOPE) lipids. Our data suggest that (1) this lipid-complexed protein particle is a promising system for delivery of RNA replicon-based vaccines and (2) it is necessary to use a degradable cross-linker for successful delivery of RNA replicon via protein-based particles. PMID- 23924219 TI - Doing more harm than good: negative health effects of intimate-partner violence campaigns. AB - This study investigates unintended negative effects of health communication campaigns surrounding intimate-partner violence. Major health organizations have identified this issue as an urgent health problem for women, but the effects of these campaigns have rarely been tested with the target audience most affected by the issue. Using qualitative methodology, 10 focus groups were conducted with female survivors of intimate-partner violence. It was found that this group viewed the campaigns as emotionally harmful, inaccurate, and misleading. The results of this research suggest these campaigns may do more harm than good for the audience most severely affected by this issue. PMID- 23924218 TI - Developing molecular tools and insights into the Penstemon genome using genomic reduction and next-generation sequencing. AB - BACKGROUND: Penstemon's unique phenotypic diversity, hardiness, and drought tolerance give it great potential for the xeric landscaping industry. Molecular markers will accelerate the breeding and domestication of drought tolerant Penstemon cultivars by, creating genetic maps, and clarifying of phylogenetic relationships. Our objectives were to identify and validate interspecific molecular markers from four diverse Penstemon species in order to gain specific insights into the Penstemon genome. RESULTS: We used a 454 pyrosequencing and GR RSC (genome reduction using restriction site conservation) to identify homologous loci across four Penstemon species (P. cyananthus, P. davidsonii, P. dissectus, and P. fruticosus) representing three diverse subgenera with considerable genome size variation. From these genomic data, we identified 133 unique interspecific markers containing SSRs and INDELs of which 51 produced viable PCR-based markers. These markers produced simple banding patterns in 90% of the species * marker interactions (~84% were polymorphic). Twelve of the markers were tested across 93, mostly xeric, Penstemon taxa (72 species), of which ~98% produced reproducible marker data. Additionally, we identified an average of one SNP per 2,890 bp per species and one per 97 bp between any two apparent homologous sequences from the four source species. We selected 192 homologous sequences, meeting stringent parameters, to create SNP markers. Of these, 75 demonstrated repeatable polymorphic marker functionality across the four sequence source species. Finally, sequence analysis indicated that repetitive elements were approximately 70% more prevalent in the P. cyananthus genome, the largest genome in the study, than in the smallest genome surveyed (P. dissectus). CONCLUSIONS: We demonstrated the utility of GR-RSC to identify homologous loci across related Penstemon taxa. Though PCR primer regions were conserved across a broadly sampled survey of Penstemon species (93 taxa), DNA sequence within these amplicons (12 SSR/INDEL markers) was highly diverse. With the continued decline in next generation sequencing costs, it will soon be feasible to use genomic reduction techniques to simultaneously sequence thousands of homologous loci across dozens of Penstemon species. Such efforts will greatly facilitate our understanding of the phylogenetic structure within this important drought tolerant genus. In the interim, this study identified thousands of SNPs and over 50 SSRs/INDELs which should provide a foundation for future Penstemon phylogenetic studies and breeding efforts. PMID- 23924220 TI - Preventive innovation: an Australian case study on HPV vaccination. AB - Much of the literature has been conducted on innovation; this research provides new insights for preventive innovations that increase our understanding of vaccination diffusion and the reasons underlying the complexity of preventive diffusion. The research uses adoption of Rogers' ( 1983 ) perceived characteristics and considers the rate by which a product diffuses in a market. Qualitative empirical evidence collected via focus groups is used to identify human papillomavirus vaccine issues against the salience of perceived characteristics. Several impediments are identified and the application of marketing strategies is suggested for preventive innovations to improve the diffusion process and for designing proactive adoption. PMID- 23924221 TI - The consumer-provider relationship in the dental industry. AB - This article explains how a consumer's level of trust and commitment to his or her dental service provider factors into the relationship between the consumer and the dental professional. Very little research has been done that describes the complexity of this relationship. This article documents the complexity of and influences on that relationship by providing an interaction model of this relationship. PMID- 23924222 TI - A new, but old business model for family physicians: cash. AB - The following study is an exploratory investigation into the opportunity identification, opportunity analysis, and strategic implications of implementing a cash-only family physician practice. The current market dynamics (i.e., increasing insurance premiums, decreasing benefits, more regulations and paperwork, and cuts in federal and state programs) suggest that there is sufficient motivation for these practitioners to change their current business model. In-depth interviews were conducted with office managers and physicians of family physician practices. The results highlighted a variety of issues, including barriers to change, strategy issues, and opportunities/benefits. The implications include theory applications, strategic marketing applications, and managerial decision-making. PMID- 23924223 TI - Development of a quality ranking model for home health care providers. AB - This research aims to increase transparency and simplify consumer decision-making regarding the selection of a home health care provider. Currently, quality information on home health care providers is fragmented and difficult to interpret. In this study, a quality-ranking model is developed by selecting multidimensional quality indicators across multiple sources and respective weights using expert judgment. Given the weights and providers' performance on each quality indicator, a composite score is calculated that summarizes a home health care provider's overall quality level. This quality information empowers consumers to narrow their search and select the best-performing, most efficient providers. PMID- 23924224 TI - Developing a strategic marketing plan for physical and occupational therapy services: a collaborative project between a critical access hospital and a graduate program in health care management. AB - The purpose of this study was to develop a marketing plan for the Physical and Occupational Therapy (PT/OT) department at a Critical Access Hospital (CAH). We took the approach of understanding and analyzing the rural community and health care environment, problems faced by the PT/OT department, and developing a strategic marketing plan to resolve those problems. We used hospital admissions data, public and physician surveys, a SWOT analysis, and tools to evaluate alternative strategies. Lack of awareness and negative perception were key issues. Recommended strategies included building relationships with physicians, partnering with the school district, and enhancing the wellness program. PMID- 23924225 TI - Getting the focus right: New Zealand baby boomers and advertisements for glasses. AB - Although baby boomers constitute an attractive market segment in terms of spending power and size, they have been largely ignored and/or misunderstood by advertisers. This article presents the results of qualitative research into New Zealand baby boomers' responses to advertisements for glasses as a specific health-related product. Key themes emphasize an advertisement's "relate-ability"; the use of "real" characters; the importance of narrative in engaging the viewer; and the standout design elements of information intensity, humor, and point of difference. Themes are related to advertisements for glasses and illustrated in a mock-up "ideal ad" for glasses. Finally, practical recommendations are made for more effective advertising of glasses to baby boomers. PMID- 23924226 TI - Triaxial electrospun nanofiber membranes for controlled dual release of functional molecules. AB - A novel dual drug delivery system is presented using triaxial structured nanofibers, which provides different release profiles for model drugs separately loaded in either the sheath or the core of the fiber. Homogenous, coaxial and triaxial fibers containing a combination of materials (PCL, polycaprolactone; PVP, polyvinylpyrrolidone) were fabricated. The drug release profiles were simulated using two color dyes (KAB, keyacid blue; KAU, keyacid uranine), whose release in physiological solution was measured using optical absorption as a function of time. To reach the level of 80% release of encapsulated dye from core, triaxial fibers with a PCL intermediate layer exhibited a ~24* slower release than that from coaxial fibers. At the same time, the hygroscopic sheath layer of the triaxial fibers provided an initial burst release (~ 80% within an hour) of a second dye as high as that from conventional single and coaxial fibers. The triaxial fiber membrane provides both a quick release from the outer sheath layer for short-term treatment and a sustained release from the fiber core for long-term treatment. The intermediate layer between inner core and outer sheath acts as a barrier to prevent leaching from the core, which can be especially important when the membranes are used in wet application. The formation of tri/multiaxially electrospun nanofibrous membranes will be greatly beneficial for biomedical applications by enabling different release profiles of two different drugs from a membrane. PMID- 23924228 TI - Santos et al. reply. PMID- 23924229 TI - Feedback on end-of-life care in dementia: the study protocol of the FOLlow-up project. AB - BACKGROUND: End-of-life care in dementia in nursing homes is often found to be suboptimal. The Feedback on End-of-Life care in dementia (FOLlow-up) project tests the effectiveness of audit- and feedback to improve the quality of end-of life care in dementia. METHODS/DESIGN: Nursing homes systematically invite the family after death of a resident with dementia to provide feedback using the End of-Life in Dementia (EOLD) - instruments. Two audit- and feedback strategies are designed and tested in a three-armed Randomized Controlled Trial (RCT): a generic feedback strategy using cumulative EOLD-scores of a group of patients and a patient specific feedback strategy using EOLD-scores on a patient level. A total of 18 nursing homes, three groups of six homes matched on size, geographic location, religious affiliation and availability of a palliative care unit were randomly assigned to an intervention group or the control group. The effect on quality of care and quality of dying and the barriers and facilitators of audit- and feedback in the nursing home setting are evaluated using mixed-method analyses. DISCUSSION: The FOLlow-up project is the first study to assess and compare the effect of two audit- and feedback strategies to improve quality of care and quality of dying in dementia. The results contribute to the development of practice guidelines for nursing homes to monitor and improve care outcomes in the realm of end-of-life care in dementia. TRIAL REGISTRATION: The Netherlands National Trial Register (NTR). TRIAL NUMBER: NTR3942. PMID- 23924230 TI - Factors associated with the introduction of prelacteal feeds in Nepal: findings from the Nepal Demographic and Health Survey 2011. AB - BACKGROUND: A prelacteal feed is any food except mother's milk provided to a newborn before initiating breastfeeding. Prelacteal feeding is a major barrier to exclusive breastfeeding. It is a prevalent practice in Nepal. Little is known about the factors associated with providing prelacteal feeds to the Nepalese newborn. This study explored the factors associated with providing prelacteal feeds to children under three years in Nepal using the Nepal Demographic and Health Survey (NDHS) 2011. METHODS: This study utilised the NDHS 2011 child dataset which is a nationally representative study. The rates of providing prelacteal feeds were reported as a proportion. Complex Sample Analysis method was used to account for the cluster design and sample weight of the study. Chi square tests and multiple logistic regression were used to analyse the factors associated with providing prelacteal feeds. RESULTS: A sample of 3948 mothers were included in the study. A total of 841 [26.5% (95% CI: 23.1%-30.3%)] weighted proportion) of mothers reported of providing prelacteal feeds to their newborn infants. Plain water (n = 75), sugar/glucose (n = 35), gripe water (n = 3), sugar/salt solution (n = 3), fruit juice (n = 3), infant formula (n = 96), tea (n = 3) and other milk other than breast milk (n = 556) were some of the types of prelacteal feeds reported. The multiple regression analysis showed that the mothers who had no education, were not working, were from the middle wealth quintile, who had not attended four antenatal care visits, were first time mothers and who were from the Terai/Plain region were more likely to provide prelacteal feeds. CONCLUSIONS: Given that one in four infants were provided with prelacteal feeds, there is a need to implement breastfeeding promotion programs to increase the practice of exclusive breastfeeding and reduce prelacteal feeding practices. Breastfeeding counseling at antenatal clinics and peer support for exclusive breastfeeding should be included as part of breastfeeding promotion programs. Mobilisation of female community health volunteers for peer counseling is also a feasible option for Nepal. PMID- 23924231 TI - Application of Illumina next-generation sequencing to characterize the bacterial community of the Upper Mississippi River. AB - AIMS: A next-generation, Illumina-based sequencing approach was used to characterize the bacterial community at ten sites along the Upper Mississippi River to evaluate shifts in the community potentially resulting from upstream inputs and land use changes. Furthermore, methodological parameters including filter size, sample volume and sample reproducibility were evaluated to determine the best sampling practices for community characterization. METHODS AND RESULTS: Community structure and diversity in the river was determined using Illumina next generation sequencing technology and the V6 hypervariable region of 16S rDNA. A total of 16,400 operational taxonomic units (OTUs) were observed (4594 +/- 824 OTUs per sample). Proteobacteria, Actinobacteria, Bacteroidetes, Cyanobacteria and Verrucomicrobia accounted for 93.6 +/- 1.3% of all sequence reads, and 90.5 +/- 2.5% belonged to OTUs shared among all sites (n = 552). Among nonshared sequence reads at each site, 33-49% were associated with potentially anthropogenic impacts upstream of the second sampling site. Alpha diversity decreased with distance from the pristine headwaters, while rainfall and pH were positively correlated with diversity. Replication and smaller filter pore sizes minimally influenced the characterization of community structure. CONCLUSIONS: Shifts in community structure are related to changes in the relative abundance, rather than presence/absence of OTUs, suggesting a 'core bacterial community' is present throughout the Upper Mississippi River. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is among the first to characterize a large riverine bacterial community using a next-generation-sequencing approach and demonstrates that upstream influences and potentially anthropogenic impacts can influence the presence and relative abundance of OTUs downstream resulting in significant variation in community structure. PMID- 23924232 TI - Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. AB - RATIONALE: The origin of cells that make pathologic fibrillar collagen matrix in lung disease has been controversial. Recent studies suggest mesenchymal cells may contribute directly to fibrosis. OBJECTIVES: To characterize discrete populations of mesenchymal cells in the normal mouse lung and to map their fate after bleomycin-induced lung injury. METHODS: We mapped the fate of Foxd1-expressing embryonic progenitors and their progeny during lung development, adult homeostasis, and after fibrosing injury in Foxd1-Cre; Rs26-tdTomato-R mice. We studied collagen-I(alpha)1-producing cells in normal and diseased lungs using Coll-GFP(Tg) mice. MEASUREMENTS AND MAIN RESULTS: Foxd1-expressing embryonic progenitors enter lung buds before 13.5 days post-conception, expand, and form an extensive lineage of mesenchymal cells that have characteristics of pericytes. A collagen-I(alpha)1-expressing mesenchymal population of distinct lineage is also found in adult lung, with features of a resident fibroblast. In contrast to resident fibroblasts, Foxd1 progenitor-derived pericytes are enriched in transcripts for innate immunity, vascular development, WNT signaling pathway, and cell migration. Foxd1 progenitor-derived pericytes expand after bleomycin lung injury, and activate expression of collagen-I(alpha)1 and the myofibroblast marker alphaSMA in fibrotic foci. In addition, our studies suggest a distinct lineage of collagen-I(alpha)1-expressing resident fibroblasts that also expands after lung injury is a second major source of myofibroblasts. CONCLUSIONS: We conclude that the lung contains an extensive population of Foxd1 progenitor derived pericytes that are an important lung myofibroblast precursor population. PMID- 23924234 TI - In situ observations of the atomistic mechanisms of Ni catalyzed low temperature graphene growth. AB - The key atomistic mechanisms of graphene formation on Ni for technologically relevant hydrocarbon exposures below 600 degrees C are directly revealed via complementary in situ scanning tunneling microscopy and X-ray photoelectron spectroscopy. For clean Ni(111) below 500 degrees C, two different surface carbide (Ni2C) conversion mechanisms are dominant which both yield epitaxial graphene, whereas above 500 degrees C, graphene predominantly grows directly on Ni(111) via replacement mechanisms leading to embedded epitaxial and/or rotated graphene domains. Upon cooling, additional carbon structures form exclusively underneath rotated graphene domains. The dominant graphene growth mechanism also critically depends on the near-surface carbon concentration and hence is intimately linked to the full history of the catalyst and all possible sources of contamination. The detailed XPS fingerprinting of these processes allows a direct link to high pressure XPS measurements of a wide range of growth conditions, including polycrystalline Ni catalysts and recipes commonly used in industrial reactors for graphene and carbon nanotube CVD. This enables an unambiguous and consistent interpretation of prior literature and an assessment of how the quality/structure of as-grown carbon nanostructures relates to the growth modes. PMID- 23924233 TI - Modulation of allergen-induced bronchoconstriction by fluticasone furoate and vilanterol alone or in combination. AB - BACKGROUND: This placebo-controlled study assessed the effects of the once-daily inhaled corticosteroid (ICS) fluticasone furoate (FF) and long-acting beta(2) agonist (LABA) vilanterol (VI) on early and late asthmatic responses (EAR/LAR) and airway hyper-responsiveness (AHR). METHODS: Patients (n = 27) were randomized to FF (100 MUg), VI (25 MUg), FF/VI (100/25 MUg), and placebo for 21 days (four periods). Allergen challenge was performed 1 h post-dose on day 21. AHR was assessed on day 22 using methacholine. RESULTS: Allergen challenge caused an early change (0-2 h) in minimum forced expiratory volume in 1 s (FEV(1)) of 1.091 l (95% CI: -1.344; -0.837) following placebo therapy; changes were -0.955 l (-1.209; -0.702), -0.826 l (-1.070; -0.581), and -0.614 l (-0.858; -0.370) following VI, FF, or FF/VI therapy, respectively. Treatment differences were significant for all comparisons between therapies. Mean changes in 0-2 h %FEV(1) were as follows: -28.05 (placebo), -23.10 (VI), -22.33 (FF), and -16.10 (FF/VI). Following placebo, the late change (4-10 h) in weighted mean FEV(1) was -0.466 l (-0.589; -0.343) and -0.298 l (-0.415; -0.181) after VI, and was +0.018 l with both FF/VI (-0.089; 0.124) and FF (-0.089; 0.125). Treatment differences were significant for all comparisons between therapies except FF/VI vs FF. Mean changes in 4-10 h %FEV(1) were as follows: -21.08 (placebo), -14.30 (VI), -5.02 (FF), and -5.83 (FF/VI). AHR 24 h after allergen challenge was significantly reduced with FF/VI and FF vs placebo, and FF/VI was superior to either component. CONCLUSION: Combined treatment with FF/VI provides additive protection from the EAR relative to its components, significant protection over VI alone from the LAR, and confers sustained protection from hyper-responsiveness 24 h post-dose. PMID- 23924235 TI - Abdominal tuberculosis following kidney transplantation: clinicopathologic features and follow-up in a unique case series. AB - BACKGROUND: Kidney transplant recipients are at a high risk of opportunistic infection. The aims of this study were to describe the epidemiology, clinical features, and prognosis of abdominal tuberculosis (TB) in kidney transplant recipients. METHODS: All cases of abdominal TB that occurred in kidney transplant recipients at our center between 1998 and 2010 were retrospectively reviewed. Detailed demographic data, clinical profile information, and the treatment response were recorded. RESULTS: Among the 7833 kidney transplantations performed during the study period, eight patients (0.1%) developed abdominal TB. There were four men and four women in this group. The mean age of the patients was 44 +/- 12 yr. The time from kidney transplantation to TB was 6.7 +/- 3.4 yr. The symptoms were weight loss (87.5%), diarrhea (87.5%), fever (75%), abdominal pain (62.5%), and lower gastrointestinal bleeding (37.5%). The delay between the identification of the clinical symptoms and the diagnosis was an average of six months. The diagnosis was confirmed histopathologically for most patients. The cecum and ascending colon were the most common sites involved. Two patients required surgical intervention. Five patients received a 4-drug regimen, and three had hepatotoxicity. The median length of antituberculous therapy was nine (6-12) months. Five patients lost their graft. Overall, the hospital mortality was 12.5%. CONCLUSIONS: Kidney transplantation increases the risk of TB, particularly as an extrapulmonary disease. The symptoms of infection are often attenuated, leading to delayed diagnosis. Therefore, a careful approach to the patient and supportive data are necessary to make the final and timely diagnosis. PMID- 23924236 TI - cis-Restricted 3-aminopyrazole analogues of combretastatins: synthesis from plant polyalkoxybenzenes and biological evaluation in the cytotoxicity and phenotypic sea urchin embryo assays. AB - We have synthesized a series of novel cis-restricted 4,5-polyalkoxydiaryl-3 aminopyrazole analogues of combretastatins via short synthetic sequences using building blocks isolated from dill and parsley seed extracts. The resulting compounds were tested in vivo in the phenotypic sea urchin embryo assay to reveal their antimitotic and antitubulin effects. The most potent aminopyrazole, 14a, altered embryonic cell division at 10 nM concentration, exhibiting microtubule destabilizing properties. Compounds 12a and 14a displayed pronounced cytotoxicity in the NCI60 anticancer drug screen, with the ability to inhibit growth of multi drug-resistant cancer cells. PMID- 23924237 TI - Safety and immunogenicity of the quadrivalent HPV vaccine in female Systemic Lupus Erythematosus patients aged 12 to 26 years. AB - BACKGROUND: Women with SLE have higher rates of persistent human papilloma virus (HPV) infections and precancerous lesions than healthy women. HPV vaccine is safe and effective in healthy females aged 9-26 years. There are limited data on the safety and immunogenicity of HPV vaccine in females with SLE, and none in adolescents with SLE. Our study evaluates the safety and immunogenicity of recombinant quadrivalent HPV vaccine, Gardasil, in adolescents and young women with SLE. METHODS: This is a prospective, open-label study. Exclusion criteria included disease exacerbation within past 30 days; rituximab or cyclophosphamide within 6 months; pregnancy. Vaccine was administered at months 0, 2, and 6. Physical examination, SLEDAI scores and laboratory studies were performed at months 0, 2, 4, 6 and 7. Each patient's SLEDAI scores and laboratory profile in the year prior to vaccine administration were used as controls for that patient. Primary outcome measures were change in SLEDAI and mean HPV antibody titers. RESULTS: 27 patients, 12 to 26 years, were enrolled; 20 completed the study. Nine had mild/moderate lupus flares. Mean SLEDAI scores decreased from 6.14 pre vaccination to 4.49 post-vaccination (p = 0.01). Of 12 patients with lupus nephritis, two experienced worsening renal function during/after the study and progressed to renal failure within 18 months of the study. Both had Class IV lupus nephritis with high chronicity scores (>= 8) on renal biopsies performed within one year prior to study entry. Seropositivity post-vaccine was >94% for HPV 6, 11, 16 and 18. CONCLUSIONS: Quadrivalent HPV vaccine seems generally safe and well tolerated in this series of adolescents and young women with SLE, with no increase in mean SLEDAI scores. Progression to renal failure in two patients was most likely secondary to pre-existing severe renal chronicity and not secondary to HPV vaccination. Immunogenicity to the quadrivalent HPV vaccine was excellent, with the seropositivity rate >94% in all four HPV types. PMID- 23924240 TI - Cocaine Addiction Treatment and Home Remedies: Use of the Scopolamine Transdermal Patch. AB - Recently, there has been an enormous increase in the number of people seeking treatment for cocaine addiction. Fifteen male cocaine users aged 20-30 years who requested hair analysis from our forensic toxicology laboratory (Perugia, Italy) from March to June 2012, reported using scopolamine without medical supervision to reduce the anxiety associated with cocaine withdrawal. Self-reports were verified with the results obtained from the hair analysis. We discuss whether the use of scopolamine in cocaine abusers could be supported by a neurobiological and pharmacological point of view. PMID- 23924239 TI - Structural analyses of experimental 13C edited amide I' IR and VCD for peptide beta-sheet aggregates and fibrils using DFT-based spectral simulations. AB - In the preceding paper, computational models based on density functional theory (DFT) were presented to characterize the sensitivity of vibrational spectroscopic methods (IR, VCD, and Raman) to structural features of beta-sheets. Isotopically edited amide I' IR for peptides labeled with (13)C in multiple different sites provides the most structurally distinct signatures of strand alignment, while VCD is sensitive to the sheet twist and intersheet stacking. In this report, we simulate the IR and VCD spectra for models approximating structures of four beta sheet forming peptides previously experimentally studied using these methods with (13)C isotopic editing. Various register alignments are tested. Agreement with experiment is evaluated based on frequency shifts of both the (12)C and (13)C IR amide I' signals, relative intensity patterns, and VCD spectra where available. While for the simulation of IR spectra canonical planar sheets provide a sufficient model system, for VCD simulation twisted, stacked sheets are required in order to reproduce strong couplet-like amide I' VCD. Effects of the solvent (water) and amino acid side chains are also tested by using a simplified, electrostatic solvent model and atomic partial charges for the side chains. Very good agreement with experimental spectra is obtained, particularly for the relative (12)C and (13)C band frequencies. All four peptide models are shown to be antiparallel as had previously been assumed. However, in some cases our simulations are consistent with different register alignment of strands than originally proposed. PMID- 23924238 TI - Level of colorectal cancer awareness: a cross sectional exploratory study among multi-ethnic rural population in Malaysia. AB - BACKGROUND: This paper presents the level of colorectal cancer awareness among multi-ethnic rural population in Malaysia. METHODS: A rural-based cross sectional survey was carried out in Perak state in Peninsular Malaysia in March 2011. The survey recruited a population-representative sample using multistage sampling. Altogether 2379 participants were included in this study. Validated bowel/colorectal cancer awareness measure questionnaire was used to assess the level of colorectal cancer awareness among study population. Analysis of variance (ANOVA) was done to identify socio-demographic variance of knowledge score on warning signs and risk factors of colorectal cancer. RESULTS: Among respondents, 38% and 32% had zero knowledge score for warning signs and risk factors respectively. Mean knowledge score for warning signs and risk factors were 2.89 (SD 2.96) and 3.49 (SD 3.17) respectively. There was a significant positive correlation between the knowledge score of warning signs and level of confidence in detecting a warning sign. Socio-demographic characteristics and having cancer in family and friends play important role in level of awareness. CONCLUSIONS: Level of awareness on colorectal cancer warning signs and risk factors in the rural population of Malaysia is very low. Therefore, it warrants an extensive health education campaign on colorectal cancer awareness as it is one of the commonest cancer in Malaysia. Health education campaign is urgently needed because respondents would seek medical attention sooner if they are aware of this problem. PMID- 23924241 TI - Exploring Smokers' Knowledge and Expectations Toward Nicotine Vaccination: A Qualitative Study. AB - Knowledge and expectations toward smoking cessation therapies may influence effectiveness. Nicotine vaccination is a novel and promising new therapy for smoking cessation. This qualitative study explored smokers' knowledge and expectations toward nicotine vaccination as well as varenicline and counseling for smoking cessation. We conducted focus group discussions and interviews in 25 smokers at Maastricht University, the Netherlands, in 2010. Data were analyzed using conventional content analysis. Participants had serious misconceptions about the purpose of nicotine vaccination, particularly the belief that nicotine vaccines reduce craving. Expectations toward counseling were highest. These results underline misconceptions smokers can have about cessation therapies. PMID- 23924242 TI - Tribology and stability of organic monolayers on CrN: a comparison among silane, phosphonate, alkene, and alkyne chemistries. AB - The fabrication of chemically and mechanically stable monolayers on the surfaces of various inorganic hard materials is crucial to the development of biomedical/electronic devices. In this Article, monolayers based on the reactivity of silane, phosphonate, 1-alkene, and 1-alkyne moieties were obtained on the hydroxyl-terminated chromium nitride surface. Their chemical stability and tribology were systematically investigated. The chemical stability of the modified CrN surfaces was tested in aqueous media at 60 degrees C at pH 3, 7, and 11 and monitored by static water contact angle measurements, X-ray photoelectron spectroscopy (XPS), ellipsometry, and Fourier transform infrared reflection absorption spectroscopy (FT-IRRAS). The tribological properties of the resulting organic monolayers with different end groups (fluorinated or nonfluorinated) were studied using atomic force microscopy (AFM). It was found that the fluorinated monolayers exhibit a dramatic reduction of adhesion and friction force as well as excellent wear resistance compared to those of nonfluorinated coatings and bare CrN substrates. The combination of remarkable chemical stability and superior tribological properties makes these fluorinated monolayers promising candidates for the development of robust high-performance devices. PMID- 23924243 TI - Spiro fused diterpene-indole alkaloids from a creek-bottom-derived Aspergillus terreus. AB - Four metabolites, teraspiridoles A-D (2-5), formed from the merger of a diterpene and modified indole scaffold were obtained from an Aspergillus terreus isolate. The structures and absolute configurations of these natural products were established using NMR, mass spectrometry, Marfey's method, VCD, and ECD data. Teraspiridole B (3) exhibited weak inhibition of planaria regeneration/survival. PMID- 23924244 TI - Navigating ambivalence: how heterosexual young adults make sense of desire differences. AB - The miscommunication hypothesis is the assumption that many incidents of acquaintance rape and coercive sex follow from miscommunication between men and women. This hypothesis is entrenched in popular, academic, and judicial understandings of sexual relationships. Recently some evidence has suggested that there is little miscommunication between sexual partners and that the hypothesis does not explain acquaintance rape or other forms of sexual violence. The present study used qualitative methodology in which men and women were asked to imagine themselves in a particular heterosexual dating situation and write what they think happened between the beginning (when sex was refused by one partner) and the end (when sex happened). Thematic analysis of the data found no evidence for miscommunication between partners under conditions of differences in desire. Instead, ambivalence about sexual activity was commonly described by women and men and was most often resolved to both parties' satisfaction. Coercion by men was present in a minority of narratives under conditions of clear understanding of women's refusals. The study thus provides a rich, experience-based representation of heterosexual sexual activity, with considerable potential for the development of effective education campaigns. PMID- 23924246 TI - Science potential from a Europa lander. AB - The prospect of a future soft landing on the surface of Europa is enticing, as it would create science opportunities that could not be achieved through flyby or orbital remote sensing, with direct relevance to Europa's potential habitability. Here, we summarize the science of a Europa lander concept, as developed by our NASA-commissioned Science Definition Team. The science concept concentrates on observations that can best be achieved by in situ examination of Europa from its surface. We discuss the suggested science objectives and investigations for a Europa lander mission, along with a model planning payload of instruments that could address these objectives. The highest priority is active sampling of Europa's non-ice material from at least two different depths (0.5-2 cm and 5-10 cm) to understand its detailed composition and chemistry and the specific nature of salts, any organic materials, and other contaminants. A secondary focus is geophysical prospecting of Europa, through seismology and magnetometry, to probe the satellite's ice shell and ocean. Finally, the surface geology can be characterized in situ at a human scale. A Europa lander could take advantage of the complex radiation environment of the satellite, landing where modeling suggests that radiation is about an order of magnitude less intense than in other regions. However, to choose a landing site that is safe and would yield the maximum science return, thorough reconnaissance of Europa would be required prior to selecting a scientifically optimized landing site. PMID- 23924245 TI - Facile chemical functionalization of proteins through intein-linked yeast display. AB - Intein-mediated expressed protein ligation (EPL) permits the site-specific chemical customization of proteins. While traditional techniques have used purified, soluble proteins, we have extended these methods to release and modify intein fusion proteins expressed on the yeast surface, thereby eliminating the need for soluble protein expression and purification. To this end, we sought to simultaneously release yeast surface-displayed proteins and selectively conjugate with chemical functionalities compatible with EPL and click chemistry. Single chain antibodies (scFv) and green fluorescent protein (GFP) were displayed on the yeast surface as fusions to the N-terminus of the Mxe GyrA intein. ScFv and GFP were released from the yeast surface with either a sulfur nucleophile (MESNA) or a nitrogen nucleophile (hydrazine) linked to an azido group. The hydrazine azide permitted the simultaneous release and azido functionalization of displayed proteins, but nonspecific reactions with other yeast proteins were detected, and cleavage efficiency was limited. In contrast, MESNA released significantly more protein from the yeast surface while also generating a unique thioester at the carboxy-terminus of the released protein. These protein thioesters were subsequently reacted with a cysteine alkyne in an EPL reaction and then employed in an azide-alkyne cycloaddition to immobilize the scFv and GFP on an azide decorated surface with >90% site-specificity. Importantly, the immobilized proteins retained their activity. Since yeast surface display is also a protein engineering platform, these approaches provide a particularly powerful tool for the rapid assessment of engineered proteins. PMID- 23924247 TI - Disaggregation of amyloid plaque in brain of Alzheimer's disease transgenic mice with daily subcutaneous administration of a tetravalent bispecific antibody that targets the transferrin receptor and the Abeta amyloid peptide. AB - Anti-amyloid antibodies (AAA) are under development as new therapeutics that disaggregate the amyloid plaque in brain in Alzheimer's disease (AD). However, the AAAs are large molecule drugs that do not cross the blood-brain barrier (BBB), in the absence of BBB disruption. In the present study, an AAA was re engineered for receptor-mediated transport across the BBB via the endogenous BBB transferrin receptor (TfR). A single chain Fv (ScFv) antibody form of an AAA was fused to the carboxyl terminus of each heavy chain of a chimeric monoclonal antibody (mAb) against the mouse TfR, and this produced a tetravalent bispecific antibody designated the cTfRMAb-ScFv fusion protein. Unlike a conventional AAA, which has a plasma half-time of weeks, the cTfRMAb-ScFv fusion protein is cleared from plasma in mice with a mean residence time of about 3 h. Therefore, a novel protocol was developed for the treatment of one year old presenilin (PS) 1/amyloid precursor protein (APP) AD double transgenic PSAPP mice, which were administered daily subcutaneous (sc) injections of 5 mg/kg of the cTfRMAb-ScFv fusion protein for 12 consecutive weeks. At the end of the treatment, brain amyloid plaques were quantified with confocal microscopy using both Thioflavin-S staining and immunostaining with the 6E10 antibody against Abeta amyloid fibrils. Fusion protein treatment caused a 57% and 61% reduction in amyloid plaque in the cortex and hippocampus, respectively. No increase in plasma immunoreactive Abeta amyloid peptide, and no cerebral microhemorrhage, was observed. Chronic daily sc treatment of the mice with the fusion protein caused no immune reactions and only a low titer antidrug antibody response. In conclusion, re-engineering AAAs for receptor-mediated BBB transport allows for reduction in brain amyloid plaque without cerebral microhemorrhage following daily sc treatment for 12 weeks. PMID- 23924248 TI - A facile method to prepare molecularly imprinted layer-by-layer nanostructured multilayers using postinfiltration and a subsequent photo-cross-linking strategy. AB - In this paper, we have demonstrated a facile strategy to prepare molecularly imprinted layer-by-layer nanostructured films. This strategy has circumvented the requirement of using photocross-linkable polymers, which suffered from tedious synthetic processes in the construction of surface molecular imprinting in layer by-layer (SMI-LbL) devices. The described SMI-LbL device was constructed by employing the traditional construction procedures of LbL systems, followed by the postinfiltration of bifunctional photosensitive cross-linking agent 4,4' diazostilbene-2,2'-disulfonic acid disodium salt into the prepared multilayers, and subsequent photocross-linking. A robust SMI-LbL device with high fatigue resistance was achieved. The preparation conditions have been optimized to achieve repeated unloading and rebinding of the targeting molecule with high fidelity. The combination of templating and cross-linking is the core factor to achieve high fidelity and high efficiency of the SMI-LbL device. PMID- 23924249 TI - Platelet reactivity changes significantly throughout all trimesters of pregnancy compared with the nonpregnant state: a prospective study. AB - OBJECTIVE: Platelets play an important role in the pathophysiology of uteroplacental disease and platelet reactivity may be an important marker of uteroplacental disease activity. However, platelet reactivity has not been evaluated comprehensively in normal pregnancy. We sought to evaluate platelet reactivity using a number of agonists at defined time points in pregnancy using a novel platelet assay and compare these with a nonpregnant cohort. DESIGN: Prospective longitudinal study. SETTING: Outpatient department of a large tertiary referral centre. SAMPLE: Eighty participants with 30 nonpregnant women and 50 pregnant women assessed longitudinally. METHODS: This was a prospective cohort study performed longitudinally throughout uncomplicated singleton pregnancies with participants recruited before 15 weeks of gestation. They were controlled for a number of factors known to affect platelet reactivity. Blood samples were obtained in each trimester. Thirty nonpregnant healthy female volunteers also had a platelet assay performed. A modification of standard light transmission aggregometry was used to assess platelet function, with light absorbance measured following the addition of five different agonists at submaximal concentrations. Dose-response curves were plotted for each agonist for the nonpregnant cohort and in each trimester for the pregnant cohort. MAIN OUTCOME MEASURES: Dose-response curves and median effective concentration. RESULTS: When compared with the nonpregnant controls a significant reduction was demonstrated in platelet reactivity to collagen during the first trimester of pregnancy (P < 0.0001). Platelet aggregation increased significantly from the first to third trimesters in response to collagen and arachidonic acid. CONCLUSION: Platelet reactivity varies according to pregnancy state, gestational age and agonist. The finding that platelet reactivity is reduced in the first trimester of pregnancy may be useful for the interpretation of further studies examining the role of platelet reactivity in the first trimester of pregnancies that develop uteroplacental disease. PMID- 23924251 TI - Outcomes of an exercise program for pain and fatigue management in adults with cerebral palsy. AB - PURPOSE: The purpose of this exploratory pilot study was to examine the effect of exercise on pain and fatigue in adults with CP. METHOD: Twenty-six participants (12 ambulatory, 14 non-ambulatory; 10 males, 16 females; mean age 42.3 +/- 11.2 years) enrolled in a study using a repeated measures design including baseline, intervention and follow-up phases of 12 weeks each; 20 participants completed all phases. Primary outcome measures used were the FACES pain scale, the count of body parts with pain and the PedsQLTM Multidimensional Fatigue Scale. RESULTS: Significant beneficial changes were found in the pain and fatigue scales among the ambulatory participants during the intervention phase. However the beneficial changes diminished during the follow-up phase. Secondary outcomes examined included, pain interference, daily physical activity and health-related quality of life. CONCLUSION: Study outcomes suggest that exercise may provide some benefit for ambulatory adults with CP. Implications for Rehabilitation Pain and fatigue are secondary conditions experienced by many adults with cerebral palsy which have a significant impact on function and quality of life. Physical activity is an intervention which has been demonstrated to decrease both pain and fatigue in other health conditions. In a relatively small sample, this study demonstrates decreased pain and fatigue after an exercise intervention in ambulatory adults with cerebral palsy. PMID- 23924250 TI - Rapid quantification of sequence repeats to resolve the size, structure and contents of bacterial genomes. AB - BACKGROUND: The numerous classes of repeats often impede the assembly of genome sequences from the short reads provided by new sequencing technologies. We demonstrate a simple and rapid means to ascertain the repeat structure and total size of a bacterial or archaeal genome without the need for assembly by directly analyzing the abundances of distinct k-mers among reads. RESULTS: The sensitivity of this procedure to resolve variation within a bacterial species is demonstrated: genome sizes and repeat structure of five environmental strains of E. coli from short Illumina reads were estimated by this method, and total genome sizes corresponded well with those obtained for the same strains by pulsed-field gel electrophoresis. In addition, this approach was applied to read-sets for completed genomes and shown to be accurate over a wide range of microbial genome sizes. CONCLUSIONS: Application of these procedures, based solely on k-mer abundances in short read data sets, allows aspects of genome structure to be resolved that are not apparent from conventional short read assemblies. This knowledge of the repetitive content of genomes provides insights into genome evolution and diversity. PMID- 23924252 TI - Using video-elicitation to assess risks and potential falls reduction strategies in long term care. AB - PURPOSE: To assess the ability to use and the usefulness of video-elicitation to study risks and potential ways to reduce transfer-related falls in long term care. METHOD: A qualitative research study was conducted in a long term care facility and included a purposeful sample of 16 subjects (6 residents, 6 health care providers, and 4 family members). Field observations, interviews, video recordings of assisted transfers, and video-elicitation sessions were conducted with the participants. The interviews and video-elicitation sessions were digitally recorded, transcribed and coded independently by at least 2 analysts. The codes were organized under themes. RESULTS: Six themes related to risks and reduction of transfer-related falls were identified - environment, behaviors, health conditions, specific activities, knowledge and awareness, and balancing values. CONCLUSIONS: We were able to implement the novel participatory video elicitation method developed and it was useful to identify risks and risk reduction strategies. Therefore, video-elicitation may be used in future studies to inform the design and testing of interventions to reduce transfer-related falls among LTC residents. Implications for Rehabilitation Falls are common among long term care residents. Visual-elicitation is a useful tool to be used in rehabilitation to assess risks and possible measures to reduce falls. The video elicitation sessions optimized the ability and engaged residents, health care providers, and family members on providing information and discussing risks and potential measures to reduce transfer-related falls. PMID- 23924254 TI - Dietary, food service, and mealtime interventions to promote food intake in acute care adult patients. AB - Malnutrition is common in acute care hospitals. During hospitalization, poor appetite, medical interventions, and food access issues can impair food intake leading to iatrogenic malnutrition. Nutritional support is a common intervention with demonstrated effectiveness. "Food first" approaches have also been developed and evaluated. This scoping review identified and summarized 35 studies (41 citations) that described and/or evaluated dietary, foodservice, or mealtime interventions with a food first focus. There were few randomized control trials. Individualized dietary treatment leads to improved food intake and other positive outcomes. Foodservices that promote point-of-care food selection are promising, but further research with food intake and nutritional outcomes is needed. Protected mealtimes have had insufficient implementation, leading to mixed results, while mealtime assistance, particularly provided by volunteers or dietary staff, appears to promote food intake. A few innovative strategies were identified but further research to develop and evaluate food first approaches is needed. PMID- 23924253 TI - Rehabilitation interventions for children living with HIV: a scoping review. AB - PURPOSE: To report the extent (how many), range (variation) and nature (qualities) of rehabilitation interventions for children living with HIV. METHOD: Electronic databases, reference lists of included articles, and grey literature were searched. Title and abstract and full text review were completed independently by two reviewers. Each study's location, research methodology, interventions, the age of the participants, whether participants were receiving antiretroviral therapy (ART), the health professions delivering the interventions, when the study was conducted and the composition of the research team were documented. The nature of the intervention goals was organized into qualitative categories. RESULTS: The 17 included studies were conducted in seven countries. Seven rehabilitation professions were involved with the interventions. The age of the participants ranged from 3 months to 24 years. The year in which the study was conducted and whether children were receiving ART were rarely specified. Studies focused on impairments. There were no studies on activity limitations and only two studies on participation restrictions. Alternative and complementary therapies were the most common interventions. CONCLUSIONS: Research in this area is limited. More rehabilitation research is needed especially in areas where the burden of the disease is highest and for those children receiving ART. Implications for Rehabilitation Many low-and-middle-income countries (LMICs) struggle with an undersupply of trained rehabilitation professionals. Due to the large number of children living with HIV in LMICs, and as more continue to receive life-saving treatment, the need will grow for more rehabilitation professionals to work with this population to address HIV-related disability. This scoping review indicates that there is a dearth of research on interventions provided by allied health professionals, including physiotherapists, occupational therapists and speech language pathologists for children living with HIV. There is a moderate literature base supporting the use of alternative and complementary therapies for children living with HIV. PMID- 23924255 TI - Defining skilled nursing facility residents' dining style preferences. AB - The desire of skilled nursing facilities to increase quality of service to meet changes in residents' expectations, improve marketability, and adhere to regulations warrant a new look at culture change and homelike dining as defined by residents in skilled nursing facilities (SNF). The objectives of this study were to determine residents' home dining practices, to define residents' desired dining style practices in the SNF, and to determine the relationship between home dining practices and dining preferences in SNF. One hundred and four residents in three SNF in the central Texas area who met the cognition criteria and consumed facility-provided food were engaged in a standardized interview using the Resident Dining Style Preferences Survey. Data were analyzed to determine the degree to which home practices determine SNF dining preferences. Our findings showed that the majority of the participants want hot, home cooked meals served in the dining room. They want to be seated at the table with friends and neighbors and served on every day plates in a quiet atmosphere, with food served restaurant or table service style. Length of stay and generational group were not significant predictors of dining style preferences. Study limitations included small sample size and lack of ethnic diversity. Our study results show that removing dining time restrictions may be the most valuable adaptation for a SNF looking to initiate culture change. PMID- 23924256 TI - Patients aged 80 years and older accrue similar benefits from total parenteral nutrition compared to middle-aged patients. AB - Age is becoming less of a consideration to aggressive medical and surgical interventions. The aim of this study was to evaluate whether patients older than 80 years showed similar gains from total parenteral nutrition (TPN) in terms of nutritional and inflammatory markers compared to patients 35 to 50 years old. A database of patients aged >=80 years old (group 1) and patients between 35 and 50 (group 2), on TPN for greater than 1 week, was compiled from the Nutrition Support Service (NSS) database. Patients had C-reactive protein (CRP), prealbumin, and albumin drawn twice weekly. Patients were matched 1:1 based on gender, diabetes, smoking, Subjective Global Assessment score, and diagnosis. Both groups showed comparable improvements in nutritional and inflammatory markers. There were no statistically significant differences in weekly changes to prealbumin, albumin, CRP, and CRP:prealbumin (C:P) ratio between group 1 and group 2 patients. Both groups had similar complication rates (line-related thrombosis, catheter-related bloodstream infections, intra-abdominal sepsis), days on TPN, length of hospitalization, and mortality rate. Patients older than 80 years benefit from aggressive nutritional support by administration of TPN. Age should not be used as an exclusion criterion for patients requiring TPN. PMID- 23924257 TI - Phylloquinone (vitamin K1) intake and pulse pressure as a measure of arterial stiffness in older adults. AB - This study examined the relationships among ethnicity/race, lifestyle factors, phylloquinone (vitamin K1) intake, and arterial pulse pressure in a nationally representative sample of older adults from four ethnic/racial groups: non Hispanic Whites, non-Hispanic Blacks, Mexican Americans, and other Hispanics. This was a cross-sectional study of U.S. representative sample with data from the National Health and Nutrition Examination Surveys, 2007-2008 and 2009-2010 of adults aged 50 years and older (N = 5296). Vitamin K intake was determined by 24 hour recall. Pulse pressure was calculated as the difference between the averages of systolic blood pressure and diastolic blood pressure. Compared to White non Hispanics, the other ethnic/racial groups were more likely to have inadequate vitamin K1 intake. Inadequate vitamin K1 intake was an independent predictor of high arterial pulse pressure. This was the first study that compared vitamin K1 inadequacy with arterial pulse pressure across ethnicities/races in U.S. older adults. These findings suggest that vitamin K screening may be a beneficial marker for the health of older adults. PMID- 23924258 TI - Evaluating the predictive abilities of nutritional screening tools in relation to health outcomes: concerns about the statistical approach. PMID- 23924259 TI - Reply to the "letter to the editor" from Andreas Rosenblad. PMID- 23924260 TI - A coupled modeling and molecular biology approach to microbial source tracking at Cowell Beach, Santa Cruz, CA, United States. AB - Consistently high levels of bacterial indicators of fecal pollution rank Cowell Beach as the most polluted beach in California. High levels of fecal indicator bacteria (FIB), E. coli and enterococci, are measured throughout the summer, resulting in beach advisories with social and economic consequences. The source of FIB, however, is unknown. Speculations have been made that the wrack accumulating on the beach is a major source of FIB to the surf zone. The present study uses spatial and temporal sampling coupled with process-modeling to investigate potential FIB sources and the relative contributions of those sources. Temporal sampling showed consistently high FIB concentrations in the surf zone, sand, and wrack at Cowell Beach, and ruled out the storm drain, the river, the harbor, and the adjacent wharf as the sources of the high concentrations observed in the surf zone. Spatial sampling confirmed that the source of FIB to the beach is terrestrial rather than marine. Modeling results showed two dominant FIB sources to the surf zone: sand for enterococci and groundwater for E. coli. FIB from wrack represented a minor contribution to bacterial levels in the water. Molecular source tracking methods indicate the FIB at the beach is of human and bird origin. The microbial source tracking (MST) approach presented here provides a framework for future efforts. PMID- 23924261 TI - Aspirin for treatment of lithium-associated sexual dysfunction in men: randomized double-blind placebo-controlled study. AB - OBJECTIVES: The aim of the present study was to assess the effect of aspirin on lithium-related sexual dysfunction in men with stable bipolar affective disorder (BAD). METHODS: In a randomized, double-blind, placebo-controlled study, 32 men with stable BAD who had been on lithium maintenance therapy randomly received aspirin (240 mg/day) or placebo for six weeks. The International Index for Erectile Function (IIEF) was used to assess sexual symptoms at baseline, Week 3, and Week 6. Depressive and mania symptoms and plasma lithium concentrations were assessed at baseline and Week 6. Side effects were assessed using a checklist. RESULTS: Thirty patients (15/group) completed the study. Baseline and endpoint lithium concentrations and mania and depressive symptoms did not differ significantly between the two groups. Significant effects of time * treatment interaction were observed for total score [Greenhouse-Geisser: F(1.410,39.466) = 6.084, p = 0.010] and erectile function [Greenhouse-Geisser: F(1.629,45.602) = 7.250, p = 0.003]. By Week 6, patients in the aspirin group showed significantly greater improvement in the total (63.9% improvement from the baseline) and erectile function domain (85.4% improvement from the baseline) scores than the placebo group (14.4% and 19.7% improvement from the baseline, p-values = 0.002 and 0.001, respectively). By Week 6, 12 (80%) patients in the aspirin group and three (20%) patients in the placebo group met the criteria of minimal clinically important change [chi(2) (1) = 10.800, p = 0.001]. Other IIEF domains also showed significant improvement at the end of the trial. The frequency of side effects was similar between the two groups. CONCLUSION: Aspirin effectively improves lithium-related sexual dysfunction in men with stable BAD. PMID- 23924262 TI - Vocational rehabilitation services and employment outcomes for adults with cerebral palsy in the United States. AB - AIM: The aim of this study was to examine the relationship between vocational rehabilitation services provided and work outcomes among people with cerebral palsy (CP), taking in to account demographic characteristics. METHOD: From the US Department of Education Rehabilitation Service Administration Case Service Report (RSA-911) database, data from 3162 individuals with CP (1820 males [57.6%] and 1342 females [42.4% age range 16-54 y) whose cases were closed in 2009, were used in this study. A total of 1567 cases (49.6%) were closed with clients being categorized as 'successful employment' and 1595 cases (50.4%) were closed with clients being classified as unemployed. RESULTS: Multivariate logistic regression was used to examine the relationship between services provided and work outcomes with regard to demographic characteristics. Males aged between 26 and 54 years old with higher education attainment were more likely to be employed. Individuals receiving disability benefits were less likely to be employed. After controlling for the effect of demographic and work disincentive variables, five vocational rehabilitation services significantly predicted employment outcomes (p<0.05), including (1) on-the-job training; (2) job placement assistance; (3) on-the-job support; (4) maintenance services; and (5) rehabilitation technology. INTERPRETATION: Medical and health professionals need to be aware of vocational rehabilitation agencies as a resource for providing medical, psychological, educational, and vocational interventions for adults with CP to help them maximize their employability, to address their much needed work adjustment skills, to establish independent living, and to eventually reach their full potential in participation in society. PMID- 23924263 TI - Efficacy to effectiveness transition of an Educational Program to Increase Colorectal Cancer Screening (EPICS): study protocol of a cluster randomized controlled trial. AB - BACKGROUND: African Americans have the highest incidence and mortality and are less likely than whites to have been screened for colorectal cancer (CRC). Many interventions have been shown to increase CRC screening in research settings, but few have been evaluated specifically for use in African-American communities in real world settings. This study aims to identify the most efficacious approach to disseminate an evidence-based intervention in promoting colorectal screening in African Americans and to identify the factors associated with its efficacy. METHODS/DESIGN: In this study, investigators will recruit 20 community coalitions and 7,200 African-Americans age 50 to 74 to test passive and active approaches to disseminating the Educational Program to Increase Colorectal Cancer Screening (EPICS); to measure the extent to which EPICS is accepted and the fidelity of implementation in various settings and to estimate the potential translatability and public health impact of EPICS. This four-arm cluster randomized trial compares the following implementation strategies: passive arms, (web access to facilitator training materials and toolkits without technical assistance (TA) and (web access, but with technical assistance (TA); active arms, (in-person access to facilitator training materials and toolkits without TA and (in-person access with TA). Primary outcome measures are the reach (the proportion of representative community coalitions and individuals participating) and efficacy (post-intervention changes in CRC screening rates). Secondary outcomes include adoption (percentage of community coalitions implementing the EPICS sessions) and implementation (quality and consistency of the intervention delivery). The extent to which community coalitions continue to implement EPICS post-implementation (maintenance) will also be measured. Cost-effectiveness analysis will be conducted. DISCUSSION: Implementing EPICS in partnership with community coalitions, we hypothesized, will result in more rapid adoption than traditional top-down approaches, and resulting changes in community CRC screening practices are more likely to be sustainable over time. With its national reach, this study has the potential to enhance our understanding of barriers and enablers to the uptake of educational programs aimed at eliminating cancer disparities. TRIAL REGISTRATION: http://www.ClinicalTrials.gov NCT01805622. PMID- 23924265 TI - The relationship between atherogenic index of plasma and epicardial adipose tissue in hemodialysis and peritoneal dialysis patients. AB - INTRODUCTION: Epicardial adipose tissue (EAT) is the true visceral fat depot of the heart. The relationship between coronary artery disease and EAT was shown in end-stage renal disease (ESRD) patients. One of the established risk factor in this population is dyslipidemia. We aimed to determine the relationship between atherogenic index of plasma (AIP) and EAT in ESRD patients. METHODS: This was a cross-sectional study involving 76 ESRD patients receiving PD or HD for >=6 months and 42 healthy subjects. EAT was measured by using an electrocardiogram gated 64-multidetector computed tomography (MDCT). Atherogenic index of plasma was calculated as the logarithmically transformed ratio of the serum trigliseride to HDL-cholesterol. RESULTS: The etiology of ESRD patients was diabetic nephropathy (n = 16), chronic glomerulonephritis (n = 10), hypertensive nephropathy (n = 23), polycystic kidney disease (n = 7), nephrolithiasis (n = 5) and unknown (n = 15). There were no differences with respect to the following variables between ESRD patients and healthy subjects: age; sex; BMI; predialysis levels of DBP; serum levels of albumin, HDL-cholesterol and hemoglobin. However, ESRD patients had higher serum levels of trigliseride, hs-CRP and AIP when compared to healthy subjects. There was a statistically significant relationship between EAT, BMI and AIP in ESRD patients (r = 0.42, p < 0.001 and r = 0.25, p = 0.028, respectively). The stepwise linear regression analysis revealed that age, as well as BMI were independent predictors of EAT. CONCLUSION: We found a relationship between EAT as defined by MDCT and AIP in ESRD patients. Further clinical and experimental studies are needed. PMID- 23924266 TI - Experimental and theoretical studies of selective thiol-ene and thiol-yne click reactions involving N-substituted maleimides. AB - A combination of experimental and computational methods has been used to understand the reactivity and selectivity of orthogonal thiol-ene and thiol-yne "click" reactions involving N-allyl maleimide (1) and N-propargyl maleimide (2). Representative thiols methyl-3-mercaptopropionate and beta-mercaptoethanol are shown to add exclusively and quantitatively to the electron poor maleimide alkene of 1 and 2 under base (Et3N) initiated thiol-Michael conditions. Subsequent radical-mediated thiol-ene or thiol-yne reactions can be carried out to further functionalize the remaining allyl or propargyl moieties in near quantitative yields (>95%). Selectivity, however, can only be achieved when base-initiated thiol-Michael reactions are carried out first, as radical-mediated reactions between equimolar amounts of thiol and N-substituted maleimides give complex mixtures of products. CBS-QB3 calculations have been used to investigate the energetics and kinetics of reactions between a representative thiol (methyl mercaptan) with N-allyl and N-propargyl maleimide under both base-initiated and radical-mediated conditions. Calculations help elucidate the factors that underlie the selective base-initiated and nonselective radical-mediated thiol ene/yne reactions. The results provide additional insights into how to design selective radical-mediated thiol-ene/yne reactions. PMID- 23924264 TI - Chronic exposure to carbon nanotubes induces invasion of human mesothelial cells through matrix metalloproteinase-2. AB - Malignant mesothelioma is one of the most aggressive forms of cancer known. Recent studies have shown that carbon nanotubes (CNTs) are biopersistent and induce mesothelioma in animals, but the underlying mechanisms are not known. Here, we investigate the effect of long-term exposure to high aspect ratio CNTs on the aggressive behaviors of human pleural mesothelial cells, the primary cellular target of human lung mesothelioma. We show that chronic exposure (4 months) to single- and multiwalled CNTs induced proliferation, migration, and invasion of the cells similar to that observed in asbestos-exposed cells. An up regulation of several key genes known to be important in cell invasion, notably matrix metalloproteinase-2 (MMP-2), was observed in the exposed mesothelial cells as determined by real-time PCR. Western blot and enzyme activity assays confirmed the increased expression and activity of MMP-2. Whole genome microarray analysis further indicated the importance of MMP-2 in the invasion gene signaling network of the exposed cells. Knockdown of MMP-2 in CNT and asbestos-exposed cells by shRNA-mediated gene silencing effectively inhibited the aggressive phenotypes. This study demonstrates CNT-induced cell invasion and indicates the role of MMP-2 in the process. PMID- 23924267 TI - S100 proteins and the skin: a review. AB - The structurally related, low-molecular weight S100 proteins constitute a family of proteins that possess a common basic structure allowing them to carry out a range of intracellular and extracellular functions. Unifying intracellular functions relate to regulation of proliferation, energy metabolism, calcium homeostasis, enzyme activities, cell growth and differentiation. Extracellular tasks, however, appear somewhat specific to select S100 members and include participation in innate and adaptive immune responses, tissue development and repair, and/or cell migration and chemotaxis. This review is an attempt to comprehensively summarize the function and expression of S100 proteins selectively expressed in normal skin and/or involved in diseased skin. PMID- 23924268 TI - Effect of Magnolia officinalis and Phellodendron amurense (Relora(r)) on cortisol and psychological mood state in moderately stressed subjects. AB - BACKGROUND: Magnolia (Magnolia officinalis) and Phellodendron (Phellodendron amurense) barks are medicinal plants commonly used as traditional remedies for reducing stress and anxiety. Modern dietary supplements are intended to induce relaxation and reduce stress as well as stress-related eating. Previous studies have shown the combination of Magnolia/Phellodendron (MP) to reduce both cortisol exposure and the perception of stress/anxiety, while improving weight loss in subjects with stress-related eating. Competitive athletes are "stressed" by their intense exercise regimens in addition to their normal activities of daily living and thus may benefit from a natural therapy intended to modulate baseline perceptions of stress and stress hormone exposure. METHODS: We assessed salivary cortisol exposure and psychological mood state in 56 subjects (35 men and 21 women) screened for moderate stress and supplemented with a standardized/patented MP combination (Relora(r), Next Pharmaceuticals) or Placebo for 4 weeks. RESULTS: After 4 weeks of supplementation, salivary cortisol exposure was significantly (p<0.05) lower (-18%) in the Relora group compared to Placebo. Compared to Placebo, the Relora group had significantly better (p<0.05) mood state parameters, including lower indices of Overall Stress (-11%), Tension (-13%), Depression (-20%), Anger (-42%), Fatigue (-31%), and Confusion (-27%), and higher indices of Global Mood State (+11%) and Vigor (+18%). CONCLUSION: These results indicate that daily supplementation with a combination of Magnolia bark extract and Phellodendron bark extract (Relora(r)) reduces cortisol exposure and perceived daily stress, while improving a variety of mood state parameters, including lower fatigue and higher vigor. These results suggest an effective natural approach to modulating the detrimental health effects of chronic stress in moderately stressed adults. Future studies should examine the possible performance and recovery benefits of Relora supplementation in athletes overstressed by the physical and psychological demands of training and competition. PMID- 23924269 TI - Assessment of the interplay between blood and skin vascular abnormalities in adult purpura fulminans. AB - RATIONALE: Purpura fulminans in adults is a rare but devastating disease. Its pathophysiology is not well known. OBJECTIVES: To understand the pathophysiology of skin lesions in purpura fulminans, the interplay between circulating blood and vascular alterations was assessed. METHODS: Prospective multicenter study in four intensive care units. Patients with severe sepsis without skin lesions were recruited as control subjects. MEASUREMENTS AND MAIN RESULTS: Twenty patients with severe sepsis and purpura fulminans were recruited for blood sampling, and skin biopsy was performed in deceased patients. High severity of disease and mortality rates (80%) was observed. Skin biopsies in purpura fulminans lesions revealed thrombosis and extensive vascular damage: vascular congestion and dilation, endothelial necrosis, alteration of markers of endothelial integrity (CD31) and of the protein C pathway receptors (endothelial protein C receptor, thrombomodulin). Elevated plasminogen activating inhibitor-1 mRNA was also observed. Comparison with control patients showed that these lesions were specific to purpura fulminans. By contrast, no difference was observed for blood hemostasis parameters, including soluble thrombomodulin, activated protein C, and disseminated intravascular coagulation markers. Bacterial presence at the vascular wall was observed specifically in areas of vascular damage in eight of nine patients tested (including patients with Streptococcus pneumoniae, Neisseria meningitidis, Escherichia coli, and Pseudomonas aeruginosa infection). CONCLUSIONS: Thrombi and extensive vascular damage with multifaceted prothrombotic local imbalance are characteristics of purpura fulminans. A "vascular wall infection" hypothesis, responsible for endothelial damage and subsequent skin lesions, can be put forward. PMID- 23924270 TI - Zolpidem induces paradoxical metabolic and vascular changes in a patient with PVS. AB - INTRODUCTION: Zolpidem is a non-benzodiazepine drug used for the therapy of insomnia, which has selectivity for stimulating the effect of GABA-A receptors. Recently, a paradoxical arousing effect of zolpidem in patients with severe brain damage has been repeatedly reported. METHODS: A placebo-controlled magnetic resonance study was conducted to evaluate its effect on BOLD and metabolites spectral signals in a patient with severe brain injuries and an age-matched healthy volunteer. A multi-modal analysis was used to assess aspects in the pharmacologically-induced changes in the resting-state brain metabolism. RESULTS: A significantly increased BOLD signal was transiently localized in the left frontal cortices, bilateral anterior cingulated areas, left thalamus and right head of the caudate nucleus. The healthy subject showed a deactivation of the frontal, parietal and temporal cortices. BOLD signal changes were found to significantly correlate with concentrations of extravascular metabolites in the left frontal cortex. It is discussed that, when zolpidem attaches to modified GABA receptors of neurodormant brain cells, brain activation is induced. This might explain the significant correlations of BOLD signal changes and proton-MRS metabolites in this patient after zolpidem. CONCLUSION: It was concluded that proton-MRS and BOLD signal assessment could be used to study zolpidem-induced metabolic modulation in a resting state. PMID- 23924271 TI - Feasibility of introducing compulsory community health fund in low resource countries: views from the communities in Liwale district of Tanzania. AB - BACKGROUND: In 1995, Tanzania introduced the voluntary Community Health Fund (CHF) with the aim of ensuring universal health coverage by increasing financial investment in the health sector. The uptake of the CHF is low, with an enrolment of only 6% compared to the national target of 75%. Mandatory models of community health financing have been suggested to increase enrolment and financial capacity. This study explores communities' views on the introduction of a mandatory model, the Compulsory Community Health Fund (CCHF) in the Liwale district of Tanzania. METHODS: A cross-sectional study which involved 387 participants in a structured face to face survey and 33 in qualitative interviews (26 in focus group discussions (FGD) and 7 in in-depth interviews (IDI). Structured survey data were analyzed using SPSS version 16 to produce descriptive statistics. Qualitative data were analyzed using content analysis. RESULTS: 387 people completed a survey (58% males), mean age 38 years. Most participants (347, 89.7%) were poor subsistence farmers and 229 (59.2%) had never subscribed to any form of health insurance scheme. The idea of a CCHF was accepted by 221 (57%) survey participants. Reasons for accepting the CCHF included: reduced out of pocket expenditure, improved quality of health care and the removal of stigma for those who receive waivers at health care delivery points. The major reason for not accepting the CCHF was the poor quality of health care services currently offered. Participants suggested that enrolment to the CCHF be done after harvesting when the population were more likely to have disposable income, and that the quality care of care and benefits package be improved. CONCLUSIONS: The CHF is acceptable to the most of study participants and feasible in rural Tanzania as an alternative mechanism to finance health care for the rural poor. Community members are willing to join the scheme provided they are well informed, involved in the design and implementation, and assured quality health care. Strong political will and a supportive environment are key ingredients for the success of the CCHF. PMID- 23924272 TI - Urinary incontinence and health-related quality of life among older Americans with and without cancer: a cross-sectional study. AB - BACKGROUND: Few studies have investigated the impact of urinary incontinence (UI) on health-related quality of life (HRQOL) among cancer survivors. UI is prevalent in the general population and can be both an indicator of cancer and a side effect of cancer treatment. UI and cancer diagnoses have been associated with decreases in HRQOL. This study evaluates the prevalence of UI and the impact on HRQOL among older cancer survivors. METHODS: The prevalence of UI among cancer survivors (breast, prostate, bladder, colorectal, lung, and endometrial/uterine cancers) and those without cancer was estimated using the SEER-MHOS database. Factors associated with UI were investigated using logistic regression and the impact of UI on SF-36 scores was determined using linear regression. RESULTS: Over 36% of SEER-MHOS beneficiaries without cancer reported UI and higher prevalence was noted among cancer survivors (37%-54% depending on cancer type). History of bladder, breast, endometrial/uterine, or prostate cancer was associated with higher prevalence of UI. UI was independently associated with both lower physical component scores (PCS) (-1.27; 95%CI:-1.34,-1.20) and mental component scores (MCS) (-1.75; 95%CI -1.83, -1.68). A suggested decreasing trend in the prevalence of UI was associated with a longer time since cancer diagnosis. CONCLUSIONS: UI was highly prevalent, especially in bladder, endometrial/uterine, and prostate cancer survivors. Improved recognition of UI risk among cancer survivors will help clinicians better anticipate and mediate the effect of UI on individuals' HRQOL. PMID- 23924274 TI - Beyond lesbian bed death: enhancing our understanding of the sexuality of sexual minority women in relationships. AB - The goal of this study was to characterize the sexuality of sexual-minority (i.e., lesbian, bisexual, queer, unlabeled, questioning) women. Participants were 586 women (87% White) in a same-sex relationship of 1 to 36 years in duration. They completed measures assessing their sexual behavior (frequency of nongenital and genital sexual activities), motivation (sexual desire), and cognitive affective responses (sexual satisfaction, sexual esteem, sexual anxiety, negative automatic thoughts). On average, the women reported experiencing their sexuality positively across all domains. Regardless of relationship duration, most of the women reported engaging in both genital and nongenital sexual behaviors with their partner once a week or more; few reported that they had not engaged in sexual activity in the previous month. A multiple regression analysis indicated that frequency of genital sexual activity, sexual desire, sexual anxiety, and automatic thoughts contributed uniquely to the prediction of sexual satisfaction over and above the other sexuality variables. The findings are discussed in terms of the idea that lesbians have sex less frequently than other couple types and that sexual frequency declines rapidly in lesbian relationships (i.e., "lesbian bed death") and descriptions of sexual-minority women's sexuality that suggest that genital sexual activity is not important to sexual satisfaction. PMID- 23924275 TI - A nitrate ester of sedative alkyl alcohol improves muscle function and structure in a murine model of Duchenne muscular dystrophy. AB - Nitric oxide (NO) has major physiological and cellular effects on muscle growth, repair, and function. In most muscle biopsies from humans with myopathies, sarcolemma-localized neuronal nitric oxide synthase (nNOS) is either reduced or not detected, particularly in dystrophin-deficient Duchenne muscular dystrophy (DMD). Abnormal NO signaling at the sarcolemmal level is integrally involved in the pathogenesis and accounts, at least in part, for the muscle weakness of DMD. Dystrophic muscle fibers exhibit an increased susceptibility to contraction induced membrane damage. Muscle relaxants function to prevent muscle wasting by decreasing nerve impulses and reducing calcium influx that regulates tensing or tightening of muscle fibers. We have recently developed a new class of nitric esters that combines the pharmacological functions of NO and muscle relaxation. Here, we report the synthesis and properties of the nitric ester (MMPN) of 2 methyl-2-n-propyl-1,3-propanediol (MPP) and its effect in mdx dystrophic mice, a murine model of DMD. MMPN produced significant improvements in biochemical, pathological, and functional phenotypes in the mouse model. The endurance of exercise was extended by 47% in time to exhaustion and 84% in running distance. Serum CK level was decreased by 30%. Additionally, MMPN decreased intracellular free calcium concentration without causing skeletal muscle weakness. No hepatic or renal toxicities were observed during the study. Our investigations unveil a potential new treatment for muscular diseases. PMID- 23924273 TI - Frequency of the congenital transmission of Trypanosoma cruzi: a systematic review and meta-analysis. AB - BACKGROUND: Chagas disease is caused by the parasite Trypanosoma cruzi and is endemic in much of Latin America. With increased globalisation and immigration, it is a risk in any country, partly through congenital transmission. The frequency of congenital transmission is unclear. OBJECTIVE: To assess the frequency of congenital transmission of T. cruzi. SEARCH STRATEGY: PubMed, Journals@Ovid Full Text, EMBASE, CINAHL, Fuente Academica and BIREME databases were searched using seven search terms related to Chagas disease or T. cruzi and congenital transmission. SELECTION CRITERIA: The inclusion criteria were the following: Dutch, English, French, Portuguese or Spanish language; case report, case series or observational study; original data on congenital T. cruzi infection in humans; congenital infection rate reported or it could be derived. This systematic review included 13 case reports/series and 51 observational studies. DATA COLLECTION AND ANALYSIS: Two investigators independently collected data on study characteristics, diagnosis and congenital infection rate. The principal summary measure--the congenital transmission rate--is defined as the number of congenitally infected infants divided by the number of infants born to infected mothers. A random effects model was used. MAIN RESULTS: The pooled congenital transmission rate was 4.7% (95% confidence interval: 3.9-5.6%). Countries where T. cruzi is endemic had a higher rate of congenital transmission compared with countries where it is not endemic (5.0% versus 2.7%). CONCLUSIONS: Congenital transmission of Chagas disease is a global problem. Overall risk of congenital infection in infants born to infected mothers is about 5%. The congenital mode of transmission requires targeted screening to prevent future cases of Chagas disease. PMID- 23924276 TI - CNS drug targeting: have we travelled in right path? AB - BACKGROUND: Brain disorders, their prevalence and central nervous system (CNS) targeting are now at the rise. However, complexities of blood brain barrier (BBB) have limited the success of CNS targeting. Basic criteria necessary for passive diffusion were believed to influence the CNS drug delivery. However, often, BBB transportation has differed from the dogma of basic criteria. PURPOSE: This communication resets the extent to which basic criteria influence the brain delivery, through commanding examples. Further, it appraises the intervention of ABC transporters in BBB transportation, with a special emphasis on P glycoprotein; and also brings forth the successful CNS transportation of therapeutics achieved through chimeric peptide technology. As a right path to travel, it flickers light on the novel CNS molecular drug targets/biomarkers which are specially expressed by diseased cells. CONCLUSION: Screening for right molecular target is of great importance for cost and time effective drug discovery process. The principle of chimeric peptide technology should be applied for CNS targeting; and every diseased cell should be screened for its biomarker. Thanks to glycan/lectin arrays technique which scans expression pattern of transporter and their possible ligands, and paves way for a new dimensional research. PMID- 23924277 TI - Nitro-methyl redox coupling: efficient approach to 2-hetarylbenzothiazoles from 2 halonitroarene, methylhetarene, and elemental sulfur. AB - A simple, straightforward, and atom economic approach to 2-hetarylbenzothiazoles starting from 2-halonitroarene, methylhetarene, and elemental sulfur under mild conditions is described. The method is highlighted by the direct redox nitro methyl reaction for carbon-nitrogen bond formation without an added oxidizing or reducing agent. PMID- 23924278 TI - Physiochemical properties of Caulobacter crescentus holdfast: a localized bacterial adhesive. AB - To colonize surfaces, the bacterium Caulobacter crescentus employs a polar polysaccharide, the holdfast, located at the end of a thin, long stalk protruding from the cell body. Unlike many other bacteria which adhere through an extended extracellular polymeric network, the holdfast footprint area is tens of thousands times smaller than that of the total bacterium cross-sectional surface, making for some very demanding adhesion requirements. At present, the mechanism of holdfast adhesion remains poorly understood. We explore it here along three lines of investigation: (a) the impact of environmental conditions on holdfast binding affinity, (b) adhesion kinetics by dynamic force spectroscopy, and (c) kinetic modeling of the attachment process to interpret the observed time-dependence of the adhesion force at short and long time scales. A picture emerged in which discrete molecular units called adhesins are responsible for initial holdfast adhesion, by acting in a cooperative manner. PMID- 23924279 TI - An intervention to improve program implementation: findings from a two-year cluster randomized trial of Assets-Getting To Outcomes. AB - BACKGROUND: Studies have shown that communities have not always been able to implement evidence-based prevention programs with quality and achieve outcomes demonstrated by prevention science. Implementation support interventions are needed to bridge this gap between science and practice. The purpose of this article is to present two-year outcomes from an evaluation of the Assets Getting To Outcomes (AGTO) intervention in 12 Maine communities engaged in promoting Developmental Assets, a positive youth development approach to prevention. AGTO is an implementation support intervention that consists of: a manual of text and tools; face-to-face training, and onsite technical assistance, focused on activities shown to be associated with obtaining positive results across any prevention program. METHODS: This study uses a nested and cross-sectional, cluster randomized controlled design. Participants were coalition members and program staff from 12 communities in Maine. Each coalition nominated up to five prevention programs to participate. At random, six coalitions and their respective 30 programs received the two-year AGTO intervention and the other six maintained routine operations. The study assessed prevention practitioner capacity (efficacy and behaviors), practitioner exposure to and use of AGTO, practitioner perceptions of AGTO, and prevention program performance. Capacity of coalition members and performance of their programs were compared between the two groups across the baseline, one-, and two-year time points. RESULTS: We found no significant differences between AGTO and control group's prevention capacity. However, within the AGTO group, significant differences were found between those with greater exposure to and use of AGTO. Programs that received the highest number of technical assistance hours showed the most program improvement. CONCLUSIONS: This study is the first of its kind to show that use of an implementation support intervention-AGTO -yielded improvements in practitioner capacity and consequently in program performance on a large sample of practitioners and programs using a randomized controlled design. CLINICALTRIALS.GOV IDENTIFIER: NCT00780338. PMID- 23924280 TI - Long-term exposure to benzalkonium chloride disinfectants results in change of microbial community structure and increased antimicrobial resistance. AB - The effect of benzalkonium chlorides (BACs), a widely used class of quaternary ammonium disinfectants, on microbial community structure and antimicrobial resistance was investigated using three aerobic microbial communities: BACs unexposed (DP, fed a mixture of dextrin/peptone), BACs-exposed (DPB, fed a mixture of dextrin/peptone and BACs), and BACs-enriched (B, fed only BACs). Long term exposure to BACs reduced community diversity and resulted in the enrichment of BAC-resistant species, predominantly Pseudomonas species. Exposure of the two microbial communities to BACs significantly decreased their susceptibility to BACs as well as three clinically relevant antibiotics (penicillin G, tetracycline, ciprofloxacin). Increased resistance to BACs and penicillin G of the two BACs-exposed communities is predominantly attributed to degradation or transformation of these compounds, whereas resistance to tetracycline and ciprofloxacin is largely due to the activity of efflux pumps. Quantification of several key multidrug resistance genes showed a much higher number of copies of these genes in the DPB and B microbial communities compared to the DP community. Collectively, our findings indicate that exposure of a microbial community to BACs results in increased antibiotic resistance, which has important implications for both human and environmental health. PMID- 23924282 TI - Boronic acid-functionalized core-shell-shell magnetic composite microspheres for the selective enrichment of glycoprotein. AB - In this work, core-shell-shell-structured boronic acid-functionalized magnetic composite microspheres Fe3O4@SiO2@poly (methyl methacrylate-co-4 vinylphenylbornoic acid) (Fe3O4@SiO2@P(MMA-co-VPBA)) with a uniform size and fine morphology were synthesized. Here, Fe3O4 magnetic particles were prepared by a solvothermal reaction, whereas the Fe3O4@SiO2 microspheres with a core-shell structure were obtained by a sol-gel process. 3-(Trimethoxysilyl) propyl methacrylate (MPS)-modified Fe3O4@SiO2 was used as the seed in the emulsion polymerization of MMA and VPBA to form the core-shell-shell-structured magnetic composite microspheres. As the boronic acid groups on the surface of Fe3O4@SiO2@P(MMA-co-VPBA) could form tight yet reversible covalent bonds with the cis-1,2-diols groups of glycoproteins, the magnetic composite microspheres were applied to enrich a standard glycoprotein, horseradish peroxidase (HRP), and the results demonstrated that the composite microspheres have a higher affinity for the glycoproteins in the presence of the nonglycoprotein bovine serum albumin (BSA) over HRP. Additionally, different monomer mole ratios of MMA/VPBA were studied, and the results implied that using MMA as the major monomer could reduce the amount of VPBA with a similar glycoprotein enrichment efficiency but a lower cost. PMID- 23924281 TI - Insights into xanthomonas axonopodis pv. citri biofilm through proteomics. AB - BACKGROUND: Xanthomonas axonopodis pv. citri (X. a. pv. citri) causes citrus canker that can result in defoliation and premature fruit drop with significant production losses worldwide. Biofilm formation is an important process in bacterial pathogens and several lines of evidence suggest that in X. a. pv. citri this process is a requirement to achieve maximal virulence since it has a major role in host interactions. In this study, proteomics was used to gain further insights into the functions of biofilms. RESULTS: In order to identify differentially expressed proteins, a comparative proteomic study using 2D difference gel electrophoresis was carried out on X. a. pv. citri mature biofilm and planktonic cells. The biofilm proteome showed major variations in the composition of outer membrane proteins and receptor or transport proteins. Among them, several porins and TonB-dependent receptor were differentially regulated in the biofilm compared to the planktonic cells, indicating that these proteins may serve in maintaining specific membrane-associated functions including signaling and cellular homeostasis. In biofilms, UDP-glucose dehydrogenase with a major role in exopolysaccharide production and the non-fimbrial adhesin YapH involved in adherence were over-expressed, while a polynucleotide phosphorylase that was demonstrated to negatively control biofilm formation in E. coli was down regulated. In addition, several proteins involved in protein synthesis, folding and stabilization were up-regulated in biofilms. Interestingly, some proteins related to energy production, such as ATP-synthase were down-regulated in biofilms. Moreover, a number of enzymes of the tricarboxylic acid cycle were differentially expressed. In addition, X. a. pv. citri biofilms also showed down regulation of several antioxidant enzymes. The respective gene expression patterns of several identified proteins in both X. a. pv. citri mature biofilm and planktonic cells were evaluated by quantitative real-time PCR and shown to consistently correlate with those deduced from the proteomic study. CONCLUSIONS: Differentially expressed proteins are enriched in functional categories. Firstly, proteins that are down-regulated in X. a. pv. citri biofilms are enriched for the gene ontology (GO) terms 'generation of precursor metabolites and energy' and secondly, the biofilm proteome mainly changes in 'outer membrane and receptor or transport'. We argue that the differentially expressed proteins have a critical role in maintaining a functional external structure as well as enabling appropriate flow of nutrients and signals specific to the biofilm lifestyle. PMID- 23924283 TI - Hemiconvulsion-hemiplegia syndrome revisited: longitudinal MRI findings in 10 children. AB - AIM: Hemiconvulsion-hemiplegia syndrome (HHS) is a rare severe epilepsy of infancy consisting of unilateral convulsive status epilepticus immediately followed by transient or lasting ipsilateral hemiplegia. HHS may occur either in patients with previous brain pathology or without any identified cause, so-called 'idiopathic HHS'. METHOD: We retrospectively analysed clinical and MRI longitudinal findings of a series of 10 patients (six females, four males) presenting with HHS. Age at the study inclusion ranged from 2 years 6 months to 15 years (mean of 5 y 10 mo, median 4 y 2 mo). After defining magnetic resonance imaging (MRI) features as 'typical', i.e. strictly unilateral involvement, and 'atypical', i.e. bilateral, we compared clinical data from both groups. Cognitive level was assessed using Brunet-Lezine or Wechsler scales. RESULTS: HHS occurred at a mean age of 20.5 months (range 8-48 mo). In all cases, status epilepticus lasted for more than 1 hour and was characterised by unilateral clonic seizures followed by ipsilateral hemiplegia (persistent in five patients). Two patients in this series died: the first from multi-organ failure 2 weeks after the status epilepticus and the other from a second episode of ipsilateral intractable febrile status epilepticus 3 years after the first episode. Early MRI (days 1-7 from status epilepticus) showed hemispheric cytotoxic oedema in all, extending to the contralateral side for one. T2 hyperintensity in the basal ganglia was disclosed in 70% of patients and in the hippocampus in 60%. After 1 month (in intermediate and chronic phases), all surviving patients but one showed hemispheric cortical atrophy corresponding to the regions involved during the early stage. Comparing clinical features of patients presenting with 'typical' features, to those with 'atypical' findings, the second group presented psychomotor delay before status epilepticus. INTERPRETATION: This series underlines the major value of early MRI for the prompt diagnosis of HHS, and shows that involvement of subcortical structures has been underestimated. Hippocampal involvement is not constant. PMID- 23924285 TI - Acute kidney injury in peripheral arterial surgery patients: a cohort study. AB - PURPOSE: The aim of the study was to evaluate the prevalence of acute kidney injury (AKI) in a cohort of surgically treated patients with peripheral artery disease (PAD) and its association with the short-term and long-term outcome. MATERIALS AND METHODS: We conducted a retrospective cohort study on all the consecutive PAD inpatients in 2008. Data on the patients' demographic characteristics, medical history, treatment, outcome and laboratory tests measurements were retrieved from the medical records. RESULTS: We analyzed 166 patients (71.6% males, mean age 63.2 years +/- SD 10.7 years) and found an AKI prevalence of 12.7%. The AKI patients' group had more chronic kidney disease (CKD) (23.8% vs. 6.2%, p = 0.005), diabetes mellitus (DM) (61.9% vs. 33.1%, p = 0.011) and a higher length of hospital stay (19.48 vs. 15.42 days, p = 0.047). At one year, the mortality was 33.3% in the AKI group compared to 1.3% in non-AKI group, with a strong association between AKI and death (OR = 35.7; 95%CI = 6.7 to 189) and AKI and major cardiovascular events (OR = 29.1; 95% CI = 6.8 to 123.4). There was no significant difference in terms of age, cardiovascular disease and medication between the two groups. CONCLUSIONS: AKI was associated with a poorer one-year outcome after the surgery of PAD patients. In our study, the presence of previous chronic kidney disease and type 2 diabetes increased the incidence of acute kidney injury after surgery. PMID- 23924286 TI - Antibiotics for acute and chronic respiratory infection in patients with chronic obstructive pulmonary disease. AB - Prevention and effective treatment of exacerbations are major objectives in the management of patients with chronic obstructive pulmonary disease (COPD). Antibiotics are mainstay treatment for patients with severe COPD with an acute exacerbation that includes increased sputum purulence and worsening shortness of breath. Although such treatment is associated with clinical benefit, treatment failure and relapse rates may be high, particularly in cases of inadequate antibiotic therapy through incomplete resolution of the initial exacerbation and persistent bacterial infection. These aspects have led to recommendations for a stratified approach to antibiotic therapy based on patient characteristics associated with increased risk factors for failure. Patients at greatest risk for poor outcome (i.e., those with severe COPD) are likely to derive greatest benefit from early treatment with antibiotics. Long-term or intermittent antibiotic treatment has been shown to prevent COPD exacerbations and hospitalizations. These effects may be achieved by reducing bacterial load in the airways in stable state and/or bronchial inflammation. Although systemic antibiotics are likely to remain the core treatment for patients with moderate to severe exacerbated COPD, inhaled antibiotics may represent a more optimal approach for the treatment and prevention of COPD exacerbations in the future. Regardless of the route of administration, further studies are required to evaluate the potential long-term adverse events of antibiotics and the development of bacterial resistance. PMID- 23924287 TI - Flexible and transparent MoS2 field-effect transistors on hexagonal boron nitride graphene heterostructures. AB - Atomically thin forms of layered materials, such as conducting graphene, insulating hexagonal boron nitride (hBN), and semiconducting molybdenum disulfide (MoS2), have generated great interests recently due to the possibility of combining diverse atomic layers by mechanical "stacking" to create novel materials and devices. In this work, we demonstrate field-effect transistors (FETs) with MoS2 channels, hBN dielectric, and graphene gate electrodes. These devices show field-effect mobilities of up to 45 cm(2)/Vs and operating gate voltage below 10 V, with greatly reduced hysteresis. Taking advantage of the mechanical strength and flexibility of these materials, we demonstrate integration onto a polymer substrate to create flexible and transparent FETs that show unchanged performance up to 1.5% strain. These heterostructure devices consisting of ultrathin two-dimensional (2D) materials open up a new route toward high-performance flexible and transparent electronics. PMID- 23924288 TI - Augmented renal clearance--an evolving risk factor to consider during the treatment with vancomycin. AB - WHAT IS KNOWN AND OBJECTIVE: Augmented renal clearance (ARC) is a new phenomenon in patients' pathophysiology without universally accepted aetiology and with various incidence rates most often described in critically ill patients in the Intensive Care Unit (ICU). The objective of this retrospective observational comparative study was to estimate the incidence rate of ARC in patients with different medical conditions employing steady state trough vancomycin serum concentrations (VSCss) for analysis. METHODS: All patients tested for VCSss during two years (2010-2011) in a tertiary level hospital were analysed and 77 VSCs were eligible for analysis: 38 (50%) and 39 cases were assigned to the ARC (eCrClCG (creatinine clearance, estimated by Cockcroft-Gault) > 130 mL/min) and the control groups (eCrClCG in the range 90-130 mL/min) respectively. RESULTS AND DISCUSSION: Patients' age, mechanical ventilation and haemodynamically unstable status had significant association with ARC occurrence (P < 0.05). Majority of ARC patients (11 patients (61 %)) were managed in non-ICU settings. ARC event showed statistically significant higher risk for under dosage (RR (relative risk for subtherapeutic VSCss), 1.84; 95% CI, 1.23?x962.74; P = 0.011), and the correlation between different thresholds (eCrClCG >130 mL/min, >=140 mL/min and >=150 mL/min) for ARC and VSCss allows to predict decrease of VSCss in case of eCrClCG >=150 mL/min: every increase of eCrClCG by 40 mL/min predicts clinically relevant decrease of VSCss by 1 mmol/L (1.49 mg/mL). WHAT IS NEW AND CONCLUSION: ARC cases lead to the doubled risk of subtherapeutic VSC, and this phenomenon is a significant event in patients in any hospital department. Investigation of medical patients' status relevant to this phenomenon needs to be continued. PMID- 23924289 TI - Continuous intraperitoneal carboplatin delivery for the treatment of late-stage ovarian cancer. AB - The rate of failure of chemotherapy treatment in ovarian cancer remains high, resulting in a low 5-year survival rate of 20-40% in patients that present with advanced-stage disease. Treatment-free periods between cycles of chemotherapy may contribute to accelerated tumor cell proliferation and decreased treatment response. The elimination of treatment-free breaks has been deemed beneficial in the context of cell-cycle-specific agents. The potential benefit of this approach for non-cell-cycle-specific agents has not yet been elucidated. The present study is the first to address this issue by investigating the impact of continuous versus intermittent intraperitoneal administration of carboplatin over a 14 day period to SCID mice bearing SKOV-3 ovarian cancer xenografts. Immunostaining of tumor sections was employed to quantify tumor proliferation, angiogenesis, and apoptosis using Ki-67, CD-31, caspase-3 (CASP3), and terminal deoxytransferase mediated dUTP nick-end labeling (TUNEL). Continuous ip administration of carboplatin resulted in greater tumor growth inhibition than intermittent therapy (p < 0.05). Significantly greater tumor cell apoptosis and less cell proliferation and angiogenesis were measured in tumors of mice treated with continuous carboplatin as compared to both intermittent and control groups. These results indicate that continuous local administration may be a promising approach to improve the effectiveness of platinum-based chemotherapy regimens. PMID- 23924290 TI - Effect of COMT Val158Met genotype on attention and response to methylphenidate following traumatic brain injury. AB - PRIMARY OBJECTIVE: To investigate whether COMT Val158Met allele status was associated with (i) attentional performance and (ii) response to methylphenidate (MP) following traumatic brain injury (TBI). METHODS: Forty healthy controls and 32 patients with moderate-severe TBI (Mean time post-injury = 68 days) completed a baseline cognitive assessment. The TBI cohort then participated in a randomized, cross-over, double blind, placebo controlled 2-week MP trial. MP was administered at 0.3 mg/kg twice daily. TBI genotype distribution: val/val n = 11; val/met n = 14; met/met n = 7. RESULTS: There were no significant differences across genotypes on baseline attentional measures. When compared with controls, the val/val group performed significantly more poorly on most measures. The met/met group performed more poorly than controls on measures of speed, but not in strategic control of attention. MP resulted in faster speed of information processing. Repeated measures mixed ANOVAs found only one significant drug * genotype interaction: (F(2,29) = 4.257, p = 0.024) the met/met group demonstrated a greater response to MP on the Symbol Digit Modalities Test. CONCLUSIONS: COMT allele status was not strongly associated with attentional performance or response to MP in the TBI sample. The met/met group, whilst performing slowly, had relatively preserved strategic control of attention. PMID- 23924291 TI - A N-(2-aminophenyl)-5-(dimethylamino)-1-naphthalenesulfonic amide (Ds-DAB) based fluorescent chemosensor for peroxynitrite. AB - A dansyl derivative (Ds-DAB) was prepared and used as a fluorescent probe for peroxynitrite (ONOO(-)) detection. The results showed that the addition of peroxynitrite to the aqueous solution of Ds-DAB would result in obvious fluorescence enhancement. This probe is highly specific for peroxynitrite in aqueous solution, avoiding interference from other reactive oxygen species (ROS) and nitrogen species (RNS). The advantages of high selectivity, fast reaction rate, and peroxynitrite bioimaging render Ds-DAB suitable for peroxynitrite detection. PMID- 23924292 TI - Maternal and neonatal morbidity in relation to the instrument used for mid-cavity rotational operative vaginal delivery: a prospective cohort study. AB - OBJECTIVE: To compare the maternal and neonatal morbidity associated with alternative instruments used to perform a mid-cavity rotational delivery. DESIGN: A prospective cohort study. SETTING: Two university teaching hospitals in Scotland and England. POPULATION: Three hundred and eighty-one nulliparous women who had a mid-cavity rotational operative vaginal delivery. METHODS: A data collection sheet was completed by the research team following delivery. MAIN OUTCOME MEASURES: Postpartum haemorrhage, third- and fourth-degree perineal tears, low cord pH, neonatal trauma, and failed or sequential operative vaginal delivery. RESULTS: One hundred and sixty-three women (42.8%) underwent manual rotation followed by non-rotational forceps delivery, 73 (19.1%) had a rotational vacuum delivery, and 145 (38.1%) delivered with the assistance of rotational (Kielland) forceps. The rates of postpartum haemorrhage were similar when comparing manual rotation with rotational vacuum (adjusted OR 1.42, 95% CI 0.66 3.98), and when comparing manual rotation with Kielland forceps (adjusted OR 1.22, 95% CI 0.71-2.88). The results were comparable for third- and fourth-degree perineal tears (adjusted OR 0.85, 95% CI 0.13-1.89; adjusted OR 0.94, 95% CI 0.39 1.82), low cord pH (adjusted OR 1.76, 95% CI 0.44-6.91; adjusted OR 1.12, 95% CI 0.44-2.83), neonatal trauma (adjusted OR 0.50, 95% CI 0.16-1.55; adjusted OR 3.25, 95% CI 0.65-16.17), and admission to the neonatal intensive care unit (adjusted OR 1.47, 95% CI 0.45-4.81; adjusted OR 1.04, 95% CI 0.49-2.19). The sequential use of instruments was less likely with manual rotation and forceps than with rotational vacuum delivery (0.6 versus 36.9%, OR 0.01, 95% CI 0.002 0.090). CONCLUSIONS: Maternal and perinatal outcomes are comparable with Kielland forceps, vacuum extraction, and manual rotation, with few serious adverse outcomes. With appropriate training mid-cavity rotational delivery can be practiced safely, including the use of Kielland forceps. PMID- 23924293 TI - Influence of the molecular weight of poly(lactide-co-glycolide) on the in vivo cartilage repair by a construct of poly(lactide-co-glycolide)/fibrin gel/mesenchymal stem cells/transforming growth factor-beta1. AB - The poly(lactide-co-glycolide) (PLGA, LA/GA 75/25) sponges with different weight average molecular weights (Mw 52, 122, and 177 kDa) were fabricated and were used to build the constructs of PLGA/fibrin gel/mesenchymal stem cells (MSCs)/transforming growth factor-beta1 (TGF-beta1). The PLGA 177 with the highest Mw (177 kDa) had the fastest degradation rate at the initial stage, whereas the PLGA 122 had the moderate degradation rate and smallest mass loss. After implantation in rabbit knees for 12 weeks, the full-thickness defects (both cartilage and subchondral bone were destroyed with a diameter and depth of 4 mm) repaired by the PLGA 122 group had formed a hyaline cartilage-like tissue with abundant glycosaminoglycans on the top layer and subchondral bone on the bottom layer. The group also achieved the best macroscopic (11.3 +/- 0.8) and histological scoring (Wakitani, 0.5 +/- 0.6). To unveil the mechanism of the cartilage repair outcome and the PLGA degradation behaviors, the chondrogenesis related genes, inflammatory cytokines, and matrix metalloproteinase (MMP) activity were analyzed by quantitative reverse transcription-polymerase chain reaction at week 1, 3, and 6 postsurgery. At each time point, the regenerated tissues by the PLGA 122 group had the highest mRNA expression of SOX9 and collagen type II, but the smallest mRNA expression of interleukin-1beta and tumor necrosis factor alpha, and MMP-13 and MMP-3. In summary, as a scaffolding matrix, the PLGA with different Mw shows a huge difference in cartilage regeneration in vivo. The one with a moderate Mw (122 kDa) causes the weakest inflammatory response and results in the best cartilage regeneration. PMID- 23924294 TI - The practice of puxa-puxa among Mozambican women: a systematic inventory of motives. AB - Puxa-puxa is the elongation of the labia minora of the genital organs. It is one of the most widespread genital practices among women in Mozambique, and the practice seems to be specific to this country. The motives underlying this practice and its abandonment were examined in a theory-driven way. A total of 616 women currently living in the provinces of Maputo, Zambezia, and Nampula, aged 18 to 62, were presented with one of two questionnaires that contained items about possible motives for practicing puxa-puxa or possible motives for not practicing it. Seven separable motives for practicing puxa-puxa were found, and the most highly rated were "Having a satisfying sexual life"; "Satisfying my sexual partner"; and "Gaining self-control." Five separable motives for not practicing puxa-puxa were found, and the most highly rated were "Disliking a painful practice"; "Affirming one's value as a person"; and "Avoiding contamination." The main findings of the study are that the practice of puxa-puxa is associated with deep psychological motives common to most women in most cultures, namely having a satisfying sexual life with a reliable partner, creating the conditions for having children, and being able to care for them. The abandonment of this practice is largely the result of personal decisions, which are not taken under constraint and which are not exclusively taken from fear of illness. PMID- 23924295 TI - Triangulating perspectives on functional neuroimaging for disorders of mental health. AB - BACKGROUND: Functional neuroimaging is being used in clinical psychiatry today despite the vigorous objections of many in the research community over issues of readiness. To date, a systematic examination of the perspectives of key stakeholders involved in this debate has not yet been attempted. To this fill this gap, we interviewed investigators who conduct functional neuroimaging studies involving adults with mood disorders, schizophrenia, obsessive compulsive disorder, and/or attention deficit hyperactivity disorder, providers who offer clinical neuroimaging services in the open marketplace, and consumers of these services, in order to understand perspectives underlying different views and practices. METHODS: Semi-structured interviews were conducted over the telephone. Verbal consent was obtained and all interviews were audio recorded. Interviews of investigators and service providers followed the same interview guide. A separate set of questions was developed for consumers. All interviews were transcribed and made software ready. We applied the qualitative methodology of constant comparison to analyze the data, whereby two researchers independently analyzed the results into textual themes. Coding discrepancies were discussed until consensus was achieved. RESULTS: Investigators, service providers, and consumers held many common perspectives about the potential or actual risks and benefits of functional neuroimaging for mental illness. However, we also found striking divergences. Service providers focused on the challenges posed by the persistence of symptoms based diagnostic categories, whereas the limitations of the science in this area was the challenge noted most frequently by investigators. The majority of consumers stated that their expectations were met. CONCLUSION: Our findings point toward a fundamental tension between academic investigators on the one hand, and commercial service providers and their customers on the other. This scenario poses dangers to the communities directly involved, and to public trust in science and medicine more generally. We conclude with recommendations for work that needs to be done to minimize tensions and maximize the potential of neurotechnology through concerted efforts to respect its limitations while leveraging the strengths, investments, and hopes of each stakeholder group. PMID- 23924296 TI - The eradication of leprosy: molecular modeling techniques for novel drug discovery. AB - INTRODUCTION: Leprosy is a slowly progressing bacterial infection caused by Mycobacterium leprae. The World Health Organization recommended multidrug therapy (MDT) which is extremely effective and halts the progress of the disease. Even though the objective of eliminating leprosy as a public health problem has been achieved successfully, leprosy is not yet eradicated. Furthermore, the long-term use of MDT results in single- and multidrug resistance. Therefore, there is still a need for new drug discovery for leprosy. AREAS COVERED: The authors explain the importance of discovery of new drug to leprosy and the significance of homology modeling to drug discovery. This review highlights the principle steps, applications, and the resources of homology modeling. Finally, the authors emphasize the application of different structure-based drug design (SBDD) approaches to design novel therapeutics for leprosy. EXPERT OPINION: MDT has proved to be effective in controlling infection, with prevalence of leprosy now predominantly isolated to the developing countries. The emergence of single- and multidrug-resistant strains of M. leprae has, however, provided some concern with the need for newer antibacterial agents. Drug resistance can be overcome by multi targeted therapy. SBDD approaches, which reported many successful drugs, depend predominantly on the three-dimensional (3D) structure of drug targets. As of 2013, only very few experimental structures are available for M. leprae proteins. Hence, SBDD, in leprosy research, relies heavily on homology modeling to predict the 3D structure of drug targets and to design better therapeutics. PMID- 23924297 TI - Re-evaluation of the role of P-glycoprotein in in vitro drug permeability studies with the bovine brain microvessel endothelial cells. AB - 1. Currently available in vitro blood-brain barrier models all have recognized restrictions. In addition to leakiness, inconsistent data about P-glycoprotein mediated efflux limit the attractiveness of the primary bovine brain microvessel endothelial cells (BBMECs). Therefore, we re-evaluated the role of P-glycoprotein mediated efflux with two culture conditions in BBMECs for prediction of drug permeability of potential P-glycoprotein substrates. 2. BBMECs were monocultured on filters on petri dishes and on filter inserts, and expression and localization of P-glycoprotein were compared by using western blot and confocal microscopy, respectively. The functionality of P-glycoprotein was assessed by using cellular uptake, calcein-AM and bidirectional transport assays. 3. P-glycoprotein expression was higher in BBMECs cultured on filter inserts decreasing the permeability of digoxin and paclitaxel, but not the permeability of vinblastine. However, the monocultured BBMECs were not able to demonstrate efflux in the bidirectional transport assays. Under certain culture conditions, occludin may not be correctly located, perhaps explaining in part the leakiness of BBMECs. 4. In conclusion, BBMECs, despite possessing a functional P-glycoprotein, under certain culture conditions may not be a suitable in vitro model for the bidirectional transport assays and for predicting the permeability of drugs and xenobiotics that are potential P-glycoprotein substrates. PMID- 23924298 TI - The modified massive cuff stitch: functional and structural outcome in massive cuff tears. AB - BACKGROUND: The massive cuff stitch (MCS) is known to be a strong suture, suitable for rotator cuff repair. We modified this technique for massive cuff tears by employing a horizontal medial mattress suture from an anchor as well as a vertically crossing transosseous suture. METHODS: We included 42 patients with massive cuff tears suitable for repair: 22 were treated with the modified MCS (MCS group), and 20 with a simple transosseous suture (STS group). The range of motion (ROM), muscle strength, visual analog scale, and the Japanese Orthopaedic Association (JOA) scores were evaluated pre-operatively and 12 and 24 months post operatively. The incidence of post-operative re-tears was examined at least 1 year post-operatively using Sugaya's classification. RESULTS: The ROM, muscle strength, degree of pain, and the JOA scores were much improved after surgery in both groups, and there was no significant intergroup difference throughout the pre- and post-operative periods. In contrast, post-operative MRI revealed a significantly lower re-tear rate in the MCS group than in the STS group (9.1% vs. 40%, P = 0.0296). CONCLUSIONS: The techniques tested were comparable in terms of functional outcome after surgical repair of massive cuff tears; however, the modified MCS repair technique produced superior structural outcomes with a significantly lower re-tear rate. PMID- 23924299 TI - Morphological control of heterostructured nanowires synthesized by sol-flame method. AB - Heterostructured nanowires, such as core/shell nanowires and nanoparticle decorated nanowires, are versatile building blocks for a wide range of applications because they integrate dissimilar materials at the nanometer scale to achieve unique functionalities. The sol-flame method is a new, rapid, low cost, versatile, and scalable method for the synthesis of heterostructured nanowires, in which arrays of nanowires are decorated with other materials in the form of shells or chains of nanoparticles. In a typical sol-flame synthesis, nanowires are dip-coated with a solution containing precursors of the materials to be decorated, then dried in air, and subsequently heated in the post-flame region of a flame at high temperature (over 900 degrees C) for only a few seconds. Here, we report the effects of the precursor solution on the final morphology of the heterostructured nanowire using Co3O4 decorated CuO nanowires as a model system. When a volatile cobalt salt precursor is used with sufficient residual solvent, both solvent and cobalt precursor evaporate during the flame annealing step, leading to the formation of Co3O4 nanoparticle chains by a gas solid transition. The length of the nanoparticle chains is mainly controlled by the temperature of combustion of the solvent. On the other hand, when a non volatile cobalt salt precursor is used, only the solvent evaporates and the cobalt salt is converted to nanoparticles by a liquid-solid transition, forming a conformal Co3O4 shell. This study facilitates the use of the sol-flame method for synthesizing heterostructured nanowires with controlled morphologies to satisfy the needs of diverse applications. PMID- 23924300 TI - Infrared, vibrational circular dichroism, and Raman spectral simulations for beta sheet structures with various isotopic labels, interstrand, and stacking arrangements using density functional theory. AB - Infrared (IR), Raman, and vibrational circular dichroism (VCD) spectral variations for different beta-sheet structures were studied using simulations based on density functional theory (DFT) force field and intensity computations. The DFT vibrational parameters were obtained for beta-sheet fragments containing nine-amides and constrained to a variety of conformations and strand arrangements. These were subsequently transferred onto corresponding larger beta sheet models, normally consisting of five strands with ten amides each, for spectral simulations. Further extension to fibril models composed of multiple stacked beta-sheets was achieved by combining the transfer of DFT parameters for each sheet with dipole coupling methods for interactions between sheets. IR spectra of the amide I show different splitting patterns for parallel and antiparallel beta-sheets, and their VCD, in the absence of intersheet stacking, have distinct sign variations. Isotopic labeling by (13)C of selected residues yields spectral shifts and intensity changes uniquely sensitive to relative alignment of strands (registry) for antiparallel sheets. Stacking of multiple planar sheets maintains the qualitative spectral character of the single sheet but evidences some reduction in the exciton splitting of the amide I mode. Rotating sheets with respect to each other leads to a significant VCD enhancement, whose sign pattern and intensity is dependent on the handedness and degree of rotation. For twisted beta-sheets, a significant VCD enhancement is computed even for sheets stacked with either the same or opposite alignments and the inter-sheet rotation, depending on the sense, can either further increase or weaken the enhanced VCD intensity. In twisted, stacked structures (without rotation), similar VCD amide I patterns (positive couplets) are predicted for both parallel and antiparallel sheets, but different IR intensity distributions still enable their differentiation. Our simulation results prove useful for interpreting experimental vibrational spectra in terms of beta-sheet and fibril structure, as illustrated in the accompanying paper. PMID- 23924301 TI - Expeditious approach to pyrrolophenanthridones, phenanthridines, and benzo[c]phenanthridines via organocatalytic direct biaryl-coupling promoted by potassium tert-butoxide. AB - A methodology involving a "transition metal-free" intramolecular biaryl-coupling of o-halo-N-arylbenzylamines has been developed in the presence of potassium tert butoxide and an organic molecule as catalyst. The reaction appears to proceed through KO(t)Bu-promoted intramolecular homolytic aromatic substitution (HAS). Interestingly, this biaryl coupling also works in the presence of potassium tert butoxide as sole promoter. On extending our approach further, we found that N acyl 2-bromo-N-arylbenzylamines undergo a one-pot N-deprotection/biaryl coupling followed by oxidation, thus offering an expeditious route to the phenanthridine and benzo[c]phenanthridine skeletons. The strategy has been applied to a concise synthesis of Amaryllidaceae alkaloids viz. oxoassoanine (1b), anhydrolycorinone (1d), 5,6-dihydrobicolorine (2d), trispheridine (2b), and benzo[c]phenanthridines alkaloids dihydronitidine (3b), dihydrochelerythidine (3d), dihydroavicine (3f), nornitidine (3h), and norchelerythrine (3j). PMID- 23924303 TI - Safety and efficacy of minimally invasive percutaneous nephrolithotomy in patients with autosomal dominant polycystic kidney disease. AB - PURPOSE: To review our experience of using minimally invasive percutaneous nephrolithotomy (MPCNL) in patients with autosomal dominant polycystic kidney disease (ADPKD). PATIENTS AND METHODS: We retrospectively reviewed 23 renal units in 23 patients with ADPKD who underwent MPCNL in our center between January 2007 and December 2012. The data on the stone burden, stone locations, patient characteristics, complications according to the modified Clavien system, and stone-free rates (SFR) were analyzed. RESULTS: The mean stone area (+/-standard deviation) was 1382.87+/-1080.17 mm2. There were 10 (43.5%) staghorn stones. Flank pain was noted in 87% of the cases. SFR after initial MPCNL was 69.6% (16/23 renal units). Of the remaining seven renal units, six underwent second look MPCNL and were rendered stone free, a 95.7% final SFR. Clavien grade I or II complications occurred in nine patients and were managed conservatively. One case needed selective arterial embolization for severe bleeding. There was no deterioration of renal function noted. The mean preoperative creatinine (Cr) and postoperative Cr concentrations were 148.17 MUmol/L and 149.24 MUmol/L (P=0.48). CONCLUSION: The MPCNL was a safe and effective treatment for upper urinary tract stones in patients with ADPKD, even in patients with staghorn stone. It provided excellent SFR without compromising renal function. This procedure could be considered as a first-line treatment option for patients with ADPKD who have a large stone burden. PMID- 23924302 TI - The prevention and reduction of weight loss in an acute tertiary care setting: protocol for a pragmatic stepped wedge randomised cluster trial (the PRoWL project). AB - BACKGROUND: Malnutrition, with accompanying weight loss, is an unnecessary risk in hospitalised persons and often remains poorly recognised and managed. The study aims to evaluate a hospital-wide multifaceted intervention co-facilitated by clinical nurses and dietitians addressing the nutritional care of patients, particularly those at risk of malnutrition. Using the best available evidence on reducing and preventing unplanned weight loss, the intervention (introducing universal nutritional screening; the provision of oral nutritional supplements; and providing red trays and additional support for patients in need of feeding) will be introduced by local ward teams in a phased way in a large tertiary acute care hospital. METHODS/DESIGN: A pragmatic stepped wedge randomised cluster trial with repeated cross section design will be conducted. The unit of randomisation is the ward, with allocation by a random numbers table. Four groups of wards (n = 6 for three groups, n = 7 for one group) will be randomly allocated to each intervention time point over the trial. Two trained local facilitators (a nurse and dietitian for each group) will introduce the intervention. The primary outcome measure is change in patient's body weight, secondary patient outcomes are: length of stay, all-cause mortality, discharge destinations, readmission rates and ED presentations. Patient outcomes will be measured on one ward per group, with 20 patients measured per ward per time period by an unblinded researcher. Including baseline, measurements will be conducted at five time periods. Staff perspectives on the context of care will be measured with the Alberta Context Tool. DISCUSSION: Unplanned and unwanted weight loss in hospital is common. Despite the evidence and growing concern about hospital nutrition there are very few evaluations of system-wide nutritional implementation programs. This project will test the implementation of a nutritional intervention across one hospital system using a staged approach, which will allow sequential rolling out of facilitation and project support. This project is one of the first evidence implementation projects to use the stepped wedge design in acute care and we will therefore be testing the appropriateness of the stepped wedge design to evaluate such interventions. TRIAL REGISTRATION: ACTRN12611000020987. PMID- 23924304 TI - Perchlorate reduction using free and encapsulated Azospira oryzae enzymes. AB - Existing methods for perchlorate remediation are hampered by the common co occurrence of nitrate, which is structurally similar and a preferred electron acceptor. In this work, the potential for perchlorate removal using cell-free bacterial enzymes as biocatalysts was investigated using crude cell lysates and soluble protein fractions of Azospira oryzae PS, as well as soluble protein fractions encapsulated in lipid and polymer vesicles. The crude lysates showed activities between 41 700 to 54 400 U L(-1) (2.49 to 3.06 U mg(-1) total protein). Soluble protein fractions had activities of 15 400 to 29 900 U L(-1) (1.70 to 1.97 U mg(-1)) and still retained an average of 58.2% of their original activity after 23 days of storage at 4 degrees C under aerobic conditions. Perchlorate was removed by the soluble protein fraction at higher rates than nitrate. Importantly, perchlorate reduction occurred even in the presence of 500 fold excess nitrate. The soluble protein fraction retained its function after encapsulation in lipid or polymer vesicles, with activities of 13.8 to 70.7 U L( 1), in agreement with theoretical calculations accounting for the volume limitation of the vesicles. Further, encapsulation mitigated enzyme inactivation by proteinase K. Enzyme-based technologies could prove effective at perchlorate removal from water cocontaminated with nitrate or sulfate. PMID- 23924305 TI - Hemiconvulsion-hemiplegia syndrome: new insights from neuroimaging. PMID- 23924306 TI - Prevalence of cardiovascular risk factors and socioeconomic level among public sector workers in Angola. AB - BACKGROUND: Cardiovascular diseases are the leading cause of death in the majority of developed and developing countries. African countries are currently facing an increase in both cardiovascular and transmitted diseases. In addition, cardiovascular risk varies among different socioeconomic groups. Thus, we determined the prevalence of modifiable cardiovascular risk factors in apparently healthy public-sector workers and investigated possible relationships with socioeconomic status. METHODS: We employed a cross-sectional study comprising 42.2% (n = 615) of the public-sector workers at Agostinho Neto University, 48% (n = 294) male and 52% (n= 321) female, with ages between 20 and 72 years and from various socioeconomic groups. The study was conducted from February 2009 to December 2010. Personal, anthropometric, biochemical, hemodynamic, socioeconomic, and physical activity data were collected. RESULTS: The prevalence rates of cardiovascular risk factors were as follows: hypertension, 45.2% (men 46.3%, women 44.2%, P > 0.05); hypercholesterolemia, 11.1% (men 10.5%, women 11.5%, P > 0.05); low high-density lipoprotein (HDL) cholesterol, 50.1% (men 36.9%, women 62.3%; P < 0.05); hypertriglyceridemia, 10.6% (men 12.6%, women 8.7%, P > 0.05); smoking, 7.2% (men 10.2%, women 4.4%; P < 0.05); diabetes, 5.7% (men 5.5%, women 5.9%, P > 0.05); overweight, 29.3% (men 27.3%, women 31.2%, P > 0.05); obesity, 19.6% (men 9.2%, women 29.0%; P < 0.05); sedentary lifestyle, 87.2% (men 83.0%, women 91,0%, P < 0.05); and left ventricular hypertrophy, 20% (men 32.0%, women 9.0%; P < 0.05). At least one risk factor was present in 27.7% of the sample; 15.2% had two risk factors, and 31.4% had three or more risk factors. Among the individuals with low socioeconomic status, 41.0% had three or more risk factors. CONCLUSIONS: The results of this study suggest the existence of a high prevalence of multiple risk factors for cardiovascular disease in apparently healthy public sector workers in Angola. The workers in lower socioeconomic groups had higher incidences of hypertension, smoking, and left ventricular hypertrophy. PMID- 23924307 TI - Australia's female military surgeons of World War I. AB - The war service of Lilian Violet Cooper, the first female surgeon of the Royal Australasian College of Surgeons, is well recognized. Not so well known however, are the other pioneering female doctors who also undertook work as military surgeons during World War I. At least four of the 14 Australian female doctors that undertook overseas war service during World War I were engaged as surgeons and treated Australian, British and Allied casualties. These women operated in London, in Egypt and on the frontlines of the Macedonian campaign. While none of these other women became Fellows of the Royal Australasian College of Surgeons, their war efforts deserve recognition. PMID- 23924308 TI - Seed-mediated growth of ultralong gold nanorods and nanowires with a wide range of length tunability. AB - This study reports a systematic approach to synthesize ultralong gold nanorods and nanowires using a seed-mediated growth approach. In the first series, the effect of growth solution pH on the lengths of nanorods prepared was investigated. Interestingly, although shorter rods (230-310 nm) were produced in a basic solution environment than in an acidic condition (330-410 nm), the nanorod yield is greatly improved with relatively few nanoplate byproducts formed. Nanorod growth proceeds quickly in a basic solution as evidenced by the fast solution color changes. By adjusting several experimental parameters with the aim to elongate the nanorod length in a tunable fashion, gold nanorods and nanowires with average lengths from 580 to 2850 nm can be synthesized by progressively increasing the HNO3 concentration in the final growth solution. Nanowire growth in a highly acidic solution is slower, and a substantially longer time is needed to reach long lengths. Further extension of the nanowire length can be achieved simply by reducing the volume of second growth solution transferred to the final growth solution. Nanorods and nanowires with lengths spanning from 700 nm to 4.5 MUm were prepared in this series of experimental conditions. The longest nanowires can reach a length of up to 6 MUm. The nanowires still maintain thin average diameters of 33-53 nm. The ability to make gold nanorods and nanowires over this exceptionally wide and useful length range is exciting because applications and demonstrations using ultralong gold nanorods and nanowires of most suitable lengths are now possible. PMID- 23924309 TI - How often are late preterm births the result of non-evidence based practices: analysis from a retrospective cohort study at two tertiary referral centres in a nationalised healthcare system. AB - OBJECTIVE: To determine the proportion, characteristics, and predictors of late preterm birth (LPTB) in relation to evidence-based (EB) and non-evidence based (NEB) indications. DESIGN: Retrospective cohort study. SETTING: Two Canadian tertiary referral centres. POPULATION: All live singleton LPTBs over 1 year from 2010 to 2011, excluding major congenital anomalies. METHODS: Indications for LPTB were classified a priori as EB (i.e. based on practice guidelines or on evidence from randomised controlled trials) or NEB. Data were abstracted from maternal antenatal and labour records. Univariate analyses were completed using Fischer's exact, Pearson's chi-square, or analysis of variance (anova) F-tests. Logistic regression included gestation at birth, delivery provider, previous stillbirth, previous caesarean section, corticosteroid administration, and previous preterm birth as predictors for NEB LPTB. MAIN OUTCOME MEASURES: The proportion, characteristics, and predictors of women with NEB versus EB LPTBs. RESULTS: Of 524 LPTBs, 25.2% (n = 132) were NEB. Logistic regression revealed that NEB LPTBs were less likely if patients were delivered by their own doctor or their doctor's practice partner (OR 0.53, 95% CI 0.34-0.83). However, NEB LPTBs were more likely in women who had experienced a previous stillbirth (OR 2.57, 95% CI 1.20-5.49). CONCLUSIONS: Approximately one-quarter of LPTBs are NEB. Further research is needed to see if a review of the indications for LPTB, and subsequent reduction in NEB LPTBs, translates into improved neonatal outcomes and cost savings. PMID- 23924310 TI - Sustainable approach toward synthesis of green functional carbonaceous 3-D micro/nanostructures from biomass. AB - This study proposes a novel technique to synthesize functional carbonaceous three dimensional (3-D) micro/nanocompounds from agricultural by-products using femtosecond laser irradiation. Biowastes of rice husk and wheat straw are value engineered to carbonaceous structures in a single-step process under ambient conditions. Our results demonstrate that by controlling the laser fluence, structures with a variety of different morphologies from nanostructures to microstructures can be achieved. Also, the results indicate that altering the laser processing parameters influences the chemical composition of the synthesized structures. This sustainable approach presents an important step towards synthesizing 3-D micro/nanofibrous compounds from biowaste materials. These structures, as-synthesized or as nanocomposite fillers, can have practical uses in electronic, sensing, biological, and environmental applications. PMID- 23924311 TI - Co3O4/carbon aerogel hybrids as anode materials for lithium-ion batteries with enhanced electrochemical properties. AB - A facile hydrothermal and sol-gel polymerization route was developed for large scale fabrication of well-designed Co3O4 nanoparticles anchored carbon aerogel (CA) architecture hybrids as anode materials for lithium-ion batteries with improved electrochemical properties. The three-dimensional (3D) mesoporous Co3O4/CA hierarchical hybrids display an improved lithium storage performance and cycling stability, because of the intimate integration and strong synergistic effects between the Co3O4 nanoparticles and CA matrices. Such an interconnected Co3O4/CA hierarchical hybrid can effectively utilize the good conductivity, large surface area, 3D interconnected mesoporous structure, mechanical flexibility, chemical stability, and the short length of Li-ion transport of the CA matrix. The incorporation of Co3O4 nanoparticles into the interconnected CA matrix effectively reduces the number of active sites of Co3O4/CA hybrids, thus greatly increasing the reversible specific capacity and the initial Coulombic efficiency of the hybrids. The Co3O4/CA hybrid material displays the best lithium storage performance and good cycling stability as the Co3O4 loading content is up to 25 wt %, retains a Coulombic efficiency of 99.5% and a specific discharge capacity of 779 mAh g(-1) after 50 cycles, 10.1 and 1.6 times larger than the specific discharge capacity of 73 mAh g(-1) and 478 mAh g(-1) for Co3O4 and CA samples, respectively. The hierarchical hybrid nanostructures with enhanced electrochemical activities using a CA matrix framework can find potential applications in the related conversion reaction electrodes. PMID- 23924312 TI - Role of B-type natriuretic peptide as a marker of mortality in acute kidney injury patients treated with continuous renal replacement therapy. AB - OBJECTIVES: Acute kidney injury (AKI) treated with continuous renal replacement therapy (CRRT) is associated with poor outcome. Plasma B-type natriuretic peptide (BNP) is a biomarker related to fluid volume overload, and is elevated in AKI patients. The purpose of the study was to assess whether BNP levels at the time of starting CRRT could be used as a predictor of mortality in patients with AKI receiving CRRT. METHODS: We conducted a prospective observational cohort study enrolling 149 patients with AKI receiving CRRT. The primary outcome was mortality during CRRT. RESULTS: The median BNP level of 84 (56.3%) patients who expired was significantly higher than that of those who survived (1812.5 vs. 475.0 pg/mL; p = 0.01). Receiver operating characteristic curves demonstrated BNP levels as a predictor of mortality during CRRT with an area under the curve of 0.77 (p = 0.000), and the optimal threshold for BNP was 1054 pg/mL. Patients with BNP levels above 1054 pg/mL had a significantly higher mortality (76.6 vs. 34.7%; p = 0.01). CONCLUSION: Elevated BNP level is associated with mortality in patients with AKI receiving CRRT. PMID- 23924313 TI - Vegetative states and minimally conscious states revisited: a Russian doll approach. PMID- 23924314 TI - Highly efficient chemoselective synthesis of polysubstituted pyrroles via isocyanide-based multicomponent domino reaction. AB - A multicomponent domino reaction for the chemoselective, catalyst-free synthesis of polysubstituted pyrroles from readily available isocyanides, primary or secondary amines, and gem-diactivated olefins has been developed. Structurally diverse pyrroles were obtained in moderate to good yields under mild conditions. PMID- 23924315 TI - In vivo production of mesenchymal stromal cells after injection of autologous platelet-rich plasma activated by recombinant human soluble tissue factor in the bone marrow of healthy volunteers. AB - Autologous mesenchymal stromal cell (MSC)-based therapies offer one of the most promising and safe methods for regeneration or reconstruction of tissues and organs. Routine procedures to obtain adequate amount of autologous stem cells need their expansion through culture, with risks of contamination and cell differentiation, leading to the loss of cell ability for therapies. We suggest the use of human bone marrow (BM) as a physiological bioreactor to produce autologous MSC by injection of autologous platelet-rich plasma activated by recombinant human soluble tissue factor (rhsTF) in iliac crest. A trial on 13 healthy volunteers showed the feasibility and harmlessness of the procedure. The phenotype and cellularity of BM cells were not modified, on day 3 after injection. Endothelial progenitor cells (EPC) were mobilized to the bloodstream, without stimulation of hematopoietic stem cells (HSC). MSC level in BM increased with a specific commitment to preosteoblastic cell population both in vivo and in vitro. This self-stimulation system of BM seems thus to be a promising feasible process 3 days before clinical cell therapy applications. PMID- 23924317 TI - Actively targeting solid tumours with thermoresponsive drug delivery systems that respond to mild hyperthermia. AB - A diverse range of drug delivery vehicles have been developed to specifically target chemotherapeutics to solid tumours while avoiding systemic dose-limiting toxicity. Many of these active targeting strategies display limited efficacy because they rely on subtle differences in expression patterns between pathogenic tissue and healthy tissue. In contrast, drug delivery systems that exploit thermoresponsive behaviour allow a clinician to spatially and temporally control the accumulation and/or release of the toxic agents within tumour tissue by simply applying mild hyperthermia (defined as 39-43 degrees C) to the desired site. Although thermally sensitive materials comprise a significant portion of the literature on novel drug delivery systems, only a few systems have been methodically tuned to respond within this narrowly defined physiological temperature range in an in vivo environment. This review discusses the materials and strategies developed to control the primary tumour through the combined application of hyperthermia and chemotherapy. PMID- 23924316 TI - Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry. AB - BACKGROUND: We previously identified two hydrolyzable tannins, chebulagic acid (CHLA) and punicalagin (PUG) that blocked herpes simplex virus type 1 (HSV-1) entry and spread. These compounds inhibited viral glycoprotein interactions with cell surface glycosaminoglycans (GAGs). Based on this property, we evaluated their antiviral efficacy against several different viruses known to employ GAGs for host cell entry. RESULTS: Extensive analysis of the tannins' mechanism of action was performed on a panel of viruses during the attachment and entry steps of infection. Virus-specific binding assays and the analysis of viral spread during treatment with these compounds were also conducted. CHLA and PUG were effective in abrogating infection by human cytomegalovirus (HCMV), hepatitis C virus (HCV), dengue virus (DENV), measles virus (MV), and respiratory syncytial virus (RSV), at MUM concentrations and in dose-dependent manners without significant cytotoxicity. Moreover, the natural compounds inhibited viral attachment, penetration, and spread, to different degrees for each virus. Specifically, the tannins blocked all these steps of infection for HCMV, HCV, and MV, but had little effect on the post-fusion spread of DENV and RSV, which could suggest intriguing differences in the roles of GAG-interactions for these viruses. CONCLUSIONS: CHLA and PUG may be of value as broad-spectrum antivirals for limiting emerging/recurring viruses known to engage host cell GAGs for entry. Further studies testing the efficacy of these tannins in vivo against certain viruses are justified. PMID- 23924321 TI - Cation-pi interactions: accurate intermolecular potential from symmetry-adapted perturbation theory. AB - Symmetry-adapted perturbation theory (SAPT) is used to decompose the total intermolecular interaction energy between the ammonium cation and a benzene molecule into four physically motivated individual contributions: electrostatics, exchange, dispersion, and induction. Based on this rigorous decomposition, it is shown unambiguously that both the electrostatic and the induction energy components contribute almost equally to the attractive forces stabilizing the dimer with a nonnegligible contribution coming from the dispersion term. A polarizable potential model for the interaction of ammonium cation with benzene is parametrized by fitting these four energy components separately using the functional forms of the AMOEBA force field augmented with the missing charge penetration energy term calculated as a sum over pairwise electrostatic energies between spherical atoms. It is shown that the proposed model is able to produce accurate intermolecular interaction energies as compared to ab initio results, thus avoiding error compensation to a large extent. PMID- 23924319 TI - Histone 3.3 participates in a self-sustaining cascade of apoptosis that contributes to the progression of chronic obstructive pulmonary disease. AB - RATIONALE: Shifts in the gene expression of nuclear protein in chronic obstructive pulmonary disease (COPD), a progressive disease that is characterized by extensive lung inflammation and apoptosis, are common; however, the extent of the elevation of the core histones, which are the major components of nuclear proteins and their consequences in COPD, has not been characterized, which is important because extracellular histones are cytotoxic to endothelial and airway epithelial cells. OBJECTIVES: To investigate the role of extracellular histones in COPD disease progression. METHODS: We analyzed the nuclear lung proteomes of ex-smokers with and without the disease. Further studies on the consequences of H3.3 were also performed. MEASUREMENTS AND MAIN RESULTS: A striking finding was a COPD-specific eightfold increase of hyperacetylated histone H3.3. The hyperacetylation renders H3.3 resistant to proteasomal degradation despite ubiquitination; when combined with the reduction in proteasome activity that is known for COPD, this resistance helps account for the increased levels of H3.3. Using anti-H3 antibodies, we found H3.3 in the airway lumen, alveolar fluid, and plasma of COPD samples. H3.3 was cytotoxic to lung structural cells via a mechanism that involves the perturbation of Ca(2+) homeostasis and mitochondrial toxicity. We used the primary human airway epithelial cells and found that the antibodies to either the C or N terminus of H3 could partially reverse H3.3 toxicity. CONCLUSIONS: Our data indicate that there is an uncontrolled positive feedback loop in which the damaged cells release acetylated H3.3, which causes more damage, adds H3.3 release, and contributes toward the disease progression. PMID- 23924320 TI - Minimally invasive percutaneous nephrolithotomy for simple and complex renal caliceal stones: a comparative analysis of more than 10,000 cases. AB - PURPOSE: To determine whether minimally invasive PCNL (MPCNL) is as safe and effective in the management of complex renal caliceal stones as it is for simple renal stones. PATIENTS AND METHODS: We retrospectively reviewed 5761(41.2%) simple caliceal stones (isolated renal pelvis including isolated calix) and 8223 (58.8%) complex caliceal stones (renal pelvis accompanying two calices at least) that were managed by MPCNL between 1992 nd 2011. The safety, efficacy, and outcome were compared and analyzed. RESULTS: Stone burden was larger in complex caliceal stones (1763.0 vs 1018.6 mm(2), P<0.05). Patients with simple stones had significantly shorter operative time, less frequency of multiple percutaneous accesses, and less hemoglobin drop. They also had a higher initial stone-free rate (SFR) (77.6% vs 66.4%) after a single session of MPCNL (P<0.05). The differences diminished in the final SFR (86.7% vs 86.1%) after relook and/or auxiliary procedures (P>0.05). The complication rate (17.9% vs 19.0%) and blood transfusion rate (grade II) (2.2% vs 3.2%) were similar in both groups (P>0.05). Both groups had a low rate of high Clavien grade complications. Renal vascular embolizations (grade III), however, were significantly higher in patients with complex caliceal stones (P<0.05). CONCLUSIONS: MPCNL is a safe and effective treatment option for patients with complex caliceal stones except there is a slightly higher frequency rate of embolization. There was a higher initial SFR in simple stones, but this difference diminished with secondary procedures. PMID- 23924318 TI - Neuroendocrine and cardiac metabolic dysfunction and NLRP3 inflammasome activation in adipose tissue and pancreas following chronic spinal cord injury in the mouse. AB - CVD (cardiovascular disease) represents a leading cause of mortality in chronic SCI (spinal cord injury). Several component risk factors are observed in SCI; however, the underlying mechanisms that contribute to these risks have not been defined. Central and peripheral chronic inflammation is associated with metabolic dysfunction and CVD, including adipokine regulation of neuroendocrine and cardiac function and inflammatory processes initiated by the innate immune response. We use female C57 Bl/6 mice to examine neuroendocrine, cardiac, adipose and pancreatic signaling related to inflammation and metabolic dysfunction in response to experimentally induced chronic SCI. Using immuno-histochemical, precipitation, and -blotting analysis, we show decreased POMC (proopiomelanocortin) and increased NPY (neuropeptide-Y) expression in the hypothalamic ARC (arcuate nucleus) and PVN (paraventricular nucleus), 1-month post-SCI. Long-form leptin receptor (Ob-Rb), JAK2 (Janus kinase)/STAT3 (signal transducer and activator of transcription 3)/p38 and RhoA/ROCK (Rho-associated kinase) signaling is significantly increased in the heart tissue post-SCI, and we observe the formation and activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome in VAT (visceral adipose tissue) and pancreas post-SCI. These data demonstrate neuroendocrine signaling peptide alterations, associated with central inflammation and metabolic dysfunction post SCI, and provide evidence for the peripheral activation of signaling mechanisms involved in cardiac, VAT and pancreatic inflammation and metabolic dysfunction post-SCI. Further understanding of biological mechanisms contributing to SCI related inflammatory processes and metabolic dysfunction associated with CVD pathology may help to direct therapeutic and rehabilitation countermeasures. PMID- 23924323 TI - Uptake and mobilization of organic chemicals with clouds: evidence from a hail sample. AB - Polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) were measured in hail samples collected during a storm that occurred on a spring morning in Toronto, Canada. The presence of these organic chemicals in hail suggests that clouds likely provide an atmospheric transport pathway for these substances in the free atmosphere. Results reported here may carry significant implications for atmospheric transport, mass balance, tropospheric cold trapping, and environmental fate of organic chemicals. Backward trajectories along with measured and modeled cloud cover show that clouds causing the hail event were formed and advected from the midwestern and southeastern United States. After being emitted to the atmosphere, the organic chemicals were likely lifted by atmospheric ascending motions to a higher atmospheric elevation and partitioned onto clouds. These clouds then carry the organic chemicals to a downwind location where they are deposited to the ground surface via precipitation. We found that the organic chemicals with high solubility and vapor pressure tend to partition into clouds through sorption to cloudwater droplets and ice particles. It was found that approximately 7-30% of pyrene could be sorbed into cloudwater droplets and ice particles in this hail event at the expense of reduced gas-phase concentrations. PMID- 23924322 TI - Hypersensitivity pneumonitis: lessons for diagnosis and treatment of a rare entity in children. AB - Hypersensitivity pneumonitis (HP) also called exogenous allergic alveolitis = extrinsic allergic alveolitis in children is an uncommon condition and may not be recognized and treated appropriately.To assess current means of diagnosis and therapy and compare this to recommendations, we used the Surveillance Unit for Rare Paediatric Disorders (ESPED) to identify incident cases of HP in Germany during 2005/6. In addition, cases of HP reported for reference from all over Germany to our center in the consecutive year were included.Twenty-three children with confirmed pediatric HP were identified. All (age 9.4 y (4.4-15.1) presented with dyspnoea at rest or with exercise, mean FVC was 39% of predicted, seven of the 23 children already had a chronic disease state at presentation. IgG against bird was elevated in 20, and against fungi in 15. Bronchoalveolar lavage was done in 18 subjects (41% lymphocytes, CD4/CD8 1.99), and lung biopsy in 6. Except 2, all children were treated with prolonged courses of systemic steroids. Outcome was not favourable in all cases.Late diagnosis in up to a quarter of the children with HP and inappropriate steroid treatment must be overcome to improve management of HP. Inclusion of children with HP into international, web-based registry studies will help to study and follow up such rare lung diseases. PMID- 23924324 TI - Reports of police beating and associated harms among people who inject drugs in Bangkok, Thailand: a serial cross-sectional study. AB - BACKGROUND: Thailand has for years attempted to address illicit drug use through aggressive drug law enforcement. Despite accounts of widespread violence by police against people who inject drugs (IDU), the impact of police violence has not been well investigated. In the wake of an intensified police crackdown in 2011, we sought to identify the prevalence and correlates of experiencing police beating among IDU in Bangkok. METHODS: Community-recruited samples of IDU in Bangkok were surveyed between June 2009 and October 2011. Multivariate log binomial regression was used to identify factors associated with reporting police beating. RESULTS: In total, 639 unique IDU participated in this serial cross sectional study, with 240 (37.6%) participants reporting that they had been beaten by police. In multivariate analyses, reports of police beating were associated with male gender (Adjusted Prevalence Ratio [APR] = 4.43), younger age (APR = 1.69), reporting barriers to accessing healthcare (APR = 1.23), and a history of incarceration (APR = 2.51), compulsory drug detention (APR = 1.22) and syringe sharing (APR = 1.44), and study enrolment in 2011 (APR = 1.27) (all p < 0.05). Participants most commonly reported police beating during the interrogation process. CONCLUSIONS: A high proportion of IDU in Bangkok reported having been beaten by the police. Experiencing police beating was independently associated with various indicators of drug-related harm. These findings suggest that the over-reliance on enforcement-based approaches is contributing to police perpetrated abuses and the perpetuation of the HIV risk behaviour among Thai IDU. PMID- 23924325 TI - Insights into Aurora-A kinase activation using unnatural amino acids incorporated by chemical modification. AB - Most protein kinases are regulated through activation loop phosphorylation, but the contributions of individual sites are largely unresolved due to insufficient control over sample phosphorylation. Aurora-A is a mitotic Ser/Thr protein kinase that has two regulatory phosphorylation sites on its activation loop, T287 and T288. While phosphorylation of T288 is known to activate the kinase, the function of T287 phosphorylation is unclear. We applied site-directed mutagenesis and selective chemical modification to specifically introduce bioisosteres for phospho-threonine and other unnatural amino acids at these positions. Modified Aurora-A proteins were characterized using a biochemical assay measuring substrate phosphorylation. Replacement of T288 with glutamate and aspartate weakly stimulated activity. Phospho-cysteine, installed by chemical synthesis from a corresponding cysteine residue introduced at position 288, showed catalytic activity approaching that of the comparable phospho-serine protein. Unnatural amino acid residues, with longer side chains, inserted at position 288 were autophosphorylated and supported substrate phosphorylation. Aurora-A activity is enhanced by phosphorylation at position 287 alone but is suppressed when position 288 is also phosphorylated. This is rationalized by competition between phosphorylated T287 and T288 for a binding site composed of arginines, based on a structure of Aurora-A in which phospho-T287 occupies this site. This is, to our knowledge, the first example of a Ser/Thr kinase whose activity is controlled by the phosphorylation state of adjacent residues in its activation loop. Overall we demonstrate an approach that combines mutagenesis and selective chemical modification of selected cysteine residues to investigate otherwise impenetrable aspects of kinase regulation. PMID- 23924327 TI - Transcending the caesura: reverie, dreaming and counter-dreaming. AB - The author reflects about our capacity to get in touch with primitive, irrepresentable, seemingly unreachable parts of the Self and with the unrepressed unconscious. It is suggested that when the patient's dreaming comes to a halt, or encounters a caesura, the analyst dreams that which the patient cannot. Getting in touch with such primitive mental states and with the origin of the Self is aspired to, not so much for discovering historical truth or recovering unconscious content, as for generating motion between different parts of the psyche. The movement itself is what expands the mind and facilitates psychic growth. Bion's brave and daring notion of 'caesura', suggesting a link between mature emotions and thinking and intra-uterine life, serves as a model for bridging seemingly unbridgeable states of mind. Bion inspires us to 'dream' creatively, to let our minds roam freely, stressing the analyst's speculative imagination and intuition often bordering on hallucination. However, being on the seam between conscious and unconscious, dreaming subverts the psychic equilibrium and poses a threat of catastrophe as a result of the confusion it affords between the psychotic and the non-psychotic parts of the personality. Hence there is a tendency to try and evade it through a more saturated mode of thinking, often relying on external reality. The analyst's dreaming and intuition, perhaps a remnant of intra-uterine life, is elaborated as means of penetrating and transcending the caesura, thus facilitating patient and analyst to bear unbearable states of mind and the painful awareness of the unknowability of the emotional experience. This is illustrated clinically. PMID- 23924326 TI - The management and outcomes of placenta accreta, increta, and percreta in the UK: a population-based descriptive study. AB - OBJECTIVE: To describe the management and outcomes of placenta accreta, increta, and percreta in the UK. DESIGN: A population-based descriptive study using the UK Obstetric Surveillance System (UKOSS). SETTING: All 221 UK hospitals with obstetrician-led maternity units. POPULATION: All women diagnosed with placenta accreta, increta, and percreta in the UK between May 2010 and April 2011. METHODS: Prospective case identification through the monthly mailing of UKOSS. MAIN OUTCOME MEASURES: Median estimated blood loss, transfusion requirements. RESULTS: A cohort of 134 women were identified with placenta accreta, increta, or percreta: 50% (66/133) were suspected to have this condition antenatally. In women with a final diagnosis of placenta increta or percreta, antenatal diagnosis was associated with reduced levels of haemorrhage (median estimated blood loss 2750 versus 6100 ml, P = 0.008) and a reduced need for blood transfusion (59 versus 94%, P = 0.014), possibly because antenatally diagnosed women were more likely to have preventative therapies for haemorrhage (74 versus 52%, P = 0.007), and were less likely to have an attempt made to remove their placenta (59 versus 93%, P < 0.001). Making no attempt to remove any of the placenta, in an attempt to conserve the uterus or prior to hysterectomy, was associated with reduced levels of haemorrhage (median estimated blood loss 1750 versus 3700 ml, P = 0.001) and a reduced need for blood transfusion (57 versus 86%, P < 0.001). CONCLUSIONS: Women with placenta accreta, increta, or percreta who have no attempt to remove any of their placenta, with the aim of conserving their uterus, or prior to hysterectomy, have reduced levels of haemorrhage and a reduced need for blood transfusion, supporting the recommendation of this practice. PMID- 23924328 TI - Bion and Tustin: the autistic phenomena. AB - This article examines the implications of the proposal of autistic transformations within the general context of Bion's theory of Transformations. The aim is to confirm the coherence of this proposal of autistic transformations within the overall structure of Bion's theory of Transformations. She examines the relation between emotional links and their negatives, particularly -K. She questions in which of the dimensions of the mind the autistic phenomena are located, the relation between autistic phenomena and beta elements, and where to place them in the Grid. The author tries to form metapsychological support for the incorporation of the autistic area in Bion's theory of Transformations. She argues that, despite the incongruence and imprecision of this incorporation, such autistic phenomena cannot be excluded from the complexus of the human mind and should therefore be accounted for in Bion's transformations. She discusses the idea that the theory of transformations includes the field of the neurosis and psychosis and deals with emotions, whereas the autistic area is dominated by sensations. The author asks how to add the autistic area to Bion's theory. Clinical material of a child for whom the non-psychotic part of the personality predominates and who presents autistic nuclei provides material for the discussion. PMID- 23924329 TI - Seeing, mirroring, desiring: the impact of the analyst's pregnant body on the patient's body image. AB - The paper explores the impact of the analyst's pregnant body on the course of two analyses, a young man, and a young woman, specifically focusing on how each patient's visual perception and affective experience of being with the analyst's pregnant body affected their own body image and subjective experience of their body. The pre-verbal or 'subsymbolic' material evoked in the analyses contributed to a greater understanding of the patients' developmental experiences in infancy and adolescence, which had resulted in both carrying a profoundly distorted body image into adulthood. The analyst's pregnancy offered a therapeutic window in which a shift in the patient's body image could be initiated. Clinical material is presented in detail with reference to the psychoanalytic literature on the pregnant analyst, and that of the development of the body image, particularly focusing on the role of visual communication and the face. The author proposes a theory of psychic change, drawing on Bucci's multiple code theory, in which the patients' unconscious or 'subsymbolic' awareness of her pregnancy, which were manifest in their bodily responses, feeling states and dreams, as well as in the analyst s countertransference, could gradually be verbalized and understood within the transference. Thus visual perception, or 'external seeing', could gradually become 'internal seeing', or insight into unconscious phantasies, leading to a shift in the patients internal object world towards a less persecutory state and more realistic appraisal of their body image. PMID- 23924330 TI - 'No entry', an invitation to intrude, or both? Reflections on a group of anorexic patients. AB - This paper describes the twice-weekly psychoanalytic psychotherapy of a young woman who had undergone major bowel surgery in her early 20s, with no clear medical indication for the surgery. Whilst the concept of 'No Entry' described by Williams (, b) aptly describes many features of more 'typical' anorexic patients, this paper describes a particular group of anorexic patients, referred by their physicians for multiple medical procedures; and proposes there is a group of anorexic patients, repeatedly referred for medical investigations, into whom particular types of entries occur. These are entries into the body 'legitimized' as medical, with a trajectory towards multiple procedures, examinations and surgical operations. Other entries (outside the medical setting) may occur in a state of altered consciousness, under the influence of alcohol or drugs, such that any wish for intrusion is disowned and denied. In both sets of events, intrusion is both invited, and consciously denied. The case example illuminates some of these features, and aspects of the countertransference are also described. Attention is drawn to relevant research focusing on surgical intrusion. Finally, there is an exploration as to how such patients may invite intrusions into the body through surgery and medical procedures. PMID- 23924331 TI - A note on the history of the Norwegian Psychoanalytic Society from 1933 to 1945. AB - The Norwegian analysts, who were trained in Berlin before 1933, were drawn into a struggle against fascism, informed by politically leftist analysts who worked at the Berlin Institute. The Norwegian group, including the analysts Wilhelm Reich and Otto Fenichel, were committed to Marxist or social democratic ideologies in order to fight down fascism and Nazism. They were a source of inspiration but also of conflict. After the war the leadership of the IPA was sceptical about the Norwegian group because of its former connections with Die Linke, as well as its relations with Wilhelm Reich. This paper in part considers the courageous efforts of Nic Waal, whom Ernest Jones used as a delegate and courier to solve problems for the IPA and who was unjustly treated after the war. PMID- 23924332 TI - Resistance in therapy and war: psychoanalysis before and during the Nazi occupation of Norway 1933-45. PMID- 23924333 TI - The wish for annihilation in 'love-death' as collapse of the need for recognition, in Wagner's Tristan und Isolde. AB - Wagner's Tristan und Isolde holds a central position in Western music and culture. It is shown to demonstrate consequences of interruption of developmental processes involving the need for recognition of subjectivity, resulting in the collapse of this need into the wish for annihilation of self and other through 'love-death' [Liebestod]. A close reading of the musical language of the opera reveals how this interruption is demonstrated, and the consequent location of identity outside of language, particularly suitable for expression in music. Isolde's dynamics are presented as distinct from that of Tristan, and in contrast to other interpretations of Tristan and Isolde's love as an attack on the Oedipal order, or as a regressive wish for pre-Oedipal union. Isolde's Act I narrative locates the origin of her desire in the protagonists' mutual gaze at a traumatic moment. In this moment powerful and contrasting emotions converge, evoking thwarted developmental needs, and arousing the fantasy of redemption in love death. By removing the magical elements, Wagner enables a deeper understanding of the characters' positions in relation to each other, each with his or her own needs for recognition and traumatic experiences. These positions invite mutual identifications resulting in rising tension between affirmation of identity and annihilation, with actual death as the only possible psychic solution. The dynamics described in the opera demonstrate the function of music and opera in conveying meaning which is not verbally expressible. PMID- 23924334 TI - Transferences in parent-infant psychoanalytic treatments. AB - In parent-infant treatments, babies sometimes exhibit symptoms such as screaming, clinging, and fearful gaze avoidance of the analyst. The paper investigates if such phenomena may be regarded as transference manifestations, and if so, if they appear both in younger and older infants. Based on three case presentations, it is concluded that some babies are capable of forming both brief and enduring transferences. The term "indirect infant transference" refers to when a baby reacts emotionally to the analyst as long as the parent's transference remains unresolved. "Direct transference" refers to when a baby reacts in a non-mediated way to the analyst. The necessary tool of investigation for discovering these phenomena is a psychoanalytic method with an explicit, though not exclusive, focus on the baby. Discerning them in the clinical encounter may help us understand the baby's predicament and when and how to address the baby or the parent. These treatments constitute an empirical field awaiting more extensive clinical and theoretical investigation. Already now, they suggest that transference may be rooted in, and may appear during, very early developmental stages. The paper's positions are compared with those put forward by other parent infant clinicians. PMID- 23924335 TI - On: at what age should a psychoanalyst retire? PMID- 23924336 TI - The concept of intersubjectivity in psychoanalysis: taking critical stock. PMID- 23924337 TI - Matte Blanco and narrativity: Hitchcock's Vertigo. PMID- 23924338 TI - Remembering Daniel Stern (1934-2012): a legacy for 21st century psychoanalytic thinking and practice. PMID- 23924339 TI - Traumatic pseudoaneurysm of the basilar artery presenting with fatal epistaxis: a rare case report. AB - BACKGROUND: To the best of the authors' knowledge, this is the first report of a traumatic pseudoaneurysm of the basilar artery presenting with epistaxis. CASE STUDY: This study reports a rare case in which a patient suffered from fatal epistaxis because of a pseudoaneurysm of basilar artery and fracture of skull base after a motorcycle accident. Clinical manifestation, diagnostic imaging and endovascular treatment are described. Formation mechanisms and the treatment of traumatic pseudoaneurysm of basilar artery are discussed. PMID- 23924340 TI - End group characterization of poly(phthalaldehyde): surprising discovery of a reversible, cationic macrocyclization mechanism. AB - End-capped poly(phthalaldehyde) (PPA) synthesized by anionic polymerization has garnered significant interest due to its ease of synthesis and rapid depolymerization. However, alternative ionic polymerizations to produce PPA have been largely unexplored. In this report, we demonstrate that a cationic polymerization of o-phthalaldehyde initiated by boron trifluoride results in cyclic PPA in high yield, with high molecular weight, and with extremely high cyclic purity. The cyclic structure is confirmed by NMR spectroscopy, MALDI-TOF mass spectrometry, and triple-detection GPC. The cyclic polymers are reversibly opened and closed under the polymerization conditions. Owing to PPA's low ceiling temperature, cyclic PPA is capable of chain extension to larger molecular weights, controlled depolymerization to smaller molecular weights, or dynamic intermixing with other polymer chains, both cyclics and end-capped linears. These unusual properties endow the system with great flexibility in the synthesis and isolation of pure cyclic polymers of high molecular weight. Further, we speculate that the absence of end groups enhances the stability of cyclic PPA and makes it an attractive candidate for lithographic applications. PMID- 23924341 TI - Spreading and brush formation by end-grafted bottle-brush polymers with adsorbing side chains. AB - We investigate structural and thermodynamic properties of surface-grafted layers of model "bottle-brush" polymers by Monte Carlo simulation. The polymers consist of a longer main chain densely grafted with shorter side chains, of which the latter have some degree of affinity to the surface. Our focus is on the effect of the side-chain surface affinity on the brush properties, which we study in terms of compression isotherms spanning a broad range of grafting densities. For low grafting densities, side-chain adsorption causes the polymers to spread on the surface. As the grafting density is increased, the layer goes through a "pancake to-brush" transition to form a brush with the main chains aligned perpendicular to the surface. We find that side-chain adsorption is decisive for the structure of dilute layers and in the transition region but has little influence on the properties of dense brushes. The close relation between compression and adsorption isotherms is discussed, and the implications of side-chain adsorption for the ability of the polymer to form a dense brush are investigated. This analysis suggests that side-chain surface affinity alone will not give rise to "brush of bottle-brushes" layers by adsorption of polymers from solution, in agreement with recent experimental results. PMID- 23924342 TI - One-pot synthesis of ferrocenyl ketones containing biaryls and 6-aryl-2 ferrocenylquinolines via Ir/Pd-cocatalyzed alpha-alkylation/Suzuki reaction. AB - An efficient PPh3-cyclometalated iridium(III) benzo[h]quinoline hydride 1/Pd(OAc)2-cocatalyzed three-component alpha-alkylation/Suzuki reaction has been developed. The three-component reaction of 4-bromobenzyl alcohol, acetylferrocene, and arylboronic acids gives ferrocenyl ketones containing biaryls in moderate to good yields. This method was successfully applied to a one pot synthesis of 6-aryl-2-ferrocenyl quinolines, using (2-amino-5 bromophenyl)methanol instead of 4-bromobenzyl alcohol. PMID- 23924343 TI - Quality of life after surgery in individuals with familial colorectal cancer: does extended surgery have an adverse impact? AB - BACKGROUND: There is controversy regarding the optimum surgical treatment of patients presenting with colorectal cancer with known or suspected genetic cancer syndromes. Although standard segmental resection may be curative, a high risk of metachronous malignancy leads many to advocate extended surgery. The current study was designed to assess whether or not extended surgery adversely impacts quality of life compared to segmental surgery. METHODS: Records at The Royal Melbourne Hospital Family Cancer Clinic were searched in order to identify patients with suspected high risk familial colon cancer. Patients who underwent surgery were identified and mailed two Standardized Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC QLQ-CR38). RESULTS: Fifty respondents met the inclusion criteria. None of the 15 patients whose primary operation was an extended procedure developed a metachronous cancer. Seventeen of the 35 (48.67%) who had an initial segmental resection had subsequent surgery for metachronous cancer. At the time of the questionnaire, 27 had extended surgery and 23 had segmental operations. The overall global health status and quality of life was very similar between the two groups. CONCLUSION: This study confirms that there is a high rate of metachronous cancer for patients undergoing segmental resection for hereditary colon cancer. Quality of life following either segmental or extended resection is not significantly different. Consequently, it is reasonable to recommend extended surgery for most patients with high risk hereditary colon cancer. PMID- 23924344 TI - An atom-economic route to thiophenes and 2,2'-bithiophenes by intramolecular transannulation of gem-dialkylthio enynes. AB - An atom-economic route to thiophenes and bithiophenes has been developed starting from the readily available gem-dialkylthio enynes. A range of functionalized thiophenes and bithiophenes, bearing a pendent vinylthio group, were obtained in good to high yields under mild conditions. PMID- 23924345 TI - Disruptive by design: a perspective on engineering in analytical chemistry. AB - Perhaps paradoxically, we argue that the biological sciences are "data-limited". In contrast to the glut of DNA sequencing data available, high-throughput protein analysis is expensive and largely inaccessible. Hence, we posit that access to robust protein-level data is inadequate. Here, we use the framework of the formal engineering design process to both identify and understand the problems facing measurement science in the 21st century. In particular, discussion centers on the notable challenge of realizing protein analyses that are as effective (and transformative) as genomics tools. This Perspective looks through the lens of a case study on protein biomarker validation and verification, to highlight the importance of iterative design in realizing significant advances over currently available measurement capabilities in the candidate or targeted proteomics space. The Perspective follows a podium presentation given by the author at The 16th International Conference on Miniaturized Systems for Chemistry and Life Sciences (MUTAS 2012), specifically focusing on novel targeted proteomic measurement tools based in microfluidic design. The role of unmet needs identification, iteration in concept generation and development, and the existing gap in rapid prototyping tools for separations are all discussed. PMID- 23924346 TI - Cutaneous meningioma: a potential diagnostic pitfall in p63 positive cutaneous neoplasms. AB - Cutaneous meningiomas are divided into three groups. Type I lesions present at birth and are derived from ectopic arachnoid cells. Type II lesions usually present in adults and are derived from arachnoid cells surrounding nerve bundles. Type III lesions are due to direct extension or metastasis from dural-based neoplasms. Dural-based meningiomas are known to express p63. The aim of our study is to examine the expression of p63 in type II and type III meningioma. Two cases of cutaneous meningioma (type II and type III) were evaluated for the expression of p63, EMA, CK 5/6, S100 and CD31. The cells of interest were spindled to epithelioid and arranged in a whorling pattern. Immunohistochemical staining showed expression of EMA and p63 in both cases, while stains for CK 5/6, S100 and CD31 were negative. Among cutaneous tumors, p63 is considered a marker of epithelial derivation, as it is positive in epidermal and adnexal neoplasms. It is important to be aware of p63 expression in the context of cutaneous meningioma to avoid misinterpretation as an epithelial tumor. On the basis of our small study, it is unlikely that p63 expression would be helpful in distinguishing between type II and type III meningioma, as both may be p63-positive. PMID- 23924347 TI - Social disorganization and history of child sexual abuse against girls in sub Saharan Africa: a multilevel analysis. AB - BACKGROUND: Child sexual abuse (CSA) is a considerable public health problem. Less focus has been paid to the role of community level factors associated with CSA. The aim of this study was to examine the association between neighbourhood level measures of social disorganization and CSA. METHODS: We applied multiple multilevel logistic regression analysis on Demographic and Health Survey data for 6,351 adolescents from six countries in sub-Saharan Africa between 2006 and 2008. RESULTS: The percentage of adolescents that had experienced CSA ranged from 1.04% to 5.84%. There was a significant variation in the odds of reporting CSA across the communities, suggesting 18% of the variation in CSA could be attributed to community level factors. Respondents currently employed were more likely to have reported CSA than those who were unemployed (odds ratio [OR]=2.05, 95% confidence interval [CI] 1.48 to 2.83). Respondents from communities with a high family disruption rate were 57% more likely to have reported CSA (OR=1.57, 95% CI 1.14 to 2.16). CONCLUSION: We found that exposure to CSA was associated with high community level of family disruption, thus suggesting that neighbourhoods may indeed have significant important effects on exposure to CSA. Further studies are needed to explore pathways that connect the individual and neighbourhood levels, that is, means through which deleterious neighbourhood effects are transmitted to individuals. PMID- 23924349 TI - Online formative tests linked to microlectures improving academic achievement. AB - BACKGROUND: Online formative tests (OFTs) are powerful tools to direct student learning behavior, especially when enriched with specific feedback. AIM: In the present study, we have investigated the effect of OFTs enriched with hyperlinks to microlectures on examination scores. METHODS: OFTs, available one week preceding each midterm and the final exams, could be used voluntarily. The use of OFTs was related to scores on midterm and final exams using ANOVA, with prior academic achievement as a covariate. RESULTS: On average, 74% of all students used the online formative tests (OFT+) while preparing for the summative midterm exam. OFT+ students obtained significantly higher grades compared to OFT students, both without and with correction for previous academic achievement. Two out of three final exam scores did not significantly improve. CONCLUSION: Students using online formative tests linked to microlectures receive higher grades especially in highly aligned summative tests. PMID- 23924348 TI - Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-beta receptor I internalization and inhibiting transforming growth factor-beta1 signaling. AB - RATIONALE: Alveolar transforming growth factor (TGF)-beta1 signaling and expression of TGF-beta1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-beta receptor TbetaRI inhibits TGF-beta signaling and could attenuate development of experimental lung fibrosis. OBJECTIVES: To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting TGF-beta1 signaling in alveolar epithelial cells. METHODS: Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with IPF versus control subjects. Transgenic mice that constitutively overexpress human syndecan 2 in macrophages were developed to test the antifibrotic properties of syndecan 2. In vitro assays were performed to determine syndecan-2-dependent changes in epithelial cell TGF-beta1 signaling, TGF-beta1, and TbetaRI internalization and apoptosis. Wild-type mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced lung injury. MEASUREMENTS AND MAIN RESULTS: We observed significant increases in alveolar macrophage syndecan-2 levels in patients with IPF. Macrophage-specific overexpression of human syndecan 2 in transgenic mice conferred antifibrotic effects after lung injury by inhibiting TGF-beta1 signaling and downstream expression of TGF-beta1 target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1-dependent internalization of TGF-beta1 and TbetaRI in alveolar epithelial cells, which inhibited TGF-beta1 signaling and epithelial cell apoptosis. Therapeutic administration of human syndecan-2 abrogated lung fibrosis in mice. CONCLUSIONS: Alveolar macrophage syndecan-2 exerts antifibrotic effects by promoting caveolin-1-dependent TGF beta1 and TbetaRI internalization and inhibiting TGF-beta1 signaling in alveolar epithelial cells. Hence, molecules that facilitate TbetaRI degradation via endocytosis represent potential therapies for pulmonary fibrosis. PMID- 23924351 TI - Self-reported pain complaints among Afghanistan/Iraq era men and women veterans with comorbid posttraumatic stress disorder and major depressive disorder. AB - OBJECTIVE: Research has shown significant rates of comorbidity among posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and pain in prior era veterans but less is known about these disorders in Iraq and Afghanistan war era veterans. This study seeks to extend previous work by evaluating the association among PTSD, MDD, and pain (back, muscle, and headache pain) in this cohort. METHOD: A sample of 1,614 veterans, recruited from 2005 to 2010, completed a structured clinical interview and questionnaires assessing trauma experiences, PTSD symptoms, depressive symptoms, and pain endorsement. RESULTS: Veterans with PTSD endorsed pain-related complaints at greater rates than veterans without PTSD. The highest rate of pain complaints was observed in veterans with comorbid PTSD/MDD. Women were more likely to endorse back pain and headaches but no gender by diagnosis interactions were significant. CONCLUSIONS: Findings highlight the complex comorbid relationship between PTSD, MDD, and pain among Iraq and Afghanistan veterans. This observed association suggests that integrated, multidisciplinary treatments may be beneficial, particularly when multiple psychological and physical health comorbidities are present with pain. Further support may be indicated for ongoing education of mental health and primary care providers about these co-occurring disorders. PMID- 23924350 TI - Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload. AB - Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mtDNA sequence variation contributes to disease susceptibility. In the present study we show a novel animal model of mtDNA polymorphisms, the MNX (mitochondrial-nuclear exchange) mouse, in which the mtDNA from the C3H/HeN mouse has been inserted on to the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harbouring the C57/BL6J mtDNA generate more ROS (reactive oxygen species) and have a higher mitochondrial membrane potential relative to those with C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the 'mitochondrial paradigm' for the development of disease susceptibility, and show that the mtDNA modulates cellular bioenergetics, mitochondrial ROS generation and susceptibility to cardiac stress. PMID- 23924352 TI - Inhibition of Cronobacter sakazakii by heat labile bacteriocins produced by probiotic LAB isolated from healthy infants. AB - Cronobacter sakazakii is an opportunistic pathogen that can cause bacteremia, meningitis, and necrotizing enterocolitis, most often in neonates with case fatality rates that may reach 80%. The antimicrobial activity of lactic acid bacteria against a wide range of foodborne pathogens is well-established in different types of food products. The objective of the current study was to investigate the antibacterial activity of Lactobacillus acidophilus and L. casei isolated from feces of healthy infants against different strains of C. sakazakii in agar and a rehydrated infant milk formula (RIMF) model. The inhibition zones of C. sakazakii around L. acidophilus or L. casei ranged from 22 to 32 mm on eMan Rogosa Sharpe (MRS) agar under aerobic conditions, while a slight reduction in antibacterial activity was noted on modified MRS (0.2% glucose) under anaerobic conditions. It was observed that pH-neutralized cell-free supernatant (CFS) of L. acidophilus or L. casei was inhibitory against tested C. sakazakii strains. The inhibition zones of neutralized CFS were lower than the antibacterial activities of live cultures. The antibacterial activity of CFS was abolished when CFS from L. acidophilus or L. casei was heated at 60 or 80 degrees C for either 10 min or 2 h, or treated with trypsin or pepsin. This was considered strong evidence that the inhibition was due to the production of bacteriocins by L. casei and L. acidophilus. Both the CFS and active growing cells of L. casei and L. acidophilus were able to reduce the viability of C. sakazakii in the RIMF model. The results may extend the use of natural antimicrobials instead of conventional preservation methods to improve the safety of RIMF. PMID- 23924354 TI - Clinical outcomes for maintenance hemodialysis patients using a high-flux (FX60) dialyzer. AB - AIMS: To investigate the clinical outcomes of maintenance hemodialysis (HD) patients using a high-flux (FX60) dialyzer. METHOD: Thirty patients undergoing dialysis for at least 2 years with a low-flux dialyzer were switched to the FX60 dialyzer for 3 years. Clinical and biochemical analysis was performed monthly for each patient. The parameters monitored included blood pressure, hemoglobin, albumin, intact parathyroid hormone (iPTH), calcium and phosphorus levels, the adequacy of dialysis (Kt/V), beta2-microglobulin (beta2-MG) clearance rate, as well as antihypertensive and erythropoietin (EPO) medications. RESULTS: After 3 years of dialysis with an FX60 dialyzer, the mean arterial blood pressure fell, hemoglobin increased, serum phosphate level decreased, iPTH declined and medication doses decreased. CONCLUSIONS: Dialysis with the FX60 dialyzer has a better clinical outcome for rectifying renal anemia, controlling hypertension and lowering serum phosphate levels making it a better choice for long-term HD patients. PMID- 23924353 TI - Utilizing core-shell fibrous collagen-alginate hydrogel cell delivery system for bone tissue engineering. AB - Three-dimensional matrices that encapsulate and deliver stem cells with defect tuned formulations are promising for bone tissue engineering. In this study, we designed a novel stem cell delivery system composed of collagen and alginate as the core and shell, respectively. Mesenchymal stem cells (MSCs) were loaded into the collagen solution and then deposited directly into a fibrous structure while simultaneously sheathing with alginate using a newly designed core-shell nozzle. Alginate encapsulation was achieved by the crosslinking within an adjusted calcium-containing solution that effectively preserved the continuous fibrous structure of the inner cell-collagen part. The constructed hydrogel carriers showed a continuous fiber with a diameter of ~700-1000 MUm for the core and 200 500 MUm for the shell area, which was largely dependent on the alginate concentration (2%-5%) as well as the injection rate (20-80 mL/h). The water uptake capacity of the core-shell carriers was as high as 98%, which could act as a pore channel to supply nutrients and oxygen to the cells. Degradation of the scaffolds showed a weight loss of ~22% at 7 days and ~43% at 14 days, suggesting a possible role as a degradable tissue-engineered construct. The MSCs encapsulated within the collagen core showed excellent viability, exhibiting significant cellular proliferation up to 21 days with levels comparable to those observed in the pure collagen gel matrix used as a control. A live/dead cell assay also confirmed similar percentages of live cells within the core-shell carrier compared to those in the pure collagen gel, suggesting the carrier was cell compatible and was effective for maintaining a cell population. Cells allowed to differentiate under osteogenic conditions expressed high levels of bone-related genes, including osteocalcin, bone sialoprotein, and osteopontin. Further, when the core-shell fibrous carriers were implanted in a rat calvarium defect, the bone healing was significantly improved when the MSCs were encapsulated, and even more so after an osteogenic induction of MSCs before implantation. Based on these results, the newly designed core-shell collagen alginate fibrous carrier is considered promising to enable the encapsulation of tissue cells and their delivery into damaged target tissues, including bone with defect-tunability for bone tissue engineering. PMID- 23924355 TI - A method for the net contra-thermodynamic isomerization of cyclic trisubstituted alkenes. AB - A simple sequence for the net contra-thermodynamic isomerization of cyclic trisubstituted alkenes is reported consisting of a radical addition of p chlorothiophenol, followed by oxidation to the sulfoxide and thermal syn elimination to give the least substituted isomeric cycloalkene. PMID- 23924356 TI - Evaluation of a support and challenge framework for nursing managers in correctional and forensic health. AB - AIM: This study evaluated a framework for nursing managers which entailed supporting and challenging participants to critically analyse the effectiveness of their workplace behaviours in facilitated discussion groups using context laden real-life scenarios. BACKGROUND: Leadership development in nursing managers has been shown to reduce burnout and promote workplace satisfaction. METHOD: Ninety per cent of nursing managers (n = 63) employed in the organisation participated in the study. Data relating to burnout, workplace satisfaction and leadership practices were collected prior to and after participation in the support and challenge framework. Qualitative feedback was sought through a survey administered at follow-up. RESULT: Nursing Unit Managers were significantly less satisfied in their intrinsic domain of workplace satisfaction at follow-up. Qualitative feedback indicated that participants experienced benefits related to networking, personal development and role development. CONCLUSION: The experience of critiquing and challenging leadership when shared with peers who practice in a similar context was qualitatively reported as beneficial and valuable, in spite of a decrease in workplace satisfaction. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing manager's leadership development is a continuous process. Supporting and challenging nursing managers is likely to generate uncertainty related to self and role. The sharing and testing of this uncertainty with peers is welcomed and warrants further exploration. PMID- 23924357 TI - Reflections on life: experiences of individuals with brain injury during the transition from hospital to home. AB - BACKGROUND: The transition from hospital to home has been described as a distinct rehabilitation phase for individuals with brain injury. As most research to date has quantitatively measured outcomes or used a sample with mixed brain injury diagnoses, less is known about the experience of transition following traumatic brain injury (TBI). AIMS: This study aimed to examine the lived experiences of individuals with TBI during the first 6 months following discharge from hospital. DESIGN: A qualitative investigation was conducted with 16 individuals with TBI using semi-structured interviews. DATA ANALYSIS: Data were analysed thematically using a Framework approach. RESULTS: Transition experiences were characterized by a desire to return to normality and a changed perspective on life, by accepting change or altering priorities. The process of transition was dynamic as individuals experienced the dominant themes in cyclical patterns. CONCLUSIONS: Research has highlighted the significant adjustment for individuals with TBI, particularly in relation to identity change, appraisal and coping. The themes of wanting normality and changing life perspective which were dominant in the current study highlight the significance of the transition phase in the process of adjustment and that transition is characterized by adapting to a new normality. PMID- 23924359 TI - Vibrational analysis of an ice Ih model from 0 to 4000 cm(-1) using the ab initio WHBB potential energy surface. AB - We present an analysis of the vibrational modes of a model of hexagonal ice, ice Ih, comprised of 192 monomers with a core region of 105 monomers, using the ab initio WHBB potential energy surface [Wang, Y.; Shepler, B.; Braams, B.; Bowman, J. M. J. Chem. Phys. 2011, 134, 094509]. A standard normal-mode analysis and a local-monomer normal-mode analysis of 105 core monomers are performed to obtain harmonic frequencies and state densities of the "pseudo-translation" (0-400 cm( 1)), "libration" (500-1100 cm(-1)), monomer bend fundamental (~1600 cm), and O-H stretch (~3000-3700 cm(-1)) bands. In addition, the coupled local-monomer model is used to obtain the vibrational density of states in the bend fundamental and O H stretch regions. The harmonic and local-monomer vibrational density of states obtained from core monomers are in good agreement with those of inelastic neutron scattering spectra, especially the latter, which accounts for anharmonic coupling of monomer modes. Full deuteration is also considered, and the vibrational density of states is again compared to experiment, where good agreement is found. PMID- 23924358 TI - Toll-like receptor 7 rapidly relaxes human airways. AB - RATIONALE: Toll-like receptors (TLRs) 7 and 8 detect respiratory virus single stranded RNA and trigger an innate immune response. We recently described rapid TLR7-mediated bronchodilation in guinea pigs. OBJECTIVES: To characterize TLR7 expression and TLR7-induced airway relaxation in humans and in eosinophilic airway inflammation in guinea pigs. To evaluate the relaxant effects of other TLRs. METHODS: Human airway smooth muscle strips were contracted with methacholine in vitro, and responses to TLR7 and TLR8 agonists were assessed. TLR7-mediated nitric oxide production was measured using a fluorescent indicator, and TLR7 expression was characterized using immunofluorescence. TLR7 signaling was also evaluated in ovalbumin-challenged guinea pigs. MEASUREMENTS AND MAIN RESULTS: The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation of methacholine-contracted human airways in vitro. This was blocked by the TLR7 antagonist IRS661 and by inhibiting nitric oxide production but not by inhibiting prostaglandin production. TLR7 activation markedly increased fluorescence of a nitric oxide detector. TLR7 was expressed on airway nerves, but not airway smooth muscle, implicating airway nerves as the source of TLR7-induced nitric oxide production. TLR7-mediated relaxation persisted in inflamed guinea pigs airways in vivo. The TLR8 agonists polyuridylic acid and polyadenylic acid also relaxed human airways, and this was not blocked by the TLR7 antagonist or by blocking nitric oxide or prostaglandin production. No other TLRs relaxed the airways. CONCLUSIONS: TLR7 is expressed on airway nerves and mediates relaxation of human and animal airways through nitric oxide production. TLR7-mediated bronchodilation may be a new therapeutic strategy in asthma. PMID- 23924360 TI - Evaluation of WO2012177707 and WO2012097269: Vertex's phosphate prodrugs of gyrase and topoisomerase antibacterial agents. AB - The two patent applications describe two novel compounds in the benzimidazole class of GyrB/ParE antibacterial agents and multiple phosphate prodrugs derived from these compounds. The new benzimidazole compounds have excellent antibacterial activity on Gram-positive strains. But like previous benzimidazoles, they have limited solubility and are highly protein bound. The phosphate prodrugs offer a drug substance with high aqueous solubility that should aid both intravenous and oral formulations. The potential utility of the prodrugs was demonstrated in efficacy studies. PMID- 23924361 TI - Electrochemical and spectroscopic analysis of Mg2+ intercalation into thin film electrodes of layered oxides: V2O5 and MoO3. AB - Electrochemical, surface, and structural studies related to rechargeable Mg batteries were carried out with monolithic thin-film cathodes comprising layered V2O5 and MoO3. The reversible intercalation reactions of these electrodes with Mg ion in nonaqueous Mg salt solutions were explored using a variety of analytical tools. These included slow-scan rate cyclic voltammetry (SSCV), chrono potentiometry (galvanostatic cycling), Raman and photoelectron spectroscopies, high-resolution microscopy, and XRD. The V2O5 electrodes exhibited reversible Mg ion intercalation at capacities around 150-180 mAh g(-1) with 100% efficiency. A capacity of 220 mAh g(-1) at >95% efficiency was obtained with MoO3 electrodes. By applying the electrochemical driving force sufficiently slowly it was possible to measure the electrodes at equilibrium conditions and verify by spectroscopy, microscopy, and diffractometry that these electrodes undergo fully reversible structural changes upon Mg-ion insertion/deinsertion cycling. PMID- 23924363 TI - Effective leadership--the way to excellence in health professions education. AB - The current times are witnessing an explosion of new knowledge in medicine. The demographic profile, geographic distribution of many diseases is changing, there have been dramatic shifts in the health care delivery, healthcare professionals are more socially and professionally accountable, patients have become more consumerist in their attitude. These factors coupled with the increasing demand for trained health care professionals has led to, firstly, a rapid increase in the health professionals education institutions and secondly curricular changes and adoption of newer teaching learning methodologies, to equip the graduates with the desirable outcomes. The scene in health professions education is one characterized by rapid activity and change. A time which demands effective leadership at these institutions for achieving excellence. Drawing from a decade long experience, at different medical schools in the gulf region, the author opines that it is effective leadership, as observed at the institutions where he worked, which is responsible for realization of institutional vision, rapid development and achievement of excellence. PMID- 23924362 TI - Community's knowledge, attitudes and practices about tuberculosis in Itang Special District, Gambella Region, South Western Ethiopia. AB - BACKGROUND: Tuberculosis (TB) is one of the primary public health problems in developing countries. HIV/AIDS, poverty, undernutrition, over-crowded living conditions and lack of knowledge about the disease have been known to increase the risk of spreading the bacteria and the risk of developing the disease. The objective of this study was to assess the level of TB knowledge, attitudes and practices of rural communities of Itang Special District of the Gambella Regional State of Ethiopia. METHODS: Between November 2011 and January 2012, a community based cross sectional study was carried out in a randomly selected rural kebeles (i.e. the smallest administrative units) of Itang communities. The study participants were interviewed using pre-tested questionnaire. The overall knowledge, attitudes and practices of the study participants were assessed using the mean score of each outcome as a cut-off value. Having a score above the mean on each of the three target outcomes was equated with having a good level of knowledge, or having favorable attitude and good practices towards TB. RESULTS: Out of 422 study participants (58.5% males and 41.5% females) only 3.3% mentioned bacteria/germ as a cause of pulmonary TB (PTB) and 9.9% mentioned cough for at least two weeks as the sign of TB. Taking the mean knowledge score as the cut-off value, 57.6% (95% CI: 52.7% to 62.3%) of the study participants had good level of knowledge about TB, 40.8% (95% CI: 36.0% to 45.6%) had favorable attitude towards TB and 45.9% (95% CI: 41.1% to 50.9%) had good practices. Female participants were less likely to have good level of knowledge [adjusted odds ratio (AOR) = 0.33, 95% CI, 0.21 to 0.51, p < 0.001], less likely to have favorable attitude (AOR = 0.23, 95% CI, 0.14 to 0.37) and less likely to have good practices (AOR = 0.37, 95% CI, 0.24 to 0.57, p < 0.001) compared to male participants. CONCLUSION: Majority of the study participants had no correct information about the causative agent of TB and the main symptom of PTB. Moreover, low level of overall knowledge, attitudes and practices about TB was associated with female participants. Hence, TB control strategy in the present study area should include community awareness raising component. PMID- 23924364 TI - Stable uranium(VI) methyl and acetylide complexes and the elucidation of an inverse trans influence ligand series. AB - Thermally stable uranium(VI)-methyl and -acetylide complexes: U(VI)OR[N(SiMe3)2]3 R = -CH3, -C=CPh were prepared in which coordination of the hydrocarbyl group is directed trans to the uranium-oxo multiple bond. The stability of the uranium carbon bond is attributed to an inverse trans influence. The hydrocarbyl complexes show greater ITI stabilization than that of structurally related U(VI)OX[N(SiMe3)2]3 (X = F(-), Cl(-), Br(-)) complexes, demonstrated both experimentally and computationally. An inverse trans influence ligand series is presented, developed from a union of theoretical and experimental results and based on correlations between the extent of cis-destabilization, the complexes stabilities toward electrochemical reduction, the thermodynamic driving forces for U?O bond formation, and the calculated destabilization of axial sigma* and pi* antibonding interactions. PMID- 23924365 TI - Diastereoselective metabolism of a novel cis-nitromethylene neonicotinoid paichongding in aerobic soils. AB - Many pesticides are chiral but used as racemic mixtures, even though their stereoisomers are often degraded stereoselectively in soils. Evaluation of degradation of chiral compounds is mostly focused on the enantioselectivity rather than diastereoselectivity/epimer preferences. In this study, we explored the diastereoselective transformation of paichongding (IPP), a novel chiral neonicotinoid with broad-spectrum insecticidal activity, to several degradation intermediates in different soils. (14)C-Labeling coupled with LC-MS/MS and high resolution MS were used to track residues of IPP and identify major transformation metabolites. The stereoisomers of IPP known as 5R, 7R-IPP (RR IPP), 5S, 7S-IPP (SS-IPP), 5S, 7R-IPP (SR-IPP), and 5R, 7S-IPP (RS-IPP) showed diastereoselective/epimer-selective persistence in all soils except an acidic clay soil. Moreover, IPP was transformed to a range of degradation intermediates (M1-M6), which also showed significant diastereoselective and soil preferential formation. Depropylation, nitrosylation, denitration, demethylation, dehydroxylation, and ketonization contributed to IPP transformation. The diastereoselective degradation of the parent compound and formation of incomplete intermediates implies that diastereomers/epimers should be regarded as different chemicals. The approach of coupling (14)C and MS may be used as an effective tool to understand the environmental processes and risks of other man-made chiral compounds. PMID- 23924366 TI - Screening for duplications, deletions and a common intronic mutation detects 35% of second mutations in patients with USH2A monoallelic mutations on Sanger sequencing. AB - BACKGROUND: Usher Syndrome is the leading cause of inherited deaf-blindness. It is divided into three subtypes, of which the most common is Usher type 2, and the USH2A gene accounts for 75-80% of cases. Despite recent sequencing strategies, in our cohort a significant proportion of individuals with Usher type 2 have just one heterozygous disease-causing mutation in USH2A, or no convincing disease causing mutations across nine Usher genes. The purpose of this study was to improve the molecular diagnosis in these families by screening USH2A for duplications, heterozygous deletions and a common pathogenic deep intronic variant USH2A: c.7595-2144A>G. METHODS: Forty-nine Usher type 2 or atypical Usher families who had missing mutations (mono-allelic USH2A or no mutations following Sanger sequencing of nine Usher genes) were screened for duplications/deletions using the USH2A SALSA MLPA reagent kit (MRC-Holland). Identification of USH2A: c.7595-2144A>G was achieved by Sanger sequencing. Mutations were confirmed by a combination of reverse transcription PCR using RNA extracted from nasal epithelial cells or fibroblasts, and by array comparative genomic hybridisation with sequencing across the genomic breakpoints. RESULTS: Eight mutations were identified in 23 Usher type 2 families (35%) with one previously identified heterozygous disease-causing mutation in USH2A. These consisted of five heterozygous deletions, one duplication, and two heterozygous instances of the pathogenic variant USH2A: c.7595-2144A>G. No variants were found in the 15 Usher type 2 families with no previously identified disease-causing mutations. In 11 atypical families, none of whom had any previously identified convincing disease causing mutations, the mutation USH2A: c.7595-2144A>G was identified in a heterozygous state in one family. All five deletions and the heterozygous duplication we report here are novel. This is the first time that a duplication in USH2A has been reported as a cause of Usher syndrome. CONCLUSIONS: We found that 8 of 23 (35%) of 'missing' mutations in Usher type 2 probands with only a single heterozygous USH2A mutation detected with Sanger sequencing could be attributed to deletions, duplications or a pathogenic deep intronic variant. Future mutation detection strategies and genetic counselling will need to take into account the prevalence of these types of mutations in order to provide a more comprehensive diagnostic service. PMID- 23924367 TI - Mammalian ribosomal and chaperone protein RPS3A counteracts alpha-synuclein aggregation and toxicity in a yeast model system. AB - Accumulation of aggregated forms of alphaSyn (alpha-synuclein) into Lewy bodies is a known hallmark associated with neuronal cell death in Parkinson's disease. When expressed in the yeast Saccharomyces cerevisiae, alphaSyn interacts with the plasma membrane, forms inclusions and causes a concentration-dependent growth defect. We have used a yeast mutant, cog6Delta, which is particularly sensitive to moderate alphaSyn expression, for screening a mouse brain-specific cDNA library in order to identify mammalian proteins that counteract alphaSyn toxicity. The mouse ribosomal and chaperone protein RPS3A was identified as a suppressor of alphaSyn [WT (wild-type) and A53T] toxicity in yeast. We demonstrated that the 50 N-terminal amino acids are essential for this function. The yeast homologues of RPS3A were not effective in suppressing the alphaSyn induced growth defect, illustrating the potential of our screening system to identify modifiers that would be missed using yeast gene overexpression as the first screening step. Co-expression of mouse RPS3A delayed the formation of alphaSyn-GFP inclusions in the yeast cells. The results of the present study suggest that the recently identified extraribosomal chaperonin function of RPS3A also acts on the neurodegeneration-related protein alphaSyn and reveal a new avenue for identifying promising candidate mammalian proteins involved in alphaSyn functioning. PMID- 23924368 TI - Uniform SiGe/Si quantum well nanorod and nanodot arrays fabricated using nanosphere lithography. AB - This study fabricates the optically active uniform SiGe/Si multiple quantum well (MQW) nanorod and nanodot arrays from the Si0.4Ge0.6/Si MQWs using nanosphere lithography (NSL) combined with the reactive ion etching (RIE) process. Compared to the as-grown sample, we observe an obvious blueshift in photoluminescence (PL) spectra for the SiGe/Si MQW nanorod and nanodot arrays, which can be attributed to the transition of PL emission from the upper multiple quantum dot-like SiGe layers to the lower MQWs. A possible mechanism associated with carrier localization is also proposed for the PL enhancement. In addition, the SiGe/Si MQW nanorod arrays are shown to exhibit excellent antireflective characteristics over a wide wavelength range. These results indicate that SiGe/Si MQW nanorod arrays fabricated using NSL combined with RIE would be potentially useful as an optoelectronic material operating in the telecommunication range. PMID- 23924369 TI - Sex differences in the stability of conditioned pain modulation (CPM) among patients with chronic pain. AB - OBJECTIVES: To examine the temporal stability of conditioned pain modulation (CPM), formerly termed diffuse noxious inhibitory controls, among a sample of patients with chronic pain. The study also examined the factors that might be responsible for the stability of CPM. DESIGN, SUBJECTS, AND METHODS: In this test retest study, patients underwent a series of standardized psychophysical pain testing procedures designed to assess CPM on two separate occasions (i.e., baseline and follow up). Patients also completed self-report measures of catastrophizing (Pain Catastrophizing Scale [PCS] and negative affect [NA]). RESULTS: Overall, results provided evidence for the stability of CPM among patients with chronic pain. Results, however, revealed considerable sex differences in the stability of CPM. For women, results revealed a significant test-retest correlation between baseline and follow-up CPM scores. For men, however, the test-retest correlation between baseline and follow-up CPM scores was not significant. Results of a Fisher's Z-test revealed that the stability of CPM was significantly greater for women than for men. Follow-up analyses revealed that the difference between men and women in the stability of CPM could not be accounted for by any demographic (e.g., age) and/or psychological factors (PCS and NA). CONCLUSIONS: Our findings suggest that CPM paradigms possess sufficient reliability to be incorporated into bedside clinical evaluation of patients with chronic pain, but only among women. The lack of CPM reproducibility/stability observed among men places limits on the potential use of CPM paradigms in clinical settings for the assessment of men's endogenous pain-inhibitory function. PMID- 23924371 TI - High-resolution HPLC-ESI-MS characterization of the contact sites of the actin thymosin beta(4) complex by chemical and enzymatic cross-linking. AB - Thymosin beta4 sequesters actin by formation of a 1:1 complex. This transient binding in the complex was stabilized by formation of covalent bonds using the cross-linking agents 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and a microbial transglutaminase. The localization of cross-linking sites was determined after separating the products using SDS-PAGE by tryptic in-gel digestion and high-resolution HPLC-ESI-MS. Three cross-linked fragments were identified after chemical cross-linking, indicating three contact sites. Because the cross-linked fragments were detected simultaneously with the corresponding non-cross-linked fragments, the three contact sites were not formed in parallel. K3 of thymosin beta4 was cross-linked to E167 of actin, K18 or K19 of thymosin beta4 to one of the first three amino acids of actin (DDE), and S43 of thymosin beta4 to H40 of actin. The imidazole ring of histidine was proven to be an acyl acceptor for carbodiimide-mediated cross-linking. Molecular modeling proved an extended conformation of thymosin beta4 along the subdomains 1 to 3 of actin. The enzymatic cross-linking using a microbial transglutaminase led to the formation of three cross-linking sites. Q41 of actin was cross-linked to K19 of thymosin beta4, and K61 of actin to Q39 of thymosin beta4. The third cross-linking site was identified between Q41 of actin and Q39 of thymosin beta4, which are simultaneously cross-linked to K16, K18, or K19 of thymosin beta4. When both cross-linking reactions are taken together, the complex formation of actin by thymosin beta4 is more likely to be flexible than rigid and is localized along the subdomains 1 to 3 of actin. PMID- 23924370 TI - Variability of antibiotic susceptibility and toxin production of Staphylococcus aureus strains isolated from skin, soft tissue, and bone related infections. AB - BACKGROUND: Staphylococcus aureus is an opportunistic commensal bacterium that mostly colonizes the skin and soft tissues. The pathogenicity of S. aureus is due to both its ability to resist antibiotics, and the production of toxins. Here, we characterize a group of genes responsible for toxin production and antibiotic resistance of S. aureus strains isolated from skin, soft tissue, and bone related infections. RESULTS: A total of 136 S. aureus strains were collected from five different types of infection: furuncles, pyomyositis, abscesses, Buruli ulcers, and osteomyelitis, from hospital admissions and out-patients in Benin. All strains were resistant to benzyl penicillin, while 25% were resistant to methicillin, and all showed sensitivity to vancomycin. Panton-Valentine leukocidin (PVL) was the most commonly produced virulence factor (70%), followed by staphylococcal enterotoxin B (44%). Exfoliative toxin B was produced by 1.3% of the strains, and was only found in isolates from Buruli ulcers. The tsst-1, sec, and seh genes were rarely detected (<=1%). CONCLUSIONS: This study provides new insight into the prevalence of toxin and antibiotic resistance genes in S. aureus strains responsible for skin, soft tissue, and bone infections. Our results showed that PVL was strongly associated with pyomyositis and osteomyelitis, and that there is a high prevalence of PVL-MRSA skin infections in Benin. PMID- 23924372 TI - The safety and efficacy of bedside removal of tunneled hemodialysis catheters by nephrology trainees. AB - BACKGROUND: Some nephrologists remove tunneled hemodialysis catheters (TDC) at the bedside, but this practice has never been formally studied. Our hypothesis was that bedside removal of TDC is a safe and effective procedure affording prompt removal, including in cases of suspected infection. METHODS: We reviewed our consecutive 3-year experience (2007-2009) with bedside TDC removal at the University of Mississippi Renal Fellowship Program. Data were collected on multiple patients and procedure-related variables, success and complication rates. Association between clinical characteristics and biomarkers of inflammation and myocardial damage was examined using correlation coefficients. RESULTS: Of 55 inpatient TDC removals (90.9% from internal jugular location), 50 (90.9%) were completed without hands-on assistance from faculty. Indications at the time of removal included bacteremia, fever or clinical sepsis with hemodynamic instability or respiratory failure. All procedures were successful, with no cuff retention noted; one patient experienced prolonged bleeding which was controlled with local pressure. Peak C-reactive protein (available in 63.6% of cohort) was 12.9 +/- 8.4 mg/dL (reference range: <0.49) and median troponin-I (34% available) was 0.534 ng/mL (IQR 0.03-0.9) (reference range: <0.034) and they did not correlate with each other. Abnormal troponin-I was associated with proven bacteremia (p < 0.05) but not with systolic and diastolic BP or clinical sepsis. CONCLUSION: Our results suggest that bedside removal of TDC remains a safe and effective procedure regardless of site or indications. Accordingly, TDC removal should be an integral part of competent Nephrology training. PMID- 23924373 TI - Solvation dynamics of formylperylene dissolved in methanol-acetonitrile liquid mixtures: a molecular dynamics study. AB - The solvation dynamics of formylperylene in methanol/acetonitrile liquid mixtures have been experimentally observed to slow down with increasing concentration of methanol. We present results from equilibrium and nonequilibrium molecular dynamics simulations that relate the slowdown to the formation of a hydrogen bonded methanol oligomer, which is hydrogen-bonded to the carbonyl group of formylperylene. PMID- 23924374 TI - Use of perfusion bioreactors and large animal models for long bone tissue engineering. AB - Tissue engineering and regenerative medicine (TERM) strategies for generation of new bone tissue includes the combined use of autologous or heterologous mesenchymal stem cells (MSC) and three-dimensional (3D) scaffold materials serving as structural support for the cells, that develop into tissue-like substitutes under appropriate in vitro culture conditions. This approach is very important due to the limitations and risks associated with autologous, as well as allogenic bone grafiting procedures currently used. However, the cultivation of osteoprogenitor cells in 3D scaffolds presents several challenges, such as the efficient transport of nutrient and oxygen and removal of waste products from the cells in the interior of the scaffold. In this context, perfusion bioreactor systems are key components for bone TERM, as many recent studies have shown that such systems can provide dynamic environments with enhanced diffusion of nutrients and therefore, perfusion can be used to generate grafts of clinically relevant sizes and shapes. Nevertheless, to determine whether a developed tissue like substitute conforms to the requirements of biocompatibility, mechanical stability and safety, it must undergo rigorous testing both in vitro and in vivo. Results from in vitro studies can be difficult to extrapolate to the in vivo situation, and for this reason, the use of animal models is often an essential step in the testing of orthopedic implants before clinical use in humans. This review provides an overview of the concepts, advantages, and challenges associated with different types of perfusion bioreactor systems, particularly focusing on systems that may enable the generation of critical size tissue engineered constructs. Furthermore, this review discusses some of the most frequently used animal models, such as sheep and goats, to study the in vivo functionality of bone implant materials, in critical size defects. PMID- 23924375 TI - High levels of variation in Salix lignocellulose genes revealed using poplar genomic resources. AB - BACKGROUND: Little is known about the levels of variation in lignin or other wood related genes in Salix, a genus that is being increasingly used for biomass and biofuel production. The lignin biosynthesis pathway is well characterized in a number of species, including the model tree Populus. We aimed to transfer the genomic resources already available in Populus to its sister genus Salix to assess levels of variation within genes involved in wood formation. RESULTS: Amplification trials for 27 gene regions were undertaken in 40 Salix taxa. Twelve of these regions were sequenced. Alignment searches of the resulting sequences against reference databases, combined with phylogenetic analyses, showed the close similarity of these Salix sequences to Populus, confirming homology of the primer regions and indicating a high level of conservation within the wood formation genes. However, all sequences were found to vary considerably among Salix species, mainly as SNPs with a smaller number of insertions-deletions. Between 25 and 176 SNPs per kbp per gene region (in predicted exons) were discovered within Salix. CONCLUSIONS: The variation found is sizeable but not unexpected as it is based on interspecific and not intraspecific comparison; it is comparable to interspecific variation in Populus. The characterisation of genetic variation is a key process in pre-breeding and for the conservation and exploitation of genetic resources in Salix. This study characterises the variation in several lignocellulose gene markers for such purposes. PMID- 23924376 TI - Dissociative photoionization of glycerol and its dimer occurs predominantly via a ternary hydrogen-bridged ion-molecule complex. AB - The photoionization and dissociative photoionization of glycerol are studied experimentally and theoretically. Time-of-flight mass spectrometry combined with vacuum ultraviolet synchrotron radiation ranging from 8 to 15 eV is used to investigate the nature of the major fragments and their corresponding appearance energies. Deuterium (1,1,2,3,3-D5) and (13)C (2-(13)C) labeling is employed to narrow down the possible dissociation mechanisms leading to the major fragment ions (C3H(x)O2(+), C2H(x)O2(+), C2H(x)O(+), CH(x)O(+)). We find that the primary fragmentation of the glycerol radical cation (m/z 92) occurs only via two routes. The first channel proceeds via a six-membered hydrogen-transfer transition state, leading to a common stable ternary intermediate, comprised of neutral water, neutral formaldehyde, and a vinyl alcohol radical cation, which exhibits a binding energy of ~42 kcal/mol and a very short (1.4 A) hydrogen bond. Fragmentation of this intermediate gives rise to experimentally observed m/z 74, 62, 44, and 45. Fragments m/z 74 and 62 both consist of hydrogen-bridged ion molecule complexes with binding energy >25 kcal/mol, whereas the m/z 44 species lacks such stabilization. This explains why water- or formaldehyde-loss products are observed first. The second primary fragmentation route arises from cleaving the elongated C-C bond. Also for this channel, intermediates comprised of hydrogen-bridged ion-molecule complexes exhibiting binding energies >24 kcal/mol are observed. Energy decomposition analysis reveals that electrostatic and charge transfer interactions are equally important in hydrogen-bridged ion-molecule complexes. Furthermore, the dissociative photoionization of the glycerol dimer is investigated and compared to the main pathways for the monomeric species. To a first approximation, the glycerol dimer radical cation can be described as a monomeric glycerol radical cation in the presence of a spectator glycerol, thus giving rise to a dissociation pattern similar to that of the monomer. PMID- 23924377 TI - Frequency of nursing tasks in medical and surgical wards. AB - AIM: To explore the frequency of different nursing tasks in medical and surgical wards. BACKGROUND: The time nurses spend on direct patient care is important for both patients and nurses. However, little is known about the time nurses spend on various nursing tasks. METHODS: A real-time, repeated measures design conducted amongst 67 (n = 39 medical, n = 28 surgical) UK hospital nurses. Between September 2011 and August 2012 participants completed an electronic diary version of a classification of nursing tasks (WOMBAT) during shifts. RESULTS: A total of 961 real-time measures of nursing task were obtained. Direct patient care [median = 37.5%, interquartile range = 27.8], indirect care (median = 11.1%, interquartile range = 19.4) and medication (median = 11.1%, interquartile range = 18.8) were most commonly reported. Participants were interrupted in 62% of entries (interquartile range = 35), reported adequate time in 78% (interquartile range = 31) and adequate resources in 89% (interquartile range = 36). Ward related tasks were significantly more frequent on medical wards than surgical wards but otherwise there were no significant differences. CONCLUSIONS: Nurses spend the highest proportion of time in direct patient care and majority of this on core nursing activities. Interruptions to tasks are common. Nurses tend to report adequate time/resources. The frequency of nursing tasks is similar in medical and surgical wards. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers should review the level of interruptions to nurses' work and ensure appropriate levels of supervision. PMID- 23924378 TI - Two-dimensional spectroscopy of coupled vibrations with the optimized mean trajectory approximation. AB - The optimized mean-trajectory (OMT) approximation is a semiclassical representation of the nonlinear vibrational response function used to compute multidimensional infrared spectra. In this method, response functions are calculated from a sequence of classical trajectories linked by discontinuities representing the effects of radiation-matter interactions, thus providing an approximation to quantum dynamics using classical inputs. This approach was previously formulated and assessed numerically for a single anharmonic degree of freedom. Our previous work is generalized here in two respects. First, the derivation of the OMT is extended to any number of coupled anharmonic vibrations by determining semiclassical approximations for pairs of double-sided Feynman diagrams. Second, an efficient numerical procedure is developed for calculating two-dimensional infrared spectra of coupled anharmonic vibrations in the OMT approximation. The OMT approximation is shown to reproduce the fundamental features of the quantum response function including both coherence and population dynamics. PMID- 23924379 TI - Plasmon excitation of supported gold nanoparticles can control molecular release from supramolecular systems. AB - Hybrid mesoporous silica materials containing gold nanoparticles (AuNPs) have been investigated as potential molecular delivery systems. The photophysical properties of AuNPs, particularly their plasmon band transitions, have been used to control the rate of the release of naproxen from the pores of mesoporous silica matrices. Two different approaches were employed to incorporate AuNPs into the silica network: that is, grafting (using 3-aminopropyltriethoxisilane) and direct absorption. In this research, the anti-inflamatory drug naproxen serves as a test molecule, showing how localized plasmon heating could be used to modify diffusion kinetics within mesoporous materials. Beyond naproxen release, the methodology developed could be employed to release other drugs, sensors, or active molecules, not just in medicine, but in many other fields where nanotechnology is leading to many innovative applications. The hybrid materials developed show a new simple system to efficiently control the release of active cargo from mesoporous silica matrices. PMID- 23924380 TI - Examining graphene field effect sensors for ferroelectric thin film studies. AB - We examine a prototype graphene field effect sensor for the study of the dielectric constant, pyroelectric coefficient, and ferroelectric polarization of 100-300 nm epitaxial (Ba,Sr)TiO3 thin films. Ferroelectric switching induces hysteresis in the resistivity and carrier density of n-layer graphene (n = 1-5) below 100 K, which competes with an antihysteresis behavior activated by the combined effects of electric field and temperature. We also discuss how the polarization asymmetry and interface charge dynamics affect the electronic properties of graphene. PMID- 23924381 TI - Diazo compounds as electrophiles to react with 1,4-dilithio-1,3-dienes: efficient synthesis of 1-imino-pyrrole derivatives. AB - 1-Imino-pyrrole and indole derivatives were synthesized in high yields from the reaction of diaryl diazomethanes with 1,4-dilithio-1,3-dienes. Diaryl diazomethanes reacted as electrophiles in this reaction. An unprecedented Zn complex was formed via transmetalation of the above reaction intermediate with ZnCl2 and was structurally characterized. The trans-MU2-eta(1):eta(1) coordination mode in the solid state for this azaallylzinc compound was observed. PMID- 23924382 TI - Quantitative structure-activity relationship analysis of antifungal (+) dihydroguaiaretic acid using 7-phenyl derivatives. AB - The relationship between antifungal activity against Alternaria alternata and structure on the 7-phenyl group of (+)-dihydroguaiaretic acid ((+)-DGA) was clarified by employing 38 synthesized (+)-DGA derivatives. The results were identified by quantitative structure-activity relationship (QSAR) analysis employing the Hansch-Fujita method. Some compounds showed higher activity than (+)-DGA. The compound showing highest activity was 3,5-difluorophenyl derivative 37. It was suggested that the small electron-withdrawing group at the meta position of the 7-phenyl group is important for the higher activity by antifungal test and Hansch-Fujita analysis. The whitening activity of 3-hydroxy-4 methoxyphenyl derivative 28, 3-hydroxy-4-ethoxyphenyl derivative 29, and 3 hydroxy-4-isopropoxyphenyl derivative 30 against A. alternata Japanese pear pathotype was also discovered. PMID- 23924383 TI - Antioxidant, antibrowning, and cytoprotective activities of Ligustrum robustum (Rxob.) Blume extract. AB - The antioxidant, antibrowning, and cytoprotective activities of Ligustrum robustum (Rxob.) Blume extract (LRE) were investigated and the main antioxidant component was isolated and identified. With its high content of phenols and flavonoids, the LRE showed remarkable antioxidant capacity to scavenge free radicals in vitro and to inhibit oil oxidation in a peanut oil system. Moreover, LRE was observed to inhibit tyrosinase action and browning of fresh-cut apple slices effectively. Furthermore, the cytoprotective activity of LRE was evaluated in a human intestine model using Caco-2 cell lines. According to the activity guided isolation and identification, by using column chromatography, high performance liquid chromatography, time-of-flight mass spectrometry, and nuclear magnetic resonance analyses, ursolic acid was characterized as the main antioxidant component of LRE; it showed the strongest free radical-scavenging activity. The results suggested that L. robustum (Rxob.) Blume could be a new resource for preparing functional food and nutraceutical products for use in food and pharmacology industries. PMID- 23924384 TI - Cryptands with 1,3,5-tris(1',3'-dioxan-2'-yl)-benzene units: synthesis and structural investigations. AB - Various cryptands based on 1,3-dioxane decorated 1,3,5-trisubstituted-benzene building blocks, connected by different chains (exhibiting ester, ether, or triazol groups) to several units with C3 symmetry, are reported. The structure of the compounds was investigated by single crystal X-ray diffraction, NMR, and MS. The role of the 1,3-dioxane units was targeted to ensure the preorganization of the substrate for the macrocyclization reactions on one side, and for easier NMR assignment of the structure of the cryptands on the other side. PMID- 23924385 TI - Did the educational campaign to support persons with cognitive dysfunction encourage them to participate in society in Northern Kyushu, Japan? AB - PRIMARY OBJECTIVE: To investigate social participation and the administration of the official certificate for cognitive dysfunction in Northern Kyushu, Japan following a government-conducted educational campaign to support persons with cognitive dysfunction. METHODS AND PROCEDURES: A questionnaire was mailed to members of the Brain Injury Association of Northern Kyushu living with traumatic brain injury; the results were compared with those of the first survey conducted in 2002. MAIN OUTCOMES AND RESULTS: This study evaluated 159 individuals (response rate: 72.6%, 135 males and 24 females), whose mean age at time of injury was 28 years. Eighty-two per cent of the participants were living at home; 72% were independent in activities of daily living. Fifty-nine per cent and 33% had certificates of physical and mental disability, respectively, and 37% were engaged in employment or school attendance. The number of participants who had obtained certificates of physical or mental disability and the number of participants who returned to employment or school significantly increased in comparison to the first survey (chi2 test, p < 0.05). CONCLUSIONS: The model project and educational campaign facilitated social participation and increased the acquisition of the official certificate of cognitive dysfunction. PMID- 23924386 TI - New {RuNO} polyoxometalate [PW11O39Ru(II)(NO)]4-: synthesis and reactivity. AB - New Ru-containing polyoxometalate [PW11O39Ru(II)(NO)](4-) (1(4-)) was obtained in high yield by reaction of [Ru(NO)Cl5](2-) with [PW11O39](7-) and characterized by multinuclear NMR, cyclic voltammetry, IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). The intrinsic reactivity of the {RuNO} site in 1(4-) toward various reagents has been studied using a versatile and simple ESI tandem mass spectrometric methodology for identification of the L attached at the Ru site; this approach relies on the preferential liberation of the L ligands attached at the Ru sites upon mass-selecting desired intermediates and subsequent promotion of their fragmentation. Reactions with both hydrazine and hydroxylamine lead to elimination of the nitroso group and quantitative formation of [PW11O39Ru(III)(H2O)](4-) (2(4-)) in aqueous solution. In the reaction with hydroxylamine, an intermediate with coordinated dinitrogen has been detected. An easy access to the NH3-coordinated [PW11O39RuNH3](4-) (3(4-)) complex was achieved upon reduction of 1(4-) with Sn(2+) in water. PMID- 23924388 TI - Introducing the therapy outcome measure for AAC services in the context of a review of other measures. AB - PURPOSE: This article discusses the importance of outcome measures in improving Augmentative and Alternative Communication (AAC) services, reviews existing methods and introduces a new approach. METHOD: Three methods were used in this study. 1. A literature review identifying outcome measures used in AAC research. 2. A questionnaire to AAC services in the UK which aimed to identify the objectives of their services and the outcome measures commonly used. 3. A working group of AAC experts provided additional information and interpretation. Central properties and conceptual framework were considered. RESULTS: The literature review and questionnaire identified 23 outcome measures none of which cover the conceptual frameworks associated with all of the overall objectives of AAC provision. The review has informed the further development of a particular outcome measure the AAC Therapy Outcome Measure (AAC TOM) ensuring that basic principles of the International Classification of Functioning (ICF-WHO) are retained and the measure can be used in benchmarking. CONCLUSION: An outcome measure needs to reflect change associated with service delivery. AAC services endeavour to impact on all of the domains of the ICF. A new measure is required in order to reflect the nature of these services. This article introduces an outcome measure which is in the process of being trialled by some services in the UK. PMID- 23924387 TI - Acceptability of HIV self-testing: a systematic literature review. AB - BACKGROUND: The uptake of HIV testing and counselling services remains low in risk groups around the world. Fear of stigmatisation, discrimination and breach of confidentiality results in low service usage among risk groups. HIV self testing (HST) is a confidential HIV testing option that enables people to find out their status in the privacy of their homes. We evaluated the acceptability of HST and the benefits and challenges linked to the introduction of HST. METHODS: A literature review was conducted on the acceptability of HST in projects in which HST was offered to study participants. Besides acceptability rates of HST, accuracy rates of self-testing, referral rates of HIV-positive individuals into medical care, disclosure rates and rates of first-time testers were assessed. In addition, the utilisation rate of a telephone hotline for counselling issues and clients' attitudes towards HST were extracted. RESULTS: Eleven studies met the inclusion criteria (HST had been offered effectively to study participants and had been administered by participants themselves) and demonstrated universally high acceptability of HST among study populations. Studies included populations from resource poor settings (Kenya and Malawi) and from high-income countries (USA, Spain and Singapore). The majority of study participants were able to perform HST accurately with no or little support from trained staff. Participants appreciated the confidentiality and privacy but felt that the provision of adequate counselling services was inadequate. CONCLUSIONS: The review demonstrates that HST is an acceptable testing alternative for risk groups and can be performed accurately by the majority of self-testers. Clients especially value the privacy and confidentiality of HST. Linkage to counselling as well as to treatment and care services remain major challenges. PMID- 23924389 TI - Vitamin D supplementation in patients with diabetes mellitus type 2 on different therapeutic regimens: a one-year prospective study. AB - BACKGROUND: Little or no research has determined the effect of vitamin D3 supplementation in conjunction with pharmacological and non-pharmacological approaches in the diabetes mellitus type 2 (DMT2) patients. The objective of this study was to determine the effect of vitamin D3 supplementation in a cohort of Saudi DMT2 population on diet, insulin and/or different oral hypoglycemic agents and compare them with a non-DMT2 control cohort. METHODS: A total of 499 randomly selected Saudi subjects divided into 8 groups [Non-DMT2 Control = 151; Rosiglitazone alone = 49; Diet = 15; Insulin alone = 55; Insulin + Orals = 12; Metformin alone = 121; Oral agents combination = 37; Sulphonylurea alone = 59] were included in this 12-month interventional study. All DMT2 patients were given 2000 IU vitamin D3 daily, while the control group received none but were advised to increase sun exposure. Anthropometrics, glucose, lipid profile and 25 hydroxyvitamin D (25-OHVitD) were measured at baseline, 6 and 12 months. RESULTS: Circulating 25-OHVitD concentrations improved in all patient groups. The metformin group showed the highest change in circulating vitamin D levels both at 6 months (62.6%) and 12 months (50.6%) as compared to baseline (p < 0.001). No significant changes were observed in the BMI and glucose in any of the DMT2 groups. In contrast, the insulin + oral agents group showed more significant improvements in the metabolic profile, which included triglycerides and total cholesterol, as well as systolic blood pressure and HDL-cholesterol in males. Also, significant decreases in triglycerides were observed in the rosiglitazone and insulin + oral hypoglycemic agent groups both at 6 and 12 months of supplementation (both p-values <0.001). CONCLUSION: While in all DMT2 groups circulating levels of 25-OHVitD increased after supplementation, in DMT2 patients on insulin in combination with other drugs benefitted the most in improving cardiovascular risk. Metformin improves 25-hydroxyvitamin D levels but did not seem to confer other added cardiometabolic benefits. PMID- 23924390 TI - EGF regulates tyrosine phosphorylation and membrane-translocation of the scaffold protein Tks5. AB - BACKGROUND: Tks5/FISH is a scaffold protein comprising of five SH3 domains and one PX domain. Tks5 is a substrate of the tyrosine kinase Src and is required for the organization of podosomes/invadopodia implicated in invasion of tumor cells. Recent data have suggested that a close homologue of Tks5, Tks4, is implicated in the EGF signaling. RESULTS: Here, we report that Tks5 is a component of the EGF signaling pathway. In EGF-treated cells, Tks5 is tyrosine phosphorylated within minutes and the level of phosphorylation is sustained for at least 2 hours. Using specific kinase inhibitors, we demonstrate that tyrosine phosphorylation of Tks5 is catalyzed by Src tyrosine kinase. We show that treatment of cells with EGF results in plasma membrane translocation of Tks5. In addition, treatment of cells with LY294002, an inhibitor of PI 3-kinase, or mutation of the PX domain reduces tyrosine phosphorylation and membrane translocation of Tks5. CONCLUSIONS: Our results identify Tks5 as a novel component of the EGF signaling pathway. PMID- 23924392 TI - Migraine with cranial autonomic features following surgically induced post ganglionic sympathetic lesion. AB - BACKGROUND: Although not typically considered as part of the clinical phenotype of migraine, cranial autonomic symptoms, such as lacrimation or conjunctival injection, can certainly occur. Their appearance can lead to the common misdiagnosis of sinus headache in clinical practice. CASE: The patient presented developed post-ganglionic sympathetic denervation at the level of the superior cervical ganglion/carotid plexus. Her subsequent partial Horner's syndrome symptoms intensified during subsequent migraine attacks indicating increasing sympathetic autonomic dysfunction. At the time of the pain, recruitment and activation of the trigeminal autonomic reflex were demonstrated by lacrimation. CONCLUSION: The clinical picture suggests peripheral unmasking of the underlying central trigeminal autonomic reflex that is active in migraine. Recognition of cranial autonomic symptoms in migraine is a key to confident differential diagnosis from trigeminal autonomic cephalalgias and from sinus-related headache disorders. PMID- 23924391 TI - Why noise is useful in functional and neural mechanisms of interval timing? AB - BACKGROUND: The ability to estimate durations in the seconds-to-minutes range - interval timing - is essential for survival, adaptation and its impairment leads to severe cognitive and/or motor dysfunctions. The response rate near a memorized duration has a Gaussian shape centered on the to-be-timed interval (criterion time). The width of the Gaussian-like distribution of responses increases linearly with the criterion time, i.e., interval timing obeys the scalar property. RESULTS: We presented analytical and numerical results based on the striatal beat frequency (SBF) model showing that parameter variability (noise) mimics behavioral data. A key functional block of the SBF model is the set of oscillators that provide the time base for the entire timing network. The implementation of the oscillators block as simplified phase (cosine) oscillators has the additional advantage that is analytically tractable. We also checked numerically that the scalar property emerges in the presence of memory variability by using biophysically realistic Morris-Lecar oscillators. First, we predicted analytically and tested numerically that in a noise-free SBF model the output function could be approximated by a Gaussian. However, in a noise-free SBF model the width of the Gaussian envelope is independent of the criterion time, which violates the scalar property. We showed analytically and verified numerically that small fluctuations of the memorized criterion time leads to scalar property of interval timing. CONCLUSIONS: Noise is ubiquitous in the form of small fluctuations of intrinsic frequencies of the neural oscillators, the errors in recording/retrieving stored information related to criterion time, fluctuation in neurotransmitters' concentration, etc. Our model suggests that the biological noise plays an essential functional role in the SBF interval timing. PMID- 23924393 TI - Electronic health record-based assessment of oral corticosteroid use in a population of primary care patients with asthma: an observational study. AB - BACKGROUND: Oral corticosteroid prescriptions are often used in clinical studies as an indicator of asthma exacerbations. However, there is rarely the ability to link a prescription to its associated diagnosis. The objective of this study was to characterize patterns of oral corticosteroid prescription orders for asthma patients using an electronic health record database, which links each prescription order to the diagnosis assigned at the time the order was placed. METHODS: This was a retrospective cohort study of the electronic health records of asthma patients enrolled in the Geisinger Health System from January 1, 2001 to August 23, 2010. Eligible patients were 12-85 years old, had a primary care physician in the Geisinger Health System, and had asthma. Each oral corticosteroid order was classified as being prescribed for an asthma-related or non-asthma-related condition based on the associated diagnosis. Asthma-related oral corticosteroid use was classified as either chronic or acute. In patient level analyses, we determined the number of asthma patients with asthma-related and non-asthma-related prescription orders and the number of patients with acute versus chronic use. Prescription-level analyses ascertained the percentages of oral corticosteroid prescription orders that were for asthma-related and non asthma-related conditions. RESULTS: Among the 21,199 asthma patients identified in the electronic health record database, 15,017 (70.8%) had an oral corticosteroid prescription order. Many patients (N = 6,827; 45.5%) had prescription orders for both asthma-related and non-asthma-related conditions, but some had prescription orders exclusively for asthma-related (N = 3,450; 23.0%) or non-asthma-related conditions (N = 4,740; 31.6%). Among the patients receiving a prescription order, most (87.5%) could be classified as acute users. A total of 60,355 oral corticosteroid prescription orders were placed for the asthma patients in this study-31,397 (52.0%) for non-asthma-related conditions, 24,487 (40.6%) for asthma-related conditions, and 4,471 (7.4%) for both asthma related and non-asthma-related conditions. CONCLUSIONS: Oral corticosteroid prescriptions for asthma patients are frequently ordered for conditions unrelated to asthma. A prescription for oral corticosteroids may be an unreliable marker of asthma exacerbations in retrospective studies utilizing administrative claims data. Investigators should consider co-morbid conditions for which oral corticosteroid use may also be indicated and/or different criteria for assessing oral corticosteroid use for asthma. PMID- 23924394 TI - A retrospective study on acute health effects due to volcanic ash exposure during the eruption of Mount Etna (Sicily) in 2002. AB - BACKGROUND: Mount Etna, located in the eastern part of Sicily (Italy), is the highest and most active volcano in Europe. During the sustained eruption that occurred in October-November 2002 huge amounts of volcanic ash fell on a densely populated area south-east of Mount Etna in Catania province. The volcanic ash fall caused extensive damage to infrastructure utilities and distress in the exposed population. This retrospective study evaluates whether or not there was an association between ash fall and acute health effects in exposed local communities. METHODS: We collected the number and type of visits to the emergency department (ED) for diseases that could be related to volcanic ash exposure in public hospitals of the Province of Catania between October 20 and November 7, 2002. We compared the magnitude of differences in ED visits between the ash exposure period in 2002 and the same period of the previous year 2001. RESULTS: We observed a significant increase of ED visits for acute respiratory and cardiovascular diseases, and ocular disturbances during the ash exposure time period. CONCLUSIONS: There was a positive association between exposure to volcanic ash from the 2002 eruption of Mount Etna and acute health effects in the Catania residents. This study documents the need for public health preparedness and response initiatives to protect nearby populations from exposure to ash fall from future eruptions of Mount Etna. PMID- 23924395 TI - Turkish version of the painDETECT questionnaire in the assessment of neuropathic pain: a validity and reliability study. AB - OBJECTIVES: The aim of this study was to develop a Turkish version of the painDETECT questionnaire (PD-Q) and assess its reliability and validity. METHODS: Two hundred and forty patients who were diagnosed by expert pain physicians in daily clinical practice and classified as having either neuropathic, nociceptive, or mixed pain for at least 3 months were enrolled in this study. After the usual translation process, the Turkish version of the PD-Q was administered to each participant twice with an interval of 48 hours. The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Douleur Neuropathique en 4 questions (DN4) and a pain visual analog scale were assessed along with the PD-Q. Chronbach's alpha was calculated to evaluate internal consistency of the PD-Q. Intraclass correlation coefficient was calculated to examine test-retest reliability. Convergent validity was assessed by correlating the scale with LANSS and DN4. Discriminant statistics-sensitivity, specificity, Youden index, positive predictive value, negative predictive value-were also assessed. RESULTS: A total of 240 patients with chronic pain, 80 patients in each neuropathic, nociceptive, and mixed pain group, were included in this study. Mean age of the patients was 54.1 years, and majority of the patients were female (52.9%). Chronbach's alpha of the Turkish version of the PD-Q was 0.81. The test-retest reliability of the Turkish version of the PD-Q was determined as 0.98 for the total score and ranged from 0.86 to 0.99 for individual items. The Turkish version of the PD-Q was possitively and significantly corralated with LANSS (r 0.89, P < 0.001) and DN4 (r 0.82, P < 0.001). When the two cutoff values in the original version were used, sensitivity was found 77.5% for a cutoff value <=19, and specificity was 82.5%. Sensitivity and specificity were 90% and 67.5%, respectively, for the other cutoff value <=12. Scores <=12 represents a negative predictive value = 87%, and scores 19<= represents a positive predictive value = 82%. When mixed pain patients were included in the neuropathic pain group, discriminant values were reduced as expected. CONCLUSIONS: The Turkish version of the PD-Q is a reliable and valid scale to be used to determine neuropathic component of chronic pain in Turkish patients. PMID- 23924397 TI - "Tunneling two-level systems" model of the low-temperature properties of glasses: are "smoking-gun" tests possible? AB - Following a brief review of the "two-level (tunneling) systems" model of the low temperature properties of amorphous solids ("glasses"), we ask whether it is in fact the unique explanation of these properties as is usually assumed, concluding that this is not necessarily the case. We point out that (a) one specific form of the model is already experimentally refuted and (b) that a definitive test of the model in its most general form, while not yet carried out, would appear to be now experimentally feasible. PMID- 23924396 TI - Structural basis for assembly of the Mn(IV)/Fe(III) cofactor in the class Ic ribonucleotide reductase from Chlamydia trachomatis. AB - The class Ic ribonucleotide reductase (RNR) from Chlamydia trachomatis (Ct) employs a Mn(IV)/Fe(III) cofactor in each monomer of its beta2 subunit to initiate nucleotide reduction. The cofactor forms by reaction of Mn(II)/Fe(II) beta2 with O2. Previously, in vitro cofactor assembly from apo beta2 and divalent metal ions produced a mixture of two forms, with Mn at site 1 (Mn(IV)/Fe(III)) or site 2 (Fe(III)/Mn(IV)), of which the more active Mn(IV)/Fe(III) product predominates. Here we have addressed the basis for metal site selectivity by determining X-ray crystal structures of apo, Mn(II), and Mn(II)/Fe(II) complexes of Ct beta2. A structure obtained anaerobically with equimolar Mn(II), Fe(II), and apoprotein reveals exclusive incorporation of Mn(II) at site 1 and Fe(II) at site 2, in contrast to the more modest site selectivity achieved previously. Site specificity is controlled thermodynamically by the apoprotein structure, as only minor adjustments of ligands occur upon metal binding. Additional structures imply that, by itself, Mn(II) binds in either site. Together, the structures are consistent with a model for in vitro cofactor assembly in which Fe(II) specificity for site 2 drives assembly of the appropriately configured heterobimetallic center, provided that Fe(II) is substoichiometric. This model suggests that use of a Mn(IV)/Fe(III) cofactor in vivo could be an adaptation to Fe(II) limitation. A 1.8 A resolution model of the Mn(II)/Fe(II)-beta2 complex reveals additional structural determinants for activation of the cofactor, including a proposed site for side-on (eta(2)) addition of O2 to Fe(II) and a short (3.2 A) Mn(II)-Fe(II) interionic distance, promoting formation of the Mn(IV)/Fe(IV) activation intermediate. PMID- 23924398 TI - The impact of introducing automated eGFR reporting on uncovering new cases of chronic kidney disease in a University Hospital in Saudi Arabia. AB - OBJECTIVE: To determine the impact of introducing eGFR automated reporting on uncovering new cases of Chronic Kidney Disease. METHODS: All serum creatinine (SCr) in adult patients attending outpatient clinics over a two-month period were recorded and eGFR estimated. Cases with a SCr within normal limits but were in CKD stage 3 (<60 mL/min) or higher were recorded and their numbers, percentages and mean ages calculated. Stages 1 and 2 were excluded from analysis because urinary albumin and other urinary abnormalities were not checked. RESULTS: A total of 26,422 SCr from different patients were included. The mean SCr was 92.5 +/- 130.9 MUmol/ and the mean eGFR was 99.8 +/- 32.4 mL/min/1.73 m(2). Of all the10,601 males with normal SCr, 0.84% were in CKD stage 3 and in all the 14,695 female, 19.24% were in stage 2 in stage. Of all the 14,695 females with serum creatinine in the normal range, 200 (1.36%) were in CKD stage 3. The patients in stages 2 and 3 were significantly older. CONCLUSION: If our findings are shown to be true for the rest of Saudi Arabia, one could extrapolate that for each 100,000 serum creatinine assayed for males, 840 new cases will be uncovered in CKD stage 3. The corresponding number for females would be 1360 cases. PMID- 23924400 TI - Job strain and stress of conscience among nurse assistants working in residential care. AB - AIM: The aim was to investigate job strain and stress of conscience among nurse assistants working in residential care and to explore associations with personal and work-related aspects and health complaints. BACKGROUND: It is important to investigate job strain and stress of conscience, both for the well-being of the nurse assistants themselves and for the impact on the quality of care they provide. METHOD: Questionnaires measuring job strain, stress of conscience, personal and work-related aspects and health complaints were completed by NAs (n = 225). Comparisons of high and low levels of job strain and stress of conscience and multiple linear regression analyses were performed. RESULT: Organisational and environmental support and low education levels were associated with low levels of job strain and stress of conscience. Personalised care provision and leadership were related to stress of conscience and the caring climate was related to job strain. CONCLUSION: There is a need for support from the managers and a supportive organisation for reducing nurse assistants work-related stress, which in turn can create a positive caring climate where the nurse assistants are able to provide high quality care. IMPLICATIONS FOR NURSING MANAGEMENT: The managers' role is essential when designing supportive measures and implementing a value-system that can facilitate personalised care provision. PMID- 23924401 TI - Mechanism of catalytic functionalization of primary C-H bonds using a silylation strategy. AB - The mechanism of Ir-catalyzed gamma-functionalization of a primary sp(3)(C-H) bond in 2-methyl cyclohexanol is examined using the density functional theory (M06). The nature of the active catalyst for the initial silylation of alcohol is identified as the monomer derived from [Ir(cod)OMe]2 while that for gamma-sp(3)(C H) activation leading to oxasilolane is [IrH(nbe)(phen)]. The rate-determining step is found to involve Si-C coupling through reductive elimination. PMID- 23924399 TI - Associations between the legal context of HIV, perceived social capital, and HIV antiretroviral adherence in North America. AB - BACKGROUND: Human rights approaches to manage HIV and efforts to decriminalize HIV exposure/transmission globally offer hope to persons living with HIV (PLWH). However, among vulnerable populations of PLWH, substantial human rights and structural challenges (disadvantage and injustice that results from everyday practices of a well-intentioned liberal society) must be addressed. These challenges span all ecosocial context levels and in North America (Canada and the United States) can include prosecution for HIV nondisclosure and HIV exposure/transmission. Our aims were to: 1) Determine if there were associations between the social structural factor of criminalization of HIV exposure/transmission, the individual factor of perceived social capital (resources to support one's life chances and overcome life's challenges), and HIV antiretroviral therapy (ART) adherence among PLWH and 2) describe the nature of associations between the social structural factor of criminalization of HIV exposure/transmission, the individual factor of perceived social capital, and HIV ART adherence among PLWH. METHODS: We used ecosocial theory and social epidemiology to guide our study. HIV related criminal law data were obtained from published literature. Perceived social capital and HIV ART adherence data were collected from adult PLWH. Correlation and logistic regression were used to identify and characterize observed associations. RESULTS: Among a sample of adult PLWH (n = 1873), significant positive associations were observed between perceived social capital, HIV disclosure required by law, and self-reported HIV ART adherence. We observed that PLWH who have higher levels of perceived social capital and who live in areas where HIV disclosure is required by law reported better average adherence. In contrast, PLWH who live in areas where HIV transmission/exposure is a crime reported lower 30-day medication adherence. Among our North American participants, being of older age, of White or Hispanic ancestry, and having higher perceived social capital, were significant predictors of better HIV ART adherence. CONCLUSIONS: Treatment approaches offer clear advantages in controlling HIV and reducing HIV transmission at the population level. These advantages, however, will have limited benefit for adherence to treatments without also addressing the social and structural challenges that allow HIV to continue to spread among society's most vulnerable populations. PMID- 23924402 TI - Shaping crystals with light: crystal-to-crystal isomerization and photomechanical effect in fluorinated azobenzenes. AB - Unusually long thermal half-lives of perhalogenated cis-azobenzenes enabled their structural characterization and the first evidence of a crystal-to-crystal cis -> trans azobenzene isomerization. Irradiation with visible light transforms a perhalogenated cis-azobenzene single crystal into a polycrystalline aggregate of its trans-isomer in a photomechanical transformation that involves a significant, controllable, and thermally irreversible change of crystal shape. This is the first demonstration of permanent photomechanical modification of crystal shape in an azobenzene. PMID- 23924403 TI - Smile esthetics from odontology students' perspectives. AB - OBJECTIVES: To analyze the perception of smile esthetics and its alterations in dental degree students; to determine whether there are differences in that perception among students in different study years on those courses and between genders; and to determine if the circumstance of having received prior orthodontic treatment could influence that perception. MATERIAL AND METHODS: Students (n = 192) in different study years of the dental degree course at the University of Valencia, Spain, analyzed two photographs of a patient in which, by means of computer software, midline diastema, upper and lower midlines, crown length of the maxillary right central incisor, occlusal cant, and "gummy" smile were altered. Students assessed the photographs on a scale from 1 to 10. Statistical analyses for assessing each group's level of perception were carried out. RESULTS: After checking the validity of the study, it was observed that the students' ability to detect alterations in smile esthetics did not improve over their degree courses, given that the differences do not present a linear development. There were no differences between genders and between those who had or had not undergone an orthodontic treatment. CONCLUSIONS: There are no statistically significant differences between the results of students in different study years or between genders. The circumstance of having undergone prior orthodontic treatment is not a determining factor in the ability to perceive such anomalies. PMID- 23924404 TI - Influence of cone-beam computed tomography image artifacts on the determination of dental arch measurements. AB - OBJECTIVE: To compare dental plaster model (DPM) and cone-beam computed tomography (CBCT) in the measurement of the dental arches, and investigate whether CBCT image artifacts compromise the reliability of such measurements. MATERIALS AND METHODS: Twenty patients were divided into two groups based on the presence or absence of metallic restorations in the posterior teeth. Both dental arches of the patients were scanned with the CBCT unit i-CAT, and DPMs were obtained. Two examiners obtained eight arch measurements on the CBCT images and DPMs and repeated this procedure 15 days later. The arch measurements of each patient group were compared separately by the Wilcoxon rank sum (Mann-Whitney U) test, with a significance level of 5% (alpha = .05). Intraclass correlation measured the level of intraobserver agreement. RESULTS: Patients with healthy teeth showed no significant difference between all DPM and CBCT arch measurements (P > .05). Patients with metallic restoration showed significant difference between DPM and CBCT for the majority of the arch measurements (P > .05). The two examiners showed excellent intraobserver agreement for both measuring methods with intraclass correlation coefficient higher than 0.95. CONCLUSION: CBCT provided the same accuracy as DPM in the measurement of the dental arches, and was negatively influenced by the presence of image artifacts. PMID- 23924405 TI - Determination of iriflophenone 3-C-beta-d-glucoside from Aquilaria spp. by an indirect competitive enzyme-linked immunosorbent assay using a specific polyclonal antibody. AB - Polyclonal antibody against iriflophenone 3-C-beta-d-glucoside (IP3G), a major compound from the leaves of Aquilaria spp., was produced for the development of an enzyme-linked immunosorbent assay (ELISA). The results showed that the antibodies were specific for IP3G. The produced antibody has low cross reactivity with iriflophenone 3,5-C-beta-d-diglucopyranoside (13%), genkwanin 5-O-beta primeveroside (3.55%) and no cross reactivity found in other compounds. The range of ELISA assay extends from 100 to 1560 ng/mL with coefficient of variation (CV) 1.19% to 2.07% for intra-assay and 3.76% to 7.15% for inter-assay precision levels. The recovery rates of IP3G in the leaves of Aquilaria spp. were in the range of 96.0% to 99.0% with CV 4.50% to 5.32%. A correlation between ELISA and high-performance liquid chromatography methods was obtained when analysis of IP3G in the plant samples (R(2) = 0.9321). These results suggest that the developed ELISA method can be applied to determine IP3G content with high specificity, rapidity, and simplicity. The developed immunosorbent assay in this study provides a useful tool for the analysis of IP3G in plant samples and products. PMID- 23924406 TI - High potency fish oil supplement improves omega-3 fatty acid status in healthy adults: an open-label study using a web-based, virtual platform. AB - BACKGROUND: The health benefits of omega-3 fatty acids from fish are well known, and fish oil supplements are used widely in a preventive manner to compensate the low intake in the general population. The aim of this open-label study was to determine if consumption of a high potency fish oil supplement could improve blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and impact SF-12 mental and physical health scores in healthy adults. METHODS: A novel virtual clinical research organization was used along with the HS-Omega-3 Index, a measure of EPA and DHA in red blood cell membranes expressed as a percentage of total fatty acids that has been shown to correlate with a reduction in cardiovascular and other risk factors. Briefly, adult subjects (mean age 44 years) were recruited from among U.S. health food store employees and supplemented with 1.1 g/d of omega-3 from fish oil (756 mg EPA, 228 mg DHA, Minami Nutrition MorEPA Platinum) for 120 days (n = 157). RESULTS: Omega-3 status and mental health scores increased with supplementation (p < 0.001), while physical health scores remained unchanged. CONCLUSIONS: The use of a virtual, web based platform shows considerable potential for engaging in clinical research with normal, healthy subjects. A high potency fish oil supplement may further improve omega-3 status in a healthy population regularly consuming an omega-3 supplement. PMID- 23924407 TI - Comparison between the six-minute walk test and the six-minute step test in post stroke patients. AB - BACKGROUND: The Stroke remains one of the major chronic diseases worldwide, and is considered a major cause of disability, which results not only in persistent neurological deficits, but also in the high physical deconditioning, nevertheless there are not many forms of assessing functional capacity in this population. We aimed to investigate the feasibility of the Six Minute Walk Teste and the Six Minute Step Test (6MST) in post-stroke patients and compare the behavior of physiological variables during the 6MST and the Six-Minute Walk Test (6MWT), by correlating the functional performance obtained in both tests. METHOD: The 6MWT was carried out according to the American Thoracic Society (ATS) and the 6MST was performed in six minutes in order to compare it to the 6MWT in a 20 cm step. Was included post-stroke individuals able to walk without aid. All of them did the 6MWT and the 6MST. RESULTS: 12 patients participated in the study. There was no statistical difference in the parameters analyzed when tests were compared. There was poor correlation between the functional performance in both tests. CONCLUSION: The 6MWT and the 6MST is feasible for post-stroke patients and physiological responses are equal during the performance of both tests. However, there was no correlation with respect to functional performance, which was assessed by the distance walked in the 6MWT and by the number of steps climbed in the 6MST. PMID- 23924408 TI - Bilateral areolar leiomyomas in a patient undergoing BRAF inhibition therapy for melanoma. AB - BRAF inhibition therapy, used to treat melanomas with BRAF mutations, is associated with both neoplastic and non-neoplastic cutaneous side effects including squamous cell carcinomas, warty dyskeratomas, verrucous keratoses, photosensitivity and widespread eruptions that present histopathologically as acantholytic dyskeratosis. We report a case of a patient undergoing BRAF inhibition therapy for disseminated melanoma with a V600E mutation who developed bilateral areolar leiomyomas, one of which was biopsied and the other of which resolved after discontinuation of vemurafenib therapy. To our knowledge, this is the first reported case of a mesenchymal neoplasm developing in association with BRAF inhibition therapy. PMID- 23924409 TI - Synergistic inhibition of lipid oxidation by pea protein hydrolysate coupled with licorice extract in a liposomal model system. AB - Fourteen pea protein hydrolysates (PPHs) were prepared using different proteases and tested for antioxidant activity in a liposomal model system under oxidative stress (100 MUM FeCl3/2 mM ascorbate). Almost all PPHs inhibited lipid oxidation, and those prepared from heated protein with Flavourzyme (Fla-PPH) or Protamex (Pro-PPH) were the most effective. Remarkable synergistic effects were observed on both Fla-PPH and Pro-PPH with licorice extract (LE). Electron microscopy revealed a self-assembled network that appeared to provide crucial protection of liposome against oxidation. The presence of LE enhanced the antioxidant potential by producing a more compact network apparently via PPH-LE complexation. Zeta potential measurements suggested electrostatic interactions are important driving forces for the accumulation of active peptides at the liposome interface. Peptides rich in leucine, lysine, glutamic acid, glutamine, valine, or proline with a hydrophobic N-terminus, as identified by mass spectrometry, were implicated in the antioxidative protection. PMID- 23924410 TI - Zero-field splitting in pseudotetrahedral Co(II) complexes: a magnetic, high frequency and -field EPR, and computational study. AB - Six pseudotetrahedral cobalt(II) complexes of the type [CoL2Cl2], with L = heterocyclic N-donor ligand, have been studied in parallel by magnetometry, and high-frequency and -field electron paramagnetic resonance (HFEPR). HFEPR powder spectra were recorded in a 50 GHz < nu < 700 GHz range in a 17 T superconducting and 25 T resistive magnet, which allowed constructing of resonance field vs frequency diagrams from which the fitting procedure yielded the S = 3/2 spin ground state Hamiltonian parameters. The sign of the axial anisotropy parameter D was determined unambiguously; the values range between -8 and +11 cm(-1) for the given series of complexes. These data agree well with magnetometric analysis. Finally, quantum chemical ab initio calculations were performed on the whole series of complexes to probe the relationship between the magnetic anisotropy, electronic, and geometric structure. PMID- 23924411 TI - Assessment of feature selection and classification approaches to enhance information from overnight oximetry in the context of apnea diagnosis. AB - This study is aimed at assessing the usefulness of different feature selection and classification methodologies in the context of sleep apnea hypopnea syndrome (SAHS) detection. Feature extraction, selection and classification stages were applied to analyze blood oxygen saturation (SaO2) recordings in order to simplify polysomnography (PSG), the gold standard diagnostic methodology for SAHS. Statistical, spectral and nonlinear measures were computed to compose the initial feature set. Principal component analysis (PCA), forward stepwise feature selection (FSFS) and genetic algorithms (GAs) were applied to select feature subsets. Fisher's linear discriminant (FLD), logistic regression (LR) and support vector machines (SVMs) were applied in the classification stage. Optimum classification algorithms from each combination of these feature selection and classification approaches were prospectively validated on datasets from two independent sleep units. FSFS + LR achieved the highest diagnostic performance using a small feature subset (4 features), reaching 83.2% accuracy in the validation set and 88.7% accuracy in the test set. Similarly, GAs + SVM also achieved high generalization capability using a small number of input features (7 features), with 84.2% accuracy on the validation set and 84.5% accuracy in the test set. Our results suggest that reduced subsets of complementary features (25% to 50% of total features) and classifiers with high generalization ability could provide high-performance screening tools in the context of SAHS. PMID- 23924412 TI - Multimodal integration of micro-Doppler sonar and auditory signals for behavior classification with convolutional networks. AB - The ability to recognize the behavior of individuals is of great interest in the general field of safety (e.g. building security, crowd control, transport analysis, independent living for the elderly). Here we report a new real-time acoustic system for human action and behavior recognition that integrates passive audio and active micro-Doppler sonar signatures over multiple time scales. The system architecture is based on a six-layer convolutional neural network, trained and evaluated using a dataset of 10 subjects performing seven different behaviors. Probabilistic combination of system output through time for each modality separately yields 94% (passive audio) and 91% (micro-Doppler sonar) correct behavior classification; probabilistic multimodal integration increases classification performance to 98%. This study supports the efficacy of micro Doppler sonar systems in characterizing human actions, which can then be efficiently classified using ConvNets. It also demonstrates that the integration of multiple sources of acoustic information can significantly improve the system's performance. PMID- 23924413 TI - Indirect adaptive control of nonlinear systems based on bilinear neuro-fuzzy approximation. AB - In this paper, we investigate the indirect adaptive regulation problem of unknown affine in the control nonlinear systems. The proposed approach consists of choosing an appropriate system approximation model and a proper control law, which will regulate the system under the certainty equivalence principle. The main difference from other relevant works of the literature lies in the proposal of a potent approximation model that is bilinear with respect to the tunable parameters. To deploy the bilinear model, the components of the nonlinear plant are initially approximated by Fuzzy subsystems. Then, using appropriately defined fuzzy rule indicator functions, the initial dynamical fuzzy system is translated to a dynamical neuro-fuzzy model, where the indicator functions are replaced by High Order Neural Networks (HONNS), trained by sampled system data. The fuzzy output partitions of the initial fuzzy components are also estimated based on sampled data. This way, the parameters to be estimated are the weights of the HONNs and the centers of the output partitions, both arranged in matrices of appropriate dimensions and leading to a matrix to matrix bilinear parametric model. Based on the bilinear parametric model and the design of appropriate control law we use a Lyapunov stability analysis to obtain parameter adaptation laws and to regulate the states of the system. The weight updating laws guarantee that both the identification error and the system states reach zero exponentially fast, while keeping all signals in the closed loop bounded. Moreover, introducing a method of "concurrent" parameter hopping, the updating laws are modified so that the existence of the control signal is always assured. The main characteristic of the proposed approach is that the a priori experts information required by the identification scheme is extremely low, limited to the knowledge of the signs of the centers of the fuzzy output partitions. Therefore, the proposed scheme is not vulnerable to initial design assumptions. Simulations on selected examples of well-known benchmarks illustrate the potency of the method. PMID- 23924414 TI - Application of intrinsic time-scale decomposition (ITD) to EEG signals for automated seizure prediction. AB - Intrinsic time-scale decomposition (ITD) is a new nonlinear method of time frequency representation which can decipher the minute changes in the nonlinear EEG signals. In this work, we have automatically classified normal, interictal and ictal EEG signals using the features derived from the ITD representation. The energy, fractal dimension and sample entropy features computed on ITD representation coupled with decision tree classifier has yielded an average classification accuracy of 95.67%, sensitivity and specificity of 99% and 99.5%, respectively using 10-fold cross validation scheme. With application of the nonlinear ITD representation, along with conceptual advancement and improvement of the accuracy, the developed system is clinically ready for mass screening in resource constrained and emerging economy scenarios. PMID- 23924415 TI - A clustering-based fuzzy wavelet neural network model for short-term load forecasting. AB - Load forecasting is a critical element of power system operation, involving prediction of the future level of demand to serve as the basis for supply and demand planning. This paper presents the development of a novel clustering-based fuzzy wavelet neural network (CB-FWNN) model and validates its prediction on the short-term electric load forecasting of the Power System of the Greek Island of Crete. The proposed model is obtained from the traditional Takagi-Sugeno-Kang fuzzy system by replacing the THEN part of fuzzy rules with a "multiplication" wavelet neural network (MWNN). Multidimensional Gaussian type of activation functions have been used in the IF part of the fuzzyrules. A Fuzzy Subtractive Clustering scheme is employed as a pre-processing technique to find out the initial set and adequate number of clusters and ultimately the number of multiplication nodes in MWNN, while Gaussian Mixture Models with the Expectation Maximization algorithm are utilized for the definition of the multidimensional Gaussians. The results corresponding to the minimum and maximum power load indicate that the proposed load forecasting model provides significantly accurate forecasts, compared to conventional neural networks models. PMID- 23924416 TI - Announcement - the 2013 Hojjat Adeli award for outstanding contributions in neural systems. PMID- 23924417 TI - Urological oncology in the BJUI. PMID- 23924418 TI - Prostate biopsy: will transperineal replace transrectal? PMID- 23924419 TI - Assessing the accuracy and generalizability of the preoperative and postoperative Karakiewicz nomograms for renal cell carcinoma: results from a multicentre European and US study. PMID- 23924420 TI - Laparoendoscopic single-site nephroureterectomy for upper urinary tract urothelial carcinoma: outcomes of an international multi-institutional study of 101 patients. PMID- 23924421 TI - Transperineal magnetic resonance imaging--ultrasound fusion targeted biopsies (MRI-US FTB) of the prostate: the future of prostate diagnostics. PMID- 23924422 TI - Regulatory T cells in renal cell carcinoma: additional fuel to the bonfire of debate. PMID- 23924423 TI - American Urological Association (AUA) guideline on prostate cancer detection: process and rationale. AB - To review the process and rationale for the American Urological Association (AUA) guideline on prostate cancer detection. The AUA guideline on detection of prostate cancer involved a systematic literature review of >300 studies that evaluated outcomes important to patients (prostate cancer, incidence/mortality, health-related quality of life, diagnostic accuracy and harms of testing). A multidisciplinary panel interpreted the evidence and formulated statements to assist the urologist and the asymptomatic average-risk man in decision-making about prostate cancer detection. Other than prostate-specific antigen (PSA)-based prostate cancer screening, there was no evidence to address the outcomes of interest to patients. The strongest evidence that benefits may outweigh harms was in men aged 55-69 years undergoing PSA-based screening. This led the panel to recommend shared decision-making for these men at average risk, but recommend against routine screening for other age groups at average risk. Further, to reduce the harms associated with screening (false positive tests, over diagnosis, over treatment), the panel recommended against annual screening for those who choose to be screened. A panel under the auspices of the AUA recommended shared decision-making for the average risk asymptomatic man aged 55-69 years considering PSA-based screening for prostate cancer detection. PMID- 23924425 TI - Polymorphism and single nucleotide polymorphisms (SNPs). PMID- 23924424 TI - De novo erectile dysfunction after anterior urethroplasty: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the likelihood of developing de novo erectile dysfunction (ED) after anterior urethroplasty and to determine if this likelihood is influenced by age, stricture length, number of previous procedures or timing of evaluation. MATERIALS AND METHODS: PubMed, Embase, Cochrane, and Google Scholar databases were searched for the terms 'urethroplasty', 'urethral obstruction', 'urethral stricture', 'sexual function', 'erection', 'erectile function', 'erectile dysfunction', 'impotence' and 'sexual dysfunction'. Two reviewers evaluated articles for inclusion based on predetermined criteria. RESULTS: In a meta-analysis of 36 studies with a total of 2323 patients, de novo ED was rare, with an incidence of 1%. In studies that assessed postoperative erectile function at more than one time point, ED was transient and resolved at between 6 and 12 months in 86% of cases. CONCLUSIONS: Men should be counselled regarding the possibility of transient or permanent de novo ED after anterior urethroplasty procedures. Increasing mean age was associated with an increased likelihood of de novo ED, but this was not statistically significant. PMID- 23924426 TI - Technique to overcome renal mobility during percutaneous tract dilatation: bi prong forceps renal parenchyma dissection. PMID- 23924427 TI - Percutaneous suprapubic tube bladder drainage after robot-assisted radical prostatectomy: a step-by-step guide. AB - OBJECTIVE: To describe our technique of maintaining bladder drainage after robot assisted radical prostatectomy (RARP) using a percutaneous suprapubic tube (PST) in place of a urethral catheter. METHODS: A watertight anastomosis permits placement of the PST. Contraindications include morbid obesity, concomitant inguinal hernia mesh repair, anticoagulation therapy, limited hand dexterity in the patient, bladder neck reconstruction and extensive adhesiolysis at RARP. The necessary equipment includes a 14-F PST balloon catheter set, a three-way connector, a connecting tube, a suture passer, 1/0 polypropylene sutures on a CT1 needle, a sterile plastic button, adhesive and steri-strips. RESULTS: The important steps for PST placement are: Step 1: robot-assisted placement of a bladder wall anchor suture; Step 2: transferring the bladder wall suture to anterior abdominal skin; Step 3: guided placement of the PST under robotic vision; Step 4: securing the PST within the bladder and abdominal wall; Step 5. postoperative care: clamping the PST on postoperative day 5, recording each void and post-void residual urine volumes in a patient diary, removal of the PST on postoperative day 7 after 48 h of voiding with residual urine <100 mL per void. CONCLUSION: We provide a concise step-by-step guide for placement of a PST during RARP as well as important management aspects for the successful adoption of this technique. PMID- 23924428 TI - Compensatory regulation of Na+ absorption by Na+/H+ exchanger and Na+-Cl- cotransporter in zebrafish (Danio rerio). AB - INTRODUCTION: In mammals, internal Na+ homeostasis is maintained through Na+ reabsorption via a variety of Na+ transport proteins with mutually compensating functions, which are expressed in different segments of the nephrons. In zebrafish, Na+ homeostasis is achieved mainly through the skin/gill ionocytes, namely Na+/H+ exchanger (NHE3b)-expressing H+-ATPase rich (HR) cells and Na+-Cl- cotransporter (NCC)-expressing NCC cells, which are functionally homologous to mammalian proximal and distal convoluted tubular cells, respectively. The present study aimed to investigate whether or not the functions of HR and NCC ionocytes are differentially regulated to compensate for disruptions of internal Na+ homeostasis and if the cell differentiation of the ionocytes is involved in this regulation pathway. RESULTS: Translational knockdown of ncc caused an increase in HR cell number and a resulting augmentation of Na+ uptake in zebrafish larvae, while NHE3b loss-of-function caused an increase in NCC cell number with a concomitant recovery of Na+ absorption. Environmental acid stress suppressed nhe3b expression in HR cells and decreased Na+ content, which was followed by up regulation of NCC cells accompanied by recovery of Na+ content. Moreover, knockdown of ncc resulted in a significant decrease of Na+ content in acid acclimated zebrafish. CONCLUSIONS: These results provide evidence that HR and NCC cells exhibit functional redundancy in Na+ absorption, similar to the regulatory mechanisms in mammalian kidney, and suggest this functional redundancy is a critical strategy used by zebrafish to survive in a harsh environment that disturbs body fluid Na+ homeostasis. PMID- 23924429 TI - Minimal oxidation and inflammogenicity of pristine graphene with residence in the lung. AB - Two-dimensional graphitic carbon, graphene, is a new form of nanomaterial with great potential in a wide variety of applications. It is therefore crucial to investigate the behaviour of graphene in biological systems to assess potential adverse effects that might follow from inhalation exposure. In this study we focussed on medium-term effects of graphene in lung tissue by investigating the pulmonary inflammation 6 weeks after pharyngeal aspiration of unoxidised multilayered graphene platelets (GPs) in mice and assessed their biopersistence in the lung tissue using Raman spectroscopy. Additionally, GP degradation in vitro was examined after horseradish peroxidase (HRP) treatment up to 1 week. Building on our previous report showing acute inflammation in mice lungs at 1 day, pristine GP showed minimal inflammation in mouse lungs after 6 weeks even though no degradation of GP in lung tissue was observed and large deposits of GP were evident in the lungs. Raman analysis of GP in tissue sections showed minimal oxidation, and in vitro examinations of enzymatic oxidation of GP via HRP and H2O2 showed only slight increases in ID/IG ratio and the appearance of the Raman D' band at 1620 cm(-1) (surrogates of graphene oxidation). Our results showing non-inflammogenicity at medium time points have important implications in the hazard identification of GPs following inhalation exposure and for their use in biomedical applications. Additionally, the biopersistence of pristine GP in vivo with no associated inflammation could open the way to applications in tissue engineering and drug delivery. PMID- 23924430 TI - Solvent-induced reversed stereoselectivity in reciprocal resolutions of mandelic acid and erythro-2-amino-1,2-diphenylethanol. AB - Solvent-induced chirality switching in reciprocal optical resolution between mandelic acid (1) and erythro-2-amino-1,2-diphenylethanol (2) has been demonstrated. The stereochemistry of the deposited salts was controlled by changing the crystallization solvent from 1-PrOH or 1-BuOH to 1,4-dioxane. It was revealed from (1)H NMR spectra, thermogravimetric analysis, and X-ray crystallography of the salts that an equimolar amount of the crystallization solvent was incorporated in each diastereomeric salt. On the basis of the crystal structures, it was found that both the hydrogen-bonding ability and the size of the solvent molecule played an important role. Differences in the formed hydrogen bonding networks (columnar or sheetlike structure) and their packing manner were found to be crucial for the reversed stereoselectivity. Furthermore, pseudopolymorphic salt crystals that incorporated 1,4-dioxane were obtained during the enantioseparation of racemic 2, and their solid-state properties were examined by measurement of their IR spectra. This solvent-induced dual stereocontrol technique was successfully applied to the successive resolution process, eliminating the need to change the resolving agent for access to both enantiomers of 1 and 2. PMID- 23924431 TI - Volcanic ash in the air we breathe. PMID- 23924434 TI - Rheological properties of methane hydrate slurries formed from AOT + water + oil microemulsions. AB - The in situ formation and flow properties of methane hydrates formed from water in-oil microemulsions composed of water, dodecane, and aerosol OT surfactant (AOT) were studied using a unique high pressure rheometer. AOT microemulsions have high stability (order of months), well-characterized composition, and yield reproducible results compared to hydrate studies in water-in-crude oil emulsions. Viscosity increases on the order of minutes upon hydrate formation, and then decreases on the order of hours. If significant unconverted water remained after the initial formation event, then viscosity increases for a time as methane slowly dissolves and converts additional water to hydrate. In addition to transient formation measurements, yield stresses and flow curves are measured for a set of experimental conditions. Hydrate slurry viscosity and yield stress increase with increasing water volume fraction, increasing initial pressure, decreasing temperature, and decreasing formation shear rate. PMID- 23924433 TI - Identification and characterization of the zinc-regulated transporters, iron regulated transporter-like protein (ZIP) gene family in maize. AB - BACKGROUND: Zinc (Zn) and iron (Fe) are essential micronutrients for plant growth and development, their deficiency or excess severely impaired physiological and biochemical reactions of plants. Therefore, a tightly controlled zinc and iron uptake and homeostasis network has been evolved in plants. The Zinc-regulated transporters, Iron-regulated transporter-like Proteins (ZIP) are capable of uptaking and transporting divalent metal ion and are suggested to play critical roles in balancing metal uptake and homeostasis, though a detailed analysis of ZIP gene family in maize is still lacking. RESULTS: Nine ZIP-coding genes were identified in maize genome. It was revealed that the ZmZIP proteins share a conserved transmembrane domain and a variable region between TM-3 and TM-4. Transiently expression in onion epidermal cells revealed that all ZmZIP proteins were localized to the endoplasmic reticulum and plasma membrane. The yeast complementation analysis was performed to test the Zn or Fe transporter activity of ZmZIP proteins. Expression analysis showed that the ZmIRT1 transcripts were dramatically induced in response to Zn- and Fe-deficiency, though the expression profiles of other ZmZIP changed variously. The expression patterns of ZmZIP genes were observed in different stages of embryo and endosperm development. The accumulations of ZmIRT1 and ZmZIP6 were increased in the late developmental stages of embryo, while ZmZIP4 was up-regulated during the early development of embryo. In addition, the expression of ZmZIP5 was dramatically induced associated with middle stage development of embryo and endosperm. CONCLUSIONS: These results suggest that ZmZIP genes encode functional Zn or Fe transporters that may be responsible for the uptake, translocation, detoxification and storage of divalent metal ion in plant cells. The various expression patterns of ZmZIP genes in embryo and endosperm indicates that they may be essential for ion translocation and storage during differential stages of embryo and endosperm development. The present study provides new insights into the evolutionary relationship and putative functional divergence of the ZmZIP gene family during the growth and development of maize. PMID- 23924435 TI - Reconstruction of large-scale regulatory networks based on perturbation graphs and transitive reduction: improved methods and their evaluation. AB - BACKGROUND: The data-driven inference of intracellular networks is one of the key challenges of computational and systems biology. As suggested by recent works, a simple yet effective approach for reconstructing regulatory networks comprises the following two steps. First, the observed effects induced by directed perturbations are collected in a signed and directed perturbation graph (PG). In a second step, Transitive Reduction (TR) is used to identify and eliminate those edges in the PG that can be explained by paths and are therefore likely to reflect indirect effects. RESULTS: In this work we introduce novel variants for PG generation and TR, leading to significantly improved performances. The key modifications concern: (i) use of novel statistical criteria for deriving a high quality PG from experimental data; (ii) the application of local TR which allows only short paths to explain (and remove) a given edge; and (iii) a novel strategy to rank the edges with respect to their confidence. To compare the new methods with existing ones we not only apply them to a recent DREAM network inference challenge but also to a novel and unprecedented synthetic compendium consisting of 30,5000-gene networks simulated with varying biological and measurement error variances resulting in a total of 270 datasets. The benchmarks clearly demonstrate the superior reconstruction performance of the novel PG and TR variants compared to existing approaches. Moreover, the benchmark enabled us to draw some general conclusions. For example, it turns out that local TR restricted to paths with a length of only two is often sufficient or even favorable. We also demonstrate that considering edge weights is highly beneficial for TR whereas consideration of edge signs is of minor importance. We explain these observations from a graph-theoretical perspective and discuss the consequences with respect to a greatly reduced computational demand to conduct TR. Finally, as a realistic application scenario, we use our framework for inferring gene interactions in yeast based on a library of gene expression data measured in mutants with single knockouts of transcription factors. The reconstructed network shows a significant enrichment of known interactions, especially within the 100 most confident (and for experimental validation most relevant) edges. CONCLUSIONS: This paper presents several major achievements. The novel methods introduced herein can be seen as state of the art for inference techniques relying on perturbation graphs and transitive reduction. Another key result of the study is the generation of a new and unprecedented large-scale in silico benchmark dataset accounting for different noise levels and providing a solid basis for unbiased testing of network inference methodologies. Finally, applying our approach to Saccharomyces cerevisiae suggested several new gene interactions with high confidence awaiting experimental validation. PMID- 23924436 TI - Differential effects of familial parkinson mutations in LRRK2 revealed by a systematic analysis of autophosphorylation. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified in pedigrees of autosomal-dominant familial Parkinson's disease (PARK8). It has been shown that the kinase activity of LRRK2 is required for its neuronal toxicity, although how familial Parkinson mutations affect the function of LRRK2 has not been well characterized. In the present study, we systematically characterized the autophosphorylation of LRRK2 by phosphopeptide mapping and identified Thr1348, Thr1349, and Thr1357 as the major autophosphorylation sites. We found that the autophosphorylation at Thr1357 is downregulated by the Y1699C mutation, possibly through a conformational alteration of the ROC domain. We also found that I2020T mutant LRRK2 undergoes excessive autophosphorylation in cell lysates in vitro at a low concentration of ATP. These results highlight the differential effects of familial mutations in LRRK2 on its conformation and enzymatic properties. PMID- 23924438 TI - Multitasking in multiple sclerosis: can it inform vocational functioning? AB - OBJECTIVE: To examine associations between multitasking ability defined by performance on a complex task integrating multiple cognitive domains and vocational functioning in multiple sclerosis (MS). DESIGN: Survey data collection. SETTING: Laboratory with referrals from an outpatient clinic. PARTICIPANTS: Community-dwelling individuals with MS (N=30) referred between October 2011 and June 2012. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The modified Six Elements Test (SET) to measure multitasking ability, Fatigue Severity Scale to measure fatigue, several neuropsychological measures of executive functioning, and vocational status. RESULTS: Among the sample, 60% of individuals have reduced their work hours because of MS symptoms (cutback employment group) and 40% had maintained their work hours. Among both groups, SET performance was significantly associated with performance on several measures of neuropsychological functioning. Individuals in the cutback employment group demonstrated significantly worse overall performance on the SET (P=.041). Logistic regression was used to evaluate associations between SET performance and vocational status, while accounting for neuropsychological performance and fatigue. The overall model was significant (chi(2)3=8.65, P=.032), with fatigue [Exp(B)=.83, P=.01] and multitasking ability [Exp(B)=.60, P=.043] retained as significant predictors. CONCLUSIONS: Multitasking ability may play an important role in performance at work for individuals with MS. Given that multitasking was associated with vocational functioning, future efforts should assess the usefulness of incorporating multitasking ability into rehabilitation planning. PMID- 23924439 TI - Factors influencing receipt of early rehabilitation after stroke. AB - OBJECTIVE: To identify patient-level characteristics associated with rehabilitation during the acute poststroke phase. DESIGN: Retrospective cohort. Generalized estimating equations modeled the likelihood of rehabilitation during the index hospitalization to account for patient clusters. SETTING: Rehabilitation facilities. PARTICIPANTS: Sample included veterans (N=9681; average age, 68.7y; 97.4% men) diagnosed with new stroke discharged from Veterans Affairs hospitals between October 1, 2006, and September 30, 2008. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Receipt of rehabilitation services. RESULTS: Of the total cohort, 73% received some type of rehabilitation. After adjustment, stroke patients with cerebral arteries occlusion were most likely to receive rehabilitation compared with other stroke types (P<.001). Patients with prestroke conditions of metastatic cancer (odds ratio [OR]=.68, P<.001) and psychosis (OR=.90, P=.045) were less likely to have rehabilitation, whereas those with hypertension (OR=1.26, P<.001) and other neurologic disorders (OR=1.29, P<.001) were more likely. Compared with patients admitted from home, patients transferred from a non-Veterans Affairs hospital (OR=1.4, P<.004) were more likely to receive rehabilitation, whereas patients admitted from extended care (OR=.59, P<.001) were less likely. Married veterans were less likely to receive rehabilitation services (OR=.87, P<.001) than unmarried veterans. CONCLUSIONS: Within the Veterans Health Administration, initiating rehabilitation in the acute phase poststroke appears to be influenced by patient clinical characteristics and living circumstances. PMID- 23924440 TI - Evaluation of an activity monitor for the objective measurement of free-living physical activity in children with cerebral palsy. AB - OBJECTIVE: To explore the use of an activity monitor (AM) to objectively characterize free-living physical activity (F-LPA) in children with mobility impairment resulting from cerebral palsy (CP). DESIGN: First, a validation study compared outcomes from the AM with video evidence. Second, multiday F-LPA was characterized. Relationships between laboratory measures and F-LPA were explored. SETTING: The evaluation study was conducted in a laboratory environment. F-LPA monitoring was conducted in the participants' free-living environment. PARTICIPANTS: Convenience sample of ambulatory children (N=15; 11 boys, 4 girls) aged 5 to 17 years with CP undergoing gait analysis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Accuracy of the AM for sitting/lying time, upright time, stepping time, and strides taken. Daily volumes of F-LPA of children with CP. RESULTS: AM outcomes in comparison with video-based analysis were (mean +/- SD) 97.4%+/-2.7%, 101.1%+/-1.5%, 99.5%+/-6.6%, 105.6%+/-15.8%, and 103.8%+/-10.1% for sitting/lying time, upright time, standing time, stepping time, and stride count, respectively. Participants' daily F-LPA demonstrated considerable variation: mean standing time +/- SD, 2.33+/-.96h/d; mean stepping time +/- SD, 1.68+/-.86h/d; mean steps per day +/- SD, 8477+/-4528; and mean sit to-stand transitions per day +/- SD, 76+/-49. Laboratory-measured cadence and mobility level were related to F-LPA, but not directly. CONCLUSIONS: The AM demonstrated excellent ability to determine sitting/lying and upright times in children with CP. Stepping time and stride count had lower levels of agreement with video-based analysis but were comparable to findings in previous studies. Crouch gait and toe walking had an adverse effect on outcomes. The F-LPA data provided additional information on children's performance not related to laboratory measures, demonstrating the added value of using this objective measurement technique. PMID- 23924441 TI - Simulations of anionic lipid membranes: development of interaction-specific ion parameters and validation using NMR data. AB - Overbinding of ions to lipid head groups is a potentially serious artifact in simulations of charged lipid bilayers. In this study, the Lennard-Jones radii in the CHARMM force field for interactions of Na(+) and lipid oxygen atoms of carboxyl, phosphate, and ester groups were revised to match osmotic pressure data on sodium acetate and electrophoresis data on palmitoyloleoyl phosphatidylcholine (POPC) vesicles. The new parameters were then validated by successfully reproducing previously published experimental NMR deuterium order parameters for dimyristoyl phosphatidylglycerol (DMPG) and newly obtained values for palmitoyloleoyl phosphatidylserine (POPS). Although the increases in Lennard Jones diameters are only 0.02-0.12 A, they are sufficient to reduce Na+ binding, and thereby increase surface areas per lipid by 5-10% compared with the unmodified parameters. PMID- 23924442 TI - Binational outbreak of Guillain-Barre syndrome associated with Campylobacter jejuni infection, Mexico and USA, 2011. AB - In June 2011, a cluster of suspected cases of Guillain-Barre syndrome (GBS), which can follow Campylobacter jejuni infection, was identified in San Luis Rio Colorado (SLRC), Sonora, Mexico and Yuma County, Arizona, USA. An outbreak investigation identified 26 patients (18 from Sonora, eight from Arizona) with onset of GBS 4 May-21 July 2011, exceeding the expected number of cases (n = 1 2). Twenty-one (81%) patients reported antecedent diarrhoea, and 61% of 18 patients tested were seropositive for C. jejuni IgM antibodies. In a case-control study matched on age group, sex, ethnicity, and neighbourhood of residence, all Arizona GBS patients travelled to SLRC during the exposure period vs. 45% of matched controls (matched odds ratio 8.1, 95% confidence interval 1.5-infinity). Exposure information and an environmental assessment suggested that GBS cases resulted from a large outbreak of C. jejuni infection from inadequately disinfected tap water in SLRC. Binational collaboration was essential in investigating this cross-border GBS outbreak, the first in mainland North America since 1976. PMID- 23924443 TI - Periocular cutaneous anthrax in Jimma Zone, Southwest Ethiopia: a case series. AB - BACKGROUND: Anthrax is a zoonotic disease caused by Bacillus anthracis. Naturally occurring human infection is rare and is generally the result of contact with anthrax-infected animals or animal products. CASE PRESENTATION: We examined three patients who had contact with presumed anthrax-infected animal and/or its product and presented with preseptal cellulitis with a localized itchy erythematous papule of the eyelid and non-pitting periorbital edema, followed by ulceration and dark eschar formation. All the three patients responded to intravenous antibiotics, and the lesion resolved leaving scars which caused cicatricial ectropion in all cases. CONCLUSION: Anthrax is a rare disease but should be considered in the differential diagnosis of ulcerative (and eschar forming) preseptal cellulitis with a history of contact with anthrax-infected animals or animal products. Furthermore, cicatrization of the eyelids, one of the sequelae of periocular cutaneous anthrax, should be addressed. Urgent case report to the local zoonotic disease and infection control body and other responsible authorities is recommended. PMID- 23924444 TI - Directing group assisted copper-catalyzed chemoselective O-aroylation of phenols and enols using alkylbenzenes. AB - By using alkylbenzenes as aroyl surrogates, copper(II) catalyzed chemoselective O aroylations of 1,3-dicarbonyl compounds and phenolic -OH ortho to carbonyl (-CHO, -COR) groups have been achieved. A dual mechanism operating in tandem for these transformations has been supported by a crossover experiment. PMID- 23924445 TI - Controversy of the prostate-specific antigen test era: should prostate cancer be detected and treated in all patients? PMID- 23924446 TI - Efficacy of immediate instillation combined with regular instillations of pirarubicin for Ta and T1 transitional cell bladder cancer after transurethral resection: a prospective, randomized, multicenter study. AB - BACKGROUND: Immediate intravesical instillation of chemotherapeutic agents after transurethral resection (TUR) of nonmuscle invasive transitional cell bladder cancer has recently been suggested and has been proven to decrease the tumor recurrence rate significantly. This study is to evaluate the efficacy and safety of immediate intravesical instillation combined with regular instillations of Pirarubicin (THP((r))) as prophylaxis compared to regular instillations only after TUR operation. METHODS: This was a prospective, randomized, multi-center, clinical study. Patients diagnosed with non-muscle invasive bladder cancer (Ta and T1) pathologically and suitable for TUR were enrolled randomly into two groups. In the study group, the patients received intravesical instillation within 24-hour post TURBT, followed by regular intravesical therapy using 30 mg/50 ml of THP((r)) once a week for 8 weeks, and then once a month to 1 year postoperatively Among the patients. In the control group, patients received regular instillation only. RESULTS: A total of 403 patients were enrolled into this study from 26 institutions in China. Among the potients, 210 were enrolled into the study group and 193 were enrolled into the control group. At the median follow-up of 18 months, the recurrence rate was 7.8% in the study group, significantly lower than that in the control group (14.3%; P = 0.042). Subgroup analysis showed that the recurrence rate in low and intermediate-risk patients was significantly lower in the study group (6.8%) than in the control group (14.0%; P = 0.047), although no significant differences were found in high-risk patients. CONCLUSION: One immediate dose of THP((r)) 30 mg after TURBT followed by regular intravesical therapy appears well tolerated and more effective than regular intravesical therapy for preventing tumor recurrence, especially in low and intermediate-risk patients. PMID- 23924447 TI - Marginal living donor in kidney transplantation: experience in a Chinese single center. AB - BACKGROUND: Living donor kidney transplantation is becoming popular in China, whereas, in clinical situations, some kidney donors may be sub-optimal, namely marginal living donor. The present study aimed to evaluate the safety and efficacy of marginal living donor kidney transplantation in a Chinese single center. METHODS: Between January 2001 and December 2009, 888 kidney transplantations were performed in our center; 149 were living donor kidney transplantations. The living donors and recipients were followed up regularly after the operation. Of the living donors, 30 donors were marginal, who were older than 60 years or suffered from kidney anomaly or some benign diseases. Among the non-marginal living kidney transplantations, 58 donors and recipients had complete perioperative and follow-up data. We compared the marginal and non marginal living donor kidney transplantations with regard to donor age, follow-up period, donor's serum creatinine at the last follow-up, recipient's serum creatinine at the last follow-up, and graft survival at the last follow-up. RESULTS: The mean age of donors in the marginal and non-marginal living donors were (55 +/- 9) (37-66) and (43 +/- 12) (30-59) years. The mean follow-up times of the marginal and non-marginal groups were (26.4 +/- 13.4) months and (28.8 +/- 14.8) months. The donor and recipient serum creatinine levels at the last follow up were (1.16 +/- 0.20) mg/dl and (1.30 +/- 0.24) mg/dl in the marginal group, and (1.12 +/- 0.32) mg/dl and (1.34 +/- 0.32) mg/dl in the non-marginal group. Three recipients in the marginal group and five recipients in the non-marginal group had acute rejection episodes during the first year. Actuarial 3-year graft survival was 96.7% in the marginal group and 100% in the non-marginal group. No significant differences were detected between the two groups with regard to these data. CONCLUSION: Utilization of highly selective marginal living donors can be a safe, feasible, and effective way for the treatment of patients with end stage renal disease. PMID- 23924448 TI - Anti-human leukocyte antigens and anti-major histocompatibility complex class I related chain A antibody expression in kidney transplantation during a four-year follow-up. AB - BACKGROUND: Humoral immunity is an important factor for long-term survival of renal allograft. Here we performed a four-year follow-up to explore the clinical significance of monitoring anti-human leukocyte antigens (HLA) and anti-major histocompatibility complex class I-related chain A (MICA) antibody expression after kidney transplantation. METHODS: We obtained serial serum samples from 84 kidney transplant patients over a four-year period. All patients were followed up at least 6 months after transplantation and had at least two follow-up points. Anti-HLA and anti-MICA antibody titres and serum creatinine (SCr) levels were evaluated at each follow-up. Patients were divided into 4 groups: HLA(+) MICA(-), HLA(-)MICA(+), HLA(+)MICA(+) and HLA(-)MICA(-). The impact of post-transplant antibody level on kidney allograft function was evaluated. RESULTS: Antibodies were detected in 38.1% (32/84) of the renal allograft recipients. HLA, MICA and HLA+MICA expression was observed in 18.89%, 14.44% and 5.93% of the recipients respectively. The most frequent anti-HLA and anti-MICA specific antibodies identified were A11, A24, A29, A32, A33, A80; B7, B13, B37; DR17, DR12, DR18, DR52, DR53, DR1, DR4, DR9, DR51; DQ7, DQ4, DQ8, DQ2, DQ9, DQ5, DQ6 and MICA02, MICA18, MICA19, MICA07, MICA27. As the time after transplantation elapsed, more recipients developed de novo antibody expression. Total 11.91% (10/84) of the recipients had de novo antibody expression during the follow up. The average level of SCr and the percentage of recipients with abnormal allograft function were significantly higher in recipients with anti-HLA and/or anti-MICA antibody expression than those without. The appearance of anti-HLA and anti-MICA antibody expression always preceded the increase in SCr value. CONCLUSIONS: Anti-HLA and anti-MICA antibody expression has predictive value for early and late allograft dysfunction. The presence of donor specific antibody is detrimental to graft function and graft survival. PMID- 23924449 TI - Matrix-assisted laser desorption/ionization time of flight mass spectrometry in the genetic basis of systemic lupus erythematosus and the complicating kidney injury. AB - BACKGROUND: It is necessary to develop some innovative methods to reveal and discover the novel (SLE)-related protein molecules. In the present study, matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) was employed to detect the differential expression of serum polypeptides in the patients with systemic lupus erythematosus (SLE) presenting with a family history or complicating with kidney injury so as to identify the proteins associated with the genetic factors and kidney injury in SLE. METHODS: The subjects recruited were divided into four groups, that is, a group of SLE patients with both family history and kidney injury, a group of SLE patients with only kidney injury but no family history, a group of SLE patients with neither family history nor kidney injury, and a control group consisting of healthy volunteers. By adopting MALDI-TOF MS analysis, the serum samples obtained from the three groups of SLE patients were examined and compared with those from the control group; the categorized peptide fingerprint profile was established via the biological data collected from the samples. RESULTS: The expression of protein with a m/z of 4207 Da increased significantly in SLE patients; the protein with a m/z of 2658 Da was expressed in all SLE patients; three proteins (with m/z of 1465, 5332, and 5900 Da respectively) were expressed in the SLE patients complicated with kidney injury and the protein with a m/z of 1943 Da was expressed in SLE patients with family history. CONCLUSION: A number of differential proteins were successfully detected and identified through MALDI-TOF MS detection and these proteins may be associated with the genetic basis of SLE and the complicating kidney injury. PMID- 23924450 TI - Evaluation of efficacy and safety of sunitinib regimen in 22 patients with metastatic renal cell carcinoma: at least 12-month follow-up. AB - BACKGROUND: Sunitinib has been proved an effective new option for treatment of metastatic renal cell carcinoma (mRCC). Analysis of clinical data of 22 patients, who were exposed to sunitinib for at least 1 year, was conducted to evaluate the long-term efficacy and safety of sunitinib for the treatment of mRCC. METHODS: A total of 54 patients with mRCC were treated with sunitinib malate, 50 mg/d orally, on a 4-weeks-on and 2-weeks-off dosing schedule in Peking University First Hospital. Treatment continued until disease progression, unacceptable adverse events (AEs), or death. Among them, 22 patients continued treatment for at least 1 year. The clinical data of these 22 patients were prospectively collected for analysis. AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0. Tumor response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors. RESULTS: Median progression-free survival was 19.5 months until last follow-up. The best efficacy results achieved were complete response, partial response, and stable disease for 2, 9, and 11 patients, respectively. Objective response rate was 50%. The most common AEs were hand-foot syndrome (95%) and hypertension (91%). Other common AEs were thyroid-stimulating hormone elevation (82%), platelet decrease (77%), and loss of appetite (77%). Only one patient withdrew from treatment for cardiac infarction. Another nine patients experienced dose modifications or short-term suspensions. CONCLUSION: Long-term exposure to sunitinib malate showed encouraging efficacy in the treatment of mRCC. At the same time, the tolerability was good. PMID- 23924451 TI - Differences in willingness to donate cadaveric organ between young donor families and adult donor families: evidence from the Hunan Province, China. AB - BACKGROUND: The Red Cross of China and Ministry of Health jointly started a pilot program of organ donation after cardiac death to overcome the shortage of available organs since 2010. The purpose of this qualitative study were to compare the consent rate of organ donation between young donor families and adult donor families; to explore and determine factors associated with differences in willingness to donate organs between them. Research objective was to provide a rationale for further preparation of professionals involved in this sensitive work. METHODS: Between March 2010 and June 2012, 24 young deceased patients including donors and non-donors and 96 potential adult donors were collected, and consent rates of young donors' families and adult donors' families were calculated. A chi(2) test analysis to compare the consent rates of the two groups was conducted. We studied through semistructured interviews 15 parents of young donors and 15 relatives of old donors who were interviewed for petition of consent. Data collection and analysis of the overall study were performed according to the grounded theory methodology. Factors that influenced the families' decisions were identified and classified. We found the differences in willingness to donate organs between the two groups. RESULTS: The consent rate of young donor families was 66.67%, while the consent rate of adult donor families was 26.04%. Young donor families easily consented to organ donation than adult donor families (P < 0.005). The donors' families had been affected by various factors throughout the process of deciding to give consent for donation. The findings led to the formulation of an empirically based model of interlinking categories that influence families' decision-making process in organ donation. These factors are grouped into five main categories: (1) personal factors, (2) conditions of organ request, (3) interpersonal factors, (4) ethical factors, and (5) traditional views. The funeral tradition influenced the young donor parents' consent to donation, but had no relation with family decision of adult donors. And the family members of young donors are relatively less, who are more likely to reach a consensus. CONCLUSIONS: Young donor families influenced by traditional funeral beliefs are easier to consent to organ donation than adult donor families. Family members of young donors are relatively less who are more likely to reach a consensus. Acceptance of the expanded criteria donors may improve the organ donation rates, especially those of the advanced age. PMID- 23924452 TI - Antitumor effects of mutant endostatin are enhanced by Bcl-2 antisense oligonucleotides in UM-UC-3 bladder cancer cell line. AB - BACKGROUND: Endostatin is a potent inhibitor of tumor angiogenesis. In the preliminary studies, we developed a mutant endostatin containing Arg-Gly-Asp-Arg Gly-Asp (RGDRGD) sequences. In this study, we compared the antitumor effects of mutant endostatin and Bcl-2 antisense oligonucleotides both in combination and individually. METHODS: The artificially synthesized Bcl-2 ASODN (antisense oligonucleotides) included a translation-initiation site and was transfected into the bladder cancer cells by Lipofectamine. Cell growth was investigated by the tumor cell growth chart, MTT assay, caspase-3 activity detection assay, AO/EB fluorescein stain, and the annexin V-FITC apoptosis detection assay. In the in vivo study, UM-UC-3 bladder cancer cells were subcutaneously implanted into nude mice and the growth of tumor was examined. The ultrastructure of the tumor tissues in the treated and control groups were observed. RESULTS: The cell growth chart showed that the cell population of the treated combination group decreased by 52.04% compared to the control group. The inhibition rate of the treated combination group was (79.66 +/- 6.79)%, whereas those of the individual ASODN and ES groups were (53.39 +/- 3.22)% and (50.22 +/- 5.46)% respectively. In the caspase-3 activity detection using AO/EB fluorescein stain and annexin V-FITC apoptosis detection assay, the co-inhibitory effect was higher than the individual inhibitory effects (P < 0.05). There were significant differences in the inhibition of the solid tumor growth in the in vivo study. CONCLUSIONS: Our findings indicated that Bcl-2 antisense oligonucleotides enhance the antitumor effects of mutant endostatin both in vitro and in vivo. We noted the synergistic effects of Bcl-2 antisense oligonucleotides combined with mutant endostatin. PMID- 23924453 TI - Efficacy evaluation for the treatment of unstable lumbar disc herniation by traditional and modified lamina osteotomy replantation. AB - BACKGROUND: The traditional lamina osteotomy replantation method is prone to nerve root injury and low back pain recurrence. Our team has proposed a modified approach that improves the osteotomy site and its fixation procedure. The aim of this study was to evaluate the clinical efficacy of traditional and modified lamina replantation methods in treating unstable lumbar disc herniation. METHODS: From March 2008 to August 2011, 124 patients with unstable lumbar disc herniation were enrolled and randomly divided into the following two groups according to random digital table: group A (traditional group) consisting of 61 patients who underwent traditional laminectomy replantation, and group B (modified group) consisting of 63 patients who underwent modified lamina replantation. Both surgeries were performed by the same surgeons. The two groups had no significant difference in gender, age, symptoms, time of onset and the prominent segment. Visual analogue scale (VAS), Oswertry disability index (ODI), and Japanese Orthopaedic Association (JOA) scores, operative time, blood loss, complication rate, radiographic healing rates, and low back pain recurrence rates were compared between the two groups. RESULTS: There were 121 patients followed up for more than one year, and the follow-up rate was 97.6%. Nerve injury occurred in two patients (3.3%) in the modified group and 12 patients (20.0%) in the traditional group. Dural injury occurred in one patient (1.6%) in the modified group and seven patients (11.7%) in the traditional group. Pseudarthrosis occurred in two patients in the modified group and in 18 patients in the traditional group with 1-year fusion rates of 96.7% and 70.0%, respectively. Recurrence of lower back pain after one year was noted in three patients (4.9%) in the modified group, and in 15 (25.0%) in the traditional group. Leg pain recurrence was noted in one patient (1.6%) in the modified group and in three cases (5.0%) in the traditional group. The one-year healing rates of nerve injury, dural injury, replantation lamina and low back pain recurrence rates after one year were significantly different (P < 0.05) between the two groups. At two weeks, three months, six months and one year postoperatively, both groups had significant improvement in VAS, ODI, and JOA scores from their preoperative values (P < 0.05). No significant difference was detected between the short term postoperative scores between groups A and B (P > 0.05). However, a significant difference was found one year later (P < 0.05). CONCLUSIONS: Compared to the traditional approach, the modified technique for lamina replantation showed lower rates of dural and nerve damage, a higher lamina healing rate, a lower back pain recurrence rate, and better clinical scores. It is a safe and effective operation for lumbar spine surgery. PMID- 23924454 TI - Effect of a combination of local flap and sequential compression-distraction osteogenesis in the reconstruction of post-traumatic tibial bone and soft tissue defects. AB - BACKGROUND: Treatment of extensive post-traumatic composite bone and soft tissue defects remains a complicated therapeutic problem and a challenge for surgeons. We investigated the application of local flaps and Ilizarov osteogenesis in the reestablishment of severe combined defects of tibial bone and soft tissue. METHODS: Sixteen patients with bone and soft tissue defects were included. The mean age of the patients was 31.5 years. The average time from injury to initial surgery was 14.4 weeks. The average soft tissue and bone defect sizes were 92.9 cm(2) and 8.7 cm, respectively. Local flaps were created to reconstruct the soft tissue defects. The Ilizarov external fixator or the Orthofix Limb Reconstruction System was used to reconstruct bony defects using delayed distraction osteogenesis. RESULTS: Two myocutaneous flaps and 14 reverse island flaps were applied. All transferred flaps survived. Fifteen patients healed with equal leg length, and one healed with a residual leg-length discrepancy of 1.5 cm. One patient with an Ilizarov external fixator developed ankle joint stiffening and a pin-track infection that was successfully treated with oral antibiotics. No patient developed pin loosening. All patients walked without assistance. Fifteen patients returned to their work, and one lost her job. The results were evaluated using the Paley bone and functional assessment scores. The bone assessment results were excellent in 14 and good in two patients. Functional assessment scores were excellent in 13, good in two, and fair in one patient. CONCLUSION: The combination of local flaps and sequential distraction osteogenesis can be used for successful reconstruction of defects of incorporated bone and soft tissue. PMID- 23924455 TI - Formative mechanism of intracanal fracture fragments in thoracolumbar burst fractures: a finite element study. AB - BACKGROUND: Thoracolumbar burst fracture is a common clinical injury, and the fracture mechanism is still controversial. The aim of this research was to study the formation of intracanal fracture fragments in thoracolumbar burst fractures and to provide information for the prevention of thoracolumbar bursts fractures and reduction of damage to the nervous system. METHODS: A nonlinear three dimensional finite element model of T11-3 segments was established, and the injury processes of thoracolumbar bursts were simulated. The intact finite element model and the finite element model after the superior articular were impacted by 100 J of energy in different directions. The distribution and variation of stress in the superior posterior region of the L1 vertebral body were analyzed. Abaqus 6.9 explicit dynamic solver was used as finite element software in calculations. RESULTS: A three-dimensional nonlinear finite element model of the thoracolumbar spine was created. In the intact model, stress was concentrated in the superior posterior region of the L1 vertebral body. The stress peak was a maximum for the extension impact load and a minimum for the flexion impact load. The stress peak and contact force in the facet joint had close correlation with time. The stress peak disappeared after excision of the superior articular process. CONCLUSIONS: The three-dimensional nonlinear finite element model was suitable for dynamic analysis. The contact force in the facet joint, which can be transferred to the superior posterior vertebral body, may explain the spinal canal fragment in thoracolumbar burst fractures. PMID- 23924456 TI - Prehospital road traffic injuries among the elderly in Beijing, China: data from the Beijing Emergency Medical Center, 2004-2010. AB - BACKGROUND: Road traffic injuries (RTIs) are a worldwide issue associated with increasing development and motorization. However, statistical studies do not include any analyses of Beijing's geriatric population. Using data from the Beijing Emergency Medical Center, we present the main characteristics of traffic injuries involving the elderly in Beijing. We also provide objective information for those concerned with the safety of traffic systems and the prevention of traffic injuries. METHODS: In a longitudinal, retrospective study, data were collected on 1706 victims aged 65 years and older who sustained traffic injuries in Beijing between 2004 and 2010. Personal information, time of injury event, emergency care response time, road user type, striking vehicle type, injury site, and severity of injury were analyzed using chi(2) tests and Logistic regression analysis. RESULTS: The annual rate of traffic injuries was 21.80 per 100 000 elderly people in Beijing, and the morbidity rate decreased from 2004 to 2010 (P < 0.001). The mean age was (72.92 +/- 5.67) years, and 911 (53.40%) of the victims were male. The majority of victims sustained head and lower limb injuries and were classified as being of medium severity. Traffic collisions occurred most frequently in the daytime excluding rush hours; these collisions included being hit by a car (85.64%) and pedestrian victim injuries (79.19%). Our statistical analysis found three factors for injury severity: abdominal injuries (P < 0.001), number of injury sites (P = 0.027), and head injuries (P = 0.034). The decline in traffic injuries is due to a decrease in victims aged 65-74 years and pedestrians; the severity of RTIs also decreased. CONCLUSIONS: This study highlights the declining trend in traffic injuries among older adults in Beijing. However, traffic injuries remain a serious public health problem for the elderly and effective measures are required to reduce their incidence. PMID- 23924457 TI - Surgical closure of apical multiple muscular septal defects via right ventriculotomy using a single patch with intermediate fixings. AB - BACKGROUND: Multiple apical muscular ventricular septal defects (VSDs) remain a challenge for surgeons because of their anatomical features. We used single patch with intermediate fixations to repair multiple apical muscular VSDs through right ventriculotomy. METHODS: We analysed the data of 16 children (median age 8 months, range 2 months to 144 months) with multiple apical muscular VSDs who underwent a single patch technique via apical right ventriculotomy. Perioperative data were collected and analysed, and the patients were followed up for three months to 66 months (median, 46 months) to investigate the outcomes. RESULTS: All patients recovered from cardiopulmonary bypass easily with median of cardiopulmonary bypass time 87 minutes and of aortic crossclamp time 53 minutes. No surgically related death occurred and no patient required reoperation. One patient died of pseudomonas pyocyanea infection on day 11 postoperatively. Residual shunt happened in one patient with a diameter of 2 mm and spontaneously closed in 12 months after operation. Two patients presented slightly reduced right ventricular volume and apical hypokinesia postoperatively and recovered 24 and 36 months later respectively. No other complication was found during the three months to 66 months follow-up. CONCLUSION: Our experiences using a single patch technique with intermediate fixations via right ventriculotomy in the management of multiple muscular VSDs had favourable outcomes. PMID- 23924458 TI - Congenital symbrachydactyly: outcomes of surgical treatment in 120 webs. AB - BACKGROUND: Symbrachydactyly is defined as a combination of short fingers with syndactyly. There are few published reports estimating the incidence of symbrachydactyly. The aim of this study was to investigate the clinical features and the outcome of surgical treatment for congenital symbrachydactyly. METHODS: One hundred and twenty webs of thirty-four patients of symbrachydactyly were involved in the study. The sex ratio was 21 males/13 females. The age ranged from 1 year to 8 years, average 2.6 years. Four cases had both hands involved and 30 patients had one hand involvement. Release of the syndactylous digits webs were completed by one surgical procedure in 14 cases and more than one surgical procedure in 20 cases; 3 to 6 months between the procedures. In the meantime, some of the associated hand deformities were treated. RESULTS: Postoperative follow-up time was 10 to 18 months, average 12 months. All the fingers involved in this study were separated successfully. However, 6 fingers had scar tissue contracture and 8 had web scar adhesion. All complications needed further surgical treatment. Parents of 94.1% of the patients were satisfied with the overall function of the hand, and 76.5% were satisfied with the cosmetic appearance of hand. CONCLUSIONS: The combination of syndactyly and brachydactyly is the main clinical feature in symbrachydactyly. Separation of the digital webs can greatly improve the function of the hand. However, more work needs to be done to improve the cosmetic appearance of the hand. PMID- 23924459 TI - Psychological trauma of funnel chest in adolescents and the appropriate age for minimally invasive surgery repair. AB - BACKGROUND: Funnel chest has a negative effect on adolescents and it has a strong effect on adolescents' psychological and behavior. This study aimed to investigate the psychological characteristics and factors that affect adolescents with funnel chest and to evaluate the relationship between the patients' age and their physiological and psychological health. We aimed to establish an age model for maximum surgery benefits for funnel chest patients to provide an objective basis for choosing surgery. METHODS: The study adopted a general evaluation approach to assess the risk and benefits of minimally invasive surgery for funnel chest. The funnel chest index, the Symptom Checklist-90, and the Eysenck Personality Questionnaire were used as assessment tools to observe physiological and psychological features in funnel chest patients. A sample of 234 adolescents with funnel chest was selected from a third-grade class-A hospital in Beijing. Age groups were adopted as an independent variable, and other factors in funnel chest patients were dependent variables. RESULTS: There was a significant difference in the relapse rate for funnel chest in the different age groups (chi(2) = 11.883, P = 0.008). There was a higher relapse rate in patients of <=10 or >=19 years old than in patients of 11-18 years old. There was a significant difference in the SCL-90 total score in the different age groups (F = 12.538, P = 0.0001), the patients older than 13 years had a higher score than those younger than 13 years in the SCL-90. There was a significant difference in the standard score of E (introversion/ extraversion) in the different age groups (F = 10.06, P = 0.0001). There was also a significance in the funnel chest index before surgery in the different psychological scales (P < 0.01), with a higher funnel chest index score associated with more obvious psychological trauma. Age and the number of variables, including the relapse rate, SCL-90 score, standard score of E, and standard score of N in the EPQ were significantly correlated (correlation indices were 0.402, 0.623, -0.505, and 0.473, respectively, P < 0.01). CONCLUSIONS: There are higher complication rates after surgery and relapse rates when funnel chest patients are too young or too old. There is more obvious psychological trauma in patients with a high funnel chest index. Our results indicate that the best age for surgery for funnel chest is 14-16 years. PMID- 23924460 TI - Relationship between magnetic resonance imaging features and miRNA gene expression in patients with glioblastoma multiforme. AB - BACKGROUND: Magnetic resonance imaging (MRI) is commonly utilized as part of the diagnostic workup for the clinical diagnosis of glioblastoma multiforme (GBM), further guiding the clinical treatment of this aggressive cancer. Recent research has shown that microRNAs (miRNAs) may act as oncogenes, or in some cases, tumor suppressor genes that in turn may reflect the genotypic features of GBM. This study aimed to investigate the relationship between MRI features and miRNA gene expression in patients with glioblastoma multiforme. METHODS: In order to identify the relationship between the radiographic findings of MRI and those identified changes in miRNA gene expression of GBM, we reviewed the MRI images of GBM patients and compared them with the identified miRNA expression profiles utilizing microarray analysis of paired GBM tumor samples. We chose five MRI imaging features: (1) contrast tumor enhanced/necrosis ratio, (2) contrast tumor enhanced/T2 ratio, (3) multiple lesions, (4) hemorrhage, and (5) necrotic volume. The relationship between these five imaging features and miRNA expression was studied using significance analysis of microarrays analysis. RESULTS: We found that the expression of miRNAs such as hsa-miR-892b, hsa-miR-892a, and hsa-miR-888 was inversely correlated with an enhanced/necrosis ratio >= 1. The miRNAs such as hsa-miR-95, hsa-miR-498, and hsa-miR-1300 were associated with a contrast tumor enhanced/T2 ratio >=1. The miRNAs such as hsa-miR-612, hsa-miR-524-3, and hsamiR 1282 were associated with multiple lesions identified on MRI and the expression of miR-221 was associated with hemorrhage by GBM. The expression of miR-let-7, including miR-let-7f, miR-let-7i, and miR-let-7f-1*, was downregulated in the hemorrhage group. The gene expression of miRNAs such as hsa-miR-140-5p, hsa-miR 30e, and hsa-miR-301a was relatively low when compared with the larger necrotic volume group as identified by MRI. CONCLUSIONS: The miRNA gene expression profiles correlate with several selected MRI features of patients with GBM. Further analysis of key imaging features of MRI with correlation with miRNA gene expression patterns may help to guide treatment decisions based on these unique correlative profiles of GBM. PMID- 23924461 TI - Nonlinear dynamics of electroencephalography study in schizophrenic patients. AB - BACKGROUND: Few characteristic changes of linear electroencephalograph (EEG) have been reported in schizophrenia. The aim of the present study was to investigate the changes in temporal-spatial dimensional properties of EEG under different cognitive tasks in patients with schizophrenia. METHODS: EEG was recorded by using EEG-1518K system and mapping system (Nihon Kohden Tomioka Corporation, Japan) in 45 schizophrenic patients and 47 healthy adults (normal control, NC) under five states: eyes closed, eyes open, mental arithmetic test with eyes closed, memory test with eyes open, and number cancellation test. Correlation dimension (D2) and point-wise correlation dimension (PD2) were calculated for all EEG analyses. RESULTS: (1) There were no significant differences of D2 and PD2 between NC and schizophrenic patients under states of eyes open and closed. (2) Compared with NC, schizophrenic patients showed decreased performance of D2 in mental arithmetic test with eyes closed and number cancellation test (mental arithmetic test with eyes closed: Nc 5.9 +/- 0.6, Sch 3.0 +/- 0.8; number cancellation test: Nc 6.0 +/- 0.6, Sch 4.4 +/- 0.7; P < 0.05 or P < 0.01). (3) Schizophrenic patients also showed decrease performance of PD2 in mental arithmetic test with eyes closed, memory test with eyes open, and number cancellation test (mental arithmetic test with eyes closed: Nc 6.9 +/- 0.7, Sch 4.0 +/- 0.8; memory test with eyes open: Nc 6.6 +/- 0.8, Sch 5.0 +/- 0.9; number cancellation test: Nc 7.1 +/- 0.7, Sch 4.8 +/- 0.9; P < 0.05 or P < 0.01). CONCLUSIONS: Nonlinear dynamic analysis provided a new approach in clinical investigation of EEG signals. It was helpful to further understand the cerebral mechanism in schizophrenic cognitive process. PMID- 23924462 TI - Analysis of post-operative endophthalmitis after pars plana vitrectomy: a 10-year experience at a single center. AB - BACKGROUND: Endophthalmitis can be a devastating complication after pars plana vitrectomy. The incidence of postvitrectomy endophthalmitis is significantly lower than that of endophthalmitis occurring after other intraocular operations. However, normal post-operative pain and inflammation may mask endophthalmitis and lead to delayed diagnosis and grave visual consequences. This study aimed to summarize the outcomes of cases that underwent pars plana vitrectomy over a 10 year period and to analyze the characteristics of post-vitrectomy endophthalmitis. METHODS: A retrospective observational case study was conducted on all the cases who underwent pars plana vitrectomy in the Beijing Tongren Hospital between January 1, 2002 and March 31, 2012. All cases of endophthalmitis that occurred during a period of 10 years and 3 months were reviewed, and the possible risk factors, clinical findings, causative organism(s), and the sources of infection were analyzed. RESULTS: Within the 10-year observational period, 14 patients developed endophthalmitis after pars plana vitrectomy. The incidence of post-vitrectomy endophthalmitis (0.05%) was lower than that reported previously from the same center (0.12%). Staphylococcus epidermidis (five patients, 35.71%) was the most common organism identified in aqueous or vitreous cultures. Eight patients (57.14%) had diabetes mellitus. There was no statistically significant difference (P > 0.05) in the incidence of endophthalmitis between period 1 (with antibiotic pretreatment) and period 2 (without antibiotic pretreatment). Surgical procedures for the treatment of endophthalmitis were performed in 10 patients (71.43%). CONCLUSIONS: This series of cases showed that the incidence of endophthalmitis after pars plana vitrectomy is lower than what was previously reported in our hospital. A variable degree of corneal edema with relatively normal or mildly increased intraocular pressure was one of the commonly observed characteristics of post-vitrectomy endophthalmitis. Staph. epidermidis was the most common causative organism, and antibiotic pretreatment did not lower the incidence of postvitrectomy endophthalmitis. PMID- 23924463 TI - Effects of plasma collected 48 hours after transient limb ischemia on blood pressure recovery in homogenic rats after myocardial ischemia reperfusion in vivo. AB - BACKGROUND: Whether plasma can transfer the protective effect(s) of remote ischemic preconditioning (RIPC) between animals remains unresolved. We therefore investigated the effects of plasma collected 48 hours after transient limb ischemia on blood pressure recovery during myocardial ischemia reperfusion (IR) in homogenic rats. METHODS: Plasma was collected from Lewis rats, and the donor rats were randomly assigned to 2 groups: transient limb ischemia and control (n = 8 each). Transient limb ischemia was achieved by four cycles of 5-minute ischemia and 5-minute reperfusion by noninvasive ligation and deligation of the both legs using elastic rubber bands after anesthesia. In the control group, no ligation was performed. Forty-eight hours later, whole blood was collected, and the plasma spun off. Study Lewis rats underwent 30-minute left anterior descending coronary artery occlusion followed by 180-minute reperfusion, and were randomly assigned to 2 groups (group A and group B, n = 24 each), each further subdivided into 3 subgroups (n = 8 each). The subgroups of group A received normal saline (group A1) , plasma of control rats (group A2), plasma of transient limb ischemia rats (group A3) respectively at 1 hour before IR; the subgroups of group B received normal saline (group B1), plasma of control rats (group B2), plasma of transient limb ischemia rats (group B3) respectively at 24 hours before IR. BIOPAC systems were used to measure hemodynamics of rats during myocardial ischemiareperfusion. RESULTS: Systolic blood pressure (SBP) after IR in group B3 was different from that in groups B1 and B2 (B3 vs. B1, P = 0.007; B3 vs. B2, P = 0.039) at the beginning of reperfusion and 30 minutes after reperfusion. SBP was higher in group B3 than in groups B1 and B2 at the beginning of perfusion (B3 vs. B1, P = 0.010; B3 vs. B2, P = 0.002) and 30 minutes after reperfusion (B3 vs. B1, P = 0.001; B3 vs. B2, P = 0.001). SBP did not differ among subgroups A1, A2 and A3. Diastolic blood pressure and heart rate did not change in group A or group B. CONCLUSIONS: The transfusion of plasma collected 48 hours after transient limb ischemia into homogenic rats 24 hours before IR can improve the SBP recovery during reperfusion. This may suggest that cardioprotective effect of late phase of RIPC is transferable via plasma. PMID- 23924464 TI - Assessment of arterial stiffness: combine the pieces of the puzzle. PMID- 23924465 TI - Efficiency of resource allocation in the hospital sector after global budgeting under National Health Insurance. AB - BACKGROUND: Taiwan has implemented a National Health Insurance (NHI) program to provide uniform comprehensive coverage since 1995. Forced by the severe financial deficit, global budgeting is introduced to replace the original payment system in Taiwan's NHI. Under global budgeting system, the total budget is distributed to six geographical regions in Taiwan. There is no pre-determined budget for each hospital. In order to investigate the longitudinal trend of how global budgeting influences health care resource, it is essential to estimate the efficiency of resource allocation in Taiwan's NHI. METHODS: Data Envelopment Analysis (DEA) and Malmquist index (MI) are used to investigate the 8-year panel data of 23 cities and counties which was collected from the annual report from the Department of Health, Taiwan, China. A value of MI greater than 1 indicates that total factor productivity progress has occurred, while a value of MI less than 1 indicates productivity loss. RESULTS: As a result, 37 of the 184 DMUs in the analysis were found to be relatively efficient during the period, in which 14 of 23 DMUs are efficient in 2002 right after adopting globe budgeting. A trend of MI declines between 2002 and 2009 implies the volume of health care services decrease after adopting global budgeting system. Production efficiency has been improved after global budgeting implies that behaviors of health providers control cost and avoid wasting resource at macro level. CONCLUSIONS: The regressive MI indicates the hospitals redistribute health care resource to eliminate unnecessary treatment and to control the growth of service volume under global budgeting system. Hence, a trend of declining MI focuses on health care resource redistribution rather than efficiency improvement in this study. PMID- 23924466 TI - Glycosylation of recombinant human thyroid peroxidase ectodomain of insect cell origin has little effect on recognition by serum thyroid peroxidase antibody. AB - BACKGROUND: Thyroid peroxidase (TPO) is an important autoantigen in Hashimoto's thyroiditis (HT), and almost all epitopes are located in TPO ectodomain. The glycosylation of TPO might contribute to breaking self-tolerance, therefore, purified glycosylated recombinant TPO ectodomain is prerequisite of elucidating its role in the pathogenesis of HT. The aim of our study was to investigate whether the glycosylation has influence on the antigenic determinants of recombinant TPO. METHODS: Bac-to-Bac baculovirus expression system was used to generate recombinant human TPO ectodomain. The antigenicity was analyzed by antigen specific enzyme-linked immunosorbant assays (ELISAs). The glycosylation of recombinant human TPO ectodomain of High Five insect cell origin was detected by lectin-ELISAs. RESULTS: TPO ectodomain was recovered from the culture media as a soluble protein, and it was fused with a hexahistidine tag which allowed purification by nickel-affinity chromatography. The recombinant TPO ectodomain could be recognized by all the 54 HT patients and three TPO monoclonal antibodies. Fucose, sialic acid and galactose were all detected on the recombinant TPO ectodomain. Sera TPOAb binding decreased slightly after non specific deglycosylation of TPO by periodic acid. CONCLUSIONS: High Five insect cells derived recombinant human TPO ectodomain had N-glycosylation sites, which might have little effect on recognition by serum TPOAb. PMID- 23924467 TI - Abnormal intrinsic brain activity in amnestic mild cognitive impairment revealed by amplitude of low-frequency fluctuation: a resting-state functional magnetic resonance imaging study. AB - BACKGROUND: Previous studies have shown that brain functional activity in the resting state is impaired in Alzheimer's disease (AD) patients. However, alterations in intrinsic brain activity patterns in mild cognitive impairment (MCI) patients are poorly understood. This study aimed to explore the differences in regional intrinsic activities throughout the whole brain between aMCI patients and controls. METHODS: In the present study, resting-state functional magnetic resonance imaging (fMRI) was performed on 18 amnestic MCI (aMCI) patients, 18 mild AD patients and 20 healthy elderly subjects. And amplitude of low-frequency fluctuation (ALFF) method was used. RESULTS: Compared with healthy elderly subjects, aMCI patients showed decreased ALFF in the right hippocampus and parahippocampal cortex, left lateral temporal cortex, and right ventral medial prefrontal cortex (vMPFC) and increased ALFF in the left temporal-parietal junction (TPJ) and inferior parietal lobule (IPL). Mild AD patients showed decreased ALFF in the left TPJ, posterior IPL (pIPL), and dorsolateral prefrontal cortex compared with aMCI patients. Mild AD patients also had decreased ALFF in the right posterior cingulate cortex, right vMPFC and bilateral dorsal MPFC (dMPFC) compared with healthy elderly subjects. CONCLUSIONS: Decreased intrinsic activities in brain regions closely related to episodic memory were found in aMCI and AD patients. Increased TPJ and IPL activity may indicate compensatory mechanisms for loss of memory function in aMCI patients. These findings suggest that the fMRI based on ALFF analysis may provide a useful tool in the study of aMCI patients. PMID- 23924468 TI - Loss of p120 catenin aggravates alveolar edema of ventilation induced lung injury. AB - BACKGROUND: p120 catenin (p120ctn) is an adheren junction protein that regulates barrier function, but its role has not been explored in alveolar edema induced by ventilation. We measured stretch-induced cell gap formation in MLE 12 cells due to the loss of p120. We hypothesized that alveolar permeability was increased by high lung inflation associated with alveolar epithelia cell tight junctions being destroyed, which resulted from the loss of p120. METHODS: Cultured MLE12 cells were subjected to being stretched or un-stretched (control) and some cells were pretreated with pp2 (c-src inhibitor). After the end of stretching for 0, 1, 2, and 4 hours, the cells were lysed, and p120 expression and c-src activation was determined by Western blotting analysis. In vivo, SD rats were taken to different tidal volumes (Vt 7 ml/kg or 40 ml/kg, PEEP = 0, respiratory rate 30-40 betas/min) for 0, 1, 2, and 4 hour and some were pretreated with pp2, and alveolar edema was calculated. RESULTS: It was found that p120 expression was reduced and c-src activation increased in a time-dependent and strain-dependent manner due to cyclic-stretch of the alveolar epithelial cells. These changes could be reversed by inhibition of c-src. We obtained similar changes in rats when they were subjected to large tidal volumes and the alveolar edema increased more than in rats in the low Vt group. Pretreated the rats with inhibition of c src had less pulmonary edema induced by the high tidal volume ventilation. CONCLUSIONS: Cyclic stretch MLE 12 cells induced the loss of p120 and may be the same reason by high tidal volume ventilation in rats can aggravate alveolar edema. Maintenance of p120 expression may be a novel therapeutic strategy for the prevention and treatment of ventilation induced lung injury (VILI). PMID- 23924469 TI - Noise-induced nitrotyrosine increase and outer hair cell death in guinea pig cochlea. AB - BACKGROUND: Modern research has provided new insights into the biological mechanisms of noise-induced hearing loss, and a number of studies showed the appearance of increased reactive oxygen species (ROS) and reactive nitrogen species (RNS) during and after noise exposure. This study was designed to investigate the noise exposure induced nitrotyrosine change and the mechanism of outer hair cells death in guinea pig cochlea. METHOD: Thirty guinea pigs were used in this study. The experimental animals were either exposed for 4 hours per day to broadband noise at 122 dB SPL (A-weighted) for 2 consecutive days or perfused cochleae with 5 mg/ml of the SIN1 solutions, an exogenous NO and superoxide donor, for 30 minutes. Then the cochleae of the animals were dissected. Propidium iodide (PI), a DNA intercalating fluorescent probe, was used to trace morphological changes in OHC nuclei. The distribution of nitrotyrosine (NT) in the organ of Corti and the cochlear lateral wall tissue from the guinea pigs were examined using fluorescence immunohistochemistry method. Whole mounts of organ of Corti were prepared. Morphological and fluorescent changes were examined under a confocal microscope. RESULTS: Either after noise exposure or after SIN1 perfusion, outer hair cells (OHCs) death with characteristics of both apoptotic and necrotic degradation appeared. Nitrotyrosine immunolabeling could be observed in the OHCs from the control animals. After noise exposure, NT immunostaining became much greater than the control animals in OHCs. The apoptotic OHC has significant increase of nitrotyrosine in and around the nucleus following noise exposure. In the normal later wall of cochleae, relatively weak nitrotyrosine immunolabeling could be observed. After noise exposure, nitrotyrosine immunoactivity became stronger in stria vascularis. CONCLUSION: Noise exposure induced increase of nitrotyrosine production is associated with OHCs death suggesting reactive nitrogen species participation in the cochlear pathophysiology of noise-induced hearing loss. PMID- 23924470 TI - A preliminary study of imaging paclitaxel-induced tumor apoptosis with (99)Tc(m) His10-Annexin V. AB - BACKGROUND: In tumors the process of apoptosis occurs over an interval of time after chemotherapy. It is important to determine the best time for detecting apoptosis by in vivo imaging. In this study, we evaluated the dynamics and feasibility of imaging non-small cell lung cancer (NSCLC) apoptosis induced by paclitaxel treatment using a (99)Tc(m)-labeled Annexin V recombinant with ten consecutive histidines (His10-Annexin V) in a mouse model. METHODS: (99)Tc(m) His10-Annexin V was prepared by one step direct labeling; radio-chemical purity (RCP) and radio-stability was tested. The binding of (99)Tc(m)-His10-Annexin V to apoptotic cells was validated in vitro using camptothecin-induced Jurkat cells. In vivo bio-distribution was determined in mice by dissection. The human H460 NSCLC tumor cell line (H460) tumor-bearing mice were treated with intravenous paclitaxel 24, 48 and 72 hours later. (99)Tc(m)-His10-Annexin V was injected intravenously, and planar images were acquired at 2, 4 and 6 hours post-injection on a dual-head gamma camera fitted with a pinhole collimator. Tumor-to-normal tissue ratios (T/NT) were calculated by ROI analysis and they reflected specific binding of (99)Tc(m)-His10-Annexin V. Mice were sacrificed after imaging. Caspase 3, as the apoptosis detector, was determined by flow cytometry, and DNA fragmentation was analyzed by the terminal deoxynucleotidytransferase mediated dUTP nick-end labeling (TUNEL) assay. Nonspecific accumulation of protein was estimated using bovine serum albumin (BSA). The imaging data were correlated with TUNEL-positive nuclei and caspase-3 activity. RESULTS: (99)Tc(m)-His10-Annexin V had a RCP > 98% and high stability 2 hours after radio-labeling, and it could bind to apoptotic cells with high affinity. Bio-distribution of (99)Tc(m)-His10 Annexin V showed predominant uptake in kidney, relatively low uptake in myocardium, liver and gastrointestinal tract, and rapid clearance from blood and kidney was observed. The T/NT was significantly increased after paclitaxel treatment, whereas it was low in untreated tumors (T/NT = 1.43 +/- 0.18). The %ID/g activity in Group 2 (24 hours), Group 3 (48 hours) and Group 4 (72 hours) after treatment was 2.55 +/- 0.73, 3.35 +/- 1.10, and 3.4 +/- 0.96, respectively. Whereas in the non-treated group, Group 1, %ID/g was 1.10 +/- 0.18. The radiotracer uptake was positively correlated to the apoptotic index (r = 0.852, P < 0.01), as well as caspase-3 activity (r = 0.816, P < 0.01). CONCLUSION: This study addresses the dynamics and feasibility of imaging non-small cell lung tumor apoptosis using (99)Tc(m)- His10-Annexin V. PMID- 23924471 TI - Neuroprotective effect of AG490 in experimental traumatic brain injury of rats. AB - BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability in children and young adults worldwide. Therefore, we investigated the role of AG490 in regulating brain oedema, expression of CD40 and neurological function after TBI. METHODS: Sprague Dawley rats (n = 240) were randomly divided into a sham operation group, TBI+saline group and TBI+AG490 (JAK/STAT inhibitor) group. Members of each group were euthanized at 6, 12, 24 or 72 hours after injury. Neurological severity score (NSS) was used to evaluate the severity of neurological damage. Brain water was quantitated by wet/dry weight method. The expression of CD40 was assessed by flow cytometry. RESULTS: In both the TBI+saline group and the TBI+AG490 group, the brain water content was elevated after TBI, reached a peak at 24-hour and remained high for the rest of the period investigated; the expression of CD40 reached a peak 24 hours after TBI; the NSS was elevated after TBI and then decreased after 6 hours. Elevations in the level of CD40, degree of brain edema and NSS after TBI were significantly reduced in TBI+AG490 group. CONCLUSION: Inhibition of the JAK/STAT signalling pathway reduces brain oedema, decreases the expression of CD40 and exerts neuroprotective effects after TBI. PMID- 23924472 TI - Long-term oncologic outcomes of laparoscopic versus open partial nephrectomy. AB - BACKGROUND: Most of the literatures on laparoscopic partial nephrectomy (LPN) versus open partial nephrectomy (OPN) focus on technical details and early or mid term oncologic outcomes, reflecting that the approach is safe and provides midterm benefits compared with traditional open surgery. However, the difference of long-term oncologic outcome between LPN and OPN remains unclear. The aim of this meta-analysis was to evaluate the long-term oncologic outcome of LPN in the treatment of localized renal tumors compared with that of OPN. METHODS: A systematic search of electronic databases including Medline, Embase, and Cochrane library was conducted. Comparative studies reporting on long-term oncologic outcome of LPN versus OPN were regarded eligible. The odds ratio (OR) and its corresponding 95% confidence intervals (CI) were calculated for the oncologic outcomes. The methodologic quality of the included studies was evaluated using the strict criteria of the Newcastle-Ottawa scale. RESULTS: Six comparative studies (1495 participants including 555 LPN and 940 OPN) were included in the present study. There was no significant difference between LPN and OPN in 5-year overall survival (OS) rates (OR = 1.83, 95% CI (0.80, 4.19)), 5-year cancer specific survival (CSS) rates (OR = 1.09, 95% CI (0.62, 1.92)), and 5-year recurrence free survival (RFS) rates (OR = 0.68, 95% CI (0.37, 1.26)). CONCLUSION: The results of this meta-analysis revealed that there was no significant difference in long-term oncologic outcome between LPN and OPN for treatment of localized renal tumors. PMID- 23924473 TI - Association between the polymorphisms of interleukin-4, the interleukin-4 receptor gene and asthma. AB - BACKGROUND: Interleukin-4 (IL4) is one of the most important cytokines involved in a variety of allergic disorders, particularly, asthma. A number of genetic epidemiological studies have identified an association between the gene polymorphisms of IL4 and interleukin-4 receptor (IL4R) and asthma in different populations. However, these studies have been inconsistent and inconclusive. The aim of this study was to investigate the association between the single nucleotide polymorphism (SNP) of IL-4, IL-4R and asthma risk in case-controlled studies using meta-analysis. METHOD: A genetic model-free approach was used to perform the meta-analysis. Asthma (atopy status nondefined), nonatopic and atopic asthma subgroups were separately analyzed. Next, the ethnic subgroup was analyzed. Heterogeneity and publication bias were also explored. RESULTS: Only two polymorphisms of IL4 (rs2243250 and rs2070874) and four polymorphisms of IL4R (rs1801275, rs1805011, rs1805010, and rs1805015) were included in the meta analysis. Polymorphisms rs2243250 and rs2070874 of IL-4 and rs1801275 and rs1805011 of IL4R were associated with asthma. The overall odds ratio (OR) of rs2243250 in the CC versus TT+TC genotypes was 0.84 (95% CI: 0.75-0.94), and the Z-test for the overall effect was 3.0 (P = 0.003). We obtained significant results from this polymorphism in the Caucasian ethnicity and adult groups. However, the overall OR of rs1801275 for the GG+AG versus AA genotype was 1.16 (95% CI: 1.00-1.35), and the Z-test for the overall effect was 1.87 (P = 0.06). Moreover, significant results were only obtained from the sub-group analysis in Asians (P = 0.02). In the rs1805011 polymorphism of IL4R, the overall OR for the CC +AC versus AA genotypes was 0.39 (95% CI: 0.16-0.95), and the Z-test for the overall effect was 2.08 (P = 0.04). CONCLUSIONS: Both the IL4 and IL4R polymorphisms were associated with asthma. The rs2243250 polymorphism of IL4 was more important in the white and adult groups. Individuals who carried the C allele for rs2070874 of the IL4 gene demonstrated increased asthma risk compared to TT homozygotes. An individual with an AA genotype in rs1805011 of the IL4R gene was less likely to suffer from asthma compared to the other two genotypes. PMID- 23924474 TI - Myogenic differentiation of mesenchymal stem cells for muscle regeneration in urinary tract. AB - OBJECTIVE: This article was to review the current status of adult mesenchymal stem cells transplantation for muscle regeneration in urinary tract and propose the future prospect in this field. DATA SOURCES: The data used in this review were mainly obtained from articles listed in Medline and PubMed (2000-2013). The search terms were "mesenchymal stem cells", "bladder", "stress urinary incontinence" and "tissue engineering". STUDY SELECTION: Articles regarding the adult mesenchymal stem cells for tissue engineering of bladder and stress urinary incontinence were selected and reviewed. RESULTS: Adult mesenchymal stem cells had been identified and well characterized in human bone marrow, adipose tissue, skeletal muscle and urine, and demonstrated the capability of differentiating into smooth muscle cells and skeletal muscle cells under myogenic differentiation conditions in vitro. Multiple preclinical and clinical studies indicated that adult mesenchymal stem cells could restore and maintain the structure and function of urinary muscle tissues after transplanted, and potentially improve the quality of life in patients. CONCLUSIONS: Smooth or skeletal myogenic differentiation of mesenchymal stem cells with regenerative medicine technology may provide a novel approach for muscle regeneration and tissue repair in urinary tract. The long-term effect and safety of mesenchymal stem cell transplantation should be further evaluated before this approach becomes widely used in patients. PMID- 23924475 TI - Novel role of microRNAs in prostate cancer. AB - OBJECTIVE: To discuss the novel biomarkers of microRNAs in prostate cancer. DATA SOURCES: The literatures about microRNAs and prostate cancer cited in this review were obtained mainly from Pubmed published in English from 2004 to 2012. STUDY SELECTION: Original articles regarding the novel role of microRNAs in prostate cancer were selected. RESULTS: MicroRNAs play an important role in prostate cancer such as cell differentiation, proliferation, apoptosis, and invasion. Especially microRNAs correlate with prostate cancer cell epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), drug sensitivity, cancer microenvironment, energy metabolism, androgen independence transformation, and diagnosis prediction. CONCLUSIONS: MicroRNAs are involved in various aspects of prostate cancer biology. The role of microRNA in the initiation and development of prostate cancer deserves further study. PMID- 23924476 TI - Fertility-preserving treatment and pregnancy outcomes in the early stage of endometrial carcinoma. AB - OBJECTIVE: This study aimed to review the available literature on fertility preserving treatment and pregnancy outcomes in patients with early-stage endometrial carcinoma who desired to preserve their fertility. DATA SOURCES: The PubMed database (1992-2012) was searched for the words "conservative "OR" fertility sparing "OR" fertility preserving" AND "endometrial neoplasms" (MeSH). All relevant articles in English and the relevant references were collected. STUDY SELECTION: Data from published articles about fertility-preserving treatment of endometrial cancer, including the response and recurrence rate of conservative treatment, strategies of infertility treatment, pregnancy, and obstetric outcomes, were selected. Data were mainly extracted from 41 studies, which are listed in the reference section of this review. RESULTS: Hormone therapy was the most common method used for early-stage endometrial carcinoma in patients who wished to preserve fertility. Sixty percent of the patients became pregnant after remission of the carcinoma. The percentage of patients who conceived in the assisted reproductive technology group was higher than that of the natural pregnancy group (80.0% vs. 43.2%, P < 0.01). A higher rate of preterm labor and multiple pregnancies was observed in the assisted reproductive technology group than that in the natural pregnancy group. The majority of pregnancies (71.4%) in the assisted reproductive technology group were achieved by in vitro fertilization-embryo transfer. The clinical pregnancy rate of transfer cycles in patients with endometrial carcinoma was 34.1%. CONCLUSIONS: Assisted reproductive technology is a good option in well-selected patients with early-stage endometrial carcinoma who have completed conservative treatment. In vitro fertilization-embryo transfer offers an opportunity to achieve an immediate pregnancy. PMID- 23924477 TI - Controversies in the treatments of prostate cancer. PMID- 23924478 TI - Multiple effects of vitamin D. PMID- 23924479 TI - Typical endoscopic appearance accurately predicts sporadic fundic gland polyps: a retrospective study of 47 771 endoscopies. PMID- 23924480 TI - Duplication anomaly of the external auditory canal involving the middle ear. PMID- 23924481 TI - Rare case of multiple pulmonary artery aneurysms with mural thrombus and right ventricle capillary hemangioma. PMID- 23924482 TI - Synchronous left atrial myxoma and adenosquamous lung carcinoma. PMID- 23924483 TI - Vitreoretinal surgery combined with C-arm fluoroscopic-guided removal of intraorbital foreign body following ocular perforating injury. PMID- 23924484 TI - Laparoscopic adrenalectomy of a large pheochromocytoma in a multiple endocrine neoplasia-2A patient with renal agenesis. PMID- 23924485 TI - Left ventricular aneurysm with a calcified thrombus in the absence of chronic coronary artery occlusion. PMID- 23924486 TI - Phlebosclerotic colitis: a rare disease in the Asian population. PMID- 23924487 TI - A giant solitary fibrous tumor of the pleura. PMID- 23924488 TI - A large left ventricular calcification presenting with ventricular tachycardia. PMID- 23924489 TI - Evaluation of an intelligent wheelchair system for older adults with cognitive impairments. AB - BACKGROUND: Older adults are the most prevalent wheelchair users in Canada. Yet, cognitive impairments may prevent an older adult from being allowed to use a powered wheelchair due to safety and usability concerns. To address this issue, an add-on Intelligent Wheelchair System (IWS) was developed to help older adults with cognitive impairments drive a powered wheelchair safely and effectively. When attached to a powered wheelchair, the IWS adds a vision-based anti-collision feature that prevents the wheelchair from hitting obstacles and a navigation assistance feature that plays audio prompts to help users manoeuvre around obstacles. METHODS: A two stage evaluation was conducted to test the efficacy of the IWS. Stage One: Environment of Use - the IWS's anti-collision and navigation features were evaluated against objects found in a long-term care facility. Six different collision scenarios (wall, walker, cane, no object, moving and stationary person) and three different navigation scenarios (object on left, object on right, and no object) were performed. Signal detection theory was used to categorize the response of the system in each scenario. Stage Two: User Trials - single-subject research design was used to evaluate the impact of the IWS on older adults with cognitive impairment. Participants were asked to drive a powered wheelchair through a structured obstacle course in two phases: 1) with the IWS and 2) without the IWS. Measurements of safety and usability were taken and compared between the two phases. Visual analysis and phase averages were used to analyze the single-subject data. RESULTS: Stage One: The IWS performed correctly for all environmental anti-collision and navigation scenarios. Stage Two: Two participants completed the trials. The IWS was able to limit the number of collisions that occurred with a powered wheelchair and lower the perceived workload for driving a powered wheelchair. However, the objective performance (time to complete course) of users navigating their environment did not improve with the IWS. CONCLUSIONS: This study shows the efficacy of the IWS in performing with a potential environment of use, and benefiting members of its desired user population to increase safety and lower perceived demands of powered wheelchair driving. PMID- 23924490 TI - Thermodynamic profiles at the solvated inorganic-organic interface: the case of gold-thiolate monolayers. AB - The thermodynamic adsorption profile at a solvated organic-inorganic interface is probed by following the binding and organization of carboxylic acid-terminated alkanethiols of varying chain lengths (C2, C3, and C6) to the surface of gold nanoparticles (NPs) (5.4 +/- 0.7, 9.5 +/- 0.6, and 19.4 +/- 1.1 nm diameter) using isothermal titration calorimetry (ITC). We discuss the effect of alkyl chain length, temperature, and Au NP size on the energetics at an organic inorganic interface. ITC allows for the quantification of the adsorption constant, enthalpy of adsorption, entropy of adsorption, and the binding stoichiometry in a single experiment. The thermodynamic parameters support a mechanism of stepwise adsorption of thiols to the surface of Au NPs and secondary ordering of the thiols at the organic-inorganic interface. The adsorption enthalpies are chain-length dependent; enthalpy becomes more exothermic as longer chains are confined, compensating for greater decreases in entropy with increasing chain length. We observe an apparent compensation effect: the negative DeltaH is compensated by a negative DeltaS as the thiols self-assemble on the Au NP surface. A comparison of the thermodynamic parameters indicates thiol-Au NP association is enthalpy-driven because of the large, exothermic enthalpies accompanied by an unfavorable entropic contribution associated with confinement of alkyl chains, reduced trans-gauche interconversion, and the apparent ordering of solvent molecules around the hydrophobic organic thiols (hydrophobic effect). Understanding the thermodynamics of adsorption at NP surfaces will provide critical insight into the role of ligands in directing size and shape during NP synthesis since thiols are a common ligand choice (i.e., Brust method). The ITC technique is applicable to a larger number of structure-directing ligands and solvent combinations and therefore should become an important tool for understanding reaction mechanisms in nanostructure synthesis. PMID- 23924491 TI - 13th Asia-Pacific Congress of Clinical Microbiology and Infection Consensus Guidelines for diagnosis and treatment of liver failure. PMID- 23924492 TI - Urinary trypsinogen-2 for diagnosing acute pancreatitis: a meta-analysis. AB - BACKGROUND: Currently, serum amylase and lipase are the most popular laboratory markers for early diagnosis of acute pancreatitis with reasonable sensitivity and specificity. Urinary trypsinogen-2 (UT-2) has been increasingly used but its clinical value for the diagnosis of acute pancreatitis and post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis has not yet been systematically assessed. DATA SOURCES: A comprehensive search was carried out using PubMed (MEDLINE), Embase, and Web of Science for clinical trials, which studied the usefulness of UT-2 as a diagnostic marker for acute pancreatitis. Sensitivity, specificity and the diagnostic odds ratios (DORs) with 95% confidence interval (CI) were calculated for each study and were compared with serum amylase and lipase. Summary receiver-operating curves were conducted and the area under the curve (AUC) was evaluated. RESULTS: A total of 18 studies were included. The pooled sensitivity and specificity of UT-2 for the diagnosis of acute pancreatitis were 80% and 92%, respectively (AUC=0.96, DOR=65.63, 95% CI: 31.65-139.09). The diagnostic value of UT-2 was comparable to serum amylase but was weaker than serum lipase. The pooled sensitivity and specificity for the diagnosis of post-ERCP pancreatitis were 86% and 94%, respectively (AUC=0.92, DOR=77.68, 95% CI: 24.99-241.48). CONCLUSIONS: UT-2 as a rapid test could be potentially used for the diagnosis of post-ERCP pancreatitis and to an extent, acute pancreatitis. Further studies are warranted to confirm these results. PMID- 23924493 TI - HBsAg, HBcAg, and combined HBsAg/HBcAg-based therapeutic vaccines in treating chronic hepatitis B virus infection. AB - BACKGROUND: As the host immunity is diminished in patients with chronic hepatitis B (CHB), different approaches have been used to up-regulate their immune responses to produce therapeutic effects. But, cytokines, growth factors and polyclonal immune modulators could not exhibit sufficient therapeutic effects in these patients. Immune therapy with HBV-related antigens (vaccine therapy) has been used in CHB patients. But there is a paucity of information about the design of HBV antigen-based immune therapy in these patients. DATA SOURCE: Preclinical and clinical studies on immune therapy with HBsAg-based vaccine, HBcAg and combination of HBsAg/HBcAg-based vaccines have been discussed. RESULTS: HBsAg based prophylactic vaccine was used as an immune therapeutic agent in CHB patients; however, monotherapy with HBsAg-based immune therapy could not lead to sustained control of HBV replication and/or liver damages. HBsAg-based vaccine was used as a combination therapy with cytokines, growth factors, and antiviral drugs. HBsAg-based vaccine was also used for cell-based therapy. However, satisfactory therapeutic effects of HBsAg-based vaccine could not be documented in CHB patients. In the mean time, evidences have supported that HBcAg-specific immunity is endowed with antiviral and liver protecting capacities in CHB patients. Recent data concentrate on the clinical use of combined HBsAg- and HBcAg-based vaccines in CHB patients. CONCLUSION: Antigen-based immune therapy with HBV-related antigens may be an alternative method for the treatment of CHB patients but proper designs of antigens, types of adjuvants, dose of vaccinations, and routes of administration need further analyses for the development of an effective regimen of immune therapy against HBV. PMID- 23924494 TI - Increase of beta-amyloid and C-reactive protein in liver transplant recipients with postoperative cognitive dysfunction. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) is an adverse condition characterized by declined cognitive functions following surgeries and anesthesia. POCD has been associated with increased hospital stay and mortality. There are histological similarities to Alzheimer's disease. Most early studies were conducted in patients receiving cardiac surgery. Since there is no information about POCD in liver transplant recipients, we measured the incidence of POCD in patients after liver transplantation and examined the correlation between neurological dysfunction and biological markers of dementia-based diseases. METHODS: We studied 25 patients who had a liver transplan-tation between July 2008 and February 2009. Patients with prior encephalopathy or risk factors associated with the development of POCD were excluded from the study. Five validated neuropsychiatric tests were used for diagnosis. The diagnosis was based on one standard deviation decline in two of the five neuropsychiatric tests. The correlation between patient variables and the development of POCD was examined. Serum levels of beta-amyloid and C-reactive protein were measured by standard ELISA and compared between patients with and without POCD. RESULTS: POCD was present in 11 (44%) of the 25 patients. Patients with POCD had significantly higher MELD scores, were more often Child-Pugh class C and received more blood transfusion during surgery. The serum beta-amyloid protein and C-reactive protein concentrations were significantly increased at 24 hours after surgery in the POCD group. CONCLUSIONS: The incidence of POCD in our group of liver transplant patients was greater than that reported in other surgical patients. The increase in the serum biomarkers of dementia in the POCD patients supports the hypothesis that chronic cognitive defects are due to a process similar to that seen in Alzheimer's disease. PMID- 23924495 TI - Liver steatosis correlates with iron overload but not with HFE gene mutations in chronic hepatitis C. AB - BACKGROUND: Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver steatosis and iron overload in Polish patients with CHC compared to non-alcoholic fatty liver disease (NAFLD) and HFE-hereditary hemochromatosis (HH) patients. METHODS: A total of 191 CHC patients were compared with 67 NAFLD and 21 HH patients. Liver function tests, serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis stages were assessed in liver specimens. HFE gene polymorphisms were investigated by PCR-RFLP. RESULTS: Liver steatosis was associated with obesity and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC patients, most of whom were infected with genotype 1. The average grade of steatosis was higher in NAFLD patients. CHC patients had significantly higher iron concentrations and transferrin saturations than NAFLD patients. Compared with CHC patients, HH patients had higher values of serum iron parameters and more intensive hepatocyte iron deposits without differences in the prevalence and intensity of liver steatosis. In the CHC group, lipids accumulation in hepatocytes was significantly associated with the presence of serum markers of iron overload. No correlation between the HFE gene polymorphism and liver steatosis in CHC patients was found. CONCLUSIONS: Liver steatosis was diagnosed in nearly half of CHC patients, most of whom were infected with genotype 1. The intensity of steatosis was lower in CHC patients than that in NAFLD patients because of a less frequent diagnosis of metabolic syndrome. Only in CHC patients were biochemical markers of iron accumulation positively correlated with liver steatosis; these findings were independent of HFE gene mutations. PMID- 23924496 TI - Potential role of diabetes mellitus in the progression of cirrhosis to hepatocellular carcinoma: a cross-sectional case-control study from Chinese patients with HBV infection. AB - BACKGROUND: Diabetes mellitus (DM) is regarded as a new risk factor for hepatocellular carcinoma (HCC), but few studies have focused on the potential role of DM in the progression of cirrhosis to HCC as well as in patients with simple HBV infection. METHODS: A cohort of 1028 patients, treated at our hospital and with a hospital discharge diagnosis of HCC and/or cirrhosis, was screened. Among them, 558 were diagnosed with chronic HBV infection and 370 were analyzed statistically according to the diagnostic, inclusion and exclusion criteria. The demographic, clinical, metabolic, virological, biochemical, radiological and pathological features were analyzed and the multivariate logistic regression model was used to determine the potential role of DM. RESULTS: In 248 cirrhotic patients, 76 were diabetic and their mean duration of DM was 4.6 years. In 122 HCC patients with cirrhosis, 25 were diabetic and their mean duration of DM was 4.4 years. Univariate analysis showed that compared with cirrhotic patients, the HCC patients had a higher percentage in males (P=0.001), a lower percentage in DM patients (P=0.039), a higher percentage in cigarette smokers (P=0.005), a higher percentage in patients with AFP>400 ng/mL (P<0.001), higher values of white blood cells (P<0.001), hemoglobin (P<0.001) and platelet (P<0.001), increased levels of ALT (P<0.001) and GGT (P<0.001), higher total bilirubin (P=0.018) and albumin levels (P<0.001), and a lower international normalized ratio (P<0.001). Multivariate logistic regression analysis showed that DM was an independent associated factor for HCC [odds ratio (OR)=0.376; 95% CI, 0.175-0.807; P=0.012]. Even after the HCC patients were restricted to those with decompensated cirrhosis and compared with decompensated cirrhotic patients, the similar result was observed (OR=0.192; 95% CI, 0.054-0.679; P=0.010). CONCLUSIONS: DM is an independent factor in the progression of cirrhosis to HCC, but the role may be contrary to our current viewpoint. To clarify the causal relationship of DM and HCC, prospective and experimental studies are required. PMID- 23924497 TI - Programmed death 1 and programmed death ligand 1 expressions in patients with chronic hepatitis B. AB - BACKGROUND: The role of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) in persistent HBV infection is controversial. Increasing PD-1 and PD-L1 expression has been found in hepatitis B patients during immune clearance phase, but not in HBV-tolerant patients. We investigated PD-1 and PD-L1 expression and inflammation in chronic hepatitis B. METHODS: Twenty patients with chronic hepatitis B participated in this study. Fifteen patients were in the immune clearance phase, and 5 were in the immune inactive phase. Circulating HBV specific T cells were analyzed by flow cytometric detection of major histocompatibility complex (MHC) class I peptide complexes, known as pentamers. Intra-hepatic PD-1 and PD-L1 expressions were analyzed by immunostaining. RESULTS: The frequency of pentamers, including core 18-27 (1.88%+/-0.36%), env 335-343 (1.85%+/-0.37%), and pol 575-583 (1.56%+/-0.29%) was 8.30-, 7.71- and 8.48-fold greater during immune clearance phase than those during the immune inactive phase. In addition, more than 70% of circulating pentamers were PD-1 positive. During immune clearance phase, the numbers of intra-hepatic PD-1 and PD L1 positive cells were 108+/-23/HPF and 97+/-20/HPF respectively, in contrast, there was a paucity of PD-1 and PD-L1 positive cells in the immune inactive phase. The numbers of intra-hepatic PD-1 and PD-L1 positive cells were positively correlated with serum alanine aminotransferase and the number of intra-hepatic CD8+ T cells. Immunofluorescence showed that almost all of the intra-hepatic CD8+ T cells were PD-1 and CCR6 positive. These cells aggregated around macrophage inflammatory protein-3 alpha (MIP3alpha) positive cells and mixed with PD-L1 positive cells. CONCLUSIONS: PD-1 and PD-L1 expressions were significantly correlated with inflammation. CCR6 and PD-1 co-expressed in the same cells; these cells were increased both in circulation and the inflamed liver and aggregated around MIP3alpha positive cells. The mixture of CCR6 and PD-1, MIP3alpha and PD L1 positive cells created immune response compartments which played an important role in specific immune response in HBV immune clearance. PMID- 23924498 TI - Verification of the Tokyo guidelines for acute cholangitis secondary to benign and malignant biliary obstruction: experience from a Chinese tertiary hospital. AB - BACKGROUND: The lack of widely-accepted guidelines for acute cholangitis largely lags behind the progress in medical and surgical technology and science for the management of acute cholangitis. This study aimed to verify the Tokyo guidelines for the management of acute cholangitis and cholecystitis of 2007 edition (TG07) in patients with obstructive cholangitis due to benign and malignant diseases. METHODS: The patients were retrieved from our existing ERCP database. Final diagnosis of acute cholangitis was made by detecting purulent bile during biliary drainage. We examined and compared the guidelines concerning benign and malignant obstruction. RESULTS: In 120 patients in our study, 82 and 38 had benign and malignant biliary obstruction, respectively. Guidelines based diagnosis was made in 68 (82.9%), 36 (94.7%), and 104 (86.7%) patients with benign, malignant, and overall biliary obstruction, respectively, which were significantly higher than 44 (53.7%), 17 (44.7%), and 61 (50.8%) diagnosed by Charcot's triad (P<0.001). Treatment consistent with the guidelines was offered to 58 (70.7%) patients with benign obstruction and 15 (39.5%) patients with malignant obstruction (P=0.001). No significant association was observed between clinical compliance, guidelines based severity grades and clinical outcomes. In the multivariate model, intrahepatic obstruction (OR=11.2, 95% CI: 1.55-226.9) and hypoalbuminemia (<=25.0 g/L; OR=17.3, 95% CI: 3.5-313.6) were independent risk factors for a 30 day mortality. CONCLUSIONS: The TG07 are more reliable than Charcot's triad for the diagnosis of acute cholangitis albeit with limited prognostic values. Intrahepatic obstruction and hypoalbuminemia are new predictors of poor prognosis and need further assessment. PMID- 23924499 TI - Impact of periampullary diverticula on the outcome and fluoroscopy time in endoscopic retrograde cholangiopancreatography. AB - BACKGROUND: It is unclear whether the presence of periampullary diverticula (PAD) affects technical success and complication rates during endoscopic retrograde cholangiopancreatography (ERCP). Moreover, the impact of PAD on fluoroscopy duration is still unknown. The present study aimed to investigate the success rate and difficulty of common bile duct (CBD) cannulation, post-procedure complications and fluoroscopy duration in patients with and without PAD. METHODS: Patients from January 2008 to December 2010 with PAD (group A) and without PAD (group B) and similar indications for therapeutic ERCP were prospectively compared. The comparison included patient characteristics, findings of ERCP, and details of procedure and fluoroscopy time. The influence of papilla's location with respect to the diverticulum on procedure was also investigated. RESULTS: A total of 428 consecutive patients who had undergone therapeutic ERCP for similar indications were divided in two groups according to the presence (group A, 107 patients) or absence (group B, 321 patients) of PAD. The mean age and ASA score of the patients with PAD were significantly higher than those patients without PAD. The main indication was choledocholithiasis. Successful final CBD cannulation was achieved in 97.20% of the patients in group A vs 99.69% in group B (P=0.05). CBD diameter, number of stones and the largest stone size were significantly higher in group A than group B (P<0.001). Complete clearance of the CBD after the first attempt was achieved in 85.86% and 94.75% of the patients in groups A and B, respectively (P=0.03). In both groups, the time needed to complete the procedure and fluoroscopy time was significantly longer in patients with PAD (22.87 vs 18.99 minutes, P<0.001; 76.51 vs 47.42 seconds, P<0.001). There was no significant difference between the two groups in the complication rate. The type of papilla's location with respect to the diverticulum did not influence the total cannulation rate and post-procedure complications. CONCLUSION: The presence of a PAD does not affect the success rate and complications of therapeutic ERCP in expert hands; however, the fluoroscopy time is significantly longer in patients with PAD. PMID- 23924500 TI - The diagnostic value of high-frequency ultrasonography in biliary atresia. AB - BACKGROUND: It is a globally challenging problem to differentially diagnose biliary atresia (BA) from other disease processes causing infantile cholestatic jaundice. The high-frequency ultrasonography (HUS) yields much improved spatial resolution and therefore, might show better image in BA diagnostic examination. The present study was to evaluate the HUS on the diagnosis of BA in infants with jaundice. METHODS: Fifty-one infants with neonatal jaundice were scanned with ultrasonography. Images included gallbladder, bile duct, right hepatic artery (RHA), portal vein (PV) and triangular cord (TC) sign, magnetic resonance imaging and additionally, laboratory tests and histopathology reports were assessed. RESULTS: Twenty-three BA and 28 non-BA cases were confirmed. The sensitivity, specificity, and accuracy of HUS were 91.3%, 92.9%, and 92.2%, respectively. All of these indices were significantly higher than those of conventional ultrasonography (P<0.01) and MR cholangiopancreatography (P<0.05). The HUS features, included a positive TC sign, an increased RHA diameter and RHA-diameter to portal-vein-diameter ratio (RHA/PV) and abnormal gallbladder, were important in the diagnosis of BA. CONCLUSION: HUS provided better imaging of BA and should be considered as a primary modality in the differential diagnosis of infantile jaundice. PMID- 23924501 TI - Endobiliary radiofrequency ablation for malignant biliary obstruction. AB - BACKGROUND: The cornerstone of palliative treatment for inoperable extrahepatic cholangiocarcinoma is the relief of malignant biliary obstruction. The most commonly applied method is endoscopic stenting. However, the procedure can be complicated with stent obstruction. In this respect, endobiliary radiofrequency ablation may serve as an adjunctive tool for prolonging the stent patency. METHODS: Patients who underwent endoscopic retrograde cholangiopancreatography for differential diagnosis and/or palliative treatment after the diagnosis of inoperable extrahepatic cholangiocarcinoma between March 2011 and January 2012 were analyzed. Those in whom endobiliary radiofrequency ablation and endoscopic stenting was successfully performed were included in the study. Technical details of the procedure, duration of stent patency, length of hospital stay, short-term morbidity and mortality rate were documented. RESULTS: Seventeen patients were analyzed, and 10 patients were included in the study. The morbidity and mortality rate within the first 30 days after the procedure was 20% and 0%, respectively. In 2 patients, mild pancreatitis occurred because of the endobiliary procedure. In 1 patient, endobiliary decompression could not be achieved, and therefore, percutaneous transhepatic biliary drainage was carried out. The median duration of stent patency in 9 patients with successful biliary decompression was 9 months (range 6-15). CONCLUSION: Endobiliary radiofrequency ablation seems to be safe and feasible as a palliative measure and may prolong the stent patency and overall survival in patients with malignant biliary obstruction due to inoperable extrahepatic cholangiocarcinoma. PMID- 23924502 TI - Effect of L-cysteine on remote organ injury in rats with severe acute pancreatitis induced by bile-pancreatic duct obstruction. AB - BACKGROUND: Remote organ failure occurs in cases of acute pancreatitis (AP); however, the reports on AP induced by pancreatic duct obstruction are rare. In this study we determined the effect of L-cysteine on pancreaticobiliary inflammation and remote organ damage in rats after pancreaticobiliary duct ligation (PBDL). METHODS: AP was induced by PBDL in rats with 5/0 silk. Sixty rats were randomly divided into 4 groups. Groups A and B were sham-operated groups that received injections of saline or L-cysteine (10 mg/kg) intraperitoneally (15 rats in each group). Groups C and D were PBDL groups that received injections of saline or L-cysteine (10 mg/kg) intraperitoneally (15 rats in each group). The tissue samples of the pancreas and remote organs such as the lung, liver, intestine and kidney were subsequently examined for pathological changes under a light microscope. The samples were also stored for the determination of malondialdehyde and glutathione levels. Blood urea nitrogen (BUN), plasma amylase, ALT and AST levels were determined spectrophotometrically using an automated analyzer. Also, we evaluated the effect of L-cysteine on remote organ injury in rats with AP induced by retrograde infusion of 3.5% sodium taurocholate (NaTc) into the bile-pancreatic duct. RESULTS: Varying degrees of injury in the pancreas, lung, liver, intestine and kidney were observed in the rats 24 hours after PBDL. The severity of injury to the lung, liver and intestine was attenuated, while injury status was not changed significantly in the pancreas and kidney after L-cysteine treatment. Oxidative stress was also affected by L cysteine in PBDL-treated rats. The concentration of tissue malondialdehyde decreased in the pancreas and remote organs of PBDL and L-cysteine administrated rats, and the concentration of glutathione increased more significantly than that of the model control group. However, L-cysteine administration reduced the severity of injury in remote organs but not in the pancreas in rats with NaTc induced AP. CONCLUSION: L-cysteine treatment attenuated multiple organ damage at an early stage of AP in rats and modulated the oxidant/antioxidant imbalance. PMID- 23924503 TI - A new veno-venous bypass type for ex-vivo liver resection in dogs. AB - Ex-vivo liver resection is a procedure in which the liver is completely removed, perfused and after bench surgery, the liver is autotransplanted to the original site. Ex-vivo liver resection is an important treatment for unresectable liver tumors. This surgical procedure requires long operation time, during which blood flow must be carefully maintained to avoid venous congestion. An effective veno venous bypass (VVB) may meet this requirement. The present study was to test our new designed VVB device which comprised one heparinized polyvinylchloride tube and three magnetic rings. The efficacy of this device was tested in five dogs. A VVB was established in 6-10 minutes. There was no leakage during the procedure. Hemodynamics was stable at anhepatic phase, which indicated that the bypass was successful. This newly-developed VVB device maintained circulation stability during ex-vivo liver resection in our dog model and thus, this VVB device significantly shortened the operation time. PMID- 23924504 TI - Hepatic abscess associated with Salmonella serotype B in a chronic alcoholic patient. AB - BACKGROUND: Hepatic abscess secondary to Salmonella is extremely rare in the United States and other Western countries. METHODS: A 43-year-old Caucasian man, with a history of chronic alcohol abuse, was admitted to the hospital for intermittent abdominal pain, fever and diarrhea. Clinical, radiological and laboratory results were analyzed. Medical literature in PubMed pertaining to similar cases was reviewed. RESULTS: Stool culture was positive for Salmonella serotype B and a CT scan of the abdomen with contrast was consistent with a solitary hepatic abscess. Appropriate intravenous antibiotics followed by oral maintenance therapy for six weeks resulted in a complete clinical recovery and radiographic resolution. CONCLUSIONS: The cause of Salmonella hepatic abscess in our patient was most likely associated with decreased mucosal resistance to the bacteria, seeding of infection via transient portal bacteremia and loss of host immunity. Our case highlights the fact that appropriate antibiotic alone is sufficient in the management of a solitary hepatic abscess less than 3-5 cm. PMID- 23924505 TI - Biliary-colonic fistula caused by cholecystectomy bile duct injury. AB - Biliary-colonic fistula is a rare complication after laparoscopic cholecystectomy. We present a case of post-cholecystectomy iatrogenic biliary injury that resulted in a fistula between the common hepatic duct and large bowel. Magnetic resonance cholangiopancreatography provided good visualization of injury even with concurrent normal level of alkaline phosphatase. Radiologic findings and surgical management of this condition are discussed in detail. PMID- 23924507 TI - Characterization of erythrose reductases from filamentous fungi. AB - Proteins with putative erythrose reductase activity have been identified in the filamentous fungi Trichoderma reesei, Aspergillus niger, and Fusarium graminearum by in silico analysis. The proteins found in T. reesei and A. niger had earlier been characterized as glycerol dehydrogenase and aldehyde reductase, respectively. Corresponding genes from all three fungi were cloned, heterologously expressed in Escherichia coli, and purified. Subsequently, they were used to establish optimal enzyme assay conditions. All three enzymes strictly require NADPH as cofactor, whereas with NADH no activity could be observed. The enzymatic characterization of the three enzymes using ten substrates revealed high substrate specificity and activity with D-erythrose and D-threose. The enzymes from T. reesei and A. niger herein showed comparable activities, whereas the one from F. graminearum reached only about a tenth of it for all tested substrates. In order to proof in vivo the proposed enzyme function, we overexpressed the erythrose reductase-encoding gene in T. reesei. An increased production of erythritol by the recombinant strain compared to the parental strain could be detected. PMID- 23924508 TI - Economic burden of acute coronary syndrome in South Korea: a national survey. AB - BACKGROUND: Acute coronary syndrome (ACS) is highly prevalent in Korea and is the third-leading cause of death in Korea; however, the economic cost of ACS on Korean society has not been investigated. This study examined the economic effect of ACS on the Korean population during the period 2004 to 2009. METHODS: The analysis used the cost of illness (COI) framework. Data on direct medical costs, direct non-medical costs, and productivity loss related to ACS morbidity and mortality were included. The Korean National Health Insurance Corporation's claim database was used to obtain data on annual healthcare utilization and expenditures for the entire South Korean population. By using a data mining technique, we identified healthcare claims with ACS-related disease codes. Costs were estimated by using a macro-costing method. RESULTS: In 2009, the prevalence of ACS in Korea was 6.4 persons per 1,000 population members and the associated mortality rate was 20.2 persons per 100,000 population members. The total cost of ACS in 2009 was USD 918.2 million. Of the total, direct medical cost was USD 425.3 million, direct non-medical cost was USD 11.4 million, and cost associated with morbidity and mortality was USD 481.5 million. CONCLUSIONS: The results show that the total cost of ACS to the Korean society is high. Early and effective management of ACS is required to reduce ACS-associated mortality and morbidity. We suggest that further research be undertaken to determine ways to reduce the economic effects of ACS and its treatment. PMID- 23924506 TI - The emerging role of dietary fructose in obesity and cognitive decline. AB - The incidence of obesity has increased dramatically over the past several years, and in parallel, so has the prevalence of type 2 diabetes (T2D). Numerous studies have demonstrated that both obesity and T2D are associated with lower cognitive performance, cognitive decline, and dementia. Intake of dietary fructose has also increased. In fact, high-fructose corn syrup (HFCS) accounts for as much as 40% of caloric sweeteners used in the United States. Given the increase in the incidence of Alzheimer's disease (AD), characterized by an age-related decline in memory and cognitive functioning, in this report we review the effects of obesity on cognitive performance and the impact of high fructose intake in promoting cognitive decline. The paper then considers the effects of omega-3 fatty acids (FAs), which have been linked to promising results in cognitive function including ameliorating the impact of a high-fructose diet. PMID- 23924510 TI - Statistics behind the headlines. Have there been 13,000 needless deaths at 14 NHS trusts? PMID- 23924509 TI - The compositional landscape of minicircle sequences isolated from active lesions and scars of American cutaneous leishmaniasis. AB - BACKGROUND: American cutaneous leishmaniasis (ACL) is characterized by cutaneous lesions that heal spontaneously or after specific treatment. This paper reports on the analysis of kDNA minicircle sequences from clinical samples (typical lesions and scars) that were PCR-amplified with specific primers for Leishmania species of the subgenus Viannia. METHODS: From 56 clinical isolates we obtained a single amplified fragment (ca. 790 bp), which after cloning and sequencing resulted in 290 minicircle sequences from both active lesions and scars. We aimed to get a compositional profile of these sequences in clinical samples and evaluate the corresponding compositional changes. Sequences were analyzed with the compseq and wordcount (Emboss package) to get the composition of di-, tri-, tetra-, penta- and hexanucleotides. Additionally, we built a nucleotide dictionary with words of 7, 8, 9 and 10 nucleotides. RESULTS: This compositional analysis showed that minicircles amplified from active cutaneous lesions and scars have a distinct compositional profile as viewed by nucleotide composition of words up to 10mer. With regard to the most frequent nucleotide words above length 6, there is also a distinct pattern for 7, 8, 9 and 10mer. CONCLUSION: These results indicate that minicircle sequences can be monitored upon direct exposure to a selection/stressing environment (e.g. chemical action) by evaluating their nucleotide compositional profile. It might be useful as a molecular tool in research concerning the evolution of infecting Leishmania in both vector and vertebrate hosts. PMID- 23924511 TI - Vanishing bone disease of the mandible - a case report. AB - BACKGROUND: Massive osteolysis (Gorham-Stout syndrome) is a rare condition of unknown etiology that is thought to result from a localized endothelial proliferation of lymphatic vessels resulting in destruction and absorption of bone. Osteolysis of the jaws has been reported in association with infection, cysts, neoplasia, and metabolic, endocrine, or hematologic abnormalities. Rare cases of idiopathic osteolysis have also been recorded. A detailed review from various peer reviewed journals has been discussed in this article. OBJECTIVES: To discuss the demographic distribution and possibilities of pathogenesis of Gorham Stout syndrome. MATERIALS AND METHOD: A case report of vanishing bone disease of the mandible in a 60 year old female patient has been discussed. A detail review of literature highlighting the demographic distribution and pathogenesis of vanishing bone disease has been made. RESULTS: Thirty eight percentages of these lesions appear in older individuals with a slight male predilection. 68.6% of the oro-facial massive osteolysis occurs in mandible has been reported. Variable etiopathogenesis such as vascular proliferation, increased levels of circulating cytokines and circulatory disturbances have been associated with this disease. CONCLUSION: The Gorham-Stout syndrome though rarely seen in the facial skeleton, it is important to consider it in the differential diagnosis of osteolytic lesions of the jaws. PMID- 23924512 TI - Bifunctional composite catalysts using Co3O4 nanofibers immobilized on nonoxidized graphene nanoflakes for high-capacity and long-cycle Li-O2 batteries. AB - Designing a highly efficient catalyst is essential to improve the electrochemical performance of Li-O2 batteries for long-term cycling. Furthermore, these batteries often show significant capacity fading due to the irreversible reaction characteristics of the Li2O2 product. To overcome these limitations, we propose a bifunctional composite catalyst composed of electrospun one-dimensional (1D) Co3O4 nanofibers (NFs) immobilized on both sides of the 2D nonoxidized graphene nanoflakes (GNFs) for an oxygen electrode in Li-O2 batteries. Highly conductive GNFs with noncovalent functionalization can facilitate a homogeneous dispersion in solution, thereby enabling simple and uniform attachment of 1D Co3O4 NFs on GNFs without restacking. High first discharge capacity of 10 500 mAh/g and superior cyclability for 80 cycles with a limited capacity of 1000 mAh/g were achieved by (i) improved catalytic activity of 1D Co3O4 NFs with large surface area, (ii) facile electron transport via interconnected GNFs functionalized by Co3O4 NFs, and (iii) fast O2 diffusion through the ultrathin GNF layer and porous Co3O4 NF networks. PMID- 23924513 TI - Resistant gram-negative infections in the outpatient setting in Latin America. AB - Latin America has a high rate of community-associated infections caused by multidrug-resistant Enterobacteriaceae relative to other world regions. A review of the literature over the last 10 years indicates that urinary tract infections (UTIs) by Escherichia coli, and intra-abdominal infections (IAIs) by E. coli and Klebsiella pneumoniae, were characterized by high rates of resistance to trimethoprim/sulfamethoxazole, quinolones, and second-generation cephalosporins, and by low levels of resistance to aminoglycosides, nitrofurantoin, and fosfomycin. In addition, preliminary data indicate an increase in IAIs by Enterobacteriaceae producing extended-spectrum beta-lactamases, with reduced susceptibilities to third- and fourth-generation cephalosporins. Primary-care physicians in Latin America should recognize the public health threat associated with UTIs and IAIs by resistant Gram-negative bacteria. As the number of therapeutic options become limited, we recommend that antimicrobial prescribing be guided by infection severity, established patient risk factors for multidrug resistant infections, acquaintance with local antimicrobial susceptibility data, and culture collection. PMID- 23924514 TI - ProteoMirExpress: inferring microRNA and protein-centered regulatory networks from high-throughput proteomic and mRNA expression data. AB - MicroRNAs (miRNAs) regulate gene expression through translational repression and RNA degradation. Recently developed high-throughput proteomic methods measure gene expression changes at protein level and therefore can reveal the direct effects of miRNAs' translational repression. Here, we present a web server, ProteoMirExpress, that integrates proteomic and mRNA expression data together to infer miRNA-centered regulatory networks. With both types of high-throughput data from the users, ProteoMirExpress is able to discover not only miRNA targets that have decreased mRNA, but also subgroups of targets with suppressed proteins whose mRNAs are not significantly changed or with decreased mRNA whose proteins are not significantly changed, which are usually ignored by most current methods. Furthermore, both direct and indirect targets of miRNAs can be detected. Therefore, ProteoMirExpress provides more comprehensive miRNA-centered regulatory networks. We used several published data to assess the quality of our inferred networks and prove the value of our server. ProteoMirExpress is available online, with free access to academic users. PMID- 23924516 TI - Identifying symptoms of depression and anxiety in students in the school setting. AB - Early detection of mental health problems in school-age children offers the opportunity for prompt referral to treatment which is critical to their success in school. School nurses are in a key position to screen for mental health issues in the school setting. This article discusses how school nurses began a new initiative to use two validated screening tools, the Patient Health Questionnaire 9 item for detecting depression and the 5-item Screen for Child Anxiety Related Emotional Disorders for detecting anxiety in middle school/high school-aged children in selected urban schools. Students having positive screens were referred to the multidisciplinary school-based Student Assistance Program team for further evaluation and referral. These screens improved the identification and referral for treatment of children suffering from anxiety and/or depression by expediting the connection to services. PMID- 23924515 TI - Interactome analysis reveals that C1QBP (complement component 1, q subcomponent binding protein) is associated with cancer cell chemotaxis and metastasis. AB - The complement component 1, q subcomponent binding protein (C1QBP/p32/HABP1) is a ubiquitously expressed and multicompartmental cellular protein involved in various biological processes. In order to further understand its biological functions, we conducted proteomics analysis of its interactome in this study. An improved sample preparation and mass spectrometric identification strategy was developed combining high-speed centrifugation, formaldehyde labeling, and two dimensional reverse-phase liquid chromatography. Using this approach, we identified 187 interacting proteins and constructed a highly connected interacting network for C1QBP. Moreover, we explored the interaction between C1QBP and protein kinase C zeta, a key regulator of cell polarity and migration. The results indicated that C1QBP regulated the activity of protein kinase C zeta and modulated EGF-induced cancer cell chemotaxis. In addition, C1QBP was required for breast cancer metastasis in a severe combined immunodeficiency mouse model. Furthermore, C1QBP was observed to be overexpressed in breast cancer tissues, and its expression level was closely linked with distant metastasis and TNM stages. In summary, C1QBP was identified as a novel regulator of cancer metastasis that may serve as a therapeutic target for breast cancer treatment. PMID- 23924518 TI - Biomechanical analysis of C4-C6 spine segment considering anisotropy of annulus fibrosus. AB - Based on computed tomography scanning images of human cervical spine, this paper develops a detailed and anatomically accurate finite element model for C4-C6 motion segment to investigate its biomechanical responses. The model includes vertebrae, intervertebral disc, and various ligaments. The annulus fibrosus is characterized by using a previously developed nonlinear, anisotropic, hyperelastic fiber-reinforced model with fiber-matrix shear interaction considered. Other materials are simplified as linear or nonlinear elastic. The proposed cervical model is first validated by comparing numerical force displacement relationship and intradiscal pressure under axial compression with experimental data available in the literature. The biomechanical responses of the spine segment under axial compression and rotation are then investigated. It is found that the fiber matrix-shear interaction of the annulus fibrosis plays an important role on appropriately predicting the biomechanical behavior of the cervical spine segment. PMID- 23924517 TI - Cell injury after ischemia and reperfusion in the porcine kidney evaluated by radiolabelled microspheres, sestamibi, and lactadherin. AB - BACKGROUND: The purpose of the present study was to quantify renal cell injury after ischemia and reperfusion in a pig model using (99m)Tc-lactadherin as a marker of apoptosis and (99m)Tc-sestamibi as a marker of mitochondrial dysfunction. METHODS: Thirty-four pigs were randomized into unilateral renal warm ischemia of 120 (WI120) or 240 min (WI240). The glomerular filtration rate (GFR) was calculated by renal clearance of (51)Cr-ethylenediaminetetraacetic acid, and apoptosis was quantified by immunohistochemical detection of caspase-3. After 240 min of reperfusion, intravenous (99m)Tc-lactadherin or (99m)Tc-sestamibi was injected simultaneously with (153)Gd microspheres into the aorta. Ex-vivo static planar images of the kidneys were acquired for determination of the differential renal function of tracer distribution using a gamma camera. RESULTS: In WI120, there was no significant difference in the uptake of microspheres in the ischemic and contralateral normal kidney indicating adequate perfusion (uptake in ischemic kidney relative to the sum of uptake in both kidneys; 46% +/- 12% and 51% +/- 5%). In WI240, the uptake of microspheres was severely reduced in both groups (17% +/- 11% and 27% +/- 17%). GFR was severely reduced in the post ischemic kidney in both groups. In both groups, the uptake of lactadherin was reduced (41% +/- 8%, 17% +/- 13%) but not different from the uptake of (153)Gd microspheres. Caspase-3-positive cell profiles were increased in the post-ischemic kidneys (p < 0.001) and increased as the length of ischemia increased (p = 0.003). In both WI120 and WI240, the amount of (99m)Tc-sestamibi in the ischemic kidney was significantly lower than the amount of (153)Gd microspheres (40 +/- 5 versus 51 +/- 5 and 20 +/- 11 versus 27 +/- 17; p < 0.05). CONCLUSIONS: In an established pig model with unilateral renal warm ischemia, we found significantly reduced (99m)Tc-sestamibi uptake relative to perfusion in the kidneys exposed to ischemia indicating a potential ability to detect renal ischemic and reperfusion injuries. However, apoptosis was not detected using (99m)Tc-lactadherin in the post ischemic kidneys despite increased number of caspase-3-positive cell profiles. TRIAL REGISTRATION: This study is approved by the Danish Inspectorate of Animal Experiments (2010/561-1837). PMID- 23924519 TI - Estimation of neural firing rate: the wavelet density estimation approach. AB - The computation of neural firing rates based on spike sequences has been introduced as a useful tool for extraction of an animal's behavior. Different estimating methods of such neural firing rates have been developed by neuroscientists, and among these methods, time histogram and kernel estimators have been used more than other approaches. In this paper, the problem in the estimation of firing rates using wavelet density estimators has been considered. The results of simulation study in estimation of underlying rates based on spike sequences sampled from two different variable firing rates show that the proposed wavelet density method provides better and more accurate estimation of firing rates with smooth results compared to two other classical approaches. Furthermore, the performance of a different family of wavelet density estimators in the estimation of the underlying firing rate of biological data have been compared with results of both time histogram and kernel estimators. All in all, the results show that the proposed method can be useful in the estimation of firing rate of neural spike trains. PMID- 23924520 TI - Mode of delivery at periviable gestational ages: impact on subsequent reproductive outcomes. AB - AIM: The aim of this study was to assess the risk of subsequent delivery complications after extremely preterm deliveries by initial (index) pregnancy mode of delivery (MOD): cesarean (CD) versus vaginal (VD). METHODS: This is a retrospective, longitudinal cohort study using Washington State birth certificate data and International Classification of Diseases, Ninth Revision codes, 1989 2008, identifying women with deliveries 20-26 weeks' gestation and linked subsequent deliveries. Index MOD was considered as a predictor of adverse subsequent maternal and neonatal outcomes, using t-test, chi(2)-test or Fisher's exact test, and regression analysis. RESULTS: Of 2472 women with periviable delivery and subsequent birth, index CD (n=386) and index VD (n=2086) showed similar risks of composite morbidity (16.1% vs. 15.4%, P=0.76) and subsequent hemorrhage (9.6% vs. 11.1%, P=0.39). Women with index CD were more likely than index VD to experience uterine rupture (1.8% vs. 0.1%, P<0.001), to deliver earlier (35.9 vs. 36.9 weeks, P<0.001), and to have lower birth weight (2736 vs. 3014 g, P<0.001) subsequently. Neonatal hospital charges and lengths of stay were also higher after index CD. CONCLUSIONS: MOD at extreme prematurity did not impact subsequent maternal hemorrhage or overall morbidity. However, CD was associated with substantial uterine rupture risk despite evidence of practice to avoid labor (lower birth weight and earlier delivery) in the subsequent pregnancy. PMID- 23924521 TI - Nitrous oxide for analgesia in external cephalic version at term: prospective comparative study. AB - OBJECTIVE: The objective of this study was to analyze the effect of using inhaled nitrous oxide (N2O) for analgesia in external cephalic version (ECV) at term on the success rate of the procedure, on pain, and on obstetric and perinatal outcomes. METHODS: A prospective comparative cohort study among 300 women with singleton pregnancy in breech presentation at term undergoing an ECV with inhaled N2O in a 50:50 mix with oxygen for analgesia and 150 ECVs with no analgesia. RESULTS: The success rate was 52.3% in the N2O cohort and 52.7% in the controls (P=0.94), whereas the median level of pain was statistically lower in women given N2O (median, 6; range, 4-7, vs. median, 7; range, 5-8; P<0.01). This improvement is mainly from a 49% decrease in severe pain. There were no significant differences in the rate of complications associated with the ECV, in the rate of cesarean sections, or in perinatal outcomes. Furthermore, there were no severe complications secondary to N2O inhalation. CONCLUSIONS: N2O inhalation at a concentration of 50% for analgesia during ECV decreases the level of severe pain experienced by women, appears to be safe both for mother and child, and has no influence on the success rate of ECV or the perinatal outcomes. PMID- 23924522 TI - Extremely short cervix in the second trimester: bed rest or modified Shirodkar cerclage? AB - OBJECTIVE: The objective of this study was to compare modified Shirodkar cerclage to bed rest for treatment of the midtrimester extremely short cervix. METHODS: This study used a concurrent retrospective cohort design at two institutions over the same period, 2000-2010. Patients were included at both institutions when midtrimester endovaginal ultrasound cervical length was <= 15 mm and had modified Shirodkar cerclage (cerclage group) at New York Hospital Queens and bed rest (control group) at Weill Cornell Medical Center. Cerclage was placed as high on the cervix as possible. Indomethacin and antibiotics were used perioperatively. RESULTS: The cerclage group included 112 patients and the control group included 55 patients. Median postoperative cervical length in the cerclage group was 3.3 cm (interquartile range 3.0-3.6). Cerclage patients were less likely to deliver preterm at 37, 35, 32, and 28 weeks (P=0.0066, 0.0004, 0.0023, and 0.03 respectively) and had longer latency (median 120 vs. 94 days P<0.0001). Kaplan Meier survival curve showed a significant benefit in favor of cerclage (P=0.0043). CONCLUSIONS: Our data suggest that modified Shirodkar cerclage as high as possible on the cervix with perioperative indomethacin and antibiotics is superior to bed rest for treatment of the midtrimester extremely short cervix (<=15 mm). We propose a randomized trial of this specific technique. PMID- 23924523 TI - Effect of recalibration of the hs-TnT assay on diagnostic performance. PMID- 23924524 TI - Planned variation in preanalytical conditions to evaluate biospecimen stability in the National Children's Study (NCS). AB - BACKGROUND: Preanalytical conditions encountered during collection, processing, and storage of biospecimens may influence laboratory results. The National Children's Study (NCS) is a planned prospective cohort study of 100,000 families to examine the influence of a wide variety of exposures on child health. In developing biospecimen collection, processing, and storage procedures for the NCS, we identified several analytes of different biochemical categories for which it was unclear to what extent deviations from NCS procedures could influence measurement results. METHODS: A pilot study was performed to examine effects of preanalytic sample handling conditions (delays in centrifugation, freezing delays, delays in separation from cells, additive delay, and tube type) on concentrations of eight different analytes. A total of 2825 measurements were made to assess 15 unique combinations of analyte and handling conditions in blood collected from 151 women of childbearing age (>= 20 individuals per handling condition). RESULTS: The majority of analytes were stable under the conditions evaluated. However, levels of plasma interleukin-6 and serum insulin were decreased in response to sample centrifugation delays of up to 5.5 h post collection (p<0.0001). In addition, delays in freezing centrifuged plasma samples (comparing 24, 48 and 72 h to immediate freezing) resulted in increased levels of adrenocorticotropic hormone (p=0.0014). CONCLUSIONS: Determining stability of proposed analytes in response to preanalytical conditions and handling helps to ensure high-quality specimens for study now and in the future. The results inform development of procedures, plans for measurement of analytes, and interpretation of laboratory results. PMID- 23924525 TI - The late effects of anticancer therapy after childhood Wilm's tumor: the role of diastolic function and ambulatory blood pressure monitoring. AB - OBJECTIVE: Wilms' tumor, or nephroblastoma, is the most common primary malignant renal tumor of childhood. The excellent outcome now expected for most children with this tumor is attributed to the combination of effective adjuvant chemotherapy, improved surgical and anesthetic techniques and also the radiosensitivity of the tumor. The numerous organ systems are subject to the late effects of anticancer therapy. The aim of this study was to investigate the blood pressure profile and ambulatory blood pressure monitoring, and also cardiac diastolic functions and pulmonary venous flow in 25 children with unilateral Wilms' tumor in remission. METHODS: The patient group consists of 25 patients who successfully completed anticancer treatment for unilateral Wilms' tumor. Thirty three age-, weight- and height-matched healthy children were considered as a control group for an echocardiographic study. Also, 20 age-, weight- and height matched healthy children were considered as a control group for the ambulatory blood pressure monitoring study. RESULTS: In our study, 24 h, daytime and night time systolic blood pressure and night-time diastolic blood pressure measurements were found to be significantly increased in the patient group compared with healthy children. We detected diastolic filling pattern abnormalities. We also found increase in pulmonary venous flow (systolic and diastolic) in Wilms' tumor group. CONCLUSIONS: We suggest the regular follow-up of survivors of Wilms' tumor for care and prevention of cardiovascular diseases. PMID- 23924526 TI - [Novel heterozygous mutation in the steroidogenic acute regulatory protein gene in a 46,XY patient with congenital lipoid adrenal hyperplasia]. AB - StAR facilitates cholesterol entry into the mitochondria as part of the transduceosome complex. Recessive mutations in the gen STAR cause classic and nonclassic congenital lipoid adrenal hyperplasia. The aim of the study was to analyze the molecular consequences of a novel heterozygous STAR mutation in a 46,XY patient with ambiguous genitalia and adrenal insufficiency. We found a de novo heterozygous IVS-2A>G STAR mutation and the reported heterozygous p.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1 and TSPO genes. RT-PCR and sequencing from patient's testicular RNA showed a -exon2 transcript and the wild-type (WT) transcript. Both 37 kDa precursor and 30 kDa mature protein were detected in COS-7 cell transfected with mutant and WT plasmids. Immunofluorescence showed almost no co-localization of mitochondria and mutant protein (delta22-59StAR). Delta22-59StAR activity was 65+/-13% of WT. Cotransfection with WT and delta22-59StAR plasmids reduced WT activity by 62.0% +/- 13.9. Novel splice-junction heterozygous STAR mutation (IVS-2A>G) resulted in the in-frame loss of amino acids 22 to 59 in the N-terminal mitochondrial targeting signal. A misfolded p.G22_L59delStAR might interfere with WT StAR activity by blocking the transduceosome complex, causing an autosomal dominant form of StAR deficiency, explaining the clinical phenotype. PMID- 23924527 TI - [Phenotypic markers of attenuation in Junin virus strains recently isolated from individuals vaccinated with Junin Candid#1 strain]. AB - Argentine hemorrhagic fever is a severe acute disease caused by Junin virus. For prevention of this disease an effective vaccine called Candid#1 has been developed, composed of a live attenuated Junin virus strain. During a clinical trial conducted at Instituto Nacional de Enfermedades Virales Humanas (INEVH) in 2005, Junin virus was isolated from two vaccinated volunteers by co-culture of peripheral mononuclear blood cells. The aim of this study was to compare the strains isolated from these human volunteers with Candid#1 strain regarding phenotypic characteristics of attenuation according to the indicators developed by Contigiani and Sabattini in 1977. The three strains were lethal to suckling mice but not to 10-12 days old mice and guinea pigs. Surviving guinea pigs from primary infection were protected when challenged by intra-muscular inoculation with lethal doses of a virulent strain. Infection and protection rates indicate that these strains are highly infective and protective in the hosts studied herein. These results demonstrate that Junin virus strains isolated from volunteers immunized with Candid#1 maintain the same attenuated phenotype of Candid#1 vaccine after one passage in humans. PMID- 23924528 TI - [Tumor necrosis factor-alpha in a children population with overweight]. AB - The child overweight is associated with overweight/obesity at the adult age. The obese adipose tissue produces an increase of proinflammatory cytokines as the tumor necrosis factor alpha (TNF-alpha), causing a deleterious effect on vascular functions. The aim of this work was to evaluate TNF-alpha levels in a children's population with overweight and its relationship with clinical and laboratory variables. Thirty overweight children were studied, with ages between 8-13 years old, and twenty control children. In both groups waist circumference was measured and body mass index (BMI) calculated. The inclusion criterium was a >85th < 95 th BMI percentile for age and sex. In both groups were determined: fasting blood glucose (glucose-oxidase method); plasma insulin (ECLIA); plasma fibrinogen (Fg, Clauss method); high sensitivity C reactive protein (hsCRP, immunoturbidimetric method); plasma myeloperoxidase (ELISA); TNF-alpha (ELISA); lipid profile (enzymatic methods); erythrosedimentation rate (ESR) and homeostasis model assessment index (HOMA). Data were expressed as the median and interquartile range. Correlations between variables were investigated with the Spearman's coefficient. A p < 0.05 was considered significant. The TNF-alpha levels were higher in overweight children [15.4 (13.2-24.0) vs. 12.7 (11.2-14.8) pg/ml; p = 0.028]. Levels of Fg, plasma insulin, HOMA index, uCRP and triglycerides were also statistically significant higher than the control group. The TNF-alpha was positively correlated with the waist circumference (r = 0.654; p = 0.021). The high TNF-alpha levels found, with the CRP and Fg levels, confirm a low grade proinflammatory state associated to abdominal obesity in the studied population. PMID- 23924529 TI - [Common variable immunodeficiency. Epidemiology and clinical manifestations in 69 patients]. AB - Common variable immunodeficiency (CVID) is characterized by an impaired antibody production and an increased susceptibility to recurrent infections of the respiratory tract, mainly by extracellular encapsulated bacteria. We analyzed the clinical characteristics of 69 patients evaluated over a period of 10 years at three centers in the city of Buenos Aires. At the onset of the study 14 patients were on follow up, and at its end the number of patients reached to 60. Most of them consulted for infection or hypogammaglobulinemia and nearly half had an established diagnosis of immunodeficiency. Sixty-five (94.2%) patients had infections by encapsulated bacteria, four (6.1%) sepsis and two tuberculosis. The average age of onset of infectious symptoms was 18.1 years; the average age at diagnosis was 29.6 years and the delay to diagnosis 11.9 years. Forty one (59.4%) patients reported a history of recurrent or chronic diarrhea. In 22 (31.9%) 13 autoimmune diseases were diagnosed, being the most frequent the hematological disorders and hypothyroidism. Eight patients had histological polyclonal lymphoproliferation, four (5.8%) with granulomatous disease affecting the liver, the larynx and/or the skin; and four as lymphoid interstitial pneumonitis (LIP). Nineteen (27.5%) patients had splenomegaly and 23/57 (40.3%) images suggestive of lymphocytic or granulomatous processes (including the 4 with LIP) in the chest CT. Three (4.3%) patients developed B cell lymphoma, four (5.8%) stomach adenocarcinoma and one breast cancer. The study had a median follow-up of 54 months, range 1-353 and four patients (5.8%) died during the follow up. PMID- 23924530 TI - [Antiretroviral treatment adherence and its association with TCD4+ lymphocyte subsets in children with HIV/AIDS]. AB - Human immunodeficiency virus infection causes a severe depletion of TCD4+ lymphocytes and a sustained immune activation state, hallmarks findings that led to numerical and phenotypic changes in the TCD4+ subsets. Highly active anti retroviral therapy has substantially modified the course of HIV infection. Correct adherence to the treatment results in a decrease in viral load at undetectable levels and a significant increase in the number of peripheral T cell lymphocytes. In the present study association between changes in T cell subsets and treatment adherence was evaluated in 28 HIV (+) infected children, before and after 9 months on average, from starting anti-retroviral therapy. The group of 18 patients with good adherence, above 95%, showed a significant increase in CD4+CD45RA+CD62L+ naive cells percentual levels and a decrease in the CD4+CD45RA CD62L+ central memory subset, between the two points of the follow-up period. Conversely, 10 children with failure in the adherence did not show significant differences in the percentual levels of both subsets. Improvement in the percentage of adherence among paediatric population, optimizing antiretroviral treatment, allows a quick and significant reduction of viral replication. This feature is associated with the progressive reconstitution of the immune system. PMID- 23924531 TI - [In-hospital mortality due to stroke]. AB - Overall mortality due to stroke has decreased in the last three decades probable due to a better control of vascular risk factors. In-hospital mortality of stroke patients has been estimated to be between 6 and 14% in most of the series reported. However, data from recent clinical trials suggest that these figures may be substantially lower. Data from FLENI Stroke Data Bank and institutional mortality records between 2000 and 2010 were reviewed. Ischemic stroke subtypes were classified according to TOAST criteria and hemorrhagic stroke subtypes were classified as intraparenchymal hematoma, aneurismatic subarachnoid hemorrhage, arterio-venous malformation, and other intraparenchymal hematomas. A total of 1514 patients were studied. Of these, 1079 (71%) were ischemic strokes,39% large vessels, 27% cardioembolic, 9% lacunar, 14% unknown etiology, and 11% others etiologies. There were 435 (29%) hemorrhagic strokes, 27% intraparenchymal hematomas, 30% aneurismatic subarachnoid hemorrhage, 25% arterio-venous malformation, and 18% other intraparenchymal hematomas. Moreover, 38 in-hospital deaths were recorded (17 ischemic strokes and 21 hemorrhagic strokes), accounting for 2.5% overall mortality (1.7% in ischemic strokes and 4.8% in hemorrhagic strokes). No deaths occurred associated with the use of intravenous fibrinolytics occurred. In our Centre in-hospital mortality in patients with stroke was low. Management of these patients in a Centre dedicated to neurological diseases along with a multidisciplinary approach from medical and non-medical staff trained in the care of cerebrovascular diseases could, at least in part, account for these results. PMID- 23924532 TI - [A simple AV block?]. PMID- 23924533 TI - [Mediastinal lipomatosis]. PMID- 23924534 TI - [Adrenal carcinoma induced hypoglycemia]. AB - Adrenal carcinoma is a rare malignancy of poor prognosis. The most common clinical presentation is secondary to hormone production, while the development of symptomatic hypoglycemia is exceptional. We report the case of a 37 year old woman admitted to hospital with severe hypoglycemia, hypertension, hypokalemia and amenorrhea. In the laboratory we found hypoglycemia, with low insulin levels, and androgen levels in tumor range. CT of abdomen and pelvis showed a heterogeneous lesion of solid appearance without a cleavage plane relative to liver parenchyma, and intense contrast enhancement. Retroperitoneal mass was removed, and the patient evolved without complications, blood glucose and potassium were normalized, blood pressure stabilized and menstrual cycles recovered. PMID- 23924535 TI - [Rituximab-induced interstitial lung disease]. AB - The introduction of the anti-CD20 antibody rituximab into clinical practice has improved substantially the prognosis of a variety of haematological and autoimmune diseases. The interstitial lung disease is one of most serious and potentially fatal complications of rituximab therapy. This diagnosis should be considered in patients who have received the drug and present with dyspnea, fever and cough without clear evidence of infection. We report a case of rituximab induced interstitial lung disease. PMID- 23924536 TI - [Ergotism and HIV]. AB - Ergotism is a complication of acute intoxication and/or chronic abuse of ergot derivatives. It expresses itself through a vasomotor syndrome with peripheral vascular disease which frequently involves extremities. We report four cases of HIV-1 infected patients treated with antiretroviral drugs including boosted protease inhibitors who had self-treated themselves with ergotamine. They developed peripheral vascular disease symptoms and their pulses where diminished or absent in the physical examination. Arterial Doppler confirmed diffused arterial spasm in two of them. Ergotism following ergotamine-protease inhibitors association was diagnosed. Patients were treated through the discontinuity of involved drugs (protease inhibitors and ergotamine), calcium blockers; antithrombotic prophylaxis with enoxaparine, antiaggregant therapy with acetylsalicylic acid, and one of them received pentoxifylline and vasodilator prostaglandins infusion, with amelioration of the symptoms. We discuss the clinical presentation of this drug interaction, difficult to diagnose properly without a strong suspicion of its existence. PMID- 23924537 TI - [Practical guidelines for the diagnosis and treatment of obstructive sleep apnea syndrome]. AB - Obstructive sleep apnoea syndrome (OSAS) is one of the most relevant chronic respiratory pathologies due to its high prevalence and impact in morbidity and mortality. In 2001, the Asociacion Argentina de Medicina Respiratoria (AAMR) published the first Argentinean Consensus on Sleep-Related breathing Disorders. Since then, wide new scientific evidence has emerged, increasing significantly the knowledge about this pathology. According to this, the Sleep-Related breathing Disorders and Oxygen Therapy Section of the AAMR, decided to update its Consensus, developing this Practical Guidelines on Management of patients with OSAS. A working group was created with members belonging to the section, experts in OSAS. They extensively reviewed the literature and wrote these guidelines, orientated to practical resolution of clinical problems and giving answers to questions emerged from dealing with patients who suffer from this syndrome. The document defines OSAS and describes the diagnosis and severity criteria, as well as the risk factors, ways of presentation and epidemiology. Clinical consequences, mainly on cognition, cardiovascular system and metabolism are pointed out. Different diagnostic methods, with their indications and technical aspects for validation and interpretation are detailed. Finally, we describe therapeutic alternatives, as well as practical aspects of their implementation. The authors' aim was to generate an accessible tool for teaching and spreading the knowledge on these disorders, which have a great impact in public health. PMID- 23924538 TI - [Citrate and renal stones]. AB - Citrate is a powerful inhibitor of the crystallization of calcium salts. Hypocitraturia is a biochemical common alteration in calcium stone formation in adults and especially in children. The acid pH (systemic, tubular and intracellular) is the main determinant of citrate excretion in the urine. While the etiology of hypocitraturia is idiopathic in most patients with kidney stones, there are a number of causes for this abnormality including distal renal tubular acidosis, hypokalemia, diets rich in animal protein and / or diets low in alkali and certain drugs, such as acetazolamide, topiramate, ACE inhibitors and thiazides. Dietary modifications that benefit these patients include high intake of fluids and fruits, especially citrus, sodium and protein restriction, with normal calcium intake. Treatment with potassium citrate is effective in patients with primary or secondary hypocitraturia and acidification disorders, which cause unduly acidic urine pH persistently. Adverse effects are low and are referred to the gastrointestinal tract. While there are various preparations of citrate (potassium citrate, sodium citrate, potassium citrate, magnesium) in our country is available only potassium citrate powder that is useful to correct both the hypocitraturia and the low urinary pH and reduce markedly the recurrence of kidney stones. PMID- 23924539 TI - [Genetic tools for risk-stratification in multiple myeloma]. AB - Genetic studies have a central role in the study of multiple myeloma (MM), as they become a critical component in the risk-based stratification of the disease. Significant efforts have been made to identify genetic changes and signatures that can predict clinical outcome and include them in the routine clinical care. Fluorescence in situ hybridization (FISH) still remains the most used genetic technique in clinical practice, mostly due to its very straightforward implementation and the simplicity of data analysis. The advent of high-resolution genomics (i.e. array CGH, exome and whole genome sequencing) and transcriptomics tests (i.e. gene expression profiling - GEP, and mRNA sequencing) provide a comprehensive analysis of the already defined genetic prognostic factors and are helpful tools for the identification of potential novel disease markers on the MM tumor clone. Indeed, GEP has been successfully implemented in MM as a risk stratification tool, holding the greatest power in outcome discrimination. Nevertheless, some technical and logistic intricacies (need of a highly purified tumor clone, cost of the assay and complexity of data analysis) need to be considered before the definitive incorporation of high-throughput technologies in routine clinical tests. Until then, FISH remains the standard tool for genomic abnormality detection and disease prognostication. PMID- 23924540 TI - [The nicking enzyme in Staphylococcus aureus, a very promising target for action]. PMID- 23924541 TI - [Myths and truths about the human genome]. PMID- 23924542 TI - [Globalization in science]. PMID- 23924543 TI - [Loquacity and attention span]. PMID- 23924545 TI - [The presence of two tick species (Acari: Ixodidae) with medical importance in Buenos Aires City]. PMID- 23924546 TI - [Unusual clinical presentation of a lung cancer]. PMID- 23924547 TI - DDT and pyrethroid resistance in Anopheles arabiensis from South Africa. AB - BACKGROUND: Pyrethroid resistance has been well documented in Anopheles arabiensis, one of the major African malaria vectors, and the predominant malaria vector in South Africa. METHODS: In this study, the genetic basis of pyrethroid resistance in a selected laboratory strain of An. arabiensis from South Africa was investigated using a custom-made microarray, known as the An. gambiae detoxification chip. RESULTS: A large number of P450 genes were over-transcribed, as well as a suite of redox genes and glutathione S-transferases. The five genes that showed the highest level of gene transcription when compared with an insecticide susceptible strain were: CYP6AG2, CYPZ1, TPX2, CYPZ2 and CYP6P1. CONCLUSIONS: Permethrin resistance in South African An. arabiensis is associated with increased transcription of multiple genes, and a large proportion of these genes were also previously recorded as over-transcribed in another An. arabiensis strain selected for resistance to DDT with cross-resistance to deltamethrin. The deltamethrin resistance developed de novo in the DDT-selected strain and is most likely due to increased transcription of those genes associated with DDT resistance. However, of particular interest was the fact that the strain selected for resistance to pyrethroids did not develop de novo resistance to DDT. These differences are compared and discussed. PMID- 23924549 TI - Diagnostic value of CD56 and nm23 markers in papillary thyroid carcinoma. AB - CONTEXT: Thyroid cancer is the most common malignant endocrine tumor. Nowadays tissue biopsy and pathological assessment are the best diagnostic modalities for thyroid lesions. Differential diagnosis between adenomas and follicular variant of papillary thyroid carcinoma (PTC) is an important issue in pathology. AIMS: This study is designed to show any association between expressions of CD56 and nm23 and types of thyroid lesions (benign vs. malignant). SETTINGS AND DESIGN: In this cross-sectional study, 78 paraffin-embedded tissue blocks of thyroid tissue from a tertiary care center were selected, and assessed by using immunohistochemistry for expressions of CD56 and nm23 genes. MATERIALS AND METHODS: we studied 39 benign and 39 malignant thyroid lesions, CD56 and nm23 expressions were determined by immunohistochemical staining, and the results were used for differentiation of benign and malignant lesions of thyroid. STATISTICAL ANALYSIS: The obtained results were analyzed and evaluated using SPSS (Version 18). RESULTS: CD56 was expressed in 93% of benign specimens and in only 5% of malignant types. The sensitivity and specificity of this test were 94.8% and 92.3, respectively (P = 0.001). All malignant specimens and 95% of benign specimens were positive for nm23. The sensitivity and specificity of nm23 were 100% and 5%, respectively. CONCLUSION: Considering high sensitivity and specificity of CD56, it is possible to apply immunohistochemistry for definite diagnosis and differentiation of benign lesions from PTC. We conclude that by using this marker, the diagnostic mistakes in pathologic diagnosis of thyroid cancer versus benign lesions like thyroid adenoma will decrease. PMID- 23924550 TI - P-cadherin as myoepithelial cell marker for differential diagnosis of benign and malignant breast lesions. AB - BACKGROUND: P-cadherin is cell-cell adhesion glycoprotein which can be used as a myoepithelial cell (MEC) marker in the breast lesions. MEC layer is retained in most benign lesions and loss of this outer layer is hallmark of infiltrating carcinomas in the breast. AIM: To evaluate the expression of P-cadherin as MEC marker in the differential diagnosis of benign and malignant breast lesions. MATERIALS AND METHODS: Immunohistochemical staining was done using P-cadherin specific antibody on formalin fixed paraffin-embedded sections of 25 benign and 15 malignant breast lumps. RESULTS: All 25 cases of benign breast lesions showed positive P-cadherin immunostaining, while only 4 out of 15 cases of infiltrating ductal carcinoma showed positive immunostaining for P-cadherin. In the case of benign lesions, staining index varied from 4 to 6 or 7 to 9, while in case of malignant lesions, 11 cases showed staining index from 1 to 3. Only 4 out of 15 malignant cases had staining index from 4 to 6. None of them showed index from 7 to 9. CONCLUSIONS: P-cadherin as a MEC marker can be used in differentiating benign and malignant breast lesions. PMID- 23924551 TI - Immunohistochemical expression of p63, p53 in urinary bladder carcinoma. AB - BACKGROUND: Urothelial carcinomas (UC) is of the most common cancers urinary bladder. AIM: The aim of the study is to assess the immunohistochemical staining differences between p63 and p53 according to the pathological stage and histological grade of the tumor in urinary bladder carcinomas. MATERIALS AND METHODS: Totally 62 urinary bladder transurethral resection materials diagnosed with urothelial carcinoma in the pathology department of our hospital were included in the study. On pathological examination, cases were dichotomized as noninvasive and invasive, whereas noninvasive cases were dichotomized as low grade and high grade and invasive cases were dichotomized as pT1 and pT2. Subsequently, the cases were evaluated by means of p63 and p53 immunohistochemical staining. Statistical analyses were performed by SPSS program, and Chi-square and Fisher's exact tests. RESULTS: When pTa was evaluated in terms of p63 immunoreactivity, no statistically significant difference was observed between LGPUC and HGPUC, noninvasive papillary UC, regarding staining percentages ( P > 0.05), whereas statistically significant relation was observed for pT1 and pT2 regarding p63 staining percentages ( P < 0.05). For pTa, no statistically significant relation was observed between LGPUC and HGPUC, noninvasive papillary UC, in terms of p53 staining percentages ( P > 0.05). However, highly significant relationship was observed for pT1 and pT2 in terms of p53 staining percentages ( P < 0.01). No significant relationship was observed between the staining percentages of p53 and p63 ( P > 0.05). CONCLUSION: The role of p53 and p63 immunoreactivities in the differential diagnosis and prognosis of urinary bladder carcinomas according to the pathological stage and histological grade of the tumor will be understood better with the increasing number of long term investigations performed with large series at a molecular level. PMID- 23924552 TI - Intensive method of assessment and classification of the bone marrow iron status: a study of 80 patients. AB - BACKGROUND: The increasing prevalence of multiple co-morbidities among anemic patients with chronic diseases have made the use of serum ferritin (which is also an acute phase reactant) and transferrin saturation more challenging in diagnosing iron deficiency. Microscopic examination of bone marrow aspirate is the gold standard" for assessing marrow iron store. However, conventional Gale's method assesses iron in marrow fragments alone which provides little valuable information about functional iron deficiency seen in many chronic diseases. AIM: To perform an intensive bone marrow iron grading by assessing iron in fragments, in macrophages around fragments and in erythroblasts and to correlate the marrow iron store results with serum ferritin. MATERIALS AND METHODS: A descriptive study of Perl's Prussian blue stained bone marrow aspirate smears of 80 adult patients with moderate to severe anemia. Bone marrow iron was assessed by both the Gale's method and the intensive method and correlated with serum ferritin. RESULTS: The intensive grading system revealed normal iron stores in 37.5% cases, depleted iron stores in 16.25% patients while 23.75% and 22.5% patients had functional iron deficiency and combined deficiency, respectively. Mean log ferritin concentration was significantly lower in patients with depleted iron stores (0.91 MUg/l) in comparison to those with normal iron stores (2.13 MUg/l; P = 0.001), functional iron deficiency (2.65 MUg/l; P = 0.000), or combined deficiency (2.04 MUg/l; P = 0.002). CONCLUSION: Intense marrow iron examination provides a useful iron status classification which is of particular importance in cases of chronic diseases and inflammation. PMID- 23924553 TI - Anti-Toxoplasma gondii antibody detection in serum and urine samples by enzyme linked immunosorbent assay in HIV-infected patients. AB - BACKGROUND: Toxoplasmosis is a common parasitic infection of man, and reactivation of latent disease in HIV-infected patients can cause fatal encephalitis. Diagnosis depends on demonstration of parasite-specific antibodies in serum. In HIV-infected patients, IgM is often undetectable, whereas IgG remains detectable in the majority. Urine sample is very easily available and has not been evaluated for immunodiagnosis of toxoplasmosis. AIM: The study was an effort to find whether urine sample can be used in place of serum for immunodiagnosis of toxoplasmosis. MATERIALS AND METHODS: Enzyme-linked immunosorbent assay (ELISA) was carried out in serum and urine samples collected from 100 HIV-infected patients to detect anti-toxoplasma IgG and IgM antibodies and whether positivity correlated with the CD4 T-cell counts of patients. RESULTS: In this study, we observed that there was no significant difference in positivity of anti-toxoplasma IgM and IgG between serum and urine samples of HIV infected patients by ELISA. There was a negative correlation between CD4 count and seropositivity. CONCLUSION: Urine sample can be satisfactorily used in place of serum for immunodiagnosis of toxoplasmosis. PMID- 23924554 TI - Virulence factors in clinical and commensal isolates of Enterococcus species. AB - BACKGROUND: Enterococci have emerged as important nosocomial pathogens and have been found to possess many virulence factors, some of which are considered very important in the pathogenesis of diseases caused by them. The following study was carried out to evaluate some of the virulence determinants elaborated by strains of enterococci in our setup and to ascertain if these strains differ considerably from commensal strains of enterococci in the expression of these virulence determinants. MATERIALS AND METHODS: One hundred and fifty-seven isolates of Enterococcus species from clinical specimens were evaluated for the presence of virulence determinants like hemolysin production, gelatinase production and biofilm formation by phenotypic tests. The presence of enterococcal surface protein (esp) gene in the isolates was detected using polymerase chain reaction (PCR). Thirty strains of Enterococcus isolated from fecal samples of patients admitted to the hospital were also tested for the presence of these virulence factors. Strains of Enterococcus from clinical specimens and those present as commensals were compared with respect to the elaboration of virulence factors using Fisher's exact test. RESULTS: The association between biofilm formation and presence of the "esp" gene was not found to be statistically significant. Among the virulence determinants studied, gelatinase production and the "esp" gene were found to be significantly more common in clinical isolates than commensal strains of Enterococcus species. CONCLUSION: Among the virulence factors, gelatinase and the "esp" gene were more common in clinical isolates than commensal strains. The association between biofilm formation and the presence of "esp" gene was not found to be statistically significant. PMID- 23924555 TI - Effect of probiotics on the fecal microflora after radiotherapy: a pilot study. AB - BACKGROUND AND AIM: The development of gastrointestinal symptoms following pelvic radiotherapy depends on morphological and functional modifications of the intestinal epithelium after radiation. The aim of this study was to evaluate and compare the effects of preventive administration of the preparation ''5'' Strain Dophilus and Hylak on the fecal microflora after radiotherapy in patients during radiotherapy. MATERIALS AND METHODS: Fourteen patients were randomly selected and subdivided into two groups: The first group was administered ''5'' Strain Dophilus (L Group) and the second group was administered Hylak (H Group). Radiation was delivered by a Cobalt 60 unit by using the four field box technique. The doses were divided into 2 Gy per day over 5 to 7 weeks to give the total cumulative dose of 50 Gy (2 Gy/day). High risk patients (e.g., patients with prostate cancer), received dosage 65 67 Gy (2 Gy/day). RESULTS: Both experimental and clinical studies have shown that probiotics can effectively modulate intestinal inflammation by altering the composition and the metabolic and functional properties of gut indigenous flora. CONCLUSIONS: Many bacteria were found to be sensitive to irradiation. It would be necessary to check the possible effects of cytostatics on bacteria in larger studies. PMID- 23924556 TI - Is high pressure liquid chromatography an effective screening tool for characterization of molecular defects in hemoglobinopathies? AB - INTRODUCTION: Hemoglobinopathies constitute entities that are generated by either abnormal hemoglobin or thalassemias. high pressure liquid chromatography (HPLC) is one of the best methods for screening and detection of various hemoglobinopathies but it has intrinsic interpretive problems. The study was designed to evaluate the different mutations seen in cases of hemoglobinopathies and compare the same with screening tests. MATERIALS AND METHODS: 68 patients of hemoglobinopathies were screened by HPLC. Mutation studies in the beta globin gene was performed using the polymerase chain reaction (PCR)-based allele specific Amplification Refractory Mutation System (ARMS). Molecular analysis for the sickle cell mutation was done by standard methods. RESULTS: The IVS 1/5 mutation was the commonest mutation seen and it was seen in 26 (38.23%) of the cases. This was followed by the IVS 1/1, codon 41/42, codon 8/9, del 22 mutation, codon 15 mutation and the -619 bp deletion. No mutation was seen in eight cases. There was a 100% concordance between the sickle cell trait as diagnosed by HPLC and genetic testing. DISCUSSION AND CONCLUSION: Our study underlies the importance of molecular testing in all cases of hemoglobinopathies. Although HPLC is a useful screening tool, molecular testing is very useful in accurately diagnosing the mutations. Molecular testing is especially applicable in cases with an abnormal hemoglobin (HbD, HbE and HbS) because there may be a concomitant inheritance of a beta thalassemia mutation. Molecular testing is the gold standard when it comes to the diagnosis of hemoglobinopathies. PMID- 23924557 TI - Metastatic renal cell carcinoma in the nasopharynx. AB - Metastatic renal cell carcinoma of the nasopharynx, nasal cavity, and paranasal sinuses can be misdiagnosed as primary malignant or benign diseases. A 33-year old male attended our outpatient clinic complaining of difficulty breathing through the nose, bloody nasal discharge, postnasal drop, snoring, and discharge of phlegm. Endoscopic nasopharyngeal examination showed a vascularized nasopharyngeal mass. Under general anesthesia, multiple punch biopsies were taken from the nasopharynx. Pathologically, the tumor cells had clear cytoplasm and were arranged in a trabecular pattern lined by a layer of endothelial cells. After the initial pathological examination, the pathologist requested more information about the patient's clinical status. A careful history revealed that the patient had undergone left a nephrectomy for a kidney mass diagnosed as renal cell carcinoma 3 years earlier. Subsequently, nasopharyngeal metastatic renal cell carcinoma was diagnosed by immunohistochemical staining with CD10 and vimentin. Radiotherapy was recommended for treatment. PMID- 23924558 TI - Collecting duct renal cell carcinoma with the syndrome of inappropriate antidiuresis: an autopsy case report. AB - A 57-year-old Japanese man visited our hospital with a moist cough. Chest radiographic imaging showed a left hilar shadow. Adenocarcinoma cells were found on cytologic screening of fresh sputum. Although multiple metastases including brain were detected, no tumor was observed in the kidneys. The patient underwent whole-brain irradiation and chemotherapy for advanced-stage lung cancer. One month before his death, carcinomatous meningitis was detected. Hyponatremia, hypo osmolality, and hypertonic urine suggested the syndrome of inappropriate antidiuresis. Restricting water intake improved the hyponatremia; however, he developed fever and hematuria. Despite systemic administration of an antibacterial drug, he died. Primary tumor in the lung was absent, but adenocarcinoma of the right kidney was evident on autopsy. Lectin histochemical analysis of the carcinoma revealed its distal nephron origin, confirming collecting duct carcinoma. Severe carcinomatous meningitis, which is possibly caused the syndrome of inappropriate antidiuresis, was observed, with no cancer involvement of the pituitary gland and hypothalamus. PMID- 23924559 TI - Pulmonary arterial intimal sarcoma with retrograde extension: report of a case and review of literature. AB - Most of the pulmonary arterial sarcomas arise from multi-potential mesenchymal intimal cells and are designated as intimal sarcomas. These tumors grow in the direction of blood flow into peripheral arteries producing clinical features mimicking pulmonary thromboembolism. Retrograde extension is rare. We report one such case of intimal sarcoma that had a retrograde extension into the right ventricular outflow tract, and review such a presentation in the last ten years. PMID- 23924560 TI - Mesonephric adenocarcinoma (endometrioid type) of endocervix with diffuse mesonephric hyperplasia involving cervical wall and myometrium: an unusual case report. AB - Malignant mesonephric tumors are rare variants of cervical adenocarcinoma, derived from remnants of mesonephric ducts and are associated with mesonephric remnants and/or mesonephric hyperplasia. Few cases have been described in literature. We report an unusual case of cervical mesonephric adenocarcinoma of endometrioid type with squamous morules in association with diffuse mesonephric hyperplasia involving the cervical walls and extending into the myometrium. PMID- 23924561 TI - Alfa-fetoprotein secreting ovarian sex cord-stromal tumor. AB - Ovarian sex cord-stromal tumors are relatively infrequent neoplasms that account for approximately 8% of all primary ovarian tumors. They are a heterogeneous group of neoplasms composed of cells derived from gonadal sex cords (granulosa and Sertoli cells), specialized gonadal stroma (theca and Leydig cells), and fibroblasts. They may show androgenic or estrogenic manifestations. We report such a tumor associated with markedly raised serum alpha-fetoprotein (AFP) levels in a young female presenting with a mass and defeminising symptoms. Serum AFP levels returned to normal on removal of tumor. PMID- 23924562 TI - Placental mesenchymal dysplasia: a report of two cases with review of literature. AB - Placental mesenchymal dysplasia (PMD) is a recently recognized, rare placental vascular anomaly characterized by placentomegaly and grape-like vesicles mimicking partial molar pregnancy. It is associated with significant fetal morbidity and mortality. We describe the histologic features of PMD in two different cases with different disease outcomes, one in a preterm intrauterine death (IUD) and another in a live birth. Placental examination in both the cases revealed large placenta with multiple vesicles and mesenchymal dysplasia. PMID- 23924563 TI - Cutaneous Rosai-Dorfman disease: report of a case. PMID- 23924564 TI - Nasopharyngeal glial heterotopia: a rare cause of airway obstruction in an infant. PMID- 23924565 TI - Retinal dysplasia mimicking retinoblastoma. PMID- 23924566 TI - Nasal pseudolipomatosis. PMID- 23924567 TI - Giant cell myocarditis with epicardial and endocardial involvement: an autopsy case report with review of literature. PMID- 23924568 TI - Giant untreated Wilms tumor with intracardiac extension: a rare case. PMID- 23924569 TI - Comment on: Primary squamous cell carcinoma of the renal parenchyma. PMID- 23924570 TI - Bizarre parosteal osteochondromatous proliferation of phalanx. PMID- 23924571 TI - Congenital erythrodermic psoriasis with atopic dermatitis: an example of immunogenetic spinoff. PMID- 23924572 TI - Detection of quinupristin-dalfopristin resistance in methicillin-resistant Staphylococcus aureus in South India. PMID- 23924574 TI - Low temperature ballistic spin transport in the S = 1/2 antiferromagnetic Heisenberg chain compound SrCuO2. AB - We report zero and longitudinal magnetic field muon spin relaxation (MUSR) measurements of the spin S = 1/2 antiferromagnetic Heisenberg chain material SrCuO2. We find that in a weak applied magnetic field B0 the spin-lattice relaxation rate lambda follows a power law lambda is proportional to B(0)(-n) with n = 0.9(3). This result is temperature independent for 5 K <= T <= 300 K. Within conformal field theory and using the Muller ansatz we conclude ballistic spin transport in SrCuO2. PMID- 23924573 TI - Common rs7138803 variant of FAIM2 and obesity in Han Chinese. AB - BACKGROUND: Obesity causes severe healthcare problem worldwide leading to numerous diseases, such as cardiovascular diseases and diabetes mellitus. Previous Genome-Wide Association Study (GWAS) identified an association between a single nucleotide polymorphism (SNP) rs7138803, on chromosome 12q13 and obesity in European Caucasians. Since the genetic architecture governing the obesity may vary among different populations, we investigate the variant rs7138803 in Chinese population to find out whether it is associated with obesity. METHODS: A population-based cohort association study was carried out using the High Resolution Melt (HRM) method with 1851 participants. The association between rs7138803 genotypes and body mass index (BMI) was modeled with a general linear model, and a case-control study for the association between rs7138803 genotypes and obesity was performed using Pearson's chi2 test. There was no indication of a deviation from Hardy-Weinberg equilibrium (HWE p value = 0.51) in our sample. RESULTS: No association was detected between SNP rs7138803 and BMI in our Chinese Han population with a P value of 0.51. SNP rs7138803 was found to be not associated with common forms of obesity after adjusting for age and sex in the Chinese population. SNP rs7138803 was not associated with other obesity related traits, including T2DM, hypertension, lipid profiles, and ischemic stroke. CONCLUSION: Our data suggest that the rs7138803 exerts no significant effect on obesity in Chinese Han population. Larger cohorts may be more appropriate to detect an effect of this SNP on common obesity. PMID- 23924575 TI - Synthesis of leukotrienes in porcine uteri with endometritis induced by infection with Escherichia coli. AB - Leukotrienes (LTs) are lipid mediators that play a significant role in the inflammatory process. Their production in inflamed uteri is not fully understood. The present experiment aimed to determine LTB4 and LTC4 amounts, 5-lipooxygenase (5-LO), LTA4 hydrolase (LTAH) and LTC4 synthase (LTCS) mRNA levels and protein expression in inflamed porcine uteri. On Day 3 of the oestrous cycle (Day 0 of the study), either Escherichia coli suspension or saline were infused into uterine horns. Collection of uterine tissues and washings took place eight or sixteen days later. In gilts suffering from endometritis increased LTB4 and LTC4 levels in the endometrium and washings and 5-LO mRNA levels in the myometrium on Days 8 and 16, 5-LO protein levels in the endometrium and myometrium on Day 8, LTAH mRNA and protein levels in the endometrium and myometrium on Days 8 and 16, respectively. Although LTCS mRNA and protein expression in the myometrium and LTCS protein expression in the endometrium were enhanced on Day 16 after Escherichia coli inoculation, LTCS mRNA levels decreased on Day 8 in both tissues. Our study shows the upregulation of LT production in inflamed porcine uteri, which suggests the importance of these factors to the process of uterine inflammation. PMID- 23924576 TI - Increased asthma risk and asthma-related health care complications associated with childhood obesity. AB - Asthma is the most common chronic condition of childhood, yet the relationship between obesity and asthma risk and the impact of obesity on clinical asthma outcomes are not well understood. For this population-based, longitudinal study, demographic and clinical data were extracted from administrative and electronic health records of 623,358 patients aged 6-19 years who were enrolled in the Kaiser Permanente Southern California health plan in 2007-2011. Crude asthma incidence ranged from 16.9 per 1,000 person-years among normal-weight youth to 22.3 per 1,000 person-years among extremely obese youth. The adjusted risks of asthma for overweight, moderately obese, and extremely obese youth relative to those of normal weight youth were 1.16 (95% confidence interval: 1.13, 1.20), 1.23 (95% confidence interval: 1.19, 1.28), and 1.37 (95% confidence interval: 1.32, 1.42), respectively (Ptrend < 0.0001). The relationship between obesity and asthma risk was strongest in Asian/Pacific Islanders and in the youngest girls (aged 6-10 years), compared with other groups. Among youth who developed asthma, those who were moderately or extremely obese had more frequent asthma exacerbations requiring emergency department services and/or treatment with oral corticosteroids. In conclusion, obese youth are not only more likely to develop asthma, but they may be more likely to have severe asthma, resulting in a greater need for health care utilization and aggressive asthma treatment. PMID- 23924578 TI - Abdelouahab et al. respond to "Maternal PBDEs and thyroid hormones". PMID- 23924577 TI - Invited commentary: Maternal plasma polybrominated diphenyl ethers and thyroid hormones--challenges and opportunities. AB - Thyroid hormones play a fundamental role in fetal and child development. While iodine deficiency-related maternal and child hypothyroidism may cause severe mental retardation, recent evidence suggests that milder forms of maternal hypothyroidism and hypothyroxinemia during pregnancy are also associated with altered neurodevelopment. On the other hand, hyperthyroidism during pregnancy has been associated with adverse fetal outcomes. Findings published by Abdelouahab et al. in the American Journal of Epidemiology (Am J Epidemiol. 2013;178(5):701-713) suggest that plasma concentrations of maternal polybrominated diphenyl ethers (PBDEs), which were used as flame retardants until recently and are detected in the tissues of virtually every North American, are associated with umbilical cord and maternal thyroid hormone levels during pregnancy. Although PBDEs have been consistently shown to reduce levels of free and total thyroxine in experimental animal studies, the direction of associations in human studies has been inconsistent. In this commentary, I discuss challenges beyond the factors often cited in the epidemiologic literature to explain inconsistent findings which more specifically apply to the study of PBDEs and thyroid hormones. These include the determination of iodine intake status, the method used to adjust for blood lipid concentrations, the measurement of free thyroid hormone levels, the possible effect of PBDE metabolites, and the potential for reverse causality. PMID- 23924579 TI - Maternal and cord-blood thyroid hormone levels and exposure to polybrominated diphenyl ethers and polychlorinated biphenyls during early pregnancy. AB - Thyroid hormones play a critical role in the growth of many organs, especially the brain. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) interact with the thyroid pathway and may disturb neurodevelopment. This prospective study was designed to examine associations between maternal blood PBDEs and PCBs in early pregnancy and levels of thyroid hormones in maternal and umbilical-cord blood. Levels of low-brominated PBDEs, 3 PCB congeners, total and free thyroid hormones (triiodothyronine (T3) and thyroxine (T4)), thyroid stimulating hormone, thyroid peroxidase antibodies, iodine, selenium, and mercury were measured in 380 pregnant women in the first trimester who were recruited at the University Hospital Center of Sherbrooke (Quebec, Canada) between September 2007 and December 2008. Thyroid hormone levels were also assessed at delivery and in cord blood (n = 260). Data were analyzed on both a volume basis and a lipid basis. At less than 20 weeks of pregnancy, no relationship was statistically significant in volume-based analysis. In lipid-based models, an inverse association between maternal PBDEs and total T3 and total T4 and a direct association with free T3 and free T4 were observed. At delivery, in both analyses, we observed negative associations between maternal total T4, free T3, cord-blood free T4, and PBDEs and between maternal free T3 and PCBs. Our results suggest that exposure to PBDEs and PCBs in pregnancy may interfere with thyroid hormone levels. PMID- 23924580 TI - Improving the end-of-life for people with dementia living in a care home: an intervention study. AB - BACKGROUND: One in three adults, most of whom are living in a care home at the time, dies with dementia. Their end-of-life is often in hospital, where they may experience uncomfortable interventions without known benefit and die rapidly with uncontrolled pain and comfort needs. This study aimed to improve end-of-life care for people with dementia in a care home by increasing the number and implementation of advanced care wishes. METHODS: We recruited staff, residents with dementia, and their relatives from a 120-bed nursing home in London, UK. The intervention was a ten-session manualized, interactive staff training program. We compared advance care wishes documentation and implementation, place of death for residents who died, and themes from staff and family carers' after-death interviews pre- and post-intervention. RESULTS: Post-intervention there were significant increases in documented advance care wishes arising from residents' and relatives' discussions with staff about end-of-life. These included do not resuscitate orders (16/22, 73% vs. 4/28, 14%; p < 0.001); and dying in the care homes as opposed to hospital (22/29, 76% vs. 14/30, 47%; p < 0.02). Bereaved relatives overall satisfaction increased from 7.5 (SD = 1.3) pre-intervention to 9.1 (SD = 2.4) post-intervention; t = 17.6, p = 0.06. Relatives reported increased consultation and satisfaction about decisions. Staff members were more confident about end-of-life planning and implementing advanced wishes. CONCLUSION: This small non-randomized study is the first end-of-life care in dementia intervention to report an increase in family satisfaction with a reduction in hospital deaths. This is promising but requires further evaluation in diverse care homes. PMID- 23924581 TI - How structure shapes (dys)function: a perspective to understanding brain region specific degeneration in prion disease. AB - Structure is a key determinant of function, with the nervous system being no exception. For example, in the nervous system the physiological properties of different synapses may be understood by comparing their structures. However, it is not clear whether specific structural properties of some neurons might play a role in driving their selective removal during chronic neurodegeneration or whether the structural properties might underpin why particular types of synapses or other neuronal compartments are more susceptible to degeneration (i.e., become dysfunctional) in certain brain regions than in others. Our recent study of the ultrastructure of the hippocampus and the cerebellum revealed that early synaptic loss is not a ubiquitous event in a brain undergoing chronic neurodegeneration. The prominent structural differences in proximity of the synaptic environment that are brought about by a degree of synaptic ensheathment by glial cells may help explain why Purkinje cell synapses remain intact, while pyramidal cell synapses progressively degenerate. The intrinsic structural organization of the hippocampal neuropil could contribute to the susceptibility of synapses to extracellular protein misfolding by a relatively higher degree of synaptic exposure to the extracellular environment. We suggest that neuronal structure may determine more than function; it might also predict dysfunction. PMID- 23924582 TI - Mitochondrial membrane lipidome defines yeast longevity. AB - Our studies revealed that lithocholic acid (LCA), a bile acid, is a potent anti aging natural compound that in yeast cultured under longevity-extending caloric restriction (CR) conditions acts in synergy with CR to enable a significant further increase in chronological lifespan. Here, we investigate a mechanism underlying this robust longevity-extending effect of LCA under CR. We found that exogenously added LCA enters yeast cells, is sorted to mitochondria, resides mainly in the inner mitochondrial membrane, and also associates with the outer mitochondrial membrane. LCA elicits an age-related remodeling of glycerophospholipid synthesis and movement within both mitochondrial membranes, thereby causing substantial changes in mitochondrial membrane lipidome and triggering major changes in mitochondrial size, number and morphology. In synergy, these changes in the membrane lipidome and morphology of mitochondria alter the age-related chronology of mitochondrial respiration, membrane potential, ATP synthesis and reactive oxygen species homeostasis. The LCA-driven alterations in the age-related dynamics of these vital mitochondrial processes extend yeast longevity. In sum, our findings suggest a mechanism underlying the ability of LCA to delay chronological aging in yeast by accumulating in both mitochondrial membranes and altering their glycerophospholipid compositions. We concluded that mitochondrial membrane lipidome plays an essential role in defining yeast longevity. PMID- 23924583 TI - Functional characterization of three MicroRNAs of the Asian tiger mosquito, Aedes albopictus. AB - BACKGROUND: Temporal and stage specific expression of microRNAs (miRNAs) in embryos, larvae, pupae and adults of Aedes albopictus showed differential expression levels across the four developmental stages, indicating their potential regulatory roles in mosquito development. The functional characterization of these miRNAs was not known. Accordingly our study evaluated the functional characterization of three miRNAs, which are temporally up regulated in the various developmental stages of Ae. albopictus mosquitoes. METHODS: miRNA mimics, inhibitors and negative controls were designed and their knock-in and knock-down efficiency were analyzed by qRT-PCR after transfecting the mosquito cell lines C6/36, and also by injecting in their specific developmental stages. The functional role of each individual miRNA was analyzed with various parameters of development such as, hatching rate and hatching time in embryos, eclosion rate in larvae, longevity and fecundity in the adult mosquitoes. RESULTS: The knock-in with the specifically designed miRNA mimics showed increased levels of expression of miRNA compared with their normal controls. We confirmed these findings using qRT-PCR, both by in vitro expression in C6/36 mosquito cell lines after transfection as well as in in vivo expression in developmental stages of mosquitoes by microinjection. The knock-down of expression with the corresponding inhibitors showed a considerable decrease in the expression levels of these miRNAs and obvious functional effects in Ae. albopictus development, detected by a decrease in the hatching rate of embryos and eclosion rate in larvae and a marked reduction in longevity and fecundity in adults. CONCLUSION: This study carried out by knock-in and knock-down of specifically and temporally expressed miRNAs in Ae. albopictus by microinjection is a novel study to delineate the importance of the miRNA expression in regulating mosquito development. The knock-down and loss of function of endogenously expressed miRNAs by the miRNA inhibitors in specific developmental stages had considerable effects on development, but enhancement of their gain of function was not observed on knock-in of these specific miRNAs. Hence, our study indicates that an optimal level of endogenous expression of miRNA is indispensable for the normal development and maintenance of the vectorial population density and pathogen transmissibility of this mosquito vector. PMID- 23924584 TI - Cognitive training and cognitive rehabilitation for persons with mild to moderate dementia of the Alzheimer's or vascular type: a review. AB - Cognitive impairments, and particularly memory deficits, are a defining feature of the early stages of Alzheimer's disease and vascular dementia. Interventions that target these cognitive deficits and the associated difficulties with activities of daily living are the subject of ever-growing interest. Cognitive training and cognitive rehabilitation are specific forms of non-pharmacological intervention to address cognitive and non-cognitive outcomes. The present review is an abridged version of a Cochrane Review and aims to systematically evaluate the evidence for these forms of intervention in people with mild Alzheimer's disease or vascular dementia. Randomized controlled trials (RCTs), published in English, comparing cognitive rehabilitation or cognitive training interventions with control conditions and reporting relevant outcomes for the person with dementia or the family caregiver (or both), were considered for inclusion. Eleven RCTs reporting cognitive training interventions were included in the review. A large number of measures were used in the different studies, and meta-analysis could be conducted for several primary and secondary outcomes of interest. Several outcomes were not measured in any of the studies. Overall estimates of the treatment effect were calculated by using a fixed-effects model, and statistical heterogeneity was measured by using a standard chi-squared statistic. One RCT of cognitive rehabilitation was identified, allowing the examination of effect sizes, but no meta-analysis could be conducted. Cognitive training was not associated with positive or negative effects in relation to any of the reported outcomes. The overall quality of the trials was low to moderate. The single RCT of cognitive rehabilitation found promising results in relation to some patient and caregiver outcomes and was generally of high quality. The available evidence regarding cognitive training remains limited, and the quality of the evidence needs to improve. However, there is still no indication of any significant benefits from cognitive training. Trial reports indicate that some gains resulting from intervention may not be captured adequately by available standardized outcome measures. The results of the single RCT of cognitive rehabilitation show promise but are preliminary in nature. Further well-designed studies of cognitive training and cognitive rehabilitation are required to provide more definitive evidence. Researchers should describe and classify their interventions appropriately by using the available terminology. PMID- 23924585 TI - Sustained virological response and baseline predictors in HIV-HCV coinfected patients retreated with pegylated interferon and ribavirin after failing a previous interferon-based therapy: systematic review and meta-analysis. AB - BACKGROUND: Published data on retreatment with pegylated interferon and ribavirin of previously failing HIV-HCV coinfected patients are sparse and limited to observational study. We aimed to evaluate efficacy and pretreatment predictors. METHODS: Systematic review and meta-analysis of observational studies. The overall and genotype-related success rate was investigated. A direct comparison was performed between genotypes 1/4 and 2/3 by evaluating the sustained virological response (SVR) rate ratio (RR). The effect of study level variables on the effect size was investigated by meta-regression. Variables that were analyzed included age, gender, advanced hepatic fibrosis, pretreatment of HCV RNA and CD4, and successful antiretroviral treatment (ART). RESULTS: The available evidence was from 5 open-label, cohort studies (275 patients). The overall SVR rate was 0.280 (95% CI,0.171-0.425). The SVR rate in genotype 1/4 infections was 0.174 (95% CI, 0.129-0.230), and in genotype 2/3 infections it was 0.474 (95% CI, 0.286-0.670). The pooled RR comparing the SVR of genotype 1/4 to 2/3 was 0.369 (95% CI, 0.239-0.568), with a decreased probability of response for genotype 1/4 (P < .001). HIV RNA suppression had a significant effect on SVR (P = .005). The other covariates had no effect on the overall SVR rate. CONCLUSIONS: The overall SVR rate was 28%, consistent with the rate reported in the retreatment of mono infected patients with the same schedule. A substantial relative reduction in the SVR rate of about one-third, when treating genotypes 1/4, was found, with a low SVR rate of 17%. Successful HIV suppression by ART predicted a higher rate of treatment success. PMID- 23924586 TI - Randomized trial to evaluate cardiometabolic and endothelial function in patients with plasma HIV-1 RNA suppression switching to darunavir/ritonavir with or without nucleoside analogues. AB - BACKGROUND: We performed a study to evaluate change in cardiometabolic and endothelial function in HIV-infected patients switching to darunavir/ritonavir (DRV/r) monotherapy versus triple therapy. METHODS: The MONARCH trial recruited 30 patients who were taking triple combination therapy and with HIV RNA<40 copies/ mL. Patients were randomized to either DRV/r 800/100 mg once daily (OD) monotherapy or DRV/r 800/100 mg OD plus 2 nucleoside reverse transcriptase inhibitors (NRTIs). The primary objective was to assess endothelial function change from baseline to 24 and 48 weeks in brachial artery flow-mediated dilation (FMD) test; changes in endothelial precursor cells (EPCs) and circulating endothelial cells (CECs) were secondary objectives. RESULTS: At baseline, the median age of participants was 43 years, 77% were men, and median CD4 cell count was 585 cells/MUL. The median FMD (%) decreased in both arms in the study period (P ? .05), with no statistically significant difference between arms (10.7% at baseline and 6.7% at week 48 in the DRV/r + 2 NRTIs arm; 11.1% at baseline and 8.8% at week 48 in the DRV/r arm). The changes at week 48 were similar in the 2 arms for EPCs and CECs. Total cholesterol and low-density lipoprotein (LDL) cholesterol showed larger rises to week 48 in the DRV/r arm monotherapy group than in the triple-therapy group (+26 vs +9 mg/dL for total cholesterol and +14 vs +5 mg/dL for LDL cholesterol). CONCLUSIONS: In the MONARCH trial, switching from triple combination treatment to DRV/r, with or without nucleoside analogues, did not translate into clinically meaningful reductions in endothelial function as measured by FMD. PMID- 23924587 TI - Baseline CD4+ T-cell counts predict HBV viral kinetics to adefovir treatment in lamivudine-resistant HBV-infected patients with or without HIV infection. AB - BACKGROUND: Coinfection with HIV and hepatitis B virus (HBV) substantially alters the course of HBV. Directly acting anti-HBV agents suppress HBV viral levels; however, the kinetics of HBV decline in mono- and coinfected persons have not been evaluated. We investigated the role of baseline CD4+ T-cell counts as a predictor of HBV response to adefovir (ADV) therapy in chronic HBV with and without HIV coinfection. METHODS: We conducted a double-blind, randomized, placebo-controlled study of HIV-infected (n = 12) and uninfected (n = 5) chronic HBV patients treated with ADV. Five HIV uninfected patients received ADV; the HIV+ patients received ADV or placebo for a total of 48 weeks. At the end of 48 weeks, all patients received open-label ADV for an additional 48 weeks. HBV, HIV viral loads, CD4+ T-cell counts, and safety labs were performed on days 0, 1, 3, 5, 7, 10, 14, and 28 and then every 4 weeks. RESULTS: Lower HBV slopes were observed among coinfected compared to monoinfected patients (P = .027 at 4 weeks, P = .019 at 24 weeks, and P = .045 at 48 weeks). Using a mixed model analysis, we found a significant difference between the slopes of the 2 groups at 48 weeks (P = .045). Baseline CD4+ T-cell count was the only independent predictor of HBV decline in all patients. CONCLUSION: HIV coinfection is associated with slower HBV response to ADV. Baseline CD4+ T-cell count and not IL28B genotype is an independent predictor of HBV decline in all patients, emphasizing the role of immune status on clearance of HBV. PMID- 23924588 TI - Flow cytometry analysis with a new FITC-conjugated monoclonal antibody-3E12 for HLA-B*57:01 rapid screening in prevention of abacavir hypersensitivity in HIV-1 infected patients. AB - BACKGROUND: Rapid screening for the detection of HLA-B*57:01 in the prevention of abacavir hypersensitivity in HIV-1-infected patients is a hallmark for clinical services. OBJECTIVE: The aim of this work was to analyze the utility of flow cytometry with a new FITC-conjugated B-17 monoclonal antibody (mAb3E12) for HLA B*57:01 screening in a Spanish cohort of 577 HIV-1+ individuals. METHODS: Cryopreserved peripheral blood mononuclear cell samples from HIV-1+ individuals were analyzed by flow cytometry with the mAb 3E12 that recognizes both HLA-B*57 and HLA-B*58 alleles (members of the group specificity, HLA-B17). Patients' DNA samples had been previously typed for HLA-B*57:01 with PCR-SSO or PCR-SSP and additional DNA sequencing (EPI Study). The results obtained by flow cytometry were compared with the results obtained by the DNA-PCR techniques. RESULTS: By flow cytometry, 46 samples (7.97%) were positive for HLA-B17, 530 (91.86%) were negative, and 1 (0.17%) was undetermined. All samples found negative by flow cytometry were negative for HLA-B*57:01 by DNA-PCR. Of the HLA-B17 positive samples, 31 (67.4%) were positive for HLA-B*57:01, 2 (3.25%) were positive for HLA-B*57:03, 11 (26.1%) were positive for HLA-B*58, and 2 (3.25%) were negative for both HLA-B*57 and HLA-B*58 antigens. The undetermined sample was negative for HLA-B*57 and HLA-B*58 alleles by DNA-PCR. CONCLUSIONS: This study shows that flow cytometry with mAb3E12 is a highly sensitive method (no false negatives) to implement prior to DNA-PCR analysis for rapid screening of HLA-B*57:01. Additional confirmation by molecular HLA typing method would be required in less than 10% of the cohort of HIV-1-infected individuals. PMID- 23924589 TI - Pilot study of younger and older HIV-infected adults using traditional and novel functional assessments. AB - OBJECTIVES: Emerging data suggest that HIV disease and its treatment affect the aging process. Accurate and reliable measures of functional status are needed to investigate this further. DESIGN: A pilot study in groups of younger and older HIV-infected adults using objective measures of function. METHODS: Evaluations included neuropsychological testing, grip strength, balance assessed by the Wii Balance Board, and actigraphy. Surveys were used for depression, fatigue, loneliness, self-reported activity level, and sexual function. Two-samplet test or Wilcoxon rank sum tests were used for continuous variables and exact chi square tests were used for comparison between groups. RESULTS: Twenty-one participants were 20 to 40 years old (younger; mean age, 31.5), and 20 were more than 50 years old (older; mean age, 56.5). There was no difference between groups for depression, fatigue, or loneliness. Overall, there was a trend to lower scores in the older age group for neuropsychologicalz score (P = .11) and for verbal learning (P = .09). Functioning in the memory domain was significantly lower in older subjects (P = .007). There was no difference in executive function, speed of processing, memory, motor skills, or total activity. Gender differences in sexual function were observed. Four older and 3 younger participants met the definition of frailty. Total activity by actigraphy did not correlate well with self-reported activity. CONCLUSIONS: Objective tests were well accepted and feasible to perform, although not all are suitable for widespread clinical or research use. Objective measurements of activity did not correlate well with patient self-report, which has implications for future studies in this area. PMID- 23924591 TI - Women's Oral Health: Is There a Hormonal Link? PMID- 23924590 TI - Immune response after a single dose of the 2010/11 trivalent, seasonal influenza vaccine in HIV-1-infected patients and healthy controls. AB - BACKGROUND: Immune response rates following influenza vaccination are often lower in HIV-infected individuals. Low vitamin D levels were correlated with weak immune response in cancer patients and are known to be lower in HIV-infected patients. METHODS: Diagnostic study to determine immune response against the H1N1v component after a single, intramuscular dose of the 2010/11 seasonal, trivalent influenza vaccine (TIV) in adult HIV-infected and healthy controls scheduled for influenza vaccination (ClinicalTrials.gov Identifier: NCT01017172). Influenza A/H1N1 antibody titers (AB) were determined before and 21 days after vaccination by hemagglutination inhibition assay. RESULTS: Immune response was not different between HIV-infected patients (n = 36) and healthy controls (n = 42) who were previously naive to the H1N1v component of the TIV. Comparing HIV infected patients (n = 55) and healthy controls (n = 63) who had received 1 or 2 doses of an AS03 adjuvanted H1N1 vaccine in the previous winter season (2009/10), seroconversion rate and the geometric mean AB titer after TIV of the HIV-infected patients were more than twice as high compared to healthy controls. This difference was mainly driven by the 2-dose schedule for HIV patients in 2009/10. Vitamin D levels were lower in HIV patients but did not correlate with immune response. CONCLUSION: HIV-infected patients who had received 1 or 2 doses of an adjuvanted H1N1 vaccine in the previous year (2009/10) had a significant higher seroconversion rate following TIV as compared to healthy controls, indicating a stronger memory cell response due to the 2-dose schedule. PMID- 23924593 TI - Prevention is the Best Medicine: Don J. Bottoni, RPh,FACA,FIACP. PMID- 23924592 TI - Androgen deficiency in women: understanding the science, controversy and art of treating our patients-part 1. PMID- 23924594 TI - Detailing your compounding specialty practice: part 1-prospecting preapproach and approach. PMID- 23924596 TI - Basics of compounding for disorders of the external ear. PMID- 23924595 TI - Developing and providing compounding services for hospitals involved in a merger. PMID- 23924597 TI - Quality-control analytical methods: selecting and analytical method. PMID- 23924598 TI - Metro atlanta board-certified specialists' attitudes toward compounding pharmacy. AB - Prescribers practicing in metropolitan Atlanta were surveyed to examine their attitudes about compounding pharmacy, their perceived uses and indicated needs for compounding services, and their interest in learning more about compounding pharmacy. A questionnaire was mailed to random samples of 100 prescribers in each of the following specialties: veterinary, internal medicine, obstetrics and gynecology, and dermatology, with 25% responding. Attitudes toward compounding pharmacy were measured using 21 items and a five-point response scale (1 = strongly disagree). Overall, the prescribers felt favorably toward compounding pharmacy, with a mean attitude of 3.94. The majority indicated that they had needs for compounding pharmacy related to medication strength, size dosage form, removal of dyes or preservatives, and commercial availability. Potential areas for detailing compounding services were identified within specialties, where prescribers were not aware of some beneficial uses of compounding pharmacy. The majority of prescribers were interested in learning more about compounding pharmacy. The desired educational methods in order of preference were written information (96%), attendance at a seminar (40%), and an office detail conducted by a compounding pharmacist (31%). PMID- 23924599 TI - Stability of Zidovudine and Dobutamine Hydrochloride Injections in 0.9% Sodium Chloride and 5% Dextrose Injections Stored at Ambient Temperature (23 +/- 2 Deg C) and 4 Deg C in 50-mL Polyvinyl Chloride Bags Up to 24 Hours. AB - The stability of a 2-mg/mL zidovudine and 1-mg/mL dobutamine hydrochloride admixture stored in 0.9% sodium chloride and 5% dextrose injections in 50-mL polyvinyl chloride bags at ambient temperature (23 +/- 2 deg C) and 4 deg C for up to 24 hours was studied. The samples were analyzed at 0, 4, 8, and 24 hours after preparation of the controls and known mixtures by means of a reverse-phase stability indicating high-performance liquid chromatographic method. The drug mixtures were stable for up to 24 hours, as shown by the greater than 90% of initial concentrations at the time of preparation. The pH of the drug solutions remained constant in the pH 6 to 7 range. These data support the stability of the zidovudine and dobutamine admixture under the storage conditions studied. PMID- 23924600 TI - Inositol-related gene knockouts mimic lithium's effect on mitochondrial function. AB - The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout (KO) mice of two genes (IMPA1 or Slc5a3), each encoding for a protein related to inositol metabolism, were studied in comparison with lithium-treated mice. Since we previously demonstrated that these KO mice exhibit a lithium-like neurochemical and behavioral phenotype, here we searched for pathways that may mediate lithium's/the KO effects. We performed a DNA-microarray study searching for pathways affected both by chronic lithium treatment and by the KO of each of the genes. The data were analyzed using three different bioinformatics approaches. We found upregulation of mitochondria related genes in frontal cortex of lithium-treated, IMPA1 and Slc5a3 KO mice. Three out of seven genes differentially expressed in all three models, Cox5a, Ndufs7, and Ndufab, all members of the mitochondrial electron transfer chain, have previously been associated with bipolar disorder and/or lithium treatment. Upregulation of the expression of these genes was verified by real-time PCR. To further support the link between mitochondrial function and lithium's effect on behavior, we determined the capacity of chronic low-dose rotenone, a mitochondrial respiratory chain complex I inhibitor, to alter lithium-induced behavior as measured by the forced-swim and the amphetamine-induced hyperlocomotion paradigms. Rontenone treatment counteracted lithium's effect on behavior, supporting the proposition suggested by the bioinformatics analysis for a mitochondrial function involvement in behavioral effects of lithium mediated by inositol metabolism alterations.The results provide support for the notion that mitochondrial dysfunction is linked to bipolar disorder and can be ameliorated by lithium. The phenotypic similarities between lithium-treated wild-type mice and the two KO models suggest that lithium may affect behavior by altering inositol metabolism. PMID- 23924601 TI - Obesity at conception programs the opioid system in the offspring brain. AB - Maternal obesity during pregnancy increases the risk for offspring obesity, in part through effects on the developing brain. Previous research has shown that perinatal consumption of highly palatable foods by the mother can influence the development of offspring taste preferences and alter gene expression within the central nervous system (CNS) reward system. Opioids stimulate consumption of both fats and carbohydrates, and overconsumption of these energy dense foods increases the risk for obesity. What has remained unclear is whether this risk can be transmitted to the offspring before gestation or if it is wholly the gestational exposure that affects offspring brain development. Utilizing an embryo transfer experimental design, 2-cell embryos were obtained from obese or control dams, and transferred to obese or control gestational carriers. Expression of the mu-opioid receptor (MOR), preproenkephalin (PENK), and the dopamine transporter was evaluated in the hypothalamus and reward circuitry (ventral tegmental area, prefrontal cortex, and nucleus accumbens) in adult and late embryonic brains. Obesity before pregnancy altered expression levels of both MOR and PENK, with males relatively more affected than females. These data are the first to demonstrate that obesity at conception, in addition to during gestation, can program the brain reward system. PMID- 23924602 TI - Screening and risk factors of exocrine pancreatic insufficiency in critically ill adult patients receiving enteral nutrition. AB - INTRODUCTION: Malnutrition is a frequent problem associated with detrimental clinical outcomes in critically ill patients. To avoid malnutrition, most studies focus on the prevention of inadequate nutrition delivery, whereas little attention is paid to the potential role of exocrine pancreatic insufficiency (EPI). In this trial, we aim to evaluate the prevalence of EPI and identify its potential risk factors in critically ill adult patients without preexisting pancreatic diseases. METHODS: In this prospective cross-sectional study, we recruited 563 adult patients with critical illnesses. All details of the patients were documented, stool samples were collected three to five days following the initiation of enteral nutrition, and faecal elastase 1 (FE-1) concentrations were assayed using an enzyme-linked immunosorbent assay kit. Blood samples were also taken to determine serum amylase and lipase activity. RESULTS: The percentages of recruited patients with EPI (FE-1 concentration <200 MUg/g) and severe EPI (FE-1 concentration <100 MUg/g) were 52.2% and 18.3%, respectively. The incidences of steatorrhea were significantly different (P < 0.05) among the patients without EPI, with moderate EPI (FE-1 concentration = 100 to 200 MUg/g) and severe EPI (FE 1 concentration < 100 MUg/g). Both multivariate logistic regression analysis and z-tests indicated that the occurrence of EPI was closely associated with shock, sepsis, diabetes, cardiac arrest, hyperlactacidemia, invasive mechanical ventilation and haemodialysis. CONCLUSIONS: More than 50% of critically ill adult patients without primary pancreatic diseases had EPI, and nearly one-fifth of them had severe EPI. The risk factors for EPI included shock, sepsis, diabetes, cardiac arrest, hyperlactacidemia, invasive mechanical ventilation and haemodialysis. TRIAL REGISTRATION: NCT01753024. PMID- 23924603 TI - Smoking and risk of treatment-induced neutralizing antibodies to interferon beta 1a. AB - BACKGROUND: Neutralizing antibodies (NAbs) to interferon beta (IFNbeta) products that develop during treatment are associated with a loss of clinical efficacy. OBJECTIVES: The aim of this study was to investigate the influence of smoking habits on the risk of developing NAbs to IFNbeta, in the treatment of multiple sclerosis (MS). METHODS: This report is based on 695 MS patients treated with IFNbeta-1a, included in two Swedish case-control studies that collected information on smoking habits. Using logistic regression, the development of NAbs to IFNbeta-1a among current smokers was compared with that of non-smokers, by calculating the odds ratio (OR) with a 95% confidence interval (CI). RESULTS: Current smokers showed an increased risk of developing NAbs to IFNbeta-1a, compared with non-smokers (OR 1.9; 95% CI 1.3-2.8; p = 0.002). There were no gender differences. We observed no association between past smoking and the risk of developing NAbs to IFNbeta-1a. CONCLUSIONS: The finding that current smokers have an increased risk of developing NAbs to IFNbeta-1a has implications, both for the practical care and the treatment of MS; it also provides an interesting perspective of the lungs as an immune-reactive organ, reacting upon irritation. PMID- 23924604 TI - Patients' experience of important factors in the healthcare environment in oncology care. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to describe what factors of the healthcare environment are perceived as being important to patients in oncology care. DESIGN: A qualitative design was adopted using focus group interviews. SETTING AND PARTICIPANTS: The sample was 11 patients with different cancer diagnoses in an oncology ward at a university hospital in west Sweden. RESULTS: Analysis of the patients' perceptions of the environment indicated a complex entity comprising several aspects. These came together in a structure consisting of three main categories: safety, partnership with the staff, and physical space. The care environment is perceived as a complex entity, made up of several physical and psychosocial aspects, where the physical factors are subordinated by the psychosocial factors. It is clearly demonstrated that the patients' primary desire was a psychosocial environment where they were seen as a unique person; the patients wanted opportunities for good encounters with staff, fellow patients, and family members, supported by a good physical environment; and the patients valued highly a place to withdraw and rest. CONCLUSIONS: This study presents those attributes that are valued by cancer patients as crucial and important for the support of their well-being and functioning. The results show that physical aspects were subordinate to psychosocial factors, which emerged strongly as being the most important in a caring environment. PMID- 23924605 TI - The role of brain noradrenergic system in the regulation of liver cytochrome P450 expression. AB - The aim of the present study was to examine the effect of the brain noradrenergic system on the expression of cytochrome P450 in the liver. The experiment was carried out on male Wistar rats. Intracerebroventricular injection of the noradrenergic neurotoxin DSP-4 diminished noradrenaline level in the brain. Simultaneously, significant decreases in the serum concentration of the growth hormone, testosterone and the thyroid hormone thyroxine, as well as an increase in corticosterone level were observed. The concentrations of triiodothyronine and the cytokines interleukine 2 (IL-2) and 6 (IL-6) were not changed by DSP-4. The neurotoxin produced complex changes in the functioning of cytochrome P450. Significant decreases in the activity of liver CYP2C11 (measured as a rate of the 2alpha- and 16alpha-hydroxylation of testosterone) and CYP3A (measured as a rate of the 2beta- and 6beta-hydroxylation of testosterone) were found. In contrast, the activity of CYP1A (measured as a rate of caffeine metabolism) rose, while that of CYP2A (measured as a rate of the 7alpha-hydroxylation of testosterone), CYP2C6 (measured as a rate of the 7-hydroxylation of warfarin) and CYP2D (the 1' hydroxylation of bufuralol) remained unchanged. The changes in the activity of CYP1A, CYP2C11 and CYP3A correlated positively with those in CYP protein levels and with the CYP mRNA levels of CYP1A1, CYP2C11 and CYP3A1/2 genes, respectively. The obtained results indicate an important role of the brain noradrenergic system in the neuroendocrine regulation of liver cytochrome P450 expression, which may be of significance in pathological states involving this system, or during pharmacotherapy with drugs affecting noradrenergic transmission. PMID- 23924606 TI - Role of hypoxia inducible factor-1alpha in the regulation of the cancer-specific variant of organic anion transporting polypeptide 1B3 (OATP1B3), in colon and pancreatic cancer. AB - Organic anion transporting polypeptide 1B3 (OATP1B3) was initially considered to be a liver-specific transporter, mediating the uptake of a variety of endogenous and xenobiotic substances. Over the past decade, several investigations reported that OATP1B3 is also expressed across multiple types of cancers. Only recently, our laboratory and others demonstrated the identity of cancer-specific OATP1B3 variants (csOATP1B3) arising from the use of an alternative transcription initiation site, different from the wildtype (WT) OATP1B3 expressed in the normal liver. However, the mechanisms regulating the expression of csOATP1B3 remained unknown. In our current study, we investigated the role of hypoxia and the involvement of hypoxia inducible factor-1alpha (HIF-1alpha) in regulating the transcription of csOATP1B3. Our RT-PCR and immunoblotting results indicated that csOATP1B3, but not WT OATP1B3, can be induced in response to ambient or chemical hypoxia (upon exposure to 1% O2 or cobalt chloride). Reporter assays with deletion and mutated constructs of the csOATP1B3 promoter revealed a functional hypoxia response element (HRE) located in the proximal upstream region. Constructs harboring the HRE displayed the upregulated reporter gene expression in response to hypoxia, but not when mutated. Electrophoretic mobility shift assays using a biotin-labeled csOATP1B3 promoter HRE probe indicated the binding of HIF-1alpha, which was blocked by an excess of unlabeled csOATP1B3 probe. Furthermore, siRNA-based knockdown of HIF-1alpha caused a substantial decrease in the expression level of csOATP1B3. Taken together, these findings demonstrate that the transcription of csOATP1B3 is actively engaged during hypoxia, through a commonly utilized pathway involving HIF-1alpha. PMID- 23924607 TI - Isolation and characterization of alpha-conotoxin LsIA with potent activity at nicotinic acetylcholine receptors. AB - A new alpha-conotoxin LsIA was isolated from the crude venom of Conus limpusi using assay-guided RP-HPLC fractionation. Synthetic LsIA was a potent antagonist of alpha3beta2, alpha3alpha5beta2 and alpha7 nAChRs, with half-maximal inhibitory concentrations of 10, 31 and 10 nM, respectively. The structure of LsIA determined by NMR spectroscopy comprised a characteristic disulfide bond stabilized alpha-helical structure and disordered N-terminal region. Potency reductions of up to 9-fold were observed for N-terminally truncated analogues of LsIA at alpha7 and alpha3beta2 nAChRs, whereas C-terminal carboxylation enhanced potency 3-fold at alpha3beta2 nAChRs but reduced potency 3-fold at alpha7 nAChRs. This study gives further insight into alpha-conotoxin pharmacology and the molecular basis of nAChR selectivity, highlighting the influence of N-terminal residues and C-terminal amidation on conotoxin pharmacology. PMID- 23924608 TI - Staging dementia from symptom profiles on a care partner website. AB - BACKGROUND: The World Wide Web allows access to patient/care partner perspectives on the lived experience of dementia. We were interested in how symptoms that care partners target for tracking relate to dementia stage, and whether dementia could be staged using only these online profiles of targeted symptoms. OBJECTIVES: To use clinical data where the dementia stage is known to develop a model that classifies an individual's stage of dementia based on their symptom profile and to apply this model to classify dementia stages for subjects from a Web-based dataset. METHODS: An Artificial Neural Network (ANN) was used to identify the relationships between the dementia stages and individualized profiles of people with dementia obtained from the 60-item SymptomGuide (SG). The clinic-based training dataset (n=320), with known dementia stages, was used to create an ANN model for classifying stages in Web-based users (n=1930). RESULTS: The ANN model was trained in 66% of the 320 Memory Clinic patients, with the remaining 34% used to test its accuracy in classification. Training and testing staging distributions were not significantly different. In the 1930 Web-based profiles, 309 people (16%) were classified as having mild cognitive impairment, 36% as mild dementia, 29% as moderate, and 19% as severe. In both the clinical and Web-based symptom profiles, most symptoms became more common as the stage of dementia worsened (eg, mean 5.6 SD 5.9 symptoms in the MCI group versus 11.9 SD 11.3 in the severe). Overall, Web profiles recorded more symptoms (mean 7.1 SD 8.0) than did clinic ones (mean 5.5 SD 1.8). Even so, symptom profiles were relatively similar between the Web-based and clinical datasets. CONCLUSION: Symptoms targeted for online tracking by care partners of people with dementia can be used to stage dementia. Even so, caution is needed to assure the validity of data collected online as the current staging algorithm should be seen as an initial step. PMID- 23924610 TI - Morphological stasis in an ongoing gastropod radiation from Lake Malawi. AB - Evolutionary processes leading to adaptive radiation regularly occur too fast to be accurately recorded in the fossil record but too slowly to be readily observed in living biota. The study of evolutionary radiations is thereby confronted with an epistemological gap between the timescales and approaches used by neontologists and paleontologists. Here we report on an ongoing radiation of extant Bellamya species (n = 4) from the African Rift Lake Malawi that provides an unusual opportunity to bridge this gap. The substantial molecular differentiation in this monophyletic Bellamya clade has arisen since Late Pleistocene megadroughts in the Malawi Basin caused by climate change. Morphological time-series analysis of a high-resolution, radiocarbon-dated sequence of 22 faunas spanning the Holocene documents stasis up to the middle Holocene in all traits studied (shell height, number of whorls, and two variables obtained from geometric morphometrics). Between deposition of the last fossil fauna (~5 ka) and the present day, a drastic increase in morphological disparity was observed (3.7-5.8 times) associated with an increase in species diversity. Comparison of the rates of morphological evolution obtained from the paleontological time-series with phylogenetic rates indicates that the divergence in two traits could be reconstructed with the slow rates documented in the fossils, that one trait required a rate reduction (stabilizing selection), and the other faster rates (divergent selection). The combined paleontological and comparative approach taken here allows recognition that morphological stasis can be the dominant evolutionary pattern within species lineages, even in very young and radiating clades. PMID- 23924611 TI - Christian de Duve: Explorer of the cell who discovered new organelles by using a centrifuge. PMID- 23924612 TI - Gram-positive siderophore-shuttle with iron-exchange from Fe-siderophore to apo siderophore by Bacillus cereus YxeB. AB - Small molecule iron-chelators, siderophores, are very important in facilitating the acquisition of Fe(III), an essential element for pathogenic bacteria. Many Gram-negative outer-membrane transporters and Gram-positive lipoprotein siderophore-binding proteins have been characterized, and the binding ability of outer-membrane transporters and siderophore-binding proteins for Fe-siderophores has been determined. However, there is little information regarding the binding ability of these proteins for apo-siderophores, the iron-free chelators. Here we report that Bacillus cereus YxeB facilitates iron-exchange from Fe-siderophore to apo-siderophore bound to the protein, the first Gram-positive siderophore-shuttle system. YxeB binds ferrioxamine B (FO, Fe-siderophore)/desferrioxamine B (DFO, apo-siderophore) in vitro. Disc-diffusion assays and growth assays using the yxeB mutant reveal that YxeB is responsible for importing the FO. Cr-DFO (a FO analog) is bound by YxeB in vitro and B. cereus imports or binds Cr-DFO in vivo. In vivo uptake assays using Cr-DFO and FO and growth assays using DFO and Cr-DFO show that B. cereus selectively imports and uses FO when DFO is present. Moreover, in vitro competition assays using Cr-DFO and FO clearly demonstrate that YxeB binds only FO, not Cr-DFO, when DFO is bound to the protein. Iron-exchange from FO to DFO bound to YxeB must occur when DFO is initially bound by YxeB. Because the metal exchange rate is generally first order in replacement ligand concentration, protein binding of the apo-siderophore acts to dramatically enhance the iron exchange rate, a key component of the Gram-positive siderophore-shuttle mechanism. PMID- 23924609 TI - Causal effect of disconnection lesions on interhemispheric functional connectivity in rhesus monkeys. AB - In the absence of external stimuli or task demands, correlations in spontaneous brain activity (functional connectivity) reflect patterns of anatomical connectivity. Hence, resting-state functional connectivity has been used as a proxy measure for structural connectivity and as a biomarker for brain changes in disease. To relate changes in functional connectivity to physiological changes in the brain, it is important to understand how correlations in functional connectivity depend on the physical integrity of brain tissue. The causal nature of this relationship has been called into question by patient data suggesting that decreased structural connectivity does not necessarily lead to decreased functional connectivity. Here we provide evidence for a causal but complex relationship between structural connectivity and functional connectivity: we tested interhemispheric functional connectivity before and after corpus callosum section in rhesus monkeys. We found that forebrain commissurotomy severely reduced interhemispheric functional connectivity, but surprisingly, this effect was greatly mitigated if the anterior commissure was left intact. Furthermore, intact structural connections increased their functional connectivity in line with the hypothesis that the inputs to each node are normalized. We conclude that functional connectivity is likely driven by corticocortical white matter connections but with complex network interactions such that a near-normal pattern of functional connectivity can be maintained by just a few indirect structural connections. These surprising results highlight the importance of network-level interactions in functional connectivity and may cast light on various paradoxical findings concerning changes in functional connectivity in disease states. PMID- 23924613 TI - A high-throughput screen for quorum-sensing inhibitors that target acyl homoserine lactone synthases. AB - Many Proteobacteria use N-acyl-homoserine lactone (acyl-HSL) quorum sensing to control specific genes. Acyl-HSL synthesis requires unique enzymes that use S adenosyl methionine as an acyl acceptor and amino acid donor. We developed and executed an enzyme-coupled high-throughput cell-free screen to discover acyl-HSL synthase inhibitors. The three strongest inhibitors were equally active against two different acyl-HSL synthases: Burkholderia mallei BmaI1 and Yersinia pestis YspI. Two of these inhibitors showed activity in whole cells. The most potent compound behaves as a noncompetitive inhibitor with a Ki of 0.7 uM and showed activity in a cell-based assay. Quorum-sensing signal synthesis inhibitors will be useful in attempts to understand acyl-HSL synthase catalysis and as a tool in studies of quorum-sensing control of gene expression. Because acyl-HSL quorum sensing controls virulence of some bacterial pathogens, anti-quorum-sensing chemicals have been sought as potential therapeutic agents. Our screen and identification of acyl-HSL synthase inhibitors serve as a basis for efforts to target quorum-sensing signal synthesis as an antivirulence approach. PMID- 23924615 TI - Nonrepresentative fish and ocean migration assumptions confound inferences in Rechisky et al. PMID- 23924614 TI - Composability of regulatory sequences controlling transcription and translation in Escherichia coli. AB - The inability to predict heterologous gene expression levels precisely hinders our ability to engineer biological systems. Using well-characterized regulatory elements offers a potential solution only if such elements behave predictably when combined. We synthesized 12,563 combinations of common promoters and ribosome binding sites and simultaneously measured DNA, RNA, and protein levels from the entire library. Using a simple model, we found that RNA and protein expression were within twofold of expected levels 80% and 64% of the time, respectively. The large dataset allowed quantitation of global effects, such as translation rate on mRNA stability and mRNA secondary structure on translation rate. However, the worst 5% of constructs deviated from prediction by 13-fold on average, which could hinder large-scale genetic engineering projects. The ease and scale this of approach indicates that rather than relying on prediction or standardization, we can screen synthetic libraries for desired behavior. PMID- 23924616 TI - Antiproliferative, cell-cycle dysregulation effects of novel asiatic acid derivatives on human non-small cell lung cancer cells. AB - Asiatic acid (AA) is a pentacyclic triterpene in Centella asiatica known to inhibit proliferation and induce apoptosis in several tumor cell lines. In the current study, we synthesized five AA derivatives and examined their inhibitory activities on growth in non-small cell lung cancer cell lines, A549 and PC9/G. Four derivatives were found to have stronger cell growth inhibitory activity than AA. Among them, compound A-3 showed the most significant antiproliferative effects on tumor. Growth of A549 and PC9/G cells was inhibited by A-3 in a dose- and time-dependent manner. To determine the cellular gene expression changes in A549 and PC9/G cells treated with A-3, Affymetrix GeneChip(r) Human Genome U133 Plus 2.0 Array were used to screen transcriptome differences. Expression levels of 1121 genes in A549 and 1873 genes in PC9/G were significantly altered upon treatment with 10 uM A-3 after 48 h, with 357 overlapping genes. The signaling pathways molecules involved in the antiproliferative and cell cycle dysregulation effects of A-3 identified using microarray were further validated via Western blot analyses. The results collectively indicate that A-3 induces inhibition of cell proliferation via downregulation of the Ras/Raf/MEK/ERK pathway and cell cycle arrest at G1/S and G2/M. PMID- 23924618 TI - Overview of USP Chapter 797 "Pharmaceutical Compounding-Sterile Preparations": The Potential Impact of Compounding Pharmacies. PMID- 23924619 TI - Androgen deficiency in women: understanding the science, controversy and art of treating our patients-part 2. PMID- 23924617 TI - Current salt reduction policies across gradients of inequality-adjusted human development in the WHO European region: minding the gaps. AB - OBJECTIVE: To assess current salt reduction policies in countries of the WHO European Region against the backdrop of varying levels of human development adjusted for income, education and health (longevity) inequalities. DESIGN: Population-based, cross-sectional study, with data gathered through systematic review of relevant databases and supplementary information provided by WHO Nutrition Counterparts. SETTING: Member States of the WHO European Region. SUBJECTS: Inequality-adjusted Human Development Index scores were analysed against assessed levels of development and implementation of national nutrition policies and initiatives targeting population-level salt reduction. RESULTS: Within the WHO European Region, Inequality-adjusted Human Development Index values among countries with no existing salt reduction initiatives (mean 0.643 (se 0.022)) were significantly lower than among those with either partially implemented/planned salt initiatives (mean 0.766 (se 0.017), P < 0.001) or fully implemented salt initiatives (mean 0.780 (se 0.021), P < 0.001). CONCLUSIONS: Where salt reduction strategies are implemented as an integral part of national policy, outcomes have been promising. However, low- and middle-income countries may face severe resource constraints that keep them from emulating more comprehensive strategies pursued in high-income countries. Care must be taken to ensure that gaps are not inadvertently widened by monitoring differential policy impacts of salt policies, particularly regarding trade flows. PMID- 23924620 TI - Pluronic lecithin organogel for local delivery of anti-inflammatory drugs. PMID- 23924622 TI - An excel spreadsheet for estimating sodium-chloride equivalents for drugs. PMID- 23924621 TI - Detailing your compounding specialty practice-part 2: the presentation. PMID- 23924623 TI - Basics of compounding for the treatment of warts. PMID- 23924624 TI - Quality-control analytical methods: osmolality and osmometry. PMID- 23924625 TI - Extemporaneous formulation and stability testing of mexiletine hydrochloride solution. AB - Mexiletine hydrochloride is an orally active class I antiarrythmic agent. An extemporaneous solution of mexiletine hydrochloride was prepared for this study. Water was chosen as the vehicle due to the high solubility of the drug in water. Sorbitol, simple syrup and raspberry syrup were used as sweeteners in an attempt to mask the bitter taste of the drug. The solution was analyzed over 91 days of storage at five temperatures, ie, 4, 30, 40, 50 and 60 deg C.The sample was analyzed at 2, 6, 24, and 48 hours and the at 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 and 91 days at each designated temperature. The peak area for the mexiletine hydrchloride peak at time t=0 was taken as 100%; and, accordingly the percentages of intact drug remaining at each interval were calculated. The log percentage of the drug remaining was lotted agaisnst time (in days) at each temperature. The first-order constants for mexiletine hydrochloride at 4, 30, 40, 50, and 60 deg C were calculated to be -0.0007, -0.0009, -0.0010. -0.0011 and 0.0013, respectively. The Arrhenius plot was obtained by plotting the first-order degradation constants against the reciprocal of the absolute temperatures. The first-order degradation constant for mexiletine hydrochloride at 25 deg C was found to be 9.053 x 10-4(day-1). The energy of activation for the reaction was calculated to be -8663.88 J/mole. The shelf lives of the formmulation at 4 and 25 deg C were found to be 173.3 and 115.5 days, respectively. An attempt was made to identify and characterize any degradation products using the high-performance liquid chromatographic-mass spectrometry technique, as none of the degradation products were detected by ultraviolet analysis. However, this attempt was unsuccessful due to coating of the injection port with the sample, which might be due to crystallization of any of the excipients of the formulation under high temperatures. A degradation mechanism has been hypothesized based on either acid or base attack on the parent compound. The products from this degradation are presented. PMID- 23924626 TI - Chemical stability of phenylephrine hydrochloride after reconstitution in 0.9% sodium chloride injection for infusion. AB - The chemical stability of phenylephrine hydrochloride (0.2 and 0.1 mg/mL) in 0.9% sodium chloride injection stored in polyvinyl chloride bags was studied at 25 deg C by means of a stability-indicating high-performance liquid chromatographic assay method. The concentrations of the drug were directly related to peak heights, and the percent relative standard deviation based on five injections was 1.0. The excipients present in the injection did not interfere with the assay procedure. The products of decomposition separated from the intact drug. At both concentrations (0.2 and 0.1 mg/mL), the loss in potency was less than 1.0% after 14 days of storage at room temperature. The pH value of the 0.2-mg/mL injection decreased from 4.3 to 4.0 after 14 days of storage, and the pH value of the 0.1 mg/mL injection decreased from 4.4 to 4.2.The physical appearance of the injection did not change. PMID- 23924628 TI - PostScription: Cleanroom Standards. PMID- 23924627 TI - Effect of freezing, long-term storage and microwave thawing on the stability of tramadol in 5% dextrose infusion in polyvinyl chloride bags. AB - Tramadol hydrochloride (Contramal) is often used as infusions for hospitalized patients to manage or prevent acute or chronic pain that requires analgesia at opioid level. Advance preparation of intravenous solutions of tramadol hydrochloride could be useful to improve quality assurance, time management and cost savings of drug delivery; but little is known about their stability after freezing followed by microwave thawing. The purpose of this study was to investigate how freezing, long-term storage and microwave thawing can affect the stability of tramadol in 5% dextrose infusion. The stability of five polyvinyl chloride bags of solution containing 100mg of tramadol/100mL of 5% dextrose was studied after the solution was frozen for 4 months at -20 deg C, followed by thawing in a microwave oven with a validated cycle and final storage at 4 deg C. Concentration of tramadol was measured by high-performance liquid chromatography using a reversed-phase column, a mobile phase consisting of 30% acetonitrile in phosphate bufer pH 2.5 and ultraviolet detecion at 230 nm. Visual inspection and pH measurement were also performed. No color change or precipitation was observed. Tramadol was stable for at least 60 days. Throughout this period, the lower confidence limit of the estimated regression line of the concentration-time profile remained at above 90% of the initial concentration. During this stability period, the pH value decreased slightly without affecting chromatographic parameters. Within these limits, tramadol in 5% dextrose infusion may be prepared frozen in advance by a centralized intravenous admixture service, then thawed before use in clinicl units. PMID- 23924629 TI - Lack of population genetic structure and host specificity in the bat fly, Cyclopodia horsfieldi, across species of Pteropus bats in Southeast Asia. AB - BACKGROUND: Population-level studies of parasites have the potential to elucidate patterns of host movement and cross-species interactions that are not evident from host genealogy alone. Bat flies are obligate and generally host-specific blood-feeding parasites of bats. Old-World flies in the family Nycteribiidae are entirely wingless and depend on their hosts for long-distance dispersal; their population genetics has been unstudied to date. METHODS: We collected a total of 125 bat flies from three Pteropus species (Pteropus vampyrus, P. hypomelanus, and P. lylei) from eight localities in Malaysia, Cambodia, and Vietnam. We identified specimens morphologically and then sequenced three mitochondrial DNA gene fragments (CoI, CoII, cytB; 1744 basepairs total) from a subset of 45 bat flies. We measured genetic diversity, molecular variance, and population genetic subdivision (FST), and used phylogenetic and haplotype network analyses to quantify parasite genetic structure across host species and localities. RESULTS: All flies were identified as Cyclopodia horsfieldi with the exception of two individuals of Eucampsipoda sundaica. Low levels of population genetic structure were detected between populations of Cyclopodia horsfieldi from across a wide geographic range (~1000 km), and tests for isolation by distance were rejected. AMOVA results support a lack of geographic and host-specific population structure, with molecular variance primarily partitioned within populations. Pairwise FST values from flies collected from island populations of Pteropus hypomelanus in East and West Peninsular Malaysia supported predictions based on previous studies of host genetic structure. CONCLUSIONS: The lack of population genetic structure and morphological variation observed in Cyclopodia horsfieldi is most likely due to frequent contact between flying fox species and subsequent high levels of parasite gene flow. Specifically, we suggest that Pteropus vampyrus may facilitate movement of bat flies between the three Pteropus species in the region. We demonstrate the utility of parasite genetics as an additional layer of information to measure host movement and interspecific host contact. These approaches may have wide implications for understanding zoonotic, epizootic, and enzootic disease dynamics. Bat flies may play a role as vectors of disease in bats, and their competence as vectors of bacterial and/or viral pathogens is in need of further investigation. PMID- 23924631 TI - Dynamic analysis of Arabidopsis AP2 sigma subunit reveals a key role in clathrin mediated endocytosis and plant development. AB - Clathrin-mediated endocytosis, which depends on the AP2 complex, plays an essential role in many cellular and developmental processes in mammalian cells. However, the function of the AP2 complex in plants remains largely unexplored. Here, we show in Arabidopsis that the AP2 sigma subunit mutant (ap2 sigma) displays various developmental defects that are similar to those of mutants defective in auxin transport and/or signaling, including single, trumpet-shaped and triple cotyledons, impaired vascular pattern, reduced vegetative growth, defective silique development and drastically reduced fertility. We demonstrate that AP2 sigma is closely associated and physically interacts with the clathrin light chain (CLC) in vivo using fluorescence cross-correlation spectroscopy (FCCS), protein proximity analyses and co-immunoprecipitation assays. Using variable-angle total internal reflection fluorescence microscopy (VA-TIRFM), we show that AP2 sigma-mCherry spots colocalize with CLC-EGFP at the plasma membrane, and that AP2 sigma-mCherry fluorescence appears and disappears before CLC-EGFP fluorescence. The density and turnover rate of the CLC-EGFP spots are significantly reduced in the ap2 sigma mutant. The internalization and recycling of the endocytic tracer FM4-64 and the auxin efflux carrier protein PIN1 are also significantly reduced in the ap2 sigma mutant. Further, the polar localization of PIN1-GFP is significantly disrupted during embryogenesis in the ap2 sigma mutant. Taken together, our results support an essential role of AP2 sigma in the assembly of a functional AP2 complex in plants, which is required for clathrin mediated endocytosis, polar auxin transport and plant growth regulation. PMID- 23924630 TI - Notch signaling represses p63 expression in the developing surface ectoderm. AB - The development of the mature epidermis requires a coordinated sequence of signaling events and transcriptional changes to specify surface ectodermal progenitor cells to the keratinocyte lineage. The initial events that specify epidermal keratinocytes from ectodermal progenitor cells are not well understood. Here, we use both developing mouse embryos and human embryonic stem cells (hESCs) to explore the mechanisms that direct keratinocyte fate from ectodermal progenitor cells. We show that both hESCs and murine embryos express p63 before keratin 14. Furthermore, we find that Notch signaling is activated before p63 expression in ectodermal progenitor cells. Inhibition of Notch signaling pharmacologically or genetically reveals a negative regulatory role for Notch signaling in p63 expression during ectodermal specification in hESCs or mouse embryos, respectively. Taken together, these data reveal a role for Notch signaling in the molecular control of ectodermal progenitor cell specification to the epidermal keratinocyte lineage. PMID- 23924633 TI - The nuage mediates retrotransposon silencing in mouse primordial ovarian follicles. AB - Mobilization of endogenous retrotransposons can destabilize the genome, an imminent danger during epigenetic reprogramming of cells in the germline. The P element-induced wimpy testis (PIWI)-interacting RNA (piRNA) pathway is known to silence retrotransposons in the mouse testes. Several piRNA pathway components localize to the unique, germline structure known as the nuage. In this study, we surveyed mouse ovaries and found, for the first time, transient appearance of nuage-like structures in oocytes of primordial follicles. Mouse vasa homolog (MVH), Piwi-like 2 (PIWIL2/MILI) and tudor domain-containing 9 (TDRD9) are present in these structures, whereas aggregates of germ cell protein with ankyrin repeats, sterile alpha motif and leucine zipper (GASZ) localize separately in the cytoplasm. Retrotransposons are silenced in primordial ovarian follicles, and de repressed upon reduction of piRNA expression in Mvh, Mili or Gasz mutants. However, these null-mutant females, unlike their male counterparts, are fertile, uncoupling retrotransposon activation from sterility. PMID- 23924632 TI - Localized Fgf10 expression is not required for lung branching morphogenesis but prevents differentiation of epithelial progenitors. AB - Localized Fgf10 expression in the distal mesenchyme adjacent to sites of lung bud formation has long been thought to drive stereotypic branching morphogenesis even though isolated lung epithelium branches in the presence of non-directional exogenous Fgf10 in Matrigel. Here, we show that lung agenesis in Fgf10 knockout mice can be rescued by ubiquitous overexpression of Fgf10, indicating that precisely localized Fgf10 expression is not required for lung branching morphogenesis in vivo. Fgf10 expression in the mesenchyme itself is regulated by Wnt signaling. Nevertheless, we found that during lung initiation simultaneous overexpression of Fgf10 is not sufficient to rescue the absence of primary lung field specification in embryos overexpressing Dkk1, a secreted inhibitor of Wnt signaling. However, after lung initiation, simultaneous overexpression of Fgf10 in lungs overexpressing Dkk1 is able to rescue defects in branching and proximal distal differentiation. We also show that Fgf10 prevents the differentiation of distal epithelial progenitors into Sox2-expressing airway epithelial cells in part by activating epithelial beta-catenin signaling, which negatively regulates Sox2 expression. As such, these findings support a model in which the main function of Fgf10 during lung development is to regulate proximal-distal differentiation. As the lung buds grow out, proximal epithelial cells become further and further displaced from the distal source of Fgf10 and differentiate into bronchial epithelial cells. Interestingly, our data presented here show that once epithelial cells are committed to the Sox2-positive airway epithelial cell fate, Fgf10 prevents ciliated cell differentiation and promotes basal cell differentiation. PMID- 23924634 TI - Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development. AB - Genetic regulation of the cell fate transition from lateral plate mesoderm to the specification of cardiomyocytes requires suppression of Wnt/beta-catenin signaling, but the mechanism for this is not well understood. By analyzing gene expression and chromatin dynamics during directed differentiation of human embryonic stem cells (hESCs), we identified a suppressor of Wnt/beta-catenin signaling, transmembrane protein 88 (TMEM88), as a potential regulator of cardiovascular progenitor cell (CVP) specification. During the transition from mesoderm to the CVP, TMEM88 has a chromatin signature of genes that mediate cell fate decisions, and its expression is highly upregulated in advance of key cardiac transcription factors in vitro and in vivo. In early zebrafish embryos, tmem88a is expressed broadly in the lateral plate mesoderm, including the bilateral heart fields. Short hairpin RNA targeting of TMEM88 during hESC cardiac differentiation increases Wnt/beta-catenin signaling, confirming its role as a suppressor of this pathway. TMEM88 knockdown has no effect on NKX2.5 or GATA4 expression, but 80% of genes most highly induced during CVP development have reduced expression, suggesting adoption of a new cell fate. In support of this, analysis of later stage cell differentiation showed that TMEM88 knockdown inhibits cardiomyocyte differentiation and promotes endothelial differentiation. Taken together, TMEM88 is crucial for heart development and acts downstream of GATA factors in the pre-cardiac mesoderm to specify lineage commitment of cardiomyocyte development through inhibition of Wnt/beta-catenin signaling. PMID- 23924635 TI - Distinct temporal requirements for Runx1 in hematopoietic progenitors and stem cells. AB - The transcription factor Runx1 is essential for the formation of yolk sac-derived erythroid/myeloid progenitors (EMPs) and hematopoietic stem cells (HSCs) from hemogenic endothelium during embryogenesis. However, long-term repopulating HSCs (LT-HSCs) persist when Runx1 is conditionally deleted in fetal liver cells, demonstrating that the requirement for Runx1 changes over time. To define more precisely when Runx1 transitions from an essential factor to a homeostatic regulator of EMPs and HSCs, and whether that transition requires fetal liver colonization, we performed conditional, timed deletions of Runx1 between E7.5 and E13.5. We determined that Runx1 loss reduces the formation or function of EMPs up through E10.5. The Runx1 requirement in HSCs ends later, as deletion up to E11.5 eliminates HSCs. At E11.5, there is an abrupt transition to Runx1 independence in at least a subset of HSCs that does not require fetal liver colonization. The transition to Runx1 independence in EMPs is not mediated by other core binding factors (Runx2 and/or Runx3); however, deleting the common non-DNA-binding beta subunit (CBFbeta) severely compromises LT-HSC function. Hence, the requirements for Runx1 in EMP and HSC formation are temporally distinct, and LT-HSC function is highly reliant on continued core binding factor activity. PMID- 23924637 TI - Magnetoplasmon excitations from integer-filled Landau levels in narrow-gap quantum wells. AB - We report a theoretical study on magnetoplasmon excitations in a perpendicular magnetic field in n-type narrow-gap quantum wells (QWs). Using the Hartree-Fock approximation based on the 8 * 8 k . p Hamiltonian, we calculate magnetoplasmon dispersions in symmetric and asymmetric InAs/AlSb QWs for the case of integer filled Landau levels. We demonstrate a significant dependence of the shape of magnetoplasmon dispersions on the 2D electron concentration, as well as a nonlinear dependence of the magnetoplasmon energy on the wavevector at small values of k. Both effects are shown to result from strong mixing between the conduction (Gamma6) and the valence (Gamma7 and Gamma8) bands. We find that cyclotron-resonance (CR) energies are affected by electron-electron interaction due to Kohn theorem violation and predict the interaction-induced enhancement of the CR line splitting in the case of even (Deltag-splitting) and odd (Deltam splitting) filling factors for the Landau levels. PMID- 23924636 TI - Transcriptional components of anteroposterior positional information during zebrafish fin regeneration. AB - Many fish and salamander species regenerate amputated fins or limbs, restoring the size and shape of the original appendage. Regeneration requires that spared cells retain or recall information encoding pattern, a phenomenon termed positional memory. Few factors have been implicated in positional memory during vertebrate appendage regeneration. Here, we investigated potential regulators of anteroposterior (AP) pattern during fin regeneration in adult zebrafish. Sequence based profiling from tissues along the AP axis of uninjured pectoral fins identified many genes with region-specific expression, several of which encoded transcription factors with known AP-specific expression or function in developing embryonic pectoral appendages. Transgenic reporter strains revealed that regulatory sequences of the transcription factor gene alx4a activated expression in fibroblasts and osteoblasts within anterior fin rays, whereas hand2 regulatory sequences activated expression in these same cell types within posterior rays. Transgenic overexpression of hand2 in all pectoral fin rays did not affect formation of the proliferative regeneration blastema, yet modified the lengths and widths of regenerating bones. Hand2 influenced the character of regenerated rays in part by elevation of the vitamin D-inactivating enzyme encoded by cyp24a1, contributing to region-specific regulation of bone metabolism. Systemic administration of vitamin D during regeneration partially rescued bone defects resulting from hand2 overexpression. Thus, bone-forming cells in a regenerating appendage maintain expression throughout life of transcription factor genes that can influence AP pattern, and differ across the AP axis in their expression signatures of these and other genes. These findings have implications for mechanisms of positional memory in vertebrate tissues. PMID- 23924638 TI - 32k Da protein improve ovariectomy-induced bone loss in rats. AB - The objective of the present study was to systematically explore the effects of 32K Da protein (32KP) on postmenopausal osteoporosis. Eighty 3-mo-old female Sprague-Dawley rats were employed and randomly divided into one sham-operated group (SHAM) and five ovariectomy (OVX) subgroups as OVX (control), OVX with 17 ethinylestradiol (E2, 25 g/kg/day), OVX with 32KP of graded doses (50, 50, or 150 mg/kg/day). 32KP or E2 diet was fed on week 4 after operation, for 16 weeks. Bone mass, bone turnover and strength were evaluated by dual-energy X-ray absorptiometry (DEXA), biochemical markers and three-point bending test, respectively. Femur marrow cavity was observed by light microscopy via hematoxylin-eosin staining. It is observed that different dosage treatment of 32KP increased the body weight and prevented the loss of bone mass induced by OVX. The prevention effect against bone loss was presumably due to the altering of the rate of bone remodeling. The bone mineral density and bone calcium content in OVX rats were lower than that in the control group, suggesting that 32KP was able to prevent significant bone loss. In addition, the data from three point bending test and femur sections showed that 32KP treatment enhanced bone strength and reduced the marrow cavity of the femur in OVX rats. In the serum and urine assay, 32KP decreased urinary deoxypyridinoline and calcium concentrations; however, serum alkaline phosphatase activities were not inhibited. It suggested that amelioration of bone loss was changed via inhibition of bone reabsorption. Our findings indicated that 32KP might be a potential alternative drug for the prevention and treatment of postmenopausal osteoporosis. PMID- 23924639 TI - WHO option B+: early experience of antiretroviral therapy sequencing after cessation of breastfeeding and risk of dermatologic toxicity. PMID- 23924640 TI - Simulation of pooled nucleic acid testing to identify antiretroviral treatment failure during HIV infection in Seoul, South Korea. PMID- 23924641 TI - HIV infection and anogenital warts. PMID- 23924643 TI - Polarity: In the plane. PMID- 23924642 TI - Rilpivirine resistance-associated mutations among antiretroviral-naive patients infected with HIV-1 in Asia. PMID- 23924644 TI - Air pollution: a potentially modifiable risk factor for lung cancer. AB - Economic growth and increased urbanization pose a new risk for cancer development: the exposure of high numbers of people to ambient air pollution. Epidemiological evidence that links air pollution to mortality from lung cancer is robust. An ability to produce high-quality scientific research that addresses these risks and the ability of local health authorities to understand and respond to these risks are basic requirements to solve the conflict between economic development and the preservation of human health. However, this is currently far from being achieved. Thus, this Science and Society article addresses the possibilities of expanding scientific networking to increase awareness of the risk of lung cancer that is promoted by air pollution. PMID- 23924646 TI - Adipose-derived stem cells inhibit the contractile myofibroblast in Dupuytren's disease. AB - BACKGROUND: In an attempt to provide minimally invasive treatment for Dupuytren's disease, percutaneous disruption of the affected tissue followed by lipografting is being tested. Contractile myofibroblasts drive this fibroproliferative disorder, whereas stem cells have recently been implicated in preventing fibrosis. Therefore, the authors tested the role of stem cells in modulating myofibroblast activity in Dupuytren's disease. METHODS: The authors compared the effect of co-culturing Dupuytren's myofibroblasts with either adipose-derived or bone-marrow-derived stem cells on isometric force contraction and associated levels of alpha-smooth muscle actin mRNA and protein expression. The authors also tested the effect of these stem cells on Dupuytren's myofibroblast proliferation and assessed whether this was mediated by cell-to-cell contact or by a paracrine mechanism. RESULTS: Addition of adipose-derived stem cells to Dupuytren's myofibroblasts reduced the contraction of the latter, with a corresponding reduction of alpha-smooth muscle actin protein expression, probably through a dilution effect. In contrast, bone marrow-derived stem cells increased myofibroblast contractility. In addition, adipose-derived stem cells inhibit myofibroblast proliferation and mediate these effects by soluble factors, influenced by cell-to-cell contact-dependent signaling. CONCLUSION: Adipose derived stem cells inhibit the contractile myofibroblast in Dupuytren's disease, and these findings lend support to the potential benefit of lipografting in conjunction with aponeurotomy as a novel strategy for the treatment of Dupuytren's disease. PMID- 23924645 TI - Fluorescence-guided surgery with live molecular navigation--a new cutting edge. AB - A glowing new era in cancer surgery may be dawning. Using fluorescently labelled markers, surgical molecular navigation means that tumours and nerves can be displayed in real time intra-operatively in contrasting pseudocolours, which allows more complete tumour resection while preserving important structures. These advances can potentially cause a paradigm shift in cancer surgery, improving patient outcome and decreasing overall health-care costs. PMID- 23924647 TI - Ulnar hammer syndrome: a systematic review of the literature. AB - BACKGROUND: Ulnar hammer syndrome is an uncommon form of arterial insufficiency. Many treatments have been described, and debate continues about the best option. The goal of this systematic review was to determine whether ulnar hammer syndrome has an occupational association, to identify the most reliable diagnostic test, and to determine the best treatment modality. METHODS: A comprehensive literature search was conducted using the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL, and EMBASE. Data from articles meeting inclusion criteria were collected in duplicate. Methodological quality of studies was assessed using the Methodological Index for Nonrandomized Studies scale. RESULTS: Thirty studies were included in the systematic review. No randomized controlled trials were identified. There is low quality evidence suggestive of an association between exposure to repetitive hand trauma and vibration and ulnar hammer syndrome. Various diagnostic investigations were used, but few were compared, making it difficult to determine the most reliable diagnostic test. Numerous nonoperative and operative treatments were reported. With nonoperative treatment, 12 percent had complete resolution and 70 percent had partial resolution of their symptoms. Of patients treated operatively, 42.5 percent had complete resolution and 42.5 percent had partial resolution of their symptoms. CONCLUSIONS: The heterogeneity in study design and outcome measures limits definitive conclusions about occupational association, best diagnostic test, and treatment for ulnar hammer syndrome. However, there is low-quality evidence that suggests that most patients with ulnar hammer syndrome will have partial relief of symptoms with nonoperative treatment, and operative treatment results in complete or partial resolution of symptoms in the majority of cases. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23924648 TI - Computer-assisted versus conventional free fibula flap technique for craniofacial reconstruction: an outcomes comparison. AB - BACKGROUND: There has been rising interest in computer-aided design/computer aided manufacturing for preoperative planning and execution of osseous free flap reconstruction. The purpose of this study was to compare outcomes between computer-assisted and conventional fibula free flap techniques for craniofacial reconstruction. METHODS: A two-center, retrospective review was carried out on patients who underwent fibula free flap surgery for craniofacial reconstruction from 2003 to 2012. Patients were categorized by the type of reconstructive technique: conventional (between 2003 and 2009) or computer-aided design/computer aided manufacturing (from 2010 to 2012). Demographics, surgical factors, and perioperative and long-term outcomes were compared. RESULTS: A total of 68 patients underwent microsurgical craniofacial reconstruction: 58 conventional and 10 computer-aided design and manufacturing fibula free flaps. By demographics, patients undergoing the computer-aided design/computer-aided manufacturing method were significantly older and had a higher rate of radiotherapy exposure compared with conventional patients. Intraoperatively, the median number of osteotomies was significantly higher (2.0 versus 1.0, p=0.002) and the median ischemia time was significantly shorter (120 minutes versus 170 minutes, p=0.004) for the computer-aided design/computer-aided manufacturing technique compared with conventional techniques; operative times were shorter for patients undergoing the computer-aided design/computer-aided manufacturing technique, although this did not reach statistical significance. Perioperative and long-term outcomes were equivalent for the two groups, notably, hospital length of stay, recipient-site infection, partial and total flap loss, and rate of soft-tissue and bony tissue revisions. CONCLUSION: Microsurgical craniofacial reconstruction using a computer assisted fibula flap technique yielded significantly shorter ischemia times amidst a higher number of osteotomies compared with conventional techniques. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 23924649 TI - The role of bacterial biofilms in device-associated infection. AB - There is increasing evidence that bacterial biofilm is responsible for the failure of medical devices, leading to device-associated infection. As plastic surgeons, we are among the leading users of prostheses in surgery, and it is important that we are kept informed of this growing problem. This article summarizes the pathogenesis of device-associated infection, outlines the evidence for such infection in a number of medical devices, and outlines operative strategies aimed at reducing the risk of bacterial contamination at the time of device deployment. It also outlines strategies under investigation to combat the development of device-associated infection. PMID- 23924650 TI - Breast reconstruction following nipple-sparing mastectomy: a systematic review of the literature with pooled analysis. AB - BACKGROUND: Nipple-sparing mastectomy is a controversial option for breast cancer treatment due to locoregional recurrence and distant metastasis. In addition to these oncologic factors, technical factors such as ideal incision type or reconstructive options are also debatable. This systematic review examines current trends with nipple-sparing mastectomy, including selection criteria, locoregional and distant metastasis rates, incision choice, and reconstructive options. METHODS: Systematic electronic searches were performed in the PubMed and Ovid databases using search terms for studies reporting outcomes following nipple sparing mastectomy and all forms of reconstruction. Studies between 1970 and 2013 were reviewed. Pooled descriptive statistics with separate analyses for incision type and reconstructive method were performed. RESULTS: Forty-eight studies met inclusion criteria, yielding 6615 nipple-sparing mastectomies for analysis. The overall pooled complication rate was 22 percent, the nipple necrosis rate was 7 percent, the locoregional recurrence rate was 1.8 percent, and the distant metastasis rate was 2.2 percent. Comparing combined patient cohorts for two-stage expander to implant, one-stage direct to implant, and autologous reconstruction demonstrated overall complication rates of 52.8, 16.7, and 23.7 percent and nipple necrosis rates of 4.5, 4.1, and 17.3 percent, respectively. Incision types were divided into five categories: radial, periareolar/circumareolar, inframammary, mastopexy, and transareolar, with nipple necrosis rates of 8.83, 17.81, 9.09, 4.76, and 81.82 percent, respectively CONCLUSIONS: Nipple-sparing mastectomy appears to be an oncologically safe option for properly selected patients, with low rates of locoregional and distant metastasis. Overall complication and nipple necrosis rates are affected by incision location and reconstruction method. Randomized controlled trials are warranted to determine best incision and reconstructive methods. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23924651 TI - Facial changes caused by smoking: a comparison between smoking and nonsmoking identical twins. AB - BACKGROUND: The purpose of this study was to identify the specific components of facial aging secondary to smoking, by comparing standardized photographs of identical twins with different smoking histories. METHODS: During the Twins Days Festival in Twinsburg, Ohio, from 2007 to 2010, 79 pairs of twins were identified, in which only one twin smokes or where one twin smoked at least 5 years longer than his or her counterpart. Questionnaires were obtained and standardized photographs were taken by professional photographers. A panel of three blinded judges analyzed the twins' facial features and graded wrinkles using the validated Lemperle Assessment Scale, and ranked age-related facial features on a four-point scale. RESULTS: Smoking twins compared with their nonsmoking counterparts had worse scores for upper eyelid skin redundancy, lower lid bags, malar bags, nasolabial folds, upper lip wrinkles, lower lip vermillion wrinkles, and jowls. Lower lid hyperpigmentation in the smoking group fell just short of statistical significance. Transverse forehead wrinkles, glabellar wrinkles, crow's feet, and lower lip lines accentuated by puckering did not have a statistically significant differences in scores. Among twins with greater than 5 years' difference in smoking duration, twins who had smoked longer had worse scores for lower lid bags, malar bags, and lower lip vermillion wrinkles. CONCLUSIONS: This study details the specifics of facial aging brought on by smoking, which primarily affects the middle and lower thirds of the face. It also demonstrates that a 5-year difference in smoking history can cause noticeable differences in facial aging in twins. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 23924652 TI - Percutaneous aponeurotomy and lipofilling: a regenerative alternative to flap reconstruction? AB - BACKGROUND: The application of a new approach is presented, percutaneous aponeurotomy and lipofilling, which is a minimally invasive, incisionless alternative to traditional flap reconstructions. METHODS: The restrictive subdermal cicatrix and/or endogenous aponeurosis is punctured, producing staggered nicks. Expansion of the restriction reconstructs the defect and creates a vascularized scaffold with micro-openings that are seeded with lipografts. Wide subcutaneous cuts that lead to macrocavities and subsequent graft failure are avoided. Postoperatively, a splint to hold open the neomatrix/graft construct in its expansive state is applied until the grafts mature. Thirty-one patients underwent one to three operations (average, two) for defects that normally require flap tissue transfer: wounds where primary closure was not possible (n=9), contour defects of the trunk and breast requiring large-volume fat grafts (n=8), burn contractures (n=5), radiation scars (n=6), and congenital constriction bands (n=3). RESULTS: The regenerated tissue was similar in texture and consistency to the surrounding tissues. Wider meshed areas had greater tissue gain (range, 20 to 30 percent). There were no significant wound-healing issues, scars, or donor-site morbidities. Advancement tension was relieved without flap undermining or decreased perfusion. CONCLUSIONS: Realizing that, whether scar or endogenous fascia, the subdermal aponeurosis limits tissue stretch and/or its three-dimensional expansion, a minimally invasive procedure that expands this cicatrix into a matrix ideally suited for fat micrografts was developed. Grafting this scaffold applies tissue-engineering principles to generate the needed tissue and represents a regenerative alternative to reconstructive flap surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 23924654 TI - Does good healthcare score as highly with the public as education and protection from crime? PMID- 23924655 TI - Declaration of transparency for each research article. PMID- 23924656 TI - Bad medicine: atrial fibrillation. PMID- 23924657 TI - Doctors in the private sector should report adverse events after immunisation to complete dataset. PMID- 23924658 TI - IFN-gamma-rich environment programs dendritic cells toward silencing of cytotoxic immune responses. AB - Lately, there is increasing evidence that emphasizes the regulatory functions of IFN-gamma, which serve as negative-feedback mechanisms after, e.g., pathogen clearance, to prevent unnecessary tissue destruction. Inflammatory processes involving Th1 and cytotoxic responses are characterized by high, local IFN-gamma concentrations, followed by resolution and immune silencing. Although this is a well-known course of events, extensive attempts to address potential differential effects of IFN-gamma in the manner of its availability (quantitatively) in the environment do not exist. We demonstrate that high doses of IFN-gamma do not induce DC maturation and activation but instead, induce specific regulatory characteristics in DCs. Considering their phenotype, high doses of IFN-gamma extensively induce the expression of ILT-4 and HLA-G inhibitory molecules. Interestingly, the well-known priming effect of IFN-gamma for IL-12p70 production is lost at these conditions, and the DC cytokine profile is switched toward an increased IL-10/IL-12p70 ratio upon subsequent stimulation with CD40L. Furthermore, such DCs are capable of silencing cellular immune responses and activation of cytotoxic CD8+ T lymphocytes, resulting in reduced cell proliferation and down-regulation of granzyme B expression. Additionally, we find that in this manner, immune regulation mediated by IFN-gamma is not mainly a result of increased enzymatic activity of IDO in DCs but rather, a result of HLA G signaling, which can be reversed by blocking mAb. Altogether, our results identify a novel mechanism by which a Th1-like environment programs the functional status of DCs to silence ongoing cytotoxic responses to prevent unwanted tissue destruction and inflammation. PMID- 23924659 TI - Type 2 innate lymphoid cells constitutively express arginase-I in the naive and inflamed lung. AB - Arg1 is produced by AAMs and is proposed to have a regulatory role during asthma and allergic inflammation. Here, we use an Arg1 reporter mouse to identify additional cellular sources of the enzyme in the lung. We demonstrate that ILC2s express Arg1 at rest and during infection with the migratory helminth Nippostrongylus brasiliensis. In contrast to AAMs, which express Arg1 following IL-4/IL-13-mediated STAT6 activation, ILC2s constitutively express the enzyme in a STAT6-independent manner. Although ILC2s deficient in the IL-33R subunit T1/ST2 maintain Arg1 expression, IL-33 can regulate total lung Arg1 by expanding the ILC2 population and by activating macrophages indirectly via STAT6. Finally, we find that ILC2 Arg1 does not mediate ILC2 accumulation, ILC2 production of IL-5 and IL-13, or collagen production during N. brasiliensis infection. Thus, ILC2s are a novel source of Arg1 in resting tissue and during allergic inflammation. PMID- 23924661 TI - Haemolytic uraemic syndrome associated with Pseudomonas aeruginosa sepsis. AB - Haemolytic uraemic syndrome (HUS) is a recognized complication of infection with Shiga toxin-producing Escherichia coli (STEC) and Shigella dysenteriae type 1. Infections with other micro-organisms, especially Streptococcus pneumoniae, have been cited as causes of HUS. In addition, influenza virus and other viruses may rarely be associated with this syndrome. A 2-year-old girl presented with severe Pseudomonas aeruginosa sepsis with renal failure and ecthyma gangrenosum. Further investigations revealed features of HUS. She was managed with antibiotics and other supportive measures including peritoneal dialysis, and subsequently made a full recovery. A possible role of neuraminidase in the pathogenesis of P. aeruginosa-associated HUS was proposed. This is the first reported case of P. aeruginosa sepsis leading to HUS. PMID- 23924662 TI - Molecular diagnosis of bloodstream infections with a new dual-priming oligonucleotide-based multiplex PCR assay. AB - Mortality from bloodstream infections (BSIs) correlates with diagnostic delay and the use of inappropriate empirical treatment. Early PCR-based diagnosis could decrease inappropriate treatment, improving patient outcome. The aim of the present study was to assess the clinical utility of this molecular technology to diagnose BSIs. We assessed a new dual-priming oligonucleotide-based multiplex PCR assay, the Magicplex Sepsis Test (MST) (Seegene), along with blood culture (BC). A total of 267 patients from the intensive care unit and haematology and emergency departments were enrolled. Clinical data were also used by physicians to determine the likelihood of infection. Ninety-eight (37 %) specimens were positive: 29 (11 %) by both the MST and BC, 29 (11 %) by the MST only, and 40 (15 %) by BC only. The proportion of agreement between the two methods was 73 % (Cohen's kappa: 0.45; 0.28-0.6; indicating fair to moderate agreement). According to clinical assessment, 63 (64 %) positive specimens were considered BSIs: 23 (36 %) were positive by both the MST and BC, 22 (35 %) were positive only by BC, and 18 (29 %) were positive only by the MST. Thirty-eight (14 %) positive specimens by the MST and/or BC were considered as contaminants. Of 101 specimens collected from patients receiving antibiotics, 20 (20 %) were positive by the MST and 32 (32 %) by BC. Sensitivity and specificity were 65 % and 92 %, respectively, for the MST and 71 % and 88 %, respectively for BC. We concluded that the MST shows a high specificity but changes in design are needed to increase bacteraemia detection. For viability in clinical laboratories, technical improvements are also required to further automate the process. PMID- 23924663 TI - An in-house assay for BK polyomavirus quantification using the Abbott m2000 RealTime system. AB - BK polyomavirus (BKPyV) quantification is useful for monitoring renal transplant patient response to therapy. The Abbott m2000 RealTime System employed by some clinical laboratories to perform US Food and Drug Administration-approved assays can also be used to develop in-house assays such as the one presented here. This study aimed to validate an in-house quantitative real-time PCR assay targeting the BKPyV major capsid VP1 gene for assessment of viral load using the Abbott m2000 RealTime System. BKPyV load was measured in 95 urine and plasma samples previously tested for BKPyV by one of three laboratories (46 BKPyV-positive samples consisting of 35 plasma and 11 urine samples; 49 samples negative for BKPyV consisting of 47 plasma and two urine samples). Two additional plasma specimens from the College of American Pathologists proficiency testing survey were also analysed. Precision studies were performed by diluting a high-viral titre patient sample into BKPyV-negative pooled plasma to create high-positive (6.16 log10 copies ml(-1)) and low-positive (3.16 log10 copies ml(-1)) samples. For precision studies of inter-assay variability, a high-positive (7.0 log10 copies ml(-1)) and a low-positive (3.0 log10 copies ml(-1)) sample were measured in 20 separate runs. The assay's limit of quantification and limit of detection were 2.70 and 2.25 log10 copies ml(-1), respectively. The assay was linear from 2.70 to 9.26 log10 copies ml(-1). Of the 48 known positives, 43 were detected as positive, with three reported by the reference laboratory as values lower than the limit of detection. Two known positives at 3.27 and 3.80 log10 copies ml(-1) tested negative by the m2000 BKPyV assay. Of the 49 known negative samples, 48 were negative by the m2000 BKPyV load assay, with one sample confirmed positive by a reference laboratory. Qualitative analysis prior to discrepancy testing demonstrated a sensitivity of 89.58 % and a specificity of 97.96 %. Precision studies demonstrated inter-assay coefficients of variation of 0.63 % (high positive) and 4.38 % (low positive). Genotyping was performed on 22 patient samples, of which 21 (95.45 %) were type I and one (4.55 %) was type II. In conclusion, the m2000 BKPyV viral load assay sensitivity, specificity, linear range, precision and cost effectiveness make it an attractive methodology for clinical laboratories using the Abbott m2000 RealTime System. PMID- 23924664 TI - Investigating the role of pneumococcal neuraminidase A activity in isolates from pneumococcal haemolytic uraemic syndrome. AB - Streptococcus pneumoniae diseases are a rare but increasingly recognized trigger of atypical haemolytic uraemic syndrome (HUS) in young children and associated with a higher mortality rate than diarrhoea-associated HUS. This study aimed to determine the importance of neuraminidase A (NanA) and genomic diversity in the pathogenesis of pneumococcal HUS (pHUS). We investigated the nanA gene sequence, gene expression, neuraminidase activity and comparative genomic hybridization of invasive pneumococcal disease (IPD) isolates from patients with pHUS and control strains matched by serotype and sequence type (ST), isolated from patients with IPD but not pHUS. The nanA sequence of 33 isolates was determined and mutations at 142 aa positions were identified. High levels of diversity were observed within the NanA protein, with mosaic blocks, insertions and repeat regions present. When comparing nanA allelic diversity with ST and disease profile in the isolates tested, nanA alleles clustered mostly by ST. No particular nanA allele was associated with pHUS. There was no significant difference in overall neuraminidase activity between pHUS isolates and controls when induced/uninduced with N-acetylneuraminic acid. Comparative genomic hybridization showed little difference in genetic content between the pHUS isolates and the controls. Results of gene expression studies identified 12 genes differentially regulated in all pHUS isolates compared with the control. Although neuraminidase enzyme activity may be important in pHUS progression and contribute to pathogenesis, the lack of a distinction between pHUS isolates and controls suggests that host factors, such as acquired abnormalities of the alternative complement cascade in young children, may play a more significant role in the outcome of pHUS. PMID- 23924660 TI - Effects of ribavirin dose reduction vs erythropoietin for boceprevir-related anemia in patients with chronic hepatitis C virus genotype 1 infection--a randomized trial. AB - BACKGROUND & AIMS: Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety. METHODS: Patients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately <=10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251). RESULTS: Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received >=50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin. CONCLUSIONS: Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035. PMID- 23924666 TI - Aging of the suprachiasmatic clock. AB - More than half of the elderly in today's society suffer from sleep disorders with detrimental effects on brain function, behavior, and social life. A major contribution to the regulation of sleep stems from the circadian system. The central circadian clock located in the suprachiasmatic nucleus of the hypothalamus is like other brain regions subject to age-associated changes. Age affects different levels of the clock machinery from molecular rhythms, intracellular messenger, and membrane properties to neuronal network synchronization. While some of the age-sensitive components of the circadian clock, like ion channels and neurotransmitters, have been described, little is known about the underlying mechanisms. In any case, the result is a reduction in the amplitude of the circadian timing signal produced by the suprachiasmatic nucleus, a weakening in the control of peripheral oscillators and a decrease in amplitude and precision of daily rhythms in physiology and behavior. The distortion in temporal organization is thought to be related to a number of serious health problems and promote neurodegeneration. Understanding the mechanisms underlying age-related deficits in circadian clock function will therefore not only benefit rhythm disorders but also alleviate age-associated diseases aggravated by clock dysfunction. PMID- 23924665 TI - Mechanisms of reward circuit dysfunction in psychiatric illness: prefrontal striatal interactions. AB - The brain's "reward circuit" has been widely implicated in the pathophysiology of mental illness. Although there has been significant progress in identifying the functional characteristics of individual nodes within the circuit and linking dysfunction of these brain areas to various forms of psychopathology, there remains a substantial gap in understanding how the nodes of the circuit interact with one another, and how the growing neurobiological knowledge may be applied to improve psychiatric patient care. In this article, we summarize what is currently known about the functions and interactions of two key nodes of this circuit-the ventral striatum and the ventromedial prefrontal/orbital frontal cortex-in relation to mental illness. PMID- 23924668 TI - Veterinary ophthalmic practice: therapeutic considerations and common ocular diseases-part 1. PMID- 23924669 TI - Andropause: new perspectives. PMID- 23924667 TI - Will calorie restriction work in humans? AB - Calorie Restriction (CR) without malnutrition slows aging and increases average and maximal lifespan in simple model organisms and rodents. In rhesus monkeys long-term CR reduces the incidence of type 2 diabetes, cardiovascular disease and cancer, and protects against age-associated sarcopenia and neurodegeneration. However, so far CR significantly increased average lifespan only in the Wisconsin, but not in the NIA monkey study. Differences in diet composition and study design between the 2 on-going trials may explain the discrepancies in survival and disease. Nevertheless, many of the metabolic and hormonal adaptations that are typical of the long-lived CR rodents did not occur in either the NIA or WNPRC CR monkeys. Whether or not CR will extend lifespan in humans is not yet known, but accumulating data indicate that moderate CR with adequate nutrition has a powerful protective effect against obesity, type 2 diabetes, inflammation, hypertension, cardiovascular disease and reduces metabolic risk factors associated with cancer. Moreover, CR in human beings improves markers of cardiovascular aging, and rejuvenates the skeletal muscle transcriptional profile. More studies are needed to understand the interactions between CR, diet composition, exercise, and other environmental and psychological factors on metabolic and molecular pathways that regulate health and longevity. PMID- 23924670 TI - Pain management in the elderly. PMID- 23924671 TI - Automatic dishwashers and detergents in the pharmacy: the basics. PMID- 23924672 TI - Pharmaceutical compounding calculations. PMID- 23924673 TI - Basics of compounding for cold sores or Fever blisters. PMID- 23924674 TI - Quality-control analytical methods: high-performance liquid chromatography. PMID- 23924675 TI - Physical and Chemical Stability of Treprostinil Sodium Injection Packaged in Plastic Syringe pump Reservoirs. AB - The objective of this study was to evaluate the physical and chemical stability of treprostinil (as sodium) injections in concentrations of 1, 2.5, 5 and 10 mg/mL packaged in MiniMed plastic syringe pump reservoirs. Test samples of treprostinil (as sodium) injections having concentrations of 1, 2.5, 5, and 10 mg/mL were packaged as 3 mL of drug solution in 3-mL MiniMed plastic syringe pump reservoirs, sealed with plastic tip caps and stored at -20 deg C, 4 deg C, 23 deg C and 37 deg C for 60 days. Evaluations for physical and chemical stability were performed initially and throughout the storage periods. Physical stability was assessed using visual observation in normal room light and using a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated by using a stability-indicating high-performance liquid chromatographic analytical technique. All samples of treprostinil (as sodium) injection remained free of visible precipitation throughout the study. Little or no change in haze level and in particulates of greater than or equal to 10 micrometers was found. Changes in treprostinil concentration were found to be small; treprostinil sodium concentrations were found to be 95% or greater over 60 days at all temperatures studied. Treprostinil (as sodium) injections at concentrations ranging from 1 to 10 mg/mL can be packaged in MiniMed plastic syringe reservoirs, stored and shipped with little or no loss of drug stability. PMID- 23924676 TI - Long-term stability of trimix: a three-drug injection used to treat erectile dysfunction. AB - A three-drug injection mixture of alprostadil 12.5 microgram/mL, papaverine hydrochloride 4.5 mg/mL and phentolamine mesylate 0.125 mg/mL in bacteriostatic 0.9% sodium chloride injection was evaluated for stability at 23 deg C, 4 deg C, 20 deg C and -70 deg C. The injection remained clear and colorless in all samples throughout the study. Chemical stability testing was performed using stability indicating high-performance liquid chromatographic analysis. Alprostadil was the least stable of the drug components at room temperature and under refrigeration. About 8% alprostadil loss occurred in five days at room temperature; under refrigeration losses of about 6% and 11% occurred after 1 and 2 months, respectively. Frozen at -20 deg C and -70 deg C, less than 5% loss of any of the drug componenets occurred in 6 months. A beyond-use date of 6 months when stored frozen at -20 deg C and 1 month when stored refrigerated at 4 deg C is appropriate for batches of the injection that have passed sterility testing. Room temperature exposure should be limited, and the vial should be returned to refrigeration as soon as possible. PMID- 23924677 TI - Stability of Zidovudine and Ranitidine in 0.9% Sodium Chloride and 5% Dextrose Injections Stored at Ambient Temperature (23 +/- 2 deg C) and 4 Deg C in 50-mL Polyvinylchloride Bags Up to 24 Hours. AB - The stability of a 2-mg/mL zidovudine and 0.5-mg/mL ranitidine admixture stored in 0.9% sodium chloride and 5% dextrose injections in 50-mL polyvinylchloride bags at ambient temperature and 4 deg C up to 24 hours was studied. The samples were analyzed at 0, 4, 8 and 24 hours after preparation of the controls and admixtures by means of a reverse-phase, stability-indicating, high-performance liquid chromatographic method. The drug mixtures were stable for up to 24 hours, showing levels of greater than 90% of the initial drug concentrations at the time of preparation. The pH of the admixtures was in the pH 5-6 range. These data support the stability of the zidovudine and ranitidine admixture under the storage conditions studied. PMID- 23924678 TI - Antiferromagnetic resonance in the Mott insulator fcc-Cs3C60. AB - The magnetic ground state of the fcc phase of the Mott insulator Cs3C60 was studied using a low-temperature electron spin resonance technique, and antiferromagnetic resonance (AFMR) below 1.57 K was directly observed at ambient pressure. The AFMR modes for the fcc phase of Cs3C60 were investigated using a conventional two-sublattice model with uniaxial anisotropy, and the spin-flop field was determined to be 4.7 kOe at 1.57 K. The static magnetic exchange interactions and anisotropy field for fcc-Cs3C60 were also estimated. PMID- 23924679 TI - Single-dose pharmacokinetics of pediatric and adult formulations of etravirine and swallowability of the 200-mg tablet: results from three Phase 1 studies. AB - OBJECTIVES: Three studies were conducted to assess the pharmacokinetics, methods of administration and ease of swallowability of etravirine tablets. METHODS: Two randomized studies in healthy adults investigated the single-dose pharmacokinetics of etravirine in various dosage strengths and the effects of dispersion in water and film-coating. A third study explored swallowability of etravirine 200-mg tablets in HIV-infected patients. First study: 37 volunteers received 1 * 100-mg non-coated tablet (reference), 4 * 25-mg noncoated tablets and 1 * 100-mg non-coated tablet dispersed in 100 ml water. Second study: 24 volunteers received 2 * 100-mg non-coated tablets (reference), 2 * 100-mg coated tablets, 1 * 200-mg non-coated and 1 * 200-mg coated tablet. Pharmacokinetic parameters were determined using non-compartmental analysis and least square means (LSM) ratios and 90% confidence intervals (CI) were calculated. Third study: 49 virologically-suppressed patients already on an etravirine-containing regimen rated the swallowability of two etravirine formulations (200-mg non coated and 200-mg coated tablets). RESULTS: In the first study LSM ratios (90% CI) for the etravirine area under the plasma concentration-time curve (AUC) administered either as 4 * 25-mg tablets or 100-mg tablet dispersed were: 0.91 (0.85 to 0.98) and 0.97 (0.90 to 1.03), respectively. In the second study, when comparing a 200-mg non-coated and coated tablet to 2 * 100-mg non-coated tablets, LSM ratios for etravirine AUC were 98 to 99%. In the third study, more patients rated the 200-mg than the 100-mg tablets as acceptable to swallow (70% vs. 43%). CONCLUSIONS: Comparable etravirine exposures were observed regardless of formulation or method of administration (i.e., dispersion); 200-mg tablets were rated as easier to swallow than 100-mg tablets. PMID- 23924680 TI - Posaconazole vs. fluconazole as invasive fungal infection prophylaxis in China: a multicenter, randomized, open-label study. AB - BACKGROUND: Invasive fungal infection (IFI) is common in neutropenic patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Posaconazole is a broad-spectrum triazole antifungal drug with efficacy in prevention of IFI; however, it has not been previously studied as prophylaxis in a Chinese population. METHODS: This multicenter, randomized study in China enrolled AML and MDS patients with persistent chemotherapy-induced neutropenia. Prophylaxis with posaconazole or fluconazole was administered for a maximum of 12 weeks, or until patients recovered from neutropenia and achieved complete remission or an IFI occurred. The primary endpoint was incidence of proven, probable, or possible IFI during treatment. Clinical failure rate, all-cause mortality and time to first systemic antifungal treatment were secondary endpoints. RESULTS: Patients were randomized to receive posaconazole (n = 129) or fluconazole (n = 123); 117 patients in each group were included in the statistical analysis. The incidence of proven, probable or possible IFI was 9.4% (11/117) and 22.2% (26/117) in the posaconazole and fluconazole groups, respectively (p = 0.0114). The clinical failure rate was numerically lower in the posaconazole group (37/117 (31.6%; 95%CI: 23.3 - 40.9)) than in the fluconazole group (49/117 (41.88%; 95% CI: 32.8 - 51.4)) (p = 0.168). Patients receiving posaconazole had a later onset of first systematic antifungal treatment than those receiving fluconazole (p = 0.0139). The most common important adverse events were liver function abnormalities (11 patients (8.8%) on posaconazole and 6 (5.0%) on fluconazole (p = 0.221)). CONCLUSIONS: Posaconazole demonstrates efficacy as prophylaxis against IFI in high-risk neutropenic Chinese patients and is well tolerated during long-term use (ClinicalTrials. gov number, NCT00811928). PMID- 23924681 TI - Patient safety: anesthesiology contributions and supplements to the American Society of Anesthesiologists' Annual Meeting. PMID- 23924682 TI - Wolbachia, Sodalis and trypanosome co-infections in natural populations of Glossina austeni and Glossina pallidipes. AB - BACKGROUND: Tsetse flies harbor at least three bacterial symbionts: Wigglesworthia glossinidia, Wolbachia pipientis and Sodalis glossinidius. Wigglesworthia and Sodalis reside in the gut in close association with trypanosomes and may influence establishment and development of midgut parasite infections. Wolbachia has been shown to induce reproductive effects in infected tsetse. This study was conducted to determine the prevalence of these endosymbionts in natural populations of G. austeni and G. pallidipes and to assess the degree of concurrent infections with trypanosomes. METHODS: Fly samples analyzed originated from Kenyan coastal forests (trapped in 2009-2011) and South African G. austeni collected in 2008. The age structure was estimated by standard methods. G. austeni (n=298) and G. pallidipes (n= 302) were analyzed for infection with Wolbachia and Sodalis using PCR. Trypanosome infection was determined either by microscopic examination of dissected organs or by PCR amplification. RESULTS: Overall we observed that G. pallidipes females had a longer lifespan (70 d) than G. austeni (54 d) in natural populations. Wolbachia infections were present in all G. austeni flies analysed, while in contrast, this symbiont was absent from G. pallidipes. The density of Wolbachia infections in the Kenyan G. austeni population was higher than that observed in South African flies. The infection prevalence of Sodalis ranged from 3.7% in G. austeni to about 16% in G. pallidipes. Microscopic examination of midguts revealed an overall trypanosome infection prevalence of 6% (n = 235) and 5% (n = 552), while evaluation with ITS1 primers indicated a prevalence of about 13% (n = 296) and 10% (n = 302) in G. austeni and G. pallidipes, respectively. The majority of infections (46%) were with T. congolense. Co-infection with all three organisms was observed at 1% and 3.3% in G. austeni and G. pallidipes, respectively. Eleven out of the thirteen (85%) co-infected flies harboured T. congolense and T. simiae parasites. While the association between trypanosomes and Sodalis infection was statistically significant in G. pallidipes (P = 0.0127), the number of co infected flies was too few for a definite conclusion. CONCLUSIONS: The tsetse populations analyzed differed in the prevalence of symbionts, despite being sympatric and therefore exposed to identical environmental factors. The density of infections with Wolbachia also differed between G. austeni populations. There were too few natural co-infections detected with the Sodalis and trypanosomes to suggest extensive inter-relations between these infections in natural populations. We discuss these findings in the context of potential symbiont mediated control interventions to reduce parasite infections and/or fly populations. PMID- 23924683 TI - Impact of peptide transporter 1 on the intestinal absorption and pharmacokinetics of valacyclovir after oral dose escalation in wild-type and PepT1 knockout mice. AB - The primary objective of this study was to determine the in vivo absorption properties of valacyclovir, including the potential for saturable proton-coupled oligopeptide transporter 1 (PepT1)-mediated intestinal uptake, after escalating oral doses of prodrug within the clinical dose range. A secondary aim was to characterize the role of PepT1 on the tissue distribution of its active metabolite, acyclovir. [3H]Valacyclovir was administered to wild-type (WT) and PepT1 knockout (KO) mice by oral gavage at doses of 10, 25, 50, and 100 nmol/g. Serial blood samples were collected over 180 minutes, and tissue distribution studies were performed 20 minutes after a 25-nmol/g oral dose of valacyclovir. We found that the C(max) and area under the curve (AUC)0-180 of acyclovir were 4- to 6-fold and 2- to 3-fold lower, respectively, in KO mice for all four oral doses of valacyclovir. The time to peak concentration of acyclovir was 3- to 10-fold longer in KO compared with WT mice. There was dose proportionality in the C(max) and AUC0-180 of acyclovir in WT and KO mice over the valacyclovir oral dose range of 10-100 nmol/g (i.e., linear absorption kinetics). No differences were observed in the peripheral tissue distribution of acyclovir once these tissues were adjusted for differences in perfusing drug concentrations in the systemic circulation. In contrast, some differences were observed between genotypes in the concentrations of acyclovir in the distal intestine. Collectively, the findings demonstrate a critical role of intestinal PepT1 in improving the rate and extent of oral absorption for valacyclovir. Moreover, this study provides definitive evidence for the rational development of a PepT1-targeted prodrug strategy. PMID- 23924684 TI - The story of stolen chaperones: how overexpression of Q/N proteins cures yeast prions. AB - Prions are self-seeding alternate protein conformations. Most yeast prions contain glutamine/asparagine (Q/N)-rich domains that promote the formation of amyloid-like prion aggregates. Chaperones, including Hsp104 and Sis1, are required to continually break these aggregates into smaller "seeds." Decreasing aggregate size and increasing the number of growing aggregate ends facilitates both aggregate transmission and growth. Our previous work showed that overexpression of 11 proteins with Q/N-rich domains facilitates the de novo aggregation of Sup35 into the [PSI(+)] prion, presumably by a cross-seeding mechanism. We now discuss our recent paper, in which we showed that overexpression of most of these same 11 Q/N-rich proteins, including Pin4C and Cyc8, destabilized pre-existing Q/N rich prions. Overexpression of both Pin4C and Cyc8 caused [PSI(+)] aggregates to enlarge. This is incompatible with a previously proposed "capping" model where the overexpressed Q/N-rich protein poisons, or "caps," the growing aggregate ends. Rather the data match what is expected of a reduction in prion severing by chaperones. Indeed, while Pin4C overexpression does not alter chaperone levels, Pin4C aggregates sequester chaperones away from the prion aggregates. Cyc8 overexpression cures [PSI(+)] by inducing an increase in Hsp104 levels, as excess Hsp104 binds to [PSI(+)] aggregates in a way that blocks their shearing. PMID- 23924686 TI - Modern management of acute non-variceal upper gastrointestinal bleeding. AB - An acute upper gastrointestinal bleed (AUGIB) often represents a life-threatening event and is recognised universally as a common cause of emergency hospitalisation. Large observational studies have improved our understanding of the disease characteristics and its impact on mortality but despite significant advancement in endoscopic management, mortality remains high, particularly in elderly patients and those with multiple comorbidities. Skilled assessment, risk stratification and prompt resuscitation are essential parts of patient care, with endoscopy playing a key role in the definitive management. A successful outcome partly relies on the clinician's familiarity with current guidelines and recommendations, including the National Institute for Clinical Excellence guidelines published in 2012. Validated risk stratification scores, such as the Blatchford and Rockall score, facilitate early discharge of low-risk patients as well as help in identifying those needing early endoscopic intervention. Major advances in therapeutic endoscopy, including more recently, the development of non-toxic proprietary powders (Hemospray and EndoClot), have resulted in the development of effective treatments of bleeding lesions, reduction in rebleeding rates and the need for emergency surgery. The role of proton-pump inhibitor therapy prior to endoscopy and the level of optimum red cell transfusion in the setting of AUGIB remain fields that require further research. PMID- 23924685 TI - Estimating the incidence of suspected epidural hematoma and the hidden imaging cost of epidural catheterization: a retrospective review of 43,200 cases. AB - BACKGROUND AND OBJECTIVES: Hematoma associated with epidural catheterization is rare, but the diagnosis might be suspected relatively frequently. We sought to estimate the incidence of suspected epidural hematoma after epidural catheterization and to determine the associated cost of excluding or diagnosing an epidural hematoma through radiologic imaging. METHODS: We conducted an electronic retrospective chart review of 43,200 patient charts using 4 distinct search strategies and cost analysis, all from a single academic institution from 2001 through 2009. The charts were reviewed for use of radiologic imaging studies to identify patients with suspected and confirmed epidural hematomas. Costs for imaging to exclude or confirm the diagnosis were related to the entire cohort. RESULTS: In our analysis, during a 9-year period that included 43,200 epidural catheterizations, 102 patients (1/430) underwent further imaging studies to exclude or confirm the presence of an epidural hematoma-revealing 6 confirmed cases and an overall incidence (per 10,000 epidural blocks) of epidural hematoma of 1.38 (95% confidence interval, 0-0.002). Among our patients, 207 imaging studies, primarily lumbar spine magnetic resonance imaging, were performed. Integrating Medicare cost expenditure data, the estimated additional cost during a 9-year period for imaging and hospital charges related to identifying epidural hematomas nets to approximately $232,000 or an additional $5.37 per epidural. CONCLUSIONS: Approximately 1 in 430 patients undergoing epidural catheterization will be suspected to have an epidural hematoma. The cost of excluding the diagnosis, when suspected, is relatively low when allocated across all patients undergoing epidural catheterization. PMID- 23924687 TI - Operator training requirements and diagnostic accuracy of Fibroscan in routine clinical practice. AB - BACKGROUND: Fibroscan is a quick, non-invasive technique used to measure liver stiffness (kPa), which correlates with fibrosis. To achieve a valid liver stiffness evaluation (LSE) the operator must obtain all the following three criteria: (1) >=10 successful liver stiffness measurements; (2) IQR/median ratio <0.30 and (3) >=60% measurement success rate. OBJECTIVES: To assess the operator training requirements and the importance of adhering to the LSE validity criteria in routine clinical practice. METHODS: We retrospectively analysed the LSE validity rates of 2311 Fibroscans performed (1 August 2008 to 31 July 2011) in our tertiary liver outpatients department at the University Hospital Birmingham, UK. The diagnostic accuracy of Fibroscan was assessed in 153 patients, by comparing LSE (valid and invalid) with the modified Ishak fibrosis stage on liver biopsy. RESULTS: Learning curve analysis highlighted that the greatest improvement in validity of LSE rates occurs in the operator's first 10 Fibroscans, reaching 64.7% validity by the 50th Fibroscan. The correlation between LSE and the fibrosis stage on liver biopsy was superior in patients with a valid LSE (n=97) compared with those with an invalid LSE (n=56) (rs 0.577 vs 0.259; p=0.022). Area under receiving operating characteristics for significant fibrosis was greater when LSE was valid (0.83 vs 0.66; p=0.048). Using an LSE cut off of 8 kPa, the negative predictive value of valid LSE was superior to invalid LSE for the detection of significant (84% vs 71%) and advanced fibrosis (100% vs 93%). CONCLUSIONS: Fibroscan requires minimal operator training (>=10 observed on patients), and when a valid LSE is obtained, it is an accurate tool for excluding advanced liver fibrosis. To ensure the diagnostic accuracy of Fibroscan it is essential that the recommended LSE validity criteria are adhered to in routine clinical practice. PMID- 23924688 TI - Rapid and accurate analysis of an X-ray fluorescence microscopy data set through gaussian mixture-based soft clustering methods. AB - X-ray fluorescence (XRF) microscopy is an important tool for studying trace metals in biology, enabling simultaneous detection of multiple elements of interest and allowing quantification of metals in organelles without the need for subcellular fractionation. Currently, analysis of XRF images is often done using manually defined regions of interest (ROIs). However, since advances in synchrotron instrumentation have enabled the collection of very large data sets encompassing hundreds of cells, manual approaches are becoming increasingly impractical. We describe here the use of soft clustering to identify cell ROIs based on elemental contents, using data collected over a sample of the malaria parasite Plasmodium falciparum as a test case. Soft clustering was able to successfully classify regions in infected erythrocytes as "parasite," "food vacuole," "host," or "background." In contrast, hard clustering using the k-means algorithm was found to have difficulty in distinguishing cells from background.While initial tests showed convergence on two or three distinct solutions in 60% of the cells studied, subsequent modifications to the clustering routine improved results to yield 100% consistency in image segmentation. Data extracted using soft cluster ROIs were found to be as accurate as data extracted using manually defined ROIs, and analysis time was considerably improved. PMID- 23924689 TI - Growing vascularized heart tissue from stem cells. AB - The promise of stem cells to repair the heart after damage or heart attack has not been realized because most such cells are lost after transplantation. A new approach is to grow substantial viable pieces of cardiac tissue from human stem cells by cardiac tissue engineering. Such constructs must be fully vascularized and perfused to ensure the viability of clinically relevant volumes of tissue. This requires careful choice of cells, culture conditions, a biomaterial to act as scaffold, and crucial strategies for vascularization. Autologous stem cells with high plasticity, which would avoid the need for antirejection therapies after transplantation, are an attractive source of both cardiomyocytes and vascular cells. Most stem cells also have inherent paracrine activity, releasing cytoprotective factors and growth-promoting cytokines that can further stimulate tissue regeneration and neovascularization through recruitment of endogenous stem and progenitor cells. Current advances for growing vascularized and functional cardiac constructs with human stem cells are described, bringing us a step closer to the engineering of complex cardiac tissues such as pacemaker, conducting tissue, or contractile myocardial flaps ideal for transplantation. From studies in rats successful transplantation of thin constructs to the ventricle has been reported, but there remain further issues to resolve before larger human constructs will be available to test in the clinic. PMID- 23924690 TI - Ambulatory blood pressure in atrial fibrillation: an irregular conundrum of rate and rhythm. PMID- 23924691 TI - Effects of black soy peptide supplementation on blood pressure and oxidative stress: a randomized controlled trial. AB - Black soy peptides have been shown to possess properties that may decrease blood pressure (BP). To examine the effects of black soy peptide supplementation on BP and oxidative stress in subjects with prehypertension or stage I hypertension, 100 participants with an initial untreated systolic blood pressure (SBP) of 130 159 mm Hg, diastolic blood pressure (DBP) of 80-99 mm Hg or both were enrolled. Participants were randomly assigned to either a group ingesting supplement containing 4.5 g black soy peptides daily or a placebo group for 8 weeks. SBP and DBP decreased after 8-week black soy peptide supplementation versus controls (P<0.001). At 8 weeks, SBP decrease was significantly greater for the black soy peptide group (-9.69 +/- 12.37 mm Hg) than for the control group (-2.91 +/- 13.29 mm Hg) after adjusting for the baseline levels (P = 0.015). Plasma malondialdehyde (MDA) and urinary 8-epi-prostaglandin F2alpha decreased (P = 0.004 and P = 0.046, respectively) and plasma superoxide dismutase (SOD) activity increased (P<0.001) following 8 weeks of black soy peptide supplementation versus baselines. The MDA decreases (P = 0.022) and SOD activity and nitric oxide (NO) increases (P = 0.022 and P<0.001, respectively) were greater for the black soy peptide group than for the control group. Changes in SBP negatively correlated with changes in NO (r = -0.343, P = 0.001). Changes in angiotensin-converting enzyme activity negatively correlated with NO decreases (r = -0.490, P<0.001) and SOD activity increases (r = -0.338, P = 0.001). Black soy peptide dietary supplementation significantly reduces SBP and oxidative stress in patients with prehypertension and stage I hypertension. PMID- 23924692 TI - Motor effects of the non-psychotropic phytocannabinoid cannabidiol that are mediated by 5-HT1A receptors. AB - The broad presence of CB1 receptors in the basal ganglia, mainly in GABA- or glutamate-containing neurons, as well as the presence of TRPV1 receptors in dopaminergic neurons and the identification of CB2 receptors in some neuronal subpopulations within the basal ganglia, explain the powerful motor effects exerted by those cannabinoids that can activate/block these receptors. By contrast, cannabidiol (CBD), a phytocannabinoid with a broad therapeutic profile, is generally presented as an example of a cannabinoid compound with no motor effects due to its poor affinity for the CB1 and the CB2 receptor, despite its activity at the TRPV1 receptor. However, recent evidence suggests that CBD may interact with the serotonin 5-HT1A receptor to produce some of its beneficial effects. This may enable CBD to directly influence motor activity through the well-demonstrated role of serotonergic transmission in the basal ganglia. We have investigated this issue in rats using three different pharmacological and neurochemical approaches. First, we compared the motor effects of various i.p. doses of CBD with the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n propylamino) tetralin (8-OH-DPAT; i.p.). Second, we investigated whether the motor effects of CBD are sensitive to 5-HT1A receptor blockade in comparison with CB1 receptor antagonism. Finally, we investigated whether CBD was able to potentiate the effect of a sub-effective dose of 8-OH-DPAT. Our results demonstrated that: (i) only high doses of CBD (>10 mg/kg) altered motor behavior measured in a computer-aided actimeter; (ii) these alterations were restricted to vertical activity (rearing) with only modest changes in other parameters; (iii) similar effects were produced by 8-OH-DPAT (1 mg/kg), although this agonist affected exclusively vertical activity, with no effects on other motor parameters, and it showed always more potency than CBD; (iv) the effects of 8-OH DPAT (1 mg/kg) and CBD (20 mg/kg) on vertical activity were reversed by the 5 HT1A receptor antagonist WAY-100,635 (0.5 mg/kg; i.p.); (v) the effects of CBD (20 mg/kg) on vertical activity were not reversed by the CB1 receptor antagonist rimonabant (0.1 mg/kg; i.p.); (vi) the effect of 8-OH-DPAT on vertical activity was associated with an increase in serotonin content in the basal ganglia, a neurochemical change not produced by CBD (20 mg/kg); and (vii) CBD at a dose of 20 mg/kg was able to enhance motor effects of a sub-effective dose of 8-OH-DPAT (0.1 mg/kg), producing the expected changes in serotonergic transmission in the basal ganglia. Collectively, these results suggest that CBD may influence motor activity, in particular vertical activity, and that this effect seems to be dependent on its ability to target the 5-HT1A receptor, a mechanism of action that has been proposed to account for its anti-emetic, anxiolytic and antidepressant effects. PMID- 23924693 TI - Vitamin D deficiency is a risk factor for obesity and diabetes type 2 in women at late reproductive age. AB - It was suggested that glucose metabolism and body fat content depend on serum levels of 25-hydroxyvitamin D [25(OH)D]. We studied 320 healthy women at late reproductive age of 40 to 52 years old (mean age 46.1+/-4.5) from St. Petersburg (North-West region of Russia). 25(ON)D levels were from 19.4 to 134.0 nMol/L (mean 52.9+/-22.7). Vitamin D deficiency (lower than 50 nMol/L) and insufficiency (50-75 nMol/L) was revealed in 59.1% and 27.8% of women, respectively. The study showed that low 25(OH)D levels were associated with obesity (r=-0.35, p$#X003C0.01), increased plasma glucose levels after OGTT (r=-0.31, p$#X003C0.01) and decreased insulin sensitivity index (r=-0.28, p$#X003C0.01). We found that 25(OH)D levels below 50 nMol/L were associated with obesity risk (OR 2.25[1.05 3.95], CI 95%) but not with risk of impaired glucose metabolism (1.07[0.54 2.12],CI95%). Our results showed that vitamin D insufficiency is highly prevalent in the population of healthy women. Low 25(OH)D levels correlated with high body fat, glucose levels and decreased insulin sensitivity. We conclude that vitamin D deficiency is a potential risk factor for obesity and development of insulin resistance leading to diabetes type 2. PMID- 23924695 TI - Proteomics-based analysis of differentially expressed proteins in the CXCR1 knockdown gastric carcinoma MKN45 cell line and its parental cell. AB - C-X-C chemokine receptor types 1 (CXCR1), a cell-surface G-protein-coupled receptor has been found to be associated with tumorigenesis, development, and progression of some tumors. Previously, we have found that CXCR1 overexpression is associated with late-stage gastric adenocarcinoma. We also have demonstrated that knockdown of CXCR1 could inhibit cell proliferation in vitro and in vivo. In this study, we compared the changes of protein expression profile between gastric carcinoma MKN45 cell line and CXCR1-knockdown MKN45 cell line by 2D electrophoresis. Among the 101 quantified proteins, 29 spots were significantly different, among which 13 were down-regulated and 16 were up-regulated after CXCR1 knockdown. These proteins were further identified by mass spectrometry analysis. Among them, several up-regulated proteins such as hCG2020155, Keratin8, heterogeneous nuclear ribonucleoprotein C (C1/C2), and several down-regulated proteins such as Sorcin, heat shock protein 27, serpin B6 isoform b, and heterogeneous nuclear ribonucleoprotein K were confirmed. These proteins are related to cell cycle, the transcription regulation, cell adherence, cellular metabolism, drug resistance, and so on. These results provide an additional support to the hypothesis that CXCR1 might play an important role in proliferation, invasion, metastasis, and prognosis, and drug resistance of gastric carcinoma. PMID- 23924696 TI - Jagged-1/Notch3 signaling transduction pathway is involved in apelin-13-induced vascular smooth muscle cells proliferation. AB - The apelin/apelin receptor (APJ, apelin-angiotensin receptor-like 1) system is a newly deorphanized G protein-coupled receptor system. Both apelin and APJ that are important regulatory factors are expressed in the cardiovascular system. Our previous studies demonstrated that apelin-13 significantly stimulated vascular smooth muscle cell (VSMC) proliferation. In this paper, our data suggested that the Jagged-1/Notch3 signaling transduction pathway is involved in apelin-13 induced VSMC proliferation by promoting the expression of Cyclin D1. Results indicated that apelin-13 stimulates the proliferation of VSMC and the expression of Jagged-1 and Notch3 in concentration- and time-dependent manners. The increased expression of Jagged-1 and Notch3 induced by apelin-13 could be abolished by extracellular signal-regulated protein kinase (ERK) blockade. PD98059 (ERK inhibitor) can inhibit the activation of Jagged-1/Notch3 induced by apelin-13. Down-regulation of Notch3 using small interfering RNA inhibits the expression of Cyclin D1 and prevents apelin-13-induced VSMC proliferation. In conclusion, Jagged-1/Notch3 signaling transduction pathway is involved in VSMC proliferation induced by apelin-13. PMID- 23924697 TI - A Primer on USP Chapter 797 "Pharmaceutical Compounding-Sterile Preparations," and USP Process for Drug and Practice Standards. PMID- 23924694 TI - Map4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling. AB - Adipose tissue lipogenesis is paradoxically impaired in human obesity, promoting ectopic triglyceride (TG) deposition, lipotoxicity, and insulin resistance. We previously identified mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4), a sterile 20 protein kinase reported to be upstream of c-Jun NH2 terminal kinase (JNK) signaling, as a novel negative regulator of insulin stimulated glucose transport in adipocytes. Using full-genome microarray analysis we uncovered a novel role for Map4k4 as a suppressor of lipid synthesis. We further report here the surprising finding that Map4k4 suppresses adipocyte lipogenesis independently of JNK. Thus, while Map4k4 silencing in adipocytes enhances the expression of lipogenic enzymes, concomitant with increased conversion of (14)C-glucose and (14)C-acetate into TGs and fatty acids, JNK1 and JNK2 depletion causes the opposite effects. Furthermore, high expression of Map4k4 fails to activate endogenous JNK, while Map4k4 depletion does not attenuate JNK activation by tumor necrosis factor alpha. Map4k4 silencing in cultured adipocytes elevates both the total protein expression and cleavage of sterol-regulated element binding protein-1 (Srebp-1) in a rapamycin-sensitive manner, consistent with Map4k4 signaling via mechanistic target of rapamycin complex 1 (mTORC1). We show Map4k4 depletion requires Srebp-1 upregulation to increase lipogenesis and further show that Map4k4 promotes AMP-protein kinase (AMPK) signaling and the phosphorylation of mTORC1 binding partner raptor (Ser792) to inhibit mTORC1. Our results indicate that Map4k4 inhibits adipose lipogenesis by suppression of Srebp-1 in an AMPK- and mTOR-dependent but JNK independent mechanism. PMID- 23924699 TI - Current topical treatments in wound healing, part 1. AB - Abstract not available. PMID- 23924698 TI - Case report: wound care of a diabetic foot ulcer. PMID- 23924700 TI - Veterinary ophthalmic practice: therapeutic considerations and common ocular diseases-part 2. PMID- 23924702 TI - Quality-control analytical methods: gas chromatography. PMID- 23924701 TI - Basics of compounding for fungal sinusitis. PMID- 23924703 TI - Enhanced release of diazepam from hollow-type suppositories. AB - The objective of this study was to develop a rapid-release diazepam suppository. Four kinds of diazepam suppositories were formulated: (1) a conventional suppository with Witepsol H-15 as a base, (2) a conventional suppository with mixed polyethylene glycols as a base, (3) a hollow-type suppository with Witepsol H-15 as a base that contained diazepam solution in its cavity and (4) a hollow type suppository with Witepsol H-15 as a base that contained diazepam powder in its cavity. The result of the differential scanning calorimetry thermograms indicated that diazepam dissolved in Witepsol base had a strong affinity to the lipophiic base while diazepam dispersed in polyethylene glycol base was still in the crystalline form. The release study of prepared suppositories showed that the release of diazepam from suppository 1 and suppository 4 was very slow. The diazepam released from suppository 2 after 5 minutes was about 30%. The diazepam released from suppository 3 after 5 minutes was about 85%, which was significantly faster than that of the other three formulations (1, 2, and 4). The hollow-type suppository that contained diazepam solution was found to be the most effective rapid-release formulation. PMID- 23924704 TI - Efficacy and tolerability of compounded bioidentical hormone replacement therapy. AB - The primary purpose of this six-week survey study of women currently taking compounded bioidentical hormone replacement therapy was to determine if compounded bioidentical hormone replacement therapy relieves symptoms of menopause and is well tolerated. The secondary purpose of this study was to compare the symptom relief and tolerability of compounded bioidentical hormone replacement therapy to previously used commercially available products. All strengths and dosage forms of bi-estrogen and tri-estrogen were included, whether used alone or in combination with progesterone, dehydroepiandrosterone or testosterone. The survey instrument consisted of nineteen questions and evaluated the outcomes and side effects for commercially available versus compounded bioidentical hormones. A total of 160 surveys was distributed and 78 were completed. Overall, 57.7% of the women surveyed reported fewer side effects and 71.8% of the women had better relief of menopausal symptoms when using bioidentical hormone replacement therapy. The occurrence and severity of menopausal symptoms decreased significantly after beginning bioidentical hormone replacement therapy. Before treatment, moderate-to-severe symptoms of hot flashes, night sweats, sleep problems, dry skin/hair, vaginal dryness, foggy thinking, mood swings and decrease in sex drive were reported in 52 % to 70% of the women. After initiating treatment the moderate-to-severe range of symptoms dropped to between 4% and 20%. The most commonly reported side effects with bioidentical hormone replacement therapy were weight gain (37.2%), breast tenderness (19.2%) and bloating (23.1%). Weight gain (56.2%), breast tenderness (54.5%), bloating (40%) and mood swings (36.4%) were most commonly seen with commercially available products. Bioidentical hormone replacement relieved the symptoms of menopause and was well tolerated. PMID- 23924706 TI - Effect of mechanical behaviour of the brachial artery on blood pressure measurement during both cuff inflation and cuff deflation. AB - OBJECTIVE: The aim of this study was to investigate the effect of different mechanical behaviour of the brachial artery on blood pressure (BP) measurements during cuff inflation and deflation. METHODS: BP measurements were taken from each of 40 participants, with three repeat sessions under three randomized cuff deflation/inflation conditions. Cuff pressure was linearly deflated and inflated at a standard rate of 2-3 mmHg/s and also linearly inflated at a fast rate of 5-6 mmHg/s. Manual auscultatory systolic and diastolic BPs, and pulse pressure (SBP, DBP, PP) were measured. Automated BPs were determined from digitally recorded cuff pressures by fitting a polynomial model to the oscillometric pulse amplitudes. The BPs from cuff deflation and inflation were then compared. RESULTS: Repeatable measurements between sessions and between the sequential order of inflation/deflation conditions (all P > 0.1) indicated stability of arterial mechanical behaviour with repeat measurements. Comparing BPs obtained by standard inflation with those from standard deflation, manual SBP was 2.6 mmHg lower (P < 0.01), manual DBP was 1.5 mmHg higher (P < 0.01), manual PP was 4.2 mmHg lower (P < 0.001), automated DBP was 6.7 mmHg higher (P < 0.001) and automatic PP was 7.5 mmHg lower (P < 0.001). There was no statistically significant difference for any automated BPs between fast and standard cuff inflation. The statistically significant BP differences between inflation and deflation suggest different arterial mechanical behaviour between arterial opening and closing during BP measurement. CONCLUSION: We have shown that the mechanical behaviour of the brachial artery during BP measurement differs between cuff deflation and cuff inflation. PMID- 23924705 TI - Analysis of the genetic diversity of the nematode parasite Baylisascaris schroederi from wild giant pandas in different mountain ranges in China. AB - BACKGROUND: Baylisascaris schroederi is one of the most common nematodes of the giant panda, and can cause severe baylisascarosis in both wild and captive giant pandas. Previous studies of the giant pandas indicated that this population is genetically distinct, implying the presence of a new subspecies. Based on the co evolution between the parasite and the host, the aim of this study was to investigate the genetic differentiation in the B. schroederi population collected from giant pandas inhabiting different mountain ranges, and further to identify whether the evolution of this parasite correlates with the evolution of giant pandas. METHODS: In this study, 48 B. schroederi were collected from 28 wild giant pandas inhabiting the Qinling, Minshan and Qionglai mountain ranges in China. The complete sequence of the mitochondrial cytochrome b (mtCytb) gene was amplified by PCR, and the corresponding population genetic diversity of the three mountain populations was determined. In addition, we discussed the evolutionary relationship between B. schroederi and its host giant panda. RESULTS: For the DNA dataset, insignificant Fst values and a significant, high level of gene flow were detected among the three mountain populations of B. schroederi, and high genetic variation within populations and a low genetic distance were observed. Both phylogenetic analyses and network mapping of the 16 haplotypes revealed a dispersed pattern and an absence of branches strictly corresponding to the three mountain range sampling sites. Neutrality tests and mismatch analysis indicated that B. schroederi experienced a population expansion in the past. CONCLUSIONS: Taken together, the dispersed haplotype map, extremely high gene flow among the three populations of B. schroederi, low genetic structure and rapid evolutionary rate suggest that the B. schroederi populations did not follow a pattern of isolation by distance, indicating the existence of physical connections before these populations became geographically separated. PMID- 23924707 TI - Functional characterization of the NfxB repressor of the mexCD-oprJ multidrug efflux operon of Pseudomonas aeruginosa. AB - The mexCD-oprJ multidrug efflux operon of Pseudomonas aeruginosa is regulated by the NfxB repressor. Two forms of NfxB have been reported [Shiba et al. (1995). J Bacteriol 177, 5872) although mutagenesis studies here confirm that the larger protein (199 amino acids, 22.4 kDa) is the functional repressor. NfxB binds upstream of the mexCD-oprJ transcription initiation site to a region containing two inverted repeats, both of which are required for binding. Two-hybrid assays confirmed that NfxB is a multimer, with the C-terminal two-thirds of the repressor required for multimerization. Random mutagenesis identified several mutations within the C-terminal region of NfxB required for multimerization, all of which mapped to a three-helix subdomain of the C-terminal region in a structural model of the repressor, which may thus represent the multimerization domain. These mutations compromised NfxB binding to its target DNA in electromobility shift assays, and their introduction into the chromosome of P. aeruginosa enhanced mexCD-oprJ expression and promoted multidrug resistance, consistent with the functional NfxB repressor being a multimer. Site-directed and spontaneous nfxB mutants showing increased mexCD-oprJ expression and multidrug resistance were also recovered, with mutations mapping to the three-helix subdomain again impacting multimerization and DNA binding. Mutations mapping to the N-terminal helix-turn-helix motif implicated in DNA binding did not impact multimerization although they did render the repressor insoluble and unsuitable for mobility shift assays. Size exclusion column chromatography demonstrated that wild-type NfxB forms tetramers in solution, although a mutant form of the repressor carrying a G192D substitution near the C terminus of the protein and compromised for DNA binding and repressor activity forms dimers. These results suggest that NfxB operates as a tetramer (dimer of dimers) and that the C terminus of the protein serves as a tetramerization domain. PMID- 23924708 TI - High-performance nonvolatile Al/AlO(x)/CdTe:Sb nanowire memory device. AB - Here we demonstrate a room temperature processed nonvolatile memory device based on an Al/AlO(x)/CdTe:Sb nanowire (NW) heterojunction. Electrical analysis shows an echelon hysteresis composed of a high-resistance state (HRS) and a low resistance state (LRS), which can allow it to write and erase data from the device. The conductance ratio is as high as 106, with a retention time of 3 * 104 s. Moreover, the SET voltages ranged from +6 to +8 V, whilst the RESET voltage ~0 V. In addition, flexible memory nano-devices on PET substrate with comparable switching performance at bending condition were fabricated. XPS analysis of the Al/AlO(x)/CdTe:Sb NW heterojunction after controlled Ar+ bombardment reveals that this memory behavior is associated with the presence of ultra-thin AlO(x) film. This Al/AlO(x)/CdTe:Sb NW heterojunction will open up opportunities for new memory devices with different configurations. PMID- 23924709 TI - Effects of a hot-water extract of porcini (Boletus aestivalis) mushrooms on the blood pressure and heart rate of spontaneously hypertensive rats. AB - The repeated once-daily oral administration of a hot-water extract of porcini, Boletus aestivalis, mushrooms (WEP) to spontaneously hypertensive rats (SHR) for 18 weeks decreased the systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate. The WEP administration also decreased blood urea nitrogen (BUN), creatinine (Cre), and triglyceride (TG), and increased high-density lipoprotein-cholesterol (HDL-C) in the blood, suggesting that WEP improved the status of hypertension, as well as the high heart rate and metabolic abnormalities involved in hypertension. PMID- 23924710 TI - Fermentative production of plant benzylisoquinoline alkaloids in microbes. AB - Higher plants produce diverse chemicals, including alkaloids, terpenoids, and phenolic compounds (phenylpropanoids and flavonoids) as secondary metabolites. These chemicals are widely used for human health and nutrition. Alkaloids, for example, are valued in medicine due to their high biological activities, but most of these metabolites accumulate at low levels in plant cells, resulting in poor extraction yields. Increasingly, attention is devoted to the production of plant metabolites by reconstructing plant biosynthetic pathways in microorganisms. This technology has been aided by advances in synthetic biology and metabolic engineering. Here, the review a fermentation platform for low-cost production of numerous alkaloids using bioengineered Escherichia coli and/or Saccharomyces cerevisiae. PMID- 23924711 TI - Breeding of a cyclic imide-assimilating bacterium, Pseudomonas putida s52, for high efficiency production of pyruvate. AB - A succinimide-assimilating bacterium, Pseudomonas putida s52, was found to be a potent producer of pyruvate from fumarate. Using washed cells from P. putida s52 as catalyst, 400 mM pyruvate was produced from 500 mM fumarate in a 36-h reaction. Bromopyruvate, a malic enzyme inhibitor, was used for the selection of mutants with higher pyruvate productivity. A bromopyruvate-resistant mutant, P. putida 15160, was found to be an effective catalyst for pyruvate production. Moreover, under batch bioreactor conditions, 767 mM of pyruvate was successfully produced from 1,000 mM fumarate in a 72-h reaction with washed cells from P. putida 15160 as catalyst. PMID- 23924712 TI - Discriminative phytoalexin accumulation in Lotus japonicus against symbiotic and non-symbiotic microorganisms and related chemical signals. AB - The phytoalexin response of Lotus japonicus seedlings to selected microbes and chemical signals was analyzed. The symbiotic rhizobium induced vestitol production weakly, while non-symbiotic rhizobia and potential pathogens led to increases in its accumulation. Whereas chitin-related molecules were ineffective, a flagellin-derived peptide not of symbiont origin induced phytoalexin production, indicating discriminative antibiotic production by the plant host. PMID- 23924713 TI - Molecular cloning and bacterial expression of the catalytic domain of the SENP1 gene of Oryzias latipes. AB - In this study, we cloned the catalytic domain of the Oryzias latipes sentrin/SUMO specific protease 1 (OlSENP1-CD) gene and produced the recombinant OlSENP1-CD protein in Escherichia coli. Experimental procedures designed to reveal the ability of the recombinant protein to show deSUMOylating activity in vitro should be helpful in future studies of other SENPs and the SUMO pathway. PMID- 23924714 TI - Oxidative stress during development of alcoholic fatty liver: therapeutic potential of cacao polyphenol. AB - The lipid and antioxidative/oxidative profiles of livers from rats fed an ethanol liquid diet for 8 weeks provided evidence for an involvement of oxidative stress (e.g., phospholipid peroxidation) in the development of alcoholic fatty liver (AFL), possibly in an early stage. Cacao polyphenol supplementation produced an ameliorating effect, and may help in AFL prevention. PMID- 23924715 TI - Development of gateway binary vectors R4L1pGWB possessing the bialaphos resistance gene (bar) and the tunicamycin resistance gene as markers for promoter analysis in plants. AB - We have developed a new series of R4L1 Gateway binary vectors (R4L1pGWB), which carry the bialaphos resistance gene (bar) or the UDP-N-acetylglucosamine:dolichol phosphate N-acetylglucosamine-1-P transferase (GPT) gene as selection markers that confer BASTA(r) and tunicamycin resistance on plants respectively. R4L1pGWBs have an attR4-attL1-reporter and can accept an attL4-promoter-attR1 entry clone for easy construction of an attB4-promoter-attB1-reporter clone. The new R4L1pGWBs facilitate promoter:reporter analysis in pre-existing transgenic plants that are resistant to kanamycin or hygromycin. PMID- 23924716 TI - Penetration and post-penetration resistance to Magnaporthe oryzae in Arabidopsis. AB - The rate of entry of Magnaporthe oryzae into the Arabidopsis pen2 quintuple (pen2 NahG pmr5 agb1 mlo2) mutant was significantly higher than those into the pen2 quadruple (pen2 NahG pmr5 agb1 and pen2 NahG pmr5 mlo2) mutants. The lengths of the infection hyphae in the pen2 quintuple mutant were intermediate between the pen2 quadruple mutants. These results suggest that different genetic networks, consisting of PEN2, PMR5, AGB1, and MLO2, control penetration and post penetration resistance to M. oryzae in Arabidopsis. PMID- 23924717 TI - Isolation of bioactive steroids from the Stropharia rugosoannulata mushroom and absolute configuration of strophasterol B. AB - The absolute configuration of strophasterol B (1) isolated from the fruiting bodies of Stropharia rugosoannulata was determined by an X-ray crystallographic analysis. Three compounds (2 to 4) were isolated from the mushroom which suppressed or promoted lettuce growth. PMID- 23924718 TI - High thermal stability and unique trimer formation of cytochrome c' from thermophilic Hydrogenophilus thermoluteolus. AB - Sequence analysis indicated that thermophilic Hydrogenophilus thermoluteolus cytochrome c' (PHCP) and its mesophilic homolog, Allochromatium vinosum cytochrome c' (AVCP), closely resemble each other in a phylogenetic tree of the cytochrome c' family, with 55% sequence identity. The denaturation temperature of PHCP was 87 degrees C, 35 degrees C higher than that of AVCP. Furthermore, PHCP exhibited a larger enthalpy change value during its thermal denaturation than AVCP. While AVCP was dimeric, as observed previously, PHCP was trimeric, and this was the first observation as a cytochrome c'. Dissociation of trimeric PHCP and its protein denaturation reversibly occurred at the same time in a two-state transition manner. Therefore, PHCP is enthalpically more stable than AVCP, perhaps due to its unique trimeric form, in addition to the lower number of Gly residues in its putative alpha-helical regions. PMID- 23924719 TI - Non-effect of an antibiotic treatment on dietary fiber-induced goblet cell proliferation in the ileum of rats. AB - We examined the effect or not of an antibiotic treatment on dietary fiber-induced goblet cell proliferation in the rat ileum. The number of goblet cells in the ileum increased when rats consumed dietary fiber. However, this effect was maintained with a concurrent treatment of antibiotics, suggesting that the fiber effect on goblet cell response would remain irrespective of a bacterial component such as endotoxin. PMID- 23924720 TI - Role of nuclear localization of PSMB1 in transcriptional activation. AB - The production of retinol binding protein 4 (RBP4) is higher in adipose tissue in type 2 diabetes. We have found that proteasome subunit beta type 1 (PSMB1) is a transcriptional activator of Rbp4. In the present study, the putative tyrosine phosphorylation site in PSMB1 was mutated to phenylalanine. The mutated form of PSMB1 displayed increased nuclear translocation, resulting in activation of transcription in adipocytes. PMID- 23924721 TI - Prevention of UVB-induced production of the inflammatory mediator in human keratinocytes by lactic acid derivatives generated from aromatic amino acids. AB - The anti-inflammatory effects of lactic acid derivatives were investigated on ultraviolet B (UVB)-irradiated HaCaT human keratinocytes. A pretreatment with indole-3-lactic acid (ILA) and 4-hydroxyphenyllactic acid (HPLA) inhibited the UVB-induced production of interlekin-6 (IL-6). The inhibitory effect of L-HPLA was equivalent to that of a corresponding racemic mixture (DL-HPLA), suggesting that optical isomerism did not affect the anti-inflammatory activity of HPLA. PMID- 23924722 TI - Glycosaminoglycan and collagen facilitate the degradation of pigment epithelium derived factor by chymotrypsin. AB - Pigment epithelium-derived factor (PEDF) is a member of the serine protease inhibitor family. It is present in a variety of tissues and organs, including plasma. Here, PEDF was purified from human plasma by use of a dermatan sulfate affinity column, and then hydroxyapatite, gel filtration and ion exchange columns. It did not form a complex with various proteases, including chymotrypsin, elastase, kallikrein, thrombin, plasmin, cathepsins G, activated protein C, and urokinase, but collagen type I facilitated the degradation of PEDF by chymotrypsin more than 10-fold. Dermatan sulfate, heparan sulfate, and heparin showed similar effects, but other glycosaminoglycans, such as hyaluronic acid, chondroitin sulfate A, C, D, E, and keratan sulfate, had no effect on PEDF degradation. PMID- 23924723 TI - Phenolics profile of mume, Japanese apricot (Prunus mume Sieb. et Zucc.) fruit. AB - The fruit of mume, Japanese apricot (Prunus mume Sieb. et Zucc.), was evaluated for its phenolics content, high performance liquid chromatography (HPLC) profile and antioxidative activities. The phenolics content of mume fruit was relatively high, the flesh of fully matured fruit containing up to 1% of phenolics on a dry weight basis. Reflecting such a high content of phenolics, the ORAC (oxygen radical absorbance capacity) value for mume fruit flesh showed high values, ranging from 150 to 320 umol/g Trolox equivalent, depending upon the stage of maturation. 5-O-Caffeoylqunic acid (chlorogenic acid), 3-O-caffeoylquinic acid and tetra-O-acylated sucrose-related compounds were isolated from the flesh of mume fruit, although many unknown peaks were also apparent in the HPLC chromatogram. An alkali hydrolysate comprised four main phenolic acids, caffeic acid, cis/trans-p-coumaric acid and ferulic acid. No flavonoids were observed in the analysis. These results suggest that the majority of phenolics in mume fruit were hydroxycinnamic acid derivatives. PMID- 23924724 TI - Stimulation of postprandial fat utilization in healthy humans by daily consumption of chlorogenic acids. AB - Long-term ingestion of coffee polyphenols (chlorogenic acids, CGAs) reduces body fat in humans and rodents. While CGA supplementation has been shown to increase fat utilization in rodents, evidence in humans is still limited. The present study clarifies the effect of daily CGA consumption on energy metabolism in humans. Eighteen healthy male subjects (36.1 +/- 7.4 y of age) participated in a placebo-controlled, double-blind, crossover, intervention study with two different test beverages. The subjects consumed 185 mL of a test beverage with or without CGAs (329 mg) daily for 4 wk. The energy metabolism was evaluated by using indirect calorimetry before and after the test period during fasting and up to 180 min postprandially. Indirect calorimetry showed that a 4-wk ingestion of the CGA beverage led to a significantly higher postprandial energy expenditure than that of the control beverage. The subjects ingesting the CGA beverage exhibited higher postprandial fat utilization than those consuming the control beverage. The daily CGA consumption therefore increased postprandial fat utilization in healthy humans. PMID- 23924725 TI - Salt-induced changes in the subunit structure of the Bacillus stearothermophilus lipoate acetyltransferase. AB - The Bacillus stearothermophilus lipoate acetyltransferase (E2), composed of sixty identical, subunits is the core component of the pyruvate dehydrogenase complex (PDC). E2 polypeptide is composed of LD, PSBD, and CD domains. Most studies had focused on a truncated E2 that is deficient in LD and PSBD, because CD mainly contributes to maintaining the multimeric structure. We examined salt-induced changes in E2 without truncation and constructed reaction models. We speculate that in the presence of KCl, E2 is dissociated into a monomer and then assembled into an aggregative complex (C(A)) and a quasi-stable complex (C(Q)). C(A) was larger than C(Q), but smaller than intact E2. C(A) and C(Q), were dominant complexes at about neutral pH and at basic pH respectively. PDC, in which PSBD is occupied by other components, and a truncated E2 undergo dissociation only. LD PSBD region besides CD might then contribute to the partial association of dissociated E2. PMID- 23924726 TI - A comparative metabolomics analysis of Saccharopolyspora spinosa WT, WH124, and LU104 revealed metabolic mechanisms correlated with increases in spinosad yield. AB - Metabolomics analysis of three Saccharopolyspora spinosa strains (wild type strain WT, ultraviolet mutant strain WH124, and metabolic engineering strain LU104) with different spinosad producing levels was performed by liquid chromatograph coupled to mass spectrometry (LC-MS). The metabolite profiles were subjected to hierarchal clustering analysis (HCA) and principal component analysis (PCA). The results of HCA on a heat map revealed that the large numbers of primary metabolism detected were more abundant in WH124 and less abundant in LU104 during the early fermentation stage as compared to the WT strain. PCA separated the three strains clearly and suggested nine metabolites that contributed predominantly to the separation. These biomarkers were associated with central carbon metabolism (succinic acid, alpha-ketoglutarate, acetyl-CoA, and ATP), amino acid metabolism (glutamate, glutamine, and valine), and secondary metabolism (pseudoaglycone), etc. These findings provide insight into the metabolomic characteristics of the two high-yield strains and for further regulation of spinosad production. PMID- 23924727 TI - Cisplatin binding and inactivation of mitochondrial glutamate oxaloacetate transaminase in cisplatin-induced rat nephrotoxicity. AB - Cisplatin is a widely used chemotherapeutic agent, but its use is limited by nephrotoxicity associated with mitochondrial dysfunction. Because its mechanisms are poorly understood, we aimed to identify the mitochondrial proteins targeted by cisplatin. We isolated renal mitochondrial proteins from Sprague-Dawley (SD) rats and performed cisplatin-affinity column chromatography. The proteins eluted were detected on SDS-PAGE and subjected to in-gel tryptic digestion and LC-MS/MS analysis. We identified glutamate oxaloacetate transaminase (GOT) and mitochondrial malate dehydrogenase (MDH). Next, we administered cisplatin intraperitoneally to SD rats to induce nephrotoxicity and assayed the activities of the enzymes. The results indicated that cisplatin caused a severe decrease in mitochondrial GOT activity on day 1 after cisplatin administration. Three d later, we also identified a decrease in mitochondrial MDH activity. Our results indicate that cisplatin binds to mitochondrial GOT and inhibits its activity, causing mitochondrial dysfunction and subsequent nephrotoxicity. PMID- 23924728 TI - Acrolein, an alpha,beta-unsaturated carbonyl, inhibits both growth and PSII activity in the cyanobacterium Synechocystis sp. PCC 6803. AB - In this study, we sought to determine whether and how an alpha,beta-unsaturated carbonyl, acrolein, can inhibit the growth of the cyanobacterium Synechocystis sp. PCC6803 (S. 6803). Treatment of S. 6803 with 200 uM acrolein for 3 d significantly and irreversibly inhibited its growth. To elucidate the inhibitory mechanism, we examined the effects of acrolein on photosynthesis. In contrast to dark conditions, the addition of acrolein to S. 6803 under conditions of illumination lowered the CO2-dependent O2 evolution rate (photosynthetic activity). Furthermore, treatment with acrolein lowered the activity reducing dimethyl benzoquinone in photosystem II (PSII). Acrolein also suppressed the reduction rate for the oxidized form of the reaction center chlorophyll of photosystem I (PSI), P700. These results indicate that acrolein inhibited PSII activity in thylakoid membranes. The addition of 200 uM acrolein to the illuminated S. 6803 cells gradually increased the steady-state level (Fs) of Chl fluorescence and decreased the quantum yield of PSII. These results suggested that acrolein damaged the acceptor side of PSII. On the other hand, acrolein did not inhibit respiration. From the above results, we gained insight into the metabolism of acrolein and its physiological effects in S. 6803. PMID- 23924729 TI - Novel small-molecule compounds that affect cellular morphogenesis in yeast and mammalian cells. AB - Drugs affecting cellular morphological changes leading to tumor cell migration and invasion are desirable for cancer therapy. In the present study, we screened for small-molecule compounds that affect the cellular morphology of both unicellular yeast and mammalian HEK293 cells to identify drug candidates. The yeast formin protein Bni1 and Src homology 3 (SH3)-pleckstrin homology (PH) domain protein Boi1, which are required for proper morphogenesis, cause growth defects when overexpressed in yeast. Using this system, we screened a chemical library consisting of ~8000 compounds to identify drug candidates that suppress these growth defects. None of the screened compounds induced morphological changes in vegetatively growing yeast cells, but several compounds had inhibitory effects on pheromone-induced projection formation and actin localization, suggesting that these compounds affected a specific stage of morphogenesis. Five of the compounds also induced morphological changes in mammalian HEK293 cells. Among the identified compounds, BTB03156, 2-[(4-chlorophenyl)sulfonyl]-1-methyl 3,5-dinitrobenzene, and BTB02467, 1-[(4-chlorophenyl)sulfonyl]-2-nitro-4 (trifluoromethyl)benzene, although they have similar structures, displayed differing effects on the yeast growth defects caused by latrunculin A, an actin polymerization inhibitor. The chemical library compounds identified using this in vivo screening approach are simple, cell-permeable molecules, and therefore may be useful in the development of therapeutic drugs for cancer metastasis and other actin-related diseases. PMID- 23924730 TI - Protective effect of detoxified Rhus verniciflua stokes on human keratinocytes and dermal fibroblasts against oxidative stress and identification of the bioactive phenolics. AB - Oxidative stress due to the over-production of reactive oxygen species (ROS) is associated with human skin aging. This study was designed to identify the bioactive phenolics in detoxified Rhus verniciflua Stokes (DRVS) that may protect human skin against oxidative stress. Under oxidative stress caused by H2O2, the 40% (v/v) aqueous methanol extract of DRVS protected human keratinocytes in a dose-dependent manner. The expression of matrix metalloproteinase-1 (MMP-1) was also inhibited by the DRVS extract in human dermal fibroblasts-neonatal cells exposed to ultraviolet A. The major bioactive phenolics of DRVS were tentatively identified by LC/Q-TOF-ESI-MS/MS, and included gallic acid, 2-(ethoxymethoxy)-3 hydroxyphenol, fustin, a fustin isomer, tetragalloyl glucose, pentagalloyl glucose, fisetin, sulfuretin, a sulfuretin isomer, and butein. The results suggest that a DRVS extract may be effective in slowing skin aging through its antioxidative properties and by down-regulating MMP-1 expression. Further studies are needed to examine whether this effect would be mediated by the phenolics identified in this study. PMID- 23924731 TI - Effects of oxidative stress on vascular reactivity in the offspring of protein restricted stroke-prone spontaneously hypertensive rats. AB - Oxidative stress was induced in 12-week-old offspring of protein-restricted (9% protein) and control (20% protein) protein-restricted stroke-prone spontaneously hypertensive rats (SHRSP) by administering phorbol 12-myristate 13-acetate (PMA) for 4 weeks to determine the effects of oxidative stress on the vascular function of the SHRSP offspring. There was no significant difference in the blood pressure of offspring of the protein-restricted dams and control dams. The plasma diacron reactive oxygen metabolite (dROM) level at 16 weeks of age was significantly higher in offspring of the protein-restricted dams, whereas the anti-oxidative enzyme activity was similar in both groups. Acetylcholine (Ach)-induced relaxation was significantly reduced in offspring of the protein-restricted dams. The expression of endothelial nitric oxide synthase (eNOS) was lower and the expression of soluble guanylic acid cyclase (sGC) was higher in offspring of the protein-restricted dams. These results indicate that SHRSP offspring of the protein-restricted dams were sensitive to oxidative stress, and displayed the vascular dysfunction. PMID- 23924732 TI - Anti-obesity effects of poly-gamma-glutamic acid with or without isoflavones on high-fat diet induced obese mice. AB - This study investigated the effects of administering poly-gamma-glutamic acid (gamma-PGA), isoflavones, and gamma-PGA with isoflavones on the lipid, fatty liver, and gene expression levels associated with fatty acid oxidation and adipose synthesis in high-fat diet (HFD)-induced C57BL/6 mice. The results demonstrate a significant decrease in the body weight gain, food intake, food efficiency, liver weight, and epididymal adipose tissue of the experimental groups in comparison with the HFD-induced control group. The serum biochemistry indices for hepatic damage, hyperlipidemia, hyperglycemia, and lipid deposits in the liver and adipose tissue were also lower in the experimental groups than in the control group. The anti-oxidative index, and cytokine and enzyme levels associated with obesity (e.g., leptin, adiponectin, AMPK, CPT-1, PPARalpha, GLUT 4, and UCP-2) were enhanced in the experimental groups in comparison with the control group. These results demonstrate that gamma-PGA and isoflavones improved the blood lipid level, insulin resistance, and hyperglycemia. Increased fatty acid oxidation inhibited the synthesis and accumulation of adipose tissue. The results suggest that gamma-PGA and isoflavones could be used as new functional foods for preventing obesity. PMID- 23924733 TI - Formulation of a universal first-order rate constant for enzymatic reactions. AB - It is a common practice to employ k(cat)[E]0/K(m) as a first-order rate constant for the analysis of an enzymatic reaction, where [E]0 is the total enzyme concentration. I describe in this report a serious shortcoming in analyzing enzymatic reactions when kcat[E]0/K(m) is employed and show that k(cat)[E]0/K(m) can only be applied under very limited conditions. I consequently propose the use of a more universal first-order rate constant, k(cat)[ES](K)/[S]0, where [ES](K) is the initial equilibrium concentration of the ES-complex derived from [E]0, [S]0 and K(m). Employing k(cat)[ES](K)/[S]0 as the first-order rate constant enables all enzymatic reactions to be reasonably simulated under a wide range of conditions, and the catalytic and binding contributions to the rate constant of any enzyme can be determined under any and all conditions. PMID- 23924734 TI - Motif-guided identification of a glycoside hydrolase family 1 alpha-L arabinofuranosidase in Bifidobacterium adolescentis. AB - Members of glycoside hydrolase family 1 (GH1) cleave glycosidic linkages with a variety of physiological roles. Here we report a unique GH1 member encoded in the genome of Bifidobacterium adolescentis ATCC 15703. This enzyme, BAD0156, was identified from over 2,000 GH1 sequences accumulated in a database by a genome mining approach based on a motif sequence. A recombinant BAD0156 protein was characterized to confirm that this enzyme alone specifically hydrolyzes p nitrophenyl-alpha-L-arabinofuranoside among the 24 p-nitrophenyl-glycosides examined. Among natural glycosides, alpha-1,5-linked arabino-oligosaccharides served as substrates, but arabinan, debranched arabinan, arabinoxylan, and arabinogalactan did not. A time course analysis of arabino-oligosaccharide hydrolysis indicated that BAD0156 is an exo-acting enzyme. These results suggest that BAD0156 is an alpha-L-arabinofuranosidase. This is the first report of a GH1 enzyme that acts specifically on arabinosides, providing information on GH1 substrate specificity. PMID- 23924735 TI - VPS37 isoforms differentially modulate the ternary complex formation of ALIX, ALG 2, and ESCRT-I. AB - The endosomal sorting complex required for transport (ESCRT) system comprises a series of protein complexes that play essential roles in multivesicular body (MVB) sorting of ubiquitylated membrane proteins, enveloped RNA virus budding, and cytokinesis in mammalian cells. The complex, named ESCRT-I, consists of four subunits (TSG101, VPS28, VPS37, and MVB12). There are four VPS37 isoforms. We have reported that ALIX (an ALG-2-interacting protein and accessory protein in the ESCRT system) is physically linked with TSG101 by ALG-2 in a Ca2+-dependent manner, but the role of ALG-2 as an adaptor protein for the ESCRT-I complex remains unknown. To characterize this adaptor function, initially we investigated the binding of ALG-2 to ESCRT-I complexes containing each one of the four different VPS37 isoforms by two approaches: first, Far-Western blot analysis with biotin-labeled ALG-2 probe, and second, a pulldown assay to determine the binding of the four recombinant ESCRT-I complexes to Strep-tagged ALG-2 after co expression in HEK293T cells. VPS37B and VPS37C appeared to interact with ALG-2 in a stronger manner than TSG101 does. The results of in vitro binding assays using purified recombinant proteins indicated that ALG-2 functions as a Ca2+-dependent adaptor protein that bridges ALIX and ESCRT-I to form a ternary complex, ESCRT I/ALIX/ALG-2. PMID- 23924736 TI - Accelerated degradation of exogenous indole by Burkholderia unamae strain CK43B exposed to pyrogallol-type polyphenols. AB - In modified Winogradsky's (MW) medium supplemented with excessive indole (1), Burkholderia unamae strain CK43B isolated from polyphenol-rich Shorea rhizosphere showed almost no cell growth, but it showed drastic cell growth given further supplementation of gallic acid, a simple plant polyphenol. This active cell growth of B. unamae CK43B was due to the stimulating effect of gallic acid on 1 degradation of bacterial cells, which acquired a nitrogen source in 1. Under aerobic culture conditions with appropriate concentrations (0.5-2.0 mM) of gallic acid, B. unamae CK43B started to decompose exogenous 1 in a dose-dependent manner, and finally accumulated catechol (5) via anthranilic acid (4). Pyrogallol also showed a cometabolic effect on decarboxylation-coupled oxidative deamination of B. unamae CK43B, producing 5 from 4, as gallic acid did. These results suggest that pyrogallol-type plant polyphenols act as stimulators on B. unamae CK43B, causing it to degrade an N-heterocyclic aromatic compound (NHAC) including nitrogen-containing humic substances. PMID- 23924737 TI - Development of a cultured cell-based human-taste evaluation system. AB - Objective quantification of taste intensity would be extremely useful for product development and quality control in the food industry. Progress has been made toward using the responses of cultured cells expressing human taste receptors as an indicator in evaluating gustatory intensity objectively. Effective utilization of such evaluation systems should not only provide information regarding taste intensities as perceived by humans, but also make possible the characterization of taste modulators to be used for commercial food products. Moreover, such an evaluation system should be also useful in advancing our understanding of the ways tastants are recognized by taste receptors. PMID- 23924738 TI - Purification and molecular analysis of a monoamine oxidase isolated from Narcissus tazetta. AB - Semicarbazide-sensitive amine oxidase activity was detected in Narcissus tazetta. The enzyme was purified to homogeneity by the criterion of native polyacrylamide gel electrophoresis (PAGE) with DEAE-Sephacel, hydroxyapatite, and phenyl Sepharose columns. The molecular mass of the enzyme, determined using a GS-520 HQ column, was estimated to be 135 kDa. SDS-PAGE yielded two bands of, 75 kDa and 65 kDa. The enzyme, which had catalytic activity for some aliphatic and aromatic monoamines, belongs to a class of monoamine oxidases (MAOs). The K(m) value for n propylamine was 5.9 * 10-5 M. A substrate analog, 2-bromoethylamine, inhibited enzyme activity. Redox-cycling staining detected a quinone in the MAO protein. By inductively coupled plasma mass analysis, it was determined that there were 2.44 moles of copper atoms per mole of the enzyme. Protein sequence analysis revealed that there was no identity between two N-terminal residues of the 75 kDa and 65 kDa proteins of narcissus MAO. PMID- 23924739 TI - ATF6alpha stimulates cholesterogenic gene expression and de novo cholesterol synthesis. AB - The activating transcription factor 6alpha (ATF6alpha) is a sensor of the endoplasmic reticulum stress response that regulates the expression of genes involved in the unfolded protein response. Here we found that forced expression of a constitutively active form of ATF6alpha, ATF6(N), stimulated the expression of cholesterogenic genes, including 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase, HMG-CoA synthase, and squalene synthase, and de novo cholesterol synthesis in hepatoma Huh-7 cells. An ATF6alpha mutant lacking the DNA-binding domain ATF6(N)DeltabZip failed to show these effects. Luciferase assays indicated that ATF6(N) overexpression stimulated the promoter activities of HMG-CoA reductase, HMG-CoA synthase, and squalene synthase. Chromatin immunoprecipitation assays revealed that ATF6(N) interacted with the promoter region of the HMG-CoA synthase gene. Collectively, these results indicate that ATF6alpha can regulate de novo cholesterol synthesis through stimulation of cholesterogenic gene expression. PMID- 23924740 TI - Perturbation of discrete sites on a single protein domain with RNA aptamers: targeting of different sides of the TATA-binding protein (TBP). AB - Control of interactions among proteins is critical in the treatment of diseases, but the specificity required is not easily incorporated into small molecules. Macromolecules could be more suitable as antagonists in this situation, and RNA aptamers have become particularly promising. Here we describe a novel selection procedure for RNA aptamers against a protein that constitutes a single structural domain, the Drosophila TATA-binding protein (TBP). In addition to the conventional filter partitioning method with free TBP as target, we performed another experiment, in which the TATA-bound form of TBP was targeted. Aptamers generated by both selections were able to bind specifically to TBP, but the two groups showed characteristics which were clearly different in terms of their capability to compete with TATA-DNA, their effects on the TATA-bound form of TBP, and their effects on in vitro transcription. The method used to generate these two groups of aptamers can be used with other targets to direct aptamer specificity to discrete sites on the surface of a protein. PMID- 23924741 TI - The impact of anaerobiosis on strain-dependent phenotypic variations in Pseudomonas aeruginosa. AB - Bacteria participate in social behaviors by communicating with each other and forming surface-associated biofilms. In Pseudomonas aeruginosa, such social behaviors are affected greatly by the environment. Although P. aeruginosa survive under anaerobic conditions, previous studies indicate that quorum sensing is attenuated under such conditions, and that this leads to decreased activity of extracellular virulence factors as compared to aerobic conditions. Hence it has come into question whether P. aeruginosa are virulent under anaerobic conditions. Here, we compared various phenotypes between PAO1 and clinical isolates under anaerobic conditions. Our data revealed that when grown anaerobically, growth and cell morphology greatly differed among the strains. One of the clinical isolates produced comparable amounts of quorum-sensing signaling molecules and extracellular virulence factors under aerobic and anaerobic conditions, while the other strains showed low production under anaerobic conditions. Biofilm formation also exhibited strain-dependent variations, suggesting that there are several mechanisms that lead to biofilm formation under anaerobic conditions. Taken together, these results indicate that the impact of anaerobiosis on the social interactions of P. aeruginosa is strain dependent, and suggest that multiple regulatory mechanisms are involved in the regulation of quorum sensing and biofilm formation under anaerobic conditions. PMID- 23924742 TI - Enhancing effect of a cysteinyl thiol on the antioxidant activity of flavonoids and identification of the antioxidative thiol adducts of myricetin. AB - The enhancing effect of a cysteinyl thiol N-benzoylcysteine methyl ester on the antioxidant activity of several flavonoids was investigated in a lipid oxidation system. Obvious enhancement was apparent for catechin, myricetin, quercetin, and taxifolin, the activity for myricetin being the most potent among them. An HPLC analysis of the products from the antioxidation reaction of myricetin in the presence of the thiol was carried out and the structures of the products were determined to clarify the enhancing effect chemically. The obtained data indicated that two thiol adducts on the B ring, and probably C-ring adducts, which were produced in the antioxidation process, exerted an enhancing effect on the antioxidant activity of myricetin. PMID- 23924743 TI - Aromatic residue on beta->alpha loop 1 in the catalytic domain is important to the transglycosylation specificity of glycoside hydrolase family 31 alpha glucosidase. AB - The specificity for the alpha-1,4- and alpha-1,6-glucosidic linkages varies among glycoside hydrolase family 31 alpha-glucosidases. This difference in substrate specificity has been considered to be due to the difference in an aromatic residue on beta->alpha loop 1 in the catalytic domain with a (beta/alpha)8 barrel fold; i.e., the enzymes having Tyr and Trp on beta->alpha loop 1 were respectively described as alpha-1,4-specific and alpha-1,6-specific alpha glucosidases. Schwanniomyces occidentalis alpha-glucosidase, however, prefers the alpha-1,4-glucosidic linkage, although the enzyme possesses Trp324 at the corresponding position. The mutation of Trp324 to Tyr decreased the ability for hydrolysis of the alpha-1,6-glucosidic linkage and formation of the alpha-1,6 glucosidic linkage in transglycosylation, indicating Trp324 to be closely associated with alpha-1,6 specificity, even if the enzyme preferred the alpha-1,4 glucosidic linkage. The mutant enzyme was found to catalyze the production of the branched oligosaccharide, 2,4-di-O-(alpha-D-glucopyranosyl)-D-glucopyranose, more efficiently than the wild-type enzyme. PMID- 23924744 TI - The changing world of healthcare delivery. PMID- 23924745 TI - ICD 10: "what orthopedic surgeons should know, how it will affect them and the cost of implementation?". AB - Orthopedic surgeons will be required to use ICD-10-CM codes for reimbursement and to substantiate the medical necessity for their services beginning October 1, 2014. Implementation of ICD10 will require significant changes in the clinical and administrative processes of orthopedic offices and hospital practices. As in other countries, implementation added costs and resulted in disruptions in physician practices with concomitant decreases in productivity and practice revenue. Through education and planning, orthopedic surgeons can mitigate the anticipated changes and reduce the potential impact these changes will have on their practices. Changes anticipated in the diagnostic part of the ICD10 coding system are reviewed with examples pertinent to orthopedic surgeons. Many will need to improve the accuracy and specificity of their documentation by using anatomically precise nomenclature and obtaining a more detailed history and physical examination. This will require eliciting external causes of patients' problems, the precise activity of causation, and the place of occurrence. PMID- 23924746 TI - Collecting outcomes data in the private practice setting: why is it important and how to get the data without disrupting the workflow. AB - Collecting data in a private practice setting has many obstacles. These obstacles include limited patient time and energy, what data to collect, and what data collection tools to develop to complete the job in an efficient manner. The method of collection must be done in a Health Insurance Portability and Accountability Act compliant way and must be deidentified before presentation. The physician must be the collection "champion" to insure that the collection process is consistent and persistent. The data collection tools must appreciate the trend for patient-reported outcomes. Insurers and regulators are keenly awaiting adequate data to validate the beneficial effects of the procedures we perform. We physicians are uniquely positioned, appropriately trained, and are the true patient advocates in modern health care and thus, the responsibility to collect accurate data is ours! PMID- 23924747 TI - Exploring new practice models delivering orthopedic care: can we significantly decrease delivery costs and improve quality? AB - Health care delivery models are undergoing rapid transformation in response to market, regulatory, and demographic trends. Many of the new models of delivery are centrally planned structures with attributes dictated by statute. An understanding of these models is essential if physicians wish to retain an influential voice in patient care. Accountable Care Organizations, Medical Homes, Bundled Payment, and Episode of Care are terms even sports medicine physicians must become familiar with to positively affect the delivery of health care in the near future. By embracing both the clinical and economic aspects of health care, surgeons will be in a better position to make health care reform responsive to actual patient needs. PMID- 23924748 TI - Using evidence-based algorithms to improve clinical decision making: the case of a first-time anterior shoulder dislocation. AB - Decision making in health care has evolved substantially over the last century. Up until the late 1970s, medical decision making was predominantly intuitive and anecdotal. It was based on trial and error and involved high levels of problem solving. The 1980s gave way to empirical medicine, which was evidence based probabilistic, and involved pattern recognition and less problem solving. Although this represented a major advance in the quality of medical decision making, limitations existed. The advantages of the gold standard of the randomized controlled clinical trial (RCT) are well-known and this technique is irreplaceable in its ability to answer critical clinical questions. However, the RCT does have drawbacks. RCTs are expensive and can only capture a snapshot in time. As treatments change and new technologies emerge, new expensive clinical trials must be undertaken to reevaluate them. Furthermore, in order to best evaluate a single intervention, other factors must be controlled. In addition, the study population may not match that of another organization or provider. Although evidence-based medicine has provided powerful data for clinicians, effectively and efficiently tailoring it to the individual has not yet evolved. We are now in a period of transition from this evidence-based era to one dominated by the personalization and customization of care. It will be fueled by policy decisions to shift financial responsibility to the patient, creating a powerful and sophisticated consumer, unlike any patient we have known before. The challenge will be to apply medical evidence and personal preferences to medical decisions and deliver it efficiently in the increasingly busy clinical setting. In this article, we provide a robust review of the concepts of customized care and some of techniques to deliver it. We will illustrate this through a personalized decision model for the treatment decision after a first-time anterior shoulder dislocation. PMID- 23924749 TI - Cost-effectiveness in orthopedics: providing essential information to both physicians and health care policy makers for appropriate allocation of medical resources. AB - Cost-effective analysis has become an important tool in helping determine what procedures are both cost-effective and appropriate in today's cost control health care. The quality-adjusted life-year (QALY) is a standard measure for health related quality-of-life in medical cost-effectiveness research. It can be used to compare different interventions to determine the cost-effectiveness of each procedure. Use of QALY to compare health care interventions has become the new gold standard. The key words arthroscopy, cost-effectiveness analysis, QALY, shoulder, hip, knee, ankle, elbow, wrist, and pubic symphysis were searched utilizing PubMed and an internet search engine. Cost/QALY ratios were determined and compared with other surgical procedures using techniques other than arthroscopy. Cost/QALYs were found for the shoulder, hip, knee, and elbow. The QALY for the shoulder was $13,092, for a simple knee was $5783, for a hip $21,700, and for an elbow $2031. General costs were found for the ankle, wrist, and pubic symphysis, that could be used to estimate QALYs without the complex formal calculation. On the basis of our findings, arthroscopy is an extremely cost-effective allocation of health care resources. PMID- 23924751 TI - The pros and cons of hospital employment. AB - The pros and cons of hospital employment vary significantly in today's economic environment. This chapter summarizes the advantages and disadvantages of hospital employment with an emphasis on the critical aspect of formalizing an agreement with the hospital employer to prevent future salary reductions and/or termination. PMID- 23924750 TI - PPD-QALY-an index for cost-effectiveness in orthopedics: providing essential information to both physicians and health care policy makers for appropriate allocation of medical resources. AB - Because of the increasing health care costs and the need for proper allocation of resources, it is important to ensure the best use of health benefits for sick and injured people of the population. An index or indicator is needed to help us quantify what is being spent so that comparisons with other options can be implemented. Cost-effective analysis seems to be well suited to provide this essential information to health care policy makers and those charged with distributing disability funds so that the proper allocation of resources can be achieved. There is currently no such index to show whether the benefits paid out are the most cost-effective. By comparing the quality-adjusted life year (QALY) of a treatment method to the disability an individual would experience, on the basis of lost wages as measure of disability, we provide decision makers more information for the basis of cost allocation in health care. To accomplish this, we describe a new term, the PPD-QALY (permanent partial disability-quality of life year). This term was developed to establish an index to which musculoskeletal care can be compared, to evaluate the cost-effectiveness of a treatment on the basis of the monetary value of the disability. This term serves to standardize the monetary value of an injury. Cost-effective analysis in arthroscopic surgery may prove to be a valuable asset in this role and to provide decision makers the information needed to determine the societal benefit from new arthroscopic procedures as they are developed and implemented. PMID- 23924752 TI - Spinal lobular capillary hemangioma with an intramedullary component. AB - Capillary hemangiomas are benign vascular neoplasms rarely involving the spinal cord, where their usual location is extramedullary. A 59-year-old man presented with a 7-month history of progressive numbness which began in the left lower extremity and progressed across the lower back, right flank, trunk and into the right lower extremity with associated pressure and pain in his lower back. On magnetic resonance imaging, there was an avidly-enhancing thoracic intradural lesion that contained an extramedullary intradural component posteriorly, with an apparent intramedullary component anteriorly. Laminectomy of T7 - 8 was performed, and intradural exploration revealed a highly vascular-appearing tumor below the arachnoid, which was not completely dissected because it was densely adherent to the spinal cord. The pathological diagnosis was lobular capillary hemangioma with extra- and intramedullary components. We suggest this lesion should be considered in the differential diagnosis of spinal cord tumors with an intramedullary component. PMID- 23924753 TI - IgA/kappa-restricted crystal storing histiocytosis involving the central nervous system characterized by proteomic analysis. AB - Crystal storing histiocytosis (CSH) is a rare disorder characterized by the accumulation of crystalline material in the cytoplasm of histiocytes. Involvement of the central nervous system (CNS) with CSH is extremely rare. Herein, we report a case of crystal storing histiocytosis involving the CNS. Using immunohistochemistry and mass spectrometry we demonstrate that the disease resulted from an IgA-kappa restricted plasma cell dyscrasia. CNS-CSH represents a rare clinicopathologic entity with an indolent course, usually lacking systemic manifestations. PMID- 23924754 TI - Is mutation p.Arg168Gly in TPM3 gene responsible for Type 1 fiber hypoplasia and cap structure formation? AB - Congenital fiber type disproportion with delayed fiber type maturation and the appearance of cap structures were analyzed in a child with p.Arg168Gly mutation in TPM3 gene. Very narrow myotube-like Type 1 fibers with single nuclei decorated by cap structures seem to be a result of a failure in fusion process and mature fiber formation. Repeated mutations in exon 5 of TPM3 gene giving cap structures may be a different consequence of the loss of specific isoform normally operating in the fusion process and sarcomer formation. PMID- 23924755 TI - Primary fourth ventricular B-cell lymphoma in an immunocompetent patient. PMID- 23924756 TI - Effect of combined naltrexone and bupropion therapy on the brain's reactivity to food cues. AB - OBJECTIVE: The significant weight loss observed with combination naltrexone sustained release (SR) 32 mg and bupropion SR 360 mg (NB32) therapy is thought to be due, in part, to bupropion stimulation of hypothalamic pro-opiomelanocortin (POMC) neurons, and naltrexone blockade of opioid receptor-mediated POMC autoinhibition, but the neurobiological mechanisms are not fully understood. We assessed changes in brain reactivity to food cues before and after NB32 treatment. METHODS: Forty women (31.1+/-8.1 years; body mass index: 32.5+/-3.9) received 4 weeks of NB32 or placebo, and were instructed to maintain their dietary and exercise habits. Functional magnetic resonance imaging responses (analyzed using SPM2 and clusters (>100 pixels)) to a 5-min food video (preparation of the subject's favorite food) and a 5-min neutral video (manipulation of neutral objects) under conditions of mild food deprivation (~14 h) were assessed before and after treatment. RESULTS: The food cues video induced positive brain activation in visual and prefrontal cortices, insula and subcortical brain regions. The group-by-treatment interaction on regional brain activation was significant and showed that whereas NB32 attenuated the activation in the hypothalamus in response to food cues (P<0.01), it enhanced activation in regions involved in inhibitory control (anterior cingulate), internal awareness (superior frontal, insula, superior parietal) and memory (hippocampal) regions (whole-brain analysis; P<0.05). CONCLUSIONS: Blunting the hypothalamic reactivity to food cues while enhancing the activation of regions involved with self-control and internal awareness by NB32 might underlie its therapeutic benefits in obesity. PMID- 23924757 TI - Short sleep duration and large variability in sleep duration are independently associated with dietary risk factors for obesity in Danish school children. AB - BACKGROUND: Lack of sleep and increased consumption of energy-dense foods and sugar-sweetened beverages (SSBs) have all been suggested as factors contributing to the increased prevalence of overweight and obesity. OBJECTIVE: To evaluate whether objectively measured sleep duration (average and day-to-day variability) as well as parent-reported sleep problems are independently associated with proposed dietary risk factors for overweight and obesity in 8-11-year-old children. DESIGN: In this cross-sectional study, data on sleep duration and day to-day variability in sleep duration were measured in 676 Danish, apparently healthy children by an objective measure (actigraphy) for 8 nights, and the Children's Sleep Habits Questionnaire (CSHQ) was filled out by the parents. Diet was recorded using a web-based food record for 7 consecutive days. Fasting blood samples were obtained for measurements of plasma leptin and ghrelin levels. RESULTS: Sleep duration (h per night) was negatively associated with energy density (ED) of the diet (beta = -0.32 kJ g(-1)), added sugar (beta = -1.50 E%) and SSBs (beta = -1.07 E%) (all P <= 0.003). Furthermore, variability in sleep duration (10-min per night) was positively associated with SSBs (beta = 0.20 E%, P = 0.03), independent of sleep duration, and CSHQ score was positively associated with ED (beta = 0.16 kJ g(-1), P = 0.04). All of these associations were independent of potential confounders (age, sex, pubertal status, height, weight, screen time, moderate-to-vigorous physical activity and parental education and ethnicity). CONCLUSION: Our study suggests that short sleep duration, high sleep duration variability and experiencing sleep problems are all associated with a poor, obesity-promoting diet in children. PMID- 23924758 TI - Fetal growth restriction promotes physical inactivity and obesity in female mice. AB - BACKGROUND: Environmental exposures during critical periods of prenatal and early postnatal life affect the development of mammalian body weight regulatory mechanisms, influencing lifelong risk of obesity. The specific biological processes that mediate the persistence of such effects, however, remain poorly understood. OBJECTIVE: The objectives of this study were to determine the developmental timing and physiological basis of the obesity-promoting effect previously reported in offspring of obese agouti viable yellow (A(vy)/a) mothers. DESIGN: Newborn offspring of obese A(vy)/a and lean (a/a) mothers were cross fostered shortly after birth to study separately the effects of in utero or suckling period exposure to A(vy)/a dams. Body composition, food intake, physical activity and energy expenditure were measured in offspring shortly after weaning and in adulthood. RESULTS: Offspring of obese A(vy)/a dams paradoxically experienced fetal growth restriction, which was followed by adult-onset obesity specifically in females. Our main analyses focused on wild-type (a/a) offspring, because a subset of adult A(vy)/a offspring contracted a kidney disease resembling diabetic nephropathy. Detailed physiological characterization demonstrated that, both shortly after weaning and in adulthood, female wild-type mice born to A(vy)/a mothers are not hyperphagic but have reduced physical activity and energy expenditure. No such coordinated changes were detected in male offspring. Mediational regression analysis of our longitudinal data supported a causal pathway in which fetal growth restriction persistently reduces physical activity, leading to adult obesity. CONCLUSIONS: Our data are consistent with several recent human epidemiological studies showing female-specific effects of perinatal nutritional restriction on later obesity, and provide the novel mechanistic insight that this may occur via permanent and sex-specific changes in one's inherent propensity for physical activity. PMID- 23924759 TI - Determination of the biochemical properties of full-length human PIF1 ATPase. AB - The PIF1 helicase family performs many cellular functions. To better understand the functions of the human PIF1 helicase, we characterized the biochemical properties of its ATPase. PIF1 is very sensitive to temperature, whereas it is not affected by pH, and the ATPase activity of human PIF1 is dependent on the divalent cations Mg (2+) and Mn (2+) but not Ca (2+) and Zn (2+). Inhibition was observed when single-stranded DNA was coated with RPA or SSB. Moreover, the ATPase activity of PIF1 proportionally decreased with decreasing oligonucleotide length due to a decreased binding ability. A minimum of 10 oligonucleotide bases are required for PIF1 binding and the hydrolysis of ATP. The analysis of the biochemical properties of PIF1 together with numerous genetic observations should aid in the understanding of its cellular functions. PMID- 23924760 TI - High-affinity binding to staphylococcal protein A by an engineered dimeric Affibody molecule. AB - Affibody molecules are engineered binding proteins, in which the three-helix bundle motif of the Z domain derived from protein A is used as a scaffold for sequence variation. We used phage display to select Affibody binders to staphylococcal protein A itself. The best binder, called ZpA963, binds with similar affinity and kinetics to the five homologous E, D, A, B and C domains of protein A, and to a five-domain protein A construct with an average dissociation constant, K(D), of ~20 nM. The structure of ZpA963 in complex with the Z domain shows that it interacts with a surface on Z that is identical in the five protein A domains, which explains the multi-domain affinity. This property allows for high-affinity binding by dimeric Affibody molecules that simultaneously engage two protein A domains in a complex. We studied two ZpA963 dimers in which the subunits were linked by a C-terminal disulfide in a symmetric dimer or head-to tail in a fusion protein, respectively. The dimers both bind protein A with high affinity, very slow off-rates and with saturation-dependent kinetics that can be understood in terms of dimer binding to multiple sites. The head-to-tail (ZpA963)2htt dimer binds with an off-rate of k(off) <= 5 * 10(-6) s(-1) and an estimated K(D) <= 16 pM. The results illustrate how dimers of selected monomer binding proteins can provide an efficient route for engineering of high-affinity binders to targets that contain multiple homologous domains or repeated structural units. PMID- 23924761 TI - Gum ghatti-chitosan polyelectrolyte nanoparticles: preparation and characterization. AB - The objective of the present study was to optimize the interaction between gum ghatti and chitosan to prepare polyelectrolyte nanoparticles using ofloxacin as the model drug. The effect of varying the concentration of gum ghatti, chitosan, Pluronic F-127, and ofloxacin on particle size and entrapment efficiency was studied using central composite experimental design. The optimized calculated parameters were concentrations of gum ghatti (0.12% w/v), chitosan (0.22% w/v), Pluronic F-127 (0.05% w/v), ofloxacin (0.1% w/v), which provided polyelectrolyte nanoparticles of size 121.6 nm and 94.49% entrapment. On screening for antibacterial activity, it was observed that polyelectrolyte nanoparticles had antibacterial activity comparable to the aqueous solution. Further, it was observed that polyelectrolyte nanoparticles released the drug by diffusion through the matrix following Higuchi's square-root kinetics. PMID- 23924762 TI - p53 and aging: role of p66Shc. PMID- 23924763 TI - Domperidone in lactation: use as a galactagogue. PMID- 23924764 TI - Case report: diagnosis and management of trigeminal neuralgia and chronic paroxysmal hemicrania in a 43-year-old woman- oral and transmucosal pharamcologic mediations. PMID- 23924765 TI - Head-to-Toe Solutions: A Quick Review of Current Therapies. PMID- 23924766 TI - Current topical treatments in wound healing, part 2. AB - Abstract not available. PMID- 23924767 TI - Veterinary ophthalmic practice: therapeutic considerations and common ocular diseases-part 3. PMID- 23924768 TI - Basics of compounding for skin discolorations. PMID- 23924769 TI - Quality-Control Analytical Methods: USP Chapter 797 Compounded Sterile Preparations Sterility Requirements and Their Relationship to Beyond-Use Dating. PMID- 23924770 TI - Compatibility and stability of aloxi (palonosetron hydrochloride) admixed with dexamethasone sodium phosphate. AB - The purpose of this study was to evaluate the physical and chemical stability of palonosetron hydrochloride 0.25 mg admixed with dexamethasone (as sodium phophate) 10 mg or 20 mg in 5% dextrose injection or 0.9% sodium chloride injection in polyvinylchloride minibags, and also admixed with dexamethasone (as sodium phosphate) 3.3 mg in 5% dextrose injection or 0.9% sodium chloride injection in polypropylene syringes, at 4 deg C stored in the dark for 14 days, and at 23 deg C exposed to normal laboratory fluorescent light over 48 hours. Test samples of palonosetron hydrochloride 5 micrograms/mL with dexamethasone (as sodium phosphate) 0.2 mg/mL and also 0.4 mg/mL were prepared in polyvinylchloride minibags of each infusion solution. Additionally, palonosetron hydrochloride 25 micrograms/mL with dexamethasone (as sodium phosphate) 0.33 mg/mL in each infusion solution were prepared as 10 mL of test solution in 20-mL polypropylene syringes. Evaluations for physical and chemical stability were performed on samples taken initially and after 1, 3, 7 and 14 days of storage at 4 deg C and after 1, 4, 24 and 48 hours at 23 deg C. Physical stability was assessed using visual observation in normal room light and using a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated by using a stability-indicating high-performance liquid chromatographic analytical technique. All samples were physically compatible throughout the study. The solutions remained clear and showed little or no change in particulate burden and haze level. Additionally, little or no loss of palonosetron hydrochloride and dexamethasone occurred in any of the samples at either temperature throughout the entire study period. Admixtures of palonosetron hydrochloride with dexamethasone sodium phosphate in 5% dextrose injection or in 0.9% sodium chloride injection packaged in polyvinylchloride minibags or in polypropylene syringes were physically compatible and chemically stable for at least 48 hours at room temperature and for 14 days under refrigeration. PMID- 23924771 TI - Chemical stability of terbutaline sulfate injection after diluting with 0.9% sodium chloride injection when stored at room temperature in polyvinylchloride bags. AB - The stability of terbutaline sulfate (0.1 mg/mL) in 0.9% sodium chloride injection was studied at 25 deg C when stored in polyvinylchloride bags, using a stability-indicating high-performance liquid chromatographic assay method. The concentrations of the drug were directly related to peak heights, and percent relative standard deviation based on five injections was 1.0. The drug decomposed when boiled after adding sodium hydroxide, and the products of decomposition did not interfere with the assay procedure. The injection did not lose any potency after 23 days of storage at 25 deg C, and the pH value of 4.3 did not change. The physical appearance of the injection remained clear throughout the study period. PMID- 23924772 TI - Introductory address for the John Howland Award recipient, Elizabeth R. McAnarney, MD. PMID- 23924774 TI - Wait and transplant for stage 2 hepatocellular carcinoma with deceased-donor liver grafts. AB - BACKGROUND: As a new scheme at our center, a Model for End-stage Liver Disease score of 18 points is assigned to candidates of deceased-donor liver transplantation (DDLT) who have hepatocellular carcinoma (HCC) remaining at stage 2 six months after their disease has been confirmed stage 2 HCC. Two points are added every 3 months if their disease remains at stage 2 or below. This study evaluated patient and tumor characteristics as well as surgical and short-term outcomes of DDLT in these patients. METHODS: Comparison of survival was made among three groups of patients who underwent liver transplantation (LT) in the same period. Group 1 consisted of 22 HCC patients who received DDLT under the new scheme. Group 2 consisted of 18 HCC patients who underwent living-donor LT. Group 3 consisted of 52 patients who underwent DDLT because of liver failure, among whom 6 had HCC but were not included in the new scheme. RESULTS: Group 1 had a median follow-up period of 17.9 months, and the 1-, 3-, and 5-year overall survival rates were 100%, 100%, and 80%, respectively. Group 2 had the corresponding rates at 100%, 100%, and 100% with a median follow-up of 19.6 months. Group 3 had the corresponding rates at 96.1%, 96.1%, and 96.1% with a median follow-up of 19.4 months. CONCLUSIONS: The policy of a 6-month wait has benefited the HCC patients who practically had no chance of undergoing living donor LT. Their survival outcomes will be excellent as long as they can stand the test of time. PMID- 23924773 TI - Using implantation biopsies as a surrogate to evaluate selection criteria for living kidney donors. AB - BACKGROUND: The acceptance criteria used for living kidney donors are largely theoretical, as they are not clearly linked to outcomes. The goal of this study was to use implantation biopsies as a surrogate outcome marker to evaluate our living kidney donor selection criteria. METHODS: One thousand six hundred sequential living kidney donor biopsies were performed between 2001 and 2011. Implantation biopsies were assessed by dedicated renal pathologists according to the Banff criteria. Biopsies with any chronic score of 2 or higher were deemed to have moderate to severe changes (MSC). RESULTS: MSC was present in 4% (n=65) of implantation biopsies and occurred across a wide range of age and other demographics. By multivariate analysis, donor age (odds ratio [95% confidence interval], 1.060 [1.035-1.086]; P<0.0001) and donor systolic blood pressure (SBP) (odds ratio [95% confidence interval], 1.022 [1.006-1.037]; P=0.0060) were associated with MSC. Donor gender, body mass index, diastolic blood pressure, glomerular filtration rate, and urinary microalbuminuria were not. MSC was further increased in donors older than 60 years with SBP>140 (30% [7 of 23]) and donors older than 60 years with SBP>140 and glomerular filtration rate above the 25th percentile (42.8% [3 of 7]). In donors younger than 60 years, combining factors did not show an increased prevalence of MSC. At follow-up, renal function was similar in donors with and without MSC. CONCLUSIONS: MSC occurred sporadically in donors with varied characteristics. Although we did not detect patterns to support specific changes in our acceptance criteria, certain subgroups of donors might benefit from close follow-up. PMID- 23924775 TI - Incidence and predictors of postoperative atrial fibrillation in kidney transplant recipients. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) is a complication of cardiothoracic and noncardiothoracic surgery. Kidney transplant recipients bear several known risk factors and may have a higher incidence of POAF. We retrospectively studied kidney and kidney/liver transplant recipients to estimate their POAF incidence and identify relevant risk factors. We also adapted a clinical score originally designed to predict thromboembolic risk in atrial fibrillation (AF; CHA2DS2-VASc) for assessing transplant patients. METHODS: We reviewed the clinical charts of kidney or kidney/liver transplant recipients from January 2005 to December 2008 at St. Orsola University Hospital Kidney Transplant Centre. Patients with and without POAF were compared on a number of clinical, laboratory, and instrumental data. RESULTS: The POAF incidence in kidney transplant recipients was 8.2%. Risk factors for POAF identified in univariate analyses included older recipient age, history of myocardial infarction, history of AF, liver/kidney transplantation, arterial stiffness, atherosclerotic plaques in the aorta or lower limbs, and diabetes mellitus. In a multivariate analysis, age, myocardial infarction history and combined liver/kidney transplantation were significant independent predictors of POAF. The modified CHA2DS2-VASc score proved to have a better predictive validity that the original CHA2DS2-VASc (area under the curve=0.71, 95% confidence interval=0.63-0.79 vs. area under the curve=0.62, 95% confidence interval=0.52-0.73, respectively). CONCLUSION: AF is a notable complication of kidney, and particularly simultaneous liver/kidney, transplant surgery. Age, previous myocardial infarction, and simultaneous liver/kidney transplant independently predicted POAF. The modified CHA2DS2-VASc score could be useful to predict POAF risk in kidney transplant candidates. PMID- 23924776 TI - Towards high-performance, low-cost quartz sensors with high-density, well separated, vertically aligned ZnO nanowires by low-temperature, seed-less, single step, double-sided growth. AB - Resonant sensors with nanostructured surfaces have long been considered as an emergent platform for high-sensitivity transduction because of the potentially very large sensing areas. Nevertheless, until now only complex, time-consuming, expensive and sub-optimal fabrication procedures have been described; in fact, especially with reference to in-liquid applications, very few devices have been reported. Here, we first demonstrate that, by immersing standard, ultra-low-cost quartz resonators with un-polished silver electrodes in a conventional zinc nitrate/HMTA equimolar nutrient solution, the gentle contamination from the metallic package allows direct growth on the electrodes of arrays of high-density (up to 10 MUm-2) and well-separated (no fusion at the roots) ZnO nanowires without any seed layer or thermal annealing. The combination of high-density and good separation is ideal for increasing the sensing area; moreover, this uniquely simple, single-step process is suitable for conventional, ultra-low-cost and high frequency quartzes, and results in devices that are already packaged and ready to use. As an additional advantage, the process parameters can be effectively optimized by measuring the quartz admittance before and after growth. As a preliminary test, we show that the sensitivity to the liquid properties of high frequency (i.e. high sensitivity) quartzes can be further increased by nearly one order of magnitude and thus show the highest ever reported frequency shifts of an admittance resonance in response to immersion in both ethanol and water. PMID- 23924777 TI - Lower limb amputation and rehabilitation in total joint arthroplasties in the ipsilateral limb. AB - BACKGROUND: Degenerative joint disease is not uncommon in amputees and reaches the orthopedic surgeon when all other conservative methods to manage these patients have failed. Several case reports describing hip and knee arthroplasties in patients with hip and knee joint diseases or fractures with the distal part amputated, either in the contralateral or ipsilateral limb, exist in literature. OBJECTIVE: This article focuses only on total knee and total hip arthroplasty in amputees who have had severe osteoarthritis of the ipsilateral hip and knee joints. STUDY DESIGN: Literature review. METHOD: Literature search in database and summary of all the cases. RESULTS: All narratives indicate positive outcomes with improvement in physical function and quality of life. CONCLUSION: The reports suggest that slight modifications in surgical procedure and in the rehabilitation protocol as compared to other patients with joint arthroplasties can alleviate pain and make such patients ambulatory and gain maximum range of motion. Therefore, it appears that careful preoperative evaluation and planning tailored to suit individual cases maximizes postoperative good end results beneficial to the patients regardless of age or cause of osteoarthritis. PMID- 23924778 TI - Anti-fatigue effect of ginsenoside Rb1 on postoperative fatigue syndrome induced by major small intestinal resection in rat. AB - Ginsenoside Rb1 (GRb1), one of the principle active ingredients of Panax ginseng, exerts multiple pharmacological activities to fight fatigue. In the present study, we investigate the anti-fatigue effect of GRb1 on postoperative fatigue syndrome (POFS) in a rat model induced by major small intestinal resection. GRb1 (10 mg/kg) was administrated intraperitoneally once daily for 1, 3, 7, and 10 d from the operation day. Anti-fatigue effect was assessed by grasping test and biochemical parameters in blood or skeletal muscle were determined by autoanalyzer or commercially available kits. Transmission electron microscope was applied to observe the ultra microstructure of skeletal muscles. The results revealed that GRb1 significantly enhanced rat maximum grip strength with POFS. Similarly, negative alterations in biochemical parameters (lactic acid, hepatic glycogen, muscle glycogen and malondialdehyde) of POFS rats were improved by GRb1. In addition, GRb1 also increased the activity of lactate dehydrogenase and superoxide dismutase in POFS. No significant differences of levels of blood urea nitrogen and ultra microstructure of skeletal muscles were found between the POFS and GRb1 treatment rats. The potent anti-fatigue effect of GRb1 on POFS might be achieved through improvement of energy metabolism and suppression of skeletal muscle oxidative stress. PMID- 23924779 TI - Successful pregnancy in each half uterus cavity of the septate uterus after transferring three embryos in one half-cavity: a case report. AB - The incidence of Mullerian duct anomalies in women is rare, associating with urinary tract anomalies such as horseshoe or pelvic kidney, renal agenesis, duplication of the collecting system, or ectopic uterus. Septate uterus is one type of congenital uterine anomalies, in which there is a septum from the fundus to the cervix. Currently, it is believed that hysteroscopic metroplasty is a leading choice for patients if their recurrent spontaneous abortion is resulted from septate uterus. But, some people refuse to have a surgery, and successfully delivery. In this case report, we report a successful pregnancy with two gestational sacs, one in each half-cavity, in a woman with septate uterus after transfer of three embryos into one half-cavity. Finally, the women gave birth to two healthy babies in our hospital. PMID- 23924780 TI - Nitrogen fixation in distinct microbial niches within a chemoautotrophy-driven cave ecosystem. AB - Microbial sulfur and carbon cycles in ecosystems driven by chemoautotrophy present at deep-sea hydrothermal vents, cold seeps and sulfidic caves-have been studied to some extent, yet little is known about nitrogen fixation in these systems. Using a comprehensive approach comprising of (15)N2 isotope labeling, acetylene reduction assay and nitrogenase gene expression analyses, we investigated nitrogen fixation in the sulfide-rich, chemoautotrophy-based Frasassi cave ecosystem (Italy). Nitrogen fixation was examined in three different microbial niches within the cave waters: (1) symbiotic bacterial community of Niphargus amphipods, (2) Beggiatoa-dominated biofilms, which occur at the sulfide-oxygen interface, and (3) sulfidic sediment. We found evidence for nitrogen fixation in all the three niches, and the nitrogenase gene (homologs of nifH) expression data clearly show niche differentiation of diazotrophic Proteobacteria within the water streams. The nifH transcript originated from the symbiotic community of Niphargus amphipods might belong to the Thiothrix ectosymbionts. Two abundantly expressed nifH genes in the Beggiatoa-dominated biofilms are closely related to those from Beggiatoa- and Desulfovibrio-related bacteria. These two diazotrophs were consistently found in Beggiatoa-dominated biofilms collected at various time points, thus illustrating species-specific associations of the diazotrophs in biofilm formation, and micron-scale niche partitioning of sulfur-oxidizing and sulfate-reducing bacteria driven by steep redox gradients within the biofilm. Finally, putative heterotrophs (Geobacter, Azoarcus and Desulfovibrio related) were the active diazotrophs in the sulfidic sediment. Our study is the first to shed light on nitrogen fixation in permanently dark caves and suggests that diazotrophy may be widespread in chemosynthetic communities. PMID- 23924781 TI - Repeated triggering of sporulation in Bacillus subtilis selects against a protein that affects the timing of cell division. AB - Bacillus subtilis sporulation is a last-resort phenotypical adaptation in response to starvation. The regulatory network underlying this developmental pathway has been studied extensively. However, how sporulation initiation is concerted in relation to the environmental nutrient availability is poorly understood. In a fed-batch fermentation set-up, in which sporulation of ultraviolet (UV)-mutagenized B. subtilis is repeatedly triggered by periods of starvation, fitter strains with mutated tagE evolved. These mutants display altered timing of phenotypical differentiation. The substrate for the wall teichoic acid (WTA)-modifying enzyme TagE, UDP-glucose, has recently been shown to be an intracellular proxy for nutrient availability, and influences the timing of cell division. Here we suggest that UDP-glucose also influences timing of cellular differentiation. PMID- 23924782 TI - Active eukaryotes in microbialites from Highborne Cay, Bahamas, and Hamelin Pool (Shark Bay), Australia. AB - Microbialites are organosedimentary structures that are formed through the interaction of benthic microbial communities and sediments and include mineral precipitation. These lithifying microbial mat structures include stromatolites and thrombolites. Exuma Sound in the Bahamas, and Hamelin Pool in Shark Bay, Western Australia, are two locations where significant stands of modern microbialites exist. Although prokaryotic diversity in these structures is reasonably well documented, little is known about the eukaryotic component of these communities and their potential to influence sedimentary fabrics through grazing, binding and burrowing activities. Accordingly, comparisons of eukaryotic communities in modern stromatolitic and thrombolitic mats can potentially provide insight into the coexistence of both laminated and clotted mat structures in close proximity to one another. Here we examine this possibility by comparing eukaryotic diversity based on Sanger and high-throughput pyrosequencing of small subunit ribosomal RNA (18S rRNA) genes. Analyses were based on total RNA extracts as template to minimize input from inactive or deceased organisms. Results identified diverse eukaryotic communities particularly stramenopiles, Alveolata, Metazoa, Amoebozoa and Rhizaria within different mat types at both locations, as well as abundant and diverse signatures of eukaryotes with <80% sequence similarity to sequences in GenBank. This suggests the presence of significant novel eukaryotic diversity, particularly in hypersaline Hamelin Pool. There was evidence of vertical structuring of protist populations and foraminiferal diversity was highest in bioturbated/clotted thrombolite mats of Highborne Cay. PMID- 23924784 TI - Allying with armored snails: the complete genome of gammaproteobacterial endosymbiont. AB - Deep-sea vents harbor dense populations of various animals that have their specific symbiotic bacteria. Scaly-foot gastropods, which are snails with mineralized scales covering the sides of its foot, have a gammaproteobacterial endosymbiont in their enlarged esophageal glands and diverse epibionts on the surface of their scales. In this study, we report the complete genome sequencing of gammaproteobacterial endosymbiont. The endosymbiont genome displays features consistent with ongoing genome reduction such as large proportions of pseudogenes and insertion elements. The genome encodes functions commonly found in deep-sea vent chemoautotrophs such as sulfur oxidation and carbon fixation. Stable carbon isotope ((13)C)-labeling experiments confirmed the endosymbiont chemoautotrophy. The genome also includes an intact hydrogenase gene cluster that potentially has been horizontally transferred from phylogenetically distant bacteria. Notable findings include the presence and transcription of genes for flagellar assembly, through which proteins are potentially exported from bacterium to the host. Symbionts of snail individuals exhibited extreme genetic homogeneity, showing only two synonymous changes in 19 different genes (13 810 positions in total) determined for 32 individual gastropods collected from a single colony at one time. The extremely low genetic individuality in endosymbionts probably reflects that the stringent symbiont selection by host prevents the random genetic drift in the small population of horizontally transmitted symbiont. This study is the first complete genome analysis of gastropod endosymbiont and offers an opportunity to study genome evolution in a recently evolved endosymbiont. PMID- 23924785 TI - Mixotrophic haptophytes are key bacterial grazers in oligotrophic coastal waters. AB - Grazing rate estimates indicate that approximately half of the bacterivory in oligotrophic oceans is due to mixotrophic flagellates (MFs). However, most estimations have considered algae as a single group. Here we aimed at opening the black-box of the phytoflagellates (PFs) <20 MUm. Haptophytes, chlorophytes, cryptophytes and pigmented dinoflagellates were identified using fluorescent in situ hybridization or by standard 4',6-diamidino-2-phenylindole staining. Their fluctuations in abundance, cell size, biomass and bacterivory rates were measured through an annual cycle in an oligotrophic coastal system. On average, we were able to assign to these groups: 37% of the total pico-PFs and 65% of the nano-PFs composition. Chlorophytes were mostly picoplanktonic and they never ingested fluorescently labeled bacteria. About 50% of the PF <20 MUm biomass was represented by mixotrophic algae. Pigmented dinoflagellates were the least abundant group with little impact on bacterioplankton. Cryptophytes were quantitatively important during the coldest periods and explained about 4% of total bacterivory. Haptophytes were the most important mixotrophic group: (i) they were mostly represented by cells 3-5 MUm in size present year-round; (ii) cell-specific grazing rates were comparable to those of other bacterivorous non photosynthetic organisms, regardless of the in situ nutrient availability conditions; (iii) these organisms could acquire a significant portion of their carbon by ingesting bacteria; and (iv) haptophytes explained on average 40% of the bacterivory exerted by MFs and were responsible for 9-27% of total bacterivory at this site. Our results, when considered alongside the widespread distribution of haptophytes in the ocean, indicate that they have a key role as bacterivores in marine ecosystems. PMID- 23924783 TI - Bacterial profiling of White Plague Disease in a comparative coral species framework. AB - Coral reefs are threatened throughout the world. A major factor contributing to their decline is outbreaks and propagation of coral diseases. Due to the complexity of coral-associated microbe communities, little is understood in terms of disease agents, hosts and vectors. It is known that compromised health in corals is correlated with shifts in bacterial assemblages colonizing coral mucus and tissue. However, general disease patterns remain, to a large extent, ambiguous as comparative studies over species, regions, or diseases are scarce. Here, we compare bacterial assemblages of samples from healthy (HH) colonies and such displaying signs of White Plague Disease (WPD) of two different coral species (Pavona duerdeni and Porites lutea) from the same reef in Koh Tao, Thailand, using 16S rRNA gene microarrays. In line with other studies, we found an increase of bacterial diversity in diseased (DD) corals, and a higher abundance of taxa from the families that include known coral pathogens (Alteromonadaceae, Rhodobacteraceae, Vibrionaceae). In our comparative framework analysis, we found differences in microbial assemblages between coral species and coral health states. Notably, patterns of bacterial community structures from HH and DD corals were maintained over species boundaries. Moreover, microbes that differentiated the two coral species did not overlap with microbes that were indicative of HH and DD corals. This suggests that while corals harbor distinct species-specific microbial assemblages, disease-specific bacterial abundance patterns exist that are maintained over coral species boundaries. PMID- 23924786 TI - CD40 therapy and surgery: a potential immunologic partnership. PMID- 23924787 TI - Cracking the stone: combination vaccination and CTLA-4 blockade in pancreatic cancer. PMID- 23924788 TI - Agonistic anti-CD40 antibody therapy is effective against postoperative cancer recurrence and metastasis in a murine tumor model. AB - Postresection recurrences of cancer arising from occult tumor deposits, either local or metastatic, represent major causes of death in patients with operable solid tumors. Thus, new therapies are required that complement existing treatments to eradicate these occult deposits. Agonistic anti-CD40 antibody is one of the most powerful new cancer immunotherapies, enhancing immune priming of effector CD8 T cells by dendritic cells, leading to increased antitumor activity. We investigated the use of anti-CD40 antibody for the treatment of postoperative recurrence and metastasis, with regional lymphadenectomy, in a murine model of cancer. Subcutaneous AB1-HA mesothelioma tumors were induced in BALB/c mice. Established tumors were surgically excised on day 16, with or without sentinel lymph node removal. On the day of surgery, animals were rechallenged with AB1-HA tumor cells at the surgical site (local recurrence) or the opposite flank (metastasis). Postoperative tumors were treated with anti-CD40 (FGK45) on emergence, delivered either intratumorally, peritumorally, or systemically. Local or systemic anti-CD40 treatment slowed postsurgical metastatic growth relative to untreated controls (P = 0.020) and improved survival from metastasis. Anti-CD40 also retarded the growth of local recurrences (P = 0.004) and improved survival from recurrence. Sentinel lymph node dissection did not impair efficacy (P > 0.05). This study demonstrates that anti-CD40 therapy, given either locally or systemically, may be a powerful and readily translatable adjuvant to cancer surgery, including in cases where regional lymphadenectomy is indicated. PMID- 23924789 TI - Irradiated and activated autologous PBMCs induce expansion of highly cytotoxic human NK cells in vitro. AB - Adoptive cell transfer of ex vivo-activated natural killer (NK) cells is a promising therapy for cancer treatment. Because of inhibitory signaling through killer immunoglobulin-like receptor (KIR)-KIR ligands, KIR-mismatched allogeneic NK cell transfer is considered to be a more effective strategy than is autologous transfer. However, purified NK cells do not expand well enough in vitro with good manufacturing practice-compliant components for clinical use. Some investigators have developed selective expansion of NK cells from peripheral blood mononuclear cells, but these cells have the risk of graft-versus-host disease in allogeneic settings because of T cells contamination. In this study, we developed a novel method for NK cell activation and expansion. Using only good manufacturing practice-compliant components and autologous feeder cells, once purified NK cells were effectively expanded (2500-fold at day 17). The expanded cells were highly purified NK cells, and the use of these cells is suitable for allogeneic transfer without the risk of graft-versus-host disease induction. Importantly, the expanded NK cells also showed enhanced cytotoxicity compared with NK cells conventionally expanded by recombinant human interleukin 2. Finally, induction of NKG2D ligand expression on feeder cells implies that the NKG2D-NKG2DL interaction may play a role in NK cell expansion. In conclusion, this method can be used to obtain NK cells for more successful allogeneic NK cell adoptive transfer for use in antitumor immune therapy. PMID- 23924790 TI - Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. AB - Preclinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma (PDA) resulting in a delayed response at a dose of 3 mg/kg. Our study evaluated ipilimumab 10 mg/kg (arm 1) and ipilimumab 10 mg/kg + GVAX (arm 2). A total of 30 patients with previously treated advanced PDA were randomized (1:1). Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks. Two patients in arm 1 showed evidence of stable disease (7 and 22 wk) but none demonstrated CA19-9 biochemical responses. In contrast, 3 patients in arm 2 had evidence of prolonged disease stabilization (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines. In 2 of these patients, disease stabilization occurred after an initial period of progression. The median overall survival (OS) (3.6 vs. 5.7 mo, hazards ratio: 0.51, P = 0.072) and 1 year OS (7 vs. 27%) favored arm 2. Similar to prior ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events. Among patients with OS > 4.3 months, there was an increase in the peak mesothelin specific T cells (P = 0.014) and enhancement of the T-cell repertoire (P = 0.031). In conclusion, checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study. PMID- 23924791 TI - Approval of the first biosimilar antibodies in Europe: a major landmark for the biopharmaceutical industry. AB - In a defining moment for the European Medicines Agency (EMA) and the biopharmaceutical industry, on June 27, 2013 EMA's Committee for Medicinal Products for Human Use adopted a positive opinion for two biosimilar infliximab products (Celltrion's Remsima(r) and Hospira's Inflectra(r)), and recommended that they be approved for marketing in the European Union (EU). The European Commission's decision on an application is typically issued 67 d after an opinion is provided; thus, decisions are expected in early September 2013. If approved, the products will comprise the first biosimilar antibody made available to patients in a highly regulated market, although launch may be delayed due to an extension of the reference product's (Remicade(r)) patent in the EU. PMID- 23924792 TI - Affinity-matured recombinant immunotoxin targeting gangliosides 3'-isoLM1 and 3',6'-isoLD1 on malignant gliomas. AB - About 60 percent of glioblastomas highly express the gangliosides 3'-isoLM1 and 3',6'-isoLD1 on the cell surface, providing ideal targets for brain tumor immunotherapy. A novel recombinant immunotoxin, DmAb14m-(scFv)-PE38KDEL (DmAb14m IT), specific for the gangliosides 3'-isoLM1 and 3',6'-isoLD1, was constructed with improved affinity and increased cytotoxicity for immunotherapeutic targeting of glioblastoma. We isolated an scFv parental clone from a previously established murine hybridoma, DmAb14, that is specific to both 3'-isoLM1 and 3',6'-isoLD1. We then performed in vitro affinity maturation by CDR hotspot random mutagenesis. The binding affinity and specificity of affinity-matured DmAb14m-IT were measured by surface-plasmon resonance, flow cytometry, and immunohistochemical analysis. In vitro cytotoxicity of DmAb14m-IT was measured by protein synthesis inhibition and cell death assays in human cell lines expressing gangliosides 3'-isoLM1 and 3',6'-isoLD1 (D54MG and D336MG) and xenograft-derived cells (D2224MG). As a result, the KD of DmAb14m-IT for gangliosides 3'-isoLM1 and 3',6'-isoLD1 was 2.6 * 10(-9)M. Also, DmAb14m-IT showed a significantly higher internalization rate in cells expressing 3'-isoLM1 and 3',6'-isoLD1. The DmAb14m-IT IC 50 was 80 ng/mL (1194 pM) on the D54MG cell line, 5 ng/ml (75 pM) on the D336MG cell line, and 0.5 ng/ml (7.5 pM) on the D2224MG xenograft-derived cells. There was no cytotoxicity on ganglioside-negative HEK293 cells. Immunohistochemical analysis confirmed the specific apparent affinity of DmAb14m-IT with 3'-isoLM1 and 3',6' isoLD1. In conclusion, DmAb14m-IT showed specific binding affinity, a significantly high internalization rate, and selective cytotoxicity on glioma cell lines and xenograft-derived cells expressing 3'-isoLM1 and 3',6'-isoLD1, thereby displaying robust therapeutic potential for testing the antitumor efficacy of DmAb14m-IT at the preclinical level and eventually in the clinical setting. PMID- 23924794 TI - Characterization and comparison of commercially available TNF receptor 2-Fc fusion protein products: letter to the editor. PMID- 23924793 TI - Cloning and expression of an anti-LDL(-) single-chain variable fragment, and its inhibitory effect on experimental atherosclerosis. AB - The in vivo modified forms of low-density lipoprotein (LDL) are important for the formation of foam cells and as mediators of the immuno-inflammatory process involved in the progression of atherosclerosis. Electronegative LDL, LDL(-), is a LDL subfraction with pro-inflammatory properties that is present in human blood. To investigate possible atheroprotective effects, an anti-LDL(-) single-chain variable fragment (scFv) was expressed in the methylotrophic yeast Pichia pastoris and its activity was evaluated in vitro against macrophages and in experimental atherosclerosis in Ldlr(-/-) mice. The recombinant 2C7 scFv was produced in a yield of 9.5 mg of protein/L. The specificity and affinity of purified 2C7 scFv against LDL(-) was confirmed by ELISA. To assess the activity of 2C7 scFv on foam cell formation, RAW 264.7 macrophages were exposed to LDL(-) in the presence or absence of 2C7 scFv. The 2C7 scFv inhibited the uptake of LDL( ) by macrophages in a dose-dependent manner, and internalization of LDL(-) by these cells was found to be mediated by the CD36 and CD14 receptor. In addition, compared with untreated cells, lipid accumulation in macrophages was decreased, and the expression of Cd36, Tlr-4 and Cox-2 was downregulated in macrophages treated with 2C7 scFv. Importantly, compared with untreated mice, the treatment of Ldlr(-/-) mice with 2C7 scFv decreased the atherosclerotic lesion area at the aortic sinus. In conclusion, our data show that 2C7 scFv inhibits foam cell formation and atherosclerotic plaque development by modulating the expression of genes relevant to atherogenesis. These results encourage further use of this antibody fragment in the development of new therapeutic strategies that neutralize the pro-atherogenic effects of LDL(-). PMID- 23924795 TI - A unique anti-CD115 monoclonal antibody which inhibits osteolysis and skews human monocyte differentiation from M2-polarized macrophages toward dendritic cells. AB - Cancer progression has been associated with the presence of tumor-associated M2 macrophages (M2-TAMs) able to inhibit anti-tumor immune responses. It is also often associated with metastasis-induced bone destruction mediated by osteoclasts. Both cell types are controlled by the CD115 (CSF-1R)/colony stimulating factor-1 (CSF-1, M-CSF) pathway, making CD115 a promising target for cancer therapy. Anti-human CD115 monoclonal antibodies (mAbs) that inhibit the receptor function have been generated in a number of laboratories. These mAbs compete with CSF-1 binding to CD115, dramatically affecting monocyte survival and preventing osteoclast and macrophage differentiation, but they also block CD115/CSF-1 internalization and degradation, which could lead to potent rebound CSF-1 effects in patients after mAb treatment has ended. We thus generated and selected a non-ligand competitive anti-CD115 mAb that exerts only partial inhibitory effects on CD115 signaling without blocking the internalization or the degradation of the CD115/CSF-1 complex. This mAb, H27K15, affects monocyte survival only minimally, but downregulates osteoclast differentiation and activity. Importantly, it inhibits monocyte differentiation to CD163(+)CD64(+) M2 polarized suppressor macrophages, skewing their differentiation toward CD14( )CD1a(+) dendritic cells (DCs). In line with this observation, H27K15 also drastically inhibits monocyte chemotactic protein-1 secretion and reduces interleukin-6 production; these two molecules are known to be involved in M2 macrophage recruitment. Thus, the non-depleting mAb H27K15 is a promising anti tumor candidate, able to inhibit osteoclast differentiation, likely decreasing metastasis-induced osteolysis, and able to prevent M2 polarization of TAMs while inducing DCs, hence contributing to the creation of more efficient anti-tumor immune responses. PMID- 23924796 TI - Target-mediated drug disposition and prolonged liver accumulation of a novel humanized anti-CD81 monoclonal antibody in cynomolgus monkeys. AB - CD81 is an essential receptor for hepatitis C virus (HCV). K21 is a novel high affinity anti-CD81 antibody with potent broad spectrum anti-HCV activity in vitro. The pharmacokinetics (PK), pharmacodynamics and liver distribution of K21 were characterized in cynomolgus monkeys after intravenous (i.v.) administration of K21. Characteristic target-mediated drug disposition (TMDD) was shown based on the PK profile of K21 and a semi-mechanistic TMDD model was used to analyze the data. From the TMDD model, the estimated size of the total target pool at baseline (V(c) * R(base)) is 16 nmol/kg and the estimated apparent Michaelis Menten constant (KM) is 4.01 nM. A simulation using estimated TMDD parameters indicated that the number of free receptors remains below 1% for at least 3 h after an i.v. bolus of 7 mg/kg. Experimentally, the availability of free CD81 on peripheral lymphocytes was measured by immunostaining with anti-CD81 antibody JS81. After K21 administration, a dose- and time-dependent reduction in free CD81 on peripheral lymphocytes was observed. Fewer than 3% of B cells could bind JS81 3 h after a 7 mg/kg dose. High concentrations of K21 were found in liver homogenates, and the liver/serum ratio of K21 increased time-dependently and reached ~160 at 168 h post-administration. The presence of K21 bound to hepatocytes was confirmed by immunohistochemistry. The fast serum clearance of K21 and accumulation in the liver are consistent with TMDD. The TMDD-driven liver accumulation of the anti-CD81 antibody K21 supports the further investigation of K21 as a therapeutic inhibitor of HCV entry. PMID- 23924799 TI - From Bretonneau to therapeutic antibodies, from specificity to specific remedies, Saint-Cyr-Sur-Loire, France, November 19, 2012. AB - Held on November 19, 2012 in Saint-Cyr-sur-Loire, France, the symposium "From Bretonneau to therapeutic antibodies, from specificity to specific remedies" focused on the historical development of antibodies as therapeutics, with an emphasis on the seminal work of the French physician Pierre-Fidele Bretonneau (1778-1862). The morning session was devoted to discussion of the evolution of the concept of specificity in medicine, which started with an epistemological definition. The contributions of Bretonneau to the emergence of the concept of specificity, notably with his studies on diphtheria, and the subsequent development of antidiphtheric serotherapy in Europe during the period 1894-1898 were then presented in detail. The afternoon session began with a presentation on the role of French physiologists during the years 1860-1890 in establishing the basic concepts of specific immunity and the principles of serotherapy. The history of antivenom serotherapy, particularly its discovery by Cesaire Phisalix, and the development of antilymphocyte globulins as successful transplantation drugs were then discussed. The symposium ended with the inauguration of a stele representing Bretonneau, who lived in Saint-Cyr-sur-Loire and died 150 y ago. PMID- 23924797 TI - Improving biophysical properties of a bispecific antibody scaffold to aid developability: quality by molecular design. AB - While the concept of Quality-by-Design is addressed at the upstream and downstream process development stages, we questioned whether there are advantages to addressing the issues of biologics quality early in the design of the molecule based on fundamental biophysical characterization, and thereby reduce complexities in the product development stages. Although limited number of bispecific therapeutics are in clinic, these developments have been plagued with difficulty in producing materials of sufficient quality and quantity for both preclinical and clinical studies. The engineered heterodimeric Fc is an industry wide favorite scaffold for the design of bispecific protein therapeutics because of its structural, and potentially pharmacokinetic, similarity to the natural antibody. Development of molecules based on this concept, however, is challenged by the presence of potential homodimer contamination and stability loss relative to the natural Fc. We engineered a heterodimeric Fc with high heterodimeric specificity that also retains natural Fc-like biophysical properties, and demonstrate here that use of engineered Fc domains that mirror the natural system translates into an efficient and robust upstream stable cell line selection process as a first step toward a more developable therapeutic. PMID- 23924800 TI - Comparing CDRH3 diversity captured from secondary lymphoid organs for the generation of recombinant human antibodies. AB - The plasticity of natural immunoglobulin repertoires can be exploited for the generation of phage display libraries. Secondary lymphoid organs, such as the spleen and the lymph nodes, constitute interesting sources of diversity because they are rich in B cells, part of which can be affinity matured. These organs, however, differ in their anatomical structure, reflecting the different fluids they drain, which affects the B cell repertoires. The CDRH3 repertoires from these organs, extracted from naive or immunized mice, were compared in the context of phage display libraries using human antibody framework families. Deep sequencing analysis revealed that all libraries displayed different CDRH3 repertoires, but the one derived from lymph nodes of naive mice was the most diverse. Library performance was assessed by in vitro selection. For both organs, immunization increased substantially the frequency of molecules able to bind to the immunogen. The library derived from lymph nodes from naive mice, however, was the most effective in generating diverse and high affinity candidates. These results illustrate that the use of a biased CDRH3 repertoire increases the performance of libraries, but reduces the clonal diversity, which may be detrimental for certain strategies. PMID- 23924801 TI - Correct primary structure assessment and extensive glyco-profiling of cetuximab by a combination of intact, middle-up, middle-down and bottom-up ESI and MALDI mass spectrometry techniques. AB - The European Medicines Agency received recently the first marketing authorization application for a biosimilar monoclonal antibody (mAb) and adopted the final guidelines on biosimilar mAbs and Fc-fusion proteins. The agency requires high similarity between biosimilar and reference products for approval. Specifically, the amino acid sequences must be identical. The glycosylation pattern of the antibody is also often considered to be a very important quality attribute due to its strong effect on quality, safety, immunogenicity, pharmacokinetics and potency. Here, we describe a case study of cetuximab, which has been marketed since 2004. Biosimilar versions of the product are now in the pipelines of numerous therapeutic antibody biosimilar developers. We applied a combination of intact, middle-down, middle-up and bottom-up electrospray ionization and matrix assisted laser desorption ionization mass spectrometry techniques to characterize the amino acid sequence and major post-translational modifications of the marketed cetuximab product, with special emphasis on glycosylation. Our results revealed a sequence error in the reported sequence of the light chain in databases and in publications, thus highlighting the potency of mass spectrometry to establish correct antibody sequences. We were also able to achieve a comprehensive identification of cetuximab's glycoforms and glycosylation profile assessment on both Fab and Fc domains. Taken together, the reported approaches and data form a solid framework for the comparability of antibodies and their biosimilar candidates that could be further applied to routine structural assessments of these and other antibody-based products. PMID- 23924802 TI - Elongation of the C-terminal domain of an anti-amyloid beta single-chain variable fragment increases its thermodynamic stability and decreases its aggregation tendency. AB - Amyloid beta (Abeta) immunotherapy is considered a promising approach to Alzheimer disease treatment. In contrast to the use of complete antibodies, administration of single-chain variable fragments (scFv) has not been associated with either meningoencephalitis or cerebral hemorrhage. ScFv-h3D6 is known to preclude cytotoxicity of the Abeta 1-42 peptide by removing its oligomers from the amyloid pathway. As is the case for other scFv molecules, the recombinant production of scFv-h3D6 is limited by its folding and stability properties. Here, we show that its urea-induced unfolding pathway is characterized by the presence of an intermediate state composed of the unfolded VL domain and the folded VH domain, which suggests the VL domain as a target for thermodynamic stability redesign. The modeling of the 3D structure revealed that the VL domain, located at the C-terminal of the molecule, was ending before its latest beta-strand was completed. Three elongation mutants, beyond VL-K107, showed increased thermodynamic stability and lower aggregation tendency, as determined from urea denaturation experiments and Fourier-transform infrared spectroscopy, respectively. Because the mutants maintained the capability of removing Abeta oligomers from the amyloid pathway, we expect these traits to increase the half life of scFv-h3D6 in vivo and, consequently, to decrease the effective doses. Our results led to the improvement of a potential Alzheimer disease treatment and may be extrapolated to other class-I scFv molecules of therapeutic interest. PMID- 23924803 TI - Immunogenicity of mAbs in non-human primates during nonclinical safety assessment. AB - The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies. PMID- 23924805 TI - Comparison of two nucleic acid extraction and testing systems for HCMV-DNA detection and quantitation on whole blood specimens from transplant patients. AB - Quantitative detection of human cytomegalovirus (HCMV) DNA on whole blood is currently the primary choice for virological monitoring in transplant patients and for determining the appropriate antiviral strategy, however specific issues of variability remain in terms of extraction methods, amplification efficiency, and variability. This study compared the performance characteristics of two nucleic acid extraction and testing systems for HCMV-DNA quantitation, the artus(r) CMV QS-RGQ kit, associated with a fully automated DNA extraction and assay set up by Qiagen (system 1) and the Q-CMV Real Time Complete kit by Nanogen, associated with a semiautomated nucleic acid extraction system by Biomerieux (system 2) in 189 specimens from transplant patients and 10 from 2012 HCMV Quality Control for Molecular Diagnostics (QCMD). The two systems exhibited a 80.4% concordance. Differences between the two systems were within +/-1 log10 copies/ml of the averaged log10 results for 88.9% of the tested specimens. For all qualitatively discordant specimens, mean viral load was <=3 log10 copies/ml. Considering viral load measurement, system 1 gave earlier positives that system 2, with a 14.8% of specimens resulted positive at low viral loads with system 1 and negative with system 2. In QCMD specimens, difference was below 0.7 log10 copies/ml for both the systems. In conclusion, the two systems provided reliable and comparable results. Some specific performance characteristic and automation could be taken into account in terms of less hands of time, fewer errors and reliability. PMID- 23924804 TI - Ch14.18 antibody produced in CHO cells in relapsed or refractory Stage 4 neuroblastoma patients: a SIOPEN Phase 1 study. AB - PURPOSE: This study aimed to assess the safety, pharmacokinetic and activity profiles of the human-mouse chimeric monoclonal anti-disialoganglioside GD2 antibody ch14.18 produced in Chinese hamster ovary (CHO) cells (ch14.18/CHO). METHODS: Sixteen children with recurrent/refractory neuroblastoma (median age 7.6 y) were enrolled in this Phase 1 dose-finding study. Patients received ch14.18/CHO courses of 10, 20 or 30 mg/m (2)/day as an eight-hour infusion over five consecutive days. Three courses at the same dose level were allowed unless disease progressed. Clearance and biodistribution of radiolabelled ch14.18/CHO in Balb/c and A/J mice were analyzed. RESULTS: A total of 41 ch14.18/CHO courses were given (10 * 3 courses, 5 * 2 courses, 1 * 1 course). Side effects were similar in expectedness, frequency and magnitude to those reported for ch14.18/SP2/0. The dose level of 20 mg/m(2)/day was confirmed. Toxicity was reversible and no treatment-related deaths occurred. In children, the peak plasma concentration was 16.51 ug/ml +/- 5.9 ug/ml and the half-life was 76.91 h +/- 52.5 h. A partial response following ch14.18/CHO was observed in 2/7 patients with residual disease. In mice, the half-lives were 22.7 h +/- 1.9h for ch14.18/CHO and 25.0 h +/- 1.9 h for ch14.18/SP2/0. The biodistribution of (125)I ch14.18/CHO in mice with neuroblastoma was identical to (125)I-ch14.18/SP2/0, indicating GD 2 targeting activity in vivo. Ch14.18 produced in CHO cells showed an unchanged toxicity profile and pharmacokinetics in neuroblastoma patients compared with ch14.18 produced in SP2/0 cells, and evidence of clinical activity was observed. In mice, analysis of pharmacokinetics and biodistribution showed comparable results between ch14.18/CHO and ch14.18/SP2/0. Based on these results, ch14.18/CHO was accepted for prospective clinical evaluation. PMID- 23924807 TI - Measuring testosterone biomarkers in serum and saliva: are they accurate? PMID- 23924806 TI - Adolescent peer choice and cigarette smoking: evidence of active gene-environment correlation? AB - Both peer groups and genetics have been associated with adolescent smoking behavior. Recently, Loehlin (Loehlin, J. C. (2010). Is there an active gene environment correlation in adolescent drinking behavior? Behavior Genetics, 40, 447-451) reported that twin differences in alcohol use were associated with differences in the number of common friends. Twins with more common friends were more similar in drinking, but only for dizygotic pairs. Using the same sample as Loehlin's (the National Merit twins), we replicated all of these findings for a composite cigarette smoking measure and for smoking initiation, but not persistence. The pattern of results is most consistent with homophily, or the tendency to associate with individuals that are like oneself. If peer influence occurs in the presence of homophily, then active genotype-environment correlation will be induced. PMID- 23924808 TI - The salivary hormone profile in the clinical evaluation of women. PMID- 23924809 TI - Compounding for the dental patient: a focus on ulcers of the mouth. PMID- 23924810 TI - Compounding for sports medicine. AB - Abstract not available. PMID- 23924812 TI - Cleaning of isolators: a vital part of a contamination program. PMID- 23924811 TI - Is veterinary compounding illegal under federal law? PMID- 23924813 TI - A need for propylene glycol-free ascorbic Acid oral liquid. PMID- 23924815 TI - Quality-control analytical methods: allowable endotoxin levels in sterile preparations. PMID- 23924814 TI - Basics of compounding for cough. PMID- 23924816 TI - Stability of extemporaneous oral ribavirin liquid preparation. AB - Ribavirin is an antiviral agent commonly used in Hong Kong for the treatment of severe acute respiratory syndrome. The choice of oral ribavirin therapeutic products available in the local market is currently limited to capsules. The present study investigated the chemical stability of an oral ribavirin suspension (200 mg/5mL) prepared extemporaneously from oral capsules using a sugar-free suspension formula. The suspension was subjected to stability testing at 4 deg C for up to 28 days. Employing a validated stability-indicating high-performance liquid chromatographic method, the ribavirin content of the extemporaneous preparation has been demonstrated to exhibit negligible changes throughout the storage period. No degradation product was observable in all high-peroformance liquid chromatograms, suggesting that the suspension remained chermically stable under the stated conditions. PMID- 23924817 TI - Chemical stability of methadone concentrate and powder diluted in orange-flavored drink. AB - Methadone, traditionally used in the treatment of heroin addiction, recently has been used to treat severe pain. The chemical stability of methadone has been studied in concentrations up to 1.5 mg/mL only. Commercial methadone concentrate (10mg/mL) and methadone powder was diluted to 5 mg/mL with orange-flavored Tang drink. Sodium benzoate was added to the solutions prepared from powder. Bottles were stored at either room temperature (22 deg C) or under refrigeration (6 deg C) for 91 days. Samples were analyzed in duplicate by a stability-indicating high performance liquid chromatographic assay, and clarity and pH were also monitored. One additional solution was preprared from powder but no preservative was added; this solution was monitored for presence of bacterial growth at room temperature only. Solutions prepared from the concentrate and powder with preservative showed no signs of change in clarity on storage. The solution made from powder only developed turbidity after 21 days, which suggested bacterial growth. There was no significant change in pH over the course of the study. After 91 days of storage at either room temperature or under refrigeration, there was no change in concentration for solutions prepared from concentrate or powder with preservative. Methadone solutions prepared from the commercial concentrate or powder with sodium benzoate are stable for 91 days at room temperature or under refrigeration. Solutions prepared from the powder but not containing a preservative showed signs of bacterial growth after 21 days at room temperature. PMID- 23924818 TI - Preparation and characterization of a compounded aqueous human insulin suspension. AB - Human insulin, used in the management of diabetes, is commercially available in the form of solutions or suspensions for injection. This study investigated the preparation and characterization of an oral suspension for insulin. The suspension was prepared by adding human insulin to aqueous soy extract and adjusting the pH of the preparation to 4.0. The mean diameters of insulin particles at this pH were measured to be 29.93 and 28.30 micrometers for volume surface mean and volume-number mean, respectively. After 24 hours of the suspension standing at room temperature, the sedimentation volume reached a constant value of 0.22. The suspension exhibited shear-thinning rheological properties, since its viscosity decreased when the rate of shear was increased. The formulation was stable for about 18 days when stored in the refrigerator (4 deg C). Compared to a simple solution of insulin stored at a similar acidic pH reported in the literature, the stability of insulin in the suspension has improved over 2000-fold. PMID- 23924819 TI - Improved thermal cycling durability and PCR compatibility of polymer coated quantum dot. AB - Quantum dots have experienced rapid development in imaging, labeling and sensing in medicine and life science. To be suitable for polymerase chain reaction (PCR) assay, we have tested QD thermal cycling durability and compatibility, which have not been addressed in previous reports. In this study, we synthesized CdSe/ZnS QDs with a surface modification with high-MW amphiphilic copolymers and observed that Mg2+ ions in the PCR reaction could induce the QDs to precipitate and reduce their fluorescence signal significantly after thermal cycling. To overcome this problem, we used mPEG2000 to conjugate the QD surface for further protection, and found that this modification enables QDs to endure 40 thermal cycles in the presence of other components essential for PCR reactions. We have also identified that QDs have different effects on rTaq and Ex Taq polymerization systems. A high QD concentration could apparently reduce the PCR efficiency, but this inhibition was relieved significantly in the Ex PCR system as the concentration of Ex Taq polymerase was increased. Real-time PCR amplification results showed that QDs could provide a sufficiently measurable fluorescence signal without excessively inhibiting the DNA amplification. Based on this improved thermal cycling durability and compatibility with the PCR system, QDs have the potential to be developed as stable fluorescent sensors in PCR and real-time PCR amplification. PMID- 23924820 TI - Quantitative assessment of minimal effective concentration of erythropoiesis stimulating agents. AB - Minimal effective concentration (MEC) was proposed to explain why subcutaneous (SC) administration of erythropoietin (EPO) induces a higher hemoglobin (HGB) increase than intravenous (IV) administration. It has been further used to explain the paradox that erythropoiesis-stimulating agent (ESA) with lower receptor binding affinity may have higher in vivo activity. We have developed a pharmacokinetic and pharmacodynamic (PK/PD) model with incorporation of the operational model of agonism to characterize the data from two clinical trials. By using model-based simulations, we demonstrate that SC route is more efficacious than IV route and explain the paradoxical behavior of ESAs. We determined that MEC can be quantified by C50, which represents the concentration of an ESA producing its half-maximal effect of stimulating the proliferation of erythroid precursor cells. The model used may allow joint PK/PD modeling of data from different ESAs, and provide a platform for dosing regimen optimizations and future clinical study designs.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e62; doi:10.1038/psp.2013.39; published online 7 August 2013. PMID- 23924821 TI - Tetrandrine potentiates the hypoglycemic efficacy of berberine by inhibiting P glycoprotein function. AB - This study was designed to improve the absorption and hypoglycemic efficacy of berberine (BBR), which is a substrate of P-glycoprotein (P-gp), by combination with a P-gp inhibitor tetrandrine (Tet). Flow cytometry and LC-MS/MS were used to determine the cellular efflux or retention of chemicals. Pharmacokinetic study was performed in ICR mice following oral administration of the study compounds. The hypoglycemic efficacies of the compounds were evaluated in diabetic KK-Ay mice. In the in vitro experiments, Tet significantly inhibited the efflux and increased the uptake of P-gp substrates rhodamine-123 as well as BBR in MCF7/DOX cells and Caco-2 intestinal cells. Meanwhile, Tet greatly reduced the expression of P-gp in Caco-2 cells. The inhibition of BBR efflux by Tet was translated into improved pharmacokinetics in vivo. When co-administered, Tet dose-dependently increased the average maximum concentration (C(max)) and area under concentration time curve (AUC0-24) of BBR in mice. Tet itself had no impact on glucose metabolism. However, it greatly potentiated the hypoglycemic efficacy of BBR in diabetic KK-Ay mice. In addition, we found that Tet had moderate inhibitory effect on the catalytic activity of CYP3A4, which played a role in the bio transformation of BBR, and this may also take part in the improvement of the pharmacokinetics of BBR. In summary, combination with P-gp inhibitors such as Tet can improve the pharmacokinetics and hypoglycemic efficacy of BBR greatly; this implicates a feasible strategy for exploring the therapeutic effects of BBR and other pharmaceuticals which are substrates of P-gp. PMID- 23924822 TI - A potential mechanism of a cationic cyclopeptide for enhancing insulin delivery across Caco-2 cell monolayers. AB - Effective delivery of therapeutic biomolecules across biomembranes is a challenging topic. A cationic cyclopeptide named TD-34 (ACSSKKSKHCG) was reported to improve insulin delivery across biomembranes effectively. Based on our previous work, we investigated the mechanism of TD-34 for enhancing insulin across Caco-2 cell monolayers. Transport studies of insulin, TD-34 and insulin accompanied with TD-34 were performed respectively using Caco-2 cell monolayers at different conditions. Transepithelial electrical resistance (TEER) value was monitored for 24 h immediately after the beginning of transport experiments. Moreover, the tight junction protein (Claudin-1) was localized by confocal immunofluorescence microscopy. Results showed the transport of insulin alone across biomembranes was attributable to multiple routes including passive diffusion. When TD-34 accompanied with or without insulin was treated on Caco-2 cell monolayers, TEER values decreased reversibly, and it was correlated with the reappearance of tight junction proteins by immunostaining assay. It was concluded that the cationic cyclopeptide (TD-34) had the potential to enhance paracellular delivery of insulin across Caco-2 cell monolayers by loosening tight junction reversibly. PMID- 23924823 TI - The effect of automated monitoring and real-time prompting on nurses' hand hygiene performance. AB - Adequate hand hygiene compliance by healthcare staff is considered an effective method to reduce hospital-acquired infections. The electronic system developed at Toronto Rehabilitation Institute automatically detects hand hygiene opportunities and records hand hygiene actions. It includes an optional visual hand hygiene status indication, generates real-time hand hygiene prompting signals, and enables automated monitoring of individual and aggregated hand hygiene performance. The system was installed on a complex continuous care unit at the entrance to 17 patient rooms and a utility room. A total of 93 alcohol gel and soap dispensers were instrumented and 14 nurses were provided with the personal wearable electronic monitors. The study included three phases with the system operating in three different modes: (1) an inactive mode during the first phase when hand hygiene opportunities and hand hygiene actions were recorded but prompting and visual indication functions were disabled, (2) only hand hygiene status indicators were enabled during the second phase, and (3) both hand hygiene status and real-time hand hygiene prompting signals were enabled during the third phase. Data collection was performed automatically during all of the three phases. The system indicated significantly higher hand hygiene activity rates and compliance during the third phase, with both hand hygiene indication and real time prompting functions enabled. To increase the efficacy of the technology, its use was supplemented with individual performance reviews of the automatically collected data. PMID- 23924824 TI - Description of musculoskeletal disorders and occupational exposure from a field pilot study of large population-based cohort (CONSTANCES). PMID- 23924825 TI - Safe lifting and apparently conflicting evidence: increase understanding for making progress in prevention of musculoskeletal disorders. PMID- 23924826 TI - Response: safe lifting. PMID- 23924827 TI - Relationship between long working hours and depression: a 3-year longitudinal study of clerical workers. AB - OBJECTIVE: To clarify how long working hours affect the likelihood of current and future depression. METHODS: Using data from four repeated measurements collected from 218 clerical workers, four models associating work-related factors to the depressive mood scale were established. The final model was constructed after comparing and testing the goodness-of-fit index using structural equation modeling. Multiple logistic regression analysis was also performed. RESULTS: The final model showed the best fit (normed fit index = 0.908; goodness-of-fit index = 0.936; root-mean-square error of approximation = 0.018). Its standardized total effect indicated that long working hours affected depression at the time of evaluation and 1 to 3 years later. The odds ratio for depression risk was 14.7 in employees who were not long-hours overworked according to the initial survey but who were long-hours overworked according to the second survey. CONCLUSIONS: Long working hours increase current and future risks of depression. PMID- 23924828 TI - Reduction in health risks and disparities with participation in an employer sponsored health promotion program. AB - There is an increasing awareness among employers and health care providers that health care needs to be tailored to address the diversity of the workforce. Population-based data have shown significant differences in health behaviors and health risks among different racial/ethnic groups in the United States. The purpose of this study was to examine health risks and changes in health risks over time in an employed population at a financial services corporation. This large financial services corporation is naturally concerned about any disparities in health among employees. The study population consists of employees who participated in the organization's medical plan and also the annual health risk appraisal questionnaire in both 2009 and 2010. Significant demographic differences exist among the four ethnic groups studied: whites, African Americans, Hispanics, and Asians. At baseline, African American employees had a significantly higher average number of health risks measured by the health risk appraisal, but they also experienced the greatest improvement in health risks by time 2. There were differences in the health risk profiles of the ethnic groups, with certain risk factors being more prevalent among some ethnicities than among others. The health care costs were not significantly different among the groups studied here. It is likely that other large employers may also find health risk differences among employees belonging to various ethnicities. Future research in this field should seek to understand the reasons behind differences in health among ethnic groups and how best to address them so that all employees can achieve a high level of health and wellness. PMID- 23924829 TI - The relationship between smoking and health care, workers' compensation, and productivity costs for a large employer. AB - OBJECTIVE: To quantify and compare employee health- and productivity-related costs for current smokers versus nonsmokers for a large US employer. METHODS: Multivariate regression models were used to compare medical, pharmacy, workers' compensation, and short-term disability costs, self-reported absenteeism, and presenteeism by smoking status. Costs were aggregated over 3 years, from 2008 to 2010. RESULTS: Controlling for demographic variables, smokers had significantly different health care utilization patterns, as well as higher absenteeism and presenteeism costs. Overall, employees who smoke were estimated to cost employers $900 to $1383 more than their nonsmoking counterparts. CONCLUSIONS: Current smokers experience incrementally greater lost productivity than nonsmokers, contributing to employer costs associated with smoking. Increased employer focus on smoking cessation may help mitigate these organizational costs. PMID- 23924832 TI - Probiotic Lactobacillus rhamnosus GG mono-association suppresses human rotavirus induced autophagy in the gnotobiotic piglet intestine. AB - BACKGROUND: Human rotavirus (HRV) is the most important cause of severe diarrhea in infants and young children. Probiotic Lactobacillus rhamnosus GG (LGG) reduces rotavirus infection and diarrhea. However, the molecular mechanisms of LGG mediated protection from rotavirus infection are poorly understood. Autophagy plays an essential role in responses to microbial pathogens. However, the role of autophagy in HRV infection and LGG treatment is unknown. We hypothesize that rotavirus gastroenteritis activates autophagy and that LGG suppresses virus induced autophagy and prevents intestinal damage in infected piglets. METHODS: We used LGG feeding to combat viral gastroenteritis in the gnotobiotic pig model of virulent HRV infection. RESULTS: We found that LGG feeding did not increase autophagy, whereas virus infection induced autophagy in the piglet intestine. Virus infection increased the protein levels of the autophagy markers ATG16L1 and Beclin-1 and the autophagy regulator mTOR. LGG treatment during viral gastroenteritis reduced autophagy marker expression to normal levels, induced apoptosis and partially prevented virus-induced tissue damage. CONCLUSION: Our study provides new insights into virus-induced autophagy and LGG suppression of uncontrolled autophagy and intestinal injury. A better understanding of the antiviral activity of LGG will lead to novel therapeutic strategies for infant infectious diseases. PMID- 23924834 TI - Galactosemia in the Turkish population with a high frequency of Q188R mutation and distribution of Duarte-1 and Duarte-2 variations. AB - Classical galactosemia is an inherited recessive disorder of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT), which is caused by mutations in the GALT gene. In this study, 56 Turkish patients diagnosed with galactosemia were screened for GALT gene mutations using Affymetrix resequencing microarrays. Eleven types of mutations were detected in these patients, including two novel mutations (R258G and G310fsX49) and nine recurrent mutations. We detected six patients who were homozygous for the E340* mutation and for N314D, L218L silent substitutions (Duarte-1 variant) in this study. The haplotype E340*, N314D and L218L has been reported only in Turkish patients, which suggests that the E340* mutation is specific for our population and might be spread by a Turk ancestor. In patients, the Duarte-1 allele was found with a frequency of 10.71%, whereas the Duarte-2 allele was not detected. Duarte-1 and Duarte-2 alleles were found to be present at a frequency of 2.3% and 1.4%, respectively, in the screening of 105 healthy individuals. Considering all detected mutations, it is a very important finding that exons 6 and 10 of the GALT gene account for 79% of all mutant alleles in the Turkish population. The most common mutation is Q188R, with a frequency of 55.35%. PMID- 23924833 TI - Association of XRCC3 and XRCC4 gene polymorphisms, family history of cancer and tobacco smoking with non-small-cell lung cancer in a Chinese population: a case control study. AB - Single-nucleotide polymorphisms (SNPs) of DNA repair genes have been reported to modify cancer risk. This study aimed to determine SNPs of the DNA repair genes X ray repair cross-complementing group 3 (XRCC3) and X-ray cross-complementing group 4 (XRCC4) and their association with non-small-cell lung cancer (NSCLC) susceptibility in a Chinese population. A total of 507 NSCLC patients and 662 healthy controls were recruited for genotyping. Epidemiological and clinical data were also collected for association studies. The data showed that the rs1799794 G allele in the XRCC3 gene and minor allele carriers of XRCC4, including rs1056503 and rs9293337, were inversely associated with NSCLC risk (GG vs homozygote AA), whereas the rs861537 AG or AA genotype and XRCC4 rs6869366 had a significantly increased NSCLC risk. Furthermore, tobacco smoking over 26 pack-years, a family history of lung cancer, exposure to environmental tobacco smoke (ETS) and negative mental status were risk factors for developing NSCLC. This study suggests that SNPs of XRCC3 and XRCC4 and other environmental factors are risk factors for developing NSCLC in this Chinese Han population. PMID- 23924836 TI - If the cap fits... PMID- 23924835 TI - Genetic variant in vitamin D binding protein is associated with serum 25 hydroxyvitamin D and vitamin D insufficiency in southern Chinese. AB - Previous large-scale genome-wide meta-analysis identified four loci affecting 25 hydroxyvitamin D (25(OH)D) concentrations. However, whether these loci are associated with 25(OH)D concentration in southern Chinese remain unknown. Our primary aim was to examine whether the four top hits (rs2282679, rs10741657, rs12785878 and rs6013897) could be replicated in 712 southern Chinese women. The associations between these single-nucleotide polymorphisms (SNPs), serum 25(OH)D concentration (continuous variable) and vitamin D insufficiency (dichotomized variable) were examined using multivariable linear regression and logistic regression, respectively. Age, body mass index and season were adjusted in the model. Among these four SNPs, rs2282679 was associated with serum 25(OH)D levels (beta=-0.066; P=9 * 10(-5)) and vitamin D insufficiency (odds ratio (OR)=1.51, 95% confidence interval (CI) 1.19-1.93; P=8.6 * 10(-4)), whereas rs12785878 was nominally associated with vitamin D insufficiency only (OR=0.79, 95% CI 0.63 0.99; P=0.042). Genotype risk score (GRS), by summing risk variants of these two SNPs, had more significant association with vitamin D insufficiency (OR=1.38; 95% CI 1.17-1.64; P(trend)=1.76 * 10(-4)) than the model that included only either SNP. The areas under receiver operating characteristic curves of rs2282679 and GRS were 0.561 (P=0.005) and 0.576 (P=5 * 10(-4)), respectively. Our study provides an independent evidence of the associations of rs2282679 and probably rs12785878 with 25(OH)D and vitamin D insufficiency in southern Chinese. PMID- 23924837 TI - Sleep disruption in patients with chronic leg ulcers. AB - OBJECTIVE: To investigate the incidence of sleep disruption in people with chronic leg ulcers and to explore which factors may contribute to sleep problems. METHOD: A questionnaire survey was completed by a convenience sample of 52 leg ulcer patients attending community-based Leg Clubs in England and Wales. The questionnaire assessed wound pain, quality of sleep, factors contributing to sleep disruption and general health. RESULTS: Sixty-nine per cent (n=36) of leg ulcer patients reported sleep disruption, with 88% stating that they wake at least once during the night. General wound pain was the most frequently-cited cause (58%), while pain associated with treatment affected the sleep of 38% of respondents. Additionally, nearly a third (n=14) expressed that worrying about their wound impacted on their sleep. A significant correlation was found between wound pain and sleep disruption. CONCLUSION: The findings suggest that the majority of leg ulcer patients suffer sleep disruption, either as a direct consequence of wound pain or due to treatment-related or psychological issues associated with the wound. This has important implications for patient quality of life and also for the healing process; therefore, assessment and management of sleep problems in leg ulcer patients is essential. DECLARATION OF INTEREST: This study was supported by a financial grant from Molnlycke Health Care. The authors have no commercial or social conflicts of interest with respect to the article or its content. PMID- 23924838 TI - Characterisation of epidermal regeneration in vivo: a 60-day follow-up study. AB - OBJECTIVE: To characterise the long-term course of epidermal regeneration in a suction-blister wound model in healthy humans. METHOD: A single-centre, prospective cohort study was conducted. Suction blister wounds of 8mm diameter were created on the volar forearms of healthy volunteers. Planimetry was used to measure the wound surface area. Transepidermal water loss was estimated to characterise the skin barrier function. Skin brightness was measured using the chromametric luminance L* parameter and skin (visco)elastic properties were measured by a controlled suction device. RESULTS: Thirty-two subjects (mean age 28.6 years) participated. Epithelisation was nearly completed after 8 days, but it took approximately 3 weeks for complete skin barrier restoration. Post inflammatory hyperpigmentation was observed at the end of day 60 in the majority of skin areas. Elastic and viscoelastic deformation and recovery at the end of the follow-up period did not reach baseline values. CONCLUSION: Newly formed epidermis requires considerable time before reaching complete recovery of the skin barrier function. Up to 2 months after the injury, regenerated epidermis in junction with the reticular dermis is stiffer compared to before. Under mechanical loading increased local stiffness might increase the risk for subsequent injuries at the same or adjacent skin areas. Due to its increased vulnerability it is recommended to protect or to offload the epidermal tissue as long as possible to support the structural long-term regeneration. Artificial suction blister wounds are well standardised and controlled models for a wide range of clinical studies and they offer advantages over uncontrolled patient conditions in wound healing studies. DECLARATION OF INTEREST: This study was funded by La Roche-Posay Laboratoire Pharmaceutique (Asnieres, France). The sponsor had no influence on the design, conduct, and analysis and presentation of the data and on the content of this manuscript. The authors have no financial interest in this article. PMID- 23924839 TI - Evaluation of a non-adherent, povidone-iodine dressing in a case series of chronic wounds. AB - Here we report a product evaluation for a non-adherent, povidone-iodine (PVP-I) dressing, determining the clinical need for the product, performing a literature review, clinical evaluation and cost-analysis, and developing a recommendation. This evaluation included 20 patients who experienced dressing pain with the previous antimicrobial dressing. Two patients discontinued the evaluation and four ulcers were non-healing; the remaining wounds closed with the PVP-I dressing. Patients indicated a preference for the PVP-I dressing, primarily due to lack of dressing pain. The PVP-I dressing was also the most cost-efficient. PMID- 23924840 TI - Wound healing and the role of fibroblasts. AB - Fibroblasts are critical in supporting normal wound healing, involved in key processes such as breaking down the fibrin clot, creating new extra cellular matrix (ECM) and collagen structures to support the other cells associated with effective wound healing, as well as contracting the wound. This article explores and summarises the research evidence on the role of fibroblasts, their origins and activation, and how they navigate the wound bed, as well as how their activity leads to wound contraction. This article also explores the local conditions at the wound site, which activate, regulate and ultimately reduce the fibroblast activity as the skin's integrity returns on healing. PMID- 23924841 TI - Point prevalence of wounds and cost impact in the acute and community setting in Denmark. AB - OBJECTIVE: To estimate the wound-care related costs in two hospitals in Denmark. METHOD: A point-prevalence survey with a focus on resource consumption was carried out during a representative 1-week period in March 20 I 0, in two hospitals in Denmark: Regional Hospital Viborg, in the Viborg Municipality and Hillerod Hospital, in the Horsholm Municipality. Data were collected during a 2 day period for inpatients and outpatients in the hospitals and over a full week in the municipalities. The survey included information on the numbers, types and locations of the wounds, as well as resource consumption related to dressing changes. The estimation of costs was based on representative cost levels, including the salaries of health professionals or nurses and the cost of dressings and hospitalisation provided. RESULTS: In total, 33% (n=830) of inpatients had a wound. The majority of these were surgical/trauma wounds (25%), while pressure ulcers, leg ulcers and diabetic foot ulcers accounted for 3.3%, 1.7% and 1.6%, respectively. In the municipalities, there was a wound patient prevalence of 2.8 per I 000 population(I I I 000 acute wounds, 0.7/ I 000 pressure ulcers, 0.5/ I 000 leg ulcers and 0.3/ I 000 diabetic foot ulcers).The extrapolated figures for nurse time related to wound care per year was equivalent to I 0 full-time nurse positions in Hillerod Hospital, three in Viborg Hospital, 17 in Viborg Municipality and three in Horsholm Municipality. The total annual costs related to wound care was estimated as ?3.6 million for Viborg Hospital, ?4.1 million for Hillemd Hospital, ? 1.2 million for Viborg Municipality and ?232 548 for Horsholm Municipality, accounting for approximately 1.8% (Viborg), 1.6% (Hillerod), 2.4% (Viborg) and1.5% (Horsholm) of the total annual budgets. CONCLUSION: In the survey, 33% of the patients treated in the hospitals had a wound. Primary costs were defined as hospitalisation costs and nurse time related to dressing changes. Total annual costs of treatment, including hospitalisation, were estimated as approximately 1.6-1.8% for the hospitals and 1.5-2.4% for the municipalities. The level of costs support the relevance of increased efforts to secure better wound prevention and treatment to reduce the staff-time consumption and hospitalisation costs. PMID- 23924842 TI - A review of PU risk assessment and prevention in Scandinavia, Iceland and Ireland (part II). AB - OBJECTIVE: To provide a critical appraisal of nurses risk assessment and pressure ulcer (PU) preventive practices across Scandinavia, Iceland and Ireland. METHOD: An integrative research review following Cooper's five stages. Studies published in peer-reviewed journals, involving any study design, but specifically exploring PU risk assessment or preventative practices, in any care setting, were included. RESULTS: Risk assessment practice was primarily investigated in the acute care setting and was found to be irregular, based on both numeric scales and clinical judgments. This irregular practice means that some vulnerable patients are not screened for pressure ulcer risk, conversely, when risk assessed, a care plan is not necessarily provided.A significant gap in nurse documentation, together with a lack of supporting evidence for repositioning and use of appropriate redistribution devices was also identified,indicating a lack of a standardised approach to pressure ulcer prevention. CONCLUSION: Despite an abundance of literature exploring this subject, it is clear that current practice in pressure ulcer prevention is not embedded within best practice recommendations. Therefore, to address the potential patient safety implications, clinical practice could benefit from exploration and identification of practical methods for improving actual pressure ulcer preventive practice. PMID- 23924843 TI - Back to basics: biophysical methods in tissue viability research. PMID- 23924844 TI - Evidence-biased medicine and the availability of silver wound dressings: a topical issue. PMID- 23924845 TI - Assessing quality of life in patients with hard-to-heal ulcers using the EQ-5D questionnaire. AB - OBJECTIVE: To assess health-related quality of life (HRQoL) in an unselected patient population with hard-to-heal ulcers from baseline through healing and at follow-up 6 months after healing. METHOD: Fifty patients were recruited and the sex and age of the patient and the ulcer aetiology, duration, and size were recorded. The generic instrument EQ-5D was used for two purposes. The first was to investigate the feasibility of this instrument for assessing HRQoL in this patient group. The second was to see if the EQ-5D results would add information to the Swedish Registry of Ulcer Treatment (RUT), a national quality registry which includes variables for pain, disturbed sleep, and mobility. RESULTS: We found a significant difference in HRQoL between patients with an open ulcer and those with a healed ulcer (p=0.02), but no significant difference between patients with a just-healed ulcer and patients at follow-up six months after ulcer healing (p=0.08). Sex, age, and length of ulcer duration at inclusion did not influence HRQoL (p=0.55, p=0.4, and p=0.9, respectively). Ulcer size seemed to influence HRQoL, though not significantly (p=0.07). CONCLUSION: This study confirms that HRQoL was improved after ulcer healing. Pain, as one of the five constructs measured by the EQ-5D, was significantly associated with open ulcers. The results from the EQ-5D questionnaire were hard to interpret in terms of capturing HRQoL in this unselected patient population. Despite some limitations, we consider that the simplicity of EQ-5D could make it feasible to use in the clinical setting. However, the results from EQ-5D did not add consistent information to RUT; therefore, this questionnaire will not be included in the registry. PMID- 23924846 TI - Morphological effect of a scallop shell on a flapping-type tidal stream generator. AB - Inspired by nature, flapping-type tidal stream generators have been introduced in recent years. The improvement in their power generation ability is known to be a critical factor in the success of these generators. So far, corrugation and camber observed in flying insects and swimming animals are known to enhance the performance of a flapping-type propulsive system. In this study, we explore the effect of corrugation and camber in a system that mimics a scallop shell in terms of its ability to extract flow energy through a two-dimensional Navier-Stokes simulation. The simulations show that the size and the activity of the leading edge vortex are strongly affected by the morphological factors of the mimicked foils, the effects of which are then advantageous in terms of the power efficiency of the flapping-type tidal stream generator. Eventually, an optimal mimicked foil, as suggested based on the morphological effects, would be a good alternative type of foil with a typical section with regard to the hydrodynamic performance and structural properties of tidal stream generators. PMID- 23924847 TI - Controllable synthesis of silver and silver sulfide nanocrystals via selective cleavage of chemical bonds. AB - A one-step colloidal process has been adopted to prepare silver (Ag) and silver sulfide (Ag2S) nanocrystals, thus avoiding presynthesis of an organometallic precursor and the injection of a toxic phosphine agent. During the reaction, a layered intermediate compound is first formed, which then acts as a precursor, decomposing into the nanocrystals. The composition of the as-obtained products can be controlled by selective cleavage of S-C bonds or Ag-S bonds. Pure Ag2S nanocrystals can be obtained by directly heating silver acetate (Ag(OAc)) and n dodecanethiol (DDT) at 200 degrees C without any surfactant, and pure Ag nanocrystals can be synthesized successfully if the reaction temperature is reduced to 190 degrees C and the amount of DDT is decreased to 1 ml in the presence of a non-coordinating organic solvent (1-octadecene, ODE). Otherwise, the mixture of Ag and Ag2S is obtained by directly heating Ag(OAc) in DDT by increasing the reaction temperature or in a mixture of DDT and ODE at 200 degrees C. The formation mechanism has been discussed in detail in terms of selective S-C and Ag-S bond dissociation due to the nucleophilic attack of DDT and the lower bonding energy of Ag-S. Interestingly, some products can easily self-assemble into two- or three-dimensional (2D or 3D) highly ordered superlattice structures on a copper grid without any additional steps. The excess DDT plays a key role in the superlattice structure due to the bundling and interdigitation of the thiolate molecules adsorbed on the as-obtained nanocrystals. PMID- 23924848 TI - Many are called but few are chosen: under-utilization of unrelated donor transplantation. PMID- 23924849 TI - Impact of adiponectin and leptin on long-term adverse events in Japanese patients with acute myocardial infarction. Results from the Nagoya Acute Myocardial Infarction Study (NAMIS). AB - BACKGROUND: Low adiponectin levels and high leptin levels are associated with a high incidence of developing cardiovascular disease. However, the relationship between the levels of these adipokines and the development of adverse events after acute myocardial infarction (AMI) remains unclear. METHODS AND RESULTS: This study enrolled 724 Japanese subjects with AMI who underwent successful emergency percutaneous coronary intervention (PCI). Their serum adiponectin and leptin levels were measured 7 days after AMI onset. There were 63 adverse events during the 3-year follow-up. The levels of adiponectin and leptin and the leptin to adiponectin ratio, were significantly associated with adverse events [hazard ratio 2.08 (95% confidence interval (CI) 1.33-3.24), P=0.001; hazard ratio 0.62 (95% CI 0.43-0.90), P=0.012; hazard ratio 0.59 (95% CI 0.45-0.76), P<0.001, respectively]. The leptin to adiponectin ratio remained a significant independent predictor of adverse events during long-term follow-up in a multivariable analysis [adjusted hazard ratio 0.60 (95% CI 0.43-0.83), P=0.002]. CONCLUSIONS: Higher adiponectin and lower leptin levels are associated with a high incidence of adverse events in Japanese patients after AMI, and the leptin to adiponectin ratio independently predicts prognosis after AMI. PMID- 23924850 TI - A decline in glomerular filtration rate rather than renal arterial stenotic lesions, per se, predicts cardiovascular-renal events in type 2 diabetic patients. AB - BACKGROUND: In diabetic patients with renal artery arteriosclerosis (RAAS), the factors associated with a greater risk for cardiovascular-renal events (CVREs) remain unclear: the decline in estimated glomerular filtration rate (eGFR) caused by RAAS or the advance of arteriosclerosis that causes RAAS. Hence, the features to determine which best predicts the onset of CVREs in such patients were compared. METHODS AND RESULTS: The renal arteries of 162 type 2 diabetes patients were assessed by using magnetic resonance angiography (RAAS diagnosed as arteriosclerotic stenosis >=50%) and they were studied longitudinally over 7 years. The influence of the presence/absence of RAAS, a decline in eGFR, clinical factors, surrogate arteriosclerotic markers and ischemic markers on patient's CVREs were assessed. A Cox regression analysis showed the detection of RAAS to be an independent risk factor for CVREs (bilateral RAAS was an extremely strong risk factor for the development of CVREs within 1,000 days), as was the decline in eGFR in a logistic regression analysis; the latter being a more powerful risk factor for CVREs. A multiple regression analysis revealed angiopoietin-2, a marker of ischemia, to be a risk factor for the decline in eGFR. CONCLUSIONS: A decline in renal function but not the renal arterial stenotic lesion itself appears to be associated with an increased incidence of CVREs in type 2 diabetic patients with RAAS. PMID- 23924851 TI - Hydroxocobalamin association during cell culture results in pink therapeutic proteins. AB - Process control of protein therapeutic manufacturing is central to ensuring the product is both safe and efficacious for patients. In this work, we investigate the cause of pink color variability in development lots of monoclonal antibody (mAb) and Fc-fusion proteins. Results show pink-colored product generated during manufacturing is due to association of hydroxocobalamin (OH-Cbl), a form of vitamin B12. OH-Cbl is not part of the product manufacturing process; however we found cyanocobalamin (CN-Cbl) in cell culture media converts to OH-Cbl in the presence of light. OH-Cbl can be released from mAb and Fc-fusion proteins by conversion with potassium cyanide to CN-Cbl, which does not bind. By exploiting the differential binding of CN-Cbl and OH-Cbl, we developed a rapid and specific assay to accurately measure B12 levels in purified protein. Analysis of multiple products and lots using this technique gives insight into color variability during manufacturing. PMID- 23924852 TI - Plating after tibial lengthening: unilateral monoaxial external fixator and locking plate. AB - Several studies recently reported the usefulness of plating methods following limb lengthening with external fixators. This study describes modification at the time of plate insertion, selection of a locking plate, and the direction of plating. From April 2006 to July 2009, 12 consecutive patients, mean age 17.8 years, were enrolled in the study. The mean follow-up period was 36.5 months. All lengthening procedures were performed at the tibia. After proximal tibial osteotomy, a monoaxial external fixator was maintained on the lateral side of the tibia. At the end of distraction, a manually bent locking plate was inserted on the anteromedial side of the tibia, and the external fixator was removed. The mean final lengthening amount was 4.23 cm (range, 3.6-5.0 cm). The mean duration of the external fixator was 54.9 days (range, 47-67 days) and the mean external fixator index was 13.0 days/cm (range, 12.3-14.4 days/cm). The mean time to bony consolidation was 195.7 days (range, 150-264 days) and the mean healing index was 46.1 days/cm (range, 38.4-55 days). There were only minor complications in four patients. This case series showed that, especially with tibia lengthening, our method allows for successful early removal of the external fixator as compared with other methods (plating after lengthening), is associated with fewer complications, and is an effective alternative. LEVEL OF EVIDENCE: Therapeutic Level IV. PMID- 23924853 TI - Deregulation of HER2 downstream signaling in breast cancer cells by a cocktail of anti-HER2 scFvs. AB - Human epidermal growth factor receptor 2 (HER2) is overexpressed in 30% of patients with breast cancer. HER2 targeting is the mainstay of targeted therapy for the treatment of invasive breast cancers. Due to biological and therapeutic advantages, single chain fragment variable (scFv) antibodies have emerged as promising alternative therapeutics. In this study, we assessed the capability of three scFvs against HER2 extracellular domains (II, III, IV) in deregulation of some key signaling mediators that have important roles in growth, survival, angiogenesis, and cell migration of breast tumor cells. Downregulation of activated Akt (p-Akt), increase of p27 protein levels, and downregulation of HER1, HER2, HER3 and epidermal growth factor (EGF), CXCR3, CXCL10, and MMP2 were observed following treatment of breast cancer cells (SKBR3 cell line) with the scFvs and their combination. Our results suggest that the combination of the three scFvs could be considered as an effective cocktail on HER2 tumorgenic signaling pathways that leads to tumor growth suppression and death. PMID- 23924854 TI - Upregulation of glycoprotein nonmetastatic B by colony-stimulating factor-1 and epithelial cell adhesion molecule in hepatocellular carcinoma cells. AB - Considerable effort has been made in elucidating the appropriate biomarkers and the mechanism and functional significance of these biomarkers in hepatocellular carcinoma (HCC). Glycoprotein nonmetastatic B (GPNMB) overexpression occurs in cutaneous melanomas and breast cancer, and it is an attractive candidate for cancer therapy. However, little is known about the expression and regulation of GPNMB in HCC. In this study, we investigated the expression of GPNMB in HCC histochemically and tested the regulation effects of the epithelial cell adhesion molecule (EpCAM) and colony-stimulating factor (CSF-1) on the expression of GPNMB in HCC cells. Our results demonstrated that GPNMB levels were significantly enhanced in HCC compared with adjacent normal liver tissues. In HCC cells, GPNMB expression was regulated by EpCAM and CSF-1 partly through their common downstream product c-myc. Taken together, these results suggest that GPNMB, the expression of which was regulated in HCC cells by the highly coordinated function of various proteins, may be a potential target for HCC therapy. PMID- 23924855 TI - Simvastatin inhibits proliferation and induces apoptosis in human lung cancer cells. AB - Lung cancer is the one of the most frequent causes of malignant tumors. In recent years, it has been documented that statins have anticancer and cancer chemopreventive properties. However, the mechanism of simvastatin on lung cancer is still unclear. In this study, the human lung cancer cell line A549 cells were incubated with simvastatin. Simvastatin inhibited the survival of A549 cells in a dose-dependent manner, decreased Bcl-2 protein expression, and increased Bax protein expression time and dose dependently. In addition, simvastatin blocked cells in the G1 phase of the cell cycle, downregulated cyclin D1 and CDKs protein expression, mediated the mitochondria-dependent caspase cascade by increasing caspase-3, -8, and -9 mRNA and protein expression, downregulated Xiap levels to induce cells apoptosis. Importantly, simvastatin suppressed decreased MMP-9 protein expression and suppressed NF-kappaB activation in A549 cells. Taken together, these results showed that the anticancer effect of simvastatin in lung cancer A549 cells via the inhibiting cell proliferation, influencing the cell cycle, downregulating cyclin D1 and CDKs expression, inducing apoptosis, and decreasing MMP-9 levels, possibly by inhibiting the activation of NF-kappaB. Statins contribute to lung cancer therapy and may be an ideal anticancer and cancer chemopreventive agent for lung cancer. PMID- 23924856 TI - Triptolide induces apoptosis and inhibits the growth and angiogenesis of human pancreatic cancer cells by downregulating COX-2 and VEGF. AB - Triptolide (TPL) inhibits the growth and proliferation of a wide range of human cancer cells, but the underlying mechanism is largely unknown. Here, we report that TPL induces apoptosis and inhibits proliferation of PANC-1 pancreatic cancer cells by downregulating cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF). Cell viability and apoptosis were measured by MTT assay and flow cytometry. Real-time PCR and Western blot were used to examine the expression of COX-2 and VEGF. The Matrigel angiogenesis and Transwell migration were employed to assess tube formation and cell migration. Pancreatic cancer mouse xenografts were established to investigate the in vivo antitumor effects of TPL. TUNEL staining and immunohistochemistry were used to detect the apoptosis rate and protein expression in tumor tissues. TPL inhibited the proliferation of pancreatic cancer cells in a time and concentration-dependent manner and decreased the expression of COX-2 and VEGF in vitro. Furthermore, medium from TPL treated PANC-1 cells inhibited the proliferation, migration, and tube formation of HUVECs. TPL significantly reduced the growth of pancreatic cancer mouse xenografts, accompanied by an induction of apoptosis, inhibition of angiogenesis, and reduction of COX-2 and VEGF. Our data indicate that suppressing the expression of COX-2 and VEGF may be one of the molecular mechanisms by which TPL induces apoptosis and inhibits the growth and angiogenesis of human pancreatic cancer cells. PMID- 23924857 TI - Oldhamianoside II, a new triterpenoid saponin, prevents tumor growth via inducing cell apoptosis and inhibiting angiogenesis. AB - Oldhamianoside II is a new triterpenoid saponin that was isolated from the roots of Gypsophila oldhamiana. The present study aims to investigate the potential inhibitory activity of oldhamianoside II on tumor growth using an S180 tumor implantation mouse model. Oldhamianoside II at doses of 5.0 and 10.0 mg/kg was given with intraperitoneal injection for 10 days following subcutaneous inoculation of S180 tumor cells in anterior flank of mice. The tumor growth, the cell apoptosis, the microvessel density (MVD) in S180 tumors, the tumor cell viability, the tubular formation in vitro, and migration of tumor cells were examined. The expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and cyclooxygenase-2 (COX-2) was determined to analyze the associated mechanisms. The results showed that oldhamianoside II potently inhibited tumor cell viability in vitro. In addition, oldhamianoside II delayed tumor growth in anterior flank, induced S180 cell apoptosis, and reduced the MVD. Oldhamianoside II was also demonstrated to decrease the number of tubular structure and vessel formation in HUVEC cultures and chick embryo chorioallantoic membrane (CAM) model, respectively. Further study indicated that oldhamianoside II reduced the expression of VEGF, bFGF, and COX-2 in tumor sections. Moreover, oldhamianoside II inhibited the activity of migration and penetration to Matrigel of SGC7901 tumor cells in scratch wound and transwell chamber. In conclusion, our work defines oldhamianoside II, a new triterpenoid saponin, as a novel compound that can effectively inhibit S180 tumor growth, induce tumor cell apoptosis, prevent tumor angiogenesis, and inhibit cancer cell migration, suggesting that oldhamianoside II is a potential drug candidate for the treatment of cancer and for the prevention of metastasis. PMID- 23924858 TI - Knockdown of Pokemon protein expression inhibits hepatocellular carcinoma cell proliferation by suppression of AKT activity. AB - Overexpression of Pokemon, which is an erythroid myeloid ontogenic factor protein, occurs in different cancers, including hepatocellular carcinoma (HCC). Pokemon is also reported to have an oncogenic activity in various human cancers. This study investigated the effect of Pokemon knockdown on the regulation of HCC growth. POK shRNA suppressed the expression of Pokemon protein in HepG2 cells compared to the negative control vector-transfected HCC cells. Pokemon knockdown also reduced HCC cell viability and enhanced cisplatin-induced apoptosis in HCC cells. AKT activation and the expression of various cell cycle-related genes were inhibited following Pokemon knockdown. These data demonstrate that Pokemon may play a role in HCC progression, suggesting that inhibition of Pokemon expression using Pokemon shRNA should be further evaluated as a novel target for the control of HCC. PMID- 23924860 TI - USP Chapter 797: Practical Solutions for Microbiology, Sterility and Pyrogen Testing. PMID- 23924859 TI - The Directive 2010/63/EU on animal experimentation may skew the conclusions of pharmacological and behavioural studies. AB - All laboratory animals shall be provided some form of environmental enrichment (EE) in the nearest future (Directive 2010/63/EU). Displacing standard housing with EE entails the possibility that data obtained under traditional housing may be reconsidered. Specifically, while EE often contrasts the abnormalities of consolidated disease models, it also indirectly demonstrates that their validity depends on housing conditions. We mimicked a situation in which the consequences of a novel pharmacological compound were addressed before and after the adoption of the Directive. We sub-chronically exposed standard- or EE-reared adolescent CD1 mice (postnatal days 23-33) to the synthetic compound JWH-018, and evaluated its short- and long-term potential cannabinoid properties on: weight gain, locomotion, analgesia, motor coordination, body temperature, brain metabolism ((1)H MRI/MRS), anxiety- and depressive-related behaviours. While several parameters are modulated by JWH-018 independently of housing, other effects are environmentally mediated. The transition from standard housing to EE shall be carefully monitored. PMID- 23924861 TI - Using ACDs in the Practice of Pharmacy. PMID- 23924862 TI - USP Chapter 797 and Preparing for a JCAHO Survey. PMID- 23924863 TI - Where does the isolator fit in? PMID- 23924864 TI - The US FDA List of Drugs NOT to Be Used in Compounded Medications for Humans (the "Negative List"). PMID- 23924865 TI - Quality-Control Analytical Methods: Microbial-Testing Aspects of USP Chapter 797 for Compounded Sterile Preparations. AB - The standards set forth by the United States Pharmacopeia (USP) Chapter 797 have now been in effect since January 1 or 2004. As the first practice standards of sterile pharmacy compounding in US history, they have "attracted both respect and criticism" because they have also been cited as a practice expectation by the Joint Commission on Accreditation of Healthcare Organizations. USP 797 expands the scope of facilities governed by the regulatinos and defines the practices covered, emphasizing the importance of environmental quality and control, verification of accuracy and sterility, training and evaluation, quality control after preparations leave the pharmacy, patient monitoring and adverse events reporting. The purpose of this article is to help the reader understand the criteria set forth by USP Chapter 797 regarding finished-product testing, including criteria for the microbial-testing aspects of sterility testing (USP Chapter 71) and endotoxin (pyrogen) testing (USP Chapter 85). PMID- 23924866 TI - Barrier Isolators, Isolators and Glove Boxes-What's the Difference. PMID- 23924867 TI - Basics of compounding with acids. AB - Compounding with acids has presented some confusion in recent years due to a lack of clarity in procedures and the labeling to be used. The difficulty centers around the availability of concentrated acids on a weeght/weight (w/w) basis and the compounding use of dilute acids on a weight/volume (w/v) basis. This article will clarify the confusing areas and attempt to provide a clear procedure for implementation in compounding pharmacies. PMID- 23924868 TI - Chemical stability of metoclopramide hydrochloride injection diluted with 0.9% sodium chloride injection in polypropylene syringes at room temperature. AB - The stability of metoclopramide hydrochloride (0.5 mg/mL) in 0.9% sodium chloride injection in polypropylene syringes was studied at 25 deg C, using a stability indicating high-performance liquid chromatographic assay method. The concentrations of the drug were directly related to peak heights, and the percent relative standard deviation based on five injections was 1.4. The drug decomposed when treated with sodium hydroxide or hydrochloric acid, and the products of decomposition did not interfere wiht the assay procedure. the injection did not lose any potency after 21 days of storage at 25 deg C, and the pH value of 5.0 did not change. The physcial appearance of the injection remained clear throughout the study period. PMID- 23924869 TI - Physical Characteristics of Selected Over-the-Counter Medications. AB - The physical characteristics of over-the-counter medications may be useful to the compounding pharmacist in preparing dosage forms by serving as physical limits for the basis of choice of vehicles and supporting ingredients for formulations. In this study, three bottles of 16 different products were tested for their specific gravity, pH, suface tension and rheological properties. All products tested were heavier than water, with the exception of the lotions. The pH value varied greatly among the products, and the lotions were neutral to slightly acidic; the other preparations were acidic with the exception of Dulcolax and Maalox, which showed a basic pH. Aqueous solutions had a surface tension very close in value to water; all other products that were tested exhibited lower surface tension than water. The viscosity of the products varied greatly; lotions and suspensions demonstrated shear-thinning properties of either plastic or pseudoplastic type; and all solutions had low viscosity similar to that of water, except for Children's Dimetapp and Vicks Nyquil, which showed a somewhat higher viscosity than water. PMID- 23924870 TI - Stability of an extemporaneously compounded propylthiouracil suspension. AB - The stability of the antithyroid drug propylthiouracil was studied in an extemporaneously formulated suspension for 91 days. A simple, rapid, reproducible and stability-indicating reverse-phase high-performance liquid chromatographic assay method was developed for detecting propylthiouracil. The mobile phase consisted of a 70:30 (v/v) combination of water and methanol at a flow rate of 0.5 mL/minute. The detector wavelength was set at 276 nm. Excellent linearity (R squared value 0.9929) was obtained over the working solution range (1 to 100 micrograms/mL). The intraday and interday precisions of the assay method were o.11% to 1.28% and 1.65%, respectively. The drug was subjected to forced degradation under acidic and basic conditions, and the method proved to be stabililty-indicating for propylthiouracil. A suspension was formulated using commercially available 50-mg propylthiouracil tablets. The formulation consisted of a combination of 0.75% carboxymethylcellulose sodium and 0.5% Veegum as the suspending agents; 25% (w/v) simple syrup, 25% (w/v)sorbitol solution and 0.15% saccharin as the sweeteners; paraben concentrate as the preservative and a mixture of wild cherry, raspberry and tangerine as the flavor. The suspension was stored at 4, 30, 50, 60 and 70 deg C and analyzed on a weekly basis for 91 days. The samples were assayed in triplicate by the high-performance liquid chromatographic assay method outlined. The apparent zero-order rate constant for degradation of propylthiouracil at each of the temperatures was obtained and used to obtain the Arrhenius plot. From the regression line of the Arrhenius plot, the rate constant for degradation (t0.9) at room temperature (25 deg C) and under refrigeration (4 deg C) was found to be 0.078% day-1 and 0.04% day-1. The shelf life of the suspension was calculated to be 127 days at room temperature and 248 days under refrigeration. PMID- 23924871 TI - Volumetric visualization of the near- and far-field wake in flapping wings. AB - The flapping wings of flying animals create complex vortex wake structure; understanding its spatial and temporal distribution is fundamental to animal flight theory. In this study, we applied the volumetric 3-component velocimetry to capture both the near- and far-field flow generated by a pair of mechanical flapping wings. For the first time, the complete three-dimensional wake structure and its evolution throughout a wing stroke were quantified and presented experimentally. The general vortex wake structure maintains a quite consistent form: vortex rings in the near field and two shear layers in the far field. Vortex rings shed periodically from the wings and are linked to each other in successive strokes. In the far field, the shed vortex rings evolve into two parallel shear layers with dominant vorticity convected from tip and root vortices. The shear layers are nearly stationary in space compared to the periodic vortex rings shed in the near field. In addition, downwash passes through the centers of the vortex rings and extends downward between the two shear layers. PMID- 23924872 TI - Diagnosis of true uncontrolled hypertension using both home and ambulatory blood pressure monitoring. AB - The definitive diagnosis of hypertension based on home blood pressure (BP) monitoring (HBPM) results may be practical, particularly in the primary care setting; however, some hypertensive patients are overlooked by HBPM alone. It is unclear which HBP cutoff value should set for patients who require ambulatory BP monitoring (ABPM). In the present study, home systolic BP (SBP) data (6 BP measurements taken for 3 days in the morning and evening) and 24-h ambulatory SBP data from 462 hypertensive subjects were obtained from a real-world clinical study. Using HBPM as an initial step for the definitive diagnosis of hypertension, 381 of 462 total subjects had a home SBP value of ?135 mm Hg. Of these 381 subjects, 90.3% had ambulatory SBP values of ?130 mm Hg. Among the other 81 subjects with home SBP values of <135 mm Hg, 60.5% had ambulatory SBP values of ?130 mm Hg ('true uncontrolled hypertension'). These percentages differed significantly (P<0.0001). The cutoff home SBP value of 135 mm Hg could discriminate between subjects who did not require ABPM (home SBP value of ?135 mm Hg) and those who did (home SBP value of <135 mm Hg) for the diagnosis of true uncontrolled hypertension. PMID- 23924873 TI - A novel mutation, IVS13+5G>A, in Ellis-van Creveld syndrome associated with haemophagocytic lymphohistiocytosis. PMID- 23924874 TI - Association between spring season of birth and Crohn's disease. AB - BACKGROUND & AIMS: As for many complex diseases, the incidence of inflammatory bowel disease (IBD) is higher among individuals born during certain seasons. This difference could arise from seasonal variations in many factors, including exposure to sunlight, antibiotics, or infectious agents. We investigated the relationship between season of birth, early childhood exposure to antibiotics, and incidence of IBD. METHODS: We performed a nested case-control analysis using data from the University of Manitoba inflammatory bowel disease epidemiology database. We compared seasons of birth among 11,145 individuals with IBD (cases) and 108,633 controls using conditional logistic regression models. We collected data on use of antibiotics in the first year of life for cases and controls from the Manitoba Drug Program Information Network-a comprehensive database of all prescriptions given to residents of Manitoba since 1995. RESULTS: Approximately 27.0% of cases were born from April through June, compared with 25.6% of controls (odds ratio, 1.07; 95% confidence interval, 1.02-1.12; P = .002). Comparisons made by sex (male vs female) and type of IBD (ulcerative colitis vs Crohn's disease) showed statistical significance only for men with Crohn's disease (odds ratio, 1.13; 95% confidence interval, 1.03-1.25; P = .009). At ages 6 months and older, cases and controls born from April through June received a significantly greater number of prescriptions for antibiotics than cases and controls born in other months. CONCLUSIONS: Men with Crohn's disease are more likely to have been born in the months of April through June. PMID- 23924875 TI - Advanced imaging in Barrett's esophagus: are we ready to relinquish the random? PMID- 23924876 TI - Deep remission in Crohn's disease: is it the end of the placebo effect? PMID- 23924877 TI - Herbs and liver injury: a clinical perspective. AB - Despite a perception that herbal and dietary supplements are safe, devastating liver injury has been reported to result from their use. The difficulty in characterizing liver injury attributable to herbal and dietary supplements stems from the permissive regulatory environment, the complexity of marketed products, and underreporting by the patients who use them. Despite these limitations, researchers, clinicians, and regulators have increasing awareness of the need for study in this area. PMID- 23924878 TI - Cervical pessaries for prevention of preterm birth in women with a multiple pregnancy (ProTWIN): a multicentre, open-label randomised controlled trial. AB - BACKGROUND: In women with a multiple pregnancy, spontaneous preterm delivery is the leading cause of perinatal morbidity and mortality. Interventions to reduce preterm birth in these women have not been successful. We assessed whether a cervical pessary could effectively prevent poor perinatal outcomes. METHODS: We undertook a multicentre, open-label randomised controlled trial in 40 hospitals in the Netherlands. We randomly assigned women with a multiple pregnancy between 12 and 20 weeks' gestation (1:1) to pessary or control groups, using a web-based application with a computer-generated list with random block sizes of two to four, stratified by hospital. Participants and investigators were aware of group allocation. For women in the pessary group, a midwife or obstetrician inserted a cervical pessary between 16 and 20 weeks' gestation. Women in the control group did not receive the pessary, but otherwise received similar obstetrical care to those in the pessary group. The primary outcome was a composite of poor perinatal outcome: stillbirth, periventricular leucomalacia, severe respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular haemorrhage, necrotising enterocolitis, proven sepsis, and neonatal death. Analyses were by modified intention to treat. This trial is registered in the Dutch trial registry, number NTR1858. FINDINGS: Between Sept 21, 2009, and March 9, 2012, 813 women underwent randomisation, of whom 808 were analysed (401 in the pessary group; 407 in the control group). At least one child of 53 women (13%) in the pessary group had poor perinatal outcome, compared with 55 (14%) in the control group (relative risk 0.98, 95% CI 0.69-1.39). INTERPRETATION: In unselected women with a multiple pregnancy, prophylactic use of a cervical pessary does not reduce poor perinatal outcome. FUNDING: The Netherlands Organisation for Health Research and Development. PMID- 23924879 TI - Preterm birth in multiple pregnancy: a glimmer of hope? PMID- 23924880 TI - Resistance genes, phage types and pulsed field gel electrophoresis pulsotypes in Salmonella enterica strains from laying hen farms in southern Italy. AB - Twenty-four Salmonella enterica isolates (13 serovar Enteritidis and 11 Typhimurium) isolated from 5,600 samples from intensive laying hen farms in Italy in 1998-2007 were characterized for antimicrobial resistance genes, pulsotype and phage type. Most of S. Typhimurium strains were pulsotype STYMXB.0147 (81.8%), phage type DT143 and resistant to sulfamethoxazole encoded by sul2. Two multidrug resistant (MDR) strains were identified. One strain, STYMXB.0061, was resistant to ampicillin (A), chloramphenicol (C), streptomycin (S), sulfamethoxazole (Su) and tetracycline (T) encoded by the Salmonella Genomic Island SGI1. The second MDR strain, STYMXB.0110, was resistant to SSuT encoded by sul1 and sul2, aadA1 and tet(C)-flanked by an IS26 element, respectively. The tet(C) gene has been reported to confer low levels of resistance and it has very rarely been detected in S. Typhimurium from poultry. In the current study, the MIC value (32 ug/mL) was consistent with the breakpoint (>=16 ug/mL) reported for Enterobacteriaceae. Most of the S. Enteritidis strains were resistant to Su (encoded by sul2). One MDR strain (ANxSSuT) was identified. With the exception of nalidixic acid (Nx), the resistances were respectively encoded by bla(TEM), strAB, sul2 and tet(A) harbored by an IncN conjugative plasmid. All isolates were pulsotype SENTXB.0001 with PT14b being the most prevalent identified phage type (57.1%). In Europe, SENTXB.0001 is the predominant PFGE profile from clinical cases and the identification of PT14b has steadily been on the increase since 2001. The findings presented in this study highlight the potential spread of S. Enteritidis phage types PT14b and S. Typhimurium DT143 in a field of particular relevance for zoonoses. Additional, the presence of resistance genes and genetic elements (conjugative plasmid and IS element) underlines the need to assess routinely studies in field, such as poultry farms, relevant fot the public health and suitable for the storage and diffusion of antimicrobial resistance. PMID- 23924881 TI - Resistance and inactivation kinetics of bacterial strains isolated from the non chlorinated and chlorinated effluents of a WWTP. AB - The microbiological quality of water from a wastewater treatment plant that uses sodium hypochlorite as a disinfectant was assessed. Mesophilic aerobic bacteria were not removed efficiently. This fact allowed for the isolation of several bacterial strains from the effluents. Molecular identification indicated that the strains were related to Aeromonas hydrophila, Escherichia coli (three strains), Enterobacter cloacae, Kluyvera cryocrescens (three strains), Kluyvera intermedia, Citrobacter freundii (two strains), Bacillus sp. and Enterobacter sp. The first five strains, which were isolated from the non-chlorinated effluent, were used to test resistance to chlorine disinfection using three sets of variables: disinfectant concentration (8, 20 and 30 mg.L(-1)), contact time (0, 15 and 30 min) and water temperature (20, 25 and 30 degrees C). The results demonstrated that the strains have independent responses to experimental conditions and that the most efficient treatment was an 8 mg.L(-1) dose of disinfectant at a temperature of 20 degrees C for 30 min. The other eight strains, which were isolated from the chlorinated effluent, were used to analyze inactivation kinetics using the disinfectant at a dose of 15 mg.L(-1) with various retention times (0, 10, 20, 30, 60 and 90 min). The results indicated that during the inactivation process, there was no relationship between removal percentage and retention time and that the strains have no common response to the treatments. PMID- 23924884 TI - Supporting Pacific Island countries to strengthen their resistance to tobacco industry interference in tobacco control: a case study of Papua New Guinea and Solomon Islands. AB - Tobacco use is the biggest single preventable cause of non-communicable diseases (NCDs) in the Western Pacific region. Currently, 14 Pacific Island countries have ratified the WHO Framework Convention on Tobacco Control (FCTC) and, in having done so, are committed to implementing tobacco control measures aligned with the FCTC. Progressing strong and effective tobacco control legislation is essential to achieving long term gains in public health in small island countries. However, survey evidence suggests that pervasive tobacco industry interference serves to undermine tobacco control and public policy in several Pacific countries. An initiative was developed to provide dedicated, in-country technical support for developing legislation and policy to support implementation of Article 5.3 of the FCTC in the Solomon Islands and Papua New Guinea. This paper examines the factors that have assisted the two Pacific countries to make progress in implementing Article 5.3 and what this might mean for supporting progress in other Pacific settings. A document analysis was undertaken to identify the process and outcome of the intervention. Two significant outputs from the project including having identified and documented specific examples of TII and the development of draft legislation for Article 5.3 and other key resources for public servants both within and outside the health sector. Key determinants of progress included a motivated and engaged Ministry of Health, active civil society group or champion and access to media to prepare tobacco industry related material to stimulate public and policy sector debate. PMID- 23924883 TI - Relationship between retinal vascular caliber and coronary artery disease in patients with non-alcoholic fatty liver disease (NAFLD). AB - OBJECTIVE: To evaluate the relationship between retinal vascular caliber and cardiovascular disease in non-alcoholic fatty liver disease (NAFLD) patients without diabetes and hypertension. METHODS: Intention to treat study of individuals who underwent cardiac computed tomography (CT) during a two year period. Coronary artery disease (CAD) was defined as stenosis of >50% in at least one major coronary artery. Liver and spleen density were measured by abdominal (CT); intima-media thickness (IMT) by Doppler ultrasound; retinal artery and vein diameter by colored-retinal angiography; and metabolic syndrome by ATP III guidelines. Serum biomarkers of insulin resistance, inflammation, and oxidant antioxidant status were assessed. RESULTS: Compared with 22 gender and age matched controls, the 29 NAFLD patients showed higher prevalence of coronary plaques (70% vs. 30%, p < 0.001), higher prevalence of coronary stenosis (30% vs. 15%, p < 0.001), lower retinal arteriole-to-venule ratio (AVR) (0.66 +/- 0.06 vs. 0.71 +/- 0.02, p < 0.01), higher IMT (0.98 +/- 0.3 vs. 0.83 +/- 0.1, p < 0.04), higher carotid plaques (60% vs. 40%, p < 0.001), higher homeostasis model assessment of insulin resistance (HOMA) (4.0 +/- 3.4 vs. 2.0 +/- 1.0, p < 0.005), and higher triglyceride levels (200 +/- 80 vs. 150 +/- 60, p < 0.005) than controls. Multivariate analysis showed fatty liver (OR 2.5; p < 0.01), IMT (OR 2.3 p < 0.001), and retinal AVR ratio (OR 1.5, p < 0.01) to be strongly associated with CAD independent of metabolic syndrome (OR 1.2, p < 0.05). CONCLUSIONS: Patients with smaller retinal AVR (<0.7) are likely to be at increased risk for CAD and carotid atherosclerosis in patients with NAFLD even without hypertension or diabetes. PMID- 23924882 TI - The dynamics of autism spectrum disorders: how neurotoxic compounds and neurotransmitters interact. AB - In recent years concern has risen about the increasing prevalence of Autism Spectrum Disorders (ASD). Accumulating evidence shows that exposure to neurotoxic compounds is related to ASD. Neurotransmitters might play a key role, as research has indicated a connection between neurotoxic compounds, neurotransmitters and ASD. In the current review a literature overview with respect to neurotoxic exposure and the effects on neurotransmitter systems is presented. The aim was to identify mechanisms and related factors which together might result in ASD. The literature reported in the current review supports the hypothesis that exposure to neurotoxic compounds can lead to alterations in the GABAergic, glutamatergic, serotonergic and dopaminergic system which have been related to ASD in previous work. However, in several studies findings were reported that are not supportive of this hypothesis. Other factors also might be related, possibly altering the mechanisms at work, such as time and length of exposure as well as dose of the compound. Future research should focus on identifying the pathway through which these factors interact with exposure to neurotoxic compounds making use of human studies. PMID- 23924885 TI - Focusing resource allocation-wellbeing as a tool for prioritizing interventions for communities at risk. AB - OBJECTIVE: This study examined whether a wellbeing approach to resilience and adaptation would provide practical insights for prioritizing support to communities experiencing environmental and socio-economic stressors. METHODS: A cross-sectional survey, based on a purposive sample of 2,196 stakeholders (landholders, hobby farmers, town resident and change agents) from three irrigation-dependent communities in Australia's Murray-Darling Basin. Respondents' adaptive capacity and wellbeing (individual and collective adaptive capacity, subjective wellbeing, social support, community connectivity, community leadership, in the context of known life stressors) were examined using chi square, comparison of mean scores, hierarchical regression and factor-cluster analysis. RESULTS: Statistically significant correlations (p < 0.05) were observed between individual (0.331) and collective (0.318) adaptive capacity and wellbeing. Taking into account respondents' self-assessed health and socio economic circumstances, perceptions of individual (15%) and collective adaptive capacity (10%) as well as community connectivity (13%) were associated with wellbeing (R2 = 0.36; F (9, 2099) = 132.9; p < 0.001). Cluster analysis found that 11% of respondents were particularly vulnerable, reporting below average scores on all indicators, with 56% of these reporting below threshold scores on subjective wellbeing. CONCLUSIONS: Addressing the capacity of individuals to work with others and to adapt to change, serve as important strategies in maintaining wellbeing in communities under stress. The human impacts of exogenous stressors appear to manifest themselves in poorer health outcomes; addressing primary stressors may in turn aid wellbeing. Longitudinal studies are indicated to verify these findings. Wellbeing may serve as a useful and parsimonious proxy measure for resilience and adaptive capacity. PMID- 23924886 TI - Aetiologies of central nervous system infections in adults in Kathmandu, Nepal: a prospective hospital-based study. AB - We conducted a prospective hospital based study from February 2009-April 2011 to identify the possible pathogens of central nervous system (CNS) infections in adults admitted to a tertiary referral hospital (Patan Hospital) in Kathmandu, Nepal. The pathogens of CNS infections were confirmed in cerebrospinal fluid (CSF) using molecular diagnostics, culture (bacteria) and serology. 87 patients were recruited for the study and the etiological diagnosis was established in 38% (n = 33). The bacterial pathogens identified were Neisseria meningitidis (n = 6); Streptococcus pneumoniae (n = 5) and Staphylococcus aureus (n = 2) in 13/87(14%). Enteroviruses were found in 12/87 (13%); Herpes Simplex virus (HSV) in 2/87(2%). IgM against Japanese encephalitis virus (JEV) was detected in the CSF of 11/73 (15%) tested samples. This is the first prospective molecular and serology based CSF analysis in adults with CNS infections in Kathmandu, Nepal. JEV and enteroviruses were the most commonly detected pathogens in this setting. PMID- 23924888 TI - Six-year follow-up of catheter ablation in paroxysmal atrial fibrillation. AB - BACKGROUND: Although pulmonary vein (PV) antrum isolation is an established therapy for drug-resistant paroxysmal atrial fibrillation (PAF), long-term (>5 years) follow-up data are limited. This study investigated long-term clinical outcome of catheter ablation. METHODS AND RESULTS: From September 2003 to August 2006, 161 patients (mean age, 60+/-9 years; 119 male) with symptomatic drug refractory PAF who underwent extensive encircling PV isolation (EEPVI) with a double Lasso technique were included. Right-sided and left-sided circular lesions encircling the ipsilateral PVs were created. The procedure endpoint was electrical isolation of the PV antrum. Patients with recurrent atrial tachyarrhythmia (ATa) had their previous lesions assessed and consolidated. Trigger ablation was added if necessary. EEPVI was successfully performed at the initial procedure. During a median follow-up of 6.4 years (25th-75th percentile, 5.8-7.1 years), 86 patients (53.4%) had recurrent ATa. Among 78, 15 and 4 patients undergoing 2nd, 3rd and 4th procedures, PV reconnections were observed in 68, 10 and 2, respectively. During a median follow-up of 6.0 years (25th-75th percentile, 5.2-6.9 years) after a mean of 1.6+/-0.7 procedures per patient, 144 patients (89.4%) were free from ATa. No progression toward persistent AF was observed in any patients. CONCLUSIONS: The vast majority of drug-resistant PAF could be controlled by EEPVI without an additional atrial substrate modification. No progression toward persistent AF was observed during a median follow-up of 6 years. PMID- 23924887 TI - Chest-compression-only bystander cardiopulmonary resuscitation in the 30:2 compression-to-ventilation ratio era. Nationwide observational study. AB - BACKGROUND: The compression-to-ventilation ratio for basic cardiopulmonary resuscitation (CPR) was changed from 15:2 to 30:2, but there are few human studies comparing chest-compression-only CPR with standard CPR. METHODS AND RESULTS: From the All-Japan Utstein Registry in the 30:2 CPR era, 173,565 adult cardiac arrests witnessed by bystanders were included. On arrival at the scene, emergency medical services responders assessed the status of dispatcher-assisted CPR instruction and bystander CPR technique (chest compression with or without rescue breathing). The primary endpoint was favorable neurological outcome 30 days after cardiac arrest. The prevalence of dispatcher-assisted CPR instruction increased year by year, contributing to an overall increase of chest-compression only bystander CPR from 20.6% to 35.0%. Among 78,150 patients receiving bystander CPR, favorable neurological outcome did not differ between dispatcher-assisted and -unassisted CPR (adjusted odds ratio [OR], 1.00; 95% confidence interval [CI]: 0.94-1.08). Chest-compression-only CPR resulted in better favorable neurological outcome than standard CPR in the whole cohort (adjusted OR, 1.09; 95% CI: 1.00-1.18) and in the subgroup with cardiac etiology (adjusted OR, 1.12; 95% CI: 1.02-1.22). The addition of rescue breathing provided no neurological benefit in the non-cardiac etiology subgroup. CONCLUSIONS: In the 30:2 CPR era, dispatcher-assisted CPR instruction contributed to an increase of chest compression-only bystander CPR, supporting the use of chest-compression-only CPR for bystander-witnessed out-of-hospital cardiac arrest in all adults. PMID- 23924889 TI - Strain rate dispersion index can predict changes in left ventricular volume and adverse cardiac events following cardiac resynchronization therapy. AB - BACKGROUND: We previously reported that the strain rate dispersion index (SRDI), an index of left ventricular (LV) contractility loss because of mechanical dyssynchrony, better predicted the acute response to cardiac resynchronization therapy (CRT) than time-delay indices. However, it remains unclear whether the SRDI can predict the chronic response. Additionally, the SRDI needs to be simplified for use in clinical practice. METHODS AND RESULTS: Echocardiography was performed in 40 heart failure patients who underwent CRT. The SRDI, the average of segmental peak systolic strain rates minus global peak systolic strain rate, was calculated, together with strain-derived time-delay indices (St-SD) in the longitudinal, circumferential and radial directions using a speckle-tracking method. As simplified indices, the longitudinal parameters were calculated from the apical 4-chamber view in addition to 3 apical views. LV end-systolic volume (ESV) significantly decreased 6 months after CRT. Although circumferential St-SD and all SRDIs correlated with the changes in ESV (DeltaESV), multivariate analysis revealed that the circumferential SRDI was the single independent determinant of DeltaESV. During the 20+/-14 months after CRT, cardiac events occurred in 14 patients. Kaplan-Meier analyses revealed that all SRDIs were significant predictors of cardiac events whereas none of St-SDs was. CONCLUSIONS: The SRDI predicted the reduction in both LV volume and cardiac events after CRT better than time-delay indices. Additionally, a simplified SRDI could be as good a predictor of CRT response as the original. PMID- 23924890 TI - An elliptical trainer may render the Wingate all-out test more anaerobic. AB - The purpose of this study was to evaluate the contribution of the 3 main energy pathways during a 30-second elliptical all-out test (EAT) compared with the Wingate all-out test (WAT). Participants were 12 male team sport players (age, 20.3 +/- 1.8 years; body mass, 74.8 +/- 12.4 kg; height, 176.0 +/- 9.10 cm; body fat, 12.1 +/- 1.0%). Net energy outputs from the oxidative, phospholytic, and glycolytic energy systems were calculated from oxygen uptake data recorded during 30-second test, the fast component of postexercise oxygen uptake kinetics, and peak blood lactate concentration, respectively. In addition, mechanical power indices were calculated. The main results showed that compared with WAT, EAT was characterized by significantly lower absolute and relative contributions of the oxidative system (16.9 +/- 2.5 J vs. 19.8 +/- 4.9 J; p <= 0.05 and 11.2 +/- 1.5% vs. 15.7 +/- 3.28%; p <= 0.001). In addition, significantly greater absolute and relative contributions of the phospholytic system (66.1 +/- 15.8 J vs. 50.7 +/- 15.9 J; p <= 0.01 and 43.8 +/- 6.62% vs. 39.1 +/- 6.87%; p <= 0.05) and a significantly greater absolute contribution of the glycolytic system (68.6 +/- 18.4 J vs. 57.4 +/- 13.7 J; p <= 0.01) were observed in EAT compared with WAT. Finally, all power indices, except the fatigue index, were significantly greater in EAT than WAT (p <= 0.05). Because of the significantly lower aerobic contribution in EAT compared with WAT, elliptical trainers may be a good alternative to cycle ergometers to assess anaerobic performance in athletes involved in whole-body activities. PMID- 23924891 TI - Factor structure of the functional movement screen in marine officer candidates. AB - Functional movement screening (FMS) is a musculoskeletal assessment that is intended to fill a gap between preparticipation examinations and performance tests. Functional movement screening consists of 7 standardized movements involving multiple muscle groups that are rated 0-3 during performance; scores are combined into a final score, which is intended to predict injury risk. This use of a sum-score in this manner assumes that the items are unidimensional and scores are internally consistent, which are measures of internal reliability. Despite research into the FMS' predictive value and interrater reliability, research has not assessed its psychometric properties. The present study is a standard psychometric analysis of the FMS and is the first to assess the internal consistency and factor structure of the FMS, using Cronbach's alpha and exploratory factor analysis (EFA). Using a cohort of 877 male and 57 female Marine officer candidates who performed the FMS, EFA of polychoric correlations with varimax rotation was conducted to explore the structure of the FMS. Tests were repeated on the original scores, which integrated feelings of pain during movement (0-3), and then on scores discounting the pain instruction and based only on the performance (1-3), to determine whether pain ratings affected the factor structure. The average FMS score was 16.7 +/- 1.8. Cronbach's alpha was 0.39. Exploratory factor analysis availed 2 components accounting for 21 and 17% and consisting of separate individual movements (shoulder mobility and deep squat, respectively). Analysis on scores discounting pain showed similar results. The factor structures were not interpretable, and the low Cronbach's alpha suggests a lack of internal consistency in FMS sum scores. Results do not offer support for validity of the FMS sum score as a unidimensional construct. In the absence of additional psychometric research, caution is warranted when using the FMS sum score. PMID- 23924892 TI - Transport-limited electrochemical formation of long nanosharp probes from tungsten. AB - We show that electrochemical formation of long probes with nanosharp tips can be controlled by choosing an appropriate thermodynamic pathway of metal to metal oxide and hydroxide transformation. Currently, convection-limited electropolishing (CLE) is extensively used. Nanosharp probes are produced by electrochemically etching a wire until it breaks into two pieces. This process is difficult to control because of the complexity of the associated hydrodynamic flows. We introduce transport-limited electropolishing (TLE), where the electrochemical reaction results in the formation of metal oxides and hydroxides which form a porous surface layer hindering the flow of electrolyte. The developed TLE method enables one to make long tapered needles. The taper can spread over more than 6 mm while the radius of tip curvature can be decreased down to 30 nm. These needles are strong and were successfully applied for piercing single smooth vascular muscle cells. PMID- 23924894 TI - Synthesis and biological evaluation of novel benzyl piperazine derivatives of 5 (5-nitroaryl)-1,3,4-thiadiazoles as Anti-Helicobacter pylori agents. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: Helicobacter pylori is recognized as the main cause of gastritis and gastroduodenal ulcers and classified as class 1 carcinogen pathogen. Different 1,3,4-thiadiazole derivatives bearing 5-nitroaryl moiety have been shown considerable anti- H. pylori activity. In attempt to find new and potent derivatives of described scaffold, a new series of 1-(substituted benzyl)-4-(5-(5-nitroaryl-2-yl)-1,3,4-thiadiazol-2-yl)piperazine derivatives were synthesized and evaluated against three metronidazole-resistant isolates of H. pylori using paper disk diffusion bioassay test. METHODS: The title compounds were prepared through the reaction of 1-(5-(5-nitroaryl-2-yl)-1,3,4-thiadiazol-2 yl) piperazine 5a-b and substituted benzyl chloride in DMF. The inhibitory activity of the new derivatives 6a-q against three metronidazole-resistant isolates of H. pylori was evaluated by the disc diffusion method and compared with the commercially available standard drug metronidazole. RESULTS AND DISCUSSION: The results of SAR study indicated that the potency and anti-H. pylori activity profile of synthesized derivatives is mainly attributed to the substituted nitroaryl moiety at the C-5 position of 1,3,4-thiadiazole ring. Most of 1,3,4-thiadiazole derivatives bearing 5-nitrofuran moiety at C-5 position of central thiadiazole ring, demonstrated more promising anti-H. pylori than the 5 nitrothiophen counterpart. CONCLUSION: The most potent nitrofuran derivative containing 3-methoxybenzyl piperazine pendant at the C-2 position of 1,3,4 thiadiazole ring (compound 6i), demonstrated strong anti-H. pylori potential at studied concentrations 100-25 MUg/disk (IZD > 20 mm) against all studied metronidazole- resistant isolates of H. pylori. PMID- 23924893 TI - Contrasting pediatric and adult cerebral malaria: the role of the endothelial barrier. AB - Malaria affects millions of people around the world and a small subset of those infected develop cerebral malaria. The clinical presentation of cerebral malaria differs between children and adults, and it has been suggested that age-related changes in the endothelial response may account for some of these differences. During cerebral malaria, parasites sequester within the brain microvasculature but do not penetrate into the brain parenchyma and yet, the infection causes severe neurological symptoms. Endothelial dysfunction is thought to play an important role in mediating these adverse clinical outcomes. During infection, the endothelium becomes activated and more permeable, which leads to increased inflammation, hemorrhages, and edema in the surrounding tissue. We hypothesize that post-natal developmental changes, occurring in both endothelial response and the neurovascular unit, account for the differences observed in the clinical presentations of cerebral malaria in children compared with adults. PMID- 23924895 TI - Regulation of ER-phagy by a Ypt/Rab GTPase module. AB - Accumulation of misfolded proteins on intracellular membranes has been implicated in neurodegenerative diseases. One cellular pathway that clears such aggregates is endoplasmic reticulum autophagy (ER-phagy), a selective autophagy pathway that delivers excess ER to the lysosome for degradation. Not much is known about the regulation of ER-phagy. The conserved Ypt/Rab GTPases regulate all membrane trafficking events in eukaryotic cells. We recently showed that a Ypt module, consisting of Ypt1 and autophagy-specific upstream activator and downstream effector, regulates the onset of selective autophagy in yeast. Here we show that this module acts at the ER. Autophagy-specific mutations in its components cause accumulation of excess membrane proteins on aberrant ER structures and induction of ER stress. This accumulation is due to a block in transport of these membranes to the lysosome, where they are normally cleared. These findings establish a role for an autophagy-specific Ypt1 module in the regulation of ER-phagy. Moreover, because Ypt1 is a known key regulator of ER-to-Golgi transport, these findings establish a second role for Ypt1 at the ER. We therefore propose that individual Ypt/Rabs, in the context of distinct modules, can coordinate alternative trafficking steps from one cellular compartment to different destinations. PMID- 23924896 TI - Membrane translocation of lumenal domains of membrane proteins powered by downstream transmembrane sequences. AB - Translocation of the N-terminus of a type I signal anchor (SA-I) sequence across the endoplasmic reticulum membrane can be arrested by tagging with a streptavidin binding peptide tag (SBP tag) and trapping by streptavidin. In the present study, we first examine the affinity required for the translocation arrest. When the SBP tag is serially truncated, the ability for arrest gradually decreases. Surface plasmon resonance analysis shows that an interaction as strong as 10(-8) M or a smaller dissociation constant is required for trapping the topogenesis of a natural SA-I sequence. Such truncated tags, however, become effective by mutating the SA-I sequence, suggesting that the translocation motivation is considerably influenced by the properties of the SA-I sequence. In addition, we introduce the SBP tag into lumenal loops of a multispanning membrane protein, human erythrocyte band 3. Among the tagged loops between transmembrane 1 (TM1) and TM8, three loops are trapped by cytosolic streptavidin. These loops are followed by TM sequences possessing topogenic properties, like the SA-I sequence, and translocation of one loop is diminished by insertion of a proline into the following TM sequence. These findings suggest that the translocation of lumenal loops by SA-I-like TM sequences has a crucial role in topogenesis of multispanning membrane proteins. PMID- 23924897 TI - Occludin OCEL-domain interactions are required for maintenance and regulation of the tight junction barrier to macromolecular flux. AB - In vitro and in vivo studies implicate occludin in the regulation of paracellular macromolecular flux at steady state and in response to tumor necrosis factor (TNF). To define the roles of occludin in these processes, we established intestinal epithelia with stable occludin knockdown. Knockdown monolayers had markedly enhanced tight junction permeability to large molecules that could be modeled by size-selective channels with radii of ~62.5 A. TNF increased paracellular flux of large molecules in occludin-sufficient, but not occludin deficient, monolayers. Complementation using full-length or C-terminal coiled coil occludin/ELL domain (OCEL)-deficient enhanced green fluorescent protein (EGFP)-occludin showed that TNF-induced occludin endocytosis and barrier regulation both required the OCEL domain. Either TNF treatment or OCEL deletion accelerated EGFP-occludin fluorescence recovery after photobleaching, but TNF treatment did not affect behavior of EGFP-occludin(DeltaOCEL). Further, the free OCEL domain prevented TNF-induced acceleration of occludin fluorescence recovery, occludin endocytosis, and barrier loss. OCEL mutated within a recently proposed ZO-1-binding domain (K433) could not inhibit TNF effects, but OCEL mutated within the ZO-1 SH3-GuK-binding region (K485/K488) remained functional. We conclude that OCEL-mediated occludin interactions are essential for limiting paracellular macromolecular flux. Moreover, our data implicate interactions mediated by the OCEL K433 region as an effector of TNF-induced barrier regulation. PMID- 23924898 TI - Different polarisome components play distinct roles in Slt2p-regulated cortical ER inheritance in Saccharomyces cerevisiae. AB - Ptc1p, a type 2C protein phosphatase, is required for a late step in cortical endoplasmic reticulum (cER) inheritance in Saccharomyces cerevisiae. In ptc1Delta cells, ER tubules migrate from the mother cell and contact the bud tip, yet fail to spread around the bud cortex. This defect results from the failure to inactivate a bud tip-associated pool of the cell wall integrity mitogen-activated protein kinase, Slt2p. Here we report that the polarisome complex affects cER inheritance through its effects on Slt2p, with different components playing distinct roles: Spa2p and Pea2p are required for Slt2p retention at the bud tip, whereas Bni1p, Bud6p, and Sph1p affect the level of Slt2p activation. Depolymerization of actin relieves the ptc1Delta cER inheritance defect, suggesting that in this mutant the ER becomes trapped on the cytoskeleton. Loss of Sec3p also blocks ER inheritance, and, as in ptc1Delta cells, this block is accompanied by activation of Slt2p and is reversed by depolymerization of actin. Our results point to a common mechanism for the regulation of ER inheritance in which Slt2p activity at the bud tip controls the association of the ER with the actin-based cytoskeleton. PMID- 23924901 TI - Dissociated human dermal papilla cells induce hair follicle neogenesis in grafted dermal-epidermal composites. PMID- 23924900 TI - VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. AB - Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX 809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR. PMID- 23924902 TI - Skin is not the largest organ. PMID- 23924899 TI - H4K20 methylation regulates quiescence and chromatin compaction. AB - The transition between proliferation and quiescence is frequently associated with changes in gene expression, extent of chromatin compaction, and histone modifications, but whether changes in chromatin state actually regulate cell cycle exit with quiescence is unclear. We find that primary human fibroblasts induced into quiescence exhibit tighter chromatin compaction. Mass spectrometry analysis of histone modifications reveals that H4K20me2 and H4K20me3 increase in quiescence and other histone modifications are present at similar levels in proliferating and quiescent cells. Analysis of cells in S, G2/M, and G1 phases shows that H4K20me1 increases after S phase and is converted to H4K20me2 and H4K20me3 in quiescence. Knockdown of the enzyme that creates H4K20me3 results in an increased fraction of cells in S phase, a defect in exiting the cell cycle, and decreased chromatin compaction. Overexpression of Suv4-20h1, the enzyme that creates H4K20me2 from H4K20me1, results in G2 arrest, consistent with a role for H4K20me1 in mitosis. The results suggest that the same lysine on H4K20 may, in its different methylation states, facilitate mitotic functions in M phase and promote chromatin compaction and cell cycle exit in quiescent cells. PMID- 23924904 TI - Rapid and severe adverse reaction to adenosine during a pharmacological stress test for a myocardial perfusion scan. PMID- 23924905 TI - Disregard for basic dosimetric principles will lead to questionable results. PMID- 23924903 TI - Propionibacterium acnes Induces an IL-17 Response in Acne Vulgaris that Is Regulated by Vitamin A and Vitamin D. AB - Acne vulgaris is the most common skin disorder affecting millions of people worldwide and inflammation resulting from the immune response targeting Propionibacterium acnes has a significant role in its pathogenesis. In this study, we have demonstrated that P. acnes is a potent inducer of T helper 17 (Th17) and Th1, but not Th2 responses in human peripheral blood mononuclear cells (PBMCs). P. acnes stimulated expression of key Th17-related genes, including IL 17A, RORalpha, RORc, IL-17RA, and IL-17RC, and triggered IL-17 secretion from CD4(+), but not from CD8(+) T cells. Supernatants from P. acnes-stimulated PBMCs were sufficient to promote the differentiation of naive CD4(+)CD45RA T cells into Th17 cells. Furthermore, we found that the combination of IL-1beta, IL-6, and transforming growth factor-beta-neutralizing antibodies completely inhibited P. acnes-induced IL-17 production. Importantly, we showed that IL-17-expressing cells were present in skin biopsies from acne patients but not from normal donors. Finally, vitamin A (all-trans retinoic acid) and vitamin D (1,25 dihydroxyvitamin D3) inhibited P. acnes-induced Th17 differentiation. Together, our data demonstrate that IL-17 is induced by P. acnes and expressed in acne lesions and that both vitamin A and D could be effective tools to modulate Th17 mediated diseases such as acne. PMID- 23924906 TI - Duration of the thoracic epidural catheter in a fast-track recovery protocol may decrease the length of stay after a major hepatectomy: a case control study. AB - BACKGROUND: Fast-track recovery protocols are applied to major surgeries, including hepatectomies. The optimal duration of thoracic epidural catheter has not yet been defined. OBJECTIVE: To determine the ideal time to remove the epidural catheter after major hepatectomy. PATIENTS-METHODS: Forty-eight consecutive patients who underwent major hepatectomy over 4 years were studied. The data from laparoscopic hepatectomy were not included. Patients who underwent hepaticojejunostomy were included. A modified protocol of rapid postoperative recovery was implemented. In the first 24 patients, an epidural catheter was maintained for 4 days (group A), while in the next 24, the catheter was maintained for 2 days (group B). The length of hospital stay, time of functional recovery, and use of opioids and laxatives were recorded. RESULTS: There was no postoperative mortality. The average length of hospital stay was 6.92 +/- 1.79 and 6.09 +/- 2.08 days for groups A and B, respectively. The mean functional recovery was 5.46 +/- 0.3 and 5.26 +/- 0.91 days for groups A and B, respectively. However, in group B, more opioid analgesics by 50% and more laxatives by 17% were used. CONCLUSIONS: After major hepatectomy, a reduction from 4 to 2 days' duration of the epidural catheter may lead to a reduction in the length of hospital stay. PMID- 23924907 TI - Early outcome after laparoscopic sleeve gastrectomy of type two diabetes mellitus patients with extremely elevated glycated hemoglobin (HbA1c). AB - BACKGROUND: Due to high prevalence of type 2 diabetes mellitus (T2DM) and increasing popularity of bariatric and metabolic operations, Surgeons are faced with patients with relatively more severe T2DM disease. High level of glycated hemoglobin (HbA1c) is widely considered as a marker for uncontrolled T2DM. The aim of this study was to explore the correlation between high level of pre operative HbA1c, peri-operative morbidity and post operative outcome after laparoscopic sleeve gastrectomy. METHODS: We conducted a retrospective study based on our medical center metabolic and bariatric registry. The inclusion criteria for selecting patients to the study group was HbA1c of 9 gram/dL and higher. A comparison control study was designed to include T2DM patients similar in all characteristics except for HbA1c of 7.5 gram/dl and less. RESULTS: We included 20 patients who underwent laparoscopic sleeve gastrectomy. Each group of patients included half of the patients. The mean pre operative HbA1c in the studied and the control group were 10.4 gram/dL and 7.1 gram/dL respectively (p<0.001). There were no differences in peri-operative morbidity and length of stay at the hospital. Mean excess weight loss, fasting glucose levels and HbA1c levels were similar six months post surgery mean. CONCLUSIONS: According to our study we have not found correlation between high HbA1c levels and increased peri operative morbidity or insufficient excess weight loss among patients who underwent laparoscopic sleeve gastrectomy. PMID- 23924909 TI - N-acetylcysteine used to decrease the incidence of contrast-induced nephropathy following radiographic pocedures: a literature review. PMID- 23924910 TI - Treatment of mercury intoxication with dimercaptopropanesulfonate. AB - Treatment of mercury toxicity is controversial and not well studied. Currently there are several proposed methods of chelation and subsequent removal of mercury from the body, including dimercaptopropanesulfonate, dimercaptosuccinic acid, intravenous vitamin C and edetate. Although many of these methods are not approved by the US Food and Drug Administration, they are being used with modest success. Because of the lack of information regarding treatment outcomes, Medical Dental Pharmacy performed a retrospective analysis of 28 randomly selected patients for whom we had suppplied dimercaptopropanesulfonate in the last 6 months. Dimercaptopropanesulfonate is used to treat mercury toxicity and as provacation to perform mercury testing. Two of the 28 selected patients who received the prescription decided against treatment. Of the remaining 26 patients, 8 patients were using dimercaptopropanesulfonate for treatment with varying success. Overall, this retrospective study shows that dimercaptopropanesulfonate is a safe and effective agent to use for initial mercury level testing. PMID- 23924908 TI - Nanoparticle-mediated delivery of TGF-beta1 miRNA plasmid for preventing flexor tendon adhesion formation. AB - Treatment of the disrupted digital flexor tendon is troublesome because of the lack of sufficient healing capacity and the formation of adhesions. Sustained gene delivery may be a promising approach of modulating gene expression in enhancing tendon healing and decreasing adhesions. In this study, a microRNA based RNAi plasmid was used to specifically silence the expression of TGF-beta1 gene associated with scar and adhesion formation in the flexor tendons. The miRNA plasmids were complexed with polylactic-co-glycolic acid (PLGA) nanoparticles to form nanoparticle/TGF-beta1 miRNA plasmid (nanoparticle/plasmid) complexes. In vitro and in vivo transfection efficiencies experiments against tenocytes revealed that nanoparticle/plasmid complexes have significantly superior transfection efficiency over the lipofectamine/plasmid complexes. The gene and protein expression associated with adhesion of tendon treated with nanoparticle/plasmid complexes were evaluated by real-time PCR and immunoblotting. The grading of adhesions for tendons treated with nanoparticle/plasmid complexes was less severe than that treated with the nanoparticle/mock plasmid complexes. However, the ultimate strength of repaired tendons treated with nanoparticle/plasmid complexes was significantly lower than that of tendons treated with the nanoparticle/mock plasmid complexes. PMID- 23924911 TI - What a pharmacist needs to know about bariatric surgery: compounding opportunities. PMID- 23924912 TI - Combating cardiovascular disease with compounded medications-part 1: combination cardiac medicines to control blood pressure. PMID- 23924913 TI - Use of domperidone as a prokinetic and antiemetic. PMID- 23924915 TI - Quality-Control Analytical Methods: Chemical Testing Aspects of USP chapter 797 for Compounded Sterile Preparations. PMID- 23924914 TI - Proposed Revisions to USP Chapter 797 Pharmaceutical Compounding-Sterile Preparations. PMID- 23924916 TI - In vitro evaluation of extemporaneously compounded slow-release capsules containing morphine sulfate or oxycodone hydrochloride. AB - The in vitro performance of extemporaneously compounded morphine sulfate and oxycodone hydrochloride slow-release capsules was evaluated. Capsules containing varying amoutns of morphine sulfate (15, 60, 200 mg) or oxycodone hydrochloride (10, 80, 200 mg) were prepared and provided by a Phoenix, Arizona, pharmacy. The capsules also contained 40% Methocel E4M Premium to slow the release of their active ingredient and sufficient lactose to fill the capsules. Three batches of each capsule strength were prepared, and replicates from each batch were evlauated using United Stated Pharmacopeia dissolution apparatus II. Samples were taken at regular time intervals over 24 hours. After 1 hour the pH of the dissolution medium was adjusted form 1.2 to 4.0, and after 2 hours the pH was adjusted to 6.8. The amount of drug released at each time point was determined spectrophotometrically. The compounded capsules released 14% to 23%, 67% to 85% and 93% to 98% of their active ingredient after 0.5, 4 and 12 hours, respectively. The relative standard deviations between the replicates from each batch were less than 10% for most time points. The percent of drug released over the first 4 hours was linear (r squared = 0.9409-0.9999) when plotted versus time 1/2, indicating adherence to the simplified Higuchi model. Statistical analysis of the Higuchi dissolution constants indicated a significant difference (P less than 0.05) between batch No.3 and the other two batches of 200-mg oxycodone hydrochloride capsules. There was also a statistical difference between most of the Higuchi dissolution constants for the different-strength slow-release capsules and most slow-release capsules and equivalent strength controlled release manufactured tablets (P less than 0.05). Using 40% Methocel E4M Premium slowed the release of morphine sulfate and oxycodone hydrochloride from extemporaneously compounded capsules. The in vitro performance of the slow release capsules showed little intrabatch variation, and only one preparation showed statistically significant interbatch variation, indicating reproducible and robust formulation. Even though changing the quantity of the formulation ingredients altered the release characteristics of the slow-release capsules, which also varied from that of equivalent strength-controlled release tablets, their release profiles were similar. Further testing is needed to determine whether these diffences are clinically significant. PMID- 23924917 TI - Chemical stability of isoniazid in an oral liquid dosage form. AB - The chemical stability of isoniazid in an oral liquid dosage form was studied by means of a specially developed stabilty-indicating high-performance liquid chromatographic assay method. The concentrations of the drug were directly related to peak heights, and the percent relative standard deviation based on five injections was 0.93. The products of decomposition and excipients present in the dosage forms did not interfere with the developed assay method. The preparation was stable for at least 42 days when stored in amber-colored glass bottles at room temperature. The pH value of the preparation decreased from 5.9 to 5.6 after 42 days of storage. The physical appearance of the preparation changed from almost colorless to light brown. PMID- 23924918 TI - Effect of acute aerobic exercise on vaccine efficacy in older adults. AB - The most effective way of avoiding influenza is through influenza vaccination. However, the vaccine is ineffective in about 25% of the older population. Immunosenescence with advancing age results in inadequate protection from disease because of ineffective responses to vaccination. Recently, a number of strategies have been tested to improve the efficacy of a vaccine in older adults. An acute bout of moderate aerobic exercise may increase the efficacy of the vaccine in young individuals, but there are limited efficacy data in older adults who would benefit most. PURPOSE: This study sought to evaluate whether acute moderate intensity endurance exercise immediately before influenza vaccination would increase the efficacy of the vaccine. METHODS: Fifty-nine healthy volunteers between 55 and 75 yr of age were randomly allocated to an exercise or control group. Antibody titers were measured at baseline before exercise and 4 wk after vaccination. C-reactive protein (CRP) and interleukin-6 (IL-6) were measured at 24 and 48 h after vaccination. RESULTS: Delta CRP and IL-6 at 24 and 48 h were significantly higher after vaccination as compared to the sham injection. There were no differences in the levels of antibody titers against the H3N2 influenza strain between groups. However, women in the exercise group had a significantly higher antibody response against the H1N1 influenza strain as compared to the men, probably because of lower prevaccine titers. There were no significant differences in seroprotection between groups. CONCLUSIONS: Acute moderate aerobic exercise was not immunostimulatory in healthy older men but may serve as a vaccine adjuvant in older women. PMID- 23924919 TI - Clotting and fibrinolytic changes after firefighting activities. AB - Approximately 45%-50% of all duty-related deaths among firefighters are due to sudden cardiovascular events, and a disproportionate number of these fatalities occur after strenuous fire suppression activities. PURPOSE: The objective of this study is to evaluate the effect of strenuous firefighting activities on platelets, coagulation, and fibrinolytic activity and to document the extent to which these variables recovered 2 h after completion of the firefighting activity. METHODS: Firefighters performed 18 min of simulated firefighting activities in a training structure that contained live fires. After firefighting activities, firefighters were provided with fluid and allowed to cool down and then recovered for 2 h in an adjacent room. Blood samples were obtained prefirefighting, postfirefighting, and 2 h postfirefighting. RESULTS: Platelet number, platelet activity, and coagulatory potential increased immediately postfirefighting and many variables (platelet function, partial thromboplastin time, and factor VIII) reflected a procoagulatory state even after 2 h of recovery. Fibrinolysis, as reflected by tissue plasminogen activator, also was enhanced immediately postfirefighting but returned to baseline values by 2 h postfirefighting. In contrast, inhibition of fibrinolysis, as evidenced by a reduction in plasminogen activator inhibitor-1, was depressed at 2 h postfirefighting. CONCLUSIONS: Firefighting resulted in elevated coagulatory and fibrinolytic activity. However, 2 h postfirefighting, tissue plasminogen activator returned to baseline and coagulatory potential remained elevated. The procoagulatory state that exists after firefighting may provide a mechanistic link to the reports of sudden cardiac events after strenuous fire suppression activities. PMID- 23924921 TI - The Simon task and aging: does acute moderate exercise influence cognitive control? AB - PURPOSE: This study aimed to investigate the influence of an acute bout of moderate exercise and examine the potential lasting improvements over time in young and old adults within the same experimental paradigm over a 2-h testing period. The study was designed to assess the efficiency of selective control and the propensity to make fast impulsive reactions through the analyses of the percentage of correct responses (CAF) and the magnitude of the interference effect (delta curve) as a function of the latency of the response. METHODS: Twelve young (23 +/- 2 yr) and 12 old (63 +/- 2 yr) volunteers performed the Simon task while cycling (30 min of cycling at 65% of age-predicted HRmax) and after exercise cessation (post 5 min, post 35 min, and post 65 min). RESULTS: Results showed that exercise did not alter cognitive control. The benefit on reaction time performance was evident for both age groups and persisted after cessation for 15-20 min. Distributional analyses showed that younger people have a higher propensity to commit impulsive errors during exercise, which was not evident in older adults. Older adults adopted more cautious strategies, especially when the risk to commit an error was elevated. Despite the larger mean interference effect compared to younger adults, the pattern of the delta curves attests to the existence of an efficient cognitive control in older people. CONCLUSIONS: This study illustrates the effectiveness of distributional analyses and supports the idea that exercise-induced facilitation on cognitive performance can be realized across the lifespan. Future investigations should explore whether accumulated bouts of acute exercise could display an aggregate cognitive benefit, which may significantly affect independent functioning in older adults. PMID- 23924920 TI - Associations of physical activity and sedentary behavior with regional fat deposition. AB - INTRODUCTION: Increased sedentary behavior predicts greater cardiovascular morbidity and mortality and does so independently of physical activity (PA). This association is only partially explained by body mass index (BMI) and overall body fat, suggesting mechanisms besides general increased adiposity. The purpose of this study was to explore associations of self-reported leisure PA and sitting time with regional fat depositions and abdominal muscle among community-dwelling older adults. METHODS: Participants were 539 diverse adults (mean age = 65 yr) who completed a study visit in 2001-2002. Areas of pericardial, intrathoracic, subcutaneous, visceral, and intermuscular fat, as well as abdominal muscle, were measured using computed tomography. Leisure PA and sitting hours were entered simultaneously into multivariate regression models to determine associations with muscle and fat areas. RESULTS: After adjusting for demographics, smoking, diabetes, hypertension, triglycerides, and cholesterol, greater PA was associated with less intrathoracic, visceral, subcutaneous, and intermuscular fat (for all P < 0.05), while greater sedentary time was associated with greater pericardial and intrathoracic fat (for both P < 0.05). After further adjusting for BMI, each hour of weekly PA was associated with 1.85 cm less visceral fat (P < 0.01) but was not associated with other fat depositions. Conversely, each hour of daily sitting was associated with 2.39 cm more pericardial fat (P < 0.05) but was not associated with any other fat depositions. There were no associations with abdominal muscle area. Adjusting for common inflammatory markers had little effect. Associations between fat and PA were stronger for men. CONCLUSIONS: Sitting and PA have distinct associations with regional fat deposition in older adults. The association between sitting and pericardial fat could partially explain the link between sitting and coronary heart disease. PMID- 23924922 TI - CD40 signal regulates CXCR4 mediating ovarian carcinoma cell migration: implications for extrapelvic metastastic factors. AB - Ovarian carcinomas are highly invasive, especially in the peritoneal cavity. SDF 1alpha and its receptor, CXCR4, play a crucial role in migration of cancer cells. Here, SDF-1alpha directed HO8910 cell migration, but not SKOV3 cells. After being educated to express CXCR4 in vivo or by treating with sCD40L, SDF-1alpha reexhibited the ability of directing SKOV3 cell migration, which could be antagonized by CXCR4-neutralizing antibody. Furthermore, concomitant expression of CXCR4/CD40 in ovarian carcinoma tissues had stronger correlation with pelvic metastasis than did each alone. It is suggest that SDF-1alpha acts through CXCR4 to induce ovarian cancer cell migration, which could be facilitated by CD40 activation. Simultaneously examining the expression of CXCR4 and CD40 will provide valuable diagnosis of pelvic metastasis for ovarian carcinomas. PMID- 23924923 TI - Hepatocyte growth factor-mediated gastrin-releasing peptide induces IL-8 expression through Ets-1 in gastric cancer cells. AB - Gastric cancer cells secrete a variety of proangiogenic molecules, including IL-8 and VEGF. However, factors regulating the expression of proangiogenic genes for gastric cancer remain largely undefined. We investigated the role of HGF-induced activation of GRP and Ets-1 transcription factor in expression of the proangiogenic factor IL-8. The genes associated with angiogenesis induced by HGF were screened using cDNA micro-array technology in two gastric cancer cell lines (NUGC-3 and MKN-28). First, GRP RNA and protein were confirmed to be upregulated. Then, expression of GRP, Ets-1, and IL-8 were further estimated by Western blot analysis. A role for Ets-1 in HGF-induced upregulation of IL-8 was determined by knockdown of Ets-1 with Ets-1 sh-RNA and a chromatin immune precipitation assay. The levels of GRP, Ets-1, and IL-8 were upregulated in cells treated with HGF in a dose-dependent manner. HGF-induced expression of Ets-1 and IL-8 was increased more by GRP treatment and inhibited by pretreatment with an ERK 1/2 inhibitor (PD098059). HGF-induced upregulation of IL-8 was repressed by Ets-1 knockdown. HGF enhanced the binding activity of Ets-1 to the IL-8 promoter in control cells, but not in the Ets-1 shRNA cells. We confirmed the functional role of HGF-induced Ets-1 in activation of the IL-8 promoter by the reporter gene assay. Downregulation of IL-8 also decreased in vitro cell invasion. In conclusion, HGF mediated the GRP induction of IL-8 expression through Ets-1, which thus might serve as a promising target for gastric cancer therapy. PMID- 23924924 TI - Invasion of histiocytic sarcoma into the spinal cord of HTLV-1 tax transgenic mice with HTLV-1-associated myelopathy/tropical spastic paraparesis-like disease. AB - Human T-cell leukemia virus type 1 (HTLV-1) can cause an aggressive malignancy known as adult T-cell leukemia/lymphoma (ATLL) as well as inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Transgenic (Tg) mice expressing HTLV-1 Tax also develop T-cell leukemia/lymphoma and an inflammatory arthropathy that resembles rheumatoid arthritis. We found that 8 of 297 Tax-Tg mice developed HAM/TSP-like disease with symmetrical paraparesis of the hind limbs, but these symptoms were absent in non-Tg littermates and in other mice strains at our animal facilities. We could perform detailed evaluations for five of these mice. These evaluations showed that the disease was not inflammatory, unlike that in HAM/TSP patients, but instead involved the invasion of histiocytic sarcoma cells into the lumbar spinal cord from the bone marrow where they had undergone extensive proliferation. PMID- 23924925 TI - Inhibition of gastric cancer cell growth in vivo by overexpression of adeno associated virus-mediated survivin mutant C84A. AB - Survivin is overexpressed in most of human cancer cells and tissues. Its overexpression is associated with apoptosis inhibition, drug resistance, and poor prognosis. In this study, we investigated the effect of adeno-associated virus (AAV)-mediated survivin mutant Cys84Ala [rAAV-Sur-Mut(C84A)] on gastric cancer growth. Sur-Mut(C84A) was subcloned into the AAV expression vector pAM/CAG to generate recombinant (r)AAV-Sur-Mut(C84A) virus. Cell survival was determined by the MTT method. Apoptosis was measured by FACS analysis and TUNEL. Tumor growth was assessed using a xenograft mouse model. Results showed that treatment of rAAV Sur-Mut(C84A) virus significantly reduced cell survival, induced apoptosis, and sensitized gastric cancer cells to 5-fluorouracil in vitro. Furthermore, treatment of rAAV-Sur-Mut(C84A) virus markedly induced apoptosis and inhibited gastric cancer growth in vivo. Moreover, rAAV-Sur-Mut(C84A) treatment strongly enhanced the antitumor activity of 5-fluorouracil. Our results suggest that the combination of rAAV-Sur-Mut(C84A) with chemotherapy may be a promising strategy for gastric cancer therapy. PMID- 23924926 TI - Therapeutic effect of oncolytic adenovirus expressing relaxin in radioresistant oral squamous cell carcinoma. AB - Radioresistance is one of the main determinants of treatment outcome in oral squamous cell carcinoma (OSCC), and treatment of radioresistant OSCC is difficult due to cross resistance to other conventional treatments. We aimed to identify whether genetically modified oncolytic adenovirus expressing relaxin (RLX), which affects collagen metabolism, can effectively inhibit growth of the radioresistant OSCC. Therapeutic effect of oncolytic adenovirus was compared between radiosensitive and radioresistant OSCC cell lines in vitro and in vivo, and spread of adenovirus throughout the tumor mass was verified by immunohistochemistry (IHC). Oncolytic adenovirus effectively killed cancer cells and there was no significant difference in the cytotoxic effect between radiosensitive and radioresistant OSCC cell lines. In animal experiments, the adenovirus significantly reduced the size of tumor, and there was no significant difference between radiosensitive and radioresistant OSCC. In IHC, RLX expressing adenovirus showed better proliferation and eliminated collagens more effectively compared to RLX nonexpressing adenovirus. These findings suggested that genetically modified oncolytic adenovirus can effectively inhibit growth of the radioresistant OSCC and might be a new therapeutic option in radioresistant OSCC. PMID- 23924927 TI - Reactive center loop moiety is essential for the maspin activity on cellular invasion and ubiquitin-proteasome level. AB - Maspin, a tumor suppressor (SERPINB5), inhibits cancer migration, invasion, and metastasis in vitro and in vivo. The tumor-suppressing effects of maspin depend in part on its ability to enhance cell adhesion to extracellular matrix. Although the molecular mechanism of maspin's action is still unclear, its functional domain is believed to be located at the reactive center loop (RCL). We have elucidated the role of maspin RCL on adhesion, migration, and invasion by transfecting the highly invasive human breast carcinoma MDA-MB-231 cell line with pcDNA3.1-His/FLAG containing wild-type maspin, ovalbumin, or maspin/ovalbumin RCL chimeric mutants in which maspin RCL is replaced by ovalbumin (MOM) and vice versa (OMO). MDA-MB-231 cells transfected with maspin- or OMO-containing recombinant expression plasmid manifested significant increase in adhesion to fibronectin and reduction in in vitro migration and invasion through Matrigel compared with mock transfection or cells transfected with ovalbumin or MOM. Proteomics analysis of maspin- or OMO-transfected MDA-MB-231 cells revealed reduction in contents of proteins known to promote cancer metastasis and those of ubiquitin-proteasome pathway, while those with tumor-suppressing properties were increased. Furthermore, MDA-MB-231 cells containing maspin or OMO transgene have significantly higher levels of ubiquitin and ubiquitinated conjugates, but reduced 20S proteasome chymotrypsin-like activity. These results clearly demonstrate that the tumor-suppressive properties of maspin reside in its RCL domain. PMID- 23924929 TI - Intraoperative assessment for mitral valve competency in a beating heart under retrograde coronary perfusion. AB - Intraoperative assessment of a repaired mitral valve is of paramount importance for reparative mitral surgery. From September 2010 through November 2012, 20 consecutive patients underwent mitral valve plasty for mitral regurgitation. The patients who underwent surgery after June 2012 received assessment of the repair with the heart beating (HB group, n = 10), and the patients who underwent the operation before May 2012 were assessed for the repair only under cardioplegic heart arrest (non-HB group, n = 10). Intermittent cold retrograde blood cardioplegia was used in all patients. In the HB-group, after completion of the procedures, pump blood without a crystalloid additive was delivered into the coronary sinus. The function of the mitral valve was assessed under beating conditions. There were no differences between the two groups in aortic cross clamp time and operation time, although operative and concomitant procedures were slightly more complicated in the HB group than in the non-HB group. Postoperative echocardiography revealed none or mild mitral regurgitation in all the patients in both groups. Reopening of the closed left atrium for additional repair was necessary only in one patient in the HB group and 3 patients in the non-HB group. In conclusion, the method of perfusing the myocardium retrogradely via the coronary sinus with warm blood is safe and effective for assessing the competency of the mitral valve in a beating heart. PMID- 23924928 TI - Clinical outcome of unprotected left main coronary artery disease in patients with acute myocardial infarction. AB - The clinical outcome of patients with acute myocardial infarction (MI) with unprotected left main coronary artery (LMCA) stenosis is not fully understood. We sought to assess the outcomes of patients with acute MI who underwent percutaneous coronary intervention (PCI) for unprotected LMCA stenosis. A total of 587 patients enrolled in the Korea Acute Myocardial Infarction Registry with LMCA stenosis were analyzed. Patients with culprit LMCA had higher inhospital mortality than patients with non-culprit LMCA (16.0% versus 8.9%, P = 0.008), but had similar clinical outcomes during a 12-month follow-up. Compared to CABG, PCI using drug-eluting stents (DES) was more frequently performed with similar early and 12-month clinical outcomes. The efficacy of sirolimus-eluting stents, paclitaxel-eluting stents, and zotarolimus-eluting stents were comparable at 12 month clinical follow-up. Predictors of 12-month mortality included mechanical ventilation, cardiogenic shock, age > 65 years, and ejection fraction < 40%. Patients with acute MI and culprit LMCA have higher early mortality than patients with non-culprit LMCA. PCI with DES is frequently performed and the clinical outcome is similar between the 3 types of first-generation DES. PMID- 23924930 TI - A novel technique for multi-track percutaneous balloon mitral valvoplasty. AB - Percutaneous balloon mitral valvoplasty (PBMV) has become the treatment of choice for severe pliable rheumatic mitral stenosis. The multi-track system is a recent variation of the double-balloon technique and is easier owing to the use of a monorail balloon and a simple, single-guidewire approach. In the present study, we used the double-coil Inoue metal wire with a multi-track balloon instead of the conventional multi-track wire. We studied 62 consecutive patients (55 females) with significant symptomatic rheumatic mitral valve stenosis who underwent multi-track PBMV. Patients were randomized into 2 groups: the first group included 32 patients treated with the novel multi-track technique using the double-coil Inoue metal wire, and the second group included 30 patients treated with the conventional multi-track technique using a balloon endhole catheter and multi-track 0.035 inch stiff wire. None of the patients had cardiac tamponade, systemic thromboembolism, or any groin complications. No statistically significant differences were found between the 2 groups regarding any of the studied variables. There were no in-hospital deaths or complications necessitating emergent cardiac surgery in either group. In conclusion, this new technique with the double-coil Inoue metal wire achieves the double benefit of being as safe as (and indeed easier than) the conventional technique, and it utilizes fewer materials, making the multi-track system more cost-effective. PMID- 23924931 TI - Usefulness of serum cardiac troponins T and I to predict cardiac molecular changes and cardiac damage in patients with hypertrophic cardiomyopathy. AB - Cardiac troponins provide diagnostic and prognostic information on ischemic heart disease, but their roles in hypertrophic cardiomyopathy (HCM) are unclear. We sought to investigate the associations between elevated serum cardiac troponins T (cTnT) and I (cTnI) levels and cardiac injury in patients with HCM. We measured serum cTnT and cTnI in a peripheral vein of 73 consecutive HCM patients in stable condition. In addition, to examine the transcardiac release of cTnT and that of cTnI, we measured them in the aortic root and coronary sinus. Mitochondrial- and Ca(2+)-handling-related gene expression assays were analyzed by endomyocardial biopsy specimens. Based on the median value of serum cTnT, we divided the patients into two groups [group A: cTnT < 0.008 ng/mL, (n = 35), group B: cTnT group >= 0.008 ng/mL, (n = 38)]. Left ventricular (LV) mass index was significantly higher, while LV ejection fraction was significantly lower, in group B than in group A. Meanwhile, there was a significantly positive correlation between the transcardiac gradient of serum cTnT or cTnI, and the mRNA level of troponin I3 (r = 0.473, r = 0.516, respectively). The mRNA level of troponin T2 significantly correlated with mRNA levels of sarco-endoplasmic reticulum Ca(2+)-ATPase 2, cytochrome c oxidase subunit 5B, and troponin I3 (r = 0.486, r = 0.957, r = 0.633, respectively). These findings indicate that both elevated serum cTnT and cTnI might be associated with cardiac dysfunction in patients with HCM, resulting from the impairment of mitochondrial function and Ca(2+)-handling protein. PMID- 23924932 TI - Long-term comparison of apical versus asymmetric hypertrophic cardiomyopathy. AB - Although apical hypertrophic cardiomyopathy (HCM) has been considered to be more benign than asymmetric HCM, few studies have directly compared their clinical features. We compared the electrocardiographic data and longterm outcomes between patients with apical HCM versus asymmetric HCM. This retrospective study enrolled 796 patients (243 apical HCM and 553 asymmetric HCM). We assessed long-term all cause and cardiac mortalities using an inverse probability of treatment weighted (IPTW) method and propensity score matched (PSM) analysis. In patients with asymmetric HCM, QT prolongation, QRS widening, PR prolongation, and pathologic Q wave were significantly more frequent. The incidences of early repolarization were similar (11% in apical and 12% in asymmetric HCM, P = 0.19). The median follow-up duration was 6.5 years. There was a borderline significant difference in overall survival rates between the apical and asymmetric HCM groups (73% versus 69%, log rank P = 0.38, IPTW: P = 0.05, PSM: P = 0.05). Regarding cardiac death, asymmetric HCM was more hazardous than apical HCM (89% versus 77%, log rank P = 0.04, IPTW: P = 0.03, PSM: P = 0.03). There was no electrocardiographic predictor for the long-term outcomes, although beta-blocker use was significantly associated with lower overall death (HR = 0.58, 95% CI = 0.41-0.81) and slightly lower cardiac death (HR = 0.86, 95% CI = 0.55-1.33). The overall survival rate of apical HCM was as high as that of asymmetric HCM, but the cardiac survival rate was significantly lower in patients with asymmetric HCM. Beta-blocker use was associated with better long-term outcomes. PMID- 23924933 TI - Assessment of left ventricular systolic and diastolic function using ECG-gated technetium-99m tetrofosmin myocardial perfusion SPECT. AB - Because left ventricular (LV) diastolic dysfunction is frequently the earliest indicator of LV dysfunction in patients with heart failure, the estimation of LV diastolic function is very important. On the other hand, electrocardiography (ECG)-gated technetium (Tc) -99m tetrofosmin single-photon emission computed tomography (SPECT) has been reported to be a useful method for evaluation of LV function. The objective of this study was to examine the usefulness of ECG-gated Tc-99m tetrofosmin SPECT in terms of estimation of cardiac diastolic function. Consecutive 145 patients underwent an ECG-gated Tc-99m tetrofosmin SPECT to estimate systolic and diastolic LV function, and were compared with those evaluated by ultrasound echocardiography (UCG). LV end-diastolic volume, LV end systolic volume, and LV ejection fraction values obtained by quantitative gated SPECT (QGS) showed significant positive linear correlations with those obtained by UCG. All 145 patients were classified into 3 groups according to diastolic function estimated by UCG. The first-third mean filling rate (1/3 MFR) and peak filling rate (PFR) that revealed the LV diastolic function of the group B (normal systolic function and mild diastolic dysfunction) patients (1.01 +/- 0.35, 1.85 +/- 0.57) were both significantly lower than those of the group A (normal systolic and diastolic function) patients (1.43 +/- 0.37, 2.43 +/- 0.56). The 1/3 MFR and PFR of the group C (moderate ~ severe systolic and diastolic dysfunction) patients (0.47 +/- 0.34, 0.92 +/- 0.62) were also significantly lower than those of the group A and B patients. QGS may be a useful method for the evaluation of cardiac systolic and diastolic function, especially in patients with normal systolic function and diastolic dysfunction. PMID- 23924934 TI - Cardio-ankle vascular index relates to left ventricular ejection fraction in patients with heart failure. A retrospective study. AB - The cardio-ankle vascular index (CAVI) has been proposed as a new noninvasive marker of arterial stiffness independent of blood pressure. Arterial stiffness is closely related to afterload, and elevated afterload aggravates heart failure. We hypothesized that CAVI is a potential marker of afterload in patients with heart failure. Thirty patients who were admitted because of acute heart failure were identified retrospectively from a review of clinical records. Plasma brain natriuretic peptide (BNP) levels, CAVI, cardiothoracic ratio (CTR), and echocardiographic parameters obtained during acute and chronic phases of heart failure were analyzed. Left ventricular ejection fraction (LVEF) increased significantly and CTR, BNP and CAVI decreased significantly after treatment of heart failure. A significant negative correlation was observed between the change in CAVI and change in LVEF in all subjects (r = -0.3272, P < 0.05). To examine the relationship between CAVI and LVEF, we divided the patients into two subgroups (?CAVI < -0.5; CAVI decrease group, ?CAVI >= -0.5; CAVI non-decrease group). CAVI was significantly improved after heart failure treatment only in the CAVI decrease group. LVEF decreased significantly in both groups, but the P value was smaller in the CAVI decrease group than in the CAVI non-decrease group. The change in LVEF correlated significantly with the change in CAVI in the CAVI decrease group (r = -0.4201, P < 0.05), whereas no significant correlation was found in the CAVI non-decrease group. CAVI correlates inversely with LVEF after heart failure treatment. Our results suggest that CAVI might partially reflect the afterload in patients with heart failure. PMID- 23924935 TI - Everolimus-incorporated immunosuppressant strategy improves renal dysfunction while maintaining low rejection rates after heart transplantation in Japanese patients. AB - The long-term survival of heart transplantation (HTx) recipients has increased significantly in recent years, however, the nephrotoxic adverse effects of calcineurin inhibitors (CNIs) are still a major concern. Recently, an inhibitor of mammalian target of rapamycin, everolimus (EVL), has emerged as an alternative immunosuppressant drug that may allow CNI dosage reduction and thereby spare renal function. Data were collected from 20 HTx recipients who had received EVL (target trough level 3-8 ng/mL) along with a dose reduction of CNIs and/or mycophenolate mophetil (MMF) and had been followed for 1 year. Estimated glomerular filtration rate increased significantly with a reduction in the CNI dosage in a dose-dependent manner (P < 0.001, r = -0.807). Neutrophil count increased significantly (P < 0.05) with a reduction in the dosage of MMF (P = 0.009, r = -0.671). Cytomegalovirus antigenemia remained negative after EVL administration among all candidates without any antiviral agents (P = 0.001). There were no significant increases in the acute rejection rates among recipients with EVL compared to those without EVL (P = 0.132). An immunosuppressant strategy incorporating EVL could reduce the CNI and MMF dosages, which resulted in improvements in renal dysfunction and neutropenia while maintaining low rejection rates among HTx recipients. PMID- 23924936 TI - Development and psychometric properties of the Japanese heart failure knowledge scale. AB - Knowledge about their own condition is important for patients with heart failure (HF). No valid, reliable, and easily administered instrument is available to measure this knowledge in clinical practice. In this study, a HF knowledge scale was developed, and its psychometric properties were tested. Items related to knowledge about HF were extracted from relevant guidelines. Content validity of the items was confirmed by an expert panel including a cardiologist and nurses specialized in treatment and care of patients with HF. A self-administered questionnaire was then distributed to 187 patients with HF (64.0 +/- 12.1 years, males 69%). In 62% patients, a left ventricular ejection fraction of < 50% was identified. Exploratory factor analysis demonstrated the one-dimensionality of the 15-item HF knowledge scale. Mean score was 10.7 +/- 3.0 (range, 0-15). Known group validity testing revealed a significant difference in HF knowledge score between patients newly diagnosed with HF and patients experienced with HF (9.4 +/ 3.2 versus 10.8 +/- 2.9, P = 0.043). In addition, HF knowledge scale scores were correlated with HF self-care scores assessed by the European Heart Failure Self Care Behavior Scale for evaluation of criterion validity (rho = -0.304, P < 0.001). Cronbach's alpha was 0.79, and item-total correlation was 0.22-0.51, thereby suggesting that the reliability of the scale was acceptable. Acceptable validity and reliability were demonstrated for the HF knowledge scale developed in this study. This instrument could be useful in evaluation of patient knowledge about HF. PMID- 23924937 TI - Five years on dual-antiplatelet therapy. DES thrombosis after clopidogrel withdrawal. AB - Drug-eluting stents (DES) have a moderately higher incidence of stent thrombosis compared to bare metal stents (BMS) and very late DES thrombosis has been frequently described. We report a case of a 66 year-old male who experienced very late stent thrombosis at 5 years after paclitaxel-eluting stent (PES) implantation and 3 days after clopidogrel withdrawal. Intravascular ultrasound (IVUS) performed during the index procedure showed that the previously implanted PES was undersized. Since the patient could not take clopidogrel, we treated him with only a noncompliant balloon (3.0 * 15 mm) with optimal expansion as confirmed by IVUS. This case report describes a patient who continued clopidogrel treatment for 5 years and was probably protected from a procedural failure. During the current hospitalization, the patient was found to be a responder to clopidogrel after a platelet function assessment with Multiplate (Dynabyte Informationssysteme GmbH, Munich, Germany). PMID- 23924938 TI - A case report of acute myocardial infarction induced by coronary spasm. Intravascular findings. AB - A 53-year-old male complaining of chest pain was admitted to our hospital with suspected acute myocardial infarction (AMI). Emergent coronary angiography (CAG) determined a totally occluded middle right coronary artery (RCA). Thrombus aspiration was conducted, followed by intravascular ultrasound (IVUS) imaging. Diffuse intima plus media thickness was identified at the obstruction site and a thrombus was observed proximally to the occlusion site on IVUS. Following isosorbide dinitrate (ISDN) administration, dilatation of the RCA was confirmed. IVUS study indicated the luminal dilatation was achieved by the release of the diffuse intima plus media thickening. Of note, plaque volume showed no significant difference after administration of ISDN at any vessel site. These results clearly show that luminal dilatation and vessel dilatation were achieved from the redistribution of plaque volume (intima plus media). A follow-up CAG showed no significant stenosis in the RCA. After a provocation test using methylergometrine maleate, the RCA was totally occluded at the very site of the initial event. The involvement of vasospasm as a cause of AMI in the present case was doubly confirmed with characteristic IVUS images of vasospasm in the acute phase and with a provocation test at follow-up. PMID- 23924939 TI - Storms of ventricular fibrillation responsive to isoproterenol in an idiopathic ventricular fibrillation patient demonstrating complete right bundle branch block. AB - A 45-year-old male was admitted to our hospital after successful resuscitation of cardiac arrest. Ventricular fibrillation (VF) had occurred during breakfast and was defibrillated by an automated external defibrillator operated by emergency medical service staff. On admission, his ECG demonstrated complete right bundle branch block as the sole abnormality. Intensive examination could not detect any structural disease leading to a diagnosis of idiopathic VF and implantation of an ICD. VF storm occurred one month after hospital discharge and beta-blocker, amiodarone, and sedative administration had no effect on VF. Likewise, catheter ablation for triggering premature ventricular beats failed to control the VF storm. The VF storm then subsided in the following weeks and the patient was discharged on amiodarone. A half month later VF storm recurred and the patient was admitted again. This time, isoproterenol infusion was effective in suppressing VF, and thereafter the patient was administered bepridil and followed up without recurrence of VF for 1.5 years. From these beneficial effects, the VF of the patient was suggested to share common arrhythmogenic characteristics to those of Brugada syndrome or J-wave associated VF. PMID- 23924940 TI - A case of marked diuresis by combined dopamine and atrial natriuretic peptide administration without renal injury in acute decompensated heart failure. AB - Renal injury is an important factor for worsening outcome in acute decompensated heart failure (ADHF). An 81-year-old woman was admitted due to ADHF with dyspnea and mild peripheral edema. The patient was managed with intravenous administration of atrial natriuretic peptide (ANP) at a dose of 0.0125 MUg/kg/minute, which did not control volume overload even at an increased dose of 0.025 MUg/kg/minute. After a low dose of dopamine (DA) of 1.0 MUg/kg/ minute was added, urine output increased markedly to 120 from 30 mL/hour. Furthermore, her heart rate decreased to 80-100 from 120 bpm and the congestion improved with a reduced brain natriuretic peptide level. Interestingly, the combination of ANP and DA therapy reduced serum creatinine as well as the levels of urinary liver type fatty acid binding protein, a novel reno-tubular stress marker, by 98.9%, and an oxidative stress marker, urinary 8-hydroxydeoxyguanosine, by 88.2% from baseline levels. Thus, this ADHF patient, a nonresponder to ANP alone, improved without renal injury when administered combination therapy consisting of low doses of ANP and DA, suggesting that this combined therapy might be useful for better management of ADHF in patients without diuretic responses with ANP alone. Further prospective studies are warranted. PMID- 23924942 TI - Arbuscular mycorrhizal fungi and plant growth-promoting pseudomonads increases anthocyanin concentration in strawberry fruits (Fragaria x ananassa var. Selva) in conditions of reduced fertilization. AB - Anthocyanins are a group of common phenolic compounds in plants. They are mainly detected in flowers and fruits, are believed to play different important roles such as in the attraction of animals and seed dispersal, and also in the increase of the antioxidant response in tissues directly or indirectly affected by biotic or abiotic stress factors. As a major group of secondary metabolites in plants commonly consumed as food, they are of importance in both the food industry and human nutrition. It is known that arbuscular mycorrhizal (AM) fungi can influence the plant secondary metabolic pathways such as the synthesis of essential oils in aromatic plants, of secondary metabolites in roots, and increase flavonoid concentration. Plant Growth-Promoting Bacteria (PGPB) are able to increase plant growth, improving plant nutrition and supporting plant development under natural or stressed conditions. Various studies confirmed that a number of bacterial species living on and inside the root system are beneficial for plant growth, yield and crop quality. In this work it is shown that inoculation with AM fungi and/or with selected and tested Pseudomonas strains, under conditions of reduced fertilization, increases anthocyanin concentration in the fruits of strawberry. PMID- 23924943 TI - Involvement of miR-20a in promoting gastric cancer progression by targeting early growth response 2 (EGR2). AB - Gastric cancer (GC) is one of the most common cancers, with high incidences in East Asia. microRNAs (miRNAs) play essential roles in the carcinogenesis of GC. miR-20a was elevated in GC, while the potential function of miR-20a was poorly understood. miR-20a expression was examined in GC tissues and cell lines. The effects of miR-20a on the growth, migration, invasion, and chemoresistance of GC cells were examined. Luciferase reporter assay and Western blot were used to screen the target of miR-20a. miR-20a was increased in GC tissues and cell lines. miR-20a promoted the growth, migration and invasion of GC cells, enhanced the chemoresistance of GC cells to cisplatin and docetaxel. Luciferase activity and Western blot confirmed that miR-20a negatively regulated EGR2 expression. Overexpression of EGR2 significantly attenuated the oncogenic effect of miR-20a. miR-20a was involved in the carcinogenesis of GC through modulation of the EGR2 signaling pathway. PMID- 23924946 TI - Multiscale distribution of oxygen puddles in 1/8 doped YBa2Cu3O6.67. AB - Despite intensive research a physical explanation of high Tc superconductors remains elusive. One reason for this is that these materials have generally a very complex structure making useless theoretical models for a homogeneous system. Little is known on the control of the critical temperature by the space disposition of defects because of lack of suitable experimental probes. X-ray diffraction and neutron scattering experiments used to investigate y oxygen dopants in YBa2Cu3O6+y lack of spatial resolution. Here we report the spatial imaging of dopants distribution inhomogeneity in YBa2Cu3O6.67 using scanning nano X-ray diffraction. By changing the X-ray beam size from 1 micron to 300 nm of diameter, the lattice inhomogeneity increases. The ordered oxygen puddles size distribution vary between 6-8 nm using 1 * 1 MUm(2) beam, while it is between 5 12 nm with a fat tail using the 300 * 300 nm(2) beam. The increased inhomogeneity at the nanoscale points toward a network of superconducting puddles made of ordered oxygen interstitials. PMID- 23924944 TI - The role of thyroid hormone signaling in the prevention of digestive system cancers. AB - Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin alphaVbeta3. Systemic thyroid hormone levels are controlled via activation and deactivation by iodothyronine deiodinases in the liver and other tissues. Given that thyroid hormone signaling has been characterized as a major effector of digestive system growth and homeostasis, numerous investigations have examined its role in the occurrence and progression of cancers in various tissues of this organ system. The present review summarizes current findings regarding the effects of thyroid hormone signaling on cancers of the esophagus, stomach, liver, pancreas, and colon. Particular attention is given to the roles of different thyroid hormone receptor isoforms, the novel integrin alphaVbeta3 receptor, and thyroid hormone-related nutrients as possible protective agents and therapeutic targets. Future investigations geared towards a better understanding of thyroid hormone signaling in digestive system cancers may provide preventive or therapeutic strategies to diminish risk, improve outcome and avert recurrence in afflicted individuals. PMID- 23924947 TI - Differential induction of apoptosis and senescence by the DNA methyltransferase inhibitors 5-azacytidine and 5-aza-2'-deoxycytidine in solid tumor cells. AB - Epigenetic alterations are a hallmark of cancer that govern the silencing of genes. Up to now, 5-azacytidine (5-aza-CR, Vidaza) and 5-aza-2'-deoxycytidine (5 aza-dC, Dacogen) are the only clinically approved DNA methyltransferase inhibitors (DNMTi). Current effort tries to exploit DNMTi application beyond acute leukemia or myelodysplastic syndrome, especially to solid tumors. Although both drugs only differ by a minimal structural difference, they trigger distinct molecular mechanisms that are highly relevant for a rational choice of new combination therapies. Therefore, we investigated cell death pathways in vitro in human hepatoma, colon, renal, and lung cancer cells and in vivo in chorioallantoic membrane and xenograft models. Real-time cancer cell monitoring and cytokine profiling revealed a profoundly distinct response pattern to both drugs. 5-aza-dC induced p53-dependent tumor cell senescence and a high number of DNA double-strand breaks. In contrast, 5-aza-CR downregulated p53, induced caspase activation and apoptosis. These individual response patterns of tumor cells could be verified in vivo in chorioallantoic membrane assays and in a hepatoma xenograft model. Although 5-aza-CR and 5-aza-dC are viewed as drugs with similar therapeutic activity, they induce a diverse molecular response in tumor cells. These findings together with other reported differences enable and facilitate a rational design of new combination strategies to further exploit the epigenetic mode of action of these two drugs in different areas of clinical oncology. PMID- 23924948 TI - Advances in the understanding of specific metabolic rates of major organs and tissues in humans. AB - PURPOSE OF REVIEW: To present recent evidence on organ and tissue metabolic rates in humans to explain the variance in resting energy expenditure (REE). RECENT FINDINGS: In humans, present knowledge on specific metabolic activities (i.e. ki values) refers to seven organs and tissues - brain, heart, liver, kidneys, skeletal muscle, adipose tissue and residual mass - with ki-values of 240, 440, 200, 440, 13, 4.5 and 12 kcal/kg/day, provided by Elia in 1992. Detailed body composition data, as derived from whole body MRI together with measurements of whole body REE, were used to validate ki-values in nonobese, healthy and middle aged adults. There is no sex difference, but minor, that is 2 and 3% deviations are found for age above 55 years and obesity, respectively. By contrast, in adolescents, differences of about 100 kcal/day or 7.3% of measured REE were observed. There is first evidence for changes in ki-values with either weight loss or weight regain after weight loss. Altogether these data suggest that in adolescence and at age above 55 years, in the obese and with weight change, organ and tissue masses differ in cellularity and/or their specific metabolic rates. Presently, direct assessment of specific organ and tissue metabolic rates in humans by either NMR spectroscopy or PET, together with detailed body composition analysis, has not been performed systematically. SUMMARY: We need to become more skilled in methods and models used for detailed body composition analysis together with detailed assessment of energy expenditure in humans. PMID- 23924945 TI - The role of antioxidation and immunomodulation in postnatal multipotent stem cell mediated cardiac repair. AB - Oxidative stress and inflammation play major roles in the pathogenesis of coronary heart disease including myocardial infarction (MI). The pathological progression following MI is very complex and involves a number of cell populations including cells localized within the heart, as well as cells recruited from the circulation and other tissues that participate in inflammatory and reparative processes. These cells, with their secretory factors, have pleiotropic effects that depend on the stage of inflammation and regeneration. Excessive inflammation leads to enlargement of the infarction site, pathological remodeling and eventually, heart dysfunction. Stem cell therapy represents a unique and innovative approach to ameliorate oxidative stress and inflammation caused by ischemic heart disease. Consequently, it is crucial to understand the crosstalk between stem cells and other cells involved in post-MI cardiac tissue repair, especially immune cells, in order to harness the beneficial effects of the immune response following MI and further improve stem cell-mediated cardiac regeneration. This paper reviews the recent findings on the role of antioxidation and immunomodulation in postnatal multipotent stem cell-mediated cardiac repair following ischemic heart disease, particularly acute MI and focuses specifically on mesenchymal, muscle and blood-vessel-derived stem cells due to their antioxidant and immunomodulatory properties. PMID- 23924949 TI - Interleukin-6 and obesity: the crosstalk between intestine, pancreas and liver. AB - PURPOSE OF REVIEW: The concept of IL-6 as a deleterious interleukin was challenged by its anti-inflammatory actions. RECENT FINDINGS: The beneficial health effects of exercise and the crosstalk between insulin-sensitive tissues and insulin-producing cells are mediated by IL-6. SUMMARY: IL-6 displays pleiotropic functions in a tissue-specific and physiological context-dependent manner. There is evidence suggesting that IL-6 worsens insulin resistance in the liver and adipose tissue, while improving insulin sensitivity in the muscle. The effects of this cytokine are influenced by its acute or chronical presence, the latter being associated with insulin resistance. IL-6 has anti-inflammatory effects and a compensatory role in obesity by increasing islet GLP-1 production. The therapeutic approach of blocking IL-6 signal can be diabetogenic. PMID- 23924950 TI - Modern treatment of short bowel syndrome. AB - PURPOSE OF REVIEW: Recently, the US Food and Drug Administration and the European Medicines Agency approved the glucagon-like peptide 2 analogue, teduglutide, for the treatment of short bowel syndrome (SBS), and this review describes the physiological basis for its clinical use. RECENT FINDINGS: By affecting the intestinal neuroendocrine system, hormones may promote the growth of the intestinal mucosa, restore a more normal gastric emptying and secretion, stimulate intestinal blood flow, increase intestinal barrier function, immunity and absorption, and thereby promote structural and functional adaptation following intestinal resection. In a 3-week, phase 2, metabolic balance study, teduglutide increased intestinal wet weight absorption by ~700 g/day and reduced faecal energy losses by ~0.8 MJ/day. In two subsequent 24-week, phase 3 studies in SBS patients with intestinal failure (SBS-IF), teduglutide reduced the need for parenteral support in the same magnitude. SUMMARY: Teduglutide adds incremental benefit to the limited medical treatment armamentarium in SBS patients. Modern treatments should aim to maximize remnant intestinal absorption, decrease malabsorption and accompanying symptoms, reduce the need, burdens and complications related to parenteral support, and ultimately improve the health related quality of life in SBS-IF patients. Future research should target and implement other key hormones with similar effects, thereby promoting intestinal adaptation and rehabilitation in SBS patients. PMID- 23924951 TI - Current world literature. Assessment of nutritional status and analytical methods. PMID- 23924953 TI - Hemispheric asymmetry of ipsilateral motor cortex activation in motor skill learning. AB - In this study, we investigated how ipsilateral motor cortex (M1) activation during unimanual hand movements and hemispheric asymmetry changed after motor skill learning. Eleven right-handed participants preformed a two-ball-rotation motor task with the right and the left hand, separately, in all experimental sessions. Before and after exercise sessions, the degree of ipsilateral M1 activation during brief execution of the motor task was measured as changes in the size of motor-evoked potentials (MEPs) of the thenar and the first dorsal interosseous muscle of the nontask hand using transcranial magnetic stimulation. Before exercise, MEPs of the nontask hand were significantly facilitated on both sides during the motor task. After exercise, facilitation of MEPs of the nontask hand during the motor task was significantly reduced for the right hand (thenar: P=0.014, first dorsal interosseous: P=0.022) but not for the left hand. We conclude that ipsilateral M1 activation, associated with a complex motor task, is first symmetrical in both hemispheres. However, on exercise, ipsilateral activation is reduced only in left M1, indicating a stronger learning-dependent modification of motor networks within the left hemisphere. PMID- 23924954 TI - Nanog attenuates lipopolysaccharide-induced inflammatory responses by blocking nuclear factor-kappaB transcriptional activity in BV-2 cells. AB - Nanog, a unique homeobox transcription factor, maintains self-renewal and pluripotency of embryonic stem cells by binding to nuclear factor kappaB proteins in order to inhibit their transcriptional and prodifferentiation activities. We previously reported that Nanog attenuated inflammatory responses in rat primary microglia cells stimulated by lipopolysaccharide. However, the effects of Nanog on another microglia cell type, BV-2 cells, are still unknown. In this study, we investigated whether Nanog attenuated inflammatory responses in lipopolysaccharide-stimulated BV-2 cells and found that Nanog significantly decreased the release of nitric oxide and the expression of inducible nitric oxide synthase at the mRNA and protein levels. The production of proinflammatory cytokines including tumor necrosis factor-alpha and interleukin-1beta was also significantly inhibited by Nanog. Further, we observed that the transcriptional activity of nuclear factor kappaB was dramatically reduced by Nanog. These results suggest that Nanog may be a potential anti-inflammatory therapy for neurological diseases caused by persistent microglia activation. PMID- 23924955 TI - Increased virulence of neuraminidase inhibitor-resistant pandemic H1N1 virus in mice: potential emergence of drug-resistant and virulent variants. AB - Pandemic H1N1 2009 (A[H1N1]pdm09) variants associated with oseltamivir resistance have emerged with a histidine-to-tyrosine substitution in the neuraminidase(NA) at position 274 (H274Y). To determine whether the H274Y variant has increased virulence potential, A(H1N1)pdm09 virus, with or without the H274Y mutation, was adapted by serial lung-to-lung passages in mice. The mouse-adapted H274Y (maCA04H274Y) variants showed increased growth properties and virulence in vitro and in vivo while maintaining high NA inhibitor resistance. Interestingly, most maCA04H274Y and maCA04 viruses acquired common mutations in HA (S183P and D222G) and NP (D101G), while only maCA04H274Y viruses had consensus additional K153E mutation in the HA gene, suggesting a potential association with the H274Y substitution. Collectively, our findings highlight the potential emergence of A(H1N1)pdm09 drug-resistant variants with increased virulence and the need for rapid development of novel antiviral drugs. PMID- 23924956 TI - Podocyte-specific deletion of NDST1, a key enzyme in the sulfation of heparan sulfate glycosaminoglycans, leads to abnormalities in podocyte organization in vivo. AB - Heparan sulfate proteoglycans have been shown to modulate podocyte adhesion to- and pedicel organization on--the glomerular basement membrane. Recent studies showed that foot process effacement developed in a mutant mouse model whose podocytes were unable to assemble heparan sulfate glycosaminoglycan chains. This study, a further refinement, explored the role of heparan N-sulfation on podocyte behavior. A novel mutant mouse (Ndst1(-/-)) was developed, having podocyte specific deletion of Ndst1, the enzyme responsible for N-sulfation of heparan sulfate chains. Podocytes having this mutation had foot process effacement and abnormal adhesion to Bowman's capsule. Although glomerular hypertrophy did develop in the kidneys of mutant animals, mesangial expansion was not seen. The lack of heparan N-sulfation did not affect the expression of agrin or perlecan proteoglycan core proteins. Loss of N-sulfation did not result in significant proteinuria, but the increase in the albumin/creatinine ratio was coincident with the development of the enlarged lysosomes in the proximal tubules. Thus, although the renal phenotype of the Ndst1(-/-) mouse is mild, the data show that heparan chain N-sulfation plays a key role in podocyte organization. PMID- 23924958 TI - Interventions provided in the acute phase for mild traumatic brain injury: a systematic review. AB - BACKGROUND: Most patients who sustain mild traumatic brain injury (mTBI) have persistent symptoms at 1 week and 1 month after injury. This systematic review investigated the effectiveness of interventions initiated in acute settings for patients who experience mTBI. METHODS: We performed a systematic review of all randomized clinical trials evaluating any intervention initiated in an acute setting for patients experiencing acute mTBI. All possible outcomes were included. The primary sources of identification were MEDLINE, Embase, PsycINFO, CINAHL, and the Cochrane Central register of Controlled Trials, from 1980 to August 2012. Hand searching of proceedings from five meetings related to mTBI was also performed. Study selection was conducted by two co-authors, and data abstraction was completed by a research assistant specialized in conducting systematic reviews. Study quality was evaluated using Cochrane's Risk of Bias assessment tool. RESULTS: From a potential 15,156 studies, 1,268 abstracts were evaluated and 120 articles were read completely. Of these, 15 studies fulfilled the inclusion/exclusion criteria. One study evaluated a pharmacological intervention, two evaluated activity restriction, one evaluated head computed tomography scan versus admission, four evaluated information interventions, and seven evaluated different follow-up interventions. Use of different outcome measures limited the possibilities for analysis. However, a meta-analysis of three studies evaluating various follow-up strategies versus routine follow-up or no follow-up failed to show any effect on three outcomes at 6 to 12 months post trauma. In addition, a meta-analysis of two studies found no effect of an information intervention on headache at 3 months post-injury. CONCLUSIONS: There is a paucity of well-designed clinical studies for patients who sustain mTBI. The large variability in outcomes measured in studies limits comparison between them. PMID- 23924957 TI - Adventitial transduction of lentivirus-shRNA-VEGF-A in arteriovenous fistula reduces venous stenosis formation. AB - Venous neointimal hyperplasia (VNH) causes hemodialysis vascular access failure. Here we tested whether VNH formation occurs in part due to local vessel hypoxia caused by surgical trauma to the vasa vasorum of the outflow vein at the time of arteriovenous fistula placement. Selective targeting of the adventitia of the outflow vein at the time of fistula creation was performed using a lentivirus delivered small-hairpin RNA that inhibits VEGF-A expression. This resulted in significant increase in mean lumen vessel area, decreased media/adventitia area, and decreased constrictive remodeling with a significant increase in apoptosis (increase in caspase 3 activity and TUNEL staining) accompanied with decreased cellular proliferation and hypoxia-inducible factor-1alpha at the outflow vein. There was significant decrease in cells staining positive for alpha-smooth muscle actin (a myofibroblast marker) and VEGFR-1 expression with a decrease in MMP-2 and MMP-9. These results were confirmed in animals that were treated with humanized monoclonal antibody to VEGF-A with similar results. Since hypoxia can cause fibroblast to differentiate into myofibroblasts, we silenced VEGF-A gene expression in fibroblasts and subjected them to hypoxia. This decreased myofibroblast production, cellular proliferation, cell invasion, MMP-2 activity, and increased caspase 3. Thus, VEGF-A reduction at the time of arteriovenous fistula placement results in increased positive vascular remodeling. PMID- 23924959 TI - First identification of 5,11-dideoxytetrodotoxin in marine animals, and characterization of major fragment ions of tetrodotoxin and its analogs by high resolution ESI-MS/MS. AB - Even though tetrodotoxin (TTX) is a widespread toxin in marine and terrestrial organisms, very little is known about the biosynthetic pathway used to produce it. By describing chemical structures of natural analogs of TTX, we can start to identify some of the precursors that might be important for TTX biosynthesis. In the present study, an analog of TTX, 5,11-dideoxyTTX, was identified for the first time in natural sources, the ovary of the pufferfish and the pharynx of a flatworm (planocerid sp. 1), by comparison with totally synthesized (-)-5,11 dideoxyTTX, using high resolution ESI-LC-MS. Based on the presence of 5,11 dideoxyTTX together with a series of known deoxy analogs, 5,6, 11-trideoxyTTX, 6,11-dideoxyTTX, 11-deoxyTTX, and 5-deoxyTTX, in these animals, we predicted two routes of stepwise oxidation pathways in the late stages of biosynthesis of TTX. Furthermore, high resolution masses of the major fragment ions of TTX, 6,11 dideoxyTTX, and 5,6,11-trideoxyTTX were also measured, and their molecular formulas and structures were predicted to compare them with each other. Although both TTX and 5,6,11-trideoxyTTX give major fragment ions that are very close, m/z 162.0660 and 162.1020, respectively, they are distinguishable and predicted to be different molecular formulas. These data will be useful for identification of TTXs using high resolution LC-MS/MS. PMID- 23924960 TI - The adverse prognostic hallmarks in identical twins with Langerhans cell histiocytosis: a clinical report and literature review. AB - Langerhans cell histiocytosis (LCH) is characterized by uncontrolled proliferation of Langerhans cells accompanying eosinophils. It often attacks children under 10 years of age. LCH in identical twins is very rare and its prognosis is different. Here we report identical-twin sisters with LCH. Computed tomography (CT) revealed osteolytic change in each twin's skull, and the elder exhibited poor eyesight. There were massive histiocyte-like cells surrounded by eosinophils in pathologic specimen of the abnormal lesions, which is typical pathologic finding in LCH. These pathologic cells were positive for S-100 and the cell surface protein CD1 antigen (CD1alpha), the known markers of LCH. After treating them with surgery, no symptoms were seen in the younger until now. While the older was found another soft mass (about 2.0 cm in diameter) in the left temporal area 18 months later. The same treatment was given to the older after admission, and she is healthy to date. To explore the relationship between hallmarks and the prognosis of identical-twin patients with LCH, we retrieved the 16 literatures (16 identical-twin pairs, 31 patients) listed in PubMed during the past 60 years. The data revealed all those patients who have disseminated to the bone marrow, spleen and liver with symptoms of fever and hepatosplenomegaly exhibited worse prognosis (9 out of the 31 patients). The other identical-twin subjects without infiltration of those organs recovered well. In conclusion, this study reveals the adverse hallmarks of prognosis in identical-twin patients with LCH by reviewing relevant literatures. PMID- 23924961 TI - Less is more: limiting the size of posterior fossa decompressions in Chiari I malformations. PMID- 23924962 TI - Prognosis for gunshot wounds to the head. PMID- 23924963 TI - Temporary artery occlusion in aneurysm surgery: patients with unruptured aneurysms. PMID- 23924964 TI - Meningiomas involving major dural sinuses: should we attempt at radical removal and venous repair? PMID- 23924965 TI - Not all roads lead to Rome.... PMID- 23924966 TI - Temporary clipping for unruptured aneurysms. PMID- 23924967 TI - Decision-making process for the treatment of intracranial chordomas. PMID- 23924968 TI - Back pain and lumbar disc disease in a military population: what conclusions can we draw? PMID- 23924969 TI - Endoscopic skull base surgery: probably not the time for meta-analyses but certainly for prospectively collected data. PMID- 23924970 TI - Perfect and good. PMID- 23924971 TI - Temporary artery occlusion in aneurysm surgery: patients with subarachnoid hemorrhage. PMID- 23924972 TI - Tiny but significant: perforators in aneurysm surgery. PMID- 23924973 TI - Enhancing surface reactivity with a noble metal. AB - Gold, the archetypal noble metal, is usually associated with an inhibition of surface reactivity by site blocking. In this paper however, we show that on Cu(100) surfaces a gold adlayer can actually increase the extent of reaction with the substrate. PMID- 23924974 TI - Dissecting the roles of Rac1 activation and deactivation in macropinocytosis using microscopic photo-manipulation. AB - Macropinocytosis, a fluid-phase endocytosis, is a crucial pathway for antigen uptake and presentation in macrophages. We attempted to characterise the activation and deactivation of a small GTPase molecular switch, Rac1, in macropinocytosis using microscopic photo-manipulation. Expression of genetically encoded photoactivatable-Rac1 (PA-Rac1) in RAW264 macrophages enabled the local, reversible control of macropinocytosis using blue laser irradiation. Marked membrane ruffling and unclosed pre-macropinosomes were observed in the irradiated region of macrophages under the persistent activation of PA-Rac1. Although phosphatidylinositol 4,5-bisphosphate and actin were also localised to this region, the recruitment of maturating endosome markers, such as phosphatidylinositol 3-phosphate and Rab21, was restricted until PA-Rac1 deactivation. After deactivating PA-Rac1 by ceasing irradiation, membrane ruffling immediately receded, and the macropinosomes acquired maturation markers. These data suggest that activation of Rac1 is sufficient to induce membrane ruffling and macropinocytic cup formation, but subsequent deactivation of Rac1 is required for macropinosome closure and further maturation. PMID- 23924976 TI - Compounding for behavior problems in companion animals. PMID- 23924975 TI - Update on transdermals for animal patients. PMID- 23924977 TI - Compounding antiangiogenic cancer therapy for animals. PMID- 23924978 TI - Combating Cardiovascular Disease with Compounded Medications-Part 2: clinical and Compounding Issues for Antihypertensive Drugs. PMID- 23924979 TI - Quality-control analytical methods: determination of tapped bulk volume for compounded prescriptions. PMID- 23924980 TI - Survey of state veterinary compounding laws and regulations. PMID- 23924981 TI - Basics of compounding for hair care-part 2: medicated conditioners. PMID- 23924982 TI - Physical and chemical stability of palonosetron hydrochloride with Lorazepam and midazolam hydrochloride during simulated y-site administration. AB - The objective of this study was to evaluate the physical and chemical stability of undiluted palonosetron hydrochloride 50 micrograms/mL in combination with lorazepam 0.5 mg/mL or midazolam hydrochloride 2 mg/mL in 5% dextrose injection during simulated Y-site administration. Triplicate test samples were prepared by admixing 5 mL of palonosetron hydrochloride with 5 mL of the lorazepam or midazolam hydrochloride admixture. Physical stability was assessed by using a multistep evaluation procedure that included both turbidimetric and particulate measurements as well as visual inspection. Chemical stabililty was assessed by using stability-indicating high-performance liquid chromatographic analytical techniques that determined drug concentrations. Evaluations were performed initially upon mixing and again 1 and 4 hours after mixing. The samples were clear and colorless when viewed in normal fluorescent room light and when viewed with a Tyndall beam. Measured turbidity remained unchanged; particulate content was low and changed little. High-performance liquid chromatographic analysis revealed that palonosetron hydrochloride, lorazepam, and midazolam hydrochloride remained stable throughout the 4-hour test with no drug loss. Palonosetron hydrochloride is physically compatible and chemically stable with lorazepam or midazolam hydrochloride during Y-site administration. PMID- 23924983 TI - Physical and chemical stability of palonosetron hydrochloride with topotecan hydrochloride and irinotecan hydrochloride during simulated y-site administration. AB - The objective of this study was to evaluate the physical and chemical stabilty of undiluted palonosetron hydrochloride 50 micrograms/mL in combination with topotecan hydrochloride 0.1 mg/mL or irinotecan hydrochloride 1 mg/mL in 5% dextrose injection during simulated Y-site administration. Triplicate test samples were prepared by admixing 5 mL of palonosetron hydrochloride with 5 mL of the topotecan hydrochloride or irinotecan hydrochloride admixture. Physical stabilty was assessed by using a multistep evaluation preocdure that included both turbidimetric and particulate measurement as well as visual inspection. Chemical stability was assessed by using stability-indicating high-performance liquid chromatographic analytical techniques to determine drug concentrations. Evaluations were performed initially upon mixing and again 1 and 4 hour after mixing. The palonosetron hydrochloride-topotecan hydrochloride samples were clear and pale yellow when viewed in normal fluorescent room light. When viewed with a Tyndall beam, the samples had a slight haziness. The palonosetron hydrochloride irinotecan hydrochloride samples were clear and colorless when viewed in in normal fluorescent room light and with a Tyndall beam. Measured turbidities remained unchanged; particulate contents were low and changed little. High performance liquid chromatographic analysis found that palonosetron hydrochloride, topotecan hydrochloride, and irinotecan hydrochloride remained stable throughout the 4-hour test. Little drug loss was observed. Palonosetron hydrochloride is physically compatible and chemically stable with topotecan hydrochloride and with irinotecan hydrochloride during Y-site administration. PMID- 23924984 TI - Bioavailability of promethazine in a topical pluronic lecithin organogel: a pilot study. AB - The purpose of this open-label, nonrandomized, crossover trial was to determine the bioavailability of promethazine formulated in a topical Pluronic lecithin organogel. The study was performed at a tertiary care facility. The study subjects were 15 healthy adult white men aged 21 to 40 years, all of whom met the inclusion criteria. Volunteers with a medical history of promethazine hypersensitivity, epileptic disorder, or extrapyramidal reactions, or who had an abnormal skin condition or were taking any medications were excluded. Promethazine 50 mg in a Pluronic lecithin organogel was applied once to the skin of the nondominant wrist of each of 15 subjects, and the application site was covered with an adhesive bandage. Blood samples were collected at baseline (time zero) before drug administration and at 15, 30, 60, 120, 240, and 360 minutes after drug administration. After a 21-day washout period, 10 of the subjects returned for administration of a single dose of intravenous promethazine 25 mg, and blood samples were again collected at the same time intervals as after the topical dose. A high-performance liquid chromatographic method was used to determine serum concentrations of promethazine. the calculated absolute bioavailability of topical promethazine was 2%. Mean AUC. were 16.63 ng.mL/hour for the topical preparation and 407.15 ng.mL/hour for the intravenous dose. At least 50% fo the subjects who received the topical promethazine preparation experieced sedation, and 73% experienced drowsiness; however, 100% of those who received intravenous promethazine experienced sedation. Although serum concentrations after application of topical promethazine were much lower than after parenteral administration, the study demonstrated that the topical promethazine formulation was absorbed systemically. These data suggest that further research regarding the bioavailability of promethazine in a topically applied Pluronic lecithin organogel is warranted. Clinical trials are needed that focus on the antiemetic efficacy of this formulation in similar and other populations. PMID- 23924985 TI - Comparison of automated and manual perimetry in patients with blepharoptosis. AB - PURPOSE: To compare Goldmann manual perimetry and Humphrey automated perimetry for sensitivity in detecting visual field loss, efficiency, and patient preference. METHODS: This prospective study compared Goldmann manual perimetry and Humphrey automated perimetry testing techniques in 20 consecutive preoperative blepharoptosis patients with unilateral or bilateral blepharoptosis with a marginal reflex distance of <=+2.5 mm, no dermatochalasis overhanging the eyelid margin, and no superior visual field defects due to glaucoma, neurologic disease, or other causes. Main outcome measures included efficiency, patient preference, and sensitivity in detecting visual field loss. Institutional review board approval was obtained prior to the start of the study. RESULTS: Goldmann perimetry had significantly shorter examination times (-Delta6.4 minutes, 95% confidence interval: 4.5-8.3, p < 0.001) and was preferred by most patients (70%). There was no statistically significant difference between the 2 techniques in detecting superior visual field loss at 90 degrees meridian. CONCLUSIONS: Goldmann manual perimetry for assessing visual field loss in blepharoptosis patients is more efficient than Humphrey automated perimetry and is preferred by patients. Both techniques are sensitive in detecting ptosis-related visual field loss. PMID- 23924986 TI - High-resolution ultrasound as an effective and practical tool to analyze eyebrow profile expansion in thyroid-associated periorbitopathy. AB - PURPOSE: Clinical, radiographic, and molecular studies have shown that patients with thyroid-associated orbitopathy exhibit volumetric expansion of eyebrow tissues. This clinicopathologic entity has been termed thyroid-associated periorbitopathy. The goal of this study was to determine whether high-resolution ultrasonography could be used to reliably quantify thyroid-associated periorbitopathy. METHODS: Institutional review board approval was obtained. The internal case-control study consisted of 12 subjects with unilateral-asymmetric thyroid-associated orbitopathy. High-resolution ultrasonography using a 15-MHz probe (Logiq p6) was performed by a single operator. Measurements were obtained 0.5 cm cephalad to the superior orbital rim at the midpupillary sagittal level. For each subject and tissue layer thickness (total tissue, dermis fat, retro orbicularis oculi fat), the measured values on the less affected side were subtracted from those on the more severely diseased side. Summary statistics were used to analyze results. RESULTS: High-resolution ultrasonography effectively demonstrated asymmetric expansion of total eyebrow tissue (p < 0.0001) and retro orbicularis oculi fat (p = 0.0003). No significant difference in dermis fat thickness was found between the 2 sides (p = 0.2). Hertel exophthalmometry measurements were statistically different between the 2 sides (p = 0.002). CONCLUSIONS: This study demonstrates that high-resolution ultrasonography independently confirms previously published studies of retro-orbicularis oculi fat expansion in patients with thyroid-associated orbitopathy. Compared with CT, MRI, and tissue biopsy, high-resolution ultrasonography is a more practical and cost-effective way to quantify and track thyroid-associated periorbitopathy over time. With its potential for real-time tissue assessment, high-resolution ultrasonography may be best suited for future studies of the dynamic relationship between globe and periorbital structures. PMID- 23924987 TI - Air reflux and other sequelae following endoscopic dacryocystorhinostomy. AB - PURPOSE: To assess postoperative sequelae of endoscopic dacryocystorhinostomy (endoDCR), including rates of air reflux and other otolaryngologic sequelae. METHODS: Patients who underwent endoDCR over a 5-year period were included in a follow-up questionnaire regarding side effects after surgery. The questionnaire included questions regarding tearing, air reflux, and nasal symptoms. RESULTS: Results were obtained on 82 patients (101 endoDCRs). Most patients were women (70.7%) and white (85.4%). The mean postoperative period was 39.7 months (range 8 66 months). The most common sequela was air reflux from the puncta (46 cases, 45.5%). Of the 82 patients, 58.7% experienced symptoms only "rarely," while 18.5% had symptoms daily. Air reflux was most commonly associated with nose blowing (73.9%). Success of endoDCR correlated with presence of air reflux (p = 0.0044). All patients with air reflux preferred having air reflux to epiphora. Epistaxis was present in 8 cases (7.9%) and nasal congestion in 21.8% of the cases. CONCLUSIONS: Treatment for epiphora with endoDCR results in air reflux in almost half of patients, which is minimally bothersome to patients. The presence of air reflux highly correlates with resolution of epiphora and has a similar incidence in external and endoDCRs. PMID- 23924988 TI - Management of congenital nasolacrimal duct obstruction--latin american study. AB - PURPOSE: To survey the management of congenital nasolacrimal duct obstruction, in particular, the timing of intervention and the use of massage, probing, nasolacrimal intubation, nasal endoscopy, and dacryocystorhinostomy. METHODS: This was an exploratory study that used an electronic questionnaire, which was sent via Internet to the members of Ojoplast, a social network composed of ophthalmologists from several Latin American countries. The responses were analyzed using adherence and the chi-square test. RESULTS: Seventy-two completed questionnaires were received. Approximately 64% of survey participants indicated that they use massage as the initial treatment for congenital nasolacrimal duct obstruction until 1 year of age and lacrimal probing (70.8%) for patients >1 year of age. Early probing used by 58.3% of the patients for a dilated lacrimal sac, and 66.7% reported that lacrimal system probing in conjunction with irrigation is effective. If the probing is not effective, 65.3% indicated that they repeat the procedure a second time. If the patient does not respond to massage or probing, 69.4% perform lacrimal system intubation. Sixty-two percent of the respondents indicated that they perform dacryocystorhinostomy for cases in which probing or intubation is not effective. CONCLUSIONS: The members of Ojoplast adopt massage as the initial treatment for congenital nasolacrimal duct obstruction for patients <1 year of age. Probing is performed on patients >1 year of age, and early probing is used only for cases of dilated lacrimal sac. When massage and probing are not effective, intubation is performed, and if intubation is unsuccessful, dacryocystorhinostomy is performed, in which the external approach to dacryocystorhinostomy is used most often. PMID- 23924989 TI - A case of nodular fasciitis causing compressive optic neuropathy. AB - A 16-year-old girl with worsening vision, new OD visual field deficits, and tumor in right orbital apex underwent biopsy and surgical excision. Orbital imaging revealed an apical tumor causing bony erosion. Histopathology confirmed the diagnosis of nodular fasciitis. This is a rare diagnosis, and one that can mimic a neoplastic process. To the authors' knowledge, this is the first case of nodular fasciitis in the deep orbit and the first case of nodular fasciitis causing an optic neuropathy. PMID- 23924990 TI - Perineural invasion of cutaneous squamous cell carcinoma along the zygomaticotemporal nerve. AB - The vast majority of periocular squamous cell carcinoma spreads intraorbitally along the supraorbital and infraorbital nerves into the cavernous sinus. A patient presented with a history of resected squamous cell carcinoma and pain in the zygomatic distribution. She was found to have temporalis involvement of the malignancy and invasion of the zygomaticotemporal nerve by histopathology. She underwent aggressive resection and adjuvant treatment with no evidence of recurrence at 8-month follow up. This case illustrates an uncommon route of squamous cell carcinoma spread through the zygomaticotemporal sensory nerve distribution. PMID- 23924992 TI - C-terminal alternative splicing of CaV1.3 channels distinctively modulates their dihydropyridine sensitivity. AB - The transcripts of L-type voltage-gated calcium channels (CaV) 1.3 undergo extensive alternative splicing. Alternative splicing, particularly in the C terminus, drastically modifies gating properties of the channel. However, little is known about whether alternative splicing could modulate the pharmacologic properties of CaV1.3 in a manner similar to the paralogous CaV1.2. Here we undertook the screening of different channel splice isoforms harboring splice variations in either the IS6 segment or the C terminus. Unexpectedly, while inclusion of exon 8a or 8, which code for IS6, did not alter dihydropyridine (DHP) sensitivity, distinct pharmacologic properties were observed for the various C-terminal splice isoforms. In the presence of external Ca(2+), fast inactivating splice variants including CaV1.342a and CaV1.343s with intact calmodulin-IQ domain interaction showed consistently low DHP sensitivity. Interestingly, attenuation of calcium-dependent inactivation with overexpression of calmodulin34 did not enhance the sensitivity of CaV1.342a, suggesting that the low DHP sensitivity may not be a result of fast channel inactivation. Alternatively, disruption of calmodulin-IQ domain binding in the CaV1.3Delta41 and full-length CaV1.342 channels was associated with heightened DHP sensitivity. In distinct contrast to the well-known modulation of DHP blockade of CaV1.2 channels, this study has therefore uncovered a novel mechanism for modulation of the pharmacologic properties of CaV1.3 channels through posttranscriptional modification of the C terminus. PMID- 23924991 TI - Gestational choriocarcinoma metastasis to the extraocular muscle: a case report. AB - This case report describes a biopsy-proven metastasis of gestational choriocarcinoma to the medial rectus muscle. Patient evaluation and follow up included comprehensive ophthalmologic history and examination, external and fundus photography, immunohistochemistry preparations of the medial rectus muscle specimen, MRI, ultrasound of the abdomen and pelvis, comprehensive blood tests, and CT scans of the chest, abdomen, and pelvis. The tissue specimen was obtained via a medial perilimbal conjunctival peritomy. MRI revealed a mass intrinsic to the right medial rectus muscle. Immunohistochemical staining confirmed gestational choriocarcinoma metastasis in medial rectus muscle biopsy. The patient showed general and orbital improvement following 7 subsequent cycles of chemotherapy. In conclusion, gestational choriocarcinoma may metastasize to the orbit in addition to the previously reported ocular site, the choroid. A chemotherapy regimen of etoposide, methotrexate, actinomycin-D, cyclophosphamide, and vincristine can effectively treat the intraorbital component of the disease. PMID- 23924994 TI - Synthesis of new acadesine (AICA-riboside) analogues having acyclic D-ribityl or 4-hydroxybutyl chains in place of the ribose. AB - The antiviral activity of certain acyclic nucleosides drew our attention to the fact that the replacement of the furanose ring by an alkyl group bearing hydroxyl(s) could be a useful structural modification to modulate the biological properties of those nucleosides. Herein, we report on the synthesis of some novel acadesine analogues, where the ribose moiety is mimicked by a D-ribityl or by a hydroxybutyl chain. PMID- 23924993 TI - Antibacterial and herbicidal activity of ring-substituted 2-hydroxynaphthalene-1 carboxanilides. AB - In this study, a series of twenty-two ring-substituted 2-hydroxynaphthalene-1 carboxanilides were prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Staphylococcus aureus, three methicillin-resistant S. aureus strains, Mycobacterium marinum, M. kasasii, M. smegmatis. and M. avium paratuberculosis. The compounds were also tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. 2-Hydroxy-N-phenylnaphthalene-1 carboxanilide and 2-hydroxy-N-(3-trifluoromethylphenyl)naphthalene-1-carboxamide (IC50 = 29 umol/L) were the most active PET inhibitors. Some of tested compounds showed the antibacterial and antimycobacterial activity against the tested strains comparable or higher than the standards ampicillin or isoniazid. Thus, for example, 2-hydroxy-N-(3-nitrophenyl)naphthalene-1-carboxamide showed MIC = 26.0 umol/L against methicillin-resistant S. aureus and MIC = 51.9 umol/L against M. marinum, or 2-hydroxy-N-phenylnaphthalene-1-carboxamide demonstrated MIC = 15.2 umol/L against M. kansasii. The structure-activity relationships for all compounds are discussed. PMID- 23924996 TI - Cautious optimism for HIV vaccine science. PMID- 23924995 TI - Validating chronic disease ascertainment algorithms for use in the Canadian longitudinal study on aging. AB - We validated seven chronic disease ascertainment algorithms for use in the Canadian Longitudinal Study on Aging. The algorithms pertained to diabetes mellitus type 2, parkinsonism, chronic airflow obstruction (CAO), hand osteoarthritis (OA), hip OA, knee OA, and ischemic heart disease. Our target recruitment was 20 cases and controls per disease; some cases were controls for unrelated diseases. Participants completed interviewer-administered disease symptom and medication use questionnaires. Diabetes cases and controls underwent fasting glucose testing; CAO cases and controls underwent spirometry testing. For each disease, the appropriate algorithm was used to classify participants' disease status (positive or negative for disease). We also calculated sensitivity and specificity using physician diagnosis as the reference standard. The final sample involved 176 participants recruited in three Canadian cities between 2009 and 2011. Most estimated sensitivities and specificities were 80 per cent or more, indicating that the seven algorithms correctly identified individuals with the target disease. PMID- 23924997 TI - Organizing the HIV vaccine development effort. AB - PURPOSE OF REVIEW: To describe and compare the diverse organizational structures and funding mechanisms applied to advance HIV preventive vaccine research and development and to help explain and inform evolving infrastructures and collaborative funding models. RECENT FINDINGS: On the basis of models that have been tried, improved or abandoned over three decades, the field seems to have settled into a relatively stable set of diverse initiatives, each with its own organizational signature. At the same time, this set of organizations is forging cross-organizational collaborations, which promise to acquire newly emergent beneficial properties. SUMMARY: Strong motivation to expedite HIV vaccine R&D has driven a diversity of customized and inventive organizational approaches, largely government and foundation funded. Although no one approach has proven a panacea, the field has evolved into a constellation of often overlapping organizations that complement or reinforce one another. The Global HIV Vaccine Enterprise, a responsive, rapidly evolving loose infrastructure, is an innovative collaboration to catalyze that evolution. PMID- 23924998 TI - Elicitation of HIV-1-neutralizing antibodies against the CD4-binding site. AB - PURPOSE OF REVIEW: The HIV-1 site of binding for the CD4 receptor has long attracted attention as a potential supersite of vulnerability to antibody mediated neutralization. We review recent findings related to effective CD4 binding site antibodies isolated from HIV-1-infected individuals and discuss implications for immunogen design. RECENT FINDINGS: Highly effective CD4-binding site antibodies such as antibody VRC01 have the ability to neutralize over 90% of circulating HIV-1 strains. Sequence and structural analysis of these antibodies from over half a dozen HIV-1-infected donors reveals remarkable similarity in their ontogenies and their modes of recognition, all of which involve mimicry of CD4 receptor by antibody-heavy chain. Meanwhile, other effective CD4-binding site neutralizers such as antibody CH103 have been shown to utilize a different mode of recognition, with next-generation sequencing of both virus and antibody suggesting co-evolution to drive the development of antibody-neutralization breadth. SUMMARY: The nexus of information concerning the CD4-binding site and its recognition by human antibodies capable of effective neutralization has expanded remarkably in the last few years. Although barriers are substantial, new insights from donor-serum responses, atomic-level structures of antibody-Env complexes, and next-generation sequencing of B-cell transcripts are invigorating vaccine-design efforts to elicit effective CD4-binding site antibodies. PMID- 23924999 TI - New paradigms for functional HIV-specific nonneutralizing antibodies. AB - PURPOSE OF REVIEW: Although a large number of novel broadly neutralizing antibodies has been recently described, the induction of such antibodies via vaccination has proven difficult. By contrast, nonneutralizing antibodies arise early during infection and have been repeatedly associated with both protection from infection and disease progression. RECENT FINDINGS: We are beginning to gain new insights into the broader landscape of antiviral mechanisms that nonneutralizing antibodies may harness to fight HIV, providing an unprecedented breadth of approaches by which HIV can be blocked and contained. SUMMARY: In this review, we summarize the characteristics of nonneutralizing antibodies, their role in HIV infection, and new paradigm-shifting functions that may be exploited by next-generation vaccine approaches aimed at blocking HIV infection. PMID- 23925001 TI - Nonreplicating vectors in HIV vaccines. AB - PURPOSE OF REVIEW: We review the broad spectrum of nonreplicating viral vectors which have been studied extensively, from preclinical studies through clinical efficacy trials, and include some of our most promising HIV vaccine candidates. RECENT FINDINGS: The success of the RV144 trial, with a canarypox virus-based regimen, contrasts with the failures of the adenovirus-5 (Ad5)-based regimens in the Step study, the Phambili study [HIV Vaccine Trials Network (HVTN) 503], and the HVTN 505 study which was recently modified to halt vaccinations because of clinical futility. SUMMARY: The safety profile, immunogenicity, and variety of available candidates make the nonreplicating viral vectors attractive in HIV vaccine development. Building from the success of the RV144 study, further studies of Orthopoxvirus-based vaccines, including vaccinia-based vaccines, are ongoing and planned for the future. Despite the failures of the Ad5-based vaccines in clinical efficacy trials, other adenovirus serotypes remain promising candidates, especially in prime-boost combination with other products, and with the potential use of mosaic inserts. Other nonreplicating viral vectors such as the rhabdoviruses, alphaviruses, and the nonhuman adenoviruses, provide additional avenues for exploration. PMID- 23925000 TI - Development of replication-competent viral vectors for HIV vaccine delivery. AB - PURPOSE OF REVIEW: To briefly describe some of the replication-competent vectors being investigated for development of candidate HIV vaccines focusing primarily on technologies that have advanced to testing in macaques or have entered clinical trials. RECENT FINDINGS: Replication-competent viral vectors have advanced to the stage at which decisions can be made regarding the future development of HIV vaccines. The viruses being used as replication-competent vector platforms vary considerably, and their unique attributes make it possible to test multiple vaccine design concepts and also mimic various aspects of an HIV infection. Replication-competent viral vectors encoding simian immunodeficiency virus or HIV proteins can be used to safely immunize macaques, and in some cases, there is evidence of significant vaccine efficacy in challenge protection studies. Several live HIV vaccine vectors are in clinical trials to evaluate immunogenicity, safety, the effect of mucosal delivery, and potential effects of preexisting immunity. SUMMARY: A variety of DNA and RNA viruses are being used to develop replication-competent viral vectors for HIV vaccine delivery. Multiple viral vector platforms have proven to be well tolerated and immunogenic with evidence of efficacy in macaques. Some of the more advanced HIV vaccine prototypes based on vesicular stomatitis virus, vaccinia virus, measles virus, and Sendai virus are in clinical trials. PMID- 23925003 TI - Risks and benefits of lifelong antiretroviral treatment for pregnant and breastfeeding women: a review of the evidence for the Option B+ approach. AB - PURPOSE OF REVIEW: Considerable debate has emerged on whether Option B+ (B+), initiation of lifelong antiretroviral therapy (ART) for all pregnant and breastfeeding women, is the best approach to achieving elimination of mother-to child-transmission. However, direct evidence and experience with B+ is limited. We review the current evidence informing the proposed benefits and potential risks of the B+ approach, distinguishing individual health concerns for mother and child from program delivery and public health issues. RECENT FINDINGS: For mothers and infants, B+ may offer significant benefits for transmission prevention and maternal health. However, several studies raise concerns about the safety of ART exposure to fetuses and infants, as well as adherence challenges for pregnant and breastfeeding mothers. For program delivery and public health, B+ presents distinct advantages in terms of transmission prevention to uninfected partners and increased simplicity potentially improving program feasibility, access, uptake, and retention in care. Despite being more costly in the short term, B+ will likely be cost effective over time. SUMMARY: This review provides a detailed analysis of risks and benefits of B+. As national programs adopt this approach, it will be critical to carefully assess both short-term and long-term maternal and infant outcomes. PMID- 23925002 TI - Elimination of perinatal HIV infection in the USA and other high-income countries: achievements and challenges. AB - PURPOSE OF REVIEW: To describe progress and challenges to elimination of mother to-child HIV transmission (EMCT) in high-income countries. RECENT FINDINGS: Despite ongoing declines in the number of perinatally HIV-infected infants in most high-income countries, the number of HIV-infected women delivering may be increasing, accompanied by apparent changes in this population, including higher percentages with antiretroviral 'pretreatment' (with possible antiretroviral resistance), other coinfections, mental health diagnoses, and recent immigration. The impact of antiretroviral resistance on mother-to-child transmission is yet to be defined. A substantial minority of infant HIV acquisitions occurs in the context of maternal acute HIV infection during pregnancy. Some infant infections occur after pregnancy, for example, by premastication of food, or breastfeeding (perhaps by an uninfected woman who acquires HIV while breastfeeding). SUMMARY: The issues of EMCT are largely those of providing proper care for HIV-infected women. Use of combination ART by increasing proportions of the infected population may function as a structural intervention important to achieving this goal. Providers and public health systems need to be alert for HIV-serodiscordant couples in which the woman is uninfected and for changes in the population of HIV infected pregnant women. Accurate data about HIV-exposed pregnancies are vital to monitor progress toward EMCT. PMID- 23925004 TI - Current world literature. Bibliography. PMID- 23925006 TI - Role of phospholipase C in cell invasion and metastasis. AB - Phospholipases are enzymes that use phospholipids as substrate and are classified in three major classes A, C and D based on the reaction they catalyse. Phosphatidylinositol-specific Phospholipase C enzymes utilize phosphatidylinositol 4,5-bisphosphate as substrate and cleave the bond between the glycerol and the phosphate to produce important second messenger such as inositol trisphosphate and diacylglycerol. The Phospholipase C members are the most well-known phospholipases for their role in lipid signalling and cell proliferation and comprise 13 isoforms classified in 6 distinct sub-families. In particular, signalling activated by Phospholipase C gamma, mostly activated by receptor and non-receptor tyrosine kinases, is well characterized in different cell systems. Increasing evidence suggest that Phospholipase C gamma plays a key role in cell migration and invasion. Because of its role in cell growth and invasion, aberrant Phospholipase C gamma signalling can contribute to carcinogenesis. A major challenge facing investigators who seek to target Phospholipase C gamma directly is the fact that it is considered an "undruggable" protein. Indeed, isoform specificity and toxicity represents a big hurdle in the development of Phospholipase C gamma small molecule inhibitors. Therefore, a future development in the field could be the identification of interacting partners as therapeutic targets that could be more druggable than Phospholipase C gamma. PMID- 23925008 TI - Trends in evolving technologies in the operating room of the future. PMID- 23925007 TI - Evidence of neurodegeneration in autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a neurological disorder in which a significant number of children experience a developmental regression characterized by a loss of previously-acquired skills and abilities. Loss of neurological function in ASD, as observed in affected children who have regressed, can be explained as neurodegeneration. Although there is research evidence of neurodegeneration or progressive encephalopathy in ASD, the issue of neurodegeneration in ASD is still under debate. Evidence of neurodegeneration in the brain in ASD includes: (1) neuronal cell loss, (2) activated microglia and astrocytes, (3) proinflammatory cytokines, (4) oxidative stress, and (5) elevated 8-oxo-guanosine levels. The evidence from this review suggests that neurodegeneration underlies the loss of neurological function in children with ASD who have experienced regression and loss of previously acquired skills and abilities, and that research into treatments to address the issue of neurodegeneration in ASD are warranted. PMID- 23925009 TI - Impact of advanced laparoscopy courses on present surgical practice. AB - BACKGROUND AND OBJECTIVES: The introduction of new surgical techniques has made training in laparoscopic procedures a necessity for the practicing surgeon, but acquisition of new surgical skills is a formidable task. This study was conducted to assess the impact of advanced laparoscopic workshops on caseload patterns of practicing surgeons. METHODS: After we obtained institutional review board approval, a survey of practicing surgeons who participated in advanced laparoscopic courses was distributed; the results were analyzed for statistical significance. The courses were held at the University of Nebraska Medical Center between January 2002 and December 2010. Questionnaires were mailed, faxed, and e mailed to surgeons. RESULTS: Of the 109 surgeons who participated in the advanced laparoscopy courses, 79 received surveys and 30 were excluded from the survey because of their affiliation with the University of Nebraska Medical Center. A total of 47 responses (59%) were received from 41 male and 6 female surgeons. The median response time from completion of the course to completion of the survey was 13.2 months (range, 6.8-19.1 months). The mean age of participating surgeons was 39.2 years (range, 29-51 years). The mean time since residency was 8.4 years (range, 0.8-21 years). Eleven surgeons had completed a minimal number of laparoscopic cases in residency (<50), 17 surgeons had completed a moderate number of laparoscopic procedures in residency (50-200), and 21 surgeons had completed a significant number of cases during residency (>200). Of the surgeons who responded, 94% were in private practice. Fifty-seven percent of the participating surgeons who responded reported a change in laparoscopic practice patterns after the courses. Of these surgeons, 24% had a limited residency laparoscopy exposure of <50 cases. Surgeons who were exposed to >=50 laparoscopic cases during their residency showed a statistically significant increase in the number of laparoscopic procedures performed after their class compared with surgeons who did not receive >=50 laparoscopic cases in residency (P = .03). In addition, regardless of the procedures learned in a specific class, surgeons with >=50 laparoscopic cases in residency had a statistically significant increase in their laparoscopic colectomy and laparoscopic hernia procedure caseload (P < .01). However, there was no statistically significant difference in laparoscopic caseload between surgeons who had completed 50 to 200 laparoscopic residency cases and those who had completed greater than 200 laparoscopic residency cases (P = .31). Furthermore, the participant's age (P = .23), practice type (P = .61), and years in practice (P = .22) had no statistical significance with regard to the adoption of laparoscopic procedures after courses taken. This finding is congruent with the findings of other researchers. Future interest in advanced laparoscopy courses was noted in 70% of surgeons and was more pronounced in surgeons with >=50 cases in residency. CONCLUSION: Advanced laparoscopic workshops provide an efficacious instrument in educating surgeons on minimally invasive surgical techniques. Participating surgeons significantly increased the number of course-specific procedures that they performed but also increased the number of other laparoscopic surgeries, suggesting that a certain proficiency in laparoscopic skills is translated to multiple surgical procedures. Laparoscopy experience of >=50 cases during residency is a strong predictor of an increase in the number of advanced laparoscopic cases after attending courses. PMID- 23925010 TI - Total laparoscopic pancreaticoduodenectomy. AB - INTRODUCTION: Total laparoscopic pancreaticoduodenectomy (TLPD) remains one of the most advanced laparoscopic procedures. Owing to the evolution in laparoscopic technology and instrumentation within the past decade, laparoscopic pancreaticoduodenectomy is beginning to gain wider acceptance. METHODS: Data were collected for all patients who underwent a TLPD at our institution. Preoperative evaluation consisted of computed tomography scan with pancreatic protocol and selective use of magnetic resonance imaging and/or endoscopic ultrasonography. The TLPD was done with 6 ports on 3 patients and 5 ports in 2 patients and included a celiac, periportal, peripancreatic, and periduodenal lymphadenectomy. Pancreatic stents were used in all 5 cases, and intestinal continuity was re established by intracorporeal anastomoses. RESULTS: Five patients underwent a TLPD for suspicion of a periampullary tumor. There were 3 women and 2 men with a mean age of 60 years and a mean body mass index of 32.8. Intraoperatively, the mean operative time was 9 hours 48 minutes, with a mean blood loss of 136 mL. Postoperatively, there were no complications and a mean length of stay of 6.6 days. There was no lymph node involvement in 4 out of 5 specimens. The pathological results included intraductal papillary mucinous neoplasm in 2 patients, pancreatic adenocarcinoma in 1 patient (R0 resection), benign 4-cm periampullary adenoma in 1 patient, and a somatostatin neuroendocrine carcinoma in 1 patient (R0, N1). CONCLUSION: TLPD is a viable alternative to the standard Whipple procedure. Our early experience suggests decreased length of stay, quicker recovery, and improved quality of life. Complication rates appear to be improved or equivalent. PMID- 23925011 TI - Single-port laparoscopic right hemicolectomy: the learning curve. AB - BACKGROUND AND OBJECTIVES: Single-port laparoscopic colectomy is described as a new technique in colorectal surgery. The initial case reports show the safety and feasibility, but the learning curve for this technique is unknown. METHODS: Between July 2009 and September 2010, 20 consecutive patients with an indication for right hemicolectomy underwent a single-port laparoscopic approach without bias in selection. The only exclusion criterion was a prior midline laparotomy. The patients were followed up for 30 days. Chart review was completed for up to 35 months to assess long-term morbidity and mortality rates. RESULTS: The median age was 65 years (range, 59-88 years). Ninety percent of patients were men. The median body mass index was 28 kg/m(2) (range, 20-35 kg/m(2)). Seventy-five percent of patients had significant comorbidities with an American Society of Anesthesiologists class of 3 or 4. The estimated blood loss was 25 mL (range, 25 250 mL). The median number of pathologic lymph nodes for patients diagnosed with adenocarcinoma was 16 (range, 8-23). There was one conversion to hand-assisted laparoscopic (case 6) and one to open colectomy (case 9) because of the inability to achieve safe vessel ligation. The median hospital stay was 4.5 days (range, 3 7 days). The length of stay for the first 10 patients was 5.1 days, and it was 3.9 days for the last 10 patients (P = .045). There were no significant postoperative complications within 30 days. The mean operative time for the first 10 cases was 198 minutes (range, 148-272 minutes), and it was 123 minutes (range, 98-150 minutes) for the subsequent 10 cases (P = .0001). All intraoperative complications (minor bleeding) occurred within the first 10 patients, with no significant bleeding recorded for the last 10 cases. CONCLUSION: Single-port laparoscopic right hemicolectomy can be safely performed in patients who are candidates for conventional or hand-assisted right hemicolectomy with very low intraoperative and postoperative complication rates. The 30-day morbidity rate remained low with this technique. The higher technical difficulty compared with conventional laparoscopy is reflected in the longer initial operative times. The learning curve for a surgeon with advanced laparoscopic skills and adequate procedure numbers seems to be short, requiring approximately 10 cases to decrease operative times to baseline. The role and feasibility of broad adaptation for single-incision laparoscopy in colorectal surgery need to be further evaluated in larger case series and trials. PMID- 23925012 TI - Laparoscopic colon resections with discharge less than 24 hours. AB - BACKGROUND AND OBJECTIVES: A short hospital stay is one of the main advantages of laparoscopic surgery. Previous studies have shown that after a multimodal fast track process, the hospital length of stay can be shortened to between 2 and 5 days. The objective of this review is to show that the hospital length of stay can, in some cases, be reduced to <24 hours. METHODS: This study retrospectively reviews a surgeon's experience with laparoscopic surgery over a 12-month period. Seven patients were discharged home within 24 hours after minimally invasive laparoscopic surgical treatment, following a modified fast-track protocol that was adopted for perioperative care. RESULTS: Of the 7 patients, 4 received laparoscopic right hemicolectomy for malignant disease and 3 underwent sigmoid colectomies for recurrent diverticulitis. The mean hospital stay was 21 hours, 47 minutes; the mean volume of intraoperative fluid (lactated Ringer) was 1850 mL; the mean surgical blood loss was only 74.3 mL; the mean duration of surgery was 118 minutes; and the patients were ambulated and fed a liquid diet after recovery from anesthesia. The reviewed patients had functional gastrointestinal tracts and were agreeable to the timing of discharge. On the follow-up visit, they showed no adverse consequences such as bleeding, infection, or anastomotic leak. CONCLUSION: Laparoscopic colon surgery that incorporated multimodal perioperative care allowed patients to be discharged within the first 24 hours. Careful postoperative outpatient follow-up is important in monitoring complications such as anastomotic leak, which may not present until postoperative day 5. PMID- 23925013 TI - Self-expanding metallic stents for palliation and as a bridge to minimally invasive surgery in colorectal obstruction. AB - BACKGROUND AND OBJECTIVES: Acute colorectal obstruction is a potentially life threatening emergency that requires immediate surgical treatment. Emergency procedures had an associated mortality rate of 10% to 30%. This encouraged development of other options, most notably self-expanding metallic stents. The primary endpoint of this study to is to report our group's experience. METHODS: We performed a retrospective review of 37 patients who underwent self-expanding metallic stent placement for colorectal obstruction between July 2000 and May 2012. Data collected were age, comorbidities, diagnosis, intent of intervention (palliative vs bridge to surgery), complications, and follow-up. RESULTS: The study comprised 21 men (56.76%) and 16 women (43.24%), with a mean age of 67 years. The intent of the procedure was definitive treatment in 22 patients (59.46%) and bridge to surgery in 15 (40.54%). The highest technical success rate was at the rectosigmoid junction (100%). The causes of technical failure were inability of the guidewire to traverse the stricture and bowel perforation related to stenting. The mean follow-up period was 9.67 months. Pain and constipation were the most common postprocedure complications. DISCUSSION: The use of a self-expanding metallic stent has been shown to be effective for palliation of malignant obstruction. It is associated with a lower incidence of intensive care unit admission, shorter hospital stay, lower stoma rate, and earlier chemotherapy administration. Laparoscopic or robotic surgery can then be performed in an elective setting on a prepared bowel. Therefore the patient benefits from advantages of the combination of 2 minimally invasive procedures in a nonemergent situation. Further large-scale prospective studies are necessary. PMID- 23925014 TI - Surgical margins and short-term results of laparoscopic total mesorectal excision for low rectal cancer. AB - BACKGROUND AND OBJECTIVES: The confines of the narrow bony pelvis make laparoscopic surgery more challenging in the treatment of low rectal cancer. Macroscopic evaluation of the completeness of the mesorectum provides detailed information about the quality of surgery. This study was performed to observe the short-term outcomes and evaluate the macroscopic quality of specimens acquired from laparoscopic total mesorectal excision versus open total mesorectal excision in patients with low rectal cancer. METHODS: A total of 177 patients with low rectal cancer underwent total mesorectal excision by either a laparoscopic (n = 87) or open (n = 90) approach. In all cases the surgical time, blood loss, intraoperative and postoperative complications, postoperative bowel opening, and hospital stay were assessed. Special attention was given to the macroscopic judgment concerning the cut edge of peritoneal reflection, Denonvilliers fascia, completeness of the mesorectum, and bowel wall below the mesorectum. RESULTS: The surgical time was 160 +/- 40 minutes in the laparoscopic group. It was not significantly different from that in the open group (P = .782). The operative blood loss was 28 +/- 5 mL in the group undergoing laparoscopic surgery and 80 +/ 20 mL in the group undergoing open surgery (P < .01). Intraoperative injuries to the pelvic autonomic nervous system were recorded in 4 cases in the laparoscopic group compared with 12 cases in the open group (P < .05). The incidences of chest infection and anastomotic leakage were similar between the 2 approaches. The postoperative bowel opening time was 2.1 +/- 1.5 days in the laparoscopic group and 3.5 +/- 1.6 days in the open group (P < .01), whereas the hospital stay was 5.2 +/- 1.8 days and 7.0 +/- 2.1 days, respectively (P < .01). Intact Denonvilliers fascia and complete total mesorectal excision were more likely to be achieved by the laparoscopic approach than the open approach (P < .01). Colorectal anastomoses were located significantly lower in the laparoscopic group than in the open group (P < .01). CONCLUSION: Laparoscopic total mesorectal excision has consistent advantages over open total mesorectal excision, including similar surgical time, less blood loss, reduced hospital stay, and shorter disability period. A complete macroscopic specimen is more likely to be acquired by laparoscopy because of the better pelvic view offered by the approach. PMID- 23925015 TI - A pilot study of surgical training using a virtual robotic surgery simulator. AB - BACKGROUND AND OBJECTIVES: Our objectives were to compare the utility of learning a suturing task on the virtual reality da Vinci Skills Simulator versus the da Vinci Surgical System dry laboratory platform and to assess user satisfaction among novice robotic surgeons. METHODS: Medical trainees were enrolled prospectively; one group trained on the virtual reality simulator, and the other group trained on the da Vinci dry laboratory platform. Trainees received pretesting and post-testing on the dry laboratory platform. Participants then completed an anonymous online user experience and satisfaction survey. RESULTS: We enrolled 20 participants. Mean pretest completion times did not significantly differ between the 2 groups. Training with either platform was associated with a similar decrease in mean time to completion (simulator platform group, 64.9 seconds [P = .04]; dry laboratory platform group, 63.9 seconds [P < .01]). Most participants (58%) preferred the virtual reality platform. The majority found the training "definitely useful" in improving robotic surgical skills (mean, 4.6) and would attend future training sessions (mean, 4.5). CONCLUSION: Training on the virtual reality robotic simulator or the dry laboratory robotic surgery platform resulted in significant improvements in time to completion and economy of motion for novice robotic surgeons. Although there was a perception that both simulators improved performance, there was a preference for the virtual reality simulator. Benefits unique to the simulator platform include autonomy of use, computerized performance feedback, and ease of setup. These features may facilitate more efficient and sophisticated simulation training above that of the conventional dry laboratory platform, without loss of efficacy. PMID- 23925016 TI - Deep infiltrating colorectal endometriosis treated with robotic-assisted rectosigmoidectomy. AB - BACKGROUND AND OBJECTIVE: Deep infiltrating pelvic endometriosis with bowel involvement is one of the most aggressive forms of endometriosis. Nowadays, robotic technology and telemanipulation systems represent the latest developments in minimally invasive surgery. The aim of this study is to present our preliminary results and evaluate the feasibility of robotic-assisted laparoscopic colorectal resection for severe endometriosis. METHODS: Between September 2009 and December 2011, 10 women with colorectal endometriosis underwent surgery with the da Vinci robotic surgical system (Intuitive Surgical, Sunnyvale, CA, USA). We evaluated the following parameters: short-term complications, clinical outcomes and long-term follow-up, pain relief recurrence rate, and fertility outcomes. RESULTS: Extensive ureterolysis was required in 8 women (80%). Ovarian cystectomy with removal of the cystic wall was performed in 7 women (70%). Torus resection was performed in all women, with unilateral and bilateral uterosacral ligament resection in 1 woman (10%) and 8 women (80%), respectively. In addition to segmental colorectal resection in all cases, partial vaginal resection was necessary in 2 women (20%). An appendectomy was performed in 2 patients (20%). The mean operative time with the robot was 157 minutes (range, 90-190 minutes). The mean hospital stay was 3 days. Six patients had infertility before surgery, with a mean infertility time of 2 years. After a 12-month follow-up period, 4 women (67%) conceived naturally and 2 (33%) underwent in vitro fertilization. CONCLUSION: We show that robotic-assisted laparoscopic surgery for the treatment of deep infiltrating bowel endometriosis is feasible, effective, and safe. PMID- 23925017 TI - Efficacy of laparoscopic sacrocervicopexy for apical support of pelvic organ prolapse. AB - BACKGROUND AND OBJECTIVES: To evaluate the efficacy of laparoscopic sacrocervicopexy for apical support in sexually active patients with pelvic organ prolapse. METHODS: One-hundred thirty-five women with symptomatic prolapse of the central compartment (Pelvic Organ Prolapse Quantitative [POP-Q] stage 2) underwent laparoscopic sacrocervicopexy. The operating physicians used synthetic mesh to attach the anterior endopelvic fascia to the anterior longitudinal ligament of the sacral promontory with subtotal hysterectomy. Anterior and posterior colporrhaphy was performed when necessary. The patients returned for follow-up examinations 1 month after surgery and then over subsequent years. On follow-up a physician evaluated each patient for the recurrence of genital prolapse and for recurrent or de novo development of urinary or bowel symptoms. We define "surgical failure" as any grade of recurrent prolapse of stage II or more of the POP-Q test. Patients also gave feedback about their satisfaction with the procedure. RESULTS: The mean follow-up period was 33 months. The success rate was 98.4% for the central compartment, 94.2% for the anterior compartment, and 99.2% for the posterior compartment. Postoperatively, the percentage of asymptomatic patients (51.6%) increased significantly (P < .01), and we observed a statistically significant reduction (P < .05) of urinary urge incontinence, recurrent cystitis, pelvic pain, dyspareunia, and discomfort. The present study showed 70.5% of patients stated they were very satisfied with the operation and 18.8% stated high satisfaction. CONCLUSION: Laparoscopic sacrocervicopexy is an effective option for sexually active women with pelvic organ prolapse. PMID- 23925018 TI - Massive subcutaneous emphysema in robotic sacrocolpopexy. AB - The advent of robotic surgery has increased the popularity of laparoscopic sacrocolpopexy. Carbon dioxide insufflation, an essential component of laparoscopy, may rarely cause massive subcutaneous emphysema, which may be coincident with life-threatening situations such as hypercarbia, pneumothorax, and pneumomediastinum. Although the literature contains several reports of massive subcutaneous emphysema after a variety of laparoscopic procedures, we were not able to identify any report of this complication associated with laparoscopic or robotic sacrocolpopexy. Massive subcutaneous emphysema occurred in 3 women after robotic sacrocolpopexy in our practice. The patients had remarkable but reversible physical deformities lasting up to 1 week. A valveless endoscopic dynamic pressure system was used in all 3 of our cases. Our objective is to define the risk of massive subcutaneous emphysema during robotic sacrocolpopexy in light of these cases and discuss probable predisposing factors including the use of valveless endoscopic dynamic pressure trocars. PMID- 23925019 TI - A comparison of laparoscopic and abdominal radical parametrectomy for cervical or vaginal apex carcinoma and stage II endometrial cancer after hysterectomy. AB - BACKGROUND AND OBJECTIVE: Radical parametrectomy (RP), performed either abdominally (ARP) or laparoscopically (LRP), is a viable alternative to radiotherapy in treating invasive cervical cancer, vaginal apex cancer, and endometrial cancer that is more advanced than initially suspected after hysterectomy. We carried out a comparative study on intra- and postoperative parameters between the two performed by similarly experienced surgeons. METHODS: Forty consecutive patients indicative for RP were reviewed: 22 and 18 underwent ARP and LRP, respectively. Information was collected on demographics, indications for initial and this surgery, tumor characteristics, intra- and postoperative parameters, and complications. The lengths of resected parametrial and vaginal tissues were measured. RESULTS: Compared with ARP, LRP resulted in shorter operative time (200 vs 239 min), less blood loss (627.8 vs 929.5 mL), shorter hospital stay (16.8 vs 19.9 days), and removal of more pelvic lymph nodes (27.4 +/- 5.9 vs 23.1 +/- 7.1). Although it was not attempted in ARP to remove lymph nodes in the deep obturator space, it was attempted in LRP and one positive node was found. In the ARP cohort there was one case of injury to the small intestine during surgery, whereas in LRP there was one instance of lower urologic fistula after surgery. CONCLUSION: LRP is superior to ARP in terms of shorter operative time, less blood loss, and shorter hospital stay while still maintaining the completeness of the procedure. It can be safely performed in the hands of experienced surgeons for cervical or vaginal apex carcinoma and stage II endometrial cancer after hysterectomy. PMID- 23925020 TI - Laparoscopic management or laparoscopy combined with transvaginal management of type II cesarean scar pregnancy. AB - OBJECTIVE: To evaluate the clinical effectiveness of laparoscopic management of cesarean scar pregnancy (CSP) by deep implantation. BACKGROUND: A pregnancy implanting within the scar from a previous cesarean delivery is a rare condition of ectopic pregnancy. There are two different types of CSPs. Type I is caused by implantation of the amniotic sac on the scar with progression toward either the cervicoisthmic space or the uterine cavity. Type II (CSP-II) is caused by deep implantation into a previous CS defect with infiltrating growth into the uterine myometrium and bulging from the uterine serosal surface, which may result in uterine rupture and severe bleeding during the first trimester of pregnancy. Thus, timely management with an early and accurate diagnosis of CSP-II is important. However, laparoscopic management in CSP-II has not yet been evaluated. METHODS: Eleven patients with CSP-II underwent conservative laparoscopic surgery or laparoscopy combined with transvaginal bilateral uterine artery ligation and resection of the scar with gestational tissue and wound repair to preserve the uterus from March 2008 to November 2011. Patients with CSP-II were diagnosed using color Doppler sonography, and the diagnosis was confirmed by laparoscopy. The operation time, the blood loss during surgery, the levels of beta-human chorionic gonadotropin (beta-hCG) before surgery, the time taken for serum beta hCG levels to return to <100 mIU/mL postoperatively, and the time for the uterine body to revert to its original state were retrospectively analyzed. RESULTS: All 11 operations were successfully performed using laparoscopy with preservation of the uterus. One patient underwent a dilation and curettage after laparoscopic bilateral uterine artery ligation. Eight patients were treated solely by laparoscopic bilateral uterine artery ligation and resection of the scar with gestational tissue and wound repair. The remaining two patients underwent laparoscopic bilateral uterine artery ligation and transvaginal resection of the CS with gestational tissue and wound repair because of dense adhesions and heavy bleeding. The average operation time was 85.5 (+/-17.5) minutes, and the blood loss was 250.0 (+/-221.4) mL. The blood serum level of beta-hCG returned to <100 mIU/mL in 16.4 (+/-5.3) days postoperatively. Among the 10 patients who underwent resection of CS and wound repair, the time for the uterus to revert to its original state (judged by ultra-sonography) was 10.8 (+/-3.0) days postoperatively. CONCLUSIONS: Laparoscopy can remove ectopic gestational tissue and allow subsequent wound repair, as well as provide diagnostic confirmation. Being a minimally invasive procedure, laparoscopic or laparoscopy combined with transvaginal bilateral uterine artery ligation and resection of the scar with gestational tissue and wound repair can become an effective alternative for the treatment of CSP-II. PMID- 23925021 TI - Quality of life following laparoscopic living-donor nephrectomy. AB - BACKGROUND AND OBJECTIVES: This study compares donor quality of life (QOL) with extirpative (simple or radical) patients' QOL after laparoscopic nephrectomy and analyzes factors predictive of mental QOL for donors. METHODS: One hundred one donors and 48 extirpative laparoscopic nephrectomy patients filled out the SF 36v2 form at pre- and postoperative visits, and scores were transformed to norm based. Donor characteristics were collected and analyzed using univariate analysis. RESULTS: Donor patients had a decline in the mental summary at all time points that became significant at 7 months (-2.9), whereas extirpative patients trended positive at 7 months (+2.6). Both groups had a significant decline in the physical summary at 1 month, which rebounded by 4 months. Female gender, positive social/psychiatric history, and major graft recipient complications were all significant predictors of a decline in mental health at 1 month. CONCLUSION: Compared with patients who undergo extirpative surgery, kidney donors have significant mental stress associated with donation that persists beyond the postoperative period. Better preoperative counseling and postoperative monitoring might lead to better outcomes, especially for those in high-risk groups. PMID- 23925022 TI - Hand-assisted laparoscopic nephrectomy for polycystic kidney disease. AB - BACKGROUND AND OBJECTIVES: Historically, nephrectomy for autosomal dominant polycystic kidney disease was performed by an open technique. We performed this study to compare outcomes in hand-assisted laparoscopic nephrectomy with open nephrectomy in this population. METHODS: Charts of patients with autosomal dominant polycystic kidney disease who underwent nephrectomy by a transplant surgeon from January 1, 2000, to December 31, 2011, were reviewed. The hand assisted laparoscopic nephrectomy group was compared with the open group. Data collected included unilateral versus bilateral nephrectomy, operative time, complications, transfusion requirement, and length of stay. RESULTS: Of the 78 patients identified, 18 underwent open transabdominal nephrectomy, 56 underwent hand-assisted laparoscopic nephrectomy, and 2 underwent hand-assisted laparoscopic nephrectomy that was converted to an open procedure. Two patients were excluded because another major procedure was performed at the same time as the nephrectomy. Operative times were similar. Patients undergoing open bilateral nephrectomy were more likely to receive transfusion (odds ratio, 3.57 [95% confidence interval, 0.74-17.19]; P = .016), and the length of stay was longer in the open groups (5.9 days vs 4.0 days for unilateral [P = .013] and 7.8 days vs 4.6 days for bilateral [P = .001]). Overall complication rates were similar. The most frequent complications associated with hand-assisted laparoscopic nephrectomy were the development of an incisional hernia at the hand-port site and arteriovenous fistula thrombosis. CONCLUSION: Hand-assisted laparoscopic nephrectomy can be safely performed without increased operative times or complications. The hand-assisted laparoscopic nephrectomy group enjoyed a shorter length of stay, and fewer patients in this group received transfusion. For patients considering renal transplantation, avoidance of transfusion is important to prevent sensitization and limiting access to compatible organs. PMID- 23925023 TI - Cost effective laparoendoscopic single-site surgery with a reusable platform. AB - BACKGROUND AND OBJECTIVES: Many disposable platforms have been applied in laparoendoscopic single-site surgery (LESS). Besides technical issues, cost is one of the limiting factors for its widespread acceptance. The current study describes the first completely reusable LESS-platform. METHODS: We performed LESS procedures in 52 patients including nephrectomy (18), adrenalectomy (2), partial nephrectomy (3), pyeloplasty (4), renal cyst ablation (4), pelvic lymphadenectomy (15), and lymphocele ablation (6). All procedures were conducted using a novel reusable single-port device (X-Cone, Karl-Storz) with a simplified set of instruments. We obtained perioperative and demographic data, including a visual analogue pain scale (VAS), and a complication reporting system based on Clavien grading. RESULTS: Mean age was 50.04 y. Conversion to standard laparoscopy was necessary in 3 cases and addition of a needlescopic instrument in 6 cases. There was no open conversion. Intra- and postoperative complications occurred in 3 (Clavien II in 2 and III in 1) cases. Mean operative time was 110, 90, and 89 min, and hospital stay was 4.9, 3.1, and 3.6 d for nephrectomy, pelvic lymphadenectomy, and pyeloplasty, respectively. Mean VAS was 2.13, 1.07, and 1.5 while blood loss was 81.3 mL, 25.67 mL, and 17.5 mL, respectively. Mean lymph node yield was 15 (range, 8 to 21). CONCLUSIONS: A completely reusable LESS platform is applicable to various uses in urology, yielding favorable functional and cosmetic results. Reusable materials are useful to reduce the cost of LESS, further increasing its acceptance. LESS with a completely reusable platform is more cost effective than standard laparoscopy. PMID- 23925024 TI - A comparison of surgical and functional outcomes of robot-assisted versus pure laparoscopic partial nephrectomy. AB - BACKGROUND AND OBJECTIVES: Robot-assisted partial nephrectomy (RAPN) is emerging as an alternative to laparoscopic partial nephrectomy (LPN) for the treatment of small renal tumors. We compare the results of LPN and RAPN performed by a single surgeon. METHODS: Data from 100 consecutive patients who underwent LPN (n=52) or RAPN (n=48) performed by a single experienced laparoscopic surgeon between October 2007 and June 2010 were analyzed retrospectively. Perioperative data, including clinical, pathological, and functional outcomes, were compared between the LPN and RAPN groups. RESULTS: No significant differences were found between groups with regard to mean estimated blood loss, main operation time, warm ischemic time, intraoperative complications, postoperative complications, hospital stay, or percent reduction of hemoglobin. The mean duration of follow-up was 16.2 months for LPN patients versus 8.9 months for RAPN patients (P<.001). With respect to the clamping method, more artery-only clamping occurred during RAPN than LPN (38.5 vs 75%, respectively, P=.001). The mean pathological tumor volume for LPN was 4.0 cm(3) vs 8.2 cm(3) for RAPN (P=.006). The mean resected healthy tissue volume was 25.1 cm(3) for LPN versus 16.1 cm(3) for RAPN (P=.044). There were no significant differences in positive margins or changes in renal function between the 2 cohorts. CONCLUSION: RAPN is a comparable and alternative option to LPN, providing equivalent oncological and functional outcomes, as well as comparable morbidity to LPN. Although RAPN could offer the advantages of saving more healthy marginal tissue, longer-term and larger studies are necessary to evaluate the functional advantages. PMID- 23925025 TI - Evaluation of applied laparoscopic urology course using validated checklist. AB - BACKGROUND AND OBJECTIVES: The objectives of this study were to investigate the effectiveness of the applied laparoscopic urology course using a validated checklist and to determine any differences in laparoscopic skills achieved by the participants at the end of the course period based on whether they began their training in a dry or wet laboratory. METHODS: To facilitate the mastering of challenging laparoscopic skills by urologists, a unique 3-day mini-training program was established at the Gulhane Military Academy of Medicine, Surgical Research Center, Ankara, Turkey. Only 30 trainees were accepted in each course, and they were divided into 3 subgroups. The primary outcome of the study was the changes in the performance and task accomplishment duration of the trainees at the beginning compared with the end of the course. The secondary outcome was any differences in the basic skills of the trainees based on whether they started their training in the dry or wet laboratory. RESULTS: The overall laparoscopic skills, which were evaluated by use of a standardized laparoscopic suturing task score, significantly improved (18.8 to 26.0, P < .001), and the time needed for task accomplishment decreased throughout the course (9.5 minutes to 5.25 minutes, P = .002). With respect to the course design, laparoscopic skills scores and the times needed for task accomplishment showed no statistically significant changes at the end of the course despite the fact that the trainees had started their training at different stages. CONCLUSION: The applied short-term laparoscopy course was shown to be an effective format particularly for achieving laparoscopic skills in which suturing and knotting are essential. This is mainly achieved through close cooperation in dry and wet laboratories. PMID- 23925026 TI - An intestinal occlusion device for prevention of small bowel distention during transgastric natural orifice transluminal endoscopic surgery. AB - BACKGROUND AND OBJECTIVES: Bowel distention from luminal gas insufflation reduces the peritoneal operative domain during natural orifice transluminal endoscopic surgery (NOTES) procedures, increases the risk for iatrogenic injury, and leads to postoperative patient discomfort. METHODS: A prototype duodenal occlusion device was placed in the duodenum before NOTES in 28 female pigs. The occlusion balloon was inflated and left in place during the procedure, and small bowel distension was subjectively graded. One animal had no balloon occlusion, and 4 animals had a noncompliant balloon placed. RESULTS: The balloon maintained its position and duodenal occlusion in 22 animals (79%) in which the bowel distention was rated as none (15), minor (4), moderate (3), or severe (0). The intestinal occlusion catheter failed in 6 animals (21%) because of balloon leak (5) or back migration into the stomach (1), with distention rated as severe in 5 of these 6 cases. CONCLUSION: The intestinal occlusion catheter that maintains duodenal occlusion significantly improves the intraabdominal working domain with enhanced visualization of the viscera during the NOTES procedure while requiring minimal time and expense. PMID- 23925027 TI - Port-site closure using a modified aptos needle. AB - BACKGROUND AND OBJECTIVES: Trocar-site incisional hernias are the most common complications in laparoscopic surgery. Fascial closure of port sites represents a challenging issue in laparoscopic surgery. METHODS: We describe a simple easy technique for fascial closure of port sites using a double-tip needle (Lasheen needle). This study included 100 patients who underwent laparoscopic surgery from January 2009 through August 2011 in the General Surgery Department, Zagazig University Hospital, Zagazig, Egypt. The mean follow-up period was 2 years for any wound complications at these trocar sites. RESULTS: The mean age of the patients was 39.5 years, and the mean time for placement of one suture was 2 minutes. No trocar-site herniation occurred with our technique during the period of follow-up. Infection developed at the trocar site in 3 patients. CONCLUSION: This technique is easy, simple, safe, fast, inexpensive, and effective for fascial closure of trocar sites. PMID- 23925028 TI - Single-incision laparoscopic ventral hernia repair with suprapubic incision. AB - INTRODUCTION: Although natural orifice transluminal endoscopic surgery promises truly scarless surgery, this has not progressed beyond the experimental setting and a few clinical cases in the field of ventral hernia repair. This is mainly because of the problem of sterilizing natural orifices, which prevents the use of any prosthetic material because of unacceptable risks of infection. Single incision laparoscopic ventral hernia repair has gained more wide-spread acceptance by specialized hernia centers. Even so, there is a special subset of patients who are young and/or scar conscious and find any visible scar unacceptable. This study illustrates an innovative way of performing single incision laparoscopic ventral hernia repair by a transverse suprapubic incision below the pubic hair/bikini line in 2 young male patients who had both umbilical and epigastric hernias as well as attenuated linea alba in the upper abdomen. CASE DESCRIPTION: Both patients underwent successful laparoscopic repair, and both were highly satisfied with the procedure, which produced no visible scars on their abdomen. DISCUSSION: Willingness to adopt new innovative procedures, such as single-incision laparoscopic surgery, has allowed modification of the incision site to produce invisible scars and hence become highly attractive to the young and scar-phobic segment of the population. PMID- 23925029 TI - Direct puncture cholangiography for clarifying difficult anatomy. AB - Laparoscopic cholecystectomy is a very frequently performed procedure. Its most dreadful complication is bile duct injury. Difficulty in appreciating the biliary anatomy plays an important role in its causation. Here we describe our technique in clarifying the difficult anatomy by directly injecting the radiologic contrast in the ambiguous area, and thus avoiding a potential injury. PMID- 23925030 TI - Diagnosis and treatment of gallbladder torsion in a 6 year old. AB - INTRODUCTION: Torsion of the gallbladder in the pediatric population is rare. A nonspecific clinical presentation is characteristic, which frequently contributes to diagnostic uncertainty. CASE DESCRIPTION: We report a case of gallbladder torsion in a 6-y-old male with abdominal distention and lethargy accompanied by a low-grade leukocytosis. An abdominal computed tomography scan suggested the finding of acute appendicitis suspicious for perforation. DISCUSSION: This case highlights the utility of laparoscopic evaluation in the setting of clinical and radiographic diagnostic uncertainty. PMID- 23925031 TI - Endoclip migration into the common bile duct with stone formation: a rare complication after laparoscopic cholecystectomy. AB - INTRODUCTION: Endoclip migration into the common bile duct after laparoscopic cholecystectomy is a rare complication. Very few cases have been reported in the literature, mostly in the form of case reports. CASE DESCRIPTION: We report a case of Endoclip migration into the bile duct with stone formation 6 y after laparoscopic cholecystectomy. The patient presented with recurrent abdominal pain and intermittent jaundice for 6 mo. Diagnosis was suspected when a computed tomography scan of the abdomen showed a metallic density artifact in the lower end of the bile duct. The diagnosis was confirmed by endoscopic retrograde cholangiopancreatography. The patient was successfully managed by endoscopic stone and clip removal. DISCUSSION: Endoclip migration with biliary complications should be considered in the differential diagnosis of postcholecystectomy problems. The clinical manifestations and management are similar to that of noniatrogenic choledocholithiasis. PMID- 23925032 TI - Cicatrical cecal volvulus following laparoscopic cholecystectomy. AB - Laparoscopic cholecystectomy is the procedure of choice for the treatment of symptomatic biliary disease. There is currently no agreement on the management of spilled gallstones, which commonly occurs during laparoscopic cholecystectomy and may produce significant morbidity. We present a case of spilled gallstones causing cicatrical cecal volvulus and also provide a review of pertinent literature. PMID- 23925034 TI - Novel approach to rectal foreign body extraction. AB - INTRODUCTION: The impacted rectal foreign body often poses a management challenge. Ideally, such objects are removed in the emergency department utilizing a combination of local anesthesia, sedation, minimal instrumentation, and manual extraction. In some instances, simple manual extraction is unsuccessful and general anesthesia may be necessary. We describe a novel approach to retrieval and removal of a rectal foreign body utilizing a SILS port. CASE DESCRIPTION: A 31-y-old male presented to the emergency department approximately 12 h after transanal insertion of a plastic cigar case. Abdominal examination revealed no evidence of peritonitis. On rectal examination, the tip of the cigar case was palpable. The foreign body, however, was unable to be removed manually in the emergency department. In the operating room, with the patient under general anesthesia, multiple attempts to remove the object were unsuccessful. A SILS port was inserted transanally. The rectum was then insufflated manually by attaching the diaphragm of the rigid sigmoidoscope to the SILS insufflation port. A 5-mm 0-degree laparoscope was placed through the SILS port. An atraumatic laparoscopic grasper was then placed through the port and used to grasp the visible end of the cigar case. The rectal foreign body was removed expeditiously. Direct visualization of the rectum revealed no evidence of mucosal injury. The patient was discharged home shortly after the procedure. DISCUSSION: The SILS port allows minimally invasive extraction of rectal foreign bodies not amenable to simple manual extraction. It provides excellent visualization and eliminates the morbidity inherent in more invasive and traditional methods of retrieval. PMID- 23925033 TI - Hybrid technique for removal of eroded adjustable gastric band. AB - BACKGROUND: Intragastric migration is a late and rare postsurgical complication in patients with gastric band placement. Gastric band erosion rate has previously been described to be 1.46%. In this report, we present the case of a 43-y-old male with gastric band erosion undergoing a laparoendoscopic retrieval of the gastric band, due to intragastric migration. METHOD: A hybrid procedure was performed to retrieve the gastric band. A laparoscopic approach was initially used to extract the connecting tube. Endoscopy was then performed to cut the gastric band with a specific cutter system and was subsequently extracted transorally. RESULTS: The postoperative course was uneventful. Clear liquids were started on day 1, and the patient was discharged on day 2. DISCUSSION: The purpose of this study was to describe a hybrid technique for the removal of an eroded gastric band, as a safe and feasible option in patients with band erosions. CONCLUSION: The laparoscopic approach enables safe extraction of the connecting tube, while endoscopy allows extraction of the band without creating a large incision in the stomach. PMID- 23925035 TI - Malignant hyperthermia during laparoscopic adjustable gastric banding. AB - BACKGROUND: We report a rare case of malignant hyperthermia during laparoscopic adjustable gastric banding. CASE DESCRIPTION: A 32-y-old female with no previous history of adverse reaction to general anesthesia underwent laparoscopic adjustable gastric banding. Intraoperative monitoring revealed a sharp increase in end-tidal carbon dioxide, autonomic instability, and metabolic and respiratory acidosis, along with other metabolic and biochemical derangements. She was diagnosed with malignant hyperthermia. Desflurane, the anesthetic agent was discontinued, and the patient was started on intravenous dantrolene. RESULTS: The surgery was completed, and the patient was brought to the surgical intensive care unit for continued postoperative care. She developed muscle weakness and phlebitis that resolved prior to discharge. CONCLUSION: Prompt diagnosis and treatment of malignant hyperthermia leads to favorable clinical outcome. This clinical entity can occur in the bariatric population with the widely used desflurane. Bariatric surgeons and anesthesiologists alike must be aware of the early clinical signs of this rare, yet potentially fatal, complication. PMID- 23925036 TI - Single-site laparoscopic management of a large adnexal mass. AB - INTRODUCTION: Single-site laparoscopy is gaining acceptance in many surgical fields including gynecology. The purpose of this report is to demonstrate the technique and outcome for removing a large adnexal mass through a single site. CASE DESCRIPTION: A 41-y-old female was referred to gynecology oncology for increased abdominal girth for 3 mo. An ultrasound confirmed a benign-appearing, 37-cm left adnexal mass. The mass was removed through a single-site laparoscopic incision with the aid of drainage and a morcellator. The operating time was 84 min. The patient was discharged 2 h and 35 min later with full return to normal activity in 5 d. CONCLUSION: Large, benign-appearing adnexal masses can be managed safely with superior cosmetic results using single-site laparoscopy. PMID- 23925037 TI - Laparoendoscopic single-site isobaric hysterectomy in endometrial cancer. PMID- 23925038 TI - Symptomatic right-sided diaphragmatic hernia in the third trimester of pregnancy. AB - BACKGROUND: Laparoscopic repair of incarcerated diaphragmatic hernias is widely recognized as both safe and effective. However, symptomatic diaphragmatic hernias encountered in the setting of pregnancy, while rare, present a significant surgical challenge. Furthermore, right-sided diaphragmatic hernias account for only 13% of cases. Here, we present a case in which a symptomatic, posterior right-sided diaphragmatic hernia, presenting in the later stages of pregnancy, was successfully repaired using a laparoscopic approach. METHODS: Our patient is a 42-y-old gravid woman who, at 27 wk gestation, was admitted to the gynecology service with a 2-d history of right upper quadrant abdominal pain, right shoulder pain, abdominal distension, and obstipation. RESULTS: Computed tomography of the chest demonstrated an incarcerated right diaphragmatic hernia. Surgical consultation was obtained, and the patient was taken to the operating room urgently for repair. Intraoperatively, the cecum was reduced and the diaphragm repaired primarily using a laparoscopic approach. The patient recovered well and was discharged home on postoperative day 8 with no complications to the patient or the pregnancy. CONCLUSION: Laparoscopic reduction and repair of symptomatic incarcerated diaphragmatic hernia can be safely performed in the third trimester of pregnancy. PMID- 23925039 TI - A universal real-time PCR assay for rapid quantification of microRNAs via the enhancement of base-stacking hybridization. AB - Via the base-stacking hybridization strategy, we have developed a universal, one step real-time quantitative PCR assay for sensitive and selective detection of microRNAs. This proposed assay has several intrinsic features including rapid response, low cost, simple handling procedures, etc. PMID- 23925040 TI - Vanadium-catalyzed deoxydehydration of glycols. AB - A survey of several metavandate (VO3(-)) and chelated dioxovanadium derivatives shows that tetrabutylammonium dioxovanadium(V)dipicolinate most effectively catalyzes the deoxydehydration (DODH) of glycols to olefins in moderate to excellent yields with triphenylphosphine or sodium sulfite as reductants. PMID- 23925041 TI - Pressure effect on structural and vibrational properties of Y-substituted BiFeO3. AB - The structural and vibrational properties of 5% Y-substituted BiFeO3 under pressure have been investigated using synchrotron x-ray diffraction (SXRD) and Raman scattering measurements. At a pressure below 30.3 GPa, distinct changes in the Raman spectra and SRXD pattern show evidence for one pressure-induced structural transition from the polar rhombohedral R3c phase to the nonpolar orthorhombic Pnma phase commencing at 3.6 and completed at 7.2 GPa, where there is a region of phase coexistence between the R3c and Pnma phases. At a higher pressure of 40.8 GPa, another phase transition from orthorhombic to cubic is observed accompanied by the insulator-metal transition. Our data do not suggest the pressure-induced re-entrance of ferroelectricity in the model multiferroic Bi0.95Fe0.05O3 in the pressure range studied. PMID- 23925043 TI - A food photograph series for identifying portion sizes of culturally specific dishes in rural areas with high incidence of oesophageal cancer. AB - Rural areas of the Eastern Cape (EC) Province, South Africa have a high incidence of squamous cell oesophageal cancer (OC) and exposure to mycotoxin fumonisin has been associated with increased OC risk. However, to assess exposure to fumonisin in Xhosas--having maize as a staple food--it is necessary to determine the amount of maize consumed per day. A maize-specific food frequency questionnaire (M-FFQ) has recently been developed. This study developed a food photograph (FP) series to improve portion size estimation of maize dishes. Two sets of photographs were developed to be used alongside the validated M-FFQ. The photographs were designed to assist quantification of intakes (portion size photographs) and to facilitate estimation of maize amounts in various combined dishes (ratio photographs) using data from 24 h recalls (n = 159), dishing-up sessions (n = 35), focus group discussions (FGD) (n = 56) and published literature. Five villages in two rural isiXhosa-speaking areas of the EC Province, known to have a high incidence of OC, were randomly selected. Women between the ages of 18-55 years were recruited by snowball sampling and invited to participate. The FP series comprised three portion size photographs (S, M, L) of 21 maize dishes and three ratio photographs of nine combined maize-based dishes. A culturally specific FP series was designed to improve portion size estimation when reporting dietary intake using a newly developed M-FFQ. PMID- 23925042 TI - Alternative dietary fiber sources in companion animal nutrition. AB - The US has a pet population of approximately 70 million dogs and 74 million cats. Humans have developed a strong emotional bond with companion animals. As a consequence, pet owners seek ways to improve health, quality of life and longevity of their pets. Advances in canine and feline nutrition have contributed to improved longevity and well-being. Dietary fibers have gained renewed interest in the pet food industry, due to their important role in affecting laxation and stool quality. More recently, because of increased awareness of the beneficial effects of dietary fibers in health, as well as the popularity of functional foods and holistic and natural diets, alternative and novel carbohydrates have become widespread in human and pet nutrition. Fiber sources from cereal grains, whole grains and fruits have received increasing attention by the pet food industry and pet owners. While limited scientific information is available on the nutritional and nutraceutical properties of alternative fiber sources, studies indicate that corn fiber is an efficacious fiber source for pets, showing no detrimental effects on palatability or nutrient digestibility, while lowering the glycemic response in adult dogs. Fruit fiber and pomaces have good water-binding properties, which may be advantageous in wet pet food production, where a greater water content is required, along with low water activity and a firm texture of the final product. Rice bran is a palatable fiber source for dogs and may be an economical alternative to prebiotic supplementation of pet foods. However, it increases the dietary requirement of taurine in cats. Barley up to 40% in a dry extruded diet is well tolerated by adult dogs. In addition, consumption of complex carbohydrates has shown a protective effect on cardiovascular disease and oxidative stress. Alternative fiber sources are suitable ingredients for pet foods. They have been shown to be nutritionally adequate and to have potential nutraceutical properties. PMID- 23925044 TI - Serum decoy receptor 3 is a useful predictor for the active status of chronic hepatitis B in hepatitis B e antigen-negative patients. AB - Hepatitis B virus (HBV) infection is a global public health problem, because patients with chronic hepatitis B (CHB) may progress to liver cirrhosis and eventually evolve into hepatocellular carcinoma. Decoy receptor 3 (DcR3) is a soluble receptor of the tumor necrosis factor receptor superfamily, and has been implicated in anti-apoptotic and anti-inflammatory pathways. In this study, we explored the clinical value of serum DcR3 in predicting the active status of CHB in hepatitis B e antigen-negative patients (active HBeAg (-) CHB), which was determined with ELISA. The serum level of DcR3 in active HBeAg (-) CHB patients (1.92 +/- 0.68 ng/ml) was higher than that in healthy controls (0.80 +/- 0.25 ng/ml, p < 0.0001) and that in inactive status of HBeAg (-) CHB (inactive hepatitis B surface antigen carrier, HBsAg-IaC) patients (0.95 +/- 0.26 ng/ml, p < 0.0001). DcR3 level was correlated with HBV DNA level (r = 0.819, p < 0.0001) and alanine transaminase level (ALT, r = 0.704, p < 0.0001) in active HBeAg (-) CHB patients. The area under the Receiver Operating Characteristics curve of DcR3 for detecting the active status of HBeAg (-) CHB patients was 0.914 (95% confidence interval, 0.851-0.977). The optimal cut-off value for DcR3 to predict active HBeAg (-) CHB was 1.22 ng/ml, which had a sensitivity of 87.5% and a specificity of 84.4%. These results suggest that serum DcR3 level may be useful for detecting HBeAg (-) CHB in the active stage, which requires medical treatment. PMID- 23925046 TI - Activity of the clinical-stage CK2-specific inhibitor CX-4945 against chronic lymphocytic leukemia. PMID- 23925047 TI - The new European Society of Cardiology Core Curriculum 2013. PMID- 23925045 TI - Transcription factor-pathway coexpression analysis reveals cooperation between SP1 and ESR1 on dysregulating cell cycle arrest in non-hyperdiploid multiple myeloma. AB - Multiple myeloma is a hematological cancer of plasma B cells and remains incurable. Two major subtypes of myeloma, hyperdiploid MM (HMM) and non hyperdiploid MM (NHMM), have distinct chromosomal alterations and different survival outcomes. Transcription factors (TrFs) have been implicated in myeloma oncogenesis, but their dysregulation in myeloma subtypes are less studied. Here, we developed a TrF-pathway coexpression analysis to identify altered coexpression between two sample types. We apply the method to the two myeloma subtypes and the cell cycle arrest pathway, which is significantly differentially expressed between the two subtypes. We find that TrFs MYC, nuclear factor-kappaB and HOXA9 have significantly lower coexpression with cell cycle arrest in HMM, co-occurring with their overactivation in HMM. In contrast, TrFs ESR1 (estrogen receptor 1), SP1 and E2F1 have significantly lower coexpression with cell cycle arrest in NHMM. SP1 chromatin immunoprecipitation targets are enriched by cell cycle arrest genes. These results motivate a cooperation model of ESR1 and SP1 in regulating cell cycle arrest, and a hypothesis that their overactivation in NHMM disrupts proper regulation of cell cycle arrest. Cotargeting ESR1 and SP1 shows a synergistic effect on inhibiting myeloma proliferation in NHMM cell lines. Therefore, studying TrF-pathway coexpression dysregulation in human cancers facilitates forming novel hypotheses toward clinical utility. PMID- 23925049 TI - Testosterone replacement therapy for female androgen insufficiency syndrome. PMID- 23925048 TI - Identification and super-resolution imaging of ligand-activated receptor dimers in live cells. AB - Molecular interactions are key to many chemical and biological processes like protein function. In many signaling processes they occur in sub-cellular areas displaying nanoscale organizations and involving molecular assemblies. The nanometric dimensions and the dynamic nature of the interactions make their investigations complex in live cells. While super-resolution fluorescence microscopies offer live-cell molecular imaging with sub-wavelength resolutions, they lack specificity for distinguishing interacting molecule populations. Here we combine super-resolution microscopy and single-molecule Forster Resonance Energy Transfer (FRET) to identify dimers of receptors induced by ligand binding and provide super-resolved images of their membrane distribution in live cells. By developing a two-color universal-Point-Accumulation-In-the-Nanoscale Topography (uPAINT) method, dimers of epidermal growth factor receptors (EGFR) activated by EGF are studied at ultra-high densities, revealing preferential cell edge sub-localization. This methodology which is specifically devoted to the study of molecules in interaction, may find other applications in biological systems where understanding of molecular organization is crucial. PMID- 23925050 TI - Guidelines for Consulting with Patients about Bioidentical Hormone Replacement Therapy. PMID- 23925051 TI - Hypothyroidism: optimizing medication with slow-release compounded thyroid replacement. PMID- 23925052 TI - Compounding for endocrine disorders in adult patients. PMID- 23925053 TI - Considerations for choosing a primary engineering control for compounding sterile products. AB - Abstract not available. PMID- 23925054 TI - Local ventilation for safe containment in the pharmaceutical industry. AB - Biomedical science and the pharmaceutical industry have made startling advances in the last 10 years, and the horizon is even more exciting. Because today's pharmaceutical chemicals are more potent and selective than ever, the risks also are greater than ever. Is is essential, therfore, that all laboratory workers understand how to minimize the threat of personal exposure to hazardous substances. Ventilation is the first line of defense to protect laboratory workers from such exposures. All too often, however, laboratory personnel do not receive sufficient training on how to properly use equipment such as laboratory hoods, and there is little understanding of the prinicples of laboratory ventilation. It is frequently assumed that because the hood is on, it is functioning properly, containing contamination, and thus preventing worker exposure. This is often not the case. Safety professionals can tell you that laboratory ventilation is their most difficult problem and that improper ventilation is usually the cause of potentially hazardous exposures. This paper is part of a series that describes the fundamentals of laboratory ventilation and how to use equipment such as laboratory hoods and vented enclosures. PMID- 23925055 TI - Basics of pharmacogenomics for the compounding pharmacist. PMID- 23925056 TI - Physical and chemical stability of palonosetron hydrochloride with Fluorouracil and with gemcitabine hydrochloride during simulated y-site administration. AB - The objective of this study was to evaluate the physical and chemical stability of undiluted palonosetron 50 micrograms/mL as the hydrochloride with fluorouracil 16 mg/mL, and with gemcitabine 10 mg/mL as the hydrochloride, in 5% dextrose injection during simulated Y-site administration. Triplicate test samples were prepared by admixing 7.5 mL of palonosetron hydrochloride with 7.5 mL of the fluorouacil and gemcitabine hydrochloride admixtures. Physical stability was assessed by using a multistep evaluation procedure that included both turbidimetric and particulate measurements as well as visual inspection. Chemical stability was assessed by using stability-indicating high-performance liquid chromatographic analytical techniques that determined drug concentrations. Evaluations were performed initially upon mixing and 1 and 4 hours after mixing. The samples were clear and colorless when viewed in normal fluorescent room light and when viewed with a Tyndall beam. Measured turbidity remained unchanged; particulate content was low and changed little. High-performance liquid chromatographic analysis revealed that palonosetron hydrochloride, fluorouracil, and gemcitabine hydrochloride remained stable throughout the 4-hour test with no drug loss. Palonosetron hydrochloride is physically compatible and chemically stable with fluorouracil and with gemcitabine hydrochloride during simulated Y site administration. PMID- 23925057 TI - Stability of nebulizer admixtures. AB - There has been an increase in the compounding of admixed respiratory preparations for nebulization. These admixtures may improve patient convenience and compliance, but there are few data regarding the stability of these admixtures. In this study, four drugs from the four major respiratory therapeutic classes were evaluated. Each drug was formulated singularly and in a combination formulation. The physical and chemical stability of each formulation was evaluated under four storage conditions over the course of 8 weeks. The combination formulation was more stable than any of the individual formualtions. The formulations stored under elevated temperatures were less stable than those stored at room temperature or in the refrigerator. PMID- 23925058 TI - PostScription-Women in Balance: A Cause Worth Advancing. PMID- 23925059 TI - Simulations to compare efficacies of tetravalent dengue vaccines and mosquito vector control. AB - SUMMARY: Infection with dengue, the most prevalent mosquito-borne virus, manifests as dengue fever (DF) or the more fatal dengue haemorrhagic fever (DHF). DHF occurs mainly when an individual who has acquired antibodies to one serotype is inoculated with another serotype. It was reported that mosquito control may have increased the incidence of DF and DHF due to age-dependency in manifesting these illnesses or an immunological mechanism. Tetravalent dengue vaccine is currently being tested in clinical trials. However, seroconversions to all four serotypes were achieved only after three doses. Therefore, vaccines may predispose vaccinees to the risk of developing DHF in future infections. This study employed an individual-based computer simulation, to emulate mosquito control and vaccination, incorporating seroconversion rates reported from actual clinical trials. It was found that mosquito control alone would have increased incidence of DF and DHF in areas of high mosquito density. A vaccination programme with very high coverage, even with a vaccine of suboptimal seroconversion rates, attenuated possible surges in the incidence of DF and DHF which would have been caused by insufficient reduction in mosquito abundance. DHF cases attributable to vaccine-derived enhancement were fewer than DHF cases prevented by a vaccine with considerably high (although not perfect) seroconversion rates. These predictions may justify vaccination programmes, at least in areas of high mosquito abundance. In such areas, mosquito control programmes should be conducted only after the vaccination programme with a high coverage has been initiated. PMID- 23925060 TI - Assessing abnormal head posture: a new paradigm. AB - PURPOSE OF REVIEW: We aim to give a systematic approach on how to assess the cause of a patient's abnormal head posture (AHP). RECENT FINDINGS: Over the decades, many important clinical observers and teachers have described diagnostic techniques for patients with AHP. Recently, Wong has added a new set of office based diagnostic criteria that expand and solidify the office assessment of AHP. SUMMARY: We describe old and new, well known and poorly known office techniques for the assessment of AHP. PMID- 23925061 TI - Treatment of unilateral congenital ptosis: putting the debate to rest. AB - PURPOSE OF REVIEW: Frontalis suspension for the surgical correction of poor levator function congenital ptosis has been a matter of debate in the last decade, but recently progress has been made. This study highlights the relevant keystones regarding sling material, surgical steps, and approach that can improve functional and esthetic results, while minimizing risk to the eye. RECENT FINDINGS: The incidence and demographics of ptosis in children have been reported by two recent studies confirming that unilateral, poor levator function congenital ptosis is the most common form, the left eye is most commonly affected, and frontalis suspension is the most commonly performed technique. Significant progress has been made concerning the sling material and the surgical technique of frontalis suspension. Although different surgical designs for sling suspension have proven to have no effect on the final result, a recent study has shown the importance of direct fixation with sutures of the sling material to the tarsal plate to increase the success rate Autologous fascia lata has been found to be an excellent sling material with the lowest complication rate and should be considered the preferred material for long-term correction. A review of the recent literature suggests that unilateral surgery is the preferred approach. SUMMARY: Although the surgical treatment of simple congenital ptosis has not radically changed through the years, recent reports have established some keystones that can positively affect the esthetic outcomes and safety of frontalis suspension. PMID- 23925062 TI - Myectomy for blepharospasm 2013. AB - PURPOSE OF REVIEW: Botulinum toxin (BTX) injections are the main medical treatment of facial dystonias, but injections are ineffective in some patients. This review discusses the indications for myectomy and surgical technique for treating benign essential blepharospasm (BEB) and apraxia of eyelid opening (ALO). RECENT FINDINGS: There are four reasons to consider myectomy for patients with BEB. The first is ALO associated with BEB. The second is patients with blepharospasm-associated deformities. The third is patients who are truly unresponsive to BTX. The fourth is patients who cannot afford or who refuse BTX injections. SUMMARY: Myectomy remains essential for treating blepharospasm patients and the most common indication is those with associated ALO. PMID- 23925063 TI - Periocular fat grafting: indications and techniques. AB - PURPOSE OF REVIEW: Autologous fat transfer (AFT) is gaining popularity in periorbital and facial rejuvenation as well as structural reconstruction because of the advantages of fat over other fillers and implants. RECENT FINDINGS: As the technique and instruments were refined over the years, the incidence of AFT morbidity decreased; however, there is still no consensus on the standardization of the procedure. Several studies have failed to demonstrate superiority of any routine technique; however, various suggestions provided by these investigations have had significant impact on the outcome of surgery. New insights are mainly focused on improving the survival of the grafted tissue, mainly through enhancing cell differentiation and angiogenesis. Clinical applications of adipose-derived stem cell (ADSC) transfer with or without other enhancers were proven to be successful; however, there is not enough human research on this topic yet. Experts made a clear distinction between AFT and ADSC transfer, and the details can be found in this report. Management of hard-to-treat maxillofacial conditions including orbital disorders evolved from AFT techniques, the so-called structural fat grafting. SUMMARY: Harvesting methods to obtain stem cells have proven helpful in many studies. The future of fat grafting relies on the basic research that includes using additive agents, enhancers, or scaffolds to fat for increased survival of the graft. PMID- 23925064 TI - Current world literature. Ocular genetics. PMID- 23925066 TI - Digitized single scattering nanoparticles for probing molecular binding. AB - Single gold nanoparticles (AuNPs), whose scattering light intensity was digitized and expressed as digital information through common software, were used as digital recorders for probing molecular binding of avidin to biotin. PMID- 23925067 TI - Two-step crystal engineering of porous nets from [Cr3(MU3-O)(RCO2)6] and [Cu3(MU3 Cl)(RNH2)6Cl6] molecular building blocks. AB - Two porous nets have been prepared via a 2-step crystal engineering approach that links decorated trigonal prismatic [Cr3(MU3-O)(CO2)6] and [Cu3(MU3-Cl)(RNH2)6Cl6] molecular building blocks, MBBs. tp-PMBB-5-acs-1 is a rare example of a rigid acs underlying net whereas tp-PMBB-6-stp-1, an stp underlying net, exhibits free NH2 groups in its channels and a relatively high isosteric heat of adsorption for CO2. PMID- 23925068 TI - Sound velocities of PbTe to 14 GPa: evidence for coupling between acoustic and optic phonons. AB - Sound velocities of PbTe have been determined to 14 GPa using an ultrasonic interferometric method, which allowed for a detailed investigation of the characteristic variations of P and S wave velocities across the phase transitions from Fm3-m (B1) to the orthorhombic Pbnm to Pm3-m (B2). Elastic bulk and shear moduli and their pressure derivatives have been determined by fitting the measured velocities using a finite-strain approach. Based on the measured velocities and Debye theory, an estimate is made of the acoustic phonon contribution to the thermal conductivity, considering inter-phonon interactions only. By combining this result with previous determinations of the thermal conductivity due to electrons, the combination was found to have a significantly lower value than the previously determined total thermal conductivity. This is interpreted as evidence for coupling between the low-lying transverse optic (TO) and longitudinal acoustic (LA) modes, allowing the transfer of thermal energy from the acoustic to the optic modes. Possible explanations are discussed in the paper. PMID- 23925069 TI - Dye-sensitized solar cells based on hydroquinone/benzoquinone as bio-inspired redox couple with different counter electrodes. AB - In the present study, tetramethylammonium hydroquinone (HQ)/benzoquinone (BQ) were developed for use as a redox couple, with poly(3,4-ethylenedioxythiophene) (PEDOT) and multiwalled carbon nanotubes (MWNT) being proposed for use as counter electrode (CE) catalysts in dye-sensitized solar cells (DSSCs). Both metal complex N719 and metal-free organic dye CM309 were employed to fabricate devices. For the devices sensitized by N719, when using PEDOT and MWNT CEs, power conversion efficiencies (PCE) of 5.2 and 4.9% were obtained, respectively, which were much higher than that of the device using the traditional Pt CE (4.7%) when HQ/BQ electrolyte was employed. However, with the HQ/BQ redox shuttle, the efficiency of the devices sensitized by N719 is much lower than that of the devices when the traditional I(-)/I3(-) based electrolyte and Pt CE were employed (7.9%). While for the CM309 sensitized solar cells, when the HQ/BQ redox shuttle was employed, PEDOT and MWNT performed much better than Pt, the DSSC using the PEDOT CE showed an efficiency of 6.2%, which was close to that of the DSSC using the traditional I(-)/I3(-) electrolyte and Pt CE (6.3%). PMID- 23925070 TI - Tailoring copper valence states in CuOdelta/gamma-Al2O3 catalysts by an in situ technique induced superior catalytic performance for simultaneous elimination of NO and CO. AB - An in situ technique is employed to tailor the valence states of copper in CuOdelta/gamma-Al2O3 catalysts with the purpose of inducing superior catalytic performance for simultaneous elimination of NO and CO. The catalyst with zero valent copper exhibits excellent catalytic performance, which is comparable with the conventional supported noble-metal catalysts. PMID- 23925071 TI - Van Cliburn, resilience, and YOU~. AB - The fast pace of change in the health care environment can lead to stress and burnout. Case managers are acutely susceptible, as they are often the front-line "go to" professionals expected to solve all problems. Some tips to decrease negativity and increase resilience are discussed. PMID- 23925072 TI - Case management: a success story. PMID- 23925075 TI - Another look at roles and functions: has hospital case management lost its way? AB - PURPOSE OF THE STUDY: The purpose of this study was to identify the roles, functions, and types of activities that hospital case managers engage in on a day to-day basis and that leverage the most amounts of time. Previous studies superimpose a priori categories on research tools. PRACTICE SETTING: Hospital case management. METHODOLOGY AND SAMPLE: This study analyzes 4,064 spontaneous, unstructured list serve postings from the American Case Management Association Learning Link list serve from August 15, 2011, to August 18, 2012. The study group was a cross section of 415 case management professionals. IMPLICATIONS FOR PRACTICE: The data suggest that hospital case managers' time is inordinately leveraged by issues related to observation status/leveling of patients and the Centers for Medicare and Medicaid Services compliance. The data also suggest that hospital case management has taken a conceptual trajectory that has deviated significantly from what was initially conceived (quality, advocacy, and care coordination) and what is publicly purported. Case management education and practical orientation will need to be commensurate with this emerging emphasis. Case management leadership will need to be adept at mitigating the stresses of role confusion, role conflict, and role ambiguity. PMID- 23925073 TI - COLLABORATE(c): A Universal Competency-Based Paradigm for Professional Case Management, Part II: Competency Clarification. AB - PURPOSE/OBJECTIVES: The purpose of this second article of a 3-article series is to clarify the competencies for a new paradigm of case management built upon a value-driven foundation that PRIMARY PRACTICE SETTING(S): : Applicable to all health care sectors where case management is practiced. FINDINGS/CONCLUSIONS: In moving forward, the one fact that rings true is that there will be a constant change in our industry. As the health care terrain shifts and new influences continually surface, there will be consequences for case management practice. These impacts require nimble clinical professionals in possession of recognized and firmly established competencies. They must be agile to frame (and reframe) their professional practice to facilitate the best possible outcomes for their patients. Case managers can choose to be GumbyTM or PokeyTM. This is exactly the time to define a competency-based case management model, highlighting one sufficiently fluid to fit into any setting of care. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: The practice of case management transcends the vast array of representative professional disciplines and educational levels. A majority of current models are driven by business priorities rather than the competencies critical to successful practice and quality patient outcomes. This results in a fragmented professional case management identity. Although there is an inherent value in what each discipline brings to the table, this advanced model unifies behind case management's unique, strengths-based identity instead of continuing to align within traditional divisions (e.g., discipline, work setting, population served). This model fosters case management's expanding career advancement opportunities, including a reflective clinical ladder. PMID- 23925077 TI - Keeping case management practice strong: avoiding fragmentation through a patient centered approach. PMID- 23925078 TI - How do you say good-bye ... And hello? PMID- 23925079 TI - Integrity and accountability the Omnibus Final Rule: part II. PMID- 23925080 TI - A "return" to best practice basics: establishing rapport in workers' compensation cases. PMID- 23925081 TI - On-site Health Clinics = Increased Productivity. PMID- 23925082 TI - Spectroscopic determination of aboveground biomass in grasslands using spectral transformations, Support Vector Machine and Partial Least Squares Regression. AB - Aboveground biomass (AGB) is one of the strategic biophysical variables of interest in vegetation studies. The main objective of this study was to evaluate the Support Vector Machine (SVM) and Partial Least Squares Regression (PLSR) for estimating the AGB of grasslands from field spectrometer data and to find out which data pre-processing approach was the most suitable. The most accurate model to predict the total AGB involved PLSR and the Maximum Band Depth index derived from the continuum removed reflectance in the absorption features between 916 1,120 nm and 1,079-1,297 nm (R2 = 0.939, RMSE = 7.120 g/m2). Regarding the green fraction of the AGB, the Area Over the Minimum index derived from the continuum removed spectra provided the most accurate model overall (R2 = 0.939, RMSE = 3.172 g/m2). Identifying the appropriate absorption features was proved to be crucial to improve the performance of PLSR to estimate the total and green aboveground biomass, by using the indices derived from those spectral regions. Ordinary Least Square Regression could be used as a surrogate for the PLSR approach with the Area Over the Minimum index as the independent variable, although the resulting model would not be as accurate. PMID- 23925083 TI - [A man is as old as his bones]. PMID- 23925084 TI - [How to diagnose older patients]. PMID- 23925085 TI - [Dementia and neurocognitive impairment]. PMID- 23925086 TI - [Gait disturbance and bradykinesia in elderly]. PMID- 23925087 TI - [Falls and fractures]. PMID- 23925088 TI - [Management of life-style related diseases]. PMID- 23925089 TI - [Infectious diseases in the aged]. PMID- 23925090 TI - [Nutrition]. PMID- 23925091 TI - [J-EDIT: aim, method and effects of intervention]. PMID- 23925092 TI - [Risk factors for atherosclerotic disease from the Japanese Elderly Diabetes Intervention Trial (J-EDIT)]. PMID- 23925093 TI - [Learn from the importance of physical activity level in the elderly. How should we encourage and keep it?]. PMID- 23925094 TI - [Risks for impaired daily life function in the elderly with type 2 diabetes in Japan]. AB - AIM: The purpose of the present investigation was to explore the process towards functional disability and predicting factors in Japanese diabetic elderly. METHODS: We recruited 317 older patients aged 65 or over among participants in the large-scale prospective study of the Japanese Elderly Diabetes Intervention Trial (J-EDIT). We analyzed the changes of daily life function prospectively for 6 years. Information about diabetes, blood examinations and complications was obtained, and basic activity of daily living (ADL) and instrumental ADL (IADL) were assessed by total Barthel index score and the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG index), respectively. RESULTS: During 6 years of follow-up, 13.6% of subjects had developed a new ADL disability (bADL) and 38.3% had developed a new functional impairment assessed by TMIG index. In the 65-74 years age group, basic ADL decreased only in males, while females became functionally impaired. In 75-84 years age group, basic and IADL decreased in both men and women. Older age and metabolic syndrome negatively affected ADL, while baseline IADL impairment, cognitive dysfunction, physical inactivity, and insulin therapy were significant predictors of a future decline in the IADL. CONCLUSION: This study identified the disability process and prognostic factors, including the future decline of basic ADL and IADL in diabetic elderly patients. There are modifiable factors for ADL impairment, comprehensive treatment and care are required to keep Japanese diabetic elderly patients healthy in daily life functioning. PMID- 23925095 TI - [Risk factors for dementia in elderly diabetics and the treatment and management]. PMID- 23925096 TI - [Nutritional intake and the relationship between diet and diabetes]. PMID- 23925097 TI - [Guidelines for non-medical care providers to manage the first steps of emergency triage of elderly evacuees, and its information transmission overseas]. PMID- 23925098 TI - [Medium and long-term management of nutrition and related gastroenterology disorders among elderly evacuees]. PMID- 23925099 TI - [Mental management of elderly people in middle-long term after the wake of disasters]. PMID- 23925100 TI - [A burden on elderlies after the Great East Japan Earthquake: epidemiological analysis of hospitalized patients with respiratory infection]. PMID- 23925101 TI - [Long-term evacuation after the nuclear accident in Fukushima ~Different daily living under low-dose radioactive suffering~]. AB - One year has passed since the Great East Japan Earthquake and the Fukushima No. 1 nuclear power plant accident. Even currently, more than 150,000 evacuees in Fukushima Prefecture are forced to leave their home and to move throughout Japan. Because of the limited space of temporary housing and the weakening of personal ties in local communities, many families need to move and have separate lives. As a consequence, Fukushima has a serious shortage of caregivers for the elderly. There have been more than 1,300 disaster-related deaths due to shock and stress after long-distance drifts from town to town. Most of the victims were the elderly, who collapsed, caught pneumonia, suffered stroke and heart attack. Concerns about the safety of low-dose radiation exposure deprived the elderly of important contact with playing outside with their grandchildren in Fukushima. Fear of invisible radioactive contamination inactivated outdoor activities such as farming, dairy, fishing, gardening, hiking and wild-vegetable/mushroom hunting, although most of these activities have been traditionally supported by the wisdom of the elderly. Several recent questionnaire investigations revealed that older evacuees wish to go home even if the environment has significant contamination. In contrast, more than half of younger generation with small children have a different attitude. Nuclear accident brought serious social pains although it did not acutely hurt our bodies. PMID- 23925102 TI - [Construction of a scale of attitude toward death in the middle-aged and elderly and its validity and reliability]. AB - AIM: The purpose of this study was to construct a scale that measures multidimensional attitudes regarding death in the middle-aged and elderly, using scale items for adolescents, and to examine its reliability and validity. METHODS: Twenty-nine items which were selected from the scale of Attitudes toward Death (Tange, 1999) were administered to subjects, consisting of 2,223 community living Japanese men and women aged 40-79 years. Both exploratory factor analysis and confirmatory factor analysis were performed to examine the factor structures. The reliability and validity of the scale were examined. RESULTS: Exploratory factor analysis was performed to examine the factor structures of death attitudes, using the data from half of the subjects, indicated 5 factors. Confirmatory factor analysis, using the data from the remaining half, supported the goodness of fit of that model. Using this structure, the attitude toward death scale for the middle-aged and elderly (ATDS-A; five subscales) was constructed; "fear of death", "belief in existence of afterlife", "intention to live out own life", "meaning of death for life", "approval of death with dignity". For these subscales, the alpha coefficients ranged from 0.59-0.87. The validity of the subscales was suggested through the relation with the ego integration score. CONCLUSIONS: This study suggested that the ATDS-A was reliable and valid, and was useful for the measurement of death attitudes in the middle aged and elderly. PMID- 23925103 TI - [Prognostic factors in patients undergoing percutaneous endoscopic gastrostomy]. AB - OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) serves as a major artificial hydration/feeding method in the terminal care of elderly patients. We surveyed the state of patients who underwent PEG at our hospital and investigated the clinical characteristics of patients in the long-term survival group, and the short-term survival group. METHODS: The subjects were 125 patients who underwent PEG at our hospital between January 2007 and June 2011. Two kinds of examination were performed. In the first examination, subjects were divided into a short-term group of 37 patients who survived <181 days and a long-term group of 88 patients who survived >=181 days. In the second examination, subjects were divided into 2 purpose-oriented groups: a prolongation of life group of 76 patients and a being able to eat group of 49 patients. We analyzed the clinical records of these patients and conducted a telephone-based survey. RESULTS: In the short-term group, there were many cases of PEG after hospitalization due to medical diseases such as pneumonia. In the long-term group, many subjects were young, female, suffered from recurrence of cranial nerve disease, or slowly developed dysphagia. The involvement of rehabilitation doctors, the rate of undergoing rehabilitation for dysphagia, and cases who were able to achieve oral ingestion were significantly high. Of 49 patients who underwent PEG with the aim of being able to eat, 24 achieved oral ingestion. CONCLUSION: Our findings suggest that involving rehabilitation doctors and undergoing rehabilitation for swallowing effectively promote long-term survival after PEG. PMID- 23925104 TI - [Influence of nutrition product type on a tube feeding administrative task man hour and the contents of nursing]. AB - AIM: The purpose of this study is to consider the influence which the form of tube feeding nutrition products has on meal delivery operating man-hours, personnel expense, and the quality of nursing. In addition, it is also considers operational efficiency improvement. METHODS: We used liquid nutrition material packaged in a paper container before we changed the nutrition product. After the change of the nutrition product, semi-solid nutrition with ready to hang (RTH) moderately viscous nutrition was used. We investigated the tube feeding administrative task and the contents of nursing using the Industry Engineering technique. RESULTS: We were able to reduce by half the man-hours required for 1 morning tube feeding in 238.1 minutes to 106.1 minutes by changing to RTH semi solid nutrition. Thereby, we were able to reduce personnel expenses by 514,290 yen per month. The total man-hours which could be spent on nursing increased to 170 from 139. CONCLUSIONS: By using the RTH semi-solid nutrition with moderate viscosity, the operating efficiency of tube feeding management has improved greatly. As a result, the time which can be spent on nursing increased. PMID- 23925105 TI - [Relationship between comprehensive quality of life and factors related to chewing and swallowing function among community-dwelling elderly individuals]. AB - AIM: The purpose of the present study was to examine the relationship between comprehensive quality of life (QOL) and some factors regarding chewing and swallowing function among community-dwelling elderly individuals. METHODS: The subjects were 675 independent elderly persons residing in the northern area of Miyazaki Prefecture, and we obtained the self-administered questionnaires from 545 elderly people. We used "active scale for the elderly (ASE)" and "dysphagia risk assessment for the community-dwelling elderly (DRACE)" to evaluate their comprehensive QOL and function of chewing and swallowing, respectively. Furthermore, we examined some factors such as age, gender, subjective satisfaction with diet and verbal communication. RESULTS: The score of ASE showed a significant decline with age (p<0.01) while the DRACE score increased significantly with age (p<0.01). Pearson's correlation coefficients revealed that the ASE score was significantly related to all of the factors regarding regulation of food intake. Partial correlation coefficients adjusted for age also revealed the same tendency. From the multiple regression analysis, subjective satisfaction with verbal communication, DRACE score, age and appetite were extracted as factors influencing ASE score (adjusted R(2)=0.43, p<0.01). CONCLUSION: Among independent elderly persons residing in the community, the comprehensive QOL was significantly related to factors such as subjective satisfaction with verbal communication, dysphagia risk, age, and appetite. PMID- 23925109 TI - [Development of the revised version of the Nagoya Graphical Symptom Scale for Elderly (NGSSE)]. PMID- 23925110 TI - Characterization of a non-aggregating silicon(IV) phthalocyanine in aqueous solution: toward red-light-driven photocatalysis based on earth-abundant materials. AB - Photophysical and photochemical characterization of a novel cationic silicon phthalocyanine with excellent water solubility properties is reported. The robust red-light responsive compound shows very attractive features as a sensitizer for reductive and oxidative quenching processes to trigger photocatalytic substrate conversion in aqueous solution. PMID- 23925111 TI - Systems biology: metabolite turns master regulator. PMID- 23925112 TI - A gustatory receptor paralogue controls rapid warmth avoidance in Drosophila. AB - Behavioural responses to temperature are critical for survival, and animals from insects to humans show strong preferences for specific temperatures. Preferred temperature selection promotes avoidance of adverse thermal environments in the short term and maintenance of optimal body temperatures over the long term, but its molecular and cellular basis is largely unknown. Recent studies have generated conflicting views of thermal preference in Drosophila, attributing importance to either internal or peripheral warmth sensors. Here we reconcile these views by showing that thermal preference is not a singular response, but involves multiple systems relevant in different contexts. We found previously that the transient receptor potential channel TRPA1 acts internally to control the slowly developing preference response of flies exposed to a shallow thermal gradient. We now find that the rapid response of flies exposed to a steep warmth gradient does not require TRPA1; rather, the gustatory receptor GR28B(D) drives this behaviour through peripheral thermosensors. Gustatory receptors are a large gene family, widely studied in insect gustation and olfaction, and are implicated in host-seeking by insect disease vectors, but have not previously been implicated in thermosensation. At the molecular level, GR28B(D) misexpression confers thermosensitivity upon diverse cell types, suggesting that it is a warmth sensor. These data reveal a new type of thermosensory molecule and uncover a functional distinction between peripheral and internal warmth sensors in this tiny ectotherm reminiscent of thermoregulatory systems in larger, endothermic animals. The use of multiple, distinct molecules to respond to a given temperature, as observed here, may facilitate independent tuning of an animal's distinct thermosensory responses. PMID- 23925113 TI - Charting a dynamic DNA methylation landscape of the human genome. AB - DNA methylation is a defining feature of mammalian cellular identity and is essential for normal development. Most cell types, except germ cells and pre implantation embryos, display relatively stable DNA methylation patterns, with 70 80% of all CpGs being methylated. Despite recent advances, we still have a limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in-depth analysis of 42 whole-genome bisulphite sequencing data sets across 30 diverse human cell and tissue types. We observe dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context, most of which are distal to transcription start sites. These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription-factor-binding sites, which allow identification of key lineage specific regulators. In addition, differentially methylated regions (DMRs) often contain single nucleotide polymorphisms associated with cell-type-related diseases as determined by genome-wide association studies. The results also highlight the general inefficiency of whole-genome bisulphite sequencing, as 70 80% of the sequencing reads across these data sets provided little or no relevant information about CpG methylation. To demonstrate further the utility of our DMR set, we use it to classify unknown samples and identify representative signature regions that recapitulate major DNA methylation dynamics. In summary, although in theory every CpG can change its methylation state, our results suggest that only a fraction does so as part of coordinated regulatory programs. Therefore, our selected DMRs can serve as a starting point to guide new, more effective reduced representation approaches to capture the most informative fraction of CpGs, as well as further pinpoint putative regulatory elements. PMID- 23925114 TI - PAAR-repeat proteins sharpen and diversify the type VI secretion system spike. AB - The bacterial type VI secretion system (T6SS) is a large multicomponent, dynamic macromolecular machine that has an important role in the ecology of many Gram negative bacteria. T6SS is responsible for translocation of a wide range of toxic effector molecules, allowing predatory cells to kill both prokaryotic as well as eukaryotic prey cells. The T6SS organelle is functionally analogous to contractile tails of bacteriophages and is thought to attack cells by initially penetrating them with a trimeric protein complex called the VgrG spike. Neither the exact protein composition of the T6SS organelle nor the mechanisms of effector selection and delivery are known. Here we report that proteins from the PAAR (proline-alanine-alanine-arginine) repeat superfamily form a sharp conical extension on the VgrG spike, which is further involved in attaching effector domains to the spike. The crystal structures of two PAAR-repeat proteins bound to VgrG-like partners show that these proteins sharpen the tip of the T6SS spike complex. We demonstrate that PAAR proteins are essential for T6SS-mediated secretion and target cell killing by Vibrio cholerae and Acinetobacter baylyi. Our results indicate a new model of the T6SS organelle in which the VgrG-PAAR spike complex is decorated with multiple effectors that are delivered simultaneously into target cells in a single contraction-driven translocation event. PMID- 23925115 TI - Microbiology: a weapon for bacterial warfare. PMID- 23925116 TI - Limited airborne transmission of H7N9 influenza A virus between ferrets. AB - Wild waterfowl form the main reservoir of influenza A viruses, from which transmission occurs directly or indirectly to various secondary hosts, including humans. Direct avian-to-human transmission has been observed for viruses of subtypes A(H5N1), A(H7N2), A(H7N3), A(H7N7), A(H9N2) and A(H10N7) upon human exposure to poultry, but a lack of sustained human-to-human transmission has prevented these viruses from causing new pandemics. Recently, avian A(H7N9) viruses were transmitted to humans, causing severe respiratory disease and deaths in China. Because transmission via respiratory droplets and aerosols (hereafter referred to as airborne transmission) is the main route for efficient transmission between humans, it is important to gain an insight into airborne transmission of the A(H7N9) virus. Here we show that although the A/Anhui/1/2013 A(H7N9) virus harbours determinants associated with human adaptation and transmissibility between mammals, its airborne transmissibility in ferrets is limited, and it is intermediate between that of typical human and avian influenza viruses. Multiple A(H7N9) virus genetic variants were transmitted. Upon ferret passage, variants with higher avian receptor binding, higher pH of fusion, and lower thermostability were selected, potentially resulting in reduced transmissibility. This A(H7N9) virus outbreak highlights the need for increased understanding of the determinants of efficient airborne transmission of avian influenza viruses between mammals. PMID- 23925118 TI - The role of spin in the kinetic control of recombination in organic photovoltaics. AB - In biological complexes, cascade structures promote the spatial separation of photogenerated electrons and holes, preventing their recombination. In contrast, the photogenerated excitons in organic photovoltaic cells are dissociated at a single donor-acceptor heterojunction formed within a de-mixed blend of the donor and acceptor semiconductors. The nanoscale morphology and high charge densities give a high rate of electron-hole encounters, which should in principle result in the formation of spin-triplet excitons, as in organic light-emitting diodes. Although organic photovoltaic cells would have poor quantum efficiencies if every encounter led to recombination, state-of-the-art examples nevertheless demonstrate near-unity quantum efficiency. Here we show that this suppression of recombination arises through the interplay between spin, energetics and delocalization of electronic excitations in organic semiconductors. We use time resolved spectroscopy to study a series of model high-efficiency polymer fullerene systems in which the lowest-energy molecular triplet exciton (T1) for the polymer is lower in energy than the intermolecular charge transfer state. We observe the formation of T1 states following bimolecular recombination, indicating that encounters of spin-uncorrelated electrons and holes generate charge transfer states with both spin-singlet ((1)CT) and spin-triplet ((3)CT) characters. We show that the formation of triplet excitons can be the main loss mechanism in organic photovoltaic cells. But we also find that, even when energetically favoured, the relaxation of (3)CT states to T1 states can be strongly suppressed by wavefunction delocalization, allowing for the dissociation of (3)CT states back to free charges, thereby reducing recombination and enhancing device performance. Our results point towards new design rules both for photoconversion systems, enabling the suppression of electron-hole recombination, and for organic light-emitting diodes, avoiding the formation of triplet excitons and enhancing fluorescence efficiency. PMID- 23925120 TI - Retraction: Bird-like fossil footprints from the Late Triassic. PMID- 23925121 TI - Second order non-linear optical activity of arsenic and antimony dithiolene complexes. AB - Synthesis and characterization of dithiolene complexes of arsenic and antimony in trivalent state have been reported. A four coordinated structural motif results in a ladder like arrangement in the arsenic complex due to the inter-anionic As-S interaction which is replaced by Sb-pi interaction with the counter cation in the solid state structure of the similar antimony complex. Electronic structure calculations on ground state geometries and the time-dependent density functional theoretical calculations were performed in order to characterize the absorption spectra incorporating solvent effects. Notably, both the complexes display intense second order optical non-linearity as has been determined using hyper Rayleigh scattering technique in dichloromethane solution and the results are corroborated by DFT calculations. PMID- 23925119 TI - Coordination of bacterial proteome with metabolism by cyclic AMP signalling. AB - The cyclic AMP (cAMP)-dependent catabolite repression effect in Escherichia coli is among the most intensely studied regulatory processes in biology. However, the physiological function(s) of cAMP signalling and its molecular triggers remain elusive. Here we use a quantitative physiological approach to show that cAMP signalling tightly coordinates the expression of catabolic proteins with biosynthetic and ribosomal proteins, in accordance with the cellular metabolic needs during exponential growth. The expression of carbon catabolic genes increased linearly with decreasing growth rates upon limitation of carbon influx, but decreased linearly with decreasing growth rate upon limitation of nitrogen or sulphur influx. In contrast, the expression of biosynthetic genes showed the opposite linear growth-rate dependence as the catabolic genes. A coarse-grained mathematical model provides a quantitative framework for understanding and predicting gene expression responses to catabolic and anabolic limitations. A scheme of integral feedback control featuring the inhibition of cAMP signalling by metabolic precursors is proposed and validated. These results reveal a key physiological role of cAMP-dependent catabolite repression: to ensure that proteomic resources are spent on distinct metabolic sectors as needed in different nutrient environments. Our findings underscore the power of quantitative physiology in unravelling the underlying functions of complex molecular signalling networks. PMID- 23925122 TI - Electric impedance microflow cytometry for characterization of cell disease states. AB - The electrical properties of biological cells have connections to their pathological states. Here we present an electric impedance microflow cytometry (EIMC) platform for the characterization of disease states of single cells. This platform entails a microfluidic device for a label-free and non-invasive cell counting assay through electric impedance sensing. We identified a dimensionless offset parameter delta obtained as a linear combination of a normalized phase shift and a normalized magnitude shift in electric impedance to differentiate cells on the basis of their pathological states. This paper discusses a representative case study on red blood cells (RBCs) invaded by the malaria parasite Plasmodium falciparum. Invasion by P. falciparum induces physical and biochemical changes on the host cells throughout a 48-h multi-stage life cycle within the RBC. As a consequence, it also induces progressive changes in electrical properties of the host cells. We demonstrate that the EIMC system in combination with data analysis involving the new offset parameter allows differentiation of P. falciparum infected RBCs from uninfected RBCs as well as among different P. falciparum intraerythrocytic asexual stages including the ring stage. The representative results provided here also point to the potential of the proposed experimental and analysis platform as a valuable tool for non invasive diagnostics of a wide variety of disease states and for cell separation. PMID- 23925124 TI - A homospin cobalt(II) topological ferrimagnet. AB - An unusual 3D homospin cobalt(II) molecular topological ferrimagnet has been successfully assembled using a mixed ligand approach, which shows a critical temperature of 9 K and a compensation temperature of 5 K. PMID- 23925123 TI - FUS-regulated region- and cell-type-specific transcriptome is associated with cell selectivity in ALS/FTLD. AB - FUS is genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To clarify the RNA metabolism cascade regulated by FUS in ALS/FTLD, we compared the FUS-regulated transcriptome profiles in different lineages of primary cells from the central nervous system. The profiles of FUS-mediated gene expression and alternative splicing in motor neurons were similar to those of cortical neurons, but not to those in cerebellar neurons despite the similarity of innate transcriptome signature. The gene expression profiles in glial cells were similar to those in motor and cortical neurons. We identified certain neurological diseases-associated genes, including Mapt, Stx1a, and Scn8a, among the profiles of gene expression and alternative splicing events regulated by FUS. Thus, FUS-regulated transcriptome profiles in each cell-type may determine cellular fate in association with FUS-mediated ALS/FTLD, and identified RNA targets for FUS could be therapeutic targets for ALS/FTLD. PMID- 23925125 TI - Selective fluorescent-free detection of biomolecules on nanobiochips by wavelength dependent-enhanced dark field illumination. AB - Individual silver nanoparticle-conjugated target protein (cTnI) molecules on gold nanopatterned chip were selectively detected by wavelength dependent-enhanced dark field illumination. Using specific nanoparticles with unique sizes and materials, the immunotargeted nanoparticle on the chips was detected at the single-molecule level by monitoring changes in the plasmonic resonance based on wavelength dependence. PMID- 23925126 TI - Histone variant Htz1 promotes histone H3 acetylation to enhance nucleotide excision repair in Htz1 nucleosomes. AB - Nucleotide excision repair (NER) is critical for maintaining genome integrity. How chromatin dynamics are regulated to facilitate this process in chromatin is still under exploration. We show here that a histone H2A variant, Htz1 (H2A.Z), in nucleosomes has a positive function in promoting efficient NER in yeast. Htz1 inherently enhances the occupancy of the histone acetyltransferase Gcn5 on chromatin to promote histone H3 acetylation after UV irradiation. Consequently, this results in an increased binding of a NER protein, Rad14, to damaged DNA. Cells without Htz1 show increased UV sensitivity and defective removal of UV induced DNA damage in the Htz1-bearing nucleosomes at the repressed MFA2 promoter, but not in the HMRa locus where Htz1 is normally absent. Thus, the effect of Htz1 on NER is specifically relevant to its presence in chromatin within a damaged region. The chromatin accessibility to micrococcal nuclease in the MFA2 promoter is unaffected by HTZ1 deletion. Acetylation on previously identified lysines of Htz1 plays little role in NER or cell survival after UV. In summary, we have identified a novel aspect of chromatin that regulates efficient NER, and we provide a model for how Htz1 influences NER in Htz1 nucleosomes. PMID- 23925127 TI - Oxidative stress-induced mutagenesis in single-strand DNA occurs primarily at cytosines and is DNA polymerase zeta-dependent only for adenines and guanines. AB - Localized hyper-mutability caused by accumulation of lesions in persistent single stranded (ss) DNA has been recently found in several types of cancers. An increase in endogenous levels of reactive oxygen species (ROS) is considered to be one of the hallmarks of cancers. Employing a yeast model system, we addressed the role of oxidative stress as a potential source of hyper-mutability in ssDNA by modulation of the endogenous ROS levels and by exposing cells to oxidative DNA damaging agents. We report here that under oxidative stress conditions the majority of base substitution mutations in ssDNA are caused by erroneous, DNA polymerase (Pol) zeta-independent bypass of cytosines, resulting in C to T transitions. For all other DNA bases Pol zeta is essential for ROS-induced mutagenesis. The density of ROS-induced mutations in ssDNA is lower, compared to that caused by UV and MMS, which suggests that ssDNA could be actively protected from oxidative damage. These findings have important implications for understanding mechanisms of oxidative mutagenesis, and could be applied to development of anticancer therapies and cancer prevention. PMID- 23925129 TI - Reply to Mohite et al. PMID- 23925128 TI - Direct assessment of transcription fidelity by high-resolution RNA sequencing. AB - Cancerous and aging cells have long been thought to be impacted by transcription errors that cause genetic and epigenetic changes. Until now, a lack of methodology for directly assessing such errors hindered evaluation of their impact to the cells. We report a high-resolution Illumina RNA-seq method that can assess noncoded base substitutions in mRNA at 10(-4)-10(-5) per base frequencies in vitro and in vivo. Statistically reliable detection of changes in transcription fidelity through ~10(3) nt DNA sites assures that the RNA-seq can analyze the fidelity in a large number of the sites where errors occur. A combination of the RNA-seq and biochemical analyses of the positions for the errors revealed two sequence-specific mechanisms that increase transcription fidelity by Escherichia coli RNA polymerase: (i) enhanced suppression of nucleotide misincorporation that improves selectivity for the cognate substrate, and (ii) increased backtracking of the RNA polymerase that decreases a chance of error propagation to the full-length transcript after misincorporation and provides an opportunity to proofread the error. This method is adoptable to a genome-wide assessment of transcription fidelity. PMID- 23925130 TI - HeartWare ventricular assist device experience in the real world. PMID- 23925131 TI - Layered pnictide-oxide Na2Ti2Pn2O (Pn=As, Sb): a candidate for spin density waves. AB - From first-principles calculations, we have studied the electronic and magnetic structures of compound Na2Ti2Pn2O (Pn=As or Sb), whose crystal structure is a bridge between or a combination of those of high-Tc superconducting cuprates and iron pnictides. We find that in the ground state Na2Ti2As2O is a novel blocked checkerboard antiferromagnetic semiconductor with a small band gap of about 0.15 eV. In contrast, Na2Ti2Sb2O is a bi-collinear antiferromagnetic semimetal, with a small moment of about 0.5 MU(B) around each Ti atom. We show that there is a strong Fermi surface nesting in Na2Ti2Pn2O, and we verify that the blocked checkerboard and bi-collinear antiferromagnetic states both are the spin density waves induced by the Fermi surface nesting. A tetramer structural distortion is found in company with the formation of a blocked checkerboard antiferromagnetic order, in good agreement with the experimentally observed commensurate structural distortion but with space group symmetry retained after the anomaly happens. PMID- 23925132 TI - Dextromethorphan, an NMDA Receptor Antagonist, as a Treatment for Pain. PMID- 23925133 TI - Formulating for the gluten-sensitive individual. PMID- 23925134 TI - Basics of compounding: using chemical conversion factors. PMID- 23925135 TI - Compounding: a well-established practice in 1938. PMID- 23925136 TI - Technology Update: An Overview of PDA-Based Software Applications for Practicing Pharmacists. AB - When it comes to the adoption of portable information technology devices called personal digital assistants and the selection of new application software to be used on the personal digital assistant, most healthcare professionals in general, including pharmacists, are in a dilemma as to which hardware and software applications are best suited for them. Having made a personal digital assistant device selection, an even more difficult task is deciding which of the hundreds of clinical applications should be installed on their personal digital assistant for everyday practice. This article provides an overview of the personal digital assistant-based clinical software applications that are most important and relevant for use by practicing pharmacists in any community setting. PMID- 23925137 TI - Stability and subjective taste acceptability of four glycopyrrolate solutions for oral administration. AB - The oral tablet form of glycopryrrolate has been discontinued in Canada because of declining use. Alternatives include injectable glycopyrrolate, which is still on the market, and an oral solution compounded from the injectable form. The stabilities of different oral solutions of gycopyrrolate formulated from the injectable form were studied by using a high-performance liquid chromatographic technique. The 0.2 mg/mL injectable solution of glycopyrrolate was diluted 1:1 with water, simple syrup, a Hospital for Sick Children vehicle, or Ora-Plus/Ora Sweet vehicle. After 35 days of storage, more than 90% of the original concentration of glycopyrrolate was still present in all solutions, regardless of whether the solution was kept at room temperature or refrigerated. A simple taste test indicated that Ora-Plus/Ora-Sweet solution and simple syrup were better choices as vehicles for the glycopyrrolate oral dosage form. PMID- 23925138 TI - Chemical stability of hydralazine hydrochloride after reconstitution in 0.9% sodium chloride injection or 5% dextrose injection for infusion. AB - The chemical stability of hydralazine hydrochloride (0.2 mg/mL) in 0.9% sodium chloride injection and in 5% dextrose injection stored in a polyvinylchloride bags at 25 deg C was studied by means of a stability-indicating high-performance liquid chromatographic assay method. The concentrations of the drug were directly related to peak heights, and the percent relative standard deviation, based on five injections, was 1.2. The excipients present in the injection did not interfere with the assay procedure. The products of decomposition separated from the intact drug. In 5% dextrose injection, the loss in potency was 5% after less than 1 hour of storage and more than 40% after 1 day of storage at room temperature. The pH value of the injection decreased from 4.0 to 3.6 after 1 day. In 0.9% sodium chloride injection, the loss in potency after 2 days of storage at room temperature was 8%, and the pH value had decreased from 4.9 to 4.1. The physical appearance of the injection did not change. PMID- 23925139 TI - Stability of sotalol hydrochloride in extemporaneously prepared oral suspension formulations. AB - The physical, chemical, and microbial stabilities of extemporaneously compounded oral liquid formulations of sotalol hydrochloride were studied. Sotalol hydrochloride oral liquid suspensions (5mg/mL) were prepared from commercially available tablets (Betapace) in a 1:1 mixture of Ora-Plus: Ora-Sweet, a 1:1 mixture of Ora-Plus:Ora-Sweet SF, and a 1:2.4 mixture of simple syrup:methylcellulose vehicle. Six batches of each formulation were prepared; three were stored at refrigerated temperature (2 deg to 8 deg C) and three at room temperature (20 deg to 25 deg C). Samples were collected from each batch weekly for 6 weeks, and again at 12 weeks. Samples were analyzed by means of a high-performance liquid chromatographic method, and the concentrations obtained were compared to the theoretical time zero value. Samples were examined for pH, odor, color, and consistency changes. The suspensions also were evaluated for their microbial stability. Sotalol hydrochloride oral liquid suspensions (5mg/mL) were chemically stable for 12 weeks regardless of storage conditions (room temperature or refrigerated). Bacterial growth was not supported by any of the formulations. Suspensions stored at refrigerated temperature retained better physical quality (e.g., odor, color, and consistency) than suspensions stored at room temperature. Overall, this study demonstrates that oral formulations of sotalol hydrochloride can be readily prepared with commercially available vehicles. The method of preparation is relatively simple, the materials are relatively inexpensive, and the products have a shelf-life of at least 12 weeks. PMID- 23925140 TI - Donor-acceptor-donor thienyl/bithienyl-benzothiadiazole/quinoxaline model oligomers: experimental and theoretical studies. AB - A comprehensive spectral and photophysical investigation of four donor-acceptor donor (DAD) oligomers consisting of electron-deficient 2,1,3-benzothiadiazole or quinoxaline moieties linked to electron-rich thienyl or bithienyl units has been undertaken. Additionally, a bis(dithienyl) substituted naphthalene was also investigated. The D-A-D nature of these oligomers resulted in the presence of an intramolecular charge transfer (ICT) state, which was further substantiated by solvatochromism studies (analysis with the Lippert-Mataga formalism). Hereby, significant differences have been obtained for the fluorescence quantum yields of the oligomers in the non-polar solvent methylcyclohexane vs. the polar ethanol. The study was further complemented with the determination of the optimized ground state molecular geometries for the oligomers together with the prediction of the lowest vertical one-electron excitation energy and the relevant molecular orbital contours using DFT calculations. The electronic transitions show a clear HOMO to LUMO charge-transfer character. In contrast to the thiophene oligomers (the oligothiophenes with n = 1-7), where the intersystem crossing (ISC) yield decreases with n, the studied DAD oligomers were found to show an increase in the ISC efficiency with the number of (donor) thienyl units. PMID- 23925141 TI - pH-triggered conformational switching along the membrane insertion pathway of the diphtheria toxin T-domain. AB - The translocation (T)-domain plays a key role in the action of diphtheria toxin and is responsible for transferring the catalytic domain across the endosomal membrane into the cytosol in response to acidification. Deciphering the molecular mechanism of pH-dependent refolding and membrane insertion of the T-domain, which is considered to be a paradigm for cell entry of other bacterial toxins, reveals general physicochemical principles underlying membrane protein assembly and signaling on membrane interfaces. Structure-function studies along the T-domain insertion pathway have been affected by the presence of multiple conformations at the same time, which hinders the application of high-resolution structural techniques. Here, we review recent progress in structural, functional and thermodynamic studies of the T-domain archived using a combination of site selective fluorescence labeling with an array of spectroscopic techniques and computer simulations. We also discuss the principles of conformational switching along the insertion pathway revealed by studies of a series of T-domain mutants with substitutions of histidine residues. PMID- 23925142 TI - A label free colorimetric assay for the detection of active botulinum neurotoxin type A by SNAP-25 conjugated colloidal gold. AB - Botulinum neurotoxins are one of the most potent toxins known to man. Current methods of detection involve the quantification of the toxin but do not take into account the percentage of the toxin that is active. At present the assay used for monitoring the activity of the toxin is the mouse bioassay, which is lengthy and has ethical issues due to the use of live animals. This report demonstrates a novel assay that utilises the endopeptidase activity of the toxin to detect Botulinum neurotoxin in a pharmaceutical sample. The cleaving of SNAP-25 is monitored via UV-Visible spectroscopy with a limit of detection of 373 fg/mL and has been further developed into a high throughput method using a microplate reader detecting down to 600 fg/mL of active toxin. The results show clear differences between the toxin product and the placebo, which contains the pharmaceutical excipients human serum albumin and lactose, showing that the assay detects the active form of the toxin. PMID- 23925144 TI - Association of human beta-defensin-2 serum levels and sepsis in preterm neonates*. AB - OBJECTIVES: To determine human beta-defensin-2 levels in term and preterm neonates at birth and to evaluate its impact on sepsis. DESIGN: Observational study. SETTING: Single tertiary care hospital. PATIENTS: Term neonates and preterm neonates were recruited and divided in groups according to important clinical events. INTERVENTIONS: Cord blood samples were drawn from all newborns immediately after birth. Human beta-defensin-2 levels were determined using enzyme-linked immunosorbent assay technology. All neonates were followed clinically during the first 30 days of life. MEASUREMENTS AND MAIN RESULTS: Forty two term and 31 preterm neonates were enrolled. Human beta-defensin-2 levels in term neonates were higher compared with preterm infants (median, 1,882 vs 918 pg/mL; p = 0.003) and correlated with gestational age and birth weight. Of 31 preterm neonates, seven suffered from late-onset sepsis, and this was associated with lower human beta-defensin-2 levels (median, 513 vs 1,411 pg/mL; p = 0.006). CONCLUSION: Preterm neonates show lower human beta-defensin-2 levels in cord blood compared with term neonates. Low human beta-defensin-2 levels in preterm neonates might be associated with an increased risk of late-onset sepsis. PMID- 23925143 TI - The relationship of fluid administration to outcome in the pediatric calfactant in acute respiratory distress syndrome trial. AB - OBJECTIVES: Adult studies have demonstrated the relationship between fluid overload and poor outcomes in acute lung injury/acute respiratory distress syndrome. The approach of pediatric intensivists to fluid management in acute lung injury/acute respiratory distress syndrome and its effect on outcomes is less clear. In a post hoc analysis of our Calfactant in Acute Respiratory Distress Syndrome trial, we examined the relationship of fluid balance to in hospital outcomes in subjects with acute lung injury/acute respiratory distress syndrome. DESIGN: Calfactant in Acute Respiratory Distress Syndrome was a masked randomized controlled trial of calfactant surfactant versus placebo in pediatric patients with acute lung injury/acute respiratory distress syndrome due to direct lung injury. Caregivers were encouraged to follow a conservative fluid management guideline based on the adult Fluid and Catheter Treatment Trial. Daily fluid balance was collected for the first 7 days after trial enrollment and correlated with clinical outcomes. PATIENTS AND SETTING: Children admitted to PICUs with acute lung injury/acute respiratory distress syndrome from 24 children's hospitals in six different countries. INTERVENTION: Post hoc analysis of daily fluid balance in subjects from the Pediatric Calfactant in Acute Respiratory Distress Syndrome trial. MEASUREMENTS AND MAIN RESULTS: Despite the conservative fluid guideline, fluid management was more consistent with a "liberal" approach. On average, study subjects accumulated 1.96 +/- 4.2 L/m over the first 7 days of the trial. Subjects who died accumulated on average 8.7 +/- 9.5 L/m versus 1.2 +/ 2.4 L/m in survivors. Increasing fluid accumulation was associated with fewer ventilator-free days and worsening oxygenation. Multivariable regression models that included age, gender, Pediatric Risk of Mortality score, initial oxygen saturation index and PaO2/FIO2 ratio, injury category, and treatment arm failed to account for the differences in fluid management. CONCLUSIONS: Pediatric intensivists generally follow a "liberal" approach to fluid management in children with acute lung injury/acute respiratory distress syndrome. Illness severity or oxygenation disturbance did not explain differences in fluid accumulation but such accumulation was associated with worsening oxygenation, a longer ventilator course, and increased mortality. A more conservative approach to fluid management may improve outcomes in children with acute lung injury/acute respiratory distress syndrome. PMID- 23925145 TI - Long-term outcomes following pediatric out-of-hospital cardiac arrest*. AB - OBJECTIVES: Pediatric out-of-hospital cardiac arrest is an uncommon event with measurable short-term survival to hospital discharge. For those who survive to hospital discharge, little is known regarding duration of survival. We sought to evaluate the arrest circumstances and long-term survival of pediatric patients who experienced an out-of-hospital cardiac arrest and survived to hospital discharge. DESIGN: Retrospective cohort study SETTING: King County, WA Emergency Medical Service Catchment and Quaternary Care Children's Hospital PATIENTS: Persons less than 19 years old who had an out-of-hospital cardiac arrest and were discharged alive from the hospital between 1976 and 2007. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: During the study period, 1,683 persons less than 19 years old were treated for pediatric out-of-hospital cardiac arrest in the study community, with 91 patients surviving to hospital discharge. Of these 91 survivors, 20 (22%) subsequently died during 1449 person-years of follow-up. Survival following hospital discharge was 92% at 1 year, 86% at 5 years, and 77% at 20 years. Compared to those who subsequently died, long-term survivors were more likely at the time of discharge to be older (mean age, 8 vs 1 yr), had a witnessed arrest (83% vs 56%), presented with a shockable rhythm (40% vs 10%), and had a favorable Pediatric Cerebral Performance Category of 1 or 2 (67% vs 0%). CONCLUSIONS: In this population-based cohort study evaluating the long-term outcome of pediatric survivors of out-of-hospital cardiac arrest, we observed that long-term survival was generally favorable. Age, arrest characteristics, and functional status at hospital discharge were associated with prognosis. These findings support efforts to improve pediatric resuscitation, stabilization, and convalescent care. PMID- 23925147 TI - Right ventricular diastolic function measured by tissue Doppler imaging predicts early outcome in congenital diaphragmatic hernia. AB - OBJECTIVE: To investigate the relationship between early right ventricular function measured by tissue Doppler imaging and early outcome measures in newborn infants with congenital diaphragmatic hernia. DESIGN: Retrospective cohort study. SETTING: Surgical neonatal ICU within a regional pediatric center. PATIENTS: Twenty newborn infants with congenital diaphragmatic hernia. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Analysis of serial echocardiograms in a cohort of 20 infants with congenital diaphragmatic hernia was done. Tissue Doppler early diastolic and systolic myocardial velocities were measured to assess diastolic and systolic function, respectively, in the basal right ventricle. Pulmonary:systemic peak pressure ratio was estimated using velocity of tricuspid regurgitation. Physiologic, treatment, and early outcome data (duration of respiratory support and length of stay) were recorded. For analysis, duration of respiratory support was selected as the main outcome measure, and infants were divided into two groups based on median duration of respiratory support of 21 days: duration of respiratory support more than 21 days and duration of respiratory support less than 21 days. In 16 surviving infants, mean right ventricular early diastolic myocardial velocity on days 1 and 2 of life correlated with length of stay and duration of respiratory support (r = -0.75, p = 0.002 and r = -0.84, p = 0.0001, respectively). Mean pulmonary:systemic peak pressure ratio on days 1 and 2 of life did not significantly correlate with outcome measures. At receiver-operating characteristics analysis, averaged right ventricular early diastolic myocardial velocity on days 1 and 2 of life of less than 4.6 cm/s predicted duration of respiratory support more than 21 days, with 100% sensitivity and 88% specificity (area under the curve = 0.96, p = 0.002). Right ventricular early diastolic myocardial velocity was significantly lower in the first week of life in the duration of respiratory support more than 21-day group on days 1 and 2 and days 7 and 8. After surgery, right ventricular early diastolic myocardial velocity decreased in the duration of respiratory support more than 21-day group and was significantly lower at days 3 and 4 postoperative. CONCLUSIONS: Tissue Doppler imaging mean right ventricular early diastolic myocardial velocity on days 1 and 2 of life predicted early outcome in surviving infants with congenital diaphragmatic hernia. Right ventricular diastolic dysfunction is associated with disease severity in congenital diaphragmatic hernia. Right ventricular function may be optimized by delaying surgical repair in infants with severe congenital diaphragmatic hernia. PMID- 23925148 TI - Theoretical mechanism studies on the competitive CO-induced N-N bond cleavage of N2O with N-O bond cleavage mediated by (eta5 C5Me5)Mo[N((i)Pr)C(Me)N((i)Pr)](CO)2. AB - The reaction mechanism for CO-induced reduction of N2O mediated by (eta(5) C5Me5)Mo[N((i)Pr)C(Me)N((i)Pr)](CO)2 is studied using density functional theory (DFT). Two competitive pathways for the N-O and N-N bond cleavage are investigated in detail. The former generates N2, CO and a coproduct terminal Mo oxo complex, which is attacked by two CO to recycle the catalyst via oxygen atom transfer (OAT) in a four-step process. The latter contains three steps yielding a nitrosyl, isocyanate complex. The N-N bond cleavage occurs in step 3. The barriers of the key steps are numerically similar in the two paths. The calculated proportion of products is consistent with the experiment. The competition of N-O and N-N bond cleavage is also supported by NBO analysis. PMID- 23925149 TI - Exceptional function of nanoporous metal organic framework particles in emulsion stabilisation. AB - A new concept of nanoporous metal organic framework particles stabilising emulsions was investigated. The copper benzenetricarboxylate MOF particles adsorbed at the oil/water interface play an exceptional role in stabilising both oil-in-water and water-in-oil emulsions. PMID- 23925146 TI - Early lactate elevations following resuscitation from pediatric cardiac arrest are associated with increased mortality*. AB - OBJECTIVE: To describe the association of lactate levels within the first 12 hours after successful resuscitation from pediatric cardiopulmonary arrest with hospital mortality. DESIGN: Retrospective cohort study. SETTING: Fifteen children's hospital associated with the Pediatric Emergency Care Applied Research Network. PATIENTS: Patients between 1 day and 18 years old who had a cardiopulmonary arrest, received chest compressions more than 1 minute, had a return of spontaneous circulation more than 20 minutes, and had lactate measurements within 6 hours of arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred sixty-four patients had a lactate sampled between 0 and 6 hours (lactate(0-6)) and were evaluable. Of those, 153 patients had a lactate sampled between 7 and 12 hours (lactate(7-12)). One hundred thirty-eight patients (52%) died. After controlling for arrest location, total number of epinephrine doses, initial rhythm, and other potential confounders, the odds of death per 1 mmol/L increase in lactate(0-6) was 1.14 (1.08, 1.19) (p < 0.001) and the odds of death per 1 mmol/L increase in lactate(7-12) was 1.20 (1.11, 1.30) (p < 0.0001). Area under the curve for in-hospital arrest mortality for lactate(0-6) was 0.72 and for lactate(7-12) was 0.76. Area under the curve for out-of-hospital arrest mortality for lactate(0-6) was 0.8 and for lactate(7-12) was 0.75. CONCLUSIONS: Elevated lactate levels in the first 12 hours after successful resuscitation from pediatric cardiac arrest are associated with increased mortality. Lactate levels alone are not able to predict outcomes accurately enough for definitive prognostication but may approximate mortality observed in this large cohort of children's hospitals. PMID- 23925151 TI - A design automation framework for computational bioenergetics in biological networks. AB - The bioenergetic activity of mitochondria can be thoroughly investigated by using computational methods. In particular, in our work we focus on ATP and NADH, namely the metabolites representing the production of energy in the cell. We develop a computational framework to perform an exhaustive investigation at the level of species, reactions, genes and metabolic pathways. The framework integrates several methods implementing the state-of-the-art algorithms for many objective optimization, sensitivity, and identifiability analysis applied to biological systems. We use this computational framework to analyze three case studies related to the human mitochondria and the algal metabolism of Chlamydomonas reinhardtii, formally described with algebraic differential equations or flux balance analysis. Integrating the results of our framework applied to interacting organelles would provide a general-purpose method for assessing the production of energy in a biological network. PMID- 23925152 TI - Arginine insertion and loss of N-linked glycosylation site in HIV-1 envelope V3 region confer CXCR4-tropism. AB - The third variable region (V3) of HIV-1 envelope glycoprotein gp120 plays a key role in determination of viral coreceptor usage (tropism). However, which combinations of mutations in V3 confer a tropism shift is still unclear. A unique pattern of mutations in antiretroviral therapy-naive HIV-1 patient was observed associated with the HIV-1 tropism shift CCR5 to CXCR4. The insertion of arginine at position 11 and the loss of the N-linked glycosylation site were indispensable for acquiring pure CXCR4-tropism, which were confirmed by cell-cell fusion assay and phenotype analysis of recombinant HIV-1 variants. The same pattern of mutations in V3 and the associated tropism shift were identified in two of 53 other patients (3.8%) with CD4(+) cell count <200/mm(3). The combination of arginine insertion and loss of N-linked glycosylation site usually confers CXCR4 tropism. Awareness of this rule will help to confirm the tropism prediction from V3 sequences by conventional rules. PMID- 23925153 TI - A case of cancer of the ampulla of Vater accompanied by malrotation. AB - Intestinal malrotation is caused by a developmental anomaly of the embryonic intestine. Most cases develop in neonates, and development in adulthood is rare and difficult to diagnose before surgery. Pancreaticoduodenectomy was performed for cancer of the ampulla of Vater accompanied by incomplete fixation in a 63 year-old male patient. A branch of the superior mesenteric artery was present on the resection line and was deemed likely to cause circulatory disorder in the small intestine, and the duodenum and jejunum were covered with a membranous structure making dissection, anatomical identification, and jejunectomy difficult. Herein, we report the case with a review of the literature. PMID- 23925154 TI - Relationship between static anterior laxity using the KT-1000 and dynamic tibial rotation during motion in patients with anatomical anterior cruciate ligament reconstruction. AB - The anterior cruciate ligament (ACL) plays an important role in controlling knee joint stability, not only by limiting tibial anterior translation but also by controlling knee axial rotation. The aim of ACL reconstruction is to reduce excessive anterior joint laxity, hoping to restore normal tibiofemoral kinematics including knee axial rotation. The purpose of this study was to investigate the relationship between static anterior instability and tibial rotation during several activities in an anterior cruciate ligament reconstructed knee. Seven patients with unilateral ACL injury performed plain walking, running, landing and side step cutting tasks after ACL reconstruction with a mean follow-up of 14 months. The kinematic data for the 4 motions was measured using a motion analysis system and the point cluster technique. The evaluation period was defined to be from the first contact to removal of the tested leg from the ground. Maximum tibial internal rotation during tasks was calculated using the point cluster technique (PCT). Passive anterior tibial translation was measured using a KT-1000 arthrometer. Regression analysis was used to determine the correlation of the maximum internal rotation with the side-to-side difference of static anterior tibial translation measured using a KT-1000 arthrometer. During side step cutting maneuvers, maximum tibial internal rotation significantly showed negative correlation with static anterior tibial translation (p<0.05, r=0.83). The anterior laxity contributed to the normal knee rotation kinematics. The normal anterior tibial translation obtained by ACL reconstruction is thought to be the key factor in successful restoration of normal knee kinematics. PMID- 23925155 TI - An immunohistochemistry-based study on aquaporin (AQP)-1, 3, 4, 5 and 8 in the parotid glands, submandibular glands and sublingual glands of Sjogren's syndrome mouse models chronically administered cevimeline. AB - Cevimeline is a muscarinic agonist that promotes saliva secretion and is used to treat Sjogren's syndrome (SS), an autoimmune disorder in which the exocrine glands that produce saliva are destroyed. Cevimeline is thought to affect the composition of saliva in part by regulating the localization of aquaporins (AQPs). In this study, we investigated the effects of chronic Cevimeline administration in the salivary glands of SS mice on the immunohistochemical localization of aquaporin (AQP)-1, 3, 4, 5 and 8. We used Cevimeline-untreated SS mice, treated SS mice, discontinued SS mice and untreated normal mice. AQP-5 was found in the apical and lateral membranes of acinar cells in the parotid and submandibular glands of cevimeline-treated SS mice and untreated normal mice. Saliva secretion and AQP-5 localization were sustained in SS mice who were chronically administered Cevimeline and at four weeks after discontinuation. Unlike AQP-5, the localization of AQP-1, 3, 4 and 8 were not affected by Cevimeline administration. Our findings demonstrated that administration of Cevimeline maintains the proper localization of AQP-5 in the acinar cells of the salivary gland, which may promote salivation in chronically treated SS mice. Clinically, this suggests that chronic Cevimeline administration may be useful therapeutically for SS patients suffering from a decrease in saliva secretion by improving the disordered AQP-5 localization. PMID- 23925156 TI - A case of late-onset systemic lupus erythematosus with severe anemia. AB - A 59-year-old woman was referred to our hospital because of severe anemia and leucopenia. Although she developed mild arthralgia without the typical symptoms of systemic lupus erythematosus (SLE), positivity for anti-Sm antibodies led us to a diagnosis of late-onset SLE. Autoimmune hemolytic anemia (AIHA) and suppression of reticulocyte production were considered to have been involved in the etiology of severe anemia. Administration of oral prednisolone (PSL) resulted in a marked improvement of the hematological abnormalities. As late-onset SLE is rare and patients tend to show the typical symptoms less frequently, close attention should be focused on latent symptoms and immunological findings. PMID- 23925157 TI - Ganglion cyst in the supraspinous fossa: arthroscopically undetectable cases. AB - Studies have demonstrated favorable outcomes of arthroscopic decompression for ganglion cyst in the supraspinous fossa; however, little attention has been paid to the difficulty in detecting these cysts during arthroscopy. In this report, we present 2 cases in which ganglion cysts in the supraspinous fossa were undetectable during arthroscopy. The ganglion cysts were not identified in these cases during surgery despite arthroscopic decompression being performed through the area in which the cyst was expected until the suprascapular nerve was entirely exposed. After surgery, magnetic resonance imaging (MRI) confirmed the disappearance of the ganglion cyst and external rotation strength was fully improved, without shoulder pain. We emphasize here that surgeons should be aware of this difficulty when performing arthroscopic decompression of ganglion cysts in the supraspinous fossa. PMID- 23925158 TI - Etomidate for critically ill patients: still a matter for pro-con debates? PMID- 23925160 TI - Compounding for a pediatric hospital. PMID- 23925159 TI - Unlocking autism: is compounding the key? AB - Abstract not available. PMID- 23925161 TI - Wiping out diaper rash. PMID- 23925162 TI - Pediatric oral liquid preparations. PMID- 23925163 TI - Compounding around the world: portugal. AB - Abstract not available. PMID- 23925164 TI - Profile: The McGuff Companies, Part 1-Compounding and Manufacturing Share Facilities and Build Corporate Success. AB - Abstract not available. PMID- 23925166 TI - Quality-control analytical methods: quality issues related to compounding with commercial products. PMID- 23925165 TI - Basics of compounding for pediatric patients: commonly prescribed oral liquid formulations, vehicles, and stock solutions. PMID- 23925167 TI - Chemical stability of fentanyl in polypropylene syringes and polyvinylchloride bags. AB - Fentanyl is a potent synthetic lipophilic opiate agonist used to control pain as a single agent or in combination with local anesthetics. The chemical stability of the undiluted commercial solution (50 micrograms/mL) in polypropylene syringes or polyvinylchloride bags has never been reported. Undiluted fentanyl solution, 50 micrograms/mL, was aseptically transferred to polypropylene syringes or polyvinylchloride bags. Samples were then stored, either at 5 deg C and protected from light, or at 22 deg C and exposed to light, for 28 days. A stability indicating high-performance liquid chromatographic method was used to monitor the fentanyl concentration of the samples. Color, clarity, and pH also were monitored. After storage for 28 days, there were no signs of chemical degradation of fentanyl packaged in either polypropylene syringes or polyvinylchloride bags at either 5 deg C or 22 deg C. All solutions remained colorless and clear over the course of the study. The pH did not change significantly after storage for 28 days. Fentanyl solutions, when packaged undiluted in polypropylene syringes or polyvinylchloride bags, are chemically stable for 28 days when stored either at 5 deg C and protected from light or at 22 deg C and exposed to light. PMID- 23925168 TI - Chemical stability of perphenazine. AB - The stability of perphenazine in oral liquid dosage forms was studied by means of a stability-indicating high-performance liquid chromatography assay method that was developed in our laboratory. There was a direct relationship between the peak heights and the concentrations, with an r value of 0.998. The percent relative standard deviation based on five injections was 0.6. The products of decomposition and excipients present in the dosage forms did not interfere with the developed assay method. The dosage forms were stable for only 30 days when stored in amber-colored glass bottles at room temperature. The pH value of the mixtures remained constant at 3.7 after 90 days of storage, and the physical appearance of the mixtures did not change. The beyond-use date of 30 days is recommended for this procduct. PMID- 23925169 TI - Compounding pharmacies and the successful treatment of autism. PMID- 23925170 TI - Heat illness and deaths--New York City, 2000-2011. PMID- 23925171 TI - Fatal West Nile virus infection after probable transfusion-associated transmission--Colorado, 2012. PMID- 23925172 TI - CDC Grand Rounds: public health approaches to reducing U.S. infant mortality. PMID- 23925173 TI - Vital signs: obesity among low-income, preschool-aged children--United States, 2008-2011. AB - BACKGROUND: The prevalence of obesity among U.S. preschoolers has doubled in recent decades. Childhood obesity increases the risk for adult obesity and is associated with negative health consequences. Trends in the state-specific prevalence of obesity among low-income U.S. preschool children have not been examined since 2008. State-specific obesity prevalence surveillance helps determine the need for and impact of state and local obesity prevention strategies. METHODS: Measured weight and height data from approximately 11.6 million low-income children aged 2-4 years from 40 states, the District of Columbia, and two U.S. territories who participated in the Pediatric Nutrition Surveillance System during 2008-2011 were used to estimate state obesity prevalence. Obesity was defined as having an age- and sex-specific body mass index >=95th percentile, according to the 2000 CDC growth charts. Logistic regression models adjusted for age, sex, and race/ethnicity were used to examine trends in the state-specific obesity prevalence. RESULTS: During 2008-2011, statistically significant downward trends in obesity prevalence were observed in 18 states and the U.S. Virgin Islands. Florida, Georgia, Missouri, New Jersey, South Dakota, and the U.S. Virgin Islands had the largest absolute decreases in obesity prevalence, each with a decrease of >=1 percentage point. Twenty states and Puerto Rico experienced no significant change, and obesity prevalence increased significantly in three states. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Small but significant declines in obesity among low-income preschoolers were observed in 19 of 43 states/territories examined. Continued prevention efforts are needed to sustain and expand the implementation and evaluation of population-level interventions to prevent childhood obesity. PMID- 23925174 TI - Electronic and optical properties of Cr and Cr-N doped anatase TiO2 from screened Coulomb hybrid calculations. AB - We studied the electronic and atomic structures of anatase TiO2 codoped with Cr and N using hybrid density functional theory calculations. The nonlocal screened Hartree-Fock exchange energy is partially mixed with the traditional semilocal exchange energy. This not only patches the bandgap underestimation but also improves the description of the anion/cation-driven impurity states and the magnetization of the dopants. Cr and/or N doping modifies the valence and conduction band edges of TiO2, leading to significant bandgap reduction. Hence, Cr, N and Cr-N doped TiO2 are promising for enhanced visible light absorbance. PMID- 23925175 TI - Improved wet weather wastewater influent modelling at Viikinmaki WWTP by on-line weather radar information. AB - Municipal wastewater treatment plant (WWTP) influent is typically dependent on diurnal variation of urban production of liquid waste, infiltration of stormwater runoff and groundwater infiltration. During wet weather conditions the infiltration phenomenon typically increases the risk of overflows in the sewer system as well as the risk of having to bypass the WWTP. Combined sewer infrastructure multiplies the role of rainwater runoff in the total influent. Due to climate change, rain intensity and magnitude is tending to rise as well, which can already be observed in the normal operation of WWTPs. Bypass control can be improved if the WWTP is prepared for the increase of influent, especially if there is some storage capacity prior to the treatment plant. One option for this bypass control is utilisation of on-line weather-radar-based forecast data of rainfall as an input for the on-line influent model. This paper reports the Viikinmaki WWTP wet weather influent modelling project results where gridded exceedance probabilities of hourly rainfall accumulations for the next 3 h from the Finnish Meteorological Institute are utilised as on-line input data for the influent model. PMID- 23925176 TI - Uncertainty analysis of coupling multiple hydrologic models and multiple objective functions in Han River, China. AB - Three different hydrological models are chosen to simulate rainfall-runoff relationships under each of three objective functions including mean squared errors of squared transformed flows, squared root transformed flows and logarithmic transformed flows; thus nine individual models are constructed. By weighted averaging over these nine models, the method of Bayesian model averaging (BMA) was used to provide both the mean value and the uncertainty intervals of flow prediction. Three kinds of uncertainty information can be generated: the uncertainty of individual member model's predictions; the total uncertainty of BMA mean prediction; the between-model and within-model uncertainties in the BMA scheme. Based on the estimated results in this study, the coupling of multiple models with multiple objective functions in general offers better results for both the mean prediction and the uncertainty intervals for the runoffs in a selected basin in Han River, China, than the individual models. PMID- 23925177 TI - An operational protocol for facilitating start-up of single-stage autotrophic nitrogen-removing reactors based on process stoichiometry. AB - Start-up and operation of single-stage nitritation-anammox sequencing batch reactors (SBRs) for completely autotrophic nitrogen removal can be challenging and far from trivial. In this study, a step-wise procedure is developed based on stoichiometric analysis of the process performance from nitrogen species measurements to systematically guide start-up and normal operation efforts (instead of trial and error). The procedure is successfully applied to laboratory scale SBRs for start-up and maintained operation over an 8-month period. This analysis can serve as a strong decision-making tool to take appropriate actions with respect to reactor operation to accelerate start-up or ensure high-rate N removal via the nitritation-anammox pathway. PMID- 23925178 TI - Sustainable biodegradation of phenolic endocrine-disrupting chemicals by Phragmites australis-rhizosphere bacteria association. AB - The efficacy of two rhizobacteria (Sphingobium fuliginis TIK1 and Sphingobium sp. IT4) of Phragmites australis for the sustainable treatment of water polluted with phenolic endocrine-disrupting chemicals (EDCs) was investigated. Strains TIK1 and IT4 have recently been isolated from Phragmites rhizosphere and shown to degrade various 4-alkylphenols-TIK1 via phenolic ring hydroxylation and meta-cleavage and IT4 via ipso-hydroxylation. The two strains also degraded bisphenol A (BPA), bisphenol B, bisphenol E, bisphenol F, bisphenol P and bisphenol S (BPS). Thus, strains TIK1 and IT4 have wide degradation spectra for phenolic EDCs. The two strains utilized Phragmites root extracts as a sole carbon source and sustainably colonized Phragmites roots, where they degraded phenolic EDCs. In sequencing batch reactor experiments using Phragmites in association with TIK1 or IT4, both associations repeatedly removed phenolic EDCs from polluted secondary effluent water (BPA, BPS, 4-tert-butylphenol, 4-tert-octylphenol and 4-nonylphenol) from polluted secondary effluent water. The results suggest that hydroponic systems using Phragmites-TIK and Phragmites-IT4 associations would be useful for sustainable treatment of polluted waters containing various phenolic EDCs. PMID- 23925179 TI - A new oxic-settling-anaerobic (NOSA((r))) activated sludge process for minimizing excess sludge in secondary biological treatment plants: a pilot-scale evaluation of the absorption-biodegradation process. AB - This study compared the sludge reduction performance of a new oxic-settling anaerobic (NOSA) process with that of a conventional adsorption-biodegradation process. A 50 m(3)/d pilot trial system with two different process configurations was operated for 6 months. The NOSA process functioned effectively in removing both chemical oxygen demand and nitrogen with the efficiencies of 86 and 92.5%, respectively, which reduced approximately 40% of the excess sludge. In this research, 0.77 kg volatile suspended solids/d sludge vanished in the anaerobic tank, which accounted for 58.9% of the total sludge loss in the NOSA process. Economic calculation suggests that the new process can dramatically upgrade the sludge reduction in wastewater treatment plants without a digestion device, and the investment for fundamental upgrading can be recovered in 5-6 years by cutting the costs of excess sludge dewatering and disposal treatment. PMID- 23925180 TI - Effect of pH and distance between electrodes on the performance of a sediment microbial fuel cell. AB - The performance of three sediment microbial fuel cells (SMFCs) was evaluated at different feed water pH and electrode spacing for chemical oxygen demand (COD) removal, total nitrogen (TN) removal, and power density; while offering in situ remediation of aquaculture pond water. SMFC-A was operated at the feed water pH of 6.5 and spacing between the electrodes of 100 cm. SMFC-B and SMFC-C were operated at feed water pHs of 8.5 and 6.5, respectively, and distance between electrodes of 50 cm. The anode and cathode were connected with concealed copper wire through an external load of 100 Omega. The average amount of total COD removal rate and TN removal rate, per unit area of cathode, were 1.72 +/- 0.06 and 0.021 +/- 0.007 g/m(2) d in SMFC-A, 1.03 +/- 0.08 and 0.024 +/- 0.005 g/m(2) d in SMFC-B, and 1.14 +/- 0.01 and 0.017 +/- 0.001 g/m(2) d in SMFC-C, respectively. SMFC-A, operated with higher distance between electrodes, demonstrated better removal of organic matter and highest open circuit voltage of 0.903 V. SMFCs with less feed pH (6.5) gave higher COD removal and feed pH of 8.5 gave higher TN removal. SMFCs operated with lesser distance between electrodes gave higher power density. PMID- 23925181 TI - Cluster analysis for characterization of rainfalls and CSO behaviours in an urban drainage area of Tokyo. AB - Combined sewer overflow (CSO) from urban areas is recognized as a major pollutant source to the receiving waters during wet weather. This study attempts to categorize rainfall events and corresponding CSO behaviours to reveal the relationship between rainfall patterns and CSO behaviours in the Shingashi urban drainage areas of Tokyo, Japan where complete service by a combined sewer system (CSS) and CSO often takes place. In addition, outfalls based on their annual overflow behaviours were characterized for effective storm water management. All 117 rainfall events recorded in 2007 were simulated by a distributed model InfoWorks CS to obtain CSO behaviours. The rainfall events were classified based on two sets of parameters of rainfall pattern as well as CSO behaviours. Clustered rainfall and CSO groups were linked by similarity analysis. Results showed that both small and extreme rainfalls had strong correlations with the CSO behaviours, while moderate rainfall had a weak relationship. This indicates that important and negligible rainfalls from the viewpoint of CSO could be identified by rainfall patterns, while influences from the drainage area and network should be taken into account when estimating moderate rainfall-induced CSO. Additionally, outfalls were finally categorized into six groups indicating different levels of impact on the environment. PMID- 23925182 TI - Ammonium nitrogen removal from wastewater with a three-dimensional electrochemical oxidation system. AB - Ammonium-containing wastewater could cause the promotion of eutrophication and a hindrance to the disinfection of water supplies. In this study, the feasibility of removing low-concentration ammonium nitrogen from synthetic and real wastewater by electrochemical oxidation was investigated. Using laboratory-scale electrochemical systems, the effects of chloride concentration, current density, anode materials, cathode materials, electrode gap, initial ammonium concentration and three-dimensional particles on the removal of ammonium nitrogen and current efficiency (CE) were evaluated. Ammonium nitrogen removal was mainly dependent upon anode materials and current density. The performance of two- and three dimensional electrochemical oxidation systems was comparatively discussed. Both particle electrodes could enhance ammonium nitrogen removal and increase CE. However, the mechanism of the process seemed to be different. Moreover, the interaction of zeolites adsorption and electrochemical oxidation on the anode in a three-dimensional system could favor the regeneration of zeolites. Surface morphology of the used Ru-Ir-Sn/Ti anode revealed its longer working life of electrocatalysis. The result of ammonium degradation for a real wastewater treatment plant effluent showed the degradation rates in a three-dimensional system increased by 1.4 times those in a two-dimensional system. PMID- 23925183 TI - Granulation of anaerobic sludge in the sulfate-reducing up-flow sludge bed (SRUSB) of SANI((r)) process. AB - This study reports on anaerobic sludge granulation in a laboratory-scale sulfate reducing up-flow sludge bed (SRUSB) in a novel sulfate reduction, autotrophic denitrification and nitrification integrated (SANI((r))) process for treatment of saline sewage. Granulation occurred in 30 d and reached full development in 90 d. The sulfate-reducing granules grew up to around 1 mm after 90 d with 21 mL/g SVI5 (sludge volume index measured after 5 min) and the biomass concentration reached 29 g/L after 4 months' operation. The reactor removed 89% chemical oxygen demand (COD) and reduced 75% sulfate within 1 h of hydraulic retention time, under a COD loading rate of up to 6.4 kg COD/(m(3) . d). PMID- 23925184 TI - Tertiary ozonation of industrial wastewater for the removal of estrogenic compounds (NP and BPA): a full-scale case study. AB - Wastewater treatment plant (WWTP) effluents are considered to be a major source for the release in the aquatic environment of endocrine-disrupting compounds (EDCs). Ozone has proved to be a suitable solution for polishing secondary domestic effluents. In this work, the performance of a full-scale ozonation plant was investigated in order to assess the removal efficiency of four target EDCs: nonylphenol, nonylphenol monoethoxylate, nonylphenol diethoxylate and bisphenol A. The studied system was the tertiary treatment stage of a municipal WWTP which receives an important industrial (textile) load. Chemical analyses showed that the considered substances occurred with a significant variability, typical of real wastewaters; based on this, ozonation performance was carefully evaluated and it appeared to be negatively affected by flow-rate increase (during rainy days, with consequent contact time reduction). Moreover, EDCs' measured removal efficiency was lower than what could be predicted based on literature data, because of the relatively high residual content of biorefractory compounds still present after biological treatment. PMID- 23925185 TI - Identification of pathogen bacteria and protozoa in treated urban wastewaters discharged in the Ebro River (Spain): water reuse possibilities. AB - The aim of this research work is to identify the presence of pathogens, bacteria and protozoa, in different treated urban wastewaters and to relate biological pollution with the processes used in wastewater treatment plants. A study of the possibilities for water reuse is carried out taking into account bacterial and parasite composition. The analysed bacteria and protozoa are: Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus, Clostridium perfringens (spore), Salmonella spp., Legionella spp., helminths eggs, Giardia, Cryptosporidium spp. and free-living amoebae (FLA). The selected municipal wastewater treatment plants (MWTPs) are located in Navarra (Spain) and the main difference between them is the use of natural lagoons as tertiary treatment in some plants. The results concerning bacteriological identification showed contamination of mainly faecal origin, and the use of natural lagoons as tertiary treatment in some MWTPs produced an important disinfection effect. Moreover, pathogen parasites such as Giardia and Cryptosporidium were not detected in the samples studied although FLA were identified in all cases. PMID- 23925186 TI - State-space adjustment of radar rainfall and skill score evaluation of stochastic volume forecasts in urban drainage systems. AB - Merging of radar rainfall data with rain gauge measurements is a common approach to overcome problems in deriving rain intensities from radar measurements. We extend an existing approach for adjustment of C-band radar data using state-space models and use the resulting rainfall intensities as input for forecasting outflow from two catchments in the Copenhagen area. Stochastic grey-box models are applied to create the runoff forecasts, providing us with not only a point forecast but also a quantification of the forecast uncertainty. Evaluating the results, we can show that using the adjusted radar data improves runoff forecasts compared with using the original radar data and that rain gauge measurements as forecast input are also outperformed. Combining the data merging approach with short-term rainfall forecasting algorithms may result in further improved runoff forecasts that can be used in real time control. PMID- 23925187 TI - Enhancement of denitrification in a down-flow hanging sponge reactor by effluent recirculation. AB - A down-flow hanging sponge reactor, constructed by connecting three identical units in series, was applied to the treatment of artificial wastewater containing phenol and ammonia under high salinity conditions (10.9 g-Cl(-)/L). The theoretical hydraulic retention time (HRT) of each unit was 4 h (total HRT = 12 h). To enhance denitrification by effluent recirculation, the effluent recirculation ratio was increased in increments ranging from 0.0 to 2.0. The concentration of total ammonia nitrogen (TAN), NO2-N, and NO3-N in the final effluent as a proportion of the TAN in the influent was determined to calculate the unrecovered, or denitrification, proportion. The denitrification proportion of the reactor was equivalent to 19.1 +/- 14.1% with no effluent recirculation; however, this was increased to 58.6 +/- 6.2% when the effluent recirculation ratio was increased to 1.5. Further increasing the effluent recirculation ratio to 2.0 resulted in a decrease in the denitrification proportion to 50.9 +/- 9.3%. Activity assays of nitrification and denitrification, as well as 16S rRNA gene sequence analysis, revealed that denitrification occurred primarily in the upper sections of the reactor, while nitrification increased in the lower sections of the reactor. Gene sequence analysis revealed that denitrification by Azoarcus like species using phenol as an electron donor was dominant. PMID- 23925188 TI - Performance of a biofilter system with agave fiber filter media for municipal wastewater treatment. AB - Agave plants grow in semi-arid regions and are used for mescal production. However, agave fiber by-products are considered waste materials. Thus, we tested agave fiber as a filter media and biofilm material carrier for removing pollutants from municipal wastewater. Three laboratory-scale biofiltration reactors were used in two trials with five hydraulic loading rates (HLRs = 0.27, 0.54, 0.80, 1.07 and 1.34 m(3) m(-2) d(-1)). One series was conducted using mechanical aeration (0.62 m(3) m(-2) h(-1)). To prevent compaction, decreasing pressure and clogging of the filter media, 4, 8 and 12 internal divisions were evaluated in the biofilter column. After 17 months of continuous operation at an HLR of 0.80 m(3) m(-2) d(-1), the removal efficiencies of the aerated biofilters were 92.0% biochemical oxygen demand, 79.7% chemical oxygen demand, 98.0% helminth eggs, 99.9% fecal coliforms and 91.9% total suspended solids. Statistical analysis showed that the chosen operational parameters significantly influenced the removal efficiencies of the biofilters. The effluent quality obtained under these conditions complied with the Mexican and US EPA standards for agricultural irrigation and green spaces, except for coliforms, which is why the effluents must be disinfected. Thus, agave fiber is a favorable choice for use as a packing material in biofiltration processes. PMID- 23925189 TI - Investigation of carbazole degradation by the sono-Fenton process. AB - The present report aimed to describe the roles of ultrasonic power and reaction time in the Fenton reagent-based degradation of carbazole in wastewater, and to analyze the effects of the Fe2SO4 and H2O2 concentrations and the initial pH on the reaction kinetics. Application of 40 or 80 W of ultrasound at a frequency of 40 KHz substantially improved the effectiveness of carbazole degradation, whereas application of 20 W of ultrasound had little effect. The optimal concentration of the Fe2SO4.7H2O catalyst was lower for extended operating times. Increased degradation was observed with increasing H2O2 concentrations below 1.8 mg L(-1), whereas decreased degradation was observed at concentrations above this value. The best performance was obtained at a neutral or slightly alkaline pH range (pH 7-9) rather than at the commonly used acidic pH range (pH 2-4). Under optimal conditions, the extent of carbazole degradation was 98% after 180 min. The degradation process followed second-order kinetics. PMID- 23925191 TI - Comparative study of fecal bacterial decay models for the simulation of plumes of submarine sewage outfalls. AB - In the literature, analytical models have been shown to be extremely useful for estimating the decay rates of coliform as fecal indicator microorganisms, providing reliable predictions of bathing conditions in coastal and continental waters. Although a number of different formulations have been developed in the literature, each one may only be suitable for specific environments, and no comparison between these methods has ever been carried out. In the present article, a comparative analysis of bacterial decay models, calculated by eight different formulations, was performed in coastal outfall plumes, considering identical environmental conditions of solar radiation, temperature and salinity. A statistical approach was applied to identify the differences in means and in behaviors of the results obtained in the various simulations. The results indicate good agreement between bacterial decay rates calculated with at least four methods that were considered more reliable, and at least one of the models was shown to be suitable for estimating bacterial decay rates under night-time conditions, considering only the combined influences of temperature and salinity. Moreover, under daytime conditions, it provides consistent decay rates when compared with measurements taken in the field. PMID- 23925190 TI - Control of odour nuisance in urban areas: the efficiency and social acceptance of the application of masking agents. AB - This paper presents and discusses the results of the project named 'Jasmin' implemented in Algiers to control the strong odours of the river named Oued El Harrach, one of the largest rivers in the centre of the city. Pending the achievement of curative solutions, a temporary option for mitigation of nuisance odour by masking agents was implemented in the vicinity of the main bridges. The efficiency of this technology has been followed by means of an odour panel with the participation of representatives of all stakeholders. A sociological study by means of 1,000 questionnaires and face-to-face interviews of the local population demonstrated the benefits and the positive outcomes of the attenuation of odour nuisance: 70% of the surveyed population is satisfied or very satisfied with the application of masking agents and 96% of respondents support the continuation of the project. In terms of size and public access, the project Jasmin is a world first demonstration of odour control in urban areas in developing countries. PMID- 23925192 TI - Solution of export coefficients of nitrogen from different land-use patterns based on Bayesian analysis. AB - The export coefficient model has been applied worldwide to the estimation of non point source (NPS) pollution. Determining the export coefficients (ECs) from each pollution source and different space-time progressions is problematic because of uncertainty in the ECs of nitrogen from different land-use patterns. Bayesian theory uses the prior probability distribution and likelihood data to generate a posterior probability distribution. The total nitrogen (TN) ECs and stream loss rates K (d(-1)) for five land-use patterns were estimated by combining published results with monthly data for ChangLe River system for 2004-08. After 10(4) iterations, the results had small Markov chain Monte Carlo errors and convergence was obtained. Average TN ECs for the entire watershed were 26.1 +/- 8.8, 70.3 +/- 9.4, 41.7 +/- 6.9, 8.9 +/- 1.6 and 6.2 +/- 0.5 kg ha(-1) yr(-1) for paddy field, dry land, residential land, woodland and barren land with coefficients of variation (CVs) of 16.9, 6.31, 8.91, 13.3 and 27.9% among sub-catchments respectively. The average K value was 0.33 d(-1) with a CV of 11.3%. Estimated ECs, K and the coupling water quality model were used to predict the years 2008 and 2009; the results validated the model. This Bayesian model can determine ECs using prior knowledge and monitored data, overcoming the problems of the regression model. The model facilitates explicit consideration of uncertainty in NPS management. PMID- 23925193 TI - The optimal dissolved oxygen profile in a nitrifying activated sludge process - comparisons with ammonium feedback control. AB - Ammonium feedback control is increasingly used to determine the dissolved oxygen (DO) set-point in aerated activated sludge processes for nitrogen removal. This study compares proportional-integral (PI) ammonium feedback control with a DO profile created from a mathematical minimisation of the daily air flow rate. All simulated scenarios are set to reach the same treatment level of ammonium, based on a daily average concentration. The influent includes daily variations only and the model has three aerated zones. Comparisons are made at different plant loads and DO concentrations, and the placement of the ammonium sensor is investigated. The results show that ammonium PI control can achieve the best performance if the DO set-point is limited at a maximum value and with little integral action in the controller. Compared with constant DO control the best-performing ammonium controller can achieve 1-3.5% savings in the air flow rate, while the optimal solution can achieve a 3-7% saving. Energy savings are larger when operating at higher DO concentrations. PMID- 23925195 TI - The adsorption of Sb(III) in aqueous solution by Fe2O3-modified carbon nanotubes. AB - A novel kind of iron oxide supported on carbon nanotubes (CNTs) was prepared for adsorption of antimony (Sb)(III) in aqueous solution. The iron (III) oxide (Fe2O3)-modified CNTs were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, nitrogen adsorption-desorption and Fourier transform infrared spectrometer. Parameters affecting the adsorption efficiencies, including solution pH value, initial Sb(III) concentration, adsorbent dosage, adsorption time and temperature, were investigated. The results indicate that the removal rate of Sb(III) by Fe2O3-modified CNTs is 99.97% under the initial Sb(III) concentration of 1.5 mg/L, adsorbents dosage of 0.5 g/L, temperature of 25 (o)C and pH value of 7.00, which is 29.81% higher than that of the raw CNTs. The adsorption capacity increased correspondingly from 3.01 to 6.23 mg/g. The equilibrium adsorption data can be fitted to the Freundlich adsorption isotherm. In addition, it has been found that the solution pH values and adsorption temperatures have no significant influence on Sb(III) removal. PMID- 23925194 TI - Diversity and dynamics of ammonia-oxidizing bacterial communities in a sponge based trickling filter treating effluent from a UASB reactor. AB - Changes in ammonia-oxidizing bacterial (AOB) population dynamics were examined in a new sponge-based trickling filter (TF) post-upflow anaerobic sludge blanket (UASB) reactor by denaturating gradient gel electrophoresis (DGGE), and these changes were linked to relevant components influencing nitrification (chemical oxygen demand (COD), nitrogen (N)). The sponge-based packing media caused strong concentration gradients along the TF, providing an ecological selection of AOB within the system. The organic loading rate (OLR) affected the population dynamics, and under higher OLR or low ammonium-nitrogen (NH4(+)-N) concentrations some AOB bands disappeared, but maintaining the overall community function for NH4(+)-N removal. The dominant bands present in the upper portions of the TF were closely related to Nitrosomonas europaea and distantly affiliated to Nitrosomonas eutropha, and thus were adapted to higher NH4(+)-N and organic matter concentrations. In the lower portions of the TF, the dominant bands were related to Nitrosomonas oligotropha, commonly found in environments with low levels of NH4(+)-N. From a technology point of view, changes in AOB structure at OLR around 0.40-0.60 kgCOD m(-3) d(-1) did not affect TF performance for NH4(+)-N removal, but AOB diversity may have been correlated with the noticeable stability of the sponge-based TF for NH4(+)-N removal at low OLR. This study is relevant because molecular biology was used to observe important features of a bioreactor, considering realistic operational conditions applied to UASB/sponge-based TF systems. PMID- 23925196 TI - Removal of methyl blue from aqueous solution by magnetic carbon nanotube. AB - Magnetic carbon nanotube (mCNT) was formed via direct mixing of carbon nanotube (CNT) with magnetic nanoparticle (MNP) in dye solution. When the mass ratio of MNP to CNT was 4:1, all CNT were magnetically collected. The adsorption performance of mCNT was evaluated using methyl blue (MB) as a model adsorbate. Equilibrium of MB adsorption was attained in 60 min, and maximum adsorption occurred at pH 3-6. MB adsorption was independent of ionic strength and followed pseudo-second-order kinetics. According to the Langmuir isotherm, adsorption capacity of mCNT for MB was 115.34 mg g(-1). Thermodynamic analysis suggested MB adsorption onto mCNT was a spontaneous process. Reusability study results showed that 97.06, 96.26, 94.33, 92.91 and 90.14% of MB were removed in five consecutive cycles. The study suggests that the mCNT has a great potential application in dye removal from industrial wastewater. PMID- 23925197 TI - Treatment of heavy metals by iron oxide coated and natural gravel media in Sustainable urban Drainage Systems. AB - Sustainable urban Drainage Systems (SuDS) filter drains are simple, low-cost systems utilized as a first defence to treat road runoff by employing biogeochemical processes to reduce pollutants. However, the mechanisms involved in pollution attenuation are poorly understood. This work aims to develop a better understanding of these mechanisms to facilitate improved SuDS design. Since heavy metals are a large fraction of pollution in road runoff, this study aimed to enhance heavy metal removal of filter drain gravel with an iron oxide mineral amendment to increase surface area for heavy metal scavenging. Experiments showed that amendment-coated and uncoated (control) gravel removed similar quantities of heavy metals. Moreover, when normalized to surface area, iron oxide coated gravels (IOCGs) showed poorer metal removal capacities than uncoated gravel. Inspection of the uncoated microgabbro gravel indicated that clay particulates on the surface (a natural product of weathering of this material) augmented heavy metal removal, generating metal sequestration capacities that were competitive compared with IOCGs. Furthermore, when the weathered surface was scrubbed and removed, metal removal capacities were reduced by 20%. When compared with other lithologies, adsorption of heavy metals by microgabbro was 10-70% higher, indicating that both the lithology of the gravel, and the presence of a weathered surface, considerably influence its ability to immobilize heavy metals. These results contradict previous assumptions which suggest that gravel lithology is not a significant factor in SuDS design. Based upon these results, weathered microgabbro is suggested to be an ideal lithology for use in SuDS. PMID- 23925198 TI - Searching for a compromise between ecological quality targets, and social and ecosystem costs for heavily modified water bodies (HMWBs): the Lambro-Seveso Olona system case study. AB - The Lambro-Seveso-Olona (L-S-O) system derives from the human regulation of the natural hydrology of the territory around Milan city area. The average population density in the L-S-O area is among the highest in Italy and Europe. Industry is also highly developed in this basin: chemical, textile, paper, pulp and food industries being the most important ones. Although, at present, the L-S-O system no longer receives the untreated wastewaters of the Milan urban area, treated wastewaters constitute about half of the streamflow. Biotic communities in this river have a long history of poor quality status, having suffered great damage due to domestic and industrial discharges. Recently, new chemical quality standards for macropollutants have been set by the Italian legislation as support for the good ecological status according to the Water Framework Directive (WFD). This new index is very restrictive, and it makes it extremely challenging to achieve the water quality objectives for the L-S-O system. The aim of this study is to analyse through a modelling exercise the restoration possibilities of the L S-O system, investigating both the source apportionment of the macropollutants, the discharge limits that should be set to achieve the good quality status and their corresponding cost. PMID- 23925199 TI - Fluctuation of densities of bacteriophages and Escherichia coli present in natural biofilms and water of a main channel and a small tributary. AB - Fluctuation of bacteriophage and Escherichia coli densities in naturally developed riverbed biofilms were investigated for a 1-year period. E. coli ranged from 1,500 to 15,500 most probable number (MPN)/100 mL and from 580 to 18,500 MPN/cm(2) in the main channel in the river water and biofilms, respectively. However, the fluctuations were much greater in the tributary, ranging from 0.8 to 100 MPN/100 mL and from 0.3 to 185 MPN/cm(2) in water and biofilms, respectively. The fluctuations of coliphages were also greater in the tributary than in the main channel. FRNA phage serotyping results indicated no significant differences in the source type of the fecal contamination in the main channel and tributary sampling stations. Significant correlations between phage groups in biofilms and water were found at both main channel and tributary. It was assumed that natural biofilms developed in the streambed captured and retained somatic phages in the biofilms for a certain period of time in the main channel site. At the location receiving constant and heavy contamination, the usage of phage indicators may provide additional information on the presence of viruses. In the small tributary it may be possible to estimate the virus concentration by monitoring the E. coli indicator. PMID- 23925200 TI - Survey on nitrogen removal and membrane filtration characteristics of Chlorella vulgaris Beij. on treating domestic type wastewaters. AB - The main objective of this study is to evaluate the nitrogen assimilation and filtration characteristics of Chlorella vulgaris Beij. when treating domestic wastewaters. Chlorella could assimilate organic nitrogen, ammonia and nitrate in wastewater, and the mean cell residence time (MCRT) to achieve the maximum biomass content in a bioreactor was different for each individual nitrogen source used. The experimental results showed that using nitrate as the only nitrogen source was the most favorable for biomass growth. With ammonia and nitrate coexisting in the aquatic phase, Chlorella possibly utilized ammonia first, and this was unfavorable to subsequent biomass growth. Nitrifying bacteria in wastewaters significantly affected Chlorella growth as they possibly competed with Chlorella in assimilating ammonia and nitrate in domestic wastewater. In a submerged ultrafiltration (UF) membrane module, with an initial concentration of 850 mg/L of Chlorella, the optimized flux was 0.02 m(3)/(m(2).h), and the filtration cycle was 30 min. A 'dual membrane bioreactor (MBR)' configuration using UF membranes for Chlorella incubation was proposed. MBR1 provides an environment with long MCRT for efficient nitrification. The converted nitrate is assimilated by Chlorella in MBR2 to sustain its growth. UF permeate from MBR1 is bacteria-free and does not affect the growth of Chlorella in MBR2. MCRT of Chlorella growth is controlled by the UF membrane of MBR2, providing the flexibility to adjust variations of nitrogen composition in the wastewater. PMID- 23925201 TI - Agent-based assessment of stormwater re-use potential of low-impact development control facilities at the site of Vlasina Lake, Serbia. AB - Vlasina Lake in south-east Serbia is classified as an Area of Distinct Land Use and, as such, is subject to high environmental protection standards applied in the Master Plan. Two open channels for stormwater and sediment transportation to two large detention basins with pumping stations for water evacuation into the lake were envisaged in the Master Plan. In the preliminary design, the stormwater system was quite different: wherever possible, on-site natural features were used for allocation of ponds, and drainage channels were led through existing road culverts. The applied design concept has been low impact development (LID), which led to potential blue-green corridors, recognized by project stakeholders. The paper studies the possibility of using ponds as a key element of both the LID concept and the blue-green corridors approach. For that purpose, an initial Vlasina Lake site agent-based simulation model has been created. A realistic physical model is included, and simulation results for two hypothetical climatic and socio-economic scenarios are presented. From the experience in creating the agent-based model, and based on the simulation results, recommendations are given for further work. It is shown that ponds have potential for the investigated water re-use purposes. PMID- 23925202 TI - A socio-technical model to explore urban water systems scenarios. AB - This article reports on the ongoing work and research involved in the development of a socio-technical model of urban water systems. Socio-technical means the model is not so much concerned with the technical or biophysical aspects of urban water systems, but rather with the social and institutional implications of the urban water infrastructure and vice versa. A socio-technical model, in the view purported in this article, produces scenarios of different urban water servicing solutions gaining or losing influence in meeting water-related societal needs, like potable water, drainage, environmental health and amenity. The urban water system is parameterised with vectors of the relative influence of each servicing solution. The model is a software implementation of the Multi-Pattern Approach, a theory on societal systems, like urban water systems, and how these develop and go through transitions under various internal and external conditions. Acknowledging that social dynamics comes with severe and non-reducible uncertainties, the model is set up to be exploratory, meaning that for any initial condition several possible future scenarios are produced. This article gives a concise overview of the necessary theoretical background, the model architecture and some initial test results using a drainage example. PMID- 23925203 TI - Effects of fluoride and chloride on the growth of Chlorella pyrenoidosa. AB - To compare the toxic action of fluoride (F(-)) and chloride (Cl(-)) on freshwater algae, effects of F(-) and Cl(-) on Chlorella pyrenoidosa growth were investigated by determination of the algal biomass and model analysis. Results showed that the exponential growth equation (D = D0 + ae(bT)) may be used to fit the relationship between cell density (D) of C. pyrenoidosa and exposure time (T), but F(-) and Cl(-) have significantly different effects on parameters a (initial quantity of algae at the exponential growth stage) and b (growth constant). In the range of experimental concentrations, F(-) inhibited C. pyrenoidosa growth, and percent inhibition increased with increasing exposure time and F(-) concentration. By contrast, Cl(-) either inhibited or enhanced C. pyrenoidosa growth depending on Cl(-) concentration and exposure time, and percent inhibition increased with increasing Cl(-) concentration but decreased with increasing exposure time. The dose-response equation: I = min + (max - min)/(1 + 10(lgEC50-lgC)) may be used to fit the relationship between percent inhibition (I) and F(-) or Cl(-) concentration (C); however, F(-) was distinct from Cl(-) in terms of effects on parameter 'min'. The EC50 values of F(-) and Cl(-) ranged from 118 to 170 mg/L and 19.73 to 36.33 g/L, respectively; the latter is much higher than the former. Thus F(-) has higher toxicity than Cl(-). PMID- 23925204 TI - On data requirements for calibration of integrated models for urban water systems. AB - Modeling of integrated urban water systems (IUWS) has seen a rapid development in recent years. Models and software are available that describe the process dynamics in sewers, wastewater treatment plants (WWTPs), receiving water systems as well as at the interfaces between the submodels. Successful applications of integrated modeling are, however, relatively scarce. One of the reasons for this is the lack of high-quality monitoring data with the required spatial and temporal resolution and accuracy to calibrate and validate the integrated models, even though the state of the art of monitoring itself is no longer the limiting factor. This paper discusses the efforts to be able to meet the data requirements associated with integrated modeling and describes the methods applied to validate the monitoring data and to use submodels as software sensor to provide the necessary input for other submodels. The main conclusion of the paper is that state of the art monitoring is in principle sufficient to provide the data necessary to calibrate integrated models, but practical limitations resulting in incomplete data-sets hamper widespread application. In order to overcome these difficulties, redundancy of future monitoring networks should be increased and, at the same time, data handling (including data validation, mining and assimilation) should receive much more attention. PMID- 23925205 TI - Oxidation of 2-arylindoles for synthesis of 2-arylbenzoxazinones with oxone as the sole oxidant. AB - A novel and efficient method for the oxidation of 2-arylindoles to synthesize 2 arylbenzoxazinones utilizing oxone as the sole oxidant has been developed. The reaction tolerates a wide range of functional groups and allows quick and atom economical assembly of a variety of valuable 2-arylbenzoxazinones in high yields. PMID- 23925217 TI - Scientists swept up in terrorism trials. PMID- 23925206 TI - Balancing privacy with public benefit. PMID- 23925218 TI - Best way to kill lab animals sought. PMID- 23925219 TI - Squeezed light mutes quantum noise. PMID- 23925220 TI - Deal done over HeLa cell line. PMID- 23925221 TI - Spin rate of black holes pinned down. PMID- 23925222 TI - Climate science: A line in the sands. PMID- 23925223 TI - Exotic optics: Metamaterial world. PMID- 23925224 TI - Biospecimen policy: Family matters. PMID- 23925225 TI - Energy policy: A low-carbon road map for China. PMID- 23925229 TI - Avian flu: Gain-of-function experiments on H7N9. PMID- 23925230 TI - Sustainability: Three reasons for eco-label failure. PMID- 23925231 TI - US sequester: Follow Obama's lead and take a pay cut. PMID- 23925232 TI - Avian flu: Extra oversight for H7N9 experiments. PMID- 23925233 TI - Neuroscience: Accurate maps of visual circuitry. PMID- 23925235 TI - Evolutionary biology: The handiwork of tinkering. PMID- 23925236 TI - Climate science: Solution proposed for ice-age mystery. PMID- 23925237 TI - Palaeontology: Jurassic fossils and mammalian antiquity. PMID- 23925238 TI - A Jurassic mammaliaform and the earliest mammalian evolutionary adaptations. AB - The earliest evolution of mammals and origins of mammalian features can be traced to the mammaliaforms of the Triassic and Jurassic periods that are extinct relatives to living mammals. Here we describe a new fossil from the Middle Jurassic that has a mandibular middle ear, a gradational transition of thoracolumbar vertebrae and primitive ankle features, but highly derived molars with a high crown and multiple roots that are partially fused. The upper molars have longitudinal cusp rows that occlude alternately with those of the lower molars. This specialization for masticating plants indicates that herbivory evolved among mammaliaforms, before the rise of crown mammals. The new species shares the distinctive dental features of the eleutherodontid clade, previously represented only by isolated teeth despite its extensive geographic distribution during the Jurassic. This eleutherodontid was terrestrial and had ambulatory gaits, analogous to extant terrestrial mammals such as armadillos or rock hyrax. Its fur corroborates that mammalian integument had originated well before the common ancestor of living mammals. PMID- 23925239 TI - Connectomic reconstruction of the inner plexiform layer in the mouse retina. AB - Comprehensive high-resolution structural maps are central to functional exploration and understanding in biology. For the nervous system, in which high resolution and large spatial extent are both needed, such maps are scarce as they challenge data acquisition and analysis capabilities. Here we present for the mouse inner plexiform layer--the main computational neuropil region in the mammalian retina--the dense reconstruction of 950 neurons and their mutual contacts. This was achieved by applying a combination of crowd-sourced manual annotation and machine-learning-based volume segmentation to serial block-face electron microscopy data. We characterize a new type of retinal bipolar interneuron and show that we can subdivide a known type based on connectivity. Circuit motifs that emerge from our data indicate a functional mechanism for a known cellular response in a ganglion cell that detects localized motion, and predict that another ganglion cell is motion sensitive. PMID- 23925240 TI - A visual motion detection circuit suggested by Drosophila connectomics. AB - Animal behaviour arises from computations in neuronal circuits, but our understanding of these computations has been frustrated by the lack of detailed synaptic connection maps, or connectomes. For example, despite intensive investigations over half a century, the neuronal implementation of local motion detection in the insect visual system remains elusive. Here we develop a semi automated pipeline using electron microscopy to reconstruct a connectome, containing 379 neurons and 8,637 chemical synaptic contacts, within the Drosophila optic medulla. By matching reconstructed neurons to examples from light microscopy, we assigned neurons to cell types and assembled a connectome of the repeating module of the medulla. Within this module, we identified cell types constituting a motion detection circuit, and showed that the connections onto individual motion-sensitive neurons in this circuit were consistent with their direction selectivity. Our results identify cellular targets for future functional investigations, and demonstrate that connectomes can provide key insights into neuronal computations. PMID- 23925241 TI - Squeezed light from a silicon micromechanical resonator. AB - Monitoring a mechanical object's motion, even with the gentle touch of light, fundamentally alters its dynamics. The experimental manifestation of this basic principle of quantum mechanics, its link to the quantum nature of light and the extension of quantum measurement to the macroscopic realm have all received extensive attention over the past half-century. The use of squeezed light, with quantum fluctuations below that of the vacuum field, was proposed nearly three decades ago as a means of reducing the optical read-out noise in precision force measurements. Conversely, it has also been proposed that a continuous measurement of a mirror's position with light may itself give rise to squeezed light. Such squeezed-light generation has recently been demonstrated in a system of ultracold gas-phase atoms whose centre-of-mass motion is analogous to the motion of a mirror. Here we describe the continuous position measurement of a solid-state, optomechanical system fabricated from a silicon microchip and comprising a micromechanical resonator coupled to a nanophotonic cavity. Laser light sent into the cavity is used to measure the fluctuations in the position of the mechanical resonator at a measurement rate comparable to its resonance frequency and greater than its thermal decoherence rate. Despite the mechanical resonator's highly excited thermal state (10(4) phonons), we observe, through homodyne detection, squeezing of the reflected light's fluctuation spectrum at a level 4.5 +/- 0.2 per cent below that of vacuum noise over a bandwidth of a few megahertz around the mechanical resonance frequency of 28 megahertz. With further device improvements, on-chip squeezing at significant levels should be possible, making such integrated microscale devices well suited for precision metrology applications. PMID- 23925242 TI - Insolation-driven 100,000-year glacial cycles and hysteresis of ice-sheet volume. AB - The growth and reduction of Northern Hemisphere ice sheets over the past million years is dominated by an approximately 100,000-year periodicity and a sawtooth pattern (gradual growth and fast termination). Milankovitch theory proposes that summer insolation at high northern latitudes drives the glacial cycles, and statistical tests have demonstrated that the glacial cycles are indeed linked to eccentricity, obliquity and precession cycles. Yet insolation alone cannot explain the strong 100,000-year cycle, suggesting that internal climatic feedbacks may also be at work. Earlier conceptual models, for example, showed that glacial terminations are associated with the build-up of Northern Hemisphere 'excess ice', but the physical mechanisms underpinning the 100,000-year cycle remain unclear. Here we show, using comprehensive climate and ice-sheet models, that insolation and internal feedbacks between the climate, the ice sheets and the lithosphere-asthenosphere system explain the 100,000-year periodicity. The responses of equilibrium states of ice sheets to summer insolation show hysteresis, with the shape and position of the hysteresis loop playing a key part in determining the periodicities of glacial cycles. The hysteresis loop of the North American ice sheet is such that after inception of the ice sheet, its mass balance remains mostly positive through several precession cycles, whose amplitudes decrease towards an eccentricity minimum. The larger the ice sheet grows and extends towards lower latitudes, the smaller is the insolation required to make the mass balance negative. Therefore, once a large ice sheet is established, a moderate increase in insolation is sufficient to trigger a negative mass balance, leading to an almost complete retreat of the ice sheet within several thousand years. This fast retreat is governed mainly by rapid ablation due to the lowered surface elevation resulting from delayed isostatic rebound, which is the lithosphere-asthenosphere response. Carbon dioxide is involved, but is not determinative, in the evolution of the 100,000-year glacial cycles. PMID- 23925243 TI - Nitrogen losses in anoxic marine sediments driven by Thioploca-anammox bacterial consortia. AB - Ninety per cent of marine organic matter burial occurs in continental margin sediments, where a substantial fraction of organic carbon escapes oxidation and enters long-term geologic storage within sedimentary rocks. In such environments, microbial metabolism is limited by the diffusive supply of electron acceptors. One strategy to optimize energy yields in a resource-limited habitat is symbiotic metabolite exchange among microbial associations. Thermodynamic and geochemical considerations indicate that microbial co-metabolisms are likely to play a critical part in sedimentary organic carbon cycling. Yet only one association, between methanotrophic archaea and sulphate-reducing bacteria, has been demonstrated in marine sediments in situ, and little is known of the role of microbial symbiotic interactions in other sedimentary biogeochemical cycles. Here we report in situ molecular and incubation-based evidence for a novel symbiotic consortium between two chemolithotrophic bacteria--anaerobic ammonium-oxidizing (anammox) bacteria and the nitrate-sequestering sulphur-oxidizing Thioploca species--in anoxic sediments of the Soledad basin at the Mexican Pacific margin. A mass balance of benthic solute fluxes and the corresponding nitrogen isotope composition of nitrate and ammonium fluxes indicate that anammox bacteria rely on Thioploca species for the supply of metabolic substrates and account for about 57 +/- 21 per cent of the total benthic N2 production. We show that Thioploca anammox symbiosis intensifies benthic fixed nitrogen losses in anoxic sediments, bypassing diffusion-imposed limitations by efficiently coupling the carbon, nitrogen and sulphur cycles. PMID- 23925244 TI - A new arboreal haramiyid shows the diversity of crown mammals in the Jurassic period. AB - A major unsolved problem in mammalian evolution is the origin of Allotheria, including Multituberculata and Haramiyida. Multituberculates are the most diverse and best known Mesozoic era mammals and ecologically resemble rodents, but haramiyids are known mainly from isolated teeth, hampering our search for their phylogenetic relationships. Here we report a new haramiyid from the Jurassic period of China, which is, to our knowledge the largest reported so far. It has a novel dentition, a mandible resembling advanced multituberculates and postcranial features adapted for arboreal life. Our phylogenetic analysis places Haramiyida within crown Mammalia, suggesting the origin of crown Mammalia in the Late Triassic period and diversification in the Jurassic, which contrasts other estimated divergence times of crown Mammalia. The new haramiyid reveals additional mammalian features of the group, helps to identify other haramiyids represented by isolated teeth, and shows again that, regardless of various phylogenetic scenarios, a complex pattern of evolution involving many convergences and/or reversals existed in Mesozoic mammals. PMID- 23925245 TI - The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. AB - The HeLa cell line was established in 1951 from cervical cancer cells taken from a patient, Henrietta Lacks. This was the first successful attempt to immortalize human-derived cells in vitro. The robust growth and unrestricted distribution of HeLa cells resulted in its broad adoption--both intentionally and through widespread cross-contamination--and for the past 60 years it has served a role analogous to that of a model organism. The cumulative impact of the HeLa cell line on research is demonstrated by its occurrence in more than 74,000 PubMed abstracts (approximately 0.3%). The genomic architecture of HeLa remains largely unexplored beyond its karyotype, partly because like many cancers, its extensive aneuploidy renders such analyses challenging. We carried out haplotype-resolved whole-genome sequencing of the HeLa CCL-2 strain, examined point- and indel mutation variations, mapped copy-number variations and loss of heterozygosity regions, and phased variants across full chromosome arms. We also investigated variation and copy-number profiles for HeLa S3 and eight additional strains. We find that HeLa is relatively stable in terms of point variation, with few new mutations accumulating after early passaging. Haplotype resolution facilitated reconstruction of an amplified, highly rearranged region of chromosome 8q24.21 at which integration of the human papilloma virus type 18 (HPV-18) genome occurred and that is likely to be the event that initiated tumorigenesis. We combined these maps with RNA-seq and ENCODE Project data sets to phase the HeLa epigenome. This revealed strong, haplotype-specific activation of the proto-oncogene MYC by the integrated HPV-18 genome approximately 500 kilobases upstream, and enabled global analyses of the relationship between gene dosage and expression. These data provide an extensively phased, high-quality reference genome for past and future experiments relying on HeLa, and demonstrate the value of haplotype resolution for characterizing cancer genomes and epigenomes. PMID- 23925246 TI - A directional tuning map of Drosophila elementary motion detectors. AB - The extraction of directional motion information from changing retinal images is one of the earliest and most important processing steps in any visual system. In the fly optic lobe, two parallel processing streams have been anatomically described, leading from two first-order interneurons, L1 and L2, via T4 and T5 cells onto large, wide-field motion-sensitive interneurons of the lobula plate. Therefore, T4 and T5 cells are thought to have a pivotal role in motion processing; however, owing to their small size, it is difficult to obtain electrical recordings of T4 and T5 cells, leaving their visual response properties largely unknown. We circumvent this problem by means of optical recording from these cells in Drosophila, using the genetically encoded calcium indicator GCaMP5 (ref. 2). Here we find that specific subpopulations of T4 and T5 cells are directionally tuned to one of the four cardinal directions; that is, front-to-back, back-to-front, upwards and downwards. Depending on their preferred direction, T4 and T5 cells terminate in specific sublayers of the lobula plate. T4 and T5 functionally segregate with respect to contrast polarity: whereas T4 cells selectively respond to moving brightness increments (ON edges), T5 cells only respond to moving brightness decrements (OFF edges). When the output from T4 or T5 cells is blocked, the responses of postsynaptic lobula plate neurons to moving ON (T4 block) or OFF edges (T5 block) are selectively compromised. The same effects are seen in turning responses of tethered walking flies. Thus, starting with L1 and L2, the visual input is split into separate ON and OFF pathways, and motion along all four cardinal directions is computed separately within each pathway. The output of these eight different motion detectors is then sorted such that ON (T4) and OFF (T5) motion detectors with the same directional tuning converge in the same layer of the lobula plate, jointly providing the input to downstream circuits and motion-driven behaviours. PMID- 23925248 TI - Pentatricopeptide repeat proteins: a set of modular RNA-specific binders massively used for organelle gene expression. PMID- 23925249 TI - Solution-processable hole-transporting material containing fluorenyl core and triple-carbazolyl terminals: synthesis and application to enhancement of electroluminescence. AB - A novel solution-processable, efficient hole-transporting material 2,4,7-tri[2-(9 hexylcarbazole)ethenyl]-9,9-dihexylfluorene (FC), composed of a fluorenyl core and triple-carbazolyl terminals, is successfully synthesized and well characterized. The FC is a thermally stable, amorphous material because of its aromatic and asymmetric structure. The highest occupied molecular orbital (HOMO) level of FC is -5.21 eV, as determined by cyclic voltammetry, implying its applicability as a hole-transporting layer (HTL) to promote hole injection. Furthermore, the FC could be deposited by a spin-coating process to obtain a homogeneous HTL film, more convenient and cost-effective than conventional NPB which must be deposited by vacuum vapor deposition. When fabricated as multi layer OLED [ITO/PEDOT:PSS/HTL(25 nm)/Alq3(50 nm)/LiF(0.5 nm)/Al(100 nm)], the maximum brightness (21,400 cd m(-2)) and current efficiency (3.20 cd A(-1)) based on the FC are superior to those using conventional NPB as the hole-transporting layer. In addition, a homogeneous FC film is readily prepared by simple wet processes (spin-coating). Our results indicate that the FC is a promising optoelectronic material which is readily processed by wet methods such as spin coating. PMID- 23925250 TI - Phrenic nerve palsy associated with brachial plexus avulsion in a pediatric patient with multitrauma. AB - Although brachial plexus injury occurring during multitrauma is frequent in adults, it is rarely observed in childhood. The most common cause of pediatric traumatic brachial palsy is motor vehicle accidents followed by pedestrian struck. Generally, phrenic nerve palsy accompanying brachial plexus trauma is observed in 10% to 20% of cases, but it is overlooked because unilateral injuries are frequently asymptomatic. Severe unilateral phrenic nerve palsy accompanying brachial plexus avulsion is very rare. Here, we present a pediatric case of unilateral phrenic nerve palsy associated with respiratory distress and brachial plexus avulsion due to multitrauma. PMID- 23925251 TI - Hair tourniquet of the circumvallate papillae: a potentially "hairy" situation. AB - Oral foreign bodies and hair-thread tourniquets are fairly common findings. The combination of the two, however, is rarer. In this article, we present a case involving a hair-thread tourniquet of a circumvallate papillae (more commonly known as a "taste bud"). We discuss methods for removal of hair-thread tourniquets as well as techniques for examining children for oral foreign bodies. PMID- 23925252 TI - Deep sedation with sevoflurane inhalation via a nasal hood for brief dental procedures in pediatric patients. AB - Nitrous oxide is widely used for dental sedation. However, weak potency of nitrous oxide requires additional sedatives for maintaining a deeper level of sedation. Sevoflurane, a mainstay in pediatric anesthesia, is a potent anesthetic agent. Some attempts have been made to use sevoflurane for conscious sedation. In this case, we successfully treat pediatric patients under deep sedation by sevoflurane inhalation without other sedatives. Sevoflurane may be useful for sedation in pediatric dental outpatient setting. PMID- 23925253 TI - An overdose of extended-release guanfacine. AB - Extended-release guanfacine is a centrally acting alpha2-adrenergic agonist that was recently approved for treatment of attention-deficit/hyperactivity disorder. The following is a case discussion of a 12-year-old boy with attention deficit/hyperactivity disorder and Tourette syndrome, who presented 18 hours after ingestion of 3 times his usual dose of extended-release guanfacine. On presentation, he was lethargic, bradycardic, and hypertensive with an otherwise nonfocal neurological examination. He remained hypertensive until administration of an intravenous antihypertensive agent (nicardipine) 24 hours after ingestion. After cessation of the calcium-channel blocker, he continued to have intermittent episodes of symptomatic hypotension for the next 21/2 days. This extremely protracted course of hypertension followed by prolonged symptomatic hypotension is rare with ingestions of centrally acting alpha2-adrenergic agonists. As this drug is increasingly prescribed for treatment of a disease with increasing prevalence, it is imperative that emergency physicians become familiar with the varying presentations of its toxicity. PMID- 23925254 TI - Ectopic lobe of right lung with abscess formation in children: a visual diagnosis case. AB - We report a 9-year-old boy who had chest pain of 3 weeks' duration caused by ectopic lobe of the right lung with abscess formation. The diagnosis was supported by chest computed tomography and video-assisted thoracoscopy. The child responded well to the operation and fully recovered. PMID- 23925255 TI - Iatrogenic tracheal rupture in a child: case study and review of literature. AB - Tracheal rupture is rare in childhood, and optimal treatment is not clear. A 14 year-old boy was admitted to a local hospital after sudden loss of consciousness. He underwent endotracheal intubation and was referred to our hospital. The patient's history revealed that he had voluntarily inhaled butane gas. The physical examination was consistent with coma and cardiogenic shock, and the chest radiograph showed pulmonary edema. The patient was admitted to the intensive care unit, and diuretic and inotropic therapy was started. In the third hour of monitoring of the patient under mechanical ventilation, subcutaneous emphysema and pneumothorax at the right hemithorax were observed without deterioration of the vital functions. Thoracic computed tomography scan findings were consistent with tracheal rupture. The patient was monitored conservatively without surgery. On the fifth day of hospitalization, his tube was removed, and he was discharged on the 12th day with a positive prognosis. In this study, a tracheal rupture case after endotracheal intubation is presented in which the patient recovered completely with conservative therapy. PMID- 23925256 TI - Burn injuries in children and the use of biological dressings. AB - Burns represent a significant cause of morbidity and mortality in children. In this article, a case discussion will serve as a platform for discussing the evaluation and treatment of burns in children. Use of various burn dressings such as hydrocolloids, polyurethane films, hydrogels, biosynthetic skin dressing, and biological dressings will be discussed. PMID- 23925257 TI - Pediatric emergency medicine: legal briefs. PMID- 23925258 TI - ECGs in the ED. PMID- 23925259 TI - Troponin T should not be considered as a screening test for pediatric myocarditis. PMID- 23925260 TI - Dealing with ketamine sedation adverse events: are coadministered anticholinergics necessary? PMID- 23925262 TI - A mixed fixed ratio/progressive ratio procedure reveals an apathy phenotype in the BAC HD and the z_Q175 KI mouse models of Huntington's disease. AB - Apathy, characterized by generally reduced interest in and likelihood to perform goal-directed actions, is a recognized symptom of Huntington's disease (HD), a devastating neurological disorder caused by a CAG repeat expansion of the Htt gene located on chromosome 4. The present experiments used a modified progressive ratio task that incorporated a fixed-ratio schedule of reinforcement component to assess consummatory behavior, and a progressive-ratio schedule component that required increasing numbers of lever-presses for successive reinforcers (0.01 ml of evaporated milk). The studies revealed an apathetic phenotype in two mouse models of HD, with decreased response rates either overall or only at higher ratio requirements in the progressive-ratio component relative to wild-type controls. Based on the procedure used (within-session fixed- and progressive ratio components), it is proposed that an observed phenotype can be ascribed either specifically to reduced motivation to work for food reinforcement or more generally to deficits in consummatory behavior. This procedure provides a simple means to assess this type of phenotype in rodents, with issues in consummatory vs. incentive motivation reflected in general alterations in fixed- versus progressive alterations on an escalating-ratio schedules respectively, providing translational measures of the amotivation/apathy construct of the human realm to the homologous construct of incentive motivation in preclinical models of human disease. PMID- 23925261 TI - A gold-carbon nanoparticle composite as an efficient catalyst for homocoupling reaction. AB - Carbon nanoparticle supported Au nanoparticles could be synthesized starting with a Au nanoparticle-chitosan composite. The composite nanoparticles efficiently converted phenylboronic acid to biphenyl through homocoupling. PMID- 23925263 TI - Reactions of Cp2M (M = Ni, V) with dilithium diamido-aryl reagents; retention and oxidation of the transition metal ions. AB - The reactions of dilithium 1,2-diamidobenzene, [1,2-(HN)2C6H4]Li2 (L(1)H2)Li2, and dilithium 1,8-diamidonaphthalene, [1,8-(NH)2C10H6]Li2 (L(2)H2)Li2, with Cp2Ni and Cp2V have been used to obtain the new complexes (L(2)H2)2Ni{Li(THF)2}2 (3), (L(2)H2)3V{Li(THF)2}3 (4) and (L(1)H2)6Ni6.{[(L(1)H2)3(L(1)H)3Ni6Li(THF)](2 ).2[Li(THF)4](+)} (5), in which retention or oxidation of the initial metal(ii) centre is observed. Whereas 3 and 4 contain one transition metal ion within ion paired structures, 5 has a complicated co-crystalline composition which contains octahedral Ni6-cages constructed from six square-planar (16e) Ni(II) centres. PMID- 23925265 TI - Mitochondrial filamentation: a therapeutic target for neurodegeneration and aging. AB - It is reflected on the recently open possibility of new studies on Alzheimer's disease, Late Stage Dementia, Cytoskeleton Live Dynamics and Mitochondria, afforded by the new emerging field of mitochondrial physiology bioenergetics, Mitochondrial Filamentation. To this area the author groups provided some initial efforts. The considerations emphasize the many important relationships ahead for possible future studies with many other fields. Especially with Genome Alterations and Proteonomics. PMID- 23925266 TI - Investigation of toilet activities in elderly patients with dementia from the viewpoint of motivation and self-awareness. AB - Toilet activities of the elderly patients with dementia were observed focusing on care conditions and investigated based on Hull's drive reduction theory (behavior = drive * habit * incentive) and our self-awareness model (consisting of theory of mind, self-evaluation, and self-consciousness) to evaluate the association between self-awareness and toilet activities in patients with dementia and to explain the time when and the reason why a series of toilet activities as habit once acquired become unfeasible. If theory of mind is lost, awareness of one's desire and intention becomes vague, and toilet activities begin to collapse. Furthermore, if incentive disappears, one's intention hardly arises and toilet activities further collapse. If self-evaluation is lost, time sense fades, future goals based on the present time cannot exist, and behavior loses directivity. As a result, toilet activities collapse, and with a decrease in drive toilet activities cease. PMID- 23925269 TI - The three-dimensional context of a double helix determines the fluorescence of the internucleoside-tethered pair of fluorophores. AB - We report a general phenomenon of the formation of either a fluorescent or an entirely quenched oligodeoxynucleotide (ODN) duplex system by hybridizing pairs of complementary ODNs with identical chemical composition. The ODNs carried internucleoside tether-linked cyanines, where the cyanines were chosen to form a Forster's resonance energy transfer (FRET) donor-acceptor pair. The fluorescent and quenched ODN duplex systems differed only in that the cyanines linked to the respective ODNs were linked either closer to the 5'- or 3'-ends of the molecule. In either case, however, the dyes were separated by an identical number (7 or 8) of base pairs. Characterization by molecular modeling and energy minimization using a conformational search algorithm in a molecular operating environment (MOE) revealed that linking of the dyes closer to the 5'-ends resulted in their reciprocal orientation across the major groove which allowed a closely interacting dye pair to be formed. This overlap between the donor and acceptor dye molecules resulted in changes in absorbance spectra consistent with the formation of H-aggregates. Conversely, dyes linked closer to 3'-ends exhibited emissive FRET and formed a pair of dyes that interacted with the DNA helix only weakly. Induced CD spectra analysis suggested that interaction with the double helix was weaker than in the case of the closely interacting cyanine dye pair. Linking the dyes such that the base pair separation was 10 or 0 favored energy transfer with subsequent acceptor emission. Our results suggest that when interpreting FRET measurements from nucleic acids, the use of a "spectroscopic ruler" principle which takes into account the 3D helical context of the double helix will allow more accurate interpretation of fluorescence emission. PMID- 23925270 TI - Susceptibility-weighted MR imaging in the grading of liver fibrosis: a feasibility study. AB - PURPOSE: To assess the feasiblity of magnetic resonance (MR) susceptibility weighted (SW) imaging as a tool to evaluate liver fibrosis grades in patients with chronic liver diseases (CLD) utilizing signal intensity (SI) measurements, with histopathologic findings as the reference standard. MATERIALS AND METHODS: This retrospective study was approved by the local ethics committee. All subjects gave written informed consent. Eighty consecutive patients (mean age, 56.8 years), 60% of whom were male [n = 48] and 40% of whom were female [n = 32], with CLD due to various underlying causes and histopathologically proved liver fibrosis were included. Biopsies were evaluated for liver fibrosis and necroinflammatory activity (according to METAVIR scoring system), iron load, and steatosis. Two radiologists, blinded to the clinical data, assessed regions of interest in the liver and spinal muscle in consensus. Liver-to-muscle SI ratios were calculated and correlated to histopathologic findings and clinical data by using univariate and multivariate regression analysis. RESULTS: Liver-to-muscle SI ratio decreased in parallel with the increasing grade of liver fibrosis and correlated strongly with liver fibrosis (r = -0.81, P < .0001) and moderately with necroinflammatory activity (r = -0.52, P < .0001) and iron load (r = -0.37, P = .0002) but did not correlate with steatosis (r = -0.18, P = .11). In multiple regression analysis, liver fibrosis and iron load independently influenced SW imaging measurements, explaining 69% of the variance of liver-to-muscle SI ratio (R(2) = 0.69, P < .001). Liver-to-muscle SI ratio performed well in grading liver fibrosis, with an area under the receiver operating characteristic curve of 0.92 for scores of F2 or higher and 0.93 for score of F4 (liver cirrhosis). CONCLUSION: SW imaging is a feasible noninvasive tool to detect moderate and advanced liver fibrosis in CLD patients. PMID- 23925272 TI - Radiofrequency ablation versus radical nephrectomy: clinical outcomes for stage T1b renal cell carcinoma. AB - PURPOSE: To compare clinical outcomes of radiofrequency (RF) ablation retrospectively with those after radical nephrectomy in patients with stage T1b renal cell carcinoma (RCC). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and the requirement to obtain written informed consent was waived. From June 2002 to March 2012, 60 patients (mean age, 65.2 years; age range, 39-86 years) with a single RCC measuring 4.1-7.0 cm (stage T1b) underwent RF ablation (n = 21) or radical nephrectomy (n = 39). Selective renal artery embolization was performed before RF ablation in eight patients. The overall, RCC-related, and disease-free survival rates, the percentage decrease in the glomerular filtration rate (GFR), and safety were compared by using the log rank (survival), paired and Student t (GFR), and Fisher exact (safety) tests. RESULTS: The overall survival rate was significantly lower in the RF ablation group than in the radical nephrectomy group (48% vs 97% at 10 years, respectively; 95% confidence interval [CI]: 12.4%, 76.7% vs 78.2%, 99.5%; P < .009). The RCC-related survival rate (94% [95% CI: 62.6%, 99.1%] with RF ablation vs 100% with radical nephrectomy at 10 years) and the disease-free survival rate (88% [95% CI: 59.2%, 96.9%] with RF ablation vs 84% [95% CI: 60.6%, 94.3%] with radical nephrectomy at 10 years, P = .99) were comparable between the two groups. No treatment-related deaths occurred. Although major complication rates were similar between the two patient groups (8.0% [two of 25 patients] vs 5.1% [two of 39 patients], P = .61), the percentage decrease in the GFR was significantly lower in the RF ablation group than in the radical nephrectomy group at the last follow-up (12.5% +/- 23.4 vs 32.3% +/- 20.8, respectively; P < .003). CONCLUSION: RF ablation is a safe procedure for patients at substantial surgical risk for radical nephrectomy, providing comparable RCC-related and disease-free survival and preserving renal function. PMID- 23925273 TI - Longitudinal MR imaging of iron in multiple sclerosis: an imaging marker of disease. AB - PURPOSE: To investigate the relationship between magnetic resonance (MR) imaging markers of iron content and disease severity in patients with multiple sclerosis (MS) over a 2-year period. MATERIALS AND METHODS: This prospective study was approved by the local ethics committee, and written informed consent was obtained from all participants. Seventeen patients with MS and 17 control subjects were examined twice, 2 years apart, by using phase imaging and transverse relaxation (R2*) mapping at 4.7 T. Quantitative differences in iron content in deep gray matter between patients and control subjects were evaluated with repeated measures multivariate analysis of variance separately for R2* mapping and phase imaging. Multiple regression analysis was used to evaluate correlations of MR imaging measures, both 2-year-difference and single-time measurements, to baseline disease severity. RESULTS: R2* mapping using 2-year-difference measurements had the highest correlation to disease severity (r = 0.905, P < .001) compared with R2* mapping using single-time measurements (r = 0.560, P = .019) and phase imaging by using either single-time (r = 0.539, P = .026) or 2 year-difference (r = 0.644, P = .005) measurements. Significant increases in R2* occur during 2 years in the substantia nigra (P < .001) and globus pallidus (P = .035), which are both predictors of disease in regression analysis, in patients compared with control subjects. There were group differences in the substantia nigra, globus pallidus, pulvinar thalamus, thalamus, and caudate nucleus, compared with control subjects with R2* mapping (P < .05), and group differences in the caudate nucleus and pulvinar thalamus, compared with control subjects with phase imaging (P < .05). CONCLUSION: There are significant changes in deep gray matter iron content in MS during 2 years measured with MR imaging, changes that are strongly related to physical disability. Longitudinal measurements may produce a higher correlation to disease severity compared with single-time measurements because baseline iron content of deep gray matter is variable among subjects. PMID- 23925271 TI - Bone marrow biopsy: RNA isolation with expression profiling in men with metastatic castration-resistant prostate cancer--factors affecting diagnostic success. AB - PURPOSE: To determine the rate at which computed tomographically guided pelvic percutaneous bone biopsy in men with metastatic castration-resistant prostate cancer (mCRPC) yields adequate tissue for genomic profiling and to identify issues likely to affect diagnostic yields. MATERIALS AND METHODS: This study was institutional review board approved, and written informed consent was obtained. In a phase II trial assessing response to everolimus, 31 men with mCRPC underwent 54 biopsy procedures (eight men before and 23 men both before and during treatment). Variables assessed were lesion location (iliac wing adjacent to sacroiliac joint, iliac wing anterior and/or superior to sacroiliac joint, sacrum, and remainder of pelvis), mean lesion attenuation, subjective lesion attenuation (purely sclerotic vs mixed), central versus peripheral lesion sampling, lesion size, core number, and use of zoledronic acid for more than 1 year. RESULTS: Of 54 biopsy procedures, 21 (39%) yielded adequate tissue for RNA isolation and genomic profiling. Three of four sacral biopsies were adequate. Biopsies of the ilium adjacent to the sacroiliac joints were more likely adequate than those from elsewhere in the ilium (48% vs 28%, respectively). All five biopsies performed in other pelvic locations yielded inadequate tissue for RNA isolation. Mean attenuation of lesions with inadequate tissue was 172 HU greater than those with adequate tissue (621.1 HU +/- 166 vs 449 HU +/- 221, respectively; P = .002). Use of zoledronic acid, peripheral sampling, core number, and lesion size affected yields, but the differences were not statistically significant. Histologic examination with hematoxylin-eosin staining showed that results of 36 (67%) biopsies were positive for cancer; only mean attenuation differences were significant (707 HU +/- 144 vs 473 HU +/- 191, negative vs positive, respectively; P < .001). CONCLUSION: In men with mCRPC, percutaneous sampling of osseous metastases for genomic profiling is possible, but use of zoledronic acid for more than 1 year may reduce the yield of adequate tissue for RNA isolation. Sampling large low-attenuating lesions at their periphery maximizes yield. PMID- 23925274 TI - Synthesis of fluorescent derivatives of praziquantel: cell-imaging and interaction with Schistosoma japonicum cercariae. AB - Schistosomiasis is one of the most burdensome of the neglected tropical diseases. Praziquantel is a recommended drug for treatment against all forms of schistosomiasis. To investigate the interaction between praziquantel and Schistosoma japonicum cercariae, two praziquantel derivatives (PZQ-2 and PZQ-3) and one praziquantel fluorescent derivative (PZQ-5) have been synthesized and characterized using nuclear magnetic resonance spectroscopy (NMR) and MS spectra. The cytotoxicity of PZQ-2, PZQ-3 and PZQ-5 was measured by performing the methyl thiazolyl tetrazolium (MTT) assay. The cell viability for them shows that the three compounds exhibit low cytotoxicity to HeLa cells. Cell imaging experiments demonstrate that PZQ-5 is biocompatible and cell-permeable, which indicates that PZQ-5 is suitable for studying their interaction. Confocal fluorescence microscopy revealed that PZQ-5 is mainly located at the cercarial tegument, which leads to the death of cercariae with the increase in time. PMID- 23925276 TI - Endoscopic submucosal dissection of early gastric neoplastic lesions: a western series. AB - OBJECTIVE: Endoscopic submucosal dissection (ESD) has been found to be effective and safe for endoscopic removal of early gastric neoplasia in large Asian series. However, few data are available on the use of ESD in western countries. We assessed the efficacy of ESD performed in patients with early gastric neoplastic lesions. METHODS: We analyzed prospectively collected data of consecutive patients who underwent the ESD procedure for gastric neoplasia at a single Italian center. Procedure-related outcomes, including complete histological resection rate (i.e. R0 resection), immediate and late complication rate, procedure-related mortality, and follow-up were evaluated. RESULTS: Forty-two patients underwent gastric ESD. The en-bloc removal of lesions was successful in all cases, whereas R0 was achieved in 39 (92.8%) patients. A bleeding episode was observed in three (7.1%) patients, which was successfully managed by endoclip positioning. No perforations and procedure-related deaths were observed. The median follow-up period was 19 months (range: 9-53). A small residue of adenomatous lesion and a recurrent dysplastic lesion were removed by endoscopic mucosal resection in two (5%) patients. CONCLUSION: Our data are comparable with those of larger Asian series. Use of ESD for removal of gastric neoplastic lesions should be implemented in western countries. PMID- 23925275 TI - Biophysical characterization and immunization studies of dominant negative inhibitor (DNI), a candidate anthrax toxin subunit vaccine. AB - Dominant Negative Inhibitor (DNI) is a translocation-deficient homolog of recombinant protective antigen of Bacillus anthracis that is a candidate for a next generation anthrax vaccine. This study demonstrates that the biophysical characteristics of the DNI protein stored in lyophilized form at 4 degrees C for 8 y were similar to recombinant Protective Antigen (rPA). To provide information on the accelerated stability of DNI, samples in the lyophilized form were subjected to thermal stress (40 degrees C and 70 degrees C for up to 4 weeks) and thoroughly evaluated using various biophysical and chemical characterization techniques. Results demonstrate preserved structural stability of the DNI protein under extreme conditions, suggesting long-term stability can be achieved for a vaccine that employs DNI, as desired for a biodefense countermeasure. Furthermore, the biological activity of the stressed DNI bound to the adjuvant Alhydrogel ((r)) was evaluated in mice and it was found that the immunogenicity DNI was not affected by thermal stress. PMID- 23925277 TI - Less iron deficiency anaemia after delayed cord-clamping. PMID- 23925278 TI - Evidence that a short frenulum hampers the establishment of breastfeeding. PMID- 23925279 TI - Prevention of nosocomial infections in developing countries, a systematic review. AB - BACKGROUND: Prevention of nosocomial infection is key to providing good quality, safe healthcare. Infection control programmes (hand-hygiene campaigns and antibiotic stewardship) are effective in reducing nosocomial infections in developed countries. However, the effectiveness of these programmes in developing countries is uncertain. OBJECTIVE: To evaluate the effectiveness of interventions for preventing nosocomial infections in developing countries. METHODS: A systematic search for studies which evaluated interventions to prevent nosocomial infection in both adults and children in developing countries was undertaken using PubMed. Only intervention trials with a randomized controlled, quasi experimental or sequential design were included. Where there was adequate homogeneity, a meta-analysis of specific interventions was performed using the Mantel-Haenzel fixed effects method to estimate the pooled risk difference. RESULTS: Thirty-four studies were found. Most studies were from South America and Asia. Most were before-and-after intervention studies from tertiary urban hospitals. Hand-hygiene campaigns that were a major component of multifaceted interventions (18 studies) showed the strongest effectiveness for reducing nosocomial infection rates (median effect 49%, effect range 12.7-100%). Hand hygiene campaigns alone and studies of antibiotic stewardship to improve rational antibiotic use reduced nosocomial infection rates in three studies [risk difference (RD) of -0.09 (95%CI -0.12 to -0.07) and RD of -0.02 (95% CI -0.02 to 0.01), respectively]. CONCLUSIONS: Multifaceted interventions including hand hygiene campaigns, antibiotic stewardship and other elementary infection control practices are effective in developing countries. The modest effect size of hand hygiene campaigns alone and negligible effect size of antibiotic stewardship reflect the limited number of studies with sufficient homogeneity to conduct meta analyses. PMID- 23925280 TI - Timing of umbilical cord-clamping and infant anaemia: the role of maternal anaemia. AB - BACKGROUND: Evidence from randomized controlled trials has shown that delayed cord-clamping is beneficial to infant iron status. The role of maternal anaemia in this relationship, however, has not been established. OBJECTIVE: To determine the effect of maternal anaemia at delivery on the association between timing of umbilical cord-clamping and infant anaemia at 4 and 8 months of age. METHODS: A cohort of pregnant women admitted to the labour room of Hospital Iquitos (Iquitos, Peru) and their newborns were recruited into the study during two time periods (18 May to 3 June and 6-20 July 2009). Between the two recruitment periods, the hospital's policy changed from early to delayed umbilical cord clamping. Maternal haemoglobin levels were measured before delivery, and the time between delivery and cord-clamping was recorded at delivery for the entire cohort. Mother-infant pairs were followed-up at 4 (n = 207) and 8 months (n = 184) post partum. Infant haemoglobin levels were measured at follow-up visits. Data were analysed using logistic regression models. RESULTS: The prevalence of maternal anaemia (Hb <11.0 g/dl) at delivery was 22%. Infant haemoglobin levels at 4 and 8 months of age were 10.4 g/dl and 10.3 g/dl, respectively. Infant haemoglobin levels did not differ significantly between infants born to anaemic mothers and those born to non-anaemic mothers at either 4 or 8 months of age. However, the association between the timing of cord-clamping and infant anaemia was modified by the mother's anaemia status. Significant benefits of delayed cord clamping in preventing anaemia were found in infants born to anaemic mothers at both 4 months (aOR = 0.59, 95% CI 0.36-0.99) and 8 months (aOR = 0.38, 95% CI 0.19-0.76) of age. CONCLUSION: The study contributes additional evidence in support of delayed cord-clamping. This intervention is likely to have most public health impact in areas with a high prevalence of anaemia during pregnancy. PMID- 23925281 TI - Lingual frenulum and effect on breastfeeding in Thai newborn infants. AB - BACKGROUND: Breastfeeding has abundant biological and psychological benefits. Effective breastfeeding requires good latching on, which is possible when the infant is able to cup around the maternal areola with his tongue. One of the most common conditions resulting in poor latching on is tongue-tie. OBJECTIVE: To determine the prevalence of tongue-tie with subsequent breastfeeding difficulties and other factors affecting the success of breastfeeding in newborn infants. METHODS: This was a prospective, cross-sectional study of healthy Thai infants without contraindications for breastfeeding. Physical examination of the infants and mothers and their breastfeeding practices were assessed between 24 and 48 hours of life. RESULTS: 2679 mother-infant dyads were recruited. The study detected a prevalence of 16% for severe tongue-tie, 37.9% of which was associated with breastfeeding difficulties. Using multiple logistic regression analysis, moderate (adjusted OR 13.3, 95% CI 7.2-24.5) and severe (adjusted OR 62, 95% CI 34.1-112.8) tongue-tie, short nipples (adjusted OR 1.5, 95% CI 1.1-2.2), mothers feeling the infant's tongue on the nipple area (adjusted OR 3.4, 95% CI 2.2-5.2) and mothers' inability to feel the infant's tongue (adjusted OR 11.8, 95% CI 4.3 32.4) independently increased the risk of breastfeeding difficulties. CONCLUSIONS: Tongue-tie is not uncommon and is associated with breastfeeding difficulty in newborn infants. Mothers of infants with severe tongue-tie should be closely and individually coached during breastfeeding and followed up, especially during the first critical weeks of the infant's life. PMID- 23925282 TI - Early mortality of very low-birthweight infants at Queen Elizabeth Central Hospital, Malawi. AB - BACKGROUND: There is little information regarding outcome of very low-birthweight (VLBW) infants in resource-poor settings. OBJECTIVES: To study early mortality outcome in VLBW infants admitted to the neonatal nursery, Queen Elizabeth Central Hospital, Blantyre and determine duration of hospital stay of surviving infants and their attendance for recommended follow-up. METHODS: Case notes were reviewed for all infants weighing <=1500 g at birth admitted to the neonatal unit during a 6-month period (May-October 2010) to establish survival to discharge and follow up attendance. RESULTS: 42% (112/268) of VLBW infants survived to discharge. Survival significantly increased with increasing birthweight (11% for infants weighing <=1000 g vs. 53% for those >1000 g, P<0.001), and greater gestation (19% for infants <32 weeks vs. 68% for ?32 weeks, P<0.001). Most deaths (88%, 137/156) occurred within the first week, 58% of them (91/156) within 48 hours of admission. Surviving infants with a birthweight of 1001-1500 g stayed in hospital for a mean 21 days (range 5-44) and those weighing <=1000 g at birth (eight) stayed for a mean 47 days (range 35-64). A total of 108 infants were discharged from hospital, 87 of whom (81%) attended at least one follow-up visit, 62 of whom (57%) completed the recommended follow-up attendance. CONCLUSION: There is considerable scope to improve survival rates of VLBW infants in this setting, although staffing and economic constraints make survival of the smallest and most premature infants unrealistic. Mothers of surviving infants <1000 g should be prepared for a lengthy hospital stay. PMID- 23925283 TI - Tumour necrosis factor gene polymorphism in dengue infection: association with risk of bleeding. AB - BACKGROUND: A single nucleotide polymorphism located at the promoter -308A of tumour necrosis factor-alpha (TNF-alpha) gene may affect transcription and increase cytokine production, leading to the severe manifestation of dengue virus infection. AIM: To study the association of the TNF-alpha -308A allele and the severity of patients with dengue infection. METHODS: 112 patients suspected of having dengue infection and 106 normal controls were enrolled in the study. Mean (SD) age was 10.4 (3.6) years. In all, 19 and 82 patients were diagnosed with dengue fever (DF) and dengue haemorrhagic fever (DHF), respectively, while 11 were diagnosed with other febrile illnesses (OFIs). They were tested for the polymorphisms at the promoter -308 position of the TNF-alpha gene and their TNF alpha levels were measured. RESULTS: In the patients with dengue infection (14/202, 6.9%) with OFIs (1/22, 4.5%) and in normal controls (17/212, 8.0%), the frequency of the TNF-alpha -308A allele was not significantly different. Moreover, no statistically significant difference was found in patients with various clinical manifestations of dengue infection involving DF (5.3%, 2/38), DHF grade I (5.0%, 2/40), DHF grade II (9.5%, 4/42), DHF grade III (2.5%, 1/40) and DHF grade IV (11.9%, 5/42). However, patients with dengue infection and significant bleeding manifestations, apart from petechiae and ecchymosis, tended to have a higher frequency of the TNF-alpha -308A allele (11.8%, 9/76) than those without significant bleeding manifestations (5/126, 4.0%) (P = 0.056). The levels of TNF-alpha were additionally measured in 67 patients but the results failed to demonstrate a functional effect in the transcriptional rate of the TNF-alpha 308A allele. CONCLUSION: In patients with dengue infection there is an association between the TNF-alpha -308A allele and the risk of bleeding. The test may be used as one of the predictors of the severity of dengue infection. PMID- 23925284 TI - Neutralizing activity and secretory IgA antibodies reactive with rotavirus SA-11 (serotype G3) in colostrum and milk from Brazilian women. AB - BACKGROUND: Rotavirus is an important aetiological agent for severe diarrhoea in infants and young children worldwide. Anti-rotavirus antibodies in human colostrum and milk may interfere with rotavirus vaccination seroconversion. AIMS: To verify the presence of anti-rotavirus secretory IgA antibodies (SIgA) and the neutralizing capacity of 30 colostrum and 30 milk samples from Brazilian women in two different centres and analyze their persistence throughout lactation. METHODS: Colostrum and milk samples from healthy nursing mothers were tested for the presence of anti-rotavirus SIgA using conventional ELISA and their capacity to neutralize rotavirus using MA-104 cell cultures. Total IgA concentrations and anti-rotavirus SIgA levels were measured in samples collected from three mothers during 90 or 240 days of the lactation period. RESULTS: Colostrum samples showed higher levels of anti-rotavirus SIgA and higher neutralizing ability than in milk. However, these antibodies levels were not statistically different. In addition, there was no correlation between antibody levels and the neutralizing activity observed in colostrum and milk samples. Follow-up of three mothers demonstrated the persistence of anti-rotavirus and total IgA levels throughout lactation. CONCLUSIONS: These results support the encouragement of breastfeeding as a mechanism of protection against rotavirus infection in lactating infants. Components other than SIgA antibodies might play an important role in virus neutralization. PMID- 23925285 TI - Five Arab children with glucose-galactose malabsorption. AB - Five children with glucose-galactose malabsorption (GGM) are presented. Two infants from Saudi Arabia were first-degree relatives, the third infant was unrelated and the other two were of Yemeni and Syrian origin, respectively. All the infants had chronic diarrhoea and four had failed to thrive since early infancy. All had stools positive for reducing substances, and sugar chromatography showed glucose and galactose malabsorption. Small bowel biopsies were normal in all. One infant developed gangrene of both legs as a complication of hypernatraemia and dehydration, necessitating bilateral amputation. Two infants had nephrolithiasis. All the infants responded well to fructose-based formulae. GGM should be considered in the differential diagnosis of chronic diarrhoea in infants breastfed or artificially fed from early life. PMID- 23925286 TI - Ocular and subcutaneous dirofilariasis in a Sri Lankan infant: an environmental hazard caused by dogs and mosquitoes. AB - An 11-month-old infant presented with a subcutaneous nodule in the right cheek which was found by ultrasonography to be a worm. Following treatment with di ethylcarbamazine, a worm emerged from the left upper eyelid which was confirmed to be Dirofilaria repens. Dirofilariasis usually manifests as a single lesion and is rare in infants. PMID- 23925287 TI - Pyridoxine-dependent epilepsy owing to antiquitin deficiency--mutation in the ALDH7A1 gene. AB - Pyridoxine-dependent epilepsy (PDE) is an inborn error of metabolism resulting from antiquitin deficiency. There is marked elevation of alpha-amino adipic semi aldehyde (alphaAASA), piperidine-6-carboxylate (P6C) and pipecolic acid. The diagnosis can be confirmed by identifying the mutation in the ALDH7A1 gene in chromosome 5q3l. An 8-year-old Indian girl presented with severe developmental delay and seizures and was found to have pyridoxine-dependent epilepsy owing to an antiquitin mutation. Genetic evaluation of the parents allowed antenatal diagnosis to be made during the next pregnancy. PMID- 23925288 TI - Treatment of congenital chylothorax with octreotide in a hydropic preterm infant. AB - Congenital chylothorax is rare in preterm infants. While most cases respond to conservative treatment, a few require surgery. Treatment with intravenous octreotide has been reported to have varying success in preterm infants. A fetus was diagnosed with bilateral hydrothoraces at 29 weeks of gestation and repeated thoracocentesis was performed antenatally to allow growth of the lungs. She was delivered electively at 32 weeks by caesarean section. Hydrops fetalis was confirmed and chest tubes were inserted bilaterally soon after birth. Intravenous octreotide was commenced on day 4 of life, titrated to a maximum of 10 MUg/kg/hr for a total of 28 days. Hydrothorax resolved at day 30 and total parenteral nutrition was given for a total of 37 days. She was successfully extubated on day 40 of life and discharged on day 80. On review at 6 months of age, she was thriving and developing normally. PMID- 23925289 TI - Rosai-Dorfman disease presenting as mediastinal lymphadenopathy: case report and review of the literature. AB - A 6-year-old boy presented with recurrent pneumonia and diarrhoea for 3 years. He had extensive mediastinal lymphadenopathy and atelectasis with low serum levels of IgA, IgG and IgG3. An inguinal lymph node biopsy demonstrated histological and histochemical features of Rosai-Dorfman disease. There was emperipolesis and histiocytes were immune-positive for S100 proteins. He responded to corticosteroids and regular infusions of immunoglobulins. PMID- 23925290 TI - Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B. AB - Hepatitis B virus (HBV) is a major human pathogen that causes immune-mediated hepatitis. Successful immunity to HBV is age dependent: viral clearance occurs in most adults, whereas neonates and young children usually develop chronic infection. Using a mouse model of HBV infection, we sought mechanisms underpinning the age-dependent outcome of HBV and demonstrated that hepatic macrophages facilitate lymphoid organization and immune priming within the adult liver and promote successful immunity. In contrast, lymphoid organization and immune priming was greatly diminished in the livers of young mice, and of macrophage-depleted adult mice, leading to abrogated HBV immunity. Furthermore, we found that CXCL13, which is involved in B lymphocyte trafficking and lymphoid architecture and development, is expressed in an age-dependent manner in both adult mouse and human hepatic macrophages and plays an integral role in facilitating an effective immune response against HBV. Taken together, these results identify some of the immunological mechanisms necessary for effective control of HBV. PMID- 23925291 TI - Nanoparticle-based flow virometry for the analysis of individual virions. AB - While flow cytometry has been used to analyze the antigenic composition of individual cells, the antigenic makeup of viral particles is still characterized predominantly in bulk. Here, we describe a technology, "flow virometry," that can be used for antigen detection on individual virions. The technology is based on binding magnetic nanoparticles to virions, staining the virions with monoclonal antibodies, separating the formed complexes with magnetic columns, and characterizing them with flow cytometers. We used this technology to study the distribution of two antigens (HLA-DR and LFA-1) that HIV-1 acquires from infected cells among individual HIV-1 virions. Flow virometry revealed that the antigenic makeup of virions from a single preparation is heterogeneous. This heterogeneity could not be detected with bulk analysis of viruses. Moreover, in two preparations of the same HIV-1 produced by different cells, the distribution of antigens among virions was different. In contrast, HIV-1 of two different HIV-1 genotypes replicating in the same cells became somewhat antigenically similar. This nanotechnology allows the study of virions in bodily fluids without virus propagation and in principle is not restricted to the analysis of HIV, but can be applied to the analysis of the individual surface antigenic makeup of any virus. PMID- 23925292 TI - Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity. AB - Retinoids are structurally related derivatives of vitamin A and are required for normal vision as well as cell proliferation and differentiation. Clinically, retinoids are effective in treating many skin disorders and cancers. Application of retinoids evokes substantial irritating side effects, including pain and inflammation; however, the precise mechanisms accounting for the sensory hypersensitivity are not understood. Here we show that both naturally occurring and synthetic retinoids activate recombinant or native transient receptor potential channel vanilloid subtype 1 (TRPV1), an irritant receptor for capsaicin, the pungent ingredient of chili peppers. In vivo, retinoids produced pain-related behaviors that were either eliminated or significantly reduced by genetic or pharmacological inhibition of TRPV1 function. These findings identify TRPV1 as an ionotropic receptor for retinoids and provide cellular and molecular insights into retinoid-evoked hypersensitivity. These findings also suggest that selective TRPV1 antagonists are potential therapeutic drugs for treating retinoid induced sensory hypersensitivity. PMID- 23925293 TI - Increased Fanconi C expression contributes to the emergency granulopoiesis response. AB - Emergency granulopoiesis is a component of the innate immune response that is induced in response to infectious or inflammatory challenge. It is characterized by the rapid expansion and differentiation of granulocyte/monocyte progenitor (GMP) populations, which is due in part to a shortened S-phase of the cell cycle. We found that IRF8 (also known as ICSBP), an interferon regulatory transcription factor that activates phagocyte effector genes during the innate immune response, activates the gene encoding Fanconi C (Fancc) in murine myeloid progenitor cells. Moreover, IRF8-induced Fancc transcription was augmented by treatment with IL 1beta, an essential cytokine for emergency granulopoiesis. The Fanconi pathway participates in repair of stalled or collapsed replication forks during DNA replication, leading us to hypothesize that the Fanconi pathway contributes to genomic stability during emergency granulopoiesis. In support of this hypothesis, Fancc(-/-) mice developed anemia and neutropenia during repeated, failed episodes of emergency granulopoiesis. Failed emergency granulopoiesis in Fancc(-/-) mice was associated with excess apoptosis of HSCs and progenitor cells in the bone marrow and impaired HSC function. These studies have implications for understanding the pathogenesis of bone marrow failure in Fanconi anemia and suggest possible therapeutic approaches. PMID- 23925294 TI - Rice-based oral antibody fragment prophylaxis and therapy against rotavirus infection. AB - Rotavirus-induced diarrhea is a life-threatening disease in immunocompromised individuals and in children in developing countries. We have developed a system for prophylaxis and therapy against rotavirus disease using transgenic rice expressing the neutralizing variable domain of a rotavirus-specific llama heavy chain antibody fragment (MucoRice-ARP1). MucoRice-ARP1 was produced at high levels in rice seeds using an overexpression system and RNAi technology to suppress the production of major rice endogenous storage proteins. Orally administered MucoRice-ARP1 markedly decreased the viral load in immunocompetent and immunodeficient mice. The antibody retained in vitro neutralizing activity after long-term storage (>1 yr) and boiling and conferred protection in mice even after heat treatment at 94 degrees C for 30 minutes. High-yield, water-soluble, and purification-free MucoRice-ARP1 thus forms the basis for orally administered prophylaxis and therapy against rotavirus infections. PMID- 23925296 TI - Fabrication of artificial toroid nanostructures by modified beta-sheet peptides. AB - Facial peptide P1 carrying repeating hydrophobic and hydrophilic residues as well as lysine terminals self-assemble into uniform toroid structures. The sensitive balance between the hydrophobic interactions and electrostatic repulsion dominates the formation of highly curved assemblies. PMID- 23925295 TI - Type III TGF-beta receptor downregulation generates an immunotolerant tumor microenvironment. AB - Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-beta receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-beta signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor expressed TGFBR3/sTGFBR3 enhanced TGF-beta signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3 dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-beta inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment. PMID- 23925297 TI - Practice gaps: Evaluating the clinical utility of autoantibodies in morphea. PMID- 23925302 TI - Interior. With Piano and Woman in Black (Strandgade 30): Vilhelm Hammershoi. PMID- 23925303 TI - Bayesian analysis of posttest predictive value of screening instruments for the psychosis high-risk state. PMID- 23925298 TI - The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. AB - Autophagy is a cellular recycling process that has an important anti-aging role, but the underlying molecular mechanism is not well understood. The mammalian transcription factor EB (TFEB) was recently shown to regulate multiple genes in the autophagy process. Here we show that the predicted TFEB orthologue HLH-30 regulates autophagy in Caenorhabditis elegans and, in addition, has a key role in lifespan determination. We demonstrate that hlh-30 is essential for the extended lifespan of Caenorhabditis elegans in six mechanistically distinct longevity models, and overexpression of HLH-30 extends lifespan. Nuclear localization of HLH-30 is increased in all six Caenorhabditis elegans models and, notably, nuclear TFEB levels are augmented in the livers of mice subjected to dietary restriction, a known longevity-extending regimen. Collectively, our results demonstrate a conserved role for HLH-30 and TFEB in autophagy, and possibly longevity, and identify HLH-30 as a uniquely important transcription factor for lifespan modulation in Caenorhabditis elegans. PMID- 23925305 TI - The changing psychology of culture from 1800 through 2000. AB - The Google Books Ngram Viewer allows researchers to quantify culture across centuries by searching millions of books. This tool was used to test theory-based predictions about implications of an urbanizing population for the psychology of culture. Adaptation to rural environments prioritizes social obligation and duty, giving to other people, social belonging, religion in everyday life, authority relations, and physical activity. Adaptation to urban environments requires more individualistic and materialistic values; such adaptation prioritizes choice, personal possessions, and child-centered socialization in order to foster the development of psychological mindedness and the unique self. The Google Ngram Viewer generated relative frequencies of words indexing these values from the years 1800 to 2000 in American English books. As urban populations increased and rural populations declined, word frequencies moved in the predicted directions. Books published in the United Kingdom replicated this pattern. The analysis established long-term relationships between ecological change and cultural change, as predicted by the theory of social change and human development (Greenfield, 2009). PMID- 23925306 TI - The polarizing effect of arousal on negotiation. AB - In this research, we examined the impact of physiological arousal on negotiation outcomes. Conventional wisdom and the prescriptive literature suggest that arousal should be minimized given its negative effect on negotiations, whereas prior research on misattribution of arousal suggests that arousal might polarize outcomes, either negatively or positively. In two experiments, we manipulated arousal and measured its effect on subjective and objective negotiation outcomes. Our results support the polarization effect. When participants had negative prior attitudes toward negotiation, arousal had a detrimental effect on outcomes, whereas when participants had positive prior attitudes toward negotiation, arousal had a beneficial effect on outcomes. These effects occurred because of the construal of arousal as negative or positive affect, respectively. Our findings have important implications not only for negotiation, but also for research on misattribution of arousal, which previously has focused on the target of evaluation, in contrast to the current research, which focused on the critical role of the perceiver. PMID- 23925307 TI - From fan to fat? Vicarious losing increases unhealthy eating, but self affirmation is an effective remedy. AB - Using archival and experimental data, we showed that vicarious defeats experienced by fans when their favorite football team loses lead them to consume less healthy food. On the Mondays following a Sunday National Football League (NFL) game, saturated-fat and food-calorie intake increase significantly in cities with losing teams, decrease in cities with winning teams, and remain at their usual levels in comparable cities without an NFL team or with an NFL team that did not play. These effects are greater in cities with the most committed fans, when the opponents are more evenly matched, and when the defeats are narrow. We found similar results when measuring the actual or intended food consumption of French soccer fans who had previously been asked to write about or watch highlights from victories or defeats of soccer teams. However, these unhealthy consequences of vicarious defeats disappear when supporters spontaneously self-affirm or are given the opportunity to do so. PMID- 23925309 TI - Reversible switching of slow magnetic relaxation in a classic lanthanide metal organic framework system. AB - The reversible sorption-desorption of terminal coordinated water molecules and the guest molecules can switch slow magnetic relaxation in a classic lanthanide metal-organic framework system, Dy(BTC)(H2O).DMF and Dy(BTC). PMID- 23925308 TI - Enacting cultural interests: how intergroup contact reduces prejudice by sparking interest in an out-group's culture. AB - In the present research, we examined the hypothesis that cues of social connectedness to a member of another social group can spark interest in the group's culture, and that such interest, when freely enacted, contributes to reductions in intergroup prejudice. In two pilot studies and Experiment 1, we found that extant and desired cross-group friendships and cues of social connectedness to an out-group member predicted increased interest in the target group's culture. In Experiments 2 and 3, we manipulated cues of social connectedness between non-Latino American participants and a Latino American (i.e., Mexican American) peer and whether participants freely worked with this peer on a Mexican cultural task. This experience reduced the participants' implicit bias against Latinos, an effect that was mediated by increased cultural engagement, and, 6 months later in an unrelated context, improved intergroup outcomes (e.g., interest in interacting with Mexican Americans; Experiment 4). The Discussion section addresses the inter- and intragroup benefits of policies that encourage people to express and share diverse cultural interests in mainstream settings. PMID- 23925310 TI - Water detection by "turn on" fluorescence of the quinone-containing complexes [Ru(phen)2(1,10-phenanthroline-5,6-dione)2+] and [Ru(phenanthroline-5,6 dione)3]2+. AB - Addition of water to the quinone functions in [Ru(phen)2(pdn)](2+) (1) and [Ru(pdn)3](2+) (2) (where phen = 1,10-phenanthroline and pdn = 1,10 phenanthroline-5,6-dione) turns on fluorescence at 605 nm, as formation of the geminal diol eliminates the predominant quinone-based non-radiative decay pathway and gives rise to a long-lived (3)MLCT state similar in nature to that seen in [Ru(phen)3](2+). Using NMR, the equilibrium constant for the hydration reaction of 1 in acetonitrile was determined to be 0.0253. From this data and experimental fitting of the luminescent titration data, the equilibrium constant for 2 of 1.62 * 10(-5) and emission yields for hydrated 1 and 2 were determined. Interestingly, all three quinone functions must be hydrated in 2 for luminescence, which is why the equilibrium constants vary so much. The 'turn on' luminescence allows for a very sensitive detection of water in aprotic solvents such as acetonitrile. PMID- 23925312 TI - Towards systematically improvable models for actinides in condensed phase: the electronic spectrum of uranyl in Cs2UO2Cl4 as a test case. AB - In this work we explore the use of frozen density embedding [Gomes et al., Phys. Chem. Chem. Phys., 2008, 10, 5353] as a way to construct models of increasing sophistication for describing the low-lying electronic absorption spectra of UO2(2+) in the Cs2UO2Cl4 crystal. We find that a relatively simple embedding model, in which all but the UO2(2+) unit are represented by an embedding potential, can already describe the main spectral features and the main environment effects can be attributed to the four chloride ions situated at the UO2(2+) equatorial plane. Contributions from species further away, albeit small, are found to be important for reaching a close agreement with experimentally observed quantities such as the excited states' relative positions. These findings suggest that such an embedding approach is a viable alternative to supermolecular calculations employing larger models of actinyl species in condensed phase. Nevertheless, we observe a slight red shift of the excitation energies calculated with our models compared to experimental results, and attribute this discrepancy to inaccuracies in the underlying structural parameters. PMID- 23925313 TI - Experimental evidence of a cyclopropylcarbinyl conjugative electronic effect. AB - Bicyclo[3.2.0]hept-2-enes undergo thermal rearrangement to norbornenes via diradical transition structures. The synthesis of exo-7 cyclopropylbicyclo[3.2.0]hept-2-ene has been achieved by cycloaddition of cyclopentadiene and cyclopropylketene, generated by treatment of cyclopropylacetyl chloride with triethylamine. A comparison of the cyclopropyl substituent effect with that of other C7 substituents provides experimental evidence of an electron-donating conjugative effect on the transient diradical transition structure in the thermal reaction of exo-7 cyclopropylbicyclo[3.2.0]hept-2-ene. PMID- 23925311 TI - PPR proteins shed a new light on RNase P biology. AB - A fast growing number of studies identify pentatricopeptide repeat (PPR) proteins as major players in gene expression processes. Among them, a subset of PPR proteins called PRORP possesses RNase P activity in several eukaryotes, both in nuclei and organelles. RNase P is the endonucleolytic activity that removes 5' leader sequences from tRNA precursors and is thus essential for translation. Before the characterization of PRORP, RNase P enzymes were thought to occur universally as ribonucleoproteins, although some evidence implied that some eukaryotes or cellular compartments did not use RNA for RNase P activity. The characterization of PRORP reveals a two-domain enzyme, with an N-terminal domain containing multiple PPR motifs and assumed to achieve target specificity and a C terminal domain holding catalytic activity. The nature of PRORP interactions with tRNAs suggests that ribonucleoprotein and protein-only RNase P enzymes share a similar substrate binding process. PMID- 23925314 TI - Histidine-rich proteins in prokaryotes: metal homeostasis and environmental habitat-related occurrence. AB - Increasing amounts of histidine-rich proteins (HRPs) have been found in microorganisms. We systematically analyzed the proteomes of 675 prokaryotes including 52 archaea and 623 bacteria for histidine-rich motifs (HRMs). We show that HRPs are widespread in prokaryotic proteomes, with the majority being involved in metal homeostasis. HRPs are frequently found in the proteomes of certain orders of rhizobia and pathogenic Gram-negative bacteria, but are essentially absent in obligate intracellular pathogenic species. The occurrence of HRPs in the proteomes of prokaryotes is related to their habitats. We further revealed a class of globally histidine-rich bacterial proteins. This approach can readily be used to identify other single amino acid rich motifs (and proteins) in microbial proteomes to facilitate the exploration of their functions. PMID- 23925315 TI - Keratoconus. PMID- 23925316 TI - Keratoconus and corneal collagen cross-linking. PMID- 23925317 TI - The paradigm change in keratoconus therapy. PMID- 23925318 TI - Epidemiology of keratoconus. AB - Prevalence of keratoconus is variable in different parts of the world. Environmental and ethnic factors and the cohort of patients selected for such studies may explain the wide variation in the reported rates. Family history, gender differences, asymmetry in the two eyes, association with ocular rubbing, and natural history of disease are discussed. PMID- 23925319 TI - Genetic and genomic perspective to understand the molecular pathogenesis of keratoconus. AB - Keratoconus (KC; Mendelian Inheritance in Man (OMIM) 14830) is a bilateral, progressive corneal defect affecting all ethnic groups around the world. It is the leading cause of corneal transplantation. The age of onset is at puberty, and the disorder is progressive until the 3 rd -4 th decade of life when it usually arrests. It is one of the major ocular problems with significant social and economic impacts as the disease affects young generation. Although genetic and environmental factors are associated with KC, but the precise etiology is still elusive. Results from complex segregation analysis suggests that genetic abnormalities may play an essential role in the susceptibility to KC. Due to genetic heterogeneity, a recent study revealed 17 different genomic loci identified in KC families by linkage mapping in various populations. The focus of this review is to provide a concise update on the current knowledge of the genetic basis of KC and genomic approaches to understand the disease pathogenesis. PMID- 23925321 TI - Keratoconus: a biomechanical perspective on loss of corneal stiffness. AB - Keratoconus (KC) is progressive disease of corneal thinning, steepening and collagen degradation. Biomechanics of the cornea is maintained by the intricate collagen network, which is responsible for its unique shape and function. With the disruption of this collagen network, the cornea loses its shape and function, resulting in progressive visual degradation. While KC is essentially a stromal disease, there is evidence that the epithelium undergoes significant thinning similar to the stroma. Several topographical approaches have been developed to detect KC early. However, it is now hypothesized that biomechanical destabilization of the cornea may precede topographic evidence of KC. Biomechanics of KC has been investigated only to a limited extent due to lack of in vivo measurement techniques and/or devices. In this review, we focus on recent work performed to characterize the biomechanical characteristics of KC. PMID- 23925320 TI - Proteomic and gene expression patterns of keratoconus. AB - Keratoconus is a progressive corneal thinning disease associated with significant tissue remodeling activities and activation of a variety of signaling networks. However, it is not understood how differential gene and protein expression direct function in keratoconus corneas to drive the underlying pathology, ectasia. Research in the field has focused on discovering differentially expressed genes and proteins and quantifying their levels and activities in keratoconus patient samples. In this study, both microarray analysis of total ribonucleic acid (RNA) and whole proteome analyses are carried out using corneal epithelium and tears from keratoconus patients and compared to healthy controls. A number of structural proteins, signaling molecules, cytokines, proteases, and enzymes have been found to be deregulated in keratoconus corneas. Together, the data provide clues to the complex process of corneal degradation which suggest novel ways to clinically diagnose and manage the disease. This review will focus on discussing these recent advances in the knowledge of keratoconus biology from a gene expression and function point-of-view. PMID- 23925322 TI - Imaging modalities in keratoconus. AB - Diagnosis of keratoconus has greatly improved from simple clinical diagnosis with the advent of better diagnostic devices like corneal topographers based on placido disc, elevation based topographers and lately optical coherence tomography (OCT). These instruments are quite sensitive to pick up early keratoconus, which could help refractive surgeons to avoid serious complications like ectasia following keratorefractive surgeries. Each of these instruments has their advantages and disadvantages; in spite of that each one of them has its own place in the clinical practice. Currently, placido disc based topographers are the most commonly used topographers all over the world. There are many different companies making such devices, which follow the different techniques and color for the display. Due to these differences they are not directly comparable to each other. Various quantitative indices based on these topographers have been suggested and validated by different authors to aid in the diagnosis and quantification of keratoconus. OCT with its higher resolution and deeper penetration has created its place in the diagnostic armamentarium for keratoconus. PMID- 23925323 TI - Scheimpflug imaging for keratoconus and ectatic disease. AB - Scheimpflug cross-sectioning anterior segment imaging offers significant advantages over traditional placido based curvature analysis and ultrasound pachymetry. The accurate measurement of both the anterior and posterior corneal surfaces and the anterior and posterior lens allows for the creation of a three dimensional reconstruction of the anterior segment. Changes on both the posterior cornea and/or corneal thickness map are earlier indicators of ectatic change than would otherwise be identifiable with only anterior curvature and ultrasonic pachymetry. Scheimpflug imaging also covers significantly more of the cornea than was possible with placido based devices. This added coverage is critical in the proper diagnosis of peripheral diseases such as pellucid marginal degeneration (PMD). PMID- 23925324 TI - Ocular allergy and keratoconus. AB - Keratoconus is the most common corneal ectatic disorder, the cause of which is largely unknown. Many factors have been implicated, and the ocular allergy is being one of them. The commonly proposed pathogenesis includes the release of inflammatory mediators due to eye rubbing which may alter the corneal collagen and lead to corneal ectasias. The onset of keratoconus is often early in cases associated with allergy and routine corneal topography may detect subtle forms of keratoconus. These cases may require early keratoplasty and are at an increased risk of having acute corneal hydrops. Surgical outcomes are similar to primary keratoconus cases. However, post-operative epithelial breakdown may be a problem in these cases. Control of allergy and eye rubbing is the best measure to prevent corneal ectasias in cases of ocular allergy. PMID- 23925325 TI - Contact lens in keratoconus. AB - Contact lenses are required for the visual improvement in patients with keratoconus. Various contact lens options, such as rigid gas permeable (RGP) lenses, soft and soft toric lenses, piggy back contact lenses (PBCL), hybrid lenses and scleral lenses are availble. This article discusses about selection of a lens depending on the type of keratoconus and the fitting philosophies of various contact lenses including the starting trial lens. A Medline search was carried out for articles in the English language with the keywords keratoconus and various contact lenses such as Rose k lens, RGP lens, hybrid lens, scleral lens and PBCL. PMID- 23925326 TI - The theory and art of corneal cross-linking. AB - Before the discovery of corneal cross-linking (CXL), patients with keratoconus would have had to undergo corneal transplantation, or wear rigid gas permeable lenses (RGPs) that would temporarily flatten the cone, thereby improving the vision. The RGP contact lens (CL) would not however alter the corneal stability and if the keratoconus was progressive, the continued steepening of the cone would occur under the RGP CL. To date, the Siena Eye has been the largest study to investigate long term effects of standard CXL. Three hundred and sixty-three eyes were treated and monitored over 4 years, producing reliable long-term results proving long-term stability of the cornea by halting the progression of keratoconus, and proving the safety of the procedure. Traditionally, CXL requires epithelial removal prior to corneal soakage of a dextran-based 0.1% riboflavin solution, followed by exposure of ultraviolet-A (UV-A) light for 30 min with an intensity of 3 mW/cm2. A series of in vitro investigations on human and porcine corneas examined the best treatment parameters for standard CXL, such as riboflavin concentration, intensity, wavelength of UV-A light, and duration of treatment. Photochemically, CXL is achieved by the generation of chemical bonds within the corneal stroma through localized photopolymerization, strengthening the cornea whilst minimizing exposure to the surrounding structures of the eye. In vitro studies have shown that CXL has an effect on the biomechanical properties of the cornea, with an increased corneal rigidity of approximately 70%. This is a result of the creation of new chemical bonds within the stroma. PMID- 23925327 TI - Collagen cross linking: current perspectives. AB - Keratoconus is a common ectatic disorder occurring in more than 1 in 1,000 individuals. The condition typically starts in adolescence and early adulthood. It is a disease with an uncertain cause and its progression is unpredictable, but in extreme cases, vision deteriorates and can require corneal transplant surgery. Corneal collagen cross-linking (CCL) with riboflavin (C3R) is a recent treatment option that can enhance the rigidity of the cornea and prevent disease progression. Since its inception, the procedure has evolved with newer instrumentation, surgical techniques, and is also now performed for expanded indications other than keratoconus. With increasing experience, newer guidelines regarding optimization of patient selection, the spectrum of complications and their management, and combination procedures are being described. This article in conjunction with the others in this issue, will try and explore the uses of collagen cross-linking (CXL) in its current form. PMID- 23925328 TI - Collagen cross-linking in thin corneas. AB - Collagen cross-linking (CXL) has become the standard of care for progressive keratoconus, after numerous clinical studies have established its efficacy and safety in suitably selected eyes. The standard protocol is applicable in eyes which have a minimum corneal thickness of 400 MUm after epithelial debridement. This prerequisite was stipulated to protect the corneal endothelium and intraocular tissues from the deleterious effect of ultraviolet-A (UVA) radiation. However, patients with keratoconus often present with corneal thickness of less than 400 MUm and could have otherwise benefited from this procedure. A few modifications of the standard procedure have been suggested to benefit these patients without a compromise in safety. Transepithelial cross-linking, pachymetry-guided epithelial debridement before cross-linking, and the use of hypoosmolar riboflavin are some of the techniques that have been attempted. Although clinical data is limited at the present time, these techniques are worth considering in patients with thin corneas. Further studies are needed to scientifically establish their efficacy and safety. PMID- 23925329 TI - Newer protocols and future in collagen cross-linking. AB - Corneal Cross-Linking (CXL) is an established surgical procedure for the treatment of corneal disorders such as corneal ectasia and keratoconus. This method of treatment stabilises the corneal structure and increases rigidity, reducing the requirement for corneal transplantation. Since its development, many scientific studies have been conducted to investigate ways of improving the procedure. Biomechanical stability of the cornea after exposure to UV-A light, and the effect of shortening procedure time has been some of the many topics explored. PMID- 23925330 TI - Current status of accelerated corneal cross-linking. AB - Corneal cross-linking with riboflavin is a technique to stabilize or reduce corneal ectasia, in diseases such as keratoconus and post-laser-assisted in situ keratomileusis (LASIK) ectasia. There is an interest by patient as well as clinicians to reduce the overall treatment time. Especially, the introduction of corneal cross-linking in combination with corneal laser surgery demands a shorter treatment time to assure a sufficient patient flow. The principles and techniques of accelerated corneal cross-linking is discussed. PMID- 23925331 TI - Review of current indications for combined very high fluence collagen cross linking and laser in situ keratomileusis surgery. AB - In this brief review we will discuss the reasoning and evolution of our current use of combined very high-fluence collagen crosslinking and laser in situ keratomileusis. Several presentations and pertinent publications are reviewed, along with the key steps of the enhanced LASIK procedure. Long term outcome data support the safety and efficacy of LASIK Xtra in stabilizing myopic but also hyperopic LASIK results.In conclusion, we have compelling evidence that LASIK Xtra is a safe and effective adjunct. PMID- 23925332 TI - Long-term results of cornea collagen cross-linking with riboflavin for keratoconus. AB - Corneal collagen cross-linking with riboflavin and UVA light (CXL) is the only method designed to arrest the progression of keratoconus. Visual improvement generally starts 3 months after treatment. Reduction is coma seen on aberrometry in early postoperative phase is also responsible for the improvement in visual acuity. In the light of currently available data we can thus say that CXL is a safe procedure that is successful in arresting keratoconus. PMID- 23925333 TI - Management of pediatric keratoconus - evolving role of corneal collagen cross linking: an update. AB - Pediatric keratoconus demonstrates several distinctive management issues in comparison with adult keratoconus with respect to under-diagnosis, poor compliance and modifications in treatment patterns. The major concerns comprise of the accelerated progression of the disease in the pediatric age group and management of co-morbidities such as vernal keratoconjuntivitis. Visual impairment in pediatric patients may affect social and educational development and overall negatively impact their quality of life. The treatment algorithm between adults and pediatric keratoconus has been similar; comprising mainly of visual rehabilitation with spectacles, contacts lenses (soft or rigid) and keratoplasty (lamellar or penetrating) depending on the stage of the disease. There is a paradigm shift in the management of keratoconus, a new treatment modality, corneal collagen crosslinking (CXL), has been utilized in adult keratoconic patients halting the progression of the disease. CXL has been utilized for over a 10 year period and based on the evidence of efficacy and safety in the adult population; this treatment has been recently utilized in management of pediatric keratoconus. This article will present an update about current management of pediatric keratoconus with special focus on CXL in this age group. PMID- 23925334 TI - Cross-linking for microbial keratitis. AB - The success of collagen cross-linking as a clinical modality to modify the clinical course in keratoconus seems to have fueled the search for alternative applications for this treatment. Current clinical data on its efficacy is limited and laboratory data seems to indicate that it performs poorly against resistant strains of bacteria and against slow growing organisms. However, the biological plausibility of crosslinking and the lack of effective strategies in managing infections with these organisms continue to focus attention on this potential treatment. Well-conducted experimental and clinical studies with controls are required to answer the questions of its efficacy in future. PMID- 23925335 TI - Topography-guided custom ablation treatment for treatment of keratoconus. AB - Keratoconus is a progressive ectatic disorder of the cornea which often presents with fluctuating refraction and high irregular astigmatism. Correcting the vision of these patients is often a challenge because glasses are unable to correct the irregular astigmatism and regular contact lenses may not fit them very well. Topography-guided custom ablation treatment (T-CAT) is a procedure of limited ablation of the cornea using excimer laser with the aim of regularizing the cornea, improving the quality of vision and possibly contact lens fit. The aim of the procedure is not to give a complete refractive correction. It has been tried with a lot of success by various groups of refractive surgeons around the world but a meticulous and methodical planning of the procedure is essential to ensure optimum results. In this paper, we attempt to elucidate the planning for a T-CAT procedure for various types of cones and asphericities. PMID- 23925336 TI - Intrastromal corneal ring segments for management of keratoconus. AB - Keratoconus is a progressive corneal ectasia, which can be managed both by conservative measures like glasses or contact lenses in non-progressive cases or surgical procedures like collagen crosslinking (CXL) with or without adjuvant measures like intrastromal corneal rings segments (ICRS) or topography guided ablation. Various kinds of ICRS are available to the surgeon, but it is most essential to be able to plan the implantation of the ring to optimize outcomes. AIMS: The aim of this study is to evaluate the visual outcome and progression in patients of keratoconus implanted with ICRS. MATERIALS AND METHODS: Two different types of ICRS-Intacs (Addition Technology) and Kerarings (Mediphacos Inc.) were implanted in 2 different cohorts of patients and were followed-up to evaluate the outcome of the procedure. All patients underwent a complete ocular examination including best spectacle corrected visual acuity, slit lamp examination fundus examination, corneal topography and pachymetry. The ICRS implantation is done with CXL to stop the progression of the disease. Improvement in uncorrected visual acuity (UCVA), best spectacle corrected visual acuity and topographic changes were analyzed. RESULTS: A significant improvement in keratometry and vision was seen in both groups. CONCLUSION: ICRS have been found to reduce corneal irregularity and flatten keratometry with improvement in UCVA and best corrected visual acuity. PMID- 23925337 TI - Toric implantable collamer lens for keratoconus. AB - Keratoconus is a progressive non-inflammatory thinning of the cornea that induces myopia and irregular astigmatism and decreases the quality of vision due to monocular diplopia, halos, or ghost images. Keratoconus patients unfit for corneal procedures and intolerant to refractive correction by spectacles or contact lenses have been implanted toric posterior chamber phakic intraocular lenses (PC pIOLs) alone or combined with other surgical procedures to correct the refractive errors associated with keratoconus as an off label procedure with special informed consent from the patients. Several reports attest to the safety and efficacy of the procedure, though the associated corneal higher order aberrations would have an impact on the final visual quality. PMID- 23925338 TI - Acute corneal hydrops in keratoconus. AB - Acute corneal hydrops is a condition characterized by stromal edema due to leakage of aqueous through a tear in descemet membrane. The patient presents with sudden onset decrease in vision, photophobia, and pain. Corneal thinning and ectasias combined with trivial trauma to the eye mostly by eye rubbing is considered as the underlying cause. With conservative approach self-resolution takes around 2 to 3 months. Surgical intervention is required in cases of non resolution of corneal edema to avoid complications and for early visual rehabilitation. Intracameral injection of air or gas such as perflouropropane is the most common surgical procedure done. Recent investigative modality such as anterior segment optical coherence tomography is an extremely useful tool for diagnosis, surgical planning, and postoperative follow up. Resolution of hydrops may improve the contact lens tolerance and visual acuity but most cases require keratoplasty for visual rehabilitation. PMID- 23925339 TI - Deep anterior lamellar keratoplasty in the management of keratoconus. AB - Advanced cases of keratoconus often require surgical intervention to restore corneal anatomy and improve eyesight. Penetrating keratoplasty (PK) although commonly performed has potential risk of immunological rejection and is now no longer automatically the first choice of surgery. DALK procedures have evolved, which allows surgical replacement of recipient's corneal stroma, leaving behind healthy descemet membrane (DM) and endothelium. This reduces the risk of allograft endothelial rejection and late graft failure. In recent times, DALK techniques have led to significant improvements in visual outcome and current results are comparable to PK. Big bubble technique of DALK has become the most popular among the various surgical techniques described. Manual near DM DALK also gives good outcome although the visual recovery is often delayed. Future integration of femtosecond laser technology along with diagnostic imaging technology is likely to further improve outcomes of DALK in keratoconus. PMID- 23925340 TI - Femtosecond laser enabled keratoplasty for advanced keratoconus. AB - PURPOSE: To assess the efficacy and advantages of femtosecond laser enabled keratoplasty (FLEK) over conventional penetrating keratoplasty (PKP) in advanced keratoconus. MATERIALS AND METHODS: Detailed review of literature of published randomized controlled trials of operative techniques in PKP and FLEK. RESULTS: Fifteen studies were identified, analyzed, and compared with our outcome. FLEK was found to have better outcome in view of better and earlier stabilization uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), and better refractive outcomes with low astigmatism as compared with conventional PKP. Wound healing also was noticed to be earlier, enabling early suture removal in FLEK. CONCLUSIONS: Studies relating to FLEK have shown better results than conventional PKP, however further studies are needed to assess the safety and intraoperative complications of the procedure. PMID- 23925341 TI - Continuous theta-burst stimulation of the right superior temporal gyrus impairs self-motion perception. AB - Sensory input from the semicircular canals (SCC) and otolith organs is centrally combined with signals from other sensory modalities to continuously update the internal estimate of self-motion. Constant velocity vertical on-axis rotation leads to decay of the nystagmus response from the horizontal SCC and of perceived angular velocity (PAV), and when the rotation stops, a similar oppositely directed post-rotatory response occurs. Case reports and electrical stimulation studies suggest an involvement of the temporo-peri-Sylvian vestibular cortex in generating the PAV. Here, we transiently inhibited the right superior temporal gyrus (STG) by use of continuous theta-burst stimulation (cTBS) and predicted an accelerated decay of PAV compared to controls (n = 5 control session first, n = 1 cTBS session first). Constant velocity (100 degrees /s) vertical on-axis rotations were applied over 75 s before (1 block) and after (3 blocks) cTBS over the right STG in six subjects. Breaks between the rotations (75 s) were initiated by abrupt stops. By use of a rotating potentiometer, subjects indicated the PAV during and after the chair rotations. Simultaneously eye positions were recorded using a scleral search coil. One subject was excluded for per-rotary analysis. Early after cTBS, the post-rotary PAV decay time constant (DTC) was significantly (9.4 +/- 5.7 vs. 13.6 +/- 5.9 s; p = 0.049) reduced (no directionality to this effect observed). Overall, post-rotary PAV showed a trend toward shortened DTC compared to the control trials (p = 0.086) in the first 25 min after cTBS, while per-rotary PAV was not significantly changed. Per-rotary and post-rotary aVOR DTC were not significantly changed after cTBS (p > 0.05). These findings support the hypothesis that the right STG is involved in mediating self-motion perception and can be modulated by cTBS. PMID- 23925343 TI - Assessing work environments: an exercise in self-care. PMID- 23925342 TI - Excitotoxic injury to thoracolumbar gray matter alters sympathetic activation and thermal pain sensitivity. AB - Studies of humans, monkeys and rodents have implicated combined gray and white matter damage as important for development of chronic pain following spinal cord injury (SCI). Below-level chronic pain and hyperalgesia following injury to the spinal white matter, including the spinothalamic tract (STT), can be enhanced by excitotoxic influences within the gray matter at the site of SCI. Also, excitotoxic injury of thoracic gray matter without interruption of the STT results in below-level heat hyperalgesia. The present study evaluates the possibility that thoracolumbar gray matter injury increases sensitivity to nociceptive heat stimulation by altering spinal sympathetic outflow. Thermal preferences of rats for heat (45 degrees C) versus cold (15 degrees C) were evaluated before and after thoracolumbar injections of quisqualic acid (QUIS). A pre-injury preference for heat changed to a post-injury preference for cold. Systemic activation of the sympathetic nervous system by restraint stress decreased the heat preference pre-injury and increased the cold preference post injury. The heat aversive effect of stress was magnified and prolonged post injury, compared to pre-injury. Also, peripheral sympathetic activation by nociceptive stimulation was evaluated pre- and post-injury by measuring thermal transfer through a hindpaw during stimulation with 44.5 degrees C. Skin temperature recordings revealed enhanced sympathetic activation by nociceptive heat stimulation following spinal QUIS injury. However, increased sympathetic activation with peripheral vasoconstriction should enhance cold aversion, in contrast to the observed increase in heat aversion. Thus, peripheral sympathetic vasoconstriction can be ruled out as a mechanism for heat hyperalgesia following excitotoxic gray matter injury. PMID- 23925344 TI - Holistic nursing: inspiration without perspiration? PMID- 23925345 TI - Relationships between flow experience, IKIGAI, and sense of coherence in Tai chi practitioners. AB - The purpose of this study was to examine the mental health effects of Tai chi on regular practitioners by investigating the relationships between flow experience, IKIGAI (Japanese: "Life worth living"), and sense of coherence. The results indicated that flow experience may influence IKIGAI and IKIGAI may influence sense of coherence; this suggests that IKIGAI may act as an intermediary between flow experience and sense of coherence. The results also indicated that the longer the Tai chi experience, the higher was the flow experience. PMID- 23925346 TI - Who is that stranger in the mirror? The mirror experience for elderly patients with dementia. AB - Use of the mirror is an everyday phenomenon for most individuals. There seems to be limited evidence-based studies that address mirror viewing and the appropriate use of mirrors for patients with dementia. Using a case study, the purpose of this study is to begin a dialogue with the nursing community on practical nursing interventions and the need for research in this area. PMID- 23925347 TI - The impact of chemotherapy in cancer patients: reflection on traditional Chinese symptom complex, cancer-related fatigue, and quality of life. AB - Traditional Chinese medicine is a trend in cancer holistic care. We found that patients undergoing chemotherapy had more traditional Chinese medicine symptom complexes with qi and blood deficiency and led poor quality of life and experienced fatigue. The traditional Chinese medicine theory based on qi and blood supply in cancer care deserves further research. PMID- 23925348 TI - A weekend and a lifetime: a linkage to empathy. AB - Introducing the complexities of today's health care environment to nursing students is challenging. This article relates an event-changing experience that led me to teach nursing students through storytelling. With instructors teaching from personal clinical experiences, students develop greater empathy and deliver more holistic nursing care, which is valued by all. PMID- 23925349 TI - Individual correlates of autonomy in activities of daily living of institutionalized elderly individuals: an exploratory study in a holistic perspective. AB - This study aimed at identifying the individual correlates of autonomy in activities of daily living (ADL) of 40 institutionalized elderly individuals. Results showed that balance skill and perception of physical functioning were significantly associated with ADL. Interventions on the physical functioning, both perceived and real, might have positive influence on the autonomy of institutionalized elderly individuals. PMID- 23925350 TI - Curiosity as holistic engagement: experiences of hospitalized patients as research participants. AB - Curiosity as holistic engagement in a recent research study between a researcher and participants is highlighted. Surgical inpatient participants initiated and extended interpersonal dialogue on the basis of their curiosity. It is argued that patient/participant curiosity should be encouraged because it is a positive component of holistic engagement and transformative in research processes. PMID- 23925351 TI - Effects of extra virgin olive oil phenolic compounds and the Mediterranean diet on cardiovascular health. PMID- 23925352 TI - High electrocatalytic activity of self-standing hollow NiCo2S4 single crystalline nanorod arrays towards sulfide redox shuttles in quantum dot-sensitized solar cells. AB - Self-standing single crystalline NiCo2S4 hollow nanorod arrays are prepared for catalysing the polysulfide redox couple in quantum dot-sensitized solar cells (QDSCs). The QDSCs using NiCo2S4 as a counter electrode (CE) achieved a power conversion efficiency of 4.22%, which exceeds the performance of QDSCs based on a Pt CE by 38.4%. PMID- 23925353 TI - [Disease-specific analgesia and sedation in critically ill patients]. PMID- 23925354 TI - [New tool to objectively measure and quantize non-steroidal antiinflammatory drugs (NSAIDs) intake: NSAIDs index]. PMID- 23925355 TI - [The value of nitrogen washout/washin method in assessing alveolar recruitment volume in acute lung injury patients]. AB - OBJECTIVE: To evaluate the precision and feasibility of nitrogen washout/washin method in assessing lung recruitment of acute lung injury (ALI) patients. METHODS: Fifteen ALI patients underwent mechanical ventilation were involved. Two positive end-expiratory pressure (PEEP) levels (high and low) were adjusted according to ARDSnet recommendations or measurement of transpulmonary pressure, each for 30 minutes. Tidal volume (Vt), plateau of airway pressure (Pplat), other respiratory mechanics, gas-exchange and hemodynamics were measured. End expiration lung volume (EELV) was measured at different PEEP levels through nitrogen washout/washin method, and formula (EELVhighPEEP-EELVlowPEEP) VtlowPEEP/(PplatlowPEEP-PEEPlowPEEP)*(PEEPhigh-PEEPlow) was used as recruitment (Rec-N2). Alveolar recruitment was measured using pressure-volume (P-V) curves (Rec-mes). Correlation and consistency of Rec-N2 and Rec-mes were compared by correlation analysis and Bland-Altman technique. RESULTS: PEEP titrated by ARDSnet recommendations or transpulmonary pressure were (7 +/- 2) cm H2O (1 cm H2O = 0.098 kPa) vs (14 +/- 5) cm H2O (P = 0.008); and there were significant differences in peak pressure (23 +/- 5) cm H2O vs (28 +/- 6) cm H2O, plateau of airway pressure (17 +/- 4)cm H2O vs (22 +/- 6) cm H2O, esophageal pressure, transpulmonary pressure and other respiratory mechanics between the two PEEP levels (P < 0.05). The P-V curve technique gave Rec-mes a value of 100 (-25 ~ 185)ml. The nitrogen washout/washin technique gave Rec-N2 a value of 180 (-19 ~ 255) ml, which showed a good correlation with a bias of 46 (8 ~ 80) ml (R(2) = 0.755, P < 0.0001). CONCLUSION: Nitrogen washout/washin technique can be used to determine lung recruitment volume of ALI patients. PMID- 23925356 TI - [An analysis of clinical characteristics of septic acute kidney injury by using criteria of Kidney Disease: Improving Global Outcomes]. AB - OBJECTIVE: To evaluate the value of Kidney Disease: Improving Global Outcomes (KDIGO) criteria in investigating clinical feature and prognosis of acute kidney injury (AKI) patients with sepsis in ICU. METHODS: Clinical data of patients with AKI defined by KDIGO criteria in ICU of Wuxi People's Hospital from June 2007 to June 2012 were collected. Clinical characteristics, prognosis and major risk factors of death of septic AKI patients were retrospectively analyzed. RESULTS: Of the enrolled 703 AKI patients, 395 (56.2%) were caused by sepsis (septic AKI), which indicated that sepsis mainly contributed to the causes of AKI. For septic AKI stratified by KDIGO classification, 146 (37.0%) patients belonged to AKI I, 154 (39.0%) to AKI II, and 95 (24.1%) to AKI III. Compared with the patients with non-septic AKI, septic AKI patients had greater APACHE II and SOFA score (25.1 +/ 4.9 vs 20.5 +/- 6.4, 12.9 +/- 2.6 vs 10.4 +/- 4.5; all P values < 0.05). Although there was no significant difference in baseline serum creatinine [(82.9 +/- 22.2) umol/L vs (83.1 +/- 30.0) umol/L, P > 0.05] between the two groups, patients with sepsis had higher serum creatinine [(143.5 +/- 21.6) umol/L vs (96.2 +/- 15.5)umol/L; P < 0.05], a higher proportion fulfilled KDIGO categories for both AKI II and III (63.0% vs 33.1%; P < 0.05), a higher renal replacement therapy (RRT) rate (22.3% vs 6.2%; P < 0.05) and a lower proportion of complete renal recovery (74.4% vs 82.8%) (all P values < 0.05). The 90-day mortality of septic AKI patients was higher than that of non-septic AKI patients (52.2% vs 34.1%; P < 0.05). Septic AKI, graded by KDIGO, was associated with an increased mortality. Logistic regression analysis showed that APACHEII score (OR = 5.451, 95%CI: 3.095 - 9.416), SOFA score (OR = 2.166, 95%CI: 1.964 - 4.515) and RRT (OR = 4.021, 95%CI: 2.975 - 6.324) were independent risk factors for mortality of septic AKI patients. CONCLUSION: Septic AKI patients have a higher burden of illness, worse renal function and higher mortality. APACHEII score, SOFA score and RRT are independent risk factors to septic AKI mortality. PMID- 23925357 TI - [An analysis of factors affecting the prognosis of patients with cardiac amyloidosis]. AB - OBJECTIVE: To analyze the clinical characteristics, diagnosis, treatment and outcome of patients with cardiac amyloidosis (CA). METHODS: Clinical data from 18 patients diagnosed as CA by endomyocardial biopsy (EMB) from 1995 to 2005 were retrospectively analyzed. RESULTS: Among the 18 patients with CA, all patients had reduced diastolic dysfunction; 12 had mitral valve early diastolic blood flow peak velocity/late diastolic blood flow peak velocity (E/A) > 2.0 and ventricular diastolic early filling deceleration time (DT) < 150 ms; 12 had left ventricular ejection fraction (LVEF) < 50%; and 13 had New York Heart Association (NYHA) classification III or IV. The 1-year, 3-year and 5-year survival rates of 18 patients with CA were 67%, 44% and 17%, respectively. Kaplan-Meier analysis showed, NYHA functional class > II, E/A > 2.0 and DT < 150 ms were associated with increased mortality (log-rank statistic P = 0.026 and 0.001, respectively). CA patients with chemotherapy before heart failure were associated with decreased mortality and extend survival. CONCLUSIONS: The mortality rate goes up and survival rate gradually descends as prolonged onset time. NYHA functional class >IIand E/A > 2.0 (DT< 150 ms) are associated with mortality. PMID- 23925358 TI - [The relationship between association of microalbuminuria and retinal vessel diameter in population with essential hypertension]. AB - OBJECTIVE: To investigate the association of urinary albumin-to-creatinine ratio (UACR) and the diameter of retinal vessel in population with essential hypertension in Fujian coastal area. METHODS: Central retinal artery and vein equivalents (CRAE and CRVE) were measured from the avoiding mydriatic digitized photographs and semi-automatic fundus analysis software, as well as albumin and urine creatinine. RESULTS: There were significant differences in CRAE levels among the normal control group, normoalbuminuria with essential hypertension group and microalbuminuria with essential hypertension group [(135.68 +/- 10.10) um, (129.79 +/- 10.48) um, (125.29 +/- 11.17) um, all P values < 0.01]. The CRAE levels were significantly negative correlated with UACR (r = -0.29, P < 0.01). Linear regression analysis showed CRAE was associated with UACR in the patients with hypertension(beta = -5.0, P < 0.01). Logistic regression analysis showed, systolic blood pressure (beta = 1.08, P = 0.02) was risk factor for CRAE abnormality. The CRAE abnormality was increased in turn in the normal control group, normoalbuminuria with the essential hypertension group and microalbuminuria with essential hypertension group (P < 0.01). CONCLUSION: The reduction of central retinal artery diameter are associated with the hypertensive renal damage. UACR and CRAE could be used to evaluate the microvascular lesions and be used as an indicator to assess the target organs damage in essential hypertension patients. PMID- 23925359 TI - [A retrospective analysis of 19 splenic abscess patients]. AB - OBJECTIVE: To analyze the clinical manifestations, diagnosis, treatment and prognosis of patients with splenic abscess. METHOD: The clinical data, including baseline clinical data, clinical features, past history, pathogen culture result, treatment and the prognosis were retrospectively analyzed in the patients with the discharge diagnosis splenic abscess from January 1991 to March 2012 in Peking Union Medical College Hospital. RESULTS: The media time from onset to Peking Union Medical College Hospital of the 19 patients were 29 days. Among them, 9 patients were cured, 8 were improved and 2 died. Risk factors, such as tumor burden, diabetes, and using immunosuppressive agents etc, can be found in most patients with splenic abscess. All the 19 patients had splenic image changes and non-specific clinical features. The most common three clinical symptoms were fever (18 cases), chills (12 cases) and shivering (11 cases). The most common three signs were abdominal tenderness (9 cases), left upper quadrant sensitive to percussion (7 cases) and splenomegaly (4 cases). The most common etiological culture results were gram negative bacilli (9 cases), gram positive coccus (8 cases), and fungi (4 cases). CONCLUSIONS: Clinical features are non-specific in splenic abscess patients. Related exam such as ultrasound should be performed on patients with splenic abscess risk factors to avoid misdiagnosis. Empiric antibiotic administration should begin right after the diagnosis based on the image. Pathogen culture should be timely conducted after pus collection. Individual therapeutical protocol should be chosen according to patient's condition. PMID- 23925360 TI - [The incidence and risk factors for heterogeneous vancomycin intermediate Staphylococcus aureus]. AB - OBJECTIVES: To investigate the prevalence of heterogeneous vancomycin intermediate Staphylococcus aureus (hVISA) and the sensitivity of hVISA to novel antibiotics, and to explore the risk factors and infection attributable mortality associated with hVISA infection. METHODS: A total of 456 methicillin resistant Staphylococcus aureus (MRSA) isolates were isolated in Zhongshan Hospital from January, 2008 to November, 2010. All MRSA isolates were investigated for hVISA by two agar screening methods BHIA5T (brain-heart infusion containing teicoplanin 5 mg/L) or BHIA6V (brain-heart infusion containing vancomycin 6 mg/L), as well as macroEtest method (MET). Possible hVISA isolates were tested by modified population analysis profile-area under the curve (PAP-AUC). The minimal inhibitory concentrations (MICs) of vancomycin, teicoplanin and linezolid were determined by microbroth dilution as recommended by Clinical Laboratory Standards Institute (CLSI). The contribution difference between hVISA and vancomycin susceptible Staphylococcus aureus (VSSA) in different MIC range was compared. A retrospective case-control study of the patients with hVISA infection or VSSA infection was carried out and statistical analysis was performed using t test, Mann-Whitney test, chi(2) test and Fisher exact test. RESULTS: A total of 105 isolates of hVISA were screened by BHIA5T and BHIA6V (23.0%) with other 23 isolates by MET (5.0%) and 21 by PAP-AUC (4.6%). All isolates were 100% sensitive to vancomycin, teicoplanin and linezolid. The vancomycin MIC [(1.76 +/- 0.16) mg/L] in hVISA group was significantly higher than that in VSSA group [(1.09 +/- 0.07) mg/L, P < 0.01], which was a potential risk factor for hVISA infection. The retrospective study showed chronic obstructive pulmonary disease (COPD) was also a risk factor for hVISA infection of the lower respiratory tract. No significant difference in infection attributable mortality was showed between the hVISA group and the VSSA group. CONCLUSIONS: The overall prevalence of hVISA in Zhongshan Hospital is estimated as 4.6%, while the prevalence of hVISA isolated from blood is as high as 12.5%. All isolates are 100% sensitive to vancomycin and linezolid. COPD is a risk factor for hVISA infection of the lower respiratory tract. PMID- 23925361 TI - [The efficacy and safety of tocilizumab combined with disease-modifying anti rheumatoid drugs in the treatment of active rheumatoid arthritis: a multi-center, randomized, double-blinded, placebo-controlled trial]. AB - OBJECTIVE: To evaluate the efficacy and safety of human anti-interleukin-6 (IL-6) receptor antibody (tocilizumab) in combination with disease-modifying anti rheumatoid drugs (DMARDs) for the treatment of rheumatoid arthritis (RA) patients with moderate to severe activity and inadequate response to DMARDs. METHODS: The present study was a multi-center, randomized, double-blinded, placebo controlled trial. Eligible patients were randomized (tocilizumab:Placebo = 2:1) to one of two groups: tocilizumab 8 mg/kg group or placebo group. The drug was administered every 4 weeks by infusion along with stable dose of DMARDs. The primary analysis evaluated at week 24 included: the proportion of patients with American College of Rheumatology (ACR)20, ACR50 and ACR70 response; the average changes of ACR core components from baseline; the proportion of patients with disease activity score (DAS28) <= 3.2 and DAS28 < 2.6. Patients who completed double-blinded phase could choose to enter 24-week open-label therapy with tocilizumab 8 mg/kg infusion every 4 weeks. RESULTS: Totally 139 patients from tocilizumab group and 69 patients from placebo group completed the 24-week double-blinded period respectively with comparable baseline characteristics. The proportion of patients with ACR20, ACR50 and ACR70 in tocilizumab group was significantly higher than that in placebo group: 69.8% vs 24.6% (P < 0.05), 38.8% vs 10.1% (P < 0.05) and 12.9% vs 2.9% (P < 0.05) respectively. ACR core components change, proportion of patients with DAS28 <= 3.2 and DAS28 < 2.6 were all better in tocilizumab group than those in the placebo group. Decreased level of biomarkers C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases (ICTP), matrix metalloproteinase 3 (MMP-3) and N-terminal propeptide of type IIA collagen (PIIANP) were observed in patients with tocilizumab treatment, indicating its positive effects on bone metabolism. A total of 202 patients received tocilizumab treatment in the study with the longest duration as 48 weeks, and all the indexes were improved further with the elongation of the treatment time. During the doubled blind phase, 42.4% of patients in the tocilizumab group had >= 1 adverse event (AE), compared with 27.9% of patients in the control group. The most common AE was infection, and most of the AEs were mild to moderate. Serious AEs occurred in 0.7% and 5.9% of patients in the tocilizumab and control groups, respectively. More patients in the tocilizumab group had higher percentage of increased alanine transaminase and aspartate transaminase (12.9% and 9.4%) compared to the placebo group (4.4% and 4.4%). Increase of total cholesterol, high density lipoprotein, low density lipoprotein, and triacylglycerol were observed in the tocilizumab group, but no increase of occurrence of cardiac events. No additional safety signals were found during the extension phase. CONCLUSION: The study showed that tocilizumab combined with DMARDs was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to DMARDs. PMID- 23925362 TI - Vegetative plaques and hemorrhagic pustules. Iododerma. PMID- 23925363 TI - Estimating the Universal Positions of Wireless Body Electrodes for Measuring Cardiac Electrical Activity. AB - A methodology is presented for estimating the wireless body electrode (WE) positions and for calculating the linear transformations that enable the synthesis of a 12-lead ECG or a multichannel ECG from three WEs, which in turn simplifies and improves the acquisition of ECGs. We present, compare, and evaluate three approaches to the synthesis: fully personalized, fully universal, and combined with universal leads and personalized transformations. The evaluation results show that WEs are an acceptable alternative to the standard 12 lead ECG device for patients with chronic myocardial ischemia, if either the fully personalized or combined approach is used. The median correlation coefficients are all higher than 0.94 and 0.92 for the fully personalized and combined approaches, respectively. The corresponding kappa and percentual diagnostic agreements between the synthesized and target 12-lead ECGs are 0.88 (95%) and 0.83 (92%), respectively. The evaluation additionally shows that the personalization of the transformations has more impact on the quality of the synthesized ECGs than the personalization of the WEs' positions. PMID- 23925364 TI - Signal-processing strategy for restoration of cross-channel suppression in hearing-impaired listeners. AB - Because frequency components interact nonlinearly with each other inside the cochlea, the loudness growth of tones is relatively simple in comparison to the loudness growth of complex sounds. The term suppression refers to a reduction in the response growth of one tone in the presence of a second tone. Suppression is a salient feature of normal cochlear processing and contributes to psychophysical masking. Suppression is evident in many measurements of cochlear function in subjects with normal hearing, including distortion-product otoacoustic emissions (DPOAEs). Suppression is also evident, to a lesser extent, in subjects with mild to-moderate hearing loss. This paper describes a hearing-aid signal-processing strategy that aims to restore both loudness growth and two-tone suppression in hearing-impaired listeners. The prescription of gain for this strategy is based on measurements of loudness by a method known as categorical loudness scaling. The proposed signal-processing strategy reproduces measured DPOAE suppression tuning curves and generalizes to any number of frequency components. The restoration of both normal suppression and normal loudness has the potential to improve hearing-aid performance and user satisfaction. PMID- 23925366 TI - Electron Microscopy Reconstruction of Brain Structure Using Sparse Representations Over Learned Dictionaries. AB - A central problem in neuroscience is reconstructing neuronal circuits on the synapse level. Due to a wide range of scales in brain architecture such reconstruction requires imaging that is both high-resolution and high-throughput. Existing electron microscopy (EM) techniques possess required resolution in the lateral plane and either high-throughput or high depth resolution but not both. Here, we exploit recent advances in unsupervised learning and signal processing to obtain high depth-resolution EM images computationally without sacrificing throughput. First, we show that the brain tissue can be represented as a sparse linear combination of localized basis functions that are learned using high resolution datasets. We then develop compressive sensing-inspired techniques that can reconstruct the brain tissue from very few (typically five) tomographic views of each section. This enables tracing of neuronal processes and, hence, high throughput reconstruction of neural circuits on the level of individual synapses. PMID- 23925365 TI - Early versus delayed hormonal treatment in locally advanced or asymptomatic metastatic prostatic cancer patient dilemma. AB - INTRODUCTION: The objective of this work is to compare the effectiveness of hormonal treatment (luteinizing hormone-releasing hormone agonists and/or antiandrogens) as an early or as a deferred intervention for patients with locally advanced prostate cancer (LAPC) and/or asymptomatic metastasis. MATERIALS AND METHODS: Systematic review of trials published in 1950-2007. Sources included MEDLINE and bibliographies of retrieved articles. Eligible trials included adults with a history of LAPC who are not suitable for curative local treatment of prostate cancer. We retrieved 22 articles for detailed review, of which 8 met inclusion criteria. The Veterans Administration Cooperative Urological Research Group suggested that delaying hormonal therapy did not compromise overall survival and that many of the patients died of causes other than prostate cancer. In European Organisation for Research and Treatment of Cancer (EORTC) 30846 trial, the median survival for delayed endocrine treatment was 6.1 year, and for immediate treatment 7.6 year, the HR for survival on delayed versus immediate treatment was 1.23 (95 % CI 0.88-1.71), indicating a 23 % nonsignificant trend in favour of early treatment. In EORTC 30891, the immediate androgen deprivation resulted in a modest but statistically significant increase in overall survival. The protocol SAKK 08/88 showed the lack of any major advantage of immediate compared with deferred hormonal treatment regarding quality of life or overall survival. CONCLUSIONS: The early intervention with hormonal treatment for patients with LAPC provides important reductions in all-cause mortality, prostate cancer-specific mortality, overall progression, and distant progression compared with deferring their use until standard care has failed to halt the disease. PMID- 23925367 TI - Curl-Based Finite Element Reconstruction of the Shear Modulus Without Assuming Local Homogeneity: Time Harmonic Case. AB - In elasticity imaging, the shear modulus is obtained from measured tissue displacement data by solving an inverse problem based on the wave equation describing the tissue motion. In most inversion approaches, the wave equation is simplified using local homogeneity and incompressibility assumptions. This causes a loss of accuracy and therefore imaging artifacts in the resulting elasticity images. In this paper we present a new curl-based finite element method inversion technique that does not rely upon these simplifying assumptions. As done in previous research, we use the curl operator to eliminate the dilatational term in the wave equation, but we do not make the assumption of local homogeneity. We evaluate our approach using simulation data from a virtual tissue phantom assuming time harmonic motion and linear, isotropic, elastic behavior of the tissue. We show that our reconstruction results are superior to those obtained using previous curl-based methods with homogeneity assumption. We also show that with our approach, in the 2-D case, multi-frequency measurements provide better results than single-frequency measurements. Experimental results from magnetic resonance elastography of a CIRS elastography phantom confirm our simulation results and further demonstrate, in a quantitative and repeatable manner, that our method is accurate and robust. PMID- 23925368 TI - Room-temperature spontaneous crystallization of porous amorphous titania into a high-surface-area anatase photocatalyst. AB - Room-temperature spontaneous crystallization of porous amorphous titania to a high-surface-area anatase material was observed in the absence of any solvent, additive and catalyst. The as-obtained porous titania serves as an efficient photocatalyst for H2 evolution, and its activity is more than twice that of the benchmark P25 TiO2. PMID- 23925369 TI - Pro-inflammatory cytokine release in rectal surgery: comparison between laparoscopic and open surgical techniques. AB - The objective of the present study was to investigate whether laparoscopic rectal surgery causes a less pronounced release of pro-inflammatory cytokines as compared to open surgical technique. Twenty-four consecutive patients undergoing rectal surgery due to cancer disease were included in a prospective and randomized trial. The patients were randomized to laparoscopic (n = 12) or open surgery (n = 12). Blood was sampled at five occasions; after induction of anesthesia before start of surgery, at 180, 360 min and 24 h after start of surgery and the last sample was taken in the late post-operative period 3-5 days after surgery. The levels of interleukin (IL)-1alpha, IL-6, IL-8, IL-10, tumor necrosis factor-alpha, C-reactive protein (CRP), white blood cells, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 were analyzed using multiplex sandwich enzyme-linked immunosorbent assay. There was a release of both pro- and anti-inflammatory cytokines during colorectal surgery. The release of IL 6, IL-10 and CRP was significantly lower in the laparoscopic group. Rectal surgery causes release of both pro- and anti-inflammatory cytokines. The inflammatory response is lower in laparoscopic rectal surgery as compared to conventional open surgery. Less tissue trauma in laparoscopic rectal surgery and/or less peri-operative bleeding in the laparoscopic cases leads to a lower degree of inflammatory response. PMID- 23925370 TI - The immunomodulatory activity of Staphylococcus aureus products derived from biofilm and planktonic cultures. AB - Biofilms are probably one of the most common structures formed by microorganisms in various environments. The higher resistance of such microbial communities to stress conditions, including antibiotics and host immune response, is recently extensively studied. However, the weak activity of phagocytic cells against microbial biofilm is not yet fully understood and explained. The aim of this study was: (1) a qualitative and quantitative comparison of cell components/products released from Staphylococcus aureus biofilm or planktonic cultures, (2) evaluation of the influence of such cell components/products on murine leukocytes secretory function. For this, mouse peritoneal leukocytes were stimulated with biofilm or planktonic staphylococcal cultures or their acellular filtrates, and then the production of cytokines (TNF-alpha, IL-6, IL-10, MCP-1 and MIP-1alpha), hemolytic activity and staphylokinase (SAK) production was determined. It was found that similar staphylococcal components/products possessing the immunomodulatory properties, were present in both, biofilm and planktonic filtrates. Moreover, these compounds were similarly active in the stimulation of TNF-alpha and MCP-1 release from leukocytes. The hemolytic activity and SAK release by planktonic and biofilm cultures were also comparable. What is interesting, stronger stimulatory activity of biofilm-derived components/products of clinical S. aureus strains in the case of MIP-1alpha, IL-6 and IL-10 was noticed. On the other hand, taking into consideration the reference strains, MIP-1alpha production was enhanced by "planktonic filtrates". Thus, in our study it was proved, first of all, that biofilm is not a structure fully separated from the external environment. Second, the influence of these S. aureus constituents/metabolites on leukocytes seems to be more strain-dependent than culture phenotype-dependent. The lack of one common profile of biofilm and planktonic S. aureus cultures/filtrates biological activity indicates that the disturbances in cytokines' production could not be the only reason for the so called "frustrated phagocytosis", connected with enhanced biofilm resistance. PMID- 23925371 TI - Molecular and physiological mechanisms associated with root exposure to mercury in barley. AB - Mercury (Hg) is a toxic metal that affects plant growth. Here the effect of Hg exposure on plant growth and leaf gas-exchange together with gene expression in roots is reported for barley. Hg was mainly accumulated in roots and only very small amounts were found in the shoots. Chlorophyll fluorescence and net photosynthesis were not affected by Hg. Nevertheless exposure to Hg reduced shoot and root growth, the shoot to root ratio, stomatal conductance, carbon isotope discrimination and expression of an aquaporin transcript, whereas abscisic acid related transcripts were over-expressed. These results suggested some degree of limitation to water uptake causing a moderate water stress when plants are exposed to Hg. Microarray (MapMan) analysis revealed changes in the transcription of genes involved in nitrogen metabolism, which were accompanied by decreased nitrogen concentrations in the shoots, together with an increase in transcripts associated with secondary metabolism, stress, inhibition of DNA synthesis/chromatin structure and cell organization elements. Moreover, Hg induced the expression of many transcripts known to be involved in the uptake, accumulation, transport and general responses to other heavy metals. It is concluded that barley is able to accumulate high amounts of Hg in roots through several transcriptional, metabolic and physiological adjustments. PMID- 23925373 TI - Photonic gratings of the metal-organic framework {Fe(bpac)[Pt(CN)4]} with synergetic spin transition and host-guest properties. AB - Surface-relief photonic gratings of the spin-crossover metal-organic framework {Fe(bpac)[Pt(CN)4]} (bpac = bis(4-pyridyl)acetylene) were elaborated by the combination of a sequential assembly process and lithographic methods. Optical diffraction, surface plasmon resonance spectroscopy and Raman micro-spectroscopy were used to investigate the temperature dependence of the spin state of the iron(II) ions and the concomitant change of the refractive index of the grating material. The refractive index change associated with the high spin ((5)T) to low spin ((1)A) transition was found to be as high as Deltan = 0.08 +/- 0.005, which was attributed to the pronounced mass density difference between the two spin states. While the grating thickness (15-90 nm) had no influence on the spin crossover properties of the gratings, the adsorption of aromatic guest molecules was found to have a substantial effect both on the spin transition temperature and the completeness of the transition. PMID- 23925372 TI - Age-associated pro-inflammatory adaptations of the mouse thoracic aorta. AB - Arterial ageing may be associated with a reduction in vasodilation due to increased reactive oxygen species (ROS) production, whereas endothelial cell activation induces procoagulant changes. However, little is known on the effect of ageing on expression of anticoagulant endothelial markers such as endothelial protein C receptor (EPCR). To study age-associated alterations in smooth muscle cell (SMC) and endothelial cell (EC) structure and function, the aorta was isolated from 10-week- and 12- and 24-month-old C57BL/6J mice and analysed for its expression of genes involved in senescence, oxidative stress production, coagulation and matrix remodelling. In addition, vasorelaxation experiments were performed using 10-week- and 24-month-old thoracic aortic ring segments in organ chamber baths. The media thickness of the thoracic aorta progressively increased with age, associated with hypertrophy of vascular SMCs. Basal nitric oxide production and sensitivity to acetylcholine-mediated vasodilation in thoracic aorta rings was reduced with age, whereas no significant differences in ROS production could be demonstrated. Gene expression of tissue factor, EPCR and von Willebrand factor was not affected by ageing of the aorta, whereas that of thrombomodulin was mildly reduced and that of xanthine dehydrogenase, NADPH oxidase 4, tumour necrosis factor-alpha and vascular cell adhesion molecule-1 significantly enhanced. In conclusion, a reduction in endothelial cell-mediated vasodilation in aged thoracic aortas of C57BL/6J mice was accompanied by a shift towards a pro-inflammatory state of the endothelium. PMID- 23925374 TI - Nonlinear Signal-Specific ADC for Efficient Neural Recording in Brain-Machine Interfaces. AB - A nonlinear ADC dedicated to the digitization of neural signals in implantable brain-machine interfaces is presented. Benefitting from an exponential quantization function, effective resolution of the proposed ADC in the digitization of action potentials is almost 2 bits more than its physical number of bits. Hence, it is shown in this paper that the choice of a proper nonlinear quantization function helps reduce the outgoing bit rate carrying the recorded neural data. Another major benefit of digitizing neural signals using the proposed signal-specific ADC is the considerable reduction in the background noise of the neural signal. The 8-b exponential ADC reported in this paper digitizes large action potentials with maximum resolution of 10.5 bits , while quantizing the small background noise is performed with a resolution of as low as 3 bits. Fully-integrated version of the circuit was designed and fabricated in a 0.18-MUm CMOS process, occupying 0.036 mm(2) silicon area. Designed based on a two-step successive-approximation register ADC architecture, the proposed ADC employs a piecewise-linear approximation of the target exponential function for quantization. Operating at a sampling frequency of 25 kS/s (typical for intra cortical neural recording) and with a supply voltage of 1.8 V, the entire chip, including the ADC and reference circuits, dissipates 87.2 MUW. According to the experiments, Noise-Content-Reduction Ratio (NCRR) of the ADC is 41.1 dB. PMID- 23925375 TI - C-C bond fragmentation by Grob/Eschenmoser reactions, applications in dendrimer synthesis. AB - C-C bond fragmentation of structurally diverse carbocycles has been applied to the divergent synthesis of dendrimers. The fragmentation has been paired to deprotection or thio-Michael reaction, allowing the preparation of a fourth generation dendrimer of narrow molecular weight distribution. Methodologies to increase water solubility have been examined using appended carboxylic acid or oligoether moieties. In addition, incorporation of chiral prolinol derivatives has resulted in the synthesis of dendrimers that have been shown to catalyse the alpha-amination of aldehydes in good yield and modest enantioselectivity. PMID- 23925376 TI - Development of sulphated and naphthylsulphonated carbosilane dendrimers as topical microbicides to prevent HIV-1 sexual transmission. AB - OBJECTIVES: For the last 20 years, the idea of alternative prevention strategies based on the use of topical vaginally products to inhibit HIV-1 infection in women has been established. The concept of a 'microbicide' product has been born out of the unavailability of a vaccine against HIV-1 and the problems of women in negotiating the use of preventive prophylaxis by their partners, especially in developing countries. DESIGN: We have developed and evaluated polyanionic carbosilane dendrimers G3-S16 and G2-NF16 with sulphated and naphthylsulphonated end groups as nonspecific microbicides. METHODS: Cellular in-vitro or in-vivo models were used to evaluate the safety, biocompatibility and anti-HIV ability of two polyanionic carbosilane dendrimers. RESULTS: Both dendrimers showed high biosafety in human epithelial cell lines derived from uterus and vagina and in primary blood human cells (PBMC). These dendrimers not only have a partial capacity to block the entry of different X4 and R5 HIV-1 isolates inside epithelial cells but protect the epithelial monolayer from cell disruption and also reduce HIV-1 infection of activated PBMC. Additionally, treatment of epithelial cells with G3-S16 or G2-NF16 dendrimers did not produce changes in proinflammatory cytokines profile, in proliferation of PBMC, on microbiota or sperm survival. Finally, no irritation or vaginal lesions were detected in female CD1(ICR) mice after dendrimers vaginal administration. CONCLUSION: These interesting results suggest that G3-S16 or G2-NF16 could be effective to inhibit HIV infection and transmission within genital mucosa as well as the spread of HIV transmission to human PBMC. PMID- 23925377 TI - Safety and immunological responses to human mesenchymal stem cell therapy in difficult-to-treat HIV-1-infected patients. AB - OBJECTIVE: HAART largely decreases morbidity and mortality in chronic HIV-1 infected patients, but immune nonresponders (INRs) with full viral suppression still fail to reverse the immune deficiency. This study evaluated the safety and immunological responses of human umbilical cord mesenchymal stem cell (MSC) therapy in HIV-1-infected INRs. DESIGN AND METHODS: A total of 13 HIV-1-infected INRs were enrolled in this pilot prospectively open-labeled controlled clinical trial. Seven patients were administered three umbilical cord-MSC transfusions at 1-month interval during 12-months of follow-up, whereas six control patients were treated with saline in parallel. Immunological parameters were monitored in these patients throughout the trial. RESULTS: All patients tolerated the umbilical cord MSC transfusions well throughout the trial. The umbilical cord-MSC transfusions preferentially increased circulating naive and central memory CD4 T-cell counts and restored HIV-1-specific IFN-gamma and IL-2 production in the INRs. These enhancements in immune reconstitution were also associated with the reduction of systemic immune activation and inflammation in vivo. CONCLUSIONS: umbilical cord MSC transfusions are well tolerated and can efficiently improve host immune reconstitution in INRs, suggesting that such treatments may be used as a novel immunotherapeutic approach to reversing immune deficiency in HIV-1-infected INRs (ClinicalTrials.gov identifier: NCT01213186). PMID- 23925378 TI - Tubular and glomerular proteinuria in HIV-infected adults with estimated glomerular filtration rate >= 60 ml/min per 1.73 m2. AB - OBJECTIVE: To assess the frequency of glomerular and tubular proteinuria in a cohort of HIV-infected patients, and to determine the factors associated with each type of injury. DESIGN: Cross-sectional study of 1210 consecutive HIV infected adults followed in HIV outpatient unit (Montpellier/France). METHODS: Spot urine protein to creatinine (uPCR), albumin to creatinine (uACR) and albumin to protein (uAPR) ratios were assessed. Glomerular injury was defined as uACR at least 30 mg/g or uPCR at least 200 mg/g with uAPR at least 0.4. Tubular injury was defined as uPCR 200 mg/g or more with uAPR less than 0.4. Multivariate logistic regression identified independent factors of each type of proteinuria, in the 1158 patients with estimated glomerular filtration rate (eGFR) at least 60 ml/min per 1.73 m, using re-expressed modification of diet in renal disease equation. RESULTS: Frequency of proteinuria was 18.2% among patients with eGFR at least 60 ml/min per 1.73 m consisting in tubular proteinuria for 50.7% of them. Factors associated with glomerular proteinuria were age [OR 1.34/10-year increment (95%CI: 1.08-1.66)], diabetes [OR 3.37 (95%CI: 1.53-7.44)], and arterial hypertension [OR 2.52 (95%CI: 1.36-4.66)]. Factors associated with tubular proteinuria were age [OR 1.43 (95%CI: 1.14-1.79)], current tenofovir use [OR 3.52 (95%CI: 1.86-6.65)], hepatitis C co-infection [OR 1.62 (95%CI: 1.00 2.65)], AIDS stage [OR 1.83 (95%CI: 1.18-2.82)], CD4 cell count less than 200 per MUl [OR 2.48 (95%CI: 1.31-4.70)]. CONCLUSION: This study distinguished risk factors for tubular injury, mainly related to HIV disease and its treatment (tenofovir), and glomerular injury, linked to non HIV-related variables (age, diabetes, hypertension). Measuring uPCR, uACR and uAPR may help with the detection and specific management of early chronic kidney disease in HIV-infected patients having normal or sub-normal eGFR. PMID- 23925380 TI - Intimate partner violence is associated with incident HIV infection in women in Uganda. AB - OBJECTIVES: To quantify the association between intimate partner violence (IPV) and incident HIV infection in women in the Rakai Community Cohort Study between 2000 and 2009. DESIGN AND METHODS: Data were from the Rakai Community Cohort Study annual surveys between 2000 and 2009. Longitudinal data analysis was used to estimate the adjusted incidence rate ratio (IRR) of incident HIV associated with IPV in sexually active women aged 15-49 years, using a multivariable Poisson regression model with random effects. The population attributable fraction was calculated. Putative mediators were assessed using Baron and Kenny's criteria and the Sobel-Goodman test. RESULTS: Women who had ever experienced IPV had an adjusted IRR of incident HIV infection of 1.55 (95% CI 1.25-1.94, P = 0.000), compared with women who had never experienced IPV. Risk of HIV infection tended to be greater for longer duration of IPV exposure and for women exposed to more severe and more frequent IPV. The adjusted population attributable fraction of incident HIV attributable to IPV was 22.2% (95% CI 12.5-30.4). There was no evidence that either condom use or number of sex partners in the past year mediated the relationship between IPV and HIV. CONCLUSION: IPV is associated with incident HIV infection in a population-based cohort in Uganda, although the adjusted population attributable fraction is modest. The prevention of IPV should be a public health priority, and could contribute to HIV prevention. PMID- 23925381 TI - HIV infection and lung function decline: challenges, clinical implications, and new questions. PMID- 23925379 TI - Higher rates of AIDS during the first year of antiretroviral therapy among migrants: the importance of tuberculosis. AB - OBJECTIVE: In lower-income countries rates of AIDS-defining events (ADEs) and death are high during the first year of combination antiretroviral therapy (ART). We investigated differences between foreign-born (migrant) and native-born (nonmigrant) patients initiating ART in Europe, the US and Canada, and examined rates of the most common ADEs and mortality during the first year of ART. DESIGN: Observational cohort study. METHODS: We studied HIV-positive adults participating in one of 12 cohorts in the Antiretroviral Therapy Cohort Collaboration (ART-CC). RESULTS: Of 48 854 patients, 25.6% were migrants: 16.1% from sub-Saharan Africa, 5.6% Latin America, 2.3% North Africa/Middle East, and 1.6% Asia. Incidence of ADEs during the first year of ART was 60.8 per 1000 person-years: 69.9 for migrants and 57.7 for nonmigrants [crude hazard ratio (HR) 1.18; 95% confidence interval (CI) 1.08-1.29], adjusted HR (for sex, age, CD4, HIV-1 RNA, ART regimen, prior ADE, probable route of infection and year of initiation, and stratified by cohort) 1.21 (95% CI 1.09-1.34). Rates of tuberculosis were substantially higher in migrants than nonmigrants (14.3 vs. 6.3; adjusted HR 1.94; 95% CI 1.53-2.46). In contrast, mortality was higher among nonmigrants than migrants (crude HR 0.71; 95% CI 0.61-0.84), although excess mortality was partially explained by patient characteristics at start of ART (adjusted HR 0.91; 95% CI 0.76-1.09). CONCLUSIONS: During the first year of ART, HIV-positive migrants had higher rates of ADEs than nonmigrants. Tuberculosis was the most common ADE among migrants, highlighting the importance of screening for tuberculosis prior to ART initiation in this population. PMID- 23925382 TI - Mesenchymal stem cell therapy in HIV-infected HAART-treated nonimmune responders restores immune competence. PMID- 23925383 TI - Efficacy and tolerance of telaprevir in HIV-hepatitis C virus genotype 1 coinfected patients failing previous antihepatitis C virus therapy: 24-week results. AB - The efficacy and tolerance of telaprevir (TVR) was examined in 20 mostly cirrhotic HIV-hepatitis C genotype 1 (HCV-G1)-infected patients failing previous treatment with pegylated-interferon and ribavirin (PR). HCV-RNA less than 12 IU/ml was observed in 35.3% of patients at W2, 55.0% at W4, 65.0% at W12 and 55.0% at W24. All patients with virological failure (n = 9) exhibited V36M/R155K mutations. Early virological response was a determinant of HCV-RNA less than 12 IU/ml at W24 (P < 0.001). No grade 3-4 dermatological side-effects were reported. TVR-PR tritherapy appeared to be rather effective and well tolerated among difficult-to-treat HIV-HCV-G1 patients. PMID- 23925384 TI - An unusual case of HIV virologic failure during treatment with boosted atazanavir. PMID- 23925387 TI - Phosphonium phosphonate-type zwitterion-water mixed systems showing variable hydrogen bonding ability as a function of temperature. AB - Zwitterion in which a long-chain alkyl phosphonium cation is tethered with a phosphonate-derivative anion shows stimuli responsible variable hydrogen bonding ability by a slight temperature change in the presence of water. PMID- 23925386 TI - Clinical utility of antigen carbohydrate 125 in heart failure. AB - In recent years, there has been a proliferation of new biomarkers with potential prognostic implication in heart failure (HF). Nevertheless, most of them do not fulfill the required criteria for being used in daily clinical practice. Tumor marker antigen carbohydrate 125 (CA125), a glycoprotein widely used for ovarian cancer monitoring, is synthesized by epithelial serous cells in response to fluid accumulation and/or cytokine stimuli. This glycoprotein has been emerged as a potential biomarker in HF. Plasma CA125 correlates with clinical, hemodynamic, and echocardiographic parameters related to the severity of the disease. High levels have shown to be present in the majority of acutely decompensated patients, and in this setting, it has shown to be independently related to mortality or subsequent admission for acute HF. In addition, certain characteristics such as wide availability and the close correlation between plasma changes with disease severity and clinical outcomes have increased the interest of researchers about the potential of this glycoprotein for monitoring and guiding therapy in HF. In this article, we have reviewed the available evidence supporting the potential role of CA125 as a biomarker in HF. PMID- 23925388 TI - Heterogeneous and homogeneous chiral Cu(II) catalysis in water: enantioselective boron conjugate additions to dienones and dienoesters. AB - It was proved that a judicious choice of counteranion played a prominent role in Cu(II) catalysis for enantioselective boron conjugate additions in water; the use of Cu(OH)2 renders heterogeneous catalysis, whereas Cu(OAc)2 renders homogeneous catalysis; cyclic dienones underwent a remarkable switch of regioselectivity between 1,4- and 1,6-modes of the additions through these catalyses. PMID- 23925389 TI - ESP Abstracts 2013. PMID- 23925390 TI - A report from Fukushima: an assessment of bone health in an area affected by the Fukushima nuclear plant incident. AB - Bone health was assessed for inhabitants of an area affected by the Fukushima nuclear plant incident. Osteoporotic patients, who had been treated with active vitamin D3 and/or bisphosphonate at Soma Central Hospital before the Fukushima incident, were enrolled. Changes in bone turnover markers and bone mineral density were retrospectively analyzed. Serum levels of a bone resorption marker, serum type I collagen cross-linked N-telopeptide were decreased in all the treated groups, whereas those of a bone formation marker, bone-specific alkaline phosphatase, were increased. Accordingly, bone mineral density, estimated by dual energy X-ray absorptiometry, was increased in the lumbar spine of all groups, but bone mass increase in the proximal femur was detected only in the group treated with the two agents in combination. From the degree of these parameter changes, the antiosteoporotic treatments looked effective and were equivalent to the expected potency of past observations. At this stage, the present study implies that the Fukushima nuclear incident did not bring an acute risk to bone health in the affected areas. PMID- 23925392 TI - Strontium ranelate: in search for the mechanism of action. AB - Strontium ranelate is a medicine with evidenced effects on the risk of fractures. The heterogeneity of strontium distribution in bone, quality of bone mineral crystals in young bone packets on bone surfaces formed during strontium ranelate administration, and activation of the calcium sensing receptor may, at least partially, explain the beneficial effects of SrR on reducing the risk of fractures. In this review, the concept of the dual action of strontium ranelate is also discussed. However, sufficient evidence for the bone anabolic effect of SrR does not exist in humans. The knowledge of the mechanism of action of SrR is important not only for the explanation of the effects of SrR upon the skeleton, but also for the safety of treatment for other tissues. PMID- 23925391 TI - Identification of novel regulators of osteoblast matrix mineralization by time series transcriptional profiling. AB - Bone mineralization is a carefully orchestrated process, regulated by a number of promoters and inhibitors that function to ensure effective hydroxyapatite formation. Here we sought to identify new regulators of this process through a time series microarray analysis of mineralising primary osteoblast cultures over a 27 day culture period. To our knowledge this is the first microarray study investigating murine calvarial osteoblasts cultured under conditions that permit both physiological extracellular matrix mineralization through the formation of discrete nodules and the terminal differentiation of osteoblasts into osteocytes. RT-qPCR was used to validate and expand the microarray findings. We demonstrate the significant up-regulation of >6,000 genes during the osteoblast mineralization process, the highest-ranked differentially expressed genes of which were those dominated by members of the PPAR-gamma signalling pathway, namely Adipoq, Cd36 and Fabp4. Furthermore, we show that the inhibition of this signalling pathway promotes matrix mineralisation in these primary osteoblast cultures. We also identify Cilp, Phex, Trb3, Sox11, and Psat1 as novel regulators of matrix mineralization. Further studies examining the precise function of the identified genes and their interactions will advance our understanding of the mechanisms underpinning biomineralization. PMID- 23925393 TI - Enhanced generation of human embryonic stem cells from single blastomeres of fair and poor-quality cleavage embryos via inhibition of glycogen synthase kinase beta and Rho-associated kinase signaling. AB - STUDY QUESTION: Could selected pluripotency-enhancing small molecules (SMs) lead to efficient derivation of human embryonic stem cells (hESCs) from cleavage embryos-derived single blastomeres (SBs)? SUMMARY ANSWER: Inhibition of glycogen synthase kinase beta (GSK3beta) and Rho-associated kinase (ROCK) signaling can enhance the derivation of hESCs from cleavage embryo-derived SBs. WHAT IS KNOWN ALREADY: Parameters involved in sustaining the pluripotency of biopsied blastomeres for generating hESCs without causing injury to a viable embryo have remained obscure. This research seeks to improve the culture conditions for increasing the efficiency of deriving hESCs from SBs from cleavage-stage embryos by using SMs. STUDY DESIGN, SIZE, DURATION: In order to identify SMs which may enhance hESC generation from SBs, 11 pluripotency-enhancing SMs were screened and CHIR99021 (CH), a GSK3beta inhibitor, was selected. To optimize culture condition in hESC generation from SMs, we used ROCK inhibitor Y27632 (Y) and basic fibroblast growth factor in combination with CH or its alternative, Kenpaullone, in different time courses over 12 days. We also assessed a critical time point for CH + Y treatment of cleavage embryos from 4- to 8-cell embryo. In total, 224 embryos and 1607 SBs were used in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blastomeres of fair and poor-quality from 6- to 8-cell stage human embryos were mechanically dispersed and individually seeded into a 96-well plate that was precoated with mitotically inactivated feeder cells. Derivation of hESC line from each SB was carried out in hESC defined medium supplemented with SMs. Randomly selected hESC lines were evaluated by immunostaining for pluripotency markers, karyotype analysis and differentiation potential into the three embryonic germ layer derivatives. MAIN RESULTS AND THE ROLE OF CHANCE: We found that 3 MUM CH was the only SM that was capable of directing SBs from fair and poor-quality 6-8-cell embryos into hESC lines. The application of hESC conditioned medium had no additive effect on hESC establishment from SBs. Also, we indicated that CH combined with Y improved hESC generation efficiency by up to 31%. By using of Kenpaullone as an alternative to CH, we confirmed the involvement of GSK3 inhibition in hESC derivation from SBs. Interestingly, by treatment of 4-cell embryos, these SMs could enhance the derivation efficiency of SB-derived hESC lines up to 73% and the maximum number of hESC lines from SBs of one embryo was achieved in this state. LIMITATIONS, REASONS FOR CAUTION: The low quality of the embryos used in this study most likely had an effect on hESC generation. Furthermore, although we attempted to minimize any differences in inter-embryo quality, we cannot exclude the possibility that small differences in starting quality between embryos may have contributed to the differences observed, other than the addition of SMs. WIDER IMPLICATIONS OF THE FINDINGS: This approach would allow the establishment of autogeneic or allogeneic matched cells from embryos fertilized in vitro without destroying them. STUDY FUNDING/COMPETING INTEREST(S): This study was financially supported by the National Elite Foundation and the Royan Institute for Stem Cell Biology and Technology. The authors have no conflict of interest to declare. PMID- 23925394 TI - Individualized decision-making in IVF: calculating the chances of pregnancy. AB - STUDY QUESTION: Are we able to develop a model to calculate the chances of pregnancy prior to the start of the first IVF cycle as well as after one or more failed cycles? SUMMARY ANSWER: Our prediction model enables the accurate individualized calculation of the probability of an ongoing pregnancy with IVF. WHAT IS KNOWN ALREADY: To improve counselling, patient selection and clinical decision-making in IVF, a number of prediction models have been developed. These models are of limited use as they were developed before current clinical and laboratory protocols were established. STUDY DESIGN, SIZE, DURATION: This was a cohort study. The development set included 2621 cycles in 1326 couples who had been treated with IVF or ICSI between January 2001 and July 2009. The validation set included additional data from 515 cycles in 440 couples treated between August 2009 and April 2011. The outcome of interest was an ongoing pregnancy after transfer of fresh or frozen-thawed embryos from the same stimulated IVF cycle. If a couple became pregnant after an IVF/ICSI cycle, the follow-up was at a gestational age of at least 11 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women treated with IVF or ICSI between January 2001 and April 2011 in a university hospital. IVF/ICSI cycles were excluded in the case of oocyte or embryo donation, surgically retrieved spermatozoa, patients positive for human immunodeficiency virus, modified natural IVF and cycles cancelled owing to poor ovarian stimulation, ovarian hyperstimulation syndrome or other unexpected medical or non-medical reasons. MAIN RESULTS AND THE ROLE OF CHANCE: Thirteen variables were included in the final prediction model. For all cycles, these were female age, duration of subfertility, previous ongoing pregnancy, male subfertility, diminished ovarian reserve, endometriosis, basal FSH and number of failed IVF cycles. After the first cycle: fertilization, number of embryos, mean morphological score per Day 3 embryo, presence of 8-cell embryos on Day 3 and presence of morulae on Day 3 were also included. In validation, the model had moderate discriminative capacity (c-statistic 0.68, 95% confidence interval: 0.63 0.73) but calibrated well, with a range from 0.01 to 0.56 in calculated probabilities. LIMITATIONS, REASONS FOR CAUTION: In our study, the outcome of interest was ongoing pregnancy. Live birth may have been a more appropriate outcome, although only 1-2% of all ongoing pregnancies result in late miscarriage or stillbirth. The model was based on data from a single centre. WIDER IMPLICATIONS OF THE FINDINGS: The IVF model presented here is the first to calculate the chances of an ongoing pregnancy with IVF, both for the first cycle and after any number of failed cycles. The generalizability of the model to other clinics has to be evaluated more extensively in future studies (geographical validation). Centres with higher or lower success rates could use the model, after recalibration, by adjusting the intercept to reflect the IVF success rates in their centre. STUDY FUNDING/COMPETING INTEREST(S): This project was funded by the NutsOhra foundation (Grant 1004-179). The NutsOhra foundation had no role in the development of our study, in the collection, analysis and interpretation of data; in writing of the manuscript, and in the decision to submit the manuscript for publication. There were no competing interests. PMID- 23925395 TI - Birth size and age at menarche: a twin perspective. AB - STUDY QUESTION: Do birthweight (BW) and co-twin sex influence the age at menarche in twins? SUMMARY ANSWER: BW, but not co-twin sex, was associated with age at menarche in twins. However, BW was not associated with age at menarche after controlling for genetics and shared rearing environment. WHAT IS KNOWN ALREADY: Nutritional deprivation during critical developmental periods can trigger long term effects on health. A small size at birth has been associated with early age at menarche in singletons. However, the relative influence of genetics and environmental factors on this association remains unresolved. STUDY DESIGN, SIZE, DURATION: In total, 2505 twin pairs were included in this cohort study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were recruited from the Danish Twin Register. Data on the age at menarche were collected by questionnaire and combined with data on BW, birth length (BL) and gestational age (GA) from the Danish Medical Birth register. The BW for GA standard deviation score (BW-SDS) was calculated. MAIN RESULTS AND THE ROLE OF CHANCE: BW-SDS [hazard ratio (HR) 0.96; 95% confidence interval (CI): 0.93-0.00], P = 0.04], but not BW, BL or GA (P >= 0.15), was positively associated with age at menarche in all twins after adjustment for zygosity and year of birth. However, BW-SDS was not associated with menarcheal age within twin pairs (HR 1.01; 95% CI: 0.91-1.12, P = 0.88). No differences were found in the age at menarche or birth size between twin girls from same sex and twin girls from opposite-sex pregnancies. Heritability of menarcheal age and BW were estimated to be 0.61 (95% CI: 0.38 0.84) and 0.27 (95% CI: 0.18-0.38), respectively. Both BW and menarcheal age were influenced by genetic and environmental factors. LIMITATIONS, REASONS FOR CAUTION: A limitation of this study is recall bias on the age at menarche. It is also not clear how these results should be extrapolated to the non-twin population. WIDER IMPLICATIONS OF THE FINDINGS: lower BW for GA is associated with earlier age at menarche in twin girls. However, the lack of within-pair differences in menarcheal age between even markedly BW-discordant twins indicates that this association is governed by environmental or genetic factors shared by both twins. Thus, within-pair differences in intrauterine nutritional factors leading to discordant growth do not seem to influence timing of menarche. STUDY FUNDING/COMPETING INTEREST(S): The authors have nothing to declare. Departmental funds were used to support all authors during the study period and preparation. PMID- 23925396 TI - Sildenafil citrate in the treatment of pain in primary dysmenorrhea: a randomized controlled trial. AB - STUDY QUESTION: Is a vaginal preparation of sildenafil citrate capable of alleviating acute menstrual pain in patients with primary dysmenorrhea (PD)? SUMMARY ANSWER: A vaginal preparation of sildenafil citrate is capable of alleviating acute menstrual pain in patients with PD with no observed adverse effects. WHAT IS KNOWN ALREADY: Oral preparations of nitric oxide (NO) donor drugs augment relaxant effects of NO on myometrial cells, reverse the vasoconstriction caused by prostaglandins and successfully alleviate pain, but the incidence of side effects is too high for routine clinical use. Sildenafil citrate inhibits type 5-specific phosphodiesterase (PDE5), thus preventing the degradation of cyclic guanosine monophosphate (cGMP) in the muscle and augmenting the vasodilatory effects of NO. Therefore, by inhibiting PDE5, the tissue remains relaxed and more blood can circulate through. It has been used previously in a vaginal form with no observed side effects, and it enhances endometrial blood flow. STUDY DESIGN, SIZE, DURATION: A double-blind, randomized, controlled trial comparing vaginal preparation of sildenafil citrate (100 mg single dose) to a placebo in 62 PD patients at the time of painful menstruation was conducted. The primary outcome was total pain relief over 4 consecutive hours (TOPAR4) comparing sildenafil citrate to placebo, where higher TOPAR4 scores represent better pain relief. Secondary outcomes were pain relief as measured by the visual analog scale (VAS) and uterine artery pulsatility index (PI). Subjects were recruited from December 2007 to January 2011. The trial was stopped due to closeout of the funding for the study. PARTICIPANTS, SETTINGS, METHODS: Participants were women in good health, were aged 18-35 years and suffered from moderate to severe PD. They were randomized to either vaginal placebo or 100 mg vaginal sildenafil citrate in a 1:1 ratio using random permuted blocks having a block size of 4. At baseline and 1, 2, 3, and 4 h post-treatment, patients were asked to provide assessment of their degree of pain using two scales: (i) pain on the 5-level ordinal scale used for TOPAR4 calculation and (ii) pain level on the VAS. The study ended 4 h after treatment initiation. MAIN RESULTS AND THE ROLE OF CHANCE: Twenty-five subjects completed the study. Using the TOPAR4 score, the sildenafil citrate group had significantly better pain relief compared with the placebo group [mean (SD): 11.9 (3.2) versus 6.4 (2.1), respectively; difference in means = 5.3; 95% CI: (2.9,7.6); P < 0.001)]. On the VAS, sildenafil citrate provided better pain relief than placebo at each time point. At the 2-h time point, the PI was significantly lower in the sildenafil citrate group compared with the placebo group [mean (SD): 1.6 (0.6) versus 2.3 (0.5), respectively; difference in means = -0.7; 95% CI: (-1.2, -0.1); P = 0.01)]. LIMITATIONS, REASONS FOR CAUTION: Since we did not meet our sample size due to the loss of funding and could not confirm our primary hypothesis, larger studies of longer duration, likely multi-center, are needed to confirm the findings from this study. WIDER IMPLICATIONS OF THE FINDINGS: A number of medications have been investigated to improve the treatment options for PD, but most have proven unsuccessful or to have an unfavorable risk/benefit ratio. Since PD is a condition that most women suffer from and seek treatment for at some point in their lives, our study offers hope that vaginal sildenafil citrate is a safe and effective option for patients who do not desire or are unresponsive to treatments now available on the market. STUDY FUNDING/COMPETING INTERESTS: Funding for this study was provided by National Institutes of Health (NIH) grants RO3 TW007438 and K24 HD01476. The authors report no relevant conflicts of interest. TRIAL REGISTRATION NUMBER: NCT00123162 (Clinical trials.gov). PMID- 23925397 TI - The success of assisted reproduction technologies in relation to composition of the total regulatory T cell (Treg) pool and different Treg subsets. AB - STUDY QUESTION: Are there differences in composition of the total regulatory T cell (Treg) pool and distinct Treg subsets (naive CD45RA(+)-Tregs, HLA-DR(-)- and HLA-DR(+)-memory Tregs) between successfully and non-successfully IVF/ICSI treated women? SUMMARY ANSWER: Non-successfully IVF/ICSI-treated women have a decreased percentage of naive CD45RA(+)-Tregs and an increased percentage of HLA DR(-)-memory Tregs within the total Treg pool. WHAT IS KNOWN ALREADY: Immunosuppressive Tregs play a significant role in human reproduction and studies have shown that their number and function are reduced in reproductive failure and complications of pregnancy such as pre-eclampsia and preterm labor. However, no data exist concerning the importance of Tregs for a successful outcome following assisted reproduction technologies. STUDY DESIGN, SIZE, DURATION: Blood samples were obtained from 210 women undergoing IVF/ICSI treatment, where 14 patients were excluded due to biochemical pregnancy or missed abortion. Age control blood samples were collected from 20 neonates and 176 healthy female volunteers. The study was performed between October 2010 and March 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: In this study, we determined prospectively the quantity and composition of the total CD4(+)CD127(low+/-)CD25(+)FoxP3(+)-Treg pool and three different Treg subsets (naive CD45RA(+)-Tregs, HLA-DR(-)- and HLA-DR(+)-memory Tregs) in all women undergoing IVF/ICSI treatment. We examined whether there were differences between those who became pregnant (n = 36) and those who did not (n = 160). The blood samples were collected within 1 h before the embryo transfer and analyzed by six-color flow cytometry. In order to evaluate these results with regard to the normal age-related changes in composition of the total Treg pool, the same analysis was performed using samples of umbilical cord blood and from healthy female volunteers aged between 17 and 76 years. The composition of the total Treg pool was documented for successfully IVF/ICSI-treated women (n = 5) throughout their pregnancy and we assessed the suppressive activity of each Treg subset in pregnant (n = 10) compared with non-pregnant women (n = 10) using suppression assays. MAIN RESULTS AND ROLE OF CHANCE: The percentage of CD4(+)CD127(low+/-)CD25(+)FoxP3(+)-Tregs within the total CD4(+)-T cell pool did not change with age and did not differ between IVF/ICSI-treated women who did or did not become pregnant. For the total Treg pool, the percentage of the naive CD45RA(+)-Tregs decreased continuously, while the percentage of HLA-DR(-)- and HLA-DR(+)-memory Tregs increased with aging. From the age of about 40 years, the increase in HLA-DR(+)-memory Tregs in particular became less pronounced, indicating that conversion of naive CD45RA(+)Tregs into HLA-DR(+)-memory Tregs decreases with age. Women who did not achieve a pregnancy with IVF/ICSI were older than those who did (P < 0.01). However, multiple logistic regression analysis revealed that irrespective of age, the percentage of naive CD45RA(+) Tregs within the total Treg pool was decreased (P < 0.05), while the percentage of HLA-DR(-)-memory Tregs was increased (P < 0.01) in women who did not become pregnant compared with those who did. At the beginning of pregnancy, naive CD45RA(+)-Tregs showed a major decrease but increased again during pregnancy and these cells showed a higher suppressive activity (P < 0.0001) in pregnant compared with non-pregnant women. LIMITATIONS, REASONS FOR CAUTION: There was a large variation in the percentages of the Treg subsets within the total Treg pool between successfully and non-successfully IVF/ICSI-treated women. Therefore, their determination would not allow us to predict the IVF/ICSI outcome with sufficient specificity and sensitivity. We did not examine the antigen specificity of the Treg subsets and therefore could not discern whether the naive CD45RA(+)-Tregs recognized maternal or paternal antigens. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that Tregs, especially the naive CD45RA(+) Treg subset, may play a role in determining the probability of both becoming pregnant and maintenance of the pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the German Research Council (DFG) grant STE 885/3-2 (to A.S.). All authors declare to have no conflict of interest. PMID- 23925399 TI - Association between neutrophil to lymphocyte ratio and severity of coronary artery disease. PMID- 23925398 TI - Morphea in adults and children cohort III: nested case-control study--the clinical significance of autoantibodies in morphea. AB - IMPORTANCE: Small studies have implicated the association of specific autoantibodies with morphea subtype or severity, but no large-scale studies have been conducted. This prospective case-control study confirmed the presence of antinuclear antibodies (ANAs) and other autoantibodies in morphea but found they are of limited significance. OBJECTIVE: To determine the prevalence of ANAs, extractable nuclear antigens such as antihistone antibodies (AHAs), and anti single-stranded DNA antibodies (ssDNA abs) in patients with morphea vs a healthy control population and their association with clinical measures of morphea severity. DESIGN, SETTING, AND PARTICIPANTS: Nested case-control study, conducted at the University of Texas Southwestern Medical Center, Dallas, and University of Texas Health Science Center, Houston. Study participants included individuals enrolled in the Morphea in Adults and Children (MAC) cohort and Scleroderma Family Registry and DNA Repository. MAIN OUTCOMES AND MEASURES: Prevalence of ANAs, AHAs, ssDNA abs in patients with morphea vs matched controls and association of the presence of autoantibodies with clinical indicators of morphea severity. RESULTS: The prevalence of ANAs, AHAs, and ssDNA abs in patients with morphea was 34%, 12%, and 8%, respectively. Antinuclear antibodies and AHAs, but not ssDNA abs, were present more frequently in cases than in controls. There was no difference in ANA prevalence among morphea subtypes. Among patients with linear morphea, the presence of autoantibodies was associated with clinical indicators of severe morphea including functional limitation (ssDNA ab, P = .005; and AHA, P = .006), extensive body surface area involvement (ssDNA ab, P = .01; and ANA, P = .005), and higher skin scores (ANA, P = .004). The presence of autoantibodies was not associated with clinical measures of morphea activity. CONCLUSIONS AND RELEVANCE: Our results demonstrate that ANAs and AHAs are more prevalent among patients with morphea but are of limited clinical utility except in linear morphea, where their presence, although infrequent, is associated with greater lesion burden and functional impairment. PMID- 23925400 TI - VEGFR-1, Bcl-2, and HO-1 Ratios in Pregnant Women With Hypertension. AB - BACKGOUND/AIM: Preeclampsia (PE) is a multisystem disease resulting in high maternal-fetal morbidity and mortality. The aim of the study was to investigate antiangiogenesis-associated alterations in antiapoptotic and antioxidative proteins in PE. METHOD: Of the 46 patients with PE, 25 (54.3%) were with gestational hypertension (GH), 12 (26%) were with mild, and 9 (19.5%) were with severe PE. The serum levels of vascular endothelial growth factor receptor 1 (VEGFR-1), heme oxygenase 1 (HO-1), and B-cell lymphoma/leukemia (Bcl-2) levels were measured by enzyme-linked immunosorbent assay. RESULTS: In the severe PE group, the VEGFR-1 serum levels (27.3 +/- 16.8 vs 13.3 +/- 10.7 ng/mL, P = .023) were higher, but the Bcl-2 levels (1.5 +/- 0.2 vs 2.1 +/- 1.7 ng/mL, P = .047) were lower than the levels in the GH-mild PE group (P = .047). Also, VEGFR-1/Bcl 2 ratio in the severe PE group was significantly higher (P = .003) than the ratio in the GH-mild PE group. CONCLUSION: The Bcl-2 and HO-1 proteins seem to have important roles in the antiangiogenic environment of preeclampsia. PMID- 23925401 TI - Testosterone therapy, thrombophilia-hypofibrinolysis, and hospitalization for deep venous thrombosis-pulmonary embolus: an exploratory, hypothesis-generating study. AB - In our study of 596 men hospitalized in the last 3 years for deep venous thrombosis-pulmonary emboli (DVT-PE), we determined the prevalence of exogenous testosterone (T) use with subsequent development of DVT-PE. Of the 596 men, 110 were now dead, 97 had cancer thought to cause DVT-PE, 250 could not be contacted, leaving 139, of whom 7 had taken T before and at the time of their admissions, 1.2% of the total cohort, a conservative estimate of the prevalence of T associated DVT-PE. In all, 5 of the 7 DVT-PE events occurred within 3 months of initiation of T, with mean and median intervals between initiation of T and hospitalization with DVT-PE 6.7 and 2 months. Of the 7 men treated with exogenous T, all 5 men who had evaluation of thrombophilia-hypofibrinolysis were found to have previously undiagnosed familial or acquired thrombophilia or hypofibrinolysis, suggesting a thrombotic interaction between exogenous T and thrombophilia-hypofibrinolysis. PMID- 23925402 TI - Speciation and identification of tellurium-containing metabolites in garlic, Allium sativum. AB - Tellurium (Te) is a widely used metalloid in industry because of its unique chemical and physical properties. However, information about the biological and toxicological activities of Te in plants and animals is limited. Although Te is expected to be metabolized in organisms via the same pathway as sulfur and selenium (Se), no precise metabolic pathways are known in organisms, particularly in plants. To reveal the metabolic pathway of Te in plants, garlic, a well-known Se accumulator, was chosen as the model plant. Garlic was hydroponically cultivated and exposed to sodium tellurate, and Te-containing metabolites in the water extract of garlic leaves were identified using HPLC coupled with inductively coupled plasma mass spectrometry (ICP-MS) or electrospray tandem mass spectrometry (ESI-MS-MS). At least three Te-containing metabolites were detected using HPLC-ICP-MS, and two of them were subjected to HPLC-ESI-MS-MS for identification. The MS spectra obtained by ESI-MS-MS indicated that the metabolite was Te-methyltellurocysteine oxide (MeTeCysO). Then, MeTeCysO was chemically synthesized and its chromatographic behavior matched with that of the Te-containing metabolite in garlic. The other was assigned as cysteine S methyltellurosulfide. These results suggest that garlic can assimilate tellurate, an inorganic Te compound, and tellurate is transformed into a Te-containing amino acid, the so-called telluroamino acid. This is the first report addressing that telluroamino acid is de novo synthesized in a higher plant. PMID- 23925403 TI - The force of transporting a single amino acid into the living cell measured using atomic force microscopy. AB - We used single molecule force spectroscopy (SMFS) to investigate the interacting force between single cysteine and amino acid transporters in eukaryotic cell membranes. We measured the transporting force of cysteine and found that its conformation on the AFM tip is important for discriminating the substrate in the transporting pathway. PMID- 23925404 TI - The Arabidopsis thaliana mutant air1 implicates SOS3 in the regulation of anthocyanins under salt stress. AB - The accumulation of anthocyanins in plants exposed to salt stress has been largely documented. However, the functional link and regulatory components underlying the biosynthesis of these molecules during exposure to stress are largely unknown. In a screen of second site suppressors of the salt overly sensitive3-1 (sos3-1) mutant, we isolated the anthocyanin-impaired-response-1 (air1) mutant. air1 is unable to accumulate anthocyanins under salt stress, a key phenotype of sos3-1 under high NaCl levels (120 mM). The air1 mutant showed a defect in anthocyanin production in response to salt stress but not to other stresses such as high light, low phosphorous, high temperature or drought stress. This specificity indicated that air1 mutation did not affect anthocyanin biosynthesis but rather its regulation in response to salt stress. Analysis of this mutant revealed a T-DNA insertion at the first exon of an Arabidopsis thaliana gene encoding for a basic region-leucine zipper transcription factor. air1 mutants displayed higher survival rates compared to wild-type in oxidative stress conditions, and presented an altered expression of anthocyanin biosynthetic genes such as F3H, F3'H and LDOX in salt stress conditions. The results presented here indicate that AIR1 is involved in the regulation of various steps of the flavonoid and anthocyanin accumulation pathways and is itself regulated by the salt-stress response signalling machinery. The discovery and characterization of AIR1 opens avenues to dissect the connections between abiotic stress and accumulation of antioxidants in the form of flavonoids and anthocyanins. PMID- 23925405 TI - Using Stake's qualitative case study approach to explore implementation of evidence-based practice. AB - Although the use of qualitative case study research has increased during the past decade, researchers have primarily reported on their findings, with less attention given to methods. When methods were described, they followed the principles of Yin; researchers paid less attention to the equally important work of Stake. When Stake's methods were acknowledged, researchers frequently used them along with Yin's. Concurrent application of their methods did not take into account differences in the philosophies of these two case study researchers. Yin's research is postpositivist whereas Stake's is constructivist. Thus, the philosophical assumptions they used to guide their work were different. In this article we describe how we used Stake's approach to explore the implementation of a falls-prevention best-practice guideline. We focus on our decisions and their congruence with Stake's recommendations, embed our decisions within the context of researching this phenomenon, describe rationale for our decisions, and present lessons learned. PMID- 23925406 TI - Introducing dyadic interviews as a method for collecting qualitative data. AB - In dyadic interviews, two participants interact in response to open-ended research questions. There are few precedents for using dyadic interviews as a technique for qualitative research. We introduce this method largely in comparison to focus groups, because both represent forms of interactive interviewing. We do not, however, view dyadic interviews as miniature focus groups, and treat them as generating their own opportunities and issues. To illustrate the nature of dyadic interviewing, we present summaries of three studies using this method. In the first study, we used dyadic interviews and photovoice techniques to examine experiences of people with early-stage dementia. In the second study, we explored the experiences of staff who provided services to elderly housing residents. In the third study, we examined barriers and facilitators to substance abuse treatment among Asian Americans and Pacific Islanders in Hawaii. We conclude with a discussion of directions for future research using dyadic interviews. PMID- 23925407 TI - Structural factors that increase HIV/STI vulnerability among indigenous people in the Peruvian amazon. AB - We examined structural factors-social, political, economic, and environmental that increase vulnerability to HIV among indigenous people in the Peruvian Amazon. Indigenous adults belonging to 12 different ethnic groups were purposively recruited in four Amazonian river ports and 16 indigenous villages. Qualitative data revealed a complex set of structural factors that give rise to environments of risk where health is constantly challenged. Ferryboats that cross Amazonian rivers are settings where unprotected sex-including transactional sex between passengers and boat crew and commercial sex work-often take place. Population mobility and mixing also occurs in settings like the river docks, mining sites, and other resource extraction camps, where heavy drinking and unprotected sex work are common. Multilevel, combination prevention strategies that integrate empirically based interventions with indigenous knowledge are urgently needed, not only to reduce vulnerability to HIV transmission, but also to eliminate the structural determinants of indigenous people's health. PMID- 23925408 TI - Characterization of blubber fatty acid signatures in northern elephant seals (Mirounga angustirostris) over the postweaning fast. AB - Phocids routinely fast for extended periods. During these fasts, energetic requirements are met primarily through the catabolism of blubber lipid. To assess whether fatty acid (FA) composition changes during the postweaning fast in northern elephant seals, blubber biopsies were acquired longitudinally from 43 pups at 2.3 +/- 1.5 and 55.2 +/- 3.7 days postweaning in 1999 and 2000. At weaning, short-chain monounsaturated FA (SC-MUFA, <=18 carbons) dominated the blubber while saturated FA (SFA) were found in the next highest proportion. The major FA (all >=1 % by mass) comprised approximately 91 % of total blubber FA. In both years, 18:1n-9 and 16:0 were the most prevalent FA. Major FA mobilized during the fast consisted of polyunsaturated FA (PUFA), SFA, and SC-MUFA. Long chain MUFA (>18 carbons) tended to be conserved. The fractional mobilization value of 20:5n-3 was the highest, resulting in significant reductions of this PUFA. Although concentrations of some blubber FA changed significantly during the postweaning fast, the general FA signature of blubber was similar at weaning and near the end of the fast. Changes in some FA differed across years. For example, the concentration of 20:4n-6, a minor PUFA, was significantly reduced in 1999 but not in 2000. FA mobilization patterns in northern elephant seal pups are somewhat similar to those reported previously for other fasting phocids and terrestrial mammals, though there are some notable differences. Differences in FA mobilization patterns across mammalian species may be related to differences in diets, geographical distribution, environmental factors, physiological adaptations, and life history stage. PMID- 23925409 TI - Measurements of substrate oxidation using (13)CO 2-breath testing reveals shifts in fuel mix during starvation. AB - Most fasting animals are believed to sequentially switch from predominantly utilizing one metabolic substrate to another from carbohydrates, to lipids, then to proteins. The timing of these physiological transitions has been estimated using measures of substrate oxidation including changes in respiratory exchange ratios, blood metabolites, nitrogen excretion, or enzyme activities in tissues. Here, we demonstrate how (13)CO2-breath testing can be used to partition among the oxidation of distinct nutrient pools in the body (i.e., carbohydrates, lipids, and proteins) that have become artificially enriched in (13)C. Seventy two Swiss Webster mice were raised to adulthood on diets supplemented with (13)C 1-L-leucine, (13)C-1-palmitic acid, (13)C-1-D-glucose, or no tracer. Mice were then fasted for 72 h during which [Formula: see text], [Formula: see text], delta(13)C of exhaled CO2, body temperature, body mass, and blood metabolites (i.e., glucose, ketone bodies, and triacylglycerols) were measured. The fasting mice exhibited reductions in body mass (29 %), body temperature (3.3 degrees C), minimum observed metabolic rates (24 %), and respiratory exchange ratio (0.18), as well as significant changes in blood metabolites; but these responses were not particularly indicative of changes in oxidative fuel mixture. Measurements of endogenous nutrient oxidation by way of (13)CO2-breath testing revealed a decrease in the rate of oxidation of carbohydrates from 61 to 10 % of the total energy expenditure during the first 6 h without food. This response was mirrored by a coincidental increase in rate of endogenous lipid oxidation from 18 to 64 %. A transient peak in carbohydrate oxidation occurred between 8 and 14 h, presumably during increased glycogen mobilization. A well-defined period of protein sparing between 8 and 12 h was observed where endogenous protein oxidation accounted for as little as 8 % of the total energy expenditure. Thereafter, protein oxidation continually increased accounting for as much as 24 % of the total energy expenditure by 72 h. This study demonstrates that (13)CO2 breath testing may provide a complementary approach to characterizing the timing and magnitude of sequential changes in substrate oxidation that occur during prolonged fasting and starvation. PMID- 23925410 TI - Comment on ''High BNP level as risk factor for acute kidney injury and predictor of all-cause mortality in STEMI patients''. PMID- 23925411 TI - [PCSK9 as new target in hyperlipidemia treatment]. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK 9) is a key regulator of cholesterol homeostasis acting via degradation of the low density lipoprotein (LDL) receptor. Loss of function PCSK 9 mutations result in very low LDL cholesterol serum levels and protection from cardiovascular disease whereas gain of function mutations increase serum LDL cholesterol. Based on in vitro and in vivo data antibodies targeting PCSK 9 have now emerged as a novel treatment option in patients with cardiovascular disease. This review briefly summarizes the biochemistry and function of PCSK9 and the results from recent phase II trials. PMID- 23925412 TI - Treating thrombus in the coronary arteries. AB - Primary percutaneous coronary intervention (PCI) has greatly improved outcomes in patients with ST-elevation myocardial infarction (STEMI) and has, therefore, become the preferred reperfusion strategy for this patient group. The goal of primary PCI is to achieve a thrombolysis in myocardial infarction (TIMI) 3 flow and also to restore adequate perfusion at the myocardial level. Distal thrombus embolization during primary PCI occurs frequently and is also associated with compromised long-term outcomes. In this article, we provide an overview of the treatment of thrombus and the role of thrombectomy in PCI for STEMI. PMID- 23925413 TI - Coronary subclavian steal syndrome: a case-based review. AB - Internal mammary artery (IMA) grafts have been shown to be superior to saphenous vein grafts in terms of rare atherosclerotic involvement, biochemical and physical qualities, and long-term patency rates. The IMA originates from the subclavian artery, just distal to the vertebral artery, and an occlusion or a hemodynamically significant stenosis proximal to the IMA ostium would cause a pressure drop distally and a reversal of flow from the coronary arteries to the IMA in patients with this graft. This condition is referred to as "coronary subclavian steal syndrome" (CSSS). In most cases, the cause of this syndrome is atherosclerotic disease; however, other causes of subclavian artery stenosis (SAS) have the potential to lead to CSSS. Patients with CSSS present with the symptoms of myocardial ischemia due to coronary steal, vertebrobasilar insufficiency, or limb ischemia. Discrepancy in the blood pressure (BP) measurements in two arms should warn the clinician of SAS. A diminished pulse or the bruit of jet flow on the lesion side can be noticed. Doppler ultrasonography, computed tomography angiography, and magnetic resonance angiography are safe and accurate noninvasive modes of diagnosis. Treatment can be surgical or percutaneous. PMID- 23925414 TI - Outcomes of the modified norwood procedure: hypoplastic left heart syndrome versus other single-ventricle malformations. AB - Recent studies have suggested that survival after the modified Norwood procedure is influenced by anatomy and is worse for patients with hypoplastic left heart syndrome (HLHS) than for patients with other forms of functional single ventricle. This study aimed to compare the outcomes of the modified Norwood procedure for these two groups at a single center. A retrospective chart review compared modified Norwood procedure outcomes between children with HLHS (n = 40) and children with other single-ventricle malformations (n = 19) from January 2002 to August 2012. The HLHS patients had a lower mean age (10.0 +/- 13.2 days) at the time of operation than the non-HLHS patients (16.5 +/- 18.5 days). The difference was not significant. The number of patients with a Sano modification was significantly higher in the HLHS group (HLHS 85 % vs non-HLHS 32 %; p < 0.001). The follow-up data did not differ between the groups (HLHS 3.6 +/- 3.2 years vs non-HLHS 4.8 +/- 3.3 years, nonsignificant difference). The overall operative survival was 85 %: 83 % for the patients with HLHS and 89 % for the patients with non-HLHS (nonsignificant difference). The Kaplan-Meier transplant free survival estimate at 10 years was 73 % and did not differ between the HLHS patients (67 %) and the non-HLHS patients (84 %, nonsignificant difference). The timing of stages 2 and 3 palliation (bidirectional Glenn and external conduit Fontan) did not differ significantly (HLHS, 7.0 +/- 2.8 months and 3.0 +/- 0.5 years vs non-HLHS 6.1 +/- 1.7 months and 2.8 +/- 0.8 years). The two groups were similar with respect to the need for post-Norwood extracorporeal membrane oxygenation support, aortic arch reinterventions, atrioventricular valve repair, pulmonary artery reconstruction, pacemaker implantation, and progression to bidirectional Glenn and Fontan completion. The modified Norwood reconstruction provides good palliation for HLHS as well as other forms of functional single ventricle anatomy. Survival, postoperative morbidity, and progression to Glenn and Fontan are not significantly different. PMID- 23925415 TI - How not to tell parents about their child's new diagnosis of congenital heart disease: an Internet survey of 841 parents. AB - An online survey for parents of children with congenital heart disease (CHD) was developed to study the perceptions and experiences of parents when receiving the diagnosis. The survey was distributed to online support groups. A total of 841 responses from parents of children with CHD in the United States were received over a 4-week period in 2010. The authors hypothesized that the counseling and demeanor of the pediatric cardiologist (PC) may be important factors in determining whether parents of children with CHD seek second opinions, and that the terminology used in counseling may be variably interpreted. Of the 841 respondents, 349 (41 %) received the diagnosis prenatally. A minority of the respondents received: support group information (14 %), Internet resources (21 %), success rates at other hospitals (16 %), or maximum ages of survivors (29 %). Among 26 % of the parents who reported seeking a second opinion from another PC, the majority (71 %) chose the second PC for long-term follow-up care. Those receiving a prenatal diagnosis were more likely to seek a second opinion than those receiving the diagnosis postnatally (32 vs 22 %; p < 0.01). Parents' perception of the PC's compassion and empathy was inversely related to the likelihood of seeking a second opinion. Parents were more likely to seek a second opinion when they were not optimistic about their child's life expectancy, felt pressured by the PC to terminate the pregnancy, were told that their child's death was "somewhat" or "very" likely, or were told the child's CHD was "rare" (all p < 0.01). Two thirds (66 %) of the respondents were told that their child's condition was "rare." The majority of these (77 %) reported that the term was used by the PC. "Rare" was interpreted as "occurring in less than a million births" by 25 %, and as "few or no other people alive with this defect" by 27 %. Parental interpretation of "rare" was unrelated to their levels of education. As reported by the respondents, 13 % felt pressured to terminate the pregnancy by the PC. Those with hypoplastic left heart syndrome were more likely to report feeling pressure to terminate the pregnancy by the PC (21 vs 9 %; p < 0.001) or the perinatologist (23 vs 14 %; p = 0.026). The approach to counseling and the demeanor of the PC have important implications for parents' perceptions of their child's chance of survival. The information given at diagnosis, the manner in which it is presented, and the parents' understanding and interpretation of that information are critical factors in shaping parents' perceptions and management decisions. PMID- 23925416 TI - A new method for evaluating tricuspid valve displacement in children with Ebstein's anomaly: using the annulus and coronary sinus as a reference point. AB - This study aimed to investigate the reference point for the downward displacement of the posterior and anterior leaflets of the tricuspid valve using echocardiography in children with Ebstein's anomaly. This study enrolled 25 patients with Ebstein's anomaly. The extent of downward displacement of the posterior and anterior leaflets of the tricuspid valve was evaluated by echocardiography using the tricuspid annulus and the coronary sinus as reference points. These results were compared with the surgical findings. The findings showed displacement of the simple septal leaflet in 1 patient, displacement of both the septal and posterior leaflets in 22 patients, displacement of both the anterior and posterior leaflets in 1 patient, and displacement of all the leaflets in 1 patient. Because the septal and posterior leaflets were close to the apex or because the posterior leaflet was nearly absent, the displacement distance of the septal and posterior leaflets could not be measured accurately in two patients. The displacement distance of the septal and posterior leaflets in the remaining 22 patients were 2.08 +/- 1.15 and 2.58 +/- 1.06 cm, respectively. The displacement distances of the anterior leaflet in two patients were respectively 1.0 and 2.2 cm. These results were similar to those measured during surgery. The direction of the valvular regurgitation flow was anterolateral in the apical four-chamber and apical right heart two-chamber views in patients with the downward displacement of the anterior leaflet. The tricuspid valve annulus and the coronary sinus are ideal reference points for evaluating the downward displacement of the posterior and anterior leaflets of the tricuspid valve. It is critical to evaluate the downward displacement of the anterior leaflet that the direction of the tricuspid regurgitation flow is changed. PMID- 23925418 TI - Doubly prenylated tryptamines: cytotoxicity, antimicrobial activity and cyclisation to the marine natural product flustramine A. AB - The marine natural product flustramine A was synthesised via oxidative cyclisation of Nb-methylated 1-prenyl-2-tert-prenyl-6-bromotryptamine and subsequent reduction of the resulting amidinium salt. Only the tert-prenyl group migrated, whereas the 1-prenyl group remained in place. Interestingly, the 2-tert prenylated precursor revealed to be the biologically most active of our entire series of 21 compounds. Required for cytotoxicity and antimicrobial activity was the presence of a non-cyclised tryptamine side chain carrying a free secondary amine, whereas the presence of a 6-bromo substituent did not enhance cytotoxicity. In a panel of 42 human tumor cell lines, most sensitive were the lung and mammary cancer cell lines LXFA629L (IC50 1.9 MUM) and MAXF401NL (IC50 2.4 MUM), respectively. In a serial dilution assay, satisfying IC50 values of 5.9 MUM against Micrococcus luteus and 7.7 MUM each against Mycobacterium phlei were determined for Nb-methyl-1-prenyl-2-tert-prenyl-6-bromotryptamine. PMID- 23925417 TI - Factors associated with remaining on initial randomized efavirenz-containing regimens. AB - OBJECTIVE: Efavirenz (EFV) along with two nucleoside reverse transcriptase inhibitors (NRTIs) is a recommended initial antiretroviral regimen. Understanding characteristics related to EFV success is clinically useful. DESIGN: Data from 2220 antiretroviral-naive participants randomized to EFV and two to three NRTIs in four ACTG trials as well as a long-term cohort were analysed. METHODS: Logistic regression, using inverse probability of censoring weighting to address selective-follow-up bias, was used to identify factors associated with EFV success (no treatment interruptions of >30 days, HIV RNA < 200 copies/ml) 1 year post initiation and at years 2-5 if successful at year 1. RESULTS: Pretreatment characteristics were median age 38 years, 82% male, 40% white, 10% history of IDU (HxIDU), median CD4+ T-lymphocyte 227 cells/MUl and 33% HIV RNA more than 100 ,000 copies/ml. In a multivariable model, factors associated with year 1 EFV success were race [white odds ratio (OR) 1.5; P < 0.001; Hispanic OR 1.5; P = 0.003 vs. black], no pretreatment sign/symptom grade 3 or higher (OR 1.7; P = 0.008) and no HxIDU (OR 1.7; P = 0.001). Predictors of EFV success at years 2-5 were no HxIDU (years 2-5; ORs 1.9-2.2); self-reported complete (4 days prior to study visit) adherence during year 1 (years 2-4; ORs 1.6-1.9); fewer missed visits during year 1 (years 2, 4, 5; ORs 0.92-0.98/1% increase); HIV RNA less than 50 copies/ml at year 1 (years 2, 3; ORs 1.9-2.2); and older age (>50 vs. <=30 years) (years 2-4: ORs 2.3-3.7). CONCLUSION: Characteristics predictive of EFV success in the short-term and longer term differed except for HxIDU. Behaviours occurring during year 1 were associated with EFV success over 5 years. PMID- 23925419 TI - A porous Mn(V) coordination framework with PtS topology: assessment of the influence of a terminal nitride on CO2 sorption. AB - A new coordination framework material, [Zn{MnN(CN)4(H2O)}].2H2O.MeOH, has been characterised crystallographically and the effect of a terminal nitride on the N2, H2 and CO2 sorption capacities of the material assessed through porosimetery measurements and DRIFTS. PMID- 23925420 TI - Apparent genotype-phenotype mismatch in a patient with MYH9-related disease: when the exception proves the rule. PMID- 23925421 TI - CuOx-TiO2 junction: what is the active component for photocatalytic H2 production? AB - CuOx based junctions e.g. CuOx-TiO2 have been demonstrated to be very effective in photocatalytic H2 production, but the active component at the junction is less understood. We herein report that an as-prepared CuOx-TiO2 photocatalyst undergoes an in situ restructuring process during photocatalytic H2 production under solar light irradiation to form the active Cu2O-TiO2 interfacial structure on the surface. These results unambiguously demonstrate that Cu2O is the active copper species in CuOx-TiO2 photocatalysts. PMID- 23925422 TI - Ni2+ and Cu2+ complexes of a phenanthroline-based ligand bind to G-quadruplexes at non-overlapping sites. AB - Transition metal complexes allow fine tuning of DNA binding affinity and selectivity. Here we report on the nucleic acid recognition properties of a phenanthroline-based ligand coordinated to Ni(2+) or Cu(2+). The resulting complexes clearly bind to telomeric G-quadruplexes at different sites according to the nature of the bound metal ion. PMID- 23925423 TI - Who are the PDCO? AB - In January 2007, the Paediatric Regulation entered into force and established the Paediatric Committee (PDCO) within the European Medicines Agency. The goal of the PDCO is to improve the health of the children of Europe by increasing high quality research for medicinal products and promoting the development and authorization of such medicines at the EU level. A major function of the PDCO is to formulate and authorize Paediatric Investigation Plans and Paediatric Use Marketing Authorisations. The EU's Seventh Framework Programme for Research has facilitated the establishment of consortia whose ultimate goal is to answer important clinical questions involving medicines commonly used "off-label", in children. The benefits of these consortia include enhanced collaboration amongst paediatricians, scientists and small to medium enterprises whose ultimate goal is to obtain an authorization for a new indication or formulation for use in the paediatric population. It will be interesting in a number of years time to measure the success of this very important European initiative. PMID- 23925424 TI - Increased SSeCKS expression in rat hepatic stellate cells upon activation in vitro and in vivo. AB - Recent reports suggest that src suppressed c kinase substrates (SSeCKS) are early inflammatory response protein. However, there is only scarce knowledge on the functional role of SSeCKS in liver under conditions of acute inflammation. In the present study, we investigated SSeCKS expression in liver after administration of carbon tetrachloride (CCl4) in rats and in isolated primary hepatic stellate cells (HSCs) upon activation on a plastic dish. We found that SSeCKS mRNA was hardly detectable in healthy liver tissue and further increased in carbon tetrachloride-mediated acute liver failure. SSeCKS protein expression was mainly found in hepatic stellate cells. In vitro, SSeCKS expression in activated rat HSCs was dramatically increased. The upregulation of SSeCKS protein expression in rat HSCs during activation in vitro and in vivo suggested the possibility of SSeCKS, an important part of function of the activated HSCs, perhaps through modulation of liver regeneration or formation of liver fibrosis after various injuries. PMID- 23925426 TI - Water adsorption properties controlled by coating/filling ordered mesoporous silica inside cellulose membranes. AB - Porous organic membranes have been utilized as hard templates not only for replication of porous macrostructures but also for fabrication of hierarchical porous solids through infiltration of precursor solutions in ordered mesoporous materials. However, such organic membranes are usually burned out as sacrificial skeletons by calcination. In addition, replicated macropores are too big to enhance properties due to inorganic oxide frameworks. In this study, when cellulose membranes were used as organic membranes, a coating/filling technology of ordered mesoporous silicas was proposed and the water adsorption-desorption properties were directly investigated by using the composite membranes after extraction of nonionic surfactants used. The composite membranes possessed enough adsorption capacity for water, which will be potentially useful for improving total energy efficiency in heat-pump and desiccant air conditioning systems. PMID- 23925425 TI - Synthesis, characterization, and biological studies of emissive rhenium-glutamine conjugates. AB - Two new rhenium complexes containing pyridine-triazole (pyta) and quinoline triazole (quinta) ligands with attached glutamine-targeting agents have been characterized and tested for uptake in the HT-29 human colon adenocarcinoma cell line. The glutamine moiety in Re(CO)3Br(pyta) (1) and Re(CO)3Br(quinta) (2) remains pendant in solution. Both complexes exhibit absorptions in the 300-400-nm range with metal-to-ligand charge transfer (MLCT) character, as predicted by time dependent density functional theory calculations. Geometrical analysis by theoretical calculations provides information on the cationic complexes 1 (+) and 2 (+) resulting from aquo for halide ligand exchange under aqueous conditions. The emissive properties of both complexes were studied under aqueous conditions, and the measured quantum yields were 0.46 % for 1 (+) and 0.18 % for 2 (+). The large Stokes shifts and oxygen sensitivity of the emission suggest a (3)MLCT process for both complexes. Cell studies in the HT-29 cell line demonstrate that both complexes are nontoxic over a large concentration range (0-1.4 mM). Preliminary uptake studies show that 2 (+), but not 1 (+), displays significant concentration-dependent uptake at 3 and 24 h. PMID- 23925427 TI - Comparison of oligomeric states and polypeptide compositions of fucoxanthin chlorophyll a/c-binding protein complexes among various diatom species. AB - Fucoxanthin chlorophyll a/c-binding protein (FCP) is a unique light-harvesting apparatus in diatoms. Several biochemical characteristics of FCP oligomer and trimer from different diatom species have been reported previously. However, the integration of information about molecular organizations and polypeptides of FCP through a comparison among diatoms has not been published. In this study, we used two-dimensional clear-native/SDS-PAGE to compare the oligomeric states and polypeptide compositions of FCP complexes from four diatoms: Chaetoceros gracilis, Thalassiosira pseudonana, Cyclotella meneghiniana, and Phaeodactylum tricornutum. FCP oligomer was found in C. gracilis, T. pseudonana, and C. meneghiniana, but not in P. tricornutum. The oligomerization varied among the three diatoms, although a predominant subunit having similar molecular weight was recovered in each FCP oligomer. These results suggest that the predominant subunit is involved in the formation of high FCP oligomerization in each diatom. In contrast, FCP trimer was found in all the diatoms. The trimerizations were quite similar, whereas the polypeptide compositions were markedly different. On the basis of this information and that from mass spectrometric analyses, the gene products in each FCP complex were identified in T. pseudonana and P. tricornutum. Based on these results, we discuss the role of FCP oligomer and trimer from the four diatoms. PMID- 23925428 TI - Comprehensive speciation of low-molecular weight selenium metabolites in mustard seeds using HPLC-electrospray linear trap/Orbitrap tandem mass spectrometry. AB - An analytical methodology based on high-resolution high mass accuracy electrospray ionization (ESI) tandem MS assisted by Se-specific detection using inductively coupled plasma mass spectrometry (ICP MS) was developed for speciation of selenium (Se) in seeds of black mustard (Brassica nigra) grown on Se-rich soil. Size-exclusion LC-ICP MS allowed the determination of the Se distribution according to the molecular mass and the control of the species stability during extraction. The optimization of hydrophilic interaction of LC and cation-exchange HPLC resulted in analytical conditions making it possible to detect and characterize over 30 Se species using ESI MS, including a number of minor (<0.5%) metabolites. Selenoglucosinolates were found to be the most important class of species accounting for at least 15% of the total Se present and over 50% of all the metabolites. They were found particularly unstable during aqueous extraction leading to the loss of Se by volatilization as methylselenonitriles and methylselenoisothiocyanates identified using gas chromatography (GC) with the parallel ICP MS and atmospheric pressure chemical ionization (APCI) MS/MS detection. However, selenoglucosinolates could be efficiently recovered by extraction with 70% methanol. Other classes of identified species included selenoamino acids, selenosugars, selenosinapine and selenourea derivatives. The three types of reactions leading to the formation of selenometabolites were: the Se-S substitution in the metabolic pathway, oxidative reactions of -SeH groups with endogenous biomolecules, and chemical reactions, e.g., esterification, of Se-containing molecules and other biomolecules through functional groups not involving Se. PMID- 23925429 TI - The causal effect of malaria on stunting: a Mendelian randomization and matching approach. AB - BACKGROUND: Previous studies on the association of malaria and stunted growth delivered inconsistent results. These conflicting results may be due to different levels of confounding and to considerable difficulties in elucidating a causal relationship. Randomized experiments are impractical and previous observational studies have not fully controlled for potential confounding including nutritional deficiencies, breastfeeding habits, other infectious diseases and socioeconomic status. METHODS: This study aims to estimate the causal effect between malaria episodes and stunted growth by applying a combination of Mendelian randomization, using the sickle cell trait, and matching. We demonstrate the method on a cohort of children in the Ashanti Region, Ghana. RESULTS: We found that the risk of stunting increases by 0.32 (P-value: 0.004, 95% CI: 0.09, 1.0) for every malaria episode. The risk estimate based on Mendelian randomization substantially differs from the multiple regression estimate of 0.02 (P-value: 0.02, 95% CI: 0.003, 0.03). In addition, based on the sensitivity analysis, our results were reasonably insensitive to unmeasured confounders. CONCLUSIONS: The method applied in this study indicates a causal relationship between malaria and stunting in young children in an area of high endemicity and demonstrates the usefulness of the sickle cell trait as an instrument for the analysis of conditions that might be causally related to malaria. PMID- 23925430 TI - Palladium-catalyzed oxidative direct C-H/C-H cross coupling of anilides with beta keto esters. AB - A Pd(II)-catalyzed oxidative direct C(sp(2))-H/C(sp(3))-H cross coupling of anilides with alpha-dicarbonyl compounds with Mn(OAc)3.2H2O as the oxidant is reported and this protocol provides facile access to alpha-aryl malonates and beta-keto esters in good yields and regioselectivity. PMID- 23925431 TI - Making beta cells from adult cells within the pancreas. AB - Cell therapy is currently considered as a potential therapeutic alternative to traditional treatments of diabetes. Islet and whole pancreas transplantations provided the proof-of-concept of glucose homeostasis restoration after replenishment of the deficiency of beta cells responsible for the disease. Current limitations of these procedures have led to the search for strategies targeting replication of pre-existing beta cells or transdifferentiation of progenitors and adult cells. These investigations revealed an unexpected plasticity towards beta cells of adult cells residing in pancreatic epithelium (eg, acinar, duct, and alpha cells). Here we discuss recent developments in beta cell replication and beta-cell transdifferentiation of adult epithelial pancreatic cells, with an emphasis on techniques with a potential for clinical translation. PMID- 23925432 TI - Use of glucagon-like peptide-1 agonists to improve islet graft performance. AB - Human islet transplantation is an effective and promising therapy for type I diabetes. However, long-term insulin independence is both difficult to achieve and inconsistent. De novo or early administration of incretin-based drugs is being explored for improving islet engraftment. In addition to its glucose dependent insulinotropic effects, incretins also lower postprandial glucose excursion by inhibiting glucagon secretion, delaying gastric emptying, and can protect beta-cell function. Incretin therapy has so far proven clinically safe and tolerable with little hypoglycemic risk. The present review aims to highlight the new frontiers in research involving incretins from both in vitro and in vivo animal studies in the field of islet transplant. It also provides an overview of the current clinical status of incretin usage in islet transplantation in the management of type I diabetes. PMID- 23925433 TI - Candidate genes expressed in human islets and their role in the pathogenesis of type 1 diabetes. AB - In type 1 diabetes (T1D), the insulin-producing beta cells are destroyed by an immune-mediated process leading to complete insulin deficiency. There is a strong genetic component in T1D. Genes located in the human leukocyte antigen (HLA) region are the most important genetic determinants of disease, but more than 40 additional loci are known to significantly affect T1D risk. Since most of the currently known genetic candidates have annotated immune cell functions, it is generally considered that most of the genetic susceptibility in T1D is caused by variation in genes affecting immune cell function. Recent studies, however, indicate that most T1D candidate genes are expressed in human islets suggesting that the functions of the genes are not restricted to immune cells, but also play roles in the islets and possibly the beta cells. Several candidates change expression levels within the islets following exposure to proinflammatory cytokines highlighting that these genes may be involved in the response of beta cells to immune attack. In this review, the compiling evidence that many of the candidate genes are expressed in islets and beta cells will be presented. Further, we perform the first systematic human islet expression analysis of all genes located in 50 T1D-associated GWAS loci using a published RNA sequencing dataset. We find that 336 out of 857 genes are expressed in human islets and that many of these interact in protein networks. Finally, the potential pathogenetic roles of some candidate genes will be discussed. PMID- 23925434 TI - Does the cation really matter? The effect of modifying an ionic liquid cation on an SN2 process. AB - The rate of reaction of a Menschutkin process in a range of ionic liquids with different cations was investigated, with temperature-dependent kinetic data giving access to activation parameters for the process in each solvent. These data, along with molecular dynamics simulations, demonstrate the importance of accessibility of the charged centre on the cation and that the key interactions are of a generalised electrostatic nature. PMID- 23925435 TI - Endoluminal ultrasound biomicroscopy as a reliable tool for in vivo assessment of colonic inflammation in rats. AB - PURPOSE: Endoscopic ultrasound (EUS) imaging of the colon is an important diagnostic tool for early neoplasia, although usually restricted to the rectum in inflammatory bowel disease (IBD). This study aimed to evaluate the ability of an endoluminal ultrasound biomicroscopic (eUBM) system to detect and characterize lesions simulating Crohn's disease in the colon of rats in vivo. METHODS: Colitis was induced with trinitrobenzene sulfonic acid instillated in the distal colon. Eighteen Wistar rats were submitted to eUBM in three time points: week 1 group (18 animals examined on day 3 after colitis induction), week 2 group (12 animals on days 3 and 10), and week 3 group (7 animals on days 3, 10, and 17). This design yielded distinct inflammation intensities. Three untreated rats were used for acquisition of control images. Scores were used for comparison with histology. RESULTS: Scores for eUBM and histology in the different moments of examination achieved a Spearman's rank correlation coefficient of 0.87 (p < 0.001). Findings of wall thickening presented positive predictive value (PPV) and sensitivity of 94 and of 100 %, respectively. Superficial and deep ulcers presented a PPV of 89 and 80 %, respectively, and negative predictive values of 100 and 85 %, respectively. CONCLUSION: Accurate detection and analysis of the lesions was achieved. The model is essential for the clinical development of the technique and a reproducible method for the evaluation of experimental colitis. eUBM might be applicable in different segments of the gut, developing into a novel adjunct method for IBD evaluation. PMID- 23925436 TI - FRET based tri-color emissive rhodamine-pyrene conjugate as an Al3+ selective colorimetric and fluorescence sensor for living cell imaging. AB - A rhodamine-pyrene hybrid molecule acts as a colorimetric and fluorimetric sensor for Al(3+) through time dependent PET-CHEF and FRET processes associated with tri color emission. Intracellular Al(3+) has been visualized through time dependent blue-green-red emission. The lowest limit of detection for Al(3+) is 0.02 MUM. PMID- 23925437 TI - Sleep duration, physical activity, and metabolic syndrome for adolescents. PMID- 23925438 TI - Identification of poor response to P2Y12 inhibitors in ACS patients with a new ELISA-based vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation assay. AB - A new ELISA technique has been developed to measure the vasodilator-associated stimulated phosphoprotein (VASP) platelet reactivity index (PRI) in clopidogrel treated patients. This technique has not been evaluated in acute coronary syndrome (ACS) patients or in prasugrel-treated patients. We assessed the accuracy of ELISA-VASP to identify high on-treatment platelet reactivity (HPR) in ACS patients in comparison with established platelet function tests. Platelet reactivity was measured in 240 ACS patients treated with clopidogrel (75 or 150 mg) or prasugrel (5 or 10 mg) using flow cytometry (FC-VASP) and the ELISA-VASP technique, light transmission aggregometry (LTA) and VerifyNow-P2Y12 assay (VN P2Y12). When using the ELISA-VASP PRI, the rate of patients with HPR in the overall ACS population was 15.5%, including a 27% rate in clopidogrel-treated patients and a 4% rate in prasugrel-treated patients. There was a strong correlation between ELISA-VASP PRI and FC-VASP PRI (r = 0.83, r2 = 0.68 p < 0.0001) with an area under the receiver-operating characteristics (ROC) curve to identify HPR (VASP-PRI >50% with FC-VASP) of 0.94, p<0.0001. The threshold of 60% for ELISA-VASP PRI provided the best accuracy (likelihood ratio= 23.67) to identify patients with HPR when compared to FC-VASP, LTA or VN-P2Y12 assays. In conclusion, ELISA-VASP is a fast, easy-to-use and specific test to identify HPR in ACS patients on thienopyridines. A 60% threshold value displays the best accuracy to identify HPR in these patients. PMID- 23925439 TI - Water swelling, brine soluble imidazole based zwitterionic polymers--synthesis and study of reversible UCST behaviour and gel-sol transitions. AB - New vinylbenzene substituted imidazole based zwitterionic polymers with unique characteristics like swelling in water and solubility in concentrated brine solution in which they exhibited a reversible upper critical solution temperature (UCST) and gel-sol transitions are reported herein. PMID- 23925441 TI - The mechanistic exploration of porous activated graphene sheets-anchored SnO2 nanocrystals for application in high-performance Li-ion battery anodes. AB - Porous activated graphene sheets have been for the first time exploited herein as encapsulating substrates for lithium ion battery (LIB) anodes. The as-fabricated SnO2 nanocrystals-porous activated graphene sheet (AGS) composite electrode exhibits improved electrochemical performance as an anode material for LIBs, such as better cycle performance and higher rate capability in comparison with graphene sheets, activated graphene sheets, bare SnO2 and SnO2-graphene sheet composites. The superior electrochemical performances of the designed anode can be ascribed to the porous AGS substrate, which improves the electrical conductivity of the electrode, inhibits agglomeration between particles and effectively buffers the strain from the volume variation during Li(+) intercalation-de-intercalation and provides more cross-plane diffusion channels for Li(+) ions. As a result, the designed anode exhibits an outstanding capacity of up to 610 mA h g(-1) at a current density of 100 mA g(-1) after 50 cycles and a good rate performance of 889, 747, 607, 482 and 372 mA h g(-1) at a current density of 100, 200, 500, 1000, and 2000 mA g(-1), respectively. This work is of importance for energy storage as it provides a new substrate for the design and implementation of next-generation LIBs exhibiting exceptional electrochemical performances. PMID- 23925440 TI - Accuracy and coverage assessment of Oryctolagus cuniculus (rabbit) genes encoding immunoglobulins in the whole genome sequence assembly (OryCun2.0) and localization of the IGH locus to chromosome 20. AB - We report on the analyses of genes encoding immunoglobulin heavy and light chains in the rabbit 6.51* whole genome assembly. This OryCun2.0 assembly confirms previous mapping of the duplicated IGK1 and IGK2 loci to chromosome 2 and the IGL lambda light chain locus to chromosome 21. The most frequently rearranged and expressed IGHV1 that is closest to IG DH and IGHJ genes encodes rabbit VHa allotypes. The partially inbred Thorbecke strain rabbit used for whole-genome sequencing was homozygous at the IGK but heterozygous with the IGHV1a1 allele in one of 79 IGHV-containing unplaced scaffolds and IGHV1a2, IGHM, IGHG, and IGHE sequences in another. Some IGKV, IGLV, and IGHA genes are also in other unplaced scaffolds. By fluorescence in situ hybridization, we assigned the previously unmapped IGH locus to the q-telomeric region of rabbit chromosome 20. An approximately 3-Mb segment of human chromosome 14 including IGH genes predicted to map to this telomeric region based on synteny analysis could not be located on assembled chromosome 20. Unplaced scaffold chrUn0053 contains some of the genes that comparative mapping predicts to be missing. We identified discrepancies between previous targeted studies and the OryCun2.0 assembly and some new BAC clones with IGH sequences that can guide other studies to further sequence and improve the OryCun2.0 assembly. Complete knowledge of gene sequences encoding variable regions of rabbit heavy, kappa, and lambda chains will lead to better understanding of how and why rabbits produce antibodies of high specificity and affinity through gene conversion and somatic hypermutation. PMID- 23925443 TI - Synthesis of beta-lactams by transition metal promoted Staudinger reactions: alternative synthetic approaches from transition metal enhanced organocatalysis to in situ, highly reactive intermediate synthesis and catalytic tandem reactions. AB - The development of new types of beta-lactam antibiotics is a relevant field of contemporary pharmaceutical research. Although many types of antibiotics are available on the market and widely used, beta-lactam antibiotics are considered to be one of the best choice as they are highly effective while having reasonable safety profiles. The wide application however has led to the appearance of resistant bacteria suppressing their efficacy. In the last decade fewer and fewer new antibiotics have been launched into the market, however more and more multiresistant germs have appeared posing significant threats especially to patients who are suffering from chronic diseases and have weakened immune systems. The development of new, highly efficient antibiotics is now direly needed. One of the options to accelerate beta-lactam antibiotic research is the development of alternative robust, convenient, versatile and cheap synthetic procedures in which the beta-lactam molecules can be easily synthesized with the desired diastereoselectivity. The most general way to introduce diastereoselectivity in the chemical reactions is the application of chiral catalyst systems. While there are several systems for the synthesis of beta lactams the transition metal assisted Staudinger reaction--[2 + 2] cycloaddition between a ketene and an imine--remained the most simple and most versatile methodology. The motivation behind this brief review is to draw the chemical community's attention to the relevance and applicability of transition metal promoted Staudinger reactions in beta-lactam based antibiotic development. This article summarizes the most relevant pioneer works completed on this field in order to open new ideas for the forthcoming organometallic systems based bioactive material development. PMID- 23925444 TI - Development of a quality-of-life instrument for autoimmune bullous disease: the Autoimmune Bullous Disease Quality of Life questionnaire. AB - IMPORTANCE: Quality-of-life (QOL) evaluation is an increasingly important outcome measure in dermatology, with disease-specific QOL instruments being the most sensitive to changes in disease status. OBJECTIVE: To develop a QOL instrument specific to autoimmune bullous disease (AIBD). DESIGN: A comprehensive item generation process was used to build a 45-item pilot Autoimmune Bullous Disease Quality of Life (ABQOL) questionnaire, distributed to 70 patients with AIBD. Experts in bullous disease refined the pilot ABQOL before factor analysis was performed to yield the final ABQOL questionnaire of 17 questions. We evaluated validity and reliability across a range of indices. SETTING: Australian dermatology outpatient clinics and private dermatology practices. PATIENTS AND EXPOSURE: Patients with a histological diagnosis of AIBD. MAIN OUTCOMES AND MEASURES: The development of an AIBD-specific QOL instrument. RESULTS: Face and content validity were established through the comprehensive patient interview process and expert review. In terms of convergent validity, the ABQOL was found to have a moderate correlation with scores on the Dermatology Life Quality Index (R = 0.63) and the General Health subscale of the 36-Item Short Form Health Survey (R = 0.69; P = .009) and low correlation with the Pemphigus Disease Area Index (R = 0.42) and Autoimmune Bullous Disease Skin Disorder Intensity Score (R = 0.48). In terms of discriminant validity, the ABQOL was found to be more sensitive than the Dermatology Life Quality Index (P = .02). The ABQOL was also found to be a reliable instrument evaluated by internal consistency (Cronbach alpha coefficient, 0.84) and test-retest reliability (mean percentage variation, 0.92). CONCLUSIONS AND RELEVANCE: The ABQOL has been shown to be a valid and reliable instrument that may serve as an end point in clinical trials. Future work should include incorporating patient weighting on questions to further increase content validity and translation of the measure to other languages. CLINICAL TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12612000750886. PMID- 23925445 TI - Sheep blood-LB agar base medium (SLM) as a simple and suitable medium for the cultivation of Leishmania major promastigotes. AB - Several methods of cultivation of Leishmania parasites are available, and among them, biphasic media like Nicolle-Novy-MacNeal medium are considered to be superior for the initial isolation of the parasites and their in vivo infectivity. In the present work, the efficacy of sheep blood-LB agar base medium (SLM) was evaluated for the cultivation of Leishmania major promastigotes. The SLM supports the proliferation of the parasites and can be used for routine isolation and cultivation of Leishmania parasites with acceptable in vivo infectivity for research purposes. PMID- 23925442 TI - Mechanisms for cachexia in heart failure. AB - The combination of profound muscle wasting and severe weight loss that occurs in heart failure is a complex phenomenon that involves the interplay of numerous factors. In this article, we describe processes that contribute to cachexia, as part of the clinical sequelae of heart failure, and their potential underlying mechanisms. While multiple mechanisms of cardiac cachexia have been described, we propose a multifactorial etiology for this condition that includes, but is not limited to, nutritional and gastrointestinal alterations, immunological and neurohormonal activation, and anabolic and catabolic imbalance. PMID- 23925446 TI - Potential efficacy of monthly administrations of spot-on moxidectin 2.5%/imidacloprid 10% in the simultaneous prevention of major canine filarioses. AB - Dirofilaria immitis, Dirofilaria repens, and Acanthocheilonema reconditum are the most important canine filariae. These species are expanding their distribution in both endemic regions and in previously free areas, thus enhancing the risk for single and mixed infestations in both dogs and humans. The present study evaluated the potential use of moxidectin in a spot-on formulation in preventing these dog filarioses in a confined area where the three major canine filariae live in sympatry. The trial was performed in a private shelter with a history of mixed infestations. Twenty-nine negative dogs were monthly treated with a spot-on formulation containing moxidectin 2.5%/imidacloprid 10% in spring and summer of 2010. The blood of the dogs was examined monthly with classical and molecular assays until December 2011. Twenty-six dogs completed the study, and they scored constantly negative to all diagnostic assays. Three further dogs completed the study in February 2011 until when they were filariae-negative. These results show that monthly treatment with moxidectin may potentially contribute in reducing the spreading of canine filarial diseases. The permanent negativity of treated dogs for the study period is discussed in relation to the potential use of this spot on formulation in the prevention of single and mixed infestations of major vector borne canine filariae. PMID- 23925447 TI - [Dermal and inhalation poisoning. Rare guests in our intensive care units?]. AB - Patients with dermal and inhalation poisoning are uncommon in intensive care treatment. We describe the diagnostics and specific toxicological treatment of patients with hydrofluoric acid burns. For inhalation poisoning, we focus on smoke inhalation, especially the management of cyanide and carbon monoxide poisoning. Special attention is given to the use of hyperbaric oxygenation for the treatment of carbon monoxide poisoning. PMID- 23925448 TI - Squeaking: Current knowledge and how to avoid it. AB - This review aims to update the reader with current thinking and research related to the well documented phenomenon of squeaking hip arthroplasties. The etiology of squeaking is multifactorial and still not well understood. We aim to share our own experience and views on the combination of factors we believe increases the likelihood of squeaking, along with mechanisms by which the sound may be generated. Recent published findings from other groups are summarized along with an appropriate management algorithm we recommend for this cohort of patients. PMID- 23925449 TI - Mammalian MT1 and MT2 metallothioneins differ in their metal binding abilities. AB - Metallothioneins (MTs) constitute a universal family of polymorphic, ubiquitous small Cys-rich metal-binding polypeptides that in mammals are represented by four highly similar isoforms (MT1 to MT4). MT1 and MT2 have generally been considered as equivalent proteins, so that they are commonly referred to as MT1/MT2. However, transcription data have suggested a differential behavior for both gene products. In the present study, the metal binding abilities of mouse MT2 (mMT2) with divalent (Zn(II) and Cd(II)) and monovalent (Cu(I)) ions were analyzed and compared to those of the mouse MT1 (mMT1) isoform, previously determined using the same methodological approach. The comprehensive consideration of all the results obtained in this work experimentally demonstrates that the mMT2 isoform exhibits metal ion binding abilities distinct from those of mMT1, with a clear preference for Zn(II) coordination, if compared to Cu(I) or even to Cd(II). This is in full agreement with the gene expression regulation pattern for the MT1 and MT2 genes, as well as with the hypothesized preferential role of mMT2 in Zn(II) homeostasis mechanisms, while MT1, possibly differentiated from a most recent duplication event in the mammalian MT gene cluster, would have evolved to detoxify Cd(II), and probably other divalent metal ions. PMID- 23925450 TI - Treatment with the CC chemokine-binding protein Evasin-4 improves post-infarction myocardial injury and survival in mice. AB - Chemokines trigger leukocyte trafficking and are implicated in cardiovascular disease pathophysiology. Chemokine-binding proteins, called "Evasins" have been shown to inhibit both CC and CXC chemokine-mediated bioactivities. Here, we investigated whether treatment with Evasin-3 (CXC chemokine inhibitor) and Evasin 4 (CC chemokine inhibitor) could influence post-infarction myocardial injury and remodelling. C57Bl/6 mice were submitted in vivo to left coronary artery permanent ligature and followed up for different times (up to 21 days). After coronary occlusion, three intraperitoneal injections of 10 MUg Evasin-3, 1 MUg Evasin-4 or equal volume of vehicle (PBS) were performed at 5 minutes, 24 hours (h) and 48 h after ischaemia onset. Both anti-chemokine treatments were associated with the beneficial reduction in infarct size as compared to controls. This effect was accompanied by a decrease in post-infarction myocardial leukocyte infiltration, reactive oxygen species release, and circulating levels of CXCL1 and CCL2. Treatment with Evasin-4 induced a more potent effect, abrogating the inflammation already at one day after ischaemia onset. At days 1 and 21 after ischaemia onset, both anti-chemokine treatments failed to significantly improve cardiac function, remodelling and scar formation. At 21-day follow-up, mouse survival was exclusively improved by Evasin-4 treatment when compared to control vehicle. In conclusion, we showed that the selective inhibition of CC chemokines (i.e. CCL5) with Evasin-4 reduced cardiac injury/inflammation and improved survival. Despite the inhibition of CXC chemokine bioactivities, Evasin-3 did not affect mouse survival. Therefore, early inhibition of CC chemokines might represent a promising therapeutic approach to reduce the development of post infarction heart failure in mice. PMID- 23925451 TI - D-dimer levels predict ischemic and hemorrhagic outcomes after acute myocardial infarction: a HORIZONS-AMI biomarker substudy. AB - D-dimer is a product of cross linked fibrin degradation and is a measure of the amount of fibrin turnover. As such, D-dimer might be of utility in the prediction of both thrombotic and hemorrhagic events. Therefore, the aim of the present study was to evaluate whether elevated D-dimer levels on admission and at discharge could predict subsequent ischemic and hemorrhagic events in patients with acute myocardial infarction (AMI). D-dimer was measured on admission and at discharge in 461 out of a total of 3,602 patients in the HORIZONS-AMI trial, as part of the formal prespecified biomarker substudy. The predictive value for major adverse cardiovascular events (MACE) and non-CABG major bleeding after 3 year follow up was investigated by stratifying patients in groups of D-dimer level and comparing event rates using Kaplan-Meier and calculating hazard ratios using Cox proportional hazards models. D-dimer levels >= 0.71 MUg/mL on admission were associated with an adjusted hazard ratio of 2.58 for MACE (p = 0.0014) and 4.61 for major bleeding (p = 0.0018). A discharge D-dimer level >= 1.26 MUg/mL was associated with a higher risk for MACE by univariate analysis (HR 1.88, p = 0.037), but lost its significance after multivariate adjustment (HR 1.77, p = 0.070). High D-dimer levels on admission were associated with a higher risk of MACE and non-CABG major bleeding in STEMI patients undergoing pPCI. PMID- 23925454 TI - [Fred Karl (2012). Transnational and translational. Current topics in the gerontological sciences]. PMID- 23925452 TI - The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: a multicenter randomized controlled trial. AB - BACKGROUND: Fatigue, cognitive deficits, and depression are frequently reported but often undertreated symptoms that can profoundly affect daily life in patients with primary brain tumors (PBTs). To evaluate the effects of the psychostimulant modafinil on fatigue, depression, health-related quality of life (HRQOL), and cognitive functioning in PBT patients, we performed a multicenter, double-blind placebo-controlled crossover trial. METHODS: Patients randomly received either 6 weeks of treatment with modafinil (up to 400 mg/day) or 6 weeks with placebo. After a 1-week washout period, the opposite treatment was provided. Assessments took place at baseline and immediately after the first and second condition. Patients completed self-report questionnaires on fatigue (Checklist Individual Strength [CIS]), depression (Center for Epidemiologic Studies Depression Scale [CES-D]), HRQOL (Short-Form Health Survey [SF-36]), and self-perceived cognitive functioning (Medical Outcomes Study [MOS]). They also underwent comprehensive neurocognitive testing. RESULTS: In total, 37 patients participated. Relative to baseline, patients reported lower fatigue severity (CIS) and better motivation (CIS) in both the modafinil (P = .010 and P = .021, respectively) and the placebo condition (P < .001 and P = .027, respectively). The same held for physical health (SF-36 Physical Component Summary score; P = .001 and P = .008, respectively), working memory (P = .040 and P = .043), and information processing capacity (P = .036 and P = .040). No improvement in depressive symptoms was found in either condition. CONCLUSIONS: Modafinil did not exceed the effects of placebo with respect to symptom management. Patient accrual was slow, and relatively many patients dropped out during the trial, due mostly to side effects. Other, preferably nonpharmacologic intervention studies should be considered to improve symptom management of PBT patients. PMID- 23925453 TI - Quantitative T2 mapping of recurrent glioblastoma under bevacizumab improves monitoring for non-enhancing tumor progression and predicts overall survival. AB - BACKGROUND: Anti-angiogenic treatment in recurrent glioblastoma patients suppresses contrast enhancement and reduces vasogenic edema while non-enhancing tumor progression is common. Thus, the importance of T2-weighted imaging is increasing. We therefore quantified T2 relaxation times, which are the basis for the image contrast on T2-weighted images. METHODS: Conventional and quantitative MRI procedures were performed on 18 patients with recurrent glioblastoma before treatment with bevacizumab and every 8 weeks thereafter until further tumor progression. We segmented the tumor on conventional MRI into 3 subvolumes: enhancing tumor, non-enhancing tumor, and edema. Using coregistered quantitative maps, we followed changes in T2 relaxation time in each subvolume. Moreover, we generated differential T2 maps by a voxelwise subtraction using the first T2 map under bevacizumab as reference. RESULTS: Visually segmented areas of tumor and edema did not differ in T2 relaxation times. Non-enhancing tumor volume did not decrease after commencement of bevacizumab treatment but strikingly increased at progression. Differential T2 maps clearly showed non-enhancing tumor progression in previously normal brain. T2 relaxation times decreased under bevacizumab without re-increasing at tumor progression. A decrease of <26 ms in the enhancing tumor following exposure to bevacizumab was associated with longer overall survival. CONCLUSIONS: Combining quantitative MRI and tumor segmentation improves monitoring of glioblastoma patients under bevacizumab. The degree of change in T2 relaxation time under bevacizumab may be an early response parameter predictive of overall survival. The sustained decrease in T2 relaxation times toward values of healthy tissue masks progressive tumor on conventional T2-weighted images. Therefore, quantitative T2 relaxation times may detect non-enhancing progression better than conventional T2-weighted imaging. PMID- 23925455 TI - Single-molecule magnet [Tb(hfac)3(2pyNO)] (2pyNO = t-butyl 2-pyridyl nitroxide) with a relatively high barrier of magnetization reversal. AB - The crystallographic analysis of the title compound shows that there are two crystallographically independent molecules in a unit cell. The magnetic study clarified that every molecule behaved as a single-molecule magnet. Two series of the out-of-phase ac susceptibility signals appeared around 10 K even at zero dc field. The activation energies (Delta) for the magnetization reversal were estimated as Delta((1))/k(B) = 39.2(3) K with tau0((1)) = 4.2(4) * 10(-8) s and Delta((2))/k(B) = 36(2) K with tau0((2)) = 4.1(12) * 10(-7) s, where tau0 stands for the pre-exponential factor in the Arrhenius analysis. Magnetic hysteresis was recorded at 1.6 K by means of a pulsed-field technique. The role of exchange coupling is discussed. PMID- 23925457 TI - Layer-by-layer self-assembly and disassembly of single charged inorganic small molecules: towards surface patterning. AB - The patterning of layer-by-layer (LbL) polyelectrolyte multilayers with metal ions is important for the facile fabrication of circuits or selective catalysis. The strategy includes two issues: the incorporation of metal ions and their controlled assembly-disassembly, which require a good understanding of the assembly mechanism. Therefore, we explored the LbL assembly between a polycation, poly-(diallyldimethylammonium chloride) (PDDA) and an inorganic single charged molecule, [AuCl4](-), which could assemble at pH = 3.7 and disassemble at lower pH values. Moreover, we have demonstrated that the driving force in the assembly is a ligand-to-metal charge transfer interaction. Combining the controlled assembly-disassembly of PDDA-[AuCl4](-) multilayers and photolithography, we obtained a surface pattern of PDDA-[AuCl4](-) multilayers. PMID- 23925456 TI - Unexpected helicity control and helix inversion: homochiral helical nanotubes consisting of an achiral ligand. AB - The ligand tppda has been designed and synthesized as molecular leverage for helicity control when reacted with Cd(2+) ions. The guests MeOH or DMF preferentially stabilize the P-helical isomer, while the guest H2O causes a helix inversion to give the M-helical isomer as the major isomer without any chiral auxiliary. PMID- 23925458 TI - Full-color CO2 gas sensing by an inverse opal photonic hydrogel. AB - CO2 gas sensing is of great importance because of the impact of CO2 on global climate change. Here, utilizing an inverse opal hydrogel, we describe a CO2 gas sensing method that allows highly sensitive and selective detection over a wide concentration range. The CO2 sensor is specific, quantitative, interference tolerant and without the need for special instruments. PMID- 23925460 TI - Li diffusion through doped and defected graphene. AB - We investigate the effect of nitrogen and boron doping on Li diffusion through defected graphene using first principles based density functional theory. While a high energy barrier rules out the possibility of Li- diffusion through the pristine graphene, the barrier reduces with the incorporation of defects. Among the most common defects in pristine graphene, Li diffusion through the divacancy encounters the lowest energy barrier of 1.34 eV. The effect of nitrogen and boron doping on the Li diffusion through doped defected-graphene sheets has been studied. N-doping in graphene with a monovacancy reduces the energy barrier significantly. The barrier reduces with the increasing number of N atoms. On the other hand, for N doped graphene with a divacancy, Li binds in the plane of the sheet, with an enhanced binding energy. The B doping in graphene with a monovacancy leads to the enhancement of the barrier. However, in the case of B doped graphene with a divacancy, the barrier reduces to 1.54 eV, which could lead to good kinetics. The barriers do not change significantly with B concentration. Therefore, divacancy, B and N doped defected graphene has emerged as a better alternative to pristine graphene as an anode material for Li ion battery. PMID- 23925459 TI - Pharmacological characterization of Solanum cernuum Vell.: 31-norcycloartanones with analgesic and anti-inflammatory properties. AB - Cycloeucalenone (1) and 24-oxo-31-norcycloartanone (2) obtained from Solanum cernuum Vell. were assayed to explore their pharmacologic roles. Previous studies showed that (2) has selective activity against lung tumor cell line (NCIH460) which expresses high levels of COX-2, suggesting its role in inflammatory process, and also a link between chronic inflammation and cancer-associated process. Dichloromethane crude extract (DCE) significantly reduced writhing and stretching induced by 0.8 % acetic acid at a dose of 100, 300, and 600 mg/kg, po; oral administration of different doses of (1) and (2) also displayed significant analgesic and anti-inflammatory effects in the writhing acetic acid test (p < 0.0001). Selected oral doses of both compounds (100 and 50 mg/kg) were assayed in the carrageenan-induced paw edema model. Compound (2) showed significant activity during the early phase (1.5-6 h) and also in the late phase (48 h) (p < 0.01). The anti-nociceptive activity observed for the compounds (1) and (2) and DCE was found to be related to the inhibition of different mediators involved in inflammation and nociceptive process. Both compounds decrease COX-2 protein expression, although only compound (2) reached a significant response (p < 0.05 vs control). However, in vitro Sirtuin 1 activity and TNF-alpha production in THP 1 macrophages were not affected. PMID- 23925461 TI - [Significantly shorter anesthesia time for surgery of the lumbar spine : process analytical comparison of spinal anesthesia and intubation narcosis]. AB - INTRODUCTION: Most surgery of the lumbar spine is performed with the patient under general anesthesia (GA); however, qualitative benefits of spinal anesthesia (SA) have been reported. The goal of this study was to compare time efficiency between these two anesthesia methods in lumbar spine surgery. To test the hypothesis that the use of SA leads to significant time saving compared to GA for lumbar spine surgery, key points in the preoperative, intraoperative and postoperative anesthesiology care times were analyzed. The focus was on anesthesia time excluding surgery time. MATERIALS AND METHODS: Electronically based data of 473 anesthesia procedures (368 SA, 105 GA) for lumbar spine interventions performed in the prone position (i. e. decompression, discectomy and transpedicular instrumentation) were analyzed retrospectively. Patient population data including gender, age, American Society of Anesthesiologists (ASA) classification and body mass index (BMI) were analyzed. The focus was on the documented perioperative key time points which are defined as follows: (1) induction, (2) positioning (turning into prone position), (3) scrubbing and covering, (4) surgery time (knife to skin closure), (5) closing (end of surgery until leaving operating room) and (6) handing over to recovery. Differences in the amount of time for each perioperative period were calculated for SA and GA. RESULTS: In 7 out of the 368 SA patients SA failed and had to be converted to GA. There were no significant differences in BMI, ASA prevalence and gender between SA and GA patients but SA patients were significantly older (median 61.7 +/- 15.4 years) than GA patients (median 56.1 +/- 14.6 years). However, SA required significantly less time for induction (SA: 17.7 +/- 7.0 min, GA: 21.6 +/- 7.2 min), preoperative preparation (SA: 9.7 +/- 3.6 min, GA: 13.3 +/- 5.4 min) and closing period (SA: 4.9 +/- 1.1 min, GA: 15.3 +/- 5.7 min) compared to GA. Total anesthesia time with exclusion of the surgery time revealed a significant time reduction using SA of 19 min (95 % confidence interval: range 13.6-24.4 min, median in SA: 56.7 min, median in GA: 75.7 min, p < 0.0001). CONCLUSIONS: This study showed that in lumbar spine surgery 19 min of anesthesia time can be saved using SA compared to GA which could have an impact on economic aspects. Gender, BMI and ASA had no statistically detectable influence on the choice between the two anesthesia methods. The fact that time-intensive complex instrumentation is mainly performed in younger patients may explain why GA patients were younger than SA patients. PMID- 23925462 TI - [Accidental hypothermia]. AB - Uncertainty exists on how to treat patients suffering from accidental hypothermia and on the optimal transport decisions. The aim of this review is to provide an updated evidence-based reference for the pre-hospital and in-hospital management of patients with accidental hypothermia and for the transport decisions required to facilitate treatment. Advances in the efficiency and availability of rewarming techniques have improved the prognosis for patients presenting with hypothermia. For hypothermic patients with a core body temperature >= 28 degrees C without cardiac instability there is increasing evidence to support the use of active external and minimally invasive rewarming techniques (e.g. chemical, electrical or forced air heating packs, blankets and warm parenteral fluids). Hypothermic patients with cardiac instability (i.e. systolic blood pressure < 90 mmHg, ventricular arrhythmia and core body temperature < 28 degrees C) should be rewarmed with active external and minimally invasive rewarming techniques in a hospital which also has circulation substituting venous-arterial extracorporeal membrane oxygenation (VA-ECMO) and cardiopulmonary bypass (CBP) facilities. In cardiac arrest patients VA-ECMO may be a better treatment option than CBP and survival rates of 100 % can be achieved compared to ~ 10 % with traditional methods (e.g. body cavity lavage). Early transport to a hospital appropriately equipped for rewarming has the potential to decrease complication rates and improve survival. PMID- 23925463 TI - [Comments on: in-flight medical emergencies]. PMID- 23925464 TI - [Hydroxyethyl starch : position statement by the Presidents of the DGAI (German Society of Anaesthesiology and Intensive Care Medicine), the BDA (Professional Association of German Anaesthetists) and the DAAF (German Academy for Further Education in Anaesthesiology)]. PMID- 23925465 TI - [Limited applications for hydroxyethyl starch : background and alternative concepts]. AB - BACKGROUND: Within the framework of a risk assessment procedure the Committee for Risk Assessment of Pharmacovigilance (PRAC) of the European Medicines Agency (EMA) came to the conclusion that the benefits of hydroxylethyl starch infusion solutions (HES) no longer outweighed the risks and on 14 June 2013 recommended that approval should be suspended. Until the procedure has finally been concluded, which could last several months, the Federal Institute for Drugs and Medical Products (BfArM) has recommended that HES should not be used. AIM: The aim of this article is to present the data situation in the most objective and compact way and to ultimately give the reader the foundations in order to be able to form a personal opinion. In addition an attempt will be made to describe a concept how infusion therapy can be carried out without using hydroxyethyl starch (HES). MATERIAL AND METHODS: The background to this decision is given based on a review of the literature and the relevance for intensive care, emergency and perioperative medicine is assessed. Furthermore, a concept of infusion therapy without hydroxyethyl starch is formulated also based on the results of current studies. RESULTS: For infusion regimens without HES it should be noted that gelatin represents a considerable risk for anaphylactic reactions, that transfer of the new variants of Creutzfeldt-Jacob disease (bovine spongiform encephalopathy BSE) cannot fundamentally be excluded and that some evidence has been found that gelatin can cause kidney injury, probably in a similar way to HES. With respect to the cost-benefit analysis of infusion solutions, blood loss in adults of approximately 1-1.5 l can be substituted by balanced crystalloids (basic therapy 4-5 times compared to the amount of blood lost). For larger blood losses small amounts of hyperoncotic albumin solution (20 %) or alternatively 5 % albumin solution can be used. The 20 % albumin solution seems to have some advantages because it has a higher volume effect (approximately 200 %) and can be more favourable for the fluid balance than 5 % albumin solution. Blood losses greater than 2-3 l normally also require administration of blood products (e.g. fresh frozen plasma FFP and erythrocyte concentrates EC). CONCLUSIONS: The third generation HES solutions cannot be completely replaced by other colloids and in future crystalloids will more strongly again broadly form the basis for infusion therapy. In this aspect balanced crystalloids have priority with respect to the acid-base equilibrium. The history of HES has impressively shown that infusion therapy must be adjusted on a scientifically founded basis, whether in intensive care medicine, perioperative or emergency medicine. Large prospective studies with clinically relevant endpoints are urgently needed. PMID- 23925467 TI - Synthesis of heterocyclic-fused benzofurans via C-H functionalization of flavones and coumarins. AB - An efficient method to effect C-O cyclization was developed via the C-H functionalization of chromones and coumarins, affording heterocyclic-fused benzofurans. PMID- 23925466 TI - Psoriasis severity and the prevalence of major medical comorbidity: a population based study. AB - IMPORTANCE: Despite the growing literature on comorbidity risks in psoriasis, there remains a critical knowledge gap on the degree to which objectively measured psoriasis severity may affect the prevalence of major medical comorbidity. OBJECTIVE: To examine the prevalence of major medical comorbidity in patients with mild, moderate, or severe psoriasis, classified objectively based on body surface area involvement, compared with that in patients without psoriasis. DESIGN, SETTING, AND PARTICIPANTS: Population-based cross-sectional study of patient data from United Kingdom-based electronic medical records; analysis included 9035 patients aged 25 to 64 years with psoriasis and 90,350 age and practice-matched patients without psoriasis. MAIN OUTCOMES AND MEASURES: Prevalence of major medical comorbidity included in the Charlson comorbidity index. RESULTS: Among patients with psoriasis, 51.8%, 35.8%, and 12.4%, respectively, had mild, moderate, or severe disease based on body surface area criteria. The mean Charlson comorbidity index was increasingly higher in patients with mild (0.375 vs 0.347), moderate (0.398 vs 0.342), or severe psoriasis (0.450 vs 0.348) (each P < .05). Psoriasis overall was associated with higher prevalence of chronic pulmonary disease (adjusted odds ratio, 1.08; 95% CI, 1.02-1.15), diabetes mellitus (1.22; 1.11-1.35), diabetes with systemic complications (1.34; 1.11-1.62), mild liver disease (1.41; 1.12-1.76), myocardial infarction (1.34; 1.07-1.69), peptic ulcer disease (1.27; 1.03-1.58), peripheral vascular disease (1.38; 1.07-1.77), renal disease (1.28; 1.11-1.48), and rheumatologic disease (2.04; 1.71-2.42). Trend analysis revealed significant associations between psoriasis severity and each of the above comorbid diseases (each P < .05). CONCLUSIONS AND RELEVANCE: The burdens of overall medical comorbidity and of specific comorbid diseases increase with increasing disease severity among patients with psoriasis. Physicians should be aware of these associations in providing comprehensive care to patients with psoriasis, especially those presenting with more severe disease. PMID- 23925468 TI - Aorto-right atrial fistula: a rare complication of trans-septal puncture and catheter ablation for atrial fibrillation. PMID- 23925469 TI - Benefits of multimodality imaging for pulmonary venous anatomy evaluation. PMID- 23925471 TI - Editorial notes. PMID- 23925470 TI - Atrioesophageal fistula secondary to pulmonary vein cryo-ablation. PMID- 23925472 TI - Temperature rise on the external root surface during removal of endodontic fractured instruments. AB - OBJECTIVES: To investigate the temperature rise (TR) on the external root surface while preparing a staging platform, for removing intra-canal fractured instruments, using Gates Glidden (GG) drills. MATERIALS AND METHODS: Thirty extracted mandibular incisors were decoronated and 3-3.5 mm of F3 ProTaper files were fractured 3 mm from the most coronal end of the root. Roots were divided into three groups. GG drills were used in a size-2 to size-5 sequence to prepare the staging platform coronal to the fractured segment. They were rotated at three speeds according to the study groups: group A for 2,000 revolutions per minute (rpm); group B for 4,000 rpm; and group C for 8,000 rpm. Temperature changes were recorded at the proximal and buccal or lingual external root surfaces while preparing the staging platform. Data were analyzed using the paired sample T, one and two-ways ANOVA tests at p <= 0.05. RESULTS: Overall, TR at the proximal root surface (5.44 degrees C) was significantly higher than that at the buccal or lingual surface (3.25 degrees C) (p < 0.001). Generally, TR increased significantly as the size of GG drills or the revolution speed increased (p < 0.05). GG5 drills rotated at 8,000 rpm produced the highest TR (10.85 degrees C). There was no interaction effect of the GG drill size and the revolution speed on TR (p = 0.272). CONCLUSION: The highest TR on the external root surface, associated with preparation of a staging platform and produced by using GG drills size-5 rotating at up to 8,000 rpm, was lower than the damaging threshold. CLINICAL RELEVANCE: A staging platform can be performed by modified GG drills (no 2 to 5) rotating at 8,000 rpm without generating a hazardous TR. PMID- 23925473 TI - Is there a need for orthodontic plaque indices?--diagnostic accuracy of four plaque indices. AB - OBJECTIVES: The aim of this study was to assess the diagnostic performance and accuracy of four plaque indices for orthodontic patients. MATERIALS AND METHODS: The plaque accumulation of 140 maxillary incisors with bonded brackets was recorded using intra-oral photographs and assessed using four different plaque indices: the orthodontic plaque (OP) index, the modified orthodontic plaque (MOP) index, the Quigley and Hein (QHP) index and the modified Navy plaque (MNP) index. The assessment was performed twice within a time interval of 4 weeks by four different examiner groups: orthodontists, dentists, students and orthodontic assistants. RESULTS: No significant differences were detected for the OP and MOP indices among the examiner groups. A significant difference was found for the QHP and MNP indices. The inter- and intra-examiner reliability of the OP and MOP indices was good. In contrast, the reliability for the QHP and MNP indices was moderate to poor with few exceptions. The discrimination performance of the OP and MOP indices was excellent. The sum of the sensitivity and specificity was generally lower for the QHP and MNP indices compared with the OP and MOP indices. CONCLUSION: OP and MOP indices showed good performance. The QHP and MNP indices are not appropriate for orthodontic purposes. CLINICAL RELEVANCE: Traditional plaque indices reflect the typical pattern of plaque accumulation for patients without multi-bracket appliances. The performance of these indices for orthodontic patients has never been investigated. Orthodontic plaque indices that focus on the surface along the gingival margin and areas around the bracket exhibit higher diagnostic performance and accuracy compared with traditional indices. PMID- 23925474 TI - Targeting folded RNA: a branched peptide boronic acid that binds to a large surface area of HIV-1 RRE RNA. AB - On-bead high-throughput screening of a medium-sized (1000-2000 Da) branched peptide boronic acid (BPBA) library consisting of 46,656 unique sequences against HIV-1 RRE RNA generated peptides with binding affinities in the low micromolar range. In particular, BPBA1 had a K(d) of 1.4 MUM with RRE IIB, preference for RNA over DNA (27 fold), and selectivity of up to >75 fold against a panel of RRE IIB variants. Structure-activity studies suggest that the boronic acid moiety and "branching" in peptides are key structural features for efficient binding and selectivity for the folded RNA target. BPBA1 was efficiently taken up by HeLa and A2780 cells. RNA-footprinting studies revealed that the BPBA1 binding site encompasses a large surface area that spans both the upper stem as well as the internal loop regions of RRE IIB. PMID- 23925475 TI - A test for enhancement of cytotype regulation in Drosophila melanogaster by the transposase-encoding P element ?2-3. AB - Transposable P elements are regulated in the germ line by piRNAs, which are small RNAs that associate with the Piwi class of proteins. This regulation, called the P cytotype, is enhanced by genetic interactions between P elements that are primary sources of these RNAs and other P elements. The enhanced regulation is thought to reflect amplification of the primary piRNAs by cleavage of mRNAs derived from the other P elements through a mechanism called the ping-pong cycle. We tested the transposase-encoding P element known as ?2-3 for its ability to enhance cytotype regulation anchored in P elements inserted at the telomere of the left arm of the X chromosome (TP elements). The ?2-3 P element lacks the intron between exons 2 and 3 in the structurally complete P element (CP). Unlike the CP element, it does not markedly enhance cytotype regulation anchored in TP elements, nor does it transmit transposase activity through the egg cytoplasm. However, mRNAs from both the CP and ?2-3 elements are maternally deposited in embryos. These observations suggest that maternally transmitted CP mRNA enhances cytotype regulation by participating in the ping-pong cycle and that it encodes the P transposase in the embryonic germ line, whereas maternally transmitted ?2-3 mRNA does not, possibly because it is not efficiently directed into the primordial embryonic germ line. Strong transposon regulation may, therefore, require ping-pong cycling with maternally inherited mRNAs in the embryo. PMID- 23925477 TI - Core-shell catalysts consisting of nanoporous cores for oxygen reduction reaction. AB - A comprehensive experimental study was conducted on the dealloying of PdNi6 nanoparticles under various conditions. A two-stage dealloying protocol was developed to leach >95% of Ni while minimizing the dissolution of Pd. The final structure of the dealloyed particle was strongly dependent on the acid used and temperature. When H2SO4 and HNO3 solutions were used in the first stage of dealloying, solid and porous particles were generated, respectively. The porous particles have a 3-fold higher electrochemical surface area per Pd mass than the solid ones. The dealloyed PdNi6 nanoparticles were then used as a core material for the synthesis of core-shell catalysts. These catalysts were synthesized in gram-size batches and involved Pt displacement of an underpotentially deposited (UPD) Cu monolayer. The resulting materials were characterized by scanning transmission electron microscopy (STEM) and in situ X-ray diffraction (XRD). The oxygen reduction reaction (ORR) activity of the core-shell catalysts is 7-fold higher than the state-of-the-art Pt/C. The high activity was confirmed by a more than 40 mV improvement in fuel cell performance with a Pt loading of 0.1 mg cm( 2) by using the core-shell catalysts. PMID- 23925478 TI - Efficient band-selective homonuclear CO-CA cross-polarization in protonated proteins. AB - Previously introduced for highly deuterated proteins, band-selective magnetization transfer between CO and CA spins by dipolar-based homonuclear cross polarization is applied here to a protonated protein. Robust and efficient recoupling is achieved when the sum of effective radio-frequency fields on CO and CA resonances equals two times the spinning rate, yielding up to 33% of magnetization transfer efficiency in protonated ubiquitin. The approach is designed for moderate magic-angle spinning rates and high external magnetic fields when the isotropic chemical shift difference of CO and CA considerably exceeds the spinning rate. This method has been implemented in NiCOi-1CAi-1 and CAi(Ni)COi-1CAi-1 two-dimensional interresidual correlation experiments for fast and efficient resonance assignment of ubiquitin by solid-state NMR spectroscopy. PMID- 23925479 TI - Analytical methods for copper, zinc and iron quantification in mammalian cells. AB - Highly complex analytical methods with different accuracies of measurement, reproducibilities and ease of analyses are currently being used to quantify metals in cellular media and tissue samples. In this review, the analytical methods commonly used for iron, copper and zinc quantification in mammalian cells are presented and discussed. Herein, we present a literature survey of the most commonly found concentrations of these metals in various mammalian cells in culture and tissues. The aim of this review is to help researchers in metallomic related areas identify the method that best suits their needs for the accurate quantification of these metals in cells. This accuracy goes beyond simple knowledge of the limit of detection of each technique and needs to be evaluated through comparisons with similar previous studies. PMID- 23925480 TI - A MU-oxo hetero dimer of silicon phthalocyanine and naphthalocyanine. AB - A novel MU-oxo hetero dimer of silicon phthalocyanine and silicon naphthalocyanine was synthesized. Its unique optical properties, such as a single Q band, which is unusual for hetero dimer species, and solvatochromic behavior, were revealed to be better interpreted by taking interchromophore interactions into consideration. PMID- 23925476 TI - Platelet count and outcome in patients with acute venous thromboembolism. AB - The relationship between platelet count and outcome in patients with acute venous thromboembolism (VTE) has not been consistently explored. RIETE is an ongoing registry of consecutive patients with acute VTE. We categorised patients as having very low- (<80,000/ul), low- (80,000/ul to 150,000/ul), normal- (150,000/ul to 300,000/ul), high- (300,000/ul to 450,000/ul), or very high (>450,000/ul) platelet count at baseline, and compared their three-month outcome. As of October 2012, 43,078 patients had been enrolled in RIETE: 21,319 presenting with pulmonary embolism and 21,759 with deep-vein thrombosis. In all, 502 patients (1.2%) had very low-; 5,472 (13%) low-; 28,386 (66%) normal-; 7,157 (17%) high-; and 1,561 (3.6%) very high platelet count. During the three-month study period, the recurrence rate was: 2.8%, 2.2%, 1.8%, 2.1% and 2.2%, respectively; the rate of major bleeding: 5.8%, 2.6%, 1.7%, 2.3% and 4.6%, respectively; the rate of fatal bleeding: 2.0%, 0.9%, 0.3%, 0.5% and 1.2%, respectively; and the mortality rate: 29%, 11%, 6.5%, 8.8% and 14%, respectively. On multivariate analysis, patients with very low-, low-, high- or very high platelet count had an increased risk for major bleeding (odds ratio [OR]: 2.70, 95% confidence interval [CI]: 1.85-3.95; 1.43 [1.18-1.72]; 1.23 [1.03-1.47]; and 2.13 [1.65-2.75]) and fatal bleeding (OR: 3.70 [1.92-7.16], 2.10 [1.48-2.97], 1.29 [0.88-1.90] and 2.49 [1.49-4.15]) compared with those with normal count. In conclusion, we found a U-shaped relationship between platelet count and the three month rate of major bleeding and fatal bleeding in patients with VTE. PMID- 23925481 TI - Hydrogeochemical factors affecting the mobilization of As into the groundwater of the Brahmaputra alluvial plains of Assam, Northeast India. AB - Groundwater in the Brahmaputra river basin is known to contain an elevated concentration of naturally occurring Arsenic (As). To better understand the mobilization processes responsible for the As enrichment in the groundwater of the alluvial plains of the Brahmaputra river, the hydrochemical characteristics of the groundwater were studied in two districts, namely the Darrang and Jorhat districts of Assam. A total of 217 groundwater samples were analyzed for 20 water quality parameters. A lower As concentration was observed in the Darrang district with a mean concentration of 0.02 MUg l(-1), while the Jorhat district had a higher As concentration (mean 100 MUg l(-1)). The groundwater in the study areas is characterized by high concentrations of dissolved Fe, Mn, HCO3(-) and PO4(3-) and low concentrations of NO3(-) and SO4(2-). The redox potential and the groundwater composition showed reducing conditions in the groundwater. A difference in the groundwater geochemistry between the two districts was observed and was mainly controlled by the redox conditions in the subsurface, which control the mobility of As in the floodplains. The saturation indices of various As associated minerals were calculated using the geochemical code PHREEQC. The mobilization of As into the groundwater was anticipated to be largely controlled by the reductive dissolution of Fe-oxides and Mn-oxides and partly by competitive anions viz. PO4(3-). PMID- 23925482 TI - Why activated protein C was not successful in severe sepsis and septic shock: are we still tilting at windmills? AB - Drotrecogin alpha activated (DAA), trade name Xigris, is a recombinant human protein C that has been the subject of controversy since 2001, when it became the first biologic agent approved for the treatment of severe sepsis and septic shock. The PROWESS trial showed a 6.1 % absolute reduction in 28-day mortality, although these findings were not replicated in later trials, ultimately leading to the withdrawal of DAA in 2011. Observational trials, however, have consistently shown a mortality benefit with the use of DAA, leading to the following questions: Did DAA truly fail and, if so, why? While these questions may never be definitively answered on the basis of available evidence, several factors may explain the conflicting results. In clinical practice, DAA may have been preferentially given to subjects more likely to survive. Contemporary treatments, including early antibiotic administration and volume resuscitation, may have mitigated the inflammatory processes leading to disordered coagulation and microvascular thrombosis and, thus, reduced or abolished the therapeutic opportunity for DAA. Later randomized clinical trials of DAA focused on the clinical phenotype of refractory shock, largely due to a strong efficacy signal in this subset from PROWESS; however, this clinical phenotype may not be tightly linked, at least after contemporary early resuscitation strategies, to the mechanistic phenotype of dysregulated coagulation that may have been a better target for DAA. Future trials of biologic therapies in severe sepsis and septic shock should use a combination of clinical phenotype and biomarkers to identify responsive populations that may benefit from such therapies. PMID- 23925483 TI - An alternative mechanism for cleistogamy in barley. AB - Cleistogamy in barley is genetically determined by the presence of the recessive allele cly1, but the dominant allele at the linked locus Cly2 is epistatic over cly1. Although the molecular basis for cly1 action is well understood, that of Cly2 is not. Here we show that anther non-extrusion can occur not just when the lodicules fail to expand adequately (a trait which is fully determined by the allelic state at the cly1 locus), but by the premature timing of anthesis before the spike has emerged from the boot. The transcription of HvAP2 at cly1 is unaffected by the timing of anthesis. Where this occurs prematurely, by the time that the spike has emerged from the boot, the lodicules have already become shrunken and have lost the capacity to push the lemma and palea apart. Premature anthesis appears to be governed by a dominant gene, probably Cly2. Of the three phases of development of a non-cleistogamous barley floret (spike emergence from the boot, floret gaping induced by lodicule expansion and anther extrusion), genetic variation is available regarding at least the former two. PMID- 23925484 TI - Exchange of extracellular domains of CCR1 and CCR5 reveals confined functions in CCL5-mediated cell recruitment. AB - The chemokine CCL5 recruits monocytes into inflamed tissues by triggering primarily CCR1-mediated arrest on endothelial cells, whereas subsequent spreading is dominated by CCR5. The CCL5-induced arrest can be enhanced by heteromer formation with CXCL4. To identify mechanisms for receptor-specific functions, we employed CCL5 mutants and transfectants expressing receptor chimeras carrying transposed extracellular regions. Mutation of the basic 50s cluster of CCL5, a coordinative site for CCL5 surface presentation, reduced CCR5- but not CCR1 mediated arrest and transmigration. Impaired arrest was restored by exchanging the CCR5-N-terminus for that of CCR1, which supported arrest even without the 50s cluster, whereas mutation of the basic 40s cluster essential for proteoglycan binding of CCL5 could not be rescued. The enhancement of CCL5-induced arrest by CXCL4 was mediated by CCR1 requiring its third extracellular loop. The domain exchanges did not affect formation and co-localisation of receptor dimers, indicating a sensing role of the third extracellular loop for hetero-oligomers in an arrest microenvironment. Our data identify confined targetable regions of CCR1 specialised to facilitate CCL5-induced arrest and enhanced responsiveness to the CXCL4-CCL5 heteromer. PMID- 23925485 TI - Alterations in the antioxidant defense system in prepubertal children with a history of extrauterine growth restriction. AB - PURPOSE: The role of oxidative stress is well known in the pathogenesis of acquired malnutrition. Intrauterine growth restriction has been associated with an imbalance in oxidative stress/antioxidant system. Therefore, early postnatal environment and, consequently, extrauterine growth restriction might be associated with alterations in the antioxidant defense system, even in the prepubertal stage. METHODS: This is a descriptive, analytical, and observational case-control study. The study included two groups; 38 Caucasian prepubertal children born prematurely and with a history of extrauterine growth restriction as the case group, and 123 gender- and age-matched controls. Plasma exogenous antioxidant (retinol, beta-carotene, and alpha-tocopherol) concentrations were measured by HPLC; antioxidant enzyme activities of catalase, glutathione reductase, glutathione peroxidase, and superoxide dismutase were determined in lysed erythrocytes by spectrophotometric techniques. RESULTS: Catalase and glutathione peroxidase concentrations were significantly lower in extrauterine growth restriction children than in controls (P < 0.001). Lower plasma retinol concentrations were found in the case group (P = 0.029), while concentrations of beta-carotene and alpha-tocopherol were higher (P < 0.001) in extrauterine growth restriction prepubertal children as compared with controls. After correction by gestational age, birth weight, and length, statistically significant differences were also found, except for retinol. CONCLUSIONS: Prepubertal children with a history of extrauterine growth restriction present alterations in their antioxidant defense system. Knowing these alterations may be important in establishing pharmacological and nutritional treatments as this situation might be associated with higher metabolic disorders in adulthood. PMID- 23925486 TI - Light-inducible activation of target mRNA translation in mammalian cells. AB - A genetically encoded optogenetic system was constructed that activates mRNA translation in mammalian cells in response to light. Blue light induces the reconstitution of an RNA binding domain and a translation initiation domain, thereby activating target mRNA translation downstream of the binding sites. PMID- 23925488 TI - Graphene-supported Au-Pd bimetallic nanoparticles with excellent catalytic performance in selective oxidation of methanol to methyl formate. AB - Graphene supported Au-Pd bimetallic nanoparticles exhibit high catalytic activity in methanol selective oxidation, with a methanol conversion of 90.2% and selectivity of 100%, to methyl formate at 70 degrees C, owing to the synergism of Au and Pd particles as well as the strong interaction between graphene and Au Pd nanoparticles. PMID- 23925487 TI - Gelsolin and ceruloplasmin as potential predictive biomarkers for cervical cancer by 2D-DIGE proteomics analysis. AB - This study aimed to identify candidate proteins which may serve as potential biological markers for cervical cancer using 2D-DIGE. Serum samples of controls, patients with cervical intraepithelial neoplasia grade 3 (CIN 3), squamous cell carcinoma of early (SCC I and II) and late (SCC III and IV) stage were subjected to 2D-DIGE. Differentially expressed spots were identified by tandem mass spectrometry. Validation of candidate proteins in serum and tissue samples were then performed by ELISA and immunohistochemistry (IHC) analysis respectively. A total of 20 differentially expressed proteins were identified. These proteins were found to play key roles in the apoptosis pathway, complement system, various types of transportation such as hormones, fatty acids, lipid, vitamin E and drug transportation, coagulation cascade, regulation of iron and immunologic response. Based on their functional relevancy to the progression of various cancers, 4 proteins namely the complement factor H, CD5-like antigen, gelsolin and ceruloplasmin were chosen for further validation using ELISA. Biological network analysis showed that ceruloplasmin and gelsolin are closely interacted with the oncogene NF-kappab. These two proteins were further validated using the IHC. Gelsolin and ceruloplasmin may serve as potential predictive biomarkers for the progression of high grade lesions. PMID- 23925490 TI - Legionella phospholipases implicated in virulence. AB - Phospholipases are diverse enzymes produced in eukaryotic hosts and their bacterial pathogens. Several pathogen phospholipases have been identified as major virulence factors acting mainly in two different modes: on the one hand, they have the capability to destroy host membranes and on the other hand they are able to manipulate host signaling pathways. Reaction products of bacterial phospholipases may act as secondary messengers within the host and therefore influence inflammatory cascades and cellular processes, such as proliferation, migration, cytoskeletal changes as well as membrane traffic. The lung pathogen and intracellularly replicating bacterium Legionella pneumophila expresses a variety of phospholipases potentially involved in disease-promoting processes. So far, genes encoding 15 phospholipases A, three phospholipases C, and one phospholipase D have been identified. These cell-associated or secreted phospholipases may contribute to intracellular establishment, to egress of the pathogen from the host cell, and to the observed lung pathology. Due to the importance of phospholipase activities for host cell processes, it is conceivable that the pathogen enzymes may mimic or substitute host cell phospholipases to drive processes for the pathogen's benefit. The following chapter summarizes the current knowledge on the L. pneumophila phospholipases, especially their substrate specificity, localization, mode of secretion, and impact on host cells. PMID- 23925489 TI - NG2 proteoglycan promotes tumor vascularization via integrin-dependent effects on pericyte function. AB - The NG2 proteoglycan stimulates the proliferation and migration of various immature cell types, including pericytes. However, the role of NG2 in mediating pericyte/endothelial cell interaction has been less clear. In this study, we show that pericyte-specific NG2 ablation causes several structural deficits in blood vessels in intracranial B16F10 melanomas, including decreased pericyte ensheathment of endothelial cells, diminished formation of endothelial junctions, and reduced assembly of the vascular basal lamina. These deficits result in decreased tumor vessel patency, increased vessel leakiness, and increased intratumoral hypoxia. NG2-dependent mechanisms of pericyte interaction with endothelial cells are further explored in pericyte/endothelial cell co-cultures. siRNA-mediated NG2 knockdown in pericytes leads to reduced formation of pericyte/endothelial networks, reduced formation of ZO-1 positive endothelial cell junctions, and increased permeability of endothelial cell monolayers. We also show that NG2 knockdown results in loss of beta1 integrin activation in endothelial cells, revealing a mechanism for NG2-dependent cross talk between pericytes and endothelial cells. PMID- 23925491 TI - Influencing medical student education via a voluntary shadowing program for trauma and acute care surgery. AB - Decreasing application into trauma surgery may be attributed to decreased exposure during medical school. We instituted a voluntary trauma call program for students to provide exposure to the field. After 3 years, participants completed a survey to gauge their experience. Of 126 students who participated, 68 completed the survey (54%). Interest in trauma surgery among students not previously planning on a career in surgery (n = 48) improved after the experience (4.4-5.3 of 10 points; P < .005). Operative experience, exposure to a higher number of trauma cases, and time with residents were associated with increased interest in trauma surgery. Witnessing patient death for the first time was associated with decreased interest in trauma surgery. A voluntary overnight shadowing program improves medical students' perceptions of trauma surgery and increases their reported likelihood to apply into a surgical residency. PMID- 23925492 TI - Sending mixed messages: a trophic cascade produced by a belowground herbivore induced cue. AB - Plants defend themselves against herbivores both directly (chemical toxins and physical barriers) and indirectly (attracting natural enemies of their herbivores). Previous work has shown that plant roots of citrus defend against root herbivores by releasing an herbivore-induced plant volatile (HIPV), pregeijerene (1,5-dimethylcyclodeca-1,5,7-triene), that attracts naturally occurring entomopathogenic nematodes (EPNs) to Diaprepes abbreviatus larvae when applied in the field. However, the soil community is complex and contains a diversity of interspecific relationships that modulate food web assemblages. Herein, we tested the hypothesis that other nematode types beyond EPNs, as well as, nematophagous fungi are affected by the same HIPV that attracts EPNs to herbivore-damaged roots. We employed molecular probes designed to detect and quantify nematodes from the Acrobeloides-group (free-living bacterivorous nematodes, FLBNs), some of which compete with EPNs by 'hyperparasitizing' insect cadavers, and five species of nematophagous fungi (NF), which attack and kill EPNs. In two different agricultural systems (citrus and blueberry), we detected diverse species of nematodes and fungi; however, only the behavior of FLBNs was affected in a manner similar to that reported previously for EPNs. Although detected, NF abundance was not statistically affected by the presence of the belowground HIPV. We provide the first evidence showing subterranean HIPVs behave much the same as those aboveground, attracting not only parasitoids, but also hyperparasites and other food web members. PMID- 23925493 TI - Rhodium(III)-catalyzed vinylic sp2 C-H bond functionalization: efficient synthesis of pyrido[1,2-alpha]benzimidazoles and imidazo[1,2-alpha]pyridines. AB - A simple approach for synthesis of novel aza-fused scaffolds such as pyrido[1,2 alpha]benzimidazoles and imidazo[1,2-alpha]pyridines was developed by Rh(III) catalyzed direct oxidative coupling between alkenes and unactivated alkynes without an extra directing group. The method would allow a broad substrate scope, providing fused heterocycles with potential biological properties. PMID- 23925494 TI - A study on the mechanism for the interaction of light with noble metal-metal oxide semiconductor nanostructures for various photophysical applications. AB - Metal oxide semiconductors hold great promise for applications in energy conversion and storage, environmental remediation, optoelectronics, memory, light emission and other areas, but critical factors such as the high rate of charge carrier recombination and limited light absorption have restricted more practical and viable applications. The remarkable ability of plasmonic noble metals to concentrate and scatter visible light has found a versatile potential in harvesting and converting solar energy. Plasmonic nanostructures of noble metals in combination with semiconductors offer a promising future for the next generation of energy needs. The overlap of the spectral range of the incident photon with absorbance wavelength of the semiconductor and the surface plasmon bands of the plasmonic metal provides a useful tool to predict the enhancement in optical and electrical properties of hybrid semiconductor-noble metal nanostructures. Here we make an attempt to comprehensively review the role of plasmonic noble metals in the enhanced functions for photocatalytic activity, photoenergy conversion in DSSCs, enhanced light emission and photochromatism. We mainly focus on the improvement of performance in TiO2 or ZnO in combination with noble metals on representative photophysical applications. The mechanism behind their interaction with light is discussed in detail in each section. PMID- 23925495 TI - Switchable supramolecular polymers from the orthogonal self-assembly of quadruple hydrogen bonding and benzo-21-crown-7-secondary ammonium salt recognition. AB - Novel linear supramolecular polymers were constructed by the orthogonal self assembly of a heteroditopic monomer and a homoditopic monomer. The polymerization is driven by a combination of quadruple hydrogen bonding and benzo-21-crown-7 based host-guest complexation. The disassembly-assembly of these novel polymers could be reversibly switched by addition/removal of K(+). PMID- 23925496 TI - Basic life support skill improvement with newly designed renewal programme: cluster randomised study of small-group-discussion method versus practice-while watching method. AB - BACKGROUND: For the basic life support (BLS) renewal course, we have devised a new educational programme entitled a small-group-discussion (SGD) programme using personalised video-based debriefing. OBJECTIVE: We compared the efficacy in BLS skill improvement of the SGD programme with the currently used practice-while watching (PWW) programme, which uses a standardised education video. METHOD: This was a prospective, cluster randomised study, conducted in a single centre, over 6 months from May 2009 to October 2009. Training was performed in two groups of participants, each group with a different renewal education programme. The efficacy of the programmes was compared using the modified Cardiff test and skill reporting manikins. RESULTS: Results from 2169 participants were analysed: 1061 in the SGD programme group and 1108 in the PWW programme group. There were no differences between groups on the pretest, either in compression or non compression skills. However, on the post-test, the SGD programme gave better results for both compression skills and non-compression skills. CONCLUSIONS: The new SGD renewal programme is more effective than the PWW programme for improving skills in BLS renewal training. PMID- 23925497 TI - Cell mediated contraction in 3D cell-matrix constructs leads to spatially regulated osteogenic differentiation. AB - During embryonic development, morphogenetic processes give rise to a variety of shapes and patterns that lead to functional tissues and organs. While the impact of chemical signals on these processes is widely studied, the role of physical cues is less understood. The aim of this study was to test the hypothesis that the interplay of cell mediated contraction and mechanical boundary conditions alone can result in spatially regulated differentiation in simple 3D constructs. An experimental model consisting of a 3D cell-gel construct and a finite element (FE) model were used to study the effect of cellular traction exerted by mesenchymal stem cells (MSCs) on an initially homogeneous matrix under inhomogeneous boundary conditions. A robust shape change is observed due to contraction under time-varying mechanical boundary conditions, which is explained by the finite element model. Furthermore, distinct local differences in osteogenic differentiation are observed, with a spatial pattern independent of osteogenic factors in the culture medium. Regions that are predicted to have experienced relatively high shear stress at any time during contraction correlate with the regions of distinct osteogenesis. Taken together, these results support the underlying hypothesis that cellular contractility and mechanical boundary conditions alone can result in spatially regulated differentiation. These results will have important implications for tissue engineering and regeneration. PMID- 23925500 TI - An extremely rare manifestation of Behcet's disease: urethrovaginal fistula. AB - Behcet's disease (BD) is a rare chronic, relapsing, multisystemic disorder characterized by mucocutaneous, ocular, vascular and central nervous system manifestations. However, the etiopathogenesis of the disease remains unknown, and diagnosis is basically dependent on clinical manifestations. Sometimes BD may be diagnosed with rare clinical entities. Herein, we presented an extremely rare case of urethrovaginal fistula which has been diagnosed as manifestation of BD. After surgical treatment of fistula, there was no complication in 6 months following surgical repair and the follow-up period has been going on. PMID- 23925498 TI - Genetics of healthy aging and longevity. AB - Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may 'buffer' the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment. PMID- 23925499 TI - Disorders with similar clinical phenotypes reveal underlying genetic interaction: SATB2 acts as an activator of the UPF3B gene. AB - Two syndromic cognitive impairment disorders have very similar craniofacial dysmorphisms. One is caused by mutations of SATB2, a transcription regulator and the other by heterozygous mutations leading to premature stop codons in UPF3B, encoding a member of the nonsense-mediated mRNA decay complex. Here we demonstrate that the products of these two causative genes function in the same pathway. We show that the SATB2 nonsense mutation in our patient leads to a truncated protein that localizes to the nucleus, forms a dimer with wild-type SATB2 and interferes with its normal activity. This suggests that the SATB2 nonsense mutation has a dominant negative effect. The patient's leukocytes had significantly decreased UPF3B mRNA compared to controls. This effect was replicated both in vitro, where siRNA knockdown of SATB2 in HEK293 cells resulted in decreased UPF3B expression, and in vivo, where embryonic tissue of Satb2 knockout mice showed significantly decreased Upf3b expression. Furthermore, chromatin immunoprecipitation demonstrates that SATB2 binds to the UPF3B promoter, and a luciferase reporter assay confirmed that SATB2 expression significantly activates gene transcription using the UPF3B promoter. These findings indicate that SATB2 activates UPF3B expression through binding to its promoter. This study emphasizes the value of recognizing disorders with similar clinical phenotypes to explore underlying mechanisms of genetic interaction. PMID- 23925501 TI - Late coexistent acute cellular and antibody-mediated rejection in non-sensitized renal transplant patients. PMID- 23925502 TI - Endoscopic realignment in the management of complete transected ureter. AB - PURPOSE: To present experience and feasibility of endoscopic realignment for treatment of delayed recognized iatrogenic complete transected ureteral injuries. PATIENTS AND METHODS: Patients suffering from iatrogenic complete transected ureteral injuries were treated by two surgeons. Five women and 3 men with a mean age of 50.8 years (range 22-69) received diagnosis during the immediate postoperative period (2-6 days after surgery). Ureteral continuity was re established using a technique combining antegrade flexible ureteroscopy and retrograde rigid ureteroscopy. Then, three ipsilateral 5F double J stents were inserted to assure ureteral patency. RESULTS: All eight realignment procedures were successful, and no major complications occurred. Average injury length was 1.9 cm (range 1.5-3.0). Average hospitalization time was 8 days (range 3-14). Nephrostomy tubes and stents were removed after a mean period of 3.9 weeks (range 2-6) and 6.8 months (range 5.9-7.1), respectively. At a mean follow-up of 21.5 months (range 10-56), 6 patients were stent-free without image evidence of obstruction, a patient developed strictures was treated with balloon dilation and another exchanged double J stents periodically. No patient has developed significant renal impairment. CONCLUSION: Endoscopic realignment is a safe and efficient method as an initial procedure to manage iatrogenic complete transected ureteral injuries in properly selected cases. PMID- 23925503 TI - Propagation of nanopores during anodic etching of n-InP in KOH. AB - We propose a three-step model of electrochemical nanopore formation in n-InP in KOH that explains how crystallographically oriented etching can occur even though the rate-determining process (hole generation) occurs only at pore tips. The model shows that competition in kinetics between hole diffusion and electrochemical reaction determines the average diffusion distance of holes along the semiconductor surface and this, in turn, determines whether etching is crystallographic. If the kinetics of reaction are slow relative to diffusion, etching can occur at preferred crystallographic sites within a zone in the vicinity of the pore tip, leading to pore propagation in preferential directions. Symmetrical etching of three {111}A faces forming the pore tip causes it to propagate in the (remaining) [111]A direction. As a pore etches, propagating atomic ledges can meet to form sites that can become new pore tips and this enables branching of pores along any of the [111]A directions. The model explains the observed uniform width of pores and its variation with temperature, carrier concentration and electrolyte concentration. It also explains pore wall thickness, and deviations of pore propagation from the [111]A directions. We believe that the model is generally applicable to electrochemical pore formation in III-V semiconductors. PMID- 23925504 TI - Two novel inhibitory anti-human factor XI antibodies prevent cessation of blood flow in a murine venous thrombosis model. AB - Coagulation factor XI (FXI) is a promising target for anticoagulation, because of its major role in thrombosis and relatively minor role in haemostasis. This implies that inhibition of FXI can prevent thrombosis without causing bleeding. It was our aim to investigate the antithrombotic properties of two novel inhibitory anti-human FXI antibodies (alphaFXI-175 and alphaFXI-203). The in vitro properties of both antibodies were analysed using standard clotting assays and calibrated automated thrombography. For the in vivo model we used FXI knockout mice, in which FXI plasma levels were restored with purified human FXI. Thrombosis was induced by applying ferric chloride to the vena cava inferior, after which time to occlusion was analysed. A tail bleeding assay was used to investigate the safety of both antibodies. Using calibrated automated thrombography, both antibodies inhibited thrombin generation initiated via the intrinsic pathway. In contrast, upon tissue factor (TF)-initiated thrombin generation, alphaFXI-203 did not inhibit thrombin generation, while alphaFXI-175 inhibited thrombin generation only at low concentrations of TF. In the murine thrombosis model, the vena cava inferior remained patent for 25 minutes (min) in mice treated with alphaFXI-175 and for 12.5 min in alphaFXI-203 treated animals, which was significantly longer than in placebo-treated animals (5 min, p<0.05). Neither antibody caused severe blood loss in a tail bleeding assay. In conclusion, the two inhibitory antibodies against FXI prevented cessation of blood flow in a murine thrombosis model without inducing a bleeding tendency. PMID- 23925505 TI - Highly efficient non-covalent energy transfer in all-organic macrocycles. AB - The use of aromatic organic macrocycles as supramolecular hosts for non-covalent energy transfer is reported herein. These macrocycles lead to stronger binding and more efficient energy transfer compared to commercially available gamma cyclodextrin. This energy transfer was particularly efficient for the highly toxic benzo[a]pyrene with a fluorescent BODIPY acceptor, with up to a 5-fold increase in the fluorophore emission observed. PMID- 23925506 TI - Impact evaluation of a quality improvement intervention on maternal and child health outcomes in Northern Ghana: early assessment of a national scale-up project. AB - OBJECTIVE: To evaluate the influence of the early phase of Project Fives Alive!, a national child survival improvement project, on key maternal and child health outcomes. DESIGN: The evaluation used multivariable interrupted time series analyses to determine whether change categories tested were associated with improvements in the outcomes of interest. PARTICIPANTS: The evaluation used program and outcome data from interventions focused on health-care staff in 27 facilities. SETTING: Northern Ghana. INTERVENTION: The project uses a quality improvement (QI) approach whereby process failures are identified by health staff and process changes are tested in the health facilities and corresponding communities to address those failures. MAIN OUTCOME MEASURES: The maternal health outcomes were early antenatal care attendance and skilled delivery, and the child health outcomes were underweight infants attending child wellness clinics, facility-level neonatal mortality and facility-level infant mortality. RESULTS: Postnatal care changes for the first 1-2 days of life (beta= 0.10, P = 0.07) and the first 6-7 days of life (beta = 0.10, P = 0.07) were associated with a higher rate of visits by underweight infants to child wellness clinics. There was an association between the early pregnancy identification change category with increased skilled delivery (beta = 1.36 P = 0.07). In addition, a greater number of change categories tested was associated with increased skilled delivery (beta = 0.05, P = 0.01). CONCLUSION: The QI approach of testing and implementing simple and low cost locally inspired changes has the potential to lead to improved health outcomes at scale both in Ghana and other low- and middle-income countries. PMID- 23925507 TI - What is known about adverse events in older medical hospital inpatients? A systematic review of the literature. AB - PURPOSE: Large international studies have shown that older hospital inpatients are at particular risk of adverse events. The purpose of this review was to synthesize data from studies designed to assess the scale and nature of this harm, with the ultimate aim of informing the development of new safety and quality measurement tools to facilitate improved hospital care for these vulnerable patients. DATA SOURCES STUDY SELECTION: and data extraction A systematic search using Ovid SP and other sources was carried out, rigorous inclusion and exclusion criteria were applied and quality assessment of included studies was conducted. Data were synthesized to give a picture of the incidence, types, causes, preventability and outcomes of adverse events in older medical inpatients. RESULTS OF DATA SYNTHESIS: Nine relevant studies were identified. A wide range of adverse event incidences were reported, from 5.29 to 6.2% in re analyses of large adverse event studies, to 60% in studies in which the development of 'geriatric syndromes' (e.g. falls, delirium, incontinence) was also considered to be adverse events. Important causative factors other than age included clinical complexity, co-morbidity, illness severity, reduced functional ability and lower quality of care. Adverse events in older people lead to unnecessary interventions with resultant complications and increased length of stay. CONCLUSION: More work is needed to understand the complex nature of adverse events in older inpatients. We must tailor safety measurement and improvement strategies to address challenges presented by the complexity of the geriatric syndromes and the processes of care encountered by older inpatients. PMID- 23925508 TI - Ecological opportunity and incumbency in the diversification of repeated continental colonizations by muroid rodents. AB - Why some clades are more species-rich than others is a central question in macroevolution. Most hypotheses explaining exceptionally diverse clades involve the emergence of an ecological opportunity caused by a major biogeographic transition or evolution of a key innovation. The radiation of muroid rodents is an ideal model for testing theories of diversification rates in relation to biogeography and ecological opportunity because the group is exceptionally species-rich (comprising nearly one-third of all mammal species), it is ecologically diverse, and it has colonized every major landmass except New Zealand and Antarctica, thus providing multiple replicate radiations. We present an extension of the conventional ecological opportunity model to include a geographic incumbency effect, develop the largest muroid phylogeny to date, and use this phylogeny to test the new model. The nearly 300-species phylogeny based on four nuclear genes is robustly resolved throughout. Consistent with the fossil record, we identified Eurasia as the most likely origin of the group and reconstructed five to seven colonizations of Africa, five of North America, four of Southeast Asia, two of South America, two of Sahul, one of Madagascar, and eight to ten recolonizations of Eurasia. We accounted for incomplete taxon sampling by using multiple statistical methods and identified three corroborated regions of the tree with significant shifts in diversification rates. In several cases, higher rates were associated with the first colonization of a continental area, but most colonizations were not followed by bursts of speciation. We found strong evidence for diversification consistent with the ecological opportunity model (initial burst followed by density-dependent slowdown) in the first colonization of South America and partial support for this model in the first colonization of Sahul. Primary colonizers appear to inhibit the ultimate diversity of secondary colonizers, a pattern of incumbency that is consistent with ecological opportunity, but they did not inhibit initial diversification rates of secondary colonizers. These results indicate that ecological opportunity may be a general but weak process in muroids and one that requires specific circumstances to lead to an adaptive radiation. The total land area, length of time between colonizations, and rank of colonizations did not influence the diversification rates of primary colonizers. Models currently employed to test ecological opportunity do a poor job of explaining muroid diversity. In addition, the various rate-shift metrics identified different clades, suggesting that caution should be used when only one is applied, and we discuss which methods are most appropriate to address different questions of diversification. PMID- 23925509 TI - Bite of the cats: relationships between functional integration and mechanical performance as revealed by mandible geometry. AB - Cat-like carnivorous mammals represent a relatively homogeneous group of species whose morphology appears constrained by exclusive adaptations for meat eating. We present the most comprehensive data set of extant and extinct cat-like species to test for evolutionary transformations in size, shape and mechanical performance, that is, von Mises stress and surface traction, of the mandible. Size and shape were both quantified by means of geometric morphometrics, whereas mechanical performance was assessed applying finite element models to 2D geometry of the mandible. Additionally, we present the first almost complete composite phylogeny of cat-like carnivorans for which well-preserved mandibles are known, including representatives of 35 extant and 59 extinct species of Felidae, Nimravidae, and Barbourofelidae. This phylogeny was used to test morphological differentiation, allometry, and covariation of mandible parts within and among clades. After taking phylogeny into account, we found that both allometry and mechanical variables exhibit a significant impact on mandible shape. We also tested whether mechanical performance was linked to morphological integration. Mechanical stress at the coronoid process is higher in sabertoothed cats than in any other clade. This is strongly related to the high degree of covariation within modules of sabertooths mandibles. We found significant correlation between integration at the clade level and per-clade averaged stress values, on both original data and by partialling out interclade allometry from shapes when calculating integration. This suggests a strong interaction between natural selection and the evolution of developmental and functional modules at the clade level. PMID- 23925510 TI - Efficient exploration of the space of reconciled gene trees. AB - Gene trees record the combination of gene-level events, such as duplication, transfer and loss (DTL), and species-level events, such as speciation and extinction. Gene tree-species tree reconciliation methods model these processes by drawing gene trees into the species tree using a series of gene and species level events. The reconstruction of gene trees based on sequence alone almost always involves choosing between statistically equivalent or weakly distinguishable relationships that could be much better resolved based on a putative species tree. To exploit this potential for accurate reconstruction of gene trees, the space of reconciled gene trees must be explored according to a joint model of sequence evolution and gene tree-species tree reconciliation. Here we present amalgamated likelihood estimation (ALE), a probabilistic approach to exhaustively explore all reconciled gene trees that can be amalgamated as a combination of clades observed in a sample of gene trees. We implement the ALE approach in the context of a reconciliation model (Szollosi et al. 2013), which allows for the DTL of genes. We use ALE to efficiently approximate the sum of the joint likelihood over amalgamations and to find the reconciled gene tree that maximizes the joint likelihood among all such trees. We demonstrate using simulations that gene trees reconstructed using the joint likelihood are substantially more accurate than those reconstructed using sequence alone. Using realistic gene tree topologies, branch lengths, and alignment sizes, we demonstrate that ALE produces more accurate gene trees even if the model of sequence evolution is greatly simplified. Finally, examining 1099 gene families from 36 cyanobacterial genomes we find that joint likelihood-based inference results in a striking reduction in apparent phylogenetic discord, with respectively. 24%, 59%, and 46% reductions in the mean numbers of duplications, transfers, and losses per gene family. The open source implementation of ALE is available from https://github.com/ssolo/ALE.git. PMID- 23925511 TI - [Device associated complications]. PMID- 23925512 TI - Molecular modeling studies give hint for the existence of a symmetric hbeta2R Galphabetagamma-homodimer. AB - Several experimental studies suggest that GPCR dimers or oligomers may play an important role in signal transduction. In 2011 the crystal structure of a hbeta2R Galphabetagamma-complex was published and crystal structures of GPCR dimers are known. But until now, no crystal structure of a GPCR dimer including the Galphabetagamma-complex is available. In order to obtain detailed insights into interactions within hbeta2R dimers including the Galphabetagamma-complex we performed a potential-energy-surface scan in order to identify favored asymmetric and symmetric hbeta2R-Galphabetagamma-homodimers. This potential energy surface scan suggests, besides the existence of asymmetric dimers, the existence of a symmetric hbeta2R-Galphabetagamma-homodimer with a TM I/VII-contact. A subsequent 20 ns MD simulation of the symmetric homodimer revealed large asymmetric conformational changes of both hbeta2Rs, especially regarding TM VII and the interaction network between Asp(2.50), Val(7.44), Ser(7.46) and Tyr(7.43). Since similar conformational changes were not observed during the molecular dynamic simulation of the monomeric hbeta2R-Galphabetagamma-complex, it may be suggested that the conformational changes in the symmetric homodimer are related to the presence of the second hbeta2R-Galphabetagamma-complex. Due to the limitations of simulation time, conformational changes within a time scale of MUs or ms may of course not be observed. However, the detected conformational changes, especially in TM VII, correspond to minima on the potential energy surface and thus, this study gives new insights into GPCR dimers on molecular level and furthermore, gives suggestions for site-directed mutagenesis studies. PMID- 23925513 TI - Molecular dynamics simulation of temperature induced unfolding of animal prion protein. AB - To elucidate the structural stability and the unfolding dynamics of the animal prion protein, the temperature induced structural evolution of turtle prion protein (tPrPc) and bank vole prion protein (bvPrPc) have been performed with molecular dynamics (MD) simulation. The unfolding behaviors of secondary structures showed that the alpha-helix was more stable than beta-sheet. Extension and disruption of beta-sheet commonly appeared in the temperature induced unfolding process. The conversion of alpha-helix to pi-helix occurred more readily at the elevating temperature. Furthermore, it was suggested in this work that the unfolding of prion protein could be regulated by the temperature. PMID- 23925515 TI - Patterns of lifetime and recent HIV testing among men who have sex with men in New York City who use Grindr. AB - Rates of HIV infection continue to rise for men who have sex with men (MSM), and may be partially due to lack of testing among groups at risk for HIV. Mobile applications have demonstrated promise to identify at-risk MSM, though more research is needed to address testing patterns among this population. We conducted an online survey of 1,351 MSM in the New York City (NYC) area recruited from Grindr and analyzed predictors of lifetime and past-year testing using Pearson's chi-squared statistic, Fisher's exact tests, and logistic regression. A majority (90 %) of men had been tested within their lifetimes, and most (71 %) had been tested within the prior year. Among those who had never been tested (n = 135), one-third had engaged in unprotected anal intercourse (UAI) in the prior 3 months and nearly one-third identified themselves as HIV-negative rather than unknown. Older age, reporting an HIV-negative (versus unknown) status, and recent UAI were independently associated with lifetime testing. Greater proportions of men who had recently engaged in UAI reported testing within the past year compared with those who had not engaged in UAI. Overall, rates of testing among MSM in this sample exceeded those of the general population, including the general population in NYC. A greater proportion of this sample had never tested compared to a population-based sample of NYC MSM, though a higher percentage had also tested in the past year. This study demonstrated that 1 in 10 NYC men using Grindr and 1 in 5 who were 18-24 years of age had never received an HIV test in their lives. Using the existing infrastructure and popularity of mobile technology such as Grindr to identify and link men to information regarding HIV testing may be a useful strategy for prevention. PMID- 23925516 TI - Sulfonylcarbamate as a versatile and unique hydroxy-protecting group: a protecting group stable under severe conditions and labile under mild conditions. AB - The sulfonylcarbamate group is a unique hydroxyl protecting group. In contrast to typical acyl protecting groups, the sulfonylcarbamate group is stable under harsh basic conditions, while showing labile behavior under mild basic conditions. Its compatibility with other hydroxyl protecting groups and application to carbohydrate chemistry is demonstrated. PMID- 23925517 TI - Reagents in microfluidics: an 'in' and 'out' challenge. AB - Microfluidic devices are excellent at downscaling chemical and biochemical reactions and thereby can make reactions faster, better and more efficient. It is therefore understandable that we are seeing these devices being developed and used for many applications and research areas. However, microfluidic devices are more complex than test tubes or microtitre plates and the integration of reagents into them is a real challenge. This review looks at state-of-the-art methods and strategies for integrating various classes of reagents inside microfluidics and similarly surveys how reagents can be released inside microfluidics. The number of methods used for integrating and releasing reagents is surprisingly large and involves reagents in dry and liquid forms, directly-integrated reagents or reagents linked to carriers, as well as active, passive and hybrid release methods. We also made a brief excursion into the field of drug release and delivery. With this review, we hope to provide a large number of examples of integrating and releasing reagents that can be used by developers and users of microfluidics for their specific needs. PMID- 23925518 TI - Prevalence of hepatitis B and C viruses among asylum seekers in Izmir. AB - Hepatitis B and C virus infections are known to be an important health problem all over the World. According to the data from World Health Organization, 350 million people are estimated to have been chronically infected by hepatitis B virus and 180 million people have been infected by hepatitis C virus. Most of the patients are not aware of their illnesses. Hepatitis B and C virus infections are the most common cause of sequel liver disease related to decompensate liver cirrhosis and hepatocellular carcinoma. Many people are obliged to leave their country due to political, economic and social reasons. In Turkey, where there is refugee and asylum seeker problem because of geographical location, we aimed to specify the demographic characteristics of asylum seekers in Izmir and to evaluate the asylum seekers in terms of blood-borne and sexually transmitted diseases such as hepatitis B and C. PMID- 23925519 TI - Russian speaking immigrants: drug use, infectious disease and related health behavior. AB - This article focuses on drug use, infectious disease and other factors comparing FSU males who became addicted before and after immigration to Israel. 810 drug users were surveyed in treatment centers from January 2002 to January 2012. The Addiction Severity Index and other data collection instruments were used. Those addicted before immigration have a higher level of infectious disease (i.e., HCV, HIV/AIDS and tuberculosis) and opiate use other than heroin. Those addicted after immigration reported higher rates of last 30 days sedative; cocaine and opiates other than heroin use. Injection drug use and ASI domain problem behavior were more prevalent among those addicted before immigration. Results evidence the impact of country of addiction origin on drug use patterns, infectious disease rates as well as other health related factors. Additional research of the relationship between acculturation and drug use is needed. PMID- 23925521 TI - Right lower quadrant pain. PMID- 23925520 TI - Substance use, age at migration, and length of residence among adult immigrants in the United States. AB - In this study we scrutinize prevalence of current smoking and binge drinking among adult US immigrants, and examine whether age at migration predicts these two behaviors and moderates the effect of length of residence. Immigrant groups include those from Latin America/Caribbean, East and South Asia, Sub-Saharan Africa, Europe/Central Asia, and Middle East/North Africa. Multivariate logistic regressions are estimated using cross-sectional data from the New Immigrant Survey (N = 7,397). Results show that patterns of smoking and binge drinking vary by gender and by region of origins. In addition, arriving at age 0-9 are directly associated with higher odds of binge drinking among adult women. Among adult men, age at migration moderates the association between length of residence and substance use. Specifically, length of residence has more detrimental effects for adolescent immigrants (arriving at age 10-18) on smoking, while its detrimental effects are more pronounced for childhood immigrants (arriving at age 0-9) on binge drinking. We interpret our findings within the critical period model in epidemiological research, concluding that adolescence and childhood are critical life stages that are associated with differential effects of length of residence when looking at smoking and binge drinking among immigrant men. PMID- 23925522 TI - Association of genetic variants of ghrelin, leptin and UCP2 with malnutrition inflammation syndrome and survival in end-stage renal disease patients. AB - Malnutrition inflammation syndrome (MIS) is common among ESRD patients. In the present study, we have investigated the association of genetic markers associated with appetite and energy regulation with malnutrition inflammation syndrome among end-stage renal disease (ESRD) patients. Two hundred and fifty-seven patients on maintenance hemodialysis and 200 normal healthy controls were included in the study. Nutritional assessment was done by subjective global assessment scores (SGA). Genotyping of leptin-2548 G/A (rs7799039), ghrelin Leu72Met (rs696217-408 C/A), Arg51Gln (rs34911341-346 G/A) and uncoupling protein 2 (UCP2) 45 bp insertion deletion was done using PCR-RFLP. Levels of leptin and acyl ghrelin were assessed using ELISA. Leptin-2548 AA genotype was associated with twofold higher risk of disease susceptibility while UCP2 insertion-deletion heterozygotes showed protective effect. Ghrelin Gln51Gln and Met72Met genotype were associated with 3.4- and 2.5-fold higher disease susceptibility. The Met72 and Gln51 allele showed 3.3- and 2.1-fold higher susceptibility to malnutrition in severe SGA group. Further, the levels of acyl ghrelin were significantly less in severe category of malnutrition and in poor appetite group. On combined analysis, the group 2 (presence of 3-4 risk alleles) showed 1.5- and twofold higher susceptibility to disease and malnutrition, respectively. On docking analysis, it was observed that higher receptor binding energy was associated with the mutant form of ghrelin (Gln51). Moderate and severe SGA were associated with 2.2- and 4.1-fold higher death hazard. Our study suggests that ghrelin may be major marker contributing to susceptibility to MIS among ESRD patients. PMID- 23925523 TI - Synthesis and biological evaluation of non-isomerizable analogues of Ala tRNA(Ala). AB - Aminoacyl-tRNAs serve as amino acid donors in many reactions in addition to protein synthesis by the ribosome, including synthesis of the peptidoglycan network in the cell wall of bacterial pathogens. Synthesis of analogs of aminoacylated tRNAs is critical to further improve the mechanism of these reactions. Here we have described the synthesis of two non-isomerizable analogues of Ala-tRNA(Ala) containing an amide bond instead of the isomerizable ester that connects the amino acid with the terminal adenosine in the natural substrate. The non-isomerizable 2' and 3' regioisomers were not used as substrates by FemX(Wv), an alanyl-transferase essential for peptidoglycan synthesis, but inhibited this enzyme with IC50 of 5.8 and 5.5 MUM, respectively. PMID- 23925525 TI - Integrating patient-reported outcomes into orthopaedic clinical practice: proof of concept from FORCE-TJR. AB - BACKGROUND: Good orthopaedic care requires a knowledge of the patient's history of musculoskeletal pain and associated limitations in daily function. Standardized measures of patient-reported outcomes (PROs) can provide this information. Integrating PROs into routine orthopaedic patient visits can provide key information to monitor changes in symptom severity over time, support shared clinical care decisions, and assess treatment effectiveness for quality initiatives and value-based reimbursement. WHERE ARE WE NOW?: Although standardized, validated PRO surveys are routinely used in clinical and comparative effectiveness research, they are not consistently or efficiently collected in clinical practice. WHERE DO WE NEED TO GO?: Ideally, PROs need to be collected directly from patients before their surgeon visit so the data are readily available to the surgeon and patient at the time of the office visit. In addition, PROs should be integrated in the electronic health record to monitor patient status over time. HOW DO WE GET THERE?: PRO integration in clinical practice requires minor modifications to the office flow, some additional staff to facilitate collection, and the technical infrastructure to score, process, and store the responses. We document successful office procedures for collecting PROs in one busy orthopaedic clinic and some suggested methods to extend this model to the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement (FORCE-TJR) consortium of 121 surgeons where the process is centralized and staff obtained consent to send the PRO directly to the patient's home. Both methods are options for the broader adoption of office-based PROs. PMID- 23925524 TI - On being the right size: scaling effects in designing a human-on-a-chip. AB - Developing a human-on-a-chip by connecting multiple model organ systems would provide an intermediate screen for therapeutic efficacy and toxic side effects of drugs prior to conducting expensive clinical trials. However, correctly designing individual organs and scaling them relative to each other to make a functional microscale human analog is challenging, and a generalized approach has yet to be identified. In this work, we demonstrate the importance of rational design of both the individual organ and its relationship with other organs, using a simple two-compartment system simulating insulin-dependent glucose uptake in adipose tissues. We demonstrate that inter-organ scaling laws depend on both the number of cells and the spatial arrangement of those cells within the microfabricated construct. We then propose a simple and novel inter-organ 'metabolically supported functional scaling' approach predicated on maintaining in vivo cellular basal metabolic rates by limiting resources available to cells on the chip. This approach leverages findings from allometric scaling models in mammals that limited resources in vivo prompt cells to behave differently than in resource rich in vitro cultures. Although applying scaling laws directly to tissues can result in systems that would be quite challenging to implement, engineering workarounds may be used to circumvent these scaling issues. Specific workarounds discussed include the limited oxygen carrying capacity of cell culture media when used as a blood substitute and the ability to engineer non-physiological structures to augment organ function, to create the transport-accessible, yet resource-limited environment necessary for cells to mimic in vivo functionality. Furthermore, designing the structure of individual tissues in each organ compartment may be a useful strategy to bypass scaling concerns at the inter organ level. PMID- 23925526 TI - CORR Insights (r): What is the current status of global health activities and opportunities in US orthopaedic residency programs? PMID- 23925527 TI - Free for service: the inadequate incentives for quality peer review. PMID- 23925528 TI - An efficient synthetic route to carbocyclic enaminonitriles via Lewis acid catalysed domino-ring-opening-cyclisation (DROC) of donor-acceptor cyclopropanes with malononitrile. AB - A highly efficient strategy for the synthesis of functionalised carbocyclic enaminonitriles in excellent yields has been described. The reaction utilises Yb(OTf)3 catalysed C-C bond cleavage and two simultaneous C-C bond formations of donor-acceptor (DA)-cyclopropanes with malononitrile anions in a domino fashion. PMID- 23925529 TI - Enhanced gellan gum production by hydrogen peroxide (H2O 2) induced oxidative stresses in Sphingomonas paucimobilis. AB - In this study, the effect of H2O2-induced oxidative stress on gellan gum production and cell growth were investigated. Gellan gum production was improved and cell growth was inhibited by H2O2. A multiple H2O2 stresses with different concentrations were developed to optimize gellan gum production. A maximal gellan gum yield (22.52 g/L), which was 35.58 % higher than the control, was observed with 2, 2, 3, 4 mmol/L H2O2 added at 6, 12, 18, 24 h, respectively. Moreover, UDP glucose pyrophosphorylase activity and glucosyltransferase activity were increased with H2O2 stresses. This new strategy of multiple H2O2-induced oxidative stresses would be further applied to gellan gum production in future study. PMID- 23925531 TI - Residual vein thrombosis and trans-popliteal reflux in patients with and without the post-thrombotic syndrome. PMID- 23925530 TI - Excess mortality after disability retirement due to mental disorders: variations by socio-demographic factors and causes of death. AB - PURPOSE: Mental disorders are the key causes of disability retirement and are associated with a high risk of mortality. Social variations in excess mortality after disability retirement are nevertheless poorly understood. We examined socio demographic differences in all-cause and cause-specific mortality after disability retirement due to depression and other mental disorders. METHODS: The data comprised a nationally representative sample of the Finnish population aged 25-64 in 1996 with no prior disability retirement due to mental disorders (N = 392,985). We used Cox regression analysis with disability retirement due to mental disorders as a time-varying covariate and mortality between 1997 and 2007 as the outcome variable. RESULTS: We found excess mortality after disability retirement due to mental disorders as compared to those with no such retirement in all specific causes of death, in particular alcohol-related causes, suicide, and other unnatural causes. Excess suicide mortality was particularly large after depression-based disability retirement. Younger age groups, non-manual classes, and those living with a partner and children had largest excess mortality, especially from unnatural and alcohol-related causes. However, the absolute number of excess deaths was not always largest in these socio-demographic groups. CONCLUSIONS: In young adulthood, disability retirement due to depression signifies severe health and other social disadvantages that lead to particularly large excess mortality, especially due to unnatural causes. The protective effects of a high socioeconomic position and family ties against unnatural and alcohol-related deaths are limited among those who have already developed depression or other mental disorders that have led to disability retirement. PMID- 23925532 TI - Expression and assembly of Norwalk virus-like particles in plants using a viral RNA silencing suppressor gene. AB - Binary vector-based transient expression of heterologous proteins in plants is a very attractive strategy due to the short time required for proceeding from planning to expression. However, this expression system is limited by comparatively lower yields due to strong post-transcriptional gene silencing (PTGS) in the host plants. The aim of this study was to optimize a procedure for expression of norovirus virus-like particles (VLPs) in plants using a binary vector with co-expression of a PTGS suppressor to increase the yield of the target protein. The effects of four plant viral PTGS suppressors on protein expression were evaluated using green fluorescent protein (GFP) as a reporter. Constructs for both GFP and PTGS suppressor genes were co-infiltrated in Nicotiana benthamiana plants, and the accumulation of GFP was evaluated. The most effective PTGS suppressor was the 126K protein of Pepper mild mottle virus. Therefore, this suppressor was selected as the norovirus capsid gene co expression partner for subsequent studies. The construct containing the major (vp1) and minor capsid (vp2) genes with a 3'UTR produced a greater amount of protein than the construct with the major capsid gene alone. Thus, the vp1-vp2 3'UTR and 126K PTGS suppressor constructs were co-infiltrated at middle scale and VLPs were purified by sucrose gradient centrifugation. Proteins of the expected size, specific to the norovirus capsid antibody, were observed by Western blot. VLPs were observed by transmission electron microscopy. It was concluded that protein expression in a binary vector co-expressed with the 126K PTGS suppressor protein enabled superior expression and assembly of norovirus VLPs. PMID- 23925533 TI - Metabolic engineering of Aspergillus oryzae NRRL 3488 for increased production of L-malic acid. AB - Malic acid, a petroleum-derived C4-dicarboxylic acid that is used in the food and beverage industries, is also produced by a number of microorganisms that follow a variety of metabolic routes. Several members of the genus Aspergillus utilize a two-step cytosolic pathway from pyruvate to malate known as the reductive tricarboxylic acid (rTCA) pathway. This simple and efficient pathway has a maximum theoretical yield of 2 mol malate/mol glucose when the starting pyruvate originates from glycolysis. Production of malic acid by Aspergillus oryzae NRRL 3488 was first improved by overexpression of a native C4-dicarboxylate transporter, leading to a greater than twofold increase in the rate of malate production. Overexpression of the native cytosolic alleles of pyruvate carboxylase and malate dehydrogenase, comprising the rTCA pathway, in conjunction with the transporter resulted in an additional 27 % increase in malate production rate. A strain overexpressing all three genes achieved a malate titer of 154 g/L in 164 h, corresponding to a production rate of 0.94 g/L/h, with an associated yield on glucose of 1.38 mol/mol (69 % of the theoretical maximum). This rate of malate production is the highest reported for any microbial system. PMID- 23925534 TI - Integrated proteomic and transcriptomic analysis reveals novel genes and regulatory mechanisms involved in salt stress responses in Synechocystis sp. PCC 6803. AB - Salt stress is a common stress that limits growth and productivity of photosynthetic microbes in natural environments. Although cellular responses of a model cyanobacterium Synechocystis sp. PCC6803 to high and changing salt concentration have been studied, it remains undefined of the gene components and their regulation in the long-term salt acclimation networks. In this study, we performed an integrated study coupling a quantitative iTRAQ-LC-MS/MS proteomics and a next-generation sequencing-based RNA-seq transcriptomics on Synechocystis under salt stress for an extended period of time. Comparative quantification of protein abundances led to the identification of 68 and 108 proteins differentially regulated by salt treatment at 24 and 48 h, respectively. RNA-seq transcriptomic analysis showed that genes involved in energy metabolism and protein synthesis, and genes encoding hypothetical proteins responded to salt stress in a phase-dependent pattern. Notably, a gene encoding CO2-uptake-related protein (CupA) and three genes encoding hypothetical proteins were induced significantly at either transcript or protein level after long-term salt stress. Gene knockout and comparative growth analysis demonstrated that these four genes were involved in salt tolerance in Synechocystis. In addition, a complementary proteome and transcriptome analysis showed that concordance between protein abundances and their corresponding mRNAs varied significantly between various gene-protein pairs, indicating divergent regulation of transcriptional and post transcriptional processes during salt stress adaptation in Synechocystis. The study provided new insights on genes and regulatory mechanism involved in salt stress response in Synechocystis. PMID- 23925535 TI - Application of micro-segmented flow for two-dimensional characterization of the combinatorial effect of zinc and copper ions on metal-tolerant Streptomyces strains. AB - The cultivation and growth behavior of metal-tolerant strains of Streptomyce acidiscabies E13 and Streptomyces sp. F4 were studied under droplet-based microfluidics conditions. It was shown that the technique of micro segmented flow is well suited for the investigation of dependence of bacterial growth on different concentrations of either single metal ions or combinations of them. This study confirms higher tolerance to Zn than to Cu by our test organism. The highly resolved dose-response curves reflect two transitions between the different growth behaviors, separating initial responses to Cu concentration ranges into those with (a) intense growth, (b) moderate growth, and (c) growth inhibition. For Streptomyces sp. F4, an initial stimulation was shown in the sublethal range of zinc sulfate. Two-dimensional screenings using computer controlled fluid actuation and in situ micro flow-through fluorimetry reflected a strong growth stimulation of strain F4 by zinc sulfate in the presence of sublethal Cu concentrations. This stimulatory effect on binary mixtures may be useful in providing optimal growth conditions in bioremediation procedures. PMID- 23925539 TI - Supramolecular gel phase crystallization: orthogonal self-assembly under non equilibrium conditions. AB - This tutorial review charts the history of gel phase crystallization from its origins in Liesegang ring formation to current research in the generation of new pharmaceutical solid forms in low molecular weight organogels. The growth of molecular crystals under a supersaturation gradient within the same space and timescale as the formation of a gel phase material is placed into context as an example of orthogonal self-assembly. Such multi-component, weakly coupled orthogonal self-assembly processes occurring far from equilibrium represent a powerful conceptual paradigm for generating fascinating emergent behaviour in chemical systems. PMID- 23925540 TI - A putative link between phagocytosis-induced apoptosis and hemocyanin-derived phenoloxidase activation. AB - Apoptosis and phagocytosis are crucial processes required for developmental morphogenesis, pathogen deterrence and immunomodulation in metazoans. We present data showing that amebocytes of the chelicerate, Limulus polyphemus, undergo phagocytosis-induced cell death after ingesting spores of the fungus, Beauveria bassiana, in vitro. The observed biochemical and morphological modifications associated with dying amebocytes are congruent with the hallmarks of apoptosis, including: extracellularisation of phosphatidylserine, intranucleosomal DNA fragmentation and an increase in caspase 3/7-like activities. Previous studies have demonstrated that phosphatidylserine is a putative endogenous activator of hemocyanin-derived phenoloxidase, inducing conformational changes that permit phenolic substrate access to the active site. Here, we observed extracellular hemocyanin-derived phenoloxidase activity levels increase in the presence of apoptotic amebocytes. Enzyme activity induced by phosphatidylserine or apoptotic amebocytes was reduced completely upon incubation with the phosphatidylserine binding protein, annexin V. We propose that phosphatidylserine redistributed to the outer plasma membrane of amebocytes undergoing phagocytosis-induced apoptosis could interact with hemocyanin, thus facilitating its conversion into a phenoloxidase-like enzyme, during immune challenge. PMID- 23925541 TI - Phosphaalkene vs. phosphinidene: the nature of the P-C bond in carbonyl-decorated carbene -> PPh adducts. AB - Treatment of dichlorophenylphosphine with two equivalents of carbonyl-decorated carbenes results in a two-electron reduction of the phosphorus centre concomitant with carbene oxidation to afford novel phosphaalkenes as confirmed via crystallographic, spectroscopic, and DFT analyses. PMID- 23925542 TI - Masuda borylation-Suzuki coupling (MBSC) sequence of vinylhalides and its application in a one-pot synthesis of 3,4-biarylpyrazoles. AB - The Masuda borylation-Suzuki coupling (MBSC) sequence was successfully extended to the challenging coupling of vinylhalides with various (hetero)arylhalides using sterically hindered phosphane ligands. Starting from (hetero)arylhalides and alpha-bromocinnamaldehyde, the sequentially Pd-catalyzed process selectively furnishes alpha,beta-substituted cinnamaldehydes without affecting the reactivity of the Michael system. These intermediates were implemented as entries into a novel synthesis of 3,4-diaryl 1H-pyrazoles in the fashion of a three-step one-pot procedure consisting of a Masuda borylation-Suzuki coupling and subsequent Michael addition-cyclocondensation-elimination sequence. PMID- 23925543 TI - Association of collagen type I alpha 1 gene polymorphism with inguinal hernia. AB - PURPOSE: A positive family history is an important risk factor for inguinal hernia development, suggesting a genetic trait for hernia disease. However, gene mutations responsible for abdominal wall hernia formation in humans have not yet been studied. We aimed to evaluate whether the functional Sp1 binding site polymorphism within intron 1 of the collagen type I, alpha 1 (COL1A1) gene was associated specifically with inguinal hernia disease. METHODS: 85 participants with surgically diagnosed inguinal hernia disease, and 82 physically active controls without any history of connective tissue disease and hernia were recruited for this case-control genetic association study. Polymerase chain reaction and restriction fragment length polymorphism and agarose gel electrophoresis techniques were used to detect these polymorphisms. RESULTS: Significantly, more patients gave a positive family history for an inguinal hernia compared to healthy controls (OR 3.646, 95 % CI 1.375-9.670, P = 0.006). COL1A1 Sp1 SNP (rs 1800012) was identified. Results demostrated statistically significant deviation from HWE for cases (P = 0.007), but not for the controls (P = 0.276). Our results revealed an increased frequency of COL1A1 Sp1 Ss genotype in inguinal hernia patients (OR 3.593, 95 % CI 1.867-6.915, P = 0.000). CONCLUSIONS: This results suggest that polymorphism of the COL1A1 Sp1 binding site is associated with an increased risk for developing inguinal hernias. So, rs 1800012 locus is a potential candidate region for susceptibility in molecular mechanism of inguinal hernia pathophysiology. PMID- 23925545 TI - A human plea. PMID- 23925544 TI - Triage of intensive care patients: identifying agreement and controversy. AB - RATIONALE: Intensive care unit (ICU) resources are limited in many hospitals. Patients with little likelihood of surviving are often admitted to ICUs. Others who might benefit from ICU are not admitted. OBJECTIVE: To provide an updated consensus statement on the principles and recommendations for the triage of patients for ICU beds. DESIGN: The previous Society of Critical Care Medicine (SCCM) consensus statement was used to develop drafts of general and specific principles and recommendations. Investigators and consultants were sent the statements and responded with their agreement or disagreement. SETTING: The Eldicus project (triage decision making for the elderly in European intensive care units). PARTICIPANTS: Eldicus investigators, consultants, and experts consisting of intensivists, users of ICU services, ethicists, administrators, and public policy officials. INTERVENTIONS: Consensus development was used to grade the statements and recommendations. MEASUREMENTS AND MAIN RESULTS: Consensus was defined as 80% agreement or more. Consensus was obtained for 54 (87%) of 62 statements including all (19) general principles, 31 (86%) of the specific principles, and 10 (71%) of the recommendations. Inconsistencies in responses were noted for ICU admission and discharge. Despite agreement for guidelines applying to individual patients and an objective triage score, there was no agreement for a survival cutoff for triage, not even for a chance of survival of 0.1%. CONCLUSIONS: Consensus was reached for most general and specific ICU triage principles and recommendations. Further debate and discussion should help resolve the remaining discrepancies. PMID- 23925546 TI - Microparticles during sepsis: target, canary or cure? PMID- 23925547 TI - Endothelial injury in sepsis. PMID- 23925548 TI - Syphilitic aortic aneurysm revealed by pericardial tamponade and brain infarction. PMID- 23925549 TI - Involvement of CD137 ligand signaling in neural stem cell death. AB - CD137 is a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Interaction of CD137 with its ligand (CD137L) affects the apoptosis, proliferation and differentiation of immune cells. Interestingly, the CD137 receptor/ligand system involves the bi-directional transduction of signals. The expression of CD137 and its ligand is not restricted to immune organs, but can also be detected in a wide variety of tissues such as the brain, kidney, lung and heart. However, its role in brain is largely unknown. This study was performed to determine the role of CD137L reverse signaling in the apoptosis of neural stem cells. We identified the expression of CD137 and its ligand in C17.2 neural stem cells derived from mouse embryonic cerebellum. We found that the activation of CD137L reverse signaling by CD137 resulted in a decrease in cell adhesion to the fibronectin-coated culture basement, thus causing detachment-induced cell death. Furthermore, we showed that the cell death induced by CD137 was completely ameliorated by integrin activators and caspase inhibitors. Therefore we suggest that CD137L reverse signaling exerts a pro-apoptotic effect by suppressing integrin-mediated survival signals in neural stem cells. PMID- 23925550 TI - Real-time monitoring of electrochemical controlled protein adsorption by a plasmonic nanowire based sensor. AB - A plasmonic sensor composed of a vertically aligned gold nanowire array was fabricated and employed for the optical detection of protein adsorption induced by an electric field. PMID- 23925551 TI - Hydrogen bond network topology in liquid water and methanol: a graph theory approach. AB - Networks are increasingly recognized as important building blocks of various systems in nature and society. Water is known to possess an extended hydrogen bond network, in which the individual bonds are broken in the sub-picosecond range and still the network structure remains intact. We investigated and compared the topological properties of liquid water and methanol at various temperatures using concepts derived within the framework of graph and network theory (neighbour number and cycle size distribution, the distribution of local cyclic and local bonding coefficients, Laplacian spectra of the network, inverse participation ratio distribution of the eigenvalues and average localization distribution of a node) and compared them to small world and Erdos-Renyi random networks. Various characteristic properties (e.g. the local cyclic and bonding coefficients) of the network in liquid water could be reproduced by small world and/or Erdos-Renyi networks, but the ring size distribution of water is unique and none of the studied graph models could describe it. Using the inverse participation ratio of the Laplacian eigenvectors we characterized the network inhomogeneities found in water and showed that similar phenomena can be observed in Erdos-Renyi and small world graphs. We demonstrated that the topological properties of the hydrogen bond network found in liquid water systematically change with the temperature and that increasing temperature leads to a broader ring size distribution. We applied the studied topological indices to the network of water molecules with four hydrogen bonds, and showed that at low temperature (250 K) these molecules form a percolated or nearly-percolated network, while at ambient or high temperatures only small clusters of four-hydrogen bonded water molecules exist. PMID- 23925552 TI - Long-term follow-up of autologous stem cell transplantation for severe paediatric systemic lupus erythematosus. AB - This study attempts to evaluate the outcome of autologous peripheral blood hematopoietic stem cell transplantation (auto-PBHSCT) in patients with severe paediatric systemic lupus erythematosus (SLE). Five patients (n = 2 females, n = 3 males) with severe or refractory paediatric SLE received autologous peripheral blood CD34+ cell transplants between July 2005 and February 2009. The patients ranged in age from 6 to 14 years, and the course of disease extended over a period from 5 to 90 months. All of the patients received conventional therapy for 3 to 87 months. After their discharge from the hospital, the patients continued to maintain their regular follow-up visits and basic quality of life. The patients exhibited decreased immune function after the auto-PBHSCT. The CD4+ and CD19+ cells were significantly reduced. Viremia occurred in four patients 2 months after the transplantation. All of the patients went into clinical remission in 3-6 months. The severity of encephalopathy, nephritis and organ damage declined in varying degrees. The disease recurred in patient 2 at 9 months and in patient 4 at 12 months after the transplantation. Because the disease was relatively mild, we were able to administer small doses of glucocorticoids that were sufficient to control the course of the disease. Macrophage activation syndrome occurred in patient 3 at 18 months after the transplantation. At the end of the follow-up period, three of the five patients were completely off their medications. Another two patients sustained small doses of glucocorticoids. The developmental levels of these patients were comparable to those of normal children at the end of the follow-up. The quality of life improved significantly. The auto-PBHSCT is effective for severe and refractory paediatric SLE. The incidence of lethal infection and other adverse reactions is low. Long-term remission can be achieved. A milder form of the disease may have recurred after the transplantation. PMID- 23925553 TI - Improved radiological outcome of rheumatoid arthritis: the importance of early treatment with methotrexate in the era of biological drugs. AB - The objective of this study is to compare the radiological progression in patients with rheumatoid arthritis (RA) diagnosed in the 1980s with those of the late 1990s until 2005 and to evaluate prognostic factors. Ninety-two RA patients who were firstly seen in our clinic from 1997 to 2005 were identified. As a control group, 89 RA patients from 1986 to 1990 were matched for the criteria disease duration (mean, 22 +/- 17 months), age, and number of x-ray controls. Radiological damage was measured by the Ratingen score (RS). The baseline RS of the 1997-2005 group was significantly lower (mean, 3.8 +/- 8.7 vs 7.7 +/- 13.0; p < 0.0001) and showed less radiological progression during follow-up than the 1986 1990 group (DeltaRS/year of 0.95 +/- 2.19 vs. 5.69 +/- 8.43; p < 0.0001). In the later group, more patients (73 vs. 28%) had methotrexate (MTX). Twenty-one (23%) of the patients in the later group received biological drugs. However, the subgroup 1997-2000 (n = 29), before the approval of TNF-inhibitors, had already lower baseline RS in comparison to 1986-1990 (2.7 +/- 4.9; p < 0.001). Multivariate analysis showed that early start of MTX (before or directly after first consultation) was a predictor of favorable outcome (p < 0.005), as were low erythrocyte sedimentation rate at baseline and belonging to the later group. In contrast, neither treatment with glucocorticoids or biological drugs nor the overall rate of MTX or other disease-modifying antirheumatic drug use was predictive. Radiological damage is markedly diminished in RA patients seen since mid of the 1990s. Early treatment with MTX seems to be the key factor for this improved prognosis. PMID- 23925554 TI - Safety of joint and soft tissue injections in patients on warfarin anticoagulation. AB - Performance of joint and soft tissue injections in patients receiving anticoagulation is subject to different protocols, some of which suggest continuing treatment within the therapeutic range, while others recommend stopping the treatment prior to procedures. The aim of this study was to evaluate the safety of two approaches to the management of patients prescribed warfarin requiring joint or soft tissue injection. A systematic literature review on this subject was undertaken. Our departmental protocol was changed from one where anticoagulation treatment was temporarily stopped prior to joint/soft tissue injection to one where treatment was continued in the context of a therapeutic international normalised ratio (INR) level within 24 h of the procedure. In patients in whom warfarin was withheld, 32 procedures were performed in 18 patients (13 rheumatoid arthritis, 11 osteoarthritis, 5 spondyloarthritis and 1 each of adhesive capsulitis, rotator cuff tendinopathy and trochanteric bursitis). Of these, 30 were joint injections and 2 were soft tissue injections. In patients who continued warfarin, 32 procedures were performed in 21 patients (11 rheumatoid arthritis, 7 osteoarthritis, 6 crystal arthritis, 4 rotator cuff tendinopathy, 2 spondyloarthritis and 1 each of adhesive capsulitis and carpal tunnel syndrome). Of these, 27 were joint injections and 5 were soft tissue injections. There were no clinical hemarthroses or complications in either group. Joint and soft tissue injections appear to be safe in patients receiving warfarin anticoagulation with an INR <3. Continuation of anticoagulants reduces staff workload and patient inconvenience with no evidence of increased risk of complications. PMID- 23925556 TI - Proteomic analysis of sarcoplasmic peptides of two related fish species for food authentication. AB - Detection of species-specific sarcoplasmic peptides can be used as proteomic markers for fish food authentication and identification of species of origin in processed products. In the present study, proteomics technology was employed for differential characterization of sarcoplasmic peptides of two closely related fish species, Sperata seenghala and Sperata aor. Species-specific peptides were searched in white muscle extracts of the two species for identification of unique peptides that might aid in differentiation of the species, under two-dimensional gel electrophoresis platform. A total of 19 proteins were identified by combined matrix-assisted laser desorption ionization time-of-flight mass spectrometry and liquid chromatography-tandem mass spectrometry, of which nine and two proteins were found to be unique to S. seenghala and S. aor, respectively. One of the proteins, triosephosphate isomerase (TPI) was found to have three isoforms, out of which two were specific to S. aor, and one was specific to S. seenghala. All the three isoforms of TPI were present in the mixed samples of raw protein extracts of S. seenghala and S. aor, an observation that can be exploited to differentiate between the species and detection of deceptive practices of fraudulent substitution of commercially valuable fish species with inferior ones and differential characterization between closely related fish species. PMID- 23925555 TI - The complete genome sequence of a south Indian isolate of Rice tungro spherical virus reveals evidence of genetic recombination between distinct isolates. AB - In this study, complete genome of a south Indian isolate of Rice tungro spherical virus (RTSV) from Andhra Pradesh (AP) was sequenced, and the predicted amino acid sequence was analysed. The RTSV RNA genome consists of 12,171 nt without the poly(A) tail, encoding a putative typical polyprotein of 3,470 amino acids. Furthermore, cleavage sites and sequence motifs of the polyprotein were predicted. Multiple alignment with other RTSV isolates showed a nucleotide sequence identity of 95% to east Indian isolates and 90% to Philippines isolates. A phylogenetic tree based on complete genome sequence showed that Indian isolates clustered together, while Vt6 and PhilA isolates of Philippines formed two separate clusters. Twelve recombination events were detected in RNA genome of RTSV using the Recombination Detection Program version 3. Recombination analysis suggested significant role of 5' end and central region of genome in virus evolution. Further, AP and Odisha isolates appeared as important RTSV isolates involved in diversification of this virus in India through recombination phenomenon. The new addition of complete genome of first south Indian isolate provided an opportunity to establish the molecular evolution of RTSV through recombination analysis and phylogenetic relationship. PMID- 23925557 TI - Old age and poor prognosis increase the likelihood of disagreement between cancer patients and their oncologists on the indication for resuscitation attempt. AB - BACKGROUND: The do-not-resuscitate decision is a common ethical problem. However, the concordance between patients' preferences and physicians' assessments of the indication for cardiopulmonary resuscitation attempt (CPR) has only been modestly investigated. PURPOSE: The purpose of this study was to determine the impact of different patient characteristics on the following outcomes: (1) patients' wishes for or against CPR, (2) assessments made by physicians of the indication for CPR, and (3) the probability of discordance between patients' wishes and physicians' assessments. METHODS: In this survey, 1,128 of 1,408 cancer patients received a questionnaire concerning their wish for CPR. In total, 904 patients responded. A total of 61 treating physicians assessed the medical indication for resuscitation. Different predefined patient characteristics were analyzed using both univariate and multivariate analyses. RESULTS: Ninety percent of responding patients wished to receive CPR. The physicians found indications supporting CPR in 89 % of patients. Age >=70 years, increasing line of treatment, poor prognosis, living alone, and poor self-rated physical and mental health enhanced both patients' wishes and physicians' assessments to withhold CPR. However, only age >=70 years, poor prognosis, and poor self-rated physical health significantly predicted rejection of CPR in multivariate analyses. The likelihood of discordance between patients and physicians was significantly higher when the patient was >=70 years and when the expected 5-year survival was <25 %. CONCLUSIONS: Factors associated with the imminence of dying influenced both patients and physicians to refrain from CPR, and perhaps more surprisingly, the probability of discordance between patients and physicians increased. PMID- 23925558 TI - The emerging role of the molecular marker p27 in the differential diagnosis of adrenocortical tumors. AB - Malignant adrenocortical tumors (ACTs) are rare and highly aggressive; conversely, benign tumors are common and frequently found incidentally (the so called incidentalomas). Currently, the use of molecular markers in the diagnosis of ACTs is still controversial. The aim of this study was to analyze the molecular profile of different ACTs with the purpose of identifying markers useful for differentiating between these tumors. The ACTs that were studied (n=31) included nonfunctioning adenomas (ACAn)/incidentalomas (n=13), functioning adenomas with Cushing's syndrome (ACAc) (n=7), and carcinomas (n=11); normal adrenal glands (n=12) were used as controls. For each sample, the percentage area stained for the markers StAR, IGF2, IGF1R, p53, MDM2, p21, p27, cyclin D1, Ki-67, beta-catenin, and E-cadherin was quantified using a morphometric computerized tool. IGF2, p27, cyclin D1, and Ki-67 were the markers for which the percentage of stained area was significantly higher in carcinoma samples than in adenoma samples. Ki-67 and p27 were the markers that exhibited the highest discriminative power for differential diagnosis between carcinomas and all type of adenomas, while IGF2 and StAR were only found to be useful for differentiating between carcinomas and ACAn and between carcinomas and ACAc respectively. The usefulness of Ki-67 has been recognized before in the differential diagnosis of malignant tumors. The additional use of p27 as an elective marker to distinguish benign ACTs from malignant ACTs should be considered. PMID- 23925559 TI - The effect of levothyroxine replacement therapy on lipid profile and oxidative stress parameters in patients with subclinical hypothyroid. AB - The purpose of this present study is to investigate the levels of oxidative stress parameters in patients with subclinical hypothyroidism (SH) and the effects of levothyroxine (LT4) replacement therapy on these parameters and lipid profile. At the beginning of the study blood samples were collected from the patients in order to analyse oxidative stress parameters, lipid profile and biochemical markers. After replacement therapy with LT4, in the third month, same tests were performed again. At the baseline superoxide dismutase (SOD) levels were found to be higher in SH patients, compared to the euthyroid group. After LT4 therapy, statistically significant decreases in SOD and catalase levels and increase in HDL-C levels were noticed. LT4 treatment was found to have positive effects on oxidative stress indicators and HDL-C levels. PMID- 23925560 TI - Luteolin mediates the antidepressant-like effects of Cirsium japonicum in mice, possibly through modulation of the GABAA receptor. AB - Cirsium japonicum (CJ) has been shown to possess antidepressant-like properties. In the present study, we sought to identify which constituent of CJ might be responsible for its antidepressant effects and determine probable mechanism of action. The ethanol extract of CJ was administered to mice then behavioral changes were evaluated in the forced-swimming test (FST) and open-field test (OFT). In addition, its effects on norepinephrine (NE) reuptake and intracellular chloride (Cl(-)) flux were determined, in vitro. The effects of CJ's major constituents (linarin, pectolinarin, chlorogenic acid, luteolin) were also evaluated. CJ showed antidepressant-like effect by significantly reducing immobile behavior of mice in the FST, without increasing locomotor activity in the OFT. CJ had no effect on monoamine (NE) uptake, but it significantly promoted Cl(-) ion influx in human neuroblastoma cells. This CJ-induced Cl(-) influx was significantly blocked by co-administration of the competitive GABAA receptor antagonist, bicuculline. Among the major constituents of the CJ extract, only luteolin produced similar antidepressant-like effect, in vivo, and Cl(-) ion influx, in vitro. Altogether, the present results suggest that the antidepressant like effect of CJ was most probably induced by its constituent luteolin, mediated through potentiation of the GABAA receptor-Cl(-) ion channel complex. PMID- 23925561 TI - "Soft, hard, or just right?" Applications and limitations of axial-strain sonoelastography and shear-wave elastography in the assessment of tendon injuries. AB - Injury to a tendon leads to alterations in the mechanical properties of the tendon. Axial-strain sonoelastography and shear-wave elastography are relatively new, real-time imaging techniques that evaluate the mechanical properties of tendons in addition to the existing morphological and vascular information that is obtained with traditional imaging tools. Axial-strain sonoelastography displays the subjective distribution of strain data on an elastogram caused by tissue compression, whereas shear-wave elastography provides a more objective, quantitative measure of the intrinsic tissue elasticity using the acoustic push pulse. Recent studies suggest that axial-strain sonoelastography is able to distinguish between asymptomatic and diseased tendons, and is potentially more sensitive than conventional ultrasound in detecting early tendinopathy. Shear wave elastography seems to be a feasible tool for depicting elasticity and functional recovery of tendons after surgical management. While initial results have been promising, axial-strain sonoelastography and shear-wave elastography have not yet found routine use in wider clinical practice. Possible barriers to the dissemination of axial-strain sonoelastography technique include operator dependency, technical limitations such as artefacts and lack of reproducibility and quantification of sonoelastography data. Shear-wave elastography may improve the reproducibility of elastography data, although there is only one published study on the topic to date. Large-scale longitudinal studies are needed to further elucidate the clinical relevance and potential applications of axial strain sonoelastography and shear-wave elastography in diagnosing, predicting, and monitoring the progress of tendon healing before they can be widely adopted into routine clinical practice. PMID- 23925563 TI - One-pot synthesis of metal-organic framework@SiO2 core-shell nanoparticles with enhanced visible-light photoactivity. AB - This paper presents a novel strategy to prepare Cu3(BTC)2@SiO2 core-shell nanoparticles in the size range of 200-400 nm using a new one-pot strategy under ultrasonic irradiation at room temperature. In this approach, the silica shell thickness could be finely tuned in the size range of 12-60 nm for various reaction times. Nanocomposite thin films were fabricated on the glass substrates by Sol-Gel spin coating using the products for 1.5 h, 2 h and 2.5 h, respectively, and heat treated using an infrared lamp heating system in air. The photocatalytic degradation of phenol in aqueous solution using Cu2(BTC)3@SiO2 thin films was investigated under visible light irradiation at pH 4. After a 45 min reaction with phenol, the degradation rate was up to 93.1%. Moreover, the thin film photocatalysts could be reused 5 times without appreciable loss of photocatalytic activity for degradation of phenol. The present work clearly shows that the films as photocatalysts showed higher photocatalytic performance. PMID- 23925562 TI - "Modeling ancient Egyptian embalming": radiological assessment of experimentally mummified human tissue by CT and MRI. AB - OBJECTIVE: To assess changes in different tissues during the process of artificial mummification by natron using computed tomography (CT) and magnetic resonance imaging (MRI), and to translate the results to image interpretation in paleoradiological studies of ancient mummies. MATERIALS AND METHODS: A human lower limb (LL) was amputated from a female donor 24 h post-mortem and mummified by artificial natron (54 % NaCl, 16 % Na2SO4, 18 % Na2CO3 12 % NaHCO3) in ancient Egyptian style. The LL was kept in a fume hood at 16-25 degrees C and 30-75 % relative humidity. CT and MRI were performed at specific intervals with quantitative evaluation of Hounsfield units (HU) and signal intensities (SI). RESULTS: Evaluated tissues showed different HU and SI changes during the experimental mummification. All tissues revealed an overall but varying increase of HU in CT examinations. All tissues except for the compact bone revealed an overall but varying decrease of SI in the IR and T2-weighted sequences of the MRI. Typical findings included a distinct increase of HU in the cutis at the end of the study and a temporary increase of SI in the IR and T2-weighted sequences in all muscle groups. CONCLUSIONS: Radiological findings showed a regular, controlled and effective dehydration by the applied natron without detectable putrefaction. Evaluated tissues revealed different radiological changes during the experiment, which altogether led to preservation of the tissues without radiologically identifiable destruction. The cutis revealed radiological signs of direct interaction with the natron in the form of covering and possibly permeation. PMID- 23925564 TI - Tuning 'de Vries-like' properties in binary mixtures of liquid crystals with different molecular lengths. AB - Smectic liquid crystals with 'de Vries-like' properties are characterized by a maximum layer contraction of <=1% upon transition from the orthogonal SmA phase to the tilted SmC phase. We show that binary mixtures of 'de Vries-like' and conventional SmC mesogens with a molecular length ratio of 1.34 undergo a SmA-SmC phase transition with a maximum layer contraction ranging from 1.0 to 1.9% depending on the mixture composition. PMID- 23925566 TI - Amyloid or tau: the chicken or the egg? PMID- 23925567 TI - Urogynecology digest : presented by Fiona M. Lindo. PMID- 23925568 TI - Integrated experimental and computational approach to understand the effects of heavy ion radiation on skin homeostasis. AB - The effects of low dose high linear energy transfer (LET) radiation on human health are of concern for space, occupational, and clinical exposures. As epidemiological data for such radiation exposures are scarce for making relevant predictions, we need to understand the mechanism of response especially in normal tissues. Our objective here is to understand the effects of heavy ion radiation on tissue homeostasis in a realistic model system. Towards this end, we exposed an in vitro three dimensional skin equivalent to low fluences of neon (Ne) ions (300 MeV u(-1)), and determined the differentiation profile as a function of time following exposure using immunohistochemistry. We found that Ne ion exposures resulted in transient increases in the tissue regions expressing the differentiation markers keratin 10, and filaggrin, and more subtle time-dependent effects on the number of basal cells in the epidermis. We analyzed the data using a mathematical model of the skin equivalent, to quantify the effect of radiation on cell proliferation and differentiation. The agent-based mathematical model for the epidermal layer treats the epidermis as a collection of heterogeneous cell types with different proliferation-differentiation properties. We obtained model parameters from the literature where available, and calibrated the unknown parameters to match the observed properties in unirradiated skin. We then used the model to rigorously examine alternate hypotheses regarding the effects of high LET radiation on the tissue. Our analysis indicates that Ne ion exposures induce rapid, but transient, changes in cell division, differentiation and proliferation. We have validated the modeling results by histology and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The integrated approach presented here can be used as a general framework to understand the responses of multicellular systems, and can be adapted to other epithelial tissues. PMID- 23925565 TI - Transfer of human alpha-synuclein from the olfactory bulb to interconnected brain regions in mice. AB - alpha-Synuclein (alpha-syn) is a protein prevalent in neural tissue and known to undergo axonal transport. Intracellular alpha-syn aggregates are a hallmark of Parkinson's disease (PD). Braak and collaborators have suggested that in people who are destined to eventually develop PD, alpha-syn aggregate pathology progresses following a stereotypic pattern, starting in the olfactory bulb (OB) and the gut. alpha-Synuclein aggregates are postulated to spread to interconnected brain regions over several years. Thus, propagation of the pathology via neural pathways can potentially explain how alpha-syn aggregates spread in PD. We have now studied if alpha-syn can transfer from the OB to other brain structures through neural connections, by injecting different molecular species of human alpha-syn (monomers, oligomers, fibrils) into the OB of wild type mice. We found that non-fibrillar human alpha-syn is taken up very quickly by OB neurons. Within minutes to hours, it is also found in neurons in structures connected to the OB. Conversely, when we injected bovine serum albumin used as a control protein, we found that it does not diffuse beyond the OB, is rarely taken up by OB cells, and does not transfer to other structures. Taken together, our results show that OB cells readily take up alpha-syn, and that monomeric and oligomeric, but not fibrillar, forms of alpha-syn are rapidly transferred to interconnected structures within the timeframe we explored. Our results support the idea that alpha-syn can transfer along neural pathways and thereby contribute to the progression of the alpha-syn-related pathology. PMID- 23925569 TI - Conflicts of interest in the regulation of food safety: a threat to scientific integrity. PMID- 23925570 TI - Interaction of electrolyte molecules with carbon materials of well-defined porosity: characterization by solid-state NMR spectroscopy. AB - Electrochemical double-layer capacitors (EDLCs or supercapacitors) are of special potential interest with respect to energy storage. Nearly all EDLCs make use of porous carbons as electrode materials. Further tuning of their performance in EDLC applications requires a better understanding of their properties. In particular, the understanding of the interactions between carbon-based materials and electrolyte solutions is of fundamental interest with respect to future applications. Since the capacitance of carbon-based electrode materials is known to depend on the pore size, we have studied different porous carbon materials of well-defined, variable pore size loaded with 1 M TEABF4 in acetonitrile or with pure acetonitrile using solid-state magic angle spinning (MAS) (1)H, (11)B, and (13)C NMR spectroscopy. PMID- 23925571 TI - Comparative in vitro studies of MR imaging probes for metabotropic glutamate subtype-5 receptor targeting. AB - A series of magnetic resonance imaging probes has been evaluated to target selectively the metabotropic glutamate receptor subtype 5 (mGluR5). Eight imaging probes based on the contrast agent [Gd.DOTA], previously derived by linking it to a series of specific and selective mGluR5 antagonists, have been extensively tested for their functionality in vitro. The Nuclear Magnetic Relaxation Dispersion (NMRD) profiles of selected probes have been examined via field cycling relaxometry in the presence and absence of a model protein. The properties of the targeted contrast agents were evaluated using a primary astrocyte model, as these cells mimic the in vivo situation effectively. The probes were non-toxic (up to 200 MUM) to these mGluR5 expressing primary cells. Cellular proton longitudinal relaxation rate enhancements of up to 35% were observed by MRI at 200 MUM of probe concentration. The antagonistic effect of all compounds was tested using an assay measuring changes of intracellular calcium levels. Furthermore, treatment at two different temperatures (4 degrees C vs. 37 degrees C) and of an mGluR5-negative cell line provided further insight into the selectivity and specificity of these probes towards cell surface mGluR5. Finally, two out of eight probes demonstrated an antagonistic effect as well as significant enhancement of receptor mediated cellular relaxation rates, strongly suggesting that they would be viable probes for the mapping of mGluR5 by MRI in vivo. PMID- 23925572 TI - Low fetuin-A level in migraine: a case-control study. AB - Migraine is a type of primary headache which is caused by the alterations in trigeminovascular system. Migraine attacks are associated with neurovascular inflammation of the cerebral and extracerebral vessels, but its pathophysiological mechanisms have not still been fully delineated. Also, migraine has been found to be associated with higher risks for various metabolic disorders. Thus, we aimed to investigate the matrix metalloproteinases (MMP), fetuin-A, ghrelin, and omentin levels which have important roles in metabolic disorders and inflammation, and to examine their relationship with migraine subtypes and attack frequency. Forty-nine migraine patients and 30 age- and sex matched healthy control subjects were enrolled. Migraine diagnosis was confirmed according to the International Classification of Headache Disorders-II diagnostic criteria. Analyses of MMP9,MMP3, ghrelin, omentin, and fetuin-A were performed by the ELISA method. Fetuin-A, MMP-9, and MMP-3 levels were significantly lower in migraine than controls (p < 0.05). There were no significant differences between groups with respect to omentin and ghrelin (p > 0.05). In migraine patients, serum fetuin-A levels were positively correlated with MMP-9 and negatively correlated with MMP-3. MMP-3, MMP-9, fetuin-A, omentin and ghrelin levels did not correlate with age, disease duration, or frequency of migraine headache (p > 0.05). Migraine patients have lower fetuin-A, MMP-3 and MMP-9 levels than healthy individuals. Migraine patients have low fetuin-A levels, which may be related to the pathogenesis of migraine. The importance and impact of our findings on the pathogenesis, characteristics, and treatment of migraine needs to be investigated in further detailed studies. PMID- 23925573 TI - Epigenetic modulation of neuronal apoptosis and cognitive functions in sepsis associated encephalopathy. AB - Sepsis-associated encephalopathy (SAE), which associates with neuronal apoptosis and cognitive disorders, is a common complication of systemic sepsis. However, the mechanism involving its modulation remains to be elucidated. Recent studies showed that histone deacetylases (HDACs) were implicated in neurodegeneration and cognitive functions. The current study was designed to investigate whether septic brain is epigenetically modulated by HDACs, using cecal ligation and peroration (CLP) rats and primary hippocampal neuronal cultures. We found that hippocampal acetylated histone 3 (AcH3), acetylated histone 4 (AcH4), cytoplasmic HDAC4 and Bcl-XL were inhibited in septic brain. Hippocampal Bax and nuclear HDAC4 expressions were enhanced in CLP rats. Administration of HDACs inhibitor, trichostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA) rescued the changes of Bcl-XL and Bax in vivo, and decreased apoptotic cells in vitro. In addition, HDAC4 shRNA transfection significantly enhanced AcH3, AcH4 and Bcl-XL, but suppressed Bax. Neuronal apoptosis was also reduced by transfection of HDAC4 shRNA. Furthermore, CLP rats exhibited significant spatial learning and memory deficits, which could be ameliorated by application of TSA or SAHA without influence on locomotive activity. These results reveal that epigenetic modulation is involved in septic brain, and the inhibition of HDACs may serve as a potential therapeutic approach for SAE treatment. PMID- 23925574 TI - Isolated and combined medial patellofemoral ligament reconstruction in revision surgery for patellofemoral instability: a prospective study. AB - BACKGROUND: Persistent pain and redislocations after surgical treatment of patellofemoral instability are described in up to 40% of patients. However, prospective outcome data about revision surgery are missing. PURPOSE: To evaluate the clinical outcome after revision medial patellofemoral ligament (MPFL) reconstruction using isolated and combined procedures, with a follow-up of 24 months. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Study participants were 42 patients (median age, 22 years; range, 13-46 years) who underwent revision surgery between January 2007 and December 2009 because of persistent patellofemoral instability after a mean of 1.8 previous failed surgical interventions (lateral release, medial imbrication/vastus medialis obliquus distalization, medialization of the tuberosity). An isolated MPFL reconstruction was performed in 15 cases, while a combination procedure was performed in 27 cases. The clinical results were evaluated preoperatively and 24 months postoperatively using the International Knee Documentation Committee (IKDC), Kujala, and Tegner scores as well as a subjective questionnaire. Patellar shift, tilt, and height, as well as level of degeneration, were defined preoperatively and at the latest follow-up on plain radiographs and magnetic resonance imaging. RESULTS: At 24-month follow-up, 87% of the patients were satisfied or very satisfied with the treatment. No apprehension or redislocation was reported at follow-up, and there was a significant decrease in pain during daily activities. There were significant improvements (P < .001) in IKDC (from 50 to 80), Kujala (from 51 to 85), and Tegner scores (from 2.4 to 4.9). Patellar shift, tilt, and height decreased significantly (P < .05) to anatomic values, and there was no aggravation to the level of pre-existing degeneration. No significant difference was noticed between the isolated and combined procedures. CONCLUSION: As patellofemoral instability is a multifactorial problem, revision surgery should be indicated only after a comprehensive examination. The results of this study show that MPFL reconstruction, alone or in combination, seems to be an effective treatment for recurrent patellar dislocations after a failed previous surgery, leading to significant increases in stability and functionality as well as a reduction in pain. PMID- 23925575 TI - How to write a systematic review. AB - BACKGROUND: The role of evidence-based medicine in sports medicine and orthopaedic surgery is rapidly growing. Systematic reviews and meta-analyses are also proliferating in the medical literature. PURPOSE: To provide the outline necessary for a practitioner to properly understand and/or conduct a systematic review for publication in a sports medicine journal. STUDY DESIGN: Review. METHODS: The steps of a successful systematic review include the following: identification of an unanswered answerable question; explicit definitions of the investigation's participant(s), intervention(s), comparison(s), and outcome(s); utilization of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta analyses) guidelines and PROSPERO registration; thorough systematic data extraction; and appropriate grading of the evidence and strength of the recommendations. RESULTS: An outline to understand and conduct a systematic review is provided, and the difference between meta-analyses and systematic reviews is described. The steps necessary to perform a systematic review are fully explained, including the study purpose, search methodology, data extraction, reporting of results, identification of bias, and reporting of the study's main findings. CONCLUSION: Systematic reviews or meta-analyses critically appraise and formally synthesize the best existing evidence to provide a statement of conclusion that answers specific clinical questions. Readers and reviewers, however, must recognize that the quality and strength of recommendations in a review are only as strong as the quality of studies that it analyzes. Thus, great care must be used in the interpretation of bias and extrapolation of the review's findings to translation to clinical practice. Without advanced education on the topic, the reader may follow the steps discussed herein to perform a systematic review. PMID- 23925576 TI - Articular cartilage lesions increase early cartilage degeneration in knees treated by anterior cruciate ligament reconstruction: T1rho mapping evaluation and 1-year follow-up. AB - BACKGROUND: Articular cartilage degeneration can develop after anterior cruciate ligament reconstruction (ACLR). Although radiological studies have identified risk factors for the progression of degenerative cartilage changes in the long term, risk factors in the early postoperative period remain to be documented. HYPOTHESIS: Cartilage lesions that are present at surgery progress to cartilage degeneration in the early phase after ACLR. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: T1rho is the spin-lattice relaxation in the rotating frame magnetic resonance imaging. Sagittal T1rho maps of the femorotibial joint were obtained before and 1 year after ACLR in 23 patients with ACL injuries. Four regions of interest (ROIs) were placed on images of the cartilage in the medial and lateral femoral condyle (MFC, LFC) and the medial and lateral tibia plateau (MTP, LTP). Changes in the T1rho value (milliseconds) of each ROI were recorded, and differences between patients with and without cartilage lesions were evaluated. The relationship between changes in the T1rho value and meniscal tears was also studied. RESULTS: Arthroscopy at ACLR detected cartilage lesions in 15 MFCs, 7 LFCs, and 2 LTPs. The baseline T1rho value of the MFC and LFC was significantly higher in patients with cartilage lesions (MFC, 40.7 ms; LFC, 42.2 ms) than in patients without cartilage lesions (MFC, 38.0 ms, P = .025; LFC, 39.4 ms, P = .010). At 1-year follow-up, the T1rho value of the MFC and LFC was also significantly higher in patients with lesions (MFC, 43.1 ms; LFC, 42.7 ms) than in patients without such lesions (MFC, 39.1 ms, P = .002; LFC, 40.4 ms, P = .023, respectively). In patients with cartilage injury, the T1rho value of the MFC increased during the year after treatment (P = .002). There was no significant difference in the baseline and follow-up T1rho value in patients with or without meniscal tears on each side although the T1rho value of the MFC, MTP, and LFC increased during the first year after surgery regardless of the presence or absence of meniscal injuries. CONCLUSION: Using T1rho mapping to detect minimal changes, our study demonstrated that cartilage lesions are related to progressive degenerative cartilage changes during the early phase after ACLR. PMID- 23925577 TI - Rapid and efficient synthesis of [11C]ureas via the incorporation of [11C]CO2 into aliphatic and aromatic amines. AB - A rapid urea radiolabelling methodology has been developed. [(11)C]CO2 was activated by 1,8-diazabicycloundec-7-ene (DBU) in the presence of aliphatic and aromatic amines and reacted with Mitsunobu reagents to produce asymmetric (11)C radiolabelled ureas in high radiochemical yields. PMID- 23925578 TI - Association of the ATM gene polymorphisms with papillary thyroid cancer. AB - Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, yet few genetic markers of PTC risk useful for screening exist. Our study aimed to evaluate the association between single nucleotide polymorphisms (SNPs) of the ataxia telangiectasia mutated (ATM) gene and PTC risk. 358 patients with PTC and 360 healthy controls were included in the case-control study. Four ATM SNPs (rs664677, rs373759, rs4988099, and rs189037) were genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). The analysis of genetic data was performed using the SNPStats program. The allele frequencies and genotype distributions of the four ATM SNPs were not different between PTC patients and controls. We did not observe any tendency of increasing the frequency of the risk allele from controls, patients without metastasis to patients with metastasis (P(trend) > 0.05). Interestingly, the AG genotype of rs373759 was associated with PTC risk under an overdominant model of inheritance (adjusted OR = 1.38; 95 % CI, 1.03-1.87; P = 0.03). No haplotype was observed to be significantly associated with PTC risk. Our results suggest that heterozygosity for the ATM rs373759 polymorphism may be a potential risk factor for PTC. PMID- 23925580 TI - Antitumor activity of new enantiopure pybox-ruthenium complexes. AB - New ruthenium complexes containing enantiopure 2,6-bis[4'(R)-phenyloxazolin-2'-il pyridine] ((R,R)-Ph-pybox), 2,6-bis[4'(S)-isopropyloxazolin-2'-il-pyridine] ((S,S)-(i)Pr-pybox) or 2,6-bis[4'(R)-isopropyloxazolin-2'-il-pyridine] ((R,R) (i)Pr-pybox) and water soluble 1,3,5-triaza-7-phosphaadamantane (PTA) or N substituted PTA phosphanes have been synthesized in high yields and fully characterized. The interactions of these compounds with plasmidic DNA and their cytotoxic activity against the human cervical cancer HeLa cell line are reported, pointing out for the first time the different behaviour of ruthenium enantiomers affecting the cell cycle in HeLa tumor cells. PMID- 23925579 TI - The BRAF V600E mutation in papillary thyroid cancer with positive or suspected pre-surgical cytological finding is not associated with advanced stages or worse prognosis. AB - The mutation BRAF V600E is thought to be a putative prognostic marker of the aggressiveness of several cancers among which is also papillary thyroid cancer. Our study aimed to evaluate whether this mutation is associated with advanced stages of disease or with a worse prognosis in a series of patients with cytological findings of Thyr 4 and Thyr 5 and who were undergoing total thyroidectomy and routine central compartment lymph-node dissection. 110 patients were consecutively enrolled over an 18-month period from September 2010 to March 2012. All patients had cytological findings that were either indicative of, or positive for papillary thyroid cancer, Thyr 4 or Thyr 5. Detection of BRAF mutation was made on fine-needle aspiration specimen by pyrosequencing after microdissection and DNA extraction of neoplastic cells. After surgical intervention, the patients underwent radioiodine ablation according to our protocol, and follow-up was performed after 8 months. The BRAF V600E mutation was found in 79 % of our cases: 85.7 % of these cases represented the classical variant, 57.8 % the follicular variant, 89.6 % the tall cell variant, and 33.3 % the solid variant. All patients had confirmation of papillary thyroid cancer after histology, with no differences being seen in pTNM presentation between patients with BRAF wild-type and patients with BRAF V600E mutation. Ninety-nine patients underwent radioiodine ablation. Results at follow-up 8 months after radioiodine ablation showed no differences in the rate of ablation between patients harboring BRAF V600E mutation and those having BRAF wild-type. The BRAF V600E mutation doesn't appear to be a reliable risk factor for the aggressiveness of a tumor. BRAF analysis should neither be the only guide for pre-surgical decisions regarding the extent of surgery nor for post-surgical decisions regarding the aggressiveness of the treatment. PMID- 23925581 TI - Efficacy of manual lymphatic drainage and intermittent pneumatic compression pump use in the treatment of lymphedema after mastectomy: a randomized controlled trial. AB - BACKGROUND: This study has two aims. The first was to investigate the efficacy and contribution of an intermittent pneumatic compression pump in the management of lymphedema, and the second was to evaluate the correlation of our measurement methods. METHODS: This study was designed as a controlled clinical trial at the Physical Medicine and Rehabilitation Department of Ataturk University Faculty of Medicine. Thirty-one patients with upper extremity lymphedema following mastectomy participated in the study. The patients were divided into two groups. The complex decongestive physical therapy (CDT) group (group 1, n = 15) received allocated treatment, including skin care, manual lymphatic drainage, compression bandages, compression garments, and exercises. The other group had CDT combined with an intermittent pneumatic compression pump (group 2, n = 16). Both groups were treated five times a week for 3 weeks (for a total of 15 sessions). Patients were assessed according to circumference measurements of landmarks, limb volume difference, dermal thickness with ultrasonography (USG), and pain. RESULTS: We observed significant difference in both groups when comparing them before and after therapy. The baseline median volume difference of group 1 was 630 (180 1,820), and after therapy it was 480 (0-1,410). In group 2, the beginning median volume difference was 840 (220-3,460), and after therapy it was 500 (60-2,160). However, no significant differences were observed between the two groups in terms of the above-mentioned parameters. CONCLUSION: We concluded that the pneumatic compression pump did not contribute to the reduction of lymphedema. In addition, gauging dermal thickness using USG may prove to be a useful measurement method in the evaluation of lymphedema. PMID- 23925582 TI - Comparison of the clinicopathological features of invasive ductal, invasive lobular, and mixed (invasive ductal + invasive lobular) carcinoma of the breast. AB - BACKGROUND: In this retrospective analysis, the clinicopathological features and pattern of metastatic spread of invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and mixed ductal/lobular carcinoma (MDLC), together with the type and outcome of surgical intervention, were comparatively evaluated. METHODS: A total of 633 breast cancer patients with histopathological subtype IDC, ILC or MDLC were included in the study. The mean age was 52.6 +/- 12.7 years. Follow-up period ranged between 0 and 33 (median 6.0) years. The groups were compared with respect to age, tumor size, nodal involvement, stage, hormonal therapy, multicentricity, multifocality, bilaterality, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2)/neu, p53, and Ki67 expression, disease-free survival (DFS) and overall survival (OS) rates, and surgical approach. RESULTS: The distribution of patients was as follows: IDC 508 (80.3 %), ILC 78 (12.3 %), MDLC 47 (7.4 %). Among the parameters evaluated, statistically significant differences were observed in mean tumor size (IDC 2.5 +/- 1.98 cm, ILC 3.0 +/- 1.8 cm, MDLC 3.2 +/- 2.4 cm), advanced T stage (T3 + T4) at diagnosis (IDC 14.7 %, ILC 21.4 %, MDLC 25.6 %), N stage (N0 was dominant in IDC and ILC; N3 was dominant in MDLC), tumor-node-metastasis (TNM) stage (stage II was dominant in IDC and ILC; stage III was dominant in MDLC), HER2/neu expression (IDC 23.8 %, ILC 11.8 %, MDLC 21.4 %), and frequency of bone metastasis (IDC 14.3 %, ILC 17.9 %, MDLC 25.5 %). CONCLUSIONS: MDLC-type tumors have different histopathological characteristics and are often diagnosed at advanced stage. However, their survival outcomes do not vary significantly from ILC and IDC. PMID- 23925583 TI - NEXUS chest: validation of a decision instrument for selective chest imaging in blunt trauma. AB - IMPORTANCE: Chest radiography (chest x-ray [CXR] and chest computed tomography [CT]) is the most common imaging in blunt trauma evaluation. Unnecessary trauma imaging leads to greater costs, emergency department time, and patient exposure to ionizing radiation. OBJECTIVE To validate our previously derived decision instrument (NEXUS Chest) for identification of blunt trauma patients with very low risk of thoracic injury seen on chest imaging (TICI). We hypothesized that NEXUS Chest would have high sensitivity (>98%) for the prediction of TICI and TICI with major clinical significance. DESIGN, SETTING, AND PARTICIPANTS: From December 2009 to January 2012, we enrolled blunt trauma patients older than 14 years who received chest radiography in this prospective, observational, diagnostic decision instrument study at 9 US level I trauma centers. Prior to viewing radiographic results, physicians recorded the presence or absence of the NEXUS Chest 7 clinical criteria (age >60 years, rapid deceleration mechanism, chest pain, intoxication, abnormal alertness/mental status, distracting painful injury, and tenderness to chest wall palpation). MAIN OUTCOMES AND MEASURES: Thoracic injury seen on chest imaging was defined as pneumothorax, hemothorax, aortic or great vessel injury, 2 or more rib fractures, ruptured diaphragm, sternal fracture, and pulmonary contusion or laceration seen on radiographs. An expert panel generated an a priori classification of clinically major, minor, and insignificant TICIs according to associated management changes. RESULTS: Of 9905 enrolled patients, 43.1% had a single CXR, 42.0% had CXR and chest CT, 6.7% had CXR and abdominal CT (without chest CT), 5.5% had multiple CXRs without CT, and 2.6% had chest CT alone in the emergency department. The most common trauma mechanisms were motorized vehicle crash (43.9%), fall (27.5%), pedestrian struck by motorized vehicle (10.7%), bicycle crash (6.3%), and struck by blunt object, fists, or kicked (5.8%). Thoracic injury seen on chest imaging was seen in 1478 (14.9%) patients with 363 (24.6%) of these having major clinical significance, 1079 (73.0%) minor clinical significance, and 36 (2.4%) no clinical significance. NEXUS Chest had a sensitivity of 98.8% (95% CI, 98.1%-99.3%), a negative predictive value of 98.5% (95% CI, 97.6%.6-99.1%), and a specificity of 13.3% (95% CI, 12.6%-14.1%) for TICI. The sensitivity and negative predictive value for TICI with clinically major injury were 99.7% (95% CI, 98.2%-100.0%) and 99.9% (95% CI, 99.4%-100.0%), respectively. CONCLUSIONS AND RELEVANCE: We have validated the NEXUS Chest decision instrument, which may safely reduce the need for chest imaging in blunt trauma patients older than 14 years. PMID- 23925584 TI - The visual system prioritizes locations near corners of surfaces (not just locations near a corner). AB - When a new visual object appears, attention is directed toward it. However, some locations along the outline of the new object may receive more resources, perhaps as a consequence of their relative importance in describing its shape. Evidence suggests that corners receive enhanced processing, relative to the straight edges of an outline (corner enhancement effect). Using a technique similar to that in an original study in which observers had to respond to a probe presented near a contour (Cole et al. in Journal of Experimental Psychology: Human Perception and Performance 27:1356-1368, 2001), we confirmed this effect. When figure-ground relations were manipulated using shaded surfaces (Exps. 1 and 2) and stereograms (Exps. 3 and 4), two novel aspects of the phenomenon emerged: We found no difference between corners perceived as being convex or concave, and we found that the enhancement was stronger when the probe was perceived as being a feature of the surface that the corner belonged to. Therefore, the enhancement is not based on spatial aspects of the regions in the image, but critically depends on figure-ground stratification, supporting the link between the prioritization of corners and the representation of surface layout. PMID- 23925585 TI - Microfluidic barcode assay for antibody-based confirmatory diagnostics. AB - Confirmatory diagnostics offer high clinical sensitivity and specificity typically by assaying multiple disease biomarkers. Employed in clinical laboratory settings, such assays confirm a positive screening diagnostic result. These important multiplexed confirmatory assays require hours to complete. To address this performance gap, we introduce a simple 'single inlet, single outlet' microchannel architecture with multiplexed analyte detection capability. A streptavidin-functionalized, channel-filling polyacrylamide gel in a straight glass microchannel operates as a 3D scaffold for a purely electrophoretic yet heterogeneous immunoassay. Biotin and biotinylated capture reagents are patterned in discrete regions along the axis of the microchannel resulting in a barcode like pattern of reagents and spacers. To characterize barcode fabrication, an empirical study of patterning behaviour was conducted across a range of electromigration and binding reaction timescales. We apply the heterogeneous barcode immunoassay to detection of human antibodies against hepatitis C virus and human immunodeficiency virus antigens. Serum was electrophoresed through the barcode patterned gel, allowing capture of antibody targets. We assess assay performance across a range of Damkohler numbers. Compared to clinical immunoblots that require 4-10 h long sample incubation steps with concomitant 8-20 h total assay durations; directed electromigration and reaction in the microfluidic barcode assay leads to a 10 min sample incubation step and a 30 min total assay duration. Further, the barcode assay reports clinically relevant sensitivity (25 ng ml(-1) in 2% human sera) comparable to standard HCV confirmatory diagnostics. Given the low voltage, low power and automated operation, we see the streamlined microfluidic barcode assay as a step towards rapid confirmatory diagnostics for a low-resource clinical laboratory setting. PMID- 23925586 TI - Clinical practice guidelines for treatment of acne vulgaris: a critical appraisal using the AGREE II instrument. AB - A significant number of clinical practice guidelines (CPGs) about the treatment of acne vulgaris in adolescents and adults have been published worldwide. However, little is known about the quality of CPGs in this field. The aim of this study was to appraise the methodological quality of published acne vulgaris CPGs. We performed a systematic review of published CPGs on acne vulgaris therapy from July 2002 to July 2012. Three reviewers independently assessed each CPG using the AGREE II instrument. A standardized score was calculated for each of the six domains. Our search strategy identified 103 citations but just six met our inclusion criteria. Agreement among reviewers was very good: 0.981. The domains that scored better were: "scope and purpose" and "clarity and presentation". Those that scored worse were "stakeholder involvement", "rigor of development", and "applicability". The European and the Malaysian CPGs were the only recommended with no further modifications. In addition, the Mexican, Colombian and the United States guidelines were recommended with provisos, with lower scores regarding stakeholder involvement, rigor of development and applicability. Only two guidelines clearly reported outcome measures for evaluating efficacy or included quality of life outcomes. CPGs varied regarding the consideration of light/laser therapy or consideration of complementary/alternative medicines. None of them included cost considerations of drugs such as systemic isotretinoin. In conclusion, published acne vulgaris CPGs for acne therapy vary in quality with a clear need to improve their methodological rigor. This could be achieved with the adherence to current CPGs development standards. PMID- 23925587 TI - Lanthanide cation-templated synthesis of rotaxanes. AB - The first lanthanide cation-templated synthesis of an interlocked structure is demonstrated through an interpenetrated assembly between a pyridine N-oxide threading component coordinating to a lanthanide cation complexed within a macrocycle. Stoppering of the pseudo-rotaxane assembly allows for preparation of the [2]rotaxane. PMID- 23925588 TI - Difficulties in diagnosing terminal ileitis due to Yersinia pseudotuberculosis. AB - We report three patients with terminal ileitis and positive fecal cultures with Yersinia pseudotuberculosis. From one patient, a virulence plasmid (pYV)-negative Y. pseudotuberculosis was isolated, which represents the second finding of a pYV negative isolate associated with human disease. All patients were treated with ciprofloxacin and fully recovered. Since conventional culture methods for yersiniosis are gradually replaced with molecular tests not recognizing Y. pseudotuberculosis, we recommend to include a specific culture medium or to apply a specific polymerase chain reaction (PCR) assay on fecal samples from patients suspected of terminal ileitis. PMID- 23925589 TI - Oral caffeine administration ameliorates acute colitis by suppressing chitinase 3 like 1 expression in intestinal epithelial cells. AB - BACKGROUND: The initial trigger of inflammatory bowel disease (IBD) can be partly attributed towards the interaction and invasion of intestinal epithelial cells (IECs) and submucosal compartments. Identifying safe and economical methods to block these interactions may help prevent the onset of early colitis. Chitinase 3 like 1 (CHI3L1) is an inducible host protein that facilitates bacterial attachment and invasion on/into IECs. Therefore, we test the hypothesis of inhibiting CHI3L1 using the pan-chitinase inhibitor caffeine to reduce the likelihood of early colitis onset. METHODS: IEC lines were treated with caffeine (2.5 or 5 mM) and analyzed for CHI3L1 expression and the impact on bacterial invasion. In vivo, mice were treated with 2.5 mM caffeine and induced with 3.5 % dextran sulfate sodium (DSS)-mediated colitis and subsequently analyzed colitis development. RESULTS: In vitro, caffeine treatment in IEC lines down-regulated CHI3L1 mRNA expression, which resulted in the reduction of bacterial invasion in a caffeine dose-dependent manner. In vivo, mice treated with caffeine displayed a delayed response towards DSS-induced colitis, characterized by lower body weight loss, clinical and histological scores. Bacterial translocation into other organs and pro-inflammatory cytokines production were also reduced in the caffeine treated mice with DSS-induced colitis. Caffeine treatment also resulted in the loss of CHI3L1-associated AKT signaling pathway activation both in vitro and in vivo. CONCLUSION: Development of acute colitis is reduced upon caffeine treatment. The mechanism involves the down-regulation of CHI3L1 expression and its associated bacterial interaction effect. Therefore, caffeine is proposed as a safe and economical candidate for successful IBD management. PMID- 23925590 TI - Highly luminescent, fluorinated semiconducting polymer dots for cellular imaging and analysis. AB - A highly fluorescent fluorinated semiconducting polymer dot (Pdot) with a quantum yield of up to 49% was developed. The fluorinated Pdot was eight times brighter in cell-labeling applications than its non-fluorinated counterpart, and was rod shaped rather than spherical. PMID- 23925592 TI - Pulsed-focused ultrasound enhances boron drug accumulation in a human head and neck cancer xenograft-bearing mouse model. AB - PURPOSE: This study aims to demonstrate that pulsed high-intensity focused ultrasound (pulsed-HIFU) may enhance the fructose-conjugated 4-borono-L phenylalanine (BPA-Fr) accumulation in tumor lesion using (18)F-FBPA-Fr microPET scans. PROCEDURES: To the mice bearing orthotopic SASC03 human tongue squamous carcinoma xenograft, a 2-min pulsed-HIFU was applied to tumor. Immediately after pulsed-HIFU treatment, (18)F-FBPA-Fr was intravenously injected, and biological characterizations including microPET imaging and biodistribution were conducted. RESULTS: Both biodistribution studies and microPET imaging performed after intravenous injection of (18)F-FBPA-Fr revealed higher tumor uptake in HIFU treated mice than that of the control. CD31 and Ki-67 histochemical staining of tumor sections and H&E staining of nearby normal tissues revealed no significant difference between the pulsed-HIFU-treated mice and the control. CONCLUSION: This study demonstrated that pulsed-HIFU was beneficial to the accumulation of boron drug in the head and neck tumor lesion and may enhance the therapeutic efficacy of clinical BNCT. PMID- 23925593 TI - Conflicts of interest in approvals of additives to food determined to be generally recognized as safe: out of balance. AB - IMPORTANCE: Food and Drug Administration (FDA) guidance allows food manufacturers to determine whether additives to food are "generally recognized as safe" (GRAS). Manufacturers are not required to notify the FDA of a GRAS determination, although in some instances they notify the agency. The individuals that companies select to make these determinations may have financial conflicts of interest. OBJECTIVE: To determine the extent to which individuals selected by manufacturers to make GRAS determinations have conflicts of interest between their obligations to ensure that the use of the additive is safe and their financial relationships to the company. DESIGN Using conflict of interest criteria developed by a committee of the Institute of Medicine, we analyzed 451 GRAS notifications that were voluntarily submitted to the FDA between 1997 and 2012. MAIN OUTCOMES AND MEASURES: Number of GRAS notices submitted to the FDA; frequency of various types of relationships between decision maker and additive manufacturer; frequency of participation on GRAS panels by individuals; and number of GRAS safety determinations identified by the FDA that were not submitted to the agency. RESULTS: For the 451 GRAS notifications, 22.4% of the safety assessments were made by an employee of an additive manufacturer, 13.3% by an employee of a consulting firm selected by the manufacturer, and 64.3% by an expert panel selected by either a consulting firm or the manufacturer. A standing expert panel selected by a third party made none of these safety assessments. The 290 panels that made GRAS determinations had an average of 3.5 members, with a maximum of 7. Ten individuals served on 27 or more panels; 1 individual served on 128 panels (44.1%). At least 1 of the 10 individuals with the most frequent service was a member of 225 panels (77.6%). CONCLUSIONS AND RELEVANCE: Between 1997 and 2012, financial conflicts of interest were ubiquitous in determinations that an additive to food was GRAS. The lack of independent review in GRAS determinations raises concerns about the integrity of the process and whether it ensures the safety of the food supply, particularly in instances where the manufacturer does not notify the FDA of the determination. The FDA should address these concerns. PMID- 23925594 TI - Cerebellar contributions to different phases of visceral aversive extinction learning. AB - The cerebellum is increasingly recognized to contribute to non-motor functions, including cognition and emotion. Although fear conditioning has been studied for elucidating the pathophysiology of anxiety, the putative role of the cerebellum is still unknown. Fear conditioning could also be important in the etiology of chronic abdominal pain which often overlaps with anxiety. Hence, in this exploratory analysis, we investigated conditioned anticipatory activity in the cerebellum in a visceral aversive fear conditioning paradigm using functional magnetic resonance imaging. We extended and reanalyzed a previous dataset for different learning phases, i.e., acquisition, extinction, and reinstatement, utilizing an advanced normalizing method of the cerebellum. In 30 healthy humans, visual conditioned stimuli (CS(+)) were paired with painful rectal distensions as unconditioned stimuli (US), while other visual stimuli (CS(-)) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. During acquisition, posterolateral cerebellar areas including Crus I, Crus II, and VIIb and parts of the dentate nucleus were activated in response to the CS(+) compared to the CS( ). During extinction, activation related to CS(+) presentation was detected in Crus I, Crus II, IV, V, VI, VIIb, IX, and vermis. Neural correlates of reinstatement were found in Crus I, Crus II, IV, V, and IX. We could show for the first time that the cerebellum is involved in abdominal pain-related associative learning processes. Together, these findings contribute to our understanding of the cerebellum in aversive learning and memory processes relevant to the pathophysiology of chronic abdominal pain. PMID- 23925598 TI - Alone in green: Antonio Henrique Amaral. PMID- 23925595 TI - Friedreich ataxia: executive control is related to disease onset and GAA repeat length. AB - Friedreich ataxia (FRDA) is the most frequent inherited ataxia. Neuropsychological studies suggest that FRDA may be associated with specific cognitive impairment. Very little is known about the relation between cognitive performance, demographics and disease-related parameters, such as GAA repeat size, age of onset and disease duration. The present investigation aimed at assessing cognitive functions in a representative sample of FRDA patients and at identifying the most relevant disease-related parameters. Twenty-nine adult FRDA patients underwent neuropsychological tests assessing executive functions, attention, memory and visual perception. Performance was compared with 28 age- and education-matched controls as well as with standardized norms. The relation between neuropsychological outcome, demographical variables and disease-related parameters was assessed. Cognitive impairment affected only a subgroup of patients and mostly concerned attentional and executive functions. Good cognitive performance was associated with a later disease onset, shorter GAA repeat length and lower burden of disease. Age at disease onset has been found to be a good predictor when a cut-off of 14 years was chosen. No correlation was found between cognitive performance and education, age or disease duration. The present study extends earlier findings in FRDA showing that performance in attentional and executive function tasks is best predicted by the age at disease onset. Moreover, executive functions show a clear relationship to disease severity and repeat size of the shorter GAA allele. These findings therefore have important implications for patient counselling regarding education and career choices. PMID- 23925599 TI - Health care under attack in Syrian conflict. PMID- 23925600 TI - Disaster training, capacity for quality trauma care key to aiding injured in Asiana Airlines crash. PMID- 23925601 TI - States take a public health approach to curb gun violence. Interview by Bridget M. Kuehn. PMID- 23925611 TI - Traumatic brain injury: an international knowledge-based approach. PMID- 23925612 TI - Implications of combat casualty care for mass casualty events. PMID- 23925613 TI - Management of acute stress, PTSD, and bereavement: WHO recommendations. PMID- 23925614 TI - An evidence-based response to intimate partner violence: WHO guidelines. PMID- 23925615 TI - A piece of my mind. A handshake. PMID- 23925616 TI - Treatment of comorbid substance dependence and posttraumatic stress disorder. PMID- 23925617 TI - Suicide, mental disorders, and the US military: time to focus on mental health service delivery. PMID- 23925618 TI - Recovery after violence and human rights abuses. PMID- 23925619 TI - Concurrent naltrexone and prolonged exposure therapy for patients with comorbid alcohol dependence and PTSD: a randomized clinical trial. AB - IMPORTANCE: Alcohol dependence comorbid with posttraumatic stress disorder (PTSD) has been found to be resistant to treatment. In addition, there is a concern that prolonged exposure therapy for PTSD may exacerbate alcohol use. OBJECTIVE: To compare the efficacy of an evidence-based treatment for alcohol dependence (naltrexone) plus an evidence-based treatment for PTSD (prolonged exposure therapy), their combination, and supportive counseling. DESIGN, SETTING, AND PARTICIPANTS: A single-blind, randomized clinical trial of 165 participants with PTSD and alcohol dependence conducted at the University of Pennsylvania and the Philadelphia Veterans Administration. Participant enrollment began on February 8, 2001, and ended on June 25, 2009. Data collection was completed on August 12, 2010. INTERVENTIONS: Participants were randomly assigned to (1) prolonged exposure therapy plus naltrexone (100 mg/d), (2) prolonged exposure therapy plus pill placebo, (3) supportive counseling plus naltrexone (100 mg/d), or (4) supportive counseling plus pill placebo. Prolonged exposure therapy was composed of 12 weekly 90-minute sessions followed by 6 biweekly sessions. All participants received supportive counseling. MAIN OUTCOMES AND MEASURES: The Timeline Follow Back Interview and the PTSD Symptom Severity Interview were used to assess the percentage of days drinking alcohol and PTSD severity, respectively, and the Penn Alcohol Craving Scale was used to assess alcohol craving. Independent evaluations occurred prior to treatment (week 0), at posttreatment (week 24), and at 6 months after treatment discontinuation (week 52). RESULTS: Participants in all 4 treatment groups had large reductions in the percentage of days drinking (mean change, -63.9% [95% CI, -73.6% to -54.2%] for prolonged exposure therapy plus naltrexone; -63.9% [95% CI, -73.9% to -53.8%] for prolonged exposure therapy plus placebo; -69.9% [95% CI, -78.7% to -61.2%] for supportive counseling plus naltrexone; and -61.0% [95% CI, -68.9% to -53.0%] for supportive counseling plus placebo). However, those who received naltrexone had lower percentages of days drinking than those who received placebo (mean difference, 7.93%; P = .008). There was also a reduction in PTSD symptoms in all 4 groups, but the main effect of prolonged exposure therapy was not statistically significant. Six months after the end of treatment, participants in all 4 groups had increases in percentage of days drinking. However, those in the prolonged exposure therapy plus naltrexone group had the smallest increases. CONCLUSIONS AND RELEVANCE: In this study of patients with alcohol dependence and PTSD, naltrexone treatment resulted in a decrease in the percentage of days drinking. Prolonged exposure therapy was not associated with an exacerbation of alcohol use disorder. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00006489. PMID- 23925620 TI - Risk factors associated with suicide in current and former US military personnel. AB - IMPORTANCE: Beginning in 2005, the incidence of suicide deaths in the US military began to sharply increase. Unique stressors, such as combat deployments, have been assumed to underlie the increasing incidence. Previous military suicide studies, however, have relied on case series and cross-sectional investigations and have not linked data during service with postservice periods. OBJECTIVE: To prospectively identify and quantify risk factors associated with suicide in current and former US military personnel including demographic, military, mental health, behavioral, and deployment characteristics. DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal study with accrual and assessment of participants in 2001, 2004, and 2007. Questionnaire data were linked with the National Death Index and the Department of Defense Medical Mortality Registry through December 31, 2008. Participants were current and former US military personnel from all service branches, including active and Reserve/National Guard, who were included in the Millennium Cohort Study (N = 151,560). MAIN OUTCOMES AND MEASURES: Death by suicide captured by the National Death Index and the Department of Defense Medical Mortality Registry. RESULTS: Through the end of 2008, findings were 83 suicides in 707,493 person-years of follow-up (11.73/100,000 person-years [95% CI, 9.21-14.26]). In Cox models adjusted for age and sex, factors significantly associated with increased risk of suicide included male sex, depression, manic-depressive disorder, heavy or binge drinking, and alcohol-related problems. None of the deployment-related factors (combat experience, cumulative days deployed, or number of deployments) were associated with increased suicide risk in any of the models. In multivariable Cox models, individuals with increased risk for suicide were men (hazard ratio [HR], 2.14; 95% CI, 1.17-3.92; P = .01; attributable risk [AR], 3.5 cases/10,000 persons), and those with depression (HR, 1.96; 95% CI, 1.05-3.64; P = .03; AR, 6.9/10,000 persons), manic-depressive disorder (HR, 4.35; 95% CI, 1.56-12.09; P = .005; AR, 35.6/10,000 persons), or alcohol-related problems (HR, 2.56; 95% CI, 1.56-4.18; P <.001; AR, 7.7/10,000 persons). A nested, matched case-control analysis using 20:1 control participants per case confirmed these findings. CONCLUSIONS AND RELEVANCE: In this sample of current and former military personnel observed July 1, 2001-December 31, 2008, suicide risk was independently associated with male sex and mental disorders but not with military-specific variables. These findings may inform approaches to mitigating suicide risk in this population. PMID- 23925621 TI - Mental health response to community disasters: a systematic review. AB - IMPORTANCE: Exposure to a disaster is common, and one-third or more of individuals severely exposed may develop posttraumatic stress disorder or other disorders. A systematic approach to the delivery of timely and appropriate disaster mental health services may facilitate their integration into the emergency medical response. OBJECTIVE: To review and summarize the evidence for how best to identify individuals in need of disaster mental health services and triage them to appropriate care. EVIDENCE REVIEW: Search of the peer-reviewed English-language literature on disaster mental health response in PsycINFO, PubMed, Cochrane Database of Systematic Reviews, Academic Search Complete, and Google Scholar (inception to September 2012) and PILOTS (inception to February 2013), using a combination of subject headings and text words (Disasters, Natural Disasters, Mental Health, Mental Health Programs, Public Health Services, Mental Disorders, Mental Health Services, Community Mental Health Services, Emergency Services Psychiatric, Emotional Trauma, Triage, and Response). FINDINGS: Unlike physical injuries, adverse mental health outcomes of disasters may not be apparent, and therefore a systematic approach to case identification and triage to appropriate interventions is required. Symptomatic individuals in postdisaster settings may experience new-onset disaster-related psychiatric disorders, exacerbations of preexisting psychopathology, and/or psychological distress. Descriptive disaster mental health studies have found that many (11%-38%) distressed individuals presenting for evaluation at shelters and family assistance centers have stress-related and adjustment disorders; bereavement, major depression, and substance use disorders were also observed, and up to 40% of distressed individuals had preexisting disorders. Individuals with more intense reactions to disaster stress were more likely to accept referral to mental health services than those with less intense reactions. Evidence-based treatments are available for patients with active psychiatric disorders, but psychosocial interventions such as psychological first aid, psychological debriefing, crisis counseling, and psychoeducation for individuals with distress have not been sufficiently evaluated to establish their benefit or harm in disaster settings. CONCLUSION AND RELEVANCE: In postdisaster settings, a systematic framework of case identification, triage, and mental health interventions should be integrated into emergency medicine and trauma care responses. PMID- 23925622 TI - Primary care management of non-English-speaking refugees who have experienced trauma: a clinical review. AB - IMPORTANCE: Refugees are a vulnerable class of immigrants who have fled their countries, typically following war, violence, or natural disaster, and who have frequently experienced trauma. In primary care, engaging refugees to develop a positive therapeutic relationship is challenging. Relative to care of other primary care patients, there are important differences in symptom evaluation and developing treatment plans. OBJECTIVES: To discuss the importance of and methods for obtaining refugee trauma histories, to recognize the psychological and physical manifestations of trauma characteristic of refugees, and to explore how cultural differences and limited English proficiency affect the refugee patient clinician relationship and how to best use interpreters. EVIDENCE REVIEW: MEDLINE and the Cochrane Library were searched from 1984 to 2012. Additional citations were obtained from lists of references from select research and review articles on this topic. FINDINGS: Engagement with a refugee patient who has experienced trauma requires an understanding of the trauma history and the trauma-related symptoms. Mental health symptoms and chronic pain are commonly experienced by refugee patients. Successful treatment requires a multidisciplinary approach that is culturally acceptable to the refugee. CONCLUSIONS AND RELEVANCE: Refugee patients frequently have experienced trauma requiring a directed history and physical examination, facilitated by an interpreter if necessary. Intervention should be sensitive to the refugee's cultural mores. PMID- 23925623 TI - Foreign body in right side of chest. PMID- 23925624 TI - Scientific publications on firearms in youth before and after Congressional action prohibiting federal research funding. PMID- 23925625 TI - BRAF V600E mutation and papillary thyroid cancer. PMID- 23925626 TI - BRAF V600E mutation and papillary thyroid cancer--in reply. PMID- 23925627 TI - BRAF V600E mutation and papillary thyroid cancer. PMID- 23925628 TI - BRAF V600E mutation and papillary thyroid cancer--in reply. PMID- 23925629 TI - Melatonin level and risk for type 2 diabetes. PMID- 23925630 TI - Therapy for chemotherapy-induced peripheral neuropathy. PMID- 23925631 TI - Melatonin level and risk for type 2 diabetes--in reply. PMID- 23925632 TI - Therapy for chemotherapy-induced peripheral neuropathy--in reply. PMID- 23925634 TI - Treatment of head wounds made by small projectiles: Paris letter--the twenty sixth annual meeting of French surgeons. PMID- 23925635 TI - JAMA patient page. Health care concerns after a disaster. PMID- 23925636 TI - Association between serum vitamin D levels and colonic carcinomatous polyps. AB - BACKGROUND: Vitamin D has been postulated to play a role in colonic carcinogenesis by modulation of apoptosis and inhibition of angiogenesis. However, data supporting this theory are conflicting, and most studies include only Asians and Caucasians. This retrospective study aims to determine whether there is a correlation between an increased total vitamin D level and a lower incidence of carcinomatous polyps in a multi-race but predominantly Hispanic population in East Harlem, New York City. METHODS: A case-control study was conducted involving all patients who underwent colonoscopy at Metropolitan Hospital Center in 2011 and who also had serum total vitamin D levels taken within 1 month before or after the date of colonoscopy. Total vitamin D levels and the presence of carcinomatous polyps were the main variables studied. Colonic polyp-positive (CP+) samples were designated as the case group, while colonic polyp-negative (CP-) samples were assigned to the control group. Logistic regression analysis was used to estimate odds ratio at a 95% confidence interval. Adjusted variables were chosen a priori and included age, sex, race, smoking and alcohol history, body mass index, and folate and aspirin use. RESULTS: We identified 1,640 patients who underwent colonoscopy from January 1 to December 31, 2011. Of these, 136 also had a vitamin D serum level drawn within 1 month before or after the colonoscopy. Forty-three were CP+ and assigned to the cases group, and 93 were CP- and assigned to the control group. Thirty-five percent of the sample had total serum vitamin D levels of <20 ng/ml, and 65% had total serum vitamin D levels 20-29 ng/ml. Using <20 ng/ml as a cutoff point, the association of vitamin D with CP+ was statistically nonsignificant. In a multivariate model using vitamin D levels of <20 and <30, the association with CP+ appeared stronger, though, here too, the associations were not statistically not significant. A post hoc analysis was done excluding vitamin D levels of 20-29. In this analysis, the association between vitamin D levels and colonic polyps grew stronger with increased cutoff levels with vitamin D level of <20, suggesting a threshold effect. CONCLUSION: Vitamin D levels, using two established cutoffs, are not significantly associated with increased odds of membership in the CP+ group. However, our data suggest a possible threshold effect of vitamin D at <30 ng/ml associated with increasing odds of being CP+. PMID- 23925637 TI - Evaluation of an infectious disease consultation programme in a German tertiary care hospital. AB - PURPOSE: To evaluate a newly implemented infectious disease (ID) consultation service in terms of patient care, outcome and antibiotic prescription and to describe factors influencing adherence to recommendations. METHODS: Data from consultations during the first 6 months of the ID consultation program were collected and evaluated. Consultation requests, diagnostic results, treatment outcomes and antibiotic recommendations were categorised. Diagnostic and therapeutic recommendations were assessed and rated for adherence and outcome. Statistical analysis was performed to identify factors influencing adherence and treatment outcome. RESULTS: A total of 251 consultations were assessed. In most cases, ID specialists were asked for further advice regarding a previously initiated anti-infective treatment (N = 131, 52 %). In 54 of 195 (28 %) first consultations, the ID specialist proposed a differential diagnosis that differed from that of the working diagnoses submitted with the consultation request, and which was subsequently confirmed in 80 % of these cases. Diagnostic and therapeutic recommendations were made in 190 (76 %) and 240 (96 %) of the consultations, respectively. A change in the current treatment was recommended in 66 % of consultations; 37 % of recommendations were cost-saving and 26 % were cost-neutral. Compliance with diagnostic and therapeutic recommendations was rated as good by pre-specified criteria in 65 and 86 % of consultations, respectively. Treatment outcome was correlated with adherence to diagnostic recommendations (P = 0.012). Twenty-nine patients (16 %) died during the same hospital stay. CONCLUSION: Infectious disease consultations may help to establish the correct diagnosis, resulting in the appropriate treatment being provided to a severely sick patient population. Treatment outcome was improved in cases of good diagnostic adherence to the recommendations of the ID specialist. PMID- 23925639 TI - Triple-meso helices as alcohol reservoirs and discriminators: structural properties and thermal behaviors of silver(I) coordination molecular braids containing diethylbis(4-pyridyl)silanes. AB - Self-assembly of silver triflate with L in alcohol solvent produces characteristic triple-meso helices [Ag3(L)3(ROH)](CF3SO3)3 (L = diethylbis(4 pyridyl)silane; R = Me, Et, n-Pr, and n-Bu) with six units in each turn. Their unit cell volumes are sensitive to the size of the coordinated alcohol molecules. An unusual "alcohol molecules at triple-meso helices" system is a characteristic reversible alcohol container and discriminator via appropriate association/dissociation. The meso helical solids are favored in the order MeOH > EtOH > n-PrOH > n-BuOH via an interaction between the silver(I) ion and the alcohol molecule. The crystals evaporate the coordinated alcohol molecules at low temperatures, and finally calcination at 600 degrees C produces micro-sized chaotic surface materials consisting of silver(0) without silicon(IV) oxide. PMID- 23925638 TI - Co-infection with Nocardia asteroides complex and Strongyloides stercoralis in a patient with autoimmune hemolytic anemia. AB - We describe an unusual case of pulmonary nocardiosis co-existing with Strongyloides stercoralis hyperinfection syndrome in a patient with autoimmune hemolytic anemia who was being treated with corticosteroids. This case highlights the importance of being aware of the possibility that infections can co-exist in immunosuppressed patients. To the best of our knowledge, this is the first report of co-infection with Nocardia asteroides and S. stercoralis. PMID- 23925640 TI - Cell patterning via diffraction-induced optoelectronic dielectrophoresis force on an organic photoconductive chip. AB - A laser diffraction-induced dielectrophoresis (DEP) phenomenon for the patterning and manipulation of individual HepG2 cells and polystyrene beads via positive/negative DEP forces is reported in this paper. The optoelectronic substrate was fabricated using an organic photoconductive material, TiOPc, via a spin-coating process on an indium tin oxide glass surface. A piece of square aperture array grid grating was utilized to transform the collimating He-Ne laser beam into the multi-spot diffraction pattern which forms the virtual electrodes as the TiOPc-coating surface was illuminated by the multi-spot diffraction light pattern. HepG2 cells were trapped at the spot centers and polystyrene beads were trapped within the dim region of the illuminated image. The simulation results of light-induced electric field and a Fresnel diffraction image illustrated the distribution of trapped microparticles. The HepG2 morphology change, adhesion, and growth during a 5-day culture period demonstrated the cell viability through our manipulation. The power density inducing DEP phenomena, the characteristics of the thin TiOPc coating layer, the operating ac voltage/frequency, the sandwiched medium, the temperature rise due to the ac electric fields and the illuminating patterns are discussed in this paper. This concept of utilizing laser diffraction images to generate virtual electrodes on our TiOPc-based optoelectronic DEP chip extends the applications of optoelectronic dielectrophoretic manipulation. PMID- 23925641 TI - Single-molecule localization microscopy-near-molecular spatial resolution in light microscopy with photoswitchable fluorophores. AB - Fluorescence imaging beyond the diffraction limit has grown into a method of choice to elucidate questions related to biological structure and organisation. Among super-resolution techniques, imaging based on the localization of individual photoswitchable fluorescent probes has become particularly popular due to its relative ease of implementation and the nature of qualitative and quantitative answers it can offer. We review the field of single-molecule localization microscopy (SMLM) by providing an overview of its underlying principles and of different categories of photoswitchable fluorophores. In addition to summarizing target-specific labelling strategies and presenting examples of successful applications of SMLM in fixed and living systems, we show how SMLM data offer unique opportunities for quantitative biomolecular counting and distribution analysis. PMID- 23925642 TI - Evaluating outcomes and costs in perioperative care. PMID- 23925643 TI - Drug-nanocarrier interaction--tracking the local structure of calcium silicate upon ibuprofen loading with X-ray absorption near edge structure (XANES). AB - The interaction between drug carrier and drug molecules is fundamental for the study of drug delivery, drug targeting, and drug release. Until now, little has been known about the interaction at the molecular level. X-Ray absorption near edge structure (XANES) spectroscopy is a sensitive tool for identifying this interaction. Herein, we report the use of calcium and silicon K-edge X-ray absorption near edge structure (XANES) spectroscopy to investigate how drug molecules interact with different functional groups in calcium silicate hydrate and anhydrous calcium silicate nanocarriers with different morphologies. Significant changes are observed in the XANES spectra after drug loading; ibuprofen (IBU) loading leads to the ordering of silicates locally and there is loss of hydrates during the IBU loading processes. PMID- 23925644 TI - Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity. AB - BACKGROUND: A core feature of chronic obstructive pulmonary disease (COPD) is the accelerated decline in forced expiratory volume in one second (FEV1). The recent Groningen and Leiden Universities study of Corticosteroids in Obstructive Lung Disease (GLUCOLD) study suggested that particular phenotypes of COPD benefit from fluticasone+/-salmeterol by reducing the rate of FEV1 decline, yet the underlying mechanisms are unknown. METHODS: Whole-genome gene expression profiling using the Affymetrix Gene ST array (V.1.0) was performed on 221 bronchial biopsies available from 89 COPD patients at baseline and after 6 and 30 months of fluticasone+/-salmeterol and placebo treatment in GLUCOLD. RESULTS: Linear mixed effects modelling revealed that the expression of 138 genes decreased, whereas the expression of 140 genes significantly upregulated after both 6 and 30 months of treatment with fluticasone+/-salmeterol versus placebo. A more pronounced treatment-induced change in the expression of 50 and 55 of these 278 genes was associated with a lower rate of decline in FEV1 and Saint George Respiratory Questionnaire, respectively. Genes decreasing with treatment were involved in pathways related to cell cycle, oxidative phosphorylation, epithelial cell signalling, p53 signalling and T cell signalling. Genes increasing with treatment were involved in pathways related to focal adhesion, gap junction and extracellular matrix deposition. Finally, the fluticasone-induced gene expression changes were enriched among genes that change in the airway epithelium in smokers with versus without COPD in an independent data set. CONCLUSIONS: The present study suggests that gene expression in biological pathways of COPD is dynamic with treatment and reflects disease activity. This study opens the gate to targeted and molecular phenotype-driven therapy of COPD. PMID- 23925645 TI - Lung imaging during acute chest syndrome in sickle cell disease: computed tomography patterns and diagnostic accuracy of bedside chest radiograph. AB - INTRODUCTION: The lung computed tomography (CT) features of acute chest syndrome (ACS) in sickle cell disease patients is not well described, and the diagnostic performance of bedside chest radiograph (CR) has not been tested. Our objectives were to describe CT features of ACS and evaluate the reproducibility and diagnostic performance of bedside CR. METHODS: We screened 127 consecutive patients during 166 ACS episodes and 145 CT scans (in 118 consecutive patients) were included in the study. RESULTS: Among the 145 CT scans, 139 (96%) exhibited a new pulmonary opacity and 84 (58%) exhibited at least one complete lung segment consolidation. Consolidations were predominant as compared with ground-glass opacities and atelectasis. Lung parenchyma was increasingly consolidated from apex to base; the right and left inferior lobes were almost always involved in patients with a new complete lung segment consolidation on CT scan (98% and 95% of cases, respectively). Patients with a new complete lung segment consolidation on CT scan had a more severe presentation and course as compared with others. The sensitivity of bedside CR for the diagnosis of ACS using CT as a reference was good (>85%), whereas the specificity was weak (<60%). CONCLUSIONS: ACS more frequently presented on CT as a consolidation pattern, predominating in lung bases. The reproducibility and diagnostic capacity of bedside CR were far from perfect. These findings may help improve the bedside imaging diagnosis of ACS. PMID- 23925646 TI - Intraperitoneal bupivacaine for pain relief after minilaparoscopy in patients with infertility. AB - AIM: To evaluate the efficacy of intraperitoneal bupivacaine to reduce post operative pain after diagnostic minilaparoscopy in patients with infertility. DESIGN: A prospective randomized study was performed. MATERIALS AND METHODS: The study group consisted of 104 women with infertility undergoing diagnostic minilaparoscopy. At the end of the procedure, the treatment group (Group A) was given 10 mL of intraperitoneal 0.25 % bupivacaine (100 mg) and the control group (Group B) given 10 mL of intraperitoneal saline. Post operative pain was recorded with the use of a visual analog scale with scores ranging from 1 to 10 at 2, 4, 6 and 8 h intervals after the surgery. Additional analgesics given to the patients in the post operative period and any other side effects were noted. RESULTS: The treatment group had significantly lower pain scores at 2, 4, 6 and 8 h after the procedure (P < 0.05). The need for post operative analgesics also was significantly lower in the treatment group (P = 0.007). CONCLUSION: Post operative intraperitoneal bupivacaine administration is beneficial for patients undergoing diagnostic minilaparoscopy. It can significantly decrease post operative pain for up to 8 h and reduce the need for additional analgesics. PMID- 23925647 TI - Characterization of cultivable bacteria from brazilian sponges. AB - Among 1,236 colony-forming units (CFU) associated with 11 species of marine sponges collected from a Brazilian coast, a total of 100 morphologically different bacterial strains were analyzed. The phylogenetic diversity of the bacterial isolates was assessed by 16S rRNA gene amplification-restriction fragment length polymorphism (RFLP) analysis, using AluI restriction endonuclease. The RFLP fingerprinting resulted in 21 different patterns with good resolution for the identification of the bacterial isolates at the genus level. The genus Bacillus was the most commonly encountered genus, followed by Kocuria. Regarding the relationship between the morphotypes and species of marine sponges, Mycale microsigmatosa presented major diversity, followed by Dragmacidon reticulatum and Polymastia janeirensis. An antibiotic susceptibility profile of the 100 sponge-associated bacterial strains was determined by the disk diffusion method, and we observed a variable resistance profile, with 15 % of the bacteria being multiresistant. In addition, 71 of 100 strains were able to produce biofilm. These 71 strains were divided into 20 strong biofilm producers, 10 moderate biofilm producers, and 41 weak biofilm producers. The plasmid profile of the 100 bacterial strains was analyzed and 38 (38 %) of these samples possessed one or more plasmids. Studies like this are important to increase the information on these associated bacteria found off the coastline of Brazil, a place which has rich biodiversity that is still unknown. PMID- 23925648 TI - Mammary gland morphology and gene expression signature of weanling male and female rats following exposure to exogenous estradiol. AB - In order to characterize the actions of xenoestrogens, it is essential to possess a solid portrait of the physiological effects of exogenous estradiol. We assessed effects of three doses of exogenous estradiol (E2) (0.1, 1.0 and 10 ug/kg/day) given between postnatal days 21 and 33 on the mammary gland morphology and gene expression profiles of male and female rats compared to vehicle-treated controls. The male mammary gland was more responsive to E2 treatment than in females, with 509 genes regulated >2-fold in a dose-dependent manner in males and only 174 in females. In males, E2 treatment significantly (P < 0.01) increased the number of terminal end buds (TEBs) and the expression of proliferating cell nuclear antigen (PCNA) protein (P < 0.05), both of which are indicators of proliferation. This change was linked to a significant increase (P < 0.05) in the expression of the gene encoding amphiregulin, which is known to induce TEB formation. There was also a dose-dependent increase (P < 0.001) in the estrogen-regulated gene encoding the progesterone receptor. In intact females, despite lack of changes in mammary morphology, we observed a dose-dependent increase (P < 0.05) in the expression of genes encoding three milk proteins: whey acidic protein, casein beta and casein kappa. There was a significant (P < 0.05) downregulation of both estrogen receptors in response to E2 treatment. These results suggest that mammary glands of male rats are very sensitive to exogenous E2 during development post-weaning. The dose-dependent increase observed in amphiregulin and progesterone receptor gene expression was linked to morphological changes and represents a reliable and sensitive tool to evaluate estrogenicity. In contrast, intact weanling female rats were less responsive. PMID- 23925649 TI - MiR-223 modulates multidrug resistance via downregulation of ABCB1 in hepatocellular carcinoma cells. AB - Multidrug resistance (MDR) has become a major impediment to a successful treatment for liver cancer patients, and one of the common reasons for MDR is the activation of ABCB1 gene, leading to the over-expression of P-glycoprotein (P gp), which conferred cancer cells be resistant to a broad range of anticancer drugs. MicroRNAs (miRNAs) are a class of short, non-coding RNA moleculars that can regulate gene expression at the post-transcriptional level. In the current study, the aim is to explore whether miRNA participates in the regulation of MDR mediated by ABCB1. We found that the expression of ABCB1 was correlated with the doxorubicin IC50 dose in eight hepatocellular carcinoma (HCC) cell lines: Hep3B, HCC3, LM-6, SMMC7721, Huh-7, SK-Hep-1, HepG2 and BEL-7402. Using the bioinformatics, we discovered that there were several miRNAs that can bind to the 3'UTR of ABCB1 gene. Among these candidate miRNAs, miR-223 was chosen for further study. Then, EGFP reporter assay, real-time PCR and Western blot were performed to verify that miR-223 targeted ABCB1 3'UTR directly, and miR-223 downregulated ABCB1 at both mRNA and protein levels. Finally, we found that the over-expression of miR-223 increased the HCC cell sensitivity to anticancer drugs, and the inhibition of miR-223 had the opposite effect. Importantly, the over-expression or silencing of ABCB1 can rescue the cell response to the anticancer drugs mediated by miR-223 over-expression or inhibition, respectively. In conclusion, our findings indicated that miR-223 played an important role in the regulation of MDR mediated by ABCB1, and it suggests that miR-223 may be considered as a therapeutic biomarker for HCC patients who had MDR problems induced by high expression of ABCB1. PMID- 23925650 TI - Galangin induces human colon cancer cell death via the mitochondrial dysfunction and caspase-dependent pathway. AB - Galangin is a member of flavonols and found in Alpinia officinarum, galangal root, and propolis. Previous studies have demonstrated that galangin has anti cancer effects on several cancers, including melanoma, hepatoma, and leukaemia cells. However, anti-cancer activity of galangin on human colon cancer has not been established yet. In this study, we investigated the anti-cancer effects of galangin on two types of human colon cancer cells (HCT-15 and HT-29). We found that galangin induced apoptosis and DNA condensation of human colon cancer cells in a dose-dependent manner. We also determined that galangin increased the activation of caspase-3 and -9, and release of apoptosis inducing factor from the mitochondria into the cytoplasm by Western blot analysis. In addition, galangin induced human colon cancer cell death through the alteration of mitochondria membrane potential and dysfunction. These results suggest that galangin induces apoptosis of HCT-15 and HT-29 human colon cancer cells and may prove useful in the development of therapeutic agents for human colon cancer. PMID- 23925652 TI - Extent of sympathectomy affects postoperative compensatory sweating and satisfaction in patients with palmar hyperhidrosis. AB - PURPOSE: Endoscopic thoracic sympathectomy (ETS) for the treatment of palmar hyperhidrosis is generally performed at one or two levels ranging between T2 and T4; however, compensatory sweating (CS) is an occasional bothersome side effect. The aim of our study was to evaluate the association between the extent of ETS and the degree of postoperative CS and palmar sweating, as well as patient satisfaction. METHODS: The participants represented a consecutive series of 76 patients who underwent bilateral ETS for palmar hyperhidrosis at level T2 and/or T3. Patients were interviewed by postal questionnaires to assess their self reported degree of postoperative palmar sweating and CS and their outcome satisfaction. Of the 53 patients who replied to the postal questionnaire, 25 underwent bilateral ETS at one level (group A), and 27 underwent bilateral ETS at two levels (group B). One patient who underwent asymmetrical sympathectomy was excluded. RESULTS: The degree of postoperative palmar sweating was significantly lower in group B than in group A. The severity of CS was significantly higher in group B than in group A. The severity of CS was significantly inversely correlated with the degree of patient satisfaction. However, the degree of postoperative palmar sweating was not correlated with the degree of patient satisfaction. CONCLUSIONS: Compared to ETS at two levels, single-level ETS of T2 or T3 reduces postoperative palmar sweating to a milder degree, and causes CS to a less severe degree. The severity of CS is inversely correlated with the degree of patient satisfaction. PMID- 23925651 TI - The associations between QCT-based vertebral bone measurements and prevalent vertebral fractures depend on the spinal locations of both bone measurement and fracture. AB - We examined how spinal location affects the relationships between quantitative computed tomography (QCT)-based bone measurements and prevalent vertebral fractures. Upper spine (T4-T10) fractures appear to be more strongly related to bone measures than lower spine (T11-L4) fractures, while lower spine measurements are at least as strongly related to fractures as upper spine measurements. INTRODUCTION: Vertebral fracture (VF), a common injury in older adults, is most prevalent in the mid-thoracic (T7-T8) and thoracolumbar (T12-L1) areas of the spine. However, measurements of bone mineral density (BMD) are typically made in the lumbar spine. It is not clear how the associations between bone measurements and VFs are affected by the spinal locations of both bone measurements and VF. METHODS: A community-based case-control study includes 40 cases with moderate or severe prevalent VF and 80 age- and sex-matched controls. Measures of vertebral BMD, strength (estimated by finite element analysis), and factor of risk (load:strength ratio) were determined based on QCT scans at the L3 and T10 vertebrae. Associations were determined between bone measures and prevalent VF occurring at any location, in the upper spine (T4-T10), or in the lower spine (T11-L4). RESULTS: Prevalent VF at any location was significantly associated with bone measures, with odds ratios (ORs) generally higher for measurements made at L3 (ORs = 1.9-3.9) than at T10 (ORs = 1.5-2.4). Upper spine fracture was associated with these measures at both T10 and L3 (ORs = 1.9-8.2), while lower spine fracture was less strongly associated (ORs = 1.0-2.4) and only reached significance for volumetric BMD measures at L3. CONCLUSIONS: Closer proximity between the locations of bone measures and prevalent VF does not strengthen associations between bone measures and fracture. Furthermore, VF etiology may vary by region, with VFs in the upper spine more strongly related to skeletal fragility. PMID- 23925653 TI - Antitumor effects of naturally occurring oligomeric resveratrol derivatives. AB - This study was designed to evaluate and characterize the molecular basis of antitumor activity of naturally occurring resveratrol (RES; 3,5,4'-trihydroxy trans-stilbene) derivatives. The compounds were isolated from plants in previous studies and characterized spectroscopically. The antitumor activities of 31 RES derivatives, including dimers, trimers, and tetramers of RES, were evaluated using cell-based assays and validated on a murine model. Several trimeric and a tetrameric stilbenoids induced tumor cell apoptosis or growth arrest of several tumor cell lines with IC50 values (2.8-19.7 MUM), significantly lower than that of RES (IC50>70 MUM). Using pauciflorol B (PauB) as an example, we showed that the compound induced apoptosis p53 dependently, inducing p53 accumulation and p53 modulated gene expression in cells with wild-type p53, but not in those with nonfunctional p53. Reexpression of p53 in p53-null cells rescued cell death response. In parallel, the MAPK/p38 was activated and critical for PauB-induced killing. Interestingly, activation of p38 in p53 deficient cells was sufficient to drive cells into senescence via the p16-pRb pathway. Finally, PauB dose dependently inhibited tumor growth on nude mice. Naturally occurring trimeric and tetrameric stilbenoids are potent antitumor agents. Those compounds exert antitumor effect through p53-dependent induction of apoptosis or senescence. PMID- 23925655 TI - HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions. AB - Numerous microarray-based gene expression studies performed on several types of solid tumors revealed significant changes in key genes involved in progression and regulation of the cell cycle, including AURKA that is known to be overexpressed in many types of human malignancies. Tumor hypoxia is associated with poor prognosis in several cancer types, including breast cancer (BC). Since hypoxia is a condition that influences the expression of many genes involved in tumorigenesis, proliferation, and cell cycle regulation, we performed a microarray-based gene expression analysis in order to identify differentially expressed genes in BC cell lines exposed to hypoxia. This analysis showed that hypoxia induces a down-regulation of AURKA expression. Although hypoxia is a tumor feature, the molecular mechanisms that regulate AURKA expression in response to hypoxia in BC are still unknown. For the first time, we demonstrated that HIF-1 activation downstream of hypoxia could drive AURKA down-regulation in BC cells. In fact, we found that siRNA-mediated knockdown of HIF-1alpha significantly reduces the AURKA down-regulation in BC cells under hypoxia. The aim of our study was to obtain new insights into AURKA transcriptional regulation in hypoxic conditions. Luciferase reporter assays showed a reduction of AURKA promoter activity in hypoxia. Unlike the previous findings, we hypothesize a new possible mechanism where HIF-1, rather than inducing transcriptional activation, could promote the AURKA down-regulation via its binding to hypoxia-responsive elements into the proximal region of the AURKA promoter. The present study shows that hypoxia directly links HIF-1 with AURKA expression, suggesting a possible pathophysiological role of this new pathway in BC and confirming HIF-1 as an important player linking an environmental signal to the AURKA promoter. Since AURKA down-regulation overrides the estrogen-mediated growth and chemoresistance in BC cells, these findings could be important for the development of new possible therapies against BC. PMID- 23925654 TI - Infection with the carcinogenic liver fluke Opisthorchis viverrini modifies intestinal and biliary microbiome. AB - Opisthorchis viverrini is a fish-borne trematode endemic in East Asia. Following ingestion, the flukes locate to the biliary tre where chronic infection frequently leads to cholangiocarcinoma (CCA). The mechanisms by which O. viverrini infection culminates in CCA remain unknown. An unexplored aspect is its influence on the host microbiome. In the hamster, infection with this pathogen reliably leads to CCA. Genomic DNAs of microbiota from colorectal contents and bile of hamsters and from whole O. viverrini were examined in this model of fluke induced CCA. Microbial communities were characterized by high-throughput sequencing of variable regions 7-9 of prokaryotic 16S ribosomal DNA. Of ~1 million sequences, 536,009 with useable reads were assignable to 29,776 operational taxonomy units (OTUs) and, in turn, to 20 phyla and 273 genera of Bacteria or Archaea. Microbial community analyses revealed that fluke infection perturbed the gastrointestinal tract microbiome, increasing Lachnospiraceae, Ruminococcaceae, and Lactobacillaceae, while decreasing Porphyromonadaceae, Erysipelotrichaceae, and Eubacteriaceae (P<=0.05). More than 60 OTUs were detected in the biliary system, which confirmed bacteriobilia and a noteworthy community of microbes associated with the parasites. The fluke-associated microorganisms included potential pathogens from the Enterobacteriaceae and Listeriaceae and others, including Cyanobacteria and Deinococci, usually found in external environments. Given that opisthorchiasis is distinguished from other helminth infections by a robust inflammatory phenotype with conspicuously elevated IL-6, and that inflammation of the biliary system leads to periductal fibrosis, which is a precursor of CCA, the flukes and their microbiota may together drive this distinctive immune response. PMID- 23925656 TI - Green synthesis of silver nanoparticles by microorganism using organic pollutant: its antimicrobial and catalytic application. AB - A novel approach for the green synthesis of silver nanoparticles (AgNPs) from aqueous solution of AgNO3 using culture supernatant of phenol degraded broth is reported in this work. The synthesis was observed within 10 h, and AgNPs showed characteristic surface plasmon resonance around 410 nm. Spherical nanoparticles of size less than 30 nm were observed in transmission electron microscopy. X-ray diffraction pattern corresponding to 111, 200, 220, and 311 revealed the crystalline nature of the as-formed nanoparticles. It was found that the colloidal solution of AgNP suspensions exhibited excellent stability over a wide range of ionic strength, pH, and temperature. The effect of pH and ionic strength indicated that stabilization is due to electrostatic repulsion arising from the negative charge of the conjugate proteins. The AgNPs showed highly potent antimicrobial activity against Gram-positive, Gram-negative, and fungal microorganisms. The as-prepared AgNPs showed excellent catalytic activity in reduction of 4-nitrophenol to 4-aminophenol by NaBH4. By manufacturing magnetic alginate beads, the reusability of the AgNPs for the catalytic reaction has been demonstrated. PMID- 23925657 TI - Dioxin-like activity in sediments from Tai Lake, China determined by use of the H4IIE-luc bioassay and quantification of individual AhR agonists. AB - Deterioration of the general ecosystem and specifically quality of the water in Tai Lake (Ch: Taihu), the third largest freshwater in China, is of great concern. However, knowledge on status and trends of dioxin-like compounds in Tai Lake was limited. This study investigated AhR-mediated potency and quantified potential aryl hydrocarbon receptor (AhR) agonists in sediments from four regions (Meiliang Bay, Zhushan Lake, Lake Center, Corner of Zhushan Lake, and Meiliang Bay) of Tai Lake by use of the in vitro H4IIE-luc, cell-based, transactivation, reporter gene assay, and instrumental analysis. Concentrations of 2,3,7,8-tetrachlorodibenzo-p dioxin equivalents (Bio-TEQs) in sediments ranged from less than the limit of detection to 114.5 pg/g, dry weight, which indicated that organic extracts of sediments exhibited significant AhR-mediated potencies. Results of the potency balance analysis demonstrated that acid-labile, dioxin-like compounds represented a greater proportion of concentrations of Bio-TEQs in sediments from Tai Lake. Concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents calculated as the sum of the product of concentrations of individual congeners and their respective relative potencies (Chem-TEQs) based on polycyclic aromatic hydrocarbons and/or polychlorinated biphenyls represented no more than 10% of the total concentrations of Bio-TEQs. PMID- 23925658 TI - Response surface modeling for optimization heterocatalytic Fenton oxidation of persistence organic pollution in high total dissolved solid containing wastewater. AB - The rice-husk-based mesoporous activated carbon (MAC) used in this study was precarbonized and activated using phosphoric acid. N2 adsorption/desorption isotherm, X-ray powder diffraction, electron spin resonance, X-ray photoelectron spectroscopy and scanning electron microscopy, transmission electron microscopy, (29)Si-NMR spectroscopy, and diffuse reflectance spectroscopy were used to characterize the MAC. The tannery wastewater carrying high total dissolved solids (TDS) discharged from leather industry lacks biodegradability despite the presence of dissolved protein. This paper demonstrates the application of free electron-rich MAC as heterogeneous catalyst along with Fenton reagent for the oxidation of persistence organic compounds in high TDS wastewater. The heterogeneous Fenton oxidation of the pretreated wastewater at optimum pH (3.5), H2O2 (4 mmol/L), FeSO4[Symbol: see text]7H2O (0.2 mmol/L), and time (4 h) removed chemical oxygen demand, biochemical oxygen demand, total organic carbon and dissolved protein by 86, 91, 83, and 90%, respectively. PMID- 23925659 TI - A bifunctional palladium/acid solid catalyst performs the direct synthesis of cyclohexylanilines and dicyclohexylamines from nitrobenzenes. AB - Nitroderivatives are transformed to cyclohexylanilines at room temperature in good yields and selectivity via a hydrogenation-amine coupling cascade reaction using Pd nanoparticles on carbon as a catalyst and a Bronsted acid. PMID- 23925660 TI - Lichen sclerosus with vaginal involvement: report of 2 cases and review of the literature. AB - IMPORTANCE: Lichen sclerosus (LS) is an uncommon chronic inflammatory disease that most commonly affects anogenital skin of postmenopausal women. It typically manifests as atrophic white plaques, which may be accompanied by purpura or fissuring. Rarely, LS has been observed to affect mucosal tissues in the mouth and the penile urethra. It is generally taught that LS does not affect the vagina, unlike lichen planus. To our knowledge, only one case report of LS with vaginal involvement exists in the literature. OBSERVATIONS: Two cases of severe vulvar LS with vaginal involvement are reported. Both cases exhibited characteristic features of LS on vaginal biopsy, and both patients were followed up clinically without further treatment of the vagina. CONCLUSIONS AND RELEVANCE: Vaginal LS may be more common than previously thought and may be underdiagnosed. Patients with more severe disease or with significant vaginal atrophy may be more likely to have involvement of the vagina. In addition, patients with pelvic organ laxity may be at increased risk if their vaginal walls are chronically exposed because of prolapse. Physicians managing patients with vulvar LS should be aware of the possibility of vaginal involvement so that vaginal lesions may be diagnosed and followed up appropriately. PMID- 23925661 TI - [Hidden care needs in elderly people: a descriptive study of an outpatient geriatric consultation practice in the Netherlands]. AB - In general older adults, even the oldest old are community dwelling and vital. However, vulnerability can silently or suddenly exist. Multidisciplinary assessment of health problems and disabilities is necessary to compose a comprehensive intervention program. In the Netherlands, a team specialised in elderly care accomplishes home-based assessments. In 2009 we conducted a case study aiming to describe the characteristics of the patients and the reasons for consultation. A total of 84 records were analysed. 60% of the clients were 85 years or older, 32% were living independently and 61% were residents in homes for elderly people. The majority of clients was female and living alone (widowed). Most clients had multiple issues and were referred for cognitive evaluation. During the process of assessment many underlying behavioural, emotional and social problems became manifest. These findings support that symptoms and complaints of frail elderly are complex. A systematic multidisciplinary approach enhances the dialogue with patients and caregivers to discuss their needs and their attitude towards care. More research, however, is necessary to evaluate the effectiveness of this intervention. PMID- 23925662 TI - Androgen receptor in human prostate cancer-associated fibroblasts promotes prostate cancer epithelial cell growth and invasion. AB - The androgens and androgen receptor (AR) play key roles in the prostate cancer (PCa) development and progression via epithelium-stroma cross talk. Prostate cancer-associated fibroblasts (CAFs) are dominant components in PCa stroma and are essential in the malignant progression by supporting tumorigenesis and metastasis. However, the AR roles in CAFs are still obscure. We isolated and immortalized the CAFs from human PCa tissues and found the CAFs are AR positive. We then knocked down their AR with siRNA and co-cultured the resultant CAFs with PCa cell line PC3. The MTT, invasion, and colony formation assays were performed to study the PC3 biological behavior. The results showed that the PCa epithelial growth, invasion, and colony formation abilities decreased when knocking down the CAFs AR. By using the real-time quantitative polymerase chain reaction, we found the IGF1, FGF7, FGF10, SDF1, HGF, and TGFb2 expression levels decreased in the AR knocked down CAFs. These results suggested that the AR in CAFs promoted PCa epithelial growth and invasion via regulating a series of growth factors. Targeting the AR in CAFs might be a potential therapeutic option for PCa in future. PMID- 23925663 TI - The role of microRNAs in lung cancer progression. AB - Lung cancer is a heterogeneous disease with currently still unknown mechanisms of development. Besides genetic and epigenetic mechanisms, microRNAs (miRNAs) have recently been discovered as one of the crucial players in lung carcinogenesis through posttranscriptional regulation of tumor suppressor and oncogenes. A substantial number of deregulated miRNAs have been revealed in lung cancer, and the biological significance of those miRNAs has been confirmed in multiple functional experiments. A growing number of studies suggest involvement of miRNAs in various steps of lung carcinogenesis. Great biological stability of miRNAs opens novel fields in biomarker research with potential clinical implementation in screening, diagnosis and prediction of prognosis. In this review, we provide the basic knowledge of miRNA biogenesis and discuss extensively the role of miRNAs in lung carcinogenesis, including potential translational clinical implementations. PMID- 23925664 TI - Phase2 study of bevacizumab with carboplatin-paclitaxel for non-small cell lung cancer with malignant pleural effusion. AB - Vascular endothelial growth factor (VEGF) is involved in non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE), but little is known regarding the efficacy of bevacizumab (Bev) with carboplatin-paclitaxel (CP) for NSCLC with MPE. Chemotherapy-naive non-SQ NSCLC patients with MPE were eligible to participate. Pleurodesis before chemotherapy was not allowed. In the first cycle, the treated patients received only CP to prevent Bev-induced wound healing delayed after chest drainage. Subsequently, they received 2-6 cycles of CP with Bev. Patients who completed more than 4 cycles of CP and Bev without disease progression or severe toxicities continued to receive Bev alone as a maintenance therapy. The primary end point was overall response, although an increase in MPE was allowed in the first cycle. The VEGF levels in plasma and MPE were measured at baseline, and the VEGF levels in plasma were measured after 3 cycles of chemotherapy. Between September 2010 and June 2012, 23 patients were enrolled. The overall response rate was 60.8 %; the disease control rate was 87.0 %. Sixteen patients received maintenance therapy, following a median of 3 cycles. Median progression-free and overall survival times were 7.1 months (95 % confidence interval [CI], 5.6-9.4 months) and 11.7 months (95 % CI, 7.4-16.8 months), respectively. Most patients experienced severe hematological toxicities, including >=grade 3 neutropenia; none experienced severe bleeding events. The MPE control rate improved on combining CP with Bev (CP, 78.3 %; CP with Bev, 91.3 %; P = 0.08). The median baseline VEGF level in MPE was 1798.6 (range 223.4 35,633.4) pg/mL. Plasma VEGF levels significantly decreased after 3 chemotherapy cycles (baseline, 513.6 +/- 326.4 pg/mL, post-chemotherapy, 25.1 +/- 14.1 pg/mL, P < 0.01). CP plus Bev was effective and tolerable in chemotherapy-naive non squamous NSCLC patients with MPE. PMID- 23925665 TI - Clinical significance of angiopoietin-like protein 4 expression in tissue and serum of esophageal squamous cell carcinoma patients. AB - Angiopoietin-like protein 4 (ANGPTL4) has been reported to promote tumor growth, metastasis, and angiogenesis under certain conditions. The aim of this study was to examine ANGPTL4 expression in tumor and serum tissues from esophageal squamous cell carcinoma (ESCC) patients. A total of 78 ESCC patients treated with radical resection were enrolled in this study. Immunohistochemistry was used to detect ANGPTL4 expression in ESCC tissues. Serum ANGPTL4 levels were determined via enzyme-linked immunosorbent assay (ELISA). The receiver operating characteristics curve was constructed to describe diagnostic specificity and sensitivity. There were 52 cases (69.2 %) showing a higher level of ANGPTL4 expression in tumor tissues than that in normal tissues, and the rate of ANGPTL4 protein high/moderate expression in ESCC and normal tissues was 55.1 % (43/78) and 6.4 % (5/78), respectively, with a significant difference (P < 0.001). Moreover, the high/moderate of ANGPTL4 protein was significantly associated with lymph metastasis, clinical stage, and adverse 2-year progression-free survival. In addition, serum ANGPTL4 level in ESCC patients was much higher than that in patients with benign esophageal disease (P < 0.001), and area under the curve was 0.94 (95 % CI 0.886390-0.978173, P < 0.001). But serum ANGPTL4 level was significantly decreased at post-operative 7-10 days (P = 0.004). ANGPTL4 upregulation may play an important role in ESCC development, and serum ANGPTL4 level may be a potential tumor marker for ESCC diagnosis and prognosis. PMID- 23925666 TI - Association analysis between MDR1 genetic variant and breast cancer risk factors in Chinese Han population. AB - The multidrug resistance 1 gene (MDR1) is an important candidate gene for influencing breast cancer susceptibility. This study aimed to evaluate the association between MDR1 genetic variants and breast cancer susceptibility. A total of 340 breast cancer patients and 348 cancer-free controls were enrolled in this study. The patients' general characteristics and related risk factors of breast cancer were collected by questionnaires. The c.4125A>C genetic variant was genotyped through created restriction site polymerase chain reaction method. Our data suggest that there are no significant differences in the allelic and genotypic frequencies between breast cancer patients and cancer-free controls. Moreover, the distribution of breast cancer patients' risk factors is not different among AA, AC, and CC genotypes. These preliminary results suggest that the c.4125A>C genetic variant is not significantly associated with breast cancer susceptibility. PMID- 23925667 TI - CIP2A expression and prognostic role in patients with esophageal adenocarcinoma. AB - CIP2A is overexpressed in many cancers, including esophageal squamous cell carcinoma. The regulation of c-MYC and CIP2A expression is characterized by a positive feedback mechanism facilitating the expression of both of them and accelerating cancer cell proliferation in gastric cancer. Increased CIP2A expression is a predictor of poor survival in some cancers. The incidence of positive CIP2A immunostaining and its association with c-MYC and its predictive value in esophageal adenocarcinoma are unknown. All esophageal adenocarcinoma patients from 1990 to 2007 with sufficient material for analysis of CIP2A and c MYC in two university hospitals were included in the study. In addition, biopsies from Barrett's epithelium from the cancer patients and control tissue from normal esophageal mucosa adjacent to the tumor were included. CIP2A was moderately or strongly positive in 77.9 %, and c-MYC in 93.8 % of the cancer specimens. These frequencies were statistically different from the expression in normal esophageal epithelium. In addition, there was a positive correlation between CIP2A and c-MYC expression (p = 0.018). According to adjusted Cox regression survival analysis, CIP2A and c-MYC had no effect on survival. However, among patients with stage IVA IVB cancer, there was a trend toward poor prognosis in CIP2A-positive patients. The expression of CIP2A and c-MYC was associated with each other, and their overexpression was found in most cases of esophageal adenocarcinoma. However, CIP2A and c-MYC had no effect on survival. PMID- 23925668 TI - Incidences of diabetes and prediabetes among female adult breast cancer patients after systemic treatment. AB - Patients with cancer frequently show glucose intolerance. This study is to estimate the status of total diabetes and prediabetes in breast cancer patients after systemic treatment through an oral glucose tolerance test (OGTT) in China. All the 119 breast cancer patients more than 3 months after systemic treatment with surgery and chemotherapy participated in the study. All the patients without the diagnosis of diabetes underwent OGTT, and fasting and 2-h glucose levels were measured to identify undiagnosed diabetes and prediabetes. Previously diagnosed diabetes were determined on the self-report and the medical record. Of the 119 breast cancer patients, with the median age of 50.1 years and the mean age of about 48 years when they were initially diagnosed with breast cancer, which showed the similar characters of China and Asia breast cancer patients, the overall incidences of total diabetes and prediabetes were 21.8 and 43.7 %, respectively. About 80 % of the diabetes were previously undiagnosed. About 80.0 % of the cases of undiagnosed diabetes and prediabetes met the criteria for elevated 2-h plasma glucose levels through OGTT but not the criteria for elevated fasting glucose levels. Our study firstly documents high incidences of previously undiagnosed diabetes and prediabetes in breast cancer patients during follow-up after systemic treatment through OGTT, indicating that greater diabetes screening, especially through OGTT, prevention, and treatment strategies among breast cancer patients, after systemic treatment for these patients is needed. PMID- 23925669 TI - Medication overuse headache: history, features, prevention and management strategies. AB - Medication overuse headache (MOH) is a daily, or almost daily, headache form that arises from overuse of one or more classes of migraine-abortive or analgesic medication. The main classes of drugs that cause MOH are opioids, butalbital containing mixed analgesics, triptans, ergotamine tartrate derivatives, simple analgesics (except for plain aspirin), and perhaps non-steroidal anti inflammatory drugs. MOH can be debilitating and results from biochemical and functional brain changes induced by certain medications taken too frequently. At this time, migraine and other primary headache disorders in which migraine or migraine-like elements occur seem exclusively vulnerable to the development of MOH. Other primary headache disorders are not currently believed to be vulnerable. The treatment of MOH consists of discontinuation of the offending drug(s), acute treatment of the withdrawal symptoms and escalating pain, establishing a preventive treatment when necessary, and the implementation of educational and behavioral programs to prevent recidivism. In most patients, MOH can be treated in the outpatient setting but, for the most difficult cases, including those with opioid or butalbital overuse, or in patients with serious medical or behavioral disturbances, effective treatment requires a multidisciplinary, comprehensive headache program, either day-hospital with infusion or an inpatient hospital setting. PMID- 23925670 TI - Improved protease stability of the antimicrobial peptide Pin2 substituted with D amino acids. AB - Cationic antimicrobial peptides (AMPs) have attracted a great interest as novel class of antibiotics that might help in the treatment of infectious diseases caused by pathogenic bacteria. However, some AMPs with high antimicrobial activities are also highly hemolytic and subject to proteolytic degradation from human and bacterial proteases that limit their pharmaceutical uses. In this work a D-diastereomer of Pandinin 2, D-Pin2, was constructed to observe if it maintained antimicrobial activity in the same range as the parental one, but with the purpose of reducing its hemolytic activity to human erythrocytes and improving its ability to resist proteolytic cleavage. Although, the hydrophobic and secondary structure characteristics of L- and D-Pin2 were to some extent similar, an important reduction in D-Pin2 hemolytic activity (30-40 %) was achieved compared to that of L-Pin2 over human erythrocytes. Furthermore, D-Pin2 had an antimicrobial activity with a MIC value of 12.5 MUM towards Staphylococcus aureus, Escherichia coli, Streptococcus agalactiae and two strains of Pseudomonas aeruginosa in agar diffusion assays, but it was half less potent than that of L Pin2. Nevertheless, the antimicrobial activity of D-Pin2 was equally effective as that of L-Pin2 in microdilution assays. Yet, when D- and L-Pin2 were incubated with trypsin, elastase and whole human serum, only D-Pin2 kept its antimicrobial activity towards all bacteria, but in diluted human serum, L- and D-Pin2 maintained similar peptide stability. Finally, when L- and D-Pin2 were incubated with proteases from P. aeruginosa DFU3 culture, a clinical isolated strain, D Pin2 kept its antibiotic activity while L-Pin2 was not effective. PMID- 23925672 TI - An iron(III) tetradentate monoamido complex as a nonheme iron-based peroxidase mimetic. AB - A mononuclear iron(III) complex of a noncyclic tetradentate monoamido ligand, Fe(III)mpaq, catalyses the oxidation of Orange II, guaiacol, ABTS and Amplex Red with H2O2 in aqueous solutions at neutral pH. Under identical conditions, other structurally related nonheme iron complexes showed only negligible activities. PMID- 23925673 TI - Structurally diverse hamigerans from the New Zealand marine sponge Hamigera tarangaensis: NMR-directed isolation, structure elucidation and antifungal activity. AB - The NMR-directed investigation of the New Zealand marine sponge Hamigera tarangaensis has afforded ten new compounds of the hamigeran family, and a new 13 epi-verrucosane congener. Notably, hamigeran F (6) possesses an unusual carbon carbon bond between C-12 and C-13, creating an unprecedented skeleton within this class. In particular, the structural features of 6, hamigeran H (10) and hamigeran J (12) imply a diterpenoid origin, which has allowed the putative biogenesis of three hamigeran carbon skeletons to be proposed based on geranyl geranyl pyrophosphate. All new hamigerans exhibited micromolar activity towards the HL-60 promyelocytic leukaemic cell line, and hamigeran G also selectively displayed antifungal activity in the budding yeast Saccharomyces cerevisiae. Homozygous deletion profiling (HOP) analysis suggests Golgi apparatus function as a potential target of this unusual class of sponge-derived terpenoids. PMID- 23925674 TI - What is the core of schizophrenia? PMID- 23925671 TI - Matching the power of high throughput screening to the chemical diversity of natural products. AB - Covering up to 2013. Application of high throughput screening technologies to natural product samples demands alterations in assay design as well as sample preparation in order to yield meaningful hit structures at the end of the campaign. PMID- 23925675 TI - Intermittent balloon occlusion to favor nidal penetration during embolization of arteriovenous malformations: a technique modification. AB - Endovascular embolization of brain arteriovenous malformations (AVMs) has improved with liquid occlusive agents, but flow-related and anatomic restrictions limit endovascular capabilities. AVM compartments supplied by leptomeningeal networks and feeding arteries too small and/or tortuous for safe catheterization are rarely penetrated by liquid occlusive agents. A case with both impediments prompted a novel solution. A balloon was inflated across the supply to a lenticulostriate feeder, thereby favoring penetration of the liquid occlusive agent, injected from a different feeding territory, back into the AVM compartment supplied by the temporarily occluded feeder. This technique may reduce the number of embolization stages in large high-flow AVMs and increase the likelihood of achieving complete occlusion. This technique is highly complex and requires meticulous monitoring of multiple events. PMID- 23925676 TI - Vertebral osteomyelitis caused by Mycobacterium abscessus. AB - Mycobacterium infection caused by non-tuberculous mycobacterial (NTBM) organisms is becoming more common. Although NTBM osteomyelitis is unusual, it can occur in otherwise healthy individuals, but it is also associated with immunocompromised states, such as steroidal therapy and AIDS, and may be observed following trauma. Mycobacterium avium is reported to be the most common causative agent, and Mycobacterium abscessus has only been described in two cases. We report the case of a 44-year-old man with history of hepatitis C diagnosed with osteomyelitis of the thoracic spine caused by M abscessus. We present a literature review of NTBM osteomyelitis and a discussion of its diagnosis and treatment. PMID- 23925677 TI - A novel use for myocardial perfusion scans: diagnosis of bile duct injury. AB - A 69-year-old woman was admitted to a tertiary care centre after suffering from an iatrogenic bile duct injury, diagnosed by the unexpected leakage of bile during laparotomy for a colectomy. On initial assessment the patient was clinically stable, although she remained intubated after her surgery. In order to diagnose whether or not she sustained a complete or partial bile duct injury, a finding that would determine if she underwent conservative management or surgical repair, a technetium-99m-hepatobiliary scan was requested. Owing to a shortage in technetium-99m-iminodiacetic acids, the radiopharmaceutical (tracer) for this imaging test, a decision was made to employ technetium-99m-tetrofosmin, the tracer for cardiac scans (traditionally used for diagnosis of myocardial perfusion) as it has been established that this tracer is excreted in the biliary tract. The imaging showed flow of bile into the bowel, thereby establishing bile duct continuity and permitting conservative management. PMID- 23925678 TI - Quetiapine may reduce hospital admission rates in patients with mental health problems and alcohol addiction. AB - A 64-year-old man presented with 40 years history of chronic alcohol excess. On average, he had six hospital admissions a year with alcohol-related problems for at least a 10-year period. In 2009, he considered reducing his alcohol intake. He was noted to have mood disturbances, was seen by a psychogeriatrician who diagnosed bipolar disorder. He tried various bipolar medications including lithium and sodium valproate which was unsuccessful. He was then started on quetiapine 600 mg a day in divided doses. Subsequently this has not only controlled the bipolar disorder but also resulted in significant reduction in alcohol intake. He now shares a bottle of wine with his wife while in the past he was consuming a bottle of scotch daily. This case illustrates the benefits of quetiapine in assisting with this man's addiction to alcohol. PMID- 23925679 TI - gamma-Benzene hexachloride poisoning leading to acute hepatorenal decompensation. AB - gamma-Benzene hexachloride is a commonly used insecticide of organochlorine group. Notable toxic effects include seizures, ataxia, confusion and other central nervous system dysfunction. A 30-year-old male farmer with suicidal ingestion of gamma-benzene hexachloride poison developed acute intrinsic renal failure with azotaemia and diminished urine output along with features of acute fulminate liver failure. Renal function recovered with haemodialysis and liver parameters gradually normalised with time. As per our knowledge simultaneous acute hepatic and kidney injury associated with gamma-benzene hexachloride poison is never reported in humans. The exact pathophysiology of this life-threatening complication is an enigma. However, oxidative stress has been postulated as a contributory factor as suggested in animal studies. Conservative management with successful outcome in our case stresses on the impact of watchful observation and aggressive management. He was discharged after 3 weeks at stable condition and was healthy at 3 months follow-up. PMID- 23925680 TI - Naltrexone may block euphoria-like placebo effect. AB - Naltrexone is a first-line treatment for alcohol use disorders in North America and Europe. It was prescribed to a 63-year-old patient in order to help control amounts of alcohol consumed per drinking occasion. The patient experienced a paradoxical, but consistent side effect of feeling inebriated each time he took naltrexone. In order to investigate this phenomenon we administered naltrexone and a placebo in a randomised double-blind fashion. The patient exhibited a 'high like' response to all placebo capsules and a decrease in the subjectively perceived euphoria shortly after ingestion of naltrexone. Given that this placebo effect could be mediated via opioid receptors we suggest that this case illustrates the ability of naltrexone to eliminate the placebo effect. This feature of naltrexone, upon further investigation, might be used in randomised clinical trials in addition to or as an alternative to a placebo. PMID- 23925681 TI - Agranulocytosis with deferiprone treatment of superficial siderosis. AB - Superficial siderosis of the central nervous system is a rare neurological disorder caused by deposits of haemosiderin on subplial brain matter. Characterised by a thin dark layer surrounding the brain stem, cerebellum and cortical fissures on the T2-weighted MRI, symptoms include sensorineural hearing loss and progressive gait ataxia. A specific aetiology for the blood in the subarachnoid space is identified in less than 50% of cases. While identification of a specific vascular defect allows for vascular repair, treatment options are limited for idiopathic superficial siderosis. Recently, a pilot safety study demonstrated promising results using an iron chelator, deferiprone. While this approach is promising, we present a potential serious complication of this therapy-the first report of agranulocytosis in the treatment of superficial siderosis following deferiprone therapy. PMID- 23925682 TI - Ovarian dermoid cyst with teeth. PMID- 23925683 TI - Full-term broad ligament pregnancy. AB - A broad ligament pregnancy is an extremely rare condition. The eventuality of such pregnancies reaching full term is even rarer. A full-term broad ligament pregnancy occurring through a rent in a previous lower segment caesarean scar has only been mentioned in literature but not reported. Our patient is an unbooked case, reported to us at 39 weeks of pregnancy. On clinical examination, an ultrasound and an MRI, a diagnosis of abdominal pregnancy was made. Ultimately the final diagnosis was made only on laparotomy. A broad ligament pregnancy was found with a rent in the previous caesarean scar communicating the fetal sac. PMID- 23925684 TI - Metatarsal metastasis as the presenting feature of occult colorectal carcinoma. PMID- 23925685 TI - Cholesterol granuloma of the breast mimicking malignancy. AB - Cholesterol granuloma of the breast is an unusual non-neoplastic condition which frequently resembles malignancy clinically as well as radiologically. We herein report a case of a 28-year-old woman who presented with a lump in the upper outer quadrant of right breast. Physical examination and ultrasonography strongly suggested a carcinomatous lesion, but histopathological examination confirmed the diagnosis to be cholestrol granulomas. This article highlights the perplexing clinical presentation of cholesterol granulomas and affirms the role of histopathological examination in diagnosing these lesions correctly. PMID- 23925686 TI - Incidental cardiac papillary fibroelastoma: a management dilemma. PMID- 23925687 TI - Recruitment bronchoscopy by trans-glottic approach successfully treated lung collapse in an intubated mechanically ventilated patient. AB - Pulmonary lower lobe atelectasis/collapse is a common problem in patients undergoing mechanical ventilation. It also occurs in non-intubated patients with traumatic brain or spinal cord injuries, morbid obesities and chest wall disorders. Conventional manoeuvres such as chest physiotherapy, bronchodilators and positive-end expiratory pressure (PEEP) administration are frequently used in its management with variable success rates. However, despite the reported success of bronchoscopic recruitment manoeuvres, selective intrabronchial air insufflation during fiberoptic bronchoscopy to re-expand collapsed lungs is an underutilised practice. Here, we report an example of successful selective intrabronchial air insufflation in an intubated patient with bilateral lower lobe collapses after surgery for an incarcerated hernia. To our knowledge, this is the first successful report of recruitment manoeuvre by trans-glottic bronchoscopy in an intubated, mechanically ventilated patient. PMID- 23925688 TI - Macrocytosis in Crohn's disease: a devastating blast. AB - A 47-year-old woman with a 36-month history of Crohn's disease with one previous bowel resection treated with azathioprine was found to have a persistently raised mean corpuscular volume (MCV) on routine complete blood count testing. Despite vitamin B12 replacement, her MCV remained elevated. A bone marrow biopsy was performed, which demonstrated myelodysplastic syndrome. Macrocytosis is a common abnormality in patients with Crohn's disease, most commonly due to vitamin B12 deficiency and secondarily due to bacterial overgrowth. However, it is important to recognise that myelodysplastic syndrome is a common under-reported complication of azathioprine therapy. One-third of cases progress to acute myeloid leukaemia with poor prognosis. In patients with suspected myelodysplastic syndrome, azathioprine therapy should be immediately discontinued. PMID- 23925689 TI - Congenital absence of superficial posterior compartment calf muscles. AB - Although various congenital abnormalities have been described, congenital absence of calf musculature is extremely rare, with only one report on its complete absence. We are the first to describe a case of congenital absence of muscles of the superficial posterior compartment of the calf presenting in a toddler. The child presented with a history of a painless limp, however no significant difference was found in functional gait analysis. We suggest that such cases should be monitored and parents can be reassured that no immediate treatment is required. PMID- 23925690 TI - Effects of binge drinking on action cascading processes: an EEG study. AB - High-dosage alcohol intoxication (i.e., binge drinking in humans) is an increasingly prevalent problem. Despite the well-known long-term consequences, the acute effects of high-dosage alcohol intoxication on cognitive control processes have not been investigated with respect to neurophysiological changes in humans. We provide insights into the effects of high-dosage ethanol intoxication on action control functions in humans on the basis of neurophysiological (EEG) data. Action control processes were examined in a stop change task. Based on a detailed analysis of behavioral and electrophysiological data, we demonstrate a specific modulation of action cascading processes. Opposed to commonly held views, high-dosage ethanol intoxication (0.9-1.13 0/00) exerts highly specific effects on cognitive subprocesses mediating action control. If action control processes are performed in succession, intoxicated and non intoxicated participants perform equally well. However, action control processes become compromised during high-dosage ethanol intoxication, when different response options require processing resources in parallel. Under high-dose ethanol intoxication, subjects are not able to prioritize different response options. We could demonstrate that the effects were of high effect sizes (eta (2) = 0.702) and rely more on response selection deficits than on deficits in attentional processing. The changes in response selection processes are mediated via the anterior cingulate cortex. The specificity of the observed effects may be due to a differential involvement of dopaminergic and GABAergic processes in action control and attentional selection processes. PMID- 23925691 TI - Melatonin as potential candidate to prevent the toxicity induced by chemical warfare agents. PMID- 23925692 TI - Regression of diabetic macular edema after subcutaneous exenatide. AB - The aim of this study is to report a case of complete regression of diabetic macular edema after subcutaneous injection of exenatide in a patient with type 2 diabetes mellitus. This study is an interventional case report. Blood investigations, complete ophthalmic examinations and optical coherence tomography were performed. A 55-year-old female affected by poorly controlled type 2 diabetes mellitus presented with visual impairment due to macular edema in the right eye. The left eye showed mild edema without visual loss. Best-corrected visual acuity (BCVA) was 20/80 and 20/20, respectively. The patient was encouraged to improve metabolic control, and the antidiabetic therapy was modified combining exenatide 10 MUg subcutaneously twice daily to her regimen of oral metformin. The patient did not receive any ocular treatment. A complete tomographic resolution of macular edema was observed after 1 month and BCVA improved to 20/63. These findings were confirmed for the entire 6-month follow-up duration. No ocular or non-ocular adverse events were recorded. This is the first reported case of complete regression of macular edema in a diabetic patient after subcutaneous injection of exenatide. PMID- 23925693 TI - The levels of circulating TRAIL at the onset of type 1 diabetes are markedly decreased in patients with ketoacidosis and with the highest insulin requirement. AB - Experimental evidence in animal models suggests that TNF-related apoptosis inducing ligand (TRAIL), a member of the TNF superfamily, might play an important role in type 1 diabetes (T1D). We have performed a retrospective study by analyzing the sera of a cohort of pediatric subjects (age <=18 years; n = 507) consisting of (1) patients diagnosed with T1D (n = 387), (2) healthy individuals (n = 98, considered as controls), and (3) healthy autoantibody-positive subjects (n = 22). Patients with T1D exhibited significantly decreased levels of circulating TRAIL with respect to the control healthy subjects, as well as to the healthy autoantibody-positive subjects. Within the T1D group, no differences in the levels of circulating TRAIL were observed between patients with or without other concomitant autoimmune pathologies. Of note, the levels of TRAIL were significantly lower in the T1D patients analyzed at onset, although reduction in TRAIL levels persisted also in patients analyzed after disease onset (>1 year from diagnosis). In particular, T1D patients who exhibited ketoacidosis at onset showed significantly lower levels of circulating TRAIL with respect to patients without ketoacidosis at onset. Moreover, the levels of TRAIL at diagnosis correlated inversely with the insulin requirement up to 21 months of follow-up. This is the first study demonstrating that the levels of circulating TRAIL are significantly decreased in T1D, with the lowest levels of TRAIL being observed in patients with ketoacidosis at the onset and with the highest insulin requirement. PMID- 23925694 TI - Tuning the dissolution kinetics of wollastonite via chelating agents for CO2 sequestration with integrated synthesis of precipitated calcium carbonates. AB - Carbon mineralization has recently received much attention as one of the most promising options for CO2 sequestration. The engineered weathering of silicate minerals as a means of permanent carbon storage has unique advantages such as the abundance of naturally occurring calcium and magnesium-bearing minerals and the formation of environmentally-benign and geologically stable solids via a thermodynamically favored carbonation reaction. However, several challenges need to be overcome to successfully deploy carbon mineralization on a large scale. In particular, the acceleration of the rate-limiting mineral dissolution step along with process optimization is essential to ensure the economic feasibility of the proposed carbon storage technology. In this study, the effect of various types of chelating agents on the dissolution rate of calcium-bearing silicate mineral, wollastonite, was explored to accelerate its weathering rate. It was found that chelating agents such as acetic acid and gluconic acid significantly improved the dissolution kinetics of wollastonite even at a much diluted concentration of 0.006 M by complexing with calcium in the mineral matrix. Calcium extracted from wollastonite was then reacted with a carbonate solution to form precipitated calcium carbonate (PCC), while tuning the particle size and the morphological structure of PCC to mimic commercially available PCC-based filler materials. PMID- 23925695 TI - Deep neck infections: risk factors for mediastinal extension. AB - The goal of the study was to find out the risk factors for the development of mediastinitis in patients with deep neck infections (DNI) and describe the differences in symptoms and clinical image between uncomplicated DNI and infections with mediastinal spread. Our study represents the retrospective analysis of 634 patients with DNI. The file was divided into two groups. There were 619 patients (97.6%) in the first group who had an uncomplicated course of DNI without spread of infection into mediastinum (DNI group). The second group included 15 patients (2.4%) with descending mediastinitis as a complication of DNI (mediastinitis group). The most frequent comorbidities were cardiac and pulmonary diseases, which were more frequent in the mediastinitis group comparing to DNI group. Dental origin of the infection was more frequent in DNI group than in the mediastinitis group. On the other hand, tonsillar origin of the infection was more frequent in the mediastinitis group than in DNI group. In both mediastinitis and DNI groups, the typical presenting symptoms were pain, oedema and dysphagia. Furthermore, dysphagia, dyspnoea, dysphonia and restriction of neck movements were more significant in the mediastinitis group than in DNI group. The incidence of airway obstruction, sepsis, pneumonia and death was significantly higher in the mediastinitis group than in DNI group. Due to our results, the predisposing factors for mediastinal extension of DNI are cardiovascular and pulmonary diseases. Mediastinitis is associated with higher morbidity and mortality than DNI. The most common complications are airway obstruction, pneumonia and sepsis. PMID- 23925697 TI - Percutaneous coronary intervention without surgery on-site is here to stay. PMID- 23925696 TI - Puerperal mastitis: a reproductive event of importance affecting anti-mucin antibody levels and ovarian cancer risk. AB - PURPOSE: Test the hypothesis that puerperal mastitis may alter immunity related to the mucin (MUC) family of glycoproteins and lower risk of ovarian cancer. METHODS: In two case-control studies conducted in New England between 1998 and 2008, we examined the association between self-reported mastitis and ovarian cancer in 1,483 women with epithelial ovarian cancer and 1,578 controls. IgG1 antibodies against (MUC1) CA15.3 and (MUC16) CA125 were measured using electrochemiluminescence assays in a subset of controls (n = 200). Preoperative CA125 was recorded in 649 cases. The association between ovarian cancer and mastitis was assessed using unconditional logistic regression to calculate adjusted odds ratios, OR, and 95 % confidence intervals (CI). Associations between mastitis and anti-CA15.3 and anti-CA125 antibodies and preoperative CA125 levels were evaluated using adjusted linear regression models. RESULTS: Prior mastitis was associated with a significantly lower risk of ovarian cancer: OR (and 95 % CI) of 0.67 (0.48, 0.94) adjusted for parity, breastfeeding, and other potential confounders. The association was strongest with 2 or more episodes of mastitis, and risk declined progressively with increasing number of children and episodes of mastitis. Among controls, prior mastitis was associated with significantly higher anti-CA15.3 and anti-CA125 antibody levels and, among cases, with significantly lower preoperative CA125 levels. CONCLUSION: Puerperal mastitis may produce long-lasting anti-mucin antibodies that may lower the risk of ovarian cancer, plausibly through enhanced immune surveillance. Studying immune reactions related to MUC1 and MUC16 in the 10-20 % of breastfeeding women who develop mastitis may suggest ways to duplicate its effects through vaccines based on both antigens. PMID- 23925698 TI - Stability of Si epoxide defects in Si nanowires: a mixed reactive force field/DFT study. AB - Modeling the oxidation process of silicon nanowires through reactive force field based molecular dynamics simulations suggests that the formation of Si epoxide defects occurs both at the Si/SiOx interface and at the nanowire surface, whereas for flat surfaces, this defect is experimentally observed to occur only at the interface as a result of stress. In this paper, we argue that the increasing curvature stabilizes the defect at the nanowire surface, as suggested by our density functional theory calculations. The latter can have important consequences for the opto-electronic properties of thin silicon nanowires, since the epoxide induces an electronic state within the band gap. Removing the epoxide defect by hydrogenation is expected to be possible but becomes increasingly difficult with a reduction of the diameter of the nanowires. PMID- 23925699 TI - Autologous hematopoietic stem cell transplantation following high dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas. AB - BACKGROUND: Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In patients with advanced local or metastatic disease, autologous hematopoietic stem cell transplantation (HSCT) applied after high-dose chemotherapy (HDCT) is a planned rescue therapy for HDCT related severe hematologic toxicity. The rationale for this update is to determine whether any randomized controlled trials (RCTs) have been conducted and to clarify whether HDCT followed by autologous HSCT has a survival advantage. OBJECTIVES: To assess the effectiveness and safety of HDCT followed by autologous HSCT for all stages of non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) in children and adults. SEARCH METHODS: For this update we modified the search strategy to improve the precision and reduce the number of irrelevant hits. All studies included in the original review were considered for re-evaluation in the update. We searched the electronic databases CENTRAL (2012, Issue 11) in The Cochrane Library , MEDLINE and EMBASE (05 December 2012) from their inception using the newly developed search strategy. Online trials registers and reference lists of systematic reviews were searched. SELECTION CRITERIA: Terms representing STS and autologous HSCT were required in the title or abstract. In studies with aggregated data, participants with NRSTS and autologous HSCT had to constitute at least 80% of the data. Single-arm studies were included in addition to studies with a control arm because the number of comparative studies was expected to be very low. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study data. Some studies identified in the original review were re examined and found not to meet the inclusion criteria and were excluded in this update. For studies with no comparator group, we synthesized the results for studies reporting aggregate data and conducted a pooled analysis of individual participant data using the Kaplan-Meyer method. The primary outcomes were overall survival (OS) and treatment-related mortality (TRM). MAIN RESULTS: The selection process was carried out from the start of the search dates for the update. We included 57 studies, from 260 full text articles screened, reporting on 275 participants that were allocated to HDCT followed by autologous HSCT. All studies were not comparable due to various subtypes. We identified a single comparative study, an RCT comparing HDCT followed by autologous HSCT versus standard chemotherapy (SDCT). The overall survival (OS) at three years was 32.7% versus 49.4% with a hazard ratio (HR) of 1.26 (95% confidence interval (CI) 0.70 to 2.29, P value 0.44) and thus not significantly different between the treatment groups. In a subgroup of patients that had a complete response before treatment, OS was higher in both treatment groups and OS at three years was 42.8% versus 83.9% with a HR of 2.92 (95% CI 1.1 to 7.6, P value 0.028) and thus was statistically significantly better in the SDCT group. We did not identify any other comparative studies. We included six single-arm studies reporting aggregate data of cases; three reported the OS at two years as 20%, 48%, and 51.4%. One other study reported the OS at three years as 40% and one further study reported a median OS of 13 months (range 3 to 19 months). In two of the single-arm studies with aggregate data, subgroup analysis showed a better OS in patients with versus without a complete response before treatment. In a survival analysis of pooled individual data of 80 participants, OS at two years was estimated as 50.6% (95% CI 38.7 to 62.5) and at three years as 36.7% (95% CI 24.4 to 49.0). Data on TRM, secondary neoplasia and severe toxicity grade 3 to 4 after transplantation were sparse. The one included RCT had a low risk of bias and the remaining 56 studies had a high risk of bias. AUTHORS' CONCLUSIONS: A single RCT with a low risk of bias shows that OS after HDCT followed by autologous HSCT is not statistically significantly different from standard-dose chemotherapy. Therefore, HDCT followed by autologous HSCT for patients with NRSTS may not improve the survival of patients and should only be used within controlled trials if ever considered. PMID- 23925700 TI - Practice gaps: Practice gaps "down there": failures in education, physical examination, recognition, diagnosis, therapy, follow-up care, and cancer surveillance in lichen sclerosus. PMID- 23925701 TI - tPA regulates neurite outgrowth by phosphorylation of LRP5/6 in neural progenitor cells. AB - Despite the important role of tissue plasminogen activator (tPA) as a neuromodulator in neurons, microglia, and astrocytes, its role in neural progenitor cell (NPC) development is not clear yet. We identified that tPA is highly expressed in NPCs compared with neurons. Inhibition of tPA activity or expression using tPA stop, PAI-1, or tPA siRNA inhibited neurite outgrowth from NPCs, while overexpression or addition of exogenous tPA increased neurite outgrowth. The expression of Wnt and beta-catenin as well as phosphorylation of LRP5 and LRP6, which has been implicated in Wnt-beta-catenin signaling, was rapidly increased after tPA treatment and was decreased by tPA siRNA transfection. Knockdown of beta-catenin or LRP5/6 expression by siRNA prevented tPA-induced neurite extension. NPCs obtained from tPA KO mice showed impaired neurite outgrowth compared with WT NPCs. In ischemic rat brains, axon density was higher in the brains transplanted with WT NPCs than in those with tPA KO NPCs, suggesting increased axonal sprouting by NPC-derived tPA. tPA-mediated regulation of neuronal maturation in NPCs may play an important role during development and in regenerative conditions. PMID- 23925702 TI - Passive movement improves the learning and memory function of rats with cerebral infarction by inhibiting neuron cell apoptosis. AB - Passive movement has been found to improve evidently ischemic stroke patients' impaired capacity of learning and memory, but the optimal time window of initiating the therapy and the underlying mechanism are not fully understood. In this study, the effect of passive movement at different time windows on learning and memory of rats with cerebral infarction was detected. The results showed that the expression of caspase-3 and escape latency in the passive movement group were all considerably lower than those in the model group (P < 0.05), while the expression of Bcl-2 mRNA was significantly higher than those in the model group (P < 0.05). Moreover, we found that there were most significant changes of escape latency and expressions of Bcl-2 mRNA and caspase-3 when the therapy started at 24 h after focal cerebral infarction. These results suggest that passive movement is able to contribute to the recovery of learning and memory of rats with cerebral infarction, which is partially mediated by inhibiting neuron cell apoptosis, and the optimal therapeutic time is at 24 h after cerebral infarction. PMID- 23925703 TI - Performance of goodness-of-fit tests for the Cox proportional hazards model with time-varying covariates. AB - There are few readily-implemented tests for goodness-of-fit for the Cox proportional hazards model with time-varying covariates. Through simulations, we assess the power of tests by Cox (J R Stat Soc B (Methodol) 34(2):187-220, 1972), Grambsch and Therneau (Biometrika 81(3):515-526, 1994), and Lin et al. (Biometrics 62:803-812, 2006). Results show that power is highly variable depending on the time to violation of proportional hazards, the magnitude of the change in hazard ratio, and the direction of the change. Because these characteristics are unknown outside of simulation studies, none of the tests examined is expected to have high power in real applications. While all of these tests are theoretically interesting, they appear to be of limited practical value. PMID- 23925704 TI - Severe congenital herpes simplex virus infection. PMID- 23925705 TI - Success case studies contribute to evaluation of complex research infrastructure. AB - The success case studies approach examines in depth what works well in a program by describing cases and examining factors leading to successful outcomes. In this article, we describe the use of success case studies as part of an evaluation of the transformation of a health sciences research support infrastructure. Using project-specific descriptions and the researchers' perceptions of the impact of improved research infrastructure, we added depth of understanding to the quantitative data required by funding agencies. Each case study included an interview with the lead researcher, along with review of documents about the research, the investigator, and their collaborators. Our analyses elucidated themes regarding contributions of the Clinical and Translational Science Awards program of the National Institutes of Health to scientific achievements and career advancement of investigators in one academic institution. PMID- 23925706 TI - Estimating return on investment in translational research: methods and protocols. AB - Assessing the value of clinical and translational research funding on accelerating the translation of scientific knowledge is a fundamental issue faced by the National Institutes of Health (NIH) and its Clinical and Translational Awards (CTSAs). To address this issue, the authors propose a model for measuring the return on investment (ROI) of one key CTSA program, the clinical research unit (CRU). By estimating the economic and social inputs and outputs of this program, this model produces multiple levels of ROI: investigator, program, and institutional estimates. A methodology, or evaluation protocol, is proposed to assess the value of this CTSA function, with specific objectives, methods, descriptions of the data to be collected, and how data are to be filtered, analyzed, and evaluated. This article provides an approach CTSAs could use to assess the economic and social returns on NIH and institutional investments in these critical activities. PMID- 23925708 TI - A magnesium-based multifunctional metal-organic framework: synthesis, thermally induced structural variation, selective gas adsorption, photoluminescence and heterogeneous catalytic study. AB - Three magnesium based carboxylate framework systems were prepared through a temperature-dependent synthesis. The compounds were synthesized by a hydrothermal method and characterized by single crystal X-ray diffraction analysis. A stepwise increase in the temperature of the medium resulted a stepwise increase in the dimensionality of the network, ultimately leading to the formation of a new 2D layered alkaline earth metal-organic framework (MOF) compound, {[Mg2(HL)2(H2O)4].H2O}n (1) (H3L = pyrazole-3,5-dicarboxylate). Compound 1 selectively adsorbs hydrogen (H2) (ca. 0.56 wt% at 77 K) over nitrogen at 1 atm and demonstrates a strong blue fluorescent emission band at 480 nm (lambda(max)) upon excitation at 270 nm. Notably, the 2D framework compound efficiently catalyzes the aldol condensation reactions of various aromatic aldehydes with ketones in a heterogeneous medium under environmentally friendly conditions. The catalyst can be recycled and reused several times without any significant loss of activity. PMID- 23925707 TI - Variability of the preC/C region of hepatitis B virus genotype A from a South African cohort predominantly infected with HIV. AB - Hepatitis B virus (HBV) is a serious global health problem, and HBV genotype is an important determinant of disease progression and treatment outcome. The aim of this study was to assess variations of the precore/core (preC/C) region in HBV genotype A. Sequencing of the preC/C and surface (S) genes of HBV was performed on plasma samples from 20 HBV/HIV co-infected and 5 HBV mono-infected individuals. All preC/C study sequences clustered with subgenotype A1, except for two which clustered with subgenotype D4 reference strains. The nucleotide and amino acid variability was far higher in the preC/C region than in the S region. Mutations associated with reduction or failure of HBV e-antigen (HBeAg) production were observed, with a preC start codon mutation being common (24%). Other mutations (e.g., P5H/L and I97L) associated with severe liver disease were also noticed, some of which were located in the major histocompatibility restricted sites. PreC/C intergenotype nucleotide divergence was >7%, while subgenotypes differed by 2.5-7%. Several study sequences were highly divergent from other African subgenotype A1 strains. This study showed that HBeAg-negative chronic hepatitis B is underestimated in subgenotype A1, and also highlighted the variant South African A1 strains. The major advantage of preC/C sequencing is that it informs patient management as HBeAg-negative chronic hepatitis B responds poorly to conventional interferon-alpha therapy, and some guidelines treat HBeAg negative chronic hepatitis B differently from HBeAg-positive chronic hepatitis B. These data suggest that subgenotype A1 may be more involved in severe HBV-related diseases. PMID- 23925709 TI - Vibrational enhancement of electron emission in CO (a3Pi) quenching at a clean metal surface. AB - We have combined a Stark decelerator with a molecular beam-surface scattering setup to accurately measure the absolute electron emission yield, gamma, of CO (a(3)Pi) quenching at a Au(111) surface with quantum state resolution. We clearly observe an enhanced probability of electron emission when scattering vibrationally excited states of CO from the surface. PMID- 23925710 TI - Reward signals, attempted suicide, and impulsivity in late-life depression. AB - IMPORTANCE-Suicide can be viewed as an escape from unendurable punishment at the cost of any future rewards. Could faulty estimation of these outcomes predispose to suicidal behavior? In behavioral studies, many of those who have attempted suicide misestimate expected rewards on gambling and probabilistic learning tasks.OBJECTIVES-To describe the neural circuit abnormalities that underlie disadvantageous choices in people at risk for suicide and to relate these abnormalities to impulsivity, which is one of the components of vulnerability to suicide.DESIGN-Case-control functional magnetic resonance imaging study of reward learning using are inforcement learning model.SETTING-University hospital and outpatient clinic.PATIENTS-Fifty-three participants 60 years or older, including 15 depressed patients who had attempted suicide, 18 depressed patients who had never attempted suicide (depressed control subjects), and 20 psychiatrically healthy controls.MAIN OUTCOMES AND MEASURES-Components of the cortical blood oxygenation level-dependent response tracking expected and unpredicted rewards.RESULTS-Depressed elderly participants displayed 2 distinct disruptions of control over reward-guided behavior. First, impulsivity and a history of suicide attempts (particularly poorly planned ones) were associated with a weakened expected reward signal in the paralimbic cortex,which in turn predicted the behavioral insensitivity to contingency change. Second, depression was associated with disrupted corticostriatothalamic encoding of unpredicted rewards, which in turn predicted the behavioral over sensitivity to punishment. These results were robust to the effects of possible brain damage from suicide attempts, depressive severity, co-occurring substance use and anxiety disorders, antidepressant and anticholinergic exposure, lifetime exposure to electroconvulsive therapy, vascular illness, and incipient dementia.CONCLUSIONS AND RELEVANCE-Altered paralimbic reward signals and impulsivity and/or carelessness may facilitate unplanned suicidal acts. This pattern, also seen in gambling and cocaine use, may reflect a primary deficit in the paralimbic cortex or in its mesolimbic input. The over reactivity to punishment in depression may be caused in part by a disruption of appetitive learning in the corticostriatothalamic circuits. PMID- 23925711 TI - Management of acute rejection in paediatric liver transplantation. AB - The success of paediatric liver transplantation is attributed to improved surgical techniques and the advent of calcineurin inhibitor-based immunosuppression. Acute rejection (AR) rarely results in graft loss with calcineurin inhibitor immunosuppressive regimens, and the advent of newer agents like interleukin (IL)-2 receptor antibodies. The latter have the benefit of reducing the incidence of AR further and may be of use in patients who are susceptible to recurrent AR, were retransplanted for graft rejection or are in a steroid-sparing regimen. A total of 60 % of all paediatric liver transplants result in AR; however, there is a 75 % response rate to initial steroid therapy. Steroid therapy remains the mainstay of initial AR management, coupled with an increase in baseline immunosuppression. Steroid-resistant rejection (SRR), previously an immediate indication for potent anti-lymphocyte preparations, is now effectively treated with chimeric or humanised IL-2 receptor monoclonal antibodies. Recurrent AR can be treated by adding adjuvant immunosuppressive agents such as mycophenolate mofetil (MMF) or sirolimus. Studies have also demonstrated the efficacy of MMF as rescue therapy for SRR. Anti-lymphocyte preparations such as anti-thymocyte globulin (ATG) and OKT3 are rarely used in SRR but may be of use as rescue therapy for severe SRR. The challenges of the management of AR remain in the management of recurrent AR and SRR. We discuss the pathogenesis, diagnosis and management of AR, including prevention, and specific management of AR and SRR based on current evidence and our own experience at the King's College Paediatric Liver, Gastroenterology and Nutrition Centre in London. PMID- 23925712 TI - Using DynaCT for the assessment of ilio-femoral arterial calibre, calcification and tortuosity index in patients selected for trans-catheter aortic valve replacement. AB - Adequate vascular access for femoral trans-catheter aortic valve replacement is fundamental to the success of the procedure. Assessment of vascular calibre, tortuosity and calcification is performed by angiography and multi-slice computed tomography (MSCT). Can DynaCT provide the same information as MSCT? 15 Patients underwent MSCT, angiography and DynaCT. Vessel diameter measurements were taken in three positions of the left and right ilio-femoral arteries. Tortuosity was assessed using an index of the direct distance and the distance taken by the artery between two points. Calcification was assessed in MSCT and DynaCT using a simple scoring system. Concordance correlation coefficient of arterial calibre between angiography and MSCT was 0.96 (95 % CI 0.94-0.97). DynaCT and angiography was 0.94 (95 % CI 0.91-0.96) and Dyna CT and MSCT, 0.95 (95 % CI 0.92-0.97). Bland-Altman tests demonstrate a mean difference between the angiogram and the MSCT of 0.06 mm (+0.97, -1.42), angiogram and DynaCT, 0.13 mm, (+1.00, -0.87), DynaCT and MSCT, 0.2 mm, (+1.15, -0.76). Tortuosity comparisons gave a median tortuosity index for MSCT 1.29 and DynaCT 1.23 (p = 0.472). Calcification comparisons of MSCT and DynaCT using correlation coefficients demonstrate a correlation of 0.245 (p = 0.378). Effective radiation doses were: DynaCT; 3.63 +/ 0.65 mSv and angiography; 0.57 +/- 0.72 mSv, MSCT; 7.15 +/- 2.58 mSv. DynaCT is equal to MSCT and angiography in assessing femoral artery calibre. Like MSCT, it can assess tortuosity and can produce 3D images but is inferior in the assessment of calcification. PMID- 23925713 TI - Automatic segmentation, detection and quantification of coronary artery stenoses on CTA. AB - Accurate detection and quantification of coronary artery stenoses is an essential requirement for treatment planning of patients with suspected coronary artery disease. We present a method to automatically detect and quantify coronary artery stenoses in computed tomography coronary angiography. First, centerlines are extracted using a two-point minimum cost path approach and a subsequent refinement step. The resulting centerlines are used as an initialization for lumen segmentation, performed using graph cuts. Then, the expected diameter of the healthy lumen is estimated by applying robust kernel regression to the coronary artery lumen diameter profile. Finally, stenoses are detected and quantified by computing the difference between estimated and expected diameter profiles. We evaluated our method using the data provided in the Coronary Artery Stenoses Detection and Quantification Evaluation Framework. Using 30 testing datasets, the method achieved a detection sensitivity of 29% and a positive predictive value (PPV) of 24% as compared to quantitative coronary angiography (QCA), and a sensitivity of 21% and a PPV of 23% as compared manual assessment based on consensus reading of CTA by 3 observers. The stenoses degree was estimated with an absolute average difference of 31%, a root mean square difference of 39.3% when compared to QCA, and a weighted kappa value of 0.29 when compared to CTA. A Dice of 68 and 65% was reported for lumen segmentation of healthy and diseased vessel segments respectively. According to the ranking of the evaluation framework, our method finished fourth for stenosis detection, second for stenosis quantification and second for lumen segmentation. PMID- 23925714 TI - Palladium-catalyzed carbenoid based N-H bond insertions: application to the synthesis of chiral alpha-amino esters. AB - A highly efficient palladium-catalyzed carbenoid based N-H bond insertion has been developed. The alpha-amino esters were obtained in high isolated yields. Moreover, by choosing a suitable chiral auxiliary, stereoselective Pd-catalyzed N H insertion has been realized. The chiral alpha-amino esters were obtained in high yields (up to 91%) and with excellent diastereoselectivities (d.r. > 19 : 1). PMID- 23925715 TI - Together for better treatment and care. Abstracts of the 4th European Conference on Schizophrenia Research. September 26-28, 2013. Berlin, Germany. PMID- 23925716 TI - Oncoplastic breast surgery combining partial mastectomy with immediate breast reshaping using a keyhole-shaped skin glandular flap for Paget's disease. AB - Oncoplastic breast surgery (OBS), which combines the concepts of oncologic and plastic surgery, is becoming more common worldwide. We herein report the results of OBS in Japanese patients with Paget's disease. We performed OBS combining partial mastectomy with immediate breast reshaping using a keyhole-shaped skin glandular flap in two patients. In these two patients, who were diagnosed as having Paget's disease with a restricted intraductal component in the central area of their non-ptotic breast, we performed oncoplastic surgery combining partial mastectomy with immediate breast reshaping using a keyhole-shaped skin glandular flap. Neither of the two patients received contralateral surgery to produce symmetrical breasts. The observation period ranged from 6 to 12 months, and the bilateral breast volumes and inframammary lines were symmetric. OBS combining partial mastectomy with immediate breast reshaping using a keyhole shaped skin glandular flap was successfully performed in two patients with Paget's disease. PMID- 23925717 TI - Cyberhealth serving to support individual intake of medication. AB - The Internet and new communication technologies are deeply affecting healthcare systems and the provision of care. The purpose of this article is to evaluate the possibility that cyberhealth, via the development of widespread easy access to wireless personal computers, tablets and smartphones, can effectively influence intake of medication and long-term medication adherence, which is a complex, difficult and dynamic behaviour to adopt and to sustain over time. Because of its novelty, the impact of cyberhealth on drug intake has not yet been well explored. Initial results have provided some evidence, but more research is needed to determine the impact of cyberhealth resources on long-term adherence and health outcomes, its user-friendliness and its adequacy in meeting e-patient needs. The purpose of such Internet-based interventions, which provide different levels of customisation, is not to take over the roles of healthcare providers; on the contrary, cyberhealth platforms should reinforce the alliance between healthcare providers and patients by filling time-gaps between visits and allowing patients to upload and/or share feedback material to be used during the visits. This shift, however, is not easily endorsed by healthcare providers, who must master new eHealth skills, but healthcare systems have a unique opportunity to invest in the Internet and to use this powerful tool to design the future of integrated care. Before this can occur, however, important issues must be addressed and resolved, for example ethical considerations, the scientific quality of programmes, reimbursement of activity, data security and the ownership of uploaded data. PMID- 23925718 TI - Satiety responsiveness and the relationship between breastfeeding and weight status of toddlers of overweight and obese women. AB - Numerous studies indicate an association between breastfeeding and decreased toddler adiposity. The mechanism behind this association is still unknown. One possibility is that children who are breastfed may have increased responsiveness to internal satiety cues. This study assessed the effect of satiety responsiveness on the association between breastfeeding and weight status among toddlers. We conducted a secondary analysis of data from 428 toddlers aged 2 years. Mothers' body mass index (BMI) and children's BMI z score were calculated from measured height and weight. Mothers completed a detailed breastfeeding survey and the satiety responsiveness subscale of the Child Eating Behaviour Questionnaire. Multiple linear regression and logistic regression were used to determine if satiety responsiveness mediated the effect of breastfeeding on BMI z score or overweight/obesity (BMI >= 85th percentile). Establishment of breastfeeding was associated with decreased BMI z score (0.40 vs. 0.60; p = 0.04), and increased breastfeeding intensity was associated with lower odds of overweight/obesity (OR 0.97, p = 0.04). Satiety responsiveness was not associated with either breastfeeding measures, suggesting it does not play a meditational role in the relationship between breastfeeding and toddler weight status. Furthermore, a relationship between satiety responsiveness and obesity does not exist after controlling for well-known confounders. This study did not find a mediation effect of satiety responsiveness on the association between breastfeeding and weight status in toddlers. More research is needed to characterize satiety responsiveness and its influence on the relationship between breastfeeding and childhood obesity. PMID- 23925719 TI - Autonomic dysfunction in adult-onset alexander disease: a case report and review of the literature. AB - BACKGROUND: Alexander disease (AxD) is an astrogliopathy, resulting from a mutation in the glial fibrillary astrocytic protein gene. Different clinical subtypes have been described, including infantile, juvenile, and adult onset, based upon the age at which symptoms begin. Patients with the adult-onset form, develop a progressive, spastic paraparesis, palatal myoclonus, ataxia, and bulbar weakness. Autonomic nervous system (ANS) dysfunction has been reported as a potential manifestation of adult-onset AxD, but has not been well characterized. OBJECTIVE: We report a case of adult-onset AxD with symptomatic orthostatic hypotension (OH) and heat intolerance that underwent formal autonomic testing. In addition, a comprehensive literature search was conducted to review the frequency and pattern of autonomic dysfunction in this patient population. RESULTS: A 51 year-old patient was diagnosed with AxD at the age of 47, following an 8-year history of vertigo, intermittent diplopia, and sleep disturbance. The patient developed symptoms of OH, erectile dysfunction, and heat intolerance soon after his diagnosis. Autonomic testing demonstrated OH on tilt-table testing (47 mmHg decrease in BP with 18 BPM heart rate increment) with absent late phase II and IV responses during the Valsalva maneuver, severe cardiovagal impairment, and preserved postganglionic sympathetic sudomotor function. These findings were interpreted as being consistent with central autonomic failure. The most common autonomic symptoms reported in other AxD cases include constipation, urinary incontinence, and sphincter dysfunction. To our knowledge, this is the first report of formal autonomic testing in AxD. CONCLUSION: Signs and symptoms of ANS impairment can occur in patients with AxD, and can include orthostatic hypotension and bowel/bladder dysfunction. Autonomic testing in our patient suggests impairment in central autonomic pathways. PMID- 23925722 TI - The effect of low concentrations versus high concentrations of local anesthetics for labour analgesia on obstetric and anesthetic outcomes: a meta-analysis. AB - INTRODUCTION: The influence that different concentrations of labour epidural local anesthetic have on assisted vaginal delivery (AVD) and many obstetric outcomes and side effects is uncertain. The purpose of this meta-analysis was to determine whether local anesthetics utilized at low concentrations (LCs) during labour are associated with a decreased incidence of AVD when compared with high concentrations (HCs). METHODS: We searched PubMed, Ovid EMBASE, Ovid MEDLINE, CINAHL, Scopus, clinicaltrials.gov, and Cochrane databases for randomized controlled trials of labouring patients that compared LCs (defined as <= 0.1% epidural bupivacaine or <= 0.17% ropivacaine) of epidural local anesthetic with HCs for maintenance of analgesia. The primary outcome was AVD and secondary outcomes included Cesarean delivery, duration of labour, analgesia, side effects (nausea and vomiting, motor block, hypotension, pruritus, and urinary retention), and neonatal outcomes. The odds ratios (OR) or weighted mean differences (WMD) and 95% confidence intervals (CI) were calculated using random effects modelling. An OR < 1 or a WMD < 0 favoured LCs. RESULTS: Eleven studies met our criteria (eight bupivacaine and three ropivacaine studies), providing 1,145 patients in the LCs group and 852 patients in the HCs group for analysis of the primary outcome. Low concentrations were associated with a reduction in the incidence of AVD (OR = 0.70; 95% CI 0.56 to 0.86; P < 0.001). There was no difference in the incidence of Cesarean delivery (OR 1.05; 95% CI 0.82 to 1.33; P = 0.7). The LCs group had less motor block (OR 3.9; 95% CI 1.59 to 9.55; P = 0.003), greater ambulation (OR 2.8; 95% CI 1.1 to 7.14; P = 0.03), less urinary retention (OR 0.42; 95% CI 0.23 to 0.73; P = 0.002), and a shorter second stage of labour (WMD 14.03; 95% CI -27.52 to -0.55; P = 0.04) compared with the HCs group. There were no differences between groups in pain scores, maternal nausea and vomiting, hypotension, fetal heart rate abnormalities, five-minute Apgar scores, and need for neonatal resuscitation. One-minute Apgar scores < 7 favoured the HCs group (OR 1.53; 95% CI 1.07 to 2.21; P = 0.02), and there was more pruritus in the LCs group (OR 3.36; 95% CI 1.00 to 11.31; P = 0.05). CONCLUSION: When compared with HCs of local anesthetics, the use of LCs for labour epidural analgesia reduces the incidence of AVD. This may be due to a reduction in the amount of local anesthetic used and the subsequent decrease in motor blockade. We therefore recommend the use of LCs of local anesthetics for epidural analgesia to optimize obstetric outcome. PMID- 23925724 TI - Temperature dependence of high field 13C dynamic nuclear polarization processes with trityl radicals below 35 Kelvin. AB - In order to facilitate versatile applications with high field dynamic nuclear polarization (DNP), it is important to be able to optimize the DNP performance, i.e. reach high nuclear hyperpolarization within a short signal build up time. Given that the solid-state DNP process is strongly temperature-dependent, it is important to benchmark the temperature dependence of various DNP and electron paramagnetic resonance (EPR) parameters that can then be used to test and develop theories and models for high field DNP mechanisms. However, DNP and EPR experiments at high fields and cryogenic temperatures below 20 Kelvin usually require home built instrumentation, and therefore even basic experimental observations are lacking in the literature. DNP and EPR experiments at 7 T (197 GHz) and 8.5 T (240 GHz), respectively, were conducted at temperatures between 35 K and 3.7 K where the electron thermal polarization changes from 13.4% to 85.6%, respectively. The samples are frozen solutions of 15 mM OX063Me trityl radicals in various mixtures of [1-(13)C]pyruvic acid, glycerol, and Gd(3+)-chelates. For all sample mixtures, the trityl EPR lines are found to be inhomogeneously broadened and the dominant DNP mechanism is shown to be the cross effect (CE). A 20%, 11%, and 6.77% (13)C polarization is achieved at 3.7 K with a [1 (13)C]pyruvic-glycerol-H2O sample, the addition of 2 mM of Gd(3+)-chelates, and pure [1-(13)C]pyruvic acid, respectively. When T1n is sufficiently long, our results seem to suggest T1e is a key variable in the DNP process, where longer T1e values correlate with larger DNP enhancements (epsilonDNP). The experimental data reported here on the temperature dependence of T1n, T1e, Tm (electron phase memory time), the EPR linewidth, TDNP and epsilon(DNP) at high fields will be helpful for testing the mechanism and theory of DNP processes. PMID- 23925723 TI - Influence of CRTC1 polymorphisms on body mass index and fat mass in psychiatric patients and the general adult population. AB - IMPORTANCE: There is a high prevalence of obesity in psychiatric patients, possibly leading to metabolic complications and reducing life expectancy. The CREB-regulated transcription coactivator 1 (CRTC1) gene is involved in energy balance and obesity in animal models, but its role in human obesity is unknown. OBJECTIVE: To determine whether polymorphisms within the CRTC1 gene are associated with adiposity markers in psychiatric patients and the general population. DESIGN, SETTING, AND PARTICIPANTS: Retrospective and prospective data analysis and population-based samples at Lausanne and Geneva university hospitals in Switzerland and a private clinic in Lausanne, Switzerland. The effect of 3 CRTC1 polymorphisms on body mass index (BMI) and/or fat mass was investigated in a discovery cohort of psychiatric outpatients taking weight gain-inducing psychotropic drugs (sample 1, n = 152). The CRTC1 variant that was significantly associated with BMI and survived Bonferroni corrections for multiple comparison was then replicated in 2 independent psychiatric samples (sample 2, n = 174 and sample 3, n = 118) and 2 white population-based samples (sample 4, n = 5338 and sample 5, n = 123,865). INTERVENTION: Noninterventional studies. MAIN OUTCOME AND MEASURE: Difference in BMI and/or fat mass between CRTC1 genotype groups. RESULTS: Among the CRTC1 variants tested in the first psychiatric sample, only rs3746266A>G was associated with BMI (P(adjusted) = .003). In the 3 psychiatric samples, carriers of the rs3746266 G allele had a lower BMI than noncarriers (AA genotype) (sample 1, P = .001; sample 2, P = .05; and sample 3, P = .0003). In the combined analysis, excluding patients taking other weight gain-inducing drugs, G allele carriers (n = 98) had a 1.81-kg/m2 lower BMI than noncarriers (n = 226; P < .0001). The strongest association was observed in women younger than 45 years, with a 3.87-kg/m2 lower BMI in G allele carriers (n = 25) compared with noncarriers (n = 48; P < .0001), explaining 9% of BMI variance. In the population based samples, the T allele of rs6510997C>T (a proxy of the rs3746266 G allele; r2 = 0.7) was associated with lower BMI (sample 5, n = 123,865; P = .01) and fat mass (sample 4, n = 5338; P = .03). The strongest association with fat mass was observed in premenopausal women (n = 1192; P = .02). CONCLUSIONS AND RELEVANCE: These findings suggest that CRTC1 contributes to the genetics of human obesity in psychiatric patients and the general population. Identification of high-risk subjects could contribute to a better individualization of the pharmacological treatment in psychiatry. PMID- 23925725 TI - SEOM guidelines 2013: a response to the needs of Spanish oncologists. PMID- 23925726 TI - Pattern formation in a model for mountain pine beetle dispersal: linking model predictions to data. AB - Pattern formation occurs in a wide range of biological systems. This pattern formation can occur in mathematical models because of diffusion-driven instability or due to the interaction between reaction, diffusion, and chemotaxis. In this paper, we investigate the spatial pattern formation of attack clusters in a system for Mountain Pine Beetle. The pattern formation (aggregation) of the Mountain Pine Beetle in order to attack susceptible trees is crucial for their survival and reproduction. We use a reaction-diffusion equation with chemotaxis to model the interaction between Mountain Pine Beetle, Mountain Pine Beetle pheromones, and susceptible trees. Mathematical analysis is utilized to discover the spacing in-between beetle attacks on the susceptible landscape. The model predictions are verified by analysing aerial detection survey data of Mountain Pine Beetle Attack from the Sawtooth National Recreation Area. We find that the distance between Mountain Pine Beetle attack clusters predicted by our model closely corresponds to the observed attack data in the Sawtooth National Recreation Area. These results clarify the spatial mechanisms controlling the transition from incipient to epidemic populations and may lead to control measures which protect forests from Mountain Pine Beetle outbreak. PMID- 23925727 TI - Cherry picking: a characterization of the temporal hybridization number for a set of phylogenies. AB - Recently, we have shown that calculating the minimum-temporal-hybridization number for a set [Formula: see text] of rooted binary phylogenetic trees is NP hard and have characterized this minimum number when [Formula: see text] consists of exactly two trees. In this paper, we give the first characterization of the problem for [Formula: see text] being arbitrarily large. The characterization is in terms of cherries and the existence of a particular type of sequence. Furthermore, in an online appendix to the paper, we show that this new characterization can be used to show that computing the minimum-temporal hybridization number for two trees is fixed-parameter tractable. PMID- 23925728 TI - The interplay between scent trails and group-mass recruitment systems in ants. AB - Large ant colonies invariably use effective scent trails to guide copious ant numbers to food sources. The success of mass recruitment hinges on the involvement of many colony members to lay powerful trails. However, many ant colonies start off as single queens. How do these same colonies forage efficiently when small, thereby overcoming the hurdles to grow large? In this paper, we study the case of combined group and mass recruitment displayed by some ant species. Using mathematical models, we explore to what extent early group recruitment may aid deployment of scent trails, making such trails available at much smaller colony sizes. We show that a competition between group and mass recruitment may cause oscillatory behaviour mediated by scent trails. This results in a further reduction of colony size to establish trails successfully. PMID- 23925729 TI - Authors' response re: Do preoperative urodynamics still have a role in female stress urinary incontinence? Neurourol Urodyn 2013;32:1144-5. PMID- 23925730 TI - Developing community support for homeless people with mental illness in transition. AB - To facilitate effective transitional services and enhance continuity of care among people with mental illness, this grounded theory study explored the practice of developing community support in critical time intervention (CTI), a time-limited, shortterm psychosocial rehabilitation program designed to facilitate the critical transition from institutional to community settings. Semi structured, one-on-one interviews with twelve CTI workers were analyzed. Results show that CTI workers self-identified as an "extra support" to develop community ties that will help clients sustain stable housing. Their practice of community support development was represented by a transient triangular relationship model, involving three dyadic relationships (worker-client, worker-primary support, primary support-client) as the building blocks and specific strategies to facilitate the relational transition. Findings also detailed identification of community supports, collaboration and boundary issues in working with primary supports, and engagement with clients in this transitional process. Recommendations were drawn from findings to enhance broad discharge and transitional services. PMID- 23925731 TI - Racial/ethnic differences in the association between symptoms of depression and self-rated mental health among older adults. AB - The study examined racial/ethnic differences in the association between symptoms of depression and self-rated mental health among older adults. Data came from the first wave of the National Social Life, Health, and Aging Project, a population based study of non-institutionalized older adults aged 57 to 85. The sample consisted of non-Hispanic Whites (n = 2,110), Blacks (n = 509), and Hispanics (n = 304). The association between symptoms of depression and self-rated mental health was weaker among minority groups than that among non-Hispanic Whites. Tests of interaction effects showed that the predictability of depressive symptoms to self-rated mental health was substantially weakened among Blacks of advanced ages and Hispanics with multiple chronic conditions. The study explored potential sources of racial/ethnic differences in subjective reports of mental health and called attention to older minorities with advanced ages and cormorbid conditions in mental health services and interventions. PMID- 23925732 TI - Quantification of cerebellar hemispheric purkinje cell linear density: 32 ET cases versus 16 controls. AB - Although essential tremor (ET) is among the most prevalent neurological diseases, its precise pathogenesis is not understood. Purkinje cell loss has been observed in some studies and is the focus of interest and debate. Expressing these data as Purkinje cells/layer length allows one to adjust for the inherent curved nature of the cerebellar folia. Capitalizing on the Essential Tremor Centralized Brain Repository, we quantified Purkinje cell linear density in cases versus controls. Free-floating 100-MUm parasagittal cerebellar hemispheric sections were subjected to rabbit polyclonal anti-Calbindin D28k antibody, and 10 random fields/brain were selected for quantification of Purkinje cells/mm(-1) Purkinje cell layer. Purkinje cell linear density was lower in 32 ET cases than in16 controls (1.14 +/ 0.32 vs. 1.35 +/- 0.31/mm(-1) , P = 0.03). Purkinje cell linear density was inversely associated with torpedo count (r = -0.38, P = 0.028). The current sample of ET cases demonstrates a reduction in Purkinje cell number relative to that of controls. Greater Purkinje cell axonal remodeling (torpedoes) was found in individuals who had the most Purkinje cell drop out. The role of Purkinje cell loss in the pathogenesis of this disorder merits additional study. PMID- 23925733 TI - Silver vanadium oxide and silver vanadium phosphorous oxide dissolution kinetics: a mechanistic study with possible impact on future ICD battery lifetimes. AB - Material design strategies for energy storage applications can be considered in two major categories: (1) control of structure and composition and (2) material dimensional control such as the implementation of nanomaterials. Characterization of electrochemical properties determines energy content and possible viability for potential application. Equally critical yet more challenging is quantifying the non-Faradaic parasitic reactions of the active materials and the relationship to battery life. Understanding the significant factors associated with battery lifetimes for the implantable cardioverter defibrillator (ICD) is critical for the development of new ICD batteries. In situ dissolution of the cathode material has been identified as a major factor in premature end of life for ICD batteries. This study contains the kinetic analyses of silver and vanadium dissolution from the benchmark silver vanadium oxide (SVO) material and two silver vanadium phosphorous oxide (SVPO-H and SVPO-R) materials with differing physical properties in a non-aqueous ICD battery electrolyte. A comparison of the kinetic and mechanistic results for SVO, SVPO-H and SVPO-R provides insight for future material design approaches. PMID- 23925734 TI - Discriminative-stimulus effects of NS9283, a nicotinic alpha4beta2* positive allosteric modulator, in nicotine-discriminating rats. AB - RATIONALE: Neuronal alpha4beta2* nicotinic acetylcholine receptors mediate cognition, pain, and the discriminative and reinforcing effects of nicotine. In addition to traditional orthosteric agonists, alpha4beta2* positive allosteric modulators (PAMs) have recently been identified. With increased subtype selectivity relative to agonists, PAMs administered alone or in combination with low-dose alpha4beta2* agonists may be used as powerful tools for increasing our understanding of alpha4beta2* pharmacology. OBJECTIVES: The present experiments tested the nicotine discriminative-stimulus effects of the alpha4beta2* PAM NS9283 (A-969933) in the presence and absence of low-dose nicotine or nicotinic subtype-selective agonist. METHODS: Rats were trained to discriminate 0.4 mg/kg nicotine from saline in a two-lever drug discrimination paradigm. In subsequent generalization tests, rats were administered nicotine, the alpha4beta2* preferring agonist ABT-594, and NS9283, alone or in two-drug combinations. RESULTS: Nicotine and ABT-594 showed dose-dependent nicotine generalization. NS9283 alone resulted in a non-significant increase in nicotine-appropriate lever selection. Combination of non-effective doses of nicotine or ABT-594 with escalating doses of NS9283 resulted in a complete conversion to 100 % nicotine appropriate choice in the case of nicotine combination and incomplete, though significant, generalization for ABT-594. CONCLUSIONS: The alpha4beta2* PAM NS9283 alone did not produce nicotine-like discriminative effects, but did demonstrate dose-related increases in nicotine lever choice when combined with a non effective dose of nicotine or the alpha4beta2* agonist ABT-594. This finding provides confirmation of the positive allosteric modulating effect of NS9283 in a functional in vivo paradigm. NS9283 is a potentially valuable tool for studying the role of alpha4beta2* receptors in various nicotinic acetylcholine receptor related functions. PMID- 23925735 TI - Giant bullae emphysema. AB - Bullous lung disease, a variant of the emphysematous process, can come in different forms and presentations, both histologically and radiographically. Giant bulla (GB) is the rarest form of bullous lung disease. Onset of disease to duration to symptoms is unclear. Presenting symptoms include cough, chest pain, and progressive dyspnea. Differentiating between other cystic lung diseases or developmental/congenital anomalies is vital. While most patients with bullous lung disease can be managed medically, those with giant bulla should be referred for careful surgical evaluation. The authors describe GB, highlight the role of imaging, and discuss the evaluation and pathophysiology of this rare presentation. PMID- 23925736 TI - Mycophenolate versus cyclophosphamide for progressive interstitial lung disease associated with systemic sclerosis: a 2-year case control study. AB - OBJECTIVE: Cyclophosphamide is considered the treatment of choice for interstitial lung disease (ILD) secondary to systemic sclerosis (SSc), albeit having a minimal effect. Although controlled evidence does not exist, mycophenolate is used increasingly in clinical practice as an alternative. We aimed to compare the long-term efficacy of these drugs. METHODS: Patients from our SSc cohort who received mycophenolate for over 1 year for progressive ILD were 1:1 matched for age, gender, and baseline forced vital capacity (FVC +/-3 %) with cyclophosphamide-treated patients. Changes in FVC, total lung capacity (TLC), diffusion capacity for carbon monoxide (DLCO), and high-resolution computed tomography (HRCT) scans were compared between groups. Changes in pulmonary function tests (PFTs) over at least 1 year in six unmatched control patients, who had denied mycophenolate or cyclophosphamide, also were examined. RESULTS: FVC, TLC, and DLCO did not change significantly in either mycophenolate (from 79.0 +/- 12.5 to 80.2 +/- 8.1 to 81.2 +/- 11.4, from 71.5 +/- 16.1 to 74.3 +/- 10.8 to 71.8 +/- 13.0, from 56.8 +/- 12.0 to 55.2 +/- 9.9 to 50.6 +/- 8.5, respectively) or cyclophosphamide group (from 77.3 +/- 12.5 to 79.7 +/- 10.3 to 82.5 +/- 12.9, from 64.7 +/- 14.9 to 68.6 +/- 16.0 to 66.1 +/- 15.5, from 53.1 +/ 14.3 to 56.4 +/- 13.5 to 56.3 +/- 6.7, respectively), after 1 or 2 years of treatment. PFTs also remained stable in the control group. In either the mycophenolate or cyclophosphamide groups, six patients remained stable, three improved, and one deteriorated according to the definitions of the American Thoracic Society. However, and despite the fact that patients in the cyclophosphamide group had more extended ILD at baseline, a deterioration of lung HRCT findings at 2 years was noticed after mycophenolate (from 10.0 +/- 8.9 to 12.7 +/- 8.2, p = 0.039) but not after cyclophosphamide. CONCLUSIONS: Although these results derive from patients selected for receiving at least 1 year of treatment and therefore they do not represent an intention-to-treat cohort, an eagerness to replace cyclophosphamide by mycophenolate in SSc-associated ILD treatment is not supported. PMID- 23925737 TI - Clinical research fails to support more aggressive management of pediatric upper extremity fractures. AB - BACKGROUND: Recent years have seen a trend toward more operative treatment of upper extremity fractures in children. The current study examines clinical research regarding pediatric upper extremity fracture treatment over the past twenty years in an attempt to identify research-based support for the increasingly aggressive treatment of these fractures. METHODS: Accepted abstracts on pediatric upper extremity fracture treatment presented at the Pediatric Orthopaedic Society of North America (POSNA) and the American Academy of Orthopaedic Surgeons (AAOS) annual meetings from 1993 through 2012 were reviewed. Abstracts were chosen rather than publications because of the larger number of abstracts that are available and because abstracts offer a more global representation of the research being performed by and presented to the members of these societies. The treatment recommendations of authors were classified as more aggressive, less aggressive, or neutral by two attending surgeons on the basis of which treatment was favored in comparative studies or how treatments in single group studies compared with the standard of care at the time. Abstracts without treatment recommendations were excluded. Relationships between level of evidence, fracture location, and treatment recommendation were statistically evaluated with use of Spearman correlations and logistic regression analysis. RESULTS: Overall, a higher proportion of studies gave less aggressive (47%, ninety of 190) or neutral (27%, fifty-one of 190) recommendations than more aggressive treatment recommendations (26%, forty-nine of 190). Only 24% of operative studies and 11% of nonoperative studies recommended more aggressive treatment (p = 0.001). Case series were more likely to recommend more aggressive treatments than comparative studies (30% versus 17%, p = 0.025). Also, studies with a smaller sample size were more likely to recommend more aggressive treatments (p = 0.006). The great majority of level-I and level-II (91%, ten of eleven), level-III (81%, thirty nine of forty-eight), and level-IV (70%, ninety-two of 131) studies, however, provided either neutral or less-aggressive treatment recommendations. CONCLUSIONS: The majority of research presented at POSNA and AAOS meetings over the past two decades fails to support the trend toward increasingly aggressive treatment of pediatric upper extremity fractures. This dichotomy between clinical research and the direction of clinical treatment must be explored in our efforts to provide evidence-based care of pediatric upper extremity fractures. PMID- 23925738 TI - Operative versus nonoperative treatment of displaced intra-articular calcaneal fractures: a prospective, randomized, controlled multicenter trial. AB - BACKGROUND: We conducted a prospective, randomized, controlled multicenter trial to compare operative with nonoperative treatment of displaced intra-articular calcaneal fractures. METHODS: Eighty-two patients who presented to five trauma centers from 1994 to 1998 with an intra-articular calcaneal fracture with >=2 mm of displacement (as verified by computed tomography) were randomized to operative or nonoperative treatment. Independent observers followed the two groups radiographically and clinically at one year and eight to twelve years. The primary outcome measures were a visual analog scale (VAS) for pain and function and the self-administrated Short Form (SF)-36 general health outcome questionnaire. The secondary outcome measures were residual pain evaluated with a VAS, the American Orthopaedic Foot & Ankle Society (AOFAS) scale, and the Olerud Molander (OM) scale. RESULTS: Forty-two patients in the operative treatment group and forty in the nonoperative group were included. The two groups were comparable with respect to age, sex, and fracture types. Seventy-six patients were available for follow-up at one year and fifty-eight at eight to twelve years. The primary and secondary outcome measures did not differ significantly between the two treatment groups at one year of follow-up. At eight to twelve years of follow-up, there was a trend toward better scores on the patient-reported primary VAS score for pain and function (p = 0.07) and the physical component of the SF-36 (p = 0.06) in the operative group. The prevalence of radiographically evident posttraumatic subtalar arthritis was lower in the operative group (risk reduction, 41%). CONCLUSIONS: Operative treatment was not superior in managing displaced intra-articular calcaneal fractures at one year of follow-up but appeared to have some benefits at eight to twelve years. Operative treatment was associated with a higher risk of complications but a reduced prevalence of posttraumatic arthritis evident on follow-up radiographs. LEVEL OF EVIDENCE: Therapeutic level II. See instructions for authors for a complete description of levels of evidence. PMID- 23925739 TI - Long-term results of intralesional curettage and cryosurgery for treatment of low grade chondrosarcoma. AB - BACKGROUND: Data regarding outcomes following intralesional curettage and cryosurgical treatment of low-grade chondrosarcoma of bone are limited. The aim of this study was to assess the long-term oncologic and functional outcomes of two different cryosurgery techniques. METHODS: Forty-three low-grade chondrosarcoma lesions (in forty-two patients) were treated with intralesional curettage and cryosurgery from June 1983 to October 2006. Eleven lesions were treated with cryoprobes and thirty-two were treated with the modified direct-pour Marcove technique. The mean patient age was 44.9 +/- 11.3 years (range, 21.8 to 66.4 years), and the mean duration of follow-up was 10.2 +/- 4.6 years (range, five to 22.5 years). Indications for treatment included a radiographic appearance consistent with a cartilage tumor with evidence of aggressive behavior. Pearson correlation and multivariate analyses were used to evaluate the relationships between predictive factors (including lesion size, soft-tissue extension, and location, patient age, cortical erosion, and presence of preoperative pain) and outcomes. RESULTS: The mean overall Musculoskeletal Tumor Society (MSTS) score was 26.5 +/- 3.1 (range, 17 to 30). There were four local recurrences, all in patients who had had tumor extension out of the bone with soft-tissue involvement at initial presentation. The mean time to recurrence was 2.4 +/- 2.3 years (range, 0.6 to 5.6 years). No patients developed metastatic disease during the follow-up period. There were no differences between the cryoprobe and Marcove techniques with respect to the MSTS score, fracture, or local recurrence. A significant correlation between tumor recurrence and soft-tissue extension was found (r = 0.79). Kaplan-Meier survivorship, with freedom from recurrence as the end point, was 90.7%. CONCLUSIONS: Intralesional curettage and cryosurgery for low-grade chondrosarcoma is safe and effective in selected patients. The presence of preoperative cortical breakthrough and soft-tissue extension was the strongest predictor of local recurrence following use of this technique. LEVEL OF EVIDENCE: Therapeutic level IV. See instructions for authors for a complete description of levels of evidence. PMID- 23925740 TI - Improved fixation in cementless unicompartmental knee replacement: five-year results of a randomized controlled trial. AB - BACKGROUND: When used for appropriate indications, unicompartmental knee replacement is associated with fewer complications, faster recovery, and better function than total knee replacement. However, joint registries demonstrate a higher revision rate for unicompartmental knee replacement. Currently, most unicompartmental knee replacements are cemented; common reasons for revision include aseptic loosening and pain. These problems could potentially be addressed by using cementless implants, with coatings designed to improve fixation. The objectives of this study were to compare the quality of fixation as well as clinical outcomes of cemented and cementless unicompartmental knee replacements at five years of follow-up. METHODS: A randomized controlled trial was established with sixty-three knees (sixty-two patients) receiving either cemented (thirty-two patients) or cementless Oxford unicompartmental knee replacements (thirty patients). Fixation was assessed with fluoroscopic radiographs aligned to the bone-implant interface at one and five years. Outcome scores, including the Oxford Knee Score, Knee Society objective and functional scores, and Tegner Activity Score, were collected preoperatively and at six months and one, two, and five years postoperatively. At each postoperative time point, these were recorded as absolute scores and change from the preoperative score. RESULTS: Four patients died during the study period. There were no revisions. Mean operative time was nine minutes shorter in the cementless group (p = 0.049). At five years, there was no significant difference in any outcome measure except the Knee Society functional score and the change in the Knee Society functional score, which were significantly better in the cementless group (p = 0.003 for both). There were significantly more tibial radiolucencies in the cemented group (twenty of thirty knees versus two of twenty-seven knees; p < 0.001). There were nine complete radiolucencies in the cemented group and none in the cementless group (p = 0.01). CONCLUSIONS: Cementless fixation provides improved fixation at five years compared with cemented fixation in mobile-bearing unicompartmental knee replacements, maintaining equivalent or superior clinical outcomes with a shorter operative time and no increase in complications. LEVEL OF EVIDENCE: Therapeutic level I. See Instructions for authors for a complete description of levels of evidence. PMID- 23925741 TI - Prevention of nerve injury during arthroscopic capsulectomy of the elbow utilizing a safety-driven strategy. AB - BACKGROUND: A major factor limiting the use of elbow arthroscopy for contracture release is concern regarding nerve injury. The purpose of this report is to document the risk of nerve injury in a large series of arthroscopic contracture releases utilizing a safety-driven strategy. METHODS: A series of 502 arthroscopic elbow contracture releases (including 388 osteocapsular arthroplasties) performed in 464 patients by one surgeon was reviewed retrospectively. The safety-driven step-wise strategy had been carried out in a standardized sequence: (1) Get In and Establish a View, (2) Create a Space in Which to Work, (3) Bone Removal, and (4) Capsulectomy. Neurologic complications were assessed and were followed until resolution. RESULTS: No patient had a permanent nerve injury. Twenty-four patients (5%) had a transient nerve injury, associated with prolonged tourniquet time, cutaneous dysesthesia attributed to open incisions, simultaneous ulnar nerve transposition, or retractor use. All nerve deficits resolved after one day to twenty-four months, with one patient lost to follow-up. CONCLUSIONS: Utilizing the technique described, arthroscopic contracture release and debridement of the elbow was performed with a low risk of nerve injury. LEVEL OF EVIDENCE: Therapeutic level III. See instructions for authors for a complete description of levels of evidence. PMID- 23925742 TI - Outcomes of ankle arthroplasty with preoperative coronal-plane varus deformity of 10 degrees or greater. AB - BACKGROUND: Preoperative talar varus deformity increases the technical difficulty of total ankle replacement and is associated with an increased failure rate. Deformity of >20 degrees has been reported to be a contraindication to arthroplasty. We determined whether clinical outcomes of total ankle replacement in patients with ankle arthritis and preoperative talar varus deformity of >=10 degrees were comparable with those of patients with varus deformity of <10 degrees . METHODS: Thirty-six ankles with preoperative coronal-plane tibiotalar varus deformity of >=10 degrees ("varus" group) and thirty-six prospectively matched ankles with varus deformity of <10 degrees ("neutral" group) underwent total ankle replacement. Preoperative and postoperative evaluations included AOFAS (American Orthopaedic Foot & Ankle Society) ankle-hindfoot scores, Ankle Osteoarthritis Scale (AOS) scores, Short Form (SF)-36 scores, and radiographic measurements of coronal-plane deformity. RESULTS: The cohorts were similar with respect to age, sex, operatively treated side, body mass index, and components used, and the mean duration of clinical follow-up was 34.7 months. Eighteen (50%) of the ankles in the varus group had a preoperative varus deformity of >=20 degrees . Patients in the varus group underwent more ancillary procedures during the index surgery to achieve a plantigrade foot. The AOFAS score improved by a mean of 57.2 points in the varus group and 51.5 points in the neutral group. The AOS pain and disability component scores decreased significantly in both groups. The improvement in AOS and SF-36 scores did not differ significantly between the groups at the time of the final follow-up. Tibiotalar deformity improved significantly toward a normal weight-bearing axis in the varus group. Thirteen ankles in the varus group and six in the neutral group underwent additional procedures at a later date. CONCLUSIONS: Satisfactory results can be achieved in patients with varus malalignment of >=10 degrees , which should not be considered a contraindication to total ankle replacement. Complication rates can be reduced by utilizing meticulous surgical technique and taking care to address all causes of the varus deformity, particularly through osteophyte debridement, correction of cavus deformity, and soft-tissue balancing. LEVEL OF EVIDENCE: Prognostic level I. See instructions for authors for a complete description of levels of evidence. PMID- 23925743 TI - The stabilizing mechanism of the Latarjet procedure: a cadaveric study. AB - BACKGROUND: The Latarjet procedure has been used commonly for extra-articular treatment of anterior glenohumeral joint instability. Recently, the technique also has been used as a bone-grafting procedure to repair large glenoid defects. The "sling effect" and the "bone-block effect" have been proposed as the stabilizing mechanisms of this procedure. The aim of this study was to determine the stabilizing mechanisms of this procedure. METHODS: Eight fresh-frozen shoulders were prepared and tested with use of a custom testing machine instrumented with a load cell. With a 50-N axial force applied to the humerus, the humeral head was translated anteriorly. Translational force was measured at both the end-range and the mid-range arm positions, with the capsule intact, after creation of a Bankart lesion, after creation of a large glenoid defect, and after the Latarjet procedure with no load and then three different sets of loads applied to the subscapularis and conjoint tendons. Then, these two tendons were removed to observe the contribution of the sling effect to the stability. Finally, the sutures attaching the coracoacromial ligament to the capsular flap were removed in order to observe the effect of that attachment. RESULTS: The translational force, which decreased significantly after creation of a Bankart lesion or a large glenoid defect, returned to the intact-condition level after the Latarjet procedure was performed. At the end-range arm position, the contribution of the sling effect by the subscapularis and conjoint tendons was 76% to 77% as the load changed, and the remaining 23% to 24% was contributed by the suturing of the capsular flap. At the mid-range position, the contribution of the sling effect was 51% to 62%, and the remaining 38% to 49% was contributed by the reconstruction of the glenoid. CONCLUSIONS: The main stabilizing mechanism of the Latarjet procedure was the sling effect at both the end-range and the mid range arm positions. CLINICAL RELEVANCE: The Latarjet procedure remains an effective procedure for restoring stability to an unstable glenohumeral joint, particularly when there is glenoid bone deficiency. PMID- 23925744 TI - Incidence of displacement after nondisplaced distal radial fractures in adults. AB - BACKGROUND: It is standard practice to closely monitor distal radial fractures treated nonoperatively to ensure that there is no fracture displacement. Patients are often asked to initially return weekly for radiographs. To our knowledge, nondisplaced distal radial fractures in adults have not been specifically evaluated to determine if this level of vigilance is required. If this subset of fractures is unlikely to displace, the cost, radiation exposure, and inconvenience of weekly office visits could be spared. METHODS: Using our billing database, we identified 642 closed distal radial fractures among the patients who presented to our institution during the four-year period from the beginning of 2006 to the end of 2009. Radiographs of the injuries were reviewed to identify fractures for which radiographic measurements were within predefined radiographic norms. Only those fractures that were believed to be nondisplaced by all reviewers were classified as nondisplaced for the purposes of this study. Radiographic measurements were made at the time of injury and at the time of fracture union to evaluate for displacement over time. The total number of clinic visits and radiographs that were received were calculated from the longitudinal medical record for each patient. RESULTS: Eighty-two fractures were identified as nondisplaced. None displaced or required operative intervention. The largest measured difference from injury to fracture union for radial inclination was 3.6 degrees (average 0.8 degrees ); for radial height, 2.1 mm (average 0.5 mm); and for palmar tilt, 3.1 degrees (average 1.0 degrees ). These numbers are all within the error of measurement. CONCLUSIONS: Nondisplaced distal radial fractures in adults appear to be inherently stable, and it may be appropriate to treat this subset of distal radial fractures with cast immobilization (when swelling allows) and a single follow-up visit with radiographs to document union at the time of cast removal. LEVEL OF EVIDENCE: Prognostic level III. See Instructions for authors for a complete description of levels of evidence. PMID- 23925745 TI - Medium to long-term outcome of thoracoscapular arthrodesis with screw fixation for facioscapulohumeral muscular dystrophy. AB - BACKGROUND: Shoulder girdle muscle weakness is the most constant feature of facioscapulohumeral muscular dystrophy and leads to scapular winging. Mechanical fixation of the scapula to the thoracic wall provides a stable fulcrum on which the deltoid muscle can exert its action on the humerus. The aim of this study was to evaluate the medium to long-term outcome of thoracoscapular arthrodesis with screw fixation (the modified Howard-Copeland technique). METHODS: All patients with facioscapulohumeral dystrophy who underwent thoracoscapular arthrodesis with screw fixation and bone-grafting from July 1997 to July 2010 were retrospectively reviewed. Preoperative and postoperative clinical assessment included active shoulder elevation, the Constant score, a patient satisfaction score, and cosmetic satisfaction. Union was determined both clinically and radiographically. RESULTS: Thoracoscapular arthrodesis was performed in thirty-five shoulders in twenty-four patients; eleven patients underwent bilateral procedures. The principal study group consisted of thirty-two shoulders in twenty-one patients with a minimum follow-up of twenty-four months (mean, eighty-eight months; range, twenty-four to 174 months). The mean Constant score increased from 30 (range, 17 to 41) preoperatively to 61 (range, 30 to 90) postoperatively. The mean satisfaction score increased from 1 (range, 0 to 4) to 8.4 (range, 4 to 10). Early complications consisted of one pneumothorax, one superficial wound infection, and four early failures, two of which were associated with noncompliance with the postoperative regimen. Late complications consisted of one posttraumatic fracture resulting in loosening and one painful nonunion; both were treated successfully with revision. CONCLUSIONS: Thoracoscapular arthrodesis with screw fixation prevented scapular winging and improved short-term and long-term shoulder function in patients with facioscapulohumeral dystrophy. LEVEL OF EVIDENCE: Therapeutic level IV. See instructions for authors for a complete description of levels of evidence. PMID- 23925746 TI - Preoperative diagnosis of infection in patients with nonunions. AB - BACKGROUND: The surgical treatment of a fracture nonunion is complicated in the presence of infection. The purpose of the present study is to report on the utility of a standardized protocol to rule out infection in high-risk patients and to evaluate the efficacy of each component of the protocol. METHODS: A single protocol of preoperative laboratory tests (white blood-cell count, C-reactive protein level, and erythrocyte sedimentation rate) and a combined white blood cell/sulfur colloid scan were performed for patients with a high risk of fracture nonunion. Infection was diagnosed on the basis of positive intraoperative cultures, evidence of gross infection at the time of the procedure, or evidence of gross infection during the immediate postoperative period. With use of infection as the end point, univariate analysis and multiple logistic regression analysis were used to compare tests. A risk stratification method was used to combine tests. RESULTS: Ninety-three patients with ninety-five nonunions were evaluated. Thirty of the ninety-five nonunions were ultimately diagnosed as being infected. With use of a combination of elevated white blood-cell count, erythrocyte sedimentation rate, and C-reactive protein level and a positive scan, the predicted probabilities of infection associated with zero, one, two, and three positive tests were 18%, 24%, 50%, and 86%, respectively. With the elimination of the nuclear scan, the predicted probabilities for zero, one, two, and three risk factors were 20%, 19%, 56%, and 100%. CONCLUSIONS: The erythrocyte sedimentation rate and the C-reactive protein level were both independently accurate predictors of infection. Use of a risk stratification method showed that the likelihood of infection increased with each additional positive test. A combined white blood cell/sulfur colloid scan was the least predictive method of revealing infection and is not cost effective, even as part of a stratification scheme. LEVEL OF EVIDENCE: Diagnostic level III. See instructions for authors for a complete description of levels of evidence. PMID- 23925747 TI - Clinical results and functional outcomes of primary and revision spinal deformity surgery in adults. AB - BACKGROUND: Few studies have examined the postsurgical functional outcomes of adults with spinal deformities, and even fewer have focused on the functional results and complications among older adults who have undergone primary or revision surgery for spinal deformity. Our goal was to compare patient characteristics, surgical characteristics, duration of hospitalization, radiographic results, complications, and functional outcomes between adults forty years of age or older who had undergone primary surgery for spinal deformity and those who had undergone revision surgery for spinal deformity. METHODS: We retrospectively reviewed the cases of 167 consecutive patients forty years of age or older who had undergone surgery for spinal deformity performed by the senior author (K.M.K.) from January 2005 through June 2009 and who were followed for a minimum of two years. We divided the patients into two groups: primary surgery (fifty-nine patients) and revision surgery (108 patients). We compared the patient characteristics (number of levels arthrodesed, type of procedure, estimated blood loss, and total operative time), duration of hospitalization, radiographic results (preoperative, six-week postoperative, and most recent follow-up Cobb angle measurements for thoracic and lumbar curves, thoracic kyphosis, and lumbar lordosis), major and minor complications, and functional outcome scores (Scoliosis Research Society-22 Patient Questionnaire and Oswestry Disability Index). RESULTS: The groups were comparable with regard to most parameters. However, the revision group had more patients with sagittal plane imbalance and more frequently required pedicle subtraction osteotomies (p < 0.01). Patients in the primary group required more correction in the coronal plane than did patients in the revision group, whereas patients in the revision group required more correction in the sagittal plane. We found no significant difference between the two groups in the rate of major complications or in the Scoliosis Research Society-22 Patient Questionnaire functional outcome scores. There were significant improvements in many functional outcome scores in both groups between the preoperative and early (six-week) postoperative periods and between the early postoperative period and the time of final follow-up. CONCLUSIONS: Revision surgery for spinal deformity in adults, although technically challenging and considered to present a higher risk than primary surgery, was shown to have a complication rate and outcomes that were comparable with those of primary spinal deformity surgery in adults. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 23925748 TI - Surgical treatment of hip abductor tendon tears. AB - BACKGROUND: Greater trochanteric pain syndrome is a common orthopaedic condition related to underlying bursitis, but it may reflect gluteal tendinopathy with tendon disruption from the greater trochanter. Our goal was to evaluate our clinical experience with surgical repair of these tears. METHODS: We retrospectively evaluated a consecutive series of twenty-two patients (twenty three hips) with a tear of the hip abductor tendons who underwent surgical reconstruction and were followed for a minimum of five years. The preoperative evaluation revealed chronic lateral hip pain, a positive Trendelenburg sign, and a tear documented by magnetic resonance imaging (MRI). The tears were defined intraoperatively with a four-tiered scheme that accounted for the dimension of the tear ranging from partial-thickness undersurface tears to complete tears of the gluteus muscle tendon insertion. RESULTS: The mean Harris hip score improved from 53 points preoperatively to 87 points at one year and 88 points at five years. The mean Lower-Extremity Activity Scale score improved from 6.7 points preoperatively to 8.9 points at one year and 8.8 points at five years. With the numbers available, no significant difference in the degree of clinical improvement was found on the basis of the severity of the tear. However, the three patients with poor results were in the group with the largest tears. Overall, sixteen of nineteen patients were satisfied with their surgical result and were willing to undergo the procedure again if necessary. CONCLUSIONS: Surgical repair of torn abductor tendons of the hip is a viable option when MRI and clinical findings are consistent with tendon disruption and weakness. There was substantial and durable improvement in strength and clinical performance in most cases. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 23925749 TI - Limb-length discrepancy after hip arthroplasty. PMID- 23925750 TI - Classification of postoperative acromial fractures following reverse shoulder arthroplasty. AB - BACKGROUND: Acromial fractures following reverse shoulder arthroplasty are difficult to identify and have variable effects on outcomes. A reproducible classification system is needed to categorize these fractures before it is possible to evaluate optimal treatment. The purposes of this study were to investigate the ability of radiographs to detect acromial fractures and establish fracture union, and to assess the reliability of a new classification system of postoperative acromial fractures based on the involvement of the deltoid origin. METHODS: Eighteen patients presenting with pain along the acromion or scapular spine following reverse shoulder arthroplasty were evaluated for acromial fractures over a period of fifty-six months. If radiographic findings were negative, computed tomography (CT) scans were performed. Sixteen acromial fractures were identified and classified into subtypes on the basis of the deltoid muscle origin: type I indicated involvement of a portion of the anterior and middle deltoid origin; type II, at least the entire middle deltoid origin with a portion but not all of the posterior deltoid origin; and type III, the entire middle and posterior deltoid origin. The average age of the patients at the time of surgery was seventy-seven years (range, fifty-seven to eighty-seven years); the average duration of follow-up after surgery was twenty-five months (range, seven to forty-eight months). All fractures were treated nonoperatively. Blinded, fellowship-trained shoulder surgeons reviewed images that best illustrated the fracture, and the interobserver reliability of the classification system was evaluated. The reliability of radiographs to detect the fracture at the time of the initial presentation of pain and to observe ultimate fracture union was evaluated. RESULTS: Interobserver reliability of the classification system was excellent (interclass correlation coefficient of 0.96). Radiographs were unreliable at detecting acromial fractures at the time of the initial presentation of pain (kappa = -0.5) and at determining fracture union (kappa = 0.05). CONCLUSIONS: Radiographs may be unreliable for detecting acromial fractures after reverse total shoulder arthroplasty, and CT scans are often needed to identify the fracture. Once identified, postoperative acromial fractures can be reliably classified into three subtypes. Nonoperative treatment of postoperative acromial fractures results in limitation of functional outcomes. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 23925751 TI - Clinical presentation of posterolateral rotatory instability of the elbow in children. AB - BACKGROUND: Posterolateral rotatory instability is a type of ulnohumeral instability seen following elbow trauma. It is caused by a deficiency in the lateral collateral ligament complex that allows the radius and ulna to subluxate as a single unit with respect to the distal part of the humerus. There are few studies on this type of instability in children. Our purpose was to evaluate cases of posterolateral rotatory instability in children to better understand its presentation and manifestation as compared with those in adults. METHODS: This was a retrospective chart review of patients from three academic centers. Eligible for inclusion were patients with a diagnosis of posterolateral rotatory instability who were treated with lateral ulnar collateral ligament reconstruction when they were less than nineteen years of age. RESULTS: Nine patients met the inclusion criteria. The mean age at the initial injury was ten years, and the average time from the initial injury to the final operation was 3.7 years. Six patients had prior elbow dislocation, and three had an isolated elbow fracture. Six of the nine patients had a forearm or elbow contracture. Only one patient had a positive pivot-shift test during the preoperative office examination, but all had a positive pivot-shift test when examined under anesthesia. Six had radiographic evidence of posterolateral rotatory instability. All patients underwent lateral ulnar collateral ligament reconstruction. At the time of follow-up, at a minimum of one year after the ligament reconstruction, there was no evidence of deformity secondary to early physeal closure and all elbows remained stable. CONCLUSIONS: Although posterolateral rotatory instability of the elbow is rare, it does exist in children. The instability may not always be recognized because of masking by contracture but, as is the case with adult patients, radiographs may show evidence of the instability. In children with contracture, the clinician should consider the possibility of a masked posterolateral rotatory instability and plan accordingly at the time of contracture release. Surgical correction is technically difficult, and traditional ligament reconstruction in skeletally immature patients may pose a risk to the lateral humeral condylar and epicondylar physes. LEVEL OF EVIDENCE: Therapeutic level IV. See instructions for authors for a complete description of levels of evidence. PMID- 23925752 TI - Occupational injury among orthopaedic surgeons. AB - BACKGROUND: Orthopaedic surgery is a physically demanding profession that requires many hours per week in body positions known to contribute to musculoskeletal injury and pain. Injuries to surgeons can affect the delivery of care and impose costs on the health care system. The aim of this study was to determine the prevalence and types of injuries sustained at the workplace during the career of an orthopaedic surgeon as well as the impact of such injuries on practicing surgeons. METHODS: A survey was developed to assess occupational injury among orthopaedic surgeons. Electronic surveys were distributed via e-mail to all orthopaedic surgeons in Tennessee. Data were analyzed to determine statistical associations of demographic and workplace factors with the rate of injury. RESULTS: One hundred and forty (28%) of 495 surveys were returned, with representation from all orthopaedic subspecialties. Sixty-one (44%) of the respondents reported sustaining one or more injuries at the workplace during their career. A significant association was found between years performing surgery and prevalence of injury (p = 0.03), with surgeons working between twenty one and thirty years reporting the most injuries. Twenty-five percent of respondents reported sustaining an injury to the hand; 19%, to the lower back; 10%, to the neck; 7%, to the shoulder; and 6%, to another area. Fourteen (10%) of all surgeons reported missing work as a result of a workplace injury, with five (4%) missing at least three weeks. Twenty-three surgeons (38% of injured respondents) reported that no institutional resources were available to support their recovery from the injury. CONCLUSIONS: Our study is the first of its kind, to our knowledge, to demonstrate that many orthopaedic surgeons sustain occupational injuries during their careers. The volume of work missed suggests that occupational injury has economic implications for the health-care system and providers. Given the number of injured respondents reporting no institutional support for occupational injuries, more attention should be focused on this issue. PMID- 23925753 TI - Critical analysis of a trauma fellowship-modeled, six-year orthopaedic surgery training program. AB - BACKGROUND: Work-hour restrictions and increased supervision requirements have altered the clinical experience of orthopaedic surgery residents, while the specialty's body of knowledge and requisite skill set continue to expand. This dilemma means that the duration and practice experience of the traditional orthopaedic residency may not meet the needs of today's trainees. For the past eighteen years, however, residency training in the Department of Orthopaedic Surgery at Brown University has included a mandatory postgraduate year six (PGY6) trauma fellowship-modeled year, during which trainees are conferred full staff admitting and operating privileges, with time allotted for completing research. They are supervised by senior attending staff, with increasing autonomy as the year progresses. A formal, critical analysis of this transition-to-practice training model in orthopaedics has not previously been described. METHODS: An anonymous thirty-one-item questionnaire was distributed to all practicing graduates of the six-year Brown University Orthopaedic Surgery training program (n = 69). A 5-point Likert scale was used to assess attitudinal questions. An independent-sample t test was used to compare the responses of pre-duty-hour trainees with those of post-duty-hour trainees, with a p value of <0.05 utilized for significance. RESULTS: All sixty-nine practicing graduates of the Brown University PGY6 trauma fellowship completed the survey (100% response rate). Most graduates (78.2%) would choose to complete the PGY6 year if they had to do residency again, and 72.4% would recommend trauma fellowship-modeled training to residents beginning their training. Trainees who completed residency during or after the imposed 2003 Accreditation Council for Graduate Medical Education duty hour restrictions (79.3%) were significantly more likely (p = 0.014) to rank the PGY6 year as their most valuable training year compared with trainees who completed residency prior to duty-hour restrictions (50.0%). Nearly half of the graduates (46.4%) thought that the PGY6 fellowship year was financially burdensome. CONCLUSIONS: The unique trauma fellowship-modeled sixth year of orthopaedic surgery training at Brown University was thought to be a valuable training experience by a large majority of graduates, although nearly half thought that the year was financially burdensome. These data suggest that a trauma fellowship-based sixth year of independent yet structured training has the potential to enhance orthopaedic education and could become an alternative standard given the current requirements imposed upon surgical residency training. These results may help guide further discussion among orthopaedic training programs to determine the optimal model for orthopaedic residency education in the twenty-first century. PMID- 23925755 TI - Recent increased use of operative treatment for pediatric fractures of the upper extremity is not supported by clinical research-should we be alarmed?: Commentary on an article by Emily A. Eismann, MS, et al.: "Clinical research fails to support more aggressive management of pediatric upper extremity fractures". PMID- 23925754 TI - 2011 AOA Symposium: Tissue Engineering and Tissue Regeneration: AOA critical issues. PMID- 23925756 TI - A calcaneal fracture study illustrates a need for better statistical methods for orthopaedic outcomes: Commentary on an article by Per-Henrik Agren, MD, et al.: "Operative versus nonoperative treatment of displaced intra-articular calcaneal fractures. a prospective, randomized, controlled multicenter trial". PMID- 23925757 TI - If you don't know where you're starting from, you can't get directions: Commentary on an article by Morteza Meftah, MD, et al.: "Long-term results of intralesional curettage and cryosurgery for treatment of low-grade chondrosarcoma". PMID- 23925759 TI - Risk factors for rare diseases can be risky to define: PML and natalizumab. PMID- 23925758 TI - Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. AB - OBJECTIVE: To investigate the relationship between neurovascular coupling and cognitive function in elderly individuals with vascular risk factors and to determine whether neurovascular coupling could be modified by cocoa consumption. METHODS: Sixty older people (aged 72.9 +/- 5.4 years) were studied in a parallel arm, double-blind clinical trial of neurovascular coupling and cognition in response to 24 hours and 30 days of cocoa consumption. Cognitive measures included Mini-Mental State Examination and Trail Making Test A and B. Neurovascular coupling was measured from the beat-to-beat blood flow velocity responses in the middle cerebral arteries to the N-Back Task. In a subset of MRI eligible participants, cerebral white matter structural integrity was also measured. RESULTS: Neurovascular coupling was associated with Trails B scores (p = 0.002) and performance on the 2-Back Task. Higher neurovascular coupling was also associated with significantly higher fractional anisotropy in cerebral white matter hyperintensities (p = 0.02). Finally, 30 days of cocoa consumption was associated with increased neurovascular coupling (5.6% +/- 7.2% vs -2.4% +/- 4.8%; p = 0.001) and improved Trails B times (116 +/- 78 seconds vs 167 +/- 110 seconds; p = 0.007) in those with impaired neurovascular coupling at baseline. CONCLUSION: There is a strong correlation between neurovascular coupling and cognitive function, and both can be improved by regular cocoa consumption in individuals with baseline impairments. Better neurovascular coupling is also associated with greater white matter structural integrity. PMID- 23925760 TI - GABAB receptor autoantibody frequency in service serologic evaluation. AB - OBJECTIVE: Small-cell lung carcinoma (SCLC) and limbic encephalitis are recognized gamma-aminobutyric acid-B receptor (GABABR) autoantibody accompaniments. We sought to determine in a diagnostic serology laboratory the frequency and accompaniments (neurologic, oncologic, and serologic) of GABABR immunoglobulin G (IgG). METHODS: We tested stored serum and CSF specimens from 3 patient groups for GABABR-IgG by indirect immunofluorescence on mouse brain tissue and transfected HEK293 cells. Group 1 included 3,989 patients tested for GABABR-IgG in service evaluation for suspected autoimmune encephalopathy. Group 2 included 49 patients with an unclassified CNS synaptic IgG detected (antedating descriptions of GABABR autoantibody). Group 3 included 384 patients in whom >=1 SCLC-predictive autoantibodies had been detected. RESULTS: GABABR-specific IgG was detected in 17 patients (serum, 14; CSF, 11). N-type calcium channel antibody coexisted with GABABR-IgG in all seropositive patients of groups 1 and 2. In group 1, 7 of 3,989 patients were positive (0.2%). All had limbic encephalitis; 5 had SCLC. Four patients received immunotherapy and improved neurologically. In group 2, 5 of 49 patients were positive (10%). Three had limbic encephalitis, 1 had rapidly progressive encephalomyelopathy, and 1 had cerebellar ataxia. Two patients had SCLC and 1 had multiple myeloma. In group 3, 5 of 384 patients were positive (1.3%); titers were low (detected only by transfected cell assay). The neurologic presentations were diverse and attributable to coexisting T-cell mediated autoimmunity (indicated by CRMP-5 IgG [2], ANNA-1 [2], and ANNA-3 [2]), rather than to GABABR-IgG. CONCLUSION: GABABR autoantibody is a marker of an uncommon but treatable paraneoplastic neurologic disorder, usually occurring in the setting of limbic encephalitis and SCLC. PMID- 23925761 TI - Cocoa, neurovascular coupling, and neurodegeneration: the good, the bad, and the ugly. PMID- 23925762 TI - Immune competence after alemtuzumab treatment of multiple sclerosis. AB - OBJECTIVE: To determine the immunocompetency of patients with multiple sclerosis treated with the lymphodepleting humanized monoclonal antibody alemtuzumab. METHODS: In this pilot case-control study, we assessed immunocompetence in 24 patients after alemtuzumab treatment by measuring antibody responses to 3 vaccines (diphtheria, tetanus, and poliomyelitis vaccine, Haemophilus influenzae type b and meningococcal group C conjugate vaccine, and pneumococcal polysaccharide vaccine). In 20 patients, antibodies to common viruses (mumps, rubella, varicella-zoster, and Epstein-Barr virus) were measured before alemtuzumab treatment, then at 1 and 9-11 months after treatment. Results were compared with well-defined historical controls. RESULTS: Serum antibodies against common viruses remained detectable after treatment, and vaccine responses were normal to T-cell-dependent recall antigens (tetanus, diphtheria, and polio), a T cell-dependent novel antigen (meningococcus C), and T-cell-independent antigens (pneumococcal). There was no evidence for a diminished response to vaccinations in 5 patients studied within 6 months of alemtuzumab treatment. CONCLUSION: In this small historically controlled pilot study, we demonstrated i) retained humoral immunologic memory (in the form of antibodies against common viruses and response to recall antigens), and ii) the retained ability to mount a humoral immune response against a novel antigen after treatment with alemtuzumab. CLASSIFICATION OF EVIDENCE: This pilot study provides Class III evidence that patients with relapsing-remitting multiple sclerosis appear immunocompetent after treatment with alemtuzumab. PMID- 23925763 TI - MRI-identified pathology in adults with new-onset seizures. AB - OBJECTIVE: To determine the frequency and nature of potentially epileptogenic lesions on MRI in adults with new-onset seizures. METHODS: We prospectively studied a consecutive series of 993 patients (597 males [61%]; mean [SD] age: 42.2 [18.8] years, range 14.3-94.3 years) who presented to an adult First Seizure Clinic over a 10-year period. The MRI scans, performed clinically on 3- and 1.5 tesla scanners, were reviewed for their diagnostic yield, nature of abnormalities, and their association with abnormal electrical activity on EEG. RESULTS: MRI scans were acquired in 764 patients (77%); potentially epileptogenic lesions were detected in 177 (23%). The frequency of potentially epileptogenic lesions was higher in patients who were diagnosed as having an epileptic seizure (28%) than in those with a nonepileptic event (8%) (p < 0.001), and highest in those who had focal-onset seizures (53%) (p < 0.001). The most common lesion type in patients with focal seizures was gliosis or encephalomalacia (49%). Other common lesion types were tumors (15%), cavernomas (9%), and mesial temporal sclerosis (9%). Abnormal MRI and EEG were concordant in 18% of patients, with EEG being normal in 55% of patients with epileptogenic lesions. CONCLUSIONS: MRI reveals potentially epileptogenic lesions in a minority of patients with a newly diagnosed seizure disorder. Lesions are most common in patients who have experienced focal seizures. The presence of a potentially epileptogenic MRI lesion did not influence the chance of having an abnormal EEG. PMID- 23925764 TI - Comment: assessing humoral immunocompetence after alemtuzumab treatment in MS. PMID- 23925765 TI - L-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients. AB - OBJECTIVE: To find biomarkers identifying patients at risk for the development of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment. METHODS: Patients were recruited from 10 European and US cohorts. Of 289 patients with multiple sclerosis (MS), 224 had been treated with natalizumab (18-80 months), 21 received other immune-modulatory treatments, and 28 were untreated. We had access to samples from 16 natalizumab PML patients. Eight of these patients had given blood before the diagnosis of PML. We also analyzed non natalizumab-treated patients who developed PML (n = 10) and age- and sex-matched healthy donors (n = 31). All flow cytometric assessments were done on previously cryopreserved, viable peripheral blood mononuclear cells. RESULTS: The percentage of l-selectin-expressing CD4+ T cells was significantly lower in patients treated long-term with natalizumab (40.2%) when compared with patients not receiving natalizumab treatment (47.2%; p = 0.016) or healthy controls (61.0%; p < 0.0001). An unusually low percentage (9-fold lower; 4.6%) was highly correlated with the risk of developing PML in the patient group with available pre-PML samples when compared with non-PML natalizumab-treated patients (p <= 0.0001). Samples were gathered between 4 and 26 months before PML diagnosis. CONCLUSIONS: The cell based assessment of the percentage of l-selectin-expressing CD4 T cells could provide an urgently needed biomarker for individual PML risk assessment. PMID- 23925784 TI - Is tracheostomy still an option in amyotrophic lateral sclerosis? Reflections of a multidisciplinary work group. AB - QUESTION UNDER STUDY: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a poor prognosis. Survival and quality of life of ALS patients have improved through the implementation of multidisciplinary approaches, the use of percutaneous gastrostomy and of noninvasive (NIV) or invasive ventilation. The question of whether or not to propose invasive ventilation (by tracheostomy: TPPV) to ALS patients remains a matter of debate. METHODS: The study reviews the medical literature, the practice in three Swiss and two large French ALS expert centres and reports the results of a workgroup on invasive ventilation in ALS. RESULTS: Improved management of secretions and use of different interfaces allows NIV to be used 24-hours-a-day for prolonged periods, thus avoiding TPPV in many cases. TPPV is frequently initiated in emergency situations with lack of prior informed consent. TPPV appears associated with a lesser quality of life and a higher risk of institutionalisation than NIV. The high burden placed on caregivers who manage ALS patients is a major problem with a clear impact on their quality of life. CONCLUSIONS: Current practice in Switzerland and France tends to discourage the use of TPPV in ALS. Fear of a "locked-in syndrome", the high burden placed on caregivers, and unmasking cognitive disorders occurring in the evolution of ALS are some of the caveats when considering TPPV. Most decisions about TPPV are taken in emergency situations in the absence of advance directives. One exception is that of young motivated patients with predominantly bulbar disease who "fail" NIV. PMID- 23925785 TI - Living with cancer: a qualitative report of the experiences of leukaemia patients in Lagos, Nigeria. AB - The study examined the qualitative, cognitive and psychosocial experiences of those living with leukaemia undergoing treatment at a teaching hospital. Twenty respondents who consented to participate were purposively selected from the cancer patients with leukaemia receiving treatment in the said teaching hospital. The in-depth interview method was used to collect data. The data was analysed using manual content analysis. Data showed that patients lack basic knowledge about leukaemia and had no beliefs regarding leukaemia. Some patients believed in God and a medical breakthrough for a cure, while for some, the hope of living was not certain. The ill-health condition had brought about financial predicament to both patients and family members and has limited their productivity in terms of income-generating activities. Good interpersonal relationships and support from their care providers aided their compliance to treatment regime and provided hope for living positively with their condition. The study concludes that there is a need to educate the patients on the causes of their condition. Financial supports should be rendered to those living with leukaemia, while health care providers should be encouraged to continue to maintain good interpersonal relationships with their patients. PMID- 23925787 TI - Schizophrenia is a cognitive illness: time for a change in focus. AB - Schizophrenia is currently classified as a psychotic disorder. This article posits that this emphasis on psychosis is a conceptual fallacy that has greatly contributed to the lack of progress in our understanding of this illness and hence has hampered the development of adequate treatments. Not only have cognitive and intellectual underperformance consistently been shown to be risk factors for schizophrenia, several studies have found that a decline in cognitive functioning precedes the onset of psychosis by almost a decade. Although the question of whether cognitive function continues to decline after psychosis onset is still debated, it is clear that cognitive function in schizophrenia is related to outcome and little influenced by antipsychotic treatment. Thus, our focus on defining (and preventing) the disorder on the basis of psychotic symptoms may be too narrow. Not only should cognition be recognized as the core component of the disorder, our diagnostic efforts should emphasize the changes in cognitive function that occur earlier in development. Putting the focus back on cognition may facilitate finding treatments for the illness before psychosis ever emerges. PMID- 23925786 TI - Impact of eating probiotic yogurt on colonization by Candida species of the oral and vaginal mucosa in HIV-infected and HIV-uninfected women. AB - BACKGROUND: Candidiasis in HIV/AIDS patients continues to be a public health problem. Antifungal therapies are not always effective and may result in complications, such as the development of drug-resistant strains of Candida species. OBJECTIVES: This study evaluated the impact of probiotic consumption on Candida colonization of the oral and vaginal mucosa. PATIENTS/METHODS: A pilot study was conducted in 24 women (17 HIV-infected, 7 HIV-uninfected) from the Women's Interagency HIV Study. The women underwent a 60-day initiation period with no probiotic consumption, followed by two 15-day consumption periods, with a different probiotic yogurt (DanActiveTM or YoPlusTM yogurt) during each interval. There was a 30-day washout period between the two yogurt consumption periods. Oral and vaginal culture swabs were collected on days 0, 60, 74, and 120. Candida was detected by inoculating each swab in both Sabouraud's dextrose agar with or without chloramphenicol and CHROMagar. RESULTS: Less fungal colonization among women was observed when the women consumed probiotic yogurts (54 % of the women had vaginal fungal colonization during the non-probiotic yogurt consumption period, 29 % during the DanActiveTM period, and 38 % during YoPlusTM yogurt consumption period), and HIV-infected women had significantly lower vaginal fungal colonization after they consumed DanActiveTM yogurt compared to the non intervention periods (54 vs 29 %, p = 0.03). CONCLUSIONS: These data are promising, but as expected in a small pilot study, there were some significant changes but also some areas where colonization was not changed. This type of conflicting data is supportive of the need for a larger trial to further elucidate the role of probiotic yogurts in fungal growth in HIV-infected women. PMID- 23925788 TI - Mitochondrial genome rearrangements in glomus species triggered by homologous recombination between distinct mtDNA haplotypes. AB - Comparative mitochondrial genomics of arbuscular mycorrhizal fungi (AMF) provide new avenues to overcome long-lasting obstacles that have hampered studies aimed at understanding the community structure, diversity, and evolution of these multinucleated and genetically polymorphic organisms.AMF mitochondrial (mt) genomes are homogeneous within isolates, and their intergenic regions harbor numerous mobile elements that have rapidly diverged, including homing endonuclease genes, small inverted repeats, and plasmid-related DNA polymerase genes (dpo), making them suitable targets for the development of reliable strain specific markers. However, these elements may also lead to genome rearrangements through homologous recombination, although this has never previously been reported in this group of obligate symbiotic fungi. To investigate whether such rearrangements are present and caused by mobile elements in AMF, the mitochondrial genomes from two Glomeraceae members (i.e., Glomus cerebriforme and Glomus sp.) with substantial mtDNA synteny divergence,were sequenced and compared with available glomeromycotan mitochondrial genomes. We used an extensive nucleotide/protein similarity network-based approach to investigated podiversity in AMF as well as in other organisms for which sequences are publicly available. We provide strong evidence of dpo-induced inter-haplotype recombination, leading to a reshuffled mitochondrial genome in Glomus sp. These findings raise questions as to whether AMF single spore cultivations artificially underestimate mtDNA genetic diversity.We assessed potential dpo dispersal mechanisms in AMF and inferred a robust phylogenetic relationship with plant mitochondrial plasmids. Along with other indirect evidence, our analyses indicate that members of the Glomeromycota phylum are potential donors of mitochondrial plasmids to plants. PMID- 23925790 TI - Perioperative laboratory assessment of diabetic foot infections undergoing amputation: a systematic review. AB - Diabetes is the leading cause of nontraumatic amputations. Although laboratory assessment may not alone determine the optimal level of amputation thorough assessment of a variety of laboratory values is critical to overall care of the patient and may place the patient into risk category. This systematic review analyzes publications related to diabetic lower extremity amputations and associated laboratory values, including lymphocyte count, albumin, hemoglobin, and glycemic control. PMID- 23925789 TI - Transcriptome sequencing reveals the character of incomplete dosage compensation across multiple tissues in flycatchers. AB - Sex chromosome divergence, which follows the cessation of recombination and degeneration of the sex-limited chromosome, can cause a reduction in expression level for sex-linked genes in the heterozygous sex, unless some mechanisms of dosage compensation develops to counter the reduction in gene dose. Because large scale perturbations in expression levels arising from changes in gene dose might have strong deleterious effects, the evolutionary response should be strong. However, in birds and in at least some other female heterogametic organisms, wholesale sex chromosome dosage compensation does not seem to occur. Using RNA seq of multiple tissues and individuals, we investigated male and female expression levels of Z-linked and autosomal genes in the collared flycatcher, a bird for which a draft genome sequence recently has been reported. We found that male expression of Z-linked genes was on average 50% higher than female expression, although there was considerable variation in the male-to-female ratio among genes. The ratio for individual genes was well correlated among tissues and there was also a correlation in the extent of compensation between flycatcher and chicken orthologs. The relative excess of male expression was positively correlated with expression breadth, expression level, and number of interacting proteins (protein connectivity), and negatively correlated with variance in expression. These observations lead to a model of compensation occurring on a gene-by-gene basis, supported by an absence of clustering of genes on the Z chromosome with respect to the extent of compensation. Equal mean expression level of autosomal and Z-linked genes in males, and 50% higher expression of autosomal than Z-linked genes in females, is compatible with that partial compensation is achieved by hypertranscription from females' single Z chromosome. A comparison with male-to-female expression ratios in orthologous Z-linked genes of ostriches, where Z-W recombination still occurs, suggests that male-biased expression of Z-linked genes is a derived trait after avian sex chromosome divergence. PMID- 23925791 TI - Anatomical reconstruction of the spring ligament complex: "internal brace" augmentation. AB - The calcaneonavicular (spring) ligament complex is a critical static support of the medial arch of the foot. Compromise of this structure has been implicated as a primary causative factor of talar derotation leading to the clinical deformity of peritalar subluxation. Few procedures have been described to address this deficiency. The technique we describe here is a simple yet effective method to reconstruct the spring ligament complex that can easily be used in conjunction with other more commonly used procedures for extra-articular reconstructions of this deformity. We believe this procedure allows for a more powerful deformity correction and may decrease dependency on other nonanatomic reconstructive procedures. PMID- 23925792 TI - New interatomic potential parameters for molecular dynamics simulations of rare earth (RE = La, Y, Lu, Sc) aluminosilicate glass structures: exploration of RE3+ field-strength effects. AB - Sets of self-consistent oxygen-rare earth (RE = La, Y, Lu, Sc) interatomic potential parameters are derived using a force-matching procedure and utilized in molecular dynamics (MD) simulations for exploring the structures of RE2O3-Al2O3 SiO2 glasses that feature a fixed molar ratio n(Al)/n(Si) = 1 but variable RE contents. The structures of RE aluminosilicate (AS) glasses depend markedly on the RE(3+) cation field strength (CFS) over both short and intermediate length scales. We explore these dependencies for glasses incorporating the cations La(3+), Y(3+), Lu(3+) and Sc(3+), whose CFSs increase due to the concomitant shrinkage of the ionic radii: R(La) > R(Y) > R(Lu) > R(Sc). This trend is mirrored in decreasing average RE(3+) coordination numbers (Z(RE)) from Z(La) = 6.4 to Z(Sc) = 5.4 in the MD-derived data. However, overall the effects from RE(3+) CFS elevations on the local glass structures are most pronounced in the O and {Al([4]), Al([5]), Al([6])} speciations. The former display minor but growing populations of O([0]) ("free oxygen ion") and O([3]) ("oxygen tricluster") moieties. The abundance of AlO5 polyhedra increases significantly from ~10% in La based glasses to ~30% in their Sc counterparts at the expense of the overall dominating AlO4 tetrahedra, whereas the amounts of AlO6 groups remain <5% throughout. We also discuss the Si([4])/Al([p]) (p = 4, 5, 6) intermixing and the nature of their oxygen bridges, where the degree of edge-sharing increases together with the RE(3+) CFS. PMID- 23925794 TI - Direct enrichment of perchlorate-reducing microbial community for efficient electroactive perchlorate reduction in biocathodes. AB - Biological reduction of perchlorate (ClO4-) has emerged as a promising solution for the removal of perchlorate in contaminated water and soils. In this work, we demonstrate a simple process to enrich perchlorate-reducing microbial communities separately using acetate as electron donor and the municipal aerobic membrane bioreactor sludge as inoculum. Inoculation of cathodes in microbial fuel cells (MFCs) with these enrichments, and further electrochemical enrichment at constant resistance operation of the MFCs, led to perchlorate-reducing biocathodes with peak reduction rates of 0.095 mM/day (2 mg/m2/day). Analysis of the microbial diversity of perchlorate-reducing biocathodes using PCR-DGGE revealed unique community profiles when compared to the denitrifying biocathode communities. More importantly, the total time taken for enrichment of the electroactive communities was reduced from several months reported previously in literature to less than a month in this work. PMID- 23925793 TI - Pediatric lymphoma diagnosis: role of FNAC, biopsy, immunohistochemistry and molecular diagnostics. AB - Peripheral lymphadenopathy in the pediatric age group is screened using fine needle aspiration cytology (FNAC). Cases found to have features suspicious for lymphoma on FNAC need to undergo biopsy with immunohistochemistry for characterization and typing. In pediatric age group, peripheral lymph nodes are common in Hodgkin's lymphoma for which biopsy is needed for subtyping. Distinction of classical Hodgkin's lymphoma of lymphocyte rich type from nodular lymphocyte predominant Hodgkin's lymphoma needs biopsy evaluation and a panel of immunostains. T lymphoblastic lymphomas and Burkitt's lymphoma are the common types of non Hodgkin's lymphoma seen in the pediatric age group. All lymphomas require a biopsy evaluation with immunohistochemistry and analysis of molecular genetic markers for proper characterization and selection of optimal treatment which are discussed in detail in this review. PMID- 23925795 TI - In situ alcoholysis of triacylglycerols by application of switchable-polarity solvents. A new derivatization procedure for the gas-chromatographic analysis of vegetable oils. AB - We describe a new use of switchable-polarity solvents for the simultaneous derivatization and extraction of triacylglycerols from vegetable oils before gas chromatographic analysis. Different equimolecular mixtures of the commercially available amidine 1,8-diazabicyclo[5.4.0]undec-7-ene and n-alkyl alcohols were tested. Triolein was used as a model compound. Very good results were achieved by using butanol (recovery of butyl oleate was 89 +/- 4%). The procedure was applied for the characterization of the fatty acid profile of different vegetable oils. No statistically significant differences from the results obtained with the application of two traditional methods were evidenced. Moreover, the use of switchable-polarity solvents showed many advantages: owing to the basicity of the amidines, no catalyst was required; the transterification reaction was conducted under mild conditions, one step and in situ; no particular matrix interferences were evidenced; the solvent was recovered. PMID- 23925796 TI - Targeting prohibited substances in doping control blood samples by means of chromatographic-mass spectrometric methods. AB - Urine samples have been the predominant matrix for doping controls for several decades. However, owing to the complementary information provided by blood (as well as serum or plasma and dried blood spots (DBS)), the benefits of its analysis have resulted in continuously increasing appreciation by anti-doping authorities. On the one hand, blood samples allow for the detection of various different methods of blood doping and the abuse of erythropoiesis-stimulating agents (ESAs) via the Athlete Biological Passport; on the other hand, targeted and non-targeted drug detection by means of chromatographic-mass spectrometric methods represents an important tool to increase doping control frequencies out of-competition and to determine drug concentrations particularly in in competition scenarios. Moreover, blood analysis seldom requires in-depth knowledge of drug metabolism, and the intact substance rather than potentially unknown or assumed metabolic products can be targeted. In this review, the recent developments in human sports drug testing concerning mass spectrometry-based techniques for qualitative and quantitative analyses of therapeutics and emerging drug candidates are summarized and reviewed. The analytical methods include both low and high molecular mass compounds (e.g., anabolic agents, stimulants, metabolic modulators, peptide hormones, and small interfering RNA (siRNA)) determined from serum, plasma, and DBS using state-of-the-art instrumentation such as liquid chromatography (LC)-high resolution/high accuracy (tandem) mass spectrometry (LC-HRMS), LC-low resolution tandem mass spectrometry (LC-MS/MS), and gas chromatography-mass spectrometry (GC-MS). PMID- 23925797 TI - Improving the performance of hollow waveguide-based infrared gas sensors via tailored chemometrics. AB - The use of chemometrics in order to improve the molecular selectivity of infrared (IR) spectra has been evaluated using classic least squares (CLS), partial least squares (PLS), science-based calibration (SBC), and multivariate curve resolution alternate least squares (MCR-ALS) techniques for improving the discriminatory and quantitative performance of infrared hollow waveguide gas sensors. Spectra of mixtures of isobutylene, methane, carbon dioxide, butane, and cyclopropane were recorded, analyzed, and validated for optimizing the prediction of associated concentrations. PLS, CLS, and SBC provided equivalent results in the absence of interferences. After addition of the spectral characteristics of water by humidifying the sample mixtures, CLS and SBC results were similar to those obtained by PLS only if the water spectrum was included in the calibration model. In the presence of an unknown interferant, CLS revealed errors up to six times higher than those obtained by PLS. However, SBC provided similar results compared to PLS by adding a measured noise matrix to the model. Using MCR-ALS provided an excellent estimation of the spectra of the unknown interference. Furthermore, this method also provided a qualitative and quantitative estimation of the components of an unknown set of samples. In summary, using the most suitable chemometrics approach could improve the selectivity and quality of the calibration model derived for a sensor system, and may avoid the need to analyze expensive calibration data sets. The results obtained in the present study demonstrated that (1) if all sample components of the system are known, CLS provides a sufficiently accurate solution; (2) the selection between PLS and SBC methods depends on whether it is easier to measure a calibration data set or a noise matrix; and (3) MCR-ALS appears to be the most suitable method for detecting interferences within a sample. However, the latter approach requires the most extensive calculations and may thus result in limited temporal resolution, if the concentration of a component should be continuously monitored. PMID- 23925798 TI - Research on the separation properties of empty-column gas chromatography (EC-GC) and conditions for simulated distillation (SIMDIS). AB - Previous studies have revealed it is possible to separate a high-boiling mixture by gas chromatography in empty fused-silica capillary tubing rather than in columns coated with stationary phase. Chromatographic separation occurs solely on the basis of the different boiling points of the substances separated. The high similarity of such separations to those in classic distillation seems advantageous when gas chromatography is used for simulated distillation. This paper presents results from further research on the separation properties of empty fused silica tubing. The efficiency of this chromatographic system has been examined. The usefulness of such conditions has been studied for simulated distillation, i.e. to determine the boiling-point distribution of complex mixtures, mainly petroleum fractions and products, on the basis of their retention relative to reference substances. The results obtained by use of empty column gas chromatography (EC-GC) and by use of classical simulated distillation columns have been compared for solutes of different polarity. Studies revealed boiling points determined by EC-GC were more accurate than those obtained by the standard method of simulated distillation. PMID- 23925799 TI - Total synchronous fluorescence spectroscopic data modeled with first- and second order algorithms for the determination of doxorubicin in human plasma. AB - In this work, we present the development of a method for the determination of doxorubicin in plasma samples in the presence of an unexpected component (riboflavin) by using total synchronous fluorescence spectroscopic data matrices. To the best of our knowledge, this is the first time that the second-order advantage is obtained with this kind of data. Two strategies including unfolding the data and: (a) processing with multivariate curve resolution coupled to alternating least-squares as first-order data or (b) processing with unfolded partial least-squares and exploiting the second-order advantage by the residual bilinearization procedure were considered. The calibration set was built with human plasma samples spiked with doxorubicin, while the validation set was prepared with human plasma samples spiked with both doxorubicin and riboflavin, a drug whose spectrum highly overlaps with the one corresponding to doxorubicin. Both methodologies reached good indicators of accuracy: recoveries of ca. 100 +/- 8% and REP of ca. 5%; and precision: coefficient of variations between 7 and 9%. PMID- 23925800 TI - Electrokinetic characterization of superparamagnetic nanoparticle-aptamer conjugates: design of new highly specific probes for miniaturized molecular diagnostics. AB - With the view of designing new nanoparticle (NP)-aptamer conjugates and proving their suitability as biorecognition tools for miniaturized molecular diagnostics, new maghemite-silica core-shell NP-aptamer conjugates were characterized for the first time in terms of grafting rate and colloidal stability under electrophoretic conditions using capillary electrophoresis. After the grafting rate (on the order of six to 50) of the lysozyme-binding aptamer had been estimated, the electrophoretic stability and peak dispersion of the resulting oligonucleotide-NP conjugates were estimated so as to determine the optimal separation conditions in terms of buffer pH, ionic strength and nature, as well as temperature and electric field strength. The effective surface charge density of the NPs was close to zero for pH lower than 5, which led to some aggregation. The NPs were stable in the pH range from 5 to 9, and an increase in electrophoretic mobility was evidenced with increasing pH. Colloidal stability was preserved at physiological pH for both non-grafted NPs and grafted NPs in the 10-100 mM ionic strength range and in the 15-60 degrees C temperature range. A strong influence of the nature of the buffer counterion on NP electrophoretic mobility and peak dispersion was evidenced, thus indicating some interactions between buffer components and NP-aptamer conjugates. Whereas an electric field effect (50-900 V cm(-1)) on NP electrophoretic mobility was evidenced, probably linked to counterion dissociation, temperature seems to have an appreciable effect on the zeta potential and aptamer configuration as well. This information is crucial for estimating the potentialities of such biorecognition tools in electrophoretic systems. PMID- 23925801 TI - Fabrication of thermally stable and active bimetallic Au-Ag nanoparticles stabilized on inner wall of mesoporous silica shell. AB - A general method has been developed for the fabrication of highly dispersed and thermally stable bimetallic Au-Ag nanoparticles (NPs) stabilized on the inner wall of a mesoporous silica shell. In our approach, gold particles were formed in the first step on carbon spheres decorated with Sn(2+) cations. Upon Ag(+) adsorption and reduction by l-ascorbic acid in the second step, specific nanoparticles with a gold-silver alloy core and a silver nanoshell have been formed. Important evidence of the core-shell configurations of the bimetallic Au Ag nanoparticles were clearly characterized by UV-vis, TEM and HAADF-STEM observations combined with elemental mapping and line scans. The mesoporous silica outer shell was obtained through the hydrolysis and condensation of the precursors tetraethoxysilane (TEOS) in a basic condition and cetyltrimethylammonium bromide (CTAB) as a structure-directing agent. On this basis, the nanoreactors were fabricated after calcination, which further serves as a nanoreactor for the reduction of p-nitrophenol. Furthermore, such particles have been found to be thermally stable and their sizes remain substantially unchanged even upon calcination in air at 500 degrees C and a reduction treatment in H2. Potentially, the method can be developed into a general approach to synthesize other highly dispersed and thermally stable bimetallic nanoparticles stabilized on the inner wall of a mesoporous silica shell. PMID- 23925802 TI - Capsule commentary on Joynt et al., The impact of neighborhood socioeconomic status and race on the prescribing of opioids in emergency departments throughout the United States. PMID- 23925803 TI - Effects of yoga exercise on salivary beta-defensin 2. AB - PURPOSE: Yoga stretching can be done comfortably and easily by beginners and older adults to compensate for lack of exercise or poor health maintenance. The aim of this study was to determine the effect of yoga stretching on mucosal immune functions, primarily human beta-defensin 2 (HBD-2) in saliva. METHODS: Fifteen healthy adults (age, 60.4 +/- 8.0 years) participated in the study. Participants rested for 90 min on the first day and performed yoga for 90 min on the second day. Measurements were carried out before and after rest or yoga. Saliva samples were collected by chewing a sterile cotton at a frequency of 60 cycles per min. Salivary HBD-2 concentration was measured using an enzyme-linked immunosorbent assay. RESULTS: HBD-2 concentration after yoga stretching (165.4 +/ 127.1 pg/mL) was significantly higher than that before yoga stretching (84.1 +/- 63.4 pg/mL; p < 0.01). HBD-2 expression rate after yoga stretching (232.8 +/- 192.9 pg/min) was significantly higher than that before yoga stretching (110.7 +/ 96.8 pg/min; p < 0.01). HBD-2 concentration (p < 0.05) and HBD-2 expression rate (p < 0.01) at post on the second day (yoga) was significantly higher than that on the first day (rest). POMS score of anger-hostility was lower after yoga than before. CONCLUSIONS: Yoga stretching for 90 min can increase salivary HBD-2 expression in older adults. Therefore, yoga stretching might be useful for older adults and athletes to maintain their health. PMID- 23925816 TI - An unusual cause of cholestatic hepatitis: syphilis. PMID- 23925817 TI - MicroRNA expression differentiates squamous epithelium from Barrett's esophagus and esophageal cancer. AB - BACKGROUND: Current strategies fail to identify most patients with esophageal adenocarcinoma (EAC) before the disease becomes advanced and incurable. Given the dismal prognosis associated with EAC, improvements in detection of early-stage esophageal neoplasia are needed. AIM: We sought to assess whether differential expression of microRNAs could discriminate between squamous epithelium, Barrett's esophagus (BE), and EAC. METHODS: We analyzed microRNA expression in a discovery cohort of human endoscopic biopsy samples from 36 patients representing normal squamous esophagus (n = 11), BE (n = 14), and high-grade dysplasia/EAC (n = 11). RNA was assessed using microarrays representing 847 human microRNAs followed by quantitative real-time polymerase chain reaction (qRT-PCR) verification of nine microRNAs. In a second cohort (n = 18), qRT-PCR validation of five miRNAs was performed. Expression of 59 microRNAs associated with BE/EAC in the literature was assessed in our training cohort. Known esophageal cell lines were used to compare miRNA expression to tissue miRNAs. RESULTS: After controlling for multiple comparisons, we found 34 miRNAs differentially expressed between squamous esophagus and BE/EAC by microarray analysis. However, miRNA expression did not reliably differentiate non-dysplastic BE from EAC. In the validation cohort, all five microRNAs selected for qRT-PCR validation differentiated between squamous samples and BE/EAC. Microarray results supported 14 of the previously reported microRNAs associated with BE/EAC in the literature. Cell lines did not generally reflect miRNA expression found in vivo. CONCLUSIONS: These data indicate that miRNAs differ between squamous esophageal epithelium and BE/EAC, but do not distinguish between BE and EAC. We suggest prospective evaluation of miRNAs in patients at high risk for EAC. PMID- 23925818 TI - The effect of melatonin on plasma markers of inflammation and on expression of nuclear factor-kappa beta in acetic acid-induced colitis in the rat. AB - BACKGROUND AND AIMS: Melatonin may be involved in gastrointestinal tract physiology and could affect inflammation-related gastrointestinal disorders. Rat models of ulcerative colitis imply melatonin is beneficial. To determine potential pathophysiological mechanisms, we assessed colonic nuclear factor-kappa beta expression and measured serum levels of pentraxin-3, lipid peroxides, and total thiols in an acetic acid model of this disease. MATERIALS AND METHODS: Thirty rats were divided into five groups: a control group, an acetic acid induced colitis group, a group treated with melatonin before colitis induction, a group treated short-term after colitis induction, and a group treated long-term after colitis induction. After four weeks, blood samples were taken for measurement of pentraxin-3, lipid peroxide, and total thiols. Sections of the colon were taken for histopathological examination and immunohistochemical detection of nuclear factor-kappa beta expression. RESULTS: Melatonin administration reduced nuclear factor-kappa beta immunohistochemical expression, reduced serum levels of lipid peroxide and pentraxin-3, and maintained serum levels of total thiols. However, in long-term treatment the protective effect of melatonin was not as marked. CONCLUSION: Melatonin is effective in prevention and short-term treatment of the inflammatory process in acetic-acid induced colitis whereas the benefit of long-term treatment is unclear. Benefit may be linked to protection mechanisms against inflammatory processes by inhibiting the nuclear factor-kappa beta and conserving endogenous antioxidant reserves of total thiols, thus reducing the level of colonic damage possibly caused by lipid peroxides. PMID- 23925819 TI - Polypharmacy and comorbidity are associated with a lower early virologic response in hepatitis C patients treated with first generation protease inhibitor triple therapy: a preliminary analysis. AB - BACKGROUND AND AIMS: The protease inhibitors (PIs) boceprevir and telaprevir are currently standard treatment as part of triple therapy regimens (TTx) for chronic HCV genotype 1 (GT1) patients. In this preliminary analysis, we have compared demographic variables, polypharmacy, and Charlson's comorbid index (CCI) with Rapid Virological Response (RVR) and extended RVR (eRVR) rates in HCV GT1 patients receiving PI containing TTx. METHODS: Retrospective descriptive cohort study. RESULTS: Among 74 HCV patients (46 M, 28 F; age: 54.43 +/- 9.52 years; African Americans: 59.5 %) in this initial analysis, 44 % achieved RVR. All these RVR patients also achieved eRVR. Patients achieving RVR and eRVR were 50 +/- 11.7 (mean +/- SD) years old, compared to 58 +/- 5.2 years without an RVR (p < 0.005). The average number of medications taken by patients achieving RVR and eRVR was 5 +/- 2.7 compared to 9.24 +/- 3.4 in patients not achieving RVR and eRVR (p < 0.005). Twenty-five percent of patients who were not on CYP3A4 inhibitors had an RVR and eRVR compared to 63.2 % who were taking CYP3A4 inhibitors (p = 0.001). Patients achieving RVR and eRVR had a lower CCI (1.61 +/- 1.37) compared to those not achieving RVR and eRVR (2.8 +/- 2.7; p = 0.02). Multivariate analysis also revealed a significant correlation between increased polypharmacy and CCI with lower RVR and eRVR rates. CONCLUSIONS: These preliminary treatment data demonstrate that increased polypharmacy and higher degrees of comorbidity decrease RVR and eRVR rates among patients receiving first generation PI containing TTx regimens. PMID- 23925820 TI - Can serum fetuin-A be regarded as an inflammatory marker among patients with familial Mediterranean fever? AB - BACKGROUND/AIM: Familial Mediterranean fever (FMF), the most frequent periodic fever syndrome, is an autosomal recessive inherited disease that predominantly affects eastern Mediterranean populations. Fetuin-A is a well known negative acute-phase protein. Studies of this glycoprotein as a marker of inflammation in FMF are limited. We have investigated the relationship between serum levels of fetuin-A and inflammatory markers in patients with FMF before, during, and after FMF attacks. METHODS: Sixty-seven patients with FMF were enrolled in this study. Serum fetuin-A, seruloplasmin, fibrinogen, C reactive protein (CRP), white blood cell count (WBC), calcium, and erythrocyte sedimentation rate (ESR) were measured three times: during the attack-free period, 12 h after FMF attacks, and 7 days after FMF attacks. Plasma fetuin-A concentration was measured by use of an enzyme linked immunoassay (ELISA) kit. Correlations and differentiation between the serum fetuin-A and other inflammatory markers in patients with FMF were investigated by use of the paired-samples T test and the Pearson correlation test (p < 0.01). RESULTS: Serum fetuin-A levels of all FMF patients in the attack period were significantly lower than in the attack-free period (p < 0.001). In contrast, serum seruloplasmin (p < 0.05), fibrinogen (p < 0.001), CRP (p < 0.05), WBC (p < 0.05), and ESR (p < 0.05) were all significantly higher than in the attack-free period. Plasma fetuin-A is significantly and inversely highly correlated with the other inflammatory markers. CONCLUSION: Fetuin-A might be a novel indicator of disease activity in patients with FMF and could be used as an adjunctive marker for differentiation of FMF attacks. The negative correlation between serum fetuin-A and other inflammatory markers may also be indicative of inflammation-dependent downregulation of fetuin-A expression in FMF patients. PMID- 23925821 TI - Chronic pouchitis versus recurrent Crohn's disease: a diagnostic challenge. PMID- 23925822 TI - Is it time to take a pass on the increased number of passes in EUS-FNA? PMID- 23925823 TI - Self-dilation as a treatment for resistant, benign esophageal strictures. AB - GOALS AND BACKGROUND: Simple benign strictures may be relieved with one to three dilation sessions. Resistant benign strictures are anatomically complex and resistant to therapy. We sought to determine the efficacy and safety of esophageal self-dilation with bougie dilators in the largest series to date. STUDY: A retrospective chart review was performed to identify patients who underwent esophageal self-dilation at two tertiary referral centers (Mayo Clinic, Scottsdale, Arizona and Mayo Clinic Rochester, Minnesota) between January 1, 2003 and June 30, 2012. Demographic details and clinical information regarding relief of dysphagia, complications, and frequency of endoscopic and self-dilation were abstracted. RESULTS: Of the 32 patients who began self-dilation for nonmalignant strictures, 30 [22 men; median (range) age, 62 years (22-86 years)] were included in the study. Median (range) follow-up was 37 months (14-281 months). Stricture etiology included radiation therapy (n = 8), anastomotic stricture (n = 9), eosinophilic esophagitis (n = 4), caustic ingestion (n = 3), photodynamic therapy (n = 2), granulation tissue (n = 2), peptic stricture (n = 1) and one patient had radiation therapy and peptic stricture. The average number (range) of physician performed dilations before self-dilation was 12 (4-55). Esophageal self-dilation was successful in treating 90 % of patients. Dysphagia score (2 vs. 1; P < 0.001), stricture diameter (median; 5 vs. 12 mm; P < 0.001) and weight (median; 73 vs. 77 kg; P < 0.001) were significantly different between EDG dilation versus self-dilation. CONCLUSIONS: Esophageal self-dilation is a safe, effective treatment for resistant, benign esophageal strictures. This management strategy should be strongly considered in this patient population. PMID- 23925824 TI - Determinants of inpatient rehabilitation length of stay and discharge modality after hip and knee replacement surgery in Switzerland - a retrospective observational study. AB - QUESTIONS UNDER STUDY / PRINCIPLES: The aims of this study were to identify the determinants influencing the inpatient rehabilitation length of stay (LoS) and discharge modality (DisMod) after hip or knee replacement surgery. METHODS: Data were retrieved for 306 patients (185 females, 121 males) who were admitted to a Swiss orthopaedic rehabilitation facility between 2007 and 2008 after hip or knee replacement surgery. LoS and DisMod were extracted from the medical files along with an additional seven binary and six continuous variables (including scores of timed-get-up-and-go [TUG], walking distance [WDT] and stair climbing tests [FIM_St]). Nonparametric procedures were used to detect differences between the gender groups. For the analysis of the LoS determinants, a linear regression model was used. The nonmotor performance test determinants of DisMod were analysed using a logistic regression model, whereas the motor performance test determinants were examined using binary classification. For both regression models, a backward procedure was used. RESULTS: Unlike DisMod, LoS calculations were conducted after stratification for gender. The simplified regression models explained 22% (females) and 31% (males) of the LoS variance and 20% (both genders) of the DisMod variance. TUG, WDT and FIM_St were all important predictors for LoS, whereas DisMod could be best predicted by WDT. CONCLUSIONS: Patients with good motor ability at admission were discharged earlier and more frequently to home. These findings might be of importance for preoperative physiotherapeutic care and might help to improve care planning as well as more accurately predict the access to inpatients beds and the allocation of resources. PMID- 23925825 TI - Differences in smoking and cessation characteristics among adult nondaily smokers in the United States: findings from the 2009-2010 National Adult Tobacco Survey. AB - INTRODUCTION: Nondaily smoking in the United States is increasing. Although differences in smoking and cessation behaviors between daily and nondaily smokers have been documented, differences among nondaily smokers are poorly understood. This study provides updated national data on smoking and cessation characteristics among nondaily versus daily smokers and between subgroups of nondaily smokers. METHODS: Data were obtained from the 2009-2010 National Adult Tobacco Survey, a stratified, dual-frame telephone survey conducted in the United States. Participants were categorized into daily smokers, never-daily nondaily smokers (NDNS), recently converted (<=1 year) nondaily smokers (RCNS), and established-converted (>1 year) nondaily smokers (ECNS). Chi-square tests were used to assess differences across groups, and multivariable logistic regression was used to identify factors associated with past-year quit attempts. RESULTS: Among nondaily smokers (17.8% of the total sample), 27.1% were NDNS, 37.4% were RCNS, and 35.4% were ECNS. RCNS were the most likely to report ever having tried to quit (p < .0001), having tried to quit in the past year (p < .0001), having used cessation treatment during their last quit attempt (p < .05), and wanting to quit smoking for good (p < .001). Compared with NDNS, RCNS had more than twice the odds of trying to quit in the past year after adjusting for demographics and smoking characteristics (adjusted odds ratio = 2.1, 95% confidence interval = 1.3 3.2). No significant differences existed between NDNS and ECNS. CONCLUSIONS: RCNS are potentially more interested in quitting and should be specifically targeted with cessation interventions to avoid relapse to daily or long-term nondaily smoking. PMID- 23925826 TI - Vitamin C for preventing and treating pneumonia. AB - BACKGROUND: Pneumonia is one of the most common serious infections, causing two million deaths annually among young children in low-income countries. In high income countries pneumonia is most significantly a problem of the elderly. OBJECTIVES: To assess the prophylactic and therapeutic effects of vitamin C on pneumonia. SEARCH METHODS: We searched CENTRAL 2013, Issue 3, MEDLINE (1950 to March week 4, 2013), EMBASE (1974 to April 2013) and Web of Science (1955 to April 2013). SELECTION CRITERIA: To assess the therapeutic effects of vitamin C, we selected placebo-controlled trials. To assess prophylactic effects, we selected controlled trials with or without a placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently read the trial reports and extracted data. MAIN RESULTS: We identified three prophylactic trials which recorded 37 cases of community-acquired pneumonia in 2335 people. Only one was satisfactorily randomised, double-blind and placebo-controlled. Two trials examined military recruits and the third studied boys from "lower wage-earning classes" attending a boarding school in the UK during World War II. Each of these three trials found a statistically significant (80% or greater) reduction in pneumonia incidence in the vitamin C group. We identified two therapeutic trials involving 197 community acquired pneumonia patients. Only one was satisfactorily randomised, double-blind and placebo-controlled. That trial studied elderly patients in the UK and found lower mortality and reduced severity in the vitamin C group; however, the benefit was restricted to the most ill patients. The other therapeutic trial studied adults with a wide age range in the former Soviet Union and found a dose dependent reduction in the duration of pneumonia with two vitamin C doses. We identified one prophylactic trial recording 13 cases of hospital-acquired pneumonia in 37 severely burned patients; one-day administration of vitamin C had no effect on pneumonia incidence. The identified studies are clinically heterogeneous which limits their comparability. The included studies did not find adverse effects of vitamin C. AUTHORS' CONCLUSIONS: The prophylactic use of vitamin C to prevent pneumonia should be further investigated in populations who have a high incidence of pneumonia, especially if dietary vitamin C intake is low. Similarly, the therapeutic effects of vitamin C should be studied, especially in patients with low plasma vitamin C levels. The current evidence is too weak to advocate prophylactic use of vitamin C to prevent pneumonia in the general population. Nevertheless, therapeutic vitamin C supplementation may be reasonable for pneumonia patients who have low vitamin C plasma levels because its cost and risks are low. PMID- 23925827 TI - Prognostic significance of CD147 in patients with glioblastoma. AB - CD147, also known as extracellular matrix metalloproteinase inducer, is a widely distributed cell surface glycoprotein that belongs to the immunoglobulin superfamily. CD147 has been proved to be enriched on the surface of many tumor cells, promoting tumor growth, invasion and metastasis by its stimulation effect on adjacent fibroblasts to produce matrix metalloproteinases. In this study, we aimed to explore the expression pattern of CD147 in glioblastoma (GBM) and investigate whether it could be used to assess subsequent prognosis of patients. For that, we recruited a total of 206 patients with pathologically confirmed GBM and 36 normal control brain tissue specimens. The expression of CD147 in GBM and normal tissues was investigated by immunohistochemistry assay. Genetic factors including MGMT and IDH1 mutation were also investigated to justify the prognostic significance of CD147. Results showed that CD147 expression was increased in GBM compared with that in normal tissues. Kaplan-Meier analysis showed that increased CD147 expression was associated with poor overall survival of patients with GBM. Moreover, Cox's proportional hazards model revealed that CD147 expression was an independent and significant prognostic marker of overall survival in GBM patients. These results proved that CD147 expression was relatively abundant in GBM and can be potentially used to predict prognosis and treatment response in GBM patients. PMID- 23925829 TI - Art and the brain: a view from dementia. AB - OBJECTIVE: Art making encompasses a range of perceptual and cognitive functions involving widely distributed brain systems. The dementias impact on these systems in different ways, raising the possibility that each dementia has a unique artistic signature. DESIGN: Here we use a review of the visual art of 14 artists with dementia (five Alzheimer's disease, seven fronto-temporal dementia and two dementia with Lewy bodies) to further our understanding of the neurobiological constituents of art production and higher artistic function. RESULTS: Artists with Alzheimer's disease had prominent changes in spatial aspects of their art and attributes of colour and contrast. These qualities were preserved in the art of fronto-temporal dementia, which was characterised by perseverative themes and a shift towards realistic representation. The art of dementia with Lewy Bodies was characterised by simple, bizarre content. CONCLUSIONS: The limitations of using visual aspects of individual artworks to infer the impact of dementia on art production are discussed with the need for a wider perspective encompassing changes in cognition, emotion, creativity and artistic personality. A novel classificatory scheme is presented to help characterise neural mechanisms of higher artistic functions in future studies. PMID- 23925828 TI - Trends in childhood brain tumor incidence, 1973-2009. AB - In the mid-1980s, there was a rise in incidence rates of childhood brain tumors (CBT) in the United States that appeared to stabilize at a higher rate in the early 1990 s. An updated analysis of the pattern of CBT over the past 2 decades, with commentary on whether the elevated incidence rate has continued, is past due. We used Surveillance, Epidemiology and End Results (SEER) data to examine trends in incidence of CBT from 1973 through 2009. We examined age-adjusted incidence rates (AAIRs) and secular trends for all malignant brain tumors combined (SEER classification) by histologic tumor type and anatomic site. The incidence of CBT remained stable from 1987 to 2009 [annual percent change (APC) = 0.10; 95 % confidence intervals (CI) -0.39 to 0.61] with an AAIR for all CBT of 3.32 (95 % CI 3.22-3.42). The stability of rates in these two decades contrast the change that occurred in the mid-1980s (1983-1986), when the incidence of CBT increased by 53 % (APC = 14.06; 95 % CI 4.05-25.0). From 1983 to 1986, statistically significant rate increases were observed for pilocytic astrocytoma, PNET/medulloblastoma, and mixed glioma. Further, the rate of increase in pilocytic astrocytoma was similar to the rate of decrease for astrocytomas NOS from 1981 to 2009, suggesting a change from a more general to more specific classification. After the increase in rates in the mid-1980s, rates of CBT over the past two decades have stabilized. Changes in incidence rates of subtypes of tumors over this time period reflect changes both in classification of CBT and in diagnostic techniques. PMID- 23925830 TI - Electrolyte system strategies for anionic isotachophoresis with electrospray ionization mass-spectrometric detection. 1. Regular isotachophoresis and free acid isotachophoresis. AB - The subject of this work is the definition of a simple model based on general ITP theory that allows describing and predicting the behavior of ITP systems compatible with ESI-MS detection. The model is exemplified by anionic ITP of weak acids that represent an interesting potential application field of ITP-ESI-MS. Suitable ESI-compatible electrolyte systems of very simple composition are proposed including a special free-acid ITP arrangement. The properties of these systems are discussed using illustrative diagrams of their stacking windows. The use of anionic ITP-ESI-MS in negative-ion ESI mode is reported for the first time and its suitability for sensitive trace analysis is demonstrated. The presented ITP-ESI-MS application example comprises a free-acid ITP system formed of formic and propionic acids and direct injection analysis of ibuprofen and diclofenac in waters with quantitation limits of the order 10(-10) M. PMID- 23925831 TI - Origins of bone repair in the armour of fossil fish: response to a deep wound by cells depositing dentine instead of dermal bone. AB - The outer armour of fossil jawless fishes (Heterostraci) is, predominantly, a bone with a superficial ornament of dentine tubercles surrounded by pores leading to flask-shaped crypts (ampullae). However, despite the extensive bone present in these early dermal skeletons, damage was repaired almost exclusively with dentine. Consolidation of bone, by dentine invading and filling the vascular spaces, was previously recognized in Psammolepis and other heterostracans but was associated with ageing and dermal shield wear (reparative). Here, we describe wound repair by deposition of dentine directly onto a bony scaffold of fragmented bone. An extensive wound response occurred from massive deposition of dentine (reactionary), traced from tubercle pulp cavities and surrounding ampullae. These structures may provide the cells to make reparative and reactionary dentine, as in mammalian teeth today in response to stimuli (functional wear or damage). We suggest in Psammolepis, repair involved mobilization of these cells in response to a local stimulatory mechanism, for example, predator damage. By comparison, almost no new bone is detected in repair of the Psammolepis shield. Dentine infilling bone vascular tissue spaces of both abraded dentine and wounded bone suggests that recruitment of this process has been evolutionarily conserved over 380 Myr and precedes osteogenic skeletal repair. PMID- 23925832 TI - Evidence of a component Allee effect driven by predispersal seed predation in a plant (Pedicularis rex, Orobanchaceae). AB - A small or sparse population may suffer a reduction in fitness owing to Allee effects. Here, we explored effects of plant density on pollination, reproduction and predation in the alpine herb Pedicularis rex over two years. We did not detect a significant difference in the pollination rate or fecundity (fruit set and the initial seed set) before predation between sparse and dense patches in either year, indicating no pollination-driven Allee effect. However, dense patches experienced significantly fewer attacks by predispersal seed predators in both years, resulting in a significantly decreased realized fecundity (final seed set), suggesting a component Allee effect driven by predispersal seed predation. Predation-driven Allee effects have been predicted by many models and demonstrated for a range of animals, but there is scant evidence for such effects in plants. Our study provides strong evidence of a component Allee effect driven by predation in a plant species. PMID- 23925833 TI - Androgen changes and flexible rutting behaviour in male giraffes. AB - The social organization of giraffes (Giraffa camelopardalis) imposes a high-cost reproductive strategy on bulls, which adopt a 'roving male' tactic. Our observations on wild giraffes confirm that bulls indeed have unsynchronized rut like periods, not unlike another tropical megaherbivore, the elephant, but on a much shorter timescale. We found profound changes in male sexual and social activities at the scale of about two weeks. This so far undescribed rutting behaviour is closely correlated with changes in androgen concentrations and appears to be driven by them. The short time scale of the changes in sexual and social activity may explain why dominance and reproductive status in male giraffe in the field seem to be unstable. PMID- 23925834 TI - Respiratory control in aquatic insects dictates their vulnerability to global warming. AB - Forecasting species responses to climatic warming requires knowledge of how temperature impacts may be exacerbated by other environmental stressors, hypoxia being a principal example in aquatic systems. Both stressors could interact directly as temperature affects both oxygen bioavailability and ectotherm oxygen demand. Insufficient oxygen has been shown to limit thermal tolerance in several aquatic ectotherms, although, the generality of this mechanism has been challenged for tracheated arthropods. Comparing species pairs spanning four different insect orders, we demonstrate that oxygen can indeed limit thermal tolerance in tracheates. Species that were poor at regulating oxygen uptake were consistently more vulnerable to the synergistic effects of warming and hypoxia, demonstrating the importance of respiratory control in setting thermal tolerance limits. PMID- 23925835 TI - Shallow gene pools in the high intertidal: extreme loss of genetic diversity in viviparous sea stars (Parvulastra). AB - We document an extreme example of reproductive trait evolution that affects population genetic structure in sister species of Parvulastra cushion stars from Australia. Self-fertilization by hermaphroditic adults and brood protection of benthic larvae causes strong inbreeding and range-wide genetic poverty. Most samples were fixed for a single allele at nearly all nuclear loci; heterozygotes were extremely rare (0.18%); mitochondrial DNA sequences were more variable, but few populations shared haplotypes in common. Isolation-with-migration models suggest that these patterns are caused by population bottlenecks (relative to ancestral population size) and low gene flow. Loss of genetic diversity and low potential for dispersal between high-intertidal habitats may have dire consequences for extinction risk and potential for future adaptive evolution in response to climate and other selective agents. PMID- 23925836 TI - Possible role of soil alkalinity in plant breeding for salt-tolerance. PMID- 23925837 TI - Density-mediated carry-over effects explain variation in breeding output across time in a seasonal population. AB - In seasonal environments, where density dependence can operate throughout the annual cycle, vital rates are typically considered to be a function of the number of individuals at the beginning of each season. However, variation in density in the previous season could also cause surviving individuals to be in poor physiological condition, which could carry over to influence individual success in the following season. We examine this hypothesis using replicated populations of Drosophila melanogaster, the common fruitfly, over 23 non-overlapping generations with distinct breeding and non-breeding seasons. We found that the density at the beginning of the non-breeding season negatively affected the fresh weight of individuals that survived the non-breeding season and resulted in a 25% decrease in per capita breeding output among those that survived to the next season to breed. At the population level, per capita breeding output was best explained by a model that incorporated density at the beginning of the previous non-breeding season (carry-over effect, COE) and density at the beginning of the breeding season. Our results support the idea that density-mediated COEs are critical for understanding population dynamics in seasonal environments. PMID- 23925838 TI - Soil alkalinity and salt tolerance: adapting to multiple stresses. PMID- 23925839 TI - Exploring the conformational and reactive dynamics of biomolecules in solution using an extended version of the glycine reactive force field. AB - In order to describe possible reaction mechanisms involving amino acids, and the evolution of the protonation state of amino acid side chains in solution, a reactive force field (ReaxFF-based description) for peptide and protein simulations has been developed as an expansion of the previously reported glycine parameters. This expansion consists of adding to the training set more than five hundred molecular systems, including all the amino acids and some short peptide structures, which have been investigated by means of quantum mechanical calculations. The performance of this ReaxFF protein force field on a relatively short time scale (500 ps) is validated by comparison with classical non-reactive simulations and experimental data of well characterized test cases, comprising capped amino acids, peptides, and small proteins, and reaction mechanisms connected to the pharmaceutical sector. A good agreement of ReaxFF predicted conformations and kinetics with reference data is obtained. PMID- 23925840 TI - Imaging bile duct tumors: pathologic concepts, classification, and early tumor detection. AB - Cholangiocarcinoma is the most common primary malignancy of the bile ducts which has several predisposing factors such as hepatolithiasis and primary sclerosing cholangitis, and can develop from precancerous conditions such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. As surgical resection of early stage cholangiocarcinoma or precancerous lesions may provide better prognosis, early detection of those lesions is very important. Imaging studies play important roles in the diagnosis of bile duct tumors followed by appropriate management. Indeed, not only diagnosis of cholangiocarcinoma but also appropriate categorization of bile duct tumors based on their morphologic features and location on cross-sectional imaging studies, including computed tomography and magnetic resonance imaging, is important to predict their biologic behaviors, and choose relevant treatment strategies. We herein review the classification system of the bile duct tumors with their radiologic and pathologic findings as well as role of imaging in the early detection of bile duct tumors. PMID- 23925852 TI - Rapid auxin-induced root growth inhibition requires the TIR and AFB auxin receptors. AB - We investigated the relation between auxin-induced gene expression and the rapid auxin-induced growth inhibition in Arabidopsis thaliana roots. The natural auxin indole-3-acetic acid (IAA) induced a strong activation of gene expression as visualized by the DR5rev::GFP reporter gene technique. This effect was specific for active auxins and was abolished in knockout mutants of the F-box auxin receptors. We measured the IAA-induced growth inhibition at high time resolution and show that the F-box auxin receptor mutants failed to display this effect. We conclude that the F-box auxin receptors are needed for the response. In hypocotyls, auxin induces an increase in elongation growth, and this effect has been earlier shown to be independent of the F-box receptors. Based on these findings, we discuss differences in the growth control modes in roots and shoots. We demonstrate that the rapid auxin-induced root growth inhibition, unlike the induction of growth in hypocotyls, requires the presence of the F-box auxin receptors. PMID- 23925853 TI - Nitrogen and phosphorus fertilization negatively affects strigolactone production and exudation in sorghum. AB - Strigolactones (SLs) are essential host recognition signals for both root parasitic plants and arbuscular mycorrhizal fungi, and SLs or their metabolites function as a novel class of plant hormones regulating shoot and root architecture. Our previous study indicated that nitrogen (N) deficiency as well as phosphorus (P) deficiency in sorghum enhanced root content and exudation of 5 deoxystrigol, one of the major SLs produced by sorghum. In the present study, we examined how N and P fertilization affects SL production and exudation in sorghum plants subjected to short- (5 days) or long-term (10 days) N or P deficiency and demonstrated their common and distinct features. The root contents and exudation of SLs in the N- or P-deficient sorghum plants grown for 6, 12 or 24 h with or without N or P fertilization were quantified by LC-MS/MS. In general, without fertilization, root contents and exudation of SLs stayed at similar levels at 6 and 12 h and then significantly increased at 24 h. The production of SLs responded more quickly to P fertilization than the secretion of SLs, while regulation of SL secretion began earlier after N fertilization. It is suggested that sorghum plants regulate SL production and exudation when they are subjected to nutrient deficiencies depending on the type of nutrient and degree of deficiency. PMID- 23925854 TI - 1H, 15N, and 13C chemical shift assignments of murine calcium-binding protein 4. AB - Calcium-binding protein 4 (CaBP4) regulates voltage-gated Ca(2+) channels in retinal rod cells and specific mutations within CaBP4 are associated with congenital stationary night blindness type 2. We report complete NMR chemical shift assignments of the Ca(2+)-saturated form of CaBP4 with Ca(2+) bound at EF1, EF3 and EF4 (BMRB no. 18877). PMID- 23925855 TI - Crop yield gaps in Cameroon. AB - Although food crop yields per hectare have generally been increasing in Cameroon since 1961, the food price crisis of 2008 and the ensuing social unrest and fatalities raised concerns about the country's ability to meet the food needs of its population. This study examines the country's potential for increasing crop yields and food production to meet this food security challenge. Fuzzy set theory is used to develop a biophysical spatial suitability model for different crops, which in turn is employed to ascertain whether crop production is carried out in biophysically suited areas. We use linear regression to examine the trend of yield development over the last half century. On the basis of yield data from experimental stations and farmers' fields we assess the yield gap for major food crops. We find that yields have generally been increasing over the last half century and that agricultural policies can have significant effects on them. To a large extent, food crops are cultivated in areas that are biophysically suited for their cultivation, meaning that the yield gap is not a problem of biophysical suitability. Notwithstanding, there are significantly large yield gaps between actual yields on farmers' farms and maximum attainable yields from research stations. We conclude that agronomy and policies are likely to be the reasons for these large yield gaps. A key challenge to be addressed in closing the yield gaps is that of replenishing and properly managing soil nutrients. PMID- 23925857 TI - Study of the EFG tensor at 75As nuclei in Ge-As-Se chalcogenide glasses. AB - Asymmetry parameters of the electric field gradient tensor at (75) As nuclei were determined for chalcogenide glassy semiconductors (CGS) of the Ge-As-Se system by comparing the experimental and simulated (75) As nuclear quadrupole resonance nutation interferograms. The electric field gradient asymmetry in CGS was analyzed, and it is believed that a structural change in these glassy semiconductors takes place at r- = 2.425. Electron paramagnetic resonance spectra of the Ge-As-Se system were obtained for the first time. A comparison was made between the results of analysis of the Ge-As-Se system by nuclear quadrupole resonance and electron paramagnetic resonance methods, and this allowed us to make the supposition that a structural phase transition occurs at r- = 2.4 from two-dimensional to three-dimensional CGS structure. PMID- 23925856 TI - Age, gender, and education are associated with cognitive performance in an older Israeli sample with type 2 diabetes. AB - OBJECTIVE: To evaluate the relationships of age, education, and gender with performance on neuropsychological tests in a cognitively intact, older Israeli sample with type 2 diabetes (T2D). METHODS: We examined 862 participants, 65-84 years old, enrolled in the Israel Diabetes and Cognitive Decline study. Multiple regression assessed associations of performance on 17 neuropsychological tests, including the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, with age, education, and gender. RESULTS: Higher education and younger age were consistently associated with better performance. Women outperformed men on all memory tasks; men outperformed women on two non verbal measures. These patterns of demographic associations with cognitive performance were very similar to those of US cohorts. CONCLUSIONS: In a cognitively intact, older Israeli sample with T2D, better test performance is associated primarily with higher education, followed by younger age and gender differences. Although T2D is associated with cognitive deficits, it recapitulates the patterns of relationships between cognitive performance and demographic characteristics seen in non-T2D diabetic samples. PMID- 23925858 TI - In-plane alloy electrodes for capacitively coupled contactless conductivity detection in poly(methylmethacrylate) electrophoretic chips. AB - A simple method for producing PMMA electrophoresis microchips with in-plane electrodes for capacitively coupled contactless conductivity detection is presented. One PMMA plate (channel plate) is embossed with the microfluidic and electrode channels and lamination bonded to a blank PMMA cover plate of equal dimensions. To incorporate the electrodes, the bonded chip is heated to 80 degrees C, above the melting point of the alloy (~ 70 degrees C) and below the glass transition temperature of the PMMA (~ 105 degrees C), and the molten alloy drawn into the electrode channels with a syringe before being allowed to cool and harden. A 0.5 mm diameter stainless steel pin is then inserted into the alloy filled reservoirs of the electrode channels to provide external connection to the capacitively coupled contactless conductivity detection detector electronics. This advance provides for a quick and simple manufacturing process and negates the need for integrating electrodes using costly and time-consuming thin film deposition methods. No additional detector cell mounting structures were required and connection to the external signal processing electronics was achieved by simply slipping commercially available shielded adaptors over the pins. With a non-optimised electrode arrangement consisting of a 1 mm detector gap and 100 MUm insulating distance, rapid separations of ammonium, sodium and lithium (<22 s) yielded LODs of approximately 1.5-3.5 ppm. PMID- 23925859 TI - The sitting position in neurosurgery: indications, complications and results. a single institution experience of 600 cases. AB - BACKGROUND: The benefit of the sitting position for surgery of the posterior fossa and cervical spine is still a matter of controversy. In our study we analyzed the outcome after sitting position surgery at our institution. We compared the incidence of venous air embolism (VAE) as recognized with different monitoring techniques and the severity of complications. METHODS: We retrospectively analyzed 600 patients, who underwent surgery for different posterior fossa and cervical spine pathologies, respectively, in the sitting position at our institution from 1995 to 2011. Intraoperative monitoring for VAE included endtidal CO2 level, Doppler ultrasound or intraoperative transesophageal echocardiography (TEE). We defined VAE as a decrease of the endtidal CO2 levels by more than 4 mm Hg, a characteristic sound in the thoracic Doppler, or any sign of air in the TEE. RESULTS: We found an overall incidence of VAE in 19 % of all patients, whereas the rate of severe complications associated with VAE such as a decline of partial oxygen pressure (pO2) or a drop of blood pressure was only 3.3 % in all patients. Only three out of 600 operations had to be terminated because of non-controllable VAE (0.5 %). There was no mortality resulting from VAE in our series. We also found a difference in the incidence of VAE depending on the monitoring technique. The VAE rate as monitored with TEE was 25.6 % whereas the incidence of VAE in patients monitored with Doppler ultrasound was 9.4 %. The rate of a significant VAE was comparable in both methods 4.8 % vs. 1.2 %. All patients were preoperatively screened for persisting foramen ovale (PFO); 24 patients with clinically confirmed PFO were included in this series. There was no case of paradox air embolism. CONCLUSIONS: In our series, VAE was detected in 19 % of all patients in the sitting position. However, in only 0.5 % of cases a termination of the surgical procedure became necessary. In all other cases, the cause of air embolism could be found and eliminated during surgery. TEE was found to be the monitoring technique with the highest sensitivity. In our opinion, the sitting position is a safe positioning technique if TEE monitoring is used. PMID- 23925860 TI - Could the types of paraclinoid aneurysm be used as a criterion in choosing endovascular treatment? Neuro-radiologists' view. AB - BACKGROUND: The type of paraclinoid aneurysm has been used to decide management methods. Our aim was to assess the relation of the types of paraclinoid aneurysms and outcomes after endovascular treatment and the efficiency of present endovascular techniques. METHODS: A retrospective analysis was performed on patients with saccular paraclinoid aneurysms that had more than 6 months of angiographic follow-up or recurrence within this period after endovascular treatment from January 2009 to December 2010. Paraclinoid aneurysms were classified into two types and then further into four subtypes by a modified classification method. A classification-based microcatheter shaping method was used in the procedure. The significant risk factors of angiographic results were determined through correlation analysis and logistic regression analysis by SPSS 17.0. RESULTS: There were 64 aneurysms in 56 patients; 28 aneurysms belonged to Type I, while 36 were Type II. A total of 12 aneurysms were managed with coil embolization, and 52 with stent-assisted coiling technique. Our classification based microcatheter shaping method was successful in all cases. Coil protrusion happened in two cases without severe complications. Recurrence were found in 13 (20.3 %) aneurysms followed up at 12.42 +/- 3.78 (mean+/-SD) months after treatment. The correlation between aneurysm types and immediate angiographic result or follow-up angiographic results did not reach statistical significance. Aneurysm types were not the risk factor of recurrence. CONCLUSIONS: The types of paraclinoid aneurysm had not been significant correlated with outcomes of endovascular treatment. Fundus size was the significant risk factor of recurrence after endovascular treatment. A classification-based microcatheter shaping method may be used in endovascular treatment paraclinoid aneurysms. The present endovascular techniques are safe and effective. PMID- 23925861 TI - Cortical metabolic deficits in a rat model of cholinergic basal forebrain degeneration. AB - Evidence indicates that the degeneration of basal forebrain cholinergic neurons may represent an important factor underlying the progressive cognitive decline characterizing Alzheimer's disease (AD). However, the nature of the relationship between cholinergic depletion and AD is not fully elucidated. This study aimed at clarifying some aspects of the relation existing between deficits in cerebral energy metabolism and degeneration of cholinergic system in AD, by investigating the neuronal metabolic activity of several cortical areas after depletion of basal forebrain cholinergic neurons. In cholinergically depleted rats, we evaluated the neuronal metabolic activity by assaying cytochrome oxidase (CO) activity in frontal, parietal and posterior parietal cortices at four different time-points after unilateral injection of 192 IgG-saporin in the nucleus basalis magnocellularis. Unilateral depletion of cholinergic cells in the basal forebrain induced a bilateral decrease of metabolic activity in all the analyzed areas. Frontal and parietal cortices showed decreased metabolic activity even 3 days after the lesion, when the cholinergic degeneration was still incomplete. In posterior parietal cortex metabolic activity decreased only 7 days after the lesion. The possible molecular mechanisms underlying these findings were also investigated. Real-time PCR showed an increase of CO mRNA levels at 3, 7 and 15 days after the lesion both in frontal and parietal cortices, followed by normalization at 30 days. Western Blot analysis did not show any change in CO protein levels at any time-point after the lesion. Our findings support a link between metabolic deficit and cholinergic hypofunctionality characterizing AD pathology. The present model of cholinergic hypofunctionality provides a useful means to study the complex mechanisms linking two fundamental and interrelated phenomena characterizing AD from the early stages. PMID- 23925862 TI - Removal of 8-quinolinecarboxylic acid pesticide from aqueous solution by adsorption on activated montmorillonites. AB - Sodium montmorillonite (Na-M), acidic montmorillonite (H-M), and organo-acidic montmorillonite (Org-H-M) were applied to remove the herbicide 8 quinolinecarboxylic acid (8-QCA). The montmorillonites containing adsorbed 8-QCA were investigated by transmission electron microscopy, FT-IR spectroscopy, X-ray diffraction analysis, X-ray fluorescence thermogravimetric analysis, and physical adsorption of gases. Experiments showed that the amount of adsorbed 8-QCA increased at lower pH, reaching a maximum at pH 2. The adsorption kinetics was found to follow the pseudo-second-order kinetic model. The Langmuir model provided the best correlation of experimental data for adsorption equilibria. The adsorption of 8-QCA decreased in the order Org-H-M > H-M > Na-M. Isotherms were also used to obtain the thermodynamic parameters. The negative values of DeltaG indicated the spontaneous nature of the adsorption process. PMID- 23925863 TI - The impact of poultry litter application on sediment chemistry of the Broadkill River estuary system, Delaware. AB - This project examined the impact of long-term poultry litter application on the chemical signatures of As, Cu, Zn, and P in stream sediments of the Broadkill River watershed within the Delmarva Peninsula, a region of intense poultry production. Thirty-seven sediment samples were collected from Broadkill River drainage systems and analyzed for litter-derived elements (As, Cu, Zn, P) and basic soil parameters such as particle size distribution, organic matter, and soluble salts. Results showed that concentrations of elements in stream sediments are approximately log-normally distributed. Spatial variability in concentrations of elements was evident, with most elements increasing in concentration and enrichment from upgradient headwaters to downgradient reaches draining predominantly agricultural areas. Results of correlation analyses showed positive significant correlation among elements; elements were also positively correlated with percent clay and silt in the sediment. Using GIS maps with overlays of hydrology and land use activities, statistical correlations between As, Cu, Zn, and P enrichment factors and land use were examined. Results showed statistically significant relationships between As, Mn, and Zn enrichment factors and residential areas within the watershed, but did not show a statistically significant relationship between element enrichment factors and agricultural land use. Factors that complicate this type of landscape-scale study include the presence of poultry processing plants, impoundments, changes in land use over time, and the influence of tides, all of which can have direct and indirect influences on element mobility. PMID- 23925864 TI - The potential effects of climate change on the distribution and productivity of Cunninghamia lanceolata in China. AB - Climate changes may have immediate implications for forest productivity and may produce dramatic shifts in tree species distributions in the future. Quantifying these implications is significant for both scientists and managers. Cunninghamia lanceolata is an important coniferous timber species due to its fast growth and wide distribution in China. This paper proposes a methodology aiming at enhancing the distribution and productivity of C. lanceolata against a background of climate change. First, we simulated the potential distributions and establishment probabilities of C. lanceolata based on a species distribution model. Second, a process-based model, the PnET-II model, was calibrated and its parameterization of water balance improved. Finally, the improved PnET-II model was used to simulate the net primary productivity (NPP) of C. lanceolata. The simulated NPP and potential distribution were combined to produce an integrated indicator, the estimated total NPP, which serves to comprehensively characterize the productivity of the forest under climate change. The results of the analysis showed that (1) the distribution of C. lanceolata will increase in central China, but the mean probability of establishment will decrease in the 2050s; (2) the PnET-II model was improved, calibrated, and successfully validated for the simulation of the NPP of C. lanceolata in China; and (3) all scenarios predicted a reduction in total NPP in the 2050s, with a markedly lower reduction under the a2 scenario than under the b2 scenario. The changes in NPP suggested that forest productivity will show a large decrease in southern China and a mild increase in central China. All of these findings could improve our understanding of the impact of climate change on forest ecosystem structure and function and could provide a basis for policy-makers to apply adaptive measures and overcome the unfavorable influences of climate change. PMID- 23925865 TI - Mineral contents of seed and seed oils of Capparis species growing wild in Turkey. AB - The mineral contents of seed and seed oils of Capparis species growing wild in Turkey were established by inductively coupled plasma-atomic emission spectrometry. Capparis spinosa var. spinosa (2010) and Capparis ovata var. canescens variety (2009) were determined to be rich in terms of mineral matter as 19,514.60 and 16,995.92 ppm as a total, respectively. C. spinosa var. spinosa collected from Mugla-Milas region (2009) had the highest amount of Ca with 1,010.67 ppm in C. spinosa species and in C. ovata species. C. ovata var. canescens collected from Ankara-Beypazari (2010) region had the highest amount of Ca with 833.92 ppm Ca amount in C. spinosa var. spinosa, inermis, herbaceae seeds decreased in 2010. C. spinosa var. inermis collected from Antalya-Serik (2010) in C. spinosa species had rich amount of Ca with 123.78 ppm and C. ovata var. palaestina seed oils collected from Mardin-Savur region (2009) had rich amount of Ca with 253.71 ppm in C. ovata species. The oil of C. spinosa var. herbaceae variety collected from Mardin-Midyat region (2010) was determined to have the highest major mineral matter (Ca, K, Mg, Na, and P) with 1,424.37 ppm in C. spinosa species. It was also determined that as a result, caper seed and oils were found to be important sources of nutrients and essential elements. PMID- 23925866 TI - [Connective tissue disease-related pulmonary arterial hypertension--a pathology beyond the precapillary vessels]. PMID- 23925867 TI - Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. AB - BACKGROUND: Anticoagulant treatment with vitamin K antagonists (VKAs) is aimed at preventing thromboembolic complications and has been the therapy of choice for most people with non-valvular atrial fibrillation (AF) for many decades. A new class of anticoagulants, the factor Xa inhibitors, appear to have several pharmacological and practical advantages over VKAs. OBJECTIVES: To assess the effectiveness and safety of treatment with factor Xa inhibitors versus VKAs for the prevention of cerebral or systemic embolic events in people with AF. SEARCH METHODS: We searched the trials registers of the Cochrane Stroke Group and the Cochrane Heart Group (June 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10), MEDLINE (1950 to April 2013) and EMBASE (1980 to April 2013). In an effort to identify further published, unpublished and ongoing trials we searched trials registers and Google Scholar (July 2012). We also screened reference lists and contacted pharmaceutical companies, authors and sponsors of relevant published trials. SELECTION CRITERIA: Randomised controlled trials that directly compared the effects of long-term treatment (more than four weeks) with factor Xa inhibitors and VKAs for the prevention of cerebral and systemic embolism in patients with AF. We included patients with and without a previous stroke or TIA. DATA COLLECTION AND ANALYSIS: The primary efficacy outcome was the composite endpoint of all strokes and other systemic embolic events. Two authors independently assessed trial quality and the risk of bias, and extracted data. We calculated a weighted estimate of the typical treatment effect across trials using the odds ratio (OR) with 95% confidence interval (CI) by means of a fixed-effect model. However, in the case of moderate or high heterogeneity of treatment effects, we used a random-effects model to compare the overall treatment effects and performed a pre-specified sensitivity analysis excluding any fully open-label studies. MAIN RESULTS: We included data from 42,084 participants randomised into 10 trials. All participants had a confirmed diagnosis of AF (or atrial flutter) and were deemed by the randomising physician to be eligible for long-term anticoagulant treatment with a VKA (warfarin) with a target International Normalised Ratio (INR) of 2.0 to 3.0 in most patients. The included trials directly compared dose-adjusted warfarin with either apixaban, betrixaban, darexaban, edoxaban, idraparinux or rivaroxaban. Four trials were double-masked, five partially-masked (that is different doses of factor Xa inhibitor administered double-masked and warfarin administered open-label) and one was open label. Median duration of follow-up ranged from 12 weeks to 1.9 years.The composite primary efficacy endpoint of all strokes (both ischaemic and haemorrhagic) and non-central nervous systemic embolic events was reported in nine of the included studies (40,777 participants). Treatment with a factor Xa inhibitor significantly decreased the number of strokes and systemic embolic events compared with dose-adjusted warfarin (OR 0.81, 95% CI 0.72 to 0.91). We also analysed both components of this composite endpoint separately: treatment with a factor Xa inhibitor significantly decreased both the number of ischaemic and haemorrhagic strokes (OR 0.78, 95% CI 0.69 to 0.89) and the number of systemic embolic events (OR 0.53, 95% CI 0.32 to 0.87).All of the included studies (42,078 participants) reported the number of major bleedings. Treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.89, 95% CI 0.81 to 0.98). There was, however, statistically significant and high heterogeneity (I2 = 81%) and an analysis using a random-effects model did not show a statistically significant decrease in the number of major bleedings (OR 0.92, 95% CI 0.63 to 1.34). The pre-specified sensitivity analysis excluding open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.84, 95% CI 0.76 to 0.92) but moderate heterogeneity was still observed (I2 = 65%). A similar sensitivity analysis using a random-effects model did not show a statistically significant decrease in the number of major bleedings in patients treated with factor Xa inhibitors (OR 0.78, 95% CI 0.57 to 1.05). Part of the observed heterogeneity can thus be explained by the increased risk of major bleedings in the factor Xa treatment arm in the single included open-label study, which studied idraparinux. Other heterogeneity might be explained by differences in baseline bleeding risks in the two largest trials of apixaban and rivaroxaban that we included in this review.Data on intracranial haemorrhages (ICHs) were reported in eight studies (39,638 participants). Treatment with a factor Xa inhibitor significantly reduced the risk of ICH compared with warfarin (OR 0.56, 95% CI 0.45 to 0.70). Again, we observed statistically significant heterogeneity (I2 = 60%). The pre-specified sensitivity analysis excluding the open-label study showed that treatment with a factor Xa inhibitor significantly reduced the number of ICHs compared with warfarin (OR 0.51, 95% CI 0.41 to 0.64), without any sign of statistical heterogeneity (I2 = 0%).The number of patients who died from any cause was reported in six studies (38,924 participants). Treatment with a factor Xa inhibitor significantly reduced the number of all-cause deaths compared with warfarin (OR 0.88, 95% 0.81 to 0.97). AUTHORS' CONCLUSIONS: Factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin in patients with AF. Factor Xa inhibitors also seem to reduce the number of major bleedings and ICHs compared with warfarin, though the evidence for a reduction of major bleedings is somewhat less robust. There is currently no conclusive evidence to determine which factor Xa inhibitor is more effective and safer for long-term anticoagulant treatment of patients with AF as head-to-head studies of the different factor Xa inhibitors have not yet been performed. PMID- 23925868 TI - Proximal humeral reconstruction using nail cement spacer in primary and metastatic tumours of proximal humerus. AB - Limb salvage surgery for malignant tumours of proximal humerus is an operative challenge, where the surgeon has to preserve elbow and hand functions and retain shoulder stability with as much function as possible. We treated 14 consecutive patients with primary malignant or isolated metastasis of proximal humerus with surgical resection and reconstruction by nail cement spacer. There were 8 females and 6 males, with a mean age of 28.92 years (range 16-51 years) and a mean follow up of 30.14 months (range 12-52 months). The diagnosis was osteosarcoma in 8 patients, chondrosarcoma in 4 patients and metastasis from thyroid and breast carcinoma in 1 patient each. One of our patients had radial nerve neuropraxia, 1 developed inferior subluxation and 3 developed distant metastasis. Two patients died of disease and one developed local recurrence leading to forequarter amputation, leaving a total of 11 patients with functional extremities for assessment at the time of final follow-up which was done using the Musculoskeletal Tumour Society (MSTS) score. Though we were able to preserve the elbow, wrist and hand functions in all patients, the abductor mechanism, deltoid muscle and axillary nerve were not salvageable in any of cases. The mean MSTS score at the time of final follow-up was 19.09. Thus, proximal humeral reconstruction using nail cement spacer is a technical simple, cost-effective and reproducible procedure which makes it a reliable option in subset of patients where the functions around the shoulder cannot be preserved despite costlier prosthesis. PMID- 23925869 TI - Effectiveness of musculoskeletal education interventions in people with low literacy levels: a systematic review. AB - OBJECTIVE: To conduct a systematic review to assess the effectiveness of patient education interventions delivered or directed by health professionals for people with musculoskeletal conditions who also have lower levels of literacy. METHODS: Electronic databases were searched from 1946 to May 2012. Randomized controlled trials with primary interventions designed specifically for individuals with musculoskeletal conditions and lower levels of literacy were eligible for inclusion. The quality of the study was determined by assessing method of randomization, allocation concealment, creation and maintenance of comparable groups, blinding of patients and providers, control of confounding, and the validity and reliability of outcome measures. RESULTS: Of the 2,440 studies located using the search strategy, 6 studies met the inclusion criteria. Three public health community studies and 3 rheumatology clinic-based studies delivered educational programs to people with musculoskeletal conditions who also had lower levels of literacy. Three moderate quality studies suggest that musculoskeletal educational interventions had a small short-term effect on knowledge and 2 moderate quality studies suggest musculoskeletal interventions had a small effect on self-efficacy (although results on self-efficacy were conflicting in 1 of these studies). Only 1 moderate quality study showed a small effect on anxiety and 1 on self-perceived health and well-being in people with lower literacy. CONCLUSION: High quality evidence is lacking on the effectiveness of musculoskeletal education interventions for people with lower literacy levels. Research programs that test the effectiveness of patient education interventions for arthritis must recruit and engage people with lower levels of literacy. PMID- 23925879 TI - Partial wrist arthrodesis versus arthroplasty for distal radius giant cell tumours. AB - PURPOSE: The purpose of this study was to evaluate the clinical efficacy of using the proximal fibular graft for partial wrist arthrodesis or arthroplasty after the resection of giant cell tumours of the distal radius. METHODS: Between February 2006 and August 2010, 14 patients (seven males, seven females; average age, 35.7 years) with grade II and III giant cell tumours of the distal radius were treated by tumour resection and autologous proximal fibular grafts to reconstruct the wrist in our hospital. Seven patients each were treated by wrist arthroplasty and partial wrist arthrodesis, and were followed up for 2.2-6.8 years (average, 3.9 years). RESULTS: All patients achieved primary healing. No tumour recurrence was observed during follow-up in any of the patients. No statistically significant difference in forearm rotation was observed between patients undergoing the two different treatments. However, wrist flexion extension activities were significantly better and the wrist grip strengths were significantly worse in the arthroplasty group than in the arthrodesis group. The Musculoskeletal Tumour Society score did not significantly differ between the groups. CONCLUSIONS: Overall, joint arthroplasty remains a favourable treatment with regard to the functional outcome for giant cell tumours of the distal radius; however, some of these patients may have a weaker grip strength. In comparison, partial wrist fusion appears to provide a durable and stable wrist with good long-term functional outcome. PMID- 23925880 TI - Evaluation of patellofemoral joint in ADVANCE Medial-pivot total knee arthroplasty. AB - PURPOSE: ADVANCE Medial Pivot (MP) (Wright Medical) total knee arthroplasty (TKA) was established to replicate normal tibio-femoral knee joint kinematics, however, its influence on the patello-femoral (PF) joint is unclear. The purpose in this study was to assess the PF joint conditions in Advance MP TKA, via radiography and three-dimensional image-matching software. METHODS: Ten subjects with osteoarthritis were treated with the ADVANCE MP TKA. Pre-operatively and one month after surgery, skyline views at 30, 60, and 90 degrees of flexion were taken, and patella shift and tilt were measured. With 2D-3D registration techniques using software, implant orientations were matched with the pre operative CT and changes in the anterior part of the femoral prosthesis, condylar twist angle (CTA) for femoral rotation, and tibial rotation were evaluated. The relationships between morphological and rotational changes were evaluated. RESULTS: There were significant differences in patella tilt at 60 degrees and patella shift at all angles between pre- and post-operation (p < 0.05). No correlation was found between morphological changes in the anterior femur with patella tilt and shift. A positive correlation between postoperative CTA and patella shift at 90 degrees was found (p < 0.05); however, no correlation was found between rotational alignment of the tibial component and patella tilt and shift. CONCLUSIONS: ADVANCE MP TKA changed patello-femoral joint kinematics, compared to that found before surgery. The kinematic features were mainly due to the design concepts for tibio-femoral joint motion, indicating the difficulty to reproduce normal patello-femoral joint kinematics after TKA. PMID- 23925881 TI - Behaviour of the ultra-short anatomic cementless femoral stem in young and elderly patients. AB - PURPOSE: The question arises as to whether it is possible to obtain rigid fixation of the ultra-short metaphyseal-fitting anatomic cementless stem without diaphyseal fixation in the elderly as well as younger patients. We investigated whether ultra-short, metaphyseal-fitting anatomic cementless femoral stem would provide similar functional improvements in the younger and elderly patients, radiographically secure implant fixation would be achieved in both groups, the bone content would be preserved in both groups, and complication rates would be similar in both groups. METHODS: A total of 100 patients (114 hips) in the younger patient group and 100 patients (112 hips) in the elderly patient group were included in the study. Their mean age was 43.9 +/- 6.11 years (range, 31-65 years) in the younger patient group and 78.9 +/- 12.1 years (range, 66-91 years) in the elderly patient group. The mean duration of follow-up was 7.5 years (range, six to nine years) in the younger patient group and 7.6 years (range, six to nine years) in the elderly patient group. RESULTS: The mean postoperative Harris hip scores (95 points versus 91 points), WOMAC scores (11 points versus 15 points), thigh pain (none in either group), UCLA activity scores (6.5 points versus 4.5 points), and radiographic results were not significantly different between the two groups. No hip in either group had an aseptic loosening. No hip in either group had clicking or squeaking sounds or ceramic fractures. CONCLUSION: The cementless ultra-short, metaphyseal-fitting anatomic cementless femoral component provides stable fixation without any need of diaphyseal fixation in both younger and elderly patients. Despite the concern, the poor bone quality in elderly patients did not compromise the stability, and osseointegration of this ultra-short, anatomic cementless femoral stem was achieved in all elderly patients. PMID- 23925882 TI - Comment on Li et al.: Single-bundle versus double-bundle anterior cruciate ligament reconstruction: an up-to-date meta-analysis. PMID- 23925883 TI - Letter regarding article by Li et al.: Single-bundle versus double-bundle anterior cruciate ligament reconstruction: an up-to-date meta-analysis. PMID- 23925884 TI - Lipids derived from virulent Francisella tularensis broadly inhibit pulmonary inflammation via toll-like receptor 2 and peroxisome proliferator-activated receptor alpha. AB - Francisella tularensis is a Gram-negative facultative intracellular pathogen that causes an acute lethal respiratory disease in humans. The heightened virulence of the pathogen is linked to its unique ability to inhibit Toll-like receptor (TLR) mediated inflammatory responses. The bacterial component and mechanism of this inhibition are unknown. Here we show that lipids isolated from virulent but not attenuated strains of F. tularensis are not detected by host cells, inhibit production of proinflammatory cytokines by primary macrophages in response to known TLR ligands, and suppress neutrophil recruitment in vivo. We further show that lipid-mediated inhibition of inflammation is dependent on TLR2, MyD88, and the nuclear hormone and fatty acid receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Pathogen lipid-mediated interference with inflammatory responses through the engagement of TLR2 and PPARalpha represents a novel manipulation of host signaling pathways consistent with the ability of highly virulent F. tularensis to efficiently evade host immune responses. PMID- 23925885 TI - Subcutaneous administration of a 10-fold-lower dose of a commercial human tuberculosis vaccine, Mycobacterium bovis bacillus Calmette-Guerin Danish, induced levels of protection against bovine tuberculosis and responses in the tuberculin intradermal test similar to those induced by a standard cattle dose. AB - Vaccination of cattle with a commercial human tuberculosis (TB) vaccine, Mycobacterium bovis bacillus Calmette-Guerin (BCG) Danish, at a dose equivalent to 5 human doses of BCG has protected these animals against TB in field and experimental trials. There is interest in determining whether a 10-fold-lower dose could still protect cattle but not induce a tuberculin intradermal test response. Two groups of calves (n = 9/group) were vaccinated subcutaneously with a lyophilized BCG Danish vaccine containing either 0.5 (1 * 10(5) to 4 * 10(5) CFU) or 5 (1 * 10(6) to 4 * 10(6) CFU) human doses of BCG Danish, with an additional group of 10 calves serving as nonvaccinated controls. Fifteen weeks after vaccination, these animals were challenged intratracheally with 5 * 10(3) CFU of virulent M. bovis and another 15 weeks later were slaughtered and examined for the presence of tuberculous lesions. Vaccination of the calves with either 0.5 or 5 equivalent human doses of BCG Danish induced similar levels of protection against challenge with M. bovis, with both groups showing significant reductions in the pathological and microbiological parameters compared to those for the the control group (P < 0.05). Vaccination with either of the two BCG doses induced similar numbers of animals responding to the tuberculin intradermal test at 11 weeks postvaccination. Vaccination with a 0.5 equivalent human dose of a commercial lyophilized BCG vaccine can protect cattle against challenge with M. bovis. PMID- 23925886 TI - Modified opsonization, phagocytosis, and killing assays to measure potentially protective antibodies against pneumococcal surface protein A. AB - The standard opsonophagocytosis killing assay (OPKA) for antibodies to pneumococcal capsular polysaccharide was modified to permit an evaluation of the protection-mediating antibodies to pneumococcal surface protein A (PspA). We found that by increasing the incubation time with the complement and phagocytes from 45 min to 75 min, the protective activity was readily detected. In another modification, we used a capsule type 2 target strain that expressed PspA but not pneumococcal surface protein C (PspC). With these modifications separately or in combination, rabbit antisera to the recombinant alpha-helical or proline-rich domains of PspA mediated >50% killing of the target strain. The ability of normal human sera to mediate the killing of pneumococci in this modified OPKA correlated with their levels of antibodies to PspA and their ability to protect mice against fatal infection with a type 3 strain. Passive protection of mice against pneumococci and killing in the modified OPKA were lost when normal human sera were adsorbed with recombinant PspA (rPspA) on Sepharose, thus supporting the potential utility of the modified OPKA to detect protective antibodies to PspA. In the standard OPKA, monoclonal antibodies to PspA were strongly protective in the presence of subprotective amounts of anti-capsule. Thus, the currently established high-throughput OPKA for antibodies to capsule could be modified in one of two ways to permit an evaluation of the opsonic efficacy of antibodies to PspA. PMID- 23925887 TI - Expansion of serotype coverage in the universal pediatric vaccination calendar: short-term effects on age- and serotype-dependent incidence of invasive pneumococcal clinical presentations in Madrid, Spain. AB - In Madrid, Spain, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 in the pediatric universal vaccination calendar in June 2010. A prospective clinical surveillance that included all children hospitalized with culture- and/or PCR-confirmed invasive pneumococcal disease (IPD) was performed in all Madrid hospitals. The incidence rates (IRs) (defined as the number of cases/100,000 inhabitants aged <15 years) in the PCV7 (May 2007 to April 2010) versus PCV13 (May 2011 to April 2012) periods were compared. There were 499 cases in the PCV7 period and 79 cases in the PCV13 period. Globally, the IR significantly decreased from 17.09 (PCV7 period) to 7.70 (PCV13 period), with significant decreases (PCV7 versus PCV13 periods) in all age groups for bacteremic pneumonia (5.51 versus 1.56), parapneumonic pneumococcal empyema (PPE) (5.72 versus 3.12), and meningitis (2.16 versus 0.97). In the PCV13 period, significant reductions (the IR in the PCV7 period versus the IR in the PCV13 period) were found in IPDs caused by PCV13 serotypes (13.49 versus 4.38), and specifically by serotypes 1 (globally [4.79 versus 2.53], for bacteremic pneumonia [2.23 versus 0.97], and for PPE [2.26 versus 1.17]), serotype 5 (globally [1.88 versus 0.00], for bacteremic pneumonia [0.89 versus 0.00], and for PPE [0.55 versus 0.00]), and serotype 19A (globally [3.77 versus 0.49], for bacteremic pneumonia [0.72 versus 0.00], for PPE [0.89 versus 0.00], and for meningitis [0.62 versus 0.00]). IPDs caused by non-PCV13 serotypes did not increase (IR, 3.60 in the PCV7 period versus 3.31 in the PCV13 period), regardless of age or presentation. No IPDs caused by the PCV13 serotypes were found in children who received 3 doses of PCV13. The number of hospitalization days and sanitary costs were significantly lower in the PCV13 period. The switch from PCV7 to PCV13 in the universal pediatric vaccination calendar provided sanitary and economical benefits without a replacement by non-PCV13 serotypes. PMID- 23925889 TI - Identification of polyproline II regions derived from the proline-rich nuclear receptor coactivators PNRC and PNRC2: new insights for ERalpha coactivator interactions. AB - Protein-protein interactions are crucial for signal transductions required for cell differentiation and proliferation. Their modulation is therefore key to the development of therapeutic alternatives, particularly in the context of cancer. According to literature data, the polyproline-rich nuclear receptor coactivators PNRC and PNRC2 interact with estrogen receptor (ERalpha) through their PxxP SH3 binding motifs. In a search to identify the molecular features governing this interaction, we explored using electronic circular dichroism (ECD) spectroscopy and molecular dynamics (MD) calculations, the capacity of a range of putative biologically active peptides derived from these proteins and containing this PxxP motif(s) to form polyproline II (PPII) domains. An additional more exhaustive structural study on a lead PPII peptide was also performed using 2D nuclear magnetic resonance (NMR) spectroscopy. With the exception of one of all the investigated peptides (PNRC-D), binding assays failed to detect any affinity for Grb2 SH3 domains, suggesting that PPII motifs issued from Grb2 antagonists have a binding mode distinct from those derived from Grb2 agonists. Instead, the peptides revealed a competitive binding ability against a synthetic peptide (ERalpha17p) with a putative PPII-cognate domain located within a coregulator recruitment region of ERalpha (AF-2 site). Our work, which constitutes the first structure-related interaction study concerning PNRC and PNRC2, supports not only the existence of PxxP-induced PPII sequences in these coregulators, but also confirms the presence of a PPII recognition site in the AF-2 of the steroid receptor ERalpha, a region important for transcription regulation. PMID- 23925888 TI - Antibody avidity in humoral immune responses in Bangladeshi children and adults following administration of an oral killed cholera vaccine. AB - Antibody avidity for antigens following disease or vaccination increases with affinity maturation and somatic hypermutation. In this study, we followed children and adults in Bangladesh for 1 year following oral cholera vaccination and measured the avidity of antibodies to the T cell-dependent antigen cholera toxin B subunit (CTB) and the T cell-independent antigen lipopolysaccharide (LPS) in comparison with responses in other immunological measurements. Children produced CTB-specific IgG and IgA antibodies of high avidity following vaccination, which persisted for several months; the magnitudes of responses were comparable to those seen in adult vaccinees. The avidity of LPS-specific IgG and IgA antibodies in vaccinees increased significantly shortly after the second dose of vaccine but waned rapidly to baseline levels thereafter. CTB-specific memory B cells were present for only a short time following vaccination, and we did not find significant memory B cell responses to LPS in any age group. For older children, there was a significant correlation between CTB-specific memory T cell responses after the second dose of vaccine and CTB-specific IgG antibody avidity indices over the subsequent year. These findings suggest that vaccination induces a longer-lasting increase in the avidity of antibodies to a T cell-dependent antigen than is measured by a memory B cell response to that antigen and that early memory T cell responses correlate well with the subsequent development of higher-avidity antibodies. PMID- 23925890 TI - Effects of bubble-liquid two-phase turbulent hydrodynamics on cell damage in sparged bioreactor. AB - According to recent experimental studies on sparged bioreactors, significant cell damage may occur at the gas inlet region near the sparger. Although shear stress was proposed to be one of the potential causes for cell damage, detailed hydrodynamic studies at the gas inlet region of gas-liquid bioreactors have not been performed to date. In this work, a second-order moment (SOM) bubble-liquid two-phase turbulent model based on the two-fluid continuum approach is used to investigate the gas-liquid hydrodynamics in the bubble column reactor and their potential impacts on cell viability, especially at the gas inlet region. By establishing fluctuation velocity and bubble-liquid two-phase fluctuation velocities correlation transport equations, the anisotropy of two-phase stresses and the bubble- liquid interactions are fully considered. Simulation results from the SOM model indicate that shear and normal stresses, turbulent energy dissipation rate, and the turbulent kinetic energy are generally smaller at the gas inlet region when compared with those in the fully developed region. In comparison, a newly proposed correlation expression, stress-induced turbulent energy production (STEP), is found to correlate well with the unusually high cell death rate at the gas inlet region. Therefore, STEP, which represents turbulent energy transfer to a controlled volume induced by a combination of shear and normal stresses, has the potential to provide better explanation for increased cell death at the sparger region. PMID- 23925891 TI - In vitro induction of oocyte maturation and steroidogenesis by gonadotropins, insulin, calcitonin and growth factor in an estuarine flat head grey mullet, Mugil cephalus L. AB - In this article, an in vitro investigation was carried out to ascertain the roles of hormones and growth factor in the inductions of oocyte maturation and steroidogenesis of the postvitellogenic follicles in an Indian estuarine grey mullet, Mugil cephalus L. Oocyte maturation was evaluated by scoring the germinal vesicle breakdown (GVBD) percent of the postvitellogenic follicles. All the sex [17alpha,20beta-dihydroxy-4-pregnane-3-one (DHP), estradiol 17beta (E2), progesterone (P), 17alpha-OH progesterone (17-OH-P) and testosterone] and other [bovine-insulin and salmon-calcitonin, human chorionic gonadotropin (hCG), luteinizing hormone (LH) or hCG+DHP] hormones and insulin-like growth factor-I (IGF-I) significantly increased GVBD% in 9 h culture. DHP had a maximum effect (75 %) compared to other effectors. Some effectors (hCG: 82.14 %, LH: 78.94 %, hCG plus DHP: 81.81 %, E2: 80 % and IGF-I: 74.19 %) including DHP (79 %) further increased GVBD% in 15-h culture. All the hormones (except DHP) and IGF-I increased DHP, E2 and testosterone productions by the postvitellogenic ovarian follicles in vitro. DHP and testosterone productions were increased with the increase of incubation time from 9 h through 15 h. E2 production was not further increased beyond 12 h. DHP production was highest by hCG compared to other effectors. The hCG of all the test compounds was most effective in both the induction of GVBD% and steroid production. DHP is the most potent inducer of oocyte maturation in Indian estuarine flat head grey mullet. Involvement of estrogen in mullet oocyte maturation is indicated. hCG, like DHP, is equally potent and induces oocyte maturation via DHP production in vitro. hCG with DHP has synergistic action on oocyte maturation in mullet ovary. Interplay of several hormones (hCG, LH, and probably E2 and testosterone) and IGF-I on oocyte maturation is suggested in the mullet. PMID- 23925892 TI - Mercury distribution in target organs and biochemical responses after subchronic and trophic exposure to neotropical fish Hoplias malabaricus. AB - In the present study, we investigated the mercury distribution, mercury bioaccumulation, and oxidative parameters in the Neotropical fish Hoplias malabaricus after trophic exposure. Forty-three individuals were distributed into three groups (two exposed and one control) and trophically exposed to fourteen doses of methylmercury each 5 days, totalizing the doses of 1.05 MUg g-1 (M1.05) and 10.5 MUg g-1 (M10.5 group). Autometallography technique revealed the presence of mercury in the intestinal epithelia, hepatocytes, and renal tubule cells. Mercury distribution was dose-dependent in the three organs: intestine, liver, and kidney. Reduced glutathione concentration, glutathione peroxidase, catalase, and glutathione S-transferase significantly decreased in the liver of M1.05, but glutathione reductase increased and lipid peroxidation levels were not altered. In the M10.5, most biomarkers were not altered; only catalase activity decreased. Hepatic and muscle mercury bioaccumulation was dose-dependent, but was not influenced by fish sex. The mercury localization and bioaccumulation corroborates some histopathological findings in this fish species (previously verified by Mela et al. in Ecotoxicol Environ Saf 68:426-435, 2007). However, the results of redox biomarkers did not explain histopathological findings previously reported in M10.5. Thus, fish accommodation to the stressor may reestablish antioxidant status at the highest dose, but not avoid cell injury. PMID- 23925893 TI - Glycerol synthesis in freeze-resistant rainbow smelt: towards the characterization of a key enzyme glycerol-3-phosphatase. AB - Rainbow smelt (Osmerus mordax) synthesize high amounts of glycerol in winter as a cryoprotectant through the direct dephosphorylation of glycerol-3-phosphate by a phosphatase, glycerol-3-phosphatase (G3Pase). Such a protein is well described in a few species including fungi, bacteria and plants but never studied beyond tissue homogenates in any animal species. Purification, identification and characterization of this enzyme is thus crucial for a better comprehension of the biochemical adaptation in rainbow smelt in response to low temperature and more generally of the biochemical mechanisms involved in glycerol synthesis in animals. This work presents the first attempt to purify G3Pase from smelt liver, the main site of glycerol synthesis for the whole animal. A partial purification was performed, and some characteristics of the protein determined, including optimal pH, K(m) and cation requirements. Smelt G3Pase is most likely a low molecular weight, Mg+-dependent and cytosolic phosphatase. PMID- 23925894 TI - Effects of salinity acclimation on the expression and activity of Phase I enzymes (CYP450 and FMOs) in coho salmon (Oncorhynchus kisutch). AB - Phase I biotransformation enzymes are critically important in the disposition of xenobiotics within biota and are regulated by multiple environmental cues, particularly in anadromous fish species. Given the importance of these enzyme systems in xenobiotic/endogenous chemical bioactivation and detoxification, the current study was designed to better characterize the expression of Phase I biotransformation enzymes in coho salmon (Oncorhynchus kisutch) and the effects of salinity acclimation on those enzymes. Livers, gills, and olfactory tissues were collected from coho salmon (O. kisutch) after they had undergone acclimation from freshwater to various salinity regimes of seawater (8, 16 and 32 g/L). Using immunoblot techniques coupled with testosterone hydroxylase catalytic activities, 4 orthologs of cytochrome P450 (CYP1A, CYP2K1, CYP2M1, and CYP3A27) were measured in each tissue. Also, the expression of 2 transcripts of flavin-containing monooxygenases (FMO A and B) and associated activities were measured. With the exception of CYP1A, which was down-regulated in liver, protein expression of the other 3 enzymes was induced at higher salinity, with the greatest increase observed in CYP2M1 from olfactory tissues. In liver and gills, 6beta- and 16beta hydroxylation of testosterone was also significantly increased after hypersaline acclimation. Similarly, FMO A was up-regulated in all 3 tissues in a salinity dependent pattern, whereas FMO B mRNA was down-regulated. FMO-catalyzed benzydamine N-oxygenase and methyl p-tolyl sulfoxidation were significantly induced in liver and gills by hypersalinity, but was either unchanged or not detected in olfactory tissues. These data demonstrate that environmental conditions may significantly alter the toxicity of environmental chemicals in salmon during freshwater/saltwater acclimation. PMID- 23925895 TI - Evaluation of noise equivalent count parameters as indicators of adult whole-body FDG-PET image quality. AB - OBJECTIVES: The aim of this study was to assess variation of qualitative and quantitative PET/CT image quality parameters with acquisition time, injection activity and body mass for a representative group of adults undergoing whole-body PET/CT imaging. METHODS: PET scan data from sixty patients were reconstructed with a scan time of 1, 2 and 3 min/bed position. These images were visually scored and three quantitative parameters were calculated: noise equivalent counts per axial length (NECpatient), noise equivalent count density (NECdensity) and liver signal to noise ratio (liver SNR). The ability of the three quantitative parameters to discriminate qualitative image quality was assessed using ROC analysis. RESULTS: The quantitative parameters were shown to discriminate images of good/excellent quality from those of poorer image quality with a high degree of accuracy (ROC area >0.9); further, NECpatient had significantly higher discrimination than either NECdensity or liver SNR (ROC area = 0.97). CONCLUSIONS: NECpatient, NECdensity and liver SNR all have high discrimination for qualitatively assessed PET image quality. NECpatient in particular is an effective objective indicator of patient image quality, which will help to assess and standardise scan protocols for purposes such as multi-centre research trials. PMID- 23925897 TI - Dipyridyl-immobilized ionic liquid type hybrid silica monolith for hydrophilic interaction electrochromatography. AB - A pyridinium-based immobilized ionic liquid type multifunctional hybrid silica monolith was prepared by the in situ polymerization of 3-chloropropyl-silica matrix and 4,4'-dipyridyl for hydrophilic interaction CEC. The obtained hybrid monolith possessed of high stable skeletal microstructures with obviously hydrophilic retention mechanism under ACN content >50% in the mobile phase. Strong and stable anodic EOF could be observed under a broad pH range from pH 3.0 to 9.0. Due to the immobilized dipyridyl groups bonded to the silica matrix surface, the resulting hydrophilic hybrid monolith possessed multiple separation interactions including hydrogen bond, pi-pi, and anion exchange. Excellent separations of various polar analytes including electroneutral phenols, charged acid nucleotides, and basic analytes were successfully achieved. The highest column efficiencies up to 120,000, 164,000, and 106,000 plates/m were obtained for nucleotides, nucleic acid bases, and nucleosides and nicotines, respectively. These results demonstrated that the dipyridyl-immobilized ionic liquid functionalized hybrid monolith possessed highly mechanical stability and good chromatographic performance for hydrophilic interaction electrochromatography. PMID- 23925896 TI - Estrogen and selective estrogen receptor modulators (SERMs) for the treatment of acromegaly: a meta-analysis of published observational studies. AB - Estrogen and selective estrogen receptor modulator (SERM) treatments for acromegaly have received limited attention since the development of newer pharmacologic therapies. There has been ongoing research evidence suggesting their utility in the biochemical control of acromegaly. Therefore, the aim of this meta-analysis was to synthesise current evidence with a view to determining to what extent and in which acromegalic patient subsets do estrogen and SERMs reduce IGF-1 levels. A literature search was conducted (finished December 2012), which included all studies pertaining to estrogen or SERM treatment and IGF-1. Seven patient subsets were identified from six published observational studies, and were pooled using meta-analytic methods. Overall, the pooled mean loss in IGF 1 was -29.09 nmol/L (95 % CI -37.23 to -20.95). A sensitivity analysis indicated that women receiving estrogen had a substantially greater reduction in IGF-1 levels compared with women receiving SERMs, with a weighted mean loss in IGF-1 of -38.12 nmol/L (95 % CI -46.78 to -29.45) compared with -22.91 nmol/L (95 % CI 32.73 to -13.09). There was a trend that did not reach statistical significance for men receiving SERM treatment at -11.41 nmol/L (95 % CI -30.14 to 7.31). It was concluded that estrogen and SERMs are a low cost and effective treatment to achieve control of IGF-1 levels in acromegalic women either as concomitant treatment for refractory disease, or where access to conventional therapy is restricted. Their use in men requires further study. PMID- 23925898 TI - A 72-year-old man with dyspnea, circumferential aortic thickening, and weight loss. PMID- 23925899 TI - Relationship between woody plant colonization and Typha L. encroachment in stormwater detention basins. AB - We studied stormwater detention basins where woody vegetation removal was suspended for 2 years in Virginia, USA to determine if woody vegetation can control Typha populations and how early woody plant succession interacts with Typha, other herbaceous vegetation, and site factors. Distribution and composition of woody vegetation, Typha and non-Typha herbaceous vegetation biomass, and site factors were assessed at 100 plots in four basins ranging in age from 7 to 17 years. A greenhouse study examined the interaction of shade and soil moisture on Typha biomass and persistence. Principal component analysis identified an environmental gradient associated with greater water table depths and decreased elevation that favored Typha but negatively influenced woody vegetation. Elevation was correlated with litter layer distribution, suggesting that initial topography influences subsequent environmental characteristics and thus plant communities. Soil organic matter at 0-10 cm ranged from 5.4 to 12.7%. Woody plants present were native species with the exception of Ailanthus altissima and Pyrus calleryana. In the greenhouse, shade and reduced soil moisture decreased Typha biomass and rhizome length. The shade effect was strongest in flooded plants and the soil moisture effect was strongest for plants in full sun. Typha in dry soil and heavy shade had 95% less total biomass and 83% smaller rhizomes than Typha in flooded soil and full sun, but even moderate soil moisture reductions decreased above- and below-ground biomass by 63 and 56%, respectively. Suspending maintenance allows restoration of woody vegetation dominated by native species and may suppress Typha invasion. PMID- 23925900 TI - Tiny light, big hope. PMID- 23925901 TI - Molecular evolution of the VP7 gene of Japanese G2 rotaviruses before vaccine introduction. AB - Changes in the prevalence of G2 rotavirus after vaccine introduction are an important issue. However, such changes in a given country should be interpreted in the global context over time. We determined 35 Japanese G2 sequences and compared them with 508 globally collected G2 sequences. The D96N substitution, a substitution known to be associated with an abrupt increase in G2 strains and antigenic changes, emerged in those strains that formed a nascent lineage outside of the currently predominant lineage (sublineage IVa). Further studies are warranted to monitor the potential of their global spread, since they also appeared in Europe and Australia. PMID- 23925903 TI - Triterpenoid saponins from the stem barks of Schefflera heptaphylla. AB - Nine new triterpenoid saponins, including four ursane-type triterpenoid saponins named heptursosides A-D (1-4), four oleanane-type triterpenoid saponins named heptoleosides A-D (5-8), and one dammarane-type triterpenoid saponin, heptdamoside A (9), along with two known saponins, asiaticoside D (10) and scheffoleoside B (11), were isolated from the stem barks of Schefflera heptaphylla. Their structures were determined on the basis of spectroscopic analysis and chemical methods. It is noteworthy in this study that the aglycone of 1-6 is reported for the first time, and to the best of our knowledge, this is the first report for the presence of the tetracyclic triterpenoid saponin from Schefflera. All the saponins were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells, and 2, 6, 7, and 10 showed anti-inflammatory activities under their noncytotoxic concentrations. PMID- 23925904 TI - An UFLC-MS/MS method for quantification of panaxadiol in rat plasma and its application to a pharmacokinetic study. AB - Panaxadiol is a novel antitumor agent extracted from the Chinese medical herb Panax ginseng. This agent is being developed for the treatment of tumor diseases. A rapid, selective, and simple method based on ultrafast liquid chromatography tandem mass spectrometry was established and validated to determine panaxadiol in rat plasma following oral and sublingual intravenous administration of panaxadiol. The plasma samples were pretreated with acetic ether, and chromatographic separation was achieved on a Shim-pack XR-ODS III column using isocratic elution with the mobile phase of 0.1 % formic acid and acetonitrile. Analytes and protopanaxadiol (internal standard) were analyzed and identified using electrospray positive ionization mass spectrometry in the multiple reaction monitoring mode. The MS/MS detection was carried out by monitoring the fragmentation of m/z 461.45 -> m/z 127.1 for panaxadiol and m/z 425.4 -> m/z 95.1 for protopanaxadiol (internal standard) on a triple-quadrupole mass spectrometer. The result showed good linearity over a wide concentration range (0.1-20 ng/mL) (R2 > 0.999) and its lower limit of detection and quantification were 0.03 and 0.1 ng/mL, respectively. The intra- and interday precision (RSD %) was within 15 % and the accuracy ranged from 94.9 % to 112.0 %. The absolute bioavailability was 12.5 %. The method was fully validated and successfully applied to the pharmacokinetic study of a single dose of panaxadiol. PMID- 23925915 TI - Lyme arthritis: a comparison of presentation, synovial fluid analysis, and treatment course in children and adults. AB - OBJECTIVE: This case series examines differences in the presentation, management, and outcome of Lyme arthritis between the pediatric and adult population. METHODS: We reviewed charts of pediatric and adult patients evaluated for Lyme arthritis by rheumatologists and pediatric infectious disease specialists in Portland, Maine between January 2002 and July 2008. Patients included for analysis had documented joint swelling and positive Lyme serology. Data on clinical presentation, synovial fluid and peripheral blood results, treatment, and clinical course were analyzed. RESULTS: Twenty-nine adults and 52 children met case criteria for Lyme arthritis. Children were more likely than adults to present acutely (P < 0.0001) and also had higher mean peripheral blood (P = 0.05) and synovial fluid white blood cell counts (P < 0.0001). Lyme arthritis was more frequently suspected in children at presentation (P = 0.04). There was no difference between children and adults with respect to suspicion for septic arthritis, hospitalization, or surgical intervention. Adults received more antibiotic courses (P = 0.007) and were more likely to have intravenous antibiotics in subsequent treatment courses (P = 0.006). Children were more likely to have normal function within 4 weeks of initiating antibiotic treatment (P < 0.0001). CONCLUSION: Children with Lyme arthritis were more likely to present acutely with higher synovial white cell counts than adults. We did not, however, observe a significant difference in hospitalization or surgical management. Children had more prompt resolution of their joint swelling and received less treatment overall. PMID- 23925905 TI - The percentage of FoxP3+Helios+ Treg cells correlates positively with disease activity in systemic lupus erythematosus. AB - OBJECTIVE: To assess the use of Helios in combination with FoxP3 as a superior method for identifying non-cytokine-producing human Treg cells in patients with systemic lupus erythematosus (SLE) and to determine if FoxP3+Helios+ Treg cells are maintained at normal levels in patients with clinically active disease. METHODS: Peripheral blood mononuclear cells (PBMCs) were purified from the blood of healthy volunteer donors and from 52 consecutive patients with SLE of varying clinical activity (Systemic Lupus Erythematosus Disease Activity Index scores of 0, 2-4, and >= 5). PBMCs (either fresh or after 4 hours of stimulation for cytokine production) were then analyzed by flow cytometry for the expression of cell surface markers (CD4, CD25, CD127, and CD45RA) and transcription factors (FoxP3 and Helios), as well as for the production of cytokines (interleukin-2 and interferon-gamma). RESULTS: FoxP3+Helios+ Treg cells were found to be non cytokine producing in both SLE patients and healthy controls. Patients with clinically active SLE had higher percentages of FoxP3+Helios+ Treg cells than did patients with inactive SLE or healthy controls. When corrected for the total CD4 cell count, the absolute numbers of FoxP3+Helios+ Treg cells in patients with moderately-to-highly active SLE were normal. CONCLUSION: Previous reports of a deficiency in Treg cell number or function in SLE are limited by their use of CD25, either alone or in combination with other markers, to identify human Treg cells. Helios in combination with FoxP3 is a superior method for detecting all non-cytokine-producing Treg cells, irrespective of CD25 or CD45RA expression. Using this method, we showed that FoxP3+Helios+ Treg cell numbers are not reduced in patients with clinically active SLE. PMID- 23925916 TI - Physical activity before and after primary total hip arthroplasty: a registry based study. AB - OBJECTIVE: Detailed assessment of activity before and after total hip arthroplasty (THA) including a long-term followup period is lacking. Our objectives were to evaluate patient activity levels prior to disease onset, prior to THA, and at 5 and 10 years after surgery, and to determine the predictors of high activity 5 years after surgery. METHODS: We included elective primary THAs performed between 1996 and 2012. A cross-sectional analysis compared mean University of California, Los Angeles (UCLA) activity scores over 4 periods: prior to symptom onset of osteoarthritis, prior to surgery, 5 years after surgery, and 10 years after surgery. Analyses of activity levels were performed and stratified by sex, age, body mass index (BMI), American Society of Anesthesiology (ASA) classes, and preoperative activity level. A prospective study was conducted to identify baseline characteristics associated with a high activity level (UCLA score >=7) 5 years after surgery using logistic regression. RESULTS: The mean UCLA activity scores prior to symptom onset (n = 189), prior to THA (n = 203), 5 years after surgery (n = 1,085), and 10 years after surgery (n = 757) were 6.9, 3.5, 5.7, and 5.5, respectively. Postoperative scores were close to values prior to symptom onset in patients ages >=55 years, but were lower in those who were younger. High activity was reported by 49% of patients prior to symptom onset, 5% of patients prior to surgery, and 28% of patients at both 5 and 10 years after surgery. The predictors of high activity at 5 years were younger age, male sex, a lower BMI, a lower ASA score, and an active lifestyle prior to surgery. CONCLUSION: Five and 10 years after primary THA, physical activity levels were substantially higher in men and women and in all age categories as compared to before surgery. PMID- 23925917 TI - Major determinants of acute primary angle closure demonstrated by anterior segment optical coherence tomography. PMID- 23925918 TI - Macrophages coming of age: their role in promoting CNV is modulated by FasL. PMID- 23925919 TI - Multicenter experience of the newly designed covered metallic ureteral stent for malignant ureteral occlusion: comparison with double J stent insertion. AB - PURPOSE: This study was designed to evaluate the effectiveness of the newly designed covered metallic stent (CMS) for malignant ureteral obstruction by comparing with double J stent (DJS). MATERIAL AND METHODS: CMSs were placed for malignant ureteral obstruction caused by various types of cancers for 42 ureters in 32 patients from 7 institutes. Retrospective data were collected for DJSs, which included 72 malignant ureteral occlusions in 56 patients from a single institute. Twenty-seven DJSs were placed percutaneously, and 45 DJSs were cystoscopically inserted. Technical failure of the CMS group was compared with that of the radiologically inserted DJS group. Primary patency of the CMS group was compared with assisted primary patency of the DJS group. RESULTS: Technical failure of the CMS group is lower than that of the radiologically inserted DJS group: 0% (0/42) vs. 25.9% (7/27; p = 0.002), respectively. Primary patency of the CMS group is better than assisted primary patency of the DJS group (p = 0.012). Primary patency of the CMSs is 100, 94.5, 74.7, 70.3, 65.3, 65.3, and 65.3% at 1, 3, 6, 9, 12, 18, and 24 months, respectively. Assisted primary patency of the DJS is 78.6, 75.1, 59.1, 48.7, 38.7, and 37.8% at 1, 3, 6, 9, 12, and 18 months, respectively. No serious complications were noted in the CMS group. Migration of the metallic stent occurred in one patient (2.3%). CONCLUSIONS: Covered metallic stent placement for malignant ureteral obstruction is superior to the double J stent placement in terms of technical success and patency. PMID- 23925920 TI - Coil-assisted RFA of poorly visible liver tumors: effectiveness and risk factors of local tumor progression. AB - OBJECTIVES: This study was designed to determine the effectiveness of a percutaneously inserted coil as a landmark before radiofrequency ablation (RFA) of poorly visible liver tumors on unenhanced computed tomography and ultrasound. METHODS: This was a single-center, retrospective study of 46 consecutive patients treated from January 2008 to June 2012 with RFA under CT guidance for 57 poorly visible liver tumors after percutaneous coil insertion. Effectiveness was evaluated by the rate of local tumor progression (LTP), and the risk factors of LTP were evaluated by multiple univariate analysis. RESULTS: After a mean follow up of 15.9 months, the overall rate of LTP was 22.8 % (13/57). An increase in the distance between the coil and the center of the tumor was a predictive factor of LTP (p = 0.005) and resulted in an increase in time to place the RFA probe. LTP was significantly reduced in case of coil placed within the tumor (10 vs. 43.5 %, p = 0.009). CONCLUSIONS: The effectiveness of the "coil-assisted" RFA for poorly visible liver tumors is improved by centering the coil in the tumor in order to facilitate the placement of the RFA probe and equal to the results of RFA under direct image guidance. PMID- 23925922 TI - Dopamine neurons are multi-neurotransmitter neurons. PMID- 23925921 TI - Characterization of a hybrid dielectrophoresis and immunocapture microfluidic system for cancer cell capture. AB - The capture of circulating tumor cells (CTCs) from cancer patient blood enables early clinical assessment as well as genetic and pharmacological evaluation of cancer and metastasis. Although there have been many microfluidic immunocapture and electrokinetic techniques developed for isolating rare cancer cells, these techniques are often limited by a capture performance tradeoff between high efficiency and high purity. We present the characterization of shear-dependent cancer cell capture in a novel hybrid DEP-immunocapture system consisting of interdigitated electrodes fabricated in a Hele-Shaw flow cell that was functionalized with a monoclonal antibody, J591, which is highly specific to prostate-specific membrane antigen expressing prostate cancer cells. We measured the positive and negative DEP response of a prostate cancer cell line, LNCaP, as a function of applied electric field frequency, and showed that DEP can control capture performance by promoting or preventing cell interactions with immunocapture surfaces, depending on the sign and magnitude of the applied DEP force, as well as on the local shear stress experienced by cells flowing in the device. This work demonstrates that DEP and immunocapture techniques can work synergistically to improve cell capture performance, and it will aid in the design of future hybrid DEP-immunocapture systems for high-efficiency CTC capture with enhanced purity. PMID- 23925924 TI - Education, self-management, and upper extremity exercise training in people with rheumatoid arthritis: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of a brief supervised education, self management, and global upper extremity exercise training program, supplementing a home exercise regimen, for people with rheumatoid arthritis (RA; the Education, Self-Management, and Upper Extremity Exercise Training in People with Rheumatoid Arthritis [EXTRA] program). METHODS: Adults with RA of <=5 years' duration were randomized to receive either usual care or the EXTRA program comprising 4 (1 hour) group education, self-management, and global upper extremity exercise training sessions supplementing the first 2 weeks of a 12-week individualized, functional home exercise regimen in addition to usual care. Outcome measures were assessed at baseline, 12 weeks (primary end point), and 36 weeks and included the Disabilities of the Arm, Shoulder, and Hand questionnaire (primary outcome measure), the Grip Ability Test, handgrip strength (N), the Arthritis Self Efficacy Scale (pain, function, and symptoms subscales), and the 28-joint Disease Activity Score. RESULTS: One hundred eight participants (26 men, mean +/- SD age 55 +/- 15 years, mean +/- SD disease duration 20 +/- 19 months) were randomized to receive either usual care (n = 56) or the EXTRA program (n = 52). At 12 weeks, there was a significant between-group difference in the mean change in disability (-6.8 [95% confidence interval (95% CI) -12.6, -1.0]; P = 0.022), function (-3.0 [95% CI -5.0, -0.5]; P = 0.011), nondominant handgrip strength (31.3N [95% CI 9.8, 52.8]; P = 0.009), self-efficacy (10.5 [95% CI 1.6, 19.5]; P = 0.021 for pain and 9.3 [95% CI 0.5, 18.2]; P = 0.039 for symptoms), and disease activity ( 0.7 [95% CI -1.4, 0.0]; P = 0.047), all favoring the EXTRA program. CONCLUSION: The EXTRA program improves upper extremity disability, function, handgrip strength, and self-efficacy in people with RA, with no adverse effects on disease activity. PMID- 23925923 TI - Clinical and laboratory features distinguishing juvenile polymyositis and muscular dystrophy. AB - OBJECTIVE: To differentiate juvenile polymyositis (PM) and muscular dystrophy, both of which may present with chronic muscle weakness and inflammation. METHODS: We studied 39 patients with probable or definite juvenile PM and 9 patients with muscular dystrophies who were initially misdiagnosed as having juvenile PM. Differences in demographic, clinical, and laboratory results; outcomes; and treatment responses were evaluated by Fisher's exact and rank sum tests. Random forests classification analysis and logistic regression were performed to examine significant differences in multivariable models. RESULTS: Clinical features and serum muscle enzyme levels were similar between juvenile PM and dystrophy patients, except 89% of dystrophy patients had muscle atrophy compared with 46% of juvenile PM patients. Dystrophy patients had a longer delay to diagnosis (median 12 versus 4 months) and were less frequently hospitalized than juvenile PM patients (22% versus 74%). No dystrophy patients, but 54% of juvenile PM patients, had a myositis autoantibody. Dystrophy patients more frequently had myopathic features on muscle biopsy, including diffuse variation of myofiber size, fiber hypertrophy, and myofiber fibrosis (44-100% versus 8-53%). Juvenile PM patients more frequently had complex repetitive discharges on electromyography and a complete response to treatment with prednisone or other immunosuppressive agents than dystrophy patients (44% versus 0%). Random forests analysis revealed that the most important features in distinguishing juvenile PM from dystrophies were myositis autoantibodies, clinical muscle atrophy, and myofiber size variation on biopsy. Logistic regression confirmed muscle atrophy, myofiber fibrosis, and hospitalization as significant predictors. CONCLUSION: Muscular dystrophy can present similarly to juvenile PM. Selected clinical and laboratory features are helpful in combination in distinguishing these conditions. PMID- 23925925 TI - Successful weaning from mechanical ventilation using phrenic nerve stimulation. PMID- 23925927 TI - Firearm injuries and death: the cost of shooting in the dark. PMID- 23925926 TI - The effect of a Rapid Access Prostate Cancer Clinic on prostate cancer patient and disease characteristics, primary treatment and surgical workload. AB - BACKGROUND: In 2009, Rapid Access Prostate Cancer Clinics (RAPC) were introduced to St. James's Hospital to improve the access and organisation of patients to prostate cancer investigations and treatment. AIMS: To observe the effects of the RAPC on prostate cancer diagnosis, primary treatment and overall workload. METHODS: Using a prospectively designed patient database, the records of all prostate cancer patients between 2007 and 2011 were retrieved and analysed. Data were obtained for age, PSA, biopsy Gleason score and primary treatment modality and charted for the observation and comparison of trends. RESULTS: Seven hundred and eighty-nine patients had a new diagnosis of prostate cancer between 2007 and 2011. The median PSA prior to the RAPC was 9.7-13.1 ng/ml, which decreased to 7.79-9 ng/ml after the RAPC. Prior to the RAPC, 77-81 biopsies were performed annually versus 149-271 in the post-RAPC era. Annual requirements for radical prostatectomy also increased from 12 to 27 in the post-RAPC era. Conversely, an initially increasing percentage of patients for radiotherapy was reversed in the post-RAPC period. An increasing trend for higher grade PCa (Gleason score 4 + 4 and higher) was also reversed. CONCLUSIONS: The introduction of a RAPC improves the overall pathological characteristics of patients with prostate cancer. However, RAPCs are also associated with a considerable increase in surgical workload. These are important considerations for units considering the incorporation of a similar facility in their institutions. PMID- 23925928 TI - Mycelium growth stimulation of the desert truffle Terfezia claveryi chatin by beta-cyclodextrin. AB - The commercial value of Terfezia claveryi, an edible desert truffle with important gastronomic, nutritional, and antioxidant properties, has led to growing interest in its cultivation. The erratic and slow growth of T. claveryi mycelium in vitro represents an impairment to obtain mycorrhizal plants, and it makes necessary to find a new culture medium able to overcome these drawbacks. In this work, we analyze the effect of cyclodextrins (CDs) on the growth of T. claveryi mycelium. Different parameters, including colony diameter, growth rate, and colony fresh weight, were evaluated, both in the presence and absence of these encapsulant agents. The results obtained confirm the ability of CDs to stimulate the growth of T. claveryi mycelium when present in the culture medium. A similar effect was observed when CDs were added to the culture medium of Tuber melanosporum. Three natural (alpha-, beta-, and gamma) and two modified (hydroxypropil-beta and methyl-beta) CDs were assayed. The best results were obtained with beta-cyclodextrin, but no improvement was observed with its chemically modified derivatives. CDs complex the different compounds present in the culture medium which impair mycelial growth. PMID- 23925929 TI - Patients with malignant hematological disorders treated on a palliative care unit: prognostic impact of clinical factors. AB - A reliable estimation of prognosis in patients receiving palliative care is desirable in order to facilitate clinical decision finding. For patients with advanced hematological malignancies, only few data are available to estimate prognosis of the individual's remaining life span. Here, we sought to investigate potential clinical prognostic parameters in patients with hematological malignancies admitted to a palliative care unit. Using a prospectively collected database, we analyzed clinical and laboratory parameters regarding their prognostic impact in 290 patients with malignant hematological diseases. The parameters included patient-related factors such as Eastern Cooperative Oncology Group (ECOG) performance status, need for transfusions, parenteral nutrition or analgetics, and laboratory values (hemoglobin, platelet count, lactic dehydrogenase (LDH), albumin, total protein, calcium, and C-reactive protein (CRP)) as well as referral symptoms (including anemia, infection, fever, fatigue, and dyspnea). In univariate analyses, LDH (>248 U/l), albumin corrected calcium (>2.55 mmol/l), CRP (>50 mg/l), albumin (<30 g/l), platelet count (<90 * 10(9)/l), total protein (<=60 g/l), hemoglobin (<10 g/dl), opioid treatment, performance status (ECOG >2), and need for parenteral nutrition or blood transfusion significantly correlated with impaired survival. Multivariate analysis showed that low performance status, low platelet count, opioid based pain therapy, high LDH, and low albumin were associated with poor prognosis. Using these five parameters, patients were divided into three "risk groups": low risk (presence of zero to one factor), intermediate risk (two to three factors), and high risk. Median survival for the poor risk patients was 10 days, and the intermediate and low risk patients survived a median of 63 and 440 days, respectively (p < 0.0001). Several clinical and laboratory parameters were associated with a poor prognosis of patients with hematological malignancies treated on a palliative care unit. These parameters might help clinicians to estimate prognosis of remaining life span and individualize treatment and/or end of-life care options for patients. PMID- 23925930 TI - Rituximab plus bendamustine is active in pretreated patients with extragastric marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma). AB - Recently, the combination of rituximab and bendamustine (R-Benda) has been defined as highly active in patients with follicular lymphomas, but little is known about the efficacy of R-Benda in mucosa-associated lymphoid tissue (MALT) lymphoma. In a retrospective analysis, we have defined 14 patients with MALT lymphoma undergoing therapy with R-Benda. Seven patients were female and seven male (aged 44-88 years), and all had relapsed extragastric MALT lymphoma. R-Benda was given at first relapse in ten patients, while four patients had more than two prior forms of therapy. Bendamustine was given at a dose of 90 mg/m(2) on days 2 and 3 in ten patients and at 70 mg/m(2) in three patients, while all received 375 mg/m(2) rituximab on day 1. Ten patients received six courses of therapy, while two patients discontinued therapy after three, and one after four courses for personal reasons, while one patient had progressive disease after four courses. Tolerance of therapy was excellent, and all except one patient responded. Ten patients achieved a complete remission (CR) (71 %), three a partial remission (21 %), while one patient progressed. Toxicities were mild and mainly hematological but did not result in relevant delays or the necessity for dose reductions. After a median follow-up of 23 months (range, 4-42+), 13 patients are alive and one patient has relapsed 23 months after initial CR. Our data suggest high activity and good tolerance of R-Benda in patients with relapsed MALT lymphoma despite intensive pretreatment in some patients. In view of this, prospective studies are warranted. PMID- 23925931 TI - Electric migration of alpha-hemolysin in supported n-bilayers: a model for transmembrane protein microelectrophoresis. AB - Proteome analysis involves separating proteins as a preliminary step toward their characterization. This paper reports on the translational migration of a model transmembrane protein (alpha-hemolysin) in supported n-bilayers (n, the number of bilayers, varies from 1 to around 500 bilayers) when an electric field parallel to the membrane plane is applied. The migration changes in direction as the charge on the protein changes its sign. Its electrophoretic mobility is shown to depend on size and charge. The electrophoretic mobility varies as 1/R(2), with R the equivalent geometric radius of the embedded part of the protein. Measuring mobilities at differing pH in our system enables us to determine the pI and the charge of the protein. Establishing all these variations points to the feasibility of electrophoretic transport of a charged object in this medium and is a first step toward electrophoretic separation of membrane proteins in n bilayer systems. PMID- 23925932 TI - [Assessing desire for suicide: first results on psychometric properties of the German version of the Interpersonal Needs Questionnaire (INQ)]. AB - OBJECTIVES: The Interpersonal Needs Questionnaire (INQ) assesses desire for suicide according to the Interpersonal Theory of Suicide. Psychometric properties of the German version of the INQ are investigated. METHODS: The INQ was applied in a sample of 281 undergraduate students to investigate dimensionality, reliability and validity. RESULTS: The 2-factorial structure of the original version was confirmed for the German version of the INQ in this sample. The subscales "Perceived Burdensomeness" (alpha = 0.88) and "Thwarted Belongingness" (alpha = 0.83) show very good internal consistencies. Both subscales show medium range correlations with depressiveness. There are significantly higher levels of "Perceived Burdensomeness" and "Thwarted Belongingness" in participants with current suicidal ideation or prior suicidal or self-injuring behaviour. CONCLUSION: These findings show that the German version of the INQ has good psychometric properties. Further research is needed to replicate these findings in clinical samples, and to test the utility of the INQ in predicting and preventing suicidal behaviour in patients at risk. PMID- 23925933 TI - [Compulsory measures and pathological creatine kinase levels in psychiatric in patients]. AB - The aim of this study was to investigate the association of compulsory measures (CM) with pathological Creatine Kinase (CK) levels in 317 patients admitted to a secure psychiatric ward. The assumptions is that CK-activity is increased prior to administration of CM because increases in CK-levels may represent aggressive behaviour as precursors of a higher chance of administrating CM. The CK-levels were assessed immediately following admission. During the course of the patients' stay the frequency of different CM was assessed by the use of the Staff Observation Aggression Scale. In a CHAID analysis pathological CK-levels were associated with subsequent administration of CM. Lifetime aggression and main diagnosis were associated with administration of CM as well. In a ROC analysis concerning pathological CK-activity the AUC for subsequent administration of CM was 70.5 % with a sensitivity of 73.5 % and a specifity of 67.5 %. Despite some methodological shortcomings the study indicates that it could be useful to measure CK-activity at the time of admission because pathological levels may indicate an increased probability of administration of CM subsequent to aggressive behaviour. PMID- 23925935 TI - Usefulness of power Doppler ultrasound for prediction of re-therapy with rituximab in rheumatoid arthritis: a prospective study of longstanding rheumatoid arthritis patients. AB - OBJECTIVE: To assess the value of gray-scale (GS) and power Doppler (PD) ultrasound (US) in detecting inflammatory/destructive changes and for prediction of necessity of re-therapy with rituximab (RTX) in patients with rheumatoid arthritis (RA) over 1 year of followup. METHODS: GSUS and PDUS were performed to assess synovitis, tenosynovitis, and erosions on the clinically dominant hand and forefoot of 20 patients with RA before and after therapy with RTX. US parameters were compared with clinical (Disease Activity Score in 28 joints, tender/swollen joint counts, and patients' visual analog scale of disease activity) and laboratory parameters (C-reactive protein level and erythrocyte sedimentation rate). Results were compared for patients with and without re-therapy with RTX. RESULTS: Significant decreases in clinical and laboratory parameters were observed after 6 and 12 months. US synovitis scores significantly decreased after 6 and 12 months (P < 0.05 for each). Regarding patients who received re-therapy between 6 and 9 months after the start of therapy (n = 9), a fair therapy response was still detectable before re-therapy. In these patients, PD-positive synovitis was the only parameter that increased up to the 6-month examination. All patients negative for rheumatoid factor and anti-cyclic citrullinated peptide (n = 4) were in the group of patients receiving a second course of treatment. Seropositive patients showed a better response to treatment with less need for re therapy. CONCLUSION: Response to therapy was measurable by clinical and laboratory parameters as well as by US. Since PDUS was able to detect the onset of disease activity before worsening of clinical symptoms occurred, PDUS is most helpful in evaluating disease activity and making earlier therapy decisions. PMID- 23925934 TI - Cholera toxin subunit B peptide fusion proteins reveal impaired oral tolerance induction in diabetes-prone but not in diabetes-resistant mice. AB - The cholera toxin B subunit (CTB) has been used as adjuvant to improve oral vaccine delivery in type 1 diabetes. The effect of CTB/peptide formulations on Ag specific CD4(+) T cells has remained largely unexplored. Here, using tetramer analysis, we investigated how oral delivery of CTB fused to two CD4(+) T-cell epitopes, the BDC-2.5 T-cell 2.5 mi mimotope and glutamic acid decarboxylase (GAD) 286-300, affected diabetogenic CD4(+) T cells in nonobese diabetic (NOD) mice. When administered i.p., CTB-2.5 mi activated 2.5 mi(+) T cells and following intragastric delivery generated Ag-specific Foxp3(+) Treg and Th2 cells. While 2.5 mi(+) and GAD-specific T cells were tolerized in diabetes resistant NODxB6.Foxp3(EGFP) F1 and nonobese resistant (NOR) mice, this did not occur in NOD mice. This indicated that NOD mice had a recessive genetic resistance to induce oral tolerance to both CTB-fused epitopes. In contrast to NODxB6.Foxp3(EGFP) F1 mice, oral treatment in NOD mice lead to strong 2.5 mi(+) T cell activation and the sequestration of these cells to the effector-memory pool. Oral treatment of NOD mice with CTB-2.5 mi failed to prevent diabetes. These findings underline the importance of investigating the effect of oral vaccine formulations on diabetogenic T cells as in selected cases they may have counterproductive consequences in human patients. PMID- 23925936 TI - Effect of carpal tunnel syndrome on grip and pinch strength compared with sex- and age-matched normative data. AB - OBJECTIVE: To compare grip and pinch strength of individuals with carpal tunnel syndrome (CTS) to normative values before and after a combined splint/stretching intervention. METHODS: Data collected on grip and pinch strength on 124 subjects with CTS were compared to age- and sex-matched normative data. RESULTS: In general, our sample had significantly lower strength than the normative sample at baseline. Although there were significant improvements in strength after 4 weeks of splinting/exercise, subjects continued to have significant deficits in comparison to the normative data. CONCLUSION: Patients with CTS have moderate to large deficits in grip and pinch strength in comparison to normative data. Splinting/stretching may reduce these deficits; however, CTS patients are often left with residual problems at 4 weeks. PMID- 23925937 TI - Alpha-synuclein: one key opens many locks. PMID- 23925938 TI - Resurgence of penicillin-susceptible Staphylococcus aureus at a hospital in New York State, USA. PMID- 23925939 TI - Seedling-herbivore interactions: insights into plant defence and regeneration patterns. AB - BACKGROUND: Herbivores have the power to shape plant evolutionary trajectories, influence the structure and function of vegetation, devastate entire crops, or halt the spread of invasive weeds, and as a consequence, research into plant herbivore interactions is pivotal to our understanding of plant ecology and evolution. However, the causes and consequences of seedling herbivory have received remarkably little attention, despite the fact that plants tend to be most susceptible to herbivory during establishment, and this damage can alter community composition and structure. SCOPE: In this Viewpoint article we review why herbivory during early plant ontogeny is important and in so doing introduce an Annals of Botany Special Issue that draws together the latest work on the topic. In a synthesis of the existing literature and a collection of new studies, we examine several linked issues. These include the development and expression of seedling defences and patterns of selection by herbivores, and how seedling selection affects plant establishment and community structure. We then examine how disruption of the seedling-herbivore interaction might affect normal patterns of plant community establishment and discuss how an understanding of patterns of seedling herbivory can aid our attempts to restore semi-natural vegetation. We finish by outlining a number of areas where more research is required. These include a need for a deeper consideration of how endogenous and exogenous factors determine investment in seedling defence, particularly for the very youngest plants, and a better understanding of the phylogenetic and biogeographical patterns of seedling defence. There is also much still be to be done on the mechanisms of seedling selection by herbivores, particularly with respect to the possible involvement of volatile cues. These inter-related issues together inform our understanding of how seedling herbivory affects plant regeneration at a time when anthropogenic change is likely to disrupt this long-established, but all-too often ignored interaction. PMID- 23925940 TI - Dietary intake of naturally occurring plant sterols is related to a lower risk of a first myocardial infarction in men but not in women in northern Sweden. AB - Dietary intake of naturally occurring plant sterols is inversely related to serum cholesterol concentrations. Elevated serum cholesterol increases the risk of myocardial infarction (MI), but it is unknown if this can be reduced by dietary intake of naturally occurring plant sterols. Our aim was to investigate if a high intake of naturally occurring plant sterols is related to a lower risk of contracting a first MI. The analysis included 1005 prospective cases (219 women, 786 men) and 3148 matched referents (723 women, 2425 men), aged 29-73 y at baseline, from the population-based Northern Sweden Health and Disease Study. A food frequency questionnaire (FFQ) was completed at baseline. Absolute plant sterol intake was inversely related to the risk of a first MI in men (OR highest vs. lowest quartile = 0.70; 95% CI: 0.53, 0.85; P-trend = 0.006) but not in women. After adjustment for confounders, the estimated risk was somewhat attenuated (OR highest vs. lowest quartile = 0.71; 95% CI: 0.55, 0.92; P-trend = 0.067), suggesting that increasing sterol intake from 150 to 340 mg/d reduces the risk of a first MI by 29%. Energy-adjusted plant sterol intake was not related to the risk of a first MI in either men or women. In conclusion, the findings of this observational study show that a high absolute intake of naturally occurring plant sterols is significantly related to a lower risk of a first MI in men in northern Sweden, whereas no significant relation was seen for energy-adjusted plant sterol intake. In women, no significant associations were found. The results from this study show that intake of plant sterols may be important in prevention of MI. PMID- 23925941 TI - Hyperbaric oxygen treatment and N-acetylcysteine ameliorate acetaminophen-induced liver injury in a rat model. AB - An overdose of acetaminophen (APAP) produces centrilobular hepatocellular necrosis. We aimed to investigate the hepatoprotective effects of N acetylcysteine (NAC) only and hyperbaric oxygen (O(2)) treatment (HBOT) combined with NAC, and their anti-inflammatory properties in liver tissue. In the current study, a total of 32 male Sprague Dawley rats were divided into 4 groups: sham, APAP, NAC, and NAC + HBOT. In the APAP, NAC, and NAC + HBOT groups, liver injury was induced by oral administration of 1 g/kg APAP. The NAC group received 100 mg/kg NAC per day. NAC + HBOT group received intraperitoneal injection of 100 mg/kg/day NAC and were given HBOT at 2.8 ATA pressure with 100% O(2) inhalation for 90 min every 12 h for 5 days. Rats in the sham group received distilled water only by gastric tube. All animals were killed on day 6 after APAP or distilled water administration. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, hepatic neopterin, tumor necrosis factor-alpha (TNF-alpha), and interleukin 6 (IL-6) levels were measured. There was a significant increase in serum AST and ALT activities in the APAP group compared with the sham group (in both p = 0.001). NAC and NAC + HBOT groups had significant decreases in hepatic neopterin, TNF-alpha, and IL-6 levels compared with the APAP group. APAP administration caused extensive hepatic necrosis. NAC and NAC + HBO treatments significantly reduced APAP-induced liver injury. Our results showed that the liver damage in APAP toxicity was attenuated by NAC and NAC + HBO treatments. NAC + HBOT exhibit hepatoprotective activity against APAP induced liver injury in rats. PMID- 23925942 TI - Effects of chromium picolinate on the viability of chick embryo fibroblast. AB - Chromium picolinate (CrPic), which is used as a nutritional supplement and to treat type 2 diabetes, has gained much attention because of its cytotoxicity. This study evaluated the effects of CrPic on the viability of the chick embryo fibroblast (CEF) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, morphological detection, and flow cytometry. The results show that lower concentrations of CrPic (8 and 16 MUM) did not damage CEF viability (p > 0.05). However, higher CrPic concentrations (400 and 600 MUM) indicated a highly significant effect on the production of intracellular reactive oxygen species, alteration of mitochondrial membrane potential, intracellular calcium ion concentration, and the apoptosis rate (p < 0.01), contrary to lower CrPic concentrations (8 and 16 MUM) and control group. Moreover, apoptotic morphological changes induced by these processes in CEF were confirmed using Hoechst 33258 staining. Cell death induced by higher concentrations of CrPic was caused by an apoptotic and a necrotic mechanism, whereas the main mechanism of oxidative stress-induced mitochondrial dysfunction was apoptotic death. PMID- 23925943 TI - Effect of flavonoids and hyperthermal intraperitoneal chemotherapy on tumour growth and micronucleus induction in mouse tumour model. AB - Hyperthermia enhanced the clastogenicity of alkylating agents. We investigated whether quercetin (QU; 3,3',4',5,7-pentahydroxy flavone) or naringenin (NAR) can sensitize Ehrlich ascites tumour (EAT) to cisplatin (CP) hyperthermal intraperitoneal chemotherapy treatment and whether these flavonoids in combination with CP can ameliorate CP-induced micronuclei (MNs) in peripheral blood reticulocytes of mice. QU or NAR were administered to mice 7 and 3 days before implantation of EAT cells, while CP (5 or 10 mg kg-1) was injected intraperitoneally to normothermic or hyperthermic-treated mice 3 days after implantation of EAT cells (2 106). Our study supports the claim that the QU or NAR in combined treatment with CP has the potential to inhibit tumour growth in both normothermic and hyperthermic conditions and attenuate number of MNs in the peripheral blood reticulocytes of mice at normothermic condition but enhanced the clastogenicity of CP agents in hyperthermal condition. PMID- 23925944 TI - Nicotine induces alteration of H3K27 demethylase UTX in kidney cancer cell. AB - Cigarette smoking is one of the most important risk factors for kidney cancer, but the molecular mechanism is poorly understood. To examine the expression change of histone H3 on lysine 27 trimethylase (H3K27me3) demethylases ubiquitously transcribed TPR gene on the X chromosome (UTX) in kidney cancer cell line 786-O after nicotine treatment, quantitative real-time-polymerase chain reaction and western blotting analysis were carried out. These results showed that nicotine can increase UTX messenger RNA and protein levels and also decrease the content of H3K27me3. The decreased content of H3K27me3 may activate specific gene expression and lead to kidney cancer. Future investigation on nicotine induced UTX expression and its epigenetic effect would deepen our understanding on nicotine toxicity and carcinogenicity. PMID- 23925945 TI - Carvacrol ameliorates thioacetamide-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in liver of Wistar rats. AB - The present study was designed to investigate the protective effects of carvacrol against thioacetamide (TAA)-induced oxidative stress, inflammation and apoptosis in liver of Wistar rats. In this study, rats were subjected to concomitant prophylactic oral pretreatment of carvacrol (25 and 50 mg kg(-1) body weight (b.w.)) against the hepatotoxicity induced by intraperitoneal administration of TAA (300 mg kg(-1) b.w.). Efficacy of carvacrol against the hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes, and expressions of inflammation and apoptosis. Carvacrol pretreatment prevented deteriorative effects induced by TAA through a protective mechanism in a dose-dependent manner that involved reduction of oxidative stress, inflammation and apoptosis. We found that the protective effect of carvacrol pretreatment is mediated by its inhibitory effect on nuclear factor kappa B activation, Bax and Bcl-2 expression, as well as by restoration of histopathological changes against TAA administration. We may suggest that carvacrol efficiently ameliorates liver injury caused by TAA. PMID- 23925946 TI - A 12-week intramuscular toxicity study of risperidone-loaded microspheres in Beagle dogs. AB - Long-acting formulations of antipsychotics are important treatment options to increase the compliance of schizophrenic patients. Risperidone, a 5-HT2 and dopaminergic D2 receptor antagonist, was developed as long-acting sustained release microspheres with poly(lactide-co-glycolide) (PLGA) as a drug carrier for the treatment of schizophrenia. In the present study, the main objective is to determine the nonclinical safety profile of risperidone-loaded microspheres (RM) in Beagle dogs after intramuscular administration for 3 months, once in 2 weeks, followed by 8-week recovery phase. No animal death was found and no special toxicological findings were observed. The findings, such as hypoactivity, ptosis, increased heart rate, and elevated serum and pituitary prolactin levels, were observed and related to the pharmacological effects of risperidone. The changes in the reproductive system (uterus, ovary, vagina, cervix, and mammary gland) were considered secondary to the prolactin elevation, and the congestion of spleen was related to risperidone. The foreign body granulomas at injection sites might be caused by PLGA. At the end of recovery phase, the above changes mostly recovered to normal, and on administering 3 mg/kg dose level once in 2 weeks on Beagle dogs showed no observed adverse effect. Taken together, RM had exhibited the acceptable safety. PMID- 23925947 TI - Different types of aqueous two-phase systems for biomolecule and bioparticle extraction and purification. AB - Upstream improvements have led to significant advances in the productivity of biomolecules and bioparticles. Today, downstream processes are the bottleneck in the production of some biopharmaceuticals, a change from previous years. Current purification platforms will reach their physical limits at some point, indicating the need for new approaches. This article reviews an alternative method to extract and purify biomolecules/bioparticles named aqueous two-phase system (ATPS). Biocompatibility and readiness to scale up are some of the ATPS characteristics. We also discuss some of ATPS applications in the biotechnology field. PMID- 23925948 TI - Nitrogen deposition weakens plant-microbe interactions in grassland ecosystems. AB - Soil carbon (C) and nitrogen (N) stoichiometry is a main driver of ecosystem functioning. Global N enrichment has greatly changed soil C : N ratios, but how altered resource stoichiometry influences the complexity of direct and indirect interactions among plants, soils, and microbial communities has rarely been explored. Here, we investigated the responses of the plant-soil-microbe system to multi-level N additions and the role of dissolved organic carbon (DOC) and inorganic N stoichiometry in regulating microbial biomass in semiarid grassland in northern China. We documented a significant positive correlation between DOC and inorganic N across the N addition gradient, which contradicts the negative nonlinear correlation between nitrate accrual and DOC availability commonly observed in natural ecosystems. Using hierarchical structural equation modeling, we found that soil acidification resulting from N addition, rather than changes in the plant community, was most closely related to shifts in soil microbial community composition and decline of microbial respiration. These findings indicate a down-regulating effect of high N availability on plant-microbe interactions. That is, with the limiting factor for microbial biomass shifting from resource stoichiometry to soil acidity, N enrichment weakens the bottom-up control of soil microorganisms by plant-derived C sources. These results highlight the importance of integratively studying the plant-soil-microbe system in improving our understanding of ecosystem functioning under conditions of global N enrichment. PMID- 23925949 TI - Characterization of human papillomavirus by capillary isoelectric focusing with whole-column imaging detection. AB - CIEF with whole-column imaging detection (WCID) can be a useful tool for the characterization and identification of human papillomavirus (HPV). This article is the initial report of the determination of the pI of HPV by CIEF-WCID method. In this study, components of the assay selected for optimization were ampholytes, additives, methylcellulose concentration, HPV concentration, salt concentration, and focusing time. Then the optimization CIEF-WCID method was validated for HPV 16L1 and HPV 18L1. As a result, a precise method to analyze the pI values of HPVs was achieved with RSD < 1.0%. The HPV peak pattern was reproducible. CIEF-WCID had great potential for HPV quality control, as WCID eliminated the mobilization step required by the conventional single-point detection. In the example, the five HPVs displayed pI values of 8.43 +/- 0.06 (n = 10; HPV 6L1), 8.70 +/- 0.04 (n = 10; HPV 11L1), 7.94 +/- 0.05 (n = 18; HPV 16L1), 7.57 +/- 0.04 (n = 18; HPV 18L1), and 8.45 +/- 0.05 (n = 10; HPV 58L1). This CIEF-WCID platform could be a powerful analytical tool for characterization, process development support, release testing, and stability study in pharmaceutical industry. PMID- 23925950 TI - Prevalence of abnormal patellofemoral congruence in elite American football players and association with quadriceps isokinetic testing. AB - Abnormal patellofemoral joint alignment has been discussed as a potential risk factor for patellofemoral disorders and can impact the longevity of any elite athlete's career. The prevalence of abnormal patellofemoral congruence in elite American football athletes is similar to the general population and does not have a relationship with quadriceps isokinetic testing. A total of 125 athletes (220 knees) from the 2011 National Football League (NFL) Combine database who had radiographic and isokinetic studies were reviewed. Congruence angles (CA) and lateral patellofemoral angles (LPA) were calculated on a Merchant radiographic view. Isokinetic testing was used to determine quadriceps-to-hamstring strength (Q/H) ratio and side-to-side deficits. The relationships between abnormal CA and LPA with Q/H ratios, side-to-side deficits, and body mass index (BMI) were examined in separate logistic regression models. A Chi-square test was used to examine the association between CA and player position. Of all, 26.8% of the knees (95% CI: 21.1-33.2%) had an abnormal CA. Knees with normal CA (n = 161) did not significantly differ from those with an abnormal CA (n = 59) in Q/H ratios (mean: 0.699 vs. 0.728, p = 0.19) or side-to-side quadriceps deficits (mean: 4.0 vs. 1.24, p = 0.45). For each point increase in BMI, the odds ratio (OR) of abnormal congruence increased by 11.4% (p = 0.002). Of all the knees, 4.1% (95% CI: 1.9-7.6%) had an abnormal LPA, and this was not associated with Q/H ratios (p = 0.13). For each point increase in BMI, the odds of abnormal LPA increased by 16% (p = 0.036). CA abnormality had much higher odds of having an abnormal LPA (OR: 5.96, p = 0.014). We found that abnormal patellofemoral radiographic alignment in elite American football players is relatively common and there was no association with isokinetic testing. PMID- 23925951 TI - Accumulation of ergot alkaloids during conidiophore development in Aspergillus fumigatus. AB - Production of ergot alkaloids in the opportunistic fungal pathogen Aspergillus fumigatus is restricted to conidiating cultures. These cultures typically accumulate several pathway intermediates at concentrations comparable to that of the pathway end product. We investigated the contribution of different cell types that constitute the multicellular conidiophore of A. fumigatus to the production of ergot alkaloid pathway intermediates versus the pathway end product, fumigaclavine C. A relatively minor share (11 %) of the ergot alkaloid yield on a molar basis was secreted into the medium, whereas the remainder was associated with the conidiating colonies. Entire conidiating cultures (containing hyphae, vesicle of conidiophore, phialides of conidiophore, and conidia) accumulated higher levels of the pathway intermediate festuclavine and lower levels of the pathway end product fumigaclavine C than did isolated, abscised conidia, indicating that conidiophores and/or hyphae have a quantitatively different ergot alkaloid profile compared to that of conidia. Differences in alkaloid accumulation among cell types also were indicated by studies with conidiophore development mutants. A ?medA mutant, in which conidiophores are numerous but develop poorly, accumulated higher levels of pathway intermediates than did the wildtype or a complemented ?medA mutant. A ?stuA mutant, which grows mainly as hyphae and produces very few, abnormal conidiophores, produced no detectable ergot alkaloids. The data indicated heterogeneous spatial distribution of ergot alkaloid pathway intermediates versus pathway end product in conidiating cultures of A. fumigatus. This skewed distribution may reflect differences in abundance or activity of pathway enzymes among cell types of those conidiating cultures. PMID- 23925952 TI - A potential perylene diimide dimer-based acceptor material for highly efficient solution-processed non-fullerene organic solar cells with 4.03% efficiency. AB - A highly efficient acceptor material for organic solar cells (OSCs)--based on perylene diimide (PDI) dimers--shows significantly reduced aggregation compared to monomeric PDI. The dimeric PDI shows a best power conversion efficiency (PCE) approximately 300 times that of the monomeric PDI when blended with a conjugate polymer (BDTTTT-C-T) and with 1,8-diiodooctane as co-solvent (5%). This shows that non-fullerene materials also hold promise for efficient OSCs. PMID- 23925953 TI - Development of a human antibody tolerant mouse model to assess the immunogenicity risk due to aggregated biotherapeutics. AB - We describe a novel human immunoglobulin G2 (IgG2 )-tolerant and immune-competent heterozygous mouse model (Xeno-het) developed by crossbreeding a human Ig tolerized XenoMouse(r) with a C57BL/6J wild-type mouse. The Xeno-het mouse expresses both mouse and human immunoglobulin G (IgG) genes, resulting in B-cells expressing human and mouse IgG, and secretion of human and mouse Ig into serum. This model was utilized to evaluate the immunogenicity risk of aggregated and chemically modified human antibodies. The mice were tested for their ability to break tolerance to self-tolerant monomeric antibodies. Aggregates made by mechanical stirring elicited an anti-drug antibody (ADA) response, but did not induce a robust and long-term memory B and T-cell response. Chemically modified antibodies made by oxidation were only weak and transient inducers of an immune response, as measured by a lack of both an ADA response and a B-cell antigen specific response. Aggregate size was an important characteristic, as specific sized protein-coated beads were able to elicit an immune response. We propose the use of this model to identify risk factors such as aggregation during manufacturing at early development for an increased potential immunogenicity risk. PMID- 23925955 TI - Feasibility, reliability, and sensitivity to change of four radiographic scoring methods in patients with psoriatic arthritis. AB - OBJECTIVE: We set out to assess the feasibility, reliability, and sensitivity to change of 4 radiographic scoring methods in psoriatic arthritis (PsA). METHODS: Hand and feet radiographs from 50 patients with PsA were scored at 2 time points by 2 assessors with each of the following methods: modified Steinbrocker score, modified Sharp score (MSS), modified Sharp/van der Heijde score (SHS), and the Ratingen score for PsA. The radiographs of 10 patients were scored by both assessors to assess reliability using intraclass correlation coefficients (ICCs). Sensitivity to change was estimated using a standardized response mean (SRM) and smallest detectable change (SDC). RESULTS: The patients' mean +/- SD age at baseline was 50 +/- 12.1 years, the mean +/- SD disease duration was 10 +/- 8.4 years, and the mean +/- SD followup period was 25 +/- 9.6 months. Intrarater reliability was excellent for all methods (ICC >0.97). Interrater reliability was highest for the SHS (ICC 0.95-0.99). The percentage SDC for the Steinbrocker method, the Ratingen method, the MSS, and the SHS was 2.9%, 2.1%, 1.4%, and 1.2%, respectively, and the SRMs were 0.46, 0.44, 0.77, and 0.79, respectively. The mean time to score each of the Steinbrocker method, the Ratingen method, the MSS, and the SHS was 6.2, 10.5, 14.6, and 14.4 minutes, respectively. CONCLUSION: The SHS method was the most reliable and sensitive to change but took longer to perform. The Steinbrocker method is the most feasible but lacks the sensitivity of the SHS. The SDC of the Ratingen method is close to that of the SHS and MSS, but is quicker to perform. PMID- 23925956 TI - Better functional and similar pain outcomes in osteoarthritis compared to rheumatoid arthritis after primary total knee arthroplasty: a cohort study. AB - OBJECTIVE: To determine the association of the underlying diagnosis with limitation in activities of daily living (ADL) and pain in patients undergoing primary total knee arthroplasty (TKA). METHODS: Prospectively collected data from the Mayo Clinic Total Joint Registry were used to assess the association of diagnosis with moderate-severe limitation in ADL and moderate-severe pain at 2 and 5 years after primary TKA, using multivariable-adjusted logistic regression analyses. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: There were 7,139 primary TKAs at 2 years and 4,234 at 5 years. In multivariable-adjusted analyses, compared with rheumatoid arthritis (RA)/inflammatory arthritis, osteoarthritis (OA) was associated with significantly lower moderate-severe ADL limitation at 2 years (OR 0.5 [95% CI 0.3 0.8]) (P = 0.004) and at 5 years (OR 0.5 [95% CI 0.3-0.9]) (P = 0.02). There was no significant association of diagnosis of OA with moderate-severe pain at 2 years (OR 1.2 [95% CI 0.5-2.7]) (P = 0.68) or at 5 years (OR 1.0 [95% CI 0.3 3.7]) (P = 1.0). CONCLUSION: We found that patients with OA who underwent primary TKA had better ADL outcomes compared to patients with RA/inflammatory arthritis at 2 and 5 years. On the other hand, the pain outcomes after primary TKA did not differ in OA versus RA. This suggests a discordant effect of underlying diagnosis on pain and function outcomes after TKA. These novel findings can be used to better inform both patients and surgeons about expected pain and function outcomes after primary TKA. PMID- 23925954 TI - Framework for understanding balance dysfunction in Parkinson's disease. AB - People with Parkinson's disease (PD) suffer from progressive impairment in their mobility. Locomotor and balance dysfunction that impairs mobility in PD is an important cause of physical and psychosocial disability. The recognition and evaluation of balance dysfunction by the clinician are an essential component of managing PD. In this review, we describe a framework for understanding balance dysfunction in PD to help clinicians recognize patients who are at risk for falling and impaired mobility. PMID- 23925957 TI - Why do some people with intellectual disability engage in offending behaviour and what can we do about it? Editorial. AB - BACKGROUND: The field of forensic intellectual disabilities has been developing rapidly over the last 15 years. Much of the work has been built on research in mainstream criminality but more recently studies have emerged that reveal issues specific to offenders with intellectual disability. METHOD: Research on pathways into offending is reviewed with reference to its relevance to the field of intellectual disability. We also summarize some findings on pathways into and through services for offenders with intellectual disability. FINDINGS: Studies reveal that developmental adversity is an important risk variable. Previous and recent aggression are potent risk factors. New evidence suggests that immediate, proximal risk factors may be more important in this client group. The studies in this issue add to the knowledge on pathways into offending, important areas for assessment and effective treatments as well as advancing knowledge in the academic literature on general criminality. PMID- 23925958 TI - Pre-trial reported defendants in the Netherlands with intellectual disability, borderline and normal intellectual functioning. AB - BACKGROUND: Intellectually disabled offenders may have different characteristics than offenders with average intellectual functioning. We therefore compared pre trial reported defendants with an IQ score <=70, 71-84 and >=85 points. METHODS: Nationwide database of pre-trial psychiatric reports requested by Dutch courts between 2000 and 2006 with a reported level of intellectual functioning (n = 12 186). RESULTS: Defendants with an IQ score between 71 and 84 (n = 2 439 reports; 20.0%) and <=70 (n = 539 reports; 4.4%) were younger, more often from an ethnic minority and more often diagnosed with psycho-organic syndromes, developmental and conduct disorders as compared with defendants with an IQ score of 85 or higher. In addition, there was an increased risk of attention deficit hyperactivity disorder and rape as indicted crime and a decreased odds ratio of having a steady job and cannabis abuse in defendants with an IQ score of 71-84. CONCLUSION: Intellectually disabled defendants have different characteristics than defendants without intellectually disability. PMID- 23925959 TI - Anti-social behaviour and police contact among 13- to 15-year-old English adolescents with and without mild/moderate intellectual disability. AB - OBJECTIVES: To describe the rates of anti-social behaviour (ASB) among adolescents with/without mild/moderate intellectual disability (MMID). To estimate whether any differences could be attributable to differences in exposure to extraneous risk factors. DESIGN: Secondary analysis of the Longitudinal Study of Young People in England. METHODS: Participants with MMID were identified through data linkage with educational records. RESULTS: Parents of children with MMID were more likely to report police contact, children with MMID were more likely to self-report fighting/public disturbance, shoplifting and graffiti. When controlling for differences in exposure to extraneous risk factors, MMID was associated with increased rates of police contact and self-reported graffiti, no difference in self-reported shoplifting, reduced rates of self-reported fighting/public disturbance and vandalism. CONCLUSIONS: Differences in the rates of exposure to extraneous risk factors play an important role in accounting for the differences in the prevalence of self-reported ASB among adolescents with and without MMID. PMID- 23925960 TI - Offending by people with intellectual disabilities in community settings: a preliminary examination of contextual factors. AB - BACKGROUND: While several validated measures of the life circumstances of people with intellectual disabilities (ID) have been developed, this stream of research has not yet been well integrated with environmentally oriented criminological theory to explain offending among people with ID. In this study, we attempt to provide a preliminary integration through an investigation of the relationship between contemporary life experiences, well-being, choice and offending among people with ID, exploring the relevance of two classic criminological theories (theories of strain and social control). MATERIALS AND METHODS: Questionnaire measures were used to compare a range of 'ordinary' life experiences [the 'Life Experiences Checklist' (LEC)], subjective well-being (the 'Personal Well-being Index - ID') and the extent of choice (the 'Choice Questionnaire'), between offenders (N = 27) and non-offenders (N = 19) with ID recruited through integrated (NHS and Local Authority) multi-disciplinary teams (community teams for adults with learning disabilities). RESULTS: Using regression analyses to explore the strength of associations with offending, it was found that an indicator of impoverished personal relationships, from the LEC provided the best predictor of offending. This finding appears to favour criminological explanations based on social control. CONCLUSIONS: Existing measures of life circumstances can be used to explore environmentally oriented criminological theories, bringing benefits to our understanding and treatment of offenders with ID living in community settings. PMID- 23925962 TI - Prospective dynamic assessment of risk of sexual reoffending in individuals with an intellectual disability and a history of sexual offending behaviour. AB - BACKGROUND: The purpose of the present study was to add to the literature on the predictive accuracy of a dynamic intellectual disability specific risk assessment tool. METHOD: A dynamic risk assessment for sexual reoffending (ARMIDILO-S), a static risk assessment for sexual offending (STATIC-99), and a static risk assessment for violence (Violence Risk Appraisal Guide [VRAG]) were completed for a sample of 64 adult males with an intellectual disability. RESULTS: The dynamic risk assessment for sexual offenders with an intellectual disability resulted in the best prediction of sexual reoffending (ARMIDILO-S area under the curve (AUC) = 0.92) this was better than an established sexual offending static risk assessment (STATIC-99 AUC = 0.75). A static tool for violent reoffending, did not perform as well in this group (VRAG AUC = 0.58). CONCLUSIONS: Results suggest that dynamic variables are useful in predicting sexual reoffending with individuals with an intellectual disability, confirming previous findings. The ARMIDILO-S is a promising dynamic risk assessment for individuals with an intellectual disability. PMID- 23925961 TI - Predicting institutional violence in offenders with intellectual disabilities: the predictive efficacy of the VRAG and the HCR-20. AB - BACKGROUND: There is a developing evidence base to support the use of risk assessment instruments in offenders with intellectual disability (ID). The aim of this study was to try to develop this literature with the inclusion of a control group of mentally disordered offenders without an ID, using the HCR-20 and VRAG. MATERIALS AND METHODS: The VRAG and the HCR-20 were completed for a group of offenders with an ID (n = 25) and a control group (n = 45), in four medium-secure units across the UK. The outcome measure was physical aggression measured over 6 months. RESULTS: Both instruments consistently produced large effect sizes predicting any physical aggression and severe physical aggression. The structured clinical judgement based on the HCR-20 was especially good. CONCLUSIONS: The HCR 20 and the VRAG have excellent predictive efficacy in offenders with an ID. A structured clinical judgement based on the HCR-20 was especially predictive. PMID- 23925963 TI - Pathways into the criminal justice system for individuals with intellectual disability. AB - BACKGROUND: Studies focusing on pathways in the criminal justice system for individuals with intellectual disability are limited in that they only study individuals once they are involved in the system and do not consider the pathways into it. The purpose of this study is to examine predisposing factors that lead to various outcomes for individuals with intellectual disability when police are called to respond to their behavioural crises. METHOD: The current study examined the outcome of police response to 138 individuals with intellectual disability in crisis. Following police intervention, 15 individuals were arrested, 76 were taken to the emergency department and 47 received on-scene resolution. Comparisons between the three groups were conducted. RESULTS: The three groups differed in terms of residence at the time of crisis, history of forensic involvement and type of crisis. Police intervention with adults with intellectual disability can happen for different reasons. Both individual and situational predictors explained this outcome. PMID- 23925964 TI - Different factors influence self-reports and third-party reports of anger by adults with intellectual disabilities. AB - BACKGROUND: Many people with intellectual disabilities display high levels of anger, and cognitive-behavioural anger management interventions are used routinely. However, for these methods to be used optimally, a better understanding is needed of different forms of anger assessment. The aim of this study was to investigate the relationship of a range of measures to self- and carer reports of anger expression, including instruments used to assess mental health and challenging behaviour. METHOD: Adults with intellectual disabilities, who had been identified as having problems with anger control, their key-workers and home carers all rated the service users' trait anger, using parallel versions of the same instrument (the Provocation Inventory). In addition, service users completed a battery of mental health assessments (the Glasgow Depression Scale, Glasgow Anxiety Scale and Rosenberg Self-Esteem Scale), and both groups of carers completed a battery of challenging behaviour measures (the Hyperactivity and Irritability domains of the Aberrant Behavior Checklist and the Modified Overt Anger Scale). RESULTS: Participants had high levels of mental health problems (depression: 34%; anxiety: 73%) and severe challenging behaviour (26%). Hierarchical linear regression analysis was used to explore the extent to which anger ratings by the three groups of respondents were predicted by demographic factors, mental health measures and challenging behaviour measures. Older service users rated themselves as less angry and were also rated as less angry by home carers, but not by key-workers. More intellectually able service users were rated as more angry by both sets of carers, but not by the service users themselves. Significantly, mental health status (but not challenging behaviour) predicted service users' self-ratings of anger, whereas challenging behaviour (but not mental health status) predicted carers' ratings of service users' anger. CONCLUSIONS: Service users and their carers appear to use different information when rating the service users' anger. Service users' self-ratings reflect their internal emotional state and mental health, as reflected by their ratings of anxiety and depression, whereas staff rate service users' anger on the basis of overt behaviours, as measured by challenging behaviour scales. PMID- 23925965 TI - Autism spectrum disorder: forensic issues and challenges for mental health professionals and courts. AB - Autism spectrum disorder (ASD), as defined in DSM-V, can be relevant in a variety of ways to decision-making by courts and tribunals. This includes the family, disciplinary, discrimination and criminal law contexts. By reviewing decisions made by superior courts in a number of common law jurisdictions, this article identifies a pivotal role for mental health professionals closely familiar with both the disorder and forensic exigencies to educate courts about the inner world of those with ASD. Highlighting areas of criminality that court decisions have dealt with, especially in relation to persons with Asperger's Disorder, as defined by DSM-IV, it calls for further research on the connection between ASD, on the one hand, and conduct, capacities and skills, on the other hand. It urges enhancement of awareness of the forensic repercussions of the disorder so that expert evidence can assist the courts more humanely and informedly to make criminal justice and other decisions. PMID- 23925966 TI - Face recognition and description abilities in people with mild intellectual disabilities. AB - BACKGROUND: People with intellectual disabilities (ID) are as likely as the general population to find themselves in the situation of having to identify and/or describe a perpetrator's face to the police. However, limited verbal and memory abilities in people with ID might prevent them to engage in standard police procedures. METHOD: Two experiments examined face recognition and description abilities in people with mild intellectual disabilities (mID) and compared their performance with that of people without ID. Experiment 1 used three old/new face recognition tasks. Experiment 2 consisted of two face description tasks, during which participants had to verbally describe faces from memory and with the target in view. RESULTS: Participants with mID performed significantly poorer on both recognition and recall tasks than control participants. However, their group performance was better than chance and they showed variability in performance depending on the measures introduced. CONCLUSIONS: The practical implications of these findings in forensic settings are discussed. PMID- 23925967 TI - The Social Information Processing model as a framework for explaining frequent aggression in adults with mild to moderate intellectual disabilities: a systematic review of the evidence. AB - BACKGROUND: There is an established evidence base con-cerning the use of anger management interventions with violent offenders who have intellectual disabilities. However, there has been limited research investigating the role of social cognitive factors underpinning problems of aggression. Psychosocial sources of agg-ression in the non-disabled population are generally discussed using Social Information Processing (SIP) models. METHOD: A systematic review of the available evidence was carried out to establish whether SIP offers a useful explanatory model for understanding the contribution of social cognitive factors to problems of aggression presented by people with intellectual disabilities. RESULTS AND CONCLUSIONS: Whilst research relating to the SIP model remains sparse for this population, there was evidence for different patterns of processing between aggressive and non-aggressive individuals. Group diff-erences included interpretation of emotional cues, inter-personal attributions and beliefs about the outcomes of aggressive behaviour. The future direction of SIP research with people who have intellectual disabilities is discussed, along with the possibility of using this framework to help build on current initiatives to develop individually tailored interventions to work at a cognitive level with those who are aggressive and offend. PMID- 23925968 TI - A comparison of anger in offenders and non-offenders who have intellectual disabilities. AB - BACKGROUND: There is growing evidence of the effectiveness of cognitive behavioural therapy to treat anger in offenders with intellectual disabilities. The aim is to lower anger levels; the rationale is that this will reduce recidivism. However, the hypothesis that anger levels amongst offenders are higher than non-offenders has not been tested. METHOD: The study utilizes a case comparison design to examine whether levels of anger are higher amongst people with intellectual disabilities who have offended in comparison with those who have not offended. Anger levels are compared for 29 offenders with intellectual disabilities and 27 non-offenders with intellectual disabilities (all male). RESULTS: No differences were found between offenders and non-offenders on measures of anger. The offending group was shown to have higher levels of aggression. CONCLUSIONS: Results suggest that there is no difference in levels of anger between offender and non-offenders to begin with. The limitations of the study are discussed, but the implication of the study questions the legitimacy of the rationale to utilize anger treatment to reduce recidivism in offenders with intellectual disabilities. PMID- 23925969 TI - 'Counterfeit deviance' revisited. AB - BACKGROUND: The field has seen a renewed interest in exploring the theory of 'counterfeit deviance' for persons with intellectual disability who sexually offend. The term was first presented in 1991 by Hingsburger, Griffiths and Quinsey as a means to differentiate in clinical assessment a subgroup of persons with intellectual disability whose behaviours appeared like paraphilia but served a function that was not related to paraphilia sexual urges or fantasies. Case observations were put forward to provide differential diagnosis of paraphilia in persons with intellectual disabilities compared to those with counterfeit deviance. The brief paper was published in a journal that is no longer available and as such much of what is currently written on the topic is based on secondary sources. METHOD: The current paper presents a theoretical piece to revisit the original counterfeit deviance theory to clarify the myths and misconceptions that have arisen and evaluate the theory based on additional research and clinical findings. The authors also propose areas where there may be a basis for expansion of the theory. RESULTS: The theory of counterfeit deviance still has relevance as a consideration for clinicians when assessing the nature of a sexual offence committed by a person with an intellectual disability. Clinical differentiation of paraphilia from counterfeit deviance provides a foundation for intervention that is designed to specifically treat the underlying factors that contributed to the offence for a given individual. DISCUSSION: Counterfeit deviance is a concept that continues to provide areas for consideration for clinicians regarding the assessment and treatment of an individual with an intellectual disability who has sexually offended. It is not and never was an explanation for all sexually offending behavior among persons with intellectual disabilities. PMID- 23925970 TI - Using behavioural skills training to treat aggression in adults with mild intellectual disability in a forensic setting. AB - BACKGROUND: Previous studies of anger management in people with intellectual disability failed to control for the effects of the number of provocative stimuli presented and lacked direct measures of behaviour and treatment integrity data. METHODS: This experiment systematically assessed and presented discriminative stimuli for aggressive behaviour, taught alternative behaviour in response to discriminative stimuli for aggressive behaviour and used behavioural skills training with three adults with mild intellectual disability. RESULTS: Following behavioural skills training, the adult's percentage of aggressive responses declined and replacement responses increased in response to provocative stimuli. Treatment gains generalized to novel antecedent events, novel staff and novel settings and were socially valid. After intervention, community trips increased for all three participants. CONCLUSIONS: Behavioural skills training to teach alternate behaviour to aggression with carefully planned procedures to promote generalization caused a socially valid increase in alternate behaviour and a socially valid decrease in aggression. PMID- 23925971 TI - Men with intellectual disabilities who have attended sex offender treatment groups: a follow-up. AB - BACKGROUND: There have been a number of studies of treatment for men with intellectual disabilities and sexually abusive behaviour but few follow-up studies. Our aim was to follow up men with intellectual disabilities who had attended group cognitive behavioural treatment (CBT) for sexually abusive behaviour. METHOD: Thirty-four men (from seven treatment sites) were followed up. All had attended SOTSEC-ID groups. The mean length of follow-up, since the end of the treatment group, was 44 months (SD 28.7, range 15-106 months). RESULTS: The statistically significant improvements in sexual knowledge, empathy and cognitive distortions that occurred during treatment were maintained at follow-up. In all, 11 of the 34 (32%) men showed further sexually abusive behaviour, but only two of these men received convictions. Analyses of the variables associated with further sexually abusive behaviour indicated that a diagnosis of autism was associated with a higher likelihood of further sexually abusive behaviour. CONCLUSIONS: This study provides some evidence of the longer-term effectiveness of group CBT for men with intellectual disabilities and sexually abusive behaviour. PMID- 23925972 TI - Basal root whorl number: a modulator of phosphorus acquisition in common bean (Phaseolus vulgaris). AB - BACKGROUND AND AIMS: Root architectural phenes enhancing topsoil foraging are important for phosphorus acquisition. In this study, the utility of a novel phene is described, basal root whorl number (BRWN), that has significant effects on topsoil foraging in common bean (Phaseolus vulgaris). METHODS: Whorls are defined as distinct tiers of basal roots that emerge in a tetrarch fashion along the base of the hypocotyl. Wild and domesticated bean taxa as well as two recombinant inbred line (RIL) populations were screened for BRWN and basal root number (BRN). A set of six RILs contrasting for BRWN was evaluated for performance under low phosphorus availability in the greenhouse and in the field. In the greenhouse, plants were grown in a sand-soil media with low or high phosphorus availability. In the field, plants were grown in an Oxisol in Mozambique under low and moderate phosphorus availability. KEY RESULTS: Wild bean accessions tended to have a BRWN of one or two, whereas cultivated accessions had BRWN reaching four and sometimes five. BRWN and BRN did not vary with phosphorus availability, i.e. BRWN was not a plastic trait in these genotypes. Greater BRWN was beneficial for phosphorus acquisition in low phosphorus soil. Genotypes with three whorls had almost twice the shoot biomass, greater root length and greater leaf area than related genotypes with two whorls. In low phosphorus soil, shoot phosphorus content was strongly correlated with BRWN (R(2) = 0.64 in the greenhouse and R(2) = 0.88 in the field). Genotypes with three whorls had shallower root systems with a greater range of basal root growth angles (from 10 to 45 degrees from horizontal) than genotypes with two whorls (angles ranged from 60 to 85 degrees from horizontal). CONCLUSIONS: The results indicate that BRWN is associated with increased phosphorus acquisition and that this trait may have value for selection of genotypes with better performance in low phosphorus soils. PMID- 23925973 TI - A novel diblock copolymer with a supramolecular polymer block and a traditional polymer block: preparation, controllable self-assembly in water, and application in controlled release. AB - A novel diblock copolymer with a hydrophobic supramolecular polymer block and a hydrophilic traditional polymer block has been prepared. Control over the chain length ratio of the two blocks is obtained by simply changing the concentration proportion of the monomer of the supramolecular polymer block to the traditional polymer block in solution. When the chain length ratio of the two blocks is changed, the formation of various self-assembly morphologies is achieved. PMID- 23925974 TI - The importance of predicting factors in the surgical outcome of peripheral nerve sheath tumors. AB - OBJECTIVE: Peripheral nerve sheath tumors (PNSTs) are tumors arising from the neural sheath cells. Surgery plays a central role in the management of this disease, with the purpose of obtaining radical tumor's resection and at the same time providing the best outcome. We retrospectively analyzed 53 PNSTs in 42 patients in an attempt to identify some factors that may improve surgical outcome. MATERIAL AND METHODS: Clinical, histologic, and imaging data of 42 patients with PNSTs treated at our Institute between 2001 and 2012 were collected and analyzed. We evaluated the outcome 1 month and 6 month after surgery using three clinical parameters (pain, motor deficits, and sensory deficits) in relation to different histotypes, the presence of neurofibromatosis type 1, tumor location, and duration of symptoms before treatment. RESULTS: The best functional results were observed in patients having neurofibromas; the worst outcomes were observed in patients with malignant PNSTs. The other factors were not associated with outcome. CONCLUSION: The timing of surgery is the most important predictive factor of surgical outcome, being the only factor that allows to improve the outcome. With the current study, we want to stress the importance of treating PNSTs as soon as possible to provide the best outcome possible. PMID- 23925975 TI - Hazard information needs and information seeking in French workers. AB - BACKGROUND: Data about perceived needs of workers for information on occupational hazards or diseases (OHDs) are scarce and the behaviour of workers seeking information on these matters is not well known. AIMS: To describe workers' needs and behaviour in seeking information about OHDs. METHODS: All workers attending for consultation at an occupational health service in Upper Normandy within 1 week were invited to fill in an anonymous questionnaire. RESULTS: Of the 2640 workers responding 58% declared a need for information about OHD, but only 37% actually sought that information. Whereas 82% of workers mentioned the internet and their general physician (GP) as sources of information on OHD, only 43% mentioned their occupational physician (OP). Furthermore, information received from OPs was not considered more reliable than that from GPs. CONCLUSIONS: Workers report a need for information about OHDs. Although most of them trust information given by OPs, they do not use OPs to obtain OHD information, but instead use less reliable sources such as the internet or their GPs. PMID- 23925976 TI - [The new WHO classification and recent results in soft tissue tumor pathology]. AB - The new World Health Organization (WHO) classification presents a comprehensive description of soft tissue tumors which was published in book format at the beginning of 2013. Changes have been made relating to the allocation of known entities, e.g. undifferentiated sarcomas are formed into a new group and are not longer assigned to the so-called fibrohistiocytic tumors and new subgroups were incorporated, such as nerve sheath tumors and gastrointestinal stroma tumors which were previously included in the tumor classification of other organ systems. This development is important from the practical point of view as most of relevant soft tissue tumors are now summarized and can be found in a single book. This is also related to the rapid increase in knowledge of the genetics and cell biology of soft tissue tumors. At present there is considerable progress in tumor pathology illustrated by the fact that important new findings have been published after completion of the classification, such as those related to the identification of the recurrent NAB2-STAT6 gene fusion in solitary fibrous tumors and the detection of frequent mutations in the promoter of the hTERT gene in malignant melanoma. In this report some new findings and clinically relevant aspects of soft tissue tumor pathology will be presented. PMID- 23925977 TI - Dopamine-angiotensin interactions in the basal ganglia and their relevance for Parkinson's disease. AB - Renin-angiotensin systems are known to act in many tissues, for example, the blood vessel wall or kidney, where a close interaction between angiotensin and dopamine has been demonstrated. Regulatory interactions between the dopaminergic and renin-angiotensin systems have recently been described in the substantia nigra and striatum. In animal models, dopamine depletion induces compensatory overactivation of the local renin-angiotensin system, which primes microglial responses and neuron vulnerability by activating NADPH-oxidase. Hyperactivation of the local renin-angiotensin system exacerbates the inflammatory microglial response, oxidative stress, and dopaminergic degeneration, all of which are inhibited by angiotensin receptor blockers and inhibitors of angiotensin converting enzymes. In this review we provide evidence suggesting that the renin angiotensin system may play an important role in dopamine's mediated neuroinflammation and oxidative stress changes in Parkinson's disease. We suggest that manipulating brain angiotensin may constitute an effective neuroprotective strategy for Parkinson's disease. PMID- 23925978 TI - Musculoskeletal ultrasound objective structured clinical examination: an assessment of the test. AB - OBJECTIVE: To determine the reliability and validity of an objective structured clinical examination (OSCE) for musculoskeletal ultrasound (MSUS). METHODS: A 9 station OSCE was administered to 35 rheumatology fellows trained in MSUS and to 3 expert faculty (controls). Participants were unaware of joint health (5 diseased/4 healthy). Faculty assessors (n = 9) graded image quality with predefined checklists and a 0-5 global rating, blinded to who performed the study. Interrater reliability, correlation between a written multiple choice question examination (MCQ) and OSCE performance, and comparison of fellow OSCE results with those of the faculty were measured to determine OSCE reliability, concurrent validity, and construct validity. RESULTS: Assessors' interrater reliability was good (intraclass correlation coefficient [ICC] 0.7). Score reliability was good in the normal wrist and ankle stations (ICC 0.7) and moderate in the abnormal wrist and ankle stations (ICC 0.4). MCQ grades significantly correlated with OSCE grades (r = 0.52, P < 0.01). The fellows in the bottom quartile of the MCQ scored 3.07 on the OSCE, significantly worse than the top quartile fellows (3.32) and the faculty (3.29; P < 0.01). Scores also significantly discriminated bottom quartile fellows from faculty in the normal wrist and ankle stations (3.38 versus 3.78; P < 0.01), but not in the abnormal stations (3.37 versus 3.49; P = 0.08). CONCLUSION: MSUS OSCE is a reliable and valid method for evaluation of MSUS skill. Normal joint assessment stations are more reliable than abnormal joint assessment stations and better discriminate poorly performing fellows from faculty. Therefore, MSUS OSCE with normal joints can be used for the assessment of MSUS skill competency. PMID- 23925979 TI - Hamiltonian replica-permutation method and its applications to an alanine dipeptide and amyloid-beta(29-42) peptides. AB - We propose the Hamiltonian replica-permutation method (RPM) (or multidimensional RPM) for molecular dynamics and Monte Carlo simulations, in which parameters in the Hamiltonian are permuted among more than two replicas with the Suwa-Todo algorithm. We apply the Coulomb RPM, which is one of realization of the Hamiltonian RPM, to an alanine dipeptide and to two amyloid-beta(29-42) molecules. The Hamiltonian RPM realizes more efficient sampling than the Hamiltonian replica-exchange method. We illustrate the protein misfolding funnel of amyloid-beta(29-42) and reveal its dimerization pathways. PMID- 23925980 TI - Lipid and lipoprotein levels and trend in rheumatoid arthritis compared to the general population. AB - OBJECTIVE: Differences in lipid levels associated with cardiovascular (CV) risk between rheumatoid arthritis (RA) patients and the general population remain unclear. Determining these differences is important in understanding the role of lipids in CV risk in RA. METHODS: We studied 2,005 RA subjects from 2 large academic medical centers. We extracted electronic medical record data on the first low-density lipoprotein (LDL) measurement, and total cholesterol and high density lipoprotein (HDL) measurements within 1 year of the LDL measurement. Subjects with an electronic statin prescription prior to the first LDL measurement were excluded. We compared lipid levels in RA patients to recently published levels from the general US population using the t-test and stratifying by published parameters, i.e., 2007-2010, and women. We determined lipid trends using separate linear regression models for total cholesterol, LDL cholesterol, and HDL cholesterol, testing the association between year of measurement (1989 2010) and lipid level, adjusted by age and sex. Lipid trends in RA were qualitatively compared to the published general population trends. RESULTS: Women with RA had a significantly lower total cholesterol (186 versus 200 mg/dl; P = 0.002) and LDL cholesterol (105 versus 118 mg/dl; P = 0.001) compared to the general population (2007-2010). HDL cholesterol was not significantly different in the 2 groups. In the RA cohort, total cholesterol and LDL cholesterol significantly decreased each year, while HDL cholesterol increased (all with P < 0.0001), consistent with overall trends observed in a previous study. CONCLUSION: RA patients appear to have an overall lower total cholesterol and LDL cholesterol than the general population despite the general overall risk of CV disease in RA from observational studies. PMID- 23925981 TI - Encapsulation of drug molecules into calix[n]arene nanobaskets. role of aminocalix[n]arenes in biopharmaceutical field. AB - Calix[n]arenes (CAs) are supramolecular compounds able to form guest-host inclusion complexes with metal ions, small organic molecules, and small moieties of larger molecules. Although the CA literature is extensive, relatively few publications deal with water-soluble CAs, especially those containing nitrogen based functionality. These CAs possess antibacterial and antifungal activity. Because of their molecular structure, they are surface active and also able to form water-soluble drug complexes, giving additional potential as enabling pharmaceutical excipients. This article provides an overview of the published data regarding synthesis, physicochemical properties, and pharmaceutical application of water-soluble CAs with emphasis on those that contain nitrogen based substituents in their structure, particularly aminoCAs. In particular, it describes state-of-the-art in complexation of water-soluble CAs with pharmaceutically relevant ions and organic molecules up to amino acids, DNA, and proteins. PMID- 23925982 TI - Protocell design through modular compartmentalization. AB - De novo synthetic biological design has the potential to significantly impact upon applications such as energy generation and nanofabrication. Current designs for constructing organisms from component parts are typically limited in scope, as they utilize a cut-and-paste ideology to create simple stepwise engineered protein-signalling pathways. We propose the addition of a new design element that segregates components into lipid-bound 'proto-organelles', which are interfaced with response elements and housed within a synthetic protocell. This design is inspired by living cells, which utilize multiple types of signalling molecules to facilitate communication between isolated compartments. This paper presents our design and validation of the components required for a simple multi-compartment protocell machine, for coupling a light transducer to a gene expression system. This represents a general design concept for the compartmentalization of different types of artificial cellular machinery and the utilization of non protein signal molecules for signal transduction. PMID- 23925983 TI - More than a safety line: jump-stabilizing silk of salticids. AB - Salticids are diurnal hunters known for acute vision, remarkable predatory strategies and jumping ability. Like other jumpers, they strive for stability and smooth landings. Instead of using inertia from swinging appendages or aerodynamic forces by flapping wings as in other organisms, we show that salticids use a different mechanism for in-air stability by using dragline silk, which was previously believed to function solely as a safety line. Analyses from high-speed images of jumps by the salticid Hasarius adansoni demonstrate that despite being subject to rearward pitch at take-off, spiders with dragline silk can change body orientation in the air. Instantaneous drag and silk forces calculated from kinematic data further suggest a comparable contribution to deceleration and energy dissipation, and reveal that adjustments by the spider to the silk force can reverse its body pitch for a predictable and optimal landing. Without silk, upright-landing spiders would slip or even tumble, deferring completion of landing. Thus, for salticids, dragline silk is critical for dynamic stability and prey-capture efficiency. The dynamic functioning of dragline silk revealed in this study can advance the understanding of silk's physiological control over material properties and its significance to spider ecology and evolution, and also provide inspiration for future manoeuvrable robot designs. PMID- 23925984 TI - Effect of counterface roughness on adhesion of mushroom-shaped microstructure. AB - In this study, the effect of the substrate roughness on adhesion of mushroom shaped microstructure was experimentally investigated. To do so, 12 substrates having different isotropic roughness were prepared from the same material by replicating topography of different surfaces. The pull-off forces generated by mushroom-shaped microstructure in contact with the tested substrates were measured and compared with the pull-off forces generated by a smooth reference. It was found that classical roughness parameters, such as average roughness (Ra) and others, cannot be used to explain topography-related variation in pull-off force. This has led us to the development of an integrated roughness parameter capable of explaining results of pull-off measurements. Using this parameter, we have also found that there is a critical roughness, above which neither smooth nor microstructured surface could generate any attachment force, which may have important implications on design of both adhesive and anti-adhesive surfaces. PMID- 23925986 TI - Laboratory diagnosis of homozygous alpha thalassaemia. AB - BACKGROUND: Alpha-thalassaemia is one of the most prevalent haemoglobinopathies in the world. The molecular basis of the condition is mainly due to deletion of one or more alpha genes and occasional point mutations. The diagnosis and treatment of microcytic hypochromic anaemia is at times a problematic medical issue in Ghana due to co-existence of a-thalassaemia traits and iron deficiency anaemia (IDA) since there is no routine laboratory procedure for the diagnosis of the former. OBJECTIVE: To identify the alpha thalassaemias and determine a simple laboratory method of differentiating them from other causes of microcytic hypochromic, anaemia. METHODS: Venous blood samples of random 216 adult OPD patients at the Central Laboratory of Korle-Bu Hospital were taken for full blood count, iron studies, PCR and restriction enzyme analysis to tag -a3.7 thalassaemia variants. RESULTS AND CONCLUSION: Of the 200 accepted subjects, 114 (57.0%) were -a/aa, 11 (5.5%) were -a/-a and 75(37.5%) aa/aa. Differences among the entire red cell indices and serum iron measurements between -a/-a and aa/aa, and-a/-a and -a/-aa were found to be statistically significant (P<0.05 in each case) and consistent with previous studies, but there were no significant (P>0.05) differences between -a/aa and aa/aa RBC parameters. However, selective analysis based on Hb<13.0 g/dl for males and <12.0 g/dl for females indicated that combination of RBC indices with iron studies can be used to differentiate a/-a from IDA. Calculation of RBC/PCV ratios of anaemic aa/aa, and -a/-a was yet another tool as the latter was found to have higher ratio. PMID- 23925985 TI - Pediatric exercise-induced bronchoconstriction: contemporary developments in epidemiology, pathogenesis, presentation, diagnosis, and therapy. AB - Exercise-induced bronchoconstriction is transient narrowing of the airways following strenuous exercise. It is the earliest sign of asthma and the last to resolve. EIB is found in 90 % of asthmatics and reflects underlying control of asthma. This review is focused on the contemporary developments in pediatric EIB: the epidemiology, pathogenesis, presentation, diagnosis and management. Proper diagnosis by objective pulmonary function and/or exercise challenge and therapy should allow the pediatric asthmatic to enjoy a healthy lifestyle including participation in the chosen sport. PMID- 23925987 TI - Quality of life outcomes of adenotonsillectomy for obstructive sleep disorders: our experience in a Tertiary Care Centre in Ghana. AB - BACKGROUND AND OBJECTIVES: Obstructive Sleep Disorders (OSDs) impacts negatively on the quality of life of children. However the long term outcomes of adenoton sillectomy remain unknown. The aims and objectives of this study was to assess the long term quality of life of Ghanaian children with OSDs undergoing adenotonsillectomy. METHODS: The subjects for this study were cohort of children who were part of a study named Study1 carried out at E.N.T. Unit, Korle Bu Teaching Hospital, Accra. These children had adenotonsillectomy for OSDs and their quality of life were evaluated preoperatively and again four to six weeks post operatively using Obstructive Sleep Apnoea 18 (OSA 18 ) questionnaire; a quality of life assessment tool. Thirty five children who were at least nine months post adenotonsillectomy were invited to a follow up E.N.T.clinic for the current study named Study 2 and their quality of life were again evaluated using OSA 18 questionnaire. RESULTS: Thirty-one children with a mean age of 5.08 +/- 0.95 years were seen. The mean OSA-18 preoperative score for Study1 was 4.27 +/- 0.27; the mean OSA 18 post operative scores for Study1 and Study 2 were 1.93 +/- 0.25 and 1.78 +/-0.31 respectively. There was a significant reduction in the mean post operative OSA 18 score for both studies compared to the corresponding preoperative mean score (p-value = 0.001). The mean postoperative overall quality of life scoresfor Study 1 and Study2 were 8.52 +/- 0.53 and 7.68 +/- 1.06 respectively. CONCLUSION: There was significant improvement in long term quality of life outcomes following adenotonsillectomy for OSDs. PMID- 23925988 TI - Cardiac arrest following spinal anaesthesia for Caesarean section: a case report. AB - BACKGROUND: Spinal anaesthesia is regarded safe for caesarean section. Serious complications resulting from spinal anaesthesia such as cardiac arrest are often times considered rare. This is a case of a 27 year old un-booked gravida1 who was scheduled for emergency caesarean section on account of cephalo-pelvic disproportion (CPD) with associated history of prolonged labour. The patient was preloaded with normal saline one hour before subarachnoid block (SAB) was established and suffered a cardiac arrest immediately after establishing SAB. She was successfully resuscitated using chest compressions, adrenaline and oxygen and a live baby was delivered during cardiopulmonary resuscitation (CPR). The patient developed seizures in the immediate postoperative period. She was treated with an anti-epileptic drug and was also mechanically ventilated. She also developed features of puerperal psychosis and was managed with anti-psychotics. The patient was on admission in the intensive care unit for four days and she made quick recovery with no apparent residual damage. PMID- 23925989 TI - Report of a case of cutaneous (furuncular) and gastrointestinal myiasis (dermatobia hominis) in a Nigerian child. AB - BACKGROUND: Myiasis is a tropical disease due to tissue invasion b ythe larvae of certain flies, principally the tumbu fly (Cordylobiaanthropophaga) and the human botfly (Dermotobia hominis).These larvae may be contracted via the bite of mosquitoes like Hypoderma bovis and Chrysomya bezziana, and may present with local or systemic clinical effects. OBJECTIVE: An unusual infestation of the skin and gastrointestinal tract by Dermatobia hominis in a Nigerian patientis reported. CASE REPORT: The index patient presented with pyrexia of unknown origin. Papules with a central pore were seen on the skin from which maggots were mechanically extracted, facilitated by the application of petroleum jelly. The extracted larvae were characterised as Dermatobia hominis. Identical larvae were isolated from the patient's stool sample. CONCLUSION: Myiasis does occur in our environment and patience and thoroughness are required in order to clinch the diagnosis. This is the first case of Dermatobia hominis reported in Nigeria either as Cutaneous/Gastrointestinal system or both and one of the few cases published in Africa in an African residing in Africa without a recent travel to South America where it is endemic. This public health importance of this condition is discussed. PMID- 23925990 TI - Recurrent depressive illness or craniopharyngioma: a diagnostic dilemma. AB - BACKGROUND: Brain tumors have been associated with various psychiatric and neurological manifestations. However in some patients with brain tumors psychiatric symptom might be the only clinical presentation for various lengths of time. As such they would be treated as straight forward psychiatric disorders. OBJECTIVE: To report a case of craniopharyngioma presenting as recurrent depressive illness in a 42 years old man. METHODS: Clinical follow up of a patient presenting with recurrent depressive illness till death RESULTS: recurrent severe depressive illness in the absence of focal neurological deficit that is unresponsive to anti-depressant might be due to intracranial neoplasm. CONCLUSION: Brain tumors can sometime present as psychiatric disorders and be difficult to detect in the absences of focal neurological deficit and Neuro imaging studies. PMID- 23925991 TI - Alterations of motor cortical excitability and anatomy in Unverricht-Lundborg disease. AB - Unverricht-Lundborg disease is the most common form of progressive myoclonus epilepsies. In addition to generalized seizures, it is characterized by myoclonus, which usually is the most disabling feature of the disease. Classically, the myoclonus has been attributed to increased excitability of the primary motor cortex. However, inhibitory cortical phenomena have also been described along with anatomical alterations. We aimed to characterize the relationship between the excitability and anatomy of the motor cortex and their association with the severity of the clinical symptoms. Seventy genetically verified patients were compared with forty healthy controls. The symptoms were evaluated with the Unified Myoclonus Rating Scale. Navigated transcranial magnetic stimulation was applied to characterize the excitability of the primary motor cortex by determining the motor thresholds and cortical silent periods. In addition, the induced cortical electric fields were estimated using individual scalp-to-cortex distances measured from MRIs. A cortical thickness analysis was performed to elucidate possible disease-related anatomical alterations. The motor thresholds, cortical electric fields, and silent periods were significantly increased in the patients (P < 0.01). The silent periods correlated with the myoclonus scores (r = 0.48 to r = 0.49, P < 0.001). The scalp-to-cortex distance increased significantly with disease duration (r = 0.56, P < 0.001) and correlated inversely with cortical thickness. The results may reflect the refractory nature of the myoclonus and indicate a possible reactive cortical inhibitory mechanism to the underlying disease process. This is the largest clinical series on Unverricht-Lundborg disease and the first study describing parallel pathophysiological and structural alterations associated with the severity of the symptoms. PMID- 23925993 TI - Carotid intima-media thickness in children with Kawasaki disease. AB - Kawasaki disease (KD) is an acute medium vessel vasculitis seen in children. The most significant long-term complication is related to coronary artery abnormalities. Use of intravenous immunoglobulins, however, has led to significant reduction in incidence of coronary aneurysms. What is more alarming is the fact that higher risk of cardiovascular disease is seen in even those children who do not have coronary artery aneurysms during subacute phase. Various factors like abnormal lipid profiles, abnormal vessel wall reactivity and endothelial dysfunction have been implicated for this. Carotid intima-media thickness (cIMT) has been used as a surrogate marker for atherosclerosis. This study was planned to evaluate cIMT in children with KD. Twenty-seven children with diagnosis of KD at least 1 year prior to enrolment were evaluated for cIMT at enrolment and then after 3 months. Fasting lipid profile was done for all patients. Mean cIMT was significantly higher in children with KD compared to controls. In lipid profiles, undesirable HDL-C and triglyceride levels were seen in 2 and 3 children, respectively. Undesirable and borderline LDL-C levels were seen in 1 and 2 patients, respectively. Undesirable and borderline total cholesterol levels were seen in 1 and 3 patients, respectively. Higher cIMTs were seen in our cohort of KD patients. Proatherogenic abnormalities in lipid profile were seen in a few patients. Both abnormalities may predict a higher risk of atherosclerosis in future. The results of this study need to be replicated on a larger study sample and over longer follow-up periods. PMID- 23925994 TI - Fractional diffusion in silicon. AB - Microscopic processes leading to ultrafast laser-induced melting of silicon are investigated by large-scale ab initio molecular dynamics simulations. Before becoming a liquid, the atoms are shown to be fractionally diffusive, which is a property that has so far been observed in crowded fluids consisting of large molecules. Here, it is found to occur in an elemental semiconductor. PMID- 23925995 TI - Risk of cardiovascular disease in patients with osteoarthritis: a prospective longitudinal study. AB - OBJECTIVE: To determine the risk of cardiovascular disease (CVD) among osteoarthritis (OA) patients using population-based administrative data from British Columbia, Canada. METHODS: The medical history of a random sample of 600,000 individuals from 1991-2009 was analyzed. A total of 12,745 OA cases and up to 3 non-OA individuals matched by age, sex, and year of diagnosis were followed for CVD events. Cox proportional hazards and Poisson regression models were used to estimate the relative risks (RRs) of CVD, myocardial infarction, ischemic heart disease (IHD), congestive heart failure (CHF), and stroke after adjusting for available sociodemographic and medical factors. RESULTS: OA was an independent predictor of CVD. The adjusted RRs were 1.15 (95% confidence interval [95% CI] 1.04-1.27), 1.26 (95% CI 1.13-1.42), and 1.17 (95% CI 1.07-1.26) among older men, younger women, and older women, respectively. Analyses were stratified by age and sex due to statistically significant interactions between OA and age and sex. RRs among older men, younger women, and older women were 1.33 (95% CI 1.11-1.62), 1.66 (95% CI 1.37-2.01), and 1.45 (95% CI 1.22-1.72) for IHD, respectively, and 1.25 (95% CI 1.02-1.54), 1.29 (95% CI 1.00-1.68), and 1.20 (95% CI 1.03-1.39) for CHF, respectively. Compared to non-OA individuals, OA cases who underwent total joint replacements had a 26% increased risk of CVD. CONCLUSION: This prospective longitudinal study suggests that OA is associated with an increased risk of CVD. Older men and adult women with OA had a higher risk of CVD, particularly IHD and CHF. Further studies are needed to confirm these results and to elucidate the potential biologic mechanisms. PMID- 23925996 TI - Comparative proteomics lends insight into genotype-specific pathogenicity. AB - Comparative proteomic analyses have emerged as a powerful tool for the identification of unique biomarkers and mechanisms of pathogenesis. In this issue of Proteomics, Murugaiyan et al. utilize difference gel electrophoresis (DIGE) to examine differential protein expression between nonpathogenic and pathogenic genotypes of Prototheca zopfii, a causative agent in bovine enteritis and mastitis. Their findings provide insights into molecular mechanisms of infection and evolutionary adaptation of pathogenic genotypes, demonstrating the power of comparative proteomic analyses. PMID- 23925997 TI - Interaction of antidepressant drug, clomipramine, with model and biological stratum corneum membrane as studied by electron paramagnetic resonance. AB - The interactions of tricyclic antidepressant drug, clomipramine (CLO), with pig ear stratum corneum (SC) and model membranes were investigated by electron paramagnetic resonance (EPR) spin labeling to get some insight into the possible application of this drug in transdermal delivery. The changes in membrane characteristics caused by CLO in the regions that are close to the water-lipid interfaces and the central parts of the membranes were searched. The experimental results were supported by computer simulation of EPR spectra, which showed heterogeneity of the membranes composed of regions with different fluidity characteristics. CLO was effective in both parts of the layers, indicating intercalation of the drug into model membranes as well as into the pig ear SC. Introduction of various molar ratios of CLO caused a decrease in the order parameter and an increase in the rotational diffusion of nitroxide moiety in different membrane regions as well as an increase in the polarity of spin probe environment. It also changed the number of resolved spectral components, which reflects the heterogeneity of the membrane. The fluidizing effect of CLO on pig ear SC throughout the whole membrane layers indicates that CLO penetrates into the SC, which is important for its transdermal delivery. PMID- 23925998 TI - Clinical biomarkers of response in advanced renal cell carcinoma. AB - There are now a range of effective targeted agents available for the first- and second-line treatment of advanced renal cell carcinoma (RCC). However, patients with advanced RCC have varied responses to therapy; some experience long-term responses while others may not respond, or even progress rapidly. Characteristics or markers that could be used to determine which patients will benefit most from which agent may enable us to select the optimal treatment of each individual patient, thereby improving efficacy and avoiding unnecessary toxic effects. These characteristics may be at the cellular or genetic level. Alternatively, the occurrence of adverse events may act as surrogate markers of a drug's on treatment activity, enabling prediction of outcomes during treatment. Recently, it has been suggested that during some targeted therapy for advanced RCC, the occurrence of specific adverse events, such as hypertension, hypothyroidism, hand foot syndrome or fatigue/asthenia, may be associated with improved efficacy. This article reviews the evidence supporting clinical biomarkers in patients with advanced RCC receiving targeted agents. We also consider how these clinical biomarkers may affect the future management of patients with advanced RCC. PMID- 23926000 TI - [Identification of novel KIT gene mutations in two Chinese families with piebaldism]. AB - OBJECTIVE: To screen for potential mutations of KIT gene for two Chinese families affected with piebaldism in order to facilitate genetic counseling and assisted reproduction. METHODS: Peripheral blood samples were collected from 2 patients of family 1 and the proband and 3 unaffected members of family 2 for the extraction of DNA and RNA. PCR-sequencing and reverse transcription PCR-sequencing were used to screen KIT mutations. RESULTS: All of the patients from family 1 were found to carry heterozygous IVS12+2-+7delinsACATCTTTA, a splicing mutation undocumented in the human gene mutation data base (HGMD) database. This mutation has resulted in c.1765-1779del in cDNA and p.Gly592Ala/del:E12, which has led to skipping of exon 12 and no expression of cDNA. The proband from family 2 has carried a heterozygous c.2401A>C mutation in KIT gene. The same mutation was not found in unaffected members. CONCLUSION: We have attained definite diagnosis for both families, which has facilitated genetic counseling and assisted reproduction for our patients and their family members. PMID- 23926001 TI - [Analysis of ALDH5A1 gene mutation in a Chinese Han family with succinic semialdehyde dehydrogenase deficiency]. AB - OBJECTIVE: To detect potential mutation in ALDH5A1 gene for a family affected with succinic semialdehyde dehydrogenase deficiency diagnosed by clinical inspection and urine screening. METHODS: Polymerase chain reaction and direct DNA sequencing were carried out for the affected child and her parents. Suspected ALDH5A1 gene mutations were verified in 100 healthy controls to exclude polymorphisms. RESULTS: The child was found to have carried 2 heterozygous missense mutations in the coding region of ALDH5A1 gene, namely c.527G>A and c.691G>A, for which her mother and father were respectively heterozygotes. The same mutations were not detected in 100 healthy controls. The child was also found to have carried two previously described polymorphisms including a heterozygous c.545C>T(derived from her father) and a homozygous c.538C>T(derived from her mother). CONCLUSION: Missense mutations of c.527G>A and c.691G>A in the ALDH5A1 gene are responsible for the pathogenesis of the disease in this family. PMID- 23925999 TI - Functional proteomics characterization of residual triple-negative breast cancer after standard neoadjuvant chemotherapy. AB - BACKGROUND: In this study, we used functional proteomics to determine the molecular characteristics of residual triple receptor-negative breast cancer (TNBC) patients after neoadjuvant systemic chemotherapy (NCT) and their relationship with patient outcomes in order to identify potential targets for therapy. PATIENTS AND METHODS: Protein was extracted from 54 residual TNBCs, and 76 proteins related to breast cancer signaling were measured by reverse phase protein arrays (RPPAs). Univariable and multivariable Cox proportional hazard models were fitted for each protein. Survival outcomes were estimated by the Kaplan-Meier product limit method. Training and cross validation were carried out. The coefficients estimated from the multivariable Cox model were used to calculate a risk score (RS) for each sample. RESULTS: Multivariable analysis using the top 25 proteins from univariable analysis at a false discovery rate (FDR) of 0.3 showed that AKT, IGFBP2, LKB1, S6 and Stathmin were predictors of recurrence-free survival (RFS). The cross-validation model was reproducible. The RS model calculated based on the multivariable analysis was -1.1086 * AKT + 0.2501 * IGFBP2 - 0.6745 * LKB1+1.0692 * S6 + 1.4086 * stathmin with a corresponding area under the curve, AUC = 0.856. The RS was an independent predictor of RFS (HR = 3.28, 95%CI = 2.07-5.20, P < 0.001). CONCLUSIONS: We found a five-protein model that independently predicted RFS risk in patients with residual TNBC disease. The PI3 K pathway may represent potential therapeutic targets in this resistant disease. PMID- 23926002 TI - [Cloning and localization of A3IP -a novel protein that interacts with ataxin-3]. AB - OBJECTIVE: To clone an A3IP gene and investigate its cellular and histological localization based on previous research which has identified part of A3IP sequence interacting with carboxyl-terminal of ataxin-3. METHODS: Bioinformatic and Northern blotting were applied to clone the A3IP gene and detect the expression of its transcripts in various human tissues and brain regions. Western blotting and immunofluorescence staining were applied to detect expression of A3IP protein in cultured cells. Immunohistochemistry staining was applied to study the expression of A3IP protein in various human tissues and brain regions. RESULTS: cDNA cloning of A3IP gene's reading frame and its sequence assembly were completed. Three transcripts (1 kb, 1.35 kb and 6 kb, respectively) of A3IP were found to express in various human tissues and brain regions. A3IP pEGFP expresses in cytoplasm of cultured COS-7 cells and various human tissues and brain regions including cerebral cortex, cerebellum, muscle, peripheral nerve, liver and kidney. CONCLUSION: The cloned A3IP gene encodes A3IP, a novel ataxin-3 interacting protein. Three transcripts of A3IP are expressed in various human tissues and brain regions. A3IP is a cytosolic protein. PMID- 23926003 TI - [Molecular genetics study of ED1 gene for two X-linked hypohidrotic ectodermal dysplasia families]. AB - OBJECTIVE: To provide genetic diagnosis and counseling for patients from two families affected with X-linked hypohidrotic ectodermal dysplasia. METHODS: Potential mutation of the ED1 gene was screened by DNA sequencing. For family 1, multiplex ligation-dependent probe amplification (MLPA) analysis and haplotyping of ED1 gene were also carried out for prenatal diagnosis. RESULTS: For the patient from family 1, deletion of the exon 1 of the ED1 gene and 2 short tandem repeat(STR) sites (DXS8269 and DXS1422) were detected. His daughter was carrier of the deletion. Upon prenatal diagnosis, the fetus was confirmed to be a normal male, for whom the haplotype of ED1 gene has differed from that of the proband. In family 2, a c.463C>T mutation in exon 3 of the ED1 gene was detected in the proband, whose mother was heterozygous for the same mutation. CONCLUSION: The deletion (exon 1) and missense (R155C) mutation in ED1 gene have probably underlied the disease in the two families. During prenatal diagnosis, it may be necessary to obtain precise results through combining mutation detection and haplotype analysis of the ED1 gene. PMID- 23926004 TI - [Molecular epidemiological analysis of alpha- and beta-thalassemia in Fujian province]. AB - OBJECTIVE: To investigate the gene prevalence and spectrum of alpha- and beta thalassemia in Fujian province. METHODS: A total of 11 234 of neonatal cord blood samples were collected for a prevalence study of alpha- and beta-thalassemia. All subjects included in this study were registered in 9 cities of Fujian province. A complete blood count and high performance liquid chromatography (HPLC) were performed in all samples, with microcytosis (MCV<= 79 f1 and MCH<= 27 pg) or HPLC positive cases further studied by DNA analysis. alpha- and beta-thalassemia were determined by using gap-PCR and reverse dot blot (RDB) assays. Unknown positive samples were analyzed directly with DNA sequencing. RESULTS: Of all 11 234 cord blood samples, 356 were identified as from alpha-thalassemia gene carriers, 7 deletion genotypes were identified including 236 (--SEA/ alpha alpha) cases, 67 (alpha 3.7/ alpha alpha) cases, 24 (alpha 4.2/alpha alpha) cases, 3 (alpha 3.7/ SEA) cases, 1 (alpha 4.2/ SEA) cases, 1 (alpha 3.7/ alpha 3.7) cases, 1 (alpha 3.7/ alpha 4.2) cases; 3 non-deletion genotypes were detected, including 7 (alpha alpha QS/ alpha alpha) cases, 3 (alpha alpha CS/alpha alpha) cases, 2 (alpha alpha WS/ alpha alpha) cases, the most common mutation was SEA/alpha alpha, which accounted for 66.29%, 148 individuals were found to have beta-hemoglobin gene mutations. 12 different mutations were identified, namely 65 IVS-2 654 (C>T) cases, 40 CD41-42(-TCTT, 12 CD17(A>T) cases, 10 -28(A>G) cases,7 CD27-28(+C) cases, 5 start codon ATG>AGG cases, 2 CD26(G>A) cases, 1 CD71-72(+A) cases, 1 IVS 1-1(G>T) cases, 1 CD43(G>T) cases, 2 -29(A>G) cases, 2 Codon 36 (-C) cases, the most common mutation was IVS-2 654(C>T) and CD41-42(-TCTT), which accounted for 70.95%. A novel beta-globin gene mutation CD36 (-C) allele was also detected. The carrier rate of thalassemia in Fujian population is 4.41%. In addition, 9 beta thalassemia carriers were found with alpha-thalassemia mutation. CONCLUSION: The research has revealed the type of gene mutations in alpha- and beta-talassemia in Fujian province. The beta-thalassemia mutations in Fujian province are complex, which were also obviously heterogeneous. This will significant value for screening the incidence, provide the valuable information for genetic counseling and prenatal diagnosis. PMID- 23926005 TI - [Mutation analysis and first-trimester prenatal diagnosis for a Chinese family with hidrotic ectodermal dysplasia]. AB - OBJECTIVE: To analyze GJB6 gene mutations in a Chinese family with hidrotic ectodermal dysplasia and to provide first-trimester prenatal diagnosis for a fetus. METHODS: Mutation scanning was carried out with PCR and bilateral direct sequencing in 2 affected and 6 unaffected individuals from the family. After the mutation was confirmed, prenatal diagnosis was performed on chorionic villi samples obtained at 11th gestational week. RESULTS: A heterozygous missense mutation c.31G>A of the GJB6 gene was discovered in all of the patients, which has led to substitution of glycine by arginine at codon 11 (p.G11R) at the N terminal of the GJB6 protein. Prenatal diagnosis indicated that the fetus had also carried the same p.G11R mutation. Following termination of the pregnancy, analysis of the aborted tissues was consistent with prenatal diagnosis. CONCLUSION: The missense mutation c.31G>A(p.G11R) of the GJB6 gene probably underlies the disease in this family. Prenatal diagnosis with DNA sequencing can facilitate genetic counseling of this family. PMID- 23926006 TI - [Detection of homozygous deletions in spinal muscular atrophy with genomic DNA sequencing]. AB - OBJECTIVE: To detect homozygous deletions of survival motor neuron (SMN) gene with genomic DNA sequencing, and to assess the value of genetic testing for the diagnosis of spinal muscular atrophy (SMA). METHODS: Polymerase chain reaction (PCR) was used for amplifying SMN gene in 100 SMA patients and 110 controls. Four different bases (g.31957, g.32006, g.32154 and g.32269) between SMN1 and SMN2 within the amplified segments were identified with genomic DNA sequencing. Homozygous deletion of SMN1 or SMN2 was determined by the presence or absence of base peaks at such four sites. Multiplex ligation-dependent probe amplification (MLPA) was carried out to confirm the results of genomic DNA sequencing. RESULTS: In the 100 SMA samples, only SMN2 specific base peaks were detected at the four sites, for which the copy numbers of SMN1 and SMN2 was 0:2 or 0:3, suggesting homozygous deletion of SMN1 gene. By contrast, only SMN1 specific base peaks were detected in 5 samples, for which the ratio of SMN1:SMN2 was 2:0, indicating homozygous deletion of SMN2. At four different sites, SMN1/SMN2 heterozygous peaks were detected in the remaining 105 samples, for which SMN1:SMN2was 2:2, suggesting non-deletion of SMN1 or SMN2. The results of sequencing were consistent with those of MLPA. CONCLUSION: Genomic DNA sequencing is a rapid, accurate and economic method for the diagnosis of homozygous deletion of SMA. PMID- 23926007 TI - [Identification of origins of marker chromosomes using fluorescence in situ hybridization]. AB - OBJECTIVE: To assess the value of fluorescence in situ hybridization (FISH) and bacterial artificial chromosome FISH (BAC-FISH) for the diagnosis for patients with marker chromosomes. METHODS: Sixteen patients with marker chromosomes were analyzed with technologies including GTG-banding, Q-banding, multiplex FISH and BAC-FISH. RESULTS: The marker chromosomes in the 16 patients were verified as der(Y) (2 cases), psu dic(Y) (1 case), psu dic(15) (1 case), dic(15) (1 case), del(Y) (1 case), r(X) (5 cases), i(14 or 22) (2 cases), i(18) (1 case). CONCLUSION: FISH and BAC-FISH can both verify the origin of marker chromosomes and provide accurate information for the diagnosis and treatment of patients. PMID- 23926008 TI - [Delineation of three structural Y chromosome aberrations combined molecular techniques]. AB - OBJECTIVE: To delineate the structure of Y chromosome aberrations and recombinant mechanisms for three patients. METHODS: Karyotype analysis, multiplex ligation dependent probe amplification (MLPA), fluorescence in situ hybridization (FISH), Y chromosome sequence tagged sites (STS) analysis, human whole genome-wide SNP array were used. RESULTS: The karyotypes of the three patients were 46, X, +mar. As suggested by MLPA analysis, case 1 has increased copy numbers of SRY, ZFY and UTY genes, case 2 had increased copies of SRY and ZFY genes, and deletion of UTY gene, and case 3 had decreased copies for subtelomeric regions of X/Yp and X/Yq. By STSs analysis, case 1 has retained SRY, sY84 and sY86 in the AZFa region, sY1227 in the AZFb region, whilst lost sY1228 in the AZFb region and other STSs in the AZFc region. Its breakpoint was thereby mapped between sY1227 and sY1228. Case 2 has retained SRY and sY1200 in the centromeric region, whilst has deletion of other STSs. Case 3 has retained SRY and STSs in the AZF regions. By SNP array, case 1 had duplicated Yp11.31-p11.2 and deletion of Yq11.22-q11.23 (approximately 5.18 Mb). Case 2 had duplicated Yp11.31-p11.2 and deletion of Yq11.21-q11.23 (approximately 14.644 Mb). Case 3 had single copy number deletion of p22.33 and q28 in the subtelomeric region of X/Yp and X/Yq. By FISH, cases 1 and 2 showed two signals for SRY and DYZ3 but no signal for DYZ1 on their marker chromosomes. Combining above results, the karyotypes of cases 1, 2 and 3 were determined as 46, X, idic(Y) (q11.23), 46, X, idic(Y) (q10) and 46, X, r(Y) (p11q12), respectively. CONCLUSION: Y chromosome aberrations are variable. Combined use of MLPA, STSs, FISH and SNP array is effective for revealing the breakpoints and recombinant mechanisms. PMID- 23926009 TI - [Mutation analysis of UGT1A1 gene in patients with unconjugated hyperbilirubinemia]. AB - OBJECTIVE: To analyze potential mutations of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in patients with unconjugated hyperbilirubinemia, and to explore the correlation between the mutations and total serum bilirubin levels. METHODS: Genomic DNA was extracted from peripheral blood samples of patients. Coding sequence and promoter region of the UGT1A1 gene were amplified. Mutations were identified through DNA sequencing. RESULTS: Mutations of the UGT1A1 gene were found in 46 out of 61 patients with unconjugated hyperbilirubinemia. Five types of mutations were detected, with a decreasing order of 211G>A, TA insertion in the TATAA promoter element, 686C>A, 1091C>T and 1352C>T. Compared with those carrying a single homozygous mutation or compound heterozygous mutations, total serum bilirubin was higher in those carrying a homozygous mutation in combination with other heterozygous mutations (P< 0.05). Based on the UGT1A1 gene mutations and level of total serum bilirubin, 44 patients were diagnosed with Gilbert syndrome, and 2 were diagnosed with Crigler-Najjar syndrome type 2. CONCLUSION: The level of total serum bilirubin is correlated with the number of UGT1A1 gene mutations as well as their heterozygous or homozygous status. PMID- 23926010 TI - [Molecular genetics study of hereditary spastic paraplegia accompanied by distal amyotrophy-an update]. AB - Hereditary spastic paraplegia(HSP or SPG) is a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive spasticity, weakness of lower limbs, and pathologically by retrograde axonal degeneration of corticospinal tracts and posterior spinal tracts. Presence of additional features allows differentiation between simple and complex forms of the disease. Genetically, 16 loci for HSP accompanied by distal amyotrophy have been mapped, for which 13 genes have been identified. With the identification of causative genes, the molecular mechanism of this disease is gradually elucidated. PMID- 23926011 TI - [Progress in genetic study of aortic dissection]. AB - Genetic study can provide important insight into the etiology of aortic dissection. To explore the pathogenesis and natural history of aortic dissection, a number of genes have been identified through microarray chip screening and undergone testing of polymorphisms to find mutations strongly associated with the disease. The results suggested aortic dissection to be a multi-gene disorder. Multiple genes probably work together to promote its development. Several diseases with a genetic predisposition are closely connected with aortic dissection, which also implied a role of genetic changes and malfunction in this disease. PMID- 23926012 TI - [Analysis of CYP17A1 gene mutation in a child patient with 17 alpha hydroxylase/17, 20-lyase deficiency]. AB - OBJECTIVE: To analyze CYP17A1 gene mutations in a child patient with 17 alpha hydroxylase/17, 20-lyase deficiency (17OHD), and to review characteristics of CYP17A1 gene mutations in Chinese patients with 17OHD. METHODS: Clinical data were collected. PCR and DNA sequencing were performed to detect mutations in the patient. RESULTS: The patient has presented classical features of 17OHD including hypertension, hypokalemia, decreased sex hormones and plasma cortisol, and elevated blood adrenocorticotrophic hormone. A compound heterozygous mutation c.987C>A and c.985del was detected in the CYP17A1 gene, which resulted in two premature stop codons at positions 328 and 417. CONCLUSION: A compound mutation, c.987C>A and c.985del, has been identified in a patient with 17OHD. Among CYP17A1 gene mutations identified in Chinese patients, missence mutations have been most common, and exons 5 and 8 have been the mutation hotspots. PMID- 23926013 TI - [Analysis of copy number variations in an infant with Cri du Chat syndrome by array-based comparative genomic hybridization]. AB - OBJECTIVE: To analyze genomic copy number variations in an infant with Cri du Chat syndrome, and to explore the underlying genetic cause. METHODS: G-banding analysis was carried out on cultured peripheral blood sample from the patient. Copy number variation analysis was performed using microarray comparative genomic hybridization, and the result was verified with fluorescence in situ hybridization. RESULTS: The infant was found to have a 46, XY, der(5) (p?) karyotype. By microarray comparative genomic hybridization, a 23.263 Mb deletion was detected in 5p14.2-p15.3 region in addition to a 14.602 Mb duplication in 12p31 region. A derivative chromosome was formed by rejoining of 12p31 region with the 5p14.2 breakpoint. The patient therefore has a karyotype of arr cgh 5p15.3p14.2 (PLEKHG4B>CDH12)* 1 pat, 12p13.33p13.1 (IQSEC3>GUC Y2C)* 3 pat. Loss of distal 5p and gain of distal 12p were verified with fluorescence in situ hybridization. CONCLUSION: The Cri du Chat syndrome manifested by the patient was caused by deletion of distal 5p from an unbalanced translocation involving chromosome 5. Microarray comparative genomic hybridization is a powerful tool for revealing genomic copy number variations for its high-resolution, high-throughput and high accuracy. PMID- 23926014 TI - [SNP-chip technology for identification of origins for prenatally detected marker chromosomes]. AB - OBJECTIVE: To determine the origin of 1 prenatally detected small supernumerary marker chromosome (sSMC) using SNP-chip technology, and to deduce the underlying mechanism. METHODS: The fetal sample was subjected to karyotype analysis. The identified sSMC was subjected to genom wide scan using a SNP microarray chip. The results were validated with fluorescence in situ hybridization (FISH). RESULTS: The karyotype of the fetus was determined as 46, X, +mar, which was verified by SNP microarray chip analysis as Yp11.2-11.3 duplication, along with loss of Yq11.2 region, FISH analysis has confirmed that the sSMC has derived from the Y chromosome. CONCLUSION: The karyotype of the fetus was determined as 46, X, idic(Y) (pter-> p11.2::11.2-> pter). Regional deletion of Yq11.2 has been associated with male azoospermia. SNP chip analysis can exclude minor deletions and duplications with a size of more than 1 Mb, which may be applied for verifying difficult cases as well as microdeletion and duplication syndromes upon prenatal diagnosis. PMID- 23926015 TI - [Association of single nucleotide polymorphism of methylenetetrahydrofolate reductase gene with susceptibility to acute leukemia]. AB - OBJECTIVE: To assess whether polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene is associated with susceptibility to acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) in Chinese Han children. METHODS: The study has included 87 patients with ALL, 22 patients with AML and 120 healthy controls. All subjects were analyzed with reverse transcriptase-polymerase chain reaction denaturing gradient gel electrophoresis and sequencing. RESULTS: A 677CT genotype of the MTHFR gene was associated with decreased risk of ALL (OR=0.23, 95%CI: 0.07 0.79). However, MTHFR A1298C genotypes were not associated with the risk of either disease. 677TT/1298AA and 677CC/1298AC genotypes were associated with increased risk of ALL(OR=3.78, 95% CI: 1.38-10.40; OR=3.17, 95% CI: 1.18-8.53, respectively), whereas the genotype 677CT/1298AA was associated with susceptibility to AML (OR=0.23, 95% CI: 0.06-0.97). CONCLUSION: Our data suggested that C677T polymorphism of MTHFR gene may increase the risk of childhood AML. PMID- 23926016 TI - [Association between 1019C/T polymorphism of Connexin 37 gene and restenosis after coronary stenting]. AB - OBJECTIVE: To assess the association between 1019C/T polymorphism of Connexin 37 (CX37) gene and susceptibility to restenosis after percutaneous coronary intervention (PCI) in ethnic Han Chinese patients from Wuxi. METHODS: Five hundred and thirty-two patients with coronary artery disease (CAD) who had undergone PCI underwent coronary angiography (CAG) in 3 months, and were divided into in stent restenosis (ISR) group (n=67) and no instent restenosis (NISR) group (n=465). Five hundred and one healthy individuals have served as the control group. All cases were genotyped with DNA sequencing. RESULTS: Compared with healthy controls, the frequency of CX37 C allele was higher in CAD patients (57.05% vs. 41.32%, P< 0.01). The frequency of C carries (CC+TC) was 79.32% in CAD patients, against 65.47% in healthy controls (P<0.01). The risk for CAD was significantly increased in carriers of C allele (CC+TC) compared with TT homozygotes (OR=2.03, 95% CI: 1.53-2.80). Stratified analysis has indicated a significant difference in the frequency of C allele carriers between both male and female CAD patients and healthy controls (79.63% vs. 72.45%, P=0.02; 78.00% vs. 51.50%, P< 0.01). For both genders, carriers of C allele had a higher risk for CAD compared with TT homozygotes (males: OR=1.48, 95% CI: 1.06-2.09; females: OR=3.34, 95% CI: 1.90-5.86). Compared with NISR group, the frequency of CX37 C allele and C carries (CC+TC) were significantly higher in ISR group (72.39% vs. 54.84%, P< 0.01; 89.55% vs. 77.85%, P=0.027). Compared with TT homozygotes, the risk for restenosis has significantly increased in carriers of C allele (CC+TC) (OR=2.44, 95% CI: 1.08-5.50). Stratified analysis also suggested that the frequency of C carriers was significantly higher in male ISR group compared with male NISR group (92. 86% vs. 77.66%, P=0.008). The risk for restenosis has increased by nearly four fold in carriers of C allele (CC+TC) compared with TT homozygotes (95% CI: 1.32-10.64). However, for female patients, no significant difference was detected in the ISR risk between carriers of CC+TC type and TT homozygotes (P=0.655). CONCLUSION: The C allele of 1019C/T polymorphism in the CX37 gene is associated with susceptibility to CAD as well as restenosis after coronary stenting in male patients from Wuxi. PMID- 23926017 TI - [Association of matrix metalloproteinase-3 gene polymorphisms with subtypes of ischemic stroke]. AB - OBJECTIVE: To assess the association between matrix metalloproteinase-3 (MM-3) gene polymorphisms and subtypes of ischemic stroke (IS) in northern Han Chinese population. METHODS: A total of 289 patients with acute IS (within 3 days after the onset, including 185 with large artery atherosclerosis (LAA) and 104 for small artery occlusion (SAO)) and 175 matched healthy controls were recruited for this case-control study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or sequenc-based typing (SBT) was carried out to analyze 3 SNPs of the MMP-3 gene. RESULTS: An incomplete linkage disequilibrium (LD) block was constructed with the 3 SNPs, and the distribution of genotypes of the 3 SNPs differed between the LAA group and controls in a dominant model: Carriers of 5A allele (5A5A+5A6A) of the rs3025058 locus were 1.72 times more susceptible to LAA stroke compared with carriers of 6A6A alleles (P=0.017, OR=1.72, 95% CI: 1.10 2.69), carriers of G alleles (GG+AG) of the rs522616 locus were 0.52 times more susceptible to LAA stroke compared with carriers of AA alleles (P=0.005, OR=0.52, 95% CI: 0.33-0.82), whilst carriers of A allele of the rs679620 locus were 1.55 times more susceptible to LAA stroke compared with carriers of GG alleles (P=0.042, OR=1.55, 95% CI: 1.01-2.37). However, no significant difference has been found between particular genotypes of such SNPs between SAO patients and controls (P> 0.05). Furthermore, 5A-A-A and 6A-A-A haplotypes were significantly more common in LAA group than the controls (P< 0.05), whilst 6A-G-G haplotype has been the opposite (P< 0.01). CONCLUSION: Our study has demonstrated that serum MMP-3 level is significantly increased at acute stage of LAA as well as SAO type strokes. There may be an association of rs3025058, rs522616 and rs679620 of MMP-3 gene with susceptibility to LAA stoke in northern Han Chinese population. PMID- 23926018 TI - [Study of the association between SNP rs7903146(C/T) in TCF7L2 and metabolic syndrome in Chinese Korean and Han populations from Yanbian]. AB - OBJECTIVE: To assess the association between a rs7903146(C/T) polymorphism of TCF7L2 gene and metabolic syndrome (MS), plasma lipoprotein, and plasma adiponectin (PA) in Chinese Korean and Han populations from Yanbian region. METHODS: Polymerase chain reaction and DNA sequencing were used to determine the genotype of rs7903146 in 310 Chinese Korean (190 in case group and 120 in control group) and 344 Chinese Han (255 in case group and 89 in control group). ELIAS was used to test serum insulin (INS) and PA. RESULTS: The frequency of T allele was higher in ethnic Han compared with ethnic Koreans (0.022 vs. 0.008), lower than that of Europeans (0.279) and Africans (0.257), but similar to those of Beijing Chinese and Japanese. For ethnic Korean Chinese, the frequencies of TT and CT genotypes as well as the T allele in patients with EH were significantly higher than those of the control group (P< 0.01), which also showed an increasing trend for both MS and T2DM groups (P=0.09 and P=0.07, respectively). By contrast, for Chinese Han, the frequencies of genotypes and particular allele in patients with MS, T2DM and EH showed no significant difference from those of the control group. For T2DM, EH, and control groups, PA level of individuals with CT or TT genotypes was significantly higher compared with that of the CC genotype (P< 0.05). The TC and LDL-C levels were significantly higher in T2DM, MS and EH groups compared with those of the control group. The PA level was lower in MS group compared with the control group. CONCLUSION: The T allele of SNP rs7903146 of TCF7L2 gene may be a risk factor for EH in Chinese Korean population from Yanbian region. The T allele also affects the PA level; lower PA is a risk factor for MS. The rs7903146 polymorphism showed a racial and ethnic difference. PMID- 23926019 TI - [Molecular basis and clinical transfusion of a family with Bw subtype of ABO blood group system]. AB - OBJECTIVE: To study a family with Bw subtype of ABO blood group system, and to review safety issues in relation with clinical transfusion. METHODS: The molecular basis for the blood type was studied with serological assay, polymerase chain reaction-sequence specific primer (PCR-SSP) and DNA sequencing, TA clone and haplotype analysis in one blood donor whose ABO blood group were difficulty typed and her family. The bioinformatics analysis was carried out by biological analysis software to investigate the change of structure and function of enzymes influenced by the change amino acid. A retrospective survey was carried out to investigate what is the actual position that the donor blood was used in the clinical transfusion. RESULTS: Three members from the family were found to have a Bw subtype. A substitution of nucleotide C by T at position 721 in exon 7 was discovered, which resulted in replacement of amino acid Arg to Trp. Review of clinical record suggested that there has been no significant abnormality association with past three blood transfusions. CONCLUSION: A 721C>T mutation of the ABO gene probably underlies the Bw subtype. Further research is needed for understanding the clinical significance of this subtype in the blood transfusion. PMID- 23926020 TI - [Association of two SNPs in 3'UTR of ETS1 gene with systemic lupus erythematosus in a northern Chinese Han population]. AB - OBJECTIVE: To assess the association between 2 single nucleotide polymorphisms (SNPs) of ETS1 gene and susceptibility to systemic lupus erythematosus (SLE) in a northern Chinese Han population. METHODS: Two SNPs within the ETS1 gene mapped to 11q23 were selected based on HapMap data. Genotyping was conducted with Taqman method in 231 patients with SLE and 474 healthy controls from Qilu Hospital, Shandong and analyzed with PLINK1.07 software. Haplotypes were analyzed with SHEsis software. RESULTS: A statistically significant difference was detected in the distribution of rs1128334 and rs4937333 genotypes between the two groups (all P< 0.01). For rs1128334, the frequency of the minor allele was 0.291 and 0.428 in controls and cases, respectively. For rs4937333, the minor allele frequency was 0.381 and 0.476 in controls and cases respectively. An A-C haplotype was found to be strongly associated with increased risk for SLE, while another haplotype G-C may reduce this risk. CONCLUSION: Our study has suggested that rs1128334 and rs4937333 are strongly associated with the risk for SLE in northern Chinese Han population. PMID- 23926021 TI - [A family affected with neurofibromatosis]. PMID- 23926022 TI - [Split hand/foot malformation: report of a family with 20 cases]. PMID- 23926023 TI - [Silver syndrome: report of a family with 5 cases]. PMID- 23926024 TI - [Non-syndromic autosomal dominant type deafness: report of a family with 26 cases]. PMID- 23926025 TI - [Benign positional paroxysmal vertigo: report of a family with 5 cases]. PMID- 23926026 TI - The central oscillatory network of orthostatic tremor. AB - Orthostatic tremor (OT) is a movement disorder of the legs and trunk that is present in the standing position but typically absent when sitting. The pathological central network involved in orthostatic tremor is still unknown. In this study we analyzed 15 patients with simultaneous high-resolution electroencephalography and electromyography recording to assess corticomuscular coherence. In 1 patient we were able to simultaneously record the local field potential in the ventrolateral thalamus and electroencephalography. Dynamic imaging of coherent source analysis was used to find the sources in the brain that are coherent with the peripheral tremor signal. When standing, the network for the tremor frequency consisted of unilateral activation in the primary motor leg area, supplementary motor area, primary sensory cortex, two prefrontal/premotor sources, thalamus, and cerebellum for the whole 30-second segment recorded. The source coherence dynamics for the primary leg area and the thalamic source signals with the tibialis anterior muscle showed that they were highly coherent for the whole 30 seconds for the contralateral side but markedly decreased after 15 seconds for the ipsilateral side. The source signal and the recorded thalamus signal followed the same time frequency dynamics of coherence in 1 patient. The corticomuscular interaction in OT follows a consistent pattern with an initially bilateral pattern and then a segregated unilateral pattern after 15 seconds. This may add to the feeling of unsteadiness. It also makes the thalamus unlikely as the main source of orthostatic tremor. PMID- 23926028 TI - Fast identification of reliable hosts for targeted cell line development from a limited-genome screening using combined phiC31 integrase and CRE-Lox technologies. AB - The use of targeted integration (TI) in cell line development (CLD) usually introduces one copy of a recombinant gene into a predetermined transcriptionally active locus. This reduces the heterogeneity typically associated with traditional random integration (RI) CLD with regards to varied productivity and instability, resulting from diverse chromosomal influences, varied copy numbers, and repeat-induced rearrangement. As such, TI CLD offers the hope of a predictable and consistent CLD process for establishing stable clones. However, given the low copy number, cell lines established from a TI CLD process tend to exhibit low productivity. Here, we describe our nonviral-based approach for quickly establishing and identifying TI hosts from a limited genome screening. Importantly, the TI hosts identified are consistent and reliable in supporting the production of diverse antibodies regardless of antibody subclass (IgG1 vs. IgG4) or prior traditional CLD performance (relatively easy vs. difficult to express antibodies). Moreover, an approximately twofold increase in titer can be achieved by using a CRE recombinase-mediated cassette exchange (RMCE) strategy with an exchange vector carrying two units of the antibody gene. Two RMCE hosts that were established were able to produce up to ~ 1.7 and 2 g/L of antibodies in nonoptimized fed-batch shake flask production cultures with chemically defined media. Potentially, this strategy may be applied to the production of bispecific antibodies with a fast turnaround time. PMID- 23926027 TI - Association of metabolic risk factors with cartilage degradation assessed by T2 relaxation time at the knee: data from the osteoarthritis initiative. AB - OBJECTIVE: To evaluate the association of metabolic risk factors with severity and 2-year progression of early degenerative cartilage changes at the knee, measured with T2 relaxation times in middle-aged subjects from the Osteoarthritis Initiative. METHODS: Cartilage segmentation and T2 map generation were performed in knee 3T magnetic resonance images from 403 subjects ages 45-60 years without radiographic osteoarthritis (OA). The influence of risk factors on baseline T2 and longitudinal progression of T2 was analyzed using linear regression, adjusting for age, sex, and other OA risk factors. RESULTS: Four metabolic risk factors, i.e., high abdominal circumference (P < 0.001), hypertension (P = 0.041), high fat consumption (P = 0.023), and self-reported diabetes mellitus (P = 0.010), were individually associated with higher baseline T2. When the 4 metabolic risk factors were considered in a multivariate regression model, higher T2 remained significantly associated with abdominal circumference (P < 0.001) and diabetes mellitus (P = 0.026), and there was a trend for high fat consumption (P = 0.096). For the individual risk factors, only diabetes mellitus remained associated with higher baseline T2 after adjustment for body mass index (BMI). After adjustment for BMI, baseline T2 increased in a dose-response manner with the number of metabolic risk factors present (P = 0.032 for linear trend), and subjects with >=3 metabolic factors (versus <3) had significantly higher baseline T2 (mean difference 1.2 msec [95% confidence interval 0.3, 2.1]; P = 0.011). Metabolic risk factors were not significantly associated with increases in T2 during followup. CONCLUSION: Metabolic risk factors are associated with higher T2, suggesting that increased cartilage degeneration may be caused by modifiable metabolic disorders. PMID- 23926029 TI - A soft-template-conversion route to fabricate nanopatterned hybrid pt/carbon for potential use in counter electrodes of dye-sensitized solar cells. AB - Hybrid Pt(platinum)/carbon nanopatterns with an extremely low loading level of Pt catalysts derived from block copolymer templates as an alternative type of counter electrodes (CEs) in dye-sensitized solar cells (DSSCs) are proposed. DSSCs employing hybrid Pt/carbon with tailored configuration as CEs exhibit higher short-circuit current and conversion efficiencies as well as stability with a lapse of time compared with conventional cells on the basis of sputtered Pt thin films, evidencing that the new class of hybrid nanostructures possess high potential for cost-effective electrodes in energy conversion devices. PMID- 23926030 TI - Purple-leaved Ficus lyrata plants produced by overexpressing a grapevine VvMybA1 gene. AB - KEY MESSAGE: This study established an efficient method of regenerating plants of Ficus lyrata and producing purple-leaved F. lyrata plants through genetic transformation using a VvMybA1 gene of grapevine. ABSTRACT: Ficus lyrata, a species with unique violin- or guitar-shaped leaves, was regenerated from leaf derived calli cultured on Murashige and Skoog (MS) basal medium supplemented with 4.5 MUM N-phenyl-N'-1, 2, 3-thiadiazol-5-yl urea (TDZ) and 0.5 MUM alpha naphthalene acetic acid (NAA). Leaf discs were inoculated with Agrobacterium tumefaciens strain EHA 105 harboring a binary vector DEAT that contains the VvMybA1 gene and neomycin phosphotransferase (npt II) gene and subsequently cultured on the established regeneration medium supplemented with 100 mg l(-1) kanamycin. Results showed that 87.5 % of the leaf discs produced kanamycin resistant callus, and 68.8 % of them produced adventitious shoots. Transgenic plants with three leaf colors including green, green-purple, and purple were produced. Regular and quantitative real-time PCR analyses confirmed the integration of transgenes into the host genome. Semi-quantitative RT-PCR analysis indicated that the VvMybA1 gene was responsible for the purple-colored phenotype. Purple-leaved plants with strong color stability grew vigorously in a greenhouse. This study illustrated the feasibility of using a genetically engineered VvMybA1 gene for drastic modification of leaf color of an important woody ornamental plant. PMID- 23926031 TI - Neural mechanisms of speed perception: transparent motion. AB - Visual motion on the macaque retina is processed by direction- and speed selective neurons in extrastriate middle temporal cortex (MT). There is strong evidence for a link between the activity of these neurons and direction perception. However, there is conflicting evidence for a link between speed selectivity of MT neurons and speed perception. Here we study this relationship by using a strong perceptual illusion in speed perception: when two transparently superimposed dot patterns move in opposite directions, their apparent speed is much larger than the perceived speed of a single pattern moving at that physical speed. Moreover, the sensitivity for speed discrimination is reduced for such bidirectional patterns. We first confirmed these behavioral findings in human subjects and extended them to a monkey subject. Second, we determined speed tuning curves of MT neurons to bidirectional motion and compared these to speed tuning curves for unidirectional motion. Consistent with previous reports, the response to bidirectional motion was often reduced compared with unidirectional motion at the preferred speed. In addition, we found that tuning curves for bidirectional motion were shifted to lower preferred speeds. As a consequence, bidirectional motion of some speeds typically evoked larger responses than unidirectional motion. Third, we showed that these changes in neural responses could explain changes in speed perception with a simple labeled line decoder. These data provide new insight into the encoding of transparent motion patterns and provide support for the hypothesis that MT activity can be decoded for speed perception with a labeled line model. PMID- 23926033 TI - Convergence and cross talk in urogenital neural circuitries. AB - Despite common comorbidity of sexual and urinary dysfunctions, the interrelationships between the neural control of these functions are poorly understood. The medullary reticular formation (MRF) contributes to both mating/arousal functions and micturition, making it a good site to test circuitry interactions. Urethane-anesthetized adult Wistar rats were used to examine the impact of electrically stimulating different nerve targets [dorsal nerve of the penis (DNP) or clitoris (DNC); L6/S1 trunk] on responses of individual extracellularly recorded MRF neurons. The effect of bladder filling on MRF neurons was also examined, as was stimulation of DNP on bladder reflexes via cystometry. In total, 236 MRF neurons responded to neurostimulation: 102 to DNP stimulation (12 males), 64 to DNC stimulation (12 females), and 70 to L6/S1 trunk stimulation (12 males). Amplitude thresholds were significantly different at DNP (15.0 +/- 0.6 MUA), DNC (10.5 +/- 0.7 MUA), and L6/S1 trunk (54.2 +/- 4.6 MUA), whereas similar frequency responses were found (max responses near 30-40 Hz). In five males, filling/voiding cycles were lengthened with DNP stimulation (11.0 +/- 0.9 MUA), with a maximal effective frequency plateau beginning at 30 Hz. Bladder effects lasted ~ 2 min after DNP stimulus offset. Many MRF neurons receiving DNP/DNC input responded to bladder filling (35.0% and 68.3%, respectively), either just before (43%) or simultaneously with (57%) the voiding reflex. Taken together, MRF-evoked responses with neurostimulation of multiple nerve targets along with different responses to bladder infusion have implications for the role of MRF in multiple aspects of urogenital functions. PMID- 23926032 TI - Sensitivity to theta-burst timing permits LTP in dorsal striatal adult brain slice. AB - Long-term potentiation (LTP) of excitatory afferents to the dorsal striatum likely occurs with learning to encode new skills and habits, yet corticostriatal LTP is challenging to evoke reliably in brain slice under physiological conditions. Here we test the hypothesis that stimulating striatal afferents with theta-burst timing, similar to recently reported in vivo temporal patterns corresponding to learning, evokes LTP. Recording from adult mouse brain slice extracellularly in 1 mM Mg(2+), we find LTP in dorsomedial and dorsolateral striatum is preferentially evoked by certain theta-burst patterns. In particular, we demonstrate that greater LTP is produced using moderate intraburst and high theta-range frequencies, and that pauses separating bursts of stimuli are critical for LTP induction. By altering temporal pattern alone, we illustrate the importance of burst-patterning for LTP induction and demonstrate that corticostriatal long-term depression is evoked in the same preparation. In accord with prior studies, LTP is greatest in dorsomedial striatum and relies on N methyl-d-aspartate receptors. We also demonstrate a requirement for both Gq- and Gs/olf-coupled pathways, as well as several kinases associated with memory storage: PKC, PKA, and ERK. Our data build on previous reports of activity directed plasticity by identifying effective values for distinct temporal parameters in variants of theta-burst LTP induction paradigms. We conclude that those variants which best match reports of striatal activity during learning behavior are most successful in evoking dorsal striatal LTP in adult brain slice without altering artificial cerebrospinal fluid. Future application of this approach will enable diverse investigations of plasticity serving striatal-based learning. PMID- 23926035 TI - Accounting for direction and speed of eye motion in planning visually guided manual tracking. AB - Accurate motor planning in a dynamic environment is a critical skill for humans because we are often required to react quickly and adequately to the visual motion of objects. Moreover, we are often in motion ourselves, and this complicates motor planning. Indeed, the retinal and spatial motions of an object are different because of the retinal motion component induced by self-motion. Many studies have investigated motion perception during smooth pursuit and concluded that eye velocity is partially taken into account by the brain. Here we investigate whether the eye velocity during ongoing smooth pursuit is taken into account for the planning of visually guided manual tracking. We had 10 human participants manually track a target while in steady-state smooth pursuit toward another target such that the difference between the retinal and spatial target motion directions could be large, depending on both the direction and the speed of the eye. We used a measure of initial arm movement direction to quantify whether motor planning occurred in retinal coordinates (not accounting for eye motion) or was spatially correct (incorporating eye velocity). Results showed that the eye velocity was nearly fully taken into account by the neuronal areas involved in the visuomotor velocity transformation (between 75% and 102%). In particular, these neuronal pathways accounted for the nonlinear effects due to the relative velocity between the target and the eye. In conclusion, the brain network transforming visual motion into a motor plan for manual tracking adequately uses extraretinal signals about eye velocity. PMID- 23926034 TI - Light adaptation alters the source of inhibition to the mouse retinal OFF pathway. AB - Sensory systems must avoid saturation to encode a wide range of stimulus intensities. One way the retina accomplishes this is by using both dim-light sensing rod and bright-light-sensing cone photoreceptor circuits. OFF cone bipolar cells are a key point in this process, as they receive both excitatory input from cones and inhibitory input from AII amacrine cells via the rod pathway. However, in addition to AII amacrine cell input, other inhibitory inputs from cone pathways also modulate OFF cone bipolar cell light signals. It is unknown how these inhibitory inputs to OFF cone bipolar cells change when switching between rod and cone pathways or whether all OFF cone bipolar cells receive rod pathway input. We found that one group of OFF cone bipolar cells (types 1, 2, and 4) receive rod-mediated inhibitory inputs that likely come from the rod-AII amacrine cell pathway, while another group of OFF cone bipolar cells (type 3) do not. In both cases, dark-adapted rod-dominant light responses showed a significant contribution of glycinergic inhibition, which decreased with light adaptation and was, surprisingly, compensated by an increase in GABAergic inhibition. As GABAergic input has distinct timing and spatial spread from glycinergic input, a shift from glycinergic to GABAergic inhibition could significantly alter OFF cone bipolar cell signaling to downstream OFF ganglion cells. Larger GABAergic input could reflect an adjustment of OFF bipolar cell spatial inhibition, which may be one mechanism that contributes to retinal spatial sensitivity in the light. PMID- 23926036 TI - Inhibition of the Aplysia sensory neuron calcium current with dopamine and serotonin. AB - The inhibition of Aplysia pleural mechanosensory neuron synapses by dopamine and serotonin through activation of endogenous dopaminergic and expressed 5 HT1Apl(a)/b receptors, respectively, involves a reduction in action potential associated calcium influx. We show that the inhibition of synaptic efficacy is downstream of the readily releasable pool, suggesting that inhibition is at the level of calcium secretion coupling, likely a result of the changes in the calcium current. Indeed, the inhibitory responses directly reduce a CaV2-like calcium current in isolated sensory neurons. The inhibition of the calcium current is voltage independent as it is not affected by a strong depolarizing prepulse, consistent with other invertebrate CaV2 calcium currents. Similar to voltage-independent inhibition of vertebrate nociceptors, inhibition was blocked with Src tyrosine kinase inhibitors. The data suggest a conserved mechanism by which G protein-coupled receptor activation can inhibit the CaV2 calcium current in nociceptive neurons. PMID- 23926037 TI - Loss of balance during balance beam walking elicits a multifocal theta band electrocortical response. AB - Determining the neural correlates of loss of balance during walking could lead to improved clinical assessment and treatment for individuals predisposed to falls. We used high-density electroencephalography (EEG) combined with independent component analysis (ICA) to study loss of balance during human walking. We examined 26 healthy young subjects performing heel-to-toe walking on a treadmill mounted balance beam as well as walking on the treadmill belt (both at 0.22 m/s). ICA identified clusters of electrocortical EEG sources located in or near anterior cingulate, anterior parietal, superior dorsolateral-prefrontal, and medial sensorimotor cortex that exhibited significantly larger mean spectral power in the theta band (4-7 Hz) during walking on the balance beam compared with treadmill walking. Left and right sensorimotor cortex clusters produced significantly less power in the beta band (12-30 Hz) during walking on the balance beam compared with treadmill walking. For each source cluster, we also computed a normalized mean time/frequency spectrogram time locked to the gait cycle during loss of balance (i.e., when subjects stepped off the balance beam). All clusters except the medial sensorimotor cluster exhibited a transient increase in theta band power during loss of balance. Cluster spectrograms demonstrated that the first electrocortical indication of impending loss of balance occurred in the left sensorimotor cortex at the transition from single support to double support prior to stepping off the beam. These findings provide new insight into the neural correlates of walking balance control and could aid future studies on elderly individuals and others with balance impairments. PMID- 23926038 TI - Pathological and physiological high-frequency oscillations in focal human epilepsy. AB - High-frequency oscillations (HFO; gamma: 40-100 Hz, ripples: 100-200 Hz, and fast ripples: 250-500 Hz) have been widely studied in health and disease. These phenomena may serve as biomarkers for epileptic brain; however, a means of differentiating between pathological and normal physiological HFO is essential. We categorized task-induced physiological HFO during periods of HFO induced by a visual or motor task by measuring frequency, duration, and spectral amplitude of each event in single trial time-frequency spectra and compared them to pathological HFO similarly measured. Pathological HFO had higher mean spectral amplitude, longer mean duration, and lower mean frequency than physiological induced HFO. In individual patients, support vector machine analysis correctly classified pathological HFO with sensitivities ranging from 70-98% and specificities >90% in all but one patient. In this patient, infrequent high amplitude HFO were observed in the motor cortex just before movement onset in the motor task. This finding raises the possibility that in epileptic brain physiological-induced gamma can assume higher spectral amplitudes similar to those seen in pathologic HFO. This method if automated and validated could provide a step towards differentiating physiological HFO from pathological HFO and improving localization of epileptogenic brain. PMID- 23926039 TI - Acetylcholine enhances excitability by lowering the threshold of spike generation in olfactory receptor cells. AB - Olfactory perception is influenced by behavioral states, presumably via efferent regulation. Using the whole cell version of patch-clamp recording technique, we discovered that acetylcholine, which is released from efferent fibers in the olfactory mucosa, can directly affect the signal encoding in newt olfactory receptor cells (ORCs). Under current-clamp conditions, application of carbachol, an acetylcholine receptor agonist, increased the spike frequency of ORCs and lowered their spike threshold. When a 3-pA current to induce near-threshold depolarization was injected into ORCs, 0.0 spikes/s were generated in control solution and 0.5 spikes/s in the presence of carbachol. By strong stimuli of injection of a 13-pA current into ORCs, 9.1 and 11.0 spikes/s were generated in control and carbachol solutions, respectively. A similar result was observed by bath application of 50 MUM acetylcholine. Under voltage-clamp conditions, carbachol increased the peak amplitude of a voltage-gated sodium current by 32% and T-type calcium current by 39%. Atropine, the specific muscarinic receptor antagonist, blocked the enhancement by carbachol of the voltage-gated sodium current and T-type calcium current, suggesting that carbachol increases those currents via the muscarinic receptor rather than via the nicotinic receptor. In contrast, carbachol did not significantly change the amplitude of the L-type calcium current or the delayed rectifier potassium current in the ORCs. Because T type calcium current is known to lower the threshold in ORCs, we suggest that acetylcholine enhance excitability by lowering the threshold of spike generation in ORCs via the muscarinic receptor. PMID- 23926041 TI - A place for time: the spatiotemporal structure of neural dynamics during natural audition. AB - We use functional magnetic resonance imaging (fMRI) to analyze neural responses to natural auditory stimuli. We characterize the fMRI time series through the shape of the voxel power spectrum and find that the timescales of neural dynamics vary along a spatial gradient, with faster dynamics in early auditory cortex and slower dynamics in higher order brain regions. The timescale gradient is observed through the unsupervised clustering of the power spectra of individual brains, both in the presence and absence of a stimulus, and is enhanced in the stimulus locked component that is shared across listeners. Moreover, intrinsically faster dynamics occur in areas that respond preferentially to momentary stimulus features, while the intrinsically slower dynamics occur in areas that integrate stimulus information over longer timescales. These observations connect the timescales of intrinsic neural dynamics to the timescales of information processing, suggesting a temporal organizing principle for neural computation across the cerebral cortex. PMID- 23926040 TI - Contrasting distribution of physiological cell types in different regions of the bed nucleus of the stria terminalis. AB - We characterized the electroresponsive and morphological properties of neurons in the bed nucleus of the stria terminalis (BNST). Previously, Rainnie and colleagues distinguished three cell types in the anterolateral region of BNST (BNST-AL): low-threshold bursting cells (LTB; type II) and regular spiking neurons that display time-dependent (RS; type I) or fast (fIR; type III) inward rectification in the hyperpolarizing direction (Hammack SE, Mania I, Rainnie DG. J Neurophysiol 98: 638-56, 2007). We report that the same neuronal types exist in the anteromedial (AM) and anteroventral (AV) regions of BNST. In addition, we observed two hitherto unreported cell types: late-firing (LF) cells, only seen in BNST-AL, that display a conspicuous delay to firing, and spontaneously active (SA) neurons, only present in BNST-AV, firing continuously at rest. However, the feature that most clearly distinguished the three BNST regions was the incidence of LTB cells (approximately 40-70%) and the strength of their bursting behavior (both higher in BNST-AM and AV relative to AL). The incidence of RS cells was similar in the three regions (~25%), whereas that of fIR cells was higher in BNST AL (~25%) than AV or AM (<=8%). With the use of biocytin, two dominant morphological cell classes were identified but they were not consistently related to particular physiological phenotypes. One neuronal class had highly branched and spiny dendrites; the second had longer but poorly branched and sparsely spiny dendrites. Both often exhibited dendritic varicosities. Since LTB cells prevail in BNST, it will be important to determine what inputs set their firing mode (tonic vs. bursting) and in what behavioral states. PMID- 23926042 TI - Encoding of near-range spatial information by descending interneurons in the stick insect antennal mechanosensory pathway. AB - Much like mammals use their whiskers, insects use their antennae for tactile near range orientation during locomotion. Stick insects rapidly transfer spatial information about antennal touch location to the front legs, allowing for aimed reach-to-grasp movements. This adaptive behavior requires a spatial coordinate transformation from "antennal contact space" to "leg posture space." Therefore, a neural pathway must convey proprioceptive and tactile information about antennal posture and contact site to thoracic motor networks. Here we analyze proprioceptive encoding properties of descending interneurons (DINs) that convey information about antennal posture and movement to the thoracic ganglia. On the basis of response properties of 110 DINs to imposed movement of the distal antennal joint, we distinguish five functional DIN groups according to their sensitivity to three parameters: movement direction, movement velocity, and antennal joint angle. These groups are simple position-sensitive DINs, which signal the antennal joint angle; dynamic position-sensitive DINs, which signal the joint angle with strong dependence on movement; unspecific movement-sensitive DINs, which signal movement but not the velocity, position, or direction of movement; and ON- and OFF-type velocity-sensitive DINs. The activity of the latter two groups is increased/attenuated during antennal movement, with the spike rate increasing/decreasing linearly with antennal joint angle velocity. Some movement-sensitive DINs convey spikes to the thorax within 11 ms, suggesting a rapid, direct pathway from antennal mechanosensory to thoracic motor networks. We discuss how the population of DINs could provide the neural basis for the intersegmental spatial coordinate transfer between a touch sensor of the head and thoracic motor networks. PMID- 23926044 TI - Startle reveals independent preparation and initiation of triphasic EMG burst components in targeted ballistic movements. AB - Muscles involved in rapid, targeted movements about a single joint often display a triphasic [agonist (AG1)-antagonist (ANT)-agonist (AG2)] electromyographic (EMG) pattern. Early work using movement perturbations suggested that for short movements, the entire EMG pattern was prepared and initiated in advance (Wadman WJ, Dernier van der Gon JJ, Geuze RH, Mol CR. J Hum Mov Stud 5: 3-17, 1979), whereas more recent transcranial magnetic stimulation evidence indicates that the ANT may be programmed separately (MacKinnon CD, Rothwell JC. J Physiol 528: 633 645, 2000) with execution of the bursts occurring serially (Irlbacher K, Voss M, Meyer BU, Rothwell JC. J Physiol 574: 917-928, 2006). The purpose of the current study was to investigate the generation of triphasic EMG bursts for movements of different amplitudes. In experiment 1, participants performed rapid elbow extension movements to 20 degrees and 60 degrees targets, and on some trials, a startling acoustic stimulus (SAS), which is thought to trigger prepared motor commands at short latency, was delivered at the onset of AG1. For short movements, this perturbation elicited ANT and AG2 early, suggesting the agonist and antagonist bursts may have been programmed independently. In contrast, the same manipulation did not disrupt EMG timing parameters for the long movements, raising the possibility that ANT and AG2 were not fully programmed in advance of movement onset. In experiment 2, an SAS was delivered later in the movement, which produced early onset of both ANT and AG2. We propose that the triphasic pattern is executed serially but believe the trigger signal for initiating the ANT burst occurs not in relation to the AG1 burst, but rather in close temporal proximity to the expected onset of ANT. PMID- 23926043 TI - Role of synaptic dynamics and heterogeneity in neuronal learning of temporal code. AB - Temporal codes are believed to play important roles in neuronal representation of information. Neuronal ability to classify and learn temporal spiking patterns is thus essential for successful extraction and processing of information. Understanding neuronal learning of temporal code has been complicated, however, by the intrinsic stochasticity of synaptic transmission. Using a computational model of a learning neuron, the tempotron, we studied the effects of synaptic unreliability and short-term dynamics on the neuron's ability to learn spike timing rules. Our results suggest that such a model neuron can learn to classify spike timing patterns even with unreliable synapses, albeit with a significantly reduced success rate. We explored strategies to improve correct spike timing classification and found that firing clustered spike bursts significantly improves learning performance. Furthermore, rapid activity-dependent modulation of synaptic unreliability, implemented with realistic models of dynamic synapses, further improved classification of different burst properties and spike timing modalities. Neuronal models with only facilitating or only depressing inputs exhibited preference for specific types of spike timing rules, but a mixture of facilitating and depressing synapses permitted much improved learning of multiple rules. We tested applicability of these findings to real neurons by considering neuronal learning models with the naturally distributed input release probabilities found in excitatory hippocampal synapses. Our results suggest that spike bursts comprise several encoding modalities that can be learned effectively with stochastic dynamic synapses, and that distributed release probabilities significantly improve learning performance. Synaptic unreliability and dynamics may thus play important roles in the neuron's ability to learn spike timing rules during decoding. PMID- 23926045 TI - Intraglomerular inhibition maintains mitral cell response contrast across input frequencies. AB - Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MTCs) and external tufted cells (ETCs); ETCs provide additional feed-forward excitation to MTCs. Both are strongly regulated by intraglomerular inhibition that can last up to 1 s and, when blocked, dramatically increases ON-evoked MC spiking. Intraglomerular inhibition thus limits the magnitude and duration of MC spike responses to sensory input. In vivo, sensory input is repetitive, dictated by sniffing rates from 1 to 8 Hz, potentially summing intraglomerular inhibition. To investigate this, we recorded MTC responses to 1- to 8-Hz ON stimulation in slices. Inhibitory postsynaptic current area (charge) following each ON stimulation was unchanged from 1 to 5 Hz and modestly paired-pulse attenuated at 8 Hz, suggesting there is no summation and only limited decrement at the highest input frequencies. Next, we investigated frequency independence of intraglomerular inhibition on MC spiking. MCs respond to single ON shocks with an initial spike burst followed by reduced spiking decaying to baseline. Upon repetitive ON stimulation peak spiking is identical across input frequencies but the ratio of peak-to-minimum rate before the stimulus (max-min) diminishes from 30:1 at 1 Hz to 15:1 at 8 Hz. When intraglomerular inhibition is selectively blocked, peak spike rate is unchanged but trough spiking increases markedly decreasing max-min firing ratios from 30:1 at 1 Hz to 2:1 at 8 Hz. Together, these results suggest intraglomerular inhibition is relatively frequency independent and can "sharpen" MC responses to input across the range of frequencies. This suggests that glomerular circuits can maintain "contrast" in MC encoding during sniff-sampled inputs. PMID- 23926046 TI - Frustration influences impact of history and disciplinary attitudes on physical discipline decision making. AB - Although intergenerational patterns of punitive physical punishment garner considerable research attention, the mechanisms by which historical, cognitive, and contextual factors interplay to influence disciplinary responding remains poorly understood. Disciplinary attitudes have been shown to mediate the association between disciplinary history and disciplinary responding. The present study investigated whether frustration influences these mediation effects. Half of a sample of 330 undergraduates was randomly assigned to frustration induction. Structural equation modeling confirmed that, for participants in the frustration condition, the relation between disciplinary history and physical discipline decision-making was fully mediated by attitudes approving physical discipline. In contrast, for respondents in the no-frustration condition, the pathway from disciplinary history to discipline decision-making was only partially mediated by attitudes. Under conditions of frustration, attitudes may become a more central means by which personal disciplinary history is associated with disciplinary decision-making. PMID- 23926049 TI - Got game? The role of coaches and coaching in improving your career and life "games". PMID- 23926047 TI - Drosophila F-BAR protein Syndapin contributes to coupling the plasma membrane and contractile ring in cytokinesis. AB - Cytokinesis is a highly ordered cellular process driven by interactions between central spindle microtubules and the actomyosin contractile ring linked to the dynamic remodelling of the plasma membrane. The mechanisms responsible for reorganizing the plasma membrane at the cell equator and its coupling to the contractile ring in cytokinesis are poorly understood. We report here that Syndapin, a protein containing an F-BAR domain required for membrane curvature, contributes to the remodelling of the plasma membrane around the contractile ring for cytokinesis. Syndapin colocalizes with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) at the cleavage furrow, where it directly interacts with a contractile ring component, Anillin. Accordingly, Anillin is mislocalized during cytokinesis in Syndapin mutants. Elevated or diminished expression of Syndapin leads to cytokinesis defects with abnormal cortical dynamics. The minimal segment of Syndapin, which is able to localize to the cleavage furrow and induce cytokinesis defects, is the F-BAR domain and its immediate C-terminal sequences. Phosphorylation of this region prevents this functional interaction, resulting in reduced ability of Syndapin to bind to and deform membranes. Thus, the dephosphorylated form of Syndapin mediates both remodelling of the plasma membrane and its proper coupling to the cytokinetic machinery. PMID- 23926048 TI - Coordinating cell polarity and cell cycle progression: what can we learn from flies and worms? AB - Spatio-temporal coordination of events during cell division is crucial for animal development. In recent years, emerging data have strengthened the notion that tight coupling of cell cycle progression and cell polarity in dividing cells is crucial for asymmetric cell division and ultimately for metazoan development. Although it is acknowledged that such coupling exists, the molecular mechanisms linking the cell cycle and cell polarity machineries are still under investigation. Key cell cycle regulators control cell polarity, and thus influence cell fate determination and/or differentiation, whereas some factors involved in cell polarity regulate cell cycle timing and proliferation potential. The scope of this review is to discuss the data linking cell polarity and cell cycle progression, and the importance of such coupling for asymmetric cell division. Because studies in model organisms such as Caenorhabditis elegans and Drosophila melanogaster have started to reveal the molecular mechanisms of this coordination, we will concentrate on these two systems. We review examples of molecular mechanisms suggesting a coupling between cell polarity and cell cycle progression. PMID- 23926050 TI - A method for building evaluation competency among community-based organizations. AB - Community-based organizations often lack the capacity (e.g., time, staff, skills) to effectively evaluate programs, policies, and environmental changes. Providing evaluation technical assistance and training can be an effective and feasible way to build individual evaluation competency. The purpose of this article is to present a practical approach and related tools that can be used by evaluators and others (e.g., academic partners, funders) providing assistance to build evaluation skills in community organizations. The approach described was developed in collaboration with local universities and a regional health foundation to provide intensive technical support to 19 community-based organizations awarded funding to implement obesity prevention projects. Technical assistance processes and tools were designed to be tailored to organizations' capacity and needs and can be used as templates by others who provide technical assistance. Evaluators, funders, and academic partners can use lessons learned from this experience to help shape and implement evaluation technical assistance approaches with community-based organizations. PMID- 23926051 TI - Leukodystrophies in idiopathic adult-onset ataxia: frequency and phenotype in 105 patients. PMID- 23926052 TI - A simple synthetic route to obtain pure trans-ruthenium(II) complexes for dye sensitized solar cell applications. AB - We report a facile synthetic route to obtain functionalized quaterpyridine ligand and its trans-dithiocyanato ruthenium complex, based on a microwave-assisted procedure. The ruthenium complex has been purified using a silica chromatographic column by protecting carboxylic acid groups as iso-butyl ester, which are subsequently hydrolyzed. The highly pure complex exhibits panchromatic response throughout the visible region. DFT/time-dependent DFT calculations have been performed on the ruthenium complex in solution and adsorbed onto TiO2 to analyze relative electronic and optical properties. The ruthenium complex endowed with the functionalized quaterpyridine ligand was used as a sensitizer in dye sensitized solar cell yielding a short-circuit photocurrent density of more than 19 mA cm(-2) with a broad incident photon to current conversion efficiency spectra ranging from 400 to 900 nm, exceeding 80 % at 700 nm. PMID- 23926053 TI - Association of incident symptomatic hip osteoarthritis with differences in hip shape by active shape modeling: the Johnston County Osteoarthritis Project. AB - OBJECTIVE: To investigate hip shape by active shape modeling (ASM) as a potential predictor of incident radiographic hip osteoarthritis (RHOA) and symptomatic hip osteoarthritis (SRHOA). METHODS: All hips developing RHOA from baseline (Kellgren/Lawrence [K/L] grade 0/1) to mean 6-year followup (K/L grade >=2, 190 hips) and 1:1 control hips (K/L grade 0/1 at both times, 192 hips) were included. Proximal femur shape was defined on baseline anteroposterior pelvis radiographs and submitted to ASM, producing a mean shape and continuous variables representing independent modes of shape variation. Mode scores (n = 14, explaining 95% of shape variance) were simultaneously included in logistic regression models with incident RHOA and SRHOA as dependent variables, adjusted for intraperson correlations, sex, race, body mass index (BMI), baseline K/L grade, and/or symptoms. RESULTS: We evaluated 382 hips from 342 individuals: 61% women and 83% white, with mean age 62 years and mean BMI 29 kg/m(2) . Several modes differed by sex and race, but no modes were associated with incident RHOA overall. Among men only, modes 1 and 2 were significantly associated (for a 1-SD decrease in mode 1 score: odds ratio [OR] 1.7 [95% confidence interval (95% CI) 1.1-2.5] and for a 1-SD increase in mode 2 score: OR 1.5 [95% CI 1.0-2.2]) with incident RHOA. A 1-SD decrease in mode 2 or 3 score increased the odds of SRHOA by 50%. CONCLUSION: This study confirms other reports that variations in proximal femur shape have a modest association with incident hip OA. The observation of proximal femur shape associations with hip symptoms requires further investigation. PMID- 23926054 TI - Simvastatin treatment showed no prophylactic effect in influenza virus-infected mice. AB - Simvastatin, a cholesterol-lowering drug, is reported to have immunomodulatory properties that attenuated acute lung injury independent of their major lipid lowering effects. Based on these reports, simvastatin is expected to be used for influenza prophylaxis and treatment. The present study evaluated the efficacy of simvastatin against influenza A/PR/8/34 virus infection in a murine model. In a first study, simvastatin was administered orally. To achieve high plasma levels, intraperitoneal application was used in a second study. Survival, body weight loss, viral titers in lung and trachea, and histologic lung injury were measured. Surprisingly, treatment with simvastatin resulted in lower survival rates and in more distinct body mass loss in comparison to virus-infected control mice. Furthermore, the viral load in lungs and tracheas as well as histopathological lesions were not reduced by simvastatin. Overall, these results showed that simvastatin failed to protect mice against influenza virus infection. PMID- 23926055 TI - Amino-acid-based zwitterionic polymer and its Cu(II)-induced aggregation into nanostructures: a template for CuS and CuO nanoparticles. AB - A convenient and water-based approach is described for the synthesis of an l lysine-based zwitterionic polymer, poly(epsilon-l-lysinyl acrylamide) (PLAM), without using protecting group chemistry, chromatographic purifications, and organic solvents as the reaction media. PLAM contains both amine and carboxylic acid groups in each repeating unit, which can either be protonated or deprotonated just by altering the pH of the solution to obtain overall positive or negative charge. PLAM is tested for its applicability as a zwitterionic polymeric buffer in water. Cu(II) ion-induced aggregation of PLAM as a function of solution pH is studied. Spherical nanogel aggregates are formed at pH 9.5 due to aggregation of PLAM through its complexation with Cu(II) ion. Spherical aggregates appear to dissociate via breaking of the complexation at a pH < 5.5 resulting in molecular dissolution of PLAM. This aggregation process is pH reversible. The Cu(II)-PLAM aggregates are used as a template for fabrication of CuO and CuS nanoparticles. PMID- 23926056 TI - Differences in bone structure between rheumatoid arthritis and psoriatic arthritis patients relative to autoantibody positivity. AB - OBJECTIVE: To investigate whether trabecular and cortical bone structure differ between patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). So far, no study has performed a detailed comparative analysis of bone structure in patients with RA and PsA. METHODS: 110 patients (60 RA, 50 PsA) received high resolution peripheral quantitative CT of the distal radius. Demographic and disease-specific parameters including anti-rheumatic treatment, bone erosion status and previous fractures were recorded. RESULTS: RA and PsA patients were comparable in age, gender, body mass index, disease duration, disease activity, functional status, antirheumatic treatment and bone erosion status. No significant differences were found for volumetric bone mineral density (BMD), including total BMD (300+/-77 vs 316+/-62 mgHA/cm(3)), trabecular BMD (152+/-46 vs 165+/-40 mgHA/cm(3)) and cortical BMD (787+/-113 vs 818+/-76 mgHA/cm(3)) when comparing RA patients to PsA patients, respectively. However, in contrast to seronegative RA, seropositive RA showed significantly reduced trabecular BMD (p=0.007), bone volume per tissue volume (p=0.007) and trabecular number (p=0.044), as well as a strong trend towards higher trabecular inhomogeneity compared to PsA patients. In the regression analysis, higher age, female gender and presence of autoantibodies were independently associated with trabecular bone loss. CONCLUSIONS: Seropositive RA exhibits more profound changes in trabecular bone architecture than seronegative RA or PsA. The data support the concept that seropositive RA is a disease entity that is distinct from seronegative RA and PsA. PMID- 23926057 TI - Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study. AB - OBJECTIVE: Studies on the association between rheumatoid arthritis (RA) and deep vein thrombosis (DVT) and pulmonary thromboembolism (PE) are scarce. This study identifies the effects of RA on the risks of developing DVT and PE in a nationwide prospective cohort study. METHODS: We studied the entire Taiwan population from 1998 to 2008, with a follow-up period extending to the end of 2010. We identified patients with RA using the catastrophic illness registry of the Taiwan National Health Insurance Research Database (NHIRD). We also selected a comparison cohort that was randomly frequency-matched by age (each 5-year span), sex and index year from the general population. We analysed the risks of DVT and PE using Cox proportional hazards regression models, including sex, age and comorbidities. RESULTS: From 23.74 million people in the cohort, 29 238 RA patients (77% women, mean age of 52.4 years) and 1 16 952 controls were followed 1 93 753 and 7 92 941 person-years, respectively. The risk of developing DVT and PE was 3.36-fold and 2.07-fold, respectively, in patients with RA compared with patients without RA, after adjusting for age, sex and comorbidities. The multiplicative increased risks of DVT and PE were also significant in patients with RA with any comorbidity. CONCLUSIONS: This nationwide prospective cohort study demonstrates that DVT and PE risks significantly increased in patients with RA compared with those of the general population. PMID- 23926058 TI - Pharmacokinetics of tedizolid following oral administration: single and multiple dose, effect of food, and comparison of two solid forms of the prodrug. AB - OBJECTIVES: The single- and multiple-dose pharmacokinetics (PK) of tedizolid were examined after oral administration of tedizolid phosphate disodium (TPD), including the effect of food on PK. The relative bioavailability of TPD to the free acid tedizolid phosphate was determined to bridge the results of these and other studies to the solid form of the prodrug selected for further development. DESIGN: Randomized placebo-controlled, double-blind single- and multiple ascending dose studies and randomized open-label, crossover food effect and relative bioavailability studies. SETTING: Clinical Research Units. PARTICIPANTS: Healthy subjects. INTERVENTION: Study TR701-101 enrolled 40 subjects in single ascending dose (200-1200 mg TPD or placebo) and 40 subjects in 21-day multiple ascending dose (200, 300, or 400 mg TPD once/day; 600 mg linezolid twice/day; or placebo) arms. Study TR701-103 was a food-effect study in 12 subjects administered 600 mg TPD. Study TR701-108 was a relative bioavailability study in 12 subjects administered 150-mg tedizolid equivalents as TPD or tedizolid phosphate. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of the prodrug tedizolid phosphate, its active moiety tedizolid, and/or linezolid were collected. After administration of 200 to 600 mg TPD, tedizolid values increased approximately dose proportionally in area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ). Tedizolid half-life values were approximately 2-fold greater compared with linezolid. TPD administration with food delayed tedizolid absorption and reduced Cmax relative to the fasted state but did not alter AUC. Minimal accumulation was predicted and observed for tedizolid, whereas observed accumulation of linezolid exceeded predictions based on single-dose PK. Comparable PK of tedizolid was observed following oral administration of either TPD or tedizolid phosphate. In the multiple-ascending dose study, 3 of 24 tedizolid subjects were withdrawn under prespecified stopping rules (one each of elevated alanine aminotransferase, low reticulocyte count, or low white blood cell count), as was 1 of 8 linezolid subjects (low reticulocyte count). CONCLUSIONS: Overall, tedizolid has a favorable PK profile, a half-life that supports once daily administration, and no nonlinearities at steady state. Tedizolid phosphate can be administered without regard to food. PMID- 23926059 TI - Safety evaluation of femtosecond lentotomy on the porcine lens by optical measurement with 50-femtosecond laser pulses. AB - BACKGROUND AND OBJECTIVE: The optimized parameters of femtosecond (fs) lentotomy, an innovative strategy for presbyopia, have been further discussed regarding the safety of the procedure for eyeballs. This article's aim was to prove the safety and feasibility of the fs lentotomy procedure with 50-fs laser pulses. STUDY DESIGN/MATERIALS AND METHODS: This was an experimental study in which the safety of fs lentotomy by optical measurement was tested. The experiment was performed on 49 porcine crystalline lenses by 50-fs laser pulses at a central wavelength of 800 nm and scanning focusing optics with a numerical aperture (NA) of 0.125. The input pulse energy was in the range of 0.35 MUJ to 0.65 MUJ. The transmitted energy throughout the eyeball was measured through a hole in the back wall of the eyeball by a power meter. The transmittance and peak power density (PPD) on the cornea, lens, and retina were illustrated. The laser cutting quality of 50-fs laser pulses on the crystalline lens were assessed, and the theoretical safety of such a procedure for the cornea, lens, and retina was evaluated. RESULTS: A sharp cut without noticeable large bubbles was obtained with 0.35 MUJ pulse energy under the optical system for which the NA was 0.125. The transmittance of the whole eyeball was measured to be 69% to 75% under 0.35 MUJ to 0.65 MUJ incident laser energy. The threshold of PPD for photodisruption on the crystalline lens, retina, and cornea was measured to be in the magnitude of 10(13) W/cm(2) , 10(8) W/cm(2) , and 10(9) W/cm(2) , respectively. CONCLUSIONS: The cutting quality in this experiment implied the feasibility of the 50-fs laser in fs lentotomy; the pulse energy for fs lentotomy descended from microjoules to hundreds of nanojoules, and the PPD on the cornea and retina during the procedure decreased further, both of which illustrated the safety of such an optical design and the parameters during fs lentotomy for the eyeball. PMID- 23926060 TI - Disruption of visual and motor connectivity in spinocerebellar ataxia type 7. AB - Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder characterized by progressive ataxia and retinal dystrophy. It is caused by a CAG trinucleotide expansion in the ataxin7 gene. Anatomical studies have shown severe cerebellar degeneration and region-specific neocortical atrophy in SCA7 patients. However, the impact of the neurodegeneration on the functional integration of the remaining tissue is still unknown. The aim of this study was to examine functional connectivity abnormalities in areas with significant gray matter atrophy in SCA7 patients and their relationship with number of CAG repeats. Using a combination of voxel-based morphometry and resting-state fMRI, we studied 26 genetically confirmed SCA7 patients and aged-matched healthy controls. In SCA7 patients we found reduced functional interaction between the cerebellum and the middle and superior frontal gyri, disrupted functional connectivity between the visual and motor cortices, and increased functional coordination between atrophied areas of the cerebellum and a range of visual cortical areas compared with healthy controls. The degree of mutation expansion showed a negative effect on both the functional interaction between the right anterior cerebellum and the left superior frontal gyrus and the connectivity between the right anterior cerebellum and left parahippocampal gyrus. We found abnormal functional connectivity patterns, including both hypo- and hyperconnectivity, compared with controls. These abnormal patterns show reasonable association with the severity of gene mutation. Our findings suggest that aberrant changes are prevalent in both motor and visual systems, adding significantly to our understanding of the pathophysiology of SCA7. PMID- 23926061 TI - Active, soluble recombinant melittin purified by extracting insoluble lysate of Escherichia coli without denaturation. AB - Cell lytic peptides are a class of drugs that can be used to selectively kill invading organisms or diseased cells. Several of these peptides have been identified as potential therapeutics. Herein, we report a novel process for purifying recombinant melittin, a cell lytic peptide that inserts into the membranes of cells causing cell lysis, from Escherichia coli. The process involves surfactant and low pH to solubilize melittin fusion proteins from the insoluble fraction of bacterial lysates. We are able to significantly improve purity of the final product and confirm the activity of the peptide. The process yields recombinant melittin that is effective when used to treat U-87 MG glioma cells and inhibits growth of the gram-positive pathogenic bacterium Streptococcus pyogenes. We demonstrate a method of repeated extraction of the insoluble protein fraction with mild detergent at a low pH that is able to generate a yield of pure, soluble melittin of ~ 0.5-1 mg/L of E. coli culture. PMID- 23926062 TI - CERBERUS and NSP1 of Lotus japonicus are common symbiosis genes that modulate arbuscular mycorrhiza development. AB - Arbuscular mycorrhizal symbiosis (AMS) and root nodule symbiosis (RNS) are mutualistic plant-microbe interactions that confer nutritional benefits to both partners. Leguminous plants possess a common genetic system for intracellular symbiosis with AM fungi and with rhizobia. Here we show that CERBERUS and NSP1, which respectively encode an E3 ubiquitin ligase and a GRAS transcriptional regulator and which have previously only been implicated in RNS, are involved in AM fungal infection in Lotus japonicus. Hyphal elongation along the longitudinal axis of the root was reduced in the cerberus mutant, giving rise to a lower colonization level. Knockout of NSP1 decreased the frequency of plants colonized by AM fungi or rhizobia. CERBERUS and NSP1 showed different patterns of expression in response to infection with symbiotic microbes. A low constitutive level of CERBERUS expression was observed in the root and an increased level of NSP1 expression was detected in arbuscule-containing cells. Induction of AM marker gene was triggered in both cerberus and nsp1 mutants by infection with symbiotic microbes; however, the mutants showed a weaker induction of marker gene expression than the wild type, mirroring their lower level of colonization. The common symbiosis genes are believed to act in an early signaling pathway for recognition of symbionts and for triggering early symbiotic responses. Our quantitative analysis of symbiotic phenotypes revealed developmental defects of the novel common symbiosis mutants in both symbioses, which demonstrates that common symbiosis mechanisms also contribute to a range of functions at later or different stages of symbiont infection. PMID- 23926063 TI - Genetic engineering of novel bluer-colored chrysanthemums produced by accumulation of delphinidin-based anthocyanins. AB - Chrysanthemums (Chrysanthemum morifolium Ramat.) have no purple-, violet- or blue flowered cultivars because they lack delphinidin-based anthocyanins. This deficiency is due to the absence of the flavonoid 3',5'-hydroxylase gene (F3'5'H), which encodes the key enzyme for delphinidin biosynthesis. In F3'5'H transformed chrysanthemums, unpredictable and unstable expression levels have hampered successful production of delphinidin and reduced desired changes in flower color. With the aim of achieving delphinidin production in chrysanthemum petals, we found that anthocyanin biosynthetic gene promoters combined with a translational enhancer increased expression of some F3'5'H genes and accompanying delphinidin-based anthocyanin accumulation in transgenic chrysanthemums. Dramatic accumulation of delphinidin (up to 95%) was achieved by simple overexpression of Campanula F3'5'H controlled by a petal-specific flavanone 3-hydroxylase promoter from chrysanthemum combined with the 5'-untranslated region of the alcohol dehydrogenase gene as a translational enhancer. The flower colors of transgenic lines producing delphinidin-based anthocyanins changed from a red-purple to a purple-violet hue in the Royal Horticultural Society Colour Charts. This result represents a promising step toward molecular breeding of blue chrysanthemums. PMID- 23926064 TI - Expression and functional analysis of the CorA-MRS2-ALR-type magnesium transporter family in rice. AB - Maintenance of an appropriate magnesium ion (Mg(2+)) concentration is essential for plant growth. In Arabidopsis thaliana, the CorA-MRS2-ALR-type proteins, named MRS2/MGT family proteins, are reportedly localized in various membranes and they function in Mg transport. However, knowledge of this family in other plant species is extremely limited. Furthermore, differential diversification among dicot and monocot plants suggested by phylogenetic analysis indicates that the role of the Arabidopsis MRS2/MGT family proteins is not the same in monocot plants. For a further understanding of this family in higher plants, functional analysis and gene expression profiling of rice MRS2/MGT family members were performed. A phylogenetic tree based on the isolated mRNA sequences of nine members of the OsMRS2 family confirmed that the MRS2/MGT family consists of five clades (A-E). A complementation assay in the yeast CM66 strain showed that four of the nine members possessed the Mg(2+) transport ability. Transient green fluorescent protein (GFP) expression in the isolated rice protoplast indicated that OsMRS2-5 and OsMRS2-6, belonging to clades D and A, respectively, localized in the chloroplast. Expression levels of these genes were low in the unexpanded yellow-green leaf, but increased considerably with leaf maturation. In addition, diurnal oscillation of expression was observed, particularly in OsMRS2-6 expression in the expanded leaf blade. We conclude that OsMRS2 family members function as Mg transporters and suggest that the genes belonging to clade A encode the chloroplast-localized Mg(2+) transporter in plants. PMID- 23926065 TI - Mutation of the Arabidopsis NAC016 transcription factor delays leaf senescence. AB - The highly ordered process of senescence forms the final stage of leaf development; a large set of senescence-associated genes (SAGs) execute this orderly dismantling of the photosynthetic apparatus and remobilization of cellular components. A number of transcription factors (TFs) modulate SAG expression to promote or delay senescence. Here we show that NAC016, the previously uncharacterized senescence-associated NAM/ATAF1/2/CUC2 (senNAC) TF in Arabidopsis thaliana, promotes senescence. Leaves of nac016 mutants remained green under senescence-inducing conditions, and leaves of NAC016-overexpressing (NAC016-OX) plants senesced early. Under dark-induced senescence (DIS) conditions, nac016 mutants had low ion leakage, and retained the proper balance of photosystem proteins and normal grana thylakoid shape much longer than wild type plants, suggesting that nac016 acts as a functional stay-green type senescence mutant. Under DIS conditions, SAGs (NYC1, PPH, SGR1/NYE1 and WRKY22), including senNACs (JUB1, NAP, ORE1, ORS1 and VNI2), were down-regulated in nac016 mutants and up-regulated in NAC016-OX plants. In addition to its role in senescence, NAC016 also affects abiotic stress. Under salt and oxidative stress conditions, NAC016 expression rapidly increased in developing leaves, possibly to promote senescence. Indeed, under the stress conditions, nac016 mutants stayed green and NAC016-OX plants senesced rapidly. To identify direct targets of the NAC016 TF in the regulation of leaf senescence, we conducted yeast one-hybrid assays, which strongly suggested that NAC016 binds to the promoters of NAP and ORS1. Based on these results, we propose that NAC016 regulatory mechanisms promoting leaf senescence exhibit cross-talk with the salt and oxidative stress responsive signaling pathways. PMID- 23926066 TI - Violet/blue chrysanthemums--metabolic engineering of the anthocyanin biosynthetic pathway results in novel petal colors. AB - Chrysanthemums (Chrysanthemum*morifolium Ramat.) are an important cut-flower and potted plant crop in the horticultural industry world wide. Chrysanthemums express the flavonoid 3'-hydroxylase (F3'H) gene and thus accumulate anthocyanins derived from cyanidin in their inflorescences which appear pink/red. Delphinidin based anthocyanins are lacking due to the deficiency of a flavonoid 3', 5' hydroxylase (F3'5'H), and so violet/blue chrysanthemum flower colors are not found. In this study, together with optimization of transgene expression and selection of the host cultivars and gene source, F3'5'H genes have been successfully utilized to produce transgenic bluish chrysanthemums that accumulate delphinidin-based anthocyanins. HPLC analysis and feeding experiments with a delphinidin precursor identified 16 cultivars of chrysanthemums out of 75 that were predicted to turn bluish upon delphinidin accumulation. A selection of eight cultivars were successfully transformed with F3'5'H genes under the control of different promoters. A pansy F3'5'H gene under the control of a chalcone synthase promoter fragment from rose resulted in the effective diversion of the anthocyanin pathway to produce delphinidin in transgenic chrysanthemum flower petals. The resultant petal color was bluish, with 40% of total anthocyanidins attributed to delphinidin. Increased delphinidin levels (up to 80%) were further achieved by hairpin RNA interference-mediated silencing of the endogenous F3'H gene. The resulting petal colors were novel bluish hues, not possible by hybridization breeding. This is the first report of the production of anthocyanins derived from delphinidin in chrysanthemum petals leading to novel flower color. PMID- 23926068 TI - Lung cancer, histologic stratification, and resection extent: something for surgeons to think about. PMID- 23926067 TI - Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2cm or smaller. AB - BACKGROUND: We sought to analyze the prognostic significance of the new International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) lung adenocarcinoma (ADC) classification for patients undergoing resection for small (<=2cm) lung ADC and to investigate whether histologic subtyping can predict recurrence after limited resection (LR) vs lobectomy (LO). METHODS: Comprehensive histologic subtyping was performed according to the IASLC/ATS/ERS classification on all consecutive patients who underwent LR or LO for small lung ADC between 1995 and 2009 at Memorial Sloan-Kettering Cancer Center. Clinical characteristics and pathologic data were retrospectively evaluated for 734 consecutive patients (LR: 258; LO: 476). Cumulative incidence of recurrence (CIR) was calculated using competing risks analysis and compared across groups using Grey's test. All statistical tests were two-sided. RESULTS: Application of IASLC/ATS/ERS lung ADC histologic subtyping to predict recurrence demonstrates that, in the LR group but not in the LO group, micropapillary (MIP) component of 5% or greater was associated with an increased risk of recurrence, compared with MIP component of less than 5% (LR: 5 year CIR = 34.2%, 95% confidence interval [CI] = 23.5% to 49.7% vs 5-year CIR = 12.4%, 95% CI = 6.9% to 22.1%, P < .001; LO: 5-year CIR = 19.1%, 95% CI = 12.0% to 30.5% vs 15-year CIR = 12.9%, 95% CI = 7.6% to 21.9%, P = .13). In the LR group, among patients with tumors with an MIP component of 5% or greater, most recurrences (63.4%) were locoregional; MIP component of 5% or greater was statistically significantly associated with increased risk of local recurrence when the surgical margin was less than 1cm (5-year CIR = 32.0%, 95% CI = 18.6% to 46.0% for MIP >= 5% vs 5-year CIR = 7.6%, 95% CI = 2.3% to 15.6% for MIP < 5%; P = .007) but not when surgical margin was 1cm or greater (5-year CIR = 13.0%, 95% CI = 4.1% to 22.1% for MIP >= 5% vs 5-year CIR = 3.4%, 95% CI = 0% to 7.7% for MIP < 5%; P = .10). CONCLUSIONS: Application of the IASLC/ATS/ERS classification identifies the presence of an MIP component of 5% or greater as independently associated with the risk of recurrence in patients treated with LR. PMID- 23926069 TI - Evolutionary pattern of reemerging influenza B/Victoria lineage viruses in Sao Paulo, Brazil, 1996-2012: Implications for vaccine composition strategy. AB - Since the 1980s, 2 antigenically distinct influenza B lineages have cocirculated in the world: B/Victoria/2/87 (first appeared in the 1980s) and B/Yamagata/16/88 (became predominant in the 1990s). B/Victoria/2/87 isolates were geographically restricted to eastern Asia during 1991-2000. During 2000-2001 and 2001-2002, B/Victoria/2/87 isolates reemerged in North America, Europe, and South America, and then spread globally. During influenza virus surveillance, season 2002, an outbreak of acute respiratory illness, which quickly spread among the population, has been notified by public health authorities living in Araraquara, Sao Paulo, Brazil. Instituto Adolfo Lutz and Secretariat of Health of Sao Paulo state teams initiate an investigation towards to describe the pattern of infection in this population temporally and by age and to characterize the strains by virus isolation and hemagglutination inhibition assay. The outbreak lasted approximately 10 weeks; many cases occurred between mid-August and mid-September. Children younger than 13 years were the most affected; the elderly were mostly immune to infection. Analysis of the clinical respiratory samples helped in identifying the B/Hong Kong/330/2001 and B/Brisbane/32/2002 subtypes-recent variants of B/Victoria/02/88, a lineage restricted to Southeast Asia until 2001. The Araraquara outbreak confirms the reemergence of the B/Victoria viruses in South America and highlights the importance of monitoring local circulating strains, especially in light of the absence of cross-protection between antigenically distinct influenza lineages. Based on influenza virus surveillance, public health authorities worldwide should decide whether trivalent vaccines or quadrivalent vaccines (containing both influenza virus B lineages) are to be used in each country. PMID- 23926070 TI - Effects of cardiovascular comorbidities on work participation in rheumatic diseases: a prospective cohort study among working individuals. AB - OBJECTIVE: To determine the risk of sick leave and work disability in relation to rheumatic diseases and cardiovascular comorbidities among working individuals. METHODS: Employees (n = 12,140) from 45 companies in The Netherlands were prospectively followed up from 1998-2008. Questionnaires were used to assess self reported diseases and employment status. Company records provided individual sick leave data for the first 2.5 years of followup. For a selected sample of the cohort (50%), verification of self-reported diseases was sought through hospital record linkage. Poisson regressions and Cox proportional hazards models were applied to determine the impact of both self-reported and verified diseases on sick leave and work disability, respectively. RESULTS: The number of days and frequency of sick leave were increased in working individuals with self-reported rheumatic and cardiovascular disease (P < 0.001), but self-reported cardiovascular comorbidity did not result in more sick leave in those who also self-reported rheumatic disease. Work disability was also increased for both self reported rheumatic disease and cardiovascular disease (P < 0.001), but again, no additive effects were found. In the sample verified by clinical review, the frequency or number of days of sick leave was significantly higher in employees with cardiovascular disease (P < 0.001), inflammatory rheumatic disease (P < 0.05), and osteoarthritis (P < 0.05) compared to employees without these diseases. Work disability in the verified sample occurred especially in patients with osteoarthritis (hazard ratio [HR] 12.36 [95% confidence interval (95% CI) 1.59-13.66]), fibromyalgia (HR 14.24 [95% CI 2.02-16.54]), and cardiovascular disease (HR 4.88 [95% CI 1.70-14.01]). CONCLUSION: Rheumatic and cardiovascular diseases increased the risk of sick leave and work disability in a working population, but there was no indication that these effects convey an additive risk. PMID- 23926071 TI - Regional anatomy of the pedunculopontine nucleus: relevance for deep brain stimulation. AB - The pedunculopontine nucleus (PPN) is currently being investigated as a potential deep brain stimulation target to improve gait and posture in Parkinson's disease. This review examines the complex anatomy of the PPN region and suggests a functional mapping of the surrounding nuclei and fiber tracts that may serve as a guide to a more accurate placement of electrodes while avoiding potentially adverse effects. The relationships of the PPN were examined in different human brain atlases. Schematic representations of those structures in the vicinity of the PPN were generated and correlated with their potential stimulation effects. By providing a functional map and representative schematics of the PPN region, we hope to optimize the placement of deep brain stimulation electrodes, thereby maximizing safety and clinical efficacy. PMID- 23926072 TI - Construction of unnatural heterodimeric receptors based on IL-2 and IL-6 receptor subunits. AB - Cells have various receptors on their surface for responding to extracellular signals that involve intercellular communication. Although the mechanism of signal transduction by such wild-type receptors has been studied intensively, there has been minimal effort in investigating whether such receptors could signal when unnaturally coupled. In this study, we investigated whether unnatural receptor pairs comprising interleukin-2 (IL-2) and interleukin-6 (IL-6) receptor subunits could transduce a signal through forced dimerization. We replaced the extracellular domain of IL-2R and IL-6R signaling subunits (IL-2Rbeta, IL 2Rgamma, and gp130) with the FK506-binding protein (FKBP) or the FKBP12-rapamycin binding (FRB) domain, the protein pair known to be heterodimerized by rapamycin. When expressed in a hematopoietic cell line, unnatural heterodimers (IL-2Rbeta gp130 and IL-2Rgamma-gp130 pairs) successfully transduced a signal. While the IL 2Rgamma-gp130 pair maximally mimicked gp130 signaling, the IL-2Rbeta-gp130 pair gave weaker gp130 signaling and no significant induction of IL-2Rbeta signaling, indicating a high potential of the IL-2Rgamma chain in terms of activating the coupled partners. This is the first report demonstrating that heterodimeric combinations of IL-2R and IL-6R subunits are functional for signaling. Further extension of this approach may attain a creative design of artificial receptor pairs that have distinct signaling properties when compared with natural receptors. PMID- 23926073 TI - HCV viremia drives an increment of CD86 expression by myeloid dendritic cells. AB - The host immune response, including innate and adaptive immunity, plays a critical role in determining the outcome of viral infection. Nevertheless, little is known about the exact reasons for the failure of the host immune system in controlling hepatitis C virus (HCV) infection. Impairment of dendritic cells (DCs) function is probably one of the mechanisms responsible for immune evasion of HCV. In this study, the frequency and phenotype of DCs subsets were analyzed in three groups: HCV-infected individuals who developed viral persistence (1), HCV-infected individuals who spontaneously cleared the virus (2) and HCV seronegative uninfected subjects (3). The results showed that the frequency of DCs subsets was not statistically significant between groups. Plasmacytoid DCs circulating exhibited an immature phenotype characterized by low expression of CD86. On the other hand, CD86 expression in myeloid DCs was significantly higher in chronic infected individuals compared to healthy controls (P=0.037). A positive correlation was observed between CD86(+) myeloid DC (mDC) and HCV viral load (r=0.4121, P=0.0263). These results suggest that HCV did not have an inhibitory effect on mDC maturation and the HCV viremia drives the increase of CD86 expression in mDC. The regulation of DCs maturation and migration lies at the level of intracellular signaling. HCV can activate or block intracellular signaling pathways and alter DC function. In conclusion, the present study suggests that imbalance of DC maturation by the virus represents a mechanism of evasion of the immune system despite the fact that HCV viremia appears to exert a "stimulatory" effect on cell-surface immune phenotype. PMID- 23926074 TI - Early amniotomy and early oxytocin for prevention of, or therapy for, delay in first stage spontaneous labour compared with routine care. AB - BACKGROUND: Caesarean section rates are over 20% in many developed countries. The main diagnosis contributing to the high rate in nulliparae is dystocia or prolonged labour. The present review assesses the effects of a policy of early amniotomy with early oxytocin administration for the prevention of, or the therapy for, delay in labour progress. OBJECTIVES: To estimate the effects of early augmentation with amniotomy and oxytocin for prevention of, or therapy for, delay in labour progress on the caesarean birth rate and on indicators of maternal and neonatal morbidity. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013), MEDLINE (1966 to 4 July 2013), Embase (1980 to 4 July 2013), CINAHL (1982 to 4 July 2013), MIDIRS (1985 to 4 July 2013) and contacted authors for data from unpublished trials. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials that compared oxytocin and amniotomy with expectant management. DATA COLLECTION AND ANALYSIS: Three review authors extracted data independently. We stratified the analyses into 'Prevention Trials' and 'Therapy Trials' according to the status of the woman at the time of randomization. Participants in the 'Prevention Trials' were unselected women, without slow progress in labour, who were randomized to a policy of early augmentation or to routine care. In 'Treatment Trials' women were eligible if they had an established delay in labour progress. MAIN RESULTS: For the 2013 update, we identified and excluded one new clinical trial. This updated review includes 14 trials, randomizing a total of 8033 women. The unstratified analysis found early intervention with amniotomy and oxytocin to be associated with a modest reduction in the risk of caesarean section; however, the confidence interval (CI) included the null effect (risk ratio (RR) 0.89; 95% CI 0.79 to 1.01; 14 trials; 8033 women). In prevention trials, early augmentation was associated with a modest reduction in the number of caesarean births (RR 0.87; 95% CI 0.77 to 0.99; 11 trials; 7753). A policy of early amniotomy and early oxytocin was associated with a shortened duration of labour (average mean difference (MD) - 1.28 hours; 95% CI -1.97 to -0.59; eight trials; 4816 women). Sensitivity analyses excluding four trials with a full package of active management did not substantially affect the point estimate for risk of caesarean section (RR 0.87; 95% CI 0.73 to 1.05; 10 trials; 5165 women). We found no other significant effects for the other indicators of maternal or neonatal morbidity. AUTHORS' CONCLUSIONS: In prevention trials, early intervention with amniotomy and oxytocin appears to be associated with a modest reduction in the rate of caesarean section over standard care. PMID- 23926075 TI - Cutaneous adverse events during treatment of chronic inflammatory rheumatic conditions with tumor necrosis factor antagonists: study using the Spanish registry of adverse events of biological therapies in rheumatic diseases. AB - OBJECTIVE: To analyze the incidence rate (IR) and risk factors of cutaneous adverse events (CAE) in patients with chronic inflammatory rheumatic diseases treated with tumor necrosis factor (TNF) antagonists. METHODS: We analyzed all patients from the BIOBADASER (Base de Datos de Productos Biologicos de la Sociedad Espanola de Reumatologia) registry treated with a TNF antagonist (infliximab, etanercept, or adalimumab). Data collected included age, sex, diagnosis and duration of rheumatic disease, type of TNF antagonist, and concomitant treatment. Type of CAE was classified as local or systemic cutaneous manifestation related to treatment administration (infusion reaction), infection, malignancy, or autoimmune skin disease. Time of onset of CAE and outcome were also recorded. The IRs of CAE per 1,000 patient-years of exposure with 95% confidence intervals (95% CIs) were estimated. Multivariable analysis was performed to identify potential risk factors for CAE. RESULTS: A total of 5,437 patients were included, representing 17,330 patient-years of exposure. A total of 920 CAE were reported; the IRs per 1,000 patient-years were 53 (95% CI 50-57) for CAE, 28 (95% CI 25-30) for infection, 15 (95% CI 13-17) for infusion reactions, 5 (95% CI 4-6) for autoimmune skin diseases, and 3 (95% CI 2-4) for skin malignancy. The mean time between starting TNF antagonist treatment and CAE was 1.78 years. In 32% of patients, CAE required TNF antagonist withdrawal. The main risk factors for CAE were female sex and treatment with infliximab, leflunomide, and glucocorticoids. CONCLUSION: The IR of CAE in patients treated with TNF antagonists is significant and should be addressed carefully, and withdrawal of therapy is required in some cases. PMID- 23926076 TI - Exposure to the smoking cessation medicine varenicline during pregnancy: a prospective nationwide cohort study. AB - PURPOSE: The purpose of this study was to investigate the extent of exposure to varenicline during pregnancy in 'real-life' post-marketing use and follow-up all pregnancy exposures to identify maternal and fetal outcomes. METHODS: This was a prospective observational cohort study conducted in New Zealand using intensive prescription event monitoring methods. A nationwide cohort of patients dispensed varenicline during a 4-year period was established from pharmacy dispensing data. Women of reproductive age were followed up with specific questionnaires to identify exposure to varenicline during pregnancy and maternal and fetal outcomes. RESULTS: Between 1 April 2007 and 31 March 2011, 23,721 patients were dispensed varenicline. Pregnancy questionnaires were sent for 6882 women of reproductive age, representing 29% all patients (54% female/unknown sex patients) in the varenicline cohort. The frequency of pregnancy exposure in women for whom a valid pregnancy questionnaire was returned was 23/2739 = 0.84%. For the 23 reports of pregnancy identified, exposure to varenicline was from the time of conception for 19 cases. Duration of exposure during pregnancy ranged from 1 day to 16 weeks. Adverse outcomes were identified in five of 17 live births: one baby had birth asphyxia and recurrent chest infections, one had gastro-oesophageal reflux, one was diagnosed with ankyloglossia and two had feeding difficulties. CONCLUSIONS: This study suggests that approximately 1% of women of reproductive age prescribed varenicline may be exposed to this medicine during pregnancy. This could result in significant fetal exposure worldwide and indicates the need for a global pregnancy register for varenicline. PMID- 23926077 TI - Multiscale metabolic modeling: dynamic flux balance analysis on a whole-plant scale. AB - Plant metabolism is characterized by a unique complexity on the cellular, tissue, and organ levels. On a whole-plant scale, changing source and sink relations accompanying plant development add another level of complexity to metabolism. With the aim of achieving a spatiotemporal resolution of source-sink interactions in crop plant metabolism, a multiscale metabolic modeling (MMM) approach was applied that integrates static organ-specific models with a whole-plant dynamic model. Allowing for a dynamic flux balance analysis on a whole-plant scale, the MMM approach was used to decipher the metabolic behavior of source and sink organs during the generative phase of the barley (Hordeum vulgare) plant. It reveals a sink-to-source shift of the barley stem caused by the senescence related decrease in leaf source capacity, which is not sufficient to meet the nutrient requirements of sink organs such as the growing seed. The MMM platform represents a novel approach for the in silico analysis of metabolism on a whole plant level, allowing for a systemic, spatiotemporally resolved understanding of metabolic processes involved in carbon partitioning, thus providing a novel tool for studying yield stability and crop improvement. PMID- 23926078 TI - Histocytological analysis of yam (Dioscorea alata) shoot tips cryopreserved by encapsulation-dehydration. AB - In this work, we performed qualitative and quantitative observations of the cytological changes occurring in cells of yam (Dioscorea alata) in vitro shoot tips cryopreserved using the encapsulation-dehydration (E-D) technique. Shoot tip osmoprotection for 24 h in 1.25 M sucrose medium induced drastic changes in cellular cytological features, including high plasmolysis in all three cellular areas studied, the external cell layer (L1), one to three (L1-3) and seven to nine (L7-9) cell layers from the surface of the meristematic dome, pyknotic nuclei in meristematic area cells and disappearance of nucleoli. Nucleus size decreased significantly in all cellular areas studied. Nucleocytoplasmic ratio decreased significantly in L1-3 and L7-9 cells. Nuclear protein content increased, particularly in L1 and L1-3 cells. After physical dehydration, plasma membrane of numerous basal part cells was broken and intracellular soluble protein leakage was observed. Nucleus area and nucleocytoplasmic ratio decreased significantly in L7-9 cells. One week after cryopreservation, shoot tips showed regrowth and living cells had recovered their original morphology. In all cellular areas studied, nuclei had retrieved their original staining and nucleoli were visible. Original nucleus area values were recovered in L1-3 and L1 cells. The nucleocytoplasmic ratio retrieved its initial value in L1 cells but remained at levels observed after osmoprotection for L1-3 and L7-9 cells. The nuclear protein content had retrieved its original level. This investigation provided new insights in changes occurring in D. alata apices throughout an E-D protocol. PMID- 23926079 TI - Post-ischemic stroke Holmes' tremor of the upper limb. PMID- 23926080 TI - Ultrasound mediated enzymatic hydrolysis of cellulose and carboxymethyl cellulose. AB - A recombinant Trichoderma reesei cellulase was used for the ultrasound-mediated hydrolysis of soluble carboxymethyl cellulose (CMC) and insoluble cellulose of various particle sizes. The hydrolysis was carried out at low intensity sonication (2.4-11.8 W cm(-2) sonication power at the tip of the sonotrode) using 10, 20, and 40% duty cycles. [A duty cycle of 10%, for example, was obtained by sonicating for 1 s followed by a rest period (no sonication) of 9 s.] The reaction pH and temperature were always 4.8 and 50 degrees C, respectively. In all cases, sonication enhanced the rate of hydrolysis relative to nonsonicated controls. The hydrolysis of CMC was characterized by Michaelis-Menten kinetics. The Michaelis-Menten parameter of the maximum reaction rate Vmax was enhanced by sonication relative to controls, but the value of the saturation constant Km was reduced. The optimal sonication conditions were found to be a 10% duty cycle and a power intensity of 11.8 W cm(-2) . Under these conditions, the maximum rate of hydrolysis of soluble CMC was nearly double relative to control. In the hydrolysis of cellulose, an increasing particle size reduced the rate of hydrolysis. At any fixed particle size, sonication at a 10% duty cycle and 11.8 W cm(-2) power intensity improved the rate of hydrolysis relative to control. Under the above mentioned optimal sonication conditions, the enzyme lost about 20% of its initial activity in 20 min. Sonication was useful in accelerating the enzyme catalyzed saccharification of cellulose. PMID- 23926081 TI - Design and synthesis of 4-alkyl-2-amino(acetamino)-6-aryl-1,3-thiazine derivatives as influenza neuraminidase inhibitors. AB - With a convenient and economical method, two series of 1,3-thiazine derivatives 1 and 2 were synthesized, and their neuraminidase (NA) inhibitory activities were evaluated. The pharmacological results showed that most of the compounds have potent NA inhibitory activity. Especially, 1g exhibited the best activity against influenza virus A (H1N1) NA (IC50=29.06 ug/mL), and its crystal structure was determined by single-crystal X-ray diffraction. The preliminary biological assay indicated that 1,3-thiazine could be used as a core structure to design novel influenza NA inhibitors. PMID- 23926082 TI - Reactivation of hepatitis B virus in patients with undetectable HBsAg undergoing chemotherapy for malignant lymphoma or multiple myeloma. AB - Despite increasing reports of hepatitis B virus (HBV) reactivation in hematological malignancies, its incidence, and risk factors are still obscure. The aim of this study was to clarify the frequency and risk factors of HBV reactivation in hepatitis B surface antigen (HBsAg) undetectable patients with malignant lymphoma or multiple myeloma, during or after chemotherapy. A total of 109 patients with undetectable HBsAg undergoing chemotherapy for malignant lymphoma or multiple myeloma were enrolled in this study. Anti-hepatitis B surface (anti-HBs) and anti-hepatitis B core (anti-HBc) were checked before treatment, and HBV DNA in sera was quantified monthly during and after chemotherapy. Out of 109 patients, 42 (38.5%) had anti-HBs and 59 (54.1%) had anti-HBc. Among the 59 anti-HBc positive patients, four patients (4/59, 6.8%) showed HBV reactivation during 20.5 median follow-up months. In all four patients with HBV reactivation, peripheral lymphocyte counts before chemotherapy were lower than those without HBV reactivation (P=0.033). HBV reactivation occurred during and after chemotherapy containing rituximab for non-Hodgkin lymphoma. Four patients, who had HBV reactivation, did not develop de novo hepatitis due to HBV reactivation and were able to undergo chemotherapy against malignant lymphoma as scheduled. Monitoring of HBV DNA in sera is useful for the early diagnosis of HBV reactivation, and preemptive therapy is an useful alternative to prevent hepatitis due to HBV reactivation. Patients must be monitored periodically for HBV-DNA levels during and after chemotherapy. PMID- 23926083 TI - Investigation of metabolic variability observed in extended fed batch cell culture. AB - A 13-day fed-batch IgG1 production process was developed by applying our proprietary chemically defined platform process. The process was highly reproducible with respect to cell growth and titer, but the cultures exhibited metabolic variability after 12 days of cultivation. This metabolic variability consisted of a subset of cultures exhibiting increased cell-specific glucose uptake rates and high lactate production rates (LPR) despite identical operating conditions. We investigated the causes of the metabolic variability by manipulating the rate at which feed medium was delivered. Overfeeding directly led to increased LPR. High LPR was found to be associated with increased mitochondrial membrane potential in a subset of cells, as measured through fluorescent staining, and feeding TCA cycle intermediates was found to prevent the high LPR phenotype. This supports the hypothesis that mitochondrial pathways are involved in inducing metabolic variability. PMID- 23926084 TI - Special issue on computational methods for biomedical image processing and analysis. PMID- 23926086 TI - Ranking filter methods for concentrating pathogens in lake water. PMID- 23926087 TI - Reply to "ranking filter methods for concentrating pathogens in lake water". PMID- 23926089 TI - Development and validation of the spondyloarthritis radiography module for calibration of readers using the modified Stoke Ankylosing Spondylitis Spine Score. AB - OBJECTIVE: To develop and validate a reference image module aimed at calibration of readers using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) to assess radiographic progression in spondyloarthritis. METHODS: Our working group comprised 6 rheumatologists and 3 musculoskeletal radiologists. The following developmental steps were conducted: (1) review of the literature to identify aspects of the mSASSS requiring methodologic clarity; (2) independent assessment of baseline and 2-year radiographs from 25 patients using the mSASSS (pilot exercise); (3) development of a training module (the Spondyloarthritis Radiography [SPAR] module) that clarifies definitions, rules, and scoring methodology and a set of reference radiographic images; (4) scoring exercise 1 by 6 readers on 39 patients, where baseline and 2-year radiographs were scored blinded to time point; and (5) revision of the SPAR module followed by scoring exercise 2 conducted by the same 6 readers on 35 patients. Reliability of status and 2-year change scores was assessed by the intraclass correlation coefficient (ICC) method. RESULTS: ICCs for change scores for the radiologist reader pair improved from 0.46 to 0.62 after minimal calibration with the SPAR module. Recalibration from exercise 1 to exercise 2 with the SPAR module led to substantial improvement in interreader reliability for change in mSASSS score from ICC 0.44 (range 0.31-0.62) to ICC 0.62 (range 0.34-0.84). Simultaneous assessment of anteroposterior and lateral lumbar radiographs did not enhance reliability or detection of progression. CONCLUSION: Calibration according to the SPAR module led to improved reliability in the scoring of the mSASSS, even for expert readers. PMID- 23926090 TI - Properties of Geobacillus stearothermophilus levansucrase as potential biocatalyst for the synthesis of levan and fructooligosaccharides. AB - The production of levansucrase (LS) by thermophilic Geobacillus stearothermophilus was investigated. LS production was more effective in the presence of sucrose (1%, w/v) than fructose, glucose, glycerol or raffinose. The results (Top 57 degrees C; stable for 6 h at 47 degrees C) indicate the high stability of the transfructosylation activity of G. stearothermophilus LS as compared with LSs from other microbial sources. Contrary to temperature, the pH had a significant effect on the selectivity of G. stearothermophilus LS-catalyzed reaction, favoring the transfructosylation reaction in the pH range of 6.0-6.5. The kinetic parameter study revealed that the catalytic efficiency of transfructosylation activity was higher as compared with the hydrolytic one. In addition to levan, G. stearothermophilus LS synthesized fructooligosaccharides in the presence of sucrose as the sole substrate. The results also demonstrated the wide acceptor specificity of G. stearothermophilus LS with maltose being the best fructosyl acceptor. This study is the first on the catalytic properties and the acceptor specificity of LS from G. stearothermophilus. PMID- 23926091 TI - Symptom complexes at the earliest phases of rheumatoid arthritis: a synthesis of the qualitative literature. AB - OBJECTIVE: Understanding the features and patterns of symptoms that characterize the earliest stages of rheumatoid arthritis (RA) is of considerable importance if patients are to be identified and started on treatment early. However, little is known about the characteristics of symptoms at the onset of a disease that eventually progresses to RA. METHODS: A systematic review of qualitative peer reviewed publications was conducted to identify the earliest symptoms associated with the onset of RA. A total of 1,736 abstracts were searched to identify relevant publications. Twenty-six publications were identified, assessed for quality, and subjected to analysis informed by thematic and grounded theory frameworks. RESULTS: Several interacting themes describing the early symptoms of RA were identified, including swelling, pain and tenderness, stiffness, fatigue and weakness, and the emotional impact of symptoms. For each symptom, different and evolving intensities were described; in some cases, patterns of symptom onset and symptom complexes at the onset of RA were highlighted. Importantly, this review has emphasized major deficiencies in the literature. None of the studies reviewed originally aimed to explore symptoms at RA onset (often discussions about symptom onset were secondary to the study's primary aim). Also, many of the articles identified sampled people diagnosed with RA many years previously, making their recollection of symptoms at onset less reliable. CONCLUSION: In order for clinicians to fully understand the earliest phases of disease, the nature of symptoms at onset needs to be understood. The current work represents a useful starting point, but this area needs further qualitative investigation, followed by quantitative explorations of symptom clusters and their associated features. PMID- 23926092 TI - Patterns of disease-modifying antirheumatic drug use in rheumatoid arthritis patients after 2002: a systematic review. AB - OBJECTIVE: To report and synthesize patterns of disease-modifying antirheumatic drug (DMARD) use reported in observational studies of patients with established and early rheumatoid arthritis (RA) after publication of the American College of Rheumatology guidelines promoting universal DMARD use. METHODS: We searched PubMed for full-length articles in English published between January 1, 2002 and October 1, 2012 that examined DMARD use. The data abstracted from articles included the patient characteristics, country of study, time period studied, patient source, and treating physician type. Study quality was assessed using a modified Newcastle-Ottawa Quality Assessment Scale. RESULTS: We reviewed 1,287 abstracts; 98 full-length articles were selected for additional review and 27 studies describing 28 cohorts of patients were included. Twelve studies described data from cohorts of patients with established RA, and DMARD use in this group of studies ranged from 73-100%. Five studies described data from patients sourced through administrative data and demonstrated consistently lower DMARD use, ranging from 30-63%. Three studies conducted population-based surveys to define cases of RA where DMARD use ranged from 47-73%. Eight studies investigated patients with early RA. DMARD use among patients followed by rheumatologists ranged from 77-98%, whereas DMARD use reported for patients seen by a mix of physicians was significantly lower (39-63%). CONCLUSION: DMARD use in studies from RA cohorts or registries (in which patients were followed by rheumatologists) ranged from 73-100%, compared with 30-73% in studies from administrative data or population-based surveys (in which patients were not necessarily receiving rheumatology subspecialty care). PMID- 23926093 TI - Grip strength and its determinants among older people in different healthcare settings. AB - BACKGROUND: low muscle strength is central to geriatric syndromes including sarcopenia and frailty. It is well described in community-dwelling older people, but the epidemiology of grip strength of older people in rehabilitation or long term care has been little explored. OBJECTIVE: to describe grip strength of older people in rehabilitation and nursing home settings. DESIGN: cross-sectional epidemiological study. SETTING: three healthcare settings in one town. SUBJECTS: hundred and one inpatients on a rehabilitation ward, 47 community rehabilitation referrals and 100 nursing home residents. METHODS: grip strength, age, height, weight, body mass index, number of co-morbidities and medications, Barthel score, Mini-Mental State Examination (MMSE), nutritional status and number of falls in the last year were recorded. RESULTS: grip strength differed substantially between healthcare settings for both men and women (P < 0.0001). Nursing home residents had the lowest age-adjusted mean grip strength and community rehabilitation referrals the highest. Broadly higher grip strength was associated in univariate analyses with younger age, greater height and weight, fewer comorbidities, higher Barthel score, higher MMSE score, better nutritional status and fewer falls. However, after mutual adjustment for these factors, the difference in grip strength between settings remained significant. The Barthel score was the characteristic most strongly associated with grip strength. CONCLUSIONS: older people in rehabilitation and care home settings had lower grip strength than reported for those living at home. Furthermore grip strength varied widely between healthcare settings independent of known major influences. Further research is required to ascertain whether grip strength may help identify people at risk of adverse health outcomes within these settings. PMID- 23926094 TI - High disease activity may not be sufficient to escalate care. AB - OBJECTIVE: Rheumatoid arthritis (RA) treatment regimens are not adjusted in response to active disease as frequently as indicated. The objective of this study was to examine how disease activity and patients' illness beliefs combine to predict future treatment changes in patients who are currently under the care of a rheumatologist. METHODS: We interviewed RA patients at baseline and at 2, 4, and 6 months. We examined the association of disease activity (Routine Assessment of Patient Index Data 4) and 5 specific illness beliefs (consequences, treatment control, symptom burden, concern, and emotional impact) with future escalation of treatment using logistic regression. Analyses were adjusted for age, current biologic agent use, and disease duration. Disease activity and illness beliefs were dichotomized at the median to create 4 dummy variables (e.g., low disease activity + high illness belief) in order to examine the combined impact of disease activity and illness beliefs on escalation. RESULTS: Twenty-nine percent of the participants (n = 41 of 142) had an escalation of treatment during the followup period. When examined separately, disease activity and 4 of the illness beliefs (consequences, symptom burden, concern, and emotional impact) were associated with future escalation. High disease activity was predictive of future escalation only when combined with high levels of consequences, concern, and emotional impact. The combinations of high disease activity and high consequences, concern, and emotional impact were much stronger predictors of future escalation than either factor in isolation. CONCLUSION: The findings suggest that patients' illness beliefs are an important determinant of treatment decisions, which are not fully captured by disease activity measures alone. PMID- 23926095 TI - Development of surface-engineered yeast cells displaying phytochelatin synthase and their application to cadmium biosensors by the combined use of pyrene-excimer fluorescence. AB - The development of simple, portable, inexpensive, and rapid analytical methods for detecting and monitoring toxic heavy metals are important for the safety and security of humans and their environment. Herein, we describe the application of phytochelatin (PC) synthase, which plays a critical role in heavy metal responses in higher plants and green algae, in a novel fluorescent sensing platform for cadmium (Cd). We first created surface-engineered yeast cells on which the PC synthase from Arabidopsis (AtPCS1) was displayed with retention of enzymatic activity. The general concept for the sensor is based on the Cd level-dependent synthesis of PC2 from glutathiones by AtPCS1-displaying yeast cells, followed by simple discriminative detection of PC2 via sensing of excimer fluorescence of thiol-labeling pyrene probes. The intensity of excimer fluorescence increased in the presence of Cd up to 1.0 MUM in an approximately dose-dependent manner. This novel biosensor achieved a detection limit of as low as 0.2 MUM (22.5 MUg/L) for Cd. Although its use may be limited by the fact that Cu and Pb can induce cross reaction, the proposed simple biosensor holds promise as a method useful for cost effective screening of Cd contamination in environmental and food samples. The AtPCS1-displaying yeast cells also might be attractive tools for dissection of the catalytic mechanisms of PCS. PMID- 23926096 TI - Evaluation of ankle swelling due to Lofgren's syndrome: a pilot study using B mode and power Doppler ultrasonography. AB - OBJECTIVE: Patients with acute sarcoidosis frequently present with bilateral painful swelling of the ankles, establishing ankle arthritis as a hallmark of Lofgren's syndrome. Standardized high-resolution musculoskeletal ultrasound (MSUS), including power Doppler, has been utilized to further characterize the nature of ankle swelling in patients presenting with Lofgren's syndrome. METHODS: The ankle joints of 36 consecutive patients with Lofgren's syndrome were investigated by high-resolution MSUS using B-mode and power Doppler mode. The presence of effusion/synovitis and tenosynovitis was determined, and hyperperfusion was scored in a semiquantitative fashion (grade 0-3). RESULTS: The majority of patients (26 [72.2%] of 36) did not present characteristic arthrosonographic findings of an acute arthritis (distension of the capsule and hyperperfusion). Ankle joint effusion was only observed in 9 (25%) of the 36 patients, with a generally mild character (grade I ankle joint effusion: n = 8 [88.8%], grade II ankle joint effusion: n = 1 [11.2%]). In contrast, an extensive subcutaneous edema indicating periarthritis was detected in 23 (92%) of 25 patients. In addition, tenosynovitis could be visualized in 14 patients (38.8%) using MSUS. CONCLUSION: Utilizing MSUS, including power Doppler, the present results clearly demonstrate that ankle swelling in patients with Lofgren's syndrome is predominantly due to periarticular soft tissue swelling and tenosynovitis. In contrast, distinct articular synovitis is rare and if present, only to a mild degree, without relevant power Doppler activity. PMID- 23926097 TI - Defining the restriction point in normal asynchronous human peripheral blood lymphocytes. AB - Although the restriction point (R-point) was proposed in animal cells several decades ago, its existence in normal cells is still controversial, because, in most studies, long-term cultured cell lines rather than primary normal cells were used. Furthermore, cell synchronization was generally applied, resulting in growth imbalance between DNA synthesis and protein expression in cells. Finally, R-point was originally proposed as a unique arrest point that may be in G0 phase; however, generally believed R-point locates within G1 phase. Thus, up to now, there is no solid experimental evidence that supports the existence of R-point in asynchronous primary normal cells. In this study, we used freshly purified peripheral human blood lymphocytes, as asynchronous primary normal cells, to confirm the existence of restriction point in G1 not G0 phase. Our findings may help uncover the mystery of the deregulation of cell cycle progression in malignant tumors. (c) 2013 International Society for Advancement of Cytometry. PMID- 23926098 TI - Non-targeted identification of prions and amyloid-forming proteins from yeast and mammalian cells. AB - The formation of amyloid aggregates is implicated both as a primary cause of cellular degeneration in multiple human diseases and as a functional mechanism for providing extraordinary strength to large protein assemblies. The recent identification and characterization of several amyloid proteins from diverse organisms argues that the amyloid phenomenon is widespread in nature. Yet identifying new amyloid-forming proteins usually requires a priori knowledge of specific candidates. Amyloid fibers can resist heat, pressure, proteolysis, and denaturation by reagents such as urea or sodium dodecyl sulfate. Here we show that these properties can be exploited to identify naturally occurring amyloid forming proteins directly from cell lysates. This proteomic-based approach utilizes a novel purification of amyloid aggregates followed by identification by mass spectrometry without the requirement for special genetic tools. We have validated this technique by blind identification of three amyloid-based yeast prions from laboratory and wild strains and disease-related polyglutamine proteins expressed in both yeast and mammalian cells. Furthermore, we found that polyglutamine aggregates specifically recruit some stress granule components, revealing a possible mechanism of toxicity. Therefore, core amyloid-forming proteins as well as strongly associated proteins can be identified directly from cells of diverse origin. PMID- 23926099 TI - The relaxin receptor (RXFP1) utilizes hydrophobic moieties on a signaling surface of its N-terminal low density lipoprotein class A module to mediate receptor activation. AB - The peptide hormone relaxin is showing potential as a treatment for acute heart failure. Although it is known that relaxin mediates its actions through the G protein-coupled receptor relaxin family peptide receptor 1 (RXFP1), little is known about the molecular mechanisms by which relaxin binding results in receptor activation. Previous studies have highlighted that the unique N-terminal low density lipoprotein class A (LDLa) module of RXFP1 is essential for receptor activation, and it has been hypothesized that this module is the true "ligand" of the receptor that directs the conformational changes necessary for G protein coupling. In this study, we confirmed that an RXFP1 receptor lacking the LDLa module binds ligand normally but cannot signal through any characterized G protein-coupled receptor signaling pathway. Furthermore, we comprehensively examined the contributions of amino acids in the LDLa module to RXFP1 activity using both gain-of-function and loss-of-function mutational analysis together with NMR structural analysis of recombinant LDLa modules. Gain-of-function studies with an inactive RXFP1 chimera containing the LDLa module of the human LDL receptor (LB2) demonstrated two key N-terminal regions of the module that were able to rescue receptor signaling. Loss-of-function mutations of residues in these regions demonstrated that Leu-7, Tyr-9, and Lys-17 all contributed to the ability of the LDLa module to drive receptor activation, and judicious amino acid substitutions suggested this involves hydrophobic interactions. Our results demonstrate that these key residues contribute to interactions driving the active receptor conformation, providing further evidence of a unique mode of G protein coupled receptor activation. PMID- 23926100 TI - Generation of transgenic rats through induced pluripotent stem cells. AB - The rat is an important animal model for human disease research. Using inhibitors of glycogen synthase kinase 3 and MAPK signaling pathways, rat embryonic stem cells and rat induced pluripotent stem cells (riPSCs) have been derived. However, unlike rat embryonic stem cells, germ line competent riPSCs have only been derived from Wistar rats at low efficiency. Here, we found that an optimized induction medium containing knock-out serum replacement and vitamin C improved the rate and efficiency of riPSCs generation from Dark Agouti rat fibroblasts and Sertoli cells. riPSCs maintained an undifferentiated status for >30 passages and could differentiate into various cells types including germ cells when injected into rat blastocysts. Moreover, transgenic riPSCs could be generated through the PiggyBac transposon, which could be used to generate transgenic rats through germ line transmission. riPSCs can be used as a novel tool in genetic and genomic studies of the rat. PMID- 23926101 TI - CSN5/JAB1 interacts with the centromeric components CENP-T and CENP-W and regulates their proteasome-mediated degradation. AB - The CENP-T.CENP-W complex is a recently identified inner centromere component that plays crucial roles in the formation of a functional kinetochore involved in cell division during mitosis. Using yeast two-hybrid screening, we identified an interaction between CENP-T and CSN5, the fifth component of the COP9 signalosome and a key modulator of the cell cycle and cancer. Co-immunoprecipitation revealed that CSN5 directly interacts with both CENP-T and CENP-W. Ectopically expressed CSN5 promoted the ubiquitin- and proteasome-dependent degradation of CENP-T.CENP W. The formation of a CENP-T.CENP-W complex greatly enhanced the stabilities of the respective proteins, possibly by blocking CSN5-mediated degradation. Furthermore, dysregulation of CSN5 induced severe defects in the recruitment of CENP-T.CENP-W to the kinetochore during the prophase stage of mitosis. Thus, our results indicate that CSN5 regulates the stability of the inner kinetochore components CENP-T and CENP-W, providing the first direct link between CSN5 and the mitotic apparatus, highlighting the role of CSN5 as a multifunctional cell cycle regulator. PMID- 23926102 TI - Neil3 and NEIL1 DNA glycosylases remove oxidative damages from quadruplex DNA and exhibit preferences for lesions in the telomeric sequence context. AB - The telomeric DNA of vertebrates consists of d(TTAGGG)n tandem repeats, which can form quadruplex DNA structures in vitro and likely in vivo. Despite the fact that the G-rich telomeric DNA is susceptible to oxidation, few biochemical studies of base excision repair in telomeric DNA and quadruplex structures have been done. Here, we show that telomeric DNA containing thymine glycol (Tg), 8-oxo-7,8 dihydroguanine (8-oxoG), guanidinohydantoin (Gh), or spiroiminodihydantoin (Sp) can form quadruplex DNA structures in vitro. We have tested the base excision activities of five mammalian DNA glycosylases (NEIL1, NEIL2, mNeil3, NTH1, and OGG1) on these lesion-containing quadruplex substrates and found that only mNeil3 had excision activity on Tg in quadruplex DNA and that the glycosylase exhibited a strong preference for Tg in the telomeric sequence context. Although Sp and Gh in quadruplex DNA were good substrates for mNeil3 and NEIL1, none of the glycosylases had activity on quadruplex DNA containing 8-oxoG. In addition, NEIL1 but not mNeil3 showed enhanced glycosylase activity on Gh in the telomeric sequence context. These data suggest that one role for Neil3 and NEIL1 is to repair DNA base damages in telomeres in vivo and that Neil3 and Neil1 may function in quadruplex-mediated cellular events, such as gene regulation via removal of damaged bases from quadruplex DNA. PMID- 23926103 TI - Actin-binding protein drebrin regulates HIV-1-triggered actin polymerization and viral infection. AB - HIV-1 contact with target cells triggers F-actin rearrangements that are essential for several steps of the viral cycle. Successful HIV entry into CD4(+) T cells requires actin reorganization induced by the interaction of the cellular receptor/co-receptor complex CD4/CXCR4 with the viral envelope complex gp120/gp41 (Env). In this report, we analyze the role of the actin modulator drebrin in HIV 1 viral infection and cell to cell fusion. We show that drebrin associates with CXCR4 before and during HIV infection. Drebrin is actively recruited toward cell virus and Env-driven cell to cell contacts. After viral internalization, drebrin clustering is retained in a fraction of the internalized particles. Through a combination of RNAi-based inhibition of endogenous drebrin and GFP-tagged expression of wild-type and mutant forms, we establish drebrin as a negative regulator of HIV entry and HIV-mediated cell fusion. Down-regulation of drebrin expression promotes HIV-1 entry, decreases F-actin polymerization, and enhances profilin local accumulation in response to HIV-1. These data underscore the negative role of drebrin in HIV infection by modulating viral entry, mainly through the control of actin cytoskeleton polymerization in response to HIV-1. PMID- 23926104 TI - Tripartite Motif-containing 33 (TRIM33) protein functions in the poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response through interaction with Amplified in Liver Cancer 1 (ALC1) protein. AB - Activation of poly(ADP-ribose) polymerase (PARP) near sites of DNA breaks facilitates recruitment of DNA repair proteins and promotes chromatin relaxation in part through the action of chromatin-remodeling enzyme Amplified in Liver Cancer 1 (ALC1). Through proteomic analysis we find that ALC1 interacts after DNA damage with Tripartite Motif-containing 33 (TRIM33), a multifunctional protein implicated in transcriptional regulation, TGF-beta signaling, and tumorigenesis. We demonstrate that TRIM33 is dynamically recruited to DNA damage sites in a PARP1- and ALC1-dependent manner. TRIM33-deficient cells show enhanced sensitivity to DNA damage and prolonged retention of ALC1 at sites of DNA breaks. Conversely, overexpression of TRIM33 alleviates the DNA repair defects conferred by ALC1 overexpression. Thus, TRIM33 plays a role in PARP-dependent DNA damage response and regulates ALC1 activity by promoting its timely removal from sites of DNA damage. PMID- 23926105 TI - Loss of epigenetic Kruppel-like factor 4 histone deacetylase (KLF-4-HDAC) mediated transcriptional suppression is crucial in increasing vascular endothelial growth factor (VEGF) expression in breast cancer. AB - Vascular endothelial growth factor (VEGF) is recognized as an important angiogenic factor that promotes angiogenesis in a series of pathological conditions, including cancer, inflammation, and ischemic disorders. We have recently shown that the inflammatory transcription factor SAF-1 is, at least in part, responsible for the marked increase of VEGF levels in breast cancer. Here, we show that SAF-1-mediated induction of VEGF is repressed by KLF-4 transcription factor. KLF-4 is abundantly present in normal breast epithelial cells, but its level is considerably reduced in breast cancer cells and clinical cancer tissues. In the human VEGF promoter, SAF-1- and KLF-4-binding elements are overlapping, whereas SAF-1 induces and KLF-4 suppresses VEGF expression. Ectopic overexpression of KLF-4 and RNAi-mediated inhibition of endogenous KLF-4 supported the role of KLF-4 as a transcriptional repressor of VEGF and an inhibitor of angiogenesis in breast cancer cells. We show that KLF-4 recruits histone deacetylases (HDACs) -2 and -3 at the VEGF promoter. Chronological ChIP assays demonstrated the occupancy of KLF-4, HDAC2, and HDAC3 in the VEGF promoter in normal MCF-10A cells but not in MDA-MB-231 cancer cells. Co-transfection of KLF-4 and HDAC expression plasmids in breast cancer cells results in synergistic repression of VEGF expression and inhibition of angiogenic potential of these carcinoma cells. Together these results identify a new mechanism of VEGF up regulation in cancer that involves concomitant loss of KLF-4-HDAC-mediated transcriptional repression and active recruitment of SAF-1-mediated transcriptional activation. PMID- 23926106 TI - Structural basis for the regulation of the mitogen-activated protein (MAP) kinase p38alpha by the dual specificity phosphatase 16 MAP kinase binding domain in solution. AB - Mitogen-activated protein kinases (MAPKs) fulfill essential biological functions and are key pharmaceutical targets. Regulation of MAPKs is achieved via a plethora of regulatory proteins including activating MAPKKs and an abundance of deactivating phosphatases. Although all regulatory proteins use an identical interaction site on MAPKs, the common docking and hydrophobic pocket, they use distinct kinase interaction motif (KIM or D-motif) sequences that are present in linear, peptide-like, or well folded protein domains. It has been recently shown that a KIM-containing MAPK-specific dual specificity phosphatase DUSP10 uses a unique binding mode to interact with p38alpha. Here we describe the interaction of the MAPK binding domain of DUSP16 with p38alpha and show that despite belonging to the same dual specificity phosphatase (DUSP) family, its interaction mode differs from that of DUSP10. Indeed, the DUSP16 MAPK binding domain uses an additional helix, alpha-helix 4, to further engage p38alpha. This leads to an additional interaction surface on p38alpha. Together, these structural and energetic differences in p38alpha engagement highlight the fine-tuning necessary to achieve MAPK specificity and regulation among multiple regulatory proteins. PMID- 23926107 TI - Lung fibrosis-associated surfactant protein A1 and C variants induce latent transforming growth factor beta1 secretion in lung epithelial cells. AB - Missense mutations of surfactant proteins are recognized as important causes of inherited lung fibrosis. Here, we study rare and common surfactant protein (SP) A1 and SP-C variants, either discovered in our familial pulmonary fibrosis cohort or described by others. We show that expression of two SP-A1 (R219W and R242*) and three SP-C (I73T, M71V, and L188Q) variant proteins lead to the secretion of the profibrotic latent transforming growth factor (TGF)-beta1 in lung epithelial cell lines. The secreted TGF-beta1 is capable of autocrine and paracrine signaling and is dependent upon expression of the latent TGF-beta1 binding proteins. The dependence upon unfolded protein response (UPR) mediators for TGF beta1 induction differs for each variant. TGF-beta1 secretion induced by the expression of the common SP-A1 R219W variant is nearly completely blocked by silencing the UPR transducers IRE-1alpha and ATF6. In contrast, the secretion of TGF-beta1 induced by two rare SP-C mutant proteins (I73T and M71V), is largely unaffected by UPR silencing or by the addition of the small molecular chaperone 4 phenylbutyric acid, implicating a UPR-independent mechanism for these variants. Blocking TGF-beta1 secretion reverses cell death of RLE-6TN cells expressing these SP-A1 and SP-C variants suggesting that anti-TGF-beta therapeutics may be beneficial to this molecularly defined subgroup of pulmonary fibrosis patients. PMID- 23926108 TI - Galectin-3 guides intracellular trafficking of some human serotransferrin glycoforms. AB - Transferrin internalization via clathrin-mediated endocytosis and subsequent recycling after iron delivery has been extensively studied. Here we demonstrate a previously unrecognized parameter regulating this recycling, the binding of galectin-3 to particular glycoforms of transferrin. Two fractions of transferrin, separated by affinity chromatography based on their binding or not to galectin-3, are targeted to kinetically different endocytic pathways in HFL-1 cells expressing galectin-3 but not in SKBR3 cells lacking galectin-3; the SKBR3 cells, however, can acquire the ability to target these transferrin glycoforms differently after preloading with exogenously added galectin-3. In all, this study provides the first evidence of a functional role for transferrin glycans, in intracellular trafficking after uptake. Moreover, the galectin-3-bound glycoform increased in cancer, suggesting a pathophysiological regulation. These are novel aspects of transferrin cell biology, which has previously considered only a degree of iron loading, but not other forms of heterogeneity. PMID- 23926109 TI - Exosomes from retinal astrocytes contain antiangiogenic components that inhibit laser-induced choroidal neovascularization. AB - Exosomes released from different types of host cells have different biological effects. We report that exosomes released from retinal astroglial cells (RACs) suppress retinal vessel leakage and inhibit choroidal neovascularization (CNV) in a laser-induced CNV model, whereas exosomes released from retinal pigmental epithelium do not. RAC exosomes inhibit the migration of macrophages and the tubule forming of mouse retinal microvascular endothelial cells. Further, we analyzed antiangiogenic components in RAC exosomes using an angiogenesis array kit and detected several endogenous inhibitors of angiogenesis exclusively present in RAC exosomes, such as endostatin. Moreover, blockade of matrix metalloproteinases in the cleavage of collagen XVIII to form endostatin using FN 439 reverses RAC exosome-mediated retinal vessel leakage. This study demonstrates that exosomes released from retinal tissue cells have different angiogenic effects, with exosomes from RACs containing antiangiogenic components that might protect the eye from angiogenesis and maintain its functional integrity. In addition, by identifying additional components and their functions of RAC exosomes, we might improve the antiangiogenic therapy for CNV in age-related macular degeneration and diabetic retinopathy. PMID- 23926110 TI - Interaction of heat shock protein 90 and the co-chaperone Cpr6 with Ura2, a bifunctional enzyme required for pyrimidine biosynthesis. AB - The molecular chaperone heat shock protein 90 (Hsp90) is an essential protein required for the activity and stability of multiple proteins termed clients. Hsp90 cooperates with a set of co-chaperone proteins that modulate Hsp90 activity and/or target clients to Hsp90 for folding. Many of the Hsp90 co-chaperones, including Cpr6 and Cpr7, contain tetratricopeptide repeat (TPR) domains that bind a common acceptor site at the carboxyl terminus of Hsp90. We found that Cpr6 and Hsp90 interacted with Ura2, a protein critical for pyrimidine biosynthesis. Mutation or inhibition of Hsp90 resulted in decreased accumulation of Ura2, indicating it is an Hsp90 client. Cpr6 interacted with Ura2 in the absence of stable Cpr6-Hsp90 interaction, suggesting a direct interaction. However, loss of Cpr6 did not alter the Ura2-Hsp90 interaction or Ura2 accumulation. The TPR domain of Cpr6 was required for Ura2 interaction, but other TPR containing co chaperones, including Cpr7, failed to interact with Ura2 or rescue CPR6-dependent growth defects. Further analysis suggests that the carboxyl-terminal 100 amino acids of Cpr6 and Cpr7 are critical for specifying their unique functions, providing new information about this important class of Hsp90 co-chaperones. PMID- 23926111 TI - COPS5 (Jab1) protein increases beta site processing of amyloid precursor protein and amyloid beta peptide generation by stabilizing RanBP9 protein levels. AB - Increased processing of amyloid precursor protein (APP) and accumulation of neurotoxic amyloid beta peptide (Abeta) in the brain is central to the pathogenesis of Alzheimer's disease (AD). Therefore, the identification of molecules that regulate Abeta generation is crucial for future therapeutic approaches for AD. We demonstrated previously that RanBP9 regulates Abeta generation in a number of cell lines and primary neuronal cultures by forming tripartite protein complexes with APP, low-density lipoprotein-related protein, and BACE1, consequently leading to increased amyloid plaque burden in the brain. RanBP9 is a scaffold protein that exists and functions in multiprotein complexes. To identify other proteins that may bind RanBP9 and regulate Abeta levels, we used a two-hybrid analysis against a human brain cDNA library and identified COPS5 as a novel RanBP9-interacting protein. This interaction was confirmed by coimmunoprecipitation experiments in both neuronal and non-neuronal cells and mouse brain. Colocalization of COPS5 and RanBP9 in the same subcellular compartments further supported the interaction of both proteins. Furthermore, like RanBP9, COPS5 robustly increased Abeta generation, followed by increased soluble APP-beta (sAPP-beta) and decreased soluble-APP-alpha (sAPP-alpha) levels. Most importantly, down-regulation of COPS5 by siRNAs reduced Abeta generation, implying that endogenous COPS5 regulates Abeta generation. Finally, COPS5 levels were increased significantly in AD brains and APDeltaE9 transgenic mice, and overexpression of COPS5 strongly increased RanBP9 protein levels by increasing its half-life. Taken together, these results suggest that COPS5 increases Abeta generation by increasing RanBP9 levels. Thus, COPS5 is a novel RanBP9-binding protein that increases APP processing and Abeta generation by stabilizing RanBP9 protein levels. PMID- 23926112 TI - Determination of allergenic load and pollen count of Cupressus arizonica pollen by flow cytometry using Cup a1 polyclonal antibody. AB - BACKGROUND: There is an increase in the incidence of pollen related allergy, thus information on pollen schedules would be a great asset for physicians to improve the clinical care of patients. Like cypress pollen sensitization shows a high prevalence among the causes of allergic rhinitis, and therefore it is of interest to use it like a model of study, distinguishing cypress pollen, pollen count, and allergenic load level. In this work, we use a flow cytometry based technique to obtain both Cupressus arizonica pollen count and allergenic load, using specific rabbit polyclonal antibody Cup a1 and its comparison with optical microscopy technique measurement. METHODS: Airborne samples were collected from Burkard Spore-Trap and Burkard Cyclone Cupressus arizonica pollen was studied using specific rabbit polyclonal antibody Cup a1, labeled with AlexaFluor((r)) 488 or 750 and analysed by Flow Cytometry in both an EPICS XL and Cyan ADP cytometers (Beckman Coulter((r)) ). Optical microscopy study was realized with a Leica optical microscope. Bland and Altman was used to determine agreement between both techniques measured. RESULTS: We can identify three different populations based on rabbit polyclonal antibody Cup a1 staining. The main region (44.5%) had 97.3% recognition, a second region (25%) with 28% and a third region (30.5%) with 68% respectively. Immunofluorescence and confocal microscopy showed that main region corresponds to whole pollen grains, the second region are pollen without exine and the third region is constituted by smaller particles with allergenic properties. Pollen schedule shows a higher correlation measured by optical microscopy and flow cytometry in the pollen count with a P-value: 0.0008 E(-2) and 0.0002 with regard to smaller particles, so the Bland and Altman measurement showed a good correlation between them, P-value: 0.0003. CONCLUSION: Determination of pollen count and allergenic load by flow cytometry represents an important tool in the determination of airborne respiratory allergens. We showed that not only whole pollen but also smaller particles could induce allergic sensitization. This is the first study where flow cytometry is used for calculating pollen counts and allergenic load. PMID- 23926113 TI - Risk-sensitive decision-making in patients with posterior parietal and ventromedial prefrontal cortex injury. AB - Successful choice under risk requires the integration of information about outcome probabilities and values and implicates a brain network including the ventromedial prefrontal cortex (vmPFC) and posterior parietal cortex (pPAR). Damage to the vmPFC is linked to poor decision-making and increased risk-taking. Electrophysiological and neuroimaging data implicate the pPAR in the processing of reward probability during choice, but the causal contribution of this area has not been established. We compared patients with lesions to the pPAR (n = 13), vmPFC (n = 13), and healthy volunteers (n = 22) on the Roulette Betting Task, a measure of risk-sensitive decision-making. Both lesion groups were impaired in adjusting their bets to the probability of winning. This impairment was correlated with the extent of pPAR, but not vmPFC, damage. In addition, the vmPFC group chose higher bets than healthy controls overall, an effect that correlated with lesion volume in the medial orbitofrontal cortex. Both lesion groups earned fewer points than healthy controls. The groups did not differ on 2 tasks assessing probabilistic reasoning outside of a risk-reward context. Our results demonstrate the causal involvement of both the pPAR and vmPFC in risk-sensitive choice and indicate distinguishable roles of these areas in probability processing and risk appetite. PMID- 23926114 TI - Sex differences in cortical thickness and their possible genetic and sex hormonal underpinnings. AB - Although it has been shown that cortical thickness (Cth) differs between sexes, the underlying mechanisms are unknown. Seeing as XXY males have 1 extra X chromosome, we investigated the possible effects of X- and sex-chromosome dosage on Cth by comparing data from 31 XXY males with 39 XY and 47 XX controls. Plasma testosterone and estrogen were also measured in an effort to differentiate between possible sex-hormone and sex-chromosome gene effects. Cth was calculated with FreeSurfer software. Parietal and occipital Cth was greater in XX females than XY males. In these regions Cth was inversely correlated with z-normalized testosterone. In the motor strip, the cortex was thinner in XY males compared with both XX females and XXY males, indicating the possibility of an X-chromosome gene-dosage effect. XXY males had thinner right superior temporal and left middle temporal cortex, and a thicker right orbitofrontal cortex and lingual cortex than both control groups. Based on these data and previous reports from women with XO monosomy, it is hypothesized that programming of the motor cortex is influenced by processes linked to X-escapee genes, which do not have Y-chromosome homologs, and that programming of the superior temporal cortex is mediated by X-chromosome escapee genes with Y-homologs. PMID- 23926116 TI - Connectivity-based parcellation of the human temporal pole using diffusion tensor imaging. AB - The temporal pole (TP) is an association cortex capable of multisensory integration and participates in various high-order cognitive functions. However, an accepted parcellation of the human TP and its connectivity patterns have not yet been well established. Here, we sought to present a scheme for the parcellation of human TP based on anatomical connectivity and to reveal its subregional connectivity patterns. Three distinct subregions with characteristic fiber pathways were identified, including the dorsal (TAr), the medial (TGm), and lateral (TGl) subregions, which are located ventrally. According to the connectivity patterns, a dorsal/ventral sensory segregation of auditory and visual processing and the medial TGm involved in the olfactory processing were observed. Combined with the complementary resting-state functional connectivity analysis, the connections of the TGm with the orbitofrontal cortex and other emotion-related areas, the TGl connections with the MPFC and major default mode network regions, and the TAr connections with the perisylvian language areas were observed. To the best of our knowledge, the present study represents the first attempt to parcel the human TP based on its anatomical connectivity features, which may help to improve our understanding of its connectional anatomy and to extend the available knowledge in TP-related clinical research. PMID- 23926115 TI - The neurobiology of thought: the groundbreaking discoveries of Patricia Goldman Rakic 1937-2003. AB - Patricia S. Goldman-Rakic (1937-2003) transformed the study of the prefrontal cortex (PFC) and the neural basis of mental representation, the basic building block of abstract thought. Her pioneering research first identified the dorsolateral PFC (dlPFC) region essential for spatial working memory, and the extensive circuits of spatial cognition. She discovered the cellular basis of working memory, illuminating the dlPFC microcircuitry underlying spatially tuned, persistent firing, whereby precise information can be held "in mind": persistent firing arises from recurrent excitation within glutamatergic pyramidal cell circuits in deep layer III, while tuning arises from GABAergic lateral inhibition. She was the first to discover that dopamine is essential for dlPFC function, particularly through D1 receptor actions. She applied a host of technical approaches, providing a new paradigm for scientific inquiry. Goldman Rakic's work has allowed the perplexing complexities of mental illness to begun to be understood at the cellular level, including atrophy of the dlPFC microcircuits subserving mental representation. She correctly predicted that impairments in dlPFC working memory activity would contribute to thought disorder, a cardinal symptom of schizophrenia. Ten years following her death, we look back to see how she inspired an entire field, fundamentally changing our view of cognition and cognitive disorders. PMID- 23926117 TI - Changes in lipoprotein particle number with ezetimibe/simvastatin coadministered with extended-release niacin in hyperlipidemic patients. AB - BACKGROUND: Combination therapy with ezetimibe/simvastatin (E/S) and extended release niacin (N) has been reported to be safe and efficacious in concomitantly reducing low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol in hyperlipidemic patients at high risk for atherosclerotic cardiovascular events. This analysis evaluated the effect of E/S coadministered with N on low-density lipoprotein particle number (LDL-P) and high density lipoprotein particle number (HDL-P) as assessed by nuclear magnetic resonance (NMR) spectroscopy in patients with type IIa or IIb hyperlipidemia. METHODS AND RESULTS: This was an analysis of a previously reported 24-week randomized, double-blind study in type IIa/IIb hyperlipidemic patients randomized to treatment with E/S (10/20 mg/day)+N (titrated to 2 g/day) or N (titrated to 2 g/day) or E/S (10/20 mg/day). Samples from a subset of patients (577 of 1220) were available for post hoc analysis of LDL-P and HDL-P by NMR spectroscopy. Increases in HDL-P (+16.2%) and decreases in LDL-P (-47.7%) were significantly greater with E/S+N compared with N (+9.8% for HDL-P and -21.5% for LDL-P) and E/S (+12.8% for HDL-P and -36.8% for LDL-P). In tertile analyses, those with the lowest baseline HDL-P had the greatest percent increase in HDL-P (N, 18.4/7.9/2.1; E/S, 19.3/12.2/5.3; and E/S+N, 26.9/13.8/6.9; all P<0.001). Individuals in the highest tertile of LDL-P had the greatest percent reduction in LDL-P (N, 18.3/23.1/24.6; E/S, 29.7/38.3/41.8; and E/S+N, 44.3/49.0/50.5; all P<0.001). CONCLUSIONS: These results suggest that E/S+N improves lipoprotein particle number, consistent with its lipid-modifying benefits in type IIa or IIb hyperlipidemia patients and may exert the greatest effect in those with high LDL P and low HDL-P at baseline. PMID- 23926118 TI - Phosphoproteomics study based on in vivo inhibition reveals sites of calmodulin dependent protein kinase II regulation in the heart. AB - BACKGROUND: The multifunctional Ca(2+)- and calmodulin-dependent protein kinase II (CaMKII) is a crucial mediator of cardiac physiology and pathology. Increased expression and activation of CaMKII has been linked to elevated risk for arrhythmic events and is a hallmark of human heart failure. A useful approach to determining CaMKII's role therein is large-scale analysis of phosphorylation events by mass spectrometry. However, current large-scale phosphoproteomics approaches have proved inadequate for high-fidelity identification of kinase specific roles. The purpose of this study was to develop a phosphoproteomics approach to specifically identify CaMKII's downstream effects in cardiac tissue. METHODS AND RESULTS: To identify putative downstream CaMKII targets in cardiac tissue, animals with myocardial-delimited expression of the specific peptide inhibitor of CaMKII (AC3-I) or an inactive control (AC3-C) were compared using quantitative phosphoproteomics. The hearts were isolated after isoproterenol injection to induce CaMKII activation downstream of beta-adrenergic receptor agonist stimulation. Enriched phosphopeptides from AC3-I and AC3-C mice were differentially quantified using stable isotope dimethyl labeling, strong cation exchange chromatography and high-resolution LC-MS/MS. Phosphorylation levels of several hundred sites could be profiled, including 39 phosphoproteins noticeably affected by AC3-I-mediated CaMKII inhibition. CONCLUSIONS: Our data set included known CaMKII substrates, as well as several new candidate proteins involved in functions not previously implicated in CaMKII signaling. PMID- 23926119 TI - Effectiveness of percutaneous coronary intervention with drug-eluting stents compared with bypass surgery in diabetics with multivessel coronary disease: comprehensive systematic review and meta-analysis of randomized clinical data. AB - BACKGROUND: Controversy persists regarding the optimal revascularization strategy for diabetic patients with multivessel coronary artery disease (MVD). Coronary artery bypass grafting (CABG) has been compared with percutaneous coronary intervention (PCI) using drug-eluting stents (DES) in recent randomized controlled trials (RCTs). METHODS AND RESULTS: RCTs comparing PCI with DES versus CABG in diabetic patients with MVD who met inclusion criteria were analyzed (protocol registration No. CRD42013003693). Primary end point (major adverse cardiac events) was a composite of death, myocardial infarction, and stroke at a mean follow-up of 4 years. Analyses were performed for each outcome by using risk ratio (RR) by fixed- and random-effects models. Four RCTS with 3052 patients met inclusion criteria (1539 PCI versus 1513 CABG). Incidence of major adverse cardiac events was 22.5% for PCI and 16.8% for CABG (RR 1.34, 95% CI 1.16 to 1.54, P<0.0001). Similar results were obtained for death (14% versus 9.7%, RR 1.51, 95% CI 1.09 to 2.10, P=0.01), and MI (10.3% versus 5.9%, RR 1.44, 95% CI 0.79 to 2.6, P=0.23). Stroke risk was significantly lower with DES (2.3% versus 3.8%, RR 0.59, 95% CI 0.39 to 0.90, P=0.01) and subsequent revascularization was several-fold higher (17.4% versus 8.0%, RR 1.85, 95% CI 1.0 to 3.40, P=0.05). CONCLUSIONS: These data demonstrate that CABG in diabetic patients with MVD at low to intermediate surgical risk (defined as EUROSCORE <5) is superior to MVD PCI with DES. CABG decreased overall death, nonfatal myocardial infarction, and repeat revascularization at the expense of an increase in stroke risk. PMID- 23926121 TI - A validated specific stability-indicating RP-HPLC assay method for Ambrisentan and its related substances. AB - A validated specific stability-indicating reverse-phase liquid chromatographic method was developed for the quantitative determination of Ambrisentan as well as its related substances in bulk samples, pharmaceutical dosage forms in the presence of degradation products and its related impurities. Forced degradation studies were performed on bulk samples of Ambrisentan as per the ICH-prescribed stress conditions using acid, base, oxidative, thermal stress and photolytic degradation to show the stability-indicating power of the LC method. Significant degradation in acidic, basic stress conditions was observed and no degradation was observed in other stress conditions. The chromatographic method was optimized using the samples generated from the forced degradation studies and the impurity spiked solution. Good resolution between the peaks corresponds to Ambrisentan related impurities and degradation products from the analyte were achieved on a SunFire C18 column using a mobile phase consisting of a mixture of potassium dihydrogen orthophosphate at a pH adjusted to 2.5 with ortho-phosphoric acid in water and a mixture of acetonitrile:methanol using a simple linear gradient. The detection was carried out at 225 nm. The limit of detection and the limit of quantification for the Ambrisentan and its related impurities were established. The stressed test solutions were assayed against the qualified working standard of Ambrisentan and the mass balance in each case was between 98.9 and 100.3%, indicating that the developed LC method was stability indicating. Validation of the developed LC method was carried out as per the ICH requirements. The developed method was found to be suitable to check the quality of bulk samples of Ambrisentan at the time of batch release and also during its storage (long-term and accelerated stability). PMID- 23926120 TI - 5-demethyltangeretin inhibits human nonsmall cell lung cancer cell growth by inducing G2/M cell cycle arrest and apoptosis. AB - SCOPE: Tangeretin (TAN) and 5-demethyltangeretin (5DT) are two closely related polymethoxyflavones found in citrus fruits. We investigated growth inhibitory effects on three human nonsmall cell lung cancer (NSCLC) cells. METHODS AND RESULTS: Cell viability assay demonstrated that 5DT inhibited NSCLC cell growth in a time- and dose-dependent manner, and IC50 s of 5DT were 79-fold, 57-fold, and 56-fold lower than those of TAN in A549, H460, and H1299 cells, respectively. Flow cytometry analysis showed that 5DT induced extensive G2/M cell cycle arrest and apoptosis in NSCLC cells, while TAN at tenfold higher concentrations did not. The apoptosis induced by 5DT was further confirmed by activation of caspase-3 and cleavage of PARP. Moreover, 5DT dose-dependently upregulated p53 and p21(Cip1/Waf1), and downregulated Cdc-2 (Cdk-1) and cyclin B1. HPLC analysis revealed that the intracellular levels of 5DT in NSCLC cells were 2.7-4.9 fold higher than those of TAN after the cells were treated with 5DT or TAN at the same concentration. CONCLUSION: Our results demonstrated that 5DT inhibited NSCLC cell growth by inducing G2/M cell cycle arrest and apoptosis. These effects were much stronger than those produced by TAN, which is partially due to the higher intracellular uptake of 5DT than TAN. PMID- 23926122 TI - Nanoporous and highly active silicon carbide supported CeO2-catalysts for the methane oxidation reaction. AB - CeOx @SiO2 nanoparticles are used for the first time for the generation of porous SiC materials with tailored pore diameter in the mesopore range containing encapsulated and catalytically active CeO2 nanoparticles. The nanocasting approach with a preceramic polymer and subsequent pyrolysis is performed at 1300 degrees C, selective leaching of the siliceous part results in CeOx /SiC catalysts with remarkable characteristics like monodisperse, spherical pores and specific surface areas of up to 438 m(2) .g(-1) . Porous SiC materials are promising supports for high temperature applications. The catalysts show excellent activities in the oxidation of methane with onset temperatures of the reaction 270 K below the onset of the homogeneous reaction. The synthesis scheme using core-shell particles is suited to functionalize silicon carbide with a high degree of stabilization of the active nanoparticles against sintering in the core of the template even at pyrolysis temperatures of 1300 degrees C rendering the novel synthesis principle as an attractive approach for a wide range of catalytic reactions. PMID- 23926123 TI - Relations between white coat effects and left ventricular mass index or arterial stiffness: role of nocturnal blood pressure dipping. AB - BACKGROUND: Whether independent relationships between white coat effects (office minus day (office-day blood pressure (BP))) and organ damage or arterial stiffness may be explained by associations with an attenuated nocturnal BP dipping, has not been determined. METHODS: In 750 participants from a sample of African ancestry, office and 24-hour BP, carotid-femoral pulse wave velocity (PWV) (applanation tonometry and SphygmoCor software) (n = 662), and left ventricular mass indexed to height(2.7) (LVMI) (echocardiography) (n = 463) were determined. RESULTS: Office-day systolic BP (SBP) was correlated with day minus night (day-night) SBP, percentage night divided by day (night/day) SBP, and night SBP (P < 0.0005), and these relationships persisted with adjustments for confounders, including day SBP (P < 0.005). With adjustments for 24-hour SBP and additional confounders, office-day SBP was associated with LVMI (P < 0.01) and PWV (P < 0.0001). With adjustments for day SBP and additional confounders, day night SBP, percentage night/day SBP, and night SBP were related to PWV (P < 0.05) but not to LVMI (P > 0.44). The relationships between office-day SBP and LVMI or PWV persisted with adjustments for either day-night or percentage night/day SBP (LVMI: P = 0.01; PWV: P < 0.0001) or night SBP (LVMI: P < 0.01; PWV: P = 0.0001), and in product of coefficient mediation analysis with appropriate adjustments, neither indexes of nocturnal BP dipping nor nocturnal BP per se contributed toward the impact of office-day BP on LVMI or PWV (P > 0.09). CONCLUSIONS: In a group of African ancestry, although white coat effects are independently associated with an attenuated nocturnal decrease in SBP, neither decreased BP dipping nor nocturnal BP contribute toward the independent relationships between white coat effects and LVMI or arterial stiffness. PMID- 23926124 TI - A functional common polymorphism of the ABCB1 gene is associated with chronic kidney disease and hypertension in Chinese. AB - BACKGROUND: Permeability glycoprotein is encoded by the ATP-binding cassette B1 gene (ABCB1) and is an extruder of toxic metabolites in the kidney. A functional common polymorphism (C3435T, rs1045642) in the human ABCB1 gene has been found to be associated with allograft outcome in kidney transplant patients. In this study, we investigated the association of the C3435T polymorphism with renal function and blood pressure (BP) in 2 Chinese populations. METHODS: The discovery and replication populations were recruited from a mountainous area (Zhejiang Province) and a newly urbanized suburban area (Shanghai), respectively. We genotyped all subjects using the ABI SNapShot method. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate <60 ml/min * 1.73 m(2) or 24-hour urinary albumin excretion >=30 mg. RESULTS: In the discovery population of 1,987 subjects, after adjustment for covariables, TT homozygosity (n = 217) was associated with a higher risk of CKD (n = 369; odds ratio (OR) = 1.73; P = 0.003) and with higher systolic BP (+3.1 mm Hg; P = 0.03) and pulse pressure (+3.4 mm Hg; P = 0.001). These associations were dependent on age (Pint <= 0.05). In subjects aged >=60 years (n = 374), the corresponding OR or difference was 2.40 for CKD, 15.1 mm Hg for systolic BP, and 12.4 mm Hg for pulse pressure (P < 0.001). In similar adjusted analyses in the replication population of 2,427 elderly (>=60 years) subjects, TT homozygosity was also associated with a higher risk of CKD (OR = 1.39; P = 0.02) and an enhanced association of hypertension with CKD (OR = 1.50; P = 0.04). CONCLUSIONS: The ABCB1 C3435T polymorphism might predict CKD, especially in the elderly. PMID- 23926125 TI - Graphene-Ruthenium(II) complex composites for sensitive ECL immunosensors. AB - Non-covalent modification method has been proven as an effective strategy for enhancing the chemical properties of graphene while the structure and electronic properties of graphene can be retained. This work describes a novel strategy to fabricate a solid-state electrochemiluminescent (ECL) immunosensor based on ruthenium(II) complex/3,4,9,10-perylenetetracarboxylic acid (PTCA)/graphene nanocomposites (Ru-PTCA/G) for sensitive detection of alpha-fetoprotein (AFP). It is found that immobilization of PTCA and reduction of GO can be simultaneously achieved in one-pot synthesis method under alkaline condition and moderate temperature, forming PTCA/G nanocomposites. Further covalent attachment of ruthenium(II) complex to the PTCA assembled on graphene sheets produces the functional Ru-PTCA/G nanocomposites which show good electrochemical activity and ca. 21 times higher luminescence quantum efficiency than the adsorbed derivative ruthenium(II) complex. The Ru-PTCA/G nanocomposites based solid-state ECL sensor exhibits high stability toward the determination of tripropylamine (TPA) coreactant. In addition, a new ECL immunosensor based on steric hindrance effect is fabricated by cross-linking alpha-fetoprotein antibody (anti-AFP) with chitosan covered on Ru-PTCA/G composites modified electrode for detection of cancer biomarker AFP. This ECL immunosensor shows an extremely sensitive response to AFP in a linear range of 5 pg.mL(-1) -10 ng.mL(-1) with a detection limit of 0.2 pg.mL(-1) . The present approach is effective for various molecules immobilization and may become a promising technique for biomolecular detection. PMID- 23926126 TI - Novel magnetic SPE method based on carbon nanotubes filled with cobalt ferrite for the analysis of organochlorine pesticides in honey and tea. AB - A novel magnetic SPE method based on magnetic cobalt ferrite filled carbon nanotubes (MFCNTs) coupled with GC with electron capture detection was developed to determine organochlorine pesticides (OCPs) in tea and honey samples. The MFCNTs were prepared through the capillarity of carbon nanotubes for drawing mixed cobalt and iron nitrates solution into their inner cavity followed by heating to 550 degrees C under Ar to form the cobalt ferrite nanoparticles. SEM images provided visible evidence of the filled cobalt ferrite nanoparticles in the multiwalled nanotubes. X-ray photoelectron spectroscopy indicated no adhesion of cobalt ferrite nanoparticles and metal salts on the outer surface of the MFCNTs. Eight OCPs were extracted with the MFCNTs. The enrichment factors were in the range of 52-68 for eight OCPs. The LODs for the eight OCPs were in the range of 1.3-3.6 ng/L. The recoveries of the OCPs for honey and tea samples were 83.2 128.7 and 72.6-111.0%, respectively. The RSDs for these samples were below 6.8%. The new method is particularly suited to extract nonpolar and weakly polar analytes from a complex matrix and could potentially be extended to other target analytes. PMID- 23926127 TI - Determination of midazolam in rabbit plasma by GC and LC following nasal and ocular administration. AB - GC with nitrogen phosphorus detection and HPLC with UV detection were used to determine midazolam (MDZ) levels in rabbit plasma following ocular and nasal administration. For GC with nitrogen phosphorus detection, the analyte was extracted from the plasma using a three-step liquid-liquid extraction including extraction with an isopropanol/butyl chloride mixture in an alkaline solution, followed by extractions with 1 M HCl, and finally with an alkaline solution of butyl chloride. The recovery of MDZ was dependent on the sample alkalization time prior to the final extraction. The procedure increased the recovery of MDZ up to 99.6%. Improved sample preparation led to a significant increase in the sensitivity of the determination by GC with nitrogen phosphorus detection. The achieved detection limit was 0.34 ng/mL, which is ten times lower than that obtained using HPLC with UV detection. The small plasma volume was another advantage of the GC with nitrogen phosphorus detection method (200 MUL per assay). Both administration routes of the anesthetic (nasal and ocular) resulted in comparable plasma MDZ levels. Kinetic simulation of the MDZ plasma was performed for both administration routes. PMID- 23926128 TI - AMP-activated protein kinase mediates myogenin expression and myogenesis via histone deacetylase 5. AB - There is a global epidemic of obesity, and obesity is known to inhibit AMP activated protein kinase (AMPK) activity and impairs myogenesis. Myogenin mediates the fusion of myoblasts into myotubes, a critical step in myogenesis. We observed that inhibition of AMPKalpha1 downregulates myogenin expression and myogenesis, but the underlying mechanisms are unclear. We postulated that AMPK regulates myogenin expression through phosphorlytion of histone deacetylase 5 (HDAC5). In C2C12 cells, HDAC5 knockdown increased while HDAC5 stablization by MC1568 reduced myogenin expression. Consistently, using luciferase assay, we observed that myogenin promoter activity was negatively regulated by HDAC5. Using RNA interference and primary myoblasts prepared from wild-type and AMPKalpha1 knockout mice, we further demonstrate that AMPKalpha1 regulates HDAC5 phosphorylation at Ser 259 and 498. Mutation of these two Ser to Ala in HDAC5 abolished the regulatory role of AMPKalpha1 on myogenin expression, clearly showing the necessity of these phosphorylation sites in mediating myogenin expression. In aggregate, these data show that AMPK inhibition downregulates myogenin transcription and myogenesis through phosphorylation of HDAC5, mediated mainly by AMPKalpha1. These data demonstrate that AMPK is a key molecular target for promoting myogenesis and muscular regeneration. Because drugs activating AMPK activity, such as metformin, are widely available, our finding has critical clinical implications to ensure proper muscle development and regeneration in obese subjects and under other pathophysiological conditions where AMPK activity is attenuated. PMID- 23926129 TI - A naturally occurring truncated Cav1.2 alpha1-subunit inhibits Ca2+ current in A7r5 cells. AB - Alternative splicing of the voltage-gated Ca(2+) (CaV) alpha1-subunit adds to the functional diversity of Ca(2+) channels. A variant with a 73-nt deletion in exon 15 of the Cav1.2 alpha1-subunit (Cav1.2Delta73) produced by alternative splicing that predicts a truncated protein has been described, but its function, if any, is unknown. We sought to determine if, by analogy to other truncated CaV alpha1 subunits, Cav1.2Delta73 acts as an inhibitor of wild-type Cav1.2 currents. HEK 293 cells were transfected with Cav1.2Delta73 in a pIRES vector with CD8 or in pcDNA3.1 with a V5/his COOH-terminal tag plus beta2 and alpha2delta1 accessory subunits and pEGFP. Production of Cav1.2Delta73 protein was confirmed by Western blotting and immunofluorescence. Voltage-clamp studies revealed the absence of functional channels in transfected cells. In contrast, cells transfected with full-length Cav1.2 plus accessory subunits and pEGFP exhibited robust Ca(2+) currents. A7r5 cells exhibited endogenous Cav1.2-based currents that were greatly reduced (>80%) without a change in voltage-dependent activation when transfected with Cav1.2Delta73-IRES-CD8 compared with empty vector or pIRES-CD8 controls. Transfection of A7r5 cells with an analogous Cav2.3Delta73-IRES-CD8 had no effect on Ca(2+) currents. Immunofluorescence showed intracellular, but not plasma membrane, localization of Cav1.2Delta73-V5/his, as well as colocalization with an endoplasmic reticulum marker, ER Organelle Lights. Expression of Cav1.2Delta73 alpha1-subunits in A7r5 cells inhibits endogenous Cav1.2 currents. The fact that this variant arises naturally by alternative splicing raises the possibility that it may represent a physiological mechanism to modulate Cav1.2 functional activity. PMID- 23926130 TI - Cytokine response of primary human myotubes in an in vitro exercise model. AB - Muscle contraction during exercise is a major stimulus for the release of peptides and proteins (myokines) that are supposed to take part in the beneficial adaptation to exercise. We hypothesize that application of an in vitro exercise stimulus as electric pulse stimulation (EPS) to human myotubes enables the investigation of the molecular response to exercise in a clearly defined model. We applied EPS for 24 h to primary human myotubes and studied the whole genome wide transcriptional response as well as the release of candidate myokines. We observed 183 differentially regulated transcripts with fold changes >1.3. The transcriptional response resembles several properties of the in vivo situation in the skeletal muscle after endurance exercise, namely significant enrichment of pathways associated with interleukin and chemokine signaling, lipid metabolism, and antioxidant defense. Multiplex immunoassays verified the translation of the transcriptional response of several cytokines into high-secretion levels (IL-6, IL-8, CXCL1, LIF, CSF3, IL-1B, and TNF) and the increased secretion of further myokines such as angiopoietin-like 4. Notably, EPS did not induce the release of creatine kinase. Inhibitor studies and immunoblotting revealed the participation of ERK1/2-, JNK-, and NF-kappaB-dependent pathways in the upregulation of myokines. To conclude, our data highlight the importance of skeletal muscle cells as endocrine cells. This in vitro exercise model is not only suitable to identify exercise-regulated myokines, but it might be applied to primary human myotubes obtained from different muscle biopsy donors to study the molecular mechanisms of the individual response to exercise. PMID- 23926131 TI - Hypertension in an experimental model of systemic lupus erythematosus occurs independently of the renal nerves. AB - Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder with prevalent hypertension and renal injury. In this study, we tested whether the renal nerves contribute to the development of hypertension in an established mouse model of SLE (NZBWF1). Female SLE and control (NZW/LacJ) mice were subjected to either bilateral renal denervation or a sham procedure at 32 wk of age. Two weeks later, blood pressure was assessed in conscious mice using carotid artery catheters. Blood pressure was higher in SLE mice compared with controls, as previously reported; however, blood pressure was not altered in the denervated SLE or control mice. The development of albuminuria was markedly blunted in denervated SLE mice; however, glomerulosclerosis was increased. Renal denervation reduced renal cortical expression of monocyte-chemoattractant protein in SLE mice but did not significantly alter renal monocyte/macrophage infiltration. Renal cortical TNF-alpha expression was also increased in sham SLE mice, but this was not impacted by denervation. This study suggests that the renal nerves do not have a significant role in the pathogenesis of hypertension, but have a complex effect on the associated renal inflammation and renal injury. PMID- 23926133 TI - Characterization of the development of renal injury in Type-1 diabetic Dahl salt sensitive rats. AB - The present study compared the progression of renal injury in Sprague-Dawley (SD) and Dahl salt-sensitive (SS) treated with streptozotocin (STZ). The rats received an injection of STZ (50 mg/kg ip) and an insulin pellet (2 U/day sc) to maintain the blood glucose levels between 400 and 600 mg/dl. Twelve weeks later, arterial pressure (143 +/- 6 vs. 107 +/- 8 mmHg) and proteinuria (557 +/- 85 vs. 81 +/- 6 mg/day) were significantly elevated in STZ-SS rats compared with the values observed in STZ-SD rats, respectively. The kidneys from STZ-SS rats exhibited thickening of glomerular basement membrane, mesangial expansion, severe glomerulosclerosis, renal interstitial fibrosis, and occasional glomerular nodule formation. In additional studies, treatment with a therapeutic dose of insulin (4 U/day sc) attenuated the development of proteinuria (212 +/- 32 mg/day) and renal injury independent of changes in arterial pressure in STZ-SS rats. Since STZ-SS rats developed severe renal injury, we characterized the time course of changes in renal hemodynamics during the progression of renal injury. Nine weeks after diabetes onset, there was a 42% increase in glomerular filtration rate in STZ-SS rats vs. time-control SS rats with reduced renal blood flow. These results indicate that SS rats treated with STZ develop hyperfiltration and progressive proteinuria and display renal histological lesions characteristic of those seen in patients with diabetic nephropathy. Overall, this model may be useful to study signaling pathways and mechanisms that play a role in the progression of diabetes induced renal disease and the development of new therapies to slow the progression of diabetic nephropathy. PMID- 23926132 TI - Post-oral appetite stimulation by sugars and nonmetabolizable sugar analogs. AB - Post-oral sugar actions enhance the intake of and preference for sugar-rich foods, a process referred to as appetition. Here, we investigated the role of intestinal sodium glucose cotransporters (SGLTs) in sugar appetition in C57BL/6J mice using sugars and nonmetabolizable sugar analogs that differ in their affinity for SGLT1 and SGLT3. In experiments 1 and 2, food-restricted mice were trained (1 h/day) to consume a flavored saccharin solution [conditioned stimulus (CS-)] paired with intragastric (IG) self-infusions of water and a different flavored solution (CS+) paired with infusions of 8 or 12% sugars (glucose, fructose, and galactose) or sugar analogs (alpha-methyl-D-glucopyranoside, MDG; 3 O-methyl-D-glucopyranoside, OMG). Subsequent two-bottle CS+ vs. CS- choice tests were conducted without coinfusions. Infusions of the SGLT1 ligands glucose, galactose, MDG, and OMG stimulated CS+ licking above CS- levels. However, only glucose, MDG, and galactose conditioned significant CS+ preferences, with the SGLT3 ligands (glucose, MDG) producing the strongest preferences. Fructose, which is not a ligand for SGLTs, failed to stimulate CS+ intake or preference. Experiment 3 revealed that IG infusion of MDG+phloridzin (an SGLT1/3 antagonist) blocked MDG appetition, whereas phloridzin had minimal effects on glucose-induced appetition. However, adding phloretin (a GLUT2 antagonist) to the glucose+phloridzin infusion blocked glucose appetition. Taken together, these findings suggest that humoral signals generated by intestinal SGLT1 and SGLT3, and to a lesser degree, GLUT2, mediate post-oral sugar appetition in mice. The MDG results indicate that sugar metabolism is not essential for the post-oral intake-stimulating and preference-conditioning actions of sugars in mice. PMID- 23926134 TI - Neuropeptide W increases mean arterial pressure as a result of behavioral arousal. AB - Neuropeptide W (NPW), an endogenous ligand for G protein-coupled receptors NPBWR1 (GPR7) and NPBWR2 (GPR8), has been detected in neurons in limbic and reticular activating system areas known to be important in arousal, as well as hypothalamic nuclei known to be important in food and water intake and the neuroendocrine response to stress. In rat, central administration of NPW increased mean arterial pressure (MAP) and behaviors associated with locomotion and grooming. We hypothesized that the NPW-induced increase in MAP was secondary to those increases in physical activity. Since peptides that stimulate arousal have been shown to increase sympathetic activity (e.g., orexin), we tested the ability of the mixed alpha1- and alpha2-adrenergic antagonist, phentolamine, to block the NPW-23-induced rise in MAP. Phentolamine pretreatment abrogated the NPW-induced MAP increase. However, we noticed the animals no longer exhibited NPW-associated behavioral arousal when pretreated with phentolamine. Anesthesia also blocked the NPW-induced increase in MAP, although the animals still were able to respond with an increase in MAP to centrally administered ANG II. Additionally, pretreatment with an orexin type 1 receptor antagonist significantly reduced the behavioral action of NPW-23 and completely blocked the peptide's action to increase MAP, suggesting that orexin neurons are downstream targets of NPW. Our results suggest that NPW increased MAP secondary to increased behavioral arousal. PMID- 23926135 TI - Nonuniform, age-related decrements in regional sweating and skin blood flow. AB - Aging is associated with attenuated thermoregulatory function that varies regionally over the body. Decrements in vasodilation and sweating are well documented with age, yet limited data are available concerning the regional relation between these responses. We aimed to examine age-related alterations in the relation between regional sweating (RSR) and skin blood flow (SkBF) to thermal and pharmacological stimuli. Four microdialysis fibers were inserted in the ventral forearm, abdomen, thigh, and lower back of eight healthy aged subjects (64 +/- 7 yr) and nine young (23 +/- 3 yr) during 1) ACh dose response (1 * 10(-7) to 0.1 M, mean skin temperature 34 degrees C) and 2) passive whole body heating to Delta1 degrees C rise in oral temperature (Tor). RSR and SkBF were measured over each microdialysis membrane using ventilated capsules and laser-Doppler flowmetry. Maximal SkBF was measured at the end of both protocols (50 mM SNP). Regional sweating thresholds and RSR were attenuated in aged vs. young at all sites (P < 0.0001) during whole body heating. Vasodilation thresholds were similar between groups (P > 0.05). Attenuated SkBF were observed at the arm and back in the aged, representing 56 and 82% of those in the young at these sites, respectively (0.5 DeltaTor). During ACh perfusion, SkBF (P = 0.137) and RSR were similar between groups (P = 0.326). Together these findings suggest regional age-related decrements in heat-activated sweat gland function but not cholinergic sensitivity. Functional consequences of such thermoregulatory impairment include the compromised ability of older individuals to defend core temperature during heat exposure and a subsequently greater susceptibility to heat-related illness and injury. PMID- 23926136 TI - Cutaneous leishmaniasis "chiclero's ulcer" in subtropical Ecuador. AB - An 18-year-old female presented with a severe ulcerative lesion on her right ear of 6 weeks duration. Her right ear was edematous and erythematous with a large, painless ulcerative lesion covering a third of the pinna and satellite papular lesions on the posterior. She was diagnosed with chiclero's ulcer. A skin smear stained with Diff-quik showed abundant Leishmania parasites. Chiclero's ulcer is a rare clinical presentation and is typically severe and difficult to treat. Physicians in Ecuador recommend administering prolonged intramuscular Glucantime. Side effects are common and can be severe resulting in low patient compliance. Because of preferences of the patient and the large volume needed for her weight, we recommended topical treatment with a lotion of Glucantime mixed half and half with white Merthiolate. After applying this lotion to the lesion 3 to 4 times a day for 6 weeks, the lesion healed. PMID- 23926137 TI - Resurgence of West Nile virus in 2012: lack of evidence for viral genetic determinants. PMID- 23926138 TI - Dogma in classifying dengue disease. PMID- 23926139 TI - Purnomo Projodipuro (April 11, 1934-May 10, 2013). PMID- 23926140 TI - A systematic review of the effectiveness of hospital- and ambulatory-based management of multidrug-resistant tuberculosis. AB - A systematic review of the literature was conducted on the effectiveness of MDR TB management. A meta-analysis of treatment outcomes of patients treated in hospitals versus ambulatory-based models was performed in accordance with PRISMA guidelines. The pooled treatment success rate was 66.4% (95% confidence interval [CI] 61.4-71.1%), with no statistical difference between ambulatory (65.5%; 55.1 74.6%) and hospital-based models (66.7%; 61.0-72.0%). The pooled death rate was 10.4% (6.3-16.5%), the pooled treatment failure rate was 9.5% (7.3-12.4%), and the defaulter rate was 14.3% (10.5-19.1%). None of the differences between the two models were statistically significant for any of the outcomes considered. This work improves the quality of the evidence available supporting the World Health Organizations (WHO) recommendation that patients be treated using mainly ambulatory care, conditional on infection control measures in the home and clinic, clinical condition of the patient, availability of treatment support to facilitate adherence to treatment, and provisions for backup facility to manage patients who need inpatient treatment care. PMID- 23926141 TI - Relapsing fever borreliae in Africa. AB - The study of relapsing fever borreliae in Africa has long suffered from the use of non-specific laboratory tools for the direct detection of these spirochetes in clinical and vector specimens. Accordingly, Borrelia hispanica, Borrelia crocidurae, Borrelia duttonii, and Borrelia recurrentis have traditionally been distinguished on the basis of geography and vector and the unproven hypothesis that each species was exclusive to one vector. The recent sequencing of three relapsing fever Borrelia genomes in our laboratory prompted the development of more specific tools and a reappraisal of the epidemiology in Africa. Five additional potential species still need to be cultured from clinical and vector sources in East Africa to further assess their uniqueness. Here, we review the molecular evidence of relapsing fever borreliae in hosts and ectoparasites in Africa and explore the diversity, geographical distribution, and vector association of these pathogens for Africans and travelers to Africa. PMID- 23926143 TI - Helicobacter pylori infection and anemia. PMID- 23926142 TI - Unresolved problems related to scrub typhus: a seriously neglected life threatening disease. PMID- 23926144 TI - In response. PMID- 23926145 TI - The Pyrexia transient receptor potential channel mediates circadian clock synchronization to low temperature cycles in Drosophila melanogaster. AB - Circadian clocks are endogenous approximately 24 h oscillators that temporally regulate many physiological and behavioural processes. In order to be beneficial for the organism, these clocks must be synchronized with the environmental cycles on a daily basis. Both light : dark and the concomitant daily temperature cycles (TCs) function as Zeitgeber ('time giver') and efficiently entrain circadian clocks. The temperature receptors mediating this synchronization have not been identified. Transient receptor potential (TRP) channels function as thermo receptors in animals, and here we show that the Pyrexia (Pyx) TRP channel mediates temperature synchronization in Drosophila melanogaster. Pyx is expressed in peripheral sensory organs (chordotonal organs), which previously have been implicated in temperature synchronization. Flies deficient for Pyx function fail to synchronize their behaviour to TCs in the lower range (16-20 degrees C), and this deficit can be partially rescued by introducing a wild-type copy of the pyx gene. Synchronization to higher TCs is not affected, demonstrating a specific role for Pyx at lower temperatures. In addition, pyx mutants speed up their clock after being exposed to TCs. Our results identify the first TRP channel involved in temperature synchronization of circadian clocks. PMID- 23926146 TI - Tracking multi-generational colonization of the breeding grounds by monarch butterflies in eastern North America. AB - Insect migration may involve movements over multiple breeding generations at continental scales, resulting in formidable challenges to their conservation and management. Using distribution models generated from citizen scientist occurrence data and stable-carbon and -hydrogen isotope measurements, we tracked multi generational colonization of the breeding grounds of monarch butterflies (Danaus plexippus) in eastern North America. We found that monarch breeding occurrence was best modelled with geographical and climatic variables resulting in an annual breeding distribution of greater than 12 million km(2) that encompassed 99% occurrence probability. Combining occurrence models with stable isotope measurements to estimate natal origin, we show that butterflies which overwintered in Mexico came from a wide breeding distribution, including southern portions of the range. There was a clear northward progression of monarchs over successive generations from May until August when reproductive butterflies began to change direction and moved south. Fifth-generation individuals breeding in Texas in the late summer/autumn tended to originate from northern breeding areas rather than regions further south. Although the Midwest was the most productive area during the breeding season, monarchs that re-colonized the Midwest were produced largely in Texas, suggesting that conserving breeding habitat in the Midwest alone is insufficient to ensure long-term persistence of the monarch butterfly population in eastern North America. PMID- 23926147 TI - Environmental and historical imprints on beta diversity: insights from variation in rates of species turnover along gradients. AB - A common approach for analysing geographical variation in biodiversity involves using linear models to determine the rate at which species similarity declines with geographical or environmental distance and comparing this rate among regions, taxa or communities. Implicit in this approach are weakly justified assumptions that the rate of species turnover remains constant along gradients and that this rate can therefore serve as a means to compare ecological systems. We use generalized dissimilarity modelling, a novel method that accommodates variation in rates of species turnover along gradients and between different gradients, to compare environmental and spatial controls on the floras of two regions with contrasting evolutionary and climatic histories: southwest Australia and northern Europe. We find stronger signals of climate history in the northern European flora and demonstrate that variation in rates of species turnover is persistent across regions, taxa and different gradients. Such variation may represent an important but often overlooked component of biodiversity that complicates comparisons of distance-decay relationships and underscores the importance of using methods that accommodate the curvilinear relationships expected when modelling beta diversity. Determining how rates of species turnover vary along and between gradients is relevant to understanding the sensitivity of ecological systems to environmental change. PMID- 23926148 TI - Unpredicted impacts of insect endosymbionts on interactions between soil organisms, plants and aphids. AB - Ecologically significant symbiotic associations are frequently studied in isolation, but such studies of two-way interactions cannot always predict the responses of organisms in a community setting. To explore this issue, we adopt a community approach to examine the role of plant-microbial and insect-microbial symbioses in modulating a plant-herbivore interaction. Potato plants were grown under glass in controlled conditions and subjected to feeding from the potato aphid Macrosiphum euphorbiae. By comparing plant growth in sterile, uncultivated and cultivated soils and the performance of M. euphorbiae clones with and without the facultative endosymbiont Hamiltonella defensa, we provide evidence for complex indirect interactions between insect- and plant-microbial systems. Plant biomass responded positively to the live soil treatments, on average increasing by 15% relative to sterile soil, while aphid feeding produced shifts (increases in stem biomass and reductions in stolon biomass) in plant resource allocation irrespective of soil treatment. Aphid fecundity also responded to soil treatment with aphids on sterile soil exhibiting higher fecundities than those in the uncultivated treatment. The relative allocation of biomass to roots was reduced in the presence of aphids harbouring H. defensa compared with plants inoculated with H. defensa-free aphids and aphid-free control plants. This study provides evidence for the potential of plant and insect symbionts to shift the dynamics of plant-herbivore interactions. PMID- 23926149 TI - Environmental stability and the evolution of cooperative breeding in hornbills. AB - Reproductive cooperation in social animals has been the focus of intensive research, yet the role of environmental factors in promoting such cooperation remains uncertain. A recent global analysis suggested that cooperative breeding in birds is a 'bet-hedging' strategy associated with climatic uncertainty, but it is unclear whether this mechanism applies generally or is restricted to the insectivorous passerines that predominate as cooperative breeders at the global scale. Here, we use a phylogenetic framework to assess the effect of climate on the evolution of cooperation in hornbills (Bucerotidae), an avian family characterized by frugivory and carnivory. We show that, in contrast to the global pattern, cooperative reproduction is positively associated with both inter- and intra-annual climatic stability. This reversed relationship implies that hornbills are relatively insensitive to climatic fluctuations, perhaps because of their dietary niche or increased body mass, both of which may remove the need for bet-hedging. We conclude that the relationship between climatic variability and cooperative breeding is inconsistent across taxa, and potentially mediated by life-history variation. These findings help to explain the mixed results of previous studies and highlight the likely shortcomings of global datasets inherently biased towards particular categories. PMID- 23926150 TI - Simple life-history traits explain key effective population size ratios across diverse taxa. AB - Effective population size (Ne) controls both the rate of random genetic drift and the effectiveness of selection and migration, but it is difficult to estimate in nature. In particular, for species with overlapping generations, it is easier to estimate the effective number of breeders in one reproductive cycle (Nb) than Ne per generation. We empirically evaluated the relationship between life history and ratios of Ne, Nb and adult census size (N) using a recently developed model (agene) and published vital rates for 63 iteroparous animals and plants. Nb/Ne varied a surprising sixfold across species and, contrary to expectations, Nb was larger than Ne in over half the species. Up to two-thirds of the variance in Nb/Ne and up to half the variance in Ne/N was explained by just two life-history traits (age at maturity and adult lifespan) that have long interested both ecologists and evolutionary biologists. These results provide novel insights into, and demonstrate a close general linkage between, demographic and evolutionary processes across diverse taxa. For the first time, our results also make it possible to interpret rapidly accumulating estimates of Nb in the context of the rich body of evolutionary theory based on Ne per generation. PMID- 23926151 TI - The evolutionary ecology of early weaning in Kilimanjaro, Tanzania. AB - Public health recommendations promote prolonged breastfeeding of all children; however, parental investment (PI) theory predicts that breastfeeding will be allocated among a mothers' offspring to maximize her reproductive success. We evaluated PI in terms of risk for weaning before age two among 283 children in Kilimanjaro, Tanzania. Results demonstrate: (i) a Trivers-Willard effect--high socioeconomic status (SES) females and low SES males were more likely to be weaned early; (ii) later-born children were less likely to be weaned early; (iii) higher birthweight children were less likely to be weaned early, and (iv) no effect of cattle (a source of supplementary milk) ownership. These associations were largely independent and remained significant in models controlling for potential confounders; however, the inverse association between early weaning and birth order lost significance in the model containing birthweight. These patterns were observed despite public health recommendations encouraging breastfeeding for at least two years. PMID- 23926152 TI - Reconsidering the importance of the past in predator-prey models: both numerical and functional responses depend on delayed prey densities. AB - We propose that delayed predator-prey models may provide superficially acceptable predictions for spurious reasons. Through experimentation and modelling, we offer a new approach: using a model experimental predator-prey system (the ciliates Didinium and Paramecium), we determine the influence of past-prey abundance at a fixed delay (approx. one generation) on both functional and numerical responses (i.e. the influence of present : past-prey abundance on ingestion and growth, respectively). We reveal a nonlinear influence of past-prey abundance on both responses, with the two responding differently. Including these responses in a model indicated that delay in the numerical response drives population oscillations, supporting the accepted (but untested) notion that reproduction, not feeding, is highly dependent on the past. We next indicate how delays impact short- and long-term population dynamics. Critically, we show that although superficially the standard (parsimonious) approach to modelling can reasonably fit independently obtained time-series data, it does so by relying on biologically unrealistic parameter values. By contrast, including our fully parametrized delayed density dependence provides a better fit, offering insights into underlying mechanisms. We therefore present a new approach to explore time series data and a revised framework for further theoretical studies. PMID- 23926153 TI - Do naive juvenile seabirds forage differently from adults? AB - Foraging skills of young individuals are assumed to be inferior to those of adults. The reduced efficiency of naive individuals may be the primary cause of the high juvenile mortality and explain the deferment of maturity in long-lived species. However, the study of juvenile and immature foraging behaviour has been limited so far. We used satellite telemetry to compare the foraging movements of juveniles, immatures and breeding adult wandering albatrosses Diomedea exulans, a species where foraging success is positively influenced by the distance covered daily. We showed that juveniles are able to use favourable winds as soon as the first month of independence, but cover shorter distances daily and spend more time sitting on water than adults during the first two months after fledging. These reduced movement capacities do not seem to be the cause of higher juvenile mortality. Moreover, juveniles almost never restrict their movement to specific areas, as adults and immatures frequently do over shelf edges or oceanic zones, which suggest that the location of appropriate areas is learned through experience. Immatures and adults have equivalent movement capacities, but when they are central place foragers, i.e. when adults breed or immatures come to the colony to display and pair, immatures make shorter trips than adults. The long duration of immaturity in this species seems to be related to a long period of learning to integrate the foraging constraints associated with reproduction and central place foraging. Our results indicate that foraging behaviour of young albatrosses is partly innate and partly learned progressively over immaturity. The first months of learning appear critical in terms of survival, whereas the long period of immaturity is necessary for young birds to attain the skills necessary for efficient breeding without fitness costs. PMID- 23926154 TI - From trickle to flood: the large-scale, cryptic invasion of California by tropical fruit flies. AB - Since 1954, when the first tropical tephritid fruit fly was detected in California, a total of 17 species in four genera and 11 386 individuals (adults/larvae) have been detected in the state at more than 3348 locations in 330 cities. We conclude from spatial mapping analyses of historical capture patterns and modelling that, despite the 250+ emergency eradication projects that have been directed against these pests by state and federal agencies, a minimum of five and as many as nine or more tephritid species are established and widespread, including the Mediterranean, Mexican and oriental fruit flies, and possibly the peach, guava and melon fruit flies. We outline and discuss the evidence for our conclusions, with particular attention to the incremental, chronic and insidious nature of the invasion, which involves ultra-small, barely detectable populations. We finish by considering the implications of our results for invasion biology and for science-based invasion policy. PMID- 23926155 TI - Environmental levels of oestrogenic and antiandrogenic compounds feminize digit ratios in male rats and their unexposed male progeny. AB - Digit length ratios, especially the second-to-fourth digit ratio (2D : 4D), are associated with various pathological and behavioural conditions in many species including humans and are dependent upon prenatal androgen to oestrogen balance. It is unknown whether digit ratios are modified by environmental exposure to ubiquitous endocrine disruptors. We studied the effect on adult male Wistar rat digit ratios of a gestational exposure to the oestrogenic and antiandrogenic compounds bisphenol A (BPA), genistein and vinclozolin, in low doses, and in combination with investigating in parallel a possible sexual dimorphism of this trait. We also investigated the effects on the male progeny not exposed during gestation. X-rays were taken of the left and right forepaws, and 2D-5D proximal to distal phalanx distances were measured by a standardized procedure based on semi-automatic image analysis. We provide evidence that there is a sexual dimorphism of digit ratios in the Wistar rat, and we found that BPA alone or in combination with genistein and vinclozolin significantly feminized digit ratios in male rats. Intriguingly, significant feminization of digit ratios was also found in the unexposed male progeny of males that had been exposed to compound mixtures. In conclusion, prenatal environmental levels of endocrine-active substances permanently disrupt digit ratios. Digit ratio measurement in adults is thus a promising biomarker of prenatal exposure to low-dose endocrine disruptors in rodents, with potential implications for future studies in humans. PMID- 23926156 TI - Escalation of aggressive vocal signals: a sequential playback study. AB - Rival conspecifics often produce stereotyped sequences of signals as agonistic interactions escalate. Successive signals in sequence are thought to convey increasingly pronounced levels of aggressive motivation. Here, we propose and test a model of aggressive escalation in black-throated blue warblers, presenting subjects with two sequential and increasingly elevated levels of threat. From a speaker outside the territorial boundary, we initiated an interaction (low-threat level), and from a second speaker inside the territory, accompanied by a taxidermic mount, we subsequently simulated a territorial intrusion (escalated threat level). Our two main predictions were that signalling behaviours in response to low-threat boundary playback would predict signalling responses to the escalated within-territory threat, and that these latter signalling behaviours would in turn reliably predict attack. We find clear support for both predictions: (i) specific song types (type II songs) produced early in the simulated interaction, in response to boundary playback, predicted later use of low-amplitude 'soft' song, in response to within-territory playback; and (ii) soft song, in turn, predicted attack of the mount. Unexpectedly, use of the early stage signal (type II song) itself did not predict attack, despite its apparent role in aggressive escalation. This raises the intriguing question of whether type II song can actually be considered a reliable aggressive signal. Overall, our results provide new empirical insights into how songbirds may use progressive vocal signalling to convey increasing levels of threat. PMID- 23926157 TI - A restatement of the natural science evidence base relevant to the control of bovine tuberculosis in Great Britain. AB - Bovine tuberculosis (bTB) is a very important disease of cattle in Great Britain, where it has been increasing in incidence and geographical distribution. In addition to cattle, it infects other species of domestic and wild animals, in particular the European badger (Meles meles). Policy to control bTB is vigorously debated and contentious because of its implications for the livestock industry and because some policy options involve culling badgers, the most important wildlife reservoir. This paper describes a project to provide a succinct summary of the natural science evidence base relevant to the control of bTB, couched in terms that are as policy-neutral as possible. Each evidence statement is placed into one of four categories describing the nature of the underlying information. The evidence summary forms the appendix to this paper and an annotated bibliography is provided in the electronic supplementary material. PMID- 23926158 TI - Lower hypoxia thresholds of cuttlefish early life stages living in a warm acidified ocean. AB - The combined effects of future ocean acidification and global warming on the hypoxia thresholds of marine biota are, to date, poorly known. Here, we show that the future warming and acidification scenario led to shorter embryonic periods, lower survival rates and the enhancement of premature hatching in the cuttlefish Sepia officinalis. Routine metabolic rates increased during the embryonic period, but environmental hypercapnia significantly depressed pre-hatchling's energy expenditures rates (independently of temperature). During embryogenesis, there was also a significant rise in the carbon dioxide partial pressure in the perivitelline fluid (PVF), bicarbonate levels, as well as a drop in pH and oxygen partial pressure (pO2). The critical partial pressure (i.e. hypoxic threshold) of the pre-hatchlings was significantly higher than the PVF oxygen partial pressure at the warmer and hypercapnic condition. Thus, the record of oxygen tensions below critical pO2 in such climate scenario indicates that the already harsh conditions inside the egg capsules are expected to be magnified in the years to come, especially in populations at the border of their thermal envelope. Such a scenario promotes untimely hatching and smaller post-hatching body sizes, thus challenging the survival and fitness of early life stages. PMID- 23926159 TI - Aberrant Classopollis pollen reveals evidence for unreduced (2n) pollen in the conifer family Cheirolepidiaceae during the Triassic-Jurassic transition. AB - Polyploidy (or whole-genome doubling) is a key mechanism for plant speciation leading to new evolutionary lineages. Several lines of evidence show that most species among flowering plants had polyploidy ancestry, but it is virtually unknown for conifers. Here, we study variability in pollen tetrad morphology and the size of the conifer pollen type Classopollis extracted from sediments of the Triassic-Jurassic transition, 200 Ma. Classopollis producing Cheirolepidiaceae were one of the most dominant and diverse groups of conifers during the Mesozoic. We show that aberrant pollen Classopollis tetrads, triads and dyads, and the large variation in pollen size indicates the presence of unreduced (2n) pollen, which is one of the main mechanisms in modern polyploid formation. Polyploid speciation may explain the high variability of growth forms and adaptation of these conifers to different environments and their resistance to extreme growth conditions. We suggest that polyploidy may have also reduced the extinction risk of these conifers during the End-Triassic biotic crisis. PMID- 23926160 TI - Decades-long social memory in bottlenose dolphins. AB - Long-term social memory is important, because it is an ecologically relevant test of cognitive capacity, it helps us understand which social relationships are remembered and it relates two seemingly disparate disciplines: cognition and sociality. For dolphins, long-term memory for conspecifics could help assess social threats as well as potential social or hunting alliances in a very fluid and complex fission-fusion social system, yet we have no idea how long dolphins can remember each other. Through a playback study conducted within a multi institution dolphin breeding consortium (where animals are moved between different facilities), recognition of unfamiliar versus familiar signature whistles of former tank mates was assessed. This research shows that dolphins have the potential for lifelong memory for each other regardless of relatedness, sex or duration of association. This is, to my knowledge, the first study to show that social recognition can last for at least 20 years in a non-human species and the first large-scale study to address long-term memory in a cetacean. These results, paired with evidence from elephants and humans, provide suggestive evidence that sociality and cognition could be related, as a good memory is necessary in a fluid social system. PMID- 23926161 TI - Longitudinal lactate levels from routine point-of-care monitoring in adult Malawian antiretroviral therapy patients: associations with stavudine toxicities. AB - INTRODUCTION: Stavudine is still widely used in under-resourced settings such as Malawi due to its low price. It frequently causes peripheral neuropathy and lipodystrophy and increases the risk of lactic acidosis and other high lactate syndromes. METHODS: We studied the association of longitudinal lactate levels, obtained by routine, 3-monthly point-of-care monitoring, with peripheral neuropathy, lipodystrophy and high lactate syndromes in adult Malawians who were in the second year of stavudine containing antiretroviral therapy (ART). RESULTS: Point-of-care lactate measurements were feasible in a busy urban ART clinic. Of 1170 lactate levels collected from 253 patients over the course of one year, 487 (41.8%) were elevated (>2.2mg/dl), 58 (5.0%) were highly elevated (>3.5mg/dl). At least one elevated lactate level occurred in 210 (83.0%) of patients and sustained hyperlactatemia in 65 (26.4%). In random effects analyses lipodystrophy and peripheral neuropathy were associated with higher lactate levels. Only five patients developed high lactate syndromes (one lactic acidosis) of whom no preceding lactate measurements were available because events had started before enrolment. Lactate levels significantly decreased over time and no high lactate syndromes were observed after the 15th month on ART. CONCLUSION: Lipodystrophy and peripheral neuropathy were associated with higher lactate levels. Lactate levels decreased over time, coinciding with absence of new high lactate syndromes after the 15th month on ART. PMID- 23926162 TI - Comparison of perirectal versus rectal swabs for detection of asymptomatic carriers of toxigenic Clostridium difficile. AB - For long-term care and spinal cord injury patients, the sensitivity, specificity, and positive and negative predictive values of perirectal versus rectal cultures for detection of asymptomatic carriers of Clostridium difficile were 95%, 100%, 100%, and 97%, respectively. Perirectal cultures provide an accurate method to detect asymptomatic carriers of C. difficile. PMID- 23926163 TI - A case of mild pulmonary disease due to Mycobacterium shimoidei with a favorable outcome. AB - We describe a case of mild Mycobacterium shimoidei disease with a favorable course after treatment. Characteristics of nine M. shimoidei isolates in Italy between 1989 and 2009 were also reviewed. The M. shimoidei genome was highly conserved. Based on antimicrobial susceptibility, the combination of ethambutol, clarithromycin, and rifabutin appears to be a reasonable treatment. PMID- 23926165 TI - Antimicrobial stewardship programs. AB - The development of antimicrobial agents represents one of the most significant achievements in medicine during the past century. However, the emergence of antimicrobial resistance combined with the downturn in the development of new antimicrobial agents in the pharmaceutical industry poses unanticipated challenges in the effective management of infection. The issue of how we can most effectively utilize these invaluable resources, antimicrobials, in the face of infections that are ever more difficult to treat arises. This issue serves as the fundamental basis for the concept of antimicrobial stewardship, the topic of this minireview. PMID- 23926164 TI - Four main virotypes among extended-spectrum-beta-lactamase-producing isolates of Escherichia coli O25b:H4-B2-ST131: bacterial, epidemiological, and clinical characteristics. AB - A total of 1,021 extended-spectrum-beta-lactamase-producing Escherichia coli (ESBLEC) isolates obtained in 2006 during a Spanish national survey conducted in 44 hospitals were analyzed for the presence of the O25b:H4-B2-ST131 (sequence type 131) clonal group. Overall, 195 (19%) O25b-ST131 isolates were detected, with prevalence rates ranging from 0% to 52% per hospital. Molecular characterization of 130 representative O25b-ST131 isolates showed that 96 (74%) were positive for CTX-M-15, 15 (12%) for CTX-M-14, 9 (7%) for SHV-12, 6 (5%) for CTX-M-9, 5 (4%) for CTX-M-32, and 1 (0.7%) each for CTX-M-3 and the new ESBL enzyme CTX-M-103. The 130 O25b-ST131 isolates exhibited relatively high virulence scores (mean, 14.4 virulence genes). Although the virulence profiles of the O25b ST131 isolates were fairly homogeneous, they could be classified into four main virotypes based on the presence or absence of four distinctive virulence genes: virotypes A (22%) (afa FM955459 positive, iroN negative, ibeA negative, sat positive or negative), B (31%) (afa FM955459 negative, iroN positive, ibeA negative, sat positive or negative), C (32%) (afa FM955459 negative, iroN negative, ibeA negative, sat positive), and D (13%) (afa FM955459 negative, iroN positive or negative, ibeA positive, sat positive or negative). The four virotypes were also identified in other countries, with virotype C being overrepresented internationally. Correspondingly, an analysis of XbaI macrorestriction profiles revealed four major clusters, which were largely virotype specific. Certain epidemiological and clinical features corresponded with the virotype. Statistically significant virotype-specific associations included, for virotype B, older age and a lower frequency of infection (versus colonization), for virotype C, a higher frequency of infection, and for virotype D, younger age and community-acquired infections. In isolates of the O25b:H4-B2 ST131 clonal group, these findings uniquely define four main virotypes, which are internationally distributed, correspond with pulsed-field gel electrophoresis (PFGE) profiles, and exhibit distinctive clinical-epidemiological associations. PMID- 23926166 TI - Multiple broad-spectrum Beta-lactamase targets for comprehensive surveillance. AB - Real-time PCR testing for blaKPC, blaNDM, blaVIM, blaIMP, and blaCTX-M was performed on rectal swabs obtained from residents of two long-term acute-care facilities. While blaKPC was detected in 69/102 swabs (67.6%), testing for four other targets increased the positivity rate for a broad-spectrum beta-lactamase to 73.5% (McNemar's P = 0.03). PMID- 23926167 TI - Long-term carriage of vancomycin-resistant enterococci in patients discharged from hospitals: a 12-year retrospective cohort study. AB - Contact precautions are recommended in hospitals to prevent the transmission of vancomycin-resistant enterococci (VRE); however, there is no clear policy for how long patients should be under contact precautions due to a lack of information on the duration of carriage of these organisms. We conducted a retrospective cohort study to understand the duration of carriage of VRE (by screening of a single stool culture) and associated factors among patients who had been identified with VRE infection and/or colonization since the year 2000 at our health facilities. Of the 345 eligible participants, 136 did not respond, 90 declined to participate, and 16 did not send in the required specimens. Of the 103 remaining participants, 13 were found to have current VRE fecal carriage. The proportion of colonized patients fell from 40% (2/5) in the first year to 23.3% (7/30) in year 4. None of the 40 patients who had VRE detected >4 years prior were found to be colonized at the time of the study. The longest duration of detected VRE positivity was 46.5 months. Univariate analysis revealed that recent exposure to any antibiotics (P = 0.016), multiple antibiotics (P = 0.001), amoxicillin clavulanic acid (P = 0.021), piperacillin-tazobactam (P = 0.007), glycopeptides (P < 0.001), meropenem (P = 0.007), aminoglycosides (P = 0.021), or fluoroquinolones (P = 0.021), being the index case in a clinical specimen (P = 0.016), and recent hospitalization (P < 0.001) were significantly associated with continued carriage on follow-up. In the surviving outpatients, a significant proportion appeared to clear VRE carriage. Our results suggest that in the absence of recent risk factors, such as hospitalization or antibiotic use, patients with a remote history of colonization (>4 years) may no longer require contact isolation precautions. PMID- 23926168 TI - Molecular characterization of reptile pathogens currently known as members of the chrysosporium anamorph of Nannizziopsis vriesii complex and relationship with some human-associated isolates. AB - In recent years, the Chrysosporium anamorph of Nannizziopsis vriesii (CANV), Chrysosporium guarroi, Chrysosporium ophiodiicola, and Chrysosporium species have been reported as the causes of dermal or deep lesions in reptiles. These infections are contagious and often fatal and affect both captive and wild animals. Forty-nine CANV isolates from reptiles and six isolates from human sources were compared with N. vriesii based on their cultural characteristics and DNA sequence data. Analyses of the sequences of the internal transcribed spacer and small subunit of the nuclear ribosomal gene revealed that the reptile pathogens and human isolates belong in well-supported clades corresponding to three lineages that are distinct from all other taxa within the family Onygenaceae of the order Onygenales. One lineage represents the genus Nannizziopsis and comprises N. vriesii, N. guarroi, and six additional species encompassing isolates from chameleons and geckos, crocodiles, agamid and iguanid lizards, and humans. Two other lineages comprise the genus Ophidiomyces, with the species Ophidiomyces ophiodiicola occurring only in snakes, and Paranannizziopsis gen. nov., with three new species infecting squamates and tuataras. The newly described species are Nannizziopsis dermatitidis, Nannizziopsis crocodili, Nannizziopsis barbata, Nannizziopsis infrequens, Nannizziopsis hominis, Nannizziopsis obscura, Paranannizziopsis australasiensis, Paranannizziopsis californiensis, and Paranannizziopsis crustacea. Chrysosporium longisporum has been reclassified as Paranannizziopsis longispora. N. guarroi causes yellow fungus disease, a common infection in bearded dragons and green iguanas, and O. ophiodiicola is an emerging pathogen of captive and wild snakes. Human-associated species were not recovered from reptiles, and reptile-associated species were recovered only from reptiles, thereby mitigating concerns related to zoonosis. PMID- 23926169 TI - Bacterial floras and biofilms of malignant wounds associated with breast cancers. AB - The risk of infections and the appearance of symptoms (e.g., odors) represent the main troubles resulting from malignant wounds. The aim of this study was to characterize the balance of bacterial floras and the relationships between biofilms and bacteria and the emergence of symptoms. Experimental research was carried out for 42 days on malignant wounds associated with breast cancer. Investigations of bacterial floras (aerobes, aero-anaerobes, and anaerobes), detection of the presence of biofilms by microscopic epifluorescence, and clinical assessment were performed. We characterized biofilms in 32 malignant wounds associated with breast cancer and bacterial floras in 25 such wounds. A mixed group of floras, composed of 54 different bacterial types, was identified, with an average number per patient of 3.6 aerobic species and 1.7 anaerobic species; the presence of strict anaerobic bacterial strains was evidenced in 70% of the wounds; biofilm was observed in 35% of the cases. Odor was a reliable indicator of colonization by anaerobes, even when this symptom was not directly linked to any of the identified anaerobic bacteria. Bacteria are more likely to be present during myelosuppression and significantly increase the emergence of odors and pain when present at amounts of >10(5) . g(-1). The presence of biofilms was not associated with clinical signs or with precise types of bacteria. No infections occurred during the 42-day evaluation period. This study provides a dynamic description of the bacterial floras of tumoral wounds. The study results highlight the absolute need for new therapeutic options that are effective for use on circulating bacteria as well as on bacteria organized in biofilm. PMID- 23926171 TI - Evaluating the reproductive performance of British beef and dairy herds using national cattle movement records. AB - National cattle movement databases provide a valuable opportunity to monitor the reproductive performance of breeding cattle on an industry-wide scale. In this analysis, records from the Cattle Tracing System database were used to derive key measures of reproductive efficiency for British beef and dairy herds, including calving spread, age at first calving, calving interval, culling rate and calf mortality rate. At the animal level, only 8.5 per cent of beef heifers and 6.9 per cent of dairy heifers calved by the target age of 24 months. The average calving interval was 394 days for beef dams (median: 371) and 426 days for dairy dams (median: 400). Differences in performance were noted between cattle breeds. An estimated 43.9 per cent calves born in dairy herds were crossbreed beef animals, which may limit the availability of replacement dairy heifers. At the herd level, calving spread and calf mortality rates increased with herd size, while average age at first calving, calving interval, and crossbreeding generally decreased with herd size. Dam age, calving month, breed and twinning were significant risk factors for culling and calf mortality at the animal level. Wide variation in performance between individual herds highlights the potential for improving the efficiency of British cattle production. PMID- 23926170 TI - Neural bases of antisocial behavior: a voxel-based meta-analysis. AB - Individuals with antisocial behavior place a great physical and economic burden on society. Deficits in emotional processing have been recognized as a fundamental cause of antisocial behavior. Emerging evidence also highlights a significant contribution of attention allocation deficits to such behavior. A comprehensive literature search identified 12 studies that were eligible for inclusion in the meta-analysis, which compared 291 individuals with antisocial problems and 247 controls. Signed Differential Mapping revealed that compared with controls, gray matter volume (GMV) in subjects with antisocial behavior was reduced in the right lentiform nucleus (P < 0.0001), left insula (P = 0.0002) and left frontopolar cortex (FPC) (P = 0.0006), and was increased in the right fusiform gyrus (P < 0.0001), right inferior parietal lobule (P = 0.0003), right superior parietal lobule (P = 0.0004), right cingulate gyrus (P = 0.0004) and the right postcentral gyrus (P = 0.0004). Given the well-known contributions of limbic and paralimbic areas to emotional processing, the observed reductions in GMV in these regions might represent neural correlates of disturbance in emotional processing underlying antisocial behavior. Previous studies have suggested an FPC role in attention allocation during emotional processing. Therefore, GMV deviations in this area may constitute a neural basis of deficits in attention allocation linked with antisocial behavior. PMID- 23926172 TI - Tuberculin sensitivity testing and treatment of latent tuberculosis remains effective for tuberculosis control in human immunodeficiency virus-infected patients in Hong Kong. AB - OBJECTIVE: To evaluate whether a policy to treat latent tuberculosis identified by annual tuberculin sensitivity testing is effective for tuberculosis control in human immunodeficiency virus-infected patients in Hong Kong. DESIGN: Historical cohort study. SETTING: Integrated Treatment Centre, Department of Health, Hong Kong. PATIENTS: Patients infected with human immunodeficiency virus without a history of tuberculosis were offered annual tuberculin sensitivity testing, coupled with treatment of latent tuberculosis if they tested positive. All such patients were followed for new tuberculosis. RESULTS: In all, 1154 patients on antiretroviral therapy, contributing to 5587 patient-years of observation, were analysed; 1032 patients (89%) received annual tuberculin sensitivity testing. Their baseline characteristics, including CD4 counts and other risk factors for tuberculosis, did not differ significantly from those who declined testing. The overall incidence rate of tuberculosis was 0.59 case per 100 patient-years. It was lower in those who received annual tuberculin sensitivity testing than those who did not (0.41 vs 3.85 per 100 patient-years; P<0.0001). Only a low baseline CD4 count and a history of tuberculin sensitivity testing were shown to be significant indicators of incident tuberculosis using multivariate analysis. The hazard ratio was 0.36 (95% confidence interval, 0.16-0.85; P=0.02) for those with a baseline CD4 count of 100/mm3 or above, and 0.26 (95% confidence interval, 0.08 0.77; P=0.016) for those who received annual tuberculin sensitivity testing. The incidence of tuberculosis was highest within 90 days of antiretroviral therapy initiation. CONCLUSION: The established policy continues to be effective. The high risk of tuberculosis during the early period of antiretroviral therapy supports early use of tuberculin sensitivity testing. Alternatively, the strategy of universal isoniazid preventive therapy at antiretroviral therapy initiation could be studied for those with very low baseline CD4 counts. PMID- 23926173 TI - Treatment outcomes after early initiation of antiretroviral therapy for human immunodeficiency virus-associated tuberculosis. AB - OBJECTIVE: To evaluate the optimal timing for initiating antiretroviral therapy in patients with human immunodeficiency virus (HIV)-associated tuberculosis in Hong Kong. DESIGN: Historical cohort. SETTING. Tuberculosis and Chest Service and Special Preventive Programme, Public Health Service Branch, Centre for Health Protection, Department of Health, Hong Kong. PATIENTS: Consecutive patients with HIV-associated tuberculosis in a territory-wide TB-HIV registry encountered from 1996 to 2009. RESULTS: Of the 260 antiretroviral therapy-naive patients with HIV associated tuberculosis, 32 (12%) had antiretroviral therapy initiated within 2 months after starting anti-tuberculosis treatment (early antiretroviral therapy). Early antiretroviral therapy was associated with a more favourable outcome (cure or treatment completion without relapse) at 24 months (91% vs 67%; P=0.007) than those with antiretroviral therapy started later or not initiated, and remained an independent predictor of a favourable outcome after adjustment for potential confounders. Adverse effects from anti-tuberculosis drugs tended to occur more frequently in patients with early antiretroviral therapy (13/32 or 41%) compared with the remainder (59/228 or 26%; P=0.08). A significantly higher proportion of patients in the former group experienced immune reconstitution inflammatory syndrome than in the latter group (7/32 or 22% vs 9/228 or 4%; P<0.001). There was no death attributable to immune reconstitution inflammatory syndrome. CONCLUSIONS: Early initiation of antiretroviral therapy is associated with more favourable tuberculosis treatment outcomes in patients with HIV-associated tuberculosis with a low CD4 count (<200/uL). Drug co-toxicity and immune reconstitution inflammatory syndrome that may be increased by earlier initiation of antiretroviral therapy does not undermine tuberculosis treatment outcomes to a significant extent. PMID- 23926174 TI - Age, tumour stage, and preoperative serum albumin level are independent predictors of mortality after radical cystectomy for treatment of bladder cancer in Hong Kong Chinese. AB - OBJECTIVES: To evaluate the association between patient age, other clinical factors and mortality following radical cystectomy for treatment of bladder cancer. DESIGN: Historical cohort study. SETTING: A urology unit in Hong Kong. PATIENTS: The outcomes of 117 patients who had radical cystectomies performed in one urological unit from 2003 to 2011 were reviewed. Demographic and perioperative data, including tumour stage, Charlson Comorbidity Index, and preoperative serum albumin levels were retrieved from computerised medical records. Risk factors for 30-day mortality, and cancer-specific, other-cause, and overall death rates at 5 years were calculated. The data were subsequently stratified and analysed according to age. RESULTS: Of the 117 patients, 83 (71%) were aged 75 years or below. The mean follow-up duration was 31 (standard deviation, 29) months. Age, tumour stage, and preoperative serum albumin level, but not the Charlson Comorbidity Index, were found to be predictors of survival following radical cystectomy. The overall 30-day mortality rate was 3% in the full sample, 1% in patients aged 75 years or below, and 10% in patients aged over 75 years. There was no significant difference in 5-year cancer-caused mortalities between patients aged 75 years or below and those aged over 75 years (33% vs 33%, P=0.956). In patients older than 75 years, the 5-year other-cause and overall mortality rates were 47% and 80%, respectively; such rates were higher than those for younger patients (13% and 46%, respectively). CONCLUSION: Age, tumour stage, and preoperative serum albumin level were predictors of survival after radical cystectomy. Non-cancer-related death played a crucial role in the overall mortality rate in elderly patients having radical cystectomy for bladder cancer. PMID- 23926175 TI - Reply to Sheng et al. PMID- 23926177 TI - Editorial commentary: flying under the radar: the stealth pandemic of Escherichia coli sequence type 131. PMID- 23926176 TI - Escherichia coli sequence type 131 (ST131) subclone H30 as an emergent multidrug resistant pathogen among US veterans. AB - BACKGROUND: Escherichia coli sequence type 131 (ST131), typically fluoroquinolone resistant (FQ-R) and/or extended-spectrum beta-lactamase (ESBL)-producing, has emerged globally. We assessed its prevalence and characteristics among US veterans. METHODS: In 2011, 595 de-identified E. coli clinical isolates were collected systematically within 3 resistance groups (FQ-susceptible [FQ-S], FQ-R, and ESBL-producing) from 24 nationally distributed Veterans Affairs Medical Centers (VAMCs). ST131 and its H30 subclone were detected by polymerase chain reaction and compared with other E. coli for molecular traits, source, and resistance profiles. RESULTS: ST131 accounted for 78% (184/236) of FQ-R and 64.2% (79/123) of ESBL-producing isolates, but only 7.2% (17/236) of FQ-S isolates (P < .001). The H30 subclone accounted for >=95% of FQ-R and ESBL-producing, but only 12.5% of FQ-S, ST131 isolates (P < .001). By back-calculation, 28% of VAMC E. coli isolates nationally represented ST131. Overall, ST131 varied minimally in prevalence by specimen type, inpatient/outpatient source, or locale; was the most prevalent ST, followed distantly by ST95 and ST12 (13% each); and accounted for >=40% (beta-lactams), >50% (trimethoprim-sulfamethoxazole , multidrug), or >70% (ciprofloxacin, gentamicin) of total antimicrobial resistance. FQ-R and ESBL producing ST131 isolates had higher virulence scores than corresponding non-ST131 isolates. ST131 pulsotypes overlapped extensively among VAMCs. CONCLUSIONS: Among US veterans, ST131, primarily its H30 subclone, accounts for most antimicrobial resistant E. coli and is the dominant E. coli strain overall. Possible contributors include multidrug resistance, extensive virulence gene content, and ongoing transmission. Focused attention to ST131, especially its H30 subclone, could reduce infection-related morbidity, mortality, and costs among veterans. PMID- 23926178 TI - Prophylactic effect of lamivudine-based antiretroviral therapy on incident hepatitis B virus infection among HIV-infected patients. PMID- 23926179 TI - Vitamin D increases plasma renin activity independently of plasma Ca2+ via hypovolemia and beta-adrenergic activity. AB - 1, 25-Dihydroxycholechalciferol (calcitriol) and 19-nor-1, 25-dihydroxyvitamin D2 (paricalcitol) are vitamin D receptor (VDR) agonists. Previous data suggest VDR agonists may actually increase renin-angiotensin activity, and this has always been assumed to be mediated by hypercalcemia. We hypothesized that calcitriol and paricalcitol would increase plasma renin activity (PRA) independently of plasma Ca(2+) via hypercalciuria-mediated polyuria, hypovolemia, and subsequent increased beta-adrenergic sympathetic activity. We found that both calcitriol and paricalcitol increased PRA threefold (P < 0.01). Calcitriol caused hypercalcemia, but paricalcitol did not. Both calcitriol and paricalcitol caused hypercalciuria (9- and 7-fold vs. control, P < 0.01) and polyuria (increasing 2.6- and 2.2-fold vs. control, P < 0.01). Paricalcitol increased renal calcium-sensing receptor (CaSR) expression, suggesting a potential cause of paricalcitol-mediated hypercalciuria and polyuria. Volume replacement completely normalized calcitriol stimulated PRA and lowered plasma epinephrine by 43% (P < 0.05). beta-Adrenergic blockade also normalized calcitriol-stimulated PRA. Cyclooxygenase-2 inhibition had no effect on calcitriol-stimulated PRA. Our data demonstrate that vitamin D increases PRA independently of plasma Ca(2+) via hypercalciuria, polyuria, hypovolemia, and increased beta-adrenergic activity. PMID- 23926180 TI - Protective role of the endothelial isoform of nitric oxide synthase in ANG II induced inflammatory responses in the kidney. AB - In the present study, we examine the hypothesis that the nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays a protective role in the development of ANG II-induced hypertension and renal injury by minimizing oxidative stress and the inflammation induced by TNF-alpha. Systolic blood pressure (SBP) and renal injury responses to chronic infusions of ANG II (via implanted minipumps) were evaluated for 2 wk in wild-type (WT) and in eNOS knockout mice (KO) cotreated with or without a superoxide (O2(-)) scavenger, tempol (400 mg/l in the drinking water), or a TNF-alpha receptor blocker, etanercept (5 mg/kg/day ip). In study 1, when ANG II was given at a dose of 25 ng/min, it increased mean SBP in WT mice (Delta36 +/- 3 mmHg; n = 7), and this effect was attenuated in mice pretreated with tempol (Delta24 +/- 3 mmHg; n = 6). In KO mice (n = 9), this dose of ANG II resulted in severe renal injury associated with high mortality. To avoid this high mortality in KO, study 2 was conducted with a lower dose of ANG II (10 ng/min) that increased SBP slightly in WT (Delta17 +/- 7 mmHg; n = 6) but exaggeratedly in KO (Delta48 +/- 12 mmHg, n = 6) associated with severe renal injury. Cotreatment with either tempol (n = 6) or etanercept (n = 6) ameliorated the hypertensive, as well as the renal injury responses in KO compared with WT. These data demonstrate a protective role for eNOS activity in preventing renal inflammatory injury and hypertension induced by chronic increases in ANG II. PMID- 23926182 TI - The direct renin inhibitor aliskiren localizes and persists in rat kidneys. AB - The aims of this study were to 1) determine whether renal localization of aliskiren and its antihypertensive and renoprotective effects persist after administration of the drug is stopped and 2) define the renal localization of aliskiren by light microscopy autoradiography. Hypertensive double transgenic rats (dTGR) overexpressing genes for human renin and angiotensinogen were treated with aliskiren (3 mg.kg(-1).day(-1) sc; osmotic minipumps) or enalapril (18 mg/l in drinking water). After a 2-wk treatment, dTGR were assigned to either continued treatment with aliskiren ("continued"), or to cessation of their respective treatment ("stopped") for a 3-wk washout. One week of treatment with aliskiren and enalapril reduced blood pressure and albuminuria vs. baseline. After cessation of either treatment, blood pressure had returned to pretreatment levels and albuminuria remained relatively low for 1 wk, but rose thereafter similarly in both groups. In contrast, renal mRNA for transforming growth factor beta and renal collagen IV was reduced by aliskiren (continued and stopped groups), but not after cessation of enalapril. Similar patterns were found for collagen IV protein expression. Even 3 wk after stopping aliskiren treatment, renal levels of the drug exceeded its IC50, whereas enalaprilat was not detected. To localize aliskiren accumulation, Wistar rats were treated with [(3)H] aliskiren for 7 days. Autoradiography demonstrated specific labeling in glomeruli, arterioles, and afferent arterioles as well as in the distal nephron. Labeling could still be observed even after 7 days' washout. These results suggest that the renophilic properties of aliskiren are different from enalapril and could have contributed to the renoprotective mechanism of this renin inhibitor. PMID- 23926181 TI - Aldosterone reprograms promoter methylation to regulate alphaENaC transcription in the collecting duct. AB - Aldosterone increases tubular Na(+) absorption largely by increasing alpha epithelial Na(+) channel (alphaENaC) transcription in collecting duct principal cells. How aldosterone reprograms basal alphaENaC transcription to high-level activity in the collecting duct is incompletely understood. Promoter methylation, a covalent but reversible epigenetic process, has been implicated in the control of gene expression in health and disease. We investigated the role of promoter methylation/demethylation in the epigenetic control of basal and aldosterone stimulated alphaENaC transcription in mIMCD3 collecting duct cells. Bisulfite treatment and sequencing analysis after treatment of the cells with the DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (5-Aza-CdR) identified clusters of methylated cytosines in a CpG island near the transcription start site of the alphaENaC promoter. 5-Aza-CdR treatment or small interfering RNA mediated knockdown of DNMT3b or methyl-CpG-binding domain protein (MBD)-4 derepressed basal alphaENaC transcription, indicating that promoter methylation suppresses basal alphaENaC transcription. Aldosterone triggered a time-dependent decrease in 5mC and DNMT3b and a concurrent enrichment in 5-hydroxymethylcytosine (5hmC) and ten-eleven translocation (Tet)2 at the alphaENaC promoter, consistent with active demethylation. 5-Aza-CdR mimicked aldosterone by enhancing Sp1 binding to the alphaENaC promoter. We conclude that DNMT3b- and MBD4-dependent methylation of the alphaENaC promoter limits basal alphaENaC transcription, in part by limiting Sp1 binding and trans-activation. Aldosterone stimulates the dispersal of DNMT3b and recruitment of Tet2 to demethylate the alphaENaC promoter to induce alphaENaC transcription. These results disclose a novel epigenetic mechanism for the control of basal and aldosterone-induced alphaENaC transcription that adds to previously described epigenetic controls exerted by histone modifications. PMID- 23926183 TI - Expression and function of transforming growth factor-beta isoforms and cognate receptors in the rat urinary bladder following cyclophosphamide-induced cystitis. AB - Numerous proinflammatory cytokines have been implicated in the reorganization of lower urinary tract function following cyclophosphamide (CYP)-induced cystitis. The present study investigated the functional profile of three pleiotropic transforming growth factor-beta (TGF-beta) isoforms and receptor (TbetaR) variants in the normal and inflamed (CYP-induced cystitis) rat urinary bladder. Our findings indicate that TGF-beta (1, 2, and 3) and TbetaR (1, 2, and 3) transcript and protein expression were regulated to varying degrees in the urothelium or detrusor smooth muscle following intermediate (48 h; 150 mg/kg ip) or chronic (75 mg/kg ip; once every 3 days for 10 days), but not acute (4 h; 150 mg/kg ip), CYP-induced cystitis. Conscious, open-outlet cystometry was performed to determine whether aberrant TGF-beta signaling contributes to urinary bladder dysfunction following intermediate (48 h) CYP-induced cystitis. TbetaR-1 inhibition with SB505124 (5 MUM) significantly (p <= 0.001) decreased voiding frequency and increased bladder capacity (2.5-fold), void volume (2.6-fold), and intercontraction intervals (2.5-fold) in CYP-treated (48 h) rats. Taken together, these results provide evidence for 1) the involvement of TGF-beta in lower urinary tract neuroplasticity following urinary bladder inflammation, 2) a functional role of TGF-beta signaling in the afferent limb of the micturition reflex, and 3) urinary bladder TbetaR-1 as a viable target to reduce voiding frequency with cystitis. PMID- 23926184 TI - 1,25(OH)2D3-enhanced hypercalciuria in genetic hypercalciuric stone-forming rats fed a low-calcium diet. AB - The inbred genetic hypercalciuric stone-forming (GHS) rats exhibit many features of human idiopathic hypercalciuria and have elevated levels of vitamin D receptors (VDR) in calcium (Ca)-transporting organs. On a normal-Ca diet, 1,25(OH)2D3 (1,25D) increases urine (U) Ca to a greater extent in GHS than in controls [Sprague-Dawley (SD)]. The additional UCa may result from an increase in intestinal Ca absorption and/or bone resorption. To determine the source, we asked whether 1,25D would increase UCa in GHS fed a low-Ca (0.02%) diet (LCD). With 1,25D, UCa in SD increased from 1.2 +/- 0.1 to 9.3 +/- 0.9 mg/day and increased more in GHS from 4.7 +/- 0.3 to 21.5 +/- 0.9 mg/day (P < 0.001). In GHS rats on LCD with or without 1,25D, UCa far exceeded daily Ca intake (2.6 mg/day). While the greater excess in UCa in GHS rats must be derived from bone mineral, there may also be a 1,25D-mediated decrease in renal tubular Ca reabsorption. RNA expression of the components of renal Ca transport indicated that 1,25D administration results in a suppression of klotho, an activator of the renal Ca reabsorption channel TRPV5, in both SD and GHS rats. This fall in klotho would decrease tubular reabsorption of the 1,25D-induced bone Ca release. Thus, the greater increase in UCa with 1,25D in GHS fed LCD strongly suggests that the additional UCa results from an increase in bone resorption, likely due to the increased number of VDR in the GHS rat bone cells, with a possible component of decreased renal tubular calcium reabsorption. PMID- 23926185 TI - Complement 3 activates the renal renin-angiotensin system by induction of epithelial-to-mesenchymal transition of the nephrotubulus in mice. AB - We have demonstrated that mesenchymal cells from spontaneously hypertensive rats genetically express complement 3 (C3). Mature tubular epithelial cells can undergo epithelial-to-mesenchymal transition (EMT) that is linked to the pathogenesis of renal fibrosis and injury. In this study, we investigated the contribution of C3 in EMT and in the renal renin-angiotensin (RA) systems associated with hypertension. C3a induced EMT in mouse TCMK-1 epithelial cells, which displayed increased expression of renin and Kruppel-like factor 5 (KLF5) and nuclear localization of liver X receptor alpha (LXRalpha). C3 and renin were strongly stained in the degenerated nephrotubulus and colocalized with LXRalpha and prorenin receptor in unilateral ureteral obstruction (UUO) kidneys from wild type mice. In C3-deficient mice, hydronephrus and EMT were suppressed, with no expression of renin and C3. After UUO, systolic blood pressure was increased in wild-type but not C3-deficient mice. In wild-type mice, intrarenal angiotensin II (ANG II) levels were markedly higher in UUO kidneys than normal kidneys and decreased with aliskiren. There were no increases in intrarenal ANG II levels after UUO in C3-deficient mice. Thus C3 induces EMT and dedifferentiation of epithelial cells, which produce renin through induction of LXRalpha. These data indicate for the first time that C3 may be a primary factor to activate the renal RA systems to induce hypertension. PMID- 23926187 TI - Restorative justice: a more understanding and humane approach to offenders. PMID- 23926186 TI - Focal segmental glomerulosclerosis is associated with a PDSS2 haplotype and, independently, with a decreased content of coenzyme Q10. AB - Focal segmental glomerulosclerosis (FSGS) and collapsing glomerulopathy are common causes of nephrotic syndrome. Variants in >20 genes, including genes critical for mitochondrial function, have been associated with these podocyte diseases. One such gene, PDSS2, is required for synthesis of the decaprenyl tail of coenzyme Q10 (Q10) in humans. The mouse gene Pdss2 is mutated in the kd/kd mouse model of collapsing glomerulopathy. We examined the hypothesis that human PDSS2 polymorphisms are associated with podocyte diseases. We genotyped 377 patients with primary FSGS or collapsing glomerulopathy, together with 900 controls, for 9 single-nucleotide polymorphisms in the PDSS2 gene in a case control study. Subjects included 247 African American (AA) and 130 European American (EA) patients and 641 AA and 259 EA controls. Among EAs, a pair of proxy SNPs was significantly associated with podocyte disease, and patients homozygous for one PDSS2 haplotype had a strongly increased risk for podocyte disease. By contrast, the distribution of PDSS2 genotypes and haplotypes was similar in AA patients and controls. Thus a PDSS2 haplotype, which has a frequency of 13% in the EA control population and a homozygote frequency of 1.2%, is associated with a significantly increased risk for FSGS and collapsing glomerulopathy in EAs. Lymphoblastoid cell lines from FSGS patients had significantly less Q10 than cell lines from controls; contrary to expectation, this finding was independent of PDSS2 haplotype. These results suggest that FSGS patients have Q10 deficiency and that this deficiency is manifested in patient-derived lymphoblastoid cell lines. PMID- 23926188 TI - Avian influenza. Critics skeptical as flu scientists argue for controversial H7N9 studies. PMID- 23926189 TI - Extra oversight for H7N9 experiments. PMID- 23926191 TI - Large polyp of the small intestine: an unexpected metastasis of ovarian carcinosarcoma. PMID- 23926192 TI - Adenomyomatous Polyp of the Endometrium With Prominent Epithelioid Smooth Muscle Differentiation: Report of Two Cases of a Hitherto Undescribed Lesion. AB - A minor component of smooth muscle may be present in the stroma of benign endometrial polyps and 2 distinctive endometrial polypoid lesions, atypical polypoid adenomyoma and adenomyoma, are characterized by stroma with a predominant smooth muscle component. In this report, we describe 2 unusual endometrial polyps in 43- and 60-year-old women in which the stromal component was predominantly composed of smooth muscle with an epithelioid appearance, a phenomenon which, as far as we are aware, has not been previously reported. PMID- 23926193 TI - Progressive radiation dose reduction from coronary computed tomography angiography in a statewide collaborative quality improvement program: results from the Advanced Cardiovascular Imaging Consortium. AB - BACKGROUND: A best-practice intervention previously demonstrated significant dose reduction over a period of one year. We sought to evaluate whether this reduction would be incremental and sustained by promoting new scanner technology in the context of an ongoing quality improvement program during a 3-year period in a statewide registry of coronary computed tomography angiography. METHODS AND RESULTS: In this prospective, controlled, nonrandomized study involving 11 901 patients at 15 Michigan centers participating in the Advanced Cardiovascular Imaging Consortium, radiation doses and image quality were compared between the following periods: control (May to June 2008) versus follow-up I (July 2008 to June 2009) and follow-up I versus follow-up II (July 2009 to April 2011). Intervention during these study periods included continuous education, feedback, and mandatory participation in this initiative. The median radiation dose remained unchanged from control to follow-up I: dose-length product of 697 (interquartile range, 407-1163) to 675 (interquartile range, 418-1146) mGy.cm (P=0.93). With the introduction of newer technology in follow-up I period, there was incremental 31% decrease during follow-up II to median dose-length product of 468 (interquartile range, 292-811) mGy.cm (P<0.0001). No significant change was noted in the percentage of diagnostic quality scans from follow-up I (92%) to follow-up II (92.7%). CONCLUSIONS: Although ongoing application of a best practice algorithm was associated with sustaining previously achieved targets, the use of newer scanner technology resulted in incremental radiation dose reduction in a statewide coronary computed tomography angiography registry without image quality degradation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00640068. PMID- 23926194 TI - Prosthesis-patient mismatch in bovine pericardial aortic valves: evaluation using 3 different modalities and associated medium-term outcomes. AB - BACKGROUND: The prevalence of prosthesis-patient mismatch (PPM) and its impact on survival after aortic valve replacement have not been clearly defined. Historically, the presence of PPM was identified from postoperative echocardiograms or preoperative manufacturer-provided charts, resulting in wide discrepancies. The 2009 American Society of Echocardiography (ASE) guidelines proposed an algorithmic approach to calculate PPM. This study compared PPM prevalence and its impact on survival using 3 modalities: (1) the ASE guidelines suggested algorithm (ASE PPM); (2) the manufacturer-provided charts (M PPM); and (3) the echocardiographically measured, body surface area-indexed, effective orifice area (EOAi PPM) measurement. METHODS AND RESULTS: A total of 614 patients underwent aortic valve replacement with bovine pericardial valves from 2004 to 2009 and had normal preoperative systolic function. EOAi PPM was severe if EOAi was <= 0.60 cm(2)/m(2), moderate if EOAi was 0.60 to 0.85 cm(2)/m(2), and absent (none) if EOAi was >= 0.85 cm(2)/m(2). ASE PPM was severe in 22 (3.6%), moderate in 6 (1%), and absent (none) in 586 (95.4%). ASE PPM was similar to manufacturer provided PPM (P=1.00). ASE PPM differed significantly from EOAi PPM (P<0.001), which identified severe mismatch in 170 (29.7%), moderate in 191 (33.4%), and absent (none) in 211 patients (36.9%). Irrespective of the PPM classification method, PPM did not adversely affect midterm survival (average follow-up, 4.1 +/- 1.8 years; median, 3.9 years; range, 0.01-8 years). There were no reoperations for PPM. CONCLUSIONS: In patients with normal systolic function undergoing bovine pericardial aortic valve replacement, the prevalence of PPM using the algorithmic ASE approach was low and correlated well with manufacturer-provided PPM. Independent of the method of PPM assessment, PPM was not associated with medium term mortality. PMID- 23926195 TI - Value of early cardiovascular magnetic resonance for the prediction of adverse arrhythmic cardiac events after a first noncomplicated ST-segment-elevation myocardial infarction. AB - BACKGROUND: Infarct size (IS) determined by cardiac magnetic resonance (CMR) has proven an additional value, on top of left ventricular ejection fraction (LVEF), in prediction of adverse arrhythmic cardiac events (AACEs) in chronic ischemic heart disease. Its value soon after an acute ST-segment-elevation myocardial infarction remains unknown. Our aim was to determine whether early CMR can improve AACE risk prediction after acute ST-segment-elevation myocardial infarction. METHODS AND RESULTS: Patients admitted for a first noncomplicated ST segment-elevation myocardial infarction were prospectively followed up. A total of 440 patients were included. All of them underwent CMR 1 week after admission. CMR-derived LVEF and IS (grams per meter squared) were quantified. AACEs included postdischarge sudden death, sustained ventricular tachycardia, and ventricular fibrillation either documented on ECG or recorded via an implantable cardioverter defibrillator. Within a median follow-up of 2 years, 11 AACEs (2.5%) were detected: 5 sudden deaths (1.1%) and 6 spontaneous ventricular tachycardia/ventricular fibrillation. In the whole group, AACEs associated with more depressed LVEF (adjusted hazard ratio [95% confidence interval], 0.90 [0.83 0.97]; P<0.01) and larger IS (adjusted hazard ratio [95% confidence interval], 1.06 [1.01-1.12]; P=0.01). According to the corresponding area under the receiver operating characteristic curve, LVEF <=36% and IS >=23.5 g/m(2) best predicted AACEs. The vast majority of AACEs (10/11) occurred in patients with simultaneous depressed LVEF <=36% and IS >=23.5 g/m(2) (n=39). CONCLUSIONS: In the era of reperfusion therapies, occurrence of AACEs in patients with an in-hospital noncomplicated first ST-segment-elevation myocardial infarction is low. In this setting, assessment of an early CMR-derived IS could be useful for further optimization of AACE risk prediction. PMID- 23926196 TI - The effect of symptoms on prehospital delay time in patients with acute myocardial infarction. AB - OBJECTIVE: To improve time to treatment, the effects of acute myocardial infarction (AMI) symptoms on prehospital delay time (PDT) were investigated. METHODS: Patients with AMI completed a questionnaire on their AMI symptoms and their general knowledge of AMI symptoms. RESULTS: In total, 116 patients completed questionnaires. The mean PDT was 7.3 +/- 2.4 h; the median PDT was 2.2 h. Each patient experienced a mean of 3.6 symptoms during their AMI. PDT was significantly shorter in the following groups: patients with chest compression pain/chest discomfort, profuse sweating or dyspnoea than in patients with other symptoms; patients presenting with typical rather than atypical symptoms; patients with pain scores >6 compared with scores <=6; patients who were aware rather than unaware of AMI symptoms. Patients actually having AMI symptoms and patients being aware of AMI symptoms were inversely correlated with PDT. There was a linear relationship between pain scores and PDT. CONCLUSION: Public awareness of AMI symptoms should be enhanced, in order to shorten PDT and improve AMI survival rates. PMID- 23926197 TI - Cup of Joe: a brain development "no"? AB - Treating pregnant mice with adenosine receptor antagonists including caffeine results in delayed migration of cortical gamma-aminobutyric acid neurons and altered brain development in mouse offspring (Silva et al.). PMID- 23926198 TI - Genomics traces carcinogen fingerprints. AB - Genome-wide sequencing highlights the distinctive pattern of mutations caused by a plant that contains a potent carcinogen. PMID- 23926199 TI - Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. AB - Aristolochic acid (AA), a natural product of Aristolochia plants found in herbal remedies and health supplements, is a group 1 carcinogen that can cause nephrotoxicity and upper urinary tract urothelial cell carcinoma (UTUC). Whole genome and exome analysis of nine AA-associated UTUCs revealed a strikingly high somatic mutation rate (150 mutations/Mb), exceeding smoking-associated lung cancer (8 mutations/Mb) and ultraviolet radiation-associated melanoma (111 mutations/Mb). The AA-UTUC mutational signature was characterized by A:T to T:A transversions at the sequence motif A[C|T]AGG, located primarily on nontranscribed strands. AA-induced mutations were also significantly enriched at splice sites, suggesting a role for splice-site mutations in UTUC pathogenesis. RNA sequencing of AA-UTUC confirmed a general up-regulation of nonsense-mediated decay machinery components and aberrant splicing events associated with splice site mutations. We observed a high frequency of somatic mutations in chromatin modifiers, particularly KDM6A, in AA-UTUC, demonstrated the sufficiency of AA to induce renal dysplasia in mice, and reproduced the AA mutational signature in experimentally treated human renal tubular cells. Finally, exploring other malignancies that were not known to be associated with AA, we screened 93 hepatocellular carcinoma genomes/exomes and identified AA-like mutational signatures in 11. Our study highlights an unusual genome-wide AA mutational signature and the potential use of mutation signatures as "molecular fingerprints" for interrogating high-throughput cancer genome data to infer previous carcinogen exposures. PMID- 23926200 TI - Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing. AB - In humans, exposure to aristolochic acid (AA) is associated with urothelial carcinoma of the upper urinary tract (UTUC). Exome sequencing of UTUCs from 19 individuals with documented exposure to AA revealed a remarkably large number of somatic mutations and an unusual mutational signature attributable to AA. Most of the mutations (72%) in these tumors were A:T-to-T:A transversions, located predominantly on the nontranscribed strand, with a strong preference for deoxyadenosine in a consensus sequence (T/CAG). This trinucleotide motif overlaps the canonical splice acceptor site, possibly accounting for the excess of splice site mutations observed in these tumors. The AA mutational fingerprint was found frequently in oncogenes and tumor suppressor genes in AA-associated UTUC. The AA mutational signature was observed in one patient's tumor from a UTUC cohort without previous indication of AA exposure. Together, these results directly link an established environmental mutagen to cancer through genome-wide sequencing and highlight its power to reveal individual exposure to carcinogens. PMID- 23926202 TI - Adenosine receptor antagonists including caffeine alter fetal brain development in mice. AB - Consumption of certain substances during pregnancy can interfere with brain development, leading to deleterious long-term neurological and cognitive impairments in offspring. To test whether modulators of adenosine receptors affect neural development, we exposed mouse dams to a subtype-selective adenosine type 2A receptor (A2AR) antagonist or to caffeine, a naturally occurring adenosine receptor antagonist, during pregnancy and lactation. We observed delayed migration and insertion of gamma-aminobutyric acid (GABA) neurons into the hippocampal circuitry during the first postnatal week in offspring of dams treated with the A2AR antagonist or caffeine. This was associated with increased neuronal network excitability and increased susceptibility to seizures in response to a seizure-inducing agent. Adult offspring of mouse dams exposed to A2AR antagonists during pregnancy and lactation displayed loss of hippocampal GABA neurons and some cognitive deficits. These results demonstrate that exposure to A2AR antagonists including caffeine during pregnancy and lactation in rodents may have adverse effects on the neural development of their offspring. PMID- 23926201 TI - Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. AB - MAGE A3, which belongs to the family of cancer-testis antigens, is an attractive target for adoptive therapy given its reactivation in various tumors and limited expression in normal tissues. We developed an affinity-enhanced T cell receptor (TCR) directed to a human leukocyte antigen (HLA)-A*01-restricted MAGE A3 antigen (EVDPIGHLY) for use in adoptive therapy. Extensive preclinical investigations revealed no off-target antigen recognition concerns; nonetheless, administration to patients of T cells expressing the affinity-enhanced MAGE A3 TCR resulted in a serious adverse event (SAE) and fatal toxicity against cardiac tissue. We present a description of the preclinical in vitro functional analysis of the MAGE A3 TCR, which failed to reveal any evidence of off-target activity, and a full analysis of the post-SAE in vitro investigations, which reveal cross-recognition of an off target peptide. Using an amino acid scanning approach, a peptide from the muscle protein Titin (ESDPIVAQY) was identified as an alternative target for the MAGE A3 TCR and the most likely cause of in vivo toxicity. These results demonstrate that affinity-enhanced TCRs have considerable effector functions in vivo and highlight the potential safety concerns for TCR-engineered T cells. Strategies such as peptide scanning and the use of more complex cell cultures are recommended in preclinical studies to mitigate the risk of off-target toxicity in future clinical investigations. PMID- 23926203 TI - Physician volume, specialty, and outcomes of care for patients with heart failure. AB - BACKGROUND: There is an urgent need to improve outcomes and reduce costs for patients with heart failure (HF). Physician volume is associated with better outcomes for patients undergoing procedures, but its association with outcomes for medically managed diseases, such as HF, is not well understood. METHODS AND RESULTS: We used Medicare inpatient data in 2009 to examine all HF admissions to acute care hospitals in the United States. We divided physicians into quintiles according to their volume of patients with HF. We used patient-level regression to compare 30-day risk-adjusted mortality, readmissions, and costs across volume groups, controlling for patient, physician, and hospital characteristics. We examined physician volume within strata of hospital volume and physician specialty. Patients cared for by the high-volume physicians had lower mortality than those by the low-volume physicians (8.9% versus 9.7%; P<0.001); this relationship was strongest in low-volume hospitals. In contrast, patients cared for by high-volume physicians had higher readmission rates (25.8% versus 21.5%; P<0001); this relationship was similar across hospital volume groups. Finally, costs were higher for the high-volume physicians ($8982 versus $8731; P=0.002, a difference that was consistent across hospital volume groups). The relationship between physician volume and mortality was strongest for internists (9.2% versus 10.6%; P<0.001) and weakest for cardiologists (6.4% versus 6.7%; P=0.485). CONCLUSIONS: Physician volume is associated with lower mortality for HF, particularly in low-volume institutions and among noncardiologist physicians. Our findings suggest that clinician expertise may play an important role in HF care. PMID- 23926205 TI - Characteristics of immigrant suicide completers in a sample of suicide victims from Greece. AB - BACKGROUND: Immigrants have higher rates of suicidal behaviour in comparison to the indigenous population. AIMS: To describe the characteristics of foreign nationality suicide completers and search for differences between them and native Greeks. This is the first study focused on immigrant suicide victims in Greece. METHODS: Data were collected for all recorded cases of completed suicide for the two-year period November 2007 to October 2009 at the Athens Department of Forensic Medicine, the largest, by far, of its kind in Greece covering approximately 35% of the country's population. The material was collected using the method of psychological autopsy as well as from the victims' forensic records. RESULTS: Nearly 10% of Greece's 11 million population are of foreign nationality. Approximately half of them live in Athens and its suburbs, an area where 35% of Greece's population lives. In our sample, 15.8% of the suicide victims were of foreign nationality (53 cases): 41 men (77.4%) and 12 women (22.6%). Higher suicide rates were found for citizens of Kuwaiti (9.1%), Somali (6.7%) and Afghan (0.9%) nationality (immigrant communities with very few members); the lower suicide rates were for individuals of Egyptian (0.01%), Ukrainian (0.01%) and Albanian (0.006%) nationality (the Albanian immigrant community is the largest in Greece). In comparison to their Greek counterparts, immigrant victims were younger (mean age 38.7 vs 54.9 years, p < .001) more often unemployed (p = .007) and with a history of alcohol abuse (p < .001). The main suicide method used by immigrants was hanging (p < .001) while for Greeks it was jumping from a height. CONCLUSIONS: Individuals who belong to small national communities seem to have the highest risk of dying by suicide. Immigrant suicide victims differ from the indigenous population in several parameters. Our data could help define the most vulnerable of them and apply more effective suicide prevention strategies. PMID- 23926206 TI - Bioinformatics approaches for improved recombinant protein production in Escherichia coli: protein solubility prediction. AB - The solubility of recombinant protein expressed in Escherichia coli often represents the production yield. However, up-to-date, instances of successful production of soluble recombinant proteins in E. coli expression system with high yield remain scarce. This is mainly due to the difficulties in improving the overall production capacity, as most of the well-established strategies usually involve a series of trial and error steps with unguaranteed success. One way to concurrently improve the production yield and minimize the production cost would be incorporating the potency of bioinformatics tools to conduct in silico studies, which forecasts the outcome before actual experimental work. In this article, we review and compare seven prediction tools available, which predict the solubility of protein expressed in E. coli, using the following criteria: prediction performance, usability, utility, prediction tool development and validation methodologies. This comprehensive review will be a valuable resource for researchers with limited prior experience in bioinformatics tools. As such, this will facilitate their choice of appropriate tools for studies related to enhancement of intracellular recombinant protein production in E. coli. PMID- 23926204 TI - Plasma free fatty acids and risk of heart failure: the Cardiovascular Health Study. AB - BACKGROUND: Although plasma free fatty acid (FFA) concentrations have been associated with lipotoxicity, apoptosis, and risk of diabetes mellitus and coronary heart disease, it is unclear whether FFA levels are associated with heart failure (HF). METHODS AND RESULTS: To test the hypothesis that plasma concentration of FFAs is positively associated with incident HF, we prospectively analyzed data on 4248 men and women free of HF at baseline and >65 years old from the Cardiovascular Health Study. FFA concentration was measured in duplicate by the Wako enzymatic method. Incident HF was validated by a centralized Events Committee. We used Cox proportional hazards to estimate the hazard ratio of HF per SD of FFAs. During a median follow-up of 10.5 years, a total of 1286 new cases of HF occurred. In a multivariable model adjusting for clinic site, comorbidity, demographic, anthropometric, and lifestyle factors, each SD (0.2 mEq/L) higher plasma FFA was associated with 12% (95% confidence interval, 6% 19%) higher risk of HF. Controlling for time-varying diabetes mellitus and coronary heart disease did not change the results (hazard ratio per SD, 1.16 [95% confidence interval, 1.09-1.23]). CONCLUSIONS: A single measure of plasma FFA obtained later in life is associated with a higher risk of HF in older adults. Additional studies are needed to explore biological mechanisms by which FFAs may influence the risk of HF and determine whether FFAs could serve as a novel pharmacological target for HF prevention. PMID- 23926207 TI - Effects of visit-to-visit variability in systolic blood pressure on macrovascular and microvascular complications in patients with type 2 diabetes mellitus: the ADVANCE trial. AB - BACKGROUND: Recent evidence suggests that visit-to-visit variability in systolic blood pressure (SBP) and maximum SBP are predictors of cardiovascular disease. However, it remains uncertain whether these parameters predict the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus. METHODS AND RESULTS: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was a factorial randomized controlled trial of blood pressure lowering and blood glucose control in patients with type 2 diabetes mellitus. The present analysis included 8811 patients without major macrovascular and microvascular events or death during the first 24 months after randomization. SBP variability (defined as standard deviation) and maximum SBP were determined during the first 24 months after randomization. During a median 2.4 years of follow-up from the 24-month visit, 407 major macrovascular (myocardial infarction, stroke, or cardiovascular death) and 476 microvascular (new or worsening nephropathy or retinopathy) events were observed. The association of major macrovascular and microvascular events with SBP variability was continuous even after adjustment for mean SBP and other confounding factors (both P<0.05 for trend). Hazard ratios (95% confidence intervals) for the highest tenth of SBP variability were 1.54 (0.99-2.39) for macrovascular events and 1.84 (1.19-2.84) for microvascular events in comparison with the lowest tenth. For maximum SBP, hazard ratios (95% confidence intervals) for the highest tenth were 3.64 (1.73-7.66) and 2.18 (1.04-4.58), respectively. CONCLUSION: Visit-to-visit variability in SBP and maximum SBP were independent risk factors for macrovascular and microvascular complications in type 2 diabetes mellitus. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. PMID- 23926208 TI - Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. AB - BACKGROUND: Elevated nonfasting remnant cholesterol and low-density lipoprotein (LDL) cholesterol are causally associated with ischemic heart disease (IHD), but whether elevated nonfasting remnant cholesterol and LDL cholesterol both cause low-grade inflammation is currently unknown. METHODS AND RESULTS: We studied 60 608 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease study, of whom 10 668 had IHD diagnosed between 1977 and 2011. We genotyped for variants affecting levels of nonfasting remnant cholesterol, LDL cholesterol, C-reactive protein by CRP alleles, and C-reactive protein by IL6R alleles. Using a multidirectional mendelian randomization design, we investigated possible causal associations between the lipoproteins and C-reactive protein and between the lipoproteins and IHD. A 1-mmol/L(39 mg/dL) higher level of nonfasting remnant cholesterol was associated observationally with a 37% (95% confidence interval, 35-39) higher C reactive protein level and causally with a 28% (95% confidence interval, 10-48) higher level. For LDL cholesterol, a 1-mmol/L (39-mg/dL) higher level was associated observationally with a 7% (95% confidence interval, 6-7) higher C reactive protein level, but we found no causal association. Likewise, higher levels of C-reactive protein did not associate causally with elevated nonfasting remnant cholesterol or LDL cholesterol. Finally, the causal risk ratio for IHD for a 1-mmol/L (39-mg/dL) higher level was 3.3 (95% confidence interval, 2.1-5.2) for nonfasting remnant cholesterol and 1.8 (95% confidence interval, 1.5-2.2) for LDL cholesterol. The causal associations for remnant cholesterol were present even in those without diabetes mellitus and obesity. CONCLUSIONS: Elevated nonfasting remnant cholesterol is causally associated with low-grade inflammation and with IHD, whereas elevated LDL cholesterol is associated causally with IHD without inflammation. PMID- 23926209 TI - The timing of neural stem cell-based virotherapy is critical for optimal therapeutic efficacy when applied with radiation and chemotherapy for the treatment of glioblastoma. AB - Glioblastoma multiforme (GBM) remains fatal despite intensive surgical, radiotherapeutic, and chemotherapeutic interventions. Neural stem cells (NSCs) have been used as cellular vehicles for the transportation of oncolytic virus (OV) to therapeutically resistant and infiltrative tumor burdens throughout the brain. The HB1.F3-CD human NSC line has demonstrated efficacy as a cell carrier for the delivery of a glioma tropic OV CRAd-Survivin-pk7 (CRAd-S-pk7) in vitro and in animal models of glioma. At this juncture, no study has investigated the effectiveness of OV-loaded NSCs when applied in conjunction with the standard of care for GBM treatment, and therefore this study was designed to fill this void. Here, we show that CRAd-S-pk7-loaded HB1.F3-CD cells retain their tumor-tropic properties and capacity to function as in situ viral manufacturers in the presence of ionizing radiation (XRT) and temozolomide (TMZ). Furthermore, for the first time, we establish a logical experimental model that aims to recapitulate the complex clinical scenario for the treatment of GBM and tests the compatibility of NSCs loaded with OV. We report that applying OV-loaded NSCs together with XRT and TMZ can increase the median survival of glioma bearing mice by approximately 46%. Most importantly, the timing and order of therapeutic implementation impact therapeutic outcome. When OV-loaded NSCs are delivered prior to rather than after XRT and TMZ treatment, the median survival of mice bearing patient-derived GBM43 glioma xenografts is extended by 30%. Together, data from this report support the testing of CRAd-S-pk7-loaded HB1.F3-CD cells in the clinical setting and argue in favor of a multimodality approach for the treatment of patients with GBM. PMID- 23926211 TI - Pellagra encephalopathy in the context of alcoholism: review and case report. AB - AIMS: The aim of the study was to review and describe the Alcoholic Pellagra Encephalopathy, a severe neuropsychiatric condition caused by a combination of niacin (vitamin B3) deficiency and alcohol abuse. METHODS: PsychInfo, Medline and Embase databases were searched for peer-reviewed studies addressing this illness. RESULTS: A historical and conceptual review of the psychopathological aspects of this condition is offered, followed by the report of a patient with a history of chronic alcohol consumption showing signs of pellagra, delusions and visual hallucinations, which was treated successfully with niacin. CONCLUSION: Pellagra encephalopathy should still be considered in the differential diagnosis of acute psychotic disorders seen in the context of chronic alcoholism. PMID- 23926210 TI - Sustained knockdown of a disease-causing gene in patient-specific induced pluripotent stem cells using lentiviral vector-based gene therapy. AB - Patient-specific induced pluripotent stem cells (iPSCs) hold great promise for studies on disease-related developmental processes and may serve as an autologous cell source for future treatment of many hereditary diseases. New genetic engineering tools such as zinc finger nucleases and transcription activator-like effector nuclease allow targeted correction of monogenetic disorders but are very cumbersome to establish. Aiming at studies on the knockdown of a disease-causing gene, lentiviral vector-mediated expression of short hairpin RNAs (shRNAs) is a valuable option, but it is limited by silencing of the knockdown construct upon epigenetic remodeling during differentiation. Here, we propose an approach for the expression of a therapeutic shRNA in disease-specific iPSCs using third generation lentiviral vectors. Targeting severe alpha-1-antitrypsin (A1AT) deficiency, we overexpressed a human microRNA 30 (miR30)-styled shRNA directed against the PiZ variant of A1AT, which is known to cause chronic liver damage in affected patients. This knockdown cassette is traceable from clonal iPSC lines to differentiated hepatic progeny via an enhanced green fluorescence protein reporter expressed from the same RNA-polymerase II promoter. Importantly, the cytomegalovirus i/e enhancer chicken beta actin (CAG) promoter-driven expression of this construct is sustained without transgene silencing during hepatic differentiation in vitro and in vivo. At low lentiviral copy numbers per genome we confirmed a functional relevant reduction (-66%) of intracellular PiZ protein in hepatic cells after differentiation of patient-specific iPSCs. In conclusion, we have demonstrated that lentiviral vector-mediated expression of shRNAs can be efficiently used to knock down and functionally evaluate disease-related genes in patient-specific iPSCs. PMID- 23926212 TI - A cross-sectional study of attitudes about the use of genetic testing for clinical care among patients with an alcohol use disorder. AB - AIM: Modification and individualization of medical treatments due to genetic testing has the potential to revolutionize healthcare delivery. As evidence mounts that genetic testing may improve treatment decisions for patients with alcohol use disorder (AUD), we explored patient concerns and attitudes toward genetic testing. METHODS: Subjects of two USA cross-sectional AUD studies were surveyed regarding their attitudes regarding the use of genetic testing for AUD treatment. RESULTS: Four hundred and fifty-seven participants were surveyed. Overall, subjects showed a high degree of willingness to provide DNA for clinical use and recognized genetics as important to the pathophysiology of a number of disorders including AUD. There were, however, significant concerns expressed related to insurance denial or employment problems. CONCLUSION: We found that patients enrolled in AUD studies had some concerns about use of genetic testing. The patients in these two samples were, however, willing and knowledgeable about providing DNA samples. PMID- 23926213 TI - Defining substance use disorders: do we really need more than heavy use? AB - AIMS: The aim of the study was to explore whether the concept of heavy substance use over time can be used as definition of substance use disorder. METHODS: Narrative review. RESULTS: Heavy use over time clearly underlies the neurobiological changes associated with current thinking of substance use disorders. In addition, there is evidence that heavy use over time can explain the majority of social problems and of burden of disease (morbidity and mortality). A definition of substance use disorders via heavy use over time would avoid some of the problems of current conceptualizations, for instance the cultural specificity of concepts such as loss of control. Finally, stressing the continuum of use may avoid the high level of stigmatization currently associated with substance use disorders. CONCLUSION: 'Heavy substance use over time' seems to be a definition of substance use disorders in line with results of basic research and epidemiology. Additionally, it reduces stigmatization. This approach should thus be further explored. PMID- 23926214 TI - Leadership lessons in global nursing and health from the Nightingale Letter Collection at the University of Alabama at Birmingham. AB - This article analyzes the components of Florence Nightingale's visionary leadership for global health and nursing within the historical context of Great Britain's colonization of India. The descriptive study used the qualitative approach of narrative analysis to analyze selected letters in the Nightingale Letter Collection at the University of Alabama at Birmingham that Nightingale wrote to or about Dr. Thomas Gillham Hewlett, a physician and health officer in Bombay, India. The authors sought to increase understanding of Nightingale's visionary leadership for global nursing and health through a study of the form and content of the letters analyzed as temporally contextualized data, focusing on how the narratives are composed and what is conveyed. Several recurring themes central to Nightingale's leadership on global nursing and health emerge throughout these letters, including health and sanitation reform, collaborative partnerships, data-driven policy development, and advocacy for public health. These themes are illustrated through her letters to and testimony about Dr. Thomas Gillham Hewlett in her vivid descriptions of health education and promotion, data-driven policy documents, public health and sanitation advice, and collaboration with citizens, medicine, policy makers, and governments to improve the health and welfare of the people of India. The focus on leadership in nursing as a global construct highlights the lessons learned from University of Alabama at Birmingham's Nightingale Letter Collection that has relevance for the future of nursing and health care, particularly Nightingale's collaboration with policy leaders, her analysis of data to set policy agendas, and public health reform centered on improving the health and well-being of underserved populations. PMID- 23926215 TI - A grounded theory of faculty's use of humanization to create online course climate. AB - The purpose of this research was to study the way faculty establish course social presence in an online course. The community of inquiry model by Garrison, Anderson, and Archer distinguished the area of social presence as an important component of online learning, and this study sought to understand how faculty perceive and create social presence in their online classroom. By employing a grounded theory approach, a substantive theory was developed to explain the way in which faculty create and maintain an online course climate. The sample consisted of 10 nursing faculty teaching various master's in nursing courses. Through a rigorous qualitative process using nursing faculty interviews and online course analysis, humanization was found to be the core category in setting online course climate. Faculty's efforts to humanize the climate lead each member of the community to view the other members as real, thereby enabling the establishment of online social presence. PMID- 23926216 TI - Stories of liminality: living with life-threatening illness. AB - PURPOSE: The purpose of the study is to examine liminal experiences of living with the uncertainty of life-threatening illness. Increasing numbers of people with life-threatening illness live in-between the promise of treatment and the threat of recurrence or progression of disease, and yet this experience is not well understood. DESIGN: A narrative inquiry methodology within a constructionist frame was used. METHOD: Semistructured in-depth interviews were conducted with 32 participants from three populations of interest: (a) 10 people living with cancer, (b) 13 people with chronic renal disease, and (c) 9 people living with HIV/AIDS. FINDINGS: An overarching theme of "pervasive liminality" and four narratives are identified: storying into fear(lessness), being alive but not living; knowing and not knowing, and the (in)visibility of disease. CONCLUSIONS: Over time, living with a life-threatening illness produces complex and paradoxical experiences that do not easily fit within familiar categories of experience. Findings highlight pervasive liminal experiences as in-between narratives that are neither problematic nor need to be resolved, and endure over time. PMID- 23926217 TI - Humor and laughter in persons with cognitive impairment and their caregivers. AB - PURPOSE: The purpose of this study was to describe humor and laughter in persons with cognitive impairment (PWCI) and caregivers who were recalling a shared experience in a focus group. DESIGN: Twenty participants attended an Art Engagement Activity at the Andy Warhol Art Museum, which included a guided tour and an art project. All PWCI had medically diagnosed cognitive disorders and all caregiver participants did not. Four focus groups were conducted and transcripts of audio-recorded sessions were transferred to a qualitative software program. METHOD: Words, phrases, and episodes of humor and laughter were used to construct codes, which were refined during group analysis using constant comparison. FINDINGS: Humor and laughter were present in all four focus groups. Emerging themes of humor included silliness, sarcasm, and commenting about hardships of dementia. Laughter was identified in segments with and without humor. Some PWCI were unable to follow social cues. CONCLUSIONS: Humor and laughter played a role in creating a safe social environment. PWCI were able to engage in humor during social interactions, yet some had difficulty recognizing social cues. Further study may reveal roles of humor and laughter in adaptation to cognitive decline and holistic interventions for improved quality of life. PMID- 23926218 TI - The health, mental health, and well-being benefits of rape crisis counseling. AB - There is very little research on interventions to alleviate the distress experienced following rape. This action research project developed and piloted the "Taking Back Control" tool that measured the impact of rape crisis counseling over time. Five rape crisis centers in the North of England agreed to pilot the tool, which was administered by the client's counselor, either on Week 1 or 2, and then repeated every 6 weeks until the end of counseling. Eighty-seven clients completed at least two questionnaires. This allowed us to measure change from their first compared with their last data collection point. The most change was made in relation to the statement "I feel empowered and in control of my life," where 61% strongly/disagreed at the first data collection point compared with 31% at the last data collection point. Large shifts were also seen in relation to "I have 'flashbacks' about what happened" and "I have panic attacks." Overall, some degree of positive change was seen for all measures. This research, despite some limitations, begins to develop an evidence base for rape crisis centers to demonstrate their benefits and to assess and develop their own practice. PMID- 23926219 TI - Toward an accurate taxonomic interpretation of Carex fossil fruits (Cyperaceae): a case study in section Phacocystis in the Western Palearctic. AB - PREMISE OF THE STUDY: Despite growing interest in the systematics and evolution of the hyperdiverse genus Carex, few studies have focused on its evolution using an absolute time framework. This is partly due to the limited knowledge of the fossil record. However, Carex fruits are not rare in certain sediments. We analyzed carpological features of modern materials from Carex sect. Phacocystis to characterize the fossil record taxonomically. METHODS: We studied 374 achenes from modern materials (18 extant species), as well as representatives from related groups, to establish the main traits within and among species. We also studied 99 achenes from sediments of living populations to assess their modification process after decay. Additionally, we characterized 145 fossil achenes from 10 different locations (from 4-0.02 mya), whose taxonomic assignment we discuss. KEY RESULTS: Five main characters were identified for establishing morphological groups of species (epidermis morphology, achene-utricle attachment, achene base, style robustness, and pericarp section). Eleven additional characters allowed the discrimination at species level of most of the taxa. Fossil samples were assigned to two extant species and one unknown, possibly extinct species. CONCLUSIONS: The analysis of fruit characters allows the distinction of groups, even up to species level. Carpology is revealed as an accurate tool in Carex paleotaxonomy, which could allow the characterization of Carex fossil fruits and assign them to subgeneric or sectional categories, or to certain species. Our conclusions could be crucial for including a temporal framework in the study of the evolution of Carex. PMID- 23926220 TI - Characterization of the stem anatomy of the Eocene fern Dennstaedtiopsis aerenchymata (Dennstaedtiaceae) by use of confocal laser scanning microscopy. AB - PREMISE OF THE STUDY: Permineralization provides the most faithful known mode of three-dimensional preservation of the morphology and cellular anatomy of fossil plants. Standard optical microscopic documentation of such structures can provide only an approximation of their true three-dimensional form and is incapable of revealing fine-structural (<300 nm) details, deficiencies that can be addressed by the use of confocal laser scanning microscopy (CLSM). METHODS: To demonstrate the usefulness of CLSM in such studies, we compare confocal laser scanning micrographs and optical photomicrographs of the permineralized tissues of rhizomes and petioles of the Eocene fern Dennstaedtiopsis aerenchymata preserved in cherts of the Clarno Formation of Oregon, USA, and the Allenby Formation (Princeton chert) of British Columbia, Canada. KEY RESULTS: The laser-induced fluorescence detected by CLSM produces crisp high-resolution images of the three dimensionally permineralized tissues of Dennstaedtiopsis aerenchymata. Tissues analyzed include the epidermis and epidermal hairs, cortex, aerenchyma, endodermis, vascular tissue, and pith-for each of which, CLSM yields results superior to those of standard optical microscopy. CLSM and previous Raman spectroscopic analyses of the same specimens provide evidence consistent with original biochemistry. CONCLUSIONS: Use of CLSM to characterize the morphology and cellular anatomy of permineralized fossil plants can provide accurate data in two and three dimensions at high spatial resolution, information that can be critically important to taxonomic, taphonomic, and developmental interpretations. Results presented here from this first detailed CLSM-based study of permineralized plant axes indicate that this nonintrusive, nondestructive technique should be widely applicable in paleobotany. PMID- 23926221 TI - From tissues to genomes. PMID- 23926222 TI - Policy uncertainty, sequencing, and cell lines. PMID- 23926223 TI - Building trust in 21st century genomics. PMID- 23926224 TI - HeLa sequencing and genomic privacy: the next chapter. PMID- 23926225 TI - Decoy-free protein-level false discovery rate estimation. AB - MOTIVATION: Statistical validation of protein identifications is an important issue in shotgun proteomics. The false discovery rate (FDR) is a powerful statistical tool for evaluating the protein identification result. Several research efforts have been made for FDR estimation at the protein level. However, there are still certain drawbacks in the existing FDR estimation methods based on the target-decoy strategy. RESULTS: In this article, we propose a decoy-free protein-level FDR estimation method. Under the null hypothesis that each candidate protein matches an identified peptide totally at random, we assign statistical significance to protein identifications in terms of the permutation P value and use these P-values to calculate the FDR. Our method consists of three key steps: (i) generating random bipartite graphs with the same structure; (ii) calculating the protein scores on these random graphs; and (iii) calculating the permutation P value and final FDR. As it is time-consuming or prohibitive to execute the protein inference algorithms for thousands of times in step ii, we first train a linear regression model using the original bipartite graph and identification scores provided by the target inference algorithm. Then we use the learned regression model as a substitute of original protein inference method to predict protein scores on shuffled graphs. We test our method on six public available datasets. The results show that our method is comparable with those state-of-the-art algorithms in terms of estimation accuracy. AVAILABILITY: The source code of our algorithm is available at: https://sourceforge.net/projects/plfdr/ PMID- 23926226 TI - nCal: an R package for non-linear calibration. AB - SUMMARY: Non-linear calibration is a widely used method for quantifying biomarkers wherein concentration-response curves estimated using samples of known concentrations are used to predict the biomarker concentrations in the samples of interest. The R package nCal fills an important gap in the open source, stand alone software for performing non-linear calibration. For curve fitting, nCal provides a new implementation of a robust, Bayesian hierarchical five-parameter logistic model. nCal supports a simple graphical user interface that can be used by laboratory scientists, and contains functionality for importing data from the multiplex bead array assay instrumentation. AVAILABILITY: The R package 'nCal' is available from http://cran.r-project.org/web/packages/nCal/ under GPL-2 or later. PMID- 23926227 TI - OncoSNP-SEQ: a statistical approach for the identification of somatic copy number alterations from next-generation sequencing of cancer genomes. AB - SUMMARY: Recent major cancer genome sequencing studies have used whole-genome sequencing to detect various types of genomic variation. However, a number of these studies have continued to rely on SNP array information to provide additional results for copy number and loss-of-heterozygosity estimation and assessing tumour purity. OncoSNP-SEQ is a statistical model-based approach for inferring copy number profiles directly from high-coverage whole genome sequencing data that is able to account for unknown tumour purity and ploidy. AVAILABILITY: MATLAB code is available at the following URL: https://sites.google.com/site/oncosnpseq/. PMID- 23926228 TI - Exploring the role of human miRNAs in virus-host interactions using systematic overlap analysis. AB - MOTIVATION: Human miRNAs have recently been found to have important roles in viral replication. Understanding the patterns and details of human miRNA interactions during virus-host interactions may help uncover novel antiviral therapies. Based on the abundance of knowledge available regarding protein protein interactions (PPI), virus-host protein interactions, experimentally validated human miRNA-target pairs and transcriptional regulation of human miRNAs, it is possible to explore the complex regulatory network that exists between viral proteins and human miRNAs at the system level. RESULTS: By integrating current data regarding the virus-human interactome and human miRNA target pairs, the overlap between targets of viral proteins and human miRNAs was identified and found to represent topologically important proteins (e.g. hubs or bottlenecks) at the global center of the human PPI network. Viral proteins and human miRNAs were also found to significantly target human PPI pairs. Furthermore, an overlap analysis of virus targets and transcription factors (TFs) of human miRNAs revealed that viral proteins preferentially target human miRNA TFs, representing a new pattern of virus-host interactions. Potential feedback loops formed by viruses, human miRNAs and miRNA TFs were also identified, and these may be exploited by viruses resulting in greater virulence and more effective replication strategies. PMID- 23926229 TI - What's in a Label? Radioimmunotherapy for metastatic prostate cancer. AB - Prostate cancer has a highly tumor-restricted prostate-specific membrane antigen (PSMA) and may be the ideal solid-organ malignancy for treatment with radioimmunotherapy. Encouraging results using lutetium-177-labeled anti-PSMA monoclonal antibody J591 from a phase II study by Tawaga and colleagues support the continued clinical and preclinical development of radioimmunotherapy for solid tumors. PMID- 23926230 TI - The initial noncovalent binding of glucose to human hemoglobin in nonenzymatic glycation. AB - Mechanisms for nonenzymatic protein glycation have been extensively studied albeit with an emphasis at the later stages that gives rise to advanced glycation end products. No detailed investigation of the initial, noncovalent binding of d glucose to human hemoglobin A (HbA) exists in the literature. Although anionic molecules 2,3-bisphosphoglycerate (BPG), inorganic phosphate (Pi) and HCO3(-) have been implicated in the latter stages of glycation, their involvement at the initial binding of glucose to HbA has not yet been assessed. Results from this computational study involving crystal structures of HbA predict that the transient, ring-opened glucose isomer, assumed to be critical in the later stages of glycation, is not directly involved in initial binding to the beta-chain of HbA. All the five structures of glucose generated upon mutorotation will undergo reversible, competitive and slow binding at multiple amino acid residues. The ring-opened structure is most likely generated from previously bound pyranoses that undergo mutarotation while bound. BPG, Pi and HCO3(-) also reversibly bind to HbA with similar energies as glucose isomers (~3-5 kcal/mol) and share common binding sites with glucose isomers. However, there was modest amino acid residue selectivity for binding of certain anionic molecules (1-3 regions) but limited selectivity for glucose structures (>= 7 regions). The clinical difference between average blood glucose and predicted HbA1c, and the presence of unstable HbA-glucose complexes may be more fully explained by initial noncovalent binding interactions and different concentrations of BPG, Pi and HCO3(-) in serum vs. erythrocytes. PMID- 23926232 TI - Detection of hypoplasia of bony cochlear nerve canal by the opening threshold of virtual endoscopy: a pilot study. AB - BACKGROUND: Dimensions of the bony cochlear nerve canal (BCNC) have been proposed as a potential diagnostic standard for BCNC hypoplasia, but the standard remains inconsistent. Some studies have revealed that computed tomography virtual endoscopy (CTVE) with variation of reconstruction threshold is good at identifying labyrinthine fistulas or semi-circular canal dehiscence. PURPOSE: To examine diagnostic accuracy of VE in the evaluation of BCNC hypoplasia on basis of opening threshold. MATERIAL AND METHODS: Twenty ears diagnosed with BCNC hypoplasia were included in this study. One hundred ears served as controls. The opening thresholds were measured by two reviewers. Intraclass correlation coefficients (ICC) were reported. The width of BCNC was obtained on transverse CT images. Association between the width of BCNC and opening threshold was assessed by using Spearman correlation coefficients. ROC curves were applied to assess the best cut-off value of opening threshold. RESULTS: The opening threshold of BCNC was significantly higher in diseased ears (926 +/- 308 Hounsfield units [HU]) than that in control ears (287 +/- 72 HU). Inter-observer agreement was very good. The mean width of BCNC for diseased ears and control ears were 0.83 +/- 0.36 mm and 2.21 +/- 0.35 mm, respectively. Significant negative linear correlation was found between opening thresholds and width of BCNC (Spearman coefficient, -0.768; P < 0.001). The area under the ROC curve was 0.981. The cut off opening thresholds of 408 for differentiation between the two groups provided the best combination of sensitivity (85%) and specificity (94%). CONCLUSION: The VE with opening threshold may be an effective optional tool for prediction of hypoplasia of BCNC. PMID- 23926231 TI - Identification of the galactosyltransferase of Cryptococcus neoformans involved in the biosynthesis of basidiomycete-type glycosylinositolphosphoceramide. AB - The pathogenic fungus Cryptococcus neoformans synthesizes a complex family of glycosylinositolphosphoceramide (GIPC) structures. These glycosphingolipids (GSLs) consist of mannosylinositolphosphoceramide (MIPC) extended by beta1-6 linked galactose, a unique structure that has to date only been identified in basidiomycetes. Further extension by up to five mannose residues and a branching xylose has been described. In this study, we identified and determined the gene structure of the enzyme Ggt1, which catalyzes the transfer of a galactose residue to MIPC. Deletion of the gene in C. neoformans resulted in complete loss of GIPCs containing galactose, a phenotype that could be restored by the episomal expression of Ggt1 in the deletion mutant. The entire annotated open reading frame, encoding a C-terminal GT31 galactosyltransferase domain and a large N terminal domain of unknown function, was required for complementation. Notably, this gene does not encode a predicted signal sequence or transmembrane domain. The demonstration that Ggt1 is responsible for the transfer of a galactose residue to a GSL thus raises questions regarding the topology of this biosynthetic pathway and the function of the N-terminal domain. Phylogenetic analysis of the GGT1 gene shows conservation in hetero- and homobasidiomycetes but no homologs in ascomycetes or outside of the fungal kingdom. PMID- 23926233 TI - Thin-section CT findings in peripheral lung cancer of 3 cm or smaller: are there any characteristic features for predicting tumor histology or do they depend only on tumor size? AB - BACKGROUND: Ground-glass opacity (GGO) is reported to be characteristic to lepidic growth of neoplasm in subsolid nodules. In solid nodules of lung cancer, however, there is no characteristic feature to be reported. PURPOSE: To study if there are any thin-section CT findings characteristic to tumor histology or if they are only related to tumor size in solid nodules of the lung cancer. MATERIAL AND METHODS: This study included 106 solid peripheral lung cancers of 3 cm or smaller (56 adenocarcinomas, 33 squamous cell carcinomas, and 17 small cell carcinomas) in which 16-slice CT with 1 mm collimation was performed before surgery. Six morphologic findings (presence or absence of lobulation, coarse spiculation, air bronchogram, cavity, pleural tag, and pleural-based lesion) and four measurements (ratio of the greatest transverse and vertical diameter to the shortest transverse diameter and density of lobulation and coarse spiculation) on thin-section CT images were evaluated. Density of lobulation (coarse spiculation) was defined as the ratio of lobulation (coarse spiculation) number to the greatest transverse diameter of a nodule. RESULTS: Air bronchogram (P < 0.01) was the only significant factor for predicting lung adenocarcinoma. The prevalence of air bronchogram was significantly greater in adenocarcinoma than in squamous cell carcinoma (P < 0.01) or small cell carcinoma (P < 0.01). As the tumor size advanced, significantly positive linear trends were seen in the prevalence of lobulation (P < 0.01), coarse spiculation (P < 0.01), and pleural tag (P < 0.01), and the mean values of density of lobulation (P < 0.01) and coarse spiculation (P < 0.01), while the significant negative linear trend was seen in the ratio of vertical diameter to the shortest transverse (P = 0.02). CONCLUSION: Air bronchogram on thin-section CT is characteristic feature of solid adenocarcinoma of the lung. However, other thin-section CT findings are irrelevant to tumor histology and related only to tumor size. PMID- 23926234 TI - Ovarian volume and antral follicle count assessed by MRI and transvaginal ultrasonography: a methodological study. AB - BACKGROUND: Ultrasonographic measurements of ovarian volume and antral follicle count are of clinical importance as diagnostic features of polycystic ovarian syndrome (PCOS), and as a parameter in estimation of ovarian follicular reserve in infertility care. PURPOSE: To compare two-dimensional (2D)/three-dimensional (3D) transvaginal ultrasonography (TVUS) and magnetic resonance imaging (MRI) for estimation of ovarian volume and antral follicle count, and to assess reproducibility and inter-observer agreement of MRI measurements. MATERIAL AND METHODS: Volumes of 172 ovaries in 99 women aged 21-37 years were calculated (length x width x height x 0.523) with conventional 2D TVUS and 2D MRI. Semi automatic estimates of ovarian volumes were obtained by 3D MRI. Antral follicles were counted manually on 2D MRI and automatically by 3D TVUS (SonoAVC), and stratified according to follicle size. RESULTS: Mean ovarian volume assessed by 2D TVUS (13.1 +/- 6.4 mL) was larger than assessed by 2D MRI (9.6 +/- 4.1) and 3D MRI (11.4 +/- 4.5) (P < 0.001). Total follicle count was higher by 2D MRI than by 3D TVUS, mean difference 14.3 +/- 16.2 follicles (P < 0.001). In the smallest size interval of 1-3 mm the mean difference was 22.2 +/- 17.6 (P < 0.001). Intra- and inter-observer absolute agreement assessment for MRI measurements of ovarian volume and total follicle count showed ICC coefficients >0.77. CONCLUSION: 2D MRI reveals more antral follicles, especially of small size, than 3D TVUS. Ovarian volume estimation by MRI provides smaller volumes than by the reference standard 2D TVUS. Ovarian volume estimation by 3D MRI, allowing independence of non ellipsoid ovarian shape measurement errors, provides volumes closer to 2D TVUS values than does 2D MRI. Reproducibility and inter-observer agreement of 2D MRI measurements of ovarian volume and total follicle count are good. PMID- 23926235 TI - Diagnosis of intracranial hemorrhagic lesions: comparison between 3D-SWAN (3D T2* weighted imaging with multi-echo acquisition) and 2D-T2*-weighted imaging. AB - BACKGROUND: 3D-susceptibility-weighted angiography (SWAN) can produce high resolution images that yield excellent susceptibility-weighted contrast at a relatively short acquisition time. PURPOSE: To compare SWAN- and 2D-T2*-weighted gradient-echo images (T2*-WI) for their sensitivity in the depiction of cerebral hemorrhagic lesions. MATERIAL AND METHODS: We subjected 75 patients with suspected cerebral hemorrhagic lesions to SWAN and T2*-WI at 3T. We first measured the contrast-to-noise ratio (CNR) using an agar phantom that contained different concentrations of superparamagnetic iron oxide (SPIO). The acquisition time for SWAN and T2*-WI was similar (182 vs. 196 s). Neuroradiologists compared the two imaging methods for lesion detectability and conspicuity. RESULTS: The CNR of the phantom was higher on SWAN images. Of the 75 patients, 50 were found to have a total of 278 cerebral hemorrhagic lesions (microbleeds, n = 229 [82.4%]; intracerebral hemorrhage, n = 18 [6.5%]; superficial siderosis, n = 13 [4.7%]; axonal injuries, n = 8 [2.9%]; subarachnoid hemorrhage [SAH] or brain contusion, n = 3 each [1.0%]; subdural hematoma, n = 2 [0.7%]; cavernous hemangioma or dural arterteriovenous fistula, n = 1 each [0.4%]). In none of the lesions was the SWAN sequence inferior to T2*-WI with respect to lesion detectability and conspicuity. In fact, SWAN yielded better lesion conspicuity in patients with superficial siderosis and SAH: it detected significantly more lesions than T2*-WI (P < 0.01) and it was particularly useful for the detection of microbleeds and lesions near the skull base. CONCLUSION: SWAN is equal or superior to standard T2*-WI for the diagnosis of various cerebral hemorrhagic lesions. Because its acquisition time is reasonable it may replace T2*-WI. PMID- 23926236 TI - Lymphoscintigraphy with peritumoral injection versus lymphoscintigraphy with subdermal periareolar injection of technetium-labeled human albumin to identify sentinel lymph nodes in breast cancer patients. AB - BACKGROUND: Preoperative lymphoscintigraphy is without doubt a valid method for the detection of the sentinel lymph node (SLN). There has been considerable debate regarding the optimal site for the introduction of the tracer; various sites include peritumoral (PT), periareolar (PA), subdermal, and intradermal injection. PURPOSE: To evaluate retrospectively the lymphoscintigraphic identification rate of peritumoral (PT) injection versus subdermal periareolar (PA) injection in the detection of SLNs in breast cancer. MATERIAL AND METHODS: Between October 2002 and December 2011, a cohort of 906 consecutive patients with biopsy proven breast cancer underwent 914 SLN biopsy procedures. A total of 339 procedures (Group A) were performed using a PT deep injection of radiotracer while 575 procedures (Group B) adopted a subdermal PA injection of radiotracer towards the upper outer quadrant, regardless of the site of the carcinoma. All the patients underwent synchronous excision of the breast cancer and SLN biopsy. RESULTS: SLNs were identified in the lymphoscintigram in 308/339 cases (90.85%) of Group A (PT injection) and in 537/575 cases (93.39%) of Group B (PA injection). Furthermore, in 2/339 patients (0.58%) of Group A, internal mammary lymph nodes were found at lymphoscintigraphy, whereas no internal mammary sentinel nodes were found in the Group B patients. The intraoperative identification rate of axillary SLNs was 99.41% (337 of 339) in the Group A patients and 99.65% (573 of 575) in the Group B patients. There was no significant difference in the two groups between the incidence of the number of SLNs detected and the incidence of identification of positive SLNs. CONCLUSION: PT versus PA injection of radiotracer showed comparable success rates for axillary SLN identification, and can be considered a rapid and reliable method. PMID- 23926237 TI - Detection of cardiac myxomas with non-contrast chest CT. AB - BACKGROUND: Cardiac myxomas are sources of systemic embolism. Currently a large volume of chest CT and calcium-scoring CT scans are performed without contrast injection. PURPOSE: To evaluate the diagnostic capability of non-contrast CT covering heart in detecting cardiac myxomas. MATERIAL AND METHODS: This retrospective study included 36 non-contrast CT scans of 36 consecutive patients (16 men, 20 women) who underwent CT scan before surgery for left atrial myxomas and 20 patients without myxoma as a control group. Two independent readers who were blinded to medical information reviewed non-contrast CT scans of 36 patients with cardiac myxomas and 20 scans in the control group patients. They determined the presence of lesions suspicious of myxomas using a five-point scale. The other reader measured attenuation number in the non-calcific areas of the tumors and sizes of the masses on the non-contrast CT images. RESULTS: The average attenuation of cardiac myxoma (22.5 Hounsfield units [HU]; range, 8.9-32.9 HU) and adjacent unopacified blood (44.6 HU; range, 31.5-57 HU) were significantly different (P < 0.001). Twelve cardiac myxomas (31.6%) had internal calcification and all of them were detected by both of readers. Cardiac myxomas were measured smaller on non-contrast CT (mean, 3.5 cm; range, 1.1-9.7 cm) than on pathologic specimens (mean, 4.1 cm, 1.4-10.0 cm) (P < 0.001). Considering grade 3-5 on a five-grade scale as the detectability, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of non contrast CT in detecting cardiac myxomas were 88.8%/86.1%, 95.0%/100%, 96.9%/100%, 82.6%/80.0%, and 91.1%/91.1%, by reader 1 and reader 2, respectively and there was good inter-observer reliability (kappa value = 0.92, P = 0.157). CONCLUSION: Non-contrast CT scan is useful for detecting cardiac myxomas. Therefore, radiologists should be familiar with imaging findings of cardiac myxomas on non-contrast CT. PMID- 23926238 TI - Three-phase, contrast-enhanced, multidetector CT in the evaluation of complicated renal cysts: comparison of the postcontrast phase combination. AB - BACKGROUND: Multiphasic multidetector computed tomography (MDCT) is widely used for the assessment and diagnosis of complicated renal cysts. PURPOSE: To determine the optimal combination of postcontrast phases of MDCT for the evaluation of complicated renal cysts. MATERIAL AND METHODS: In 164 renal cysts with pathology confirmation or follow-up >2 years, the Bosniak category was recorded by two radiologists in consensus. They reviewed the MDCT images during three interpretation sessions. In the first session, the radiologists evaluated two phases of images (unenhanced and corticomedullary phases), while during the second session, they evaluated two phases of images (unenhanced and parenchymal phases), and in the third session, they evaluated all three phases of images (unenhanced, corticomedullary, and parenchymal phases). The diagnostic accuracy for evaluating renal cysts was compared in each session using receiver-operating characteristics (ROC) analysis. RESULTS: There were 106 benign renal cysts and 58 malignant renal cysts. The areas under the ROC curves (AUCs) of the second and third sessions were greater than that of the first session (P < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value of the first session were 74%, 88%, 77%, and 86%, respectively, and those of the second session were 90%, 85%, 77%, and 94%, respectively. The values of the third session were identical to those of the second session. CONCLUSION: Unenhanced and parenchymal phase CT scans are sufficient for differentiating malignant from benign renal cysts and there was no additional value by adding the corticomedullary phase to the combination of unenhanced and parenchymal phase CT. PMID- 23926240 TI - The role of 5-HT1A receptors in the anti-aversive effects of cannabidiol on panic attack-like behaviors evoked in the presence of the wild snake Epicrates cenchria crassus (Reptilia, Boidae). AB - The potential anxiolytic and antipanic properties of cannabidiol have been shown; however, its mechanism of action seems to recruit other receptors than those involved in the endocannabinoid-mediated system. It was recently shown that the model of panic-like behaviors elicited by the encounters between mice and snakes is a good tool to investigate innate fear-related responses, and cannabidiol causes a panicolytic-like effect in this model. The aim of the present study was to investigate the 5-hydroxytryptamine (5-HT) co-participation in the panicolytic like effects of cannabidiol on the innate fear-related behaviors evoked by a prey versus predator interaction-based paradigm. Male Swiss mice were treated with intraperitoneal (i.p.) administrations of cannabidiol (3 mg/kg, i.p.) and its vehicle and the effects of the peripheral pre-treatment with increasing doses of the 5-HT1A receptor antagonist WAY-100635 (0.1, 0.3 and 0.9 mg/kg, i.p.) on instinctive fear-induced responses evoked by the presence of a wild snake were evaluated. The present results showed that the panicolytic-like effects of cannabidiol were blocked by the pre-treatment with WAY-100635 at different doses. These findings demonstrate that cannabidiol modulates the defensive behaviors evoked by the presence of threatening stimuli, and the effects of cannabidiol are at least partially dependent on the recruitment of 5-HT1A receptors. PMID- 23926239 TI - Mood stabilizer treatment increases serotonin type 1A receptor binding in bipolar depression. AB - Abnormal serotonin type 1A (5-HT1A) receptor function and binding have been implicated in the pathophysiology of mood disorders. Preclinical studies have consistently shown that stress decreases the gene expression of 5-HT1A receptors in experimental animals, and that the associated increase in hormone secretion plays a crucial role in mediating this effect. Chronic administration of the mood stabilizers lithium and divalproex (valproate semisodium) reduces glucocorticoid signaling and function in the hippocampus. Lithium has further been shown to enhance 5-HT1A receptor function. To assess whether these effects translate to human subject with bipolar disorder (BD), positron emission tomography (PET) and [18F]trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazino]-ethyl)-N-(2-pyridyl) cyclohexanecarboxamide ([(18)F]FCWAY) were used to acquire PET images of 5-HT1A receptor binding in 10 subjects with BD, before and after treatment with lithium or divalproex. Mean 5-HT1A binding potential (BPP) significantly increased following mood stabilizer treatment, most prominently in the mesiotemporal cortex (hippocampus plus amygdala). When mood state was also controlled for, treatment was associated with increases in BPP in widespread cortical areas. These preliminary findings are consistent with the hypothesis that these mood stabilizers enhance 5-HT1A receptor expression in BD, which may underscore an important component of these agents' mechanism of action. PMID- 23926241 TI - Single bright light exposure decreases sweet taste threshold in healthy volunteers. AB - INTRODUCTION: Bright light exposure can alter circulating serotonin levels, and alteration of available serotonin by acute selective serotonin reuptake inhibition significantly lowers sweet but not salt taste recognition thresholds. We tested the hypothesis that bright light exposure would increase sweet but not salt taste sensitivity in healthy adults. METHODS: Fourteen healthy volunteers were exposed to bright (10,000 lux) and dim (<20 lux) light for 30 min each, in counterbalanced order. Measures of taste perception (salt and sweet) and mood were determined at baseline, and before and after each light exposure period. RESULTS: Recognition thresholds for sucrose were significantly lower after bright but not dim light exposure. Thresholds for salt were unaffected by either condition. There were no significant changes in taste acuity, intensity or pleasantness for both the taste modalities and on visual analogue scales (VASs) for mood, anxiety, sleepiness and alertness, under either light condition. CONCLUSION: Brief bright light exposure reduces sweet but not salt taste recognition thresholds in healthy humans. PMID- 23926242 TI - Cannabinoid modulation of chronic mild stress-induced selective enhancement of trace fear conditioning in adolescent rats. AB - History of stress is considered a major risk factor for the development of major depression and posttraumatic stress disorder (PTSD). Elucidating the neurobiological mechanisms of Pavlovian fear conditioning may provide insight into the etiology of PTSD. In the current study, adolescent male Sprague-Dawley rats were exposed to 3 weeks of a chronic-mild-unpredictable stress (CMS) protocol. Immediately following the CMS, the animals were subjected to hippocampal-dependent (trace and contextual) and hippocampal-independent (delay) fear conditioning. CMS exposure enhanced trace freezing behavior compared to non stress controls. This effect was not observed in contextual or delay conditioned animals. Given that the endocannabinoid system is negatively affected by CMS procedures, separate groups of stressed rats were administered the CB1 receptor agonist, ACEA (0.1 mg/kg), prior to trace fear conditioning or a memory-recall test. Regardless of administration time, ACEA significantly reduced freezing behavior in stressed animals. Furthermore, when administered during the first memory recall test, ACEA enhanced long-term extinction in both stress and non stress groups. The results demonstrate that chronic unpredictable stress selectively enhances hippocampal-dependent episodic fear memories. Pathologies of the episodic memory and fear response may increase the susceptibility of developing PTSD. Reduction in fear responses via exogenous activation of the CB1 receptor suggests that a deficiency in the endocannabinoid system contributes to this pathology. PMID- 23926243 TI - Whole-exome sequencing identifies a polymorphism in the BMP5 gene associated with SSRI treatment response in major depression. AB - Although antidepressants are widely used in the pharmacotherapy of major depressive disorder (MDD), their efficacy is still insufficient as approximately one-third of the patients do not fully recover even after several treatment trials. Inter-individual genetic differences are thought to contribute to the variability in antidepressant response; however, current findings from pharmacogenetic studies are uncertain or not clearly replicated. Here we report the first application of full exome sequencing for the analysis of pharmacogenomics on antidepressant treatment. After 12 weeks of treatment with the selective serotonin re-uptake inhibitor escitalopram, we selected five clear responders and five clear non-responders for exome sequencing. By comparing the allele counts of previously known single nucleotide polymorphisms and novel polymorphisms we selected 38 markers for further genotyping in two independent patient samples treated with escitalopram (n=116 and n=394). The A allele, carried by approximately 30% of the patients with MDD, of rs41271330 in the bone morphogenetic protein (BMP5) gene showed strong association with worse treatment response in both sample sets (p=0.001), indicating that this is an promising pharmacogenetic marker for prediction of antidepressant therapeutic outcome. PMID- 23926244 TI - Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. AB - OBJECTIVE: The early intestinal microbiota exerts important stimuli for immune development, and a reduced microbial exposure as well as caesarean section (CS) has been associated with the development of allergic disease. Here we address how microbiota development in infants is affected by mode of delivery, and relate differences in colonisation patterns to the maturation of a balanced Th1/Th2 immune response. DESIGN: The postnatal intestinal colonisation pattern was investigated in 24 infants, born vaginally (15) or by CS (nine). The intestinal microbiota were characterised using pyrosequencing of 16S rRNA genes at 1 week and 1, 3, 6, 12 and 24 months after birth. Venous blood levels of Th1- and Th2 associated chemokines were measured at 6, 12 and 24 months. RESULTS: Infants born through CS had lower total microbiota diversity during the first 2 years of life. CS delivered infants also had a lower abundance and diversity of the Bacteroidetes phylum and were less often colonised with the Bacteroidetes phylum. Infants born through CS had significantly lower levels of the Th1-associated chemokines CXCL10 and CXCL11 in blood. CONCLUSIONS: CS was associated with a lower total microbial diversity, delayed colonisation of the Bacteroidetes phylum and reduced Th1 responses during the first 2 years of life. PMID- 23926246 TI - The role of beta-amyloid in alzheimer's disease-related neurodegeneration. PMID- 23926247 TI - Interactions between resting-state and task-evoked brain activity suggest a different approach to fMRI analysis. PMID- 23926248 TI - Postnatal disruption of the disintegrin/metalloproteinase ADAM10 in brain causes epileptic seizures, learning deficits, altered spine morphology, and defective synaptic functions. AB - The metalloproteinase ADAM10 is of importance for Notch-dependent cortical brain development. The protease is tightly linked with alpha-secretase activity toward the amyloid precursor protein (APP) substrate. Increasing ADAM10 activity is suggested as a therapy to prevent the production of the neurotoxic amyloid beta (Abeta) peptide in Alzheimer's disease. To investigate the function of ADAM10 in postnatal brain, we generated Adam10 conditional knock-out (A10cKO) mice using a CaMKIIalpha-Cre deleter strain. The lack of ADAM10 protein expression was evident in the brain cortex leading to a reduced generation of sAPPalpha and increased levels of sAPPbeta and endogenous Abeta peptides. The A10cKO mice are characterized by weight loss and increased mortality after weaning associated with seizures. Behavioral comparison of adult mice revealed that the loss of ADAM10 in the A10cKO mice resulted in decreased neuromotor abilities and reduced learning performance, which were associated with altered in vivo network activities in the hippocampal CA1 region and impaired synaptic function. Histological and ultrastructural analysis of ADAM10-depleted brain revealed astrogliosis, microglia activation, and impaired number and altered morphology of postsynaptic spine structures. A defect in spine morphology was further supported by a reduction of the expression of NMDA receptors subunit 2A and 2B. The reduced shedding of essential postsynaptic cell adhesion proteins such as N-Cadherin, Nectin-1, and APP may explain the postsynaptic defects and the impaired learning, altered network activity, and synaptic plasticity of the A10cKO mice. Our study reveals that ADAM10 is instrumental for synaptic and neuronal network function in the adult murine brain. PMID- 23926249 TI - Rich club organization and intermodule communication in the cat connectome. AB - Macroscopic brain networks have been shown to display several properties of an efficient communication architecture. In light of global communication, the formation of a densely connected neural "rich club" of hubs is of particular interest, because brain hubs have been suggested to play a key role in enabling short communication pathways within neural networks. Here, analyzing the cat connectome as reconstructed from tract tracing data (Scannell et al., 1995), we provide several lines of evidence of an important role of the structural rich club to interlink functional domains. First, rich club hub nodes were found to be mostly present at the boundaries between functional communities and well represented among intermodule hubs, displaying a diverse connectivity profile. Second, rich club connections, linking nodes of the rich club, and feeder connections, linking non-rich club nodes to rich club nodes, were found to comprise 86% of the intermodule connections, whereas local connections between peripheral nodes mostly spanned between nodes of the same functional community. Third, almost 90% of all intermodule communication paths were found to follow a sequence or "path motif" that involved rich club or feeder edges and thus traversed a rich club node. Together, our findings provide evidence of the structural rich club to form a central infrastructure for intermodule communication in the brain. PMID- 23926250 TI - Rines E3 ubiquitin ligase regulates MAO-A levels and emotional responses. AB - Monoamine oxidase A (MAO-A), the catabolic enzyme of norepinephrine and serotonin, plays a critical role in emotional and social behavior. However, the control and impact of endogenous MAO-A levels in the brain remains unknown. Here we show that the RING finger-type E3 ubiquitin ligase Rines/RNF180 regulates brain MAO-A subset, monoamine levels, and emotional behavior. Rines interacted with MAO-A and promoted its ubiquitination and degradation. Rines knock-out mice displayed impaired stress responses, enhanced anxiety, and affiliative behavior. Norepinephrine and serotonin levels were altered in the locus ceruleus, prefrontal cortex, and amygdala in either stressed or resting conditions, and MAO A enzymatic activity was enhanced in the locus ceruleus in Rines knock-out mice. Treatment of Rines knock-out mice with MAO inhibitors showed genotype-specific effects on some of the abnormal affective behaviors. These results indicated that the control of emotional behavior by Rines is partly due to the regulation of MAO A levels. These findings verify that Rines is a critical regulator of the monoaminergic system and emotional behavior and identify a promising candidate drug target for treating diseases associated with emotion. PMID- 23926251 TI - Synaptic inputs compete during rapid formation of the calyx of Held: a new model system for neural development. AB - Hallmark features of neural circuit development include early exuberant innervation followed by competition and pruning to mature innervation topography. Several neural systems, including the neuromuscular junction and climbing fiber innervation of Purkinje cells, are models to study neural development in part because they establish a recognizable endpoint of monoinnervation of their targets and because the presynaptic terminals are large and easily monitored. We demonstrate here that calyx of Held (CH) innervation of its target, which forms a key element of auditory brainstem binaural circuitry, exhibits all of these characteristics. To investigate CH development, we made the first application of serial block-face scanning electron microscopy to neural development with fine temporal resolution and thereby accomplished the first time series for 3D ultrastructural analysis of neural circuit formation. This approach revealed a growth spurt of added apposed surface area (ASA)>200 MUm2/d centered on a single age at postnatal day 3 in mice and an initial rapid phase of growth and competition that resolved to monoinnervation in two-thirds of cells within 3 d. This rapid growth occurred in parallel with an increase in action potential threshold, which may mediate selection of the strongest input as the winning competitor. ASAs of competing inputs were segregated on the cell body surface. These data suggest mechanisms to select "winning" inputs by regional reinforcement of postsynaptic membrane to mediate size and strength of competing synaptic inputs. PMID- 23926252 TI - Autonomic dysreflexia causes chronic immune suppression after spinal cord injury. AB - Autonomic dysreflexia (AD), a potentially dangerous complication of high-level spinal cord injury (SCI) characterized by exaggerated activation of spinal autonomic (sympathetic) reflexes, can cause pulmonary embolism, stroke, and, in severe cases, death. People with high-level SCI also are immune compromised, rendering them more susceptible to infectious morbidity and mortality. The mechanisms underlying postinjury immune suppression are not known. Data presented herein indicate that AD causes immune suppression. Using in vivo telemetry, we show that AD develops spontaneously in SCI mice with the frequency of dysreflexic episodes increasing as a function of time postinjury. As the frequency of AD increases, there is a corresponding increase in splenic leucopenia and immune suppression. Experimental activation of spinal sympathetic reflexes in SCI mice (e.g., via colorectal distension) elicits AD and exacerbates immune suppression via a mechanism that involves aberrant accumulation of norepinephrine and glucocorticoids. Reversal of postinjury immune suppression in SCI mice can be achieved by pharmacological inhibition of receptors for norepinephrine and glucocorticoids during the onset and progression of AD. In a human subject with C5 SCI, stimulating the micturition reflex caused AD with exaggerated catecholamine release and impaired immune function, thus confirming the relevance of the mouse data. These data implicate AD as a cause of secondary immune deficiency after SCI and reveal novel therapeutic targets for overcoming infectious complications that arise due to deficits in immune function. PMID- 23926253 TI - Dopamine modulates risk-taking as a function of baseline sensation-seeking trait. AB - Trait sensation-seeking, defined as a need for varied, complex, and intense sensations, represents a relatively underexplored hedonic drive in human behavioral neuroscience research. It is related to increased risk for a range of behaviors including substance use, gambling, and risky sexual practice. Individual differences in self-reported sensation-seeking have been linked to brain dopamine function, particularly at D2-like receptors, but so far no causal evidence exists for a role of dopamine in sensation-seeking behavior in humans. Here, we investigated the effects of the selective D2/D3 agonist cabergoline on performance of a probabilistic risky choice task in healthy humans using a sensitive within-subject, placebo-controlled design. Cabergoline significantly influenced the way participants combined different explicit signals regarding probability and loss when choosing between response options associated with uncertain outcomes. Importantly, these effects were strongly dependent on baseline sensation-seeking score. Overall, cabergoline increased sensitivity of choice to information about probability of winning; while decreasing discrimination according to magnitude of potential losses associated with different options. The largest effects of the drug were observed in participants with lower sensation-seeking scores. These findings provide evidence that risk taking behavior in humans can be directly manipulated by a dopaminergic drug, but that the effectiveness of such a manipulation depends on baseline differences in sensation-seeking trait. This emphasizes the importance of considering individual differences when investigating manipulation of risky decision-making, and may have relevance for the development of pharmacotherapies for disorders involving excessive risk-taking in humans, such as pathological gambling. PMID- 23926254 TI - Goofy coordinates the acuity of olfactory signaling. AB - The basic scheme of odor perception and signaling from olfactory cilia to the brain is well understood. However, factors that affect olfactory acuity of an animal, the threshold sensitivity to odorants, are less well studied. Using signal sequence trap screening of a mouse olfactory epithelium cDNA library, we identified a novel molecule, Goofy, that is essential for olfactory acuity in mice. Goofy encodes an integral membrane protein with specific expression in the olfactory and vomeronasal sensory neurons and predominant localization to the Golgi compartment. Goofy-deficient mice display aberrant olfactory phenotypes, including the impaired trafficking of adenylyl cyclase III, stunted olfactory cilia, and a higher threshold for physiological and behavioral responses to odorants. In addition, the expression of dominant-negative form of cAMP-dependent protein kinase results in shortening of olfactory cilia, implying a possible mechanistic link between cAMP and ciliogenesis in the olfactory sensory neurons. These results demonstrate that Goofy plays an important role in establishing the acuity of olfactory sensory signaling. PMID- 23926255 TI - Dendritic spine instability leads to progressive neocortical spine loss in a mouse model of Huntington's disease. AB - In Huntington's disease (HD), cognitive symptoms and cellular dysfunction precede the onset of classical motor symptoms and neuronal death in the striatum and cortex by almost a decade. This suggests that the early cognitive deficits may be due to a cellular dysfunction rather than being a consequence of neuronal loss. Abnormalities in dendritic spines are described in HD patients and in HD animal models. Available evidence indicates that altered spine and synaptic plasticity could underlie the motor as well as cognitive symptoms in HD. However, the exact kinetics of spine alterations and plasticity in HD remain unknown. We used long term two-photon imaging through a cranial window, to track individual dendritic spines in a mouse model of HD (R6/2) as the disease progressed. In vivo imaging over a period of 6 weeks revealed a steady decrease in the density and survival of dendritic spines on cortical neurons of R6/2 mice compared with control littermates. Interestingly, we also observed increased spine formation in R6/2 mice throughout the disease. However, the probability that newly formed spines stabilized and transformed into persistent spines was greatly reduced compared with controls. In cultured neurons we found that mutant huntingtin causes a loss, in particular of mature spines. Furthermore, in R6/2 mice, aggregates of mutant huntingtin associate with dendritic spines. Alterations in dendritic spine dynamics, survival, and density in R6/2 mice were evident before the onset of motor symptoms, suggesting that decreased stability of the cortical synaptic circuitry underlies the early symptoms in HD. PMID- 23926256 TI - Atypical retinotopic organization of visual cortex in patients with central brain damage: congenital and adult onset. AB - It remains unclear to what extent retinotopic maps can undergo large-scale plasticity following damage to human visual cortex. The literature has predominately focused on retinotopic changes in patients with retinal pathologies or congenital brain malformations. Yet, damage to the adult visual cortex itself is common in cases such as stroke, tumor, or trauma. To address this issue, we used a unique database of fMRI vision maps in patients with adult-onset (n=25) and congenital (n=2) pathology of the visual cortex. We identified atypical retinotopic organization in three patients (two with adult-onset, and one with congenital pathology) consisting of an expanded ipsilateral field representation that was on average 3.2 times greater than healthy controls. The expanded representations were located at the vertical meridian borders between visual areas such as V1/V2. Additionally, two of the three patients had apparently an ectopic (topographically inconsistent) representation of the ipsilateral field within lateral occipital cortex that is normally associated with visual areas V3/V3A (and possibly other areas). Both adult-onset cases had direct damage to early visual cortex itself (rather than to the afferent drive only), resulting in a mostly nonfunctional hemisphere. The congenital case had severe cortical malformation of the visual cortex and was acallosal. Our results are consistent with a competitive model in which unilateral damage to visual cortex or disruption of the transcallosal connections removes interhemispheric suppression from retino-geniculate afferents in intact visual cortex that represent the vertical meridian and ipsilateral visual field. PMID- 23926257 TI - A sodium-pump-mediated afterhyperpolarization in pyramidal neurons. AB - The sodium-potassium ATPase (i.e., the "sodium pump") plays a central role in maintaining ionic homeostasis in all cells. Although the sodium pump is intrinsically electrogenic and responsive to dynamic changes in intracellular sodium concentration, its role in regulating neuronal excitability remains unclear. Here we describe a physiological role for the sodium pump in regulating the excitability of mouse neocortical layer 5 and hippocampal CA1 pyramidal neurons. Trains of action potentials produced long-lasting (~20 s) afterhyperpolarizations (AHPs) that were insensitive to blockade of voltage-gated calcium channels or chelation of intracellular calcium, but were blocked by tetrodotoxin, ouabain, or the removal of extracellular potassium. Correspondingly, the AHP time course was similar to the decay of activity-induced increases in intracellular sodium, whereas intracellular calcium decayed at much faster rates. To determine whether physiological patterns of activity engage the sodium pump, we replayed in vitro a place-specific burst of 15 action potentials recorded originally in vivo in a CA1 "place cell" as the animal traversed the associated place field. In both layer 5 and CA1 pyramidal neurons, this "place cell train" generated small, long-lasting AHPs capable of reducing neuronal excitability for many seconds. Place-cell-train-induced AHPs were blocked by ouabain or removal of extracellular potassium, but not by intracellular calcium chelation. Finally, we found calcium contributions to the AHP to be temperature dependent: prominent at room temperature, but largely absent at 35 degrees C. Our results demonstrate a previously unappreciated role for the sodium-potassium ATPase in regulating the excitability of neocortical and hippocampal pyramidal neurons. PMID- 23926258 TI - Protection of spiral ganglion neurons from degeneration using small-molecule TrkB receptor agonists. AB - Neurotrophins (NTs) play essential roles in the development and survival of neurons in PNS and CNS. In the cochlea, NTs [e.g., NT-3, brain-derived neurotrophic factor (BDNF)] are required for the survival of spiral ganglion neurons (SGNs). Preservation of SGNs in the cochlea of patients suffering sensorineural deafness caused by loss of hair cells is needed for the optimal performance of the cochlear implant. Directly applying exogenous BDNF into the cochlea prevents secondary degeneration of SGNs when hair cells are lost. However, a common translational barrier for in vivo applications of BDNF is the poor pharmacokinetics, which severely limits the efficacy. Here we report that 7,8-dihydroxyflavone and 7,8,3'-trihydroxyflavone, both small-molecule agonists of tyrosine receptor kinase B (TrkB), promoted SGN survival with high potency both in vitro and in vivo. These compounds increased the phosphorylated TrkB and downstream MAPK and protected the SGNs in a TrkB-dependent manner. Their applications in the bulla of conditional connexin26 null mice offered significant protection for SGN survival. The function of survived SGNs was assessed by measuring evoked action potentials (APs) in vitro and electrically evoked auditory brainstem response (eABR) thresholds in vivo. APs were reliably evoked in cultured single SGNs treated with the compounds. In addition, eABR thresholds measured from the treated cochleae were significantly lower than untreated controls. Our findings suggest that these novel small-molecule TrkB agonists are promising in vivo therapeutic agents for preventing degeneration of SGNs. PMID- 23926260 TI - Impaired D-serine-mediated cotransmission mediates cognitive dysfunction in epilepsy. AB - The modulation of synaptic plasticity by NMDA receptor (NMDAR)-mediated processes is essential for many forms of learning and memory. Activation of NMDARs by glutamate requires the binding of a coagonist to a regulatory site of the receptor. In many forebrain regions, this coagonist is d-serine. Here, we show that experimental epilepsy in rats is associated with a reduction in the CNS levels of d-serine, which leads to a desaturation of the coagonist binding site of synaptic and extrasynaptic NMDARs. In addition, the subunit composition of synaptic NMDARs changes in chronic epilepsy. The desaturation of NMDARs causes a deficit in hippocampal long-term potentiation, which can be rescued with exogenously supplied d-serine. Importantly, exogenous d-serine improves spatial learning in epileptic animals. These results strongly suggest that d-serine deficiency is important in the amnestic symptoms of temporal lobe epilepsy. Our results point to a possible clinical utility of d-serine to alleviate these disease manifestations. PMID- 23926261 TI - Nocturnal light exposure impairs affective responses in a wavelength-dependent manner. AB - Life on earth is entrained to a 24 h solar cycle that synchronizes circadian rhythms in physiology and behavior; light is the most potent entraining cue. In mammals, light is detected by (1) rods and cones, which mediate visual function, and (2) intrinsically photosensitive retinal ganglion cells (ipRGCs), which primarily project to the suprachiasmatic nucleus (SCN) in the hypothalamus to regulate circadian rhythms. Recent evidence, however, demonstrates that ipRGCs also project to limbic brain regions, suggesting that, through this pathway, light may have a role in cognition and mood. Therefore, it follows that unnatural exposure to light may have negative consequences for mood or behavior. Modern environmental lighting conditions have led to excessive exposure to light at night (LAN), and particularly to blue wavelength lights. We hypothesized that nocturnal light exposure (i.e., dim LAN) would induce depressive responses and alter neuronal structure in hamsters (Phodopus sungorus). If this effect is mediated by ipRGCs, which have reduced sensitivity to red wavelength light, then we predicted that red LAN would have limited effects on brain and behavior compared with shorter wavelengths. Additionally, red LAN would not induce c-Fos activation in the SCN. Our results demonstrate that exposure to LAN influences behavior and neuronal plasticity and that this effect is likely mediated by ipRGCs. Modern sources of LAN that contain blue wavelengths may be particularly disruptive to the circadian system, potentially contributing to altered mood regulation. PMID- 23926259 TI - Onecut1 is essential for horizontal cell genesis and retinal integrity. AB - Horizontal cells are interneurons that synapse with photoreceptors in the outer retina. Their genesis during development is subject to regulation by transcription factors in a hierarchical manner. Previously, we showed that Onecut 1 (Oc1), an atypical homeodomain transcription factor, is expressed in developing horizontal cells (HCs) and retinal ganglion cells (RGCs) in the mouse retina. Herein, by knocking out Oc1 specifically in the developing retina, we show that the majority (~80%) of HCs fail to form during early retinal development, implying that Oc1 is essential for HC genesis. However, no other retinal cell types, including RGCs, were affected in the Oc1 knock-out. Analysis of the genetic relationship between Oc1 and other transcription factor genes required for HC development revealed that Oc1 functions downstream of FoxN4, in parallel with Ptf1a, but upstream of Lim1 and Prox1. By in utero electroporation, we found that Oc1 and Ptf1a together are not only essential, but also sufficient for determination of HC fate. In addition, the synaptic connections in the outer plexiform layer are defective in Oc1-null mice, and photoreceptors undergo age dependent degeneration, indicating that HCs are not only an integral part of the retinal circuitry, but also are essential for the survival of photoreceptors. In sum, these results demonstrate that Oc1 is a critical determinant of HC fate, and reveal that HCs are essential for photoreceptor viability, retinal integrity, and normal visual function. PMID- 23926262 TI - KIBRA polymorphism is associated with individual differences in hippocampal subregions: evidence from anatomical segmentation using high-resolution MRI. AB - The KIBRA gene has been associated with episodic memory in several recent reports; carriers of the T-allele show enhanced episodic memory performance relative to noncarriers. Gene expression studies in human and rodent species show high levels of KIBRA in the hippocampus, particularly in the subfields. The goal of the present study was to determine whether the KIBRA C->T polymorphism is also associated with volume differences in the human hippocampus and whether specific subfields are differentially affected by KIBRA genotype. High-resolution magnetic resonance imaging (T2-weighted, voxel size=0.4*0.4 mm, in-plane) was used to manually segment hippocampal cornu ammonis (CA) subfields, dentate gyrus (DG), and the subiculum as well as adjacent medial temporal lobe cortices in healthy carriers and noncarriers of the KIBRA T-allele (rs17070145). Overall, we found that T-carriers had a larger hippocampal volume relative to noncarriers. The structural differences observed were specific to the CA fields and DG regions of the hippocampus, suggesting a potential neural mechanism for the effects of KIBRA on episodic memory performance reported previously. PMID- 23926263 TI - Matching dynamics of presynaptic and postsynaptic scaffolds. AB - Synapses undergo substantial activity-dependent and independent remodeling over time scales of minutes, hours, and days. Presumably, changes in presynaptic properties should be matched by corresponding changes in postsynaptic properties and vice versa. Wherever measured, presynaptic and postsynaptic molecular properties tend to correlate, yet these correlations are often quite imperfect, raising questions as the origins of such mismatches: Are these the outcome of "single snapshot" analyses of asynchronous remodeling processes? Alternatively, do these indicate that synapses genuinely vary in the "stoichiometries" of their presynaptic and postsynaptic molecular contents? If so, are these "stoichiometries" preserved over time? To address these questions, we followed the matching dynamics of the presynaptic active-zone molecule Munc13-1 and the postsynaptic molecule PSD-95 in networks of cultured cortical mouse neurons. We find that presynaptic and postsynaptic remodeling were generally well correlated, but the degree of this correlation was highly variable, with little and even negative correlation observed at some synapses. No evidence was found that remodeling in one compartment consistently preceded remodeling in the other. Interestingly, even though the Munc13-1 and PSD-95 contents of individual synapses changed considerably over 15-22 h, Munc13-1/PSD-95 ratios, which varied over a fourfold range, were well conserved over these durations. These findings indicate that the "stoichiometries" of presynaptic and postsynaptic molecules can genuinely differ among synapses and that synapses can maintain their specific stoichiometries even in face of extensive presynaptic and postsynaptic remodeling. PMID- 23926265 TI - The basolateral amygdala is critical for learning about neutral stimuli in the presence of danger, and the perirhinal cortex is critical in the absence of danger. AB - The perirhinal cortex (PRh) and basolateral amygdala (BLA) appear to mediate distinct aspects of learning and memory. Here, we used rats to investigate the involvement of the PRh and BLA in acquisition and extinction of associations between two different environmental stimuli (e.g., a tone and a light) in higher order conditioning. When both stimuli were neutral, infusion of the GABAA, muscimol, or the NMDA receptor (NMDAR) antagonist ifenprodil into the PRh impaired associative formation. However, when one stimulus was neutral and the other was a learned danger signal, acquisition and extinction of the association between them was unaffected by manipulations targeting the PRh. Temporary inactivation of the BLA had the opposite effect: formation and extinction of an association between two stimuli was spared when both stimuli were neutral, but impaired when one stimulus was a learned danger signal. Subsequent experiments showed that the experience of fear per se shifts processing of an association between neutral stimuli from the PRh to the BLA. When training was conducted in a dangerous environment, formation and extinction of an association between neutral stimuli was impaired by BLA inactivation or NMDAR blockade in this region, but was unaffected by PRh inactivation. These double dissociations in the roles of the PRh and BLA in learning under different stimulus and environmental conditions imply that fear-induced activation of the amygdala changes how the brain processes sensory stimuli. Harmless stimuli are treated as potentially harmful, resulting in a shift from cortical to subcortical processing in the BLA. PMID- 23926264 TI - Elevated MMP-9 in the lumbar cord early after thoracic spinal cord injury impedes motor relearning in mice. AB - Spinal cord injury results in distant pathology around putative locomotor networks that may jeopardize the recovery of locomotion. We previously showed that activated microglia and increased cytokine expression extend at least 10 segments below the injury to influence sensory function. Matrix metalloproteinase 9 (MMP-9) is a potent regulator of acute neuroinflammation. Whether MMP-9 is produced remote to the injury or influences locomotor plasticity remains unexamined. Therefore, we characterized the lumbar enlargement after a T9 spinal cord injury in C57BL/6 (wild-type [WT]) and MMP-9-null (knock-out [KO]) mice. Within 24 h, resident microglia displayed an activated phenotype alongside increased expression of progelatinase MMP-3 in WT mice. By 7 d, increases in active MMP-9 around lumbar vasculature and production of proinflammatory TNF alpha were evident. Deletion of MMP-9 attenuated remote microglial activation and restored TNF-alpha expression to homeostatic levels. To determine whether MMP-9 impedes locomotor plasticity, we delivered lumbar-focused treadmill training in WT and KO mice during early (2-9 d) or late (35-42 d) phases of recovery. Robust behavioral improvements were observed by 7 d, when only trained KO mice stepped in the open field. Locomotor improvements were retained for 4 weeks as identified using state of the art mouse kinematics. Neither training nor MMP-9 depletion alone promoted recovery. The same intervention delivered late was ineffective, suggesting that lesion site sparing is insufficient to facilitate activity-based training and recovery. Our work suggests that by attenuating remote mechanisms of inflammation, acute treadmill training can harness endogenous spinal plasticity to promote robust recovery. PMID- 23926266 TI - Behavioral modulation of neural encoding of click-trains in the primary and nonprimary auditory cortex of cats. AB - Neural representation of acoustic stimuli in the mammal auditory cortex (AC) has been extensively studied using anesthetized or awake nonbehaving animals. Recently, several studies have shown that active engagement in an auditory behavioral task can substantially change the neuron response properties compared with when animals were passively listening to the same sounds; however, these studies mainly investigated the effect of behavioral state on the primary auditory cortex and the reported effects were inconsistent. Here, we examined the single-unit spike activities in both the primary and nonprimary areas along the dorsal-to-ventral direction of the cat's AC, when the cat was actively discriminating click-trains at different repetition rates and when it was passively listening to the same stimuli. We found that the changes due to task engagement were heterogeneous in the primary AC; some neurons showed significant increases in driven firing rate, others showed decreases. But in the nonprimary AC, task engagement predominantly enhanced the neural responses, resulting in a substantial improvement of the neural discriminability of click-trains. Additionally, our results revealed that neural responses synchronizing to click trains gradually decreased along the dorsal-to-ventral direction of cat AC, while nonsynchronizing responses remained less changed. The present study provides new insights into the hierarchical organization of AC along the dorsal-to-ventral direction and highlights the importance of using behavioral animals to investigate the later stages of cortical processing. PMID- 23926267 TI - Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both beta-amyloid production and clearance. AB - Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The beta-amyloid (Abeta)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Abeta production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Abeta production by suppressing beta-site amyloid precursor protein cleavage enzyme 1 expression and promote Abeta clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Abeta formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery. PMID- 23926268 TI - Brain activity in valuation regions while thinking about the future predicts individual discount rates. AB - People vary widely in how much they discount delayed rewards, yet little is known about the sources of these differences. Here we demonstrate that neural activity in ventromedial prefrontal cortex (VMPFC) and ventral striatum (VS) when human subjects are asked to merely think about the future--specifically, to judge the subjective length of future time intervals--predicts delay discounting. High discounters showed lower activity for longer time delays, while low discounters showed the opposite pattern. Our results demonstrate that the correlation between VMPFC and VS activity and discounting occurs even in the absence of choices about future rewards, and does not depend on a person explicitly evaluating future outcomes or judging their self-relevance. This suggests a link between discounting and basic processes involved in thinking about the future, such as temporal perception. Our results also suggest that reducing impatience requires not suppression of VMPFC and VS activity altogether, but rather modulation of how these regions respond to the present versus the future. PMID- 23926269 TI - A comparison of lateral and medial intraparietal areas during a visual categorization task. AB - Categorization is essential for interpreting sensory stimuli and guiding our actions. Recent studies have revealed robust neuronal category representations in the lateral intraparietal area (LIP). Here, we examine the specialization of LIP for categorization and the roles of other parietal areas by comparing LIP and the medial intraparietal area (MIP) during a visual categorization task. MIP is involved in goal-directed arm movements and visuomotor coordination but has not been implicated in non-motor cognitive functions, such as categorization. As expected, we found strong category encoding in LIP. Interestingly, we also observed category signals in MIP. However, category signals were stronger and appeared with a shorter latency in LIP than MIP. In this task, monkeys indicated whether a test stimulus was a category match to a previous sample with a manual response. Test-period activity in LIP showed category encoding and distinguished between matches and non-matches. In contrast, MIP primarily reflected the match/non-match status of test stimuli, with a strong preference for matches (which required a motor response). This suggests that, although category representations are distributed across parietal cortex, LIP and MIP play distinct roles: LIP appears more involved in the categorization process itself, whereas MIP is more closely tied to decision-related motor actions. PMID- 23926270 TI - Adrenergic gating of Hebbian spike-timing-dependent plasticity in cortical interneurons. AB - In pyramidal cells, the induction of spike-dependent plasticity (STDP) follows a simple Hebbian rule in which the order of presynaptic and postsynaptic firing dictates the induction of LTP or LTD. In contrast, cortical fast spiking (FS) interneurons, which control the rate and timing of pyramidal cell firing, reportedly express timing-dependent LTD, but not timing-dependent LTP. Because a mismatch in STDP rules could impact the maintenance of the excitation/inhibition balance, we examined the neuromodulation of STDP in FS cells of mouse visual cortex. We found that stimulation of adrenergic receptors enables the induction of Hebbian bidirectional STDP in FS cells in a manner consistent with a pull-push mechanism previously characterized in pyramidal cells. However, in pyramidal cells, STDP induction depends on NMDA receptors, whereas in FS cells it depends on mGluR5 receptors. We propose that neuromodulators control the polarity of STDP in different synapses in the same manner, and independently of the induction mechanism, by acting downstream in the plasticity cascade. By doing so, neuromodulators may allow coordinated plastic changes in FS and pyramidal cells. PMID- 23926271 TI - How to scale down postsynaptic strength. AB - Synaptic scaling is a form of synaptic plasticity that contributes to the homeostatic regulation of neuronal activity both in vitro and in vivo, by bidirectionally and proportionally adjusting postsynaptic AMPA receptor (AMPAR) abundance to compensate for chronic perturbations in activity. This proportional regulation of synaptic strength allows synaptic scaling to normalize activity without disrupting the synapse-specific differences in strength thought to underlie memory storage, but how such proportional scaling of synaptic strength is accomplished at the biophysical level is unknown. Here we addressed this question in cultured rat visual cortical pyramidal neurons. We used photoactivation and fluorescence recovery after photobleaching of fluorescently tagged AMPAR to show that scaling down, but not up, decreases the steady-state accumulation of synaptic AMPAR by increasing the rate at which they unbind from and exit the postsynaptic density (Koff). This increase in Koff was not diffusion limited, was independent of AMPAR endocytosis, and was prevented by a scaffold manipulation that specifically blocks scaling down, suggesting that it is accomplished through enhanced dissociation of AMPAR from synaptic scaffold tethers. Finally, simulations show that increasing Koff decreases synaptic strength multiplicatively, by reducing the fractional occupancy of available scaffold "slots." These data demonstrate that scaling down is accomplished through a regulated increase in Koff, which in turn reduces the fractional occupancy of synaptic scaffolds to proportionally reduce synaptic strength. PMID- 23926273 TI - Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95. AB - The spatiotemporal organization of neurotransmitter receptors in postsynaptic membranes is a fundamental determinant of synaptic transmission and information processing by the brain. Using four independent super-resolution light imaging methods and EM of genetically tagged and endogenous receptors, we show that, in rat hippocampal neurons, AMPARs are often highly concentrated inside synapses into a few clusters of ~70 nm that contain ~20 receptors. AMPARs are stabilized reversibly in these nanodomains and diffuse freely outside them. Nanodomains are dynamic in their shape and position within synapses and can form or disappear within minutes, although they are mostly stable for up to 1 h. AMPAR nanodomains are often, but not systematically, colocalized with clusters of the scaffold protein PSD95, which are generally of larger size than AMPAR nanoclusters. PSD95 expression level regulates AMPAR nanodomain size and compactness in parallel to miniature EPSC amplitude. Monte Carlo simulations further indicate the impact of AMPAR concentration in clusters on the efficacy of synaptic transmission. The observation that AMPARs are highly concentrated in nanodomains, instead of diffusively distributed in the PSD as generally thought, has important consequences on our understanding of excitatory neurotransmission. Furthermore, our results indicate that glutamatergic synaptic transmission is controlled by the nanometer-scale regulation of the size of these highly concentrated nanodomains. PMID- 23926274 TI - Correlation between OFF and ON channels underlies dark target selectivity in an insect visual system. AB - In both vertebrates and invertebrates, evidence supports separation of luminance increments and decrements (ON and OFF channels) in early stages of visual processing (Hartline, 1938; Joesch et al., 2010); however, less is known about how these parallel pathways are recombined to encode form and motion. In Drosophila, genetic knockdown of inputs to putative ON and OFF pathways and direct recording from downstream neurons in the wide-field motion pathway reveal that local elementary motion detectors exist in pairs that separately correlate contrast polarity channels, ON with ON and OFF with OFF (Joesch et al., 2013). However, behavioral responses to reverse-phi motion of discrete features reveal additional correlations of the opposite signs (Clark et al., 2011). We here present intracellular recordings from feature detecting neurons in the dragonfly that provide direct physiological evidence for the correlation of OFF and ON pathways. These neurons show clear polarity selectivity for feature contrast, responding strongly to targets that are darker than the background and only weakly to dark contrasting edges. These dark target responses are much stronger than the linear combination of responses to ON and OFF edges. We compare these data with output from elementary motion detector-based models (Eichner et al., 2011; Clark et al., 2011), with and without stages of strong center-surround antagonism. Our data support an alternative elementary small target motion detector model, which derives dark target selectivity from the correlation of a delayed OFF with an un-delayed ON signal at each individual visual processing unit (Wiederman et al., 2008, 2009). PMID- 23926272 TI - Ordered recruitment of dynactin to the microtubule plus-end is required for efficient initiation of retrograde axonal transport. AB - Long-range retrograde axonal transport in neurons is driven exclusively by the microtubule motor cytoplasmic dynein. The efficient initiation of dynein-mediated transport from the distal axon is critical for normal neuronal function, and neurodegenerative disease-associated mutations have been shown to specifically disrupt this process. Here, we examine the role of dynamic microtubules and microtubule plus-end binding proteins (+TIPs) in the initiation of dynein mediated retrograde axonal transport using live-cell imaging of cargo motility in primary mouse dorsal root ganglion neurons. We show that end-binding (EB) positive dynamic microtubules are enriched in the distal axon. The +TIPs EB1, EB3, and cytoplasmic linker protein-170 (CLIP-170) interact with these dynamic microtubules, recruiting the dynein activator dynactin in an ordered pathway, leading to the initiation of retrograde transport by the motor dynein. Once transport has initiated, however, neither the EBs nor CLIP-170 are required to maintain transport flux along the mid-axon. In contrast, the +TIP Lis1 activates transport through a distinct mechanism and is required to maintain processive organelle transport along both the distal and mid-axon. Further, we show that the EB/CLIP-170/dynactin-dependent mechanism is required for the efficient initiation of transport from the distal axon for multiple distinct cargos, including mitochondria, Rab5-positive early endosomes, late endosomes/lysosomes, and TrkA-, TrkB-, and APP-positive organelles. Our observations indicate that there is an essential role for +TIPs in the regulation of retrograde transport initiation in the neuron. PMID- 23926275 TI - Disruption of dorsolateral but not ventrolateral prefrontal cortex improves unconscious perceptual memories. AB - Attentive encoding often leads to more accurate responses in recognition memory tests. However, previous studies have described conditions under which taxing explicit memory resources by attentional distraction improved perceptual recognition memory without awareness. These findings lead to the hypothesis that explicit memory processes mediated by the prefrontal cortex (PFC) can interfere with memory processes necessary for implicit recognition memory. The present study directly tested this hypothesis by applying transcranial magnetic stimulation separately over either dorsolateral (DLPFC) or ventrolateral PFC (VLPFC) in humans before performance of a visual memory task. Disruption of DLPFC function led to improvement in recognition accuracy only in responses in which the participant's awareness of memory retrieval was absent. However, disruption of VLPFC function led to subtle shifts in recollection and familiarity accuracy. We conclude that explicit memory processes mediated by the DLPFC can indirectly interfere with implicit recognition memory. PMID- 23926276 TI - Rectifying electrical synapses can affect the influence of synaptic modulation on output pattern robustness. AB - Rectifying electrical synapses are commonplace, but surprisingly little is known about how rectification alters the dynamics of neuronal networks. In this study, we use computational models to investigate how rectifying electrical synapses change the behavior of a small neuronal network that exhibits complex rhythmic output patterns. We begin with an electrically coupled circuit of three oscillatory neurons with different starting frequencies, and subsequently add two additional neurons and inhibitory chemical synapses. The five-cell model represents a pattern-generating neuronal network with two simultaneous rhythms competing for the recruitment of a hub neuron. We compare four different configurations of rectifying synapse placement and polarity, and we investigate how rectification changes the functional output of this network. Rectification can have a striking effect on the network's sensitivity to alterations of the strengths of the chemical synapses in the network. For some configurations, the rectification makes the circuit dynamics remarkably robust against changes in synaptic strength compared with the nonrectifying case. Based on our findings, we predict that modulation of rectifying electrical synapses could have functional consequences for the neuronal circuits that express them. PMID- 23926277 TI - A simple solution to a difficult problem: mitral pannus removal using a minimal access approach. PMID- 23926278 TI - Sera from patients with multifocal motor neuropathy disrupt the blood-nerve barrier. AB - OBJECTIVE: In multifocal motor neuropathy (MMN), the destruction of the blood nerve barrier (BNB) has been considered to be the key step in the disease process. The purpose of the present study was to ascertain whether sera from patients with MMN can open the BNB, and which component of patient sera is the most important for this disruption. METHODS: We evaluated the effects of sera from patients with MMN, patients with amyotrophic lateral sclerosis, and control subjects on the expression of tight junction proteins and vascular cell adhesion molecule-1 (VCAM-1), and on the transendothelial electrical resistance (TEER) in human peripheral nerve microvascular endothelial cells (PnMECs). RESULTS: The sera from patients with MMN decreased the claudin-5 protein expression and the TEER in PnMECs. However, this effect was reversed after application of an anti vascular endothelial growth factor (anti-VEGF) neutralising antibody. The VEGF secreted by PnMECs was significantly increased after exposure to the sera from patients with MMN. The sera from patients with MMN also increased the VCAM-1 protein expression by upregulating the nuclear factor kappa-B (NF-kappaB) signalling. The immunoglobulin G purified from MMN sera decreased the expression of claudin-5 and increased the VCAM-1 expression in PnMECs. CONCLUSIONS: The sera from MMN patients may disrupt the BNB function via the autocrine secretion of VEGF in PnMECs, or the exposure to autoantibodies against PnMECs that are contained in the MMN sera. Autoantibodies against PnMECs in MMN sera may activate the BNB by upregulating the VCAM-1 expression, thereby allowing for the entry of a large number of circulating inflammatory cells into the peripheral nervous system. PMID- 23926279 TI - Posterior cingulate epilepsy: clinical and neurophysiological analysis. AB - OBJECTIVE: Posterior cingulate epilepsy (PCE) is misleading because the seizure onset is located in an anatomically deep and semiologically silent area. This type of epilepsy is rare and has not been well described yet. Knowledge of the characteristics of PCE is important for the interpretation of presurgical evaluation and better surgical strategy. The purpose of this study was to better characterise the clinical and neurophysiological features of PCE. METHODS: This retrospective analysis included seven intractable PCE patients. Six patients had postcingulate ictal onset identified by stereotactic EEG (SEEG) evaluations. One patient had a postcingulate tumour. We analysed clinical semiology, the scalp EEG/SEEG findings and cortico-cortical evoked potential (CCEP). RESULTS: The classifications of scalp EEG were various, including non-localisible, lateralised to the seizure onset side, regional parieto-occipital, regional frontocentral and regional temporal. Three of seven patients showed motor manifestations, including bilateral asymmetric tonic seizures and hypermotor seizures. In these patients, ictal activities spread to frontal (lateral premotor area, orbitofrontal cortex, supplementary motor area, anteior cingulate gyrus) and parietal (precuneus, posterior cingulate gyrus, inferior parietal lobule (IPL), postcentral gyrus) areas. Four patients showed dialeptic seizures or automotor seizures, with seizure spread to medial temporal or IPL areas. CCEP was performed in four patients, suggesting electrophysiological connections from the posterior cingulate gyrus to parietal, temporal, mesial occipital and mesial frontal areas. CONCLUSIONS: This study revealed that the network from the posterior cingulate gyrus and the semiology of PCE (motor manifestation vs dialeptic/automotor seizure) varies depending upon the seizure spread patterns. PMID- 23926280 TI - Incretin-based therapies: can we achieve glycemic control and cardioprotection? AB - Glucagon-like (GLP-1) is a peptide hormone secreted from the small intestine in response to nutrient ingestion. GLP-1 stimulates insulin secretion in a glucose dependent manner, inhibits glucagon secretion and gastric emptying, and reduces appetite. Because of the short circulating half-life of the native GLP-1, novel GLP-1 receptor (GLP-1R) agonists and analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors have been developed to facilitate clinical use. Emerging evidence indicates that GLP-1-based therapies are safe and may provide cardiovascular (CV) benefits beyond glycemic control. Preclinical and clinical studies are providing increasing evidence that GLP-1 therapies may positively affect CV function and metabolism by salutary effects on CV risk factors as well as via direct cardioprotective actions. However, the mechanisms whereby the various classes of incretin-based therapies exert CV effects may be mechanistically distinct and may not necessarily lead to similar CV outcomes. In this review, we will discuss the potential mechanisms and current understanding of CV benefits of native GLP-1, GLP-1R agonists and analogs, and of DPP-4 inhibitor therapies as a means to compare their putative CV benefits. PMID- 23926281 TI - The effect of cilostamide on gap junction communication dynamics, chromatin remodeling, and competence acquisition in pig oocytes following parthenogenetic activation and nuclear transfer. AB - In the pig, the efficiency of in vitro embryo production and somatic cell nuclear transfer (SCNT) procedures remains limited. It has been suggested that prematuration treatments (pre-IVM) based on the prolongation of a patent, bidirectional crosstalk between the oocyte and the cumulus cells through gap junction mediate communication (GJC), with the maintenance of a proper level of cAMP, could improve the developmental capability of oocytes. The aim of this study was to assess: 1) dose-dependent effects of cilostamide on nuclear maturation kinetics, 2) the relationship between treatments on GJC functionality and large-scale chromatin configuration changes, and 3) the impact of treatments on developmental competence acquisition after parthenogenetic activation (PA) and SCNT. Accordingly, cumulus-oocyte complexes were collected from 3- to 6-mm antral follicles and cultured for 24 h in defined culture medium with or without 1 MUM cilostamide. GJC functionality was assessed by Lucifer yellow microinjection, while chromatin configuration was evaluated by fluorescence microscopy after nuclear staining. Cilostamide administration sustained functional coupling for up to 24 h of culture and delayed meiotic resumption, as only 25.6% of cilostamide treated oocytes reached the pro-metaphase I stage compared to the control (69.7%; P < 0.05). Moreover, progressive chromatin condensation was delayed before meiotic resumption based upon G2/M biomarker phosphoprotein epitope acquisition using immunolocalization. Importantly, cilostamide treatment under these conditions improved oocyte developmental competence, as reflected in higher blastocyst quality after both parthenogenetic activation and SCNT. PMID- 23926282 TI - Trypsin regulates meiotic initiation in the Japanese eel (Anguilla japonica) by promoting the uptake of taurine into germ cells during spermatogenesis. AB - Meiosis is a unique and critical process in reproduction. Although the key molecular components of meiosis have been identified, the molecular mechanisms regulating the entry into this pathway remain unclear. We previously demonstrated that a progestin in teleost fish, 17alpha, 20beta-dihydroxy-4-pregnen-3-one, is essential for meiotic initiation, and up-regulates taurine synthesis and the production of trypsin in Sertoli cells. In the present study, we found that trypsin promotes the uptake of taurine into germ cells through the up-regulation of solute carrier family 6 (neurotransmitter transporter, taurine), member 6 (Slc6a6) expression. We further found that this up-regulation of the taurine signal is required for Spo11a expression and meiotic initiation. PMID- 23926283 TI - Macrophage phenotype in the mammary gland fluctuates over the course of the estrous cycle and is regulated by ovarian steroid hormones. AB - The mammary gland undergoes development and regression over the course of the ovarian cycle under the regulation of ovarian hormones. Macrophages are implicated as local mediators of this tissue remodeling and may also affect immune surveillance and tumor incidence. To investigate cycle-related changes in macrophage phenotype, mammary gland cells from naturally cycling Cfms-Gfp mice recovered at estrus, metestrus, diestrus, and proestrus were analyzed by flow cytometry. Macrophage expression of MHCII was highest in the proestrus phase, with a 1.6-fold increase compared to the metestrus phase. Similarly, macrophage expression of CD204 was 1.9-fold higher at proestrus compared to estrus. Conversely, macrophage expression of NKG2D was increased at metestrus and diestrus by 7-fold and 5-fold, respectively, compared to estrus. To investigate hormonal regulation of macrophage phenotype, an ovariectomy and hormone replacement model was utilized. Ovariectomized mice were stimulated with exogenous estradiol and progesterone to induce early alveolar development, then given progesterone receptor antagonist RU486 to elicit alveolar bud regression. Progesterone and estradiol in combination reduced macrophage expression of MHCII and CD204 by 5-fold and 3-fold, respectively, and increased macrophage expression of NKG2D by 4-fold. Administration of RU486, following estradiol and progesterone, reversed the macrophage phenotype. These results reveal an essential requirement for ovarian hormones in regulating macrophage phenotype in the mammary gland and indicate that progesterone is particularly critical for controlling macrophage antigen presentation and immune surveillance capacity. PMID- 23926284 TI - Sex-specific regulation of AMP-activated protein kinase (AMPK) in the Pacific oyster Crassostrea gigas. AB - The hermaphrodite Pacific oyster Crassostrea gigas displays a high energy allocation to reproduction. We studied the expression of AMP-activated protein kinase (AMPK) during gametogenesis in the gonad and characterized the mRNA sequences of the AMPK subunits: the AMPK alpha mRNA sequence was previously characterized; we identified AMPK beta, AMPK gamma, and mRNAs of putative AMPK related targets following bioinformatics mining on existing genomic resources. We analyzed the mRNA expression of the AMPK alpha, beta, and gamma subunits in the gonads of male and female oysters through a reproductive cycle, and we quantified the mRNA expression of genes belonging to fatty acid and glucose metabolism. AMPK alpha mRNA levels were more abundant in males at the first stage of gametogenesis, when mitotic activity and the differentiation of germinal cells occur, and were always more abundant in males than in females. Some targets of fatty acid and glucose metabolism appeared to be correlated with the expression of AMPK subunits at the mRNA level. We then analyzed the sex-specific AMPK activity by measuring the phosphorylation of the catalytic AMPK alpha protein and its expression at the protein level. Both the amount of AMPK alpha protein and threonine 172 phosphorylation appeared to be almost totally inhibited in mature female gonads at stage 3, at the time when accumulation of reserves in oocytes was promoted, while it remained at a high level in mature spermatozoa. Its activation might play a sex-dependent role in the management of energy during gametogenesis in oyster. PMID- 23926285 TI - Translational activation of developmental messenger RNAs during neonatal mouse testis development. AB - The basic tenets of germ cell development are conserved among metazoans. Following lineage commitment in the embryo, germ cells proliferate, transition into meiosis, and then differentiate into gametes capable of fertilization. In lower organisms such as Drosophila and C. elegans, germline stem cells make the decision to proliferate or enter meiosis based in large part on the regulated expression of genes by translational control. This study undertakes a direct characterization of mRNAs that experience translational control and their involvement in similar decisions in the mammalian testis. We previously showed that translation of mRNA encoding the germ cell-specific gene Rhox13 was suppressed in the fetal and neonatal testis. By investigating changes in message utilization during neonatal testis development, we found that a large number of mRNAs encoding both housekeeping and germ cell-specific proteins experience enhanced translational efficiency, rather than increase in abundance, in the testis as quiescent gonocytes transition to mitotic spermatogonia. Our results indicate that translational control is a significant regulator of the germ cell proteome during neonatal testis development. PMID- 23926286 TI - Transforming growth factor-beta 1 (TGF-B1) liberation from its latent complex during embryo implantation and its regulation by estradiol in mouse. AB - Transforming growth factor-beta (TGF-B) plays an important role in embryo implantation; however, TGF-B requires liberation from its inactive latent forms (i.e., large latent TGF-B complex [LLC] and small latent TGF-B complex [SLC]) to its biologically active (i.e., monomer or dimer) forms in order to act on its receptors (TGF-BRs), which in turn activate SMAD2/3. Activation of TGF-B1 from its latent complexes in the uterus is not yet deciphered. We investigated uterine latent TGF-B1 complex and its biologically active form during implantation, decidualization, and delayed implantation. Our study, utilizing nonreducing SDS PAGE followed by Western blotting and immunoblotting with TGF-B1, LTBP1, and latency-associated peptide, showed the presence of LLC and SLC in the uterine extracellular matrix and plasma membranous protein fraction during stages of the implantation period. A biologically active form of TGF-B1 (~17-kDa monomer) was highly elevated in the uterine plasma membranous compartment at the peri implantation stage (implantation and nonimplantation sites). Administration of hydroxychloroquine (an inhibitor of pro-TGF-B processing) at the preimplantation stage was able to block the liberation of biologically active TGF-B1 from its latent complex at the postimplantation stage; as a consequence, the number of implantation sites was reduced at Day 5 (1000 h), as was the number of fetuses at Day 13. The inhibition of TGF-B1 showed reduced levels of phosphorylated SMAD3. Further, the delayed-implantation mouse model showed progesterone and estradiol coordination to release the active TGF-B1 form from its latent complex in the receptive endometrium. This study demonstrates the importance of liberation of biologically active TGF-B1 during the implantation period and its regulation by estradiol. PMID- 23926287 TI - Evaluation of Oatp and Mrp2 activities in hepatobiliary excretion using newly developed positron emission tomography tracer [11C]dehydropravastatin in rats. AB - We developed a pravastatin derivative, sodium (3R,5R)-3,5-dihydroxy-7 ((1S,2S,6S,8S)-6-hydroxy-2-methyl-8-((1-[(11)C]-(E)-2-methyl-but-2-enoyl)oxy) 1,2,6,7,8,8a-hexahydronaphthalen-1-yl)heptanoate ([(11)C]DPV), as a positron emission tomography (PET) probe for noninvasive measurement of hepatobiliary transport, and conducted pharmacokinetic analysis in rats as a feasibility study for future clinical study. Transport activities of DPV in freshly isolated rat hepatocytes and rodent multidrug resistance-associated protein 2 (rMrp2; human, MRP2)-expressing membrane vesicles were similar to those of pravastatin. Rifampicin diminished the uptake of DPV and pravastatin by the hepatocytes, with similar inhibition potency. [(11)C]DPV underwent biotransformation to produce at least two metabolites in rat, but metabolism of [(11)C]DPV occurred negligibly in human hepatocytes during a 90-minute incubation. After intravenous injection, [(11)C]DPV was mainly distributed to the liver and kidneys, where the tissue uptake clearances (CLuptake,liver and CLuptake,kidney) were blood-flow-limited (73.6 +/- 4.8 and 24.6 +/- 0.6 ml/min per kilogram, respectively). Systemic elimination of [(11)C]DPV was delayed in rifampicin-treated rat and an Mrp2 deficient mutant rat, Eisai hyperbilirubinemic mutant rat (EHBR). Rifampicin treatment decreased both CLuptake,liver and CLuptake,kidney of [(11)C]DPV by 30% (P < 0.05), whereas these parameters were unchanged in EHBR. Meanwhile, the canalicular efflux clearance (CLint,bile) of [(11)C]DPV, which was 12.2 +/- 1.5 ml/min per kilogram in the control rat, decreased by 60% and 89% in rifampicin treated rat and EHBR (P < 0.05), respectively. These results indicate that [(11)C]DPV is taken up into the liver by organic anion-transporting polypeptides (rodent, Oatps; human, OATP) and excreted into bile by Mrp2 in rat, and that rifampicin may inhibit Mrp2 as well as Oatps, and consequently increase systemic exposure of [(11)C]DPV. PET using [(11)C]DPV is feasible for studies prior to the future clinical investigation of OATP and MRP2 functionality, especially for personalized medicine. PMID- 23926288 TI - Bimodal concentration-response of nicotine involves the nicotinic acetylcholine receptor, transient receptor potential vanilloid type 1, and transient receptor potential ankyrin 1 channels in mouse trachea and sensory neurons. AB - High concentrations of nicotine, as in the saliva of oral tobacco consumers or in smoking cessation aids, have been shown to sensitize/activate recombinant transient receptor potential vanilloid type 1 (rTRPV1) and mouse TRPA1 (mTRPA1) channels. By measuring stimulated calcitonin gene-related peptide (CGRP) release from the isolated mouse trachea, we established a bimodal concentration-response relationship with a threshold below 10 uM (-)-nicotine, a maximum at 100 uM, an apparent nadir between 0.5 and 10 mM, and a renewed increase at 20 mM. The first peak was unchanged in TRPV1/A1 double-null mutants as compared with wild-types and was abolished by specific nicotinic acetylcholine receptor (nAChR) inhibitors and by camphor, discovered to act as nicotinic antagonist. The nicotine response at 20 mM was strongly pHe-dependent, - five times greater at pH 9.0 than 7.4, indicating that intracellular permeation of the (uncharged) alkaloid was required to reach the TRPV1/A1 binding sites. The response was strongly reduced in both null mutants, and more so in double-null mutants. Upon measuring calcium transients in nodose/jugular and dorsal root ganglion neurons in response to 100 uM nicotine, 48% of the vagal (but only 14% of the somatic) sensory neurons were activated, the latter very weakly. However, nicotine 20 mM at pH 9.0 repeatedly activated almost every single cultured neuron, partly by releasing intracellular calcium and independent of TRPV1/A1 and nAChRs. In conclusion, in mouse tracheal sensory nerves nAChRs are 200-fold more sensitive to nicotine than TRPV1/A1; they are widely coexpressed with the capsaicin receptor among vagal sensory neurons and twice as abundant as TRPA1. Nicotine is the major stimulant in tobacco, and its sensory impact through nAChRs should not be disregarded. PMID- 23926290 TI - Articulating novel words: children's oromotor skills predict nonword repetition abilities. AB - PURPOSE: Pronouncing a novel word for the first time requires the transformation of a newly encoded speech signal into a series of coordinated, exquisitely timed oromotor movements. Individual differences in children's ability to repeat novel nonwords are associated with vocabulary development and later literacy. Nonword repetition (NWR) is often used to test clinical populations. While phonological/auditory memory contributions to learning and pronouncing nonwords have been extensively studied, much less is known about the contribution of children's oromotor skills to this process. METHOD: Two independent cohorts of children (7-13 years [N = 40] and 6.9-7.7 years [N = 37]) were tested on a battery of linguistic and nonlinguistic tests, including NWR and oromotor tasks. RESULTS: In both cohorts, individual differences in oromotor control were a significant contributor to NWR abilities; moreover, in an omnibus analysis including experimental and standardized tasks, oromotor control predicted the most unique variance in NWR. CONCLUSION: Results indicate that nonlinguistic oromotor skills contribute to children's NWR ability and suggest that important aspects of language learning and consequent language deficits may be rooted in the ability to perform complex sensorimotor transformations. PMID- 23926289 TI - Olanzapine activates hepatic mammalian target of rapamycin: new mechanistic insight into metabolic dysregulation with atypical antipsychotic drugs. AB - Olanzapine (OLZ), an effective treatment of schizophrenia and other disorders, causes weight gain and metabolic syndrome. Most studies to date have focused on the potential effects of OLZ on the central nervous system's mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in the systemic effects of OLZ. Thus, the purpose of this study was to investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg per day) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a pseudo-fasted state, which depleted hepatic glycogen reserves. OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMP-activated protein kinase (AMPK) signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mammalian target of rapamycin) pathways, which yields new insight into the metabolic side effects of this drug. PMID- 23926291 TI - Auditory and cognitive effects of aging on perception of environmental sounds in natural auditory scenes. AB - PURPOSE: Previously, Gygi and Shafiro (2011) found that when environmental sounds are semantically incongruent with the background scene (e.g., horse galloping in a restaurant), they can be identified more accurately by young normal-hearing listeners (YNH) than sounds congruent with the scene (e.g., horse galloping at a racetrack). This study investigated how age and high-frequency audibility affect this Incongruency Advantage (IA) effect. METHOD: In Experiments 1a and 1b, elderly listeners ( N = 18 for 1a; N = 10 for 1b) with age-appropriate hearing (EAH) were tested on target sounds and auditory scenes in 5 sound-to-scene ratios (So/Sc) between -3 and -18 dB. Experiment 2 tested 11 YNH on the same sound-scene pairings lowpass-filtered at 4 kHz (YNH-4k). RESULTS: The EAH and YNH-4k groups exhibited an almost identical pattern of significant IA effects, but both were at approximately 3.9 dB higher So/Sc than the previously tested YNH listeners. However, the psychometric functions revealed a shallower slope for EAH listeners compared with YNH listeners for the congruent stimuli only, suggesting a greater difficulty for the EAH listeners in attending to sounds expected to occur in a scene. CONCLUSIONS: These findings indicate that semantic relationships between environmental sounds in soundscapes are mediated by both audibility and cognitive factors and suggest a method for dissociating these factors. PMID- 23926292 TI - Kinematic parameters of signed verbs. AB - PURPOSE: Sign language users recruit physical properties of visual motion to convey linguistic information. Research on American Sign Language (ASL) indicates that signers systematically use kinematic features (e.g., velocity, deceleration) of dominant hand motion for distinguishing specific semantic properties of verb classes in production ( Malaia & Wilbur, 2012a) and process these distinctions as part of the phonological structure of these verb classes in comprehension ( Malaia, Ranaweera, Wilbur, & Talavage, 2012). These studies are driven by the event visibility hypothesis by Wilbur (2003), who proposed that such use of kinematic features should be universal to sign language (SL) by the grammaticalization of physics and geometry for linguistic purposes. In a prior motion capture study, Malaia and Wilbur (2012a) lent support for the event visibility hypothesis in ASL, but there has not been quantitative data from other SLs to test the generalization to other languages. METHOD: The authors investigated the kinematic parameters of predicates in Croatian Sign Language ( Hrvatskom Znakovnom Jeziku [HZJ]). RESULTS: Kinematic features of verb signs were affected both by event structure of the predicate (semantics) and phrase position within the sentence (prosody). CONCLUSION: The data demonstrate that kinematic features of motion in HZJ verb signs are recruited to convey morphological and prosodic information. This is the first crosslinguistic motion capture confirmation that specific kinematic properties of articulator motion are grammaticalized in other SLs to express linguistic features. PMID- 23926293 TI - Listeners' attitudes toward children with voice problems. AB - PURPOSE: To investigate the attitudes of school teachers toward children with voice problems in a Chinese population. METHOD: Three groups of listeners participated in this study: primary school teachers, speech-language pathology students, and general university students. The participants were required to make attitude judgments on 12 voice samples using a semantic differential scale with 22 bipolar adjective pairs. The voice samples were collected from 6 children with healthy voices and 6 children with dysphonia. The 22 bipolar adjective pairs were intended to cover nonspeech characteristics about the child's personality, social characteristics, and physical appearance. RESULTS: The mean attitude ratings received by children with dysphonic voice were significantly lower (i.e., less favorable) than those received by children with healthy voices in all of the 22 adjective pairs (all ps < .002). The attitude ratings made by the 3 groups of listeners were not significantly different from one another ( ps > .05). CONCLUSION: To our knowledge, this is the first study in which the authors examine listeners' perception toward children with voice problems in the Chinese population. The results suggest that voice problems in children warrant attention, and their effects on the child should not be underestimated. The findings also highlight the importance of early identification and intervention for children with voice problems. PMID- 23926294 TI - Developmental change is key to understanding primary language impairment: the case of phonotactic probability and nonword repetition. AB - PURPOSE: In this study, the authors aimed to explore the relationship between lexical and phonological knowledge in children with primary language impairment (PLI) through the application of a developmental methodology. Specifically, they tested whether there is evidence for an impairment in the process of phonological abstraction in this group of children over and above that which would be predicted by their vocabulary growth. METHOD: The authors measured developmental change in the abilities of typically developing (TD) children ( n = 38, chronological age [CA] = 3;0-5;6 [years;months]) and those with PLI ( n = 13, CA = 3;0-6;6 and 4;6-8;0) to repeat nonwords with high and low phonotactic probability (PP) to uncover group differences in the process of abstraction of phonological representations. RESULTS: Cross-sectional developmental trajectories of change in nonword repetition abilities were compared across CA and vocabulary growth. Unlike TD children, the children with PLI did not evince a narrowing gap in the influence of PP across development, and they reached a plateau in their development. CONCLUSION: These results suggest slowed emergence of phonological representations in PLI, with a plateau in the development of lexical-phonological representations. This plateau may represent entrenchment and "fixing" due to a missed critical period and/or atypical word learning biases in PLI. PMID- 23926295 TI - The relationship between parent report of adaptive behavior and direct assessment of reading ability in children with autism spectrum disorder. AB - PURPOSE: This study was designed to shed light on the profile of reading ability in children with autism spectrum disorder (ASD). A key aim was to examine the relationship between parent report of adaptive behavior and direct assessment of reading ability in these children. METHOD: The authors investigated children's reading ability using the Wide Range Achievement Test-Fourth Edition (Wilkinson & Robertson, 2006) and the Neale Analysis of Reading Ability-Third Edition (Neale, 2007). Parent report data was collected using the Vineland Adaptive Behavior Scales-Second Edition (Sparrow, Cicchetti, & Balla, 2005). Participants were 21 children with ASD (6-11 years) and their primary caregivers. RESULTS: Direct assessment of children's reading ability showed that some children with ASD have difficulty learning to read and exhibit particular weaknesses in comprehension. The results revealed positive relationships between Vineland Adaptive Behavior Scales scores in the Adaptive Communication domain and direct assessment of children's reading ability across 3 measures of reading (word-level accuracy, passage-level accuracy, and passage-level comprehension). CONCLUSIONS: Although literacy levels vary among children with ASD, some clearly struggle with reading. There is a significant relationship between parent self-report of adaptive behavior and direct assessment of children's reading ability. PMID- 23926296 TI - Early predictors of language and social communication impairments at ages 9-11 years: a follow-up study of early-referred children. AB - PURPOSE: In this study, the authors aimed to evaluate hypotheses that early sociocognition will predict later social communication and early phonology will predict later morphosyntax in clinically referred preschoolers. METHOD: Participants were 108 children ages 9-11 years who had been referred to clinical services with concerns about language at age 21/2-31/2 years. Predictors at Time 1 (T1) were measures of sociocognition, word/nonword repetition, and receptive language. Outcome measures at Time 3 (T3) included a social communication questionnaire completed by parents and tests of nonword repetition, morphosyntax, and receptive language. RESULTS: Group- and case-level analyses revealed early sociocognition to be the strongest predictor of social communication problems, which by T3 affected almost one third of the sample. At the group level, early phonology, which was a significant problem for the majority of children at T1, was a weak predictor of morphosyntax at T3. However, at the case level the majority of children with poor morphosyntax and nonword repetition at outcome had had very low repetition scores at T1. CONCLUSIONS: In early language referrals, it is important to identify and address sociocognitive problems, a considerable risk for later social communication and autism spectrum disorders. The majority of early-referred children had phonological problems, often severe, but these require further investigation to determine their longer term significance for language. PMID- 23926297 TI - STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients. AB - Large granular lymphocyte leukemia (LGL) is often associated with immune cytopenias and can cooccur in the context of aplastic anemia (AA) and myelodysplastic syndromes (MDS). We took advantage of the recent description of signal transducer and activator of transcription 3 (STAT3) mutations in LGL clonal expansions to test, using sensitive methods, for the presence of these mutations in a large cohort of 367 MDS and 140 AA cases. STAT3 clones can be found not only in known LGL concomitant cases, but in a small proportion of unsuspected ones (7% AA and 2.5% MDS). In STAT3-mutated AA patients, an interesting trend toward better responses of immunosuppressive therapy and an association with the presence of human leukocyte antigen-DR15 were found. MDSs harboring a STAT3 mutant clone showed a lower degree of bone marrow cellularity and a higher frequency of developing chromosome 7 abnormalities. STAT3-mutant LGL clones may facilitate a persistently dysregulated autoimmune activation, responsible for the primary induction of bone marrow failure in a subset of AA and MDS patients. PMID- 23926299 TI - JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia. AB - The transcription factor signal transducers and activators of transcription 5 (STAT5) has an important and unique role in Breakpoint Cluster Region - Abelson 1 (BCR-ABL1)-driven neoplasias. STAT5 is an essential component in the signaling network that maintains the survival and growth of chronic myeloid leukemia (CML) cells. In contrast, the function of the prototypical upstream kinase of STAT5, the Janus kinase JAK2, in CML is still under debate. Although there is widespread agreement that JAK2 is part of the signaling network downstream of BCR-ABL1, it is unclear whether and under what circumstances JAK2 inhibitors may be beneficial for CML patients. Recent studies in murine models have cast doubt on the importance of JAK2 in CML maintenance. Nevertheless, JAK2 has been proposed to have a central role in the cytokine signaling machinery that allows the survival of CML stem cells in the presence of BCR-ABL1 tyrosine kinase inhibitors. In this review, we summarize the current debate and provide an overview of the arguments on both sides of the fence. We present recent evidence showing that CML stem cells do not depend on BCR-ABL1 kinase activity but require the continuous support of the hematopoietic niche and its distinct cytokine environment and suggest that it has the potential to resolve the dispute. PMID- 23926298 TI - Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hematologic malignancies. AB - FTY720 (Fingolimod, Gilenya) is a sphingosine analog used as an immunosuppressant in multiple sclerosis patients. FTY720 is also a potent protein phosphatase 2A (PP2A)-activating drug (PAD). PP2A is a tumor suppressor found inactivated in different types of cancer. We show here that PP2A is inactive in polycythemia vera (PV) and other myeloproliferative neoplasms characterized by the expression of the transforming Jak2(V617F) oncogene. PP2A inactivation occurs in a Jak2(V617F) dose/kinase-dependent manner through the PI-3Kgamma-PKC-induced phosphorylation of the PP2A inhibitor SET. Genetic or PAD-mediated PP2A reactivation induces Jak2(V617F) inactivation/downregulation and impairs clonogenic potential of Jak2(V617F) cell lines and PV but not normal CD34(+) progenitors. Likewise, FTY720 decreases leukemic allelic burden, reduces splenomegaly, and significantly increases survival of Jak2(V617F) leukemic mice without adverse effects. Mechanistically, we show that in Jak2(V617F) cells, FTY720 antileukemic activity requires neither FTY720 phosphorylation (FTY720-P) nor SET dimerization or ceramide induction but depends on interaction with SET K209. Moreover, we show that Jak2(V617F) also utilizes an alternative sphingosine kinase-1-mediated pathway to inhibit PP2A and that FTY720-P, acting as a sphingosine-1-phosphate-receptor-1 agonist, elicits signals leading to the Jak2 PI-3Kgamma-PKC-SET-mediated PP2A inhibition. Thus, PADs (eg, FTY720) represent suitable therapeutic alternatives for Jak2(V617F) MPNs. PMID- 23926300 TI - Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. AB - Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0 6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A. PMID- 23926301 TI - Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. DLBCL is a heterogeneous disease characterized by different genetic lesions. We herein report the functional characterization of a recurrent gain mapping on chromosome 11q24.3, found in 23% of 166 DLBCL cases analyzed. The transcription factors ETS1 and FLI1, located within the 11q24.3 region, had significantly higher expression in clinical samples carrying the gain. Functional studies on cell lines showed that ETS1 and FLI1 cooperate in sustaining DLBCL proliferation and viability and regulate genes involved in germinal center differentiation. Taken together, these data identify the 11q24.3 gain as a recurrent lesion in DLBCL leading to ETS1 and FLI1 deregulated expression, which can contribute to the pathogenesis of this disease. PMID- 23926302 TI - Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia. AB - Sitosterolemia is a rare, autosomal recessive disease caused by mutations in the adenosine triphosphate-binding cassette transporter genes ABCG5 or ABCG8 that result in accumulation of xenosterols in the body. Clinical manifestations include tendon xanthomas, premature coronary artery disease, hemolytic anemia, macrothrombocytopenia, and bleeding. Although the effect of sterol accumulation on the predisposition for atherosclerosis is evident, how xenosterol accumulation leads to defects in platelet physiology is unknown. Sitosterolemia induced in Abcg5- and Abcg8-deficient mice fed a high plant sterol diet resulted in accumulation of free sterols in platelet plasma membranes, leading to hyperactivatable platelets characterized by constitutive binding of fibrinogen to its alphaIIbbeta3 integrin receptor, internalization of the alphaIIbbeta3 complex, generation of platelet-derived microparticles, and changes in the quantity and subcellular localization of filamin. The latter was associated with macrothrombocytopenia, shedding of GPIbalpha, impaired platelet adhesion to von Willebrand factor, and inability to form stable thrombi. Plasma levels of soluble GPIbalpha were strongly correlated with plasma sitosterol levels in samples from human sitosterolemic patients, implicating a similar mechanism of sterol-induced platelet passivation in the human disease. Intercalation of plant sterols into the plasma membrane therefore results in dysregulation of multiple platelet activation pathways, leading to macrothrombocytopenia and bleeding. PMID- 23926303 TI - A role for IRF4 in the development of CLL. AB - Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator of B-cell development and function. A recent genome-wide single-nucleotide polymorphism (SNP) association study identified IRF4 as a major susceptibility gene in chronic lymphocytic leukemia (CLL). Although the SNPs located in the IRF4 gene were linked to a downregulation of IRF4 in CLL patients, whether a low level of IRF4 is critical for CLL development remains unclear. In rodents, CLL cells are derived from B1 cells whose population is dramatically expanded in immunoglobulin heavy chain Vh11 knock-in mice. We bred a Vh11 knock-in allele into IRF4-deficient mice (IRF4(-/-)Vh11). Here, we report that IRF4(-/-)Vh11 mice develop spontaneous early-onset CLL with 100% penetrance. Further analysis shows that IRF4(-/-)Vh11 CLL cells proliferate predominantly in spleen and express high levels of Mcl-1. IRF4(-/-)Vh11 CLL cells are resistant to apoptosis but reconstitution of IRF4 expression in the IRF4(-/-)Vh11 CLL cells inhibits their survival. Thus, our study demonstrates for the first time a causal relationship between low levels of IRF4 and the development of CLL. Moreover, our findings establish IRF4(-/-)Vh11 mice as a novel mouse model of CLL that not only is valuable for dissecting molecular pathogenesis of CLL but could also be used for therapeutic purposes. PMID- 23926305 TI - Requirement for Lyl1 in a model of Lmo2-driven early T-cell precursor ALL. AB - Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T cell acute lymphoblastic leukemia (T-ALL), including early T-cell precursor ALL (ETP-ALL) cases with poor prognosis. Lmo2 must be recruited to DNA by binding to the hematopoietic basic helix-loop-helix factors Scl/Tal1 or Lyl1. However, it is unknown which of these factors can mediate the leukemic activity of Lmo2. To address this, we have generated Lmo2-transgenic mice lacking either Scl or Lyl1 in the thymus. We show that although Scl is dispensable for Lmo2-driven leukemia, Lyl1 is critical for all oncogenic functions of Lmo2, including upregulation of a stem cell-like gene signature, aberrant self-renewal of thymocytes, and subsequent generation of T-cell leukemia. Lyl1 expression is restricted to preleukemic and leukemic stem cell populations in this model, providing a molecular explanation for the stage-specific expression of the Lmo2-induced gene expression program. Moreover, LMO2 and LYL1 are coexpressed in ETP-ALL patient samples, and LYL1 is required for growth of ETP-ALL cell lines. Thus, the LMO2 LYL1 interaction is a promising therapeutic target for inhibiting self-renewing cancer stem cells in T-ALL, including poor-prognosis ETP-ALL cases. PMID- 23926304 TI - Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study. AB - We retrospectively analyzed 110 patients with juvenile myelomonocytic leukemia, given single-unit, unrelated donor umbilical cord blood transplantation. Median age at diagnosis and at transplantation was 1.4 years (age range, 0.1-6.4 years) and 2.2 years (age range, 0.5-7.4 years), respectively. Before transplantation, 88 patients received chemotherapy; splenectomy was performed in 24 patients. Monosomy of chromosome 7 was the most frequent cytogenetic abnormality, found in 24% of patients. All but 8 patients received myeloablative conditioning; cyclosporine plus steroids was the most common graft-versus-host disease prophylaxis. Sixteen percent of units were HLA-matched with the recipient, whereas 43% and 35% had either 1 or 2 to 3 HLA disparities, respectively. The median number of nucleated cells infused was 7.1 * 10(7)/kg (range, 1.7-27.6 * 10(7)/kg). With a median follow-up of 64 months (range, 14-174 months), the 5 year cumulative incidences of transplantation-related mortality and relapse were 22% and 33%, respectively. The 5-year disease-free survival rate was 44%. In multivariate analysis, factors predicting better disease-free survival were age younger than 1.4 years at diagnosis (hazard ratio [HR], 0.42; P = .005), 0 to 1 HLA disparities in the donor/recipient pair (HR, 0.4; P = .009), and karyotype other than monosomy 7 (HR, 0.5; P = .02). Umbilical cord blood transplantation may cure a relevant proportion of children with juvenile myelomonocytic leukemia. Because disease recurrence remains the major cause of treatment failure, strategies to reduce incidence of relapse are warranted. PMID- 23926306 TI - Thalidomide corrects impaired mesenchymal stem cell function in inducing tolerogenic DCs in patients with immune thrombocytopenia. AB - Thalidomide (THD) is an immunomodulatory agent used to treat immune-mediated diseases. Immune thrombocytopenia (ITP) is an autoimmune disorder in which impaired mesenchymal stem cells (MSCs) are potentially involved. We demonstrated that MSCs in ITP patients had reduced proliferative capacity and lost their immunosuppressive function, which could be corrected with THD treatment. According to the gene profile, the downregulation of caspase-8 and caspase-10, and upregulation of oct3/4 and tgf-beta1, may be associated with THD modulation. Dendritic cells (DCs) played an important role in mediating the inhibitory activity of MSCs. To study the functional alteration of DCs elicited by MSCs, we sorted DCs after incubation with MSCs and performed T-lymphocyte reaction assays. The THD-modulated MSCs from ITP patients induced mature DCs to become tolerogenic DCs, whereas unmodulated MSCs had no effect. The induction of tolerogenicity in DCs by MSCs was dependent on the expression of TIEG1 in DCs. The study reveals the inability of MSCs from ITP patients to induce tolerogenic ability in DCs. THD could restore the regulatory effect of MSCs on DCs. These findings will help us understand the pathogenesis of ITP, and with appropriate safeguards, THD may benefit patients with ITP. PMID- 23926307 TI - JEB author selected for NASA astronaut training. PMID- 23926308 TI - Sound production mechanism in Gobius paganellus (Gobiidae). AB - Gobiidae, the largest fish family (>1500 species), has species from at least 10 genera that produce sounds for communication. Studies focused on goby sound production mechanisms have suggested that sounds are produced by the forcible ejection of water through small apertures in the opercles (hydrodynamic mechanism). The present study was a multidisciplinary investigation (morphology, muscle histology, high-speed video, sound analysis and electromyography) of the sound emission mechanism in Gobius paganellus, which produces both pulsed and tonal calls. Two populations were used, from Brittany and Venice. In the French population, sounds were accompanied by a suite of coordinated movements of the buccal, branchial and opercular regions. This was not the case in the Venetian population, and thus the direct role of head movements in sound production was rejected. The hydrodynamic mechanism hypothesis was also rejected in G. paganellus on the basis of sound oscillogram shape and because sounds are still produced after the opercles and hyohyoid muscles are cut. The use of both electromyography and electron microscopy showed that the levator pectoralis muscle, which originates on the skull and inserts on the dorsal tip of the cleithrum, is involved in sound production. We propose that the contraction of this muscle and associated vibration of the large radials is used to make sounds. In addition, we propose that different sound types (pulsed sounds and tonal calls) could occur because of differences in fish size. PMID- 23926309 TI - Vibrational long-distance communication in the termites Macrotermes natalensis and Odontotermes sp. AB - Fungus-growing higher termites build long subterranean galleries that lead outwards from the nest to foraging sites. When soldiers are disturbed, they tend to drum with their heads against the substrate and thereby create vibrational alarm signals. The present study aimed at describing these acoustic signals, how they are elicited, produced and perceived, and how these signals propagate within the galleries and nests over long distances in two termite species of the Southern African savannah, Macrotermes natalensis and an Odontotermes sp. The signals consist of trains of pulses with a pulse repetition rate of 10-20 Hz. The galleries have physical features that promote vibrational communication and are used as channels for long-distance communication. In M. natalensis, the signal propagation velocity is ~130 m s(-1) and the signals are attenuated by ~0.4 dB per centimetre distance. Nestmates are extremely sensitive to these vibrations with a behavioural threshold amplitude of 0.012 m s(-2). Workers respond by a fast retreat into the nest and soldiers are recruited to the source of vibration. Soldiers also start to drum with a reaction time of about 0.3 s, thereby amplifying the intensity of the signal. This social long-distance communication through chains of signal-reamplifying termites results in a relatively slow propagation (1.3 m s(-1)) of the signal without decrement over distances of several metres. PMID- 23926311 TI - Sex-specific divergence for adaptations to dehydration stress in Drosophila kikkawai. AB - Several studies on diverse Drosophila species have reported higher desiccation resistance of females, but the physiological basis of such sex-specific differences has received less attention. We tested whether sex-specific differences in cuticular traits (melanic females and non-melanic males) of Drosophila kikkawai correspond with divergence in their water balance mechanisms. Our results are interesting in several respects. First, positive clinal variation in desiccation resistance was correlated with cuticular melanisation in females but with changes in cuticular lipid mass in males, despite a lack of differences between the sexes for the rate of water loss. Second, a comparative analysis of water budget showed that females of the northern population stored more body water as well as hemolymph content and exhibited greater dehydration tolerance than flies from the southern tropics. In contrast, we found no geographical variation in the males for water content and dehydration tolerance. Third, an ~10 fold increase in the rate of water loss after organic solvent treatment of male D. kikkawai suggested a role of cuticular lipids in cuticular transpiration, but had no effect in the females. Fourth, geographical differences in the storage of carbohydrate content (metabolic fuel) were observed in females but not in males. Interestingly, in females, the rate of utilization of carbohydrates did not vary geographically, but males from drier localities showed a 50% reduction compared with wetter localities. Thus, body melanisation, increased body water, hemolymph, carbohydrate content and greater dehydration tolerance confer greater desiccation resistance in females, but a reduced rate of water loss is the only possible mechanism to cope with drought stress in males. Finally, acclimated females showed a significant increase in drought resistance associated with higher trehalose content as well as dehydration tolerance, while males showed no acclimation response. Thus, sex-specific differences in desiccation resistance of D. kikkawai are associated with divergence in some water balance strategies, despite a lack of differences in the rate of water loss between the two sexes. PMID- 23926310 TI - Beating oxygen: chronic anoxia exposure reduces mitochondrial F1FO-ATPase activity in turtle (Trachemys scripta) heart. AB - The freshwater turtle Trachemys scripta can survive in the complete absence of O2 (anoxia) for periods lasting several months. In mammals, anoxia leads to mitochondrial dysfunction, which culminates in cellular necrosis and apoptosis. Despite the obvious clinical benefits of understanding anoxia tolerance, little is known about the effects of chronic oxygen deprivation on the function of turtle mitochondria. In this study, we compared mitochondrial function in hearts of T. scripta exposed to either normoxia or 2 weeks of complete anoxia at 5 degrees C and during simulated acute anoxia/reoxygenation. Mitochondrial respiration, electron transport chain activities, enzyme activities, proton conductance and membrane potential were measured in permeabilised cardiac fibres and isolated mitochondria. Two weeks of anoxia exposure at 5 degrees C resulted in an increase in lactate, and decreases in ATP, glycogen, pH and phosphocreatine in the heart. Mitochondrial proton conductance and membrane potential were similar between experimental groups, while aerobic capacity was dramatically reduced. The reduced aerobic capacity was the result of a severe downregulation of the F1FO-ATPase (Complex V), which we assessed as a decrease in enzyme activity. Furthermore, in stark contrast to mammalian paradigms, isolated turtle heart mitochondria endured 20 min of anoxia followed by reoxygenation without any impact on subsequent ADP-stimulated O2 consumption (State III respiration) or State IV respiration. Results from this study demonstrate that turtle mitochondria remodel in response to chronic anoxia exposure and a reduction in Complex V activity is a fundamental component of mitochondrial and cellular anoxia survival. PMID- 23926312 TI - Insights from venous oxygen profiles: oxygen utilization and management in diving California sea lions. AB - The management and depletion of O2 stores underlie the aerobic dive capacities of marine mammals. The California sea lion (Zalophus californianus) presumably optimizes O2 store management during all dives, but approaches its physiological limits during deep dives to greater than 300 m depth. Blood O2 comprises the largest component of total body O2 stores in adult sea lions. Therefore, we investigated venous blood O2 depletion during dives of California sea lions during maternal foraging trips to sea by: (1) recording venous partial pressure of O2 (P(O2)) profiles during dives, (2) characterizing the O2-hemoglobin (Hb) dissociation curve of sea lion Hb and (3) converting the P(O2) profiles into percent Hb saturation (S(O2)) profiles using the dissociation curve. The O2-Hb dissociation curve was typical of other pinnipeds (P50=28+/-2 mmHg at pH 7.4). In 43% of dives, initial venous S(O2) values were greater than 78% (estimated resting venous S(O2)), indicative of arterialization of venous blood. Blood O2 was far from depleted during routine shallow dives, with minimum venous S(O2) values routinely greater than 50%. However, in deep dives greater than 4 min in duration, venous S(O2) reached minimum values below 5% prior to the end of the dive, but then increased during the last 30-60 s of ascent. These deep dive profiles were consistent with transient venous blood O2 depletion followed by partial restoration of venous O2 through pulmonary gas exchange and peripheral blood flow during ascent. These differences in venous O2 profiles between shallow and deep dives of sea lions reflect distinct strategies of O2 store management and suggest that underlying cardiovascular responses will also differ. PMID- 23926313 TI - Diagnosis and treatment of Barrett's oesophagus. AB - INTRODUCTION: Barrett's oesophagus (BO) is a common premalignant condition, which carries a risk of progression to oesophageal adenocarcinoma. Recent advances include quantifying the risk of neoplasia progression, novel diagnostic tools and development of new endoscopic techniques to treat early Barrett's cancer. SOURCES OF DATA: A selective search was performed on recent advances in BO and this was supplemented with guidelines from the American and British Society of Gastroenterology. AREAS OF AGREEMENT: All cases of dysplasia should be confirmed by a second expert histopathologist. Endoscopic therapy is the preferred option for high-grade dysplasia and intra-mucosal (T1a) carcinoma using endomucosal resection (EMR) and/or radiofrequency ablation. EMR also provides accurate staging information and any remaining Barrett segment should be ablated to reduce the risk of metachronous lesions. AREAS OF CONTROVERSY: The cell of origin for BO is not certain. The merits and cost effectiveness of endoscopic screening and surveillance still remain controversial. The risk of neoplasia progression in low grade dysplasia is inconsistently reported. The role of chemoprevention remains unclear. GROWING POINTS: The use of radical endotherapy in early Barrett's neoplasia is promising with some data supporting long-term durability. AREAS TIMELY FOR DEVELOPING RESEARCH: The development of non-endoscopic diagnostic tools and radical endotherapy to treat early cancer strengthens the argument for surveillance and suggests the possibility of screening in the near future. Identification of a biomarker may help to select high-risk patients. PMID- 23926314 TI - Mechanical control of morphogenesis at the shoot apex. AB - Morphogenesis does not just require the correct expression of patterning genes; these genes must induce the precise mechanical changes necessary to produce a new form. Mechanical characterization of plant growth is not new; however, in recent years, new technologies and interdisciplinary collaborations have made it feasible in young tissues such as the shoot apex. Analysis of tissues where active growth and developmental patterning are taking place has revealed biologically significant variability in mechanical properties and has even suggested that mechanical changes in the tissue can feed back to direct morphogenesis. Here, an overview is given of the current understanding of the mechanical dynamics and its influence on cellular and developmental processes in the shoot apex. We are only starting to uncover the mechanical basis of morphogenesis, and many exciting questions remain to be answered. PMID- 23926316 TI - Developing role of HPV in cervical cancer prevention. PMID- 23926315 TI - Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy. AB - OBJECTIVE: To do a systematic review and meta-analysis of studies comparing sequential therapy for eradication of Helicobacter pylori with pre-existing and new therapies, thus providing a glimpse of eradication success worldwide. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2013; abstract books of major European, American, and Asian gastroenterological meetings. STUDY SELECTION: Randomised controlled trials in previously untreated adults, in which sequential therapy was compared with a pre-existing or new therapy. RESULTS: 46 randomised controlled trials were reviewed and analysed. 5666 patients were randomised to sequential therapy and 7866 to other (established and new) treatments. The overall eradication rate of sequential therapy was 84.3% (95% confidence interval 82.1% to 86.4%). Sequential therapy was superior to seven day triple therapy (relative risk 1.21, 95% confidence interval 1.17 to 1.25; I(2)=29.3%; number needed to treat 6, 95% confidence interval 5% to 7%), marginally superior to 10 day triple therapy (1.11, 1.04 to 1.19; I(2)= 67.2%; NNT 10, 7 to 15), but not superior to 14 day triple therapy (1.00, 0.94 to 1.06; I(2)=54.3%), bismuth based therapy (1.01, 0.95 to 1.06; I(2)=21.1%), and non-bismuth based therapy (0.99, 0.94 to 1.05; I(2)=52.3%). Data on eradication according to pre-treatment antimicrobial susceptibility testing were available in eight studies, and sequential therapy was able to eradicate 72.8% (61.6% to 82.8%) of the strains resistant to clarithromycin. CONCLUSIONS: Eradication rates with pre-existing and new therapies for H pylori are suboptimal. Regional monitoring of resistance rates should help to guide treatment, and new agents for treatment need to be developed. PMID- 23926318 TI - Attacks on medical personnel in Turkey. PMID- 23926319 TI - Operable adrenal nodules are responsible for at least 5% of cases of hypertension. PMID- 23926320 TI - Serious errors and neglect in the NHS should be a criminal offence, says safety expert. PMID- 23926321 TI - The RodA hydrophobin on Aspergillus fumigatus spores masks dectin-1- and dectin-2 dependent responses and enhances fungal survival in vivo. AB - Aspergillus and Fusarium species are important causes of fungal infections worldwide. Airborne spores (conidia) of these filamentous fungi express a surface protein that confers hydrophobicity (hydrophobin) and covers cell wall components that would otherwise induce a host immune cell response. Using a mutant Aspergillus fumigatus strain (DeltarodA) that does not express the RodA hydrophobin, and Aspergillus and Fusarium conidia from clinical isolates that were treated with hydrofluoric acid (which removes the A. fumigatus RodA protein), we observed increased surface exposure of beta1,3-glucan and alpha mannose on Aspergillus and Fusarium conidia. We also found that DeltarodA and hydrofluoric acid-treated conidia stimulate significantly higher NF-kappaB p65 nuclear translocation and cytokine production by macrophages from C57BL/6, but not from Dectin-1(-/-) or Dectin-2(-/-) mice. Using a murine model of A. fumigatus corneal infection, we showed that DeltarodA conidia induced significantly higher cytokine production, neutrophil infiltration, and more rapid fungal clearance from C57BL/6 corneas compared with the parent G10 strain, which was dependent on Dectin-1 and Dectin-2. Together, these findings identify the hydrophobin RodA as a virulence factor that masks Dectin-1 and Dectin-2 recognition of conidia, resulting in impaired neutrophil recruitment to the cornea and increased fungal survival and clinical disease. PMID- 23926322 TI - Noncovalent association of protein and capsular polysaccharide on bacteria-sized latex beads as a model for polysaccharide-specific humoral immunity to intact gram-positive extracellular bacteria. AB - Intact Streptococcus pneumoniae expressing type 14 capsular polysaccharide (PPS14) and type III S. agalactiae containing a PPS14 core capsule identical to PPS14 exhibit noncovalent associations of PPS14 and bacterial protein, in contrast to soluble covalent conjugates of these respective Ags. Both bacteria and conjugates induce murine PPS14-specific IgG responses dependent on CD4+ T cells. Further, secondary immunization with conjugate and S. agalactiae, although not S. pneumoniae, results in a boosted response. However, in contrast to conjugate, PPS14-specific IgG responses to bacteria lack affinity maturation use the 44.1-idiotype and are dependent on marginal zone B cells. To better understand the mechanism underlying this dichotomy, we developed a minimal model of intact bacteria in which PPS14 and pneumococcal surface protein A (PspA) were stably attached to 1 MUm (bacteria-sized) latex beads, but not directly linked to each other, in contrast to PPS14-PspA conjugate. Beads coated simultaneously with PPS14+[PspA], similar to conjugate, induced in mice boosted PPS14-specific IgG secondary responses, dependent on T cells and ICOS-dependent costimulation, and in which priming could be achieved with PspA alone. In contrast to conjugate, but similar to intact bacteria, the primary PPS14-specific IgG response to beads coated simultaneously with PPS14+[PspA] peaked rapidly, with the secondary response highly enriched for the 44.1-idiotype and lacking affinity maturation. These results demonstrate that noncovalent association in a particle, of polysaccharide and protein, recapitulates essential immunologic characteristics of intact bacteria that are distinct from soluble covalent conjugates of these respective Ags. PMID- 23926323 TI - Melanoma differentiation-associated gene 5 senses hepatitis B virus and activates innate immune signaling to suppress virus replication. AB - Retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) belong to the RIG-I-like receptors family of pattern recognition receptors. Both RIG-I and MDA5 have been shown to recognize various viral RNAs, but whether they mediate hepatitis B virus (HBV) infection remains unclear. In this study, we demonstrated that the expression of MDA5, but not RIG-I, was increased in Huh7 cells transfected with the HBV replicative plasmid and in the livers of mice hydrodynamically injected with the HBV replicative plasmid. To further determine the effect of RIG-I-like receptors on HBV replication, we cotransfected the HBV replicative plasmid with RIG-I or MDA5 expression plasmid into Huh7 cells and found that MDA5, but not RIG-I at a similar protein level, significantly inhibited HBV replication. Knockdown of endogenous MDA5, but not RIG-I, in Huh7 cells transfected with the HBV replicative plasmid significantly increased HBV replication. Of particular interest, we found that MDA5, but not RIG-I, was able to associate with HBV-specific nucleic acids, suggesting that MDA5 may sense HBV. Finally, we performed in vivo experiments by hydrodynamic injection of the HBV replicative plasmid into wild-type, MDA5-/-, MDA5+/-, or RIG I+/- mice, and found that MDA5-/- and MDA5+/- mice, but not RIG-I+/- mice, exhibited an increase of HBV replication as compared with wild-type mice. Collectively, our in vitro and in vivo studies both support a critical role for MDA5 in the innate immune response against HBV infection. PMID- 23926324 TI - Peripheral tissue homing receptors enable T cell entry into lymph nodes and affect the anatomical distribution of memory cells. AB - Peripheral tissue homing receptors enable T cells to access inflamed nonlymphoid tissues. In this study, we show that two such molecules, E-selectin ligand and alpha4beta1 integrin, enable activated and memory T cells to enter lymph nodes (LN) as well. This affects the quantitative and qualitative distribution of these cells among regional LN beds. CD8 memory T cells in LN that express these molecules were mostly CD62L(lo) and would normally be classified as effector memory cells. However, similar to central memory cells, they expanded upon Ag re encounter. This led to differences in the magnitude of the recall response that depended on the route of immunization. These novel cells share properties of both central and effector memory cells and reside in LN based on previously undescribed mechanisms of entry. PMID- 23926325 TI - Secretory IgA induces tolerogenic dendritic cells through SIGNR1 dampening autoimmunity in mice. AB - IgA plays ambivalent roles in the immune system. The balance between inhibitory and activating responses relies on the multimerization status of IgA and interaction with their cognate receptors. In mucosal sites, secretory IgA (SIgA) protects the host through immune-exclusion mechanisms, but its function in the bloodstream remains unknown. Using bone marrow-derived dendritic cells, we found that both human and mouse SIgA induce tolerogenic dendritic cells (DCs) following binding to specific ICAM-3 grabbing nonintegrin receptor 1. This interaction was dependent on Ca(2+) and mannose residues. SIgA-primed DCs (SIgA-DCs) are resistant to TLR-dependent maturation. Although SIgA-DCs fail to induce efficient proliferation and Th1 differentiation of naive responder T cells, they generate the expansion of regulatory T cells through IL-10 production. SIgA-DCs are highly potent in inhibiting autoimmune responses in mouse models of type 1 diabetes and multiple sclerosis. This discovery may offer new insights about mucosal-derived DC immunoregulation through SIgA opening new therapeutic approaches to autoimmune diseases. PMID- 23926326 TI - Identification of a phage-encoded Ig-binding protein from invasive Neisseria meningitidis. AB - Ig-binding proteins are employed by a variety of organisms to evade the immune system. To our knowledge, we now report for the first time that meningococcal strains from several capsular groups exhibit Ig-binding activity that is dependent on human serum factors. A protein mediating Ig binding was identified as T and B cell-stimulating protein B (TspB) by immunoprecipitation and by mass spectroscopic analysis of tryptic peptides. Recombinant TspB and derivatives verified Ig binding, with a preference for human IgG2 Fc, and localized the IgG binding region to a highly conserved subdomain of TspB. Antiserum produced in mice against the conserved subdomain detected the presence of TspB on the cell surface by flow cytometry when bacteria were grown in the presence of human serum. By fluorescence microscopy, we observed formation of an extracellular matrix having characteristics of a biofilm containing TspB, human IgG, DNA, and large aggregates of bacteria. TspB is encoded by gene ORF6 in prophage DNA, which others have shown is associated with invasive meningococcal strains. Knocking out ORF6 genes eliminated IgG binding and formation of large bacterial aggregates in biofilm. Reintroduction of a wild-type ORF6 gene by phage transduction restored the phenotype. The results show that TspB mediated IgG binding and aggregate/biofilm formation triggered by factors in human serum. As has been observed for other Ig-binding proteins, the activities mediated by TspB may provide protection against immune responses, which is in accordance with the association of prophage DNA carrying ORF6 with invasive meningococcal strains. PMID- 23926327 TI - Inflammation-mediated notch signaling skews fanconi anemia hematopoietic stem cell differentiation. AB - Hematopoietic stem cells (HSCs) can either self-renew or differentiate into various types of cells of the blood lineage. Signaling pathways that regulate this choice of self-renewal versus differentiation are currently under extensive investigation. In this study, we report that deregulation of Notch signaling skews HSC differentiation in mouse models of Fanconi anemia (FA), a genetic disorder associated with bone marrow failure and progression to leukemia and other cancers. In mice expressing a transgenic Notch reporter, deletion of the Fanca or Fancc gene enhances Notch signaling in multipotential progenitors (MPPs), which is correlated with decreased phenotypic long-term HSCs and increased formation of MPP1 progenitors. Furthermore, we found an inverse correlation between Notch signaling and self-renewal capacity in FA hematopoietic stem and progenitor cells. Significantly, FA deficiency in MPPs deregulates a complex network of genes in the Notch and canonical NF-kappaB pathways. Genetic ablation or pharmacologic inhibition of NF-kappaB reduces Notch signaling in FA MPPs to near wild type level, and blocking either NF-kappaB or Notch signaling partially restores FA HSC quiescence and self-renewal capacity. These results suggest a functional crosstalk between Notch signaling and NF-kappaB pathway in regulation of HSC differentiation. PMID- 23926328 TI - Seroepidemiology of hepatitis E virus infection in an urban population in Zambia: strong association with HIV and environmental enteropathy. AB - BACKGROUND: Hepatitis E virus (HEV) infection causes major epidemics of infectious hepatitis, with high mortality rates in pregnant women. Recent reports indicate that HEV coinfections with human immunodeficiency virus (HIV) may have a more protracted course. However, the impact of HEV infections in communities heavily affected by HIV remains poorly studied. We set out to examine age-related seroprevalence in a community where we have previously carried out studies on environmental enteropathy. METHODS: Blood samples from 194 children and 106 adults were examined for immunoglobulin G and immunoglobulin M antibodies for HEV. HEV data were correlated with HIV status and morphometric analysis of small intestinal biopsies. RESULTS: Seroprevalence rose throughout childhood, from 8% in children aged 1-4 years, to 36% in children aged 10-14 years. In adults, the overall prevalence was 42%, with 28% in HIV-seronegative adults and 71% in HIV seropositive adults (odds ratio, 6.2; 95% confidence interval, 2.2-18; P = .0001). In adults, villous height and crypt depth measurements showed that HEV seropositivity was associated with worse enteropathy (P = .05 and P = .005, respectively). CONCLUSIONS: HEV infection is common in Zambia. In adults it is strongly associated with HIV status, and also with environmental enteropathy. PMID- 23926329 TI - A randomized comparison of dihydroartemisinin-piperaquine and artesunate amodiaquine combined with primaquine for radical treatment of vivax malaria in Sumatera, Indonesia. AB - BACKGROUND: A high prevalence of chloroquine-resistant Plasmodium vivax in Indonesia has shifted first-line treatment to artemisinin-based combination therapies, combined with primaquine (PQ) for radical cure. Which combination is most effective and safe remains to be established. METHODS: We conducted a prospective open-label randomized comparison of 14 days of PQ (0.25 mg base/kg) plus either artesunate-amodiaquine (AAQ + PQ) or dihydroartemisinin-piperaquine (DHP + PQ) for the treatment of uncomplicated monoinfection P. vivax malaria in North Sumatera, Indonesia. Patients were randomized and treatments were given without prior testing for G6PD status. The primary outcome was parasitological failure at day 42. Patients were followed up to 1 year. RESULTS: Between December 2010 and April 2012, 331 patients were included. After treatment with AAQ + PQ, recurrent infection occurred in 0 of 167 patients within 42 days and in 15 of 130 (11.5%; 95% confidence interval [CI], 6.6%-18.3%) within a year. With DHP + PQ, this was 1 of 164 (0.6%; 95% CI, 0.01%-3.4%) and 13 of 143 (9.1%; 95% CI, 4.9% 15.0%), respectively (P > .2). Intravascular hemolysis occurred in 5 patients, of which 3 males were hemizygous for the G6PD-Mahidol mutation. Minor adverse events were more frequent with AAQ + PQ. CONCLUSIONS: In North Sumatera, Indonesia, AAQ and DHP, both combined with PQ, were effective for blood-stage parasite clearance of uncomplicated P. vivax malaria. Both treatments were safe, but DHP + PQ was better tolerated. CLINICAL TRIALS REGISTRATION: NCT01288820. PMID- 23926330 TI - The contribution of matched envelope dynamic range to the binaural benefits in simulated bilateral electric hearing. AB - PURPOSE: This study examined the effects of envelope dynamic-range mismatch on the intelligibility of Mandarin speech in noise by simulated bilateral electric hearing. METHOD: Noise-vocoded Mandarin speech, corrupted by speech-shaped noise at 5 and 0 dB signal-to-noise ratios, was presented unilaterally or bilaterally to 10 normal-hearing listeners for recognition. For unilateral conditions, the right ear was presented with the 8-channel noise-vocoded stimuli generated using a 15-dB envelope dynamic range (DR). To simulate the envelope DR mismatch between the 2 ears, the left ear was presented with the 8-channel noise-vocoded stimuli generated using a 5-, 10-, or 15-dB envelope DR, respectively. RESULTS: Significant binaural summation benefits for Mandarin speech recognition were observed only with matched envelope DR between the 2 ears. With reduced DR, the performance of tone identification was more consistent in the steady-state speech shaped noise than that of sentence recognition. CONCLUSIONS: Consistent with previous findings, the present results suggest that Mandarin speech-perception performance of bilateral electric listening in noise is affected by the difference of envelope DR between the 2 implanted ears, and the binaural summation benefits are maximized when DR mismatch is minimized between the 2 implanted ears. PMID- 23926331 TI - Test-retest reliability of eye tracking in the visual world paradigm for the study of real-time spoken word recognition. AB - PURPOSE: Researchers have begun to use eye tracking in the visual world paradigm (VWP) to study clinical differences in language processing, but the reliability of such laboratory tests has rarely been assessed. In this article, the authors assess test-retest reliability of the VWP for spoken word recognition. Methods Participants performed an auditory VWP task in repeated sessions and a visual only VWP task in a third session. The authors performed correlation and regression analyses on several parameters to determine which reflect reliable behavior and which are predictive of behavior in later sessions. RESULTS: Results showed that the fixation parameters most closely related to timing and degree of fixations were moderately-to-strongly correlated across days, whereas the parameters related to rate of increase or decrease of fixations to particular items were less strongly correlated. Moreover, when including factors derived from the visual-only task, the performance of the regression model was at least moderately correlated with Day 2 performance on all parameters ( R > .30). CONCLUSION: The VWP is stable enough (with some caveats) to serve as an individual measure. These findings suggest guidelines for future use of the paradigm and for areas of improvement in both methodology and analysis. PMID- 23926332 TI - Mov10 and APOBEC3G localization to processing bodies is not required for virion incorporation and antiviral activity. AB - Mov10 and APOBEC3G (A3G) localize to cytoplasmic granules called processing bodies (P bodies), incorporate into human immunodeficiency virus type 1 (HIV-1) virions, and inhibit viral replication. The functional relevance of Mov10/A3G P body localization to virion incorporation and antiviral activity has not been fully explored. We found that a helicase V mutant of Mov10 exhibits significantly reduced localization to P bodies but still efficiently inhibits viral infectivity via virion incorporation. Disruption of the P bodies by DDX6 knockdown also confirmed Mov10 antiviral activity without P-body localization. In addition, overexpression of SRP19, which binds to 7SL RNA, depleted A3G from P bodies but did not affect its virion incorporation. Sucrose gradient sedimentation assays revealed that the majority of Mov10, A3G, HIV-1 RNA, and Gag formed high molecular-mass (HMM) complexes that are converted to low-molecular-mass (LMM) complexes after RNase A treatment. In contrast, the P-body markers DCP2, LSM1, eIF4e, DDX6, and AGO1 were in LMM complexes, whereas AGO2, an effector protein of the RNA-induced silencing complex that localizes to P bodies, was present in both LMM and HMM complexes. Depletion of AGO2 indicated that RNA-induced silencing function is required for Mov10's ability to reduce Gag expression upon overexpression, but not its virion incorporation or effect on virus infectivity. We conclude that the majority of Mov10 and A3G are in HMM complexes, whereas most of the P-body markers are in LMM complexes, and that virion incorporation and the antiviral activities of Mov10 and A3G do not require their localization to P bodies. PMID- 23926333 TI - The Golgi protein ACBD3, an interactor for poliovirus protein 3A, modulates poliovirus replication. AB - We have shown that the circulating vaccine-derived polioviruses responsible for poliomyelitis outbreaks in Madagascar have recombinant genomes composed of sequences encoding capsid proteins derived from poliovaccine Sabin, mostly type 2 (PVS2), and sequences encoding nonstructural proteins derived from other human enteroviruses. Interestingly, almost all of these recombinant genomes encode a nonstructural 3A protein related to that of field coxsackievirus A17 (CV-A17) strains. Here, we investigated the repercussions of this exchange, by assessing the role of the 3A proteins of PVS2 and CV-A17 and their putative cellular partners in viral replication. We found that the Golgi protein acyl-coenzyme A binding domain-containing 3 (ACBD3), recently identified as an interactor for the 3A proteins of several picornaviruses, interacts with the 3A proteins of PVS2 and CV-A17 at viral RNA replication sites, in human neuroblastoma cells infected with either PVS2 or a PVS2 recombinant encoding a 3A protein from CV-A17 [PVS2-3A(CV A17)]. The small interfering RNA-mediated downregulation of ACBD3 significantly increased the growth of both viruses, suggesting that ACBD3 slowed viral replication. This was confirmed with replicons. Furthermore, PVS2-3A(CV-A17) was more resistant to the replication-inhibiting effect of ACBD3 than the PVS2 strain, and the amino acid in position 12 of 3A was involved in modulating the sensitivity of viral replication to ACBD3. Overall, our results indicate that exchanges of nonstructural proteins can modify the relationships between enterovirus recombinants and cellular interactors and may thus be one of the factors favoring their emergence. PMID- 23926334 TI - Dual myxovirus screen identifies a small-molecule agonist of the host antiviral response. AB - As we are confronted with an increasing number of emerging and reemerging viral pathogens, the identification of novel pathogen-specific and broad-spectrum antivirals has become a major developmental objective. Targeting of host factors required for virus replication presents a tangible approach toward obtaining novel hits with a broadened indication range. However, the identification of developable host-directed antiviral candidates remains challenging. We describe a novel screening protocol that interrogates the myxovirus host-pathogen interactome for broad-spectrum drug candidates and simultaneously probes for conventional, pathogen-directed hits. With resource efficiency and pan-myxovirus activity as the central developmental parameters, we explored coscreening against two distinct, independently traceable myxoviruses in a single-well setting. Having identified a pair of unrelated pathogenic myxoviruses (influenza A virus and measles virus) with comparable replication kinetics, we observed unimpaired coreplication of both viruses, generated suitable firefly and Renilla luciferase reporter constructs, respectively, and validated the protocol for up to a 384 well plate format. Combined with an independent counterscreen using a recombinant respiratory syncytial virus luciferase reporter, implementation of the protocol identified candidates with a broadened antimyxovirus profile, in addition to pathogen-specific hits. Mechanistic characterization revealed a newly discovered broad-spectrum lead that does not block viral entry but stimulates effector pathways of the innate cellular antiviral response. In summary, we provide proof of concept for the efficient discovery of broad-spectrum myxovirus inhibitors in parallel to para- and orthomyxovirus-specific hit candidates in a single screening campaign. The newly identified compound provides a basis for the development of a novel broad-spectrum small-molecule antiviral class. PMID- 23926335 TI - Sustained protein kinase D activation mediates respiratory syncytial virus induced airway barrier disruption. AB - Understanding the regulation of airway epithelial barrier function is a new frontier in asthma and respiratory viral infections. Despite recent progress, little is known about how respiratory syncytial virus (RSV) acts at mucosal sites, and very little is known about its ability to influence airway epithelial barrier function. Here, we studied the effect of RSV infection on the airway epithelial barrier using model epithelia. 16HBE14o- bronchial epithelial cells were grown on Transwell inserts and infected with RSV strain A2. We analyzed (i) epithelial apical junction complex (AJC) function, measuring transepithelial electrical resistance (TEER) and permeability to fluorescein isothiocyanate (FITC)-conjugated dextran, and (ii) AJC structure using immunofluorescent staining. Cells were pretreated or not with protein kinase D (PKD) inhibitors. UV irradiated RSV served as a negative control. RSV infection led to a significant reduction in TEER and increase in permeability. Additionally it caused disruption of the AJC and remodeling of the apical actin cytoskeleton. Pretreatment with two structurally unrelated PKD inhibitors markedly attenuated RSV-induced effects. RSV induced phosphorylation of the actin binding protein cortactin in a PKD dependent manner. UV-inactivated RSV had no effect on AJC function or structure. Our results suggest that RSV-induced airway epithelial barrier disruption involves PKD-dependent actin cytoskeletal remodeling, possibly dependent on cortactin activation. Defining the mechanisms by which RSV disrupts epithelial structure and function should enhance our understanding of the association between respiratory viral infections, airway inflammation, and allergen sensitization. Impaired barrier function may open a potential new therapeutic target for RSV-mediated lung diseases. PMID- 23926336 TI - Thiazolides, a new class of antiviral agents effective against rotavirus infection, target viral morphogenesis, inhibiting viroplasm formation. AB - Rotaviruses, nonenveloped viruses presenting a distinctive triple-layered particle architecture enclosing a segmented double-stranded RNA genome, exhibit a unique morphogenetic pathway requiring the formation of cytoplasmic inclusion bodies called viroplasms in a process involving the nonstructural viral proteins NSP5 and NSP2. In these structures the concerted packaging and replication of the 11 positive-polarity single-stranded RNAs take place to generate the viral double stranded RNA (dsRNA) genomic segments. Rotavirus infection is a leading cause of gastroenteritis-associated severe morbidity and mortality in young children, but no effective antiviral therapy exists. Herein we investigate the antirotaviral activity of the thiazolide anti-infective nitazoxanide and reveal a novel mechanism by which thiazolides act against rotaviruses. Nitazoxanide and its active circulating metabolite, tizoxanide, inhibit simian A/SA11-G3P[2] and human Wa-G1P[8] rotavirus replication in different types of cells with 50% effective concentrations (EC50s) ranging from 0.3 to 2 MUg/ml and 50% cytotoxic concentrations (CC50s) higher than 50 MUg/ml. Thiazolides do not affect virus infectivity, binding, or entry into target cells and do not cause a general inhibition of viral protein expression, whereas they reduce the size and alter the architecture of viroplasms, decreasing rotavirus dsRNA formation. As revealed by protein/protein interaction analysis, confocal immunofluorescence microscopy, and viroplasm-like structure formation analysis, thiazolides act by hindering the interaction between the nonstructural proteins NSP5 and NSP2. Altogether the results indicate that thiazolides inhibit rotavirus replication by interfering with viral morphogenesis and may represent a novel class of antiviral drugs effective against rotavirus gastroenteritis. PMID- 23926337 TI - Transient compartmentalization of simian immunodeficiency virus variants in the breast milk of african green monkeys. AB - Natural hosts of simian immunodeficiency virus (SIV), African green monkeys (AGMs), rarely transmit SIV via breast-feeding. In order to examine the genetic diversity of breast milk SIV variants in this limited-transmission setting, we performed phylogenetic analysis on envelope sequences of milk and plasma SIV variants of AGMs. Low-diversity milk virus populations were compartmentalized from that in plasma. However, this compartmentalization was transient, as the milk virus lineages did not persist longitudinally. PMID- 23926338 TI - Lack of B cell dysfunction is associated with functional, gp120-dominant antibody responses in breast milk of simian immunodeficiency virus-infected African green monkeys. AB - The design of an effective vaccine to reduce the incidence of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) via breastfeeding will require identification of protective immune responses that block postnatal virus acquisition. Natural hosts of simian immunodeficiency virus (SIV) sustain nonpathogenic infection and rarely transmit the virus to their infants despite high milk virus RNA loads. This is in contrast to HIV-infected women and SIV infected rhesus macaques (RhMs), nonnatural hosts which exhibit higher rates of postnatal virus transmission. In this study, we compared the systemic and mucosal B cell responses of lactating, SIV-infected African green monkeys (AGMs), a natural host species, to that of SIV-infected RhMs and HIV-infected women. AGMs did not demonstrate hypergammaglobulinemia or accumulate circulating memory B cells during chronic SIV infection. Moreover, the milk of SIV-infected AGMs contained higher proportions of naive B cells than RhMs. Interestingly, AGMs exhibited robust milk and plasma Env binding antibody responses that were one to two logs higher than those in RhMs and humans and demonstrated autologous neutralizing responses in milk at 1 year postinfection. Furthermore, the plasma and milk Env gp120-binding antibody responses were equivalent to or predominant over Env gp140-binding antibody responses in AGMs, in contrast to that in RhMs and humans. The strong gp120-specific, functional antibody responses in the milk of SIV-infected AGMs may contribute to the rarity of postnatal transmission observed in natural SIV hosts. PMID- 23926339 TI - 6-o- and N-sulfated syndecan-1 promotes baculovirus binding and entry into Mammalian cells. AB - Baculoviruses are insect-specific viruses commonly found in nature. They are not able to replicate in mammalian cells but can transduce them when equipped with an appropriate mammalian cell active expression cassette. Although the viruses have been studied in several types of mammalian cells from different origins, the receptor that baculovirus uses to enter or interact with mammalian cells has not yet been identified. Due to the wide tropism of the virus, the receptor has been suggested to be a generally found cell surface molecule. In this article, we investigated the interaction of baculovirus and mammalian cell surface heparan sulfate proteoglycans (HSPG) in more detail. Our data show that baculovirus requires HSPG sulfation, particularly N- and 6-O-sulfation, to bind to and transduce mammalian cells. According to our results, baculovirus binds specifically to syndecan-1 (SDC-1) but does not interact with SDC-2 to SDC-4 or with glypicans. Competition experiments performed with SDC-1 antibody or recombinant SDC-1 protein inhibited baculovirus binding, and SDC-1 overexpression enhanced baculovirus-mediated transduction. In conclusion, we show that SDC-1, a commonly found cell surface HSPG molecule, has a role in the binding and entry of baculovirus in vertebrate cells. The results presented here reveal important aspects of baculovirus entry and can serve as a basis for next-generation baculovirus vector development for gene delivery. PMID- 23926340 TI - The PA and HA gene-mediated high viral load and intense innate immune response in the brain contribute to the high pathogenicity of H5N1 avian influenza virus in mallard ducks. AB - Most highly pathogenic avian influenza A viruses cause only mild clinical signs in ducks, serving as an important natural reservoir of influenza A viruses. However, we isolated two H5N1 viruses that are genetically similar but differ greatly in virulence in ducks. A/Chicken/Jiangsu/k0402/2010 (CK10) is highly pathogenic, whereas A/Goose/Jiangsu/k0403/2010 (GS10) is low pathogenic. To determine the genetic basis for the high virulence of CK10 in ducks, we generated a series of single-gene reassortants between CK10 and GS10 and tested their virulence in ducks. Expression of the CK10 PA or hemagglutinin (HA) gene in the GS10 context resulted in increased virulence and virus replication. Conversely, inclusion of the GS10 PA or HA gene in the CK10 background attenuated the virulence and virus replication. Moreover, the PA gene had a greater contribution. We further determined that residues 101G and 237E in the PA gene contribute to the high virulence of CK10. Mutations at these two positions produced changes in virulence, virus replication, and polymerase activity of CK10 or GS10. Position 237 plays a greater role in determining these phenotypes. Moreover, the K237E mutation in the GS10 PA gene increased PA nuclear accumulation. Mutant GS10 viruses carrying the CK10 HA gene or the PA101G or PA237E mutation induced an enhanced innate immune response. A sustained innate response was detected in the brain rather than in the lung and spleen. Our results suggest that the PA and HA gene-mediated high virus replication and the intense innate immune response in the brain contribute to the high virulence of H5N1 virus in ducks. PMID- 23926341 TI - Cytomegalovirus vaccine strain towne-derived dense bodies induce broad cellular immune responses and neutralizing antibodies that prevent infection of fibroblasts and epithelial cells. AB - Human cytomegalovirus (HCMV), a betaherpesvirus, can cause severe disease in immunosuppressed patients and following congenital infection. A vaccine that induces both humoral and cellular immunity may be required to prevent congenital infection. Dense bodies (DBs) are complex, noninfectious particles produced by HCMV-infected cells and may represent a vaccine option. As knowledge of the antigenicity and immunogenicity of DB is incomplete, we explored characterization methods and defined DB production methods, followed by systematic evaluation of neutralization and cell-mediated immune responses to the DB material in BALB/c mice. DBs purified from Towne-infected cultures treated with the viral terminase inhibitor 2-bromo-5,6-dichloro-1-beta-d-ribofuranosyl benzimidazole riboside (BDCRB) were characterized by nanoparticle tracking analysis (NTA), two dimensional fluorescence difference gel electrophoresis (2D-DIGE), immunoblotting, quantitative enzyme-linked immunosorbent assay, and other methods. The humoral and cellular immune responses to DBs were compared to the immunogenicity of glycoprotein B (gB) administered with the adjuvant AddaVax (gB/AddaVax). DBs induced neutralizing antibodies that prevented viral infection of cultured fibroblasts and epithelial cells and robust cell-mediated immune responses to multiple viral proteins, including pp65, gB, and UL48. In contrast, gB/AddaVax failed to induce neutralizing antibodies that prevented infection of epithelial cells, highlighting a critical difference in the humoral responses induced by these vaccine candidates. Our data advance the potential for the DB vaccine approach, demonstrate important immunogenicity properties, and strongly support the further evaluation of DBs as a CMV vaccine candidate. PMID- 23926342 TI - Divergent MicroRNA targetomes of closely related circulating strains of a polyomavirus. AB - Hundreds of virus-encoded microRNAs (miRNAs) have been uncovered, but an in-depth functional understanding is lacking for most. A major challenge for the field is separating those miRNA targets that are biologically relevant from those that are not advantageous to the virus. Here, we show that miRNAs from related variants of the polyomavirus simian vacuolating virus 40 (SV40) have differing host target repertoires (targetomes) while their direct autoregulatory activity on virus encoded early gene products is completely preserved. These results underscore the importance of miRNA-mediated viral gene autoregulation in some polyomavirus life cycles. More broadly, these findings imply that some host targets of virus encoded miRNAs are likely to be of little selective advantage to the virus, and our approach provides a strategy for prioritizing relevant targets. PMID- 23926343 TI - Compensatory mutants of the bovine papillomavirus E5 protein and the platelet derived growth factor beta receptor reveal a complex direct transmembrane interaction. AB - The 44-amino-acid E5 protein of bovine papillomavirus is a dimeric transmembrane protein that exists in a stable complex with the platelet-derived growth factor (PDGF) beta receptor, causing receptor activation and cell transformation. The transmembrane domain of the PDGF beta receptor is required for complex formation, but it is not known if the two proteins contact one another directly. Here, we studied a PDGF beta receptor mutant containing a leucine-to-isoleucine substitution in its transmembrane domain, which prevents complex formation with the wild-type E5 protein in mouse BaF3 cells and inhibits receptor activation by the E5 protein. We selected E5 mutants containing either a small deletion or multiple substitution mutations that restored binding to the mutant PDGF beta receptor, resulting in receptor activation and growth factor independence. These E5 mutants displayed lower activity with PDGF beta receptor mutants containing other transmembrane substitutions in the vicinity of the original mutation, and one of them cooperated with a receptor mutant containing a distal mutation in the juxtamembrane domain. These results provide strong genetic evidence that the transmembrane domains of the E5 protein and the PDGF beta receptor contact one another directly. They also demonstrate that different mutations in the E5 protein allow it to tolerate the same mutation in the PDGF beta receptor transmembrane domain and that a mutation in the E5 protein can allow it to tolerate different mutations in the PDGF beta receptor. Thus, the rules governing direct interactions between transmembrane helices are complex and not restricted to local interactions. PMID- 23926344 TI - Compensatory hemagglutinin mutations alter antigenic properties of influenza viruses. AB - Influenza viruses routinely acquire mutations in antigenic sites on the globular head of the hemagglutinin (HA) protein. Since these antigenic sites are near the receptor binding pocket of HA, many antigenic mutations simultaneously alter the receptor binding properties of HA. We previously reported that a K165E mutation in the Sa antigenic site of A/Puerto Rico/8/34 (PR8) HA is associated with secondary neuraminidase (NA) mutations that decrease NA activity. Here, using reverse genetics, we show that the K165E HA mutation dramatically decreases HA binding to sialic acid receptors on cell surfaces. We sequentially passaged reverse-genetics-derived PR8 viruses with the K165E antigenic HA mutation in fertilized chicken eggs, and to our surprise, viruses with secondary NA mutations did not emerge. Instead, viruses with secondary HA mutations emerged in 3 independent passaging experiments, and each of these mutations increased HA binding to sialic acid receptors. Importantly, these compensatory HA mutations were located in the Ca antigenic site and prevented binding of Ca-specific monoclonal antibodies. Taken together, these data indicate that HA antigenic mutations that alter receptor binding avidity can be compensated for by secondary HA or NA mutations. Antigenic diversification of influenza viruses can therefore occur irrespective of direct antibody pressure, since compensatory HA mutations can be located in distinct antibody binding sites. PMID- 23926346 TI - Subviral dense bodies of human cytomegalovirus stimulate maturation and activation of monocyte-derived immature dendritic cells. AB - Dendritic cells play a central role in the immune control of human cytomegalovirus (HCMV) infection. This work aimed at investigating the impact of noninfectious, subviral dense bodies of HCMV on the maturation and activation of dendritic cells (DC). Treatment of immature DC with dense bodies led to the maturation of these cells and significantly increased their capacity for cytokine release and antigen presentation. Dense body-activated DC may thereby contribute to the development of antiviral immunity. PMID- 23926345 TI - The genome-packaging signal of the influenza A virus genome comprises a genome incorporation signal and a genome-bundling signal. AB - The influenza A virus genome comprises eight single-stranded negative-sense RNA segments (vRNAs). All eight vRNAs are selectively packaged into each progeny virion via so-called segment-specific genome-packaging signal sequences that are located in the noncoding and terminal coding regions of both the 3' and the 5' ends of the vRNAs. However, it remains unclear how these signals ensure that eight different vRNAs are packaged. Here, by using a reverse genetics system, we demonstrated that, in the absence of the other seven vRNAs, a recombinant NP vRNA bearing only a reporter gene flanked by the noncoding NP regions was incorporated into virus-like particles (VLPs) as efficiently as a recombinant NP vRNA bearing the reporter gene flanked by the complete NP packaging signals (i.e., the noncoding sequences and the terminal coding regions). Viruses that comprised a recombinant NP vRNA whose packaging signal was disrupted, and the remaining seven authentic vRNAs, did not undergo multiple cycles of replication; however, a recombinant NP vRNA with only the noncoding regions was readily incorporated into VLPs, suggesting that the packaging signal as currently defined is not necessarily essential for the packaging of the vRNA in which it resides; rather, it is required for the packaging of the full set of vRNAs. We propose that the 3' and 5' noncoding regions of each vRNA bear a virion incorporation signal for that vRNA and that the terminal coding regions serve as a bundling signal that ensures the incorporation of the complete set of eight vRNAs into the virion. PMID- 23926347 TI - Emergence of a C-terminal seven-amino-acid elongation of NS1 in around 1950 conferred a minor growth advantage to former seasonal influenza A viruses. AB - Influenza A viruses circulating in humans from ~1950 to ~1987 featured a nonstructural (NS1) protein with a C-terminal extension of seven amino acids. The biological significance of this NS1 elongation remained elusive. We observed that replication kinetics of the wild-type virus A/Hong Kong/01/68 (H3N2) and a mutant encoding a truncated NS1 were indistinguishable in most experimental systems. However, wild-type virus outcompeted the mutant during mixed infections, suggesting that the NS1 extension conferred minor growth advantages. PMID- 23926348 TI - Bovine herpesvirus 1 regulatory proteins bICP0 and VP16 are readily detected in trigeminal ganglionic neurons expressing the glucocorticoid receptor during the early stages of reactivation from latency. AB - Bovine herpesvirus 1 (BHV-1) establishes a lifelong latent infection in sensory neurons following acute infection. Increased corticosteroid levels, due to stress, increases the incidence of reactivation from latency. Within minutes, corticosteroids activate the glucocorticoid receptor and transcription of promoters containing a glucocorticoid receptor element. A single intravenous injection of the synthetic corticosteroid dexamethasone consistently induces reactivation from latency in calves. Lytic cycle viral gene expression is detected within 6 h after dexamethasone treatment of calves latently infected with BHV-1. Cellular transcription factors are induced by dexamethasone in trigeminal ganglionic neurons within 1.5 h after dexamethasone treatment, suggesting they promote viral gene expression during the early phases of reactivation from latency, which we operationally defined as the escape from latency. In this study, immunohistochemistry was utilized to examine viral protein expression during the escape from latency. Within 1.5 h after dexamethasone treatment, bICP0 and a late protein (VP16) were consistently detected in a subset of trigeminal ganglionic neurons. Most neurons expressing bICP0 also expressed VP16. Additional studies revealed that neurons expressing the glucocorticoid receptor also expressed bICP0 or VP16 at 1.5 h after dexamethasone treatment. Two other late proteins, glycoprotein C and D, were not detected until 6 h after dexamethasone treatment and were detected in only a few neurons. These studies provide evidence that VP16 and the promiscuous viral trans activator (bICP0) are expressed during the escape from latency, suggesting they promote the production of infectious virus in a small subset of latently infected neurons. PMID- 23926349 TI - Rotavirus NSP4 Triggers Secretion of Proinflammatory Cytokines from Macrophages via Toll-Like Receptor 2. AB - Nonstructural protein 4 (NSP4), encoded by rotavirus, exhibits various properties linked to viral pathogenesis, including enterotoxic activity. A recent study (O. V. Kavanagh et al., Vaccine 28:3106-3111, 2010) indicated that NSP4 also has adjuvant properties, suggesting a possible role in the innate immune response to rotavirus infection. We report here that NSP4 purified from the medium of rotavirus-infected Caco-2 cells triggers the secretion of proinflammatory cytokines from macrophage-like THP-1 cells and nitric oxide from murine RAW 264.7 cells. Secretion is accompanied by the stimulation of p38 and JNK mitogen activated protein kinases (MAPKs) and nuclear factor NF-kappaB. NSP4 triggered the secretion of cytokines from murine macrophages derived from wild-type but not MyD88(-/-) or Toll-like receptor 2 (TLR2(-/-)) mice and induced secretion of interleukin-8 (IL-8) from human embryonic kidney cells transfected with TLR2 but not TLR4. Our studies identify NSP4 as a pathogen-associated molecular pattern (PAMP) encoded by rotavirus and provide a mechanism for the production of proinflammatory cytokines associated with the clinical symptoms of infection in humans and animals. PMID- 23926350 TI - Regulatory T cells prevent Th2 immune responses and pulmonary eosinophilia during respiratory syncytial virus infection in mice. AB - During viral infection, inflammation and recovery are tightly controlled by competing proinflammatory and regulatory immune pathways. Respiratory syncytial virus (RSV) is the leading global cause of infantile bronchiolitis, which is associated with recurrent wheeze and asthma diagnosis in later life. Th2-driven disease has been well described under some conditions for RSV-infected mice. In the present studies, we used the Foxp3(DTR) mice (which allow specific conditional depletion of Foxp3(+) T cells) to investigate the functional effects of regulatory T cells (Tregs) during A2-strain RSV infection. Infected Treg depleted mice lost significantly more weight than wild-type mice, indicating enhanced disease. This enhancement was characterized by increased cellularity in the bronchoalveolar lavage (BAL) fluid and notable lung eosinophilia not seen in control mice. This was accompanied by abundant CD4(+) and CD8(+) T cells exhibiting an activated phenotype and induction of interleukin 13 (IL-13)- and GATA3-expressing Th2-type CD4(+) T cells that remained present in the airways even 14 days after infection. Therefore, Treg cells perform vital anti inflammatory functions during RSV infection, suppressing pathogenic T cell responses and inhibiting lung eosinophilia. These findings provide additional evidence that dysregulation of normal immune responses to viral infection may contribute to severe RSV disease. PMID- 23926351 TI - A viral histone h4 joins to eukaryotic nucleosomes and alters host gene expression. AB - A viral histone H4 (CpBV-H4) is encoded in a polydnavirus, Cotesia plutellae bracovirus. Its predicted amino acid sequence is highly homologous to that of host insect histone H4 except for an extended N-terminal tail containing 38 amino acids with nine lysine residues. Its expression induces an immunosuppression of target insects by suppressing immune-associated genes, presumably through an epigenetic control. This study analyzed its molecular interaction with eukaryotic host nucleosomes and subsequent regulation of host gene expression. Purified recombinant CpBV-H4 could associate with nucleosomal components (H2A, H2B, H3, and H4) and form an octamer. Transient expression of CpBV-H4 in an insect, Tribolium castaneum, was performed by microinjection of a recombinant expression vector and confirmed by both reverse transcriptase PCR (RT-PCR) and immunoblotting assays. Under this transient expression condition, total RNAs were extracted and read by a deep-sequencing technique. Annotated transcripts were classified into different gene ontology (GO) categories and compared with those of control insects injected with a truncated CpBV-H4. Target genes manipulated by CpBV-H4 expression showing significant differences (fold changes > 10(9)) included all GO categories, including development and immune-associated genes. When the target genes were physically mapped, they were found to be scattered on entire chromosomes of T. castaneum. In addition, chromatin immunoprecipitation against CpBV-H4 determined 16 nucleosome sites (P < 10(-5)) of the viral histone incorporation, which were noncoding regions near DNA-binding and inducible genes. These findings suggest that the viral histone H4 alters host gene expression by a direct molecular interaction with insect nucleosomes. PMID- 23926352 TI - Limited nucleotide changes in the Rev response element (RRE) during HIV-1 infection alter overall Rev-RRE activity and Rev multimerization. AB - HIV-1 Rev and the Rev response element (RRE) enable a critical step in the viral replication cycle by facilitating the nuclear export of intron-containing mRNAs, yet their activities have rarely been analyzed in natural infections. This study characterized their genetic and functional variation in a small cohort of HIV infected individuals. Multiple Rev and RRE sequences were obtained using single genome sequencing (SGS) of plasma samples collected within 6 months after seroconversion and at a later time. This allowed the identification of cognate sequences that were linked in vivo in the same viral genome and acted together as a functional unit. Phylogenetic analyses of these sequences indicated that 4/5 infections were founded by a single transmission event. Rev and RRE variants from each time point were subjected to functional analysis as both cognate pairs and as individual components. While a range of Rev-RRE activities were seen, the activity of cognate pairs from a single time point clustered to a discrete level, which was termed the set point. In 3/5 patients, this set point changed significantly over the time period studied. In all patients, RRE activity was more sensitive to sequence variation than Rev activity and acted as the primary driver of the cognate set point. Selected patient RREs were also shown to have differences in Rev multimerization using gel shift binding assays. Thus, rather than acting as a simple on-off switch or maintaining a constant level of activity throughout infection, the Rev-RRE system can fluctuate, presumably to control replication. PMID- 23926353 TI - Morphogenesis of mimivirus and its viral factories: an atomic force microscopy study of infected cells. AB - Amoebas infected with mimivirus were disrupted at sequential stages of virus production and were visualized by atomic force microscopy. The development of virus factories proceeded over 3 to 4 h postinfection and resulted from the coalescence of 0.5- to 2-MUm vesicles, possibly bearing nucleic acid, derived from either the nuclear membrane or the closely associated rough endoplasmic reticulum. Virus factories actively producing virus capsids on their surfaces were imaged, and this allowed the morphogenesis of the capsids to be delineated. The first feature to appear on a virus factory surface when a new capsid is born is the center of a stargate, which is a pentameric protein oligomer. As the arms of the stargate grow from the pentamer, a rough disk the diameter of a capsid thickens around it. This marks the initial emergence of a protein-coated membrane vesicle. The capsid self-assembles on the vesicle. Hillocks capped by different pentameric proteins spontaneously appear on the emerging vesicle at positions that are ultimately occupied by 5-fold icosahedral vertices. A lattice of coat protein nucleates at each of the 5-fold vertices, but not at the stargate, and then spreads outward from the vertices over the surface, merging seamlessly to complete the icosahedral capsid. Filling with DNA and associated proteins occurs by the transfer of nucleic acid from the interior of the virus factory into the nearly completed capsids. The portal, through which the DNA enters, is sealed by a plug of protein having a diameter of about 40 nm. A layer of integument protein that anchors the surface fibers is acquired by the passage of capsids through a membrane enriched in the protein. The coating of surface fibers is similarly acquired when the integument protein-coated capsids pass through a second membrane that has a forest of surface fibers embedded on one side. PMID- 23926354 TI - Isolation, identification, and characterization of novel arenaviruses, the etiological agents of boid inclusion body disease. AB - Boid inclusion body disease (BIBD) is a progressive, usually fatal disease of constrictor snakes, characterized by cytoplasmic inclusion bodies (IB) in a wide range of cell types. To identify the causative agent of the disease, we established cell cultures from BIBD-positive and -negative boa constrictors. The IB phenotype was maintained in cultured cells of affected animals, and supernatants from these cultures caused the phenotype in cultures originating from BIBD-negative snakes. Viruses were purified from the supernatants by ultracentrifugation and subsequently identified as arenaviruses. Purified virus also induced the IB phenotype in naive cells, which fulfilled Koch's postulates in vitro. One isolate, tentatively designated University of Helsinki virus (UHV), was studied in depth. Sequencing confirmed that UHV is a novel arenavirus species that is distinct from other known arenaviruses including those recently identified in snakes with BIBD. The morphology of UHV was established by cryoelectron tomography and subtomographic averaging, revealing the trimeric arenavirus spike structure at 3.2-nm resolution. Immunofluorescence, immunohistochemistry, and immunoblotting with a polyclonal rabbit antiserum against UHV and reverse transcription-PCR (RT-PCR) revealed the presence of genetically diverse arenaviruses in a large cohort of snakes with BIBD, confirming the causative role of arenaviruses. Some snakes were also found to carry arenavirus antibodies. Furthermore, mammalian cells (Vero E6) were productively infected with UHV, demonstrating the potential of arenaviruses to cross species barriers. In conclusion, we propose the newly identified lineage of arenaviruses associated with BIBD as a novel taxonomic entity, boid inclusion body disease-associated arenaviruses (BIBDAV), in the family Arenaviridae. PMID- 23926355 TI - Staufen-1 interacts with the human endogenous retrovirus family HERV-K(HML-2) rec and gag proteins and increases virion production. AB - The human endogenous retrovirus family HERV-K(HML-2) Rec protein is an RNA transport factor that enhances nuclear export of intron-containing retroviral transcripts. Using the yeast two-hybrid approach, we have newly identified human Staufen-1 as a Rec-interacting protein. The interaction was confirmed by coimmunoprecipitation experiments, and the relevant site in Staufen-1 has been mapped to double-stranded RNA binding domain 4 (RBD4). Staufen-1 is in several aspects functionally related to retroviral RNA transport proteins. It binds mRNAs and targets its ribonuclear cargo to polysomes for efficient translation. We observed an accumulation of Staufen-1 in the nucleus of Rec-expressing cells and colocalization in the nucleoli as well as in the cytoplasm. Overexpression of Staufen-1 resulted in a 5-fold enhancement in nuclear export and/or translation of unspliced HERV-K(HML-2) viral RNAs in the presence of Rec and its Rec responsive element (RcRE) binding site together with a clear increase in virus production. Staufen-1 was previously shown to interact with the Gag protein of HIV-1, promoting Gag oligomerization and RNA encapsidation. We demonstrate here that Staufen-1 also binds to the Gag protein of HERV-K(HML-2). Under stress conditions, Rec colocalizes with Staufen-1 in stress granules in cells that express viral RNA but not in mRNA-decay-related processing bodies. Our results suggest a new role for Staufen-1 as a cellular Rec and HERV-K(HML-2) Gag cofactor. PMID- 23926360 TI - Collecting Knowledge for the Family: Recipes, Gender and Practical Knowledge in the Early Modern English Household. AB - When Mary Cholmeley married Henry Fairfax in 1627, she carried to her new home in Yorkshire a leather-bound notebook filled with medical recipes. Over the next few decades, Mary and Henry, their children and various members of the Fairfax and Cholmeley families continually entered new medical and culinary information into this 'treasury for health.' Consequently, as it stands now, the manuscript can be read both as a repository of household medical knowledge and as a family archive. Focusing on two Fairfax 'family books,' this essay traces on the process through which early modern recipe books were created. In particular, it explores the role of the family collective in compiling books of knowledge. In contrast to past studies where household recipe books have largely been described as the products of exclusively female endeavors, I argue that the majority of early modern recipe collections were created by family collectives and that the members of these collectives worked in collaboration across spatial, geographical and temporal boundaries. This new reading of recipe books as testaments of the interests and needs of particular families encourages renewed examination of the role played by gender in the transmission and production of knowledge in early modern households. PMID- 23926357 TI - Directed evolution of a virus exclusively utilizing human epidermal growth factor receptor as the entry receptor. AB - Rational design and directed evolution are powerful tools to generate and improve protein function; however, their uses are mostly limited to enzyme and antibody engineering. Here we describe a directed-evolution strategy, named the tandem selection and enrichment system (TSES), and its use in generating virus with exclusive specificity for a particular cellular receptor. In TSES, evolving viruses are sequentially and iteratively transferred between two different host cells, one for selection of receptor specificity and the other for enrichment of the fittest virus. By combining rational design and TSES, we generated human epidermal growth factor receptor (EGFR)-specific virus 1 (ESV1). ESV1 has the backbone of Sindbis virus (SINV) and displays an EGF domain engrafted onto structural protein E2 after residue Pro192, together with eight amino acid changes stabilizing the E2-EGF chimera. ESV1 uses EGFR to initiate infection and has lost the capacity to interact with all known SINV receptors. A 12.2-A cryoelectron microscopic (cryoEM) reconstruction of ESV1 reveals that the E2-EGF fusion adopts a fixed conformation, with EGF sitting at the top of the E2 spike; The EGFR binding interface faces outward, and the EGF domain completely masks SINV receptor binding. The cryoEM structure of ESV1 explains the desirable properties of ESV1 and provides insights for its further modification. TSES expands the scope of directed evolution and can be easily extended to other targeting molecules and viral systems. PMID- 23926356 TI - Structural insights into adeno-associated virus serotype 5. AB - The adeno-associated viruses (AAVs) display differential cell binding, transduction, and antigenic characteristics specified by their capsid viral protein (VP) composition. Toward structure-function annotation, the crystal structure of AAV5, one of the most sequence diverse AAV serotypes, was determined to 3.45-A resolution. The AAV5 VP and capsid conserve topological features previously described for other AAVs but uniquely differ in the surface-exposed HI loop between betaH and betaI of the core beta-barrel motif and have pronounced conformational differences in two of the AAV surface variable regions (VRs), VR IV and VR-VII. The HI loop is structurally conserved in other AAVs despite amino acid differences but is smaller in AAV5 due to an amino acid deletion. This HI loop is adjacent to VR-VII, which is largest in AAV5. The VR-IV, which forms the larger outermost finger-like loop contributing to the protrusions surrounding the icosahedral 3-fold axes of the AAVs, is shorter in AAV5, creating a smoother capsid surface topology. The HI loop plays a role in AAV capsid assembly and genome packaging, and VR-IV and VR-VII are associated with transduction and antigenic differences, respectively, between the AAVs. A comparison of interior capsid surface charge and volume of AAV5 to AAV2 and AAV4 showed a higher propensity of acidic residues but similar volumes, consistent with comparable DNA packaging capacities. This structure provided a three-dimensional (3D) template for functional annotation of the AAV5 capsid with respect to regions that confer assembly efficiency, dictate cellular transduction phenotypes, and control antigenicity. PMID- 23926361 TI - Effects of the ant Formica fusca on the transmission of microsporidia infecting gypsy moth larvae. AB - Transmission plays an integral part in the intimate relationship between a host insect and its pathogen that can be altered by abiotic or biotic factors. The latter include other pathogens, parasitoids, or predators. Ants are important species in food webs that act on various levels in a community structure. Their social behavior allows them to prey on and transport larger prey, or they can dismember the prey where it was found. Thereby they can also influence the horizontal transmission of a pathogen in its host's population. We tested the hypothesis that an ant species like Formica fusca L. (Hymenoptera: Formicidae) can affect the horizontal transmission of two microsporidian pathogens, Nosema lymantriae Weiser (Microsporidia: Nosematidae) and Vairimorpha disparis (Timofejeva) (Microsporidia: Burenellidae), infecting the gypsy moth, Lymantria dispar L. (Lepidoptera: Erebidae: Lymantriinae). Observational studies showed that uninfected and infected L. dispar larvae are potential prey items for F. fusca. Laboratory choice experiments led to the conclusion that F. fusca did not prefer L. dispar larvae infected with N. lymantriae and avoided L. dispar larvae infected with V. disparis over uninfected larvae when given the choice. Experiments carried out on small potted oak, Quercus petraea (Mattuschka) Liebl. (Fagaceae), saplings showed that predation of F. fusca on infected larvae did not significantly change the transmission of either microsporidian species to L. dispar test larvae. Microscopic examination indicated that F. fusca workers never became infected with N. lymantriae or V. disparis after feeding on infected prey. PMID- 23926362 TI - Decoding the drivers of bank erosion on the Mekong river: The roles of the Asian monsoon, tropical storms, and snowmelt. AB - We evaluate links between climate and simulated river bank erosion for one of the world's largest rivers, the Mekong. We employ a process-based model to reconstruct multidecadal time series of bank erosion at study sites within the Mekong's two main hydrological response zones, defining a new parameter, accumulated excess runoff (AER), pertinent to bank erosion. We employ a hydrological model to isolate how snowmelt, tropical storms and monsoon precipitation each contribute to AER and thus modeled bank erosion. Our results show that melt (23.9% at the upstream study site, declining to 11.1% downstream) and tropical cyclones (17.5% and 26.4% at the upstream and downstream sites, respectively) both force significant fractions of bank erosion on the Mekong. We also show (i) small, but significant, declines in AER and hence assumed bank erosion during the 20th century, and; (ii) that significant correlations exist between AER and the Indian Ocean Dipole (IOD) and El Nino Southern Oscillation (ENSO). Of these modes of climate variability, we find that IOD events exert a greater control on simulated bank erosion than ENSO events; but the influences of both ENSO and IOD when averaged over several decades are found to be relatively weak. However, importantly, relationships between ENSO, IOD, and AER and hence inferred river bank erosion are not time invariant. Specifically, we show that there is an intense and prolonged epoch of strong coherence between ENSO and AER from the early 1980s to present, such that in recent decades derived Mekong River bank erosion has been more strongly affected by ENSO. PMID- 23926363 TI - Data-Driven Learning of Q-Matrix. AB - The recent surge of interests in cognitive assessment has led to developments of novel statistical models for diagnostic classification. Central to many such models is the well-known Q-matrix, which specifies the item-attribute relationships. This article proposes a data-driven approach to identification of the Q-matrix and estimation of related model parameters. A key ingredient is a flexible T-matrix that relates the Q-matrix to response patterns. The flexibility of the T-matrix allows the construction of a natural criterion function as well as a computationally amenable algorithm. Simulations results are presented to demonstrate usefulness and applicability of the proposed method. Extension to handling of the Q-matrix with partial information is presented. The proposed method also provides a platform on which important statistical issues, such as hypothesis testing and model selection, may be formally addressed. PMID- 23926364 TI - Measurement of Serum 17alpha-hydroxyprogesterone in Newborn Infants by Stable Isotope Dilution-Gas Chromatography/Mass Spectrometry. AB - Immunochemical measurement of serum 17alpha-hydroxyprogesterone (17OHP), the most important parameter for diagnosis of classical 21-hydroxylase deficiency (21OHD) in newborn infants, is known to be inaccurate due to the cross-reactivity of antibodies with a large quantity of fetal adrenal steroids. The aims of this study were 1) to establish reference values for the serum 17OHP level in Japanese newborn infants using non-immunochemical stable isotope dilution -gas chromatography/mass spectrometry (SID-GC/MS) and 2) to compare the serum 17OHP levels determined by SID-GC/MS with those determined by radioimmunoassay (RIA). The first study subjects were used for determination of reference values and included 57 healthy full-term newborn infants (4-5 d of age). The second study subjects were used for comparison of SID-GC/MS with RIA and included 27 healthy full-term newborn infants (3-6 d of age) and two subjects with neonatal transient hyper 17OHPnemia; these two subjects were 16 and 27 d of age, respectively. In the first study subjects, the intra-assay coefficient of variation for SID-GC/MS was 3% (n=5), the recovery rate was 98%, the sensitivity was 0.2 ng/ml, and the range of linearity was 0.5-200 ng/ml. The reference values for the serum 17OHP level determined by SID-GC/MS ranged from 0.3-1.5 (0.6) (ng/ml) (median). In the second study subjects, the serum 17OHP levels determined by SID-GC/MS were lower in one of the 27 subjects and both of the two subjects with neonatal transient hyper 17OHPnemia compared with the levels determined by RIA. Measurement of the serum 17OHP level using SID-GC/MS may be clinically useful for definitive diagnosis of classical 21OHD in newborn infants. PMID- 23926365 TI - A Japanese male patient with 'fibular aplasia, tibial campomelia and oligodactyly': an additional case report. AB - We report a male infant with FATCO syndrome, an acronym for fibular aplasia, tibial campomelia, and oligosyndactyly. Courtens et al. reported an infant with oligosyndactyly of the left hand, complete absence of the right fibula, bowing of the right tibia, and absence of the right fifth metatarsal and phalanges. They noted 5 patients with similar clinical features, and proposed the FATCO syndrome. Our patient had a left-sided cleft lip, cleft palate, oligosyndactyly of the right hand and bilateral feet, and bilateral anterior bowing of the limbs associated with overlying skin dimpling. Radiographs showed a short angulated tibia with left fibular aplasia and right fibular hypoplasia. We consider our case the 6th patient with FATCO syndrome, and the cleft lip and palate, not reported in the previous 5 patients, may allow us to further understand the development of the extremities and facies. PMID- 23926366 TI - Late-onset Lymphedema and Protein-losing Enteropathy with Noonan Syndrome. AB - Noonan syndrome is characterized by facial dysmorphology, congenital heart disease and growth failure. Although it is also accompanied by deranged lymph vessel formation, protein-losing enteropathy (PLE) with Noonan syndrome is rarely reported. We report clinical information about a boy with Noonan syndrome and late-onset lymphedema and PLE after standing for long periods of time during athletic practice sessions. The boy recovered from lymphedema and PLE after administration of 2.5 g of albumin followed by resting and raising his legs. They did not recur after he began walking again. Standing for long periods of time congested the lymph stream at the abdominal lymph vessel, whose formation is frequently disturbed in Noonan syndrome, and the increased pressure caused lymphedema and PLE. PLE is one of the clinical manifestations of Noonan syndrome. PMID- 23926367 TI - Genetic analysis in children with transient thyroid dysfunction or subclinical hypothyroidism detected on neonatal screening. AB - About 30% of children with elevated TSH levels during neonatal screening have a transient form of disorder. On the other hand, it has been reported that subclinical hypothyroidism persists in late childhood in about 30% of children found to be false-positive during neonatal screening. The aim of this study was to determine whether transient thyroid dysfunction and subclinical hypothyroidism detected during neonatal screening are influenced by genetic background. The TSH receptor (TSHR), thyroid peroxidase (TPO) and dual oxidase 2 (DUOX2) genes, for which it has been reported that heterozygous defects cause neonatal transient thyroid dysfunction, were analyzed. Nine children with transient thyroid dysfunction or subclinical hypothyroidism detected during neonatal screening were studied. One child was heterozygous for a TSHR gene mutation (R450H), and another child was heterozygous for a TPO gene mutation (P883S). No children with mutation of the DUOX2 gene were identified. Genetic background may contribute to development of transient thyroid dysfunction and subclinical hypothyroidism detected during neonatal screening. PMID- 23926368 TI - Turner syndrome with ulcerative colitis. AB - Turner syndrome is a chromosomal disease frequently associated with autoimmune disorders including diabetes mellitus, thyroid disease and inflammatory bowel disease (IBD). Although the etiology of IBD has not been fully elucidated, genetic analysis has recently revealed several susceptibility genes. Recently, cases with Turner syndrome associated with IBD have been reported. We report here a 13-yr-old girl with Turner syndrome associated with ulcerative colitis. The patient was undergoing growth hormone treatment and presented with abdominal discomfort and bloody diarrhea. Her karyotype pattern was 46,X,i(Xq). Barium enema revealed punctate collections of barium suggesting microulcerations in the descending and sigmoid colon with loss of haustra. Flexible sigmoidoscopy showed that the mucosa was erythematous and friable upon touch and that the wall had frank hemorrhage and inflammatory polyp formation from the anal verge through the splenic flexure. Histologically, mucosal and submucosal inflammation was prominent, suggesting cryptitis and crypt abscess formation. Based on these findings, she was diagnosed as having ulcerative colitis, and 5-aminosalicylic acid, prednisolone and dietary therapy were initiated. Our observations in this patient suggest that X chromosome abnormality may influence the development of IBD and that screening for gastrointestinal disease in patients with Turner syndrome may help lengthen life expectancy in these patients. PMID- 23926369 TI - Utility of an Increment in the Basal Rate during Mealtime in Place of Pre-meal Boluses for Preschool-aged Children with Type 1 Diabetes Using CSII. PMID- 23926370 TI - H62L Mutation of CYP21A2 Identified in the Non-classical Form of 21-Hydroxylase Deficiency. PMID- 23926371 TI - Association between Sex, Age, Insulin Regimens and Glycemic Control in Children and Adolescents with Type 1 Diabetes. AB - We examined the association between sex, age, insulin regimens and glycemic control in 133 Japanese children and adolescents, 42 males and 61 females aged 16.8 +/- 7.0 yr, with type 1 diabetes mellitus (T1DM). The patients were divided into 5 age groups and were also classified according to the insulin regimen. The annual median HbA1c level in males (7.3 +/- 0.2%) was similar to that in females (7.2 +/- 0.2%). In regard to the age of the patients, the median HbA1c levels in patients aged 15-19 yr (7.9 +/- 0.4%) was significantly higher than those aged 5 9 yr (7.2 +/- 0.1%) and those aged 20<= yr (6.6 +/- 0.4%, p<0.05, respectively). On the other hand, there were no significant relationships between the HbA1c values and the insulin regimens. In conclusion, difficulty in management of diabetes due to emotional issues and endocrinological factors during adolescence may play a possible role in the deterioration of diabetes control. On the other hand, the insulin regimen does not seem to have a major impact on the metabolic outcome in young people with T1DM. PMID- 23926372 TI - Clinical characteristics of perinatal lethal hypophosphatasia: a report of 6 cases. AB - Hypophosphatasia is a rare inherited disorder caused by deficient tissue nonspecific alkaline phosphatase activity. It is classified into 6 subtypes, and the perinatal lethal form of hypophosphatasia is the most severe. Patients with this form suffer from various symptoms, including respiratory failure, premature craniosynostosis, rachitic changes in the metaphyses, convulsions and hypercalcemia. This report presents 6 cases of the perinatal lethal form of hypophosphatasia. All of the patients showed shortening of the long bones in utero in ultrasonographic examinations. Two of the six patients died at birth because they could not establish spontaneous breathing. Three of the remaining four patients also died before 1 yr of age. The major cause of death was respiratory failure due to hypoplastic lung. All of the patients, except for the two who died at birth, experienced convulsions in their clinical courses. Vitamin B6 therapy effectively reduced the frequency and severity of convulsions. However, it could not always make the patients convulsion free. Three patients underwent a genetic analysis. The 1559delT mutation, which abolishes Alkaline Phosphatase (ALP) activity, was a hot spot. A homozygous 1559delT mutation was observed in two patients. However, they differed in severity of symptoms. Although a good genotype-phenotype correlation has been reported in hypophosphatasia, the genotype alone does not always predict the life span of the patients. These cases therefore suggested the importance of genetic counseling. PMID- 23926373 TI - Recurrent Anion Gap Acidosis: An Unusual Presentation of X-Linked Adrenoleukodystrophy in a Five-year-old Male. AB - We are presenting a five-year-old male with recurrent anion gap acidosis. During his last admission, it was detected that he had elevated VLCFA and the evaluation discovered that he had X-linked Adrenooleukodystrophy. He had the Addisonian only phenotype without any clinical or radiographic CNS findings. We were unable to find any other reports of this presentation of ALD. If the work-up of recurrent anion gap acidosis does not uncover an etiology, X-linked ALD should be considered in the differential diagnosis. PMID- 23926374 TI - Leydig Cell Testicular Tumour Presenting as Isosexual Precocious Pseudopuberty in a 5 Year-old Boy with No Palpable Testicular Mass. AB - Leydig cell testicular tumors are very rare in children and cause isosexual precocious puberty. Palpable testicular mass or asymmetric testes are common findings on routine examination. We report on a 5-yr-old boy with a Leydig cell tumor of the testis presented with isosexual precocious puberty but no scrotal palpable mass. To our knowledge, this is the first reported Leydig cell tumor in a boy without palpable scrotal mass. PMID- 23926375 TI - Contiguous Xp11.4 Gene Deletion Leading to Ornithine Transcarbamylase Deficiency Detected by High-density Single-nucleotide Array. AB - Ornithine transcarbamylase (OTC) is one of the enzymes involved in the urea cycle. OTC deficiency, which is caused by impaired synthesis of OTC in the liver, is the most common inherited disease of urea cycle disorders. In this paper, we describe the case of an OTC-deficient Japanese boy wherein an analysis based on high-density single-nucleotide polymorphisms (SNPs) revealed the absence of the entire OTC locus and nearby genes. We identified a deletion on Xp11.4; the size of the deletion fragment was approximately 1 Mb. The deleted region included genes encoding transmembrane 4 superfamily member 2 (TSPAN7), MID1 interacting protein 1 (MID1IP1) and part of the retinitis pigmentosa GTPase regulator (RPGR) in addition to OTC. The results of a high-density SNP assay and PCR confirmed that the mother of the patient was a carrier of the mutation. Previously, determination of breakpoints for large unknown deletions was timeconsuming and laborintensive. However, the use of the widely available DNA chip technology allows for rapid determination of deletion breakpoints; therefore, it will become a standard technique in study of patients with a large genomic deletion of contiguous genes for provision of comprehensive genetic counseling and initiation of clinical management. PMID- 23926376 TI - Two cases of precocious puberty associated with hypothalamic hamartoma. AB - Hypothalamic hamartoma (HH) is a congenital malformation diagnosed based on magnetic resonance imaging (MRI) and histological findings; it is often associated with central precocious puberty (CPP), gelastic seizures, abnormal behavior and mental retardation. In the present paper, we report our retrospective hypothesis that there is a relationship between symptoms and therapy, as well as the treatment for HH, and describe two cases of HH associated with CPP. Both cases had sessile masses located in the interpeduncular cistern, with extension to the hypothalamus on MRI (1.2 * 1.5 cm and 2.0 * 2.5 cm, respectively). The first case had intractable seizures, while the second had no seizures with paroxysmal discharge. In both patients, the hamartomas were partially removed, by gamma-knife and surgical operation in the first case and surgically in the second, and a gonadotropin releasing hormone (GnRH) analogue was prescribed. One case showed improvement of both intelligence quotient (IQ) score and seizures, and the other showed improvements in IQ and abnormal behavior. It was difficult to determine any topology/symptom relationships. Surgery and GnRH analogue treatment can alleviate seizures, abnormal behavior and mental retardation associated with HH. PMID- 23926377 TI - Prolonged Intracranial Hypertension after Recombinant Growth Hormone Therapy due to Impaired CSF Absorption. AB - We experienced a case of a Japanese boy who developed intractable idiopathic intracranial hypertension (IIH) during growth hormone (GH) treatment. At the age of 4 yr, the boy was diagnosed with idiopathic growth hormone deficiency, and recombinant human GH replacement was initiated. Nine months after initiation of the GH therapy, he began to complain of headache, but papilledema was not observed. His headache persisted thereafter, and right esotropia occurred 10 mo after the initiation of GH therapy, at which time papilledema was detected. No other neurological abnormalities were detected, and the findings of computed tomography and magnetic resonance imaging were normal. In a cerebrospinal fluid (CSF) examination, the pressure was markedly elevated to 450 mmH2O, but no other abnormality was recognized. Impaired CSF absorption was detected using the pressure-volume index technique. The CSF levels of GH and insulin-like growth factor I were not increased. GH therapy was withdrawn after it was suggested that the IIH was associated with the GH therapy, but the headache persisted. The intracranial hypertension did not respond to diuretics, and prednisolone was only transiently effective. Although the funduscopic findings were normalized, increased CSF pressure was still observed. For over 2 yr, repeated lumbar puncture was necessary to protect against visual defect. IIH is an uncommon adverse event during GH therapy, but it must be considered carefully. PMID- 23926378 TI - A Novel Mutation of the Glucokinase Gene in Maturity-onset Diabetes of the Young Type 2 (MODY2). PMID- 23926379 TI - Wnt signaling in bone. AB - Wnt signaling is involved not only in embryonic development but also in maintenance of homeostasis in postnatal tissues. Multiple lines of evidence have increased understanding of the roles of Wnt signaling in bone since mutations in the LRP5 gene were identified in human bone diseases. Canonical Wnt signaling promotes mesenchymal progenitor cells to differentiate into osteoblasts. The canonical Wnt/beta-catenin pathway possibly through Lrp6, a co-receptor for Wnts as well as Lrp5, in osteoblasts regulates bone resorption by increasing the OPG/RANKL ratio. However, endogenous inhibitors of Wnt signaling including sclerostin block bone formation. Regulation of sclerostin appears to be one of the mechanisms of PTH anabolic actions on bone. Since sclerostin is almost exclusively expressed in osteocytes, inhibition of sclerostin is the most promising design. Surprisingly, Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum, but not by directly promoting bone formation. Pharmacological intervention may be considered in many components of the canonical Wnt signaling pathway, although adverse effects and tumorigenicity to other tissues are important. More studies will be needed to fully understand how the Wnt signaling pathway actually influences bone metabolism and to assure the safety of new interventions. PMID- 23926380 TI - A case report of dysosteosclerosis observed from the prenatal period. AB - Dysosteosclerosis is a sclerosing bone dysplasia with skeletal changes resembling those of osteopetrosis. The disorder is associated with dental anomalies and occasionally mental retardation. Because of the rarity and phenotypic diversity of dysosteosclerosis, it remains unsolved whether or not the disorder is heterogeneous. We report here on an affected boy associated with brain calcification and epilepsy with developmental delay. Prenatal ultrasound revealed ventriculomegaly, and brain CT in the neonatal period showed periventricular calcifications. At 13 mo of age, he presented with generalized convulsion with developmental delay. Metaphyseal sclerosis, metaphyseal undermodeling, and oval shaped vertebral bodies on skeletal survey warranted a diagnosis of dysosteosclerosis. Retrospective review of radiographs as a neonate showed metaphyseal radiolucency, but not metaphyseal sclerosis. Since then, neither the bone changes nor neurological symptom has progressively worsened up to 4 yr of age. Thus, it is thought that the clinical and radiological manifestations of the sclerotic disorder become obvious during infancy. Brain calcification of prenatal onset may be an essential syndromic constituent of the disorder. PMID- 23926381 TI - Adult heights of 258 girls with turner syndrome on low dose of growth hormone therapy in Japan. AB - Growth hormone (GH) therapy was approved in 1999 for only GH-deficient Turner syndrome (TS) in Japan. It was subsequently approved for all cases of TS regardless of GH secretory status since 1999. The dose of GH is 1.0 u (0.35 mg)/kg/wk at present, but it was 0.5 u (0.175 mg)/kg/wk before 1999. The adult height in patients with TS on the dose of 0.5 u/kg/wk was studied from the report on of Foundation for Growth Science in 2000. GH therapy was registered for 920 cases, and 258 cases reached adult height. The mean adult height was 145.7 cm. The adult height in patients with TS without GH therapy was reported to be 138 cm in Japan. Thus, the height gain by GH treatment was 7.7 cm. The mean age at the start of GH therapy was 12.0 yr old. The mean duration of GH therapy was 5.6 yr. The mean age at the start of estrogen therapy was 17.0 yr old. Patients in Japan were older at the start of GH and estrogen therapy than in the US and Europe at that time. The adult height and gain of height SD were not correlated with age at the start GH therapy in this study. This may be the result of the older age at the start of GH therapy and the low dose of the GH therapy. Patients are beginning to start GH therapy at a much earlier age and the dose has been doubled in Japan. We expect that the recent data concerning adult height in the patients with TS after GH therapy will improve better than this report. PMID- 23926382 TI - Proposal of new auxological standards for Japanese girls with turner syndrome. AB - We recently published new reference growth charts for Japanese girls with Turner syndrome (TS) based on the cross-sectional data of 1,447 subjects beyond the secular trend of growth in Japan. This study was undertaken for their validation and, if necessary, modification before general application. For validation, 24 subjects who had data both at younger (<=5 yr) and older ages (>=13 yr) were used. We analyzed the concordance/discordance of their height standard deviation score (SDS) defined by the charts between the two age periods. For modification, the LMS method was used with 5,772 longitudinal measurements obtained both from the previously analyzed subjects and 118 newly recruited subjects who had been followed up at the National Center for Child Health and Development or Toranomon Hospital. Significant and critical discordance (mean difference, 1.95 SDS; 95% confidence interval (CI), 1.53-2.36; p<0.0001) was detected in height SDS. This prompted us to perform the modifications. A similar analysis using the modified charts revealed no significant discordance (mean difference, 0.27 SDS; 95%CI: 0.17 - 0.71; p=0.22). They seem more adequate for clinical applications for girls with TS born after 1970. New auxological standards for Japanese girls with TS were proposed. PMID- 23926383 TI - Epidemiological studies of the developmental origins of adult health and disease in Japan: a pediatric perspective in present day Japan. AB - The origins of adult disease are considered to relate to fetal undernutrition, and this concept is termed "developmental origins of adult health and disease" (DOHaD). Here, we describe several epidemiological studies performed in Japan and discuss whether DOHaD is applicable to children in present day Japan. In a study of healthy children and young adults, it was found that systolic blood pressure, total cholesterol and adiponectin were associated with birth weight. Hyperinsulinemia, high blood pressure, elevated transaminase levels and prevalence of metabolic syndrome in obese children were inversely correlated with birth weight and positively correlated with current weight and waist circumference. Birth weight was related to the development of type 2 diabetes in children. DOHaD is therefore considered to be applicable in Japan. The key considerations of DOHaD are the following two mismatches. The first mismatch pertains to growth and development in response to environmental influences, especially those of nutrition. The second mismatch pertains to the prenatal versus postnatal environment. We consider that the chance of children in present day Japan developing adult diseases is determined by the above mismatches. Pediatricians and schoolteachers should therefore understand the concept of DOHaD, so that they can educate both children and their families regarding an appropriate diet to reduce the likelihood of developing adult diseases in later life. PMID- 23926384 TI - One Novel and Two Recurrent THRB Mutations Associated with Resistance to Thyroid Hormone: Structure-based Computational Mutation Prediction. AB - Inactivating mutations of THRB, which encodes the thyroid hormone receptor beta (TRbeta), cause resistance to thyroid hormone (RTH; OMIM 190160). To date, more than 100 THRB mutations have been reported among RTH patients. Most mutations substitute a single amino-acid residue in the ligand-binding domain. In this report, we describe clinical and molecular findings of three families with RTH. Three families harbored one novel (p.I431M) and two recurrent (p.R320H and p.R383C) THRB mutations. To examine the pathogenicity of identified mutations, we introduced a novel computational mutation prediction method based on three dimensional structure data of TRbeta-T3 complex. First, to define the accuracy of our prediction system, we evaluated ten previously reported 'positive control' mutations, as well as 30 seemingly benign sequence variations observed among vertebral species as 'negative controls'. We found that our system had a sensitivity of 80% and a specificity of 93%. We then analyzed three mutations detected in the present study and found that all three mutations are predicted to be deleterious. Our data suggest that our structure-based prediction system would be a prompt, inexpensive and feasible method for evaluating the pathogenicity of missense THRB mutations. PMID- 23926385 TI - Initial Treatment of Pediatric Graves' Disease with Methimazole: A Retrospective Follow-up Study. AB - Antithyroid drugs are widely used in the therapy of Graves' disease (GD), and methimazole (MMI) is preferred for treatment of pediatric GD. The recommended initial dosage of MMI is 0.5-1.0 mg/kg/d for pediatric GD, although there are few studies on the optimal MMI dosage for initial treatment in children. We retrospectively compared the efficacy of different doses of MMI in 35 children with GD. Eight children were excluded due to lack of follow-up, etc. The remaining 27 children were divided into a high-dose group (HD; MMI>=0.7 (0.85 +/- 0.13) mg/kg/d, n=8) and a low-dose group (LD; MMI<0.7 (0.51 +/- 0.12) mg/kg/d, n=19), and we compared the time needed for the serum FT4 levels to normalize (<=1.6 ng/dl) between the groups. There were no significant differences between the FT4 levels (HD: 5.5 +/- 2.8 ng/dl; LD: 5.0 +/- 2.4 ng/dl p=0.59) or thyroid stimulating hormone receptor antibody levels (HD: 56.2 +/- 29.3%; LD: 60.9 +/- 27.2% p=0.69) between the groups before treatment. The mean time required to normalize the FT4 levels was 22.5 +/- 7.4 d in the HD group and 28.8 +/- 16.2 d in the LD group (p=0.30). In addition, no other factor influenced the time to efficacy of MMI. A dose of MMI<0.7 (0.51 +/- 0.12) mg/kg/d appears to as effective as a higher dose in normalizing the serum FT4 level in children with mild or moderate GD. PMID- 23926386 TI - Congenital adrenal hyperplasia and brain magnetic resonance imaging abnormalities. AB - A 15-yr-old male patient with congenital adrenal hyperplasia (CAH) was referred to our department with a one year history of gradual worsening of tremors. He was diagnosed with salt-wasting 21-hydroxylase deficiency CAH at 40 d old and was started on hydrocortisone, fludrocortisone and salt. He was found to have hypertension at 8 yr of age. Detailed investigations failed to detect any cause for secondary hypertension. Physical findings on the current hospitalization objectified obesity, blood pressure of 150/80 mmHg, postural and action tremor, left cerebellar syndrome, reflex tetra pyramidal syndrome and mental decline. Brain magnetic resonance imaging (MRI) showed bilateral periventricular white matter hyperintensity that was more pronounced in the posterior regions and associated with cortico-subcortical atrophy and complete agenesis of the corpus callosum. All investigations for leukoencephalopathy were negative. A diagnosis of brain MRI abnormalities related to CAH was made, and the patient received symptomatic treatment of tremors. Our case report provides evidence of an increased frequency of brain MRI abnormalities in CAH. The literature suggests hormonal imbalance and exposure to excess exogenous glucocorticoids as main probable mechanisms. Thus, in clinical practice, CAH should be considered as one of the possible causes of brain white matter involvement associated with or without cerebral atrophy. PMID- 23926387 TI - Insulin Resistance during Puberty in Non-obese Japanese Children. AB - We examined whether non-obese Japanese children without diabetes exhibited insulin resistance during puberty. The study subjects were 201 Japanese school students, consisting 95 males and 106 females, aged 11.5 +/- 2.6 yr. None of the subjects were obese, with the mean percent of overweight being 0.7 +/- 10.5%, or had diabetes at the time of the study. Overnight fasting plasma values of insulin (FIRI) and HOMA-R were measured, with concomitant measurement of the plasma glucose (FPG) levels. The mean FPG, FIRI and HOMA-R values were 89.6 +/- 7.3 (70 109) mg/dl, 9.0 +/- 3.6 (1.7-24.4) uU/ml and 2.0 +/- 0.9 (0.3-5.2), respectively. The mean FIRI value was significantly higher in females than in males (8.3 +/- 3.4 vs. 9.6 +/- 3.7 uU/ml, p=0.0060). The FIRI and HOMA-R values of the pubertal students were significantly higher compared with those of the prepubertal students (FIRI, 10.0 +/- 3.4 vs. 6.5 +/- 2.8 uU/ml; HOMA-R, 2.3 +/- 0.8 vs. 1.4 +/- 0.7; p<0.0001 for both). Similar trends were observed between the two genders. The mean FIRI levels and HOMA-R values were positively correlated with age (FIRI, r=0.280, p<0.0001; HOMA-R, r=0.300, p<0.0001). In conclusion, we demonstrated that the FIRI and HOMA-R values were significantly associated with pubertal development in non-obese Japanese children without diabetes, consistent with the results of studies in white and black children. PMID- 23926388 TI - Elevated Bone Turnover in an Infantile Patient with Mucolipidosis II; No Association with Hyperparathyroidism. AB - This present report concerns an infantile patient with mucolipidosis II, who showed transient cortical bone hyperostosis followed by severe osteopenia. The diagnosis of mucolipidosis II was made based on the leakage of lysosomal enzymes in serum and conditioned media of the patient's skin fibroblasts, low activity of lysosomal enzymes of the fibroblasts and mutation of c.2086_2089insC (p.L697fs) and c.3565C>T (p.R1189X) in the GNPTAB gene. Bone X-ray analysis demonstrated a periosteal reaction and elevated bone resorption at the age of 2 mo. Bone markers, including alkaline phosphatase, osteocalcin and urine deoxypyridinoline, also indicated a high turnover of bone metabolism; however, no apparent rickets like changes and no increased levels of PTH were observed. Elevated bone resorption is possibly associated with the leakage of lysosomal enzyme from osteoclasts into bone matrices. Bone formation gradually reduced, and increased bone resorption persisted. This led to severe osteopenia at the age of 6 mo. Characteristic bone findings may contribute to early diagnosis of mucolipidosis II, but their pathogenesis remains to be clarified. PMID- 23926389 TI - The Relationship between Preheparin Lipoprotein Lipase and Metabolic Derangements in Obese Japanese Children. AB - The aim of this study was to clarify the relationship between preheparin lipoprotein lipase (LPL) and derangements of metabolic status in obese Japanese children. We examined 102 obese children (55 boys and 47 girls; mean age 10.9 yr). Anthropometry, blood pressure and levels of liver transaminases, serum lipids and lipoproteins, uric acid, fasting blood glucose (FBG), serum insulin, LPL, leptin and adiponectin were measured. The subjects were divided into the metabolic syndrome (MS) and non-MS groups. The levels of LPL were compared between these groups. Statistical analysis showed that the LPL levels were significantly lower in the MS group compared with the non-MS group, with the levels decreasing progressively as the number of MS components increased. We conclude that LPL levels decrease also in obese Japanese children with a deteriorated metabolic status in the same way as in adults. PMID- 23926390 TI - A Novel Splicing Mutation of the GNAS Gene in a Patient with Pseudohypoparathyroidism Ia. PMID- 23926391 TI - Relation between Delayed Superfluous Insulin Secretion during An Oral Glucose Tolerance Test and Metabolic Disorders in Obese Japanese Children. AB - The aim of this study was to clarify the relation between postprandial hyperinsulinemia and metabolic disorders in obese children. Twenty-eight obese Japanese children (8.8-16.2 yr) were divided into four groups: without impaired liver function and dyslipidemia (Group A), with impaired liver function (Group B), with dyslipidemia (Group C), and with impaired liver function and dyslipidemia (Group D). The levels of PG, serum immunoreactive insulin (IRI) and serum C-peptide (CPR) were measured during an oral glucose tolerance test (OGTT). The subjects had delayed superfluous insulin and CPR secretion during the OGTT compared with healthy references. In regard to the insulin secretion pattern, Group A's response peaked at 60 min and then decreased gradually until 120 min, Group B's response peaked at 60 min, remained at the peak until 120 min and then decreased gradually until 180 min, Group C's response peaked at 120 min and then decreased gradually until 180 min, and Group D's response peaked at 120 min and remained at the peak until 180 min. These results suggest that delayed superfluous insulin secretion during an OGTT is related to metabolic disorders in obese Japanese children and that these patients will experience a vicious cycle of postprandial hyperinsulinemia and metabolic disorders. It is important to prevent healthy children from becoming obese and to improve management of childhood obesity. PMID- 23926392 TI - Characterization of diabetes mellitus in Japanese prader-willi syndrome. AB - Prader-Willi syndrome (PWS) is frequently associated with marked obesity and diabetes mellitus (DM). Although the overall frequency of DM in PWS ranges from 7 20%, there is only limited data available on Japanese patients. This study evaluated five factors associated with DM in PWS: 1) frequency, 2) age of onset, 3) risk factors, 4) long-term complications and 5) treatment. Sixty-five patients, ranging in age from 10 to 53 yr, were studied retrospectively. The frequency of DM in patients over 10 yr of age was 26.2% (17/65 patients). The age of DM onset ranged from 10 to 29 yr with a median age of 15 yr. The body mass index (BMI) was significantly higher in the DM group in comparison with the non DM group. The number of patients using growth hormone (GH) in the DM group was significantly lower than the number that did not. Proteinuria (urinary excretion of albumin/creatinine at spot collection: U-Alb/Cr >=300 mg/gCr) was observed in 1/17 patients (5.9%), microalbuminuria (U-Alb/Cr 30-300 mg/gCr) was observed in 4/17 patients (23.5%) and nonproliferative retinopathy was observed in 2/17 patients (11.8%). Among oral hypoglycemic agents, alpha-glucosidase inhibitors (alpha-GI) were most often used in our patients (10/17, 58.8%). Eleven out of 17 patients (64.7%) had been treated with insulin. PMID- 23926393 TI - A Report of Three Girls with Antithyroid Drug-Induced Agranulocytosis; Retrospective Analysis of 18 Cases Aged 15 Years or Younger Reported between 1995 and 2009. AB - Agranulocytosis is an extremely serious, although rare, adverse effect of antithyroid drugs (ATDs), including methimazole (MMI) and propylthiouracil (PTU), in children and adolescents. There are few reports about the characteristics of ATD-induced agranulocytosis in Japanese children and adolescents. This report presents the cases of three girls with ATD-induced agranulocytosis and a retrospective analysis of 18 patients with ATD-induced agranulocytosis, whose cases had been referred to the drug manufacturer, Chugai Pharmaceutical Co., Ltd. Our 3 patients, ranging in age from 12 to 14 yr, developed ATD-induced agranulocytosis between the 15th and 57th day of ATD treatment for hyperthyroidism. Fever and sore throat were the earliest symptoms of agranulocytosis. The patients were rescued by ceasing ATD therapy and administering antibiotics, potassium iodide, glucocorticoid, immunoglobulin and granulocyte colony-stimulating factor (G-CSF). We retrospectively analyzed 18 cases of ATD-induced agranulocytosis treated with MMI in 16 cases and PTU in 2 cases. Twelve patients were treated with 20-45 mg/d MMI. Agranulocytosis developed between the 15th and 1,344th day of therapy. In conclusion, considering the risk of ATD-induced agranulocytosis, we recommend low-dose MMI therapy for treatment of Graves' disease. PMID- 23926394 TI - The Cubic Functions for Spline Smoothed L, S and M Values for BMI Reference Data of Japanese Children. PMID- 23926395 TI - Treatment of Hypothyroidism due to Iodine Deficiency Using Daily Powdered Kelp in Patients Receiving Long-term Total Enteral Nutrition. AB - We investigated thyroid function and urinary iodine concentration (UIC) in seven patients with severe motor intellectual disabilities. All seven received total enteral nutrition (TEN) for more than three years with a daily iodine intake of less than 20 ug. They were diagnosed as hypothyroidism due to iodine deficiency (HID) because of high TSH levels (7.6-82.3 uIU/ml), lower free T4 (FT4 0.4-1.5 ng/dl), negative anti-thyroid antibodies (anti-thyroglobulin antibody, anti thyroidal peroxidase antibody) and extremely low UIC (<25-58 ug/l) levels. We gave them 1-2 g powdered kelp (200-400 ug as iodine) once a day, which restored their thyroid function and normalized their UICs. We proposed that daily powdered kelp would be effective and safe to treat HID in patient receiving long term TEN. PMID- 23926396 TI - An Unusual Presentation of Addison's Disease-A Case Report. AB - Addison's disease is most commonly due to autoimmune adrenalitis and tuberculosis and refers to primary hypoadrenalism caused by a total or near total destruction or dysfunction of both adrenal cortices. Usual manifestations involve chronic fatigue, muscle weakness, loss of appetite, nausea, vomiting, diarrhea, hypotension and hyperpigmentation of skin. We herein report a case of primary adrenal insufficiency presenting with fever and seizures in an 11-yr-old boy. His symptoms resolved after starting specific therapy. This kind of presentation of Addison's disease is rather unusual. PMID- 23926397 TI - Thymic Hyperplasia Associated with Graves' Disease in a 10-year-old Boy. AB - Thymic hyperplasia associated with Graves' disease is rarely reported in children, although it is not uncommon in adults. Occasionally, an enlarged thymus presents as an anterior mediastinal mass on a radiographic examination. Such patients often undergo invasive procedures such as a thymus biopsy or thymectomy because of suspected malignancy. However, an enlarged thymus with Graves' disease is known to shrink after treatment with antithyroid drugs. Therefore, recognition of this benign course would avoid unnecessary surgical resection. This report presents the case of a 10-yr-old boy with Graves' disease complicated with an anterior mediastinal mass. Computed tomography showed a homogenous mass with no invasion into the surrounding tissue. A gallium-67 scintigraphy showed no abnormal uptake. Shrinkage of the mass after treatment with an antithyroid drug (methyl-mercaptoimidazole) supported the diagnosis of thymic hyperplasia with Graves' disease. This case report illustrates two important points. First, pediatricians should be aware that thymic hyperplasia can coexist with Graves' disease, even in children. Second, close radiographic assessment would support a diagnosis of thymic hyperplasia and eliminate invasive diagnostic procedures. PMID- 23926398 TI - A Male Patient with Humoral Hypercalcemia of Malignancy (HHM) with Leukocytosis Caused by Cutaneous Squamous Cell Carcinoma Resulting from Recessive Dystrophic Epidermolysis Bullosa. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disorder. Although the patients are at risk for cutaneous squamous cell carcinoma (SCC), no case of cutaneous SCC derived from RDEB with humoral hypercalcemia of malignancy (HHM) has been reported. We present the first case report of a male patient with HHM with leukocytosis caused by cutaneous SCC resulting from RDEB. A 20-yr-old Japanese male patient with RDEB; the diagnosis was confirmed by electron microscopic examination, suffered an intractable skin ulcer and hypercalcemia and leukocytosis. PTH-rP, SCC antigen and Granulocyte colony-stimulating factor (G CSF) levels were elevated. The histological diagnosis of the skin lesion was made well-differentiated SCC. Immunohistochemical staining showed the expression of PTH-rP in atypical tumor cells. For the control of hypercalcemia before an amputation, we used zoledronate safely and could control the serum Ca concentration in the normal range. After the amputation of his right leg including SCC, leukocytosis improved immediately and PTH-rP in blood decreased to the normal range. One month after the amputation, local recurrence of cutaneous SCC and multiple lung metastases were observed. PTH-rP increased gradually associated with hypercalcemia. Although the patient reached an unfortunate turning point about 4 mo after the amputation, we propose that zoledronate is an effective and safe treatment for HHM with cardiorenal complications. PMID- 23926399 TI - Role of counterregulatory hormones for glucose metabolism in children and adolescents with type 1 diabetes. AB - To elucidate the mechanism of insulin resistance due to insulin counterregulatory hormones (ICRHs) and evaluate ICRH secretion kinetics, ICRH concentrations were measured and correlated with blood glucose levels in 28 type 1 diabetic patients. Blood glucose was measured before bedtime. Early morning urine samples were collected the next morning before insulin injection and breakfast. Fasting blood glucose, cortisol, glucagon and HbA1c levels were measured. Growth hormone (GH), adrenaline, cortisol and C-peptide levels in morning urine samples were measured; SD scores were calculated for urine GH. The laboratory values (mean +/- SD) were as follows; HbA1c of 8.1% +/- 1.4%; pre-bedtime glucose of 203 +/- 105 mg/dl; fasting blood glucose of 145 +/- 87 mg/dl; serum cortisol of 21.6 +/- 5.5 ug/dl; plasma glucagon of 98 +/- 41 pg/ml; urinary GH, 27.2 +/- 13.0 ng/gCr; urinary cortisol of 238 +/- 197 ng/gCr; and urinary Adrenaline of 22.9 +/- 21.0 ng/gCr. The mean urinary GH SD score was increased (+1.01 +/- 0.70; p=0.000); the mean plasma glucagon lebel (98 +/- 41 pg/ml) was not. Fasting blood glucose was positively correlated with plasma glucagon (R=0.378, p=0.0471) and negatively correlated with urinary cortisol (R=-0.476, p=0.010). Urinary adrenaline correlated positively with urinary GH (R=0.470, p=0.013) and urinary cortisol (R=0.522, p=0.004). In type 1 diabetes, GH, glucagon and cortisol hypersecretion may contribute to insulin resistance, but the mechanism remains unclear. PMID- 23926400 TI - Premature thelarche in later childhood demonstrates a pubertal response to GnRH stimulation test at one year after breast development. AB - Premature thelarche in later childhood (such as at 5-7 yr of age) is not always easy to distinguish from GnRH-dependent precocious puberty. In this study, a GnRH stimulation test was performed on 21 girls from 5 to 7.5 yr of age with early breast development. In 8 of 11 girls within 1 yr after thelarche, i.e., breast development, the GnRH stimulation test showed a prepubertal response, and in all 10 girls at more than 1 yr after breast development, the GnRH stimulation test showed a pubertal response. In observations of 4 girls with a prepubertal response, the GnRH stimulation test showed to a pubertal response by 1 yr or more after breast development in 3 of 4 the girls. These results indicate the possibility that almost all cases of breast development in later childhood consist of premature thelarche and that premature thelarche in later childhood may easily lead to early puberty at 1 yr or more after breast development. Careful observations are therefore recommended for at least 1 yr, even if early breast development is considered to be associated with premature thelarche in later childhood. PMID- 23926401 TI - Diagnostic usefulness of 3 tesla MRI of the brain for cushing disease in a child. AB - It is sometimes difficult to confirm the location of a microadenoma in Cushing disease. Recently, we experienced an 11-yr-old female case of Cushing disease with hyperprolactinemia. She was referred to our hospital because of decrease of height velocity with body weight gain. On admission, she had typical symptoms of Cushing syndrome. Although no pituitary microadenomas were detected on 1.5 Tesla MRI of the brain, endocrinological examinations including IPS and CS sampling were consistent with Cushing disease with hyperprolactinemia. Oral administration of methyrapone instead of neurosurgery was started after discharge, but subsequent 3 Tesla MRI of the brain clearly demonstrated a 3-mm less-enhanced lesion in the left side of the pituitary gland. Finally, transsphenoidal surgery was performed, and a 3.5-mm left-sided microadenoma was resected. Compared with 1.5 Tesla MRI, 3 Tesla MRI offers the advantage of a higher signal to noise ratio (SNR), which provides higher resolution and proper image quality. Therefore, 3 Tesla MRI is a very useful tool to localize microadenomas in Cushing disease in children as well as in adults. It will be the first choice of radiological examinations in suspected cases of Cushing disease. PMID- 23926402 TI - Fabry disease superimposed on overt autoimmune hypothyroidism. AB - Fabry disease (FD) is an X-linked recessive disorder caused by lysosomal alpha galactosidase A deficiency. FD is characterized by the systemic accumulation of globotriaosylceramide with involvement of the heart, kidney, brain and gastrointestinal system. Recently, nonautoimmune thyroid dysfunction was recognized as an additional clinical feature of FD. In the present study, we describe a patient suffering from FD superimposed on overt autoimmune hypothyroidism. The patient was an 11-yr-old boy who presented with goiter and stunted growth, and was diagnosed with primary hypothyroidism due to autoimmune thyroiditis. During levothyroxine replacement therapy, the patient complained of burning pain in his feet and was diagnosed as suffering from FD based on low blood alpha-galactosidase A activity. In conclusion, we have described the first FD patient preceded by overt autoimmune hypothyroidism. PMID- 23926403 TI - Acquired cryptorchidism in a boy with disorder of sex development. AB - Recently, it has been reported that boys with severe hypospadias are at increased risk for acquired cryptorchidism. The reports suggested that prenatal and postnatal androgen disruption might be correlated with this condition. We experienced a case of ovotesticular disorder of sex development (DSD), which was ultimately diagnosed at surgery for acquired cryptorchidism. Ascent of the scrotal contents of the left side was detected in a 7-yr-old boy with the 46, XX karyotype, who had a history of perineal hypospadias repair. Intraoperative findings revealed the left gonad consisted of 2 segments, and this was histologically diagnosed as ovotestis by biopsy specimen. Resection of the ovarian segment was performed simultaneously. Exploration of the contralateral gonad showed the same findings. This is the first report of acquired cryptorchidism observed in a patient with DSD presenting with ambiguous genitalia. PMID- 23926404 TI - Familial Hyperkalemic Hypertension: A New Early-onset Pediatric Case. PMID- 23926405 TI - A Case of Allgrove Syndrome with a Novel IVS7 +1 G>A Mutation of The AAAS Gene. PMID- 23926406 TI - Favorable Impacts of Growth Hormone (GH) Replacement Therapy on Atherogenic Risks in Japanese Children with GH Deficiency. AB - Growth hormone (GH) affects body composition and atherogenic risk factors. Severe hyperlipidemia may develop in GH-deficient adults as a consequence of continuous GH deficiency. We investigated changes in lipid profiles in 158 Japanese children (103 boys and 55 girls) with GH deficiency who had been enrolled in the Pfizer International Growth Database Japan during 3 yr of GH replacement therapy to evaluate whether GH treatment has beneficial effects on atherogenic risk factors. Total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC) and atherogenic index were evaluated before treatment and then once a year during treatment. The mean baseline TC was within the normal range in both boys and girls. Seventeen (16.5%) of the 103 boys and 18 (32.7%) of the 55 girls, however, had a TC level over 200 mg/dl before treatment. The mean TC level showed a significant decrease in girls. In a separate analysis, patients of both sexes with a TC level > 200 mg/dl showed significantly decreased TC. LDLC decreased significantly only in girls, while HDLC showed no change in either sex. The atherogenic index decreased significantly in girls. GH replacement therapy in children with GH deficiency had beneficial effects on lipid metabolism and atherogenic risk in both sexes. Early GH treatment would produce lipid metabolism benefits in these patients. PMID- 23926407 TI - An Infantile Case of Transient, Severe Hypercholesterolemia with Normalization after Complete Weaning from Breast-feeding. AB - A 20-d-old boy was referred to our department because of hyperthyrotropinemia at neonatal mass screening and diagnosed with neonatal transient hyperthyrotropinemia. A follow-up examination when the patient was 5 mo old revealed severe hypercholesterolemia. Familial hypercholesterolemia was first suspected because of the patient's significantly high levels of total and low density lipoprotein cholesterol. The parent's serum lipid profiles were examined and found to be normal. He was completely breast-fed until 6 mo of age. Breast milk was still the main source of food for a period following weaning. At 14 mo old, the patient was weaned completely from breast milk, and his serum cholesterol levels decreased dramatically. According to the normal lipid profiles of the patient's parents and the spontaneous normalization of serum cholesterol levels after complete weaning from breast milk, breast-feeding was suggested to be responsible for his transient severe hypercholesterolemia. It is well documented that breast-fed infants have higher serum cholesterol levels than formula-fed infants. However, there is no reported case with severe hypercholesterolemia equivalent to or higher than the levels observed in the case of familial hypercholesterolemia. Although the exact mechanism is unknown, it is necessary to consider that a small number of cases develop severe hypercholesterolemia related to breast-feeding. PMID- 23926408 TI - Favorable impact of growth hormone treatment on cholesterol levels in turner syndrome. AB - BACKGROUND: Patients with Turner syndrome (TS) are prone to having metabolic abnormalities, such as obesity, dyslipidemia, hypertension, hyperinsulinemia and type 2 diabetes mellitus, resulting in increased risks of developing atherosclerotic diseases. OBJECTIVE: To determine the effect of growth hormone (GH) therapy on serum cholesterol levels in prepubertal girls with TS enrolled in the Turner syndrome Research Collaboration (TRC) in Japan. PATIENTS AND METHODS: Eighty-one girls with TS were enrolled in the TRC, and their total cholesterol (TC) levels before GH therapy were compared with reported levels of healthy school-aged Japanese girls. TC levels after 1, 2 and 3 yr of GH treatment were available for 28 of the 81 patients with TS. GH was administered by daily subcutaneous injections, 6 or 7 times/wk, with a weekly dose of 0.35 mg/kg body weight. RESULTS: Baseline TC levels revealed an age-related increase in TS that was in contrast to healthy girls showing unchanged levels. During GH therapy, TC decreased significantly after 1 yr of GH treatment and remained low thereafter. CONCLUSIONS: Girls with untreated TS showed an age-related increase in TC that was a striking contrast to healthy girls, who showed unchanged levels. GH therapy in girls with TS brought about a favorable change in TC that indicates the beneficial impact of GH on atherogenic risk. PMID- 23926409 TI - Combined Treatment with Gonadotropin-releasing Hormone Analog and Anabolic Steroid Hormone Increased Pubertal Height Gain and Adult Height in Boys with Early Puberty for Height. AB - Twenty-one boys with a height of 135 cm or less at onset of puberty were treated with a combination of GnRH analog and anabolic steroid hormone, and their pubertal height gain and adult height were compared with those of untreated 29 boys who enter puberty below 135 cm. The mean age at the start of treatment with a GnRH analog, leuprorelin acetate depot (Leuplin((r))) was 12.3 yr, a mean of 1.3 yr after the onset of puberty, and GnRH analog was administered every 3 to 5 wk thereafter for a mean duration of 4.1 yr. The anabolic steroid hormone was started approximately 1 yr after initiation of treatment with the GnRH analog. The mean pubertal height gain from onset of puberty till adult height was significantly greater in the combination treatment group (33.9 cm) than in the untreated group (26.4 cm) (p<0.0001). The mean adult height was significantly greater in the combination treatment group (164.3 cm) than in the untreated group (156.9 cm) (p<0.0001). The percentage of subjects with an adult height of 160 cm or taller was 90.5% (19/21) in the combination treatment group, and it was 13.8% (4/29) in the untreated group (p<0.0001). Since growth of the penis and pubic hair is promoted by the anabolic steroid hormone, no psychosocial problems arose because of delayed puberty. No clinically significant adverse events appeared. Combined treatment with GnRH analog and anabolic steroid hormone significantly increased height gain during puberty and adult height in boys who entered puberty with a short stature, since the period until epiphyseal closure was extended due to deceleration of the bone age maturation by administration of the GnRH analog and the growth rate at this time was maintained by the anabolic steroid hormone. PMID- 23926410 TI - Nateglinide is Effective for Diabetes Mellitus with Reactive Hypoglycemia in a Child with a Compound Heterozygous ABCC8 Mutation. AB - ABCC8 encodes the sulfonylurea receptor 1 (SUR1) subunits of the beta-cell ATP sensitive potassium (K-ATP) channel playing a critical role in the regulation of insulin secretion, and inactivating mutations in ABCC8 cause congenital hyperinsulinism. Recently, ABCC8 inactivating mutations were reported to be involved in the development of diabetes mellitus later in life. We report a girl who was born macrosomic with transient hypoglycemia and thereafter developed diabetes mellitus accompanied by severe reactive hypoglycemia at the age of 11 yr. An OGTT (oral glucose tolerance test) revealed hyperglycemia due to poor early insulin response and subsequent hypoglycemia due to delayed prolonged insulin secretion. Hypoglycemia was improved by the combination of nateglinide, which stimulates early insulin secretion, and an alpha-glucosidase inhibitor, voglibose. Sequencing of the ABCC8 identified a compound heterozygous mutation (R1420H/F591fs604X), suggesting that this mutation may alter regulation of insulin secretion with advancing age, leading to diabetes mellitus with reactive hypoglycemia from hyperinsulinism. Therefore, long-term follow-up and periodic OGTTs are important for early detection of insulin dysregulation in congenital hyperinsulinism patients carrying the ABCC8 mutation, even though hypoglycemia resolves spontaneously during infancy. Furthermore, nateglinide may be useful therapeutically in the treatment of not only diabetes mellitus but also reactive hypoglycemia. PMID- 23926411 TI - A Case of Novel Mutation of HNF1B in Maturity-onset Diabetes of the Young Type 5 (MODY5). PMID- 23926412 TI - Efficacy and Safety of Up to 8 Years of Long-term Growth Hormone Treatment in Short Children Born Small for Gestational Age in Japan: Analysis of the Subpopulation According to the Japanese Guideline. AB - The efficacy and safety of 8 yr of GH treatment was assessed in 44 Japanese children with small for gestational age (SGA) short stature who met the criteria for GH treatment initiation (height SD score (SDS) <-2.5 SD) of the Japanese guidelines. Height SDS in subjects improved throughout the study period, and average height SDS improved from -3.5 to -1.6 and from -3.4 to -1.9 in the 0.033/0.067 mg and 0.067/0.067 mg groups, respectively, after 8 yr of GH treatment. Delta height SD was approximately +2 after 4 yr of treatment, and ? IGF-1 showed a significant positive correlation with ? height SD after both 1 and 2 yr (r = 0.415 and 0.488, respectively) of treatment. There was no correlation between the age at the start of treatment and age at onset of puberty, and the median age at the onset of puberty in the subjects was almost the same as that in healthy children. In conclusion, clinically significant improvements in the height SDS was confirmed in short children born SGA after 8 yr of GH treatment without any safety problems. PMID- 23926413 TI - A case series of five sri lankan patients with ovotesticular disorder of sex development. AB - Ovotesticular disorder of sex development (OT-DSD) is a rare disorder of sexual differentiation in which the gonads of an individual are characterized by the presence of both mature ovarian and testicular tissues. The objective of this paper is to report the clinical, cytogenetic and histopathological findings in Sri Lankan patients diagnosed with OT-DSD who were referred to the Human Genetics Unit for cytogenetic evaluation during 2005 to 2011. Five patients had histopathologically confirmed OT-DSD. Their ages at presentation ranged from 2 mo to 47 yr. Clinical symptoms varied from ambiguous genitalia and inguinal hernias at birth to a lower abdominal mass presenting in adulthood. All 5 were reared as phenotypic males. An ovotestis was detected in all cases except one, and the predominant karyotype was 46,XY. The findings in this series of predominantly 46,XY karyotype are in contrast to previously published reports that have reported 46,XX as being the predominant karyotype. It is therefore recommended that individuals with ambiguous genitalia who have the 46,XY karyotype should be thoroughly investigated by ultrasonographic or laparoscopic assessment to determine the exact nature of their internal genital organs. OT-DSD should also be considered in the differential diagnosis of patients with cryptorchidism and inguinal hernia. PMID- 23926414 TI - Partially reversible hypopituitarism in an adolescent with a rathke cleft cyst. AB - Rathke cleft cysts are remnants of the Rathke pouch. Most of them are asymptomatic, but sometimes they can grow enough to cause compression of structures within and/or close to the sella, thus eliciting symptoms such as visual disturbance, pituitary defects, and headache. Asymptomatic cysts can safely be followed up with serial imaging, while the standard treatment for symptomatic lesions is surgical removal. We describe a 14-yr-old boy, admitted for anorexia, fatigue, weight loss, recurrent headache and vomiting. Magnetic resonance imaging showed an intra- and suprasellar cystic lesion, which was surgically removed. Histology was consistent with Rathke's cleft cyst. Diabetes insipidus and multiple anterior pituitary defects (GH, ACTH and TSH) were found preoperatively, and substitutive therapy was started. No additional hormonal defect appeared after surgery. After 4 yr of follow up, pituitary function was retested, and there were no confirmed GH or ACTH defects, allowing a partial withdrawal of replacement therapy. Our report confirms that pituitary defects, in patients with a Rathke cleft cyst, may recover even year after surgery. Thus, retesting of pituitary axes is indicated during long-term follow up. PMID- 23926415 TI - Understanding oral reading fluency among adults with low literacy: Dominance analysis of contributing component skills. PMID- 23926416 TI - The Impact of a Science Education Game on Students' Learning and Perception of Inhalants as Body Pollutants. AB - This study investigated the knowledge gains and attitude shifts attributable to a unique online science education game, Uncommon Scents. The game was developed to teach middle school students about the biological consequences of exposure to toxic chemicals in an environmental science context, as well as the risks associated with abusing these chemicals as inhalants. Middle school students (n = 444) grades six through eight participated in the study consisting of a pre-test, three game-play sessions, and a delayed post-test. After playing the game, students demonstrated significant gains in science content knowledge, with game usability ratings emerging as the strongest predictor of post-test content knowledge scores. The intervention also resulted in a shift to more negative attitudes toward inhalants, with the most negative shift occurring among eighth grade students and post-test knowledge gains as the strongest predictor of attitude change across all grade levels. These findings suggest that the environmental science approach used in Uncommon Scents is an efficacious strategy for delivering both basic science content and influencing perceived harm relating to the inhalation of toxic chemicals from common household products. PMID- 23926417 TI - Identification of differentially evolved genes: an alternative approach to detection of accelerated molecular evolution from genome-wide comparative data. AB - One of the most important measures for detecting molecular adaptations between species/lineages at the gene level is the comparison of relative fixation rates of synonymous (dS) and non-synonymous (dN) mutations. This study shows that the branch model is sensitive to tree topology and proposes an alternative approach, devogs, which does not require phylogenetic topology for analysis. We compared devogs with a branch model method using virtual data and a varying omega ratio, in which parameters were obtained from real data. The positive predictive value, sensitivity, and specificity of the branch model were affected by the phylogenic tree topology. Devogs showed greater positive predictive value, whereas the branch model method had greater sensitivity. In a working example using devogs, a group of human RNA polymerase II-related genes, which are important in mediating alternative splicing, were significantly accelerated compared to four other mammals. PMID- 23926419 TI - Evaluation of in vitro glistening formation in hydrophobic acrylic intraocular lenses. AB - PURPOSE: To evaluate the impact of continuous manufacturing process improvements on glistening formation in AcrySof hydrophobic acrylic intraocular lenses (IOLs) by comparing lenses manufactured in 2003 with lenses manufactured in 2012. METHODS: Glistenings were experimentally created as aqueous-filled microvacuoles utilizing an accelerated laboratory method by immersing the lens in water at 45 degrees C for 24 hours and then reducing the temperature to 37 degrees C for 2.5 hours. To determine the impact of continuous improvements on glistening formation, AcrySof IOLs (Alcon Laboratories, Inc) Model SB30 AL manufactured in 2003 were compared with AcrySof IOLs Model SN60 WF manufactured in 2012. RESULTS: Glistenings were present in all lenses after the accelerated microvacuole test method. The mean microvacuole density for IOLs manufactured in 2003 was 315.7 microvacuoles per square millimeter (MVs/mm(2)) with a glistening severity less than 100 MVs/mm(2) in 1.0% of the IOLs. The mean microvacuole density for IOLs manufactured in 2012 was 39.9 MVs/mm(2) with a glistening severity less than 100 MVs/mm(2) in 95.2% of the IOLs. Laboratory-induced microvacuole density was significantly lower in IOLs manufactured in 2012 (mean 39.9 MVs/mm(2)) relative to IOLs manufactured in 2003 (mean 315.7 MVs/mm(2)) as indicated by the Wilcoxon test of significance (P < 0.0005). CONCLUSION: AcrySof IOLs recently manufactured in 2012 demonstrated a significant reduction in glistening density (87% reduction in mean density) as a result of continuous manufacturing process improvements compared with IOLs manufactured in 2003. PMID- 23926418 TI - Evolutionary Modeling of Genotype-Phenotype Associations, and Application to Primate Coding and Non-coding mtDNA Rate Variation. AB - Variation in substitution rates across a phylogeny can be indicative of shifts in the evolutionary dynamics of a protein or non-protein coding regions. One way to understand these signals is to seek the phenotypic correlates of rate variation. Here, we extended a previously published likelihood method designed to detect evolutionary associations between genotypic evolutionary rate and phenotype over a phylogeny. In simulation with two discrete categories of phenotype, the method has a low false-positive rate and detects greater than 80% of true-positives with a tree length of three or greater and a three-fold or greater change in substitution rate given the phenotype. In addition, we successfully extend the test from two to four phenotype categories and evaluated its performance. We then applied the method to two major hypotheses for rate variation in the mitochondrial genome of primates-longevity and generation time as well as body mass which is correlated with many aspects of life history-using three categories of phenotype through discretization of continuous values. Similar to previous results for mammals, we find that the majority of mitochondrial protein-coding genes show associations consistent with the longevity and body mass predictions and that the predominant signal of association comes from the third codon position. We also found a significant association between maximum lifespan and the evolutionary rate of the control region of the mtDNA. In contrast, 24 protein coding genes from the nuclear genome do not show a consistent pattern of association, which is inconsistent with the generation time hypothesis. These results show the extended method can robustly identify genotype-phenotype associations up to at least four phenotypic categories, and demonstrate the successful application of the method to study factors affecting neutral evolutionary rate in protein-coding and non-coding loci. PMID- 23926420 TI - Assessing acute systemic effects of an inhaled drug with serial echocardiography: a placebo-controlled comparison of inhaled and intravenous dihydroergotamine. AB - OBJECTIVE: MAP0004 is an investigational product which delivers dihydroergotamine (DHE) through the lung via a breath-synchronized metered dose inhaler. The objective of this study was to compare the acute effects of orally inhaled and intravenous (IV) DHE to placebo on maximum change and area under the curve for pulmonary arterial systolic pressure (PASP). RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled, 3-period, crossover study of 24 health adults. Trial registration NCT01089062. Study assessments included pharmacokinetics, electrocardiograms (ECG), and validated echocardiographic (Doppler)-derived measures of PASP by echocardiogram. The primary endpoint was the absolute change in calculated PASP using area under the curve, 0 to 2 hours (AUC(0-2h)). RESULTS: The change in PASP with IV DHE was significantly different than MAP0004 and placebo (AUC(0-2h)2857, 2624, and 2453 mmHg*min, respectively). After a second dose of MAP0004, AUC(0-4h) remained lower with MAP0004 than with a single dose of IV DHE. Adverse events were more common with IV DHE than with MAP0004 or placebo. None of the treatments produced clinically significant changes in PASP or other cardiac parameters. Changes in PASP were significantly smaller with MAP0004 compared with IV DHE. CONCLUSION: These results indicate the effects 1 mg of orally inhaled DHE on the cardiovascular system are less than with 1 mg of IV DHE, and that serial echocardiography can be a useful noninvasive means of assessing acute systemic effects. PMID- 23926421 TI - Successful application of extracorporeal membrane oxygenation due to pulmonary hemorrhage secondary to granulomatosis with polyangiitis. AB - Extracorporeal membrane oxygenation (ECMO) is increasingly applied in adults with acute refractory respiratory failure that is deemed reversible. Bleeding is the most frequent complication during ECMO support. Severe pre-existing bleeding has been considered a contraindication to ECMO application. Nevertheless, there are cases of successful ECMO application in patients with multiple trauma and hemorrhagic shock or head trauma and intracranial hemorrhage. ECMO has proved to be life-saving in several cases of life-threatening respiratory failure associated with pulmonary hemorrhage of various causes, including granulomatosis with polyangiitis (Wegener's disease). We successfully applied ECMO in a 65-year old woman with acute life-threatening respiratory failure due to diffuse massive pulmonary hemorrhage secondary to granulomatosis with polyangiitis, manifested as severe pulmonary-renal syndrome. ECMO sustained life and allowed disease control, together with plasmapheresis, cyclophosphamide, corticoids, and renal replacement therapy. The patient was successfully weaned from ECMO, extubated, and discharged home. She remains alive on dialysis at 17 months follow-up. PMID- 23926423 TI - Transjecting growth hormone: continuous nightmare or controlled nuisance? Evaluation of a new needle-free device. AB - BACKGROUND: Administering growth-hormone therapy (GHT) is a long-term treatment, associated with avoidance and phobic behaviors in the children involved. The current study examined GHT users' perceptions of a new needle-free device (ZomaJet Vision X [10 mg/mL]) with a lower injection volume compared to the traditional device. METHODS: A total of 73 persons participated (mean age +/- standard deviation, 10.10 +/- 3.60 years) in a longitudinal design. Users' views were studied 4 weeks after having applied both the old and the new device for a period of at least 4 weeks. Satisfaction, ease and frequency of restitution, local sensations, bruises during administering GHT, affective response to local sensations, and subject preference were assessed on the basis of the users' responses. RESULTS: Subjects' satisfaction with the new device was equal compared with the previous device for the total group of 73 children. However, the subgroup of 59 children who proved tolerant to meta-cresol (new preservative for Vision X only) reported a significantly higher satisfaction rating with the new device compared to the old device (7.7 vs 6.6, P=0.0002). Vision X was evaluated as better on ease and frequency of restitution and the number of bruises. Pain sensations did not differ meaningfully between the two devices. The new device was favored over the previous one in a majority of respondents. Vision X allows easy reconstitution of the solution, which was reflected in the percentage of young children able to prepare transjections themselves being more than doubled, illustrating the greater sense of empowerment in these users. Self-reported adherence to the therapy was good (less than 10% of injections missed) with both devices. CONCLUSION: The new device ZomaJet Vision X appears to be evaluated more positively than the previous version on criteria that refect users' preferences. PMID- 23926422 TI - Quetiapine versus haloperidol in the treatment of delirium: a double-blind, randomized, controlled trial. AB - BACKGROUND: Atypical antipsychotic drugs may have low propensity to induce extrapyramidal side effects in delirious patients. This study aimed to compare the efficacy and tolerability between quetiapine and haloperidol in controlling delirious behavior. METHODS: A 7-day prospective, double-blind, randomized controlled trial was conducted from June 2009 to April 2011 in medically ill patients with delirium. Measures used for daily assessment included the Delirium Rating Scale-revised-98 (DRS-R-98) and total sleep time. The Clinical Global Impression, Improvement (CGI-I) and the Modified (nine-item) Simpson- Angus Scale were applied daily. The primary outcome was the DRS-R-98 severity scores. The data were analyzed on an intention-to-treat basis. RESULTS: Fifty-two subjects (35 males and 17 females) were randomized to receive 25-100 mg/day of quetiapine (n = 24) or 0.5-2.0 mg/day of haloperidol (n = 28). Mean (standard deviation) doses of quetiapine and haloperidol were 67.6 (9.7) and 0.8 (0.3) mg/day, respectively. Over the trial period, means (standard deviation) of the DRS-R-98 severity scores were not significantly different between the quetiapine and haloperidol groups (-22.9 [6.9] versus -21.7 [6.7]; P = 0.59). The DRS-R-98 noncognitive and cognitive subscale scores were not significantly different. At end point, the response and remission rates, the total sleep time, and the Modified (nine-item) Simpson-Angus scores were also not significantly different between groups. Hypersomnia was common in the quetiapine-treated patients (33.3%), but not significantly higher than that in the haloperidol-treated group (21.4%). LIMITATIONS: Patients were excluded if they were not able to take oral medications, and the sample size was small. CONCLUSION: Low-dose quetiapine and haloperidol may be equally effective and safe for controlling delirium symptoms. CLINICAL TRIALS REGISTRATION NUMBER: clinicaltrials.gov NCT00954603. PMID- 23926424 TI - Systematic verification of upstream regulators of a computable cellular proliferation network model on non-diseased lung cells using a dedicated dataset. AB - We recently constructed a computable cell proliferation network (CPN) model focused on lung tissue to unravel complex biological processes and their exposure related perturbations from molecular profiling data. The CPN consists of edges and nodes representing upstream controllers of gene expression largely generated from transcriptomics datasets using Reverse Causal Reasoning (RCR). Here, we report an approach to biologically verify the correctness of upstream controller nodes using a specifically designed, independent lung cell proliferation dataset. Normal human bronchial epithelial cells were arrested at G1/S with a cell cycle inhibitor. Gene expression changes and cell proliferation were captured at different time points after release from inhibition. Gene set enrichment analysis demonstrated cell cycle response specificity via an overrepresentation of proliferation related gene sets. Coverage analysis of RCR-derived hypotheses returned statistical significance for cell cycle response specificity across the whole model as well as for the Growth Factor and Cell Cycle sub-network models. PMID- 23926425 TI - Lower body positive pressure: an emerging technology in the battle against knee osteoarthritis? AB - BACKGROUND: Knee osteoarthritis (OA) is the most prevalent medical condition in individuals over the age of 65 years, and is a progressive joint degenerative condition with no known cure. Research suggests that there is a strong relationship between knee pain and loss of physical function. The resulting lifestyle modifications negatively impact not only disease onset and progression but also overall health, work productivity, and quality of life of the affected individual. PURPOSE: The goal of this investigation was to examine the feasibility of using an emerging technology called lower body positive pressure (LBPP) to simulate weight loss and reduce acute knee pain during treadmill walking exercise in overweight individuals with radiographically confirmed symptomatic knee OA. DESIGN: Prospective case series. METHODS: Twenty-two overweight individuals with knee OA completed two 20-minute treadmill walking sessions (one full weight bearing and one LBPP supported) at a speed of 3.1 mph, 0% incline. Acute knee pain was assessed using a visual analog scale, and the percentage of LBPP support required to minimize knee pain was evaluated every 5 minutes. Knee Osteoarthritis Outcome Scores were used to quantify knee pain and functional status between walking sessions. The order of testing was randomized, with sessions occurring a minimum of 1 week apart. RESULTS: A mean LBPP of 12.4% of body weight provided participants with significant pain relief during walking, and prevented exacerbation of acute knee pain over the duration of the 20-minute exercise session. Patients felt safe and confident walking with LBPP support on the treadmill, and demonstrated no change in Knee Osteoarthritis Outcome Scores over the duration of the investigation. CONCLUSION: Results suggest that LBPP technology can be used safely and effectively to simulate weight loss and reduce acute knee pain during weight-bearing exercise in an overweight knee OA patient population. These results could have important implications for the development of future treatment strategies used in the management of at-risk patients with progressive knee OA. PMID- 23926426 TI - Echo intensity obtained from ultrasonography images reflecting muscle strength in elderly men. AB - BACKGROUND: It is well known that loss of muscle mass (quantitative change) is a major change that occurs with aging. Qualitative changes in skeletal muscle, such as increased intramuscular fat, also occur as one ages. Enhanced echo intensity (EI) on ultrasonography images of skeletal muscle is believed to reflect muscle quality. Recent studies evaluating the quality of skeletal muscle using computer aided gray scale analysis showed that EI is associated with muscle strength independently of age or muscle size in middle-aged and elderly women. The aim of the present study was to investigate whether muscle quality based on EI is associated with muscle strength independently of muscle size for elderly men. METHODS: A total of 184 elderly men (65-91 years) living independently in Kyoto, Japan, participated in this study. The EI, muscle thickness (MT), and subcutaneous fat thickness (FT) of the anterior compartment of the right thigh were determined by assessing ultrasonography images. The maximum isometric torque of knee extension at a knee angle of 90 degrees was measured. RESULTS: The EI showed a significant negative correlation with muscle strength (r = -0.333, P < 0.001). Multivariate regression analysis revealed that the MT and EI of the knee extensor muscle were independently associated with maximum isometric knee extension strength. Even when partial correlation analysis was performed with age, height, weight, and FT as control variables, EI was still significantly correlated with muscle strength. CONCLUSION: The results of this study indicate that aging-related changes in muscle quality contribute to diminishing muscle strength. Ultrasonography is a low-cost, easily accessible, and safe method suitable for the assessment of EI as an index of muscle quality. PMID- 23926427 TI - In situ tissue engineering with synthetic self-assembling peptide nanofiber scaffolds, PuraMatrix, for mucosal regeneration in the rat middle-ear. AB - Middle-ear mucosa maintains middle-ear pressure. However, the majority of surgical cases exhibit inadequate middle-ear mucosal regeneration, and mucosal transplantation is necessary in such cases. The aim of the present study was to assess the feasibility of transplantation of isolated mucosal cells encapsulated within synthetic self-assembling peptide nanofiber scaffolds using PuraMatrix, which has been successfully used as scaffolding in tissue engineering, for the repair of damaged middle-ear. Middle-ear bullae with mucosa were removed from Sprague Dawley (SD) transgenic rats, transfected with enhanced green fluorescent protein (EGFP) transgene and excised into small pieces, then cultured up to the third passage. After surgical elimination of middle-ear mucosa in SD recipient rats, donor cells were encapsulated within PuraMatrix and transplanted into these immunosuppressed rats. Primary cultured cells were positive for pancytokeratin but not for vimentin, and retained the character of middle-ear epithelial cells. A high proportion of EGFP-expressing cells were found in the recipient middle-ear after transplantation with PuraMatrix, but not without PuraMatrix. These cells retained normal morphology and function, as confirmed by histological examination, immunohistochemistry, and electron microscopy, and multiplied to form new epithelial and subepithelial layers together with basement membrane. The present study demonstrated the feasibility of transplantation of cultured middle ear mucosal epithelial cells encapsulated within PuraMatrix for regeneration of surgically eliminated mucosa of the middle-ear in SD rats. PMID- 23926428 TI - Accelerated killing of cancer cells using a multifunctional single-walled carbon nanotube-based system for targeted drug delivery in combination with photothermal therapy. AB - The photothermal effect of single-walled carbon nanotubes (SWCNTs) in combination with the anticancer drug doxorubicin (DOX) for targeting and accelerated destruction of breast cancer cells is demonstrated in this paper. A targeted drug delivery system was developed for selective killing of breast cancer cells with polyethylene glycol biofunctionalized and DOX-loaded SWCNTs conjugated with folic acid. In our work, in vitro drug-release studies showed that the drug (DOX) binds at physiological pH (pH 7.4) and is released only at a lower pH, ie, lysosomal pH (pH 4.0), which is the characteristic pH of the tumor environment. A sustained release of DOX from the SWCNTs was observed for a period of 3 days. SWCNTs have strong optical absorbance in the near-infrared (NIR) region. In this special spectral window, biological systems are highly transparent. Our study reports that under laser irradiation at 800 nm, SWCNTs exhibited strong light-heat transfer characteristics. These optical properties of SWCNTs open the way for selective photothermal ablation in cancer therapy. It was also observed that internalization and uptake of folate-conjugated NTs into cancer cells was achieved by a receptor-mediated endocytosis mechanism. Results of the in vitro experiments show that laser was effective in destroying the cancer cells, while sparing the normal cells. When the above laser effect was combined with DOX conjugated SWCNTs, we found enhanced and accelerated killing of breast cancer cells. Thus, this nanodrug-delivery system, consisting of laser, drug, and SWCNTs, looks to be a promising selective modality with high treatment efficacy and low side effects for cancer therapy. PMID- 23926429 TI - In vitro evaluation of 5-aminolevulinic acid (ALA) loaded PLGA nanoparticles. AB - BACKGROUND: 5-Aminolevulinic acid (ALA) is a prodrug for topical photodynamic therapy. The effectiveness of topical ALA can be limited by its bioavailability. The aim of this study was to develop a novel ALA delivery approach using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). METHODS: A modified double emulsion solvent evaporation method was used to prepare ALA loaded PLGA NPs (ALA PLGA NPs). The characteristics, uptake, protoporphyrin IX fluorescence kinetics, and cytotoxicity of ALA PLGA NPs toward a human skin squamous cell carcinoma cell line were examined. RESULTS: The mean particle size of spherical ALA PLGA NPs was 65.6 nm+/-26 nm with a polydispersity index of 0.62. The encapsulation efficiency was 65.8%+/-7.2% and ALA loading capacity was 0.62%+/ 0.27%. When ALA was dispersed in PLGA NPs, it turned into an amorphous phase. ALA PLGA NPs could be taken up by squamous cell carcinoma cells and localized in the cytoplasm. The protoporphyrin IX fluorescence kinetics and 3-[4,5-dimethylthiazol 2-yl]-2,5-diphenyltetrazolium bromide assay showed that ALA PLGA NPs were more effective than free ALA of the same concentration. CONCLUSION: PLGA NPs provide a promising ALA delivery strategy for topical ALA-photodynamic therapy of skin squamous cell carcinoma. PMID- 23926432 TI - Presurgical EEG-fMRI in a complex clinical case with seizure recurrence after epilepsy surgery. AB - Epilepsy surgery has improved over the last decade, but non-seizure-free outcome remains at 10%-40% in temporal lobe epilepsy (TLE) and 40%-60% in extratemporal lobe epilepsy (ETLE). This paper reports a complex multifocal case. With a normal magnetic resonance imaging (MRI) result and nonlocalizing electroencephalography (EEG) findings (bilateral TLE and ETLE, with more interictal epileptiform discharges [IEDs] in the right frontal and temporal regions), a presurgical EEG functional MRI (fMRI) was performed before the intraoperative intracranial EEG (icEEG) monitoring (icEEG with right hemispheric coverage). Our previous EEG-fMRI analysis results (IEDs in the left hemisphere alone) were contradictory to the EEG and icEEG findings (IEDs in the right frontal and temporal regions). Thus, the EEG-fMRI data were reanalyzed with newly identified IED onsets and different fMRI model options. The reanalyzed EEG-fMRI findings were largely concordant with those of EEG and icEEG, and the failure of our previous EEG-fMRI analysis may lie in the inaccurate identification of IEDs and wrong usage of model options. The right frontal and temporal regions were resected in surgery, and dual pathology (hippocampus sclerosis and focal cortical dysplasia in the extrahippocampal region) was found. The patient became seizure-free for 3 months, but his seizures restarted after antiepileptic drugs (AEDs) were stopped. The seizures were not well controlled after resuming AEDs. Postsurgical EEGs indicated that ictal spikes in the right frontal and temporal regions reduced, while those in the left hemisphere became prominent. This case suggested that (1) EEG-fMRI is valuable in presurgical evaluation, but requires caution; and (2) the intact seizure focus in the remaining brain may cause the non-seizure-free outcome. PMID- 23926433 TI - Meperidine: a continuing problem. AB - Letter to the Editor regarding meperidine prescriptions in Queensland, Australia, 1999 to 2010. PMID- 23926430 TI - Applications of nanotechnology for melanoma treatment, diagnosis, and theranostics. AB - Melanoma is the most aggressive type of skin cancer and has very high rates of mortality. An early stage melanoma can be surgically removed, with a survival rate of 99%. However, metastasized melanoma is difficult to cure. The 5-year survival rates for patients with metastasized melanoma are still below 20%. Metastasized melanoma is currently treated by chemotherapy, targeted therapy, immunotherapy and radiotherapy. The outcome of most of the current therapies is far from optimistic. Although melanoma patients with a mutation in the oncogene v Raf murine sarcoma viral oncogene homolog B1 (BRAF) have an initially higher positive response rate to targeted therapy, the majority develop acquired drug resistance after 6 months of the therapy. To increase treatment efficacy, early diagnosis, more potent pharmacological agents, and more effective delivery systems are urgently needed. Nanotechnology has been extensively studied for melanoma treatment and diagnosis, to decrease drug resistance, increase therapeutic efficacy, and reduce side effects. In this review, we summarize the recent progress on the development of various nanoparticles for melanoma treatment and diagnosis. Several common nanoparticles, including liposome, polymersomes, dendrimers, carbon-based nanoparticles, and human albumin, have been used to deliver chemotherapeutic agents, and small interfering ribonucleic acids (siRNAs) against signaling molecules have also been tested for the treatment of melanoma. Indeed, several nanoparticle-delivered drugs have been approved by the US Food and Drug Administration and are currently in clinical trials. The application of nanoparticles could produce side effects, which will need to be reduced so that nanoparticle-delivered drugs can be safely applied in the clinical setting. PMID- 23926431 TI - Advanced drug delivery to the lymphatic system: lipid-based nanoformulations. AB - The delivery of drugs and bioactive compounds via the lymphatic system is complex and dependent on the physiological uniqueness of the system. The lymphatic route plays an important role in transporting extracellular fluid to maintain homeostasis and in transferring immune cells to injury sites, and is able to avoid first-pass metabolism, thus acting as a bypass route for compounds with lower bioavailability, ie, those undergoing more hepatic metabolism. The lymphatic route also provides an option for the delivery of therapeutic molecules, such as drugs to treat cancer and human immunodeficiency virus, which can travel through the lymphatic system. Lymphatic imaging is useful in evaluating disease states and treatment plans for progressive diseases of the lymph system. Novel lipid-based nanoformulations, such as solid lipid nanoparticles and nanostructured lipid carriers, have unique characteristics that make them promising candidates for lymphatic delivery. These formulations are superior to colloidal carrier systems because they have controlled release properties and provide better chemical stability for drug molecules. However, multiple factors regulate the lymphatic delivery of drugs. Prior to lymphatic uptake, lipid-based nanoformulations are required to undergo interstitial hindrance that modulates drug delivery. Therefore, uptake and distribution of lipid-based nanoformulations by the lymphatic system depends on factors such as particle size, surface charge, molecular weight, and hydrophobicity. Types of lipid and concentration of the emulsifier are also important factors affecting drug delivery via the lymphatic system. All of these factors can cause changes in intermolecular interactions between the lipid nanoparticle matrix and the incorporated drug, which in turn affects uptake of drug into the lymphatic system. Two lipid-based nanoformulations, ie, solid lipid nanoparticles and nanostructured lipid carriers, have been administered via multiple routes (subcutaneous, pulmonary, and intestinal) for targeting of the lymphatic system. This paper provides a detailed review of novel lipid-based nanoformulations and their lymphatic delivery via different routes, as well as the in vivo and in vitro models used to study drug transport in the lymphatic system. Physicochemical properties that influence lymphatic delivery as well as the advantages of lipid-based nanoformulations for lymphatic delivery are also discussed. PMID- 23926434 TI - Text Categorization of Heart, Lung, and Blood Studies in the Database of Genotypes and Phenotypes (dbGaP) Utilizing n-grams and Metadata Features. AB - The database of Genotypes and Phenotypes (dbGaP) allows researchers to understand phenotypic contribution to genetic conditions, generate new hypotheses, confirm previous study results, and identify control populations. However, effective use of the database is hindered by suboptimal study retrieval. Our objective is to evaluate text classification techniques to improve study retrieval in the context of the dbGaP database. We utilized standard machine learning algorithms (naive Bayes, support vector machines, and the C4.5 decision tree) trained on dbGaP study text and incorporated n-gram features and study metadata to identify heart, lung, and blood studies. We used the chi(2) feature selection algorithm to identify features that contributed most to classification performance and experimented with dbGaP associated PubMed papers as a proxy for topicality. Classifier performance was favorable in comparison to keyword-based search results. It was determined that text categorization is a useful complement to document retrieval techniques in the dbGaP. PMID- 23926435 TI - Results of a randomized and controlled clinical trial evaluating the efficacy and safety of combination therapy with Endostar and S-1 combined with oxaliplatin in advanced gastric cancer. AB - OBJECTIVES: We aimed to evaluate the efficacy and safety of combination therapy of Endostar (recombinant human endostatin) and S-1 combined with oxaliplatin (SOX) in patients with advanced gastric cancer. METHODS: In this randomized, controlled trial, 165 late-stage gastric cancer patients were assigned to the experimental arm with Endostar in combination with SOX (80 patients) and the control arm with SOX alone (85 patients). The end points of this study included progression-free survival, response rate, and disease-control rate. RESULTS: There was no statistically significant difference in response rate between the experimental arm and the control arm (53.8% vs 42.4%, P=0.188). The difference in disease-control rate was also statistically insignificant between the two arms (85.0% vs 72.9%, P=0.188). Progression-free survival in the experimental arm was significantly higher than that in the control arm (15.0 months vs 12.0 months, P=0.0001). Common adverse events included immunosuppression, gastrointestinal distress, and neuropathy. There was no statistical difference in the incidences of adverse events. CONCLUSION: Combination therapy of Endostar and SOX provides therapeutic benefits to advanced gastric cancer patients, with tolerable adverse effects. PMID- 23926436 TI - Nimotuzumab as a radiosensitizing agent in the treatment of high grade glioma: challenges and opportunities. AB - Nimotuzumab is a humanized monoclonal antibody that binds specifically to human epidermal growth factor receptor, blocking receptor activation. Evidence of its radiosensitizing capacity has been widely evaluated. This article integrates published research findings regarding the role of nimotuzumab in the treatment of high grade glioma in combination with radiotherapy or radiochemotherapy in adult and pediatric populations. First, the mechanisms of action of nimotuzumab and its current applications in clinical trials containing both radiation and chemoradiation therapies are reviewed. Second, a comprehensive explanation of potential mechanisms driving radiosensitization by nimotuzumab in experimental settings is given. Finally, future directions of epidermal growth factor receptor targeting with nimotuzumab in combination with radiation containing regimens, based on its favorable toxicity profile, are proposed. It is hoped that this review may provide further insight into the rational design of new approaches employing nimotuzumab as a useful alternative for the therapeutic management of high grade glioma. PMID- 23926437 TI - Overexpression of epidermal growth factor receptor as a prognostic factor in colorectal cancer on the basis of the Allred scoring system. AB - BACKGROUND: Overexpression of epidermal growth factor receptor (EGFR) is found in many types of neoplasms. The aim of the study was to evaluate EGFR expression in colorectal cancer (CRC) specimens and to determine whether EGFR expression correlates with clinicopathological data and overall survival. PATIENTS AND METHODS: Tissue specimens from 181 consecutive CRC patients treated at the Military Institute of Medicine in 2006-2010 were collected and examined for EGFR expression, by immunohistochemistry staining. The staining intensity and percentage of cells with membranous EGFR expression were scored and then grouped according to the parameters of the Allred Scoring system. Cutoff values were subjected to further statistical analysis. Univariate tests and a multivariate Cox proportional hazards model were used in data analysis. RESULTS: EGFR was overexpressed in 96 of 181 CRC specimens (53%). EGFR expression was not correlated with other clinicopathological variables. On univariate analysis, overexpression of EGFR, determined by PS (percentage score) (>3) and total score (sum of PS and intensity score) (>4), was associated with poor overall survival. On multivariate analysis, EGFR overexpression (PS > 3) was an independent adverse prognostic factor (hazard ratio [HR] 1.62; 95% confidence interval [CI]: 1.03 2.53). Elevated carcinoembryonic antigen (CEA) serum concentration before treatment, performance status (Word Health Organization [WHO]-2), and tumor localized in colon and liver metastases were also independent unfavorable prognostic factors. CONCLUSION: EGFR overexpression (PS > 3) in a CRC patient population was an independent adverse prognostic factor. Implementation of the Allred Scoring system criteria into clinical practice might facilitate treatment decisions in CRC patients. PMID- 23926438 TI - Cordycepin enhances cisplatin apoptotic effect through caspase/MAPK pathways in human head and neck tumor cells. AB - PURPOSE: The present study aims to investigate whether the combination treatment of cordycepin (an extracted pure compound from Cordyceps sinensis) and cisplatin (a platinum-based chemotherapy drug) has better apoptotic effect in head and neck squamous cell carcinoma (HNSCC). METHODS: The apoptotic influences of cordycepin and/or cisplatin treatments to human OC3, OEC-M1, and FaDu HNSCC cells were investigated by morphological observations, viability assay, flow cytometry assay, and Western blotting methods. RESULTS: Data showed that the cell death phenomenon increased as the dosage of cordycepin or cisplatin increased, and it appeared more in cordycepin plus cisplatin cotreatment among three cell lines. Cell survival rates significantly decreased as the dosage of cordycepin or cisplatin increased, and the better apoptotic effects were observed in cotreatment. Cell cycle analysis further demonstrated that percentages of subG1 cells in cordycepin or cisplatin treatments significantly increased, suggesting that cells underwent apoptosis, and cordycepin plus cisplatin induced many more subG1 cells. Furthermore, cordycepin or cisplatin induced caspase-8, caspase-9, caspase-3, and poly adenosine diphosphate-ribose polymerase protein cleavages, and stimulated c-Jun NH2-terminal kinase, extracellular signal-regulated kinase, and p38 protein phosphorylations. Moreover, cordycepin plus cisplatin cotreatment significantly activated those proteins with much better effects among three cell lines. CONCLUSION: Cordycepin plus cisplatin have better apoptotic effect by activating caspase activation with possible MAPK pathway involvement in HNSCC cells. PMID- 23926439 TI - Cancer-associated thrombosis: clinical presentation and survival. AB - BACKGROUND: Thromboembolic events are important causes of morbidity and mortality in cancer patients. Clinical presentation in a community-based setting has not been fully clarified. The purpose of this study was to evaluate the incidence, risk factors, role of thrombophilia, and subsequent survival following thrombosis in cancer patients. METHODS: A retrospective review was undertaken of clinical data for all consecutive patients with histologically confirmed cancer seen by the author at a regional cancer center, with emphasis on cancer-related thrombosis. RESULTS: Between 2005 and 2012, of 1874 cancer patients, 307 (16.4%) developed thrombosis during their lifetime. Of these patients, 37 (2%) had a history of thrombosis, while the remaining 270 (14.4%) patients developed thrombosis 3 months before or any time after diagnosis of cancer, which was considered to be cancer-related. These patients included 230 (12.3%) with venous thrombosis, 28 (1.5%) cases with arterial occlusion, and 12 (0.6%) with combined venous and arterial thrombosis. Patients of Caucasian ancestry were more prone to develop thrombosis, with a higher frequency of multiple genetic thrombophilia compared with other ethnic groups. In regression analysis, only advanced stages of cancer and the presence of atherosclerosis were predictive of thrombosis. There were no significant differences between venous and arterial thrombosis. The worst survival was noted in patients who developed thrombosis 3 months prior to or shortly after their diagnosis of cancer. There has been a recent improved survival outcome following therapy. CONCLUSION: In addition to venous thrombosis, arterial occlusion with stroke and anginal symptoms is relatively common among cancer patients, especially those of Caucasian ancestry, and is possibly related to genetic predisposition. PMID- 23926440 TI - Effect of Bevacizumab Injection before Vitrectomy on Intravitreal Hemorrhage in Pseudophakic Patients with Proliferative Diabetic Retinopathy. AB - We evaluated the effect of intravitreal bevacizumab (IVB) injection before pars plana vitrectomy (PPV) on intravitreal hemorrhage (VH) during and after vitrectomy for postoperative the first day and the first month in pseudophakic patients with proliferative diabetic retinopathy (PDR). This retrospective study was performed on 44 eyes of 44 patients who underwent vitrectomy for PDR. Patients were divided into PPV (n = 22 eyes) and PPV + IVB (n = 22 eyes) groups. Injection of bevacizumab (1.25 mg/0.05 mL) was performed 3 days before vitrectomy. Outcomes of visual acuity as well as intraoperative and postoperative VH were compared between the two groups. One month after surgery, visual acuity improved in PPV and PPV + IVB groups (P = 0.005, P = 0.006), respectively. There was no difference between the two groups in best corrected visual acuity at baseline and after vitrectomy (P = 0.71). Intraoperative bleeding into the vitreous was recorded in 14 (63.6%) cases in the PPV group and in 7 (31.8%) cases in the PPV + IVB group. The first month, intravitreal hemorrhage was recorded in six patients in the PPV group and in two patients in the PPV + IVB group (P = 0.03). The mean pre-postoperative central macular thickness was similar in both groups. Intravitreal injection of IVB before vitrectomy decreased the rate of VH at the time of surgery and at the first postoperative month in patients with PDR. PMID- 23926441 TI - Second generation drug-eluting stents: a review of the everolimus-eluting platform. AB - Everolimus-eluting stents (EES) represent the next generation of drug-eluting stents (DES). Important design modifications include thin strut stent backbones, less inflammatory and more biocompatible polymers, and lower drug dosing. The cobalt chromium EES fluoropolymer XIENCE V stent has been the most extensively studied of such stents. In animal models, this stent demonstrated minimal vessel inflammation, a biologically active endothelium with strut coverage similar to a bare metal stent, and inhibition of intimal hyperplasia comparable to that seen with sirolimus-eluting stents. The SPIRIT family of clinical trials demonstrated low rates of late loss, and clinical restenosis, as well as low rates of very late stent thrombosis. These excellent clinical outcomes addressed limitations of the 1st generation DES, and substantiated widespread clinical use of the EES platform. PMID- 23926442 TI - Influence of immunotherapy with autologous dendritic cells on innate and adaptive immune response in cancer. AB - The objective of this study was to evaluate some of the mechanisms involved in the activation of the immune system in patients with advanced-stage cancer (n = 7) who received an autologous dendritic cell vaccine. We examined the immune response mediated by macrophages (CD14+), natural killer cells (CD56+), and B lymphocytes (CD19+) by flow cytometry and assessed the expression of Th1 (IFN gamma, TNF-alpha, IL-2, and IL-12), Th2 (IL-4), and Treg (TGF-beta) cytokines by flow cytometry and an enzyme-linked immunosorbent assay. The CD14+ TNF-alpha+ population was significantly increased (P < 0.04) when patients received the vaccine; IL-2 expression in both NK cells and in B lymphocytes was increased after a transient initial increase showed a nearly significant decrease (P < 0.07 and P < 0.06 respectively), whereas the CD19+ and CD56+ populations did not show significant changes. Dendritic cell-based immunotherapy led to increased secretion of IFN-gamma and IL-12 and reduced secretion of TGF-beta. In conclusion, it is likely that the autologous dendritic cell vaccine stimulated the immune cells from the peripheral blood of patients with cancer and generally increased the production of Th1 cytokines, which are related to immunomodulatory responses against cancer. PMID- 23926443 TI - Multi-Voxel 1H-MRS in Metachromatic Leukodystrophy. AB - Metachromatic leukodystrophy (MLD) is characterized by the accumulation of sulfatide sphingolipids in the brain and peripheral nerves. We report metabolite alterations recorded using multi-voxel proton spectroscopy of the brain in four children with MLD. The data revealed elevated myoinositol/creatine and lactate/creatine ratios as well as decreased N-acetyl aspartate/creatine ratios. We propose that elevation in myoinositol and lactate are caused by astrocytic gliosis and may be used as biomarkers for disease progression in MLD. PMID- 23926444 TI - The Role of Adoption Communicative Openness in Information Seeking Among Adoptees From Adolescence to Emerging Adulthood. AB - Adoption Communicative Openness was examined as a predictor of information seeking from adolescence to emerging adulthood in a group of adoptees who did not have direct contact with birth relatives during adolescence. Changes in information seeking intentions and behaviors between adolescence and emerging adulthood were also examined. Data from 119 infant-placed adoptees and their adoptive mothers were used from Waves 2 (1996-2000) and 3 (2005-2008) of the Minnesota-Texas Adoption Research Project (Grotevant & McRoy, 1998). Adoptive mothers' Communicative Openness was positively associated with degree of information seeking in emerging adulthood. Degree of information seeking between adolescence (Wave 2) and emerging adulthood (Wave 3) increased for the majority of adoptees (62.2%). Approximately 16% of adoptees experienced no change in information seeking and 22% of adoptees experienced a decrease in information seeking. Females were more likely to exhibit a greater increase in information seeking change between Waves 2 and 3 and information seeking at Wave 3 than males. Results suggest that adoptee information seeking is a dynamic process that takes place over several life stages and that open communication about adoption within the adoptive family supports adoptee information seeking. PMID- 23926445 TI - Joint Modeling of Longitudinal and Cure-survival Data. AB - This article presents semiparametric joint models to analyze longitudinal measurements and survival data with a cure fraction. We consider a broad class of transformations for the cure-survival model, which includes the popular proportional hazards structure and the proportional odds structure as special cases. We propose to estimate all the parameters using the nonparametric maximum likelihood estimators (NPMLE). We provide the simple and efficient EM algorithms to implement the proposed inference procedure. Asymptotic properties of the estimators are shown to be asymptotically normal and semiparametrically efficient. Finally, we demonstrate the good performance of the method through extensive simulation studies and a real-data application. PMID- 23926446 TI - Synthesis and Biological Activity of N-Sulfonyltripeptides with C-Terminal Arginine as Potential Serine Proteases Inhibitors. AB - Tripeptides of the general X-SO2-d-Ser-AA-Arg-CO-Y formula, where X = alpha tolyl, p-tolyl, 2,4,6-triisopropylphenyl; AA = alanine, glycine, norvaline and Y = OH, NH-(CH2)5NH2 were obtained and tested for their effect on the amidolytic activities of urokinase, thrombin, trypsin, plasmin, t-PA and kallikrein. The most active compound towards urokinase was PhCH2SO2-d-Ser-Gly-Arg-OH with Ki value 5.4 MUM and the most active compound toward thrombin was PhCH2SO2-d-Ser-NVa Arg-OH with Ki value 0.82 MUM. The peptides were nontoxic against porcine erythrocytes in vitro. PhCH2SO2-d-Ser-Gly-Arg-OH showed cytotoxic effect against DLD cell lines with IC50 values of 5 MUM. For the highly selective determination of the interaction of some of the synthesised acids of tripeptides with urokinase and plasmin the Surface Plasmon Resonance Imaging sensor has been applied. These compounds bind to urokinase and plasmin in 0.05 mM concentration. PMID- 23926447 TI - Determination of Hexapeptide ALA-ASP-LEU-LYS-PRO-THR by MALDI MS. AB - The hexapeptide ALA-ASP-LEU-LYS-PRO-THR is currently widely used as an active ingredient in commercially available creams. Therefore, the proper analytical procedure to detect this compound is a very important issue. This paper presents the determination of the hexapeptide in solution and in cosmetic formulations by matrix assisted laser desorption ionisation mass spectrometry. We developed a procedure for the selective binding of the low molecular weight peptide by using a two-component matrix which enabled us to characterize the hexapeptide directly without any initial processing. Furthermore, the extensive computer simulations were carried out to assist in this analysis of the MS spectra. PMID- 23926449 TI - Architecture effects on L-selectin shedding induced by polypeptide-based multivalent ligands. AB - Multivalent interactions between selectins and their ligands play key roles in mediating the rolling and tethering of leukocytes in the early steps of the inflammatory response, as well as in lymphocyte circulation. L-selectin shedding, which is the proteolytic cleavage of L-selectin, can be induced by L-selectin clustering through the binding of multivalent ligands to multiple L-selectin molecules, and it has been shown to regulate leukocyte rolling and subsequent integrin activation for firm adhesion. In this paper, we report the production of homogenous glycopolypeptides modified with a 3,6-disulfo-galactopyranoside equipped with a caproyl linker. The saccharide residue was chemically attached to various polypeptide backbones of differing architectures; the composition and purity of the sulfated glycopolypeptides was confirmed via1H-NMR spectroscopy, amino acid analysis (AAA), and electrophoretic analysis. The retention of the conformation of the polypeptide backbone was confirmed via circular dichroic spectroscopy. The shedding of l-selectin from the surface of Jurkat cells induced by these sulfated glycopolypeptides, determined via ELISA-based methods, varied based on differences in the architectures of the polypeptide scaffolds, suggesting opportunities for these strategies in probing cell-surface receptor arrays and directing cell signaling events. PMID- 23926448 TI - Bacterial Swarming: A Model System for Studying Dynamic Self-assembly. AB - Bacterial swarming is an example of dynamic self-assembly in microbiology in which the collective interaction of a population of bacterial cells leads to emergent behavior. Swarming occurs when cells interact with surfaces, reprogram their physiology and behavior, and adapt to changes in their environment by coordinating their growth and motility with other cells in the colony. This review summarizes the salient biological and biophysical features of this system and describes our current understanding of swarming motility. We have organized this review into four sections: 1) The biophysics and mechanisms of bacterial motility in fluids and its relevance to swarming. 2) The role of cell/molecule, cell/surface, and cell/cell interactions during swarming. 3) The changes in physiology and behavior that accompany swarming motility. 4) A concluding discussion of several interesting, unanswered questions that is particularly relevant to soft matter scientists. PMID- 23926450 TI - Interplay Between Cytokine-Induced and Cyclic Equibiaxial Deformation-Induced Nitric Oxide Production and Metalloproteases Expression in Human Alveolar Epithelial Cells. AB - Ventilator-induced lung overdistension has been a growing concern in the management of mechanically ventilated patients. Mechanical ventilation triggers or enhances the net inflammatory and tissue remodeling activities. Although it has been shown that proinflammatory and tissue remodeling factors play important roles during airway remodeling, the interplay between them is not well understood. Thus, our objective was to study and characterize the molecular mechanism of cyclic equibiaxial deformation-induced airway inflammation and remodeling either in the presence or absence of a pre-existing inflammatory condition. This study was done using an in vitro dynamic model, which can simulate different mechanical ventilative conditions. Type II alveolar epithelial cell (A549) monolayers were exposed to the different levels of mechanical ventilative conditions using the Flexcell(r) Tension PlusTM 4000T system, which generated the different levels of cyclic equibiaxial deformation (5, 10, 15, and 20%) at 0.2 Hz deformation frequency. The production of nitric oxide (NO), the expression of metalloprotease-2 (MMP-2)/tissue inhibitor metalloprotease-2 (TIMP 2), and the activation of MMP-2 were measured under the different levels of cyclic equibiaxial deformation either in the presence or absence of TNF-alpha. Our study indicated that cyclic equibiaxial deformation-induced production of NO and MMP-2/TIMP-2. Higher levels of cyclic equibiaxial deformation increased the expression of the active form of MMP-2. In particular, in the presence of TNF alpha, the more active form of MMP-2 was detected during both cyclic equibiaxial deformation and remodeling periods. PMID- 23926451 TI - Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke. AB - Neonatal stroke occurs in one in 4,000 live births and leads to significant morbidity and mortality. Approximately two thirds of the survivors have long-term sequelae including seizures and neurological deficits. However, the pathophysiological mechanisms of recovery after neonatal stroke are not clearly understood, and preventive measures and treatments are nonexistent in the clinical setting. In this study, we investigated the effect of vascular endothelial growth factor (VEGF) treatment on histological recovery and angiogenic response to the developing brain after an ischemic insult. Ten-day-old Sprague-Dawley rats underwent right middle cerebral arterial occlusion (MCAO) for 1.5 h. Diffusion-weighted MRI during occlusion confirmed focal ischemia that was then followed by reperfusion. On group of animals received 5-bromo-2-deoxyuridine and sacrificed at postnatal day (P)18 or P25. A second group of animals was treated with VEGF (1.5 ug/kg, icv) or phosphate-buffered saline (PBS) at P18 and perfusion fixed at P25. Based on Nissl and iron staining, a single VEGF injection reduced the injury score, compared to the animals that underwent MCAO and PBS injection. Furthermore, neurodegeneration represented by neuronal nuclei staining was markedly diminished. In addition, animals treated with VEGF revealed a positive trend in endothelial proliferation and a significant increase in total vessel volume in the peri-infarct region of the caudate. The number of Iba1 positive microglial cells was significantly reduced after a single VEGF injection, and myelin basic protein expression was enhanced in the caudate after ischemia without an effect of VEGF treatment. In conclusion, delayed treatment with VEGF ameliorates injury, promotes endothelial cell proliferation, and increases total vascular volume following neonatal stroke. These results suggest that VEGF has a neuroprotective effect, in part by enhancing endogenous angiogenesis. These data contribute to a better understanding of neonatal stroke. PMID- 23926453 TI - In vitro apoptosis effects of GnRHII on endometrial stromal cells from patients with endometriosis. AB - PURPOSE: To study the effect of gonadotropin-releasing hormone II (GnRHII) on the cell apoptosis of ectopic, eutopic and normal endometrial stromal cells cultured in vitro from endometriosis patients, and to provide theoretical basis for exploring new treatments for endometriosis (EMs). METHODS: Ectopic, eutopic and normal endometrial stromal cells were isolated, cultured and identified in vitro, then treated with different concentrations of GnRHII (0, 10(-10) M, 10(-8) M and 10(-6) M). Cell apoptosis was detected by Hoechst staining and flow cytometry. RESULTS: GnRHII increased apoptosis in ectopic, eutopic and normal stromal cells in a dosage-dependent manner (P<0.05), and apoptosis of ectopic stroma cells was significantly higher than that of eutopic and normal cells (P<0.05); apoptosis in eutopic and normal cells had no different (P>0.05). CONCLUSION: GnRHII can significantly induce apoptosis in ectopic, eutopic and normal endometrial stromal cells from patients with endometriosis, especially to the ectopic. PMID- 23926454 TI - Early recognition of speech. AB - Classic research on the perception of speech sought to identify minimal acoustic correlates of each consonant and vowel. In explaining perception, this view designated momentary components of an acoustic spectrum as cues to the recognition of elementary phonemes. This conceptualization of speech perception is untenable given the findings of phonetic sensitivity to modulation independent of the acoustic and auditory form of the carrier. The empirical key is provided by studies of the perceptual organization of speech, a low-level integrative function that finds and follows the sensory effects of speech amid concurrent events. These projects have shown that the perceptual organization of speech is keyed to modulation; fast; unlearned; nonsymbolic; indifferent to short-term auditory properties; and organization requires attention. The ineluctably multisensory nature of speech perception also imposes conditions that distinguish language among cognitive systems. WIREs Cogn Sci 2013, 4:213-223. doi: 10.1002/wcs.1213 This article is categorized under: Psychology > Language. PMID- 23926455 TI - Isotuberculosinol: the unusual case of an immunomodulatory diterpenoid from Mycobacterium tuberculosis. PMID- 23926456 TI - Editorial. PMID- 23926457 TI - Inherited predisposition to myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPNs) are haematological disorders characterized by an overproduction of mature myeloid cells with a tendency to transform to acute myeloid leukaemia. Clonal proliferation of myeloid progenitor cells is driven by somatically acquired mutations, most notably JAK2 V617F, but there are important features relating to pathogenesis and phenotypic diversity that cannot be explained by acquired mutations alone. In this review we consider what is currently known about the role that inherited factors play in the development and biology of both sporadic and familial forms of MPN. Although most MPN cases appear to be sporadic, familial predisposition has been recognized for many years in a subset of cases and epidemiological studies have indicated the presence of common susceptibility alleles. Currently the JAK2 46/1 haplotype (also referred to as 'GGCC') is the strongest known predisposition factor for sporadic MPNs carrying a JAK2 V617F mutation, explaining a large proportion of the heritability of this disorder. Less is known about what genetic variants predispose to MPNs that lack JAK2 V617F, but there have been recent reports of interesting associations in biologically plausible candidates, and more loci are set to emerge with the application of systematic genome-wide association methodologies. Several highly penetrant predisposition variants that affect erythropoietin signalling, thrombopoietin signalling or oxygen sensing have been characterized in families with nonclonal hereditary erythrocytosis or thrombocytosis, but much less is known about familial predisposition to true clonal MPN. The heterogeneous pattern of inheritance and presumed genetic heterogeneity in these families makes analysis difficult, but whole exome or genome sequencing should provide novel insights into these elusive disorders. PMID- 23926458 TI - Recognizing familial myeloid leukemia in adults. AB - Germline testing for familial cases of myeloid leukemia in adults is becoming more common with the recognition of multiple genetic syndromes predisposing people to bone marrow disease. Currently, Clinical Laboratory Improvement Amendments approved testing exists for several myeloid leukemia predisposition syndromes: familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML), caused by mutations in RUNX1; familial AML with mutated CEBPA; familial myelodysplastic syndrome and acute leukemia with mutated GATA2; and the inherited bone marrow failure syndromes, including dyskeratosis congenita, a disease of abnormal telomere maintenance. With the recognition of additional families with a genetic component to their leukemia, new predisposition alleles will likely be identified. We highlight how to recognize and manage these cases as well as outline the characteristics of the major known syndromes. We look forward to future research increasing our understanding of the scope of inherited myeloid leukemia syndromes. PMID- 23926460 TI - Inherited predisposition to multiple myeloma. AB - Multiple myeloma (MM) is the second most common hematologic malignancy in the United States, after non-Hodgkin lymphoma. Family pedigree analyses of high-risk families, case-control studies and racial disparities in disease incidence all point to a potential inherited predisposition to MM. Genome-wide association studies (GWASs) have identified susceptibility loci in a number of cancers and such studies are currently underway in MM. To date, GWASs in MM have identified several potential regions of interest for further study on chromosomes 3p22, 7p15.3, 8q24 and 2p23.3. In addition, several targets of paraproteins (so called 'paratargs') in MM have been identified. Hyperphosphorylation of the paratarg protein, which is inherited in an autosomal dominant manner, appears a common mechanism underlying the antigenicity of these proteins. One particular protein, hyperphosphorylated paratarg-7 (pP-7) is a common target in persons with myeloma and has also been identified in affected members of several high-risk MM families. It appears that the frequency of pP-7 as an antigenic target may be particularly high in African American patients with MM, which could be part of the explanation for observed racial disparities in the incidence of MM. In this review we focus on available data in the area of inherited predisposition to MM, and highlight future research directions. PMID- 23926459 TI - Genetic predispositions to childhood leukemia. AB - While the majority of leukemia cases occur in the absence of any known predisposing factor, there are germline mutations that significantly increase the risk of developing hematopoietic malignancies in childhood. In this review article, we describe a number of these mutations and their clinical features. These predispositions can be broadly classified as those leading to bone marrow failure, those involving tumor suppressor genes, DNA repair defects, immunodeficiencies or other congenital syndromes associated with transient myeloid disorders. While leukemia can develop as a secondary event in the aforementioned syndromes, there are also several syndromes that specifically lead to the development of leukemia as their primary phenotype. Many of the genes discussed in this review can also be somatically mutated in other cancers, highlighting the importance of understanding shared alterations and mechanisms underpinning syndromic and sporadic leukemia. PMID- 23926461 TI - Inherited susceptibility to chronic lymphocytic leukemia: evidence and prospects for the future. AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States and one of the most heritable cancers. A family history of the disease is perhaps the best defined risk factor, and approximately 15-20% of CLL patients have a family member with CLL or a related lymphoproliferative disorder. Much effort has been devoted to trying to elucidate the mechanisms underlying this genetic risk. Familial CLL appears to be clinically and biologically similar to sporadic CLL, and most if not all CLL appears to be preceded by monoclonal B-cell lymphocytosis (MBL), which does appear to occur at higher frequency in relatives in families with CLL. Neither linkage studies nor candidate gene association studies have proven particularly informative in CLL, but genomewide association studies have identified multiple low-risk variants that together explain about 16% of the familial risk of CLL. Studies of individual families have identified higher-risk single nucleotide polymorphisms or copy number variants associated with disease risk in those families. Current efforts to identify additional risk loci are focused on applying next-generation sequencing to the germline of informative CLL families as well as individuals with sporadic CLL. PMID- 23926463 TI - Removing extra CO2 in COPD patients. AB - For patients experiencing acute respiratory failure due to a severe exacerbation of chronic obstructive pulmonary disease (COPD), noninvasive positive pressure ventilation has been shown to significantly reduce mortality and hospital length of stay compared to respiratory support with invasive mechanical ventilation. Despite continued improvements in the administration of noninvasive ventilation (NIV), refractory hypercapnia and hypercapnic acidosis continue to prevent its successful use in many patients. Recent advances in extracorporeal gas exchange technology have led to the development of systems designed to be safer and simpler by focusing on the clinical benefits of partial extracorporeal carbon dioxide removal (ECCO2R), as opposed to full cardiopulmonary support. While the use of ECCO2R has been studied in the treatment of acute respiratory distress syndrome (ARDS), its use for acute hypercapnic respiratory during COPD exacerbations has not been evaluated until recently. This review will focus on literature published over the last year on the use of ECCO2R for removing extra CO2 in patients experiencing an acute exacerbation of COPD. PMID- 23926462 TI - Neurogenetics and Nutrigenomics of Neuro-Nutrient Therapy for Reward Deficiency Syndrome (RDS): Clinical Ramifications as a Function of Molecular Neurobiological Mechanisms. AB - In accord with the new definition of addiction published by American Society of Addiction Medicine (ASAM) it is well-known that individuals who present to a treatment center involved in chemical dependency or other documented reward dependence behaviors have impaired brain reward circuitry. They have hypodopaminergic function due to genetic and/or environmental negative pressures upon the reward neuro-circuitry. This impairment leads to aberrant craving behavior and other behaviors such as Substance Use Disorder (SUD). Neurogenetic research in both animal and humans revealed that there is a well-defined cascade in the reward site of the brain that leads to normal dopamine release. This cascade has been termed the "Brain Reward Cascade" (BRC). Any impairment due to either genetics or environmental influences on this cascade will result in a reduced amount of dopamine release in the brain reward site. Manipulation of the BRC has been successfully achieved with neuro-nutrient therapy utilizing nutrigenomic principles. After over four decades of development, neuro-nutrient therapy has provided important clinical benefits when appropriately utilized. This is a review, with some illustrative case histories from a number of addiction professionals, of certain molecular neurobiological mechanisms which if ignored may lead to clinical complications. PMID- 23926465 TI - Editorial. PMID- 23926464 TI - Human DNA Glycosylase NEIL1's Interactions with Downstream Repair Proteins Is Critical for Efficient Repair of Oxidized DNA Base Damage and Enhanced Cell Survival. AB - NEIL1 is unique among the oxidatively damaged base repair-initiating DNA glycosylases in the human genome due to its S phase-specific activation and ability to excise substrate base lesions from single-stranded DNA. We recently characterized NEIL1's specific binding to downstream canonical repair and non canonical accessory proteins, all of which involve NEIL1's disordered C-terminal segment as the common interaction domain (CID). This domain is dispensable for NEIL1's base excision and abasic (AP) lyase activities, but is required for its interactions with other repair proteins. Here, we show that truncated NEIL1 lacking the CID is markedly deficient in initiating in vitro repair of 5 hydroxyuracil (an oxidative deamination product of C) in a plasmid substrate compared to the wild-type NEIL1, thus suggesting a critical role of CID in the coordination of overall repair. Furthermore, while NEIL1 downregulation significantly sensitized human embryonic kidney (HEK) 293 cells to reactive oxygen species (ROS), ectopic wild-type NEIL1, but not the truncated mutant, restored resistance to ROS. These results demonstrate that cell survival and NEIL1-dependent repair of oxidative DNA base damage require interactions among repair proteins, which could be explored as a cancer therapeutic target in order to increase the efficiency of chemo/radiation treatment. PMID- 23926466 TI - Indoleamine 2,3-dioxygenase (IDO) is expressed at feto-placental unit throughout mouse gestation: An immunohistochemical study. AB - INTRODUCTION: The cells expressing Indoleamine 2, 3-dioxygenase (IDO) in feto maternal interface mediate tryptophan catabolism, hence protect allogeneic fetus from lethal rejection by maternal immune responses. In this study, we report immuno-localization of IDO(+) cells in murine reproductive tract and placenta throughout mouse pregnancy by immunohistochemistry. MATERIALS AND METHODS: Syngeneic pregnant mice were examined for vaginal plug to discover about their state of pregnancy. A total of three pregnant mice were examined at each stage.The examination was further confirmed by the detection of sperm in vaginal smear. On the gestational days of 2(nd), 12(th) and 18(th), the uterus and oviduct were removed and expression of IDO was investigated in the endometrium, placenta and oviduct by immunohistochemistry. RESULTS: Our results showed that IDO is expressed consistently in feto-maternal interface throughout pregnancy. In endometrium, expression of IDO was predominantly confined to luminal and glandular epithelial cells. Cells at junctional and labyrinth zones of placenta showed strong IDO immunoreactivity as well. CONCLUSION: Expression of IDO at the protein level in reproductive tract of pregnant mice during entire periods of gestation points to its potential protective role in maintenance of pregnancy. In our knowledge this is the first report of expression of IDO in feto-maternal phase during murine pregnancy. PMID- 23926467 TI - Tyrosine phosphorylation pattern in sperm proteins isolated from normospermic and teratospermic men. AB - INTRODUCTION: In mammalian system, spermatozoa are not able to fertilize the oocyte immediately upon ejaculation, thus they undergo a series of biochemical and molecular changes which is termed capacitation. During sperm capacitation, signal transduction pathways are activated which lead to protein tyrosine phosphorylation. Tyrosine phosphorylated proteins have an important role in sperm capacitation such as hyperactive motility, interaction with zona pellucida and acrosome reaction. Evaluation of tyrosine phosphorylation pattern is important for further understanding of molecular mechanisms of fertilization and the etiology of sperm dysfunctions and abnormalities such as teratospermia. The goal of this study is to characterize tyrosine phosphorylation pattern in sperm proteins isolated from normospermic and teratospermic infertile men attending Avicenna Infertility Clinic in Tehran. MATERIALS AND METHODS: Semen samples were collected and the spermatozoa were isolated using Percoll gradient centrifugation. Then the spermatozoa were incubated up to 6h at 37 degrees C with 5% CO2 in 3% Bovine Serum Albumin-supplemented Ham's F-10 for capacitation to take place. The total proteins from spermatozoa were extracted and were subjected to SDS-PAGE before and after capacitation. To evaluate protein tyrosine phosphorylation pattern, western blotting with specific antibody against phosphorylated tyrosines was performed. RESULTS: THE RESULTS UPON WESTERN BLOTTING SHOWED: 1) at least six protein bands were detected before capacitation in the spermatozoa from normospermic samples. However, comparable levels of tyrosine phosphorylation was not observed in the spermatozoa from teratospermic samples. 2) The intensity of protein tyrosine phosphorylation appears to have been increased during capacitation in the normospermic relative to the teratospermic group. CONCLUSION: For the first time, these findings demonstrate and suggest that the differences in the types of proteins and diminished tyrosine phosphorylation efficiency in sperm from teratospermic men may be responsible for their compromised capacitation and low fertilization success rates. PMID- 23926468 TI - Producing Recombinant mTEX101; a Murine Testis Specific Protein. AB - INTRODUCTION: Production of antibodies against specific proteins of testis germ cells is of great significance for the investigation of processes involved in spermatogenesis, study of infertility problems and determination of the probable role of these proteins as cancer-testis antigens. Murine Testis Specific Recombinant Protein 101 (mTEX101) is a 38kDa, GPI-anchored protein which is expressed in testis germ cells of adult mice but it seems to be absent in other tissues. The structure and function of mTEX101 is not completely understood yet, but it is speculated that it may transduce biochemical signals into the cytoplasm since mTEX101 does not have an intracellular domain but the precise mechanisms are still ambiguous. MATERIALS AND METHODS: RNA was extracted from three adult mice testis. The RNA was used in RT-PCR, employing a pair of specific primers for mTEX101 ORF region. TA-cloning technique was performed by the insertion of mTEX101 into a pGEM-T Easy Vector, followed by its subcloning into a His-tagged expression vector, pET-28a (+). The recombinant mTEX101 was then produced by transfection of the expression vector into BL 21 (DE3) E. coli strain. RESULTS: A recombinant protein, weighing 27kDa, was produced upon IPTG-induction of the bacterial host. The presence of mTEX101 protein was detected through Western blot analysis by anti-mTEX101 peptide antibodies. CONCLUSION: We produced mTEX101 recombinant protein that could be used for the production of mono and polyclonal antibodies. PMID- 23926469 TI - A Novel Human Lipid Binding Protein Coding Gene: PERF15, Sequence and Cloning. AB - INTRODUCTION: PERF15 is a testicular germ-cell specific fatty-acid binding protein (FABP) isolated from mammals, originally from rats. It encodes one of the most abundant proteins of rat spermatozoa localized in the perinuclear theca. Northern blot analysis has demonstrated that rat PERF15 mRNA is exclusively transcribed during meiosis and post-meiosis. In this study, we cloned and sequenced human PERF15 gene. MATERIALS AND METHODS: According to the open reading frame of automated computational analysis of Homo sapiens similar to testis fatty acid binding protein nine, two specific Primers were designed to amplify human PERF15 gene. To confirm the identity of the amplified gene, PCR products of PERF15 were cloned into appropriate plasmid vectors followed by sequencing of the inserts. RESULTS: A unique band of ~3kb was obtained after PCR amplification. Restriction enzyme digestion using PvuII confirmed that the fragment was related to PERF15. Gene alignment, direct sequencing and application of specific primers to the gene showed 100% similarity between this gene and the computational data by gel extraction of the ~3 kb band. The human PERF15 gene contained four exons and three introns. Exons one, two, three and four, respectively, coded for 24, 57, 34 and 17 amino acids. The existing three introns were composed of 2113, 461, and 168 nucleotides. CONCLUSION: In spite of the homology between exonic regions and exon-intron boundaries of human PERF15 gene and that of animals, human PERF15 gene is different in size and sequence from corresponding introns in rat and murine PERF15. PMID- 23926470 TI - Correlation of prolactin and thyroid hormone concentration with menstrual patterns in infertile women. AB - INTRODUCTION: The increased prevalence of upper normal limit of TSH and raised anti-thyroperoxidase antibody titer indicate, relatively more frequent occurrence of compensated thyroid function in infertile women. This finding necessitates considering such cases for a thorough investigation of pituitary-thyroid axis. In addition, as some patients may exhibit the clinical picture of hypothyroidism despite normal TSH and free thyroxin (FT4) concentrations, this hospital-based study was undertaken to review the impact of thyroid status on the menstrual function and fertility of the subjects. MATERIALS AND METHODS: In this study, we investigated 160 women with primary infertility who attended the Biochemistry department, Maulana Azad Medical College (MAMC), New Delhi for hormonal evaluations. Eighty fertile women with similar age and socioeconomic status were enrolled as the controls. The association between thyroid dysfunction and levels of serum prolactin, LH and FSH as their menstrual status were reviewed. RESULTS: The majority of the infertile and fertile women were euthyroid. In infertile group, the crude prevalence of hypothyroidism was slightly higher in the infertile group in comparison with that of the general population. There was a positive correlation between serum TSH and prolactin levels in the infertile subjects. Menstrual disorders (mainly oligomenorrhea), were reported by about 60% of the infertile women. Hyperprolactinemia was depicted in 41% of the infertile women while it was only 15% in the control group. The infertile women with hypothyroidism had significantly higher prolactin levels when compared to the subjects with hyper- or euthyroidism. There was a significant association between abnormal menstrual patterns and anovulatory cycles, as observed on endometrial examination of infertile subjects with raised serum prolactin levels. CONCLUSION: There is a greater propensity for thyroid disorder in infertile women than the fertile ones. There is also a higher prevalence of hyperprolactinemia in infertile patients. PMID- 23926471 TI - An overview of the epidemiology of primary infertility in iran. AB - INTRODUCTION: This article compares the prevalence of primary infertility in Iran estimates provided by different studies. No other study had provided a review about the researches related to epidemiology of infertility in the country. MATERIALS AND METHODS: A literature review was undertaken using the scientific resources on the internet and the list of national projects obtained from Deputy of Research and Technology, of Iran Ministry of Health and Medical Education (MOH & ME) and relevant research centers. These resources were attentively reviewed to find about national studies on the epidemiology of primary infertility in Iran during the last decade. Based on their design quality, the National Infertility Study (NIS) (2004-2005), National Health Survey (NHS) (2001) and Tehran Study (1997) were considered for the research. RESULTS: Current primary infertility estimated by National Health Survey (NHS) was 2.8% and by National Infertility Survey (NIS) 3.4%. Tehran study and NIS estimated the prevalence of lifetime primary infertility to be 21.9% and 24.9%, respectively. The minimum prevalence of lifetime primary infertility was found to be 15.8% for the marriage age of 19 27 by Tehran study and 17.2% for the marriage age of 21-26 by NIS. CONCLUSION: On the average, 21-22% of women experience primary infertility during their marital life. The best age of marriage for women in Iran seems to be 20-27 years. At this age group, the lowest number of women (16-18%) would experience primary infertility. PMID- 23926472 TI - Perceived environmental stressors and pain perception during labor among primiparous and multiparous women. AB - INTRODUCTION: Pain experienced during labor is probably the most painful event in the lives of women. Environment itself influences a mother's experience of pain. Tension and stress resulting from pregnancy crisis and labor increase when the mother is hospitalized, which is concomitant with stressful situations and factors that affect pain perception during labor. The purpose of this study was to explore selected aspects of labor stress and specifically study the relationship between environmental factors and pain perception among parturient women. MATERIALS AND METHODS: This descriptive-comparative study was carried out in Tabriz Alzahra Hospital during 2005-2006. In this study, 300 primiparous and 300 multiparous women who were candidates for vaginal delivery, were randomly selected and interviewed. The data were collected by a questionnaire and the intensity of pain was determined by Visual Analogue Scale (VAS). RESULTS: Significant positive correlations were found between pain and tension from environmental factors in primiparous (r=0.16, p<0.01) and in multiparous (r=0.22, p<0.05) women. Furthermore, primiparous women believed that a crowded delivery room (70%) and restriction of movement and mobility (67%) contributed to their environmental stresses. Multiparas women believed that noise in the delivery ward (84%) and restrict of fluid intake (78%) increased their stresses. CONCLUSION: Performance of routine diagnostic tests in hospitalized pregnant woman, provision of invasive medical care during labor process and a noisy and crowded environment all influence the mother's experience and perception of pain. Therefore, the medical staffs seem to play a great role in alleviating labor pain by reducing stressors, especially the objective ones that are more stressful. PMID- 23926473 TI - Successful Pregnancies in Two Orthotopic Liver Transplant (OLT) Recipients in Iran; Two Case Reports. AB - INTRODUCTION: Pregnancy and parenting have been part of human life throughout history and liver transplant recipients are not any exception. This paper reports successful pregnancies in two liver transplant recipients in Iran. CASE PRESENTATION: The first case was a 34-year old woman who had undergone orthotopic liver transplantation (OLT) at Shiraz Namazi Educational Hospital in 2002. She decided to get pregnant seven years after the operation. During pregnancy, immunosuppressive therapy continued, except Mycophenolate Mofetil which has an absolute contra-indication in pregnancy. The patient was followed up during pregnancy by the transplant team as well as a gynecologist. She faced no significant complications and the liver function was stable during pregnancy. She later underwent a Cesarean section in the 38(th) week of gestation and the newborn was a healthy girl weighing 2480g with an Apgar score of 8 at the time of birth. There were no evidences of prematurity or structural abnormalities in the newborn. The second case was a 31-year old primipara who had received an orthotopic liver transplant (OLT) in Shiraz in 2002. She had a smooth pregnancy without any complications and the newborn was a boy weighing 3100g with Apgar scores of 8 and 10 at the time of birth and 5 minutes thereafter, respectively. CONCLUSION: As the number of transplant recipients is growing along with the number of recipients who are in their fertility years, it is vital to ensure a proper medical care by a coordinated multidisciplinary team during pregnancy. PMID- 23926474 TI - Editorial. PMID- 23926476 TI - Prevalence of Iron Deficiency Anemia among Iranian Pregnant Women; a Systematic Review and Meta-analysis. AB - INTRODUCTION: Anemia, particularly Iron Deficiency Anemia (IDA), is the most common hematological disorder during pregnancy with considerable complications in both mothers and fetuses. The estimation of anemia prevalence is an important step for health policy makers. Despite being considered a hot topic in epidemiological studies in Iran for the last twenty years, lack of a comprehensive overview on the findings encouraged the authors to carry out this study. MATERIALS AND METHODS: All published papers in main national and international databases were systematically searched for some specific keywords to find the related studies between the years 1993 and 2007. All published studies which had reported the prevalence of anemia were included in the study except studies on refugees, patients undergoing hemodialysis, patients with thalassemia or cancer or other selective sub-populations. Two trained reviewers independently assessed the inclusion/exclusion criteria and the quality of the selected papers, summarized them and eventually analyzed the data. RESULTS: Ten eligible papers including 11,037 participants were entered into the analysis. The maximum and minimum reported prevalence rates of anemia during pregnancy were 4.3% and 21.5%, respectively. The overall estimate of anemia prevalence in Iranian pregnant women was 13.6 (95% CI: 8.3 - 18.9). Excluding the only out layer from the meta-analysis, the overall estimated prevalence was 12.4% (95% CI: 9.6% - 17.9%). CONCLUSION: The prevalence of anemia in Iranian women during pregnancy is considerably lower than that of most EMRO countries or the one reported by WHO for Iran (> 40%) which had been performed on a small group 16 years ago. The lower prevalence rate of anemia in pregnant women versus the regional rates could be due to the improvements of the national health system and prenatal programs in recent years. PMID- 23926475 TI - Techniques for ovarian tissue, whole ovary, oocyte and embryo cryopreservation. AB - In recent years, preservation of fertility in women has been of great importance, especially in patients exposed to deleterious conditions on fertility. Thus, cryopreservation of human gametes, embryos and ovarian tissue has become an essential part of assisted reproduction. This approach limits the number of embryos transferred, while supernumerary oocytes and/ or embryos can be used in subsequent treatment cycles. Furthermore, cryopreservation reduces the potential risk of hyperstimulation syndrome. Cryopreservation is carried out by two techniques; the slow freezing method, and the more recent rapid procedure called vitrification technology. Recently due the success and simplicity of vitrification, the balance between those two methods has been changed in advantage of vitrification. The use of slow freezing method has become controversial due to its difficulties, expense and respective low success rates in artificial reproduction. Therefore, vitrification seems to win the battle and will be the cryopreservation method of the future. PMID- 23926477 TI - Effects of Timing on Cell Biopsy from Pre-compacted Morula Stage Bovine Embryos on Subsequent Embryonic Development. AB - INTRODUCTION: Embryo biopsy has potential applications in molecular research processes in domestic animals, besides its application in sex determination in embryo transfer programs. The objective of the present study was to assess the in vitro development of bovine embryos biopsied on different days of precompacted morula stage. MATERIALS AND METHODS: Slaughterhouse-derived oocytes were matured in vitro, fertilized (Day-0) by frozen-thawed, Percol-separated spermatozoa and cultured on oviductal cell monolayer. The embryos were subjected to cell biopsy on Days 2, 3, and 4 postinsemination at 4-16-cell stages. The data were analyzed using ANOVA and Chi-squared tests (SigmaStat, version 2). A p-value < 0.05 was considered significant. RESULTS: Biopsies carried out at 16-cell stage (Day-4) resulted in 94% of embryos developing to the blastocyst stage, which was significantly higher (p < 0.05) than the ones biopsied at 8-cell stage on Day-4 (64%), and those undergoing the procedure on Day-3 (49% and 46% at 4-cell and 8 cell stages, respectively) and Day-2 (39% and 33% at 4-cell and 8-cell stages, respectively). No significant differences were observed between biopsied and non biopsied embryos on a given day. The total cell number in biopsy-derived blastocysts ranged between 103 and 135. The difference in the number of total cells, dead cells and cell allocation to trophectoderm and inner cell mass between non-biopsied and biopsy-derived blastocysts was insignificant. CONCLUSION: Biopsy of bovine embryos at 4-16-cell stages had no adverse effects on in vitro developmental potentials and the 16-cell stage embryos, biopsied on Day-4 was the best stage for blastomere removal. PMID- 23926478 TI - Association of vascular endothelial growth factor (VEGF) +405 g>c polymorphism with endometriosis in an Iranian population. AB - INTRODUCTION: Angiogenesis, growth of new blood vessels from pre-existing vessels, is a crucial physiological process for tissue regeneration. This state is also seen in pathological processes such as malignancies and endometriosis. Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis and vascular permeability which is known to play an important role in the development of endometriosis. The aim of this study was to investigate the relationship between +405 G>C VEGF polymorphism and endometriosis in an Iranian population. MATERIALS AND METHODS: The study population was comprised of 105 women with and 150 women without laparoscopic evidence of endometriosis. Genomic DNA from blood cells was extracted using salting out method. Genotype and allele frequency of +405 G>C polymorphism was compared between women with endometriosis and the controls using PCR-RFLP. Statistical analysis was performed using SPSS 13.0 software. Chi-squared test and odds ratio plus 95% confidence interval were determined. A p-value less than 0.05 was considered statistically significant. RESULTS: While the +405 VEGF genotype frequencies in the case group were 41.3% G/G, 46.2% C/G and %12.5 C/C, they were 32% GG, %53.3 GC and 14.7% CC in the control group. The distribution of three genotypes and allele frequencies of +405 G>C VEGF polymorphism between the case and control groups did not demonstrate any significant difference. CONCLUSION: In contrast to previous studies, no significant correlation was found between +405 G>C VEGF polymorphism and endometriosis. Since this was the first study in an Iranian population, further investigation with bigger sample sizes may be indicated to be able to generalize the findings. PMID- 23926479 TI - Comparing Seminal Plasma Biomarkers between Normospermic and Azoospermic Men. AB - INTRODUCTION: Azoospermia affects more than 10% - 15% of infertile male subjects attending infertilty clinics. At present, testicular biopsy is the golden standard procedure for evaluating spermatogenesis status in men with azoospermia. Semen collection and analysis is a non-invasive method and has proven to be valuable in the evaluation of spermatogenesis. Identification of seminal plasma markers with testicular or extra-testicular origins have a great value in predicting the prescence of sperm in testicular tissue and presumptive cause of azoospermia. The aim of this study was to find such markers by comparing the content of seminal plasma using different methods in normospermic and azoospermic men. MATERIALS AND METHODS: Semen samples were collected from 200 men attending Avicenna Infertility Clinic (AIC) in Tehran, Iran. Semen samples were analysed according to WHO guidlines. The subjects were divided into two groups: normospermic (n = 100; group one) and azoospermic men (n = 100; group two) according to semen analysis results. Seminal plasma was separated by high speed centrifuagation and stored in -20 degrees C. Four markers including fructose, neutral alpha glucosidase (NalphaG), inhibin B and anti-Mullerian hormone (AMH) were measured in seminal plasma. Fructose and NalphaG were evaluated by spectrophotometry, while inhibin B and AMH were assessed by ELISA method. The spermatogenesis status in the azoospermic group was evaluated by histopathological method following testicular biopsy. RESULTS: Fructose concentration showed no difference between the two groups. However, it was significantly correlated with sperm count (p < 0.01, r = -0.408). Seminal plasma inhibin B (OR: 1.01; 95%: CI: 1.005 - 1.016), AMH (OR: 1.63; 95% CI: 1.17 - 2.28) and NalphaG, (OR: 1.07; 95% CI: 1.04 - 1.1) levels were higher in normospermic subjects compared to azoospermic men. There were significant differences in inhibin B and AMH concentrations between the two groups based on the presence or absence of mature sperm in testicular biopsies (p < 0.01). Inhibin B concentration was positively correlated with sperm count in the normospermic group, however, NalphaG concentration correlated with sperm count of normospermic men (p < 0.01, r = 0.345) and the subjects' age in both groups. CONCLUSION: Inhibin B and AMH were correlated with the presence of sperm in testicular tissue samples. According to non-specific changes in inhibin B and AMH concentrations, identification of more specific molecular markers in seminal plasma to definitely evaluate the status of spermatogenesis is recommended. PMID- 23926480 TI - Serum leptin levels in women with immunological recurrent abortion. AB - INTRODUCTION: Recurrent abortion (RA) may be a consequence of aberrant expression of immunological factors during pregnancy. Although the relative importance of immunological factors in human reproduction remains controversial, substantial evidence suggests that autoantibodies contribute to reproductive failure. Production of such antibodies is under the control of cytokines; and leptin, besides its role in reproductive success, has a profound effect on directing the cytokine profile toward Th1 (cellular) pattern. Therefore, the present study was performed to assess serum leptin levels in women with immunological recurrent abortion. MATERIALS AND METHODS: In this prospective study, 250 women who attended Avicenna Infertility Clinic with RA were screened for known causes of abortion from July to December 2008 in Tehran, Iran. Eighty-one patients with normal karyotypes and hormonal profile with normal ovaries and uterus and no signs of infection were categorized as patients with immunological (IRA, n = 39) or unexplained (URA, n = 42) recurrent abortion based on presence or absence of autoantibodies. After blood sampling, levels of anti-nuclear antibody (ANA), anti double stranded DNA antibody (anti-dsDNA), lupus anti-coagulant antibody (LACAb), anti-phospholipid antibody (APA), anti-cardiolipin antibody (ACA), anti thyroglobulin antibody (TgAb), anti-thyroperoxidase antibody (TPOAb) and anti thrombin III antibody (ATIIIAb) were measured by enzyme-linked immunosorbent assay (ELISA) or chemiluminescent enzyme immunoassay (CLEIA). RESULTS: In IRA group, 9 (23.1%), 24 (61.5%), 25(64.1%) and 1 (2.6%) women were above the normal cut-off point for ANA, TgAbs, TPOAbs and AT-III Abs, respectively. IRA patients had normal values of LACAbs, APA and ACA. With normal level of fasting blood sugar (FBS), IRA and URA groups had similar serum leptin levels (23.7 +/- 13.2 ng/ml vs. 22.7 +/- 12.5 ng/ml, respectively). Serum leptin concentrations showed a positive correlation with weight and BMI in both groups. CONCLUSION: This study suggests that serum leptin levels are higher in IRA and URA patients than normal women. The findings of this study suggest the need for a more comprehensive study and comparison of leptin levels in IRA and URA patients to women with no history of miscarriages. PMID- 23926482 TI - Spontaneous pregnancy in primary amenorrhea; a case report. AB - INTRODUCTION: Primary ovarian failure (POF) is a syndrome composed of amenorrhea, estrogen deficiency and Follicular Stimulating Hormone (FSH) of menopausal ranges in young women. In this article, we report a case of primary amenorrhea that presented with full term pregnancy. CASE PRESENTATION: A 29-year old woman with a history of primary amenorrhea attended hospital with full term pregnancy. She had experienced a few episodes of withdrawal bleeding on hormonal treatment initially and she had conceived spontaneously. Subsequently, she had uneventful pregnancy and caesarean delivery on maternal request. CONCLUSION: This case was presented to emphasize the real chances of spontaneous conceptions due to intermittent and unpredictable ovarian function in patients with POI. Nevertheless, egg donation is still considered the best option for infertility in such women. PMID- 23926481 TI - Preventing Mother-to-Child Transmission of HIV/AIDS: Do Iranian Pregnant Mothers Know about it? AB - INTRODUCTION: Nowadays, HIV is mostly spreading in Asian countries. One of the important routes for HIV transmission in these countries is the vertical route which infects 35% to 45% of newborns. Mother's education, drug prophylaxis and Cesarean section, accompanied by banning breastfeeding will decrease this rate to 2%. Therefore, mothers' knowledge about Prevention of Mother to Child Transmission (PMTCT) has a great role in HIV/AIDS prevention. This study was designed to evaluate knowledge of pregnant women about HIV, its vertical transmission and prevention in Tehran, Iran. MATERIALS AND METHODS: This cross sectional study was conducted on 1577 pregnant women aged 15 - 46 years who were attending prenatal care clinics in Tehran, Iran. The research material was a questionnaire which was completed daily by trained midwives. The data were statistically analyzed by ANOVA, independent sample t-test, Pearson correlation and linear regression with a significance level of p = 0.05. RESULTS: About 16.5% of the participants had good knowledge about HIV/AIDS and 54.1% about its transmission routes but awareness about its prevention was only 5.7%. Fifty-seven percent of the participant had not been tested for HIV earlier and 20.2% were not willing to undergo such tests. About 86.2% of the participants had no idea about the availability of drug prophylaxis in Iran for PMTCT. CONCLUSION: The fact that 28.2% of the participants were not willing to undergo HIV testing reflects negative attitude about HIV infection. Although the overall awareness about the infection and its transmission was good but knowledge about its prevention especially by PMTCT and its availability in Iran was low. Educational programs through mass media or prenatal care programs by focusing on HIV/AIDS prevention maybe useful. PMID- 23926483 TI - The New 2010 WHO Manual and the Need to Address some Related Dilemmas. PMID- 23926484 TI - Macroprolactin; a frequent cause of misdiagnosed hyperprolactinemia in clinical practice. AB - INTRODUCTION: Macroprolactin is a significant cause of misdiagnosis, unnecessary investigation, and inappropriate treatment in patients with hyperprolactinemia. Its frequency has not been clearly established due to technical difficulties in identifying it. Most laboratories and clinicians are unaware of macroprolactin interferences in prolactin assays. MATERIALS AND METHODS: A comprehensive literature search was conducted on the websites of the National Library of Medicine (http://www.ncbl.nlm.nih.gov) and PubMed Central, the US National Library of Medicine's digital archive of life sciences literature (http://www.pubmedcentral.nih.gov/). The data were also looked for in relevant books and journal. RESULTS: Macroprolactin is a non-bioactive prolactin isoform usually composed of a prolactin monomer and an IgG molecule having a prolonged clearance rate similar to that of immunoglobulins. This isoform is clinically non reactive but it interferes with immunological assays used for the detection of prolactin. CONCLUSION: There is a need to understand and explore the recent progress in the diagnosis and pathophysiology of macroprolactinemia for improving patient care. PMID- 23926485 TI - Effects of chamomile extract on biochemical and clinical parameters in a rat model of polycystic ovary syndrome. AB - INTRODUCTION: Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction. Presently, little is known about the primary factors that initiate PCOS. Chamomile flowers are used in alternative medicine for its anti-spasmolytic and anti-inflammatory effects. Antispasmodic properties of chamomile ease menstrual cramps and lessen the possibility of premature labor. This medicinal herb also stimulates menstruation. In this study, we evaluated the effects of Chamomile alcoholic-extract on the biochemical and clinical parameters in a rat model of PCOS. MATERIALS AND METHODS: Estrous cyclicity of 30 virgin adult cycling rats was monitored by vaginal smears obtained between 0800 and 1200 hours. After about 4 days, each rat received an i.m. injection of Estradiol Valerate (Aburaihan Co., Iran), 2 mg in 0.2 ml of corn oil, to induce PCO. Corn oil was injected to the rats in the control group. All the rats in the experimental group were evaluated for follicular cysts 60 days after the injection. Rats with PCOS were treated by multiple doses (25, 50, 75 mg/kg) of intraperitoneal injections of Chamomile alcoholic-extract for ten days. The data were statistically analyzed at a significance level of p<0.05 by ANOVA, followed by the Student Newman-Keuls post hoc test. RESULTS: The histological and hormonal results showed that Chamomile can decrease the signs of PCOS in the ovarian tissue and help LH secretion in rats (p<0.05). CONCLUSION: The alcoholic-extract of dried Matricaria chamomilla L. flowers can not only induce recovery from a PCO induced state in rats, but also increase dominant follicles. Additionally better endometrial tissue arrangements can be regarded as another therapeutic effect of Chamomile. PMID- 23926486 TI - Chromosomal abnormalities in infertile men referred to iran blood transfusion organization research center. AB - INTRODUCTION: The prevalence of somatic chromosomal abnormalities in infertile male individuals has been reported to vary in different literatures. The aim of this study was to investigate the frequency of chromosomal aberrations among infertile men referred to the Cytogenetic Laboratory of Iran Blood Transfusion Organization Research Centre (IBTO). MATERIALS AND METHODS: Chromosomal analysis was performed on phytohemag-glutinin (PHA)-stimulated peripheral lymphocyte cultures of 1052 infertile men using standard cytogenetic methods. The study took place during 1997 to 2007. RESULTS: Total chromosome alterations were revealed in 161 (15.30%) infertile men. The most prevalent chromosomal abnormality in the infertile men was 47, XXY, that was seen in 94 (58.38%) men while one of them had a mosaic karyotype: mos 47, XX[54]/47,XXY[18]/46,XY[9]. In 37 (22.98%) cases, structural aberrations were detected. There were 30 (18.63%) cases of sex reversal. CONCLUSION: Cytogenetic studies of these patients showed increased chromosomal abnormalities in infertile men in comparison with that of the normal population, justifying the need for cytogenetic analysis of men with idiopathic infertility. PMID- 23926487 TI - Cytogenetic results of patients with infertility in middle anatolia, Turkey: do heterochromatin polymorphisms affect fertility? AB - INTRODUCTION: Infertility is a significant multifactorial disorder that can be caused by chromosomal abnormalities. In this study, we aimed to cytogenetically investigate male and female patients admitted to the Genetic Diagnostic Laboratory of Kayseri Educational Hospital in Kayseri, Turkey with varied clinical prediagnoses of infertility. MATERIALS AND METHODS: Chromosomes from cultured peripheral blood lymphocytes of 274 patients and 427 individuals as the controls were analyzed using GiemsaTrypsin-Giemsa (GTG) banding. The individuals with sex chromosome aneuploidy or mosaicism were classified as carriers and with chromosomal polymorphism, respectively. The results of the two groups were compared statistically. RESULTS: Pure sex chromosome aneuploidy was found in 29 (10.5%) patients and mosaic sex chromosome aneuploidy in 15 (5.5%) cases and the total rate of abnormalities was 16%. Karyotypes were composed of an overall polymorphism rate of 8% in the patient and 4% in the control groups with no statistically significant difference (p = 0.2 and p > 0.05, respectively). CONCLUSION: The present study shows that chromosomal polymorphisms are common among infertile patients. Chromosomal abnormalities and even heteromorphisms are significant etiologic factors leading to fertility problems. The overall high prevalence of chromosomal polymorphisms in infertile couples, compared to the normal population, needs to be confirmed with further investigations and larger study populations to delineate the role of "harmless" chromosomal aberrations in the etiology of infertility. PMID- 23926488 TI - Comparing the effects of continuous hormone replacement therapy and tibolone on the genital tract of menopausal women; a randomized controlled trial. AB - INTRODUCTION: Many postmenopausal women who are on hormone replacement therapy discontinue medications due to vaginal bleeding. Tibolone, a synthetic steroid, has minimal stimulatory effect on the endometrium. The aim of this study was to assess the effects of continuous HRT regimen and tibolone on the onset of vaginal bleeding and vaginal maturation value. MATERIALS AND METHODS: A total of 150 healthy women in postmenopausal period were randomly enrolled in this controlled clinical trial. Patients were randomly allocated into three groups, and were followed for six months. The first 50 women received 2.5 mg tibolone plus a Cal+D tablet (500 mg Calcium and 200 IU vitamin D) daily, the second 50 women received 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (CEE/MPA) plus one Cal+D tablet daily, and the remaining 50 received only one Cal+D tablet per day and served as the control group. Symptoms were recorded using a questionnaire that assessed vaginal bleeding or spotting, vaginal dryness and intention to continue the medications. Vaginal maturation value was assessed by examining vaginal smears before and after the treatment. The results for the three groups were analyzed using statistical methods. RESULTS: In comparison with the control group, CEE/MPA and tibolone increased vaginal maturation value and decreased the frequency of vaginal dryness (p < 0.01). Women in tibolone group were more likely to continue the treatment regimen than those in the CEE/MPA or the control groups (p < 0.01). CONCLUSION: Tibolone can serve as an appropriate choice for HRT as it has low rates of vaginal bleeding/ spotting episodes and high acceptance rate in postmenopausal women. PMID- 23926489 TI - Knowledge and Attitudes of a Number of Iranian Policy-makers towards Abortion. AB - INTRODUCTION: Unsafe and illegal abortions are the third leading cause of maternal death. It affects physical, emotional and social health of women and their families. Abortion is a multi-dimensional phenomenon with several social, legal, and religious implications. The views of policy-makers affect the approach to abortion in every society. Understanding the attitudes and knowledge of high ranking decision makers towards abortion was the purpose of this study. MATERIALS AND METHODS: A qualitative research was implemented by carrying out individual interviews with 29 out of a selection of 80 presidents of medical sciences universities, senior executive managers in the legal system, forensic medicine and decision-makers in the health system and a number of top Muslim clerics, using a semi-structured questionnaire for data gathering. Content analysis revealed the results. RESULTS: There were considerable unwillingness and reluctance among the interviewees to participate in the study. The majority of participants fairly knew about the prevalence of illegal abortions and their complications. There was strong agreement on abortion when health of the mother or the fetus was at risk. Abortion for reproductive health reasons was supported by a minority of the respondents. The majority of them disagreed with abortion when pregnancy was the result of a rape, temporary marriage or out of wedlock affairs. Making decision for abortion by the pregnant mother, as a matter of her right, did not gain too much approval. CONCLUSION: It seemed that physical health of the mother or the fetus was of more importance to the respondents than their mental or social health. The mother's hardship was not any indication for induced abortion in the viewpoints of the interviewed policy-makers. Strengthening family planning programs, making appropriate laws in lines with religious orders and advocacy programs targeting decision makers are determined as strategies for improving women's health rights. PMID- 23926490 TI - A Robertsonian Translocation rob (14;15) (q10:q10) in a Patient with Recurrent Abortions: A Case Report. AB - INTRODUCTION: Robertsonian translocation is one of the major chromosomal rearrangements with a prevalence rate of 0.1% of the general population and 1% of the infertile population. In this report, we present a nonhomologous Robertsonian translocation in a female patient with a history of repeated abortions. CASE PRESENTATION: A couple with the complaint of repeated abortions was admitted in the Institute of Genetics and Hospital for Genetic Diseases in Begumpet, Hyderabad, India for cytogenetic evaluation. Chromosomal analysis of the couple revealed an abnormal karyotype in the female partner with 45, XX, rob (14, 15) (q10; q10) chromosomal constitution, while the male partner showed normal 46, XY karyotype. CONCLUSION: The cytogenetic analysis of couples with repeated abortions is mandatory to identify any probable chromosomal aberrations. Prenatal diagnosis should be offered to couples with repeated abortions in the case of future pregnancies. PMID- 23926491 TI - Ectopic molar pregnancy: a rare entity. AB - INTRODUCTION: Ectopic molar pregnancy is a rare occurrence and consequently not often considered as a diagnostic possibility. In this article, an attempt was made to stress on the need for histopathological examination and follow up of every case of ectopic pregnancy. This was substantiated with the help of a case report. CASE PRESENTATION: A 30-year-old gravida 4, para 3, pregnant woman with a 7-week history of amenorrhea attended hospital with abdominal pain. Per vaginal examination revealed a tender left adnexal mass measuring 4x4 cm and on ultrasonography there was a live fetus corresponding to a 7-week and 6 days gestation with free fluid in the pelvic cavity. Laparotomy, revealed a ruptured left tubal ectopic pregnancy and histopathological examination was suggestive of a molar pregnancy. CONCLUSION: Although rare, molar changes can occur at any site of an ectopic pregnancy. Clinical diagnosis of a molar pregnancy is difficult but histopathology is the gold standard for diagnosis. PMID- 23926492 TI - Epigenetic Alterations and their Impact on Assisted Reproduction Technology Outcomes. PMID- 23926493 TI - Effects of Kamdhenu Ark and Active Immunization by Gonadotropin Releasing Hormone Conjugate (GnRH-BSA) on Gonadosomatic Indices (GSI) and Sperm Parameters in Male Mus musculus. AB - BACKGROUND: Active immunization against GnRH decreases the secretion of gonadotropins and causes cessation of gonadal function, thereby, inducing infertility. Based on the immunoenhancing activity of Kamdhenu ark (distilled cow urine), this study was performed to evaluate its effects on the gonadosomatic indices (GSI) and sperm parameters in male mice receiving a GnRH contraceptive vaccine. METHODS: Sixty adult male mice of Parke's strain were divided into three groups of twenty. Group I served as the controls, while group II was immunized by GnRH-BSA conjugate (50/0.2/35 ug/ml/g BW) by four intraperitoneal injections at different intervals on days 1, 30, 60 and 90. However, group III was supplemented daily by oral Kamdhenu ark (100 ppm) along with GnRH-BSA immunizations. The animals were sacrificed after 30, 60, 90 and 120 days and their testis and epididymis were dissected out weighed and semen analysis was performed. RESULTS: GSI values, sperm motility, sperm count and sperm morphology in male Mus musculus were decreased significantly in all the experimental groups as compared to the control group (p<0.01). Kamdhenu ark significantly enhanced the effect of GnRH vaccine on the aforesaid parameters especially in 90 and 120 days treated groups (p<0.05). CONCLUSION: The changes witnessed in sperm parameters suggested that the GnRH-BSA immunization suppressed the activities of gonadotropins and testosterone directly through hypothalamo-hypophysial-gonadal axis and indirectly by acting on the testes which may modulate the sperm morphology, sperm count and motility. However, Kamdhenu ark seems to have enhanced these effects because of its immune-modulatory properties too. PMID- 23926494 TI - PCR-Based Evaluation of Tuberculous Endometritis in Infertile Women of North India. AB - BACKGROUND: Tuberculous endometritis is often a diagnostic dilemma for gynecologists in the evaluation of infertility. This study evaluated and compared different diagnostic methods in tuberculous endometritis. METHODS: 100 infertile women were investigated for tuberculous endometritis. The endometrial samples obtained by curettage were evaluated by Ziehl-Neelsen (ZN) staining of the smears for acid-fast bacilli (AFB), the samples were also cultured on Lowenstein-Jensen medium, and histopathological examination and nested PCR targeting 'hupB' gene (Rv 2986c in M. tuberculosis and Mb3010c in M. bovis) which can differentiate between M. tuberculosis and M. bovis were performed. Antibodies against 38-kDa and 16-kDa mycobacterial antigens were detected in serum using ELISA. Statistical analysis was done by online GraphPad Prism software, version 5.0. McNemar's test was applied and Kappa agreement coefficient was calculated for agreement between various methods. A p-value < 0.05 was considered significant. RESULTS: Among the 100 evaluated endometrial samples, one was AFB smear positive, none was positive by culture, four were positive by histopathology and 13 were positive by PCR. Of the 13 PCR-positive cases, 38.4% were positive for M. tuberculosis, 23.07% for M. bovis, and 38.4% showed co-infection with both species. 40% of the patients had raised IgG against M. tuberculosis 38-kDa antigen. McNemar's test was applied to PCR and the conventional methods of TB diagnosis (AFB, Culture and histopathology) and the p-value was < 0.001 (highly significant) for PCR. Detection by PCR showed a fair agreement with detection by Mantoux test and ELISA. CONCLUSION: In paucibacillary endometrial tuberculosis, the positive detection rate was found to be significantly higher for PCR compared to other methods. The 'in-house' nested PCR assay targeting the hupB gene and used in this study, can serve as a rapid diagnostic aid for tubercular endometritis. It can also differentiate between members of the Mycobacterium tuberculosis complex, namely M. tuberculosis and M. bovis. PMID- 23926495 TI - Effects of maternal caffeine consumption on ovarian follicle development in wistar rats offspring. AB - BACKGROUND: In recent years concerns have been raised about human reproductive disorders, specially the effects of environmental factors on human fertility and pregnancy outcome. Therefore, the present study was designed to assess the effects of maternal caffeine consumption on ovarian follicles development in rat offspring. METHODS: 60 pregnant female rats were randomly divided into a control and two experimental groups. The rats in the two experimental groups received caffeine via drinking water during gestation (26 and 45 mg/kg) and lactation (25 and 35 mg/kg). The ovaries of the offspring were removed at 7, 14, 28, 60, 90 and 120 days after birth, and fixed in Bouin's solution. By preparing serial tissue sections, structural changes in ovarian follicles and corpora lutea were studied during postnatal development. RESULTS: The weight of ovaries decreased significantly (p<0.05) in the high dose caffeine-treated group at all stages of postnatal development. Significant (p<0.05) decreases were seen in the number of primordial follicles from day 7 to 120 after birth in the high dose caffeine treated group. Moreover, the number of primary and secondary follicles decreased significantly on days 7, 14 and 28 as did the number of antral follicles on days 14 and 28 after birth (p<0.05) in the high dose caffeine-treated group. The diameter of secondary and antral follicles decreased significantly (p<0.05) in high dose caffeine-treated group on the early days of postnatal development. No statistically significant differences were seen in the number of corpora lutea between the groups. CONCLUSION: The present study shows that caffeine consumption during gestation and lactation affects the early stages of ovarian follicle development and reduces reproductive efficiency in the offspring of Wistar rats. PMID- 23926496 TI - Reproductive health rights of women in the rural areas of meherpur district in bangladesh. AB - BACKGROUND: This study evaluated the reproductive health rights, women empowerment and gender equity in a rural area of Bangladesh. METHODS: Three hundred married women of reproductive age (15-49 years) in Meherpur District, Bangladesh were interviewed using a structured questionnaire and purposing sampling techniques. The logistic regression analysis was used to determine the dominating factors affecting reproductive health rights. To fulfill the objectives of the study the two main factors, age at marriage and family planning acceptance of the respondents, were regarded as the determinants. RESULTS: The study results revealed that almost all the respondents were housewives (82.3%), one-third (31.0%) did not avail any modern facility, and their yearly income was very low. Moreover, about half of the women (52.7%) were very young (<=30 years), most of them (79.0%) had married early (<18 years) and about half of them (53.3%) had taken contraceptives based on their husbands' choice. Finally, multi-variate analysis identified the relationship between the profession of the respondents, yearly income, number of family members, and the availability of modern facilities with age at marriage (Model 1). The study also identified the relationship between the age of respondents, education, occupation, yearly income, and the total number of family members with family planning acceptance (Model 2). CONCLUSION: Regarding the results of this study, women's reproductive health rights, marriage after the age of 18 and family planning acceptance among couples needs to be enhanced in Mehrpur District in Bangladesh. PMID- 23926497 TI - Iranian Oncologists' Attitude towards Fertility Preservation in a Sample Group. AB - BACKGROUND: Recent advances in cancer treatment have resulted in an increased number of cancer survivors. Fertility might be impaired by cancer itself or through gonadal damage as a consequence of radio-chemotherapy. Damages to reproductive organs are seen in minimally upto 30% of cancer patients. The aim of the present study was evaluate the attitude of Iranian oncologists toward fertility preservation. METHODS: Thirty oncologists filled an author-designed questionnaire which included five multiple choice questions at Mahak hospital, Tehran in 2009. The data were collected and analyzed by SPSS 11.5 software. RESULTS: More than half of the oncologists believed that radio-chemotherapy has destructive effects on reproductive organs. This study showed that as high as 67% of the respondants believed fertility preservation should be offered to all patients at risk, but 40% of them insisted that the patients should bring up the topic themselves. Only 46% of the oncologist knew about fertility preservation techniques. The greatest barriers for accepting fertility preservation by the parents of children undergoing cancer treatment were: lack of information (41%), hopelessness from treatment prognosis (33%), fear of delay in starting the treatment (15%) and the priority of child survival (11%). CONCLUSION: The specific challenges of counseling are time pressure between diagnosis and start of treatment, little knowledge about fertility preservation both by treating oncologists and parents; therefore a team consisting of oncologists, infertility specialists and social workers is recommended in these settings. PMID- 23926499 TI - Publications about Sperm during the Years 1897 to 2010. PMID- 23926498 TI - Post-delivery cardiomyopathy in a patient admitted to critical care unit; a rare case report. AB - BACKGROUND: Peripartum cardiomyopathy (PPCM) is an uncommon disease that affects women in the last month of pregnancy or within the first five months postpartum, occurring in about 1 in 3500 live births. The disease bears potentially devastating effects both on mother and the fetus if not treated early in its course. CASE PRESENTATION: The case was a 34-year old woman with a triple pregnancy who presented to the ward immediately after cesarean section with signs of dyspnea, cyanosis and pulmonary edema. She was diagnosed with PPCM upon echocardiography. The patient improved remarkably despite the PPCM's devastating complications. This case report aims to describe a female patient who developed PPCM after a triple delivery. CONCLUSION: Regarding the high risks of developing PPCM in subsequent pregnancies and avoiding multiparty, especially in older age, a reliable contraception in childbearing women would be helpful. The best prevention of PPCM is to avoid subsequent pregnancies. PMID- 23926500 TI - Post-thaw Embryo Transfer Cycles as the Future Hope for Boosting IVF Success Rates. PMID- 23926501 TI - The genetic bases of uterine fibroids; a review. AB - Uterine leiomyomas/fibroids are the most common pelvic tumors of the female genital tract. The initiators remaining unknown, estrogens and progesterone are considered as promoters of fibroid growth. Fibroids are monoclonal tumors showing 40-50% karyo-typically detectable chromosomal abnormalities. Cytogenetic aberrations involving chromosomes 6, 7, 12 and 14 constitute the major chromosome abnormalities seen in leiomyomata. This has led to the discovery that disruptions or dysregulations of HMGIC and HMGIY genes contribute to the development of these tumors. Genes such as RAD51L1 act as translocation partners to HMGIC and lead to disruption of gene structure leading to the pathogenesis of uterine fibroids. The mechanism underlying this disease is yet to be identified. The occurrence of PCOLCE amid a cluster of at least eight Alu sequences is potentially relevant to the possible involvement of PCOLCE in the 7q22 rearrangements that occur in many leiomyomata. PCOLCE is implicated in cell growth processes. Involvement of Alu sequences in rearrangements can lead to the disruption of this gene and, hence, loss of control for gene expression leading to uncontrolled cell growth. This can also lead to the formation of fibroids. Though, cytogenetics provides a broad perspective on uterine fibroid formation, further molecular analysis is required to understand the etiopathogenesis of uterine fibroids. PMID- 23926502 TI - The Profile of Human Sperm Proteome; A Mini-review. AB - New advances in mass spectrometry-based proteomics technology are having a major impact on our understanding of how human spermatozoa acquire their capacity for fertilization. A complete analysis of the proteins found in the human spermatozoa is essential for understanding the events leading up to, and including, fertilization and early embryo development. In this short review, we have collected the human sperm proteome from the literature and analyzed it by the Database for Annotation, Visualization and Integrated Discovery (DAVID) software. Bioinformatics analysis demonstrated that the collected 1,300 proteins were involved in various metabolic pathways including catabolic processes. Additionally, the majority of the collected human sperm proteome belonged to cytoplasm. Application of the multi-dimensional protein identification technology (MudPIT) for obtaining a better coverage of the hydrophobic and basic proteins of the human sperm proteome is recommended. PMID- 23926503 TI - Effects of nicotine on sperm characteristics and fertility profile in adult male rats: a possible role of cessation. AB - INTRODUCTION: Infertility is common among couples of child-bearing age and approximately half of known causes of primary infertility are attributable to male factor. It is still unclear whether the injurious effects of cigarette smoking on sperm characteristics and infertility are due to nicotine. Therefore, the present study investtigated the effects of orally administered of nicotine on sperm characteristics and libido in adult male albino rats. The study also sought nicotine effects on fertility rate, litter size and weight in female animals cohabited with nicotine treated male rats. METHODS: Forty male and twenty-five female rats were used for the study. The male rats were divided into five groups and were treated for a period of 30 days with nicotine 0.5 mg/kg (low dose) and 1.0 mg/kg (high dose) per body weight while the control rats received 0.2 ml/kg normal saline. The fourth and fifth groups were gavaged with 0.5 mg/kg and 1.0 mg/kg body weight of nicotine but were left untreated for another 30 days. These groups served as the recovery groups. At the end of each experimental period, sperm analysis, fertility study, litter weight and size were determined. RESULTS: Sperm motility and count significantly decreased (P < 0.05) while the percentage of abnormality significantly increased (P < 0.05) in both treatment groups. However, there was an insignificant decrease (P > 0.05) in the viability and semen volume of the treated groups. Fertility studies revealed that nicotine reduced libido in male rats, litter weight and number delivered by the untreated female during the experiments. CONCLUSION: The present study showed that nicotine has a dose-dependent deleterious effect on the sperm characteristics and that fertility is ameliorated by nicotine cessation in male rats. PMID- 23926504 TI - Protective effects of rutin and naringin in testicular ischemia-reperfusion induced oxidative stress in rats. AB - INTRODUCTION: Testicular torsion and detorsion causes reperfusion injury which damages the testicular tissue and affects the quality of sperm. Deterioration in the quality of sperm worldwide is the recent scenario and one of its reasons is testicular ischemic/ reperfusion (IR) injury. Therefore the present study aims at producing new drugs for the treatment of testicular IR injury. METHODS: 42 animals were selected for the study and divided into 7 groups, each containing 6 rats. Bioflavonoids were tested for their efficacy in reversing the damage done to the testicular tissue by causing testicular torsion and detorsion in rats. As oxidative stress produced in the above condition causes tissue damage, MDA level was measured and antioxidant enzymes SOD and catalse were evaluated. Histological examination was conducted to find the extent of damage and the protective effect of rutin and naringin. One-way ANOVA and Tukey's post-hoc test were used for data analysis. A p-value<0.001 was considered statistically significant. RESULTS: MDA levels increased and antioxidant enzymes decreased drastically in the group of rats with testicular torsion and detorsion which clearly indicates a rise in oxidative stress (68% rise in the case of MDA and 20% and 16% decrease in SOD and catalase concentrations, respectively). Rutin and naringin-treated groups showed the beneficial effects of the medicinal drugs, particularly in higher doses. Rutin, 10 mg/kg, was effective when compared to naringin in providing protection. Compared to the animals in the control group, there was a 30% reduction in MDA levels and a 20% increment in SOD levels plus a five-fold increase in catalse in the rutin-treated group (10 mg/kg). Histological examination supported the above claims. CONCLUSION: Oxidative stress in testicular injury affects the quality of sperm. Rutin and naringin in higher doses protected testicular tissue effectively. Further studies in this direction may prove beneficial. PMID- 23926505 TI - Down-regulation of HLA-G Attenuates Cleavage Rate in Human Triploid Embryos. AB - INTRODUCTION: HLA-G is a major histocompatibility complex (MHC), class Ib molecule that is selectively expressed at the fetal-maternal interface. It is thought to play a role in protecting the fetus from the maternal immune response. Interestingly, the preimplantation embryo development (Ped) gene product Qa-2 is also a mouse MHC class Ib protein that affects cleavage and division of preimplantation mouse embryos and subsequent embryonic survival. Data from many human in vitro fertilization (IVF) clinics suggest that the mouse Ped phenomenon also exists in human because embryos fertilized at the same time have different cleavage rates and consequently different IVF outcomes. As HLA-G is expressed in human early embryos, it is highly regarded as the functional homologue of Qa-2. Whether HLA-G expression is correlated with the cleavage rate of human embryos has great potential clinical value. METHODS: In this study, 45 human early abnormal fertilized embryos (3 PN) from patients undergoing in vitro fertilization were used to test the effects of HLA-G knock-down via infection with adenovirus carrying its specific siRNA on the cleavage rate in a 2-day culture period. One-way ANOVA, Post hoc and Chi-square were used to compare groups. A p-value smaller than 0.05 was considered statistically significant. RESULTS: Knocking-down HLA-G in human pre-implantation stage embryos resulted in a higher cell arrest rate and a slower cleavage rate. CONCLUSION: The results from the present study suggested that HLA-G might play an important role in early human embryo development. PMID- 23926506 TI - Comparing the Effects of Echinophora-platyloba, Fennel and Placebo on Pre menstrual Syndrome. AB - INTRODUCTION: Premenstrual syndrome (PMS) is a condition characterized by a number of behavioral, psychological and physical symptoms recurring cyclically during the luteal phase of the menstrual cycle. The uncertainty in the pathogenesis of PMS has led to many treatment protocols being suggested as possible therapies. The present study was carried out to compare the effects of echinophora-platyloba and fennel extracts on the PMS against placebo in students of Shahrekord University of Medical Sciences in 2008. METHODS: In this single blind randomized clinical trial, 90 students with moderate to severe PMS enrolled in the study and were randomely divided into three equal groups. The first group received echinophora-platyloba extract, the second group received fennel extracts and the third group received placebo. The severity of PMS was measured by Daily Record of Severity of Problems (DRSP) questionnaire at the end of the first and second menstrual cycles before the intervention and the results were compared with them after the intervention. Data was analyzed using Dunn, Kruskal Wallis, and Pearson correlation tests by SPSS (v. 11.5) and p < 0.05 was considered statistically significant. RESULTS: There were not any significant differences in the means of premenstrual syndrome scores before the intervention among the three groups (100.8+/-22.1 in echinophora-platyloba group, 101.3+/-27.1 in fennel group and 104.3+/-19.5 in placebo group, p > 0.05), but the differences were significant after the intervention (49.7+/-23.2 in echinophora-platyloba group, 64.4+/-27.5 in fennel group and 79.1+/-28.1 in placebo group, respectively, p < 0.001). No significant differences were seen between the echinophora-platyloba and fennel groups. CONCLUSION: The echinophora-platyloba and fennel extracts could reduce the severity of PMS. The effects of echinophora-platyloba and fennel were similar and greater than the placebo. Administration of the extracts of these herbs is suggested for relieving the signs and symptoms of PMS. PMID- 23926507 TI - Risk factors for hypertensive disorders in pregnancy: a report from the maroua regional hospital, cameroon. AB - INTRODUCTION: A recent study at the Maroua Provincial Hospital revealed that hypertension in pregnancy was the first cause of maternal death, representing 17.5% of the 63 maternal deaths recorded between 2003 and 2005. Knowing little about the causes, this study was to identify the possible risk factors for hypertensive disorders in pregnancy. METHODS: This case-control study was-done at the Maroua Regional Hospital, Cameroon between June 2005 and May 2007. All the 152 deliveries complicated with hypertension were compared and analyzed with 414 pregnancies that were not complicated with the disease. Data analysis was performed using EPI Info 3.5.1. The differences were considered to be significant if the p-values were less than 0.05. RESULTS: Using univariate analysis, several factors linked to hypertensive disorder in pregnancy were identified. They included early adolescence, nulliparity, illiteracy, lack of occupation and family history of hypertension. At multivariate analysis, the risk of having hypertension during pregnancy remained greater for illiterate women (OR: 1.6; 95%CI: 1.0-2.3), housewives (OR: 2.8; 95%CI: 1.1-6.9), nulliparae (OR: 2.8; 95%CI: 1.5-3.6), women with family histories of hypertension (OR: 3.6; 95%CI: 1.6 8.5) and women with histories of hypertension during pregnancy (OR: 7.0; 95%CI: 3.0-16.4). CONCLUSION: Risk factors for hypertensive diseases in pregnancy in Maroua, Cameroon seem to include early teenage status, illiteracy, housewife status, nulliparity and family or personal histories of hypertension. The knowledge about the aforesaid factors seems to lay the tracks for its prevention in Cameroon. PMID- 23926508 TI - An unusual etiology of spontaneous pyometra perforation; a case report. AB - INTRODUCTION: By presenting this case we aimed to describe an uncommon complication of generalized peritonitis following spontaneous pyometra perforation in untreated cervical carcinoma. CASE PRESENTATION: This report describes a 60-year-old postmenopausal woman presenting with clinical features mimicking intestinal perforation who was later diagnosed as cervical carcinoma with pyometra perforation at exploratory laparotomy. The patient had good post operative recovery following drainage and peritoneal lavage. CONCLUSION: Spontaneous pyometra perforation in a case of untreated carcinoma of cervix is a rare condition, yet it should be suspected and kept in the differential diagnosis of acute abdomen in elderly women. PMID- 23926509 TI - Standardized Infertility Treatments not only Ensure Maternal-Fetal Health but also Provide Higher Success Rates. PMID- 23926510 TI - Prediction and diagnosis of poor ovarian response: the dilemma. AB - Failure to respond adequately to standard protocols and to recruit adequate follicles is called 'poor response'. This results in decreased oocyte production, cycle cancellation and, overall, is associated with a significantly diminished probability of pregnancy. It has been shown that ovarian reserve tests, such as basal FSH, antimullarian hormone (AMH), inhibin B, basal estradiol, antral follicular count (AFC), ovarian volume, ovarian vascular flow, ovarian biopsy and multivariate prediction models, have little clinical value in the prediction of a poor response. Although recent evidence points that AMH and AFC may be better than other testsbut they still continue to be used and form the basis for the exclusion of women from fertility treatments. Despite the rigorous efforts made in this regard, a test that could reliably predict poor ovarian response in all clients that undergo IVF is currently lacking. PMID- 23926511 TI - Long-term administration of artesunate induces reproductive toxicity in male rats. AB - BACKGROUND: Artesunate is commonly used in malaria therapy. Many antimalarial drugs have been associated with male reproductive dysfunction. The effect of artesunate on male reproductive activities was studied using in-vivo and in-vitro experimental models. METHODS: Adult male rats (n=6) were orally given artesunate (2.9 mg/kg body weight) on daily basis for five days. Artesunate (2.9 mg/kg body weight) was administered to another group of rats daily for six weeks, while there was a recovery group of rats too. The control animals received the vehicle only. At the end of the treatment, sperm characteristics, serum follicle stimulating hormone, luteinizing hormone and testosterone levels, testicular and epididymal histology and fertility were assessed. Cultured Sertoli cells were treated with 0.3 uM to 10 uM artesunate for five days after which Sertoli cell viability, double-stranded deoxyribonucleic acid (ds-DNA) integrity and genetic expression of Glial cell line-derived neurotrophic factor (GDNF) and transferrin were assessed. The data were analyzed using Graphpad Instat Statistical software. A probability value of p <0.05 was considered significant. RESULTS: Artesunate did not cause any significant effects in short-term administration but significantly reduced the aforesaid parameters in long-term administration. There were visible lesions in the testicular and epididymal histological studies, although fertility was not significantly reduced. These changes were restored in the recovery experiment. In-vitro studies showed dose and duration dependent changes in Sertoli cell viability and ds-DNA integrity. However, transferrin and GDNF gene expressions were normal. CONCLUSION: The results suggest that long-term administration of artesunate could induce reversible infertility in rats which may act via distortion of blood-testis barrier formed by Sertoli cells. PMID- 23926512 TI - Frequency of antisperm antibodies in infertile women. AB - BACKGROUND: Infertility is one of the common problems seen in couples of reproductive age. Presence of antisperm antibodies in semen and serum are amongst the causes of immunoinfertility. This study was performed to determine antisperm antibodies in cervicovaginal secretions and serum of infertile women and also measure serum levels of immunoglobulins (IgG, IgM and IgA). METHODS: The study consisted of 45 infertile women consulting the Kammal El-Sammrari Hospital for infertility from 2008 to 2009 and the control group consisted of 30 fertile women. Serum levels of immunoglobulins (IgG, IgA and IgM) were measured in the participants using single radial immune diffusion. Antisperm antibodies (ASAs) were detected in the serum of both infertile and control groups using indirect immune fluorescence test. ASAs were also detected in cervicovaginal secretion using direct sperm agglutination test in both infertile and control groups. RESULTS: Antisperm antibodies were found in the cervicovaginal secretions (62.2%) and sera (64.4%) of infertile women which were significantly higher (p <0.001) than those of the control group (3.3% and 3.3% respectively). There was a significant increase (p <0.001) in serum levels of IgG and IgA of infertile women (16.2 and 3.25 g/L respectively) compared with the healthy control group (7 and 1.2 g/L). CONCLUSION: Humoral immune response and antisperm antibodies may contribute to reproductive failure in couples of reproductive age. PMID- 23926513 TI - Idiopathic recurrent pregnancy loss: role of paternal factors; a pilot study. AB - BACKGROUND: This case-control study was designed with the aim of evaluating the role of sperm, oxidative stress and DNA damage in idiopathic recurrent pregnancy loss (iRPL). This pilot study is the first study done on the Indian population which reports the association between DFI, TAC and ROS in couples experiencing iRSA. METHODS: Twenty infertile men with a history of iRPL and 20 fertile controls (having fathered a child a year earlier) were included in the study which was performed in Laboratory for Molecular Reproduction and Genetics, India, from March 2010 to July 2011. The female partners of the participants were normal on gynaecological examination and had normal endocrine and blood profiles. Conventional semen analysis was performed (concentration, motility, morphology; WHO criteria, 2010) within 1 hour of sample collection. Levels of reactive oxygen species (ROS) were assessed by luminol-dependant chemiluminescence. The total antioxidant capacity (TAC) was quantified by ELISA. The Sperm chromatin structure assay (SCSA) was performed by flow cytometry to determine DNA fragmentation Index (DFI). Statistical analysis was performed using SPSS version 15 and parameters were compared by Mann-Whitney test. Pearson correlation test was used to find the correlation between parameters and a p-value <0.05 was considered significant. Receiver operating characteristics (ROC) curve analysis was applied to find out the cut-off value of DNA fragmentation index. RESULTS: No significant differences in age, seminal volume, liquefaction time, pH and sperm concentration were observed between the male partner of iRPL cases and the controls, but sperm morphology and motility were significantly (p <0.05) lower in the male partner of cases with idiopathic recurrent spontaneous abortion (RSA). The mean ROS levels observed were 47427.00 relative light unit (RLU)/min/20 million sperm in the male partners as compared to 13644.57 RLU/ min/20 million sperm in the controls (normal <15000 RLU/min/20 million). The mean TAC levels in the controls (6.95 mM trolox) were significantly (p <0.05) higher as compared to the male partners of women with IRPL (2.98 mM trolox). The average mean DFI of male partners were found to be 23.37+/-9.9 and the mean DFI of controls was 13.89+/-5.40. The mean DFI was significantly (p <0.05) higher when compared to the controls. The range of DFI in male partners was 8.50-44.07. However, in the controls the range was 7.70-23.50. CONCLUSION: Sperm DNA integrity is critical for normal embryonic development and birth of healthy offspring. Oxidative stress due to the imbalance between raised free radical levels and low total antioxidant capacity is one of the critical causes of DNA damage. Thus assay of oxidative stress and sperm genomic integrity is essential in couples with iRSA following natural and spontaneous conception. PMID- 23926514 TI - The role of cervical cerclage in pregnancy outcome in women with uterine anomaly. AB - BACKGROUND: Congenital uterine malformations are the result of disturbances in mullerian duct development. In patients with recurrent miscarriage, the reported frequency of uterine anomalies varies widely, from 1.8% to 37.6%. There are reports in which cervical cerclage has been shown to prevent preterm labor in uterine anomalies. The aim of this study was to compare the role of cervical cerclage in the pregnancy outcome of women with uterine anomaly. METHODS: In this historical cohort study, 40 pregnant women with uterine anomaly were investigated for outcomes of pregnancy in regards to preterm and term deliveries. The participants were divided into two groups: the case group included 26 women with uterine anomaly for whom cervical cerclage was done and the control group was composed of 14 women with uterine anomaly in whom cervical cerclage was not performed. Comparison between the two groups was done and the data were analyzed by the use of chi square, Fisher's exact test and t-test with SPSS software (version 11) and p <0.05 was considered significant. RESULTS: In patients with bicornuate uterus and cervical cerclage, term delivery occurred in 76.2% and preterm delivery in 23.8%. In patients with bicornuate uterus and without cervical cerclage, term delivery occurred in 27.3% and preterm delivery in 72.7% (p <0.05). In patients with arcuate uterus and cervical cerclage, term and preterm deliveries were equal (50% vs. 50%), but in patients with arcuate uterus and without cervical cerclage, term and preterm deliveries occurred in 66.6% and 33.3% of the participants, respectively. CONCLUSION: Cervical cerclage is an effective procedure in bicornuate uterus for the prevention of preterm deliveries but it has no effect on the outcome of pregnancy in arcuate uterus. PMID- 23926515 TI - Married Iranian Women's Knowledge, Attitude and Sense of Self-efficacy about Oral Contraceptives: Focus Group Discussion. AB - BACKGROUND: Oral contraceptive pills effectiveness is lower in actual use than in clinical trials. The views of a group of married Iranian women were sought as a step toward improving the enhanced use of contraceptive pills. METHODS: Two focus groups of current pill users (n=13) and two focus groups of women not currently taking the pills (n=14) were held. Leaders trained facilitators; themes were identified from line-by-line analysis of transcripts. RESULTS: The majority of the participants were primary school graduates with a mean age of 34 years. Knowledge about mechanisms of action was low; some women wanted more information. Both users and non-users recognized positive and negative characteristics of contraceptive pills. For non-users, physical and emotional side-effects were the most important; and anecdotal information from their social network was more important. They tended to trust more traditional methods. For users, their own experience and more reality-based understanding of side-effects mitigated concerns about side-effects. They also felt that health clinic staff had a negative attitude toward the pills. A stronger expression of self-efficacy seemed to be associated with more positive attitudes toward oral contraceptive pills. CONCLUSION: Although Iran has had a government-funded family planning program since 1990, and pills are the single most popular modern contraceptive method, women who take OCPs can provide important information that could increase effective health education about their use. PMID- 23926516 TI - Specialists' Attitude toward Appropriate Number of Transferable Embryos in Assisted Reproductive Technology in Iran. AB - BACKGROUND: In recent years, the high likelihood of the implantation of transferred embryos has led to an increase in the number of multiple pregnancies and consequently an increased risk of complications in fetuses and mothers. Since the aim of infertility treatment is the birth of a healthy child while preserving the mother's health, therefore, attempts should be made to avoid multiple pregnancies as much as possible besides maintaining the women's chance of pregnancy by transferring an appropriate number of embryos. METHODS: The population under study consisted of specialists (gynecologists and embryologists) who worked in ART clinics across the country and had attended an infertility congress in Tehran in 2008. The devised questionnaire enquired about the infertility specialists' attitude towards the appropriate number of transferable embryos. The questions were designed on a Likert scale of strongly agree, agree, indifferent, disagree and strongly disagree. The scores of the questionnaire ranged from 0-60 which were later scaled up to 100 for ease of data analysis. Accordingly, scores below 50 were considered as "negative", 50-75 "moderate" and greater than 75 as "positive". RESULTS: Overall, 9.9% of the specialists gained a score less than 50 (negative view), 67.3% between 50-75 (moderate) and 22.8% greater than 75 (positive view). CONCLUSION: The infertility specialists in Iran are relatively reluctant to transfer a high number of embryos for infertility treatments. PMID- 23926517 TI - Study of body image in fertile and infertile men. AB - BACKGROUND: Body Image as a multidimensional entity is related to both physical and psychological aspects of the image one has of his or her own body. Lack/absence of an acceptable body image is one of the reasons of mental distress in infertile individuals. METHODS: In this study, an equal number (No=120) of fertile and infertile men attending Avicenna Infertility Clinic (AIC) were enrolled. The participants were compared in regard to body image variables based on the "Multidimensional Body-Self Relations Questionnaire (MBSRQ)" consisting of 10 subscales. Data was analyzed by SPSS, version 11.5, using Chi square and independent t-tests. RESULTS: Fertile men had a more positive body image as compared to infertile individuals. Significant statistical differences were observed when body image subscales were compared in both groups; in other words appearance evaluation, appearance orientation, Novy, health evaluation, health orientation, illness orientation, body satisfaction, overweight preoccupation and self-classified weight showed differences, while no significant difference was observed in regard to fitness orientation. CONCLUSION: It seems that the ability and efficiency of body image is affected by infertility leading to dissatisfaction of one's body image. PMID- 23926518 TI - Present and Prospective Diagnostic and Therapeutic Options for Repeated IVF Failures. PMID- 23926519 TI - Effects of pharmaceutical medications on male fertility. AB - The number of couples seeking consultation for infertility problems has steadily increased over the past decade, affecting 10%-15% of the sexually active population. Abnormal semen production, a male factor infertility (MFI), is thought to be the cause of up to 50% of all infertilities in developed countries. There are potentially many different causes of male infertility, including hormonal, anatomical, and secondary to exposure to exogenous substances. In many cases of MFI, a definitive cause for abnormalities is never identified. Recently, the research community has given greater attention to identifying causes of MFI ranging from genetic Y chromosome microdeletions to mechanisms of environmental damage on sperm production. Still evolving, is a clear understanding of how many pharmaceutical medications may cause MFI, which is often treatable and reversible. In this review we will outline the data regarding various pharmaceutical medications that have been investigated as possible causes of MFI. PMID- 23926520 TI - The Effect of Macromolecule Source and Type of Media During in vitro Maturation of Sheep Oocytes on Subsequent Embryo Development. AB - BACKGROUND: Oocyte maturation and subsequent in vitro production (IVP) of embryos are affected by diverse groups of chemicals in maturation medium which are needed for successful mammalian oocyte maturation during which the dramatic cytoplasmic and nuclear reprogramming events take place. This study was designed to evaluate the effects of protein source (fetal bovine serum, FBS, and bovine serum albumin, BSA) as well as two different maturation media during in vitro maturation of ovine oocytes on subsequent embryo development. METHODS: Cumulus oocyte complexes were recovered from ovaries obtained from slaughter house and cultured for 24 hr in either TCM-199 or SOFaa maturation medium supplemented with 10% (v/v) FBS or 0.8% (w/v) BSA. Data were analyzed by one-way ANOVA using Sigma Stat (Ver. 2). A p-value smaller than 0.05 was considered statistically significant. RESULTS: The proportions of cleavage and total blastocyst (evaluated on days 3 and 6, respectively) were significantly higher in FBS than BSA supplemented groups, though no differences were observed between the two used different maturation media. The cryotolerance of blastocysts was negatively influenced by the presence of FBS rather than BSA during IVM. The quality of produced embryos, however, was affected neither by the source of macromolecules nor the maturation medium in terms of hatching rate, total blastocyst cells and inner cell mass/total cell ratio. CONCLUSION: The rate of oocyte development was improved by the presence of FBS, though the cryosurvival of resulting blastocysts was negatively influenced by the presence of the serum during in vitro production of sheep oocytes. PMID- 23926522 TI - Acute Effects of Ruta graveolens L. on Sperm Parameters and DNA Integrity in Rats. AB - BACKGROUND: Increase in world population is one of the serious and threatening issues in this century. Therefore, it is vitally important to find safe and effective contraceptive methods, especially for men which already have few choices in this regard. Medicinal plants that were used for contraception in ancient times could be good sources of investigation in this filed. Ruta graveolens L. is one the plants introduced in the Iranian traditional medicine as an oral male contraception to be used before intercourse. In this study we tried to investigate the probable effects of the plant on the spermatozoa of male rats. METHODS: Ruta graveolens L. aqueous extract (5 g/kg) was administered orally to five groups of male rats and sperm motility was checked after half, one, two, four and six hours later. Moreover, one group of rats served as the control group. Subsequently, viability of cells (Eosin-Nigrosin staining), morphological changes (Diff-Quick staining), DNA status (acridine orange dye) and serum testosterone levels were assessed in the treated groups which had significant immotile spermatozoa. For statistical analysis, Student's t-test and one-way ANOVA with Tukey's post-hoc test were employed for comparison between groups. RESULTS: A significant reduction in sperm motility was seen one hour after administration of the extract in the case groups compared to the controls (36% vs. 68.15%, respectively, p <0.01). The motility gradually increased afterwards, and by 6 hours, it was the same as the control group (65.43% and 68.15%, respectively). No significant changes were seen in viability, morphology or DNA structure of spermatozoa in each group. Testosterone levels did not show any significant changes in the treated groups when compared with the controls. CONCLUSION: Since a significant temporary immobility of spermatozoa without any adverse effects on other sperm characteristics occurred upon the administration of Ruta graveolens L. aqueous extract, it seems that this plant might have the potential to be used for the suggested male contraception. PMID- 23926521 TI - Modulation of Cx43 and Gap Junctional Intercellular Communication by Androstenedione in Rat Polycystic Ovary and Granulosa Cells in vitro. AB - BACKGROUND: Gap-junctional intercellular communication (GJIC) is implicated in physicological processes and it is vitally important for granulosa cell (GC) differentiation and oocyte growth. We investigated the expression of connexin 43 (Cx43), a gap junctional protein, in normal and androstenedione-induced polycystic ovary (PCO), the effects of androstenedione on Cx43 expression, GJIC and progesterone production in granulosa cells in vitro. METHODS: Isolated GCs from rat ovary were supplemented with FSH and dripped with EHS-matrix (EHS-drip) in culture media, were treated with physiological (10(-7) M) or pathological (10( 5) M) androstenedione concentrations to induce differentiation. Cx43 protein levels were assessed by Western blotting. Immunohistochemistry was also used to determine the localization of Cx43 in GCs and corpus luteum (CL) of controls and PCOs. Differentiation of GCs was determined by progesterone assay and Lucifer yellow dye transfer for GJIC status. The degree of significance of variations between the results was analyzed by ANOVA using SPSS (version 11.5; 2002). RESULTS: Cx43 localized in the GC layer of both the control and PCOs. Its protein levels were upregulated in PCO rat ovaries. GCs in culture with or without androstenedione had a punctate membranous distribution of Cx43. However, androstenedione increased GJIC and upregulated progesterone and Cx43 protein levels. Inhibiting GJIC by 18-alpha GA in androstenedione-treated GCs caused partial inhibition of progesterone production, suggesting a possible role of GJIC in mediating the action of androstenedione on GC differentiation. CONCLUSION: This study presented a suitable culture model for polycystic ovary syndrome and showed that Cx43 and GJIC might contribute to the pathogenesis of polycystic ovary syndrome. PMID- 23926523 TI - Correlates and Determinants of Reproductive Behavior among Female University Students in Tehran. AB - BACKGROUND: This paper aims to examine the reproductive health and behaviors which might expose young people at risks of STIs/HIV and potential correlates of such behaviors among female college students in Tehran. METHODS: This paper focuses on the study conducted on a sample of 1743 female undergraduate students in four multidisciplinary universities in Tehran during 2005- 2006 using a two stage stratified cluster sampling. The main focus was to determine the predictors of premarital heterosexual reproductive behavior among female students. RESULTS: The mean age of the unmarried students was 21.4 years. Low self-efficacy (OR=7.87, p <0.001), perceived peers' liberal attitude on virginity (OR= 4.33), perception of parents' liberal attitude towards relationship with the opposite sex and poor family atmosphere (OR=3.04 and 2.20, p <0.001, respectively) were predictors of ever having any type of sexual experience after controlling for other factors. The only predictors of penetrative sex remained in the logistic model were older age (OR=5.95), low self-efficacy (OR=10.86), poor family atmosphere (OR= 2.96), liberal parental attitude (OR=4.29) and liberal peer norms on virginity (OR= 4.90). CONCLUSION: Interventional programs need to be designed at various levels such as enhancing self-efficacy, informing families of the protective role of a balanced control and monitoring over adolescents' behavior and choices of peer network against premarital sexual activity. PMID- 23926524 TI - Effects of Vitrification on Immature and in vitro Matured, Denuded and Cumulus Compact Goat Oocytes and Their Subsequent Fertilization. AB - BACKGROUND: Vitrification has proven to be more effective than slow freezing methods to cryopreserve mammalian oocytes. The objectives of this study were to evaluate the effects of vitrification on immature and in vitro matured, denuded and cumulus compact goat oocytes and their subsequent fertilization. METHODS: Oocytes were either cryopreserved as immature cumulus compact (IMCC) (n=98 Exp 1; 102 Exp 2) and immature denuded (IMDN) (n=127 Exp 1; 109 Exp 2) or were first matured in vitro for 28 h and then cryopreserved as mature cumulus compact (MCC) (n=109 Exp 1; 89 Exp 2) or mature denuded (MDN) (n=112 Exp 1; 110 Exp 2) oocytes in four groups. The vitrification solution comprised of Dulbecco's phosphate buffered saline supplemented with 0.5% sucrose, 0.4% bovine serum albumin and 8 M propylene glycol. After 7 days of cryopreservation in liquid nitrogen, oocytes in all groups were evaluated for normal morphologic survival and in vitro maturation (Experiment 1) and fertilization in vitro using epididymal buck spermatozoa (Experiment 2). RESULTS: The number of oocytes retaining normal morphology was significantly higher (p <0.05) for cumulus compact oocytes (IMCC: 94.12% vs. IMDN: 89.22%, experiment 1 and MCC: 87.80% vs. MDN: 82.17%, experiment 2) compared to the denuded oocytes. The in vitro maturation of oocytes was highest for non-vitrified control oocytes. The maturation of vitrified IMCC oocytes was significantly higher than IMDN and their fertilizability was higher than MCC and MDN oocytes. CONCLUSION: The results suggest that immature cumulus compact goat oocytes better tolerate cryopreservation stress by vitrification in terms of fertilization rate. PMID- 23926525 TI - Placenta Accreta Causing Uterine Rupture in Second Trimester of Pregnancy after in vitro Fertilization: A Case Report. AB - BACKGROUND: Placenta accreta is a rare obstetrical condition that mainly occurs in the third trimester leading to life-threatening complications. Hereby, a case of uterine rupture due to placenta accreta occuring in the second trimester is presented. CASE PRESENTATION: A forty-year old patient who conceived after in vitro fertilization treatment (oocyte donation and embryo transfer) presented in emergency department in the nineteen weeks of gestation with acute abdominal pain, heamoperitoneum and fetal death. Emergency laprotomy showed uterine rupture along with placenta accreta for which the patient underwent subtotal hysterectomy. CONCLUSION: Although, an uncommon occurrence, physicians in assisted reproductive techniques (ART) clinics should consider placenta accreta in gravid patients who present with acute abdominal pain and shock, considering the fact that they usually have associated high risk factors for abnormal placentation. PMID- 23926526 TI - Detection of Congenital Mullerian Anomalies by Real-time 3D Sonography. PMID- 23926527 TI - Introduction of sensitive and specific biomarkers can improve infertility treatment success rates. PMID- 23926528 TI - Investigating marital relationship in infertility: a systematic review of quantitative studies. AB - BACKGROUND: Infertility is a complex issue that affects individuals and groups, and also it has serious implications for the mental and social well-being of those involved. The aim of this review was to assess marital relationship in the context of infertility, using data from infertile individuals or both couples. METHODS: A literature search was undertaken using multiple databases (Medline, PsycInfo and Scopus) to identify and synthesize all relevant literature published from 1990 to 2011. All studies in the systematic review were confirmed using specific inclusion criteria; the methodological quality of these studies were examined according to a checklist. RESULTS: Of the potential 794 articles, 18 studies were included in the final analysis, of which 6 were graded as high quality and 12 as moderate. The results indicated male factor infertility did not have a negative marital impact. In addition, infertile male participants expressed higher marital satisfaction than their wives. Infertile females had significantly less stable marital relationship compared to fertile females, which was associated with their socio-demographics and treatment experience. For infertile couples, the infertile subjects or their partners' marital relationship was affected by either member's infertility, experience specifically coping strategies. Moreover other factors such as sexual satisfaction, age of the infertile couples, education level, and congruency of couples' perceptions of infertility were associated with the quality of martial relationship. CONCLUSION: Although the review can provide an outline of marital relationship in infertility, future studies should focus on the perspective from both infertile couple, across a range of different infertility types, including extended sample sizes and longitudinal study designs. In addition, more consideration should be given to qualitative study. PMID- 23926529 TI - Lipid Peroxidation and Nitric Oxide Levels in Male Smokers' Spermatozoa and their Relation with Sperm Motility. AB - BACKGROUND: Nitric oxide (NO) is synthesized from L-arginine by a family of enzymes known as nitric oxide synthases. Low concentrations of NO is essential in biology and physiology of spermatozoa, but high amounts of NO is toxic and has negative effects on sperm functions. Moreover, sperm membrane contains high concentrations of polyunsaturated fatty acids that are highly susceptible to oxidative damage that interferes with fertilization ability. Therefore, we investigated the correlation between levels of sperm malondialdehyde (MDA) and NO with sperm motility in male smokers. METHODS: Semen samples were collected from normozoospermic smoker (n=64) and nonsmoker (n=83) men. The content of sperm lipid peroxidation was determined by measuring malondialdehyde (MDA). The sperm NO were also measured using Griess reagent. Data was analyzed by SPSS, (version 15.0), using independent t-test and Pearson analysis. RESULTS: The mean MDA and NO concentrations in the sperm of normozoospermic male smokers were significantly higher than the control group or normozoospermic nonsmokers, (p <0.001). A significant negative relationship was noted between sperm motility and sperm MDA levels (r=-0.32, p=0.01); and sperm motility and sperm NO concentration (for nitrite, r=-0.34, p=0.006 and for nitrate, r=-0.38, p=0.002). CONCLUSION: It was concluded that the increase in MDA and NO production in sperm can influence sperm motility in normozoospermic smokers. Therefore, it seems that cigarette smoking may affect the fertility of male smokers via increasing the amount of sperm MDA/lipid peroxidation and NO concentrations. PMID- 23926530 TI - Combination of thrombophilic gene polymorphisms as a cause of increased the risk of recurrent pregnancy loss. AB - BACKGROUND: Recurrent pregnancy loss is (RPL) a heterogeneous condition. While the role of acquired thrombophilia has been accepted as an etiology for RPL, the contribution of specific inherited thrombophilic gene polymorphisms to the disorder has been remained controversial. METHODS: One hundred women with a history of two or more consecutive abortions and 100 women with at least two live births and no miscarriages were included in the study and evaluated for the presence of 11 thrombophilic gene polymorphisms (Factor V LEIDEN, Factor V 4070 A/G, Factor V 5279 A/G, Factor XIII 103 G/T, Factor XIII 614 A/T, Factor XIII 1694 C/T, PAI-1 -675 4G/5G, ITGB3 1565 T/C, beta-Fibrinogen -455G/A, MTHFR 677 C/T, MTHFR 1298 A/C) using PCR-RFLP technique. The data were statistically analyzed using Mann-Whitney test and logistic regression model. RESULTS: There was no relation between factor XIII 103G/T gene polymorphism with increased risk of RPL. However, the other 10 gene polymorphisms were found to be associated with increased/decreased risk of RPL. Multiple logistic regression model for analyzing the simultaneous effects of these polymorphisms on the risk of RPL showed that six of these 11 polymorphisms (Factor V 1691G/A, Factor V 5279A/G, Factor XIII 614A/T, beta-Fibrinogen -455G/A, ITGB3 1565T/C, and MTHFR 1298A/ C) were associated with RPL. CONCLUSION: It is possible to calculate the risk of abortion in a patient with RPL by determining only six of the 10 polymorphisms that are individually associated with RPL. PMID- 23926531 TI - Body Mass Index (BMI) and Glucose Intolerance during Pregnancy in White European Women. AB - BACKGROUND: The risk of gestational diabetes mellitus (GDM) in accordance to Body Mass Index (BMI) is often based on studies where the calculation of BMI is frequently self-reported and is usually unreliable. We evaluated the risk of an abnormal oral glucose tolerance test (OGTT) in a population where BMI was measured and selective screening for GDM was practiced. METHODS: We carried out a prospective observational study where 1935 white European women with a singleton pregnancy were recruited. In the first trimester maternal height and weight were measured digitally. Statistical analysis was performed using SPSS version 15.0. BMI centiles were calculated from the study population. A Chi-square test was used to test the differences in categorical variables between the groups. A p value <0.05 was considered significant. RESULTS: In 1935 women, 547 OGTTs were performed and 70 of these were abnormal. The prevalence of an abnormal OGTT was higher in women with Class 2 and 3 obesity compared to women with Class 1 obesity (23.3% vs. 10.1%, respectively; p= 0.008). The frequency of an abnormal OGTT was higher in women with a BMI >=90th centile (>=33.1 kg/m (2) ) compared to women with a BMI between the 80th and 90th centiles (>=29.3 and <33.1 kg/mm (2) ), (21.5% vs 8.1% respectively; p = 0.005). CONCLUSION: When BMI is measured, we recommend to increase the cut-off point for selective screening of GDM to >=33.0 kg/m (2) . This may decrease unnecessary obstetric interventions and healthcare costs. PMID- 23926532 TI - Adolescent males and young females in tehran: differing perspectives, behaviors and needs for reproductive health and implications for gender sensitive interventions. AB - BACKGROUND: Despite cultural and religious prohibitions against premarital heterosexual relationships and intimacy, some recent evidence suggests some rise in premarital heterosexual interactions and relationships among young people. On the other hand, although HIV in Iran is a concentrated epidemic and mainly reported among high risk groups such as injecting drug users (IDUs), but there are evidences that the mode of transmission is shifting towards sexual contacts. This trend has caused concern among health policy makers in terms of prevention of STDs and HIV/AIDS particularly, among young people. This paper was prepared with the aim of highlighting how gender contributes to variation in reproductive health needs and conduct of young people in Iran. METHOD: This paper is based on a secondary analysis and compares comparable reproductive beliefs and conducts of women and men based on the data of two surveys conducted in Tehran in 2002 and 2005. A survey among 1385 adolescent males and another survey among 1743 female undergraduate students in four multidisciplinary universities in Tehran. Both surveys used anonymous self-administered questionnaires. To make the two samples comparable, the data of unmarried female university undergraduate students who resided in Tehran were merged with the data of adolescent male students who intended to pursue higher education. Common variables of the two surveys were identified, homogenized, merged and analysed. RESULTS: Reproductive health knowledge among male adolescents was poor compared to that of their female peers. Although premarital friendships were moderately acceptable from view points of both males and females, the majority were against premarital sex, particularly among female participants. There were evidences of gender-based double standards in perceptions of premarital sexuality among both males and females; particularly, it was stronger among males than females. Male adolescents reported earlier and greater experiences of premarital heterosexual intimacy and sexual contact than females. Multiple partners were also more common among males than females. Females had a tendency to regret first sexual contact more than males, which reflects that first sex is more likely to be unplanned and unwanted among females compared to males. CONCLUSION: Significant gender-based double standards prevailed current sexual attitudes and conduct of young people in Iran. Gender norms which encourage unmarried men to practice premarital sex lead to an earlier transition of men to sexual relations and multiple sexual partners. Due to poor knowledge and various misconceptions about sexual health and lack of consistent contraceptive and condom use among adolescents and young people in Iran, both young men and women are susceptible to sexual and reproductive health hazards such as sexually transmitted infections (STIs), HIV/AIDS, pregnancy and unsafe abortion. Changing gender norms associated with sexuality may lead to promotion of safer sexual behaviors particularly among young people. Current reproductive health and HIV prevention programs should take into account gender-based double standards among young people and their unmet reproductive health needs. PMID- 23926533 TI - Psychological distress in women with polycystic ovary syndrome from imam khomeini hospital, tehran. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex, multifaceted, heterogeneous disorder, affecting 4%-18% of reproductive-aged women and it is associated with reproductive, metabolic and psychological dysfunctions. PCOS affects quality of life and can worsen anxiety and depression either due to the features of PCOS or due to the diagnosis of a chronic disease. METHODS: In this descriptive-analytical study, 81 patients with PCOS were recruited from Vali-e Asr Reproductive Health Research Center. A questionnaire with items related to pieces of information about stress was used for data collection. Stress symptoms were assessed using the Understanding Yourself questionnaire. Statistical analyses were performed using SPSS Ver. 13.0 (SPSS Inc., Chicago, ILL, USA). The data are presented as mean+/-SD or as frequency with percentages. A p-value less than 0.05 was considered as statistically significant. RESULTS: The descriptive results showed that 8 (9.9%) participants did not have any signs of stress, 32 (39.5%) had neurotic stress, 29 (35.8%) had high and 12 (14.8%) had extremely high levels of stress. The odds of high levels of anxiety in women with hirsutism was 3.1 (95% CI, 1.00-9.59). The odds of high levels of obsession in overweight patients was 3.2 (95% CI, 1.12-9.234). The odds of high levels of worries in patients with touchy personality was 3.4 (95% CI, 1.10 - 11.19) obsession score. CONCLUSION: The present study showed that clinical signs of PCOS were most closely associated with psychological distress which has important implications in the diagnosis and treatment of disorders. PMID- 23926534 TI - Postpartum peripheral symmetrical gangrene: a case report. AB - BACKGROUND: Symmetrical peripheral gangrene is usually associated with underlying medical problems and it is seldom seen in pregnancy. Sepsis though common in a setting of delivery by unskilled midwife is rarely accompanied by symmetrical gangrene. CASE PRESENTATION: We report a case of symmetrical peripheral gangrene which occurred in the winter, triggered possibly by sepsis and a single dose of ergot. A high index of suspicion, early diagnosis and intervention with appropriate measures will result in favorable outcome in such cases. CONCLUSION: Although postpartum period is of high risk for sepsis and use of ergot alkaloids is common in labor but occurrence of peripheral symmetrical gangrene is rare. A high index of suspicion for the diagnosis and timely intervention will prevent irreparable damage and loss of limb. PMID- 23926535 TI - Low Success Rate of ART, an Illusion, a Reality or Simply a Too High Expectation? PMID- 23926536 TI - Strategies for Pituitary Down-regulation to Optimize IVF/ICSI Outcome in Poor Ovarian Responders. AB - The ovarian stimulation of poor responders still remains a challenging task for clinicians. There are numerous strategies that have been suggested to improve the outcome in poor responders but there is still no one pituitary down-regulation protocol that best suits all women with such condition. Traditional GnRH agonist flare and long luteal phase protocols do not appear to be advantageous. Reduction of GnRH agonist doses, "stop" protocols, and microdose GnRH agonist flare regimes all appear to improve outcomes, although the proportional benefit of one approach over another has not been convincingly established. GnRH antagonists improve outcomes in this patient population, although, in general, pregnancy rates appear to be lower in comparison to microdose GnRH agonist flare regimes. PMID- 23926537 TI - RHAMM Expression in the Rat Endometrium during the Estrous Cycle and following Implantation. AB - BACKGROUND: Receptor for hyaluronic acid mediated motility (RHAMM) has intracellular and extracellular functions. In this study, we focus on the expression of RHAMM in the rat uterus during estrous cycle and implantation period. METHODS: The female adult rats were divided into six groups following estrous cycle determination (n = 36). The utreri of rats were collected according to estrous cycle phases (menstruation group). For the implantation groups, uteri were obtained on D4, D5 and D6 (day of implantation) of pregnancy. The tissue samples were fixed and cut into 5 um thick sections. RHAMM was investigated using immunohisto-chemical techniques and the intensity of RHAMM was evaluated by using the H-score technique. Comparisons between groups were performed using Kruskal Wallis test. RESULTS: The RHAMM immunoreactivity of uterine antimesometrial epithelium (343.00+/-12.81), mesometrial subepithelium (285.00+/-27.26) and mesometrial stroma (270.00+/-36.00) were more prominent (p < 0.05) in the proestrus than estrus (275.00+/- 25.96; 220.00+/-14.48; 218.00+/-11.19) and diestrus (262.00+/-20.71; 192.50+/- 29.25; 216.00+/-12.97) groups, respectively. The most intense staining was seen in the epithelium on day four (275.50+/-30.06) and six (293.50+/-34.47) of pregnancy (p < 0.05). Strong RHAMM expressions were in both mature and predecidual cells on D5 (256.00+/-18.71), (247.50+/-22.14) and D6 (256.00+/-30.72), (265.00+/-14.87), respectively. RHAMM expression was prominent in the nondecidual region on D5 (270.00+/- 13.36). CONCLUSION: Considering the role of RHAMM in cell proliferation, differentiation and angiogenesis, spatiotemporal expression of RHAMM in the uterus during estrous cycle and peri-implantation period is a means through which uterus becomes receptive for developing an embryo. PMID- 23926538 TI - Antispasmodic Effects of Aqueous and Hydroalcoholic Punica granatum Flower Extracts on the Uterus of Non-pregnant Rats. AB - BACKGROUND: Punica granatum Linn. (PG) is native to the Mediterranean region. Its flower exhibited antioxidant activity. The present study attempt to investigate the effect of these extract on uterine contraction and its possible mechanism(s). METHODS: Thirty five female Wistar rats (200-300 g) at estrous phases of cycle was examined in this study; pieces of virgin adult rat uterus (1.5 cm) were suspended in an organ bath containing 10 ml of De Jalon solution at 29 degrees C. Tissue contractility was isometrically recorded. KCl (60 mM), BaCl2 (4 mM) and oxytocin (10 mU/ml) were applied to the tissue in the presence and absence of aqueous and hydroalcoholic extracts of the plant (0.05, 0.1, 0.2, 0.4 and 0.8 mg/ml). Propranolol (1 uM) and naloxane (1 uM) were added in KCl induced contractions. The results were analyzed by ANOVA and p < 0.05 were considered as significant. RESULTS: Cumulative concentration of extracts reduced uterine contractions induced by KCl dose-dependently (p < 0.01). Extracts in a dose dependent (p < 0.05) reduced uterine contractions decreased dose-dependently after of addition oxytocin. The extracts added cumulatively to the organ bath reduced contractions but they did not affect uterine contractions induced by BaCl2 except the last dose. Spasmolytic effects of the extracts were not affected by propranolol or naloxane in KCl induced contractions. CONCLUSION: Extracts diminished K(+)-induced contraction in uterus, therefore it seems that substances that decrease K(+)-induced contraction can also block voltage dependent calcium channel. The extracts did not have any effect on beta-adrenoceptors or potassium channels. PMID- 23926539 TI - The Protective Effects of Exogenous Melatonin on Nicotine-induced Changes in Mouse Ovarian Follicles. AB - BACKGROUND: Nicotine exposure causes impaired fertility and ovarian dysfunction. The aim of this study was to investigate the possible protective role of melatonin, which is known as an antioxidant agent on altered ovarian functions upon nicotine exposure. METHODS: A total of 32 female adult NMRI mice were divided randomly into four groups (n = 8). The control group received vehicle, while group 2 received nicotine (40 ug/kg) for 15 days and group 3 melatonin (10 mg/kg) for 5 days. Group 4 received both nicotine (40 ug/kg) and melatonin (10 mg/kg) for the same periods. All animals were treated intraperitoneally. After autopsy on the 16th day, histopathological and morphometrical examinations were performed and serum estradiol concentrations were measured. The data were analyzed using ANOVA and Tukey post hoc test. A value of p < 0.05 was considered significant. RESULTS: Nicotine significantly reduced the number of pre-antral and antral follicles, as well as estradiol concentration compared to the control group (p < 0.05). However, the decrease in the number of primordial follicles was not significant in the nicotine treated group. A significant increase in the atretic follicles were observed in group 2 compared to the control group (p < 0.05). Moreover, melatonin caused a marked normalization in the number of ovarian follicles and estradiol levels in group 4 compared to group 2. CONCLUSION: The results from this study suggest that melatonin may have a protective effect against nicotine-induced ovarian changes on the number of different stages of follicle growth. PMID- 23926540 TI - Derivation of Adipocytes from Human Endometrial Stem Cells (EnSCs). AB - BACKGROUND: Due to increasing clinical demand for adipose tissue, a suitable cell for reconstructive adipose tissue constructs is needed. In this study, we investigated the ability of Human Endometrial-derived stem cells (EnSCs) as a new source of mesenchymal stem cells to differentiate into adipocytes. EnSCs are the abundant and easy available source with no immunological response, for cell replacement therapy. METHODS: Single-cell suspensions of EnSCs were obtained from endometrial tissues from 10 women experiencing normal menstrual cycles, and were cultured at clonal density (10 cells/cm (2) ) or limiting dilution. Endometrial mesenchymal stem cell markers were examined flow cytometry. These cells were treated with adipogenic-inducing medium for 28 days. The adipogenic differentiation of the EnSC was assessed by cellular morphology and further confirmed by Oil Red O staining and RT-PCR. The BM-MSC differentiated into adipocytes in the presence of adipogenic stimuli for 3 weeks. RESULTS: The flow cytometric analysis showed that the cells were positive for CD90, CD105, CD146 and were negative for CD31, CD34.We showed that the key adipocytes marker PPARa was expressed in mRNA level after 28 days post treatment (PT). CONCLUSION: According to our finding, it can be concluded that EnSCs represent a useful in vitro model for human adipogenesis, and provide opportunities to study the stages prior to commitment to the adipocyte lineage. PMID- 23926541 TI - Pregnancy predictors after intrauterine insemination: analysis of 3012 cycles in 1201 couples. AB - BACKGROUND: Intrauterine insemination (IUI) is the first therapeutic step in assisted reproductive techniques and many factors, including male and female infertility and technique-dependent factors, have been reported to influence pregnancy rates after IUI. METHODS: We carried out this retrospective study on 1201 couples undergoing 3012 intrauterine insemination cycles during 2002 to 2009. Pregnancy rate per cycle in terms of female infertility factors, male infertility factors, and technique-dependent factors were evaluated. The chi (2) , t-test, Kaplan-meier method, and multiple logistics regression model, were used for data analysis. The p < 0.05 was considered statistically significant. RESULTS: The highest pregnancy rates were obtained in cases whose infertility duration was shorter (p < 0.05), Body Mass Index (BMI) was >=25 (p < 0.05), FSH < 9 IU/L (p < 0.05), anovulation due to polycystic ovary syndrome (p < 0.05), donor sperm was used due to azoospermia (p < 0.01), three IUI cycles (p < 0.01), at least two follicles were recruited through controlled ovarian hyperstimulation (p < 0.01), and where higher total doses of FSH were administered as necessary (p < 0.05). CONCLUSION: This study characterizes predictors of pregnancy following IUI, for cases with shorter periods of infertility, BMI of 25 or more, FSH value below 9 IU/L, anovulation, donor sperm and performance of three intrauterine insemination cycles. PMID- 23926542 TI - Contraception Use among Egyptian Women: Results from Egypt Demographic and Health Survey in 2005. AB - BACKGROUND: THE REPORTS OF A RISE IN CONTRACEPTIVE PRACTICES HAVE NOT BEEN MATCHED BY A SIMILAR DECREASE IN POPULATION: therefore, there is a need to look into the causes of this discrepancy. The objectives of this study were to determine the prevalence of different methods of contraception used by Egyptian women, to compare different contraception methods used among various socio demographic groups and, finally, to identify the main decision makers of contraception use within Egyptian families. METHODS: The 2005 Egypt Demographic and Health Survey (EDHS) is a nationally representative household survey of 18134 married women aged 15-49 years. The 2005 EDHS provides a wealth of information on fertility, family planning, maternal and child health and nutrition, and violence against women. The study sample was selected using a multistage sampling technique. A face-to-face structured interview was conducted with each of the selected women. The response rate was 99.5% for completing the questionnaires. RESULTS: The prevalence of contraception was 57.5%, nearly one third of the participants (33.1%) used IUD as a method of contraception. Both male and female were responsible for decision making regarding the use of contraception among different educational levels. Most women reporting use of contraceptive methods were 30-39 years old, were employed, were rich, educated and belonged to urban governorates. CONCLUSION: More than half of the participants used contraception while IUDs and pills were the most commonly used methods. Whatever the level of education, the majority of women thought that family planning decisions should be made by both partners. PMID- 23926543 TI - Detection of Partial Deletions of Y-chromosome AZFc in Infertile Men Using the Multiplex Ligation-dependent Probe Amplification Assay. AB - BACKGROUND: In recent studies, partial deletions of the azoospermia factor c region (AZFc) on the Y-chromosome have been detected in males with infertility problems. However, there has been a lot of debate about their significance. In order to study such deletions, a simple but accurate method for their detection was applied in this study. METHODS: We present data obtained from the Multiplex Ligation-dependent Probe Amplification (MLPA) assay using a new Y-chromosome specific MLPA probemix (P360) which allows the easy detection of partial AZFc deletions. RESULTS: Partial AZFc deletions were detected in 8% of our cohort of previously mutation-negative infertile males (and 0% of the fertile control cohort). CONCLUSION: These results provide further evidence of the causality of partial AZFc deletions. None of the partial AZFc deletions were detectable by the standard multiplex PCR method, demonstrating the advantage of the MLPA method. PMID- 23926544 TI - How should we deal with the barrage of new infertility treatments and innovative technologies? PMID- 23926545 TI - Lineage and the rights of cloned child in the islamic jurisprudence. AB - Lineage in the Islamic law is one of the most basic human rights each individual inherits from his family. When modern assisted reproductive technologies appeared in recent decades, the issue of lineage and the child's rights did not encounter serious challenges. But with the advent of these technologies, the issue of the child's lineage resulting from new technologies has become the center of attention. These technologies have a large share in the field of medicine. A new technique known as cloning has entered the realm of science and technology. Considering the possibility of the widespread use of this technique, the subject of cloned child's lineage and his/her rights would be one of the major issues related to this subject. In this paper, the authors have examined the various aspects of the subject and the opinions of theologians in this regard in order to present a best solution to this issue. In fact, the fundamental concern in this paper is to figure out the relationship between the cloned child, the cell donor, the egg donor and the owner of the uterus. In this paper, after considering the concepts of the parentage and identical twins' relationship would be explored and then a detailed analysis of the parental relationship and the Shiite jurisprudence scholars' opinion on these issues would be presented. Finally, the rights of cloned children would be taken into consideration. PMID- 23926547 TI - Current Chlamydia trachomatis Infection, A Major Cause of Infertility. AB - BACKGROUND: In India, the impact of current Chlamydia trachomatis (C. trachomatis) in reproductive health remains a neglected area of investigation. The present study evaluates if current Chlamydia infection is associated with any clinical complication that needs the attention of clinical investigators. METHODS: In this cross-sectional study, we enrolled 896 women attending the Gynecology Out Patient for the detection of C. trachomatis infection. Polymerase chain reaction was used to diagnose current C. trachomatis infection and ELISA for past infections. Bacterial vaginosis, Candida and Trichomonas were screened. The results of symptomatic and asymptomatic groups were compared. The data was analyzed using Epi Info version 6 and "Z" test. A probability value of p<=0.05 was considered as significant.. RESULTS: Statistical analysis revealed significant association between current C. trachomatis infection with infertility when comparing infected fertile (18.6% vs. 9.4%, odds ratio: 2.19, p<0.0005) and uninfected infertile women (45.6% vs. 27.3%, odds ratio: 2.24, p<0.0001). Average infection rate was 12.1%, highest in women with infertility (18.6%) or with ectopic pregnancy (25%). Significant proportions of infected women with infertility (p<0.01) or with recent pregnancy (p<0.001) were asymptomatic. Follow up of infected women who became negative after treatment [28 women from infertility group and 9 women with recurrent spontaneous abortion (RSA)] revealed live birth in 8 (21.6%) women within one year, 4 with infertility and 4 with RSA. CONCLUSION: Study findings suggest association between current C. trachomatis infection and infertility. Absence of signs and symptoms associated with this infection highlights its diagnosis in women with a history of infertility and RSA for their better management, as revealed by live births with one year of follow up. PMID- 23926546 TI - Uterine artery interruption: evidence for follicular growth and histochemical and biochemical changes. AB - BACKGROUND: The present study was conducted in order to evaluate the effects of bilateral uterine artery ligation (BUAL) on the ovarian follicular fate, and alterations in carbohydrate, lipid, lipase and serum levels of F9SH, LH, prolactin, estrogen and progesterone. METHODS: Twenty-four mature female rabbits divided into two test and control-sham groups. The animals underwent ovariohystrectomy on days 23, 43 and 63 after BUAL. Later serum and tissue samples were processed for histological and bio-chemical analyses. Two-way ANOVA test was used for statistical analyses and p<0.05 was considered as significant. RESULTS: The ovaries from the case groups exhibited markedly increased atretic follicles, which were characterized by early antrum formation, ooplasmic vacoulation, granulosa cells dissociation and oocyte deformation. Lipid foci were remarkably present in the cytoplasm of oocytes, granulosa and theca cells in BUAL rabbits. Smaller sized atretic follicles showed higher lipid reactions than large ones. The PAS reaction was highly positive in zona pellucida (ZP), basement membrane, granulosa cells and follicular fluid of atretic follicles. Early atresiated follicles showed remarkable reaction sites for lipase. Significant (p<0.05) increase in serum levels of FSH, LH, progesterone, and prolactin was revealed in BUAL rabbits compared to the control group while serum levels of estrogen decreased time-dependently in the test groups. CONCLUSION: The current study suggests the critical role of the uterine artery in controlling ovulation and follicular growth. Moreover atresia processes might relate to lipid accumulation in the cells along with attenuation of lipase activity. PMID- 23926548 TI - Effects of Post-coital Administration of Alkaloids from Senna alata (Linn. Roxb) Leaves on some Fetal and Maternal Outcomes of Pregnant Rats. AB - BACKGROUND: The abortifacient claim of Senna alata (S. alata) was scientifically validated recently with alkaloids speculated to be the bioactive agent. This speculation is yet to be substantiated or refuted by scientific evidence. The present study was aimed to investigate the pregnancy terminating effects of the alkaloids from S. alata leaves. METHODS: Twenty four Pregnant rats (143.99+/-1.21 g) allocated randomly to four groups: A, B, C and D respectively received, 0.5 ml of distilled water, 250, 500 and 1000 mg/kg body weight of the S. alata extracted alkaloids orally, once daily from day 10 until day 18 post-coitum. The indices of abortifacient were evaluated at the end of the exposure period. The results were analyzed by both the analysis of variance and Duncan's multiple range test and p < 0.05 was considered as statistically significant. RESULTS: Thin-layer chromatographic separation produced five spots with Rf values of 0.28, 0.33, 0.39, 0.47 and 0.55 which gave positive reaction with Meyer's and Wagner's reagents, respectively. The number of implantation sites and corpora lutea, as well as the concentrations of FSH, LH, progesterone, weight of uterus, uterine/ body weight ratio, glucose and cholesterol decreased significantly (p < 0.05) whereas the resorption index, pre- and post-implantation losses, uterine protein content and alkaline phosphatase activity increased significantly. None of the alkaloid treated animals presented with provoked vaginal opening or bleeding except fetal deaths. The alkaloid decreased the maternal weight gain, as well as feed and water intake. CONCLUSION: Overall, the alkaloids from S. alata leaves exhibited anti-implantation, anti-gonadotropic, anti-progesteronic, embryonic resorptive, feto-maternal toxic activities but not complete abortifacient. The alkaloids alone may not be the sole abortifacient bioactive agent in the leaf extract. PMID- 23926549 TI - Experimental Testicular Torsion in a Rat Model: Effects of Treatment with Pausinystalia macroceras on Testis Functions. AB - BACKGROUND: Testicular torsion is a medical emergency with catastrophic sequelae that deserves the same treatment considerations and concerted efforts in research as any other complicated medical condition. The aim of this study was to investigate the effect of Pausinystalia macroceras (PM) bark extract on sperm quality and serum testosterone levels in testicular torsion in a rat model. METHODS: Sixty-five (65) mature male Wistar rats apportioned randomly into four experimental groups of A to C; were further divided into four subgroups according to duration of torsion. Group D were the normal regular rats. Each group/subgroup comprised five rats. Testis maintained in the torted position (T) for 1, 2, 3 and 4 hr in Group A (subgroups: AT1+PM, AT2+PM, AT3+PM, and AT4+PM). Group B (sub- groups: B1+PM, B2+PM, B3+PM, B4+PM) were sham-operated animals, which did not undergo torsion and served as the sham control group. Group C subgroups: CT1, CT2, CT3 and CT4 were torted as in A. All animals (except groups C and D) were treated by PM extract (0.1 g/kg b.w. per day) for 56 days. Group D rats were fed distilled water. Serum testosterone concentrations and sperm quality (motility and count) were measured. Analyses of variance with Scheffe's post-hoc test were carried out on the data. RESULTS: PM extract had a positive effect (significant; p < 0.5) on the sperm count and motility in rats with testicular torsion compared to those not receiving the extract. There was also an increase in serum testosterone levels in the former groups. CONCLUSION: Treatment of rats following testicular torsion result to the enhancement of sperm production in comparison with untreated rats. PMID- 23926550 TI - Effect of Pre-ovulatory Single Dose GnRH agonist Therapy on IVF Outcome in GnRH Antagonist Cycles; A Prospective Study. AB - BACKGROUND: The purpose of present study was to evaluate the role of pre ovulatory GnRH agonist therapy on IVF outcomes in GnRH antagonist cycles. METHODS: In this prospective study we recruited 100 infertile women undergoing IVF cycles with GnRH antagonists. The patients were assigned to two groups: Group A (the study group, n = 42) were assigned for receiving hCG + triptorelin for the final oocyte maturation and group B (the control group, n = 58) were assigned for only hCG. The t-test, chi-square (chi(2)), and Fisher's exact test were used for data analysis. A p < 0.05 was taken as statistically significant. The results are presented by mean+/- SD, and in percents (%). RESULTS: LH levels significantly (p < 0.001) increased in the study group on the day of oocyte retrieval. All embryological parameters including the number of mature oocytes, fertilization and cleavage rates, number of high quality embryos and number of cases whose embryos were frozen were non-significantly higher in the study group. There were small but non-significant improvements in the clinical pregnancy, ongoing pregnancy, live birth and implantation rates in the study group. CONCLUSION: Administering a single dose of GnRH agonist before oocyte retrieval in antagonist cycles may be helpful in improving the pregnancy rate but the results need to be verified in a larger trials. PMID- 23926551 TI - The effect of chronic administration of methylphenidate on morphometric parameters of testes and fertility in male mice. AB - BACKGROUND: Due to common use of methylphenidate (MPH) for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and the role of the reproductive system in the production of gametes, studying the effects of this medication on the morphometry of testes, serum testosterone concentration, leydig cells function, and fertility rate was the aim of this study. METHODS: Twenty seven male mice (Balb/C), eight weeks old, were randomly divided into one control and two treated groups. After weighing the mice, the treated groups received MPH (produced in Novartis company) at the doses of 2 mg/kg and 10 mg/kg for 40 days. The control group received only normal saline. Subsequently, after weighing the animals, the weights of testes, dimensions of the testis, and the serum testosterone concentration were measured in six mice belonging to each group. After tissue processing, the samples were stained with hematoxylin and eosin, then the leydig cells were counted. In order to assess male fertility in each group, 3 male mice were chosen and each of them was kept with three female mice in a separate cage. After 10 days, the fertility rates of the male mice were determined by counting the number of embryos in uterus and the corpora lutea in their ovaries. RESULTS: The results of this study revealed that prescription of different doses of MPH can cause a significant decrease of the body weight. It reduces the number of leydig cells, too (p<0.01). Moreover, serum testosterone concentration (67.72+/-8.24 ng/ml in control group and 0.302+/-0.416 ng/ml after treatment with 2 mg/kg/day MPH) and fertility rate (95.42%+/-4.68% in control group and 64.96%+/-18.51% after treatment with 2 mg/kg/day MPH) of the male mice declined significantly in the treated groups compared with the control group (p<0.01), but it did not cause any changes in the weight or morphometric parameters of testes. CONCLUSION: The results of this study confirmed that MPH can negatively affect serum testosterone concentration and fertility rate of the male mice by decreasing the number of leydig cells and reducing the body weight. PMID- 23926553 TI - New hopes for the treatment of primary ovarian insufficiency/premature ovarian failure. PMID- 23926552 TI - Reasons for Elective Cesarean Section amongst Pregnant Women; A Qualitative Study. AB - BACKGROUND: A qualitative study was carried out on 200 pregnant women attending obstetric offices and Imam Ali Women's Clinic in Zahedan, Iran during January 2010 to August 2011. Twenty-nine focus group discussions (FGDs) with 5-8 participants in each group were formed. The study included women in the third trimester of pregnancy with the intention or decision to undergo elective cesarean section. The women's views were explored and analyzed in group sessions. Subsequently, the responses were divided into four major categories. The majority (50%) of the opinions expressed were psychological in origin, or stemmed from low perceived behavioral control, improper subjective norms, or wrong attitudes about vaginal delivery. METHODS: Twenty-nine focus group discussions (FGDs) with 5-8 participants in each group were formed. The study included women in the third trimester of pregnancy with the intention or decision to undergo elective cesarean section. The women's views were explored and analyzed in group sessions. RESULTS: The responses were divided into four major categories. The majority (50%) of the opinions expressed were psychological in origin, or stemmed from low perceived behavioral control, improper subjective norms, or wrong attitudes about vaginal delivery. CONCLUSION: It is necessary to hold psychological skills training classes for pregnant women and their husbands to persuade them attend group discussion sessions to increase their control on perceived behavior, highlight their positive attitudes and direct them toward natural vaginal delivery. PMID- 23926554 TI - The Concepts and Consequences of Early Ovarian Ageing: A Caveat to Women's Health. AB - Apparent rise in the incidence of infertility in females and the trend shifting towards delayed child bearing brought up the concept of ovarian ageing. Women in their early thirties show poor ovarian reserve which is an entity named as early ovarian ageing. Early ovarian ageing is mostly genetically determined, but acquired modifiable factors like smoking, or ovarian surgery have some roles. Infertility and subfertility are the only clinical recognizable sequelae in the early ovarian ageing. The worrisome fact is that the outcome of assisted reproductive techniques is also not that much encouraging. Even if ovarian priming with DHEA has raised hope in the assisted reproductive techniques for these patients, but more randomized trials are needed to support this. Screening of these women with antimullerian hormone, antral follicle count and genetic analysis may be useful for recommendation at appropriate biological time regarding conception or fertility preservation. PMID- 23926555 TI - The In vitro Fertilization of Ovine Oocytes in the Presence of Oviductal Cells and its Effect on the Expression of Zygote Arrest 1 (Zar1) and Subsequent Embryonic Development. AB - BACKGROUND: The cells of mammalian female reproductive tract have been widely used for in vitro fertilization (IVF). This study was designed to study the effects of oviductal epithelial cells (OECs) and their conditioned medium during IVF on subsequent embryonic development and the relative abundance of zygote arrest 1 (Zar1) transcript in ovine zygotes. METHODS: The in vitro matured ovine oocytes were randomly fertilized in the following culture conditions: I) SOFaaBSA+20% sheep serum (control), II) SOFaa BSA+20% sheep serum (50 ul) in the presence of OECs, III) SOFaaBSA+20% sheep serum (100 ul) in the presence of OECs, and IV) OECs conditioned medium (CM). Sigma Stat (Version 2.0) software and one way ANOVA were considered for statistical analysis. A p<0.05 was considered statistically significant. RESULTS: The cleavage, blastocyst, and hatched blastocyst rates in OECs and CM groups were significantly lower than the control group (p<0.01). In co-cultured groups, the application of two different volumes of IVF medium showed no difference in embryonic developmental indices. The Zar1 gene expression in zygotes produced in the presence of OECs was significantly higher than those produced in the control and CM groups (p<0.05). CONCLUSION: Neither the presence of oviductal epithelial cells nor their conditioned medium could improve the developmental potential of ovine embryos during IVF. Moreover, no relationship was observed between the relative abundance of Zar1 transcript in zygotes produced in different conditions and the corresponding subsequent embryonic development. PMID- 23926556 TI - In vitro Culture of Human Testicular Stem Cells on Feeder-Free Condition. AB - BACKGROUND: Spermatogonial stem cells are subpopulation of spermatogonial cells in testis tissue that support beginning and maintenance of spermatogenesis. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) could be a specific marker for identification of spermatogonial stem cells including spermatogonial sperm cells (SSCs) in testis tissue and during the culture; therefore we undertook this study to culture these human testicular stem cells (hTSCs) in vitro and approved the presence of human testicular stem cells (hTSCs) by UCHL1, also known as PGP9.5. METHODS: Enzymatic digestion of human testicular biopsies was done by collagenase IV (4 mg/ml) and trypsin (0.25%). Differential plating of testicular cells in DMEM/F12 and 10% FBS was applied for 16 hr. Floating cells were collected and transferred onto laminin-coated plates with Stem-Pro 34 media supplemented with growth factors of GDNF, bFGF, EGF and LIF to support self-renewal divisions; testicular stem cell clusters were passaged every 14 days for two months. Spermatogonial cells propagation was studied through Expression of UCHL1 in testis tissue and the entire testicular stem cell culture. RESULTS: Testicular stem cell clusters from 10 patients with obstructive azoospermia were cultured on laminin-coated plates and subsequently propagated for two months. The average of harvested viable cells was approximately 89.6%. UCHL1 was expressed as specific marker in testicular stem cells entire the culture. CONCLUSION: Human testicular stem cells could be obtained from human testicular tissue by a simple digestion, culturing and propagation method for long-term in vitro conditions. Propagation of these cells approved by specific marker UCHL1, during the culture period. PMID- 23926557 TI - Correlation of the Day 3 FSH/LH Ratio and LH Concentration in Predicting IVF Outcome. AB - BACKGROUND: This study was undertaken to evaluate the role of day 3 FSH/LH ratio and day 3 LH level as predictors of IVF cycle outcomes. METHODS: This prospective observational study was undertaken in the IVF and Reproductive Biology Centre and Lok Nayak Hospital, affiliated to Maulana Azad Medical College, in New Delhi, India. The study included 105 women who underwent controlled ovarian hyperstimulation for in vitro fertilization. Characteristics of IVF cycles and outcomes were studied in patient subgroups based on day 3 FSH/LH ratio (<2 and >=2) and day 3 LH levels (>3 and <=3 mIU/ml). The student t-test, Bartlett's test, chi-squred (chi(2) ) and Fisher's exact test, and linear regression model were used for data analysis. A p-value less than 0.05 was considered as statistically significant. RESULTS: Women with an elevated FSH/LH ratio >=2 (n = 31) required higher doses of gonadotrophins (3019.34 vs. 2482.43 IU). The outcome of IVF was poor in these patients and they had fewer number of mature follicles (>16 mm) (5.44 vs. 6.09), less E2/mature follicle ratio (4.65 vs. 6.36), fewer retrieved oocytes (6.67 vs. 9.09) and fewer pregnancy rates (11.1% vs. 33.8%). On the other hand, patients with low basal LH levels (<=3 mIU/ml) did not differ significantly in terms of response to controlled ovarian hyperstimulation except for fewer number of retrieved oocytes (7.33 vs. 7.91) but there was a trend towards poor pregnancy rates (7.33 vs. 7.91) but there was a trend towards poor pregnancy rates as compared to subgroup with LH levels >3 mIU/ml. CONCLUSION: Elevated day 3 FSH/LH ratio is associated with inferior outcome in IVF treatment cycles and it could be used as an additional predictor of decreased ovarian reserve. PMID- 23926558 TI - Classical and Molecular Methods for Evaluation of Chlamydia trachomatis Infection in Women with Tubal Factor Infertility. AB - BACKGROUND: Chlamydia trachomatis is the most reported bacterial sexually transmitted disease, especially among young women worldwide. The aim of this study was comparison the prevalence of Chlamydia trachomatis infection in woman with tubal infertility by means of PCR and cell culture techniques. METHODS: Fifty-one women with confirmed TFI were enrolled in this study in (avicenna infertility Clinic) between January 2010 and January 2011. Cervical swab and cytobrush specimens were collected from each patient by gynecologists and sent to laboratory in transport media. Detection of Chlamydia trachomatis in samples was performed using PCR and bacteria culture in MacCoy cell line. The data were analyzed by Fisher's exact test and independent t-test. Statistical significance was established at a p-value <0.05. RESULTS: A significant relation was observed between increased the age of first intercourse and chlamydial infection. Six (11.7%) samples had positive PCR result, whereas cell culture results were positive in only 2 (3.9%) samples. A significant relation was also identified between the duration of infertility and infection (p < 0.05) by PCR versus cell culture method. CONCLUSION: The results showed that PCR is a rapid method, compared to cell culture for detecting Chlamydial organism. It also became clear that the age at first intercourse is important to predict the likelihood of Chlamydia trachomatis. PMID- 23926559 TI - Sexual behavior of married Iranian women, attending taleghani public health center. AB - BACKGROUND: Sexual practices as an important aspect of reproductive health have many physical and psychological effects on people's lives, there is limited evidence on such practices and their pattern among Iranian women. Hence we aimed to determine different types of sexual practices among 19-45 year old married Iranian women. METHODS: This cross-sectional study was conducted among 200 married women, aged 19-45 years, attending Taleghani Public Health Center for annual gynecologic examination during November 2008 to May 2009 using convenient sampling. The participants were enquired about their experience regarding different types of sex, as well as their views and feelings about such practices, using an anonymous questionnaire. RESULTS: The mean age of the participants was 34 years. All had ever experienced vaginal sex and 50.9% reported ever experience of other types of sex (non-vaginal), as well. Due to some stigma attached to non vaginal sexual practices among women in Iran, the feelings of women with regard to different sexual practices were also examined in this paper. CONCLUSION: This study showed that non-vaginal sex among women is considerable and because of less favourable views of women towards such practices, it seems that these practices might have psychologically impacts on women's life. Hence, counseling and educational programs designed for married men and women can include some factual information about different types of sex. PMID- 23926560 TI - The Anti-fertility Effects of Acacia nilotica in Male Wistar Rats. AB - BACKGROUND: A bulk of contraceptives on the market is women-oriented today. The aim of this study was to investigate the effect of a medicinal herb, Acacia nilotica on various parameters of male fertility using a rat model. METHODS: Male Wistar rats (n = 40) were randomly divided in to two groups. One group received Acacia nilotica, while the other acted as controls. Ten animals from each group were sacrificed after 16 weeks. Treatment was withdrawn for the remaining animals for 8 weeks. Blood was collected for hormonal analysis. The testis was removed for histological examination, while epididymal spermatozoa were retrieved for motility and morphological analysis. The data were analyzed using ANOVA and Bonferroni post hoc test. A value of p<0.05 was considered statistically significant. RESULTS: Sperm motility, progressive motility and sperm concentration significantly decreased in treated animals compared to the controls (p<0.05). Withdrawing the treatment did not restore these parameters (p<0.05). Abnormal sperm morphology significantly increased in both the treated and treatment withdrawn groups when compared to the controls (p<0.05). Testosterone concentrations were significantly lower in the treated group when compared to the controls (p<0.05) and no significant differences were observed between the controls and the treated animals when treatment was withdrawn. Histological observations showed that Acacia nilotica treatment disrupted semeniferous tubule architechture and consequently the spermatogenesis process. CONCLUSION: These results show that Acacia nilotica severely affects sperm morphology, progressive motility and sperm concentration irreversibly in Wistar rats. PMID- 23926561 TI - Incomplete cesarean scar rupture. AB - BACKGROUND: Uterine rupture at the site of a previous cesarean scar is an uncommon but catastrophic complication of pregnancy, which is associated with significant maternal and fetal morbidity and mortality. CASE PRESENTATION: A 30 year old woman at 24th week of gestation and complaint of pain, contractions and spotting was admitted in Royan Institute in Tehran, Iran. She had a past medical history of an EP and a cesarean section delivery, respectively 4 and 2 years before hospitalization. Herniation of an amniotic membrane into the maternal bladder was found on ultrasound examination. CONCLUSION: Risk factors of cesarean scar rupture should be considered in women undergoing subsequent pregnancies as they need extra care. Ultrasonography can be used to evaluate women with previous cesarean section to assess the risks of scar rupture during subsequent pregnancies. PMID- 23926562 TI - Endometriosis: a history written by aberrant hoxa10 gene expression and epidermal growth factor (EGF) system polymorphism? PMID- 23926563 TI - In vitro Human Embryo Culture; When Questions Outweigh Answers. PMID- 23926564 TI - Investigation of apelin expression in endometriosis. AB - BACKGROUND: Apelin is a mitogenic peptide; it has functions in vessel formation and cell proliferation. In this study we aimed to evaluate the serum and tissue levels and local expression pattern of apelin in eutopic and ectopic endometrium from patients with and without endometriosis and to compare the proliferative and secretory phase differences. METHODS: Thirty women with endometriosis and 15 women without endometriosis undergoing surgery for benign indications as control group were included in the study. Serum and tissue concentrations and proliferative and secretory phase expression patterns of apelin were evaluated in the ectopic and eutopic endometrium using immunoassay and immunohistochemistry methods. The results were compared with Mann-Whitney U test. The p-values smaller than 0.05 were considered as statistically significant. RESULTS: Apelin expression was detected in eutopic and ectopic endometrium of women with endometriosis and endometrium of control group. Intense immunoreactivity of apelin was observed in glandular cells of eutopic and ectopic endometrial tissues of women with endometriosis and endometrium of control group during secretory phase (p<0.01). In both groups, tissue concentrations of apelin were higher than of the serum (p=0.03) but, there were no significant differences between the two groups for tissue and serum concentrations of apelin. CONCLUSION: Apelin expression showed cyclic changes in eutopic and ectopic endometrium. Its expression may be related to menstrual changes of angiogenesis in endometrium of women. PMID- 23926565 TI - Effects of L-carnitine and Pentoxifylline on the Activity of Lactate Dehydrogenase C4 isozyme and Motility of Testicular Spermatozoa in Mice. AB - BACKGROUND: Extracted sperm from the testis have poor motility. Moreover, their motility changes during their journey through epidydimis. Meanwhile, they face high concentration of L-carnitin. In addition, lactate dehydrogenase C4 (LDH-C4) gene disorders has been shown to cause impaired sperm motility, leading to infertility in male mice. The aim of this study was to evaluate sperm motility and LDH-C4 enzyme activity upon L-carnitine (LC) and Pentoxifylline (PTX) administrations in mice. METHODS: We extracted testicular sperm of 48 mice and divided them into three equal parts. One part was incubated with Ham's F10 medium (control), the other parts were treated with Ham's F10 containing LC and PTX with a final concentration of 1.76 mM, for 30 min at room temperature. Sperm motility was assessed according to the World Health Organization (WHO) criteria. Sperm LDH C4 enzyme activity was measured by spectrophotometery method. Statistical analyses were performed using ANOVA and Fisher's LSD test, and a p-value less than 0.05 was considered as a statistically significant difference. RESULTS: Sperm motility increased after 30 min of incubation in LC- and PTX-treated group (p<0.001). LC and PTX administrations showed a significant increase in the LDHC4 enzyme activity of sperm compared to that of the controls after 30 min (P=0.04 and 0.01, respectively). CONCLUSION: The effects of LC and PTX on motility of sperm can be explained by an increase in LDH-C4 enzyme activity that may influence male fertility status. We suggest that LC as a non-toxic antioxidant is more suitable for use in assisted reproductive technique protocols than PTX. PMID- 23926566 TI - Evaluation of Interleukin-10 (G-1082A) Promoter Polymorphism in Preeclampsia. AB - BACKGROUND: Preeclampsia is a pregnancy-specific syndrome that may be life threatening, especially to the fetus. Several causes have been reported that may have a possible role in the development of the disorder. Interleukin-10 affect maternal intravascular inflammation, as well as endothelial dysfunction. The aim of this study was to investigate the association between IL-10 G-1082A polymorphism and preeclampsia. METHODS: A total of eighty-eight pregnant women with preeclampsia and 100 women with normal pregnancy attending the Gynecological unit of Government Maternity Hospital, Petlaburz, Hyderabad, India, were considered for the study. A standard amplification refractory mutation system (ARMS) PCR was carried out for genotyping IL-10 G-1082A promoter polymorphism in all the participants. Genotypic distribution of the control and patient groups were compared with values predicted by Hardy-Weinberg equilibrium using chi(2) test. Odd ratios (OR) and their respective 95% confidence intervals were used to measure the strength of association between IL-10 gene polymorphism and preeclampsia. RESULTS: The frequencies of IL-10 G-1082A genotypes, GG, GA and AA, were 17.8%, 41.09% and 41.09% in women with preeclampsia and 25%, 28% and 47% in the controls respectively. There was no significant difference in the distribution of genotypes and alleles of IL-10 G-1082A between the two groups (Test power=0.66). CONCLUSION: The present study suggests that the IL-10 G-1082A gene promoter polymorphism is not a major genetic regulator in the etiology of preeclampsia. PMID- 23926567 TI - Effects of Chlamydia trachomatis Infection on Fertility; A Case-Control Study. AB - BACKGROUND: Nowadays, Chlamydia trachomatis is known as a causative agent of infertility. Because of, asymptomatic nature of infection, many may suffer from its lasting complications such as infertility. This study was performed in Tehran during April 2007 to April 2008 to compare the prevalence of Chlamydia trachomatis infection in fertile and infertile women using ELISA and PCR methods. METHODS: Overall, 234 infertile and 223 pregnant women, as the fertile group, participated in this hospital-based case-control study. After completing an informed consent form and the questionnaire, first catch urine and blood sample were obtained for PCR and ELISA (IgG, IgM) tests, respectively. Logistic regression analysis was used to control possible confounding factors, and determine adjusted odds ratio of infertility due to the infection. RESULTS: PCR results revealed that 29 (12.4%) of the infertile and 19 (8.5%) of the fertile women were positive for C. trachomatis infection (p = 0.440). IgG was positive in 21 (9.0%) of the infertile and 11 (5.0%) in the fertile group (p = 0.093). IgM assays identified that 2 (0.9%) of the infertile and 4 (1.8%) of the fertile women were positive for the micro-organism (p = 0.375). CONCLUSION: We found no significant differences among fertile and infertile women for Chlamydia trachomatis infection. Nevertheless, molecular techniques which are more sensitive, more specific and non-invasive can be used to detect C. trachomatis infection. PMID- 23926568 TI - Effects of Varicocelectomy on Anti-sperm Antibody in Patients with Varicocele. AB - BACKGROUND: Anti-sperm antibody (ASA) can decrease sperm motility and, therefore, it is a cause of male infertility. The aim of this study was to evaluate the effects of varicocelectomy on anti-sperm antibody in patients with varicocele. METHODS: This observational study was conducted on 90 patients with varicocele at Sina and Imam Khomeini hospitals during 2006 to 2009. All varicocelectomy candidates were selected for ASA assessment both in semen and serum before and after surgery. ASA level was measured using a direct method for semen and an indirect method of Sperm MAR test, for serum. Paired t-test and McNemar's test were used for data analysis, and p<0.05 was considered statistically significant. RESULTS: ASA level in semen was 13.7% before, and 15.7% after three month of varicocelectomy (p=0.881). Serum level of ASA before and after surgery were 13.6% and 21.7%, respectively (p=0.033). Three parameters including sperm count, motility and morphology showed recovery following, varicocelectomy, but only the difference in sperm motility was significant (p<0.05). CONCLUSION: This study showed that varicocelectomy has no effect on semen ASA. Although serum antibody has been shown to increase after varicocelectomy but sperm motility will improve. Varicocelectomy seems to have a beneficial effect on semen parameters in infertile men with varicocele. PMID- 23926569 TI - Using Fresh and Frozen Testicular Sperm Samples in Couples Undergoing ICSI MicroTESE Treatment. AB - BACKGROUND: We performed this study to evaluate use of fresh and frozen sperm samples in non-obstructive azoospermia microdissection testicular sperm extraction (micro-TESE-ICSI) treatment. METHODS: We performed a total of 82 consecutive in vitro fertilization (IVF) cycles at Fertijin IVF Center in Istanbul, Turkey from January 2010 to March 2012. In 43 participants we used fresh sperm and frozen sperm in the remaining 39 cases. We used fresh and frozen thawed micro surgical testicular sperm extraction (micro TESE) sperm for ICSI with metaphase II (MII) oocytes. RESULTS: Frozen microTESE sperm was used in 39 cycles, while 43 ICSI cycles were performed using fresh microTESE. Neither the age of male partners (38.33+/-5.93 and 38.13+/-8.28) nor that of the female participants (33.16+/-6.38 and 33.33+/-6.97) showed significant difference between fresh versus the microTESE and frozen treatment groups, respectively. FSH concentrations were (14.66+/-13.93 mIU/ml) in fresh TESE group and (17.91+/-16.29 mIU/ml) in frozen group with no correlations or differences between the two groups. The average number of mature oocytes injected with sperm was 9.23+/-3.77, versus 9.26+/-5.26 in cycles using fresh and frozen microTESE sperm, respectively. Fertilization rate was not significantly different in the fresh microTESE (44.79%) than frozen TESE sperm group (46.76%). The average number of transferred embryos was 1.60+/-0.49 in fresh sperm group and 1.59+/-0.50 in frozen sperm group. All embryo transfers were performed on day 3. CONCLUSION: Cryopreservation of testicular sperm tissues is more suitable and of great benefite if carried out before ovulation induction and not after, especially in cases with non-obstructive azoospermia. PMID- 23926570 TI - Sexual activity of adolescent school girls in an urban secondary school in cameroon. AB - BACKGROUND: The objective of this study was to describe the extent of sexual activity in adolescent school girls. METHODS: This was a cross-sectional study with prolective collection of data carried out at Lycee General Leclerc, Yaounde (Cameroon), from October 1 to November 30, 2011. Heterosexual coitus was considered as sexual activity. A pretested self-administered questionnaire was proposed to all consenting girl students aged 10 to 19 years. The data were analyzed using Epi Info 3.2.1 and Microsoft Excel 2007 software. RESULTS: Of the 2660 students who responded to the questionnaire, 21.3% (566) admitted being sexually active. Out of these, 64.3% (364) were aged between 10 and 16 years at their first heterosexual contact. The mean age at the first sexual intercourse was 15.3 years. Although 56.4% (319) of the sexually active respondents had only one sexual partner, 43.6% (247) of them had at least two partners. Sexual activity was occasional in 71.4% of those being sexually active. Meanwhile, 52.1% (295) of the sexually active adolescent girls used condoms during sexual intercourse, 41.5% (235) did so occasionally, and 6.4% (36) had regular unprotected sex. CONCLUSION: More than one-fifth of adolescent girls were sexually active in this study. Sexual intercourse started mostly at the age of 16 or less, and it was mostly occasional. Half of the cases had multiple sexual partners, and half were not using condoms during sexual intercourse. We, thus, recommend the implementation of interventions aimed at delaying the age of the first sexual intercourse and accessibility of condoms to students in this setting. PMID- 23926571 TI - Aspects of psychosocial development in infertile versus fertile men. AB - BACKGROUND: Infertility is one of the most difficult life experiences that a couple might encounter. Infertility as a bio-psycho-social phenomenon, could influence all aspects of life. While paying special attention to the psychological aspects of infertility in couples; many studies have investigated the non-clinical aspects of infertility, however, they rarely have evaluated the psychosocial development of infertile versus fertile men. We aimed to study the effects of infertility on psychosocial development in men. METHODS: In fact, we designed the study based on "Erikson's theory of psychosocial development". We focused on the relationship between psychosocial development and some self conceived indices. For this purpose, we divided the participants volunteers into two groups of cases (80 infertile men) and controls (40 fertile men) and asked them to complete a 112 (questions questionnaire based on "self description"). The statistical analysis was performed by SPSS (version 13) using independent t-test, Pearson correlation coefficient and analysis of covariance. A p-value <0.05 was considered significant. RESULTS: Data analysis showed significant inter and intra group differences. Infertile and fertile groups showed significant differences in trust, autonomy, generativity and integrity stages (p < 0.05). Infertile intergroup analysis represents us to higher scores in positive than negative stages. CONCLUSION: Infertility as a phenomenon had its own effects on the psychosocial development of infertile men. However, good coping skills are powerful tools to manage these myriad of feelings surrounding infertile men. PMID- 23926572 TI - Changes to DSM-5 are not as drastic as they may seem. PMID- 23926573 TI - Metabolic and body mass parameters after treatment with JNJ-37822681, a novel fast-dissociating D2 receptor antagonist, vs olanzapine in patients with schizophrenia. AB - BACKGROUND: The highly selective and fast dissociating D2 receptor antagonist JNJ 37822681 may be associated with lower risk for weight gain and undesirable metabolic effects compared with available antipsychotics. METHODS: In this double blind, randomized study, patients were randomly assigned (1:1:1:1:1) to 12 weeks of JNJ-37822681 (10 mg, 20 mg, or 30 mg, twice daily) or olanzapine (10 mg/d during week 1; 15 mg/d after week 1), or 6 weeks of placebo (followed by 6 weeks of olanzapine, 15 mg/d). Metabolic and body mass parameters were assessed at weeks 6 and 12. RESULTS: For metabolic parameters, at week 6 none of the JNJ 37822681 groups demonstrated significant change vs placebo; however, significant changes (P < .05) were observed in the olanzapine vs placebo group in triglycerides, low-density lipoprotein (LDL) and very-LDL cholesterol, and free fatty acids. For all JNJ-37822681 groups, mean weight changes at week 12 (-0.3 [10 mg], + 0.3 [20 mg], + 0.8 kg [30 mg]) were significantly less (P < .001) than for the olanzapine group (+ 2.7 kg). A higher percentage of overweight or obese patients (baseline body mass index: >=25 kg/m2) receiving olanzapine had >=7% increase in weight than those receiving JNJ-37822681 (9.8% vs 2.3%, respectively). CONCLUSIONS: JNJ-37822681 treatment was associated with a more favorable outcome on weight and metabolic adverse effects vs olanzapine for treating schizophrenia; the 10 mg twice-daily dose demonstrated minimal to no weight gain. PMID- 23926574 TI - Compulsive sexual behavior in young adults. AB - BACKGROUND: Compulsive sexual behavior (CSB) is estimated to affect 3% to 6% of adults, although limited information is available on the true prevalence and impact of CSB in young adults. This epidemiological study aims to estimate the prevalence and health correlates of CSB using a large sample of students. METHODS: The survey examined sexual behaviors and their consequences, stress and mood states, psychiatric comorbidity, and psychosocial functioning. RESULTS: The estimated prevalence of CSB was 2.0%. Compared with respondents without CSB, individuals with CSB reported more depressive and anxiety symptoms, higher levels of stress, poorer self-esteem, and higher rates of social anxiety disorder, attention-deficit/hyperactivity disorder, compulsive buying, pathological gambling, and kleptomania. CONCLUSIONS: CSB is common among young adults and is associated with symptoms of anxiety, depression, and a range of psychosocial impairments. Significant distress and diminished behavioral control suggest that CSB often may have significant associated morbidity. PMID- 23926575 TI - High rates of OCD symptom misidentification by mental health professionals. AB - BACKGROUND: More than a decade may pass between the onset of obsessive-compulsive disorder (OCD) symptoms and initiation of treatment. One explanation may be health care professionals' limited awareness of OCD symptom presentations. We assessed mental health care providers' ability to identify taboo thoughts as manifestations of OCD. METHODS: A random sample of 2,550 American Psychological Association members were asked to give diagnostic impressions based on 1 of 5 OCD vignettes: 4 about taboo thoughts and 1 about contamination obsessions. RESULTS: Three-hundred sixty (14.1%) providers completed the survey. The overall misidentification rate across all vignettes was 38.9%. Rates of incorrect (non OCD) responses were significantly higher for the taboo thoughts vignettes (obsessions about homosexuality, 77.0%; sexual obsessions about children, 42.9%; aggressive obsessions, 31.5%; and religious obsessions, 28.8%) vs the contamination obsessions vignette (15.8%). CONCLUSIONS: Mental health professionals commonly misidentify OCD symptom presentations, particularly sexual obsessions, highlighting a need for education and training. PMID- 23926576 TI - A comparison of comorbidity in body dysmorphic disorder and obsessive-compulsive disorder. AB - BACKGROUND: The aim of this study is to compare 3 groups of patients with body dysmorphic disorder (BDD), obsessive-compulsive disorder (OCD), and comorbid BDD and OCD with respect to clinical characteristics and to study their similarities and differences. METHODS: Twenty-nine patients diagnosed with BDD, 20 diagnosed with comorbid BDD/OCD and 49 diagnosed with OCD were included in the study. Patients with BDD, comorbid BDD/OCD, and OCD were compared in terms of demographic and clinical variables and scores obtained from various scales. RESULTS: Patients in the comorbid BDD/OCD and OCD groups tended to have higher anxiety scores than in BDD group. Any depressive disorder was more common in the comorbid BDD/OCD and OCD groups than in the BDD group. A significantly higher proportion of patients with BDD/OCD had any anxiety disorder than those with BDD. Subjects with BDD were significantly more likely than subjects with OCD to have narcissistic and avoidant personality disorders and any Axis II personality disorder. Finally, the rate of any cluster B personality disorder was higher in the BDD and BDD/OCD groups than in the OCD group. CONCLUSIONS: Despite the similarities between BDD and OCD, these disorders appear to have different aspects especially on psychiatric comorbidity. PMID- 23926577 TI - Advances in brain stimulation for depression. AB - BACKGROUND: Major depressive disorder is a common and debilitating psychiatric disorder that negatively impacts a large portion of the population. Although a range of antidepressant treatments have been developed, many patients are unable to obtain an adequate therapeutic response despite completing several antidepressant medication trials. As a result, neurostimulation treatment modalities have been developed as potential alternatives. This article provides an overview of advances in neurostimulation for treating depression. METHODS: We conducted a comprehensive review of the neurostimulation literature to identify recent findings involving the description and rationale, efficacy, and side effects of vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), and deep brain stimulation (DBS). RESULTS: VNS and TMS are the newest neurostimulation modalities that have been approved by the FDA for treating depression. VNS is approved for patients with treatment resistant depression (TRD), while TMS has demonstrated efficacy only for milder forms of TRD. Despite demonstrated efficacy, further research is needed to address certain limitations and/or determine how best to utilize these forms of neurostimulation. Investigational forms of neurostimulation include MST and DBS. Although MST and DBS have demonstrated promise as a depression treatment, research is still being conducted to determine and/or enhance their antidepressant properties. CONCLUSIONS: Although electroconvulsive therapy remains the primary and most effective treatment option for patients with severe TRD, there have been considerable gains in the field of neurostimulation. Many of the neurostimulation techniques described in this review represent promising treatment alternatives for patients with TRD. PMID- 23926578 TI - Computer-analyzed quantitative EEG findings in Capgras syndrome. PMID- 23926579 TI - Response to agomelatine: treatment of an obsessive skin picking episode. PMID- 23926580 TI - Stressor-related disorders in tuberous sclerosis. AB - BACKGROUND: Patients with tuberous sclerosis complex (TSC) have high rates of psychiatric comorbidity, including mood and anxiety disorders. The aim of this study is to identify patients with stressor-related disorders such as posttraumatic stress disorder (PTSD) or adjustment disorder (AD) and to describe their clinical picture in the setting of TSC. METHODS: Retrospective review of medical charts of TSC patients referred for a stressor-related disorder to a TSC psychiatric clinic. RESULTS: We identified 7 females and 2 males (3 PTSD, 6 AD), including 4 children. Two patients with severe intellectual disability presented with aggression and the remaining patients presented with avoidance. The mean duration of symptoms at the time of the study was 21 months (range: 7 to 48 months) and 7 of the 9 patients still were having trauma-related symptoms. All the patients who received an initial diagnosis of AD had their diagnosis changed to another category because their symptoms lasted >6 months. In most cases, selective serotonin reuptake inhibitors improved the symptoms. CONCLUSIONS: Stressor-related disorders in TSC frequently linger beyond 6 months and may appear with triggering events that typically are not viewed as trauma in a normal population. PMID- 23926581 TI - Complete sleep-wake cycle reversal related to ADHD detected by actigraphy. PMID- 23926582 TI - The bright and dark sides of evidence-based implantology. PMID- 23926583 TI - The adjunctive use of light-activated disinfection (LAD) with FotoSan is ineffective in the treatment of peri-implantitis: 1-year results from a multicentre pragmatic randomised controlled trial. AB - PURPOSE: To evaluate possible benefits of the adjunctive use of light-activated disinfection (LAD) in the treatment of peri-implantitis. MATERIALS AND METHODS: A total of 80 patients with at least one implant affected by peri-implantitis defined as at least 3 mm of bone loss on baseline radiographs in the presence of signs of infection (pus exudation and/or soft tissue swelling and/or soft tissue redness) were non-surgically or surgically treated for peri-implantitis and 50% of them were randomly allocated to receive an additional LAD treatment (FotoSan) according to a parallel group design at four different centres. Only one implant per patient was considered. Outcome measures were implant failures, recurrence of peri-implantitis, complications, peri-implant marginal bone level (RAD) changes, probing pocket depth (PPD) changes and number of re-treatment sessions recorded by blinded assessors. Patients were followed up for 1 year after treatment. RESULTS: Five treated patients did not fit the original inclusion criteria: 4 because they were not affected by the present definition of peri-implantitis and 1 due to being treated with antibiotics. However, they were included according to an intention-to-treat-analysis concept. Nine patients of the LAD group were treated surgically versus 10 control patients. After 1 year, 3 patients dropped out, all from the LAD group. One implant treated with the LAD therapy failed versus none of the control group. Four complications occurred: 3 in 3 patients of the LAD group and 1 in the control group. Recurrence of peri-implantitis defined as 2 mm of peri-implant bone loss or more recorded on standardised periapical radiographs was observed in 6 patients, 3 from each group. In total, 29 implants were re-treated 1 to 4 times in the LAD group versus 33 implants 1 to 4 times in the control group; the difference was not statistically significant. Peri-implant marginal bone levels remained stable up to 1 year with no statistically significant differences between groups (0.13 mm favouring LAD therapy; 95% CI of difference -0.47 to 0.72; P = 0.68). PPD significantly reduced in both groups, and at 1 year there were no significant differences between groups (difference 0.19 mm favouring LAD therapy; 95% CI of difference -0.70 to 1.07; P = 0.68). There were significant differences between centres for the number of re-treatment sessions delivered, PPD changes, plaque and marginal bleeding 1 year after treatment, but not for implant failures, complications, RAD changes and recurrence of peri-implantitis. The results did not change when removing the 5 patients who did not match the original inclusion criteria. CONCLUSIONS: Adjunctive use of LAD therapy (FotoSan) with mechanical cleaning of implants affected by peri-implantitis did not improve any clinical outcomes when compared to mechanical cleaning alone up to 1 year after treatment. PMID- 23926584 TI - Immediate loading of 2(all-on-2) versus 4 (all-on-4) implants placed with a flapless technique supporting mandibular cross-arch fixed prostheses: 1-year results from a pilot randomised controlled trial. AB - PURPOSE: To evaluate the outcome of 2 versus 4 implants placed flapless in fully edentulous mandibles and immediately restored with metal-resin screw-retained cross-arch prostheses. MATERIALS AND METHODS: Sixty patients from two different centres were randomised: 30 to the allon- 2 group and 30 to the all-on-4 group according to a parallel group design. To be immediately loaded, implants had to be inserted with a minimum torque of 40 Ncm. Outcome measures were prosthesis and implant failures, complications, and marginal bone level changes. RESULTS: Flaps were raised in 18 patients. A total of 2 implants in 2 patients did not reach the planned insertion torque and were immediately replaced by larger diameter ones. One year after loading, no drop-out or implant failure occurred. Eight biomechanical complications occurred in the all-on-2 group versus 8 complications in the all-on-4 group. There were no statistically significant differences for complications between groups. There were no statistically significant differences for marginal peri-implant bone levels between the two groups (estimate of the difference = -0.16; 95%CI -0.40 to 0.08; P (ANCOVA) = 0.074), with both groups losing a statistically significant amount of marginal bone (0.74 mm for all-on-2 implants and 0.58 mm for all-on-4 implants). There were statistically significant differences between the two centres, with more bone being lost for the Bologna centre (0.26 mm versus 1.07 mm). CONCLUSIONS: These preliminary results, up to 1 year after loading, suggest that immediately loaded mandibular cross-arch fixed prostheses can be supported by only 2 dental implants. Longer followups (approximately 10 years) are needed to properly evaluate this therapeutic option. PMID- 23926585 TI - Manual versus sonic-powered toothbrushing for plaque reduction in patients with dental implants: an explanatory randomised controlled trial. AB - PURPOSE: The aim of the present study was to investigate plaque levels following sonic-powered and manual toothbrushing in subjects with dental implants. MATERIALS AND METHODS: This study included 36 male and 47 female partially edentulous patients (age range 45-78 years, mean age 59.8 years) that were randomly assigned to one of two treatment groups: the sonic toothbrush group (n = 42; Philips Sonicare FlexCare(r) toothbrush) or the manual toothbrush group (n = 41; Oral-B P40(r)). Clinical, microbiological and immunological examinations were performed blinded at baseline and after 3, 6, 9 and 12 months. Microbiological analyses were performed by real-time polymerase chain reaction. Immunological analyses (prostaglandin E2) were performed by chromatography-electrospray spectrometry. RESULTS: The plaque index difference between baseline and 12 months at implants showed no significant difference between sonic or manual toothbrushing in a two-sided Mann-Whitney test (W = 773.5, P = 0.426, 95% CI 0.64 to 0.20). At the end of the study, there were no significant changes in plaque index, bleeding on probing, gingival index, pocket probing depth, gingival recession, clinical attachment level or the microbiological and immunological outcomes at implants or teeth in either group. CONCLUSIONS: This study uncovered no significant difference between sonic and manual toothbrushing for plaque reduction at implants and teeth. Both toothbrushes maintain healthy peri-implant soft tissue. PMID- 23926586 TI - The comparison of acellular dermal matrix allografts with free gingival grafts in the augmentation of peri-implant attached mucosa: a randomised controlled trial. AB - PURPOSE: The purpose of this randomised controlled trial is to compare the efficacy of two techniques for enhancing peri-implant keratinised mucosa: acellular dermal matrix allograft versus free gingival grafts. MATERIALS AND METHODS: Thirty-six patients having implant sites with less than 1.5 mm of keratinised mucosa width were randomly assigned to two groups. Thirty-six implants placed in 18 patients received acellular dermal matrix allografts (ADM group), while 36 implants placed in 18 individuals received free gingival grafts (FGG group). Plaque index (PI), gingival index (GI), probing depth (PD) and the width of attached mucosa (WAM) were measured at baseline and at 1, 3 and 6 months following surgery. RESULTS: WAM in the FGG group was significantly greater than the ADM group at 3 (P = 0.026) and 6 months (P < 0.001). In the FGG group, final gain of WAM was greater (1.58 mm in ADM group, 2.57 mm in FGG group) (P < 0.001) and postoperative relapse was smaller (2.68 mm in the ADM group, 1.73 mm in the FGG group) (P < 0.001). PI and GI scores were greater in the ADM group at 6 months (P = 0.016 and P = 0.61, respectively). The FGG group demonstrated a greater PD value at 3 months (P < 0.001), however there was no significant difference between the groups at 6 months (P = 0.317). CONCLUSIONS: Although ADM allografts are capable of increasing the width of peri-implant keratinised mucosa, FGGs seem to be more effective. ADM allografts may be the application of choice at implant sites in need of major grafts and in patients where a donor site should be avoided for medical or psychological reasons. PMID- 23926587 TI - 1-stage versus 2-stage lateral maxillary sinus lift procedures: 4-month post loading results of a multicenter randomised controlled trial. AB - PURPOSE: To compare the efficacy of 1-stage versus 2-stage lateral maxillary sinus lift procedures. MATERIALS AND METHODS: Sixty partially edentulous patients requiring 1 to 3 implants and having 1 to 3 mm of residual bone height and at least 5 mm of bone width below the maxillary sinus, as measured on CT scans, were randomised into two equal groups to receive either a 1-stage lateral window sinus lift with simultaneous implant placement or a 2-stage procedure with implant placement delayed by 4 months using a bone substitute in 3 different centres. Implants were submerged for 4 months and loaded with reinforced provisional prostheses, which were replaced, after 4 months, by definitive prostheses. Outcome measures were augmentation procedure failures, prosthesis failures, implant failures, complications and marginal peri-implant bone loss assessed by a blinded outcome assessor. Patients were followed up to 4 months after loading. Only data of implants placed in 1 to 3 mm of bone height were reported. RESULTS: Two patients dropped out from the 1-stage group and none from the 2-stage group. No sinus lift procedure failed in the 1-stage group but 1 failed in the 2-stage group, the difference was not statistically significant (P = 1.00). Two prostheses failed or could not be placed in the planned time in the 1-stage group and 1 in the 2-stage group, the difference was not statistically significant (P = 0.51). Three implants failed in 3 patients of the 1-stage group versus 1 implant in the 2-stage group, the difference was not statistically significant (P = 0.28). Two complications occurred in the 1-stage group and 1 in the 2-stage group, the difference was not statistically significant (P = 0.61). There were no statistically significant differences in bone loss between groups at loading (0.05 mm). Sites treated in 1 stage lost an average of 0.56 mm (SD: 0.36; 95% CI: -0.70 to -0.42; P < 0.001) of peri-implant bone and 2-stage sites approximately 0.61 mm (SD: 0.34; 95% CI: -0.74 to -0.48; P < 0.001). CONCLUSIONS: No statistically significant differences were observed between implants placed according to 1- or 2-stage sinus lift procedures. However, this study may suggest that in patients having a residual bone height between 1 and 3 mm below the maxillary sinus there might be a slightly higher risk for implant failures when performing a 1-stage lateral sinus lift procedure. PMID- 23926588 TI - A comparison of two dental implant systems in partially edentulous patients: 4 month post-loading results from a pragmatic multicentre randomised controlled trial. AB - PURPOSE: To compare the clinical effectiveness of two implant systems: Way Milano and Kentron (Geass, Pozzuolo del Friuli, UD, Italy). MATERIALS AND METHODS: A total of 64 patients requiring at least two single crowns or partial fixed dental prostheses supported by a maximum of three implants had their sites randomised according to a split-mouth design to receive both implant systems at six centres. Patients were followed up for 4 months after initial loading. Outcome measures were prosthesis/implant failures, any complication and clinician preference. RESULTS: In total, 71 Way Milano and 73 Kentron implants were placed. One patient died 45 days after placement of 2 implants, but all remaining patients were followed up to 4 months post-loading. No Way Milano implant failed whereas 3 Kentron implants failed before loading. Two complications were reported, one at each implant type. There were no statistically significant differences for prosthesis/ implant success and complications between the implant systems. Three operators preferred Way Milano implants whereas the other 3 had no preference. CONCLUSIONS: Preliminary short-term data (4 months post-loading) showed no statistically significant differences between the two implant systems, however trends were suggestive of a better clinical performance for Way Milano implants. PMID- 23926590 TI - Worldwide promotion of adhesion in dentistry - a dream? PMID- 23926589 TI - Efficacy and preference of manual toothbrushes: a randomised, single blind, controlled trial. AB - PURPOSE: Toothbrushes are manufactured in different designs but it is unclear whether these differences may lead to improvement in the removal of bacterial plaque or make the toothbrushes more appealing to users. The aim of this study is to compare the efficacy of 11 toothbrushes in terms of plaque removal and their acceptance by patients. MATERIALS AND METHODS: Eleven toothbrushes were randomly assigned to one of the 12 sectors of the mouth of 48 patients. Each patient underwent one plaque recording before and after toothbrushing. Eleven sectors of the mouth were brushed by 11 different toothbrushes, while one sector was used as a control (no toothbrushing). Two questionnaires were also administered to investigate the aesthetic and comfort preference by each participant. RESULTS: All 11 toothbrushes resulted in effective plaque reduction with respect to the control sector (P < 0.0001). No significant differences were found between them. Colgate Massager showed the highest score for aesthetic preference by the patients when compared with Butler 311 and Gum Super Tip 463 (P = 0.0148). Oral-B Indicator 35 exhibited the highest score in terms of comfort felt by the patients compared to Colgate Omni and Gum Technique 493 (P = 0.0095). CONCLUSIONS: All of the tested toothbrushes, even though different with respect to shape and scope of function, demonstrated efficacious plaque removal. PMID- 23926592 TI - Air abrasion of zirconia resin-bonded fixed dental prostheses prior to adhesive cementation: why and how? PMID- 23926593 TI - Two 2D metal-calixarene aggregates incorporating pre-designed coordination nanocages. AB - Two 2D metal-calixarene aggregates were designed and assembled by M4-TC4A (M = Fe, Co; TC4A = p-tert-butylthiacalix[4]arene) SBUs and {MCl2} units with isonicotinic acid molecules, which presents a possible way to build the extended metal-calixarene assemblies incorporating pre-designed nanocages using multifunctional linkers. PMID- 23926595 TI - Highly sensitive detection of self-aggregated single-walled carbon nanotubes using a DNA-immobilized resonator. AB - By using DNA linkers, we are able to conjugate self-crosslinked SWNTs which could be detected upon hybridization with a DNA immobilized resonator. The DNA immobilized resonator is able to detect SWNTs with a detection limit of 10 ng ml( 1) which was 2-3 orders of magnitude smaller than the reported SWNT toxicity concentration. PMID- 23926594 TI - Crosstalk between Cu(I) and Zn(II) homeostasis via Atx1 and cognate domains. AB - The copper metallochaperone Atx1 and the N-terminal metal-binding domain of a copper-transporting ATP-ase can form tight Zn(II)-mediated hetero-complexes in both cyanobacteria and humans. Copper and zinc homeostasis could be linked by metal binding to these CXXC-containing proteins. PMID- 23926596 TI - Domino Rh-catalyzed hydroformylation-double cyclization of o-amino cinnamyl derivatives: applications to the formal total syntheses of physostigmine and physovenine. AB - A parallel, versatile and efficient route to synthesis of pyrrolidinoindoline and tetrahydrofuranoindoline alkaloids from cinnamyl derivatives has been developed, featuring a domino Rh-catalyzed hydroformylation-double cyclization sequence. This method can be applied to the syntheses of anti-Alzheimer drugs such as physostigmine and physovenine. PMID- 23926597 TI - Deoxyribozyme-loaded nano-graphene oxide for simultaneous sensing and silencing of the hepatitis C virus gene in liver cells. AB - The multifunctional DNAzyme (Dz) delivery system is developed based on nano-sized graphene oxide (nGO) for simultaneous detection and knockdown of the target gene. The Dz/nGO complex system allowed convenient monitoring of HCV mRNA in living cells and silencing of the HCV gene expression by Dz-mediated catalytic cleavage concurrently. PMID- 23926598 TI - A homochiral porous metal-organic framework for enantioselective adsorption of mandelates and photocyclizaton of tropolone ethers. AB - A chiral porous metal-organic framework of an axially C2-symmetric 1,1'-biphenol ligand is constructed and can be used as a solid-state host to enanioselectively adsorb mandelates with up to 93.1% ee and to entrap achiral tropolone ethers and induce their asymmetric photocyclization with up to 98.5% ee. PMID- 23926599 TI - [Comment on "Reduction in inappropriate therapy and mortality through ICD programming"]. PMID- 23926600 TI - Summary of the 2013 American Association for Cancer Research (AACR) Annual Meeting. PMID- 23926602 TI - Prenatal sensitization of a postnatal trigger for metabolic disease. AB - Intrahepatic cholestasis of pregnancy (ICP), marked by elevated maternal serum bile acid levels, occurs in late pregnancy and is often associated with poor perinatal outcomes. In this issue of the JCI, Papacleovoulou et al. analyze the long-term consequences of ICP and find that teens born to mothers with ICP exhibit enhanced characteristics of metabolic syndrome relative to controls. The authors also used a new ICP mouse model to support and extend these findings, demonstrating that in utero exposure to bile acids induces persistent epigenetic alterations and abnormal placental lipogenesis,setting the stage for later metabolic dysfunction. PMID- 23926604 TI - Informal sector activities: Economic influences on waste management systems. PMID- 23926603 TI - Mitochondrial TCA cycle intermediates regulate body fluid and acid-base balance. AB - Intrarenal control mechanisms play an important role in the maintenance of body fluid and electrolyte balance and pH homeostasis. Recent discoveries of new ion transport and regulatory pathways in the distal nephron and collecting duct system have helped to better our understanding of these critical kidney functions and identified new potential therapeutic targets and approaches. In this issue of the JCI, Tokonami et al. report on the function of an exciting new paracrine mediator, the mitochondrial the citric acid(TCA) cycle intermediate alpha ketoglutarate (alphaKG), which via its OXGR1 receptor plays an unexpected, nontraditional role in the adaptive regulation of renal HCO(3-) secretion and salt reabsorption. PMID- 23926605 TI - How can new-age medicine be developed in a cash-strapped world? PMID- 23926606 TI - Don Poldermans MD PhD, replies to European heart journal editorial. PMID- 23926607 TI - Percutaneous implantation of a 26 mm Edwards SAPIEN-XT aortic valve prosthesis in a degenerated 30 mm mitral annuloplasty ring. PMID- 23926608 TI - [Adhesive capsulitis.Intraarticular corticosteroid: it does not reach the dose]. PMID- 23926609 TI - [Fractures of the upper extremity. "Doctor, can I drive the car with a broken arm?"]. PMID- 23926610 TI - [Chronic Achilles tendon lesion. Minimally invasive treatment with autologous semitendinosus graft]. PMID- 23926611 TI - [Osteoporotic vertebral fractures. No relevant differences between VBS and kyphoplasty in vivo]. PMID- 23926612 TI - Clinical pathologic conference case 1: Lesion presenting as a hemorrhagic mass of the alveolar ridge. PMID- 23926614 TI - Clinical pathologic conference case 3: a challenging case of an enlarging swelling of the maxilla. PMID- 23926613 TI - Clinical pathologic conference case 2: a diffuse swelling affecting soft palate and oropharynx. PMID- 23926615 TI - Clinical pathologic conference case 4: a 15-year-old boy with radiographic changes in the left mandible. PMID- 23926616 TI - Trans-Atlantic debate: External diameter for abdominal aortic aneurysm (AAA) size versus volume. PMID- 23926617 TI - Trans-Atlantic debate: External diameter for abdominal aortic aneurysm (AAA) size versus volume. PMID- 23926618 TI - A star rises, another fades. PMID- 23926619 TI - 19th annual ranking: moderate growth for providers, but rebasing, ACO participation will impact long-term picture. PMID- 23926624 TI - 10 myths about heart disease. Believing in these outdated ideas may increase your risk of a heart attack. Here's what you need to know to protect yourself. PMID- 23926625 TI - Ask the doctors. I recently felt a sudden, sharp pain in my upper back and could not imagine what caused it. Do you have any idea? I was worried it was a heart attack. PMID- 23926626 TI - Ask the doctors. I have had high blood pressure for a decade. It has been well controlled with a combination pill that contains two medications. But after I hurt my knee recently, my blood pressure went way up. What should I do? PMID- 23926627 TI - Ways to reduce your dependence on blood pressure medications. These diet and lifestyle interventions can make a big impact. PMID- 23926628 TI - Avoid these with heart medications. Interactions with common foods, beverages, vitamins, and supplements can change how your medicine works. PMID- 23926629 TI - When a drug you take comes under fire. Ask these questions to determine whether the benefits of the drug outweigh its risks. PMID- 23926630 TI - How to prepare for a safe vacation. If you have heart disease, take these precautions before you leave home. PMID- 23926631 TI - Weight gain after quitting smoking does not increase heart risk. PMID- 23926632 TI - For best results, take your medications as prescribed. PMID- 23926633 TI - Mental decline from arrhythmia. PMID- 23926635 TI - [The proceedings of the 22nd SIDUO (International Society for Diagnostic Ultrasonics in Ophthalmology) Meeting, September 6-10, 2008, Dubrovnik, Croatia]. PMID- 23926634 TI - Abstracts of the 56th Annual Meeting of the Japanese Society of Nephrology. May 10-12, 2013. Tokyo, Japan. PMID- 23926638 TI - [Perianal dermatoses]. AB - Perinatal skin disease present a frequent problem in clinical practise. Their treatment confronts different medical specialties. For the sake of modesty, it often takes a long time until patients seek medical attention. Common complaints entail a variety of differential diagnoses including infectious , primary inflammatory, allergic and neoplastic skin disease, systemic diseases, drug side effects and diseases of the ano-rectum. A systematic approach to diagnosis and treatment, with emphasis on interdisciplinary collaboration is therefore essential to achieve rapid and sustained healing. PMID- 23926639 TI - New staffing structure builds on success of specialty team model. PMID- 23926640 TI - Focus shifts to device fragments, small miscellaneous items in RSIs. PMID- 23926641 TI - OR noise levels linked with increased risk for error. PMID- 23926636 TI - Genetically Engineered Mouse Models Reveal the Importance of Proteases as Osteoarthritis Drug Targets. AB - More than two decades of research has revealed a combination of proteases that determine cartilage degradation in osteoarthritis. These include metalloproteinases, which degrade the major macromolecules in cartilage, aggrecan and type II collagen, serine proteases, and cysteine proteases, for example cathepsin K. This review summarizes the function of proteases in osteoarthritis progression, as revealed by studies of genetically engineered mouse models. A brief overview of the biochemical characteristics and features of several important proteases is provided, with the objective of increasing understanding of their function. Published data reveal at least three enzymes to be major targets for osteoarthritis drug development: ADAMTS-5, MMP-13, and cathepsin K. In surgical models of osteoarthritis, mice lacking these enzymes are protected from cartilage damage and, to varying degrees, from bone changes. In-vivo studies targeting these proteases with selective small-molecule inhibitors have been performed for a variety of animal models. Mouse models will provide opportunities for future tests of the therapeutic effect of protease inhibitors, both on progression of structural damage to the joint and on associated pain. PMID- 23926642 TI - 'Just Culture' encourages error reporting, improves patient safety. PMID- 23926643 TI - Unprocessed tray incident prompts investigation, leads to process improvements. PMID- 23926644 TI - Fewer surgical cancellations occur after preoperative screening. PMID- 23926645 TI - Can your OR documentation stand up to a RAC audit? PMID- 23926646 TI - Taking small steps to control supply costs yields a much better bottom line. PMID- 23926647 TI - Guidelines addressing preoperative assessment of geriatric patients aim to enhance outcomes. PMID- 23926648 TI - [Thyroid hormones and their precursors I. Biochemical properties]. AB - This paper and the following one (see the next issue of Acta Pharmaceutica Hungarica) survey the biological roles and the related site-specific physico chemical parameters (basicity and lipophilicity) of the presently known thyroid hormones (thyroxine, liothyronine and reverse liothyronine) and their biological precursors (monoiodotyrosine and diiodotyrosine). Here the literature of the thyroid hormone biochemistry, biosynthesis, plasma- and membrane transport is summarized, focusing on the pH-dependent processes. Biosyntheses of the thyroid hormones take place by oxidative coupling of two iodotyrosine residues catalyzed by thyreoperoxidase in thyreoglobulin. The protonation state of the precursors, especially that of the phenolic OH is crucial for the biosynthesis, since anionic iodotyrosine residues can only be coupled in the thyroid hormone biosyntheses. In the blood more than 99% of the circulating thyroid hormone is bound to plasma proteins among which the thyroxine-binding globulin and transthyretin are crucial. The amphiphilic character of the hormones is assumed to be the reason why their membrane transport is an energy-dependent, transport-mediated process, in which the organic anion transporter family, mainly OATP1C1, and the amino acid transporters, such as MCT8 play important roles. Liothyronine is the biologically active hormone; it binds the thyroid hormone receptor, a type of nuclear receptor. There are two major thyroid hormone receptor (TR) isoforms, alfa (TRalpha) and beta (TRbeta). The activation of the TRalpha is associated with modifications in cardiac behavior, while activation of the TRbeta is associated with increasing metabolic rates, resulting in weight loss and reduction of blood plasma lipid levels. The affinity of the thyroid hormones for different proteins depends on the ionization state of the ligands. The site-specific physico chemical characterization of the thyroid hormones is of fundamental importance to understand their (patho)physiological behavior and also, to influence their therapeutic properties at the molecular level. PMID- 23926649 TI - [Developing FGFR inhibitors as potential anti-cancer agents]. AB - Fibroblast Growth Factor Receptor (FGFR) family is a sequentially highly related subgroup of membrane proteins consisting of four tyrosine kinase type enzyme: FGFR1, FGFR2, FGFR3 and FGFR4. These are kinases of great interest in a wide spectrum of physiological processes such as tissue repair via controlling cell proliferation. As initiatiors of cell proliferation, in some cases they have leading roles in several types of cancer, eg. breast cancer, pancreas cancer, gastric tumors and multiple myeloma via overexpression and/or mutation. This phenomenon makes them promising targets for drug development in order to develop signal transduction therapies based on small molecule FGFR inhibitors. We have developed two main groups of lead molecules: compounds with benzotiophene and oxindole cores utilizing numerous methods from in silico modelling via in vitro biochemichal assays and testing on relevant cell lines to cytotoxicity assays. PMID- 23926650 TI - [Pharmaceutical applications of sulfobuthylether-beta-cyclodextrin]. AB - Sulfobuthylether-beta-cyclodextrin (SBECD) is a substituted derivative of a cyclic oligosaccharide containing seven glucopyranose units, which bear pH independent negative charges because of sulfonate groups. This derivative has better solubility and toxicological characteristics than the unsubstituted beta cyclodextrin, and the presence of sulfobuthyl groups opens new dimensions in the interactions acting the part of the complex formation. These create opportunities for the pharmaceutical applications of this compound. Currently six pharmaceutical preparations circulate--moiety of these circulates in Hungary also -which have a composition containing SBECD as pharmaceutical excipient. Out of the main effects of the complex-forming agent the solubility enhancement is utilized in these compositions to achieve the solution of a therapeutic dose in the case of intravascular administration. Available experimental evidences and published patents are indicative of broadening the circle of the applications in point of both technological advantages and dosage forms. PMID- 23926651 TI - Working memory impairment in pilots exposed to acute hypobaric hypoxia. AB - INTRODUCTION: During an acute hypoxia exposure, impairment of memory is one of the most frequently reported symptoms, either during hypoxia awareness training of aircrews or after an in-flight hypoxic incident. However, the effects of acute hypoxia on memory have been little studied in laboratory-controlled conditions. Moreover, none of these studies were performed in hypobaric conditions. The main aim of our study was to investigate the effects of acute hypobaric hypoxia on working memory (WM). This study also aimed to find links between physiological measurements and cognitive performance during acute hypoxia exposure. METHODS: During hypoxia awareness training, 28 subjects (experimental group) were exposed to a simulated altitude level of 10,000 m (31,000 ft) in a hypobaric chamber, while 29 subjects (control group) stayed at sea level. WM was assessed in both groups with the Paced Auditory Serial Addition Test (PASAT). Peripheral oxygen saturation (SpO2) and heart rate were recorded. RESULTS: WM was strongly impaired in the hypoxic group. One major finding is that hypoxia highly increased the mean error frequency rate. WM performance decreased linearly with hypoxemia, but SpO2 was weakly predictive of PASAT performance and vice versa. DISCUSSION: WM is impaired by acute hypobaric hypoxia. Given the importance of WM in aircraft piloting and its sensitivity to hypoxia, the PASAT, in association with SpO2 and EEG recordings, could improve both hypoxia training and our understanding of the effects of hypoxia on memory. PMID- 23926652 TI - Computational model of sustained acceleration effects on human cognitive performance. AB - INTRODUCTION: Extreme acceleration maneuvers encountered in modern agile fighter aircraft can wreak havoc on human physiology, thereby significantly influencing cognitive task performance. As oxygen content declines under acceleration stress, the activity of high order cortical tissue reduces to ensure sufficient metabolic resources are available for critical life-sustaining autonomic functions. Consequently, cognitive abilities reliant on these affected areas suffer significant performance degradations. The goal was to develop and validate a model capable of predicting human cognitive performance under acceleration stress. METHODS: Development began with creation of a proportional control cardiovascular model that produced predictions of several hemodynamic parameters, including eye-level blood pressure and regional cerebral oxygen saturation (rSo2). An algorithm was derived to relate changes in rSo2 within specific brain structures to performance on cognitive tasks that require engagement of different brain areas. Data from the "precision timing" experiment were then used to validate the model predicting cognitive performance as a function of G(z) profile. RESULTS: The following are value ranges. Results showed high agreement between the measured and predicted values for the rSo2 (correlation coefficient: 0.7483-0.8687; linear best-fit slope: 0.5760-0.9484; mean percent error: 0.75 3.33) and cognitive performance models (motion inference task--correlation coefficient: 0.7103-0.9451; linear best-fit slope: 0.7416-0.9144; mean percent error: 6.35-38.21; precision timing task--correlation coefficient: 0.6856-0.9726; linear best-fit slope: 0.5795-1.027; mean percent error: 6.30-17.28). DISCUSSION: The evidence suggests that the model is capable of accurately predicting cognitive performance of simplistic tasks under high acceleration stress. PMID- 23926653 TI - Muscle-specific substrate use during cycle exercise at 1 G: implications for astronaut muscle health. AB - INTRODUCTION: Studies of real and simulated microgravity exposure show the lower limb muscles atrophy to the greatest extent, with the calf muscles being most affected and most difficult to target with exercise countermeasures. This ground based study examined the metabolic involvement of the thigh and calf muscles during two cycle exercise protocols (moderate and high intensity) central to the exercise countermeasures program on the International Space Station. METHODS: Intramuscular glycogen and triglyceride levels were quantified in the vastus lateralis and soleus muscles before and after a moderate (current ISS prescription: 45 min at 55% VO(2max), 131 +/- 12 W) and high (proposed ISS prescription: 8 x 30-s intervals at 150% VO(2max), 459 +/- 34 W) intensity cycle exercise bout in nine individuals. RESULTS: During moderate intensity cycling, glycogen was significantly reduced in the vastus lateralis (114 +/- 27 mmol x kg( 1) dry weight) and remained unchanged in the soleus. High intensity cycling significantly reduced glycogen in both muscles, but the vastus lateralis (151 +/- 25 mmol x kg(-1) dry weight) used significantly more (-160%) than the soleus (59 +/- 11 mmol x kg(-1) dry weight). Intramuscular triglycerides were unchanged in both muscles at both intensities. DISCUSSION: These findings, coupled with other ground-based studies, provide strong support for high intensity cycling being a more appropriate component of the ISS prescription for upper and lower leg skeletal muscle health and cardiorespiratory fitness, although additional exercise paradigms that target the calf are warranted. These muscle-specific findings should be considered when designing exercise strategies for combating conditions of sarcopenia and muscle wasting on Earth. PMID- 23926654 TI - Two environmental symptoms questionnaires during 10 days of exercise-heat acclimation. AB - BACKGROUND: The purpose was to: 1) correlate and compare the long Environmental Symptoms Questionnaire (56-ESQ) with markers of heat acclimation; 2) compare the 56-ESQ with a modified version of the ESQ (14-ESQ) over a 10-d exercise heat acclimation protocol; 3) correlate both scales with physiological data; and 4) determine those questions most sensitive to heat acclimation responses to further refine the 14-ESQ. This is reported as a 12-question ESQ (12-ESQ), which was correlated with physiological data. METHODS: There were 10 non-trained, non-heat acclimatized men (age 20 +/- 1 yr; height 184 +/- 8 cm; weight 81.7 +/- 12.2 kg; percent body fat 10.1 +/- 2.9%) who undertook 10 consecutive days of heat acclimation (walking at 5.6 km x h(-1), 5% grade, 90 min duration; 33 degrees C, 30-50% relative humidity). ESQ forms were completed on days 1, 4, 7, and 10 pre- and post-exercise. During exercise, rectal temperature (T(r)), heart rate (HR), and rating of perceived exertion (RPE) were recorded. RESULTS: Verification of heat acclimation was based on T(r) and HR, which were significantly lower on day 4 (38.11 +/- 0.25 degrees C, 143 +/- 13 bpm) vs. day 1 (38.46 +/- 0.47 degrees C, 158 +/- 17 bpm) and all subsequent days. All ESQ scales demonstrated a significant effect of time, supporting evidence of heat acclimation. The 56-, 14 , and 12-ESQ post-exercise scores were significantly correlated with HR (r2 = 0.424, 0.353, and 0.430, respectively). The 12-ESQ was correlated with T(r) (r2 = 0.400). DISCUSSION: The 12- and 14-ESQ tracked well with the 56-ESQ. All ESQs were able to track physiological variables and symptoms of heat stress. All ESQ forms may be used as an efficient method to indicate environmental heat stress and symptoms. PMID- 23926655 TI - Exploring human error in military aviation flight safety events using post incident classification systems. AB - INTRODUCTION: Human error classification systems theoretically allow researchers to analyze postaccident data in an objective and consistent manner. The Human Factors Analysis and Classification System (HFACS) framework is one such practical analysis tool that has been widely used to classify human error in aviation. The Cognitive Error Taxonomy (CET) is another. It has been postulated that the focus on interrelationships within HFACS can facilitate the identification of the underlying causes of pilot error. The CET provides increased granularity at the level of unsafe acts. The aim was to analyze the influence of factors at higher organizational levels on the unsafe acts of front line operators and to compare the errors of fixed-wing and rotary-wing operations. METHOD: This study analyzed 288 aircraft incidents involving human error from an Australasian military organization occurring between 2001 and 2008. RESULTS: Action errors accounted for almost twice (44%) the proportion of rotary wing compared to fixed wing (23%) incidents. Both classificatory systems showed significant relationships between precursor factors such as the physical environment, mental and physiological states, crew resource management, training and personal readiness, and skill-based, but not decision-based, acts. The CET analysis showed different predisposing factors for different aspects of skill based behaviors. DISCUSSION: Skill-based errors in military operations are more prevalent in rotary wing incidents and are related to higher level supervisory processes in the organization. The Cognitive Error Taxonomy provides increased granularity to HFACS analyses of unsafe acts. PMID- 23926656 TI - Military aircrew eyewear survey: operational issues. AB - BACKGROUND: Army aircrew are required to operate under stressful conditions within a degraded visual environment. To gain an understanding of current eyewear mission needs, we surveyed aircrew regarding operational issues associated with the current U.S. Army-issue aircrew eyewear. METHODS: An anonymous online survey was completed by 976 U.S. Army aircrew personnel recruited through an invitational e-mail. RESULTS: Of the respondents, 34% reported wearing corrective lenses. Nearly 50% of them reported dissatisfaction with the HGU-4/P Aviator spectacles. The leading problems reported were discomfort (15%), "hot spots" around the ears (13%), and break of the earcup seal (11%). Nearly 41% of the respondents wore multifocal lenses and, of those, 16% reported that the HGU-4/P's restricted field of view (FOV) adversely affected duty performance. Of those who wore Modified HGU-4/P Apache spectacles, 79% had an unacceptable FOV with the helmet display unit. A similar number of aircrew modified the Apache eyewear to increase the FOV. In addition, wind and dust created eye discomfort or affected the vision of 46% of all respondents when performing flight duties. Over 82% expressed the need for an improved aircrew spectacles and 73% desired aviation compatible protective eyewear. DISCUSSION: The current Army HGU-4/P Aviator and the Modified HGU-4/P Apache spectacles have significant operational deficiencies and compatibility issues. Such deficiencies have led to poor wear compliance and unauthorized modification of the Army-issue Aviator eyewear, posing readiness and safety issues. The results of this survey formally identify the need for military combat eye protection that is compatible with flight systems. PMID- 23926657 TI - Influence of vision and dental occlusion on body posture in pilots. AB - INTRODUCTION: Air force pilots have great postural control, movement coordination, motor learning, and motor transformation. They undergo abnormal stresses during flight that affect their organs and systems, with consequences such as barodontalgia, bruxism, TMJ dysfunctions, and cervical pain. The aim of this study was to evaluate the influence of dental occlusion and vision on their body posture. METHODS: In collaboration with the "A. Mosso" Legal Medical Institute (Aeronautica Militare), two groups, consisting of 20 air force and 20 civilian pilots, were selected for the study using a protocol approved by the Italian Air Force. An oral examination and a force platform test were performed in order to evaluate the subjects' postural system efficiency. A MANOVA (Multivariate analysis of variance) analysis was performed by using the Wilkes' criterion, in order to statistically evaluate the influence of each factor. RESULTS: Both the sway area and velocity parameters are very strongly influenced by vision: the sway area increases by approximately 32% and the sway velocity increases by approximately 50% when the pilot closes his eyes. Only the sway area parameter was significantly influenced by the mandibular position: the mandibular position with eyes open changed the sway area by about 51% and with eyes closed by about 40%. No statistically significant differences were found between air force and civilian pilots. DISCUSSION: The results of this analysis show that occlusion and visual function could influence posture in air force and civilian pilots. PMID- 23926658 TI - Prevalence of fatigue in a group of airline pilots. AB - BACKGROUND: Fatigue is a common phenomenon in airline pilots that can impair alertness and ability of crewmembers to safely operate an aircraft and perform safety related tasks. Fatigue can increase the risk of an incident or even an accident. This study provides the first prevalence values for clinically significant fatigue in Portuguese airline pilots. The hypothesis that medium/short-haul pilots may currently present different levels of fatigue than long-haul pilots was also tested. METHODS: A survey was conducted by requesting Portuguese airline pilots to complete questionnaires placed in the pilots' personal lockers from 1 April until 15 May 2012. The questionnaire included the self-response Fatigue Severity Scale (FSS) to measure subjective fatigue and some additional questions concerning perception of fatigue by pilots. RESULTS: The prevalence values for total and mental fatigue achieved in the Portuguese airline pilots were: 89.3% (FSS > or = 4) and 94.1% (FSS > or = 4) when splitting the sample in two subsamples, long- and medium/short-haul pilots. Levels of total and mental fatigue were higher for medium/short-haul pilots. DISCUSSION: The analysis of fatigue levels in each type of aviator showed that medium/short-haul pilots presented the highest levels of total and mental fatigue. This study produced the first prevalence values of total and mental fatigue among Portuguese airline pilots, which represents a great step to understanding and addressing this critical phenomenon. PMID- 23926659 TI - Flying with a pneumothorax: a model of altitude limitations due to gas expansion. AB - BACKGROUND: Pneumothorax(PTX) is considered an absolute contraindication to flying. Guidelines for recovery time are arbitrary and fail to acknowledge that some passengers with PTX have flown without incident. One concern is pleural air expansion, causing extrinsic lung compression, increased intrathoracic pressure, and the subsequent risk of tension pneumothorax. We used a model to investigate critical endpoints resulting from PTX expansion at altitude. METHODS: Pneumothorax expansion was investigated using physiological simulation in the form of a mathematical model comprising elastic lungs, rib cage, hemidiaphragms, mediastinum, and abdomen. Compliance curves were assigned to each compartment based on published data. Cyclical muscle pressures drive normal ventilation. Initial sea-level pleural air volumes were set in the range from 10 to 60% pneumothorax. Pressures, volumes, and mediastinal shift were tracked during ascent to cruising altitude at 8000 ft (2438 m) and during cabin depressurization to 30,000 ft (9144 m). RESULTS: Pleural pressure oscillations during normal breathing became less negative during ascent. Positive pleural pressure was encountered at cabin altitude only if sea-level PTX exceeded 45%. Corresponding peak pressure gradient across the mediastinum did not exceed 5 cm H2O. CONCLUSIONS: Our results provide insight into the mechanics of pneumothorax expansion during flight. Sea-level PTX up to 45% would be tolerable in otherwise healthy persons if positive intrathoracic pressure is the dominant mechanism causing respiratory discomfort. Critical limitation in our model is more likely due to hypoxemia caused by altitude and pulmonary shunt from lung collapse. Studies of PTX tolerance to altitude should be conducted with caution. PMID- 23926660 TI - Simulated flight, muscle genetics, and inflammatory indicators in mice. AB - INTRODUCTION: Skeletal muscle discomfort commonly occurs during long-distance air travel. Although the effects of high altitude on muscle have been well-studied, the effects of short-term exposure to the altitude at which aircraft cabins are pressurized, 2438 m, have not. The primary aim of this study was to examine global gene expression in the gastrocnemius muscle after simulated flight. Inflammatory indicators were also assessed in the muscle. METHODS: Thirty-five mice were evenly exposed to normobaria or hypobaria (2438 m) for -8-9 h. Microarray and ribonucleic acid (RNA) analyses were performed. Additionally, macrophage and neutrophil presence was examined. RESULTS: Fourteen genes were downregulated in females after hypobaria. These genes included those related to epithelial homeostasis, such as the keratins, and genes activated by cellular insult. In contrast, four noncoding, regulatory RNAs were upregulated in males. No difference in proinflammatory cytokine gene and messenger RNA (mRNA) expression was detected between normobaria and hypobaria. The mean number of CD68 positive leukocytes per mm2 and mean area percentage of the CD68 antigen in muscle of normobaric (NB) and hypobaric (HB) mice were 53-54 and -0.2%, respectively. DISCUSSION: Simulated flight does not activate a proinflammatory response in healthy muscle. However, epithelial and cellular defense genes may be downregulated in females, whereas regulatory RNAs may be upregulated in males. PMID- 23926661 TI - Reaction time in pilots at sustained acceleration of +4.5 G(z). AB - INTRODUCTION: Pilots flying at very high speed are exposed to the effects of prolonged accelerations while changing their flight path. The aim of this research was to assess the impact of sustained accelerations on the visual-motor response times of pilots and the acceleration tolerance level (ATL) as a measure of pilots' endurance to applied +G(z). METHOD: The study involved 18 young pilots, 23-25 yr of age. The subjects' task was to quickly and accurately respond to the light stimuli presented on a light bar during exposure to acceleration at +4.5 G(z) and until reaching the ATL. Simple response time (SRT) measurements were performed using a visual-motor analysis system throughout the exposures, which allowed the assessment of a pilot's ATL. RESULTS: The pilots' ATL ranged from 270 to 366 s (Mean = 317.7 +/- 26.15 SD). The analysis of the SRT indicated a significant effect of duration of acceleration on the visual response time. The results of the post hoc comparisons showed that SRT increased with longer durations of the same level of +G(z) load and then decreased, reaching values similar to the controls. CONCLUSION: Exposure to prolonged acceleration of +4.5 G(z) significantly increases SRT. There was no statistically significant difference in SRT between the pilots with "short" and "long" time exposures. A pilot's SRT during a prolonged +4.5 G(z) exposure could be a reliable indicator of pilot G performance in the fast jet. Deterioration of SRT may be used to predict imminent +G(z) endurance limits between pilots with widely varying endurance abilities. PMID- 23926662 TI - Responses to sudden cold-water immersion in inexperienced swimmers following training. AB - BACKGROUND: When suddenly immersed in cold water, humans typically exhibit the cold shock response, although training can attenuate hyperventilation. This study extends previous findings by considering the influence of physical activity to maintain buoyancy and subsequent swimming performance. METHODS: Six inexperienced swimmers (three men and three women; mean age 22.8) received 1 wk of cold-water head-out immersions (10 x 3 min at 15 degrees C) alongside mental skills training to improve their treading water technique and to control hyperventilation upon immersion. Six inexperienced control swimmers (four men and two women; mean age 21.8) received immersions in temperate water (27 degrees C). Ventilation, brain blood flow velocity, and blood oxygenation were measured during a physiological test in which participants trod water for 150 s. In a subsequent simulated survival test, performance (swimming duration and distance) and perception of effort were recorded. All the tests were in 10 degrees C water with the head out. RESULTS: There were significant improvements in the intervention group's ability to suppress rapid increases in respiratory frequency; 62 +/- 24 breaths x min(-1) to 33 +/- 12. The drop in brain blood flow was smaller and more transient than that previously reported due to the hypertensive response associated with treading water. DISCUSSION: Inexperienced swimmers could benefit from cold-water habituation combined with mental skills training in order to improve voluntary control over the respiratory portion of the cold shock response as part of learning to tread water. This may improve survival prospects in a real-life emergency scenario such as an overturned boat. PMID- 23926663 TI - Ejection in hostile environments: medico-psychological aspects for the fighter pilot. AB - INTRODUCTION: In the French Air Force, commitment of fighter squadrons in Afghanistan revives the fear among pilots of being ejected in a hostile environment, along with the prospect of being captured. CLINICAL OBSERVATIONS: Although ejection in a hostile environment is an exceptional event, it is what flight crews fear most strongly over enemy territory. Since the widespread use of ejection seats in fighter aircraft in the 1950s, ejection has become a means of protecting the crews' lives. Ejection is a breaking point when the pilot suddenly passes from an intense activity to a passive position in which he (or she) is often helpless and sometimes exposed to the hostility of the environment where he lands. It is always important to analyze the circumstances surrounding an ejection. Some clinical observations allow us to understand the psycho-traumatic potential of this brutal experience. In a hostile environment, ejection quite rapidly becomes a question of survival. DISCUSSION: The pilot is technically and physically prepared during training. He (or she) regularly trains for the use of the ejection seat and the equipment to protect himself, to report, and ensure his survival until his recovery. Because it is always a singular event, on a case-by case basis, no psychological reaction to such a situation can be modeled with a view to predicting psycho-traumatic disorders. CONCLUSION: Since 2007, there has been a medico-psychological supporting device, organized by the French Air Force, to be used after this type of event. PMID- 23926664 TI - Detection of renal and urinary tract proteins before and after spaceflight. AB - BACKGROUND: The recent evolution of genomics and subsequently proteomics offers a major advance in the ability to understand individual human variation in disease and the molecular level changes induced by certain environmental exposures. This original study examines urinary proteome composition to enable the understanding of molecular homeostatic mechanisms in spaceflight and presents the potential for early detection of subclinical disease, microgravity risk mitigation strategies, and countermeasure development for exploration-class missions. METHODS: The urinary proteome composition of six Russian cosmonauts (men, ages 35-51) who flew long-duration missions of 169-199 d was determined 30 d before flight and compared to repeat studies 1 and 7 d postflight. RESULTS: There were 430 proteins identified. Of those, 15 proteins originated in the renal tissues. Of the 15 urinary proteins, 10 were consistently present in the urine. However, the presence of five of the urinary proteins--neutral endopeptidase (NEP), afamin (AFAM), aquaporin-2 (AQP2), aminopeptidase A (AMPE), and dipeptidyl peptidase 4 (DPP4)--was dependent on spaceflight exposure. DISCUSSION: Proteomic investigation of pre- and postflight urine and bioinformation approaches to proteome analysis provide important data relative the mechanism of kidney function in spaceflight. In this initial study, we determined that the evaluation of urinary proteins may help investigators understand changes that are occurring in microgravity. Once additional ground-based and in-flight data are collected, it is feasible to develop targeted studies for tracking specific spaceflight related changes, determine countermeasure and risk-mitigation effectiveness, and possibly detect subclinical disease in flight crewmembers. PMID- 23926665 TI - Petechiae: reproducible pattern of distribution and increased appearance after bed rest. AB - BACKGROUND: Exposure to acceleration can cause petechial hemorrhages, called G measles. Petechiae usually start to develop between 5 and 9 G with a high interindividual variance. Centrifuge training delays the onset to higher G levels. One might expect onset at lower G levels after bed rest; however, there is no evidence in the literature. A case of petechiae formation after bed rest is presented here. CASE REPORT: Orthostatic tolerance was tested using a tilt table and lower body negative pressure before and after bed rest in both campaigns of a 2 x 21-d bed rest study with 6 degrees head-down tilt. A 42-yr-old male Caucasian without any history of thrombosis, venous disease, hemorrhage, or petechiae, and with a negative thrombophilia screening, took part in the bed rest study as 1 out of 10 subjects. He was the only one to develop petechiae during the orthostatic tests after, but not before, bed rest in both campaigns. Petechiae were distributed throughout the lower legs and most pronounced at the shin in a stocking-like fashion, surprisingly reoccurring in an identical pattern of distribution. Petechiae appeared slowly over minutes during hyperemia. DISCUSSION: This case indicates that prolonged bed rest decreases the threshold for petechiae formation. A reproducible distribution pattern suggests that factors predisposing to petechiae formation keep their local distribution over time (possibly due to local vessel structures). Mechanisms of adaptation and interindividual variance are unclear. Findings are of clinical relevance as such cases might occur after prolonged bed rest in patients without need of expensive testing. PMID- 23926666 TI - An isolation and confinement facility for the selection of astronaut candidates. AB - BACKGROUND: In 2008, JAXA conducted its fifth astronaut candidate recruitment. The final stage involved 10 of 963 applicants undergoing the first and second examination stages based on physical checks, written tests, and interviews. The third (final) stage focused on evaluating the behavioral attitudes required for ISS crewmembers. Since it is difficult to assess these attitudes by paper testing or interview alone, JAXA has established an environment in which the assessors could observe the behavior of examinees on a continuous basis. METHODS: The 10 examinees stayed in the isolation and confinement facility for 1 wk. During their stay, several group and personal tasks were assigned along with predetermined daily schedules covering aspects of leadership, teamwork ability, productivity (performance), and so on. Subsequently, psychologists, psychiatrists, and JAXA officials/managers experienced in practical human space development evaluated them. RESULTS: During the confinement, no examinees showed any excessive character traits or psychopathologic behavior. Repeated observations led to a convergence of opinions among the experts. Three examinees ultimately passed this assessment and were assigned as new Japanese astronaut candidates. DISCUSSION: This unique assessment enabled the assessors to conduct longitudinal evaluations, evaluations based on observing detailed behavior, and easy control of test conditions and safety. Although "selection of the right stuff" may differ among each space agency, this method offers the unique advantage of allowing experts in various fields to evaluate the competencies of examinees both synthetically and longitudinally. PMID- 23926667 TI - Vasodilation associated with supplement use: potential concern for military aviators. AB - Military aviators are exposed to high G environments while performing certain tactical aircraft maneuvers. G forces endured during such maneuvering have been shown to reduce mean arterial blood pressure (MAP) at eye level by 22 mmHg for every G endured, leaving the average aviator with a resting G tolerance of approximately 5 to 5.5 G before losing consciousness. Many sports performance supplements on the market today contain compounds that are boasted to increase vascularity and reduce muscle recovery time. Usage of such supplements has demonstrated a reduction of MAP by as much as 16 mmHg after 1 h of dosing and could potentially lower one's G tolerance by 14%. Military aviators should proceed on the side of caution due to the potential threats that exist with consuming such products until a formal study can be conducted to investigate this matter further. PMID- 23926668 TI - Aviation-related light-emitting diode (LED) perception research. PMID- 23926670 TI - This month in aerospace medicine history. PMID- 23926669 TI - You're the flight surgeon: Horner's syndrome and carotid artery dissection. PMID- 23926671 TI - [UPOINT system: a new diagnostic/therapeutic algorithm for chronic prostatitis/chronic pelvic pain syndrome]. AB - Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition in urological outpatients, and is often improperly treated for its multifactorial etiology and non-specific clinical phenotype. Doctor Shoskes proposed a clinical phenotype system for CP/CPPS--the UPOINT system, which is a new diagnostic/therapeutic algorithm addressing 6 CP/CPPS phenotypic domains, including the urinary, psychosocial, organ specific, infection, neurological/systemic and muscle tenderness domains. Under the guidance of UPOINT, doctors can give a multimodal therapy for patients with CP/CPPS according to its clinical phenotype, and several clinical studies have demonstrated obvious clinical benefit from the UPOINT-based therapy. PMID- 23926672 TI - [Arsenic trioxide induces the apoptosis of prostate cancer PC-3 cells via the P38 signaling pathway]. AB - OBJECTIVE: To explore the role of the P38 signaling pathway in the apoptosis of arsenic trioxide (As2 O3)-induced androgen-independent prostate cancer PC-3 cells. METHODS: Androgen-independent prostate cancer PC-3 cells were treated with different concentrations of As2 O3 for 24, 48 and 72 hours. The inhibitory effect of As2 O3 on the cell growth was measured by MTT, the expression of p- P38 detected by Western blot, and the rate of cell apoptosis determined by Annexin V and PI double staining before and after interfering the P38 signaling pathway by SB203580, a highly selective P38 inhibitor. RESULTS: As2 O3 inhibited the proliferation of PC-3 cells in a concentration- and time-dependent manner, and quickly activated P38 phosphorylation, thus giving full play to its biological activities. After 24 hours of treatment with As2 O3 at the concentrations of 2, 10 and 20 micromol/L, the apoptosis rates of the PC-3 cells were (18.9 +/- 0.43), (24.7 +/- 0.29) and (49.7 +/- 1.79)%, respectively, which were reduced to (14.8 +/- 0.81), (22.1 +/- 0.51) and (39.6 +/- 1.74)% after interfering the P38 pathway with SB203580. Inhibition of the P38 pathway significantly reduced the apoptosis of the PC-3 cells induced by As2 O3 (P < 0.05). CONCLUSION: As2 O3 can induce the apoptosis of prostate cancer PC-3 cells by activating the P38 signaling pathway, and interfering the P38 signaling pathway can reduce their apoptosis, which suggests that the P38 signaling pathway is involved in the apoptosis of As2 O3 induced androgen-independent prostate cancer PC-3 cells. PMID- 23926673 TI - [Hypobaric hypoxia increases the expression of death receptor 5 and inhibits that of FLICE-like inhibitory protein in the rat testis]. AB - OBJECTIVE: To evaluate the effects of hypobaric hypoxia on the expressions of death receptor 5 (DR5) and cellular FLICE-like inhibitory protein (c-FLIP) and the distribution of c-FLIP in the rat testis. METHODS: Forty adult male SD rats were randomly divided into four groups of equal number: normoxia control, 3 d hypoxia, 15 d hypoxia and 30 d hypoxia. The control rats were raised at 300 m above the sea level, while the latter three groups of rats in a hypobaric chamber at a simulated altitude of 4000 m for 5, 15 and 30 days, respectively. Then the expressions of DR5 and c-FLIP were detected by immunoblotting and the distribution of c-FLIP in the testis observed by immunofluorescence. RESULTS: The expressions of DR5 were 2.04 +/- 0.11, 1.97 +/- 0.12 and 2.34 +/- 0.11 in the 3 d, 15 d and 30 d hypoxia groups, respectively, significantly higher than 1.78 +/- 0.09 in the normoxia group (P < 0.05). The expressions of c-FLIP were 0.87 +/- 0.03 and 0.74 +/- 0.07 in the 15 d and 30 d hypoxia groups, respectively, significantly lower than 1.03 +/- 0.02 in the normoxia group (P < 0.05). CONCLUSION: Simulated hypobaric hypoxia at 4000 m above the sea level increased the expression of DR5 and inhibited that of c-FLIP in the rat testis. PMID- 23926674 TI - [ICSI causes abnormal H3K9 methylation in the male pronuclei and growth retardation of mouse embryos]. AB - OBJECTIVE: To evaluate the safety of intracytoplasmic sperm injection (ICSI) in the mouse model. METHODS: We simulated clinical ICSI technology and comprehensively evaluated it by parthenogenetic activation, immunofluorescence, embryo transplantation, examination of early implantation, and measurement of the crown-rump length (CRL). RESULTS: ICSI significantly reduced the ability of preimplantation embryo development of the mouse, especially after the 8-cell stage (P < 0.01). The fluorescence of H3K9 dimethylation was abnormal at the male pronuclei of the embryos derived from ICSI. Further examination of the development of the transferred ICSI embryos indicated no significant difference in the rate of early implantation at E5. 5 days as compared with normal fertilization (P = 0.6), but the percentage of "normal embryos" was decreased significantly at E9.5 days (P < 0.01). Obvious growth retardation phenotype was observed even in the normal ICSI embryos at E9.5 days. CONCLUSION: ICSI might result in growth retardation of embryos by affecting H3K9 dimethylation in the male pronuclei. PMID- 23926675 TI - [Expressions of cystathionine-beta-synthase and cystathionine-gamma-lyase in the corpus cavernosum smooth muscle of castrated rats]. AB - OBJECTIVE: To study the expressions of cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) in the corpus cavernosum smooth muscle of castrated rats and their roles in erectile dysfunction after castration. METHODS: We randomly assigned 40 eight-week-old male SD rats to groups A (2-week sham operation), B (4-week sham-operation), C (2-week castration) and D (4-week castration). We determined the level of serum testosterone (T) and the expressions of CBS and CSE in the corpus cavernosum smooth muscle of the rats after operation using immunohistochemistry and RT-PCR. RESULTS: The T level was significantly decreased in groups C ([11.85 +/- 6.73] nmol/L) and D ([1.96 +/- 1.23] nmol/L) as compared with A ([89.65 +/- 17.13] nmol/L) and B ([106.75 +/- 19.68] nmol/L) (P < 0.05). CBS and CSE were expressed in all groups of rats, but the relative expressions of CBS and CSE mRNA were significantly lower in groups C (0.93 +/- 0.14 and 0.87 +/- 0.20) and D (0.79 +/- 0.17 and 0.71 +/- 0.12) than in A (2.13 +/- 0.65 and 1.93 +/- 0.15) and B (2.07 +/- 0.53 and 1.89 +/- 0.45) (P < 0. 05), so were the optical density values (IA) of the CBS and CSE proteins, 130.35 +/- 23.56 and 93.56 +/- 36.64 in group C and 80.29 +/- 29.65 and 58.56 +/- 19.95 in group D, as compared with 310.57 +/- 130.56 and 269.56 +/- 116.76 in group A and 349.68 +/-112.35 and 298.35 +/- 100.76 in group B (P < 0.05). The androgen level was positively correlated with the expressions of CBS and CSE in the corpus cavernosum smooth muscle of the rats. CONCLUSION: Androgen regulates erectile function via the expressions of CBS and CSE. PMID- 23926676 TI - [Histological effects of unilateral spermatic cord torsion without removal of the ipsilateral necrotic testis on the contralateral testis in rats]. AB - OBJECTIVE: To investigate the protective effect of retarded removal of the unilateral necrotic testis after long-time (> 24 h) spermatic cord torsion on the contralateral testis in rats. METHODS: Thirty-three male SD rats aged 21 -42 days were divided into a sham-operation group (n = 11), a torsion-reservation group (n = 12) and a torsion-orchiectomy group (n = 10). The rats of the sham-operation group received dartos pouch orchidopexy on the left testis, while those of the latter two groups underwent 720 degrees unilateral spermatic cord torsion on the left side. Ninety-six hours later, the rats of the torsion-reservation group received detorsion with the ipsilateral testis preserved, while those of the torsion-orchiectomy group underwent orchiectomy. Three months after operation, blood samples were obtained from the rats for measurement of serum testosterone and antisperm antibodies by ELISA, and meanwhile testes and epididymides were harvested for determination of the volumes of various structures and the diameter of seminiferous tubules with stereological methods. RESULTS: There were no significant differences in the level of serum testosterone among the three groups. Anti-sperm antibody positive was found in only 1 animal in the torsion reservation group. The Leydig cell nuclei in the contralateral testis appeared larger in the torsion groups than in the sham-operation group. Marked morphological changes were observed in 1, 3 and 0 of the animals in the sham operation, torsion-reservation and torsion-orchiectomy group, respectively, mainly including atrophy of seminiferous tubules and reduced number of spermatogenic cells. The volume of the contralateral testis was increased by 19% and 21% in the torsion-reservation and torsion-orchiectomy group, respectively, in comparison with that in the sham-operation group (P < 0.05). No significant differences were observed in the volume of seminiferous tubules of the contralateral testis among the sham-operation, torsion-reservation and torsion orchiectomy groups ([1.15 +/- 0.07], [1.30 +/- 0.04] and [1.35 +/- 0.05] cm3). The volume of the interstitial tissue was significantly increased in the latter two groups ([0.36 +/- 0.02 and 0.34 +/- 0.03] cm3) as compared with the former ([0.25 +/- 0.02] cm3) (P < 0.05). The diameters of the seminiferous tubules exhibited no significant differences among the three groups ([226.00 +/- 7.00], [223.00 +/- 6.00] and [221.00 +/- 3.0] microm). CONCLUSION: Long-time unilateral spermatic cord torsion may result in compensatory hypertrophy of the contralateral testis, and orchiectomy does not significantly affect the histology of the contralateral testis and epididymis. PMID- 23926677 TI - [Effects of glial cell-derived neurotrophic factor on SCF protein and antioxidant enzyme activity in the testis of unilateral cryptorchidism rats]. AB - OBJECTIVE: To explore the effects of glial cell-derived neurotrophic factor (GDNF) on the stem cell factor (SCF), superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) in the undescended testis tissue of rats. METHODS: Models of left cryptorchidism were made in 48 healthy male rats weighing (200 +/- 20) g and randomly divided into four groups: model control, GDNF 7 d, GDNF 14 d and GDNF 21 d. The rats in the latter three groups were killed at 7, 14 and 21 days after intravenous injection of GDNF, their left testes harvested for measurement of the activities of SOD and CAT and the content of MDA. The apoptosis index of spermatogenic cells was detected by TUNEL, the histological changes of the testis tissue observed under the light microscope, and the gene and protein expressions of SCF determined by real-time quantitative PCR and Western blotting, respectively. RESULTS: The apoptosis indexes of spermatogenic cells were obviously decreased in the GDNF 7 d, GDNF 14 d and GDNF 21 d groups (8.42 +/- 0.16, 4.45 +/- 0.34 and 7.32 +/- 0.09) as compared with that of the model control (13.5 +/- 0.64), with statistically significant difference between the GDNF 14 d and control groups (P < 0.01). The SCF expression and SOD activity were remarkably increased while the MDA content markedly reduced in the GDNF groups in comparison with those in the model control (P < 0.01). CONCLUSION: GDNF had a protective effect on the spermatogenic function of rat testes with unilateral cryptorchidism. It could enhance the antioxidant enzyme activity of the antioxidant enzyme system, elevate the expression of SCF and thus improve the testicular reproductivity, which were best indicated in the GDNF 14 d group. PMID- 23926678 TI - [Combination of transrectal 125I seeds implantation brachytherapy and intermittent hormonal therapy for locally advanced prostate cancer]. AB - OBJECTIVE: To evaluate the clinical efficacy of transrectal 125 I seeds implantation brachytherapy (BT) combined with intermittent hormonal therapy (IHT) in the treatment of locally advanced prostate cancer. METHODS: We treated 27 patients with locally advanced prostate cancer by transrectal 125I seeds implantation BT combined with IHT, and dynamically observed the changes in the PSA level, prostate volume, maximum urinary flow rate (Qmax) and International Prostate Symptoms Score (IPSS). RESULTS: All the implantation procedures were completed smoothly, lasting 20 to 35 minutes, with 40 to 58 seeds implanted. At 6 months after implantation, the PSA level was < 0.2 microg/L in all the patients (< 0.1 microg/L in 19 cases), the prostate volume was significantly reduced (P < 0.05), and Qmax and IPSS remarkably improved (P < 0.05). At 3 years after implantation, 19 cases were in the first cycle and the other 8 in the third cycle of IHT, of which 2 progressed to androgen-independent prostate cancer, and another 2 developed early bone metastasis. The rates of 3-year biochemically and clinically progression-free survival were 70.3% and 85.2%, respectively, and the rate of therapeutic effectiveness was 92.6%. No severe complications occurred in any of the cases. CONCLUSION: Transrectal 125I seeds implantation BT combined with IHT is a safe and minimally invasive procedure for locally advanced prostate cancer, which can effectively retard its clinical progression with no such complications as severe urethral, rectal or erectile dysfunction. PMID- 23926679 TI - [Spermatic cord seal-up injection for acute epididymitis: clinical observation of 56 cases]. AB - OBJECTIVE: To investigate the clinical effect of spermatic cord seal-up injection on acute epididymitis and its mechanisms. METHODS: A total of 120 cases of acute epididymitis were allocated to a trial group (n = 56), aged 18 - 78 (38.4 +/- 9.6) years, and a control group (n = 64), aged 14 -82 (41.3 +/- 7.2) years. The patients in the trial group were given seal-up injections of a mixture of lidocaine, gentamicin (or Amikacin) and dexamethasone into the spermatic cord, qd or bid, for 2 courses of 5 days each, with an interval of 3 to 5 days. Those in the control group were treated by intravenous drip of penicillin, qd, intramuscular injection of Streptomycin, bid, and oral medication of SMZCo (SMZ TMP), bid, with the initial dose doubled. After less than 2 weeks of treatment, we compared the therapeutic effects between the two groups of patients. RESULTS: In the trial group, 53.6% of the patients were basically cured, 37.5% obviously improved and 91.1% improved (total rate of effectiveness). The average treatment time for the improved cases was (9.2 +/- 0.5) d. In the control group, 40.6% of the patients were basically cured, 31.2% obviously improved and 71.8% improved (total rate of effectiveness). The average treatment time for the improved cases was (12.8 +/- 0.7) d. There were significant differences between the two groups in the total rate of effectiveness and the average treatment time for the improved cases (P < 0.05). CONCLUSION: Spermatic cord seal-up injection for acute epididymitis deserves wide clinical application for its simple operation, good tolerance, short therapeutic course and high safety and efficacy. PMID- 23926680 TI - [Penile erectile function after lumbar discectomy for intervertebral disc herniation in different age groups of male patients]. AB - OBJECTIVE: To investigate the treatment effect on penile erectile function after lumbar discectomy in different age groups of men. METHODS: We included in this study 90 male patients with intervertebral disc herniation treated by lumbar discectomy, who were divided into three age groups of equal number: groups A (< 45 yr), B (45 - 55 yr) and C ( > 55 yr). We obtained the IIEF-5 scores of the patients preoperatively and at 12 months after surgery. RESULTS: The IIEF-5 scores at 12 months after surgery were 21.3 +/- 3.3, 16.8 +/- 1.3 and 14.1 +/- 1.0 in groups A, B and C, respectively, significantly higher than 10.4 +/- 2.6, 10.7 +/- 2.8 and 11.2 +/- 1.9 preoperatively (P < 0.05). Group A showed better improved erectile function than B and C ([51.17 +/- 6.25 ]% vs [36.31 +/- 4.28]% and [22.71 +/- 5.68]%, P < 0.05). CONCLUSION: Penile erectile function of the male patient is one of the major factors in evaluating lumbar discectomy for intervertebral disc herniation. Early decompression surgery according to different etiological factors is very important for erectile function recovery in the young and middle-aged male patients. PMID- 23926681 TI - [Low-dose testosterone undecanoate capsules combined with tadalafil for late onset hypogonadism accompanied with ED]. AB - OBJECTIVE: To observe the clinical effect of low-dose testosterone undecanoate capsules combined with tadalafil on late-onset hypogonadism (LOH) accompanied with ED. METHODS: Ninety cases of LOH accompanied with ED who met the inclusion criteria were randomly divided into a control group and a combination therapy group, the former treated with tadalafil and the latter with low-dose testosterone undecanoate capsules combined with tadalafil. The LOH symptoms, IIEF 5 scores, sexual encounter profile (SEP) scores, prostate volumes, and the levels of total testosterone (TT), free testosterone (FT) and prostatic specific antigen (PSA) were recorded and compared between the two groups before and after treatment. RESULTS: The IIEF-5 and SEP scores and the TT and FT levels were 20.6 +/- 3.8, 4.02 +/- 1.08, (15.4 +/- 3.4) nmol/L and (0.391 +/- 0.062) nmol/L, respectively, in the combination therapy group after treatment, significantly higher both than 15.7 +/- 3.9, 1.49 +/- 0.82, (10.1 +/- 1.2) nmol/L and (0.200 +/ 0.045) nmol/L before treatment (P < 0.01) and than 8.6 +/- 3.6, 3.50 +/- 1.21, (10.2 +/- 1.2) nmol/L and (0.210 +/- 0.051) nmol/L in the control group after treatment (P < 0.01). CONCLUSION: Low-dose testosterone undecanoate capsules combined with tadalafil has a definite clinical effect and no obvious adverse reactions in the treatment of LOH accompanied with ED. PMID- 23926682 TI - [Waist-hip ratio correlates with the levels of reproductive endocrine hormones in abdominally obese males]. AB - OBJECTIVE: To study the impact of abdominal obesity on the production of male reproductive endocrine hormones. METHODS: This study included 342 male patients at the andrology clinic, aged 19 -47 years and higher than 160 cm. We measured their waistlines, hiplines and waist-hip ratio, detected the levels of serum estradiol (E2), testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and free testosterone (FT) by chemiluminescence and radioimmunoassay, and analyzed the correlation of the waist-hip ratio with the levels of reproductive endocrine hormones. Abdominal obesity was defined as the waist-hip ratio > 0.9. RESULTS: In the 342 male patients, there were 62 cases of abdominal obesity and 280 cases of the normal somatotype (waist-hip ratio < or = 0.9). The waist-hip ratio was negatively correlated with the T level (r = -0.163, P = 0.003) and the T/LH ratio (r = -0.13, P = 0.02). Both the T level and T/LH ratio were significantly reduced in the abdominal obesity patients ([14.51 +/- 4.53] nmol/L and 2.26 +/- 0.36) as compared with the normal somatotype controls ([17.21 +/- 4.23] nmol/L and 4.61 +/- 0.19) (P < 0.05). CONCLUSION: The waist-hip ratio has a significant negative correlation with the T level and T/LH ratio, and the serum T level is significantly lower in men with abdominal obesity than in those of the normal somatotype. PMID- 23926683 TI - [Influence of serum storage on the laboratory results of prostate-specific antigen]. AB - OBJECTIVE: To investigate the influence of serum storage on the laboratory results of serum T-PSA, F-PSA and FPSA%. METHODS: Using automated chemiluminescence, we detected and compared the values of serum T-PSA, F-PSA and F-PSA% in the serum stored in different conditions. RESULTS: When the serum was stored at 4 degrees C or at the room temperature (22 - 26 degrees C), FPSA was unstable as compared with T-PSA. Compared with the initial value, after 4 hours at the room temperature, F-PSA was decreased to (0.392 +/- 0.246) microg/L (P < 0.01), while T-PSA and F-PSA% to (1.522 +/- 1.085) microg/L and (25.03 +/- 5.94)%, respectively, with no significant difference; after 8 hours at the room temperature, T-PSA and F-PSA were reduced to (1.513 +/- 1.083) and (0.389 +/- 0.247) microg/L (P < 0.05 and P < 0.01). At 4 degrees C, T-PSA, F-PSA and F-PSA% were decreased to (9.418 +/- 7.965) microg/L, (2.168 +/- 1.558) micro/L and (26.6 +/- 6.63)%, respectively, after 2 days (P < 0.05), and to (9.203 +/- 7.736) microg/L, (2.047 +/- 1.478) microg/L and (25.64 +/- 6.56)% after 1 week (P < 0.01). At -40 degrees C, T-PSA, F-PSA and F-PSA% were (4.532 +/- 4.393) microg/L, (1.178 +/- 1.034) microg/L and (24.45 +/- 8.81)% after 4 weeks. When the serum was stored at -40 degrees C and after 3 freeze-thaws, F-PSA and T-PSA were (5.982 +/- 5.314) and (1.341 +/- 1.029) microg/L, respectively, with no significant difference from the initial values. CONCLUSION: Different conditions of serum storage have different influences on the laboratory results of serum TPSA, F-PSA and F-PSA%, more on F-PSA than on T-PSA, while F-PSA% is relatively stable. At 40 degrees C, T-PSA and F-PSA may remain stable for a month at least. Repeated freeze-thaws of the serum do not affect the laboratory results of F-PSA and T PSA. PMID- 23926684 TI - [Cytogenetic and molecular analysis of idic(Yp) in 1 infertile man and 1 prenatal fetus]. AB - OBJECTIVE: To evaluate idic(Yp) in genetic diagnosis by examining 1 infertile man and 1 prenatal fetus using cytogenetic and molecular techniques. METHODS: Following conventional chromosome preparation, we performed G- and C-banding karyo. typing and fluorescence in situ hybridization (FISH). Then we extracted genomic DNA using standard procedures and analyzed it by array-CGH and multiplex ligation-dependent probe amplification (MLPA). RESULTS: Both cases were diagnosed as 45, X/46, X, idic (Yp11.31) mosaicism. The man showed 2 intact copies of Yp11.31-q12 (chrY:2, 710, 250-57, 428, 567, SRY, ZFY, UTY and AZF), and the prenatal fetus exhibited similar findings except a paternal deletion in the AZFc region. CONCLUSION: idic(Y) (p11.31) causes short stature and male infertility. Array-CGH and MLPA can improve the accuracy of the diagnosis of 45, X/46, X, idic (Y) mosaicism, which may contribute to the studies of the phenotype-genotype correlation and clinical genetic counseling. PMID- 23926685 TI - [The method of tonifying kidneys and activating blood circulation increases testosterone secretion index in late-onset hypogonadism males with kidney deficiency]. AB - OBJECTIVE: To investigate the effect of the method of tonifying the kidney and activating blood circulation on the testosterone secretion index (TSI) in late onset hypogonadism (LOH) male patients with kidney deficiency and its possible mechanisms. METHODS: We screened 60 LOH male patients with kidney deficiency based on the scores on Partial Androgen Deficiency in Aging Males (PADAM), the levels of serum total testosterone (TT) and luteinizing hormone (LH), and TSI (TT/LH). We randomly divided the patients into a Nan Geng Ning (NGN) group (n = 40, aged 55.02 +/- 11.37 years) and a control group (n = 20, aged 54.56 +/- 12.12 years) to be treated orally with NGN decoction and testosterone undecanoate capsules, respectively, both for 12 consecutive weeks. We obtained the scores on psychological status, physical status and sexual function and observed the changes in serum TT, LH and TSI after 4, 8 and 12 weeks of treatment. RESULTS: Compared with the baseline, both the NGN and control groups showed a significant reduction after 12 weeks of medication in the LH level ([5.32 +/- 2.08] vs [4.89 +/- 1.46] IU/L and [5.36 +/- 2.07] vs [4.81 +/- 1.75] IU/L, P < 0.05), psychological status score (5.2 +/- 1.3 vs 2.7 +/- 1.4 and 4.8 +/- 2.2 vs 2.9 +/- 1.2, P < 0.05), physical status score (6.9 +/- 2.5 vs 2.9 +/- 1.6 and 7.1 +/- 2.7 vs 3.1 +/- 1.5, P < 0.05) and sexual function score (10.2 +/- 3.3 vs 4.5 +/- 2.9 and 9.8 +/- 3.1 vs 4.8 +/- 3.0, P < 0.05), but a remarkable increase in the TT level ([11.13 +/- 0.69] vs [14.55 +/- 0.75] nmol/L and [10.99 +/- 0.74] vs [14.74 +/- 0.83] nmol/L, P < 0.05) and TSI ([2.14 +/- 0.65] vs [2.99 +/- 0.72] nmol/IU and ([2.05 +/- 0.73] vs [3.11 +/- 0.65] nmol/IU, P < 0.05). However, no significant differences were found between the NGN and control groups at 12 weeks in LH ([4.89 +/- 1.46] vs [4.81 +/- 1.75] IU/L, P > 0.05), TT ([14.55 +/- 0.75] vs [14.74 +/- 0.83] nmol/L, P > 0.05), TSI ([2.99 +/- 0.72] vs [3.11 +/- 0.65] nmol/IU, P > 0.05), psychological status score (2.7 +/- 1.4 vs 2.9 +/- 1.2, P > 0.05), physi- cal status score (2.9 +/- 1.6 vs 3.1 +/- 1.5, P > 0.05) and sexual function score (4.5 +/- 2.9 vs 4.8 +/- 3.0, P > 0.05). There were no adverse events in either of the two groups throughout the whole experiment. CONCLUSION: The method of tonifying the kidney and activating blood circulation could significantly improve the clinical symptoms of LOH with kidney deficiency and increase the patient's serum TT level and TSI. NGN decoction works on LOH by acting on the hypothalamic-pituitary-gonad axis. PMID- 23926686 TI - [Advances in the studies of cell-free seminal DNA]. AB - Cell-free DNA, also referred to as extracellular DNA, has been detected in many kinds of human body fluids, including blood plasma, urine, cerebrospinal fluid, bronchoalveolar lavage fluid, amniotic fluid, and seminal plasma. At present, cell-free DNA has been reported widely as promising noninvasive biomarkers for disease diagnosis and research. Recent years have witnessed some progress in the studies of the general characteristics of cell-free DNA, such as its concentration, extent of molecular weight, origin and existing forms, as well as in its clinical application. Cell-free seminal DNA has been proposed as promising noninvasive biomarkers for the studies and diagnosis of male idiopathic infertility, and the early diagnosis, treatment evaluation and outcome prediction of testicular germ cell tumors and prostatic cancer. This review summarizes the general characteristics and biological functions of cell-free DNA, and outlines the research status and application perspective of cell-free seminal DNA. PMID- 23926687 TI - [Relationship between aberrant expression of miRNAs and prostate cancer]. AB - MicroRNAs (miRNAs) are a kind of small non-coding single-stranded RNA molecules that negatively regulate gene expressions by binding to imperfect complementary sites in the 3 untranslated region of targeted mRNAs at the post-transcriptional level. The aberrant expression of some miRNAs has been discovered to be involved in the pathogenesis of various cancers, including prostate cancer. By analyzing miRNA expressions in prostate cancer tissues, serum and cell lines, and then investigating their mechanisms, we expect to provide some new theoretic bases for the clinical diagnosis and treatment of prostate cancer. PMID- 23926688 TI - [Phosphatidylserine and male reproduction]. AB - Phosphatidylserine (PS) is an amphiphilic phospholipid ubiquitously present in the inside of the membrane of prokaryotic and eukaryotic cells. In mammalian cells, there are two synthetic pathways for PS that are different from those of bacterial biosynthesis. The translocation of sperm PS from the inner to the outer leaflet of the plasma membrane is considered to be associated with sperm apoptosis and male infertility. The level of PS externalization in human sperm is used as an indicator for the evaluation of sperm quality. Fast separation of PS externalized sperm at the molecular level by flow cytometry or magnetic activated cell sorting can effectively improve the quality of sperm and the success rate of assisted reproductive technology. This paper reviews the structure properties, distribution, biological activity and synthesis of PS, as well as its association with male reproduction. PMID- 23926689 TI - Isolation, purification and characterization of the egg-yolk proteins from the oocytes of the indian freshwater murrel, Channa punctatus (Bloch). AB - In oviparous organisms, yolk accumulation in the oocytes is critical and indispensable for the development of the newly hatched young ones. In fish and many other oviparous vertebrates, the major constituents of the egg-yolk are synthesized as a precursor in the liver. The precursor is transported to the oocyte for uptake and cleaved into major yolk proteins lipovitellin, phosvitin and beta'-components. The eggs of Channa punctatus are pelagic, have large oil globule and exceptionally high lipid content. Lipovitellin was isolated by single step gel filtration chromatography on Sepharose 6B. Purified native lipovitellin showed immunological reactivity with vitellogenin antiserum. Phosvitin isolated by phenol extraction method could not be visualized with routine protein staining methods, whereas incorporation of trivalent ions in the coomassie brilliant blue stained phosvitin. It was characterized by in vivo labeling of egg-yolk proteins with 32P. The molecular mass of murrel phosvitin was less than 14,000 kDa. PMID- 23926690 TI - The lld mutation in Pisum sativum used as a genetic tool to discern the plant leaflet/leaf developmental process. AB - Leaves of P. sativum the double mutant genotype tendril-less (tl) leaflet development (lld), due to the action of lld mutation, produce many leaflets that are aborted at different stages of development. Morphological, vein pattern and histological observations showed that aborted leaflets became cup/bell/trumpet (cup) shaped because of segmental differentiation in the leaflet primordium. Cup's inside lamina surface was adaxial and outer surfaces of cup and its stem were abaxial. The lld cups were phenotypically homologous to aborted leaves described in Arabidopsis thaliana mutants, angustifolia and those which underexpressed the HD-ZIP III proteins. Leaflet primordium was found to grow and establish three dimensional polarities apex-downwards. Primordium produced lateral outgrowth on one side of midvein. Differentiation, in the outgrowth of secondary veins, whose xylem tissues faced each other, established the adaxial abaxial polarity. Lateral outgrowth then developed a cavity which got bounded by future adaxial epidermis. Further growth, veinlet formation, differentiation of palisade parenchyma and spongy parenchyma followed. Opening of lateral outgrowth at its outer midline produced a flat leaflet with lateral lamina spans. The structural and functional correspondence between leaflet and simple leaves suggested commonality between leaf and leaflet development mechanisms. A molecular model for the lld led leaflet abortion was also provided. PMID- 23926691 TI - Anti-depressant like activity of N-n-butyl-3-methoxyquinoxaline-2-carboxamide (6o) a 5-HT3 receptor antagonist. AB - The compound 6o (at 0.5, 1 and 2 mg/kg, ip) with optimum log P and pA2 value, was subjected to forced swim test (FST) and tail suspension test (TST). The compound 6o significantly reduced the duration of immobility in mice without affecting the base line locomotion in actophotometer. Moreover, 6o (2 mg/kg, ip), potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and at 1 and 2 mg/kg, ip antagonized the reserpine-induced hypothermia (RIH) in rats. In interaction studies with various standard drugs/ligands using FST, 6o (1 and 2 mg/kg, ip) potentiated the anti-depressant effect fluoxetine (5 mg/kg, ip) and reversed the depressant effect of parthenolide (1 mg/kg, ip) by reducing the duration of immobility. Furthermore, 6o (1 and 2 mg/kg, ip) potentiated the effect of bupropion (10 mg/kg, ip) in TST. The behavioural anomalies of the olfactory bulbectomised (OBX) rats were augmented by chronic 6o (1 and 2 mg/kg) treatment as observed from the modified open field test (parameters: ambulation, rearing, fecal pellet). The results suggest that compound 6o exhibited anti depressant like effect in rodent models of depression. PMID- 23926693 TI - Anxiolytic and anticonvulsant activity of methanol extract of leaves of Alternanthera brasiliana (L.) Kuntze (Amaranthaceae) in laboratory animals. AB - Anxiety related disorders are the most common mental illnesses and major cause of disability in man. Anxiolytic activity of methanol extract of leaves of A. brasiliana (L.) Kuntze (MEAB) was evaluated using hole board (HB), open field (OF), elevated plus maze (EPM) and light/dark exploration test (LDE) in mice. Its locomotor activity was studied using actophotometer and anticonvulsant effect was studied using maximal electroshock-induced seizures and pentylenetetrazole induced seizures in mice. Single oral administration of MEAB at different doses (100, 300 and 600 mg/kg, ip) significantly increased the number and duration of head poking in the HB test; rearing, assisted rearing and number of square traveled in the OF test; entries and time spent in open arm in the EPM test; time spent in lighted box, and numbers of crossings and transfer latency time in the LDE test. There was significant reduction in the time spent in close arm in the EPM test and time spent in dark box in LDE test. In the actophotometer, the activity count was reduced in MEAB and diazepam treated group than control group. All the three doses of the extract significantly reduced the duration of seizures induced by pentylenetetrazole (chemoshock convulsion). However, the extract did not show any appreciable effect in electroshock convulsion model. The results of the present study suggest promising anxiolytic and anticonvulsant activity of MEAB which might be accredited to different phytoconstituents like alkaloids, steroids and triterpenes present in the methanol extract of A. brasiliana. PMID- 23926692 TI - Anxiolytic-like effect of etazolate, a type 4 phosphodiesterase inhibitor in experimental models of anxiety. AB - Etazolate is a selective inhibitor of type 4 phosphodiesterase (PDE4) class enzyme. Antidepressant-like effect of etazolate has been previously demonstrated in the rodent models of depression. The present study was designed to investigate the anxiolytic-like activity of etazolate in experimental mouse models of anxiety. The putative anxiolytic effect of etazolate (0.25-1 mg/kg, ip) was studied in mice by using a battery of behavioural tests of anxiety such as elevated plus maze (EPM), light/dark (L/D) aversion, hole board (HB) and open field (OFT) with diazepam (2 mg/kg, ip) as reference anxiolytic. Like diazepam (2 mg/kg, ip), etazolate (0.5 and 1 mg/kg, ip) significantly increased the percentage of both time spent and entries into open arms in the EPM test. In the L/D test etazolate (0.5 and 1 mg/kg, ip) increased the both total time spent in and latency time to leave the light compartment. Etazolate (0.5 and 1 mg/kg, ip) also significantly increased head dipping scores and time spent in head dipping, whereas significantly decreased the head dipping latency in HB test. In addition, etazolate (0.5 and 1 mg/kg, ip) significantly increased the ambulation scores (square crossed) and number of rearing in OFT. In conclusion, these findings indicated that etazolate exhibited an anxiolytic-like effect in experimental models of anxiety and may be considered an alternative approach for the management of anxiety disorder. PMID- 23926694 TI - Hypolipidemic effect of a novel biflavonoid from shells of Camellia oleifera (Abel.). AB - Camellia oleifera Abel. [C. oleosa (Lour.) Rehd.], an evergreen plant, is used for healthful oil production, but the shells are always discarded and need to be utilized. The present study was undertaken to explore the effect of extracts from the shells of C. oleifera on adjusting cardiovascular system. A flavonoid was obtained by reflux extraction of the shells in 70% methanol, hydrolysis in 2 M hydrochloric acid, and crystallization in acetone. Its structure was identified as a novel biflavonoid. Mice model of hyperlipidemia was setup by high fat diet for 30 d to evaluate the hypolipidemic effect of the biflavonoid at dose of 50, 100 and 200 mg/kg/d (ig). Antioxidative activity was determined by levels of malondialdehyde (MDA), superoxidase dismutase (SOD) and glutathione peroxidase (GSH-Px) in mice serum. The biflavonoid significantly controlled mice weight and liver coefficient, decreased the content of total cholesterol and triglyceride, promoted the level of high density lipoprotein in a dose dependent manner. The significant decrease of MDA content and increase of SOD and GSH-Px activity indicated it enhanced antioxidative capacity in vivo and was ascribed to hypolipidemic effect. The biflavonoid is useful in the prevention of high fat diet induced hyperlipidemia. PMID- 23926695 TI - Effect of Aegle marmelos (L.) Correa on alloxan induced early stage diabetic nephropathy in rats. AB - Diabetic nephropathy (DN) has a complex pathogenesis and poor prognosis due to the lack of therapeutic interventions. The present study investigates the effect of A. marmelos leaf extract (AME) on early alloxan induced DN. The treatment with AME was found to significantly decrease the fasting blood sugar, total cholesterol, blood urea, creatinine and renal TBARS and increased the levels of renal reduced glutathione and catalase significantly as compared to the diabetic control group. The maximum dose-dependent protection was observed at a dose of 200 mg kg(-1). Histological examination revealed marked reversal of the morphological derangements with AME treatment as indicated by a decrease in glomerular expansion, tubular dilatation and inflammatory cells. The present results conclude that AME treatment has a significant ameliorative effect on early changes induced in the kidneys by alloxan and improves the outcome of DN. PMID- 23926696 TI - In planta detection of Xanthomonas axonopodis pv. commiphorae using fyuA and rpoD genes. AB - Guggal is tapped for extraction of medicinally important oleo-gum-resin (guggul) by inoculating the stem bark with natural gum suspension containing pathogenic bacterium Xanthomonas axonopodis pv. commiphorae (Xac). The tree dies in the process. In absence of any specific medium for isolation of Xac, it is difficult to assess spread of the pathogen within the plant. A PCR based molecular detection technique usingfyuA and rpoD gene specific primers is described here. The primers amplified products only from Xac and not from host tissues or common saprophytes. The method was sensitive enough to produce positive signals for up to 4.4 bacterial cells or 2 pg target DNA per reaction mixture. However, PCR inhibitors present in plant tissues drastically reduced the limit of detection. A simple overnight incubation of surface sterilised plant tissues in nutrient medium was introduced to increase pathogen titre and to overcome this problem. This technique was successfully used to measure spread of Xac in plant tissues away from the site of inoculation. The pathogen showed preference for acropetal movement and did not spread to 7-8 cm below the site of inoculation till 15 days after inoculation. This suggests possibility to manage the disease through plant surgery. PMID- 23926697 TI - Effects of low concentrations of a polychlorinated biphenyl, Aroclor 1254 on membrane bound ion dependent ATPases in mice liver. AB - Aroclor 1254, a polychlorinated biphenyl, is present in the environment in low concentration but references on its toxic effects on liver cell membrane proteins and the mechanism of actions are not abundantly available. Therefore, the present study was undertaken to investigate the low level, sub-acute dose and exposure duration dependent effects of Aroclor 1254 on total, Na+, K+, Ca2+ and Mg(2+) ATPases of the mouse liver. The hypotheses tested in the present study were, (a) whether the low, environmentally available dose and the exposure durations of Aroclor 1254 affects the membrane-bound ion dependent ATPases, and (b) if a response was observed, whether it is a direct or indirect effects of the toxicant. Groups of mice were exposed to different doses (0.1 and 1 mg kg(-1) body weight d(-1)) and exposure durations (4 d, 8 d and 12 d) of Aroclor 1254. The results indicated significant exposure duration dependent changes in the specific activity of the selected membrane bound ATPases. As the observed changes were mostly enzyme stimulation after toxication through oral administration, the effects of the Aroclor were possibly indirect, through complex chain of reactions. PMID- 23926698 TI - [What is medical insurance?]. PMID- 23926699 TI - [Diagnosis, therapy and assessment of chronic lower back pain]. AB - Evaluation of lower back pain (LBP) in terms of legal assessment is important since pain, as the most frequent symptom of diseases of the human musculoskeletal system, is a subjective sensation. Frequently, medical findings are not consistent with the subjective pain sensation. Because of multi-dimensional causes of (chronic) LBP and a high impact of psychosomatic comorbidity, the assessor has to prove all complaints of a test subject in terms of consistency with the (objective) findings. Therefore, it is often necessary to include psychosomatic aspects into the evaluation of multi-dimensional origins of LBP. PMID- 23926700 TI - [Is family history dispensable?]. AB - As an element of risk assessment in applications for life insurance, family medical history has a particular significance since given impairments can occur more frequently within families. Family history is not only genetic in nature. Depending on the impairment, it is also explained by external factors. There has been little literature on this topic so far, although the spectrum of family history-related impairments is very large, and their effect is highly dependent on the type of product. This paper presents a new method for assessing the effects of information contained in family history on claims, based on typical age patterns for German life insurance products (life, disability and long term care insurance), using the example of breast cancer and schizophrenia. This method helps life insurers to better understand what impact questions on family history during the stage of application have on the risk. Thus, the study contributes to the often discussed question on how essential questions on family history are. PMID- 23926701 TI - [Cancer-related fatigue]. AB - Cancer-related Fatigue (CrF) is a common disease that occurs in connection with oncological disease, characterised by feelings of fatigue and lack of energy and even after successful primary treatment of the underlying disease as an independent event in impairment of the health and quality of life as well as the ability to work can lead to vocational disability. There are indications that the affected persons suffer more from CrF than from pain. PMID- 23926702 TI - [Complementary and alternative medicine in oncology]. AB - Complementary and alternative medicine are frequently used by cancer patients. The main benefit of complementary medicine is that it gives patients the chance to become active. Complementary therapy can reduce the side effects of conventional therapy. However, we have to give due consideration to side effects and interactions: the latter being able to reduce the effectiveness of cancer therapy and so to jeopardise the success of therapy. Therefore, complementary therapy should be managed by the oncologist. It is based on a common concept of cancerogenesis with conventional therapy. Complement therapy can be assessed in studies. Alternative medicine in contrast rejects common rules of evidence-based medicine. It starts from its own concepts of cancerogenesis, which is often in line with the thinking of lay persons. Alternative medicine is offered as either "alternative" to recommended cancer treatment or is used at the same time but without due regard for the interactions. Alternative medicine is a high risk to patients. In the following two parts of the article, the most important complementary and alternative therapies cancer patients use nowadays are presented and assessed according to published evidence. PMID- 23926703 TI - [Stress and "anniversary reactions": rising mortality on birthdays and other anniversaries]. AB - Certain fatal casualties or psychic decompensations occur significantly more frequently on birthdays and other biographically important anniversaries. Analyses of life tables have clearly confirmed this clinical evidence. The stress model and the concept of "anniversary reactions" are the two most convincing explanations for these associations. Both concepts and meaningful opportunities for prevention of "anniversary reactions" will be presented. PMID- 23926704 TI - [Health-related quality of life of people with severe traumatic injury: a longitudinal study using the SF-36 health survey]. AB - Even though 85 percent of those who have been severely injured in an accident in Germany survive, complex and serious long-term consequences are still a major problem not only for health and care insurance providers but also for the accident victims themselves because their quality of life is affected permanently. Therefore the aim of the current study is to identify factors that significantly improve the quality of life after a severe traumatic injury and to investigate whether the support by a reintegration service has a positive effect on the victims' quality of life. The sample consisted of severely injured accident victims who were supported by a reintegration service. The data collection comprised three data points. At every data point the SF-36 questionnaire was used to assess the participants' quality of life. The results indicate that an individual medical-vocational support by a reintegration service has the potential to significantly and stably improve the physical aspects of quality of life, even if the accident dates back several years. Furthermore it appears to be important to support the independence of the accident victims because assistance by a third person correlates with a lower degree of physical quality of life, regardless of severity or type of injury. Moreover it becomes clear that it is important to pay more attention to the treatment of psychological consequences of severe accidents. PMID- 23926705 TI - [Increases in pharmaceutical expenditures of PHI by monoclonal antibodies]. AB - The dynamics of one of the most innovative segments of health care and its impact on pharmaceutical expenditure of private health insurance (PHI) is examined on the basis of drug prescription data from private health insurance companies. The study shows that the increase in pharmaceutical expenditure can be explained partly by the new treatment possibilities available with monoclonal antibodies. The per capita expenditure on drugs with monoclonal antibodies increased by 255% from 2006 to 2010 in private health insurance, while the corresponding expenditure of all pharmaceuticals has risen by only 19% in the same period. In the coming years, growth on this scale will be a challenge for all payers in the health system. PMID- 23926706 TI - [Impression management and self-presentation in occupational life]. AB - Impression management serves self-preservation as part of self-experience. It is adapted to a given situation as an expression of understanding of the role it plays in striving for success. Impression management and self-presentation mutually influence each other throughout life. Cliches in the traditional self presentation of men and woman in their gender-specific domain in occupation belong to the past. In employment, contentment as much as discontent are of prime importance for success or failure in the workplace. As role models attract mainly juveniles, they should be held up to critical scrutiny. PMID- 23926707 TI - [Pandemic scenario in PHI]. PMID- 23926708 TI - [Treatment of ulcerated lower leg eczema with high-dose vitamin C therapy]. PMID- 23926709 TI - [Letter to C. Licha, A. Stevens: anxiety and anxiety disorders--differential diagnosis, causes and recommendations for the assessment. in: Insurance Medicine 64 (2012) No. 2, pp. 74, Issue 3 Issue 4 p 119 and p 178]. PMID- 23926711 TI - Focusing on restorative dentistry. PMID- 23926710 TI - [Conclusion]. PMID- 23926712 TI - An overview of evidence-based dentistry research. PMID- 23926713 TI - Focus on: Anterior indirect restorations. PMID- 23926714 TI - Management of plaque-related soft-tissue trauma. PMID- 23926715 TI - Maxillary small-diameter implant-retained overdentures. PMID- 23926716 TI - Improving the way to detect cracks in teeth. PMID- 23926717 TI - Implant wisdom: an endodontist's approach. PMID- 23926718 TI - Direct composite resin restorations for today's practice. PMID- 23926719 TI - A new perspective on minimally invasive veneer techniques. PMID- 23926720 TI - Discovering the artist inside: A three-step approach to predictable aesthetic smile designs, part 2. PMID- 23926721 TI - Management of occlusion over implants, part 2: three 10-year case follow-ups and evaluations. PMID- 23926722 TI - The reintroduction of an effective cavity liner. PMID- 23926723 TI - Dupuytren disease: on our way to a cure? AB - Despite its high prevalence, the clinical presentation and severity of Dupuytren disease is extremely variable. The disease features a broad spectrum of symptoms, from simple nodules without the slightest clinical impact towards an extremely disabling form requiring multiple surgical procedures, sometimes even partial hand amputations. Recurrence after surgery is considered a failure for both patient and surgeon, but its definition is vague. The term 'recontracture' was coined by a patient and reflects the disappointment of recurrent disease. Wether or not a treatment option will insure a definite result, may depend more on the severity of the disease, which is patient specific, than on the treatment method itself. If a patient presents with Dupuytren disease, one should not merely evaluate his hands. Different clinical and personal history features may uncover a severe fibrosis diathesis and both correct information to the patient and an individualized treatment plan are needed. In the near future, a simple genetic test may help to identify patients at risk. Similar to the evolving knowledge and treatment modalities seen in rheumatoid arthritis, treatment of Dupuytren disease is likely to advance in the direction of disease control with pharmacotherapy and single shot minimal invasive enzymatic fasciotomy with collagenase to correct established contractures. PMID- 23926724 TI - New possible pathways in improving outcome and patient satisfaction after TKA. AB - Patient dissatisfaction after TKA has not been improved dramatically since the introduction of new alignment (navigation, custom guides) and balancing techniques. Orthopaedic surgeons consider the ligaments as essentially passive stabilizing structures. However, during the activities of daily living, the joints are stabilized primarily by our muscle actions that both move and stabilize the joints. Isometric motion of the joint does not cause the distance separating the bone attachments to change. The practical importance of isometry is confirmed by the fact that ligaments are elongated irreversibly if the strain exceeds a given level (5%). In ligament surgery as well as in TKA, the concept of isometry is highly important. In this paper we wish to highlight the fact that the role of the soft tissue envelope goes beyond structural and mechanical support. The presence of mechano- and nocireceptors in the structures around the human knee joint has long been reported but is underrecognised by TKA surgeons. PMID- 23926726 TI - Long-term survival of proximal humerus allografts for reconstruction following resection of malignant bone tumours. AB - We previously reported early favourable results concerning allograft use in proximal humerus reconstruction following malignancy. We now present the long term follow-up of patients who underwent tumour resection with massive humeral allograft reconstruction. This is a retrospective review of 8 consecutive patients who underwent massive proximal humeral allograft for primary or secondary bone tumours. The median age at first surgery was 41 years; the median followup is 11.1 years. The overall revision rate of the allografts was 75%. A total of 10 revision procedures were required in this cohort. Five-year survival for implants was 44%; at ten years no implants were intact. Five-year survival for patients was 88%; it was 60% at ten years. In our experience, proximal humerus allograft reconstruction was associated with a high complication rate and resulted in multiple revision procedures in the long-term. We no longer perform or recommend this procedure. PMID- 23926725 TI - The effect of shoulder manipulation on rotator cuff integrity. AB - The use of shoulder manipulation in the treatment of frozen shoulder remains controversial. Humeral fractures and neurological damage are the risks associated with the procedure. A concern of causing a rotator cuff tear exists but the incidence of iatrogenic rotator cuff tears is not reported. The purpose of this study was to assess the effect of shoulder manipulation for frozen shoulder on the integrity of the rotator cuff. In a prospective study, 32 consecutive patients (33 shoulders) with the diagnosis of frozen shoulder underwent manipulation of the shoulder under anaesthesia (MUA), 18 female and 15 males with mean age at manipulation of 503 years (range: 42-63). The average duration of symptoms before treatment was 6.2 months (range: 2-18 months). The patients were examined prior to the manipulation and at follow-up for combined shoulder range of motion, external and internal rotation and strength. All patients had an ultrasound assessment of the rotator cuff before and at 3 weeks after manipulation of the shoulder. Mean time between manipulation and last follow-up was 133 weeks. None of the patients had ultrasound findings of a rotator cuff tear, prior to the manipulation. In all patients the rotator cuff remained undamaged on ultrasound examination at 3 weeks after the procedure. The mean improvement in motion was 81.2 degrees (from 933 degrees pre-op to 174.5 degrees at last follow-up) for forward flexion; 102.6 degrees (from 68.8 degrees pre-op to 171.4 degrees at last follow-up) for abduction, 49.4 degrees (from 8.8 degrees pre-op to 58.2 degrees at last follow-up) for external rotation and 3.5 levels of internal rotation (range: 2 to 5 levels). These gains in motion were all highly significant (p < 0.0001). No fractures, dislocations or nerve palsies were observed. In this study, manipulation of the shoulder has not been associated with rotator cuff tears. If done properly the procedure appeared to be safe and to result in a marked improvement of range of movement and function. PMID- 23926727 TI - Extensor tendon and fascia sectioning of extensors at the musculotendinous unit in lateral epicondylitis. AB - Different surgical techniques exist to treat lateral epicondylitis. In most techniques, release of the common extensor origin is performed adjacent to the humeral epicondyle. The purpose of the present study was to assess the outcome of transverse sectioning of the intermuscular septum and the aponeuroses of the extensor carpi radialis brevis and extensor digitorum communis, 3 to 5 cm distally to the radial epicondyle. Forty-nine elbows were operated on in 44 patients. Subjective results were obtained after a mean followup of 33 months. Mean age of patients was 44 years. Mean disabilities of arm, shoulder and hand score was 6, mean visual analogue scale score for pain was 1 and for satisfaction 9. The result was excellent in 26, good in 15 and poor in 8 elbows following Spencer and Herndon. Mean absence from work was 40 days. We conclude that tendon release in the musculotendinous unit can be used to treat lateral epicondylitis. PMID- 23926728 TI - Does the "three-ligament tenodesis" procedure restore carpal architecture in static chronic scapholunate dissociation? AB - The effect of the three-ligament tenodesis on the scapholunate angle and scapholunate gap was studied. A comparison was made between these angles preoperatively and postoperatively in 12 patients. There was a significant decrease in the scapholunate angle from 77 to 68 degrees, and the scapholunate gap was reduced from 4.25 mm to 3.29 mm. We also studied the correlation between scapholunate angle and scapholunate gap postoperatively in a cohort of 25 patients and found a significant correlation. This suggests that the principle of the procedure is correct, but the aims are not fully achieved, and that the procedure has a similar effect on SL gap and SL angle. PMID- 23926729 TI - The value of delayed MRI scans in the assessment of acute wrist injuries. AB - The aim of this study was to better quantify the role of delayed MRI scans in acute wrist injuries, and to assess the prevalence and distribution of multiple occult injuries of the wrist. A retrospective study was made of all patients who had been referred to the orthopaedic trauma clinic for a possible scaphoid fracture and with normal radiographs over a two year period. There were 110 patients. Patients were initially treated conservatively with a scaphoid cast or a futura splint for two weeks. This was then removed and the wrist examined and further radiographs taken. The patients with normal radiographs who had positive clinical findings for a scaphoid fracture at two weeks or persisting pain at six weeks had an MRI scan. MRI was performed with and without fat saturation sequences. A total of 110 wrists were analysed. Twenty-eight (25.4%) were reported as normal; 24 patients (21.8%) had occult bone fractures. Three (2.7%) had scaphoid fractures diagnosed by MRI scans. There were nine (8.1%) distal radius, two trapezium and five hook of hamate fractures. Bone bruising was seen in 12 (10.9%). Carpal degeneration was seen in ten and a TFC tear was noted in five (4.5%). Other findings were a ganglion in 14 (12.7%) and three (2.7%) had Kienbock's disease. The MRI scan is a useful tool in obtaining a definite diagnosis in acute wrist injuries. Among other findings, an occult scaphoid fracture was diagnosed on MRI in 2.7% of cases in this study. To conclude, in the majority of patients with persisting symptoms after two weeks following a wrist trauma, the cause of symptoms was pathology in other tissues in the wrist including soft tissues, other carpal bones and distal forearm. PMID- 23926730 TI - Chronic osteomyelitis of the pelvis. AB - The aim of this study was to examine the aetiology and response to treatment of a series of patients with pelvic osteomyelitis. Criteria for selection were multiple positive intra-operative cultures and/or a positive radiological diagnosis. Twenty patients met these criteria (age range: 21-78 years, mean = 46). Data was recorded on host status using the Cierny-Mader classification, neurological status, causative organisms; sensitivities were recorded and the treatment and its outcome. Pelvic osteomyelitis was frequently caused by unusual organisms; a high incidence (45%) of neurologically compromised patients was noted. There were important differences in infective organisms, treatment and outcome in the paraplegic and non-paraplegic population. A high mortality and a high incidence of squamous cell carcinoma was observed. Pelvic osteomyelitis should be managed differently to long bone osteomyelitis as far as the antibiotic therapy is concerned, with a greater need for broad spectrum antibiotics in pelvic osteomyelitis. The response to surgical resection was similar to long bone osteomyelitis with a high chance of success with marginal resection in type A hosts and with wide resection in type B hosts. PMID- 23926731 TI - Cementless total hip arthroplasty with a double chevron subtrochanteric shortening osteotomy in patients with Crowe type-IV hip dysplasia. AB - The authors describe a modified double chevron subtrochanteric shortening osteotomy combined with cementless total hip arthroplasty for Crowe type-IV hip dysplasia. Shortening the femur allows to relax the shortened musculature. This operation was performed in 18 patients (22 hips) between January 2000 and February 2006. The mean follow-up period was 5.6 years (range: 3 to 8 years). The mean amount of femoral subtrochanteric shortening was 38 mm (range: 25 to 60 mm). The mean Harris hip score improved from 47 (range: 35 to 65) preoperatively to 88 points (range: 75 to 97) at final follow-up. The Trendelenburg sign was corrected from positive to negative in 12 of 22 hips. No acetabular or femoral components loosened or required revision during the follow-up period. All osteotomy sites healed in 3 to 6 months without complications. Cementless total hip arthroplasty using the modified double chevron subtrochanteric osteotomy provided good short- to midterm results in all 22 Crowe type-IV hip dislocations. Moreover, it restored the anatomic hip center and the limb length, which contributed to correction of the preoperative limp. PMID- 23926732 TI - The Thrust Plate Prosthesis: long-term clinical and radiological results. AB - The Thrust Plate Prosthesis is a femoral implant designed for total hip arthroplasty, based on the principles of physiologic loading of the metaphysis of the proximal femur, and preserving the bone stock. This study presents the long term clinical and radiological results of 34 patients with 36 Thrust Plate Prostheses. In a retrospective analysis, we investigated the reoperation-free survival as well as the clinical and radiological results. Mean age at operation was 51 +/- 6.4 years. Mean follow-up length was 11.9 +/- 1.6 years. Reoperation free survival was 88.9%. Four (11.1%) reoperations were performed, in three patients due to aseptic loosening and in one patient because of a fracture distal to the lateral plate. Three of the reoperations were performed between 12 and 32 months postoperatively. The major complaint was pain at the lateral side of the hip (44%). Radiolucencies did not exceed 1 mm, but 35% of the hips showed resorption of the cortex directly under the thrust plate, together with cancellous bone hypertrophy at the calcar, noted in 97%. Because of the relatively high reoperation-free survival and favourable radiological results, the Thrust Plate Prosthesis appears as a possible alternative to stemmed total hip arthroplasty, especially in relatively young patients. PMID- 23926733 TI - Primary total knee arthroplasty in patients with Parkinson's disease: analysis of outcomes. AB - The prevalence of Parkinson's disease is expected to rise. We evaluated the short term clinical outcomes following primary Total Knee Arthroplasty (TKA) in a group of patients with Parkinson's disease in a case controlled study. Within the review period 32 TKAs were implanted in patients with Parkinson's disease and 33 TKAs were implanted in an age-matched control group (mean age: 73 years). Pre operatively there were no between-group differences in Knee Society Score, Pain score, Knee Society Function Score or range of movement. Knee Society Score (KSS) improved in both groups post-operatively with no significant between-group differences (p = 0.707). Pain score also improved in both groups. There was no functional improvement following TKA in the Parkinson group. Total Knee Arthroplasty provided excellent pain relief in patients with Parkinson's disease with an acceptable complication profile, although functional ability did not improve. PMID- 23926734 TI - Patient-matched total knee arthroplasty: does it offer any clinical advantages? AB - This study aimed to assess if patient-matched cutting blocks reduce operating time, blood loss and length of stay on top of improving implant alignment and offer operational or economic benefits, as claimed by manufacturers. We retrospectively reviewed patients undergoing TKA using patient matched technology and compared them with patients undergoing TKA using standard instrumentation; all were operated on between September 2010 and June 2012. All procedures were performed by a single surgeon at a single centre using the same implants. We collected data on operating time, length of stay and blood loss and also measured component alignment. Thirty-nine patients underwent TKA using patient-matched technology during the study period. Data was compared with that from 50 patients undergoing TKA using standard instrumentation during the same period. We found no significant difference in operating time, length of stay or blood loss between the two groups. There was also no difference in femoral or tibial component alignment although we did observe that the femorotibial angle of TKAs using patient-matched technology was 0.9 degrees more valgus (183.5 degrees versus 182.6 degrees, p = 0.035). In this study, patient-matched technology did not appear to give any clinical advantages over standard techniques although, equally, it did not appear to show any disadvantages. Further studies are needed to evaluate whether operational or economic benefits may be achieved by adoption of patient matched instrumentation. PMID- 23926735 TI - Revision surgery for failed unicompartmental knee replacement: technical aspects and clinical outcome. AB - The aims of this study were to determine the complexity of surgery required to revise failed unicompartmental knee replacements and to evaluate the outcome following revision. Between 2000 and 2009, 494 cemented Oxford phase 3 medial unicompartmental knee replacements were implanted, with 24 (4.9%) requiring revision (mean age: 63.5 years; 58% male). Mean time to revision was 3.0 years. All cases were revised to a cemented total knee replacement, with primary components used in 67% and revision components in 33%. At a mean follow-up of 3.2 years the median Oxford knee score was 333% with one knee requiring re-revision (5-year survival 933%). Most failed unicompartmental knee replacements could be revised without the need for stemmed implants, augmentation, or bone allograft. When bone loss occured it was commonly on the tibial side. Good functional outcome for the revised unicompartmental knee replacement was achieved and was comparable to primary knee replacement. PMID- 23926736 TI - A surgical algorithm for the treatment of recurrent patellar dislocation. Results at 5 year follow-up. AB - Several options exist for the treatment of recurrent patellar dislocation. In our institution a specific treatment algorithm for patellofemoral maltracking, depending on skeletal maturity and the recognition of local risk factors has been in use for several years. The aim of our study was to evaluate the overall results of using this algorithm and to compare the outcome of the different subgroups. A total of 110 patients were studied with an average follow-up of 53 years. The patients were classified into 6 groups depending on the surgical treatment they had received. Eighty-seven percent of patients remained free of dislocation at final follow-up, and 66% of patients no longer experienced any patellar instability or subluxation. There was no statistically significant difference between skeletally mature and immature patients in the incidence of redislocation or recurrent instability, nor in functional or clinical outcome scores. Skeletally immature patients who underwent isolated medial retinacular imbrication experienced the highest redislocation rate (29%), whereas skeletally mature patients who were treated with combined proximal and distal realignment procedures demonstrated the lowest redislocation rate (6%). Skeletally mature patients with combined proximal and distal procedures reached lower clinical and functional outcome scores. Based upon the results from this study we believe that our surgical algorithm can serve as a model for the treatment of recurrent patellofemoral dislocation. PMID- 23926737 TI - Intra-articular versus serum C-reactive protein analysis in suspected periprosthetic knee joint infection. AB - The purpose of this study was to investigate the comparative diagnostic strength of C-reactive protein (CRP) values in synovial fluid and serum in patients with presumed periprosthetic joint infection. We collected 44 synovial fluid samples and 24 serum samples from 43 patients. Patients were judged to be uninfected or infected based on standardized criteria. Synovial and serum samples were obtained simultaneously. We determined the diagnostic strength of our assay by using receiver operating characteristic curve analysis, calculated the cutoff value and calculated the difference in diagnostic strength for periprosthetic joint infection between synovial fluid and blood serum analysis. The area under the curve was 0.977 for intra-articular CRP analysis and 0.979 for serum CRP analysis. The cutoff points for intra-articular CRP analysis where 1.8 mg/L and 2.8 mg/L. Both tests showed a very high diagnostic strength; the difference in diagnostic strength between synovial fluid and blood serum analysis was not significant (p = 0.66). PMID- 23926738 TI - Surgical management of grade I chondrosarcoma of the long bones. AB - The aim of this study was to compare the rates of local recurrence according to surgical treatment options in low-grade chondrosarcomas of the long bones. A retrospective review was made of 30 consecutive patients (12 male, 18 female) with a mean age of 40.7 years (range: 16-69 years) with intramedullary low-grade chondrosarcoma of the long bones treated either by intralesional curettage or wide resection at our institution between 1995 and 2011. The mean overall follow up was 74 months (range : 24-186 months). There was no difference in local recurrence rates between patients treated with intralesional resection or wide resection (p = 0.98). Intralesional curettage seems to be feasible in selected cases to reduce the patient's postoperative morbidity in Grade I chondrosarcoma cases. PMID- 23926739 TI - Comparison of cervical disc arthroplasty with anterior cervical discectomy and fusion for the treatment of cervical spondylotic myelopathy. AB - The clinical outcome of cervical disc arthroplasty for cervical spondylotic myelopathy (CSM) is still controversial. The authors retrospectively compared the intermediate term clinical outcome of cervical disc arthroplasty and traditional anterior cervical discectomy and fusion (ACDF). Seventy-six cases of single-level CSM with a minimum follow-up of two years were retrospectively analyzed. Thirty seven patients underwent single-level cervical disc arthroplasty (Bryan disc: 12 cases; Prestige LP disc: 25 cases), while the other 39 patients underwent single level ACDF. Significant improvement in SF-36 physical/ mental component scores and NDI score was found in both groups (p < 0.05); however, the arthroplasty group had significantly greater score improvement at each follow-up time point (p < 0.05). The JOA score and Nurick grade improved significantly at each time point in both groups (p < 0.05), but there were no significant differences between the groups (p > 0.05). The range of motion (surgical level and C2C7) remained unchanged in the arthroplasty group (p > 0.05), whereas it decreased significantly in the ACDF group (p < 0.05). The arthroplasty group had a lower incidence of complications than the ACDF group. The intermediate outcomes of cervical disc arthroplasty compared favourably to those of ACDF. Arthroplasty avoids complications from spinal fusion by preserving mobility. PMID- 23926740 TI - Total knee arthroplasty after former knee fusion in a patient with Ehlers Danlos syndrome. AB - A 46-year-old female patient with Ehlers-Danlos Syndrome had undergone fusion of her right knee 25 years before presentation. This markedly affected her quality of life. She underwent a two-stage conversion to a constrained rotating-hinge total knee arthroplasty. She regained a satisfying range of motion and she has a painfree, mobile and stable knee at 42 months follow-up. Conversion of knee fusion to TKA is a demanding procedure that should only be performed by experienced knee surgeons, in selected cases and on highly motivated patients. Complication and revision rates are reportedly very high but global satisfaction is surprisingly good. Ehlers-Danlos Syndrome was not shown to be a contraindication for such surgeries. PMID- 23926741 TI - Cerebrovascular infarction following bilateral total knee arthroplasty and tranexamic acid administration. AB - Tranexamic acid has been shown to reduce perioperative blood loss without increasing the risk of venous thromboembolism after total knee replacement. However studies to date were designed to assess efficacy as the primary outcome and were not powered to assess safety. We report the case of a 65-year-old male with a previously undiagnosed patent foramen ovale who suffered pulmonary emboli and cerebrovascular infarction after synchronous bilateral total knee replacement during which tranexamic acid was administered intravenously. PMID- 23926742 TI - Service knows no season. PMID- 23926743 TI - It's fruitcake season. PMID- 23926744 TI - The gold standard: MDA 2013 guest of honor Thomas McCarter. PMID- 23926745 TI - The top ten list of things we don't do anymore/the best of now. Part one. PMID- 23926746 TI - The effect of powder:liquid ratio and pre-mixing on sealing properties of Roth 801 sealer. AB - OBJECTIVES: To investigate the sealing ability of Roth 801 sealer mixed using two different powder/liquid ratios and prepared up to seven days prior to canal obturation. STUDY DESIGN: Of the 152 maxillary anterior teeth endodontically instrumented for this study, 144 were randomly assigned to the treatment group, and eight were assigned to the control group. Of the 144 teeth in the treatment group, 72 were obturated using gutta-percha and Roth 801 sealer mixed with a 10:1 ratio, while the remaining 72 were obturated with a sealer ratio of 7.5:1. Within both treatment groups, the teeth were further subdivided into six groups of 12 teeth based upon the amount of time between sealer mixing and canal obturation, which varied from 0 days to seven days. Teeth were analyzed with fluid filtration either immediately after obturation or 14 weeks after obturation. The data were analyzed using a three-way analysis of variance. RESULTS: For teeth tested at the time of obturation, leakage decreased for older sealer, p < 0.0001. After the 14 week storage period, there was no significant difference in leakage. No significant differences were noted between either powder/liquid ratios. CONCLUSIONS: Pre-mixed Roth 801 sealer maintained an apical seal when prepared up to seven days prior to canal obturation. Varying the powder/liquid ratio of Roth 801 sealer did not significantly affect the apical seal. PMID- 23926747 TI - Investment risk: too scared, or not scared enough? PMID- 23926748 TI - A question of balance. PMID- 23926749 TI - The power of family history. PMID- 23926750 TI - Helping children gain asthma control: bundled school-based interventions. AB - Following the success of a community asthma quality improvement initiative to improve outcomes for children with asthma attending Cincinnati Public Schools with school-based health centers (SBHC), several members of the original initiative formed a new asthma improvement collaborative to spread the initiative's improvement work to inner-city children with asthma attending other schools with and without SBHCs. This article describes the collaborative's plan, which features a nurse practitioner using bundled, evidence-based, school-based interventions to improve asthma control for inner-city children in high poverty schools. PMID- 23926751 TI - A telephone coaching intervention to improve asthma self-management behaviors. AB - Long recognizing that asthma, one of the most common chronic childhood diseases, is difficult to manage, the National Asthma Education Prevention Program developed clinical practice guidelines to assist health care providers, particularly those in the primary care setting. Yet, maintenance asthma care still fails to meet national standards. Therefore, in an attempt to improve and support asthma self-management behaviors for parents of children 5 to 12 years of age with persistent asthma, a novel nurse telephone coaching intervention was tested in a randomized, controlled trial. A detailed description of the intervention is provided along with parent satisfaction results, an overview of the training used to prepare the nurses, and a discussion of the challenges experienced and lessons learned. PMID- 23926752 TI - Children with autism spectrum disorder at a pediatric hospital: a systematic review of the literature. AB - This review of literature describes the behaviors of hospitalized children with autism spectrum disorder (ASD) that health care providers find challenging. It also identifies strategies used to address these challenging behaviors. The systematic review of literature identified 34 articles from databases on health care of challenging behaviors of children with ASD. The review identified four categories of challenging behaviors (non-compliance, hyperactivity, sensory defensiveness, self-injury) and several strategies for reducing these behaviors. Partnering with parents to develop strategies is important for children with ASD to deliver timely and safe care. PMID- 23926753 TI - Supporting refugee Somali Bantu mothers with children with disabilities. AB - This study sought to understand how local Somali Bantu refugee mothers perceive education or health needs of their children with disabilities. Using a grounded theory qualitative design, the investigator interviewed five Somali Bantu mothers and one father in their homes. Four predominant categories emerged from the data: Native Healing, Unmet Needs, Ongoing Challenges, and Helpful Helping. Study findings demonstrate the need for nurses and other health care providers to understand the refugee experience in raising children with special needs in Vermont. Better communication between providers and families on critical topics, such as etiology and treatment of disabilities, negotiating systems of care, and managing health and safety issues at home, is needed. The small number of participants with limited interaction is the greatest limitation of this study. PMID- 23926754 TI - Designing culturally appropriate studies. PMID- 23926755 TI - Making meaning after the death of a child: bereaved parents share their experiences. AB - Some 50,000 families experience the death of a child each year in the United States (Field & Behrman, 2003). Over time, some bereaved families find or develop approaches for "making meaning" from the experience in ways that allow them to maintain a sense of connection to their child, keep the child's memory alive, and help other families who may face similar circumstances. Interviews of three families demonstrate that the process of "making meaning" is individual and often builds on past strengths and interests. The stories shared by these three families demonstrate their individual approaches as well as common themes. PMID- 23926756 TI - Why does she have a rash at age four weeks? PMID- 23926757 TI - Super Storm Sandy. PMID- 23926758 TI - Reciprocal access agreements between BJOT, AJOT, and CJOT: new resources for occupational therapists around the world. PMID- 23926759 TI - Components of cognitive competence predictive of occupational competence in persons with dementia: a Delphi study. AB - BACKGROUND: Within the area of dementia care, occupational therapists are asked to predict occupational competence in everyday living and often do so by assessing cognitive competence. Considering the cognitive changes that occur with dementia over time, the construct of cognitive competence is a key consideration. Still, a gap exists in the literature examining the relationship between cognitive competence and occupational competence. PURPOSE: This study developed a consensus among participating Canadian occupational therapists regarding the components of cognitive competence they considered essential to predict occupational competence in people with dementia. METHOD: A three-round Delphi study was completed with English- and French-speaking occupational therapists (n = 127; 116; 125) experienced in dementia care. FINDINGS: Ten cognitive components were identified as essential to predict occupational competence in individuals with dementia. IMPLICATIONS: The 10 identified components provide direction for assessment practices and education in dementia care and for development of measurement tools. PMID- 23926760 TI - Working with transgender clients: learning from physicians and nurses to improve occupational therapy practice. AB - BACKGROUND: Gender identity disorder and the process of transitioning involve both mental and physical health, yet there is virtually no discussion of transgender health care in occupational therapy. PURPOSE: This study draws on interviews with primary-care nurses and physicians about their experience with transgender health care, extending the insights gleaned there to make suggestions for occupational therapy practice with this population. METHOD: Semi-structured interviews were conducted with 12 primary care nurses and 9 physicians who had clinical experience with lesbian, gay, and bisexual patients. FINDINGS: Participants felt uncertain about transgender care, wanting more specialized knowledge. Collaborating with patients, acknowledging stigma, ensuring inclusive systems and procedures, navigating health care, and providing holistic care emerged as key elements for best practice. Advocacy was a crucial part of care provision. IMPLICATIONS: Suggestions are provided for therapists to ensure that space and interactions are welcoming to transgender clients as well as suggestions for occupational therapy intervention in the transitioning process. PMID- 23926761 TI - Observation patterns of dynamic occupational performance. AB - BACKGROUND: Visual observation is a key component of both formal and informal occupational performance assessment, but it is unknown how therapists gather this visual information. PURPOSE: The purpose of this study was to explore observational behaviour of occupational therapists and non-health care professionals when watching videos of simulated clients post-stroke participating in everyday activity. METHOD: Ten licensed occupational therapists and 10 age-, gender-, and education level-matched participants completed this eye-tracking study. FINDINGS: Contrary to our past work with static image viewing, we found limited evidence of differences in eye movement characteristics between the two groups, although results did support the role of bottom-up information, such as visual motion, as a determinant of looking behaviour. IMPLICATIONS: These results suggest that understanding observational behaviour in therapists can be aided with eye-tracking methodology, but future studies should probe a broad range of factors that might influence observational behaviour and performance, such as assessment goals, knowledge, and therapist experience. PMID- 23926762 TI - Psychometric testing of a self-report measure of engagement in productive occupations. AB - BACKGROUND: Occupational therapists working with clients in productive occupations explicitly or implicitly assess their clients' occupational engagement. PURPOSE: To investigate the psychometric properties of the Profiles of Occupational Engagement in People with Severe Mental Illness: Productive Occupations (POES-P) in terms of internal consistency, initial construct validation, and floor and ceiling effects. METHOD: Participants (n = 93) from six day centres completed the data collection. Correlations between the POES-P and instruments measuring similar and dissimilar attributes, such as satisfaction, psychosocial functioning, and unmet needs, were studied. FINDINGS: A moderate relationship was found between the POES-P and occupational satisfaction (r(s) = 0.43) and a weak one with psychosocial functioning (r(s) = 0.22). The association with researcher-assessed participant engagement was slightly higher (r(s) = 0.37), and the relationship with unmet needs was nonsignificant (r(s) = -0.15). Internal consistency of the POES-P (alpha = 0.85) was good, but the distribution of responses indicated a ceiling effect. IMPLICATIONS: The POES-P seems promising for assessing engagement in work-like occupations but would benefit from further development. PMID- 23926763 TI - Promoting an occupational perspective in public health. AB - BACKGROUND: Although the value of occupation for health and well-being is fundamental to the occupational therapy profession, this view is not well recognized in the field of public health. PURPOSE: In this article, we argue that occupational therapists have a unique and valuable perspective to bring to the field of public health, particularly with respect to the importance of occupational engagement in promoting the health and well-being of Canadians. KEY ISSUES: There are many compelling reasons for public health advocacy, including the need to increase awareness of the health benefits and risks of occupational engagement for individuals and communities. Challenges that lie ahead, however, include issues related to terminology, the complexity of occupation, the need to consider multidimensional outcomes, and diversity of evidence. IMPLICATIONS: To move forward, the profession of occupational therapy in Canada needs to position health promotion messaging in a way that clearly captures the complexity and value of occupation and resonates with Canadians of all ages and abilities. PMID- 23926764 TI - A new species of Tunga (Siphonaptera: Tungidae) parasitizing cattle from Brazil. AB - Tunga hexalobulata (Siphonaptera: Tungidae), new species oftungid sand flea belonging to the penetrans group, is described with illustrations of adult female parasitizing Bos indicus (L., 1758) from Brazil. It differs from the 12 other known species of Tunginae by the presence of six anterior humps in the neosome. It also can be differentiated from other species of the penetrans group by lesser size of the neosome, presence of three posterodorsally bristles in antennal segment II, and the extension of the posterior arm of the preoral internal sclerotization. PMID- 23926765 TI - A new species of Rhipicephalus (Acari: Ixodidae), a parasite of giraffes in Kenya. AB - A new tick species belonging to the genus Rhipicephalus Koch, 1844 (Acari: Ixodidae), namely, Rhipicephalus walkerae n. sp., is described. The male and female of this species are similar to those of several species in the Rhipicephalus appendiculatus group but can be distinguished from them by the very dense pattern of medium-sized punctations covering the conscutum and scutum, long and narrow dorsal prolongation of the spiracular plate, and relatively short dorsal cornua; in addition, the male has long and narrow adanal plates without a posterolateral angle. R. walkerae is known only from Kenya, where the adults were collected from giraffes, Giraffa camelopardalis (L.). PMID- 23926766 TI - Reinstatement of Dermacentor kamshadalus Neumann (Acari: Ixodidae) as a valid species parasitizing mountain goats and sheep in the United States, Canada, and Russia. AB - Reexamination of Dermacentor albipictus (Packard, 1869) holdings stored in the United States National Tick Collection revealed several collections of a morphologically distinct Dermacentor species. Comparison of these specimens with other Dermacentor taxa showed that they are identical to an old taxon originally described as Dermacentor variegatus kamshadalus Neumann, 1908. For more than a century, this taxon was known only from the male holotype specimen collected in Russia, and the name was considered a junior synonym of D. albipictus. D. kamshadalus is reinstated here to a full species rank, and its male is redescribed and its female and nymph are described for the first time. Adults of D. kamshadalus can be distinguished from those of D. albipictus by a short spur on trochanters I, shorter spurs on coxae I, shorter dorsal cornua, more numerous perforations on spiracular plates, less numerous and shorter setae on idiosoma, especially around spiracular plates, and considerably paler coloration of the conscutum and scutum. The nymph of D. kamshadalus can be differentiated from that of D. albipictus by shorter spurs on coxae I and the numerous perforations on the spiracular plates. Adults and nymphs ofD. kamshadalus are recorded from the United States, Canada, and Russia, where they have been collected from mountain goats, Oreamnos americanus (de Blainville), bighorn sheep, Ovis canadensis Shaw, and sheep, Ovis sp. of which the species was not stated. PMID- 23926767 TI - A new species of Simulium (Gomphostilbia) (Diptera: Simuliidae) from Langkawi Island, Malaysia. AB - ABSTRACT A new black fly species, Simulium (Comphostilbia) langkawiense, is described based on adult female, adult male, pupal, and larval specimens collected from Langkawi Island, Malaysia. This new species is similar in the configuration of the pupal gill to Simulium (Comphostilbia) gombakense Takaoka & Davies, 1995, originally described from Peninsular Malaysia, but differs from the latter species by the female genital fork with an anterolaterally angulated plate on each arm, the female tarsal claw tooth shorter than one half of the claw, the small number of male upper-eye large facets, the ventral plate with its ventral margin nearly flat in the middle when viewed posteriorly, and the inflated structure of the pupal gill with a less produced middle portion (width of middle inflated portion: length of inflated structure = 0.24). Taxonomic notes are also given to separate this new species from two other related species from Nepal and India. This represents another example of a unique species of black fly on one of the continental islands of Peninsular Malaysia. PMID- 23926768 TI - First description of the immature stages and redescription of the adults of Cosmiomma hippopotamensis (Acari: Ixodidae) with notes on its bionomics. AB - Cosmiomma hippopotamensis (Denny, 1843) is one of the most unusual, beautiful, and rare tick species known to the world. All stages of this species possess a unique morphology, on the one hand making them easy to identify, while on the other they exhibit similarities to certain species of Amblyomma Koch, 1844, Dermacentor Koch, 1844, and Hyalomma Koch, 1844. Adults of C. hippopotamensis have been collected on only two occasions from their hosts, namely Hippopotamus amphibius L. and Diceros bicornis (L.), and have been recorded from only a few widely separated localities in East and southern Africa. Here, the larva and nymph are described and illustrated for the first time, while the male and female are illustrated and redescribed. Data on hosts, geographic distribution, and life cycle of C. hippopotamensis are also provided. PMID- 23926769 TI - Determinants of male Aedes aegypti and Aedes polynesiensis (Diptera: Culicidae) response to sound: efficacy and considerations for use of sound traps in the field. AB - Understanding the mating competitiveness of male mosquitoes in field settings is essential to programs relying on the mass release of modified male mosquitoes, yet studies on male ecology have been hampered by the lack of a convenient trapping method. An existing promising method makes use of the innate attraction of males to female flight tones. Here, we present laboratory, greenhouse, and field experiments on the efficacy of sound traps for the collection of Aedes aegypti (L.) and Aedes polynesiensis Marks, and laboratory experiments with Ae. aegypti on the effects of male age, size, and mating status on responsiveness to a range of frequencies. Age and mating status influenced the overall responsiveness to sound, whereas male size did not. There were no interactions between these factors and sound frequency. A Centers for Disease Control and Prevention miniature light trap modified to produce a tone of 465 Hz collected 76.2% of Ae. aegypti males in laboratory cages, and 49.7% of males in a greenhouse enclosure. In two sets of experiments in laboratory cages, 50.8 and 46.5% of male Ae. polynesiensis were captured with a trap producing a tone of 440 Hz. In the field, CDC miniature light traps or BG-Sentinel traps fitted with a portable speaker producing tones of 440 or 465 Hz captured significantly more male Ae. polynesiensis when placed near a male swarm than did traps that did not produce sound. When the trap was placed at a distance of 16.5 m from the nearest swarm, there was no significant difference in the number of males caught between control and sound-producing traps. The numbers of Ae. aegypti males captured were low under all circumstances in the field. PMID- 23926770 TI - Field evaluation of selected traps and lures for monitoring the filarial and arbovirus vector, Aedes polynesiensis (Diptera: Culicidae), in French Polynesia. AB - The efficacy of the BG-Sentinel (BGS) and the BG-Mosquitito (BGM) mosquito traps for sampling populations of the important filariasis and dengue vector Aedes (Stegomyia) polynesiensis (Marks) was evaluated in French Polynesia against human bait collections (HBC) using a modified Centers for Disease Control and Prevention backpack aspirator. Traps were baited with BG-Lure (a combination of lactic acid, ammonia, and caproic acid) or carbon dioxide plus octenol (1-octen-3 ol) known as attractants to aedine mosquitoes. Mosquito sampling was conducted on two typical islands of French Polynesia: the high, volcanic island of Moorea, and the low, coral island (atoll) of Tetiaroa Sampling efficacy was measured in a randomized Latin Square design. Production of carbon dioxide from yeast-sugar fermentation was used as an alternative source of CO2 because supply via dry ice, gas cylinders, or propane combustion in remote tropical islands is costly and challenging. Although the BGS trap captured the greatest number ofAe. polynesiensis in both island settings, catch rates of BGS or BGM baited with either lure were not significantly different from that of HBC. On Moorea, the number of collected aedes species in the BGS trap baited with either lure was significantly greater than the BGM with BG-lure. On Tetiaroa, BGM trapping was severely hampered by damage from rats, and the traps were removed from the study. Our study confirms the efficiency, comparability, and convenience of the BGS trap, a robust and safe alternative to HBC for sampling Aedes mosquitoes in research and surveillance efforts against filariasis and arboviruses in the South Pacific. PMID- 23926771 TI - Swarming behavior of Aedes polynesiensis (Diptera: Culicidae) and characterization of swarm markers in American Samoa. AB - We characterize the swarming behavior of male Aedes polynesiensis (Marks) in American Samoa. Instead of swarming around a blood host, males used the base of certain trees as a marker. Repeated sampling proved nondestructive and allowed us to investigate the impact of static (e.g., tree species) and dynamic (e.g., barometric pressure) characters on the likelihood of swarm presence and intensity. Tree circumference and oviposition activity (number of Ae. polynesiensis reared from oviposition cups) were significant positive predictors of the number of males in a swarm. Tree circumference and diameter were significantly positively associated, and canopy height was significantly negatively associated, with swarm occurrence. Comparisons between males swarming early and late during the swarming period allowed for insight into swarm composition in terms of male size and the amount of putative fluid (e.g., nectar) in the crop, indicators of energetic reserves. Males collected during the late period had significantly larger wings and less crop contents than did males of the early cohort. Because the ecology of male Ae. polynesiensis remains understudied, we consider how the current results could facilitate further studies related to applied autocidal strategies as well as the evolution of host based mating behavior. PMID- 23926772 TI - Gonotrophic development and survival in field populations of Musca domestica (Diptera: Muscidae) at dairies in California, Minnesota, and Georgia, and the relationship of fly age to relative abundance of (Z)-9-tricosene (muscalure). AB - Adult female Musca domestica L. were collected in 2004 and 2005 from dairies in California, Minnesota, and Georgia. Relative abundance of (Z)-9-tricosene (muscalure) among the dominant eight hydrocarbons was determined. Fly heads then were removed to quantify pterin levels and estimate fly age, abdomens were dissected to score gonotrophic development and parity (follicular relics), and spermathecae were examined for sperm. Daily survival was assessed using two estimates of time required to become gravid: laboratory-based degree-day (DD) estimates and estimates based on pterin values in field-collected flies matched to their stages of gonotrophic development. Among newly emerged females (oocyte stage 1) with detectable muscalure, it comprised < approximately 1.5% of cuticular hydrocarbons. In muscalure-positive flies, muscalure comprised a higher proportion of cuticular hydrocarbons in older flies from California and Minnesota (6-9% when gravid) versus flies from Georgia (<2% when gravid). Females mated in early-intermediate stages of egg development. Life expectancy, using laboratory derived estimates of time needed to become gravid, ranged from 3.6 to 10.6 d. Using equivalent pterin-based time estimates, life expectancy ranged from 4.0 to 19.5 d. Mean DD ages (12 degrees C threshold) of gravid flies varied widely (53 95 DD) and were congruent with laboratory-based estimates (52-57 DD) in only 7 of 12 farm-year combinations. Thus, house flies under natural conditions often required more time to develop eggs than laboratory models would predict, extending daily survival estimates based on gonotrophic age by 11-74%. PMID- 23926773 TI - Sand fly (Diptera: Psychodidae) abundance and species diversity in relation to environmental factors in parts of coastal plains of southern India. AB - Abundance pattern of sand flies in relation to several environmental factors, such as type of areas, dwellings, landforms, land usage pattern, and surface soil pH, was assessed in 81 areas or villages of Puducherry district, Puducherry Union Territory, located on the coastal plain of southern India, for three seasons, between November 2006 and October 2008, adopting hand-catch method. In total, 1,319 sand fly specimens comprising 12 species under two genera, viz., Phlebotomus and Sergentomyia, were collected. Among them, Phlebotomus (Euphlebotomus) argentipes Annandale & Brunetti, the vector of visceral leishmaniasis in India, was the predominant species in all habitats surveyed. The hierarchical cluster analysis showed that the density of sand flies was 10-fold higher in high-density group and fivefold higher in medium-density group, compared with the no or low-density group. Sand fly density was found to be influenced significantly with the type of areas, dwellings, landforms, land usage pattern, and surface soil pH in different groups. Rural areas located on fluvial landform with alkaline surface soil pH, supporting rice cultivation and luxuriant vegetation, are the most influencing factors that favor sand fly abundance and diversity in this district. PMID- 23926774 TI - Socioeconomic status affects mosquito (Diptera: Culicidae) larval habitat type availability and infestation level. AB - Mosquito populations are largely regulated by processes occurring at the larval stage. We sampled mosquito larval microhabitats (mostly water-holding containers) in six neighborhoods in the Washington, DC, area that varied in socioeconomic status (SES) and housing structure (row houses vs. stand-alone houses) to test associations among these neighborhood characteristics, microhabitat abundance and parameters, and mosquito occurrence and densities. Thirty-four percent (33.9%) of sampled microhabitats contained mosquito larvae, and 93.1% of larvae were Aedes albopictus Skuse or Culex pipiens L. Five specific container types (drains, corrugated flexible drainpipes, planters, garbage cans, and buckets) accounted for the majority of water-holding (56.0%) and mosquito-positive (50.6%) microhabitats sampled. We found no associations between SES or housing structure with total microhabitat abundance per yard, mosquito occurrence or mosquito densities per microhabitat. In contrast, container purpose varied with SES, with low SES neighborhoods having greater numbers of disused containers and lower numbers of functional containers than low and medium SES neighborhoods. Ae. albopictus were 83% more abundant in disused containers, whereas Cx. pipiens were more abundant in structural and functional containers, possibly owing to species specific oviposition and development related to water quality. Ae. albopictus densities increased over the summer, whereas Cx. pipiens densities remained constant. Ae. albopictus is usually the dominant pest in urban areas in the eastern United States; therefore, integrated mosquito management programs should incorporate the elimination of disused containers to reduce its infestation and adult production, especially in low SES neighborhoods where they occur most frequently. PMID- 23926776 TI - Flight height preference for oviposition of mosquito (Diptera: Culicidae) vectors of sylvatic yellow fever virus near the hydroelectric reservoir of Simplicio, Minas Gerais, Brazil. AB - In this study, the oviposition behavior of mosquito species exhibiting acrodendrophilic habits was investigated. The study was conducted near the Simplicio Hydroelectic Reservoir (SHR) located on the border of the states of Minas Gerais and Rio de Janeiro, Brazil. Samples were collected using oviposition traps installed in forest vegetation cover between 1.70 and 4.30 m above ground level during the months of April, June, August, October, and December of 2011. Haemagogus janthinomys (Dyar), Haemagogus leucocelaenus (Dyar and Shannon), Aedes albopictus (Skuse), and Aedes terrens (Walker) specimens were present among the collected samples, the first two of which being proven vectors of sylvatic yellow fever (SYF) in Brazil and the latter is a vector of dengue in mainland Asia. As the data set was zero-inflated, a specific Poisson-based model was used for the statistical analysis. When all four species were considered in the model, only heights used for egg laying and months of sampling were explaining the distribution. However, grouping the species under the genera Haemagogus Williston and Aedes Meigen showed a significant preference for higher traps of the former. Considering the local working population of SHR is very large, fluctuating, and potentially exposed to SYF, and that this virus occurs in almost all Brazilian states, monitoring of Culicidae in Brazil is essential for assessing the risk of transmission of this arbovirus. PMID- 23926775 TI - Overwintering biology of Culex (Diptera: Culicidae) mosquitoes in the Sacramento Valley of California. AB - At temperate latitudes, Culex (Diptera: Culicidae) mosquitoes typically overwinter as adult females in reproductive arrest and also may serve as reservoir hosts for arboviruses when cold temperatures arrest viral replication. To evaluate their role in the persistence of West Nile virus (WNV) in the Sacramento Valley of California, the induction and termination of diapause were investigated for members of the Culex pipiens (L.) complex, Culex tarsalis Coquillett, and Culex stigmatosoma Dyar under field, seminatural, and experimental conditions. All Culex spp. remained vagile throughout winter, enabling the collection of 3,174 females and 1,706 males from diverse habitats during the winters of 2010-2012. Overwintering strategies included both quiescence and diapause. In addition, Cx. pipiens form molestus Forskal females remained reproductively active in both underground and aboveground habitats. Some blood-fed, gravid, and parous Cx. tarsalis and Cx. pipiens complex females were collected throughout the winter period. Under both field and experimental conditions, Cx. tarsalis and Cx. stigmatosoma females exposed to autumnal conditions arrested primary follicular maturation at previtellogenic stage I, with primary to secondary follicular ratios <1.5 (indicative of a hormonally induced diapause). In contrast, most Cx. pipiens complex females did not enter reproductive diapause and ovarian follicles matured to >or=stage I-II (host seeking arrest) or were found in various stages of degeneration. Diapause was initiated in the majority of Cx. tarsalis and Cx. stigmatosoma females by mid late October and was terminated after the winter solstice, but host-seeking seemed limited by temperature. An accrual of 97.52 +/- 30.7 and 162.85 +/- 79.3 degree-days after the winter solstice was estimated to be necessary for diapause termination in Cx. tarsalis under field and seminatural conditions, respectively. An increase in the proportion of blood-fed Culex females in resting collections occurred concurrently with diapause termination in field populations based on ovarian morphometrics. WNV RNA was detected in one pool of 18 males and in a single blood-fed female Cx. tarsalis collected during winter. Therefore, both vertically and horizontally infected Culex females may persist through winter and possibly transmit WNV after diapause termination in late winter or early spring in the Sacramento Valley of California. PMID- 23926777 TI - Infectivity of Metarhizium anisopliae (Hypocreales: Clavicipitaceae) to Phlebotomus papatasi (Diptera: Psychodidae) under laboratory conditions. AB - Susceptibility of Phlebotomus papatasi Scopoli (Diptera: Psychodidae) larvae to the entomopathogenic fungus Metarhizium anisopliae (Metschinkoff) Sorokin (Ma79) (Hypocreales: Clavicipitaceae) was evaluated at two different temperatures. The ability of the fungus to reinfect healthy sand flies was followed up for approximately 20 wk and the effect of in vivo repassage on the enhancement of its virulence was assessed. The fungus reduced the adult emergence at 26 +/- 1 degrees C when applied to larval diet. Six spore concentrations were used in the bioassays ranging from 1 x 10(6) to 5 x 10(8) spores/ml. Mortality decreased significantly when the temperature was raised to 31 +/- 1 degrees C at all tested concentrations. Fungus-treated vials were assayed against sand fly larvae at different time lapses without additional reapplication of the fungus in the media to determine whether the level of inocula persisting in the media was sufficient to reinfect healthy sand flies. Twenty weeks postapplication, there were still enough infectious propagules of Ma79 to infect 40% of P. papatasi larvae. A comparison between the infectivity of 10 subsequent in vitro cultures and the host-passed inocula of the fungus against sand fly larvae was conducted. Mortalities of P. papatasi larvae changed significantly when exposed to inocula passed through different insects. Presented data can provide vector control decision makers and end users with fundamental information for the introduction and application of M. anisopliae as an effective control agent against the main cutaneous leishmaniasis old-world vector P. papatasi. PMID- 23926778 TI - Innovative sugar-insecticide feeding bioassay for adult female Anopheles gambiae (Diptera: Culicidae). AB - The primary malaria vector in sub-Saharan Africa, Anopheles gambiae Giles (Diptera: Culicidae), is an anthropophagic and endophilic mosquito targeted for control with insecticides applied to interior resting surfaces and impregnated onto bed net materials. Effective malaria vector management involves monitoring the insecticide susceptibility of mosquito populations. Contemporary bioassays are based on mosquito contact with insecticide residues. We developed an innovative insecticide bioassay system that involves mosquito ingestion of a sugar-insecticide solution. The sucrose-permethrin solution in our bioassay system contained Trypan blue dye, creating a visual marker of insecticide ingestion in the mosquito's abdomen. Blue fecal spots deposited in the bioassay container provided further evidence of mosquito feeding. We used our bioassay to characterize the permethrin susceptibility of adult females of two strains of A. gambiae, one of which was susceptible and the other exhibited reduced susceptibility to permethrin. We compared the dose-response of both strains to permethrin in a forced-contact filter paper bioassay. Both assay approaches produced similar dose-dependent mortality, indicating that the feeding bioassay had appropriately characterized permethrin susceptibility for both mosquito strains. PMID- 23926779 TI - Expression of insecticide resistance in immature life stages of Triatoma infestans (Hemiptera: Reduviidae). AB - The aim of the current study was to investigate the susceptibility to the insecticide deltamethrin and the expression of resistance to this insecticide in developing eggs and neonate nymphs of Triatoma infestans from two areas of Argentina (Campo Largo) and Bolivia (Entre Rios), where resistance to this pyrethroid is suspected. Both nymphal populations showed resistance to deltamethrin, with lower resistance ratio for Entre Rios (173X) than Campo Largo (1108X). Efficacy of deltamethrin on 4-, 7-, and 12-d-old eggs for both field populations were significantly lower than efficacy on eggs of the susceptible strain. This is the first documented evidence of the expression of pyrethroid resistance during the embryonic development of Chagas Disease vectors. PMID- 23926780 TI - Efficiency of three diets for larval development in mass rearing Aedes albopictus (Diptera: Culicidae). AB - A fundamental step in establishing a mass production system is the development of a larval diet that promotes high adult performance at a reasonable cost. To identify a suitable larval diet for Aedes albopictus (Skuse), three diets were compared: a standard laboratory diet used at the Centro Agricoltura Ambiente, Italy (CAA) and two diets developed specifically for mosquito mass rearing at the FAO/IAEA Laboratory, Austria. The two IAEA diets, without affecting survival to the pupal stage, resulted in a shorter time to pupation and to emergence when compared with the CAA diet. At 24 h from pupation onset, 50 and 90% of the male pupae produced on the CAA and IAEA diets, respectively, had formed and could be collected. The diet received during the larval stage affected the longevity of adult males with access to water only, with best results observed when using the CAA larval diet. However, similar longevity among diet treatments was observed when males were supplied with sucrose solution. No differences were observed in the effects of larval diet on adult male size or female fecundity and fertility. Considering these results, along with the relative costs of the three diets, the IAEA 2 diet is found to be the preferred choice for mass rearing of Aedes albopictus, particularly if a sugar meal can be given to adult males before release, to ensure their teneral reserves are sufficient for survival, dispersal, and mating in the field. PMID- 23926781 TI - Plant essential oils affect the toxicities of carbaryl and permethrin against Aedes aegypti (Diptera: Culicidae). AB - ABSTRACT Phytochemicals have been considered as alternatives for conventional pesticides because of their low mammalian toxicity and environmental safety. They usually display less potent insecticidal effects than synthetic compounds, but may express as yet unknown modes of action. In the current study, we evaluated 14 plant essential oils for their toxicities and synergistic effects with carbaryl and permethrin against fourth instars of Aedes aegypti (L.) as well as 5-7-d-old adults. Six essential oils showed significant synergistic effects with carbaryl at 10-50 mg/liter, but paradoxically all of them decreased the toxicity of permethrin against Ae. aegypti larvae. None showed toxicity or synergistic effects on Ae. aegypti adults, at doses up to 2,000 ng/ insect. The six essential oils displaying synergistic effects in Ae. aegypti larvae inhibited the in vitro activities of cytochrome P450 monooxygenases and carboxylesterases in the low milligram per liter range. The data indicated that cytochrome P450 monooxygenases and carboxylesterase were probably targets for these natural synergists. Thus, the mechanism of synergism was most likely inhibition of metabolism and not interacting target site effects. PMID- 23926782 TI - Evaluation of fipronil oral dosing to cattle for control of adult and larval sand flies under controlled conditions. AB - Visceral Leishmaniasis (VL) is a vector-borne disease endemic to the Indian subcontinent. The Phlebotomus genus of sand flies is the vector for VL in the Old World, with the vector on the Indian Subcontinent being Phlebotomus argentipes. Cattle are a commodity in this region and a frequent host source of P. argentipes bloodmeals. The purpose of this study was to determine the efficacy of a single oral dose fipronil against adult and larval P. argentipes. Ten Bos indicus cattle were used during the study in a controlled environment. The study was conducted in Bihar, India, and involved adult and larval bioassays using laboratory-reared P. argentipes. The results were positive in that they led to up to 100% mortality in both adult and larval sand flies over a 21-d period after a single dose of fipronil. PMID- 23926783 TI - Multiple blood feeding and host-seeking behavior in Aedes aegypti and Aedes albopictus (Diptera: Culicidae). AB - The body size of mosquitoes can influence a number of bionomic factors, such as their blood-feeding ability, host attack rate, and fecundity. All of these traits are important determinants of their potential to transmit diseases. Among abiotic and biotic factors, high temperature and low nutrition in the developing stages of mosquitoes generally result in small adults. We studied the relationship between body size and multiple feeding in a gonotrophic cycle and some fecundity attributes by using three strains of two competent vector species, Aedes aegypti (L.) and Aedes albopictus (Skuse). We raised small and large mosquitoes under low and high food conditions in the laboratory to measure parameters of fecundity and blood-feeding behavior. Fecundity was positively correlated with body size in both species, whereas the number of bloodmeals, the frequency of host-seeking behavior, and egg retention were negatively correlated with body size in the Ae. albopictus Nagasaki strain. We found that multiple feeding and host-seeking behavior were negatively correlated with body size, i.e., small mosquitoes tended to have more contact with hosts. We found that two mechanisms that inhibit engorged mosquitoes from seeking out hosts, distension-induced and oocyte-induced inhibition, were not strong enough to limit host-seeking behavior, and multiple feeding increased fecundity. Size-dependent multiple feeding and host-seeking behavior affect contact frequency with hosts and should be considered when predicting how changes in mosquito body size affect disease transmission. PMID- 23926784 TI - Expression of lysozyme in the life history of the house fly (Musca domestica l.). AB - From egg to adult, all life history stages of house flies associate with septic environments teeming with bacteria. House fly lysozyme was first identified in the larval midgut, where it is used for digestion of microbe-rich meals because of its broad-spectrum activity against gram-positive and gram-negative bacteria as well as fungi. This study aimed to determine the temporal expression of lysozyme in the life history of house flies (from egg through adults) on both the mRNA and protein level, and to determine the tissue-specific expression of lysozyme in adult flies induced by feeding Staphylococcus aureus. From 30-min postoviposition through adulthood, all life history stages of the house fly express lysozyme on the mRNA level. In adult flies, lysozyme is expressed both locally in the alimentary canal and systemically in the fat body. Interestingly, we found that during the normal life history of flies, lysozyme protein was only detected in larval stages and older adults, likely because of ingestion of immune stimulating levels of bacteria, not experienced during egg, pupa, and teneral adult stages. Constitutive expression on the mRNA level implies that this effector is a primary defense molecule in all stages of the house fly life history, and that a mechanism for posttranscriptional control of mature lysozyme enzyme expression may be present. Lysozyme active enzyme primarily serves both a digestive and defensive function in larval and adult flies, and may be a key player in the ability of Musca domestica L. to thrive in microbe-rich environments. PMID- 23926786 TI - Field responses of Anopheles gambiae complex (Diptera: Culicidae) in Liberia using yeast-generated carbon dioxide and synthetic lure-baited light traps. AB - Malaria infection is a serious public health problem throughout Liberia, but vector surveillance is limited or nonexistent in remote regions of the country. To better understand the spatial and temporal distribution of malaria vectors in Liberia and to support vector and malaria activities of the Liberian Ministry of Health, a study was conducted to determine the efficacy of light traps baited with a synthetic lure and CO2 for capturing Anopheles gambiae sensu lato (Giles). Traps with a ultraviolet, light-emitting diode, and incandescent lights baited with a synthetic skin lure and CO2 combinations were evaluated at four field sites in three counties of Liberia for five consecutive nights every 8 wk during 2011. In total, 4,788 mosquitoes representing 56 species from nine genera were collected throughout the 30-wk study; An. gambiae s. l. comprised 32% and of the148 An. gambiae s. s. collected, 85% were of the S form. A greater percentage of An. gambiae s. l. were collected in ultraviolet traps baited with a synthetic lure and CO2 compared with any other trap configuration. The influence of trap configuration on conclusions from surveillance efforts, specifically with regards to An. gambiae is discussed. PMID- 23926785 TI - Vector competence of Argentine mosquitoes (Diptera: Culicidae) for West Nile virus (Flaviviridae: Flavivirus). AB - We examined the ability of Culex pipiens L. complex mosquitoes from Argentina to vector West Nile virus (WNV) to assess their role in the transmission of WNV in South America. Several egg rafts of Culex spp. were collected from different breeding sites in the suburbs of the city of La Plata, Argentina, and a subset of each progeny was scored with morphological and genetic species indicators. Surprisingly, we did not find Cx. pipiens form pipiens, but found evidence of genetic hybrids of Culex quinquefasciatus and Cx. pipiens f. molestus. We then used morphological traits to create two colonies predominantly composed of one of these two taxa, although some hybrids are likely to have been included in both. These colonies were used in vector competence studies using NY99 and WN02 genotype strains of WNV obtained in New York State. As controls, we also tested colonies of U.S. Cx. quinquefasciatus and Cx. pipiens f. molestus. Additional Culex larvae from three drainage ditches near the cities of La Plata and Berisso, Argentina, were identified by morphological and high-resolution molecular markers (microsatellites) as Cx. quinquefasciatus Say, Cx. pipiens form molestus, and hybrids. Results indicate that Argentinian Culex are competent but only moderately efficient vectors of WNV and are less susceptible to this virus than comparable U.S. mosquito strains. Studies of vertical transmission of NY99 virus by Cx. pipiens f. molestus hybrids from Argentina yielded a minimal filial infection rate of 1.19 from females feeding during their second and later bloodmeals. PMID- 23926787 TI - Prevalence of Dirofilaria immitis (Nematoda: Filarioidea) in mosquitoes from northeast Arkansas, the United States. AB - A mosquito survey was conducted to identify which species of mosquitoes carry Dirofilaria immitis (Leidy) (Nematoda: Filarioidea), dog heartworm, in northeast Arkansas. Using polymerase chain reaction, mosquitoes were analyzed for D. immitis, Dirofilaria repens Railliet & Henry, and Acanthocheilonema dracunculoides Cobbold. Mosquitoes were collected from April to October 2009 using black light ultraviolet traps baited with dry ice. Sixteen mosquito species were identified. D. immitis was identified in nine mosquito species, which included Aedes vexans (Meigen), Anopheles quadrimaculatus Say, Anopheles punctipennis (Say), Culex pipiens quinquefasciatus Say, Culex erraticus (Dyer & Knab), Culiseta inornata (Williston), Psorophora columbiae (Dyer & Knab), Psorophora ferox (Humboldt), and Psorophora howardii Coquillett. No D. repens or A. dracunculoides DNA was amplified. Of the 1,212 mosquito pools tested, 7.3% were positive for D. immitis. Frequency of D. immitis infections from six collection sites ranged from 2.1 to 19.4%. Ae. vexans and An. quadrimaculatus were the two most abundant species, composing 58.7 and 23.7% of the total mosquitoes collected, with 9.6 and 6.9% of pools positive for D. immitis, respectively. To investigate localized vector infection rates of D. immitis, mosquitoes were collected from inside the kennel of a heartworm-positive dog. Of the 114 mosquitoes collected, 84 (73.7%) were positive for D. immitis. The frequency of D. immitis-infected mosquitoes collected near a heartworm-positive dog was considerably higher than in the original six collection sites, suggesting a single heartworm-positive dog potentially increases infection pressure on susceptible animals sharing mosquito exposure. PMID- 23926788 TI - Cell phone-based system (Chaak) for surveillance of immatures of dengue virus mosquito vectors. AB - Capture of surveillance data on mobile devices and rapid transfer of such data from these devices into an electronic database or data management and decision support systems promote timely data analyses and public health response during disease outbreaks. Mobile data capture is used increasingly for malaria surveillance and holds great promise for surveillance of other neglected tropical diseases. We focused on mosquito-borne dengue, with the primary aims of: 1) developing and field-testing a cell phone-based system (called Chaak) for capture of data relating to the surveillance of the mosquito immature stages, and 2) assessing, in the dengue endemic setting of Merida, Mexico, the cost effectiveness of this new technology versus paper-based data collection. Chaak includes a desktop component, where a manager selects premises to be surveyed for mosquito immatures, and a cell phone component, where the surveyor receives the assigned tasks and captures the data. Data collected on the cell phone can be transferred to a central database through different modes of transmission, including near-real time where data are transferred immediately (e.g., over the Internet) or by first storing data on the cell phone for future transmission. Spatial data are handled in a novel, semantically driven, geographic information system. Compared with a pen-and-paper-based method, use of Chaak improved the accuracy and increased the speed of data transcription into an electronic database. The cost-effectiveness of using the Chaak system will depend largely on the up-front cost of purchasing cell phones and the recurring cost of data transfer over a cellular network. PMID- 23926789 TI - Effect of variable rates of daily sampling of fly larvae on decomposition and carrion insect community assembly: implications for forensic entomology field study protocols. AB - Experimental protocols in forensic entomology successional field studies generally involve daily sampling of insects to document temporal changes in species composition on animal carcasses. One challenge with that method has been to adjust the sampling intensity to obtain the best representation of the community present without affecting the said community. To this date, little is known about how such investigator perturbations affect decomposition-related processes. Here, we investigated how different levels of daily sampling of fly eggs and fly larvae affected, over time, carcass decomposition rate and the carrion insect community. Results indicated that a daily sampling of <5% of the egg and larvae volumes present on a carcass, a sampling intensity believed to be consistent with current accepted practices in successional field studies, had little effect overall. Higher sampling intensities, however, slowed down carcass decomposition, affected the abundance of certain carrion insects, and caused an increase in the volume of eggs laid by dipterans. This study suggests that the carrion insect community not only has a limited resilience to recurrent perturbations but that a daily sampling intensity equal to or <5% of the egg and larvae volumes appears adequate to ensure that the system is representative of unsampled conditions. Hence we propose that this threshold be accepted as best practice in future forensic entomology successional field studies. PMID- 23926790 TI - Influence of resources on Hermetia illucens (Diptera: Stratiomyidae) larval development. AB - Arthropod development can be used to determine the time of colonization of human remains to infer a minimum postmortem interval. The black soldier fly, Hermetia illucens L. (Diptera. Stratiomyidae) is native to North America and is unique in that its larvae can consume a wide range of decomposing organic material, including carrion. Larvae development was observed on six resources: control poultry feed, liver, manure, kitchen waste, fruits and vegetables, and fish rendering. Larvae fed manure were shorter, weighed less, and took longer to develop. Kitchen waste produced longer and heavier larvae, whereas larvae fed fish had almost 100% mortality. Black soldier flies can colonize human remains, which in many instances can coincide with food and organic wastes. Therefore, it is necessary to understand black soldier fly development on different food resources other than carrion tissue to properly estimate their age when recovered from human remains. PMID- 23926791 TI - Household model of Chagas disease vectors (Hemiptera: Reduviidae) considering domestic, peridomestic, and sylvatic vector populations. AB - ABSTRACT Disease transmission is difficult to model because most vectors and hosts have different generation times. Chagas disease is such a situation, where insect vectors have 1-2 generations annually and mammalian hosts, including humans, can live for decades. The hemataphagous triatominae vectors (Hemiptera: Reduviidae) of the causative parasite Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae) usually feed on sleeping hosts, making vector infestation of houses, peridomestic areas, and wild animal burrows a central factor in transmission. Because of difficulties with different generation times, we developed a model considering the dwelling as the unit of infection, changing the dynamics from an indirect to a direct transmission model. In some regions, vectors only infest houses; in others, they infest corrals; and in some regions, they also infest wild animal burrows. We examined the effect of sylvatic and peridomestic vector populations on household infestation rates. Both sylvatic and peridomestic vectors increase house infestation rates, sylvatic much more than peridomestic, as measured by the reproductive number R0. The efficacy of manipulating parameters in the model to control vector populations was examined. When R0 > 1, the number of infested houses increases. The presence of sylvatic vectors increases R0 by at least an order of magnitude. When there are no sylvatic vectors, spraying rate is the most influential parameter. Spraying rate is relatively unimportant when there are sylvatic vectors; in this case, community size, especially the ratio of houses to sylvatic burrows, is most important. The application of this modeling approach to other parasites and enhancements of the model are discussed. PMID- 23926792 TI - A new ovitrap made of slow release natural materials containing pyriproxyfen for Aedes aegypti (Diptera:Culicidae) control. AB - ABSTRACT This initial study is aimed to measure the performance of incorporating pyriproxyfen in natural materials with low environmental impact to obtain slow release formulations that can be used as larvicidal or autocidal ovitraps avoiding hatched Aedes aegypti (L.) eggs to emerge as adults. Hollow candles made of beeswax or paraffin:stearin 1:1 mixture containing pyriproxyfen 0.01 and 0.05% were prepared and used as holding water containers for larval bioassay. Pyriproxyfen was released quickly into the larvae-breeding water. Ae. aegypti larvae were introduced immediately after the addition of tap water to the hollow candles (t = 1 min) or after 1, 4, and 8 h. More than 40% of the larvae did not emerge as adults for t = 1 min, reaching 80-100% when the larvae were added after 1 or 4 h, respectively. The hollow candles were kept at room temperature, and water was replaced every 15 d. Bioassays performed every 30 d showed that the residual activity obtained for both matrices and both concentrations of pyriproxyfen was higher than 360 d, with 100% inhibition of adult emergence. PMID- 23926793 TI - Molecular identification of sand flies (Diptera: Psychodidae) in eastern North America by using PCR-RFLP. AB - Sand flies (Diptera: Psychodidae) are small blood-feeding dipterans that are primary vectors of numerous human and livestock pathogens. Effective surveillance programs with accurate identification tools are critical in development and implementation of modern integrated pest management programs. Although morphological keys are available for North American species, identification can still be challenging owing to the nature of sample preparation and incompatibility with molecular or biochemical-based pathology assays. Further, the potential for introduction of Old World or other exotic species is not accounted for by current keys. Herein, we present the development and validation of a restriction fragment-length polymorphism-based molecular identification method. Specifically, cytochrome c oxidase subunit I, a mitochondrial DNA marker, was used to distinguish two species of adult sand flies indigenous to eastern North America with two exotic species not yet known to occur in the United States. PMID- 23926794 TI - Discovery of microRNAs of the stable fly (Diptera: Muscidae) by High-throughput sequencing. AB - The stable fly, Stomoxys calcitrans (L.), is a serious ectoparasite affecting animal production and health of both animals and humans. Stable fly control relies largely on chemical insecticides; however, the development of insecticide resistance as well as environmental considerations requires continued discovery research to develop novel control technologies. MicroRNAs (miRNAs) are a class of short noncoding RNAs that have been shown to be important regulators of gene expression across a wide variety of organisms, and may provide an innovative approach with regard to development of safer more targeted control technologies. The current study reports discovery ad initial comparative analysis of 88 presumptive miRNA sequences from the stable fly, obtained using high-throughput sequencing of small RNAs. The majority of stable fly miRNAs were 22-23 nt in length. Many miRNAs were arthropod specific, and several mature miRNA sequences showed greater sequence identity to miRNAs from other blood-feeding dipterans such as mosquitoes rather than to Drosophilids. This initial step in characterizing the stable fly microRNAome provides a basis for further analyses of life stage-specific and tissue-specific expression to elucidate their functional roles in stable fly biology. PMID- 23926795 TI - PCR detection of the 14.5 antibacterial NlpC/P60-like Dermatophagoides pteronyssinus protein in Dermatophagoides farinae (Acari: Pyroglyphidae). AB - House dust mites produce antibacterial proteins suppressing bacterial growth. The 14.5-kDa bacteriolytic protein (UniProtKB Q8MWR6) has been known in Dermatophagoides pteronyssinus Trouessart. We have applied polymerase chain reaction and reverse transcription-PCR to detect a homologous gene sequence coding for a Q8MWR6-related protein in Dermatophagoides farinae (Hughes) using genomic DNA and total RNA, respectively. The resulting PCR product of expected size, 243 bp, was obtained from both Dermatophagoides spp., while no amplification was achieved from stored product mite samples. Sequence of the gene fragment from D. farinae showed 83% similarity to the previously described one in D. pteronyssinus. Successful amplification of the expected product from cDNA generated with oligo-dT primer implies that the NlpC/P60-like protein in Dermatophagoides mites is of eukaryotic or mite origin. PMID- 23926796 TI - Control of cytolocalization and mechanism of cell death by encapsulation of a photosensitizer. AB - The most challenging and wanted development in photodynamic therapy is the control of photosensitizer (PS) cytolocalization and the mechanism of cell death. 5,10,15-triphenyl-20-(3-N-methylpyridinium-yl)porphyrin (3MMe) administered to HeLa cells as DMSO solution accumulates in the cytoplasmic membrane (CM) where it causes severe photodamage and cell necrosis. In contrast, when incorporated in marine atelocollagen/xantham gum polymeric nanocapsules, the PS is shuttled through CM allowing its gradual release and accumulation in mitochondria and lysosomes. Little photodamage was caused to cells in this case, but compelling evidences are presented showing that encapsulation changes the cytolocalization and shifts the cell death mechanism from necrosis to apoptosis. In conclusion, both of those challenges can be overcome by encapsulation of typical PSs such as 3MMe by using the new concept of photodynamic treatment with minimal cell damage by targeting specifically some key organelles. We are confident that these findings are important for the development of more efficient photosensitizers tailored to induce apoptosis while minimizing undesirable side effects such as over-inflammation. PMID- 23926797 TI - Vascular-inducing poly(glycolic acid)-collagen nanocomposite-fiber scaffold. AB - For regenerative medicine with scaffolds, the immediate cellularization of the scaffold accompanied by angiogenesis inside is an important event. Such the aim is generally pursued by combining basic fibroblast growth factor (b-FGF) or vascular endothelial growth factor (VEGF) with the scaffold. In this study, we produced the nanocomposite nanofiber composed of poly(glycolic acid), PGA, and collagen to accomplish the recruitment of host cells and peripheral blood vessels without the bio-derived matter like growth factors. Structural analysis revealed that the fiber has the sheath-core like structure in which the surface region is abundant in PGA and the core region is abundant in collagen. This peculiar fibrous structure probably contributes the fragility of the fiber under the swelling in body fluid. The results of the animal experiment demonstrated that the PGA-collagen nanofiber sponge was entirely populated and vascularized within 5 days after the implantation. We hypothesized that the early fragmentation of the implanted fibrous sponge accelerated the host's inflammation reaction by phagocytized by macrophage, which followed by the recruitment of the fibroblasts and endothelial cells from the host tissue. Designing the suitable nanoscale structure of materials makes cellularization and vascularization of the scaffold possible without bio-derived factors. PMID- 23926798 TI - Surface modification of stainless steel orthopedic implants by sol-gel ZrTiO4 and ZrTiO4-PMMA coatings. AB - In this paper, the biocompatibility of a medical-grade stainless steel coated with sol-gel derived, nanostructured inorganic ZrTiO4 and hybrid ZrTiO4-PMMA thin films is correlated with surface characteristics. The surfaces of the samples are characterized by atomic force microscopy, the sessile drop technique, and electrochemical corrosion experiments. The viability of adult human mesenchymal stem cells on the surfaces after one day of culture is also assessed quantitatively and morphologically. According to the results, both of the coatings improve the hydrophilicity, corrosion resistance, and thereby cytocompatibility of the substrate. Despite the higher corrosion protection by the hybrid coating, the sample coated with the inorganic thin film exhibits a better cell response, suggesting the domination of wettability. In summary, the ZrTiO4-based sol-gel films can be considered to improve the biocompatibility of metallic implants. PMID- 23926799 TI - Novel nanoparticles generated by polymeric amphiphiles with pi-pi conjugated small molecules for anti-tumor drug delivery. AB - In recent years, the self-assembly polymeric nanoparticles are widely used for anti-tumor drug delivery. Multiple interactions such as hydrogen bonding, host guest interaction, hydrophobic interaction and electrostatic interaction have been utilized to generate the nanoparticles. Herein, a new polymeric amphiphile with methoxy poly(ethylene glycol) (mPEG) as hydrophilic block and pi-pi conjugated small molecule N-(9-Fluorenylmethoxycarbonyl)-L-phenylalanines (Fmoc Phe-OH) instead of hydrophobic polymer chain as lipophilic segment was synthesized. Anti-tumor drug doxorubicin (DOX) was trapped in the self-assembly nanoparticles via the dual hydrophobic and pi-pi stacking interactions. The synthesis and morphology of the self-assembly nanoparticles were studied. The interactions between drug and carrier, release profile, cellular uptake and in vitro anti-tumor efficiency of the drug loaded nanoparticles were investigated in details. The results showed that the amphiphiles self-assembled into spindle nanoparticles with the size around 200 nanometers. The pi-pi stacking interaction between DOX and Fmoc-Phe-OH achieved great performance for the efficient drug encapsulation. The DOX could be sustaingly released for 50 hours. The drug loaded nanoparticles were internalized in HepG2 cancer cells efficiently and exhibited good anti-tumor activity in vitro. The nanoparticles generated by mPEG-Phe-Fmoc amphiphiles provided a new strategy to fabricate polymeric nanoparticles for anti tumor drug delivery. PMID- 23926800 TI - A tissue engineered renovascular graft composed of proteins, polymers, smooth muscle and endothelial cells for renal artery stenosis. AB - Endarterectomy and bypass surgery to treat renal artery stenosis are increasingly shunned these days due to high risks of complications during and after the surgery. Striving to find a sound alternative solution, we pioneered the construction of a tissue engineered renovascular graft that could immediately restore the normal blood flow to kidneys and sustain renal functions without suffering restenosis after the surgery. A highly porous scaffold was first constructed by electrospinning polycaprolactone, poliglecaprone, gelatin and elastin, giving the vast majority of non-woven fibers in the scaffold a diameter below 1200 nm. To recapitulate the anatomical and functional signatures of renal arteries, a bi-layer vasculature comprising a smooth muscle layer topped by an endothelial layer was built on the scaffold. The vasculature witnessed a sustained proliferation for up to 10 days in vitro and robustly secreted prostacyclin and endothelin-1, evidencing that the vasculature was functionally comparable to native renal arteries. After 30 days as a renovascular graft in mice, the luminal diameter of the graft remained clear without a restenosis and an increased confluence of the endothelial layer was observed. The tensile test confirmed that the renovascular graft was mechanically superior to native renal arteries and retained this advantage within 30 days in vivo. Also, this renovascular graft sustained renal functions as evidenced by normal levels of serum creatinine, urine creatinine and serum urea nitrogen and the lack of edema in the kidney cortex. These results demonstrate that this renovascular graft holds a great therapeutic promise for renal artery stenosis. PMID- 23926801 TI - Tumor delivery efficiency and apoptosis enhancement by EVO nanoparticles on murie hepatic carcinoma cell line H22. AB - Nanoscale particles, as drug carriers, have a potential to improve drug therapeutic efficiency. However, the feasible design of the nanostructure containing chemotherapeutic agents and the behavior of the delivery to tumor tissues and cells has not been adequately investigated. In this study, we developed a novel nanoparticle, consisting of a gelatinase-cleavage peptide with poly(ethylene glycol) (PEG) and poly(epsilon-caprolactone) (PCL)-based structure for tumor-targeted EVO (an alkaloid isolated from Evodia rutaecarpa) delivery. We found that EVO-NPs were transformed by gelatinases, which could significantly promote drug release and enhance the cellular uptake of EVO (P < 0.01). In vivo biodistribution study demonstrated that targeted EVO-NPs could accumulate and remain in the tumor regions. Moreover, EVO-NPs exhibited higher tumor growth suppression than EVO on hepatic H22 tumor model via intravenous administration (P < 0.01). Both in vitro and in vivo experiments suggested that the gelatinase mediated nanoscale delivery system was promising for improvement of antitumor efficacy in various over-expressed gelatinase cancers. PMID- 23926802 TI - Surface functionalized gold nanoparticles for drug delivery. AB - Gold nanoparticles have been widely explored as cancer therapeutics and diagnostic agents in recent years. With their unique subcellular size and good biocompatibility, gold nanoparticles are a promising drug delivery vehicle. In this study, folic acid-coated gold nanoparticles conjugated with fluorophore FITC through amine terminated poly(ethylene glycol) were prepared and confocal microscopy together with bright-field differential interference contrast imaging data showed that folic acid-coated gold nanoparticles accumulated mainly in cytoplasm of primary human fibroblasts, without causing any observable cytotoxicity upon exposure for 48 hours. Through the further development of a drug delivery system that conjugates doxorubicin onto the surface of gold nanoparticles with a poly(ethylene glycol) spacer via an SMCC linker, we demonstrated that multidrug resistance in cancer cells can be significantly overcome by a combination of highly efficient cellular entry and enhanced cytotoxicity of Au-SMCC-DOX nanoconjugates, as revealed both by confocal microscopy imaging and cytotoxicity assay. The prepared Au-SMCC-DOX nanoconjugates demonstrated enhanced drug accumulation and retention in multidrug resistant hepG2-R cancer cells when it was compared with free doxorubicin, with a cytoplasm accumulation profile. The results indicated that gold nanoparticles are a kind of promising drug delivery vehicle with good biocompatibility and suitable for further applications in drug delivery for improved chemotherapy, especially for overcoming multidrug resistance. PMID- 23926803 TI - Human dental pulp stem cell behavior using natural nanotolith/bacterial cellulose scaffolds for regenerative medicine. AB - Adhesion and Viability study with human dental pulp stem cell using natural nanotolith/bacterial cellulose scaffolds for regenerative medicine are presented at first time in this work. Nanotolith, are osteoinductors, i.e., they stimulate bone regeneration, enabling higher cells migration for bone tissue regeneration formation. This is mainly because nanotoliths are rich minerals present in the internal ear of bony fish. In addition, are part of a system which acts as a depth sensor and balance, acting as a sound vibrations detector and considered essential for the bone mineralization process, as in hydroxiapatites. Nanotoliths influence in bacterial cellulose was analyzed using transmission infrared spectroscopy (FTIR). Results shows that fermentation process and nanotoliths agglomeration decrease initial human dental pulp stem cell adhesion however tested bionanocomposite behavior has cell viability increase over time. PMID- 23926804 TI - Fabrication of an electrochemical biosensor array for simultaneous detection of L glutamate and acetylcholine. AB - Using two nano-porous pseudo carbon paste electrodes (Nano-PPCPEs) as the working electrodes, a saturated calomel electrode as the reference electrode, and a Pt electrode as the counter electrode to form a four-electrode system, a novel type of glutamate-acetylcholine electrochemical biosensor array was successfully fabricated. It was shown that the biosensor array displayed a high selectivity and sensitivity and the selective and simultaneous determination of glutamate and acetylcholine (ATCh) is feasible. For L-glutamate, a linear range from 5 x 10(-7) M to 1 x 10(-5) M with the detection limit of 2.5 x 10(-7) M was demonstrated, while for ATChl the linear range is from 5 x 10(-6) M to 2 x 10(-4) M with the detection limit of 1.5 x 10(-7) M. This research means a possibility to simultaneously detect more neurotransmitters with a nano-PPCPEs electrochemical biosensor array. PMID- 23926805 TI - Biocompatibility of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) nanofibers for skin tissue engineering. AB - Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) a biodegradable polymer, was electrospun to obtain defect-free nanofibers. The structural similarity of PHBV nanofibers and the extracellular matrix in skin may present well for fibroblast cell adhesion and proliferation. The average fiber diameter of the electrospun fibers was 583 +/- 90 nm. The potential of PHBV scaffolds for human keratinocytes (HaCaT) adhesion, proliferation and gene expression were evaluated. Our results demonstrated that PHBV nanofibers favor HaCaT adhesion and proliferation. After 14 days of culture, loricrin and keratin-1 gene expression were significantly higher when compared to 3 and 7 days (p < 0.05). The expression of genes associated with T lymphocyte activation (HLA-DRB, thymosin beta 10 (h-Tim)) and IL-2 mediated lymphocyte activation genes (h-Tim, Tumour Rejection Antigen (TRA 1), nRap 2) were investigated in human lymphocyte cultured on PHBV nanofibers. T Lymphocyte activation and IL-2 mediated lymphocyte activation genes were down regulated after 48 and 72 hours of culture. After 24, 48 and 72 hours of culture there was no inflammatory cytokines production by the cultured lymphocytes. Thus, our results confirm the biocompatibility of PHBV nanofibers and suggest that consideration can be given to the use of PHBV nanofibers for skin tissue engineering applications. PMID- 23926806 TI - Nanostructural response of mitomycin C application on human scleral tissues. AB - This study quantitatively examined short-term effects of 0.02% Mitomycin C (MMC) treatment on the nanostructural changes in human scleral collagen fibrils. Histologic analysis and non-contact mode atomic force microscopy (AFM) were employed to assess the ultrastructural changes in the morphological characteristics of human sclera before and after 0.02% MMC application for 1 and 3 min. The scleral collagen fibrils treated with 0.02% MMC for 1 min showed no significant change in the morphology of collagen fibrils, and a significant change (p < 0.05) in the thickness of scleral tissues and collagen density, compared to the controls. 0.02% MMC application for 3 min led to a significant increase (p < 0.001) in the mean fibril diameter (185.43 +/- 22.64 nm vs. 140.72 +/- 18.06 nm), thickness (0.81 +/- 0.03 mm vs. 0.54 +/- 0.05 mm) and collagen density (1.16 times), compared to the controls This study examined the nanostructural changes in the scleral collagen fibrils before and after MMC application by AFM technique combined with conventional histological analysis (Hematoxylin-eosin and Masson's trichrome). This result indirectly suggests that long-term MMC application might increase the incidence of complications like a scleromalcia. PMID- 23926807 TI - Fabrication of carbon nanotubes/RGD peptide composites to enhance electrochemical performance of cell chip. AB - A cell chip is a valuable tool to evaluate the effects of anticancer drugs, antibiotics and environmental toxicants on various kinds of cells. In this study, a conductive composite material composed of multi-walled carbon nanotubes (CNTs) and RGD-MAP-C peptide was fabricated on gold electrode surface for enhancing electrochemical signals from HEK293T cells. The topological characteristics and electrochemical performance of composite materials with different concentrations of CNTs were analyzed by scanning electron microscopy and cyclic voltammetry (CV), respectively. CNTs/RGD peptide composites (CP) electrode containing 20 microg/ml CNT was found to be excellent for improving the sensitivity of cell chip compared with that of bare gold or RGD peptide modified electrode. Finally, two kinds of nephrotoxic antibiotics were treated to HEK293T cells and their toxicity were successfully monitored by CV. Our CP composites can be used as a suitable conducting material for the fabrication of various kinds of cell-based chips. PMID- 23926808 TI - Inflammatory effect of monopolar radiofrequency treatment on collagen fibrils in rabbit skins. AB - This study quantitatively examined the effects of monopolar radiofrequency (RF) treatment on the progressive nanostructural changes in the inflammatory effect of in vivo rabbit dermal collagen fibrils during postoperative 7 days. Conventional histologic analysis and atomic force microscopy (AFM) were employed to assess the nanostructural dermal response in 6 RF groups that underwent 2 passes of RF treatments (10 and 20 W), and 1 untreated control rabbit. After monopolar RF treatment, the rabbit skin clearly showed changes in the collagen network structure. The RF-treated group showed regular parallel arrangement of collagen fibrils whereas normal group showed tangled nanostructures. This phenomenon was remarkable at postoperative 7 days. Therefore, monopolar RF treatment leads to underlying collagen contracture and promotes new collagen formation. A multi-pass treatment of low-energy RF led to the highest contraction of collagen fibrils at the nanostructural level, compared to a single pass of high-energy RF. PMID- 23926809 TI - Stimulatory effects of zinc oxide nanoparticles on visual sensitivity and electroretinography b-waves in the bullfrog eye. AB - During the last decade, a large number of studies have focused on the development of nanomaterials for medical applications. Therefore, the present study was designed to evaluate the stimulatory effects of zinc oxide nanoparticles in the vertebrate visual system. Zinc oxide nanoparticles were synthesized and characterized through photoluminescence, ultraviolet (UV)-visible spectroscopy, field emission scanning electron microscopy and X-ray diffraction measurements. Furthermore, various electrophysiological recordings were obtained from the bullfrog eyecup preparations under various treatment conditions. Photoluminescence data showed a central peak at 386 nm while the UV-visible spectrum showed a sharp absorption band centered around 367 nm. Field emission scanning electron microscopy and X-ray diffraction measurements showed that synthesized zinc oxide nanoparticles have a polycrystalline wurtzite structure, with a round to oval shape and an average particle size of > 40 nm. Electroretinography (ERG) demonstrated that zinc oxide nanoparticles significantly increased the ERG b-wave amplitude in dark-adapted bullfrog eyecups and in the presence of background illumination. Zinc oxide nanoparticles also improved the visual sensitivity by 0.7 log unit of light intensity and shortened the duration of rhodopsin regeneration. Based on the results obtained, it was concluded that zinc oxide nanoparticles may be used to improve visual functions. The present study may add new dimensions to the biomedical applications of nanomaterials in eye research. PMID- 23926810 TI - Novel multifunctional biocompatible gelatin-oleic acid conjugate: self-assembled nanoparticles for drug delivery. AB - In this work, a novel, biocompatible conjugates of gelatin and oleic acid (GOC) were synthesized by a novel aqueous solvent-based method that overcame challenges of completely contrary solubility between gelatin and oleic acid (OA). The GO nanoparticles (GONs) and Paclitaxel encapsulated nanoparticles (PTX-GON) were prepared by self-assembly in water. These nanoparticles (NPs) were then conjugated with folic acid (FA) for targeting cervical cancer cells (Hela cells) and were characterized for their various physicochemical and pharmaceutical properties. Fourier transform infrared spectroscopy (FT-IR) and 1H NMR studies indicated the successful synthesis of GOC which showed low critical aggregation concentration in water (0.015 mg/ml). All NPs were stable in human blood serum and their mean diameters were below 300 nm suitable for passive targeting. Powder X-ray diffraction (PXRD) diffractograms showed the reduction in drug crystallinity and hence, leading to the solubility enhancement of PTX. The release of PTX from both PTX-GON and FA conjugated PTX-GON (PTX-FA-GON) was controlled for a long time. The cytotoxicity results demonstrated great advantages of PTX-FA-GON and PTX-GON over the conventional dosage form of pacliaxel (Taxol). These results, therefore, indicate that GOC is a promising material to prepare drug encapsulated NP as a controlled delivery system and PTX FA-GON is a potential targeted delivery system for cancer therapy. PMID- 23926812 TI - [Advances in cataract surgery]. PMID- 23926811 TI - Evaluation of a new biocompatible poly(N-(morpholino ethyl methacrylate)-based copolymer for the delivery of ruthenium oligonucleotides, targeting HPV16 E6 oncogene. AB - This study investigates the use of a new biocompatible block copolymer poly(2 (dimethylamino)ethyl methacrylate-N-(morpholino)ethyl methacrylate (PDMAEMA-b PMEMA) for the delivery of a particular antisense oligonucleotide targeting E6 gene from human papilloma virus. This antisense oligonucleotide was derivatized with a polyazaaromatic Ru(II) complex which, under visible illumination, is able to produce an irreversible crosslink with the complementary targeted sequence. The purpose of this study is to determine whether by the use of a suitable transfection agent, it is possible to increase the efficiency of the antisense oligonucleotide targeting E6 gene, named Ru-P-4. In a recent study, we showed that Oligofectamine transfected Ru-P-4 antisense oligonucleotide failed to inhibit efficiently the growth of cervical cancer cell line SiHa, contrarily to the Ru-P-6 antisense oligonucleotide, another sequence also targeting the E6 gene. The ability of PDMAEMA-b-PMEMA to form polyplexes with optimal physicochemical characteristics was investigated first. Then the ability of the PDMAEMA-b-PMEMA/Ru-P-4 antisense oligonucleotide polyplexes to transfect two keratinocyte cell lines (SiHa and HaCat) and the capacity of polyplexes to inhibit HPV16+ cervical cancer cell growth was evaluated. PDMAEMA-b-PMEMA base polyplexes at the optimal molar ratio of polymer nitrogen atoms to DNA phosphates (N/P), were able to deliver Ru-P-4 antisense oligonucleotide and to induce a higher growth inhibition in human cervical cancer SiHa cells, compared to other formulations based on Oligofectamine. PMID- 23926813 TI - [A questionnaire survey of indication for cataract surgery]. AB - PURPOSE: Advances in cataract surgery merits changes in its indication as well as related preoperative eye examinations. This, however, has not been reported in Japan. We performed a questionnaire survey to provide data for these changes. METHOD: The subjects were 121 facilities in university hospitals and 1,413 randomly sampled doctors from 14,134 Japanese Ophthalmology Society members. The questionnaire involved the indications and pre-operative examinations for cataract surgery. The results were compared separately amang two groups: operating and non-operating facilities. RESULTS: The number of respondents was 552 (36%). Operating facilities were 72%, and the annual operation volume was an average of 568 cases (0-4,000). The most important item when the surgery was recommended was the degree of life inconvenience, followed by corrected visual acuity, and there was no difference between the two groups in either. As for the examination to determine the surgery, distant visual acuity, specular microscopy, near visual acuity and corneal topography were high. The highest value of corrected visual acuity was less than 0.7 to indicate surgery in both groups. However, there were significantly more operating facilities in which the corrected visual acuity for the indication of the surgery was 0.7 or more. There was little use of the interview list and image analysis equipment. CONCLUSION: There was no difference in the indications for cataract surgery and the pre operative examinations between the two groups; the most important item among the indications was the degree of life inconvenience. The corrected visual acuity to indicate surgery in operating facilities was higher than in non-operating facilities. PMID- 23926814 TI - [Nocturnal dipping of heart rate in patients with proliferative diabetic retinopathy and iris and/or angle neovascularization]. AB - PURPOSE: To evaluate the relationship between nocturnal dipping in heart rates and iris and/or angle neovascularization (NV) in patients with proliferative diabetic retinopathy(PDR). SUBJECTS AND METHOD: One hundred fifty-one patients with PDR who underwent surgery were divided into groups based on either the presence or absence of iris and/or angle NV (NV group, 37; non-NV group, 114 patients). Pulse oximetry was conducted overnight and the heart rates were measured both before and during sleep; the resting and nocturnal heart rates and the resting-nocturnal heart rate dip ratio were calculated. RESULTS: The resting and nocturnal heart rates did not differ significantly between the two groups. The resting-nocturnal heart rate dip ratio was significantly lower in the NV group than in the non-NV group (p = 0.006). In the NV group, the frequency of insulin therapy (p = 0.003) and a history of coronary artery disease were significantly (p = 0.033) higher than in the non-NV group. Pearson's correlation analysis showed that only the NV group was significantly negatively correlated with the resting-nocturnal heart rate dip ratio (r = -0.18, t value = -2.2, p = 0.028). CONCLUSION: In patients with PDR, the non-occurrent of nocturnal dip in heart rate may be a related factor for iris and/or angle neovascularization. PMID- 23926815 TI - [Solitary pigment epithelial lesion accompanied by uveal effusion with bullous retinal detachment]. AB - PURPOSE: To report a case of solitary pigment epithelial lesion accompanied by uveal effusion (UE) with bullous retinal detachment (RD). CASE: A 63-year-old man was referred to our hospital for RD in his right eye. Best corrected visual acuity was 20/20 and intraocular pressure was 14 mmHg in the right eye. Fundus examination showed UE in the entire peripheral zone with bullous RD in the inferior retina and a grayish-white placoid lesion with indistinct border at the level of the retinal pigment epithelium at the temporal area near the macula in the right eye. No retinal tear was found, and anterior chamber depth and axial length were within the normal range. Fluorescein angiography indicated dye leakage from the placoid lesion, but pooling of dye was not intensive. Since posterior scleritis was not excluded, a systemic corticosteroid was administered but the UE with bullous RD did not improve, thererfore, photocoagulation for the placoid lesion was performed. This gradually ameliorated the UE with bullous RD, and it resolved at 4 months after the first visit without any further recurrence. CONCLUSION: Solitary pigment epithelial lesion can cause UE with bullous RD as in multifocal posterior pigment epitheliopathy (MPPE). PMID- 23926816 TI - [Corneal subepithelial infiltrates that developed following intravitreous injection of bevacizumab]. AB - BACKGROUND: Anti-vascular endothelial growth factor (anti-VEGF) therapies including intravitrous bevacizumab injection (IVB) emerged as an effective treatment for various fundus diseases. Reports of adverse reactions derived from bevacizumab itself are rare. We report a case in which corneal subepithelial infiltrates developed following IVB. CASE: A sixty-six-year-old man presented with visual acuity loss due to cystic macular edema secondary to branch retinal vein occlusion. He developed vascular congestion and subepithelial infiltrates in the peripheral cornea on day 2 following the first IVB. The findings resolved with topical steroid in twelve days. CONCLUSION: A case of subepithelial infiltrate in the peripheral cornea following IVB is reported. Since infiltrates were located along, and associated with the congestion of, the limbal vascular arcade, an innate immune response to bevacizumab may be indicated. PMID- 23926817 TI - [A case of atypical serpiginous choroiditis with chorioretinal lesions along retinal blood vessels]. AB - BACKGROUND: Serpiginous choroiditis, a chronic disease affecting the choroid and retinal pigment epithelium, is characterized by acute lesions located adjacent to atrophic scars initiated from the peripapillary region. This report describes a chorioretinal disease accompanied with retinal phlebitis finally diagnosed as serpiginous choroiditis by the characteristic extension of the lesions. CASE: A 68-year-old man was referred to our hospital with blurred vision in his both eyes. A small amount of cells infiltrating the vitreous, partial vitreous opacity, retinal phlebitis, grayish-white lesions around the optic disc and retinal phlebitis, and cystoid macular edema were observed in the both eyes. Since active lesions were found at the border of the inactive lesions and appeared in an interlocking polygonal pattern that spread out continuously, the condition was diagnosed as serpiginous choroiditis with retinal phlebitis. Systemic administration of predonisolone was initiated, which resolved the retinal phlebitis, and the active lesions were turned to scars. No recurrence has been observed since. CONCLUSION: Atypical serpiginous choroiditis accompanied with retinal phlebitis responds to systemic steroid administration. PMID- 23926818 TI - [A review 55: an up-to-date medical therapy for glaucoma]. PMID- 23926820 TI - Public program snapshot. PMID- 23926819 TI - Measuring up. PMID- 23926821 TI - Finally...a policy on policies. PMID- 23926823 TI - Pricing problem. PMID- 23926822 TI - Troubles for teaching programs. PMID- 23926824 TI - Lost in translation. PMID- 23926825 TI - Clearing the air. PMID- 23926826 TI - MMA kicks off policy forums. PMID- 23926827 TI - Change is up to you. PMID- 23926828 TI - Beyond Obamacare. PMID- 23926829 TI - Paying for and delivering pregnancy care. PMID- 23926830 TI - Care of the frail elder: the nexus of geriatrics and palliative care. AB - The number of frail elderly individuals living in the United States is expected to increase. Frail patients tend to suffer from a number of chronic symptoms including pain, weakness and depression, and frailty is associated with dependence on others and increased mortality. Thus, palliative care is often appropriate for these individuals. This article describes frailty among the elderly, how frail patients might benefit from palliative care and several community-based programs that can improve the quality of life for home-bound frail elders. PMID- 23926831 TI - Value-based purchasing for physician services. AB - Growth in Medicare expenditures has forced legislators and policymakers to look for ways to slow spending and get more value for their money. This article reviews previous federal efforts to control Medicare costs as well as current ones required by the Patient Protection and Affordable Care Act. It also describes a proposal for value-based purchasing that the authors developed under contract to the Centers for Medicare and Medicaid Services. This approach uses two measurement systems-one for physicians who practice primarily in outpatient settings and one for physicians who practice primarily in the hospital. PMID- 23926832 TI - Measuring medical productivity to gauge the value of Medicare. AB - Having a measure of productivity that relates funds and effort spent on medical treatment to health outcomes could help policymakers better understand whether they are getting value for the money spent on public health insurance programs. This article describes such a metric, the medical productivity index (MPI), and illustrates how it was used to analyze a sampling of Medicare claims from 2007 through 2009. PMID- 23926833 TI - The C.A.S.E. approach: guidance for talking to vaccine-hesitant parents. AB - Primary care physicians are encountering a growing number of parents who have concerns about vaccinating their children. This article describes the C.A.S.E. (Corroborate, About me, Science, Explain/Advise) approach to talking to such parents about the importance of vaccination. PMID- 23926834 TI - Liar, liar. People lie, that's all. it's not personal. PMID- 23926835 TI - Staying sharp with Occam's razor. PMID- 23926836 TI - Time management. PMID- 23926837 TI - FInding a new seat at the healthcare table. PMID- 23926838 TI - Readying the rails: the New Jersey EMS railway plan. PMID- 23926839 TI - Multidisciplinary training for multidisciplinary response. PMID- 23926840 TI - New and nontraditional partners in care. PMID- 23926841 TI - An EMS guide to chronic pain. PMID- 23926842 TI - Out of service. PMID- 23926843 TI - Response to "Mu, Y., and X. Mu. 2013. Energy conservation in the Earth's crust and climate change, J Air & Waste Manage. Assoc. 63(2): 150-160". PMID- 23926844 TI - Response to comments by John W. Russell on "Energy conservation in the Earth's crust and climate change". PMID- 23926845 TI - Evaluation of PM10 forecasting based on the artificial neural network model and intake fraction in an urban area: a case study in Taiyuan City, China. AB - Primary fine particulate matters with a diameter of less than 10 microm (PM10) are important air emissions causing human health damage. PM10 concentration forecast is important and necessary to perform in order to assess the impact of air on the health of living beings. To better understand the PM10 pollution health risk in Taiyuan City, China, this paper forecasted the temporal and spatial distribution of PM10 yearly average concentration, using Back Propagation Artificial Neural Network (BPANN) model with various air quality parameters. The predicted results of the models were consistent with the observations with a correlation coefficient of 0.72. The PM10 yearly average concentrations combined with the population data from 2002 to 2008 were given into the Intake Fraction (IF) model to calculate the IFs, which are defined as the integrated incremental intake of a pollutant released from a source category or a region over all exposed individuals. The results in this study are only for main stationary sources of the research area, and the traffic sources have not been included. The computed IFs results are therefore under-estimations. The IFs of PM10 from Taiyuan with a mean of 8.5 per million were relatively high compared with other IFs of the United States, Northern Europe and other cities in China. The results of this study indicate that the artificial neural network is an effective method for PM10 pollution modeling, and the Intake Fraction model provides a rapid population risk estimate for pollutant emission reduction strategies and policies. IMPLICATIONS: The PM10 (particulate matter with an aerodynamic diameter < or = 10 microm) yearly average concentration of Taiyuan, with a mean of 0.176 mg/m3, was higher than the 65 microg/m3 recommended by the U.S. Environmental Protection Agency (EPA). The spatial distribution of PM10 yearly average concentrations showed that wind direction and wind speed played an important role, whereas temperature and humidity had a lower effect than expected. Intake fraction estimates of Taiyuan were relatively high compared with those observed in other cities. Population density was the major factor influencing PM10 spatial distribution. The results indicated that the artificial neural network was an effective method for PM10 pollution modeling. PMID- 23926846 TI - Characterization of summertime coarse particulate matter in the Desert Southwest- Arizona, USA. AB - A year-long study was conducted in Pinal County, AZ, to characterize coarse (2.5 10 microm aerodynamic diameter, AD) and fine (< 2.5 microm AD) particulate matter (PMc and PMf, respectively) to further understand spatial and temporal variations in ambient PM concentrations and composition in rural, arid environments. Measurements of PMc and PMf mass, ions, elements, and carbon concentrations at one-in-six day resolution were obtained at three sites within the region. Results from the summer of 2009 and specifically the local monsoon period are presented. The summer monsoon season (July - September) and associated rain and/or high wind events, has historically had the largest number of PM10 NAAQS exceedances within a year. Rain events served to clean the atmosphere, decreasing PMc concentrations resulting in a more uniform spatial gradient among the sites. The monsoon period also is characterized by high wind events, increasing PMc mass concentrations, possibly due to increased local wind-driven soil erosion or transport. Two PM10 NAAQS exceedances at the urban monitoring site were explained by high wind events and can likely be excluded from PM10 compliance calculations as exceptional events. At the more rural Cowtown site, PM10 NAAQS exceedances were more frequent, likely due to the impact from local dust sources. PM mass concentrations at the Cowtown site were typically higher than at the Pinal County Housing and Casa Grande sites. Crustal material was equal to 52-63% of the PMc mass concentration on average. High concentrations of phosphate and organic carbon found at the rural Cowtown were associated with local cattle feeding operations. A relatively high correlation between PMc and PMf (R2 = 0.63) indicated that the lower tail of the coarse particle fraction often impacts the fine particle fraction, increasing the PMf concentrations. Therefore, reductions in PMc sources will likely also reduce PMf concentrations, which also are near the value of the 24-hr PM2.5 NAAQS. IMPLICATIONS: In the desert southwest, summer monsoons are often associated with above average PM10 (< 10 microm AD) mass concentrations. Competing influences of monsoon rain and wind events showed that rain suppresses ambient concentrations while high wind increase them. In this region, the PMc fraction dominates PM10 and crustal sources contribute 52-63% to local PMc mass concentrations on average. Cattle feedlot emissions are also an important source and a unique chemical signature was identified for this source. Observations suggest monsoon wind events alone cannot explain PM10 NAAQS exceedances, thus requiring these values to remain in compliance calculations rather than being removed as exceptional wind events. PMID- 23926847 TI - Assessment of background particulate matter concentrations in small cities and rural locations--Prince George, Canada. AB - This study investigates the development and application of a simple method to calculate annual and seasonal PM2.5 and PM10 background concentrations in small cities and rural areas. The Low Pollution Sectors and Conditions (LPSC) method is based on existing measured long-term data sets and is designed for locations where particulate matter (PM) monitors are only influenced by local anthropogenic emission sources from particular wind sectors. The LPSC method combines the analysis of measured hourly meteorological data, PM concentrations, and geographical emission source distributions. PM background levels emerge from measured data for specific wind conditions, where air parcel trajectories measured at a monitoring station are assumed to have passed over geographic sectors with negligible local emissions. Seasonal and annual background levels were estimated for two monitoring stations in Prince George, Canada, and the method was also applied to four other small cities (Burns Lake, Houston, Quesnel, Smithers) in northern British Columbia. The analysis showed reasonable background concentrations for both monitoring stations in Prince George, whereas annual PM10 background concentrations at two of the other locations and PM2.5 background concentrations at one other location were implausibly high. For those locations where the LPSC method was successful, annual background levels ranged between 1.8 +/- 0.1 microg/m3 and 2.5 +/- 0.1 microg/m3 for PM2.5 and between 6.3 +/- 0.3 microg/m3 and 8.5 +/- 0.3 microg/m3 for PM10. Precipitation effects and patterns of seasonal variability in the estimated background concentrations were detectable for all locations where the method was successful. Overall the method was dependent on the configuration of local geography and sources with respect to the monitoring location, and may fail at some locations and under some conditions. Where applicable, the LPSC method can provide a fast and cost efficient way to estimate background PM concentrations for small cities in sparsely populated regions like northern British Columbia. IMPLICATIONS: In rural areas like northern British Columbia, particulate matter (PM) monitoring stations are usually located close to emission sources and residential areas in order to assess the PM impact on human health. Thus there is a lack of accurate PM background concentration data that represent PM ambient concentrations in the absence of local emissions. The background calculation method developed in this study uses observed meteorological data as well as local source emission locations and provides annual, seasonal and precipitation-related PM background concentrations that are comparable to literature values for four out of six monitoring stations. PMID- 23926848 TI - Assessment of emissions and removal of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) at start-up periods in a hazardous waste incinerator. AB - A study was conducted to observe the changes in polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) levels and congener profiles in the flue gas of a hazardous waste incinerator during two start-up periods. Flue gas samplings were performed simultaneously through Air Pollution Control Devices (APCDs) (including boiler outlet, electrostatic precipitator (ESP) outlet, wet scrubbers (WS) outlet, and activated carbon (AC) filter outlet) in different combustion temperatures during a planned cold (long) start-up and an unplanned warm (short) start-up. The results showed that PCDD/F concentrations could be elevated during the start-up periods up to levels 3-4 times higher than those observed in the normal operation. Especially lower combustion temperatures in the short start-ups may cause high PCDD/F concentrations in the raw flue gas. Assessment of combustion temperatures and Furans/Dioxins values indicated that surface-catalyzed de novo synthesis was the dominant pathway in the formation of PCDD/Fs in the combustion units. PCDD/F removal efficiencies of Air Pollution Control Devices suggested that formation by de novo synthesis existed in ESP also when in operation, leading to increase of gaseous phase PCDD/Fs in ESP Particle bound PCDD/Fs were removed mainly by ESP and WS, while gaseous phase PCDD/Fs were removed by WS, and more efficiently by AC filter. IMPLICATIONS: This paper evaluates PCDD/F emissions and removal performances of APCDs (ESP, wet scrubbers, and activated carbon) during two start-up periods in an incinerator. The main implications are the following: (1) start-up periods increase PCDD/F emissions up to 2-3 times in the incinerator; (2) low combustion temperatures in start-ups cause high PCDD/F emissions in raw gas; (3) formation of PCDD/Fs by de novo synthesis occurs in ESP; (4) AC is efficient in removing gaseous PCDD/Fs, but may increase particle-bound ones; and (5) scrubbers remove both gaseous and particle bound PCDD/Fs efficiently. PMID- 23926849 TI - Disinfection efficiency of chlorine dioxide gas in student cafeterias in Taiwan. AB - In Taiwan, the food and drink requirements of students and faculty members are met by student cafeterias. The air quality within these cafeterias should satisfy the guidelines laid down by the Taiwan Environmental Protection Agency (Taiwan EPA). Accordingly, this study performed an experimental investigation into the efficiency of two different gaseous chlorine dioxide (ClO2) treatments in disinfecting a local student cafeteria, namely a single, one-off application and a twice-daily application. In both cases, the ClO2 was applied using strategically placed aerosol devices. The air quality before and after disinfection was evaluated by measuring the bioaerosol levels of bacteria and fungi. Moreover, a stepwise discriminant analysis method was applied for predicting the residual concentrations of bacteria and fungi, as a function of the environmental parameters and the ClO2 concentration. The experimental results showed that the average background levels of bacteria and fungi prior to ClO2 disinfection were 972.5 +/- 623.6 and 1534.1 +/- 631.8 colony-forming units (CFU)/m3, respectively. A single ClO2 application was found to reduce the bacterial and fungal concentration levels by as much as 65% and 30%, respectively. By contrast, a twice-daily ClO2 application was found to reduce the bacterial and fungal concentration levels by as much as 74% and 38%, respectively. The statistical analysis results showed that the residual bacterial concentration level was determined primarily by the number of individuals present in the cafeteria, the temperature, and the ClO2 concentration, whereas the residual fungal concentration level was determined mainly by the temperature, the total number of suspended particles, and the ClO2 concentration. Thus, the integrated results suggest that the air quality guidelines prescribed by the Taiwan EPA for student cafeteria can best be achieved by applying ClO2 twice daily using an appropriate deployment of aerosol devices. IMPLICATIONS: ClO2 gas can destroy all manner of microorganisms, including bacteria, spores, fungi, viruses, and even protozoans, in indoor environments. Moreover, it is popularly known that bioaerosols are able to grow and propagate on a wide variety of building materials and indoor surfaces. Thus, through optimal ClO2 disinfection methodology, the indoor microbial contaminants can be decreased and the residual concentrations of bacteria and fungi as a function of the environmental parameters and the ClO2 concentration can be predicted via some statistical techniques. PMID- 23926850 TI - Fugitive particulate emission factors for dry fly ash disposal. AB - Dry fly ash disposal involves dropping ash from a truck and the movement of a heavy grader or similar vehicle across the ash surface. These operations are known to produce fugitive particulate emissions that are not readily quantifiable using standard emission measurement techniques. However there are numerous situations--such as applying for a source air permit--that require these emissions be quantified. Engineers traditionally use emission factors (EFs) derived from measurements of related processes to estimate fly ash disposal emissions. This study near a dry fly ash disposal site using state-of-the-art particulate monitoring equipment examines for the first time fugitive emissions specific to fly ash handling at an active disposal site. The study measured hourly airborne mass concentrations for particles smaller than 2.5 microm (PM2.5) and 10 microm (PM10) along with meteorological conditions and atmospheric turbidity at high temporal resolution to characterize and quantify fugitive fly ash emissions. Fugitive fly ash transport and dispersion were computed using the on-site meteorological data and a regulatory air pollutant dispersion model (AERMOD). Model outputs coupled with ambient measurements yielded fugitive fly ash EFs that averaged 96 g Mg(-1) (of ash processed) for the PM(c) fraction (= PM10 - PM2.5) and 18 g Mg(-1) for PM2.5. Median EFs were much lower due to the strongly skewed shape of the derived EF distributions. Fugitive EFs from nearby unpaved roads were also characterized. Our primary finding is that EFs for dry fly ash disposal are considerably less than EFs derived using US Environmental Protection Agency AP-42 Emissions Handbook formulations for generic aggregate materials. This appears to be due to a large difference (a factor of 10+) between fugitive vehicular EFs estimated using the AP-42 formulation for vehicles driving on industrial roads (in this case, heavy slow-moving grading equipment) and EFs derived by the current study. IMPLICATIONS: Fugitive fly ash emission factors (EFs) derived by this study contribute to the small existing knowledge base for a type of pollutant that will become increasingly important as ambient particulate standards become tighter. In areas that are not in attainment with standards, realistic EFs can be used for compliance modeling and can help identify which classes of sources are best targeted to achieve desired air quality levels. In addition, understanding the natural variability in fugitive fly ash emissions can suggest methods that are most likely to be successful in controlling fugitive emissions related to dry fly ash storage. PMID- 23926851 TI - Using a traffic simulation model (VISSIM) with an emissions model (MOVES) to predict emissions from vehicles on a limited-access highway. AB - The Intergovernmental Panel on Climate Change (IPCC) estimates that baseline global GHG emissions may increase 25-90% from 2000 to 2030, with carbon dioxide (CO2 emissions growing 40-110% over the same period. On-road vehicles are a major source of CO2 emissions in all the developed countries, and in many of the developing countries in the world. Similarly, several criteria air pollutants are associated with transportation, for example, carbon monoxide (CO), nitrogen oxides (NO(x)), and particulate matter (PM). Therefore, the need to accurately quantify transportation-related emissions from vehicles is essential. The new US. Environmental Protection Agency (EPA) mobile source emissions model, MOVES2010a (MOVES), can estimate vehicle emissions on a second-by-second basis, creating the opportunity to combine a microscopic traffic simulation model (such as VISSIM) with MOVES to obtain accurate results. This paper presents an examination of four different approaches to capture the environmental impacts of vehicular operations on a 10-mile stretch of Interstate 4 (I-4), an urban limited-access highway in Orlando, FL. First (at the most basic level), emissions were estimated for the entire 10-mile section "by hand" using one average traffic volume and average speed. Then three advanced levels of detail were studied using VISSIM/MOVES to analyze smaller links: average speeds and volumes (AVG), second-by-second link drive schedules (LDS), and second-by-second operating mode distributions (OPMODE). This paper analyzes how the various approaches affect predicted emissions of CO, NO(x), PM2.5, PM10, and CO2. The results demonstrate that obtaining precise and comprehensive operating mode distributions on a second-by second basis provides more accurate emission estimates. Specifically, emission rates are highly sensitive to stop-and-go traffic and the associated driving cycles of acceleration, deceleration, and idling. Using the AVG or LDS approach may overestimate or underestimate emissions, respectively, compared to an operating mode distribution approach. IMPLICATIONS: Transportation agencies and researchers in the past have estimated emissions using one average speed and volume on a long stretch of roadway. With MOVES, there is an opportunity for higher precision and accuracy. Integrating a microscopic traffic simulation model (such as VISSIM) with MOVES allows one to obtain precise and accurate emissions estimates. The proposed emission rate estimation process also can be extended to gridded emissions for ozone modeling, or to localized air quality dispersion modeling, where temporal and spatial resolution of emissions is essential to predict the concentration of pollutants near roadways. PMID- 23926853 TI - Evaluation of NO2 predictions by the plume volume molar ratio method (PVMRM) and ozone limiting method (OLM) in AERMOD using new field observations. AB - The U.S. Environmental Protection Agency (EPA) plume volume molar ratio method (PVMRM) and the ozone limiting method (OLM) are in the AERMOD model to predict the 1-hr average NO2/NO(x) concentration ratio. These ratios are multiplied by the AERMOD predicted NO(x) concentration to predict the 1-hr average NO2 concentration. This paper first briefly reviews PVMRM and OLM and points out some scientific parameterizations that could be improved (such as specification of relative dispersion coefficients) and then discusses an evaluation of the PVMRM and OLM methods as implemented in AERMOD using a new data set. While AERMOD has undergone many model evaluation studies in its default mode, PVMRM and OLM are nondefault options, and to date only three NO2 field data sets have been used in their evaluations. Here AERMOD/PVMRM and AERMOD/OLM codes are evaluated with a new data set from a northern Alaskan village with a small power plant. Hourly pollutant concentrations (NO, NO2, ozone) as well as meteorological variables were measured at a single monitor 500 m from the plant. Power plant operating parameters and emissions were calculated based on hourly operator logs. Hourly observations covering 1 yr were considered, but the evaluations only used hours when the wind was in a 60 degrees sector including the monitor and when concentrations were above a threshold. PVMRM is found to have little bias in predictions of the C(NO2)/C(NO(x)) ratio, which mostly ranged from 0.2 to 0.4 at this site. OLM overpredicted the ratio. AERMOD overpredicts the maximum NO(x) concentration but has an underprediction bias for lower concentrations. AERMOD/PVMRM overpredicts the maximum C(NO2) by about 50%, while AERMOD/OLM overpredicts by a factor of 2. For 381 hours evaluated, there is a relative mean bias in C(NO2) predictions of near zero for AERMOD/PVMRM, while the relative mean bias reflects a factor of 2 overprediction for AERMOD/OLM. IMPLICATIONS: This study was initiated because the new stringent 1-hr NO2 NAAQS has prompted modelers to more widely use the PVMRM and OLM methods for conversion of NO(x) to NO2 in the AERMOD regulatory model. To date these methods have been evaluated with a limited number of data sets. This study identified a new data set of ambient pollutant and meteorological monitoring near an isolated power plant in Wainwright, Alaska. To supplement the existing evaluations, this new data were used to evaluate PVMRM and OLM. This new data set has been and will be made available to other scientists for future investigations. PMID- 23926852 TI - Emissions and risks associated with oxyfuel combustion: state of the science and critical data gaps. AB - Oxyfuel combustion is a promising technology that may greatly facilitate carbon capture and sequestration by increasing the relative CO2 content of the combustion emission stream. However, the potential effect of enhanced oxygen combustion conditions on emissions of criteria and hazardous air pollutants (e.g., acid gases, particulates, metals and organics) is not well studied. It is possible that combustion under oxyfuel conditions could produce emissions posing different risks than those currently being managed by the power industry (e.g., by changing the valence state of metals). The data available for addressing these concerns are quite limited and are typically derived from laboratory-scale or pilot-scale tests. A review of the available data does suggest that oxyfuel combustion may decrease the air emissions of some pollutants (e.g., SO2, NO(x), particulates) whereas data for other pollutants are too limited to draw any conclusions. The oxy-combustion systems that have been proposed to date do not have a conventional "stack" and combustion flue gas is treated in such a way that solid or liquid waste streams are the major outputs. Use of this technology will therefore shift emissions from air to solid or liquid waste streams, but the risk management implications of this potential change have yet to be assessed. Truly useful studies of the potential effects of oxyfuel combustion on power plant emissions will require construction of integrated systems containing a combustion system coupled to a CO2 processing unit. Sampling and analysis to assess potential emission effects should be an essential part of integrated system tests. IMPLICATIONS: Oxyfuel combustion may facilitate carbon capture and sequestration by increasing the relative CO2 content of the combustion emission stream. However, the potential effect of enhanced oxygen combustion conditions on emissions of criteria and hazardous air pollutants has not been well studied. Combustion under oxyfuel conditions could produce emissions posing different risks than those currently being managed by the power industry. Therefore, before moving further with oxyfuel combustion as a new technology, it is appropriate to summarize the current understanding of potential emissions risk and to identify data gaps as priorities for future research. PMID- 23926854 TI - Field testing of new-technology ambient air ozone monitors. AB - Multibillion-dollar strategies control ambient air ozone (O3) levels in the United States, so it is essential that the measurements made to assess compliance with regulations be accurate. The predominant method employed to monitor O3 is ultraviolet (UV) photometry. Instruments employ a selective manganese dioxide or heated silver wool "scrubber" to remove O3 to provide a zero reference signal. Unfortunately, such scrubbers remove atmospheric constituents that absorb 254-nm light, causing measurement interference. Water vapor also interferes with the measurement under some circumstances. We report results of a 3-month field test of two new instruments designed to minimize interferences (2B Technologies model 211; Teledyne-API model 265E) that were operated in parallel with a conventional Thermo Scientific model 49C O3 monitor. The field test was hosted by the Houston Regional Monitoring Corporation (HRM). The model 211 photometer scrubs O3 with excess nitric oxide (NO) generated in situ by photolysis of added nitrous oxide (N2O) to provide a reference signal, eliminating the need for a conventional O3 scrubber. The model 265E analyzer directly measures O3-NO chemiluminescence from added excess NO to quantify O3 in the sample stream. Extensive quality control (QC) and collocated monitoring data are assessed to evaluate potential improvements to the accuracy of O3 compliance monitoring. IMPLICATIONS: Two new technology ozone monitors were compared with a conventional monitor under field conditions. Over 3 months the conventional monitor reported more exceedances of the current standard than the new instruments, which could potentially result in an area being misjudged as "nonattainment." Instrument drift can affect O3 data accuracy, and the same degree of drift has a proportionally greater compliance effect as standard stringency is increased. Enhanced data quality assurance and data adjustment may be necessary to achieve the improved accuracy required to judge compliance with tighter standards. PMID- 23926855 TI - Hazardous airborne carbonyls emissions in industrial workplaces in China. AB - A pilot hazardous airborne carbonyls study was carried out in Hong Kong and the Mainland of China. Workplace air samples in 14 factories of various types of manufacturing and industrial operations were collected and analyzed for a panel of 21 carbonyl compounds. The factories can be classified into five general categories, including food processing, electroplating, textile dyeing, chemical manufacturer, and petroleum refinery. Formaldehyde was invariably the most abundant carbonyl compound among all the workplace air samples, accounting for 22.0-44.0% of the total measured amount of carbonyls on a molar basis. Acetone was also found to be an abundant carbonyl in workplace settings; among the selected industrial sectors, chemical manufacturers' workplaces had the highest percentage (an average of 42.6%) of acetone in the total amount of carbonyls measured in air. Benzaldehyde accounted for an average of 20.5% of the total amount of detected carbonyls in electroplating factories, but its contribution was minor in other industrial workplaces. Long-chain aliphatic carbonyls (C6-C10) accounted for a large portion (37.2%) of the total carbonyls in food-processing factories. Glyoxal and methylglyoxal existed at variable levels in the selected workplaces, ranging from 0.2% to 5.5%. The mixing ratio of formaldehyde ranged from 8.6 to 101.2 ppbv in the sampled workplaces. The observed amount of formaldehyde in two paint and wax manufacturers and food-processing factories exceeded the World Health Organization (WHO) air quality guideline of 81.8 ppbv. Carcinogenic risks of chronic exposure to formaldehyde and acetaldehyde by the workers were evaluated. The lifetime cancer hazard risks associated with formaldehyde exposure to male and female workers ranged from 2.01 x 10(-5) to 2.37 x 10(-4) and 2.68 x 10(-5) to 3.16 x 10(-4), respectively. Such elevated risk values suggest that the negative health impact of formaldehyde exposure represents a valid concern, and proper actions should be taken to protect workers from such risks. IMPLICATIONS: Many carbonyl species (e.g., formaldehyde, acetaldehyde, and acrolein) are air toxins and they pose public healt risks. The scope of this investigation covers 21 types of carbonyls based on samples collected from 14 different workplaces. Findings of the study will not only provide a comprehensive assessment of indoor air quality with regard to workers' healthy and safety, but also establish a theoretical foundation for future formulation of intervention strategies to reduce occupational carbonyl exposures. No similar study has been carried out either in Hong Kong or the Mainland of China. PMID- 23926856 TI - Surrogate consent for dementia research: factors influencing five stakeholder groups from the SCORES study. PMID- 23926857 TI - Readability of consent form templates: a second look. PMID- 23926858 TI - Clarification, continued. PMID- 23926859 TI - Habits of successful boards. AB - High-performing boards rely on five leadership habits. PMID- 23926860 TI - Creating a culture of safety. AB - Trustees and CEOs from several hospitals share their strategies for organizationwide reductions in harm. PMID- 23926861 TI - Protecting what matters. AB - The ability to preserve local services after a merger comes from the contract, not the number of board seats. PMID- 23926862 TI - Trustee mentoring: for orientation, leadership development and more. PMID- 23926863 TI - The courage to come forward. AB - Whistleblowers uncover fraud and other issues. Can your hospital protect them? PMID- 23926865 TI - Seven qualities to seek. AB - What makes an ideal board member? A veteran trustee identifies seven traits. PMID- 23926864 TI - The hospital of tomorrow. AB - Advances in technology will address health care's biggest challenges: engagement, service and value. PMID- 23926866 TI - Getting ready to govern. AB - Taking time to "check in" at meetings unites board members. PMID- 23926867 TI - 70% of hospitals electronically deliver quality scores to clinical leaders. AB - With their boards' oversight, IT-savvy hospitals are using clinical analytics to improve outcomes. PMID- 23926868 TI - The truth about computer-assisted coding. PMID- 23926869 TI - Coding with integrity. PMID- 23926870 TI - Clinical documentation improvement--a physician perspective. PMID- 23926871 TI - Transitioning transcriptionists. PMID- 23926872 TI - CDI programs support meeting meaningful use. PMID- 23926873 TI - CDI programs used to improve quality reporting accuracy. PMID- 23926874 TI - Strategizing clinical documentation improvement. PMID- 23926875 TI - Study reveals hard facts on CAC. PMID- 23926876 TI - Recruitment, selection, and orientation for CDI specialists. PMID- 23926877 TI - Flowing with coding's changing tide. PMID- 23926878 TI - Coding root operations with ICD-10-PCS. PMID- 23926879 TI - Real time analysis of binding between Rituximab (anti-CD20 antibody) and B lymphoma cells. AB - CD20, expressed on greater than 90% of B-lymphocytic lymphomas, is an attractive target for antibody therapy. Rituximab is a chimeric murine/human-engineered monoclonal antibody which can selectively deplete CD20-expressing cells in peripheral blood and lymphoid tissues. The immobilization of B-lymphoblast-like Burkitt's lymphoma Raji cells on the quartz crystal microbalance (QCM) gold electrode surface using arginine-glycine-aspartic acid (RGD) tripeptide was electrochemically confirmed. The real-time processes of attachment of Raji cells on the gold electrode and the subsequent binding of Rituximab to the cells were studied using a QCM biosensor. The interaction between Rituximab and Raji cells led to the increased resonant frequency shifts (Deltaf0) in the studied antibody concentration range from 5 to 250 MUg mL(-1) following the Langmuir adsorption model. From these observations, the apparent binding constant between a single layer of Rituximab and Raji cells was calculated to be 1.6 * 10(6) M(-1). Control experiments using other therapeutic antibodies (i.e., Trastuzumab and Bevacizumab) and different cells (i.e., T cells and endothelial cells) proved the specific interaction between Rituximab and B cells. The effects of Ca(2+) and Mn(2+) ions on the Rituximab-Raji cell interaction were also studied providing the enhanced QCM signals, in particular with Ca(2+), further indicating that CD20 is a calcium ion channel that can transport these metal ions into the cells and accelerate the cell lysis induced by Rituximab. Thus, the real time capability of QCM and its simplicity of operation are shown to be highly suitable for multipurpose studies on living cells including cell-immobilization, cytotoxicity of drugs, and the cell action mechanisms. PMID- 23926880 TI - Enhanced antimicrobial activity of peptide-cocktails against common bacterial contaminants of ex vivo stored platelets. AB - Bacterial contamination of blood components such as ex vivo-stored platelets is a major safety risk in transfusion medicine. We have recently shown that synthetic antimicrobial peptides named PD1-PD4 derived from the thrombin-induced human platelet-derived antimicrobial proteins, and repeats of Arg-Trp (RW1-RW5) demonstrate microbicidal activity against selected bacteria and viruses. In the present study, we selected PD3, PD4, RW2, RW3 and RW4 and evaluated each individual peptide and their various combinations to see whether the cocktail regimen enhances the antimicrobial activity above and over the individual peptides. Stored platelet or plasma samples spiked with known titres of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Bacillus cereus were treated with either individual peptides or with peptides in various combinations. Analyses revealed that individual peptides show moderate microbicidal activity (10- to 100-fold reduction) against the tested bacteria relative to their combined regimen. The peptide combinations (RW2 + RW4, RW2 + RW3 + RW4 and PD4 + RW3 + RW4) on the other hand enhanced the microbicidal activity (c.10 000-fold reduction) and revealed a minimal inhibitory concentration of 5 MUM. Time-kill kinetics indicated that these three peptide combinations exhibited enhanced antimicrobial activity bringing about a 100-fold reduction of bacterial titres within 20 min of incubation. The present study therefore demonstrates the synergistic effect of antimicrobial peptides when used in combinations and provides a proof-of-concept of its potential application as a molecular tool towards pathogen reduction and further extends the possibility of using peptide combinatorial therapeutics as broad-spectrum antibiotics or as alternatives to combat drug-resistant bacteria. PMID- 23926881 TI - Organocatalyzed formal [2 + 2] cycloaddition of ketimines with allenoates: facile access to azetidines with a chiral tetrasubstituted carbon stereogenic center. AB - An enantioselective organocatalyzed aza-MBH-type reaction of ketimines and allenoates has been developed. The present formal [2 + 2] cycloaddition produces highly functionalized azetidines with a chiral tetrasubstituted carbon stereogenic center in good to excellent yields and high enantioselectivities. PMID- 23926882 TI - Binding of O2 and NO to heme in heme-nitric oxide/oxygen-binding (H-NOX) proteins. A theoretical study. AB - The binding of O2 and NO to heme in heme-nitric oxide/oxygen-binding (H-NOX) proteins has been investigated with DFT as well as dispersion-corrected DFT methods. The local protein environment was accounted for by including the six nearest surrounding residues in the studied systems. Attention was also paid to the effects of the protein environment, particularly the distal Tyr140, on the proximal iron-histidine (Fe-His) binding. The Heme-AB (AB = O2, NO) and Fe-His binding energies in iron porphyrin FeP(His)(AB), myoglobin Mb(AB), H-NOX(AB), and Tyr140 -> Phe mutated H-NOX[Y140F(AB)] were determined for comparison. The calculated stabilization of bound O2 is even higher in H-NOX than that in a myoglobin (Mb), consistent with the observation that the H-NOX domain of T. tengcongensis has a very high affinity for its oxygen molecule. Among the two different X-ray crystal structures for the Tt H-NOX protein, the calculated results for both AB = O2 and NO appear to support the crystal structure with the PDB code 1XBN , where the Trp9 and Asn74 residues do not form a hydrogen-bonding network with Tyr140. A hydrogen bond interaction from the polar residue does not have obvious effects on the Fe-His binding strength, but a dispersion contribution to Ebind(Fe-His) may be significant, depending on the crystal structure used. We speculate that the Fe-His binding strength in the deoxy form of a native protein could be an important factor in determining whether the bond of His to Fe is broken or maintained upon binding of NO to Fe. PMID- 23926883 TI - Sensors for breath testing: from nanomaterials to comprehensive disease detection. AB - The analysis of volatile organic compounds in exhaled breath samples represents a new frontier in medical diagnostics because it is a noninvasive and potentially inexpensive way to detect illnesses. Clinical trials with spectrometry and spectroscopy techniques, the standard volatile-compound detection methods, have shown the potential for diagnosing illnesses including cancer, multiple sclerosis, Parkinson's disease, tuberculosis, diabetes, and more via breath tests. Unfortunately, this approach requires expensive equipment and high levels of expertise to operate the necessary instruments, and the tests must be done quickly and use preconcentration techniques, all of which impede its adoption. Sensing matrices based on nanomaterials are likely to become a clinical and laboratory diagnostic tool because they are significantly smaller, easier-to-use, and less expensive than spectrometry or spectroscopy. An ideal nanomaterial-based sensor for breath testing should be sensitive at very low concentrations of volatile organic compounds, even in the presence of environmental or physiological confounding factors. It should also respond rapidly and proportionately to small changes in concentration and provide a consistent output that is specific to a given volatile organic compound. When not in contact with the volatile organic compounds, the sensor should quickly return to its baseline state or be simple and inexpensive enough to be disposable. Several reviews have focused on the methodological, biochemical, and clinical aspects of breath analysis in attempts to bring breath testing closer to practice for comprehensive disease detection. This Account pays particular attention to the technological gaps and confounding factors that impede nanomaterial-sensor-based breath testing, in the hope of directing future research and development efforts towards the best possible approaches to overcome these obstacles. We discuss breath testing as a complex process involving numerous steps, each of which has several possible technological alternatives with advantages and drawbacks that might affect the performance of the nanomaterial-based sensors in a breath-testing system. With this in mind, we discuss how to choose nanomaterial-based sensors, considering the profile of the targeted breath markers and the possible limitations of the approach, and how to design the surrounding breath-testing setup. We also discuss how to tailor the dynamic range and selectivity of the applied sensors to detect the disease-related volatile organic compounds of interest. Finally, we describe approaches to overcome other obstacles by improving the sensing elements and the supporting techniques such as preconcentration and dehumidification. PMID- 23926884 TI - Cardiac index assessment: validation of a new non-invasive very low current thoracic bioimpedance device by thermodilution. AB - INTRODUCTION: The accuracy of impedance cardiography for cardiac index assessment is matter of debate, with available studies reporting inconsistent results. Our study aimed at evaluating the agreement between measurements of cardiac index provided by a new-generation thoracic electrical bioimpedance device (Hotman System) and an invasive approach based on thermodilution in humans. METHODS: Cardiac index was assessed simultaneously with thoracic electrical bioimpedance and conventional thermodilution through comparison of five consecutive measurements in 51 cardiac patients, hospitalized in an intensive care unit (mean+/- SD age: 60 +/- 11 years; 68% males). The agreement between cardiac index values measured by both methods was assessed by the Bland-Altman approach, adjusted for repeated measures. The repeatability coefficient and the intraclass correlation coefficient were used to assess reproducibility of replicates. RESULTS: Average (+/- SD) cardiac index was 3.05 +/- 0.91 l/min/m(2) with Hotman System and 3.14 +/- 1.12 l/min/m(2) with thermodilution. The bias of precision was -0.09 +/- 0.41. The coefficients of repeatability and intraclass correlation coefficients were high and similar for the two techniques (0.95 l/min/m(2) and 0.91 for Hotman System vs 0.78 l/min/m(2) and 0.90 for thermodilution). CONCLUSIONS: Cardiac index values yielded by Hotman system compares favorably with that obtained with thermodilution in cardiac patients. PMID- 23926886 TI - The influence of microgravity on Euglena gracilis as studied on Shenzhou 8. AB - The German Aerospace Center (DLR) enabled German participation in the joint space campaign on the unmanned Shenzhou 8 spacecraft in November 2011. In this report, the effect of microgravity on Euglena gracilis cells is described. Custom-made dual compartment cell fixation units (containing cells in one chamber and fixative - RNA lysis buffer - in another one) were enclosed in a small container and placed in the Simbox incubator, which is an experiment support system. Cells were fixed by injecting them with fixative at different time intervals. In addition to stationary experiment slots, Simbox provides a 1 g reference centrifuge. Cell fixation units were mounted in microgravity and 1 g reference positions of Simbox. Two Simbox incubators were used, one for space flight and the other as ground reference. Cells were fixed soon after launch and shortly before return of the spaceship. Due to technical problems, only early in-flight samples (about 40 min after launch microgravity and corresponding 1 g reference) were fully mixed with fixative, therefore only data from those samples are presented. Transcription of several genes involved in signal transduction, oxidative stress defence, cell cycle regulation and heat shock responses was investigated with quantitative PCR. The data indicate that Euglena cells suffer stress upon short-term exposure to microgravity; various stress-induced genes were up-regulated. Of 32 tested genes, 18 were up-regulated, one down-regulated and the rest remained unaltered. These findings are in a good agreement with results from other research groups using other organisms. PMID- 23926887 TI - Decreased enteric fatty acid amide hydrolase activity is associated with colonic inertia in slow transit constipation. AB - BACKGROUND: Constipation is one of the most common chronic digestive complaints. Gastrointestinal transit studies have divided it into three patterns: normal transit, slow transit constipation (STC), and outlet obstruction. It has been demonstrated that STC patients respond poorly to standard therapies, and the etiology of STC remains poorly understood. Animal studies have also shown that fatty acid amide hydrolase (FAAH) controls intestinal motility through its putative receptors or non-receptor-mediated pathways. However, the role of FAAH in STC has not been elaborated. METHODS: A case series was carried out on thirty two STC patients fulfilling the Rome II criteria and on 24 controls. All of the subjects underwent a laparotomy in Shengjing Hospital. Colonic specimens were obtained and used for FAAH expression analysis, enzyme activity assay, and cannabinoid detection. RESULTS: FAAH immunoreactivity occurred in the enteric neurons and in the surface epithelial and glands. The expression level and enzyme activity of FAAH in the STC group were both significantly lower than those in the control group (P < 0.05). The amounts of anandamide, 2-arachidonylglycerol, and palmitoylethanolamide, which are negatively correlated with enzyme activity, were significantly higher in the constipation group than that in the control group. In the STC group, cannabinoid receptor type 1 immunoreactivity occurred predominantly in the submucosal and myenteric fibers that were obviously strong and wave-like in their appearance. Enteric ganglions decreased or disappeared. CONCLUSIONS: The tone of the enteric cannabinoids system is disturbed in STC, and the decreased enteric FAAH activity contributes to colonic inertia in STC. PMID- 23926888 TI - Comparing insulin vials to pens--comparison of charges, not healthcare benefits. PMID- 23926889 TI - Mentoring review and reflections. AB - This paper reviews mentoring definitions, mentor and protegee characteristics, and the process and outcomes of the mentoring process. In addition, the faculty provides some personal reflections about their mentoring process. Reflections of this nature may inspire us to consider further the adoption and investigation of formal and informal overt mentoring programs in our institutions in order to promote mentoring relationships that can foster personal and professional achievement and satisfaction. PMID- 23926890 TI - The community reintegration project: occupational therapy at work in a county jail. AB - The incarcerated population in U.S jails has more than doubled in the last thirty years while prison populations have quintupled. Over half of those released from incarceration return to correctional systems within one year of release. One of the reasons for these high rates of recidivism is that many inmates lack the community living skills necessary for community reintegration. Successful community reintegration for ex-offenders requires a skill set that occupational therapists have long addressed in their domain of practice. Compared to practitioners in the United Kingdom and Australia, U.S. practitioners have been slow to develop occupational therapy programming in correctional settings. This article describes a community reintegration program for jail inmates built through a collaborative partnership between a university occupational therapy program, community non-profit organizations and a county jail. PMID- 23926885 TI - Diagnostic techniques for inflammatory eye disease: past, present and future: a review. AB - Investigations used to aid diagnosis and prognosticate outcomes in ocular inflammatory disorders are based on techniques that have evolved over the last two centuries have dramatically evolved with the advances in molecular biological and imaging technology. Our improved understanding of basic biological processes of infective drives of innate immunity bridging the engagement of adaptive immunity have formed techniques to tailor and develop assays, and deliver targeted treatment options. Diagnostic techniques are paramount to distinguish infective from non-infective intraocular inflammatory disease, particularly in atypical cases. The advances have enabled our ability to multiplex assay small amount of specimen quantities of intraocular samples including aqueous, vitreous or small tissue samples. Nevertheless to achieve diagnosis, techniques often require a range of assays from traditional hypersensitivity reactions and microbe specific immunoglobulin analysis to modern molecular techniques and cytokine analysis. Such approaches capitalise on the advantages of each technique, thereby improving the sensitivity and specificity of diagnoses. This review article highlights the development of laboratory diagnostic techniques for intraocular inflammatory disorders now readily available to assist in accurate identification of infective agents and appropriation of appropriate therapies as well as formulating patient stratification alongside clinical diagnoses into disease groups for clinical trials. PMID- 23926891 TI - Fueling the engines: a role for occupational therapy in promoting healthy life transitions. AB - This article explores the potential role of occupational therapy in promoting healthy life transitions among people without illness or disease, The story of Roxana, a woman who moved with her family from Mexico to the United States, is described. The many transitions Roxana experienced are examined using the Person Environment-Occupation Model. Implications for practice focus on assessment and intervention strategies that can help practitioners and individuals experiencing transitions use occupation to prevent illness and promote health. PMID- 23926892 TI - Employment needs of people with multiple sclerosis: a review of current literature and application to occupational therapy practice. AB - Individuals with multiple sclerosis (MS) are often diagnosed during a period of life when career exploration and development occurs. The purpose of this paper is to examine the literature that has been published from 1996 to 2004 about the employment needs of people with MS in order to build upon Rumrill's (1996a) text and develop a set of treatment priorities for occupational therapists working with this population. The current literature highlights the potential employment challenges and incentives, programmatic barriers, and challenges specific to women with MS. The literature also highlights the changing meaning of work, the importance of coping with these changes, and the scope of needed intervention. Outlined are occupational therapy treatment priorities for people with MS in the performance area of work. PMID- 23926893 TI - From the internet editor. PMID- 23926895 TI - Novel optical fiber reflectometric CUPRAC sensor for total antioxidant capacity measurement of food extracts and biological samples. AB - A novel fiber optic sensor was developed for screening the total antioxidant capacity (TAC) based on the use of cupric-neocuproine (Cu(II)-Nc) immobilized onto a Nafion cation-exchange membrane with reflectance spectrometric measurement. The reflectance change associated with the formation of the highly colored Cu(I)-Nc chelate on the membrane as a result of reaction with antioxidants was measured at 530 nm by using a miniature reflectance spectrometer. The calibration graph of trolox (TR) was linear with a slope of 3.40 * 10(3) L mol(-1) mm(-1). The limit of detection (LOD) and limit of quantification (LOQ) for TR in the reflectometric cupric reducing antioxidant capacity (CUPRAC) method were found as 0.53 and 1.76 MUM, respectively. The trolox equivalent antioxidant capacities (TEAC) of various antioxidant compounds using the proposed method were comparable to those of the main CUPRAC assay. This assay was validated through linearity, additivity, precision, and recovery. The developed reflectance sensor was used to screen the TAC of some commercial fruit juices and mice tissue homogenates without preliminary treatment. The method is rapid, inexpensive, versatile, and nonlaborious, uses stable reagents on the sensor, and enables the in situ estimation of antioxidant capacity of food extracts and biological samples. PMID- 23926896 TI - A systematic review of outcome reporting in colorectal cancer surgery. AB - AIM: Evaluation of surgery for colorectal cancer (CRC) is necessary to inform clinical decision-making and healthcare policy. The standards of outcome reporting after CRC surgery have not previously been considered. METHOD: Systematic literature searches identified randomized and nonrandomized prospective studies reporting clinical outcomes of CRC surgery. Outcomes were listed verbatim, categorized into broad groups (outcome domains) and examined for a definition (an appropriate textual explanation or a supporting citation). Outcome reporting was considered inconsistent if results of the outcome specified in the methods were not reported. Outcome reporting was compared between randomized and nonrandomized studies. RESULTS: Of 5644 abstracts, 194 articles (34 randomized and 160 nonrandomized studies) were included reporting 766 different clinical outcomes, categorized into seven domains. A mean of 14 +/- 8 individual outcomes were reported per study. 'Anastomotic leak', 'overall survival' and 'wound infection' were the three most frequently reported outcomes in 72, 60 and 44 (37.1%, 30.9% and 22.7%) studies, respectively, and no single outcome was reported in every publication. Outcome definitions were significantly more often provided in randomized studies than in nonrandomized studies (19.0% vs 14.9%, P = 0.015). One-hundred and twenty-seven (65.5%) papers reported results of all outcomes specified in the methods (randomized studies, n = 21, 61.5%; nonrandomized studies, n = 106, 66.2%; P = 0.617). CONCLUSION: Outcome reporting in CRC surgery lacks consistency and method. Improved standards of outcome measurement are recommended to permit data synthesis and transparent cross-study comparisons. PMID- 23926897 TI - Transfusion-transmitted emerging infectious diseases: 30 years of challenges and progress. PMID- 23926898 TI - State of science: human factors and ergonomics in healthcare. AB - The past decade has seen an increase in the application of human factors and ergonomics (HFE) techniques to healthcare delivery in a broad range of contexts (domains, locations and environments). This paper provides a state of science commentary using four examples of HFE in healthcare to review and discuss analytical and implementation challenges and to identify future issues for HFE. The examples include two domain areas (occupational ergonomics and surgical safety) to illustrate a traditional application of HFE and the area that has probably received the most research attention. The other two examples show how systems and design have been addressed in healthcare with theoretical approaches for organisational and socio-technical systems and design for patient safety. Future opportunities are identified to develop and embed HFE systems thinking in healthcare including new theoretical models and long-term collaborative partnerships. HFE can contribute to systems and design initiatives for both patients and clinicians to improve everyday performance and safety, and help to reduce and control spiralling healthcare costs. PRACTITIONER SUMMARY: There has been an increase in the application of HFE techniques to healthcare delivery in the past 10 years. This paper provides a state of science commentary using four illustrative examples (occupational ergonomics, design for patient safety, surgical safety and organisational and socio-technical systems) to review and discuss analytical and implementation challenges and identify future issues for HFE. PMID- 23926899 TI - Retraction: Risks of avian influenza (H5) in duck farms in the Ayeyarwaddy Delta Region, Myanmar. AB - The following article from Zoonoses and Public Health, 'Risks of Avian Influenza (H5) in Duck Farms in the Ayeyarwaddy Delta Region, Myanmar' by H. H. Win, C. C. Su Mon, K. M. Aung, K. N. Oo, K. Sunn, T. Htun, T. Tiensin, M. Maclean, W. Kalpravidh and A. Amonsin published online on 09 August 2013 on Wiley Online Library (http://onlinelibrary.wiley. com/) has been retracted by the journal Editor-in-Chief, Mary Torrence, the Authors, and Blackwell Verlag GmbH, as the article has already been published in the Myanmar Veterinary Journal [Myanmar Veterinary Journal 2013, Vol. 15, No. 1, 43-50]. PMID- 23926900 TI - Carbohydrate-binding agents act as potent trypanocidals that elicit modifications in VSG glycosylation and reduced virulence in Trypanosoma brucei. AB - The surface of Trypanosoma brucei is covered by a dense coat of glycosylphosphatidylinositol-anchored glycoproteins. The major component is the variant surface glycoprotein (VSG) which is glycosylated by both paucimannose and oligomannose N-glycans. Surface glycans are poorly accessible and killing mediated by peptide lectin-VSG complexes is hindered by active endocytosis. However, contrary to previous observations, here we show that high-affinity carbohydrate binding agents bind to surface glycoproteins and abrogate growth of T. brucei bloodstream forms. Specifically, binding of the mannose-specific Hippeastrum hybrid agglutinin (HHA) resulted in profound perturbations in endocytosis and parasite lysis. Prolonged exposure to HHA led to the loss of triantennary oligomannose structures in surface glycoproteins as a result of genetic rearrangements that abolished expression of the oligosaccharyltransferase TbSTT3B gene and yielded novel chimeric enzymes. Mutant parasites exhibited markedly reduced infectivity thus demonstrating the importance of specific glycosylation patterns in parasite virulence. PMID- 23926901 TI - Oligonucleotide adsorption affects phase transition but not interdigitation of diC14-amidine bilayers. AB - In this work, we investigate the effect of a small single-stranded oligonucleotide (ODN) on the colloid stability and structure of cationic diC14 amidine liposomes. Dynamic light scattering (DLS) shows that small, stable, anionic assemblies are formed in presence of excess ODN negative charge. This charge overcompensation condition was further characterized. A less cooperative bilayer phase transition is observed by differential scanning calorimetry (DSC). Electron spin resonance (ESR) spectra of probes at different bilayer depths show that ODN electrostatic adsorption increases the rigidity of both interdigitated gel and lamellar fluid phases. The increase in gel phase rigidity could be explained by the transformation of an adjacent to an interpenetrated interdigitation. Interdigitated fusogenic bilayers may find interesting applications in delivery of therapeutic oligonucleotides. PMID- 23926902 TI - Does reducing length of stay increase rehospitalization of medicare fee-for service beneficiaries discharged to skilled nursing facilities? AB - OBJECTIVES: To analyze the relationship between length of stay and rehospitalization. DESIGN: Retrospective cohort study. SETTING: Six thousand five hundred thirty-seven hospitals nationwide from January 1999 through September 2005. PARTICIPANTS: Medicare fee-for-service beneficiaries associated with 2,101,481 hospitalizations. MEASUREMENTS: Thirty-day rehospitalization derived from Medicare hospital claims using the implementation of Medicare's post-acute care transfer policy as a quasi-experiment. RESULTS: Medicare's post-acute care transfer policy led to immediate declines in length of stay. A 1-day decrease in length of stay was associated with an absolute increase in 30-day rehospitalization of 1.56 percentage points (95% confidence interval (CI) = 0.30 2.82) for acute myocardial infarction (AMI) with major complications and 0.81 percentage points (95% CI = 0.03-1.60) for kidney infection or urinary tract infection (UTI) without major complications. Individuals hospitalized for AMI without major complications, heart failure, or kidney infection or UTI with major complications had no increase in 30-day rehospitalization. CONCLUSION: A 1-day reduction in hospital length of stay was not consistently associated with a higher rate of rehospitalization. PMID- 23926903 TI - The intrinsic growth rate as a predictor of population viability under climate warming. AB - 1. Lately, there has been interest in using the intrinsic growth rate (rm) to predict the effects of climate warming on ectotherm population viability. However, because rm is calculated using the Euler-Lotka equation, its reliability in predicting population persistence depends on whether ectotherm populations can achieve a stable age/stage distribution in thermally variable environments. Here, we investigate this issue using a mathematical framework that incorporates mechanistic descriptions of temperature effects on vital rates into a stage structured population model that realistically captures the temperature-induced variability in developmental delays that characterize ectotherm life cycles. 2. We find that populations experiencing seasonal temperature variation converge to a stage distribution whose intra-annual pattern remains invariant across years. As a result, the mean annual per capita growth rate also remains constant between years. The key insight is the mechanism that allows populations converge to a stationary stage distribution. Temperature effects on the biochemical processes (e.g. enzyme kinetics, hormonal regulation) that underlie life-history traits (reproduction, development and mortality) exhibit well-defined thermodynamical properties (e.g. changes in entropy and enthalpy) that lead to predictable outcomes (e.g. reduction in reaction rates or hormonal action at temperature extremes). As a result, life-history traits exhibit a systematic and predictable response to seasonal temperature variation. This in turn leads to temporally predictable temperature responses of the stage distribution and the per capita growth rate. 3. When climate warming causes an increase in the mean annual temperature and/or the amplitude of seasonal fluctuations, the population model predicts the mean annual per capita growth rate to decline to zero within 100 years when warming is slow relative to the developmental period of the organism (0.03-0.05 degrees C per year) and to become negative, causing population extinction, well before 100 years when warming is fast (e.g. 0.1 degrees C per year). The Euler-Lotka equation predicts a slower decrease in rm when warming is slow and a longer persistence time when warming is fast, with the deviation between the two metrics increasing with increasing developmental period. These results suggest that predictions of ectotherm population viability based on rm may be valid only for species with short developmental delays, and even then, only over short time-scales and under slow warming regimes. PMID- 23926904 TI - Iodine(III)-mediated [3 + 2] cyclization for one-pot synthesis of benzo[d]isoxazole-4,7-diols in aqueous medium. AB - A one-pot [3 + 2] cycloadditive synthesis of benzo[d]isoxazole-4,7-diols in aqueous medium was carried out via nitrile oxides and benzoquinone intermediates by taking advantage of iodobenzene diacetate as an oxidant. This method can also be used to synthesize benzodiisoxazole-4,8-diols, isoxazolo[5,4-a]phenazines, and indazole-4,7-diols, which are difficult to obtain by classical methods. PMID- 23926905 TI - Hydroxyethyl starch - the importance of being earnest. AB - Despite ongoing controversial expert discussions the European Medicines Agency (EMA) recently recommended to suspend marketing authorisations for hydroxyethyl starch. This comment critically evaluates the line of arguments. Basically, the only indication for a colloid is intravascular hypovolemia. Crystalloid use appears reasonable to compensate ongoing extracellular losses beyond. In the hemodynamically instable patient this leads to the distinction between an initial resuscitation phase where colloids might be indicated and a crystalloidal maintenance phase thereafter. It is important to bear this in mind when reevaluating the studies the EMA referred to in the context of its recent decision: i) VISEP compared ringer's lactate to 10% HES 200/0.5 in septic patients and found an increased incidence of renal failure in HES receivers. Unfortunately, study treatment was started only after initial stabilization with HES, randomizing hemodynamically stable patients into a rational (crystalloids) and an irrational (high dose starch until ICU discharge) maintenance treatment. ii) 6S compared ringer's acetate to 6% HES 130/0.42 for fluid resuscitation in septic patients and found an increased need of renal replacement therapy and a higher mortality in the HES group. However, patients of both groups were again randomized only after initial stabilization with colloids, the actual comparison was, therefore, again rational vs. irrational. Beyond that, the documentation is partly fragmentary, leaving many important questions around the fate of the patients unanswered. iii) CHEST randomized ICU patients to receive saline or 6% HES 130/0.4 for fluid resuscitation. Actually, despite partly discussed in a different way, this trial showed no relevant differences in outcome. In all, two studies showed what happens to septic patients if starches are used in a way we do not observe in daily practice. The third one actually proves their safety. The benefit of perioperative goal-directed preload optimization using starches is unquestioned. Taking these informations into account, the recommendation of the EMA starches to be generally dangerous remains mysterious and incomprehensible. An authority being able to dictate behavior should stand clear from oppressively ending a worldwide expert discussion and step back into the role of the observer until science achieves an agreement. PMID- 23926906 TI - The comparison of two negative-pressure wound therapy systems in a porcine model of wound healing. AB - The purpose of this study was to compare two negative-pressure wound healing systems (NPWT), -75 mmHg with a silicone-coated (SC) dressing and -125 mmHg with polyurethane foam dressing (standard of care). In addition, this study compared the effects of two different dressing interfaces, SC dressing and gauze, with -75 mmHg pressure. For both comparisons, two groups of five pigs were evaluated over a 21-day time course. Two excisional wounds were made on each animal and NPWT dressings were applied. A canvas saddle was constructed to hold the NPWT device so the animal had free range of the pen. Dressings were changed twice a week and wound measurements were taken. Specimens for histology and gene expression analyses were taken on day 7 and 21. These data show that there is increased expression in a few genes associated with remodeling and inflammatory processes in the NPWT-125 with polyurethane foam as compared with the NPWT-75 with SC dressing. These two systems, however, are equivalent with respect to wound healing, histology, and gene expression over 21 days of healing. Further, we demonstrate that there is no difference in measure of healing between the SC dressing and a basic gauze dressing. PMID- 23926907 TI - Geographically linking population and facility surveys: methodological considerations. AB - BACKGROUND: The relationship between health services and population outcomes is an important area of public health research that requires bringing together data on outcomes and the relevant service environment. Linking independent, existing datasets geographically is potentially an efficient approach; however, it raises a number of methodological issues which have not been extensively explored. This sensitivity analysis explores the potential misclassification error introduced when a sample rather than a census of health facilities is used and when household survey clusters are geographically displaced for confidentiality. METHODS: Using the 2007 Rwanda Service Provision Assessment (RSPA) of all public health facilities and the 2007-2008 Rwanda Interim Demographic and Health Survey (RIDHS), five health facility samples and five household cluster displacements were created to simulate typical SPA samples and household cluster datasets. Facility datasets were matched with cluster datasets to create 36 paired datasets. Four geographic techniques were employed to link clusters with facilities in each paired dataset. The links between clusters and facilities were operationalized by creating health service variables from the RSPA and attaching them to linked RIDHS clusters. Comparisons between the original facility census and undisplaced clusters dataset with the multiple samples and displaced clusters datasets enabled measurement of error due to sampling and displacement. RESULTS: Facility sampling produced larger misclassification errors than cluster displacement, underestimating access to services. Distance to the nearest facility was misclassified for over 50% of the clusters when directly linked, while linking to all facilities within an administrative boundary produced the lowest misclassification error. Measuring relative service environment produced equally poor results with over half of the clusters assigned to the incorrect quintile when linked with a sample of facilities and more than one-third misclassified due to displacement. CONCLUSIONS: At low levels of geographic disaggregation, linking independent facility samples and household clusters is not recommended. Linking facility census data with population data at the cluster level is possible, but misclassification errors associated with geographic displacement of clusters will bias estimates of relationships between service environment and health outcomes. The potential need to link facility and population-based data requires consideration when designing a facility survey. PMID- 23926908 TI - Exploring the potential of a conditional cash transfer intervention to reduce HIV risk among young women in Iringa, Tanzania. AB - Cash transfer programs seek to alter structural determinants of HIV risk such as poverty and gender inequality. We sought to explore the feasibility and potential effectiveness of a cash transfer intervention for young women as part of combination HIV prevention in Iringa, Tanzania. Qualitative, in-depth interviews were conducted with 116 stakeholders and residents from the region, including key informants, service delivery users, and members of key populations. Most respondents felt a cash transfer program would assist young women in Iringa to have more control over sexual decision-making and reduce poverty-driven transactional sex. Respondents were divided on who should receive funds: young women themselves, their parents/guardians, or community leaders. Cash amounts and suggested target groups varied, and several respondents suggested providing microcredit or small business capital instead of cash. Potential concerns included jealousy, dependency, and corruption. However, most respondents felt that some intervention was needed to address underlying poverty driving some sexual risk behavior. A cash transfer program could fill this role, ultimately reducing HIV, sexually transmitted infections, and unintended pregnancies. As increased attention is given to economic and structural interventions for HIV prevention, local input and knowledge should be considered in a program design. PMID- 23926909 TI - Are labour-intensive efforts to prevent pressure ulcers cost-effective? AB - BACKGROUND: Pressure ulcers are a major problem in Danish healthcare with a prevalence of 13-43% among hospitalized patients. The associated costs to the Danish Health Care Sector are estimated to be ?174.5 million annually. In 2010, The Danish Society for Patient Safety introduced the Pressure Ulcer Bundle (PUB) in order to reduce hospital-acquired pressure ulcers by a minimum of 50% in five hospitals. The PUB consists of evidence-based preventive initiatives implemented by ward staff using the Model for Improvement. OBJECTIVE: To investigate the cost effectiveness of labour-intensive efforts to reduce pressure ulcers in the Danish Health Care Sector, comparing the PUB with standard care. METHODS: A decision analytic model was constructed to assess the costs and consequences of hospital acquired pressure ulcers during an average hospital admission in Denmark. The model inputs were based on a systematic review of clinical efficacy data combined with local cost and effectiveness data from the Thy-Mors Hospital, Denmark. A probabilistic sensitivity analysis (PSA) was conducted to assess the uncertainty. RESULTS: Prevention of hospital-acquired pressure ulcers by implementing labour intensive effects according to the PUB was cost-saving and resulted in an improved effect compared to standard care. The incremental cost of the PUB was ?38.62. The incremental effects were a reduction of 9.3% prevented pressure ulcers and 0.47% prevented deaths. The PSAs confirmed the incremental cost effectiveness ratio (ICER)'s dominance for both prevented pressure ulcers and saved lives with the PUB. CONCLUSION: This study shows that labour-intensive efforts to reduce pressure ulcers on hospital wards can be cost-effective and lead to savings in total costs of hospital and social care. KEY LIMITATIONS: The data included in the study regarding costs and effects of the PUB in Denmark were based on preliminary findings from a pilot study at Thy-Mors Hospital and literature. PMID- 23926910 TI - Occupation as a vehicle to surmount the psychosocial challenges of cancer. AB - Research indicates that cancer presents challenges to one's social relationships, identity, and ability to live each day to the fullest. Occupation can be a powerful vehicle that one can use to respond to and cope with these psychosocial challenges. However, literature also suggests that occupation can be a problematic vehicle because many persons with cancer report frustration with their ability to engage in daily occupations. This paper synthesizes the research describing these psychosocial challenges and explores the nature of occupational engagement for persons with the life-threatening illness of cancer. Interpreting the research from the standpoint of the Person-Environment-Occupation Model suggests that variations in the congruence between person, environment, and occupation is an intuitively plausible explanation for differing perceptions of the quality of occupational engagement for persons with cancer. PMID- 23926911 TI - The effectiveness of low vision rehabilitation on quality of life: an evidence based practice approach to answer clinical questions. AB - The goal of this article is to demonstrate to occupational therapy practitioners how an evidence-based approach to practice can assist them in providing high quality client-centered care. A case scenario of a client with low vision was utilized to outline the steps of evidence-based practice to answer clinical questions. A critical appraisal of the literature regarding the effectiveness of low vision rehabilitation on quality of life was conducted. The appraisal included 5 quantitative studies and 2 literature reviews. Mixed results were found. A variety of low vision rehabilitation models exist. Informing the client of the current evidence and local services will allow the client to make educated decisions regarding their health care options. PMID- 23926912 TI - The effectiveness of constraint-induced therapy as a stroke intervention: a meta analysis. AB - Stroke is one of the most disabling conditions affecting adults today. Much research has been performed on rehabilitation interventions targeting hemiparesis after stroke. Constraint-induced therapy is a treatment technique that focuses on restraining the unaffected upper extremity while forcing use of the affected extremity to promote purposeful movement. This study presents a meta-analysis of applicable current literature on this treatment approach. It is concluded that constraint-induced therapy may be an effective treatment option for hemiparesis experienced after stroke. PMID- 23926913 TI - An exploration of mothers' perceptions regarding mothering occupations and experiences. AB - The objective of this phenomenological study was to explore mothers' perceptions related to the occupational experiences of mothering. Seven women between the ages of 24 and 42, with children ranging in age from 13 months to 18 years, were interviewed in two separate focus groups. Areas addressed in the semi-structured interviews included mothering role descriptions, experiences as mothers, and feelings about mothering. Data were collected by the use of field notes and audio recording. An inductive method of data analysis was used to code the transcribed narratives. Four major themes emerged that included socio-cultural influence, activities and occupations of mothering, range of feelings, and role management. Some differences between older and younger women emerged in the analysis. Perceptions of mothering occupations influence the manner in which mothers participate in their everyday activities. Exploring the perceptions of mothering among women of typical children is valuable for occupational scientists and occupational therapists seeking to understand families better. Increased awareness may lead to more optimal family-centered care. PMID- 23926914 TI - Student reflections as evidence of interactive clinical reasoning skills. AB - A graduate level occupational therapy course in the experience of chronic illness is described for its unique method in helping students to broaden clinical reasoning skills. When students are faced with having to participate in a difficult situation with patients, they have the opportunity to discuss their own reactions, to understand better their own stressful experiences, and to more easily formulate questions for those who are chronically ill. Learning is facilitated through reading autopathographies; viewing videos of people dealing with illness, both sudden and gradual; participating in small group discussions, and writing reflective journals about the challenging community experience that is required of the course. The combination of methods serves to promote interactive clinical reasoning skills. PMID- 23926915 TI - From the internet editor. PMID- 23926917 TI - Dvd review. PMID- 23926918 TI - Antithyroid drug treatment for graves' disease in children: a long-term retrospective study at a single institution. AB - BACKGROUND: The management of Graves' disease (GD) in children is associated with a dilemma. Although the established initial treatment for GD in children is antithyroid drug (ATD) treatment, the remission rate in children is said to be lower than in adults, and severe propylthiouracil-induced adverse events (AEs) are an issue. Definitive treatments are effective, but they often result in permanent hypothyroidism and the need for lifelong T4 supplementation. OBJECTIVE: The objective of this study was to investigate the outcome of ATD treatment, identify significant predictors of a remission, and evaluate the AEs of ATDs in a large pediatric population of GD patients. METHODS: We retrospectively assessed the reports of 1138 children up to 18 years of age who had been newly diagnosed with GD at our institution between 1982 and 2006. Their median age at diagnosis was 16 years (range: 3-18 years), and there were 995 females and 143 males. All patients were initially treated with an ATD. Remission was defined as maintenance of euthyroidism for more than 12 months after discontinuing ATD treatment and the absence of any relapses during the follow-up period. RESULTS: Of the 1138 patients, 723 continued on ATD treatment, 271 underwent surgery or radioactive iodine therapy, and 144 dropped out. Of the 723 patients who continued on ATD treatment, ATD treatment was subsequently ongoing in 84 and was discontinued in 639 (median duration of treatment: 3.8 years; range: 0.3-24.8 years). Of the 639 patients who discontinued ATD treatment, 334 (46.2%) achieved a remission, 247 (34.2%) experienced a relapse, and 58 (8.0%) dropped out. The cumulative remission rate increased with the duration of ATD treatment up until five years. No significant predictors of a remission were identified. The overall incidences of AEs associated with methimazole and propylthiouracil were 21.4% and 18.8% respectively. There were no fatal AEs in our population. While most AEs (91.6%) occurred within the first three months of ATD treatment, 2.7% developed more than two years after the start of ATD treatment. Seven of the eight late-onset AEs were induced by propylthiouracil. CONCLUSION: Long-term ATD treatment is a useful treatment option for GD in children. PMID- 23926920 TI - Ionic liquid-induced formation of the alpha-helical structure of beta lactoglobulin. AB - Structural modification of bovine milk beta-lactoglobulin (beta-LG) in aqueous 1 butyl-3-methylimidazolium nitrate ([bmim][NO3]) and ethylammonium nitrate ([EAN][NO3]) solutions has been investigated by Fourier transform infrared and circular dichroism spectroscopy. Remarkably, high ionic liquid (IL) concentrations (>15 mol %IL) caused formation of a non-native alpha-helical structure of beta-LG and disruption of its tertiary structure. Furthermore, while [bmim][NO3] promoted protein aggregation, [EAN][NO3] inhibited it probably owing to differences in the unique solution structure (nanoheterogeneity) of the ILs by the different cationic species. The IL-induced alpha-helical formation of beta-LG shows a behavior similar to the alcohol denaturation, but a disordered structure rich state was observed in the beta-alpha transition process by adding IL, in contrast to the case of an aqueous alcohol solution of protein. We propose that the molten salt-like property of aqueous IL solutions strongly support alpha helical formation of proteins. PMID- 23926921 TI - Correction: Reduced infarct size in neuroglobin-null mice after experimental stroke in vivo. PMID- 23926922 TI - Synthesis and biological evaluation of a polyyne-containing sphingoid base probe as a chemical tool. AB - The sphingolipid metabolites have emerged as a starting point for the development of novel therapeutics for many diseases. However, details of the functions and mechanisms of sphingolipids remain unknown. To better understand the roles of sphingolipids, chemical tools with unique biological and physicochemical properties are needed. In this regard, we previously reported the synthesis of sphingoid base analogues in which the carbon chains are restricted by triple bonds. Here, we have conjugated a fluorescent dye to the polyyne analogues of the sphingoid bases to generate optical probes. Like the parent polyyne-containing sphingoid base, the 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-labeled triyne sphingosine inhibited cancer cell growth far more effectively than did the corresponding sphingosine. NBD-triyne-sphingosine was rapidly incorporated into the cells and displayed broad cytoplasmic distribution. According to the results of a flow cytometric analysis, cancer cells fed with NBD-triyne-sphingosine showed significantly increased fluorescence intensity compared with the NBD sphingosine treated cells. The metabolism of NBD-triyne-sphingosine was somewhat different from that of NBD-sphingosine. These results indicated that the incorporated rigid polyyne moiety in the sphingoid base altered the physicochemical properties of the sphingolipid, thereby affecting its biological behavior. The higher antiproliferative activity in the SRB assay and the significantly higher fluorescence intensity observed in the flow cytometric analysis are some of the interesting and distinct aspects of NBD-triyne sphingosine compared to standard NBD-sphingosine probes. Thus, it is believed that the fluorescently labeled polyyne-containing sphingoid base developed in this study will be a useful chemical tool in sphingolipid research. PMID- 23926924 TI - Patient satisfaction with anaesthesia - Part 1: satisfaction as part of outcome - and what satisfies patients. AB - Patients' involvement in all decision processes is becoming increasingly important in modern healthcare. Patient satisfaction is a sensitive measure of a well-functioning health service system. The objective of this review is to discuss patient satisfaction as part of outcome quality, to define the somewhat abstract term 'satisfaction', and to discuss the role of surrogate markers within the field of satisfaction with anaesthesia care. We critically discuss what is relevant to satisfy patients with anaesthesia care, and we provide guidance on improving satisfaction. PMID- 23926923 TI - Immunohistochemical evaluation of MYC expression in mantle cell lymphoma. AB - AIM: To assess the validity and potential clinical utility of evaluating MYC expression by immunohistochemistry (IHC) in mantle cell lymphoma (MCL). METHODS AND RESULTS: MYC IHC was scored on a tissue microarray containing 62 MCLs and 29 controls by two pathologists. Inter-observer correlation was high (intra-class correlation of 0.98). MYC IHC scores correlated with MYC expression (Spearman's rank correlation 0.69, P < 0.0001) and weakly with Ki67 proliferation index (Spearman's rank correlation 0.30, P = 0.03). Six blastic MCLs did not have higher mean MYC IHC scores or MYC mRNA expression than non-blastic MCLs. None of 57 cases assessed, including all of the blastic cases, showed MYC rearrangement by fluorescence in-situ hybridization. Multivariate analysis with backward selection from potential predictors including age, lactate dehydrogenase, leukocyte count, MIPI score, ECOG performance status, blastic morphology and Ki67 index showed that MYC IHC score is an independent predictor of progression-free survival (hazard ratio 2.34, 95% CI 1.42-3.88, P = 0.0009) and overall survival (hazard ratio 1.90, 95% CI 1.05-3.43, P = 0.034). CONCLUSIONS: We show that a new monoclonal anti-MYC antibody can enable accurate and reproducible visual assessment of MYC expression that is independently predictive of clinical outcomes in MCL. PMID- 23926925 TI - Interactions and competition processes among tree species in young experimental mixed forests, assessed with chlorophyll fluorescence and leaf morphology. AB - Chlorophyll a fluorescence (ChlF) and leaf morphology were assessed in two sites in Europe (Kaltenborn, Germany, and Satakunta, Finland) within a forest diversity experiment. Trees at Satakunta, planted in 1999, form a stratified canopy, while in Kaltenborn the trees are 7 years old, with no apparent canopy connection among broadleaf species. The following ChlF parameters from measured OJIP transient curves were examined: F(V)/F(M) (a proxy for maximum quantum yield); PsiEo (a proxy for efficiency in transferring an electron from reduced QA to the electron transport chain); I-P phase (a proxy for efficiency of reducing final acceptors beyond PSI); and PItot (total performance index for potential energy conservation from photons absorbed by PSII to reduction of PSI end acceptors). At Satakunta F(V)/F(M) and PsiEo in Betula pendula were higher in monocultures and lower in mixed plots, perhaps due to increasing light availability in mixed plots, which can induce photoinhibition. The opposite trend was observed in Picea abies, which was shaded in mixed plots. At Kaltenborn F(V)/F(M) decreased in Fagus sylvatica and P. abies in mixed plots due to competition both above- and belowground. At Satakunta LMA increased in B. pendula leaves with increasing species richness. Leaf area of ten leaves was reduced in F. sylvatica in mixed plots at Kaltenborn. By up-scaling the overall fluorescence response to plot level (PItot_plot ), a significant positive correlation with tree diversity was found at Kaltenborn, but not at Satakunta. This could suggest that competition/facilitation processes in mixed stands play a significant role in the early stages of forest establishment, but then tend to be compensated in more mature stands. PMID- 23926926 TI - Gastroesophageal reflux symptoms in typical and atypical GERD: roles of gastroesophageal acid refluxes and esophageal motility. AB - BACKGROUND/AIM: To determine the roles of gastroesophageal acid reflux (GER) and esophageal dysmotility on typical and atypical GERD symptoms. METHODS: Two hundred thirty-six patients (159 females, age 47 +/- 14 years) with typical and atypical GERD symptom(s) for > 3 months underwent standard water perfused esophageal manometry (EM) and 24 h esophageal pH studies during off therapy. RESULTS: Eighty seven and 93 patients had positive lower esophageal pH tests and abnormal EM, respectively. Patients with positive lower esophageal pH test were significantly older (50 +/- 13 vs 45 +/- 13 years, P < 0.005) and had higher prevalence of acid regurgitation symptoms than patients with negative test (56/87 vs 72/149, P < 0.05). Patients with positive upper esophageal pH test (n = 67) also had significantly higher prevalence of acid regurgitation symptoms (43/67 vs 74/152, P < 0.05). Prevalence of other upper gastrointestinal and respiratory symptoms were similar between patients with positive and negative upper and lower pH test. Patients with abnormal EM were significantly older (49 +/- 14 vs 45 +/- 13 years, P < 0.05) and had higher prevalence of chronic cough than patients with normal EM(30/93 vs 26/143, P < 0.05). In patients with positive pH tests, the prevalence of dysphagia, chronic cough, and hoarseness of voice were significantly higher in patients with abnormal than those with normal EM (18/31 vs 18/56, P < 0.05; 12/31 vs 6/56, P < 0.005 and 19/31 vs 18/56, P < 0.01, respectively). Whereas in patients with negative lower pH tests, only the prevalence of heartburn was significantly lower in patients with normal than those with abnormal EM (26/87 vs 30/62, P < 0.05). CONCLUSIONS: Acid regurgitation but not heartburn was associated with GER. Esophageal dysmotility had no significant effect on acid regurgitation symptom but associated with chronic cough, hoarseness of voice, and dysphagia only in patients with abnormal esophageal acid exposure. PMID- 23926919 TI - Chemistry meets biology in colitis-associated carcinogenesis. AB - The intestine comprises an exceptional venue for a dynamic and complex interplay of numerous chemical and biological processes. Here, multiple chemical and biological systems, including the intestinal tissue itself, its associated immune system, the gut microbiota, xenobiotics, and metabolites meet and interact to form a sophisticated and tightly regulated state of tissue homoeostasis. Disturbance of this homeostasis can cause inflammatory bowel disease (IBD)-a chronic disease of multifactorial etiology that is strongly associated with increased risk for cancer development. This review addresses recent developments in research into chemical and biological mechanisms underlying the etiology of inflammation-induced colon cancer. Beginning with a general overview of reactive chemical species generated during colonic inflammation, the mechanistic interplay between chemical and biological mediators of inflammation, the role of genetic toxicology, and microbial pathogenesis in disease development are discussed. When possible, we systematically compare evidence from studies utilizing human IBD patients with experimental investigations in mice. The comparison reveals that many strong pathological and mechanistic correlates exist between mouse models of colitis-associated cancer, and the clinically relevant situation in humans. We also summarize several emerging issues in the field, such as the carcinogenic potential of novel inflammation-related DNA adducts and genotoxic microbial factors, the systemic dimension of inflammation-induced genotoxicity, and the complex role of genome maintenance mechanisms during these processes. Taken together, current evidence points to the induction of genetic and epigenetic alterations by chemical and biological inflammatory stimuli ultimately leading to cancer formation. PMID- 23926927 TI - Bilateral optic disc oedema and associated optic neuropathy in the setting of FOLFOX chemotherapy. AB - BACKGROUND: To report a case of bilateral optic disc oedema and associated optic neuropathy in the setting of FOLFOX chemotherapy. CASE PRESENTATION: A case of a 57-year-old male being treated with FOLFOX chemotherapy for stage 3B colorectal cancer, who developed bilateral optic disc oedema and associated left sided optic neuropathy is described. The patient presented following cycles 7, 8 and 9 of chemotherapy with a history of bilateral simultaneous intermittent inferior altitudinal field defects. These episodes progressed to bilateral optic nerve oedema and a subsequent left sided optic neuropathy. The patient's symptoms and oedema regressed with discontinuation of chemotherapy. CONCLUSION: This is the first report suggesting a vasospastic role of 5-fluoruracil in 5-FU associated optic neuropathy. It highlights that 5-FU may have the potential to cause arterial vasospasm outside the cardiac vasculature, resulting in end-organ optic nerve ischaemia. PMID- 23926928 TI - Surface tension, surface energy, and chemical potential due to their difference. AB - It is well-known that surface tension and surface energy are distinct quantities for solids. Each can be regarded as a thermodynamic property related first by Shuttleworth. Mullins and others have suggested that the difference between surface tension and surface energy cannot be sustained and that the two will approach each other over time. In this work we show that in a single-component system where changes in elastic energy can be neglected, the chemical potential difference between the surface and bulk is proportional to the difference between surface tension and surface energy. By further assuming that mass transfer is driven by this chemical potential difference, we establish a model for the kinetics by which mass transfer removes the difference between surface tension and surface energy. PMID- 23926929 TI - The status of occupational therapy: addressing the needs of people experiencing homelessness. AB - SUMMARY This paper discusses the move of occupational therapy practitioners towards providing services for people who are homeless, presents the results of an internet-based survey of assessment tools used with this population, and provides an overview of this volume's papers while discussing the current status of occupational therapy interventions. PMID- 23926930 TI - Homelessness: perspectives, misconceptions, and considerations for occupational therapy. AB - SUMMARY Like poverty, the problem of homelessness has been with us to varying degrees since the founding of our nation. Attempts to explain homelessness have an equally long history. Hence, the literature and popular media are home to divergent perspectives, explanations, and characterizations of homelessness. The objectives of this paper are to present a unifying taxonomy of prominent perspectives on homelessness, and to illustrate how various perspectives lead to particular characterizations of persons who become homeless. The taxonomy traces the connection between perspectives and interpretations of the problem and helps to illuminate implicit and often unexamined assumptions about who becomes homeless and why. Critical examination of these perspectives is vital because our individual and collective understanding of homelessness is a powerful determinant of how we approach occupational therapy practice with this population. Implications for community practice and program planning for individuals and families in homeless shelters are also discussed. PMID- 23926931 TI - Systems of care for persons who are homeless in the United States. AB - SUMMARY Occupational therapists work within various systems that provide services to persons who are homeless, including housing, health care, social service, education, and work programs. This article describes the typologies of homelessness, the continuum of care, trends in service delivery, the federal organization and primary sources of funding for homeless services. It is important for therapists to understand these systems and resources in order to deliver and advocate for effective services for persons who are homeless. PMID- 23926932 TI - Occupational concerns of women who are homeless and have children: an occupational justice critique. AB - SUMMARY The purpose of this exploratory study was to describe the occupational goals and concerns of women who are homeless with children. Twenty-seven women with children living in homeless shelters completed interviews using the Canadian Occupational Performance Measure (COPM). Occupational issues and concerns were identified for each participant, and then they were pooled. A total of 169 occupational concerns were described and analyzed. The most common occupational issues identified by participants concerned finances, employment, education, transportation, housing, time for self, personal appearance, home management, and parenting. Analysis of identified occupational concerns suggests that the homeless women with children experienced a range of institutional and social barriers to occupational participation: essentially a form of occupational injustice. This study raises questions concerning the most effective roles for occupational therapists to facilitate empowerment so that women who are homeless may fully participate in the communities where they live. PMID- 23926933 TI - Describing the phenomenon of homelessness through the theory of occupational adaptation. AB - SUMMARY The purpose of this study was to illustrate the value of the theory of Occupational Adaptation (Schkade & Schultz, 1992; Schultz & Schkade, 1992) in describing the phenomenon of homelessness. Case studies portray the experience of four individuals residing in a homeless shelter. Utilizing Occupational Adaptation to guide the assessment and intervention process, the results suggest that this theory may be useful in describing the individuals' internal adaptation process necessary to live independent and productive lives. PMID- 23926934 TI - Mother-toddler interactions during child-focused activity in transitional housing. AB - SUMMARY This report describes the videotaped interactions of five mother-toddler dyads living in transitional housing. This study was designed to specifically examine the interactions as a function of routine in different types of child focused activity. The interactions were described using the Parent-Toddler Coding System and Rating Scales of Dyadic Interaction (Ray & Tickle-Degnen, 2004). The focus was to examine the socio-emotional and task-supporting interactions that relate to the child's engagement in child-focused activity. Interactions were examined during free play, block play, slide play, and while having a snack. Positive moderate associations were noted between maternal and child socio emotional dimensions of interactions in all activity conditions. The associations between maternal socio-emotional and task-related dimensions of interactions with child task-related dimensions of interaction were small in a positive direction, with higher associations noted in more familiar tasks such as during slide play or while having a snack. These preliminary findings suggest that familiarity with routines should be considered when examining the interactions that support child activity in families living in transitional housing for the homeless. PMID- 23926935 TI - Homeless youth: causes, consequences and the role of occupational therapy. AB - SUMMARY This paper reviews the current literature on youth homelessness in the United States and the role of occupational therapy with this population. Youth homelessness is increasing with many youths becoming homeless due to a myriad of causes such as abusive situations in their homes and decreases in affordable housing. Definitions, causes, physical and mental health consequences and the impact of homelessness on youths' development into adult roles are discussed. The role of occupational therapy is described with a focus on useful assessments and intervention principles. Finally, a case study is presented to illustrate the use of these assessments and occupational therapy intervention with a female youth living in an emergency shelter. PMID- 23926936 TI - The after-school occupations of homeless youth: three narrative accounts. AB - SUMMARY This study describes the after-school and weekend time use of young adolescents residing in a temporary shelter for homeless families in Los Angeles County. Data were collected from three individual interviews, focus groups with 24 young adolescents and one-week time use journals. Data were analyzed qualitatively using the constant comparative method. Three narrative profiles were constructed from these data. Emergent themes and concepts describing the occupational participation of young adolescents during the non-school hours were summarized into three major concepts. These were the following: (a) Occupational Necessity: Social Intensity; (b) Boredom and Shelter Living: Occupational Advantages and Disadvantages; and, (c) Designing a Life: Taking Control. Implications for occupational science, occupational therapy, and public policy were identified with relevant recommendations. PMID- 23926937 TI - Assessing the occupational performance priorities of people who are homeless. AB - SUMMARY This study examined retrospective data for 65 participants enrolled in an occupational therapy supportive employment program. The Canadian Occupational Performance Measure (COPM) was used to identify self-perceived occupational performance problems specific to this population. Over half of the identified problems fell in the self-care domain (59%), about one-third (31%) were in the productivity domain and the final 10% were in the leisure domain. Narrative analysis of verbatim goals suggests that these individuals identified different types of self-care and productivity problems than samples in previous studies. The results of this study indicate that the COPM can facilitate person-centered, culturally responsive assessment with individuals who are homeless. PMID- 23926938 TI - Occupational therapy intervention to foster goal setting skills for homeless mothers. AB - SUMMARY Occupational therapy intervention was provided to two mothers living in a homeless shelter to foster goal setting skills and the ability to develop a systematic method to meet those goals. The Model of Human Occupation (MOHO) was used as the theoretical framework to guide intervention. Both mothers were able to establish personal goals and work towards meeting those goals but the outcomes varied. The difference in outcomes between the two mothers is described using MOHO with analysis of how occupational therapy services can be used with homeless mothers. PMID- 23926939 TI - Building productive roles: occupational therapy in a homeless shelter. AB - SUMMARY Project Employ is a grant-funded program providing occupational therapy services to persons who are homeless. At Project Employ productive role involvement is the primary program outcome. Choices for productive role involvement are keyed by the person's interests and preferences, assessment is an ongoing process, prevocational training and rapid job placement are both available, and support and work-place interventions, while not unlimited, can continue for up to two years. This article describes the process of assessing factors that act as supports or barriers to productive role functioning and shares intervention methods that support role competence and adaptation in this vulnerable population. PMID- 23926940 TI - Life skill interventions with homeless youth, domestic violence victims and adults with mental illness. AB - SUMMARY This paper presents three exploratory studies of life skills interventions (employment, money management or food/nutrition) with 73 homeless individuals from four shelters and supportive housing programs located in the urban Midwest for youth, victims of domestic violence and adults with mental illness. The Ansell Casey Life Skills Assessment was administered prior to the eight group and individual sessions. Quizzes and posttests indicated clinical change in all groups, with statistical significance in the domestic violence group. The intervention implementation, challenges encountered, and strategies developed for implementing shelter-based interventions are discussed. Recommendations for successfully providing collaborative university-shelter clinical interventions are provided. PMID- 23926941 TI - Direct conversion of N-alkoxyamides to carboxylic esters through tandem NBS mediated oxidative homocoupling and thermal denitrogenation. AB - Treatment of N-alkoxyamides with NBS in toluene was found to conveniently afford the corresponding carboxylic esters, including those bearing a bulky or long chain substituent, in satisfactory to excellent yields. This approach not only represents a convenient and economic approach to a direct transformation of an alkoxyamide moiety into the carboxylic ester functional group, via oxidative homocoupling and the subsequent thermal denitrogenation, but also facilitates the synthesis of sterically hindered carboxylic esters. PMID- 23926942 TI - Structure-activity relationship of flavonoids on their anti-Escherichia coli activity and inhibition of DNA gyrase. AB - Flavonoids are potential sources of natural preservatives. The inhibitory activities of three polymethoxylated flavones (PMFs), three flavones, and four flavonols against Escherichia coli were determined using the microbroth dilution method. Flavonoid inhibitory activities against DNA gyrase from E. coli were estimated by DNA supercoiling. Kaempferol exhibited the greatest antibacterial activity [minimal inhibitory concentration (MIC) = 25 MUg/mL], while nobiletin showed the lowest activity (MIC = 177 MUg/mL). A good correlation was found between the pIC50 values and the corresponding pMIC values for the purified DNA gyrase (r = 0.9582). The structure-activity relationship analysis suggests that, for a good inhibitory effect, the hydroxyl group substitution at C-5 in the A ring and C-4' in the B ring and the methoxyl group substitution at C-3 and C-8 in the A ring are essential. The presence of the hydroxyl group at C-6 in the A ring, C-3' and C-5' in the B ring, and C-3 in the C ring and the methoxyl group at C-3' in the B ring greatly reduced inhibition of bacteria. These findings provide a theoretical basis for the development of high-bioactive and low toxicity natural preservatives. PMID- 23926943 TI - Wound hypoxia in deep tissue after incision in rats. AB - Our previous studies using rat models of incisional pain have shown that tissue lactate levels increase and pH decreases for several days after incision, suggesting the presence of an ischemic-like condition. The purpose of this study was to evaluate the time course and the extent of tissue hypoxia that develops in incised muscle and skin. We directly measured oxygen tension at several time points after incisions of the gastrocnemius muscle, the paraspinal skin, and the plantar hindpaw in anesthetized rats using an oxygen-sensitive microelectrode. In vivo hypoxia of the incised tissues was also evaluated immunohistochemically using a hypoxia marker, pimonidazole hydrochloride. To minimize intersubject variability, unincised contralateral tissues were used as a control. Tissue oxygen tension was decreased in both skeletal muscle and skin compared with control, for several days after incision. When measured directly, oxygen tension decreased immediately and remained low for several days after incisions. Pimonidazole immunostaining revealed hypoxic areas in incised muscle and skin for several days. By postoperative day 10, tissue oxygen tension recovered to that of control tissue. These results support the evidence that a hypoxic condition is present in deep tissue after incisions and that an ischemic-like mechanism may contribute to postoperative pain. PMID- 23926944 TI - A family cluster of giardiasis with variable treatment responses: refractory giardiasis in a family after a trip to India. AB - Persistence of giardiasis after some of the recommended drugs is occurring with increasing frequency. We describe the follow-up of four members of a family with giardiasis through microscopic observation, immunochromatography and PCRs of tpi and beta-giardin genes. Three patients did not respond to tinidazole but they were cured after quinacrine. However, PCR became negative at 2 months after negativization of stools in two patients and after 1 year in one patient. In all cases Giardia assemblage B was characterized with high homology between all isolates. Further studies are needed to determine the value of PCR in the diagnosis of Giardia infections. PMID- 23926945 TI - Impact of host nutritional status on infection dynamics and parasite virulence in a bird-malaria system. AB - Host resources can drive the optimal parasite exploitation strategy by offering a good or a poor environment to pathogens. Hosts living in resource-rich habitats might offer a favourable environment to developing parasites because they provide a wealth of resources. However, hosts living in resource-rich habitats might afford a higher investment into costly immune defences providing an effective barrier against infection. Understanding how parasites can adapt to hosts living in habitats of different quality is a major challenge in the light of the current human-driven environmental changes. We studied the role of nutritional resources as a source of phenotypic variation in host exploitation by the avian malaria parasite Plasmodium relictum. We investigated how the nutritional status of birds altered parasite within-host dynamics and virulence, and how the interaction between past and current environments experienced by the parasite accounts for the variation in the infection dynamics. Experimentally infected canaries were allocated to control or supplemented diets. Plasmodium parasites experiencing the two different environments were subsequently transmitted in a full-factorial design to new hosts reared under similar control or supplemented diets. Food supplementation was effective since supplemented hosts gained body mass during a 15-day period that preceded the infection. Host nutrition had strong effects on infection dynamics and parasite virulence. Overall, parasites were more successful in control nonsupplemented birds, reaching larger population sizes and producing more sexual (transmissible) stages. However, supplemented hosts paid a higher cost of infection, and when keeping parasitaemia constant, they had lower haematocrit than control hosts. Parasites grown on control hosts were better able to exploit the subsequent hosts since they reached higher parasitaemia than parasites originating from supplemented hosts. They were also more virulent since they induced higher mass and haematocrit loss. Our study highlights that parasite virulence can be shaped by the host nutritional status and that parasite can adapt to the environment provided by their hosts, possibly through genetic selection. PMID- 23926946 TI - ExoSensor 517: a dual-analyte fluorescent chemosensor for visualizing neurotransmitter exocytosis. AB - A dual-analyte fluorescent chemosensor (ExoSensor 517) for the direct visualization of neurotransmitters released upon exocytosis is presented. The sensor exploits the high concentration of neurotransmitters (e.g., glutamate, norepinephrine, and dopamine) and the pH gradient between the vesicle and synaptic cleft. The cooperative recognition elements require both binding and a change in environmental pH to afford a fluorescence response which makes ExoSensor 517 one of the first integrated molecular logic gates to be used for biological applications. PMID- 23926947 TI - Oligomerization of the chitin synthase Chs3 is monitored at the Golgi and affects its endocytic recycling. AB - Chs3, the catalytic subunit of chitin synthase III in Saccharomyces cerevisiae, is a complex polytopic membrane protein whose plasma membrane expression is tightly controlled: export from the ER requires interaction with Chs7; exit from the Golgi is dependent on the exomer complex, and precise bud neck localization relies on endocytosis. Moreover, Chs3 is efficiently recycled from endosomes to the TGN in an AP-1-dependent manner. Here we show that the export of Chs3 requires the cargo receptor Erv14, in a step that is independent of Chs7. Chs3 oligomerized in the ER through its N-terminal cytosolic region. However, the truncated (Delta126)Chs3 was still exported by Erv14, but was sent back from the Golgi to the ER in a COPI- and Rer1-dependent manner. A subset of the oligomerization-deficient Chs3 proteins evaded Golgi quality control and reached the plasma membrane, where they were enzymatically active but poorly endocytosed. This resulted in high CSIII levels, but calcofluor white resistance, explained by the reduced intercalation of calcofluor white between nascent chitin fibres. Our data show that the oligomerization of Chs3 through its N-terminus is essential for proper protein trafficking and chitin synthesis and is therefore monitored intracellularly. PMID- 23926948 TI - Heavy-duty truck emissions in the South Coast Air Basin of California. AB - California and Federal emissions regulations for 2007 and newer heavy-duty diesel engines require an order of magnitude reduction in particulate matter and oxides of nitrogen spurring the introduction of new aftertreatment systems. Since 2008, four emission measurement campaigns have been conducted at a Port of Los Angeles location and an inland weigh station in the South Coast Air Basin of California. Fuel specific oxides of nitrogen emissions at the Port have decreased 12% since 2010 while infrared opacity (a measure of particulate matter) remained low, showing no diesel particulate filter deterioration. The weigh station truck's fuel specific oxides of nitrogen emission reductions since 2010 (18.5%) almost double the previous three year's reductions and are the result of new trucks using selective catalytic reduction systems. Trucks at the weigh station equipped with these systems have a skewed oxides of nitrogen emissions distribution (half of the emissions were from 6% of the measurements) and had significantly lower emissions than similarly equipped Port trucks. Infrared thermographs of truck exhaust pipes revealed that the mean temperature observed at the weigh station (225 +/- 4.5 degrees C) was 70 degrees C higher than for Port trucks, suggesting that the catalytic aftertreatment systems on trucks at our Port site were often below minimum operating temperatures. PMID- 23926949 TI - Formation of three-dimensional ordered hierarchically porous metal oxides via a hybridized epoxide assisted/colloidal crystal templating approach. AB - Three-dimensionally ordered hierarchically porous alumina, iron(III) oxide, yttria, and nickel oxide have been prepared through the hybridization of colloidal crystal-templating and a modified sol-gel method. Simply, highly ordered arrays of poly(methyl methacrylate) (PMMA) were infiltrated with a precursor solution of metal salt and epoxide. Calcination after solidification of the material removed the polymer template while forming the inverse replicas, simultaneously. These hierarchical structures possessing macropore windows and mesopore walls were characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and N2 adsorption/desorption techniques to probe the structural integrity. It was revealed by PXRD that the prepared 3D frameworks were single-phase polycrystalline structures with grain sizes between 5 and 27 nm. The thermal stability as studied by TGA illustrates expected weight losses and full decomposition of the PMMA template. SEM reveals the bimodal, hierarchical macroporous frameworks with well-defined macropore windows and mesoporous walls. Gas sorption measurements of the ordered materials display surface areas as high as 93 m(2) g(-1), and average mesopore diameter up to 33 nm. Due to the versatility of this method, we expect these materials will be ideal candidates for applications in catalysis, adsorption, and separations. Furthermore, the implementation of this technology for production of three-dimensionally ordered macroporous materials can improve the cost and efficiency of metal oxide frameworks (MOFs) due to its high versatility and amenability to numerous systems. PMID- 23926950 TI - Constitutive expression of cell wall invertase genes increases grain yield and starch content in maize. AB - Grain size, number and starch content are important determinants of grain yield and quality. One of the most important biological processes that determine these components is the carbon partitioning during the early grain filling, which requires the function of cell wall invertase. Here, we showed the constitutive expression of cell wall invertase-encoding gene from Arabidopsis, rice (Oryza sativa) or maize (Zea mays), driven by the cauliflower mosaic virus (CaMV) 35S promoter, all increased cell wall invertase activities in different tissues and organs, including leaves and developing seeds, and substantially improved grain yield up to 145.3% in transgenic maize plants as compared to the wild-type plants, an effect that was reproduced in our 2-year field trials at different locations. The dramatically increased grain yield is due to the enlarged ears with both enhanced grain size and grain number. Constitutive expression of the invertase-encoding gene also increased total starch content up to 20% in the transgenic kernels. Our results suggest that cell wall invertase gene can be genetically engineered to improve both grain yield and grain quality in crop plants. PMID- 23926951 TI - The components of self-rated health among adults in Ouagadougou, Burkina Faso. AB - BACKGROUND: Although the relationship between self-rated health (SRH) and physical and mental health is well documented in developed countries, very few studies have analyzed this association in the developing world, particularly in Africa. In this study, we examine the associations of SRH with measures of physical and mental health (chronic diseases, functional limitations, and depression) among adults in Ouagadougou, Burkina Faso, and how these associations vary by sex, age, and education level. METHODS: This study was based on 2195 individuals aged 15 years or older who participated in a cross-sectional interviewer-administered health survey conducted in 2010 in areas of the Ouagadougou Health and Demographic Surveillance System. Logistic regression models were used to analyze the associations of poor SRH with chronic diseases, functional limitations, and depression, first in the whole sample and then stratified by sex, age, and education level. RESULTS: Poor SRH was strongly correlated with chronic diseases and functional limitations, but not with depression, suggesting that in this context, physical health probably makes up most of people's perceptions of their health status. The effect of functional limitations on poor SRH increased with age, probably because the ability to circumvent or compensate for a disability diminishes with age. The effect of functional limitations was also stronger among the least educated, probably because physical integrity is more important for people who depend on it for their livelihood. In contrast, the effect of chronic diseases appeared to decrease with age. No variation by sex was observed in the associations of SRH with chronic diseases, functional limitations, or depression. CONCLUSIONS: Our findings suggest that different subpopulations delineated by age and education level weight the components of health differently in their self-rated health in Ouagadougou, Burkina Faso. In-depth studies are needed to understand why and how these groups do so. PMID- 23926952 TI - Task-specific noise exposure during manual concrete surface grinding in enclosed areas-influence of operation variables and dust control methods. AB - Noise exposure is a distinct hazard during hand-held concrete grinding activities, and its assessment is challenging because of the many variables involved. Noise dosimeters were used to examine the extent of personal noise exposure while concrete grinding was performed with a variety of grinder sizes, types, accessories, and available dust control methods. Noise monitoring was conducted in an enclosed area covering 52 task-specific grinding sessions lasting from 6 to 72 minutes. Noise levels, either in minute average noise level (Lavg, dBA) or in minute peak (dBC), during concrete grinding were significantly (P < 0.01) correlated with general ventilation (GV: on, off), dust control methods (uncontrolled, wet, Shop-Vac, HEPA, HEPA-Cyclone), grinding cup wheel (blade) sizes of 4-inch (100 mm), 5-inch (125 mm) and 6-inch (150 mm), and surface orientation (horizontal, inclined). Overall, minute Lavg during grinding was 97.0 +/- 3.3 (mean +/- SD), ranging from 87.9 to 113. The levels of minute Lavg during uncontrolled grinding (98.9 +/- 5.2) or wet-grinding (98.5 +/- 2.7) were significantly higher than those during local exhaust ventilation (LEV) grinding (96.2 +/- 2.8). A 6-inch grinding cup wheel generated significantly higher noise levels (98.7 +/- 2.8) than 5-inch (96.3 +/- 3.2) or 4-inch (95.3 +/- 3.5) cup wheels. The minute peak noise levels (dBC) during grinding was 113 +/- 5.2 ranging from 104 to 153. The minute peak noise levels during uncontrolled grinding (119 +/- 10.2) were significantly higher than those during wet-grinding (115 +/- 4.5) and LEV-grinding (112 +/- 3.4). A 6-inch grinding cup wheel generated significantly higher minute peak noise levels (115 +/- 5.3) than 5-inch (112 +/- 4.5) or 4-inch (111 +/- 5.4) cup wheels. Assuming an 8-hour work shift, the results indicated that noise exposure levels during concrete grinding in enclosed areas exceeded the recommended permissible exposure limits and workers should be protected by engineering control methods, safe work practices, and/or personal protective devices. PMID- 23926953 TI - Assessing the Risk of African Swine Fever Introduction into the European Union by Wild Boar. AB - The presence of African swine fever (ASF) in the Caucasus region and Russian Federation has increased concerns that wild boars may introduce the ASF virus into the European Union (EU). This study describes a semi-quantitative approach for evaluating the risk of ASF introduction into the EU by wild boar movements based on the following risk estimators: the susceptible population of (1) wild boars and (2) domestic pigs in the country of origin; the outbreak density in (3) wild boars and (4) domestic pigs in the countries of origin, the (5) suitable habitat for wild boars along the EU border; and the distance between the EU border and the nearest ASF outbreak in (6) wild boars or (7) domestic pigs. Sensitivity analysis was performed to identify the most influential risk estimators. The highest risk was found to be concentrated in Finland, Romania, Latvia and Poland, and wild boar habitat and outbreak density were the two most important risk estimators. Animal health authorities in at-risk countries should be aware of these risk estimators and should communicate closely with wild boar hunters and pig farmers to rapidly detect and control ASF. PMID- 23926954 TI - Oxidative potential of smoke from burning wood and mixed biomass fuels. AB - More than half the world's population still rely on burning biomass fuels to heat and light their homes and cook food. Household air pollution, a common component of which is inhalable particulate matter (PM), emitted from biomass burning is associated with increased vulnerability to respiratory infection and an enhanced risk of developing chronic obstructive pulmonary disease. In the light of an emerging hypothesis linking chronic PM exposure during childhood and increased vulnerability to respiratory diseases in adulthood, in a chain of events involving oxidative stress, reduced immunity and subsequent infection, the aim of this study was to characterise the oxidative potential (OP) of PM collected during the burning of wood and mixed biomass, whilst cooking food in the Kathmandu Valley, Nepal. Our assessments were based on the capacity of the particles to deplete the physiologically relevant antioxidants from a validated, synthetic respiratory tract lining fluid (RTLF). Incubation of mixed biomass and wood smoke particles suspensions with the synthetic RTLF for 4 h resulted in a mean loss of ascorbate of 64.76 +/- 16.83% and 83.37 +/- 14.12% at 50 MUg/ml, respectively. Reduced glutathione was depleted by 49.29 +/- 15.22% in mixed biomass and 65.33 +/- 13.01% in wood smoke particles under the same conditions. Co-incubation with the transition metal chelator diethylenetriaminepentaacetate did not inhibit the rate of ascorbate oxidation, indicating a negligible contribution by redox-active metals in these samples. The capacity of biomass smoke particles to elicit oxidative stress certainly has the potential to contribute towards negative health impacts associated with traditional domestic fuels in the developing world. PMID- 23926956 TI - Activity rhythms and masking response in the diurnal fat sand rat under laboratory conditions. AB - Daily rhythms are heavily influenced by light in two major ways. One is through photic entrainment of a circadian clock, and the other is through a more direct process, referred to as masking. Whereas entraining effects of photic stimuli are quite similar in nocturnal and diurnal species, masking is very different. Laboratory conditions differ greatly from what is experienced by individuals in their natural habitat, and several studies have shown that activity patterns can greatly differ between laboratory environment and natural condition. This is especially prevalent in diurnal rodents. We studied the daily rhythms and masking response in the fat sand rat (Psammomys obesus), a diurnal desert rodent, and activity rhythms of Tristram's jird (Meriones tristrami), a nocturnal member of the same subfamily (Gerbillinae). We found that most sand rats kept on a 12 h:12 h light-dark (LD) cycles at two light intensities (500 and 1000 lux) have a nocturnal phase preferences of general activity and higher body temperature during the dark phase. In most individuals, activity was not as stable that of the nocturnal Tritram's jirds, which showed a clear and stable nocturnal activity pattern under the same conditions. Sand rats responded to a 6-h phase advance and 6-h phase delay as expected, and, under constant conditions, all tested animals free ran. In contrast with the nocturnal phase preference, fat sand rats did not show a masking response to light pulses during the dark phase or to a dark pulse during the light phase. They did, however, have a significant preference to the light phase under a 3.5 h:3.5 h LD schedule. Currently, we could not identify the underlying mechanisms responsible for the temporal niche switch in this species. However, our results provide us with a valuable tool for further studies of the circadian system of diurnal species, and will hopefully lead us to understanding diurnality, its mechanisms, causes, and consequences. PMID- 23926955 TI - Sex differences in the circadian variation of cytochrome p450 genes and corresponding nuclear receptors in mouse liver. AB - Sex differences and circadian variation are two major factors that affect the expression of drug-processing genes. This study aimed to examine sex differences in the circadian variation of hepatic cytochrome P450 (Cyp) genes and corresponding nuclear receptors. Adult mice were acclimated to environmentally controlled facilities for 2 wks, and livers were collected every 4 h during a 24 h period. Total RNA and protein were isolated and subjected to real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis. The mRNA expression of the aryl hydrocarbon receptor (AhR) and AhR-regulated Cyp1a1 and Cyp1a2 were higher in females and higher during the light phase. The mRNA expression of constitutive and rostane receptor (CAR) and CYP2B10 protein was female-predominant and higher in the dark phase. Pregnane X receptor (PXR) peaked around 18:00 h, but PXR-regulated Cyp3a11 and Cyp3a25 were higher at 10:00 h, without apparent sex dimorphism at protein levels. Peroxisome proliferator activated receptor-alpha (PPARalpha), Cyp4a10, and Cyp4a14 were higher in females and peaked between 14:00 and 18:00 h. The mRNA levels of farnesoid X receptor (FXR), Cyp7a1, and Cyp27a1 peaked around 18:00 h and CYP7A1 protein was higher during the dark phase and higher in females. Cyp7b1(male-predominant) and Cyp2a4 (female-predominant) both showed circadian variation. Circadian variation of hepatic clock genes such as nuclear receptor Rev-erbalpha, cryptochrome 1 (Cry1), and brain muscle ARNT-like protein 1 (Bmal1) showed distinct patterns. Sex differences and circadian rhythmicity of Cyp genes and corresponding nuclear receptors exist in mouse liver that could impact xenobiotic metabolism and toxicity at different times of the day. PMID- 23926957 TI - Abeta(16-22) peptides can assemble into ordered beta-barrels and bilayer beta sheets, while substitution of phenylalanine 19 by tryptophan increases the population of disordered aggregates. AB - A recent experimental study reported that termini-uncapped Abeta(16-22) (with sequence KLVFFAE) peptides self-assembled into nanofibrils at pH 2.0. The oligomerization of this uncapped peptide at atomic level in acidic pH condition remains to be determined, as computational studies mainly focus on the self assembly of capped Abeta(16-22) peptides at neutral pH condition. In this study, using replica exchange molecular dynamics (REMD) simulations with explicit solvent, we investigated the octameric structures of the uncapped Abeta(16-22) and its F19W variant at acidic pH condition. Our simulations reveal that the Abeta(16-22) octamers adopt various conformations, including closed beta-barrels, bilayer beta-sheets, and disordered aggregates. The closed beta-barrel conformation is particularly interesting, as the cylindrical beta-barrel has been reported recently as a cytotoxic species. Interpeptide contact probability analyses between all pairs of residues reveal that the hydrophobic and aromatic stacking interactions between F19 residues play an essential role in the formation of beta-barrels and bilayer beta-sheets. The importance of F19 and the steric effect on the structures of Abeta(16-22) octamers are further examined by REMD simulation of F19W mutant. This REMD run shows that substitution of F19 by W with a more bulky aromatic side chain significantly reduces the beta-sheet content and in turn enhances the population of disordered aggregates, indicating that the steric effect significantly affect the self-assembly of low molecular weight Abeta(16-22) oligomers. PMID- 23926959 TI - Patient satisfaction with anaesthesia - Part 2: construction and quality assessment of questionnaires. AB - The construction of a new, valid and reliable questionnaire to measure patient satisfaction is a complex and time-consuming task. It must follow a rigorous, step-by-step approach, and should as a minimum include elements of content validity, criterion validity, construct validity and reliability. The objective of this review is to present a protocol for the construction of a psychometric questionnaire, supplemented by practical aspects for researchers and clinicians. PMID- 23926960 TI - Long-term visual outcomes in patients with orbitotemporal neurofibromatosis. AB - BACKGROUND: The study aimed to review the presentation and long-term visual outcomes of patients with orbitotemporal neurofibromatosis. DESIGN: Retrospective case series. PARTICIPANTS: Patients with orbitotemporal neurofibromatosis presenting from 1981 to 2009. METHODS: Demographic data, examination findings, causes of vision impairment and interventions performed were recorded for each patient from presentation through subsequent follow-up encounters. Visual impairment was defined as an ipsilateral Snellen acuity of <6/12. MAIN OUTCOME MEASURES: The proportion of patients with visual impairment or enucleation, the rate of new vision loss during follow up; and causes for vision loss or enucleation. RESULTS: Thirty-seven patients (17 female) were included. Median presenting age was 15 years (range 2-45) with an average follow up of 7.4 years (range 0.5-20.3). Visual impairment occurred in 54% of patients at presentation. Causes were amblyopia (13 of 37), optic atrophy (4 of 37), previous enucleation/evisceration (2 of 37), and optic nerve glioma (1 of 37). At presentation, 76% of patients had ptosis, and 51% had strabismus. Thirty-one patients had surgery, with an average of two procedures per patient. At final follow up, 62% had visual impairment. The rate of visual decline was 2% per patient-years. Causes of visual decline were two patients with optic nerve atrophy, one with exposure keratitis and one whose cause was unknown. Five blind patients had enucleation. CONCLUSIONS: The first series of orbitotemporal neurofibromatosis to focus on visual outcomes was presented. Vision loss is common, with a high prevalence of amblyopia. Close monitoring from an early age is needed to prevent visual impairment. PMID- 23926961 TI - Rapid shoot-to-root signalling regulates root hydraulic conductance via aquaporins. AB - We investigated how root hydraulic conductance (normalized to root dry weight, Lo ) is regulated by the shoot. Shoot topping (about 30% reduction in leaf area) reduced Lo of grapevine (Vitis vinifera L.), soybean (Glycine max L.) and maize (Zea mays L.) by 50 to 60%. More detailed investigations with soybean and grapevine showed that the reduction in Lo was not correlated with the reduction in leaf area, and shading or cutting single leaves had a similar effect. Percentage reduction in Lo was largest when initial Lo was high in soybean. Inhibition of Lo by weak acid (low pH) was smaller after shoot damage or leaf shading. The half time of reduction in Lo was approximately 5 min after total shoot decapitation. These characteristics indicate involvement of aquaporins. We excluded phloem-borne signals and auxin-mediated signals. Xylem-mediated hydraulic signals are possible since turgor rapidly decreased within root cortex cells after shoot topping. There was a significant reduction in the expression of several aquaporins in the plasma membrane intrinsic protein (PIP) family of both grapevine and soybean. In soybean, there was a five- to 10-fold reduction in GmPIP1;6 expression over 0.5-1 h which was sustained over the period of reduced Lo . PMID- 23926958 TI - The Sex Chromosome Trisomy mouse model of XXY and XYY: metabolism and motor performance. AB - BACKGROUND: Klinefelter syndrome (KS), caused by XXY karyotype, is characterized by low testosterone, infertility, cognitive deficits, and increased prevalence of health problems including obesity and diabetes. It has been difficult to separate direct genetic effects from hormonal effects in human studies or in mouse models of KS because low testosterone levels are confounded with sex chromosome complement. METHODS: In this study, we present the Sex Chromosome Trisomy (SCT) mouse model that produces XXY, XYY, XY, and XX mice in the same litters, each genotype with either testes or ovaries. The independence of sex chromosome complement and gonadal type allows for improved recognition of sex chromosome effects that are not dependent on levels of gonadal hormones. All mice were gonadectomized and treated with testosterone for 3 weeks. Body weight, body composition, and motor function were measured. RESULTS: Before hormonal manipulation, XXY mice of both sexes had significantly greater body weight and relative fat mass compared to XY mice. After gonadectomy and testosterone replacement, XXY mice (both sexes) still had significantly greater body weight and relative fat mass, but less relative lean mass compared to XY mice. Liver, gonadal fat pad, and inguinal fat pad weights were also higher in XXY mice, independent of gonadal sex. In several of these measures, XX mice also differed from XY mice, and gonadal males and females differed significantly on almost every metabolic measure. The sex chromosome effects (except for testis size) were also seen in gonadally female mice before and after ovariectomy and testosterone treatment, indicating that they do not reflect group differences in levels of testicular secretions. XYY mice were similar to XY mice on body weight and metabolic variables but performed worse on motor tasks compared to other groups. CONCLUSIONS: We find that the new SCT mouse model for XXY and XYY recapitulates features found in humans with these aneuploidies. We illustrate that this model has significant promise for unveiling the role of genetic effects compared to hormonal effects in these syndromes, because many phenotypes are different in XXY vs. XY gonadal female mice which have never been exposed to testicular secretions. PMID- 23926963 TI - Polymeric premicelles as efficient lipophilic nanocarriers: extending drug uptake to the submicellar regime. AB - A multitechnique investigation on the self-assembly behavior of a biocompatible polymer in the high dilution regime is reported herein. The obtained results unambiguously reveal the existence of premicellar structures that may further extend the efficiency of traditional polymeric micelles as drug-delivery vehicles. Such an expansion in the excipient capacity arises from (i) the increased drug retention of submicellar assemblies due to their higher resistance to dilution and therefore to their improved circulation time and (ii) the superior carrier permeability of these premicellar aggregates as a result of their smaller size, which makes these drug vehicles more effectively targeted to the tumors through the so-called enhanced permeability and retention effect. The uptake ability of the polymeric premicelles described in this work has been tested through the use of Nile Red as drug model given its intermediate lipophilicity (log P ~ 3-5) similar to that of potent chemotherapy agents and its microenvironment-sensitive fluorescence properties relevant for localization purposes. Thus, it has been found that an efficient drug encapsulation can be achieved under conditions well below the normally required critical micelle concentration. These results may constitute a promising strategy in order to develop new and more efficient polymeric formulations in drug delivery technology. PMID- 23926962 TI - Assessment of the feasibility and coverage of a modified universal hearing screening protocol for use with newborn babies of migrant workers in Beijing. AB - BACKGROUND: Although migrant workers account for the majority of newborns in Beijing, their children are less likely to undergo appropriate universal newborn hearing screening/rescreening (UNHS) than newborns of local non-migrant residents. We hypothesised that this was at least in part due to the inadequacy of the UNHS protocol currently employed for newborn babies, and therefore aimed to modify the protocol to specifically reflect the needs of the migrant population. METHODS: A total of 10,983 healthy babies born to migrant mothers between January 2007 and December 2009 at a Beijing public hospital were investigated for hearing abnormalities according to a modified UNHS protocol. This incorporated two additional/optional otoacoustic emissions (OAE) tests at 24 48 hours and 2 months after birth. Infants not passing a screening test were referred to the next test, until any hearing loss was confirmed by the auditory brainstem response (ABR) test. RESULTS: A total of 98.91% (10983/11104) of all newborn children underwent the initial OAE test, of which 27.22% (2990/10983) failed the test. 1712 of the failed babies underwent the second inpatient OAE test, with739 failing again; thus significantly decreasing the overall positive rate for abnormal hearing from 27.22% to 18.36% ([2990-973 /10983)]; p = 0). Overall, 1147(56.87%) babies underwent the outpatient OAE test again after1 month, of whom 228 failed and were referred for the second outpatient OAE test (i.e. 2.08% (228/10983) referral rate at 1month of age). 141 of these infants underwent the referral test, of whom 103 (73.05%) tested positive again and were referred for a final ABR test for hearing loss (i.e. final referral rate of 1.73% ([228-38/10983] at 2 months of age). Only 54 infants attended the ABR test and 35 (0.32% of the original cohort tested) were diagnosed with abnormal hearing. CONCLUSIONS: Our study shows that it is feasible and practical to achieve high coverage rates for screening hearing loss and decrease the referral rates in newborn babies of migrant workers, using a modification of the currently employed UNHS protocol. PMID- 23926965 TI - Introduction. PMID- 23926964 TI - Upregulation of iron regulatory hormone hepcidin by interferon alpha. AB - BACKGROUND AND AIM: Interferon (IFN) activates various immune systems in vivo and is administered to patients with diseases such as viral hepatitis B, C, and malignant tumors. Iron dysregulation has been reported during treatment with IFN; however, it remains unclear whether IFN itself affects iron metabolism. We therefore determined the effect of IFN on iron metabolism. METHODS: Mouse IFNalpha was administered to mice, and serum, spleen, bone marrow, liver, and duodenum tissue samples were subsequently collected. The messenger RNA (mRNA) and protein expression of genes involved in iron metabolism were then analyzed by real-time reverse transcription-polymerase chain reaction, Western blotting, and liquid chromatography-tandem mass spectrometry. Immunofluorescence for ferroportin was also performed. RESULTS: Among the gene expressions analyzed, we found that the expression of hepcidin, an iron regulatory hormone produced in the liver, was highly upregulated after IFNalpha treatment. Serum hepcidin levels and hepcidin mRNA expression in the liver were both found to be increased in the IFNalpha-treated mice. The expression of ferroportin (the target molecule of hepcidin) in the duodenum of the IFNalpha-treated mice was observed to be decreased, indicating that hepcidin upregulation could be physiologically functional. In vitro analysis of primary hepatocytes treated with IFNalpha and human hepatoma-derived cells showed an upregulation of hepcidin mRNA, including an activation of signal transducer and activator of transcription3, which was shown to be involved in the hepcidin upregulation. CONCLUSIONS: Results indicate that iron absorption is decreased during IFN treatment; this favorable effect could inhibit iron overload during IFN treatment and may enhance the action of IFN. PMID- 23926966 TI - Reciprocal service-learning: Texas border head start and master of occupational therapy students. AB - This paper describes a reciprocal service-learning project between Master of Occupational Therapy (MOT) students and a Head Start program on the Texas-Mexico border. Education of occupational therapy students at the University of Texas Health Science Center at San Antonio includes local community learning experiences. However, this project challenged the students and faculty to step outside of and beyond their boundaries to address the unique needs of children in Del Rio, Texas. In a reciprocal service-learning situation, students provided developmental screenings, presentations, and classroom suggestions to the Head Start staff. In turn, the Head Start staff reciprocated by providing presentations and classroom cultural inclusion experiences to the students. The project outcomes suggest that collaborative participation can give students and their community partners broader frameworks from which to view enablement and a sense of mutual responsibility. From this starting point students can be encouraged to explore issues of social inclusion and occupational justice. PMID- 23926967 TI - Service learning: meaningful, community-centered professional skill development for occupational therapy students. AB - The profession of Occupational Therapy advocates for new and emerging areas of practice that more fully embrace our moral responsibility to address significant social injustices that exist in our communities (Kronenberg, Algado, & Pollard, 2005). The service-learning pedagogy is impacted by the philosophical and theoretical influences of John Dewey, the mission and purpose of American higher education including Boyer's (1994) call for an engaged citizenry, and the social vision of occupational therapy. The pedagogy of service learning provides a natural context for students to experience community practice while contributing to reducing existing social injustices. This paper provides an overview of service learning (SL) as a philosophical and pedagogical approach in occupational therapy education, key processes in developing successful service learning experiences and community partnerships to support service learning. Characteristics of effective service learning, assessment of community and institutional outcomes of service learning and the scholarship of service learning are also discussed. Most importantly, strategies for developing service learning scholarship, an important but frequently neglected requisite to validate any educational practice, are delineated. The authors conclude that service learning provides educators with an opportunity to provide students with experiences in natural, community contexts while developing life-long commitment to civic engagement and social responsibility. PMID- 23926968 TI - Exploring ordinary childhood occupations through community partnerships. AB - The purpose of this paper is to discuss an innovative assignment, The Occupational Outline and Disability Status Report, and to describe how a community-academic partnership was formed. Community-academic collaborations provide students with the opportunity to observe children in natural environments. This partnership facilitates the development of clinical reasoning skills necessary for pediatric practice in community settings. Through observation of ordinary childhood occupations at a children's museum and a written assignment, students identify the significance of play and social participation while hypothesizing about the influence of impairments on performance. PMID- 23926969 TI - Service learning in an occupation-based curriculum: student commentary. AB - Recent trends toward occupation-based practice and the move toward masters-level occupational therapy (OT) education has forced OT educators to reevaluate their programs to meet the needs of the contemporary health care environment. Service learning is one way to bridge the gap between theory and practice. The Master of Occupational Therapy (MOT) Program at Cleveland State University (CSU), in keeping with its focus on occupation, incorporates three service-learning components into its curriculum. This paper, written by a second-year MOT student at CSU, discusses two of these experiences in depth. The first, which took place at a homeless shelter, included both a didactic and "clinical" component, with an emphasis on community-based mental health OT services. The second, which included a training component and a structured program, involved co-leading after-school social-emotional learning groups for low-income urban youth. Both experiences served to expand the clinical skills and reasoning of the MOT students while introducing both the students and agencies to the role of OT in non-traditional community settings. Based on these experiences, the author highly recommends that all masters-level OT programs should, if they have not done so already, institute service learning as a core component of their curricula, in order to prepare their students for contemporary OT practice. PMID- 23926970 TI - Entry-Level OTR and COTA Intervention Utilization Derived from NBCOT Practice Analysis: Implications for Fieldwork Experiences. AB - Effective fieldwork provides students with learning experiences in preparation for entry-level practice as occupational therapists (OT) or occupational therapy assistants (OTA). In 2003, the National Board for Certification in Occupational Therapy, Inc.(r) (NBCOT) conducted a practice analysis of entry-level certified occupational therapy practitioners (OTR & COTA) to validate a test blueprint for the national certification examinations. This study reports a novel, elective survey reflecting the total percentage of entry-level practitioners, who reported use of 88 different interventions. The purpose of this paper is to translate the practice analysis intervention data gathered in the optional survey to plan and implement effective fieldwork that prepares fieldwork students for entry-level practice. The results of this study will provide understanding of intervention use among entry-level practitioners (OTR = 479; COTA = 168) as a function of practice context. An initial correlation of a random sample of 100 OTRs and COTAs found group equivalency, meaning that the OTR information could be used for the major analyses and generalized to include COTA. Fourteen interventions were found commonly across all practice settings for OTR. These fourteen were factored into three areas or themes (preparatory and activities of daily living; motor skills, posture and coordination; and mental functions) with significant frequency of intervention utilization. Further analysis indicated a high variability of the top thirty interventions for each setting with regard to utilization of interventions above and below the 50 percentile. This snapshot of practice regarding entry-level intervention utilization in occupational therapy across seven major practice settings is described and application to fieldwork processes elaborated. The information provides a description of practice in each setting that can be used by academic fieldwork coordinators for student placement decisions. Fieldwork educators can use this information as a guide for planning comprehensive fieldwork-learning activities, as well as supervising students. Fieldwork students can use this intervention utilization information to assess their readiness for entry-level practice in each setting. PMID- 23926971 TI - Interfacing with Community Mental Health Services: Opportunities for Occupational Therapy and Level II Fieldwork Education. AB - A three-year $54,000 grant has provided an opportunity for students in the Master of Occupational Therapy Programs at The University of Findlay to complete Level II fieldwork experiences in a community mental health setting. Occupational Therapy Program faculty and Level II fieldwork students were involved in the evaluation and intervention process for individuals who have severe mental illness and were participating in a supported employment program. After the first year of completion with the addition of these occupational therapy services, results indicate a 69% increase in secured competitive employment for individuals who have participated in this grant project. PMID- 23926972 TI - When fieldwork takes a detour. AB - This study explored the experience of occupational therapists who encountered counterproductive events during their fieldwork training. Interviews were conducted to gather information regarding the participant's perception of factors that contributed to a negative fieldwork experience. The results were divided into major categories: (1) the role of the supervisor, (2) poor supervisory characteristics, (3) the fieldwork infrastructure, (4) misconceptions in the fieldwork experience, (5) student coping strategies, (6) student responses, (7) positive outcomes, (8) negative consequential outcomes, and (9) cycle of the ineffective fieldwork experience. The results showed challenging supervisory events were the major factor in contributing to a negative fieldwork experience; however, the situation was magnified by other factors such as lack of academic program support. To help prevent this phenomenon from occurring or to minimize negative outcomes, positive resolutions such as solutions to dilemmas presented by the current health care system may minimize the difficulties impinging on fieldwork in occupational therapy. PMID- 23926973 TI - An aggregate fieldwork model: interdisciplinary training/intervention component. AB - An aggregate fieldwork model, a level two fieldwork model that combines cooperative learning, interdisciplinary training and intervention, and research or clinical project publication, was implemented over a two-and-a-half year period on an acute inpatient psychiatric setting with a multidisciplinary staff and interns at a metropolitan hospital. This study describes the interdisciplinary training/intervention component of the aggregate fieldwork model. Efficacy outcomes based on 50 occupational therapy interns' (OTIs') logs and verbal reports in supervision and staff surveys are reported. The purpose of this paper is to educate OTI supervisors about interdisciplinary training/intervention through a description of a successful program in hope that they will be stimulated to incorporate this component into their fieldwork training. PMID- 23926974 TI - A course in autoethnography: fostering reflective practitioners in occupational therapy. AB - This paper describes an academic course designed to lay the foundation for reflective practice in occupational therapy. In this course, students conduct highly personalized research based on experiences in Level II fieldwork that leads to writing an autoethnography. The paper describes autoethnography, details its use in occupational therapy literature, and discusses the design and outcomes of the course. Students' experiences with this autobiographical genre of qualitative research are illustrated. In the writing process, students find clinical stories that must be told and learn to "move around" in their stories. The outcomes of the course include integration of personal and professional experiences, closure to academic preparation, and deep reflection about what it means to be an occupational therapist. PMID- 23926975 TI - Low Vision Rehabilitation Curriculum: A Design Using the AOTA Standards for Continuing Competence. AB - This paper describes development of a comprehensive Web-based distance education occupational therapy (OT) curriculum leading to a graduate certificate in low vision rehabilitation. The program was designed as post-professional education to develop continuing professional competence in OT practitioners in this specialty area of practice. The AOTA Standards of Continuing Competence were used as part of the framework for curriculum development. The rationale for using the standards as a curriculum framework is discussed with examples of the way in which it was used to guide development of course content and instructional materials. Outcome evaluation results indicate that the curriculum adds positive value to the practice of occupational therapists completing the program. PMID- 23926976 TI - Distance education pedagogy and instructional design and development for occupational therapy educational programs. AB - Distance education in occupational therapy programs is increasingly becoming an instructional norm. Technological advances and the common expected use of the Internet and its multiple options to communicate and share information have made its use also commonplace for occupational therapy educators. As with any instructional modality, Web-based instruction can offer a vibrant learning environment created through different teaching strategies, activities, and technologies. This article briefly outlines educational models and instructional designs that can be part of every occupational therapy program as they incorporate distance education and Web-based learning into their programs. The primary focus is on the incorporation of the constructivist approach. PMID- 23926977 TI - Student experiences of learning portfolios in occupational therapy education. AB - Learning portfolios are used extensively in general education; however, limited information is available regarding its usage and value in occupational therapy education. This article discusses the experiences of 30 senior-level occupational therapy students who used student-learning portfolios as a method of comprehensive learning within an upper extremity orthotics and prosthetics course. Results indicated that portfolios assisted students in structuring their learning environment, documented their learning journey, highlighted their achievements, and developed professional skills of organization, motivation, and higher-ordered thinking. Implications of this study lend support towards using student-learning portfolios as a teaching tool to facilitate more holistic and effective student-centered learning environments. PMID- 23926978 TI - Achieving curricular themes through learner-centered teaching. AB - This paper focuses on the use of the four specific learner-centered teaching approaches: service-learning, learning through discussion, team-based learning, and a structured research course sequence in an occupational therapy curriculum. These methods are used to develop the four curriculum themes of engagement, critical thinking, innovations in practice, and clinical reasoning. The outcome of these approaches has been that students have taken more responsibility for their learning and shown increased maturity while promoting faculty creativity. Additionally, students have developed skills and interests in social and community engagement, and have sought jobs in community-based practice areas. PMID- 23926979 TI - Shortening the distance between the "i" and the "it": a transformative approach to improving teaching. AB - "It" science focuses on the external and technical dimensions of action. "I" science focuses on the internal experiences and meaning particular actions hold for people. Elevating "It" science over "I" science can deform occupational therapy's body of knowledge and, consequently, stunt its practices. Similarly, elevating the technical or instrumental dimension of teaching over the internal experiences of educators can deform education and even do harm to students. A transformative learning approach to improving teaching foregrounds the inner lives of educators, thus balancing the instrumental with the deeply personal aspects of teaching. Such a balance is vital given the hopes that ride on occupational therapy education. PMID- 23926980 TI - Education and practice: connecting with research. AB - This paper discusses a faculty project that explored community research needs to guide and shape the research curriculum and class assignments for a master of occupational therapy education program. Thirteen community partners were identified and interviewed. Eleven of 13 valued or greatly valued research. Those same 11 expressed an interest in collaborating with the Department of Occupational Therapy. The community partners identified 86 potential future topics for research covering many areas of practice; the majority of them focused on pediatrics. The community partners also identified several research supports already in place such as team work, administrative support, and access to clients. They identified barriers to implementing research including lack of time and assistance for the research process. This information will be incorporated in student research projects, course assignments, and faculty research agendas to provide students with an authentic learning experience while meeting community partners' needs. PMID- 23926981 TI - Responsible decision-making through measured criteria for faculty time use. AB - The demands upon faculty's time use within the three missions of universities have always created shared tensions in many academic settings. However, the move to post-baccalaureate entry in occupational therapy education has added complexity to this mix, with increasing expectations of graduate education and scholarship both for faculty and students. This article will present the development of the EKU-OT Faculty Work Profile, a model for categorizing faculty's time use during an academic year. The model provides a mechanism for faculty exploration of occupational patterns in an academic setting. The need for increased scholarship in occupational therapy education is addressed as an outcome measure for strategic planning. Potential use and implications will be presented as they relate to the complexities of faculty work inherent in higher education settings. PMID- 23926983 TI - Introduction to special forum on educational leadership. PMID- 23926982 TI - Future of mental health occupational therapy: student perspective and concerns. AB - Occupational therapy has been gradually slipping away from its foundation in mental health practice. In order to provide the best services to individuals with mental health disorders, the occupational therapy profession must maintain and expand its involvement in this area of practice. The purpose of this paper is to explore the threats and opportunities to promote education and practice in mental health from a student perspective. The authors reviewed the literature, distributed questionnaires, and conducted focus groups with occupational therapy students at a southeastern university. Based on findings in the literature and of the focus groups with students, the authors have drawn a list of suggestions to improve the visibility of occupational therapy in mental health care. These suggestions are for occupational therapy educational programs, mental health practitioners, AOTA, and state associations. PMID- 23926984 TI - For everything there is a season. AB - Describes the "seasons" of professional life and conscious decision-making regarding role changes. PMID- 23926985 TI - From program director to senior faculty: a new direction? AB - Describes the transition from program director to senior scholar in the life of an occupational therapy academic. PMID- 23926986 TI - Stepping Down-or Is It Up ... or Over? AB - Describes a personal journey of professional development and the difficulties of relinquishing control. PMID- 23926988 TI - Introduction. PMID- 23926987 TI - Reflections on a transitional transformation. AB - Describes personal reflections on changing professional paths in academe and the losses and gains in the transition. PMID- 23926989 TI - Commentary. AB - Leadership in education is needed to ensure that the American Occupational Therapy Association's 2017 vision is achieved. Education prepares tomorrow's leaders. Ultimately, the profession needs to commit to developing leaders in practice, research and education to move our profession forward. PMID- 23926990 TI - Future considerations in occupational therapy education. AB - In order to ensure the profession's success in the future, access to education, implementing uniform entry-level educational competencies for the profesional and technical levels of education and the globalization of educational programs and accreditation need to be addressed. PMID- 23926991 TI - Achieving AOTA's Centennial Vision: The Role of the Educators-Viewpoint. AB - Utilizing the latest technology, improving our communication skills, celebrating diversity wherever we encounter it, and increasing our political activism are the keys to success for OT's next 100 years. PMID- 23926992 TI - The innovation imperative. AB - An improved healthcare system will require significant departures from current practices. Leadership capacity will provide the abilities to innovate and creative thinking needed to be effective in championing the value of occupational therapy in the future. PMID- 23926993 TI - Achieving AOTA's Centennial Vision: The Role of Educators. AB - The Centennial Vision requires us to finally, and definitively, address specific concerns with regard to our educational processes and their outcomes. They include: the quality of fieldwork placements, the collaboration between education and practice, and utilization of scientific evidence to support practice efficacy and our participation in the academy, and, finally, the education of practitioners who capably and willingly fulfill a range of roles. PMID- 23926994 TI - How Does ACOTE Help Educators Support the AOTA Vision. AB - Educators must use many resources as they choose how to transmit an ever-changing body of knowledge and skills for practice. As educators use ACOTE Standards, they can be assured that their educational program is strong and that their graduates will lead the profession towards fulfillment of the AOTA centennial vision. PMID- 23926995 TI - Educating Leaders for the AOTA Centennial Vision. AB - In order to make the Centennial Vision a reality the education of occupational therapists and occupational therapy assistants should be based on constructivism because this pedagogy emphasizes renewal, interdisciplinary collaboration, drawing strength from diversity, and a focus on transformation of practice. PMID- 23926996 TI - Refocusing our education efforts for the 2017 centennial vision. AB - The role of Occupational Therapy educators and students in working toward the AOTA 2017 Centennial Vision will mirror the efforts of our founders in establishing our profession. PMID- 23926997 TI - Commentary: realizing the vision through fieldwork education. AB - A systematic process for students to actively direct their own professional competence is needed with careful realignment of fieldwork placements to ensure acquisition of future professional competencies. This transformative habit should begin in the academic portion of their learning and further developed during field-work. PMID- 23926998 TI - Autologous skin substitute for hard-to-heal ulcers: retrospective analysis on safety, applicability, and efficacy in an outpatient and hospitalized setting. AB - Chronic ulcers ((arterio)venous, decubitus, or postoperative) have no tendency to heal within a period of at least 3 months despite optimal therapy according to internationally accepted guidelines. This retrospective study evaluates the safety and efficacy of an autologous, dermal-epidermal skin substitute (SS) for treating ulcers of various origins. Ulcers were treated within 7 Dutch centers over 5 years. Sixty-six ulcers (size: 0.75-150 cm2; duration: 0.25-32 years) with a follow-up time of 24 weeks after a single-skin substitute application were assessed. Wound-bed preparation consisted of vacuum-assisted-closure-therapy (5 days, hospitalized) or application of acellular dermis (5-7 days, outpatient). Time to heal, adverse events, and recurrence 1 year after complete healing were recorded. Complete ulcer healing occurred in 36 of 66 ulcers (55%) at 24 weeks. At that time point, a further 29% of ulcers showed decrease in ulcer size between 50 and 99%. No difference was observed between the hospitalized vs. outpatient treatment with complete healing. There were 32 of 36 healed ulcers that were available for follow-up 1 year after complete closure, of which 27 (84%) were still closed. Only two minor/moderate possibly related adverse events were recorded. This retrospective analysis shows that SS provides a safe and successful treatment for particularly chronic ulcers of various origins. PMID- 23927000 TI - One-pot synthesis of optically enriched 2-piperidinones from aliphatic aldehydes and cyanoacrylamides. AB - A highly stereoselective one-pot reaction of aliphatic aldehydes and cyanoacrylamides has been developed. The one-pot reaction includes an organocatalytic Michael addition followed by an intramolecular hemiaminalization. After reduction, optically enriched 2-piperidinones with three contiguous chiral centers were obtained in up to 95% yield and 9:1 dr with 99% ee. PMID- 23926999 TI - Evaluating pH-induced gastrointestinal aggregation of Arachis hypogaea 1 fragments as potential components of peanut allergy. AB - The seed storage glycoprotein Arachis hypogaea (Ara h) 1 is a major allergen found in peanuts. The biochemical resistance of food proteins to protease digestion contributes to their allergenicity. The rapid proteolysis of Ara h 1 under gastric conditions challenges this model. Biophysical and in vitro digestion experiments were carried out to identify how Ara h 1 epitopes might survive digestion, despite their facile degradation. The bicupin core of Ara h 1 can be unfolded at low pH and reversibly folded at higher pH. Additionally, peptide fragments from simulated gastric digestion predominantly form noncovalent aggregates when transferred to base. Disulfide cross-links within these aggregates occur as intermediates in relatively low amounts only at early times and play no role in shielding peptides from degradation. It is proposed that peptide fragments which survive gastric conditions form large aggregates in basic environments such as the small intestine, making epitopes available for triggering an allergic response. PMID- 23927001 TI - Genome-wide single nucleotide polymorphism-based assay for high-resolution epidemiological analysis of the methicillin-resistant Staphylococcus aureus hospital clone EMRSA-15. AB - The EMRSA-15 clone is a major cause of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK and elsewhere but existing typing methodologies have limited capacity to discriminate closely related strains, and are often poorly reproducible between laboratories. Here, we report the design, development and validation of a genome-wide single nucleotide polymorphism (SNP) typing method and compare it to established methods for typing of EMRSA-15. In order to identify discriminatory SNPs, the genomes of 17 EMRSA-15 strains, selected to represent the breadth of genotypic and phenotypic diversity of EMRSA-15 isolates in Scotland, were determined and phylogenetic reconstruction was carried out. In addition to 17 phylogenetically informative SNPs, five binary markers were included to form the basis of an EMRSA-15 genotyping assay. The SNP based typing assay was as discriminatory as pulsed-field gel electrophoresis, and significantly more discriminatory than staphylococcal protein A (spa) typing for typing of a representative panel of diverse EMRSA-15 strains, isolates from two EMRSA-15 hospital outbreak investigations, and a panel of bacteraemia isolates obtained in healthcare facilities in the east of Scotland during a 12-month period. The assay is a rapid, and reproducible approach for epidemiological analysis of EMRSA-15 clinical isolates in Scotland. Unlike established methods the DNA sequence-based method is ideally suited for inter-laboratory comparison of identified genotypes, and its flexibility lends itself to supplementation with additional SNPs or markers for the identification of novel S. aureus strains in other regions of the world. PMID- 23927002 TI - Offending behaviours of child and adolescent firesetters over a 10-year follow up. AB - BACKGROUND: To assess the postintervention arson recidivism and other offending rates of a group of 182 firesetting children and adolescents referred to the New Zealand Fire Awareness and Intervention Program (FAIP) over a follow-up period of 10 years. To investigate predictors of offending behaviour as well as variables associated with previous involvement in firesetting behaviour and offending severity. METHOD: Data collected at the time of the FAIP intervention was provided by the New Zealand Fire Service and the offence histories of the sample were accessed from the New Zealand Police database (NIA). Data were analyzed using both descriptive and inferential statistics. RESULTS: Although the arson recidivism rate was low (2%), rates of general offending were high, with 59% of the sample having committed an offence during the follow-up period. Fifteen percent of the sample was classified as severe offenders, 40% as moderate and 4% as minor. Of offenders, 12.6% had been imprisoned during the follow-up period. Offending was predicted by experience of abuse and a previous firesetting behaviour at the time of the FAIP intervention. Living with both parents at the time of intervention decreased the probability of an individual engaging in future offending behaviour. The presence of family stress and a diagnosis of Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder (ADD/ADHD) were associated with previous firesetting behaviour. In addition, involvement with family violence (as a perpetrator, complainant or victim) was associated with more severe offending behaviour. CONCLUSIONS: In light of existing research, the findings of this study indicate that many firesetters are at risk for future offending and that identification of high-risk individuals is therefore an important consideration for any organization involved with firesetters. To minimize this risk, there is a need for a collaborative, multiagency approach to firesetting behaviour involving comprehensive risk assessment and appropriate referral for at-risk individuals. PMID- 23927003 TI - Total synthesis of nhatrangin A. AB - A concise and stereoselective approach for the synthesis of key intermediates for aplysiatoxins, oscillatoxins, and nhatrangins and their utility for the total synthesis of nhatrangin A has been demonstrated. The advanced intermediates aromatic aldehyde 11 and dihydroxy acid 12 were synthesized in eight steps (44% overall yield) and three steps (55% overall yield), respectively. An asymmetric Michael addition, CBS reduction, and proline-catalyzed crossed-aldol reactions were utilized as key steps for the generation of all the chirality of main chain hydroxyaldehyde, while the appended side-chain-protected 3,4-dihydroxypentanoic acid was achieved in a shortest route, using Sharpless dihydroxylation, diol protection, and RuO4-catalyzed aromatic over-oxidation reactions. Synthesis of nhatrangin A was accomplished by coupling of dihydroxy acid 12 with beta hydroxyallyl ester (obtained from 11) under Yamaguchi reaction conditions followed by a one-pot deprotection of all protecting groups. PMID- 23927004 TI - Disubstituted 1-aryl-4-aminopiperidine library synthesis using computational drug design and high-throughput batch and flow technologies. AB - A platform that incorporates computational library design, parallel solution phase synthesis, continuous flow hydrogenation, and automated high throughput purification and reformatting technologies was applied to the production of a 120 member library of 1-aryl-4-aminopiperidine analogues for drug discovery screening. The application described herein demonstrates the advantages of computational library design coupled with a flexible, modular approach to library synthesis. The enabling technologies described can be readily adopted by the traditional medicinal chemist without extensive training and lengthy process development times. PMID- 23927005 TI - The crystal structure of the cell division amidase AmiC reveals the fold of the AMIN domain, a new peptidoglycan binding domain. AB - Binary fission is the ultimate step of the prokaryotic cell cycle. In Gram negative bacteria like Escherichia coli, this step implies the invagination of three biological layers (cytoplasmic membrane, peptidoglycan and outer membrane), biosynthesis of the new poles and eventually, daughter cells separation. The latter requires the coordinated action of the N-acetylmuramyl-L-alanine amidases AmiA/B/C and their LytM activators EnvC and NlpD to cleave the septal peptidoglycan. We present here the 2.5 A crystal structure of AmiC which includes the first report of an AMIN domain structure, a beta-sandwich of two symmetrical four-stranded beta-sheets exposing highly conserved motifs on the two outer faces. We show that this N-terminal domain, involved in the localization of AmiC at the division site, is a new peptidoglycan-binding domain. The C-terminal catalytic domain shows an auto-inhibitory alpha helix obstructing the active site. AmiC lacking this helix exhibits by itself an activity comparable to that of the wild type AmiC activated by NlpD. We also demonstrate the interaction between AmiC and NlpD by microscale thermophoresis and confirm the importance of the active site blocking alpha helix in the regulation of the amidase activity. PMID- 23927006 TI - Risk for congenital malformations in offspring of women who have undergone bariatric surgery. A national cohort. AB - OBJECTIVE: To study the risk for congenital anomalies in the first child of women after bariatric surgery compared with all other women giving birth to their first child and divided by maternal body mass index (BMI) groups. DESIGN: Prospective, population-based register study. SETTING: Sweden. SAMPLE: All firstborn children to women born 1973-83 were studied to determine if they had a congenital anomaly and a mother who had undergone bariatric surgery before pregnancy. METHODS: A total of 270,805 firstborns; of which 341 had mothers who had had bariatric surgery before delivery. We retrieved information on the women's marital or cohabitation status, smoking, BMI, diabetes and hypertension during pregnancy. MAIN OUTCOME MEASURES: Congenital malformations. RESULTS: Of the firstborn children to mothers who had had bariatric surgery before pregnancy, 4.1% (95% confidence interval [95% CI] 2.2-6.0) were malformed compared with 3.4% (95% CI 3.3-3.5) of those whose mothers had not undergone bariatric surgery. The risk for congenital malformation in firstborn children increased with increasing maternal BMI. The adjusted odds ratio (OR) for congenital malformation among children whose mothers' BMI ranged between 25 and 29 kg/m(2) was 1.09 (95% CI 1.03-1.15), whose mothers' BMI ranged between 30 and 34 kg/m(2) was 1.14 (1.05-1.24) and whose mothers' BMI was >=35 kg/m(2) was 1.30 (95% CI 1.16-1.45) compared with those whose mothers had a normal BMI. Bariatric surgery before pregnancy did not have any effect on the odds ratio for having congenital malformation (OR = 1.09, 95% CI 0.63-1.91). CONCLUSIONS: Preconception bariatric surgery does not seem to affect the risk for congenital malformations but a high to very high BMI does appear to increase the risk. PMID- 23927008 TI - Nanoparticle filtration performance of filtering facepiece respirators and canister/cartridge filters. AB - Respiratory protection offered by a particulate respirator is a function of the filter efficiency and face seal leakage. A previous study in our laboratory measured the filter penetration and total inward leakage (TIL) of 20-1000 nm size particles for N95 filtering facepiece respirators (FFRs) using a breathing manikin. The results showed relatively higher filter penetration and TIL value under different leak sizes and flow rates at the most penetrating particle size (MPPS), ~45 nm for electrostatic FFRs,and ~150 nm for the same FFRs after charge removal. This indicates an advantage of mechanical filters over electrostatic filters rated for similar filter efficiencies in providing respiratory protection in nanoparticle workplaces. To better understand the influence of the MPPS, the filtration performance of commonly used one N95 and one N100 FFR models, and four P100 canister/cartridge models were measured with monodisperse NaCl aerosols, and polydisperse NaCl aerosols employed in the National Institute for Occupational Safety and Health (NIOSH) certification test method. As expected, the polydisperse aerosol penetration was below 5% for the N95 FFR, and below 0.03% for the N100 FFR and P100 canister/cartridge filters. Monodisperse aerosol penetration results showed a MPPS of ~40 nm for both the N95 and N100 FFRs. All four P100 canister/cartridge filters had a MPPS of >=150 nm, similar to expectations for mechanical filters. The P100 canister/cartridge filters showed lower penetration values for different size nanoparticles than the N100 FFRs. The results indicate that a mechanical filter would offer a relatively higher filtration performance for nanoparticles than an electrostatic counterpart rated for the same filter efficiency. Overall, the results obtained in the study suggest that MPPS should be considered as a key factor in the development of respirator standards and recommendations for protection against nanoparticles. PMID- 23927009 TI - Effect of fermented moist feed on performance, gut bacteria and gut histo morphology in broilers. AB - 1. Fermented feed has been shown to be beneficial in pig nutrition as a tool to reduce gut microbial disorders. Experiments with fermented feed in poultry are scarce, probably because of the belief that wet feed is less suitable for this species and causes wet litter. 2. A total of 280 one-d-old Ross 308 chickens were used in a completely randomised design with two dietary treatments (7 replicates of 20 birds/treatment); air-dry feed versus the same feed in moist form (water:feed ratio of 1.3:1, on a weight basis), inoculated with Lactobacillus plantarum NCIMB 40087 (9 log10 CFU/kg feed) and batch-fermented for 48 h at 26 degrees C. The birds were given starter (d 0-13), grower (d 4-26) and finisher (d 27-39) diets ad libitum. At the end of the grower and finisher period, two birds per pen were removed to sample intestinal contents for cultivating bacteria and intestinal tissue to determine villus height and crypt depth. 3. Fermented moist feed (FMF) batches showed good characteristics, with a pH between 3.9 and 4.4 and DL-lactic acid between 137 and 286 mmol/l. Daily feed intake and gain were reduced considerably in the FMF group in the starter (-40 and -44%, respectively) and grower (-23 and -16%) period, though in the finisher period these birds performed better, with an improved feed utilisation. Concomitant with the latter, villus height at the mid-jejunum and mid-ileum on d 39 was higher (+22.6% and +16.0%). Significantly more Lactobacilli and less coliforms were found in the foregut and less Streptococci in ileum and caeca of birds given FMF. 4. This trial showed that FMF was detrimental for early bird growth but affected beneficially feed efficiency, the composition of the gut bacteria and villus height in the small intestine in the finisher period in broilers. PMID- 23927007 TI - Exploring the abomasal lymph node transcriptome for genes associated with resistance to the sheep nematode Teladorsagia circumcincta. AB - This study exploited Blackface lambs that varied in their resistance to the abomasal nematode parasite, Teladorsagia circumcincta. Infection of these lambs over 3 months identified susceptible (high adult worm count, high faecal egg count and low IgA antibody) and resistant animals that had excluded all parasites. Previous work had shown that susceptibility and resistance is dependent on the differential immune response to the parasite, which occurs within the abomasal (gastric) lymph node (ALN) that drains the site of infection. The Affymetrix ovine gene array was used to interrogate the transcriptome of the ALN to identify genes and physiological pathways associated with resistance. We used a bovine RT-qPCR array of 84 genes to validate the gene array, and also report digital gene expression analysis on the same tissues, reanalysed using the Oar v3.1 sheep genome assembly. These analyses identified Humoral Immune Response, Protein Synthesis, Inflammatory Response and Hematological System Development and Function as the two top-ranked networks associated with resistance. Central genes within these networks were IL4, IL5, IL13RA2 and in particular IL13, which confirmed that differential activation of Th2 polarized responses is critical to the resistance phenotype. Furthermore, in resistant sheep there was up-regulation of genes linked to control and suppression of inflammation. The identity of differentially-expressed chemokines and receptors in the resistant and susceptible sheep also begins to explain the cellular nature of the host response to infection. This work will greatly help in the identification of candidate genes as potential selectable markers of genetic resistance. PMID- 23927010 TI - The price of access: capitalization of neighborhood contextual factors. AB - BACKGROUND: Studies of neighborhood context on health behavior have not considered that the health benefits of context may be 'capitalized' into, or included in, higher housing values. This study examines the associations of better neighborhood context with neighborhood housing values. METHODS: We use the third wave of Add Health (2000-2001) to estimate the association of neighborhood contextual variables and housing values first across then within income types. This is a census block group-level analysis. RESULTS: We find that neighborhood context, especially access to fruit and vegetable outlets, is capitalized into, or associated with, higher housing values. Fast food and convenience store access are associated with lower housing values. Capitalization differs by income quartile of the neighborhood. Even those in the poorest neighborhoods value access to fresh fruits and vegetables, and those in the wealthier neighborhoods value activity resources. All neighborhood incomes types place negative value on fast food access and convenience store access. CONCLUSIONS: Access to health related contextual attributes is capitalized into higher housing prices. Access to fresh fruits and vegetables is valued in neighborhoods of all income levels. Modeling these associations by neighborhood income levels helps explain the mixed results in the literature on the built environment in terms of linking health outcomes to access. PMID- 23927011 TI - Contemporary chiropractic practice in the UK: a field study of a chiropractor and his patients in a suburban chiropractic clinic. AB - BACKGROUND: Two recent surveys of chiropractors in Great Britain suggest that there are discrepancies between chiropractic practice as defined in regulatory guidelines and day-to-day chiropractic clinical practice and there is in general a paucity of information regarding the characteristics of contemporary chiropractic practice in the United Kingdom. This field study describes the daily practice of a contemporary British UK-trained chiropractor. METHODS: The fieldwork took place during the spring and summer of 2008 when the author spent one day per week observing consultations and interviewing patients in a chiropractic clinic. The chiropractor was subjected to interviews on two occasions. The author also registered as a patient. Field notes were taken by the author, interviews were recorded and the transcripts were corrected and analysed by the author. RESULTS: A total of 25 patients took part in the study. The interaction that took place between patients and staff in reception could be considered as a prelude to consultation facilitating the transformation from individual to patient and back to individual. Coupled with the continuous physical contact between the chiropractor and each patient there was a substantial amount of verbal and non-verbal communication throughout treatment visits. The patients presented with predominantly musculo-skeletal pain and the majority had consulted the chiropractor as a result of recommendations from others in their close social environment. The majority of the interviewed patients had either an inaccurate or at best rudimentary understanding of the mechanisms of chiropractic treatment. A few of the interviewed patients indicated that they had at first experienced concerns about the nature of chiropractic treatment or getting undressed. The author was able to gain some insight into how the chiropractor's experiences, opinions and beliefs had shaped his approach to chiropractic treatment and how this formed the basis of his clinical modus operandi. CONCLUSION: Although no robust conclusions should be drawn from this small scale field study it does show that the clinical chiropractic practice as carried out by this UK trained British chiropractor contains a number of elements described in earlier qualitative studies in the United States, Canada, and Australia. PMID- 23927012 TI - Combination of multistep IMAC enrichment with high-pH reverse phase separation for in-depth phosphoproteomic profiling. AB - Typical mass spectrometric phosphoproteome studies are complicated by the need for large amounts of starting material and extensive sample preparation to ensure sufficient phosphopeptide identifications. In this paper, we present a novel strategy to perform optimized multistep IMAC enrichment from whole cell lysates followed by high-pH reverse phase fractionation (multi-IMAC-HLB; HLB means hydrophilic-lipophilic-balanced reversed-phase cartridge). The peptide-to-IMAC ratio was optimized to maximize IMAC performance, while multistep IMAC enrichment enabled improved phosphopeptide acquisition. The addition of the HLB step further fractionates the IMAC enriched phosphopeptides while desalting the samples, which dramatically reduces the sample manipulation time and sample loss compared to other popular strategies. We compared the phosphopeptide identification results of the multi-IMAC-HLB method with 3 mg of starting material to the well established SCX-IMAC method with 15 mg of starting material. We identified 8969 unique phosphopeptides with the multi-IMAC-HLB method, compared to 5519 unique phosphopeptides identified with the SCX-IMAC method, an increase of 62.5%. The increase in the numbers of identified phosphopeptides is due to the increase in the ratio of identified phosphopeptides out of all detected peptides, 70.5% with multi-IMAC-HLB method compared to 32.3% with the SCX-IMAC method. Multi-IMAC-HLB is a robust and efficient method for in-depth phosphoproteomic research. PMID- 23927013 TI - Multimodal mapping of human skin. AB - BACKGROUND: The combination of coherent anti-Stokes Raman scattering (CARS), second harmonic generation (SHG) and two-photon excited fluorescence (TPEF) imaging--referred to as multimodal imaging--provides complementary contrast based on molecular vibrations, the structure of various tissue components and endogenous fluorophores, respectively. OBJECTIVES: To present a comprehensive overview of the appearance of human skin in multimodal imaging. METHODS: Multimodal imaging of unstained skin cross-sections of 32 individuals was performed using a laser scanning microscope and picosecond laser pulse for excitation. RESULTS: The epidermis, dermis and subcutis are distinguishable in all three applied modalities, but are unveiled best in multimodal images. While the subcutis is dominated by the CARS signal, predominately SHG and the secondary TPEF signal detect the dermis. In contrast, no SHG signal is detected in the epidermis, whereas CARS and TPEF show equal contributions. Additionally, the appearance of the major skin appendages is described, i.e. the hair follicle, sebaceous and sweat glands, and blood vessels belonging to the vascular system. All four investigated functional units show a characteristic morphochemistry in TPEF and CARS, allowing identification of further subunits, e.g. the major components of the hair follicle, while the SHG signal delineates the localization of the functional units. CONCLUSIONS: Multimodal imaging is a powerful tool to investigate human skin by providing high contrast based on the molecular constitution. It is therefore suggested that multimodal imaging has a high potential in application to dermatological research and clinical diagnostics of various skin alterations. PMID- 23927014 TI - Caffeic acid phenethyl ester suppresses oxidative stress in 3T3-L1 adipocytes. AB - The generation of oxidative stress, characterized by enhanced reactive oxygen species (ROS) formation, has been found in obesity. ROS production was increased during the differentiation of 3T3-L1 cells into adipocytes. We previously reported that caffeic acid phenethyl ester (CAPE) suppresses 3T3-L1 differentiation to adipocytes through the inhibition of peroxisome proliferator activated receptor gamma. In this study, the preventive effect of CAPE on oxidative stress in 3T3-L1 cells was observed. The results were as follows: (1) ROS production during 3T3-L1 cell differentiation to adipocytes was significantly (p < 0.05) suppressed by CAPE treatment in a concentration-dependent manner, (2) with CAPE treatment, the extracellular superoxide dismutase mRNA expression level significantly increased, but the NOX4 mRNA expression level did not change, and (3) CAPE treatment significantly increased superoxide dismutase (SOD) activity in 3T3-L1 cells. From these results, we suggest that the increased oxidative stress in 3T3-L1 differentiation to adipocytes is attenuated by CAPE treatment. This attenuation may be partly caused by increased SOD production. PMID- 23927015 TI - Growth rate affects the responses of the green alga Tetraselmis suecica to external perturbations. AB - Acclimation to environmental changes involves a modification of the expressed proteome and metabolome. The reproductive advantage associated with the higher fitness that acclimation provides to the new conditions more than compensates for the costs of acclimation. To exploit such an advantage, however, the duration of the perturbation must be sufficiently long relative to the growth rate. Otherwise, a selective pressure may exist in favour of responses that minimize changes in carbon allocation and resource use and do not require reversal of the acclimation after the perturbation ceases (compositional homeostasis). We hypothesize that the choice between acclimation and homeostasis depends on the duration of the perturbation relative to the length of the cell cycle. To test this hypothesis, we cultured the green alga Tetraselmis suecica at two growth rates and subjected the cultures to three environmental perturbations. Carbon allocation was studied with Fourier transform infrared (FTIR) spectroscopy; elemental stoichiometry was investigated by total reflection X-ray fluorescence (TXRF) spectroscopy. Our data confirmed that growth rate is a crucial factor for C allocation in response to external changes, with a higher degree of compositional homeostasis in cells with lower growth rate. PMID- 23927017 TI - Counterfactuals and causal models: introduction to the special issue. AB - Judea Pearl won the 2010 Rumelhart Prize in computational cognitive science due to his seminal contributions to the development of Bayes nets and causal Bayes nets, frameworks that are central to multiple domains of the computational study of mind. At the heart of the causal Bayes nets formalism is the notion of a counterfactual, a representation of something false or nonexistent. Pearl refers to Bayes nets as oracles for intervention, and interventions can tell us what the effect of action will be or what the effect of counterfactual possibilities would be. Counterfactuals turn out to be necessary to understand thought, perception, and language. This selection of papers tells us why, sometimes in ways that support the Bayes net framework and sometimes in ways that challenge it. PMID- 23927016 TI - Association between chronic obstructive pulmonary disease and gastroesophageal reflux disease: a national cross-sectional cohort study. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is one of the most common causes of chronic cough and a potential risk factor for exacerbation of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the prevalence and risk factors of GERD in patients with COPD and association between GERD and COPD exacerbation. METHODS: Data were collected from the National Health Insurance Database of Korea. The subjects were 40 years old and older, who had COPD as primary or secondary diagnosis codes and utilized health care resource to receive prescriptions of COPD medication at least twice in 2009. Univariate logistic regression was performed to understand the relationship between COPD and GERD, and multiple logistic regression analysis was performed with adjustment for several confounding factors. RESULTS: The prevalence of GERD in COPD patients was 28% (39,987/141,057). Old age, female gender, medical aid insurance type, hospitalization, and emergency room (ER) visit were associated with GERD. Most of COPD medications except inhaled muscarinic antagonists were associated with GERD. The logistic regression analysis showed that the presence of GERD was associated with increased risk of hospitalization (OR 1.54, CI 1.50 to 1.58, p<0.001) and frequent ER visits (OR 1.55, CI 1.48 to 1.62, p<0.001). CONCLUSIONS: The prevalence of GERD in patients with COPD was high. Old age, female gender, medical aid insurance type, and many COPD medications except inhaled muscarinic antagonists were associated with GERD. The presence of GERD was associated with COPD exacerbation. PMID- 23927018 TI - Structural counterfactuals: a brief introduction. AB - Recent advances in causal reasoning have given rise to a computational model that emulates the process by which humans generate, evaluate, and distinguish counterfactual sentences. Contrasted with the "possible worlds" account of counterfactuals, this "structural" model enjoys the advantages of representational economy, algorithmic simplicity, and conceptual clarity. This introduction traces the emergence of the structural model and gives a panoramic view of several applications where counterfactual reasoning has benefited problem areas in the empirical sciences. PMID- 23927019 TI - A ranking-theoretic approach to conditionals. AB - Conditionals somehow express conditional beliefs. However, conditional belief is a bi-propositional attitude that is generally not truth-evaluable, in contrast to unconditional belief. Therefore, this article opts for an expressivistic semantics for conditionals, grounds this semantics in the arguably most adequate account of conditional belief, that is, ranking theory, and dismisses probability theory for that purpose, because probabilities cannot represent belief. Various expressive options are then explained in terms of ranking theory, with the intention to set out a general interpretive scheme that is able to account for the most variegated usage of conditionals. The Ramsey test is only the first option. Relevance is another, familiar, but little understood item, which comes in several versions. This article adds a further family of expressive options, which is able to subsume also counterfactuals and causal conditionals, and indicates at the end how this family allows for partial recovery of truth conditions for conditionals. PMID- 23927020 TI - Causal premise semantics. AB - The rise of causality and the attendant graph-theoretic modeling tools in the study of counterfactual reasoning has had resounding effects in many areas of cognitive science, but it has thus far not permeated the mainstream in linguistic theory to a comparable degree. In this study I show that a version of the predominant framework for the formal semantic analysis of conditionals, Kratzer style premise semantics, allows for a straightforward implementation of the crucial ideas and insights of Pearl-style causal networks. I spell out the details of such an implementation, focusing especially on the notions of intervention on a network and backtracking interpretations of counterfactuals. PMID- 23927021 TI - Limited propagation of lattice distortion in trilayer Langmuir-Blodgett films: correlation with mesoscopic structure. AB - The structure of trilayer Langmuir-Blodgett (LB) films on oxidized silicon wafers has been investigated using grazing incidence X-ray diffraction at various incidence angles and atomic force microscopy (AFM). These films are formed by two behenic acid (BA) layers and a third monolayer of amphiphilic molecules having different architectures. These molecules have the same polar head and differ from each other by the chain, either saturated or unsaturated hydrogenated or semi fluorinated. The structure of the first BA monolayer appears as unchanged in all cases, whereas a condensation of the second BA monolayer is evidenced when the third layer is not formed with the saturated hydrogenated chain. We interpret this condensation as resulting from the mismatch between the lattices of the second BA layer and the external monolayer, possibly associated with the formation of a new monolayer-air interface creating line tension effects. Line tension estimation has also been made from the size of the holes observed in the different LB films. PMID- 23927022 TI - Glutathione S-transferase omega-2 polymorphism Asn142Asp modifies the risk of age related cataract in smokers and subjects exposed to ultraviolet irradiation. AB - BACKGROUND: Glutathione S-transferase omega-1 and 2 have a unique range of enzymatic activities, including the regeneration of ascorbate by their dehydroascorbate reductase activities. Because these enzymes could have a protective role from oxidative damage in the lens, the question of whether the two coding glutathione S-transferase omega polymorphisms confer the risk of age related cataract was addressed. METHODS: rs4925 (Ala140Asp) of glutathione S transferase omega-1 and rs156697 (Asn142Asp) of glutathione S-transferase omega-2 polymorphisms in 100 patients with age-related cataract and 130 controls were assessed. RESULTS: Presence of one mutant GSTO1*Asp or GSTO2*Asp allele did not contribute independently towards the risk of cataract; however, homozygous carriers of GSTO1*Asp/GSTO2*Asp haplotype demonstrated 3.42-fold enhanced risk of cataract development (95% confidence interval = 0.84-13.93; P = 0.086). When GSTO genotype was analysed in association with smoking or professional exposure to ultraviolet irradiation, carriers of at least one mutant GSTO2*Asp allele had increased risk of cataract development in comparison with individuals with wild type GSTO2*Asn/Asn with no history of smoking or ultraviolet exposure (odds ratio = 6.89, 95% confidence interval = 1.81-16.21, P = 0.005; odds ratio = 4.10, 95% confidence interval = 1.23-13.74, P = 0.022, respectively). Regarding the distribution of particular glutathione S-transferase omega genotype and cataract type, the highest frequency of mutant GSTO2*Asp allele was found in patients with nuclear cataract. CONCLUSION: The results indicate that mutant GSTO2*Asp genotype is associated with increased risk of age-related cataract in smokers and ultraviolet-exposed subjects, suggesting a role of inefficient ascorbate regeneration in cataract development. PMID- 23927023 TI - Local blockade of glucocorticoid activation reverses stress- and glucocorticoid induced delays in cutaneous wound healing. AB - Stress slows cutaneous wound healing (WH) in an endogenous glucocorticoid (GC) dependent fashion. We investigated whether stress/GC-induced delays in WH require further intracutaneous activation of endogenous GC; and whether blockade or down regulation of peripheral activation normalizes WH in the face of stress. Delayed WH in our motion-restricted murine model of stress could be attributed to elevated systemic GC, because blockade of GC production (using corticotropin releasing factor inhibitor, antalarmin), or of peripheral binding to the GC receptor [GCr], with an antagonist, Ru-486, normalized WH. We next investigated whether local blockade or down-regulation of the peripheral GC-activating enzyme, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), accelerates cutaneous WH. Topical applications of nonspecific (carbenoxolone) as well as an isoform specific 11beta-HSD1 inhibitor overcame stress and exogenous GC-induced delays in WH. Moreover, two liver X receptor ligands, TO901317 and GW3695, down-regulated expression of 11beta-HSD1, attenuating stress-induced delays in WH. Combined inhibitor and liver X receptor ligand applications accelerated WH in the face of stress/systemic GC. Thus: (1) intracutaneous conversion of inactive-to-active GC accounts for stress (GC)-induced delays in WH; and (2) blockade or down regulation of 11beta-HSD1 and/or GCr normalize cutaneous WH in the face of stress/GC. Local blockade or down-regulation of cutaneous GC activation could help enhance WH in various clinical settings. PMID- 23927024 TI - Epithelial-mesenchymal transition-related protein expression in biliary epithelial cells associated with hepatolithiasis. AB - BACKGROUND AND AIM: Epithelial-mesenchymal transition (EMT) of biliary epithelial cells (BECs) plays major roles in many cholangiopathies. This study evaluated whether EMT of BECs has a role in hepatolithiasis-induced biliary fibrosis and types of BECs that are involved. METHODS: The expression of EMT-related proteins and epidermal growth factor receptor was evaluated by immunohistochemistry of liver tissues from 102 patients with hepatolithiasis, 32 patients with post hepatitis cirrhosis, and 48 normal livers. Antibodies against E-cadherin, beta catenin, and cytokeratin were used to identify epithelial cells and antibodies against vimentin, S100A4, podoplanin, and alpha-smooth muscle actin (alpha-SMA) were used to identify mesenchymal cells. The relationship between clinical and histological parameters and immunohistochemistry findings in BECs, and the surrounding stroma were evaluated. RESULTS: Loss of E-cadherin and acquisition of S100A4 and vimentin were observed in BECs. In all BECs, cytokeratin and beta catenin expression were unchanged, while podoplanin and alpha-SMA were not expressed. Although hepatic fibrosis was more severe in post-hepatitis cirrhosis, EMT of BECs was more widespread in hepatolithiasis. In hepatolithiasis, EMT related proteins were more highly expressed in small bile ducts than in medium or large bile ducts. Their expression was associated with the severity of biliary fibrosis and the expressions of epidermal growth factor receptor. Expression of alpha-SMA in fibroblasts from the portal space was closely linked to pathological changes in small bile ducts and EMT-related protein expressions in BECs. CONCLUSIONS: Proliferating cholangiocytes that form small bile ducts may contribute to cholangiopathies in hepatolithiasis through an EMT-like phenomenon or through interactions with stromal myofibroblasts. PMID- 23927025 TI - Occupational therapy in diabetic care-areas of need perceived by older adults with diabetes. AB - This study explored the perception of older adults with diabetes regarding the areas of service considered helpful to their daily activities and routines. A survey questionnaire was designed and given to 52 community-dwelling older adults with diabetes. Results showed that cholesterol control, managing blood sugar, foot care, fatigue management and pacing, and pain management/reduction were the areas of most concern that deserve services. The findings suggest that, in providing holistic client-centered interventions to individuals with diabetes, occupational therapists need to be able to prioritize clients' concerns and help them incorporate diabetes management into their routines and lifestyle. PMID- 23927026 TI - The nature of emerging practice in occupational therapy: a pilot study. AB - The profession of occupational therapy is responding to changes in the health care system by expanding the contexts and models for service provision, typically referred to as emerging practice. As a pilot study, a survey was completed by 174 occupational therapists to gather information and opinions about emerging practice. Results indicated occupational therapists hold diverse perceptions about emerging practice settings and services as well as the role and significance of emerging practice within the profession. Occupational therapists engaged in emerging practice described numerous rewards and challenges inherent within the process of developing and delivering services. The findings indicate continued professional dialogue and research are needed to support the development and efficacy of occupational therapy services in emerging settings and roles. PMID- 23927027 TI - Team intervention in food selectivity in a medically complex child in rural appalachia. AB - "Food selective" is the term used to describe children who eat an unusually limited variety and/or amount of foods and often have serious medical problems that inhibit the normal development of eating. While many urban areas have programs to address these complex eating problems, families in rural areas must rely on sometimes fragmented local resources. This paper describes how a university-based interdisciplinary team of professionals employ a reasoning process during the assessment and intervention with a child with food selectivity in manner supportive of prevailing Appalachian cultural beliefs and values. Issues of this model for occupational therapy is discussed using occupation-based culturally sensitive reasoning and intervention strategies when responding to illustrate the complex interaction of sensory processing and participation in daily occupations modeled in this case report. PMID- 23927028 TI - A model of mentorship in occupational therapy: the leadership of a. Jean ayres. AB - Over a period of 30 years, Dr. A. Jean Ayres conducted and disseminated research related to the theory and practice of sensory integration. The Center for the Study of Sensory Integrative Dysfunction was established to promote Ayres' research with 66 faculty members recruited by 1982. To describe how Dr. Ayres may have influenced the occupational therapy profession, a survey was conducted to document the scholarly/leadership productivity of Sensory Integration faculty. Of the 66 faculty members, 48 were located and sent survey packets. The return rate was 79% (n = 38). Respondents documented their productivity in eight categories and answered 18 questions about their leadership qualities. Ninety-seven percent of respondents indicated that Ayres had professionally influenced them. Fifty-one percent of respondents had doctorate degrees with 78% reported having academic teaching experience. This group of 38 professionals had produced 438 peer reviewed articles, 707 nonpeer-reviewed publications, and 265 grants. Ayres' legacy is continued with the scholarly work of the Sensory Integration faculty who received professional mentorship. PMID- 23927029 TI - From the internet editor. PMID- 23927030 TI - Oxyarylation and aminoarylation of styrenes using photoredox catalysis. AB - A three-component coupling of styrenes is reported, using photoredox catalysis to achieve simultaneous arylation and C-O or C-N bond formation across the styrene double bond. PMID- 23927031 TI - Yellow fever revaccination guidelines change - a decision too feverish? PMID- 23927033 TI - Enantiomeric recognition of amino acid salts by macrocyclic crown ethers derived from enantiomerically pure 1,8,9,16-tetrahydroxytetraphenylenes. AB - Asymmetric synthesis of (R,R)- and (S,S)-1,8,9,16-tetrahydroxytetraphenylenes was achieved from starting material (2R,3R)-butane-2,3-diol and (2S,3S)-butane-2,3 diol respectively by utilizing a center-to-axis strategy. A series of crown ether compounds 20, 24, and 25 and their corresponding enantiomers derived from chiral tetrahydroxytetraphenylene were synthesized in enantiomerically pure forms. Enantiomeric recognition properties of these hosts toward l- and d-amino acid methyl ester hydrochloride were studied by the UV spectroscopy titration. The tetramer hosts (S,S,S,S,S,S,S,S)-20 and (R,R,R,R,R,R,R,R)-20 exhibited the best enantioselectivities toward L- and D-alanine methyl ester hydrochloride salt with K(L)/K(D) = 4.1 and KD/KL = 3.9, respectively. The new chiral macrocyclic hosts would further enrich the host-guest chemistry. PMID- 23927032 TI - Lactate administration reproduces specific brain and liver exercise-related changes. AB - The effects of exercise are not limited to muscle, and its ability to mitigate some chronic diseases is under study. A more complete understanding of how exercise impacts non-muscle tissues might facilitate design of clinical trials and exercise mimetics. Here, we focused on lactate's ability to mediate changes in liver and brain bioenergetic-associated parameters. In one group of experiments, C57BL/6 mice underwent 7 weeks of treadmill exercise sessions at intensities intended to exceed the lactate threshold. Over time, the mice dramatically increased their lactate threshold. To ensure that plasma lactate accumulated during the final week, the mice were run to exhaustion. In the liver, mRNA levels of gluconeogenesis-promoting genes increased. While peroxisome proliferator-activated receptor-gamma co-activator 1 alpha (PGC-1alpha) expression increased, there was a decrease in PGC-1beta expression, and overall gene expression changes favored respiratory chain down-regulation. In the brain, PGC-1alpha and PGC-1beta were unchanged, but PGC-1-related co-activator expression and mitochondrial DNA copy number increased. Brain tumor necrosis factor alpha expression fell, whereas vascular endothelial growth factor A expression rose. In another group of experiments, exogenously administered lactate was found to reproduce some but not all of these observed liver and brain changes. Our data suggest that lactate, an exercise byproduct, could mediate some of the effects exercise has on the liver and the brain, and that lactate itself can act as a partial exercise mimetic. PMID- 23927034 TI - Tracking of single receptor molecule mobility in neuronal membranes: a quick theoretical and practical guide. AB - Single-molecule detection enables us to visualise the real-time dynamics of individual molecules in live cells. We review the recent advancements in single molecule fluorescence tracking of receptor protein mobility in the neuronal membrane. First, we discuss the practical consideration of single-molecule tracking in neurones, including the choice of cells and possible fluorescent labelling, as well as the appropriate optical set-up and imaging technology. We then describe the analysis of the single-molecule imaging data, including its theoretical and practical aspects of and relevant estimations of the biophysical parameters. Finally, we provide an example of a single-molecule tracking study in neuroendocrinology and highlight the next frontiers of single-molecule detection technologies. PMID- 23927037 TI - GOParGenPy: a high throughput method to generate gene ontology data matrices. AB - BACKGROUND: Gene Ontology (GO) is a popular standard in the annotation of gene products and provides information related to genes across all species. The structure of GO is dynamic and is updated on a daily basis. However, the popular existing methods use outdated versions of GO. Moreover, these tools are slow to process large datasets consisting of more than 20,000 genes. RESULTS: We have developed GOParGenPy, a platform independent software tool to generate the binary data matrix showing the GO class membership, including parental classes, of a set of GO annotated genes. GOParGenPy is at least an order of magnitude faster than popular tools for Gene Ontology analysis and it can handle larger datasets than the existing tools. It can use any available version of the GO structure and allows the user to select the source of GO annotation. GO structure selection is critical for analysis, as we show that GO classes have rapid turnover between different GO structure releases. CONCLUSIONS: GOParGenPy is an easy to use software tool which can generate sparse or full binary matrices from GO annotated gene sets. The obtained binary matrix can then be used with any analysis environment and with any analysis methods. PMID- 23927036 TI - Post-translational modification by cysteine protects Cu/Zn-superoxide dismutase from oxidative damage. AB - Reactive oxygen species (ROS) are cytotoxic. To remove ROS, cells have developed ROS-specific defense mechanisms, including the enzyme Cu/Zn superoxide dismutase (SOD1), which catalyzes the disproportionation of superoxide anions into molecular oxygen and hydrogen peroxide. Although hydrogen peroxide is less reactive than superoxide, it is still capable of oxidizing, unfolding, and inactivating SOD1, at least in vitro. To explore the relevance of post translational modification (PTM) of SOD1, including peroxide-related modifications, SOD1 was purified from postmortem human nervous tissue. As much as half of all purified SOD1 protein contained non-native post-translational modifications (PTMs), the most prevalent modifications being cysteinylation and peroxide-related oxidations. Many PTMs targeted a single reactive SOD1 cysteine, Cys111. An intriguing observation was that unlike native SOD1, cysteinylated SOD1 was not oxidized. To further characterize how cysteinylation may protect SOD1 from oxidation, cysteine-modified SOD1 was prepared in vitro and exposed to peroxide. Cysteinylation conferred nearly complete protection from peroxide induced oxidation of SOD1. Moreover, SOD1 that has been cysteinylated and peroxide oxidized in vitro comprised a set of PTMs that bear a striking resemblance to the myriad of PTMs observed in SOD1 purified from human tissue. PMID- 23927038 TI - Sudden cardiac death and cardioprotection. PMID- 23927039 TI - Age-related dystrophic changes in corneal endothelium from DNA repair-deficient mice. AB - The corneal endothelium (CE) is a single layer of cells lining the posterior face of the cornea providing metabolic functions essential for maintenance of corneal transparency. Adult CE cells lack regenerative potential, and the number of CE cells decreases throughout life. To determine whether endogenous DNA damage contributes to the age-related spontaneous loss of CE, we characterized CE in Ercc1(-/Delta) mice, which have impaired capacity to repair DNA damage and age prematurely. Eyes from 4.5- to 6-month-old Ercc1(-/Delta) mice, age-matched wild type (WT) littermates, and old WT mice (24- to 34-month-old) were compared by spectral domain optical coherence tomography and corneal confocal microscopy. Histopathological changes in CE were further identified in paraffin tissue sections, whole-mount immunostaining, and scanning electron and transmission electron microscopy. The CE of old WT mice displayed polymorphism and polymegathism, polyploidy, decreased cell density, increased cell size, increases in Descemet's thickness, and the presence of posterior projections originating from the CE toward the anterior chamber, similar to changes documented for aging human corneas. Similar changes were observed in young adult Ercc1(-/Delta) mice CE, demonstrating spontaneous premature aging of the CE of these DNA repair deficient mice. CD45(+) immune cells were associated with the posterior surface of CE from Ercc1(-/Delta) mice and the tissue expressed increased IL-1alpha, Cxcl2, and TNFalpha, pro-inflammatory proteins associated with senescence associated secretory phenotype. These data provide strong experimental evidence that DNA damage can promote aging of the CE and that Ercc1(-/Delta) mice offer a rapid and accurate model to study CE pathogenesis and therapy. PMID- 23927040 TI - Efficacy of vitamin D supplementation in depression in adults: a systematic review protocol. AB - BACKGROUND: The role of vitamin D in management of depression is unclear. Results from observational and emerging randomized controlled trials (RCTs) investigating the efficacy of vitamin D in depression lack consistency - with some suggesting a positive association while others show a negative or inconclusive association. METHODS/DESIGN: The primary aim of this study is to conduct a systematic review of RCTs to assess the effect of oral vitamin D supplementation versus placebo on depression symptoms measured by scales and the proportion of patients with symptomatic improvement according to the authors' original definition. Secondary aims include assessing the change in quality of life, adverse events and treatment discontinuation. We will conduct the systematic review and meta analysis according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to present), EMBASE (1980 to present), CINAHL (1982 to present), PsychINFO (1967 to present) and ClinicalTrials.gov. Unpublished work will be identified by searching two major conferences: the International Vitamin Conference, the Anxiety Disorders and Depression Conference, while grey literature will be acquired by contacting authors of included studies. We will use the random-effects meta-analysis to synthesize the data by pooling the results of included studies. DISCUSSION: The results of this systematic review will be helpful in clarifying the efficacy of vitamin D supplementation and providing evidence to establish guidelines for implementation of vitamin D for depression in general practice and other relevant settings. STUDY REGISTRATION: Unique identifier: CRD42013003849. PMID- 23927041 TI - The hierarchy of environmental health and safety practices in the U.S. nanotechnology workplace. AB - Manufacturing of nanoscale materials (nanomaterials) is a major outcome of nanotechnology. However, the potential adverse human health effects of manufactured nanomaterial exposure are not yet fully understood, and exposures in humans are mostly uncharacterized. Appropriate exposure control strategies to protect workers are still being developed and evaluated, and regulatory approaches rely largely on industry self-regulation and self-reporting. In this context of soft regulation, the authors sought to: 1) assess current company reported environmental health and safety practices in the United States throughout the product life cycle, 2) consider their implications for the manufactured nanomaterial workforce, and 3) identify the needs of manufactured nanomaterial companies in developing nano-protective environmental health and safety practices. Analysis was based on the responses of 45 U.S.-based company participants in a 2009-2010 international survey of private companies that use and/or produce nanomaterials. Companies reported practices that span all aspects of the current government-recommended hierarchical approach to manufactured nanomaterials' exposure controls. However, practices that were tailored to current manufactured nanomaterials' hazard and exposure knowledge, whether within or outside the hierarchical approach, were reported less frequently than general chemical hygiene practices. Product stewardship and waste management practices the influences of which are substantially downstream-were reported less frequently than most other environmental health and safety practices. Larger companies had more workers handling nanomaterials, but smaller companies had proportionally more employees handling nanomaterials and more frequently identified impediments to implementing nano-protective practices. Company reported environmental health and safety practices suggest more attention to environmental health and safety is necessary, especially with regard to practices that can cause external effects. Given reported impediments, smaller companies may especially benefit from more attention. However, the manufactured nanomaterial workforce within smaller companies is particularly difficult to identify and hence locate, posing challenges to developing and enforcing appropriate workplace environmental health and safety. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a file containing Survey of Current Health and Safety Practices in the Nanomaterial Industry and a file containing figures.]. PMID- 23927042 TI - Filaggrin gene mutations and risk of basal cell carcinoma. PMID- 23927044 TI - Are current dietary habits in Mediterranean islands a reflection of the past? Results from the MEDIS study. AB - In the 1960s, the recorded dietary pattern of Southern European populations was typical of the traditional Mediterranean diet. However, diets have been rapidly changing. The aim of the current work was to examine the extent by which present food habits of inhabitants residing in various Mediterranean islands uphold past dietary traditions of the Mediterranean diet. A population-based, multi-stage sampling method was used to voluntarily enroll 876 men and 936 women (aged > 65 years) from 12 Mediterranean islands. Demographic, behavioral, clinical, and dietary data were collected. Principal component analysis derived fruits, vegetables, and greens as part of the main dietary pattern across most Mediterranean regions. Surprisingly, Crete had the highest frequency of fast-food and sweets consumption. Malta had the lowest frequency of fish and vegetable consumption and the lowest MedDietScore. As Mediterranean populations gradually move away from traditional dietary patterns, public-health efforts to preserve these diets are needed. PMID- 23927043 TI - Independent and joint associations of TV viewing time and snack food consumption with the metabolic syndrome and its components; a cross-sectional study in Australian adults. AB - BACKGROUND: Television (TV) viewing time is positively associated with the metabolic syndrome (MetS) in adults. However, the mechanisms through which TV viewing time is associated with MetS risk remain unclear. There is evidence that the consumption of energy-dense, nutrient poor snack foods increases during TV viewing time among adults, suggesting that these behaviors may jointly contribute towards MetS risk. While the association between TV viewing time and the MetS has previously been shown to be independent of adult's overall dietary intake, the specific influence of snack food consumption on the relationship is yet to be investigated. The purpose of this study was to examine the independent and joint associations of daily TV viewing time and snack food consumption with the MetS and its components in a sample of Australian adults. METHODS: Population-based, cross-sectional study of 3,110 women and 2,572 men (>35 years) without diabetes or cardiovascular disease. Participants were recruited between May 1999 and Dec 2000 in the six states and the Northern Territory of Australia. Participants were categorised according to self-reported TV viewing time (low: 0-2 hr/d; high: >2 hr/d) and/or consumption of snack foods (low: 0-3 serves/d; high: >3 serves/d). Multivariate odds ratios [95% CI] for the MetS and its components were estimated using gender-specific, forced entry logistic regression. RESULTS: OR [95% CI] for the MetS was 3.59 [2.25, 5.74] (p<=0.001) in women and 1.45 [1.02, 3.45] (p = 0.04) in men who jointly reported high TV viewing time and high snack food consumption. Obesity, insulin resistance and hypertension (women only) were also jointly associated with high TV viewing time and high snack food consumption. Further adjustment for diet quality and central adiposity maintained the associations in women. High snack food consumption was also shown to be independently associated with MetS risk [OR: 1.94 (95% CI: 1.45, 2.60), p < 0.001] and hypertension [OR: 1.43 (95% CI: 1.01, 2.02), p = 0.05] in women only. For both men and women, high TV viewing time was independently associated with the MetS and its individual components (except hypertension). CONCLUSION: TV viewing time and snack food consumption are independently and jointly associated with the MetS and its components, particularly in women. In addition to physical activity, population strategies targeting MetS prevention should address high TV time and excessive snack food intake. PMID- 23927045 TI - Effects of sedentary lifestyle and dietary habits on body mass index change among adult women in India: findings from a follow-up study. AB - We examined the effects of sedentary lifestyle and dietary habits on body mass index (BMI) change in a follow-up study of 325 women (aged 15-49 years) in Delhi, systematically selected from the 1998-1999 National Family Health Survey samples who were re-interviewed after 4 years in 2003. Information was collected on height, weight, dietary habits, and sedentary lifestyle through face-to-face interviews. Overall, a 2.0-point increase in mean BMI was found among women in just 4 years. Every second normal-BMI woman, two in five overweight women, and every fourth obese woman experienced a > 2.0-point increase in her mean BMI. High sedentary lifestyle (OR: 2.63; 95% CI: 1.29-5.35) emerged as the main predictor of a > 2.0-point increase in mean BMI in adjusted analysis, but there was weak evidence of association with the dietary covariates. Our findings suggest that a high sedentary lifestyle is a determinant of weight gain among adult women in urban India. PMID- 23927046 TI - Piecework (ganyu) as an indicator of household vulnerability in rural Zambia. AB - Piecework (ganyu) is short-term, casual labor common in rural Zambia and neighboring countries. Reliance on piecework as a strategy to cope during food shortages in the rainy/cultivation season can restrict own-farm production, and thus, is regarded as an indicator of a household's vulnerability to food insecurity. Based on a household's level of participation in piecework, we explore this claim in rural Zambia using survey data collected during the rainy and dry seasons in 2009. We argue that seasonal assessments are essential if such dependence on piecework is used as a robust measure of a household's vulnerability to food insecurity. PMID- 23927047 TI - The management of cassava toxicity and its changing sociocultural context in the Kei Islands, eastern Indonesia. AB - Over a period of 150 years the Kei Islands have undergone environmental change, from rainforest to dryland savanna woodland. This has been accompanied by a shift in starch staple from sago, tubers, and grain to cassava. We show how this has been an effective ecological adaptation with social ramifications, not least the adoption of bitter cassava as a cultural identity marker. One of the problems of bitter cassava diets where people have become dependent upon them in poor parts of the Old World tropics are the effects of toxicity. We show how through a combination of factors and strategies this has not been a major issue in the Kei Islands, and how through a government-assisted agricultural project, attempts are being made to build upon this successful transition. The viability of present trends are evaluated. PMID- 23927048 TI - alpha-Synuclein as an intrinsically disordered monomer--fact or artefact? AB - Fibrillization of the protein alpha-synuclein (alpha-syn) is a hallmark of Parkinson's disease and other alpha-synucleinopathies. The well-established idea that alpha-syn is a natively disordered monomer prone to forming fibrils was recently challenged by data showing that the protein mostly exists in vitro and in vivo as helically folded tetramers that are resistant to fibrillization. These apparently conflicting findings may be reconciled by the idea that alpha-syn exists as a disordered monomer in equilibrium with variable amounts of dynamic oligomeric species. In this context, varying the approaches used for protein purification, such as the method used to lyse cells or the inclusion of denaturing agents, could dramatically perturb this equilibrium and hence alter the relative abundance of the disordered monomer. In the present study, we investigated how the current methods for alpha-syn purification affect the structure and oligomeric state of the protein, and we discuss the main pitfalls associated with the production of recombinant alpha-syn in Escherichia coli. We demonstrate that alpha-syn was expressed in E. coli as a disordered monomer independent of both the cell lysis method and the use of heating/acidification for protein purification. In addition, we provide convincing evidence that the disordered monomer exists in equilibrium with a dynamic dimer, which is not an artefact of the cross-linking protocol as previously suggested. Unlike the helically folded tetramer, alpha-syn dimer is prone to fibrillate and thus it may be an interesting target for anti-fibrillogenic molecules. PMID- 23927050 TI - Ultralow percolation threshold in aerogel and cryogel templated composites. AB - We demonstrate a novel concept for preparing percolating composites with ultralow filler content by utilizing nanofiller-loaded aerogel and cryogels as a conductive template. This concept is investigated for several porous systems, including resorcinol-formaldehyde (RF), silica, and polyacrylamide (PAM) gels, and both graphene and carbon nanotubes are utilized as nanofiller. In each case, a stable, aqueous nanofiller dispersion is mixed with a sol-gel precursor and polymerized to form a hydrogel, which can then be converted to an aerogel by critical point drying or cryogel by freeze-drying. Epoxy resin is infused into the pores of the gels by capillary action without disrupting the monolithic structure. We show that conductive graphene/epoxy composites are formed with a very low graphene loading; a percolation threshold as low as 0.012 vol % is obtained for graphene-RF cryogel/epoxy composite. This is the lowest reported threshold of any graphene-based nanocomposites. Similar values are achieved in other aerogel and nanofiller systems, which demonstrates the versatility of this method. PMID- 23927051 TI - Optical performance of two new trifocal intraocular lenses: through-focus modulation transfer function and influence of pupil size. AB - BACKGROUND: To compare the in vitro optical quality of two new trifocal intraocular lenses at different focal points as a function of pupil size. METHODS: Two intraocular lenses having different design approaches were evaluated: the AT LISA tri 839MP with a trifocal diffractive design, and the FineVision, which combines two distinct apodized bifocal diffractive profiles resulting in three foci. A PMTF optical bench was used to assess the intraocular lenses' performance, and as optical quality metrics, the through-focus modulation transfer function was selected; that is, it was measured at 10 focal points and for four different apertures (2.0, 3.0, 3.75 and 4.5 mm). RESULTS: For both lenses, the through-focus curve showed three peaks, corresponding to far, intermediate and near focal point. At the 0.0 D focal point, the FineVision yielded better results for larger pupils. At the -1.5 D focal point, both lenses performed worse for larger pupils. At the -3.0 D, the FineVision provided better results for all apertures. However, at the -3.5 D focal point, it was the AT LISA tri 839MP that outperformed the FineVision for larger pupils. CONCLUSIONS: The two trifocal intraocular lenses under analysis have modulation transfer function peaks that correspond to the far, intermediate and near focal points. For larger pupil sizes, the FineVision seems to provide better results at far focal points, while the AT LISA tri 839MP not only provides better results at the intermediate and near focal points, but is also less pupil size-dependent. PMID- 23927049 TI - Characterization of bacterial communities associated with the pine sawyer beetle Monochamus galloprovincialis, the insect vector of the pinewood nematode Bursaphelenchus xylophilus. AB - Pine wilt disease (PWD) has a tremendous impact on worldwide forestlands, both from the environmental and economical viewpoints. Monochamus sp., a xylophagous insect from the Cerambycidae family, plays an important role in dissemination of the pinewood nematode, Bursaphelenchus xylophilus, the primary pathogenic agent of PWD. This study investigates, for the first time, the bacterial communities of Monochamus galloprovincialis collected from Portuguese Pinus pinaster trees and B. xylophilus free, using a metagenomics approach. Overall, our results show that natural bacterial communities of M. galloprovincialis are mainly composed by gamma-proteobacteria, Firmicutes and Bacteroidetes, which may be a reflection of insects' feeding diet and habitat characteristics. We also report different bacterial communities' composition in the thorax and abdomen of M. galloprovincialis, with high abundance of Serratia sp. in both. Our results encourage further studies in the possible relationship between bacteria from the insect vector and B. xylophilus. PMID- 23927052 TI - Rice flooding negatively impacts root branching and arbuscular mycorrhizal colonization, but not fungal viability. AB - Rice is mostly cultivated in wetlands, where arbuscular mycorrhization (AM) is reported to decrease. The mechanisms regulating such events are largely unknown. Rice uninoculated and inoculated with Rhizophagus irregularis were grown in dry and flooded conditions, allowing also for the transfer of plants from one water regime to the other. Roots were sampled at different times, from 7 to 35 d post inoculation (dpi). The morphological and molecular parameters (root branching, aerenchyma formation, mycorrhizal colonization, AM marker gene expression) were evaluated. Root branching was more pronounced in dry conditions, and such phenotype was enhanced by the fungus. In wetlands, the colonization level was comparable till 21 dpi, when the mycorrhization then decreased, paralleled by an increase in aerenchyma. Expression of the fungal transporters was comparable under the two conditions. The root apparatus, when shifted from one water regime to the other, rapidly adapted to the new condition, revealing a marked plasticity. The reversibility of the AM rice symbiosis was also mirrored by expression changes of plant marker genes. The results demonstrate that the water regime is the driving force that regulates AM colonization under flooding conditions, by directly influencing root architecture and anatomy, but without impacting the basic AM functionality. PMID- 23927053 TI - Stereotactic ablative body radiotherapy for previously untreated solitary hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Stereotactic ablative body radiotherapy (SABR) is a relatively new treatment for hepatocellular carcinoma (HCC). The outcomes of SABR for previously untreated solitary HCC unfit for ablation and surgical resection were evaluated. METHODS: Untreated solitary HCC patients treated with SABR were retrospectively studied. Between 2005 and 2012, 221 HCC patients underwent SABR. Among them, patients with untreated solitary HCC, treated with only SABR or SABR preceded by transarterial chemoembolization, were eligible. Based on baseline liver function and liver volume receiving >= 20 Gy, 35-40 Gy in five fractions was prescribed to the planning target volume surface. RESULTS: Sixty-three patients were eligible, with a median follow-up duration of 31.1 (range 12.0 88.1) months. No patients were lost to follow-up. Twenty patients were treated with only SABR. In 43 patients treated with SABR preceded by transarterial chemoembolization, accumulation of lipiodol in the tumor remained complete in five, a partial defect in 38 on pre-SABR computed tomography. The 1-, 2-, and 3 year local control rates were 100%, 95%, and 92%, respectively; the intrahepatic recurrence-free rates were 76%, 55%, and 36%, respectively; and the overall survival rates were 100%, 87%, and 73%, respectively. Grade 3 laboratory toxicities in the acute, subacute, and chronic phases were observed in 10, 9, and 13 patients, respectively, and ascites occurred in one patient. CONCLUSIONS: Local control and overall survival after SABR for untreated solitary HCC were excellent despite the candidates being unfit for resection and ablation. SABR is safe and might be an alternative to resection and ablation. PMID- 23927055 TI - Cardiovascular disease in patients with chronic kidney disease. PMID- 23927054 TI - Effects of systemic pretreatment with CpG oligodeoxynucleotides on skin wound healing in mice. AB - Unmethylated CpG oligodeoxynucleotides (ODN) bind to the Toll-like receptor 9, thus stimulating the immune system. To study the effects of systemic pretreatment with CpG ODN on dermal regeneration, C57BL6/J Tyr mice were treated with CpG or control ODN 6 days prior to implantation of a dorsal skinfold chamber and skin wounding. Wound epithelialization was analyzed by planimetric microscopy. On day 18, wound tissues were taken for (immuno)histochemical staining. CpG ODN increased epithelialization compared with control ODN treatment. Histological analysis revealed reduced capillary density, reduced wound cellularity, and reduced numbers of infiltrating leukocytes, as well as reduced F4/80-positive macrophages, but increased numbers of RELM-alpha-positive M2 macrophages after CpG ODN treatment, reflecting a better quality of wound healing on day 18 compared with control ODN treatment. Reverse transcription-polymerase chain reaction analysis of Toll-like receptor 9 showed the receptor expression on both fibroblasts and keratinocytes. Fibroblasts showed an increase of migration upon increasing dosages of CpG and not control ODN, reaching ~50% of the response of basic fibroblast growth factor-exposed cells. Keratinocytes dose-dependently responded to both CpG and control ODN up to values found in keratinocyte growth factor-exposed cells. In summary, CpG ODN support late tissue-remodeling processes that contribute to resolution of inflammation and solid wounds during skin regeneration. PMID- 23927057 TI - Editorial: the mental health of our deploying generation. PMID- 23927056 TI - Radiographic and safety details of vertebral body stenting: results from a multicenter chart review. AB - BACKGROUND: Up to one third of BKP treated cases shows no appreciable height restoration due to loss of both restored height and kyphotic realignment after balloon deflation. This shortcoming has called for an improved method that maintains the height and realignment reached by the fully inflated balloon until stabilization of the vertebral body by PMMA-based cementation. Restoration of the physiological vertebral body height for pain relief and for preventing further fractures of adjacent and distant vertebral bodies must be the main aim for such a method. A new vertebral body stenting system (VBS) stabilizes the vertebral body after balloon deflation until cementation. The radiographic and safety results of the first 100 cases where VBS was applied are presented. METHODS: During the planning phase of an ongoing international multicenter RCT, radiographic, procedural and followup details were retrospectively transcribed from charts and xrays for developing and testing the case report forms. Radiographs were centrally assessed at the institution of the first/senior author. RESULTS: 100 patients (62 with osteoporosis) with a total of 103 fractured vertebral bodies were treated with the VBS system. 49 were females with a mean age of 73.2 years; males were 66.7 years old. The mean preoperative anterior-middle-posterior heights were 20.3-17.6-28.0 mm, respectively. The mean local kyphotic angle was 13.1 degrees . The mean preoperative Beck Index (anterior edge height/posterior edge height) was 0.73, the mean alternative Beck Index (middle height/posterior edge height) was 0.63. The mean postoperative heights were restored to 24.5-24.6-30.4 mm, respectively. The mean local kyphotic angle was reduced to 8.9 degrees . The mean postoperative Beck Index was 0.81, the mean alternative one was 0.82. The overall extrusion rate was 29.1%, the symptomatic one was 1%. In the osteoporosis subgroup there were 23.8% extrusions. Within the three months followup interval there were 9% of adjacent and 4% of remote new fractures, all in the osteoporotic group. CONCLUSIONS: VBS showed its strengths especially in realignment of crush and biconcave fractures. Given that fracture mobility is present, the realignment potential is sound and increases with the severity of preoperative vertebral body deformation. PMID- 23927058 TI - Summary of mental disorder hospitalizations, active and reserve components, U.S. Armed Forces, 2000-2012. AB - Mental disorders are the leading cause of hospital bed days and the second leading cause of medical encounters for active component service members in the U.S. military. Mental disorder-related hospitalizations among military members have increased in both number and duration since 2006; mental disorders are the only illness/injury category for which hospitalization rates have markedly increased during the first 11 years of the Iraq and Afghanistan wars. Between 2000 and 2012, 159,107 active component service members experienced 192,317 mental disorder hospitalizations. There were approximately 87 percent more mental disorder-related hospitalizations in 2011 (n=21,646) than in 2000 (n=11,604); in 2012, this number declined slightly (n=21,360). The overall increase since 2006 was largely due to sharp increases in hospitalizations for post-traumatic stress disorder (PTSD), depression, alcohol abuse and dependence, and adjustment disorder (% increases in hospitalizations, 2006-2012: PTSD: 192%; depression: 66%; alcohol abuse and dependence: 110%; adjustment disorders: 52%). Similar rates of increase occured among members of the reserve component. The percentage of mental disorder hospitalization records with a second (concurrent) mental disorder diagnosis increased during the surveillance period; more than half of all service members hospitalized for a mental disorder have a second mental disorder diagnosis documented during the same hospitalization. PMID- 23927060 TI - Mental disorders and mental health problems among recruit trainees, U.S. Armed Forces, 2000-2012. AB - Annual counts and rates of incident diagnoses of mental disorders or mental health problems have increased in the U.S. military active component since 2000, but less is known about recruit trainees. From 2000 to 2012, 49,999 active component recruit trainees were diagnosed with at least one mental disorder, and 7,917 had multiple mental disorder diagnoses. Annual incidence rates of at least one mental disorder decreased by approximately 37.4 percent over the last 13 years. Approximately 80.5 percent of all incident mental disorder diagnoses were attributable to adjustment disorders, depression and "other" mental disorders. Rates of incident mental disorder diagnoses were higher in females than males. Even though the Army had the highest overall incidence rates of mental disorders, the Air Force had slightly higher rates for adjustment disorder, and the Navy had higher rates of alcohol abuse-related disorders, post-traumatic stress disorder (PTSD), anxiety, other psychoses, and personality disorders. These findings document differences in the mental disorders experienced by recruit trainees compared to members of the active component of the U.S. military overall. Continued focus on detection and treatment of mental health issues during basic training is warranted. PMID- 23927062 TI - Malingering and factitious disorders and illnesses, active component, U.S. Armed Forces, 1998-2012. AB - Malingering refers to the intentional fabrication or exaggeration of mental or physical symptoms by a person who is motivated by external incentives (e.g., avoiding military duty, work, or incarceration, obtaining financial compensation, or procuring drugs). Factitious disorders and illnesses are similar to malingering with respect to the fabrication of symptoms; however, these individuals seek to assume "sick roles" (e.g., hospitalization, medical evaluation, treatment). During the 15-year surveillance period, 5,311 service members had at least one health care encounter during which a provider recorded a diagnosis of malingering or factitious illness in the first diagnostic position of the administrative record of the encounter. Over 80 percent of the subject service members had only one such encounter and most (83.9%) of the diagnoses were for malingering. There were higher (unadjusted) rates of these diagnoses among recruit trainees, those under the age of 20, and junior enlisted service members. Trends in these diagnoses during the surveillance period and the small numbers of diagnoses made during deployment do not suggest a discernible correlation between malingering and factitious illness and deployment to combat theater. PMID- 23927065 TI - Actin stimulates reduction of the MICAL-2 monooxygenase domain. AB - MICALs are large, multidomain flavin-dependent monooxygenases that use redox chemistry to cause actin to depolymerize. Little enzymology has been reported for MICALs, and none has been reported for MICAL-2, an enzyme vital for the proliferation of prostate cancer. The monooxygenase domains of MICALs resemble aromatic hydroxylases, but their substrate is the sulfur of a methionine of actin. In order to determine how closely MICAL-2 conforms to the aromatic hydroxylase paradigm, we studied its reaction with NAD(P)H. The enzyme has a strong preference for NADPH over NADH caused by a large difference in binding NADPH. A comparison of the reduction kinetics using protio-NADPH and [4R-(2)H] NADPH showed that MICAL-2 is specific for the proR hydride of NADPH, as evidenced by a 4.8-fold kinetic isotope effect. The reductive half-reaction of the MICAL-2 hydroxylase domain is stimulated by f-actin. In the absence of actin, NADPH reduces the flavin relatively slowly; actin speeds that reaction significantly. The separate monooxygenase domain of MICAL-2 has the classic regulatory behavior of flavin-dependent aromatic hydroxylases (Class A monooxygenases): slow reduction of the flavin when the substrate to be oxygenated is absent. This prevents the wasteful consumption of reduced pyridine nucleotide and the production of harmful H2O2. Our results show that this strategy is used by MICAL 2. Thus, our data suggest that MICAL-2 could regulate catalysis through the monooxygenase domain alone; control by interactions with other domains of MICAL in the full-length enzyme may not be needed. PMID- 23927066 TI - A photoelastic stress analysis of screw- and cement-retained implant prostheses with marginal gaps. AB - BACKGROUND: The precise fit of an implant prosthesis is considered to be a prerequisite for the success and maintenance of osseointegration. It is unknown how much static stress can be tolerated at the implant-bone interface with ill fitting prostheses for the two different types of retention (cement vs screw). PURPOSE: The purpose of this study was to evaluate the stress pattern and magnitude in the supporting tissues around ITI (Straumann AG, Waldenburg, Switzerland) implants with screw- or cement-retained prostheses with marginal gaps by photoelastic analysis. MATERIALS AND METHODS: A photoelastic model of a human mandible, partially edentulous distal to the canine, was made of PL-2 resin. Three ITI implants (4.1 * 10 mm, Straumann AG, Waldenburg, Switzerland) were placed in the posterior edentulous region, and screw- or cement-retained three-unit fixed partial dentures (FPDs) were fabricated. Ill-fitting prostheses were made by placing a 100-MUm gap between the abutments and the superstructures on the second premolar or the first molar. A static vertical force of 134 N was applied at three loading points on each prosthesis. Photoelastic stress analysis was carried out to measure the fringe order around the implant-supporting structures. RESULTS: Even in the unloaded condition, low-level stresses were generated around the implants after screw tightening or cementing the three-unit FPDs with marginal gaps. Loading on the terminal implants developed high concentrated stresses around the loaded implant, regardless of the types of restorations or the presence of gaps. However, when the middle implant was loaded, moderate stresses were distributed to the anterior and posterior implants. CONCLUSIONS: Screw-retained FPDs with gaps exhibited a wider range of stresses on the interproximal region of adjacent implants than cement-retained FPDs. However, severe misfit in the prosthesis caused the nonaxial stress transfer to the adjacent implants in the cement-retained FPDs with gaps. PMID- 23927064 TI - Urban air pollutants reduce synaptic function of CA1 neurons via an NMDA/NO pathway in vitro. AB - Airborne particulate matter (PM) from urban vehicular aerosols altered glutamate receptor functions and induced glial inflammatory responses in rodent models after chronic exposure. Potential neurotoxic mechanisms were analyzed in vitro. In hippocampal slices, 2 h exposure to aqueous nanosized PM (nPM) selectively altered post-synaptic proteins in cornu ammonis area 1 (CA1) neurons: increased GluA1, GluN2A, and GluN2B, but not GluA2, GluN1, or mGlur5; increased post synaptic density 95 and spinophilin, but not synaptophysin, while dentate gyrus (DG) neurons were unresponsive. In hippocampal slices and neurons, MitoSOX red fluorescence was increased by nPM, implying free radical production. Specifically, NO production by slices was increased within 15 min of exposure to nPM with dose dependence, 1-10 MUg/mL. Correspondingly, CA1 neurons exhibited increased nitrosylation of the GluN2A receptor and dephosphorylation of GluN2B (S1303) and of GluA1 (S831 & S845). Again, DG neurons were unresponsive to nPM. The induction of NO and nitrosylation were inhibited by AP5, an NMDA receptor antagonist, which also protects neurite outgrowth in vitro from inhibition by nPM. Membrane injury (EthidiumD-1 uptake) showed parallel specificity. Finally, nPM decreased evoked excitatory post-synaptic currents of CA1 neurons. These findings further document the selective impact of nPM on glutamatergic functions and identify novel responses of NMDA receptor-stimulated NO production and nitrosylation reactions during nPM-mediated neurotoxicity. We present three new findings of rapid hippocampal slice responses to nPM (nano-sized particulate matter from urban traffic): increased NO production within 15 min; nitrosylation of glutamatergic NMDA receptors; and, reduced excitatory postsynaptic currents in CA1 neurons. AP5 (NMDA receptor antagonist) blocked nPM-mediated NO and receptor nitrosylation. Ca(2+) influx is a likely mechanism. PMID- 23927067 TI - The association of antenatal corticosteroids with neonatal hypoglycemia and hyperbilirubinemia. AB - OBJECTIVE: While antenatal corticosteroids reduce the risk of neonatal morbidity and mortality, perhaps the maternal hyperglycemia they produce has other neonatal effects. Thus, we sought to examine the association between antenatal betamethasone exposure and neonatal hypoglycemia and hyperbilirubinemia. METHODS: We designed a retrospective cohort study of all preterm deliveries from 32 to 37 weeks of gestation at a single university hospital from 1990 to 2007. Data were collected on antenatal betamethasone administration and the neonatal outcomes. Univariable, multivariable and stratified analyses were conducted. RESULTS: Of 6675 preterm deliveries, significantly higher rates of neonatal hypoglycemia (5.7% versus 4.2%, p<0.05) and hyperbilirubinemia (45.9% versus 24.1%, p<0.05) were observed in neonates exposed to antenatal betamethasone. Controlling for potential confounders including gestational age, these findings persisted with betamethasone-exposed neonates 1.6 times more likely to have hypoglycemia (aOR 1.60, 95% CI 1.24-2.07) and 3.2 times more likely to have hyperbilirubinemia (aOR 3.23, 95% CI 2.92-3.58). CONCLUSIONS: Antenatal betamethasone was associated with neonatal hypoglycemia and hyperbilirubinemia. Further work to determine whether this association is related to maternal hyperglycemia should be conducted, given this could be addressed with strict maternal glycemic control during betamethasone administration. PMID- 23927068 TI - ALK-1 positive orbital inflammatory myofibroblastic tumour (IMT) associated with prominent numbers of IgG4 plasma cells - a case report. AB - A 14-year-old boy presented with a 2-year history of a supraorbital mass, associated with loss of vision and phthisis. A lack of response to systemic steroids led to an incisional biopsy. This showed a spindle cell lesion with a prominent inflammatory component, with numerous plasma cells. The spindle cells were positive for anaplastic lymphoma kinase (ALK-1). Over 90% of the plasma cells were surprisingly positive for IgG4. The presence of ALK-1 positivity within the spindle cells, coupled with the prominent inflammation indicated a diagnosis of ALK-1 positive inflammatory myofibroblastic tumour (IMT-the neoplastic member of the so called inflammatory pseudotumours). However, the level of IgG4 positivity within the plasma cell population would have otherwise lead to a diagnosis of IgG4 related disease, if the ALK-1 positive spindle cells population was not represented. Recent literature from systemic IMT has alluded to the presence of IgG4 plasma cell positivity in IMT and argues that in the absence of other supporting histological features of IgG4 disease (phlebitis and lymphoid aggregates), as in this case, the presence of IgG4 plasma cells, even in high numbers should not lead to a kneejerk diagnosis of co-existing IgG4 disease. This case report is the first to make this association in the orbit and argues that in the presence of IMT, the IgG4 plasma cells are not necessarily pathogenic. PMID- 23927069 TI - A multi-calibrated mitochondrial phylogeny of extant Bovidae (Artiodactyla, Ruminantia) and the importance of the fossil record to systematics. AB - BACKGROUND: Molecular phylogenetics has provided unprecedented resolution in the ruminant evolutionary tree. However, molecular age estimates using only one or a few (often misapplied) fossil calibration points have produced a diversity of conflicting ages for important evolutionary events within this clade. I here identify 16 fossil calibration points of relevance to the phylogeny of Bovidae and Ruminantia and use these, individually and together, to construct a dated molecular phylogeny through a reanalysis of the full mitochondrial genome of over 100 ruminant species. RESULTS: The new multi-calibrated tree provides ages that are younger overall than found in previous studies. Among these are young ages for the origin of crown Ruminantia (39.3-28.8 Ma), and crown Bovidae (17.3-15.1 Ma). These are argued to be reasonable hypotheses given that many basal fossils assigned to these taxa may in fact lie on the stem groups leading to the crown clades, thus inflating previous age estimates. Areas of conflict between molecular and fossil dates do persist, however, especially with regard to the base of the rapid Pecoran radiation and the sister relationship of Moschidae to Bovidae. Results of the single-calibrated analyses also show that a very wide range of molecular age estimates are obtainable using different calibration points, and that the choice of calibration point can influence the topology of the resulting tree. Compared to the single-calibrated trees, the multi-calibrated tree exhibits smaller variance in estimated ages and better reflects the fossil record. CONCLUSIONS: The use of a large number of vetted fossil calibration points with soft bounds is promoted as a better approach than using just one or a few calibrations, or relying on internal-congruency metrics to discard good fossil data. This study also highlights the importance of considering morphological and ecological characteristics of clades when delimiting higher taxa. I also illustrate how phylogeographic and paleoenvironmental hypotheses inferred from a tree containing only extant taxa can be problematic without consideration of the fossil record. Incorporating the fossil record of Ruminantia is a necessary step for future analyses aiming to reconstruct the evolutionary history of this clade. PMID- 23927070 TI - Resolution of the plantar hyperkeratosis of pachyonychia congenita during chemotherapy for Ewing sarcoma. PMID- 23927071 TI - Kisspeptin neurones do not directly signal to RFRP-3 neurones but RFRP-3 may directly modulate a subset of hypothalamic kisspeptin cells in mice. AB - The neuropeptides kisspeptin (encoded by Kiss1) and RFamide-related peptide-3 (also known as GnIH; encoded by Rfrp) are potent stimulators and inhibitors, respectively, of reproduction. Whether kisspeptin or RFRP-3 might act directly on each other's neuronal populations to indirectly modulate reproductive status is unknown. To examine possible interconnectivity of the kisspeptin and RFRP-3 systems, we performed double-label in situ hybridisation (ISH) for the RFRP-3 receptors, Gpr147 and Gpr74, in hypothalamic Kiss1 neurones of adult male and female mice, as well as double-label ISH for the kisspeptin receptor, Kiss1r, in Rfrp-expressing neurones of the hypothalamic dorsal-medial nucleus (DMN). Only a very small proportion (5-10%) of Kiss1 neurones of the anteroventral periventricular region expressed Gpr147 or Gpr74 in either sex, whereas higher co expression (approximately 25%) existed in Kiss1 neurones in the arcuate nucleus. Thus, RFRP-3 could signal to a small, primarily arcuate, subset of Kiss1 neurones, a conclusion supported by the finding of approximately 35% of arcuate kisspeptin cells receiving RFRP-3-immunoreactive fibre contacts. By contrast to the former situation, no Rfrp neurones co-expressed Kiss1r in either sex, and Tacr3, the receptor for neurokinin B (NKB; a neuropeptide co-expressed with arcuate kisspeptin neurones) was found in <10% of Rfrp neurones. Moreover, kisspeptin-immunoreactive fibres did not readily appose RFRP-3 cells in either sex, further excluding the likelihood that kisspeptin neurones directly communicate to RFRP-3 neurones. Lastly, despite abundant NKB in the DMN region where RFRP-3 soma reside, NKB was not co-expressed in the majority of Rfrp neurones. Our results suggest that RFRP-3 may modulate a small proportion of kisspeptin-producing neurones in mice, particularly in the arcuate nucleus, whereas kisspeptin neurones are unlikely to have any direct reciprocal actions on RFRP-3 neurones. PMID- 23927073 TI - Developing a new simplified method to determine diffusive uptake rates of volatile organic compounds in workplaces based on a fractional factorial designs approach. AB - Exposure to organic vapors in the workplace is a source of occupational risk. Admissible exposure levels are tightly regulated and must be closely monitored. However, the complexity and slowness of the existing complete protocols to determine diffusive uptake rates through passive sampling have limited the use of this tool despite obvious advantages. In this study, we experimentally validate two simplified protocols to determine diffusive uptake rates with passive sampling. The proposed 2(6-3) and 2(6-2) fractional factorial designs were validated for toluene sampling using a (Gas Adsorbent Badge for Individual Exposure) GABIE-activated charcoal sampler in a controlled atmosphere. The uptake rate for this sampler had been determined previously using a full protocol. The uptake rates for all three protocols were similar, indicating that the proposed new designs can be substituted for classical full protocols. After validation of our protocols, uptake rates for new substances used as fuel additives (methyl and ethyl tert-butyl ethers, MTBE and ETBE) were determined on the same sampler using the 2(6-2) design. In these experiments, temperature appears to have a non negligible influence on the uptake rates measured for these compounds. With some precautions of usage (ambient temperature below a determined limit temperature or at least exposure time >=4 h) and storage (storage temperature = 4 degrees C) of the sampler, the experimental diffusive uptake rates determined by this method can be used with good confidence. Field experiments confirmed the experimental results, showing good agreement between active and passive sampling using the experimentally determined uptake rates. PMID- 23927074 TI - Understanding attitudes toward the control of nonnative wild and feral mammals: similarities and differences in the opinions of the general public, animal protectionists, and conservationists in New Zealand (aotearoa). AB - Lethal control is used extensively in New Zealand to control nonnative nonhuman mammals. Respondents were surveyed about 8 mammal groups considered pests and their attitudes toward their control and pest status. They also identified the most appropriate method of control for the 8 different mammals. Information was gathered from 3 groups of respondents: nonhuman animal protectionists, conservationists, and the general public. Conservationists routinely rated all animal groups as more severe pests than the general public or animal protectionists, who provided the lowest scores. Rats, stoats, brushtail possums, and rabbits were identified as the 4 most serious pests by all 3 groups. Conservationists were 5.7 and 2.6 times more likely to prefer a lethal method of control than protectionists and the general public, respectively. For all 3 groups an increase in pest score for a given animal saw a decline in importance placed upon the animal's welfare. This relationship was strong for the general public but weak for conservationists and animal protectionists. Understanding aspects of potentially opposing viewpoints may be invaluable in supporting the development of new welfare-focused control methods. PMID- 23927072 TI - Harnessing the genome for characterization of G-protein coupled receptors in cancer pathogenesis. AB - G-protein coupled receptors (GPCRs) mediate numerous physiological processes and represent the targets for a vast array of therapeutics for diseases ranging from depression to hypertension to reflux. Despite the recognition that GPCRs can act as oncogenes and tumour suppressors by regulating oncogenic signalling networks, few drugs targeting GPCRs are utilized in cancer therapy. Recent large-scale genome-wide analyses of multiple human tumours have uncovered novel GPCRs altered in cancer. However, work aiming to determine which GPCRs from these lists are the drivers of tumourigenesis, and hence valid therapeutic targets, comprises a formidable challenge. The present review highlights recent studies providing evidence that GPCRs are relevant targets for cancer therapy through their effects on known cancer signalling pathways, tumour progression, invasion and metastasis, and the microenvironment. Furthermore, the review also explores how genomic analysis is beginning to highlight GPCRs as therapeutic targets in the age of personalized medicine. PMID- 23927075 TI - DNA barcoding the commercial Chinese caterpillar fungus. AB - Chinese caterpillar fungus (Ophiocordyceps sinensis) has been widely used as tonic in Asian medicine. Considering its curative effect and high cost, various counterfeit versions of O. sinensis have been introduced and are commercially available. These counterfeits have morphological characteristics that are difficult to distinguish based on morphology alone, thereby causing confusion and threatening its safe use. In this study, internal transcribed spacer (ITS) sequences as a DNA barcode were analyzed and assessed for rapid and accurate identification of 131 O. sinensis samples and 12 common counterfeits and closely related species. Results showed that sufficient ITS sequence differences, also known as 'barcode gaps', existed to distinguish between O. sinensis and counterfeit species. ITS sequence correctly identified 100% of the samples at the species and genus level using the Basic Local Alignment Search Tool 1 and the nearest distance method. Furthermore, O. sinensis, counterfeits, and closely related species can be successfully identified using tree-based methods including maximum parsimony, neighbor-joining, and maximum likelihood analysis. These results indicated that DNA barcoding could be used as a fast and accurate identification method to distinguish O. sinensis from counterfeits and closely related species to ensure its safe use. PMID- 23927076 TI - Rational adjustment of multicolor emissions by cucurbiturils-based host-guest chemistry and photochemistry. AB - The host-guest chemistry of cucurbiturils and the photochemistry of azastilbene derivatives are combined for the rationally adjusting multicolor emissions through forming different host-guest complexes and their corresponding photochemical products. Cucurbit[8]uril (CB[8]) can bind with azastilbene derivatives to form supramolecular polymers emitting orange light. The supramolecular polymers further facilitate the [2 + 2] cycloaddition of C?C bonds in azastilbenes by UV irradiation, emitting blue light. Different from CB[8], cucurbit[7]uril (CB[7]) encapsulates azastilbene derivatives to form a dumbbell shaped host-guest complex, emitting dark-purple light. This dumbbell-shaped host guest complex undergoes cis-isomerization after UV irradiation, thus emitting green light. Therefore, this strategy is promising for fabricating advanced stimuli-responsive fluorescent materials. PMID- 23927077 TI - Glyceraldehyde-3-phosphate dehydrogenase of the parasitic nematode Haemonchus contortus binds to complement C3 and inhibits its activity. AB - Haemonchus contortus is an economically important gastrointestinal parasite that infects primarily sheep and goats. To survive inside the host, the parasite must overcome the host immune response. In this study, we have identified and characterized a complement-C3-binding protein (H.c-C3BP) from this parasite employing biochemical and molecular biology tools. Initially, a truncated form of the protein was isolated from the excretory-secretory products of the parasite using C3-Sepharose column that facilitated its identification by mass spectroscopy. Subsequently, the parent molecule was generated in E. coli, and sequence analysis confirmed it as glyceraldehyde-3-phosphate dehydrogenase (GAPDH). GAPDH reacted with the antiserum raised against the truncated protein, and the truncated protein reacted with anti-GAPDH antiserum. The protein inhibited complement function as measured by haemolytic assay and membrane attack complex (MAC) formation. Sera from H. contortus-infected animals reacted with GAPDH as well as the truncated form of the protein, which further lend support to protein secretion. Thus, the C3-binding property of H. contortus GAPDH is a new function, and it represents a new entity of complement-binding protein. Identification and characterization of H.c-C3BP should facilitate development of new therapeutics considering a key role of this protein in immune modulation. PMID- 23927078 TI - Balloon-occluded retrograde transvenous obliteration using a microballoon catheter for intractable gastric fundal varices. AB - BACKGROUND AND AIM: Balloon-occluded retrograde transvenous obliteration (B-RTO) is recognized as the standard therapy for patients with gastric fundal varices in Japan; however, the procedure is difficult when drainage veins other than the gastrorenal shunt developed. The efficacy and safety of B-RTO using a microballoon catheter for such patients were evaluated. METHODS: The subjects were 99 patients with gastric fundal varices who fulfilled the criteria for receiving endoscopic and/or interventional therapies. Among these, 95 patients underwent B-RTO. Of the 95 patients, 14 were treated with the use of microballoon catheters, including nine in whom the left inferior phrenic vein was found as a secondary drainage vein in addition to the gastrorenal shunt, and five in whom a gastrorenal shunt was absent. The B-RTO procedure performed using a microballoon catheter inserted through the left inferior phrenic vein in 13 patients, and through the pericardiophrenic vein in one patient. RESULTS: The B-RTO procedure using microballoon catheters was successful in 13 of the 14 patients (93%), while in the remaining one patient, multiple drainage veins were visualized on venography. Complete obliteration of the varices was achieved in all the 13 patients by injection of 5% ethanolamine oleate iopamidol at a median volume of 25 mL (range, 11 to 40 mL) through the catheters. None of the patients showed injuries of the drainage veins or any systemic complications. CONCLUSIONS: B-RTO using a microballoon catheter is useful for the treatment of gastric fundal varices in which drainage veins other than the gastrorenal shunt developed. PMID- 23927079 TI - High bacterial load in negative pressure wound therapy (NPWT) foams used in the treatment of chronic wounds. AB - No earlier study has investigated the microbiology of negative pressure wound therapy (NPWT) foam using a standardized manner. The purpose of this study is to investigate the bacterial load and microbiological dynamics in NPWT foam removed from chronic wounds (>3 months). To determine the bacterial load, a standardized size of the removed NPWT foam was sonicated. The resulting sonication fluid was cultured, and the colony-forming units (CFU) of each species were enumerated. Sixty-eight foams from 17 patients (mean age 63 years, 71% males) were investigated. In 65 (97%) foams, >= 1 and in 37 (54%) >= 2 bacterial types were found. The bacterial load remained high during NPWT treatment, ranging from 10(4) to 10(6) CFU/ml. In three patients (27%), additional type of bacteria was found in subsequent foam cultures. The mean bacterial count +/- standard deviation was higher in polyvinyl alcohol foam (6.1 +/- 0.5 CFU/ml) than in polyurethane (5.5 +/- 0.8 CFU/ml) (p = 0.02). The mean of log of sum of CFU/ml in foam from 125 mmHg (5.5 +/- 0.8) was lower than in foam from 100 mmHg pressure (5.9 +/- 0.5) (p = 0.01). Concluding, bacterial load remains high in NPWT foam, and routine changing does not reduce the load. PMID- 23927080 TI - Vascular endothelial growth factor gene polymorphism prevalence in patients with diabetic macular oedema and its correlation with anti-vascular endothelial growth factor treatment outcomes. AB - BACKGROUND: To study the possible association between vascular endothelial growth factor gene polymorphism and diabetic macular oedema, and its correlation to the outcomes of anti-vascular endothelial growth factor treatment. DESIGN: Prospective study. PARTICIPANTS: 392 diabetic patients were included; 180 patients of them had no retinopathy, 212 patients had diabetic retinopathy. Diabetic retinopathy patients were classified into four groups as defined by the absence or presence of macular oedema or proliferative retinopathy. METHODS: In all subjects, polymerase chain reaction-restriction fragment length polymorphism was conducted to detect the vascular endothelial growth factor gene C-634G polymorphism. Serum levels of vascular endothelial growth factor were estimated. Changes of visual acuity and central macular thickness after bevacizumab treatment in diabetic macular oedema patients of different genotypes were monitored for 9-12 months. MAIN OUTCOME MEASURES: Vascular endothelial growth factor C-634G genotypes distribution in different groups; correlation between genotypes, and changes in visual acuity and central macular thickness after intravitreal bevacizumab treatment. RESULTS: CC genotype was significantly prevalent among diabetic macular oedema patients (P = 0.019). Significant higher serum levels of vascular endothelial growth factor were detected in diabetic retinopathy and diabetic macular oedema patients with CC genotype (P = 0.02, 0.016). After bevacizumab treatment, individuals with genotypes CG and GG have a decreased chance of positive treatment outcomes compared t with CC genotype (P < 0.001). CONCLUSIONS: Vascular endothelial growth factor C-634G polymorphism (CC genotype) is a genetic risk factor for diabetic macular oedema, and its presence provides significantly better visual outcome following bevacizumab treatment. PMID- 23927081 TI - Assessment of risk of bias in translational science. AB - Risk of bias in translational medicine may take one of three forms: A. a systematic error of methodology as it pertains to measurement or sampling (e.g., selection bias), B. a systematic defect of design that leads to estimates of experimental and control groups, and of effect sizes that substantially deviate from true values (e.g., information bias), and C. a systematic distortion of the analytical process, which results in a misrepresentation of the data with consequential errors of inference (e.g., inferential bias). Risk of bias can seriously adulterate the internal and the external validity of a clinical study, and, unless it is identified and systematically evaluated, can seriously hamper the process of comparative effectiveness and efficacy research and analysis for practice. The Cochrane Group and the Agency for Healthcare Research and Quality have independently developed instruments for assessing the meta-construct of risk of bias. The present article begins to discuss this dialectic. PMID- 23927082 TI - Tunable interactions of polyoxometalate-based brushlike hybrids in solvents of variable quality: from self-recognition to supramolecular recognition. AB - The controllable interactions of a spherical polymer brush modeled by a poly(styrene-b-4-vinylpyridinium methyl iodide)-polyoxometalate composite micelle, SVP-6, with a polyoxometalate-based supramolecular star polymer, PSP-4, in solvents of variable quality allow us to tune their self-assembly behaviors from self-recognition to supramolecular recognition. In the former case, isolated, contractive spheres together with a few vesicles formed by PSP-4 coexist with multimicelle aggregates formed by SVP-6, whereas SVP-6 is hosted inside the vesicle of PSP-4 in the latter case. This work represents an important step toward the development and understanding of programmable self-assembly of brushlike polymers into complex materials. PMID- 23927083 TI - Repair of large segmental bone defects: BMP-2 gene activated muscle grafts vs. autologous bone grafting. AB - BACKGROUND: Common cell based strategies for the treatment of osseous defects require the isolation and expansion of autologous cells. Since this makes such approaches time-consuming and expensive, we developed a novel expedited technology creating gene activated muscle grafts. We have previously shown that large segmental bone defects in rats can be regenerated by implantation of muscle tissue fragments activated by BMP-2 gene transfer. RESULTS: In the present study, we compared the bone healing capacities of such gene activated muscle grafts with bone isografts, mimicking autologous bone grafting, the clinical gold standard for treatment of bone defects in patients. Two of 14 male, syngeneic Fischer 344 rats used for this experiment served as donors for muscle and bone. Muscle tissue was harvested from both hind limbs and incubated with an adenoviral vector carrying the cDNA encoding BMP-2. Bone was harvested from the iliac crest and long bone epiphyses. Bone defects (5 mm) were created in the right femora of 12 rats and were filled with either BMP-2 activated muscle tissue or bone grafts. After eight weeks, femora were evaluated by radiographs, micro-computed tomography (MUCT), and biomechanical testing. In the group receiving BMP-2 activated muscle grafts as well as in the bone-grafting group, 100% of the bone defects were healed, as documented by radiographs and MUCT-imaging. Bone volume was similar in both groups and biomechanical stability of the two groups was statistically indistinguishable. CONCLUSIONS: This study demonstrates that treatment of large bone defects by implantation of BMP-2 gene activated muscle tissue leads to similar bone volume and stability as bone isografts, mimicking autologous bone grafting. PMID- 23927084 TI - Lessons from history: morbidity of cold injury in the Royal Marines during the Falklands Conflict of 1982. AB - Some themes echo through history, the protection provided to our troops is again topical; in 1982 it almost determined the outcome of the Falkland's campaign. Thirty years on, Frank Golden (who I first met in April of 1982 just after watching the Falkland's Task Force sail out of Portsmouth) can now tell the story of cold injury in the Royal Marines during the Falklands Conflict (Extreme Physiol Med 2: 23, 2013). It is a fascinating account of hardship, physical endurance, bravery, physiology, pathophysiology, first class scientific operational support and history. PMID- 23927085 TI - Cytomegalovirus & Epstein Barr Virus serostatus as a predictor of the long-term outcome of kidney transplantation. AB - AIM: Cytomegalovirus (CMV) and Epstein Barr Virus (EBV) disease and asymptomatic infection have been associated with poor outcomes in kidney transplantation. Recipients who acquire primary infection through transplantation from a seropositive donor may be at particular risk of complications. The primary aim of this study was to evaluate the relationship between donor/recipient (D/R) CMV and EBV serostatus pretransplant and allograft and patient survival in a large cohort of kidney transplant recipients. METHODS: Data were obtained from the Australian and New Zealand Dialysis and Transplant Registry and the Australian and New Zealand Organ Donation Registry on 4516 first deceased donor kidney transplants performed between 1998 and 2010. Graft and patient survival were analysed using the Kaplan-Meier method. RESULTS: Pretransplant CMV D/R serostatus was available for the whole cohort, with EBV D/R serostatus available for 2566 transplants (56.8%). Serostatus for both viruses was significantly associated with donor and recipient age and recipient smoking status. For both viruses the majority of transplants were in a D+/R+ serostatus setting: 45.3% for CMV and 77.9% for EBV. D/R serostatus for either virus did not have a significant effect on graft or patient survival. CONCLUSION: We conclude that in the current era of viral prophylaxis and surveillance, long-term outcome for the kidney transplant population is unaffected by D/R CMV and EBV serostatus. PMID- 23927086 TI - Biocompatible pillararene-assembly-based carriers for dual bioimaging. AB - Present research provides a successful example to use biocompatible pillararene based assemblies for delivering mixed dyes in dual bioimaging. A series of tadpole-like and bola amphiphilic pillararenes 1-4 were synthesized by selectively employing water-soluble ethylene glycols and hydrophobic alkyl units as the starting materials. In comparison with their monomers, these amphiphilic pillararenes not only show improved biocompatibility to cells but also could form homogeneous supramolecular self-assemblies. Interestingly, different types of amphiphilic pillararene-based assemblies exhibit various performances on the delivery of dyes with different aqueous solubility. All assemblies can deliver water-soluble rhodamine B to cells, while only tadpole-like amphiphilic pillararene-based assemblies performed better on delivering hydrophobic fluorescein isothiocyanate for imaging. In addition, pillararene derivatives 1, 3, and 4 could complex with a viologen guest, further forming stable assemblies for bioimaging. In such cases, the assembly formed from the complex of tadpole like amphiphile pillararene 1 with the viologen guest performed better in delivering mixed dyes. Finally, an anticancer drug, doxorubicin, was successfully delivered to cells by using the pillararene-based assemblies. The current research has determined the capacities of pillararene-based assemblies to deliver different dyes for bioimaging and paves the way for using these biocompatible carriers toward combined cancer therapy. PMID- 23927087 TI - The impact of practice on the adjustment of interaural cues in a lateralization task. AB - Lang and Buchner [J. Acoust. Soc. Am. 124, 3120-3131 (2008)] conducted trading experiments showing that the phenomenon of different trading ratios depending on which cue is adjusted by the listener is independent of the presentation of an explicit reference tone. Four experiments were conducted to test whether implicit reference tones during the preceding practice phase may have caused the different trading ratios. The results of Lang and Buchner were replicated, showing that an implicit reference learned during the practice phase cannot account for different trading ratios in experiments without the presentation of a reference tone. PMID- 23927088 TI - Efficient use of bandwidth for underwater acoustic communication. AB - In a recent shallow water experiment, acoustic communication transmissions were carried out over the 10 to 32 kHz band in ~100 m deep water over a 3 km range. A natural question is how best to utilize that bandwidth. In one multiband approach discussed previously, the band was divided into four smaller subbands that were processed independently using time reversal decision-feedback equalizers (TR DFEs). This letter presents a complementary wideband approach using data from the same experiment achieving a data rate of up to 60 kbits/s with 32 quadrature amplitude modulation. These results suggest that a wideband approach can be beneficial in terms of spectral efficiency with modest computational complexity using a TR-DFE. PMID- 23927089 TI - The influence of glottal cross-section shape on theoretical flow models. AB - Physical and mathematical phonation models commonly rely on a quasi-one dimensional flow model. The assumption of quasi-one-dimensional flow through a glottis with fixed length is analyzed for different cross-section shapes: Circle, rectangle, ellipse, and circular segment. A simplified flow model is formulated which accounts for kinetic losses, viscosity, and cross-section shape. It is seen that the cross-section shape cannot be neglected since it alters boundary layer development and hence the viscous contribution to the pressure drop across the glottis. The commonly applied quasi-one-dimensional flow model is shown to be inaccurate, indicating the potential benefit of taking into account the cross section shape. PMID- 23927090 TI - Response to "Comments on 'A theoretical model of the pressure distributions arising from asymmetric intraglottal flows applied to a two-mass model of the vocal folds'" [J. Acoust. Soc. Am. 130, 389-403 (2011)]. AB - Hirschberg [J. Acoust. Soc. Am. 134, 9-12 (2013)] presents a commentary and criticisms of the viscous flow model presented by Erath et al. [J. Acoust. Soc. Am. 130, 389-403 (2011)] that solves for the asymmetric pressure loading on the vocal fold walls. This pressure loading arises from asymmetric flow attachment to one vocal fold wall when the glottal channel forms a divergent configuration. Hirschberg proposes an alternative model for the asymmetric loading based upon inviscid flow curvature at the glottal inlet. In this manuscript further evidence is provided in support of the model of Erath et al. and the underlying assumptions, and demonstrates that the primary criticisms presented by Hirschberg are unwarranted. The model presented by Hirschberg is compared with the model from the original paper by Erath et al., and it is shown that each model describes different and complementary aspects of divergent glottal flows. PMID- 23927091 TI - High amplitude nonlinear acoustic wave driven flow fields in cylindrical and conical resonators. AB - A high fidelity computational fluid dynamic model is used to simulate the flow, pressure, and density fields generated in a cylindrical and a conical resonator by a vibrating end wall/piston producing high-amplitude standing waves. The waves in the conical resonator are found to be shock-less and can generate peak acoustic overpressures that exceed the initial undisturbed pressure by two to three times. A cylindrical (consonant) acoustic resonator has limitations to the output response observed at one end when the opposite end is acoustically excited. In the conical geometry (dissonant acoustic resonator) the linear acoustic input is converted to high energy un-shocked nonlinear acoustic output. The model is validated using past numerical results of standing waves in cylindrical resonators. The nonlinear nature of the harmonic response in the conical resonator system is further investigated for two different working fluids (carbon dioxide and argon) operating at various values of piston amplitude. The high amplitude nonlinear oscillations observed in the conical resonator can potentially enhance the performance of pulse tube thermoacoustic refrigerators and these conical resonators can be used as efficient mixers. PMID- 23927092 TI - Non-paraxial model for a parametric acoustic array. AB - This study is concerned with parametric radiation from an arbitrary axisymmetric planar source with a special focus on low-frequency difference-frequency fields. As a model equation accounting for nonlinearity, diffraction, and dissipation, the Westervelt equation is used. The difference-frequency-field patterns are calculated in the quasi-linear approximation by the method of successive approximations. A multi-layer integral for calculation of the acoustic field is reduced to a three-dimensional one by employing an approximate analytical description of the primary field with the use of a multi-Gaussian beam expansion. This integral is subsequently reduced in the paraxial approximation to a one dimensional form which has previously been published in literature and which represents a means for fast calculations of secondary acoustic fields. The three dimensional integral is calculated numerically and the numerical results predict nonzero amplitude of the low-frequency field in the vicinity of the source which is an effect that cannot be correctly encompassed in the paraxial approximation. PMID- 23927093 TI - An eigenvalue correction due to scattering by a rough wall of an acoustic waveguide. AB - In this paper a derivation of the attenuation factor in a waveguide with stochastic walls is presented. The perturbation method and Fourier analysis are employed to derive asymptotically consistent boundary-value problems at each asymptotic order. The derived approximation predicts the attenuation of the propagating mode in a rough waveguide through a correction to the eigenvalue corresponding to smooth walls. The proposed approach can be used to derive results that are consistent with those obtained by Bass et al. [IEEE Trans. Antennas Propag. 22, 278-288 (1974)]. The novelty of the method is that it does not involve the integral Dyson-type equation and, as a result, the large number of statistical moments included in the equation in the form of the mass operator of the volume scattering theory. The derived eigenvalue correction is described by the correlation function of the randomly rough surface. The averaged solution in the plane wave regime is approximated by the exponential function dependent on the derived eigenvalue correction. The approximations are compared with numerical results obtained using the finite element method (FEM). An approach to retrieve the correct deviation in roughness height and correlation length from multiple numerical realizations of the stochastic surface is proposed to account for the oversampling of the rough surface occurring in the FEM meshing procedure. PMID- 23927094 TI - Theory of the directionality and spatial coherence of wind-driven ambient noise in a deep ocean with attenuation. AB - Acoustic attenuation in seawater usually has little effect on the spatial statistics of ambient noise in the ocean. This expectation does not hold, however, at higher frequencies, above 10 kHz, and extreme depths, in excess of 6 km, an operating regime that is within the capabilities of the most recently developed acoustic instrument platforms. To quantify the effects of attenuation, theoretical models for the vertical directionality and the spatial coherence of wind-generated ambient noise are developed in this paper, based on a uniform distribution of surface sources above a semi-infinite, homogeneous ocean. Since there are no bottom reflections, all the noise is downward traveling; and the angular width of the directional density function becomes progressively narrower with increasing frequency because sound from the more distant sources experiences greater attenuation than acoustic arrivals from overhead. This narrowing of the noise lobe modifies the spatial coherence, shifting the zeros in the horizontal (vertical) coherence function to higher (lower) frequencies. In addition, the attenuation modifies the amplitudes of the higher-order oscillations in the horizontal and vertical coherence functions, tending to suppress the former and enhance the latter. These effects are large enough to be detectable with the latest deep-diving sensor technology. PMID- 23927095 TI - An inter-comparison of sediment classification methods based on multi-beam echo sounder backscatter and sediment natural radioactivity data. AB - This contribution presents sediment classification results derived from different sources of data collected at the Dordtse Kil river, the Netherlands. The first source is a multi-beam echo-sounder (MBES). The second source is measurements taken with a gamma-ray scintillation detector, i.e., the Multi-Element Detection System for Underwater Sediment Activity (Medusa), towed over the sediments and measuring sediment natural radioactivity. Two analysis methods are employed for sediment classification based on the MBES data. The first is a Bayesian estimation method that uses the average backscatter data per beam and, therefore, is independent of the quality of the MBES calibration. The second is a model based method that matches the measured backscatter curves to theoretical curves, predicted by a physics-based model. Medusa provides estimates for the concentrations of potassium, uranium, thorium, and cesium, known to be indicative for sediment properties, viz. mean grain size, silt content, and the presence of organic matter. In addition, a hydrophone attached to the Medusa system provides information regarding the sediment roughness. This paper presents an inter comparison between the sediment classification results using the above-mentioned methods. It is shown that although originating from completely different sources, the MBES and Medusa provide similar information, revealing the same sediment distribution. PMID- 23927096 TI - Particle smoothers in sequential geoacoustic inversion. AB - Sequential Bayesian methods such as particle filters have been used to track a moving source in an unknown and space/time-evolving ocean environment. These methods treat both the source and the ocean parameters as non-stationary unknown random variables and track them via the multivariate posterior probability density function. Particle filters are numerical methods that can operate on nonlinear systems with non-Gaussian probability density functions. Particle smoothers are a natural extension to these filters. A smoother is appropriate in applications where data before and after the time of interest are readily available. Both past and "future" measurements are exploited in smoothers, whereas filters just use past measurements. Geoacoustic and source tracking is performed here using two smoother algorithms, the forward-backward smoother and the two-filter smoother. Smoothing is demonstrated on experimental data from both the SWellEx-96 and SW06 experiments where the parameter uncertainty is reduced relative to just filtering alone. PMID- 23927097 TI - Mode-converted diffuse ultrasonic backscatter. AB - Diffuse ultrasonic backscatter describes the scattering of elastic waves from interfaces within heterogeneous materials. Previously, theoretical models have been developed for the diffuse backscatter of longitudinal-to-longitudinal (L-L) wave scattering within polycrystalline materials. Following a similar formalism, a mode-conversion scattering model is presented here to quantify the component of an incident longitudinal wave that scatters and is converted to a transverse (shear) wave within a polycrystalline sample. The model is then used to fit experimental measurements associated with a pitch-catch transducer configuration performed using a sample of 1040 steel. From these measurements, an average material correlation length is determined. This value is found to be in agreement with results from L-L scattering measurements and is on the order of the grain size as determined from optical micrographs. Mode-converted ultrasonic backscatter is influenced much less by the front-wall reflection than an L-L measurement and it provides additional microstructural information that is not accessible in any other manner. PMID- 23927098 TI - Dynamics of bubbles created by plasma in heptane for micro-gap conditions. AB - The determination of the initial pressure at the bubble wall created by a discharge in heptane for micro-gap conditions cannot be determined straightforwardly by modeling the time-oscillations of the bubble. The resolution of the Gilmore equation gives the same solutions beyond 1 MUs typically for various sets of initial parameters, making impossible the determination of the initial pressure at the bubble wall. Furthermore, the very first instant of the bubble formation is not easily accessible at very short time scales because of the plasma emission. Since the pressure waves propagate in the liquid, it is much easier to gain information on the first instants of the bubble formation by studying the pressure field far from the emission source. Then, it is possible to deduce by modeling what happened at the beginning of the emission of the pressure waves. The proposed solution consists in looking at the oscillations affecting another bubble located at least twice farther from the interelectrode gap than the maximum radius reached by the discharge bubble. The initial plasma pressure can be determined by this method. PMID- 23927099 TI - Quantitative non-linear ultrasonic imaging of targets with significant acoustic impedance contrast--an experimental study. AB - This study deals with the reconstruction, from ultrasonic measured data, of the sound speed profile of a penetrable two-dimensional target of arbitrary cross section embedded in an infinite medium. Green's theorem is used to obtain a domain integral representation of the acoustical scattered field, and a discrete formulation of the inverse problem is obtained using a moment method. An iterative non-linear algorithm minimizing the discrepancy between the measured and computed scattered fields is used to reconstruct the sound speed profile in the region of interest. The minimization process is performed using a conjugated gradient method. An experimental study with significant acoustical impedance contrast targets immersed in water was performed. Images of the sound speed profile obtained by inversion of experimental data are presented. PMID- 23927100 TI - Acoustic Doppler velocity measurement system using capacitive micromachined ultrasound transducer array technology. AB - This paper describes the design, fabrication, modeling, and characterization of a small (1 cm(2) transducer chip) acoustic Doppler velocity measurement system using microelectromechanical systems capacitive micromachined ultrasound transducer (cMUT) array technology. The cMUT sensor has a 185 kHz resonant frequency to achieve a 13 degrees beam width for a 1 cm aperture. A model for the cMUT and the acoustic system which includes electrical, mechanical, and acoustic components is provided. Furthermore, this paper shows characterization of the cMUT sensor with a variety of testing procedures including Laser Doppler Vibrometry (LDV), beampattern measurement, reflection testing, and velocity testing. LDV measurements demonstrate that the membrane displacement at the center point is 0.4 nm/V(2) at 185 kHz. The maximum range of the sensor is 60 cm (30 cm out and 30 cm back). A velocity sled was constructed and used to demonstrate measureable Doppler shifts at velocities from 0.2 to 1.0 m/s. The Doppler shifts agree well with the expected frequency shifts over this range. PMID- 23927101 TI - Piezoelectric circular ring flexural transducers. AB - An analytical treatment of the piezoelectric ceramic complete ring transducer undergoing flexural vibrations is presented. Conditions for the electromechanical excitation of the flexural vibrations are discussed and it is shown that the fundamental mode of the flexural vibration of a complete ring can be considered as sufficiently dominant over a broad frequency range. Hence, the one-dimensional equivalent electromechanical circuit representation of the transducer is applicable and all the parameters of the equivalent circuit are determined. Possibilities to optimize the effective coupling coefficient of the transducer by changing the extent of the electrodes on the piezoelectric body are considered. It is shown that for effective operation of the flexural ring transducer as a low frequency hydroacoustic projector the opposing quadrants (or three quadrants in case of a planar array configuration) have to be covered with baffles. The radiation impedance and directional factors of the transducers with baffles are considered. Limitations of the acoustical power radiated by the transducers are discussed. PMID- 23927102 TI - Fabrication and performance of a single-crystal lead magnesium niobate-lead titanate cylindrical hydrophone. AB - The development of a piezoelectric hydrophone based on lead magnesium niobate lead titanate [PbMg1/3Nb2/3O3-PbTiO3 (PMN-PT)] single-crystal piezoelectric as the hydrophone substrate is reported. Although PMN-PT can possess much higher piezoelectric sensitivity than traditional lead zirconate titanate (PZT) piezoelectrics, it is highly anisotropic and therefore there is a large gain in sensitivity only when the crystal structure is oriented in a specific direction. Because of this, simply replacing the PZT substrate with a PMN-PT cylinder is not an optimal solution because the crystal orientation does not uniformly align with the circumferential axis of the hydrophone. Therefore, a composite hydrophone that maintains the optimal crystal axis around the hydrophone circumference has been developed. An 11.3 mm diameter composite hydrophone cylinder was fabricated from a single <110> cut PMN-PT rectangular plate. Solid end caps were applied to the cylinder and the sensitivity was directly compared with a solid PZT-5A cylindrical hydrophone of equal dimensions in a hydrophone test tank. The charge sensitivity showed a 9.1 dB improvement over the PZT hydrophone and the voltage sensitivity showed a 3.5 dB improvement. This was in good agreement with the expected theoretical improvements of 10.1 and 4.5 dB, respectively. PMID- 23927103 TI - Continuum-based free vibration of circular trigonal and isotropic plates. AB - The free vibration behavior of completely unrestrained elastic circular plates with trigonal and isotropic material symmetry is studied with an approach involving approximate continuum solutions to the three-dimensional theory of linear elasticity. Of primary interest are (1) the influence of trigonal material symmetry on the modes of free vibration and (2) the accuracy of thin plate theory relative to the more exact three-dimensional theory. Resonant frequencies are calculated from the weak form of the equations of motion for the plate through the use of approximation functions and the Ritz method formulated in cylindrical coordinates. This approach enables the resulting eigenvalue problem to be split through group-theoretical symmetry analysis. Representative examples are given and quantitative limits are discussed. PMID- 23927104 TI - Increasing the modal density in plates for mono-element focusing in air. AB - Acoustic focusing experiments usually require large arrays of transducers. It has been shown by Etaix et al. [J. Acoust. Soc. Am. 131, 395-399 (2012)] that the use of a cavity allows reducing this number of transducers. This paper presents experiments with Duralumin plates (the cavities) containing scatterers to improve the contrast of focusing. The use of a scatterer array in the plate allows increasing the modal density at given frequencies. The scatterers used are membranes and buttons that are manufactured in Duralumin plates. Their resonances are studied both experimentally and numerically. Such scatterers present the advantage of having a tunable frequency resonance, which allows controlling the frequencies at which the modal density increases. The dispersion relations of plates with scatterer array show high modal density at given frequencies. Finally acoustic focusing experiments in air, using these plates, are compared to the ones of simple duralumin plates demonstrating the improvement of contrast. Acoustic source localization is also realized using these plates. PMID- 23927105 TI - Convolution formulations for non-negative intensity. AB - Previously unknown spatial convolution formulas for a variant of the active normal intensity in planar coordinates have been derived that use measured pressure or normal velocity near-field holograms to construct a positive-only (outward) intensity distribution in the plane, quantifying the areas of the vibrating structure that produce radiation to the far-field. This is an extension of the outgoing-only (unipolar) intensity technique recently developed for arbitrary geometries by Steffen Marburg. The method is applied independently to pressure and velocity data measured in a plane close to the surface of a point driven, unbaffled rectangular plate in the laboratory. It is demonstrated that the sound producing regions of the structure are clearly revealed using the derived formulas and that the spatial resolution is limited to a half-wavelength. A second set of formulas called the hybrid-intensity formulas are also derived which yield a bipolar intensity using a different spatial convolution operator, again using either the measured pressure or velocity. It is demonstrated from the experiment results that the velocity formula yields the classical active intensity and the pressure formula an interesting hybrid intensity that may be useful for source localization. Computations are fast and carried out in real space without Fourier transforms into wavenumber space. PMID- 23927106 TI - Optimal apparent damping as a function of the bandwidth of an array of vibration absorbers. AB - The transient response of a resonant structure can be altered by the attachment of one or more substantially smaller resonators. Considered here is a coupled array of damped harmonic oscillators whose resonant frequencies are distributed across a frequency band that encompasses the natural frequency of the primary structure. Vibration energy introduced to the primary structure, which has little to no intrinsic damping, is transferred into and trapped by the attached array. It is shown that, when the properties of the array are optimized to reduce the settling time of the primary structure's transient response, the apparent damping is approximately proportional to the bandwidth of the array (the span of resonant frequencies of the attached oscillators). Numerical simulations were conducted using an unconstrained nonlinear minimization algorithm to find system parameters that result in the fastest settling time. This minimization was conducted for a range of system characteristics including the overall bandwidth of the array, the ratio of the total array mass to that of the primary structure, and the distributions of mass, stiffness, and damping among the array elements. This paper reports optimal values of these parameters and demonstrates that the resulting minimum settling time decreases with increasing bandwidth. PMID- 23927107 TI - Effect of train type on annoyance and acoustic features of the rolling noise. AB - This study investigated the annoyance associated with the rolling noise of different railway stock. Passbys of nine train types (passenger and freight trains) equipped with different braking systems were recorded. Acoustic features showed a clear distinction of the braking system with the A-weighted energy equivalent sound level (LAeq) showing a difference in the range of 10 dB between cast-iron braked trains and trains with disk or K-block brakes. Further, annoyance was evaluated in a psychoacoustic experiment where listeners rated the relative annoyance of the rolling noise for the different train types. Stimuli with and without the original LAeq differences were tested. For the original LAeq differences, the braking system significantly affected the annoyance with cast iron brakes being most annoying, most likely as a consequence of the increased wheel roughness causing an increased LAeq. Contribution of the acoustic features to the annoyance was investigated revealing that the LAeq explained up to 94% of the variance. For the stimuli without differences in the LAeq, cast-iron braked train types were significantly less annoying and the spectral features explained up to 60% of the variance in the annoyance. The effect of these spectral features on the annoyance of the rolling noise is discussed. PMID- 23927108 TI - On the in situ impedance measurement with pu-probes--simulation of the measurement setup. AB - High-quality numerical simulations in room acoustics require a detailed knowledge of the acoustic reflection characteristics of the materials in the room, in order to realistically model the interferences between multiple sound reflections at the room boundaries. While different standardized measurement methods exist for the determination of the absorption coefficient and reflection factor these methods can generally not be applied in situ. Thus time-consuming laboratory measurements and the supply of material samples are required. Driven by the obvious demand for a reliable in situ measurement technique, a pu-probe based method has emerged during the last years, which derives the reflection factor based on the simultaneous measurement of sound pressure and velocity. However, previous investigations of the setup and publications by other authors have shown that the measurement results are affected by various uncertainty factors. The present study aims at the identification, separation, and quantitative assessment of the uncertainty factors related to reflection and diffraction effects at the loudspeaker, sensor, and the absorber geometry. Therefore, a purely simulative approach will be used that replicates the actual measurement situation in every detail, including the geometries of sensor, loudspeaker, and absorber. The simulation setup is validated by measurements and is used to systematically separate the different uncertainty factors. PMID- 23927109 TI - High frequency acoustic transmission loss of perforated plates at normal incidence. AB - A study has been conducted on the transmission loss of perforated plates at normal incidence. The investigation includes a theoretical analysis of the problem with validation through experimentation. The experiments comprised microphone measurements of transmission loss for 11 perforated plates with variable thickness, hole size, and porosity. The theoretical model is based on planar wave propagation through a single contraction/expansion chamber with modifications to account for hole interaction effects. The resulting formula for transmission loss yields superior predictions over past theories for the range of properties investigated. Deviations between experimental measurements and theoretical predictions of transmission loss are less than about 1.5 dB for dimensionless hole diameter d/lambda < 0.5. The accuracy of the model does not show a strong dependence on plate thickness-to-diameter ratio or porosity. PMID- 23927110 TI - Optical multi-point measurements of the acoustic particle velocity with frequency modulated Doppler global velocimetry. AB - To reduce the noise of machines such as aircraft engines, the development and propagation of sound has to be investigated. Since the applicability of microphones is limited due to their intrusiveness, contactless measurement techniques are required. For this reason, the present study describes an optical method based on the Doppler effect and its application for acoustic particle velocity (APV) measurements. While former APV measurements with Doppler techniques are point measurements, the applied system is capable of simultaneous measurements at multiple points. In its current state, the system provides linear array measurements of one component of the APV demonstrated by multi-tone experiments with tones up to 17 kHz for the first time. PMID- 23927111 TI - Using channel-specific statistical models to detect reverberation in cochlear implant stimuli. AB - Reverberation is especially detrimental for cochlear implant listeners; thus, mitigating its effects has the potential to provide significant improvements to cochlear implant communication. Efforts to model and correct for reverberation in acoustic listening scenarios can be quite complex, requiring estimation of the room transfer function and localization of the source and receiver. However, due to the limited resolution associated with cochlear implant stimulation, simpler processing for reverberation detection and mitigation may be possible for cochlear implants. This study models speech stimuli in a cochlear implant on a per-channel basis both in quiet and in reverberation, and assesses the efficacy of these models for detecting the presence of reverberation. This study was able to successfully detect reverberation in cochlear implant pulse trains, and the results appear to be robust to varying room conditions and cochlear implant stimulation parameters. Reverberant signals were detected 100% of the time for a long reverberation time of 1.2 s and 86% of the time for a shorter reverberation time of 0.5 s. PMID- 23927112 TI - Influence of stimulus parameters on amplitude-modulated stimulus frequency otoacoustic emissions. AB - The present study evaluated the influence of suppressor frequency (fs) and level (Ls) on stimulus-frequency otoacoustic emissions (SFOAEs) recorded using the amplitude-modulated (AM) suppressor technique described by Neely et al. [J. Acoust. Soc. Am. 118, 2124-2127 (2005a)]. Data were collected in normal-hearing subjects, with data collection occurring in two phases. In phase 1, SFOAEs were recorded with probe frequency (fp) = 1, 2, and 4 kHz and probe levels (Lp) ranging from 0 to 60 dB sound pressure level (SPL). At each fp, Ls ranged from Ls = Lp to Ls = Lp + 30 dB. Additionally, nine relationships between fs and fp were evaluated, ranging from fs/fp = 0.80 to fs/fp = 1.16. Results indicated that for low suppressor levels, suppressors higher in frequency than fp (fs > fp) resulted in higher AM-SFOAE levels than suppressors lower in frequency than fp (fs < fp). At higher suppressor levels, suppressors both higher and lower in frequency than fp produced similar AM-SFOAE levels, and, in many cases, low-frequency suppressors produced the largest response. Recommendations for stimulus parameters that maximize AM-SFOAE level were derived from these data. In phase 2, AM-SFOAEs were recorded using these parameters for fp = 0.7-8 kHz and Lp = 20-60 dB SPL. Robust AM-SFOAE responses were recorded in this group of subjects using the parameters developed in phase 1. PMID- 23927113 TI - Bayesian adaptive estimation of the auditory filter. AB - A Bayesian adaptive procedure for estimating the auditory-filter shape was proposed and evaluated using young, normal-hearing listeners at moderate stimulus levels. The resulting quick-auditory-filter (qAF) procedure assumed the power spectrum model of masking with the auditory-filter shape being modeled using a spectrally symmetric, two-parameter rounded-exponential (roex) function. During data collection using the qAF procedure, listeners detected the presence of a pure-tone signal presented in the spectral notch of a noise masker. Dependent on the listener's response on each trial, the posterior probability distributions of the model parameters were updated, and the resulting parameter estimates were then used to optimize the choice of stimulus parameters for the subsequent trials. Results showed that the qAF procedure gave similar parameter estimates to the traditional threshold-based procedure in many cases and was able to reasonably predict the masked signal thresholds. Additional measurements suggested that occasional failures of the qAF procedure to reliably converge could be a consequence of incorrect responses early in a qAF track. The addition of a parameter describing lapses of attention reduced the likelihood of such failures. PMID- 23927114 TI - Binaural speech intelligibility in rooms with variations in spatial location of sources and modulation depth of noise interferers. AB - Four experiments investigated the effects on speech intelligibility of reverberation, sound source locations, and amplitude modulation of the interferers. Speech reception thresholds (SRTs) were measured using headphones and stimuli that simulated real-room listening, considering one or two interferers which were stationary or speech-modulated noises. In experiment 1, SRTs for modulated noises showed little variation with increasing interferer reverberation. Reverberation might have increased masking by filling in the modulated noise gaps, but simultaneously changed the noise spectra making them less effective maskers. In experiment 2, SRTs were lower when measured using a unique one-voice modulated interferer rather than a different interferer for each target sentence, suggesting that listeners could take advantage of the predictability of the interferer gaps. In experiment 3, increasing speech reverberation did not significantly affect the difference of SRTs measured with stationary and modulated noises, indicating that the ability to exploit noise modulations was still useful for temporally smeared speech. In experiment 4, spatial unmasking remained constant when applying modulations to the interferers, suggesting an independence of the abilities to exploit these modulations and the spatial separation of sources. Finally, a model predicting binaural intelligibility for modulated noises was developed and provided a good fit to the experimental data. PMID- 23927115 TI - Simultaneous masking additivity for short Gaussian-shaped tones: spectral effects. AB - Laback et al. [(2011). J. Acoust. Soc. Am. 129, 888-897] investigated the additivity of nonsimultaneous masking using short Gaussian-shaped tones as maskers and target. The present study involved Gaussian stimuli to measure the additivity of simultaneous masking for combinations of up to four spectrally separated maskers. According to most basilar membrane measurements, the maskers should be processed linearly at the characteristic frequency (CF) of the target. Assuming also compression of the target, all masker combinations should produce excess masking (exceeding linear additivity). The results for a pair of maskers flanking the target indeed showed excess masking. The amount of excess masking could be predicted by a model assuming summation of masker-evoked excitations in intensity units at the target CF and compression of the target, using compressive input/output functions derived from the nonsimultaneous masking study. However, the combinations of lower-frequency maskers showed much less excess masking than predicted by the model. This cannot easily be attributed to factors like off frequency listening, combination tone perception, or between-masker suppression. It was better predicted, however, by assuming weighted intensity summation of masker excitations. The optimum weights for the lower-frequency maskers were smaller than one, consistent with partial masker compression as indicated by recent psychoacoustic data. PMID- 23927116 TI - Learning, worsening, and generalization in response to auditory perceptual training during adolescence. AB - While it is commonly held that the capacity to learn is greatest in the young, there have been few direct comparisons of the response to training across age groups. Here, adolescents (11-17 years, n = 20) and adults (>=18 years, n = 11) practiced detecting a backward-masked tone for ~1 h/day for 10 days. Nearly every adult, but only half of the adolescents improved across sessions, and the adolescents who learned did so more slowly than adults. Nevertheless, the adolescent and adult learners showed the same generalization pattern, improving on untrained backward- but not forward- or simultaneous-masking conditions. Another subset of adolescents (n = 6) actually got worse on the trained condition. This worsening, unlike learning, generalized to an untrained forward masking, but not backward-masking condition. Within sessions, both age groups got worse, but the worsening was greater for adolescents. These maturational changes in the response to training largely followed those previously reported for temporal-interval discrimination. Overall, the results suggest that late-maturing processes affect the response to perceptual training and that some of these processes may be shared between tasks. Further, the different developmental rates for learning and generalization, and different generalization patterns for learning and worsening imply that learning, generalization, and worsening may have different origins. PMID- 23927117 TI - Priming of lowpass-filtered speech affects response bias, not sensitivity, in a bandwidth discrimination task. AB - Priming is demonstrated when prior information about the content of a distorted, filtered, or masked auditory message improves its clarity. The current experiment attempted to quantify aspects of priming by determining its effects on performance and bias in a lowpass-filter-cutoff frequency discrimination task. Nonsense sentences recorded by a female talker were sharply lowpass filtered at a nominal cutoff frequency (F) of 0.5 or 0.75 kHz or at a higher cutoff frequency (F + DeltaF). The listeners' task was to determine which interval of a two interval-forced-choice trial contained the nonsense sentence filtered with F + DeltaF. On priming trials, the interval 1 sentence was displayed on a computer screen prior to the auditory portion of the trial. The prime markedly affected bias, increasing the number of correct and incorrect interval 1 responses but did not affect overall discrimination performance substantially. These findings were supported through a second experiment that required listeners to make confidence judgments. The paradigm has the potential to help quantify the limits of speech perception when uncertainty about the auditory message is removed. PMID- 23927118 TI - The dominant region for the pitch of complex tones with low fundamental frequencies. AB - The dominant region for pitch for complex tones with low fundamental frequency (F0) was investigated. Thresholds for detection of a change in F0 (F0DLs) were measured for a group of harmonics (group B) embedded in a group of fixed non overlapping harmonics (group A) with the same mean F0. It was assumed that F0DLs would be smallest when the harmonics in group B fell in the dominant region. The rank of the lowest harmonic in group B, N, was varied from 1 to 15. When all components had the same level, F0DLs increased with increasing N, but the increase started at a lower value of N for F0 = 200 Hz than for F0 = 50 or 100 Hz, the opposite of what would be expected if the dominant region corresponds to resolved harmonics. When the component levels followed an equal-loudness contour, F0DLs for F0 = 50 Hz were lowest for N = 1, but overall performance was much worse than for equal-level components, suggesting that the lowest harmonics were masking information from the higher harmonics. PMID- 23927119 TI - Across-frequency envelope correlation discrimination and masked signal detection. AB - This study compared the dependence of comodulation masking release (CMR) and monaural envelope correlation perception (MECP) on the degree of envelope correlation for the same narrowband noise stimuli. Envelope correlation across noise bands was systematically varied by mixing independent bands with a base set of comodulated bands. The magnitude of CMR fell monotonically with reductions in envelope correlation, and CMR varied over a range of envelope correlations that were not discriminable from each other in the MECP paradigm. For complexes of 100 Hz-wide noise bands, discrimination thresholds in the MECP task were similar whether the standard was a comodulated set of noise bands or a completely independent set of noise bands. This was not the case for 25-Hz-wide noise bands. Although the data demonstrate that CMR and MECP exhibit different dependencies on the degree of envelope correlation, some commonality across the two phenomena was observed. Specifically, for 25-Hz-wide bands of noise, there was a robust relationship between individual listeners' sensitivity to decorrelation from an otherwise comodulated set of noise bands and the magnitude of CMR measured for those same comodulated noise bands. PMID- 23927121 TI - The effect of interaural-level-difference fluctuations on the externalization of sound. AB - Real-world sound sources are usually perceived as externalized and thus properly localized in both direction and distance. This is largely due to (1) the acoustic filtering by the head, torso, and pinna, resulting in modifications of the signal spectrum and thereby a frequency-dependent shaping of interaural cues and (2) interaural cues provided by the reverberation inside an enclosed space. This study first investigated the effect of room reverberation on the spectro-temporal behavior of interaural level differences (ILDs) by analyzing dummy-head recordings of speech played at different distances in a standard listening room. Next, the effect of ILD fluctuations on the degree of externalization was investigated in a psychoacoustic experiment performed in the same listening room. Individual binaural impulse responses were used to simulate a distant sound source delivered via headphones. The ILDs were altered using a gammatone filterbank for analysis and resynthesis, where the envelopes of the left and right-ear signals were modified such that the naturally occurring fluctuations of the ILDs were restricted. This manipulation reduced the perceived degree of externalization. This was consistent with the analysis of short-term ILDs at different distances showing that a decreased distance to the sound source also reduced the ILD fluctuations. PMID- 23927120 TI - Perceiving sequential dependencies in auditory streams. AB - This study examined the ability of human listeners to detect the presence and judge the strength of a statistical dependency among the elements comprising sequences of sounds. The statistical dependency was imposed by specifying transition matrices that determined the likelihood of occurrence of the sound elements. Markov chains were constructed from these transition matrices having states that were pure tones/noise bursts that varied along the stimulus dimensions of frequency and/or interaural time difference. Listeners reliably detected the presence of a statistical dependency in sequences of sounds varying along these stimulus dimensions. Furthermore, listeners were able to discriminate the relative strength of the dependency in pairs of successive sound sequences. Random variation along an irrelevant stimulus dimension had small but significant adverse effects on performance. A much greater decrement in performance was found when the sound sequences were concurrent. Likelihood ratios were computed based on the transition matrices to specify Ideal Observer performance for the experimental conditions. Preliminary modeling efforts were made based on degradations of Ideal Observer performance intended to represent human observer limitations. This experimental approach appears to be useful for examining auditory "stream" formation and maintenance over time based on the predictability of the constituent sound elements. PMID- 23927122 TI - Temporal weighting functions for interaural time and level differences. III. Temporal weighting for lateral position judgments. AB - Temporal variation in listeners' sensitivity to interaural time and level differences (ITD and ILD) was assessed using the temporal weighting function (TWF) paradigm [Stecker and Hafter (2002). J. Acoust. Soc. Am. 112, 1046-1057] in the context of sound-source lateralization. Brief Gabor click trains were presented over headphones with overall ITD and/or ILD ranging +/-500 MUs ITD and/or +/-5 dB ILD across trials; values for individual clicks within each train varied by an additional +/-100 MUs or +/-2 dB to allow TWF calculation by multiple regression. In separate conditions, TWFs were measured for (i) ITD alone, (ii) ILD alone, (iii) ITD and ILD covarying ("in agreement"), and (iv) ITD and ILD varying independently across clicks. Consistent with past studies that measured TWF for binaural discrimination, TWFs demonstrated high weight on the first click for stimuli with short interclick interval (ICI = 2 ms), but flatter weighting for longer ICI (5-10 ms). Some conditions additionally demonstrated greater weight for clicks near the offset than near the middle of the train [Stecker and Hafter (2009). J. Acoust. Soc. Am. 125, 3914-3924]. The latter result was observed only when stimuli carried ILD, and appeared more reliably for 5 ms than for 2 or 10 ms ICI. PMID- 23927123 TI - Viscous effects in a static physical model of the uniform glottis. AB - The classic work on laryngeal flow resistance by van den Berg et al. [J. Acoust. Soc. Am. 29, 626-631 (1957)] is revisited. These authors used a formula to summarize their measurements, and thus they separated the effects of entrance loss and pressure recovery from those of viscosity within the glottis. Analysis of intraglottal pressure distributions obtained from the physical model M5 [R. Scherer et al., J. Acoust. Soc. Am. 109, 1616-1630 (2001)] reveals substantial regions within the glottis where the pressure gradient is almost constant for glottal diameters from 0.005 to 0.16 cm, as expected when viscous effects dominate the flow resistance of a narrow channel. For this set of glottal diameters, the part of the pressure gradient that has a linear dependence on the glottal volume velocity is isolated. The inverse cube diameter of the Poiseuille expression for glottal flows is examined with the data set provided by the M5 intraglottal pressure distributions. The Poiseuille effect is found to give a reasonable account of viscous effects in the diameter interval from 0.0075 to 0.02 cm, but an inverse 2.59 power law gives a closer fit across all diameters. PMID- 23927124 TI - Material and shape optimization for multi-layered vocal fold models using transient loadings. AB - Commonly applied models to study vocal fold vibrations in combination with air flow distributions are self-sustained physical models of the larynx consisting of artificial silicone vocal folds. Choosing appropriate mechanical parameters and layer geometries for these vocal fold models while considering simplifications due to manufacturing restrictions is difficult but crucial for achieving realistic behavior. In earlier work by Schmidt et al. [J. Acoust. Soc. Am. 129, 2168-2180 (2011)], the authors presented an approach in which material parameters of a static numerical vocal fold model were optimized to achieve an agreement of the displacement field with data retrieved from hemilarynx experiments. This method is now generalized to a fully transient setting. Moreover in addition to the material parameters, the extended approach is capable of finding optimized layer geometries. Depending on chosen material restriction, significant modifications of the reference geometry are predicted. The additional flexibility in the design space leads to a significantly more realistic deformation behavior. At the same time, the predicted biomechanical and geometrical results are still feasible for manufacturing physical vocal fold models consisting of several silicone layers. As a consequence, the proposed combined experimental and numerical method is suited to guide the construction of physical vocal fold models. PMID- 23927126 TI - Phonological theory informs the analysis of intonational exaggeration in Japanese infant-directed speech. AB - To date, the intonation of infant-directed speech (IDS) has been analyzed without reference to its phonological structure. Intonational phonology should, however, inform IDS research, discovering important properties that have previously been overlooked. The present study investigated "intonational exaggeration" in Japanese IDS using the intonational phonological framework. Although intonational exaggeration, which is most often measured by pitch-range expansion, is one of the best-known characteristics of IDS, Japanese has been reported to lack such exaggeration. The present results demonstrated that intonational exaggeration is in fact present and observed most notably at the location of boundary pitch movements, and that the effects of lexical pitch accents in the remainder of the utterances superficially mask the exaggeration. These results not only reveal dynamic aspects of Japanese IDS, but also in turn contribute to the theory of intonational phonology, suggesting that paralinguistic pitch-range modifications most clearly emerge where the intonation system of a language allows maximum flexibility in varying intonational contours. PMID- 23927125 TI - The coarticulation/invariance scale: mutual information as a measure of coarticulation resistance, motor synergy, and articulatory invariance. AB - Coarticulation and invariance are two topics at the center of theorizing about speech production and speech perception. In this paper, a quantitative scale is proposed that places coarticulation and invariance at the two ends of the scale. This scale is based on physical information flow in the articulatory signal, and uses Information Theory, especially the concept of mutual information, to quantify these central concepts of speech research. Mutual Information measures the amount of physical information shared across phonological units. In the proposed quantitative scale, coarticulation corresponds to greater and invariance to lesser information sharing. The measurement scale is tested by data from three languages: German, Catalan, and English. The relation between the proposed scale and several existing theories of coarticulation is discussed, and implications for existing theories of speech production and perception are presented. PMID- 23927127 TI - Formant frequency estimation of high-pitched vowels using weighted linear prediction. AB - All-pole modeling is a widely used formant estimation method, but its performance is known to deteriorate for high-pitched voices. In order to address this problem, several all-pole modeling methods robust to fundamental frequency have been proposed. This study compares five such previously known methods and introduces a technique, Weighted Linear Prediction with Attenuated Main Excitation (WLP-AME). WLP-AME utilizes temporally weighted linear prediction (LP) in which the square of the prediction error is multiplied by a given parametric weighting function. The weighting downgrades the contribution of the main excitation of the vocal tract in optimizing the filter coefficients. Consequently, the resulting all-pole model is affected more by the characteristics of the vocal tract leading to less biased formant estimates. By using synthetic vowels created with a physical modeling approach, the results showed that WLP-AME yields improved formant frequencies for high-pitched sounds in comparison to the previously known methods (e.g., relative error in the first formant of the vowel [a] decreased from 11% to 3% when conventional LP was replaced with WLP-AME). Experiments conducted on natural vowels indicate that the formants detected by WLP-AME changed in a more regular manner between repetitions of different pitch than those computed by conventional LP. PMID- 23927129 TI - High stimulus variability in nonnative speech learning supports formation of abstract categories: evidence from Japanese geminates. AB - This study reports effects of a high-variability training procedure on nonnative learning of a Japanese geminate-singleton fricative contrast. Thirty native speakers of Dutch took part in a 5-day training procedure in which they identified geminate and singleton variants of the Japanese fricative /s/. Participants were trained with either many repetitions of a limited set of words recorded by a single speaker (low-variability training) or with fewer repetitions of a more variable set of words recorded by multiple speakers (high-variability training). Both types of training enhanced identification of speech but not of nonspeech materials, indicating that learning was domain specific. High variability training led to superior performance in identification but not in discrimination tests, and supported better generalization of learning as shown by transfer from the trained fricatives to the identification of untrained stops and affricates. Variability thus helps nonnative listeners to form abstract categories rather than to enhance early acoustic analysis. PMID- 23927128 TI - The role of vowel perceptual cues in compensatory responses to perturbations of speech auditory feedback. AB - The perturbation of acoustic features in a speaker's auditory feedback elicits rapid compensatory responses that demonstrate the importance of auditory feedback for control of speech output. The current study investigated whether responses to a perturbation of speech auditory feedback vary depending on the importance of the perturbed feature to perception of the vowel being produced. Auditory feedback of speakers' first formant frequency (F1) was shifted upward by 130 mels in randomly selected trials during the speakers' production of consonant-vowel consonant words containing either the vowel /Lambda/ or the vowel /?/. Although these vowels exhibit comparable F1 frequencies, the contribution of F1 to perception of /Lambda/ is greater than its contribution to perception of /?/. Compensation to the F1 perturbation was observed during production of both vowels, but compensatory responses during /Lambda/ occurred at significantly shorter latencies and exhibited significantly larger magnitudes than compensatory responses during /?/. The finding that perturbation of vowel F1 during /Lambda/ and /?/ yielded compensatory differences that mirrored the contributions of F1 to perception of these vowels indicates that some portion of feedback control is weighted toward monitoring and preservation of acoustic cues for speech perception. PMID- 23927130 TI - Automatic pronunciation error detection in non-native speech: the case of vowel errors in Dutch. AB - This research is aimed at analyzing and improving automatic pronunciation error detection in a second language. Dutch vowels spoken by adult non-native learners of Dutch are used as a test case. A first study on Dutch pronunciation by L2 learners with different L1s revealed that vowel pronunciation errors are relatively frequent and often concern subtle acoustic differences between the realization and the target sound. In a second study automatic pronunciation error detection experiments were conducted to compare existing measures to a metric that takes account of the error patterns observed to capture relevant acoustic differences. The results of the two studies do indeed show that error patterns bear information that can be usefully employed in weighted automatic measures of pronunciation quality. In addition, it appears that combining such a weighted metric with existing measures improves the equal error rate by 6.1 percentage points from 0.297, for the Goodness of Pronunciation (GOP) algorithm, to 0.236. PMID- 23927131 TI - Simulating the effect of interaural mismatch in the insertion depth of bilateral cochlear implants on speech perception. AB - A bilateral advantage for diotically presented stimuli has been observed for cochlear implant (CI) users and is suggested to be dependent on symmetrical implant performance. Studies using CI simulations have not shown a true "bilateral" advantage, but a "better ear" effect and have demonstrated that performance decreases with increasing basalward shift in insertion depth. This study aimed to determine whether there is a bilateral advantage for CI simulations with interaurally matched insertions and the extent to which performance is affected by interaural insertion depth mismatch. Speech perception in noise and self-reported ease of listening were measured using matched bilateral, mismatched bilateral and unilateral CI simulations over four insertion depths for seventeen normal hearing listeners. Speech scores and ease of listening reduced with increasing basalward shift in (interaurally matched) insertion depth. A bilateral advantage for speech perception was only observed when the insertion depths were interaurally matched and deep. No advantage was observed for small to moderate interaural insertion-depth mismatches, consistent with a better ear effect. Finally, both measures were poorer than expected for a better ear effect for large mismatches, suggesting that misalignment of the electrode arrays may prevent a bilateral advantage and detrimentally affect perception of diotically presented speech. PMID- 23927132 TI - Vocabulary influences older and younger listeners' processing of dysarthric speech. AB - This study examined younger (n = 16) and older (n = 16) listeners' processing of dysarthric speech-a naturally occurring form of signal degradation. It aimed to determine how age, hearing acuity, memory, and vocabulary knowledge interacted in speech recognition and lexical segmentation. Listener transcripts were coded for accuracy and pattern of lexical boundary errors. For younger listeners, transcription accuracy was predicted by receptive vocabulary. For older listeners, this same effect existed but was moderated by pure-tone hearing thresholds. While both groups employed syllabic stress cues to inform lexical segmentation, older listeners were less reliant on this perceptual strategy. The results were interpreted to suggest that individuals with larger receptive vocabularies, with their presumed greater language familiarity, were better able to leverage cue redundancies within the speech signal to form lexical hypothesis leading to an improved ability to comprehend dysarthric speech. This advantage was minimized as hearing thresholds increased. While the differing levels of reliance on stress cues across the listener groups could not be attributed to specific individual differences, it was hypothesized that some combination of larger vocabularies and reduced hearing thresholds in the older participant group led to them prioritize lexical cues as a segmentation frame. PMID- 23927133 TI - Adaptation to spectrally-rotated speech. AB - Much recent interest surrounds listeners' abilities to adapt to various transformations that distort speech. An extreme example is spectral rotation, in which the spectrum of low-pass filtered speech is inverted around a center frequency (2 kHz here). Spectral shape and its dynamics are completely altered, rendering speech virtually unintelligible initially. However, intonation, rhythm, and contrasts in periodicity and aperiodicity are largely unaffected. Four normal hearing adults underwent 6 h of training with spectrally-rotated speech using Continuous Discourse Tracking. They and an untrained control group completed pre- and post-training speech perception tests, for which talkers differed from the training talker. Significantly improved recognition of spectrally-rotated sentences was observed for trained, but not untrained, participants. However, there were no significant improvements in the identification of medial vowels in /bVd/ syllables or intervocalic consonants. Additional tests were performed with speech materials manipulated so as to isolate the contribution of various speech features. These showed that preserving intonational contrasts did not contribute to the comprehension of spectrally-rotated speech after training, and suggested that improvements involved adaptation to altered spectral shape and dynamics, rather than just learning to focus on speech features relatively unaffected by the transformation. PMID- 23927134 TI - Spatio-temporal articulatory movement primitives during speech production: extraction, interpretation, and validation. AB - This paper presents a computational approach to derive interpretable movement primitives from speech articulation data. It puts forth a convolutive Nonnegative Matrix Factorization algorithm with sparseness constraints (cNMFsc) to decompose a given data matrix into a set of spatiotemporal basis sequences and an activation matrix. The algorithm optimizes a cost function that trades off the mismatch between the proposed model and the input data against the number of primitives that are active at any given instant. The method is applied to both measured articulatory data obtained through electromagnetic articulography as well as synthetic data generated using an articulatory synthesizer. The paper then describes how to evaluate the algorithm performance quantitatively and further performs a qualitative assessment of the algorithm's ability to recover compositional structure from data. This is done using pseudo ground-truth primitives generated by the articulatory synthesizer based on an Articulatory Phonology frame-work [Browman and Goldstein (1995). "Dynamics and articulatory phonology," in Mind as motion: Explorations in the dynamics of cognition, edited by R. F. Port and T.van Gelder (MIT Press, Cambridge, MA), pp. 175-194]. The results suggest that the proposed algorithm extracts movement primitives from human speech production data that are linguistically interpretable. Such a framework might aid the understanding of longstanding issues in speech production such as motor control and coarticulation. PMID- 23927135 TI - Wave separation in the trumpet under playing conditions and comparison with time domain finite difference simulation. AB - Wave separation within a trumpet is presented using three high pressure microphones to measure pressure waves within the curved, constant cross-section tuning slide of the instrument while the instrument was being played by a virtuoso trumpet player. A closer inter-microphone spacing was possible in comparison to previous work through the use of time domain windowing on non causal transfer functions and performing wave separation in the frequency domain. Time domain plots of the experimental wave separation were then compared to simulations using a physical model based on a time domain finite difference simulation of the trumpet bore coupled to a one mass, two degree of freedom lip model. The time domain and frequency spectra of the measured and synthesized sounds showed a similar profile, with the sound produced by the player showing broader spectral peaks in experimental data. Using a quality factor of 5 for the lip model was found to give greater agreement between the simulated and experimental starting transients in comparison to the values in the range 1-3 often assumed. Deviations in the spectral content and wave shape provide insights into the areas where future research may be directed in improving the accuracy of physical modeling synthesis. PMID- 23927136 TI - Pitch- and spectral-based dynamic time warping methods for comparing field recordings of harmonic avian vocalizations. AB - Quantitative measures of acoustic similarity can reveal patterns of shared vocal behavior in social species. Many methods for computing similarity have been developed, but their performance has not been extensively characterized in noisy environments and with vocalizations characterized by complex frequency modulations. This paper describes methods of bioacoustic comparison based on dynamic time warping (DTW) of the fundamental frequency or spectrogram. Fundamental frequency is estimated using a Bayesian particle filter adaptation of harmonic template matching. The methods were tested on field recordings of flight calls from superb starlings, Lamprotornis superbus, for how well they could separate distinct categories of call elements (motifs). The fundamental-frequency based method performed best, but the spectrogram-based method was less sensitive to noise. Both DTW methods provided better separation of categories than spectrographic cross correlation, likely due to substantial variability in the duration of superb starling flight call motifs. PMID- 23927137 TI - Surfactant shedding and gas diffusion during pulsed ultrasound through a microbubble contrast agent suspension. AB - Interest in coated microbubbles as agents for therapeutic and quantitative imaging applications in biomedical ultrasound has increased the need for their accurate theoretical characterization. Effects such as gas diffusion, variation in the properties of the coating and the resulting changes in bubble behavior under repeated exposure to ultrasound pulses are, however, still not well understood. In this study, a revised equation for microbubble motion is proposed that includes the effects of gas diffusion, as well as adsorption, desorption and shedding of a surfactant from the bubble surface. This is incorporated into a nonlinear wave propagation model to account for these additional time dependent effects in the response of microbubble populations. The results from the model indicate there can be significant changes in both bubble behavior and the propagated pulse over time. This is in agreement with existing experimental data but is not predicted by existing propagation models. The analysis indicates that changes in bubble dynamics are dominated by surfactant shedding on the timescale of a diagnostic ultrasound pulse and gas diffusion over the timescale of the pulse repetition frequency. The implications of these results for the development of more accurate algorithms for quantitative imaging and for therapeutic applications are discussed. PMID- 23927183 TI - Introduction to the special issue on therapeutic ultrasound. PMID- 23927184 TI - Computation of nonlinear ultrasound fields using a linearized contrast source method. AB - Nonlinear ultrasound is important in medical diagnostics because imaging of the higher harmonics improves resolution and reduces scattering artifacts. Second harmonic imaging is currently standard, and higher harmonic imaging is under investigation. The efficient development of novel imaging modalities and equipment requires accurate simulations of nonlinear wave fields in large volumes of realistic (lossy, inhomogeneous) media. The Iterative Nonlinear Contrast Source (INCS) method has been developed to deal with spatiotemporal domains measuring hundreds of wavelengths and periods. This full wave method considers the nonlinear term of the Westervelt equation as a nonlinear contrast source, and solves the equivalent integral equation via the Neumann iterative solution. Recently, the method has been extended with a contrast source that accounts for spatially varying attenuation. The current paper addresses the problem that the Neumann iterative solution converges badly for strong contrast sources. The remedy is linearization of the nonlinear contrast source, combined with application of more advanced methods for solving the resulting integral equation. Numerical results show that linearization in combination with a Bi-Conjugate Gradient Stabilized method allows the INCS method to deal with fairly strong, inhomogeneous attenuation, while the error due to the linearization can be eliminated by restarting the iterative scheme. PMID- 23927185 TI - Model for the dynamics of a spherical bubble undergoing small shape oscillations between parallel soft elastic layers. AB - A model is developed for a pulsating and translating gas bubble immersed in liquid in a channel formed by two soft, thin elastic parallel layers having densities equal to that of the surrounding liquid and small, but finite, shear moduli. The bubble is nominally spherical but free to undergo small shape deformations. Shear strain in the elastic layers is estimated in a way which is valid for short, transient excitations of the system. Coupled nonlinear second order differential equations are obtained for the shape and position of the bubble, and numerical integration of an expression for the liquid velocity at the layer interfaces yields an estimate of the elastic layer displacement. Numerical integration of the dynamical equations reveals behavior consistent with laboratory observations of acoustically excited bubbles in ex vivo vessels reported by Chen et al. [Phys. Rev. Lett. 106, 034301 (2011) and Ultrasound Med. Biol. 37, 2139-2148 (2011)]. PMID- 23927186 TI - Nonlinear focal shift beyond the geometrical focus in moderately focused acoustic beams. AB - The phenomenon of the displacement of the position along the axis of the pressure, intensity, and radiation force maxima of focused acoustic beams under increasing driving voltages (nonlinear focal shift) is studied for the case of a moderately focused beam. The theoretical and experimental results show the existence of this shift along the axis when the initial pressure in the transducer increases until the acoustic field reaches the fully developed nonlinear regime of propagation. Experimental data show that at high amplitudes and for moderate focusing, the position of the on-axis pressure maximum and radiation force maximum can surpass the geometrical focal length. On the contrary, the on-axis pressure minimum approaches the transducer under increasing driving voltages, increasing the distance between the positive and negative peak pressure in the beam. These results are in agreement with numerical KZK model predictions and the existed data of other authors and can be explained according to the effect of self-refraction characteristic of the nonlinear regime of propagation. PMID- 23927187 TI - Phase-shift perfluorocarbon agents enhance high intensity focused ultrasound thermal delivery with reduced near-field heating. AB - Ultrasound contrast agents are known to enhance high intensity focused ultrasound (HIFU) ablation, but these perfluorocarbon microbubbles are limited to the vasculature, have a short half-life in vivo, and may result in unintended heating away from the target site. Herein, a nano-sized (100-300 nm), dual perfluorocarbon (decafluorobutane/dodecafluoropentane) droplet that is stable, is sufficiently small to extravasate, and is convertible to micron-sized bubbles upon acoustic activation was investigated. Microbubbles and nanodroplets were incorporated into tissue-mimicking acrylamide-albumin phantoms. Microbubbles or nanodroplets at 0.1 * 10(6) per cm(3) resulted in mean lesion volumes of 80.4 +/- 33.1 mm(3) and 52.8 +/- 14.2 mm(3) (mean +/- s.e.), respectively, after 20 s of continuous 1 MHz HIFU at a peak negative pressure of 4 MPa, compared to a lesion volume of 1.0 +/- 0.8 mm(3) in agent-free control phantoms. Magnetic resonance thermometry mapping during HIFU confirmed undesired surface heating in phantoms containing microbubbles, whereas heating occurred at the acoustic focus of phantoms containing the nanodroplets. Maximal change in temperature at the target site was enhanced by 16.9% and 37.0% by microbubbles and nanodroplets, respectively. This perfluorocarbon nanodroplet has the potential to reduce the time to ablate tumors by one-third during focused ultrasound surgery while also safely enhancing thermal deposition at the target site. PMID- 23927188 TI - Spatial patterning of endothelial cells and vascular network formation using ultrasound standing wave fields. AB - The spatial organization of cells is essential for proper tissue assembly and organ function. Thus, successful engineering of complex tissues and organs requires methods to control cell organization in three dimensions. In particular, technologies that facilitate endothelial cell alignment and vascular network formation in three-dimensional tissue constructs would provide a means to supply essential oxygen and nutrients to newly forming tissue. Acoustic radiation forces associated with ultrasound standing wave fields can rapidly and non-invasively organize cells into distinct multicellular planar bands within three-dimensional collagen gels. Results presented herein demonstrate that the spatial pattern of endothelial cells within three-dimensional collagen gels can be controlled by design of acoustic parameters of the sound field. Different ultrasound standing wave field exposure parameters were used to organize endothelial cells into either loosely aggregated or densely packed planar bands. The rate of vessel formation and the morphology of the resulting endothelial cell networks were affected by the initial density of the ultrasound-induced planar bands of cells. Ultrasound standing wave fields provide a rapid, non-invasive approach to pattern cells in three-dimensions and direct vascular network formation and morphology within engineered tissue constructs. PMID- 23927189 TI - Controlling collagen fiber microstructure in three-dimensional hydrogels using ultrasound. AB - Type I collagen is the primary fibrillar component of the extracellular matrix, and functional properties of collagen arise from variations in fiber structure. This study investigated the ability of ultrasound to control collagen microstructure during hydrogel fabrication. Under appropriate conditions, ultrasound exposure of type I collagen during polymerization altered fiber microstructure. Scanning electron microscopy and second-harmonic generation microscopy revealed decreased collagen fiber diameters in response to ultrasound compared to sham-exposed samples. Results of mechanistic investigations were consistent with a thermal mechanism for the effects of ultrasound on collagen fiber structure. To control collagen microstructure site-specifically, a high frequency, 8.3-MHz, ultrasound beam was directed within the center of a large collagen sample producing dense networks of short, thin collagen fibrils within the central core of the gel and longer, thicker fibers outside the beam area. Fibroblasts seeded onto these gels migrated rapidly into small, circularly arranged aggregates only within the beam area, and clustered fibroblasts remodeled the central, ultrasound-exposed collagen fibrils into dense sheets. These investigations demonstrate the capability of ultrasound to spatially pattern various collagen microstructures within an engineered tissue noninvasively, thus enhancing the level of complexity of extracellular matrix microenvironments and cellular functions achievable within three-dimensional engineered tissues. PMID- 23927190 TI - Transcostal high-intensity focused ultrasound treatment using phased array with geometric correction. AB - In the high-intensity focused ultrasound treatment of liver tumors, ultrasound propagation is affected by the rib cage. Because of the diffraction and absorption of the bone, the sound distribution at the focal plane is altered, and more importantly, overheating on the rib surface might occur. To overcome these problems, a geometric correction method is applied to turn off the elements blocked by the ribs. The potential of steering the focus of the phased-array along the propagation direction to improve the transcostal treatment was investigated by simulations and experiments using different rib models and transducers. The ultrasound propagation through the ribs was computed by a hybrid method including the Rayleigh-Sommerfeld integral, k-space method, and angular spectrum method. A modified correction method was proposed to adjust the output of elements based on their relative area in the projected "shadow" of the ribs. The simulation results showed that an increase in the specific absorption rate gain up to 300% was obtained by varying the focal length although the optimal value varied in each situation. Therefore, acoustic simulation is required for each clinical case to determine a satisfactory treatment plan. PMID- 23927191 TI - High-speed observation of bubble cloud generation near a rigid wall by second harmonic superimposed ultrasound. AB - Cavitation bubbles are known to accelerate therapeutic effects of ultrasound. Although negative acoustic pressure is the principle factor of cavitation, positive acoustic pressure has a role for bubble cloud formation at a high intensity of focused ultrasound when cavitation bubbles provide pressure release surfaces converting the pressure from highly positive to negative. In this study, the second-harmonic was superimposed onto the fundamental acoustic pressure to emphasize either peak positive or negative pressure. The peak negative and positive pressure emphasized waves were focused on a surface of an aluminum block. Cavitation bubbles induced near the block were observed with a high-speed camera by backlight and the size of the cavitation generation region was measured from the high-speed images. The negative pressure emphasized waves showed an advantage in cavitation inception over the positive pressure emphasized waves. In the sequence of the negative pressure emphasized waves immediately followed by the positive pressure emphasized waves, cavitation bubbles were generated on the block by the former waves and the cavitation region were expanded toward the transducer in the latter waves with high reproducibility. The sequence demonstrated its potential usefulness in enhancing the effects of therapeutic ultrasound at a high acoustic intensity. PMID- 23927192 TI - Rapid ultrasonic stimulation of inflamed tissue with diagnostic intent. AB - Previous studies have observed that individual pulses of intense focused ultrasound (iFU) applied to inflamed and normal tissue can generate sensations, where inflamed tissue responds at a lower intensity than normal tissue. It was hypothesized that successively applied iFU pulses will generate sensation in inflamed tissue at a lower intensity and dose than application of a single iFU pulse. This hypothesis was tested using an animal model of chronic inflammatory pain, created by injecting an irritant into the rat hind paw. Ultrasound pulses were applied in rapid succession or individually to rats' rear paws beginning at low peak intensities and progressing to higher peak intensities, until the rats withdrew their paws immediately after iFU application. Focused ultrasound protocols consisting of successively and rapidly applied pulses elicited inflamed paw withdrawal at lower intensity and estimated tissue displacement values than single pulse protocols. However, both successively applied pulses and single pulses produced comparable threshold acoustic dose values and estimates of temperature increases. This raises the possibility that temperature increase contributed to paw withdrawal after rapid iFU stimulation. While iFU-induction of temporal summation may also play a role, electrophysiological studies are necessary to tease out these potential contributors to iFU stimulation. PMID- 23927193 TI - Ultrasound thermal mapping based on a hybrid method combining cross-correlation and zero-crossing tracking. AB - A hybrid method for estimating temperature with spatial mapping using diagnostic ultrasound, based on detection of echo shifts from tissue undergoing thermal treatment, is proposed. Cross-correlation and zero-crossing tracking are two conventional algorithms used for detecting echo shifts, but their practical applications are limited. The proposed hybrid method combines the advantages of both algorithms with improved accuracy in temperature estimation. In vitro experiments were performed on porcine muscle for preliminary validation and temperature calibration. In addition, thermal mapping of rabbit thigh muscle in vivo during high-intensity focused ultrasound heating was conducted. Results from the in vitro experiments indicated that the difference between the estimated temperature change by the proposed hybrid method and the actual temperature change measured by the thermocouple was generally less than 1 degrees C when the increase in temperature due to heating was less than 10 degrees C. For the in vivo study, the area predicted to experience the highest temperature coincided well with the focal point of the high-intensity focused ultrasound transducer. The computational efficiency of the hybrid algorithm was similar to that of the fast cross-correlation algorithm, but with an improved accuracy. The proposed hybrid method could provide an alternative means for non-invasive monitoring of limited temperature changes during hyperthermia therapy. PMID- 23927194 TI - Low-frequency (<100 kHz), low-intensity (<100 mW/cm(2)) ultrasound to treat venous ulcers: a human study and in vitro experiments. AB - The purpose of this study was to examine whether low frequency (<100 kHz), low intensity (<100 mW/cm(2), spatial peak temporal peak) ultrasound can be an effective treatment of venous stasis ulcers, which affect 500 000 patients annually costing over $1 billion per year. Twenty subjects were treated with either 20 or 100 kHz ultrasound for between 15 and 45 min per session for a maximum of four treatments. Healing was monitored by changes in wound area. Additionally, two in vitro studies were conducted using fibroblasts exposed to 20 kHz ultrasound to confirm the ultrasound's effects on proliferation and cellular metabolism. Subjects receiving 20 kHz ultrasound for 15 min showed statistically faster (p < 0.03) rate of wound closure. All five of these subjects fully healed by the fourth treatment session. The in vitro results indicated that 20 kHz ultrasound at 100 mW/cm(2) caused an average of 32% increased metabolism (p < 0.05) and 40% increased cell proliferation (p < 0.01) after 24 h when compared to the control, non-treated cells. Although statistically limited, this work supports the notion that low-intensity, low-frequency ultrasound is beneficial for treating venous ulcers. PMID- 23927195 TI - A heuristic model of stone comminution in shock wave lithotripsy. AB - A heuristic model is presented to describe the overall progression of stone comminution in shock wave lithotripsy (SWL), accounting for the effects of shock wave dose and the average peak pressure, P+(avg), incident on the stone during the treatment. The model is developed through adaptation of the Weibull theory for brittle fracture, incorporating threshold values in dose and P+(avg) that are required to initiate fragmentation. The model is validated against experimental data of stone comminution from two stone types (hard and soft BegoStone) obtained at various positions in lithotripter fields produced by two shock wave sources of different beam width and pulse profile both in water and in 1,3-butanediol (which suppresses cavitation). Subsequently, the model is used to assess the performance of a newly developed acoustic lens for electromagnetic lithotripters in comparison with its original counterpart both under static and simulated respiratory motion. The results have demonstrated the predictive value of this heuristic model in elucidating the physical basis for improved performance of the new lens. The model also provides a rationale for the selection of SWL treatment protocols to achieve effective stone comminution without elevating the risk of tissue injury. PMID- 23927196 TI - Assessment of high-intensity focused ultrasound treatment of rodent mammary tumors using ultrasound backscatter coefficients. AB - Fischer 344 rats with subcutaneous mammary adenocarcinoma tumors were exposed to therapeutic ultrasound at one of three exposure levels (335, 360, and 502 W/cm(2) spatial-peak temporal-average intensity). Quantitative ultrasound estimates were generated from ultrasound radio frequency (RF) data from tumors before and after high-intensity focused ultrasound treatment. Treatment outcome was independently assessed by triphenyl tetrazolium chloride (TTC) staining, histological analysis by a pathologist, and thermocouple data. The average backscatter coefficient (BSC) and integrated backscatter coefficient (IBSC) were estimated before and after therapeutic ultrasound exposure for each tumor from RF data collected using clinical (Ultrasonix Sonix RP) and small-animal (Visualsonics Vevo 2100) array systems. Changes in the BSC with treatment were comparable to inter-sample variation of untreated tumors, but statistically significant differences in the change in the IBSCs were observed when comparing the exposures collectively (p < 0.10 for Sonix RP, p < 0.05 for Vevo 2100). Several exposure levels produced statistically significant differences in the change in IBSC when examined pair wise, including two exposures having similar intensities (p < 0.05, Vevo 2100). A comparison of the IBSC results with temperature data, histology, and TTC staining revealed that the BSC was not always sensitive to thermal insult and that peak exposure pressure appeared to correlate with observed BSC increases. PMID- 23927197 TI - Time-reversal acoustics and ultrasound-assisted convection-enhanced drug delivery to the brain. AB - Time-reversal acoustics is an effective way of focusing ultrasound deep inside heterogeneous media such as biological tissues. Convection-enhanced delivery is a method of delivering drugs into the brain by infusing them directly into the brain interstitium. These two technologies are combined in a focusing system that uses a "smart needle" to simultaneously infuse fluid into the brain and provide the necessary feedback for focusing ultrasound using time-reversal acoustics. The effects of time-reversal acoustics-focused ultrasound on the spatial distribution of infused low- and high-molecular weight tracer molecules are examined in live, anesthetized rats. Results show that exposing the rat brain to focused ultrasound significantly increases the penetration of infused compounds into the brain. The addition of stabilized microbubbles enhances the effect of ultrasound exposure. PMID- 23927198 TI - Microbubble behavior in an ultrasound field for high intensity focused ultrasound therapy enhancement. AB - The enhancement of heating due to inertial cavitation has been focused to reduce the long treatment time of conventional high-intensity focused ultrasound (HIFU) therapy. The influences of the physical properties of surrounding tissues, initial void fraction, and spatial distribution of bubbles on microbubble enhanced HIFU are examined. A bubble dynamics equation based on the Keller-Miksis equation is employed in consideration of the elasticity of surrounding tissue. The mixture phase and bubbles are coupled by the Euler-Lagrange method to take into account the interaction between ultrasound and bubbles. As a result, the temperature around the target increases with the initial void fraction. But at the high void fraction of 10(-5), ultrasound is too attenuated to heat the target, and the heating region moves to the transducer side. On the other hand, both the viscosity and shear elasticity of the surrounding media reduce the attenuation of ultrasound propagation through the bubbly mixture. Numerical results show that localized heating is induced with increasing viscosity or shear elasticity, though it depends on the pressure amplitudes. In addition, it was numerically confirmed that the localization of the microbubble distribution is important to obtain efficient localized heating. PMID- 23927199 TI - Infrared mapping of ultrasound fields generated by medical transducers: feasibility of determining absolute intensity levels. AB - Considerable progress has been achieved in the use of infrared (IR) techniques for qualitative mapping of acoustic fields of high intensity focused ultrasound (HIFU) transducers. The authors have previously developed and demonstrated a method based on IR camera measurement of the temperature rise induced in an absorber less than 2 mm thick by ultrasonic bursts of less than 1 s duration. The goal of this paper was to make the method more quantitative and estimate the absolute intensity distributions by determining an overall calibration factor for the absorber and camera system. The implemented approach involved correlating the temperature rise measured in an absorber using an IR camera with the pressure distribution measured in water using a hydrophone. The measurements were conducted for two HIFU transducers and a flat physiotherapy transducer of 1 MHz frequency. Corresponding correction factors between the free field intensity and temperature were obtained and allowed the conversion of temperature images to intensity distributions. The system described here was able to map in good detail focused and unfocused ultrasound fields with sub-millimeter structure and with local time average intensity from below 0.1 W/cm(2) to at least 50 W/cm(2). Significantly higher intensities could be measured simply by reducing the duty cycle. PMID- 23927200 TI - Experimentally validated multiphysics computational model of focusing and shock wave formation in an electromagnetic lithotripter. AB - A multiphysics computational model of the focusing of an acoustic pulse and subsequent shock wave formation that occurs during extracorporeal shock wave lithotripsy is presented. In the electromagnetic lithotripter modeled in this work the focusing is achieved via a polystyrene acoustic lens. The transition of the acoustic pulse through the solid lens is modeled by the linear elasticity equations and the subsequent shock wave formation in water is modeled by the Euler equations with a Tait equation of state. Both sets of equations are solved simultaneously in subsets of a single computational domain within the BEARCLAW framework which uses a finite-volume Riemann solver approach. This model is first validated against experimental measurements with a standard (or original) lens design. The model is then used to successfully predict the effects of a lens modification in the form of an annular ring cut. A second model which includes a kidney stone simulant in the domain is also presented. Within the stone the linear elasticity equations incorporate a simple damage model. PMID- 23927201 TI - Ultrafast dynamics of the acoustic vaporization of phase-change microdroplets. AB - Acoustically sensitive emulsions are a promising tool for medical applications such as localized drug delivery. The physical mechanisms underlying the ultrasound-triggered nucleation and subsequent vaporization of these phase-change emulsions are largely unexplored. Here, the acoustic vaporization of individual micron-sized perfluoropentane (PFP) droplets is studied at a nanoseconds timescale. Highly diluted emulsions of PFP-in-water and oil-in-PFP-in-water droplets, ranging from 3.5 to 11 MUm in radius, were prepared and the nucleation and growth of the vapor bubbles was imaged at frame rates of up to 20 Mfps. The droplet vaporization dynamics was observed to have three distinct regimes: (1) prior to nucleation, a regime of droplet deformation and oscillatory translations within the surrounding fluid along the propagation direction of the applied ultrasound; (2) a regime characterized by the rapid growth of a vapor bubble enhanced by ultrasound-driven rectified heat transfer; and (3) a final phase characterized by a relatively slow expansion, after ultrasound stops, that is fully dominated by heat transfer. A method to measure the moment of inception of the nucleation event with respect to the phase of the ultrasound wave is proposed. A simple physical model captures quantitatively all of the features of the subsequent vapor bubble growth. PMID- 23927202 TI - Investigation on the inertial cavitation threshold and shell properties of commercialized ultrasound contrast agent microbubbles. AB - The inertial cavitation (IC) activity of ultrasound contrast agents (UCAs) plays an important role in the development and improvement of ultrasound diagnostic and therapeutic applications. However, various diagnostic and therapeutic applications have different requirements for IC characteristics. Here through IC dose quantifications based on passive cavitation detection, IC thresholds were measured for two commercialized UCAs, albumin-shelled KangRun((r)) and lipid shelled SonoVue((r)) microbubbles, at varied UCA volume concentrations (viz., 0.125 and 0.25 vol. %) and acoustic pulse lengths (viz., 5, 10, 20, 50, and 100 cycles). Shell elastic and viscous coefficients of UCAs were estimated by fitting measured acoustic attenuation spectra with Sarkar's model. The influences of sonication condition (viz., acoustic pulse length) and UCA shell properties on IC threshold were discussed based on numerical simulations. Both experimental measurements and numerical simulations indicate that IC thresholds of UCAs decrease with increasing UCA volume concentration and acoustic pulse length. The shell interfacial tension and dilatational viscosity estimated for SonoVue (0.7 +/- 0.11 N/m, 6.5 +/- 1.01 * 10(-8) kg/s) are smaller than those of KangRun (1.05 +/- 0.18 N/m, 1.66 +/- 0.38 * 10(-7) kg/s); this might result in lower IC threshold for SonoVue. The current results will be helpful for selecting and utilizing commercialized UCAs for specific clinical applications, while minimizing undesired IC-induced bioeffects. PMID- 23927203 TI - Non-invasive ultrasonic surgery of the brain in non-human primates. AB - High-intensity focused ultrasound causes selective tissue necrosis efficiently and safely, namely, in the prostate, liver, and uterine fibroid. Nevertheless, ablation of brain tissue using focused ultrasound remains limited due to strong aberrations induced by the skull. To achieve ultrasonic transcranial brain ablation, such aberrations have to be compensated. In this study, non-invasive therapy was performed on monkeys using adaptive correction of the therapeutic beam and 3D simulations of transcranial wave propagation based on 3D computed tomographic (CT) scan information. The aim of the study was two-fold: induce lesions in a non-human primate brain non-invasively and investigate the potential side effects. Stereotactic targeting was performed on five Macaca fascicularis individuals. Each hemisphere was treated separately with a 15-day interval and animals were sacrificed two days after the last treatment. The ultrasonic dose delivered at the focus was increased from one treatment location to the other to estimate the thermal dose for tissue alteration. Thermal doses in the brain were determined by numerical computations. Treatment efficiency and safety were evaluated histologically. The threshold for tissue damage in the brain was measured to be between 90 and 280 cumulative equivalent minutes at 43 degrees C. Intravenous injection of corticoids before the treatment limited the side effects. PMID- 23927204 TI - Control of inertial acoustic cavitation in pulsed sonication using a real-time feedback loop system. AB - Owing to the complex behavior of ultrasound-induced bubble clouds (nucleation, linear and nonlinear oscillations, collapse), acoustic cavitation remains a hardly controllable phenomenon, leading to poorly reproducible ultrasound-based therapies. A better control of the various aspects of cavitation phenomena for in vivo applications is a key requirement to improve emerging ultrasound therapies. Previous publications have reported on systems performing regulation of acoustic cavitation in continuous sonication when applied in vitro, but the main challenge today is to achieve real-time control of cavitation activity in pulsed sonication when used in vivo. The present work aims at developing a system to control acoustic cavitation in a pulsed wave condition using a real-time feedback loop. The experimental setup consists of a water bath in which is submerged a focused transducer (pulsed waves, frequency 550 kHz) used for sonication and a hydrophone used to listen to inertial cavitation. The designed regulation process allows the cavitation activity to be controlled through a 300 MUs feedback loop. Without regulation, cavitation exhibits numerous bursts of intense activity and large variations of inertial cavitation level over time. In a regulated regime, the control of inertial cavitation activity within a pulse leads to consistent cavitation levels over time with an enhancement of the reproducibility. PMID- 23927205 TI - A multi-element interstitial ultrasound applicator for the thermal therapy of brain tumors. AB - Interstitial thermal therapy is a minimally invasive treatment modality that has been used clinically for ablating both primary and secondary brain tumors. Here a multi-element interstitial ultrasound applicator is described that allows for increased spatial control during thermal ablation of tumors as compared to existing clinical devices. The device consists of an array of 56 ultrasound elements operating at 6 MHz, oriented on the seven faces of a 3.2 mm flexible catheter. The device was first characterized using the acoustic holography method to examine the functioning of the array. Then experiments were performed to measure heating in tissue-mimicking gel phantoms and ex vivo tissue samples using magnetic resonance imaging-based thermometry. Experimental measurements were compared with results obtained using numerical simulations. Last, simulations were performed to study the feasibility of using the device for thermal ablation in the brain. Experimental results show that the device can be used to induce a temperature rise of greater than 20 degrees C in ex vivo tissue samples and numerical simulations further demonstrate that tumors with diameters of greater than 30-mm could potentially be treated. PMID- 23927206 TI - Surface vibration and nearby cavitation of an ex vivo bovine femur exposed to high intensity focused ultrasound. AB - The acoustic pressure distribution, thermal ablation, and sonochemiluminescence (SCL) generated by cavitation near the surface of an ex vivo bovine femur were investigated at normal and oblique incidences of high intensity focused ultrasound (HIFU), as were the characteristics of bone surface vibrations. The acoustic pressure at the HIFU focus, the width of thermal ablation, and the SCL intensity in the pre-focal region were 1.3 MPa, 7 mm, and 454 electrons, respectively, in the control group at normal incidence, and they respectively increased to 1.5 MPa, 12 mm and 968 electrons in the presence of the bone. At oblique incidence from the left, the acoustic pressure at 3 mm to the right of the HIFU focus was 0.6 MPa and decreased to 0.4 MPa at 3 mm to the left of the focus. The thermal ablation was 20 mm in width and extended along the front surface of the bone to the right of the HIFU focus. The SCL intensity on the right of the HIFU focus was 394 electrons and was 362 electrons on the left. The presence of bone would directionally change the spatial distribution of acoustic pressure, thermal and cavitation effects for oblique incidence of HIFU. PMID- 23927208 TI - Cavitation microstreaming generated by a bubble pair in an ultrasound field. AB - An analytical theory has been developed to calculate the acoustic streaming velocity inside and outside bubbles for the case of a bubble pair suspended in an unbounded viscous liquid, taking into account the two predominant modes of a bubble pair: The volume and translation modes. It was demonstrated that the interaction between bubbles can affect the magnitude and direction of acoustic streaming, especially for tangential components outside of bubbles. The acoustic streaming intensifies as the radius of the neighboring bubble increases and is weakened as the distance between the bubbles increases. PMID- 23927207 TI - Acoustic field characterization of the Duolith: measurements and modeling of a clinical shock wave therapy device. AB - Extracorporeal shock wave therapy (ESWT) uses acoustic pulses to treat certain musculoskeletal disorders. In this paper the acoustic field of a clinical portable ESWT device (Duolith SD1) was characterized. Field mapping was performed in water for two different standoffs of the electromagnetic head (15 or 30 mm) using a fiber optic probe hydrophone. Peak positive pressures at the focus ranged from 2 to 45 MPa, while peak negative pressures ranged from -2 to -11 MPa. Pulse rise times ranged from 8 to 500 ns; shock formation did not occur for any machine settings. The maximum standard deviation in peak pressure at the focus was 1.2%, indicating that the Duolith SD1 generates stable pulses. The results compare qualitatively, but not quantitatively with manufacturer specifications. Simulations were carried out for the short standoff by matching a Khokhlov Zabolotskaya-Kuznetzov equation to the measured field at a plane near the source, and then propagating the wave outward. The results of modeling agree well with experimental data. The model was used to analyze the spatial structure of the peak pressures. Predictions from the model suggest that a true shock wave could be obtained in water if the initial pressure output of the device were doubled. PMID- 23927209 TI - Variations of bubble cavitation and temperature elevation during lesion formation by high-intensity focused ultrasound. AB - High-intensity focused ultrasound (HIFU) is emerging as an effective therapeutic modality in both thermal ablations for solid tumor/cancer and soft-tissue fragmentation. Mechanical and thermal effects, which play an important role in the HIFU treatment simultaneously, are dependent on the operating parameters and may vary with the progress of therapy. Mechanical erosion in the shape of a "squid," a "dumbbell" lesion with both mechanical and thermal lesions, or a "tadpole" lesion with mechanical erosion at the center and thermal necrosis on the boundary in the transparent gel phantom could be produced correspondingly with the pulse duration of 5-30 ms, which is much longer than histotripsy burst but shorter than the time for tissue boiling, and pulse repetition frequency (PRF) of 0.2-5 Hz. Meanwhile, variations of bubble cavitation (both inertial and stable cavitation) and temperature elevation in the focal region (i.e., z = -2.5, 0, and 2.5 mm) were measured by passive cavitation detection (PCD) and thermocouples during the therapeutic procedure, respectively. Stable cavitation increased with the pulse duration, PRF, and the number of pulses delivered. However, inertial cavitation was found to increase initially and then decrease with long pulse duration and high PRF. Temperature in the pre-focal region is always higher than those at the focal and post-focal position in all tests. Great variations of PCD signals and temperature elevation are due to the generation and persistence of large bubble, which is resistant to collapse and occurs with the increase of pulse duration and PRF. Similar lesion pattern and variations were also observed in ex vivo porcine kidneys. Hyperechoes in the B-mode ultrasound image were comparable to the shape and size of lesions in the dissected tissue. Thermal lesion volume increased with the increase of pulse duration and PRF, but mechanical erosion reached its maximum volume with the pulse duration of 20 ms and PRF of 1 Hz. Altogether, bubble cavitation and thermal field vary with the progress of HIFU treatment with different sonication parameters, which provide insights into the interaction of ultrasound burst with the induced bubbles for both soft tissue fractionation and enhancement in thermal accumulation. Appropriate synergy and monitoring of mechanical and thermal effects would broaden the HIFU application and enhance its efficiency as well as safety. PMID- 23927210 TI - High intensity focused ultrasound ablation and antitumor immune response. AB - The ideal cancer therapy not only induces the death of all localized tumor cells without damage to surrounding normal tissue, but also activates a systemic antitumor immunity. High intensity focused ultrasound (HIFU) has the potential to be such a treatment, as it can non-invasively ablate a targeted tumor below the skin surface, and may subsequently augment host antitumor immunity. This paper is to review increasing pre-clinical and clinical evidence linking antitumor immune response to HIFU ablation, and to discuss the potential mechanisms involved in HIFU-enhanced host antitumor immunity. The seminal studies performed so far indicate that although it is not possible to conclude definitively on the connection between HIFU treatment and antitumor immune response, it is nonetheless important to conduct extensive studies on the subject in order to elucidate the processes involved. PMID- 23927211 TI - Computational study on the propagation of strongly focused nonlinear ultrasound in tissue with rib-like structures. AB - The presence of a rib cage is a significant hindrance to the potential applications of focused ultrasound as a noninvasive extracorporeal surgery modality for various internal organs. Here the influence of ribs on the propagation of strongly focused high-intensity nonlinear ultrasound beam inside the body is studied. Based on the spheroidal beam equation, a three-dimensional numerical algorithm is developed to solve the nonlinear acoustic field generated by a focused ultrasonic transducer with a large aperture angle. Idealized ribs, of rectangular cross sectional, with high absorption and impedance, and various dimensions, are used to simulate human anatomical configurations. The changes in the spatial distribution of acoustic intensity and the reduction of the acoustic pressure amplitude and heat deposition rate due to the presence of "ribs" are investigated. It is somewhat surprising that in some cases, the axial peak positions shift less than 2 mm and more than 80% of the sound energy can propagate through the space of the rib cage in the strongly focused sound field. This study also includes quantitative analyses of the effects of different rib configurations and transducers of various f-numbers. The results can be used as reference information for further study and clinical applications. PMID- 23927212 TI - Split-mode ultrasonic transducer. AB - A split-mode ultrasonic transducer is investigated in both theory and experiment. This transducer is a two-dimensional structure of periodically poled domains in a ferroelectric wafer with free surfaces. The acoustic vibrations are excited by a radio frequency electric current applied along the length of the wafer, which allows the basal-plane surfaces to be free of metal coatings and thus ready for further biomedical applications. A specific physical property of this transducer consists of the multiple acousto-electric resonances, which occur due to an acoustic mode split when the acoustic half-wavelength is equal to the domain length. Possible applications include ultrasonic generation and detection at the micro-scale, intravascular sonification and visualization, ultrasound therapy of localized small areas such as the eye, biomedical applications for cell cultures, and traditional nondestructive testing including bones and tissues. A potential use of a non-metallized wafer is a therapeutic application with double action that is both ultrasound itself and an electric field over the wafer. The experimental measurements and theoretical calculations are in good agreement. PMID- 23927213 TI - Changes in backscatter of liver tissue due to thermal coagulation induced by focused ultrasound. AB - Ultrasonic imaging has advantages in its self-consistency in guiding and monitoring ultrasonic treatment such as high-intensity focused ultrasound (HIFU) treatment. Changes in ultrasonic backscatter of tissues due to HIFU treatment have been observed, but their mechanism is still under discussion. In this paper, ultrasonic backscatter of excised and degassed porcine liver tissue was observed before and after HIFU exposure using a diagnostic scanner, and its acoustic impedance was mapped using an ultrasonic microscope. The histology of its pathological specimen was also observed using an optical microscope. The observed decrease in backscatter intensity due to HIFU exposure was consistent with a spatial Fourier analysis of the histology, which also showed changes due to the exposure. The observed increase in acoustic impedance due to the exposure was also consistent with the histological change assuming that the increase was primarily caused by the increase in the concentration of hepatic cells. PMID- 23927214 TI - Acoustic discrimination of healthy swallows from upper airway movements. AB - Spontaneous swallowing in dysphagic individuals has been shown to occur at a lower rate compared to healthy controls, and passive swallowing detection may function as a valid screening test to identify dysphagia in at-risk populations. To automate swallow identification, acoustic source and vocal tract features were extracted from two types of swallows and eight upper airway movements from nine healthy subjects. Swallow vs non-swallow classification accuracy was 96.3 +/- 1.1%. The results provide useful methods for further development of automated tools for identification of patients with swallowing impairment. PMID- 23927215 TI - Effects of tone training on Cantonese tone-word learning. AB - The present study examined the effect of improving lexical tone identification abilities on Cantonese tone-word learning. Native English non-musicians received training on Cantonese tones before learning the meanings of words distinguished by these tones. Their results were compared to English non-musicians and musicians who received no tone training. The tone-trainees obtained a similar level of word identification proficiency as musicians by the end of training and were significantly better than non-tone trained non-musicians. These results lend support for phonetic-phonological-lexical continuity in learning because enhancing listeners' perception of lower-level tonal information significantly contributed to success in a higher-level linguistic task. PMID- 23927216 TI - Diel variation in high-frequency acoustic backscatter from Cochlodinium polykrikoides. AB - The integrated backscatter power (IBP) from Cochlodinium polykrikoides was measured every 15 min by a 5-MHz acoustic system during a 5-day cultivation with an irradiation cycle. IBP increased by 0.6 dB in 5 days, but varied by 0.83 dB during the irradiation cycle. The daily increase and diel variation in IBP were postulated to be affected by an increase in cell numbers and a diel variation in cell biovolume or density via photosynthesis, respectively. Cell division/separation might also affect a total variation in IBP. This study suggests that high-frequency acoustics may be a potential tool for investigating phytoplankton cell functions. PMID- 23927217 TI - The importance of interaural time differences and level differences in spatial release from masking. AB - Numerous studies have described improvements in speech understanding when interaural time differences (ITDs) and interaural level differences (ILDs) are present. The present study aimed to investigate whether either cue in isolation can elicit spatial release from masking (SRM) in a speech-on-speech masking paradigm with maskers positioned symmetrically around the listener. Twelve adults were tested using three presentations of the Listening in Spatialized Noise Sentences Test, with each presentation modified to contain different interaural cues in the stimuli. Results suggest that ILDs provide a similar amount of SRM as ITDs and ILDs combined. ITDs alone provide significantly less benefit. PMID- 23927218 TI - Directivity control and efficiency of parametric loudspeakers with horns. AB - This manuscript presents some recent results on directivity control and efficiency of parametric loudspeakers utilizing horns. Horns act both like an acoustic transformer and a directivity control method. An experimental device has been built and measurements have revealed that the horn has a clear influence on the audible sound levels and directivity of the parametric loudspeakers. When compared with a conventional megaphone, a much more flat frequency response is obtained and the resulting directivity is shown to be almost frequency independent. PMID- 23927219 TI - Effect of spectral overlap on the echo suppression threshold for single reflection conditions. AB - In performing arts venues, the spectra of direct and reflected sound at a receiving location differ, due to seat dip effect, diffusive and absorptive surfaces, and source directivity. This paper examines the influence of differing lead and lag spectral contents on echo suppression threshold. The results indicate, that for a highpass filtered direct sound and a broadband reflection, attenuation of low frequencies initially results in an increase in echo suppression threshold, while for higher cutoff frequencies echo suppression threshold drastically decreases. For broadband direct sound and filtered reflections, the echo suppression threshold is inversely related to high frequency content. PMID- 23927220 TI - Influence of preparation time and pitch separation in switching of auditory attention between streams. AB - The ability to consciously switch attention between speakers of interest is necessary for communication in many environments, especially when multiple talkers speak simultaneously. Segregating sounds of interest from the background, which is necessary for selective attention, depends on stimulus acoustics such as differences in spectrotemporal properties of the target and masker. However, the relationship between top-down attention control and bottom-up stimulus segregation is not well understood. Here, two experiments were conducted to examine the time necessary for listeners to switch auditory attention, and how the ability to switch attention relates to the pitch separation cue available for bottom-up stream segregation. PMID- 23927221 TI - The effects of lexical neighbors on stop consonant articulation. AB - Lexical neighbors (words sharing phonological structure with a target word) have been shown to influence the expression of phonetic contrasts for vowels and initial voiceless consonants. Focusing on minimal pair neighbors (e.g., bud-but), this research extends this work by examining the production of voiced as well as voiceless stops in both initial and final syllable/word position. The results show minimal pair neighbors can result both in enhancement and reduction of voicing contrasts (in initial vs final position), and differentially affect voiced vs voiceless consonants. These diverse effects of minimal pair neighbors serve to constrain interactive theories of language processing. PMID- 23927222 TI - Assessing the perceptual contributions of vowels and consonants to Mandarin sentence intelligibility. AB - This study investigated the perceptual contributions of vowels and consonants to Mandarin sentence intelligibility. Mandarin sentences were edited using a noise replacement paradigm to preserve various amounts of segmental information and presented to normal-hearing listeners to recognize. The vowel-only Mandarin sentences yielded a remarkable 3:1 intelligibility advantage over the consonant only sentences. This advantage is larger than that obtained with English sentences, suggesting that vowels may have a greater contribution to sentence intelligibility in Mandarin than in English. Although providing information redundant to contributions from vowel centers, a little vowel-consonant boundary transition would significantly improve the intelligibility of the consonant-only Mandarin sentences. PMID- 23927223 TI - Full-scale tests of reflective noise-reducing devices for balconies on high-rise buildings. AB - In the present report, the noise-shielding efficiency of balconies with ceiling mounted reflectors on the facades of high-rise buildings is examined through full scale field measurements. The reflectors are designed to reflect direct and diffracted waves incident on the balcony ceiling outside the balcony. Field measurements are conducted to investigate the performance of the reflectors on intermediate floors of a high-rise dwelling adjacent to a railway. The reflectors reduce railway noise by approximately 5 dB, in A-weighted sound pressure level, compared to an ordinary balcony. The noise-shielding efficiency of a balcony equipped with reflectors is greater than that of an absorbing balcony. PMID- 23927224 TI - Sparse array design using statistical restricted isometry property. AB - The numerical application of the statistical reduced isometry property (StRIP) and statistical null space property (SNSP) is presented and demonstrated for the design of underwater acoustic line arrays. This recent approach predicts the theoretical utility of specific subsampled arrays for compressive sensing. Three subsamplings are presented: Random, Golomb, and Wichmann. The Golomb array has no repeated spacings. The Wichmann array includes every possible interval of spacings. The SNSP is shown insensitive to the cases presented. The StRIP of the Golomb array predicts superior invertibility and is shown to perform well using at-sea data. PMID- 23927225 TI - Acoustic mode coupling due to subaqueous sand dunes in the South China Sea. AB - The large subaqueous sand dunes on the upper continental slope of the South China Sea are expected to couple acoustic propagating normal modes. In this letter, the criterion of adiabatic invariance is extended to the case of a waveguide possessing bedforms. Using the extended criterion to examine mode propagation over the bedforms observed in the sand dune field in 2012, results demonstrate that bedforms increase mode coupling strength such that the criterion for adiabatic propagation is exceeded for waveguides with small bedform amplitude to water depth ratios; increasing bedform amplitude enhances mode coupling. Numerical simulations confirm the extended criterion parameterization. PMID- 23927226 TI - Effects of low-frequency naval sonar exposure on three species of fish. AB - To address growing concern over the impact of anthropogenic sound on fishes, a series of experiments was conducted that exposed several fish species to high intensity low-frequency naval sonar. This study extends auditory findings by adding largemouth bass, yellow perch, and channel catfish. No effects on hearing were found in largemouth bass and yellow perch and only small effects in channel catfish (a fish with morphological adaptations for enhanced pressure reception). Together with prior findings, these results suggest limited impact on hearing from high-intensity sonar. Susceptibility may be due to genetic stock, developmental conditions, seasonal variation, and/or buoyancy during exposure. PMID- 23927227 TI - Applying diffuse ultrasound under dynamic loading to improve closed crack characterization in concrete. AB - Recent studies show the ability of diffuse ultrasound to characterize surface breaking cracks in concrete. However, derived parameters are sensitive to the presence of partially opened zones along the crack whose pattern may differ from one sample to another. The aim of this letter is to study the variation of diffuse ultrasound parameters while the sample is driven by a low frequency bending load which alternatively opens and closes the crack, allowing to access supplementary information about its morphology. The results show the sensitivity of the method for various crack depths and highlight its potential for concrete nondestructive evaluation. PMID- 23927228 TI - The development of a modified spectral ripple test. AB - Poor spectral resolution can be a limiting factor for hearing impaired listeners, particularly for complex listening tasks such as speech understanding in noise. Spectral ripple tests are commonly used to measure spectral resolution, but these tests contain a number of potential confounds that can make interpretation of the results difficult. To measure spectral resolution while avoiding those confounds, a modified spectral ripple test with dynamically changing ripples was created, referred to as the spectral-temporally modulated ripple test (SMRT). This paper describes the SMRT and provides evidence that it is sensitive to changes in spectral resolution. PMID- 23927230 TI - Passive estimation of the waveguide invariant per pair of modes. AB - In many oceanic waveguides, acoustic propagation is characterized by a parameter called waveguide invariant. This property is used in many passive and active sonar applications where knowledge of the waveguide invariant value is required. The waveguide invariant is classically considered as scalar but several studies show that it is better modeled by a distribution because of its dependence on frequency and mode pairs. This paper presents a new method for estimating the waveguide invariant distribution. Using the noise radiated by a distant ship and a single hydrophone, the proposed methodology allows estimating the waveguide invariant for each pair of modes in shallow water. Performance is evaluated on simulated data. PMID- 23927229 TI - Comparison of head-related impulse response measurement approaches. AB - The well-established static head-related transfer function (HRTF) measurement approaches using maximum length sequences and sine sweeps are compared with a recent HRTF estimation approach using normalized least mean square adaptive filters, which enables a continuous movement of the person to be measured during the recording of the excitation signal. By using continuous movement HRTF measurement, a huge amount of time for the individual HRTF estimation can be saved to create a dense HRTF database for headphone-based sound synthesis or applications such as crosstalk cancellation for loudspeaker-based sound synthesis. The different approaches are implemented and experimentally compared by objective and subjective evaluation. PMID- 23927231 TI - Level dominance for the detection of changes in level distribution in sound streams. AB - Sound streams were generated by randomly choosing the levels of tone pips from two different distributions, A and B. Of the 18 tone pips, the first nine were drawn from distribution A and the second nine from distribution B, or the opposite. The listeners' task was to indicate order, A-B or B-A. In two conditions the A and B distributions differed in mean (condition 1) or variance (condition 2). In contrast to an ideal observer, listeners' strategies were consistent across the two conditions. Analyses suggest that listeners relied primarily on the more intense tone pips in making their decisions. PMID- 23927232 TI - When intelligibilities of paired speech bands do not behave the way they are supposed to. AB - Two rectangular 1/3-octave passbands were derived from different spectral regions of everyday sentences, with the intelligibility of one band approximately twice the others. Both passbands were then filtered to produce a series of narrower rectangular passbands. Each of the original 1/3-octave passbands in turn served as the fixed bandwidth "pedestal" and was paired with each of the series of narrower passbands of the other band. Remarkably, dual band intelligibilities were the same, regardless of which band served as pedestal, so the summed bandwidths determined intelligibility: The summed intelligibilities were irrelevant. Implications of this paradoxical "summed bandwidth rule" are discussed. PMID- 23927233 TI - A higher-order tangent linear parabolic-equation solution of three-dimensional sound propagation. AB - A higher-order square-root operator splitting algorithm is employed to derive a tangent linear solution for the three-dimensional parabolic wave equation due to small variations of the sound speed in the medium. The solution shown in this paper unifies other solutions obtained from less accurate approximations. Examples of three-dimensional acoustic ducts are presented to demonstrate the accuracy of the solution. Future work on the applications of associated adjoint models for acoustic inversions is proposed and discussed. PMID- 23927234 TI - On smoothing articulatory trajectories obtained from Gaussian mixture model based acoustic-to-articulatory inversion. AB - It is well-known that the performance of acoustic-to-articulatory inversion improves by smoothing the articulatory trajectories estimated using Gaussian mixture model (GMM) mapping (denoted by GMM + Smoothing). GMM + Smoothing also provides similar performance with GMM mapping using dynamic features, which integrates smoothing directly in the mapping criterion. Due to the separation between smoothing and mapping, what objective criterion GMM + Smoothing optimizes remains unclear. In this work a new integrated smoothness criterion, the smoothed GMM (SGMM), is proposed. GMM + Smoothing is shown, both analytically and experimentally, to be identical to the asymptotic solution of SGMM suggesting GMM + Smoothing to be a near optimal solution of SGMM. PMID- 23927235 TI - Time course of a perceptual enhancement effect for noise-masked speech in reverberant environments. AB - Speech intelligibility has been shown to improve with prior exposure to a reverberant room environment [Brandewie and Zahorik (2010). J. Acoust. Soc. Am. 128, 291-299] with a spatially separated noise masker. Here, this speech enhancement effect was examined in multiple room environments using carrier phrases of varying lengths in order to control the amount of exposure. Speech intelligibility enhancement of between 5% and 18% was observed with as little as 850 ms of exposure, although the effect's time course varied considerably with reverberation and signal-to-noise ratio. In agreement with previous work, greater speech enhancement was found for reverberant environments compared to anechoic space. PMID- 23927236 TI - Communication: favorable dimensionality scaling of rectangular collocation with adaptable basis functions up to 7 dimensions. AB - We show that by using a rectangular collocation method with a small basis of parameterized functions, it is possible to compute a vibrational spectrum by solving the Schrodinger equation in 7D from a small number of ab initio calculations without a potential surface. The method is ideal for spectra of molecules adsorbed on a surface. In this paper, it is applied to calculate experimentally relevant energy levels of acetic acid adsorbed on the (101) surface of anatase TiO2. In this case, to obtain levels of experimental accuracy, increasing the number of dimensions from 4 to 7 increases the number of required potential points from about 1000 to about 10,000 and the number of basis functions from 126 to 792: the scaling is very attractive. PMID- 23927237 TI - A convergent reaction-diffusion master equation. AB - The reaction-diffusion master equation (RDME) is a lattice stochastic reaction diffusion model that has been used to study spatially distributed cellular processes. The RDME is often interpreted as an approximation to spatially continuous models in which molecules move by Brownian motion and react by one of several mechanisms when sufficiently close. In the limit that the lattice spacing approaches zero, in two or more dimensions, the RDME has been shown to lose bimolecular reactions. The RDME is therefore not a convergent approximation to any spatially continuous model that incorporates bimolecular reactions. In this work we derive a new convergent RDME (CRDME) by finite volume discretization of a spatially continuous stochastic reaction-diffusion model popularized by Doi. We demonstrate the numerical convergence of reaction time statistics associated with the CRDME. For sufficiently large lattice spacings or slow bimolecular reaction rates, we also show that the reaction time statistics of the CRDME may be approximated by those from the RDME. The original RDME may therefore be interpreted as an approximation to the CRDME in several asymptotic limits. PMID- 23927238 TI - Calculation of the "absolute" free energy of a beta-hairpin in an all-atom force field. AB - We propose a new approach to calculate the conformational free energy of a macromolecule in a compact stable state in implicit solvent. The free energy is evaluated with respect to an artificial reference system without internal interactions that is confined to a small well-defined multidimensional volume of a regular shape occupying approximately the same part of the conformational space as the macromolecule of interest. We present a practical implementation of our method, successfully apply it to a beta-hairpin in all-atom representation, verify the results with direct parallel tempering simulations, and discuss the possibilities of further improvements. PMID- 23927239 TI - A qubit coupled with confined phonons: the interplay between true and fake decoherence. AB - The decoherence of a qubit coupled with the phonons of a finite-size lattice is investigated. The confined phonons no longer behave as a reservoir. They remain sensitive to the qubit so that the origin of the decoherence is twofold. First, a qubit-phonon entanglement yields an incomplete true decoherence. Second, the qubit renormalizes the phonon frequency resulting in fake decoherence when a thermal average is performed. To account for the initial thermalization of the lattice, the qua- ntum Langevin theory is applied so that the phonons are viewed as an open system coupled with a thermal bath of harmonic oscillators. Consequently, it is shown that the finite lifetime of the phonons does not modify fake decoherence but strongly affects true decoherence. Depending on the values of the model parameters, the interplay between fake and true decoherence yields a very rich dynamics with various regimes. PMID- 23927240 TI - Orbital-optimized coupled-electron pair theory and its analytic gradients: accurate equilibrium geometries, harmonic vibrational frequencies, and hydrogen transfer reactions. AB - Orbital-optimized coupled-electron pair theory [or simply "optimized CEPA(0)," OCEPA(0), for short] and its analytic energy gradients are presented. For variational optimization of the molecular orbitals for the OCEPA(0) method, a Lagrangian-based approach is used along with an orbital direct inversion of the iterative subspace algorithm. The cost of the method is comparable to that of CCSD [O(N(6)) scaling] for energy computations. However, for analytic gradient computations the OCEPA(0) method is only half as expensive as CCSD since there is no need to solve the lambda2-amplitude equation for OCEPA(0). The performance of the OCEPA(0) method is compared with that of the canonical MP2, CEPA(0), CCSD, and CCSD(T) methods, for equilibrium geometries, harmonic vibrational frequencies, and hydrogen transfer reactions between radicals. For bond lengths of both closed and open-shell molecules, the OCEPA(0) method improves upon CEPA(0) and CCSD by 25%-43% and 38%-53%, respectively, with Dunning's cc-pCVQZ basis set. Especially for the open-shell test set, the performance of OCEPA(0) is comparable with that of CCSD(T) (DeltaR is 0.0003 A on average). For harmonic vibrational frequencies of closed-shell molecules, the OCEPA(0) method again outperforms CEPA(0) and CCSD by 33%-79% and 53%-79%, respectively. For harmonic vibrational frequencies of open-shell molecules, the mean absolute error (MAE) of the OCEPA(0) method (39 cm(-1)) is fortuitously even better than that of CCSD(T) (50 cm(-1)), while the MAEs of CEPA(0) (184 cm(-1)) and CCSD (84 cm(-1)) are considerably higher. For complete basis set estimates of hydrogen transfer reaction energies, the OCEPA(0) method again exhibits a substantially better performance than CEPA(0), providing a mean absolute error of 0.7 kcal mol(-1), which is more than 6 times lower than that of CEPA(0) (4.6 kcal mol(-1)), and comparing to MP2 (7.7 kcal mol(-1)) there is a more than 10-fold reduction in errors. Whereas the MAE for the CCSD method is only 0.1 kcal mol(-1) lower than that of OCEPA(0). Overall, the present application results indicate that the OCEPA(0) method is very promising not only for challenging open-shell systems but also for closed-shell molecules. PMID- 23927241 TI - Treatment of scalar-relativistic effects on nuclear magnetic shieldings using a spin-free exact-two-component approach. AB - A cost-effective treatment of scalar-relativistic effects on nuclear magnetic shieldings based on the spin-free exact-two-component theory in its one-electron variant (SFX2C-1e) is presented. The SFX2C-1e scheme gains its computational efficiency, in comparison to the four-component approach, from a focus on spin free contributions and from the elimination of the small component. For the calculation of nuclear magnetic shieldings, the separation of spin-free and spin dependent terms in the parent four-component theory is carried out here for the matrix representation of the Dirac equation in terms of a restricted-magnetically balanced gauge-including atomic orbital basis. The resulting spin-free four component matrix elements required to calculate nuclear magnetic shieldings are then used to construct the corresponding SFX2C-1e Hamiltonian and its perturbed counterpart in the context of SFX2C-1e analytic derivative theory. To demonstrate the applicability of the approach, we report coupled-cluster calculations for prototypical problems such as the (17)O shieldings of transition-metal oxo complexes (MO4(2-), M = Cr, Mo, and W) and the (129)Xe shieldings of xenon fluorides (XeF2, XeF4, and XeF6). PMID- 23927242 TI - Van der Waals interactions in density functional theory by combining the quantum harmonic oscillator-model with localized Wannier functions. AB - We present a new scheme to include the van der Waals (vdW) interactions in approximated Density Functional Theory (DFT) by combining the quantum harmonic oscillator model with the maximally localized Wannier function technique. With respect to the recently developed DFT/vdW-WF2 method, also based on Wannier Functions, the new approach is more general, being no longer restricted to the case of well separated interacting fragments. Moreover, it includes higher than pairwise energy contributions, coming from the dipole-dipole coupling among quantum oscillators. The method is successfully applied to the popular S22 molecular database, and also to extended systems, namely graphite and H2 adsorbed on the Cu(111) metal surface (in this case metal screening effects are taken into account). The results are also compared with those obtained by other vdW corrected DFT schemes. PMID- 23927243 TI - A variational method for density functional theory calculations on metallic systems with thousands of atoms. AB - A new method for finite-temperature density functional theory calculations which significantly increases the number of atoms that can be simulated in metallic systems is presented. A self-consistent, direct minimization technique is used to obtain the Helmholtz free energy of the electronic system, described in terms of a set of non-orthogonal, localized functions which are optimized in situ using a periodic-sinc basis set, equivalent to plane waves. Most parts of the calculation, including the demanding operation of building the Hamiltonian matrix, have a computational cost that scales linearly with the number of atoms in the system. Also, this approach ensures that the Hamiltonian matrix has a minimal size, which reduces the computational overhead due to diagonalization, a cubic-scaling operation that is still required. Large basis set accuracy is retained via the optimization of the localized functions. This method allows accurate simulations of entire metallic nanostructures, demonstrated with calculations on a supercell of bulk copper with 500 atoms and on gold nanoparticles with up to 2057 atoms. PMID- 23927244 TI - Ad hoc methods for accurate determination of Bader's atomic boundary. AB - In addition to the recently published triangulation method [P. M. Polestshuk, J. Comput. Chem. 34, 206 (2013)], two new highly accurate approaches, ZFSX and SINTY, for the integration over an atomic region covered by a zero-flux surface (zfs) were developed and efficiently interfaced into the TWOE program. ZFSX method was realized as three independent modules (ZFSX-1, ZFSX-3, and ZFSX-5) handling interatomic surfaces of a different complexity. Details of algorithmic implementation of ZFSX and SINTY are discussed. A special attention to an extended analysis of errors in calculations of atomic properties is paid. It was shown that uncertainties in zfs determination caused by ZFSX and SINTY approaches contribute negligibly (less than 10(-6) a.u.) to the total atomic integration errors. Moreover, the new methods are able to evaluate atomic integrals with a reasonable time and can be universally applied for the systems of any complexity. It is suggested, therefore, that ZFSX and SINTY can be regarded as benchmark methods for the computation of any Quantum Theory of Atoms in Molecules atomic property. PMID- 23927245 TI - Improving the accuracy and efficiency of time-resolved electronic spectra calculations: cellular dephasing representation with a prefactor. AB - Time-resolved electronic spectra can be obtained as the Fourier transform of a special type of time correlation function known as fidelity amplitude, which, in turn, can be evaluated approximately and efficiently with the dephasing representation. Here we improve both the accuracy of this approximation-with an amplitude correction derived from the phase-space propagator-and its efficiency with an improved cellular scheme employing inverse Weierstrass transform and optimal scaling of the cell size. We demonstrate the advantages of the new methodology by computing dispersed time-resolved stimulated emission spectra in the harmonic potential, pyrazine, and the NCO molecule. In contrast, we show that in strongly chaotic systems such as the quartic oscillator the original dephasing representation is more appropriate than either the cellular or prefactor corrected methods. PMID- 23927246 TI - The tensor hypercontracted parametric reduced density matrix algorithm: coupled cluster accuracy with O(r(4)) scaling. AB - Tensor hypercontraction is a method that allows the representation of a high-rank tensor as a product of lower-rank tensors. In this paper, we show how tensor hypercontraction can be applied to both the electron repulsion integral tensor and the two-particle excitation amplitudes used in the parametric 2-electron reduced density matrix (p2RDM) algorithm. Because only O(r) auxiliary functions are needed in both of these approximations, our overall algorithm can be shown to scale as O(r(4)), where r is the number of single-particle basis functions. We apply our algorithm to several small molecules, hydrogen chains, and alkanes to demonstrate its low formal scaling and practical utility. Provided we use enough auxiliary functions, we obtain accuracy similar to that of the standard p2RDM algorithm, somewhere between that of CCSD and CCSD(T). PMID- 23927247 TI - Domain decomposition for implicit solvation models. AB - This article is the first of a series of papers dealing with domain decomposition algorithms for implicit solvent models. We show that, in the framework of the COSMO model, with van der Waals molecular cavities and classical charge distributions, the electrostatic energy contribution to the solvation energy, usually computed by solving an integral equation on the whole surface of the molecular cavity, can be computed more efficiently by using an integral equation formulation of Schwarz's domain decomposition method for boundary value problems. In addition, the so-obtained potential energy surface is smooth, which is a critical property to perform geometry optimization and molecular dynamics simulations. The purpose of this first article is to detail the methodology, set up the theoretical foundations of the approach, and study the accuracies and convergence rates of the resulting algorithms. The full efficiency of the method and its applicability to large molecular systems of biological interest is demonstrated elsewhere. PMID- 23927248 TI - Permutation invariant polynomial neural network approach to fitting potential energy surfaces. AB - A simple, general, and rigorous scheme for adapting permutation symmetry in molecular systems is proposed and tested for fitting global potential energy surfaces using neural networks (NNs). The symmetry adaptation is realized by using low-order permutation invariant polynomials (PIPs) as inputs for the NNs. This so-called PIP-NN approach is applied to the H + H2 and Cl + H2 systems and the analytical potential energy surfaces for these two systems were accurately reproduced by PIP-NN. The accuracy of the NN potential energy surfaces was confirmed by quantum scattering calculations. PMID- 23927249 TI - Interacting hard rods on a lattice: distribution of microstates and density functionals. AB - We derive exact density functionals for systems of hard rods with first-neighbor interactions of arbitrary shape but limited range on a one-dimensional lattice. The size of all rods is the same integer unit of the lattice constant. The derivation, constructed from conditional probabilities in a Markov chain approach, yields the exact joint probability distribution for the positions of the rods as a functional of their density profile. For contact interaction ("sticky core model") between rods, we give a lattice fundamental measure form of the density functional and present explicit results for contact correlators, entropy, free energy, and chemical potential. Our treatment includes inhomogeneous couplings and external potentials. PMID- 23927250 TI - The accuracy of the Gaussian-and-finite-element-Coulomb (GFC) method for the calculation of Coulomb integrals. AB - We analyze the accuracy of the Coulomb energy calculated using the Gaussian-and finite-element-Coulomb (GFC) method. In this approach, the electrostatic potential associated with the molecular electronic density is obtained by solving the Poisson equation and then used to calculate matrix elements of the Coulomb operator. The molecular electrostatic potential is expanded in a mixed Gaussian finite-element (GF) basis set consisting of Gaussian functions of s symmetry centered on the nuclei (with exponents obtained from a full optimization of the atomic potentials generated by the atomic densities from symmetry-averaged restricted open-shell Hartree-Fock theory) and shape functions defined on uniform finite elements. The quality of the GF basis is controlled by means of a small set of parameters; for a given width of the finite elements d, the highest accuracy is achieved at smallest computational cost when tricubic (n = 3) elements are used in combination with two (gamma(H) = 2) and eight (gamma(1st) = 8) Gaussians on hydrogen and first-row atoms, respectively, with exponents greater than a given threshold (alphamin (G)=0.5). The error in the calculated Coulomb energy divided by the number of atoms in the system depends on the system type but is independent of the system size or the orbital basis set, vanishing approximately like d(4) with decreasing d. If the boundary conditions for the Poisson equation are calculated in an approximate way, the GFC method may lose its variational character when the finite elements are too small; with larger elements, it is less sensitive to inaccuracies in the boundary values. As it is possible to obtain accurate boundary conditions in linear time, the overall scaling of the GFC method for large systems is governed by another computational step-namely, the generation of the three-center overlap integrals with three Gaussian orbitals. The most unfavorable (nearly quadratic) scaling is observed for compact, truly three-dimensional systems; however, this scaling can be reduced to linear by introducing more effective techniques for recognizing significant three-center overlap distributions. PMID- 23927251 TI - Polarization as a field variable from molecular dynamics simulations. AB - A theoretical and computational framework for systematically calculating the macroscopic polarization density as a field variable from molecular dynamics simulations is presented. This is done by extending the celebrated Irving and Kirkwood [J. Chem. Phys. 18, 817 (1950)] procedure, which expresses macroscopic stresses and heat fluxes in terms of the atomic variables, to the case of electrostatics. The resultant macroscopic polarization density contains molecular dipole, quadrupole, and higher-order moments, and can be calculated to a desired accuracy depending on the degree of the coarse-graining function used to connect the molecular and continuum scales. The theoretical and computational framework is verified by recovering the dielectric constant of bulk water. Finally, the theory is applied to calculate the spatial variation of the polarization vector in the electrical double layer of a 1:1 electrolyte solution. Here, an intermediate asymptotic length scale is revealed in a specific region, which validates the application of mean field Poisson-Boltzmann theory to describe this region. Also, using the existence of this asymptotic length scale, the lengths of the diffuse and condensed/Stern layers are identified accurately, demonstrating that this framework may be used to characterize electrical double layers over a wide range of concentrations of solutions and surface charges. PMID- 23927252 TI - When is the next extending of Fick-Jacobs equation necessary? AB - Applicability of the effective one-dimensional equations, such as Fick-Jacobs equation and its extensions, describing diffusion of particles in 2D or 3D channels with varying cross section A(x) along the longitudinal coordinate x, is studied. The leading nonstationary correction to Zwanzig-Reguera-Rubi equation [R. Zwanzig, J. Phys. Chem. 96, 3926 (1992); D. Reguera and J. M. Rubi, Phys. Rev. E 64, 061106 (2001)] is derived and tested on the exactly solvable model, diffusion in a 2D linear cone. The effects of such correction are demonstrated and discussed on elementary nonstationary processes, a time dependent perturbation of the stationary flow and calculation of the mean first passage time. PMID- 23927253 TI - Multiscale enhanced path sampling based on the Onsager-Machlup action: application to a model polymer. AB - We propose a novel path sampling method based on the Onsager-Machlup (OM) action by generalizing the multiscale enhanced sampling technique suggested by Moritsugu and co-workers [J. Chem. Phys. 133, 224105 (2010)]. The basic idea of this method is that the system we want to study (for example, some molecular system described by molecular mechanics) is coupled to a coarse-grained (CG) system, which can move more quickly and can be computed more efficiently than the original system. We simulate this combined system (original + CG system) using Langevin dynamics where different heat baths are coupled to the two systems. When the coupling is strong enough, the original system is guided by the CG system, and is able to sample the configuration and path space with more efficiency. We need to correct the bias caused by the coupling, however, by employing the Hamiltonian replica exchange, where we prepare many path replicas with different coupling strengths. As a result, an unbiased path ensemble for the original system can be found in the weakest coupling path ensemble. This strategy is easily implemented because a weight for a path calculated by the OM action is formally the same as the Boltzmann weight if we properly define the path "Hamiltonian." We apply this method to a model polymer with Asakura-Oosawa interaction, and compare the results with the conventional transition path sampling method. PMID- 23927254 TI - Dynamics of a two-level system under the simultaneous influence of a spin bath and a boson bath. AB - We study dynamics of a two-level system coupled simultaneously to a pair of dissimilar reservoirs, namely, a spin bath and a boson bath, which are connected via finite interbath coupling. It is found that the steady-state population transfer in the two-level system increases with its coupling to the spin bath, while optimal transfer occurs at intermediate coupling in the transient process. If the two-level system is strongly coupled to the spin bath, the population transfer is unidirectional barring minor population oscillations of minute amplitudes. If the spin bath is viewed as an atomic ensemble, robust generation of macroscopic superposition states exists against parameter variations of the two-level system and the boson bath. PMID- 23927255 TI - Experimental observation and analysis of the 3nu(1)(Sigma(g)) stretching vibrational state of acetylene using continuous-wave infrared stimulated emission. AB - We present a sensitive experimental method for molecular spectroscopy that can be used to determine ro-vibrational states using mid-infrared stimulated emission. Our infrared stimulated emission probing (IRSEP) experiment is based on using a narrow-line, continuous-wave Ti:sapphire laser beam (pump) to excite the molecules to an upper vibrational state and a continuous-wave, mid-infrared beam from an optical parametric oscillator (probe) to detect the stimulated emission by the excited molecules. Spectroscopic data are gathered by tuning the wavelengths of the beams. The molecules are probed before their velocity distribution is disturbed by collisions, which leads to a sub-Doppler resolution. The full width at half maximum of the emission peaks is below 10 MHz. The stimulated emission lines are measured with an accuracy of at least 0.005 cm(-1). We use the IRSEP experiment to observe and analyze the symmetric ro-vibrational state [21+] (3nu1(Sigmag)) of acetylene (C2H2). This state is not accessible via one photon transitions from the ground vibrational state. We use the least squares method to determine that the band center is at 9991.9725 (12) cm(-1) and the rotational parameters are B = 1.156145 (22) and D = 1.608 (87) * 10(-6) cm( 1), where the uncertainties in parentheses are one-standard errors in the least significant digit. PMID- 23927256 TI - Dynamics of the D(+) + H2 -> HD + H(+) reaction at the low energy regime by means of a statistical quantum method. AB - The D(+) +H2(v = 0, j = 0, 1) -> HD+H(+) reaction has been investigated at the low energy regime by means of a statistical quantum mechanical (SQM) method. Reaction probabilities and integral cross sections (ICSs) between a collisional energy of 10(-4) eV and 0.1 eV have been calculated and compared with previously reported results of a time independent quantum mechanical (TIQM) approach. The TIQM results exhibit a dense profile with numerous narrow resonances down to Ec ~ 10(-2) eV and for the case of H2(v = 0, j = 0) a prominent peak is found at ~2.5 * 10(-4) eV. The analysis at the state-to-state level reveals that this feature is originated in those processes which yield the formation of rotationally excited HD(v' = 0, j' > 0). The statistical predictions reproduce reasonably well the overall behaviour of the TIQM ICSs at the larger energy range (Ec >= 10(-3) eV). Thermal rate constants are in qualitative agreement for the whole range of temperatures investigated in this work, 10-100 K, although the SQM values remain above the TIQM results for both initial H2 rotational states, j = 0 and 1. The enlargement of the asymptotic region for the statistical approach is crucial for a proper description at low energies. In particular, we find that the SQM method leads to rate coefficients in terms of the energy in perfect agreement with previously reported measurements if the maximum distance at which the calculation is performed increases noticeably with respect to the value employed to reproduce the TIQM results. PMID- 23927257 TI - An efficient method to study highly excited states at the ab initio level and application to ultralong Rydberg CsNe molecules. AB - An efficient method to study highly excited states at the ab initio level has been introduced and applied to ultralong Rydberg CsNe molecules. Vibrational properties of Rydberg CsNe molecules are investigated on corresponding potential energy curves obtained by perturbation theory. The Rydberg CsNe molecules are associated with a Rydberg Cs(ns/np) atom (n = 20-60) and a ground state Ne((1)S0) atom. The starting point for the perturbation treatment of corresponding Rydberg molecular potential energy curves is to generate accurate atomic Rydberg states from realistic ab initio effective core potential. According to the authors' knowledge this is a good reference for ultralong range molecules (order of 1000 Bohr radii) to be studied at the ab initio level. PMID- 23927258 TI - On the parameterization of vibronic Hamiltonians for molecular aggregates using absorption line-shapes as an input. AB - Absorption line-shapes of molecular aggregates are often calculated using a simple form for a vibronic Hamiltonian. Parameters which enter into the model are usually taken from measured spectra. Here, we address the question in how far different sets of input parameters used to calculate the spectra lead to similar spectral features. Therefore, we first present analytical expressions which illustrate the relation between the various parameters such as Huang-Rhys factors, electronic coupling elements, and aggregate size. Numerical calculations show that identical peak ratios and spectra can be obtained for different sets of parameters. This illustrates the basic difficulties in extracting reliable molecular information from a comparison of calculated and measured spectra. PMID- 23927259 TI - Multi-photon UV photolysis of gaseous polycyclic aromatic hydrocarbons: extinction spectra and dynamics. AB - The extinction spectra of static naphthalene and static biphenylene vapor, each buffered with a noble gas at room temperature, were measured as a function of time in the region between 390 and 850 nm after UV multi-photon laser photolysis at 308 nm. Employing incoherent broadband cavity enhanced absorption spectroscopy (IBBCEAS), the spectra were found to be unstructured with a general lack of isolated features suggesting that the extinction was not solely based on absorption but was in fact dominated by scattering from particles formed in the photolysis of the respective polycyclic aromatic hydrocarbon. Following UV multi photon photolysis, the extinction dynamics of the static (unstirred) closed gas phase system exhibits extraordinary quasi-periodic and complex oscillations with periods ranging from seconds to many minutes, persisting for up to several hours. Depending on buffer gas type and pressure, several types of dynamical responses could be generated (classified as types I, II, and III). They were studied as a function of temperature and chamber volume for different experimental conditions and possible explanations for the oscillations are discussed. A conclusive model for the observed phenomena has not been established. However, a number of key hypotheses have made based on the measurements in this publication: (a) Following the multi-photon UV photolysis of naphthalene (or biphenylene), particles are formed on a timescale not observable using IBBCEAS. (b) The observed temporal behavior cannot be described on basis of a chemical reaction scheme alone. (c) The pressure dependence of the system's responses is due to transport phenomena of particles in the chamber. (d) The size distribution and the refractive indices of particles are time dependent and evolve on a timescale of minutes to hours. The rate of particle coagulation, involving coalescent growth and particle agglomeration, affects the observed oscillations. (e) The walls of the chamber act as a sink. The wall conditions (which could not be quantitatively characterized) have a profound influence on the dynamics of the system and on its slow return to an equilibrium state. PMID- 23927260 TI - Are trinuclear superhalogens promising candidates for building blocks of novel magnetic materials? A theoretical prospect from combined broken-symmetry density functional theory and ab initio study. AB - The structures, relative stabilities, vertical electron detachment energies, and magnetic properties of a series of trinuclear clusters are explored via combined broken-symmetry density functional theory and ab initio study. Several exchange correlation functionals are utilized to investigate the effects of different halogen elements and central atoms on the properties of the clusters. These clusters are shown to possess stronger superhalogen properties than previously reported dinuclear superhalogens. The calculated exchange coupling constants indicate the antiferromagnetic coupling between the transition metal ions. Spin density analysis demonstrates the importance of spin delocalization in determining the strengths of various couplings. Spin frustration is shown to occur in some of the trinuclear superhalogens. The coexistence of strong superhalogen properties and spin frustration implies the possibility of trinuclear superhalogens working as the building block of new materials of novel magnetic properties. PMID- 23927261 TI - Direct observation of internal energy distributions of C5(-). AB - Photon induced decay of C5(-) has been measured in an electrostatic storage ring. The time dependence of the photo-enhanced decay is close to a 1/t decay which indicates a thermal process. The deviation from the expected power of -1 is quantitatively explained by the small heat capacity of the anion. Measurements of the photo-enhanced decay at different storage times and photon energies allow a determination of the radiative cooling rate and the energy distribution of the ions. The average energy content between 15 and 70 ms is found to vary as time to the power -0.72, and at 50 ms the ions contain an average excitation energy of 0.5 eV. The time dependent energy distribution is consistent with cooling by infrared photon emission if published oscillator strengths are reduced by a factor 2.5, in contrast to cooling of larger molecular carbon-based ions where electronic transitions cause a much stronger cooling. PMID- 23927262 TI - Magnesium cluster film synthesis by helium nanodroplets. AB - Atomic and molecular clusters are a unique class of substances with properties that differ greatly from those of the bulk or single atoms due to changes in surface to volume ratio and finite size effects. Here, we demonstrate the ability to create cluster matter films using helium droplet mediated cluster assembly and deposition, a recently developed methodology that condenses atoms or molecules within liquid helium droplets and then gently deposits them onto a surface. In this work, we examine magnesium nanocluster films, which exhibit growth behavior comparable to low-energy cluster beam methods, and demonstrate physical properties and morphology dependent on helium droplet size. PMID- 23927263 TI - Computational studies of catalyst-free single walled carbon nanotube growth. AB - Semiempirical tight binding (TB) and density functional theory (DFT) methods have been used to study the mechanism of single walled carbon nanotube (SWNT) growth. The results are compared with similar calculations on graphene. Both TB and DFT geometry optimized structures of relevance to SWNT growth show that the minimum energy growth mechanism is via the formation of hexagons at the SWNT end. This is similar to the result for graphene where growth occurs via the formation of hexagons at the edge of the graphene flake. However, due to the SWNT curvature, defects such as pentagons are more stable in SWNTs than in graphene. Monte Carlo simulations based on the TB energies show that SWNTs close under conditions that are proper for growth of large defect-free graphene flakes, and that a particle such as a Ni cluster is required to maintain an open SWNT end under these conditions. The calculations also show that the proper combination of growth parameters such as temperature and chemical potential are required to prevent detachment of the SWNTs from the Ni cluster or encapsulation of the cluster by the feedstock carbon atoms. PMID- 23927264 TI - Equilibrium theory of the hard sphere fluid and glasses in the metastable regime up to jamming. I. Thermodynamics. AB - We formulate and apply a non-replica equilibrium theory for the fluid-glass transition, glass thermodynamic properties, and jamming of hard spheres in three and all higher spatial dimensions. Numerical predictions for the zero complexity glass transition and jamming packing fractions, and a "densest" equilibrium glass, are made. The equilibrium glass equation of state is regarded as the practical continuation of its fluid analog up to jamming. The analysis provides a possible resolution to the inability of any fluid virial series re-summation based equation of state to capture jamming at a reasonable volume fraction. The numerical results are quantitatively compared with various simulation data for equilibrium hard sphere glasses in 3 to 12 dimensions. Although there are uncertainties in this comparison, the predicted zero complexity or configurational entropy and corresponding jamming packing fractions do agree well with two characteristic packing fractions deduced from the dynamic simulation data. The similarities and differences of our approach compared to the replica approach are discussed. The high dimensional scaling of the equilibrium glass transition and jamming volume fractions are also derived. The developments in this paper serve as input to Paper II [R. Jadrich and K. S. Schweizer, J. Chem. Phys. 139, 054502 (2013)] that constructs a self-consistent integral equation theory of the 3-dimensional hard sphere pair structure, in real and Fourier space, in the metastable regime up to jamming. The latter is employed as input to a microscopic dynamical theory of single particle activated barrier hopping. PMID- 23927265 TI - Equilibrium theory of the hard sphere fluid and glasses in the metastable regime up to jamming. II. Structure and application to hopping dynamics. AB - Building on the equation-of-state theory of Paper I, we construct a new thermodynamically consistent integral equation theory for the equilibrium pair structure of 3-dimensional monodisperse hard spheres applicable up to the jamming transition. The approach is built on a two Yukawa generalized mean spherical approximation closure for the direct correlation function (DCF) beyond contact that reproduces the exact contact value of the pair correlation function and isothermal compressibility. The detailed construction of the DCF is guided by the desire to capture its distinctive features as jamming is approached. Comparison of the theory with jamming limit simulations reveals good agreement for many, but not all, of the key features of the pair correlation function. The theory is more accurate in Fourier space where predictions for the structure factor and DCF are accurate over a wide range of wavevectors from significantly below the first cage peak to very high wavevectors. New features of the equilibrium pair structure are predicted for packing fractions below jamming but well above crystallization. For example, the oscillatory DCF decays very slowly at large wavevectors for high packing fractions as a consequence of the unusual structure of the radial distribution function at small separations. The structural theory is used as input to the nonlinear Langevin equation theory of activated dynamics, and calculations of the alpha relaxation time based on single particle hopping are compared to recent colloid experiments and simulations at very high volume fractions. PMID- 23927266 TI - Quantum mechanical force field for water with explicit electronic polarization. AB - A quantum mechanical force field (QMFF) for water is described. Unlike traditional approaches that use quantum mechanical results and experimental data to parameterize empirical potential energy functions, the present QMFF uses a quantum mechanical framework to represent intramolecular and intermolecular interactions in an entire condensed-phase system. In particular, the internal energy terms used in molecular mechanics are replaced by a quantum mechanical formalism that naturally includes electronic polarization due to intermolecular interactions and its effects on the force constants of the intramolecular force field. As a quantum mechanical force field, both intermolecular interactions and the Hamiltonian describing the individual molecular fragments can be parameterized to strive for accuracy and computational efficiency. In this work, we introduce a polarizable molecular orbital model Hamiltonian for water and for oxygen- and hydrogen-containing compounds, whereas the electrostatic potential responsible for intermolecular interactions in the liquid and in solution is modeled by a three-point charge representation that realistically reproduces the total molecular dipole moment and the local hybridization contributions. The present QMFF for water, which is called the XP3P (explicit polarization with three-point-charge potential) model, is suitable for modeling both gas-phase clusters and liquid water. The paper demonstrates the performance of the XP3P model for water and proton clusters and the properties of the pure liquid from about 900 * 10(6) self-consistent-field calculations on a periodic system consisting of 267 water molecules. The unusual dipole derivative behavior of water, which is incorrectly modeled in molecular mechanics, is naturally reproduced as a result of an electronic structural treatment of chemical bonding by XP3P. We anticipate that the XP3P model will be useful for studying proton transport in solution and solid phases as well as across biological ion channels through membranes. PMID- 23927267 TI - Solvation of fluoroform and fluoroform-dimethylether dimer in liquid krypton: a theoretical cryospectroscopic study. AB - A hybrid, sequential statistical physics-quantum mechanical electronic-quantum mechanical nuclei approach has been applied to study the C-H stretching frequencies of bare fluoroform dissolved in liquid krypton under cryogenic conditions (at ~130 K), as well as upon blue shifting hydrogen bonding interactions with dimethylether in the same solvent. The structure of the liquid at 130 K was generated by Monte Carlo simulations of cryogenic Kr solutions containing either fluoroform or fluoroform and dimethylether molecules. Statistically uncorrelated configurations were appropriately chosen from the equilibrated MC runs and supermolecular clusters containing solute and solvent molecules (either standalone or embedded in the "bulk" part of the solvent treated as a polarizable continuum) were subjected to quantum mechanical electronic (QMel) and subsequent quantum mechanical nuclei (QMnuc) calculations. QMel calculations were implemented to generate the in-liquid 1D intramolecular C H stretching vibrational potential of the fluoroform moiety and subsequently in the QMnuc phase the corresponding anharmonic C-H stretching frequency was computed by diagonalization techniques. Finally, the constructed vibrational density of states histograms were compared to the experimental Raman bands. The calculated anharmonic vibrational frequency shifts of the fluoroform C-H stretching mode upon interaction with dimethylether in liquid Kr are in very good agreement with the experimental data (20.3 at MP2 level vs. 16.6 cm(-1) experimentally). Most of this relatively large frequency blue shift is governed by configurations characterized by a direct C-H...O contact between monomers. The second population detected during MC simulations, characterized by reversed orientation of the monomers, has a minor contribution to the spectral appearance. The experimentally observed trend in the corresponding bandwidths is also correctly reproduced by our theoretical approach. Solvation of the fluoroform monomer, according to experiment, results in small C-H stretching frequency red shift (~-2 cm(-1)), while our approach predicts a blue shift of about 10 cm(-1). By a detailed analysis of the anharmonic C-H stretching frequency dependence on the position of the nearest solvent krypton atom and also by analyzing the vibrational Stark effect induced by the local fluctuating field component parallel to the C-H axis, we have derived several conclusions related to these observations. The frequency vs. C...Kr distance dependence shows appreciable fluctuations and even changes in sign at R values close to the maximum of the C...Kr radial distribution function, so that most of the first-shell Kr atoms are located at positions at which the CH frequency shifts acquire either small negative or small positive values. It so happens, therefore, that even the actual sign of the frequency shift is strongly dependent on the correct description of the first solvation shell around CF3H by the Monte Carlo method, much more than the other in-liquid properties calculated by similar approaches. PMID- 23927269 TI - 2D IR spectra of cyanide in water investigated by molecular dynamics simulations. AB - Using classical molecular dynamics simulations, the 2D infrared (IR) spectroscopy of CN(-) solvated in D2O is investigated. Depending on the force field parametrizations, most of which are based on multipolar interactions for the CN( ) molecule, the frequency-frequency correlation function and observables computed from it differ. Most notably, models based on multipoles for CN(-) and TIP3P for water yield quantitatively correct results when compared with experiments. Furthermore, the recent finding that T1 times are sensitive to the van der Waals ranges on the CN(-) is confirmed in the present study. For the linear IR spectrum, the best model reproduces the full widths at half maximum almost quantitatively (13.0 cm(-1) vs. 14.9 cm(-1)) if the rotational contribution to the linewidth is included. Without the rotational contribution, the lines are too narrow by about a factor of two, which agrees with Raman and IR experiments. The computed and experimental tilt angles (or nodal slopes) alpha as a function of the 2D IR waiting time compare favorably with the measured ones and the frequency fluctuation correlation function is invariably found to contain three time scales: a sub-ps, 1 ps, and one on the 10-ps time scale. These time scales are discussed in terms of the structural dynamics of the surrounding solvent and it is found that the longest time scale (~10 ps) most likely corresponds to solvent exchange between the first and second solvation shell, in agreement with interpretations from nuclear magnetic resonance measurements. PMID- 23927268 TI - Examining the phase transition behavior of amphiphilic lipids in solution using statistical temperature molecular dynamics and replica-exchange Wang-Landau methods. AB - Two different techniques - replica-exchange Wang-Landau (REWL) and statistical temperature molecular dynamics (STMD) - were applied to systematically study the phase transition behavior of self-assembling lipids as a function of temperature using an off-lattice lipid model. Both methods allow the direct calculation of the density of states with improved efficiency compared to the original Wang Landau method. A 3-segment model of amphiphilic lipids solvated in water has been studied with varied particle interaction energies (epsilon) and lipid concentrations. The phase behavior of the lipid molecules with respect to bilayer formation has been characterized through the calculation of the heat capacity as a function of temperature, in addition to various order parameters and general visual inspection. The simulations conducted by both methods can go to very low temperatures with the whole system exhibiting well-ordered structures. With optimized parameters, several bilayer phases are observed within the temperature range studied, including gel phase bilayers with frozen water, mixed water (i.e., frozen and liquid water), and liquid water, and a more fluid bilayer with liquid water. The results obtained from both methods, STMD and REWL, are consistently in excellent agreement with each other, thereby validating both the methods and the results. PMID- 23927270 TI - Characterization of a high pressure, high temperature modification of ammonia borane (BH3NH3). AB - At elevated pressures (above 1.5 GPa) dihydrogen bonded ammonia borane, BH3NH3, undergoes a solid-solid phase transition with increasing temperature. The high pressure, high temperature (HPHT) phase precedes decomposition and evolves from the known high pressure, low temperature form with space group symmetry Cmc21 (Z = 4). Structural changes of BH3NH3 with temperature were studied at around 6 GPa in a diamond anvil cell by synchrotron powder diffraction. At this pressure the Cmc21 phase transforms into the HPHT phase at around 140 degrees C. The crystal system, unit cell, and B and N atom position parameters of the HPHT phase were extracted from diffraction data, and a hydrogen ordered model with space group symmetry Pnma (Z = 4) subsequently established from density functional calculations. However, there is strong experimental evidence that HPHT-BH3NH3 is a hydrogen disordered rotator phase. A reverse transition to the Cmc21 phase is not observed. When releasing pressure at room temperature to below 1.5 GPa the ambient pressure (hydrogen disordered) I4mm phase of BH3NH3 is obtained. PMID- 23927271 TI - Structural evolution of Ga-Ge-Te glasses by combined EXAFS and XPS analysis. AB - The structural evolution of GaxGeyTe100-x-y glasses in the vicinity of GeTe4 GaTe3 pseudo-binary tie-line is determined with high-resolution X-ray photoelectron (XPS) and extended X-ray absorption fine structure (EXAFS) spectroscopies. The analysis of XPS data is complicated by similar electronegativity values for the constituent chemical elements, but then the interpretation is facilitated by information from complementary EXAFS analysis of the structure around each element independently. The results show 4/4/2 coordination for Ga/Ge/Te atoms and absence of Ga(Ge)-Ge(Ga) bonds or extended Te clusters in significant concentrations within the whole range of studied composition. The observed structural features correlate well with the measured basic physical properties of Ga-containing germanium telluride glasses. PMID- 23927272 TI - Investigation of attractive and repulsive interactions associated with ketones in supercritical CO2, based on Raman spectroscopy and theoretical calculations. AB - Carbonyl compounds are solutes that are highly soluble in supercritical CO2 (scCO2). Their solubility governs the efficiency of chemical reactions, and is significantly increased by changing a chromophore. To effectively use scCO2 as solvent, it is crucial to understand the high solubility of carbonyl compounds, the solvation structure, and the solute-solvent intermolecular interactions. We report Raman spectroscopic data, for three prototypical ketones dissolved in scCO2, and four theoretical analyses. The vibrational Raman spectra of the C=O stretching modes of ketones (acetone, acetophenone, and benzophenone) were measured in scCO2 along the reduced temperature Tr = T/Tc = 1.02 isotherm as a function of the reduced density rhor = rho/rhoc in the range 0.05-1.5. The peak frequencies of the C=O stretching modes shifted toward lower energies as the fluid density increased. The density dependence was analyzed by using perturbed hard-sphere theory, and the shift was decomposed into attractive and repulsive energy components. The attractive energy between the ketones and CO2 was up to nine times higher than the repulsive energy, and its magnitude increased in the following order: acetone < acetophenone < benzophenone. The Mulliken charges of the three solutes and CO2 molecules obtained by using quantum chemistry calculations described the order of the magnitude of the attractive energy and optimized the relative configuration between each solute and CO2. According to theoretical calculations for the dispersion energy, the dipole-induced-dipole interaction energy, and the frequency shift due to their interactions, the experimentally determined attractive energy differences in the three solutes were attributed to the dispersion energies that depended on a chromophore attached to the carbonyl groups. It was found that the major intermolecular interaction with the attractive shift varied from dipole-induced dipole to dispersion depending on the chromophore in the ketones in scCO2. As the common conclusion for the Raman spectral measurements and the four theoretical calculations, solute polarizability, modified by the chromophore, was at the core of the solute solvent interactions of the ketones in scCO2. PMID- 23927273 TI - Pressure effect on vibrational frequency and dephasing of 1-alkyl-3 methylimidazolium hexafluorophosphate ionic liquids. AB - Raman spectra in the range of the totally symmetric stretching mode of the [PF6]( ) anion, nus(PF6), have been measured for 1-alkyl-3-methylimidazolium ionic liquids [CnC1im][PF6], for n = 4, 6, and 8, as a function of pressure at room temperature. The ionic liquids [C6C1im][PF6] and [C8C1im][PF6] remain in an amorphous phase up to 3.5 GPa, in contrast to [C4C1im][PF6], which crystallizes above ~0.5 GPa. Equations of state based either on a group contribution model or Carnahan-Starling-van der Waals model have been used to estimate the densities of the ionic liquids at high pressures. The shifts of the vibrational frequency of nus(PF6) with density observed in [C6C1im][PF6] and in [C8C1im][PF6] have been calculated by a hard-sphere model of a pseudo-diatomic solute under short-range repulsive interactions with the neighboring particles. The stochastic model of Kubo for vibrational dephasing has been used to obtain the amplitude of vibrational frequency fluctuation, , and the relaxation time of frequency fluctuation, tauc, as a function of density by Raman band shape analysis of the nus(PF6) mode of [C6C1im][PF6] and [C8C1im][PF6]. PMID- 23927274 TI - Thermodynamic and structural signatures of water-driven methane-methane attraction in coarse-grained mW water. AB - Hydrophobic interactions are responsible for water-driven processes such as protein folding and self-assembly of biomolecules. Microscopic theories and molecular simulations have been used to study association of a pair of methanes in water, the paradigmatic example of hydrophobic attraction, and determined that entropy is the driving force for the association of the methane pair, while the enthalpy disfavors it. An open question is to which extent coarse-grained water models can still produce correct thermodynamic and structural signatures of hydrophobic interaction. In this work, we investigate the hydrophobic interaction between a methane pair in water at temperatures from 260 to 340 K through molecular dynamics simulations with the coarse-grained monatomic water model mW. We find that the coarse-grained model correctly represents the free energy of association of the methane pair, the temperature dependence of free energy, and the positive change in entropy and enthalpy upon association. We investigate the relationship between thermodynamic signatures and structural order of water through the analysis of the spatial distribution of the density, energy, and tetrahedral order parameter Qt of water. The simulations reveal an enhancement of tetrahedral order in the region between the first and second hydration shells of the methane molecules. The increase in tetrahedral order, however, is far from what would be expected for a clathrate-like or ice-like shell around the solutes. This work shows that the mW water model reproduces the key signatures of hydrophobic interaction without long ranged electrostatics or the need to be re parameterized for different thermodynamic states. These characteristics, and its hundred-fold increase in efficiency with respect to atomistic models, make mW a promising water model for studying water-driven hydrophobic processes in more complex systems. PMID- 23927275 TI - Direct observation of self-assembled chain-like water structures in a nanoscopic water meniscus. AB - Sawtooth-like oscillatory forces generated by water molecules confined between two oxidized silicon surfaces were observed using a cantilever-based optical interfacial force microscope when the two surfaces approached each other in ambient environments. The humidity-dependent oscillatory amplitude and periodicity were 3-12 nN and 3-4 water diameters, respectively. Half of each period was matched with a freely jointed chain model, possibly suggesting that the confined water behaved like a bundle of water chains. The analysis also indicated that water molecules self-assembled to form chain-like structures in a nanoscopic meniscus between two hydrophilic surfaces in air. From the friction force data measured simultaneously, the viscosity of the chain-like water was estimated to be between 10(8) and 10(10) times greater than that of bulk water. The suggested chain-like structure resolves many unexplained properties of confined water at the nanometer scale, thus dramatically improving the understanding of a variety of water systems in nature. PMID- 23927276 TI - Spherical seed mediated vapor condensation of Lennard-Jones fluid: a density functional theory approach. AB - Vapor to liquid condensation in presence of spherical seed particle of any arbitrary radius ranging from zero to infinity has been investigated using density functional theory, by modeling the local Helmholtz free energy density functional as well as the density profile at the vapor-liquid interface. A general theory is, thus, obtained which provides the different modes of nucleation based on the size of the seed ranging from zero (corresponding to the homogeneous mode of nucleation) to infinity (corresponding to the heterogeneous nucleation on flat surface). The theory is applied to the Lennard-Jones fluid and the optimized shape (i.e., contact angle) and formation free energy of droplets of any arbitrary size have been obtained in this work. The change of the shape (optimized) with the variation of the size of the liquid droplet as well as with the size of the solid substrate has been studied, thus predicting the shape-size relationship in the course of vapor to liquid heterogeneous nucleation on a spherical solid substrate of any particular size. The spinodal decomposition of vapor has also been observed at higher strength of the solid-fluid interaction. The results have been compared with the results of the conventional classical nucleation theory. PMID- 23927277 TI - Influence of anisotropic ion shape on structure and capacitance of an electric double layer: a Monte Carlo and density functional study. AB - The effect of anisotropic ion shapes on the structure and the differential capacitance of an electric double layer in the electrolyte solution regime is studied using the density functional theory and Monte Carlo simulations. The double layer is modelled by a uniformly charged, non-polarizable planar electrode next to an electrolyte where the cation is a dimer consisting of two tangentially touching rigid spheres one of which is positively charged while the other is neutral, the anion is a negatively charged rigid sphere, and the solvent is a dielectric continuum. Numerical results are reported for monovalent electrolytes at room temperature for a series of electrolyte concentrations and varying electrode surface charge densities. Asymmetry in ionic shape leads to more structure near the electrode when its charge is opposite to that of the non spherical ions. Overall, the theoretically predicted density and mean electrostatic profiles reproduce the corresponding simulation results to a very good degree. The asymmetry of the ion shape also yields asymmetry in the differential capacitance curve plotted as a function of the electrode charge density. The differential capacity evolves from being distorted bactrian camel shaped (a minimum flanked by a maximum on either side) at low electrolyte concentrations to being bell-like (a single broad maximum) at higher concentrations. The theoretical capacitance results again agree well with the simulations. PMID- 23927279 TI - Molecular theory for the phase equilibria and cluster distribution of associating fluids with small bond angles. AB - We develop a new theory for associating fluids with multiple association sites. The theory accounts for small bond angle effects such as steric hindrance, ring formation, and double bonding. The theory is validated against Monte Carlo simulations for the case of a fluid of patchy colloid particles with three patches and is found to be very accurate. Once validated, the theory is applied to study the phase diagram of a fluid composed of three patch colloids. It is found that bond angle has a significant effect on the phase diagram and the very existence of a liquid-vapor transition. PMID- 23927278 TI - Structure-based coarse-graining for inhomogeneous liquid polymer systems. AB - The iterative Boltzmann inversion (IBI) method is used to derive interaction potentials for coarse-grained (CG) systems by matching structural properties of a reference atomistic system. However, because it depends on such thermodynamic conditions as density and pressure of the reference system, the derived CG nonbonded potential is probably not applicable to inhomogeneous systems containing different density regimes. In this paper, we propose a structure-based coarse-graining scheme to devise CG nonbonded potentials that are applicable to different density bulk systems and inhomogeneous systems with interfaces. Similar to the IBI, the radial distribution function (RDF) of a reference atomistic bulk system is used for iteratively refining the CG nonbonded potential. In contrast to the IBI, however, our scheme employs an appropriately estimated initial guess and a small amount of refinement to suppress transfer of the many-body interaction effects included in the reference RDF into the CG nonbonded potential. To demonstrate the application of our approach to inhomogeneous systems, we perform coarse-graining for a liquid perfluoropolyether (PFPE) film coated on a carbon surface. The constructed CG PFPE model favorably reproduces structural and density distribution functions, not only for bulk systems, but also at the liquid-vacuum and liquid-solid interfaces, demonstrating that our CG scheme offers an easy and practical way to accurately determine nonbonded potentials for inhomogeneous systems. PMID- 23927280 TI - Molecular dynamics of polymer crystallization revisited: crystallization from the melt and the glass in longer polyethylene. AB - Molecular mechanisms of the steady-state growth of the chain folded lamella and the cold crystallization across the glass transition temperature Tg are investigated by molecular dynamics simulation for a system of long polyethylene (PE)-like polymers made of 512 united atoms C512. The present paper aims to reconsider results of our previous simulations for short PE-like polymers C100 by carrying out very long simulations up to 1 MUs for more realistic systems of much longer chains, thereby to establish the firm molecular image of chain-folded crystallization and clarify the specific molecular process of cold crystallization. We observe that the chain-folded lamella shows fast thickening growth keeping marked tapered growth front. Despite the fast growth in much longer chains, the fold-surface is found to be predominantly of adjacent-reentry. Detailed inspections of the molecular pathway give an insightful image that can explain the apparently contradicting results. In addition, the fold-structure with specific spatial heterogeneity is found to give rise to heterogeneous mobility within the crystalline region. On the other hand, investigations of the cold crystallization during slow heating of the glassy film across Tg is found to give a granular texture made of small crystallites. The crystallites are found to nucleate preferentially near the free surfaces having lower Tg, and to be dominantly edge-on showing a definite tendency to orient their chain axes parallel to the free surface. PMID- 23927281 TI - Effective protein-protein interaction from structure factor data of a lysozyme solution. AB - We report the determination of an effective protein-protein central potential for a lysozyme solution, obtained from the direct inversion of the total structure factor of the system, as extracted from small angle neutron scattering. The inversion scheme rests on a hypernetted-chain relationship between the effective potential and the structural functions, and is preliminarily tested for the case of a Lennard-Jones interaction. The characteristics of our potential are discussed in comparison with current models of effective interactions in complex fluids. The phase behavior predictions are also investigated. PMID- 23927282 TI - Effective interactions between solid particles mediated by free polymer in solution. AB - Effective potentials of interaction between solid non-adsorbing surfaces in semidilute or concentrated polymer solutions are calculated using two approaches: the numerical self-consistent-field theory (SCFT) and the analytical theory generalizing the ground-state dominance approximation by taking into account the finite chain-length (chain-end) effects (GSDE). A good agreement between the two approaches is demonstrated within the natural region of validity of the asymptotically exact GSDE theory. It is shown that in most cases the interaction potentials involve the short-range depletion attraction which is replaced by the polymer-mediated repulsion at longer separations ranging from roughly 10xi to 3Rg (xi is the concentration correlation length and Rg is the polymer coil gyration radius). For a given polymer concentration and molecular weight the highest repulsion energy barrier, Um, is predicted for xi/Rg ~ 0.2 and in the theta solvent conditions. The fluctuation-induced (anti-Casimir) polymer-mediated repulsion forces are analyzed as well. It is shown that the overall polymer mediated repulsion energy between naked spherical particles of radius Rc = 200 nm is typically not enough for their kinetic stabilization. There are, however, a few special cases where colloidal stability can be imparted by free polymers only. PMID- 23927283 TI - A new perspective on correlated polyelectrolyte adsorption: positioning, conformation, and patterns. AB - This work focuses on multiple chain deposition, using a coarse-grained model. The phenomenon is assessed from a novel perspective which emphasizes the conformation and relative arrangement of the deposited chains. Variations in chain number and length are considered, and the surface charge in the different systems ranges from partially neutralized to reversed by backbone deposition. New tools are proposed for the analysis of these systems, in which focus is given to configuration-wise approaches that allow the interpretation of correlated multi chain behavior. It is seen that adsorption occurs, with a minimal effect upon the bulk conformation, even when overcharging occurs. Also, chain ends create a lower electrostatic potential, which makes them both the least adsorbed region of the backbone, and the prevalent site of closer proximity with other chains. Additionally, adsorption into the most favorable region of the surface overrides, to a large degree, interchain repulsion. PMID- 23927284 TI - Equivalence of chain conformations in the surface region of a polymer melt and a single Gaussian chain under critical conditions. AB - In the melt polymer conformations are nearly ideal according to Flory's ideality hypothesis. Silberberg generalized this statement for chains in the interfacial region. We check the Silberberg argument by analyzing the conformations of a probe chain end-grafted at a solid surface in a sea of floating free chains of concentration phi by the self-consistent field (SCF) method. Apart from the grafting, probe chain and floating chains are identical. Most of the results were obtained for a standard SCF model with freely jointed chains on a six-choice lattice, where immediate step reversals are allowed. A few data were generated for a five-choice lattice, where such step reversals are forbidden. These coarse grained models describe the equilibrium properties of flexible atactic polymer chains at the scale of the segment length. The concentration was varied over the whole range from phi = 0 (single grafted chain) to phi = 1 (probe chain in the melt). The number of contacts with the surface, average height of the free end and its dispersion, average loop and train length, tail size distribution, end point and overall segment distributions were calculated for a grafted probe chain as a function of phi, for several chain lengths and substrate/polymer interactions, which were varied from strong repulsion to strong adsorption. The computations show that the conformations of the probe chain in the melt do not depend on substrate/polymer interactions and are very similar to the conformations of a single end-grafted chain under critical conditions, and can thus be described analytically. When the substrate/polymer interaction is fixed at the value corresponding to critical conditions, all equilibrium properties of a probe chain are independent of phi, over the whole range from a dilute solution to the melt. We believe that the conformations of all flexible chains in the surface region of the melt are close to those of an appropriate single chain in critical conditions, provided that one end of the single chain is fixed at the same point as a chain in the melt. PMID- 23927285 TI - Stability and orientation of lamellae in diblock copolymer films. AB - The dynamics of microphase separation and the orientation of lamellae in diblock copolymers are investigated in terms of a mean-field model. The formation of lamellar structures and their stable states are explored and it is shown that lamellae are stable not only for the period of the structure corresponding to the minimum of the free energy. The range of wavelengths of stable lamellae is determined by an efficient functional approach introduced with this work. The effects of the interaction of diblock copolymers with two confining substrates on the lamellae orientation are studied by an extensive analysis of the total free energy. By changing the wetting property at one boundary, a transition from a preferentially perpendicular to a parallel lamellar orientation with respect to the confining plates is found, which is rather independent of the distance between the boundaries. Simulations of the dynamics of microphase separation reveal that the time scale of the lamellar orientational order dynamics, which is quantitatively characterized in terms of an orientational order parameter and the structure factor, depends significantly on the properties of the confining boundaries as well as on the quench depth. PMID- 23927286 TI - Dissociative electron attachment to DNA-diamine thin films: impact of the DNA close environment on the OH- and O- decay channels. AB - We measure the desorption of anions stimulated by the impact of 0-20 eV electrons on highly uniform thin films of plasmid DNA-diaminopropane. The results are accurately correlated with film thickness and composition by AFM and XPS measurements, respectively. Resonant structures in the H(-), O(-), and OH(-) yield functions are attributed to the decay of transient anions into the dissociative electron attachment (DEA) channel. The diamine induces ammonium phosphate bridges along the DNA backbone, which suppresses the DEA O(-) channel and in counter-part increases considerably the desorption of OH(-). The close environment of the phosphate groups may therefore play an important role in modulating the rate and type of DNA damages induced by low energy electrons. PMID- 23927287 TI - Acidic pH retards the fibrillization of human Islet Amyloid Polypeptide due to electrostatic repulsion of histidines. AB - The human Islet Amyloid Polypeptide (hIAPP) is the major constituent of amyloid deposits in pancreatic islets of type-II diabetes. IAPP is secreted together with insulin from the acidic secretory granules at a low pH of approximately 5.5 to the extracellular environment at a neutral pH. The increased accumulation of extracellular hIAPP in diabetes indicates that changes in pH may promote amyloid formation. To gain insights and underlying mechanisms of the pH effect on hIAPP fibrillogenesis, all-atom molecular dynamics simulations in explicit solvent model were performed to study the structural properties of five hIAPP protofibrillar oligomers, under acidic and neutral pH, respectively. In consistent with experimental findings, simulation results show that acidic pH is not conducive to the structural stability of these oligomers. This provides a direct evidence for a recent experiment [L. Khemtemourian, E. Domenech, J. P. F. Doux, M. C. Koorengevel, and J. A. Killian, J. Am. Chem. Soc. 133, 15598 (2011)], which suggests that acidic pH inhibits the fibril formation of hIAPP. In addition, a complementary coarse-grained simulation shows the repulsive electrostatic interactions among charged His18 residues slow down the dimerization process of hIAPP by twofold. Besides, our all-atom simulations reveal acidic pH mainly affects the local structure around residue His18 by destroying the surrounding hydrogen-bonding network, due to the repulsive interactions between protonated interchain His18 residues at acidic pH. It is also disclosed that the local interactions nearby His18 operating between adjacent beta-strands trigger the structural transition, which gives hints to the experimental findings that the rate of hIAPP fibril formation and the morphologies of the fibrillar structures are strongly pH-dependent. PMID- 23927288 TI - The role of solvation in the binding selectivity of the L-type calcium channel. AB - We present grand canonical Monte Carlo simulation results for a reduced model of the L-type calcium channel. While charged residues of the protein amino acids in the selectivity filter are treated explicitly, most of the degrees of freedom (including the rest of the protein and the solvent) are represented by their dielectric response, i.e., dielectric continua. The new aspect of this paper is that the dielectric coefficient in the channel is different from that in the baths. The ions entering the channel, thus, cross a dielectric boundary at the entrance of the channel. Simulating this case has been made possible by our recent methodological development [D. Boda, D. Henderson, B. Eisenberg, and D. Gillespie, J. Chem. Phys. 135, 064105 (2011)]. Our main focus is on the effect of solvation energy (represented by the Born energy) on monovalent vs. divalent ion selectivity in the channel. We find no significant change in selectivity by changing the dielectric coefficient in the channel because the larger solvation penalty is counterbalanced by the enhanced Coulomb attraction inside the channel as soon as we use the Born radii (fitted to experimental hydration energies) to compute the solvation penalty from the Born equation. PMID- 23927289 TI - Absolute cross section for loss of supercoiled topology induced by 10 eV electrons in highly uniform /DNA/1,3-diaminopropane films deposited on highly ordered pyrolitic graphite. AB - It was recently shown that the affinity of doubly charged, 1-3 diaminopropane (Dap(2+)) for DNA permits the growth on highly ordered pyrolitic graphite (HOPG) substrates, of plasmid DNA films, of known uniform thickness [O. Boulanouar, A. Khatyr, G. Herlem, F. Palmino, L. Sanche, and M. Fromm, J. Phys. Chem. C 115, 21291-21298 (2011)]. Post-irradiation analysis by electrophoresis of such targets confirms that electron impact at 10 eV produces a maximum in the yield of single strand breaks that can be associated with the formation of a DNA(-) transient anion. Using a well-adapted deterministic survival model for the variation of electron damage with fluence and film thickness, we have determined an absolute cross section for strand-break damage by 10 eV electrons and inelastic scattering attenuation length in DNA-Dap complex films. PMID- 23927291 TI - Note: absolute photoionization cross-section of the vinyl radical. PMID- 23927290 TI - Rapid estimation of hydration thermodynamics of macromolecular regions. AB - This work describes a novel protocol to efficiently calculate the local free energy of hydration of specific regions in macromolecules. The method employs Monte Carlo simulations in the grand canonical ensemble to generate water configurations in a selected spherical region in the macromolecule. Excess energy and entropy of hydration are calculated by analyzing the water configurational distributions following the recently published grid inhomogeneous solvation theory method [C. N. Nguyen, T. K. Young, and M. K. Gilson, J. Chem. Phys. 137, 044101 (2012)]. Our method involves the approximations of treating the macromolecule and distant solvent as rigid and performing calculations on multiple such conformations to account for conformational diversity. These approximations are tested against water configurations obtained from a molecular dynamics simulation. The method is validated by predicting the number and location of water molecules in 5 pockets in the protein Interleukin-1beta for which experimental water occupancy data are available. Free energy values are validated against decoupling free energy perturbation calculations. The results indicate that the approximations used in the method enable efficient prediction of free energies of water displacement. PMID- 23927293 TI - Point/Counterpoint. Brachytherapy is better than external beam therapy for partial breast irradiation. PMID- 23927294 TI - Dosimetric characterization of the GammaClipTM 169Yb low dose rate permanent implant brachytherapy source for the treatment of nonsmall cell lung cancer postwedge resection. AB - PURPOSE: A novel (169)Yb low dose rate permanent implant brachytherapy source, the GammaClipTM, was developed by Source Production & Equipment Co. (New Orleans, LA) which is designed similar to a surgical staple while delivering therapeutic radiation. In this report, the brachytherapy source was characterized in terms of "Dose calculation for photon-emitting brachytherapy sources with average energy higher than 50 keV: Report of the AAPM and ESTRO" by Perez-Calatayud et al. [Med. Phys. 39, 2904-2929 (2012)] using the updated AAPM Task Group Report No. 43 formalism. METHODS: Monte Carlo calculations were performed using Monte Carlo N Particle 5, version 1.6 in water and air, the in-air photon spectrum filtered to remove photon energies below 10 keV in accordance with TG-43U1 recommendations and previously reviewed (169)Yb energy cutoff levels [D. C. Medich, M. A. Tries, and J. M. Munro, "Monte Carlo characterization of an Ytterbium-169 high dose rate brachytherapy source with analysis of statistical uncertainty," Med. Phys. 33, 163-172 (2006)]. TG-43U1 dosimetric data, including SK, D(r,theta), Lambda, gL(r), F(r, theta), phian(r), and phian were calculated along with their statistical uncertainties. Since the source is not axially symmetric, an additional set of calculations were performed to assess the resulting axial anisotropy. RESULTS: The brachytherapy source's dose rate constant was calculated to be (1.22+/-0.03) cGy h(-1) U(-1). The uncertainty in the dose to water calculations, D(r,theta), was determined to be 2.5%, dominated by the uncertainties in the cross sections. The anisotropy constant, phian, was calculated to be 0.960+/-0.011 and was obtained by integrating the anisotropy factor between 1 and 10 cm using a weighting factor proportional to r(-2). The radial dose function was calculated at distances between 0.5 and 12 cm, with a maximum value of 1.20 at 5.15+/-0.03 cm. Radial dose values were fit to a fifth order polynomial and dual exponential regression. Since the source is not axially symmetric, angular Monte Carlo calculations were performed at 1 cm which determined that the maximum azimuthal anisotropy was less than 8%. CONCLUSIONS: With a higher photon energy, shorter half-life and higher initial dose rate 169Yb is an interesting alternative to 125I for the treatment of nonsmall cell lung cancer. PMID- 23927295 TI - Experimental demonstration of direct L-shell x-ray fluorescence imaging of gold nanoparticles using a benchtop x-ray source. AB - PURPOSE: To develop a proof-of-principle L-shell x-ray fluorescence (XRF) imaging system that locates and quantifies sparse concentrations of gold nanoparticles (GNPs) using a benchtop polychromatic x-ray source and a silicon (Si)-PIN diode x ray detector system. METHODS: 12-mm-diameter water-filled cylindrical tubes with GNP concentrations of 20, 10, 5, 0.5, 0.05, 0.005, and 0 mg/cm3 served as calibration phantoms. An imaging phantom was created using the same cylindrical tube but filled with tissue-equivalent gel containing structures mimicking a GNP loaded blood vessel and approximately 1 cm3 tumor. Phantoms were irradiated by a 3-mm-diameter pencil-beam of 62 kVp x-rays filtered by 1 mm aluminum. Fluorescence/scatter photons from phantoms were detected at 90 degrees with respect to the beam direction using a Si-PIN detector placed behind a 2.5-mm diameter lead collimator. The imaging phantom was translated horizontally and vertically in 0.3-mm steps to image a 6 mm*15 mm region of interest (ROI). For each phantom, the net L-shell XRF signal from GNPs was extracted from background, and then corrected for detection efficiency and in-phantom attenuation using a fluorescence-to-scatter normalization algorithm. RESULTS: XRF measurements with calibration phantoms provided a calibration curve showing a linear relationship between corrected XRF signal and GNP mass per imaged voxel. Using the calibration curve, the detection limit (at the 95% confidence level) of the current experimental setup was estimated to be a GNP mass of 0.35 MUg per imaged voxel (1.73*10(-2) cm3). A 2D XRF map of the ROI was also successfully generated, reasonably matching the known spatial distribution as well as showing the local variation of GNP concentrations. CONCLUSIONS: L-shell XRF imaging can be a highly sensitive tool that has the capability of simultaneously imaging the spatial distribution and determining the local concentration of GNPs presented on the order of parts-per-million level within subcentimeter-sized ex vivo samples and superficial tumors during preclinical animal studies. PMID- 23927297 TI - Absolute calibration of optical power for PDT: report of AAPM TG140. AB - This report is primarily concerned with methods for optical calibration of laser power for continuous wave (CW) light sources, predominantly used in photodynamic therapy (PDT). Light power calibration is very important for PDT, however, no clear standard has been established for the calibration procedure nor the requirements of power meters suitable for optical power calibration. The purposes of the report are to provide guidance for establishing calibration procedures for thermopile type power meters and establish calibration uncertainties for most commercially available detectors and readout assemblies. The authors have also provided a review of the use of various power meters for CW and pulsed optical sources, and provided recommended temporal frequencies for optical power meter calibrations and guidance for routine quality assurance procedure. PMID- 23927298 TI - Evaluation of normalized metal artifact reduction (NMAR) in kVCT using MVCT prior images for radiotherapy treatment planning. AB - PURPOSE: To evaluate the metal artifacts in kilovoltage computed tomography (kVCT) images that are corrected using a normalized metal artifact reduction (NMAR) method with megavoltage CT (MVCT) prior images. METHODS: Tissue characterization phantoms containing bilateral steel inserts are used in all experiments. Two MVCT images, one without any metal artifact corrections and the other corrected using a modified iterative maximum likelihood polychromatic algorithm for CT (IMPACT) are translated to pseudo-kVCT images. These are then used as prior images without tissue classification in an NMAR technique for correcting the experimental kVCT image. The IMPACT method in MVCT included an additional model for the pair/triplet production process and the energy dependent response of the MVCT detectors. An experimental kVCT image, without the metal inserts and reconstructed using the filtered back projection (FBP) method, is artificially patched with the known steel inserts to get a reference image. The regular NMAR image containing the steel inserts that uses tissue classified kVCT prior and the NMAR images reconstructed using MVCT priors are compared with the reference image for metal artifact reduction. The Eclipse treatment planning system is used to calculate radiotherapy dose distributions on the corrected images and on the reference image using the Anisotropic Analytical Algorithm with 6 MV parallel opposed 5*10 cm2 fields passing through the bilateral steel inserts, and the results are compared. Gafchromic film is used to measure the actual dose delivered in a plane perpendicular to the beams at the isocenter. RESULTS: The streaking and shading in the NMAR image using tissue classifications are significantly reduced. However, the structures, including metal, are deformed. Some uniform regions appear to have eroded from one side. There is a large variation of attenuation values inside the metal inserts. Similar results are seen in commercially corrected image. Use of MVCT prior images without tissue classification in NMAR significantly reduces these problems. The radiation dose calculated on the reference image is close to the dose measured using the film. Compared to the reference image, the calculated dose difference in the conventional NMAR image, the corrected images using uncorrected MVCT image, and IMPACT corrected MVCT image as priors is ~15.5%, ~5%, and ~2.7%, respectively, at the isocenter. CONCLUSIONS: The deformation and erosion of the structures present in regular NMAR corrected images can be largely reduced by using MVCT priors without tissue segmentation. The attenuation value of metal being incorrect, large dose differences relative to the true value can result when using the conventional NMAR image. This difference can be significantly reduced if MVCT images are used as priors. Reduced tissue deformation, better tissue visualization, and correct information about the electron density of the tissues and metals in the artifact corrected images could help delineate the structures better, as well as calculate radiation dose more correctly, thus enhancing the quality of the radiotherapy treatment planning. PMID- 23927299 TI - 3D inpatient dose reconstruction from the PET-CT imaging of 90Y microspheres for metastatic cancer to the liver: feasibility study. AB - PURPOSE: The introduction of radioembolization with microspheres represents a significant step forward in the treatment of patients with metastatic disease to the liver. This technique uses semiempirical formulae based on body surface area or liver and target volumes to calculate the required total activity for a given patient. However, this treatment modality lacks extremely important information, which is the three-dimensional (3D) dose delivered by microspheres to different organs after their administration. The absence of this information dramatically limits the clinical efficacy of this modality, specifically the predictive power of the treatment. Therefore, the aim of this study is to develop a 3D dose calculation technique that is based on the PET imaging of the infused microspheres. METHODS: The Fluka Monte Carlo code was used to calculate the voxel dose kernel for 90Y source with voxel size equal to that of the PET scan. The measured PET activity distribution was converted to total activity distribution for the subsequent convolution with the voxel dose kernel to obtain the 3D dose distribution. In addition, dose-volume histograms were generated to analyze the dose to the tumor and critical structures. RESULTS: The 3D inpatient dose distribution can be reconstructed from the PET data of a patient scanned after the infusion of microspheres. A total of seven patients have been analyzed so far using the proposed reconstruction method. Four patients underwent treatment with SIR-Spheres for liver metastases from colorectal cancer and three patients were treated with Therasphere for hepatocellular cancer. A total of 14 target tumors were contoured on post-treatment PET-CT scans for dosimetric evaluation. Mean prescription activity was 1.7 GBq (range: 0.58-3.8 GBq). The resulting mean maximum measured dose to targets was 167 Gy (range: 71-311 Gy). Mean minimum dose to 70% of target (D70) was 68 Gy (range: 25-155 Gy). Mean minimum dose to 90% of target (D90) was 53 Gy (range: 13-125 Gy). CONCLUSIONS: A three-dimensional inpatient dose reconstruction method has been developed that is based on the PET/CT data of a patient treated with 90Y microspheres. It allows for a complete description of the absorbed dose by the tumor and critical structures. It represents the first step in building predictive models for treatment outcomes for patients receiving this therapeutic modality as well as it allows for better analysis of patients' dose response and will ultimately improve future treatment administration. PMID- 23927300 TI - A model to simulate the oxygen distribution in hypoxic tumors for different vascular architectures. AB - PURPOSE: As hypoxic cells are more resistant to photon radiation, it is desirable to obtain information about the oxygen distribution in tumors prior to the radiation treatment. Noninvasive techniques are currently not able to provide reliable oxygenation maps with sufficient spatial resolution; therefore mathematical models may help to simulate microvascular architectures and the resulting oxygen distributions in the surrounding tissue. Here, the authors present a new computer model, which uses the vascular fraction of tumor voxels, in principle measurable noninvasively in vivo, as input parameter for simulating realistic PO2 histograms in tumors, assuming certain 3D vascular architectures. METHODS: Oxygen distributions were calculated by solving a reaction-diffusion equation in a reference volume using the particle strength exchange method. Different types of vessel architectures as well as different degrees of vascular heterogeneities are considered. Two types of acute hypoxia (ischemic and hypoxemic) occurring additionally to diffusion-limited (chronic) hypoxia were implemented as well. RESULTS: No statistically significant differences were observed when comparing 2D- and 3D-vessel architectures (p>0.79 in all cases) and highly heterogeneously distributed linear vessels show good agreement, when comparing with published experimental intervessel distance distributions and PO2 histograms. It could be shown that, if information about additional acute hypoxia is available, its contribution to the hypoxic fraction (HF) can be simulated as well. Increases of 128% and 168% in the HF were obtained when representative cases of ischemic and hypoxemic acute hypoxia, respectively, were considered in the simulations. CONCLUSIONS: The presented model is able to simulate realistic microscopic oxygen distributions in tumors assuming reasonable vessel architectures and using the vascular fraction as macroscopic input parameter. The model may be used to generate PO2 histograms, which are needed as input in models predicting the radiation response of hypoxic tumors. PMID- 23927301 TI - An algorithm to assess the need for clinical Monte Carlo dose calculation for small proton therapy fields based on quantification of tissue heterogeneity. AB - PURPOSE: In proton therapy, complex density heterogeneities within the beam path constitute a challenge to dose calculation algorithms. This might question the reliability of dose distributions predicted by treatment planning systems based on analytical dose calculation. For cases in which substantial dose errors are expected, resorting to Monte Carlo dose calculations might be essential to ensure a successful treatment outcome and therefore the benefit is worth a presumably long computation time. The aim of this study was to define an indicator for the accuracy of dose delivery based on analytical dose calculations in treatment planning systems for small proton therapy fields to identify those patients for which Monte Carlo dose calculation is warranted. METHODS: Fourteen patients treated at our facility with small passively scattered proton beams (apertures diameters below 7 cm) were selected. Plans were generated in the XiO treatment planning system in combination with a pencil beam algorithm developed at the Massachusetts General Hospital and compared to Monte Carlo dose calculations. Differences in the dose to the 50% of the gross tumor volume (D50, GTV) were assessed in a field-by-field basis. A simple and fast methodology was developed to quantify the inhomogeneity of the tissue traversed by a single small proton beam using a heterogeneity index (HI)-a concept presented by Plugfelder et al. [Med. Phys. 34, 1506-1513 (2007)] for scanned proton beams. Finally, the potential correlation between the error made by the pencil beam based treatment planning algorithm for each field and the level of tissue heterogeneity traversed by the proton beam given by the HI was evaluated. RESULTS: Discrepancies up to 5.4% were found in D50 for single fields, although dose differences were within clinical tolerance levels (<3%) when combining all of the fields involved in the treatment. The discrepancies found for each field exhibited a strong correlation to their associated HI-values (Spearman's rho=0.8, p<0.0001); the higher the level of tissue inhomogeneities for a particular field, the larger the error by the analytical algorithm. With the established correlation a threshold for HI can be set by choosing a tolerance level of 2-3%-commonly accepted in radiotherapy. CONCLUSIONS: The HI is a good indicator for the accuracy of proton field delivery in terms of GTV prescription dose coverage when small fields are delivered. Each HI-value was obtained from the CT image in less than 3 min on a computer with 2 GHz CPU allowing implementation of this methodology in clinical routine. For HI values exceeding the threshold, either a change in beam direction (if feasible) or a recalculation of the dose with Monte Carlo would be highly recommended. PMID- 23927302 TI - A linear programming model for optimizing HDR brachytherapy dose distributions with respect to mean dose in the DVH-tail. AB - PURPOSE: Recent research has shown that the optimization model hitherto used in high-dose-rate (HDR) brachytherapy corresponds weakly to the dosimetric indices used to evaluate the quality of a dose distribution. Although alternative models that explicitly include such dosimetric indices have been presented, the inclusion of the dosimetric indices explicitly yields intractable models. The purpose of this paper is to develop a model for optimizing dosimetric indices that is easier to solve than those proposed earlier. METHODS: In this paper, the authors present an alternative approach for optimizing dose distributions for HDR brachytherapy where dosimetric indices are taken into account through surrogates based on the conditional value-at-risk concept. This yields a linear optimization model that is easy to solve, and has the advantage that the constraints are easy to interpret and modify to obtain satisfactory dose distributions. RESULTS: The authors show by experimental comparisons, carried out retrospectively for a set of prostate cancer patients, that their proposed model corresponds well with constraining dosimetric indices. All modifications of the parameters in the authors' model yield the expected result. The dose distributions generated are also comparable to those generated by the standard model with respect to the dosimetric indices that are used for evaluating quality. CONCLUSIONS: The authors' new model is a viable surrogate to optimizing dosimetric indices and quickly and easily yields high quality dose distributions. PMID- 23927296 TI - MR-guided focused ultrasound surgery, present and future. AB - MR-guided focused ultrasound surgery (MRgFUS) is a quickly developing technology with potential applications across a spectrum of indications traditionally within the domain of radiation oncology. Especially for applications where focal treatment is the preferred technique (for example, radiosurgery), MRgFUS has the potential to be a disruptive technology that could shift traditional patterns of care. While currently cleared in the United States for the noninvasive treatment of uterine fibroids and bone metastases, a wide range of clinical trials are currently underway, and the number of publications describing advances in MRgFUS is increasing. However, for MRgFUS to make the transition from a research curiosity to a clinical standard of care, a variety of challenges, technical, financial, clinical, and practical, must be overcome. This installment of the Vision 20/20 series examines the current status of MRgFUS, focusing on the hurdles the technology faces before it can cross over from a research technique to a standard fixture in the clinic. It then reviews current and near-term technical developments which may overcome these hurdles and allow MRgFUS to break through into clinical practice. PMID- 23927303 TI - Implementation and commissioning of an integrated micro-CT/RT system with computerized independent jaw collimation. AB - PURPOSE: To design, construct, and commission a set of computer-controlled motorized jaws for a micro-CT/RT system to perform conformal image-guided small animal radiotherapy. METHODS: The authors designed and evaluated a system of custom-built motorized orthogonal jaws, which allows the delivery of off-axis rectangular fields on a GE eXplore CT 120 preclinical imaging system. The jaws in the x direction are independently driven, while the y-direction jaws are symmetric. All motors have backup encoders, verifying jaw positions. Mechanical performance of the jaws was characterized. Square beam profiles ranging from 2*2 to 60*60 mm2 were measured using EBT2 film in the center of a 70*70*22 mm3 solid water block. Similarly, absolute depth dose was measured in a solid water and EBT2 film stack 50*50*50 mm3. A calibrated Farmer ion chamber in a 70*70*20 mm3 solid water block was used to measure the output of three field sizes: 50*50, 40*40, and 30*30 mm2. Elliptical target plans were delivered to films to assess overall system performance. Respiratory-gated treatment was implemented on the system and initially proved using a simple sinusoidal motion phantom. All films were scanned on a flatbed scanner (Epson 1000XL) and converted to dose using a fitted calibration curve. A Monte Carlo beam model of the micro-CT with the jaws has been created using BEAMnrc for comparison with the measurements. An example image-guided partial lung irradiation in a rat is demonstrated. RESULTS: The averaged random error of positioning each jaw is less than 0.1 mm. Relative output factors measured with the ion chamber agree with Monte Carlo simulations within 2%. Beam profiles and absolute depth dose curves measured from the films agree with simulations within measurement uncertainty. Respiratory-gated treatments applied to a phantom moving with a peak-to-peak amplitude of 5 mm showed improved beam penumbra (80%-20%) from 3.9 to 0.8 mm. CONCLUSIONS: A set of computer-controlled motorized jaws for a micro-CT/RT system were constructed with position reliably better than a tenth of a millimeter. The hardware system is ready for image-guided conformal radiotherapy for small animals with capability of respiratory-gated delivery. PMID- 23927304 TI - The usefulness of vinyl polysiloxane dental impression material as a proton beam stopper to save normal tissue during irradiation of the oral cavity: basic and clinical verifications. AB - PURPOSE: To evaluate the feasibility and usefulness of vinyl polysiloxane (VPS) dental impression material as a proton beam stopper for oral cavity irradiation. METHODS: VPS compounds with different base-catalyst mixture ratios were created, and the relative linear stopping power (RLSP) of each VPS compound was measured to compare with the RLSPs obtained from converted CT data. Then, a model plan was created to simulate oral cancer, and depth-dose distributions that were calculated using radiation treatment planning (RTP) were investigated by comparing the distribution with the measurements. The radioactivation of the VPS material was also measured after 2-Gy proton beam irradiations. For clinical use, a T4 gingival squamous cell carcinoma was treated using proton beam therapy with a VPS bite block. Treatment plans with and without the VPS bite block were created, and the dose-volume histograms (DVH) of the tongues were compared. RESULTS: Both the RLSPs and the CT numbers were constant of the ratio of VPS mixtures. The measured RLSP of the VPS was 1.51+/-0.01, which was approximately 4% greater than the CT-converted RLSP. In a model simulation, the measured depth dose distribution inside the VPS dropped steeply compared to the RTP calculation, and the dose behind the VPS bite block was less than 0.1% of the prescribed dose. The equivalent dose rates for VPS immediately after irradiation were below 1 MUSv/h and reached background levels within 30 min. In clinical use, VPS reduced a 10 cc local overdose region as well as the mean dose in the tongue compared to the plan without VPS, while the DVH of the planning target volume was maintained. The onset of severe mucositis was not observed behind the VPS bite block. CONCLUSIONS: VPS is easy to shape and reproducible. The authors succeeded in demonstrating its safety and accuracy as a proton beam stopper. PMID- 23927305 TI - Toward a planning scheme for emission guided radiation therapy (EGRT): FDG based tumor tracking in a metastatic breast cancer patient. AB - PURPOSE: Emission guided radiation therapy (EGRT) is a new modality that uses PET emissions in real-time for direct tumor tracking during radiation delivery. Radiation beamlets are delivered along positron emission tomography (PET) lines of response (LORs) by a fast rotating ring therapy unit consisting of a linear accelerator (Linac) and PET detectors. The feasibility of tumor tracking and a primitive modulation method to compensate for attenuation have been demonstrated using a 4D digital phantom in our prior work. However, the essential capability of achieving dose modulation as in conventional intensity modulated radiation therapy (IMRT) treatments remains absent. In this work, the authors develop a planning scheme for EGRT to accomplish sophisticated intensity modulation based on an IMRT plan while preserving tumor tracking. METHODS: The planning scheme utilizes a precomputed LOR response probability distribution to achieve desired IMRT planning modulation with effects of inhomogeneous attenuation and nonuniform background activity distribution accounted for. Evaluation studies are performed on a 4D digital patient with a simulated lung tumor and a clinical patient who has a moving breast cancer metastasis in the lung. The Linac dose delivery is simulated using a voxel-based Monte Carlo algorithm. The IMRT plan is optimized for a planning target volume (PTV) that encompasses the tumor motion using the MOSEK package and a Pinnacle3TM workstation (Philips Healthcare, Fitchburg, WI) for digital and clinical patients, respectively. To obtain the emission data for both patients, the Geant4 application for tomographic emission (GATE) package and a commercial PET scanner are used. As a comparison, 3D and helical IMRT treatments covering the same PTV based on the same IMRT plan are simulated. RESULTS: 3D and helical IMRT treatments show similar dose distribution. In the digital patient case, compared with the 3D IMRT treatment, EGRT achieves a 15.1% relative increase in dose to 95% of the gross tumor volume (GTV) and a 31.8% increase to 50% of the GTV. In the patient case, EGRT yields a 15.2% relative increase in dose to 95% of the GTV and a 20.7% increase to 50% of the GTV. The organs at risk (OARs) doses are kept similar or lower for EGRT in both cases. Tumor tracking is observed in the presence of planning modulation in all EGRT treatments. CONCLUSIONS: As compared to conventional IMRT treatments, the proposed EGRT planning scheme allows an escalated target dose while keeping dose to the OARs within the same planning limits. With the capabilities of incorporating planning modulation and accurate tumor tracking, EGRT has the potential to greatly improve targeting in radiation therapy and enable a practical and effective implementation of 4D radiation therapy for planning and delivery. PMID- 23927306 TI - Preliminary evaluation of multifield and single-field optimization for the treatment planning of spot-scanning proton therapy of head and neck cancer. AB - PURPOSE: Spot-scanning proton therapy (SSPT) using multifield optimization (MFO) can generate highly conformal dose distributions, but it is more sensitive to setup and range uncertainties than SSPT using single-field optimization (SFO). The authors compared the two optimization methods for the treatment of head and neck cancer with bilateral targets and determined the superior method on the basis of both the plan quality and the plan robustness in the face of setup and range uncertainties. METHODS: Four patients with head and neck cancer with bilateral targets who received SSPT treatment in the authors' institution were studied. The patients had each been treated with a MFO plan using three fields. A three-field SFO plan (3F-SFO) and a two-field SFO plan (2F-SFO) with the use of a range shifter in the beam line were retrospectively generated for each patient. The authors compared the plan quality and robustness to uncertainties of the SFO plans with the MFO plans. Robustness analysis of each plan was performed to generate the two dose distributions consisting of the highest and the lowest possible doses (worst-case doses) from the spatial and range perturbations at every voxel. Dosimetric indices from the nominal and worst-case plans were compared. RESULTS: The 3F-SFO plans generally yielded D95 and D5 values in the targets that were similar to those of the MFO plans. 3F-SFO resulted in a lower dose to the oral cavity than MFO in all four patients by an average of 9.9 Gy, but the dose to the two parotids was on average 6.7 Gy higher for 3F-SFO than for MFO. 3F-SFO plans reduced the variations of dosimetric indices under uncertainties in the targets by 22.8% compared to the MFO plans. Variations of dosimetric indices under uncertainties in the organs at risk (OARs) varied between organs and between patients, although they were on average 9.2% less for the 3F-SFO plans than for the MFO plans. Compared with the MFO plans, the 2F-SFO plans showed a reduced dose to the parotids for both the nominal dose and in the worst-case scenario, but the plan robustness in the target of the 2F-SFO plans was not notably greater than that of the MFO plans. CONCLUSIONS: Compared with MFO, 3F-SFO improves plan robustness in the targets but degrades dose sparing in the parotids in both the nominal and worst-case scenarios. Although 2F-SFO improves parotid sparing compared with MFO, it produces little improvement in plan robustness. Therefore, considering its tolerable target coverage and sparing of OARs in worst-case scenarios, the authors recommend MFO as the planning method for the treatment of head and neck cancer with bilateral targets. PMID- 23927307 TI - Cobalt-60 tomotherapy: clinical treatment planning and phantom dose delivery studies. AB - PURPOSE: Investigations have shown that a Cobalt-60 (Co-60) radioactive source has the potential to play a role in intensity modulated radiation therapy (IMRT). In this paper, Co-60 tomotherapy's conformal dose delivery potential is evaluated by delivering conformal dose plans on a cylindrical homogeneous phantom containing clinical structures similar to those found in a typical head and neck (H&N) cancer. Also, the clinical potential of Co-60 tomotherapy is investigated by generating 2D clinical treatment plans for H&N and prostate anatomical regions. These plans are compared with the 6 MV based treatment plans for modalities such as linear accelerator-based tomotherapy and broad beam IMRT, and 15 MV based 3D conformal radiation therapy (3DCRT). METHODS: For experimental validation studies, clinical and nonclinical conformal dose patterns were delivered on circular, homogeneous phantoms containing GafChromic film. For clinical planning study, dose calculations were performed with the EGSnrc Monte Carlo program, where a Theratronics 780C Co-60 unit and a 6 MV linear accelerator were modeled with a MIMiC binary multileaf collimator. An inhouse inverse treatment planning system was used to optimize tomotherapy plans using the same optimization parameters for both Co-60 and 6 MV beams. The IMRT and 3DCRT plans for the clinical cases were generated entirely in the Eclipse treatment planning system based on inhouse IMRT and 3DCRT site specific protocols. RESULTS: The doses delivered to the homogeneous phantoms agreed with the calculations, indicating that it is possible to deliver highly conformal doses with the Co-60 unit. The dose distributions for Co-60 tomotherapy clinical plans for both clinical cases were similar to those obtained with 6 MV based tomotherapy and IMRT, and much more conformal compared to 3DCRT plans. The dose area histograms showed that the Co-60 plans achieve the dose objectives for the targets and organs at risk. CONCLUSIONS: These results confirm that Co-60 tomotherapy is capable of providing state-of-the-art conformal dose delivery and could be used for the treatment of targets in both small and larger separation anatomical regions. PMID- 23927308 TI - A measurement technique to determine the calibration accuracy of an electromagnetic tracking system to radiation isocenter. AB - PURPOSE: To present and characterize a measurement technique to quantify the calibration accuracy of an electromagnetic tracking system to radiation isocenter. METHODS: This technique was developed as a quality assurance method for electromagnetic tracking systems used in a multi-institutional clinical hypofractionated prostate study. In this technique, the electromagnetic tracking system is calibrated to isocenter with the manufacturers recommended technique, using laser-based alignment. A test patient is created with a transponder at isocenter whose position is measured electromagnetically. Four portal images of the transponder are taken with collimator rotations of 45 degrees 135 degrees , 225 degrees , and 315 degrees , at each of four gantry angles (0 degrees , 90 degrees , 180 degrees , 270 degrees ) using a 3*6 cm2 radiation field. In each image, the center of the copper-wrapped iron core of the transponder is determined. All measurements are made relative to this transponder position to remove gantry and imager sag effects. For each of the 16 images, the 50% collimation edges are identified and used to find a ray representing the rotational axis of each collimation edge. The 16 collimator rotation rays from four gantry angles pass through and bound the radiation isocenter volume. The center of the bounded region, relative to the transponder, is calculated and then transformed to tracking system coordinates using the transponder position, allowing the tracking system's calibration offset from radiation isocenter to be found. All image analysis and calculations are automated with inhouse software for user-independent accuracy. Three different tracking systems at two different sites were evaluated for this study. RESULTS: The magnitude of the calibration offset was always less than the manufacturer's stated accuracy of 0.2 cm using their standard clinical calibration procedure, and ranged from 0.014 to 0.175 cm. On three systems in clinical use, the magnitude of the offset was found to be 0.053+/-0.036, 0.121+/-0.023, and 0.093+/-0.013 cm. CONCLUSIONS: The method presented here provides an independent technique to verify the calibration of an electromagnetic tracking system to radiation isocenter. The calibration accuracy of the system was better than the 0.2 cm accuracy stated by the manufacturer. However, it should not be assumed to be zero, especially for stereotactic radiation therapy treatments where planning target volume margins are very small. PMID- 23927309 TI - Spatial and dose-response analysis of fibrotic lung changes after stereotactic body radiation therapy. AB - PURPOSE: Stereotactic body radiation therapy (SBRT) is becoming the standard of care for early stage nonoperable lung cancers. Accurate dose-response modeling is challenging for SBRT because of the decreased number of clinical toxicity events. As a surrogate for a clinical toxicity endpoint, studies have proposed to use radiographic changes in follow up computed tomography (CT) scans to evaluate lung SBRT normal tissue effects. The purpose of the current study was to use local fibrotic lung regions to spatially and dosimetrically evaluate lung changes in patients that underwent SBRT. METHODS: Forty seven SBRT patients treated at our institution from 2003 to 2009 were used for the current study. Our patient cohort had a total of 148 follow up CT scans ranging from 3 to 48 months post-therapy. Post-treatment scans were binned into intervals of 3, 6, 12, 18, 24, 30, and 36 months after the completion of treatment. Deformable image registration was used to align the follow up CT scans with the pretreatment CT and dose distribution. Areas of visible fibrotic changes were contoured. The centroid of each gross tumor volume (GTV) and contoured fibrosis volume was calculated and the fibrosis volume location and movement (magnitude and direction) relative to the GTV and 30 Gy isodose centroid were analyzed. To perform a dose-response analysis, each voxel in the fibrosis volume was sorted into 10 Gy dose bins and the average CT number value for each dose bin was calculated. Dose-response curves were generated by plotting the CT number as a function of dose bin and time posttherapy. RESULTS: Both fibrosis and GTV centroids were concentrated in the upper third of the lung. The average radial movement of fibrosis centroids relative to the GTV centroids was 2.6 cm with movement greater than 5 cm occurring in 11% of patients. Evaluating dose-response curves revealed an overall trend of increasing CT number as a function of dose. The authors observed a CT number plateau at doses ranging from 30 to 50 Gy for the 3, 6, and 12 months posttherapy time points. There was no evident plateau for the dose-response curves generated using data from the 18, 24, 30, and 36 months posttherapy time points. CONCLUSIONS: Regions of local fibrotic lung changes in patients that underwent SBRT were evaluated spatially and dosimetrically. The authors found that the average fibrosis movement was 2.6 cm with movement greater than 5 cm possible. Evaluating dose-response curves revealed an overall trend of increasing CT number as a function of dose. Furthermore, our dose-response data also suggest that one of the possible explanations of the CT number plateau effect may be the time posttherapy of the acquired data. Understanding normal tissue dose-response is important for reducing toxicity after SBRT, especially in cases where larger tumors are treated. The methods presented in the current work build on prior quantitative studies and further enhance the understanding of normal lung dose response after SBRT. PMID- 23927310 TI - Flattening filter removal for improved image quality of megavoltage fluoroscopy. AB - PURPOSE: Removal of the linear accelerator (linac) flattening filter enables a high rate of dose deposition with reduced treatment time. When used for megavoltage imaging, an unflat beam has reduced primary beam scatter resulting in sharper images. In fluoroscopic imaging mode, the unflat beam has higher photon count per image frame yielding higher contrast-to-noise ratio. The authors' goal was to quantify the effects of an unflat beam on the image quality of megavoltage portal and fluoroscopic images. METHODS: 6 MV projection images were acquired in fluoroscopic and portal modes using an electronic flat-panel imager. The effects of the flattening filter on the relative modulation transfer function (MTF) and contrast-to-noise ratio were quantified using the QC3 phantom. The impact of FF removal on the contrast-to-noise ratio of gold fiducial markers also was studied under various scatter conditions. RESULTS: The unflat beam had improved contrast resolution, up to 40% increase in MTF contrast at the highest frequency measured (0.75 line pairs/mm). The contrast-to-noise ratio was increased as expected from the increased photon flux. The visualization of fiducial markers was markedly better using the unflat beam under all scatter conditions, enabling visualization of thin gold fiducial markers, the thinnest of which was not visible using the unflat beam. CONCLUSIONS: The removal of the flattening filter from a clinical linac leads to quantifiable improvements in the image quality of megavoltage projection images. These gains enable observers to more easily visualize thin fiducial markers and track their motion on fluoroscopic images. PMID- 23927311 TI - The impacts of dental filling materials on RapidArc treatment planning and dose delivery: challenges and solution. AB - PURPOSE: The presence of high-density material in the oral cavity creates dose perturbation in both downstream and upstream directions at the surfaces of dental filling materials (DFM). In this study, the authors have investigated the effect of DFM on head and neck RapidArc treatment plans and delivery. Solutions are proposed to address (1) the issue of downstream dose perturbation, which might cause target under dosage, and (2) to reduce the upstream dose from DFM which may be the primary source of mucositis. In addition, an investigation of the clinical role of a custom-made plastic dental mold/gutter (PDM) in sparing the oral mucosa and tongue reaction is outlined. METHODS: The influence of the dental filling artifacts on dose distribution was investigated using a geometrically well defined head and neck intensity modulated radiation therapy (IMRT) verification phantom (PTW, Freiberg, Germany) with DFM inserts called amalgam, which contained 50% mercury, 25% silver, 14% tin, 8% copper, and 3% other trace metals. Three RapidArc plans were generated in the Varian Eclipse System to treat the oral cavity using the same computer tomography (CT) dataset, including (1) a raw CT image, (2) a streaking artifacts region, which was replaced with a mask of 10 HU, and (3) a 2 cm-thick 6000 HU virtual filter [a volume created in treatment planning system to compensate for beam attenuation, where the thickness of this virtual filter is based on the measured percent depth dose (PDD) data and Eclipse calculation]. The dose delivery for the three plans was verified using Gafchromic EBT2 film measurements. The custom-made PDM technique to reduce backscatter dose was clinically tested on four head and neck cancer patients (T3, N1, M0) with DFM, two patients with PDM and the other two patients without PDM. The thickness calculation of the PDM toward the mucosa and tongue was purely based on the measured upstream dose. Patients' with oral mucosal reaction was clinically examined initially and weekly during the course of radiotherapy. RESULTS: For a RapidArc treatment technique, the backscatter dose from the DFM insert was measured to be 9.25+/-2.17 in the IMRT-verification-phantom. The measured backscatter upstream dose from DFM for a single-field was 22% higher than without the DFM, whereas the downstream dose was lower by 14%. The values of homogeneity index for the plans with and without the application of mask were 0.09 and 0.14, respectively. The calculated mean treatment planning volume (PTV) dose differed from the delivered dose by 13% and was reduced to 2% when using the mask and virtual filter together. A grade 3 mucosa reaction was observed in the control group after 22-24 fractions (44-48 Gy). In contrast, no grade 3 mucositis was observed in the patients wearing the PDM after 25-26 fractions (50-52 Gy). CONCLUSIONS: The backscatter from the DFM for a single, parallel-opposed fields, and RapidArc treatment technique was found significant. The application of mask in replacing streaking artifacts can be useful in improving dose homogeneity in the PTV. The use of a virtual filter around the teeth during the planning phase reduces the target underdosage issue in the phantom. Furthermore, a reduction in mucositis is observed in the head and neck patients with the use of PDM. PMID- 23927312 TI - Gantry-angle resolved VMAT pretreatment verification using EPID image prediction. AB - PURPOSE: Pretreatment verification of volumetric modulated arc therapy (VMAT) dose delivery with electronic portal imaging device (EPID) uses images integrated over the entire delivery or over large subarcs. This work aims to develop a new method for gantry-angle-resolved verification of VMAT dose delivery using EPID. METHODS: An EPID dose prediction model was used to calculate EPID images as a function of gantry angle for eight prostate patient deliveries. EPID image frames at 7.5 frames per second were acquired during delivery via a frame-grabber system. The gantry angle for each image was encoded in kV frames which were synchronized to the MV frames. Gamma analysis results as a function of gantry angle were assessed by integrating the frames over 2 degrees subarcs with an angle-to-agreement tolerance of 0.5 degrees about the measured image angle. RESULTS: The model agreed with EPID images integrated over the entire delivery with average Gamma pass-rates at 2%, 2 mm of 99.7% (10% threshold). The accuracy of the kV derived gantry angle for each image was found to be 0.1 degrees (1 SD) using a phantom test. For the gantry-resolved analysis all Gamma pass-rates were greater than 90% at 3%, 3 mm criteria (with only two exceptions), and more than 90% had a 95% pass-rate, with an average of 97.3%. The measured gantry angle lagged behind the predicted angle by a mean of 0.3 degrees +/-0.3 degrees , with a maximum lag of 1.3 degrees . CONCLUSIONS: The method provides a comprehensive and highly efficient pretreatment verification of VMAT delivery using EPID. Dose delivery accuracy is assessed as a function of gantry angle to ensure accurate treatment. PMID- 23927313 TI - Effect of radiation protraction on BED in the case of large fraction dose. AB - PURPOSE: To investigate the effect of radiation protraction on biologically effective dose (BED) in the case when dose per fraction is significantly greater than the standard dose of 2 Gy. METHODS: By using the modified linear-quadratic model with monoexponential repair, the authors investigate the effect of long treatment times combined with dose escalation. RESULTS: The dependences of the protraction factor and the corresponding BED on fraction time were determined for different doses per fraction typical for stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). In the calculations, the authors consider changes in the BED to the normal tissue under the condition of fixed BED to the target. CONCLUSION: The obtained results demonstrate that simultaneous increase in fraction time and dose per fraction can be beneficial for SRS and SBRT because of the related decrease in BED to normal structures while BED to the target is fixed. PMID- 23927314 TI - Failure-probability driven dose painting. AB - PURPOSE: To demonstrate a data-driven dose-painting strategy based on the spatial distribution of recurrences in previously treated patients. The result is a quantitative way to define a dose prescription function, optimizing the predicted local control at constant treatment intensity. A dose planning study using the optimized dose prescription in 20 patients is performed. METHODS: Patients treated at our center have five tumor subvolumes from the center of the tumor (PET positive volume) and out delineated. The spatial distribution of 48 failures in patients with complete clinical response after (chemo)radiation is used to derive a model for tumor control probability (TCP). The total TCP is fixed to the clinically observed 70% actuarial TCP at five years. Additionally, the authors match the distribution of failures between the five subvolumes to the observed distribution. The steepness of the dose-response is extracted from the literature and the authors assume 30% and 20% risk of subclinical involvement in the elective volumes. The result is a five-compartment dose response model matching the observed distribution of failures. The model is used to optimize the distribution of dose in individual patients, while keeping the treatment intensity constant and the maximum prescribed dose below 85 Gy. RESULTS: The vast majority of failures occur centrally despite the small volumes of the central regions. Thus, optimizing the dose prescription yields higher doses to the central target volumes and lower doses to the elective volumes. The dose planning study shows that the modified prescription is clinically feasible. The optimized TCP is 89% (range: 82%-91%) as compared to the observed TCP of 70%. CONCLUSIONS: The observed distribution of locoregional failures was used to derive an objective, data-driven dose prescription function. The optimized dose is predicted to result in a substantial increase in local control without increasing the predicted risk of toxicity. PMID- 23927315 TI - A novel approach to mammographic breast compression: Improved standardization and reduced discomfort by controlling pressure instead of force. AB - PURPOSE: In x-ray mammography, flattening of the breast improves image quality and reduces absorbed dose. Current mammographic compression guidelines are based on applying a standardized force to each breast. Because breast size is not taken into consideration, this approach leads to large variations in applied pressure (force applied per unit contact area). It is the authors' hypothesis that a pressure-controlled compression protocol, which takes contact area into account, (1) improves standardization across the population in terms of physiological conditions in the compressed breast (blood pressure), and (2) reduces discomfort and pain, particularly the number of severe pain complaints, (3) with limited effects on image quality and absorbed glandular dose (AGD). METHODS: A prospective observational study including 291 craniocaudal (CC) and 299 mediolateral oblique (MLO) breast compressions in 196 women following the authors' hospital's standard compression protocol with 18 decanewton (daN) target force was performed. Breast thickness, applied force, area of contact between breast and compression paddle, and mean pressure were recorded during the entire compression. Pain scores before and after breast compressions were obtained using an 11-point numerical rating scale (NRS). Scores of 7 and higher were considered to indicate severe pain. The authors analyzed differences between the CC and MLO compressions, correlation coefficients (rho) between compression parameters, and odds-ratios (OR) for all parameters as possible predictors for experiencing severe pain using multivariate logistic regression. The observed data were used in two models to estimate what breast thickness, required force, and pain score would be for pressure-controlled compression protocols with target pressures ranging from 4 to 28 kilopascal (kPa). For a selection of 79 mammograms having a 10% or more thickness difference with respect to the prior mammogram, the authors performed a retrospective observer study to assess whether such thickness differences have significant effects on image quality or AGD. RESULTS: In a standard 18 daN force-controlled compression protocol, the authors observed an average pressure of 21.3 kPa+/-54% standard deviation for CC compressions and 14.2 kPa+/-32% for MLO compressions. Women with smaller breasts endured higher pressures and experienced more pain, as indicated by a significant negative correlation (rho=-0.19, p<0.01) between contact area and pain score. Multivariate regression showed that contact area is a strong and significant predictor for severe pain (ORNRS>=7 (CC)=0.10/dm2, p<0.05), as is the case with any pain already present before compression (ORNRS>=7 (CC)=1.61 per NRS-point, p<0.05). Model estimations showed that mammographic breast compression with a standardized pressure of 10 kPa, corresponding with normal arterial blood pressure, may significantly reduce the number of severe pain complaints with an average increase in breast thickness of 9% for small breasts and 2% for large breasts. For an average 16.5% thickness difference in prior-current mammogram pairs, the authors found no differences in image quality and AGD CONCLUSIONS: Model estimations and an observer study showed that pressure-controlled mammographic compression protocols may improve standardization and reduce discomfort with limited effects on image quality and AGD. PMID- 23927316 TI - Modeling lung deformation: a combined deformable image registration method with spatially varying Young's modulus estimates. AB - PURPOSE: Respiratory motion introduces uncertainties in tumor location and lung deformation, which often results in difficulties calculating dose distributions in thoracic radiation therapy. Deformable image registration (DIR) has ability to describe respiratory-induced lung deformation, with which the radiotherapy techniques can deliver high dose to tumors while reducing radiation in surrounding normal tissue. The authors' goal is to propose a DIR method to overcome two main challenges of the previous biomechanical model for lung deformation, i.e., the requirement of precise boundary conditions and the lack of elasticity distribution. METHODS: As opposed to typical methods in biomechanical modeling, the authors' method assumes that lung tissue is inhomogeneous. The authors thus propose a DIR method combining a varying intensity flow (VF) block matching algorithm with the finite element method (FEM) for lung deformation from end-expiratory phase to end-inspiratory phase. Specifically, the lung deformation is formulated as a stress-strain problem, for which the boundary conditions are obtained from the VF block-matching algorithm and the element specific Young's modulus distribution is estimated by solving an optimization problem with a quasi Newton method. The authors measure the spatial accuracy of their nonuniform model as well as a standard uniform model by applying both methods to four-dimensional computed tomography images of six patients. The spatial errors produced by the registrations are computed using large numbers (>1000) of expert-determined landmark point pairs. RESULTS: In right-left, anterior-posterior, and superior inferior directions, the mean errors (standard deviation) produced by the standard uniform FEM model are 1.42(1.42), 1.06(1.05), and 1.98(2.10) mm whereas the authors' proposed nonuniform model reduces these errors to 0.59(0.61), 0.52(0.51), and 0.78(0.89) mm. The overall 3D mean errors are 3.05(2.36) and 1.30(0.97) mm for the uniform and nonuniform models, respectively. CONCLUSIONS: The results indicate that the proposed nonuniform model can simulate patient specific and position-specific lung deformation via spatially varying Young's modulus estimates, which improves registration accuracy compared to the uniform model and is therefore a more suitable description of lung deformation. PMID- 23927317 TI - Metal artifact reduction in CT using fusion based prior image. AB - PURPOSE: In computed tomography, metallic objects in the scanning field create the so-called metal artifacts in the reconstructed images. Interpolation-based methods for metal artifact reduction (MAR) replace the metal-corrupted projection data with surrogate data obtained from interpolation using the surrounding uncorrupted sinogram information. Prior-based MAR methods further improve interpolation-based methods by better estimating the surrogate data using forward projections from a prior image. However, the prior images in most existing prior based methods are obtained from segmented images and misclassification in segmentation often leads to residual artifacts and tissue structure loss in the final corrected images. To overcome these drawbacks, the authors propose a fusion scheme, named fusion prior-based MAR (FP-MAR). METHODS: The FP-MAR method consists of (i) precorrect the image by means of an interpolation-based MAR method and an edge-preserving blur filter; (ii) generate a prior image from the fusion of this precorrected image and the originally reconstructed image with metal parts removed; (iii) forward project this prior image to guide the estimation of the surrogate data using well-developed replacement techniques. RESULTS: Both simulations and clinical image tests are carried out to show that the proposed FP-MAR method can effectively reduce metal artifacts. A comparison with other MAR methods demonstrates that the FP-MAR method performs better in artifact suppression and tissue feature preservation. CONCLUSIONS: From a wide range of clinical cases to which FP-MAR has been tested (single or multiple pieces of metal, various shapes, and sizes), it can be concluded that the proposed fusion based prior image preserves more tissue information than other segmentation-based prior approaches and can provide better estimates of the surrogate data in prior-based MAR methods. PMID- 23927318 TI - Investigation of statistical iterative reconstruction for dedicated breast CT. AB - PURPOSE: Dedicated breast CT has great potential for improving the detection and diagnosis of breast cancer. Statistical iterative reconstruction (SIR) in dedicated breast CT is a promising alternative to traditional filtered backprojection (FBP). One of the difficulties in using SIR is the presence of free parameters in the algorithm that control the appearance of the resulting image. These parameters require tuning in order to achieve high quality reconstructions. In this study, the authors investigated the penalized maximum likelihood (PML) method with two commonly used types of roughness penalty functions: hyperbolic potential and anisotropic total variation (TV) norm. Reconstructed images were compared with images obtained using standard FBP. Optimal parameters for PML with the hyperbolic prior are reported for the task of detecting microcalcifications embedded in breast tissue. METHODS: Computer simulations were used to acquire projections in a half-cone beam geometry. The modeled setup describes a realistic breast CT benchtop system, with an x-ray spectra produced by a point source and an a-Si, CsI:Tl flat-panel detector. A voxelized anthropomorphic breast phantom with 280 MUm microcalcification spheres embedded in it was used to model attenuation properties of the uncompressed woman's breast in a pendant position. The reconstruction of 3D images was performed using the separable paraboloidal surrogates algorithm with ordered subsets. Task performance was assessed with the ideal observer detectability index to determine optimal PML parameters. RESULTS: The authors' findings suggest that there is a preferred range of values of the roughness penalty weight and the edge preservation threshold in the penalized objective function with the hyperbolic potential, which resulted in low noise images with high contrast microcalcifications preserved. In terms of numerical observer detectability index, the PML method with optimal parameters yielded substantially improved performance (by a factor of greater than 10) compared to FBP. The hyperbolic prior was also observed to be superior to the TV norm. A few of the best performing parameter pairs for the PML method also demonstrated superior performance for various radiation doses. In fact, using PML with certain parameter values results in better images, acquired using 2 mGy dose, than FBP reconstructed images acquired using 6 mGy dose. CONCLUSIONS: A range of optimal free parameters for the PML algorithm with hyperbolic and TV norm-based potentials is presented for the microcalcification detection task, in dedicated breast CT. The reported values can be used as starting values of the free parameters, when SIR techniques are used for image reconstruction. Significant improvement in image quality can be achieved by using PML with optimal combination of parameters, as compared to FBP. Importantly, these results suggest improved detection of microcalcifications can be obtained by using PML with lower radiation dose to the patient, than using FBP with higher dose. PMID- 23927319 TI - Kidney segmentation in CT sequences using graph cuts based active contours model and contextual continuity. AB - PURPOSE: Accurate segmentation of renal tissues in abdominal computed tomography (CT) image sequences is an indispensable step for computer-aided diagnosis and pathology detection in clinical applications. In this study, the goal is to develop a radiology tool to extract renal tissues in CT sequences for the management of renal diagnosis and treatments. METHODS: In this paper, the authors propose a new graph-cuts-based active contours model with an adaptive width of narrow band for kidney extraction in CT image sequences. Based on graph cuts and contextual continuity, the segmentation is carried out slice-by-slice. In the first stage, the middle two adjacent slices in a CT sequence are segmented interactively based on the graph cuts approach. Subsequently, the deformable contour evolves toward the renal boundaries by the proposed model for the kidney extraction of the remaining slices. In this model, the energy function combining boundary with regional information is optimized in the constructed graph and the adaptive search range is determined by contextual continuity and the object size. In addition, in order to reduce the complexity of the min-cut computation, the nodes in the graph only have n-links for fewer edges. RESULTS: The total 30 CT images sequences with normal and pathological renal tissues are used to evaluate the accuracy and effectiveness of our method. The experimental results reveal that the average dice similarity coefficient of these image sequences is from 92.37% to 95.71% and the corresponding standard deviation for each dataset is from 2.18% to 3.87%. In addition, the average automatic segmentation time for one kidney in each slice is about 0.36 s. CONCLUSIONS: Integrating the graph-cuts based active contours model with contextual continuity, the algorithm takes advantages of energy minimization and the characteristics of image sequences. The proposed method achieves effective results for kidney segmentation in CT sequences. PMID- 23927320 TI - Development of a dynamic quality assurance testing protocol for multisite clinical trial DCE-CT accreditation. AB - PURPOSE: Credentialing can have an impact on whether or not a clinical trial produces useful quality data that is comparable between various institutions and scanners. With the recent increase of dynamic contrast enhanced-computed tomography (DCE-CT) usage as a companion biomarker in clinical trials, effective quality assurance, and control methods are required to ensure there is minimal deviation in the results between different scanners and protocols at various institutions. This paper attempts to address this problem by utilizing a dynamic flow imaging phantom to develop and evaluate a DCE-CT quality assurance (QA) protocol. METHODS: A previously designed flow phantom, capable of producing predictable and reproducible time concentration curves from contrast injection was fully validated and then utilized to design a DCE-CT QA protocol. The QA protocol involved a set of quantitative metrics including injected and total mass error, as well as goodness of fit comparison to the known truth concentration curves. An additional region of interest (ROI) sensitivity analysis was also developed to provide additional details on intrascanner variability and determine appropriate ROI sizes for quantitative analysis. Both the QA protocol and ROI sensitivity analysis were utilized to test variations in DCE-CT results using different imaging parameters (tube voltage and current) as well as alternate reconstruction methods and imaging techniques. The developed QA protocol and ROI sensitivity analysis was then applied at three institutions that were part of clinical trial involving DCE-CT and results were compared. RESULTS: The inherent specificity of robustness of the phantom was determined through calculation of the total intraday variability and determined to be less than 2.2+/-1.1% (total calculated output contrast mass error) with a goodness of fit (R2) of greater than 0.99+/-0.0035 (n=10). The DCE-CT QA protocol was capable of detecting significant deviations from the expected phantom result when scanning at low mAs and low kVp in terms of quantitative metrics (Injected Mass Error 15.4%), goodness of fit (R2) of 0.91, and ROI sensitivity (increase in minimum input function ROI radius by 146+/-86%). These tests also confirmed that the ASIR reconstruction process was beneficial in reducing noise without substantially increasing partial volume effects and that vendor specific modes (e.g., axial shuttle) did not significantly affect the phantom results. The phantom and QA protocol were finally able to quickly (<90 min) and successfully validate the DCE CT imaging protocol utilized at the three separate institutions of a multicenter clinical trial; thereby enhancing the confidence in the patient data collected. CONCLUSIONS: A DCE QA protocol was developed that, in combination with a dynamic multimodality flow phantom, allows the intrascanner variability to be separated from other sources of variability such as the impact of injection protocol and ROI selection. This provides a valuable resource that can be utilized at various clinical trial institutions to test conformance with imaging protocols and accuracy requirements as well as ensure that the scanners are performing as expected for dynamic scans. PMID- 23927321 TI - Anatomical noise in contrast-enhanced digital mammography. Part II. Dual-energy imaging. AB - PURPOSE: Dual-energy (DE) contrast-enhanced digital mammography (CEDM) uses an iodinated contrast agent in combination with digital mammography (DM) to evaluate lesions on the basis of tumor angiogenesis. In DE imaging, low-energy (LE) and high-energy (HE) images are acquired after contrast administration and their logarithms are subtracted to cancel the appearance of normal breast tissue. Often there is incomplete signal cancellation in the subtracted images, creating a background "clutter" that can impair lesion detection. This is the second component of a two-part report on anatomical noise in CEDM. In Part I the authors characterized the anatomical noise for single-energy (SE) temporal subtraction CEDM by a power law, with model parameters alpha and beta. In this work the authors quantify the anatomical noise in DE CEDM clinical images and compare this with the noise in SE CEDM. The influence on the anatomical noise of the presence of iodine in the breast, the timing of imaging postcontrast administration, and the x-ray energy used for acquisition are each evaluated. METHODS: The power law parameters, alpha and beta, were measured from unprocessed LE and HE images and from DE subtracted images to quantify the anatomical noise. A total of 98 DE CEDM cases acquired in a previous clinical pilot study were assessed. Conventional DM images from 75 of the women were evaluated for comparison with DE CEDM. The influence of the imaging technique on anatomical noise was determined from an analysis of differences between the power law parameters as measured in DM, LE, HE, and DE subtracted images for each subject. RESULTS: In DE CEDM, weighted image subtraction lowers beta to about 1.1 from 3.2 and 3.1 in LE and HE unprocessed images, respectively. The presence of iodine has a small but significant effect in LE images, reducing beta by about 0.07 compared to DM, with alpha unchanged. Increasing the x-ray energy, from that typical in DM to a HE beam, significantly decreases alpha by about 2*10(-5) mm2, and lowers beta by about 0.14 compared to LE images. A comparison of SE and DE CEDM at 4 min postcontrast shows equivalent power law parameters in unprocessed images, and lower alpha and beta by about 3*10(-5) mm2 and 0.50, respectively, in DE versus SE subtracted images. CONCLUSIONS: Image subtraction in both SE and DE CEDM reduces beta by over a factor of 2, while maintaining alpha below that in DM. Given the equivalent alpha between SE and DE unprocessed CEDM images, and the smaller anatomical noise in the DE subtracted images, the DE approach may have an advantage over SE CEDM. It will be necessary to test this potential advantage in future lesion detectability experiments, which account for realistic lesion signals. The authors' results suggest that LE images could be used in place of DM images in CEDM exam interpretation. PMID- 23927322 TI - Correlation between model observer and human observer performance in CT imaging when lesion location is uncertain. AB - PURPOSE: The purpose of this study was to investigate the correlation between model observer and human observer performance in CT imaging for the task of lesion detection and localization when the lesion location is uncertain. METHODS: Two cylindrical rods (3-mm and 5-mm diameters) were placed in a 35*26 cm torso shaped water phantom to simulate lesions with -15 HU contrast at 120 kV. The phantom was scanned 100 times on a 128-slice CT scanner at each of four dose levels (CTDIvol=5.7, 11.4, 17.1, and 22.8 mGy). Regions of interest (ROIs) around each lesion were extracted to generate images with signal-present, with each ROI containing 128*128 pixels. Corresponding ROIs of signal-absent images were generated from images without lesion mimicking rods. The location of the lesion (rod) in each ROI was randomly distributed by moving the ROIs around each lesion. Human observer studies were performed by having three trained observers identify the presence or absence of lesions, indicating the lesion location in each image and scoring confidence for the detection task on a 6-point scale. The same image data were analyzed using a channelized Hotelling model observer (CHO) with Gabor channels. Internal noise was added to the decision variables for the model observer study. Area under the curve (AUC) of ROC and localization ROC (LROC) curves were calculated using a nonparametric approach. The Spearman's rank order correlation between the average performance of the human observers and the model observer performance was calculated for the AUC of both ROC and LROC curves for both the 3- and 5-mm diameter lesions. RESULTS: In both ROC and LROC analyses, AUC values for the model observer agreed well with the average values across the three human observers. The Spearman's rank order correlation values for both ROC and LROC analyses for both the 3- and 5-mm diameter lesions were all 1.0, indicating perfect rank ordering agreement of the figures of merit (AUC) between the average performance of the human observers and the model observer performance. CONCLUSIONS: In CT imaging of different sizes of low-contrast lesions (-15 HU), the performance of CHO with Gabor channels was highly correlated with human observer performance for the detection and localization tasks with uncertain lesion location in CT imaging at four clinically relevant dose levels. This suggests the ability of Gabor CHO model observers to meaningfully assess CT image quality for the purpose of optimizing scan protocols and radiation dose levels in detection and localization tasks for low-contrast lesions. PMID- 23927323 TI - Technical note: algebraic iterative image reconstruction using a cylindrical image grid for tetrahedron beam computed tomography. AB - PURPOSE: To accelerate iterative algebraic reconstruction algorithms using a cylindrical image grid. METHODS: Tetrahedron beam computed tomography (TBCT) is designed to overcome the scatter and detector problems of cone beam computed tomography (CBCT). Iterative algebraic reconstruction algorithms have been shown to mitigate approximate reconstruction artifacts that appear at large cone angles, but clinical implementation is limited by their high computational cost. In this study, a cylindrical voxelization method on a cylindrical grid is developed in order to take advantage of the symmetries of the cylindrical geometry. The cylindrical geometry is a natural fit for the circular scanning trajectory employed in volumetric CT methods such as CBCT and TBCT. This method was implemented in combination with the simultaneous algebraic reconstruction technique (SART). Both two- and three-dimensional numerical phantoms as well as a patient CT image were utilized to generate the projection sets used for reconstruction. The reconstructed images were compared to the original phantoms using a set of three figures of merit (FOM). RESULTS: The cylindrical voxelization on a cylindrical reconstruction grid was successfully implemented in combination with the SART reconstruction algorithm. The FOM results showed that the cylindrical reconstructions were able to maintain the accuracy of the Cartesian reconstructions. In three dimensions, the cylindrical method provided better accuracy than the Cartesian methods. At the same time, the cylindrical method was able to provide a speedup factor of approximately 40 while also reducing the system matrix storage size by 2 orders of magnitude. CONCLUSIONS: TBCT image reconstruction using a cylindrical image grid was able to provide a significant improvement in the reconstruction time and a more compact system matrix for storage on the hard drive and in memory while maintaining the image quality provided by the Cartesian voxelization on a Cartesian grid. PMID- 23927324 TI - DQE of wireless digital detectors: comparative performance with differing filtration schemes. AB - PURPOSE: Wireless flat panel detectors are gaining increased usage in portable medical imaging. Two such detectors were evaluated and compared with a conventional flat-panel detector using the formalism of the International Electrotechnical Commission (IEC 62220-1) for measuring modulation transfer function (MTF), normalized noise power spectrum (NNPS), and detective quantum efficiency (DQE) using two different filtration schemes. METHODS: Raw images were acquired for three image receptors (DRX-1C and DRX-1, Carestream Health; Inc., Pixium 4600, Trixell) using a radiographic system with a well-characterized output (Philips Super80 CP, Philips Healthcare). Free in-air exposures were measured using a calibrated radiation meter (Unfors Mult-O-Meter Type 407, Unfors Instruments AB). Additional aluminum filtration and a new alternative combined copper-aluminum filtration were used to conform the x ray output to IEC-specified beam quality definitions RQA5 and RQA9. Using the IEC 62220-1 formalism, each detector was evaluated at XN/2, XN, and 2XN, where the normal exposure level to the detector surface (XN) was set to 8.73 MUGy (1.0 mR). The prescribed edge test device was used to evaluate the MTF, while the NNPS was measured using uniform images. The DQE was then calculated from the MTF and NNPS and compared across detectors, exposures, and filtration schemes. RESULTS: The three DR systems had largely comparable MTFs with DRX-1 demonstrating lower values above 1.0 cycles/mm. At each exposure, DRX-1C and Pixium detectors demonstrated better noise performance than that of DRX-1. Zero-frequency DQEs for DRX-1C, Pixium, and DRX-1 detectors were approximately 74%, 63%, and 38% for RQA5 and 50%, 42%, and 28% for RQA9, respectively. CONCLUSIONS: DRX-1C detector exhibited superior DQE performance compared to Pixium and DRX-1. In terms of filtration, the alternative filtration was found to provide comparable performance in terms of rank ordering of different detectors with the added convenience of being less bulky for in-the field measurements. PMID- 23927325 TI - In-line phase shift tomosynthesis. AB - PURPOSE: The purpose of this work is to (1) demonstrate laboratory measurements of phase shift images derived from in-line phase-contrast radiographs using the attenuation-partition based algorithm (APBA) of Yan et al. [Opt. Express 18(15), 16074-16089 (2010)], (2) verify that the APBA reconstructed images obey the linearity principle, and (3) reconstruct tomosynthesis phase shift images from a collection of angularly sampled planar phase shift images. METHODS: An unmodified, commercially available cabinet x-ray system (Faxitron LX-60) was used in this experiment. This system contains a tungsten anode x-ray tube with a nominal focal spot size of 10 MUm. The digital detector uses CsI/CMOS with a pixel size of 50*50 MUm. The phantoms used consisted of one acrylic plate, two polystyrene plates, and a habanero pepper. Tomosynthesis images were reconstructed from 51 images acquired over a +/-25 degrees arc. All phase shift images were reconstructed using the APBA. RESULTS: Image contrast derived from the planar phase shift image of an acrylic plate of uniform thickness exceeded the contrast of the traditional attenuation image by an approximate factor of two. Comparison of the planar phase shift images from a single, uniform thickness polystyrene plate with two polystyrene plates demonstrated an approximate linearity of the estimated phase shift with plate thickness (-1600 rad vs -2970 rad). Tomographic phase shift images of the habanero pepper exhibited acceptable spatial resolution and contrast comparable to the corresponding attenuation image. CONCLUSIONS: This work demonstrated the feasibility of laboratory-based phase shift tomosynthesis and suggests that phase shift imaging could potentially provide a new imaging biomarker. Further investigation will be needed to determine if phase shift contrast will be able to provide new tissue contrast information or improved clinical performance. PMID- 23927326 TI - Automated iterative neutrosophic lung segmentation for image analysis in thoracic computed tomography. AB - PURPOSE: Lung segmentation is a fundamental step in many image analysis applications for lung diseases and abnormalities in thoracic computed tomography (CT). The authors have previously developed a lung segmentation method based on expectation-maximization (EM) analysis and morphological operations (EMM) for our computer-aided detection (CAD) system for pulmonary embolism (PE) in CT pulmonary angiography (CTPA). However, due to the large variations in pathology that may be present in thoracic CT images, it is difficult to extract the lung regions accurately, especially when the lung parenchyma contains extensive lung diseases. The purpose of this study is to develop a new method that can provide accurate lung segmentation, including those affected by lung diseases. METHODS: An iterative neutrosophic lung segmentation (INLS) method was developed to improve the EMM segmentation utilizing the anatomic features of the ribs and lungs. The initial lung regions (ILRs) were extracted using our previously developed EMM method, in which the ribs were extracted using 3D hierarchical EM segmentation and the ribcage was constructed using morphological operations. Based on the anatomic features of ribs and lungs, the initial EMM segmentation was refined using INLS to obtain the final lung regions. In the INLS method, the anatomic features were mapped into a neutrosophic domain, and the neutrosophic operation was performed iteratively to refine the ILRs. With IRB approval, 5 and 58 CTPA scans were collected retrospectively and used as training and test sets, of which 2 and 34 cases had lung diseases, respectively. The lung regions manually outlined by an experienced thoracic radiologist were used as reference standard for performance evaluation of the automated lung segmentation. The percentage overlap area (POA), the Hausdorff distance (Hdist), and the average distance (AvgDist) of the lung boundaries relative to the reference standard were used as performance metrics. RESULTS: The proposed method achieved larger POAs and smaller distance errors than the EMM method. For the 58 test cases, the average POA, Hdist, and AvgDist were improved from 85.4+/-18.4%, 22.6+/-29.4 mm, and 3.5+/-5.4 mm using EMM to 91.2+/-6.7%, 16.0+/-11.3 mm, and 2.5+/-1.0 mm using INLS, respectively. The improvements were statistically significant (p<0.05). To evaluate the accuracy of the INLS method in the identification of the lung boundaries affected by lung diseases, the authors separately analyzed the performance of the proposed method on the cases with versus without the lung diseases. The results showed that the cases without lung diseases were segmented more accurately than the cases with lung diseases by both the EMM and the INLS methods, but the INLS method achieved better performance than the EMM method in both cases. CONCLUSIONS: The new INLS method utilizing the anatomic features of the rib and lung significantly improved the accuracy of lung segmentation, especially for the cases affected by lung diseases. Improvement in lung segmentation will facilitate many image analysis tasks and CAD applications for lung diseases and abnormalities in thoracic CT, including automated PE detection. PMID- 23927327 TI - Heel effect adaptive flat field correction of digital x-ray detectors. AB - PURPOSE: Anode heel effect renders large-scale background nonuniformities in digital radiographs. Conventional offset/gain calibration is performed at mono source-to-image distance (SID), and disregards the SID-dependent characteristic of heel effect. It results in a residual nonuniform background in the corrected radiographs when the SID settings for calibration and correction differ. In this work, the authors develop a robust and efficient computational method for digital x-ray detector gain correction adapted to SID-variant heel effect, without resorting to physical filters, phantoms, complicated heel effect models, or multiple-SID calibration and interpolation. METHODS: The authors present the Duo SID projection correction method. In our approach, conventional offset/gain calibrations are performed only twice, at the minimum and maximum SIDs of the system in typical clinical use. A fast iterative separation algorithm is devised to extract the detector gain and basis heel patterns from the min/max SID calibrations. The resultant detector gain is independent of SID, while the basis heel patterns are parameterized by the min- and max-SID. The heel pattern at any SID is obtained from the min-SID basis heel pattern via projection imaging principles. The system gain desired at a specific acquisition SID is then constructed using the projected heel pattern and detector gain map. RESULTS: The method was evaluated for flat field and anatomical phantom image corrections. It demonstrated promising improvements over interpolation and conventional gain calibration/correction methods, lowering their correction errors by approximately 70% and 80%, respectively. The separation algorithm was able to extract the detector gain and heel patterns with less than 2% error, and the Duo-SID corrected images showed perceptually appealing uniform background across the detector. CONCLUSIONS: The Duo-SID correction method has substantially improved on conventional offset/gain corrections for digital x-ray imaging in an SID variant environment. The technique is relatively simple, and can be easily incorporated into multiple-point gain calibration/correction techniques. It offers a potentially valuable tool for preprocessing digital x-ray images to boost image quality of mammography, chest and cardiac radiography, as well as automated computer aided diagnostic radiology. PMID- 23927328 TI - Calculations of two new dose metrics proposed by AAPM Task Group 111 using the measurements with standard CT dosimetry phantoms. AB - PURPOSE: AAPM Task Group 111 proposed to measure the equilibrium dose-pitch product Deq for scan modes involving table translation and the midpoint dose DL(0) for stationary-table modes on the central and peripheral axes of sufficiently long (e.g., at least 40 cm) phantoms. This paper presents an alternative approach to calculate both metrics using the measurements of scanning the standard computed tomographic (CT) dosimetry phantoms on CT scanners. METHODS: Deq was calculated from CTDI100 and epsilon(CTDI100) (CTDI100 efficiency), and DL(0) was calculated from Deq and the approach to equilibrium function H(L) = DL(0)/Deq, where Deq was the equilibrium dose. CTDI100 may be directly obtained from several sources (such as medical physicist's CT scanner performance evaluation or the IMPACT CT patient dosimetry calculator), or be derived from CTDIVol using the central to peripheral CTDI100 ratio (R100). The authors have provided the required epsilon(CTDI100) and H(L) data in two previous papers [X. Li, D. Zhang, and B. Liu, Med. Phys. 39, 901-905 (2012); and ibid. 40, 031903 (10pp.) (2013)]. R100 was assessed for a series of GE, Siemens, Philips, and Toshiba CT scanners with multiple settings of scan field of view, tube voltage, and bowtie filter. RESULTS: The calculated DL(0) and DL(0)/Deq in PMMA and water cylinders were consistent with the measurements on two GE CT scanners (LightSpeed 16 and VCT) by Dixon and Ballard [Med. Phys. 34, 3399-3413 (2007)], the measurements on a Siemens CT scanner (SOMATOM Spirit Power) by Descamps et al. [J. Appl. Clin. Med. Phys. 13, 293-302 (2012)], and the Monte Carlo simulations by Boone [Med. Phys. 36, 4547-4554 (2009)]. CONCLUSIONS: Deq and DL(0) can be calculated using the alternative approach. The authors have provided the required epsilon(CTDI100) and H(L) data in two previous papers. R100 is presented for a majority of multidetector CT scanners currently on the market, and can be easily assessed for other CT scanners or operating conditions not covered in this study. The central to peripheral Deq ratio is about 1.50 and 1.12 times of R100 for the 32- and 16-cm diameter PMMA phantom, respectively. PMID- 23927329 TI - Can nontriggered thoracic CT be used for coronary artery calcium scoring? A phantom study. AB - PURPOSE: Coronary artery calcium score, traditionally based on electrocardiography (ECG)-triggered computed tomography (CT), predicts cardiovascular risk. However, nontriggered CT is extensively utilized. The study purpose is to evaluate the in vitro agreement in coronary calcium score between nontriggered thoracic CT and ECG-triggered cardiac CT. METHODS: Three artificial coronary arteries containing calcifications of different densities (high, medium, and low), and sizes (large, medium, and small), were studied in a moving cardiac phantom. Two 64-detector CT systems were used. The phantom moved at 0-90 mm/s in nontriggered low-dose CT as index test, and at 0-30 mm/s in ECG-triggered CT as reference. Differences in calcium scores between nontriggered and ECG-triggered CT were analyzed by t-test and 95% confidence interval. The sensitivity to detect calcification was calculated as the percentage of positive calcium scores. RESULTS: Overall, calcium scores in nontriggered CT were not significantly different to those in ECG-triggered CT (p>0.05). Calcium scores in nontriggered CT were within the 95% confidence interval of calcium scores in ECG-triggered CT, except predominantly at higher velocities (>=50 mm/s) for the high-density and large-size calcifications. The sensitivity for a nonzero calcium score was 100% for large calcifications, but 46%+/-11% for small calcifications in nontriggered CT. CONCLUSIONS: When performing multiple measurements, good agreement in positive calcium scores is found between nontriggered thoracic and ECG-triggered cardiac CT. Agreement decreases with increasing coronary velocity. From this phantom study, it can be concluded that a high calcium score can be detected by nontriggered CT, and thus, that nontriggered CT likely can identify individuals at high risk of cardiovascular disease. On the other hand, a zero calcium score in nontriggered CT does not reliably exclude coronary calcification. PMID- 23927330 TI - Variability of tumor area measurements for response assessment in malignant pleural mesothelioma. AB - PURPOSE: The measurement of malignant pleural mesothelioma is critical to the assessment of tumor response to therapy. Current response assessment standards utilize summed linear measurements acquired on three computed tomography (CT) sections. The purpose of this study was to evaluate manual area measurements as an alternate response assessment metric, specifically through the study of measurement interobserver variability. METHODS: Two CT scans from each of 31 patients were collected. Using a computer interface, five observers contoured tumor on three selected CT sections from each baseline scan. Four observers also constructed matched follow-up scan tumor contours for the same 31 patients. Area measurements extracted from these contours were compared using a random effects analysis of variance model to assess relative interobserver variability. The sums of section area measurements were also analyzed, since these area sums are more clinically relevant for response assessment. RESULTS: When each observer's measurements were compared with those of the other four observers, strong correlation was observed. The 95% confidence interval for relative interobserver variability of baseline scan summed area measurements was [-71%, +240%], spanning 311%. For the follow-up scan summed area measurements, the 95% confidence interval for relative interobserver variability was [-41%, +70%], spanning 111%. At both baseline and follow-up, the variability among observers was a significant component of the total variability in both per-section and summed area measurements (p<0.0001). CONCLUSIONS: Despite the ability of tumor area measurements to capture tumor burden with greater fidelity than linear tumor thickness measurements, manual area measurements may not be a robust means of response assessment in mesothelioma patients. PMID- 23927331 TI - CT head-scan dosimetry in an anthropomorphic phantom and associated measurement of ACR accreditation-phantom imaging metrics under clinically representative scan conditions. AB - PURPOSE: To measure radiation absorbed dose and its distribution in an anthropomorphic head phantom under clinically representative scan conditions in three widely used computed tomography (CT) scanners, and to relate those dose values to metrics such as high-contrast resolution, noise, and contrast-to-noise ratio (CNR) in the American College of Radiology CT accreditation phantom. METHODS: By inserting optically stimulated luminescence dosimeters (OSLDs) in the head of an anthropomorphic phantom specially developed for CT dosimetry (University of Florida, Gainesville), we measured dose with three commonly used scanners (GE Discovery CT750 HD, Siemens Definition, Philips Brilliance 64) at two different clinical sites (Walter Reed National Military Medical Center, National Institutes of Health). The scanners were set to operate with the same data-acquisition and image-reconstruction protocols as used clinically for typical head scans, respective of the practices of each facility for each scanner. We also analyzed images of the ACR CT accreditation phantom with the corresponding protocols. While the Siemens Definition and the Philips Brilliance protocols utilized only conventional, filtered back-projection (FBP) image reconstruction methods, the GE Discovery also employed its particular version of an adaptive statistical iterative reconstruction (ASIR) algorithm that can be blended in desired proportions with the FBP algorithm. We did an objective image metrics analysis evaluating the modulation transfer function (MTF), noise power spectrum (NPS), and CNR for images reconstructed with FBP. For images reconstructed with ASIR, we only analyzed the CNR, since MTF and NPS results are expected to depend on the object for iterative reconstruction algorithms. RESULTS: The OSLD measurements showed that the Siemens Definition and the Philips Brilliance scanners (located at two different clinical facilities) yield average absorbed doses in tissue of 42.6 and 43.1 mGy, respectively. The GE Discovery delivers about the same amount of dose (43.7 mGy) when run under similar operating and image-reconstruction conditions, i.e., without tube current modulation and ASIR. The image-metrics analysis likewise showed that the MTF, NPS, and CNR associated with the reconstructed images are mutually comparable when the three scanners are run with similar settings, and differences can be attributed to different edge-enhancement properties of the applied reconstruction filters. Moreover, when the GE scanner was operated with the facility's scanner settings for routine head exams, which apply 50% ASIR and use only approximately half of the 100%-FBP dose, the CNR of the images showed no significant change. Even though the CNR alone is not sufficient to characterize the image quality and justify any dose reduction claims, it can be useful as a constancy test metric. CONCLUSIONS: This work presents a straightforward method to connect direct measurements of CT dose with objective image metrics such as high-contrast resolution, noise, and CNR. It demonstrates that OSLD measurements in an anthropomorphic head phantom allow a realistic and locally precise estimation of magnitude and spatial distribution of dose in tissue delivered during a typical CT head scan. Additional objective analysis of the images of the ACR accreditation phantom can be used to relate the measured doses to high contrast resolution, noise, and CNR. PMID- 23927332 TI - A method to acquire CT organ dose map using OSL dosimeters and ATOM anthropomorphic phantoms. AB - PURPOSE: To present the design and procedure of an experimental method for acquiring densely sampled organ dose map for CT applications, based on optically stimulated luminescence (OSL) dosimeters "nanoDots" and standard ATOM anthropomorphic phantoms; and to provide the results of applying the method--a dose data set with good statistics for the comparison with Monte Carlo simulation result in the future. METHODS: A standard ATOM phantom has densely located holes (in 3*3 cm or 1.5*1.5 cm grids), which are too small (5 mm in diameter) to host many types of dosimeters, including the nanoDots. The authors modified the conventional way in which nanoDots are used, by removing the OSL disks from the holders before inserting them inside a standard ATOM phantom for dose measurements. The authors solved three technical difficulties introduced by this modification: (1) energy dependent dose calibration for raw OSL readings; (2) influence of the brief background exposure of OSL disks to dimmed room light; (3) correct pairing between the dose readings and measurement locations. The authors acquired 100 dose measurements at various positions in the phantom, which was scanned using a clinical chest protocol with both angular and z-axis tube current modulations. RESULTS: Dose calibration was performed according to the beam qualities inside the phantom as determined from an established Monte Carlo model of the scanner. The influence of the brief exposure to dimmed room light was evaluated and deemed negligible. Pairing between the OSL readings and measurement locations was ensured by the experimental design. The organ doses measured for a routine adult chest scan protocol ranged from 9.4 to 18.8 mGy, depending on the composition, location, and surrounding anatomy of the organs. The dose distribution across different slices of the phantom strongly depended on the z axis mA modulation. In the same slice, doses to the soft tissues other than the spinal cord demonstrated relatively small variations, with the maximum COV around 11.4%. This might be attributed to the angular mA modulation, the placement of the dosimeters, the chest cavity of the scanned region, and the size of the phantom. Doses to the spinal cord were consistently lower than those to other soft tissues. CONCLUSIONS: The method is suited for acquiring densely sampled organ dose maps, and can be used for studying dose distributions relevant to subject size, organ location, and clinical CT protocols. PMID- 23927333 TI - Megavoltage CT imaging quality improvement on TomoTherapy via tensor framelet. AB - PURPOSE: This work is to investigate the feasibility of improving megavoltage imaging quality for TomoTherapy using a novel reconstruction technique based on tensor framelet, with either full-view or partial-view data. METHODS: The reconstruction problem is formulated as a least-square L1-type optimization problem, with the tensor framelet for the image regularization, which is a generalization of L1, total variation, and wavelet. The high-order derivatives of the image are simultaneously regularized in L1 norm at multilevel along the x, y, and z directions. This convex formulation is efficiently solved using the Split Bregman method. In addition, a GPU-based parallel algorithm was developed to accelerate image reconstruction. The new method was compared with the filtered backprojection and the total variation based method in both phantom and patient studies with full or partial projection views. RESULTS: The tensor framelet based method improved the image quality from the filtered backprojection and the total variation based method. The new method was robust when only 25% of the projection views were used. It required ~2 min for the GPU-based solver to reconstruct a 40 slice 1 mm-resolution 350*350 3D image with 200 projection views per slice and 528 detection pixels per view. CONCLUSIONS: The authors have developed a GPU based tensor framelet reconstruction method with improved image quality for the megavoltage CT imaging on TomoTherapy with full or undersampled projection views. In particular, the phantom and patient studies suggest that the imaging quality enhancement via tensor framelet method is prominent for the low-dose imaging on TomoTherapy with up to a 75% projection view reduction. PMID- 23927334 TI - Comparative power law analysis of structured breast phantom and patient images in digital mammography and breast tomosynthesis. AB - PURPOSE: This work characterizes three candidate mammography phantoms with structured background in terms of power law analysis in the low frequency region of the power spectrum for 2D (planar) mammography and digital breast tomosynthesis (DBT). METHODS: The study was performed using three phantoms (spheres in water, Voxmam, and BR3D CIRS phantoms) on two DBT systems from two different vendors (Siemens Inspiration and Hologic Selenia Dimensions). Power spectra (PS) were calculated for planar projection, DBT projection, and reconstructed images and curve fitted in the low frequency region from 0.2 to 0.7 mm(-1) with a power law function characterized by an exponent beta and magnitude kappa. The influence of acquisition dose and tube voltage on the power law parameters was first explored. Then power law parameters were calculated from images acquired with the same anode/filter combination and tube voltage for the three test objects, and compared with each other. Finally, PS curves for automatic exposure controlled acquisitions (anode/filter combination and tube voltages selected by the systems based on the breast equivalent thickness of the test objects) were compared against PS analysis performed on patient data (for Siemens 80 and for Hologic 48 mammograms and DBT series). Dosimetric aspects of the three test objects were also examined. RESULTS: The power law exponent (beta) was found to be independent of acquisition dose for planar mammography but varied more for DBT projections of the sphere-phantom. Systematic increase of tube voltage did not affect beta but decreased kappa, both in planar and DBT projection phantom images. Power spectra of the BR3D phantom were closer to those of the patients than these of the Voxmam phantom; the Voxmam phantom gave high values of kappa compared to the other phantoms and the patient series. The magnitude of the PS curves of the BR3D phantom was within the patient range but beta was lower than the average patient value. Finally, PS magnitude for the sphere-phantom coincided with the patient curves for Siemens but was lower for the Hologic system. Close agreement of doses for all three phantoms with patient doses was found. CONCLUSIONS: Power law parameters of the phantoms were close to those of the patients but no single phantom matched in terms of both magnitude (kappa) and texture (beta) for the x-ray systems in this work. PS analysis of structured phantoms is feasible and this methodology can be used to suggest improvements in phantom design. PMID- 23927335 TI - Reducing radiation dose to the female breast during CT coronary angiography: a simulation study comparing breast shielding, angular tube current modulation, reduced kV, and partial angle protocols using an unknown-location signal detectability metric. AB - PURPOSE: The authors compared the performance of five protocols intended to reduce dose to the breast during computed tomography (CT) coronary angiography scans using a model observer unknown-location signal-detectability metric. METHODS: The authors simulated CT images of an anthropomorphic female thorax phantom for a 120 kV reference protocol and five "dose reduction" protocols intended to reduce dose to the breast: 120 kV partial angle (posteriorly centered), 120 kV tube-current modulated (TCM), 120 kV with shielded breasts, 80 kV, and 80 kV partial angle (posteriorly centered). Two image quality tasks were investigated: the detection and localization of 4-mm, 3.25 mg/ml and 1-mm, 6.0 mg/ml iodine contrast signals randomly located in the heart region. For each protocol, the authors plotted the signal detectability, as quantified by the area under the exponentially transformed free response characteristic curve estimator (AFE), as well as noise and contrast-to-noise ratio (CNR) versus breast and lung dose. In addition, the authors quantified each protocol's dose performance as the percent difference in dose relative to the reference protocol achieved while maintaining equivalent AFE. RESULTS: For the 4-mm signal-size task, the 80 kV full scan and 80 kV partial angle protocols decreased dose to the breast (80.5% and 85.3%, respectively) and lung (80.5% and 76.7%, respectively) with AFE=0.96, but also resulted in an approximate three-fold increase in image noise. The 120 kV partial protocol reduced dose to the breast (17.6%) at the expense of increased lung dose (25.3%). The TCM algorithm decreased dose to the breast (6.0%) and lung (10.4%). Breast shielding increased breast dose (67.8%) and lung dose (103.4%). The 80 kV and 80 kV partial protocols demonstrated greater dose reductions for the 4-mm task than for the 1-mm task, and the shielded protocol showed a larger increase in dose for the 4-mm task than for the 1-mm task. In general, the CNR curves indicate a similar relative ranking of protocol performance as the corresponding AFE curves, however, the CNR metric overestimated the performance of the shielded protocol for both tasks, leading to corresponding underestimates in the relative dose increases compared to those obtained when using the AFE metric. CONCLUSIONS: The 80 kV and 80 kV partial angle protocols demonstrated the greatest reduction to breast and lung dose, however, the subsequent increase in image noise may be deemed clinically unacceptable. Tube output for these protocols can be adjusted to achieve a more desirable noise level with lesser breast dose savings. Breast shielding increased breast and lung dose when maintaining equivalent AFE. The results demonstrated that comparisons of dose performance depend on both the image quality metric and the specific task, and that CNR may not be a reliable metric of signal detectability. PMID- 23927336 TI - A translation-based data acquisition method for computed tomography: theoretical analysis and simulation study. AB - PURPOSE: In this paper, the authors propose a new method for computed tomography (CT) data acquisition, which requires almost no rotational movement of the system or the object, respectively. METHODS: The new method is taking advantage of the fact that variations of magnification, e.g., by change of distance between x-ray focal spot and detector, will provide both different beam angles and ray paths with respect to the object. In other words, the rotational movement is substituted by one or more linear movements of the x-ray source toward the object under inspection. The authors present a theoretical evaluation of this new translational acquisition scheme. RESULTS: The mathematical implementation of image reconstruction are discussed and results from simulations with varying measurement parameters are shown. The image quality is evaluated by quantitative numbers. CONCLUSIONS: Translational x-ray CT generally allows for reconstructing images with adequate quality. However, the image quality suffers from the lack of data compared to conventional 180 degrees acquisition methods and, due to the irregular sampling of Radon space, spatial resolution as well as artifacts depend on the position within the image. PMID- 23927337 TI - Investigation of energy weighting using an energy discriminating photon counting detector for breast CT. AB - PURPOSE: Breast CT is an emerging imaging technique that can portray the breast in 3D and improve visualization of important diagnostic features. Early clinical studies have suggested that breast CT has sufficient spatial and contrast resolution for accurate detection of masses and microcalcifications in the breast, reducing structural overlap that is often a limiting factor in reading mammographic images. For a number of reasons, image quality in breast CT may be improved by use of an energy resolving photon counting detector. In this study, the authors investigate the improvements in image quality obtained when using energy weighting with an energy resolving photon counting detector as compared to that with a conventional energy integrating detector. METHODS: Using computer simulation, realistic CT images of multiple breast phantoms were generated. The simulation modeled a prototype breast CT system using an amorphous silicon (a Si), CsI based energy integrating detector with different x-ray spectra, and a hypothetical, ideal CZT based photon counting detector with capability of energy discrimination. Three biological signals of interest were modeled as spherical lesions and inserted into breast phantoms; hydroxyapatite (HA) to represent microcalcification, infiltrating ductal carcinoma (IDC), and iodine enhanced infiltrating ductal carcinoma (IIDC). Signal-to-noise ratio (SNR) of these three lesions was measured from the CT reconstructions. In addition, a psychophysical study was conducted to evaluate observer performance in detecting microcalcifications embedded into a realistic anthropomorphic breast phantom. RESULTS: In the energy range tested, improvements in SNR with a photon counting detector using energy weighting was higher (than the energy integrating detector method) by 30%-63% and 4%-34%, for HA and IDC lesions and 12%-30% (with Al filtration) and 32%-38% (with Ce filtration) for the IIDC lesion, respectively. The average area under the receiver operating characteristic curve (AUC) for detection of microcalcifications was higher by greater than 19% (for the different energy weighting methods tested) as compared to the AUC obtained with an energy integrating detector. CONCLUSIONS: This study showed that breast CT with a CZT photon counting detector using energy weighting can provide improvements in pixel SNR, and detectability of microcalcifications as compared to that with a conventional energy integrating detector. Since a number of degrading physical factors were not modeled into the photon counting detector, this improvement should be considered as an upper bound on achievable performance. PMID- 23927338 TI - 3D evaluation of 3DVH program using BANG3 polymer gel dosimeter. AB - PURPOSE: With the recent introduction of intensity modulated arc therapy techniques, there is an increasing need for validation of treatment delivery in three-dimensional (3D) space. A commercial dosimetry device ArcCHECKTM (Sun Nuclear Corporation, Melbourne, FL, USA) can be used in conjunction with 3DVH program. With this system, one can reconstruct the 3D dose distribution produced in the actual patient. In this work the authors evaluate the relative accuracy of the ArcCHECKTM-3DVH system using BANG3 (MGS Research, Guilford, CT, USA) polymer gel dosimeter. METHODS: About 15-cm diameter and 20-cm long cylindrical phantoms filled with BANG3 was used to simulate a patient, to which a volumetrically modulated arc therapy plan was created with Pinnacle3 treatment planning software (Philips Healthcare, Andover, MA, USA). The plan (76 Gy total in 38 fractions) was designed for prostate radiotherapy using a 6 MV photon beam from an Elekta Synergy linear accelerator (Elekta AB, Stockholm, Sweden). The treatment was delivered to the simulated patient. The same plan was used to irradiate an ArcCHECKTM device with an insert plug. The point dose at the isocenter was measured using a Farmer-type ionization chamber. The measured dose data were imported into the 3DVH program, which generated the 3D dose distributions projected onto the simulated patient. The dose data recorded in the polymer gel were read out using a MRI scanner and the 3D dose distribution delivered to the simulated patient was analyzed and compared with those from the 3DVH program and the Pinnacle3 software. The comparison was accomplished by using the gamma index, overlaying the isodose lines for a set of data on selected planes, and computing dose-volume histogram of structures. RESULTS: The dose at the center of the ArcCHECKTM device measured with an ionization chamber was 1.82% lower than the dose predicted by Pinnacle3. The 3D dose distribution generated by Pinnacle3 was compared with those obtained by the ArcCHECKTM-3DVH system and BANG3. The gamma passing rates for criteria of 3% dose difference, 3 mm distance-to-agreement, and 25% lower dose threshold were 99.1% for the former and 95.7% for the latter. The mean and maximum PTV doses estimated by the 3DVH were 74.0 and 79.3 Gy in comparison to 74.4 and 76.5 Gy with Pinnacle3. Those values for BANG3 measurements were 74.7 and 79.5 Gy. The mean doses to rectum were 40.2, 39.8, and 38.8 Gy for Pinnacle3, 3DVH, and BANG3, whereas the mean doses to the bladder were 26.7, 25.7, and 21.7 Gy, respectively. CONCLUSIONS: The ArcCHECKTM-3DVH system provides an accurate estimation of 3D dose distribution in an actual patient within a clinically meaningful tolerance level. However, both 3DVH and BANG3 showed two noticeable differences from Pinnacle3. First, the measured dose throughout the PTV region was less uniform than Pinnacle3. Second, the dose gradient at the interface between PTV and rectum was steeper than Pinnacle3 prediction. Further investigation may be able to identify the cause for these findings. PMID- 23927339 TI - Detector density and small field dosimetry: integral versus point dose measurement schemes. AB - PURPOSE: The Alfonso et al. [Med. Phys. 35, 5179-5186 (2008)] formalism for small field dosimetry proposes a set of correction factors (kQclin,Qmsrfclin,fmsr) which account for differences between the detector response in nonstandard (clinical) and machine-specific-reference fields. In this study, the Monte Carlo method was used to investigate the viability of such small field correction factors for four different detectors irradiated under a variety of conditions. Because kQclin,Qmsrfclin,fmsr values for single detector position measurements are influenced by several factors, a new theoretical formalism for integrated detector-position [dose area product (DAP)] measurements is also presented and was tested using Monte Carlo simulations. METHODS: A BEAMnrc linac model was built and validated for a Varian Clinac iX accelerator. Using the egs++ geometry package, detailed virtual models were built for four different detectors: a PTW 60012 unshielded diode, a PTW 60003 Diamond detector, a PTW 31006 PinPoint (ionization chamber), and a PTW 31018 MicroLion (liquid-filled ionization chamber). The egs_chamber code was used to investigate the variation of kQclin,Qmsrfclin,fmsr with detector type, detector construction, field size, off axis position, and the azimuthal angle between the detector and beam axis. Simulations were also used to consider the DAP obtained by each detector: virtual detectors and water voxels were scanned through high resolution grids of positions extending far beyond the boundaries of the fields under consideration. RESULTS: For each detector, the correction factor (kQclin,Qmsrfclin,fmsr) was shown to depend strongly on detector off-axis position and detector azimuthal angle in addition to field size. In line with previous studies, substantial interdetector variation was also observed. However, it was demonstrated that by considering DAPs rather than single-detector-position dose measurements the high level of interdetector variation could be eliminated. Under small field conditions, mass density was found to be the principal determinant of water equivalence. Additionally, the mass densities of components outside the sensitive volumes were found to influence the detector response. CONCLUSIONS: kQclin,Qmsrfclin,fmsr values for existing detector designs depend on a host of variables and their calculation typically relies on the use of time-intensive Monte Carlo methods. Future moves toward density-compensated detector designs or DAP based protocols may simplify the methodology of small field dosimetry. PMID- 23927341 TI - Preliminary investigations on the determination of three-dimensional dose distributions using scintillator blocks and optical tomography. AB - PURPOSE: Clinical QA in teletherapy as well as the characterization of experimental radiation sources for future medical applications requires effective methods for measuring three-dimensional (3D) dose distributions generated in a water-equivalent medium. Current dosimeters based on ionization chambers, diodes, thermoluminescence detectors, radiochromic films, or polymer gels exhibit various drawbacks: High quality 3D dose determination is either very sophisticated and expensive or requires high amounts of effort and time for the preparation or read out. New detectors based on scintillator blocks in combination with optical tomography are studied, since they have the potential to facilitate the desired cost-effective, transportable, and long-term stable dosimetry system that is able to determine 3D dose distributions with high spatial resolution in a short time. METHODS: A portable detector prototype was set up based on a plastic scintillator block and four digital cameras. During irradiation the scintillator emits light, which is detected by the fixed cameras. The light distribution is then reconstructed by optical tomography, using maximum-likelihood expectation maximization. The result of the reconstruction approximates the 3D dose distribution. First performance tests of the prototype using laser light were carried out. Irradiation experiments were performed with ionizing radiation, i.e., bremsstrahlung (6 to 21 MV), electrons (6 to 21 MeV), and protons (68 MeV), provided by clinical and research accelerators. RESULTS: Laser experiments show that the current imaging properties differ from the design specifications: The imaging scale of the optical systems is position dependent, ranging from 0.185 mm/pixel to 0.225 mm/pixel. Nevertheless, the developed dosimetry method is proven to be functional for electron and proton beams. Induced radiation doses of 50 mGy or more made 3D dose reconstructions possible. Taking the imaging properties into account, determined dose profiles are in agreement with reference measurements. An inherent drawback of the scintillator is the nonlinear light output for high stopping-power radiation due to the quenching effect. It impacts the depth dose curves measured with the dosimeter. For single Bragg peak distributions this leads to a peak to plateau ratio of 2.8 instead of 4.5 for the reference ionization chamber measurement. Furthermore, the transmission of the clinical bremsstrahlung beams through the scintillator leads to the saturation of one camera, making dose reconstructions in that case presently not feasible. CONCLUSIONS: It is shown that distributions of scintillation light generated by proton or electron beams can be reconstructed by the dosimetry system within minutes. The quenching apparent for proton irradiation, and the yet not precisely determined position dependency of the imaging scale, require further investigation and corrections. Upgrading the prototype with larger or inorganic scintillators would increase the detectable proton and electron energy range. The presented results show that the determination of 3D dose distributions using scintillator blocks and optical tomography is a promising dosimetry method. PMID- 23927340 TI - Trapping volumetric measurement by multidetector CT in chronic obstructive pulmonary disease: effect of CT threshold. AB - PURPOSE: The purpose of this study was to evaluate the effect of various computed tomography (CT) thresholds on trapping volumetric measurements by multidetector CT in chronic obstructive pulmonary disease (COPD). METHODS: Twenty-three COPD patients were scanned with a 64-slice CT scanner in both the inspiratory and expiratory phase. CT thresholds of -950 Hu in inspiration and -950 to -890 Hu in expiration were used, after which trapping volumetric measurements were made using computer software. Trapping volume percentage (Vtrap%) under the different CT thresholds in the expiratory phase and below -950 Hu in the inspiratory phase was compared and correlated with lung function. RESULTS: Mean Vtrap% was similar under -930 Hu in the expiratory phase and below -950 Hu in the inspiratory phase, being 13.18+/-9.66 and 13.95+/-6.72 (both lungs), respectively; this difference was not significant (P=0.240). Vtrap% under -950 Hu in the inspiratory phase and below the -950 to -890 Hu threshold in the expiratory phase was moderately negatively correlated with the ratio of forced expiratory volume in one second to forced vital capacity and the measured value of forced expiratory volume in one second as a percentage of the predicted value. CONCLUSIONS: Trapping volumetric measurement with multidetector CT is a promising method for the quantification of COPD. It is important to know the effect of various CT thresholds on trapping volumetric measurements. PMID- 23927342 TI - Comparison of Gafchromic EBT2 and EBT3 for patient-specific quality assurance: cranial stereotactic radiosurgery using volumetric modulated arc therapy with multiple noncoplanar arcs. AB - PURPOSE: Patient-specific quality assurance in volumetric modulated arc therapy (VMAT) brain stereotactic radiosurgery raises specific issues on dosimetric procedures, mainly represented by the small radiation fields associated with the lack of lateral electronic equilibrium, the need of small detectors and the high dose delivered (up to 30 Gy). GafchromicTM EBT2 and EBT3 films may be considered the dosimeter of choice, and the authors here provide some additional data about uniformity correction for this new generation of radiochromic films. METHODS: A new analysis method using blue channel for marker dye correction was proposed for uniformity correction both for EBT2 and EBT3 films. Symmetry, flatness, and field width of a reference field were analyzed to provide an evaluation in a high spatial resolution of the film uniformity for EBT3. Absolute doses were compared with thermoluminescent dosimeters (TLD) as baseline. VMAT plans with multiple noncoplanar arcs were generated with a treatment planning system on a selected pool of eleven patients with cranial lesions and then recalculated on a water equivalent plastic phantom by Monte Carlo algorithm for patient-specific QA. 2D quantitative dose comparison parameters were calculated, for the computed and measured dose distributions, and tested for statistically significant differences. RESULTS: Sensitometric curves showed a different behavior above dose of 5 Gy for EBT2 and EBT3 films; with the use of inhouse marker-dye correction method, the authors obtained values of 2.5% for flatness, 1.5% of symmetry, and a field width of 4.8 cm for a 5*5 cm2 reference field. Compared with TLD and selecting a 5% dose tolerance, the percentage of points with ICRU index below 1 was 100% for EBT2 and 83% for EBT3. Patients analysis revealed statistically significant differences (p<0.05) between EBT2 and EBT3 in the percentage of points with gamma values<1 (p=0.009 and p=0.016); the percent difference as well as the mean difference between calculated and measured isodoses (20% and 80%) were found not to be significant (p=0.074, p=0.185, and p=0.57). CONCLUSIONS: Excellent performances in terms of dose homogeneity were obtained using a new blue channel method for marker-dye correction on both EBT2 and EBT3 GafchromicTM films. In comparison with TLD, the passing rates for the EBT2 film were higher than for EBT3; a good agreement with estimated data by Monte Carlo algorithm was found for both films, with some statistically significant differences again in favor of EBT2. These results suggest that the use of GafchromicTM EBT2 and EBT3 films is appropriate for dose verification measurements in VMAT stereotactic radiosurgery; taking into account the uncertainty associated with Gafchromic film dosimetry, the use of adequate action levels is strongly advised, in particular, for EBT3. PMID- 23927343 TI - Performance parameters of a liquid filled ionization chamber array. AB - PURPOSE: In this work, the properties of the two-dimensional liquid filled ionization chamber array Octavius 1000SRS (PTW-Freiburg, Germany) for use in clinical photon-beam dosimetry are investigated. METHODS: Measurements were carried out at an Elekta Synergy and Siemens Primus accelerator. For measurements of stability, linearity, and saturation effects of the 1000SRS array a Semiflex 31013 ionization chamber (PTW-Freiburg, Germany) was used as a reference. The effective point of measurement was determined by TPR measurements of the array in comparison with a Roos chamber (type 31004, PTW-Freiburg, Germany). The response of the array with varying field size and depth of measurement was evaluated using a Semiflex 31010 ionization chamber as a reference. Output factor measurements were carried out with a Semiflex 31010 ionization chamber, a diode (type 60012, PTW-Freiburg, Germany), and the detector array under investigation. The dose response function for a single detector of the array was determined by measuring 1 cm wide slit-beam dose profiles and comparing them against diode-measured profiles. Theoretical aspects of the low pass properties and of the sampling frequency of the detector array were evaluated. Dose profiles measured with the array and the diode detector were compared, and an intensity modulated radiation therapy (IMRT) field was verified using the Gamma-Index method and the visualization of line dose profiles. RESULTS: The array showed a short and long term stability better than 0.1% and 0.2%, respectively. Fluctuations in linearity were found to be within +/-0.2% for the vendor specified dose range. Saturation effects were found to be similar to those reported in other studies for liquid filled ionization chambers. The detector's relative response varied with field size and depth of measurement, showing a small energy dependence accounting for maximum signal deviations of +/-2.6% from the reference condition for the setup used. The sigma-values of the Gaussian dose response function for a single detector of the array were found to be (0.72+/-0.25) mm at 6 MV and (0.74+/-0.25) mm at 15 MV and the corresponding low pass cutoff frequencies are 0.22 and 0.21 mm(-1), respectively. For the inner 5*5 cm2 region and the outer 11*11 cm2 region of the array the Nyquist theorem is fulfilled for maximum sampling frequencies of 0.2 and 0.1 mm(-1), respectively. An IMRT field verification with a Gamma-Index analysis yielded a passing rate of 95.2% for a 3 mm/3% criterion with a TPS calculation as reference. CONCLUSIONS: This study shows the applicability of the Octavius 1000SRS in modern dosimetry. Output factor and dose profile measurements illustrated the applicability of the array in small field and stereotactic dosimetry. The high spatial resolution ensures adequate measurements of dose profiles in regular and intensity modulated photon-beam fields. PMID- 23927344 TI - Integrated PET/MR imaging: automatic attenuation correction of flexible RF coils. AB - PURPOSE: Flexible radiofrequency (RF) surface coils used in simultaneous PET/MR imaging are currently disregarded in PET attenuation correction (AC) since their position and individual geometry are unknown in whole-body patient scans. The attenuation of PET emission data due to the presence of RF surface coils has been investigated by several research groups but so far no automatic approach for the incorporation of RF surface coils into PET AC has been described. In this work, an algorithm is presented and evaluated which automatically determines the position of multiple RF surface coils and corrects for their attenuation of the PET emission data. METHODS: The presented algorithm nonrigidly registers pre acquired CT-based three-dimensional attenuation templates of RF surface coils into attenuation maps used for PET AC. Transformation parameters are obtained by nonrigid B-spline landmark registration of marker positions in the CT-based attenuation templates of the RF surface coils to marker positions in the current MR images of the patient. The use of different marker patterns enables the registration algorithm to distinguish multiple partly overlapping RF surface coils. To evaluate the registration algorithm, two different PET emission scans of a NEMA standard body phantom with six active lesions and of a large rectangular body phantom were performed on an integrated whole-body PET/MR scanner. The phantoms were scanned with and without one (NEMA phantom scan) or three (large body phantom scan) flexible six-channel RF surface coils placed on top. Additionally, the accuracy and performance of the algorithm were evaluated on volunteer scans (n=5) and on a patient scan using a typical clinical setup of three RF surface coils. RESULTS: Overall loss of true counts due to the presence of the RF surface coils was 5.1% for the NEMA phantom, 3.6% for the large body phantom, and 2.1% for the patient scan. Considerable local underestimation of measured activity concentration up to 15.4% in the top part of the phantoms and 15.5% for a lesion near the body surface of the patient was measured close to the high attenuating hardware components of the RF coils. The attenuation maps generated by the registration algorithm reduced the quantification errors due to the RF surface coils to values ranging from -3.9% to 4.3%. Concerning the volunteer examinations, the attenuation templates of the three RF surface coils were registered to their correct positions with an overall accuracy of about 3 mm. CONCLUSIONS: The presence of flexible RF surface coils leads to considerable local errors in the simultaneously measured PET activity concentration up to 15.5% especially in regions close to the coils. The presented automatic algorithm accurately and reliably reduces the PET quantification errors caused by multiple partly overlapping flexible RF surface coils to values of 4.3% or better. PMID- 23927345 TI - A comparison of five standard methods for evaluating image intensity uniformity in partially parallel imaging MRI. AB - PURPOSE: To investigate the utility of five different standard measurement methods for determining image uniformity for partially parallel imaging (PPI) acquisitions in terms of consistency across a variety of pulse sequences and reconstruction strategies. METHODS: Images were produced with a phantom using a 12-channel head matrix coil in a 3T MRI system (TIM TRIO, Siemens Medical Solutions, Erlangen, Germany). Images produced using echo-planar, fast spin echo, gradient echo, and balanced steady state free precession pulse sequences were evaluated. Two different PPI reconstruction methods were investigated, generalized autocalibrating partially parallel acquisition algorithm (GRAPPA) and modified sensitivity-encoding (mSENSE) with acceleration factors (R) of 2, 3, and 4. Additionally images were acquired with conventional, two-dimensional Fourier imaging methods (R=1). Five measurement methods of uniformity, recommended by the American College of Radiology (ACR) and the National Electrical Manufacturers Association (NEMA) were considered. The methods investigated were (1) an ACR method and a (2) NEMA method for calculating the peak deviation nonuniformity, (3) a modification of a NEMA method used to produce a gray scale uniformity map, (4) determining the normalized absolute average deviation uniformity, and (5) a NEMA method that focused on 17 areas of the image to measure uniformity. Changes in uniformity as a function of reconstruction method at the same R-value were also investigated. Two-way analysis of variance (ANOVA) was used to determine whether R-value or reconstruction method had a greater influence on signal intensity uniformity measurements for partially parallel MRI. RESULTS: Two of the methods studied had consistently negative slopes when signal intensity uniformity was plotted against R-value. The results obtained comparing mSENSE against GRAPPA found no consistent difference between GRAPPA and mSENSE with regard to signal intensity uniformity. The results of the two-way ANOVA analysis suggest that R value and pulse sequence type produce the largest influences on uniformity and PPI reconstruction method had relatively little effect. CONCLUSIONS: Two of the methods of measuring signal intensity uniformity, described by the (NEMA) MRI standards, consistently indicated a decrease in uniformity with an increase in R value. Other methods investigated did not demonstrate consistent results for evaluating signal uniformity in MR images obtained by partially parallel methods. However, because the spatial distribution of noise affects uniformity, it is recommended that additional uniformity quality metrics be investigated for partially parallel MR images. PMID- 23927346 TI - Quantitative simultaneous 111In/99mTc SPECT-CT of osteomyelitis. AB - PURPOSE: A well-established approach for diagnostic imaging of osteomyelitis (OM), a bone infection, is simultaneous SPECT-CT of 99mTc sulfur colloid (SC) and 111In white blood cells (WBC). This method provides essentially perfect spatial registration of the tracers within anatomic sites of interest. Currently, diagnosis is based purely on a visual assessment-where relative discordance between 99mTc and 111In uptake in bone, i.e., high 111In and low 99mTc, suggests OM. To achieve more quantitative images, noise, scatter, and crosstalk between radionuclides must be addressed through reconstruction. Here the authors compare their Monte Carlo-based joint OSEM (MC-JOSEM) algorithm, which reconstructs both radionuclides simultaneously, to a more conventional triple-energy window-based reconstruction (TEW-OSEM), and to iterative reconstruction with no compensation for scatter (NC-OSEM). METHODS: The authors created numerical phantoms of the foot and torso. Multiple bone-infection sites were modeled using high-count Monte Carlo simulation. Counts per voxel were then scaled to values appropriate for 111In WBC and 99mTc SC imaging. Ten independent noisy projection image sets were generated by drawing random Poisson deviates from these very low-noise images. Data were reconstructed using the two iterative scatter-compensation methods, TEW OSEM and MC-JOSEM, as well as the uncorrected method (NC-OSEM). Mean counts in volumes of interest (VOIs) were used to evaluate the bias and precision of each method. Data were also acquired using a phantom, approximately the size of an adult ankle, consisting of regions representing infected and normal bone marrow, within a bone-like attenuator and surrounding soft tissue; each compartment contained a mixture of 111In and 99mTc. Low-noise data were acquired during multiple short scans over 29 h on a Siemens Symbia T6 SPECT-CT with medium-energy collimators. Pure 99mTc and 111In projection datasets were derived by fitting the acquired projections to the sum of 99mTc and 111In contributions, using the known half-lives. Uncontaminated data were scaled and recombined into six datasets with different activity ratios; ten Poisson noise realizations were then generated for each ratio. VOIs in each of the compartments were used to evaluate the bias and precision of each method with respect to reconstructions of uncontaminated datasets. In addition to the simulated and acquired phantom images, the authors reconstructed patient images with MC-JOSEM and TEW-OSEM. Patient reconstructions were assessed qualitatively for lesion contrast, spatial definition, and scatter. RESULTS: For all simulated and acquired infection phantoms, the root-mean squared error of measured 99mTc activity was significantly improved with MC-JOSEM and TEW OSEM in comparison to NC-OSEM reconstructions. While MC-JOSEM trended toward outperforming TEW-OSEM, the improvement was only found to be significant (p<0.001) for the acquired bone phantom in which a wide range of 111In/99mTc concentration ratios were tested. In all cases, scatter correction did not significantly improve 111In quantitation. CONCLUSIONS: Compensation for scatter and crosstalk is useful for improving quality, bias, and precision of 99mTc activity estimates in simultaneous dual-radionuclide imaging of OM. The use of the more rigorous MC-based estimates provided marginal improvements over TEW. While the phantom results were encouraging, more subjects are needed to evaluate the usefulness of quantitative 111In/99mTc SPECT-CT in the clinic. PMID- 23927347 TI - A fast method for rescaling voxel S values for arbitrary voxel sizes in targeted radionuclide therapy from a single Monte Carlo calculation. AB - PURPOSE: In targeted radionuclide therapy, patient-specific dosimetry based on voxel S values (VSVs) is preferable to dosimetry based on mathematical phantoms. Monte-Carlo (MC) simulations are necessary to deduce VSVs for those voxel sizes required by quantitative imaging. The aim of this study is, starting from a single set of high-resolution VSVs obtained by MC simulations for a small voxel size along one single axis perpendicular to the source voxel, to present a suitable method to accurately calculate VSVs for larger voxel sizes. METHODS: Accurate sets of VSVs for target voxel to source voxel distances up to 10 cm were obtained for high-resolution voxel sizes (0.5 mm for electrons and 1.0 mm for photons) from MC simulations for Y-90, Lu-177, and I-131 using the radiation transport code MCNPX v.2.7a. To make these values suitable to any larger voxel size, different analytical methods (based on resamplings, interpolations, and fits) were tested and compared to values obtained by direct MC simulations. As a result, an optimal calculation procedure is proposed. This procedure consisted of: (1) MC simulation for obtaining of a starting set of VSVs along a single line of voxels for a small voxel size for each radionuclide and type of radiation; (2) interpolation within the values obtained in point (1) for obtaining the VSVs for voxels within a spherical volume; (3) resampling of the data obtained in (1) and (2) for obtaining VSVs for voxels sizes larger than the one used for the MC calculation for integer voxel ratios (voxel ratio=new voxel size/voxel size MC simulation); (4) interpolation on within the data obtained in (3) for integer voxel ratios. The results were also compared to results from other authors. RESULTS: The results obtained with the method proposed in this work show deviations relative to the source voxel below 1% for I-131 and Lu-177 and below 1.5% for Y-90 as compared with values obtained by direct MC simulations for voxel sizes ranging between 1.0 and 10.0 cm. The results obtained in this work show differences between the scored deposited energy and the emitted energy lower than 2% for electron radiation. Higher differences, attributable to the short considered radius of 10 cm in comparison with their penetration, can be found for photons. The authors' results agree well with previously published data obtained by other authors using different methods. CONCLUSIONS: A reliable and fast approach for obtaining accurate VSVs for voxel sizes larger than the voxel size used for the MC calculation of the starting set of high-resolution VSVs was developed and successfully tested for three different radionuclides of interest for targeted radiotherapy: one pure beta (Y-90) and 2 beta-gamma emitters (Lu-177 und I-131). Applying the method of this work allows any interested reader to repeat the calculations for arbitrary radionuclides of interest and/or smaller high-resolution voxel sizes, provided the means for running MC simulations are available. PMID- 23927348 TI - An automatic method for accurate volume delineation of heterogeneous tumors in PET. AB - PURPOSE: Accurate volumetric tumor delineation is of increasing importance in radiation treatment planning. Many tumors exhibit only moderate tracer uptake heterogeneity and delineation methods using an adaptive threshold lead to robust results. These methods use a tumor reference value R (e.g., ROI maximum) and the tumor background Bg to compute the volume reproducing threshold. This threshold corresponds to an isocontour which defines the tumor boundary. However, the boundaries of strongly heterogeneous tumors can not be described by an isocontour anymore and therefore conventional threshold methods are not suitable for accurate delineation. The aim of this work is the development and validation of a delineation method for heterogeneous tumors. METHODS: The new method (voxel specific threshold method, VTM) can be considered as an extension of an adaptive threshold method (lesion-specific threshold method, LTM), where instead of a lesion-specific threshold for the whole ROI, a voxel-specific threshold is computed by determining for each voxel Bg and R in the close vicinity of the voxel. The absolute threshold for the considered voxel is then given by Tabs=T*(R Bg)+Bg, where T=0.39 was determined with phantom measurements. VALIDATION: 30 clinical datasets from patients with non-small-cell lung cancer were used to generate 30 realistic anthropomorphic software phantoms of tumors with different heterogeneities and well-known volumes and boundaries. Volume delineation was performed with VTM and LTM and compared with the known lesion volumes and boundaries. RESULTS: In contrast to LTM, VTM was able to reproduce the true tumor boundaries accurately, independent of the heterogeneity. The deviation of the determined volume from the true volume was (0.8+/-4.2)% for VTM and (11.0+/ 16.4)% for LTM. CONCLUSIONS: In anthropomorphic software phantoms, the new method leads to promising results and to a clear improvement of volume delineation in comparison to conventional background-corrected thresholding. In the next step, the suitability for clinical routine will be further investigated. PMID- 23927349 TI - A collimator optimization method for quantitative imaging: application to Y-90 bremsstrahlung SPECT. AB - PURPOSE: Post-therapy quantitative 90Y bremsstrahlung single photon emission computed tomography (SPECT) has shown great potential to provide reliable activity estimates, which are essential for dose verification. Typically 90Y imaging is performed with high- or medium-energy collimators. However, the energy spectrum of 90Y bremsstrahlung photons is substantially different than typical for these collimators. In addition, dosimetry requires quantitative images, and collimators are not typically optimized for such tasks. Optimizing a collimator for 90Y imaging is both novel and potentially important. Conventional optimization methods are not appropriate for 90Y bremsstrahlung photons, which have a continuous and broad energy distribution. In this work, the authors developed a parallel-hole collimator optimization method for quantitative tasks that is particularly applicable to radionuclides with complex emission energy spectra. The authors applied the proposed method to develop an optimal collimator for quantitative 90Y bremsstrahlung SPECT in the context of microsphere radioembolization. METHODS: To account for the effects of the collimator on both the bias and the variance of the activity estimates, the authors used the root mean squared error (RMSE) of the volume of interest activity estimates as the figure of merit (FOM). In the FOM, the bias due to the null space of the image formation process was taken in account. The RMSE was weighted by the inverse mass to reflect the application to dosimetry; for a different application, more relevant weighting could easily be adopted. The authors proposed a parameterization for the collimator that facilitates the incorporation of the important factors (geometric sensitivity, geometric resolution, and septal penetration fraction) determining collimator performance, while keeping the number of free parameters describing the collimator small (i.e., two parameters). To make the optimization results for quantitative 90Y bremsstrahlung SPECT more general, the authors simulated multiple tumors of various sizes in the liver. The authors realistically simulated human anatomy using a digital phantom and the image formation process using a previously validated and computationally efficient method for modeling the image-degrading effects including object scatter, attenuation, and the full collimator-detector response (CDR). The scatter kernels and CDR function tables used in the modeling method were generated using a previously validated Monte Carlo simulation code. RESULTS: The hole length, hole diameter, and septal thickness of the obtained optimal collimator were 84, 3.5, and 1.4 mm, respectively. Compared to a commercial high energy general-purpose collimator, the optimal collimator improved the resolution and FOM by 27% and 18%, respectively. CONCLUSIONS: The proposed collimator optimization method may be useful for improving quantitative SPECT imaging for radionuclides with complex energy spectra. The obtained optimal collimator provided a substantial improvement in quantitative performance for the microsphere radioembolization task considered. PMID- 23927350 TI - Influence of cold walls on PET image quantification and volume segmentation: a phantom study. AB - PURPOSE: Commercially available fillable plastic inserts used in positron emission tomography phantoms usually have thick plastic walls, separating their content from the background activity. These "cold" walls can modify the intensity values of neighboring active regions due to the partial volume effect, resulting in errors in the estimation of standardized uptake values. Numerous papers suggest that this is an issue for phantom work simulating tumor tissue, quality control, and calibration work. This study aims to investigate the influence of the cold plastic wall thickness on the quantification of 18F-fluorodeoxyglucose on the image activity recovery and on the performance of advanced automatic segmentation algorithms for the delineation of active regions delimited by plastic walls. METHODS: A commercial set of six spheres of different diameters was replicated using a manufacturing technique which achieves a reduction in plastic walls thickness of up to 90%, while keeping the same internal volume. Both sets of thin- and thick-wall inserts were imaged simultaneously in a custom phantom for six different tumor-to-background ratios. Intensity values were compared in terms of mean and maximum standardized uptake values (SUVs) in the spheres and mean SUV of the hottest 1 ml region (SUVmax, SUVmean, and SUVpeak). The recovery coefficient (RC) was also derived for each sphere. The results were compared against the values predicted by a theoretical model of the PET-intensity profiles for the same tumor-to-background ratios (TBRs), sphere sizes, and wall thicknesses. In addition, ten automatic segmentation methods, written in house, were applied to both thin- and thick-wall inserts. The contours obtained were compared to computed tomography derived gold standard ("ground truth"), using five different accuracy metrics. RESULTS: The authors' results showed that thin wall inserts achieved significantly higher SUVmean, SUVmax, and RC values (up to 25%, 16%, and 25% higher, respectively) compared to thick-wall inserts, which was in agreement with the theory. This effect decreased with increasing sphere size and TBR, and resulted in substantial (>5%) differences between thin- and thick wall inserts for spheres up to 30 mm diameter and TBR up to 4. Thinner plastic walls were also shown to significantly improve the delineation accuracy for the majority of the segmentation methods tested, by increasing the proportion of lesion voxels detected, although the errors in image quantification remained non negligible. CONCLUSIONS: This study quantified the significant effect of a 90% reduction in the thickness of insert walls on SUV quantification and PET-based boundary detection. Mean SUVs inside the inserts and recovery coefficients were particularly affected by the presence of thick cold walls, as predicted by a theoretical approach. The accuracy of some delineation algorithms was also significantly improved by the introduction of thin wall inserts instead of thick wall inserts. This study demonstrates the risk of errors deriving from the use of cold wall inserts to assess and compare the performance of PET segmentation methods. PMID- 23927351 TI - Use of measured scatter data for the attenuation correction of single photon emission tomography without transmission scanning. AB - PURPOSE: Attenuation correction is essential for reliable interpretation of emission tomography, however, the use of transmission measurements to generate attenuation maps is limited by availability of equipment and potential mismatches between the transmission and emission measurements. The authors present a first step toward a method of estimating an attenuation map from measured scatter data without a transmission scan. METHODS: A scatter model has been developed that accurately predicts the distribution of photons which have been scattered once. The scatter model has been used as the basis of a maximum likelihood gradient ascent method to estimate an attenuation map from measured scatter data. In order to estimate both the attenuation map and activity distribution, iterations of the derived scatter based algorithm have been alternated with the maximum likelihood expectation maximization algorithm in a joint estimation process. For each iteration of the attenuation map estimation, the activity distribution is fixed at the values estimated during the previous activity iteration, and in each iteration of the activity distribution estimation the attenuation map is fixed at the values estimated during the previous attenuation iteration. The use of photopeak data to enhance the estimation of the attenuation map compared to the use of scatter data alone has also been considered. The algorithm derived has been used to reconstruct data simulated for an idealized two-dimensional situation and using a physical phantom. RESULTS: The reconstruction of idealized data demonstrated good reconstruction of both the activity distribution and attenuation map. The inclusion of information recorded in the photopeak energy window in the attenuation map estimation step demonstrated an improvement in the accuracy of the reconstruction, enabling an accurate attenuation map to be recovered. Validation of the results with physical phantom data demonstrated that different regions of attenuation could be distinguished in a real situation and produces results that represent a promising first step toward the use of scatter data to estimate the activity distribution and attenuation map from single photon emission tomography (SPECT) data without a transmission scan. CONCLUSIONS: The technique presented shows promise as a method of attenuation correction for SPECT data without the need for a separate transmission scan. Further work is required to further improve the method and to compensate for the assumptions used in the scatter model. PMID- 23927352 TI - Contourlet-based active contour model for PET image segmentation. AB - PURPOSE: PET-guided radiation therapy treatment planning, clinical diagnosis, assessment of tumor growth, and therapy response rely on the accurate delineation of the tumor volume and quantification of tracer uptake. Most PET image segmentation techniques proposed thus far are suboptimal in the presence of heterogeneity of tracer uptake within the lesion. This work presents an active contour model approach based on the method of Chan and Vese ["Active contours without edges," IEEE Trans. Image Process. 10, 266-277 (2001)] designed to take into account the high level of statistical uncertainty (noise) and to handle the heterogeneity of tumor uptake typically present in PET images. METHODS: In the proposed method, the fitting terms in the Chan-Vese formulation are modified by introducing new input images, including the smoothed version of the original image using anisotropic diffusion filtering (ADF) and the contourlet transform of the image. The advantage of utilizing ADF for image smoothing is that it avoids blurring the object's edges and preserves the average activity within a region, which is important for accurate PET quantification. Moreover, incorporating the contourlet transform of the image into the fitting terms makes the energy functional more effective in directing the evolving curve toward the object boundaries due to the enhancement of the tumor-to-background ratio (TBR). The proper choice of the energy functional parameters has been formulated by making a clear consensus based on tumor heterogeneity and TBR levels. This cautious parameter selection leads to proper handling of heterogeneous lesions. The algorithm was evaluated using simulated phantom and clinical studies, where the ground truth and histology, respectively, were available for accurate quantitative analysis of the segmentation results. The proposed technique was also compared to a number of previously reported image segmentation techniques. RESULTS: The results were quantitatively analyzed using three evaluation metrics, including the spatial overlap index (SOI), the mean relative error (MRE), and the mean classification error (MCE). Although the performance of the proposed method was analogous to other methods for some datasets, overall the proposed algorithm outperforms all other techniques. In the largest clinical group comprising nine datasets, the proposed approach improved the SOI from 0.41+/-0.14 obtained using the best-performing algorithm to 0.54+/-0.12 and reduced the MRE from 54.23+/ 103.29 to 0.19+/-16.63 and the MCE from 112.86+/-69.07 to 60.58+/-18.43. CONCLUSIONS: The proposed segmentation technique is superior to other representative segmentation techniques in terms of highest overlap between the segmented volume and the ground truth/histology and minimum relative and classification errors. Therefore, the proposed active contour model can result in more accurate tumor volume delineation from PET images. PMID- 23927353 TI - Investigating the use of nonattenuation corrected PET images for the attenuation correction of PET data. AB - PURPOSE: The aim of this study is to investigate the feasibility of using the nonattenuated PET images (PET-NAC) as a means for the AC of PET data. METHODS: A three-step iterative segmentation process is proposed. In step 1, a patient's body contour is segmented from the PET-NAC using an active contour algorithm. Voxels inside the contour are then assigned a value of 0.096 cm(-1) to represent the attenuation coefficient of soft tissue at 511 keV. This segmented attenuation map is then used to correct for attenuation the raw PET data and the resulting PET images are used as the input to Step 2 of the process. In step 2, the lung region is segmented using an optimal thresholding approach and the corresponding voxels are assigned a value of 0.024 cm(-1) representing the attenuation coefficients of lung tissue at 511 keV. The updated attenuation map is then used for a second time to correct for attenuation the raw PET data, and the resulting PET images are used as the input to step 3. The purpose of Step 3 is to delineate parts of the heart and liver in the lung contour using a region growing approach since these parts were unavoidably excluded in the lung contour in step 2. These parts are then corrected by using a value of 0.096 cm(-1) in the attenuation map. Finally the attenuation coefficients of the bed are included based on CT images to eliminate the impact of the couch on the accuracy of AC. The final attenuation map is then used to AC the raw PET data and generates the final PET image, which we name iterative AC PET (PET-IAC). To assess the proposed segmentation approach, a phantom and 14 patients (with a total of 55 lesions including bone) were scanned on a GE Discovery-RX PET/CT scanner. PET-IAC images were generated using the proposed process and compared to those of CT-AC PET (PET-CTAC). Visual inspection, lesion SUV, and voxel by voxel histograms between PET-IAC and PET CTAC for phantom and patient studies were performed to assess the accuracy of image quantification. RESULTS: Visual inspection showed a small difference in lung parenchyma between the PET-IAC and PET-CTAC. Tumor SUV based on PET-IAC were on average different by 3%+/-9% (6%+/-7%) compared to the SUVs from the PET-CTAC in the phantom (patient) studies. For bone lesions only, the average difference was 3%+/-6%. The histogram comparing PET-CTAC and PET-IAC resulted in an average regression line of y=(1.08+/-0.07)x+(0.00007+/-0.0013), with R2=0.978+/-0.0057. CONCLUSIONS: Preliminary results suggest that PET-NAC for the AC of PET images is feasible. Such an approach can potentially be used for dedicated PET or PET/MR hybrid systems while minimizing scan time or potential image artifacts, respectively. PMID- 23927354 TI - Description and assessment of a registration-based approach to include bones for attenuation correction of whole-body PET/MRI. AB - PURPOSE: Attenuation correction for whole-body PET/MRI is challenging. Most commercial systems compute the attenuation map from MRI using a four-tissue segmentation approach. Bones, the most electron-dense tissue, are neglected because they are difficult to segment. In this work, the authors build on this segmentation approach by adding bones using a registration technique and assessing its performance on human PET images. METHODS: Twelve oncology patients were imaged with FDG PET/CT and MRI using a Turbo-FLASH pulse sequence. A database of 121 attenuation correction quality CT scans was also collected. Each patient MRI was compared to the CT database via weighted heuristic measures to find the "most similar" CT in terms of body geometry. The similar CT was aligned to the MRI with a deformable registration method. Two MRI-based attenuation maps were computed. One was a standard four-tissue segmentation (air, lung, fat, and lean tissue) using basic image processing techniques. The other was identical, except the bones from the aligned CT were added. The PET data were reconstructed with the patient's CT-based attenuation map (the silver standard) and both MRI based attenuation maps. The relative errors of the MRI-based attenuation corrections were computed in 14 standardized volumes of interest, in lesions, and over whole tissues. The squared Pearson correlation coefficient was also calculated over whole tissues. Statistical testing was done with ANOVAs and paired t-tests. RESULTS: The MRI-based attenuation correction ignoring bone had relative errors ranging from -37% to -8% in volumes of interest containing bone. By including bone, the magnitude of the relative error was reduced in all cases (p<0.001), ranging from -3% to 4%. Further, the relative error in volumes of interest adjacent to bone was improved from a mean of -7.5% to 2% (p<0.001). In the other seven volumes of interest, including bone reduced the magnitude of relative error in three cases (p<0.001), had no effect in three cases, and increased relative error in one case. There was no statistically significant difference in the relative error in lesions. Over whole tissues, including bone slightly increased relative error in lung from 7.7% to 8.0% (p=0.002), in fat from 8.5% to 9.2% (p<0.001), and in lean tissue from -2.1% to 2.6% (p<0.001), but reduced the magnitude of relative error in bone from -14.6% to 1.3% (p<0.001). The correlation coefficient was essentially unchanged in all tissues regardless of whether bone was included or not. CONCLUSIONS: The approach to include bones in MRI-based attenuation maps described in this work improves quantification of whole-body PET images in and around bony anatomy. The reduction in error is often large (tens of percents), and could alter image interpretation and subsequent patient care. Changes in other parts of the PET image are minimal and likely not of clinical significance. PMID- 23927355 TI - Calibration of time-of-flight cameras for accurate intraoperative surface reconstruction. AB - PURPOSE: In image-guided surgery (IGS) intraoperative image acquisition of tissue shape, motion, and morphology is one of the main challenges. Recently, time-of flight (ToF) cameras have emerged as a new means for fast range image acquisition that can be used for multimodal registration of the patient anatomy during surgery. The major drawbacks of ToF cameras are systematic errors in the image acquisition technique that compromise the quality of the measured range images. In this paper, we propose a calibration concept that, for the first time, accounts for all known systematic errors affecting the quality of ToF range images. Laboratory and in vitro experiments assess its performance in the context of IGS. METHODS: For calibration the camera-related error sources depending on the sensor, the sensor temperature and the set integration time are corrected first, followed by the scene-specific errors, which are modeled as function of the measured distance, the amplitude and the radial distance to the principal point of the camera. Accounting for the high accuracy demands in IGS, we use a custom-made calibration device to provide reference distance data, the cameras are calibrated too. To evaluate the mitigation of the error, the remaining residual error after ToF depth calibration was compared with that arising from using the manufacturer routines for several state-of-the-art ToF cameras. The accuracy of reconstructed ToF surfaces was investigated after multimodal registration with computed tomography (CT) data of liver models by assessment of the target registration error (TRE) of markers introduced in the livers. RESULTS: For the inspected distance range of up to 2 m, our calibration approach yielded a mean residual error to reference data ranging from 1.5+/-4.3 mm for the best camera to 7.2+/-11.0 mm. When compared to the data obtained from the manufacturer routines, the residual error was reduced by at least 78% from worst calibration result to most accurate manufacturer data. After registration of the CT data with the ToF data, the mean TRE ranged from 3.7+/-2.1 mm for point-based and 5.7+/-1.9 mm for surface-based registration for the best camera to 6.2+/-3.4 and 11.1+/-2.8 mm, respectively. Compared to data provided by the manufacturer, the mean TRE decreased by 8%-60% for point-based and by 18%-74% for surface-based registration. CONCLUSIONS: Using the proposed calibration approach improved the measurement accuracy of all investigated ToF cameras. Although evaluated in the context of intraoperative image acquisition, the proposed calibration procedure can easily be applied to other medical applications using ToF cameras, such as patient positioning or respiratory motion tracking in radiotherapy. PMID- 23927356 TI - Low-frequency quantitative ultrasound imaging of cell death in vivo. AB - PURPOSE: Currently, no clinical imaging modality is used routinely to assess tumor response to cancer therapies within hours to days of the delivery of treatment. Here, the authors demonstrate the efficacy of ultrasound at a clinically relevant frequency to quantitatively detect changes in tumors in response to cancer therapies using preclinical mouse models. METHODS: Conventional low-frequency and corresponding high-frequency ultrasound (ranging from 4 to 28 MHz) were used along with quantitative spectroscopic and signal envelope statistical analyses on data obtained from xenograft tumors treated with chemotherapy, x-ray radiation, as well as a novel vascular targeting microbubble therapy. RESULTS: Ultrasound-based spectroscopic biomarkers indicated significant changes in cell-death associated parameters in responsive tumors. Specifically changes in the midband fit, spectral slope, and 0-MHz intercept biomarkers were investigated for different types of treatment and demonstrated cell-death related changes. The midband fit and 0-MHz intercept biomarker derived from low-frequency data demonstrated increases ranging approximately from 0 to 6 dBr and 0 to 8 dBr, respectively, depending on treatments administrated. These data paralleled results observed for high-frequency ultrasound data. Statistical analysis of ultrasound signal envelope was performed as an alternative method to obtain histogram-based biomarkers and provided confirmatory results. Histological analysis of tumor specimens indicated up to 61% cell death present in the tumors depending on treatments administered, consistent with quantitative ultrasound findings indicating cell death. Ultrasound-based spectroscopic biomarkers demonstrated a good correlation with histological morphological findings indicative of cell death (r2=0.71, 0.82; p<0.001). CONCLUSIONS: In summary, the results provide preclinical evidence, for the first time, that quantitative ultrasound used at a clinically relevant frequency, in addition to high-frequency ultrasound, can detect tissue changes associated with cell death in vivo in response to cancer treatments. PMID- 23927357 TI - Influence of the pressure field distribution in transcranial ultrasonic neurostimulation. AB - PURPOSE: Low-intensity focused ultrasound has been shown to stimulate the brain noninvasively and without noticeable tissue damage. Such a noninvasive and localized neurostimulation is expected to have a major impact in neuroscience in the coming years. This emerging field will require many animal experiments to fully understand the link between ultrasound and stimulation. The primary goal of this paper is to investigate transcranial ultrasonic neurostimulation at low frequency (320 kHz) on anesthetized rats for different acoustic pressures and estimate the in situ pressure field distribution and the corresponding motor threshold, if any. The corresponding acoustic pressure distribution inside the brain, which cannot be measured in vivo, is investigated based on numerical simulations of the ultrasound propagation inside the head cavity, reproducing at best the experiments conducted in the first part, both in terms of transducer and head geometry and in terms of acoustic parameters. METHODS: In this study, 37 ultrasonic neurostimulation sessions were achieved in rats (N=8) using a 320 kHz transducer. The corresponding beam profile in the entire head was simulated in order to investigate the in situ pressure and intensity level as well as the spatial pressure distribution, thanks to a rat microcomputed tomography scan (CT) based 3D finite differences time domain solver. RESULTS: Ultrasound pulse evoked a motor response in more than 60% of the experimental sessions. In those sessions, the stimulation was always present, repeatable with a pressure threshold under which no motor response occurred. This average acoustic pressure threshold was found to be 0.68+/-0.1 MPa (corresponding mechanical index, MI=1.2 and spatial peak, pulse averaged intensity, Isppa=7.5 W cm(-2)), as calibrated in free water. A slight variation was observed between deep anesthesia stage (0.77+/ 0.04 MPa) and light anesthesia stage (0.61+/-0.03 MPa), assessed from the pedal reflex. Several kinds of motor responses were observed: movements of the tail, the hind legs, the forelimbs, the eye, and even a single whisker were induced separately. Numerical simulations of an equivalent experiment with identical acoustic parameters showed that the acoustic field was spread over the whole rat brain with the presence of several secondary pressure peaks. Due to reverberations, a 1.8-fold increase of the spatial peak, temporal peak acoustic pressure (Psptp) (+/-0.4 standard deviation), a 3.6-fold increase (+/-1.8) for the spatial peak, temporal peak acoustic intensity (Isptp), and 2.3 for the spatial peak, pulse averaged acoustic intensity (Isppa), were found compared to simulations of the beam in free water. Applying such corrections due to reverberations on the experimental results would yield a higher estimation for the average acoustic pressure threshold for motor neurostimulation at 320 KHz at 1.2+/-0.3 MPa (MI=2.2+/-0.5 and Isppa=17.5+/-7.5 W cm(-2)). CONCLUSIONS: Transcranial ultrasonic stimulation is pressure- and anesthesia-dependent in the rat model. Numerical simulations have shown that the acoustic pattern can be complex inside the rat head and that special care must be taken for small animal studies relating acoustic parameters to neurostimulation effects, especially at a low frequency. PMID- 23927358 TI - Modifying the size distribution of microbubble contrast agents for high-frequency subharmonic imaging. AB - PURPOSE: Subharmonic imaging is of interest for high frequency (>10 MHz) nonlinear imaging, because it can specifically detect the response of ultrasound contrast agents (UCA). However, conventional UCA produce a weak subharmonic response at high frequencies, which limits the sensitivity of subharmonic imaging. We hypothesized that modifying the size distribution of the agent can enhance its high-frequency subharmonic response. The overall goal of this study was to investigate size-manipulated populations of the agent to determine the range of sizes that produce the strongest subharmonic response at high frequencies (in this case, 20 MHz). A secondary goal was to assess whether the number or the volume-weighted size distribution better represents the efficacy of the agent for high-frequency subharmonic imaging. METHODS: The authors created six distinct agent size distributions from the native distribution of a commercially available UCA (Targestar-P(r)). The median (number-weighted) diameter of the native agent was 1.63 MUm, while the median diameters of the size manipulated populations ranged from 1.35 to 2.99 MUm. The authors conducted acoustic measurements with native and size-manipulated agent populations to assess their subharmonic response to 20 MHz excitation (pulse duration 1.5 MUs, pressure amplitudes 100-398 kPa). RESULTS: The results showed a considerable difference between the subharmonic response of the agent populations that were investigated. The subharmonic response peaked for the agent population with a median diameter of 2.15 MUm, which demonstrated a subharmonic signal that was 8 dB higher than the native agent. Comparing the subharmonic response of different UCA populations indicated that microbubbles with diameters between 1.3 and 3 MUm are the dominant contributors to the subharmonic response at 20 MHz. Additionally, a better correlation was observed between the subharmonic response of the agent and the number-weighted size-distribution (R2=0.98) than with the volume-weighted size distribution (R2=0.53). CONCLUSIONS: Modifying the size distribution of the agent appears to be a viable strategy to improve the sensitivity of high-frequency subharmonic imaging. In addition, when the size distribution of the UCA has not been suitably modified, the number-weighted size distribution is a useful parameter to accurately describe the efficacy of the agent for high-frequency subharmonic imaging. PMID- 23927359 TI - Evaluation of the impact of backscatter intensity variations on ultrasound attenuation estimation. AB - PURPOSE: Quantitative ultrasound based approaches such as attenuation slope estimation can be used to determine underlying tissue properties and eventually used as a supplemental diagnostic technique to B-mode imaging. The authors investigate the impact of backscatter intensity and frequency dependence variations on the attenuation slope estimation accuracy. METHODS: The authors compare three frequency domain based attenuation slope estimation algorithms, namely, a spectral difference method, the reference phantom method, and two spectral shift methods: a hybrid method and centroid downshift method. Both the reference phantom and hybrid method use a tissue-mimicking phantom with well defined acoustic properties to reduce system dependencies and diffraction effects. The normalized power spectral ratio obtained is then filtered by a Gaussian filter centered at the transmit center frequency in the hybrid method. A spectral shift method is then used to estimate the attenuation coefficient from the normalized and filtered spectrum. The centroid downshift method utilizes the shift in power spectrum toward lower frequencies with depth. Numerical phantoms that incorporate variations in the backscatter intensity from -3 to 3 dB, by varying the scatterer number density and variations in the scatterer diameters ranging from 10 to 100 MUm are simulated. Experimental tissue mimicking phantoms with three different scatterer diameter ranges (5-40, 75-90, and 125-150 MUm) are also used to evaluate the accuracy of the estimation methods. RESULTS: The reference phantom method provided accurate results when the acoustical properties of the reference and the sample are well matched. Underestimation occurs when the reference phantom possessed a higher sound speed than the sample, and overestimation occurs when the reference phantom had a lower sound speed than the sample. The centroid downshift method depends significantly on the bandwidth of the power spectrum, which in turn depends on the frequency dependence of the backscattering. The hybrid method was the least susceptible to changes in the sample's acoustic properties and provided the lowest standard deviation in the numerical simulations and experimental evaluations. CONCLUSIONS: No significant variations in the estimation accuracy of the attenuation coefficient were observed with an increase in the scatterer number density in the simulated numerical phantoms for the three methods. Changes in the scatterer diameters, which result in different frequency dependence of backscatter, do not significantly affect attenuation slope estimation with the reference phantom and hybrid approaches. The centroid method is sensitive to variations in the scatterer diameter due to the frequency shift introduced in the power spectrum. PMID- 23927361 TI - Organ S values and effective doses for family members exposed to adult patients following I-131 treatment: a Monte Carlo simulation study. AB - PURPOSE: To calculate organ S values (mGy/Bq-s) and effective doses per time integrated activity (mSv/Bq-s) for pediatric and adult family members exposed to an adult male or female patient treated with I-131 using a series of hybrid computational phantoms coupled with a Monte Carlo radiation transport technique. METHODS: A series of pediatric and adult hybrid computational phantoms were employed in the study. Three different exposure scenarios were considered: (1) standing face-to-face exposures between an adult patient and pediatric or adult family phantoms at five different separation distances; (2) an adult female patient holding her newborn child, and (3) a 1-yr-old child standing on the lap of an adult female patient. For the adult patient model, two different thyroid related diseases were considered: hyperthyroidism and differentiated thyroid cancer (DTC) with corresponding internal distributions of 131I. A general purpose Monte Carlo code, MCNPX v2.7, was used to perform the Monte Carlo radiation transport. RESULTS: The S values show a strong dependency on age and organ location within the family phantoms at short distances. The S values and effective dose per time-integrated activity from the adult female patient phantom are relatively high at shorter distances and to younger family phantoms. At a distance of 1 m, effective doses per time-integrated activity are lower than those values based on the NRC (Nuclear Regulatory Commission) by a factor of 2 for both adult male and female patient phantoms. The S values to target organs from the hyperthyroid-patient source distribution strongly depend on the height of the exposed family phantom, so that their values rapidly decrease with decreasing height of the family phantom. Active marrow of the 10-yr-old phantom shows the highest S values among family phantoms for the DTC-patient source distribution. In the exposure scenario of mother and baby, S values and effective doses per time-integrated activity to the newborn and 1-yr-old phantoms for a hyperthyroid-patient source are higher than values for a DTC-patient source. CONCLUSIONS: The authors performed realistic assessments of 131I organ S values and effective dose per time-integrated activity from adult patients treated for hyperthyroidism and DTC to family members. In addition, the authors' studies consider Monte Carlo simulated "mother and baby/child" exposure scenarios for the first time. Based on these results, the authors reconfirm the strong conservatism underlying the point source method recommended by the US NRC. The authors recommend that various factors such as the type of the patient's disease, the age of family members, and the distance/posture between the patient and family members must be carefully considered to provide realistic dose estimates for patient-to-family exposures. PMID- 23927360 TI - A phantom for visualization of three-dimensional drug release by ultrasound induced mild hyperthermia. AB - PURPOSE: Ultrasound-induced mild hyperthermia has advantages for noninvasive, localized and controlled drug delivery. In this study, a tissue-mimicking agarose based phantom with a thermally sensitive indicator was developed for studying the spatial drug delivery profile using ultrasound-induced mild hyperthermia. METHODS: Agarose powder, regular evaporated milk, Dulbecco's phosphate-buffered saline (DPBS), n-propanol, and silicon carbide powder were homogeneously mixed with low temperature sensitive liposomes (LTSLs) loaded with a self-quenched near infrared (NIR) fluorescent dye. A dual-mode linear array ultrasound transducer was used for insonation at 1.54 MHz with a total acoustic power and acoustic pressure of 2.0 W and 1.5 MPa, respectively. After insonation, the dye release pattern in the phantom was quantified based on optical images, and the three dimensional release profile was reconstructed and analyzed. A finite-difference time-domain-based algorithm was developed to simulate both the temperature distribution and spatial dye diffusion as a function of time. Finally, the simulated dye diffusion patterns were compared to experimental measurements. RESULTS: Self-quenching of the fluorescent dye in DPBS was substantial at a concentration of 6.25*10(-2) mM or greater. The transition temperature of LTSLs in the phantom was 35 degrees C, and the release reached 90% at 37 degrees C. The simulated temperature for hyperthermia correlated with the thermocouple measurements with a mean error between 0.03+/-0.01 and 0.06+/-0.02 degrees C. The R2 value between the experimental and simulated spatial extent of the dye diffusion, defined by the half-peak level in the elevation, lateral and depth directions, was 0.99 (slope=1.08), 0.95 (slope=0.99), and 0.80 (slope=1.04), respectively, indicating the experimental and simulated dye release profiles were similar. CONCLUSIONS: The combination of LTSLs encapsulating a fluorescent dye and an optically transparent phantom is useful for visualizing and modeling drug release in vitro following ultrasound-induced mild hyperthermia. The coupled temperature simulation and dye-diffusion simulation tools were validated with the experimental system and can be used to optimize the thermal dose and spatial and temporal dye release pattern. PMID- 23927362 TI - The effect of a paraffin screen on the neutron dose at the maze door of a 15 MV linear accelerator. AB - PURPOSE: The purpose of this study was to explore the effects of a paraffin screen located at various positions in the maze on the neutron dose equivalent at the maze door. METHODS: The neutron dose equivalent was measured at the maze door of a room containing a 15 MV linear accelerator for x-ray therapy. Measurements were performed for several positions of the paraffin screen covering only 27.5% of the cross-sectional area of the maze. The neutron dose equivalent was also measured at all screen positions. Two simple models of the neutron source were considered in which the first assumed that the source was the cross-sectional area at the inner entrance of the maze, radiating neutrons in an isotropic manner. In the second model the reduction in the neutron dose equivalent at the maze door due to the paraffin screen was considered to be a function of the mean values of the neutron fluence and energy at the screen. RESULTS: The results of this study indicate that the equivalent dose at the maze door was reduced by a factor of 3 through the use of a paraffin screen that was placed inside the maze. It was also determined that the contributions to the dosage from areas that were not covered by the paraffin screen as viewed from the dosimeter, were 2.5 times higher than the contributions from the covered areas. This study also concluded that the contributions of the maze walls, ceiling, and floor to the total neutron dose equivalent were an order of magnitude lower than those from the surface at the far end of the maze. CONCLUSIONS: This study demonstrated that a paraffin screen could be used to reduce the neutron dose equivalent at the maze door by a factor of 3. This paper also found that the reduction of the neutron dose equivalent was a linear function of the area covered by the maze screen and that the decrease in the dose at the maze door could be modeled as an exponential function of the product phi.E at the screen. PMID- 23927363 TI - A novel dose-volume metric for optimizing therapeutic ratio through fractionation: retrospective analysis of lung cancer treatments. AB - PURPOSE: To explore the potential of a novel dose-volume based metric to assist in the selection of optimal fractionation schedules for lung cancer patients. METHODS: Selecting the dose per fraction that maximizes the therapeutic ratio via a linear-quadratic effect on normal tissue complication probability and tumor cell survival is an optimization problem. The mathematical solution reveals that the optimal fractionation schedule is determined by a generalized dose ratio between the normal tissue and the tumor, here termed the bifurcation number B, that can be derived from the dose-volume histogram of the normal tissue. The bifurcation number characterizes the volume effect of a normal tissue and its dependency on the fractionation schedule. The clinical relevance of the bifurcation number was evaluated in 46 patients previously treated for nonsmall cell lung cancer (NSCLC) according to various fractionation protocols. Bifurcation numbers were computed for both lung and esophagus as the normal tissues. RESULTS: The value of the bifurcation number determines whether the volume effect reverses the traditional radiobiological advantage of small dose per fraction for the normal tissue. If B is smaller than the ratio of alpha/beta ratios between normal tissue and tumor, then a single fraction is optimal; otherwise the optimal treatment is an infinite number of doses (hence the name "bifurcation" number). These fractionation schedules correspond clinically to hypo- and standard/hyperfractionation, respectively. Compared with traditional dose-volume metrics, the bifurcation number is a unitless ratio and independent of dose fractionation. The B-numbers derived from the clinical treatment plans are also strongly consistent with historically prescribed clinical fractionation protocols for NSCLC treatments. The B-numbers for esophagus and lung for all patients receiving a high dose per fraction protocol (>7.5 Gy/fraction) were all smaller than the B-numbers for the patients receiving standard 2 Gy/fraction, with the numbers for the 3 Gy/fraction group in between. CONCLUSIONS: The bifurcation numbers are strongly consistent with prescribed clinical fractionation protocols for NSCLC treatments. Due to their scale-free property the B-numbers may assist in the selection of an appropriate fractionation once the dose distribution has been optimized. PMID- 23927364 TI - Assessment of patient dose from CT localizer radiographs. AB - PURPOSE: With recently introduced technical innovations for CT systems, the dose of CT scan acquisitions has been substantially reduced; even effective dose values below 1 mSv have been reported. Due to this development, dose of the localizer radiograph may contribute substantially to dose of the whole CT examination. Since there are only limited data in the literature regarding patient dose for the different types of localizer radiographs, patient dose values were estimated in our study by measurements and Monte Carlo simulations and compared to dose values of typical CT examinations. METHODS: First, dose distributions were measured in anthropomorphic phantoms for three different body regions (head, thorax, abdomen-pelvic) and three positions of the x-ray tube (AP, PA, and lateral views); measured values were compared to simulated data using Monte Carlo techniques for validation purposes. Second, organ and effective dose values for the various investigated localizer radiograph scenarios were calculated and compared with published dose values for standard CT and low-dose CT examinations. RESULTS: For the anthropomorphic phantom, deviations of the dose values between measured and calculated results were in the range of 15%. Organ and effective dose values showed a strong dependence on the tube position. The largest differences were observed for chest localizer radiographs in the female phantom for the dose to the breast (AP: 1.01 mGy vs PA: 0.24 mGy). Overall effective dose values were in the range of 0.04-0.42 mSv per localizer radiograph acquisition. CONCLUSIONS: In view of the technical dose-reducing innovations in CT, localizer radiographs may substantially contribute to the total dose of the whole CT examination, particularly in the case of dedicated low-dose scans used, e.g., for young patients or screening purposes. Optimization of dose in localizer radiographs should be pursued further in the same way as it was done in CT. PMID- 23927366 TI - Immediate implant placement into fresh extraction socket in the mandibular molar sites: a preliminary study of a modified insertion technique. AB - BACKGROUND: Immediate implant insertion in mandibular molar extraction sockets raises a series of challenges for clinicians. PURPOSE: This preliminary study demonstrates the use of a modified insertion technique of implant placement at the time of mandibular molar extraction. MATERIALS AND METHODS: Immediate implants were placed at the time of molar extraction in 20 patients; a sulcular buccal incision with releasing periosteal incisions were made around the mandibular molar to be replaced, and implant insertion into the interseptal/interradicular bone was performed. The remnants of roots were atraumatically extracted, and the bony defects around the implant were grafted with synthetic resorbable bone substitute beta- Tricalcium phosphate, and the flap was sutured. Three months later, implants were restored with single crown fixed prostheses. Patients were followed up at 6, 12, and 18 months after insertion using periapical standardized radiographs to monitor the changes in the marginal bone level. RESULTS: Our modified insertion techniques showed an implant survival rate of 95%; one implant failed 4 weeks after insertion. No significant marginal bone loss around the implant was recorded at all times of follow-up. Satisfactory soft issue parameters were achieved. CONCLUSIONS: The combination of immediate implant placement with engagement of the interseptal/interradicular bone, atraumatic extraction of remnant roots, and concomitant regenerative therapy showed preliminary favorable outcomes. However, wider application of this technique for longer following up periods is required for further conclusive recommendations. PMID- 23927367 TI - A survey of Toxoplasma gondii and Neospora caninum infecting house mice from a hybrid zone. AB - Toxoplasma gondii and Neospora caninum are closely related coccidian parasites infecting a wide range of wild and domestic animals as intermediate hosts, and rodents serve as important reservoir hosts during the life cycles of these parasites. The present study is aimed at identifying T. gondii and N. caninum infection in 360 wild house mice (Mus musculus) collected across the Czech-German border, where 2 genetically distinct mouse subspecies meet and hybridize. Toxoplasma gondii or N. caninum DNA was detected in the brains of individual mice by PCR, but mixed infections were never observed. No significant differences in gender or trapping localities were found in the positive mice. The survey reveals a low frequency of T. gondii (0.6%) and N. caninum (3.6%) occurrence in the house mice population of the monitored part of the hybrid zone. PMID- 23927365 TI - Evaluation of computer-aided detection and diagnosis systems. AB - Computer-aided detection and diagnosis (CAD) systems are increasingly being used as an aid by clinicians for detection and interpretation of diseases. Computer aided detection systems mark regions of an image that may reveal specific abnormalities and are used to alert clinicians to these regions during image interpretation. Computer-aided diagnosis systems provide an assessment of a disease using image-based information alone or in combination with other relevant diagnostic data and are used by clinicians as a decision support in developing their diagnoses. While CAD systems are commercially available, standardized approaches for evaluating and reporting their performance have not yet been fully formalized in the literature or in a standardization effort. This deficiency has led to difficulty in the comparison of CAD devices and in understanding how the reported performance might translate into clinical practice. To address these important issues, the American Association of Physicists in Medicine (AAPM) formed the Computer Aided Detection in Diagnostic Imaging Subcommittee (CADSC), in part, to develop recommendations on approaches for assessing CAD system performance. The purpose of this paper is to convey the opinions of the AAPM CADSC members and to stimulate the development of consensus approaches and "best practices" for evaluating CAD systems. Both the assessment of a standalone CAD system and the evaluation of the impact of CAD on end-users are discussed. It is hoped that awareness of these important evaluation elements and the CADSC recommendations will lead to further development of structured guidelines for CAD performance assessment. Proper assessment of CAD system performance is expected to increase the understanding of a CAD system's effectiveness and limitations, which is expected to stimulate further research and development efforts on CAD technologies, reduce problems due to improper use, and eventually improve the utility and efficacy of CAD in clinical practice. PMID- 23927368 TI - Prenatal education is an opportunity for improved outcomes in hypertensive disorders of pregnancy: results from an Internet-based survey. AB - Current prenatal care (PNC) practice guidelines provide little information on educating patients about preeclampsia. Our survey of 754 women who visited the Preeclampsia Foundation website found that most received PNC and regular screenings, but only 42% "definitely" recalled specific education about preeclampsia; furthermore, only half "fully understood" the explanation. However, 27 of the 169 women (75.0%) who understood acted on this knowledge by promptly reporting symptoms and complying with treatment. Of the 46 who did not remember some or any of the education, 3 (6.0%) took any action; the difference between these two groups is highly significant. We conclude that knowledge enables women to spot signs and symptoms, leading to earlier diagnosis and management, and reduced morbidity and mortality. We propose the adoption of formal guidelines on preeclampsia education. PMID- 23927369 TI - GalR3 activation promotes adult neural stem cell survival in response to a diabetic milieu. AB - Type 2 diabetes impairs adult neurogenesis which could play a role in the CNS complications of this serious disease. The goal of this study was to determine the potential role of galanin in protecting adult neural stem cells (NSCs) from glucolipotoxicity and to analyze whether apoptosis and the unfolded protein response were involved in the galanin-mediated effect. We also studied the regulation of galanin and its receptor subtypes under diabetes in NSCs in vitro and in the subventricular zone (SVZ) in vivo. The viability of mouse SVZ-derived NSCs and the involvement of apoptosis (Bcl-2, cleaved caspase-3) and unfolded protein response [C/EBP homologous protein (CHOP) Glucose-regulated protein 78/immunoglobulin heavy-chain binding protein (GRP78/BiP), spliced X-box binding protein 1 (XBP1), c-Jun N-terminal kinases (JNK) phosphorylation] were assessed in the presence of glucolipotoxic conditions after 24 h. The effect of diabetes on the regulation of galanin and its receptor subtypes was assessed on NSCs in vitro and in SVZ tissues isolated from normal and type 2 diabetes ob/ob mice. We show increased NSC viability following galanin receptor (GalR)3 activation. This protective effect correlated with decreased apoptosis and CHOP levels. We also report how galanin and its receptors are regulated by diabetes in vitro and in vivo. This study shows GalR3-mediated neuroprotection, supporting a potential future therapeutic development, based on GalR3 activation, for the treatment of brain disorders. PMID- 23927370 TI - Molecular simulations of aromatase reveal new insights into the mechanism of ligand binding. AB - CYP19A1, also known as aromatase or estrogen synthetase, is the rate-limiting enzyme in the biosynthesis of estrogens from their corresponding androgens. Several clinically used breast cancer therapies target aromatase. In this work, explicitly solvated all-atom molecular dynamics simulations of aromatase with a model of the lipid bilayer and the transmembrane helix are performed. The dynamics of aromatase and the role of titration of an important amino acid residue involved in aromatization of androgens are investigated via two 250-ns long simulations. One simulation treats the protonated form of the catalytic aspartate 309, which appears more consistent with crystallographic data for the active site, while the simulation of the deprotonated form shows some notable conformational shifts. Ensemble-based computational solvent mapping experiments indicate possible novel druggable binding sites that could be utilized by next generation inhibitors. In addition, the effects of protonation on the ligand positioning and channel dynamics are investigated using geometrical models that estimate the opening width of critical channels. Significant differences in channel dynamics between the protonated and deprotonated trajectories are exhibited, suggesting that the mechanism for substrate and product entry and the aromatization process may be coupled to a "locking" mechanism and channel opening. Our results may be particularly relevant in the design of novel drugs, which may be useful therapeutic treatments of cancers such as those of the breast and prostate. PMID- 23927371 TI - A phase I/II trial of bortezomib combined concurrently with gemcitabine for relapsed or refractory DLBCL and peripheral T-cell lymphomas. AB - There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL). We conducted a phase I/II trial with bortezomib (dose-escalated to 1.6 mg/m(2) ) given concurrently with gemcitabine (800 mg/m(2) ) days 1 + 8 q21 d. Of 32 patients, 16 each had relapsed/refractory PTCL and DLBCL. Median prior therapies were 3 and 35% had failed transplant. Among the first 18 patients, 67% experienced grade 3/4 neutropenia and/or grade 3/4 thrombocytopenia resulting in repeated treatment delays (relative dose intensity: 46%). Thus, the study was amended to give bortezomib and gemcitabine days 1 + 15 q28 d, which resulted in markedly improved tolerability. Among all patients, the overall response rate (ORR) was 24% with 19% complete remission (CR; intent-to-treat (ITT) ORR 16%, CR 13%), which met criteria for futility. The ORR for DLBCL was 10% (CR 10%) vs. 36% for PTCL (CR 27%). Among 6 PTCL patients treated on the modified schedule, ORR by ITT was 50% (CR 30%). Altogether, concurrent bortezomib/gemcitabine given days 1 + 8 q21 d was not tolerable, while modification to a bi-monthly schedule allowed consistent treatment delivery. Whereas efficacy of this combination was low in heavily pre-treated DLBCL, there was a signal of activity in relapsed/refractory PTCL utilizing the modified schedule. PMID- 23927372 TI - UGT2B17 copy number gain in a large ankylosing spondylitis multiplex family. AB - BACKGROUND: The primary objective of this study is to identify novel copy number variations (CNVs) associated with familial ankylosing spondylitis (AS). A customized genome-wide microarray was designed to detect CNVs and applied to a multiplex AS family with six (6) affected family members. CNVs were detected using the built-in DNA analytics aberration detection method-2 (ADM-2) algorithm. Gene enrichment analysis was performed to observe the segregation. Subsequent validation was performed using real time quantitative fluorescence polymerase reaction (QF-PCR). The frequency of copy number variation for the UGT2B17 gene was then performed on two well-defined AS cohorts. Fisher exact test was performed to quantify the association. RESULTS: Our family-based analysis revealed ten gene-enriched CNVs that segregate with all six family members affected with AS. Based on the proposed function and the polymorphic nature of the UGT2B17 gene, the UGT2B17 gene CNV was selected for validation using real time QF-PCR with full concordance. The frequency of two copies of the UGT2B17 gene CNV was 0.41 in the Newfoundland AS cases and 0.35 in the Newfoundland controls (OR = 1.26(0.99-1.59); p < 0.05)), whereas the frequency of two (2) copies of the UGT2B17 gene CNV was 0.40 in the Alberta AS cases and 0.39 in the Alberta controls (OR = 1.05(95% CI: 0.83-1.33); p < 0.71)). CONCLUSIONS: A genome wide microarray interrogation of a large multiplex AS family revealed segregation of the UGT2B17 gene CNV among all affected family members. The association of the UGT2B17 CNV with AS is particularly interesting given the recent association of this CNV with osteoporosis and the proposed function as it encodes a key enzyme that inhibits androgens. However, two copies of the UGT2B17 gene CNV were only marginally significant in a uniplex AS cohort from Newfoundland but not in a uniplex AS cohort from Alberta. PMID- 23927373 TI - Femtosecond laser-induced micropattern and Ca/P deposition on Ti implant surface and its acceleration on early osseointegration. AB - Surface microstructure and chemical composition of the implant are very important for its osseointegration in vivo. In this paper, a hierarchical micropattern covered with calcium phosphate (Ca/P phase) was obtained on titanium (Ti) implant surface by femtosecond lasers (FSL) irradiation in hydroxyapatite suspension. The hierachical micropattern as well as Ca/P phase increased osteoblastic cell adhesion. Higher expression of osteogenic markers (osteocalcin, osteopontin, and runt related transcription factor-2) on the surface treated by FSL of 2.55 J/cm(2) indicated the favorable effect of laser treatment on cell differentiation. In vivo studies were carried out to evaluate the effect of laser treatment and Ca/P deposition on the osseointegration. It showed that the binding capacity between bone and FSL-treated Ti implants was obviously stronger than that between bone and polished or sand blasting and acid etching (SLA) Ti implants. Bone trabecula surrounded the FSL-treated implants without fibrous tissue after 8-week implantation. Also, higher bone mineral density was seen surrounding the FSL-treated implants. Our in vitro and in vivo studies demonstrated that the FSL induced micropattern and Ca/P phase had positive effects on the acceleration of early osseointegration of Ti implants with bone tissue. PMID- 23927374 TI - Identification of key amino acid residues in the catalytic mechanism of diaminopropionate ammonialyase from Salmonella typhimurium. AB - Diaminopropionate ammonialyase (DAPAL), a fold-type II pyridoxal 5'-phosphate dependent enzyme, catalyzes the alpha,beta-elimination of diaminopropionate (DAP) to pyruvate and ammonia. DAPAL was able to utilize both d- and l-DAP as substrates with almost equal efficiency. Mutational analysis of functionally important residues such as Thr385, Asp125 and Asp194 was carried out to understand the mechanism by which the isomers are hydrolyzed. Further, the putative residues involved in the formation of disulfide bond Cys271 and Cys299 were also mutated. T385S, T385D sDAPAL were as active with dl-DAP as substrate as sDAPAL, whereas the later exhibited a threefold increase in catalytic efficiency with d-Ser as substrate. Further analysis of these mutants suggested that DAPAL might follow an anti-E2 mechanism of catalysis that does not involve the formation of a quinonoid intermediate. Of the two mutants of Asp125, D125E showed complete loss of activity with d-DAP as substrate, whereas the reaction with l DAP was not affected significantly, demonstrating that Asp125 was essential for abstraction of protons from the d-isomer. By contrast, mutational analysis of Asp194 showed that the residue may not be directly involved in proton abstraction from l-DAP. sDAPAL does not form a disulfide bond in solution, although the position of Cys299 and Cys271 in the modeled structure of sDAPAL favored the formation of a disulfide bond. Further, unlike eDAPAL, sDAPAL could be activated by monovalent cations. Mutation of the cysteine residues showed that Cys271 may be involved in coordinating the monovalent cation, as observed in the case of other fold-type II enzymes. PMID- 23927375 TI - Evidence-based psychosocial treatments for child and adolescent bipolar spectrum disorders. AB - Pediatric bipolar spectrum disorders (BPSDs) are serious conditions associated with morbidity and mortality. Although most treatment research has examined pharmacotherapy for pediatric BPSDs, growing literature suggests that psychosocial interventions are also important to provide families with an understanding of symptoms, course, and treatment of BPSDs; teach youth and parents methods for coping with symptoms (e.g., problem solving, communication, emotion regulation, cognitive-behavioral skills); and prevent relapse. Thirteen psychosocial intervention trials for pediatric BPSDs were identified via a comprehensive literature search and evaluated according to the Task Force on the Promotion and Dissemination of Psychological Procedures guidelines. All interventions were examined adjunctive to pharmacotherapy and/or treatment as usual (TAU). No well-established or questionably efficacious treatments were identified. Family psychoeducation plus skill building was probably efficacious (i.e., Multi-Family Psychoeducational Psychotherapy, Family-Focused Treatment); cognitive-behavioral therapy (CBT) was possibly efficacious. Dialectical behavior therapy (DBT) and interpersonal and social rhythm therapy (IPSRT) were experimental. Limited research precluded subdivision of treatments by format and age. Only single- and multiple-family psychoeducation plus skill building and CBT were evaluated with children. Only single-family psychoeducation plus skill building and DBT, and individual (commonly with limited familial involvement) CBT and IPSRT were evaluated with adolescents. In conclusion, psychosocial interventions that involve families, psychoeducation, and skill building may offer added benefit to pharmacotherapy and/or other TAU. Limitations of current research include few outcome studies, small samples, and failure to use stringent control conditions or randomization. The review concludes with a discussion of mediators and moderators, recommendations for best practice, and suggestions for future research. PMID- 23927376 TI - Laboratory faceseal leakage evaluation of n95 filtering facepiece respirators against nanoparticles and "all size" particles. AB - National Institute for Occupational Safety and Health (NIOSH)-certified N95 filtering facepiece respirators (FFRs) are used for respiratory protection in some workplaces handling engineered nanomaterials. Previous NIOSH research has focused on filtration performance against nanoparticles. This article is the first NIOSH study using human test subjects to compare N95 FFR faceseal leakage (FSL) performance against nanoparticles and "all size" particles. In this study, estimates of FSL were obtained from fit factor (FF) measurements from nine test subjects who participated in previous fit-test studies. These data were analyzed to compare values obtained by: 1) using the PortaCount Plus (8020A, TSI, Inc., MN, USA) alone (measureable particle size range 20 nm to > 1,000 nm, hereby referred to as the "all size particles test"), and 2) using the PortaCount Plus with N95-Companion(TM) accessory (8095, TSI, Inc., Minn.) accessory (negatively charged particles, size range ~40 to 60 nm, hereby referred to as the "nanoparticles test"). Log-transformed FF values were compared for the "all size particles test" and "nanoparticles test" using one-way analysis of variance tests (significant at P < 0.05). For individual FFR models, geometric mean (GM) FF using the "nanoparticles test" was the same or higher than the GM FFs using "all size particles test." For all three FFR models combined, GM FF using the "nanoparticles test" was significantly higher than the GM FF using "all size particles test" (P < 0.05). These data suggest that FSL for negatively charged ~40-60 nm nanoparticles is not greater than the FSL for the larger distribution of charged and uncharged 20 to > 1,000 nm particles. PMID- 23927377 TI - Development of fluorogenic probes for quick no-wash live-cell imaging of intracellular proteins. AB - We developed novel fluorogenic probes for no-wash live-cell imaging of proteins fused to PYP-tag, which is a small protein tag recently reported by our group. Through the design of a new PYP-tag ligand, specific intracellular protein labeling with rapid kinetics and fluorogenic response was accomplished. The probes crossed the cell membrane, and cytosolic and nuclear localizations of PYP tagged proteins without cell washing were visualized within a 6-min reaction time. The fluorogenic response was due to the environmental effect of fluorophore upon binding to PYP-tag. Furthermore, the PYP-tag-based method was applied to the imaging of methyl-CpG-binding domain localization. This rapid protein-labeling system combined with the small protein tag and designed fluorogenic probes offers a powerful method to study the localization, movement, and function of cellular proteins. PMID- 23927379 TI - Predictive factors for erythema nodosum and pyoderma gangrenosum in inflammatory bowel disease. AB - BACKGROUND AND AIM: To identify predictive factors related to the development of erythema nodosum and pyoderma gangrenosum, in patients with inflammatory bowel disease (IBD). METHODS: Epidemiological and clinical data from 270 patients with Crohn's disease (CD) and 125 patients with ulcerative colitis (UC) were collected between 2003 and 2011. The variables retrospectively analyzed were: gender, age at diagnosis, type of IBD (CD or UC), smoking habit, pattern of disease (IBD), location and extension, family history, previous IBD-related surgery, other extraintestinal manifestations (EIMs), and previous biological and immunosuppressive therapy. RESULTS: Thirty-seven patients showed at least one cutaneous manifestation. These lesions were more frequent in women (15.4%) than in men (4.2%; P = 0.0001) and in CD (12.2%) than in UC patients (3.2%; P = 0.005). These manifestations were more frequently associated with other EIMs (25% vs 7.2%; P = 0.0001), and they were less frequent in patients who received a previous biological therapy for IBD (6.8% vs 11.2%; P = 0.1). Patients with skin manifestations were younger at diagnosis of IBD than those patients without them (26.3 +/- 10 vs 32.9 +/- 14.5, P = 0.008). Independent variables significantly associated with development of skin manifestations were: female (P = 0.008), previous biological therapy (P = 0.007), age at diagnosis (young, P = 0.026), type of IBD (CD, P = 0.043) and presence of other EIMs (P = 0.0001). CONCLUSION: Predictive factors involved in the development of main cutaneous manifestations are: female, CD, young age at diagnosis of IBD, and presence of other EIMs. Early use of biological therapies prevents the development of cutaneous manifestations. PMID- 23927378 TI - Early histone modifications in the ventromedial hypothalamus and preoptic area following oestradiol administration. AB - Expression of the primary female sex behaviour, lordosis, in laboratory animals depends on oestrogen-induced expression of progesterone receptor (PgR) within a defined cell group in the ventrolateral portion of the ventromedial nucleus of the hypothalamus (VMH). The minimal latency from oestradiol administration to lordosis is 18 h. During that time, ligand-bound oestrogen receptors (ER), members of a nuclear receptor superfamily, recruit transcriptional coregulators, which induce covalent modifications of histone proteins, thus leading to transcriptional activation or repression of target genes. The present study aimed to investigate the early molecular epigenetic events underlying oestrogen regulated transcriptional activation of the Pgr gene in the VMH of female mice. Oestradiol (E2) administration induced rapid and transient global histone modifications in the VMH of ovariectomised female mice. Histone H3 N-terminus phosphorylation (H3S10phK14Ac), acetylation (H3Ac) and methylation (H3K4me3) exhibited distinct temporal patterns facilitative to the induction of transcription. A transcriptional repressive (H3K9me3) modification showed a different temporal pattern. Collectively, this should create a permissive environment for the transcriptional activity necessary for lordosis, within 3-6 h after E2 treatment. In the VMH, changes in the H3Ac and H3K4me3 levels of histone H3 were also detected at the promoter region of the Pgr gene within the same time window, although they were delayed in the preoptic area. Moreover, examination of histone modifications associated with the promoter of another ER-target gene, oxytocin receptor (Oxtr), revealed gene- and brain-region specific effects of E2 treatment. In the VMH of female mice, E2 treatment resulted in the recruitment of ERalpha to the oestrogen-response-elements-containing putative enhancer site of Pgr gene, approximately 200 kb upstream of the transcription start site, although it failed to increase ERalpha association with the more proximal promoter region. Finally, E2 administration led to significant changes in the mRNA expression of several ER coregulators in a brain-region dependent manner. Taken together, these data indicate that, in the hypothalamus and preoptic area of female mice, early responses to E2 treatment involve highly specific changes in chromatin structure, dependent on cell group, gene, histone modification studied, promoter/enhancer site and time following E2. PMID- 23927380 TI - Prophylactic digital cryotherapy is associated with decreased incidence of laminitis in horses diagnosed with colitis. AB - REASONS FOR PERFORMING THE STUDY: Recent research suggested that prophylactic digital cryotherapy (ICE) improved lameness scores, diminished histological changes and early laminar inflammatory signalling in horses following oligofructose administration. In clinical practice, horses at risk for sepsis associated laminitis receive ICE. Evidence to support this practice is lacking. OBJECTIVES: To determine factors associated with development of laminitis in horses diagnosed with colitis, including ICE. STUDY DESIGN: Multicentre retrospective case series. METHODS: Medical records for horses admitted to 2 university hospitals diagnosed with colitis with evidence of systemic inflammatory response from 2002 to 2012 were reviewed. Horses were excluded if they exhibited signs of laminitis at admission, were ponies, miniature or draught breeds, or <2 years old. Data were analysed using univariate and multivariate logistic regression. RESULTS: Twenty-seven of 130 horses (21%) developed laminitis. Seven of 69 (10%) horses treated with ICE developed laminitis compared with 20/61 (33%) horses that developed laminitis but did not receive ICE. Factors associated with laminitis included site of hospitalisation, admission respiratory rate (?) and blood L-lactate (?), and ICE (?), P<0.05. Horses treated with ICE had 10 times less odds of developing laminitis compared with horses treated without ICE (odds ratio 0.11, 95% confidence limit 0.03-0.44). Sixteen horses (16/130, 12%) were subjected to euthanasia in hospital. Fourteen of these horses had laminitis and 2 did not develop laminitis. Survival for horses with colitis that developed laminitis was 13/27 (48%) compared with survival for horses with colitis that did not develop laminitis, 101/103 (98%). CONCLUSION: Laminitis occurred in more clinically compromised horses. Use of ICE reduced the incidence of clinical laminitis in the study population suggesting that digital cryotherapy is an effective prophylactic strategy for the prevention of laminitis in horses with colitis. PMID- 23927381 TI - Wrinkle reduction in post-menopausal women consuming a novel oral supplement: a double-blind placebo-controlled randomized study. AB - OBJECTIVE: The maintenance of youthful skin appearance is strongly desired by a large proportion of the world's population. The aim of the present study was therefore to evaluate the effect on skin wrinkling, of a combination of ingredients reported to influence key factors involved in skin ageing, namely inflammation, collagen synthesis and oxidative/UV stress. A supplemented drink was developed containing soy isoflavones, lycopene, vitamin C and vitamin E and given to post-menopausal women with a capsule containing fish oil. METHOD: We have performed a double-blind randomized controlled human clinical study to assess whether this cocktail of dietary ingredients can significantly improve the appearance of facial wrinkles. RESULTS: We have shown that this unique combination of micronutrients can significantly reduce the depth of facial wrinkles and that this improvement is associated with increased deposition of new collagen fibres in the dermis. CONCLUSION: This study demonstrates that consumption of a mixture of soy isoflavones, lycopene, vitamin C, vitamin E and fish oil is able to induce a clinically measureable improvement in the depth of facial wrinkles following long-term use. We have also shown, for the first time with an oral product, that the improvement is associated with increased deposition of new collagen fibres in the dermis. PMID- 23927383 TI - Prevalence of dry eye syndrome in an adult population. AB - BACKGROUND: To determine the prevalence of dry eye syndrome in the general 40- to 64-year-old population of Shahroud, Iran. DESIGN: Population-based cross sectional study. PARTICIPANTS: Through cluster sampling, 6311 people were selected and 5190 participated. Assessment of dry eye was done in a random subsample of 1008 people. METHODS: Subjective assessment for dry eye syndrome was performed using Ocular Surface Disease Index questionnaire. In addition, the following objective tests of dry eye syndrome were employed: Schirmer test, tear break-up time, and fluorescein and Rose Bengal staining using the Oxford grading scheme. MAIN OUTCOME MEASURES: Those with an Ocular Surface Disease Index score >=23 were considered symptomatic, and dry eye syndrome was defined as having symptoms and at least one positive objective sign. RESULTS: The prevalence of dry eye syndrome was 8.7% (95% confidence interval 6.9-10.6). Assessment of signs showed an abnormal Schirmer score in 17.8% (95% confidence interval 15.5-20.0), tear break-up time in 34.2% (95% confidence interval 29.5-38.8), corneal fluorescein staining (>=1) in 11.3% (95% confidence interval 8.5-14.1) and Rose Bengal staining (>=3 for cornea and/or conjunctiva) in 4.9% (95% confidence interval 3.4-6.5). According to the Ocular Surface Disease Index scores, 18.3% (95% confidence interval 15.9-20.6) had dry eye syndrome symptoms. The prevalence of dry eye syndrome was significantly higher in women (P = 0.010) and not significantly associated with age (P = 0.291). The objective dry eye syndrome signs significantly increased with age. CONCLUSIONS: Based on the findings, the prevalence of dry eye syndrome in the studied population is in the mid-range. The prevalence is higher in women. Also, objective tests tend to turn abnormal at higher age. Pterygium is associated with dry eye syndrome and increased its symptoms. PMID- 23927385 TI - Ion fluxes and electro-osmotic fluid flow in electrolytes around a metallic nanowire tip under large applied ac voltage. AB - Motivated by the analysis of electrochemical growth of metallic nanowires from solution, we studied ion fluxes near nanoelectrodes in a binary symmetric electrolyte on the basis of the modified Poisson-Nernst-Planck equations in the strongly nonlinear region at large applied ac voltage. For an approximate calculation of the electric field near the nanowire tip, concentric spherical blocking electrodes were considered with radius of the inner electrode being of typically a few ten nanometers. The spatiotemporal evolution of the ion concentrations within this spherical model was calculated numerically by using the finite element method. The potential drop at the electric double layer, the electric field enhancement at the electrode surface, and the field screening in the bulk solution were determined for different bulk concentrations, ac voltages, and frequencies. The appearance of ac electro-osmotic fluid flow at the tip of a growing metallic nanowire is discussed, based on an estimation of the body force in the liquid near the nanowire tip, which was modeled by a cylinder with hemispherical cap. Electric field components tangential to the electrode surface exist near the contact between cylinder and hemisphere. Our analysis suggests that ac electro-osmotic flow causes an additional convective transport of metal complexes to the tip of the growing metal nanowire and thus affects the nanowire growth velocity. PMID- 23927384 TI - Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry. AB - BACKGROUND: Hypoxia inducible factor-1 alpha (HIF-1alpha), induced by tumor hypoxia, regulates tumor cell metabolism and metastasis by up-regulation of c Met, carbonic anhydrase 9 (CA9) and glucose transporter 1 (GLUT1). The prognostic significance of hypoxia and metabolic markers is not clearly defined in cervical cancer. Here, we have examined the primary players in the hypoxia signaling pathway, by immunohistochemistry, but confirming their interactions, as well as defining which proteins are associated with outcome. METHODS: The study subjects were comprised of cervical intraepithelial neoplasia (CIN, n = 209), carcinoma in situ (CIS, n = 74), cervical cancer (n = 179), and matched nonadjacent normal tissues (n = 357). Immunohistochemistry (IHC) was performed to identify HIF 1alpha, c-Met, CA9, and GLUT1. IHC scoring was performed using automated digital image analysis and the association of hypoxic markers with prognostic outcome was evaluated. RESULTS: HIF-1alpha, c-Met, CA9 and GLUT1 expression were higher in cervical cancer than in CIN and normal cervix (all P < 0.001). Among these markers, expression of HIF-1alpha and c-Met were significantly different in FIGO stage (P < 0.001 and P = 0.019, respectively) and patients with lymph node metastasis (P < 0.001 and P = 0.010, respectively). HIF-1alpha expression was correlated with c-Met expression in cervical cancer (P < 0.001). High expression of HIF-1alpha and c-Met showed worse 5-year overall survival rate (P = 0.047 and P = 0.005, respectively) than low expression group, but CA9 and GLUT1 did not show significant survival difference. After adjusting the prognostic covariates, c-Met was found to be an independent risk factor (HR=3.27; 95% CI, 1.05-10.23, P = 0.041) for overall survival in cervical cancer. CONCLUSIONS: We demonstrate that c-Met correlates with HIF-1alpha and is a poor prognostic factor in survival in cervical cancer. PMID- 23927386 TI - Research priorities in modeling the transmission risks of H7N9 bird flu. AB - The epidemic of H7N9 bird flu in eastern China in early 2013 has caused much attention from researchers as well as public health workers. The issue on modeling the transmission risks is very interesting topic. In this article, this issue is debated and discussed in order to promote further researches on prediction and prevention of avian influenza viruses supported by better interdisciplinary datasets from the surveillance and response system. PMID- 23927388 TI - Mesenteric fat thickness is associated with increased risk of obstructive sleep apnoea. AB - BACKGROUND AND OBJECTIVE: Mesenteric fat is a type of intraperitoneal adipose tissue draining into portal circulation. The objective of this study was to investigate the relationships between mesenteric fat thickness and obstructive sleep apnoea (OSA) in patients with suspected OSA. METHODS: One hundred forty nine subjects (men: 114; women: 35) with suspected OSA underwent ultrasound examinations of mesenteric, preperitoneal and subcutaneous fat thickness after overnight polysomnography. Body mass index (BMI) and neck circumference were recorded. RESULTS: The subjects with OSA (n = 130, apnoea/hypopnoea index (AHI) >5/h) had greater neck circumference, higher BMI, and greater mesenteric and preperitoneal fat thickness than those without OSA (n = 19, AHI <= 5/h). There was positive correlation of AHI with mesenteric (r = 0.43, P < 0.001) and preperitoneal fat thickness (r = 0.3, P < 0.001), whereas no significant association was observed between AHI and subcutaneous fat thickness (r = 0.09, P = 0.27). On multivariate logistic regression, after adjustments for gender, age, BMI, neck circumference, and preperitoneal and subcutaneous fat thickness, the mesenteric fat thickness had a positive association with the presence of moderate OSA and severe OSA, with odds ratios of 7.18 and 7.45 for every 1 cm increase in mesenteric fat thickness when AHI was defined as >=15/h and AHI >= 30/h, respectively. CONCLUSIONS: Mesenteric fat thickness is associated with increased risk of OSA, independent of other abdominal fat thickness, BMI and neck circumference. Sonographic measurement is potentially a useful tool for further evaluating the complex association of visceral fat, metabolic syndrome and OSA. PMID- 23927387 TI - Levonorgestrel releasing intrauterine system (Mirena) versus endometrial ablation (Novasure) in women with heavy menstrual bleeding: a multicentre randomised controlled trial. AB - BACKGROUND: Heavy menstrual bleeding is an important health problem. Two frequently used therapies are the levonorgestrel intra-uterine system (LNG-IUS) and endometrial ablation. The LNG-IUS can be applied easily by the general practitioner, which saves costs, but has considerable failure rates. As an alternative, endometrial ablation is also very effective, but this treatment has to be performed by a gynaecologist. Due to lack of direct comparison of LNG-IUS with endometrial ablation, there is no evidence based preferred advice for the use of one of these treatment possibilities. METHOD/DESIGN: A multicenter randomised controlled trial, organised in a network infrastructure in the Netherlands in which general practitioners and gynaecologists collaborate. DISCUSSON: This study, considering both effectiveness and cost effectiveness of LNG-IUS versus endometrial ablation may well improve care for women with heavy menstrual bleeding. TRIAL REGISTRATION: Dutch trial register, number NTR2984. PMID- 23927389 TI - Speech generating devices and modality of short-term word storage. AB - Persons with severe speech impairments frequently communicate via non-speech means, such as speech-generating devices (SGDs). In studies of people without disabilities, use of non-speech responses has activated non-phonological modalities for short-term word storage. In the current study, short-term word storage was evaluated in 23 pre-trained adult speakers without disabilities and in four individuals who use SGDs for communication. Results indicated that participants without disabilities stored lists of words phonologically when using SGDs. Individuals who used SGDs were most successful in recall of high- frequency words, with preliminary evidence of phonological encoding for short-term storage in preparation for non-speech responses. Further research is needed to describe possible concurrent storage modalities. PMID- 23927390 TI - Using the Optimality Index-US to Teach Midwifery Students to Recognize and Implement Evidence-Based Practices That Promote Optimal Outcomes in Perinatal Health. AB - INTRODUCTION: Perinatal optimality means achieving maximal perinatal outcomes with minimal interventions considering women's past and present histories. The Optimality Index-US (OI-US) is a research tool designed to measure potential associations between evidence-based perinatal care processes and outcomes in aggregate groups of women against an optimal standard. This article describes how the Shenandoah University Nurse-Midwifery Program uses the OI-US to teach students to recognize evidence-based care, reflect on the influences that care processes may have on outcomes, and consider the value of measuring the relationship between interventions and outcomes. Case studies and individual presentations apply the optimality concept by illustrating different care processes, identifying evidence-based care, and evaluating management through the optimality lens. METHODS: A pilot study was performed in which a 10-question interview was administered to 9 midwifery students before graduation. Two research questions were addressed: "Is the OI-US an effective teaching tool?" and "How can the program improve this strategy?" Narrative analysis was used to interpret students' understandings of the tool, how it affected their clinical learning, and its potential to use in future practices. RESULTS: Four themes were identified: 1) students felt the OI-US gave them a foundation to assess their management and the confidence to plan future management, 2) students used the OI US as a teaching tool to help women prevent nonoptimal events from occurring, 3) students thought the OI-US would be feasible to use in their future practices, and 4) lack of accessibility to a printed version of the tool while providing care was an obstacle for efficient use. Students suggested increasing the tool's accessibility and using it in other learning activities. DISCUSSION: The use of the OI-US should be explored further to teach evidence-based care, to generate reflection concerning potential associations between perinatal care processes and outcomes, and to challenge students to question non-evidence-based practices. PMID- 23927392 TI - Prevalence of autoimmune hematologic and non-hematologic conditions in large granular lymphocytic leukemia: exploratory analysis of a series of consecutive patients. PMID- 23927391 TI - Patient-driven discontinuation of tyrosine kinase inhibitors: single institution experience. AB - Abstract With improved outcome for patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs), treatment discontinuation has become increasingly attractive to patients. We analyzed the outcomes of patients who chose to discontinue TKI therapy regardless of their ongoing response. Thirty five patients with chronic phase CML discontinued TKI in complete cytogenetic response. Of them, 51% discontinued due to adverse effects, 23% due to long complete molecular response (CMR) (> 5 years), 9% due to pregnancy and 17% due to financial problems. After TKI discontinuation, patients were followed for a median of 16 months. Among 27 patients (77%) who discontinued TKIs in CMR, 11 (41%) had a molecular relapse after a median of 3.5 months. In univariate analysis we observed that patients with >= 64 months of CMR before TKI discontinuation had superior cumulative proportions of sustained CMR and major molecular response (MMR) at 12 months after discontinuation: 88.9% vs. 45.5% (p = 0.02) and 100% vs. 75% (p = 0.05), respectively. Patients treated with high dose imatinib or second generation TKIs had a higher cumulative proportion of sustained MMR at 12 months after discontinuation than patients treated with standard dose imatinib: 100% vs. 72.2% (p = 0.03), respectively. Of the five patients who stopped TKI in MR(4.5) (molecular response of 4.5-log reduction) one lost cytogenetic response. All three patients who discontinued TKIs in MMR lost cytogenetic response; one progressed to accelerated phase. Thirteen patients (37%) restarted TKIs after loss of response: 11 improved their response, and for two it is too early to assess. Treatment discontinuation can lead to sustained CMR in some patients, but risk of relapse is higher if patients discontinue TKIs when not in CMR. PMID- 23927393 TI - Quantitative and qualitative analysis of metabolic response at interim positron emission tomography scan combined with International Prognostic Index is highly predictive of outcome in diffuse large B-cell lymphoma. AB - The prognostic value of interim (18)fluorodeoxyglucose positron emission tomography (i-PET) was investigated in 73 patients (median age 60 years) with diffuse large B-cell lymphoma (DLBCL). i-PET was analyzed using the Deauville score (DS) and change in maximum standardized uptake value (DeltaSUV(max)). Patients with a DS of 1-3 demonstrated a significantly (p < 0.0001) better outcome (median follow-up 2.4 years) than patients with a score of 4 or 5 in terms of event-free survival (EFS) (79% vs. 36%), progression-free survival (PFS) (84% vs. 47%) and overall survival (OS) (91% vs. 51%). EFS (73% vs. 42%), PFS (78% vs. 50%) and OS (88% vs. 56%) were also significantly (p = 0.023) different between patients with DeltaSUV(max) > 66% or <= 66%. Patients (n = 33) combining a favorable age-adjusted International Prognostic Index (IPI) (0 or 1) and a negative i-PET either by DS or DeltaSUV(max) criteria showed a particularly good outcome (EFS: 85%, PFS: 88%, OS: 94%). Overall, i-PET was highly and independently predictive of any outcome, and its negative predictive value was improved by combination with IPI. PMID- 23927394 TI - Hematopathologic discrepancies between referral and review diagnoses: a gap between general pathologists and hematopathologists. AB - Abstract The World Health Organization (WHO) lymphoma classification has been widely adopted by hematopathologists. However, its practical application by general pathologists is largely unknown. Using a hematopathology consultation program in Taiwan, we reviewed 406 cases. Diagnostic discrepancies were scored based upon whether the divergence would alter disease management according to National Comprehensive Cancer Network guidelines. Major discrepancies accounted for 55% (222/406), minor discrepancies for 5% (20/406) and agreement for 40% (164/406) cases. The more common groups in major discrepancies were non diagnostic/ambiguous referral reports (116/222, 52%), tumor type revisions (52/222, 23%) and changes from malignant to benign lesions (32/222, 14%). In a total of 259 cases of lymphoma, the concordance rates were 41% (77/187) and 33% (24/72) for B-cell and T/natural killer (NK)-cell lymphomas, respectively. It appears that the WHO approach has made lymphoma classification rather poorly reproducible at least in countries where extensive use of an ancillary technique is not employed by general pathologists. PMID- 23927395 TI - Indolent mantle cell lymphoma. AB - Over the past decade, it has become increasingly clear that mantle cell lymphoma (MCL) is a more heterogeneous disease than originally recognized. Several groups have reported on a subgroup of patients with a less aggressive course than expected resulting in the term "indolent MCL". Unlike the recognized histologic variants, the definition of indolent mantle cell lymphoma is unclear, and patients with indolent MCL are often identified only after having undergone prolonged periods of observation. In this review, we will discuss clinical and biologic features and provide a framework for the approach in identifying patients with indolent MCL. PMID- 23927396 TI - NPM-RAR, not the RAR-NPM reciprocal t(5;17)(q35;q21) acute promyelocytic leukemia fusion protein, inhibits myeloid differentiation. AB - The t(5;17) variant of acute promyelocytic leukemia (APL) fuses the nucleophosmin (NPM) gene at 5q35 with the retinoic acid receptor alpha (RARA) at 17q12-22. We have previously shown that leukemic cells express both NPM-RAR and RAR- NPM reciprocal translocation products. In this study we investigated the potential role of both proteins in modulating myeloid differentiation. Expression of NPM RAR inhibited vitamin D3/transforming growth factor beta (TGFbeta)-mediated differentiation of U937 cells by more than 50%. In contrast, RAR-NPM expression did not alter vitamin D3/TGFbeta-induced differentiation of U937 clones. These results indicate that NPM-RAR, not RAR-NPM, is the prime mediator of myeloid differentiation arrest in t(5;17) APL. PMID- 23927397 TI - Bortezomib-induced acute pancreatitis in a patient with multiple myeloma. PMID- 23927398 TI - Algorithms for early identification of poor mobilization and for on-demand use of plerixafor in patients mobilized by chemotherapy and granulocyte-colony stimulating factor. PMID- 23927399 TI - Paediatric follicular lymphoma. PMID- 23927400 TI - Teratoid hepatoblastoma with abundant cholangioblastic component in a child with full trisomy 13. AB - Teratoid hepatoblastoma is a rare histological subtype of hepatoblastoma. A 15 month-old girl with full trisomy 13 presented with a liver mass (6 * 4.4 * 3.4 cm). Histological examination showed a teratoid hepatoblastoma with very different differentiation patterns intermixed with each other. Approximately 30% of the tumor demonstrated a primitive glandular epithelium component, which had a moderate to well-differentiated adenocarcinoma-like morphology, and features of mucinous epithelium with a biliary immunophenotype. We designated it as cholangioblastic component. The child received 4 cycles of monotherapy with doxorubicin after complete resection and showed no evidence of residual tumor 8 months after surgery. Our case is not only the 1st report of hepatoblastoma in trisomy 13 but also represents a unique example with a large glandular epithelium component with cholangioblastic features. Increased awareness of this entity and further molecular studies are needed for better understanding of the pathogenesis of teratoid hepatoblastoma. PMID- 23927403 TI - Viologens as charge carriers in a polymer-based battery anode. AB - Viologens, either as anions in solution or as pendant substituents to pyrrole, were incorporated as dopants to electrodeposited films of polypyrrole. The resulting polymer films exhibited redox activity at -0.5 V vs Ag/AgCl. The film consisting of polypyrrole with pendant viologens exhibited the best charge discharge behavior with a maximum capacity of 55 mAh/g at a discharge current of 0.25 mA/cm(2). An anode consisting of polypyrrole (pPy) doped with viologen (V) was coupled to a cathode consisting of pPy doped with 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS) to yield a polymer-based battery with a cell electromotive force (emf) of 1.0 V, maximum capacity of 16 mAh/g, and energy density of 15 Wh/kg. PMID- 23927401 TI - Analysis of the transcriptome of the Indonesian coelacanth Latimeria menadoensis. AB - BACKGROUND: Latimeria menadoensis is a coelacanth species first identified in 1997 in Indonesia, at 10,000 Km of distance from its African congener. To date, only six specimens have been caught and just a very limited molecular data is available. In the present work we describe the de novo transcriptome assembly obtained from liver and testis samples collected from the fifth specimen ever caught of this species. RESULTS: The deep RNA sequencing performed with Illumina technologies generated 145,435,156 paired-end reads, accounting for ~14 GB of sequence data, which were de novo assembled using a Trinity/CLC combined strategy. The assembly output was processed and filtered producing a set of 66,308 contigs, whose quality was thoroughly assessed. The comparison with the recently sequenced genome of the African congener Latimeria chalumnae and with the available genomic resources of other vertebrates revealed a good reconstruction of full length transcripts and a high coverage of the predicted full coelacanth transcriptome. CONCLUSION: Given the high genomic affinity between the two coelacanth species, the here described de novo transcriptome assembly can be considered a valuable support tool for the improvement of gene prediction within the genome of L. chalumnae and a valuable resource for investigation of many aspects of tetrapod evolution. PMID- 23927405 TI - Erbium laser for the treatment of disseminated superficial actinic porokeratosis: a case report. PMID- 23927406 TI - Differential effects of thapsigargin analogues on apoptosis of prostate cancer cells: complex regulation by intracellular calcium. AB - The inhibition of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) by thapsigargin (Tg) and Tg-type analogues is considered to trigger cell death by activation of apoptotic pathways. Some of these analogues may be useful as antineoplastic agents after appropriate targeting as peptide conjugated prodrugs to cancer cells. With this in mind, this study evaluates the effect on LNCaP androgen sensitive cancer cells of thapsigargin substituted with 12-aminododecanoyl linkers and Leu (Leu-8ADT), aspartate (Asp-8ADT) or Boc-8ADT. Our results show that both Leu-8ADT and Asp-8ADT result in rapid ER calcium depletion and an influx of calcium across the plasma membrane by activation of store-operated calcium entry. By contrast, ER Ca(2+) depletion by Boc-8ADT is a very slow process that does not perceptibly increase cytosolic Ca(2+) and activate store operated calcium entry, because the inhibition of SERCA with this compound is very slow. Nevertheless, we find that Boc-8ADT is a more efficient inducer of apoptosis than both Tg and Leu-8ADT. Compared with Tg and the other analogues, apoptosis induced by Asp-8ADT is very modest, although this compound also activates store-operated calcium entry and at high concentrations (1 MUm) causes severe morphological changes, reflecting decreased cell viability. We conclude that many factors need to be considered for optimization of these compounds in antineoplastic drug design. Among these ER stress induced by Ca(2+) endoplasmic reticulum mobilization seems particularly important, whereas the early cytosolic increase of Ca(2+) concentration preceding the executive phase of apoptosis appears to be of no, or little, consequence for a subsequent apoptotic effect. PMID- 23927407 TI - Volume change during thermal [4 + 4] cycloaddition of [2.2] (9,10)anthracenophane. AB - We show that the reaction path connecting the tethered bi(anthracene-9,10 dimethylene) and its photodimer proceeds stepwise via a diradicaloid transition state where one sigma-bond is made before a second. The newly found transition state (TS) has a smaller molecular volume than either the reactant or the product giving an atomistic explanation to the recently found pressure catalyzed barrier lowering and rate enhancement. The density functional methods used include long range contributions as required in a system where the dispersion interactions are significant. We discuss this transformation in the context of the diamond-to graphite transition owing to the similarity of sigma-bond breakage into a delocalized pi-system. We also comment on the controversy surrounding the equilibrium geometries of photoisomerized cyclophanes, concluding that D2h symmetry in the photoisomer of the title molecule is a transition structure connecting a pair of degenerate ground state D2 geometries. PMID- 23927408 TI - Disease defence through generations: leaf-cutter ants and their symbiotic bacteria. AB - Microbial ecology of animals is taking on significance in the modern dialogue for the biology of species. Similar to a nuclear genome, the entire bacterial assemblage maintains an ancestral signal of the host's evolution leading to cophylogeny between the host and the microbes they harbour (Brucker & Bordenstein 2012b). The stability of such associations is of great interest as they provide a means for species to acquire new traits and genetic diversity that their own genomes lack (McFall-Ngai et al. 2013). The role of gut microbiota, for example, in host health and nutrition is widely recognized and a shared characteristic among animals. The role of bacteria colonizing the outside surfaces of animals is less well understood, but rather than random colonization, these microbes on skin, cuticles, scales and feathers in many cases provide benefits to the host. The symbiosis of leaf-cutter ants, their fungus gardens and their microbiota is a fascinating and complex system. Whether culture-independent bacterial diversity on the cuticle of leaf-cutter ants is high or highly constrained by subcuticular gland secretions is one prominent question. In this issue of Molecular Ecology, Andersen et al. (2013) show that leaf-cutting ants, Acromyrmex echinatior, maintain a dominant and colony-specific bacterium called Pseudonocardia on their cuticles (the laterocervical plates in particular). This bacterium is involved in protecting the ants and their fungal gardens from disease. Other fungus-gardening attine species as well as soil and vegetation can harbour Pseudonocardia. However, it was previously unknown how stable the bacterial strain-ant colony association was through the lifetime of the colony. PMID- 23927409 TI - Unravelling migratory connections: the next level. AB - Migration is widespread among birds, and the strength of the link between the breeding and wintering grounds, migratory connectivity, influences many ecological and evolutionary processes. Despite its importance, migratory connectivity is poorly estimated for most species. Traditionally, visual observations and bird ringing have been used to monitor migration, but these methods require more effort for relatively little return. Genetic markers and stable isotope signatures have increasingly been used to study connectivity. Each approach has its distinct strengths and weaknesses, and as is often the case, a combination may yield the most insight. In this issue of Molecular Ecology, Rundel and colleagues (2013) present a novel Bayesian statistical framework in which genetics and stable isotope data can be combined to improve the assignment of individuals to different winter or breeding regions. The development of such new statistical methods combined with the increasing number and ease of access of isotopic and genetic data sets will greatly enhance our understanding of migratory connectivity. Add to this the developments of miniature devices to track movements of individuals, and the field is destined to make major progression in the decades to come. PMID- 23927410 TI - Evidence for selective sweeps by Wolbachia infections: phylogeny of Altica leaf beetles and their reproductive parasites. AB - Infections with maternally inherited Wolbachia bacteria may have dramatic influences on reproductive traits and speciation patterns of their hosts. We here show that in the beetle genus Altica, infection has influenced phylogenetic patterns of the host's mtDNA and different strains led to repeated selective sweeps. By comparing a COI/II-based phylogeny of the hosts with a phylogeny of the bacteria based on ftsZ, we show that cospeciation is rare and restricted to few recently diverged species. While in general each species apparently harbours a single Wolbachia strain, Altica lythri presents a strikingly different pattern: in the polyphyletic species, three highly divergent mtDNA haplotypes (2.1-4.6% p distance) are coupled with three different Wolbachia strains (wLytA1, wLytA2 and wLytB). These haplotypes and Wolbachia strains are widely distributed and mostly found in sympatry. A phylogeny based on microsatellite data supports the monophyly of A. lythri. The discrepancy between mtDNA and nuclear phylogeny may best be explained by interspecific hybridization that led to introgression of mtDNA coupled with a different Wolbachia strain. Selective sweeps apparently drove the introgressed haplotypes to widespread distribution. As for effects of Wolbachia on reproduction, infection with wLytA1 appears to be correlated with a substantial sex ratio distortion, which was most prominent in A. lythri. PMID- 23927411 TI - Phylogeography of Sophora davidii (Leguminosae) across the 'Tanaka-Kaiyong Line', an important phytogeographic boundary in Southwest China. AB - The 'Tanaka-Kaiyong Line' (TKL) is a major phytogeographic boundary in Southwest China, separating East Asia's Sino-Himalayan and Sino-Japanese Floras. However, little is known about the importance of this boundary in promoting intraspecific phylogeographic subdivision and divergence. Using chloroplast (cpDNA) and nuclear intron (nDNA) sequence data, we reconstructed the population history of Sophora davidii, a drought-tolerant riparian shrub widely distributed on either side of the TKL. Specifically, we aimed at testing two long-standing explanations for possible vicariant events across the TKL: (i) Late Pliocene (c. 3 Ma) geological uplift of the eastern Qinghai-Tibetan Plateau (QTP) or (ii) a sharp environmental gradient associated with the establishment of different monsoon regimes on either side of the TKL during the (Late) Pleistocene. Our genealogical analyses detected a major west-east split in cpDNA, geographically largely consistent with the TKL, and dated to c. 1.28 Ma (95% HPD: 0.21-2.96 Ma), hence postdating the latest phase of eastern QTP uplift. Furthermore, integrating cpDNA phylogeographic patterns with mismatch analyses, we found multiple refugial isolation and long term demographic stability of populations in the west (Hengduan Mountain Range) compared with extensive range expansions in the east, possibly during the last glacial period(s) and followed by differentiation into regional sublineages (southeast: Yunnan-Guizhou Plateau vs. northeast: Qinling Mts./Loess Plateau). Although nuclear differentiation was less marked, the geographical pattern of nDNA haplotypes provided some further indication of the species' eastward expansion, possibly from source populations located just east of the TKL (lower Jinshajiang region). Overall, the present data reject the geological (tectonic) explanation for the TKL and, instead, provide supportive evidence for its role as a climatically driven barrier to present-day plant dispersal. In addition, our study highlights changing temperatures and vegetation types during the last glacial period(s), along with aspects of regional topography, to be important determinants of the glacial eastward expansion of S. davidii. In consequence, our study lends support to a 'glacial out-of-Hengduan Mts'. hypothesis for the xerophytic-riparian flora of Southwest China, which in turn is inconsistent with the traditional view of the TKL as a 'classical' vicariant-biogeographic boundary. PMID- 23927412 TI - Treatment and long-term follow-up of distichiasis, with special reference to the Friesian horse: a case series. AB - REASONS FOR PERFORMING STUDY: Distichiasis is very uncommon in horses and treatment options and outcome remain unknown. OBJECTIVES: To describe treatment and long-term follow-up of distichiasis in the horse. STUDY DESIGN: Retrospective clinical study. METHODS: Case records of horses admitted for diagnosis and treatment of uni- or bilateral distichiasis between 2003 and 2012 were reviewed. Long-term (>6 months after last treatment) follow-up was by telephone conversation with the owner or referring veterinarian. Data were analysed using a Chi-squared test. RESULTS: Eighteen cases were identified, of which 17 were Friesians. All horses had signs of corneal irritation or ulceration concurrent with distichiasis. In total, 29 eyes were affected with distichiasis of which 23 had clinical signs. All corneas were stained with fluorescein and 13 had fluorescein positive defects (45%). The lower eyelid was affected more often. Two different electrocautery devices were used for treatment. The complications were slight scarring of the eyelids (100%) and clinical recurrence (54%). Successful resolution of the clinical signs after one treatment occurred in 46% of the horses and in 77% of the horses satisfactory long-term results were found after a mean of 2 treatments (range: 1- 6 treatments). There was significant correlation between number of hairs and recurrence (P<0.002). CONCLUSIONS: There is a breed predisposition of distichiasis in the Friesian horse. In Friesian horses that present with uni- or bilateral corneal irritation or corneal ulceration, careful examination of the eyelid margins should be performed to diagnose distichiasis. Electrocautery is a valid and successful therapeutic modality which is minimally invasive, inexpensive, has a low complication rate and is easy to perform in the standing sedated horse. The recurrence rate is low in horses with less than 5 distichiae. PMID- 23927413 TI - Long-term outcomes after adjunctive topical 5-flurouracil or mitomycin C for the treatment of surgically excised, localized ocular surface squamous neoplasia. AB - BACKGROUND: To report rates of recurrence and complications of localized ocular surface squamous neoplasia treated with 5-fluorouracil or mitomycin C as adjunctive treatment to surgical excision. DESIGN: Long-term follow up of two prospective, non-comparative interventional case series. PARTICIPANTS: One hundred fifty-three eyes with histologically confirmed localized, non-invasive ocular surface squamous neoplasia. 89 eyes were treated with adjuvant 5 fluorouracil and 64 eyes were treated with adjuvant mitomycin C. METHODS: Following surgical excision+/-cryotherapy patients received topical 5 fluorouracil 1% four times daily for two weeks or topical mitomycin C 0.04% four times daily for two to three 1-week cycles. MAIN OUTCOME MEASURES: Ocular surface squamous neoplasia recurrence, complications of therapy and compliance. RESULTS: Median follow up was 33.6 (range 12-84) months and 57.9 (range 12-160) months in 5-fluorouracil and mitomycin C groups, respectively. There was one recurrence in the 5-fluorouracil group and no recurrences in the mitomycin C group. Side effects occurred in 69% of 5-fluorouracil patients and 41% of mitomycin C patients. Five patients (6%) required intervention for treatment-related side effects in the 5-fluorouracil group versus 11 (17%) in the mitomycin C group. No vision-threatening complications were noted. CONCLUSIONS: Long-term recurrence of localised ocular surface squamous neoplasia is rare when topical 5-fluorouracil or mitomycin C are used as adjunctive treatment to surgical excision. While side effects are common, the majority are transient and rarely limit compliance. PMID- 23927414 TI - Tinzaparin and other low-molecular-weight heparins: what is the evidence for differential dependence on renal clearance? AB - Since low-molecular-weight heparins (LMWHs) are eliminated preferentially via the kidneys, the potential for accumulation of these agents (and an increased risk of bleeding) is of particular concern in populations with a high prevalence of renal impairment, such as the elderly and patients with cancer. The risk of clinically relevant accumulation of anticoagulant activity as a result of a reduction in renal elimination appears to differ between LMWHs. This review describes the elimination pathways for LMWHs and assesses whether the relative balance between renal and non-renal (cellular) clearance may provide a mechanistic explanation for the differences in accumulation that have been observed between LMWHs in patients with impaired renal function. Clearance studies in animals, cellular binding studies and clinical studies all indicate that the balance between renal and non-renal clearance is dependent on the molecular weight (MW): the higher the MW of the LMWH, the more the balance is shifted towards non-renal clearance. Animal studies have also provided insights into the balance between renal and non renal clearance by examining the effect of selective blocking of one of the elimination pathways, and it is most likely that cellular clearance is increased to compensate for decreased renal function. Tinzaparin (6,500 Da) has the highest average MW of the marketed LMWHs, and there is both clinical and preclinical evidence for significant non-renal elimination of tinzaparin, making it less likely that tinzaparin accumulates in patients with renal impairment compared with LMWHs with a lower MW distribution. On the basis of our findings, LMWHs that are less dependent on renal clearance may be preferred in patient populations with a high prevalence of renal insufficiency. PMID- 23927415 TI - Public preferences for donor kidney allocation: a study in Iran. AB - INTRODUCTION: Fair allocation of donor organs is essential to maintain public trust in a public healthcare system. A study of the public's views and opinions of this could clarify non-medical prioritization criteria. We report our survey of public opinion of criteria for donor kidney allocation. METHODS: This was a cross-sectional study using random digit dialing to phone interview 706 Tehran residents. Patient scenarios were presented to determine interviewee opinions on nine recipient criteria: probability for survival, previous transplant history, time on the waiting list, age, an individual's role in developing their kidney failure, gender, marital status, social status, and financial situation. Each scenario introduced two patients and interviewees then chose the better candidate for transplantation. RESULTS: More than 50% of the participants chose length of waiting time, a patient's role in causing their disease, age, and survival time after transplantation as important allograft allocation criteria. CONCLUSION: This study disclosed other criteria in addition to the likelihood for successful transplantation-the patient's role in the development of their disease and patient age-which should be prioritization considerations. PMID- 23927416 TI - Co-encapsulation of tamoxifen and quercetin in polymeric nanoparticles: implications on oral bioavailability, antitumor efficacy, and drug-induced toxicity. AB - The present investigation reports the preparation, optimization, and characterization of orally administrable PLGA-NPs co-encapsulated with tamoxifen (Tmx) and quercetin (QT). The developed formulation was found to have particle size 185.3 +/- 1.20 nm, PDI 0.184 +/- 0.004, entrapment efficiency 67.16 +/- 1.24% Tmx, 68.60 +/- 1.58% QT at a Tmx/QT ratio of 1:2 w/w. The stability of the freeze-dried formulation was established in simulated gastrointestinal fluids for 8 h and at accelerated stability condition for 3 months. DPPH free radical scavenging assay confirmed that the functional architecture of QT was retained in freeze-dried NPs. Higher cellular uptake, cytotoxicity, and nuclear co localization of Tmx-QT-NPs in MCF-7 cells revealed higher efficiency of the formulation. At the same time, higher Caco-2 cell uptake revealed its potential for oral delivery, which was well corroborated with in vivo pharmacokinetics, which suggested ~ 5-fold and ~ 3-fold increase in oral bioavailability as compared to the free Tmx citrate and free QT, respectively. Concomitantly, significantly higher tumor suppression was observed in the case of the developed formulation in contrast to respective free drug(s) and their combination when tested against a DMBA-induced breast cancer model in female SD rats. Multiple oral administrations of Tmx-QT-NPs efficiently controlled the tumor angiogenesis as revealed by normalized levels of respective markers (MMP-2 and MMP-9). The safety profile of Tmx-QT-NPs was also established, and no measurable hepatotoxicity or oxidative stress was observed when measured as a function of respective biochemical markers in contrast to free drug(s) and their combinations. In a nutshell, the co-encapsulation strategy with PLGA-NPs could be a promising approach in improving oral delivery of Tmx and QT for cancer therapy. PMID- 23927417 TI - How the pilidium larva feeds. AB - INTRODUCTION: The nemertean pilidium is a long-lived feeding larva unique to the life cycle of a single monophyletic group, the Pilidiophora, which is characterized by this innovation. That the pilidium feeds on small planktonic unicells seems clear; how it does so is unknown and not readily inferred, because it shares little morphological similarity with other planktotrophic larvae. RESULTS: Using high-speed video of trapped lab-reared pilidia of Micrura alaskensis, we documented a multi-stage feeding mechanism. First, the external ciliation of the pilidium creates a swimming and feeding current which carries suspended prey past the primary ciliated band spanning the posterior margins of the larval body. Next, the larva detects prey that pass within reach, then conducts rapid and coordinated deformations of the larval body to re-direct passing cells and surrounding water into a vestibular space between the lappets, isolated from external currents but not quite inside the larva. Once a prey cell is thus captured, internal ciliary bands arranged within this vestibule prevent prey escape. Finally, captured cells are transported by currents within a buccal funnel toward the stomach entrance. Remarkably, we observed that the prey of choice - various cultured cryptomonads - attempt to escape their fate. CONCLUSIONS: The feeding mechanism deployed by the pilidium larva coordinates local control of cilia-driven water transport with sensorimotor behavior, in a manner clearly distinct from any other well-studied larval feeding mechanisms. We hypothesize that the pilidium's feeding strategy may be adapted to counter escape responses such as those deployed by cryptomonads, and speculate that similar needs may underlie convergences among disparate planktotrophic larval forms. PMID- 23927418 TI - Skin temperature measurement using an infrared thermometer on patients who have been exposed to cold. AB - BACKGROUND: The aim of this study was to determine if the skin temperature of febrile children is affected by the child's exposure to cold outdoor temperatures immediately prior to the taking of that temperature. METHODS: A total of 150 febrile and non-febrile children (aged 3-10 years) who had walked to the hospital's pediatric emergency department and were thus exposed to outside cold weather were enrolled in the study. Using infrared thermometry, forehead and chest skin temperatures were simultaneously measured every 2 min during the first 14 min after presentation. Temperatures were recorded and differences between the two measurements were calculated. RESULTS: By the fifth evaluation (10 min from the first reading), skin temperatures from forehead and chest had equalized. CONCLUSION: Determination of fever from the body parts that had been exposed to cold environmental conditions may cause contradictory results if taken while the child is still chilled from exposure to the cold. For accuracy, children should be acclimated to the indoor temperature before taking body temperature readings. Acclimation takes at least 10 min after coming in from cold weather outside. PMID- 23927419 TI - Dynamic left ventricular outflow tract obstruction: hemodynamic pitfall ahead. PMID- 23927420 TI - Asynchronous vs didactic education: it's too early to throw in the towel on tradition. AB - BACKGROUND: Asynchronous, computer based instruction is cost effective, allows self-directed pacing and review, and addresses preferences of millennial learners. Current research suggests there is no significant difference in learning compared to traditional classroom instruction. Data are limited for novice learners in emergency medicine. The objective of this study was to compare asynchronous, computer-based instruction with traditional didactics for senior medical students during a week-long intensive course in acute care. We hypothesized both modalities would be equivalent. METHODS: This was a prospective observational quasi-experimental study of 4th year medical students who were novice learners with minimal prior exposure to curricular elements. We assessed baseline knowledge with an objective pre-test. The curriculum was delivered in either traditional lecture format (shock, acute abdomen, dyspnea, field trauma) or via asynchronous, computer-based modules (chest pain, EKG interpretation, pain management, trauma). An interactive review covering all topics was followed by a post-test. Knowledge retention was measured after 10 weeks. Pre and post-test items were written by a panel of medical educators and validated with a reference group of learners. Mean scores were analyzed using dependent t-test and attitudes were assessed by a 5-point Likert scale. RESULTS: 44 of 48 students completed the protocol. Students initially acquired more knowledge from didactic education as demonstrated by mean gain scores (didactic: 28.39% +/- 18.06; asynchronous 9.93% +/- 23.22). Mean difference between didactic and asynchronous = 18.45% with 95% CI [10.40 to 26.50]; p = 0.0001. Retention testing demonstrated similar knowledge attrition: mean gain scores -14.94% (didactic); -17.61% (asynchronous), which was not significantly different: 2.68% +/- 20.85, 95% CI [-3.66 to 9.02], p = 0.399. The attitudinal survey revealed that 60.4% of students believed the asynchronous modules were educational and 95.8% enjoyed the flexibility of the method. 39.6% of students preferred asynchronous education for required didactics; 37.5% were neutral; 23% preferred traditional lectures. CONCLUSIONS: Asynchronous, computer based instruction was not equivalent to traditional didactics for novice learners of acute care topics. Interactive, standard didactic education was valuable. Retention rates were similar between instructional methods. Students had mixed attitudes toward asynchronous learning but enjoyed the flexibility. We urge caution in trading in traditional didactic lectures in favor of asynchronous education for novice learners in acute care. PMID- 23927421 TI - Jordanian teachers' perceptions of voice handicap. AB - This study aimed to investigate if Jordanian school teachers perceive their voice as handicapped using the Voice Handicap Index (VHI)-Arab. The effect of teachers' age, gender, years of teaching, class taught, and education level on VHI was examined. A total of 289 teachers and a control group of 100 participants took part in the study. The teachers' group differed significantly from the control group in the physical, emotional, and functional subscales and the total score of the VHI-Arab. There was no significant difference among teachers in any of the three VHI subscales or total regarding gender, age, years of teaching experience, education level, and classes taught. Jordanian teachers have a strong perception of voice handicap. Thus, preventive and treatment vocal programs are strongly advised. PMID- 23927423 TI - Lifelong pathways to longevity: personality, relationships, flourishing, and health. AB - Building upon decades of research with the lifelong (nine-decade) Terman Life Cycle Study, we present a life pathway model for understanding human thriving that accounts for long-term individual difference in health and longevity, with a particular focus on child personality and adult social relationships. Developing data derived and supplemented from the Terman study (N = 570 males, 451 females), we employed regression and survival analyses to test models of childhood personality predicting adult psychosocial factors (subjective well-being, family relationships, community involvement, subjective achievement, hardships) and subsequent longevity. Child personality differentially related to midlife social relationships, well-being, and hardships. Conscientiousness and good social relationships predicted longer life, whereas subjective well-being was unrelated to mortality risk. Examining multiple life factors across long time periods uncovers important pathways through which personality relates to premature mortality or longevity. Typical stress-and-illness models are untenable and should be replaced with life span trajectory approaches. PMID- 23927422 TI - Genome-wide analysis of H4K5 acetylation associated with fear memory in mice. AB - BACKGROUND: Histone acetylation has been implicated in learning and memory in the brain, however, its function at the level of the genome and at individual genetic loci remains poorly investigated. This study examines a key acetylation mark, histone H4 lysine 5 acetylation (H4K5ac), genome-wide and its role in activity dependent gene transcription in the adult mouse hippocampus following contextual fear conditioning. RESULTS: Using ChIP-Seq, we identified 23,235 genes in which H4K5ac correlates with absolute gene expression in the hippocampus. However, in the absence of transcription factor binding sites 150 bp upstream of the transcription start site, genes were associated with higher H4K5ac and expression levels. We further establish H4K5ac as a ubiquitous modification across the genome. Approximately one-third of all genes have above average H4K5ac, of which ~15% are specific to memory formation and ~65% are co-acetylated for H4K12. Although H4K5ac is prevalent across the genome, enrichment of H4K5ac at specific regions in the promoter and coding region are associated with different levels of gene expression. Additionally, unbiased peak calling for genes differentially acetylated for H4K5ac identified 114 unique genes specific to fear memory, over half of which have not previously been associated with memory processes. CONCLUSIONS: Our data provide novel insights into potential mechanisms of gene priming and bookmarking by histone acetylation following hippocampal memory activation. Specifically, we propose that hyperacetylation of H4K5 may prime genes for rapid expression following activity. More broadly, this study strengthens the importance of histone posttranslational modifications for the differential regulation of transcriptional programs in cognitive processes. PMID- 23927424 TI - Combination of two anti-CD5 monoclonal antibodies synergistically induces complement-dependent cytotoxicity of chronic lymphocytic leukaemia cells. AB - The treatment of chronic lymphocytic leukaemia (CLL) has been improved by introduction of monoclonal antibodies (mAbs) that exert their effect through secondary effector mechanisms. CLL cells are characterized by expression of CD5 and CD23 along with CD19 and CD20, hence anti-CD5 Abs that engage secondary effector functions represent an attractive opportunity for CLL treatment. Here, a repertoire of mAbs against human CD5 was generated and tested for ability to induce complement-dependent cytotoxicity (CDC) and antibody-dependent cell mediated cytotoxicity (ADCC) both as single mAbs and combinations of two mAbs against non-overlapping epitopes on human CD5. The results demonstrated that combinations of two mAbs significantly increased the level of CDC compared to the single mAbs, while no enhancement of ADCC was seen with anti-CD5 mAb combinations. High levels of CDC and ADCC correlated with low levels of Ab induced CD5 internalization and degradation. Importantly, an anti-CD5 mAb combination enhanced CDC of CLL cells when combined with the anti-CD20 mAbs rituximab and ofatumumab as well as with the anti-CD52 mAb alemtuzumab. These results suggest that an anti-CD5 mAb combination inducing CDC and ADCC may be effective alone, in combination with mAbs against other targets or combined with chemotherapy for CLL and other CD5-expressing haematological or lymphoid malignancies. PMID- 23927426 TI - Genetic and virulence variability among Erwinia tracheiphila strains recovered from different cucurbit hosts. AB - The causal agent of cucurbit bacterial wilt, Erwinia tracheiphila, has a wide host range in the family Cucurbitaceae, including economically important crops such as muskmelon (Cucumis melo), cucumber (C. sativus), and squash (Cucurbita spp.). Genetic variability of 69 E. tracheiphila strains was investigated by repetitive-element polymerase chain reaction (rep-PCR) using BOXA1R and ERIC1-2 primers. Fingerprint profiles revealed significant variability associated with crop host; strains isolated from Cucumis spp. were clearly distinguishable from Cucurbita spp.-isolated strains regardless of geographic origin. Twelve E. tracheiphila strains isolated from muskmelon, cucumber, or summer squash were inoculated onto muskmelon and summer squash seedlings, followed by incubation in a growth chamber. Wilt symptoms were assessed over 3 weeks, strains were reisolated, and rep-PCR profiles were compared with the inoculated strains. Wilting occurred significantly faster when seedlings were inoculated with strains that originated from the same crop host genus (P<0.001). In the first run of the experiment, cucumber and muskmelon strains caused wilting on muskmelon seedlings at a median of 7.8 and 5.6 days after inoculation (dai), respectively. Summer squash seedlings wilted 18.0, 15.7, and 5.7 dai when inoculated with muskmelon-, cucumber-, and squash-origin strains, respectively. In a second run of the experiment, cucumber and muskmelon strains caused wilting on muskmelon at 7.0 and 6.9 dai, respectively, whereas summer squash seedlings wilted at 23.6, 29.0 and 9.0 dai when inoculated with muskmelon-, cucumber-, and squash-origin strains, respectively. Our results provide the first evidence of genetic diversity within E. tracheiphila and suggest that strain specificity is associated with plant host. This advance is a first step toward understanding the genetic and population structure of E. tracheiphila. PMID- 23927427 TI - Role of soybean mosaic virus-encoded proteins in seed and aphid transmission in soybean. AB - Soybean mosaic virus (SMV) is seed and aphid transmitted and can cause significant reductions in yield and seed quality in soybean (Glycine max). The roles in seed and aphid transmission of selected SMV-encoded proteins were investigated by constructing mutants in and chimeric recombinants between SMV 413 (efficiently aphid and seed transmitted) and an isolate of SMV G2 (not aphid or seed transmitted). As previously reported, the DAG amino acid sequence motif near the amino terminus of the coat protein (CP) was the major determinant in differences in aphid transmissibility of the two SMV isolates, and helper component proteinase (HC-Pro) played a secondary role. Seed transmission of SMV was influenced by P1, HC-Pro, and CP. Replacement of the P1 coding region of SMV 413 with that of SMV G2 significantly enhanced seed transmissibility of SMV 413. Substitution in SMV 413 of the two amino acids that varied in the CPs of the two isolates with those from SMV G2, G to D in the DAG motif and Q to P near the carboxyl terminus, significantly reduced seed transmission. The Q-to-P substitution in SMV 413 also abolished virus-induced seed-coat mottling in plant introduction 68671. This is the first report associating P1, CP, and the DAG motif with seed transmission of a potyvirus and suggests that HC-Pro interactions with CP are important for multiple functions in the virus infection cycle. PMID- 23927428 TI - Induction of antiviral responses by acibenzolar-s-methyl against cucurbit chlorotic yellows virus in Melon. AB - Cucurbit chlorotic yellows virus (CCYV) (family Closteroviridae, genus Crinivirus) is an emerging virus which causes severe diseases on melon (Cucumis melo) plants. CCYV-infected melon plants display yellowing, mottling, chlorosis, or chlorotic spots on leaves. To develop a new control strategy, the potential for 1,2,3-benzothiadiazole-7-thiocarboxylic acid-S-methyl-ester (ASM) to suppress CCYV infection was evaluated. ASM treatment on melon plants greatly increased the expression levels of pathogenesis-related 1a gene, a marker gene for systemic acquired resistance. ASM treatment on melon plants before inoculation of CCYV suppressed systemic symptoms and decreased CCYV accumulation. ASM treatment on melon even after inoculation of CCYV reduced disease severity and accumulation levels of CCYV. The results show the potential for ASM treatment on attenuation of the CCYV disease symptoms. PMID- 23927429 TI - Modulation of Y356 photooxidation in E. coli class Ia ribonucleotide reductase by Y731 across the alpha2:beta2 interface. AB - Substrate turnover in class Ia ribonucleotide reductase (RNR) requires reversible radical transport across two subunits over 35 A, which occurs by a multistep proton-coupled electron-transfer mechanism. Using a photooxidant-labeled beta2 subunit of Escherichia coli class Ia RNR, we demonstrate photoinitiated oxidation of a tyrosine in an alpha2:beta2 complex, which results in substrate turnover. Using site-directed mutations of the redox-active tyrosines at the subunit interface, Y356F(beta) and Y731F(alpha), this oxidation is identified to be localized on Y356. The rate of Y356 oxidation depends on the presence of Y731 across the interface. This observation supports the proposal that unidirectional PCET across the Y356(beta)-Y731(alpha)-Y730(alpha) triad is crucial to radical transport in RNR. PMID- 23927430 TI - Profile of cataract surgery in Varamin Iran: a population-based study. AB - BACKGROUND: Cataract is the most popular cause of blindness. This study addresses some aspects of cataract surgery in an Iranian population. DESIGN: A cross sectional study. PARTICIPANTS: 3000 adults over 50 in Varamin district. METHODS: Cataract surgical coverage was defined as the proportion of (pseudo) aphakic eyes of all operable and operated eyes with cataract. If there was obvious lens opacity in either or both eyes in combination with best corrected visual acuity less than 6/18, the person was asked why the operation for cataract was not done to find out about barriers of cataract surgery. Outcomes of cataract surgery were categorized as good, intermediate and poor using presenting visual acuity which were defined as visual acuity >= 6/18, 6/60 <= visual acuity < 6/18 and visual acuity < 6/60, respectively. MAIN OUTCOME MEASURES: Cataract surgical coverage, barriers and outcomes of cataract surgery. RESULTS: Out of 5638 examined eyes, 526 eyes (9.3%) had history of cataract surgery. 156 subjects (45.7%) had a unilateral and 185 subjects (54.2%) had bilateral operated eyes. Cataract surgical coverage was 66.4% in visually impaired eyes (visual acuity < 6/18), 90.4% in blind eyes (visual acuity < 3/60), 80.5% in visually impaired persons and 97.6% in blind persons. Cataract surgery in the majority of eyes (71.9%) had a good visual outcome. The main barrier of cataract surgery was unawareness of treatment. CONCLUSION: Overall, the cataract services in the studied population were acceptable, although it should be improved, to achieve vision 2020 objectives. PMID- 23927431 TI - Harmonized guidance for disseminated intravascular coagulation from the International Society on Thrombosis and Haemostasis and the current status of anticoagulant therapy in Japan: a rebuttal. PMID- 23927432 TI - First evidence of cryptic species diversity and significant population structure in a widespread freshwater nematode morphospecies (Tobrilus gracilis). AB - Free-living nematodes are ubiquitous and highly abundant in terrestrial and aquatic environments, where they sustain ecosystem functioning by mineralization processes and nutrient cycling. Nevertheless, very little is known about their true diversity and intraspecific population structure. Recent molecular studies on marine nematodes indicated cryptic diversity and strong genetic differentiation of distinct populations, but for freshwater nematode species, analogous studies are lacking. Here, we present the first extensive molecular study exploring cryptic species diversity and genetic population structure of a widespread freshwater nematode morphospecies, Tobrilus gracilis, from nine postglacially formed European lakes. Taxonomic species status of individuals, analysed for fragments of the mitochondrial COI gene and for the large (LSU) and small (SSU) ribosomal subunits, were determined by morphological characteristics. Mitochondrial and nuclear markers strongly supported the existence of three distinct genetic lineages (Tg I-III) within Tobrilus gracilis, suggesting that this morphospecies indeed represents a complex of highly differentiated biological species. High genetic diversity was also observed at the population level. Across the nine lakes, 19 mitochondrial, and seven (LSU) and four (SSU) nuclear haplotypes were determined. A phylogeographical analysis revealed remarkable genetic differentiation even among neighbouring lake populations for one cryptic lineage. Priority and persistent founder effects are possible explanations for the observed population structure in the postglacially colonized lakes, but ask for future studies providing direct estimates of freshwater nematode dispersal rates. Our study suggests therefore that overall diversity of limnetic nematodes has been so far drastically underestimated and challenges the assumed ubiquitous distribution of other, single freshwater nematode morphospecies. PMID- 23927433 TI - Hairy cell leukemia in kidney transplantation: lesson from a rare disorder. AB - We report here on the diagnosis and successful treatment of a case of hairy cell leukemia (HCL) that arose 15 years after kidney transplantation in a 51-year-old patient. As soon as the diagnosis was made, HCL was treated with 2-CDA, obtaining complete hematological remission. Immunosuppression with the calcineurin inhibitor cyclosporin was maintained, and the graft was preserved. In kidney transplant recipients supported with immunosuppressive drugs, post-transplant lymphoproliferative diseases (PTLDs) are frequent and typically related to immunosuppression via a loss of control of infectious/EBV-related proliferative stimuli. To date, HCL has not been considered among PTLDs. Recently, however, the oncogenic mutation V600E of the BRAF protein kinase has been found to be a hallmark of HCL, and calcineurin inhibitors have been shown to interfere with signaling downstream of V600E BRAF early on by counteracting senescence associated mechanisms that protect against the oncogenic potential of the mutated kinase. Such a biochemical link between the oncogene-dependent signaling and calcineurin inhibitor activities suggests that HCL in transplanted patients might be a peculiar type of PTLD based on the presence of a specific mutation. This mechanism might also be involved in other neoplasias bearing the same or similar mutations, such as melanoma and non-melanoma skin cancer. PMID- 23927434 TI - Clinically targeted screening for congenital CMV - potential for integration into the National Hearing Screening Programme. AB - Screening for a condition should only be undertaken if certain strict criteria are met. Congenital CMV (cCMV) is a leading cause of sensorineuronal hearing loss (SNHL) and meets many of these criteria, but is not currently screened for in the UK. Ganciclovir reduces CMV-induced progressive SNHL if treatment is begun in the first month of life. The Newborn Hearing Screening Programme (NHSP) has been shown to identify SNHL at the earliest possible age. The potential of integrating screening for cCMV into the NHSP is discussed to consolidate the link between screening, early diagnosis and management. CONCLUSION: The early diagnosis and treatment of cCMV may prevent a small proportion of late SNHL. In the absence of any screening programme, we provide evidence that clinically targeted screening through the NHSP is a potential option in the UK, enhancing the diagnostic pathway and enabling appropriate early treatment to reduce long-term morbidity. PMID- 23927435 TI - Graphene-supported Ag-based core-shell nanoparticles for hydrogen generation in hydrolysis of ammonia borane and methylamine borane. AB - Well-dispersed magnetically recyclable core-shell Ag@M (M = Co, Ni, Fe) nanoparticles (NPs) supported on graphene have been synthesized via a facile in situ one-step procedure, using methylamine borane (MeAB) as a reducing agent under ambient condition. Their catalytic activity toward hydrolysis of ammonia borane (AB) were studied. Although the Ag@Fe/graphene NPs are almost inactive, the as-prepared Ag@Co/graphene NPs are the most reactive catalysts, followed by Ag@Ni/graphene NPs. Compared with AB and NaBH4, the as-synthesized Ag@Co/graphene catalysts which reduced by MeAB exert the highest catalytic activity. Additionally, the Ag@Co NPs supported on graphene exhibit higher catalytic activity than the catalysts with other conventional supports, such as the SiO2, carbon black, and gamma-Al2O3. The as-synthesized Ag@Co/graphene NPs exert satisfied catalytic activity, with the turnover frequency (TOF) value of 102.4 (mol H2 min(-1) (mol Ag)(-1)), and the activation energy Ea value of 20.03 kJ/mol. Furthermore, the as-synthesized Ag@Co/graphene NPs show good recyclability and magnetically reusability for the hydrolytic dehydrogenation of AB and MeAB, which make the practical reusing application of the catalysts more convenient. Moreover, this simple synthetic method indicates that MeAB could be used as not only a potential hydrogen storage material but also an efficient reducing agent. It can be easily extended to facile preparation of other graphene supported metal NPs. PMID- 23927436 TI - Probing the effects of hapten stability on cocaine vaccine immunogenicity. AB - Judicious hapten design has been shown to be of importance when trying to generate a viable vaccine against a drug of abuse. Hapten design has typically been predicated upon faithfully emulating the unique chemical architecture that each drug presents. However, the need for drug-hapten congruency may also compromise vaccine immunogenicity if the drug-hapten conjugate possesses chemical epitope instability. There has been no systematic study on the impact of hapten stability as it relates to vaccine immunogenicity. As a starting point, we have probed the stability of a series of cocaine haptens through varying several of its structural elements, including functionality at the C2-position, the nature of the linker, and its site of attachment. Accordingly, a hydrolytic stability profile of four cocaine haptens (GNNA, GNNS, GNE, and GNC) was produced, and these results were compared through each hapten's immunological properties, which were generated via active vaccination. From this group of four, three of the haptens, GNE, GNNA, and GNC, were further examined in an animal behavioral model, and findings here were again measured in relationship to hapten stability. We demonstrate a corresponding relationship between the half-life of the hapten and its immunogenicity, wherein haptens presenting a fully representative cocaine framework elicited higher concentrations of cocaine-specific IgG in sera and also conferred better protection against cocaine-induced locomotor activity. Our results indicate that hapten half-life plays an important role in vaccine immunogenicity and this in turn can impact animal behavioral effects when challenged with a drug of abuse. PMID- 23927437 TI - Long-term safety and tolerability of romiplostim in patients with primary immune thrombocytopenia: a pooled analysis of 13 clinical trials. AB - BACKGROUND AND OBJECTIVES: Thrombopoietin receptor agonists (TPOra) are the only treatments for immune thrombocytopenia (ITP) for which evidence of efficacy and safety from randomized, placebo-controlled trials is available. We sought to determine the long-term tolerability of the TPOra romiplostim, with a particular focus on thrombosis, bleeding, bone marrow (BM) reticulin, neoplasms/haematological malignancies and fatal events. METHODS: Data from 13 romiplostim clinical trials in which 653 patients with ITP received romiplostim for up to 5 yr (921.5 patient-years) were pooled; subject incidence rates and exposure-adjusted event rates (per 100 patient-years) were calculated. RESULTS: The rate of thrombotic events (6% of patients, 7.5 events per 100 patient-years) did not appear to increase over time; 9 events were associated with platelet counts >400 * 10(9) /L and 10 with romiplostim doses exceeding current recommendations. Serious and grade >=3 bleeding each occurred in approximately 8% of patients (~11 events per 100 patient-years). Adverse events of BM reticulin were recorded for 12 patients (1.8%, 1.3 events per 100 patient-years, confirmed by bone biopsy in ten patients) and BM collagen for one patient (0.2%, 0.1 event per 100 patient-years, confirmed by trichrome staining). Neoplasms and haematological malignancies occurred in 2.1% and 0.8% of patients, respectively (2.2 and 0.7 events per 100 patient-years). Fatal events occurred in 3.7% of patients (2.6 events per 100 patient-years, four events treatment-related). CONCLUSIONS: Romiplostim is the TPOra for which the longest duration of safety data is available. Our data demonstrate that long-term romiplostim treatment is well tolerated, with no new safety signals, even in patients treated for up to 5 yr. PMID- 23927438 TI - Antiphospholipid syndrome as a cause for recurrent myocardial infarction. AB - INTRODUCTION: This case describes a patient who suffered three myocardial infarctions over a two-week period. Testing confirmed thrombophilia as the etiology. CASE: A 55-year old male initially presented to the emergency department with a complaint of chest pain. Testing showed an elevated troponin at 2.2 ng/ml and ST elevations on electrocardiogram. The patient was transferred to the cardiac catheterization laboratory and a drug-eluting stent was placed. One day after the initial stent placement, in-stent thrombosis of the drug-eluting stent was discovered. Angioplasty and aspiration thrombectomy were performed, and the patient was released from the hospital three days later. 72 h after his discharge, the patient returned to the emergency department due to recurrent chest pain and diaphoresis. Shortly after arrival he became unresponsive and telemetry showed ventricular tachycardia which resolved with cardioversion. Reocclusion of the right coronary artery was again noted in the catheterization laboratory and three bare metal stents were placed. Laboratory testing found presence of anticardiolipin antibody and evidence of PT20201A mutation. CONCLUSION: Hypercoagulable states, although an uncommon cause of myocardial infarction, should be considered when investigating the etiology of recurrent coronary events. Prompt treatment is important in the prevention of future occurrences. PMID- 23927439 TI - The role of variable DNA tandem repeats in bacterial adaptation. AB - DNA tandem repeats (TRs), also designated as satellite DNA, are inter- or intragenic nucleotide sequences that are repeated two or more times in a head-to tail manner. Because TR tracts are prone to strand-slippage replication and recombination events that cause the TR copy number to increase or decrease, loci containing TRs are hypermutable. An increasing number of examples illustrate that bacteria can exploit this instability of TRs to reversibly shut down or modulate the function of specific genes, allowing them to adapt to changing environments on short evolutionary time scales without an increased overall mutation rate. In this review, we discuss the prevalence and distribution of inter- and intragenic TRs in bacteria and the mechanisms of their instability. In addition, we review evidence demonstrating a role of TR variations in bacterial adaptation strategies, ranging from immune evasion and tissue tropism to the modulation of environmental stress tolerance. Nevertheless, while bioinformatic analysis reveals that most bacterial genomes contain a few up to several dozens of intra- and intergenic TRs, only a small fraction of these have been functionally studied to date. PMID- 23927440 TI - The toxicity, transport and uptake of nanoparticles in the in vitro BeWo b30 placental cell barrier model used within NanoTEST. AB - Despite the rapid ongoing expansion in the use of nanomaterials, we still know little about their biological interaction and biodistribution within the human body. If medically relevant nanoparticles can cross specific cell barriers they may disseminate through the body beyond the original target and may reach particularly sensitive areas such as the foetus. This study utilised an in vitro barrier model of the placenta to explore toxicity, uptake and transport of iron oxide and silica nanoparticles. The findings indicate that these nanoparticles can transfer extensively across the placental barrier model but physico-chemical characteristics such as surface chemistry impact upon both uptake and transport. Iron oxide cytotoxicity was evident at lower doses and shorter exposure compared with silica and may be of clinical relevance. In vivo correlation of in vitro findings is essential but in vitro models may provide worst case-exposure estimates to help reduce the amount of testing required. PMID- 23927442 TI - Smoking, postmenopausal hormone therapy and the risk of venous thrombosis: a population-based, case-control study. PMID- 23927443 TI - Designed nanocage displaying ligand-specific Peptide bunches for high affinity and biological activity. AB - Protein-cage nanoparticles are promising multifunctional platforms for targeted delivery of imaging and therapeutic agents owing to their biocompatibility, biodegradability, and low toxicity. The major advantage of protein-cage nanoparticles is the ability to decorate their surfaces with multiple functionalities through genetic and chemical modification to achieve desired properties for therapeutic and/or diagnostic purposes. Specific peptides identified by phage display can be genetically fused onto the surface of cage proteins to promote the association of nanoparticles with a particular cell type or tissue. Upon symmetrical assembly of the cage, peptides are clustered on the surface of the cage protein in bunches. The resulting PBNC (peptide bunches on nanocage) offers the potential of synergistically increasing the avidity of the peptide ligands, thereby enhancing their blocking ability for therapeutic purposes. Here, we demonstrated a proof-of-principle of PBNCs, fusing the interleukin-4 receptor (IL-4R)-targeting peptide, AP-1, identified previously by phage display, with ferritin-L-chain (FTL), which undergoes 24-subunit assembly to form highly stable AP-1-containing nanocage proteins (AP1-PBNCs). AP1-PBNCs bound specifically to the IL-4R-expressing cell line, A549, and their binding and internalization were specifically blocked by anti-IL-4R antibody. AP1-PBNCs exhibited dramatically enhanced binding avidity to IL-4R compared with AP-1 peptide, measured by surface plasmon resonance spectroscopy. Furthermore, treatment with AP1-PBNCs in a murine model of experimental asthma diminished airway hyper-responsiveness and eosinophilic airway inflammation along with decreased mucus hyperproduction. These findings hold great promise for the application of various PBNCs with ligand-specific peptides in therapeutics for different diseases, such as cancer. PMID- 23927441 TI - Genetic variants in IL1A and IL1B contribute to the susceptibility to 2009 pandemic H1N1 influenza A virus. AB - BACKGROUND: Host genetic variations may contribute to disease susceptibility of influenza. IL-1A and IL-1B are important inflammatory cytokines that mediate the inflammation and initiate the immune response against virus infection. In this study, we investigated the relationship between single-nucleotide polymorphisms (SNPs) of Interleukin-1A (IL-1A) and Interleukin-1B (IL-1B) and the susceptibility to 2009 pandemic A/H1N1 influenza (A(H1N1)pdm09). 167 patients whom were confirmed with A(H1N1)pdm09 and 192 healthy controls were included in this study. Four SNPs (rs1304037, rs16347, rs17561, rs2071373) in IL1A gene and three SNPs (rs1143623, rs3917345, rs1143627) in IL1B gene were genotyped by using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform, and the associations of the genetic variants of IL-1 with susceptibility to A(H1N1)pdm09 were then assessed. RESULTS: The polymorphisms of rs17561 in IL1A gene and rs1143627 in IL1B gene were found to be associated with susceptibility to A(H1N1)pdm09 with P values of 0.003 (OR 2.08, 95% CI 1.27-3.41) and 0.002 (OR 1.62 , 95% CI 1.20-2.18), respectively. However, no significant difference in allelic frequency was observed for other SNPs between cases and controls. CONCLUSIONS: This study provides a new insight into pathogenesis of A(H1N1)pdm09, suggesting that genetic variants of IL-1A and IL-1B may exert a substantial impact on the susceptibility of A(H1N1)pdm09 virus infection. PMID- 23927444 TI - Diabetes mellitus unawareness is a strong determinant of mortality in patients manifesting myocardial infarction. AB - OBJECTIVE: Often, as diabetes mellitus type 2 (T2DM) evolves insidiously, prevention is commenced late and diagnosis is made when vascular damage has been set. Hence, our hypothesis is that T2DM awareness may influence the outcome of atherothrombotic events. METHODS: A consecutive cohort of patients manifesting ST elevation myocardial infarction (MI) was classified according to the presence and awareness of the diagnosis of T2DM: known diabetes (kT2DM, n = 72), unknown diabetes (uT2DM, n = 80) and no diabetes (ND, n = 333). Medical history, laboratory data, and angiographic findings including myocardial blush grade (MBG) were prospectively obtained. The primary endpoint was in-hospital death and secondary endpoint was major adverse cardiac events (MACE) defined as sudden cardiac death, fatal MI and nonfatal MI that occurred from 30 days of study entry onwards. RESULTS: With the exception of glycated hemoglobin (p = 0.001) and triglycerides (p = 0.04), no differences were found between groups for all other biochemical, clinical or angiographic admission characteristics. Myocardial tissue reperfusion defined as MBG 3 was observed in 62% in the ND group, 50% in the kT2DM group and 23% in the uT2DM group (p = 0.01). All-cause in-hospital mortality was higher in uT2DM (16.7%) than in kT2DM (8.4%) and both groups had a higher mortality rate as compared with the ND group (3.8%, p = 0.01). During follow-up (653 +/- 26 days), the incidence of MACE was higher in uT2DM than in kT2DM and in both compared to the ND group (p = 0.002). CONCLUSION: Unawareness of T2DM diagnosis is strongly associated with a poor short- and long-term outcome after MI. PMID- 23927445 TI - Personality-relationship transactions revisited. AB - The transactional paradigm states that people create, maintain, and change their environments according to their personalities. At the same time, the environment reacts back on personality. As social relationships are part of an individual's environment, this likewise implies that there are reciprocal transactions between personality and relationships. However, earlier studies have concluded that adult personality traits are so stable that they have a stronger effect on later relationships, but that relationship effects on personality are negligible. In this article, we contend that personality-relationship transactions should be revisited. We submit that the relative powers of personality versus relationship effects depend on the type of life transition during which the effects take place: Relationship effects on personality development are more likely to emerge in the context of rather normative and highly scripted life transitions, whereas personality effects on relationship development are more likely to occur in the context of rather non-normative life transitions that are less regulated by social expectations. We illustrate these assumptions with examples from our own work and other findings reported in the literature. Furthermore, we theorize that effects of personality-relationship transactions on health also vary with the normativeness of the eliciting life transition. PMID- 23927447 TI - Abstracts of presentations at the 2013 north central division meeting. PMID- 23927448 TI - Abstracts of presentations at the 2013 caribbean/pacific division joint meeting. PMID- 23927446 TI - Review of fall risk assessment in geriatric populations using inertial sensors. AB - BACKGROUND: Falls are a prevalent issue in the geriatric population and can result in damaging physical and psychological consequences. Fall risk assessment can provide information to enable appropriate interventions for those at risk of falling. Wearable inertial-sensor-based systems can provide quantitative measures indicative of fall risk in the geriatric population. METHODS: Forty studies that used inertial sensors to evaluate geriatric fall risk were reviewed and pertinent methodological features were extracted; including, sensor placement, derived parameters used to assess fall risk, fall risk classification method, and fall risk classification model outcomes. RESULTS: Inertial sensors were placed only on the lower back in the majority of papers (65%). One hundred and thirty distinct variables were assessed, which were categorized as position and angle (7.7%), angular velocity (11.5%), linear acceleration (20%), spatial (3.8%), temporal (23.1%), energy (3.8%), frequency (15.4%), and other (14.6%). Fallers were classified using retrospective fall history (30%), prospective fall occurrence (15%), and clinical assessment (32.5%), with 22.5% using a combination of retrospective fall occurrence and clinical assessments. Half of the studies derived models for fall risk prediction, which reached high levels of accuracy (62-100%), specificity (35-100%), and sensitivity (55-99%). CONCLUSIONS: Inertial sensors are promising sensors for fall risk assessment. Future studies should identify fallers using prospective techniques and focus on determining the most promising sensor sites, in conjunction with determination of optimally predictive variables. Further research should also attempt to link predictive variables to specific fall risk factors and investigate disease populations that are at high risk of falls. PMID- 23927449 TI - Peters' anomaly imaged with an infrared anterior segment camera. PMID- 23927450 TI - Using reduced catalysts for oxidation reactions: mechanistic studies of the "Periana-Catalytica" system for CH4 oxidation. AB - Designing oxidation catalysts based on CH activation with reduced, low oxidation state species is a seeming dilemma given the proclivity for catalyst deactivation by overoxidation. This dilemma has been recognized in the Shilov system where reduced Pt(II) is used to catalyze methane functionalization. Thus, it is generally accepted that key to replacing Pt(IV) in that system with more practical oxidants is ensuring that the oxidant does not over-oxidize the reduced Pt(II) species. The "Periana-Catalytica" system, which utilizes (bpym)Pt(II)Cl2 in concentrated sulfuric acid solvent at 200 degrees C, is a highly stable catalyst for the selective, high yield oxy-functionalization of methane. In lieu of the over-oxidation dilemma, the high stability and observed rapid oxidation of (bpym)Pt(II)Cl2 to Pt(IV) in the absence of methane would seem to contradict the originally proposed mechanism involving CH activation by a reduced Pt(II) species. Mechanistic studies show that the originally proposed mechanism is incomplete and that while CH activation does proceed with Pt(II) there is a solution to the over-oxidation dilemma. Importantly, contrary to the accepted view to minimize Pt(II) overoxidation, these studies also show that increasing that rate could increase the rate of catalysis and catalyst stability. The mechanistic basis for this counterintuitive prediction could help to guide the design of new catalysts for alkane oxidation that operate by CH activation. PMID- 23927451 TI - A cost-minimisation study of 1,001 NHS Direct users. AB - BACKGROUND: To determine financial and quality of life impact of patients calling the '0845' NHS Direct (NHS Direct) telephone helpline from the perspective of NHS service providers. METHODS: Cost-minimisation of repeated cohort measures from a National Survey of NHS Direct's telephone service using telephone survey results. 1,001 people contacting NHS Direct's 0845 telephone service in 2009 who agreed to a 4-6 week follow-up. A cost comparison between NHS Direct recommendation and patient-stated first alternative had NHS Direct not been available. Analysis also considers impact on quality of life of NHS Direct recommendations using the Visual Analogue Scale of the EQ-5D. RESULTS: Significant referral pattern differences were observed between NHS Direct recommendation and patient-stated first alternatives (p < 0.001). Per patient cost savings resulted from NHS Direct's recommendation to attend A&E (L36.54); GP Practice (L19.41); Walk-In Centre (L49.85); Pharmacist (L25.80); Dentist (L2.35) and do nothing/treat at home (L19.77), while it was marginally more costly for 999 calls (L3.33). Overall an average per patient saving of L19.55 was found (a 36% saving compared with patient-stated first alternatives). For 5 million NHS Direct telephone calls per year, this represents an annual cost saving of L97,756,013. Significant quality of life differences were observed at baseline and follow-up between those who believed their problem was 'urgent' (p = 0.001) and those who said it was 'non urgent' (p = 0.045). Whilst both groups improved, self-classified 'urgent' cases made greater health gains than those who said they were 'non-urgent' (urgent by 21.5 points; non-urgent by 16.1 points). CONCLUSIONS: The '0845' service of NHS Direct produced substantial cost savings in terms of referrals to the other parts of the NHS when compared with patients' own stated first alternative. Health related quality of life also improved for users of this service demonstrating that these savings can be produced without perceived harm to patients. PMID- 23927452 TI - A novel prothrombin mutation in two families with prominent thrombophilia--the first cases of antithrombin resistance in a Caucasian population. PMID- 23927453 TI - Pitfalls in accurate estimation of overdiagnosis: implications for screening policy and compliance. AB - Stories in the public media that 30 to 50% of screen-detected breast cancers are overdiagnosed dissuade women from being screened because overdiagnosed cancers would never result in death if undetected yet do result in unnecessary treatment. However, such concerns are unwarranted because the frequency of overdiagnosis, when properly calculated, is only 0 to 5%. In the previous issue of Breast Cancer Research, Duffy and Parmar report that accurate estimation of the rate of overdiagnosis recognizes the effect of lead time on detection rates and the consequent requirement for an adequate number of years of follow-up. These indispensable elements were absent from highly publicized studies that overestimated the frequency of overdiagnosis. PMID- 23927454 TI - Specificity of the neutralizers as the cause of errors in evaluating disinfectant efficacy: an assessment of triclosan. AB - One of the most commonly used methods for assessing disinfectants in vitro is the dilution-neutralization test. Although it is known that using an effective neutralizer is essential for obtaining reliable results, in the case of disinfectants like triclosan, whose neutralization is more complicated, an adequate neutralizer is not always used. Here, we compare the efficacy of different neutralizers described previously, and others that have been modified, against several antiseptic formulations of triclosan. The strains of reference used were Pseudomonas aeruginosa, Enterococcus faecium, Staphylococcus aureus and Escherichia coli. The solutions of antiseptic were triclosan 2% aqueous solution, and three alcoholic solutions containing 2, 0.068 and 0.5% triclosan, respectively. In the dilution-neutralization test, six neutralizers with different degrees of complexity were assayed. Our results show that the antiseptic solutions studied are effective against the strains of reference, with the exception of triclosan 2% aqueous solution against Ps. aeruginosa. Most neutralizers proved ineffective, depending on the antiseptic solution and the bacterial species, particularly in the case of Staph. aureus. These findings confirm a need to test every neutralizer specifically for each disinfectant, at the maximum concentration used, and for every specific bacterial strain. SIGNIFICANCE AND IMPACT OF THE STUDY: The choice of an adequate neutralizing agent is essential for obtaining precise results in the evaluation of disinfectants using the dilution-neutralization method. In this study, we show that the neutralization of triclosan and some of its commercial solutions is not a simple task, requiring complex neutralizers. Moreover, the action of the neutralizer is shown to depend on the micro-organism tested. Specificity in view of the disinfectant and the micro-organism calls for performing the neutralizing assay in each particular case of application of the dilution-neutralization method. We also demonstrate that some of the neutralizers described for triclosan in previous studies are not sufficiently effective. PMID- 23927455 TI - Overlapping decline in orbitofrontal gray matter volume related to cocaine use and body mass index. AB - Loss of control over hedonically motivated actions is a defining component of impulse control disorders, such as drug dependence and the proposed 'food addiction' model of obesity. Devolution from goal-directed to compulsively maintained behaviors is partially attributed to abnormalities in the orbitofrontal cortex, an area critical in reward valuation. In the current study, overlapping reductions in orbitofrontal gray matter volume relating to body mass index were seen in healthy control and cocaine-dependent individuals, as well as in relation to duration of cocaine abuse, providing support for a shared neuropathology between the two conditions potentially related to dysfunctional reward-seeking behavior. PMID- 23927456 TI - Influence of preoperative docetaxel, cisplatin, and 5-fluorouracil on the incidence of complications after esophagectomy for resectable advanced esophageal cancer. AB - A limited number of patients with resectable advanced esophageal cancer can be cured by surgery alone. Although a regimen that consists of docetaxel, cisplatin, and 5-fluorouracil (DCF) is a potential preoperative chemotherapy (PCT) option for squamous cell carcinoma of the esophagus, the influence of DCF on subsequent esophagectomies remains unclear. A total of 80 patients who received preoperative DCF chemotherapy, and 174 patients who did not receive any preoperative treatment were retrospectively analyzed. There were no treatment-related deaths. No delays in surgery due to adverse events related to DCF were reported. Although patients who received PCT had significantly more advanced cancers and worse preoperative conditions, the incidence rates of complications did not increase. Although the frequency of severe complications was significantly higher in patients who received PCT, this treatment was not an independent factor for the occurrence of severe complications. PCT with DCF did not negatively affect subsequent esophagectomies with regard to the frequency of complications. PMID- 23927457 TI - High connectivity across the fragmented chemosynthetic ecosystems of the deep Atlantic Equatorial Belt: efficient dispersal mechanisms or questionable endemism? AB - Chemosynthetic ecosystems are distributed worldwide in fragmented habitats harbouring seemingly highly specialized communities. Yet, shared taxa have been reported from highly distant chemosynthetic communities. These habitats are distributed in distinct biogeographical regions, one of these being the so-called Atlantic Equatorial Belt (AEB). Here, we combined genetic data (COI) from several taxa to assess the possible existence of cryptic or synonymous species and to detect the possible occurrence of contemporary gene flow among populations of chemosynthetic species located on both sides of the Atlantic. Several Evolutionary Significant Units (ESUs) of Alvinocarididae shrimp and Vesicomyidae bivalves were found to be shared across seeps of the AEB. Some were also common to hydrothermal vent communities of the Mid-Atlantic Ridge (MAR), encompassing taxa morphologically described as distinct species or even genera. The hypothesis of current or very recent large-scale gene flow among seeps and vents was supported by microsatellite analysis of the shrimp species Alvinocaris muricola/Alvinocaris markensis across the AEB and MAR. Two nonmutually exclusive hypotheses may explain these findings. The dispersion of larvae or adults following strong deep-sea currents, possibly combined with biochemical cues influencing the duration of larval development and timing of metamorphosis, may result in large-scale effective migration among distant spots scattered on the oceanic seafloor. Alternatively, these results may arise from the prevailing lack of knowledge on the ocean seabed, apart from emblematic ecosystems (chemosynthetic ecosystems, coral reefs or seamounts), where the widespread classification of endemism associated with many chemosynthetic taxa might hide wider distributions in overlooked parts of the deep sea. PMID- 23927458 TI - A novel aliphatic 18F-labeled probe for PET imaging of melanoma. AB - Radiofluorinated benzamide and nicotinamide analogues are promising molecular probes for the positron emission tomography (PET) imaging of melanoma. Compounds containing aromatic (benzene or pyridine) and N,N-diethylethylenediamine groups have been successfully used for development of melanin targeted PET and single photon emission computed tomography (SPECT) imaging agents for melanoma. The objective of this study was to determine the feasibility of using aliphatic compounds as a molecular platform for the development of a new generation of PET probes for melanoma detection. An aliphatic N,N-diethylethylenediamine precursor was directly coupled to a radiofluorination synthon, p-nitrophenyl 2-(18)F fluoropropionate ((18)F-NFP), to produce the probe N-(2-(diethylamino)ethyl)-2 (18)F-fluoropropanamide ((18)F-FPDA). The melanoma-targeting ability of (18)F FPDA was further evaluated both in vitro and in vivo through cell uptake assays, biodistribution studies, and small animal PET imaging in C57BL/6 mice bearing B16F10 murine melanoma tumors. Beginning with the precursor (18)F-NFP, the total preparation time for (18)F-FPDA, including the final high-performance liquid chromatography purification step, was approximately 30 min, with a decay corrected radiochemical yield of 79.8%. The melanin-targeting specificity of (18)F-FPDA was demonstrated by significantly different uptake rates in tyrosine treated and untreated B16F10 cells in vitro. The tumor uptake of (18)F-FPDA in vivo reached 2.65 +/- 0.48 %ID/g at 2 h postinjection (p.i.) in pigment-enriched B16F10 xenografts, whereas the tumor uptake of (18)F-FPDA was close to the background levels, with rates of only 0.37 +/- 0.07 %ID/g at 2 h p.i. in the nonpigmented U87MG tumor mouse model. Furthermore, small animal PET imaging studies revealed that (18)F-FPDA specifically targeted the melanotic B16F10 tumor, yielding a tumor-to-muscle ratio of approximately 4:1 at 1 h p.i. and 7:1 at 2 h p.i. In summary, we report the development of a novel (18)F-labeled aliphatic compound for melanoma imaging that can be easily synthesized in high yields using the radiosynthon (18)F-NFP. The PET probe (18)F-FPDA exhibits high B16F10 tumor-targeting efficacy and favorable in vivo pharmacokinetics. Our study demonstrates that aliphatic compounds can be used as a new generation molecular platform for the development of novel melanoma targeting agents. Further evaluation and optimization of (18)F-FPDA for melanin targeted molecular imaging are therefore warranted. PMID- 23927459 TI - One-step surface doping of organic nanofibers to achieve high dark conductivity and chemiresistor sensing of amines. AB - High dark electrical conductivity was obtained for a p-type organic nanofibril material simply through a one-step surface doping. The nanofibril composite thus fabricated has been proven robust under ambient conditions. The high conductivity, combined with the intrinsic large surface area of the nanofibers, enables development of chemiresistor sensors for trace vapor detection of amines, with detection limit down to sub-parts per billion range. PMID- 23927460 TI - Redox-responsive alginate nanogels with enhanced anticancer cytotoxicity. AB - Although doxorubicin (Dox) has been widely used in the treatment of different types of cancer, its insufficient cellular uptake and intracellular release is still a limitation. Herein, we report an easy process for the preparation of redox-sensitive nanogels that were shown to be highly efficient in the intracellular delivery of Dox. The nanogels (AG/Cys) were obtained through in situ cross-linking of alginate (AG) using cystamine (Cys) as a cross-linker via a miniemulsion method. Dox was loaded into the AG/Cys nanogels by simply mixing it in aqueous solution with the nanogels, that is, by the establishment of electrostatic interactions between the anionic AG and the cationic Dox. The results demonstrated that the AG/Cys nanogels are cytocompatible, have a high drug encapsulation efficiency (95.2 +/- 4.7%), show an in vitro accelerated release of Dox in conditions that mimic the intracellular reductive conditions, and can quickly be taken up by CAL-72 cells (an osteosarcoma cell line), resulting in higher Dox intracellular accumulation and a remarkable cell death extension when compared with free Dox. The developed nanogels can be used as a tool to overcome the problem of Dox resistance in anticancer treatments and possibly be used for the delivery of other cationic drugs in applications beyond cancer. PMID- 23927461 TI - Therapeutic superiority and safety of combined hydroxyurea with recombinant human erythropoietin over hydroxyurea in young beta-thalassemia intermedia patients. AB - OBJECTIVE: To assess the efficacy and safety of combined hydroxyurea (HU) and recombinant human erythropoietin (rHuEPO) in beta-thalassemia intermedia (TI) patients compared with single HU therapy. METHODS: An interventional prospective randomized study registered in the ClinicalTrials.gov (NCT01624038) was performed on 80 TI patients (<= 18 yr) divided into group A (40 patients received combined HU and rHuEPO) and group B (40 patients received single HU therapy). Baseline serum EPO levels were measured, and both groups were followed up for a mean period of 1 yr with regular assessment of transfusion requirements, blood pressure, ferritin, liver and renal functions, hemoglobin, and HbF. Quality of life (QoL) was assessed at the start and end of the study. RESULTS: Transfusion frequency and index were significantly decreased, while QoL was increased in group A compared with group B where 85% of patients showed improvement on combined therapy compared with 50% of patients on HU. Hemoglobin and HbF were significantly increased in both TI groups; however, this was more evident in group A than in group B. Also, 37.5% of patients in group A became transfusion independent compared with 15% in group B. EPO levels were negatively related to increments of hemoglobin and HbF. Splenectomized patients and those with initial HbF% >40% had the best response to combined therapy. No serious adverse events necessitating discontinuation of therapy in both groups. CONCLUSIONS: HU was effective in management of TI; however, combination with rHuEPO gave a superior therapeutic effect resulting in the best clinical and hematological responses without adverse events. PMID- 23927462 TI - Silver nanoparticle-specific mitotoxicity in Daphnia magna. AB - Silver nanoparticles (Ag NPs) are gaining popularity as bactericidal agents in commercial products; however, the mechanisms of toxicity (MOT) of Ag NPs to other organisms are not fully understood. It is the goal of this research to determine differences in MOT induced by ionic Ag(+) and Ag NPs in Daphnia magna, by incorporating a battery of traditional and novel methods. Daphnia embryos were exposed to sublethal concentrations of AgNO3 and Ag NPs (130-650 ng/L), with uptake of the latter confirmed by confocal reflectance microscopy. Mitochondrial function was non-invasively monitored by measuring proton flux using self referencing microsensors. Proton flux measurements revealed that while both forms of silver significantly affected proton efflux, the change induced by Ag NPs was greater than that of Ag(+). This could be correlated with the effects of Ag NPs on mitochondrial dysfunction, as determined by confocal fluorescence microscopy and JC-1, an indicator of mitochondrial permeability. However, Ag(+) was more efficient than Ag NPs at displacing Na(+) within embryonic Daphnia, based on inductively coupled plasma-mass spectroscopy (ICP-MS) analysis. The abnormalities in mitochondrial activity for Ag NP-exposed organisms suggest a nanoparticle specific MOT, distinct from that induced by Ag ions. We propose that the MOT of each form of silver are complementary, and can act in synergy to produce a greater toxic response overall. PMID- 23927463 TI - Enzymatic ligation of large biomolecules to DNA. AB - The ability to synthesize, characterize, and manipulate DNA forms the foundation of a range of advanced disciplines including genomics, molecular biology, and biomolecular engineering. In particular for the latter field, DNA has proven useful as a structural or functional component in nanoscale self-assembled structures, antisense therapeutics, microarray diagnostics, and biosensors. Such applications frequently require DNA to be modified and conjugated to other macromolecules, including proteins, polymers, or fatty acids, in order to equip the system with properties required for a particular application. However, conjugation of DNA to large molecular components using classical chemistries often suffers from suboptimal yields. Here, we report the use of terminal deoxynucleotidyl transferase (TdT) for direct enzymatic ligation of native DNA to nucleotide triphosphates coupled to proteins and other large macromolecules. We demonstrate facile synthesis routes for a range of NTP-activated macromolecules and subsequent ligation to the 3' hydroxyl group of oligodeoxynucleotides using TdT. The reaction is highly specific and proceeds rapidly and essentially to completion at micromolar concentrations. As a proof of principle, parallelly labeled oligonucleotides were used to produce nanopatterned DNA origami structures, demonstrating rapid and versatile incorporation of non-DNA components into DNA nanoarchitectures. PMID- 23927464 TI - Loss to follow-up and mortality rates in HIV-1-infected patients in Curacao before and after the start of combination antiretroviral therapy. AB - We estimated the impact of loss to follow-up (LTFU) on the mortality rate among HIV-1-infected patients in Curacao. A total of 214 therapy-naive HIV-1-infected patients aged 15 years or older upon entering into HIV care between January 2005 and July 2009 were included. Persons who discontinued follow-up for more than 365 days were defined as LTFU and traced with the aim of registering their vital status. If no personal contact could be made, data were matched with the Curacao National Death Registry. Mortality rates were estimated before and after starting combination antiretroviral therapy (cART). We used log-rank tests to compare survival rates among patients LTFU and patients who experienced continuous follow up. Pre-cART mortality in patients LTFU was similar to pre-cART mortality in those with continuous follow-up (p=0.79). All pre-cART deaths occurred within 6 months after entry. Low CD4 cell count was predictive of a shorter time to death after entry. Adjusting for those who were LTFU, the mortality rate after starting cART increased from 4.3 to 5.5 per 100 person years of observation (p=0.06). Mortality after starting cART was highest in the first 2 months after starting cART, especially for those who had late disease stage. Mortality rates were lower in patients with continuous follow-up compared to LTFUs (p<0.001). Mortality rates in HIV-1-infected patients who have started cART in Curacao are underestimated as a result of inefficient patient administration combined with people starting cART at a very late disease stage. Monitoring HIV treatment could help in reducing the risk of LTFU and may improve the effect of treatment. PMID- 23927465 TI - Very high frequencies of leukaemia-initiating cells in precursor T-acute lymphoblastic leukaemia may be obscured by cryopreservation. PMID- 23927466 TI - The genus Eremophila (Scrophulariaceae): an ethnobotanical, biological and phytochemical review. AB - OBJECTIVES: Eremophila (Scrophulariaceae) is an endemic Australian genus with 214 species, which is commonly known as Fuchsia bush, Emu bush or Poverty bush. Plants of this genus played an important role for the Australian Aborigines who used them widely for medicinal and ceremonial purposes. Many studies have been carried out on many species of this genus and have generated immense data about the chemical composition and corresponding biological activity of extracts and isolated secondary metabolites. KEY FINDINGS: Thorough phytochemical investigations of different Eremophila species have resulted in the isolation of more than 200 secondary metabolites of different classes with diterpenes as major constituents. Biological studies and traditional clinical practice demonstrated that Eremophila and its bioactive compounds possess various pharmacological properties. Plants were employed especially as a cardiotonic drug and also as potent anti-inflammatory, antimicrobial and antiviral agents. SUMMARY: Further investigations are required to explore other Eremophila species, to evaluate the different biological activities of either their extracts or the isolated compounds and the possible underlying modes of action. PMID- 23927467 TI - Finding chemo: the search for marine-based pharmaceutical drugs active against cancer. AB - OBJECTIVES: Cancer affects the health of many people globally. The most common treatment that is used for cancer is chemotherapy, which has shown promising results but not without side effects. Some of these side effects jeopardise further treatment, and this eventually leads to advanced stages of malignancy and mortality. As a result, there is a need for better and safer anticancer compounds such as those found naturally. One of the most abundant natural environments to find such compounds is the sea, and this vast resource has been biomined since the 1950s. KEY FINDINGS: There are currently three marine anticancer agents marketed (Yondelis, Cytosar-U and Halaven), with several others undergoing clinical trials. This review discusses marine-derived products in clinical use and in clinical trials, and discusses available literature on the growth suppression or pro-apoptotic properties of these compounds, and the molecular mechanisms underpinning these cell biological phenomena. SUMMARY: The marine environment may hold promising anticancer compounds within its depths, warranting further research to be performed in this area, albeit with respect for the natural ecosystems that are being explored for drug discover and subsequently used for drug development. PMID- 23927468 TI - Isoniazid-gelatin conjugate microparticles containing rifampicin for the treatment of tuberculosis. AB - OBJECTIVES: In this work, a new polymeric microparticle system based on gelatin covalently bound to isoniazid (ISN) and containing rifampicin (RFP) was prepared by spray-drying technique. Microparticle aptitude to nebulisation and their capability of interacting with A549, alveolar basal epithelial cells, were evaluated in vitro. METHODS: Microparticles were obtained by spray drying, and their morphology, size, zeta potential, thermotropic behaviour and nebulisation ability were evaluated. KEY FINDINGS: Microparticles were positively charged with a mean size of 4.88 +/- 0.3 MUm. Microspheres were able to incorporate both RFP and ISN: encapsulation efficiency was 51 +/- 6% and 22 +/- 1%, respectively. X ray diffraction study showed a new extensive and flattened diffraction peak providing evidence that the drugs were dispersed into the microparticles. Differential scanning calorimetry analysis confirmed effective interactions between gelatin and drug molecules by the presence of new transition peaks. Fifty nine per cent of used microparticles were aerosolised. In-vitro toxicity studies on A549 alveolar basal epithelial cells showed that microparticles decreased cytotoxicity in comparison with the RFP solution. Laser scanning confocal microscopy observation confirmed that fluorescent probes delivered by microparticles are efficiently internalised in A549 cells. CONCLUSIONS: Overall, microparticles based on gelatin covalently bound to ISN and containing RFP showed a promising behaviour for pulmonary drug delivery. PMID- 23927469 TI - Evaluation of palatability of 10 commercial amlodipine orally disintegrating tablets by gustatory sensation testing, OD-mate as a new disintegration apparatus and the artificial taste sensor. AB - OBJECTIVES: The purpose of this study was to evaluate and compare the palatability of 10 formulations (the original manufacturer's formulation and nine generics) of amlodipine orally disintegrating tablets (ODTs) by means of human gustatory sensation testing, disintegration/dissolution testing and the evaluation of bitterness intensity using a taste sensor. METHODS: Initially, the palatability, dissolution and bitterness intensity of the ODTs were evaluated in gustatory sensation tests. Second, the disintegration times of the ODTs were measured using the OD-mate, a newly developed apparatus for measuring the disintegration of ODTs, and lastly, the bitterness intensities were evaluated using an artificial taste sensor. KEY FINDINGS: Using factor analysis, the factors most affecting the palatability of amlodipine ODTs were found to be disintegration and taste. There was high correlation between the disintegration times of the 10 amlodipine ODTs estimated in human gustatory testing and those found using the OD-mate. The bitterness intensities of amlodipine ODTs 10, 20 and 30 s after starting the conventional brief dissolution test and the values determined by the taste sensor were highly correlated with the bitterness intensities determined in gustatory sensation testing. CONCLUSIONS: The OD-mate and the taste sensor may be useful for predicting the disintegration and bitterness intensity of amlodipine ODTs in the mouth. PMID- 23927470 TI - Blockade of the human ether-a-go-go-related gene potassium channel by ketamine. AB - OBJECTIVES: The inhibition of the cardiac rapid delayed rectifier potassium current (IKr ) and its cloned equivalent human ether-a-go-go-related gene (hERG) channel illustrate QT interval prolonging effects of a wide range of clinically used drugs. In this study, the direct interaction of the intravenous anaesthetic ketamine with wild-type (WT) and mutation hERG currents (IhERG ) was investigated. METHODS: The hERG channel (WT, Y652A and F656A) was expressed in Xenopus oocytes and studied using standard two-microelectrode voltage-clamp techniques. KEY FINDINGS: WT hERG is blocked in a concentration-dependent manner with IC50 = 12.05 +/- 1.38 MUm by ketamine, and the steady-state inactivation curves are shifted to more negative potentials (about -27 mV). The mutation to Ala of Y652 and F656 located on the S6 domain attenuate IhERG blockade by ketamine, and produced approximately 9-fold and 2.5-fold increases in IC50 compared with that of WT hERG channel, respectively. CONCLUSIONS: Ketamine blocks WT IhERG expressed in Xenopus oocytes in a concentration-dependent manner and predominantly interacts with the open hERG channels. The interaction of ketamine with hERG channel may involve the aromatic residues Tyr652 and Phe656. PMID- 23927471 TI - Cellular distribution studies of the nitric oxide-generating antineoplastic prodrug O(2) -(2,4-dinitrophenyl)1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium 1,2-diolate formulated in Pluronic P123 micelles. AB - OBJECTIVE: Nitric oxide (NO) possesses antitumour activity. It induces differentiation and apoptosis in acute myeloid leukaemia (AML) cells. The NO prodrug O(2) -(2,4-dinitrophenyl)1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium 1,2-diolate, or JS-K, has potent antileukaemic activity. JS-K is also active in vitro and in vivo against multiple myeloma, prostate cancer, non-small-cell lung cancer, glioma and liver cancer. Using the Pluronic P123 polymer, we have developed a micelle formulation for JS-K to increase its solubility and stability. The goal of the current study was to investigate the cellular distribution of JS-K in AML cells. METHODS: We investigated the intracellular distribution of JS-K (free drug) and JS-K formulated in P123 micelles (P123/JS-K) using HL-60 AML cells. We also studied the S-glutathionylating effects of JS-K on proteins in the cytoplasmic and nuclear cellular fractions. KEY FINDINGS: Both free JS-K and P123/JS-K accumulate primarily in the nucleus. Both free JS-K and P123/JS-K induced S-glutathionylation of nuclear proteins, although the effect produced was more pronounced with P123/JS-K. Minimal S-glutathionylation of cytoplasmic proteins was observed. CONCLUSIONS: We conclude that a micelle formulation of JS-K increases its accumulation in the nucleus. Post-translational protein modification through S-glutathionylation may contribute to JS-K's antileukaemic properties. PMID- 23927472 TI - Cross-talk with beta2 -adrenoceptors enhances ligand affinity properties from endothelial alpha1 D -adrenoceptors that mediates carotid relaxation. AB - OBJECTIVES: Our main objectives were to investigate the affinity properties of endothelial and muscular alpha1D -adrenoceptors and to characterize the cross talk between endothelial alpha1D -adrenoceptors and beta2 -adrenoceptors in rat carotid. METHODS: Relaxation and contraction concentration-response curves for phenylephrine (alpha1 -adrenergic agonist) were obtained in carotid rings in absence or presence of increasing concentrations of BMY7378 (alpha1D -adrenergic antagonist), combined or not with increasing concentration of ICI-118,551 (beta2 adrenergic antagonist). Schild analysis was used to estimate the affinity constant from pA2 values of BMY7378. KEY FINDINGS: BMY7378 produced an unsurmountable antagonism on phenylephrine-induced relaxation but a surmountable antagonism on phenylephrine-induced contraction. BMY7378 potency was higher in inhibiting the relaxation than the contraction induced by phenylephrine because the rightward shifts induced by BMY7378 were greater in the relaxation. The apparent pA2 value for BMY7378 in phenylephrine-induced relaxation was greater than in contraction. When combined with ICI-118,551, BMY7378 yielded a surmountable antagonism on phenylephrine-induced relaxation and presented a pA2 value similar to that obtained in phenylephrine-induced contraction. CONCLUSIONS: Endothelial alpha1D -adrenoceptors, which mediates rat carotid relaxation, present high ligand affinity because of the cross-talk with beta2 -adrenoceptors, which explains the higher potency of phenylephrine in inducing relaxation than contraction and the atypical unsurmountable antagonism produced by BMY7378 on phenylephrine-induced relaxation. PMID- 23927473 TI - Metoprolol oxidation polymorphism in Brazilian elderly cardiac patients. AB - OBJECTIVES: The purpose of this study was to phenotype the CYP2D6 in elderly with heart disease classified as extensive metabolizer or poor metabolizers (PM) of metoprolol, develop and validate the method of analysis of metoprolol tartrate and its metabolite in urine using HPLC, and identify potential correlations between anthropometric factors with metabolic ratios of metoprolol/alpha-OH metoprolol in urine. METHODS: The sample was composed of 130 elderly individuals with a previously identified type of heart condition, with normal renal and hepatic functions. The urine of all the patients were collected 0-8 h after the administration of a pill of 100 mg of metoprolol to determine concentrations of metoprolol and alpha-hydroxymetoprolol. Those patients presenting a metabolic ratio greater than 12.6 were phenotyped as PM. KEY FINDINGS: The median age of patients was 71.0 years, with a minimum of 60 and maximum of 93 years old. Three patients (2.3%) were phenotyped as PM of metoprolol different from the rate (7 10%) of PM existing in the Caucasian population. CONCLUSIONS: Most of the studied individuals were women, and the proportion of elderly with heart disease classified as PM was smaller than what is usually found among Caucasian populations. PMID- 23927474 TI - New insights on cytotoxic activity of group 3 and lanthanide compounds: complexes with [N,N,N]-scorpionate ligands. AB - OBJECTIVES: In this work was to evaluate the cytotoxic activity of a series of monomeric group 3 and lanthanide (N,N,N)-heteroscorpionate-triflate complexes (M (OTf) 2 (cybpamd) (THF)) (Ln = Sc (2), Y (3), La (4), Nd (5), Sm (6), Dy (7), Yb (8); OTf = SO3CF3; cybpamd = N, N'-dicyclohexyl-2,2-bis-(3,5-dimethyl-pyrazol-1 yl)-acetamidinate) having octahedral geometry around the metal atoms on the human epithelial lung adenocarcinoma (A549), human melanoma (A375), human cervical epithelial adenocarcinoma, human embryonic kidney (HEK-293) and murine macrophages (J774.A1) cell lines. METHODS: All the tested compounds were incubated with cells for 72 h and their growth inhibition assessed by using MTT assay. KEY FINDINGS: On the cell line HEK-293 complexes 5 and 7 show a reasonable activities, while the murine macrophage cell line (J774.A1), only the scandium 2 complex is not very active. All complexes tested are poorly active on human health adenocarcinoma lung epithelial (A549) and human melanoma (A375). CONCLUSIONS: The group 3 and lanthanide (N,N,N)-heteroscorpionate triflate complexes (M(OTf)2(cybpamd)(THF)) on murine macrophage (J774.A1) cell line, except that of scandium, show a reasonable activity. On human epithelial cervix adenocarcinoma (HeLa) complexes 3, 5 and 6 are significantly more active than cis platinum, as well as complex 5 is more active on human embryonic kidney (HEK-293) cell line. All the tested complexes are poorly active on human epithelial lung adenocarcinoma (A549) and human melanoma (A375). The different behaviour of the complexes examined (2-8) let us hypothesize that the cytotoxic activity is related to the molecule as a whole and not only to the ligand or the metal ion separately. PMID- 23927475 TI - Hypoxia alters pharmacokinetics of argirein because of mitochondrial dysfunction that is alleviated by apocynin. AB - OBJECTIVES: Pharmacokinetics (PK) of argirein might be changed in response to mitochondrial (MITO) dysfunction and activated nicotinamide adenine dinucleotide phosphate oxidase (NOX) on hypoxia. We hypothesized that hypoxic changes in MITO and NOX could alter PK and tissue distribution of argirein. We tested if these changes in PK of argirein by hypoxia could be relieved by apocynin (APO), a blocker of NOX, through normalizing MITO and NOX. METHODS: Male Sprague-Dawley rats were exposed to hypoxia (O2 10% +/- 5% 8 h per day) for 7 days and treated with APO (80 mg/kg, i.g.) in the last 4 days. The PK and tissue distribution of argirein were monitored by measuring its main metabolite rhein using HPLC analysis. Manganese superoxide dismutase (MnSOD) and NOX were assayed. KEY FINDINGS: The PK parameters and concentrations of rhein in the kidney, liver, heart and testes were significantly altered under hypoxia, accompanied with a reduced MnSOD and upregulated NOX compared with the normal. Altered argirein PK and distribution in these organs were relieved following APO administration. CONCLUSION: Abnormal PK and distribution of argirein by assaying its metabolite rhein are significant, consequent to hypoxic injury that is significantly ameliorated by APO through normalizing MITO and NOX. PMID- 23927476 TI - Gualou Xiebai Decoction prevents myocardial fibrosis by blocking TGF-beta/Smad signalling. AB - OBJECTIVES: The present study is aimed to investigate the effect of Gualou Xiebai Decoction (GXD) ethanol extract on myocardial fibrosis and clarify the possible mechanism. METHODS: Rats with ligated left anterior descending coronary artery were treated with GXD ethanol extract (1.14 g/kg, 2.27 g/kg, 4.53 g/kg) daily via gavage for 4 weeks. Histopathological changes and collagen distribution were evaluated by haematoxylin and eosin and Masson staining. The mRNA levels of Collagen I and Collagen III were detected by real-time PCR. The expressions of TGF-beta1, TGFbeta receptor (TGFbetaR)I, TGFbetaRII, P-Smad2/3 and Smad7 were determined by Western blot. RESULTS: GXD treatment was significantly reduced the heart weight/body weight ratio (P < 0.05) as well as the left ventricle weight/body weight ratio (P < 0.05). It also significantly alleviated the degree of inflammation, decreased myocardial collagen volume fraction (P < 0.05 ~ 0.01), together with markedly prevented the upregulations of Collagen I and Collagen III (P < 0.05 ~ 0.01). Moreover, GXD downregulated expressions of TGF-beta1, TGFbetaRI, TGFbetaRII, Smad2/3 whereas improved Smad7 expression in the myocardial fibrosis rats. CONCLUSIONS: GXD ameliorates myocardial fibrosis induced by cardiac infarction with ligated left anterior descending coronary artery, the mechanism maybe involve in inhibiting the TGF-beta1 signalling pathway. PMID- 23927477 TI - Enhanced intestinal absorption activity and hepatoprotective effect of herpetrione via preparation of nanosuspensions using pH-dependent dissolving precipitating/homogenization process. AB - OBJECTIVES: The main purpose of this study was to enhance the intestinal absorption activity and hepatoprotective effect of herpetrione by drug nanosuspensions. METHODS: Herpetrione nanosuspensions (HNS) were prepared using pH-dependent dissolving-precipitating/homogenization process and then systematically characterized. The intestinal absorption activity of HNS were studied using the recirculating perfusion technique in comparison with herpetrione coarse suspensions (HCS) and pure herpetrione using the recirculating perfusion technique. The protective effect of HNS against acute liver injury induced by carbon tetrachloride (CCl4 ) in mice was also investigated and compared with that of HCS. KEY FINDINGS: The mean particle size of HNS was 269 +/ 7 nm with a polydispersity index of 0.187 +/- 0.021. The result of X-ray powder diffraction indicated that herpetrione was in amorphous state in both coarse powder and nanosuspensions. The intestinal absorption activity of HNS were superior to the HCS and pure herpetrione. As evidenced by the lowering of serum aminotransferase levels and the improvement of the degree of liver lesion, pretreatment with HNS markedly enhanced the hepatoprotective effect of herpetrione against acute liver injury induced by CCl4 in mice. CONCLUSION: HNS prepared using pH-dependent dissolving-precipitating/homogenization technique are able to significantly enhance the intestinal absorption activity and the hepatoprotective effect of herpetrione due to the particle size reduction. PMID- 23927478 TI - Compounds isolated from Psoralea corylifolia seeds inhibit protein kinase activity and induce apoptotic cell death in mammalian cells. AB - OBJECTIVES: Psoralea corylifolia is a plant widely used in traditional Chinese medicine, e.g. for its chemopreventive effect. To identify active substances responsible for this effect, we investigated pharmacological effects of 11 compounds isolated from the seeds of this plant (newly described substances: 7, 2', 4'-trihydroxy-3-arylcoumarin and psoracoumestan). METHODS: The influence of distinct compounds on different signal transduction pathways (cell proliferation, survival, angiogenesis and metastasis) was screened via analysis of the activity of 24 protein kinases, mitogen activated protein kinase phosphorylation via Western blot, cytotoxicity was shown using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay and determination of caspase activity. Oxidative stress was detected via 2',7'-dichlorofluorescein fluorescence. KEY FINDINGS: Some compounds showed cytotoxic effects (H4IIE, Hct116, C6 cells) mainly mediated via induction of apoptosis. Distinct compounds caused a strong inhibition of MAPK/ERK kinase (MEK) phosphorylation, weak effects on extracellular-signal regulated kinase (ERK) phosphorylation and no significant effect on p38 and c-Jun amino-terminal kinase. Corylifol C and, to a lesser extent, xanthoangelol are potent protein kinase inhibitors (inhibitory concentration 50% values for epidermal growth factor receptor (EGFR): 1.1 and 4.4 * 10(-6) MUg/ml, respectively). Because EGFR, MEK and ERK are kinases involved in cellular proliferation, an inhibition of these enzymes may be useful to cause chemopreventive effects. CONCLUSIONS: Distinct compounds isolated from P. corylifolia showed a high potential to influence cellular pathways, e.g. by inhibition of protein kinases that may be interesting for pharmacological purposes. PMID- 23927479 TI - Nephroprotective effects of Isaria felina in rats with adenine-induced chronic renal failure. AB - OBJECTIVE: Chronic renal failure (CRF) is a progressive, life-threatening condition with limited treatment options. Cordyceps sinensis is a fungus that has nephroprotective effects, and Isaria felina (IF) is a fungus isolated from C. sinensis fruiting bodies. We evaluated IF efficacy using an adenine-induced CRF animal model. METHODS: Forty male Sprague-Dawley rats were divided into normal control (n = 8) and adenine groups (n = 32; 100 mg/kg for 30 days). The adenine group was subdivided into a model control group (n = 7), a positive control group (200 mg/kg Jinshuibao capsule (JSB; n = 8), and two IF groups (200 mg/kg, n = 8; 100 mg/kg, n = 8). After treatment for 30 days, animals were narcotized and abdominal aortic blood was analysed. Kidney functions were evaluated. KEY FINDINGS: Higher serum creatinine, blood urea nitrogen and uric acid levels, and lower creatinine clearance was observed in the model control group compared with JSB and IF groups (P < 0.05). Red blood cell count, haemoglobin and haematocrit levels in the 200 mg/kg IF group were higher than in the model control group (P < 0.05). Transforming growth factor-beta1 mRNA expression in the model control group was higher than the normal control and 200 mg/kg IF groups (P < 0.05). Epidermal growth factor mRNA in the model control group was lower than in the normal control and both IF-treated groups (P < 0.05). Structural renal damage was observed in all adenine-treated rats, but was less severe in the JSB and IF groups. CONCLUSION: IF may reverse the damaged kidney functions-induced with adenine in rats. PMID- 23927480 TI - Antitumour and free radical scavenging effects of gamma-mangostin isolated from Garcinia mangostana pericarps against hepatocellular carcinoma cell. AB - OBJECTIVES: Liver cancer is one of the highest rate diseases in southeastern Asia. Recently, many of functional foods and alternative medicines are very popularly utilized to prevent chronic diseases and cancer in Taiwan. In this study, we wanted to select and develop some of novel effectual agents or phytochemicals of gamma-mangostin for clinical management or prevent hepatocellular carcinoma cell (HCC). METHODS: Lipid peroxidation (LPO) is an autocatalytic mechanism which induced tissue injure and carcinogenesis. In this study, the inhibitory activity of gamma-mangostin on oxidative damage induced rat mitochondria LPO, the free radical scavenging of gamma-mangostin and the apoptotic effects of gamma-mangostin on HepG2 cells were investigated. KEY FINDINGS: gamma-Mangostin processed activity to inhibit LPO and scavenge 2,2 diphenyl-1-picrylhydrazyl. gamma-Mangostin showed antiproliferative activity and induced nuclear condensation and apoptotic bodies appearance under Giemsa staining by microscopic observation. In addition, gamma-mangostin showed increases of hypodiploid cells via propidium iodide, 2'7'-dichlorofluorescein diacetate, and 3,3'-dihexyloxacarbocyanine iodide staining by flow cytometry analysis in HepG2 cells. CONCLUSIONS: gamma-Mangostin has demonstrated free radical scavenging activity, and antiproliferative and apoptotic activity in HepG2 cells. The proof suggests that gamma-mangostin is a lead compound candidate for clinical management or prevent HCC. PMID- 23927481 TI - Efficacy of gemcitabine-based chemotherapy in metastatic breast cancer: a meta analysis of randomized controlled trials. AB - OBJECTIVES: To compare the effects of gemcitabine-based chemotherapy and gemcitabine-free regimens, a meta-analysis of all relevant randomized controlled trials was performed to investigate the improvement in overall response rate (ORR), time to progression (TTP), and overall survival (OS). A subgroup of gemcitabine-based doublet compared with single agent was also analyzed. METHODS: The PubMed and Embase databases were searched for relevant publications reporting randomized controlled trials comparing gemcitabine-based chemotherapy and gemcitabine-free regimens between January 1990 and December 2012. Hazard ratios (HRs) with their 95% confidence intervals (CIs), or data for calculating HRs with 95% CI were derived. RESULTS: Nine trials with a total of 2651 patients were included in this meta-analysis. Compared with gemcitabine-free chemotherapy, gemcitabine-based therapy demonstrated no improvement in terms of ORR (HR 1.09, 95% CI 0.73-1.62; P = 0.67), TTP (HR 0.91, 95% CI 0.72-1.15; P = 0.44) and OS (HR 1.05, 95% CI 0.88-1.25; P = 0.60). In a subgroup including patients who received adjuvant chemotherapy containing anthracyclines or taxanes, sub-analysis assessment revealed that gemcitabine-based doublets were superior to monotherapy in ORR (HR 1.64, 95% CI 1.26-2.12; P = 0.0002) and TTP (HR 0.71, 95% CI 0.62 0.81; P < 0.00001), but no benefit was observed for OS (HR 0.90, 95% CI 0.79 1.03; P = 0.14). The rates of grade 3 and 4 anemia (HR 2.02, 95% CI 1.35-3.02; P = 0.006), neutropenia (HR 2.33, 95% CI 1.37-3.63; P = 0.01), and thrombocytopenia (HR 8.31, 95% CI 5.00-13.82; P < 0.0001) were significantly higher in the gemcitabine-based arm. CONCLUSIONS: The present study suggests that gemcitabine based chemotherapy was as effective as gemcitabine-free chemotherapy in patients with metastatic breast cancer with increased hematological toxicity. Subgroup analysis indicated that adding gemcitabine to monotherapy might be more effective. PMID- 23927482 TI - Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: potential for new antibacterial agents. AB - Escherichia coli (Ec) cells possess two purine salvage enzymes: xanthine-guanine phosphoribosyltransferase (XGPRT) and hypoxanthine phosphoribosyltransferase (HPRT). EcXGPRT shares a common structural feature with other members of this family, a flexible loop that closes over the active site during catalysis. The replacement of six of these amino acids by alanine has no effect on the Km for the two substrates. However, the Ki for the nucleoside monophosphate increases by 27-fold, and the kcat is reduced by ~200-fold. Nucleoside phosphonates (NP) are good inhibitors of EcXGPRT and EcHPRT, with Ki values as low as 10 nM. In the absence of the flexible loop, these values increase by 5- to 30-fold, indicating the importance of the loop for high-affinity inhibition. Crystal structures of two NPs in complex with EcXGPRT explain the tight binding. Prodrugs of NPs with low Ki values for EcXGPRT or EcHPRT exhibit IC50 values between 5 and 23 MUM against Mycobacterium tuberculosis in cell-based assays, suggesting that these compounds are therapeutic leads against pathogenic bacteria. PMID- 23927483 TI - The effect of different meal compositions on the oral bioavailability of treprostinil diolamine in healthy volunteers. AB - WHAT IS KNOWN: Treprostinil diolamine (oral treprostinil) is a prostacyclin analogue currently being evaluated for the treatment of pulmonary arterial hypertension as a sustained-release (SR) oral tablet. Previous data have demonstrated that the oral bioavailability of treprostinil was improved when taken with a meal containing at least 500 calories. OBJECTIVE: As twice-daily intake of a high-fat, high-calorie meal may be undesirable or not feasible for some patients, this open-label, randomized, crossover study evaluated the effect of different meal compositions [a 500-calorie well-balanced meal (WB500), a 250 calorie well-balanced meal (WB250), a 250-calorie high-fat meal (HF250) and a 250 calorie well-balanced liquid meal (Ensure(r))] on the relative bioavailability of oral treprostinil. METHODS: Thirty-two healthy volunteers were administered a single 1-mg SR tablet of oral treprostinil immediately following each study meal. Each dose of oral treprostinil was separated by a 7-day washout period. Serial plasma samples were obtained over a 36-h postdose. Safety was assessed in all patients who received study drug. RESULTS AND DISCUSSION: Treprostinil plasma exposure (Cmax and AUC0-inf) decreased only slightly, 5-15% with decreasing caloric and increasing fat content. Headache was the most commonly reported prostacyclin-related adverse event (three reports). WHAT IS NEW AND CONCLUSION: Overall, there were no clinically significant differences in the relative bioavailability of oral treprostinil when administered immediately after meals containing 250-500 calories and 30-50% fat. These data support the administration of oral treprostinil with a meal containing as few as 250 calories and 30-50% fat, which is significant for ensuring patient convenience and compliance, particularly as consistency with regard to meals may impact oral treprostinil pharmacokinetics. PMID- 23927484 TI - Morphine regulates Argonaute 2 and TH expression and activity but not miR-133b in midbrain dopaminergic neurons. AB - Epigenetic changes such as microRNAs (miRs)/Ago2-induced gene silencing represent complex molecular signature that regulate cellular plasticity. Recent studies showed involvement of miRs and Ago2 in drug addiction. In this study, we show that changes in gene expression induced by morphine and morphine withdrawal occur with concomitant epigenetic modifications in the mesolimbic dopaminergic (DA) pathway [ventral tegmental area (VTA)/nucleus accumbens (NAc) shell], which is critically involved in drug-induced dependence. We found that acute or chronic morphine administration as well as morphine withdrawal did not modify miR-133b messenger RNA (mRNA) expression in the VTA, whereas Ago2 protein levels were decreased and increased in morphine-dependent rats and after morphine withdrawal, respectively. These changes were paralleled with enhanced and decreased NAc tyrosine hydroxylase (TH) protein (an early DA marker) in morphine-dependent rats and after withdrawal, respectively. We also observed changes in TH mRNA expression in the VTA that could be related to Ago2-induced translational repression of TH mRNA during morphine withdrawal. However, the VTA number of TH positive neurons suffered no alterations after the different treatment. Acute morphine administration produced a marked increase in TH activity and DA turnover in the NAc (shell). In contrast, precipitated morphine withdrawal decreased TH activation and did not change DA turnover. These findings provide new information into the possible correlation between Ago2/miRs complex regulation and DA neurons plasticity during opiate addiction. PMID- 23927485 TI - Ethanolamine oleate as a novel therapy is effective in resistant idiopathic achalasia. AB - Idiopathic achalasia (IA) is a primary motor disorder of the esophagus. Recently, ethanolamine oleate (EO) has been introduced as a novel therapy in IA. We investigate the long-term efficacy of EO injection in the selected IA patients. Two hundred twenty patients with IA were evaluated prospectively. Thirty-one patients who were resistant to or poor candidate of pneumatic balloon dilation and/or cardiomyotomy were enrolled in this study. EO was injected into the lower esophageal sphincter three times at 2-week intervals. Patients were evaluated with the achalasia symptom score (ASS), timed barium esophagogram, and manometry before and after the injections. A good response was defined as a greater than 50% reduction from baseline in the ASS, height and/or volume of barium in TBE, and absence of severe dysphagia or regurgitation at 1.5 months after the last injection. Relapse was defined as two or more points increase in dysphagia score after an initial good response. The mean age of patients was 49.32 +/- 19.3 years. Twenty-nine patients had a good response and two had a poor response. The mean ASS decreased from 12.48 (+/-2.06) to 4.50 (+/-2.96) (P = 0.0001), and the mean volume of barium decreased from 115.35 (+/-93.40) to 45.50 (+/-60.86) mL at 1.5 months after the last injection (P = 0.0001).The mean lower esophageal sphincter pressure was 30.47 +/- 13.95 before the treatment and decreased to 14.30 +/- 11.89 at 1.5 months after the treatment. (P = 0.0001). The mean duration of follow up was 30.16 +/- 11.3 (18-68) months. Twelve patients in whom symptoms relapsed were treated effectively with reinjection. In some patients, minor complications (chest pain and erosion in the distal esophagus) occurred. This study indicates that EO has a long-term effect and can be considered for use in the selected IA patients. PMID- 23927486 TI - Quorum sensing influences growth and photosynthetic membrane production in high cell-density cultivations of Rhodospirillum rubrum. AB - BACKGROUND: The facultative anoxygenic photosynthetic bacterium Rhodospirillum rubrum exhibits versatile metabolic activity allowing the adaptation to rapidly changing growth conditions in its natural habitat, the microaerobic and anoxic zones of stagnant waters. The microaerobic growth mode is of special interest as it allows the high-level expression of photosynthetic membranes when grown on succinate and fructose in the dark, which could significantly simplify the industrial production of compounds associated with PM formation. However, recently we showed that PM synthesis is no longer inducible when R. rubrum cultures are grown to high cell densities under aerobic conditions. In addition a reduction of the growth rate and the continued accumulation of precursor molecules for bacteriochlorophyll synthesis were observed under high cell densities conditions. RESULTS: In the present work, we demonstrate that the cell density-dependent effects are reversible if the culture supernatant is replaced by fresh medium. We identified six N-acylhomoserine lactones and show that four of them are produced in varying amounts according to the growth phase and the applied growth conditions. Further, we demonstrate that N-acylhomoserine lactones and tetrapyrrole compounds released into the growth medium affect the growth rate and PM expression in high cell density cultures. CONCLUSIONS: In summary, we provide evidence that R. rubrum possesses a Lux-type quorum sensing system which influences the biosynthesis of PM and the growth rate and is thus likely to be involved in the phenotypes of high cell density cultures and the rapid adaptation to changing environmental conditions. PMID- 23927487 TI - Ophthalmic support in developing countries. PMID- 23927488 TI - Suppression of phagosome proteolysis and Matrigel migration with the alpha2 adrenergic receptor agonist dexmedetomidine in murine dendritic cells. AB - Dexmedetomidine is a highly-selective alpha2-adrenergic receptor agonist used for sedation of critically ill patients in an intensive care setting. Dendritic cells (DCs) in peripheral tissues sense certain foreign antigens and ingest and process them, while migrating to the regional lymph node. Then, DCs present the processed antigen on their surface to stimulate the clonal proliferation of cognitive lymphocytes, leading to the establishment of adaptive immunity. In murine bone marrow-derived DCs, dexmedetomidine significantly delayed the intracellular proteolytic degradation of ovalbumin, while it did not affect phagocytosis, decreased the expression of the surface molecules I-A(b) and CD86, and suppressed cognitive helper T-cell proliferation. Furthermore, dexmedetomidine significantly suppressed DC migration both in vitro, using a Matrigel migration assay, and in vivo, using a foot pad-popliteal lymph node migration assay, which may be ascribed to the inhibition of type IV collagenase/gelatinase activity. Finally, vaccination with dexmedetomidine-treated DCs significantly suppressed the contact hypersensitivity reaction in vivo. These results indicate that dexmedetomidine may suppress immunity by inhibiting DC antigen processing/presentation and migration. PMID- 23927489 TI - The mouse and ferret models for studying the novel avian-origin human influenza A (H7N9) virus. AB - BACKGROUND: The current study was conducted to establish animal models (including mouse and ferret) for the novel avian-origin H7N9 influenza virus. FINDINGS: A/Anhui/1/2013 (H7N9) virus was administered by intranasal instillation to groups of mice and ferrets, and animals developed typical clinical signs including body weight loss (mice and ferrets), ruffled fur (mice), sneezing (ferrets), and death (mice). Peak virus shedding from respiratory tract was observed on 2 days post inoculation (d.p.i.) for mice and 3-5 d.p.i. for ferrets. Virus could also be detected in brain, liver, spleen, kidney, and intestine from inoculated mice, and in heart, liver, and olfactory bulb from inoculated ferrets. The inoculation of H7N9 could elicit seroconversion titers up to 1280 in ferrets and 160 in mice. Leukopenia, significantly reduced lymphocytes but increased neutrophils were also observed in mouse and ferret models. CONCLUSIONS: The mouse and ferret model enables detailed studies of the pathogenesis of this illness and lay the foundation for drug or vaccine evaluation. PMID- 23927490 TI - Shared decision making for patients with type 2 diabetes: a randomized trial in primary care. AB - BACKGROUND: Patient-centered diabetes care requires shared decision making (SDM). Decision aids promote SDM, but their efficacy in nonacademic and rural primary care clinics is unclear. METHODS: We cluster-randomized 10 practices in a concealed fashion to implement either a decision aid (DA) about starting statins or one about choosing antihyperglycemic agents. Each practice served as a control group for another practice implementing the other type of DA. From April 2011 to July 2012, 103 (DA=53) patients with type 2 diabetes participated in the trial. We used patient and clinician surveys administered after the clinical encounter to collect decisional outcomes (patient knowledge and comfort with decision making, patient and clinician satisfaction). Medical records provided data on metabolic control. Pharmacy fill profiles provided data for estimating adherence to therapy. RESULTS: Compared to usual care, patients receiving the DA were more likely to report discussing medications (77% vs. 45%, p<.001), were more likely to answer knowledge questions correctly (risk reduction with statins 61% vs. 33%, p=.07; knowledge about options 57% vs. 33%, p=.002) and were more engaged by their clinicians in decision making (50. vs. 28, difference 21.4 (95% CI 6.4, 36.3), p=.01). We found no significant impact on patient satisfaction, medication starts, adherence or clinical outcomes, in part due to limited statistical power. CONCLUSION: DAs improved decisional outcomes without significant effect on clinical outcomes. DAs designed for point-of-care use with type 2 diabetes patients promoted shared decision making in nonacademic and rural primary care practices. TRIAL REGISTRATION: NCT01029288. PMID- 23927491 TI - Translation enhancer improves the ribosome liberation from translation initiation. AB - For translation initiation in bacteria, the Shine-Dalgarno (SD) and anti-SD sequence of the 30S subunit play key roles for specific interactions between ribosomes and mRNAs to determine the exact position of the translation initiation region. However, ribosomes also must dissociate from the translation initiation region to slide toward the downstream sequence during mRNA translation. Translation enhancers upstream of the SD sequences of mRNAs, which likely contribute to a direct interaction with ribosome protein S1, enhance the yields of protein biosynthesis. Nevertheless, the mechanism of the effect of translation enhancers to initiate the translation is still unknown. In this paper, we investigated the effects of the SD and enhancer sequences on the binding kinetics of the 30S ribosomal subunits to mRNAs and their translation efficiencies. mRNAs with both the SD and translation enhancers promoted the amount of protein synthesis but destabilized the interaction between the 30S subunit and mRNA by increasing the dissociation rate constant (koff) of the 30S subunit. Based on a model for kinetic parameters, a 16-fold translation efficiency could be achieved by introducing a tandem repeat of adenine sequences (A20) between the SD and translation enhancer sequences. Considering the results of this study, translation enhancers with an SD sequence regulate ribosomal liberation from translation initiation to determine the translation efficiency of the downstream coding region. PMID- 23927492 TI - GFI1B mutation causes a bleeding disorder with abnormal platelet function. AB - BACKGROUND: GFI1B is a transcription factor important for erythropoiesis and megakaryocyte development but previously unknown to be associated with human disease. METHODS: A family with a novel bleeding disorder was identified and characterized. Genetic linkage analysis and massively parallel sequencing were used to localize the mutation causing the disease phenotype on chromosome 9. Functional studies were then performed in megakaryocytic cell lines to determine the biological effects of the mutant transcript. RESULTS: We have identified a family with an autosomal dominant bleeding disorder associated with macrothrombocytopenia, red cell anisopoikilocytosis, and platelet dysfunction. The severity of bleeding is variable with some affected individuals experiencing spontaneous bleeding while other family members exhibit only abnormal bleeding with surgery. A single nucleotide insertion was identified in GFI1B that predicts a frameshift mutation in the fifth zinc finger DNA-binding domain. This mutation alters the transcriptional activity of the protein, resulting in a reduction in platelet alpha-granule content and aberrant expression of key platelet proteins. CONCLUSIONS: GFI1B mutation represents a novel human bleeding disorder, and the described phenotype identifies GFI1B as a critical regulator of platelet shape, number, and function. PMID- 23927493 TI - Coupling of random amplified polymorphic DNA profiles analysis and high resolution capillary electrophoresis system for the assessment of chemical genotoxicity. AB - Cadmium (Cd) can be toxic to terrestrial snails, but few data are available about its genotoxic effects on early life stages (ELS). The aim of this study was to investigate the genotoxic potential of Cd in embryos of Helix aspersa using a new approach that couples Random Amplified Polymorphic DNA (RAPD) and a high resolution capillary electrophoresis system (HRS). Clutches of H. aspersa were exposed to Cd solutions (2, 4, and 6 mg/L) from the beginning of their embryonic development. In addition to a dose-dependent effect of Cd on hatching rate, DNA fragmentation was observed in embryos that were exposed to 6 mg Cd/L. The analysis of RAPD products with HRS showed differences between the profiles of exposed and nonexposed embryos, starting at 2 mg Cd/L. In comparison to the profiles of the control samples, all profiles from the exposed snails exhibited an additional 270 bp DNA fragment and lacked a 450 bp DNA fragment. These profile modifications are related to the genotoxic effect of Cd on the ELS of H. aspersa . Our study demonstrates the efficacy of coupling RAPD and HRS for a rapid and efficient screening of the effects of chemicals on DNA. PMID- 23927494 TI - Metal-organic pathways for anisotropic growth of a highly symmetrical crystal structure: example of the fcc Ni. AB - The control of the metallic nanocrystal shape is of prime importance for a wide variety of applications. We report a detailed research work on metal-organic chemical routes for the synthesis of a highly symmetrical crystal structure. In particular, this study shows the key parameters ensuring the anisotropic growth of nickel nanostructures (fcc crystal). Numerous reaction conditions are investigated (precursors, solvents, temperature, reducing agents, reaction time, and types and ratios of surfactants, such as alkyl amines, carboxylic acids, and phosphine oxides), and their effects on the size and shape of the final product are reported. The role of the growth modifiers and the structuring of the reaction media on the anisotropic growth are demonstrated. This metal-organic approach generates several novel anisotropic nanostructures in a wide size range depending on the reaction conditions. In this way, nanomaterials with reproducible size, shape, and composition are obtained with good yield. Transmission electron microscopy techniques (TEM and HRTEM) are the principal methods for monitoring the morphology. PMID- 23927495 TI - Effect of surface energy on dispersion and mechanical properties of polymer/nanocrystalline cellulose nanocomposites. AB - Dispersion quality and polymer-filler interaction are important factors in determining the final properties of polymer nanocomposites. Surface energy of nanocrystalline cellulose (NCC) and some polymers (polypropylene, PP, and polylactic acid, PLA) was measured at room and high temperatures. NCC had higher polarity and surface energy than PP and PLA at room temperature but had a lower surface energy at higher temperatures. The effect of surface modification with alkenyl succinic anhydride (ASA) on NCC surface energy at room and high temperature was studied. Total surface energy of NCC was lowered after surface modification. Thermodynamic work of adhesion for PP/NCC and PLA/NCC was lowered by NCC surface modification. A thermodynamic analysis is proposed to estimate the dispersion energy, based on surface energy measurements at room and high temperatures. Also, a dispersion factor is defined to provide a quantitative indication of the dispersibility of nanoparticles in a polymer matrix under various conditions. The required dispersion energy was reduced by lowering the interfacial tension. On the other hand, it increased as the quality of NCC dispersion (i.e., the nanoparticle surface area) in the system was improved. Surface modification of NCC with ASA had a negative effect on the compatibility between NCC and PLA, whereas it had a positive influence on compatibility between PP and NCC. PMID- 23927496 TI - Hyperoxia-triggered aversion behavior in Drosophila foraging larvae is mediated by sensory detection of hydrogen peroxide. AB - Reactive oxygen species (ROS) in excess have been implicated in numerous chronic illnesses, including asthma, diabetes, aging, cardiovascular disease, and neurodegenerative illness. However, at lower concentrations, ROS can also serve essential routine functions as part of cellular signal transduction pathways. As products of atmospheric oxygen, ROS-mediated signals can function to coordinate external environmental conditions with growth and development. A central challenge has been a mechanistic distinction between the toxic effects of oxidative stress and endogenous ROS functions occurring at much lower concentrations. Drosophila larval aerotactic behavioral assays revealed strong developmentally regulated aversion to mild hyperoxia mediated by H2O2-dependent activation of class IV multidendritic (mdIV) sensory neurons expressing the Degenerin/epithelial Na(+) channel subunit, Pickpocket1 (PPK1). Electrophysiological recordings in foraging-stage larvae (78-84 h after egg laying [AEL]) demonstrated PPK1-dependent activation of mdIV neurons by nanomolar levels of H2O2 well below levels normally associated with oxidative stress. Acute sensitivity was reduced > 100-fold during the larval developmental transition to wandering stage (> 96 h AEL), corresponding to a loss of hyperoxia aversion behavior during the same period. Degradation of endogenous H2O2 by transgenic overexpression of catalase in larval epidermis caused a suppression of hyperoxia aversion behavior. Conversely, disruption of endogenous catalase activity using a UAS-CatRNAi transposon resulted in an enhanced hyperoxia-aversive response. These results demonstrate an essential role for low-level endogenous H2O2 as an environment-derived signal coordinating developmental behavioral transitions. PMID- 23927497 TI - Infrared photodissociation spectroscopy of vanadium oxide-carbonyl cations. AB - Mass selected vanadium oxide-carbonyl cations of the form VO(m)(CO)(n)(+) (m = 0 3 and n = 3-6) are studied via infrared laser photodissociation spectroscopy in the 600-2300 cm(-1) region. Insight into the structure and bonding of these complexes is obtained from the number of infrared active bands, their relative intensities and their frequency positions. Density functional theory calculations are carried out in support of the experimental data. The effect of oxidation on the carbonyl stretching frequencies of VO(CO)(n)(+), VO2(CO)(n)(+), and VO3(CO)(n)(+) complexes is investigated. All of these oxide-carbonyl species have C-O stretch vibrations blue-shifted from those of the pure vanadium ion carbonyls. The V-O stretches of these complexes are also investigated, revealing the effects of CO coordination on these vibrations. The oxide-carbonyls all have a hexacoordinate core analogous to that of V(CO)6(+). The fully coordinated vanadium monoxide-carbonyl species is VO(CO)5(+), and those of the dioxide and trioxide are VO2(CO)4(+) and VO3(CO)3(+), respectively. PMID- 23927498 TI - Late-glacial recolonization and phylogeography of European red deer (Cervus elaphus L.). AB - The Pleistocene was an epoch of extreme climatic and environmental changes. How individual species responded to the repeated cycles of warm and cold stages is a major topic of debate. For the European fauna and flora, an expansion-contraction model has been suggested, whereby temperate species were restricted to southern refugia during glacial times and expanded northwards during interglacials, including the present interglacial (Holocene). Here, we test this model on the red deer (Cervus elaphus) a large and highly mobile herbivore, using both modern and ancient mitochondrial DNA from the entire European range of the species over the last c. 40,000 years. Our results indicate that this species was sensitive to the effects of climate change. Prior to the Last Glacial Maximum (LGM) haplogroups restricted today to South-East Europe and Western Asia reached as far west as the UK. During the LGM, red deer was mainly restricted to southern refugia, in Iberia, the Balkans and possibly in Italy and South-Western Asia. At the end of the LGM, red deer expanded from the Iberian refugium, to Central and Northern Europe, including the UK, Belgium, Scandinavia, Germany, Poland and Belarus. Ancient DNA data cannot rule out refugial survival of red deer in North West Europe through the LGM. Had such deer survived, though, they were replaced by deer migrating from Iberia at the end of the glacial. The Balkans served as a separate LGM refugium and were probably connected to Western Asia with genetic exchange between the two areas. PMID- 23927499 TI - Comparison of LiVPO4F to Li4Ti5O12 as anode materials for lithium-ion batteries. AB - In this paper, we reported on a comparison of LiVPO4F to Li4Ti5O12 as anode materials for lithium-ion batteries. Combined with powder X-ray diffraction, scanning electron microscopy, high-resolution transmission electron microscopy, galvanostatic discharge/charge tests and in situ X-ray diffraction technologies, we explore and compare the insertion/extraction mechanisms of LiVPO4F based on the V3+/V2+/V+ redox couples and Li4Ti5O12 based on the Ti4+/Ti3+ redox couple cycled in 1.0-3.0 V and 0.0-3.0 V. The electrochemical results indicate that both LiVPO4F and Li4Ti5O12 are solid electrolyte interphase free materials in 1.0-3.0 V. The insertion/extraction mechanisms of LiVPO4F and Li4Ti5O12 are similar with each other in 1.0-3.0 V as proved by in situ X-ray diffraction. It also demonstrates that both samples possess stable structure in 0.0-3.0 V. Additionally, the electrochemical performance tests of LiVPO4F and Li4Ti5O12 indicate that both samples cycled in 0.0-3.0 V exhibit much higher capacities than those cycled in 1.0-3.0 V but display worse cycle performance. The rate performance of Li4Ti5O12 far exceeds that of LiVPO4F in the same electrochemical potential window. In particular, the capacity retention of Li4Ti5O12 cycled in 1.0-3.0 V is as high as 98.2% after 20 cycles. By contrast, Li4Ti5O12 is expected to be a candidate anode material considering its high working potential, structural zero-strain property, and excellent cycle stability and rate performance. PMID- 23927500 TI - BCR-ABL1 molecular remission after 90Y-epratuzumab tetraxetan radioimmunotherapy in CD22+ Ph+ B-ALL: proof of principle. AB - Although targeted therapies are used increasingly in hematologic malignancies, we are unaware of any prior studies of radioimmunotherapy (RAIT) in B-acute lymphoblastic leukemia (ALL), even though this radiosensitive tumor expresses CD22, potentially a good target for this approach. Here, we report a patient with Philadelphia chromosome-positive B-ALL in third relapse who received RAIT with (90) yttrium ((90) Y)-labeled anti-CD22 epratuzumab tetraxetan. Seven weeks after initiating therapy, the patient achieved a BCR-ABL1 molecular remission documented by RT-qPCR, which is now continuing at 6 months while awaiting an allogeneic hematopoietic stem cell transplant. (90) Y-Epratuzumab tetraxetan may be a promising therapeutic option for CD22(+) B-ALL patients. PMID- 23927501 TI - Why it is hard to find genes associated with social science traits: theoretical and empirical considerations. AB - OBJECTIVES: We explain why traits of interest to behavioral scientists may have a genetic architecture featuring hundreds or thousands of loci with tiny individual effects rather than a few with large effects and why such an architecture makes it difficult to find robust associations between traits and genes. METHODS: We conducted a genome-wide association study at 2 sites, Harvard University and Union College, measuring more than 100 physical and behavioral traits with a sample size typical of candidate gene studies. We evaluated predictions that alleles with large effect sizes would be rare and most traits of interest to social science are likely characterized by a lack of strong directional selection. We also carried out a theoretical analysis of the genetic architecture of traits based on R.A. Fisher's geometric model of natural selection and empirical analyses of the effects of selection bias and phenotype measurement stability on the results of genetic association studies. RESULTS: Although we replicated several known genetic associations with physical traits, we found only 2 associations with behavioral traits that met the nominal genome-wide significance threshold, indicating that physical and behavioral traits are mainly affected by numerous genes with small effects. CONCLUSIONS: The challenge for social science genomics is the likelihood that genes are connected to behavioral variation by lengthy, nonlinear, interactive causal chains, and unraveling these chains requires allying with personal genomics to take advantage of the potential for large sample sizes as well as continuing with traditional epidemiological studies. PMID- 23927502 TI - Gene-environment correlation: difficulties and a natural experiment-based strategy. AB - OBJECTIVES: We explored how gene-environment correlations can result in endogenous models, how natural experiments can protect against this threat, and if unbiased estimates from natural experiments are generalizable to other contexts. METHODS: We compared a natural experiment, the College Roommate Study, which measured genes and behaviors of college students and their randomly assigned roommates in a southern public university, with observational data from the National Longitudinal Study of Adolescent Health in 2008. We predicted exposure to exercising peers using genetic markers and estimated environmental effects on alcohol consumption. A mixed-linear model estimated an alcohol consumption variance that was attributable to genetic markers and across peer environments. RESULTS: Peer exercise environment was associated with respondent genotype in observational data, but not in the natural experiment. The effects of peer drinking and presence of a general gene-environment interaction were similar between data sets. CONCLUSIONS: Natural experiments, like random roommate assignment, could protect against potential bias introduced by gene-environment correlations. When combined with representative observational data, unbiased and generalizable causal effects could be estimated. PMID- 23927503 TI - Conceptual shifts needed to understand the dynamic interactions of genes, environment, epigenetics, social processes, and behavioral choices. AB - Social and behavioral research in public health is often intimately tied to profound, but frequently neglected, biological influences from underlying genetic, environmental, and epigenetic events. The dynamic interplay between the life, social, and behavioral sciences often remains underappreciated and underutilized in addressing complex diseases and disorders and in developing effective remediation strategies. Using a case-study format, we present examples as to how the inclusion of genetic, environmental, and epigenetic data can augment social and behavioral health research by expanding the parameters of such studies, adding specificity to phenotypic assessments, and providing additional internal control in comparative studies. We highlight the important roles of gene environment interactions and epigenetics as sources of phenotypic change and as a bridge between the life and social and behavioral sciences in the development of robust interdisciplinary analyses. PMID- 23927504 TI - How genes and the social environment moderate each other. AB - Recent research has suggested that the social environment can moderate the expression of genetic influences on health and that genetic influences can shape an individual's sensitivity to the social environment. Evidence supports 4 major mechanisms: genes can influence an individual's response to environmental stress, genes may enhance an individual's sensitivity to both favorable and adverse environments, inherited characteristics may better fit with some environments than with others, and inherited capabilities may only become manifest in challenging or responsive environments. Further progress depends on better recognition of patterns of gene-environment interaction, improved methods of assessing the environment and its impact on genetic mechanisms, the use of appropriately designed laboratory studies, identification of heritable differences in an individual before environmental moderation occurs, and clarification of the timing of the impact of social and genetic moderation. PMID- 23927505 TI - Social, behavioral, and genetic linkages from adolescence into adulthood. AB - The influence of genetic factors on health and behavior is conditioned by social, cultural, institutional, and physical environments in which individuals live, work, and play. We encourage studies supporting multilevel integrative approaches to understanding these contributions to health, and describe the Add Health study as an exemplar. Add Health is a large sample of US adolescents in grades 7 to 12 in 1994-1995 followed into adulthood with 4 in-home interviews and biomarker collections, including DNA. In addition to sampling multiple environments and measuring diverse social and health behavior, Add Health features a fully articulated behavioral genetic sample (3000 pairs) and ongoing genotyping of 12,000 archived samples. We illustrate approaches to understanding health through investigation of the interplay among biological, psychosocial, and physical, contextual, or cultural experiences. PMID- 23927506 TI - Social regulation of human gene expression: mechanisms and implications for public health. AB - Recent analyses have discovered broad alterations in the expression of human genes across different social environments. The emerging field of social genomics has begun to identify the types of genes sensitive to social regulation, the biological signaling pathways mediating these effects, and the genetic polymorphisms that modify their individual impact. The human genome appears to have evolved specific "social programs" to adapt molecular physiology to the changing patterns of threat and opportunity ancestrally associated with changing social conditions. In the context of the immune system, this programming now fosters many of the diseases that dominate public health. The embedding of individual genomes within a broader metagenomic network provides a framework for integrating molecular, physiologic, and social perspectives on human health. PMID- 23927507 TI - Genetic differential sensitivity to social environments: implications for research. AB - Researchers have proposed a genetic differential sensitivity to social environmental (GDSE) model positing that individuals with certain genetic makeups are more sensitive to favorable and unfavorable environmental influences than those without these genetic makeups. We discuss several issues facing researchers who want to use GDSE to examine health: (1) the need for greater theorizing about the social environment to properly understand the size and direction of environmental influences; (2) the potential for combining multiple genetic markers to measure an individual's genetic sensitivity to environmental influence; (3) how this model and exogenous shocks deal with gene-environment correlations; (4) implications of this model for public health and prevention; and (5) how life course and developmental theories may be used to inform GDSE research. PMID- 23927509 TI - Deep integration: letting the epigenome out of the bottle without losing sight of the structural origins of population health. AB - Advances in stress physiology and molecular dynamics can illuminate population health inequality. The "weathering" hypothesis posits that socially structured, repeated stress process activation can accumulate and increase disease vulnerability across the life course in marginalized groups. The developmental origins of health and disease (DOHaD) hypothesis focuses on youthful programming for later life disease via epigenetic modifications to limiting uterine or early environments. Weathering and DOHaD are overlapping biopsychosocial models; yet, their emphases and implications vary. Evidence for the primacy of early development over experiences in young through middle adulthood for explaining population health inequality is lacking. By considering weathering and DOHaD together, we call for biomedical researchers to be more cautious in their claims about the social world and for a broader range of social researchers--including qualitative ones--to collaborate with them. PMID- 23927508 TI - Assessment of genetic and nongenetic interactions for the prediction of depressive symptomatology: an analysis of the Wisconsin Longitudinal Study using machine learning algorithms. AB - OBJECTIVES: We examined depression within a multidimensional framework consisting of genetic, environmental, and sociobehavioral factors and, using machine learning algorithms, explored interactions among these factors that might better explain the etiology of depressive symptoms. METHODS: We measured current depressive symptoms using the Center for Epidemiologic Studies Depression Scale (n = 6378 participants in the Wisconsin Longitudinal Study). Genetic factors were 78 single nucleotide polymorphisms (SNPs); environmental factors-13 stressful life events (SLEs), plus a composite proportion of SLEs index; and sociobehavioral factors-18 personality, intelligence, and other health or behavioral measures. We performed traditional SNP associations via logistic regression likelihood ratio testing and explored interactions with support vector machines and Bayesian networks. RESULTS: After correction for multiple testing, we found no significant single genotypic associations with depressive symptoms. Machine learning algorithms showed no evidence of interactions. Naive Bayes produced the best models in both subsets and included only environmental and sociobehavioral factors. CONCLUSIONS: We found no single or interactive associations with genetic factors and depressive symptoms. Various environmental and sociobehavioral factors were more predictive of depressive symptoms, yet their impacts were independent of one another. A genome-wide analysis of genetic alterations using machine learning methodologies will provide a framework for identifying genetic-environmental-sociobehavioral interactions in depressive symptoms. PMID- 23927510 TI - Early hits and long-term consequences: tracking the lasting impact of prenatal smoke exposure on telomere length in children. AB - We examined the association between telomere length and prenatal tobacco exposure (PTE) in 104 children aged 4 to 14 years. Salivary telomere length (STL) was determined from salivary DNA using quantitative polymerase chain reaction. Of the children, 18% had maternal reported PTE. Mean STL was significantly lower among children with PTE (6.4 vs 7.5, P < .05). Findings extend the literature demonstrating the negative long-term effects of PTE to include a cellular marker of aging linked to multiple negative health outcomes. PMID- 23927512 TI - Rethinking our public health genetics research paradigm. AB - Since the sequencing of the human genome, tremendous resources have been dedicated to understanding how genetic determinants may drive the production of disease. Despite some successes, the promise of genetics research in these areas remains largely unrealized. The focus on isolating individual (or clusters of) genes that may be associated with narrowly defined phenotypes in large part explains this discrepancy. In particular, efforts to identify genotypes associated with narrow phenotypes force the field to use study designs that capitalize on homogeneous samples to minimize the potential for competing influences or confounders, which imposes important limitations on understanding the role of genes in human health. We argue that a population health genetics that incorporates genetics into large, multiwave, multilevel cohorts has the best potential to clarify how genes, in combination and with the environment, jointly influence population health. PMID- 23927511 TI - Genetics in population health science: strategies and opportunities. AB - Translational research is needed to leverage discoveries from the frontiers of genome science to improve public health. So far, public health researchers have largely ignored genetic discoveries, and geneticists have ignored important aspects of population health science. This mutual neglect should end. In this article, we discuss 3 areas where public health researchers can help to advance translation: (1) risk assessment: investigate genetic profiles as components in composite risk assessments; (2) targeted intervention: conduct life-course longitudinal studies to understand when genetic risks manifest in development and whether intervention during sensitive periods can have lasting effects; and (3) improved understanding of environmental causation: collaborate with geneticists on gene-environment interaction research. We illustrate with examples from our own research on obesity and smoking. PMID- 23927513 TI - Integrating social science and behavioral genetics: testing the origin of socioeconomic disparities in depression using a genetically informed design. AB - OBJECTIVES: We tested 3 hypotheses-social causation, social drift, and common cause-regarding the origin of socioeconomic disparities in major depression and determined whether the relationship between socioeconomic status (SES) and major depression varied by genetic liability for major depression. METHODS: Data were from a sample of female twins in the baseline Virginia Adult Twin Study of Psychiatric and Substance Use Disorders interviewed between 1987 and 1989 (n = 2153). We used logistic regression and structural equation twin models to evaluate these 3 hypotheses. RESULTS: Consistent with the social causation hypothesis, education (odds ratio [OR] = 0.78; 95% confidence interval [CI] = 0.66, 0.93; P < .01) and income (OR = 0.93; 95% CI = 0.89, 0.98; P < .01) were significantly related to past-year major depression. Upward social mobility was associated with lower risk of depression. There was no evidence that childhood SES was related to development of major depression (OR = 0.98; 95% CI = 0.89, 1.09; P > .1). Consistent with a common genetic cause, there was a negative correlation between the genetic components of major depression and education (r(2) = -0.22). Co-twin control analyses indicated a protective effect of education and income on major depression even after accounting for genetic liability. CONCLUSIONS: This study utilized a genetically informed design to address how social position relates to major depression. Results generally supported the social causation model. PMID- 23927514 TI - Defining the environment in gene-environment research: lessons from social epidemiology. AB - In this article, we make the case that social epidemiology provides a useful framework to define the environment within gene-environment (G * E) research. We describe the environment in a multilevel, multidomain, longitudinal framework that accounts for upstream processes influencing health outcomes. We then illustrate the utility of this approach by describing how intermediate levels of social organization, such as neighborhoods or schools, are key environmental components of G * E research. We discuss different models of G * E research and encourage public health researchers to consider the value of including genetic information from their study participants. We also encourage researchers interested in G * E interplay to consider the merits of the social epidemiology model when defining the environment. PMID- 23927515 TI - Using genetically informed, randomized prevention trials to test etiological hypotheses about child and adolescent drug use and psychopathology. AB - In this essay, we describe a new era of public health research in which prevention science principles are combined with genomic science to produce gene * intervention (G * I) research. We note the roles of behavioral and molecular genetics in risk and protective mechanisms for drug use and psychopathology among children and adolescents, and the results of first-generation genetically informed prevention trials are reviewed. We also consider the need for second generation research that focuses on G * I effects on mediators or intermediate processes. This research can be used to further understanding of etiological processes, to identify individual differences in children's and adolescents' responses to risk, and to increase the precision of prevention programs. We note the caveats about using genetic data to select intervention participants. PMID- 23927517 TI - Sex, gender, genetics, and health. AB - This article addresses 2 questions. First, to what extent are sex and gender incorporated into research on genetics and health? Second, how might social science understandings of sex and gender, and gender differences in health, become more integrated into scholarship in this area? We review articles on genetics and health published in selected peer-reviewed journals. Although sex is included frequently as a control or stratifying variable, few articles articulate a conceptual frame or methodological justification for conducting research in this way, and most are not motivated by sex or gender differences in health. Gender differences in health are persistent, unexplained, and shaped by multilevel social factors. Future scholarship on genetics and health needs to incorporate more systematic attention to sex and gender, gender as an environment, and the intertwining of social and biological variation over the life course. Such integration will advance understandings of gender differences in health, and may yield insight regarding the processes and circumstances that make genomic variation relevant for health and well-being. PMID- 23927516 TI - Critical need for family-based, quasi-experimental designs in integrating genetic and social science research. AB - Researchers have identified environmental risks that predict subsequent psychological and medical problems. Based on these correlational findings, researchers have developed and tested complex developmental models and have examined biological moderating factors (e.g., gene-environment interactions). In this context, we stress the critical need for researchers to use family-based, quasi-experimental designs when trying to integrate genetic and social science research involving environmental variables because these designs rigorously examine causal inferences by testing competing hypotheses. We argue that sibling comparison, offspring of twins or siblings, in vitro fertilization designs, and other genetically informed approaches play a unique role in bridging gaps between basic biological and social science research. We use studies on maternal smoking during pregnancy to exemplify these principles. PMID- 23927518 TI - The challenge of causal inference in gene-environment interaction research: leveraging research designs from the social sciences. AB - The integration of genetics and the social sciences will lead to a more complex understanding of the articulation between social and biological processes, although the empirical difficulties inherent in this integration are large. One key challenge is the implications of moving "outside the lab" and away from the experimental tools available for research with model organisms. Social science research methods used to examine human behavior in nonexperimental, real-world settings to date have not been fully taken advantage of during this disciplinary integration, especially in the form of gene-environment interaction research. This article outlines and provides examples of several prominent research designs that should be used in gene-environment research and highlights a key benefit to geneticists of working with social scientists. PMID- 23927519 TI - Unbinding pathways from the glucocorticoid receptor shed light on the reduced sensitivity of glucocorticoid ligands to a naturally occurring, clinically relevant mutant receptor. AB - Glucocorticoids are endogenous steroid hormones that regulate essential biological functions, including metabolism, growth, and apoptosis. Glucocorticoids represent the most effective anti-inflammatory agents for the treatment of several inflammatory conditions. However, the clinical use of such drugs is hampered by severe side effects. Therefore, the development of novel glucocorticoid receptor (GR) modulators with an increased therapeutic index is impelling. Herein, using steered molecular dynamics (SMD) simulations, we provide a detailed picture of the unbinding process of three clinically relevant GR modulators from GR ligand binding domains. The SMD protocol described here can be used to prioritize the synthesis of structural analogues on the basis of their potentials of mean force and calculated unbinding energies. Moreover, our results are instrumental in explaining at atomic resolution the weakened ability of dexamethasone to activate the naturally occurring mutant I747M GR, which is implicated in rare familial glucocorticoid resistance, clinically characterized by glucocorticoid insensitivity. PMID- 23927521 TI - Positioning of the Bronchitis Severity Score (BSS) for standardised use in clinical studies. AB - OBJECTIVE: Diagnosis and assessment of response to treatment in acute bronchitis depends on clinical findings. We evaluated published data on the Bronchitis Severity Score (BSS) used to diagnose acute bronchitis and to evaluate the impact of treatment in clinical studies. METHODS: We conducted a literature search using PubMed (search terms: acute bronchitis, treatment, score, and BSS; publication date April 2012 or earlier) and asked the manufacturer for relevant publications. Articles were reviewed and relevant studies were classified according to author, study design, measurements made and duration of study, study drug(s), outcome, and statistical significance. RESULTS: The medication most frequently evaluated by the BSS is a herbal drug preparation from the roots of Pelargonium sidoides (EPs 7630). The BSS consistently demonstrated statistically significant differences between active treatments and placebo as well as between different doses of active treatment. The proportion of responders was considerably higher in the EPs 7630 group than in the placebo group. Because of the subjective components of the BSS, inter-individual differences in results may exist. However, the BSS outcome was supported by the results of secondary outcome measures, such as the Integrated Medicine Patient Satisfaction Scale (IMPSS), documenting that patients were more often 'satisfied' or 'very satisfied' with EPs 7630 than placebo. CONCLUSIONS: We recommend further use of the BSS as a reliable and convenient clinical trial tool for selecting and evaluating patients in studies of acute bronchitis. Improvement in the BSS correlates with outcomes reported by these patients. PMID- 23927520 TI - Genetic susceptibility to anthracycline-related congestive heart failure in survivors of haematopoietic cell transplantation. AB - Haematopoietic cell transplantation (HCT) survivors are at increased risk for developing congestive heart failure (CHF), primarily due to pre-HCT exposure to anthracyclines. We examined the association between the development of CHF after HCT and polymorphisms in 16 candidate genes involved in anthracycline metabolism, iron homeostasis, anti-oxidant defence, and myocardial remodelling. A nested case control study design was used. Cases (post-HCT CHF) were identified from 2950 patients who underwent HCT between 1988 and 2007 at City of Hope and had survived >=1 year. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age, race/ethnicity, cumulative anthracycline exposure, stem cell source (allogeneic, autologous), and length of follow-up. Seventy-seven cases with pre-HCT germline DNA and 178 controls were genotyped. Multivariate analysis revealed that the odds of CHF was higher in females [Odds Ratio (OR) = 2.9, P < 0.01], individuals with pre-HCT chest radiation (OR = 4.7, P = 0.05), hypertension (OR = 2.9, P = 0.01), and with variants of genes coding for the NAD(P)H-oxidase subunit RAC2 (rs13058338, 7508T->A; OR = 2.8, P < 0.01), HFE (rs1799945, 63C->G; OR = 2.5, P = 0.05) or the doxorubicin efflux transporter ABCC2 (rs8187710, 1515G->A; OR = 4.3, P < 0.01). A combined (clinical and genetic) CHF predictive model performed better [area under the curve (AUC), 0.79] than the genetic (AUC = 0.67) or the clinical (AUC = 0.69) models alone. PMID- 23927522 TI - Predicting quality of life 5 years after medical discharge for traumatic spinal cord injury. AB - OBJECTIVES: This study tested an a priori contextual model of the mediating effects of participation on the predictive relationships of functional impairment, family satisfaction, and pain to quality of life (QoL) following traumatic spinal cord injury (SCI). DESIGN: A longitudinal design was used to study 144 persons following discharge for traumatic SCI. Predictor variables included functional impairment and family satisfaction (at 12 months post discharge) and the presence of pain (at 24 months), and mediating variables were two indicators of participation (assessed 48 months post-discharge). Life satisfaction and self-rated health status at 60 months post-discharge were the outcome variables. METHODS: A path model tested hypothesized prospective effects of functional impairment, family satisfaction and pain on participation and the subsequent effects of participation on the QoL variables. RESULTS: Greater functional impairment and pain were predictive of less participation, and participation significantly predicted both indicators of QoL. The two participation variables mediated the relationship of functional impairment and pain to life satisfaction over time. Family satisfaction had an indirect effect on QoL through its association with social integration. CONCLUSIONS: Participation appears to mediate the prospective influence of functional impairment, family satisfaction, and pain on QoL in the years following SCI. These findings provide insight into factors that can predict QoL post-SCI and support the use of contextual models to understand the temporal influence of disability and psychological variables on participation and subsequent QoL. STATEMENT OF CONTRIBUTION: What is already known on this subject? Life satisfaction and self-rated health status are important aspects of quality of life following traumatic spinal cord injury. Functional impairment has been inconsistently predictive of these variables over time. Prospective research to date has not examined the mediating effects of participation in predicting quality of life. What does this study add? The results indicate that greater functional impairment and pain are prospectively predictive of lower participation. Greater participation, in turn, is prospectively predictive of greater quality of life. Participation appears to mediate the prospective influence of functional impairment, family satisfaction, and pain to quality of life. PMID- 23927523 TI - Neuromuscular diseases in children: a practical approach. PMID- 23927524 TI - A suction catheter is a simple technique to aid nasal intubation with the GlideScope. PMID- 23927525 TI - Brain herniation due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) after posterior spine fusion. PMID- 23927526 TI - Arytenoid prolapse and inability to ventilate. PMID- 23927527 TI - Alpha-2 agonists as first-line sedative agents in hyperammonemia-induced hyperexcitability? PMID- 23927528 TI - The auriculo-vagal afferent pathway and its role in seizure suppression in rats. AB - BACKGROUND: The afferent projections from the auricular branch of the vagus nerve (ABVN) to the nucleus tractus solitaries (NTS) have been proposed as the anatomical basis for the increased parasympathetic tone seen in auriculo-vagal reflexes. As the afferent center of the vagus nerve, the NTS has been considered to play roles in the anticonvulsant effect of cervical vagus nerve stimulation (VNS). Here we proposed an "auriculo-vagal afferent pathway" (AVAP), by which transcutaneous auricular vagus nerve stimulation (ta-VNS) suppresses pentylenetetrazol (PTZ)-induced epileptic seizures by activating the NTS neurons in rats. RESULTS: The afferent projections from the ABVN to the NTS were firstly observed in rats. ta-VNS increased the first grand mal latency of the epileptic seizure and decreased the seizure scores in awake rats. Furthermore, when the firing rates of the NTS neurons decreased, epileptiform activity manifested as electroencephalogram (EEG) synchronization increased with 0.37+/-0.12 s delay in anaesthetized rats. The change of instantaneous frequency, mean frequency of the NTS neurons was negative correlated with the amplitude of the epileptic activity in EEG traces. ta-VNS significantly suppressed epileptiform activity in EEG traces via increasing the firing rates of the neurons of the NTS. In comparison with tan-VNS, the anticonvulsant durations of VNS and ta-VNS were significantly longer (P<0.01). There was no significant difference between the anticonvulsant durations of VNS and ta-VNS (P>0.05). The anticonvulsant effect of ta-VNS was weakened by reversible cold block of the NTS. CONCLUSIONS: There existed an anatomical relationship between the ABVN and the NTS, which strongly supports the concept that ta-VNS has the potential for suppressing epileptiform activity via the AVAP in rats. ta-VNS will provide alternative treatments for neurological disorders, which can avoid the disadvantage of VNS. PMID- 23927529 TI - Effects of parecoxib on the prevention of postoperative peritoneal adhesions in rats. AB - BACKGROUND: No systemic preventive therapy has been successful in inhibiting the development of postoperative peritoneal adhesions (PPAs). OBJECTIVE: The aim of this study was to evaluate the potential effects of 5 day administration of parecoxib, on PPA prevention and on suture or wound healing in rats. METHODS: In a model of PPAs induced by peritoneal electrical burn, 30 rats were randomized into 3 groups according to parecoxib administration route (control; intraperitoneal (IP); intramuscular (IM)). Plasma and peritoneal levels of PAI-1 and tPA were measured at T0, after 90 min of surgery (T90), and on postoperative day 10 (D10). In a cecum resection model, 20 rats were randomized into two groups (control and IP parecoxib), and abdominal wound healing and suture leakage were assessed at D10. In both models, PPAs were evaluated quantitatively and qualitatively on D10. RESULTS: Administration of parecoxib significantly decreased the quantity (p < .05) and the severity (p < .01) of PPAs in both models. In addition, parecoxib administration did not cause healing defects or infectious complications in the two models. In the peritoneal burn model, IP or IM parecoxib administration inhibited the increase of postoperative plasma and peritoneum PAI-1 levels, an increase that was observed in the control group (p < .01). No anastomosis leakage could be demonstrated in both groups in the cecum resection model. CONCLUSION: This study showed that, in these rat models, parecoxib might reduce PPA formation. Confirmation of the safety of parecoxib on intestinal anastomoses is required and should be investigated in further animal models. PMID- 23927531 TI - Measuring governance at health facility level: developing and validation of simple governance tool in Zambia. AB - BACKGROUND: Governance has been cited as a key determinant of economic growth, social advancement and overall development. Achievement of millennium development goals is partly dependant on governance practices. In 2007, Health Systems 20/20 conducted an Internet-based survey on the practice of good governance. The survey posed a set of good practices related to health governance and asked respondents to indicate whether their experience confirmed or disconfirmed those practices. We applied the 17 governance statements in rural health facilities of Zambia. The aim was to establish whether the statements were reliable and valid for assessing governance practices at primary care level. METHODS: Both quantitative and qualitative methods were used. We first applied the governance statements developed by the health system 20/20 and then conducted focus group discussion and In-depth interviews to explore some elements of governance including accountability and community participation. The target respondents were the health facility management team and community members. The sample size include 42 health facilities. Data was analyzed using SPSS version 17 and Nvivo version 9. RESULTS: The 95% one-sided confidence interval for Cronbach's alpha was between 0.69 and 0.74 for the 16 items.The mean score for most of the items was above 3. Factor analysis yielded five principle components: Transparency, community participation, Intelligence & vision, Accountability and Regulation & oversight. Most of the items (6) clustered around the transparency latent factor. Chongwe district performed poorly in overall mean governance score and across the five domains of governance. The overall scores in Chongwe ranged between 51 and 94% with the mean of 80%. Kafue and Luangwa districts had similar overall mean governance scores (88%). Community participation was generally low. Generally, it was noted that community members lacked capacity to hold health workers accountable for drugs and medical supplies. CONCLUSIONS: The study successfully validated and applied the new tool for evaluating health system governance at health facility level. The results have shown that it is feasible to measure governance practices at health facility level and that the adapted tool is fairly reliable with the 95% one-sided confidence interval for Cronbach's alpha laying between 0.69 and 0.74 for the 16 items. Caution should be taken when interpreting overall scores as they tended to mask domain specific variations. PMID- 23927530 TI - Extrapulmonary transport of MWCNT following inhalation exposure. AB - BACKGROUND: Inhalation exposure studies of mice were conducted to determine if multi-walled carbon nanotubes (MWCNT) distribute to the tracheobronchial lymphatics, parietal pleura, respiratory musculature and/or extrapulmonary organs. Male C57BL/6 J mice were exposed in a whole-body inhalation system to a 5 mg/m3 MWCNT aerosol for 5 hours/day for 12 days (4 times/week for 3 weeks, lung burden 28.1 ug/lung). At 1 day and 336 days after the 12 day exposure period, mice were anesthetized and lungs, lymph nodes and extrapulmonary tissues were preserved by whole body vascular perfusion of paraformaldehyde while the lungs were inflated with air. Separate, clean-air control groups were studied at 1 day and 336 days post-exposure. Sirius Red stained sections from lung, tracheobronchial lymph nodes, diaphragm, chest wall, heart, brain, kidney and liver were analyzed. Enhanced darkfield microscopy and morphometric methods were used to detect and count MWCNT in tissue sections. Counts in tissue sections were expressed as number of MWCNT per g of tissue and as a percentage of total lung burden (Mean +/- S.E., N = 8 mice per group). MWCNT burden in tracheobronchial lymph nodes was determined separately based on the volume density in the lymph nodes relative to the volume density in the lungs. Field emission scanning electron microscopy (FESEM) was used to examine MWCNT structure in the various tissues. RESULTS: Tracheobronchial lymph nodes were found to contain 1.08 and 7.34 percent of the lung burden at 1 day and 336 days post-exposure, respectively. Although agglomerates account for approximately 54% of lung burden, only singlet MWCNT were observed in the diaphragm, chest wall, liver, kidney, heart and brain. At one day post exposure, the average length of singlet MWCNT in liver and kidney, was comparable to that of singlet MWCNT in the lungs 8.2 +/- 0.3 versus 7.5 +/- 0.4 um, respectively. On average, there were 15,371 and 109,885 fibers per gram in liver, kidney, heart and brain at 1 day and 336 days post-exposure, respectively. The burden of singlet MWCNT in the lymph nodes, diaphragm, chest wall and extrapulmonary organs at 336 days post-exposure was significantly higher than at 1 day post-exposure. CONCLUSIONS: Inhaled MWCNT, which deposit in the lungs, are transported to the parietal pleura, the respiratory musculature, liver, kidney, heart and brain in a singlet form and accumulate with time following exposure. The tracheobronchial lymph nodes contain high levels of MWCNT following exposure and further accumulate over nearly a year to levels that are a significant fraction of the lung burden 1 day post-exposure. PMID- 23927532 TI - Inverse kinetic isotope effect in the excited-state relaxation of a Ru(II)-aquo complex: revealing the impact of hydrogen-bond dynamics on nonradiative decay. AB - Photophysics of the MLCT excited-state of [Ru(bpy)(tpy)(OH2)](2+) (1) and [Ru(bpy)(tpy)(OD2)](2+) (2) (bpy = 2,2'-bipyridine and tpy = 2,2':6',2" terpyridine) have been investigated in room-temperature H2O and D2O using ultrafast transient pump-probe spectroscopy. An inverse isotope effect is observed in the ground-state recovery for the two complexes. These data indicate control of excited-state lifetime via a pre-equilibrium between the (3)MLCT state that initiates H-bond dynamics with the solvent and the (3)MC state that serves as the principal pathway for nonradiative decay. PMID- 23927533 TI - Complement activation and mortality during an acute episode of thrombotic thrombocytopenic purpura. PMID- 23927534 TI - Endotoxins in indoor air and settled dust in primary schools in a subtropical climate. AB - Endotoxins can significantly affect the air quality in school environments. However, there is currently no reliable method for the measurement of endotoxins, and there is a lack of reference values for endotoxin concentrations to aid in the interpretation of measurement results in school settings. We benchmarked the "baseline" range of endotoxin concentration in indoor air, together with endotoxin load in floor dust, and evaluated the correlation between endotoxin levels in indoor air and settled dust, as well as the effects of temperature and humidity on these levels in subtropical school settings. Bayesian hierarchical modeling indicated that the concentration in indoor air and the load in floor dust were generally (<95th percentile) <13 EU/m(3) and <24,570 EU/m(2), respectively. Exceeding these levels would indicate abnormal sources of endotoxins in the school environment and the need for further investigation. Metaregression indicated no relationship between endotoxin concentration and load, which points to the necessity for measuring endotoxin levels in both the air and settled dust. Temperature increases were associated with lower concentrations in indoor air and higher loads in floor dust. Higher levels of humidity may be associated with lower airborne endotoxin concentrations. PMID- 23927535 TI - Two-color laser printing of individual gold nanorods. AB - We report on the deposition of individual gold nanorods from an optical trap using two different laser wavelengths. Laser light, not being resonant to the plasmon resonances of the nanorods, is used for stable trapping and in situ alignment of individual nanorods. Laser light, being resonant to the transversal mode of the nanorods, is used for depositing nanorods at desired locations. The power and polarization dependence of the process is investigated and discussed in terms of force balances between gradient and scattering forces, plasmonic heating, and rotational diffusion of the nanorods. This two-color approach enables faster printing than its one-color equivalent and provides control over the angular orientation (+/-16 degrees ) and location of the deposited nanorods at the single-nanorod level. PMID- 23927536 TI - Metabolism, physiology, and analyses of primary fatty acid amides. PMID- 23927537 TI - Silane radical cation: a theoretical account on the Jahn-Teller effect at a triple degeneracy. AB - An ab initio quantum dynamics study is performed to examine the complex nuclear motion underlying the first photoelectron band of the silane molecule due to Jahn Teller distortion via T2?(e+t2+t2) coupling. The problem is investigated by employing a quadratic vibronic coupling model for the Hamiltonian. All sheets of the required potential energy surface are established through extensive electronic structure calculations using the multireference configuration interaction method. They cover at most two dimensions of the full 9D coordinate space, with the parameters defining the model Hamiltonian being determined by a least-squares fitting procedure. The results are compared with the available experimental data and discussed in relation to those obtained for the methane radical cation. The quadratic couplings of Jahn-Teller active vibrational modes are found to have a crucial role on the irregular vibronic structure, intensity of the spectral excitations, and overall width of the first photoelectron band of the title molecule. The impact of large amplitude motions on the vibronic structure and dynamics of the first photoelectron band has also been examined by varying their linear coupling parameters up to +/-10%. PMID- 23927539 TI - Host-associated genomic differentiation in congeneric butterflies: now you see it, now you do not. AB - Ecotypic variation among populations may become associated with widespread genomic differentiation, but theory predicts that this should happen only under particular conditions of gene flow, selection and population size. In closely related species, we might expect the strength of host-associated genomic differentiation (HAD) to be correlated with the degree of phenotypic differentiation in host-adaptive traits. Using microsatellite and Amplified Fragment Length Polymorphism (AFLP) markers, and controlling for isolation by distance between populations, we sought HAD in two congeneric species of butterflies with different degrees of host plant specialization. Prior work on Euphydryas editha had shown strong interpopulation differentiation in host adapted traits, resulting in incipient reproductive isolation among host associated ecotypes. We show here that Euphydryas aurinia had much weaker host associated phenotypic differentiation. Contrary to our expectations, we detected HAD in Euphydryas aurinia, but not in E. editha. Even within an E. aurinia population that fed on both hosts, we found weak but significant sympatric HAD that persisted in samples taken 9 years apart. The finding of significantly stronger HAD in the system with less phenotypic differentiation may seem paradoxical. Our findings can be explained by multiple factors, ranging from differences in dispersal or effective population size, to spatial variation in genomic or phenotypic traits and to structure induced by past histories of host adapted populations. Other infrequently measured factors, such as differences in recombination rates, may also play a role. Our result adds to recent work as a further caution against assumptions of simple relationships between genomic and adaptive phenotypic differentiation. PMID- 23927540 TI - Facile synthesis of poly(3,4-ethylenedioxythiophene) film via solid-state polymerization as high-performance Pt-free counter electrodes for plastic dye sensitized solar cells. AB - A high-performance Pt-free counter electrode (CE) based on poly(3,4 ethylenedioxythiophene) (PEDOT) film for plastic dye-sensitized solar cells (DSCs) has been developed via a facile solid-state polymerization (SSP) approach. The polymerization was simply initiated by sintering the monomer, 2,5-dibromo-3,4 ethylenedioxythiophene (DBEDOT), at the temperature of 80 degrees C, which can be applied on the plastic substrate. The cyclic voltammetry measurements revealed that the catalytic activity of the SSP-PEDOT CE for triiodide reduction is comparable with that of the Pt CE. Under optimized conditions, the power conversion efficiency of a DSC with a N719-sensitized TiO2 photoanode and the SSP PEDOT CE is 7.04% measured under standard 1 sun illumination (100 mW cm(-2), AM 1.5), which is very close to that of the device fabricated under the same conditions with a conventional thermally deposited Pt CE (7.35%). Furthermore, taking advantage of the compatibility of the SSP-PEDOT with the plastic substrates, a full plastic N719-sensitized TiO2 solar cell was demonstrated, and an efficiency of 4.65% was achieved, which is comparable with the performance of a plastic DSC with a sputter-deposited Pt CE (5.38%). These results demonstrated that solid-state polymerization initiated at low temperature is a facile and low cost method of fabricating the high-performance Pt-free CEs for plastic DSCs. PMID- 23927541 TI - Modulation of murine gastric vagal afferent mechanosensitivity by neuropeptide W. AB - AIM: Neuropeptide W (NPW) is an endogenous ligand for the receptors GPR7 and GPR8 and is involved in central regulation of energy homeostasis. NPW in the periphery is found in gastric gastrin (G) cells. In the stomach, energy intake is influenced by vagal afferent signals, so we aimed to determine the effect of NPW on mechanosensitive gastric vagal afferents under different feeding conditions. METHODS: Female C57BL/6 mice (N > 10 per group) were fed a standard laboratory diet (SLD), high-fat diet (HFD) or were food restricted. The relationship between NPW immunopositive cells and gastric vagal afferent endings was determined by anterograde tracing and NPW immunohistochemistry. An in vitro gastro-oesophageal preparation was used to determine the functional effects of NPW on gastric vagal afferents. Expression of NPW in the gastric mucosa and GPR7 in whole nodose ganglia was determined by quantitative RT-PCR (QRT-PCR). The expression of GPR7 in gastric vagal afferent neurones was determined by retrograde tracing and QRT PCR. RESULTS: Neuropeptide W immunoreactive cells were found in close proximity to traced vagal afferents. NPW selectively inhibited responses of gastric vagal tension receptors to stretch in SLD but not HFD or fasted mice. In the nodose ganglia, GPR7 mRNA was specifically expressed in gastric vagal afferent neurones. In fasted mice gastric mucosal NPW and nodose GPR7, mRNA was reduced compared with SLD. A HFD had no effect on gastric NPW mRNA, but down-regulated nodose GPR7 expression. CONCLUSION: Neuropeptide W modulates gastric vagal afferent activity, but the effect is dynamic and related to feeding status. PMID- 23927542 TI - Posterior reversible encephalopathy syndrome during induction chemotherapy for acute myeloid leukaemia. PMID- 23927544 TI - The dialogue between social environments and the genome. PMID- 23927543 TI - Population disparities in mental health: insights from cultural neuroscience. AB - By 2050, nearly 1 in 5 Americans (19%) will be an immigrant, including Hispanics, Blacks, and Asians, compared to the 1 in 8 (12%) in 2005. They will vary in the extent to which they are at risk for mental health disorders. Given this increase in cultural diversity within the United States and costly population health disparities across cultural groups, it is essential to develop a more comprehensive understanding of how culture affects basic psychological and biological mechanisms. We examine these basic mechanisms that underlie population disparities in mental health through cultural neuroscience. We discuss the challenges to and opportunities for cultural neuroscience research to determine sociocultural and biological factors that confer risk for and resilience to mental health disorders across the globe. PMID- 23927545 TI - Genes can point to environments that matter to advance public health. PMID- 23927546 TI - Genomics and the nature of behavioral and social risk. PMID- 23927547 TI - Integration of behavioral, social science and genetics research: exploring public health significance. PMID- 23927548 TI - Advancing scientific inquiry by blurring research boundaries. PMID- 23927549 TI - A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population. AB - Alport syndrome is an inherited progressive nephropathy arising from mutations in the type IV collagen genes, COL4A3, COL4A4, and COL4A5. Symptoms also include sensorineural hearing loss and ocular lesions. We determined the molecular basis of Alport syndrome in a non-consanguineous Ashkenazi Jewish family with multiple affected females using linkage analysis and next generation sequencing. We identified a homozygous COL4A3 mutation, c.40_63del, in affected individuals with mutant alleles inherited from each parent on partially conserved haplotypes. Large-scale population screening of 2017 unrelated Ashkenazi Jewish samples revealed a carrier frequency of 1 in 183 indicating that COL4A3 c.40_63del is a founder mutation which may be a common cause of Alport syndrome in this population. Additionally, we determined that heterozygous mutation carriers in this family do not meet criteria for a diagnosis of Thin Basement Membrane Nephropathy and concluded that carriers of c.40_63del are not likely to develop benign familial hematuria. PMID- 23927550 TI - Screen of pseudopeptidic inhibitors of human sirtuins 1-3: two lead compounds with antiproliferative effects in cancer cells. AB - In the past few years sirtuins have gained growing attention for their involvement in many biological processes such as cellular metabolism, apoptosis, aging and inflammation. In this contribution, we report the synthesis of a library of thioacetylated pseudopeptides that were screened against human sirtuins 1-3 to reveal their in vitro inhibition activities. Molecular modeling studies were performed to acquire data about the binding modes of the inhibitors. Three sirtuin inhibitors were subjected to cellular studies, and all of them showed an increase in acetylation of Lys382 of p53 after DNA damage. Furthermore, two of the compounds were able to inhibit both A549 lung carcinoma and MCF-7 breast carcinoma cell growth in micromolar concentration with the ability to arrest cancer cell cycle in the G1 phase. PMID- 23927551 TI - The clinical significance of Ki-67 as a marker of prognostic value and chemosensitivity prediction in hormone-receptor-positive breast cancer: a meta analysis of the published literature. AB - OBJECTIVES: Hormone-receptor (HR)-positive breast cancer is associated with a poor response to adjuvant chemotherapy. Thus, it is important to identify HR positive patients who can benefit from chemotherapy and the Ki-67 index may help to predict chemotherapy efficacy in such populations. However, controversies exist regarding the prognostic and predictive role of Ki-67 and its exact cut-off value in HR-positive patients. Therefore, we conducted this study. METHODS: The meta-analysis included 4512 patients in five trials. Due to different data formats provided by studies, we classified the trials into two groups to facilitate analysis. Group 1 included the PACS01, USON 01062, and IBCSG VIII and IX trials, while Group 2 included the BCIRG001, USON 01062, and IBCSG VIII and IX trials. RESULTS: In Group 1, Ki-67 high patients had a worse prognosis in disease free survival (DFS) than Ki-67 low counterparts (risk ratio [RR] = 1.62, 95% confidence index [CI] = 1.36-1.94, P < 0.001). In Group 2, Ki-67 high patients had a better prognosis in DFS (RR = 0.53, 95% CI = 0.45-0.61, P < 0.001) and overall survival (OS) (RR = 0.32, 95% CI = 0.25-0.42, P < 0.001). In Ki-67 high patients administered anthracycline/taxane-based chemotherapy, the experimental group (FAC -> T, AC -> TX) achieved a better DFS than the control group (FAC, AC > T, respectively) (RR = 0.60, 95% CI = 0.39-0.90, P = 0.014). With a cut-off point >=19%, Ki-67 high patients achieved a worse DFS (RR = 1.49, 95% CI = 1.28 1.72, P < 0.001). CONCLUSION: This study had limitations due to its retrospective nature and the lack of standardized Ki-67 measurement methods. Nevertheless, our findings indicate that Ki-67 high patients have a worse prognosis and may be more sensitive to anthracycline/taxane-based regimens. The ideal Ki-67 cut-off point for predicting chemosensitivity may be a certain value among a range of values >=19% in HR-positive patients. PMID- 23927552 TI - Continuous postoperative analgesia via quadratus lumborum block - an alternative to transversus abdominis plane block. AB - Different transversus abdominis plane blocks techniques cause variations in postoperative analgesia characteristics. We report the use of unilateral quadratus lumborum catheter for analgesia following colostomy closure. The catheter was placed under direct ultrasound visualization and had good outcomes: low pain scores and minimal use of rescue analgesic medication. No complications were reported in this pediatric patient. More studies are needed to evaluate the effectiveness and safety of this regional anesthesia technique. PMID- 23927553 TI - Comparative evaluation of published real-time PCR assays for the detection of malaria following MIQE guidelines. AB - BACKGROUND: The use of malaria-specific quantitative real-time PCR (qPCR) is increasing due to its high sensitivity, speciation and quantification of malaria parasites. However, due to the lack of consensus or standardized methods in performing qPCR, it is difficult to evaluate and/or compare the quality of work reported by different authors for a cross-study and/or cross-platform assay analysis. METHODS: The performances of seven published qPCR assays that detect Plasmodium spp or Plasmodium falciparum were compared using standard DNA and samples from a clinical trial. Amplification and qPCR measurements were performed using the Applied Biosystems 7500 Fast Real-Time PCR System. All the analyses were automatically established using the default settings. For the TaqMan probe format, the assays were performed in the background of QuantiFast Probe Master Mix whereas in SYBR Green format, the assays were performed in the background of QuantiFast SYBR Green Master Mix and QuantiTect SYBR Green Master Mix background. RESULTS: Assays with high PCR efficiencies outperformed those with low efficiencies in all categories including sensitivity, precision and consistency regardless of the assay format and background. With the exception of one assay, all assays evaluated showed lower sensitivity compared to what have been published. When samples from a malaria challenge study were analysed, the qPCR assay with the overall best performance detected parasites in subjects earliest and with most consistency. CONCLUSION: The data demonstrate the need for increased consensus and guidelines that will encourage better experimental practices, allowing more consistent and unambiguous interpretation of qPCR results. PMID- 23927556 TI - Fe-catalyzed regiodivergent [1,2]-shift of alpha-aryl aldehydes. AB - An Fe-catalyzed conversion of aldehydes to ketones via [1,2]-shift has been developed. This skeletal rearrangement shows a wide substrate scope and chemoselectivity profile while exhibiting an excellent [1,2]-aryl or [1,2]-alkyl shift selectivity that is easily switched by electronic effects. PMID- 23927554 TI - Interventionally implanted port catheter systems for hepatic arterial infusion of chemotherapy in patients with primary liver cancer: a phase II-study (NCT00356161). AB - BACKGROUND: Hepatic arterial infusion (HAI) of chemotherapy requires the implantation of a transcatheter application system which is traditionally performed by surgery. This procedure, but particularly the adjacent drug application via pump or port is often hampered by specific complications and device failure. Interventionally implanted port catheter systems (IIPCS) facilitate the commencement of HAI without need for laparatomy, and are associated with favorable complication rates. We here present an evaluation of the most important technical endpoints associated with the use of IIPCS for HAI in patients with primary liver cancers. METHODS: 70 patients (pts) with hepatocellular (HCC, n=33) and biliary tract cancer (BTC, n=37) were enrolled into a phase II -study. Of those, n=43 had recurrent disease and n=31 suffered from liver-predominant UICC-stage IVb. All pts were provided with IIPCSs before being treated with biweekly, intraarterial chemotherapy (oxaliplatin, 5 Flourouracil, folinic acid). The primary objective of the trial was defined as evaluation of device-related complications and port duration. RESULTS: Implantation of port catheters was successful in all patients. Mean treatment duration was 5.8 months, and median duration of port patency was not reached. Disease-progression was the most common reason for treatment discontinuation (44 pts., 63%), followed by chemotherapy-related toxicity (12 pts., 17%), and irreversible device failure (5 pts., 7%). A total of 28 port complications occurred in 21 pts (30%). No unexpected complications were observed. CONCLUSIONS: HAI via interventionally implanted port catheters can be safely applied to patients with primary liver tumors far advanced or/and pretreated. PMID- 23927555 TI - Molecular diagnosis and phylogenetic analysis of Babesia bigemina and Babesia bovis hemoparasites from cattle in South Africa. AB - BACKGROUND: Babesia parasites, mainly Babesia bovis and B. bigemina, are tick borne hemoparasites inducing bovine babesiosis in cattle globally. The clinical signs of the disease include, among others, anemia, fever and hemoglobinuria. Babesiosis is known to occur in tropical and subtropical regions of the world. In this study, we aim to provide information about the occurrence and phylogenetic relationship of B. bigemina and B. bovis species in cattle from different locations in nine provinces of South Africa. A total of 430 blood samples were randomly collected from apparently healthy cattle. These samples were genetically tested for Babesia parasitic infections using nested PCR assays with species specific primers. RESULTS: Nested PCR assays with Group I primer sets revealed that the overall prevalence of B. bigemina and B. bovis in all bovine samples tested was 64.7% (95% CI = 60.0-69.0) and 35.1% (95% CI = 30.6-39.8), respectively. Only 117/430 (27.2%) animals had a mixed infection. The highest prevalence of 87.5% (95% CI = 77.2-93.5) for B. bigemina was recorded in the Free State province collection sites (Ficksburg, Philippolis and Botshabelo), while North West collection sites had the highest number of animals infected with B. bovis (65.5%; 95% CI = 52.7-76.4). Phylograms were inferred based on B. bigemina specific gp45 and B. bovis-specific rap-1 nucleotide sequences obtained with Group II nested PCR primers. Phylogenetic analysis of gp45 sequences revealed significant differences in the genotypes of B. bigemina isolates investigated, including those of strains published in GenBank. On the other hand, a phylogeny based on B. bovis rap-1 sequences indicated a similar trend of clustering among the sequences of B. bovis isolates investigated in this study. CONCLUSION: This study demonstrates the occurrence of Babesia parasites in cattle from different provinces of South Africa. It was also noted that the situation of Babesia parasitic infection in cattle from certain areas within the surveyed provinces had either reached endemic stability or was progressing towards stability. PMID- 23927557 TI - Endotoxin levels in settled airborne dust in European schools: the HITEA school study. AB - Indoor exposure to microbial agents is known to influence respiratory health. Besides home exposure, exposure in schools can affect respiratory health. In this study, we measured endotoxin in settled dust in primary schools in three European countries from three different geographical regions with different climates. Our aim was to characterize endotoxin levels in primary schools and evaluate associations with potential determinants. Endotoxin levels were repeatedly assessed in 23 schools in Spain (n = 7), the Netherlands (n = 10), and Finland (n = 6) using electrostatic dustfall collectors. In total, 645 measurements were taken in 237 classrooms. Endotoxin levels differed significantly between countries; Dutch schools had the highest levels, while Finnish schools showed the lowest levels. In each country, differences in endotoxin levels were observed between schools and over the sampling periods. Estimates improved after adjustment for sampling period. Factors affecting endotoxin levels in a school differed per country. In general, endotoxin levels were higher in lower grades and in classrooms with higher occupancy. School endotoxin levels may contribute significantly to total endotoxin exposure in children and teachers. As the correlation between the repeated measurements is reasonable, single endotoxin measurements form a reasonable basis for estimating annual endotoxin levels in schools. PMID- 23927558 TI - Highly stable photoelectrochemical water splitting and hydrogen generation using a double-band InGaN/GaN core/shell nanowire photoanode. AB - We report on the first demonstration of stable photoelectrochemical water splitting and hydrogen generation on a double-band photoanode in acidic solution (hydrogen bromide), which is achieved by InGaN/GaN core/shell nanowire arrays grown on Si substrate using catalyst-free molecular beam epitaxy. The nanowires are doped n-type using Si to reduce the surface depletion region and increase current conduction. Relatively high incident-photon-to-current-conversion efficiency (up to ~27%) is measured under ultraviolet and visible light irradiation. Under simulated sunlight illumination, steady evolution of molecular hydrogen is further demonstrated. PMID- 23927559 TI - Structural assembly from phosphate to germanophosphate by applying germanate as a binder. AB - Structural assembly from phosphate to germanophosphate by applying germanate as a binder has been achieved. Two isotypic porous compounds, K3[M(II)4(HPO4)2][Ge2O(OH)(PO4)4].xH2O (M(II) = Fe, Cd; x = 2 for Fe and 3 for Cd, denoted as KFeGePO-1 and KCdGePO-1, respectively), contain a known transition metal phosphate (TMPO) layer, (infinity)(2){[M2(HPO4)3]2-}, which is built from chains of trans-edge-sharing MO6 octahedra bridged by MO5 trigonal bipyramids that were further linked and decorated by phosphate tetrahedra. The layers are bound by infinite chains of GeO5(OH) octahedra, resulting in a 3D open-framework structure with 1D 12-ring channels that are occupied by K+ ions and water molecules. The curvature of the TMPO layers and shape of the 12-ring windows can be tuned by the transition metals because of their Jahn-Teller effect. PMID- 23927560 TI - Comparison of platelet activity measurements by use of arterial and venous blood sampling. PMID- 23927561 TI - Implementation of an evidence-based extubation readiness bundle in 499 brain injured patients. a before-after evaluation of a quality improvement project. AB - RATIONALE: Mechanical ventilation is associated with morbidity in patients with brain injury. OBJECTIVES: This study aims to assess the effectiveness of an extubation readiness bundle to decrease ventilator time in patients with brain injury. METHODS: Before-after design in two intensive care units (ICUs) in one university hospital. Brain-injured patients ventilated more than 24 hours were evaluated during two phases (a 3-yr control phase followed by a 22-mo intervention phase). Bundle components were protective ventilation, early enteral nutrition, standardization of antibiotherapy for hospital-acquired pneumonia, and systematic approach to extubation. The primary endpoint was the duration of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: A total of 299 and 200 patients, respectively, were analyzed in the control and the intervention phases of this before-after study. The intervention phase was associated with lower tidal volume (P < 0.01), higher positive end-expiratory pressure (P < 0.01), and higher enteral intake in the first 7 days (P = 0.01). The duration of mechanical ventilation was 14.9 +/- 11.7 days in the control phase and 12.6 +/- 10.3 days in the intervention phase (P = 0.02). The hazard ratio for extubation was 1.28 (95% confidence interval [CI], 1.04-1.57; P = 0.02) in the intervention phase. Adjusted hazard ratio was 1.40 (95% CI, 1.12-1.76; P < 0.01) in multivariate analysis and 1.34 (95% CI, 1.03-1.74; P = 0.02) in propensity score-adjusted analysis. ICU-free days at Day 90 increased from 50 +/- 33 in the control phase to 57 +/- 29 in the intervention phase (P < 0.01). Mortality at Day 90 was 28.4% in the control phase and 23.5% in the intervention phase (P = 0.22). CONCLUSIONS: The implementation of an evidence-based extubation readiness bundle was associated with a reduction in the duration of ventilation in patients with brain injury. PMID- 23927562 TI - DFT study of the ExBox.aromatic hydrocarbon host-guest complex. AB - The structures of ExBox(4+) 1 and its host-guest complexes with the linear acenes benzene, naphthalene, anthracene, and tetracene were optimized using DFT (omegaB97X-D/6-311G(d,p)) in both the gas and solution phases. The structure of 1 systematically varies as it moves from the gas to solution to the solid phase: the outward bending of the triaryl fragment diminishes in this series. The structures of the complexes with anthracene and tetracene are in very good agreement with their X-ray structures. The gas phase binding energy is linearly related to the size of the acene, with the binding free energy of all complexes predicted to be exoergonic in both gas and solution phases. PMID- 23927563 TI - Role of interleukin-1beta in radiation-enhancement of MDA-MB-231 breast cancer cell invasion. AB - The ability of radiation to increase the invasiveness of cancer cells is associated with the inflammatory response, which is induced in almost all irradiated patients. For breast cancer patients, elevated plasma levels of the inflammatory cytokine interleukin-1beta (IL1beta) persisted for a few weeks after completion of radiotherapy. The aim of this study was to determine whether IL1beta is involved in the enhancement of breast cancer cell invasion induced by radiation. The role of IL1beta was assessed with invasion chambers where irradiated fibroblasts were used as chemoattractant for the MDA-MB-231 breast cancer cells plated in the upper compartment. The ability of IL1beta to stimulate the expression of cyclooxygenase-2 (COX-2) and biosynthesis of the prostaglandin E2 (PGE2) in MDA-MB-231 cells were also determined. Our results show that radiation-enhancement of MDA-MB-231 cell invasion was prevented with an anti IL1beta antibody. The production of IL1beta was increased in irradiated fibroblasts, while the invasiveness of the MDA-MB-231 cells not exposed to irradiated fibroblasts was favored by adding this cytokine. Furthermore, addition of the COX-2 inhibitor NS-398 prevented the stimulation of cancer cell invasion induced either by irradiated fibroblasts or IL1beta. We propose that the effect of IL1beta on the invasiveness of the MDA-MB-231 cells involves elevation of matrix metalloproteinase-9 (MMP-9) production, induction of COX-2 expression and PGE2 biosynthesis. In conclusion, this study supports the involvement of IL1beta in the radiation-enhancement of breast cancer cell invasion. PMID- 23927564 TI - Multiple sclerosis in the Levant: a regional consensus statement. AB - The epidemiology of multiple sclerosis (MS) is rapidly changing in many parts of the world. In a geographic area that was previously associated with low prevalence, recent studies showing high prevalence and fast rising incidence of MS in the Levant countries led us neurologists of this region to meet in a consensus panel, in order to share our latest findings in terms of MS epidemiology and consent on MS management in the Levant. Twelve neurologists and MS experts representing various countries of the Levant (Lebanon, Syria, Jordan and Iraq) have met in Beirut on the 17(th) of February 2013, shared their latest epidemiological findings, discussed recent MS aspects in the region, and drafted a consensus on MS management relevant to this geographic area. PMID- 23927565 TI - Incivility, retention and new graduate nurses: an integrated review of the literature. AB - AIM: To evaluate the influence of incivility on the new graduate nurse transition experience. BACKGROUND: Incivility in the work environment is a major source of dissatisfaction and new graduate nurses are especially vulnerable. Incivility contributes to the high levels of turnover associated within the first 2 years of new graduate nurse employment. EVALUATION: An integrated review of the literature was conducted using MEDLINE-EBSCOhost, PsycInfo and CINAHL databases. Relevant articles were reviewed for appropriateness related to inclusion/exclusion criteria and for quality using established criteria. Sixteen studies were included in the final analysis. KEY ISSUES: Themes that emerged included workplace incivility, nurse residency programmes, mentoring through preceptors and empowerment/work environment. Findings indicated that incivility in the workplace was a significant predictor of low job satisfaction in new graduate nurses transitioning into practice. CONCLUSIONS: While graduate nurse transition programmes are associated with improved satisfaction and retention, they appear to address incivility by acculturating new graduate nurses to the experience of incivility. There is little evidence that the culture of incivility has been addressed. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers have the responsibility to be aware of the prevalence of incivility, assess for its occurrence, and implement strategies which eliminate workplace incivility and tolerance for uncivil behaviours. PMID- 23927566 TI - Live-fibroblast IR imaging of a cytoprotective PhotoCORM Activated with Visible Light. AB - Carbon monoxide releasing molecules (CORMs) are an emerging class of pharmaceutical compounds currently evaluated in several preclinical disease models. There is general consensus that the therapeutic effects elicited by the molecules may be directly ascribed to the biological function of the released CO. It remains unclear, however, if cellular internalization of CORMs is a critical event in their therapeutic action. To address the problem of cellular delivery, we have devised a general strategy which entails conjugation of a CO-releasing molecule (here a photoactivated CORM) to the 5'-OH ribose group of vitamin B12. Cyanocobalamin (B12) functions as the biocompatible water-soluble scaffold which actively transports the CORM against a concentration gradient into the cells. The uptake and cellular distribution of this B12-photoCORM conjugate is demonstrated via synchrotron FTIR spectromicroscopy measurements on living cells. Intracellular photoinduced CO release prevents fibroblasts from dying under conditions of hypoxia and metabolic depletion, conditions that may occur in vivo during insufficient blood supply to oxygen-sensitive tissues such as the heart or brain. PMID- 23927567 TI - Cyclometalated ruthenium sensitizers bearing a triphenylamino group for p-type NiO dye-sensitized solar cells. AB - We report the synthesis, photophysical, and electrochemical studies of a series of cyclometalated ruthenium sensitizers carrying triphenylamino linkers for p type NiO dye-sensitized solar cells (DSSCs). The general structure of these ruthenium sensitizers is Ru[N?N]2[N?C], where [N?N] is a diimine ligand and [N?C] is a cyclometalated ligand. The triphenylamino group is attached to the -para position of the ruthenium-carbon bond of the [N?)] ligand as a linker to bridge the ruthenium chromophore and the NiO surface and to enhance the electronic coupling for hole injection. As a result, cells made with these sensitizers generate higher short-circuit currents (Jsc) than cells sensitized with our prior sensitizers with phenylene linkers. Morever the N?N ligands are systematically tuned from 2,2'-bipyridine (O3), to 1,10-phenanthroline (O13), and to bathophenanthroline (O17). Following the series, the conjugation of the N?N ligand is increased, which results in the enhancement of extinction coefficient and the red shift of light absorption. However the solar cell sensitized with O3 still gives the largest Jsc of 3.04 mA/cm2. The large Jsc highlights the promising potential of using these cyclometalated ruthenium sensitizers for NiO DSSCs. In addition, the carrier dynamics of these solar cells has been systematically studied by intensity-modulated photovoltage spectroscopy (IMVS) and intensity-modulated photocurrent spectroscopy (IMPS). The results suggest that the O3 solar cell giving the largest Jsc is likely caused by the slow geminate charge recombination and efficient dye regeneration. PMID- 23927568 TI - Comparative effects of sitagliptin and metformin in patients with type 2 diabetes mellitus: a meta-analysis. AB - BACKGROUND: Sitagliptin has been widely used in the treatment of type 2 diabetes mellitus (T2DM); however, the therapeutic efficacy of sitagliptin remains inconclusive in randomized controlled studies on T2DM in which metformin has served as a control. OBJECTIVES: The present meta-analysis aimed to compare the therapeutic efficacy of sitagliptin and metformin in the treatment of T2DM. METHODS: We searched the following databases (Medline, Embase, Cochrane databases, Chinese Medical Journal Database, and the Chinese National Knowledge Infrastructure from inception until April 2013), and identified randomized controlled trials (RCTs) involving sitagliptin and metformin for T2DM. Two independent authors determined whether or not these trials met the inclusion criteria. Then, the variance of results from each study was calculated, and I(2) was employed for evaluation of heterogeneity. RESULTS: One hundred and twenty-one studies were identified, of which seven were included for further analysis. For T2DM, the therapeutic efficacy of sitagliptin and metformin was comparable in reducing HbA1c (P = 0.148, standard mean difference [SMD] = 0.13, 95% confidence interval [CI] = -0.05, 0.30), decreasing BMI (P = 0.063, SMD = 0.26, 95% CI = 0.01, 0.54), and improving the homeostasis model assessment (HOMA)-beta (P = 0.285, SMD = -0.05, 95% CI = -0.15, 0.04), but sitagliptin was inferior to metformin in improving HOMA-IR (P = 0.003, SMD = 0.16, 95% CI = 0.06, 0.27). CONCLUSIONS: Sitagliptin is similar to metformin in reducing HbA1c, decreasing body weight, and improving the function of beta cells, but is inferior to metformin in improving insulin sensitivity. More RCTs with large sample sizes are required to provide evidence for the rational application of sitagliptin. PMID- 23927569 TI - Bicarbonate-dependent transport of acetate and butyrate across the basolateral membrane of sheep rumen epithelium. AB - AIM: This study aimed to assess the role of HCO3- in the transport of acetate and butyrate across the basolateral membrane of rumen epithelium and to identify transport proteins involved. METHODS: The effects of basolateral variation in HCO3- concentrations on acetate and butyrate efflux out of the epithelium and the transepithelial flux of these short-chain fatty acids were tested in Ussing chamber experiments using (14)C-labelled substrates. HCO3--dependent transport mechanisms were characterized by adding specific inhibitors of candidate proteins to the serosal side. RESULTS: Effluxes of acetate and butyrate out of the epithelium were higher to the serosal side than to the mucosal side. Acetate and butyrate effluxes to both sides of rumen epithelium consisted of HCO3- independent and -dependent parts. HCO3--dependent transport across the basolateral membrane was confirmed in studies of transepithelial fluxes. Mucosal to serosal fluxes of acetate and butyrate decreased with lowering serosal HCO3- concentrations. In the presence of 25 mm HCO3-, transepithelial flux of acetate was inhibited effectively by p-hydroxymercuribenzoic acid or alpha-cyano-4 hydroxycinnamic acid, while butyrate flux was unaffected by the blockers. Fluxes of both acetate and butyrate from the serosal to the mucosal side were diminished largely by the addition of NO3- to the serosal side, with this effect being more pronounced for acetate. CONCLUSION: Our results indicate the existence of a basolateral short-chain fatty acid/HCO3- exchanger, with monocarboxylate transporter 1 as a primary candidate for acetate transfer. PMID- 23927570 TI - A sophisticated multi-step secretion mechanism: how the type 3 secretion system is regulated. AB - Many Gram-negative pathogens utilize type 3 secretion systems (T3SSs) for a successful infection. The T3SS is a large macromolecular complex which spans both bacterial membranes and delivers effector proteins into the host cell. The infection requires spatiotemporal control of diverse sets of secreted effectors and various mechanisms have evolved to regulate T3SS in response to external stimuli. This review will describe mechanisms that may control type 3 secretion, revealing a multi-step regulatory strategy. We then propose an updated model of T3SS that illustrates different stages of secretion and integrates the most recent structural and functional data. PMID- 23927571 TI - Envelope protein gene based molecular characterization of Japanese encephalitis virus clinical isolates from West Bengal, India: a comparative approach with respect to SA14-14-2 live attenuated vaccine strain. AB - BACKGROUND: Increasing virulence of Japanese encephalitis virus (JEV), a mosquito borne zoonotic pathogen is of grave concern because it causes a neurotrophic killer disease Japanese Encephalitis (JE) which, in turn, is responsible globally for viral acute encephalitis syndrome (AES). Despite the availability of vaccine, JE/AES cases and deaths have become regular features in the different rural districts of West Bengal (WB) state, India, indicating either the partial coverage of vaccine or the emergence of new strain of JEV. Therefore, a study was undertaken to characterize and compare the complete envelope (E) protein gene based molecular changes/patterns of JEVs circulating in WB. METHODS: Total of 98 AES case-patients' samples were tested to detect the presence of JEV specific immunoglobulin M (IgM) antibody by Mac-ELISA method. Only JEV IgM negative samples with a history of <=3 days' illness were screened for virus isolation and RT-PCR. E gene sequences of JEV isolates were subjected to molecular phylogeny and immunoinformatics analysis. RESULTS: Present study confirmed JEV etiology in 39.7% and 29.1% of patients presenting <=15 days' febrile illness, as determined by Mac-ELISA and RT-PCR respectively. Phylogenetic analysis based on complete E gene sequences of JEV isolates showed the co-circulation of JEV genotype I (GI) with genotype III (GIII). This study also demonstrated that isolate-specific crucial amino acid substitutions were closely related to neurovirulence/neuroinvasiveness of JE. On the basis of immunoinformatics analysis, some substitutions were predicted to disrupt T-cell epitope immunogenicity/antigenicity that might largely influence the outcome of vaccine derived from JEV GIII SA14-14-2 strain and this has been observed in a previously vaccinated boy with mild JE/AES due to JEV GI infection. CONCLUSIONS: Based on molecular evolutionary and bioinformatic approaches, we report evolution of JEV at a local level. Such naturally occurring evolution is likely to affect the disease profile and the vaccine efficacy to protect against JEV GI may demand careful evaluation. PMID- 23927572 TI - Baker's yeast beta glucan supplementation increases salivary IgA and decreases cold/flu symptomatic days after intense exercise. AB - Strenuous exercise, such as running a marathon, is known to suppress mucosal immunity for up to 24 hr, which can increase the risk of developing an upper respiratory tract infection (URTI) and reduced performance capacity (Allgrove JE, Geneen L, Latif S, Gleeson M. Influence of a fed or fasted state on the s-IgA response to prolonged cycling in active men and women. Int J Sport Nutr Exerc Metab. 2009;19(3):209-221; Barrett B, Locken K, Maberry R, Schwamman J, Brown R, Bobula J, Stauffacher EA. The Wisconsin Upper Respiratory Symptom Survey (WURSS): a new research instrument for assessing the common cold. J Fam Pract. 2002;51(3):265; Carpenter KC, Breslin WL, Davidson T, Adams A, McFarlin BK. Baker's yeast beta glucan supplementation increases monocytes and cytokines post exercise: implications for infection risk? Br J Nutr. 2012;1-9). While many dietary interventions have been used to combat postexercise immune suppression, most have been ineffective. The key purpose of this study was to determine if baker's yeast beta-glucan (BG) could positively affect the immune system of individuals undergoing intense exercise stress using two experiments. In the first (E1; N = 182 men and women), BG was compared to placebo supplementation for the incidence of URTI symptoms for 28 days postmarathon. In the second (E2; N = 60 men and women) changes in salivary immunoglobulin A (IgA) were evaluated after 50-min of strenuous cycling when participants had been supplemented for 10 days with either BG (250 mg/day) or placebo (rice flour). For E1, subjects reported URTI symptoms using a daily health log. For E2, saliva was collected prior to, immediately, and 2-hr postexercise using a salivette. Data for E1 and E2 were analyzed using separate analyses of variance (ANOVAs) with repeated measures (p < .05). In E1, BG was associated with a 37% reduction in the number of cold/flu symptom days postmarathon compared to placebo (p = .026). In E2, BG was associated with a 32% increase in salivary IgA (p = .048) at 2 hr after exercise compared to placebo. In summary, the present study demonstrates that BG may reduce URTI symptomatic days and improve mucosal immunity (salivary IgA) postexercise. PMID- 23927573 TI - Assessing the Applicability of Singlet Oxygen Photosensitizers in Leaf Studies. AB - Singlet oxygen ((1) O2 ) is of special interest in plant stress physiology. Studies focused on internal, chlorophyll-mediated production are often complemented with the use of artificial (1) O2 photosensitizers. Here, we report a comparative study on the effects of Rose Bengal (RB), Methylene Violet (MVI), Neutral Red (NR) and Indigo Carmine (IC). These were infiltrated into tobacco leaves at concentrations generating the same fluxes of (1) O2 in solution. Following green light-induced (1) O2 production from these dyes, leaf photosynthesis was characterized by Photosystem (PS) II and PSI electron transport and oxidative damage was monitored as degradation of D1, a PSII core protein. Cellular localizations were identified on the basis of the dyes' fluorescence using confocal laser scanning microscopy. We found that RB and NR were both localized in chloroplasts but the latter had very little effect, probably due to its pH-dependent photosensitizing. Both RB and intracellular, nonplastid MVI decreased PSII electron transport, but the effect of RB was stronger than that of MVI and only RB was capable of damaging the D1 protein. Intercellularly localized IC had no significant effect. Our results also suggest caution when using RB as photosensitizer because it affects PSII electron transport. PMID- 23927574 TI - Clostridium difficile PCR ribotype 046 is common among neonatal pigs and humans in Sweden. AB - Clostridium difficile PCR ribotype 046 was found in 67% of neonatal piglets (45/67) sampled from three separate pig-breeding farms in Sweden. Sows from the same farms were tested and 50% were colonized in faeces and 30% were colonized on skin. An environmental source was suggested because identical PCR ribotypes were isolated from faeces as well as externally. Human C. difficile infection outbreaks in southern Sweden by the identical PCR ribotype 046 indicate its zoonotic potential. PMID- 23927575 TI - The effect of interleukin-2 on canine peripheral nerve sheath tumours after marginal surgical excision: a double-blind randomized study. AB - BACKGROUND: The objective of this study was to evaluate the effect on outcomes of intraoperative recombinant human interleukin-2 injection after surgical resection of peripheral nerve sheath tumours. In this double-blind trial, 40 patients due to undergo surgical excision (<5 mm margins) of presumed peripheral nerve sheath tumours were randomized to receive intraoperative injection of interleukin-2 or placebo into the wound bed. RESULTS: There were no significant differences in any variable investigated or in median survival between the two groups. The median recurrence free interval was 874 days (range 48-2141 days), The recurrence-free interval and overall survival time were significantly longer in dogs that undergone the primary surgery by a specialist-certified surgeon compared to a referring veterinarian regardless of whether additional adjunct therapy was given. CONCLUSION: Overall, marginal excision of peripheral nerve sheath tumours in dogs resulted in a long survival time, but adjuvant treatment with recombinant human interleukin-2 (rhIL-2) did not provide a survival advantage. PMID- 23927576 TI - The design and statistical power of treatment re-infection studies of the association between pre-erythrocytic immunity and infection with Plasmodium falciparum. AB - BACKGROUND: Understanding the role of pre-erythrocytic immune responses to Plasmodium falciparum parasites is crucial for understanding the epidemiology of malaria. However, published studies have reported inconsistent results on the association between markers of pre-erythrocytic immunity and protection from malaria. METHODS: The design and statistical methods of studies of pre erythrocytic immunity were reviewed, and factors affecting the likelihood of detecting statistically significant associations were assessed. Treatment re infection studies were simulated to estimate the effects of study size, transmission intensity, and sampling frequency on the statistical power to detect an association between markers of pre-erythrocytic immunity and protection from infection. RESULTS: Nine of nineteen studies reviewed reported statistically significant associations between markers of pre-erythrocytic immunity and protection from infection. Studies with large numbers of participants in high transmission settings, followed longitudinally with active detection of infection and with immune responses analysed as continuous variables, were most likely to detect statistically significant associations. Simulation of treatment re infection studies highlights that many studies are underpowered to detect statistically significant associations, providing an explanation for the finding that only some studies report significant associations between pre-erythrocytic immune responses and protection from infection. CONCLUSIONS: The findings of the review and model simulations are consistent with the hypothesis that pre erythrocytic immune responses prevent P. falciparum infections, but that many studies are underpowered to consistently detect this effect. PMID- 23927578 TI - D-cycloserine or similar physiochemical compounds may be uniquely suited for use in Bacillus anthracis spore decontamination strategies. AB - AIMS: As observed in the aftermath of the anthrax attacks of 2001, decontamination and remediation of a site contaminated by the accidental or intentional release of Bacillus anthracis spores is difficult, costly and potentially damaging to the environment. The identification of novel strategies that neutralize the threat of spores while minimizing environmental damage remains a high priority. We investigated the efficacy of d-cycloserine (DCS), an antibiotic and inhibitor of the spore-associated enzyme (alanine racemase) responsible for converting l-alanine to d-alanine, as a spore germination enhancer and antimicrobial agent. METHODS AND RESULTS: We characterized the impact of DCS exposure on both germinating spores and vegetative cells of fully virulent B. anthracis by evaluating spore germination kinetics, determining the minimum inhibitory concentrations (MICs) required to affect growth of the bacteria and performing macrophage viability assays. DCS enhanced germination induced by l-alanine and also efficiently killed the newly germinated spores. Furthermore, DCS proved nontoxic to macrophages at concentrations that provided protection from the killing effects of spores. Similar tests were conducted with Bacillus thuringiensis (subspecies kurstaki and Al Hakam) to determine its potential as a possible surrogate for B. anthracis field trials. Bacillus thuringiensis spores responded in a similar manner to B. anthracis spores when exposed to DCS. CONCLUSIONS: These results further support that DCS augments the germination response of spores in the presence of l-alanine but also reveal that DCS is bactericidal towards germinating spores. SIGNIFICANCE AND IMPACT OF THE STUDY: DCS (or similar compounds) may be uniquely suited for use as part of decontamination strategies by augmenting the induction of spore germination and then rendering the germinated spores nonviable. PMID- 23927577 TI - Effect of a monofunctional phenanthriplatin-DNA adduct on RNA polymerase II transcriptional fidelity and translesion synthesis. AB - Transcription inhibition by platinum anticancer drugs is an important component of their mechanism of action. Phenanthriplatin, a cisplatin derivative containing phenanthridine in place of one of the chloride ligands, forms highly potent monofunctional adducts on DNA having a structure and spectrum of anticancer activity distinct from those of the parent drug. Understanding the functional consequences of DNA damage by phenanthriplatin for the normal functions of RNA polymerase II (Pol II), the major cellular transcription machinery component, is an important step toward elucidating its mechanism of action. In this study, we present the first systematic mechanistic investigation that addresses how a site specific phenanthriplatin-DNA d(G) monofunctional adduct affects the Pol II elongation and transcriptional fidelity checkpoint steps. Pol II processing of the phenanthriplatin lesion differs significantly from that of the canonical cisplatin-DNA 1,2-d(GpG) intrastrand cross-link. A majority of Pol II elongation complexes stall after successful addition of CTP opposite the phenanthriplatin-dG adduct in an error-free manner, with specificity for CTP incorporation being essentially the same as for undamaged dG on the template. A small portion of Pol II undergoes slow, error-prone bypass of the phenanthriplatin-dG lesion, which resembles DNA polymerases that similarly switch from high-fidelity replicative DNA processing (error-free) to low-fidelity translesion DNA synthesis (error prone) at DNA damage sites. These results provide the first insights into how the Pol II transcription machinery processes the most abundant DNA lesion of the monofunctional phenanthriplatin anticancer drug candidate and enrich our general understanding of Pol II transcription fidelity maintenance, lesion bypass, and transcription-derived mutagenesis. Because of the current interest in monofunctional, DNA-damaging metallodrugs, these results are of likely relevance to a broad spectrum of next-generation anticancer agents being developed by the medicinal inorganic chemistry community. PMID- 23927579 TI - The authors' reply. PMID- 23927580 TI - Characterization of the transient oxaphosphetane BChE inhibitor formed from spontaneously activated ethephon. AB - The major plant growth regulator ethephon degrades to ethylene and phosphate in aqueous solutions and plants and is spontaneously activated to a butyrylcholinesterase (BChE) inhibitor in alkaline solutions and animal tissues. In the present (31)P NMR kinetic study of the reactions of ethephon in pH 7.4 carbonate buffer, we observed a transient peak at 28.11 ppm. The time course for the appearance and disappearance of this peak matches the activation/degradation kinetic profile of the BChE inhibitor, and the chemical shift supports the proposed 2-oxo-2-hydroxy-1,2-oxaphosphetane structure. PMID- 23927581 TI - A trigonal prismatic ligand in the metal-mediated self-assembly of one- and two dimensional metallosupramolecular polymers. AB - A novel trispyrazine-pillared prismatic bicycooxacalixaromatic ligand L is synthesized, and its application in metal-mediated self-assembly is described. Under self-assembly conditions, single chain, double-stranded cross-linked coordination polymer and two-dimensional (2D) coordination polymeric networks were formed via M-L (Ag(+), Cu(2+), and Zn(2+)) coordinative interactions. Structural analyses revealed that the antiparallelly arranged one-dimensional coordination polymers (Cu(2+) and Zn(2+)) are arranged to generate well-defined voids to host aromatic guests (benzene) via C-H...pi and pi...pi interactions, while the double-stranded cross-linked coordination polymer (Ag(+)) contains a rhomboidal [Ag2(L(3))2] (L(3): tridentate ligand) cage motif to include a benzene guest; the "thicker" (thickness: ac 5 A) 2D coordination polymeric networks (Ag(+), Cu(2+), and Zn(2+)), however, are all formed by connection of one or two kinds of topologically different metallomacrocyclic cage units. These unique metallomacrocyclic cage units in the 2D coordination polymeric networks are capable of hosting different guest species. For instance, the rhomboidal [M2(L(3))2] (M = Ag(+), Cu(2+)) cage units were found to host a benzene or a nitrate anion; a hexahedral [M3(L(3))3] (M = Ag(+)) cage was found to host a ligand L or a DMF molecule; the hexahedral [M4(L(3))4] (M = Cu(2+)) cage was found to host four solvent molecules of benzene; and the rectangular [M3(L(3))3] (M = Cu(2+), Zn(2+)) cage units, however, were found to host two THF molecules. The results highlight the potential of ligand L for applications in the construction of "thicker" 2D coordination polymeric networks with well-defined metallomacrocyclic cage units capable of hosting various guest species. PMID- 23927583 TI - Dapsone for primary immune thrombocytopenia in adults and children: an evidence based review. AB - Primary immune thrombocytopenia is a potentially life-threatening condition. Approximately two-thirds of adult patients do not have a sustained response to steroids (first-line therapy). For these patients, a number of other treatment options exist, such as rituximab, splenectomy, immunosuppressants, and thrombopoietin receptor agonists, but they are costly and have side effects. Dapsone is an inexpensive drug with a well-established safety profile. Unfortunately, this treatment option has not been explored adequately. This review is aimed at analyzing the currently available evidence for the use of dapsone as second-line or third-line therapy in primary immune thrombocytopenia. PMID- 23927582 TI - Comparison of levofloxacin versus moxifloxacin for multidrug-resistant tuberculosis. AB - RATIONALE: Levofloxacin (LFX) and moxifloxacin (MXF) are the two most frequently recommended fluoroquinolones for treatment of patients with multidrug-resistant tuberculosis (MDR-TB). However, studies comparing the effectiveness of LFX and MXF among patients with MDR-TB are lacking. OBJECTIVES: To compare the effectiveness of LFX and MXF in terms of culture conversion after 3 months of treatment for MDR-TB. METHODS: In this prospective multicenter randomized open label trial, we randomly assigned 182 patients with MDR-TB (sensitive to LFX and MXF) to receive either LFX (750 mg/day; 90 patients) or MXF (400 mg/day; 92 patients) with a background drug regimen. The primary outcome was the proportion of patients who achieved sputum culture conversion at 3 months of treatment. Secondary outcomes were time to culture conversion and time to smear conversion, with data censored at 3 months, and the proportions of adverse drug reactions. MEASUREMENTS AND MAIN RESULTS: At 3 months of treatment, 68 (88.3%) of the 77 patients in the LFX group and 67 (90.5%) of the 74 in the MXF group showed conversion to negative sputum cultures (odds ratio for LFX compared with MXF, 0.78; 95% confidence interval, 0.27-2.20). Adverse drug reactions were reported in six patients (7.7%) in the LFX group and four (5.2%) in the MXF group (P = 0.75). CONCLUSIONS: The choice of LFX or MXF for treatment of patients with MDR TB may not affect sputum culture conversion at 3 months of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01055145). PMID- 23927584 TI - The oppressive nature of work in healthcare: predictors of aggression against nurses and administrative staff. AB - AIMS: To assess the antecedents of workplace aggression (bullying and violence) among nurses and administration staff. BACKGROUND: As a result of power structures within the healthcare industry, nurses and administration staff may be more vulnerable to workplace aggression. Environmental and individual characteristics have been linked to the occurrence of such aggression among other groups. However, most research focuses on bullying, rarely extending these ideas to violence or nurses and administration staff specifically. METHODS: Surveys were distributed to nurses and administration staff employed by an Australian healthcare organisation. Aggression types (bullying and violence), as well as environmental (demands, control and support) and individual (negative affectivity, NA) characteristics were measured. RESULTS: External emotional abuse was most frequently reported for nurses (29%) and bullying for administration staff (27%). Demands, support and NA were associated with different aggression types in nurses, whereas for administration staff, control, support and NA were linked. CONCLUSION(S): Low support and high NA are particularly important to nurses and administration staff and their experiences of aggression. IMPLICATIONS FOR NURSING MANAGEMENT: Appropriate training for managers in providing support and acknowledging individual factors associated with aggression is essential. Further, managers should monitor aggression risk from patients and their associations towards staff in busy times. PMID- 23927585 TI - Comment on "High-active anatase TiO2 nanosheets exposed with 95% {100} facets toward efficient H2 evolution and CO2 photoreduction". PMID- 23927586 TI - Comparison of Bayley-2 and Bayley-3 scores at 18 months in term infants following neonatal encephalopathy and therapeutic hypothermia. AB - AIM: Neuroprotection trials for neonatal encephalopathy use moderate or severe disability as an outcome, with the Bayley Scales of Infant Development, Second Edition (Bayley-2) Index scores of <70 as part of the criteria. The Bayley Scales of Infant and Toddler, 3rd Development, Third Edition (Bayley-3) have superseded Bayley-2 and yield higher than expected scores in typically developing and high risk infants. The aim of this study, therefore, was to compare Bayley-2 scores and Bayley-3 scores in term-born infants surviving neonatal encephalopathy treated with hypothermia. METHOD: Sixty-one term-born infants (37 males, 24 females; median gestational age at birth 40 wks, range 36-42 wks; median birthweight 3280 g, range 2295-5050) following neonatal encephalopathy and hypothermia had contemporaneous assessment at 18 months using the Bayley-2 and Bayley-3. RESULTS: The median Bayley-3 Cognitive Composite score was 7 points higher than the median Bayley-2 Mental Developmental Index (MDI) score and the median Bayley-3 Motor Composite score was 18 points higher than the median Bayley 2 Psychomotor Developmental Index (PDI) score. Ten children had a Bayley-2 MDI of <70; only three children had Bayley-3 combined Cognitive/Language scores of <70. Eleven children had Bayley-2 PDI scores of <70 and four had modified Bayley-3 Motor Composite scores of <70. Applying regression equations to Bayley-3 scores adjusted rates of severe delay to similar proportions found using Bayley-2 scores. INTERPRETATION: Fewer children were classified with severe delay using the Bayley-3 than the Bayley-2, which prohibits direct comparison of scores. Increased Bayley-3 cut-off thresholds for classifying severe disability are recommended when comparing studies in this clinical group using Bayley-2 scores. PMID- 23927587 TI - Experimental evidence of the relevance of orientational correlations in photoinduced bimolecular reactions in solution. AB - A major problem in the extraction of the reaction probability in bimolecular processes is the disentanglement from the influence of molecular diffusion. One of the strategies to overcome it makes use of reactive solvents in which the reactants do not need to diffuse to encounter each other. However, most of our quantitative understanding of chemical reactions in solution between free partners is based on the assumption that they can be approximated by spheres because rotation averages their mutual orientations. This condition may not be fulfilled when the reaction takes place on time scales faster than that of molecular reorientation. In this work, the fluorescence quenching of two very similar polyaromatic hydrocarbons with different electric dipole moments is measured. The concentration of a liquid electron-donating quencher is varied from very dilute solutions to pure quencher solutions. In both cases, the thermodynamics of the reactions are very similar and, according to the Marcus expression, the kinetics are expected to proceed at similar rates. However, one of them is 10 times faster in the pure quencher solution. This difference starts at relatively low quencher concentrations. An explanation based on the fluorophore-solvent dipole-dipole interaction and the consequent orientational solvent structure is provided. The orientational correlation between fluorophore and quencher is calculated by means of computer simulations. Important differences depending on the fluorophore dipole moment are found. The kinetics can be explained quantitatively with a reaction-diffusion model that incorporates the effects of the presence of the dipole moment and the rotational diffusion, only in the highest quencher concentration case, but not in dilute solutions, most likely due to fundamental limitations of the kinetic theory. PMID- 23927588 TI - The authors' reply: Nonsustained hypercalcaemia and primary hyperparathyroidism in the PEARS cohort. PMID- 23927591 TI - Photophysical Properties of Lanthanide (Eu(3+) , Tb(3+) ) Hybrid Soft Gels of Double Functional Linker of Ionic Liquid-Modified Silane. AB - Four kinds of luminescent hybrid soft gels have been assembled by introducing the lanthanide (Eu(3+) , Tb(3+) ) tetrakis beta-diketonate into the covalently bonded imidazolium-based silica through electrostatic interactions. Here, the imidazolium-based silica matrices are prepared from imidazolium-derived organotriethoxysilanes by the sol-gel process, in which the imidazolium cations are strongly anchored within the silica matrices while anions can still be exchanged following application for functionalization of lanthanide complexes. The photoluminescence measurements indicated that these hybrid soft gels exhibit characteristic red and green luminescence originating from the corresponding ternary lanthanide ions (Eu(3+) , Tb(3+) ). Further investigation of photophysical properties reveals that these soft gels have inherited the outstanding luminescent properties from the lanthanide tetrakis beta-diketonate complexes such as strong luminescence intensities, long lifetimes and high luminescence quantum efficiencies. PMID- 23927590 TI - Formulation and characterization of atovaquone nanosuspension for improved oral delivery in the treatment of malaria. AB - AIM: The objective of the present study was to develop an atovaquone (ATQ) nanosuspension and evaluate its ability to improve the pharmacokinetic and therapeutic efficacy on oral administration. MATERIALS & METHODS: The ATQ nanosuspension was prepared by a combination of microprecipitation and high pressure homogenization. It was freeze dried and characterized for various physiochemical properties. In vivo pharmacokinetics was performed in rats whereas antimalarial efficacy was assessed in mice using a 4-day suppressive test. RESULTS: The ATQ nanosuspension stabilized with Solutol((r)) HS 15 (BASF India Ltd, Mumbai, India) and CapryolTM 90 (Gattefosse, Mumbai, India) exhibited a z average diameter of 371.50 nm and a polydispersity index of 0.19. X-ray diffraction and differential scanning calorimetry analysis indicated no substantial changes in the crystalline state of ATQ nanocrystals. The aqueous solubility and in vitro dissolution rate were significantly increased by reducing the particle size. An in vivo pharmacokinetics study of the nanosuspension compared with a drug suspension and Malarone((r)) (GlaxoSmithKline, Brentford, UK) exhibited an approximately 4.6-3.2-fold improvement in area under plasma concentration. A significant increase in Cmax and decrease in time to reach peak plasma concentration after administration was also observed. ATQ in nanosized form, even at one-quarter lower doses, exhibited greater reduction in parasitemia and prolonged survival compared with its reference formulations. CONCLUSION: Results of this pilot study highlight the potential of nanosuspension as an efficient and commercially viable strategy for improving delivery of ATQ for malaria treatment. PMID- 23927592 TI - Analysis of surface protein expression in human bone marrow stromal cells: new aspects of culture-induced changes, inter-donor differences and intracellular expression. AB - The most widely used technique for isolation of human bone marrow stromal cells (hBMSCs) from bone marrow includes density gradient centrifugation, recovery of the mononuclear cell population, and subsequent isolation of hBMSCs by virtue of their plastic adherence. During subsequent in vitro cultivation, they may lose their original characteristics since in vitro the stem cell niche cannot yet be properly mimicked. To further characterize these culture-induced changes in regard to mRNA and extra- and intracellular protein expression, as well as potential differences between hBMSCs from different donors, we investigated a panel of CD antigens for their presence on in vitro cultured hBMSCs. Interestingly, after culture-induced downregulation of their extracellular expression, both CD146 and CD271 persist intracellularly, which hints at the possibility that culture-induced changes may be reversed by appropriate stimuli. Further, CD34-a protein whose expression on hBMSCs is still controversial-is expressed at the intracellular level in hBMSCs of all donors independently of passage number. CD34 mRNA levels are significantly higher in female than in male donors. In summary, we further elucidate phenotypical changes induced by in vitro culture of hBMSCs, highlight interindividual differences in the phenotype of these cells and for the first time show the intracellular expression of CD34. PMID- 23927594 TI - A randomized, double-blind, placebo-controlled clinical trial to investigate the effect of Cynatine(r) FLX on symptoms of osteoarthritis. AB - OBJECTIVE: A novel product Cynatine(r) FLX was evaluated on symptoms associated with knee osteoarthritis in a randomized, double-blind, placebo-controlled clinical trial. METHODS: A total of 50 males and females were included and randomized into two groups. The active group (n = 25) received two capsules totaling 500 mg of Cynatine(r) FLX per day and the placebo group (n = 25) received an identical two capsules of maltodextrin per day for 60 days. The WOMAC(r) Osteoarthritis Index, SF-36, and Lequesne Index of Severity were used to evaluate the symptoms. RESULTS: The results show that Cynatine(r) FLX was twice as effective in reducing pain scores as compared to placebo. Cynatine(r) FLX showed the same effectiveness in reducing stiffness. CONCLUSION: This new product may be effective in relieving symptoms of knee osteoarthritis. PMID- 23927595 TI - Mechanisms of cytolysin-induced cell damage -- a role for auto- and paracrine signalling. AB - Cytolysins inflict cell damage by forming pores in the plasma membrane. The Na(+) conductivity of these pores results in an ion influx that exceeds the capacity of the Na(+) /K(+) -pump to extrude Na(+) . This net load of intracellular osmolytes results in swelling and eventual lysis of the attacked cell. Many nucleated cells have the capacity to reduce the potential damage of pore-forming proteins, whereas erythrocytes have been regarded as essentially defenceless against cytolysin-induced cell damage. This review addresses how autocrine/paracrine signalling and the cells intrinsic volume regulation markedly influence the fate of the cell after membrane insertion of cytolysins. Moreover, it regards the various steps that may explain the relative large degree of diversity between cell types and species as well as highlights some of the current gaps in the mechanistic understanding of cytolysin-induced cell injury. PMID- 23927593 TI - Intimate host attachment: enteropathogenic and enterohaemorrhagic Escherichia coli. AB - Enteropathogenic and enterohaemorrhagic Escherichia coli use a novel infection strategy to colonize the gut epithelium, involving translocation of their own receptor, Tir, via a type III secretion system and subsequent formation of attaching and effecting (A/E) lesions. Following integration into the host cell plasma membrane of cultured cells, and clustering by the outer membrane adhesin intimin, Tir triggers multiple actin polymerization pathways involving host and bacterial adaptor proteins that converge on the host Arp2/3 actin nucleator. Although initially thought to be involved in A/E lesion formation, recent data have shown that the known Tir-induced actin polymerization pathways are dispensable for this activity, but can play other major roles in colonization efficiency, in vivo fitness and systemic disease. In this review we summarize the roadmap leading from the discovery of Tir, through the different actin polymerization pathways it triggers, to our current understanding of their physiological functions. PMID- 23927596 TI - Is a Plasmodium lactate dehydrogenase (pLDH) enzyme-linked immunosorbent (ELISA) based assay a valid tool for detecting risky malaria blood donations in Africa? AB - BACKGROUND: Malaria is a leading cause of mortality in southern Benin. The main causative agent, Plasmodium falciparum, poses a threat on critical transfusions in pregnant women and children. This study's objective was to compare the performance of different malaria screening methods in blood donors in southern Benin, a malaria-endemic country. METHODS: Blood from 2,515 voluntary blood donors in Benin was collected over a period of 10 months in ethylenediaminetetraacetic acid (EDTA) tubes, which were then classified according to extraction time: long rainy season, short dry season, short rainy season, and long dry season. Microscopic examination was used to count parasites. Parasite density (PD) was expressed as the number of parasites per MUL of blood. Pan Plasmodium pLDH detection was assessed by an ELISA-malaria antigen test. Using crude soluble P. falciparum antigens, an ELISA-malaria antibody test detected anti-Plasmodium antibodies. RESULTS: Among the 2,515 blood donors (2,025 males and 488 females) screened, the rate of asymptomatic Plasmodium carriage was 295/2,515 (11.72%, 95% CI: 10.5-13.1%). Males had a higher infection rate (12.4%) than did females (8.8%). Parasite density was very low: between seven and100 parasites per MUL of blood was reported in 80% of donors with parasitaemia. Three Plasmodium species were diagnosed: P. falciparum in 280/295 patients (95.0%), Plasmodium malariae in 14/295 (5.0%), and Plasmodium ovale in 1/295 (0.34%). Malaria prevalence in donors was higher during the rainy seasons (13.7%) compared with the dry seasons (9.9%). The use of a highly sensitive assay enabled pan Plasmodium pLDH detection in 966/2,515 (38.4%, 95% CI: 36.5%-40.3%). Malaria antibody prevalence was 1,859/2,515 (73.9%, 95% CI: 72.16-75.6%). Donors' antigenaemia and antibody levels varied significantly (P <0.05) over the course of the four seasons. The highest antigenaemia rate 323/630 (51.3%), was observed during the short rainy season, while the highest antibody prevalence, 751/886 (84.7%), was recorded during the long dry season. CONCLUSION: Blood donations infected with Plasmodium can transmit malaria to donation recipients. Malaria diagnostic methods are currently available, but the feasibility criteria for mass screening in endemic areas become preponderant. Detection of the pLDH antigen seems to be an adequate screening tool in endemic areas, for this antigen indicates parasite presence. Routine screening of all donated blood would prevent infected blood donations and reduce P. falciparum transmission in critical patients, such as children and pregnant women. This tool would also decrease medical prophylaxis in donation recipients and contribute to lower Plasmodium resistance. PMID- 23927597 TI - Multi-centre evaluation of mass spectrometric identification of anaerobic bacteria using the VITEK(r) MS system. AB - Accurate and timely identification of anaerobic bacteria is critical to successful treatment. Classic phenotypic methods for identification require long turnaround times and can exhibit poor species level identification. Matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is an identification method that can provide rapid identification of anaerobes. We present a multi-centre study assessing the clinical performance of the VITEK((r)) MS in the identification of anaerobic bacteria. Five different test sites analysed a collection of 651 unique anaerobic isolates comprising 11 different genera. Multiple species were included for several of the genera. Briefly, anaerobic isolates were applied directly to a well of a target plate. Matrix solution (alpha-cyano-4-hydroxycinnamic acid) was added and allowed to dry. Mass spectra results were generated with the VITEK((r)) MS, and the comparative spectral analysis and organism identification were determined using the VITEK((r)) MS database 2.0. Results were confirmed by 16S rRNA gene sequencing. Of the 651 isolates analysed, 91.2% (594/651) exhibited the correct species identification. An additional eight isolates were correctly identified to genus level, raising the rate of identification to 92.5%. Genus-level identification consisted of Actinomyces, Bacteroides and Prevotella species. Fusobacterium nucleatum, Actinomyces neuii and Bacteroides uniformis were notable for an increased percentage of no-identification results compared with the other anaerobes tested. VITEK((r)) MS identification of clinically relevant anaerobes is highly accurate and represents a dramatic improvement over other phenotypic methods in accuracy and turnaround time. PMID- 23927598 TI - Positive predispositions, quality of life and chronic illness. AB - This study assessed the extent to which being predisposed towards engaging in acts of gratitude and forgiveness is associated with enhanced quality of life (QoL), and whether these associations are mediated by positive and negative affective states. The study sample comprised 327 people with one of three chronic illnesses (arthritis, chronic obstructive pulmonary disease and diabetes). Participants completed self-report measures of two positive predispositions (the tendencies towards gratitude and forgiveness), two affective states (positive and negative) and three indices of QoL (physical, psychological and satisfaction with life). As hypothesised, gratitude, and to a lesser extent forgiveness, predicted enhanced QoL, with most effects mediated via increased positive affect. Findings support the view that predispositions towards interpersonal gratitude, and possibly interpersonal forgiveness, may bolster the QoL of people living with chronic physical illness. Consistent with contemporary theories of positive emotion, gratitude appears to have its effects via enhancing positive affect. The study adds to the emerging evidence that a predisposition towards gratitude benefits QoL and extends past findings by identifying a mechanism that is important in people with chronic illnesses. PMID- 23927599 TI - Cell-based medicinal chemistry optimization of high throughput screening hits for orally active antimalarials. Part 2: hits from SoftFocus kinase and other libraries. AB - In the second part of this Miniperspectives series, we highlight our medicinal chemistry efforts involving progression of hits from whole cell high-throughput screening (HTS) of a SoftFocus kinase library against the malaria parasite Plasmodium falciparum . Successful SAR exploration in Hit-to-Lead and Lead Optimization efforts leading to the selection of a preclinical development candidate are demonstrated. Related efforts by researchers from Broad/Genzyme, Anacor, and GSK are briefly covered. PMID- 23927600 TI - Prolonged polyarthralgia in a German traveller with Mayaro virus infection without inflammatory correlates. AB - BACKGROUND: Mayaro virus is endemic in South America and sporadic outbreaks have been described. It causes a dengue-like febrile illness accompanied by severe and long-lasting polyarthralgias. Outside endemic regions, however, the disease is not well known and can be misdiagnosed as dengue. International travellers are at risk to acquire Mayaro virus and due to increased worldwide travel infectious disease specialists need to be aware of such rare clinical entities. CASE PRESENTATION: We report the first Mayaro virus infection imported into Germany. A 20-year-old woman developed fever, myalgia, maculopapular rash, and polyarthralgias following a 10-day trip in the Rurrenabaque region of Bolivia. Severe polyarthralgias persisted for 5 months and were treated with non-steroidal anti-inflammatory drugs. Serological analysis demonstrated Mayaro virus-specific IgM and -IgG antibodies two months after onset of symptoms. Except for CXCL8/IL-8 other proinflammatory chemokines and cytokines were unremarkable at this time. CONCLUSIONS: Dissemination of knowledge on rare disease might improve patient management. Understanding the inherent features of Mayaro virus infection and how the virus interacts with its host are essential for optimal patient care and therapy. PMID- 23927601 TI - Sulfoxides as response elements for fluorescent chemosensors. AB - Sulfoxides are shown to be viable reporting groups for fluorescent chemosensor development. Metal coordination of sulfoxide-appended fluorophores suppresses excited-state pyramidal inversion of the sulfoxide, leading to enhanced fluorescence emission. This new structural motif allows the construction of fluorescent chemosensors that do not require nitrogen coordination as part of the signaling process, that have a range of selectivities and affinities for oxophilic metal ions, and that can function in water. PMID- 23927602 TI - Epidemiology of nontuberculous mycobacterial infections and associated chronic macrolide use among persons with cystic fibrosis. AB - RATIONALE: Persons with cystic fibrosis (CF) are at high risk of nontuberculous mycobacterial (NTM) infection, with treatment requiring prolonged multidrug regimens that include macrolides. Although macrolides, specifically azithromycin, are used in the management of patients with CF with chronic Pseudomonas, macrolide-resistant NTM infections are of growing concern. OBJECTIVES: To evaluate the relationship between chronic macrolide use and NTM infection among patients with CF included in the 2011 CF Patient Registry (CFPR). METHODS: We performed a nested case-control study: incident NTM cases were persons aged more than 5 years with at least one positive culture for NTM in 2011. Controls were persons with negative cultures in 2010 and 2011. MEASUREMENTS AND MAIN RESULTS: The 2011 CFPR included 27,112 patients; 5,403 (20%) were cultured for mycobacteria in 2010-2011 and met all inclusion criteria. Of these, 191 (4%) were NTM-positive in 2011 only (cases); 5,212 (96%) were NTM-negative in 2010 and 2011 (control subjects). Among the cases, 122 (64%) were culture-positive for Mycobacterium avium complex (MAC) and 69 (36%) for M. abscessus. Azithromycin use in 2010 was less frequently reported among MAC cases (57%; odds ratio = 0.7, P < 0.05) and M. abscessus cases (51%; odds ratio = 0.5, P < 0.01) than in control subjects (66%). Among adolescents and adults, patients with the greatest number of years on chronic macrolides were the least likely to develop incident NTM in 2011 (P < 0.01). CONCLUSIONS: Patients with incident NTM infections from either MAC or M. abscessus were less likely to have had chronic azithromycin treatment in the past year. However, because macrolide monotherapy may lead to macrolide resistance, routine screening for NTM should be considered for persons with CF. PMID- 23927603 TI - Improving evidence-based primary care for chronic kidney disease: study protocol for a cluster randomized control trial for translating evidence into practice (TRANSLATE CKD). AB - BACKGROUND: Chronic kidney disease (CKD) and end stage renal disease (ESRD) are steadily increasing in prevalence in the United States. While there is reasonable evidence that specific activities can be implemented by primary care physicians (PCPs) to delay CKD progression and reduce mortality, CKD is under-recognized and undertreated in primary care offices, and PCPs are generally not familiar with treatment guidelines. The current study addresses the question of whether the facilitated TRANSLATE model compared to computer decision support (CDS) alone will lead to improved evidence-based care for CKD in primary care offices. METHODS/DESIGN: This protocol consists of a cluster randomized controlled trial (CRCT) followed by a process and cost analysis. Only practices providing ambulatory primary care as their principal function, located in non-hospital settings, employing at least one primary care physician, with a minimum of 2,000 patients seen in the prior year, are eligible. The intervention will occur at the cluster level and consists of providing CKD-specific CDS versus CKD-specific CDS plus practice facilitation for all elements of the TRANSLATE model. Patient-level data will be collected from each participating practice to examine adherence to guideline-concordant care, progression of CKD and all-cause mortality. Patients are considered to meet stage three CKD criteria if at least two consecutive estimated glomerular filtration rate (eGFR) measurements at least three months apart fall below 60 ml/min. The process evaluation (cluster level) will determine through qualitative methods the fidelity of the facilitated TRANSLATE program and find the challenges and enablers of the implementation process. The cost effectiveness analysis will compare the benefit of the intervention of CDS alone against the intervention of CDS plus TRANSLATE (practice facilitation) in relationship to overall cost per quality adjusted years of life. DISCUSSION: This study has three major innovations. First, this study adapts the TRANSLATE method, proven effective in diabetes care, to CKD. Second, we are creating a generalizable CDS specific to the Kidney Disease Outcome Quality Initiative (KDOQI) guidelines for CKD. Additionally, this study will evaluate the effects of CDS versus CDS with facilitation and answer key questions regarding the cost effectiveness of a facilitated model for improving CKD outcomes. The study is testing virtual facilitation and Academic detailing making the findings generalizable to any area of the country. TRIAL REGISTRATION: Registered as NCT01767883 on clinicaltrials.gov PMID- 23927604 TI - Aryl-linked salicylaldoxime-based copper(II) helicates and "boxes": synthesis, X ray analysis, and anion influence on complex structure. AB - The synthesis and spectroscopic analysis of both "metal-only" and anion encapsulated salicylaldoxime-based complexes utilizing a new 1,3-xylyl strap are described. X-ray crystallographic analysis reveals that the aromatic spacer restricts the confirmation flexibility of the resulting complexes leading to dicopper(II) double helicate and dicopper(II) 2 + 2 "box" structural forms. The choice of the structural motif is influenced by the anion present, with the copper(II) nitrate-containing complex [NO3?(Cu2L(3)2)](NO3)3, 4, adopting a double helicate form, whereas the analogous copper(II) bromide complexes [2Br?(Cu2L(3)2)](Br)2, 5, and [2Br?(Cu2L(3)2)](BF4)2, 6, both adopt 2 + 2 "box" structural configurations. Spectroscopic analysis has shown an enhancement in the binding strength of ClO4(-) over the anions SO4(2-) and NO3(-). The enhanced rigidity caused by the use of the 1,3-xylyl spacer in this series of complexes has favored the formation of the "double loaded" dibromide complex. PMID- 23927605 TI - Developmental hemostasis: age-specific differences in the levels of hemostatic proteins. AB - INTRODUCTION: Developmental hemostasis recognizes the physiologic differences between the hemostatic system of neonates and children and that of adults. As compared with the knowledge of hemostatic system physiology in adults, our understanding in neonates and children remains inadequate. Routine clinical coagulation testing most commonly measures functional parameters of the hemostatic system. Very few studies have measured age-specific levels of hemostatic proteins. An understanding of the normal fluctuations in the levels of hemostatic proteins is vital in the prevention, diagnosis and treatment of hemostatic problems during infancy and childhood. This study was designed as the first comprehensive study of the age-specific changes in the levels of important hemostatic proteins in healthy neonates, children, and adults. METHODS: Plasma samples were obtained from 120 healthy individuals from the following age groups: neonates (day 1 and day 3), 28 days to 1 year, 1-5 years, 6-10 years, 11-16 years, and adults. Factor II, FV, FVII, FVIII, FIX, FX, FXI, FXII, FXIII, plasminogen, protein C and total and free protein S were quantified with commercially available ELISA kits. RESULTS: The levels of 10 proteins were significantly different between neonates and adults, and these differences persisted throughout childhood for most of these proteins. CONCLUSION: The results of this study confirm that the levels of the majority of coagulation proteins vary significantly with age. Future studies should investigate how hemostatic protein level relates to functional changes with age. PMID- 23927606 TI - Liver resection after chemotherapy and tumour downsizing in patients with initially unresectable colorectal cancer liver metastases. AB - OBJECTIVES: Among patients with initially unresectable colorectal cancer liver metastases (CLM), a subset are rendered resectable following the administration of systemic chemotherapy. This study reports the results achieved in liver resections performed at a single hepatobiliary referral centre after downsizing chemotherapy in patients with initially unresectable CLM. METHODS: All liver resections for CLM performed over a 10-year period at the Toronto General Hospital were considered. Data on initially non-resectable patients who received systemic therapy and later underwent surgery were included for analysis. RESULTS: Between January 2002 and July 2012, 754 liver resections for CLM were performed. A total of 24 patients were found to meet the study inclusion criteria. Bilobar CLM were present in 23 of these 24 patients. The median number of tumours was seven (range: 2-15) and median tumour size was 7.0 cm (range: 1.0-12.8 cm) before systemic therapy. All patients received oxaliplatin- or irinotecan-based chemotherapy. Fourteen patients received combined treatment with bevacizumab. Negative margin (R0) resection was accomplished in 21 of 24 patients. There was no perioperative mortality. Ten patients suffered perioperative morbidity. Eighteen patients suffered recurrence of disease within 9 months. Rates of disease-free survival at 1, 2 and 3 years were 47.6% [95% confidence interval (CI) 30.4-74.6%], 23.8% (95% CI 11.1-51.2%) and 19.0% (95% CI 7.9-46.0%), respectively. Overall survival at 1, 2 and 3 years was 91.5% (95% CI 80.8-100%), 65.3% (95% CI 48.5-88.0%) and 55.2% (95% CI 37.7-80.7%), respectively. CONCLUSIONS: Liver resection in initially unresectable CLM can be performed with low rates of morbidity and mortality in patients who respond to systemic chemotherapy, although these patients do experience a high frequency of disease recurrence. PMID- 23927607 TI - Relationship between occupational stress and coping strategy among operating theatre nurses in China: a questionnaire survey. AB - AIM: To explore the relationship between occupational stress and coping strategies among operating theatre nurses in China. BACKGROUND: Studies on occupational stress and burnout in nurses are common, but there is a dearth of research on the coping strategies of operating theatre nurses. METHODS: A cross sectional study was conducted in a typical operating theatre in China. A questionnaire survey was conducted among 70 nurses. The data were analysed using correlation and regression methods. RESULTS: Nurses reported high stress levels in the workload and time pressure subscales. Female nurses' occupational stress was positively correlated with designation and negatively correlated with operation sets per day and night shifts. Nurses preferred self-control as a coping strategy. Active coping was positively related to resource and environmental problems, and passive coping was positively related to workload and time pressure, and to interpersonal relationship and management issues. CONCLUSION: Nursing managers could reduce operating theatre nurses' passive coping by decreasing the stressors of workload and time pressure, and interpersonal relationships and management problems. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing managers could employ more nurses to reduce nurses' workload and occupational stress. In addition, managers should consider fortifying nurses' active coping strategies and training nurses in problem-solving skills. PMID- 23927608 TI - A new approach to reducing the flammability of layered double hydroxide (LDH) based polymer composites: preparation and characterization of dye structure intercalated LDH and its effect on the flammability of polypropylene-grafted maleic anhydride/d-LDH composites. AB - Dye structure-intercalated layered double hydroxide (d-LDH) was synthesized using a one-step method, and its intercalated behaviors have been characterized by Fourier transform infrared spectroscopy (FTIR), wide angle X-ray scattering (WAXS), scanning electron microscopy, thermogravimetric analysis (TGA), etc. As a novel functional potential fire-retarding nanofiller, it was used to prepare a polypropylene-grafted maleic anhydride (PP-g-MA)/d-LDH composite by refluxing the mixture of d-LDH and PP-g-MA in xylene, aiming to investigate its effect on the flammability of the PP-g-MA composite. The morphological properties, thermal stability, and flame retardant properties of the PP-g-MA/d-LDH composite were determined by FTIR, WAXS, transmission electron microscopy, TGA, and microscale combustion calorimetry. Compared with NO3-LDH (unmodified LDH) and LDH intercalated by sodium dodecylbenzenesulfonate (conventional organo-modified LDH), d-LDH can significantly decrease the heat release rate and the total heat release of the PP-g-MA composite, offering a new approach to imparting low flammability to LDH-based polymer composites. PMID- 23927609 TI - Identification of the strongest bonds in chemistry. AB - Increasing the effective electronegativity of two atoms forming a triple bond can increase the strength of the latter. The strongest bonds found in chemistry involve protonated species of hydrogen cyanide, carbon monoxide, and dinitrogen. CCSD(T)/CBS (complete basis set) and G4 calculations reveal that bond dissociation energies are misleading strength descriptors. The strength of the bond is assessed via the local stretching force constants, which suggest relative bond strength orders (RBSO) between 2.9 and 3.4 for heavy atom bonding (relative to the CO bond strength in methanol (RBSO = 1) and formaldehyde (RBSO = 2)) in [HCNH](+)((1)Sigma(+)), [HCO](+)((1)Sigma(+)), [HNN](+)((1)Sigma(+)), and [HNNH](2+)((1)Sigmag(+)). The increase in strength is caused by protonation, which increases the electronegativity of the heavy atom and thereby decreases the energy of the bonding AB orbitals (A, B: C, N, O). A similar effect can be achieved by ionization of a nonbonding or antibonding electron in CO or NO. The strongest bond with a RBSO value of 3.38 is found for [HNNH](2+) using scaled CCSD(T)/CBS frequencies determined for CCSD(T)/CBS geometries. Less strong is the NN bond in [FNNH](2+) and [FNNF](2+). PMID- 23927610 TI - Effect of Light Environment on Growth and Phenylpropanoids of Yarrow (Achillea collina cv. SPAK) Grown in the Alps. AB - A 2-year field study on the effect of different light environments, obtained by using cladding materials (polyethylene films and shade net) able to cut off specific regions of the photosynthetically active radiation and ultraviolet wavebands, on the growth and phenylpropanoids content of Achillea collina grown in the Alps was conducted. Overall the plant growth was strongly enhanced in the second growing season irrespective of radiation treatment. The light environment did not affect total biomass accumulation, but only carbon allocation to leaves or inflorescences. Indeed the phenylpropanoid levels in inflorescences appeared to be more sensitive to the light environment than leaves as the latter showed high constitutive amounts of these compounds. However, the use of polyethylene films improved to some extent the content of caffeic acid derivatives in leaves. Our results showed that yarrow production, in the alpine situation considered, is influenced by the growing season and the light environment, providing a basis to optimize its quality, depending on the concentration of bioactive compounds, by means of proper agronomic practices. PMID- 23927611 TI - Functional consequences of a novel point mutation in the CYP21A2 gene identified in a Chinese Han patient with nonclassic 21-hydroxylase deficiency. PMID- 23927613 TI - Gait analysis is a viable tool for the assessment of transverse plane motion in children with cerebral palsy. PMID- 23927614 TI - Management of dyspnea guidelines for practice for adults with chronic obstructive pulmonary disease. AB - Dyspnea is an important symptom to address in occupational therapy since it significantly contributes to decreased functional status and health-related quality of life in adults with chronic obstructive pulmonary disease (COPD). This article presents the Management of Dyspnea Guidelines for Practice. The guidelines direct the clinician to help adult patients with COPD overcome the disabling effects of dyspnea by helping patients to master combining controlled breathing with activity exertion and by desensitizing them to dyspnea. An example of an occupational therapy treatment program based on the practice guidelines is described. A case study example is also provided to illustrate how the guidelines can be applied to occupational therapy practice. PMID- 23927612 TI - The potential for motivational interviewing to improve outcomes in the management of diabetes and obesity in paediatric and adult populations: a clinical review. AB - Having good intentions to engage in healthy behaviours, to change our lives in a positive direction and make substantial, lasting changes may not always translate into actions or behaviour that is maintained. Motivational Interviewing is a directive person-centred approach designed to explore ambivalence and activate motivation for change [Miller WR, Rollnick S. Motivational Interviewing: Preparing People to Change Addictive Behaviour. London: Guilford Press, 1991]. A key component of a motivational interviewing conversation is to acknowledge that clients have every right to make no change. It uses a guiding communication style which invites people to consider their own situation and find their own solutions to situations that they identify as problematic that are preventing change. Motivational Interviewing was first introduced in adult health addiction services in the early 1980s. It has developed in the physical health specialties, and in the last 20 years or so attention has turned to the potential of Motivational Interviewing in the paediatric setting and the challenges of using it in families with children at differing ages and developmental stages. This article summarizes studies published from 2006 to 2011 of Motivational Interviewing in individuals across the lifespan with type 1 and type 2 diabetes and obesity. PMID- 23927615 TI - Developing and implementing a senior community based fall prevention and home safety program. AB - Occupational therapists are primary candidates in taking a proactive role in meeting the community dwelling senior citizen's safety, environmental, and cognitive needs through the development of community based programs in conjunction with aging organizations. The purpose of this paper is to provide recommendations to occupational therapists in developing, implementing, and marketing a senior community based fall prevention and home safety program in conjunction with a Council on Aging and occupational therapy outpatient private practice. PMID- 23927616 TI - Chronic fatigue syndrome: is there a role for occupational therapy? AB - Chronic Fatigue Syndrome (CFS) continues to evolve as a disabling phenomenon characterized by debilitating fatigue and consequential components that limit the functional ability of persons afflicted with the disease. A composite review of the current literature addresses a brief history, etiology, legitimacy, incidence and prevalence, prognosis, diagnosis, impact, and treatment of CFS. The primary focus illustrates available treatment strategies that have been incorporated into occupational therapy practice. As a profession that has made contributions to populations with chronic disease and symptoms similar to those suffering from CFS, the use of effective methods should reinforce the need for occupational therapy intervention with this population. PMID- 23927617 TI - Changes in daily experiences: perceptions of the care provider of the traumatic brain injured. AB - Occupational therapy practitioners are rapidly becoming more involved in community-based services. Practitioners must understand the effect on program participants as well as family or paid care providers. This study gives voice to care providers in a community-based program for survivors of traumatic brain injury run by occupational therapists and occupational therapy students. Roles, routines, and occupational choices of care providers changed dramatically with program involvement. These findings have implications for community-based programming and the collaborative integration of care providers. Implications for program outcomes and the health and well being of care providers are discussed. PMID- 23927618 TI - A Model Mentor: Virginia Scardina, MA, MEd, OTR/L, FAOTA. AB - The purpose of this study was to document the influence Virginia (Ginny) Scardina, MA, MEd, OTR/L, FAOTA, occupational therapist extraordinaire, had on individuals whom she mentored. Scardina's influence was documented in a former unpublished qualitative study that conducted interviews with two of her former colleagues and six former students. This study, through the voices of five original participants and a second layer of data analysis, identified Scardina as a model mentor who was a master teacher. As a master teacher Scardina believed that, "You've got to teach to learn." Furthermore, Scardina, as a model mentor, facilitated growth in others by, "Bringing out the best," in them. Scardina's skills as a model mentor are discussed in relationship to the role of a mentor who supports, challenges others, and provides vision. Fieldwork and academic educators can learn from Scardina while reflecting upon their own influence and role in mentoring others. PMID- 23927619 TI - From the internet editor. PMID- 23927621 TI - The Role of Drinking Beliefs to Explain Ethnic Variation in Drinking Practices Among U.S. College Students. AB - This study, funded by the National Institute on Alcohol Abuse and Alcoholism, examines psychosocial mediators to explain discrepancies in past-30-day drinking between African American and White college student drinkers in the United States. Between 2008 and 2010, 5,845 college drinkers completed an online survey about their alcohol use. Using latent variable structural equations modeling, we investigated the relationships between ethnicity, drinking beliefs, and students' past 30-day alcohol use. Drinking beliefs-i.e., positive expectancies, perceived norms, and disapproval of alcohol use-fully mediated the relationship between ethnicity and drinking behaviors. Study limitations and directions for future research are discussed. PMID- 23927622 TI - Hepatoprotective, antioxidant, and ameliorative effects of ginger (Zingiber officinale Roscoe) and vitamin E in acetaminophen treated rats. AB - Ginger is a remedy known to possess a number of pharmacological properties. This study investigated efficacy of ginger pretreatment in alleviating acetaminophen induced acute hepatotoxicity in rats. Rats were divided into six groups; negative control, acetaminophen (APAP) (600 mg/kg single intraperitoneal injection); vitamin E (75 mg/kg), ginger (100 mg/kg), vitamin E + APAP, and ginger + APAP. Administration of APAP elicited significant liver injury that was manifested by remarkable increase in plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), arginase activities, and total bilirubin concentration. Meanwhile, APAP significantly decreased plasma total proteins and albumin levels. APAP administration resulted in substantial increase in each of plasma triacylglycerols (TAGs), malondialdhyde (MDA) levels, and total antioxidant capacity (TAC). However, ginger or vitamin E treatment prior to APAP showed significant hepatoprotective effect by lowering the hepatic marker enzymes (AST, ALT, ALP, and arginase) and total bilirubin in plasma. In addition, they remarkably ameliorated the APAP-induced oxidative stress by inhibiting lipid peroxidation (MDA). Pretreatment by ginger or vitamin E significantly restored TAGs, and total protein levels. Histopathological examination of APAP treated rats showed alterations in normal hepatic histoarchitecture, with necrosis and vacuolization of cells. These alterations were substantially decreased by ginger or vitamin E. Our results demonstrated that ginger can prevent hepatic injuries, alleviating oxidative stress in a manner comparable to that of vitamin E. Combination therapy of ginger and APAP is recommended especially in cases with hepatic disorders or when high doses of APAP are required. PMID- 23927623 TI - Combined meatoplasty and canalplasty for intractable chronic otitis externa: our experience of twenty cases with audiometric and patient-reported outcomes. PMID- 23927624 TI - An analysis of characteristics of subjects examined for incretin effects on pancreatic pathology. AB - A recent autopsy analysis asserted that incretin drugs have the potential of increasing the risk for pancreatic cancer and for pancreatic neuroendocrine tumors. We examined the Network for Pancreatic Organ Donors with Diabetes (nPOD) database from which that analysis was derived. Our findings raise important questions about the comparability of the two groups of diabetes patients used for the analysis. Our review of the data available on the nPOD Web site and our reading of the earlier article lead us to the conclusion that the data, and the implications of the data, as expressed by the authors of the autopsy analysis are vastly overstated and are a misrepresentation of the information available. PMID- 23927625 TI - Phenotypic screening as a strategic component of drug discovery programs targeting novel antiparasitic and antimycobacterial agents: an editorial. AB - Drug development for neglected tropical diseases, defined as a collection of infectious diseases affecting over 4 billion people worldwide (especially endemic to poverty-stricken populations in underdeveloped regions of Africa, Asia, the Pacific Rim, and Latin America), has been underfunded and stagnant. A much needed resurgence of R&D activity in this area is currently developing. Target-directed screening and whole-cell phenotypic screening represent two complementary approaches to discover viable new starting point scaffolds for medicinal chemistry optimization. This editorial will provide introductory comments to a series of six miniperspectives that focus on the special challenges faced by scientists in discovering potential new chemical leads that could be optimized into promising clinical candidates for neglected tropical diseases. PMID- 23927626 TI - Four-year epidemiological study of extended-spectrum beta-lactamase-producing Enterobacteriaceae in a French teaching hospital. AB - Since the end of the last century resistance to oxyimino beta-lactams has steadily increased in Enterobacteriaceae. In the present work we studied extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae strains isolated in the teaching hospital of Clermont-Ferrand, France, between 2006 and 2009. A total of 1368 ESBL-producing isolates were collected. Most of these isolates (69%) were CTX-M-producing Escherichia coli. During the study, the clinical incidence increased by more than 400%, even in the emergency department, and especially in community-acquired infections, as is the case elsewhere in the world. Most of the ESBL-producing isolates remained susceptible to furans and fosfomycin, but only 50% to fluoroquinolons. In conclusion, ESBL-producing bacteria constantly increased during the study period. Unlike many studies, this increase was associated with the wide dissemination of three different CTX-M enzymes: CTX-M 14, CTX-M-15 and CTX-M-1. PMID- 23927628 TI - Sorting nanoparticles with intertwined plasmonic and thermo-hydrodynamical forces. AB - We exploit plasmonic and thermo-hydrodynamical forces to sort gold nanoparticles in a microfluidic environment. In the appropriate regime, the experimental data extracted from a Brownian statistical analysis of the kinetic motions are in good agreement with Mie-type theoretical evaluations of the optical forces acting on the nanoparticles in the plasmonic near field. This analysis enables us to demonstrate the importance of thermal and hydrodynamical effects in a sorting perspective. PMID- 23927627 TI - CT of the chest with model-based, fully iterative reconstruction: comparison with adaptive statistical iterative reconstruction. AB - BACKGROUND: The recently developed model-based iterative reconstruction (MBIR) enables significant reduction of image noise and artifacts, compared with adaptive statistical iterative reconstruction (ASIR) and filtered back projection (FBP). The purpose of this study was to evaluate lesion detectability of low-dose chest computed tomography (CT) with MBIR in comparison with ASIR and FBP. METHODS: Chest CT was acquired with 64-slice CT (Discovery CT750HD) with standard dose (5.7 +/- 2.3 mSv) and low-dose (1.6 +/- 0.8 mSv) conditions in 55 patients (aged 72 +/- 7 years) who were suspected of lung disease on chest radiograms. Low dose CT images were reconstructed with MBIR, ASIR 50% and FBP, and standard-dose CT images were reconstructed with FBP, using a reconstructed slice thickness of 0.625 mm. Two observers evaluated the image quality of abnormal lung and mediastinal structures on a 5-point scale (Score 5 = excellent and score 1 = non diagnostic). The objective image noise was also measured as the standard deviation of CT intensity in the descending aorta. RESULTS: The image quality score of enlarged mediastinal lymph nodes on low-dose MBIR CT (4.7 +/- 0.5) was significantly improved in comparison with low-dose FBP and ASIR CT (3.0 +/- 0.5, p = 0.004; 4.0 +/- 0.5, p = 0.02, respectively), and was nearly identical to the score of standard-dose FBP image (4.8 +/- 0.4, p = 0.66). Concerning decreased lung attenuation (bulla, emphysema, or cyst), the image quality score on low-dose MBIR CT (4.9 +/- 0.2) was slightly better compared to low-dose FBP and ASIR CT (4.5 +/- 0.6, p = 0.01; 4.6 +/- 0.5, p = 0.01, respectively). There were no significant differences in image quality scores of visualization of consolidation or mass, ground-glass attenuation, or reticular opacity among low- and standard dose CT series. Image noise with low-dose MBIR CT (11.6 +/- 1.0 Hounsfield units (HU)) were significantly lower than with low-dose ASIR (21.1 +/- 2.6 HU, p < 0.0005), low-dose FBP CT (30.9 +/- 3.9 HU, p < 0.0005), and standard-dose FBP CT (16.6 +/- 2.3 HU, p < 0.0005). CONCLUSION: MBIR shows greater potential than ASIR for providing diagnostically acceptable low-dose CT without compromising image quality. With radiation dose reduction of >70%, MBIR can provide equivalent lesion detectability of standard-dose FBP CT. PMID- 23927629 TI - Palladium-catalyzed selective fluorination of o-carboranes. AB - A Pd(II)-catalyzed direct selective fluorination reaction of carboranes using a F(+) reagent has been developed, leading to a series of polyfluorocarboranes in high isolated yields. The mechanism involving electrophilic B-H activation, oxidation of Pd(II) by F(+) species, and reductive elimination is proposed. PMID- 23927630 TI - Synergism from combinations of infection-blocking malaria vaccines. AB - Plasmodium falciparum infections present novel challenges for vaccine development, including parasite replication dynamics not previously encountered for viral pathogens, and enormous diversity in target antigens. These challenges are illustrated by using a mathematical model to describe the association between the proportion of pre-erythrocytic or blood-stage parasites eliminated by vaccine induced immune responses and the proportion of infections prevented. It is hypothesized that due to the requirement for all sporozoites to be eliminated to prevent infection, combining infection-blocking vaccines that confer protection through different biological mechanisms could lead to synergistic combinations of efficacy. Vaccines targeting blood-stage parasites may also combine synergistically if they combine to reduce the parasite multiplication rate to below the threshold of 1. PMID- 23927631 TI - Clinical isolates and laboratory reference Candida species and strains have varying abilities to form biofilms. AB - Candida biofilms are a major virulence trait for this yeast. In this study, the biofilm-forming ability of the major medically important clinical and laboratory reference strains was compared. Biofilms were quantified using traditional methods, that is, crystal violet (CV), tetrazolium (XTT) reduction and colony forming unit assays (CFU), and two new methods: an automated cell counter (ACC) and biofilm suspension turbidity (BST) method. Biofilms could be categorized based on biofilm biomass (high, medium and low) and growth state (high and low). Candida albicans genotypes, A, B and C, showed medium biofilm mass and low growth rate, and only one C. albicans laboratory strain, ATCC MYA-2719, matched this biofilm category. Of all non-albicans Candida species tested, only Candida dubliniensis and Candida glabrata laboratory and clinical isolates had similar biofilm development. The ACC and BST methods for measuring biofilm significantly correlated with CV and CFU biofilm mass measurements. Thus, biofilm mass can be rapidly assessed using biofilm disruptive/cellular nondestructive methods allowing yeast biofilm cells to be used for further analysis. In conclusion, Candida laboratory reference strains and clinical isolates have been shown to form biofilms at different rates; hence for validity, the selection of laboratory reference strains in biofilm studies may be critical for virulence assessment. PMID- 23927633 TI - Dilution-triggered SMM behavior under zero field in a luminescent Zn2Dy2 tetranuclear complex incorporating carbonato-bridging ligands derived from atmospheric CO2 fixation. AB - The synthesis, structure, magnetic, and luminescence properties of the Zn2Dy2 tetranuclear complex of formula {(MU3-CO3)2[Zn(MU-L)Dy(NO3)]2}.4CH3OH (1), where H2L is the compartmental ligand N,N',N"-trimethyl-N,N"-bis(2-hydroxy-3-methoxy-5 methylbenzyl)diethylenetriamine, are reported. The carbonate anions that bridge two Zn(MU-L)Dy units come from the atmospheric CO2 fixation in a basic medium. Fast quantum tunneling relaxation of the magnetization (QTM) is very effective in this compound, so that single-molecule magnet (SMM) behavior is only observed in the presence of an applied dc field of 1000 Oe, which is able to partly suppress the QTM relaxation process. At variance, a 1:10 Dy:Y magnetic diluted sample, namely, 1', exhibits SMM behavior at zero applied direct-current (dc) field with about 3 times higher thermal energy barrier than that in 1 (U(eff) = 68 K), thus demonstrating the important role of intermolecular dipolar interactions in favoring the fast QTM relaxation process. When a dc field of 1000 Oe is applied to 1', the QTM is almost fully suppressed, the reversal of the magnetization slightly slows, and U(eff) increases to 78 K. The dilution results combined with micro-SQUID magnetization measurements clearly indicate that the SMM behavior comes from single-ion relaxation of the Dy(3+) ions. Analysis of the relaxation data points out that a Raman relaxation process could significantly affect the Orbach relaxation process, reducing the thermal energy barrier U(eff) for slow relaxation of the magnetization. PMID- 23927634 TI - Characterization of sporadic acute hepatitis E and comparison of hepatitis E virus genomes in acute hepatitis patients and pig liver sold as food in Mie, Japan. AB - AIM: To characterize hepatitis E in Mie prefecture and to investigate whether raw pig liver sold as food in Mie is contaminated with hepatitis E virus (HEV) strains similar to those recovered from patients. METHODS: Seventeen patients with sporadic acute hepatitis E treated from 2004 to 2012 were studied. A total of 243 packages of raw pig liver from regional grocery stores were tested for the presence of HEV RNA. The partial genomic sequences of human and swine HEV isolates were determined and subjected to the phylogenetic analyses. RESULTS: The HEV isolates recovered from the 17 patients segregated into genotype 3 (n = 15) and genotype 4 (n = 2), and 15 genotype 3 isolates further segregated into 3e (n = 11) and 3b (n = 4). Pig liver specimens from 12 (4.9%) of the 243 packages had detectable HEV RNA. All 12 swine HEV isolates were grouped into genotype 3 (3a or 3b). Although no 3e strains were isolated from pig liver specimens, two 3b swine strains were 99.5-100% identical to two HEV strains recovered from hepatitis patients, within 412-nt partial sequences. CONCLUSION: The 3e HEV was prevalent among hepatitis E patients. HEV RNA was detected in approximately 5% of pig liver sold as food. The presence of identical HEV strains between hepatitis patients and pig liver indicated that pigs play an important role as reservoirs for HEV in humans in Mie. Further studies are needed to clarify the source of 3e HEV in the animal and environmental reservoirs. PMID- 23927636 TI - Iron and ice. PMID- 23927635 TI - Association between thyroid hormones and body fat in euthyroid subjects. AB - OBJECTIVE: Thyroid hormones disorders are associated with changes of body composition. However, the relationship between thyroid hormones and body fat in a euthyroid population is unclear. The aim of this study was to explore the association between thyroid hormones and body fat in a euthyriod population. SUBJECTS: A total of 865 euthyroid individuals were recruited in this study. Subjects with thyroid diseases or diabetes and who were taking medications that could influence thyroid hormones, weight or glucose metabolism were excluded. MEASUREMENTS: FT3, FT4, lipid parameters, fasting insulin (FINS) and blood glucose were determined, and homeostasis model assessment for insulin resistance (HOMA-IR) was calculated. Anthropometric measurements were taken, and body fat parameters were assessed. RESULTS: Serum FT3 was slightly higher in body mass index (BMI) >=25 kg/m(2) group than that in BMI <25 kg/m(2) group (P < 0.05). However, the difference was too small to have clinical significance. FT4 levels were not significantly different between the two groups. Body weight, BMI, waist circumference, hip circumference, waist-to-hip ratio (WHR), percentage of body fat (PBF), waist-fat-to-hip-fat ratio, FINS and HOMA-IR increased linearly with the elevation of FT3 adjusted for age and gender. A multivariate linear regression analysis revealed that fat mass, PBF, HOMA-IR and FT4 contributed significantly to FT3 levels. CONCLUSION: Grouped according to BMI, overweight and obese subjects have similar thyroid hormones compared to those with normal weight. Body composition parameters increase with the elevation of FT3, and FT3 is associated with body fat parameters in euthyroid subjects. PMID- 23927637 TI - Transfusion medicine illustrated. Hurricane Ike: refrigerators and freezers float; irradiators don't. PMID- 23927638 TI - Detecting hypermethylated fetal RASSF1A sequences in maternal plasma: implications for noninvasive paternity testing in pregnancy. PMID- 23927639 TI - Reflections on medical literature searches. PMID- 23927640 TI - Therapeutic plasma exchange for massive anti-JK3-mediated hemolysis. PMID- 23927641 TI - In search of plentiful universal donor plasma: what might Landsteiner say? PMID- 23927642 TI - Thrombotic thrombocytopenic purpura does not show seasonal variation in Alabama. PMID- 23927643 TI - Molecular magnetic resonance imaging of pulmonary fibrosis in mice. AB - Idiopathic pulmonary fibrosis is a chronic, progressive, fibrosing interstitial pneumonia of unknown cause resulting in dyspnea and functional decline until death. There are currently no effective noninvasive tools to monitor disease progression and response to treatment. The objective of the present study was to determine whether molecular magnetic resonance imaging of the lung using a probe targeted to type I collagen could provide a direct, noninvasive method for assessment of pulmonary fibrosis in a mouse model. Pulmonary fibrosis was generated in mice by transtracheal instillation of bleomycin (BM). Six cohorts were imaged before and immediately after intravenous administration of molecular imaging probe: (1) BM plus collagen-targeted probe, EP-3533; (2) sham plus EP 3533; (3) BM plus nonbinding control probe, EP-3612; (4) sham plus EP-3612; (5) BM plus EP-3533 imaged early; and (6) BM plus EP-3533 imaged late. Signal-to noise ratio (SNR) enhancement was quantified in the lungs and muscle. Lung tissue was subjected to pathologic scoring of fibrosis and analyzed for gadolinium and hydroxyproline. BM-treated mice had 35% higher lung collagen than sham mice (P < 0.0001). The SNR increase in the lungs of fibrotic mice after EP-3533 administration was twofold higher than in sham animals and twofold higher than in fibrotic or sham mice that received control probe, EP-3612 (P < 0.0001). The SNR increase in muscle was similar for all cohorts. For EP-3533, we observed a strong, positive, linear correlation between lung SNR increase and hydroxyproline levels (r = 0.72). Collagen-targeted probe EP-3533-enhanced magnetic resonance imaging specifically detects pulmonary fibrosis in a mouse model of disease. PMID- 23927644 TI - Intrahepatic cholestasis in common chronic liver diseases. AB - BACKGROUND AND OBJECTIVE: Cholestasis represents the consequence of impaired bile formation and decrease in bile flow, generally classified as extra- and intrahepatic. Cholestasis is the pivotal hallmark of the so-called primary cholestatic liver diseases but may also emerge in other forms of chronic liver injury. The aim now was to summarise the current state of knowledge on intrahepatic cholestasis related to chronic liver diseases. METHODS: For this overview on intrahepatic cholestasis in chronic liver disorders other than the 'classic' cholestatic liver diseases, selected references were retrieved by literature search in MEDLINE and textbooks were reviewed. All articles were selected that discussed pathophysiological and clinical aspects of intrahepatic cholestasis in the context of alcoholic liver disease, nonalcoholic fatty liver disease, chronic hepatitis B and C virus infections as well as drug-induced and granulomatous liver diseases. Titles referring to primary biliary cirrhosis and sclerosing cholangitis were excluded. RESULTS AND CONCLUSIONS: Dependent on the aetiology, intrahepatic cholestasis is present at variable frequencies and in different disease stages in chronic liver diseases. Cholestasis secondary to chronic liver injury may denote a severe disease course and development of end stage liver disease or specific disease variants. These findings indicate that 'secondary intrahepatic cholestasis' (SIC) can occur in the natural course of chronic liver diseases other than the primary cholestatic diseases, in particular in the setting of advanced disease progression. PMID- 23927645 TI - Factors that influence the approach to leadership: directors of nursing working in rural health services. AB - AIM: To identify factors that influence directors of nursing in their approach to leadership when working in rural Victoria, Australia. BACKGROUND: In rural areas, nurses account for the largest component of the health workforce and must be equipped with leadership knowledge and skills to lead reform at a service level. METHOD: A qualitative descriptive design was used. In-depth semi-structured interviews were undertaken with directors of nursing from rural Victoria. Data were analysed using thematic analysis and a thematic network was developed. RESULTS: Empowerment emerged as the highest order category in the thematic network. This was derived from three organising themes: influence, capital and contextual understanding and the respective basic themes: formal power, informal power, self-knowledge; information, support, resources; and situational factors, career trajectory, connectedness. CONCLUSION: Rural nurse leaders contend with several issues that influence their approach to leadership. This study provides a platform for further research to foster nurse leadership in rural healthcare services. IMPLICATIONS FOR NURSING MANAGEMENT: Acknowledgement of what influences the rural nurse leaders' approach to leadership may assist in the implementation of initiatives designed to develop leadership in a manner that is contextually sensitive. PMID- 23927646 TI - Patterning of gold nanoparticles on fluoropolymer films by using patterned surface grafting and layer-by-layer deposition techniques. AB - The patterning of gold nanoparticles (GNPs) on the surface of a fluoropolymer substrate by using patterned surface grafting and layer-by-layer deposition techniques is described. The surface of a poly(tetrafluoroethylene-co perfluorovinyl ether) (PFA) substrate was selectively implanted with 150 keV proton ions. Peroxide groups were successfully formed on the implanted PFA surface, and their concentration depended on the fluence. Acrylic acid was graft polymerized onto the implanted regions of the PFA substrate, resulting in well defined patterns of poly(acrylic acid) (PAA) on the PFA substrate. The surface properties of the PAA-patterned PFA surface, such as chemical compositions, wettability, and morphology, were investigated. The surface analysis results revealed that PAA was definitely present on the implanted regions of the PFA surface, and the degree of grafting was dependent on three factors: fluence, grafting time, and monomer concentration. Furthermore, GNP patterns were generated on the prepared PAA-patterned PFA surface by layer-by-layer deposition of GNPs and poly(diallyldimethyl ammonium chloride). The multilayers of GNPs were deposited only onto the PAA-grafted regions separated by bare PFA regions, and the resulting GNP patterns exhibited good electrical conductivity. PMID- 23927647 TI - Response to Reshef et al.: Colectomy with ileorectal anastomosis has a worse 30 day outcome when performed for colonic inertia than for a neoplastic indication. PMID- 23927648 TI - When the swimming gets tough, the tough form a biofilm. AB - Bacteria live either as independent planktonic cells or as members of surface attached communities called biofilms. Motility and biofilm development are mutually exclusive events, and control of the phase of this 'swim-or-stick' switch involves the ability of the bacterium to sense and respond appropriately to a surface. Cairns et al. (2013) report that the Bacillus subtilis flagellum functions in surface-sensing. Using mutants of B. subtilis that prevent flagellum rotation, they measured the expression and activity of DegU, the response regulator of the two-component DegS-DegU circuit. DegU activity and degU transcription increased when flagellum rotation was prevented, and were dependent on the DegS kinase. Inhibiting flagellar rotation by overexpressing the EpsE flagellar 'clutch' or addition of anti-flagellin antiserum also increased degU transcription and activity. These results suggest B. subtilis senses restriction of flagellum rotation as the cell nears a surface. Inhibition of the flagellum activates the DegS-DegU circuit to turn on biofilm formation, i.e. the flagellum is acting as a mechanosensor of surfaces. B. subtilis joins an ever-expanding group of bacteria, including species of Vibrio, Proteus and Caulobacter that use the flagellum as a surface sensor. PMID- 23927649 TI - Order of information: impact on perceived level of functional independence. AB - The order in which information is reviewed can influence judgment. The present study examined the impact of information order on ratings of functional independence by occupational therapists and occupational therapy students. Eighty six occupational therapists and students were assessed in a pretest-posttest design. At pretest participants read identical background information about an independent, elderly gentleman with suspected memory problems, and then estimated his functional independence. Then the participants read the same clinically relevant information in one of two randomly assigned orders. One group received information from a clinical interview first, followed by assessment results. The other group received the same information in the reverse order. Analysis revealed that information order affected the final estimation of functional independence. Participants who read the assessment results first rated the elderly gentleman as less independent than those who read the interview data first. The clinical relevance of these findings and future directions are discussed. PMID- 23927650 TI - Students' perceptions of their acquired knowledge during a problem based learning case study. AB - Problem based learning (PBL) in occupational therapy education has become very popular, although the efficacy of this teaching method has not been well documented. The purpose of this study was to evaluate the effectiveness of a PBL case in meeting faculty generated learning objectives. A pretest/posttest design was utilized to evaluate students' perceptions of content acquisition. A two-way ANOVA with repeated measures was completed; results yielded a significant difference among the pretest and posttest scores (p-v < 0.01). The posttest mean scores were higher, which indicated that students perceived they acquired the intended knowledge and PBL was an effective method to facilitating learning. PMID- 23927651 TI - Evidence for occupational therapy interventions: a student educational assignment. AB - As an educational assignment, two classes of graduate students who had recently completed Level II fieldwork listed interventions they had either witnessed or implemented at their sites. Interventions were then randomly assigned to a different group of graduate students in an upper level research class. Searching the literature from the past 10 years, students located the literature providing evidence for the efficacy of these interventions and categorized them according to five hierarchical levels of effectiveness. Results across both classes indicated support at the two highest levels (I and II) for the following interventions: Constraint-Induced Treatment; Hippotherapy; Proprioceptive Neuromuscular Facilitation and Multisensory Handwriting Programs. Students indicated that this educational experience greatly helped to improve their understanding of research and emphasized the importance of researching the literature supporting interventions as they relate to current practice. PMID- 23927652 TI - Functional performance and grip strength after total hip replacement. AB - Objective. The progress of adults after total hip replacement (THR) was measured baseline to discharge using the Functional Independence Measure (FIM). Measures of effectiveness and efficiency were investigated. Additionally, although grip strength is frequently evaluated, its relationship to impact on functional gains after THR is unknown and was explored in this study. Method. A retrospective chart review was conducted on 41 patients' progress in acute rehabilitation following THR. Baseline and discharge FIM subscales of self-care, mobility, and locomotion were compared using paired t-tests with post hoc correction for type I error. Effectiveness and efficiency indicators on FIM subscale improvement were calculated. Grip strength was compared to expected values by age and gender using one-sample t-tests. Then, grip strength and FIM subscale scores were correlated using Pearson correlation. Results. FIM subscale scores each improved 2.1 points on average. Statistically significant improvement was made in 10 subscales of self-care, mobility, and locomotion. Grip strength was significantly less than expected norms in six of 14 subgroups after surgery; four of eight were female subgroups. There were no significant correlations between grip strength and any FIM subscale. Conclusion. Improvement in functional performance, as measured by FIM, was made on all FIM subscales. Grip strength after THR was moderately decreased from the norm. Results suggest that loss of grip strength alone may not adversely affect functional performance. PMID- 23927653 TI - Spirituality and disability: an analysis of select themes. AB - This paper is a thematic analysis of the literature regarding spirituality, which is applied to the understanding of spirituality and disability. Implications for occupational therapy practice are suggested. The themes of "connectedness" and "expressiveness" as aspects of spirituality were generated from both the occupational therapy literature and literature from other health professions. A definition of spirituality is proposed by the author for use by the profession of occupational therapy, as follows: experiencing a meaningful connection to our core selves, other humans, the world, and/or a greater power as expressed through our reflections, narratives, and actions. Persons with disabilities described a sense of disconnectedness to others, to the world, and to a greater power. They expressed their spirituality through actions to rectify that sense of disconnection. This study suggests that further research is warranted that explores the scope of spirituality in the lives of individuals with disabilities and how spirituality relates to the theoretical and philosophical realm of occupational therapy. PMID- 23927654 TI - Opening the self to an exploration of diversity: an introductory in-class activity. PMID- 23927655 TI - From the internet editor. PMID- 23927656 TI - Bridelia ferruginea promotes reactive oxygen species detoxification in N nitrosodiethylamine-treated rats. AB - This study was aimed at investigating the in vitro and in vivo reactive oxygen species (ROS) scavenging and detoxification potentials of aqueous extract of Bridelia ferruginea (B. ferruginea). Reactive oxygen species scavenging potentials of the aqueous leaf extract of B. ferruginea (0.2-1.0 mg/ml) was investigated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, superoxide ion, hydrogen peroxide, hydroxyl radical, and ferric ion reducing system. The detoxification of ROS was evaluated in N-nitrosodiethylamine-induced redox imbalance in the liver of rats. B. ferruginea extract at 1.0 mg/ml scavenged the DPPH, superoxide ion, hydrogen peroxide, and hydroxyl radical at 87%, 83%, 92%, and 86%, respectively, it also reduced ferric ion significantly. ROS detoxifying enzymes (superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione reductase, and glucose 6-phosphate dehydrogenase) activities were significantly (p < .05) induced by B. ferruginea. These inductions significantly (p < .05) attenuated the N-nitrosodiethylamine-mediated decrease in ROS detoxifying enzymes and compared favorably with Vitamin C. N-nitrosodiethylamine mediated elevation in the concentrations of malondialdehyde, conjugated dienes, lipid hydroperoxides, protein carbonyl, and percentage DNA fragmentation were significantly (p < .05) lowered by B. ferruginea extract. Overall, the results of this study show that B. ferruginea leaf extract possess ROS scavenging and detoxification potentials. PMID- 23927657 TI - Attention HIV: older African American women define sexual risk. AB - Understanding sexual-risk behaviours as defined by a culture presents new challenges for human service professionals. Older African American women constitute the fastest growing group of new cases of HIV in the USA. With heterosexual sex as the primary mode of transmission among this group, there exist minimal programmes that are culture and age-specific in terms of primary and secondary prevention. In an attempt to address this gap in knowledge, this study examined how a group of older African American women defined sexual-risk behaviour. A focus group was conducted with seven women age 45 and older, who were recruited from a community centre. This paper examines the way that sexual risk behaviour was defined through thematic analysis and conceptualises the locus of sexual risk behaviour as defined by the participants. The major theme of the study was social prescription, how to behave sexually as an ageing adult. Underlying ideas that arose were that unprotected sex occurred out of habit, that impulsivity was associated with risky sex and that older women needed to be aware of warning signs and behaviours of potential mates. Micro- and macro-level implications for human service professionals are discussed. PMID- 23927659 TI - A disc diffusion assay for detection of class A, B and OXA-48 carbapenemases in Enterobacteriaceae using phenyl boronic acid, dipicolinic acid and temocillin. AB - Class A and B carbapenemases in Enterobacteriaceae may be detected using carbapenemase inhibition tests with boronic acid derivatives (BA) and dipicolinic acid (DPA)/EDTA, respectively. However, for OXA-48 (like) carbapenemases, no specific inhibitor is available. Because OXA-48 confers high-level temocillin resistance, a disc diffusion assay using temocillin as well as BA and DPA inhibition tests was evaluated for detection of class A, B and OXA-48 carbapenemases. The test collection included 128 well-characterized non-repeat Enterobacteriaceae isolates suspected of carbapenemase production; that is, with meropenem MICs >= 0.5 mg/L, including 99 carbapenemase producers (36 KPC, one GES, 31 MBL, four KPC plus VIM, 25 OXA-48, two OXA-162), and 29 ESBL and/or AmpC producing isolates. PCR and sequencing of beta-lactamase genes was used as a reference test. Phenotypic carbapenemase detection was performed with discs (Rosco) containing meropenem (10 MUg), temocillin (30 MUg), meropenem + phenyl boronic acid (PBA), meropenem + DPA, meropenem + BA + DPA, and meropenem + cloxacillin (CL). Absence of synergy between meropenem and BA and/or DPA and a temocillin zone <=10 mm was used to identify OXA-48. The sensitivity for identification of class A, B and OXA-48 carbapenemases was 95%, 90% and 100%, with 96-100% specificity. In non-Proteus species, the sensitivity for class B carbapenemase detection was 97%. All isolates without PBA or DPA synergy and a temocillin disc zone <=10 mm were OXA-48 (like) positive. In conclusion, carbapenemase inhibition tests with PBA and DPA combined with a temocillin disc provide a reliable phenotypic confirmation method for class A, B and OXA-48 carbapenemases in Enterobacteriaceae. PMID- 23927660 TI - Gram-negative superbugs: inappropriate antimicrobial therapy and mortality. PMID- 23927658 TI - Using genetic methods to define the targets of compounds with antimalarial activity. AB - Although phenotypic cellular screening has been used to drive antimalarial drug discovery in recent years, in some cases target-based drug discovery remains more attractive. This is especially true when appropriate high-throughput cellular assays are lacking, as is the case for drug discovery efforts that aim to provide a replacement for primaquine (4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine), the only drug that can block Plasmodium transmission to Anopheles mosquitoes and eliminate liver-stage hypnozoites. At present, however, there are no known chemically validated parasite protein targets that are important in all Plasmodium parasite developmental stages and that can be used in traditional biochemical compound screens. We propose that a plethora of novel, chemically validated, cross-stage antimalarial targets still remain to be discovered from the ~5,500 proteins encoded by the Plasmodium genomes. Here we discuss how in vitro evolution of drug-resistant strains of Plasmodium falciparum and subsequent whole-genome analysis can be used to find the targets of some of the many compounds discovered in whole-cell phenotypic screens. PMID- 23927662 TI - Dimethyl fumarate (BG-12) for the treatment of multiple sclerosis. AB - Treatments for multiple sclerosis (MS) are only partially effective and most require a parenteral route of administration and/or may have severe side effects. Dimethyl fumarate is the active compound of BG-12 recently licensed for the treatment of relapsing-remitting MS. The pivotal Phase III trials have demonstrated an approximately 50% reduction of relapse rates compared with placebo paralleled by a reduction in new lesion formation on MRI. A dose of 240 mg two-times a day had an optimal effect. Flushing and gastrointestinal symptoms (diarrhea, abdominal pain, nausea) were common adverse events in the first month(s) of treatment. Severe side effects were not more common than in the placebo group for a treatment period of 2 years. The mode of action is not exactly clear and both immunomodulatory effects and an activation of the transcription factor Nrf2 are suggested. This new oral drug will be a welcome addition to existing MS treatments. PMID- 23927663 TI - Advances in stem cells technologies and their commercialization potential. AB - The World Stem Cells & Regenerative Medicine Congress Asia 2013 held in Singapore from 19-21 March 2013 was attended by over 2000 industry attendees and 5000 registered visitors. The focus of the congress was to discuss potential uses of stem cells for various diagnostic and therapeutic applications, their market opportunity and the latest R&D, which would potentially find its way into the market in not too distant future. In addition to the traditional lectures presented by academic and industry experts, there were forums, discussions, posters and exhibits, which provided various platforms for researchers, potential industry partners and even various interest groups to discuss prospective development of the stem cell-related industry. PMID- 23927664 TI - Melatonin replacement therapy in preterm infants: the impact of pharmacokinetics. AB - The paper by Merchant et al. demonstrates that the pharmacokinetic profile of melatonin differs in preterm infants from that of adults. The findings of this study can guide the necessary future preventive and therapeutic clinical trials on melatonin in preterm infants. These studies are urgently needed to further evaluate the protective potential of melatonin in preterm infants. Melatonin acts as a potent endogenous antioxidant agent that antagonizes oxidative stress, and melatonin replacement therapy could thereby prevent the development of many disorders and diseases that can afflict preterm infants such as sepsis, asphyxia, respiratory distress or surgical complications. Since preterm infants are melatonin deficient, administration of the compound may provide the necessary levels to assure their health and well-being. Pharmacokinetic data such as those provided in the evaluated paper are necessary to establish safe and efficient melatonin treatment regimens in this highly susceptible population. PMID- 23927665 TI - Cognitive interviewing in risk minimization survey development: patient and healthcare professional surveys. AB - Risk minimization programs are often required for selected drugs and other products to ensure that the benefits of these prescription products outweigh their risks. Regulators in the USA and Europe have recently called for more rigorous standards in developing measures for risk minimization program assessment. Cognitive pretesting interviews are a critical step in the development of survey instruments used to evaluate patients' and healthcare professionals' knowledge and behaviors associated with the safe use of products requiring a risk minimization program. This article is intended as a guide for the researcher who is charged with the development of survey instruments used in these programs and focuses on the role of cognitive pretesting interviews in successful survey instrument design, data analysis and interpretation. PMID- 23927667 TI - Applications of systems biology in cancer immunotherapy: from target discovery to biomarkers of clinical outcome. AB - Immunotherapies are coming to the forefront as a treatment paradigm in cancer with multiple US FDA approvals in recent years and a better understanding of their therapeutic mode of action. The control of tumor growth by the immune system is orchestrated by a complex array of cellular interactions and molecular pathways, both in the immune cells as well as the tumor. Although research over the past three decades has elucidated many aspects of tumor immunosurveillance, given the inherent complexity of the immune cell phenotypes and function, high throughput molecular profiling ('omics') approaches have now become essential to support the discovery and development of new therapies. Technologies, such as DNA and protein microarrays, deep sequencing, mass spectrometry, as well as the computational methods for their analyses, are advancing the contributions of systems biology towards the development and mechanistic understanding of cancer immunotherapies. In this review, the authors illustrate this through some recently reported studies. PMID- 23927668 TI - Assessing vaccine efficacy in influenza clinical trials: challenges and difficulties. AB - The efficacy assessment of an influenza vaccine often requires conducting large and expensive clinical trials. Specificities of influenza increase the complexity of the study designs, of the subsequent statistical analysis and of the interpretation of the results. They include low attack rates, seasonality, multiplicity and frequent mutations of flu viruses as well as heterogeneity of virus circulation, varying annual vaccine composition and so on. The authors discuss how those factors may impact the design, the conduct and the analysis of an efficacy trial and explain why it may fail whatever the true vaccine efficacy. The authors then argue that extending the length to several consecutive seasons is an alternative to the frequently used 1-year design and propose refinements of the statistical models. PMID- 23927666 TI - An EGFRvIII-targeted bispecific T-cell engager overcomes limitations of the standard of care for glioblastoma. AB - While advanced surgical techniques, radiation therapy and chemotherapeutic regimens provide a tangible benefit for patients with glioblastoma (GBM), the average survival from the time of diagnosis remains less than 15 months. Current therapy for GBM is limited by the nonspecific nature of treatment, prohibiting therapy that is aggressive and prolonged enough to eliminate all malignant cells. As an alternative, bispecific antibodies can redirect the immune system to eliminate malignant cells with exquisite potency and specificity. We have recently developed an EGF receptor variant III (EGFRvIII)-targeted bispecific antibody that redirects T cells to eliminate EGFRvIII-expressing GBM. The absolute tumor specificity of EGFRvIII and the lack of immunologic crossreactivity with healthy cells allow this therapeutic to overcome limitations associated with the nonspecific nature of the current standard of care for GBM. Evidence indicates that the molecule can exert therapeutically significant effects in the CNS following systemic administration. Additional advantages in terms of ease-of-production and off-the-shelf availability further the clinical utility of this class of therapeutics. PMID- 23927669 TI - Dose-dispensing service as an intervention to improve adherence to polymedication. AB - Given the importance of high adherence to long-term pharmacotherapy and the growing need to improve medication adherence, choosing the best intervention represents a challenge for healthcare providers. A dose-dispensing service is defined as the repackaging of solid oral medication into dose-dispensing aids by a healthcare provider, mostly in a community pharmacy or hospital pharmacy, in order to assist patients in the management of their polymedication. The personalized dose-dispensing aid organizes individual oral doses according to their prescribed intake schedule throughout the day and the week. This review aims to describe the pros and cons of different dose-dispensing services and technologies, summarizes current evidence and addresses research gaps. PMID- 23927670 TI - Novel disease-modifying therapeutics for the treatment of Alzheimer's disease. AB - Alzheimer's disease is the most common cause of dementia and is becoming a global health concern. Despite a well-established understanding of the molecular mechanism involved in its pathogenesis, and millions of dollars of investment in drug discovery and clinical trials, no single molecule has yet been approved for its treatment since the advent of cholinesterase inhibitors and memantine. This review examines first the optimal use of currently approved agents and then explores in detail the current Phase II and III clinical trial landscape, while spending some time on the mechanistic details. Driven by the increasing knowledge gleaned from numerous Phase III failures and improvements in early detection and biomarkers, there is renewed enthusiasm that a cure is taking shape along the visible horizon. PMID- 23927671 TI - Perils and pitfalls of long-term effects of proton pump inhibitors. AB - This review summarizes the literature regarding long-term adverse effects of proton pump inhibitors (PPIs). A PubMed search (1966 to February 2013) for English language studies was conducted using key terms PPI: omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, pneumonia, Clostridium difficile, osteoporosis, risk of fractures, thrombocytopenia, rhabdomyolysis, anemia, iron deficiency, hypomagnesemia, vitamin B12 and nephritis. The risk of pneumonia was increased 27-39% in short term use of PPIs in three meta-analyses. C. difficile infections were also associated with the use of PPIs (odds ratio: 2.15; 95% CI: 1.81-2.55; p < 0.00001). This effect appears to be dose related. The US FDA has recently issued a warning regarding fractures and the impaired magnesium absorption associated with the use of PPI. Thrombocytopenia, iron deficiency, vitamin B12 deficiency, rhabdomyolysis and acute interstitial nephritis have also been reported with the use of PPIs. There is mounting evidence that PPIs are associated with serious adverse effects. Practitioners should be vigilant and counsel patients accordingly. PMID- 23927672 TI - An electrically excited nanoscale light source with active angular control of the emitted light. AB - We report on the angular distribution, polarization, and spectrum of the light emitted from an electrically controlled nanoscale light source. This nanosource of light arises from the local, low-energy, electrical excitation of localized surface plasmons (LSP) on individual gold nanoparticles using a scanning tunneling microscope (STM). The gold nanoparticles (NP) are chemically synthesized truncated bitetrahedrons. The emitted light is collected through the transparent substrate and the emission characteristics (angular distribution, polarization, and spectrum) are analyzed. These three observables are found to strongly depend on the lateral position of the STM tip with respect to the triangular upper face of the gold NP. In particular, the resulting light emission changes orientation when the electrical excitation via the STM tip is moved from the base to the vertex of the triangular face. On the basis of the comparison of the experimental observations with an analytical dipole model and finite difference time-domain (FDTD) calculations, we show that this behavior is linked to the selective excitation of the out-of-plane and in-plane dipolar LSP modes of the NP. This selective excitation is achieved through the lateral position of the tip with respect to the symmetry center of the NP. PMID- 23927674 TI - Epithelial pearl formation following tympanic membrane regeneration therapy using an atelocollagen/silicone membrane and basic fibroblast growth factor: our experience from a retrospective study of one hundred sixteen patients. PMID- 23927673 TI - Increased T cell glucose uptake reflects acute rejection in lung grafts. AB - Although T cells are required for acute lung rejection, other graft-infiltrating cells such as neutrophils accumulate in allografts and are also high glucose utilizers. Positron emission tomography (PET) with the glucose probe [(18)F]fluorodeoxyglucose ([(18)F]FDG) has been employed to image solid organ acute rejection, but the sources of glucose utilization remain undefined. Using a mouse model of orthotopic lung transplantation, we analyzed glucose probe uptake in the grafts of syngeneic and allogeneic recipients with or without immunosuppression treatment. Pulmonary microPET scans demonstrated significantly higher [(18)F]FDG uptake in rejecting allografts when compared to transplanted lungs of either immunosuppressed or syngeneic recipients. [(18)F]FDG uptake was also markedly attenuated following T cell depletion therapy in lung recipients with ongoing acute rejection. Flow cytometric analysis using the fluorescent deoxyglucose analog 2-NBDG revealed that T cells, and in particular CD8(+) T cells, were the largest glucose utilizers in acutely rejecting lung grafts followed by neutrophils and antigen-presenting cells. These data indicate that imaging modalities tailored toward assessing T cell metabolism may be useful in identifying acute rejection in lung recipients. PMID- 23927675 TI - Influence of safety warnings on ESA prescribing among dialysis patients using an interrupted time series. AB - BACKGROUND: In March, 2007, a black box warning was issued by the Food and Drug Administration (FDA) to use the lowest possible erythropoiesis-stimulating agents (ESA) doses for treatment of anemia associated with renal disease. The goal is to determine if a change in ESA use was observed following the warning among US dialysis patients. METHODS: ESA therapy was examined from September 2004 through August 2009 (thirty months before and after the FDA black box warning) among adult Medicare hemodialysis patients. An interrupted time series model assessed the impact of the warnings. RESULTS: The FDA black box warning did not appear to influence ESA prescribing among the overall dialysis population. However, significant declines in ESA therapy after the FDA warnings were observed for selected populations. Patients with a hematocrit>=36% had a declining month-to month trend before (-164 units/week, p=<0.0001) and after the warnings (-80 units/week, p=.001), and a large drop in ESA level immediately after the black box (-4,744 units/week, p=<.0001). Not-for-profit facilities had a declining month-to-month trend before the warnings (-90 units/week, p=.009) and a large drop in ESA dose immediately afterwards (-2,487 units/week, p=0.015). In contrast, for-profit facilities did not have a significant change in ESA prescribing. CONCLUSIONS: ESA therapy had been both profitable for providers and controversial regarding benefits for nearly two decades. The extent to which a FDA black box warning highlighting important safety concerns influenced use of ESA therapy among nephrologists and dialysis providers was unknown. Our study found no evidence of changes in ESA prescribing for the overall dialysis population resulting from a FDA black box warning. PMID- 23927676 TI - Prevalence of bovine genital campylobacteriosis and trichomonosis of bulls in northern Nigeria. AB - BACKGROUND: A survey was conducted to determine the prevalence of campylobacteriosis and trichomonosis, and their concurrence with brucellosis, in cattle in three states of northern Nigeria. METHODS: A total of 602 preputial samples was collected from bulls in 250 herds and tested using culture and identification. Various indigenous and exotic breeds were studied and four major management systems were encountered. Age of the cattle was estimated using dentition, farm records or cornual rings. RESULTS: The estimated true animal level prevalence of Campylobacter fetus infection was 16.4% (95% CI: 13.0-20.7), of which 18.5% was C. f. fetus and 81.5% was C. f. venerealis. Of the latter, 92% were C. f. venerealis biovar intermedius strains. Animal-level prevalences in Adamawa, Kano and Kaduna states were 31.8%, 11.6% and 8.3% respectively, and were highest in bulls>7 years old (33.4%) and in the Gudali breed (28.8%). Of the 250 herds, 78 (25.5%, 95% CI: 19.4-32.7) had at least one infected bull, and herd prevalence was highest in the pastoral management system (43.5%). After adjustment for confounding using multivariable analysis, the odds of C. fetus infection were highest in Adamawa state (P<0.01), in the pastoral management system (P<0.01), and in bulls>7 years old (P=0.01), and tended to be higher in Bos taurus breeds (P=0.06). There was a strong positive association between the presence of campylobacteriosis and brucellosis (P<0.01), both within bulls (OR=8.3) and within herds (OR=16.0). Trichomonosis was not detected in any herds. CONCLUSION: Bovine genital campylobacteriosis is prevalent particularly in the pastoral management system in northern Nigeria, with C. f. venerealis biovar intermedius as the major aetiology. There was a strong positive correlation between the occurrence of campylobacteriosis and brucellosis. No evidence of trichomonosis was found in herds in this study. PMID- 23927677 TI - Development of a complex amino acid supplement, Fatigue RevivaTM, for oral ingestion: initial evaluations of product concept and impact on symptoms of sub health in a group of males. AB - BACKGROUND: A new dietary supplement, Fatigue RevivaTM, has been recently developed to address issues related to amino acid depletion following illness or in conditions of sub-health where altered amino acid homeostasis has been associated with fatigue. Complex formulations of amino acids present significant challenges due to solubility and taste constraints. This initial study sets out to provide an initial appraisal of product palatability and to gather pilot evidence for efficacy. METHODS: Males reporting symptoms of sub-health were recruited on the basis of being free from any significant medical or psychological condition. Each participant took an amino acid based dietary supplement (Fatigue RevivaTM) daily for 30 days. Comparisons were then made between pre- and post-supplement general health symptoms and urinary amino acid profiles. RESULTS: Seventeen men took part in the study. Following amino acid supplementation the total Chalder fatigue score improved significantly (mean +/- SEM, 12.5 +/- 0.9 versus 10.0 +/- 1.0, P<0.03). When asked whether they thought that the supplement had improved their health, 65% of participants responded positively. A subgroup of participants reported gastrointestinal symptoms which were attributed to the supplement and which were believed to result from the component fructooligosaccharide. Analysis of urinary amino acids revealed significant alterations in the relative abundances of a number of amino acids after supplementation including an increase in valine, isoleucine and glutamic acid and reduced levels of glutamine and ornithine. Discriminant function analysis of the urinary amino acid data revealed significant differences between the pre- and post-supplement urine excretion profiles. CONCLUSIONS: The results indicated that Fatigue RevivaTM was palatable and that 65% of the study group reported that they felt the product had improved their health. The product could provide an effective tool for the management of unexplained fatigue and symptoms of sub-health. Further product development may yield additional options for those patients susceptible to fructooligosaccharide. PMID- 23927678 TI - Human tracheobronchial basal cells. Normal versus remodeling/repairing phenotypes in vivo and in vitro. AB - Human tracheobronchial epithelial (TBE) basal cells (BCs) function as progenitors in normal tissue. However, mechanistic studies are typically performed in vitro and frequently use BCs recovered from patients who die of nonrespiratory disease. It is not known whether the cadaveric epithelium (1) is undergoing homeostatic remodeling and/or repair, or (2) yields BC clones that represent homeostatic processes identified in tissue. We sought to compare the phenotype of TBE-BCs with that of BCs cultured under optimal clone-forming conditions. TBE pathology was evaluated using quantitative histomorphometry. The cultured BC phenotype was determined by fluorescence-activated cell sorter analysis. Clone organization and cell phenotype were determined by immunostaining. The cadaveric TBE is 20% normal. In these regions, BCs are keratin (K)-5(+) and tetraspanin CD151(+), and demonstrate a low mitotic index. In contrast, 80% of the cadaveric TBE exhibits homeostatic remodeling/repair processes. In these regions, BCs are K5(+)/K14(+), and a subset expresses tissue factor (TF). Passage 1 TBE cells are BCs that are K5(+)/TF(+), and half coexpress CD151. Optimal clone formation conditions use an irradiated NIH3T3 fibroblast feeder layer (American Type Culture Collection, Frederick, MD) and serum-supplemented Epicult-B medium (Stemcell Technologies, La Jolla, CA). The TF(+)/CD151(-) BC subpopulation is the most clonogenic BC subtype, and is enriched with K14(+) cells. TF(+)/CD151(-) BCs generate clones containing BCs that are K5(+)/Trp63(+), but K14(-)/CD151(-). TF(+) cells are limited to the clone edge. In conclusion, clonogenic human TBE BCs (1) exhibit a molecular phenotype that is a composite of the normal and remodeling/reparative BC phenotypes observed in tissue, and (2) generate organoid clones that contain phenotypically distinct BC subpopulations. PMID- 23927680 TI - Hyperplastic hepatocellular nodule with localized hemangiomatosis: A hither-to unrecognized type of hypervascular hepatic lesion. AB - AIM: The differential diagnosis of hypervascular hepatocellular nodular lesion includes hepatocellular carcinoma and it is sometimes difficult to image. We report herein two patients with hyperplastic hepatocellular nodule associated with localized hemangiomatosis. METHODS: A hypervascular hepatic nodule approximately 10 mm in diameter was incidentally detected in a 79-year-old woman and a 58-year-old man. Hepatocellular carcinoma was suspected and partial hepatectomy was performed. RESULTS: Hepatitis viral markers and tumor markers were negative in both patients. On histology, the nodular lesions had an ill defined border and included hemangioma-like vessels and sinusoidal dilatation showing immunoreactivity for CD34. There were no abnormal unpaired arteries or a central stellate scar suggesting focal nodular hyperplasia. Hepatic columns in the lesion were thickened to two to three cell layers and cellular density was mildly more increased than the background liver. Cellular atypia and diminished reticulin fibers around the hepatic column were not observed. A survey of the background livers of 13 patients with cavernous hemangioma disclosed similar hemangioma-like vessels in hepatic parenchyma in six patients (46%), but similar nodular lesions were not detected in any patients. CONCLUSION: Taken together, the hepatic lesions in these two patients may be hither-to unrecognized types of hyperplastic hepatocellular lesion associated with localized hemangiomatous lesion that may cause irregular blood flow. PMID- 23927679 TI - Prevalence of vertebral fractures, vascular calcifications, and mortality in warfarin treated hemodialysis patients. AB - Warfarin inhibits vitamin-K dependent proteins involved in bone mineralization and the prevention of vascular calcification (bone Gla protein BGP, matrix Gla protein MGP). In this multicenter, cross-sectional study with 3-year follow-up, data from 387 patients on hemodialysis for >=1 year at 18 dialysis units were analyzed. Patients on warfarin treatment for > 1 year (11.9% of the population) were compared with the remaining cohort for vertebral fractures, vascular calcifications and mortality. Vertebral fractures and vascular calcifications were sought in L-L vertebral X-rays (D5 to L4). Compared with controls, warfarin treated male patients had more vertebral fractures (77.8 vs. 57.7%, p<0.04), but not females (42.1% vs. 48.4%, p=0.6); total BGP was significantly reduced (82.35 vs. 202 ug/L, p<0.0001), with lower levels in treated men (69.5 vs. women 117.0 ug/L, p=0.03). In multivariate logistic regression analyses, the use of warfarin was associated with increased odds of aortic (OR 2.58, p<0.001) and iliac calcifications (OR 2.86, p<0.001); identified confounders were age, atrial fibrillation, angina, PPI use and total BGP. Seventy-seven patients died during a 2.7+/-0.5 year follow-up. In univariate Cox regression analysis, patients on warfarin had a higher risk of all-cause mortality (HR 2.42, 95% CI 1.42-4.16, p=0.001) when compared with those untreated and data adjustment for confounders attenuated but confirmed the significant warfarin-mortality link (HR: 1.97, 95% CI: 1.02-3.84, P=0.046). In hemodialysis patients, additional studies are warranted to verify the risk/benefit ratio of warfarin, which appears to be associated with significant morbidity and increased mortality. PMID- 23927681 TI - P1/P2 genotyping of known and novel null alleles in the P1PK and GLOB histo-blood group systems. AB - BACKGROUND: The rare but clinically important null phenotypes of the P1PK and GLOB blood group systems are due to alterations in A4GALT and B3GALNT1, respectively. A recently identified single-nucleotide polymorphism in Exon 2a of A4GALT predicts the common P1 and P2 phenotypes but rare variants have not been tested. STUDY DESIGN AND METHODS: The aim of this study was to analyze 84 p, P1 (k) , and P2 (k) samples, with special emphasis on unknown alleles and the P(1) /P(2) marker. Of these, 27 samples came from individuals not previously investigated genetically and were therefore subjected to sequencing of A4GALT or B3GALNT1, and a subset was tested by flow cytometry. RESULTS: The P(1) /P(2) genotyping linked 20 p-inducing mutations in A4GALT to P(1) or P(2) allelic background. Eight p alleles remain unlinked due to compound heterozygosity. For 23 of 25 P(k) samples, concordant results were observed: P1 (k) samples had at least one P(1) allele while P2 (k) had P(2) only. The two remaining samples typed as P1+ and P1+(w) but were genetically P(2) /P(2) . A tendency toward higher P(k) antigen expression was observed on P1 (k) cells compared to P2 (k) . In total, six previously unknown null mutations were found and characterized in A4GALT while four new changes were revealed in B3GALNT1. CONCLUSION: For the first time, p alleles were shown to occur on both P(1) and P(2) allelic backgrounds. Furthermore, P(1) /P(2) genotyping predicted the P1 (k) versus P2 (k) phenotype in more than 90% of globoside-deficient samples. The number of GLOB-null alleles was increased by 50% and several P1PK-null alleles were identified. PMID- 23927682 TI - Different colonization patterns of Aspergillus terreus in patients with cystic fibrosis. AB - Aspergillus terreus is a common soil saprophyte. After Aspergillus fumigatus and Scedosporium apiospermum it ranks third amongst the filamentous fungi colonizing the airways of patients with cystic fibrosis. In this context, the clinical presentation of A. terreus infection mainly corresponds to allergic broncho pulmonary aspergillosis. In the work presented here, we studied colonization patterns of A. terreus in CF patients by genotyping using nine short tandem repeat markers. A total of 115 clinical isolates from respiratory secretions collected from five French CF patients were studied. The number of isolates varied from 15 to 39 per patient, and the duration of the follow-up period ranged from 2 months to 7.5 years. Seventeen genotypes were identified, corresponding to three distinct colonization patterns. The first colonization pattern consisted of a chronic colonization by one dominant genotype associated with few other genotypes found only incidentally. The second colonization pattern consisted of a prolonged colonization by two distinct genotypes detected simultaneously. The last pattern was characterized by multiple different genotypes that were present only transiently. These results demonstrate the importance of genotyping clinical isolates before making conclusions about chronic colonization of the airways in CF patients in the case of repeated isolation of the fungus. PMID- 23927683 TI - Development of Mycobacterium tuberculosis whole cell screening hits as potential antituberculosis agents. AB - The global pandemic of drug sensitive tuberculosis (TB) as well as the increasing threat from various multidrug resistant forms of TB drives the quest for newer, safer, more effective TB treatment options. The general lack of success in progressing novel chemical matter from high throughput screens of Mycobacterium tuberculosis (M.tb) biochemical targets has prompted resurgence in interest and efforts in prosecuting mycobacterial phenotypic screens. Whole cell active compounds identified from such screens offer significant intrinsic advantages over biochemical screening hits, and derivatives of many of these have proven invaluable in helping to fill the current TB drug development pipeline. Modern techniques for "de-orphaning" such screening hits (i.e., determining their specific biological mechanism of action) offer the possibility of ultimately identifying improved next-generation chemical series by screening these essential, pharmacologically validated biochemical targets as well. PMID- 23927684 TI - Structure of the receptacular nectary and circadian metabolism of starch in the ant-guarded plant Ipomoea cairica (Convolvulaceae). AB - Nectaries occur widely in Convolvulaceae. These structures remain little studied despite their possible importance in plant-animal interactions. In this paper, we sought to describe the structure and ultrastructure of the receptacular nectaries (RNs) of Ipomoea cairica, together with the dynamics of nectar secretion. Samples of floral buds, flowers at anthesis and immature fruits were collected, fixed and processed using routine methods for light, scanning and transmission electron microscopy. Circadian starch dynamics were determined through starch measurements on nectary sections. The secretion samples were subjected to thin layer chromatography. RNs of I. cairica were cryptic, having patches of nectar secreting trichomes, subglandular parenchyma cells and thick-walled cells delimiting the nectary aperture. The glandular trichomes were peltate type and had typical ultrastructural features related to nectar secretion. The nectar is composed of sucrose, fructose and glucose. Nectar secretion was observed in young floral buds and continued as the flower developed, lasting until the fruit matured. The starch content of the subglandular tissue showed circadian variation, increasing during the day and decreasing at night. The plastids were distinct in different portions of the nectary. The continuous day-night secretory pattern of the RNs of I. cairica is associated with pre-nectar source circadian changes in which the starch acts as a buffer, ensuring uninterrupted nectar secretion. This circadian variation may be present in other extrafloral nectaries and be responsible for full daytime secretion. We conclude that sampling time is relevant in ultrastructural studies of dynamic extranuptial nectaries that undergo various changes throughout the day. PMID- 23927685 TI - Amino acid-functionalized ionic liquid solid sorbents for post-combustion carbon capture. AB - Amino acid ionic liquids (AAILs) are potential green substitutes of aqueous amine solutions for carbon dioxide (CO2) capture. However, the viscous nature of AAILs greatly hinders their further development in CO2 capture applications. In this contribution, 1-ethyl-3-methylimidazolium lysine ([EMIM][Lys]) was synthesized and immobilized into a porous poly(methyl methacrylate) (PMMA) microsphere support for post-combustion CO2 capture. The [EMIM][Lys] exhibited good thermal stability and could be facilely immobilized into porous microspheres. Significantly, the [EMIM][Lys]-PMMA sorbents retained their porous structure after [EMIM][Lys] loading and exhibited fast kinetics. When exposed to CO2 at 40 degrees C, [EMIM][Lys]-PMMA sorbent exhibited the highest CO2 capacity compared to other counterparts studied and achieved a capacity of 0.87 mol/(mol AAIL) or 1.67 mmol/(g sorbent). The capture process may be characterized by two stages: CO2 adsorption on the surface of sorbent and CO2 diffusion into sorbent for further adsorption. The calculated activation energies of the two-stage CO2 sorption were 4.1 and 4.3 kJ/mol, respectively, indicating that, overall, the CO2 can easily adsorb onto this sorbent. Furthermore, multiple cycle tests indicated that the developed sorbents had good long-term stability. The developed sorbent may be a promising candidate for post-combustion CO2 capture. PMID- 23927686 TI - An offer you cannot refuse: down-regulation of immunity in response to a pathogen's retaliation threat. AB - According to the Red Queen hypothesis, hosts and pathogens are engaged in an escalating coevolutionary arms race between resistance and virulence. However, the vast majority of symbionts colonize their hosts' mucosal compartments without triggering any immune response, resulting in durable commensal associations. Here, I propose a simple extension of previous mathematical models for antagonistic coevolution in which the host can mount a delayed immune response; in response, the symbiont can change its virulence following this activation. Even though the levels of virulence in both phases are assumed to be genetically determined, this simple form of plasticity can select for commensal associations. In particular, coevolution can result in hosts that do not activate their immune response, thus preventing phenotypically plastic pathogens from switching to a higher virulence level. I argue that, from the host's point of view, this state is analogous to the mafia behaviour previously described in avian brood parasites. More importantly, this study provides a new hypothesis for the maintenance of a commensal relationship through antagonistic coevolution. PMID- 23927687 TI - A conserved ClpP-like protease involved in spore outgrowth in Bacillus subtilis. AB - Germination and outgrowth of endospores of the Gram-positive bacterium Bacillus subtilis involves the degradation and conversion to free amino acids of abundant proteins located in the spore core known as small acid-soluble proteins (SASP). This degradation is mediated primarily by the germination protease Gpr. Here we show that YmfB, a distant homologue of ClpP serine proteases that is highly conserved among endospore-forming bacteria, contributes to SASP degradation but that its function is normally masked by Gpr. Spores from a ymfB gpr double mutant were more delayed in spore outgrowth and more impaired in SASP degradation than were spores from a gpr single mutant. The activity of YmfB relied on three putative active-site residues as well as on the product of a small gene ylzJ located immediately downstream of, and overlapping with, ymfB. We propose that YmfB is an orphan ClpP protease that is dedicated to the degradation of a specialized family of small protein substrates. PMID- 23927688 TI - Hydrogen bonding and electron transfer between dimetal paddlewheel compounds containing pendant 2-pyridone functional groups. AB - The compounds M2(TiPB)3(HDON) (TiPB = 2,4,6-triisopropylbenzoic acid; H2DON = 2,7 dihdroxy-1,8-napthyridine; M = Mo (1a) or W (1b)) and Mo2(TiPB)2(O2CCH2Cl)(HDON) (1c) which contain a pendant 2-pyridone functional group have been prepared. These compounds are capable of forming self-complementary hydrogen bonds, resulting in the formation of "dimers of dimers" ([1a-c]2) in CH2Cl2 solutions. Electrochemical studies reveal two successive one-electron redox processes for [1a-c]2 in CH2Cl2 solutions that correspond to successive oxidations of the dimetal core, indicating stabilization of the mixed-valence state. Only small changes in the value of Kc are observed upon changing the ancillary ligand or metal, implying that proton coupled mixed valency is responsible for the stabilization. Dimethylsulfoxide (DMSO) disrupts the hydrogen bonding interactions in these compounds, and a single oxidation process is observed in DMSO which shifts to lower potential as the number of HDON ligands increases. Further substitution of carboxylate ligands with HDON leads to the formation of Mo2(TiPB)2(HDON)2 (2) and Mo2(HDON)4 (3), which adopt trans-1,1 and cis-2,2 regioisomers in the solid-state. (1)H NMR spectroscopy indicates that there are at least two regioisomers present in solution for both compounds. The lowest energy transition in the electronic absorption spectra of these compounds corresponds to a M2-delta -> HDON-pi* transition. The electrochemical, spectroscopic and structural results were rationalized with the aid of density functional theory (DFT) calculations. PMID- 23927689 TI - Screening ability of faecal haemoglobin concentration for excluding colorectal diseases: statistical validity of the receiver operating characteristic curve analysis. PMID- 23927690 TI - Effect of Spirulina (Arthrospira) supplementation on the immune response to tetanus toxoid vaccination in a mouse model. AB - The aim of this study was to investigate whether Spirulina (Arthrospira) supplementation could enhance the immune response to tetanus toxoid (TT) vaccine in a mouse model. Vaccination of TT was performed on day 7 and 21 in mice fed daily with Spirulina (50 and 150 mg/kg body weight). Both Spirulina supplementation and TT vaccination did not significantly affect body weight gain of the mice. Supplementation of Spirulina significantly enhanced IgG level (p = .01) after the first but not after the second TT vaccination. The anti-TT IgG levels of the groups that received low dose and high dose of Spirulina were not significantly different. Spirulina supplementation did not show significant effects on in vitro splenocyte proliferation and cytokine (IFN-gamma and IL-4) production induced by Con A and TT. This study showed that Spirulina supplementation could enhance primary immune response in terms of antibody production, but not secondary immune response following TT vaccination in a mouse model. PMID- 23927691 TI - Substance use, gender inequity, violence and sexual risk among couples in Cape Town. AB - Alcohol and other drug use, gender power inequities and violence are key contributors to sexual risks for HIV among South African men and women. Little is known about the intersection between these sex-risk behaviours among couples in established heterosexual relationships. We conducted 10 focus-group discussions with men and women in relationships of 1 year or longer recruited from shebeens (informal taverns) in Cape Town, South Africa. Participants described: high levels of alcohol consumption at shebeens; low levels of condom use with main and casual sex partners; gender roles disfavouring women's condom negotiating power that also promoted economic dependency on male partners; men often spending a portion of the household income on alcohol and other drugs and sex with others in shebeens; loss of household income driving women to trade sex to provide for their families; and sexual violence and the exploitation of women occurring in shebeens. Findings highlight how the social contexts of alcohol and other drug use, gender inequitable norms and gender violence promote HIV risk within established heterosexual relationships in South African communities. Evidence of this kind should inform the design of HIV-risk-reduction interventions tailored to heterosexual couples who drink alcohol in shebeens. PMID- 23927692 TI - Pharmacological mitigation of tissue damage during brain microdialysis. AB - Microdialysis sampling in the brain is employed frequently in the chemical analysis of neurological function and disease, but implanting the probes, which are substantially larger than the size and spacing of brain cells and blood vessels, is injurious and triggers ischemia, gliosis, and cell death at the sampling site. The nature of the interface between the brain and the microdialysis probe is critical to the use of microdialysis as a neurochemical analysis technique. The objective of the work reported here was to investigate the potential of two compounds, dexamethasone, a glucocorticoid anti-inflammatory agent, and XJB-5-131, a mitochondrially targeted reactive oxygen species scavenger, to mitigate the penetration injury. Measurements were performed in the rat brain striatum, which is densely innervated by axons that release dopamine, an electroactive neurotransmitter. We used voltammetry to measure electrically evoked dopamine release next to microdialysis probes during the retrodialysis of dexamethasone or XJB-5-131. After the in vivo measurements, the brain tissue containing the microdialysis probe tracks was examined by fluorescence microscopy using markers for ischemia, neuronal nuclei, macrophages, and dopamine axons and terminals. Dexamethasone and XJB-5-131 each diminished the loss of evoked dopamine activity, diminished ischemia, diminished the loss of neuronal nuclei, diminished the appearance of extravasated macrophages, and diminished the loss of dopamine axons and terminals next to the probes. Our findings confirm the ability of dexamethasone and XJB-5-131 to mitigate, but not eliminate, the effects of the penetration injury caused by implanting microdialysis probes into brain tissue. PMID- 23927693 TI - NetMHCstab - predicting stability of peptide-MHC-I complexes; impacts for cytotoxic T lymphocyte epitope discovery. AB - Major histocompatibility complex class I (MHC-I) molecules play an essential role in the cellular immune response, presenting peptides to cytotoxic T lymphocytes (CTLs) allowing the immune system to scrutinize ongoing intracellular production of proteins. In the early 1990s, immunogenicity and stability of the peptide-MHC I (pMHC-I) complex were shown to be correlated. At that time, measuring stability was cumbersome and time consuming and only small data sets were analysed. Here, we investigate this fairly unexplored area on a large scale compared with earlier studies. A recent small-scale study demonstrated that pMHC-I complex stability was a better correlate of CTL immunogenicity than peptide-MHC-I affinity. We here extended this study and analysed a total of 5509 distinct peptide stability measurements covering 10 different HLA class I molecules. Artificial neural networks were used to construct stability predictors capable of predicting the half-life of the pMHC-I complex. These predictors were shown to predict T-cell epitopes and MHC ligands from SYFPEITHI and IEDB to form significantly more stable MHC-I complexes compared with affinity-matched non-epitopes. Combining the stability predictions with a state-of-the-art affinity predictions NetMHCcons significantly improved the performance for identification of T-cell epitopes and ligands. For the HLA alleles included in the study, we could identify distinct sub-motifs that differentiate between stable and unstable peptide binders and demonstrate that anchor positions in the N-terminal of the binding motif (primarily P2 and P3) play a critical role for the formation of stable pMHC-I complexes. A webserver implementing the method is available at www.cbs.dtu.dk/services/NetMHCstab. PMID- 23927694 TI - Desogestrel-only contraception may reduce headache frequency and improve quality of life in women suffering from migraine. AB - OBJECTIVE: To analyse the effects of a three-month course of progestogen-only contraception with desogestrel 75 MUg on disability, headache frequency and headache intensity in migraineurs. MATERIALS AND METHODS: Migraine disability headache questionnaires (MIDAS) were collected from 37 migraineurs during counselling, and at the end of three months treatment with desogestrel. Another ten women initiated but did not complete treatment. They are included in the overall evaluations of the effect of the regimen on migraine status. RESULTS: Desogestrel was associated with significant reductions in headache days and intensity (p < 0.001; p < 0.006), and a significant improvement in quality of life. Days missed at work and days missing leisure activities diminished (p < 0.001; p < 0.001). The MIDAS migraine disability score improved significantly (from 27.4 to 11.1 points) (p < 0.001). While 25 of the 37 women (68%) experienced a decrease of at least one grade, this level of benefit cannot be extrapolated to all initiators. When dropouts are considered, MIDAS grades decrease in 53% (25/47) of the cases. CONCLUSION: The majority of migraineurs experienced a clinically significant reduction in headache frequency and improvement of quality of life with use of desogestrel. Prospective randomised controlled trials are needed to substantiate our results. PMID- 23927695 TI - Infant neurodevelopment following in utero exposure to antidepressant medication. AB - AIM: To examine the impact of pregnancy exposure to antidepressants on infant neurodevelopment. METHODS: A prospective, longitudinal study in which antidepressant-exposed (n = 35) and nonexposed (n = 23) infants were administered the Bayley Scales of Infant Development (BSID-III) at 18 months, which measures neurodevelopment across five domains. Data on obstetric and perinatal complications, maternal IQ, presence of mood disorder in pregnancy and up to and including 18 months, and psychosocial status were also collected. RESULTS: Almost 90% of infants were exposed throughout the second and third trimesters to therapeutic antidepressant doses. Bivariate analysis showed no difference between exposed and unexposed infants in any of the neurodevelopmental outcomes. Maternal depression around birth or up to time of developmental testing was not associated with neurodevelopmental outcomes. CONCLUSION: Our results suggest that pregnancy antidepressant exposure (mostly serotonin reuptake inhibitors) is not associated with poorer cognitive, motor or language development outcomes in infants at 18 months. This information supports earlier studies and adds into the available data used by clinicians and mothers making key decisions around the use of antidepressants in pregnancy. However, given the small sample size, and some degree of heterogeneity in terms of antidepressant exposure, these results need to be treated with caution. PMID- 23927697 TI - Editors' overview. PMID- 23927698 TI - A scholarship of practice: creating discourse between theory, research and practice. AB - SUMMARY Occupational therapy has experienced a tremendous growth both of theory and research. However, there is little evidence that this renaissance of knowledge has been paralleled by changes in practice. Instead, academics tend to express concern that practice lags behind scholarship while clinicians bemoan the irrelevance of theory and research to their everyday work. This paper discusses the scholarship of practice. This approach is based on the assumption that those who ultimately will use the knowledge must be partners in its generation. Thus, it emphasizes cooperative efforts in which practitioners and scholars work together as partners to advance both knowledge and practice. PMID- 23927696 TI - COBRApy: COnstraints-Based Reconstruction and Analysis for Python. AB - BACKGROUND: COnstraint-Based Reconstruction and Analysis (COBRA) methods are widely used for genome-scale modeling of metabolic networks in both prokaryotes and eukaryotes. Due to the successes with metabolism, there is an increasing effort to apply COBRA methods to reconstruct and analyze integrated models of cellular processes. The COBRA Toolbox for MATLAB is a leading software package for genome-scale analysis of metabolism; however, it was not designed to elegantly capture the complexity inherent in integrated biological networks and lacks an integration framework for the multiomics data used in systems biology. The openCOBRA Project is a community effort to promote constraints-based research through the distribution of freely available software. RESULTS: Here, we describe COBRA for Python (COBRApy), a Python package that provides support for basic COBRA methods. COBRApy is designed in an object-oriented fashion that facilitates the representation of the complex biological processes of metabolism and gene expression. COBRApy does not require MATLAB to function; however, it includes an interface to the COBRA Toolbox for MATLAB to facilitate use of legacy codes. For improved performance, COBRApy includes parallel processing support for computationally intensive processes. CONCLUSION: COBRApy is an object-oriented framework designed to meet the computational challenges associated with the next generation of stoichiometric constraint-based models and high-density omics data sets. AVAILABILITY: http://opencobra.sourceforge.net/ PMID- 23927699 TI - Scholarship of practice in the United kingdom: an occupational therapy service case study. AB - SUMMARY Occupational therapy is required to deliver and generate evidence-based practice. This paper illustrates an approach to meeting these evidence-based expectations. Specifically, there is a description of the development of a partnership between the United Kingdom Centre for Outcomes Research and Education (UKCORE) and The State Hospital which is a forensic mental health service. This case study will illuminate (a) a rationale for partnership, (b) the process of building the partnership, and (c) outcomes of the partnership. Principles of scholarship of practice will be identified and ways of supporting services to integrate occupational therapy knowledge generation and utilisation will be outlined. PMID- 23927700 TI - Completing the cycle of scholarship of practice: a model for dissemination and utilization of evidence-based interventions. AB - SUMMARY The scholarship of practice stresses that knowledge should arise out of a dialogue and collaboration between scholars and practitioners. Bringing evidence back to practice completes the scholarship of practice cycle. This article describes a strategic approach to the process of knowledge dissemination and utilization and how that approach was used to increase knowledge and utilization of the Matter of Balance fear of falling intervention among occupational therapy practitioners. To illustrate how the approach supported clinicians' efforts to engage in evidence-based practice, the paper features a description of actions taken by a Maine-based health care system to successfully integrate Matter of Balance into its programming. Recommendations to policy makers, researchers and clinicians based on the authors' experiences with approach are presented. PMID- 23927701 TI - A model of university-community partnerships for occupational therapy scholarship and practice. AB - SUMMARY University-community partnerships are at the heart of community-based Occupational Therapy and the Scholarship of Practice that links practice with theory and research. In these partnerships, academicians, students, practitioners and staff from community organizations work in collaboration with a variety of community settings and programs, involving community leaders, agency staff, and/or members of grassroots groups. This paper presents a framework of seven characteristics that are typical of successful partnership endeavors, such as building a relationship based on trust and mutual respect. We illustrate how this model can be used to promote praxis between theory, research and practice with two examples of ongoing community partnerships that involve an educational community practicum for all entry-level OT students. We also discuss the benefits and challenges of such partnership and discuss the implications for community based OT. PMID- 23927702 TI - The practice-scholar program: an academic-practice partnership to promote the scholarship of "best practices". AB - SUMMARY Faculty-practitioner partnerships that address mutually established, practice-relevant priorities have great potential to bridge academy and practice. Each partner has a different purpose or mission but together embracing mutually beneficial opportunities through sustainable partnerships, exponentially increases the outcomes that could result. The purpose of this paper is to report the evolution of a new program, called the Practice-Scholar Program at Duquesne University. The goal was to develop new partnerships between practice and our Department to support mutual interests in teaching, research and service focusing on the scholarship of occupational therapy 'best practices' in a variety of settings. These 'best practice' sites are to develop model programs in occupational therapy stressing occupation-based practice, application of evidence in clinical decision-making and embed scholarship activities into their every day practice. The selection, development and sustenance of our Practice-Scholar program and our first four partnership sites are described in this paper. Our Practice-Scholars sites have been at a collaborative speech-language/occupational therapy pediatric clinic, and at three community sites: three day-care sites in a marginalized underserved community; a homeless shelter for women; and the county jail. This paper describes how faculty have woven the Practice-Scholar program into our teaching, research and service responsibilities while helping our Practice-Scholars develop 'best practices.' Faculty, practitioner, and students benefits are described. Both the funding and outcomes from the Practice-Scholar program will be presented. Finally, new developments, modifications and challenges in sustaining these Practice Scholar partnerships and scholarship of practice activities are discussed. PMID- 23927703 TI - Academic-clinician partnerships: a model for outcomes research. AB - SUMMARY While practitioners are now asked to provide evidence that supports the services we deliver, there is little empirical evidence concerning occupational therapy interventions. Research by clinicians is limited, often due to a lack of time, institutional support and research skills. Establishing collaborative research relationships between faculty, clinicians, and graduate students has been suggested as a means of addressing these barriers. Implementation of a model teaming students with clinicians to conduct outcomes studies is described. The model will be illustrated using a case example of a collaborative research project evaluating the efficacy of a home management skills program for individuals with chronic mental illness. The benefits and challenges of the collaborative process will be described. PMID- 23927704 TI - Synthesizing research, education, and practice according to the scholarship of practice model: two faculty examples. AB - SUMMARY The Scholarship of Practice involves an ongoing, reflective discourse among the theoretical concepts of occupational therapy, the empirical verification of those concepts through research, and the application of those concepts in real-world clinical practice. This article illustrates how the Scholarship of Practice framework is applied by occupational therapy faculty members as a key aspect of their scholarly and teaching roles. Two distinct perspectives are provided-one describes the scholarship and teaching of a clinical-track faculty member and the other describes that of a research-track faculty member. Both examples illustrate how each faculty member's work involves an integration of teaching and advising, scholarship (i.e., developing occupational therapy theory and conducting research), and practice. In both cases, the faculty member uses the Scholarship of Practice approach to better understand the kinds of problems and needs of clients and the ways in which practitioners can use knowledge generated by theory and research to most effectively address them. In turn, each faculty member relies heavily on the feedback from students and practitioners regarding the outcomes of the practical application of the concepts offered by theory and research. This feedback is then utilized to revise and refine existing theory, generate new research questions, and ultimately inform best occupational therapy practice. Finally the process serves as an ideal context for teaching and advising. PMID- 23927705 TI - A collaborative scholarly project: constraint-induced movement therapy. AB - SUMMARY This paper describes the phases of a scholarly project process within one occupational therapy (OT) professional program. Using the example of a scholarly project on constraint-induced movement therapy, the collective endeavor among two OT graduate students, a faculty advisor, and two occupational therapists is demonstrated. The process leading toward a clinically-relevant outcome provided benefits to all collaborators. The students experienced evidence-based scholarship firsthand, while the advisor and practitioners experienced the rewards of shaping a clinically useful product and received outcomes research assistance. The description of this scholarly project process serves as a model for future scholarly collaboration among graduate students, practitioners, and faculty members. PMID- 23927706 TI - New doors: a community program development model. AB - SUMMARY The need to provide occupational therapy services across a continuum of care has stimulated interest in moving into community-based arenas of practice. Limited job opportunities and lack of awareness of the benefits of occupational therapy are common barriers to this movement. This case study illustrates the "New Doors Model" and describes how a partnership between the university, master clinicians, students, and community agencies can result in (1) expanding occupational therapy services to facilities that have not historically interacted with occupational therapy, (2) training occupational therapists and occupational therapy students, and (3) promoting employment of occupational therapists by community organizations, and (4) a scholarship of practice that studies and supports the development of occupation based practice in community settings. The New Doors Model begins with exposing new sites to occupational therapy through level I fieldwork, progressing to level II fieldwork, and ending with creation of permanent occupational therapy positions. PMID- 23927707 TI - A participatory action research approach for identifying health service needs of Hispanic immigrants: implications for occupational therapy. AB - SUMMARY Recently, the field of Community Occupational Therapy has started to enter into new research areas, one being participatory research. This paper illustrates a participatory research methodology adapted by community residents and a research team to identify the service needs of an underserved Hispanic population as well as set action agendas to meet their needs. In order to plan and implement health programs, community residents participated actively in the needs assessment, action agenda development and brainstorming of solutions to address health and community needs and concerns. Concerns identified included the lack of affordable bilingual dentists and youth involvement in gangs, drugs, and alcohol. The results of the needs assessment were shared and discussed during five public forums in which 180 Hispanics from the community discussed the dimensions of the issues and alternative solutions. This process resulted in an agenda of health issues and ideas for improvement from the perspective of Hispanics. We emphasized the advantages of using participatory methodologies when developing health and community services within Hispanic communities. Additionally, the implications for advancing a Scholarship of Practice agenda for Community Occupational Therapy are discussed. PMID- 23927708 TI - Brief or new: interagency collaboration to support adults with developmental disabilities in college campus living. AB - SUMMARY Interagency collaboration in provision of a campus transition living program for young adults with developmental disabilities is described. Given the current imbalance of available resources versus need for service provision, creative teamwork is imperative. Schools and community agencies interact with young adults to apply classroom learning to real-life experiences. This project demonstrates through specific student experiences successful behavioral strategies, challenges and benefits of this life skills program as the evidence of the efficacy of this model. The purpose of this model is three-fold: (1) to provide real-life transitional living experiences in combination with classroom learning for young adults with developmental disabilities; (2) to provide an innovative service delivery model for collaboration of community agencies utilizing alternative funding; (3) to relate the service delivery process to occupation and address the care, values, choices, needs, and interventions used to support and improve performance in occupational engagement and participation. PMID- 23927709 TI - Therapists' and clients' perceptions of the occupational performance history interview. AB - SUMMARY The Occupational Performance History Interview-Second Version (OPHI-II) is a semi-structured interview that gathers life history information. The interview data is used to score three rating scales and complete a narrative slope. Previous research has primarily examined the validity of the scales. This qualitative study sought to understand from the perspectives of therapists and clients how they experienced the interview process and narrative slope of the OPHI-II. Clients and therapists agreed that the OPHI-II interview built rapport, generated insights into the client's life experiences, and was helpful in planning goals and services and both groups generally found the narrative slope valuable. Both therapists and clients indicated the importance of tailoring the interview process and the narrative slope to each client's unique perspective and needs. Study findings both support the usefulness of the OPHI-II and provide suggestions for how it can be used most effectively. PMID- 23927710 TI - Education and practice collaborations: a pilot case study between a university faculty and county jail practitioners. AB - SUMMARY The purpose of this case study is to present a partnership between faculty and practitioners that initiated a systematic evaluation data collection approach to support program development and study practice in a newly developing occupational therapy program. The Department of Occupational Therapy at Duquesne University collaborated with Goodwill Industries of Pittsburgh to introduce occupational therapy as part of a grant-supported community re-integration program at the Allegheny County Jail. In developing the program, the absence of published data regarding the occupational needs among jail inmates was evident. This paper is presented as a case study to demonstrate that faculty-practitioner collaborations can promote the implementation of a viable, systematic evaluation process when implemented as soon as possible in the practice setting. The community-university partnership ensured that a wide variety of knowledge and resource applied to the development of an evaluation process that generated relevant data for each of the partners. The intent of providing systematic evidence for practice can enhance the intervention process and provide valuable professional information. This paper also presents pilot descriptive results from the Occupational Self Assessment (2002) from the initial 67 (61 men & 6 women) inmates in the local Allegheny County Jail Community regarding perceptions of their own occupational competence and of the impact of their environment on their overall occupational adaptation. Using OSA responses, a difference score between reported occupational competence in an activity (rated low) and the correlated importance of the occupation (rated high), the top eight occupational performance areas of concern were identified for the total group, men only and women only. Caution in using the woman data due to the small n is advised. The top eight occupational performance areas of concern for this population included managing my finances, handling my responsibilities, working towards my goals, accomplishing what I set out to do, a place to live and take care of myself, basic things I need to live and take care of myself, things I need to be productive, and a place where I can be productive. Notably, four of these eight items captured the inmates' perceptions of the impact of the environment on their occupational adaptation. This study demonstrates the viability of the academic practice partnership to support the scholarship of practice and provide a model to embed evidence-gathering through systematic evaluation processes. PMID- 23927711 TI - Achieving evidence-based practice: a process of continuing education through practitioner-academic partnership. AB - SUMMARY Occupational therapy is required to deliver and generate evidence-based practice. As currently articulated, evidence-based practice requires particular skills and takes time and is rarely realized. This paper illustrates a collaborative approach to building an evidence based training program within a practice context. The aim of the training program was to enable therapists in a large mental health setting to engage in evidence-based practice. Specifically, the partnership between the United Kingdom Centre for Outcomes Research and Education (UK CORE) and Gloucestershire Partnership NHS Trust (GPT) will be described. This article describes the GPT/UKCORE partnership, the process of building an evidence-based practice training program, the final structure of the evidence-based practice training program, and the evaluation of the evidence based practice training program. PMID- 23927712 TI - Theory of mind and the social brain: implications for understanding the genetic basis of schizophrenia. AB - Genome-wide association studies in schizophrenia have recently made significant progress in our understanding of the complex genetic architecture of this disorder. Many genetic loci have been identified and now require functional investigation. One approach involves studying their correlation with neuroimaging and neurocognitive endophenotypes. Theory of Mind (ToM) deficits are well established in schizophrenia and they appear to fulfill criteria for being considered an endophenotype. We aim to review the behavioral and neuroimaging based studies of ToM in schizophrenia, assess its suitability as an endophenotype, discuss current findings, and propose future research directions. Suitable research articles were sourced from a comprehensive literature search and from references identified through other studies. ToM deficits are repeatable, stable, and heritable: First-episode patients, those in remission and unaffected relatives all show deficits. Activation and structural differences in brain regions believed important for ToM are also consistently reported in schizophrenia patients at all stages of illness, although no research to date has examined unaffected relatives. Studies using ToM as an endophenotype are providing interesting genetic associations with both single nucleotide polymorphisms (SNPs) and specific copy number variations (CNVs) such as the 22q11.2 deletion syndrome. We conclude that ToM is an important cognitive endophenotype for consideration in future studies addressing the complex genetic architecture of schizophrenia, and may help identify more homogeneous clinical sub-types for further study. PMID- 23927713 TI - A(H1N1)pdm09 hemagglutinin D222G and D222N variants are frequently harbored by patients requiring extracorporeal membrane oxygenation and advanced respiratory assistance for severe A(H1N1)pdm09 infection. AB - BACKGROUND: In patients with A(H1N1)pdm09 infection, severe lung involvement requiring admission to intensive care units (ICU) has been reported. Mutations at the hemagglutinin (HA) receptor binding site (RBS) have been associated with increased virulence and disease severity, representing a potential marker of critical illness. OBJECTIVES: To assess the contribution of HA-RBS variability in critically ill patients, A(H1N1)pdm09 virus from adult patients with severe infection admitted to ICU for extracorporeal membrane oxygenation support (ECMO) during influenza season 2009-2011 in Piemonte (4.2 million inhabitants), northwestern Italy, was studied. PATIENTS AND METHODS: We retrospectively analyzed HA-RBS polymorphisms in ICU patients and compared with those from randomly selected inpatients with mild A(H1N1)pdm09 disease and outpatients with influenza from the local surveillance program. RESULTS: By HA-RBS direct sequencing of respiratory specimens, D222G and D222N viral variants were identified in a higher proportion in ICU patients (n=8/24, 33.3%) than in patients with mild disease (n=2/34, 6%) or in outpatients (n=0/44) (Fisher's exact test P<0.0001; OR 38.5; CI 95% 4.494-329.9). Eleven ICU patients died (42%), three of them carrying the D222G variant, which was associated with RBS mutation S183P in two. D222G and D222N mutants were identified in upper and lower respiratory samples. CONCLUSIONS: A(H1N1)pdm09 HA substitutions D222G and D222N were harbored in a significantly higher proportion by patients with acute respiratory distress for A(H1N1)pdm09 severe infection requiring ICU admission and ECMO. These data emphasize the importance of monitoring viral evolution for understanding virus-host adaptation aimed at the surveillance of strain circulation and the study of viral correlates of disease severity. PMID- 23927715 TI - Passively transferred human NMO-IgG exacerbates demyelination in mouse experimental autoimmune encephalomyelitis. AB - BACKGROUND: Neuromyelitis optica (NMO) is a devastating inflammatory disorder of the optic nerves and spinal cord characterized by frequently recurring exacerbations of humoral inflammation. NMO is associated with the highly specific NMO-IgG biomarker, an antibody that binds the aquaporin-4 water channel. Aquaporin-4 is present on glial endfeet in the central nervous system (CNS). In humans, the NMO-IgG portends more frequent exacerbations and a worse long-term clinical outcome. METHODS: We tested the longer-term outcome of mice with EAE injected with NMO-IgG and followed them for 60 days. Clinical exams and pathology of the spinal cord and optic nerves were compared to mice that received control human IgG. RESULTS: Passively transferred human NMO-IgG leads to more severe neurology disability over two months after onset of disease. Clinical worsening is associated with an increased concentration of large demyelinating lesions primarily to subpial AQP4-rich regions of the spinal cord. CONCLUSIONS: NMO-IgG is pathogenic in the context of EAE in mice. PMID- 23927716 TI - Controlled, defect-guided, metal-nanoparticle incorporation onto MoS2 via chemical and microwave routes: electrical, thermal, and structural properties. AB - Ultrathin (0.3-3 nm) metal dichalcogenides exhibit confinement of carriers, evolution of band-structure and photophysical properties with thickness, high on/off rectification (in MoS2, WS2, and so forth) and high thermal absorption. Here, we leverage the stable sulfur/nobel-metal binding to incorporate highly capacitive gold nanoparticles (Au NPs) onto MoS2 to raise the effective gate voltage by an order of magnitude. Functionalization is achieved via both diffusion limited aggregation and instantaneous reaction arresting (using microwaves) with selective deposition on crystallographic edges (with 60 degrees displacement). The electrical, thermal, and Raman studies show a highly capacitive interaction between Au NP and MoS2 flakes (CAu-MoS2 = 2.17 MUF/cm(2)), a low Schottky barrier (14.52 meV), a reduced carrier-transport thermal-barrier (253 to 44.18 meV after Au NP functionalization), and increased thermal conductivity (from 15 to 23 W/mK post NP deposition). The process could be employed to attach electrodes to heterostructures of graphene and MoS2, where a gold film could be grown to act as an electron-tunneling gate-electrode connected to MoS2. PMID- 23927717 TI - Impacts of palatal coverage on bolus formation during mastication and swallowing and subsequent adaptive changes. AB - Palatal coverage is often required for elderly edentulous patients with complete dentures. The purpose of this study was to clarify impacts of palatal coverage on bolus formation and subsequent adaptive changes. Subjects were 18 healthy young dentulous adults who wore 1.5-mm-thick palatal plates. Subjects were asked to feed 12 g of bicoloured rice as usual, and the bolus formation by mastication and swallowing in the pharynx was observed using a nasal videoendoscopy. The bolus formation index (BFI), number of mastication strokes until swallowing, visual analogue scale about swallowing easiness and masticatory performance using colour changeable gum were measured under three conditions: before placement of the palatal plate (day 0), immediately after placement (day 1) and after 7 days of wearing the plate (day 7). BFI and visual analogue scale on day 1 were significantly lower than those on day 0, but those on day 7 significantly recovered to the level of day 0. The number of mastication strokes did not change from day 0 to day 1, however, that on day 7 was significantly higher. Masticatory performance on days 1 and 7 was significantly lower than that on day 0. Although palatal coverage inhibits bolus formation during feeding, subjects increased the number of mastication strokes until swallowing threshold as they adapted to palatal coverage over time. This adaptive change was due to compensate for the lowered masticatory performance to achieve bolus formation for comfortable swallowing. PMID- 23927719 TI - Functional locked-in syndrome as recovery phase of vegetative state. PMID- 23927718 TI - Major food sources of calories, added sugars, and saturated fat and their contribution to essential nutrient intakes in the U.S. diet: data from the National Health and Nutrition Examination Survey (2003-2006). AB - BACKGROUND: The risk of chronic disease cannot be predicted simply by the content of a single nutrient in a food or food group in the diet. The contribution of food sources of calories, added sugars and saturated fat (SFA) to intakes of dietary fiber and micronutrients of public health importance is also relevant to understanding the overall dietary impact of these foods. OBJECTIVE: Identify the top food sources of calories, added sugars and SFA in the U.S. diet and quantify their contribution to fiber and micronutrient intakes. METHODS: Single 24-hour dietary recalls (Day 1) collected from participants >=2 years (n = 16,822) of the What We Eat in America, National Health and Nutrition Examination Survey (WWEIA/NHANES 2003-2006) were analyzed. All analyses included sample weights to account for the survey design. Calorie and nutrient intakes from foods included contributions from disaggregated food mixtures and tabulated by rank order. RESULTS: No one food category contributes more than 7.2% of calories to the overall U.S. diet, but half of the top 10 contribute 10% or more of total dietary fiber and micronutrients. Three of the top 10 sources of calories and SFA (beef, milk and cheese) contribute 46.3% of the calcium, 49.5% of the vitamin D, 42.3% of the vitamin B12 as well as other essential nutrients to the American diet. On the other hand, foods categorized as desserts, snacks, or beverages, contribute 13.6% of total calories, 83% of added sugar intake, and provide little or no nutritional value. Including food components of disaggregated recipes more accurately estimated the contribution of foods like beef, milk or cheese to overall nutrient intake compared to "as consumed" food categorizations. CONCLUSIONS: Some food sources of calories, added sugars and SFA make major contributions to American dietary fiber and micronutrient intakes. Dietary modifications targeting reductions in calories, added sugar, or SFA need to take these key micronutrient sources into account so as not to have the unintended consequence of lowering overall dietary quality. PMID- 23927720 TI - Cell-based medicinal chemistry optimization of high-throughput screening (HTS) hits for orally active antimalarials. Part 1: challenges in potency and absorption, distribution, metabolism, excretion/pharmacokinetics (ADME/PK). AB - Malaria represents a significant health issue, and novel and effective drugs are needed to address parasite resistance that has emerged to the current drug arsenal. Antimalarial drug discovery has historically benefited from a whole-cell (phenotypic) screening approach to identify lead molecules. This approach has been utilized by several groups to optimize weakly active antimalarial pharmacophores, such as the quinolone scaffold, to yield potent and highly efficacious compounds that are now poised to enter clinical trials. More recently, GNF/Novartis, GSK, and others have employed the same approach in high throughput screening (HTS) of large compound libraries to find novel scaffolds that have also been optimized to clinical candidates by GNF/Novartis. This perspective outlines some of the inherent challenges in cell-based medicinal chemistry optimization, including optimization of oral exposure and hERG activity. PMID- 23927721 TI - Immunoassay with single-walled carbon nanotubes as near-infrared fluorescent labels. AB - The intrinsic photoluminescence of single-walled carbon nanotubes (CNTs) in the near-infrared (NIR) above 1000 nm makes them promising candidates for biological probes owing to low interference by bioorganic molecules and deep tissue penetration. We here demonstrate an immunoassay by using a NIR CNT labels conjugated to immunoglobulin G (IgG) antibodies. Most of the CNT-conjugated IgG was successfully immunoprecipitated with protein G-attached magnetic beads and eluted from them, which was confirmed by the NIR emission of the conjugated CNTs at 1000-1200 nm. The photoluminescence intensity of the CNT labels was strong enough to detect antigens at 600 pM by our simple procedures. PMID- 23927722 TI - Survival of influenza virus on human fingers. AB - Indirect transmission of the influenza virus via finger contamination with respiratory mucus droplets has been hypothesized to contribute to transmission in the community. Under laboratory conditions, influenza-infected respiratory droplets were reconstituted as close as possible to natural conditions. We investigated experimentally the survival of influenza A (H3N2) and A (H1N1)pdm09 viruses on human fingers. Infectious virus was easily recoverable on all fingers 1 min after fingertip contamination but then decreased very rapidly. After 30 min, infectious virus was detectable in only a small minority of subjects. Infectious viruses were detected for a longer period of time when droplets of larger size containing a higher number of particles were tested or when the viral concentration increased. A rapid decrease in infectiousness was observed when droplet integrity was disrupted. Our findings could help to set up the promotion of hand hygiene to prevent influenza hand contamination. PMID- 23927723 TI - Actin cytoskeleton and organelle movement in the sporangiophore of the zygomycete Phycomyces blakesleeanus. AB - Growth, photo- and gravitropism of sporangiophores of the zygomycete Phycomyces blakesleeanus occur within the apical growing zone, a cylindrical structure (diameter about 100 MUm) that reaches about 1.5-2.5 mm below the tip and has growth rates up to 50 MUm.min(-1) . To better understand morphogenesis and growth of the giant aerial hypha, we investigated with confocal microscopy and inhibitors the actin cytoskeleton and by in-vivo particle tracking the associated organelle movement. We found stage-1 sporangiophores (without sporangium) possess an actin cytoskeleton with polar zonation. (i) In the apex, abundant microfilaments without preferential orientation entangled numerous nuclei as well as a conspicious complex of some 200 lipid globules. Microfilament patches (~ 1.6 MUm diameter) are clustered in the tip and were found in the apical cortex, whereas short, curved microfilament bundles (~ 2.3-MUm long) prevailed in the subapex. (ii) In a transition zone downwards to the shaft, the microfilaments rearranged into a dense mat of longitudinal microfilaments that was parallel close to the periphery but more random towards the cell centre. Numerous microfilament patches were found near the cortex (~ 10/100 MUm(2) ); their number decreased rapidly in the subcortex. In contrast, the short, curved microfilament bundles were found only in the subcortex. (iii) The basal shaft segment of the sporangiophore (with central vacuole) exhibited bidirectional particle movement over long distances (velocity ~ 2 MUm.s(-1) ) along massive longitudinal, subcortical microfilament cables. The zonation of the cytoskeleton density correlated well with the local growth rates at the tip of the sporangiophore, and appears thus as a structural prerequisite for growth and bending. PMID- 23927724 TI - Circulating levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with incisional hernia. AB - Incisional hernia formation is a common complication to laparotomy and possibly associated with alterations in connective tissue metabolism. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are closely involved in the metabolism of the extracellular matrix. Our aim was to study serum levels of multiple MMPs and TIMPs in patients with and without incisional hernia. Out of 305 patients who underwent laparotomy, 79 (25.9%) developed incisional hernia over a median follow-up period of 3.7 years. Pooled sera from a subset (n = 72) of these patients were screened for MMP-1, MMP-2, MMP 3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, MMP-13, TIMP-1, TIMP-2, and TIMP-4 using a multiplex sandwich fluorescent immunoassay supplemented with gelatin zymography. The screening indicated differences in serum MMP-9 and TIMP-1 levels. Consequently, MMP-9 and TIMP-1 levels were measured in serum in the whole patient cohort with enzyme-linked immunosorbent assay. There were no significant differences in either MMP-9 (p = 0.411) or TIMP-1 (p = 0.679) levels between hernia and hernia-free patients. MMP-9 was significantly increased in smokers compared with nonsmokers (p = 0.016). In conclusion, a possible involvement of MMPs and TIMPs in the pathogenesis of incisional hernia formation was not reflected systemically. PMID- 23927725 TI - A pragmatic approach to embedding patient blood management in a tertiary hospital. AB - BACKGROUND: We describe the implementation and impact of a patient blood management program (PBMP) in an Australian teaching hospital. STUDY DESIGN AND METHODS: A PBMP was introduced at a single tertiary care hospital in 2009 as a pilot for the Western Australian Health Department statewide PBMP. The first 3 years of interventions aimed to make effective use of preoperative clinics, manage perioperative anemia, improve perioperative hemostasis, reduce blood sample volumes, and implement restrictive transfusion triggers and a single-unit transfusion policy. RESULTS: Between 2008 and 2011, admissions to Fremantle Hospital and Health Services increased by 22%. Using 2008 as a reference year, the mean number of red blood cell (RBC) units per admission declined 26% by 2011. Use of fresh-frozen plasma and platelets showed 38 and 16% declines, respectively. Cryoprecipitate increased 7% over the 4-year period. For elective admissions between 2008 and 2011, the leading decline in RBC transfusion rate was seen in cardiothoracic surgery (27.5% to 12.8%). The proportion of single RBC unit use increased from 13% to 28% (p < 0.001), and the proportion of double units decreased from 48% to 37% (p < 0.001). CONCLUSION: This is the first tertiary hospital in Australia to establish a multidisciplinary multimodal PBMP. Interventions across disciplines resulted in decreased use of RBC units especially in orthopedic and cardiothoracic surgery. Continuing education and feedback to specialties will maintain the program, improve patient outcomes, and decrease the transfusion rate. PMID- 23927726 TI - Structural determinants stabilizing the axial channel of ClpP for substrate translocation. AB - Acyldepsipeptides (ADEPs) antibiotics bind to Escherichia coli ClpP mimicking the interactions that the IGL/F loops in ClpA or ClpX ATPases establish with the hydrophobic pockets surrounding the axial pore of the tetradecamer that the protease forms. ADEP binding induces opening of the gates blocking the axial channel of ClpP and allowing protein substrates to be translocated and hydrolysed in the degradation chamber. To identify the structural determinants stabilizing the open conformation of the axial channel for efficient substrate translocation, we constructed ClpP variants with amino acid substitutions in the N-terminal region that forms the axial gates. We found that adoption of a beta-hairpin loop by this region and the integrity of the hydrophobic cluster at the base of this loop are necessary elements for the axial gate to efficiently translocate protein substrates. Analysis of ClpP variants from Bacillus subtilis suggested that the identified structural requirements of the axial channel for efficient translocation are conserved between Gram-positive and Gram-negative bacteria. These findings provide mechanistic insights into the activation of ClpP by ADEPs as well as the gating mechanism of the protease in the context of the ClpAP and ClpXP complexes. PMID- 23927727 TI - Sacral transcutaneous stimulation for faecal incontinence may have a different mechanism of action to sacral nerve stimulation. PMID- 23927728 TI - Multi-tissue stable isotope analysis and acoustic telemetry reveal seasonal variability in the trophic interactions of juvenile bull sharks in a coastal estuary. AB - Understanding how natural and anthropogenic drivers affect extant food webs is critical to predicting the impacts of climate change and habitat alterations on ecosystem dynamics. In the Florida Everglades, seasonal reductions in freshwater flow and precipitation lead to annual migrations of aquatic taxa from marsh habitats to deep-water refugia in estuaries. The timing and intensity of freshwater reductions, however, will be modified by ongoing ecosystem restoration and predicted climate change. Understanding the importance of seasonally pulsed resources to predators is critical to predicting the impacts of management and climate change on their populations. As with many large predators, however, it is difficult to determine to what extent predators like bull sharks (Carcharhinus leucas) in the coastal Everglades make use of prey pulses currently. We used passive acoustic telemetry to determine whether shark movements responded to the pulse of marsh prey. To investigate the possibility that sharks fed on marsh prey, we modelled the predicted dynamics of stable isotope values in bull shark blood and plasma under different assumptions of temporal variability in shark diets and physiological dynamics of tissue turnover and isotopic discrimination. Bull sharks increased their use of upstream channels during the late dry season, and although our previous work shows long-term specialization in the diets of sharks, stable isotope values suggested that some individuals adjusted their diets to take advantage of prey entering the system from the marsh, and as such this may be an important resource for the nursery. Restoration efforts are predicted to increase hydroperiods and marsh water levels, likely shifting the timing, duration and intensity of prey pulses, which could have negative consequences for the bull shark population and/or induce shifts in behaviour. Understanding the factors influencing the propensity to specialize or adopt more flexible trophic interactions will be an important step in fully understanding the ecological role of predators and how ecological roles may vary with environmental and anthropogenic changes. PMID- 23927729 TI - Direct isolation of myofibroblasts and fibroblasts from bleomycin-injured lungs reveals their functional similarities and differences. AB - BACKGROUND: Myofibroblasts play a crucial role in tissue repair. The functional similarities and differences between myofibroblasts and fibroblasts are not fully understood because they have not been separately isolated from a living body. The purpose of this study was to establish a method for the direct isolation of myofibroblasts and fibroblasts from injured lungs by using fluorescence-activated cell sorting and to compare their functions. RESULTS: We demonstrated that lineage-specific cell surface markers (lin), such as CD31, CD45, CD146, EpCAM (CD326), TER119, and Lyve-1 were not expressed in myofibroblasts or fibroblasts. Fibroblasts of bleomycin-injured lungs and saline-treated lungs were shown to be enriched in linneg Sca-1high, and myofibroblasts of bleomycin-injured lungs were shown to be enriched in linneg Sca-1low CD49ehigh. Results from in-vitro proliferation assays indicated in-vitro proliferation of fibroblasts but not myofibroblasts of bleomycin-injured lungs and of fibroblasts of saline-treated lungs. However, fibroblasts and myofibroblasts might have a low proliferative capacity in vivo. Analysis of genes for collagen and collagen synthesis enzymes by qRT-PCR showed that the expression levels of about half of the genes were significantly higher in fibroblasts and myofibroblasts of bleomycin-injured lungs than in fibroblasts of saline-treated lungs. By contrast, the expression levels of 8 of 11 chemokine genes of myofibroblasts were significantly lower than those of fibroblasts. CONCLUSIONS: This is the first study showing a direct isolation method of myofibroblasts and fibroblasts from injured lungs. We demonstrated functional similarities and differences between myofibroblasts and fibroblasts in terms of both their proliferative capacity and the expression levels of genes for collagen, collagen synthesis enzymes, and chemokines. Thus, this direct isolation method has great potential for obtaining useful information from myofibroblasts and fibroblasts. PMID- 23927730 TI - Monitoring Doppler patterns and clinical parameters may predict feeding tolerance in intrauterine growth-restricted infants. AB - AIM: To detect predictors of feeding tolerance in intrauterine growth restriction (IUGR) infants with or without brain-sparing effect (BS). METHODS: We conducted a case-control study in 70 IUGR infants (35 IUGR with BS, matched for gestational age with 35 IUGR infants with no BS). BS was classified as pulsatility index (PI) ratio [umbilical artery (UAPI) to middle cerebral artery (MCAPI) (U/C ratio)] > 1. Clinical parameters of feeding tolerance - days to achieve full enteral feeding (FEF) - were compared between the IUGR with BS and IUGR without BS infants. Age at the start of minimal enteral feeding (MEF) was analysed. RESULTS: Achievement of FEF was significantly shorter in IUGR infants without BS than in IUGR with BS. IUGR with BS started MEF later than IUGR without BS infants. Significant correlation of MEF and FEF with UA PI, U/C ratio and CRIB score was found. Multiple linear regression analysis showed significant correlations with CRIB score and caffeine administration (MEF only), and sepsis (FEF only) and U/C ratio (for both). CONCLUSION: Impaired gut function can be early detected by monitoring Doppler patterns and clinical parameters. PMID- 23927732 TI - Effect of deodorization of camelina (Camelina sativa) oil on its phenolic content and the radical scavenging effectiveness of its extracts. AB - The influence of deodorization parameters (temperature (T), steam flow (S), time (t)) on the phenolic content and radical scavenging effectiveness (RSE) of methanolic extracts of camelina oil was investigated and analyzed by response surface methodology (RSM). The phenolic content can be considered to be a linear function of all three parameters. A positive linear relationship between the content of phenolic compounds in deodorized oils and RSE was observed. Deodorization at 210 degrees C with a steam flow of 3 mL/h for 90 min resulted in the best preservation of phenolics, amounting to 29.9 mg/kg. The lowest reduction from RSE of 12.4 MUM Trolox equivalents (TE)/g oil for the crude oil was observed for oil treated at 195 degrees C and 18 mL/h for 60 min with RSE of 10.1 MUM TE/g oil. The lack of correlation between RSE or total phenolic content and oxidative stability (OS) of the deodorized oils suggests that antioxidants in scavenging radicals react by different mechanisms, depending on radical type and reaction medium. PMID- 23927733 TI - Second harmonic correlation spectroscopy: a method for determining surface binding kinetics and thermodynamics. AB - These studies describe the implementation of second harmonic correlation spectroscopy (SHCS) to measure the adsorption and desorption kinetics of molecular species associated with a surface. Specifically, the local fluctuations of the measured second harmonic (SH) signal were used to determine the binding kinetics and thermodynamics of (S)-(+)-1,1'-bi-2-napthol SBN intercalation into a 1,2-dioleoyl-sn-glycero-3-phosphocoline (DOPC) bilayer. In order to determine the adsorption and desorption rates, the SH signal was collected above saturation concentration at steady-state equilibrium as a function of time. The autocorrelated SH signal was then fit to a correlation model developed for molecules binding at a surface when there is no contribution from molecules in solution. The measured adsorption rate for SBN to DOPC was 2.7 +/- 0.2 * 10(3) s( 1) M(-1) and the desorption rate was 9 +/- 4 * 10(-4) s(-1). The kinetic rates as well as the calculated equilibrium binding constant, 3.0 +/- 1.3 * 10(6) M(-1) obtained from SHCS were compared with those obtained from a conventional binding isotherm and found to be statistically consistent. The primary advantage of using SHCS is both the absorption and desorption rates were determined in the same experiment using only a single bulk concentration of SBN. The results of these studies demonstrate that SHCS can be used to provide accurate kinetic and thermodynamic binding data in a label-free manner in lieu of conventional isotherm studies, especially where time and analyte are scarce. PMID- 23927731 TI - Cyclic tensile strain enhances osteogenesis and angiogenesis in mesenchymal stem cells from osteoporotic donors. AB - We have shown that the uniaxial cyclic tensile strain of magnitude 10% promotes and enhances osteogenesis of human mesenchymal stem cells (hMSC) and human adipose-derived stem cells (hASC) from normal, nonosteoporotic donors. In the present study, MSC from osteoporotic donors were analyzed for changes in mRNA expression in response to 10% uniaxial tensile strain to identify potential mechanisms underlying the use of this mechanical loading paradigm for prevention and treatment of osteoporosis. Human MSC isolated from three female, postmenopausal osteoporotic donors were analyzed for their responses to mechanical loading using microarray analysis of over 47,000 gene probes. Human MSC were seeded in three-dimensional collagen type I constructs to mimic the organic extracellular matrix of bone and 10% uniaxial cyclic tensile strain was applied to promote osteogenesis. Seventy-nine genes were shown to be regulated within hMSC from osteoporotic donors in response to 10% cyclic tensile strain. Upregulation of six genes were further confirmed with real-time RT-PCR: jun D proto-oncogene (JUND) and plasminogen activator, urokinase receptor (PLAUR), two genes identified as potential key molecules from network analysis; phosphoinositide-3-kinase, catalytic, delta polypeptide (PIK3CD) and wingless type MMTV integration site family, member 5B (WNT5B), two genes with known importance in bone biology; and, PDZ and LIM domain 4 (PDLIM4) and vascular endothelial growth factor A (VEGFA), two genes that we have previously shown are significantly regulated in hASC in response to this mechanical stimulus. Function analysis indicated that 10% cyclic tensile strain induced expression of genes associated with cell movement, cell proliferation, and tissue development, including development in musculoskeletal and cardiovascular systems. Our results demonstrate that hMSC from aged, osteoporotic donors are capable of enhanced osteogenic differentiation in response to 10% cyclic tensile strain with significant increases in the expression of genes associated with enhanced cell proliferation, musculoskeletal development, and angiogenesis. Surprisingly, cyclic tensile strain of magnitude 10% not only enhanced osteogenesis in hMSC from osteoporotic donors, but also enhanced expression of angiogenic factors. Better understanding and methodologies to promote osteogenesis in hMSC from elderly, osteoporotic donors may greatly facilitate achieving long-term success in bone regeneration and functional bone tissue engineering for this ever-growing patient population. PMID- 23927734 TI - Fluorodeoxyglucose-positron-emission tomography/computed tomography imaging for adrenal masses in patients with lung cancer: review and diagnostic algorithm. AB - BACKGROUND AND PURPOSE: Positron-emission tomography/computed tomography (PET/CT) with fluorine-18 fluorodeoxyglucose (FDG) is used as first-line staging for patients with newly diagnosed non-small cell lung cancer (NSCLC). Our purpose was to review the accuracy of FDG-PET/CT to predict adrenal gland metastasis, explain the causes for false-positive PET, and provide a diagnostic algorithm. PATIENTS AND METHODS: Two patients with incidentally discovered lung masses were found to have hypermetabolic adrenal activity by FDG-PET/CT with maximal standard uptake value (SUV) of 4.5 and 6.5. A MEDLINE search was performed on the topic of FDG PET/CT, adrenal gland metastasis, and NSCLC. Literature was reviewed with regard to diagnosis, accuracy, outcomes, and alternative imaging or diagnostic strategies. RESULTS: Both patients underwent transabdominal laparoscopic adrenalectomy and were found to have nodular hyperplasia without evidence of adrenal tumor. A total of seven articles containing 343 patients were identified as having pertinent oncologic information for NSCLC patients with adrenal lesions. Sensitivity and specificity of PET/CT for distant metastasis was 94% and 85%, respectively, but only 13% (44/343) of these patients had histologically confirmed adrenal diagnoses. Based on this, a diagnostic algorithm was created to aid in decision making. CONCLUSIONS: Although PET/CT has high sensitivity and specificity for adrenal metastasis in the setting of NSCLC, adrenal biopsy or other secondary imaging should be considered to confirm the finding. Adrenalectomy in lieu of biopsy may have both diagnostic and therapeutic benefit in cases where the adrenal mass is >=10 mm with high PET maximum SUV (>=3.1) and SUV ratios (>2.5), where washout CT or chemical shift MRI is positive, or where percutaneous biopsy is deemed too difficult or unsafe. PMID- 23927735 TI - Spatio-temporal expression of paired immunoglobulin-like receptor-B in the adult mouse brain after focal cerebral ischaemia. AB - PRIMARY OBJECTIVE: Paired immunoglobulin-like receptor-B (PirB) is another receptor, except for the Nogo receptor, that is involved in inhibition of axons regeneration after central nervous system injury. However, the expression of PirB in focal cerebral ischaemic brain remains unclear. Herein, this study investigated spatial-temporal expression of PirB in the mouse brain following transient focal cerebral ischaemia. METHODS AND PROCEDURE: Adult male C57BL/6 mice underwent a 60-minute transient occlusion of middle cerebral artery. Mice were killed and brain samples were harvested at 30 minutes, 2 hours, 24 hours, 3 days and 7 days after reperfusion. Expression of PirB in the brain was determined by reverse transcriptase-polymerase chain reaction (RT-PCR), western blot analysis and immunohistochemical staining. MAIN OUTCOMES AND RESULTS: The results showed that PirB was mainly expressed in ischaemic penumbra. PirB mRNA and protein expression began to increase at 2 hours, peaked at 24 hours and lasted for 7 days after reperfusion in the ischaemic penumbra. By using immunofluorescence, PirB signals were co-localized with NeuN-positive neurons. CONCLUSION: PirB expression is up-regulated in ischaemic penumbra following transient focal cerebral ischaemia. PirB expression in neurons may play important pathological roles in the inhibition of axonal regeneration after stroke, suggesting that the inhibition of PirB expression may enhance axonal regeneration and functional recovery after stroke. PMID- 23927736 TI - Transient kinetic analyses of the ribonuclease H cleavage activity of HIV-1 reverse transcriptase in complex with efavirenz and/or a beta-thujaplicinol analogue. AB - EFV (efavirenz) and beta-thujaplicinol [2,7-dihydroxy-4-1(methylethyl)-2,4,6 cycloheptatrien-1-one] have contrasting effects on the RNase H activity of HIV-1 RT (reverse transcriptase). EFV binds in the non-nucleoside inhibitor-binding pocket and accelerates this activity, whereas beta-thujaplicinol binds in the RNase H active site and inhibits it. We have used pre-steady-state kinetic analyses to gain an insight into the mechanism by which EFV and a beta thujaplicinol analogue [19616 (2,7-dihydroxy-2,4,6-cyclo-heptatrien-1-one)] modulate RT RNase H activity. Our data show that EFV and 19616 have no effect on polymerase-dependent RNase H cleavages. However, both compounds significantly affected the rates of polymerase-independent RNase H cleavages. In regard to the latter, we found no evidence that the bound RNA/DNA template/primer substrate restricted 19616 from interacting with RT. In light of these data, we propose a model in which 19616 binds to the RNase H active site of RT after the primary polymerase-dependent RNase H cleavage has occurred and stabilizes the 3'-end of the DNA primer in the polymerase active site thus blocking the enzyme's ability to carry out the polymerase-independent cleavages. By contrast, EFV destabilizes the 3'-end of the DNA primer in the DNA polymerase active site and promotes RT mediated polymerase-independent cleavages. Consistent with this model, we show antagonism between EFV and 19616. PMID- 23927737 TI - Increased symplasmic permeability in barley root epidermal cells correlates with defects in root hair development. AB - It is well known that the process of plant cell differentiation depends on the symplasmic isolation of cells. Before starting the differentiation programme, the individual cell or group of cells should restrict symplasmic communication with neighbouring cells. We tested the symplasmic communication between epidermal cells in the different root zones of parental barley plants Hordeum vulgare L., cv. 'Karat' with normal root hair development, and two root hairless mutants (rhl1.a and rhl1.b). The results clearly show that symplasmic communication was limited during root hair differentiation in the parental variety, whereas in both root hairless mutants epidermal cells were still symplasmically connected in the corresponding root zone. This paper is the first report on the role of symplasmic isolation in barley root cell differentiation, and additionally shows that a disturbance in the restriction of symplasmic communication is present in root hairless mutants. PMID- 23927738 TI - Detrimental dermal wound healing: what can we learn from the oral mucosa? AB - Wounds in adults are frequently accompanied by scar formation. This scar can become fibrotic due to an imbalance between extracellular matrix (ECM) synthesis and ECM degradation. Oral mucosal wounds, however, heal in an accelerated fashion, displaying minimal scar formation. The exact mechanisms of scarless oral healing are yet to be revealed. This review highlights possible mechanisms involved in the difference between scar-forming dermal vs. scarless oral mucosal wound healing. Differences were found in expression of ECM components, such as procollagen I and tenascin-C. Oral wounds contained fewer immune mediators, blood vessels, and profibrotic mediators but had more bone marrow-derived cells, a higher reepithelialization rate, and faster proliferation of fibroblasts compared with dermal wounds. These results form a basis for further research that should be focused on the relations among ECM, immune cells, growth factors, and fibroblast phenotypes, as understanding scarless oral mucosal healing may ultimately lead to novel therapeutic strategies to prevent fibrotic scars. PMID- 23927739 TI - Autonomic functioning in irritable bowel syndrome measured by heart rate variability: a meta-analysis. AB - OBJECTIVE: To analyze autonomic functioning which presented as the high frequency (HF) component of heart rate variability, a measurement of vagal tone, and the ratio of low frequency (LF) to HF (LF : HF), an indicator of sympathovagal balance in irritable bowel syndrome (IBS) patients. METHODS: We identified relevant studies by performing a literature search of MEDLINE, EMBASE and the ISI Web of Knowledge to 31 March 2013. Pooled effect sizes with 95% confidence interval (CI) were calculated using a random effects model. Between-study heterogeneity was assessed using the Q test and I(2) statistic. RESULTS: In all, 11 articles including 392 IBS patients and 263 controls met the inclusion criteria of the analysis. IBS patients had lower HF band power (Hedges's g = 0.38, 95% CI -0.68 to -0.09) than the controls (I(2) = 63.6%, P = 0.003). Moreover, IBS patients showed a higher LF : HF (Hedges's g = 0.43, 95% CI 0.13 0.74), with no significant heterogeneity. A subgroup analysis of the HF index according to the recording time yielded different results for the IBS patients and controls. Additionally, constipation-predominant IBS (IBS-C) patients had decreased HF band power, whereas no significant difference was found in LF : HF. CONCLUSIONS: Impaired parasympathetic functioning and abnormal sympathovagal balance may be involved in the pathogenesis of IBS. Vagal dysfunction is more obvious in the IBS-C subgroup. PMID- 23927740 TI - Hierarchical self-assembly: well-defined supramolecular nanostructures and metallohydrogels via amphiphilic discrete organoplatinum(II) metallacycles. AB - Metallacyclic cores provide a scaffold upon which pendant functionalities can be organized to direct the formation of dimensionally controllable nanostructures. Because of the modularity of coordination-driven self-assembly, the properties of a given supramolecular core can be readily tuned, which has a significant effect on the resulting nanostructured material. Herein we report the efficient preparation of two amphiphilic rhomboids that can subsequently order into 0D micelles, 1D nanofibers, or 2D nanoribbons. This structural diversity is enforced by three parameters: the nature of the hydrophilic moieties decorating the parent rhomboids, the concentration of precursors during self-assembly, and the reaction duration. These nanoscopic constructs further interact to generate metallohydrogels at high concentrations, driven by intermolecular hydrophobic and pi-pi interactions, demonstrating the utility of coordination-driven self assembly as a first-order structural element for the hierarchical design of functional soft materials. PMID- 23927741 TI - Probing the effects of cysteine residues on protein adsorption onto gold nanoparticles using wild-type and mutated GB3 proteins. AB - The role of cysteine residues in the protein binding kinetics and stability on gold nanoparticles (AuNP) was studied using AuNP localized surface plasmon resonance (LSPR) in combination with an organothiol (OT) displacement method. GB3, the third IgG-binding domain of protein G, was used to model protein-AuNP adsorption. While wild-type GB3 (GB30) contains no cysteine residues, bioengineered GB3 variants containing one (GB31) and two (GB32) cysteine residues were also tested. The cysteine content has no significant effect on GB3 binding kinetics with AuNPs, and most protein adsorption occurs within the first few seconds upon protein/AuNP mixing. However, the stability of GB3 on the AuNP surface against OT displacement depends strongly on the cysteine content and the age of the AuNP/GB3 mixture. The GB30 covered AuNPs can be completely destabilized and aggregated by OTs, regardless of the age of the GB30/AuNP mixtures. Long-time incubation of GB31 or GB32 with AuNPs can stabilize AuNPs against the OT adsorption inducted aggregation. This study indicates that multiple forces involved in the GB3/AuNP interaction, and covalent binding between cysteine and AuNP is essential for a stable protein/AuNP complex. PMID- 23927743 TI - Message from the editor. PMID- 23927742 TI - Can head trauma trigger celiac disease? Nation-wide case-control study. AB - BACKGROUND: TG6, a brain expressed transglutaminase, is implicated in the neurological manifestations of celiac disease (CD). We hypothesized that earlier brain injury due to head trauma may be more common in patients with CD, potentially through trauma-induced TG6 leading to interaction with TG2. METHODS: Through biopsy reports from all 28 pathology departments in Sweden we identified 29,096 individuals with CD (in this study defined as villous atrophy). We then examined the risk of earlier head trauma in CD compared to the risk in 144,522 controls matched for age, sex, county and calendar year. Odds ratios (ORs) were calculated using conditional logistic regression. RESULTS: 981 (3.4%) individuals with CD and 4,449 (3.1%) controls had a record of earlier head trauma. Individuals with head trauma were hence at a 1.10-fold increased risk of future CD (95% CI = 1.02-1.17). ORs were independent of sex or age at CD. The highest risk of future CD was seen during the first year after trauma. There was no association between severity of trauma and risk of developing CD. CONCLUSIONS: This study found a very small excess risk for future CD in individuals with an earlier head trauma. PMID- 23927744 TI - Dr. Herbert j. Hall: originator of honest work for occupational therapy 1904-1923 [part I]. AB - Within his cultural environment, as a physician, Herbert J. Hall (1870-1923) incorporated the Arts and Crafts movement ideology with medicine. He studied neurasthenia and the rest cure, which was the current treatment. He envisioned a better way and opened a sanatorium that incorporated work cure theories and employed craftsmen as guides. With success, Hall expanded, trained apprentices, and made occupational therapy equipment and kits for hospitals and asylums. He also published textbooks and essays and articles in scientific journals. Although the occupational therapy field has recognized some of his innovative ideas, the information presented here is a comprehensive review of his contributions that may not be recorded elsewhere. PMID- 23927745 TI - Dr. Herbert J. Hall: Originator of Honest Work for Occupational Therapy 1904-1923 [Part II]. AB - While establishing a sanatorium and confirming the value of his innovative use of crafts as a medical tool, Dr. Herbert J. Hall gave lectures and published many articles and books to proclaim his discoveries. Others were experimenting with occupational therapy practices in different forms within mental institutions. Their views and perspectives differed from Hall's practice, the main issues being the market value of crafts and their use as a diversion. This article also includes Hall's psychological principles of indirection, equivalents, immunity, and substitution, and the graded process as observed and applied to the disabled. PMID- 23927746 TI - Dr. Hall and the work cure. AB - Herbert James Hall, MD (1870-1923), was a pioneer in the systematic and organized study of occupation as therapy for persons with nervous and mental disorders that he called the "work cure." He began his work in 1904 during the early years of the Arts and Crafts Movement in the United States. His primary interest was the disorder neurasthenia, a condition with many symptoms including chronic fatigue, stress, and inability to work or perform everyday tasks. The prevailing treatment of the day was absolute bed rest known as the "rest cure." Hall believed that neurasthenia was not caused by overwork but by faulty living habits that could be corrected through an ordered life schedule and selected occupations. He identified several principles of therapy that are still used today including graded activity and energy conservation. Dr. Adolph Meyer credits Hall for organizing the ideas on the therapeutic use of occupation (Meyer, 1922). Hall also provided the name American Occupational Therapy Association for the professional organization and served as the fourth president. For his many contributions to the profession Hall deserves to be recognized as a major contributor to the development and organization of occupational therapy. PMID- 23927747 TI - The Evolving Postbaccalaureate Entry: Analysis of Occupational Therapy Entry Level Master's Degree in the United States. AB - At the American Occupational Therapy Association's Annual Conference in 1999, the Representative Assembly passed Resolution J, which became Resolution 670-99 and mandated that entry to the professional level of practice in occupational therapy be at the post-baccalaureate degree level. The Accreditation Council for Occupational Therapy Education (ACOTE) set the effective date as 2007. As a result, more than 50 of the existing 157 occupational therapy educational programs faced the challenge of developing postbaccalaureate entry degree programs. These programs had previously offered only baccalaureate entry degrees. This article compiles the expectations that were articulated as outcomes of transitioning to postbaccalaureate entry, describes findings from an analysis of the current structure of the evolving master's entry level occupational therapy education and identifies concerns for consideration by educational programs and practitioners. PMID- 23927748 TI - Characteristics of the occupational therapy journal of research: the first twenty years. AB - As evidence-based practitioners, occupational therapists are required to keep abreast of the relevant professional literature, be able to understand and critique research, and to incorporate improvements into daily practice for the benefit of clients (Barber, 1990). The current study proposes to assist readers in this responsibility through a retrospective analysis of the Occupational Therapy Journal of Research (OTJR) between 1981 and 2000. A total of 452 manuscripts were published on a broad range of topics in the OTJR during this period, 75.4% of which were feature articles with a strong research focus. Author characteristics and collaboration, subject and specialty themes, and reference list citations are examined and implications discussed. As a primary research journal together with publications that have a clinical or practice orientation, the OTJR is an important reference source for evidence-based practice. It will be interesting to monitor how OTJR evolves as the primary occupational therapy research journal since changing its focus in 2002. PMID- 23927749 TI - Collaborative teaching models for health professionals. AB - Multidisciplinary faculty collaboration within the health professions educational system is explored. The definitions for the concepts of intradisciplinary, multidisciplinary, interdisciplinary and transdisciplinary faculty teams are provided along with the strengths and weaknesses of collaborative teaching and course development across various health profession programs. Examples of these teaching models are described using case studies to illustrate collaborative course development by faculty from Occupational Therapy, Nursing, Physician Assistant, Social Work and Dental Hygiene, Nurse Anesthesia, and Health Services Management programs offered at the University of New England in Portland, Maine, United States of America. PMID- 23927750 TI - Students teaching students: learning through doing, being, and becoming. AB - This paper describes a creative teaching strategy that may be used by occupational therapy educators. The strategy is illustrated through the learning experience of five occupational therapy students in Pi Theta Epsilon (PTE) who participated in a project which involved teaching first year occupational therapy students. With guidance from their faculty advisor, the students developed a lecture on Occupational Science and designed a pre and posttest instrument to measure the first year student's learning as well as their own performance and learning. Qualitative data from the five PTE students provided insight into their teaching experience. This project afforded an opportunity for the five students to apply and strengthen their problem-solving, interpersonal, and leadership skills, and teamwork. The doing aspect of preparing a lecture required various skills and knowledge that will benefit the students as future practitioners. The actual teaching of others allowed the students to experience being in the role of an educator. Such learning activities help to prepare students for their journey to becoming occupational therapists. PMID- 23927751 TI - Flexible sigmoidoscopy following a positive faecal occult blood test within a bowel screening programme may reduce the detection of neoplasia. AB - AIM: Colorectal cancer screening using the faecal occult blood test (FOBt) detects a disproportionate number of left-sided tumours. This study aims to examine the theoretical impact on neoplasia detection rates of a sigmoidoscopy first protocol in FOBt-positive patients undergoing colonoscopy. METHOD: From retrieved endoscopy/pathology reports, pathology up to and including the splenic flexure was assumed detectable by sigmoidoscopy. High-risk polyps prompting subsequent colonoscopy were classed as three or more polyps, one polyp of >= 1 cm, villous or tubulovillous components or the presence of high-grade dysplasia. RESULTS: Between April 2009 and April 2011, 4631 patients underwent colonoscopy as a result of a positive FOBt in Greater Glasgow and Clyde. Cancer was detected in 398 (9%) and adenomas were detected in 1985 (47%) of which 1323 (67%) were deemed significant according to British Society of Gastroenterology guidelines. Applying the flexible sigmoidoscopy-first model, cancer would have been detected in 329 (8%) patients and adenomas in 1640 (39%), of which 1140 (70%) would have been significant. In total, 1546 (37%) patients would have required subsequent colonoscopy, following which 21 patients would have a new diagnosis of cancer. The positive predictive values (PPVs) for neoplasia (47 vs 57%, P < 0.001), significant neoplasia (35 vs 41%, P < 0.001) and cancer (8 vs 9%, P = 0.007) were all lower in the sigmoidoscopy-first model. CONCLUSION: A significant reduction in the detection of both adenomas and cancers would be seen if the sigmoidoscopy first protocol were to be used following a positive FOBt. Furthermore, a significant proportion of patients would be subjected to two procedures, with considerable implications for both the patient and cost. PMID- 23927752 TI - A rare case of primary malignant small cell carcinoma combined with urothelial cell carcinoma in the ureter. AB - BACKGROUND: Extrapulmonary small cell carcinomas have been reported in a variety of organs, and their incidence in the genitourinary tract is second only to that in the gastrointestinal tract. To date, however, only a few cases of small cell carcinoma of the ureter have been reported. Because the extreme rarity of this type of carcinoma, its clinical behaviour, diagnostic methods, and effective treatment modalities have not yet been determined. CASE PRESENTATION: A 59-year old man presented with a 1-month history of painless gross haematuria. Urine cytopathology revealed a urothelial carcinoma and computed tomography revealed left hydronephroureterosis with a distal ureteral stone and a mildly enhanced fungating mass just below the stone-impacted site. The preoperative TNM stage was T2N0M0. The patient underwent simultaneous diagnostic ureterorenoscopy and left laparoscopic nephroureterectomy with bladder cuff resection. Gross examination showed a 3.5 * 3.0 * 0.8 cm white, partly yellow mass in the left distal ureter. Light microscopy showed a small cell carcinoma, overlaid on a urothelial carcinoma in situ, invading the ureter and external lateral resection margins. The small cell carcinoma was diffusely positive for neuron-specific enolase, and exhibited focal positivity for CD 56, synaptophysin, chromogranin and cytokeratin 20. The patient was treated with adjuvant chemotherapy, consisting of cisplatin and etoposide, and radiation therapy, and has been well, without evidence of tumour recurrence or metastasis in the 10 months after surgery. CONCLUSION: Small cell carcinoma of the ureter is rare. Although its clinical behaviour and diagnostic modalities have not been determined and it has yet to be diagnosed immunohistopathologically, multimodality treatment including surgery, chemotherapy and radiotherapy may improve patient survival. PMID- 23927753 TI - Two-colour chewing gum mixing ability: digitalisation and spatial heterogeneity analysis. AB - Many techniques are available to assess masticatory performance, but not all are appropriate for every population. A proxy suitable for elderly persons suffering from dementia was lacking, and a two-colour chewing gum mixing ability test was investigated for this purpose. A fully automated digital analysis algorithm was applied to a mixing ability test using two-coloured gum samples in a stepwise increased number of chewing cycles protocol (Experiment 1: n = 14; seven men, 19 63 years), a test-retest assessment (Experiment 2: n = 10; four men, 20-49 years) and compared to an established wax cubes mixing ability test (Experiment 3: n = 13; 0 men, 21-31 years). Data were analysed with repeated measures anova (Experiment 1), the calculation of the intraclass correlation coefficient (ICC; Experiment 2) and Spearman's rho correlation coefficient (Experiment 3). The method was sensitive to increasing numbers of chewing cycles (F5,65 = 57.270, P = 0.000) and reliable in the test-retest (ICC value of 0.714, P = 0.004). There was no significant correlation between the two-coloured gum test and the wax cubes test. The two-coloured gum mixing ability test was able to adequately assess masticatory function and is recommended for use in a population of elderly persons with dementia. PMID- 23927754 TI - Synthesis of porous carbon supported palladium nanoparticle catalysts by atomic layer deposition: application for rechargeable lithium-O2 battery. AB - In this study, atomic layer deposition (ALD) was used to deposit nanostructured palladium on porous carbon as the cathode material for Li-O2 cells. Scanning transmission electron microscopy showed discrete crystalline nanoparticles decorating the surface of the porous carbon support, where the size could be controlled in the range of 2-8 nm and depended on the number of Pd ALD cycles performed. X-ray absorption spectroscopy at the Pd K-edge revealed that the carbon supported Pd existed in a mixed phase of metallic palladium and palladium oxide. The conformality of ALD allowed us to uniformly disperse the Pd catalyst onto the carbon support while preserving the initial porous structure. As a result, the charging and discharging performance of the oxygen cathode in a Li-O2 cell was improved. Our results suggest that ALD is a promising technique for tailoring the surface composition and structure of nanoporous supports in energy storage devices. PMID- 23927755 TI - Comparison of skin conductance measurements and subjective pain scores in children with minor injuries. AB - AIM: Objective measures of perceived pain may aid clinicians in decision-making regarding analgesia. This study aimed to assess the effectiveness of an algesimeter to assess the pain response of children to minor injury when compared with self-report. METHODS: A commercially available skin conductance algesimeter was used to record pain in children presenting with a minor injury to a district general hospital. The recordings were compared with self-reported pain scores using the Wong-Baker FACES((r)) Pain Rating Scale. RESULTS: Sixty-seven children below 16 years of age (36 females, 53.7%, mean age 11.9 years, standard deviation 3.1 years) were assessed. There was a significant correlation between self reported pain and number of fluctuations in skin conductance per second for girls (r = 0.325, p = 0.027), but not for boys (r = 0.160, p = 0.194). There was no significant association between self-reported pain and number of fluctuation in skin conductance per second and patient age. CONCLUSION: There was a significant correlation between self-reported pain and the number of fluctuations in skin conductance in girls, but not boys. There may be a number of reasons for this gender variation, including difficulty in rating pain and lack of sensitivity in the pain rating scale. PMID- 23927756 TI - Solvothermal synthesis of microporous, crystalline covalent organic framework nanofibers and their colorimetric nanohybrid structures. AB - This paper reports a facile solvothermal approach for the design and synthesis of novel crystalline COF nanofibers with amazing properties. An interesting morphological transformation from microsphere to nanofibers was observed, which could be supported by the unique dissolution-recrystallization mechanism due to the reversible nature of dynamic imine bonding. Interestingly, it was also found that the COF nanofibers could epitaxial grow on the aramid microfiber surface. This functional nanocomposite showed an interesting colorimetric humidity responsive behavior. Our study provides a general methodology for the fabrication of COFs with designated micronanostructures and has more implications on their applications in catalyst and sensors. PMID- 23927757 TI - High rate of faecal carriage of extended-spectrum beta-lactamase and OXA-48 carbapenemase-producing Enterobacteriaceae at a university hospital in Morocco. AB - Carbapenemase-producing Enterobacteriaceae isolates are being increasingly reported, particularly from countries surrounding the Mediterranean area. We aimed to quantify the prevalence of carbapenemase- and extended-spectrum beta lactamase (ESBL)-producing Enterobacteriaceae in rectal swabs from hospitalized patients in a University hospital in Morocco, and to compare the performance of three screening media: ChromID ESBL (bioMerieux), Brilliance CRE (OXOID, Thermofisher) and SUPERCARBA (home made). Genetic detection and plasmid analysis were performed by PCR and sequencing. Strain comparison was performed by multi locus sequence typing and the Diversilab technique (bioMerieux). The prevalence of multidrug-resistant Enterobacteriaceae was high, with 33 ESBL producers (42.85%, mainly CTX-M-15) and 10 OXA-48 producers (13%), corresponding to two major clones of K. pneumoniae (70%) and a clone of Enterobacter cloacae (30%). The three screening media showed the same sensitivity for detection of carbapenemase-producing Enterobacteriaceae, whereas the SUPERCARBA medium was more specific than the two other media. The average faecal carriage of ESBL or carbapenemase-producing Enterobacteriaceae varied from 1 * 10(2) to >1 * 10(8) CFU/g of stools. This study shows a high prevalence of multidrug-resistant Enterobacteriaceae, and particularly of OXA-48 producers. The new carbapenem containing medium, SUPERCARBA, was as sensitive as Brilliance CRE and ChromID ESBL, and more specific for the detection of Enterobacteriaceae expressing those carbapenemases. PMID- 23927759 TI - Donors' perspectives on self-deferral of men having sex with men from blood donation. AB - BACKGROUND: Self-deferral of men having sex with men (MSM) from blood donation is a means of protecting blood safety. There has recently been a strategy change from permanent to time-limited deferral in some countries. Awareness and attitudes of donors is crucial for effective implementation of MSM deferral or any change of the strategy. STUDY DESIGN AND METHODS: A postdonation survey was administered using a Web-based questionnaire, after explanation by trained volunteers, to evaluate donors' awareness and compliance toward the health history enquiry (HHE, the deferral questionnaire) of the Hong Kong Red Cross Blood Transfusion Service, sexual experiences, and opinions on permanent versus time-limited deferral. RESULTS: A total of 1373 Chinese donors (male:female 1.28:1), a majority (89.1%) of whom were repeat donors, completed the survey at eight blood donation centers. Almost all (98.7%) were aware of HHE, although only half read it in detail, the latter comprising more experienced donors. Most did not hold strong views on deferral, with more than half (59.4%) concurring with both permanent and time-limited deferral. Seventeen (3.2%) of the sexually active male donors were MSM, of whom six disagreed with permanent deferral while seven agreed with changing to time-limited deferral. A simpler question structure was preferred by 57% of the respondents for screening MSM to achieve self-deferral. CONCLUSIONS: Donors generally do not read through the deferral questionnaire in sufficient detail for making an informed decision. Blood safety would eventually depend on donors' compliance with the deferral mechanism, irrespective of whether it is permanent or time-limited. PMID- 23927758 TI - Gemcitabine-oxaliplatin (GEMOX) as salvage treatment in pretreated epithelial ovarian cancer patients. AB - BACKGROUND: Currently, no clearly superior management strategy exists for recurrent, platinum-resistant ovarian cancer. We tested the efficacy and safety of gemcitabine combined with oxaliplatin (GEMOX) in a multicentre phase II clinical trial. METHODS: Forty one patients with recurrent, platinum-resistant ovarian cancer were enrolled. Prior to study entry, all the participants had received at least one platinum-based regimen. Gemcitabine was administered at 1000 mg/m2 as protracted infusion (100 min) on day 1, and oxaliplatin at the dose of 100 mg/m2 on day 2 in a 2 hour infusion. Cycles were repeated every two weeks. RESULTS: We observed an overall response rate of 37% [95% Confidence Interval (CI), 22.3-51.7]. Objective responses plus disease stabilization (clinical benefit) occurred in 78% of patients. Median progression-free survival was 6.8 months (95% CI, 5.8-7.8), and median overall survival was 16.5 months (95% CI, 12.2-20.8). Median time to self-reported symptom relief, which was described by 22 out of 27 symptomatic patients (81.5%), was 4 weeks (range, 2-8). Grade 4 neutropenia and febrile neutropenia were observed in 2 (5%) and 1 (2.5%) patients, while grade 3 anemia was encountered in 2 (5%) patients, respectively. The most common adverse effects of any grade were gastrointestinal symptoms, fatigue and neutropenia. Nine patients (22%) experienced mild allergic reaction to oxaliplatin, with no treatment discontinuation. CONCLUSIONS: In our cohort of recurrent, platinum-resistant ovarian cancer patients, GEMOX showed encouraging activity and manageable toxicity. Under circumstances requiring a rapid disease control, this combination regimen may offer a particularly viable option, particularly in heavily pretreated patients. PMID- 23927760 TI - Hot tadpoles from cold environments need more nutrients--life history and stoichiometry reflects latitudinal adaptation. AB - 1. High-latitude species (and populations within species) are adapted to short and cold summers. They often have high growth and development rates to fully use the short growing season and mature before the onset of winter. 2. Within the context of ecological stoichiometry theory, this study combines ecology with evolution by relating latitudinal life-history adaptations to their molecular consequences in body nutrient composition in Rana temporaria tadpoles. 3. Temperature and food quality were manipulated during the development of tadpoles from Arctic and Boreal origins. We determined tadpole growth rate, development rate, body size and nutrient content, to test whether (i) Arctic tadpoles could realize higher growth rates and development rates with the help of higher-quality food even when food quantity was unchanged, (ii) Arctic and Boreal tadpoles differed in their stoichiometric (and life history) response to temperature changes, (iii) higher growth rates lead to higher tadpole P content (growth rate hypothesis) and (iv) allometric scaling affects tadpole nutrient allocation. 4. We found that especially Arctic tadpoles grew and developed faster with the help of higher-quality food and that tadpoles differed in their stoichiometric (and life history) response to temperature changes depending on region of origin (probably due to different temperature optima). There was no evidence that higher growth rates mediated the positive effect of temperature on tadpole P content. On the contrary, the covariate growth rate was negatively connected with tadpole P content (refuting the growth rate hypothesis). Lastly, tadpole P content was not related to body size, but tadpole C content was higher in larger tadpoles, probably due to increased fat storage. 5. We conclude that temperature had a strong effect on tadpole life history, nutrient demand and stoichiometry and that this effect depended on the evolved life history. PMID- 23927761 TI - Oriented gold nanoparticle aggregation for colorimetric sensors with surprisingly high analytical figures of merit. AB - The common drawbacks of current colorimetric sensors using gold nanoparticle aggregation is its relatively low sensitivity and narrow dynamic range, which restrict their application in real sample analysis when competing with other analytical techniques such as fluorescence and chemiluminescence. In this article, we demonstrate a novel strategy to construct colorimetric sensors based on gold nanoparticle aggregation. Unlike the conventional colorimetric sensors which cause the formation of large nanoparticle aggregates, in our strategy, dimers are selectively formed upon target binding, which results in significantly improved long-term stability and a more than 2 orders of magnitude wider dynamic range of detection than that of the conventional colorimetric sensors. In addition, a strategy to minimize the interparticle gap through the formation of a Y-shaped DNA duplex enables to increase the limit of detection by 10,000 times. The analytical figures of merit of the proposed sensor are comparable to those of the fluorescence-based sensors. PMID- 23927762 TI - Superabsorbent cryogels decorated with silver nanoparticles as a novel water technology for point-of-use disinfection. AB - This paper reports the preparation of poly(sodium acrylate) (PSA) cryogels decorated with silver nanoparticles (AgNPs) for point-of-use (POU) water disinfection. The PSA/Ag cryogels combine the high porosity, excellent mechanical and water absorption properties of cryogels, and uniform dispersion of fine AgNPs on the cryogel pore surface for rapid disinfection with minimal Ag release (<100 MUg L(-1)). They were used in a process that employed their ability to absorb water, which subsequently could be released via application of mild pressure. Their antibacterial performance was evaluated based on the disinfection efficacies of E. coli and B. subtilis . The PSA/Ag cryogels had excellent disinfection efficacies showing close to a 3 log reduction of viable bacteria after a brief 15 s contact time. They were highly reusable as there was no significant difference in the disinfection efficacies over five cycles of operation. The biocidal action of the PSA/Ag cryogels is believed to be dominated by surface-controlled mechanisms that are dependent on direct contact of the interface of PSA/Ag cryogels with the bacterial cells. The PSA/Ag cryogels are thought to offer a simpler approach for drinking water disinfection in disaster relief applications. PMID- 23927763 TI - Approaches to protozoan drug discovery: phenotypic screening. AB - Determining the activity of a compound and the potential impact on a diseased state is frequently undertaken using phenotypic or target-based approaches. Phenotypic screens have the advantage of the whole organism being exposed to the compound and thus all the targets and biological pathways associated with it. Cell penetration and access to targets in their "natural" environment are taken into account. Unless utilizing a genetically modified organism with an additional target associated indicator, elucidation of specific target(s) of active compounds is necessary. Target discovery is desirable to allow development of chemical entities based upon knowledge of the target structure. Phenotypic drug discovery has successfully identified new molecular entities for neglected protozoan disease research. In this perspective, the phenotypic approaches used to identify chemical entities for drug discovery and for use as tools against the parasites Plasmodium falciparum, Trypanosoma brucei brucei, and Trypanosoma cruzi will be outlined. PMID- 23927764 TI - Determination of the structures of molecularly imprinted polymers and xerogels using an automated stochastic approach. AB - An automated stochastic docking program with a graphical user interface, RANDOMDOCK (RD), has been developed to aid the development of molecularly imprinted polymers and xerogels. RD supports computations with ab initio and semiempirical quantum chemistry programs. The RD algorithms have been tested by searching for the most stable geometries of a varying number of methacrylic acid molecules interacting with nicotinamide. The optimal structures found are either as stable or more stable than those previously proposed for this molecularly imprinted polymer, illustrating that RD is capable of identifying the lowest energy structures out of a potentially vast number of possible configurations. RD was subsequently applied to determine the most favorable binding sites between silane molecules and tetracycline (TC) as well as TC analogues. Hydrogen bonding between the templates and a silane is an important determinant of stability. Dispersion interactions are also sizable, sometimes dominant, especially between the largest silane and TC analogues not possessing a site readily available for hydrogen bonding. We highlight the importance of exploring the full intermolecular potential energy landscape when studying systems which may not afford highly specific interactions. PMID- 23927765 TI - Triggering sporulation in Bacillus subtilis with artificial two-component systems reveals the importance of proper Spo0A activation dynamics. AB - Sporulation initiation in Bacillus subtilis is controlled by the phosphorylated form of the master regulator Spo0A which controls transcription of a multitude of sporulation genes. In this study, we investigated the importance of temporal dynamics of phosphorylated Spo0A (Spo0A~P) accumulation by rewiring the network controlling its phosphorylation. We showed that simultaneous induction of KinC, a kinase that can directly phosphorylate Spo0A, and Spo0A itself from separately controlled inducible promoters can efficiently trigger sporulation even under nutrient rich conditions. However, the sporulation efficiency in this artificial two-component system was significantly impaired when KinC and/or Spo0A induction was too high. Using mathematical modelling, we showed that gradual accumulation of Spo0A~P is essential for the proper temporal order of the Spo0A regulon expression, and that reduction in sporulation efficiency results from the reversal of that order. These insights led us to identify premature repression of DivIVA as one possible explanation for the adverse effects of accelerated accumulation of Spo0A~P on sporulation. Moreover, we found that positive feedback resulting from autoregulation of the native spo0A promoter leads to robust control of Spo0A~P accumulation kinetics. Thus we propose that a major function of the conserved architecture of the sporulation network is controlling Spo0A activation dynamics. PMID- 23927766 TI - Quantifying the biomechanics of conception: L-selectin-mediated blastocyst implantation mechanics with engineered "trophospheres". AB - An estimated 12% of women in the United States suffer from some form of infertility. In vitro fertilization (IVF) is the most common treatment for infertility encompassing over 99% of all assisted reproductive technologies. However, IVF has a low success rate. Live birth rates using IVF can range from 40% in women younger than 35 years to 4% in women older than 42 years. Costs for a successful IVF outcome can be upward of $61,000. The low success rate of IVF has been attributed to the inability of the blastocyst to implant to the uterus. Blastocyst implantation is initiated by L-selectin expressing cells, trophoblasts, binding to L-selectin ligands, primarily sialyl Lewis X (sLeX), on the uterine surface endometrium. Legal and ethical considerations have limited the research on human subjects and tissues, whereas animal models are costly or do not properly mimic human implantation biochemistry. In this work, we describe a cellular model system for quantifying L-selectin adhesion mechanics. L-selectin expression was confirmed in Jeg-3, JAR, and BeWo cell lines, with only Jeg-3 cells exhibiting surface expression. Jeg-3 cells were cultured into three dimensional spheres, termed "trophospheres," as a mimic to human blastocysts. Detachment assays using a custom-built parallel plate flow chamber show that trophospheres detach from sLeX functionalized slides with 2.75 * 10(-3) dyn of force and 7.5 * 10(-5) dyn-cm of torque. This work marks the first time a three dimensional cell model has been utilized for quantifying L-selectin binding mechanics related to blastocyst implantation. PMID- 23927767 TI - The Citrus clementina putative allergens: from proteomic analysis to structural features. AB - Several allergens have been identified and characterized in the genus Citrus, which belongs to the germin-like proteins (GPLs), profilins, and non-specific lipid transfer proteins (nsLTPs). In this work, in silico sequence analysis, protein purification, mass spectrometry identification, and the spectral counting method were integrated to identify new putative allergens of Citrus clementina and their expression level in the fruit peel. The in silico analysis revealed fifteen new sequences belonging to GLPs (Cit cl 1), and two more belonging to nsLTPs (Cit cl 3). No other new sequences were found as regards profilins (Cit cl 2). Each putative allergen from fruit peel was obtained using different protein extraction methods, and the protein sequences of the putative allergens were identified by means of LTQ-Orbitrap XL mass spectrometer. The spectral counting strategy revealed that Cit cl 1 had a higher expression level than Cit cl 2 and Cit cl 3. To predict the quaternary structure and deduced function of Cit cl 1, its primary sequence was used as a template to search a homologous protein structure in the RCSB PDB Database, getting high correspondence with the oxalate oxidase protein in barley. PMID- 23927768 TI - Preeclampsia is associated with increased maternal body weight in a northeastern Brazilian population. AB - BACKGROUND: Preeclampsia is a disease with great variability in incidence across the world. The mortality is higher in lower income countries, where it is the leading cause of maternal mortality. This study aimed to determine the frequency of and risk factors for preeclampsia in a low income population from an urban area of Brazil. METHODS: A prospective case control study of 242 women of which 30 developed preeclampsia, 4 had gestational hypertension, 2 had superimposed hypertension, 11 had spontaneous abortion, 13 were lost to follow up and 192 had normal pregnancy. This latter group was considered the normotensive controls. The rate of preeclampsia and the risk of cardiovascular disease, after onset of preeclampsia, were determined. RESULTS: Of the 218 women who completed the study, the frequency of hypertensive disorder of pregnancy was 16.5% (36 of 218) and of preeclampsia was 13.8% (30 of 218). Women with preeclampsia had a higher body mass index (BMI), mean of 25.3 +/- 4.8 compared to 23.5 +/- 3.7 for the normotensive controls, p = 0.02. The risk of preeclampsia increased with BMI [Odds ratio (OR) 1.12, 95% Confidence Interval (CI = 1.02;1.24, p-value = 0.023)]. Women with preeclampsia developed chronic hypertension more often than normotensive controls (p = 0.043) and their systolic and ambulatory blood pressure monitoring was elevated (p = 0.034). Women with preeclampsia had higher BMI even 5 years post-pregnancy (p = 0.008). CONCLUSIONS: Women who are overweight or older have an increased risk of preeclampsia. Previous history of preeclampsia increases the risk of early onset of chronic hypertension. Therefore, effective preventive measures are needed, particularly women at lower social economic stratum who have less access to proper medical care and adequate nutrition. PMID- 23927769 TI - Capture and printing of fixed stromal cell membranes for bioactive display on PDMS surfaces. AB - Poly(dimethylsiloxane) (PDMS) has emerged as an extremely useful polymer for various biological applications. The conjugation of PDMS with bioactive molecules to create functional surfaces is feasible yet limited to a single-molecule display with imprecise localization of the molecules on PDMS. Here we report a robust technique that can transfer and print the membrane surface of glutaraldehyde-fixed stromal cells intact onto a PDMS substrate using an intermediate polyvinylalcohol (PVA) film as a transporter system. The cell-PVA film capturing the entirety of surface molecules can be peeled off and subsequently printed onto PDMS while maintaining the spatial display of the original cell surface molecules. Proof-of-concept studies are described using human bone marrow stromal cell membranes including a demonstration of the bioactivity of transferred membranes to capture and adhere hematopoietic cells. The presented process is applicable to virtually any adherent cell and can broaden the functional display of biomolecules on PDMS for biotechnology applications. PMID- 23927770 TI - Evaluation of adding item-response theory analysis for evaluation of the European Board of Ophthalmology Diploma examination. AB - PURPOSE: To investigate whether introduction of item-response theory (IRT) analysis, in parallel to the 'traditional' statistical analysis methods available for performance evaluation of multiple T/F items as used in the European Board of Ophthalmology Diploma (EBOD) examination, has proved beneficial, and secondly, to study whether the overall assessment performance of the current written part of EBOD is sufficiently high (KR-20>= 0.90) to be kept as examination format in future EBOD editions. METHODS: 'Traditional' analysis methods for individual MCQ item performance comprise P-statistics, Rit-statistics and item discrimination, while overall reliability is evaluated through KR-20 for multiple T/F items. The additional set of statistical analysis methods for the evaluation of EBOD comprises mainly IRT analysis. These analysis techniques are used to monitor whether the introduction of negative marking for incorrect answers (since EBOD 2010) has a positive influence on the statistical performance of EBOD as a whole and its individual test items in particular. RESULTS: Item-response theory analysis demonstrated that item performance parameters should not be evaluated individually, but should be related to one another. Before the introduction of negative marking, the overall EBOD reliability (KR-20) was good though with room for improvement (EBOD 2008: 0.81; EBOD 2009: 0.78). After the introduction of negative marking, the overall reliability of EBOD improved significantly (EBOD 2010: 0.92; EBOD 2011:0.91; EBOD 2012: 0.91). CONCLUSION: Although many statistical performance parameters are available to evaluate individual items, our study demonstrates that the overall reliability assessment remains the only crucial parameter to be evaluated allowing comparison. While individual item performance analysis is worthwhile to undertake as secondary analysis, drawing final conclusions seems to be more difficult. Performance parameters need to be related, as shown by IRT analysis. Therefore, IRT analysis has proved beneficial for the statistical analysis of EBOD. Introduction of negative marking has led to a significant increase in the reliability (KR-20 > 0.90), indicating that the current examination format can be kept for future EBOD examinations. PMID- 23927771 TI - Neurobiology of secure infant attachment and attachment despite adversity: a mouse model. AB - Attachment to an abusive caregiver has wide phylogenetic representation, suggesting that animal models are useful in understanding the neural basis underlying this phenomenon and subsequent behavioral outcomes. We previously developed a rat model, in which we use classical conditioning to parallel learning processes evoked during secure attachment (odor-stroke, with stroke mimicking tactile stimulation from the caregiver) or attachment despite adversity (odor-shock, with shock mimicking maltreatment). Here we extend this model to mice. We conditioned infant mice (postnatal day (PN) 7-9 or 13-14) with presentations of peppermint odor and either stroking or shock. We used (14) C 2 deoxyglucose (2-DG) to assess olfactory bulb and amygdala metabolic changes following learning. PN7-9 mice learned to prefer an odor following either odor stroke or shock conditioning, whereas odor-shock conditioning at PN13-14 resulted in aversion/fear learning. 2-DG data indicated enhanced bulbar activity in PN7-9 preference learning, whereas significant amygdala activity was present following aversion learning at PN13-14. Overall, the mouse results parallel behavioral and neural results in the rat model of attachment, and provide the foundation for the use of transgenic and knockout models to assess the impact of both genetic (biological vulnerabilities) and environmental factors (abusive) on attachment related behaviors and behavioral development. PMID- 23927772 TI - Treatment of paediatric laryngeal papillomas: web survey of British Association of Paediatric Otolaryngologists. AB - BACKGROUND AND OBJECTIVE: Recurrent respiratory papillomatosis is the most common benign neoplasm of the larynx in children. Intralesional injection of cidofovir may have some potential as an adjunctive treatment. There is no standardised protocol in the UK for the management of recurrent respiratory papillomatosis. This study aimed to investigate the management practices of surgeons treating paediatric recurrent respiratory papillomatosis in the UK. METHOD: A web questionnaire survey was sent by e-mail to all members of the British Association of Paediatric Otorhinolaryngology. RESULTS: Out of 35 respondents, 23 were at that time treating children with recurrent respiratory papillomatosis. Nineteen respondents preferred to use a microdebrider, 12 preferred laser, and 5 preferred cold steel along with either laser or a microdebrider. Twelve surgeons used cidofovir for selected patients and 12 surgeons did not use cidofovir for any patients. Cidofovir was considered after 0-4 surgical procedures by seven respondents, after 4-6 surgical procedures by four respondents and after 6 surgical procedures by six respondents. Eleven respondents warned patients about the possible side effects of cidofovir and five gave no warning. CONCLUSION: There was no consensus as to when it would be appropriate to use cidofovir, indicating the need for cidofovir usage guidelines. PMID- 23927773 TI - Systematic review and meta-analysis of laparoscopic and open gastrectomy for advanced gastric cancer. AB - BACKGROUND: The use of laparoscopic gastrectomy (LG) in advanced gastric cancer (AGC) remains a controversial topic, mainly because of doubts about its oncologic validity. This study is a systematic review and meta-analysis of the available evidence. METHODS: A comprehensive search was performed until June 2013 to identify comparative studies evaluating survival rates, recurrence rates, surgical outcomes and complications. Pooled risk ratios (RR) and weighted mean differences (WMD) with 95% confidence intervals (CI) were calculated using the random effects model. Data synthesis and statistical analysis were carried out using RevMan 5.1 software. RESULTS: Fifteen trials were involved in this analysis. Compared to open gastrectomy (OG), LG involved a longer operating time (WMD = 48.67 min, 95% CI 34.09 to 63.26, P < 0.001); less blood loss (WMD = 139.01 ml, 95% CI -174.57 to -103.44, P < 0.001); earlier time to flatus (WMD = 0.79 days, 95% CI -1.14 to -0.44, P < 0.001); shorter hospital stay (WMD = -3.11 days, 95% CI -4.13 to -2.09, P < 0.001); and a decrease in complications (RR = 0.74, 95% CI 0.61 to 0.90, P = 0.003). There was no significant difference in the number of harvested lymph nodes, margin distance, mortality, cancer recurrence rate and long-term survival rate between the AGC patients treated with LG or OG (P > 0.05). CONCLUSIONS: Despite a longer operation, LG is a safe technical alternative to OG for AGC with a lower complication rate and enhanced postoperative recovery. Moreover, there were similar outcomes between both approaches in terms of cancer recurrence and the long-term survival rate. Because of the limitation of this study, methodologically high-quality studies are needed for further evaluation. PMID- 23927775 TI - Message from the editor. PMID- 23927774 TI - Statement of retraction. PMID- 23927776 TI - Linkages between goal attainment and quality of life for individuals with chronic fatigue syndrome. AB - Goal setting was the cornerstone of a rehabilitation program for people with chronic fatigue syndrome. This study examines the relationship between goal attainment and quality of life. Participants (N = 47) set goals over eight supportive and educational group sessions. Group members reported goal progress and confidence level for goal attainment. Using a forward, stepwise linear regression analysis, goal attainment emerged as the only significant predictor of quality of life improvement (B = 0.234, 95% CI for B: 0.050 to 0.419, SE = 0.091, beta = 0.372, p <. 05) independently of fatigue severity, symptom severity, and comorbid psychiatric diagnosis. PMID- 23927777 TI - The relationship between frequency of participation in play activities and kindergarten readiness. AB - This correlational study examined the relationship between the frequency of participation in specific play activities prior to the kindergarten year and the performance of school readiness skills as measured by the Daberon-2 Screening Device for School Readiness. A researcher-adapted Kindergarten Questionnaire was used to elicit information from parents about the frequency of their child's engagement in 19 different play activities. Ten of the play activities, most notably those considered fine motor in nature, correlated significantly with subsections of the Dabron-2. Although constraints in the design of the study limit generalization to other populations, the results suggest that frequent engagement in specific types of play is associated with enhanced performance of kindergarten readiness skills. PMID- 23927778 TI - Understanding the occupational human being as a complex, dynamical, adaptive system. AB - The purpose of this pilot study was to investigate whether the complex occupational human being may be understood using constructs derived from chaos theory such as dependence on initial conditions, fractality, and attractor conditions (Bassingthwaighte, Liebovich, & West, 1994; Buell & Cassidy, 2001; Fraser & Greenhalgh, 2001). Quantitative and qualitative data consisting of daily activities engaged in for 21 days by nine students at the University of Scranton, Scranton, Pennsylvania, was collected using activity inventories. Data analysis revealed that although the findings need to be interpreted with caution due to a small, homogeneous sample, there are indications that the above mentioned constructs from chaos theory may be used to understand the complex occupational human being. PMID- 23927779 TI - Commonalities in Level II Fieldwork Failure. AB - Despite the efforts of academic educators and fieldwork supervisors, not all students successfully complete their Level II field-work experience (AOTA, 1997). This study used quantitative and qualitative data to identify common characteristics surrounding Level II fieldwork failure. Eleven participants responded to a questionnaire regarding their experience in supervising a student who failed a Level II fieldwork experience; six also participated in a telephone interview to provide additional information regarding the experience. Students in this study who failed a Level II fieldwork experience exhibited poor problem solving skills, poor clinical reasoning skills, had difficulty getting the "big picture," and had difficulty responding to constructive feedback. Additionally, supervisors reportedly believe students were academically unprepared for the fieldwork experience. In this study, there were common characteristics, including student attributes and supervisors' strategies for dealing with problematic behaviors, which existed in the circumstances surrounding Level II fieldwork failure. PMID- 23927781 TI - From the internet editor. PMID- 23927780 TI - Learning styles of university students in a Hispanic-serving institution. AB - The purpose of this study was to examine the learning styles of university students in an occupational therapy program in a Hispanic-serving institution. Forty-four university students completed the Self-Directed Learning Style Check. This 80-item questionnaire identifies preferred self-directed learning styles and corresponding strategies to enhance learning. Analysis revealed a preference for the learning styles of organizing, personalizing, doing, and imagining in contrast to the styles of reflecting, collaborating, observing, and envisioning. Strategies to facilitate learning by building on preferred learning styles, while also encouraging flexibility of learning strategies, are presented. PMID- 23927783 TI - Massively calcified low-grade glioma - a rare and distinctive entity. PMID- 23927784 TI - Disruptive behaviour disorder with and without attention deficit hyperactivity disorder is a risk of psychiatric hospitalization. AB - AIM: To evaluate the psychiatric hospitalization among adolescents diagnosed with disruptive behaviour disorders (DBD) and/or attention deficit hyperactivity disorder (ADHD). METHODS: The sample (N = 457) was drawn from the Northern Finland Birth Cohort 1986. Four groups were formed, based on the K-SADS-PL diagnostic interview procedure: adolescents with DBD (n = 44), ADHD (n = 91), comorbid DBD and ADHD (n = 72) and without either DBD or ADHD (n = 250). Information from the Finnish Hospital Discharge Register (FHDR) was used to evaluate the psychiatric hospitalization among the study subjects. RESULTS: When compared with no diagnosis group, the adolescents with behavioural disorders had an increased risk (adjusted odds ratios: DBD = 4.4, ADHD = 2.2, comorbid DBD & ADHD = 5.6) of having also psychiatric disorder in the FHDR. The onset age of the psychiatric disorders in the FHDR (medians: DBD = 14.9, ADHD = 7.5 and DBD & ADHD = 15.3 years) and the combined length of hospitalization (medians: 25, 50 and 26 days, respectively) differed among adolescents with behavioural disorders compared with those with no diagnosis (median age 12.1 years and length of hospitalization 4 days). CONCLUSION: Adolescents diagnosed with DBD (with and without ADHD) are at high risk of undergoing psychiatric hospitalization during their life. PMID- 23927785 TI - Phenanthridine synthesis through iron-catalyzed intramolecular N-arylation of O acetyl oxime. AB - O-Acetyl oximes derived from 2'-arylacetophenones undergo N-O bond cleavage/intramolecular N-arylation in the presence of a catalytic amount of iron(III) acetylacetonate in acetic acid. In combination with the conventional cross-coupling or directed C-H arylation, the reaction offers a convenient route to substituted phenanthridines. PMID- 23927786 TI - Meta-analysis of ventricular premature complexes and their relation to cardiac mortality in general populations. AB - Although previous studies have shown that frequent ventricular premature complexes (VPCs) in patients with established heart disease are associated with increased risk of cardiac mortality, the significance of VPCs in general populations is unclear. The aim of this study was to assess the association between VPCs and risk of sudden cardiac death or total cardiac death in general populations by conducting a meta-analysis of published research. The electronic databases MEDLINE and Embase were searched for relevant studies. Data were abstracted using standardized forms. Study-specific relative risk estimates were pooled using a random-effects meta-analysis model. Eleven studies comprising a total of 106,195 participants sampled from general populations were included. Studies generally defined frequent VPCs as occurring >=1 time during a standard electrocardiographic recording or >=30 times over a 1-hour recording. The prevalence of frequent VPCs in the studies ranged from 1.2% to 10.7%. The overall adjusted relative risk for sudden cardiac death comparing participants with frequent VPCs versus those without frequent VPCs was 2.64 (95% confidence interval 1.93 to 3.63). The corresponding value for total cardiac death was 2.07 (95% confidence interval 1.71 to 2.50). Although most studies made attempts to exclude high-risk subjects, such as those with histories of cardiovascular disease, they did not test participants for underlying structural heart disease. In conclusion, findings from observational studies in general populations indicate that frequent VPCs are associated with a substantial increase in the risk for sudden cardiac death and total cardiac death. Further study is needed to determine the role of confounding and underlying structural heart disease in the observed association and its utility in cardiovascular risk prediction. PMID- 23927787 TI - Heterogeneity of regional function and relation to ventricular morphology in patients with fontan circulation. AB - The relation between underlying ventricular morphology and regional function in patients with Fontan circulation remains unclear. The aim of this study was to compare regional function and its heterogeneity in patients with tricuspid atresia (TA), biventricular apex-forming morphology (BiV), and controls. Nineteen patients (median age 12 years) with Fontan circulation who presented consecutively were prospectively enrolled and compared with age- and heart rate matched controls. Most patients were in New York Heart Association class I (63%). Longitudinal systolic strain (S), systolic strain rate (SRsys), and early diastolic strain rate (SRdia) peaks were obtained from 6 ventricular segments, and a coefficient of variation by segment was calculated as a measure of regional heterogeneity. Systolic S, SRsys and SRdia peaks were decreased at the right and left lateral walls in both patient groups compared with controls (p <=0.001 for all). Patients with TA had higher systolic S and SRsys in the middle of the right lateral wall than those with BiV morphology (p = 0.009 and p = 0.001, respectively). The mean coefficients of variation assessed by S and SRsys were similar in controls and patients with TA but lower in those with BiV than in controls and patients with TA (p <0.001 and p = 0.01, respectively). The mean coefficient of variation assessed by SRdia was greater only in patients with BiV than in controls (p = 0.001). In conclusion, patients with Fontan circulation have more heterogeneous systolic and early diastolic regional function than healthy control subjects, and patients with TA have better systolic regional function in the middle of the right lateral wall and less systolic heterogeneity than patients with BiV morphology. PMID- 23927788 TI - Small-molecule-based protein-labeling technology in live cell studies: probe design concepts and applications. AB - The use of genetic engineering techniques allows researchers to combine functional proteins with fluorescent proteins (FPs) to produce fusion proteins that can be visualized in living cells, tissues, and animals. However, several limitations of FPs, such as slow maturation kinetics or issues with photostability under laser illumination, have led researchers to examine new technologies beyond FP-based imaging. Recently, new protein-labeling technologies using protein/peptide tags and tag-specific probes have attracted increasing attention. Although several protein-labeling systems are com mercially available, researchers continue to work on addressing some of the limitations of this technology. To reduce the level of background fluorescence from unlabeled probes, researchers have pursued fluorogenic labeling, in which the labeling probes do not fluoresce until the target proteins are labeled. In this Account, we review two different fluorogenic protein-labeling systems that we have recently developed. First we give a brief history of protein labeling technologies and describe the challenges involved in protein labeling. In the second section, we discuss a fluorogenic labeling system based on a noncatalytic mutant of beta lactamase, which forms specific covalent bonds with beta-lactam antibiotics such as ampicillin or cephalosporin. Based on fluorescence (or Forster) resonance energy transfer and other physicochemical principles, we have developed several types of fluorogenic labeling probes. To extend the utility of this labeling system, we took advantage of a hydrophobic beta-lactam prodrug structure to achieve intracellular protein labeling. We also describe a small protein tag, photoactive yellow protein (PYP)-tag, and its probes. By utilizing a quenching mechanism based on close intramolecular contact, we incorporated a turn-on switch into the probes for fluorogenic protein labeling. One of these probes allowed us to rapidly image a protein while avoiding washout. In the future, we expect that protein-labeling systems with finely designed probes will lead to novel methodologies that allow researchers to image biomolecules and to perturb protein functions. PMID- 23927789 TI - Monitoring DNA hybridization and thermal dissociation at the silica/water interface using resonantly enhanced second harmonic generation spectroscopy. AB - The immobilization of oligonucleotide sequences onto glass supports is central to the field of biodiagnostics and molecular biology with the widespread use of DNA microarrays. However, the influence of confinement on the behavior of DNA immobilized on silica is not well understood owing to the difficulties associated with monitoring this buried interface. Second harmonic generation (SHG) is an inherently surface specific technique making it well suited to observe processes at insulator interfaces like silica. Using a universal 3-nitropyrolle nucleotide as an SHG-active label, we monitored the hybridization rate and thermal dissociation of a 15-mer of DNA immobilized at the silica/aqueous interface. The immobilized DNA exhibits hybridization rates on the minute time scale, which is much slower than hybridization kinetics in solution but on par with hybridization behavior observed at electrochemical interfaces. In contrast, the thermal dissociation temperature of the DNA immobilized on silica is on average 12 degrees C lower than the analogous duplex in solution, which is more significant than that observed on other surfaces like gold. We attribute the destabilizing affect of silica to its negatively charged surface at neutral pH that repels the hybridizing complementary DNA. PMID- 23927790 TI - Detection of EGFR mutations in circulating free DNA by PNA-mediated PCR clamping. AB - BACKGROUND: Epidermal growth factor receptor (EGFR)-activating mutations are major determinants in predicting the tumor response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). Noninvasive test for the detection of EGFR mutations is required, especially in NSCLC patients from whom tissue is not available. In this study, we assessed the feasibility of detection of EGFR mutations in free DNA circulating in plasma. METHODS: Plasma samples of 60 patients with partial response to gefitinib were analyzed to detect EGFR activating mutations in exons 19 and 21. Forty (66.7%) of patients had tumor EGFR mutation results. EGFR mutations in plasma were detected using the peptide nucleic acid (PNA)-mediated polymerase chain reaction (PCR) clamping method. All clinical data and plasma samples were obtained from 11 centers of the Korean Molecular Lung Cancer Group (KMLCG). RESULTS: Of the 60 patients, 39 were female and the median age was 62.5 years. Forty-three patients never smoked, 53 had adenocarcinomas, and seven had other histologic types. EGFR-activating mutation was detected in plasma of 10 cases (exon 19 deletion in seven and exon 21 L858R point mutation in three). It could not be found in plasma after treatment for 2 months. When only patients with confirmed EGFR mutation in tumor were analyzed, 17% (6 of 35) of them showed positive plasma EGFR mutation and the mutation type was completely matched with that in tumor. There was no statistically significant difference in clinical parameters between patients with EGFR mutations in plasma and those without EGFR mutations. CONCLUSIONS: The detection rate of EGFR mutations from plasma was not so high despite highly sensitive EGFR mutation test suggesting that more advances in detection methods and further exploration of characteristics of circulating free DNA are required. PMID- 23927791 TI - Mannitol-adenine-phosphate: a novel solution for intraoperative blood salvage. AB - BACKGROUND: Intraoperative blood salvage (IBS) procedures include washing with normal saline (NS), which may deplete red blood cell (RBC) nutrients. The mannitol-adenine-phosphate (MAP) solution, commonly used for RBC preservation, provides glycolytic substrates; therefore, MAP should be a better solution than NS in IBS. In this study, we determined whether using MAP could reduce washing associated RBC damage and destruction. STUDY DESIGN AND METHODS: Adenine nucleotide contents, RBC morphology, and plasma free hemoglobin (PF-Hb) level of RBCs treated with NS or MAP solution were compared under three conditions: (1) 4 hour preservation of fresh blood from healthy volunteers, (2) collection from the shed blood of patients, and 3) incubation of the collected shed blood with plasma. RESULTS: Adenine nucleotide level and RBC elongation index were greater and PF-Hb level was lower in MAP groups than NS groups (p < 0.05) after preservation and incubation. In NS, RBCs lost their deformability and became stomatocytes, and even RBC "ghosts" 48 hours after incubation, while they remained normal in MAP solution. CONCLUSION: The MAP solution helps preserve RBC morphology and function, and reduces hemolysis, possibly due to improved energy production. Therefore, MAP should replace NS during IBS. PMID- 23927792 TI - Induced ectopic expression of HigB toxin in Mycobacterium tuberculosis results in growth inhibition, reduced abundance of a subset of mRNAs and cleavage of tmRNA. AB - In Mycobacterium tuberculosis, the genes Rv1954A-Rv1957 form an operon that includes Rv1955 and Rv1956 which encode the HigB toxin and the HigA antitoxin respectively. We are interested in the role and regulation of this operon, since toxin-antitoxin systems have been suggested to play a part in the formation of persister cells in mycobacteria. To investigate the function of the higBA locus, effects of toxin expression on mycobacterial growth and transcript levels were assessed in M. tuberculosis H37Rv wild type and in an operon deletion background. We show that expression of HigB toxin in the absence of HigA antitoxin arrests growth and causes cell death in M. tuberculosis. We demonstrate HigB expression to reduce the abundance of IdeR and Zur regulated mRNAs and to cleave tmRNA in M. tuberculosis, Escherichia coli and Mycobacterium smegmatis. This study provides the first identification of possible target transcripts of HigB in M. tuberculosis. PMID- 23927794 TI - [Treatment of invasive fungal diseases in children]. PMID- 23927795 TI - [Clinical diagnosis of invasive fungal diseases in children]. PMID- 23927793 TI - Exploring natural product chemistry and biology with multicomponent reactions. 5. Discovery of a novel tubulin-targeting scaffold derived from the rigidin family of marine alkaloids. AB - We developed synthetic chemistry to access the marine alkaloid rigidins and over 40 synthetic analogues based on the 7-deazaxanthine, 7-deazaadenine, 7 deazapurine, and 7-deazahypoxanthine skeletons. Analogues based on the 7 deazahypoxanthine skeleton exhibited nanomolar potencies against cell lines representing cancers with dismal prognoses, tumor metastases, and multidrug resistant cells. Studies aimed at elucidating the mode(s) of action of the 7 deazahypoxanthines in cancer cells revealed that they inhibited in vitro tubulin polymerization and disorganized microtubules in live HeLa cells. Experiments evaluating the effects of the 7-deazahypoxanthines on the binding of [(3)H]colchicine to tubulin identified the colchicine site on tubulin as the most likely target for these compounds in cancer cells. Because many microtubule targeting compounds are successfully used to fight cancer in the clinic, we believe the new chemical class of antitubulin agents represented by the 7 deazahypoxanthine rigidin analogues have significant potential as new anticancer agents. PMID- 23927796 TI - [Pay much attention to laboratory diagnosis of invasive fungal diseases in children]. PMID- 23927797 TI - [Viral etiology of acute respiratory tract infection among pediatric inpatients and outpatients from 2010 to 2012 in Beijing, China]. AB - OBJECTIVE: Acute respiratory tract infections (ARI) are the leading cause of pediatric morbidity and mortality worldwide, particularly in developing countries. Viruses are the main pathogens of ARI in children. The purpose of the present study was to determine the epidemiologic features of respiratory viruses, including novel viruses, in outpatient and hospitalized children with ARI. METHOD: From March 2010 to February 2012, 2066 children with ARI, including 1050 outpatients and 1016 inpatients, were involved in this study. One nasopharyngeal aspirate or throat swab specimen was collected from each patient. Reverse transcription (RT) PCRs were performed to detect common respiratory tract viruses including respiratory syncytial virus (RSV), human rhinovirus (HRV), influenza virus (IFV), parainfluenza virus (PIV) type 1-4, adenovirus (ADV), enterovirus (EV), human coronavirus (HCOV), human metapneumonia virus (HMPV) and human bocavirus (HBOV). RESULT: At least one viral pathogen was identified in each of 1274 out of 2066 patients and the overall positive rate was 61.7%. The positive rate in inpatient (69.7%) was higher than that in outpatient (53.9%). The frequencies of detection of various viruses among in- and outpatients were different. RSV was the most prevalent virus detected among hospitalized children, followed by HRV and PIV, whereas IFV was the most frequently identified virus in the outpatient group, followed by ADV and PIV. Simultaneous detection of two or more viruses was found in 377 cases. Coinfection was more frequent in inpatients than in outpatients (30.1% vs. 6.8%, P < 0.001). CONCLUSION: Respiratory viruses play an important role in children with ARI, especially in young children. RSV was the most prevalent virus detected among hospitalized children, whereas IFV was the most frequently identified virus in the outpatient group. Viral coinfections are frequently identified, particularly in hospitalized patients. Further studies are required to better understand the impact of coinfections in children with ARI. PMID- 23927798 TI - [Studies on genotype of human cytomegalovirus glycoprotein H from infantile clinical isolates]. AB - OBJECTIVE: To investigate the genetic polymorphism of human cytomegalovirus (HCMV) glycoprotein H (gH) from infantile clinical isolates, to analyze the genotypic distribution of gH in different diseases of HCMV infection and try to find the correlations between the diseases and genotypes. METHOD: Fresh urine specimens were collected from the hospitalized children with different diseases whose blood HCMV-IgM and HCMV-IgG were positive. Virus was isolated from these specimens. Glycoprotein H of harvest clinical isolates was genotyped by nested PCR combined with restriction fragment length polymorphism (RFLP), the purified PCR products were digested by restriction endonuclease HhaI. The digested products were genotyped by polyacrylamide gel electrophoresis and silver staining. Classification and results of sequencing were compared. RESULT: Totally 102 HCMV clinical isolates were obtained. Glycoprotein H gene of these clinical isolates (43 cases had infantile hepatitis syndrome, 38 cases had anicteric hepatitis, 13 pneumonia, 7 thrombocytopenic purpura, and 1 congenital CMV infection) were positive by nested-PCR, whose positive rate was 100%. The results showed that 62 strains were gH1 genotypes (60.8%), while 40 strains were gH2 (39.2%), mixed type or new genotype was not observed. In infantile hepatitis syndrome (26 clinical isolates were gH1 genotypes, 17 clinical isolates were gH2 genotypes), anicteric hepatitis (25 were gH1, 13 were gH2) and pneumonia (9 were gH1, 4 were gH2), the distribution of HCMV gH genotypes of infantile clinical isolates was consistent with the overall trend (chi(2) = 0.357, P > 0.05). However , the gH2 was more common than gH1 in the clinical isolates of patients with thrombocytopenic purpura (6 were gH2, 1 were gH2, chi(2) = 6.083, P < 0.05). CONCLUSION: Genotype 1 was the dominant genotype of glycoprotein H in HCMV clinical isolates from our hospital infants. There was no significant difference between the distribution of gH genotypes in infantile hepatitis syndrome, anicteric hepatitis and pneumonia. However, gH2 was the dominant genotype in thrombocytopenic purpura. These findings suggested that there may be a certain relevance between gH genotype and different clinical manifestations. PMID- 23927799 TI - [Retrospective analysis of clinical and epidemiological characteristics of hand foot-and-mouth disease deceased cases in Zhejiang Province]. AB - OBJECTIVE: To understand the clinical and epidemiological characteristics of hand foot-and-mouth disease (HFMD) deceased cases. METHOD: Information of demographics, diagnosis and treatment, clinical symptoms and signs, laboratory test results, and epidemiological contact history of 72 HFMD cases who died between May 2008 and September 2011, in Zhejiang Province, were collected and analyzed. RESULT: The average age of the 72 cases was 1.8 years, 45 were males, accounting for 62.5%, 63 (87.5%) of the cases were scattered children. Eighteen counties reported 2 or more deaths, accounting for 46.1% (18/39) among the counties where the deaths were reported. The deaths occurred mainly in April to August, the peak occurred in May and June. Fever (98.4%, 63/64) and rash (95.1%, 58/61) were the most common symptoms, but the rash was not obvious at the first diagnosis. Fever occurred before the rash (79.0%, 49/62), persisted for 4 days in average. Vomiting (71.9%, 46/64), dyspnea (65.6%, 42/64), cyanosis (53.1%, 34/64) and impaired consciousness (51.6%, 33/64) were often seen among the cases; 53.1% (34/64) cases went to see the doctor on the first day, but 82.5%(52/63)cases were misdiagnosed. Time to diagnosis of HFMD was in average 3 days. About 3 to 4 days after the onset, the disease deteriorated sharply, deaths occurred within 1 day after admission in 78.9%(45/57)of the deceased cases; 85.0% (34/40) cases had high white blood cells level, mainly neutrophils increased, the ratio of neutrophil was more than 70% in 55.6% (15/27) of cases. Enterovirus 71 (EV71) infection was found in 93.3% (56/60) cases, the deceased cases often died of pulmonary hemorrhage (42.9%, 21/49) and encephalitis (34.7%, 17/49). The sanitary conditions of the cases' family were poor (65.5%, 36/55), but 73.3% (33/45) cases had no exposure history. CONCLUSION: The HFMD deceased cases were mostly younger aged boys, scattered children, nonlocal-residents, and had poor sanitation. They were often infected with EV71, had high fever but had no typical rash, no clear exposure history, they had increased leukocyte, and were often misdiagnosed. Three or 4 days after onset, the disease deteriorated abruptly, most cases died within 1 week after onset. To decrease the HFMD mortality, early detection of severe cases should be stressed, and relative measures should be taken. The guardian should be aware of having good sanitary situation and healthy habits. PMID- 23927800 TI - [Detecting human respiratory syncytial virus in respiratory samples collected from children with acute respiratory infections by reverse transcription-loop mediated isothermal amplification]. AB - OBJECTIVE: To establish a rapid, sensitive and specific reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for detecting human respiratory syncytial virus (RSV) in respiratory samples collected from children with acute respiratory infections. METHOD: According to the conserved matrix gene sequences of respiratory syncytial virus subtypes A and B downloaded from GenBank, primers were designed and RT-LAMP assay was developed to detect RNA of RSV sensitivity of the RT-LAMP method was evaluated by using ten-fold serially diluted in vitro-transcribed matrix RNA fragments from RSV A and RSV B, respectively. Specificity of the RT-LAMP method was tested through cross-reaction with other RNA and DNA viruses. Then 5 RSV strains isolated from clinical specimens using tissue cultures were tested by RT-LAMP assay. A total of 101 nasopharyngeal aspirates from hospitalized patients with acute respiratory infections which had been tested by direct immunofluorescence assay (DFA), including 40 positive for RSV and 61 negative for RSV, were tested by RT-LAMP assay and by RT-nested PCR. RESULT: Sensitivity analysis indicated that this RT LAMP method was able to detect 1 copy/ul of RSV A and RSV B RNA, no amplification was shown in RT-LAMP with DNA or cDNA from other viruses in 60 min, revealed that the RT-LAMP assay is highly specific. Five RSV isolates confirmed as 4 RSV A and 1 RSV B previously were detected by RT-LAMP method as positive in 30 min. For those 101 specimens tested, 37 were RSV positive determined by RT-LAMP assay, as well as 35 RSV positive by RT-nested PCR. The total coincidence rate of RT-LAMP assay with DFA and RT-nested PCR in detecting RSV is 95.0%, 94.1% with Kappa value 0.895 and 0.871, respectively. CONCLUSION: A new, sensitive, accurate and rapid method, RT-LAMP assay for detecting human respiratory syncytial viruses from nasopharyngeal aspirates was developed, which should be helpful in rapid detection of RSV from respiratory tract samples of children. PMID- 23927801 TI - [Prospective multicenter study on long-term ketogenic diet therapy for intractable childhood epilepsy]. AB - OBJECTIVE: To evaluate the efficacy and safety of long-term ketogenic diet (KD) on the children with intractable epilepsy. METHOD: This was a prospective, open label study of intractable epilepsy patients treated with the classic KD with a lipid-to-nonlipid ratio 4:1 between October 2004 and July 2011 at five Chinese epilepsy centers. A total of 299 patients were enrolled. The patients were divided into different groups according to age (including the below-1-year-old group, 1-to-3-year-old group, 3-to-6-year-old group, 6-to-10-year-old group, and over-10-year-old group), etiology (cryptogenic epilepsy, symptomatic epilepsy, and idiopathic epilepsy), and the seizure types (included infantile spasm, Lennox Gastaut syndrome, Ohtahara syndrome, tuberous sclerosis, Dravet syndrome, generalized epilepsy, and partial epilepsy). Parents were assigned to write seizure diaries which recorded the seizure presentations, tolerability, and complications associated with the KD. Patients' weight and height were measured every week. Blood beta-hydroxybutyric acid, blood sugar, and urinary ketone bodies were monitored closely. Patients were followed up through telephone calls by the nutritionists every month and regular outpatient visits or hospitalizations were recommended at all time-points which included the third, sixth and twelfth month after initiation. Efficacy was measured through seizure frequency. The variables related to the efficacy were also analyzed. SPSS 17.0 was used for all statistical analysis. RESULT: At 3, 6, and 12 months after initiation, 65.9%, 44.8%, and 26.4% patients remained on the diet, and 37.4%, 26.1%, and 20.4% had a > 50% reduction in their seizure frequency, including 21.7%, 10.7%, and 11.0% who became seizure free, respectively. At 24 months after initiation, 29 patients remained on the diet, and 28 patients had a > 90% seizure reduction, including five became seizure free. At 36 months after initiation, 7 patients remained on the diet, and all of them had a > 90% seizure reduction, including five became seizure free. No significant variables were related to the efficacy. Most complications were mild and reversible by conservative treatment. Gastrointestinal disturbances were the main complications, which included vomiting, diarrhea, constipation, and abdominal cramp. Severe complications occurred in four cases, including severe metabolic disturbances and severe pneumonia. CONCLUSION: The KD is a safe and effective alternative therapy for intractable childhood epilepsy. PMID- 23927802 TI - [Retrospective clinical features and renal pathological analysis of 15 children with anti-neutrophil cytoplasmic antibody-associated vasculitis]. AB - OBJECTIVE: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a disorder with poor prognosis. This study aimed to improve the diagnosis and treatment of ANCA associated vasculitis of children, to analyze the clinical features, pathological characteristics and the prognosis of children with ANCA associated vasculitis. METHOD: Fifteen children with ANCA associated vasculitis who were hospitalized from 2003 to 2012 in our hospital were included. Their data of pre-diagnosis status, clinical manifestations, renal pathology, treatment and prognosis were reviewed retrospectively. RESULT: Of the 15 children, 11 were girls and 4 boys with a mean age of 10.7 years. Fourteen children were categorized as microscopic polyangitis. The time to diagnosis varied from 0.5 month to 40 months. Hematuria and proteinuria were revealed by urine analysis in all of them, only 6 children complained with gross hematuria or edema of oliguria. Decreased glomerular filtration rate was revealed in 13 children, 8 of whom had a creatinine clearance rate of less than 15 ml/(min.1.73 m(2)). Twelve children underwent renal biopsy, crescent formation was found in 11 children. Most of the crescents were cellular fibrous crescents or fibrous crescents. Six children were diagnosed as crescentic nephritis; the process of rapidly progressive nephritis was only observed in 2 children. Segmental glomerulosclerosis or global glomerulosclerosis were found in 10 children, 3 of them were diagnosed as sclerotic glomerulonephritis. Anemia and pulmonary injury were the most common extra renal manifestations. Other extra renal manifestations included rash, pain joint, gastrointestinal symptoms, abnormal findings of cardiac ultrasonography and headache. Eight children were treated with steroid combined with cyclophosphamide, 4 were treated with steroid and mycophenolate mofetil, 2 were treated with steroid, cyclophosphamide and mycophenolate mofetil, 3 children were treated with plasma exchange. Fourteen children were followed up for 0.5 month to 4 years. The renal function did not recover in children with creatinine clearance rate of less than 30 ml/(min.1.73 m(2)), who showed crescentic glomerulonephritis or sclerotic glomerulonephritis. The children who had creatinine clearance rate of more than 30 ml/(min.1.73 m(2))had better prognosis. CONCLUSION: More attention should be paid to ANCA-associated vasculitis among school age girls with anemia or pulmonary diseases. The renal damage was serious in children; however, the clinical manifestations were not obvious. Children with a creatinine clearance rate of less than 30 ml/(min.1.73 m(2)) had poor prognosis. Early accurate diagnosis is very important. PMID- 23927803 TI - [Recent incidences and trends of childhood malignant solid tumors in Shanghai, 2002-2010]. AB - OBJECTIVE: To examine the recent incidences and trends of childhood malignant solid tumors in Shanghai. METHOD: Data from the population-based Shanghai Cancer Registry and related retrospective survey were used to analyze the patterns of incidence and trends of malignant solid tumors diagnosed between 2002 and 2010 in children aged 0-14 years. The distributions of incidences were described according to gender, age and cancer types which were classified according to International Classification of Childhood Cancer (ICCC). Annual age-standardized rates (ASRs) were adjusted by the world standard population. Approximate confidence intervals for standardized rate ratios (SRR) based Poisson distribution test-based methods were used to assess changes in incidence over the period 2002 - 2006 and 2007 - 2010. RESULT: (1)A total of 868 cases of childhood malignant solid tumors were diagnosed in Shanghai during 2002 - 2010, accounting for 65.8% of all childhood cancers. The ASR of 2002 - 2010 was 80.2 per million for all solid tumors. (2) The ASR was higher in boys (86.3 per million) than in girls (73.8 per million) with SRR 1.2 (95%CI 1.0 - 1.3). Incidence rate was the highest in the first five years of life with 93.4 per million. The age-specific incidence rates in 5 - 9 and 10 - 14 age groups were 65.2 and 79.3 per million, respectively. (3) CNS tumors, lymphomas, germ cell tumors, neuroblastoma, and soft tissue sarcomas were the top 5 most common solid tumors in children, with the incidence rate of 23.8, 11.0, 7.8, 7.7 and 6.8 per million, respectively. The patterns of subgroups varied in different age groups. Blastomas, such as neuroblastoma, retinoblastoma, were more common in the children aged 0 - 4 years, whereas epithelial carcinomas and bone tumors developed more frequently in elder children aged 10 - 14 years. (4) Compared with the ASR in 2002 - 2006, the ASR for both genders in 2007 - 2010 had no substantial changes (78.7 per million in 2002 - 2006 and 82.9 per million in 2007 - 2010). However, among boys, the incidence rate in 2007 - 2010 was significantly higher than that in 2002 - 2006 with SRR 1.2 (95%CI: 1.0 - 1.4). For specific subgroups of cancer, there were no substantial changes. Some cautions should be taken when interpreting results involving a small number of cases per year and those with wide 95% confidence intervals. CONCLUSION: The incidence rate of pediatric malignant solid tumors among males was higher than females during 2002 - 2010, and it differed among different age groups with the highest in the first five years of life. CNS tumor was the most common type of solid tumors in children. This was a unique characteristics comparing with adult reflected in disease spectrum and age of onset. The patterns of incidence and its trends for childhood malignant solid tumors in Shanghai could provide a basis for etiologic research and preventive interventions. The findings also suggest an urgent need for longer population based surveillance to verify the pattern and changing trends. PMID- 23927804 TI - [Clinical analysis of 41 children's urinary calculus and acute renal failure]. AB - OBJECTIVE: To analyze the treatment of acute renal failure caused by irrational drug use. METHOD: Data of 41 cases of acute renal failure seen from July 2008 to June 2012 in our hospital were reviewed. Bilateral renal parenchymas diffuse echo was found enhanced by ultrasound in all cases. Calculus image was not found by X ray. All children had medical history of using cephalosporins or others. Alkalinization of urine and antispasmodic treatment were given to all children immediately, 17 children were treated with hemodialysis and 4 children accepted intraureteral cannula placement. RESULT: In 24 children who accepted alkalinization of urine and antispasmodic treatment micturition could be restored within 24 hours, in 11 children micturition recovered after only one hemodialysis treatment and 2 children gradually restored micturition after hemodialysis twice, 4 children who accepted intraureteral cannula immediately restored micturition. In all children micturition recovered gradually after a week of treatment. Ultrasound examination showed that 39 children's calculus disappeared totally and renal parenchymas echo recovered to normal. The residual calculi with diameter less than 5 mm were found in 2 children, but they had no symptoms. The children received potassium sodium hydrogen citrate granules per os and were discharged from hospital. Ultrasound showed calculus disappeared totally one month later. CONCLUSION: Irrational drug use can cause children urolithiasis combined with acute renal failure, while renal dysfunction can reverse by drug withdrawal and early alkalinization of urine, antispasmodic treatment, intraureteral cannula or hemodialysis when necessary, most calculus can be expelled after micturition recovered to normal. PMID- 23927805 TI - [Clinical analysis of 22 cases community-acquired Pseudomonas aeruginosa urinary tract infection]. AB - OBJECTIVE: To study the characteristics of community-acquired urinary tract infections (CAUTIs) in children, analyze the risk factors and the susceptibility of antibiotics, thus to provide references to the diagnosis and medication of Pseudomonas aeruginosa (PA)-CAUTIs. Mothod Totally 22 cases of PA-CAUTIs were selected in one hospital from Jan, 2006 to Jan, 2012, their clinical information, laboratory results and radiological images were collected, and were compared with the CAUTIs cased by E. coli of those randomly selected over the same period. RESULT: In those 22 cases with PA-CAUTIs, the mean value of protein level was (32.25 +/- 13.81) mg/ml, 19 of them were hospitalized, 6 had urinary operation history, 7 of them had long-term usage of glucocorticoids or immunosuppressive agents, and 20 had underlying diseases. A total of 22 children with 26 PA-CAUTIs episodes were compared to E. coli-CAUTIs. Compared with E. coli-CAUTIs patients, children with PA-CAUTIs more often presented with a lower albumin (P = 0.017), a history of urinary operation(P = 0.03), more cases had a history of urinary operation (P = 0.03), a long-term usage of glucocorticoids or immunosuppressive medication (P = 0.044). Through multivariate logistic regression of variables that were significant in univariate analysis (with hospitalizations, long-term usage of glucocorticoids or immunosuppressive, albumin, underlying disease and urinary operation histories), and it turned out that underlying diseases (odds ratio 8.500, 95% CI 1.513 - 47.761, P = 0.037) and with urinary operation histories (odds ratio 6.196, 95% CI 1.120 - 34.273, P = 0.037) were proved as the independent risk factors for PA-CAUTIs. Those PA bacterial strains had a 36.36% resistance rate to piperacillin, aztreonam and gentamicin, a 31.82% resistance rate to cefepime and ceftazidime, while the resistance rate (4.55%) to carbapenem antibiotics was relatively low, only to bacillosporin all the strains were sensitive. CONCLUSION: Underlying diseases and the urinary operation histories are the independent risk factors of the occurrence of PA-CAUTIs, carbapenem antibiotics and bacillosporin can be considered as the drugs of choice for its treatment. PMID- 23927806 TI - [Mutation analysis of FAH gene in patients with tyrosinemia type 1]. AB - OBJECTIVE: To investigate the clinical features and mutations of the FAH gene. METHOD: Clinical records of two cases were collected, and diagnosis was made according to the diagnostic criteria of the International Organization for Rare Disorders (NORD). Genomic DNA was extracted from peripheral blood leukocytes with QIAamp DNA Mini Kit. The DNA extracts were subjected to direct sequencing for 14 exons together with adjacent fragments of FAH gene using ABI Prism 3730 Genetic Analyzer (Applied Biosystems, Foster City, CA) after PCR based on genomic DNA. The mutation source was verified by analyzing parents' exons corresponding to patients' mutation exons. The homology between human FAH enzyme and that of other species was surveyed using software Clustal X(European Bioinformatics Institute, Hinxton, Saffron Walde, UK). Polyphen (Polymorphism Phenotyping), available online, were used to predict possible impact of an amino acid substitution on structure and function of FAH enzyme. Polyphen calculates position-specific independent counts (PISC) scores for two amino acid variants in polymorphic position. A PISC scores that differ by > 2 were regarded as indicating the probability of damaging variants. RESULT: Patient 1 was a 5 months and 21 days old boy who suffered from persistent diarrhea, hepatomegaly, ascites; Alpha fetoprotein > 1210 ug/L, levels of tyrosine in blood and succinylacetone in urine were 110.8 umol/L and 83.7 umol/L. His sister suffered from tyrosinemia type 1. Direct sequencing showed a G to A transition in CDS position 455 and 1027. He was compound heterozygous for the mutation c.455G > A/c.1027G > A, which predicts a change from tryptophan to a stop codon (TGG > TAG) at position 152 (W152X) and a change from glycine to arginine (GGG > AGG) at position 343 respectively. Patient 2 was a 6 year and 1 month-old girl with late-onset rickets who had signs of hepatosplenomegaly, rachitic rosary, windswept knees. Hypophosphatemia and alkaline phosphatase 1620 IU/L were detected. Alpha-fetoprotein 412.8 ug/L, levels of tyrosine in blood and succinylacetone in urine were 835.8 umol/L and 27.48 umol/L. Rickets did not improve after administration of calcium and vitamine D3. She is homozygous for the mutation c.1027G > A/c.1027G > A, which predicts G343R. The parents were mutation carriers. Analysis by Clustal X on the alignment of amino acids residual reservation among different species showed that the locative amino acid was highly conserved. Polyphen software predicted G343R was probably damaging (PISC score 3.235). CONCLUSION: Children with tyrosinemia type 1 can have manifestations of persistent diarrhea or late-onset rickets. Physical examination can reveal hepatosplenomegaly, laboratory tests indicate markedly elevated serum concentration of alpha-fetoprotein and alkaline phosphatase in plasma and succinylacetone in urine, other members in family may have tyrosinemias or parents are consanguineous. Mutations c.455G > A and c.1027G > A can be detected in FAH gene of Chinese children. PMID- 23927807 TI - [Ring chromosome 22 in a case]. PMID- 23927808 TI - [Autoimmune lymphoproliferative syndrome: a case report]. PMID- 23927809 TI - [Gene diagnosis and clinical characteristics of autosomal recessive polycystic kidney disease]. PMID- 23927810 TI - [Advances in the clinical and laboratory studies on methylmalonic aciduria combined with homocysteinemia type cblC]. PMID- 23927811 TI - [The eleventh National Children's Liver Disease & tenth National Pediatric Infectious Diseases conference minutes]. PMID- 23927812 TI - Structures of oligomers of a peptide from beta-amyloid. AB - Amyloid oligomers play a central role in Alzheimer's and other amyloid diseases, and yet the structures of these heterogeneous and unstable species are not well understood. To better understand the structures of oligomers formed by amyloid beta peptide (Abeta), we have incorporated a key amyloidogenic region of Abeta into a macrocyclic peptide that stabilizes oligomers and facilitates structural elucidation by X-ray crystallography. This paper reports the crystallographic structures of oligomers and oligomer assemblies formed by a macrocycle containing the Abeta(15-23) nonapeptide. The macrocycle forms hydrogen-bonded beta-sheets that assemble into cruciform tetramers consisting of eight beta-strands in a two layered assembly. Three of the cruciform tetramers assemble into a triangular dodecamer. These oligomers further assemble in the lattice to form hexagonal pores. Molecular modeling studies suggest that the natural Abeta peptide can form similar oligomers and oligomer assemblies. The crystallographic and molecular modeling studies suggest the potential for interaction of the oligomers with cell membranes and provide insights into the role of oligomers in amyloid diseases. PMID- 23927813 TI - Ethanol self-administration in serotonin transporter knockout mice: unconstrained demand and elasticity. AB - Low serotonin function is associated with alcoholism, leading to speculation that increasing serotonin function could decrease ethanol consumption. Mice with one or two deletions of the serotonin transporter (SERT) gene have increased extracellular serotonin. To examine the relationship between SERT genotype and motivation for alcohol, we compared ethanol self-administration in mice with zero (knockout, KO), one (HET) or two copies (WT) of the SERT gene. All three genotypes learned to self-administer ethanol. The SSRI, fluvoxamine, decreased responding for ethanol in the HET and WT, but not the KO mice. When tested under a progressive ratio schedule, KO mice had lower breakpoints than HET or WT. As work requirements were increased across sessions, behavioral economic analysis of ethanol self-administration indicated that the decreased breakpoint in KO as compared to HET or WT mice was a result of lower levels of unconstrained demand, rather than differences in elasticity, i.e. the proportional decreases in ethanol earned with increasing work requirements were similar across genotypes. The difference in unconstrained demand was unlikely to result from motor or general motivational factors, as both WT and KO mice responded at high levels for a 50% condensed milk solution. As elasticity is hypothesized to measure essential value, these results indicate that KO value ethanol similarly to WT or HET mice despite having lower break points for ethanol. PMID- 23927814 TI - Intravascular papillary endothelial hyperplasia of the skull base and intracranial compartment. PMID- 23927815 TI - Small cell carcinoma of the head and neck: report of three cases. AB - OBJECTIVE: Small cell carcinoma of the head and neck is rare and has unique histopathological characteristics that make it difficult to diagnose and treat. In this report, the Japanese Lung Cancer Treatment Guidelines were adapted to treat three patients with small cell carcinoma of the head and neck, and outcomes evaluated. METHODS: There was one case each of stage I small cell carcinoma of the nasal cavity, stage IV-B small cell carcinoma of the ethmoid sinus, and stage IV-A small cell carcinoma of the submandibular gland. All patients underwent chemoradiotherapy and achieved a partial response. RESULTS: Only case one underwent surgery after chemoradiotherapy; 31 months after treatment, this patient had suffered no recurrence. Case two died three months after treatment due to bone marrow metastasis. Case three had experienced no progression after 12 months of follow up. CONCLUSION: In this small patient series, short-term results were equivalent to or better than usual treatment outcomes for small cell carcinoma of the lung. PMID- 23927816 TI - WITHDRAWN: The challenges of selenium determination in biological samples with graphite furnace using line source and high resolution continuum source atomic absorption spectrometry. AB - This article has been withdrawn at the request of the author. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23927817 TI - Calculating disability-adjusted-life-years lost (DALYs) in discrete-time. AB - Disability-adjusted-life-years lost (DALYs) is a common outcome metric for cost effectiveness analyses, and the equations used for such calculations have been presented previously by Fox-Rushby and Hanson (see, e.g., "Health Policy and Planning 16:326-331, 2001"). While the equations are clear, the logic behind them is opaque at best for a large share of public health practitioners and students. The objective of this paper is to show how to calculate DALYs using a discrete time formulation that is easy to teach to students and public health practitioners, is easy to apply for those with basic discounting skills, and is consistent with the discounting methods typically included on the costing side of cost-effectiveness analysis. A continuous-time adjustment factor is derived that can be used to ensure exact consistency between the continuous and discrete time approaches, but this level of precision is typically unnecessary for cost effectiveness analyses. To illustrate the approach, both a new, simple example and the same example presented in Fox-Rushby and Hanson are used throughout the paper. PMID- 23927818 TI - Combined arthroscopic Bankart repair and remplissage for recurrent shoulder instability. AB - PURPOSE: The objective of our study was to summarize the available clinical evidence pertaining to the combined arthroscopic Bankart repair and remplissage procedure (BRR) for the management of recurrent anterior glenohumeral instability. METHODS: We searched Medline (1946 to the third week of November, 2012), the Cochrane Central Register of Controlled Trials, Embase (1947 to the 50th week of 2012), and PubMed for studies that reported clinical outcome data at a minimum of 1 year after BRR. Two independent reviewers selected studies for inclusion, assessed methodological quality, and extracted relevant data. Clinical outcome data were pooled and summarized. RESULTS: Seven clinical studies with a total of 220 patients met the inclusion criteria. Mean patient age was 29 years and mean follow-up was 26 months. Among all studies, the pooled rate of recurrent dislocation after BRR was 3.4%. Compared with preoperative range of motion (ROM) and ROM after Bankart repair (BR) for similar pathologic conditions, there were no clinically significant losses in glenohumeral motion after BRR. Moreover, BRR resulted in favorable functional outcome scores and high patient satisfaction. Four studies reported on postoperative imaging and found high rates of healing and tissue fill-in at the site of infraspinatus tenodesis. CONCLUSIONS: After BRR, the rate of recurrent dislocation is low and there are no clinically significant losses in glenohumeral ROM. Moreover, functional outcome scores are good and there is a high rate of patient satisfaction. Going forward, there is a need for high-level clinical studies to support the findings of this systematic review and to develop an evidence-based approach to the management of patients with recurrent glenohumeral instability in the setting of a Hill-Sachs defect (HSD). PMID- 23927819 TI - Older adults recently discharged from the hospital: effect of aerobic interval exercise on health-related quality of life, physical fitness, and physical activity. AB - OBJECTIVES: To compare the effect of high-intensity aerobic interval exercise (HIA) with home-based exercise (HB) in older adults with chronic disease soon after discharge from the hospital. DESIGN: Randomized controlled trial. SETTING: Hospital. PARTICIPANTS: Community-dwelling older adults aged 70 to 92 (N = 115) were recruited while in the hospital. After discharge, they were randomized to HIA group (n = 59) or HB (n = 56). INTERVENTION: High-intensity aerobic interval exercise (HIA) consisted of endurance, strength, and balance exercises. The HB consisted of low-intensity exercises and telephone follow-up from a physical therapist. MEASUREMENTS: Health-related quality of life (HRQOL) was assessed using the Medical Outcomes Study 36-item Short Form Survey, physical fitness was measured using the Senior Fitness Test, and physical activity was assessed using the Physical Activity Scale for the Elderly. RESULTS: Intention-to-treat analysis showed that both groups improved their HRQOL and physical activity after 3 months. Improvements on the Senior Fitness Test (chair stand, arm curl and 6 minute walk (6MWT)) were significantly greater in the HIA group than the HB group. The mean difference was 25.9 m on the 6MWT (P = .001, effect size d = 0.2), 1.3 per 30 seconds on the chair stands mean (P = .001, effect size d = 0.3), and 1.6 per 30 seconds on the arm curl (P = .001, effect size d = 0.4). CONCLUSION: High-intensity aerobic interval exercise (HIA) participants significantly improved their physical fitness. Both groups increased their HRQOL and physical activity. The findings suggest that exercise therapy should be incorporated as a part of the treatment for older people at risk for functional decline. PMID- 23927820 TI - Rapid detection of methicillin-resistant Staphylococcus aureus by a newly developed dry reagent-based polymerase chain reaction assay. AB - BACKGROUND/PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen responsible for significant numbers of nosocomial and community-acquired infections worldwide. Molecular diagnosis for MRSA nasal carriers is increasingly important for rapid detection and screening of MRSA colonization because the conventional methods are time consuming and labor intensive. However, conventional polymerase chain reaction (PCR) tests still require cold-chain storage as well as trained personnel, which makes them unsuitable for rapid high throughput analysis. The aim of this study was to develop a thermostabilized PCR assay for MRSA in a ready-to-use form that requires no cold chain. METHODS: The thermostabilized PCR assay detects the following targets simultaneously: (1) 16S rRNA of the Staphylococcus genus; (2) femA gene specific for S. aureus; (3) mecA gene conferring methicillin resistance; and (4) lukS gene, which encodes the virulent toxin. The thermostabilized PCR incorporates an internal amplification control that helps to verify the presence of PCR inhibitors in samples. PCR reagents and specific primers were lyophilized into a pellet form with an enzyme stabilizer. RESULTS: The PCR was validated with 235 nasal swabs specimens and was found to be 100% sensitive and specific. The stability of the thermostabilized PCR was evaluated using the Q10 method and it was found to be stable for approximately 6 months at 24 degrees C. The limit of detection of thermostabilized PCR assay was determined by probit regression (95% confidence interval) was 10(6) colony forming units at the bacterial cell level and 10 ng of DNA at the genomic DNA level, which is comparable with conventional PCR methods. CONCLUSION: A rapid thermostabilized PCR assay that requires minimal pipetting steps and is cold chain-free was developed for detecting MRSA nasal carriers. PMID- 23927821 TI - Childhood tuberculosis in southern Taiwan, with emphasis on central nervous system complications. AB - BACKGROUND/PURPOSE: Childhood tuberculosis (TB) continues to be a major public health problem in Taiwan. Taiwan remains a highly endemic area despite neonatal Bacillus Calmette-Guerin (BCG) vaccination and the availability of anti-TB therapy. The presentation is highly variable and it is often difficult to make an accurate diagnosis. This study was designed to evaluate the demographic, clinical, and laboratory findings and outcomes of TB in children with emphasis on central nervous system (CNS) complications. METHODS: The medical records of 80 children diagnosed with TB at a medical center in southern Taiwan over the past 24 years (1988-2012) were reviewed. RESULTS: Among them, 48.8% (39/80) had pulmonary TB, 27.5% (22/80) had isolated extrapulmonary TB, and 23.7% (19/80) had disseminated TB. Most infected cases were aged either < 4 years or > 12 years. TB contact history was found in 42.5% (34/80) cases. Fourteen (17.5%) of the cases had CNS involvement. The most common presentations were fever (85.7%), signs of increased intracranial pressure (71.4%), drowsiness (64.3%), and focal neurological signs (57.1%). The major radiological findings were tuberculoma (50%), basilar enhancement (41.6%), infarction (41.6%), hydrocephalus (16.6%), and transverse myelitis (16.6%). The case fatality of CNS TB was 14.3% and 21.4% had neurologic sequelae. CONCLUSION: Findings suggest that positive exposure history and suspicious clinical presentations are important clues for further confirmatory laboratory and image studies in childhood TB. CNS TB usually presented as part of disseminated TB in children. Early diagnosis and treatment may lead to favorable outcomes in CNS TB. PMID- 23927822 TI - Clinical manifestations of Kawasaki disease shock syndrome: a case-control study. AB - BACKGROUND: Kawasaki disease shock syndrome (KDSS) is a severe condition related to Kawasaki disease (KD), and sometimes it is difficult to diagnose. This is a case-control study to ascertain the clinical presentations, risk factors, and clinical outcomes of children who had KDSS. MATERIALS AND METHODS: Children who were hospitalized during 2001-2011 with the diagnosis of KD combined with hypotension, sepsis, or shock were retrospectively reviewed and were defined as case patients. For each case patient, three season-matched patients diagnosed as having KD with normal blood pressure were identified to serve as control patients. Demographic characteristics, clinical presentations, laboratory features, therapies, and outcomes were analyzed. RESULTS: Nine KDSS patients and 27 control patients were identified. The average age of patients with KDSS was 3.2 +/- 3.2 years. Compared with controls, KDSS patients were less likely to have a diagnosis of KD at admission (22.2% vs. 66.7%) and had a higher risk of coronary artery dilatation (77.8% vs. 11.1%). Risk factors for KDSS included higher neutrophil counts and proportions of bands, higher C-reactive protein (CRP), and lower platelet counts. All case patients received aspirin therapy; eight patients received intravenous immunoglobulin therapy, with two receiving more than one course. Seven KDSS patients required fluid resuscitation, and eight patients required vasoactive infusions. CONCLUSION: Patients with KDSS may have uneven clinical course and may be misdiagnosed in the beginning. They may have more prominent inflammatory markers in the early phase and higher risk of coronary artery dilatation. PMID- 23927823 TI - Bacillus cereus septicemia in a patient with acute lymphoblastic leukemia: A case report and review of the literature. AB - Bacillus cereus is an aerobic Gram-positive, spore-forming, rod-shaped bacterium that is responsible for foodborne illnesses. We report on a 15-year-old girl with B-cell acute lymphoblastic leukemia, who fell into a somnolent state after presenting with a 12-hour history of fever, muscle soreness, myalgia in both calves, sore throat, and vomiting. Fulminant septicemic syndrome caused by B. cereus was finally identified. The aim of this work is the introduction of B. cereus as a differential diagnosis of sepsis in patients with acute leukemia in induction chemotherapy, to prevent delayed treatment. PMID- 23927824 TI - A multidisciplinary team care bundle for reducing ventilator-associated pneumonia at a hospital in southern Taiwan. PMID- 23927825 TI - Impact of bacterial and viral coinfection on mycoplasmal pneumonia in childhood community-acquired pneumonia. AB - BACKGROUND/PURPOSE: Coinfection of Mycoplasma pneumoniae is not uncommon in children with respiratory syndromes. The purpose of this study was to investigate the impact of bacterial and viral coinfection on mycoplasmal pneumonia in hospitalized children with community-acquired pneumonia (CAP). METHODS: Children coinfected with M. pneumoniae in a prospective study of the etiology of CAP at a tertiary pediatric facility Children's Hospital were enrolled and retrospectively reviewed. The data of clinical characteristics, complications, and outcomes of these children were collected and analyzed. RESULTS: A total of 59 children were enrolled and stratified into three groups: M. pneumoniae infection alone (n = 31), M. pneumoniae with Streptococcus pneumoniae coinfection (n = 9), and M. pneumoniae with virus coinfection (n = 19). As compared with children infected with M. pneumoniae alone, coinfection of children with S. pneumoniae was more likely to occur under the age of 5 years with a longer duration of fever and hospital stay. Furthermore, total leukocyte count and serum C-reactive protein level were also significantly higher in these children (p < 0.01). However, no significant difference in clinical characteristics, complications, and outcomes was observed between the patients infected with either M. pneumoniae alone or with virus coinfection. CONCLUSION: In children with CAP, the influence on the clinical outcomes of M. pneumoniae infection may be heavily dependent on the coinfected pathogen. A potential coexistence of M. pneumoniae infection should be considered in children with features suggesting typical bacterial pneumonia. PMID- 23927826 TI - Occurrence of methicillin-resistant Staphylococcus aureus in the nasal cavity of healthy volunteer students of the University of Valencia (Spain). PMID- 23927828 TI - In situ grazing incidence small-angle X-ray scattering investigation of polystyrene nanoparticle spray deposition onto silicon. AB - We investigated the spray deposition and subsequent self-assembly during drying of a polystyrene nanoparticle dispersion with in situ grazing incidence small angle X-ray scattering at high time resolution. During the fast deposition of the dispersion and the subsequent evaporation of the solvent, different transient stages of nanoparticle assembly can be identified. In the first stage, the solvent starts to evaporate without ordering of the nanoparticles. During the second stage, large-scale structures imposed by the breakup of the liquid film are observable. In this stage, the solvent evaporates further and nanoparticle ordering starts. In the late third drying stage, the nanoparticles self-assemble into the final layer structure. PMID- 23927827 TI - Combination of carbonic anhydrase inhibitor, acetazolamide, and sulforaphane, reduces the viability and growth of bronchial carcinoid cell lines. AB - BACKGROUND: Bronchial carcinoids are pulmonary neuroendocrine cell-derived tumors comprising typical (TC) and atypical (AC) malignant phenotypes. The 5-year survival rate in metastatic carcinoid, despite multiple current therapies, is 14 25%. Hence, we are testing novel therapies that can affect the proliferation and survival of bronchial carcinoids. METHODS: In vitro studies were used for the dose-response (AlamarBlue) effects of acetazolamide (AZ) and sulforaphane (SFN) on clonogenicity, serotonin-induced growth effect and serotonin content (LC-MS) on H-727 (TC) and H-720 (AC) bronchial carcinoid cell lines and their derived NOD/SCID mice subcutaneous xenografts. Tumor ultra structure was studied by electron microscopy. Invasive fraction of the tumors was determined by matrigel invasion assay. Immunohistochemistry was conducted to study the effect of treatment(s) on proliferation (Ki67, phospho histone-H3) and neuroendocrine phenotype (chromogranin-A, tryptophan hydroxylase). RESULTS: Both compounds significantly reduced cell viability and colony formation in a dose-dependent manner (0-80 MUM, 48 hours and 7 days) in H-727 and H-720 cell lines. Treatment of H-727 and H-720 subcutaneous xenografts in NOD/SCID mice with the combination of AZ + SFN for two weeks demonstrated highly significant growth inhibition and reduction of 5-HT content and reduced the invasive capacity of H-727 tumor cells. In terms of the tumor ultra structure, a marked reduction in secretory vesicles correlated with the decrease in 5-HT content. CONCLUSIONS: The combination of AZ and SFN was more effective than either single agent. Since the effective doses are well within clinical range and bioavailability, our results suggest a potential new therapeutic strategy for the treatment of bronchial carcinoids. PMID- 23927829 TI - Investigating missing sources of sulfur at Fairbanks, Alaska. AB - We investigated disparities in elemental sulfur and inorganic sulfate concentrations in ambient fine particulate matter (PM2.5) data from 2005 to 2012 at a monitoring station in Fairbanks, AK. In approximately 28% of the observations from 2005 to 2012, elemental sulfur by X-ray fluorescence (XRF) spectroscopy significantly exceeded the inorganic sulfur by ion chromatography (IC), suggesting the presence of a significant quantity of unmeasured sulfur compounds. The mean ratio of sulfur by XRF to that by IC for only these cases was 1.22 +/- 0.11. The largest discrepancies between elemental sulfur and sulfate were most frequently observed in the summer, although discrepancies were observed year round. Assuming the additional sulfur (other than inorganic sulfate) as the upper limit estimate, this work shows that organosulfur species (or the additional sulfur) account for 1.29% of organic carbon (OC) and 0.75% of PM2.5 in Fairbanks. An analysis of all available air quality system (AQS) data suggests that these recurring phenomena are linked to seasons, total carbon, inorganic nitrate, and elemental sources during cold periods and ozone during warm periods. PMID- 23927830 TI - Relationship between foot function and medial knee joint loading in people with medial compartment knee osteoarthritis. AB - BACKGROUND: Dynamic joint loading, particularly the external knee adduction moment (KAM), is an important surrogate measure for the medio-lateral distribution of force across the knee joint in people with knee osteoarthritis (OA). Foot motion may alter the load on the medial tibiofemoral joint and hence affect the KAM. Therefore, this study aimed to investigate the relationship between tibia, rearfoot and forefoot motion in the frontal and transverse planes and the KAM in people with medial compartment knee OA. METHOD: Motion of the knee, tibia, rearfoot and forefoot and knee moments were evaluated in 32 patients with clinically and radiographically-confirmed OA, predominantly in the medial compartment. Pearson's correlation coefficient was used to investigate the association between peak values of tibia, rearfoot and forefoot motion in the frontal and transverse planes and 1st peak KAM, 2nd peak KAM, and the knee adduction angular impulse (KAAI). RESULTS: Lateral tilt of the tibia was significantly associated with increased 1st peak KAM (r = 0.60, p < 0.001), 2nd peak KAM (r = 0.67, p = 0.001) and KAAI (r = 0.82, p = 0.001). Increased peak rearfoot eversion was significantly correlated with decreased 2nd peak KAM (r = 0.59, p < 0.001) and KAAI (r = 0.50, p = 0.004). Decreased rearfoot internal rotation was significantly associated with increased 2nd peak KAM (r = -0.44, p = 0.01) and KAAI (r = -0.38, p = 0.02), while decreased rearfoot internal rotation relative to the tibia was significantly associated with increased 2nd peak KAM (r = 0.43, p = 0.01). Significant negative correlations were found between peak forefoot eversion relative to the rearfoot and 2nd peak KAM (r = -0.53, p = 0.002) and KAAI (r = -0.51, p = 0.003) and between peak forefoot inversion and 2nd peak KAM (r = -0.54, p = 0.001) and KAAI (r = -0.48, p = 0.005). CONCLUSION: Increased rearfoot eversion, rearfoot internal rotation and forefoot inversion are associated with reduced knee adduction moments during the stance phase of gait, suggesting that medial knee joint loading is reduced in people with OA who walk with greater foot pronation. These findings have implications for the design of load-modifying interventions in people with knee OA. PMID- 23927831 TI - Development of a novel ex vivo porcine skin explant model for the assessment of mature bacterial biofilms. AB - Bacterial biofilms have been proposed to be a major factor contributing to the failure of chronic wounds to heal because of their increased tolerance to antimicrobial agents and the prolonged inflammation they cause. Phenotypic characteristics of bacterial biofilms vary depending on the substratum to which they attach, the nutritional environment, and the microorganisms within the biofilm community. To develop an ex vivo biofilm model that more closely mimics biofilms in chronic skin wounds, we developed an optimal procedure to grow mature biofilms on a central partial-thickness wound in 12-mm porcine skin explants. Chlorine gas produced optimal sterilization of explants while preserving histological properties of the epidermis and dermis. Pseudomonas aeruginosa and Staphylococcus aureus developed mature biofilms after 3 days that had dramatically increased tolerance to gentamicin and oxacillin (~100* and 8,000* minimal inhibitory concentration, respectively) and to sodium hypochlorite (0.6% active chlorine). Scanning electron microscopy and confocal microscopy verified extensive exopolymeric biofilm structures on the explants. Despite a significant delay, a DeltalasI quorum-sensing mutant of P. aeruginosa developed biofilm as antibiotic-tolerant as wild-type after 3 days. This ex vivo model simulates growth of biofilms on skin wounds and provides an accurate model to assess effects of antimicrobial agents on mature biofilms. PMID- 23927832 TI - Cell-selective metabolic labeling of biomolecules with bioorthogonal functionalities. AB - Metabolic labeling of biomolecules with bioorthogonal functionalities enables visualization, enrichment, and analysis of the biomolecules of interest in their physiological environments. This versatile strategy has found utility in probing various classes of biomolecules in a broad range of biological processes. On the other hand, metabolic labeling is nonselective with respect to cell type, which imposes limitations for studies performed in complex biological systems. Herein, we review the recent methodological developments aiming to endow metabolic labeling strategies with cell-type selectivity. The cell-selective metabolic labeling strategies have emerged from protein and glycan labeling. We envision that these strategies can be readily extended to labeling of other classes of biomolecules. PMID- 23927833 TI - Role of cervical vestibular evoked myogenic potential response in identifying vestibular dysfunction. AB - OBJECTIVES: To analyse cervical vestibular evoked myogenic potential response parameters in normal volunteers and vertiginous patients. SUBJECTS AND METHODS: A prospective study of 50 normal subjects and 50 patients with vertigo was conducted at Chiang Mai University Hospital, Thailand. Cervical vestibular evoked myogenic potential responses were measured using air-conducted, 500-Hz, tone burst stimuli with subjects in a sitting position with their head turned toward the contralateral shoulder. RESULTS: The mean +/- standard deviation age and male:female ratio in the normal (44.0 +/- 9.3 years; 12:38) and vertigo groups (44.7 +/- 9.8 years; 17:33) were not significantly different. The prevalence of absent responses in the normal (14 per cent) and vertigo ears (46 per cent) differed significantly (p < 0.0001). Other cervical vestibular evoked myogenic potential parameters (i.e. response threshold, P1 and N1 latency, P1-N1 interlatency and interamplitude, inter-ear difference in P1 threshold, and asymmetry ratio) showed no inter-group differences. CONCLUSION: The absence of a cervical vestibular evoked myogenic potential response is useful in the identification of vestibular dysfunction. However, patients should undergo a comprehensive battery of other vestibular tests to supplement their cervical vestibular evoked myogenic potential response findings. PMID- 23927834 TI - On the spatial dynamics and oscillatory behavior of a predator-prey model based on cellular automata and local particle swarm optimization. AB - A two-dimensional lattice model based on Cellular Automata theory and swarm intelligence is used to study the spatial and population dynamics of a theoretical ecosystem. It is found that the social interactions among predators provoke the formation of clusters, and that by increasing the mobility of predators the model enters into an oscillatory behavior. PMID- 23927835 TI - Erythema and erosions of the perianal region in a 49-year-old man. PMID- 23927836 TI - Identification of phospholipase C zeta in normospermic and teratospermic domestic cat sperm. AB - In mammalian species, oocyte activation is initiated by oscillations in the intracellular concentration of free calcium ([Ca(2+)]i), which are also essential to allow embryonic development. To date, evidence supporting the hypothesis that a sperm factor is responsible for initiating oocyte activation has been presented in various mammalian species. Among the possible candidates to be the active sperm factor is the novel sperm-specific phospholipase C zeta (PLCzeta), which besides its testis-specific expression is capable of initiating [Ca(2+)]i oscillations. In this study, we investigated the presence of PLCzeta in the sperm of the domestic cat and whether normospermic and teratospermic cats differ in their PLCzeta expression. Immunoblotting with anti-PLCzeta antibodies confirmed the presence of an immunoreactive band of ~70 kDa in whole sperm lysates of domestic cat as well as in both soluble and "insoluble" fractions from this sperm. Additional immunoreactive bands, probably C- and N-terminal truncated versions of PLCzeta, were also visualized in the soluble sperm fractions. Interestingly, immunoreactivity of PLCzeta was detectable in teratospermic sperm, although with slightly less intensity than in normospermic sperm. In conclusion, domestic cat sperm express PLCzeta in both cytosolic and high-pH fractions, which is consistent with data in other mammals. Sperm from teratospermic cats also express PLCzeta, albeit at reduced concentrations, which may affect the fertility of these males. PMID- 23927837 TI - Self-assembly of amphiphilic peptide (AF)6H5K15: coarse-grained molecular dynamics simulation. AB - Amphiphilic peptides are receiving considerable interest for drug delivery because of their self-assembly nature. A molecular dynamics simulation study is reported here to investigate the self-assembly of FA32 peptide composed of 32 amino acid (AF)6H5K15. The peptide, as well as water and counterions, are represented by the MARTINI coarse-grained model. Within 5 MUs simulation duration, the peptide is observed to form micelles. Ala and Phe stay in the hydrophobic core, Lys in the hydrophilic shell, and amphiphilic His at the interface. The assembly process and microscopic structures are analyzed in terms of the number of clusters, the radii of micelle, core and shell, and the density profiles of residues. A three-step process is proposed for the assembly: small clusters are initially aggregated and then merged into large clusters, eventually micelles are formed. The effects of simulation box size and peptide concentration are examined in detail. It is found that the micellar structures and microscopic properties are essentially independent of box size. With increasing concentration, quasi-spherical micelles change to elongated shape and micelle size generally increases. The simulation study provides microscopic insight into the assembly process of FA32 peptide and the microscopic structures. PMID- 23927838 TI - 3S: shotgun secondary structure determination of long non-coding RNAs. AB - Long non-coding RNAs (lncRNAs) have emerged as an important class of RNAs playing key roles in development, disease and epigenetics. Knowledge of lncRNA structure may be critical in understanding function for many lncRNA systems. Due to the enormous number of possible folds for these sequences, secondary structure determination presents a significant challenge, both experimentally and computationally. Here, we present a new strategy capable of determining the RNA secondary structure in the wet lab without significant reliance on computational predictions. First, we chemically probe the entire lncRNA. Next, using a shotgun approach, we divide the RNA into overlapping fragments and probe these fragments. We then compare probing profiles of fragments with the profiles of the full RNA and identify similarities. Sequence regions with profiles that are similar in the fragment and full-length transcript possess only base pairing partners within the fragment. Thus, by experimentally folding smaller and smaller fragments of the full RNA and probing these chemically, we are able to isolate modular sub domains, dramatically reducing the number of possible folds. The method also eliminates the possibility of pseudoknots within a modular sub-domain. The 3S technique is ideally suited for lncRNAs because it is designed for long RNA sequences. The 3S-determined secondary structure of a specific lncRNA in one species (e.g., human) enables searches for instances of the same lncRNA in other species. PMID- 23927839 TI - Maximizing the quantitative accuracy and reproducibility of Forster resonance energy transfer measurement for screening by high throughput widefield microscopy. AB - Forster resonance energy transfer (FRET) between fluorescent proteins (FPs) provides insights into the proximities and orientations of FPs as surrogates of the biochemical interactions and structures of the factors to which the FPs are genetically fused. As powerful as FRET methods are, technical issues have impeded their broad adoption in the biologic sciences. One hurdle to accurate and reproducible FRET microscopy measurement stems from variable fluorescence backgrounds both within a field and between different fields. Those variations introduce errors into the precise quantification of fluorescence levels on which the quantitative accuracy of FRET measurement is highly dependent. This measurement error is particularly problematic for screening campaigns since minimal well-to-well variation is necessary to faithfully identify wells with altered values. High content screening depends also upon maximizing the numbers of cells imaged, which is best achieved by low magnification high throughput microscopy. But, low magnification introduces flat-field correction issues that degrade the accuracy of background correction to cause poor reproducibility in FRET measurement. For live cell imaging, fluorescence of cell culture media in the fluorescence collection channels for the FPs commonly used for FRET analysis is a high source of background error. These signal-to-noise problems are compounded by the desire to express proteins at biologically meaningful levels that may only be marginally above the strong fluorescence background. Here, techniques are presented that correct for background fluctuations. Accurate calculation of FRET is realized even from images in which a non-flat background is 10-fold higher than the signal. PMID- 23927840 TI - Home telemonitoring or structured telephone support programmes after recent discharge in patients with heart failure: systematic review and economic evaluation. AB - BACKGROUND: Remote monitoring (RM) strategies have the potential to deliver specialised care and management to patients with heart failure (HF). OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of home telemonitoring (TM) or structured telephone support (STS) strategies compared with usual care for adult patients who have been recently discharged (within 28 days) from acute care after a recent exacerbation of HF. DATA SOURCES: Fourteen electronic databases (including MEDLINE, EMBASE, PsycINFO and The Cochrane Library) and research registers were searched to January 2012, supplemented by hand-searching relevant articles and contact with experts. The review included randomised controlled trials (RCTs) or observational cohort studies with a contemporaneous control group that included the following RM interventions: (1) TM (including cardiovascular implanted monitoring devices) with medical support provided during office hours or 24/7; (2) STS programmes delivered by human-to human contact (HH) or human-to-machine interface (HM). REVIEW METHODS: A systematic review and network meta-analysis (where appropriate) of the clinical evidence was carried out using standard methods. A Markov model was developed to evaluate the cost-effectiveness of different RM packages compared with usual care for recently discharged HF patients. TM 24/7 or using cardiovascular monitoring devices was not considered in the economic model because of the lack of data and/or unsuitability for the UK setting. Given the heterogeneity in the components of usual care and RM interventions, the cost-effectiveness analysis was performed using a set of costing scenarios designed to reflect the different configurations of usual care and RM in the UK. RESULTS: The literature searches identified 3060 citations. Six RCTs met the inclusion criteria and were added to the 15 trials identified from the previous systematic reviews giving a total of 21 RCTs included in the systematic review. No trials of cardiovascular implanted monitoring devices or observational studies met the inclusion criteria. The methodological quality of the studies varied widely and reporting was generally poor. Compared with usual care, RM was beneficial in reducing all-cause mortality for STS HH [hazard ratio (HR) 0.77, 95% credible interval (CrI) 0.55 to 1.08], TM during office hours (HR 0.76, 95% CrI 0.49 to 1.18) and TM 24/7 (HR 0.49, 95% CrI 0.20 to 1.18); however, these results were statistically inconclusive. The results for TM 24/7 should be treated with caution because of the poor methodological quality of the only included study in this network. No favourable effect on mortality was observed with STS HM. Similar reductions were observed in all-cause hospitalisations for TM interventions, whereas STS interventions had no major effect. A sensitivity analysis, in which a study was excluded because it provided better-than-usual support to the control group, showed larger beneficial effects for most outcomes, particularly for TM during office hours. In the cost effectiveness analyses, TM during office hours was the most cost-effective strategy with an estimated incremental cost-effectiveness ratio (ICER) of L11,873 per quality-adjusted life-year (QALY) compared with usual care, whereas STS HH had an ICER of L228,035 per QALY compared with TM during office hours. STS HM was dominated by usual care. Similar results were observed in scenario analyses performed using higher costs of usual care, higher costs of STS HH and lower costs of TM during office hours. LIMITATIONS: The RM interventions included in the review were heterogeneous in terms of monitored parameters and HF selection criteria and lacked detail in the components of the RM care packages and usual care (e.g. communication protocols, routine staff visits and resources used). As a result, the economic model developed scenarios for different RM classifications and their costs were estimated using bottom-up costing methods. Although the users can decide which of these scenarios is most representative of their setting, uncertainties still remain about the assumptions made in the estimation of these costs. In addition, the model assumed that the effectiveness of the interventions was constant over time, irrespective of the duration of deployment, and that the intervention was equally effective in different age/severity groups. CONCLUSION: Despite wide variation in usual care and RM strategies, cost effectiveness analyses suggest that TM during office hours was an optimal strategy (in most costing scenarios). However, clarity was lacking among descriptions of the components of RM packages and usual care and there was a lack of robust estimation of costs. Further research is needed in these areas. STUDY REGISTRATION: PROSPERO registration no. CRD42011001368. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 23927841 TI - Advancing age and 30-day adverse outcomes after nonemergent general surgeries. AB - OBJECTIVES: To determine whether 30-day postoperative mortality, complications, failure-to-rescue (FTR) rates, and postoperative length of stay increase with advancing age. DESIGN: Retrospective cohort study. SETTING: Hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program. PARTICIPANTS: Individuals undergoing nonemergent major general surgeries between 2005 and 2008 were studied (N = 165,600). MEASUREMENTS: Postoperative outcomes of interest were complications occurring within 30 days of the index operation, return to the operating room within 30 days, FTR after a postoperative complication, postsurgical length of stay, and 30-day mortality. RESULTS: Postoperative mortality, overall morbidity, and each type of postoperative complication increased with increasing age. Rates of FTR after each type of postoperative complication also increased with age. Mortality in individuals aged 80 and older after renal insufficiency (43.3%), stroke (36.5%), myocardial infarction (MI) (35.6%), and pulmonary complications (25-39%) were particularly high. Median postoperative length of stay increased with age after surgical site infection, urinary tract infection, pneumonia, return to the operating room, and overall morbidity but not after venous thromboembolism, stroke, MI, renal insufficiency, failure to wean from the ventilator, or reintubation. CONCLUSION: Thirty-day mortality and complication and FTR rates increase with age after nonemergent general surgeries. Individuals aged 80 and older have especially high mortality after renal, cardiovascular, and pulmonary complications. Surgeons need to be more selective with advancing age regarding who will benefit from the surgical intervention. PMID- 23927842 TI - Secreted aspartic peptidases of Candida albicans liberate bactericidal hemocidins from human hemoglobin. AB - Secreted aspartic peptidases (Saps) are a group of ten acidic hydrolases considered as key virulence factors of Candida albicans. These enzymes supply the fungus with nutrient amino acids as well as are able to degrade the selected host's proteins involved in the immune defense. Our previous studies showed that the human menstrual discharge is exceptionally rich in bactericidal hemoglobin (Hb) fragments - hemocidins. However, to date, the genesis of such peptides is unclear. The presented study demonstrates that the action of C. albicans isozymes Sap1-Sap6, Sap8 and Sap9, but not Sap7 and Sap10, toward human hemoglobin leads to limited proteolysis of this protein and generates a variety of antimicrobial hemocidins. We have identified these peptides and checked their activity against selected microorganisms representative for human vagina. We have also demonstrated that the process of Hb hydrolysis is most effective at pH 4.0, characteristic for vagina, and the liberated peptides showed pronounced killing activity toward Lactobacillus acidophilus, and to a lower degree, Escherichia coli. However, only a very weak activity toward Staphylococcus aureus and C. albicans was noticed. These findings provide interesting new insights into pathophysiology of human vaginal candidiasis and suggest that C. albicans may be able to compete with the other microorganisms of the same physiological niche using the microbicidal peptides generated from the host protein. PMID- 23927844 TI - Functional activity of murine intestinal mucosal cells is regulated by the glucagon-like peptide-1 receptor. AB - To determine whether the glucagon-like peptide-1 receptor (GLP-1r) plays a role in the regulation of intestinal functional activity, we analyzed the distribution of the GLP-1r in mouse tissues and tested if tissues expressing the receptor respond to exendin-4 and exendin (9-39) amide, a GLP-1r agonist and antagonist respectively. In ileum, Glp1r mRNA level was two fold higher in extracts from epithelial cells than non-epithelial tissues. By immunohistochemistry, the receptor was localized to the mucosal cell layer of villi of ileum and colon, to the myenteric and submucosal plexus and to Paneth cells. Intravenous administration of exendin-4 to CD-1 mice induced expression of the immediate early gene c-fos in mucosal cells but not in cells of the enteric plexuses or in L cells of ileum. The induction of c-fos was inhibited by the voltage-gated sodium channel blocker tetrodotoxin. Exendin-4 also increased c-fos expression in ileal segments in vitro, suggesting that this action of the analog was independent of an extrinsic input. The induction of c-fos expression by exendin-4 was inhibited by exendin (9-39) amide, indicating that the action of exendin-4 was mediated by activation of the receptor. Our findings indicate that the GLP-1r is involved in ileal enterocyte and Paneth cell function, that the GLP-1 analog activates c-fos expression in the absence of an extrinsic input and that some of the actions of the receptor is/are mediated by voltage-gated Na channels. PMID- 23927843 TI - Endothelial permeability in vitro and in vivo: protective actions of ANP and omapatrilat in experimental atherosclerosis. AB - Increased arterial endothelial cell permeability (ECP) is considered an initial step in atherosclerosis. Atrial natriuretic peptide (ANP) which is rapidly degraded by neprilysin (NEP) may reduce injury-induced endothelial cell leakiness. Omapatrilat represents a first in class of pharmacological agents which inhibits both NEP and angiotensin converting enzyme (ACE). We hypothesized that ANP prevents thrombin-induced increases of ECP in human aortic ECs (HAECs) and that omapatrilat would reduce aortic leakiness and atherogenesis and enhance ANP mediated vasorelaxation of isolated aortas. Thrombin induced ECP determined by I(125) albumin flux was assessed in HAECs with and without ANP pretreatment. Next we examined the effects of chronic oral administration of omapatrilat (12 mg/kg/day, n=13) or placebo (n=13) for 8 weeks on aortic leakiness, atherogenesis and ANP-mediated vasorelaxation in isolated aortas in a rabbit model of atherosclerosis produced by high cholesterol diet. In HAECs, thrombin-induced increases in ECP were prevented by ANP. Omapatrilat reduced the area of increased aortic leakiness determined by Evans-blue dye and area of atheroma formation assessed by Oil-Red staining compared to placebo. In isolated arterial rings, omapatrilat enhanced vasorelaxation to ANP compared to placebo with and without the endothelium. ANP prevents thrombin-induced increases in ECP in HAECs. Chronic oral administration of omapatrilat reduces aortic leakiness and atheroma formation with enhanced endothelial independent vasorelaxation to ANP. These studies support the therapeutic potential of dual inhibition of NEP and ACE in the prevention of increased arterial ECP and atherogenesis which may be linked to the ANP/cGMP system. PMID- 23927845 TI - The Belgian Health System Performance Report 2012: snapshot of results and recommendations to policy makers. AB - Following the commitments of the Tallinn Charter, Belgium publishes the second report on the performance of its health system. A set of 74 measurable indicators is analysed, and results are interpreted following the five dimensions of the conceptual framework: accessibility, quality of care, efficiency, sustainability and equity. All domains of care are covered (preventive, curative, long-term and end-of-life care), as well as health status and health promotion. For all indicators, national/regional values are presented with their evolution over time. Benchmarking to results of other EU-15 countries is also systematic. The policy recommendations represent the most important output of the report. PMID- 23927846 TI - Disparities in access to health care in three French regions. AB - OBJECTIVES: This paper compares access to primary and specialty care in three metropolitan regions of France: Ile de France (IDF), Nord-Pas-de-Calais (NPC) and Provence-Alpes-Cote d'Azur (PACA); and identifies the factors that contribute to disparities in access to care within and among these regions. METHODS: To assess access to primary care, we compare variation among residence-based, age-adjusted hospital discharge rates for ambulatory care sensitive conditions (ASC). To assess access on one dimension of specialty care, we compare residence-based, age adjusted hospital discharge rates for revascularization - bypass surgery and angioplasty - among patients diagnosed with ischemic heart disease (IHD). In addition, for each region we rely on a multilevel generalized linear mixed effect model to identify a range of individual and area-level factors that affect the discharge rates for ASC and revascularization. RESULTS: In comparison with other large metropolitan regions, in France, access to primary care is greater in Paris and its surrounding region (IDF) than in NPC but worse than in PACA. With regard to revascularization, after controlling for the burden of IHD, use of services is highest in PACA followed by IDF and NPC. In all three regions, disparities in access are much greater for revascularization than for ASC. Residents of low income areas and those who are treated in public hospitals have poorer access to primary care and revascularizations. In addition, the odds of hospitalization for ASC and revascularization are higher for men. Finally, people who are treated in public hospitals, have poorer access to primary care and revascularization services than those who are admitted for ASC and revascularization services in private hospitals. CONCLUSIONS: Within each region, we find significant income disparities among geographic areas in access to primary care as well as revascularization. Even within a national health insurance system that minimizes the financial barriers to health care and has one of the highest rates of spending on health care in Europe, the challenge of minimizing these disparities remains. PMID- 23927847 TI - Durability of healing from spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a 6 month follow-up. AB - Patients who participated in a Phase 2 trial of HP802-247 for venous leg ulcers were invited to participate in this 24-week follow-up study to assess the durability of healing, document additional ulcer closures, and evaluate posttreatment safety. Consent was given by 90% (206/228), with 80% (183/228) completing all visits. Blinding was retained from the previous trial in which subjects had been randomized to vehicle or one of four cell therapy regimens. Visits were every 8 weeks. Among the 183 subjects, 43% (21/49) previously treated with cells and entering follow-up with an open wound achieved closure, compared with 35% (7/20) previously treated with vehicle, while 10% (11/106) and 17% (3/18), respectively, experienced reopening of a previously closed wound. Subjects previously treated with cells closed more open wounds than those previously treated with vehicle (OR 1.39, 95% CI 0.47-4.10; p = 0.739), and less subjects with a previously closed wound reopened (OR 0.65, CI 0.16-2.60; p = 0.821); however, these findings were not statistically significant. At the final visit, the difference in proportion of subjects with wounds closed continued to favor the best dose from the prior trial (83% closed vs. 58%, delta 25%). Follow up beyond 12 weeks is necessary to evaluate the full benefit of this therapy, as treatment with cells may provide stimulus toward healing that persists for up to several weeks following the last application. The results show that the greater proportional benefit achieved by HP802-247 relative to standard care after 12 weeks of treatment persists over a meaningful timeframe. PMID- 23927848 TI - Writing science that your colleagues can read. PMID- 23927849 TI - Carcinoma of the oral tongue in patients younger than 30 years: comparison with patients older than 60 years. AB - OBJECTIVES: The incidence of oral tongue squamous cell carcinoma is rising in young patients. This study evaluated the clinical, pathological, and prognostic characteristics of oral tongue squamous cell carcinoma in the under-30-year age group. MATERIALS AND METHODS: The computerized database of the Department of Otolaryngology-Head and Neck Surgery of a tertiary, university-affiliated medical center was searched for all patients with oral tongue squamous cell carcinoma treated by glossectomy with curative intent in 1996-2012. Data were collected by chart review. RESULTS: Of the 113 patients identified, 16 (14%) were aged ?30years at presentation and 62 (55%) >60years. Mean follow-up time was 30months. Comparison by age group revealed no sex predilection and no differences in histologic grade or rates of advanced T-stage, perineural and vascular invasion, or nodal extracapsular extension. Rates of node-positive disease were 75% in the younger group and 19% in the older group (p<0.001). Kaplan-Meier analysis yielded no between-group difference in disease-free or overall survival. Recurrence was documented in a similar proportion of patients (38% and 29.9%, respectively), but half the recurrences in the younger group were distant versus none in the older group (p=0.01) All younger patients with recurrent disease died within 16months of its appearance compared to 50% 3-year disease-specific survival in the older group. CONCLUSIONS: Oral tongue squamous cell carcinoma is more advanced at presentation in younger than in older patients, with higher rates of regional metastases and distant failure. Recurrent disease is more aggressive, with a fatality rate of 100%. PMID- 23927850 TI - Do lesbian women have a better body image? Comparisons with heterosexual women and model of lesbian-specific factors. AB - Body dissatisfaction is prevalent among women but may be less common among lesbian women. Although research trends toward this conclusion when samples are well-matched and body mass index (BMI) is controlled for, many studies do not exhibit these characteristics. Furthermore, few studies have examined sociocultural contributors to group differences. I addressed limitations of past research with a large community sample of lesbian (n=479) and heterosexual (n=400) women. I contrasted the two sexual identity groups on several body dissatisfaction measures, and tested theoretically derived relationships between lesbian-specific cultural factors and body dissatisfaction. As predicted, lesbian women reported lower body dissatisfaction than did heterosexual women on three of four measures, and expressed a larger ideal body size. A structural equation model of lesbian-specific risk and protective factors for body dissatisfaction did not reveal significant relationships. This study represents a first attempt to model culturally specific influences on lesbian body image. PMID- 23927851 TI - Chronic cough and sputum production are associated with worse clinical outcomes in stable asthma. AB - BACKGROUND: Chronic cough and sputum production (chronic mucus hypersecretion) is a poorly described clinical feature of asthma. Our objective was to identify clinical, immunological and computed tomography (CT) measures of airway wall dimensions associated with these symptoms in smokers and never smokers with asthma. METHODS: Cross-sectional data was analysed from 120 smokers and never smokers with asthma. Participants with and without a history of chronic mucus hypersecretion were compared for clinical outcomes, sputum differential cell counts and CT measures of airway dimensions (wall thickness, luminal area and percent wall area). RESULTS: Chronic mucus hypersecretion occurred in a higher proportion of smokers with asthma (56%) than never smokers with asthma (20%), (p < 0.001) and the proportion of patients with these symptoms increased with asthma severity (p = 0.003). Smokers with asthma and chronic mucus hypersecretion had worse current clinical control than smokers without those symptoms [ACQ score 2.3 versus 1.6, p = 0.002]. A greater proportion of never smokers with chronic mucus hypersecretion required short courses of oral corticosteroids in the last year (58% versus 19%, p = 0.011). Sputum neutrophil and eosinophil counts were similar in asthma patients with or without chronic mucus hypersecretion. Of those with severe asthma and chronic mucus hypersecretion, a CT measure of airway lumen area was reduced in smokers compared to never smokers (11.4 mm(2) versus 18.4 mm(2); p = 0.017). CONCLUSIONS: Chronic mucus hypersecretion occurs frequently in adults with stable asthma, particularly in smokers with severe disease and is associated with worse current clinical control in smokers and more exacerbations in never smokers. PMID- 23927852 TI - Differences between asthma in young and elderly: results from the COREA study. AB - BACKGROUND: There has been no large-scale and comprehensive study of the differences between asthma in elderly asthmatics (EA) and non-elderly (i.e. young) asthmatics (NEA). METHODS: We performed principal component analysis (PCA) using 2067 asthmatics (434 EA and 1633 NEA) from the Korean Cohort for Reality and Evolution of adult Asthma (COREA). EA was defined as asthmatics with the chronological age of 65 or more and eleven clinical variables measured at enrollment were used for PCA; symptom score, symptom duration, number of exacerbation during previous one year, smoking pack year, number of controller medications, body mass index, predicted % of FEV1, predicted % FVC, post bronchodilator FEV1/FVC ratio, atopy index and number of eosinophils in peripheral blood. RESULTS: PCA of all asthmatics showed that EA and NEA were distinctly separated by the first and second principal component on the plot of individual asthmatics according to their scores. For further analysis, we divided all asthmatics into the EA and the NEA group and performed PCA again in each group. The first four principal components with eigenvalues >= 1.0 were identified in both groups and they explained 55.5% of the variance in the EA group and 52.4% in the NEA group respectively. Clinical variables showed distinctly different patterns of loading on the first four principal components between the EA and the NEA group. CONCLUSION: EA and NEA have different compositional patterns underlying their clinical variables. These observations helped in understanding the differences between EA and NEA from the integrated view covering various clinical aspects. PMID- 23927853 TI - Exploring critical uncertainties in pathway assessments of human-assisted introductions of alien forest species in Canada. AB - Long-distance introductions of alien species are often driven by socioeconomic factors, such that conventional "biological" invasion models may not be capable of estimating spread fully and reliably. In this study, we demonstrate a new technique for assessing and reconstructing human-mediated pathways of alien forest species entries to major settlements in Canada via commercial road transportation and domestic trade. We undertook our analysis in three steps. First, we used existing data on movement of commodities associated with bark- and wood-boring forest pests to build a probabilistic model of how the organisms may be moved from one location to another through a transportation network. We then used this model to generate multiple sets of predictions of species arrival rates at every location in the transportation network, and to identify the locations with the highest likelihood of new incursions. Finally, we evaluated the sensitivity of the species arrival rates to uncertainty in key model assumptions by testing the impact of additive and multiplicative errors (by respectively adding a uniform random variate or symmetric variation bounds to the arrival rate values) on the probabilities of pest transmission from one location to another, as well as the impact of the removal of one or more nodes and all connecting links to other nodes from the underlying transportation network. Overall, the identification of potential pest arrival hotspots is moderately robust to uncertainties in key modeling assumptions. Large urban areas and major border crossings that have the highest predicted species arrival rates have the lowest sensitivities to uncertainty in the pest transmission potential and to random changes in the structure of the transportation network. The roadside survey data appears to be sufficient to delineate major hubs and hotspots where pests are likely to arrive from other locations in the network via commercial truck transport. However, "pass-through" locations with few incoming and outgoing routes can be identified with lower precision. The arrival rates of alien forest pests appear to be highly sensitive to additive errors. Surprisingly, the impact of random changes in the structure of the transportation network was relatively low. PMID- 23927854 TI - Optimal policies of non-cross-resistant chemotherapy on Goldie and Coldman's cancer model. AB - Mathematical models can be used to study the chemotherapy on tumor cells. Especially, in 1979, Goldie and Coldman proposed the first mathematical model to relate the drug sensitivity of tumors to their mutation rates. Many scientists have since referred to this pioneering work because of its simplicity and elegance. Its original idea has also been extended and further investigated in massive follow-up studies of cancer modeling and optimal treatment. Goldie and Coldman, together with Guaduskas, later used their model to explain why an alternating non-cross-resistant chemotherapy is optimal with a simulation approach. Subsequently in 1983, Goldie and Coldman proposed an extended stochastic based model and provided a rigorous mathematical proof to their earlier simulation work when the extended model is approximated by its quasi approximation. However, Goldie and Coldman's analytic study of optimal treatments majorly focused on a process with symmetrical parameter settings, and presented few theoretical results for asymmetrical settings. In this paper, we recast and restate Goldie, Coldman, and Guaduskas' model as a multi-stage optimization problem. Under an asymmetrical assumption, the conditions under which a treatment policy can be optimal are derived. The proposed framework enables us to consider some optimal policies on the model analytically. In addition, Goldie, Coldman and Guaduskas' work with symmetrical settings can be treated as a special case of our framework. Based on the derived conditions, this study provides an alternative proof to Goldie and Coldman's work. In addition to the theoretical derivation, numerical results are included to justify the correctness of our work. PMID- 23927855 TI - Computational optimization for S-type biological systems: cockroach genetic algorithm. AB - S-type biological systems (S-systems) are demonstrated to be universal approximations of continuous biological systems. S-systems are easy to be generalized to large systems. The systems are identified through data-driven identification techniques (cluster-based algorithms or computational methods). However, S-systems' identification is challenging because multiple attractors exist in such highly nonlinear systems. Moreover, in some biological systems the interactive effect cannot be neglected even the interaction order is small. Therefore, learning should be focused on increasing the gap between the true and redundant interaction. In addition, a wide searching space is necessary because no prior information is provided. The used technologies should have the ability to achieve convergence enhancement and diversity preservation. Cockroaches live in nearly all habitats and survive for more than 300 million years. In this paper, we mimic cockroaches' competitive swarm behavior and integrated it with advanced evolutionary operations. The proposed cockroach genetic algorithm (CGA) possesses strong snatching-food ability to rush forward to a target and high migration ability to escape from local minimum. CGA was tested with three small scale systems, a twenty-state medium-scale system and a thirty-state large-scale system. A wide search space ([0,100] for rate constants and [-100,100] for kinetic orders) with random or bad initial starts are used to show the high exploration performance. PMID- 23927856 TI - The false thyroid capsule: new findings. AB - PURPOSE: The false thyroid capsule is an important anatomical structure involved in thyroidectomy, yet it is rarely studied. This study aimed to define the anatomy of the false thyroid capsule, and its clinical significance. METHODS: A prospective study was performed involving 151 patients with goitre who underwent thyroid lobectomy. The anatomy of the false thyroid capsule was carefully documented intra-operatively. RESULTS: The false thyroid capsule enclosed the inferior and middle thyroid veins and the superior thyroid vessels, forming a mesentery-like structure by attaching to the gland. Once the unilateral lobe had been removed, the thyroid mesentery could be seen to have a C-shaped edge. The recurrent laryngeal nerve, inferior thyroid artery and parathyroid glands were located beneath the C-shaped edge of the thyroid mesentery. CONCLUSION: The thyroid mesentery is a distinctive structure that can be used as a guide for surgical dissection. PMID- 23927857 TI - Good pharma, bad pharma. PMID- 23927858 TI - C-reactive protein, vitamin D deficiency, and slow gait speed. AB - OBJECTIVES: To evaluate the independent and joint effects of C-reactive protein (CRP) and 25-OH vitamin D (25(OH)D) levels on mobility disability in older persons. DESIGN: U.S. population-based cross-sectional study. SETTING: National Health and Nutrition Examination Surveys (2001-2002). PARTICIPANTS: Individuals aged 50 and older (N = 1,826). MEASUREMENTS: C-reactive protein (mg/dL), with high CRP defined as >= 0.2 mg/dL, and 25(OH)D levels (ng/mL) operationalized as severe deficiency (<10 ng/mL), deficiency (10-19.9 ng/mL), insufficiency (20-29.9 ng/mL), and normal (>= 30 ng/mL). Mobility disability was operationalized as gait speed of <0.8 m/s while completing a 20-foot walk (6.1 m). RESULTS: High CRP and low 25(OH)D levels were associated with slow gait speed. Individuals with high CRP levels and severe vitamin D deficiency were more likely to have slow gait speed than were those with neither risk factor (odds ratio = 3.54, 95% confidence interval = 1.42-8.84, P = .007). A significant positive association between vitamin D level and gait speed was found only in those with high CRP in stratified analyses. Whites and blacks showed similar findings as the overall population. CONCLUSION: These findings provide evidence of a potential joint effect of vitamin D and CRP on gait speed, suggesting that evaluation and correction of vitamin D levels may be especially important in individuals with high CRP levels. PMID- 23927859 TI - Reorganizing a resuscitation room using Six Sigma (6S) principles. PMID- 23927860 TI - Bath salt abuse: more than just hot water. PMID- 23927861 TI - Analysis of public dental service waiting lists in Queensland. AB - Information on public dental service waiting lists is available as part of the Queensland Government open data policy. Data were summarised across the care categories and health districts to present the total number and percentage of people waiting for care and who have waited beyond the desirable period. As of 31 December 2012 there were 130546 people on the dental waiting list; of these 85.8%, 8.5% and 2.2% were waiting for general care desirable within 24, 12 and 3 months, respectively. Across all care categories, almost 56% of those on the waiting list were beyond the desirable waiting period. The average number of people on the waiting list and the average number waiting beyond the desirable time differ substantially per clinic by district. Ongoing analysis of the Queensland public dental service waiting list database will determine the impact on patient waiting times of Federal Government initiatives announced in 2012 to treat an estimated 400000 patients on waiting lists nationwide over the next 3 years and to expand services to assist low-income adults to receive dental services. PMID- 23927862 TI - Temporal expression profile of CXC chemokines in serum of patients with spinal cord injury. AB - Chemokines, a subclass of cytokine superfamily have both pro-inflammatory and migratory role and serve as chemoattractant of immune cells during the inflammatory responses ensuing spinal cord injury (SCI). The chemokines, especially CXCL-1, CXCL-9, CXCL-10 and CXCL-12 contribute significant part in the inflammatory secondary damage of SCI. Inhibiting chemokine's activity and thereby the secondary damage cascades has been suggested as a chemokine-targeted therapeutic approach to SCI. To optimize the inhibition of secondary injury through targeted chemokine therapy, accurate knowledge about the temporal profile of these cytokines following SCI is required. Hence, the present study was planned to determine the serum levels of CXCL-1, CXCL-9, CXCL-10 and CXCL-12 at 3 6h, 7 and 28days and 3m after SCI in male and female SCI patients (n=78) and compare with age- and sex-matched patients with non-spinal cord injuries (NSCI, n=70) and healthy volunteers (n=100). ANOVA with Tukey post hoc analysis was used to determine the differences between the groups. The data from the present study show that the serum level of CXCL-1, CXCL-9 and CXCL-10 peaked on day 7 post-SCI and then declined to the control level. In contrast, significantly elevated level of CXCL-12 persisted for 28 days post SCI. In addition, post-SCI expression of CXCL-12 was found to be sex-dependent. Male SCI patients expressed significantly higher CXCL-12 when compared to control and SCI female. We did not observe any change in chemokines level of NSCI. Further, the age of the patients did not influence chemokines expression after SCI. These observations along with SCI induced CSF-chemokine level should contribute to the identification of selective and temporal chemokine targeted therapy after SCI. PMID- 23927863 TI - Proteomic analysis of global protein expression changes in the endothelin-1 rat model for cerebral ischemia: rescue effect of mild hypothermia. AB - Mild hypothermia is a promising neuroprotective therapy in stroke management. However, little is known about its effects on the global protein expression patterns in brain regions affected by ischemic stroke. We investigated protein expression changes associated with the neuroprotective effects of hypothermia via a functional proteomics approach through the analysis of the core (striatum) and the penumbra (cortex) after an ischemic insult in rats induced by endothelin-1 (Et-1). Functional outcome, infarct volume and related global protein expression changes were assessed 24h after the insult using two-dimensional difference gel electrophoresis. Mild hypothermia, induced 20 min after endothelin-1 infusion, improved the neurological outcome, reflected by a 36% reduction in infarct volume and a significantly better neurological deficit score. Hypothermia was typically associated with opposite protein expression changes inthe cortex to those induced by stroke under normothermic conditions, but not in the striatum. The main cellular processes rescued by hypothermia and potentially involved in the protection of the cortex are cellular assembly and organization, followed by cell signaling, thereby confirming that hypothermia is neuroprotective through multiple molecular and cellular pathways. PMID- 23927864 TI - The PPARgamma agonist rosiglitazone prevents neuronal loss and attenuates development of spontaneous recurrent seizures through BDNF/TrkB signaling following pilocarpine-induced status epilepticus. AB - Hippocampal neuronal loss plays an important role in epileptogenesis, and it is considered a trigger of repeated spontaneous recurrent seizures (SRS). The BDNF/TrkB signaling pathway regulates neuronal plasticity in the CNS, and promotes epileptogenesis. Previous studies have shown that Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists exert neuroprotective effects by inhibiting oxidative stress and inflammation in epilepsy. In the present study, the PPARgamma agonist rosiglitazone inhibited increases in BDNF and TrkB after status epilepticus (SE), and also prevented hippocampal neuronal loss. More importantly, our study showed that rosiglitazone suppressed SRS. However, the effects of rosiglitazone were significantly reversed by cotreatment with K252a, an antagonist of TrkB. Additionally, rosiglitazone did not affect the development and severity of SE. Thus, our data provide evidence that rosiglitazone exerts neuroprotective and antiepileptic effects involve BDNF/TrkB signaling. Our study also offers new perspectives for the treatment of epilepsy. PMID- 23927866 TI - Low incidence of procedure-related major adverse cardiac events after alcohol septal ablation for symptomatic hypertrophic obstructive cardiomyopathy. AB - BACKGROUND: Alcohol septal ablation (ASA) is a catheter-based intervention that has been used as an alternative to surgical myectomy in highly symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM). However, clinically relevant complications can result, including death and complete heart block (CHB) associated with syncope or resuscitation. This study was designed to evaluate the incidence of major ASA-related adverse cardiac events. METHODS: This international multicentre retrospective study included 421 patients in 8 European centres who were treated using ASA from April 1998 to January 2011. Clinical and echocardiographic follow-up (3-6 months) was completed in 394 patients (94%). RESULTS: ASA led to a significant reduction in symptoms and outflow gradients, with 0.7% mortality. A total of 70 patients (17%) experienced mostly transient CHB during and after the procedure; in 30% of them, CHB occurred or recurred later than 24 hours after ASA. Ninety-seven percent of CHB occurred up to the fifth day after ASA. Permanent pacemakers for CHB were implanted in 35 patients (8%). Multivariate analysis identified intraprocedural bundle branch block and age as independent predictors of CHB. CONCLUSIONS: The results of the multicentre study demonstrate that ASA appears safe and efficacious, with low early mortality. The most frequent major complication after ASA was CHB (17%), which occurred late or was recurrent in almost one-third of these patients; 8% of patients required permanent pacemaker implantation. Independent predictors of CHB development were intraprocedural bundle branch block and age. Difficulty in predicting CHB should lead to close postprocedural monitoring and hospital stays lasting at least 5 days. PMID- 23927867 TI - Determinants of percutaneous coronary intervention vs coronary artery bypass grafting: an interprovincial comparison. AB - BACKGROUND: Marked variation exists concerning the utilization of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). The objective of this study was to examine differences in predictors of mode of revascularization across 3 provincial jurisdictions. METHODS: All patients who underwent PCI and isolated CABG in British Columbia, Alberta, and Nova Scotia between 1996 and 2007 were considered. Age- and sex-standardized rates of PCI and CABG per 100,000 population and PCI to CABG ratios were calculated by year and province. Logistic regression models were constructed to identify independent predictors of mode of revascularization in each province. RESULTS: A total of 32,190 and 69,409 patients underwent CABG and PCI, respectively, during the study period. Significant increases in the age- and sex-adjusted PCI to CABG ratios were observed in all 3 provinces, but these ratios differed between provinces. Across all 3 jurisdictions, female sex and diagnosis of acute coronary syndrome favoured increased PCI vs CABG, and increased age, left main, or 3-vessel disease occurring before myocardial infarction, and diabetes favoured lower PCI vs CABG. After adjusting for clinical and angiographic factors, there remained a significant variation in choice of PCI vs CABG between the 3 provinces over time. CONCLUSIONS: Significant interprovincial variability in PCI to CABG ratios was observed. Though certain patient-related factors predictive of either PCI or CABG were identified, factors beyond clinical presentation played a role in the choice of revascularization approach. PMID- 23927865 TI - The zebrafish as a model for complex tissue regeneration. AB - For centuries, philosophers and scientists have been fascinated by the principles and implications of regeneration in lower vertebrate species. Two features have made zebrafish an informative model system for determining mechanisms of regenerative events. First, they are highly regenerative, able to regrow amputated fins, as well as a lesioned brain, retina, spinal cord, heart, and other tissues. Second, they are amenable to both forward and reverse genetic approaches, with a research toolset regularly updated by an expanding community of zebrafish researchers. Zebrafish studies have helped identify new mechanistic underpinnings of regeneration in multiple tissues and, in some cases, have served as a guide for contemplating regenerative strategies in mammals. Here, we review the recent history of zebrafish as a genetic model system for understanding how and why tissue regeneration occurs. PMID- 23927868 TI - Early signaling network in rice PRR-mediated and R-mediated immunity. AB - Recent studies on plant immunity and pathogen infection have revealed sophisticated forms of plant-pathogen interaction. Considerable progress has been made recently in our understanding of the molecular mechanism underlying chitin signaling in rice. The identification and characterization of two direct substrates, OsRacGEF1 and OsRLCK185, as components in the chitin receptor complex of OsCERK1 have revealed how pattern recognition receptors transduce pathogen signals to downstream molecules in rice. In this review, we highlight these and other recent studies that have contributed to our current understanding of the signaling network in rice immunity, especially with regard to pattern recognition receptors, disease resistance (R) proteins, and their downstream targets. PMID- 23927870 TI - The symphony of cell movement: how cells orchestrate diverse signals and forces to control migration. PMID- 23927871 TI - Surgical treatment of hypermotor seizures originating from the temporal lobe. AB - PURPOSE: To describe the characteristics of electroclinical manifestations in patients with hypermotor seizures (HMSs) originating from the temporal lobe. METHODS: We retrospectively reviewed the data of patients who underwent surgical treatments for seizure to identify patients with HMSs of temporal origin. We systematically reviewed patient seizure histories, imaging reports, video-EEG monitoring data, operative records and pathological findings. RESULTS: Eight of the 9 patients reported auras. The ictal behavior included marked agitation in 5 patients and mild agitation in 4 patients. All of the 9 patients exhibited stiffness or dystonia of the upper limb or contralateral limbs during ictus. Seven of the 9 patients completed intracranial recording and at least 3 seizures were recorded for each patient. The intracranial recordings showed ictal activity originating from mesial temporal lobe in 6 patients and the lateral temporal lobe in 1 patient. The time interval of ictal propagation from the temporal to frontal lobe was 15.0 +/- 8.3 s. While the time interval from EEG origination to the beginning of hypermotor behavior was 21.0 +/- 8.1 s. Brain MRIs revealed hippocampal sclerosis in 3, neoplastic lesion in 1, and normal images in the remaining 5 patients. Patients were followed for 1-5 years after the anterior temporal lobectomy; 7 patients remained seizure-free throughout follow-up. CONCLUSION: Some HMSs can originate from the temporal lobe. In carefully selected patients, surgical resection may lead to good outcomes. PMID- 23927869 TI - Feedback loops and reciprocal regulation: recurring motifs in the systems biology of the cell cycle. AB - The study of eukaryotic cell cycle regulation over the last several decades has led to a remarkably detailed understanding of the complex regulatory system that drives this fundamental process. This allows us to now look for recurring motifs in the regulatory system. Among these are negative feedback loops, which underpin checkpoints and generate cell cycle oscillations; positive feedback loops, which promote oscillations and make cell cycle transitions switch-like and unidirectional; and reciprocal regulation, which can increase the control a key regulator exerts. These simple motifs are found at multiple points in the cell cycle (e.g. S-phase and M-phase control) and are conserved in diverse organisms. These findings argue for an underlying unity in the principles of cell cycle control. PMID- 23927872 TI - Low voltage EELS-how low? AB - Using low beam energies in a (scanning) transmission electron microscope (S/TEM) has numerous advantages over higher beam energies. We discuss the performance of commonly available electron microscopes when being operated at reduced beam energies. Further on, we discuss the merits of low beam energies concerning the determination of the optical properties of Si as well as of buried quantum structures. For this purpose we have aligned a conventional S/TEM and the attached energy loss spectrometer for 13keV and 60keV, respectively. Finally we identify the key parameters for setting up a low voltage electron energy loss spectrometry (EELS) experiment. PMID- 23927873 TI - Mammalian DNA repair: HATs and HDACs make their mark through histone acetylation. AB - Genetic information is recorded in specific DNA sequences that must be protected to preserve normal cellular function. Genome maintenance pathways have evolved to sense and repair DNA damage. Importantly, deleterious mutations that occur from mis-repaired lesions can lead to diseases such as cancer. As eukaryotic DNA is bound by histone proteins and organized into chromatin, the true in vivo substrate of transcription, replication and DNA repair is chromatin. Almost 50 years ago, it was found that histones contained the post-translational modification (PTM), acetylation. With the cloning and identification of transcription associated histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes that write and erase the histone acetylation mark respectively, it was realized that this histone modification could be dynamically regulated. Chromatin is subjected to numerous PTMs that regulate chromatin structure and function, including DNA repair. As different organisms contain different histone modifications, chromatin-associated proteins and chromatin states, it is likely that chromatin-templated processes such as DNA repair will exhibit organismal differences. This article focuses on the DNA damage response (DDR) in mammalian cells and how the concerted activities of HAT and HDAC enzymes, and their histone acetylation targets, specifically participate in DNA double-strand break (DSB) repair. Defects in DNA repair and chromatin pathways are observed in cancer, and these pathways represent cancer therapeutic targets. Therefore, understanding the relationship between DNA repair and histone acetylations is important for providing mechanistic details of DSB repair within chromatin that has the potential to be exploited in the clinic. PMID- 23927874 TI - Cytokine expression in head-kidney leucocytes of European sea bass (Dicentrarchus labrax L.) after incubation with the probiotic Vagococcus fluvialis L-21. AB - The European sea bass (Dicentrarchus labrax L.) is one of the most extensively farmed marine fish in the Mediterranean sea. Under the high-density condition, common in aquaculture, the infectious diseases can cause significant economic losses. Probiotics are presented as an alternative to antibiotics for the control of aquaculture diseases. This study used real-time PCR to investigate in vitro the dynamic of expression of immune-related genes in sea bass after incubation with live and inactivated (heat and Uv-light) probiotic Vagoccus fluvialis L-21 at different times (T1, T12, T24, T48). The immune associated genes, interleukin 1 (IL-1), interleukin-6 (IL-6), interleukin 10 (IL-10), TumourTumour necrosis factor- (TNF-), ciclo-oxigenase-2 (COX-2), caspase-3 (Casp-3) and Mx were studied in head-kidney (HK) leucocytes of sea bass after incubation with the probiotic strain. Transcript of proinflammatory cytokines (IL-1, TNF-, COX-2) was highly up regulated after 1 h of incubation with the probiotic strain V. fluvialis L-21. We found statistically significant difference in pick of expression of TNF-, after 1 h of incubation with Uv-light inactivated probiotic strain. The COX-2 expression was highly up-regulated at all times studied, with the exception of 12 and 24 h post incubation for the Uv-light inactivated bacteria. Transcript of IL-10 and Casp-3 showed the higher statistically significant differences of expression after 48 h post incubation with live bacteria. In the contrast, sea bass HK leucocytes expressed Mx at 12 and 48 h without statistically differences among treatments. Our results suggest that V. fluvialis L-21 is able to stimulate in vitro some immune-related genes associated with the early inflammatory response. Future studies in vivo are necessary to clarify this process in sea bass. PMID- 23927875 TI - Effect of urinary incontinence on older nursing home residents' self-reported quality of life. AB - OBJECTIVES: To evaluate the effect of urinary incontinence (UI) on elderly nursing home (NH) residents' self-reported quality of life (QOL), especially on the specific QOL domains most closely associated with UI. DESIGN: Retrospective cross-sectional study using the Minimum Data Set (MDS) and Minnesota Nursing Home Report Card data in 2010 to compare overall QOL and its domains of residents with and without UI using propensity scores and inverse probability weighting (IPW) adjustments to reduce selection bias. SETTING: All Medicare- or Medicaid-licensed NHs in Minnesota. PARTICIPANTS: All residents aged 65 and older except those with conditions that could readily overwhelm the effect of UI on QOL, such as coma and cerebral palsy. MEASUREMENTS: Urinary incontinence (UI) was defined as leakage two or more times a week (score >= 2 on MDS 5-point scale), and continence was defined as continent or usually continent (score 0 or 1 on MDS 5-point scale). QOL was assessed using a self-reported QOL questionnaire that measured general QOL, not QOL specific to UI symptoms. RESULTS: Urinary incontinence (UI) prevalence was 65.8% in 10,683 older NH residents. Self-reported QOL was good (>0.7 on a scale from 0 to 1) in 8,620 eligible residents in 371 NHs. Mood and meaningful activity domains had lower scores; dignity had the highest score. UI was associated with being older and female, ADL dependence, impaired cognitive ability, Alzheimer's disease, non-Alzheimer's dementia, bowel incontinence, diabetes mellitus, and long-term NH stay. Bivariate analysis found that residents with UI had lower QOL than those without. Using IPW to reduce selection bias, it was found that, although UI was not associated with overall QOL, it decreased the QOL domains of dignity, autonomy, and mood. CONCLUSION: To improve the QOL of residents with UI, attention should be paid to dignity, autonomy, and mood. PMID- 23927876 TI - Comparative toxicity and apoptosis induced by diorganotins in rat pheochromocytoma (PC12) cells. AB - As ubiquitous environmental toxicants, organotin (IV) compounds (OTC) accumulate in the food chain and potential effects on human health are disquieting. The present study compared the cytotoxicity of three diorganotins, namely, dimethyltin (DMT), dibutyltin (DBT) and diphenyltin (DPT), in rat pheochromocytoma (PC12) cells, and the molecular mechanisms responsible for their cytotoxic effects were also explored. Twenty-four hours exposure of PC12 cells to DBT and DPT resulted in a concentration-dependent decrease in cell viability with median lethal concentration (LC50) of 2.97 MUM and 7.24 MUM, respectively. However, DMT at concentrations up to 128 MUM had no obvious effect on cell viability. The mechanistic study revealed that the extent of apoptosis was greater for DBT than that for DPT, followed by DMT, as evidenced by acridine orange/ethidium bromide (AO/EB) fluorescent staining method and annexin V-FITC/PI staining flow cytometry analysis, as well as generation of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP) disruption, release of cytochrome c (Cyt c), and consequent activation of caspase-9, and -3. These investigations suggested that the cytotoxic potency of three diorganotins in PC12 cells was in the order of DBT>DPT?DMT, and these compounds could induce PC12 cells apoptosis through ROS mediated mitochondrial pathway. PMID- 23927877 TI - Anti-diabetic effects of puerarin, isolated from Pueraria lobata (Willd.), on streptozotocin-diabetogenic mice through promoting insulin expression and ameliorating metabolic function. AB - Diabetes is a chronic disease characterized by the metabolic disorder in specific tissues. Our present study was designed to assess the potential benefits of puerarin (PR) on hypoglycemic and hypolipemic effects in diabetic mice induced by streptozotocin (STZ). The results achieved from these experiments showed that glycemia in STZ-diabetogenic mice were significantly reduced following the PR administration, while serum insulin concentration was increased. In addition, PR contributed to improving the dyslipidemia conditions. Histopathological examination indicated that the STZ-lesioned pancreas tissue in PR-administrated mice was effectively alleviated. Meanwhile, intrapancreatic protein levels of insulin receptor substrate-1 (IRS-1) and insulin-like growth factor-1 (IGF-1) were up-regulated, respectively. On the other hand, endogenous mRNA levels of skeletal muscle insulin receptor (InsR) and peroxisome proliferators-activated receptor alpha (PPARalpha) were increased after administration of PR. Taken together, these findings reveal that puerarin effectively exerts the hypoglycemic and hypolipemic roles, which its potential anti-diabetic activity is associated with elevating insulin expression and maintaining metabolic homoeostasis in STZ diabetogenic mice. PMID- 23927878 TI - Similarities in lindane induced alteration in cytochrome P450s and associated signaling events in peripheral blood lymphocytes and brain. AB - Studies were initiated to investigate the similarities in alterations in cytochrome P450s (CYPs) and associated signaling events in brain and peripheral blood lymphocytes (PBL) induced by lindane, an organochlorine pesticide. Adult male albino wistar rats were treated orally with different doses (2.5- or 5.0- or 10- or 15 mg/kg/body weight) of lindane daily for 4 days. In another experiment, the treatment of low dose (2.5mg/kg) of lindane was continued for 15- and 21 days. A dose- and time-dependent increase was observed in the activity of CYP dependent enzymes in brain microsomes and PBL isolated from the treated rats. However, the magnitude of induction was several folds less in PBL. As observed in brain, RT-PCR and Western immunoblotting demonstrated that increase in CYP enzymes in PBL is due to the increase in the mRNA expression of specific CYP isoenzymes. Similarities were also observed in activation of ERK and JNK MAP kinases and c-jun in PBL or brain isolated from rats treated with lindane. Similarities in the induction of CYPs and activation of MAP kinases in PBL and brain suggest that CYP expression profiles in PBL could be used for monitoring the exposure and toxicity of environmental chemicals. PMID- 23927879 TI - Suppression of T-cell activation in vitro and in vivo by cordycepin from Cordyceps militaris. AB - BACKGROUND: In addition to achieving a balance between the positive (controlling rejection) and the negative (infection and malignancy) aspects of drug-induced immunodeficiency, new immunosuppressive combinations must address the issue of nonimmune drug toxicity that may be dose limiting. Cordycepin is a type of adenosine analog extracted from Cordyceps militaris. In the present study, we investigated its immunosuppressive effect on T cell both in vitro and in vivo. METHODS: We evaluated the effects of cordycepin on concanavalin A-induced production of immune mediators in mouse splenocyte by enzyme-linked immunosorbent assay and flow cytometry. Furthermore, using Western blotting, we studied signal transduction mechanisms to determine how cordycepin inhibited T-cell activation in purified mouse T lymphocytes. To confirm the immunosuppressive activity of cordycepin in vivo, we induced the T cell-mediated delayed-type hypersensitivity reaction in a 2,4-dinitro-1-fluorobenzene-induced mouse model. RESULTS: The in vitro results showed that cordycepin markedly suppressed concanavalin A-induced splenocyte proliferation, Th1 and Th2 cytokine production, and the ratio of CD4(+)-to-CD8(+) T cells. The administration of cordycepin in vivo markedly suppressed the T cell-mediated delayed-type hypersensitivity reaction. The data revealed that cordycepin effectively shocked the nuclear factor kappa B and nuclear factor of activated T cells 2 signal transduction pathways but had no effect on the mitogen activated protein kinase signal transduction pathway. CONCLUSIONS: These observations indicated that cordycepin has a potential role in downregulating the immune system and could be developed as a useful immunosuppressive agent for treating undesired immune responses. PMID- 23927880 TI - Long-term ventilation tubes: for how long should they be used? PMID- 23927882 TI - Usefulness of immunohistochemistry for the detection of the BRAF V600E mutation in Japanese lung adenocarcinoma. AB - PURPOSE: Mutations in components of the mitogen-activated protein kinase (MAPK) cascade may be a new candidate for target for lung cancer. The usefulness of immunohistochemistry (IHC) as a new approach for the detection of BRAF V600E in cancer patients has been recently reported. METHODS: To increase the sensitivity, we modified BRAF V600E expression detection assay by IHC using mutation specific antibody. From the screening step, we found a novel 599 insertion T BRAF mutation in lung adenocarcinoma. In this study included 26 surgically removed cases with EGFR, Kras, erbB2, EML4-ALK and KIF5B-RET wild-type (wt) lung adenocarcinomas, including 7 BRAF mutants (5 V600E, 1 N581I, and 1 novel 599 insertion T mutation) analyzed by DNA sequencing. Detection of the BRAF V600E mutation was carried out by the Dako EnVisionTM FLEX detection system using the VE1 clone antibody and compared with the results of direct sequencing. RESULTS: The autostainer IHC VE1 assay was positive in 5 of 5 (100%) BRAF V600E-mutated tumors and negative in 20 of 21 (95.2%) BRAF non-V600E tumors, except for a novel 599 insertion T case. CONCLUSION: IHC using the VE1 clone and FLEX linker is a specific method for the detection BRAF V600E and may be an alternative to molecular biology for the detection of mutations in lung adenocarcinomas. This method might be useful for screening to use molecular target therapy for lung adenocarcinomas. PMID- 23927883 TI - EGFR mutation analysis in sputum of lung cancer patients: a multitechnique study. AB - OBJECTIVES: Epidermal growth factor receptor (EGFR) mutations have been identified in lung adenocarcinomas and are associated with high response chance to EGFR tyrosine kinase inhibitors. EGFR mutations can be detected in tumour tissue, cytology specimens and blood from lung cancer patients. Thus far, EGFR mutation analysis has not been systematically demonstrated for sputum samples. The aim of the present study was to determine whether EGFR mutation analysis is attainable on sputum samples, employing different assays in a multicenter study. MATERIALS AND METHODS: Sputum DNA from 10 lung cancer patients with confirmed EGFR mutation in their tumour tissue, 10 lung cancer patients without evidence of an EGFR mutation, and 10 patients with chronic obstructive pulmonary disease (COPD) was used for mutation analysis by Cycleave PCR, COLD-PCR, PangaeaBiotech SL Technology (PST), and High Resolution Melting, respectively. Targeted resequencing (TruSeq Amplicon Cancer Panel) and droplet digital PCR were additionally performed on the 10 samples with EGFR mutation. RESULTS: Dependent on the assay, EGFR mutations could be detected in 30-50% of the sputum samples of patients with EGFR mutations. The different techniques revealed consistent results, with slightly higher sensitivity for PST. Neither the lung cancer patients without EGFR mutation nor the COPD controls tested positive for EGFR mutations in their sputum samples, indicating high clinical specificity of all assays. CONCLUSION: EGFR mutations can be detected in sputum samples from patients with EGFR-mutated non-small cell lung cancer, which may replace biopsy procedure for some patients. PMID- 23927881 TI - Biomimetic remineralization of dentin. AB - OBJECTIVES: Remineralization of demineralized dentin is important for improving dentin bonding stability and controlling primary and secondary caries. Nevertheless, conventional dentin remineralization strategy is not suitable for remineralizing completely demineralized dentin within hybrid layers created by etch-and-rinse and moderately aggressive self-etch adhesive systems, or the superficial part of a caries-affected dentin lesion left behind after minimally invasive caries removal. Biomimetic remineralization represents a different approach to this problem by attempting to backfill the demineralized dentin collagen with liquid-like amorphous calcium phosphate nanoprecursor particles that are stabilized by biomimetic analogs of noncollagenous proteins. METHODS: This paper reviewed the changing concepts in calcium phosphate mineralization of fibrillar collagen, including the recently discovered, non-classical particle based crystallization concept, formation of polymer-induced liquid-precursors (PILP), experimental collagen models for mineralization, and the need for using phosphate-containing biomimetic analogs for biomimetic mineralization of collagen. Published work on the remineralization of resin-dentin bonds and artificial caries-like lesions by various research groups was then reviewed. Finally, the problems and progress associated with the translation of a scientifically sound concept into a clinically applicable approach are discussed. RESULTS AND SIGNIFICANCE: The particle-based biomimetic remineralization strategy based on the PILP process demonstrates great potential in remineralizing faulty hybrid layers or caries-like dentin. Based on this concept, research in the development of more clinically feasible dentin remineralization strategy, such as incorporating poly(anionic) acid-stabilized amorphous calcium phosphate nanoprecursor-containing mesoporous silica nanofillers in dentin adhesives, may provide a promising strategy for increasing of the durability of resin-dentin bonding and remineralizing caries-affected dentin. PMID- 23927884 TI - Phase II study of oral S-1 plus cisplatin with bevacizumab for advanced non squamous non-small cell lung cancer. AB - BACKGROUND: We conducted a phase II study to evaluate the efficacy and safety of S-1 plus cisplatin with bevacizumab followed by maintenance bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients received S-1 plus cisplatin with bevacizumab. S-1 (80 mg/m(2)) was administered orally twice daily for 14 days, cisplatin (60 mg/m(2)) on day 1, and bevacizumab (15 mg/kg) on day 1 and every 3 weeks for 4-6 cycles. Patients with an objective response or stable disease received maintenance bevacizumab every 3 weeks until disease progression. RESULTS: Thirty patients were enrolled in this study. The median number of chemotherapy was four (range, 1-6 cycles), and the median number of bevacizumab alone was three (range, 1-31 cycles). The grade 3/4 toxicities were neutropaenia (23%), thrombocytopaenia (10%), febrile neutropaenia (3%), hypertension (17%), pneumonia (7%), and bowel perforation (3%). The objective response rate was 71% (95% CI, 55-88%) for a disease control rate of 100%. The median progression-free and overall survival times were 7.0 months and 20.0 months, respectively. CONCLUSIONS: S-1 plus cisplatin with bevacizumab is an active and well-tolerated regimen in patients with chemotherapy-naive non-squamous NSCLC. PMID- 23927885 TI - Adequacy of CT-guided biopsies with histomolecular subtyping of pulmonary adenocarcinomas: influence of ATS/ERS/IASLC guidelines. AB - INTRODUCTION: As metastatic pulmonary adenocarcinomas are routinely investigated for EGFR, KRAS, and ALK mutations/rearrangement, adequacy of CT-guided trans thoracic needle biopsies (TTNB) needs to be evaluated in respect with the 2011 ATS/ERS/IASLC guidelines. METHODS: Two series of consecutive TTNB with 18-gauge needles performed before and after the publication of the ATS/ERS/IASLC guidelines, were retrospectively compared regarding their adequacy for histological sub-typing and EGFR/KRAS mutations and ALK rearrangement testing; the first series included 43 TTNB collected from January 2010 to February 2011, and the second one 48 TTNB collected from March 2011 to December 2012. RESULTS: 28 women and 63 men were included; the 2 groups were comparable in age, in mean size of lesions (32.5 mm), and distance of the lesion from the pleura. By comparing the first to the second series, the number of biopsies increased from 1.6 to 1.85, their mean length increased from 10.9 to 12.5mm, and the mean number of stainings (TTF1, P63, CK5-6, mucins) per biopsy decreased from 2.6 to 1. Mean tumor cell percentage was 42%, mean total DNA extracted increased from 2.7 to 3.8 MUg. In the first series, 85% of TTNB allowed EGFR exons 19 and 21 and KRAS mutations pyrosequencing and 72% additional EGFR exons 18 and 20 mutation analyses, versus 98% and 92% in the second. CONCLUSIONS: With respect to ATS/ERS/IASLC guidelines, radiologists, biologists and pathologists have improved their practice; accordingly, CT-guided TTNB enable a precise histological sub typing and provide sufficient DNA amount for genetic analyses. PMID- 23927886 TI - JERM model of care: an in-principle model for dental health policy. AB - Oral diseases are the most prevalent conditions in the community. Their economic burden is high and their impact on quality of life is profound. There is an increasing body of evidence indicating that oral diseases have wider implications beyond the confines of the mouth. The importance of oral health has not been unnoticed by the government. The Commonwealth (Federal) government under the Howard-led Coalition in 2004 had broken tradition by placing dentistry in its universal health insurance scheme, Medicare. Known as the Chronic Disease Dental Scheme (CDDS), the program aimed to manage patients with chronic conditions as part of the Enhanced Primary Care initiative. This scheme was a landmark policy for several reasons. Besides being the first major dental policy under Medicare, the program proved to be the most expensive and controversial. Unfortunately, cost containment and problems with service provision led to its cessation in 2012 by the Gillard Labor Government. Despite being seen as a failure, the CDDS provided a unique opportunity to assess national policy in practice. By analysing the policy-relevant effects of the CDDS, important lessons can be learnt for policy development. This paper discusses these lessons and has formulated a set of principles recommended for effective oral health policy. The JERM model represents the principles of a justified, economical and research-based model of care. PMID- 23927887 TI - Predicting participation restriction in community-dwelling older men: the Concord Health and Ageing in Men Project. AB - BACKGROUND: participation restriction, defined as 'problems an individual may experience in involvement in life situations' (e.g. work and leisure), reflects difficulty functioning at a societal level and is a key component of disability. Our objective was to describe changes in participation in older men over a 2-year period and to identify baseline variables associated with participation and change in participation over the 2-year period. METHODS: one thousand and three hundred and twenty-seven community-dwelling men aged 70 years or over who completed the baseline and 2-year follow-up phases of the Concord Health and Ageing in Men Project, a population-based cohort study in Sydney, Australia, were studied. Participation restriction and a range of other variables were measured using self-report and performance measures. Regression analyses were conducted to examine factors associated with participation and change in participation. RESULTS: over the 2-year period, participation in life roles deteriorated in 47.3% (627/1,327) of men, stayed the same in 20.7% (275/1,327) and improved in the remainder (32.0%). Overall, there was a significant deterioration in participation (P < 0.001). Reduced participation at 2-year follow-up was significantly associated with the following baseline factors: age, more comorbidities, mild cognitive impairment or dementia, lower mood, weakness, slower gait, worse activities of daily living performance, driving and baseline participation score. These variables explained 56% of the variance in participation at 2 years. CONCLUSION: participation in life roles worsened over a 2-year period in some community-dwelling older men. A number of associated factors were identified, which may provide targets for intervention to improve participation among older men. PMID- 23927888 TI - Inappropriate prescribing in older fallers presenting to an Irish emergency department. AB - BACKGROUND: certain medications increase falls risk in older people. OBJECTIVE: to assess if prescribing modification occurs in older falls presenting to an emergency department (ED). DESIGN: before-and-after design: presentation to ED with a fall as the index event. SUBJECTS: over 70's who presented to ED with a fall over a 4-year period. METHODS: dispensed medication in the 12 months pre- and post-fall was identified using a primary care reimbursement services pharmacy claims database. Screening Tool of Older Person's PIP (STOPP) and Beers prescribing criteria were applied to identify potentially inappropriate prescribing (PIP). Polypharmacy was defined as four or more regular medicines. Psychotropic medication was identified using the WHO Anatomical Therapeutic Chemical classification system. Changes in prescribing were compared using McNemar's test (significance P < 0.05). RESULTS: One thousand sixteen patients were eligible for analysis; 53.1% had at least one STOPP criteria pre-fall with no change post-fall (53.7%, P = 0.64). Beers criteria were identified in 44.0% pre-fall, with no change post-fall (41.5%, P = 0.125). The most significant individual indicators to change were neuroleptics, which decreased from 17.5 to 14.7% (P = 0.02) and long-acting benzodiazepines decreased from 10.7 to 8.6% (P = 0.005). Polypharmacy was observed in 63% and was strongly predictive of PIP, OR 4.0 (95% CI 3.0, 5.32). A high prevalence of psychotropic medication was identified pre-fall: anxiolytics (15.7%), antidepressants (26%), hypnosedatives (30%). New initiation of anxiolytics and hypnosedatives occurred in 9-15%, respectively, post-fall. CONCLUSION: a significant prevalence of PIP was observed in older fallers presenting to the ED. No substantial improvements in PIP occurred in the 12 months post-fall, suggesting the need for focused intervention studies to be undertaken in this area. PMID- 23927889 TI - Interpersonal therapy with parenting enhancement does not reduce depression symptoms in low-income mothers compared with control. PMID- 23927890 TI - Cumulative radiation dose in patients with hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations. AB - PURPOSE: To determine the cumulative effective dose (CED) of radiation from medical imaging and intervention in patients with hereditary hemorrhagic telangiectasia (HHT) who have pulmonary arteriovenous malformations and to identify clinical factors associated with exposure to high levels of radiation. METHODS: All patients with at least 1 pulmonary arteriovenous malformation were identified from the dedicated patient database of a tertiary HHT referral centre. Computerized imaging and electronic patient records were systematically examined to identify all imaging studies performed from 1989-2010. The effective dose was determined for each study, and CED was calculated retrospectively. RESULTS: Among 246 patients (mean age, 53 years; 62.2% women) with a total of 2065 patient years, 3309 procedures that involved ionizing radiation were performed. CED ranged from 0.2-307.6 mSv, with a mean of 51.7 mSv. CED exceeded 100 mSv in 26 patients (11%). Interventional procedures and computed tomography (CT) were the greatest contributors, which accounted for 51% and 46% of the total CED, respectively. Factors associated with high cumulative exposure were epistaxis (odds ratio 2.7 [95% confidence interval, 1.1-6.3]; P = .02), HHT-related gastrointestinal bleeding (odds ratio 2.0 [95% confidence interval, 1.0-3.8]; P = .04) and number of patient-years (P < .0001). CONCLUSIONS: Patients with HHT are exposed to a significant cumulative radiation dose from diagnostic and therapeutic interventions. Identifiable subsets of patients are at increased risk. A proportion of patients receive doses at levels that are associated with harm. Imaging indications and doses should be optimized to reduce radiation exposure in this population. PMID- 23927891 TI - Absorption of resveratrol by vascular endothelial cells through passive diffusion and an SGLT1-mediated pathway. AB - Resveratrol is a natural polyphenol that exerts potent effects to suppress atherosclerosis. However, its low concentration in plasma has placed this role in doubt. Thus, resveratrol effects might be dependent on its transport into vascular endothelium, a question not previously addressed in spite of its obvious and fundamental importance. Via high-performance liquid chromatography and liquid chromatography/mass spectrometry, we found that resveratrol was absorbed by human umbilical vein endothelial cells in a temperature-, concentration- and time dependent manner, suggesting the involvement of passive diffusion and active transport. As determined by confocal laser scanning microscopy, resveratrol primarily distributed throughout the cytoplasm. Furthermore, resveratrol absorption was modulated by serum proteins and sodium-dependent glucose transporter 1 (SGLT1) yet inhibited by glucose (an SGLT1 substrate) and phlorizin (an SGLT1 selective inhibitor), as well as SGLT1 siRNA transfection. Additionally, Sprague-Dawley rats were intragastrically administrated with 100mg/kg of resveratrol and the concentration of resveratrol in blood vessels declined more slowly up to 24h compared to that in the blood. Our results suggested that resveratrol uptake by vascular endothelial cells involved both passive diffusion and an SGLT1-mediated process, at least partially. Moreover, the intracellular resveratrol pool may be more important than the serum level in vivo. These provide new insights into the cardiovascular benefits of resveratrol. PMID- 23927892 TI - The role of macrophage class a scavenger receptors in a laser-induced murine choroidal neovascularization model. AB - PURPOSE: Laser-induced choroidal neovascularization (CNV) is a widely used model to mimic many features of CNV resulting from wet AMD. Macrophages have been implicated in the pathogenesis of AMD. Class A scavenger receptors, scavenger receptor-A (SR-A) and macrophage receptor with collagenous domain (MARCO), are expressed on macrophages and are associated with macrophage function. The goal of this study is to examine the role of macrophage scavenger receptors in immune cell recruitment and the formation of CNV. METHODS: Laser photocoagulation was performed in wild-type and knockout mice with deletion of SR-A (SR-A(-/-)), MARCO (MARCO(-/-)), or both SR-A and MARCO double knockout (DKO). Immune cell recruitment at different time points and CNV lesions at 14 days after laser treatment were evaluated through immunostaining and confocal microscopy. Microarray analysis was performed in eyes 1 day after laser injury. RESULTS: Wild type eyes showed higher chemokine/receptor expression compared with knockout eyes after laser injury. Scavenger receptor deficiency markedly impaired the recruitment of neutrophils and macrophages to CNV lesions at 1- and 3-days post laser injury, respectively. Significantly reduced CNV volumes were found in the eyes from scavenger receptor knockout mice compared with wild-type mice. CONCLUSIONS: The deficiency of scavenger receptors impairs the formation of CNV and immune cell recruitment. Our findings suggest a potential role for scavenger receptors in contributing to CNV formation and inflammation in AMD. PMID- 23927893 TI - Influence of shape and gradient refractive index in the accommodative changes of spherical aberration in nonhuman primate crystalline lenses. AB - PURPOSE: To estimate changes in surface shape and gradient refractive index (GRIN) profile in primate lenses as a function of accommodation. To quantify the contribution of surface shape and GRIN to spherical aberration changes with accommodation. METHODS: Crystalline lenses from 15 cynomolgus monkeys were studied in vitro under different levels of accommodation produced by a stretching system. Lens shape was obtained from optical coherence tomography (OCT) cross sectional images. The GRIN was reconstructed with a search algorithm using the optical path measured from OCT images and the measured back focal length. The spherical aberration of the lens was estimated as a function of accommodation using the reconstructed GRIN and a homogeneous refractive index. RESULTS: The lens anterior and posterior radii of curvature decreased with increasing lens power. Both surfaces exhibited negative asphericities in the unaccommodated state. The anterior surface conic constant shifted toward less negative values with accommodation, while the value of the posterior remained constant. GRIN parameters remained constant with accommodation. The lens spherical aberration with GRIN distribution was negative and higher in magnitude than that with a homogeneous equivalent refractive index (by 29% and 53% in the unaccommodated and fully accommodated states, respectively). Spherical aberration with the equivalent refractive index shifted with accommodation toward negative values ( 0.070 MUm/diopter [D]), but the reconstructed GRIN shifted it farther (-0.124 MUm/D). CONCLUSIONS: When compared with the lens with the homogeneous equivalent refractive index, the reconstructed GRIN lens has more negative spherical aberration and a larger shift toward more negative values with accommodation. PMID- 23927895 TI - Iron acquisition in the human fungal pathogen Cryptococcus neoformans. AB - Iron sequestration by the vertebrate host is considered an efficient defense mechanism against pathogenic microbes. However, this mechanism, so called nutritional immunity, is often overcome by the iron acquisition systems that have evolved in microbial pathogens. Numerous studies have been carried out to identify the key components of these systems and to understand their underlying mechanisms, including recent investigations in the basidiomycete fungal pathogen Cryptococcus neoformans. Iron acquisition is essential for the survival and pathogenesis of this fungus within vertebrate hosts. Growing evidence suggests that the fungus is able to utilize several different iron sources available in the host, and that the intracellular or extracellular localization of the pathogen influences its iron acquisition strategy. Herein, we review current findings on the components and regulatory elements of the iron acquisition systems in C. neoformans. PMID- 23927894 TI - The metabolic roles of the endosymbiotic organelles of Toxoplasma and Plasmodium spp. AB - The apicoplast and the mitochondrion of Apicomplexa cooperate in providing essential metabolites. Their co-evolution during the ancestral acquisition of a plastid and subsequent loss of photosynthesis resulted in divergent metabolic pathways compared with mammals and plants. This is most evident in their chimerical haem synthesis pathway. Toxoplasma and Plasmodium mitochondria operate canonical tricarboxylic acid (TCA) cycles and electron transport chains, although the roles differ between Toxoplasma tachyzoites and Plasmodium erythrocytic stages. Glutamine catabolism provides TCA intermediates in both parasites. Isoprenoid precursor synthesis is the only essential role of the apicoplast in Plasmodium erythrocytic stages. An apicoplast-located fatty acid synthesis is dispensable in these stages, which instead predominantly salvage fatty acids, while in Plasmodium liver stages and in Toxoplasma tachyzoites fatty acid synthesis is an essential role of the plastid. PMID- 23927896 TI - Virus diversity and evolution. PMID- 23927897 TI - Coexistence of structured populations with size-based prey selection. AB - Species with a large adult-offspring size ratio and a preferred predator-prey mass ratio undergo ontogenetic trophic niche shift(s) throughout life. Trophic interactions between such species vary throughout life, resulting in different species-level interaction motifs depending on the maximum adult sizes and population size distributions. We explore the assembly and potential for coexistence of small communities where all species experience ontogenetic trophic niche shifts. The life-history of each species is described by a physiologically structured model and species identity is characterised by the trait: size at maturation. We show that a single species can exist in two different states: a 'resource driven state' and a 'cannibalistic state' with a large scope for emergent Allee effects and bistable states. Two species can coexist in two different configurations: in a 'competitive coexistence' state when the ratio between sizes at maturation of the two species is less than a predator-prey mass ratio and the resource level is low to intermediate, or in a 'trophic ladder' state if the ratio of sizes at maturation is larger than the predator-prey mass ratio at all resource levels. While there is a large scope for coexistence of two species, the scope for coexistence of three species is limited and we conclude that further trait differentiation is required for coexistence of more species rich size-structured communities. PMID- 23927898 TI - Effects of temperature and in-office bleaching agents on surface and subsurface properties of aesthetic restorative materials. AB - OBJECTIVES: To investigate the effects of in-office bleaching agents on surface and subsurface properties of dental materials at different environmental temperatures. METHODS: Four composite resins, a compomer, a conventional glass ionomer cement (CGIC), and an industrially sintered ceramic material were evaluated in the present study. Four groups of each material (n=10) were treated: bleaching with 40% hydrogen peroxide at 25 degrees C and 37 degrees C, stored in artificial saliva at 25 degrees C and 37 degrees C. The specimens from bleaching groups were bleached for two sessions, each of two 20 min application, at respective temperatures. After bleaching, the surface and subsurface (0.1-0.5mm) microhardness were evaluated using a Vickers microhardness tester. The substance loss was determined by surface profilometry. The data were statistically analyzed with ANOVA and the Tukey's post hoc test. RESULTS: All materials were found to have surface softening after bleaching, and bleaching effects on surface micorhardness increased at 37 degrees C compared with 25 degrees C, except for the ceramic. After being bleached at 37 degrees C, the microhardness values of flowable composite resin significantly reduced at a depth of 0.1mm compared with control specimen stored at 37 degrees C. No significant difference was found between the control and bleached specimens with respect to substance loss for any of the materials. CONCLUSION: The influence of environmental temperature on the in-office bleaching effects on surface and subsurface microhardness of dental materials was material-dependent. However, no substance loss was detected due to the tested bleaching regimen. CLINICAL SIGNIFICANCE: Environmental temperature should be considered when evaluating the possible bleaching effects on restorative materials. Moreover, dentists should be aware that there might be a need for polishing of restorative materials in clinical situations in which restorations are accidentally exposed to bleaching gels. PMID- 23927899 TI - Kidney transplant options for the diabetic patient. AB - For patients with diabetes and progressive chronic kidney disease, kidney transplantation is the optimal mode of renal replacement therapy, with or without a pancreas transplant. Additional benefits of pancreas transplant have become increasingly apparent due to advances in surgical outcomes and immunosuppression, and may be reasonably considered even in selected patients with type 2 diabetes. In general, pancreas transplantation is associated with long-term survival advantages despite an increased short-term morbidity and mortality risk. This is true with simultaneous pancreas kidney transplantation or pancreas after kidney transplantation compared to kidney transplantation alone, regardless of kidney donor status (living or deceased). Individual patient preferences, comorbidities, and expected waiting time influence selection of transplant modality, rather than a clear survival benefit of one strategy versus the other. In selected patients with type 2 diabetes, recent outcomes data support cautious utilization of simultaneous pancreas kidney transplantation when a living kidney donor transplant is not an option. The purpose of this review is to summarize current data regarding kidney and pancreas transplant treatment options in patients with both type 1 and 2 diabetes and the influence of current organ allocation policies to better understand the advantages and disadvantages of each of these strategies. PMID- 23927900 TI - MEG-based decoding of the spatiotemporal dynamics of visual category perception. AB - Visual processing is a complex task which is best investigated using sensitive multivariate analysis methods that can capture representation-specific brain activity over both time and space. In this study, we applied a multivariate decoding algorithm to MEG data of subjects engaged in passive viewing of images of faces, scenes, bodies and tools. We used reconstructed source-space time courses as input to the algorithm in order to localize brain regions involved in optimal image discrimination. Applying this method to the interval of 115 to 315 ms after stimulus onset, we show a focal localization of regression coefficients in the inferior occipital, middle occipital, and lingual gyrus that drive decoding of the different perceived image categories. Classifier accuracy was highest (over 90% correctly classified trials, compared to a chance level accuracy of 50%) when dissociating the perception of faces from perception of other object categories. Furthermore, we applied this method to each single time point to extract the temporal evolution of visual perception. This allowed for the detection of differences in visual category perception as early as 85 ms after stimulus onset. Furthermore, localizing the corresponding regression coefficients of each time point allowed us to capture the spatiotemporal dynamics of visual category perception. This revealed initial involvement of sources in the inferior occipital, inferior temporal and superior occipital gyrus. During sustained stimulation additional sources in the anterior inferior temporal gyrus and superior parietal gyrus became involved. We conclude that decoding of source space MEG data provides a suitable method to investigate the spatiotemporal dynamics of ongoing cognitive processing. PMID- 23927901 TI - Post-hoc power estimation for topological inference in fMRI. AB - When analyzing functional MRI data, several thresholding procedures are available to account for the huge number of volume units or features that are tested simultaneously. The main focus of these methods is to prevent an inflation of false positives. However, this comes with a serious decrease in power and leads to a problematic imbalance between type I and type II errors. In this paper, we show how estimating the number of activated peaks or clusters enables one to estimate post-hoc how powerful the selection procedure performs. This procedure can be used in real studies as a diagnostics tool, and raises awareness on how much activation is potentially missed. The method is evaluated and illustrated using simulations and a real data example. Our real data example illustrates the lack of power in current fMRI research. PMID- 23927902 TI - Brain structure is changed in congenital anosmia. AB - Olfactory function in healthy people correlates with structural features of both the olfactory bulb and higher order olfactory processing areas, but we do not yet know how congenital anosmia affects these latter structures. In order to examine this question closer, we acquired T1 weighted magnetic resonance images from 17 subjects with congenital anosmia and from 17 age- and sex-matched controls. We compared white and gray matter volumes as well as cortical thickness between both groups. We found subjects with congenital anosmia to exhibit larger gray matter volumes in the left entorhinal and piriform cortices. Further, they had thicker orbitofrontal cortices bilaterally. Their left piriform cortex was also thicker than that of controls. These findings are in contrast to those observed in acquired anosmia, where reduced olfactory function is associated with reduced volumes and thickness. However, they fit well with observations from other sensory systems, e.g., vision, where congenital sensory loss is associated with a thicker primary cortex. This finding has been attributed to reduced or absent synaptic pruning as a result of missing peripheral sensory input. Our findings suggest that similar mechanisms take place in the olfactory system. PMID- 23927903 TI - Automatic magnetic resonance spinal cord segmentation with topology constraints for variable fields of view. AB - Spinal cord segmentation is an important step in the analysis of neurological diseases such as multiple sclerosis. Several studies have shown correlations between disease progression and metrics relating to spinal cord atrophy and shape changes. Current practices primarily involve segmenting the spinal cord manually or semi-automatically, which can be inconsistent and time-consuming for large datasets. An automatic method that segments the spinal cord and cerebrospinal fluid from magnetic resonance images is presented. The method uses a deformable atlas and topology constraints to produce results that are robust to noise and artifacts. The method is designed to be easily extended to new data with different modalities, resolutions, and fields of view. Validation was performed on two distinct datasets. The first consists of magnetization transfer-prepared T2*-weighted gradient-echo MRI centered only on the cervical vertebrae (C1-C5). The second consists of T1-weighted MRI that covers both the cervical and portions of the thoracic vertebrae (C1-T4). Results were found to be highly accurate in comparison to manual segmentations. A pilot study was carried out to demonstrate the potential utility of this new method for research and clinical studies of multiple sclerosis. PMID- 23927905 TI - Recursive calibration of the fiber response function for spherical deconvolution of diffusion MRI data. AB - There is accumulating evidence that at current acquisition resolutions for diffusion-weighted (DW) MRI, the vast majority of white matter voxels contains "crossing fibers", referring to complex fiber configurations in which multiple and distinctly differently oriented fiber populations exist. Spherical deconvolution based techniques are appealing to characterize this DW intra-voxel signal heterogeneity, as they provide a balanced trade-off between constraints on the required hardware performance and acquisition time on the one hand, and the reliability of the reconstructed fiber orientation distribution function (fODF) on the other hand. Recent findings, however, suggest that an inaccurate calibration of the response function (RF), which represents the DW signal profile of a single fiber orientation, can lead to the detection of spurious fODF peaks which, in turn, can have a severe impact on tractography results. Currently, the computation of this RF is either model-based or estimated from selected voxels that have a fractional anisotropy (FA) value above a predefined threshold. For both approaches, however, there are user-defined settings that affect the RF and, consequently, fODF estimation and tractography. Moreover, these settings still rely on the second-rank diffusion tensor, which may not be the appropriate model, especially at high b-values. In this work, we circumvent these issues for RF calibration by excluding "crossing fibers" voxels in a recursive framework. Our approach is evaluated with simulations and applied to in vivo and ex vivo data sets with different acquisition settings. The results demonstrate that with the proposed method the RF can be calibrated in a robust and automated way without needing to define ad-hoc FA threshold settings. Our framework facilitates the use of spherical deconvolution approaches in data sets in which it is not straightforward to define RF settings a priori. PMID- 23927904 TI - Identifying the default mode network structure using dynamic causal modeling on resting-state functional magnetic resonance imaging. AB - The default mode network is part of the brain structure that shows higher neural activity and energy consumption when one is at rest. The key regions in the default mode network are highly interconnected as conveyed by both the white matter fiber tracing and the synchrony of resting-state functional magnetic resonance imaging signals. However, the causal information flow within the default mode network is still poorly understood. The current study used the dynamic causal modeling on a resting-state fMRI data set to identify the network structure underlying the default mode network. The endogenous brain fluctuations were explicitly modeled by Fourier series at the low frequency band of 0.01 0.08Hz, and those Fourier series were set as driving inputs of the DCM models. Model comparison procedures favored a model wherein the MPFC sends information to the PCC and the bilateral inferior parietal lobule sends information to both the PCC and MPFC. Further analyses provide evidence that the endogenous connectivity might be higher in the right hemisphere than in the left hemisphere. These data provided insight into the functions of each node in the DMN, and also validate the usage of DCM on resting-state fMRI data. PMID- 23927906 TI - Intraoperative measurements of femoral anterior tangent (FAT) line for determining the rotational alignment of femoral component of total knee arthroplasty. AB - Previously, we reported using CT images that the anterior surface of the femur immediately proximal to the trochlea and its tangent line (femoral anterior tangent line; FAT line) could be used as a good index of the femoral rotation. In this study, we developed a jig that allowed us to measure the FAT line during surgery, and we examine the relation between preoperative and intraoperative measurement values. The results indicated that the average intraoperative measurement value of the 'surgical' FAT line was 9.8 degrees +/- 3.2 degrees internally rotated using surgical transepicondylar axis reference. This value significantly correlated to preoperative FAT line/clinical transepicondylar axis angle. These findings demonstrated that FAT line is a useful index for appropriate rotational alignment of femoral component, both before and during TKA. PMID- 23927907 TI - Oversized cups as a major risk factor of postoperative pain after total hip arthroplasty. AB - After total hip arthroplasty (THA) some patients have persistent postoperative pain (POP). Some of these POP are anterior and are caused by an anterior iliopsoas impingement (AIPI). We have hypothesized that oversized implanted cups could be responsible for POP and especially AIPI. We screened 237 patients who had a primary THA and compared the size difference (DeltaS) between the native femoral head and the implanted cup, in patients with and without POP. Median DeltaS was 2 mm [-6; 11 mm] and patients with POP had a significantly increased DeltaS (P < 0.0001). The threshold above which pain was significantly more frequent was DeltaS >= 6 mm. Odds ratio was 14.4 for POP and 26 for AIPI pain when DeltaS >= 6 mm. PMID- 23927908 TI - The effect of payer type on clinical outcomes in total knee arthroplasty. AB - This was a retrospective cohort analysis of 112 patients undergoing primary total knee arthroplasty, wherein baseline demographics, resource utilization, and outcomes were compared by insurance type: Medicaid, Medicare, or private. At the time of surgery, Medicaid patients were younger (P<.0001) and had lower preoperative Knee Society Scores than Medicare and private patients (P=.0125). Medicaid postoperative scores were lower than those of private patients (P=.0223). The magnitude of benefit received by Medicaid patients was similar to Medicare and private patients. Medicaid patients had a higher number of cancelled (P=.01) and missed (P=.0022) appointments relative to Medicare and private patients. Medicaid patients also had shorter average follow-up periods compared to private patients (P=.0003). Access to care and socioeconomic factors may be responsible for these findings. PMID- 23927909 TI - Celecoxib and heterotopic bone formation after total hip arthroplasty. AB - We assessed the effectiveness of celecoxib in the prevention of heterotopic ossification (HO) following primary total hip replacement (THR). We studied 170 consecutive THRs. Sixty-three patients received celecoxib after surgery (200mg twice/daily) for 28 days and 84 did not. HO was more common in non-celecoxib patients than in the celecoxib-group at 3, 6, and 12 months (P =0.005, 0.004 and 0.01, respectively). At 1 year, fewer celecoxib recipients had Brooker classes II or III. None of the celecoxib patients developed HO Brooker class IV, while 2% in the non-celecoxib group did. No patient discontinued treatment or had revision for aseptic loosening. A short course of celecoxib for pain aids in the prevention of HO after primary THR, and could be a useful and safe option that does not interfere with anticoagulation. PMID- 23927910 TI - Predictors of early complications of total shoulder arthroplasty. AB - The authors hypothesized that age, body mass index (BMI), and medical comorbidities (graded with the Charleson Comorbidiy index [CCI]) could be used to predict early complications after TSA. The authors performed a retrospective review of primary TSAs with a minimum of 90-day follow-up. One hundred twenty seven patients met the inclusion criteria. Complications occurred in 12 (9.4%) of patients. Major complications occurred in 1 patient (0.8%), medical in 8 (6.3%), and surgical in 4 (3.1%). CCI significantly correlated with complication rates and multivariate regression analysis demonstrated CCI to be the only significant determinant of overall complication rates (P = 0.005) and medical complication rates (P = 0.015). While BMI subgroup did not affect complication rates, transfusion rates, intra-operative blood loss, or operative time, our study may have been underpowered for this variable. PMID- 23927912 TI - Oral bisphosphonates for paediatric osteogenesis imperfecta? PMID- 23927911 TI - Does social isolation predict hospitalization and mortality among HIV+ and uninfected older veterans? AB - OBJECTIVES: To compare levels of social isolation in aging veterans with and without the human immunodeficiency virus (HIV) and determine associations with hospital admission and mortality. DESIGN: Longitudinal data analysis. SETTING: The Veterans Aging Cohort Study (VACS), at eight VA Medical Centers nationally. PARTICIPANTS: Veterans aged 55 and older enrolled in VACS from 2002 to 2008 (N = 1,836). MEASUREMENTS: A Social Isolation Score (SIS) was created using baseline survey responses about relationship status; number of friends and family and frequency of visits; and involvement in volunteer work, religious or self-help groups, and other community activities. Scores were compared according to age and HIV status, and multivariable regression was used to assess effects of SIS on hospital admission and all-cause mortality. RESULTS: Mean SIS was higher for HIV positive (HIV+) individuals, with increasing difference according to age (P = .01 for trend). Social isolation was also more prevalent for HIV+ (59%) than uninfected participants (51%, P < .001). In multivariable regression analysis of HIV+ and uninfected groups combined, adjusted for demographic and clinical features, isolation was independently associated with greater risk of incident hospitalization (hazard rate (HR) = 1.25, 95% confidence interval (CI) = 1.09 1.42) and risk of all-cause mortality (HR=1.28, 95% CI = 1.06-1.54). Risk estimates calculated for HIV+ and uninfected groups separately were not significantly different. CONCLUSION: Social isolation is associated with greater risk of hospitalization and death in HIV+ and uninfected older veterans. Despite similar effects in both groups, the population-level effect of social isolation may be greater in those who are HIV+ because of the higher prevalence of social isolation, particularly in the oldest individuals. PMID- 23927913 TI - Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease. METHODS: In this multicentre, randomised, parallel, double blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2.5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028. FINDINGS: Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16.3% in the risedronate group and 7.6% in the placebo group (difference 8.7%, 95% CI 5.7-11.7; p<0.0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0.0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. INTERPRETATION: Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. FUNDING: Alliance for Better Bone Health (Warner Chilcott and Sanofi). PMID- 23927914 TI - Genetics of dementia. AB - 25% of all people aged 55 years and older have a family history of dementia. For most, the family history is due to genetically complex disease, where many genetic variations of small effect interact to increase risk of dementia. The lifetime risk of dementia for these families is about 20%, compared with 10% in the general population. A small proportion of families have an autosomal dominant family history of early-onset dementia, which is often due to mendelian disease, caused by a mutation in one of the dementia genes. Each family member has a 50% chance of inheriting the mutation, which confers a lifetime dementia risk of over 95%. In this Review, we focus on the evidence for, and the approach to, genetic testing in Alzheimer's disease (APP, PSEN1, and PSEN2 genes), frontotemporal dementia (MAPT, GRN, C9ORF72, and other genes), and other familial dementias. We conclude by discussing the practical aspects of genetic counselling. PMID- 23927915 TI - The effect of purified condensed tannins of forage plants from Botswana on the free-living stages of gastrointestinal nematode parasites of livestock. AB - The effect of condensed tannins (CT) extracted from forage plants from Botswana on the free-living stages of a number of species of gastrointestinal nematode parasites derived from infected sheep were investigated using in vitro assays. Fresh samples of five different plants (Viscum rotundifolium, Viscum verrucosum, Tapinanthus oleifolius, Grewia flava and Ipomoea sinensis) were collected over two summers (February 2009 and 2010). Fractionation of each crude extract on a Sephadex LH-20 column yielded low molecular weight phenolics and CT-containing fractions. The effect of each purified CT fraction on parasites was evaluated using either egg hatch, larval development or larval migration inhibition assays. Three gastrointestinal nematode species (Haemonchus contortus, Trichostrongylus colubriformis and Teladorsagia circumcincta) derived from infected sheep were evaluated in the study. CT from V. rotundifolium and I. sinensis fractions from samples collected in 2009 and 2010 did not inhibit larval development. However, CT isolated from V. verrucosum, T. oleifolius and G. flava collected in 2009 completely inhibited the development of all parasite species. These CT fractions were more potent in inhibiting larval development of H. contortus than fractions from the same plant species collected in 2010. However, a slight effect on larval migration was observed with some CT extracts. The results suggest that CT extracts of some forage plants from Botswana have anti-parasitic properties in vitro, and that further research is required to determine any in vivo efficacy from feeding the plants to goats in a field situation. PMID- 23927916 TI - Combination of monoclonal antibodies improves immunohistochemical diagnosis of Neospora caninum. AB - Histological analysis is commonly used for a conclusive diagnosis of neosporosis. Immunohistochemistry (IHC) using monoclonal (mAb) and polyclonal (pAb) antibodies can improve diagnosis; however, the use of pAb may induce cross-reactivity with other related parasites. The aims of this study were to compare the performance of mAbs and their combinations with that of pAb in IHC and evaluate the usefulness of mAb to identify Neospora caninum infection in aborted bovine fetal tissues. For this purpose, mAbs targeting NcSRS2 (4.15.15) or NcGRA7 (4.11.5 and 1/24-12) and one pAb collected from a rabbit inoculated with N. caninum tachyzoites were tested by IHC. Artificial standardized tissue sections were prepared as positive controls using homogenized bovine brain spiked with cultured tachyzoites of N. caninum. The numbers of labeled parasites were counted in each positive control section. In addition, four equal proportional combinations of the mAbs were also analyzed in the IHC. Finally, the pAb and the best combination of mAbs obtained in the positive control experiments were tested with tissue sections of naturally-infected cattle. To confirm analytical specificity, mAbs and a pAb were tested with Toxoplasma gondii and Besnoitia besnoiti positive control slides and tissues sections from naturally infected cattle containing Sarcocystis spp. and B. besnoiti antigens. The mAb 4.15.15 detected 57% of the total parasites in sections while 4.11.5 and 1/24-12 were able to detect 49% and 41%, respectively. For the mAb combinations (I: 1/24-12+4.11.5, II: 1/24 12+4.15.15, III: 4.15.15+4.11.5, IV: 1/24-12+4.11.5+4.15.15), the detection capacity was 32.4%, 79.4%, 66.6% and 60.7% for each combination, respectively. The best mAb combination (1/24-12 and 4.15.15) and the pAb serum detected 100% (18/18) of naturally-infected animals. Sarcocystis spp. or B. besnoiti were not detected by mAb combinations in IHC, however the pAb cross-reacted with Sarcocystis spp. cysts. These results confirm the usefulness of mAb application in IHC to N. caninum. PMID- 23927917 TI - Characterization and differentiation of Italian Parma, San Daniele and Toscano dry-cured hams: a multi-disciplinary approach. AB - This study aimed at characterizing the sensory quality of Italian PDO dry-cured Parma, San Daniele and Toscano hams, applying a multi-disciplinary approach. Ham sensory profile as well as physico-chemical, aromatic, morphological and textural characteristics was investigated. There was a great difference between Toscano ham and Parma and San Daniele hams, which were more similar even though differentiated. Toscano ham showed higher scores for pork-meat odor, saltiness, dryness, fibrousness and hardness; accordingly, this ham was described by a high NaCl content and by high values of instrumental hardness, cohesiveness, gumminess and chewiness. Parma ham was characterized by a cured flavor, whereas San Daniele ham showed a wider fatty area and higher pH values. Parma and San Daniele hams were also described by higher values of sweetness, RGB color values and water activity. Sensory characteristics evaluated by trained assessors were correlated to instrumental measures, indicating that instrumental devices can be effectively applied for dry-cured ham characterization. PMID- 23927918 TI - Scale-up of the process to obtain functional ingredients based in plasma protein concentrates from porcine blood. AB - The feasibility of a scaled-up process to obtain two protein concentrates from porcine blood plasma, i.e. serum and albumin, for use as functional food ingredients was assessed. The process consisted of fractionating plasma proteins by salting out, concentrating and purifying fractions by means of membrane technology, and subsequently dehydrating through spray-drying. The fractionation process allowed a good isolation of the desired proteins, which were then concentrated and desalted in a tangential flow filtration (TFF) process combining ultra and diafiltration. Purification, pre-concentration and dehydration were successfully achieved. The functional properties of dehydrated serum and albumin were determined. As compared to the same hemoderivatives obtained by a lab-scale production system, serum maintained the gelling properties; albumin exhibited similar foaming properties; and both serum and albumin concentrates showed slightly improved emulsifying properties. PMID- 23927919 TI - Curing and diffusion coefficient study in pastirma, a Turkish traditional meat product. AB - Changes in water activity (a(w)), moisture and salt contents and salt effective diffusion coefficients (D(eff)) of pastirma samples during the curing process were determined. At the end of the curing stage, a(w) values decreased to 0.942. The average initial moisture content of the samples decreased from 74.56% to 66.64%, depending on the curing time and the average salt content increased to 15.65 g NaCl/100 g dry matter at the end of the 48-hour curing process. Pastirma samples were assumed the geometry of endless slices, and the analytical solution of Fick's second equation was used for determination of salt D(eff) values. Salt D(eff) values were found to vary between 1.49*10(-9)-4.08*10(-9) m(2)/s. PMID- 23927920 TI - Influence of on-farm production practices on sensory and technological quality characteristics of pork loin. AB - Quality of pork from pigs raised either traditionally (outdoor access or bedded settings with no sub-therapeutic antibiotics or growth promotants in feed) or conventionally (commercial indoor) was evaluated. Pork loins (m. longissimus thoracis et lumborum, LTL) from four hundred pigs from either traditional or conventional production systems (n=200) fed commercially formulated diets ad libitum were harvested at slaughter. Intramuscular crude fat content and lean color (L* and b*) values were significantly decreased in conventional pork loins. LTL from conventionally-raised pig carcasses showed increased (P<0.05) mean pH, moisture content and reduced cooking loss and shear force values and had increased tenderness and juiciness scores compared to those from traditionally raised pig carcasses. Results indicated that pork from conventionally raised pigs was superior to that from traditionally raised pigs in terms of tenderness and juiciness, suggesting that consumers may value pork from traditionally raised pigs on the basis of factors other than eating quality and appearance. PMID- 23927921 TI - Pre-rigor temperature and the relationship between lamb tenderisation, free water production, bound water and dry matter. AB - The M. longissimus from lambs electrically stimulated at 15 min post-mortem were removed after grading, wrapped in polythene film and held at 4 (n=6), 7 (n=6), 15 (n=6, n=8) and 35 degrees C (n=6), until rigor mortis then aged at 15 degrees C for 0, 4, 24 and 72 h post-rigor. Centrifuged free water increased exponentially, and bound water, dry matter and shear force decreased exponentially over time. Decreases in shear force and increases in free water were closely related (r(2)=0.52) and were unaffected by pre-rigor temperatures. PMID- 23927922 TI - The assembly and distribution in vivo of the Escherichia coli RNA degradosome. AB - We report an analysis in vivo of the RNA degradosome assembly of Escherichia coli. Employing fluorescence microscopy imaging and fluorescence energy transfer (FRET) measurements, we present evidence for in vivo pairwise interactions between RNase E-PNPase (polynucleotide phosphorylase), and RNase E-Enolase. These interactions are absent in a mutant strain with genomically encoded RNase E that lacks the C-terminal half, supporting the role of the carboxy-end domain as the scaffold for the degradosome. We also present evidence for in vivo proximity of Enolase-PNPase and Enolase-RhlB. The data support a model for the RNA degradosome (RNAD), in which the RNase E carboxy-end is proximal to PNPase, more distant to Enolase, and more than 10 nm from RhlB helicase. Our measurements were made in strains with mono-copy chromosomal fusions of the RNAD enzymes with fluorescent proteins, allowing measurement of the expression of the different proteins under different growth and stress conditions. PMID- 23927923 TI - Possible transmission of Candida albicans on an intensive care unit: genotype and temporal cluster analyses. AB - BACKGROUND: Nosocomial transmission of Candida spp. has not been fully explored and previous studies have shown conflicting results. AIM: To evaluate the possible nosocomial transmission of Candida spp. on an intensive care unit (ICU). METHODS: A prospective study was conducted for a period of 19 months, including all patients on our ICU with growth of Candida spp. from surveillance and directed cultures. Molecular typing with repetitive sequence-based polymerase chain reaction was used to define genotype relationships between the Candida albicans and Candida glabrata isolates. Candida isolates obtained from blood cultures taken from patients in our county outside the ICU were used as a reference. Temporal cluster analysis was performed to evaluate genotype distribution over time. FINDINGS: Seventy-seven patients with 78 ICU stays, representing 12% of all ICU stays, were found to harbour 180 isolates of Candida spp. Molecular typing revealed 27 C. albicans genotypes and 10 of C. glabrata. Possible clustering, indicated by overlapping stays of patients with indistinguishable candida genotypes, was observed on seven occasions with C. albicans and on two occasions with C. glabrata. Two C. albicans genotypes were found significantly more often in the ICU group compared with the reference group. Moreover, C. albicans genotypes isolated from more than one patient were significantly more often found in the ICU group. Temporal cluster analysis revealed a significantly increased number of pairs with indistinguishable genotypes at a 21-day interval, indicating clustering. CONCLUSION: This study indicates possible transmission of C. albicans between ICU patients based on genotyping and temporal cluster analysis. PMID- 23927924 TI - Summertime Bacillus cereus colonization of hospital newborns traced to contaminated, laundered linen. AB - BACKGROUND: Routine screening of premature newborns for haemolytic streptococci, Staphylococcus aureus and enteric Gram-negative bacteria done at birth using umbilical swabs identified clustering of babies colonized with Bacillus cereus in summers of 2009 and 2010 at a 400-bedded UK general hospital. AIM: To determine the source of this organism by focusing on the clinical environment. METHODS: Umbilical swab screening was extended to all newborns and the labour ward environment, including construction-related dust, was sampled for B. cereus. FINDINGS: During the summer of 2009, 65% of newborns had umbilical swabs which were culture positive for B. cereus. Blood agar and B. cereus selective agar impression plates of unused labour ward linen, and freshly received linen from the hospital's external laundry, gave mainly confluent growth of B. cereus in >85% of items sampled. In-use and exposed healthcare products including liquid handwashing agents, paper hand-towels, vaginal lubricants, labour ward dust and air were culture negative. Linen contamination and umbilical swab culture positivity both approached zero in autumn. B. cereus colonization of newborn umbilici recurred in summer 2010 and unused laundered linen was again found to be as contaminated. Washing linen at the laundry in a washer-extractor, with higher dilution than the continuous tunnel washer normally used, coincided with lowering of detectable B. cereus numbers in unused washed linen and no clustering in newborns the following summer (2011). CONCLUSION: Freshly laundered linen can be contaminated with B. cereus with subsequent spread and colonization of newborns. This contamination appears to be associated with low-dilution washing and high ambient temperatures. PMID- 23927926 TI - Special issue on "Toxins: from threats to benefits". PMID- 23927925 TI - Characteristics and outcome predictors of patients involved in an outbreak of Burkholderia cepacia complex. AB - A Burkholderia cepacia complex outbreak occurred among ventilated non-cystic fibrosis patients in an intensive care unit (ICU) in Italy: 33 colonized and 13 infected patients were included in a retrospective study aimed at investigating factors related to clinical infection and mortality. Demographic/clinical conditions and mortality did not vary significantly between colonized and infected patients, both groups showing high mortality rates compared with the overall ICU population and similar to that observed in patients with other infections. In multivariate regression analysis, disease severity (defined by the Simplified Acute Physiology Score II) and age were the only independent predictors of early mortality (odds ratio: 1.12; 95% confidence interval: 1.02 1.26; and 1.07; 1.01-1.15, respectively). PMID- 23927927 TI - Determinants of thoughts of death or suicide in depressed older persons. AB - BACKGROUND: In depressed persons, thoughts of death and suicide are assumed to represent different degrees of a construct: suicidality. However, this can be questioned in older persons facing physical and social losses. Thoughts of death in depressed older persons are hardly examined in the absence of suicidal ideation. Furthermore, most depression instruments do not discriminate suicidal ideation from thoughts of death only. We examined whether determinants of thoughts of death differ from determinants of suicidal ideation in late life depression. METHODS: Past month's thoughts of death and suicidal ideation were assessed with the Composite International Diagnostic Interview in 378 depressed older persons (>60 years of age). Multinomial logistic regression analyses adjusted for age and depression severity were used to identify socio-demographic, lifestyle, clinical and somatic determinants of past month's thoughts of death, and suicidal ideation. RESULTS: Compared with patients without thoughts of death or suicide (n = 267), patients reporting thoughts of death but no suicidal ideation (n = 74) were older (OR (95% confidence interval) = 1.04 (1.00-1.08)) and more severely depressed (OR = 1.06 (1.04-1.08)), whereas patients with suicidal ideation (n = 37) were also more severely depressed (OR = 1.09 (1.06 1.13)), but not older. This latter group was further characterized by more psychiatric comorbidity (dysthymia OR = 2.28 (1.08-4.85)), panic disorder (OR = 2.27 (1.00-518)), at-risk alcohol use (OR = 4.10 (1.42-11.90)), lifetime suicide attempts (OR = 3.37 (1.46-7.75)), loneliness (OR = 1.24 (1.07-1.43)), and recent life events (OR = 3.14 (1.48-6.67)). CONCLUSIONS: In depressed older persons thoughts of death and suicide differ in relevant demographic, social, and clinical characteristics, suggesting that the risks and consequences of the two conditions differ. PMID- 23927928 TI - Process development for recovery of copper and precious metals from waste printed circuit boards with emphasize on palladium and gold leaching and precipitation. AB - A novel hydrometallurgical process was proposed for selective recovery of Cu, Ag, Au and Pd from waste printed circuit boards (PCBs). More than 99% of copper content was dissolved by using two consecutive sulfuric acid leaching steps in the presence of H2O2 as oxidizing agents. The solid residue of 2nd leaching step was treated by acidic thiourea in the presence of ferric iron as oxidizing agent and 85.76% Au and 71.36% Ag dissolution was achieved. The precipitation of Au and Ag from acidic thiourea leachate was investigated by using different amounts of sodium borohydride (SBH) as a reducing agent. The leaching of Pd and remained gold from the solid reside of 3rd leaching step was performed in NaClO-HCl-H2O2 leaching system and the effect of different parameters was investigated. The leaching of Pd and specially Au increased by increasing the NaClO concentration up to 10V% and any further increasing the NaClO concentration has a negligible effect. The leaching of Pd and Au increased by increasing the HCl concentration from 2.5 to 5M. The leaching of Pd and Au were endothermic and raising the temperature had a positive effect on leaching efficiency. The kinetics of Pd leaching was quite fast and after 30min complete leaching of Pd was achieved, while the leaching of Au need a longer contact time. The best conditions for leaching of Pd and Au in NaClO-HCl-H2O2 leaching system were determined to be 5M HCl, 1V% H2O2, 10V% NaClO at 336K for 3h with a solid/liquid ratio of 1/10. 100% of Pd and Au of what was in the chloride leachate were precipitated by using 2g/L SBH. Finally, a process flow sheet for the recovery of Cu, Ag, Au and Pd from PCB was proposed. PMID- 23927929 TI - Research resource: loss of the steroid receptor coactivators confers neurobehavioral consequences. AB - Steroid receptor coactivators (SRCs) are important transcriptional modulators that regulate nuclear receptor and transcription factor activity to adjust transcriptional output to cellular demands. Highlighting their pleiotropic effects, dysfunction of the SRCs has been found in numerous pathologies including cancer, inflammation, and metabolic disorders. The SRC family is expressed strongly in the brain including the hippocampus, cortex, and hypothalamus. Studies focusing on the effect of SRC loss using congenic SRC knockout mice (SRC( /-)) are limited in number, yet strongly indicate that the SRCs play important roles in regulating reproductive behavior, development, and motor coordination. To better understand the unique functions of the SRCs, we performed a neurobehavioral test battery focusing on anxiety and exploratory behaviors, motor coordination, sensorimotor gating, and nociception in both male and female null mice and compared them with their wild-type (WT) littermates. Results from the test battery reveal a role for SRC1 in motor coordination. Additionally, we found that SRC1 regulates anxiety responses in SRC1(-/-) male and female mice, and nociception sensitivity in SRC1(-/-) male but not female mice. By comparison, SRC2 regulates anxiety response with SRC2(-/-) females showing decreased anxiety in novel environments, as well as increased exploratory behavior in the open field compared with WT littermates. Additionally, SRC2(-/-) males were shown to have deficits in sensorimotor gating. Loss of SRC3 also shows sex differences in anxiety and exploratory behaviors. In particular, SRC3(-/-) female mice have increased anxiety and reduced exploratory activity and impairments in prepulse inhibition, whereas SRC3(-/-) male mice show no significant behavioral differences. In both genders, ablation of SRC3 decreases nocifensive behaviors. Collectively, these resource data suggest that loss of the SRCs results in behavioral phenotypes, underscoring the importance of understanding both the general and gender-based activity of SRCs in the brain. PMID- 23927930 TI - Pid1 induces insulin resistance in both human and mouse skeletal muscle during obesity. AB - Obesity is associated with insulin resistance and abnormal peripheral tissue glucose uptake. However, the mechanisms that interfere with insulin signaling and glucose uptake in human skeletal muscle during obesity are not fully characterized. Using microarray, we have identified that the expression of Pid1 gene, which encodes for a protein that contains a phosphotyrosine-interacting domain, is increased in myoblasts established from overweight insulin-resistant individuals. Molecular analysis further validated that both Pid1 mRNA and protein levels are increased in cell culture models of insulin resistance. Consistent with these results, overexpression of phosphotyrosine interaction domain containing protein 1 (PID1) in human myoblasts resulted in reduced insulin signaling and glucose uptake, whereas knockdown of PID1 enhanced glucose uptake and insulin signaling in human myoblasts and improved the insulin sensitivity following palmitate-, TNF-alpha-, or myostatin-induced insulin resistance in human myoblasts. Furthermore, the number of mitochondria in myoblasts that ectopically express PID1 was significantly reduced. In addition to overweight humans, we find that Pid1 levels are also increased in all 3 peripheral tissues (liver, skeletal muscle, and adipose tissue) in mouse models of diet-induced obesity and insulin resistance. An in silico search for regulators of Pid1 expression revealed the presence of nuclear factor-kappaB (NF-kappaB) binding sites in the Pid1 promoter. Luciferase reporter assays and chromatin immunoprecipitation studies confirmed that NF-kappaB is sufficient to transcriptionally up-regulate the Pid1 promoter. Furthermore, we find that myostatin up-regulates Pid1 expression via an NF-kappaB signaling mechanism. Collectively these results indicate that Pid1 is a potent intracellular inhibitor of insulin signaling pathway during obesity in humans and mice. PMID- 23927931 TI - The Kruppel-like protein Gli-similar 3 (Glis3) functions as a key regulator of insulin transcription. AB - Transcriptional regulation of insulin in pancreatic beta-cells is mediated primarily through enhancer elements located within the 5' upstream regulatory region of the preproinsulin gene. Recently, the Kruppel-like transcription factor, Gli-similar 3 (Glis3), was shown to bind the insulin (INS) promoter and positively influence insulin transcription. In this report, we examined in detail the synergistic activation of insulin transcription by Glis3 with coregulators, CREB-binding protein (CBP)/p300, pancreatic and duodenal homeobox 1 (Pdx1), neuronal differentiation 1 (NeuroD1), and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA). Our data show that Glis3 expression, the binding of Glis3 to GlisBS, and its recruitment of CBP are required for optimal activation of the insulin promoter in pancreatic beta-cells not only by Glis3, but also by Pdx1, MafA, and NeuroD1. Mutations in the GlisBS or small interfering RNA directed knockdown of GLIS3 diminished insulin promoter activation by Pdx1, NeuroD1, and MafA, and neither Pdx1 nor MafA was able to stably associate with the insulin promoter when the GlisBS were mutated. In addition, a GlisBS mutation in the INS promoter implicated in the development of neonatal diabetes similarly abated activation by Pdx1, NeuroD1, and MafA that could be reversed by increased expression of exogenous Glis3. We therefore propose that recruitment of CBP/p300 by Glis3 provides a scaffold for the formation of a larger transcriptional regulatory complex that stabilizes the binding of Pdx1, NeuroD1, and MafA complexes to their respective binding sites within the insulin promoter. Taken together, these results indicate that Glis3 plays a pivotal role in the transcriptional regulation of insulin and may serve as an important therapeutic target for the treatment of diabetes. PMID- 23927932 TI - Transplantation of autologous endothelial progenitor cells in porous PLGA scaffolds create a microenvironment for the regeneration of hyaline cartilage in rabbits. AB - OBJECTIVE: Repairing articular cartilage is clinically challenging. We investigated a simple, effective and clinically feasible cell-based therapeutic approach using a poly(lactide-co-glycolide) (PLGA) scaffold seeded with autologous endothelial progenitor cells (EPC) to repair a full-thickness osteochondral defect in rabbits using a one-step surgery. METHODS: EPC obtained by purifying a small amount of peripheral blood from rabbits were seeded into a highly porous, biocompatible PLGA scaffold, namely, EPC-PLGA, and implanted into the osteochondral defect in the medial femoral condyle. Twenty two rabbits were randomized into one of three groups: the empty defect group (ED), the PLGA-only group or the EPC-PLGA group. The defect sites were evaluated 4 and 12 weeks after implantation. RESULTS: At the end of testing, only the EPC-PLGA group showed the development of new cartilage tissue with a smooth, transparent and integrated articular surface. Moreover, histological analysis showed obvious differences in cartilage regeneration. At week 4, the EPC-PLGA group showed considerably higher TGF-beta2 and TGF-beta3 expression, a greater amount of synthesized glycosaminoglycan (GAG) content, and a higher degree of osteochondral angiogenesis in repaired tissues. At week 12, the EPC-PLGA group showed enhanced hyaline cartilage regeneration with a normal columnar chondrocyte arrangement, higher SOX9 expression, and greater GAG and collagen type II (COLII) content. Moreover, the EPC-PLGA group showed organized osteochondral integration, the formation of vessel-rich tubercular bone and significantly higher bone volume per tissue volume and trabecular thickness (Tb.Th). CONCLUSION: The present EPC-PLGA cell delivery system generates a suitable in situ microenvironment for osteochondral regeneration without the supplement of exogenous growth factors. PMID- 23927933 TI - Prospective study of acute health effects in relation to exposure to cyanobacteria. AB - We conducted a study to investigate the relationship between exposure to cyanobacteria and microcystins and the incidence of symptoms in humans living in close proximity to lakes affected by cyanobacteria. The design was a prospective study of residents living around three lakes (Canada), one of which has a water treatment plant supplying potable water to local residents. Participants had to keep a daily journal of symptoms and record contact (full or limited) with the water body. Samples were collected to document cyanobacteria and microcystin concentrations. Symptoms potentially associated with cyanobacteria (gastrointestinal: 2 indices (GI1: diarrhea or abdominal pain or nausea or vomiting; GI2: diarrhea or vomiting or [nausea and fever] or [abdominal cramps and fever]); upper and lower respiratory tract; eye; ear; skin; muscle pain; headaches; mouth ulcers) were examined in relation with exposure to cyanobacteria and microcystin by using Poisson regression. Only gastrointestinal symptoms were associated with recreational contact. Globally, there was a significant increase in adjusted relative risk (RR) with higher cyanobacterial cell counts for GI2 (<20,000 cells/mL: RR=1.52, 95% CI=0.65-3.51; 20,000-100,000 cells/mL: RR=2.71, 95% CI=1.02-7.16; >100,000 cells/mL: RR=3.28, 95% CI=1.69-6.37, p-trend=0.001). In participants who received their drinking water supply from a plant whose source was contaminated by cyanobacteria, an increase in muscle pain (RR=5.16; 95% CI=2.93-9.07) and gastrointestinal (GI1: RR=3.87; 95% CI=1.62-9.21; GI2: RR=2.84; 95% CI=0.82-9.79), skin (RR=2.65; 95% CI=1.09-6.44) and ear symptoms (RR=6.10; 95% CI=2.48-15.03) was observed. The population should be made aware of the risks of gastrointestinal symptoms associated with contact (full or limited) with cyanobacteria. A risk management plan is needed for water treatment plants that draw their water from a source contaminated with cyanobacteria. PMID- 23927934 TI - Reprint of "new complete structure of Hafnia alvei clinical isolate strain PCM 2670 semi-rough lipopolysaccharide". AB - Hafnia alvei strain PCM 2670 is a clinical isolate from a patient with chronic reproductive tract infection. The novel structure of the semi-rough lipopolysaccharide was established with the use of NMR spectroscopy and mass spectrometry as well as immunochemical techniques. According to the mass spectrometry data, heptose in the oligosaccharide is partially substituted by glycine. H. alvei PCM 2670 core structure encompasses the common core of H. alvei which is modified with two additional galactose units. [formula see text] The 6 substituted galactose is the O-antigen repeating unit substitution residue. The repeating unit consists of five monosaccharide residues and has the following structure: ->2)-beta-Galp-(1->6)-alpha-Glcp-(1->6)-alphaGlcpNAc3OAc-(1->4)-alpha GalpA-(1->3)-beta-GlcpNAc6OAc-(1->6)-core. PMID- 23927935 TI - A longitudinal biosocial study of cortisol and peer influence on the development of adolescent antisocial behavior. AB - It is increasingly recognized that in order to understand the complex phenomenon of antisocial behavior, interrelations between biological and social risk factors should be taken into account. In the current study, this biosocial approach was applied to examine the mediating role of deviant peers in longitudinal associations linking the level of hypothalamic-pituitary-adrenal (HPA) axis activity to aggression and rule-breaking. Participants were 425 boys and girls from the general population, who were assessed yearly at ages 15, 16, and 17. As a measure of HPA axis activity, cortisol was assessed at awakening, 30, and 60 min later (the cortisol awakening response, CAR). Participants, as well as their best friend, reported on their own aggressive and rule-breaking behavior, thereby allowing to assess bidirectional influences within friendships. Aggression was only predicted by a decreased cortisol level at awakening, and not by aggressive behavior of their friend. Decreased levels of cortisol at awakening predicted adolescents' rule-breaking, which subsequently predicted increased rule-breaking of their best friend. The latter was only found for adolescents who changed friends, as compared to adolescents with the same friend in every year. Gender differences were not found. These findings suggest that interrelations between biological and social risk factors are different for the development of aggression versus rule-breaking. Furthermore, decreased levels of HPA axis activity may represent a susceptibility to selecting deviant peers. PMID- 23927936 TI - The use of biomarkers in the military: from theory to practice. AB - This paper provides a summary of relevant issues covered in the conference, "The Use of Biomarkers in the Military: Theory to Practice" held at the New York Academy of Science on September 14, 2012. The conference covered the state of the science in identification of PTSD biomarkers, including, the definition of different classes of biomarkers pertaining to PTSD. The aim of the satellite conference was to bring together researchers who have been supported by the Department of Defense, Veterans Administration, National Institutes of Health, and other agencies around the world, who are interested in the identification of biomarkers for PTSD risk, diagnosis, symptom severity and treatment response, for a discussion of salient issues regarding biomarker development for PTSD, as well as special considerations for the use of biomarkers in the military. PMID- 23927937 TI - Insights into antibody-associated encephalitis--Bickerstaff's 1950's papers revisited. AB - Edwin Bickerstaff and Philip Cloake reported in the 1950's three cases of reversible encephalitis. The concept of antibody associated encephalitis had not been proposed at the time they astutely recognized the importance of disease pattern recognition and postulated a potential immune based mechanism. The syndrome defined by Bickerstaff of progressive, external ophthalmoplegia and ataxia, with disturbance of consciousness or hyperreflexia, has subsequently been associated with anti-GQ1b antibodies. Interestingly one of the three original cases, a young woman who developed seizures, an eye movement disorder and acute psychosis while awaiting ovarian cystectomy, has features that may be more consistent with anti-NMDA receptor encephalitis. PMID- 23927938 TI - A brief olfactory test for Alzheimer's disease. AB - BACKGROUND: The early diagnosis of Alzheimer's disease (AD) may help reduce disability, enhance quality of life, and aid clinical trials. Portions of olfactory cortex are the initial sites of AD pathology and patients with AD often have more degeneration of their left than right hemisphere. Since the olfactory epithelium projects mainly to the ipsilateral olfactory cortex, patients with AD may demonstrate an asymmetrical (left greater than right) decrement of odor detection sensitivity. This retrospective, case-control study assessed a quick olfactory test that may help diagnose AD. METHODS: Participants with probable AD (N=18), mild cognitive impairment (MCI, N=24), other causes of dementia (OD, N=26) and matched controls (OC, N=26) were tested, with closed eyes, for their ability to detect an odor, one nostril at a time. A container of 14g of peanut butter was opened, held medially at the bottom of a 30cm ruler, and moved up 1cm at a time during the participants' exhale. Upon odor detection, the distance between the subject's nostril and container was measured. RESULTS: The mean odor detection distance of AD patients' left nostril (5.1cm), and not their right (17.4cm), was significantly less (F(3,90)=22.28, p<0.0001) than the other groups. The mean, standard error, and 95% Confidence Interval of the L-R nostril odor detection difference (cm) for AD were -12.4+/-0.5, (-15.0,-9.8); for MCI were 1.9+/-1.2, (-4.2,0.4); for OD were 4.8+/-1.0, (2.6,6.9); and for OC were 0.0+/ 1.4 (-2.2,2.1). CONCLUSION: This non-invasive and inexpensive left-right nostril odor detection test appears to be a sensitive and specific test for probable AD. PMID- 23927939 TI - A follow up study of non-demented patients with primary visual cortical hypometabolism: prodromal dementia with Lewy bodies. AB - We previously reported non-demented patients with glucose hypometabolism in the primary visual cortex (PVC), which is the preferentially affected region in patients with dementia with Lewy bodies (DLB). It remains unknown, however, whether these patients represent a prodromal DLB state. Eleven non-demented patients who attended our memory clinic for more than three years (mean follow-up period: 44 +/- 5 months) were examined. All the patients had glucose hypometabolism in the PVC on [(18)F]-fluoro-d-glucose (FDG) positron emission tomography (PET) scans at baseline. Four patients, including one with a clinical history of occipital bleeding, exhibited no core or suggestive features of DLB. Seven patients reported recurrent nocturnal dream-enactment behavior, which is consistent with probable rapid eye movement (REM) sleep behavior disorder (RBD). The condition of the patient with occipital bleeding was stable, which is consistent with an underlying non-neurodegenerative disorder. Of the remaining 10 patients, 5 had stable cognitive conditions (non-converters) and 5 exhibited progression to dementia (converters). The clinical diagnoses of 4 patients with probable RBD were changed to probable DLB. Despite no differences in psychological profiles at baseline between non-converters and converters, the initial pattern of cortical metabolism differed: converters had lower glucose hypometabolism in the parietal and the lateral occipital cortex compared to non converters. The metabolic reduction in the PVC is present in patients with prodromal DLB. Moreover, the spatial profiles of reduced glucose metabolism at baseline could help to define the distinct prognostic subgroup that has a greater risk of conversion to DLB. PMID- 23927941 TI - Behavior observation of major noise sources in critical care wards. AB - PURPOSE: This study aimed to investigate the behavior patterns of typical noise sources in critical care wards and relate their patterns to health care environment in which the sources adapt themselves in several different forms. METHODS: An effective observation approach was designed for noise behavior in the critical care environment. Five descriptors have been identified for the behavior observations, namely, interval, frequency, duration, perceived loudness, and location. Both the single-bed and the multiple-bed wards at the selected Critical Care Department were randomly observed for 3 inconsecutive nights, from 11:30 pm to 7:00 am the following morning. The Matlab distribution fitting tool was applied afterward to plot several types of distributions and estimate the corresponding parameters. RESULTS: The lognormal distribution was considered the most appropriate statistical distribution for noise behaviors in terms of the interval and duration patterns. The turning of patients by staff was closely related to the increasing occurrences of noises. Among the observed noises, talking was identified with the highest frequency, shortest intervals, and the longest durations, followed by monitor alarms. The perceived loudness of talking in the nighttime wards was classified into 3 levels (raised, normal, and low). Most people engaged in verbal communication in the single-bed wards that occurred around the Entrance Zone, whereas talking in the multiple-bed wards was more likely to be situated in the Staff Work Zone. As expected, more occurrences of noises along with longer duration were observed in multiple-bed wards rather than single-bed wards. "Monitor plus ventilator alarms" was the most commonly observed combination of multiple noises. PMID- 23927940 TI - Bilateral claw hand: an uncommon presentation of regional Guillain-Barre syndrome. AB - We present an uncommon case of a 38-year-old man presented with bilateral subacute weakness of intrinsic hand muscles, manifesting as bilateral claw-hand, without sensory deficits and absent tendon reflexes in upper arms. Nerve conduction studies showed findings consistent with demyelinating GBS. During the fourth day of hospitalization the patient presented symmetrical distal leg weakness and was treated with intravenous immunoglobulin. PMID- 23927942 TI - Altered resting state effective connectivity in long-standing vegetative state patients: an EEG study. AB - OBJECTIVE: Recent evidence mainly based on hemodynamic measures suggests that the impairment of functional connections between different brain areas may help to clarify the neuronal dysfunction occurring in patients with disorders of consciousness (DOC). The aim of this study was to evaluate effective EEG connectivity in a cohort of 18 patients in a chronic vegetative state (VS) observed years after the occurrence of hypoxic (eight) and traumatic or hemorrhagic brain insult. METHODS: we analysed the EEG signals recorded under resting conditions using a frequency domain linear index of connectivity (partial directed coherence: PDC) estimated from a multivariate autoregressive model. The results were compared with those obtained in ten healthy controls. RESULTS: Our findings indicated significant connectivity changes in EEG activities in delta and alpha bands. The VS patients showed a significant and widespread decrease in delta band connectivity, whereas the alpha activity was hyper-connected in the central and posterior cortical regions. CONCLUSION: These changes suggest the occurrence of severe circuitry derangements probably due to the loose control of the subcortical connections. The alpha hyper-synchronisation may be due to simplified networks mainly involving the short-range connections between intrinsically oscillatory cortical neurons that generate aberrant EEG alpha sources. This increased connectivity may be interpreted as a reduction in information capacity, implying an increasing prevalence of stereotypic activity patterns. SIGNIFICANCE: Our observations suggest a remarkable rearrangement of connectivity in patients with long-standing VS. We hypothesize that in persistent VS, after a first period characterized by a breakdown of cortical connectivity, neurodegenerative processes, largely independent from the type of initial insult, lead to cortex de-afferentation and to a severe reduction of possible cortical activity patterns and states. PMID- 23927944 TI - Indirect calorimetry: a guide for optimizing nutritional support in the critically ill child. AB - The metabolic response of critically ill children is characterized by an increase in resting energy expenditure and metabolism, and energy needs of the critically ill child are dynamic, changing from a hypermetabolic to hypometabolic state through the continuum of the intensive care unit (ICU) stay. It therefore appears essential to have a precise evaluation of energy needs in these patients in order to avoid underfeeding and overfeeding, loss of critical lean body mass, and worsening of any existing nutrient deficiencies. However, there are no clear definitions regarding either the exact requirements or the ideal method for determining metabolic needs. In clinical practice, energy needs are determined either by using predictive equations or by actual measurement using indirect calorimetry. Although many equations exist for predicting resting energy expenditure, their accuracy is not clear. In addition, very few clinical trials have been performed so that no firm evidence-based recommendations are available regarding optimal nutritional management of critically ill children and infants. Most studies have come to the same conclusion (i.e., current predictive equations do not accurately predict required energy needs in the pediatric ICU population and predictive equations are unreliable compared with indirect calorimetry). The recent American Society for Parenteral and Enteral Nutrition clinical guidelines for nutrition support of the critically ill child suggest that indirect calorimetry measurements be obtained when possible in pediatric patients with suspected metabolic alterations or malnutrition, according to a list of criteria that may lead to metabolic instability, thus making standardized predictive equations even less reliable. Although the standard use of indirect calorimetry is limited due to equipment availability, staffing, and cost, the accuracy of the commercially available devices continues to improve and the measurements have become more reliable and easier to perform. In the absence of sufficient data, prospective controlled studies need to be conducted in order to evaluate the benefit of tight calorie control achieved by accurately measuring the energy needs of the critically ill child. Optimizing measuring techniques could make this more feasible and decrease the need to rely on inaccurate equations while providing appropriate energy requirements. PMID- 23927943 TI - Impaired CD4+ and T-helper 17 cell memory response to Streptococcus pneumoniae is associated with elevated glucose and percent glycated hemoglobin A1c in Mexican Americans with type 2 diabetes mellitus. AB - Individuals with type 2 diabetes are significantly more susceptible to pneumococcal infections than healthy individuals of the same age. Increased susceptibility is the result of impairments in both innate and adaptive immune systems. Given the central role of T-helper 17 (Th17) and T-regulatory (Treg) cells in pneumococcal infection and their altered phenotype in diabetes, this study was designed to analyze the Th17 and Treg cell responses to a whole heat killed capsular type 2 strain of Streptococcus pneumoniae. Patients with diabetes demonstrated a lower frequency of total CD+T-cells, which showed a significant inverse association with elevated fasting blood glucose. Measurement of specific subsets indicated that those with diabetes had, low intracellular levels of interleukin (IL)-17, and lower pathogen-specific memory CD4+ and IL-17+ cell numbers. No significant difference was observed in the frequency of CD4+ and Th17 cells between those with and without diabetes. However, stratification of data by obesity indicated a significant increase in frequency of CD4+ and Th17 cells in obese individuals with diabetes compared with nonobese individual with diabetes. The memory CD+T-cell response was associated inversely with both fasting blood glucose and percent glycated hemoglobin A1c. This study demonstrated that those with type 2 diabetes have a diminished pathogen-specific memory CD4+ and Th17 response, and low percentages of CD+T-cells in response to S. pneumoniae stimulation. PMID- 23927945 TI - The gene-diet interaction, LPL PvuII and HindIII and carbohydrate, on the criteria of metabolic syndrome: KMSRI-Seoul Study. AB - OBJECTIVE: The objective of this study was to investigate the effects of the interaction between lipoprotein lipase (LPL) PvuII and HindIII haplotypes and carbohydrate intakes on the components of metabolic syndrome (MetSyn) in Koreans. METHODS: LPL PvuII and HindIII genotype, LPL mass, triglyceride, high-density lipoprotein cholesterol, blood pressure (BP), waist circumference (WC), insulin, and Homeostasis Model of Assessment - Insulin Resistance were determined using a cross-sectional design in 269 controls and 280 MetSyn patients. RESULTS: LPL mass was significantly lower in patients with PvuII and HindIII mutant alleles (P2 and H2) and decreased as the number of MetSyn components increased in all PvuII and HindIII haplotypes. Both LPL mass-adjusted WC and systolic BP (SBP) were positively associated with a ratio of percent energy from carbohydrate to percent energy from fat in individuals with P2H2 haplotype. After adjustment for age, sex, and LPL mass, the odds ratio (OR) for excessive WC was higher in carriers of P2H2 in the highest carbohydrate intake tertile compared with carriers of P1H1 in the lowest carbohydrate intake tertile (OR, 6.94; 95% confidence interval [CI], 1.39-34.62). Moreover, the OR for high SBP were higher in carriers of P1H2/P2H1 in the highest carbohydrate intake tertile (OR, 7.84; 95% CI, 1.79-34.46) and in carriers of P2H2 in the highest carbohydrate intake tertile (OR, 4.24; 95% CI, 1.16-15.48) than P1H1 carriers. CONCLUSION: This study suggests that P2H2 carriers in the highest carbohydrate intake tertile may be at risk for MetSyn because they had increased odds of excessive WC and high SBP. PMID- 23927946 TI - The association of sleep duration and cardiometabolic risk factors in a national sample of children and adolescents: the CASPIAN III study. AB - OBJECTIVES: Although sleep duration is one of the most important health-related factors, its association with risk factors for chronic diseases has not been completely clarified, especially among children and adolescents. The aim of this study was to evaluate the association between sleep duration and CVD risk factors among a nationally representative sample of Iranian children and adolescents. METHODS: This cross-sectional national study was performed on a representative sample of 5528 Iranian students, ages 10 to 18 y living in central cities of 27 provinces of Iran. Physical examinations and laboratory tests were performed using standard protocols. To determine the association between sleep duration and cardiometabolic risk factors, multivariable logistic regression was used and odds ratios (OR; with 95% confidence intervals) are reported. RESULTS: The mean +/- SD age was not significantly different among boys (14.69 +/- 2.45 y) and girls (14.7 +/- 2.38 y). In a crude model, boys who slept > 8 h and 5 to 8 h had lower OR for abdominal obesity compared with those who had slept <5 h in a crude model (ORs, 0.70, 0.80, 1.0, respectively; P = 0.008). A similar result was observed in an age- adjusted model for the prevalence of abdominal obesity (ORs, 0.69, 0.76, 1.0, respectively; P = 0.011). Girls who had slept > 8 h per day had lower OR for high serum low-density lipoprotein levels compared with those who slept < 5 h per day (P = 0.002). These differences remained significant even in the fully adjusted model for all the confounding variables (P = 0.008). Moreover, among boys ages 10 to 14 y, longer sleep duration increased the risk for high total cholesterol in all models. CONCLUSION: Shorter sleep duration increased the risk for some cardiometabolic risk factors among adolescents. The clinical significance of our findings should be determined in longitudinal studies. PMID- 23927947 TI - Parathyroid hormone has an important role in blood pressure regulation in vitamin D-insufficient individuals. AB - OBJECTIVE: The aim of the present study was to evaluate whether vitamin D status is related to blood pressure (BP) in adults. METHODS: We evaluated the relationship between vitamin D status, intact parathyroid hormone (iPTH) and BP in 332 adults. Anthropometric measurements, BP, and a fasting blood sample was obtained. Participants were stratified into the following BP categories: 1) normal BP; 2) high BP; 3) normal BP through medication. Vitamin D insufficiency was defined as 25-hydroxvitamin D <= 75 nmol/L; high iPTH as > 65 pg/mL. The relationships between vitamin D status, iPTH and BP were adjusted for body mass index, waist circumference, blood lipids, physical activity, and sunscreen use. RESULTS: No differences in prevalences of vitamin D insufficiency and high iPTH were observed among BP groups. No significant association was observed between BP and vitamin D status. Positive correlations were observed between iPTH and systolic BP (r = 0.168; P = 0.002) and between iPTH and diastolic BP (r = 0.168; P = 0.002). iPTH remained correlated with BP even with adjustments. CONCLUSIONS: The present study contributes to the understanding of calcemic hormones and BP regulation. PMID- 23927948 TI - Long-term effect of green tea extract during lactation on AMPK expression in rat offspring exposed to fetal malnutrition. AB - OBJECTIVE: The fetal and neonatal environments are important determinants of disease risk in adult life. The aim of this study was to determine whether maternal green tea extract (GTE) intake during lactation affects the expression and activity of adenosine monophosphate-activated protein kinase (AMPK) in the kidneys of male offspring of protein-restricted dams during gestation. METHODS: Pregnant Wistar rats were fed control (C) or low-protein diets (LP) during gestation. Following delivery, dams received a control or GTE-containing control diet during lactation as follows: C on control diet (CC), LP on control diet (LPC), LP on 0.12% GTE-containing control diet (LPL), or LP on 0.24% GTE containing control diet (LPH). Some of the male pups from each dam were sacrificed at week 3, and the remaining male pups were fed a standard diet and sacrificed at week 30. Blood chemistry and expression levels of AMPKalpha, mammalian target of rapamycin (mTOR), and Akt in the kidneys of the male offspring were examined. RESULTS: The level of phosphorylated AMPKalpha in the LPH group at week 3 was higher than that in the LPC group. At week 30, the protein levels of total and phosphorylated AMPK in the LPL and LPH groups were lower than those in the LPC group. The protein levels of mTOR and Akt at week 30 in the LPL and LPH groups were lower than those in the LPC group. CONCLUSION: GTE intake during lactation modulates AMPK, Akt, and mTOR expression in the kidneys of the adult male offspring of dams fed a protein-restricted diet and may induce long-term alterations in the expressions of these proteins in the kidneys. PMID- 23927949 TI - Author response. PMID- 23927950 TI - Author response. PMID- 23927951 TI - Substitute consent practices in the face of uncertainty: a survey of Canadian researchers in aging. AB - BACKGROUND: In Canada and elsewhere, research policies require researchers to secure consent from a legally authorized representative (LAR) for prospective participants unable to consent. Few jurisdictions, however, offer a clear legislative basis for LAR identification. We investigated Canadian researchers' practices regarding the involvement of decisionally incapacitated participants and tested whether reported practices were associated with (1) researchers' understanding of the law on third-party authorization of research and (2) their comfort with allowing a family member to consent on behalf of an incapacitated relative. METHODS: We surveyed researchers in aging from four Canadian provinces about their practices with prospective participants deemed incapable of consent, their understanding of relevant law, and comfort with family consent for research purposes. Understanding and comfort were measured with research vignettes that briefly described hypothetical studies in which an adult who lacks the capacity to consent was invited to participate. RESULTS: Many respondents reported soliciting consent from a family member (45.7% for low-risk studies and 10.7% for serious risks studies), even in jurisdictions where such authority is uncertain at law. Researchers' tendency to solicit family consent was associated with their comfort in doing so, but not with their understanding of the law on substitute consent for research. CONCLUSIONS: Findings underscore the need to clarify who may authorize an incapacitated adult's participation in research. Meanwhile, people should inform their relatives of their desire to participate or not in research in the event of incapacity, given researchers' tendency to turn to family for consent, even where not supported by law. PMID- 23927952 TI - Microfluidics-generated pancreatic islet microfibers for enhanced immunoprotection. AB - Pancreatic islet transplantation is a promising method for treatment of type 1 diabetes mellitus. However, transplanted islets can be destroyed due to host immune reactions. To immunologically protect transplanted islets, here an immunoprotective microfiber including islets by using a polydimethylsiloxane (PDMS)-based microfluidic device is newly designed. A cylindrical-flow channel in the microfluidic platform is used for producing collagen-alginate composite (CAC) fibers. This enables mass production and uniform diameter distribution (<250 MUm) without protruding islets. Collagen, which is the main extracellular matrix component, is added to alginate to mimic the native islet microenvironment. Compared to free islets (control) and alginate-fiber-encapsulated islets, CAC fiber-encapsulated islets show higher viability and normal insulin secretion. When CAC-fiber-encapsulated islets (1200 islet equivalent) are implanted into the intraperitoneal cavity of streptozotocin-induced diabetic BALB/C mice, the blood glucose levels of all mice return to normoglycemia. Moreover, intraperitoneal glucose tolerance tests demonstrate that islets in the CAC-fiber have similar glucose responsiveness to those of non-diabetic normal mice. These results are attributed to the immunoprotection of the transplanted islets from host immune reactions. On the other hand, all free islets are completely rejected within a week due to severe immune responses. Collectively, fabrication of CAC fibers using microfluidic devices can be used for successful islet transplantation. PMID- 23927953 TI - End-of-life care in the emergency department: nurses who invest in the nurse patient relationship are better able to manage the emotional aspects of caring for dying people and their relatives. PMID- 23927954 TI - Periodontitis contributes to initiation, progress and aggravation of septic shock; a feasible hypothesis. AB - This hypothesis states that active aggressive periodontitis is an important source of putative endotoxin contributing to the onset of septic shock syndrome [SSS]. Consequently patients with periodontitis may be more prone to developing SSS in predisposing conditions. PMID- 23927955 TI - Early cardiac catheterization is associated with improved survival in comatose survivors of cardiac arrest without STEMI. AB - AIM: To determine if early cardiac catheterization (CC) is associated with improved survival in comatose patients who are resuscitated after cardiac arrest when electrocardiographic evidence of ST-elevation myocardial infarction (STEMI) is absent. METHODS: We conducted a retrospective observational study of a prospective cohort of 754 consecutive comatose patients treated with therapeutic hypothermia (TH) following cardiac arrest. RESULTS: A total of 269 (35.7%) patients had cardiac arrest due to a ventricular arrhythmia without STEMI and were treated with TH. Of these, 122 (45.4%) received CC while comatose (early CC). Acute coronary occlusion was discovered in 26.6% of patients treated with early CC compared to 29.3% of patients treated with late CC (p=0.381). Patients treated with early CC were more likely to survive to hospital discharge compared to those not treated with CC (65.6% vs. 48.6%; p=0.017). In a multivariate regression model that included study site, age, bystander CPR, shock on admission, comorbid medical conditions, witnessed arrest, and time to return of spontaneous circulation, early CC was independently associated with a significant reduction in the risk of death (OR 0.35, 95% CI 0.18-0.70, p=0.003). CONCLUSIONS: In comatose survivors of cardiac arrest without STEMI who are treated with TH, early CC is associated with significantly decreased mortality. The incidence of acute coronary occlusion is high, even when STEMI is not present on the postresuscitation electrocardiogram. PMID- 23927956 TI - The European Resuscitation Council: its history and development. PMID- 23927957 TI - High levels of secreted frizzled-related protein 1 correlate with poor prognosis and promote tumourigenesis in gastric cancer. AB - BACKGROUND: Secreted frizzled-related protein 1 (sFRP1), Wnt signalling regulator, can positively or negatively regulate tumourigenesis and progression. We sought to determine the clinical relevance and the role of sFRP1 in gastric cancer development and progression. METHODS: We investigated the sFRP1 protein expression levels and its clinicopathological correlations using 85 cases of human gastric samples with survival information (JWCI cohort). mRNA levels of sFRP1 and coexpressed genes were analysed using 131-sample cDNA microarray data (Ruijin cohort). The effects of sFRP1 alteration were investigated using cell proliferation, colony formation, migration, and invasion and xenograft models. RESULTS: We show that sFRP1 is overexpressed in some human cancers and is significantly associated with lymph node metastasis and decreased overall survival in gastric cancer patients. Using gastric cancer cell models, we demonstrate that sFRP1 overexpression is correlated with the activation of TGFbeta (transforming growth factor-beta) signalling pathway and thereby induces cell proliferation, epithelial-mesenchymal transition (EMT), and invasion. Conversely, sFRP1 knockdown shows the opposite effects. Furthermore, sFRP1 overexpression promotes tumourigenesis and metastasis in a xenograft model. CONCLUSION: Our studies demonstrate that sFRP1 is a biomarker for aggressive subgroups of human gastric cancer and a prognostic biomarker for patients with poor survival. Our data provide insight into a crosstalk between Wnt and TGFbeta pathways which underlies gastric cancer development and progression. PMID- 23927958 TI - Increase in pediatric magnet-related foreign bodies requiring emergency care. AB - STUDY OBJECTIVE: We describe magnetic foreign body injuries among children and obtain national estimates of magnetic foreign body injury incidence over time. METHODS: We searched the National Electronic Injury Surveillance System for cases of magnetic foreign bodies in children younger than 21 years in the United States, from 2002 to 2011. Cases were analyzed by location: alimentary or respiratory tract, nasal cavity, ear canal, or genital area. RESULTS: We identified 893 cases of magnetic foreign bodies, corresponding to 22,581 magnetic foreign body cases during a 10-year period (95% confidence interval [CI] 17,694 to 27,469). Most magnetic foreign bodies were ingested (74%) or intranasal (21%). Mean age was 5.2 years for ingested magnetic foreign bodies and 10.1 years for nasal magnetic foreign bodies (difference 4.9; 95% CI 4.1 to 5.6), suggesting different circumstances of injury. The incidence of pediatric magnet ingestions increased from 2002 to 2003 from 0.57 cases per 100,000 children per year (95% CI 0.22 to 0.92) to a peak in 2010 to 2011 of 3.06 cases per 100,000 children per year (95% CI 2.16 to 3.96). Most ingested magnetic foreign bodies (73%) and multiple magnet ingestions (91%) occurred in 2007 or later. Patients were admitted in 15.7% of multiple magnet ingestions versus 2.3% of single magnet ingestions (difference 13.4%; 95% CI 2.8% to 24.0%). CONCLUSION: Magnet-related injuries are an increasing public health problem for young children, as well for older children who may use magnets for play or to imitate piercings. Education and improved magnet safety standards may decrease the risk small magnets pose to children. PMID- 23927959 TI - Do corticosteroids benefit patients with sore throat? PMID- 23927960 TI - Is intravenous acetylcysteine more effective than oral administration for the prevention of hepatotoxicity in acetaminophen overdose? PMID- 23927961 TI - Genetic variations in EGFR and ERBB4 increase susceptibility to cervical cancer. AB - OBJECTIVES: Inherited genetic variability contributes to susceptibility to cervical cancer. We investigated the association of single nucleotide polymorphisms (SNPs) in the human epidermal growth factor receptor (ERBB) family with cervical cancer. METHODS: We used the transmission disequilibrium test (TDT) to look for excessive transmission of tag single nucleotide polymorphisms (tSNPs) in ERBB family members EGFR, ERBB2, ERBB3, and ERBB4 in a large sample of women with invasive and in situ cervical cancer and their biological parents (628 trios). The study used a discovery set of trios (244) analyzed by Illumina GoldenGate in which SNPs reaching a P<.05 were re-tested by TaqMan in the combined set of 628. We also explored collaborative effects of different ERBB alleles. RESULTS: Based on single SNP TDT tests we identified 16 significant SNPs in the discover stage and six of 14 SNPs that could be assayed by TaqMan were significantly overtransmitted in women with cervical cancer in the combined replication set. Four SNPs were located in intron 1 of EGFR and two SNPs in intron 24 of ERBB4. The EGFR variants are located near multiple enhancers, silencers, and the previously identified functional common polymorphisms in intron 1. CONCLUSIONS: Our data provide evidence for the involvement of intron 1 EGFR variants and intron 24 ERBB4 variants in modulating risk for the development of in situ and invasive cervical cancer. These variants should be examined in additional populations and functional studies would be needed to confirm this hypothesis. PMID- 23927962 TI - SOX1 suppresses cell growth and invasion in cervical cancer. AB - OBJECTIVE: Abnormal activation of the Wnt/beta-catenin signaling pathway is common in human cancers, including cervical cancer. Many papers have shown that SRY (sex-determining region Y)-box (SOX) family genes serve as either tumor suppressor genes (TSGs) or oncogenes by regulating the Wnt signaling pathway in different cancers. We have demonstrated recently that epigenetic silencing of SOX1 gene occurs frequently in cervical cancer. However, the possible role of SOX1 in cervical cancer remains unclear. This study aimed to explore whether SOX1 functions as a TSG in cervical cancer. METHODS: We established a constitutive and an inducible system that overexpressed SOX1 and monitored its function by in vitro experiments. To confirm SOX1 function, we manipulated SOX1 using an inducible expression approach in cell lines. The effect of SOX1 on tumorigenesis was also analyzed in animal models. RESULTS: Overexpression of SOX1 inhibited cell proliferation, anchorage independency, and invasion in vitro. SOX1 suppressed tumor growth in nonobese diabetic/severe combined immunodeficiency mice. After induction of SOX1 by doxycycline (DOX), SOX1 inhibited cell growth and invasion in the inducible system. Repression of SOX1 by withdrawal of DOX partially reversed the malignant phenotype in cervical cells. SOX1 inhibited TCF dependent transcriptional activity and the Wnt target genes. SOX1 also repressed the invasive phenotype by regulating the expression of invasion-related genes. CONCLUSIONS: Taken together, these data suggest that SOX1 can function as a tumor suppressor partly by interfering with Wnt/beta-catenin signaling in cervical cancer. PMID- 23927964 TI - Use of CT in the management of anterior cruciate ligament revision surgery. AB - Anterior cruciate ligament (ACL) injuries occur most commonly in individuals between 18 and 29 years of age and are strongly correlated with sporting activity, with female athletes being at higher risk of ACL rupture than their male counterparts. ACL reconstruction is one of the most frequently performed procedures in orthopaedic surgery, having a reported incidence of 85 per 100,000 head of population in the at-risk age group. Subsequent graft failure is most commonly caused by recurrent trauma, followed by tunnel malpositioning, although the choice of graft type does not appear to affect outcome. The Danish ACL registry reported that ACL revisions accounted for 7.5% of all ACL reconstruction surgery performed between 2005 and 2008. Revision of ACL reconstruction is recognized to carry a worse outcome than primary reconstruction. Preoperative imaging has become a crucial part of surgical planning in these patients, with great reliance placed on computed tomography (CT). The radiologist should be able to recognize the types of primary repair and must be able to assess for the complications of primary surgery, such as tunnel malpositioning, tunnel widening, and fixation device failure. Revision is commonly a two-stage procedure with bone grafting of the tunnels prior to the definitive ligament repair. The radiologist should be able to asses for adequate bone graft incorporation. The purpose of this article is to present a review of the use of CT in the management of ACL revision surgery with examples of commonly used fixation devices; complications, such as tunnel widening and tunnel malpositioning; and bone graft incorporation. PMID- 23927963 TI - Complexity of Escherichia coli bacteremia pathophysiology evidenced by comparison of isolates from blood and portal of entry within single patients. AB - The portal of entry of Escherichia coli bacteremia, a frequent and severe disease, is most commonly the urinary tract followed by the digestive tract. Recent reports have evidenced the presence of several distinct E. coli clones within a single patient suffering of extra-intestinal infection. To explore the relationships between the blood and portal of entry strains, we thoroughly studied 98 bacteremic patients from the French prospective COLIBAFI cohort. In these patients, we compared genotypically and phenotypically E. coli strains isolated from the blood and the suspected portal of entry [non-urinary pus (n=52) and urine (n=52)]. We found genetically distinct strains exhibiting distinct antibiotypes in the blood and pus samples (8 patients; 15%) and the blood and urine samples (2 patients; 3.8%) (p=0.09). These data highlight the complexity of pathophysiology of E. coli bacteremia and should be taken into consideration when strain antibiotic susceptibility is tested, especially in bacteremia of pus origin. PMID- 23927965 TI - Reciprocal expression of enteric antimicrobial proteins in intestinal graft versus-host disease. AB - We recently demonstrated that expression of alpha-defensins, the major antimicrobial peptides produced by Paneth cells, was severely suppressed in mice with graft-versus-host disease (GVHD). In this study, we found that antibacterial lectin, regenerating islet-derived IIIgamma (RegIIIgamma) was upregulated in villous enterocytes, thus demonstrating the reciprocal control of enteric antimicrobial proteins in GVHD. Upregulation of RegIIIgamma was mediated by a mechanism independent upon radiation-induced intestinal tract damage. MyD88 mediated signaling in intestinal epithelium was required for RegIIIgamma upregulation in GVHD and antibiotic therapy downregulated RegIIIgamma expression. These results suggest that MyD88-mediated sensing of the intestinal microbes disregulated in GVHD induces RegIIIgamma upregulation in GVHD and argue a role for RegIIIgamma in the pathogenesis of GVHD. PMID- 23927966 TI - Colorectal cancer defeating? Challenge accepted! AB - Colorectal tumours are actually considered as aberrant organs, within it is possible to notice a different stage of cell growth and differentiation. Their origin is reported to arise from a subpopulation of tumour cells endowed with, just like the healthy stem cells, self-renewal and aberrant multi-lineage differentiation capacity likely to be called colorectal cancer stem cells (CCSCs). Cancer stem cells (CSCs) fate, since their origin, reflects the influences from their microenvironment (or niche) both in the maintenance of stemness, in promoting their differentiation, and in inducing epithelial mesenchymal transition, responsible of CSCs dissemination and subsequent formation of metastatic lesions. The tumour cells heterogeneity and their immuno response resistance nowadays probably responsible of the failure of the conventional therapies, make this research field an open issue. Even more importantly, our increasing understanding of the cellular and molecular mechanisms that regulate CSC quiescence and cell cycle regulation, self-renewal, chemotaxis and resistance to cytotoxic agents, is expected to eventually result in tailor-made therapies with a significant impact on the morbidity and overall survival of colorectal cancer patients. PMID- 23927967 TI - ETS transcription factors in hematopoietic stem cell development. AB - Hematopoietic stem cells (HSCs) are essential for the maintenance of the hematopoietic system. However, these cells cannot be maintained or created in vitro, and very little is known about their generation during embryogenesis. Many transcription factors and signaling pathways play essential roles at various stages of HSC development. Members of the ETS ('E twenty-six') family of transcription factors are recognized as key regulators within the gene regulatory networks governing hematopoiesis, including the ontogeny of HSCs. Remarkably, although all ETS transcription factors bind the same DNA consensus sequence and overlapping tissue expression is observed, individual ETS transcription factors play unique roles in the development of HSCs. Also, these transcription factors are recurrently used throughout development and their functions are context dependent, increasing the challenge of studying their mechanism of action. Critically, ETS factors also play roles under pathological conditions, such as leukemia and, therefore, deciphering their mechanism of action will not only enhance our knowledge of normal hematopoiesis, but also inform protocols for their creation in vitro from pluripotent stem cells and the design of new therapeutic approaches for the treatment of malignant blood cell diseases. In this review, we summarize the key findings on the roles of ETS transcription factors in HSC development and discuss novel mechanisms by which they could control hematopoiesis. PMID- 23927968 TI - Notch and Wnt signaling in the emergence of hematopoietic stem cells. AB - Hematopoietic stem cells (HSC), which reside in the marrow of adult mammals and sustain hematopoiesis for the lifetime of the organism, are specified and generated during embryonic development. We are just beginning to understand how HSC develop from more primitive cells and the complexity of the signaling pathways involved. In this work, we review the role of two crucial pathways, Notch and Wnt, in the specification and development of HSC and their nascent microenvironment, the arterial vessels. PMID- 23927969 TI - Substituted pyrrolo[2,3-d]pyrimidines as Cryptosporidium hominis thymidylate synthase inhibitors. AB - Cryptosporidiosis, a gastrointestinal disease caused by a protozoan Cryptosporidium hominis is often fatal in immunocompromised individuals. There is little clinical data to show that the existing treatment by nitazoxanide and paromomycin is effective in immunocompromised individuals. Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are essential enzymes in the folate biosynthesis pathway and are well established as drug targets in cancer and malaria. A novel series of classical antifolates, 2-amino-4-oxo-5-substituted pyrrolo[2,3-d]pyrimidines have been evaluated as Cryptosporidium hominis thymidylate synthase (ChTS) inhibitors. Crystal structure in complex with the most potent compound, a 2'-chlorophenyl with a sulfur bridge with a Ki of 8.83+/ 0.67 nM is discussed in terms of several Van der Waals, hydrophobic and hydrogen bond interactions with the protein residues and the substrate analog 5 fluorodeoxyuridine monophosphate. Of these interactions, two interactions with the non-conserved residues (A287 and S290) offer an opportunity to develop ChTS specific inhibitors. Compound 6 serves as a lead compound for analog design and its crystal structure provides clues for the design of ChTS specific inhibitors. PMID- 23927970 TI - Synthesis, cytotoxicity and DNA-binding properties of Pd(II), Cu(II) and Zn(II) complexes with 4'-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-2,2':6',2"-terpyridine. AB - Pd(II), Cu(II) and Zn(II) complexes (1-3) based on 4'-(4-(2-(piperidin-1 yl)ethoxy)phenyl)-2,2':6',2"-terpyridine were synthesized and characterized by UV, IR, NMR, EPR, HRMS, elemental analyses, and molar conductivity measurements. The cytotoxicity of these complexes against HL-60, BGC-823, KB, Bel-7402, A549, Hela, K562 and MCF-7 cell lines in vitro was measured by MTT method. The DNA binding property of the complexes was evaluated by UV, fluorescence, CD spectroscopies and thermal denaturation. The cytotoxicity of complexes 1 and 3 against all the tested cell lines is better than that of cisplatin. Complexes 1 and 2 exhibit 7- and 4-folds higher cytotoxicity than cisplatin against Bel-7402 cell line. Complex 3 displays the highest cytotoxicity against all the cell lines tested, and shows 7-, 14-, 8-, 11- and 8-folds higher cytotoxicity than cisplatin against Bel-7402, A549, Hela, K562 and MCF-7 cell lines. The complexes bind to DNA via intercalation mode and complex 3 stabilizes the G-quadruplex. The results reveal that all the complexes display high cytotoxicity against all the tested cancer cell lines, and complex 3 is selective for G-quadruplex over duplex DNA. PMID- 23927971 TI - Design, synthesis, and in vitro hMAO-B inhibitory evaluation of some 1-methyl-3,5 diphenyl-4,5-dihydro-1H-pyrazoles. AB - A series of 1-methyl-3,5-diphenyl-4,5-dihydro-1H-pyrazoles (3a-k and 4a-u) were designed, synthesized, and evaluated for their inhibitory efficacy towards the two hMAO isoforms. Most of the derivatives were found to be potent and selective hMAO-B inhibitors. In particular, derivative 3g showed greater hMAO-B affinity than selective inhibitor selegiline coupled with high selectivity index (SI=145). The most selective hMAO-B inhibitor was the 3-methyl analogue 3f with an SI higher than 909. PMID- 23927972 TI - Synthesis and SAR studies of marine natural products ma'edamines A, B and their analogues. AB - The synthesis of several analogues of ma'edamines A and B are reported. The synthesized compounds were tested on hormone receptor positive and HER2 positive breast cancer cell lines, by MTT assay. MED-114, 115, 117, 119, 120, 124, 128 and 131 were found to be equally active as Lapatinib on HER2 +ve cell line SKBR3. PMID- 23927973 TI - Discovery of nonbenzamidine factor VIIa inhibitors using a biaryl acid scaffold. AB - In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2 Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa. PMID- 23927974 TI - Potential neuroprotective flavonoid-based inhibitors of CDK5/p25 from Rhus parviflora. AB - Rhus parviflora (Anacardiaceae) is an indigenous medicinal shrub found in South Asia with flavonoid rich edible fruit. This study examined flavonoid derivatives of R. parviflora fruit with CDK5/p25 inhibition activity. Evaluation by in vitro assay and docking simulations for CDK5/p25 revealed that the aurones, sulfuretin (1) and aureusidin (2), the aurone glycoside, aureusidin-6-O-beta-D glucopyranoside (3) and hovetrichoside C (4), the flavonoid glycoside, quercetin 3-O-beta-D-galactopyranoside (5), and the biflavonoid, cupressuflavone (6), had the potential to inhibit CDK5/p25, which could be useful in the treatment of neurodegenerative disorders such as Alzheimer's disease. Compound2 showed the significant in vitro inhibition capacity (IC50 value of 4.81 MUM) as well as binding affinity with docking energy of -8.73 (kcal/mol) for active sites CYS83 and GLN130 of CDK5/p25 enzyme in comparison to reference compound R-roscovitine. PMID- 23927975 TI - Utility of intraindividual reaction time variability to predict white matter hyperintensities: a potential assessment tool for clinical contexts? AB - Intraindividual variability (IIV) refers to reaction time (RT) variation across the trials of a given cognitive task. Little research has contrasted different measures of IIV or assessed how many RT trials are required to provide a robust measure of the construct. We, therefore, investigated three measures of IIV (raw SD, coefficient of variation, and intraindividual SD statistically removing time on-task effects) in relation to frontal white matter hyperintensities (obtained through structural MRI) in 415 cognitively normal community-dwelling adults aged 44 to 48 years. Results indicated the three IIV measures did not differ greatly in predictions of white matter hyperintensities, although it is possible that time-on-task effects were influential. As few as 20 trials taking approximately 52 s to administer provided a reliable prediction of frontal white matter hyperintensities. We conclude that future work should evaluate the comparative utility of different IIV measures in relation to persons exhibiting clear neuropathology. PMID- 23927976 TI - The emerging HIV epidemic among men who have sex with men in Taiwan. PMID- 23927978 TI - Evaluate root and canal morphology of primary mandibular second molars in Chinese individuals by using cone-beam computed tomography. AB - BACKGROUND/PURPOSE: More detailed knowledge of root and canal morphology is important in order to improve the success in the endodontics of primary teeth. The purpose of this study was to evaluate the root and canal morphology of primary mandibular second molars (PMSMs) in a Chinese population using cone-beam computed tomography (CBCT). METHODS: CBCT images, which had been obtained previously in the West China Hospital of Stomatology at Sichuan University, Chengdu, China between May 2009 and December 2011, were screened retrospectively. Finally, 283 individuals-207 male and 76 female with a mean age of 7.2 years (range 3-10 years)-and 487 PMSMs with clear images of root and canal morphology were enrolled. The number of roots and morphology of canals were recorded. The patient's gender, and the symmetry and frequency of three roots in PMSMs were analyzed. RESULTS: The majority of PMSMs had two (72.28%) or three roots (27.52%). The symmetrical incidence of three-root PMSMs in this Chinese population was 50.65%. There is no difference between genders in the prevalence of an extra root and the incidence of symmetry (p > 0.05). Of the individuals enrolled, 25.26% of PMSMs had three canals and 73.31% had four canals. The root canal systems of the PMSMs in the present study were categorized into seven variants. CONCLUSION: This study indicated that three-rooted PMSMs occur frequently in the Chinese population. There was no difference between the two genders on incidence and symmetry. The majority of PMSMs have three to four canals and the diversity of the root canal variants should be considered when performing clinical procedures. CBCT is a good option for studying the root and canal morphology of primary teeth. PMID- 23927977 TI - Bcl-6 expression and lactate dehydrogenase level predict prognosis of primary gastric diffuse large B-cell lymphoma. AB - BACKGROUND/PURPOSE: The gastrointestinal tract is the most common site of primary extranodal non-Hodgkin lymphoma, and the prognostic factors of primary gastric diffuse large B-cell lymphoma (PG-DLBCL) differ in various studies. METHODS: We retrospectively searched for PG-DLBCL in a single institution, performed immunohistochemical analysis, classified tumor phenotype (Hans and Muris algorithms), reviewed medical records, and analyzed the clinical and immunophenotypic variables using Cox proportional hazard regression model. RESULTS: A total of 46 cases were identified including 25 males and 21 females with a median age of 63.5; 18 (39%) were at stage I and 28 (61%) at stage II. Seven (15%) patients underwent surgery as initial treatment including total (n = 3, 7%) and subtotal (n = 4, 9%) gastrectomy. Thirty-three patients (72%) received frontline chemotherapy treatment including ten with additional rituximab (MabThera) injection, and two (6%) of these patients developed perforation after chemotherapy. Four patients passed away shortly after diagnosis and the remaining three were lost to follow-up. The overall 2- and 5- year survival rates were 55% and 50%, respectively. The expression of various differentiation markers was CD10 (25%), bcl-2 (50%), bcl-6 (84%), and MUM1 (64%). Half of the cases studied (22/44) were classified as germinal center B-cell (GCB) phenotype and the remaining half as non-GCB according to Hans algorithm; 66% and 34% cases belonged to groups 1 and 2, respectively, according to Muris algorithm. Univariate analysis showed the expression of bcl-6 by the tumor cells as a favorable factor, while elevated serum lactate dehydrogenase (LDH) level, bcl-2 expression, and Muris group 2 were associated with poorer outcome. Multivariate analysis revealed that the two prognostic factors were bcl-6 expression and elevated LDH level, with hazard ratios of 0.09 (p = 0.002) and 3.72 (p = 0.024), respectively. CONCLUSION: In this retrospective study with heterogeneous treatment modality, we identified bcl-6 expression and elevated LDH level as two prognostic factors for PG-DLBCL. PMID- 23927979 TI - ADHD-related symptoms, emotional/behavioral problems, and physical conditions in Taiwanese children with epilepsy. AB - BACKGROUND/PURPOSE: Little is known about whether Asian children with epilepsy have more attention-deficit hyperactivity disorder (ADHD)-related symptoms, emotional/ behavioral problems, and physical conditions compared with those described in Western studies. The authors investigated the rates of ADHD-related symptoms, emotional/behavioral problems, and physical conditions among pediatric patients with epilepsy. METHODS: We recruited 61 patients with epilepsy, aged 6 16 years, and 122 age-, sex-, and parental education-matched school controls. Data on demographics, parental reports on the Child Behavior Checklist (CBCL) and Swanson, Nolan, and Pelham, version IV scale (SNAP-IV), and medical records were collected. RESULTS: The average full-scale intelligence quotient of the case group was 95.8. There were 11 (18.0%), 7 (11.5%), 26 (42.6%), and 26 (42.6%) of children with epilepsy ever clinically diagnosed with developmental delay, overt ADHD symptoms, allergies reported by physicians, and behavior problems measured by the CBCL, respectively. Those children with epilepsy had more severe ADHD related symptoms and a wider range of emotional/behavioral problems than controls (Cohen's d 0.36-0.80). The rate of potential cases of ADHD among children with epilepsy was 24.6%. A history of developmental delay predicted ADHD- related symptoms and internalizing and externalizing problems. Among children with epilepsy, a longer duration of treatment with antiepileptic drugs predicted externalizing problems, and an earlier onset of epilepsy predicted inattention and hyperactivity/impulsivity. CONCLUSION: Our findings imply that clinicians should assess physical and emotional/behavioral problems among children with epilepsy in order to provide interventions to offset possible adverse psychiatric outcomes. PMID- 23927980 TI - Potential benefits of palliative care for polysymptomatic patients with late stage nonmalignant disease in Taiwan. AB - BACKGROUND/PURPOSE: Taiwan is only now beginning to offer palliative care to patients who do not have cancer. This study aimed to document the polysymptomatic presentation of illness in Taiwanese patients with late-stage nonmalignant disease and to evaluate the potential benefits of palliative care for these patients. The results may help to educate healthcare personnel regarding the need for and importance of palliative treatment as comprehensive, appropriate end-of life care for patients with nonmalignant disease. METHODS: We retrospectively analyzed 115 patients without cancer hospitalized in a community hospital in Taiwan: 61 had organic brain disease, 31 had chronic obstructive pulmonary disease, 17 had chronic renal failure, 14 had congestive heart failure, 12 had liver cirrhosis, and 20 had multiple illnesses. The median age was 81 years (interquartile range 69-86 years), and 51% of patients were enrolled from intensive care. Symptoms and their severity were analyzed. Patients' and their families' understanding of the diagnosis and prognosis and "Do Not Resuscitate" (DNR) consent were evaluated pre- and post-palliative care. RESULTS: The four leading symptoms were fatigue (96%), fever (86%), cough (81%), and dyspnea (79%). No significant differences in symptom prevalence were found between different sexes, ages, performance statuses, ward locations, or underlying diseases, except for fewer episodes of dizziness, more frequent episodes of cough in patients older than 80 years, and more episodes of jaundice in ward service subjects. Only the presence of abdominal distension differed significantly between surviving and deceased patients (22.9% vs. 40.3%; p=0.004). After the start of palliative care, patients' DNR consent increased (105/115 before, 114/115 after). Patients' recognition of the diagnosis and prognosis increased from 13 to 64, respectively, with a simultaneous increase in family members' recognition (66 before, 114 after). CONCLUSION: Hospice care with good symptom control is warranted for patients with late-stage nonmalignant disease who need appropriate end-of-life care. Medical personnel need education in the importance of palliative care and the identification of patients who could benefit from it. In addition, patients should be informed of its availability. PMID- 23927981 TI - Long-term follow-up of patients with surgical intractable acromegaly after linear accelerator radiosurgery. AB - BACKGROUND/PURPOSE: Radiotherapy is a crucial treatment for acromegalic patients with growth hormone (GH)-secreting pituitary tumors. However, its effect takes time. We retrospectively reviewed the long-term outcome of linear accelerator stereotactic radiosurgery (LINAC SRS) for patients with acromegaly from the perspective of biochemical remission and associated factors. METHODS: Twenty-two patients presenting with residual or recurrent (GH)-secreting functional pituitary tumor between 1994 and 2004 who received LINAC SRS were enrolled and followed up for at least 3 years. Residual or recurrent tumor was defined as persistent elevated GH or insulin-like growth factor-1 (IGF-1) level and image confirmed tumor after previous surgical treatment. Biochemical remission was defined as fasting GH less than 2.5 ng/mL with normal sex-and-age adjusted IGF-1. RESULTS: The mean follow-up period was 94.7 months (range 36-161 months). Overall mean biochemical remission time was 53 months (median 30 months). Biochemical control was achieved in 15 patients (68.2%) over the follow up period. One patient experienced recurrence after SRS and underwent another operation. Initial GH at diagnosis and pre-SRS GH correlated with biochemical control (p = 0.005 and p < 0.0001, respectively). Further evaluation demonstrated that biochemical control stabilized after 7.5 years. Overall post-SRS hormone deficit persisted in five patients (22.7%). CONCLUSION: In comparison to other radiosurgery modalities, LINAC radiosurgery also provides a satisfactory outcome. SRS has maximum effect over the first 2 years and stabilizes after 7.5 years. Moreover, SRS elicits long-term biochemical effects and requires longer follow-up for better biochemical remission. PMID- 23927982 TI - Body mass index and buttock circumference are independent predictors of disintegration failure in extracorporeal shock wave lithotripsy for ureteral calculi. AB - BACKGROUND/PURPOSE: Effective stone disintegration by extracorporeal shockwave lithotripsy (ESWL) may depend on patient- and stone-related factors. We investigated predictors of disintegration failure in ESWL for a solitary ureteral calculus. METHODS: From July 2008 to May 2010, 203 patients who underwent ESWL for a solitary ureteral calculus were enrolled. Clinical and radiologic data were collected, and factors related to ESWL failure were analyzed. RESULTS: Fifty-two patients (25.6%) showed ESWL failure, with a mean follow-up of 41 days. Forty patients (19.7%) required retreatment, including 12 who underwent repeat ESWL and 28 who underwent curative ureteroscopy. Patients with ESWL failure had significantly higher body weight, body mass index (BMI), and buttock circumference (BC) than patients for whom ESWL was successful. Univariate analysis showed that stone burden (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.03-1.06) and BC (OR, 1.06; 95% CI, 1.01-1.11) were predictors of ESWL failure, while BMI was a potential predictor with borderline significance (OR, 1.09; 95% CI, 0.99-1.20). Multivariate analysis showed that stone burden (OR, 1.04; 95% CI, 1.03-1.06) was a significant predictor for all patients. On stratifying patients according to the level of ureteral calculi, BC was found to be an independent predictor (OR, 1.35; 95% CI, 1.02-1.80) for ESWL failure for middle/lower ureteral calculi and BMI (OR, 1.47; 95% CI, 1.13-1.91) for upper ureteral calculi. CONCLUSION: Stone burden is the main predictor of ESWL failure for all patients with ureteral calculi. BC and BMI are independent predictors for ESWL failure for middle/lower and upper ureteral calculi, respectively. PMID- 23927983 TI - Balloon-occluded retrograde transvenous obliteration for intractable gastric variceal bleeding. AB - Balloon-occluded retrograde transvenous obliteration (BRTO) is an interventional radiologic technique that obliterates gastric varices (GV) from draining veins under balloon occlusion. A 54-year-old man presented with Stage IV hepatocellular carcinoma and tumor thrombi in main portal vein. Intractable GV bleeding had no response to repeated endoscopic sclerotherapy and pharmacotherapy well. Additionally, his medical condition could not allow transjugular intrahepatic portosystemic shunt or surgical portal decompression. Due to spontaneous gastrorenal shunt proved with abdominal computed tomography, we conducted BRTO to prevent further bleeding. The immediate postprocedural venogram showed total occlusion of the gastrorenal shunt and no visualization of the GV. Follow-up endoscopy was performed at 1 month, 2 months, and 4 months after BRTO. It revealed shrinkage of gastric varices and no worsening of esophageal varices after 4 months of BRTO. The patient was free from repeated GV bleeding for 4 months. Our experience proved BRTO could be the other effective treatment for intractable GV bleeding. PMID- 23927984 TI - Zoonotic atypical pneumonia due to Chlamydophila psittaci: first reported psittacosis case in Taiwan. AB - Human psittacosis caused by Chlamydophila psittaci is one of the most common zoonotic atypical pneumonias featuring pulmonary as well as extrapulmonary infections. Most of the cases involve avian contact history especially with psittacine birds. Herein we report a 44-year-old male patient displaying atypical pneumonia symptoms of intermittent fever, dry cough, chest pain, dyspnea, headache, hepatitis, and hyponatremia. He had two sick cockatiels, one of which had died a month previously. A microimmunofluorescence test was performed to check the serum antibody levels against Chlamydophila psittaci. The serum IgM titer showed positive titer of 1:256, 1:256, and 1:128 on Days 11, 23, and 43 after disease onset, respectively. His fever subsided soon and clinical symptoms improved after minocycline was administrated on Day 12. The psittacosis case was confirmed by history of psittacine bird contact, clinical symptoms, treatment response, and positive IgM titer. To our knowledge, this is the first report of a psittacosis case in Taiwan. PMID- 23927985 TI - Neck abscess caused by Salmonella enterica serotype Enteritidis. PMID- 23927986 TI - Infected bronchogenic cyst diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration. PMID- 23927987 TI - Non-albicans Candida related candidemia among patients with chronic hemodialysis in the intensive care unit: true incidence or cluster infections? PMID- 23927988 TI - Reply to "Non-albicans Candida related candidemia among patients with chronic hemodialysis in the intensive care unit: true incidence or cluster infections?". PMID- 23927989 TI - Can monitoring in language comprehension in Autism Spectrum Disorder be modulated? Evidence from event-related potentials. AB - The present study examined language comprehension in Autism Spectrum Disorder (ASD) in light of monitoring. It was studied whether individuals with ASD monitor their language perception, and whether monitoring during language perception could be modulated with instructions. We presented higher-level (semantic) linguistic violations and lower-level (orthographic) linguistic violations in a free reading condition and in an instructed condition, recording event-related potentials. For control participants, a monitoring response as tapped by the P600 effect was found to semantically and orthographically incorrect input in both conditions. For participants with ASD, however, a monitoring response to semantically implausible input, tapped by the P600, was found only in the instructed condition. For orthographic errors monitoring was observed both in the free reading and in the instructed condition. This suggests that people with ASD are less inclined than typical individuals to monitor their perception of higher level linguistic input, but that this can be enhanced with instructions. PMID- 23927990 TI - Objective measurement of weekly physical activity and sensory modulation problems in children with attention deficit hyperactivity disorder. AB - This study aimed to objectively compare the daily physical activity (PA), as indicated by moderate-to-vigorous physical activity (MVPA) during a week and metabolic equivalents (METs) per minute, between children with attention deficit hyperactivity disorder (ADHD) and typically developing children. Moreover, sensory modulation problems were examined using behavioral and physiological measures. Twenty boys with ADHD (mean age 8.64 +/- 2.57 years), and 20 matched typically developing boys (mean age 9.10 +/- 1.79 years) participated in our study. Each child wore a PA monitor for 14 h a day, seven days a week. All participants' parents were asked to fill out daily activity logs for their children. The problems of sensory modulation were detected using sensory profile (SP) questionnaires and Sensory Challenge Protocol that measured electrodermal response (EDR) to repeated sensory stimulation. Compared with the controls, the children with ADHD had a generally higher level of PA (1.48 +/- 0.10 vs. 1.60 +/- 0.12 METs/min; p=001), and tended to spend more time in MVPA on weekdays (35.71%) and the weekend (57.14%). However, when analyzing hourly recorded PA, the group differences were obvious only for certain hours. Our data suggested that children with ADHD were more hyperactive in structure-free than structured settings. The ADHD group showed their sensory modulation problems on the SP but not on the EDR. We found some correlations between sensory modulation problems and hyperactivity in children with ADHD. PMID- 23927991 TI - The effect of video-guidance on passive movement in patients with cerebral palsy: fMRI study. AB - In patients with cerebral palsy (CP), neuroimaging studies have demonstrated that passive movement and action-observation tasks have in common to share neuronal activation in all or part of areas involved in motor system. Action observation with simultaneous congruent passive movements may have additional effects in the recruitment of brain motor areas. The aim of this functional magnetic resonance imaging (fMRI) study was to examine brain activation in patients with unilateral CP during passive movement with and without simultaneous observation of simple hand movement. Eighteen patients with unilateral CP (fourteen male, mean age 14 years and 2 months) participated in the study. Using fMRI block design, brain activation following passive simple opening-closing hand movement of either the paretic or nonparetic hand with and without simultaneous observation of a similar movement performed by either the left or right hand of an actor was compared. Passive movement of the paretic hand performed simultaneously to the observation of congruent movement activated more "higher motor areas" including contralesional pre-supplementary motor area, superior frontal gyrus (extending to premotor cortex), and superior and inferior parietal regions than nonvideo-guided passive movement of the paretic hand. Passive movement of the paretic hand recruited more ipsilesional sensorimotor areas compared to passive movement of the nonparetic hand. Our study showed that the combination of observation of congruent hand movement simultaneously to passive movement of the paretic hand recruits more motor areas, giving neuronal substrate to propose video-guided passive movement of paretic hand in CP rehabilitation. PMID- 23927993 TI - t(11;14) multiple myeloma: a subtype associated with distinct immunological features, immunophenotypic characteristics but divergent outcome. AB - t(11;14)(q13;q32) is the most common chromosome translocation in multiple myeloma (MM), but a consensus of clinicopathological features and impact on survival is yet to be reached. We analyzed a cohort of 350 patients with various plasma cell malignancies, including newly diagnosed MM (NDMM, n=253), relapsed/refractory MM (RRMM, n=77), as well as primary and secondary plasma cell leukemia (PCL, n=10 and n=10, respectively). RESULTS: A remarkably higher frequency of t(11;14) was observed in the PCL than in the NDMM. A high incidence of t(11;14) was detected in the IgD, IgM, and nonsecretory MM. The t(11;14) MM group was associated with a significantly higher positive rate of B-lineage associated antigens CD20 and CD79a as well as the lack of CD56 expression. t(11;14) was less likely to be accompanied by 13q14 deletion than 13q14 deletion frequency in non-t(11;14) population (p=0.026), and fewer patients displaying t(11;14) were identified as belonging to the high-risk cytogenetic group due to the extremely low incidence of t(4;14) and t(14;16). As a whole, patients exhibiting t(11;14) had a comparable outcome with the control cohort in NDMM, but CD20 was able to identify two subsets of the disease with dissimilar outcomes. Among patients receiving bortezomib-based treatment, patients harboring t(11;14) without CD20 expression had a significantly shortened PFS (11.0 versus 43.0 months, p=0.005) and OS (16.5 versus 54.0 months, p=0.016) compared with patients displaying t(11;14) with CD20. Our findings suggest that although the t(11;14) plasma cell disorder displayed distinct biological, clinical and laboratory features, it was a heterogeneous disease with divergent outcome. PMID- 23927992 TI - The population genomics of repeated evolution in the blind cavefish Astyanax mexicanus. AB - Distinct populations of Astyanax mexicanus cavefish offer striking examples of repeatable convergence or parallelism in their independent evolutions from surface to cave phenotypes. However, the extent to which the repeatability of evolution occurred at the genetic level remains poorly understood. To address this, we first characterized the genetic diversity of 518 single-nucleotide polymorphisms (SNPs), obtained through RAD tag sequencing and distributed throughout the genome, in seven cave and three groups of surface populations. The cave populations represented two distinct lineages (old and new). Thirty-one SNPs were significantly differentiated between surface and old cave populations, two SNPs were differentiated between surface and new cave populations, and 44 SNPs were significantly differentiated in both old and new cave populations. In addition, we determined whether these SNPs map to the same locations of previously described quantitative trait loci (QTL) between surface and cave populations. A total of 25 differentiated SNPs co-map with several QTL, such as one containing a fibroblast growth factor gene (Fgf8) involved in eye development and lens size. Further, the identity of many SNPs that co-mapped with QTL was the same in independently derived cave populations. These conclusions were further confirmed by haplotype analyses of SNPs within QTL regions. Our findings indicate that the repeatability of evolution at the genetic level is substantial, suggesting that ancestral standing genetic variation significantly contributed to the population genetic variability used in adaptation to the cave environment. PMID- 23927994 TI - Absolute monocyte count in follicular lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. AB - Elevated absolute monocyte counts (AMCs) have been reported to indicate poor prognosis for patients with lymphoproliferative disease, including those with follicular lymphoma (FL) receiving various treatments. We evaluated the prognostic impact of AMC in 150 consecutive FL patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Progression-free survival (PFS) did not differ significantly according to the AMC level. Univariate and multivariate analyses did not indicate a prognostic significance of AMC for PFS. Thus, the AMC is not a prognostic factor for FL patients treated with R-CHOP. However, immunochemotherapy might influence the prognostic impact of AMC. PMID- 23927995 TI - Gentamicin-enriched, water-soluble polymer wax reduces the burden of infection after sternotomy in pigs. AB - OBJECTIVES: One of the most frequent complications in cardiac surgery is postoperative bleeding from the sternum. To diminish the risk of bleeding, bone wax is frequently used for haemostasis. However, we have previously shown that bone wax impairs bone healing and induces inflammation in the sternum. A new, water-soluble polymer wax enriched with gentamicin has haemostatic properties similar to bone wax and may diminish the risk of infection. The purpose of this study was to determine whether the gentamicin-enriched, water-soluble polymer wax could reduce infection rates when compared with bone wax in a porcine model. METHODS: Thirty-two Landrace/Yorkshire pigs were sternotomized and randomized to haemostasis by gentamicin-enriched, water-soluble polymer wax (Gen group) or bone wax (Wax group). After 4 weeks the pigs were euthanized. Blood samples were analysed for the fraction and concentration of neutrophil granulocytes and C reactive protein and the surgical site was biopsied. Stereology was performed on histological samples, and the magnitude of infection was quantified as the areas of microabscesses, granulomas and tissue with acute inflammation compared with the total tissue area. RESULTS: The temperature was 38.2 degrees C in the Gen group vs 38.6 degrees C in the Wax group, P < 0.05. No animals in the Gen group and three in the Wax group showed a temperature >39.3 degrees C. Neutrophil granulocyte concentration was 5.00 * 10(9)/l in the Gen group and 6.92 * 10(9)/l in the Wax group, P = 0.277, with a leucocyte fraction of 20.9% vs 29.3%, P = 0.119. C-reactive protein (CRP) was 142 mg/l in the Gen group compared with 318 mg/l in the Wax group, P = 0.106. Histological samples showed acute inflammatory changes in 5.0% of the tissue in the Gen group vs 18.3% in the Wax group, P < 0.001. Microabscesses were present in 0.3% of the sample tissue in the Gen group vs 2.2% in the Wax group, P < 0.001. Concentrations of gentamicin were >100 mg/l in mediastinal fluid and <2 mg/l in venous blood. CONCLUSIONS: When used for haemostasis after sternotomy in a porcine model, gentamicin-enriched, water soluble polymer wax reduces sign of infection when compared with bone wax and therefore appears to be a more suitable choice for preventing postoperative, sternal osteomyelitis. PMID- 23927996 TI - Imaging of atherosclerosis: can molecular imaging do more? PMID- 23927997 TI - The effect of BMP-2, BMP-4 and BMP-6 on bone destruction of cholesteatoma presence. AB - OBJECTIVE: The aim of our study was to investigate the relationship between the destruction of temporal bone structures, ossicular chain destruction, dissemination of cholesteatoma and the expressions of bone morphogenetic proteins (BMPs), BMP-2, BMP-4 and BMP-6 in patients with acquired cholesteatoma. MATERIAL AND METHODS: This study was performed in a total of 80 patients with cholesteatoma and without cholesteatoma who had undergone surgery due to chronic otitis media. The patients were grouped as the study and the control groups. The study group comprised patients with primary acquired cholesteatoma, and the control group consisted of chronic otitis media patients without cholesteatoma. The samples were obtained from cholesteatoma tissue and the external acoustic meatus skin in study group patients and they were obtained from the external acoustic meatus skin only in control group patients. The Reverse Transcriptase Polymerase Chain Reaction method was used for the measurements of BMPs, BMP-2, BMP-4 and BMP-6 expressions. Polymerase Chain Reaction was studied by isolation of Ribonucleic Acid from the tissue samples. RESULTS: When the expressions of BMP in the external acoustic meatus skin were compared between the study and the control groups, the BMPs, BMP-2 and BMP-6 were determined to have a statistically significant relation in the study group (p<0.05), but BMP-4 was not significant (p>0.05). When the expression of BMP in cholesteatoma tissue was investigated in the study group patients, the BMPs, BMP-2 and BMP-6 were determined with statistically significant positivity (p<0.05), but there was no significant positivity for BMP-4 (p>0.05). In the study group, there was no statistical significance between the expressions of BMPs, BMP-2, BMP-4 and BMP-6 in cholesteatoma tissue, in the external acoustic meatus skin, and temporal and ossicular chain destruction, and dissemination of cholesteatoma (p>0.05). A statistically significant positivity for BMPs expression in cholesteatoma tissue was determined in patients with destruction of the incus+malleus+stapes (p<0.05). CONCLUSION: The expressions of BMPs, BMP-2 and BMP-6, were elevated in cholesteatoma tissue. Furthermore, the positivity of BMPs expression was statistically significant in patients with destruction of all the ossicles, and we think that this marker can be used for evaluation of the aggressiveness of cholesteatoma. PMID- 23927998 TI - Complicated necrotizing otitis externa. AB - Necrotizing (malignant) otitis externa (NOE) is a rare and invasive infection originating in the external acoustic meatus seen most commonly in diabetes and other immunocompromised states. After a protracted course, disease can smolder and extend into the mastoid, skull base, dural sinuses, and intracranially. We present a case of NOE complicated by mastoiditis, dural sinus thrombosis, and Bezold's abscess in an uncontrolled diabetic presenting with a prolonged course of facial nerve palsy. We stress the importance of maintaining a high index of clinical suspicion for NOE in diabetic patients and offering timely, aggressive treatment to mitigate its complications. PMID- 23927999 TI - Common (and multiple) neural substrates for static and dynamic motion after effects: a rTMS investigation. AB - INTRODUCTION: Prolonged exposure to directional motion (adaptation) biases the perceived direction of subsequently presented test stimuli towards the opposite direction with respect to that of adaptation (i.e., motion after-effect; MAE). Different neural populations seem to be involved in the generation of the MAE, depending on the spatiotemporal characteristics of both adapting and test stimuli. Although the tuning mechanisms of the neural populations involved in the MAE have been psychophysically identified, the specific loci along the motion processing hierarchy where the different types of MAE take place is still debated. METHOD: In this study, by using repetitive transcranial magnetic stimulation (rTMS) delivered during the inter-stimulus interval (ISI) between adapting and test patterns, we investigated the cortical locus of processing of static MAE (sMAE) and dynamic MAE (dMAE). RESULTS: Results showed that rTMS over V2/V3 or V5/MT decreased the perceived duration of both sMAE and dMAE, although rTMS over V2/V3 decreased mainly the perceived duration of sMAE. CONCLUSIONS: sMAE and dMAE rely on the same cortical structures present at intermediate and low-levels of motion processing, although low-level visual areas (e.g., V2/V3) show a prevalence of neurons responsible for sMAE. PMID- 23928000 TI - Abilities and genes for PAH biodegradation of bacteria isolated from mangrove sediments from the central of Thailand. AB - PAH-degrading bacteria, including Novosphingobium sp. PCY, Microbacterium sp. BPW, Ralstonia sp. BPH, Alcaligenes sp. SSK1B, and Achromobacter sp. SSK4, were isolated from mangrove sediments. These isolates degraded 50-76% of 100 mg/l phenanthrene within 2 weeks. Strains PCY and BPW also degraded pyrene at 98% and 71%, respectively. Furthermore, all of them probably produced biosurfactants in the presence of hydrocarbons. Interestingly, PCY has a versatility to degrade various PAHs. Molecular techniques and plasmid curing remarkably revealed the presence of the alpha subunit of pyrene dioxygenase gene (nidA), involving in its pyrene/phenanthrene degrading ability, located on megaplasmid of PCY which has never before been reported in sphingomonads. Moreover, genes encoding ferredoxin, reductase, extradiol dioxygenase (bphA3A4C) and exopolysaccharide biosynthetase, which may be involved in PAH degradation and biosurfactant production, were also found in PCY. Therefore, we conclude that these isolates, especially PCY, can be the candidates for use as inoculums in the bioremediation. PMID- 23928001 TI - Long-term treatment with fasudil improves bleomycin-induced pulmonary fibrosis and pulmonary hypertension via inhibition of Smad2/3 phosphorylation. AB - Pulmonary hypertension (PH) associated with pulmonary fibrosis (PF) considerably worsens prognosis of interstitial lung diseases (ILD). RhoA/Rho-kinases (ROCK) pathway is implicated in high pulmonary vascular tone and pulmonary fibrosis but the effect of ROCK inhibitors on PH associated with PF is not known. We therefore aimed to determine whether long-term treatment with fasudil, a selective ROCK inhibitor, could attenuate PF and PH induced by bleomycin in mice. Male C57BL/6 mice received a single dose of intratracheal bleomycin (3.3 U/kg) to induce PF. Treatment with fasudil (30 mg kg(-1) day(-1)) was given intraperitoneally for 7, 14 or 21 days until mice underwent hemodynamic measurements. Right ventricular systolic pressure (RVSP) and RV/(LV + S) ratio were assessed. Lung inflammatory cells profiles, including macrophages, neutrophils, lymphocytes B and lymphocytes T were assessed by immunohistochemistry. Lung fibrosis was evaluated by histological and biochemical methods. Pulmonary arteriole muscularization and medial wall thickness (MWT) were evaluated by immunohistochemical staining for alpha-SMA. Bleomycin induced severe PF and PH in mice, associated with an increased RhoA/ROCK activity in the lung. Fasudil reduced lung inflammation and lung collagen content, and attenuated the increased RVSP, RV hypertrophy, and pulmonary vascular remodeling in bleomycin-intoxicated mice. Fasudil inhibited the increased activity of RhoA/ROCK pathway, and partly altered bleomycin associated activation of TGF-beta1/Smad pathway, via inhibition of Smad2/3 phosphorylation. The efficacy of long-term treatment with fasudil suggests that the blockade of RhoA/ROCK pathway may be a promising therapy for patients with ILD-associated PH. PMID- 23928003 TI - Pediatric cataract surgery with hydrophilic acrylic intraocular lens. AB - PURPOSE: To assess the outcomes after hydrophilic acrylic intraocular lens (IOL) implantation during pediatric cataract surgery. METHODS: This was a retrospective chart review of children who underwent cataract surgery or secondary IOL implantation at Beirut Eye Specialist Centre, Rizk Hospital, between March 2002 and August 2007. RESULTS: A total of 57 eyes of 40 patients (20 boys) were included in this study. The average age at surgery was 48 +/- 40 months (range, 5 172 months). Of these, 54 eyes had congenital or developmental cataracts and 3 eyes had traumatic cataracts. Primary cataract removal and IOL implantation accounted for 45 surgeries, and secondary IOL implantation accounted for 12 surgeries. Hydrophilic acrylic IOLs were implanted in all surgeries. Average follow-up time was 47 +/- 21 months (range, 9-97 months). No intraoperative complications were recorded. Of the 57 eyes, 12 (21%) had postoperative complications, but only 7 (12%) required secondary intervention. Average best corrected visual acuity improved from 2.0 +/- 1.0 logMAR preoperatively to 0.8 +/ 1.0 logMAR at last follow-up. Improved visual acuity was observed in 47 eyes (82.5%); 31 eyes (54.4%) had a visual acuity of >= 20/40 at the last follow-up. CONCLUSIONS: Hydrophilic acrylic IOLs appear to be suitable for use in pediatric cataract surgery. Results from this study suggest that, compared with hydrophobic IOLs, these IOLs produce similar complication rates, secondary intervention rates, and visual acuity results. PMID- 23928002 TI - A systematic approach for designing a HBM pilot study for Europe. AB - The objective of COPHES (Consortium to Perform Human biomonitoring on a European Scale) was to develop a harmonised approach to conduct human biomonitoring on a European scale. COPHES developed a systematic approach for designing and conducting a pilot study for an EU-wide cross-sectional human biomonitoring (HBM) study and for the implementation of the fieldwork procedures. The approach gave the basis for discussion of the main aspects of study design and conduct, and provided a decision making tool which can be applied to many other studies. Each decision that had to be taken was listed in a table of options with their advantages and disadvantages. Based on this the rationale of the decisions could be explained and be transparent. This was important because an EU-wide HBM study demands openness of all decisions taken to encourage as many countries as possible to participate and accept the initiative undertaken. Based on this approach the following study design was suggested: a cross-sectional study including 120 children aged 6-11 years and their mothers aged up to 45 years from each participating country. For the pilot study the children should be sampled in equal shares in an urban and a rural location. Only healthy children and mothers (no metabolic disturbances) should be included, who have a sufficient knowledge of the local language and have been living at least for 5 years at the sampling location. Occupational exposure should not be an exclusion criterion. Recruitment should be performed via inhabitant registries or schools as an alternative option. Measures suitable to increase the response rate should be applied. Preferably, the families should be visited at home and interviewed face-to-face. Various quality control measures to guarantee a good fieldwork performance were recommended. This comprehensive overview aims to provide scientists, EU officials, partners and stakeholders involved in the EU implementation process full transparency of the work carried out in COPHES. Thus this report presents the discussion and consensus in COPHES on the main aspects of designing and conducting fieldwork of a human biomonitoring study. Furthermore, it provides an example for a systematic approach that may be useful to other research groups or pan-European research initiatives. In the study protocol that will be published elsewhere these aspects are elaborated and additional aspects are covered (Casteleyn et al., 2012). Meanwhile the respective pilot study DEMOCOPHES had been conducted and assessed. The results and lessons learned will be published elsewhere. PMID- 23928004 TI - The plusoptiX S08 photoscreener as a vision screening tool for children with autism. AB - PURPOSE: Children with autism and related disorders reportedly have an increased prevalence (40%) of ocular disorders, and comprehensive eye examinations by a pediatric ophthalmologist are recommended. Examinations can be very time consuming, expensive, and stressful for the child. A photoscreener such as the plusoptiX S08 may be a cost-effective, time-saving, and less invasive method for testing patients with autism. The purpose of this study was to determine the efficacy of photoscreening with the plusoptiX S08 in detecting amblyopia risk factors in children with autism. METHODS: Photoscreening and complete ophthalmologic examinations were performed on 43 children with autism. Prevalence, sensitivity, specificity, positive predictive value, and negative predictive value were calculated using ophthalmologic examination as the gold standard. RESULTS: The gold standard examination used American Association for Pediatric Ophthalmology and Strabismus Vision Screening Committee guidelines for the definition of amblyopia risk factors. The plusoptiX S08 referred 29 (67%) of 43 children. On examination, 16 patients (37%) had amblyopia risk factors. The plusoptiX S08 had a sensitivity of 94% (95% CI, 0.68-0.99). The specificity was 48% (95% CI, 0.29-0.68), the positive predictive value was 52% (95% CI, 0.33 0.70), and the negative predictive value was 93% (95% CI, 0.64-0.99). CONCLUSIONS: The plusoptiX S08 is sensitive but less specific at detecting treatable ocular conditions in children with autism. The majority of children with autism and amblyopia risk factors were detected on screening; however, about half of all referrals had no amblyopia risk factors. The plusoptiX S08 reduced the need for a full examination in one-third of the children screened. PMID- 23928005 TI - Strabismus among aged Medicare beneficiaries: impact of health status and region. AB - PURPOSE: To describe the effect of health status and geographic region of the United States on the prevalence of strabismus and strabismus surgery in the aged Medicare fee-for-service population. METHODS: A 5% sample of Medicare claims was used to identify aged beneficiaries diagnosed with strabismus and those having strabismus surgery between 2002 and 2010. The Charlson Comorbidity Index (CCI), a measure of systemic health, was calculated. The regional analysis divided the United States into East, West, Midwest, and South. Analyses were adjusted for age, sex, race, CCI, and region. RESULTS: The 5% sample for 2010 included 1,237,469 unique beneficiaries. Strabismus was diagnosed in 8,470 (0.68%) and strabismus surgery was performed on 197 (0.016%). Pooled data from 2002 through 2010 found the prevalence of strabismus increasing significantly with increasing comorbidity (P < 0.0001): 0.52% (CCI, 0), 0.65% (CCI, 1-2), 0.77% (CCI, 3-4), and 0.82% (CCI, 5 or higher). Conversely, the prevalence of strabismus surgery declined slightly with increasing comorbidity (P = 0.088): 0.016% (CCI, 0), 0.017% (CCI, 1-2), 0.015% (CCI, 3-4), and 0.015% (CCI, 5 or higher). The diagnosis of strabismus was made least frequently in the South (P < 0.0001), whereas strabismus surgery was performed more often in the West (P = 0.006). All significant effects remained after adjustment. CONCLUSIONS: The prevalence of strabismus increases significantly with declining health status; however, health status had little effect on the rate of strabismus surgery. Regional rates of strabismus diagnosis and surgery differ widely. PMID- 23928006 TI - Scientific Globish versus scientific English. AB - The proposed adoption of 'scientific Globish' as a simplified language standard for scholarly communication may appeal to authors who have difficulty with English proficiency. However, Globish might not justify the hopes being pinned on it and might open the door to further deterioration of the quality of English language scientific writing. PMID- 23928007 TI - A motive for the use of a posterior approach in shoulder arthography: ventral leakage of contrast medium. AB - BACKGROUND: Some orthopedic surgeons request a posterior approach for shoulder magnetic resonance (MR) arthrography, especially in patients with anterior shoulder instability, to avoid interpretive difficulties in differentiating anterior extraarticular contrast injection when using an anterior approach from ventral leakage of contrast. PURPOSE: To determine the occurrence of ventral leakage of contrast in shoulder MR arthrography when using a posterior approach. MATERIAL AND METHODS: Retrospectively, we included 73 consecutive patients who underwent shoulder MR arthrography (1.0 Tesla) using the posterior approach. Three unsuccessful procedures were excluded. Ventral leakage of contrast, defined as contrast seen around the musculus subscapularis without distention of the posterior capsule, was recorded. Descriptive statistics were used. RESULTS: Seventy shoulders were included. Forty-one left shoulders were involved (59%). Mean age of patients was 49 years (range, 17-76 years). Thirty-five patients were women (50%). Ventral leakage of contrast was seen in 12 shoulders (17%). CONCLUSION: As ventral leakage of contrast was seen in a substantial number of cases when using a posterior approach in shoulder MR arthrography, the use of a posterior approach is advised to avoid misinterpretation of ventral contrast leakage with accidental extra articular contrast injection, and to increase confidence in the final radiological diagnosis. PMID- 23928008 TI - Bronchial artery hypertrophy is correlated with coronary artery disease. AB - BACKGROUND: Bronchial arteries support the systemic pulmonary vasculature and physiologically communicate with pulmonary arteries and coronary arteries. While there is evidence supporting the link between pulmonary diseases and bronchial artery hypertrophy (BAH), few data on the correlation between coronary artery disease (CAD) and BAH have been published. PURPOSE: To evaluate a possible association between BAH and CAD in patients without known pulmonary diseases undergoing computed tomography coronary angiography (CTCA). MATERIAL AND METHODS: This retrospective study was approved by the local ethics committee. One hundred patients with varying degrees of CAD underwent CTCA. Patients were stratified into four groups as follows: group I, 25 patients without CAD or with non significant CAD; group II, 25 untreated patients with significant CAD; group III, 25 stented patients; group IV, 25 patients with coronary artery bypass grafts. The number and diameter of bronchial arteries were recorded. Correlation between age, CAD, and BAH was estimated. RESULTS: One hundred and ninety-nine bronchial arteries were detected. Approximately 51% were hypertrophic (diameter, >1.5 mm) with a mean diameter of 1.7 +/- 0.5 mm. Seventy-six patients showed no pulmonary alterations; 24 were found to have previously undiagnosed pulmonary findings, six of which were severe. Presence and degree of CAD correlated with patients' mean age (60 in group I, 68 in group II, 65 in group III, 69 in group IV; P = 0.023), and mean bronchial artery transverse diameter (1.6 mm, 1.7 mm, 1.8 mm, and 2.0 mm, respectively; P = 0.009). The bronchial artery diameter was not associated with pulmonary findings (P = 0.390). CONCLUSION: There is an association between CAD and BAH. In patients with no pulmonary alterations, BAH could be caused by undiagnosed underlying CAD. PMID- 23928009 TI - Posterior root of lateral meniscus: the detailed anatomic description on 3T MRI. AB - BACKGROUND: Although there have been some attempts to reveal the anatomy of the posterior root of the lateral meniscus (PRLM) through cadaver studies, arthroscopy, or imaging, it has not yet been described fully. PURPOSE: To describe clearly the unique features of the PRLM, including its course, configuration, and size, using 3.0-T magnetic resonance imaging (MRI). MATERIAL AND METHODS: A total of 105 knee 3.0-T MR examinations of 103 patients with arthroscopically proven intact PRLM were reviewed retrospectively. Based on fat saturated, proton-density-weighted (PDW) axial/coronal images and PDW sagittal images, the course, configuration, and attachment sites of the PRLM were evaluated. RESULTS: The majority of PRLM (76.2%) had two attachment sites: the medial tubercle along the intertubercular crest, just posteromedial to the tibial attachment of the anterior cruciate ligament (ACL), and the posterior slope of the lateral tubercle. The remaining cases (23.8%) had a solitary insertion on the intertubercular area (17 cases), or the posterior slope of the lateral tubercle (eight cases). The PRLM of the intertubercular area appeared as a dark signal line parallel to the tibial plateau on the mid-sagittal image and dark signal foci traversing the intertubercular crest on contiguous coronal images. CONCLUSION: The PRLM inserts mainly in the intertubercular area with a thin, long anterior extension to the point just posteromedial to the tibial attachment of the ACL. It is well delineated on PDW 3.0-T MRI as a dark signal line parallel to the tibial plateau on mid-sagittal images and dark signal foci traversing the intertubercular crest on contiguous coronal images. PMID- 23928010 TI - Diagnostic role of Gallium-68 DOTATOC and Gallium-68 DOTATATE PET in patients with neuroendocrine tumors: a meta-analysis. AB - BACKGROUND: Gallium-68 somatostatin receptor positron emission tomography (PET) has been used in the diagnosis of neuroendocrine tumors (NETs). The compounds often used in molecular imaging of NETs with PET are 68Ga-DOTATOC, 68Ga-DOTATATE, and 68Ga-DOTANOC. There is varying affinity to different somatostatin receptors. PURPOSE: To systematically review and perform a meta-analysis of published data regarding the diagnostic role of 68Ga-DOTATOC and 68Ga-DOTATATE PET in the diagnosis of NETs. MATERIAL AND METHODS: A comprehensive literature search of studies published through 30 April 2013 regarding 68Ga-DOTATOC and 68Ga-DOTATATE PET in the diagnosis of NETs was performed using the PubMed/MEDLINE, Embase, and Scopus databases. Pooled sensitivity and specificity of 68Ga-DOTATOC and 68Ga DOTATATE PET in the diagnosis of NETs were calculated. The area under the receiver-operating characteristic (ROC) curve was calculated to measure the accuracy of 68Ga-DOTATOC and 68Ga-DOTATATE PET in the diagnosis of NETs. RESULTS: Ten studies comprising 416 patients with NETs were included in this meta analysis. The pooled sensitivity of 68Ga-DOTATOC and 68Ga-DOTATATE PET in the diagnosis of NETs calculated on a per-patient-based analysis was 93% (95% confidence interval [CI] 89-96%) and 96% (95% CI 91-99%). The pooled specificity of 68Ga-DOTATOC and 68Ga-DOTATATE PET in diagnosing NETs was 85% (95% CI 74-93%) and 100% (95% CI 82-100%). The area under the ROC curve of 68Ga-DOTATOC and 68Ga DOTATATE PET was 0.96 and 0.98, respectively, on a per-patient-based analysis. CONCLUSION: The molecular imaging agents 68Ga-DOTATOC and 68Ga-DOTATATE demonstrated high sensitivity and specificity in the diagnosis of NETs on PET scan. Although both are accurate tools in the diagnosis of NETs, 68Ga-DOTATATE PET may be more sensitive and specific than 68Ga-DOTATOC PET scan. PMID- 23928011 TI - Fabrication of nano-fibrous poly(L-lactic acid) scaffold reinforced by surface modified chitosan micro-fiber. AB - To mimic the fibrillar structure of natural extracellular matrix and optimize the chemical composition of the scaffold, a nano-fibrous poly(L-lactic acid) (PLLA) scaffold reinforced by surface modified chitosan micro-fiber (MCTSF) was fabricated using the thermally induced phase separation method. The composite scaffold has a novel structure comprised of a nano-matrix with reinforcing micro fibers, in which the nano-fibrous PLLA matrix promotes cell adhesion and proliferation, while the MCTSF provides the mechanical support and adjusts the biocompatibility. The morphology of the composite scaffold showed a nano-fibrous PLLA matrix (100-500 nm fiber diameter), an interconnected microporous structure (1.0-8.0 MUm pore size), and high porosity (>90%). MCTSF were homogeneously distributed in the composite scaffold and had intimate interactions with PLLA matrix. As a result, the compressive modulus of PLLA/MCTSF (100:40, w/w) increased 4.7-fold compared with that of a pristine PLLA scaffold. The prepared composite scaffold also showed good properties including buffering the acidic degradation of PLLA during in vitro degradation, enhanced protein adsorption capacity, and good cytocompatibility, suggesting that the PLLA/MCTSF composite scaffolds are potential candidate materials in tissue engineering. PMID- 23928012 TI - PEG-calf thymus DNA interactions: conformational, morphological and spectroscopic thermal studies. AB - The main aim of this study is to provide understanding for the interaction modes and the binding affinity based on the study of PEG 400 that binds to ctDNA. The effects of the PEG-400-to-ctDNA ratio, pH, incubation time and thermal stability of ctDNA on PEG-ctDNA biocomplex formation were studied. UV-vis-NIR absorption analysis indicated that PEG forms a complex with ctDNA via a mechanism other than intercalation. The results of thermal denaturation studies showed that the PEG ctDNA biocomplex helix was stabilised, with a resulting increase in the PEG-ctDNA melting temperature. FTIR analysis indicated that the PEG binds to ctDNA through weak to moderately strong hydrophilic and hydrophobic interactions with the base pairs of ctDNA. TEM micrographs showed that the addition of PEG to ctDNA caused ctDNA to condense with PEG molecules into an irregular aggregate structure. These results demonstrate that the PEG-ctDNA biocomplex has potential applications in biomedical sciences. PMID- 23928013 TI - Reconstruction of chronic thumb metacarpophalangeal joint radial collateral ligament injuries with a half-slip of the abductor pollicis brevis tendon. AB - PURPOSE: To evaluate a reconstructive method for chronic radial collateral ligament (RCL) injuries of the thumb metacarpophalangeal (MCP) joint using a combination of RCL advancement and the transfer of a half-slip of the abductor pollicis brevis tendon. METHODS: Eight patients (4 male and 4 female; mean age, 25 y) with chronic RCL injury of the thumb MCP joint were enrolled. All patients were referred to our institution because of continuing pain and instability on the radial side of the MCP joint when grasping or pinching objects. The mechanism of the injury was adduction stress to the thumb during sporting activities in 5 patients, a heavy object falling on the thumb in 1, and a fall in 2. The mean duration from RCL injury to surgery was 20 weeks. The average postoperative follow-up was 51 months. We evaluated postoperative outcomes including pain, range of motion of the thumb MCP joint, grip strength, key pinch strength, Disabilities of the Arm, Shoulder, and Hand score, and ability to return to preinjury work or sporting activities. RESULTS: No patients demonstrated continuing symptoms, and the MCP joint was stable after surgery. Postoperative grip and pinch strength (37 and 6.3 kg, respectively) were increased compared with preoperative values (34 and 3.9 kg, respectively). All patients returned fully to their preinjury work or sporting activities within 6 months after surgery. Although postoperative flexion was decreased by an average of 6 degrees , no patients noted functional deficiency. CONCLUSIONS: We recommend the reconstructive method of RCL advancement and transfer of a half-slip of the abductor pollicis brevis tendon to alleviate pain and improve grip and pinch strength in chronic RCL injuries of the thumb MCP joint. PMID- 23928014 TI - Evidence-based reviews for hand and upper extremity surgery. PMID- 23928015 TI - Voluminous arteriovenous malformation of a child's forearm treated by sequential embolizations: case report. AB - An arteriovenous malformation (AVM) is a congenital lesion with high vascular flow resulting from direct connections between arteries and veins. Its treatment is often complex, and most authors recommend a multidisciplinary approach combining surgical and endovascular treatments. We report the case of a 6-month old boy with a voluminous AVM of the left forearm inducing osteolysis of the radius, with bowing of its diaphysis and subsequent radial head dislocation. Surgical excision of the AVM was not possible, but 2 sequential coil embolizations achieved control of the lesion. After 3.5 years, the AVM was undetectable, and notable improvement was noted both in symptoms and radiographic findings. This case underlines how an AVM can have noteworthy influence on surrounding tissues and shows that embolization alone can achieve a satisfying midterm outcome even when surgery is not possible. PMID- 23928016 TI - Treatment of little finger carpometacarpal posttraumatic arthritis with a silicone implant. AB - PURPOSE: To evaluate the short-term clinical and radiographic outcome of a flexible silicone proximal interphalangeal joint implant between the hamate and the metacarpal, to treat posttraumatic little finger carpometacarpal (CMC) osteoarthritis. METHODS: We treated 3 men with a mean age of 30 years by means of a proximal interphalangeal silicone implant arthroplasty for CMC osteoarthritis of the little finger. Indications were disabling pain on the ulnar side of the hand, grip weakness, loss of CMC joint mobility, and disability for work and daily activities. RESULTS: All patients were free of pain at a mean follow-up of 20 months. Transverse metacarpal arch mobility and grip strength were restored. The appearance was acceptable, without misalignment, malrotation, or shortening of the little finger ray. Radiographic evaluation showed no fractures or dislocations of the implant and no signs of foreign body reaction to silicone particles. CONCLUSIONS: This technique offers the advantages of eliminating pain, maintaining length, and restoring mobility of the transverse metacarpal arch, and results in acceptable function and grip strength. PMID- 23928017 TI - Preiser disease. PMID- 23928018 TI - Salvage options for flexor carpi radialis tendon disruption during ligament reconstruction and tendon interposition or suspension arthroplasty of the trapeziometacarpal joint. AB - Several techniques of thumb basilar joint arthroplasty depend on an intact flexor carpi radialis (FCR) tendon. There are situations, however, when the FCR tendon may be attenuated or iatrogenically injured, which make these techniques difficult or unfeasible. Familiarity with intraoperative salvage techniques in this setting is imperative. We present techniques for stabilizing the base of the thumb metacarpal when the FCR is deficient or injured. PMID- 23928019 TI - Groundwater contamination from landfill leachate: when appearances are deceiving! PMID- 23928020 TI - Cancer patients and spiritual experiences: redefining the self through initiatory ordeals. AB - OBJECTIVES: When one explores the paths that sick people follow in search of meaning and a cure, one is quite likely to encounter religious knowledge and practices. Examining this facet and the spiritual experiences that arise therein leads us to the subject of identity, which systematically comes up as soon as we consider the impact of serious illness on people's lives. We need to follow the identity-building process that occurs in the disease, ruptures, and redefinitions if we are to understand how religious practices and knowledge contribute to the process. METHODS: This article discusses these elements using data collected in a qualitative research study of 10 cancer patients, carried out in Quebec. Drawing on the sociology of religions, particularly the contemporary transformation of the religious and the spiritual, we attempted to understand the patients' spiritual experiences by focusing on the self-discovery that occurred through the initiatory ordeal of their illness. RESULTS: We observe that these resources are particularly helpful when the patients use them to turn inwards, to pay attention to themselves, to unite the mind and body, to connect with something greater than themselves, and to transform their values so as to develop a new psychosocial version of themselves. SIGNIFICANCE OF RESULTS: Our analysis shows that there is a complementary relationship between religion and illness at the crossroad of the identity-building process. This relevance demands to be attentive to the initiatory process that leads to the self-discovery and a renewal of the relationship with the self. PMID- 23928021 TI - Quality control ranges for tylosin 30 MUg and 15 MUg discs applicable to Staphylococcus aureus ATCC(R) 25923. PMID- 23928022 TI - A multicentre evaluation of the effectiveness and safety of high-dose daptomycin for the treatment of infective endocarditis. AB - OBJECTIVES: Despite significant medical advances, infective endocarditis (IE) remains an infection associated with high morbidity and mortality. The objective was to assess the safety and efficacy of high-dose daptomycin, defined as >= 8 mg/kg/day, in patients with confirmed or suspected staphylococcal and/or enterococcal IE. METHODS: This was a multicentre, retrospective observational study (2005-11). Adult patients, not undergoing haemodialysis, with blood cultures positive for staphylococci or enterococci and a definitive or possible diagnosis of IE, who received daptomycin >= 8 mg/kg/day (based on total body weight) for >= 72 h were included. RESULTS: Seventy patients met the inclusion criteria and comprised 33 (47.1%) with right-sided IE (RIE), 35 (50%) with left sided IE (LIE) and 2 with both RIE and LIE. Several patients had concomitant sites of infection, with bone/joint infection being most prevalent (12.9%). Sixty five patients received daptomycin as salvage therapy. Pathogens were isolated from 64 patients, with methicillin-resistant Staphylococcus aureus as the most common organism (84.4%), followed by vancomycin-resistant Enterococcus faecium (7.8%). The median (IQR) daptomycin dose was 9.8 mg/kg/day (8.2-10.0 mg/kg/day), and was similar in RIE and LIE patients (9.8 and 9.3 mg/kg/day, respectively). A total of 24 (34.3%) received combination therapy. For those patients with pathogens isolated (n = 64), the organism was eradicated in 57 (89.1%) patients. Among 64 clinically evaluable patients, 55 (85.9%) achieved clinical success. No patients required discontinuation of high-dose daptomycin due to creatine phosphokinase elevations. CONCLUSIONS: Patients with both RIE and LIE had successful outcomes with high-dose daptomycin therapy. Additional clinical trials evaluating high daptomycin dosages in patients with IE are warranted. PMID- 23928023 TI - Association of norB overexpression and fluoroquinolone resistance in clinical isolates of Staphylococcus aureus from Korea. AB - OBJECTIVES: Although the prevalence of fluoroquinolone resistance among methicillin-resistant Staphylococcus aureus (MRSA) is known to be higher than in methicillin-susceptible S. aureus (MSSA), the reasons have never been identified. METHODS: We randomly selected 115 isolates of S. aureus collected from 10 different hospitals in Korea between June 2009 and May 2011. To investigate the difference in fluoroquinolone resistance mechanisms between MRSA and MSSA, we evaluated gyrA and parC mutations and the relative expression of the multidrug efflux pump genes norA, norB and norC. RESULTS: All 62 ciprofloxacin-resistant S. aureus had either gyrA or parC mutations. The S84L mutation of gyrA (59/62, 95.2%) and the S80F mutation of parC (61/62, 98.4%) were the most common. Fifty eight (93.6%) strains had both the S84L mutation of gyrA and the S80F mutation of parC. Among the 115 isolates, norB overexpression was the most common, occurring in 49 (42.6%) strains. There were only two (1.7%) strains with norA overexpression and none with norC overexpression. Strains overexpressing norB were more common among ciprofloxacin-resistant S. aureus (33/62, 53.2%) than ciprofloxacin-susceptible S. aureus (16/53, 30.2%) (P = 0.013). When we analysed 62 ciprofloxacin-resistant S. aureus strains, those overexpressing norB were more common in ciprofloxacin-resistant MRSA (28/46, 60.9%) than in ciprofloxacin resistant MSSA (5/16, 31.3%) (P = 0.041). CONCLUSIONS: Increased expression of norB can be a factor that contributes to ciprofloxacin resistance in MRSA strains. PMID- 23928024 TI - Decreased susceptibility to tigecycline in Acinetobacter baumannii mediated by a mutation in trm encoding SAM-dependent methyltransferase. AB - OBJECTIVES: Acinetobacter baumannii is an important opportunistic pathogen and multidrug-resistant isolate. Although tigecycline is a potent antibiotic for treating infections with multidrug-resistant isolates, resistance is becoming a problem. This study aimed to explore the mechanism of tigecycline resistance in A. baumannii. METHODS: A serial passage experiment was performed to collect isolates selected by tigecycline. The expression of efflux pumps was quantified in the final selected isolate, 19606-T8. The whole genome of 19606-T8 was sequenced and the putative mutations were confirmed using PCR and Sanger sequencing. A complementation experiment was performed to evaluate the contribution of the mutations to decreased susceptibility to tigecycline. The significance of a deletion mutation was further investigated in terms of growth rate and antibiotic susceptibilities. RESULTS: We collected serial isolates by selective pressure of tigecycline, and designated them 19606-T1 to 19606-T8. The efflux pumps AdeABC, AdeFGH and AdeIJK were not overexpressed in 19606-T8, which had decreased susceptibility to tigecycline. Isolate 19606-T8 carried one deletion mutation in trm and three non-synonymous substitutions in msbA (A84V), lolA (P91L) and filC (N168K). The deletion mutation in trm (encoding S-adenosyl-L methionine-dependent methyltransferase) resulted in decreased susceptibility to tigecycline as well as to minocycline and doxycycline. In complementation experiments, the MICs of tigecycline, minocycline and doxycycline in a tigecycline-resistant isolate were restored by complementation with wild-type trm. CONCLUSIONS: Given that the deletion mutation in trm was associated with decreased susceptibility to tigecycline and that a wild-type trm plasmid could restore the susceptibility, trm is considered to play an important role in decreased susceptibility to tigecycline in A. baumannii. PMID- 23928025 TI - Characterization of plasmid pAX22, encoding VIM-1 metallo-beta-lactamase, reveals a new putative mechanism of In70 integron mobilization. AB - OBJECTIVES: VIM-type enzymes are among the most widespread acquired metallo-beta lactamases among Gram-negative pathogens. Integron In70 is a class 1 integron that has emerged as a successful genetic support for blaVIM-1 (one of the most prevalent blaVIM allelic variants) in Gram-negative non-fermenters, and is usually chromosome borne. The objective of this study was to characterize plasmid pAX22 from Achromobacter xylosoxidans AX22, which represents the only In70 harbouring plasmid known so far, to gather insights into the mechanisms of evolution and dissemination of In70-like elements. METHODS: The complete sequence of pAX22 was obtained by pyrosequencing and assembled with Roche Newbler software. The draft sequence, completed using a PCR-based strategy, was annotated via the BASys tool and compared with known sequences using BLAST algorithms. RESULTS: The backbone of pAX22 showed significant similarity with that of pNOR 2000, a blaVIM-2-harbouring plasmid from Pseudomonas aeruginosa, and with the TnCP23 transposon. The three elements differed from each other mainly by the class 1 integron cassette arrays and by some integron-associated structures. In pAX22, In70 was associated with a novel putative transposon, Tn7017, composed of a defective Tn402-like transposon carrying In70 and the ISPa17 insertion sequence. CONCLUSION: Plasmid pAX22 belongs to a lineage of plasmids circulating among Gram-negative non-fermenters. In70 was probably acquired by pAX22 by transposition of Tn7017, revealing a novel putative mechanism of In70 mobilization. Our results highlight the potential role that ISPa17 could have in mobilizing defective Tn402-like transposons carrying class 1 integrons. PMID- 23928026 TI - The impact of communication on adherence in pain management. AB - Despite a high prevalence of pain and ongoing effort to understand and reduce pain, studies show that there remains a considerable unmet need for pain relief and management. In part, this may be due to patient's not adhering to treatment recommendations. Models such the health belief model, self-regulation theory, and the theory of planned behavior suggest two key factors in promoting adherence: (1) good health care provider-patient communication and (2) interventions that are tailored to individuals' reasons for non-adherence. Hence, communication skills that express a nonjudgmental approach, allow open exploration of patient beliefs and concerns, and use a negotiating approach that fosters shared decision making are crucial. Randomized, controlled trials of brief communication skills training have shown improved outcomes in primary care settings for patients with fibromyalgia and acute pain. Thus, although treatment of chronic pain is challenging, good communication between health providers and patients can promote adherence and improve outcomes. PMID- 23928027 TI - Levels, distribution and air-soil exchange fluxes of polychlorinated biphenyls (PCBs) in the environment of Punjab Province, Pakistan. AB - An initial survey of the concentrations of polychlorinated biphenyl (PCB) compounds in air and soils across industrial and agricultural areas of Punjab Province, Pakistan, was conducted from January to March 2011. The total concentration of all PCBs (31 PCBs) ranged from 34 to 389pgm(-3) in air and from 7 to 45ngg(-1) dry weight in soils, where both ranges were similar to the average ranges in other areas of the world. PCBs were elevated across industrial regions near urban and industrial sources. Consistently low air concentrations of PCBs at the agricultural sites suggest that they are less widespread or uniformly distributed in the Pakistani atmosphere. The calculated air and soil fugacity fraction values indicated that soils are a potential secondary source of PCBs in agricultural areas, whereas they are in equilibrium or atmospheric deposition in industrial and urban areas. TEQ concentrations of dioxin-like PCBs for soil samples met the Canadian standard. However, local authorities should address the human health threats from urban and industrial soils in Punjab Province, Pakistan. PMID- 23928028 TI - Effects of toxicants with different modes of action on Myriophyllum spicatum in test systems with varying complexity. AB - At the international workshop Aquatic Macrophyte Risk Assessment for Pesticides (AMRAP), it was noted that the EU risk assessment under the directive 91/414/EEC for herbicides, based only on algae and the monocotyledonous duckweed species Lemna sp., offers no certain protection against some growth regulating auxins. Therefore, AMRAP members proposed the introduction of the dicotyledonous water milfoil Myriophyllum as additional test species. This study was aimed to compare toxicity results from three test systems (TS) with varying complexity, namely Water TS, Sediment TS and Microcosm TS using Myriophyllum spicatum as test organism. As test substances, the photosynthesis inhibiting herbicide isoproturon, the growth regulating auxins fluroxypyr and 2,4 dichlorophenoxyacetic acid (2,4-D), and the non-specific acting toxicant 3,5 dichlorophenol (3,5-DCP) were chosen. It was assessed if and why the sensitivity of M. spicatum towards the four toxicants varied in the different test systems and if the addition of sucrose to the medium used in the Water TS had an effect on the sensitivity of Myriophyllum. All TS were suitable for detecting negative effects of toxicants with different modes of action on M. spicatum. The lowest variability of endpoints was found in the Water TS with lowest experimental complexity. For auxins, the endpoint weight did not result in robust EC50 values in all TS, whereas root related endpoints, which are also ecologically relevant, turned out to be very sensitive with low variance. Sucrose in the medium of the Water TS did not seem to influence the sensitivity of M. spicatum towards isoproturon and 3,5-DCP but may have increased the sensitivity of M. spicatum roots when exposed to 2,4-D. However, the findings of all TS resulted in similar risk estimations if root endpoints were not considered. PMID- 23928029 TI - Measles and pertussis outbreaks: an important role for travel clinics. PMID- 23928030 TI - Healthcare-associated infections studies project: an American Journal of Infection Control and National Healthcare Safety Network data quality collaboration-LabID Clostridium Difficile event 2013. AB - This is the first in a series of case studies that will be published in American Journal of Infection Control following the Centers for Disease Control and Prevention/National Healthcare Safety Network (NHSN) surveillance definition update of 2013. These cases reflect some of the complex patient scenarios infection professionals encounter during daily surveillance of health care associated infections using NHSN definitions. Answers to the questions posed and immediate feedback in the form of answers and explanations are available at: http://www.surveymonkey.com/s/AJIC-NHSN-LbId2013. All individual participant answers will remain confidential, although it is the authors' hope to share a summary of the findings at a later date. Cases, answers, and explanations have been reviewed and approved by NHSN staff. Active participation is encouraged and recommended. Review/reference Chapter 12-Multidrug-resistant organism &C difficile infection module protocol, of the NHSN Patient Safety Component Manual (http://www.cdc.gov/nhsn/PDFs/pscManual/12pscMDRO_CDADcurrent.pdf), for information you may need to answer the case study questions. PMID- 23928031 TI - Job satisfaction evaluation in low back pain: a literature review and tools appraisal. AB - Among occupational risk factors of recurrence, chronicity and no return to work in low back pain, poor job satisfaction is the only high evidence-based factor. OBJECTIVE: To find out any validated questionnaire usable to assess job satisfaction in low back pain patients, both in clinical practice and research setting. METHOD: A systematic literature search on Pubmed and Cochrane library databases and un-indexed literature was made. "Job satisfaction" and "low back pain" keywords were used. Only English and French relevant articles were retained. A double assessment was made of listed questionnaires according to psychometric properties and daily practice use. RESULTS: Among the 40 articles retained only four used a validated questionnaire. Among the 12 different questionnaires, only two are validated in their English version (Job Descriptive Index [JDI] and the Work Environment Scale [WES]) and one in its French Version (JDI). Because they are time consuming, use these questionnaires in daily practice seems difficult. CONCLUSION: Based on literature review and questionnaire heterogeneity, at this time, there is no reference job satisfaction questionnaire. For daily practice, global job satisfaction visual analog scale could be useful. For research and intervention, JDI is more suitable despite its validity is still questionable. PMID- 23928032 TI - The Ihh signal is essential for regulating proliferation and hypertrophy of cultured chicken chondrocytes. AB - The Indian hedgehog (Ihh) signal plays a vital role in regulating proliferation and hypertrophy of chondrocytes. To investigate its function in postnatal chicken (Gallus gallus) chondrocytes, cyclopamine was used to inhibit Ihh signaling. The MTT and ALP assays revealed the downgrade-proliferation and upgrade differentiation of chondrocytes. To further elucidate the mechanism, the mRNA expression levels of Ihh, parathyroid hormone related protein (PTHrP), Gli-2, Bcl 2, Bone Morphogenetic Protein 6 (BMP-6), type X collagen (Col X) and type II collagen (Col II) were detected by quantitative real-time RT-PCR analysis, and the protein expressions of Ihh, Col X, and Col II were determined using Western blot analysis. After the Ihh signal was blocked, chondrocytes demonstrated high expression levels of PTHrP and Col X and low levels of Gli-2, BMP-6, Bcl-2 and Col II although Ihh expression was increased. Based on these results, the Ihh signal is essential for balancing chicken chondrocyte proliferation and hypertrophy, and the regulatory function of PTHrP acts in an Ihh-dependent manner. Furthermore, BMP-6 and Bcl-2 played roles in maintaining the development of chondrocytes and may be downstream regulatory factors of Ihh signaling. PMID- 23928033 TI - Arrhythmogenicity of hypothermia - a large animal model of hypothermia. AB - BACKGROUND: Therapeutic hypothermia (TH) is used to mitigate cerebral injury after an out of hospital cardiac arrest. There is a perceived risk of increased arrhythmias with temperatures lower than the current target of 32-34 degrees C for TH. This study sought to develop and investigate the electrophysiological changes in a sheep model of systemic hypothermia regarding the susceptibility to ventricular arrhythmias. METHODS: Ten sheep underwent systemic hypothermia using a venous-venous extra-corporeal circuit whilst instrumented with a 12 lead ECG. An epicardial sock recorded potentials to 30 degrees C (N=10) or 26 degrees C (N=6). Activation times (AT) and Activation Recovery Intervals (ARI) were calculated using custom software. RESULTS: The AT and ARI were significantly prolonged with increased heterogeneity during hypothermia. This effect was most pronounced between normothermia and 34 degrees C during sinus rhythm (SR). For ventricular pacing (VP) however heterogeneity continued to increase with progressive hypothermia. CONCLUSIONS: Hypothermia causes a significant increase in the heterogeneity of depolarisation and repolarisation. There is evidence to suggest that SR is protective with most of the increase in heterogeneity occurring with cooling to 34 degrees C. This raises the possibility that the current target temperatures for therapeutic hypothermia may be safely lowered to provide a gain in cerebral protection. PMID- 23928034 TI - Guidelines for the safe introduction of minimally invasive mitral valve surgery. PMID- 23928035 TI - Guidelines for the establishment of an adult cardiac surgery unit (CSU). PMID- 23928036 TI - Perfluoroalkyl acids in subarctic wild male mink (Neovison vison) in relation to age, season and geographical area. AB - This study investigates the influence of biological and environmental factors on the concentrations of perfluoroalkyl acids (PFAAs) in a top predator; the American mink. Perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS) and perfluoroalkyl carboxylates (PFCAs) with C8-C13 perfluorinated carbon chains were analyzed in livers from wild male mink liver (n=101) from four areas in Sweden representing two inland environments (rural and highly anthropogenic, respectively) and two different coastal environments. Mean PFOS concentrations were 1250ng/g wet weight and some mink from the urban inland area had among the highest PFOS concentrations ever recorded in mink (up to 21 800ng/g wet weight). PFBS was detected in 89% of the samples, but in low concentrations (mean 0.6ng/g ww). There were significant differences in PFAA concentrations between the geographical areas (p<0.001-0.01). Age, body condition and body weight did not influence the concentrations significantly, but there was a seasonal influence on the concentrations of perfluorodecanoic acid (PFDA) and perfluoroundecanoic acid (PFUnDA) (p<0.01 and p<0.05, respectively), with lower concentrations in autumn samples than in samples taken in the winter and spring. It is thus recommended to take possible seasonal differences into account when using mink exposure data. The overall results suggest that the mink is a suitable sentinel species for assessing and monitoring environmental levels of PFAAs. PMID- 23928037 TI - Probabilistic mercury multimedia exposure assessment in small children and risk assessment. AB - OBJECTIVES: Emissions of mercury in the environment have been decreasing for several years. However, mercury species are still found in different media (food, water, air and breast-milk). Due to mercury toxicity and typical behaviour in children, we have conducted a mercury exposure assessment in French babies, and small children aged 0 to 36months. METHOD: Consumption and mercury concentration data were chosen for the exposure assessment. The Monte Carlo technique has been used to calculate the weekly exposure dose in order to integrate inter-individual variability and parameter uncertainty. Exposure values have been compared to toxicological reference values for health risk assessment. RESULTS: Inorganic mercury median exposure levels ranged from 0.160 to 1.649MUg/kg of body weight per week (95th percentile (P95): 0.298-2.027ug/kg bw/week); elemental mercury median exposure level in children was 0.11ng/kg bw/week (P95: 28ng/kg bw/week); and methylmercury median exposure level ranged from 0.247 to 0.273ug/kg bw/week (P95: 0.425-0.463ug/kg bw/week). Only elemental mercury by inhalation route (indoor air) and methylmercury by ingestion (fish and breast-milk) seem to lead to a health risk in small children. CONCLUSIONS: These results confirm the importance of assessing total mercury concentration in media like breast-milk, indoor air and dust and methylmercury level in food, other than fish and seafood. In this way, informed monitoring plan and risk assessment in an at-risk sub population can be set. PMID- 23928038 TI - Association between several persistent organic pollutants and thyroid hormone levels in serum among the pregnant women of Korea. AB - Persistent organic pollutants such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (OCPs) are of global concern because of their widespread contamination and adverse health effects. Potential endocrine disruption, especially of thyroid status by PCBs has been repeatedly suggested in both experimental and epidemiological studies. However the associations with PBDEs or OCPs have been arguable especially in human populations. We investigated the associations between major groups of POPs and thyroid hormone balances among pregnant women. One hundred five pregnant women at delivery were recruited from four cities of Korea in 2011 and were investigated. Blood samples were collected within a day before delivery. Serum was then analyzed for 19 PCBs, 19 PBDEs, and 19 OCPs, along with five thyroid hormones (free and total T3 and T4, and TSH). Several PCBs such as PCB28, 52, and 118 showed negative associations with T3 or T4. BDE47 and total PBDEs showed significant associations with T3 or T4. For OCPs, dichlorodiphenyltrichloroethanes (DDTs) and hexachlorobenzene (HCB) were generally associated with reduction of T3 or T4. The thyroid hormone levels of all subjects were within the reference range, however exposure to several target POPs were clearly related with potential for disrupting thyroid hormone balance among pregnant women, at the current level of exposure. Although subtle, the changes in thyroid hormones should be seen with caution because even minor changes within pregnant women may have significant consequences especially on sensitive population like fetus. PMID- 23928039 TI - Expression analysis and clinical correlation of aquaporin 1 and 4 genes in human hippocampal sclerosis. AB - Mesial temporal sclerosis (MTS) is the most frequent cause of drug resistant symptomatic partial epilepsy. The mechanism and genetic background of this unique pathology are not well understood. Aquaporins (AQP) are regulators of water homeostasis in the brain and are expressed in the human hippocampus. We explored the role of AQP genes in the pathogenetic mechanisms of MTS through an evaluation of gene expression in surgically removed human brain tissue. We analyzed AQP1 and 4 mRNA levels by quantitative real-time polymerase chain reaction and normalized to ABL and cyclophilin genes, followed by immunohistochemistry for AQP4. Relative expressions were calculated according to the delta Ct method and the results were compared using the Mann-Whitney U test. Brain specimens of 23 patients with epilepsy who had undergone surgery for MTS and seven control autopsy specimens were investigated. Clinical findings were concordant with previous studies and 61% of the patients were seizure-free in the postoperative period. AQP1 and 4 gene expression levels did not differ between MTS patients and control groups. Immunofluorescence analysis of AQP4 supported the expression results, showing no difference. Previous studies have reported contradictory results about the expression levels of AQP in MTS. To our knowledge, only one study has suggested upregulation whereas the other indicated downregulation of perivascular AQP4. Our study did not support these findings and may rule out the involvement of AQP in human MTS. PMID- 23928040 TI - Multi-institutional validation of a preoperative scoring system which predicts survival for patients with glioblastoma. AB - Glioblastoma is the most common and aggressive type of primary brain tumor in adults. Average survival is approximately 1 year, but individual survival is heterogeneous. Using a single institutional experience, we have previously identified preoperative factors associated with survival and devised a prognostic scoring system based on these factors. The aims of the present study are to validate these preoperative factors and verify the efficacy of this scoring system using a multi-institutional cohort. Of the 334 patients in this study from three different institutions, the preoperative factors found to be negatively associated with survival in a Cox analysis were age >60 years (p<0.0001), Karnofsky Performance Scale score <=80 (p=0.03), motor deficit (p=0.02), language deficit (p=0.04), and periventricular tumor location (p=0.04). Patients possessing 0-1, 2, 3, and 4-5 of these variables were assigned a preoperative grade of 1, 2, 3, and 4, respectively. Patients with a preoperative grade of 1, 2, 3, and 4 had a median survival of 17.9, 12.3, 10, and 7.5 months, respectively. Survival of each of these grades was statistically significant (p<0.05) in log-rank analysis. This grading system, based only on preoperative variables, may provide patients and physicians with prognostic information that may guide medical and surgical therapy before any intervention is pursued. PMID- 23928041 TI - Certain Strongylocentrotus purpuratus sperm mitochondrial proteins co-purify with low density detergent-insoluble membranes and are PKA or PKC-substrates possibly involved in sperm motility regulation. AB - BACKGROUND: Sea urchin sperm motility is regulated by Speract, a sperm-activating peptide (SAP) secreted from the outer egg coat. Upon binding to its receptor in the sperm flagellum, Speract induces a series of ionic and metabolic changes in Strongylocentrotus purpuratus spermatozoa that regulate their motility. Among these events, protein phosphorylation is one of the most relevant and evidence indicates that some proteins of the Speract signaling cascade localize in low density detergent-insoluble membranes (LD-DIM). METHODS: LD-DIM-derived proteins from immotile, motile or Speract-stimulated S. purpuratus sperm were resolved in 2-D gels and the PKA and PKC substrates detected with specific antibodies were identified by LC-MS/MS. RESULTS: Differential PKA and PKC substrate phosphorylation levels among the LD-DIM isolated from sperm in different motility conditions were found and identified by mass spectrometry as: ATP synthase, creatine kinase, NADH dehydrogenase (ubiquinone) flavoprotein 2, succinyl-CoA ligase and the voltage-dependent anion channel 2 (VDAC2), which are mitochondrial proteins, as well as, the cAMP-dependent protein kinase type II regulatory (PKA RII) subunit, Tubulin beta chain and Actin Cy I changed their phosphorylation state. CONCLUSIONS: Some mitochondrial proteins regulated by PKA or PKC may influence sea urchin sperm motility. GENERAL SIGNIFICANCE: The fact that a high percentage (66%) of the PKA or PKC substrates identified in LD-DIM are mitochondrial proteins suggests that the phosphorylation of these proteins modulates sea urchin sperm motility via Speract stimulation by providing sufficient energy to sperm physiology. Those mitochondrial proteins are indeed PKA- or PKC-substrates in the sea urchin spermatozoa. PMID- 23928042 TI - Application of the ligation-independent cloning (LIC) method for rapid construction of a minigenome rescue system for Newcastle disease virus VG/GA strain. AB - Newcastle disease virus (NDV) can cause serious diseases and substantial economic losses to the poultry industry. To gain a better understanding of NDV pathogenesis, several reverse genetics systems for different NDV strains have been established. However, the construction of infectious cDNA clone by conventional restriction digestion/ligation cloning methods is a time-consuming process and has many drawbacks by its nature. To address the problems, we employed a novel and robust ligation-independent cloning (LIC) method for efficient assembly of multiple DNA fragments. Using this method, we successfully generated a NDV minigenome construct within three weeks by assembling RT-PCR products of the VG/GA strain genomic termini and a cDNA coding for the green fluorescence protein (GFP), as a reporter, into a modified pBluescript vector. Co transfection of the NDV minigenome with three supporting plasmids expressing the N, P, and L proteins into MVA-T7 infected HEp-2 cells and followed by infection with NDV VG/GA resulted in the minigenome replication, transcription, and packaging as evidenced by the reporter gene GFP expression. These results suggest that this LIC approach is a powerful tool for all sequence-independent DNA cloning and multi-DNA fragment assembly, which has a potential application for rapid development of gene therapy and recombinant vaccines. PMID- 23928043 TI - Prolonged grievers: a qualitative evaluation of a support group intervention. AB - OBJECTIVE: The aim of this project was to study prolonged grievers psychosocial processes and experience during participation in a group intervention and 6-8 weeks after discontinuation. The intervention in this study was a group therapy with the aim of getting in contact with their pain and loss and confronting and working with this loss. METHODS: Data was collected by using diaries and tape recorded interviews, analyzed with grounded theory. The participants were 11 females between the ages of 33 and 71. RESULTS: The main process that was found in the qualitative data was: Ambivalence when struggling and learning through work and rest towards a balance. Sub-processes were: To share and be confirmed in the group through sense of cohesion; To dare/venture to discover problems and solutions; To react when you get emotionally involved, and to compare and discover. SIGNIFICANCE OF RESULTS: This study gives insight into prolonged grievers' thinking, which is valuable knowledge. Rather than assuming that all individuals suffering from prolonged grief need the same treatment, we suggest that there should be a range of different therapies. PMID- 23928045 TI - Penicillin-binding protein 3 of Streptococcus pneumoniae and its application in screening of beta-lactams in milk. AB - The soluble form of penicillin-binding protein 3 (sPBP3(*)) from Streptococcus pneumoniae was expressed in Escherichia coli as a six-histidine fusion protein. The protein was purified and used to develop a microplate assay in direct competitive format for the detection of penicillins and cephalosporins in milk. The assay was based on competitive inhibition of the binding of horseradish peroxidase-labeled ampicillin (HRP-Amp) to the sPBP3(*) by free beta-lactam antibiotics in milk. Under optimized conditions, most of the beta-lactam antibiotics (11 penicillins and 16 cephalosporins) could be detected at concentrations corresponding to the maximum residue limits (MRLs) set by the European Union. Analysis of spiked milk samples showed that acceptable recoveries ranged from 74.06 to 106.31% in skimmed milk and from 63.97 to 107.26% in whole milk, with coefficients of variation (CVs) less than 16%. With the high sensitivity and wide-range affinities to penicillins and cephalosporins, the developed assay based on sPBP3(*) exhibited the potential to be a screening assay for fast detection of beta-lactam antibiotics in milk. PMID- 23928044 TI - Rapid parallel flow cytometry assays of active GTPases using effector beads. AB - We describe a rapid assay for measuring the cellular activity of small guanine triphosphatases (GTPases) in response to a specific stimulus. Effector functionalized beads are used to quantify in parallel multiple GTP-bound GTPases in the same cell lysate by flow cytometry. In a biologically relevant example, five different Ras family GTPases are shown for the first time to be involved in a concerted signaling cascade downstream of receptor ligation by Sin Nombre hantavirus. PMID- 23928046 TI - A membrane-based near-infrared fluorescence assay for detecting DNA methylation and transcription. AB - DNA methylation is a common epigenetic modification. The epigenetic silencing of a variety of genes by hypermethylation of promoter-associated CpG islands is often associated with diseases. Therefore, a reliable but uncomplicated method for detecting DNA methylation is preferred for research and clinical practice. In this paper, a membrane-based near-infrared fluorescence assay for detecting DNA methylation and its effect on gene transcription was established for this purpose. This assay consisted of two detection systems, i.e., transcription and methylation detection systems. The former detected gene transcription by using biotinylated cDNA and the latter detected DNA methylation by using anti-5 methylcytidine antibody (5MC-Ab). The biotin and 5MC-Ab signals were reported by near-infrared fluorescence-labeled streptavidin and secondary antibody, respectively. The feasibility of the two systems was fully verified with the synthesized biotinylated and methylated oligonucleotides. The reliability of the two systems was demonstrated by successfully detecting the methylation and transcription of a reported hypermethylated gene, p14(ARF), in LOVO cells. This study provides a new method for simultaneously detecting DNA methylation and transcription, which is helpful for exploring the gene expression regulatory role of DNA methylation. The method is free of bisulfite treatment and PCR amplification but has wide dynamic range and high sensitivity. PMID- 23928047 TI - Strategies for crystallizing a chromatin protein in complex with the nucleosome core particle. AB - The molecular details of how chromatin factors and enzymes interact with the nucleosome are critical to understanding fundamental genetic processes including cell division and gene regulation. A structural understanding of such processes has been hindered by the difficulty in producing diffraction-quality crystals of chromatin proteins in complex with the nucleosome. We describe here the steps used to grow crystals of the 300-kDa RCC1 chromatin factor/nucleosome core particle complex that diffract to 2.9-A resolution. These steps include both pre- and postcrystallization strategies potentially useful to other complexes. We screened multiple variant RCC1/nucleosome core particle complexes assembled using different RCC1 homologs and deletion variants, and nucleosomes containing nucleosomal DNA with different sequences and lengths, as well as histone deletion variants. We found that using RCC1 from different species produced different crystal forms of the RCC1/nucleosome complex consistent with key crystal packing interactions mediated by RCC1. Optimization of postcrystallization soaks to dehydrate the crystals dramatically improved the diffraction quality of the RCC1/nucleosome crystal from 5.0- to 2.9-A resolution. PMID- 23928048 TI - Sequence-specific and DNA structure-dependent interactions of Escherichia coli MutS and human p53 with DNA. AB - Many proteins involved in DNA repair systems interact with DNA that has structure altered from the typical B-form helix. Using magnetic beads to immobilize DNAs containing various types of structures, we evaluated the in vitro binding activities of two well-characterized DNA repair proteins, Escherichia coli MutS and human p53. E. coli MutS bound to double-stranded DNAs, with higher affinity for a G/T mismatch compared to a G/A mismatch and highest affinity for larger non B-DNA structures. E. coli MutS bound best to DNA between pH 6 and 9. Experiments discriminated between modes of p53-DNA binding, and increasing ionic strength reduced p53 binding to nonspecific double-stranded DNA, but had minor effects on binding to consensus response sequences or single-stranded DNA. Compared to nonspecific DNA sequences, p53 bound with a higher affinity to mismatches and base insertions, while binding to various hairpin structures was similar to that observed to its consensus DNA sequence. For hairpins containing CTG repeats, the extent of p53 binding was proportional to the size of the repeat. In summary, using the flexibility of the magnetic bead separation assay we demonstrate that pH and ionic strength influence the binding of two DNA repair proteins to a variety of DNA structures. PMID- 23928049 TI - An assay for functional xylose transporters in Saccharomyces cerevisiae. AB - It has been considered that more efficient uptake of xylose could promote increased xylose metabolic capacity of several microorganisms. In this study, an assay to screen xylose transporters was established in the Saccharomyces cerevisiae strain, which expresses the xylosidase gene of Bacillus pumilus intracellularly. The absorbed xylose analog p-nitrophenyl-beta-d-xylopyranoside (pNPX) rapidly hydrolyzed to p-nitrophenol (pNP), which displayed a yellow tint when exposed to xylosidase in vivo. The xylose transporter activities of the strain were computed using the pNP production rate, which was detected extracellularly. This method could be used for both high-throughput screening and smaller scale investigations. AraEp, which is a pentose transporter of Corynebacterium glutamicum, was expressed in S. cerevisiae and exhibited better transport capacity than the endogenous transporters Hxt7p and Gal2p. Moreover, a mutant of AraEp with 103% greater transport capacity was screened out, and the computer simulation suggested that transmembrane domain 5 was an important factor for the transport capacity of AraEp in S. cerevisiae. PMID- 23928050 TI - Quantitative affinity electrophoresis of RNA-small molecule interactions by cross linking the ligand to acrylamide. AB - We show that the affinity electrophoresis analysis of RNA-small molecule interactions can be made quantifiable by cross-linking the ligand to the gel matrix. Using an RNA-aminoglycoside model system to verify our method, we attached an acryloyl chloride molecule to the aminoglycosides paromomycin and neomycin B to synthesize an acrylamide-aminoglycoside monomer. This molecule was then used as a component in gel polymerization for affinity electrophoresis, covalently attaching an aminoglycoside molecule to the gel matrix. To test RNA binding to the cross-linked aminoglycosides, we used the aminoglycoside binding RNA molecule derived from thymidylate synthase messenger RNA (mRNA) that contains a C-C mismatch. Binding is indicated by the difference in RNA mobility between gels with cross-linked ligand, with ligand embedded during polymerization, and with no ligand present. Critically, the predicted straight line relationship between the reciprocal of the relative migration of the RNA and the ligand concentration is obtained when using cross-linked aminoglycosides, whereas a straight line is not obtained using embedded aminoglycosides. Average apparent dissociation constants are determined from the slope of the line from these plots. This method allows an easy quantitative comparison between different nucleic acid molecules for a small molecule ligand. PMID- 23928051 TI - Serum N-glycan and O-glycan analysis by mass spectrometry for diagnosis of congenital disorders of glycosylation. AB - Congenital disorders of glycosylation (CDGs) are caused by defects in genes that participate in biosynthetic glycosylation pathways. To date, 19 different genetic defects in N-glycosylation, 17 in O-glycosylation, and 21 in multiple glycosylation are known. Current diagnostic testing of CDGs largely relies on indirect analysis of glycosylation of serum transferrin. Such analysis alone is insufficient to diagnose many of the known glycosylation disorders. To improve the diagnosis of these groups of CDGs, we have developed serum or plasma N- and O glycan profiling using a combination of MALDI-TOF/MS and LC-MS/MS technologies. Using this approach, we analyzed samples from nine patients with different known multiple glycosylation disorders, including three with COG deficiencies, one with TMEM165-CDG, two with PGM1-CDG, and three with SLC35A2-CDG, and one patient with combined type I and type II of unknown molecular etiology. Measurement of the relative quantities of various N- and O-glycan species clearly differentiates patients and controls. Our study demonstrates that structural analysis and quantitation of combined N- and O-glycan profiles are reliable diagnostic tools for CDGs. PMID- 23928052 TI - Tuberculosis, drug use and HIV infection in Central Asia: an urgent need for attention. AB - INTRODUCTION: Rates of tuberculosis in Central Asia are extremely high, and even more alarming are the very high rates of multidrug-resistant tuberculosis (MDR TB) in Kazakhstan, Uzbekistan, Tajikistan and Kyrgyzstan. In addition, rates of HIV infection related to injection drug use seems to be rising as well, thus creating conditions for a potentially devastating co-epidemic of TB/HIV and MDR TB/HIV which would have terrible consequences for public health in these countries. CURRENT STATUS: In many countries of Central Asia, diagnosis of tuberculosis still rests on clinical grounds or simple technologies such as chest radiograph and sputum smear examination. Modern molecular techniques such as GenExpert are being introduced in Kazakhstan and Uzbekistan, and perhaps soon in Kyrgyzstan. Treatment of TB is still often centered around prolonged inpatient stay at TB hospitals. Only a minority of patients with HIV infection are receiving ART, and TB and HIV services are not well integrated. Needle exchange programs are becoming increasingly available, but opioid substitution therapy is rarely used in Central Asia. TB, drug treatment and HIV services are generally not well-integrated. CONCLUSIONS: To combat this developing storm, integration of TB services, HIV care, and substance abuse treatment programs is needed urgently to allow efficient and effective diagnosis and treatment of these conditions in a coordinated manner. PMID- 23928053 TI - Simultaneous depletion of immunoglobulin G and albumin from human plasma using novel monolithic cryogel columns. AB - In this study, we aimed to develop an alternative matrix able to deplete the albumin (Alb) and immunoglobulin G (IgG) from blood plasma simultaneously to prepare plasma samples for large-scale applications of blood-related proteomics. As a first step, nano-protein A nanoparticles (nanoProA) were prepared and characterized. Subsequently, cibacron blue F3GA (CB) was immobilized onto the nanoProA's to enhance their specific affinity for Alb molecules. Finally, both nanoparticles, specifically, nanoProA and CB-nanoProA, were separately embedded into cryogel structures to combine advantages of the nanoparticles with those of the cryogels. The protein adsorption was optimized using aqueous Alb and IgG solutions separately. Subsequently, competitive protein adsorption was performed using a protein mixture prepared with Alb and IgG adhering to their plasma protein ratios. Because of the CB-immobilization, the Alb depletion performance of the cryogels increased whereas the IgG depleting performance decreased. Using the nanoProA, embedded cryogel removed 99.3% of the IgG, while using the CB nanoProA embedded cryogel removed 97.5% of the Alb content. The simultaneous depletion performances of the cryogels for Alb and IgG were characterized using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In this study, the monolithic cryogel-based adsorbents were classified as an alternative matrix to prepare plasma samples for proteomics applications at the preparative scale. PMID- 23928054 TI - An integrated buccal delivery system combining chitosan films impregnated with peptide loaded PEG-b-PLA nanoparticles. AB - Peptide (insulin) loaded nanoparticles (NPs) have been embedded into buccal chitosan films (Ch-films-NPs). These films were produced by solvent casting and involved incorporating in chitosan gel (1.25% w/v), NPs-Insulin suspensions at three different concentrations (1, 3, and 5mg of NPs per film) using glycerol as plasticiser. Film swelling and mucoadhesion were investigated using 0.01M PBS at 37 degrees C and texture analyzer, respectively. Formulations containing 3mg of NPs per film produced optimised films with excellent mucoadhesion and swelling properties. Dynamic laser scattering measurements showed that the erosion of the chitosan backbone controlled the release of NPs from the films, preceding in vitro drug (insulin) release from Ch-films-NPs after 6h. Modulated release was observed with 70% of encapsulated insulin released after 360h. The use of chitosan films yielded a 1.8-fold enhancement of ex vivo insulin permeation via EpiOralTM buccal tissue construct relative to the pure drug. Flux and apparent permeation coefficient of 0.1MUg/cm(2)/h and 4*10(-2)cm(2)/h were respectively obtained for insulin released from Ch-films-NPs-3. Circular dichroism and FTIR spectroscopy demonstrated that the conformational structure of the model peptide drug (insulin) released from Ch-films-NPs was preserved during the formulation process. PMID- 23928055 TI - Caring for a spouse with end-stage heart failure through implantation of a left ventricular assist device as a destination therapy. PMID- 23928056 TI - Cancer gene discovery: exploiting insertional mutagenesis. AB - Insertional mutagenesis has been used as a functional forward genetics screen for the identification of novel genes involved in the pathogenesis of human cancers. Different insertional mutagens have been successfully used to reveal new cancer genes. For example, retroviruses are integrating viruses with the capacity to induce the deregulation of genes in the neighborhood of the insertion site. Retroviruses have been used for more than 30 years to identify cancer genes in the hematopoietic system and mammary gland. Similarly, another tool that has revolutionized cancer gene discovery is the cut-and-paste transposons. These DNA elements have been engineered to contain strong promoters and stop cassettes that may function to perturb gene expression upon integration proximal to genes. In addition, complex mouse models characterized by tissue-restricted activity of transposons have been developed to identify oncogenes and tumor suppressor genes that control the development of a wide range of solid tumor types, extending beyond those tissues accessible using retrovirus-based approaches. Most recently, lentiviral vectors have appeared on the scene for use in cancer gene screens. Lentiviral vectors are replication-defective integrating vectors that have the advantage of being able to infect nondividing cells, in a wide range of cell types and tissues. In this review, we describe the various insertional mutagens focusing on their advantages/limitations, and we discuss the new and promising tools that will improve the insertional mutagenesis screens of the future. PMID- 23928058 TI - The small cell lung cancer-specific isoform of RE1-silencing transcription factor (REST) is regulated by neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100). AB - Small cell lung cancer (SCLC) is a highly malignant form of cancer, which originates from primitive neuroendocrine cells in the lung. SCLC cells express several autocrine neurotransmitters/neuropeptides and their respective receptors. Expression of these neuronal markers is frequently regulated by RE1-silencing transcription factor (REST). In SCLC cells, an SCLC-specific isoform of REST (sREST) is highly expressed, whereas REST expression is undetectable, suggesting that the expression of sREST correlates with the pathogenesis of SCLC. Expression of sREST, which is derived through alternative splicing of REST, is abnormally regulated in SCLC cells, but the mechanism is unknown. Most recently, nSR100 (SRRM4) was described as an activator of REST alternative splicing. We now show that nSR100 is highly expressed in SCLC cells correlating with high sREST and low REST expression. Adhesion to the extracellular matrix (ECM) is thought to enhance tumorigenicity and confer resistance to apoptosis. Interestingly, nSR100 expression is enhanced in cells grown with ECM. Overexpression of REST caused repression of sREST and nSR100, the latter containing RE1 element controlled by REST. Culturing the SCLC cell line NCI-N417 cells with ECM also upregulated RE1 containing gene, the voltage-gated calcium channel subunit. Inhibition of the PI3K/Akt/mTOR pathway by LY294002 induced nSR100 expression, whereas the specific MEK/ERK inhibitor U0126 inhibited nSR100 expression. Repressing nSR100 by siRNA effectively repressed sREST, and conversely increased REST in NCI-N417 cells. Taken together, this report clarifies the ECM-dependent signaling pathway that impacts nSR100 expression and its regulation of alternative splicing in SCLC. IMPLICATIONS: The splicing factor nSR100 may be novel SCLC-specific biomarker, as well as a therapeutic target. PMID- 23928057 TI - Menin directly represses Gli1 expression independent of canonical Hedgehog signaling. AB - Multiple endocrine neoplasia type 1 (MEN-1), is a familial tumor syndrome resulting from mutations in the tumor suppressor gene menin (MEN1). Menin plays an essential role in both repressing and activating gene expression. However, it is not well understood how menin represses expression of multiple genes. Upon MEN1 excision, the transcription factor Gli1 and its target genes, including Ptch1 and c-Myc, were shown to be elevated in the absence of an apparent Hedgehog) pathway-activating ligand or when Smoothened (SMO), a key component of the pathway, is inhibited. Menin binds to the GLI1 promoter and recruits PRMT5, a histone arginine methyltransferase associated with transcriptional repression. Both PRMT5 binding and histone H4 arginine 3 methylation (H4R3m2s) are decreased at the GLI1 promoter in MEN1-excised cells. Moreover, MEN1 ablation resulted in increased binding of transcriptionally active Gli1 at the GLI1 promoter in a manner not influenced by the canonical Hedgehog signaling pathway. Inhibition of Gli1 by the small-molecule inhibitor GANT-61 led to decreased expression of Gli1 and its target genes in MEN1-depeleted cells. Furthermore, GANT-61 potently suppressed proliferation of MEN1-excised cells as compared with control cells. These findings uncover a novel epigenetic link whereby menin directly represses Gli1 expression, independent of the canonical Hedgehog signaling pathway, via PRMT5 and its repressive H4R3m2s mark. IMPLICATIONS: Inhibition of GLI1 suppresses neuroendocrine tumors harboring mutations in the MEN1 gene. PMID- 23928059 TI - Dynamic and nuclear expression of PDGFRalpha and IGF-1R in alveolar Rhabdomyosarcoma. AB - Since the advent of tyrosine kinase inhibitors as targeted therapies in cancer, several receptor tyrosine kinases (RTK) have been identified as operationally important for disease progression. Rhabdomyosarcoma (RMS) is a malignancy in need of new treatment options; therefore, better understanding of the heterogeneity of RTKs would advance this goal. Here, alveolar RMS (aRMS) tumor cells derived from a transgenic mouse model expressing two such RTKs, platelet-derived growth factor (PDGFR)alpha and insulin-like growth factor (IGF)-1R, were investigated by fluorescence-activated cell sorting (FACS). Sorted subpopulations that were positive or negative for PDGFRalpha and IGF-1R dynamically altered their cell surface RTK expression profiles as early as the first cell division. Interestingly, a difference in total PDGFRalpha expression and nuclear IGF-1R expression was conserved in populations. Nuclear IGF-1R expression was greater than cytoplasmic IGF-1R in cells with initially high cell surface IGF-1R, and cells with high nuclear IGF-1R established tumors more efficiently in vivo. RNA interference-mediated silencing of IGF-1R in the subpopulation of cells initially harboring higher cell surface and total IGF-1R resulted in significantly reduced anchorage-independent colony formation as compared with cells with initially lower cell surface and total IGF-1R expression. Finally, in accordance with the findings observed in murine aRMS, human aRMS also had robust expression of nuclear IGF-1R. IMPLICATIONS: RTK expression status and subcellular localization dynamics are important considerations for personalized medicine. PMID- 23928060 TI - [Perceptions of female immigrant domestic workers on the effects of the sector regulation in Spain]. AB - OBJECTIVE: To examine the perceptions of female immigrant domestic workers of the effect of Royal Decree 1620/2011, which regulates the relationship of domestic workers in the family home and their employment conditions in Spain. METHODS: An exploratory study was performed using qualitative content analysis of three focus group discussions with immigrant women from Colombia, Ecuador and Morocco. RESULTS: Immigrant women positively assessed the theoretical benefits of the new regulation, but identified legal and economic barriers to obtaining a contract and being registered in the social security system by their employers, and to employers accepting the cost of these measures, especially for workers hired by the hour. These difficulties affected their possibilities of legalizing their status. The economic crisis posed a serious challenge to compliance with the new regulation. CONCLUSIONS: Although the new regime encourages job creation with stronger working rights for these workers, immigrant women perceived that its implementation has been hampered by the current financial crisis and has not, therefore, improved their employment conditions. PMID- 23928061 TI - A comprehensive immunohistochemistry of prostaglandins F2alpha and E2 synthetic enzymes in rat ovary and uterus around parturition. AB - A comprehensive immunohistochemistry with the isoform-distinguishable antibodies against prostaglandin (PG) F2alpha and PGE2 biosynthetic enzymes was undertaken to identify the cellular types and enzyme isoforms in rat ovary and uterus around parturition. In general ovarian and uterine cells showed positive immunoreactions for phospholipase A2 groups 4A and 6A, but not group 2A, and cyclooxygenase (COX) 1 rather than COX-2. Their immunoreactions for PGF2alpha synthase and PGE2 synthase were cell type-dependently variable. The putative PGF2alpha and PGE2 producing cell types included, as expected, ovarian luteal cells, uterine endometrial epithelium and myometrium, and cervical connective tissue and, unexpectedly, ovarian stromal cells and basal lamina of cervical endometrium. Obtained data indicate the generation of PGF2alpha and PGE2 by multiple sites, which are entirely the same as established sites of actions, in parturition processes and tissue-dependent differential usage of PG biosynthetic pathway. PMID- 23928063 TI - [Adult onset Niemann-Pick type C disease and psychosis: literature review]. AB - INTRODUCTION: Niemann-Pick type C disease (NPC) is a rare hereditary disease, which psychiatrists do not face often in France. Indeed, only a couple of articles specifically describing the psychiatric-disorders in the adult form have been published. And for the most part, they were not written by psychiatrists. This comprehensive international literature review aims at providing knowledge on this disease to French psychiatrists. METHODS: To achieve this literature review, we used the "PubMed" search engine, looking for the following keywords: Niemann Pick type C AND (schizophrenia OR psychosis). RESULTS: Niemann-Pick type C disease (NPC) is a rare, neurovisceral, autosomal recessive disease, with an extremely heterogeneous clinical presentation. It is characterized by a wide range of symptoms that are not specific, such as neurological, systemic or psychiatric symptoms. The adult form of the disease concerns a small proportion (5 %) of the people affected and is usually expressed as a neurological form. A variety of progressive and disabling symptoms are encountered, mainly cerebellar signs (cerebellar ataxia, impaired gait, dysarthria), but also movement disorders, cataplexy, seizures and dysphagia. Patients face constant cognitive deterioration, which can result in severe dementia. Abnormal saccadic eye movement is often the first manifestation of the disease. Supranuclear gaze palsy is considered to be a specific sign and should be systematically searched for. In terms of systemic signs, the usual infantile hepatosplenomegaly is very fickle in the adult form; if present, it is usually asymptomatic. Non-specific psychiatric symptoms are often associated with NPC disease. For one third of cases, it can also express as an isolated psychiatric-disorder form, such as schizophrenia-like psychosis (paranoid delusions, auditory hallucinations, interpretative thoughts, and disorganization), depression, bipolar disorder, obsessive-compulsive behaviour and behavioural problems (sleep disorders, hyperactivity, agitation, aggressiveness or self-mutilations). This psychiatric overview is mostly atypical and is accompanied by visual hallucinations, confusion, symptom fluctuations, treatment resistance or aggravation with neuroleptic drugs, catatonia, progressive cognitive decline, but also seizures. The late appearance of neurological manifestations is often wrongfully attributed to the effects of antipsychotic medication, which generates tardy diagnosis. Most of NPC affected patients die prematurely. NPC diagnosis is based on a filipin test on a fibroblast culture from a skin biopsy and also on a sequencing of the NPC1 and NPC2 genes. Routine laboratory biochemistry profiles are generally normal. The early diagnosis is fundamental to deploy the best follow-up care. The patient should therefore be in contact with a reference centre. Until recently, NPC treatment consisted in supportive therapies and symptomatic drugs, useful, however, with variable efficacy. The recent discovery of a medicine called Miglustat (N-butyldeoxynojirimycin; NB-DJN; Zavesca((r)), Actelion Pharmaceuticals Ltd.) which improves the disease evolution, should encourage psychiatrists to look for it in every atypical psychosis. PMID- 23928064 TI - [Motivations for cannabis cessation, coping and adaptation strategies, and perceived benefits: impact on cannabis use relapse and abstinence]. AB - OBJECTIVES: While cannabis has been recognized as the most illicit drug use in the world, few studies focusing on cannabis self-change and cannabis relapse or abstinence in adult non-treatment samples have been conducted. The first aim of this study was to understand cannabis self-change motives, coping and adaptation strategies and evaluating perceived benefits from cannabis cessation. The second aim was to compare, in a convenience sample of non-treatment-seeking adult cannabis smokers, motivations to quit smoking cannabis, coping and adaptive strategies, as well as perceived benefit from cessation between cannabis abstinent and participants who relapse. METHOD: Sixty-three participants (31 men and 32 women) who attempted to quit cannabis in a non-controlled environment without medical help and were enrolled. They completed the Marijuana Quit Questionnaire (MJQQ), a self-report questionnaire collecting information in three areas: sociodemographic characteristics, cannabis use history (including any associated problems), and participants' characteristics regarding their "most difficult" (self-defined) attempt to quit in a non-controlled environment. For this study the index quit attempt was characterized in two areas: reasons for quitting marijuana, coping strategies used while quitting. Two additional questionnaires were added to the MJQQ; the Brief Cope, and a questionnaire assessing perceived benefit of the cannabis quit attempt. The participants were on average 28.5 years old (+/-5.1), and started using cannabis on average at 15.8 years (+/-2.8). Seventy-four percent (n=45) of the participants met the DSM-IV criteria for cannabis dependence before cannabis cessation. T-tests were used to compare abstainers and participants who relapsed after the quit attempt. RESULTS: Realizing that cannabis induces disabling cognitive disorders such as affection of memory, concentration and attention were reported by 71% of the participant as a motivation for quitting cannabis use. Then, being more energetic (reported by 68%) and more active during the day (62%), being able to control their life (67%), proving themselves they could quit (60%), saving money (60%), as well being less worried about their health (57%) were also reported as motivations to quit cannabis use. Different coping and adaptation strategies were also reported. First, environmental strategies such as disposing of both cannabis (71%) and equipment to smoke (71%), no longer going to places where cannabis is smoked (33%) or lifestyle changes (68%) were used to cope with cannabis cessation. Then cognitive strategies such as motivation, willingness (71%), self-control and having a positive perception of the situation (68%) were also reported. Regarding coping strategies, participants accepted and learned how to live with the new situation (68%), and social support from family (32%) and friends (30%) were reported. Perceived benefits were linked with motivations for cannabis cessation. Thus, participants reported having more energy (75%), being more active (73%), less tired (70%) and recovering memory (57%) after cannabis cessation. Fifty-two percent of participants relapsed after the quit attempt. Abstainers had significantly higher scores on two subscales: the "negative impact of cannabis use on one's health and on self and social image" (t(61)=-3.84; P<0.001; d=-0.76) and "negative reinforcement (e.g. seeking relief for specific physical symptoms or social problems caused by cannabis)" (t(61)=3.56; P=0.01; d=-0.51) than non anstainers. Non-abstainers reported significantly less social support from family (t(61)=-3.85; P<0.001, d=-0.76) and friends (t(61)=-2.22; P=00.03, d=-0.51) than abstainers. CONCLUSION: This study underlines different aspects of cannabis cessation, self-change, relapse, and abstinence. Social and family support, as well as social network appears to be of prime importance in relapses and prevention programs for cannabis use. New perspectives for research on cannabis cessation self-change and relapses are thus highlighted, notably regarding factors that could predict relapse or success in cessation of smoking cannabis. Research on cannabis self-change and relapse are warranted for both prevention and therapeutic programs. PMID- 23928062 TI - B cell receptor signaling in chronic lymphocytic leukemia. AB - B cell receptor (BCR) signaling plays an important pathogenic role in chronic lymphocytic leukemia (CLL) and B cell lymphomas, based on structural restrictions of the BCR, and BCR-dependent survival and growth of the malignant B cells. In CLL and lymphoma subtypes, ligand-independent ('tonic') and ligand-dependent BCR signaling have been characterized, which can involve mutations of BCR pathway components or be triggered by (auto)antigens present in the tissue microenvironment. In CLL, based on high response rates and durable remissions in early-stage clinical trials, there is rapid clinical development of inhibitors targeting BCR-associated kinases [Bruton's tyrosine kinase (BTK), phosphoinositide 3-kinase (PI3K)delta], which will change treatment paradigms in CLL and other B cell malignancies. Here, we discuss the evolution of this field, from BCR-related prognostic markers, to mechanisms of BCR activation, and targeting of BCR-associated kinases, the emerging Achilles' heel in CLL pathogenesis. PMID- 23928065 TI - [Self-esteem, coping, perceived social support and substance use in young adults with a cannabis dependence disorder]. AB - INTRODUCTION: Self-esteem, coping strategies and perceived social support play a role in the adaptive functioning of the human being: they allow the adjustment of the subject to his/her environment. These dimensions could be protective factors regarding multiple risks associated with adolescent development, and particularly substance use. Thus our objective was twofold: to evaluate self-esteem, coping strategies and perceived social support in adolescents and young adults with a cannabis dependence in comparison with subjects from the general population; to establish the correspondence between these psychological dimensions and the patients' substance use pattern. METHOD: Data from 43 young patients (36 males; mean age=19.6+/-3), consulting for their cannabis dependence, and 50 young adults from the general population (39 males; mean age=19.7+/-3.4) were included. Participants completed the Rosenberg Self-Esteem Inventory, the Social Self Esteem Inventory of Lawson, the Coping Inventory for Stressful Situation of Endler & Parker, and the Perceived Social Support Questionnaire of Sarason. The MINI was administered to evaluate cannabis abuse or dependence; a semi-structured clinical interview was given to determine psychoactive substance use. RESULTS: Between-group comparisons (two independent sample t-tests) showed that the patients had significantly lower scores on global (P=0.002) and social (P=0.035) self-esteem, task-oriented coping (P<0.001) and both availability and satisfaction regarding perceived social support (respectively P=0.029 and P<0.001). Conversely, patients had significantly higher scores on emotion-focused coping subscale (P=0.003). Logistic regressions showed that the satisfaction regarding social support and task-oriented coping scores were the more powerful to distinguish the patients from the controls (respectively beta=1.16, P=0.043 and beta=1.06, P=0.015). Unvaried linear regression analyses revealed a negative association between the age of first cannabis use and the avoidant-social coping score (P=0.025), and positive associations between the length of daily cannabis use and emotion-focused coping score (P=0.028), and frequency of cannabis use and global self-esteem scores (P=0.028). Moreover, polysubstance misuse is associated with low distraction-avoidant coping scores. No association was found between clinical scores and tobacco and alcohol uses variables. CONCLUSION: These results suggest that cannabis dependent patients may present a lack in individual and interpersonal resources. This clinical study underscores the potential contribution of maladaptive coping to the development or maintenance of substance use in young adulthood. PMID- 23928066 TI - [Antipsychotic-drug-induced hyperprolactinemia: physiopathology, clinical features and guidance]. AB - BACKGROUND: Hyperprolactinemia is a frequent but neglected adverse effect observed in patients treated with antipsychotic-drugs. In this review, we summarize its physiopathogenetic mechanism, its clinical manifestations in men and women, and the way to manage it. LITERATURE FINDINGS: Prolactin is a hormone secreted by lactotroph cells in the anterior pituitary. Its synthesis and release are under the control of peptides, steroids and neurotransmitters. The main inhibitory regulation is made by dopamine, which binds dopamine receptors D2 on the membrane of lactotroph cells. Antipsychotic-drugs block these receptors and thus remove the inhibitory effect of dopamine on prolactin secretion. All antipsychotic-drugs block D2 receptors and all can induce hyperprolactinemia. Nonetheless, it seems that the faster the antipsychotic-drug dissociates from D2 receptors, the lesser the increase of prolactin in the plasma. Another way to explain hyperprolactinemia is the ability of antipsychotic-drugs to cross the blood-brain barrier. The role of their metabolites should also be considered. For these reasons, one can distinguish prolactin-raising (conventional neuroleptics, amisulpride, risperidone) and prolactin-sparing (clozapine, aripiprazole, olanzapine) antipsychotics. An English study showed that 18% of men and 47% of women treated with antipsychotics for severe mental illness had a prolactin level above the normal range. Hyperprolactinemia is in fact more frequent in women than in men. Sometimes it is asymptomatic, but the higher the prolactin level is, the more patients have clinical manifestations. Some symptoms are due to the hypogonadism caused by prolactin, which disturbs hypothalamic-pituitary axis function, and others are due to direct effects on target tissues. Consequently, patients can suffer from sexual dysfunction, infertility, amenorrhea, gynecomastia or galactorrhoea. Data suggest that these symptoms are common, but patients don't mention them spontaneously and clinicians underestimate their prevalence. In the long-term, hypogonadism involves a premature bone loss in men and women. Klibanski and colleagues showed that this loss is significant only in women with hyperprolactinemia associated with amenorrhea. That suggests that prolactin is not directly responsible for this clinical feature. Nevertheless, prolactin seems to be involved in the development of breast cancer, but its role is unclear for prostate cancer. DISCUSSION: Our review promotes a check-up before beginning a treatment with antipsychotic agents. First, a baseline prolactin level should be measured. It should also include the research on previous treatment with antipsychotic-drugs and the assessment of adverse effects suggestive of hyperprolactinemia. Questioning should finally look for any contra indication to antipsychotics. Monitoring during antipsychotic treatment has been studied by a group of international experts in psychiatry, medicine, toxicology and pharmacy who made a critical review of clinical guidance on hyperprolactinemia. Experts notify that it is important to check whether patients have any sexual dysfunction, such as loss of libido or menstrual irregularity, and galactorrhoea. Prolactin level should also be controlled after three months of stable dose treatment, or if any clinical feature of hyperprolactinemia appears. If a patient prescribed antipsychotic-drugs has a confirmed prolactin level above the normal range, it is necessary to exclude other causes of hyperprolactinemia. If antipsychotics are really involved, the management should be adapted with the prolactin level and the patient him/herself. To summarize, clinicians can decrease the dose of the antipsychotic or switch to a prolactin sparing drug. Oral contraceptives can be added whether to prevent pregnancy or to prevent bone loss and osteoporosis. Finally, experts recommend reserving dopamine agonists to treat antipsychotic-induced hyperprolactinemia in very exceptional circumstances as it can worsen the mental illness. PMID- 23928067 TI - [Decision of emergency involuntary hospitalization: categorical or dimensional approach?]. AB - BACKGROUND: In 2005, in its recommendations on the modalities of decision making for compulsory hospitalization, the French Health High Authority (HAS) had already stressed the need for rapid implementation of studies and epidemiological analyses on the subject to compensate the lack of adequate data in France. The new French law of July 5, 2011, on the rights and protection of persons under psychiatric care, establishes a judicial review of decisions for compulsory hospitalization. Therefore, healthcare professionals need to better define and characterize the criteria for such decisions, especially in their relation to psychopathology. The concept of capacity to consent to treatment includes the ability to understand (to receive information about the disease), the ability to appreciate (to weigh the risks and benefits of treatment), the ability to reason (determining the best choice rationally) and the ability to freely express a decision. However, assessment tools of capacity to consent to treatment seem to fail to predict the modality of hospitalization. OBJECTIVE: This study examined the impact of clinical and contextual characteristics on the decision in emergency services to admit patients to compulsory inpatient psychiatric units. METHOD: Data was collected from 442 successive patients admitted to hospital for care from five psychiatric emergency facilities in Paris and covered sociodemographic information, previous hospitalizations, recent course of care, clinical diagnosis, Global Assessment of Functioning scale (GAF) and Insight measured by the Q8 Bourgeois questionnaire. Patients were also assessed based on criteria established by the HAS for the severity of mental disorders and the necessity of emergency care. RESULTS: Multivariable logistic regression shows that diagnosis does not affect the decision of hospitalization. Agitation, aggressiveness toward others, being married as well as being referred by a doctor or family are all factors that increase the risk of involuntary hospitalization. Last, low Q8 and GAF scores are strong predictors for compulsory admission. CONCLUSION: Our study shows a dimensional rather than categorical assessment of patients by clinicians. Assessment of insight is the main operational criterion used by clinicians in our study. This supports using insight and GAF evaluation in clinical practice to clarify assessment and decision-making in an emergency setting regarding compulsory hospitalization. PMID- 23928068 TI - [Secondary benefits of cognitive rehabilitation for a chronic ethylic patient: effects on disorder consciousness, motivation, and global therapeutic cooperation]. AB - INTRODUCTION: Alcoholism causes psychological, behavioral and cognitive symptoms that need to be addressed together. The neuropsychological alterations among alcohol-dependent people are considered to make the therapeutic work complex and longer. A cognitive rehabilitation program is sometimes difficult to achieve with these patients. Functional results are often difficult to anticipate. However, the consequences of this therapeutic approach are multiple and there are many interactions between psycho-affective, behavioral and cognitive components. A neuropsychological approach can be used like a tool to improve metacognition. A bad contribution to treatment programs is often secondary to the illusion of a satisfying intellectual functioning. Patients' motivation for the therapeutic work is very changeable. A complete consciousness of impairments can help them to stay involved. CASE REPORT: The following case shows the cognitive effects and secondary benefits associated with a neuropsychological work, which was carried out by a chronic ethylic patient with severe physical and cognitive symptoms. The patient aged 50, with a good qualification level (scientific section in the final year of secondary school, with no diploma, then attended a training program to become a croupier) was suffering from chronic alcoholism since his adolescence. He arrived in the closed unit after many hospitalizations in psychiatric and hepato-gastroenterology units. He had been showing mental confusion. He presented a frontal and subcortical profile of alcohol-related dementia according to Oslin's criteria. MRI revealed global cerebral atrophy, more pronounced on the fronto-parietal cortex with cerebellar leukoencephalopathy, but no pontine central myelinolysis. The neurocognitive program had two main lines: reducing attentional, executive and graphical deficits with training exercises (individual and group sessions) and compensating memory, and executive disorders with an external aid. The cognitive program had been assessed by means of repeated psychometric measures, behavior and metacognition estimated by direct clinical observations. The cognitive remediation was carried out during a 10-month hospitalization, and then in an outpatient rehabilitation setting over a 12-month period. The external individual sessions were associated with medical consultations and support for reintegration at home provided by the mobile psychiatric team. RESULTS: The test results showed a significant improvement in attentional processes and executive functions. On graphic level, his writing was recovered after 10 months. Impairment within episodic memory processes-encoding was observed, and prospective memory was reinforced by external aids. At the end of the program, the use of an agenda proved to be effective even if updating was difficult once back home. Although a part of these effects could be expected, their psychological influence on the patient must be underlined: his perception of the alcohol related problem had been modified with more consciousness of the neurobiological consequences and a strong desire of personal implication. He worked a lot on his own (always under supervision) on cognitive exercises and succeeded in remaining abstinent for nearly 2 years. He died of complications of acute hepatitis. DISCUSSION: All the cognitive assessments and rehabilitation results seem to have increased his participation in the global therapeutic care. Therapeutic tools used for cognitive work give a concrete picture of the consequences of alcohol consumption and the necessary time to retrieve brain capacities. Visible improvements in terms of reduction in disability-handicaps encouraged the patient, valued his efforts, and increased his determination to solve his alcohol related problem. Thus, cognitive programs can help to reduce passiveness and develop activeness. This patient regarded therapeutic difficulties as a challenge, not as an obstacle. We can reasonably assume the effect of the cognitive rehabilitation on the Persistence of the Cloninger's biosocial model. This increase in temperament corresponds to a certain form of tenacity, which would facilitate abstinence. PMID- 23928069 TI - [Cortical spreading depolarization: a new pathophysiological mechanism in neurological diseases]. AB - Cortical spreading depolarization is a wave of almost complete depolarization of the neuronal and glial cells that occurs in different neurological diseases such as migraine with aura, subarachnoid hemorrhage, intracerebral hemorrhage, head trauma and stroke. These depolarization waves are characterized by a change in the negative potential with an amplitude between -10 and -30mV, duration of ~1min and changes in the ion homeostasis between the intra- and extracellular space. This results in neuronal edema and dendritic distortion. Under pathologic states of hypoperfusion, cortical spreading depolarization can produce oxidative stress, worsen hypoxia and induce neuronal death. This is due to intense arterial vasoconstriction produced by an inverse response called spreading ischemia. Only in the last years there has been an electrophysiological confirmation of cortical spreading depolarization in human brains. Occurrence of cortical spreading depolarization has been associated with worse outcome in patients. Currently, increased knowledge regarding the pathophysiologic mechanisms supports the hypothetical correlation of cortical spreading depolarization with brain damage in humans. There are diverse therapeutic alternatives that promise inhibition of cortical spreading depolarization and subsequent better outcomes. PMID- 23928070 TI - Spectroscopic, computational modeling and cytotoxicity of a series of meso-phenyl and meso-thienyl-BODIPYs. AB - A series of twenty-two BODIPY compounds were synthesized, containing various meso phenyl and meso-thienyl groups, and their spectroscopic and structural properties were investigated using both experimental and computational methods. Further functionalization of the BODIPY framework via iodination at the 2,6-pyrrolic positions was explored in order to determine the effect of these heavy atoms on the photophysical and cytotoxicity of the meso-aryl-BODIPYs. BODIPYs bearing meso thienyl substituents showed the largest red-shifted absorptions and emissions and reduced fluorescence quantum yields. The phototoxicity of the BODIPYs in human carcinoma HEp2 cells depends on both the presence of iodines and the nature of the meso-aryl groups. Six of the eleven 2,6-diiodo-BODIPYs investigated showed at least a sevenfold enhancement in phototoxicity (IC50 = 3.5-28 MUM at 1.5 J/cm(2)) compared with the non-iodinated BODIPYs, while the others showed no cytotoxicity, while their singlet oxygen quantum yields ranged from 0.02 to 0.76. Among the series investigated, BODIPYs 2a and 4a bearing electron-donating meso dimethoxyphenyl substituents showed the highest phototoxicity and dark/phototoxicity ratio, and are therefore the most promising for application in PDT. PMID- 23928071 TI - Design, stereoselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists. AB - We recently reported the discovery of octahydropyrrolo[1,2-a]pyrazine A as a lead compound for an inhibitor of apoptosis proteins (IAP) antagonist. To develop IAP antagonists with favorable PK profiles, we designed novel tri-cyclic compounds, octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazines 1 and 2 based on co-crystal structural analysis of A with cellular IAP-1 (cIAP-1). The additional cyclopropane moiety was used to block the predicted metabolic site of compound A without detriment to the binding affinity for cIAP. Compounds 1 and 2 were stereoselectively synthesized via intermediates 4a and 5b', which were obtained by Simmons-Smith cyclopropanation of ethylester 3a and silyl ether 3b'. Compounds 1 and 2 showed strong growth inhibition in MDA-MB-231 breast cancer cells and improved metabolic stability in comparison to A. Compound 2 exhibited significant in vivo PD effects to increase tumor necrosis factor-alpha mRNA in a dose dependent manner. PMID- 23928072 TI - Attachment style, social support and finding meaning among spouses of colorectal cancer patients: gender differences. AB - OBJECTIVES: The current study explores the relationship between attachment styles, social support, gender and finding meaning in caregiving among spousal caregivers of colorectal cancer patients. METHODS: Sixty caregivers (30 men and 30 women) were administered questionnaires assessing attachment styles, social support and finding meaning in caregiving, using a cross-sectional design. RESULTS: For male caregivers avoidance attachment is associated with their finding meaning, whereas for female caregivers social support is associated with their finding meaning. SIGNIFICANCE OF RESULTS: Psychological interventions for caregivers should take into consideration gender differences and might benefit from addressing the process of finding meaning in caregiving. PMID- 23928074 TI - Revisiting perceptions of quality of hospice care: managing for the ultimate referral. AB - Hospice services provided in the final months of life are delivered through complex interpersonal relationships between caregivers, patients, and families. Often, service value and quality are defined by these interpersonal interactions. This understanding provides hospice leaders with an enormous opportunity to create processes that provide the optimal level of care during the last months of life. The authors argue that the ultimate referral is attained when a family member observes the care of a loved one, and the family member conveys a desire to receive the same quality of services their loved one received at that facility. The point of this article is to provide evidence that supports the methods to ultimately enhance the patient's and family's experience and increase the potential for the ultimate referral. PMID- 23928073 TI - IL-1beta induces GFAP expression in vitro and in vivo and protects neurons from traumatic injury-associated apoptosis in rat brain striatum via NFkappaB/Ca2+ calmodulin/ERK mitogen-activated protein kinase signaling pathway. AB - Reactive astrogliosis, a feature of neuro-inflammation is induced by a number of endogenous mediators including cytokines. Despite interleukin-1 beta (IL-1beta) stands out as the major inducer of this process, the underlying mechanism and its role on neuronal viability remain elusive. We investigated in human astrocytoma cells and the rat brain striatum, the role of the nuclear factor-kB (NF-kB) intracellular Ca(2+) concentration ([Ca(2+)]i) calmodulin (CaM) and extracellular regulated mitogen-activated protein kinases (ERK1/2) in IL-1beta-induced expression of glial fibrillary acidic protein (GFAP) and neuronal apoptosis associated to a brain trauma. Cell data showed that IL-1beta (1 ng/ml) increased NF-kB, pERK1/2 and GFAP expression. Nevertheless, further increase in IL-1beta levels reversed progressively these responses. Preventing ERK1/2 activation with 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthiol]-butadiene antagonized IL 1beta-induced GFAP expression while inhibiting selectively nuclear translocation of NF-kB with caffeic-acid phenethyl-ester down-regulated both ERK1/2 and GFAP expression induced by IL-1beta. The GFAP response was also prevented by antagonizing selectively increase in [Ca(2+)]i, CaM activity or inducible nitric oxide synthase expression with respectively ryanodine plus 2-aminoethoxydiphenyl borate, N-(6-aminohexyl)-5-chloro-1-naphthalensulfonamide hydrochloride and N-[(3 (aminomethyl)-phenyl]methyl]-ethanimidamide dihydrochloride. Data in vivo supported these findings and showed that GFAP expression induced by IL-1beta (50 ng/ml) correlated with attenuated glial scar formation and reduced neuronal apoptosis. Our data identified the NF-kB/Ca(2+)-CaM/ERK signaling pathway as a novel in vivo key regulator of IL-1beta-induced astrogliosis which may represent a potential target in neurodegeneration. PMID- 23928075 TI - The deathbed confession. PMID- 23928076 TI - Utilization and cost of services in the last 6 months of life of patients with cancer - with and without home hospice care. AB - This study examined the utilization and cost of all health services consumed during the last six months of life by cancer patients, and compared those with and without home-hospice care. Detailed information was extracted from the health care electronic administrative data files on 193 deceased cancer patients that their family approved the study (out of 429, 45%). About 88% had been hospitalized for 19 days on average and 53% visited the ER. One quarter received home-hospice care. Their average cost was $13,648 compared to $18,503 for patients without home-hospice care. Hospitalization contributed 32% to the total cost of patients with home-hospice care and 64% for those with it. The findings support the justification for significant expansion of home-hospice care. PMID- 23928077 TI - Soft robots. PMID- 23928078 TI - The essential nature of iron usage and regulation. AB - The facile ability of iron to gain and lose electrons has made iron an important participant in a wide variety of biochemical reactions. Binding of ligands to iron modifies its redox potential, thereby permitting iron to transfer electrons with greater or lesser facility. The ability to transfer electrons, coupled with its abundance, as iron is the fourth most abundant mineral in the earth's crust, have contributed to iron being an element required by almost all species in the six kingdoms of life. Iron became an essential element for both Eubacteria and Archeabacteria in the early oxygen-free stages of the earth's evolution. With the advent of an oxygen-rich environment, the redox properties of iron made it extremely useful, as much of iron utilization in eukaryotes is focused on oxygen metabolism, either as an oxygen carrier or as an electron carrier that can facilitate oxygen-based chemistry. PMID- 23928079 TI - Pupil responses allow communication in locked-in syndrome patients. AB - For patients with severe motor disabilities, a robust means of communication is a crucial factor for their well-being [1]. We report here that pupil size measured by a bedside camera can be used to communicate with patients with locked-in syndrome. With the same protocol we demonstrate command-following for a patient in a minimally conscious state, suggesting its potential as a diagnostic tool for patients whose state of consciousness is in question. Importantly, neither training nor individual adjustment of our system's decoding parameters were required for successful decoding of patients' responses. PMID- 23928080 TI - Strong genome-wide divergence between sympatric European river and brook lampreys. AB - Lampreys, together with hagfishes, are the only extant representatives of jawless vertebrates and thus of prime interest for the study of vertebrate evolution [1]. Most lamprey genera occur in two forms with divergent life histories: a parasitic, anadromous and a non-parasitic, freshwater resident form [2-8]. The taxonomic status of such 'paired species' is disputed, however. While indistinguishable at larval stages, but clearly distinct as adults, they cannot be differentiated with available genetic data [6,7], which has fuelled speculations that the two forms may in fact represent products of phenotypic plasticity within a single species. Here, we use restriction site-associated DNA sequencing (RADseq) to examine the genetic population structure of sympatric European river (Lampetra fluviatilis L., 1758) and brook (Lampetra planeri Bloch, 1784) lampreys. We find strong genetic differentiation and identify numerous fixed and diagnostic single nucleotide polymorphisms (SNPs) between the two species, 12 of which can be unequivocally assigned to specific genes. PMID- 23928081 TI - Animal biomechanics: a new silent partner in the control of motion. AB - A new kind of passive force has been discovered in the joints of insects, one that is a large contributor to almost every leg motion, from posture to scratching to locomotion. PMID- 23928082 TI - Development: scaling to size by protease inhibition. AB - The dorsal half of bisected Xenopus laevis embryos can regenerate a well proportioned organism on a smaller scale. A new study indicates that the removal of ventral tissue generates a steeper Chordin gradient by reducing Sizzled, a secreted inhibitor of Tolloid chordinases. PMID- 23928083 TI - Invertebrate vision: peripheral adaptation to repeated object motion. AB - Visual systems adapt rapidly to objects moving repeatedly within the visual field, because such objects are likely irrelevant. In the crab, the neural switch for such adaptation has been found to take place at a surprisingly early stage of the visual processing pathway. PMID- 23928084 TI - Genome evolution: a bacterium with a Napoleon complex. AB - New work on an important agricultural pest reveals an unexpected toxin-producing defensive bacterial symbiont. Surprisingly, the symbiont's genome is highly reduced, with genes devoted to polyketide synthesis making up a large fraction of its coding capacity. PMID- 23928085 TI - Centriole engagement: it's not just cohesin any more. AB - The belief that cohesin complexes link mother to daughter centrioles has received substantial experimental support. New studies challenge the primacy of cohesin in centriole engagement and provide a more nuanced view into the mechanisms for centriole disengagement in anaphase. PMID- 23928086 TI - Fishery management: is Europe turning the corner? AB - Fishery management is widely perceived to be failing, and proposals for new approaches abound. However, evidence is accumulating that traditional approaches, where properly applied, do work. European management of fish stocks in the north east Atlantic may be the latest case in point. PMID- 23928087 TI - Lineage specification: reading the instructions may help! AB - Understanding lineage specification is biologically important and critical for the production of cells for regenerative medicine. Extrinsic cues are clearly necessary but do they direct or select lineage? Single-cell analysis now suggests that cytokine signaling can instruct lineage choice in blood stem cells. PMID- 23928088 TI - From gaze cueing to dual eye-tracking: novel approaches to investigate the neural correlates of gaze in social interaction. AB - Tracking eye-movements provides easy access to cognitive processes involved in visual and sensorimotor processing. More recently, the underlying neural mechanisms have been examined by combining eye-tracking and functional neuroimaging methods. Apart from extracting visual information, gaze also serves important functions in social interactions. As a deictic cue, gaze can be used to direct the attention of another person to an object. Conversely, by following other persons' gaze we gain access to their attentional focus, which is essential for understanding their mental states. Social gaze has therefore been studied extensively to understand the social brain. In this endeavor, gaze has mostly been investigated from an observational perspective using static displays of faces and eyes. However, there is growing consent that observational paradigms are insufficient for an understanding of the neural mechanisms of social gaze behavior, which typically involve active engagement in social interactions. Recent methodological advances have allowed increasing ecological validity by studying gaze in face-to-face encounters in real-time. Such improvements include interactions using virtual agents in gaze-contingent eye-tracking paradigms, live interactions via video feeds, and dual eye-tracking in two-person setups. These novel approaches can be used to analyze brain activity related to social gaze behavior. This review introduces these methodologies and discusses recent findings on the behavioral functions and neural mechanisms of gaze processing in social interaction. PMID- 23928089 TI - Neural correlates of dysfunctional emotion regulation in major depressive disorder. A systematic review of neuroimaging studies. AB - Abnormal emotion processing is a core feature of major depressive disorder (MDD). Since the emergence of functional neuroimaging techniques, many studies have been conducted in MDD subjects to elucidate the underlying abnormalities in the neural systems involved in emotion regulation. In this systematic review, we discuss this research in the context of the neural model of emotion regulation previously described by Phillips et al. (2008). This model differentiates between automatic and voluntary emotion regulation subprocesses. Automatic regulation subprocesses were shown to involve predominantly medial prefrontal cortical structures, in addition to the hippocampus and parahippocampus, while voluntary regulation processes additionally recruited lateral prefrontal cortical regions. In conclusion, although the available data is limited, findings suggest that MDD subjects demonstrate abnormally reduced activity in lateral prefrontal cortices during explicit voluntary control of emotional experience. During early, automatic stages of emotion regulation, on the other hand, MDD subjects appear to achieve successful emotion regulation by recruiting additional lateral prefrontal neural regions, that may be mediated by medial prefrontal, especially rostral/dorsal anterior cingulate gyrus (ACG) functioning. Dysfunctional automatic regulation may impair successful voluntary emotion regulation, and may present a target for novel therapeutic approaches in MDD. PMID- 23928090 TI - Ventral-striatal responsiveness during reward anticipation in ADHD and its relation to trait impulsivity in the healthy population: a meta-analytic review of the fMRI literature. AB - A review of the existing functional magnetic resonance imaging (fMRI) studies on reward anticipation in patients with attention-deficit/hyperactivity disorder (ADHD) is provided. Meta-analysis showed a significant medium effect size (Cohen's d=0.48-0.58) in terms of ventral-striatal (VS)-hyporesponsiveness in ADHD. Studies on VS-responsiveness and trait impulsivity in the healthy population demonstrate the opposite relationship, i.e. impulsivity-scores positively correlated with VS activation during reward processing. Against the background that ADHD may represent an extreme on a continuum of normal variability, the question arises as to how these contrasting findings can be integrated. We discuss three theoretical approaches, each of which integrates the opposing findings: (1) an inverted-u-shape model; (2) a (genetic) moderator model; and (3) the "unrelated model". We conclude that at the present stage the number of existing studies in the healthy population as well as in ADHD groups is too small for a final answer. Therefore, our presented integrative approaches should be understood as an attempt to frame future research directions by generating testable hypotheses and giving practical suggestions for future studies. PMID- 23928092 TI - Thousand-fold fluorescent signal amplification for mHealth diagnostics. AB - The low sensitivity of Mobile Health (mHealth) optical detectors, such as those found on mobile phones, is a limiting factor for many mHealth clinical applications. To improve sensitivity, we have combined two approaches for optical signal amplification: (1) a computational approach based on an image stacking algorithm to decrease the image noise and enhance weak signals, and (2) an optical signal amplifier utilizing a capillary tube array. These approaches were used in a detection system which includes multi-wavelength LEDs capable of exciting many fluorophores in multiple wavelengths, a mobile phone or a webcam as a detector, and capillary tube array configured with 36 capillary tubes for signal enhancement. The capillary array enables a ~100* increase in signal sensitivity for fluorescein, reducing the limit of detection (LOD) for mobile phones and webcams from 1000 nM to 10nM. Computational image stacking enables another ~10* increase in signal sensitivity, further reducing the LOD for webcam from 10nM to 1 nM. To demonstrate the feasibility of the device for the detection of disease-related biomarkers, adenovirus DNA labeled with SYBR green or fluorescein was analyzed by both our capillary array and a commercial plate reader. The LOD for the capillary array was 5 ug/mL, and that of the plate reader was 1 ug/mL. Similar results were obtained using DNA stained with fluorescein. The combination of the two signal amplification approaches enables a ~1000* increase in LOD for the webcam platform. This brings it into the range of a conventional plate reader while using a smaller sample volume (10 ul) than the plate reader requires (100 ul). This suggests that such a device could be suitable for biosensing applications where up to 10 fold smaller sample sizes are needed. The simple optical configuration for mHealth described in this paper employing the combined capillary and image processing signal amplification is capable of measuring weak fluorescent signals without the need of dedicated laboratories. It has the potential to be used to increase sensitivity of other optically based mHealth technologies, and may increase mHealth's clinical utility, especially for telemedicine and for resource-poor settings and global health applications. PMID- 23928091 TI - Tricuspid annular plane systolic excursion in the assessment of right ventricular function in children and adolescents after repair of tetralogy of Fallot. AB - BACKGROUND: Assessing right ventricular (RV) performance is essential for patients with tetralogy of Fallot (TOF). The aim of this study was to investigate the reliability and validity of tricuspid annular plane systolic excursion (TAPSE) against cardiac magnetic resonance imaging measures and cardiopulmonary exercise testing. METHODS: A retrospective study was performed in 125 outpatients with repaired TOF with available protocol-driven echocardiography, cardiac magnetic resonance imaging, and exercise stress testing obtained as part of a cross-sectional study. TAPSE was measured on the two-dimensional apical four chamber view on echocardiography by two readers. Multivariate linear regression was used to examine the association between TAPSE and measures of RV function and exercise capacity. RESULTS: The mean age was 12.6 +/- 3.3 years, 41 patients (33%) were female, and 104 (83%) were white. TAPSE averaged 1.6 +/- 0.37 cm, with an interreader intraclass correlation coefficient of 0.78 (n = 18). TAPSE was significantly associated with cardiac magnetic resonance-based RV stroke volume after adjustment for gender and body surface area (beta = 13.8; 95% confidence interval, 2.25-25.30; P = .02). TAPSE was not associated with cardiac magnetic resonance-based RV ejection fraction (P = .77). On exercise testing, TAPSE was not associated with peak oxygen consumption, percentage of predicted oxygen consumption, oxygen pulse, or the ventilatory equivalent for carbon dioxide in patients with maximal exercise stress testing (n = 73 [58%]). CONCLUSIONS: TAPSE is reproducibly measured by echocardiography in patients with TOF. It is not associated with RV ejection fraction or exercise performance, and its association with RV stroke volume may be confounded by body size. On the basis of these results, TAPSE is not representative of global RV performance in patients with TOF. PMID- 23928093 TI - Lanthanide-labeled immunochromatographic strips for the rapid detection of Pantoea stewartii subsp. stewartii. AB - The lateral flow immunoassay is used in commercial pregnancy detection, and is an accepted point-of-care testing technique. The most widely used format for lateral flow immunochromatographic strips uses gold nanoparticles for colorimetric detection. However, this method often suffers from poor quantitative discrimination and low analytical sensitivity. To address these limitations, lanthanide chelate-loaded silica nanoparticles have been used as fluorescent labels. The fluorescent nanoparticles can easily bind to antibodies, with dextran as a linker. The strip reader described here was based on a sandwich immunoreaction performed on a strip, using lanthanide-labeled antibodies that served as signal vehicles for the fluorescent readout. The strip reader was used as a quantitative test system. In this work, Pantoea stewartii subsp. stewartii (Pss) was used as a model analyte to demonstrate the use of the strip reader. Under optimal conditions, the detection limit was determined as 10(3)cfu/mL. The quantification limit was calculated to be 10(4)cfu/mL. The detection limit for Pss was 100 times lower than those displayed by colloidal gold-labeled strips or ELISAs. No cross-reactions were observed with the other nine strains, indicating the good specificity of the Pss strip. This strip showed good stability in repeated tests. The tests using the fluorescence immunochromatographic strip were easy to perform, rapid, and sensitive. Methods using fluorescence strips and a strip reader have the potential to be a powerful tool for the quantification of bacteria. PMID- 23928094 TI - Safety, tolerability, pharmacokinetics, and pharmacodynamics of anti-TWEAK monoclonal antibody in patients with rheumatoid arthritis. AB - BACKGROUND: Persistent upregulation of signaling by cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) through its receptor fibroblast growth factor-inducible molecule-14 (Fn14) promotes chronic inflammation and tissue destruction. OBJECTIVE: The aim of this study was to explore the safety and tolerability of the TWEAK-blocking monoclonal antibody BIIB023 and determine its pharmacokinetics and effects on TWEAK pathway pharmacodynamic markers in rheumatoid arthritis (RA). METHODS: Phase I, first-in-human, 2-part, multicenter, double-blind, dose-escalation study. Patients were randomized to a single dose of BIIB023 (0.03-20 mg/kg) (n = 38) or placebo (n = 15) as an add-on to methotrexate. Three open-label cohorts of RA patients taking background disease modifying antirheumatic drugs and stable tumor necrosis factor (TNF) inhibitor therapy (n = 12) received a single-dose of BIIB023 of 2, 10, or 20 mg/kg and were assessed over 70 days. RESULTS: The incidence of treatment-emergent adverse events for the BIIB023 monotherapy cohorts and open-label cohorts of BIIB023 as add-on therapy to TNF inhibitors compared with placebo were 47% and 50% versus 33%, respectively. Serum exposure to BIIB023 increased in a dose-dependent manner from 0.03 to 20 mg/kg, but not in direct proportion to dose level. After administration, the time course of BIIB023 serum concentration was multiphasic and showed expedited elimination when levels decreased to < 10 ug/mL. Serum soluble TWEAK levels were suppressed at all dose levels by 6 hours post-dose and recovered to baseline between days 7 and 28. A trend toward downward modulation of serum biomarkers of inflammatory response was suggested in monocyte chemoattractant protein 1, inducible protein 10, macrophage inflammatory protein 1beta, and tissue inhibitor of metalloproteinase 1 in the BIIB023 group versus placebo. CONCLUSIONS: Single-dose BIIB023 showed a favorable safety and tolerability profile in RA. Suppression of serum-soluble TWEAK for <= 28 days was observed and downward trends in serum biomarkers suggested. PMID- 23928095 TI - Structural basis of substrate selectivity of Delta(1)-pyrroline-5-carboxylate dehydrogenase (ALDH4A1): semialdehyde chain length. AB - The enzyme Delta(1)-pyrroline-5-carboxylate (P5C) dehydrogenase (aka P5CDH and ALDH4A1) is an aldehyde dehydrogenase that catalyzes the oxidation of gamma glutamate semialdehyde to l-glutamate. The crystal structures of mouse P5CDH complexed with glutarate, succinate, malonate, glyoxylate, and acetate are reported. The structures are used to build a structure-activity relationship that describes the semialdehyde carbon chain length and the position of the aldehyde group in relation to the cysteine nucleophile and oxyanion hole. Efficient 4- and 5-carbon substrates share the common feature of being long enough to span the distance between the anchor loop at the bottom of the active site and the oxyanion hole at the top of the active site. The inactive 2- and 3-carbon semialdehydes bind the anchor loop but are too short to reach the oxyanion hole. Inhibition of P5CDH by glyoxylate, malonate, succinate, glutarate, and l glutamate is also examined. The Ki values are 0.27 mM for glyoxylate, 58 mM for succinate, 30 mM for glutarate, and 12 mM for l-glutamate. Curiously, malonate is not an inhibitor. The trends in Ki likely reflect a trade-off between the penalty for desolvating the carboxylates of the free inhibitor and the number of compensating hydrogen bonds formed in the enzyme-inhibitor complex. PMID- 23928096 TI - [Large granular lymphocyte leukemia: clinical and pathogenic aspects]. AB - Large granular lymphocyte leukemia (LGL) is a hematologic disorder characterized by a monoclonal expansion of large lymphocytes containing azurophilic granules with a T CD3(+)CD57(+) or Natural Killer (NK) CD3(-)CD56(+) phenotype. The World Health Organization (WHO) classification identifies three entities: the T LGL, the chronic lymphoproliferative disorder of NK-cells, and the aggressive NK-cell leukemia. T LGL and chronic lymphoproliferative disorder of NK-cells are indolent diseases frequently associated with cytopenias and a wide spectrum of auto-immune manifestations. Neutropenia can lead to recurrent bacterial infections, which represent an indication of initiating a treatment in most of the cases. Immunosuppressive therapies are usually used in this context. In contrast, aggressive NK-cell leukemia follows a fulminant course with a poor prognosis because patients are refractory to most of the treatments. There is now a considerable interest in the pathophysiology of the disease with the perspective of new therapeutic options. PMID- 23928097 TI - Hydrogen/deuterium exchange mass spectrometry for probing higher order structure of protein therapeutics: methodology and applications. AB - The higher order structure of protein therapeutics can be interrogated with hydrogen/deuterium exchange mass spectrometry (HDX-MS). HDX-MS is now a widely used tool in the structural characterization of protein therapeutics. In this review, HDX-MS based workflows designed for protein therapeutic discovery and development processes are presented, focusing on the specific applications of epitope mapping for protein/drug interactions and biopharmaceutical comparability studies. Future trends in the application of HDX-MS in protein therapeutics characterization are also described. PMID- 23928098 TI - Killing them softly: managing pathogen polymorphism and virulence in spatially variable environments. AB - Understanding why pathogen populations are genetically variable is vital because genetic variation fuels evolution, which often hampers disease control efforts. Here I argue that classical models of evolution in spatially variable environments - specifically, models of hard and soft selection - provide a useful framework to understand the maintenance of pathogen polymorphism and the evolution of virulence. First, the similarities between models of hard and soft selection and pathogen life cycles are described, highlighting how the type and timing of pathogen control measures impose density regulation that may affect both the level of pathogen polymorphism and virulence. The article concludes with an outline of potential lines of future theoretical and experimental work. PMID- 23928099 TI - Feline lungworms: what a dilemma. AB - Aelurostrongylus abstrusus is regarded as the major lungworm infecting Felis catus, although other, albeit poorly studied, nematodes have been described from the respiratory system of domestic cats. Recent records of these neglected parasites have renewed the attention of the scientific community, but their actual role in respiratory disease in cats is blurred. The epidemiology, pathogenic role, and diagnosis of Troglostrongylus spp., Oslerus rostratus, and Capillaria aerophila in domestic cats are far from being clarified. Indeed, recent studies have provided novel information but have also given rise to relevant doubts. We discuss here the state of current knowledge regarding felid lungworms together with the dilemmas recently roused in the scientific literature. PMID- 23928101 TI - Effect of high-frequency repetitive transcranial magnetic stimulation on brain excitability in severely brain-injured patients in minimally conscious or vegetative state. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) induces prolonged functional changes in the cerebral cortex in normal conditions and in altered states of consciousness. Its therapeutic effects have been variously documented. OBJECTIVE: The aim of this study was to investigate the reactivity of electroencephalography (EEG) and the clinical response in six severely brain injured patients in an altered state of consciousness (minimally conscious state [MCS] or vegetative state [VS]). EEG rhythm and brain excitability were measured before and after a protocol of high-frequency rTMS. METHODS: All six patients underwent clinical and neurophysiological evaluation before rTMS and immediately thereafter. EEG data in resting state were acquired at the beginning of the exam (T0), after rTMS (T1), and 38 min after rTMS (T2). From these data the power values were computed using Fast Fourier Transform. RESULTS: rTMS over the motor cortex induced long-lasting behavioral and neurophysiological modifications in only one patient in MCS. No significant clinical or EEG modifications were detected in any of the other patients, except for changes in motor threshold and motor evoked potential amplitude over the stimulated motor areas. CONCLUSIONS: The main finding of the study is the correlation between EEG reactivity and clinical response after rTMS. Reappearance of fast activity and an increase in slow activity were noted in the one patient with transitory arousal, whereas no significant reliable changes were observed in the other patients showing no clinical reactivity. PMID- 23928100 TI - Targeting tumors with nonreplicating Toxoplasma gondii uracil auxotroph vaccines. AB - Toxoplasma gondii is an intracellular parasite that has evolved to actively control its invaded host cells. Toxoplasma triggers then actively regulates host innate interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) responses that elicit T cell control of infection. A live, nonreplicating avirulent uracil auxotroph vaccine strain (cps) of Toxoplasma triggers novel innate immune responses that stimulate amplified CD8(+) T cell responses and life-long immunity in vaccinated mice. Here, we review recent reports showing that intratumoral treatment with cps activated immune-mediated regression of established solid tumors in mice. We speculate that a better understanding of host-parasite interaction at the molecular level and applying improved genetic models based on Deltaku80 Toxoplasma strains will stimulate development of highly effective immunotherapeutic cancer vaccine strategies using engineered uracil auxotrophs. PMID- 23928102 TI - State-dependent effects of prefrontal repetitive transcranial magnetic stimulation on emotional working memory. AB - BACKGROUND: A growing body of findings illustrates the importance of state dependency in studies using brain stimulation. OBJECTIVE: We aimed to investigate the effects of tDCS priming followed by rTMS applied over the right dorsolateral prefrontal cortex (DLPFC) on emotional working memory. METHODS: In a randomized single-blind within-subjects design, participants performed an emotional 3-back task at baseline and after tDCS priming (anodal, cathodal) and subsequent low frequency rTMS (active, sham) of the right DLPFC. Stimuli consisted of words related to the distinct emotion categories fear and anger as well as neutral words. RESULTS: Task accuracy increased for fear-related words and decreased for neutral words across stimulation conditions. No general state-dependent effects of prefrontal rTMS on working memory were found. We further showed a detrimental effect of negative emotional content on working memory performance. CONCLUSIONS: Our findings support a hemispheric lateralization of emotion processing by demonstrating that the withdrawal-related emotion fear is associated with the right DLPFC and contribute to clarifying the interaction between working memory and emotion. PMID- 23928103 TI - Theta burst stimulation modulates cerebellar-cortical connectivity in patients with progressive supranuclear palsy. AB - BACKGROUND: Progressive Supranuclear Palsy (PSP) is an atypical degenerative Parkinsonism characterized by postural instability, supranuclear gaze palsy and frontal deficits. Recent imaging studies revealed that the volume of cerebellar peduncles and midbrain were reduced in PSP. Transcranial magnetic stimulation (TMS) studies demonstrated a cerebellar involvement in PSP showing an impairment of functional connectivity between the cerebellar hemisphere (Cb) and the contralateral primary motor cortex (M1) (cerebellar brain inhibition-CBI). OBJECTIVE: To investigate the plasticity of the cerebello-thalamo-cortical circuits in ten PSP patients after two-week course of cerebellar intermittent theta burst stimulation (iTBS), a form of repetitive TMS. METHODS: Before and after the iTBS sessions we measured functional connectivity between Cb and contralateral M1 (CBI), short intracortical inhibition (SICI) and intracortical facilitation (ICF) and short latency afferent inhibition (SLAI) in contralateral M1. We also performed resting state functional magnetic resonance (rs-fMRI) and we administered clinical rating scale (PSP-RS). RESULTS: At baseline PSP patients had decreased efficiency of CBI, SICI and SLAI in comparison to PD patients and healthy subjects. Cerebellar iTBS increased the deficient functional cerebellar motor connectivity as assessed by CBI. No effect was seen for SICI/ICF and SLAI circuits. Following iTBS there was an increased signal in the head of the caudate nucleus bilaterally as shown by rs-fMRI. Moreover, PSP-RS showed an improvement of dysarthria in all patients. CONCLUSIONS: iTBS enhanced functional connectivity between the cerebellar hemisphere, the caudate nucleus and the cortex, that was paralleled by some clinical improvement. Future randomized, sham-stimulation controlled studies are warranted to support the clinical efficacy of this technique. PMID- 23928104 TI - Antidepressant efficacy of high and low frequency rTMS at 110% of motor threshold versus sham stimulation over left prefrontal cortex. AB - BACKGROUND: While the efficacy of repetitive transcranial magnetic stimulation (rTMS) at 10 Hz over the left prefrontal cortex has been repeatedly demonstrated, it is not clear that the optimal parameters for the treatment of depression have been adequately elucidated. OBJECTIVES: We sought to assess the antidepressant effectiveness of high and low frequency at a higher intensity rTMS compared to sham in patients with moderately treatment resistant depression. METHOD: The authors conducted a three-week, double-blind, randomized, sham-controlled study of 24 acutely depressed patients given either active 20 Hz (n = 8) or 1 Hz (n = 8) rTMS (at 110% of motor threshold [MT]) or sham treatments (n = 8) over the left prefrontal cortex. Hamilton Depression ratings were analyzed by ANOVA. RESULTS: Patients on both frequencies showed greater improvement than on sham, which was associated with minor increases in depression. During open continuation to allow 7 weeks of active treatment in all individuals, additional improvement was observed. CONCLUSIONS: The results seen here using 110% of MT for 3 weeks were more robust than those of previous studies of 1-Hz or 20-Hz rTMS for 2 weeks (at 80% and 100% of MT). The results also raise the possibility that both high and low frequency rTMS over left prefrontal cortex (and not just low frequency over the right prefrontal cortex) exert antidepressant effects, but further work is required to assess what parameters may be most effective in general and for a given individual. PMID- 23928105 TI - Methionine restriction prevents the progression of hepatic steatosis in leptin deficient obese mice. AB - OBJECTIVE: This study investigated the effects of dietary methionine restriction (MR) on the progression of established hepatic steatosis in the leptin-deficient ob/ob mouse. MATERIAL/METHODS: Ten-week-old ob/ob mice were fed diets containing 0.86% (control-fed; CF) or 0.12% methionine (MR) for 14 weeks. At 14 weeks, liver and fat were excised and blood was collected for analysis. In another study, blood was collected to determine in vivo triglyceride (TG) and very-low-density lipoprotein (VLDL) secretion rates. Liver histology was conducted to determine the severity of steatosis. Hepatic TG, free fatty acid levels, and fatty acid oxidation (FAO) were also measured. Gene expression was analyzed by quantitative PCR. RESULTS: MR reversed the severity of steatosis in the ob/ob mouse. This was accompanied by reduced body weight despite similar weight-specific food intake. Compared with the CF group, hepatic TG levels were significantly reduced in response to MR, but adipose tissue weight was not decreased. MR reduced insulin and HOMA ratios but increased total and high-molecular-weight adiponectin levels. Scd1 gene expression was significantly downregulated, while Acadvl, Hadha, and Hadhb were upregulated in MR, corresponding with increased beta-hydroxybutyrate levels and a trend toward increased FAO. The VLDL secretion rate was also significantly increased in the MR mice, as were the mRNA levels of ApoB and Mttp. The expression of inflammatory markers, such as Tnf-alpha and Ccr2, was also downregulated by MR. CONCLUSIONS: Our data indicate that MR reverses steatosis in the ob/ob mouse liver by promoting FAO, increasing the export of lipids, and reducing obesity-related inflammatory responses. PMID- 23928107 TI - Biosynthesis and microscopic study of metallic nanoparticles. AB - Nanobiotechnology, bionanotechnology, and nanobiology are terms that have emerged in reference to the combination of nanotechnology and biology. Through the convergence of these disciplines, the production of metallic nanoparticles (NPs) using biological material as reducing agents is rapidly progressing. In the near future, the application of clean, non-toxic, and eco-friendly nanostructured material will be possible in industry and/or biomedicine. Currently, there is a wide range of organisms that have been reported to be useful in producing NPs. However, the development of finer protocols and the applicability of biosynthesized nanostructures are presently under study. Silver and gold are among the most studied metals due to their potential use in medical treatment. In fact, silver NPs have been evaluated as antimicrobial agents, having been successfully used against several types of fungi and bacteria. However, the use of such material in our daily life must be carefully evaluated. This article summarizes some of the most significant results using organisms to produce metallic NPs as well as the microscopic analyses used to characterize the nanostructured material obtained, providing a valuable database for future research. PMID- 23928106 TI - Alteration of cardiac glucose metabolism in association to low birth weight: experimental evidence in lambs with left ventricular hypertrophy. AB - OBJECTIVE: Intrauterine growth restriction that results in low birth weight (LBW) has been linked to the onset of pathological cardiac hypertrophy. An altered transition from a fetal to an adult energy metabolism phenotype, with increased reliance on glucose rather than fatty acids for energy production, could help explain this connection. We have therefore investigated cardiac metabolism in relation to left ventricular hypertrophy in LBW lambs, at 21days after birth. MATERIALS/METHODS: The expression of regulatory molecules involved in cardiac glucose and fatty acid metabolism was measured using real-time PCR and Western blotting. A section of the left ventricle was fixed for Periodic Acid Schiff staining to determine tissue glycogen content. RESULTS: There was increased abundance of insulin signalling pathway proteins (phospho-insulin receptor, insulin receptor and phospho-Akt) and the glucose transporter (GLUT)-1, but no change in GLUT-4 or glycogen content in the heart of LBW compared to ABW lambs. There was, however, increased abundance of cardiac pyruvate dehydrogenase kinase 4 (PDK-4) in LBW compared to ABW lambs. There were no significant changes in the mRNA expression of components of the peroxisome proliferator activated receptor regulatory complex or proteins involved in fatty acid metabolism. CONCLUSION: We concluded that LBW induced left ventricular hypertrophy was associated with increased GLUT-1 and PDK-4, suggesting increased glucose uptake, but decreased efficacy for the conversion of glucose to ATP. A reduced capacity for energy conversion could have significant implications for vulnerability to cardiovascular disease in adults who are born LBW. PMID- 23928108 TI - Cat eye syndrome and growth hormone deficiency with pituitary anomalies: a case report and review of the literature. AB - Cat eye syndrome is a rare congenital disease characterized by the existence of a supernumerary chromosome derived from chromosome 22, with a variable phenotype comprising anal atresia, coloboma of the iris and preauricular tags or pits. We report a girl with cat eye syndrome, presenting short stature, with growth hormone deficiency due to posterior pituitary ectopia. Short stature is a common feature of this syndrome, and the association with a structural pituitary anomaly has been described, however growth hormone deficiency and the underlying mechanisms are rarely reported. A review on short stature and growth hormone deficiency in cat eye syndrome is conducted. PMID- 23928109 TI - Cancer markers: integratively annotated classification. AB - Translational cancer genomics research aims to ensure that experimental knowledge is subject to computational analysis, and integrated with a variety of records from omics and clinical sources. The data retrieval from such sources is not trivial, due to their redundancy and heterogeneity, and the presence of false evidence. In silico marker identification, therefore, remains a complex task that is mainly motivated by the impact that target identification from the elucidation of gene co-expression dynamics and regulation mechanisms, combined with the discovery of genotype-phenotype associations, may have for clinical validation. Based on the reuse of publicly available gene expression data, our aim is to propose cancer marker classification by integrating the prediction power of multiple annotation sources. In particular, with reference to the functional annotation for colorectal markers, we indicate a classification of markers into diagnostic and prognostic classes combined with susceptibility and risk factors. PMID- 23928110 TI - Allele frequencies of 19 autosomal STR loci in Manchu population of China with phylogenetic structure among worldwide populations. AB - The aim of this study was to estimate the allelic frequencies of the 19 STR loci with the GoldeneyeTM DNA ID system 20A kit in a sample of 150 Manchu individuals from China to be used for forensic purposes and population studies. The observed heterozygosity(HO)values of these 19 STR loci ranged from 0.600 (D3S1358) to 0.914 (D18S51), the expected (HE) ranged from 0.615 (TPOX) to 0.876 (D16S1043). The power of discrimination (PD) values were found to range from 0.793 (TPOX) to 0.950 (D16S1043) and the probability of exclusion (PE) varies between 0.291 (D3S1358) and 0.825 (D18S51 and Penta E). Among all the 19 loci, D16S1043 had the highest polymorphism (PIC=0.860), whereas TPOX had the lowest (PIC=0.550). For the 19 loci, the combined power of discrimination and the combined probability of exclusion are 0.9999999999999999999942 and 0.999999996777, respectively. The phylogenetic tree established among worldwide population shows different populations who say the same language usually have a close genetic relationship with each other across the three language families studied (Sino-Tibetan, Altaic and Arabic). PMID- 23928111 TI - Predicting metabolic rate across walking speed: one fit for all body sizes? AB - We formulated a "one-size-fits-all" model that predicts the energy requirements of level human walking from height, weight, and walking speed. Our three component model theorizes that the energy expended per kilogram per stride is independent of stature at mechanically equivalent walking speeds. We measured steady-state rates of oxygen uptake of 78 subjects who spanned a nearly twofold range of statures (1.07-2.11 m) and sevenfold range of body masses (16-112 kg) at treadmill speeds from 0.4 to 1.9 m/s. We tested the size independence of the model by deriving best-fit equations in the form of the model on four stature groups (n >= 15): short, moderately short, moderately tall, and tall. The mean walking metabolic rates predicted by these four independently derived equations for the same set of reference subjects (n = 16; stature range: 1.30-1.90 m) agreed with one another to within an average of 5.2 +/- 3.7% at the four intermediate speeds in our protocol. We next evaluated the model's gross predictive accuracy by dividing our 78 subjects into 39 stature-matched pairs of experimental and validation group subjects. The model best-fit equation derived on the experimental group subjects predicted the walking metabolic rates of the validation group subjects to within an average of 8.1 +/- 6.7% (R(2) = 0.90; standard error of estimate = 1.34 ml O2.kg(-1).min(-1)). The predictive error of the American College of Sports Medicine equation (18.0 +/- 13.1%), which does not include stature as a predictor, was more than twice as large for the same subject group. We conclude that the energy cost of level human walking can be accurately predicted from height, weight, and walking speed. PMID- 23928112 TI - Heat stroke activates a stress-induced cytokine response in skeletal muscle. AB - Heat stroke (HS) induces a rapid elevation in a number of circulating cytokines. This is often attributed to the stimulatory effects of endotoxin, released from damaged intestine, on immune cells. However, parenchymal cells also produce cytokines, and skeletal muscle, comprising a large proportion of body mass, is thought to participate. We tested the hypothesis that skeletal muscle exhibits a cytokine response to HS that parallels the systemic response in conscious mice heated to a core temperature of 42.4 degrees C (TcMax). Diaphragm and hindlimb muscles showed a rapid rise in interleukin-6 (IL-6) and interleuin-10 (IL-10) mRNA and transient inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) throughout early recovery, a pattern that parallels changes in circulating cytokines. IL-6 protein was transiently elevated in both muscles at ~32 min after reaching TcMax. Other responses observed included an upregulation of toll-like receptor-4 (TLR-4) and heat shock protein-72 (HSP-72) mRNA but no change in TLR-2 or HSP25 mRNA. Furthermore, c-jun and c-fos mRNA increased. Together, c-jun/c-fos form the activator protein-1 (AP-1) transcription factor, critical for stress-induced regulation of IL-6. Interestingly, a second "late-phase" (24 h) cytokine response, with increases in IL-6, IL-10, IL-1beta, and TNF-alpha protein, were observed in hindlimb but not diaphragm muscle. These results demonstrate that skeletal muscle responds to HS with a distinct "stress-induced immune response," characterized by an early upregulation of IL-6, IL-10, and TLR-4 and suppression of IL-1beta and TNF-alpha mRNA, a pattern discrete from classic innate immune cytokine responses. PMID- 23928113 TI - Estimation of individual-specific progression to impending cardiovascular instability using arterial waveforms. AB - Trauma patients with "compensated" internal hemorrhage may not be identified with standard medical monitors until signs of shock appear, at which point it may be difficult or too late to pursue life-saving interventions. We tested the hypothesis that a novel machine-learning model called the compensatory reserve index (CRI) could differentiate tolerance to acute volume loss of individuals well in advance of changes in stroke volume (SV) or standard vital signs. Two hundred one healthy humans underwent progressive lower body negative pressure (LBNP) until the onset of hemodynamic instability (decompensation). Continuously measured photoplethysmogram signals were used to estimate SV and develop a model for estimating CRI. Validation of the CRI was tested on 101 subjects who were classified into two groups: low tolerance (LT; n = 33) and high tolerance (HT; n = 68) to LBNP (mean LBNP time: LT = 16.23 min vs. HT = 25.86 min). On an arbitrary scale of 1 to 0, the LT group CRI reached 0.6 at an average time of 5.27 +/- 1.18 (95% confidence interval) min followed by 0.3 at 11.39 +/- 1.14 min. In comparison, the HT group reached CRI of 0.6 at 7.62 +/- 0.94 min followed by 0.3 at 15.35 +/- 1.03 min. Changes in heart rate, blood pressure, and SV did not differentiate HT from LT groups. Machine modeling of the photoplethysmogram response to reduced central blood volume can accurately trend individual-specific progression to hemodynamic decompensation. These findings foretell early identification of blood loss, anticipating hemodynamic instability, and timely application of life-saving interventions. PMID- 23928115 TI - Residual force depression following muscle shortening is exaggerated by prior eccentric drop jump exercise. AB - We studied the relation between two common force modifications in skeletal muscle: the prolonged force depression induced by unaccustomed eccentric contractions, and the residual force depression (rFD) observed immediately after active shortening. We hypothesized that rFD originates from distortion within the sarcomeres and the extent of rFD: 1) correlates to the force and work performed during the shortening steps, which depend on sarcomeric integrity; and 2) is increased by sarcomeric disorganization induced by eccentric contractions. Nine healthy untrained men (mean age 26 yr) participated in the study. rFD was studied in electrically stimulated knee extensor muscles. rFD was defined as the reduction in isometric torque after active shortening compared with the torque in a purely isometric contraction. Eccentric contractions were performed as 50 repeated drop jumps with active deceleration to 90 degrees knee angle, immediately followed by a maximal upward jump. rFD was assessed before and 5 min to 72 h after drop jumps. The series of drop jumps caused a prolonged force depression, which was about two times larger at 20-Hz than at 50-Hz stimulation. There was a significant correlation between increasing rFD and increasing mechanical work performed during active shortening both before and after drop jumps. In addition, a given rFD was obtained at a markedly lower mechanical work after drop jumps. In conclusion, the extent of rFD correlates to the mechanical work performed during active shortening. A series of eccentric contractions causes a prolonged reduction of isometric force. In addition, eccentric contractions exaggerate rFD, which further decreases muscle performance during dynamic contractions. PMID- 23928114 TI - Fetuin-A is linked to improved glucose tolerance after short-term exercise training in nonalcoholic fatty liver disease. AB - Fetuin-A is synthesized in the liver and may be associated with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. Lifestyle-induced weight loss reduces fetuin-A, but the effect of exercise alone is unknown. We determined the effect of short-term exercise training on plasma fetuin-A in 13 (50.5 +/- 3.4 yr) obese adults (body mass index, 33.3 +/- 0.9 kg/m(2)) with clinically diagnosed NAFLD. Subjects participated in 7 days of supervised exercise training (60 min/day at ~85% maximum heart rate) and were instructed to maintain their normal caloric and macronutrient intake. Insulin resistance was assessed by an oral glucose tolerance test. Hepatic triglyceride content (HTGC) was determined by proton MRI. We used C2C12 skeletal muscle cells to examine the direct effect of fetuin-A on 2-deoxyglucose uptake, insulin signaling [phosphorylation of Akt and AS160 (pAkt and pAS160, respectively)], and glucose transporter-4 (GLUT-4) translocation. Insulin resistance was reduced by 29% (P < 0.05), and glucose area under the curve (AUC) was decreased by 13% (P < 0.01) after the 7 days of exercise. Furthermore, circulating fetuin-A was decreased by 11% (4.2 +/- 03 vs. 3.6 +/- 0.2 nM; P < 0.02), and this change correlated with reduced insulin resistance (r = 0.62; P < 0.04) and glucose AUC (r = 0.58; P < 0.04). Importantly, the exercise program did not change body weight (P = 0.12), HTGC (P = 0.73), or aerobic capacity (P = 0.14). In vitro experiments revealed that fetuin-A decreased skeletal muscle glucose uptake by downregulating pAkt and pAS160 and subsequent GLUT-4 translocation to the plasma membrane. Together, our findings highlight a role for fetuin-A in skeletal muscle insulin resistance and suggest that part of the exercise-induced improvement in glucose tolerance in patients with NAFLD may be due to lowering fetuin-A. PMID- 23928116 TI - Routine application of a novel MLPA-based first-line screening test uncovers clinically relevant copy number aberrations in haematological malignancies undetectable by conventional cytogenetics. AB - OBJECTIVE: The presence of numerical and/or structural chromosomal abnormalities is a frequent finding in clonal hematopoietic malignant disease, typically diagnosed through routine karyotyping and/or fluorescent in situ hybridization (FISH) analysis. Recently, the application of array comparative genomic hybridization (aCGH) has uncovered many new cryptic genomic copy number imbalances, most of which are now recognized as clinically useful markers of haematological malignancies. In view of the limitations of both FISH and aCGH techniques, in terms of their routine application as a first line screening test, we designed a new multiple ligation-dependent probe amplification (MLPA) probemix for use in addition to classic karyotype analysis. METHODS: A novel MLPA probemix was developed to interrogate copy number changes involving chromosomal regions: 2p23-24 (MYCN, ALK), 5q32-34 (MIR145A, EBF1, MIR146A), 6q21-27, 7p12.2 (IKZF1), 7q21-36, 8q24.21 (MYC), 9p24 (JAK2 V617F point mutation), 9p21.3 (CDKN2A/2B), 9p13.2 (PAX5), 10q23 (PTEN), 11q22.3 (ATM), 12p13.2 (ETV6), 13q14 (RB1, MIR15A, DLEU2, DLEU1), 17p13.1 (TP53), and 21q22.1 (RUNX1/AML1) and was applied to DNA extracted from 313 consecutive bone marrow patient samples, referred for routine karyotype analysis. RESULTS: More than half of the samples originated from newly investigated patients. We discovered clinically relevant genomic aberrations, involving a total of 24 patients (8%) all with a normal karyotype, which would have remained undiagnosed. DISCUSSION: Our data clearly indicate that routine application of this MLPA screening panel, as an adjunct to karyotype analysis, provides a sensitive, robust, rapid and low-cost approach for uncovering clinically important genomic abnormalities, which would have otherwise remained undetected. PMID- 23928117 TI - Dichlorvos exposure to the Kolliker-fuse nuclei is sufficient but not necessary for OP induced apnea. AB - Patients exposed to organophosphate (OP) compounds demonstrate a central apnea. The Kolliker-fuse nuclei (KF) are cholinergic nuclei in the brainstem involved in central respiratory control. We hypothesize that exposure of the KF is both necessary and sufficient for OP induced central apnea. We performed an animal study of acute OP exposure. Anesthetized and spontaneously breathing Wistar rats (n=24) were exposed to a lethal dose of dichlorvos using three experimental models. Experiment 1 (n=8) involved systemic OP poisoning using subcutaneous (SQ) 2,2-dichlorovinyl dimethyl phosphate (dichlorvos) at 100mg/kg or 3* LD50. Experiment 2 (n=8) involved isolated poisoning of the KF using stereotactic microinjections of dichlorvos (625MUg in 50MUl) into the KF. Experiment 3 (n=8) involved systemic OP poisoning with isolated protection of the KF using SQ dichlorvos (100mg/kg) and stereotactic microinjections of organophosphatase A (OpdA), an enzyme that degrades dichlorvos. Respiratory and cardiovascular parameters were recorded continuously. Animals were followed post exposure for 1h or until death. There was no difference in respiratory depression between animals with SQ dichlorvos and those with dichlorvos microinjected into the KF. Despite differences in amount of dichlorvos (100mg/kg vs. 1.8mg/kg) and method of exposure (SQ vs. CNS microinjection), 10min following dichlorvos both groups (SQ vs. microinjection respectively) demonstrated a similar percent decrease in respiratory rate (51.5 vs. 72.2), minute ventilation (49.2 vs. 68.8) and volume of expired gas (17.5 vs. 0.0). Animals with OpdA exposure to the KF during systemic OP exposure demonstrated less respiratory depression, compared to SQ dichlorvos alone (p<0.04). No animals with SQ dichlorvos survived past 25min post exposure, compared to 50% of animals with OpdA exposure to the KF. In conclusion, exposure of the KF is sufficient but not necessary for OP induced apnea. Protection of the KF during systemic OP exposure mitigates OP induced apnea. PMID- 23928118 TI - White matter integrity and executive abilities following treatment with tetrahydrobiopterin (BH4) in individuals with phenylketonuria. AB - Tetrahydrobiopterin (BH(4)) lowers blood phenylalanine (Phe) in individuals with PKU who are responders, but its effects on the brain and cognition have not been explored thoroughly. We examined blood Phe, microstructural white matter integrity, and executive abilities in 12 BH(4) responders before (i.e., baseline) and after (i.e., follow-up) six months of treatment with BH(4). Compared with baseline, Phe in these responders decreased by 51% during a 4 week screening period after initiation of treatment and remained lowered by 37% over the 6 month follow-up period. Significant improvements in white matter integrity, evaluated by mean diffusivity from diffusion tensor imaging, were also found following six months of treatment. Improvements in executive abilities were not identified, although six months may have been a period too brief for changes in cognition to follow changes in the brain. To our knowledge, our study is the first to explore relationships among Phe, white matter integrity, executive abilities, and BH(4) treatment within a single study. PMID- 23928119 TI - Culture-independent identification of bacteria associated with ovine 'broken mouth' periodontitis. AB - 'Broken mouth' periodontitis (BMP) is a painful condition of sheep grazed on rough pasture and involves periodontal infection of the incisor teeth and progressive tooth loss. This can reduce the efficiency of grazing of sheep, which contributes to malnutrition, weight loss, systemic health problems, poor quality of life and early culling from flocks. Consequently, this condition is a major economic problem to sheep farmers. However, there are no treatment or control methods available. The aim of this study was to identify the bacteria associated with BMP and oral health in sheep. Swabs were collected from the gingival pockets of three sheep with BMP and from the gingival margin of three orally healthy (normal) sheep. Bacteria were identified using culture-independent (16S rRNA gene sequencing) methods. In the normal samples, 26 phylotypes were identified. The most prevalent species were Enterobacter hormaechei (21.3% of analysed clones) and Hafnia alvei (21.3%), with uncultured (4.4%) and novel (5.0%) phylotypes also being identified. For the BMP samples, 24 phylotypes were identified. The most prevalent species were Mannheimia ruminalis (28.4%) and Moraxella caprae (13.5%), with uncultured (2.6%) and novel (24.5%) phylotypes also being identified. In conclusion, a distinct microflora is associated with BMP and oral health in sheep and M. ruminalis may be involved in the aetiology of BMP. PMID- 23928120 TI - Generation of a Tn5 transposon library in Haemophilus parasuis and analysis by transposon-directed insertion-site sequencing (TraDIS). AB - Haemophilus parasuis is an important respiratory tract pathogen of swine and the etiological agent of Glasser's disease. The molecular pathogenesis of H. parasuis is not well studied, mainly due to the lack of efficient tools for genetic manipulation of this bacterium. In this study we describe a Tn5-based random mutagenesis method for use in H. parasuis. A novel chloramphenicol-resistant Tn5 transposome was electroporated into the virulent H. parasuis serovar 5 strain 29755. High transposition efficiency of Tn5, up to 10(4) transformants/MUg of transposon DNA, was obtained by modification of the Tn5 DNA in the H. parasuis strain HS071 and establishment of optimal electrotransformation conditions, and a library of approximately 10,500 mutants was constructed. Analysis of the library using transposon-directed insertion-site sequencing (TraDIS) revealed that the insertion of Tn5 was evenly distributed throughout the genome. 10,001 individual mutants were identified, with 1561 genes being disrupted (69.4% of the genome). This newly-developed, efficient mutagenesis approach will be a powerful tool for genetic manipulation of H. parasuis in order to study its physiology and pathogenesis. PMID- 23928121 TI - Detection of the Schmallenberg virus in nulliparous Culicoides obsoletus/scoticus complex and C. punctatus--the possibility of transovarial virus transmission in the midge population and of a new vector. AB - The arthropod-borne Schmallenberg virus (SBV) emerged in Europe in the late summer/autumn of 2011. SBV spread across the continent until 2012. This paper presents SBV detection in female Culicoides spp. caught in UV traps located in 23 different locations in Poland. The midges were divided into pools containing 20.5 individual insects on average according to species and parity status. The study was based on duplex real-time reverse transcription PCR (RT-PCR) for the detection of the SBV S segment and culicoid 18S gene fragments. Forty-four out of 402 midge pools tested (10.9%) were found to be positive for the presence of viral RNA. The SBV positive Culicoides came from 10 traps spread randomly across the country and were collected between August and October 2012. The timing of the SBV positive midge collections and the locations of the traps corresponded to the epizootic situation of SBV in ruminants. SBV RNA was most frequently identified in gravid midges (36.4%), while in nulliparous, blood-fed and parous midges the percentages were 10.8% 13.0% and 8.1%, respectively. The majority (82%) of SBV positive pools belonged to Culicoides obsoletus/scoticus complex; however, viral RNA was also found in 8 out of the 149 (5.4%) Culicoides punctatus pools tested. While no statistical differences in the Ct values between different parity groups were found, the bimodal distribution observed at the Ct frequency plots suggested active SBV replication, especially in parous and gravid midge females, and sub transmissible infection in nulliparous and blood-fed insects. The most important findings included identification of C. punctatus as a new possible vector of SBV and the recovery of viral RNA from the nulliparous females which may suggest transovarial transmission in C. obsoletus/scoticus complex and C. punctatus. PMID- 23928122 TI - Why isn't evidence based practice improving health care for minorities in the United States? AB - Achieving health equity by improving the health care of all racial/ethnic groups is one of the key goals of Healthy People 2020. The implementation of evidence based practice (EBP) has been a major recommendation to achieve health equity in hopes of eliminating the subjectivity of clinical decision making. However, health disparities among racial/ethnic minorities are persistent in spite of the adoption of standardized care based on evidence. The EBP with racial and ethnic minorities is often seen as a possible cause of health and health care disparities. Three potential issues of using EBP to reduce health disparities have been identified: (1) a lack of data for EBP with ethnic/racial minority populations; (2) limited research on the generalizability of the evidence based on a European-American middle-class; and (3) sociocultural considerations in the context of EBP. Using EBP to reduce disparities in health care and health outcomes requires that nurse professionals should know how to use relevant evidence in a particular situation as well as to generate knowledge and theory which is relevant to racial/ethnic minorities. In addition, EBP implementation should be contextualized within the sociocultural environments in which patients are treated rather than solely focusing on the health problems. PMID- 23928123 TI - District nurses' self-reported clinical activities, beliefs about and attitudes towards obesity management. AB - AIM: To describe district nurses' self-reported clinical activities, beliefs about and attitudes towards obesity management; and to examine associations between the variables. BACKGROUND: Obesity is increasing worldwide and primary care could play a central role in the management. METHODS: Questionnaire data were collected from 247 nurses in 33 centres. RESULTS: The most common activities performed weekly were; advice about physical activity (40.1%) and general lifestyle advice (34.8%). However, nearly one third seldom/never performed these activities. Approximately half seldom/never performed BMI assessment and even fewer waist circumference (78.1%). Values for the factors Importance of obesity and Personal effectiveness were skewed towards a positive view and Negative view close to neutral. Multivariate analysis revealed that nurses with specialized tasks, longer working experience and higher perceived personal effectiveness performed more clinical activities. CONCLUSION: Managers need to make efforts to engage all personnel in obesity management; and strategies to increase self efficacy are called for. PMID- 23928124 TI - Microwave-assisted chemical oxidation of biological waste sludge: simultaneous micropollutant degradation and sludge solubilization. AB - Microwave-assisted hydrogen peroxide (MW/H2O2) treatment and microwave-assisted persulfate (MW/S2O8(2-)) treatment of biological waste sludge were compared in terms of simultaneous antibiotic degradation and sludge solubilization. A 2(3) full factorial design was utilized to evaluate the influences of temperature, oxidant dose, and holding time on the efficiency of these processes. Although both MW/H2O2 and MW/S2O8(2-) yielded >=97% antibiotic degradation with 1.2g H2O2 and 0.87 g S2O8(2-) per gram total solids, respectively, at 160 degrees C in 15 min, MW/S2O8(2-) was found to be more promising for efficient sludge treatment at a lower temperature and a lower oxidant dosage, as it allows more effective activation of persulfate to produce the SO4(-) radical. Relative to MW/H2O2, MW/S2O8(2-) gives 48% more overall metal solubilization, twofold higher improvement in dewaterability, and the oxidation of solubilized ammonia to nitrate in a shorter treatment period. PMID- 23928125 TI - Mean platelet volume and acute coronary syndrome. PMID- 23928126 TI - Free-standing lipid films stabilized by Annexin-A5. AB - Free-standing lipid bilayers in nano- and micro-pores are interesting membrane models and attractive for biotechnological applications. We describe here the controlled preparation of proteo-lipid mono- and bilayers using the Langmuir Schaefer transfer or Langmuir-Blodgett technique, respectively on hydrophobic and hydrophilic surfaces. We demonstrate the formation of suspended proteo-lipid layers by Transmission Electron Microscopy (TEM) and in situ Atomic Force Microscopy (AFM) imaging. Using Annexin-A5 as a membrane-associated protein, continuous proteo-lipid mono- and bilayers were formed, which span pore arrays over areas of several square-micrometers. The 2D organization of proteins associated to lipid monolayer is well preserved during the transfer process and the protein association is Ca(2+)-dependent and therefore reversible. The simple formation and reliable transfer of stabilized free-standing lipid films is a first crucial step to create biomimetic membranes for biotechnological applications and membrane protein research. PMID- 23928127 TI - The important role of epidermal triacylglycerol metabolism for maintenance of the skin permeability barrier function. AB - Survival in a terrestrial, dry environment necessitates a permeability barrier for regulated permeation of water and electrolytes in the cornified layer of the skin (the stratum corneum) to minimize desiccation of the body. This barrier is formed during cornification and involves a cross-linking of corneocyte proteins as well as an extensive remodeling of lipids. The cleavage of precursor lipids from lamellar bodies by various hydrolytic enzymes generates ceramides, cholesterol, and non-esterified fatty acids for the extracellular lipid lamellae in the stratum corneum. However, the important role of epidermal triacylglycerol (TAG) metabolism during formation of a functional permeability barrier in the skin was only recently discovered. Humans with mutations in the ABHD5/CGI-58 (alpha/beta hydrolase domain containing protein 5, also known as comparative gene identification-58, CGI-58) gene suffer from a defect in TAG catabolism that causes neutral lipid storage disease with ichthyosis. In addition, mice with deficiencies in genes involved in TAG catabolism (Abhd5/Cgi-58 knock-out mice) or TAG synthesis (acyl-CoA:diacylglycerol acyltransferase-2, Dgat2 knock-out mice) also develop severe skin permeability barrier dysfunctions and die soon after birth due to increased dehydration. As a result of these defects in epidermal TAG metabolism, humans and mice lack omega-(O)-acylceramides, which leads to malformation of the cornified lipid envelope of the skin. In healthy skin, this epidermal structure provides an interface for the linkage of lamellar membranes with corneocyte proteins to maintain permeability barrier homeostasis. This review focuses on recent advances in the understanding of biochemical mechanisms involved in epidermal neutral lipid metabolism and the generation of a functional skin permeability barrier. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias. PMID- 23928128 TI - Quantitative evaluation of plasma after methylene blue and white light treatment in four Chinese blood centers. AB - BACKGROUND: Pathogen reduction technology is an important process in the blood safety system, including solvent/detergent treatment, filtration and methylene blue-photochemical technology (MB-PCT). To investigate the quality of MB-PCT treated plasma, plasma samples from four Chinese blood centers were analyzed over 12 months of storage to determine the recovery of activities and levels of various plasma proteins. MATERIALS AND METHODS: Ten plasma units each from the Suzhou, Yancheng, Chongqing and Shandong blood centers were divided into two aliquots. One was subjected to treatment with one of two methylene blue photochemical technology instruments and the other was used as control. The treated and untreated sample pairs were stored at -30 degrees C. The recovery rates of coagulation factors, inhibitor proteins, total protein, immunoglobulins, and complement proteins were measured at different time points after storage. RESULTS: The mean recovery of most proteins exceeded 80% after MB treatment. The exceptions were factor XI and fibrinogen, of which only 71.3-74% and 69.0-92.3% were retained during storage. The two equipment types differed in terms of residual MB concentration in the plasma samples (0.18 MUM and 0.29 MUM, respectively). They had similar protein recovery rates at 0.5 month but differed at later time points. The four blood centers differed significantly with regard to factor II, V, VIII and fibrinogen activities. Only the samples from the Shandong blood center met the methylene blue treated fresh frozen plasma requirement. The major factor that influenced the quality of the MB-FFP samples was the time taken between blood collection and storage. DISCUSSION: Methylene blue treated plasma showed reduced coagulation factor (CF) activity and protein levels. The MB treatment-induced damage to the proteins was acceptable at the four Chinese blood centers, but the quality of the MB-treated plasma in general was not satisfactory. The main factor affecting plasma quality may be the duration of the collection and processing. PMID- 23928129 TI - Transfusion and Apheresis Science. Editorial. PMID- 23928130 TI - Era of blood component therapy: time for mandatory pre-donation platelet count for maximizing donor safety and optimizing quality of platelets. AB - Blood bank regulatory agencies including the Drug and Cosmetics Act (DCA) of India do not mandate a predonation platelet count in whole blood donation. Mandating such practice will definitely optimize the quality of random donor platelets (RDP) in terms of platelet yield and patient therapeutic benefit. We observed poor platelet yield in RDP concentrates prepared at our center with a significant number not meeting the DCA guideline of >= 4.5 * 10(10) per bag processed from 450 ml of whole blood. Therefore we planned this study to evaluate the pre-donation hematological values in our blood donor population and effect of these values on the quality of platelet concentrates. The prospective study included 221 blood donors eligible for donating 450 ml of whole blood (WB). Following the departmental standard operating procedure (SOP) RDPs were prepared using the 'Top & Bottom' quadruple bag system and automated component extractor. Quality of RDP was assessed as per departmental protocol. All results were recorded and subsequently transcribed to SPSS working sheet. A significant (p<0.001) decrement of donor blood counts has been observed after WB donation. Mean donor Hb and platelets reduced by 0.72 g/dl and 22.1 * 10(6)/ml respectively. Quality of RDPs in terms of platelet yield was significantly better (p<0.001) when donor platelet count was >200 * 10(6)/ml. Although platelet yield significantly correlated with the donor platelet count however quality of RDPs in terms of red cell contamination showed no correlation with the donor hematocrit. Platelet yield in random donor platelets is a concern in Eastern India. A platelet yield of 4.5 * 10(10) per bag as mandated by the DCA of India was only achieved when the donor platelet count was >200 * 10(6)/ml. Posttransfusion platelet recovery (PPR) was unsatisfactory in the transfused patient. Introduction of pre-donation platelet count in whole blood donation will maximize donor safety and optimize patient platelet transfusion management. PMID- 23928131 TI - Acute pancreatitis revealing an annular pancreas. PMID- 23928132 TI - A temporal regulatory mechanism controls the different contribution of endoplasmic reticulum and plastidial omega-3 desaturases to trienoic fatty acid content during leaf development in soybean (Glycine max cv Volania). AB - We analyzed the molecular mechanism controlling omega-3 fatty acid desaturases during seed germination and leaf development in soybean. During germination, soybean seeds were characterized by a high 18:2(Delta9,12) level (more than 50%) and reduced 18:3(Delta9,12,15) content (10%). Interestingly, transcripts from all endoplasmic reticulum (GmFAD3A and GmFAD3B) and plastidial (GmFAD7-1/GmFAD7-2 or GmFAD8-1/GmFAD8-2) desaturase genes were detected during seed germination. Upon germination, soybean trifoliate leaf development was accompanied by an increase in linolenic acid (18:3(Delta9,12,15)). Our data showed that transcripts corresponding to the endoplasmic reticulum omega-3 desaturases GmFAD3A and GmFAD3B decreased with leaf development. No changes in the expression profile of the plastidial omega-3 desaturases GmFAD7-1 and GmFAD7-2 genes were detected. On the contrary, GmFAD8-2 transcript levels increased while GmFAD8-1 transcripts decreased during leaf development. Given this expression profile, our data suggested the existence of a temporal regulatory mechanism controlling omega-3 desaturases during leaf development in which the endoplasmic reticulum omega-3 desaturases would be more important in young leaves while plastidial omega-3 desaturases might contribute to 18:3(Delta9,12,15) production in mature leaves. Photosynthetic cell cultures showed 18:3(Delta9,12,15) levels similar to those from leaves. No changes in the 18:3(Delta9,12,15) content or expression of the omega-3 desaturase genes were detected along the cell culture cycle. A comparison of our data with those available in Arabidopsis or wheat suggested that the regulatory mechanism controlling the expression and activity of both endoplasmic reticulum and plastidial desaturases during leaf development might differ among plant species. PMID- 23928133 TI - Yield of neck CT and barium esophagram in patients with globus sensation. AB - BACKGROUND AND PURPOSE: Globus sensation is common and difficult to treat. The purpose of our study was to compare the diagnostic and therapeutic efficacy of barium esophagram and neck CT in patients with isolated globus sensation, to determine which of these modalities should be preferred in the evaluation of this condition. MATERIALS AND METHODS: We retrospectively identified patients presenting with isolated globus sensation from January 1, 2005, to December 31, 2012, who underwent neck CT or barium esophagram. We calculated the proportion of patients with abnormal findings, tabulated the nature of the abnormality, and reviewed the medical records to determine whether imaging changed management. RESULTS: One hundred forty-eight neck CTs and 104 barium esophagrams were included. Five (3.4%) patients with neck CTs and 4 (3.9%) with barium esophagrams demonstrated significant findings related to the history of globus sensation. Of these, 1 (0.7%) neck CT and 1 (1.0%) barium esophagram resulted in a change in clinical management. CONCLUSIONS: Imaging evaluation of the patient with uncomplicated globus sensation is unlikely to identify clinically significant imaging findings and is very unlikely to result in a change in clinical management, with a combined therapeutic efficacy of 0.8%. Thus, the routine use of imaging in the evaluation of patients with globus sensation cannot be recommended. PMID- 23928134 TI - Perfusion measurement in brain gliomas with intravoxel incoherent motion MRI. AB - BACKGROUND AND PURPOSE: Intravoxel incoherent motion MRI has been proposed as an alternative method to measure brain perfusion. Our aim was to evaluate the utility of intravoxel incoherent motion perfusion parameters (the perfusion fraction, the pseudodiffusion coefficient, and the flow-related parameter) to differentiate high- and low-grade brain gliomas. MATERIALS AND METHODS: The intravoxel incoherent motion perfusion parameters were assessed in 21 brain gliomas (16 high-grade, 5 low-grade). Images were acquired by using a Stejskal Tanner diffusion pulse sequence, with 16 values of b (0-900 s/mm(2)) in 3 orthogonal directions on 3T systems equipped with 32 multichannel receiver head coils. The intravoxel incoherent motion perfusion parameters were derived by fitting the intravoxel incoherent motion biexponential model. Regions of interest were drawn in regions of maximum intravoxel incoherent motion perfusion fraction and contralateral control regions. Statistical significance was assessed by using the Student t test. In addition, regions of interest were drawn around all whole tumors and were evaluated with the help of histograms. RESULTS: In the regions of maximum perfusion fraction, perfusion fraction was significantly higher in the high-grade group (0.127 +/- 0.031) than in the low-grade group (0.084 +/- 0.016, P < .001) and in the contralateral control region (0.061 +/- 0.011, P < .001). No statistically significant difference was observed for the pseudodiffusion coefficient. The perfusion fraction correlated moderately with dynamic susceptibility contrast relative CBV (r = 0.59). The histograms of the perfusion fraction showed a "heavy-tailed" distribution for high-grade but not low-grade gliomas. CONCLUSIONS: The intravoxel incoherent motion perfusion fraction is helpful for differentiating high- from low-grade brain gliomas. PMID- 23928135 TI - Improving clinical fMRI: better paradigms or higher field strength? PMID- 23928136 TI - When is carotid angioplasty and stenting the cost-effective alternative for revascularization of symptomatic carotid stenosis? A Canadian health system perspective. AB - BACKGROUND AND PURPOSE: Carotid revascularization procedures can be complicated by stroke. Additional disability adds to the already high costs of the procedure. To weigh the cost and benefit, we estimated the cost-utility of carotid angioplasty and stenting compared with carotid endarterectomy among patients with symptomatic carotid stenosis, with special emphasis on scenario analyses that would yield carotid angioplasty and stenting as the cost-effective alternative relative to carotid endarterectomy. MATERIALS AND METHODS: A cost-utility analysis from the perspective of the health system payer was performed by using a Markov analytic model. Clinical estimates were based on a meta-analysis. The procedural costs were derived from a microcosting data base. The costs for hospitalization and rehabilitation of patients with stroke were based on a Canadian multicenter study. Utilities were based on a randomized controlled trial. RESULTS: In the base case analysis, carotid angioplasty and stenting were more expensive (incremental cost of $6107) and had a lower utility (-0.12 quality adjusted life years) than carotid endarterectomy. The results are sensitive to changes in the risk of clinical events and the relative risk of death and stroke. Carotid angioplasty and stenting were more economically attractive among high risk surgical patients. For carotid angioplasty and stenting to become the preferred option, their costs would need to fall from more than $7300 to $4350 or less and the risks of the periprocedural and annual minor strokes would have to be equivalent to that of carotid endarterectomy. CONCLUSIONS: In the base case analysis, carotid angioplasty and stenting were associated with higher costs and lower utility compared with carotid endarterectomy for patients with symptomatic carotid stenosis. Carotid angioplasty and stenting were cost-effective for patients with high surgical risk. PMID- 23928137 TI - Parkes Weber syndrome and spinal arteriovenous malformations. PMID- 23928138 TI - Toward an endovascular internal carotid artery classification system. AB - SUMMARY: Does the world need another ICA classification scheme? We believe so. The purpose of proposed angiography-driven classification is to optimize description of the carotid artery from the endovascular perspective. A review of existing, predominantly surgically-driven classifications is performed, and a new scheme, based on the study of NYU aneurysm angiographic and cross-sectional databases is proposed. Seven segments - cervical, petrous, cavernous, paraophthlamic, posterior communicating, choroidal, and terminus - are named. This nomenclature recognizes intrinsic uncertainty in precise angiographic and cross-sectional localization of aneurysms adjacent to the dural rings, regarding all lesions distal to the cavernous segment as potentially intradural. Rather than subdividing various transitional, ophthalmic, and hypophyseal aneurysm subtypes, as necessitated by their varied surgical approaches and risks, the proposed classification emphasizes their common endovascular treatment features, while recognizing that many complex, trans-segmental, and fusiform aneurysms not readily classifiable into presently available, saccular aneurysm-driven schemes, are being increasingly addressed by endovascular means. We believe this classification may find utility in standardizing nomenclature for outcome tracking, treatment trials and physician communication. PMID- 23928139 TI - Tumor consistency of pituitary macroadenomas: predictive analysis on the basis of imaging features with contrast-enhanced 3D FIESTA at 3T. AB - BACKGROUND AND PURPOSE: Preoperative evaluation of pituitary macroadenoma tumor consistency is important for neurosurgery. Thus, we aimed to retrospectively assess the role of contrast-enhanced FIESTA in predicting the tumor consistency of pituitary macroadenomas. MATERIALS AND METHODS: Twenty-nine patients with pituitary macroadenomas underwent conventional MR imaging sequences and contrast enhanced FIESTA before surgery. Two neuroradiologists assessed the contrast enhanced FIESTA, contrast-enhanced T1WI, and T2WI. On the basis of surgical findings, the macroadenomas were classified by the neurosurgeons as either soft or hard. Finally, Fisher exact probability tests and unpaired t tests were used to compare predictions on the basis of the MR imaging findings with the tumor consistency, collagen content, and postoperative tumor size. RESULTS: The 29 pituitary macroadenomas were classified as either solid or mosaic types. Solid type was characterized by a homogeneous pattern of tumor signal intensity without intratumoral hyperintense dots, whereas the mosaic type was characterized by many intratumoral hyperintense dots on each MR image. Statistical analyses revealed a significant correlation between tumor consistency and contrast-enhanced FIESTA findings. Sensitivity and specificity were higher for contrast-enhanced FIESTA (1.00 and 0.88-0.92, respectively) than for contrast-enhanced T1WI (0.80 and 0.25 0.33, respectively) and T2WI (0.60 and 0.38-0.54, respectively). Compared with mosaic-type adenomas, solid-type adenomas tended to have a hard tumor consistency as well as a significantly higher collagen content and lower postoperative tumor size. CONCLUSIONS: Contrast-enhanced FIESTA may provide preoperative information regarding the consistency of macroadenomas that appears to be related to the tumor collagen content. PMID- 23928140 TI - (62)Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) PET in human gliomas: comparative study with [(18)F]fluorodeoxyglucose and L-methyl-[(11)C]methionine PET. AB - BACKGROUND AND PURPOSE: (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) was developed as a hypoxic radiotracer in PET. We compared imaging features among MR imaging and (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)-PET, FDG-PET, and L methyl-[(11)C]methionine)-PET in gliomas. MATERIALS AND METHODS: We enrolled 23 patients who underwent (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)-PET and FDG-PET and 19 (82.6%) who underwent L-methyl-[(11)C]methionine)-PET, with all 23 patients undergoing surgery and their diagnosis being then confirmed by histologic examination as a glioma. Semiquantitative and volumetric analysis were used for the comparison. RESULTS: There were 10 newly diagnosed glioblastoma multiforme and 13 nonglioblastoma multiforme (grades II and III), including 4 recurrences without any adjuvant treatment. The maximum standardized uptake value and tumor/background ratios of (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone), as well as L-methyl-[(11)C]methionine, were significantly higher in glioblastoma multiforme than in nonglioblastoma multiforme (P = .03 and P = .03, respectively); no significant differences were observed on FDG. At a tumor/background ratio cutoff threshold of 1.9, (62)Cu-diacetyl-bis(N(4) methylthiosemicarbazone) was most predictive of glioblastoma multiforme, with 90.0% sensitivity and 76.9% specificity. The positive and negative predictive values, respectively, for glioblastoma multiforme were 75.0% and 85.7% on (62)Cu diacetyl-bis(N(4)-methylthiosemicarbazone), 83.3% and 60.0% on L-methyl [(11)C]methionine, and 72.7% and 75.0% on MR imaging. In glioblastoma multiforme, volumetric analysis demonstrated that (62)Cu-diacetyl-bis(N(4) methylthiosemicarbazone) uptake had significant correlations with FDG (r = 0.68, P = .03) and L-methyl-[(11)C]methionine (r = 0.87, P = .03). However, the (62)Cu diacetyl-bis(N(4)-methylthiosemicarbazone)-active region was heterogeneously distributed in 50.0% (5/10) of FDG-active and 0% (0/6) of L-methyl [(11)C]methionine)-active regions. CONCLUSIONS: (62)Cu-diacetyl-bis(N(4) methylthiosemicarbazone) may be a practical radiotracer in the prediction of glioblastoma multiforme. In addition to FDG-PET, L-methyl-[(11)C]methionine)-PET, and MR imaging, (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)-PET may provide intratumoral hypoxic information useful in establishing targeted therapeutic strategies for patients with glioblastoma multiforme. PMID- 23928141 TI - Use of FLAIR imaging to identify onset time of cerebral ischemia in a canine model. AB - BACKGROUND AND PURPOSE: Stroke is a leading cause of death and disability, and many studies have focused on the evolution of FLAIR imaging in the acute and chronic time window. The purpose of this study was to evaluate the potential efficacy of FLAIR-related techniques in identifying the onset time of cerebral ischemia in a canine embolic stroke model. MATERIALS AND METHODS: An embolic ischemic model was generated through the use of an autologous clot in 20 beagle dogs. Both FLAIR and DWI were performed at 3 hours, 4 hours, 5 hours, 6 hours, and 24 hours after embolization, respectively. Visual "DWI-FLAIR mismatch" was defined as hyperintense signal detected on DWI but not on FLAIR. The relative signal intensity of FLAIR-positive lesions and the degree of DWI-FLAIR mismatch was calculated as relative FLAIR = relative signal intensity of FLAIR positive lesions, mismatch degree = (100-VFLAIR/VDWI) * 100%. RESULTS: The ischemic model was successfully established in all animals. FLAIR-positive lesions were seen in 3, 11, 16, 19, and 20 beagle dogs at 5 time points after embolization, respectively. There was significant correlation between the relative FLAIR, degree of DWI-FLAIR mismatch, and the onset time (relative FLAIR: r = +0.42; 95% CI, 0.20-0.60; mismatch degree: r = -0.85; 95% CI, 0.89-0.78). Receiver operating characteristic curves showed that the degree of DWI-FLAIR mismatch could identify the hyperacute ischemic lesions with a sensitivity range from 1.00-0.76; visual DWI-FLAIR mismatch sensitivity ranged from 0.85-0.39, whereas specificity was 0.83-0.95 versus 0.85-1.00. CONCLUSIONS: The relative FLAIR and DWI-FLAIR mismatch values were useful in predicting the onset time in our canine embolic stroke model. The degree of DWI-FLAIR mismatch proposed in our study could be a good indicator with high sensitivity for identifying the hyperacute ischemic stroke. PMID- 23928142 TI - Quantifying the large-scale hemodynamics of intracranial aneurysms. AB - BACKGROUND AND PURPOSE: Hemodynamics play an important role in the mechanisms that govern the initiation, growth, and possible rupture of intracranial aneurysms. The purpose of this study was to objectively characterize these dynamics, classify them, and connect them to aneurysm rupture. MATERIALS AND METHODS: Image-based computational fluid dynamic simulations were used to re create the hemodynamics of 210 patient-specific intracranial aneurysm geometries. The hemodynamics were then classified according to their spatial complexity and temporal stability by using quantities derived from vortex core lines and proper orthogonal decomposition. RESULTS: The quantitative classification was compared with a previous qualitative classification performed by visual inspection. Receiver operating characteristic curves provided area-under-the-curve estimates for spatial complexity (0.905) and temporal stability (0.85) to show that the 2 classifications were in agreement. Statistically significant differences were observed in the quantities describing the hemodynamics of ruptured and unruptured intracranial aneurysms. Specifically, ruptured aneurysms had more complex and more unstable flow patterns than unruptured aneurysms. Spatial complexity was more strongly associated with rupture than temporal stability. CONCLUSIONS: Complex-unstable blood flow dynamics characterized by longer core line length and higher entropy could induce biologic processes that predispose an aneurysm for rupture. PMID- 23928143 TI - Actinomycosis in the mandible: CT and MR findings. AB - SUMMARY: Mandibular actinomycosis is an uncommon disease. We retrospectively reviewed 6 patients with pathologically proven mandibular actinomycosis who underwent both CT and MR imaging to evaluate the characteristic imaging findings. CT results showed an irregularly marginated lesion with increased bone marrow attenuation, osteolysis, and involvement of the skin in all patients. Periosteal reaction and intralesional gas were seen in 4 patients. MR imaging results revealed low signal on T1-weighted and high signal on T2-weighted images of the mandible, and moderate heterogeneous enhancement was seen in all patients who received intravenous contrast. Cervical lymphadenopathy was not observed. Involvement of the masseter, lateral pterygoid, and medial pterygoid muscles was seen in 4 patients, whereas parotid gland and submandibular gland as well as parapharyngeal space involvement were seen in 3 patients. Familiarity with the imaging findings of mandibular actinomycosis may help to diagnosis this entity. PMID- 23928144 TI - Utility of proton MR spectroscopy for differentiating typical and atypical primary central nervous system lymphomas from tumefactive demyelinating lesions. AB - BACKGROUND AND PURPOSE: It may be challenging to differentiate primary CNS lymphomas, especially primary CNS lymphomas with atypical MR features, from tumefactive demyelinating lesions by the use of conventional MR. This study aimed to investigate the usefulness of (1)H-MR spectroscopy for making this discrimination. MATERIALS AND METHODS: Forty-four patients with primary CNS lymphomas and 21 with tumefactive demyelinating lesions were enrolled. Single voxel (TE = 144 ms) (1)H-MR spectroscopy scans with the use of the point-resolved spectroscopy sequence were retrospectively analyzed. The Cho/Cr and Cho/NAA area ratios were calculated. The lipid and/or lactate peak was visually categorized into 5 grades on the basis of comparison with the height of the Cr peak. The (1)H MR spectroscopy findings were compared in all of the primary CNS lymphomas and the tumefactive demyelinating lesions and in the subgroup of atypical primary CNS lymphomas and tumefactive demyelinating lesions. The thresholds and added value of (1)H-MR spectroscopy to conventional MR were calculated by use of receiver operating characteristic curves. RESULTS: Discrepancies between all of the primary CNS lymphomas and tumefactive demyelinating lesions were found in the Cho/Cr ratio (P = .000), Cho/NAA ratio (P = .000), and the lipid and/or lactate peak grade (P = .000). Lymphoma rather than tumefactive demyelinating lesions was suggested when the Cho/Cr ratio was >2.58, the Cho/NAA ratio was >1.73, and a high lipid and/or lactate peak grade (grade >3) was seen. Higher Cho/Cr ratios, Cho/NAA ratios, and lipid and/or lactate peak grades were found in atypical primary CNS lymphomas when compared with those of tumefactive demyelinating lesions. The area under the receiver operating characteristic curve of conventional MR was improved from 0.827 to 0.870 when Cho/NAA ratio was added in the uncertain cases. CONCLUSIONS: (1)H-MR spectroscopy may be useful for differentiating primary CNS lymphomas from tumefactive demyelinating lesions. Cho/NAA ratio could provide added value to conventional MR imaging. PMID- 23928145 TI - Quantification of internal carotid artery flow with digital subtraction angiography: validation of an optical flow approach with Doppler ultrasound. AB - BACKGROUND AND PURPOSE: Digital subtraction angiography is the reference standard technique to evaluate intracranial vascular anatomy and used on the endovascular treatment of vascular diseases. A dedicated optical flow-based algorithm was applied to DSA to measure arterial flow. The first quantification results of internal carotid artery flow validated with Doppler sonography are reported. MATERIALS AND METHODS: We included 22 consecutive patients who underwent endovascular procedures. To assess the sensitivity of the algorithm to contrast agent-blood mixing dynamics, we acquired high-frame DSA series (60 images/s) with different injection rates: 1.5 mL/s (n = 19), 2.0 mL/s (n = 18), and 3.0 mL/s (n = 13). 3D rotational angiography was used to extract the centerline of the vessel and the arterial section necessary for volume flow calculation. Optical flow was used to measure flow velocities in straight parts of the ICAs; these data were further compared with Doppler sonography data. DSA mean flow rates were linearly regressed on Doppler sonography measurements, and regression slope coefficient bias from value 1 was analyzed within the 95% confidence interval. RESULTS: DSA mean flow rates measured with the optical flow approach significantly matched Doppler sonography measurements (slope regression coefficient, b = 0.83 +/- 0.19, P = .05) for injection rate = 2.0 mL/s and circulating volumetric blood flow <6 mL/s. For injection rate = 1.5 mL/s, volumetric blood flow <3 mL/s correlated well with Doppler sonography (b = 0.67 +/- 0.33, P = .05). Injection rate = 3.0 mL/s failed to provide DSA-optical flow measurements correlating with Doppler sonography because of the lack of measurable pulsatility. CONCLUSIONS: A new model-free optical flow technique was tested reliably on the ICA. DSA-based blood flow velocity measurements were essentially validated with Doppler sonography whenever the conditions of measurable pulsatility were achieved (injection rates = 1.5 and 2.0 mL/s). PMID- 23928146 TI - Diffusion measures indicate fight exposure-related damage to cerebral white matter in boxers and mixed martial arts fighters. AB - BACKGROUND AND PURPOSE: Traumatic brain injury is common in fighting athletes such as boxers, given the frequency of blows to the head. Because DTI is sensitive to microstructural changes in white matter, this technique is often used to investigate white matter integrity in patients with traumatic brain injury. We hypothesized that previous fight exposure would predict DTI abnormalities in fighting athletes after controlling for individual variation. MATERIALS AND METHODS: A total of 74 boxers and 81 mixed martial arts fighters were included in the analysis and scanned by use of DTI. Individual information and data on fight exposures, including number of fights and knockouts, were collected. A multiple hierarchical linear regression model was used in region-of interest analysis to test the hypothesis that fight-related exposure could predict DTI values separately in boxers and mixed martial arts fighters. Age, weight, and years of education were controlled to ensure that these factors would not account for the hypothesized effects. RESULTS: We found that the number of knockouts among boxers predicted increased longitudinal diffusivity and transversal diffusivity in white matter and subcortical gray matter regions, including corpus callosum, isthmus cingulate, pericalcarine, precuneus, and amygdala, leading to increased mean diffusivity and decreased fractional anisotropy in the corresponding regions. The mixed martial arts fighters had increased transversal diffusivity in the posterior cingulate. The number of fights did not predict any DTI measures in either group. CONCLUSIONS: These findings suggest that the history of fight exposure in a fighter population can be used to predict microstructural brain damage. PMID- 23928147 TI - Preparation, characterization, biodistribution and antitumor efficacy of hydroxycamptothecin nanosuspensions. AB - Hydroxycamptothecin (HCPT) has shown activity against a broad spectrum of cancers, but its therapeutic efficacy is impaired by its poor solubility and delivery challenges. In this study, HCPT nanosuspensions were prepared with precipitation-combined ultrasonication and characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM) and X-ray powder diffraction (XRD). The HCPT nanosuspensions were spherical with a smooth surface and a small size of 150-200 nm. The lyophilized powders for the HCPT nanosuspensions were amorphous and displayed sustained release in vitro. Compared to commercial HCPT injection, in vivo experiments with HCPT nanosuspensions showed significantly increased HCPT concentrations in the blood and all tissues of the tested as well as improved tumor targetability and liver targetability. Meanwhile, nanosuspensions displayed better anticancer efficacy than injection on H22 bearing mice (81.20% vs. 56.39%, in tumor inhibition rate). Therefore, HCPT nanosuspensions seem very promising for the treatment of hepatic cancer. PMID- 23928148 TI - Evaluation of pluronic nanosuspensions loading a novel insoluble anticancer drug both in vitro and in vivo. AB - To improve the solubility, stability and the antitumor activity of a novel anticancer drug, 3-(4-bromopheny l)-2-(ethyl-sulfonyl)-6-methylquinoxaline1,4 dioxide (Q39), a poloxamer nanosuspension was developed by precipitation combined with high pressure homogenization in present study. In vitro characterizations of Q39 nanosuspension (Q39/NS), including particle size, polydispersity index (PI), morphology, crystalline, saturation solubility, stability and releases were evaluated. BABL/c nude mice bearing HepG2 cells were used as in vivo tumor models to evaluate the anti-tumor activity of Q39/NS after intravenous administration. The particle size and PI for Poloxamer188 nanosuspension (P188/NS) were (304+/-3) nm, and (0.123+/-0.005) respectively, and it was (307+/-5) nm and (0.120+/-0.007) for Poloxamer85 nanosuspension (P85/NS) correspondingly. The morphology of P188/NS was spherical shape while elliptoid shape for P85/NS. The crystalline of Q39/NS did not change as shown by the X-ray diffraction analysis. The stability of Q39/NS improved compared with the solution. The solubility of Q39 in P188/NS was 7.3 times higher than the original solubility, while it was 6 times for P85/NS. Sustained release as shown from the in vitro release test, together with the tumor-targeting as shown from in vivo NS distribution, may contribute to the enhanced in vivo antitumor activity of Q39/NS. PMID- 23928149 TI - Use of polyglycerol (PG), instead of polyethylene glycol (PEG), prevents induction of the accelerated blood clearance phenomenon against long-circulating liposomes upon repeated administration. AB - The accelerated blood clearance (ABC) phenomenon accounts for the rapid systemic clearance of PEGylated nanocarriers upon repeated administrations. IgM production against the polyethylene glycol (PEG) coating in PEGylated liposomes is now known to be responsible for such unexpected pharmacokinetical alterations. The ABC phenomenon poses a remarkable clinical challenge by reducing the therapeutic efficacy of encapsulated drugs and causing harmful effects due to the altered tissue distribution pattern of the drugs. In this study, we investigated the in vivo performance of liposomes modified with polyglycerol (PG) upon repeated injection, and the in vivo therapeutic efficacy of such liposomes when they encapsulated a cytotoxic agent, doxorubicin (DXR). Repeated injection of PEG coated liposomes in rats induced the ABC phenomenon, while repeated injection of PG-coated liposomes did not. In addition, DXR-containing PG-coated liposomes showed antitumor activity that was superior to that of free DXR and similar to that of DXR-containing PEG-coated liposomes upon repeated administration. These results indicate that polyglycerol (PG) might represent a promising alternative to PEG via enhancing the in vivo performance of liposomes by not eliciting the ABC phenomenon upon repeated administration. PMID- 23928150 TI - [The most prevalent environmental risk factors in respiratory syncytial virus bronchiolitis in infants from 0 to 24 months in a seasonal study performed in two hospitals]. AB - OBJECTIVE: Our aim is to describe the environmental aspects of children between 0 and 24 months, who arrived in the Emergency Department of the Hospital General de Cataluna and Hospital Parc Tauli (both within Barcelona province), and were diagnosed with respiratory syncytial virus bronchiolitis from November 2010 to February 2011. METHOD: A cross-sectional observational study was conducted on children of both sexes, with ages from 0 to 24 months, and diagnosed with bronchiolitits respiratory syncytial virus +. Data was obtained by completing a non-validated questionnaire, with information provided by parents and the medical history. RESULTS: The most common features in the study were: a mean age of 3.8 months, most were males, with siblings of school age, mothers who did not smoke during pregnancy, were in a non-smoking environment in their home, and finally, less than 5 people living together in their home. CONCLUSIONS: The most common risk factors n order of prevalence were, having siblings of school age, male sex, and living in smoking environment. It was observed that the majority of children had risk associated factors associated, with only 8.2% of samples not presenting any risk factors. PMID- 23928151 TI - A rodent model of partial muscle re-innervation. AB - BACKGROUND: There is limited appreciation of the risks and benefits of the few salvage treatment options available for inadequate motor function following incomplete spontaneous recovery or surgical repair of major peripheral nerve injuries. The lack of a reliable and economical animal model has hindered laboratory investigation into this difficult clinical problem. We propose a straightforward and reproducible rodent model of partial re-innervation of a hind limb muscle. NEW METHOD: Twelve Sprague-Dawley rats underwent identical surgical manipulations: the left tibial nerve was isolated, partially transected (2/3rds), and the remaining intact portion crushed. Eight weeks later, bilateral (1) gastrocnemius (2) soleus and (3) flexor digitorum longus muscles underwent maximal isometric contraction force testing before being excised and weighed. RESULTS: Only the gastrocnemius muscles were statistically weaker (p<0.05) in the experimental limb compared with the contralateral (control) limb. There was no difference in muscle weights between experimental and control sides. COMPARISON WITH EXISTING METHODS: Our model differs from other published models by: allowing time for compensatory axonal sprouting as would be seen in clinical scenarios, precisely identifying the portion of the tibial nerve to be transected to ensure reproducibility, and achieving temporary but complete denervation by crushing the intact portion of the nerve. CONCLUSIONS: Controlled partial transection and crushing of the rodent tibial nerve results in a consistently partially re innervated and clinically weakened gastrocnemius muscle that can serve as a model in studying incomplete recovery following nerve injury. PMID- 23928153 TI - Multivariate synchronization index for frequency recognition of SSVEP-based brain computer interface. AB - Multichannel frequency recognition methods are prevalent in SSVEP-BCI systems. These methods increase the convenience of the BCI system for users and require no calibration data. A novel multivariate synchronization index (MSI) for frequency recognition was proposed in this paper. This measure characterized the synchronization between multichannel EEGs and the reference signals, the latter of which were defined according to the stimulus frequency. For the simulation and real data, the proposed method showed better performance than the widely used canonical correlation analysis (CCA) and minimum energy combination (MEC), especially for short data length and a small number of channels. The MSI was also implemented successfully in an online SSVEP-based BCI system, thus further confirming its feasibility for application systems. Because fast and accurate recognition is crucial for practical systems, we recommend MSI as a potential method for frequency recognition in future SSVEP-BCI. PMID- 23928152 TI - Immunomagnetic enrichment and flow cytometric characterization of mouse microglia. AB - BACKGROUND: The inflammatory response after a CNS injury is regulated by microglia/macrophages. Changes in the ratio of M1 classically activated pro inflammatory cells versus M2 alternatively activated anti-inflammatory cells reveal the direction of the immune response. These cells are routinely identified and enumerated by morphology and cell-surface markers using immunohistochemistry. NEW METHOD: We used a controlled cortical impact (CCI) mouse model for traumatic brain injury (TBI), then isolated microglia/macrophages from neural cell suspensions using magnetic beads conjugated to CD11b monoclonal antibody to obtain the entire myeloid population. Polarization states of CD11b(+)CD45(lo) microglia were evaluated by expression of M1 surface marker FcgammaRII/III and M2 surface marker CD206. RESULTS: After TBI, we observed an increase in M1:M2 ratio in the ipsilateral hemisphere when compared to the contralateral side, indicating that 24h after CCI, a shift in microglia polarization occurs localized to the hemisphere of injury. Comparison with existing method(s): The major impetus for developing and refining the methods was the need to accurately quantify microglial activation states without reliance on manual morphometric counting of serial immunohistochemistry slides. Flow cytometric analysis of enriched cell suspensions provides quantitative measurement of microglial polarization states complementary to existing methods, but for entire populations of cells. CONCLUSIONS: In summary, we used immunomagnetic beads to isolate myeloid cells from injured brain, then stained surface antigens to flow cytometrically identify and categorize microglia as either classically activated M1 or alternatively activated M2, generating a ratio of M1:M2 cells which is useful in studying attempts to reduce or redirect neuroinflammation. PMID- 23928154 TI - The influence of cow and management factors on reproductive performance of Irish seasonal calving dairy cows. AB - Herd management record analysis facilitates accurate assessment of the current herd reproductive status; a crucial decision making tool to implement effective change. To determine the relative importance of cow and management factors on reproductive indices in moderate-yielding Irish seasonal-calving dairy herds, breeding records of 1173 cows were collected from 10 seasonal calving herds between 2007 and 2009. Backward-stepwise multivariable logistic regression analysis was utilised to determine the effect of cow factors including parity, calving timing, days post partum, heat detection accuracy and herd factors including herd size and heat detection efficiency on key reproductive indices. Mean farm six-week pregnancy and end of season not-in-calf rate were 46% (range 14-72%) and 22% (range 3-40%), respectively. Oestrous detection efficiency (P<0.001), timing of calving (P<0.001) relative to start of breeding, history of abnormal repeat intervals (P<0.001) and length of post partum interval (P<0.001) were each associated with lower six-week pregnancy rates. Timing of calving (P<0.001) and history of abnormal repeat intervals (P<0.001) were associated with higher not-in-calf rates. Herd size and cow parity were not associated (P>0.05) with either outcome when factors including existing calving pattern and heat detection accuracy and efficiency were accounted for. The existing spread in calving pattern, heat detection quality and length of voluntary waiting period were the most influential factors that reduced fertility performance in seasonal calving herds. PMID- 23928155 TI - A comparative analysis of the efficacy of cortical screws as lag screws and miniplates for internal fixation of mandibular symphyseal region fractures: a randomized prospective study. AB - The management of facial trauma is one of the most rewarding and demanding aspects of oral and maxillofacial surgery. Being the most prominent mobile bone of the facial skeleton, mandible fracture occurs more frequently than any other fracture. In this study, open reduction and internal fixation was performed for isolated mandibular symphyseal region fractures using cortical screws (as lag screws) in 40 patients and using miniplates in 40 patients. Clinical and radiological evaluations were made at 6 months postoperatively. Primary stability of fracture segments, postoperative swelling, restricted lip mobility, infection, wound dehiscence, implant removal, and mal-union or non-union of fracture segments was evaluated. Primary stability was achieved in 100% of cases treated with cortical screws, whereas for patients treated with miniplates, 97.5% attained primary stability, while one case (2.5%) showed persistent clinical mobility. Postoperative complications were noted in 13 (16.25%) of the total 80 patients. The duration of postoperative swelling was less in patients treated with cortical screws compared to patients treated with miniplates. It is concluded that cortical screw fixation is an effective procedure for the treatment of symphyseal region fractures, but the procedure is somewhat technically sensitive. PMID- 23928156 TI - PainDETECT: a suitable screening tool for neuropathic pain in patients with painful post-traumatic trigeminal nerve injuries? AB - The PainDETECT questionnaire (PD-Q), originally developed and validated in a multicentre study of neuropathic pain (NeP) patients with back pain, is increasingly being applied to other pain conditions. The present study assessed whether the PD-Q would be a suitable screening tool for detecting NeP in patients with post-traumatic inferior alveolar nerve injury (IANI) and lingual nerve injury (LNI). A prospective cohort of patients with clinically diagnosed neuropathy was given the PD-Q at their clinic appointment, or it was sent to them after their consultation. Eighty-nine patients (IANI = 56, LNI = 33) were included in the study, 75 of whom suffered from painful neuropathy. Of the patients who completed the questionnaire fully (n = 56), allowing a summary score to be calculated, 34% were classified as having 'likely NeP' according to the PD Q; 41% of patients scored in the uncertain classification range and the remaining quarter in the 'likely nociceptive' classification. There was a significant association between PD-Q scores and pain intensity levels across the sample, with those classified as likely NeP reporting high levels of pain. The results suggest that the PD-Q in its current format is not a suitable screening tool for NeP associated with IANI or LNI. PMID- 23928157 TI - Telomere length and telomerase activity during oocyte maturation and early embryo development in mammalian species. AB - Telomeres are located at the ends of all eukaryotic chromosomes and protect them from deleterious events such as inappropriate DNA repair, illegitimate recombination or improper segregation of the chromosomes during mitotic or meiotic divisions. However, telomeres gradually shorten primarily due to successive rounds of genomic DNA replication and also as the result of the adverse effects of oxidative stress, genotoxic agents, diseases related to ageing and environmental factors on the nuclear materials of dividing or non-dividing cells. Germline cells, proliferative granulosa cells, early embryos, stem cells, highly proliferative somatic cells and many cancer cells contain the enzyme telomerase so that they are capable of elongating the shortened telomeres. Although numerous studies have revealed the length of telomeres and telomerase activity in oocytes, granulosa cells and early embryos, only a few studies have analyzed and compared the work performed on distinct mammalian species. In this comprehensive review article, we compare and discuss telomere length and telomerase activity in oocytes, granulosa cells and early embryos in different mammalian species including mice, bovines and humans. PMID- 23928158 TI - Differential binding modes of anti-cancer, anti-HIV drugs belonging to isatin family with a model transport protein: a joint refinement from spectroscopic and molecular modeling approaches. AB - The present contribution reports a detailed characterization of the binding interaction of two potential anticancer, anti-HIV drugs isatin (IST) and 1 methylisatin (MI) with model transport protein Bovine Serum Albumin (BSA). Thermodynamic parameters e.g., DeltaH, DeltaS and DeltaG for the binding phenomenon have been evaluated on the basis of van't Hoff equation to understand the force behind the binding process. A combined application of steady-state and time-resolved fluorescence spectroscopic techniques substantiate the observed drug-induced quenching of intrinsic tryptophanyl fluorescence of the protein to proceed through a static mechanism. Circular dichroic (CD), synchronous fluorescence and excitation-emission matrix fluorescence spectroscopic techniques have been exploited to delineate the secondary and tertiary conformational changes in the protein structure induced by the binding of drugs (IST/MI). The probable binding location of the drug molecules within the protein cavity (hydrophobic subdomain IIIA) has been explored from AutoDock-based blind docking simulation. Examination of drug-protein binding kinetics using stopped-flow fluorescence technique reveals that the association constants (ka) for IST-BSA and MI-BSA interactions are 1.09*10(-3) s(-1) (+/-5%) and 1.73*10(-3) s(-1) (+/ 5%), respectively, at the experimental temperature (T) of 298K. The present study also delves into the effect of drug-binding on the esterase activity of the protein which is found to be reduced in the drug-protein conjugate system in comparison with the native protein. PMID- 23928159 TI - A novel chlorin-PEG-folate conjugate with higher water solubility, lower cytotoxicity, better tumor targeting and photodynamic activity. AB - Techniques to enhance tumor targeting and to improve the aqueous solubility of anticancer drugs and photosensitizers have recently been the focus of much research. In this study, a folate-PEG-conjugated chlorin was synthesized and characterized. Because of the use of PEG as a linker, the new chlorin displayed increased aqueous solubility, with a solubility of 40.1mg/mL in PBS, and showed lower aggregation and cytotoxicity than its precursor, chlorin. Meanwhile, the introduction of folic acid to the new chlorin resulted in increased selectivity for folate-receptor-positive tumor cells (HeLa and Hep-2 cells); the cellular uptake of the new chlorin by HeLa and Hep-2 cells was strikingly higher than that of the precursor chlorin, and the photocytotoxicities of the new chlorin to HeLa and Hep-2 cells were 2.5 and 3.5 times greater than that of folate-free conjugate chlorin. During photodynamic therapy mediated by the new chlorin, both type I and type II reactions occur simultaneously. PMID- 23928160 TI - Near-infrared fluorescence glucose sensing based on glucose/galactose-binding protein coupled to 651-Blue Oxazine. AB - Near-infrared (NIR) fluorescent dyes that are environmentally sensitive or solvatochromic are useful tools for protein labelling in in vivo biosensor applications such as glucose monitoring in diabetes since their spectral properties are mostly independent of tissue autofluorescence and light scattering, and they offer potential for non-invasive analyte sensing. We showed that the fluorophore 651-Blue Oxazine is polarity-sensitive, with a marked reduction in NIR fluorescence on increasing solvent polarity. Mutants of glucose/galactose-binding protein (GBP) used as the glucose receptor were site specifically and covalently labelled with Blue Oxazine using click chemistry. Mutants H152C/A213R and H152C/A213R/L238S showed fluorescence increases of 15% and 21% on addition of saturating glucose concentrations and binding constants of 6 and 25mM respectively. Fluorescence responses to glucose were preserved when GBP-Blue Oxazine was immobilised to agarose beads, and the beads were excited by NIR light through a mouse skin preparation studied in vitro. We conclude GBP-Blue Oxazine shows proof-of-concept as a non-invasive continuous glucose sensing system. PMID- 23928161 TI - Acyldepsipeptides inhibit the growth of renal cancer cells through G1 phase cell cycle arrest. AB - Acyldepsipeptides are a group of potent antibiotics discovered in the secondary metabolites of Streptomyces species. However, besides the function of antibiotics, no other activities have been reported about these important compounds so far. In the course of searching the natural products as chemotherapeutic agents for renal cell carcinoma, we found that ADEP1, a major metabolic component of Streptomyces hawaiiensis NRRL 15010, could effectively inhibit the growth of 786-O, 769-P, and ACHN renal carcinoma cells in MTT assay. Flow cytometric analysis demonstrated that ADEP1 could block the cell cycle arrested at G1 phase. Moreover, it was found that ADEP1 down-regulated the expressions of cyclin D1, CDK4 and PCNA and inhibited activity of MAPK-ERK pathway by detection of decreased expression of phosphorylated ERK1/2 and c-Fos in 786-O and 769-P cells by Western blotting. To our knowledge, this is the first report concerning to the antitumor activities of acyldepsipeptides. Based on these results, ADEP1 may become a promising lead compound to be developed a novel chemotherapeutic agent for treatment of renal carcinoma. PMID- 23928162 TI - The eye of the beholder: tuberculosis screening for elderly long-term care residents. PMID- 23928163 TI - Scaling up public-private mix: collaborate or regulate? PMID- 23928164 TI - Unraveling restrictive chronic lung disease in sickle cell disease. PMID- 23928166 TI - Tuberculosis screening for long-term care: a cost-effectiveness analysis. AB - SETTING: Long-term care facilities in Canada, a low tuberculosis (TB) incidence country. OBJECTIVE: To compare the impact and cost-effectiveness of three screening strategies for TB on entry to long-term care: no screening, screening for latent tuberculous infection (LTBI) using the tuberculin skin test (TST) or screening for active disease with a chest X-ray. DESIGN: Cost effectiveness analysis. RESULTS: With the LTBI screening strategy, the number needed to screen to prevent one active case was 1410 and the cost per case averted was Canadian $109 913. The number needed to screen to prevent one case using the active screening strategy was 1266, and the cost per case averted was $672 298. CONCLUSIONS: Our findings suggest that TB screening strategies on entry to long term care are costly, with large numbers needed to screen. Screening with TST was more cost-effective than chest X-ray screening. Higher risk of reactivation of LTBI is associated with improved cost-effectiveness of screening. Short time horizons and test performance characteristics place limitations on screening programmes in this setting. Future considerations include the changing demographics of the institutionalised elderly. PMID- 23928165 TI - Tuberculosis screening in high human immunodeficiency virus prevalence settings: turning promise into reality. AB - Twenty years of sky-high tuberculosis (TB) incidence rates and high TB mortality in high human immunodeficiency virus (HIV) prevalence countries have so far not been matched by the same magnitude or breadth of responses as seen in malaria or HIV programmes. Instead, recommendations have been narrowly focused on people presenting to health facilities for investigation of TB symptoms, or for HIV testing and care. However, despite the recent major investment and scale-up of TB and HIV services, undiagnosed TB remains highly prevalent at community level, implying that diagnosis of TB remains slow and incomplete. This maintains high transmission rates and exposes people living with HIV to high rates of morbidity and mortality. More intensive use of TB screening, with broader definitions of target populations, expanded indications for screening both inside and outside of health facilities, and appropriate selection of new diagnostic tools, offers the prospect of rapidly improving population-level control of TB. Diagnostic accuracy of suitable (high throughput) algorithms remains the major barrier to realising this goal. In the present study, we review the evidence available to guide expanded TB screening in HIV-prevalent settings, ideally through combined TB-HIV interventions that provide screening for both TB and HIV, and maximise entry to HIV and TB care and prevention. Ideally, we would systematically test, treat and prevent TB and HIV comprehensively, offering both TB and HIV screening to all health facility attendees, TB households and all adults in the highest risk communities. However, we are still held back by inadequate diagnostics, financing and paucity of population-impact data. Relevant contemporary research showing the high need for potential gains, and pitfalls from expanded and intensified TB screening in high HIV prevalence settings are discussed in this review. PMID- 23928167 TI - Can a peer-based intervention impact adherence to the treatment of latent tuberculous infection? AB - OBJECTIVE: To assess the effectiveness of a peer-based intervention on adherence to and completion of latent tuberculous infection (LTBI) treatment. METHODS: Patients prescribed self-administered LTBI treatment were enrolled in a randomized controlled trial of an experimental, peer-based adherence support intervention. Primary outcomes were treatment adherence and completion. Adherence was assessed through self-report, electronic monitoring devices and clinic visits. RESULTS: Of 250 participants, 70% were male; 71% were Black and 20% Latino; the mean age was 40 years; 67% were foreign-born and 39% were married. No significant baseline differences were noted between the intervention groups. Treatment completion was 61% in the intervention group compared to 57% in the controls (P = 0.482). The corresponding completion rate for other clinic patients was 44%. Foreign birth, marriage and history of mental illness were associated with non-completion of treatment after controlling for the intervention group; increased completion rates were found among foreign-born married persons and older participants. A substantial difference in adherence rates was observed between the intervention groups. Adherence among non-completers decreased early, while adherence among completers remained constant. CONCLUSIONS: The peer-based intervention was not significantly associated with LTBI treatment completion, but was associated with greater adherence. Findings suggest the importance of interventions to support adherence that target early non-adherence with LTBI treatment, particularly in the first 2 months, when there is a substantial risk of default. PMID- 23928168 TI - Public-private mix for TB and TB-HIV care in Lagos, Nigeria. AB - SETTING: Private and public tuberculosis (TB) treatment centres in Lagos State, Nigeria. OBJECTIVE: To assess the contribution of private health care providers to TB and TB-HIV (human immunodeficiency virus) case finding in Lagos State. DESIGN: A retrospective review of programme data submitted to the Lagos State TB and Leprosy Control Programme in 2011 by public, private for-profit (PFP) and private not-for-profit (PNFP) health care providers. RESULTS: A total of 8425 TB cases were notified by 31 private (11 PFP and 20 PNFP) and 99 public health facilities in Lagos State. Overall, the private facilities were responsible for 10.3% (866/8425) of the total TB cases notified. The proportion of TB patients tested for HIV was respectively 86.2%, 53.1% and 96.5% among public, PFP and PNFP facilities. Overall, 22.4% of the TB patients were HIV-positive. The HIV positivity rate among public, PFP and PNFP facilities was respectively 23.8%, 7.8% and 9.9%. Uptake of cotrimoxazole preventive therapy was respectively 69.6%, 25% and 38.2% among public, PFP and PNFP facilities, while that of antiretroviral therapy was respectively 23.8%, 8.3% and 9.1% in public, PFP and PNFP facilities. CONCLUSION: There is a need to scale up collaboration with the private sector, and particularly PNFP health providers. PMID- 23928169 TI - Predictors of delay in the diagnosis and treatment of suspected tuberculosis in HIV co-infected patients in South Africa. AB - SETTING: In South Africa, the majority of tuberculosis (TB) patients are co infected with the human immunodeficiency virus (HIV), and delays in diagnosis and treatment likely exacerbate morbidity and mortality. OBJECTIVE: To determine predictors of delays in the diagnosis and treatment of hospitalised suspected pulmonary TB patients co-infected with HIV. DESIGN: Post-analysis of data collected in a three-centre prospective cohort of in-patients clinically diagnosed with active TB in three hospitals in South Africa between 2006 and 2009 during the first 24 h of admission. Delay was assessed by asking time of first symptoms and any prior health-seeking behaviour for this episode of illness. RESULTS: Data from a total of 891 participants with a median age of 36 years and a CD4 count of 67 cells/mm(3) were analysed. Median patient, system and total delays were respectively 28, 1 and 28 days. Unemployment, treatment at Tshepong Hospital, alcohol consumption, crowding index, seeking prior treatment, cotrimoxazole treatment and WHO Stage 4 disease predicted prolonged total delay. CONCLUSION: Patient delay in seeking care for TB in this high HIV prevalence setting is substantial. Factors identified with delay could be used to develop interventions to improve care seeking and earlier diagnosis of TB. PMID- 23928170 TI - Blinded rechecking of acid-fast bacilli smears by light-emitting diode microscopy. AB - BACKGROUND: Blinded rechecking of auramine-stained acid-fast bacilli (AFB) sputum smears using fluorescence microscopy (FM), especially FM using light-emitting diode (LED), is not well understood. OBJECTIVE: To examine the rechecking of auramine-stained sputum smears without restaining within a month using LED FM. METHODS: A total of 4799 centrifuged smears of sputum samples were stained by the auramine phenol method and examined using LED FM; 564 systematically selected smears were subjected to blinded rechecking without restaining by controllers. The initial results of the readers were compared to those of the controllers. Discrepancies were resolved by a referee. The quality of LED FM was assessed by the referee using the culture result as gold standard. RESULTS: Among the rechecked smears, one high false-negative error was made by a reader, while one high false-positive error and 19 high false-negative errors were made by the controllers. The errors were resolved by culture. Smear results for 18 slides were not available due to AFB fading. CONCLUSION: AFB colour fading using LED FM, which affected the accurate evaluation of blinded rechecking of AFB smears without restaining within a month, is confirmed in this large study. PMID- 23928171 TI - Defective Mycobacterium tuberculosis antigen presentation by monocytes from tuberculosis patients. AB - OBJECTIVE: To determine whether there were any defects in the presentation of the Mycobacterium tuberculosis antigen by monocytes from patients with tuberculosis (TB) and the role of vitamin D in the defence against M. tuberculosis. DESIGN: A prospective study aimed at analysing the presentation of the M. tuberculosis antigen by monocytes and the response to vitamin D treatment in three groups of participants: 1) those with active TB, 2) those with healed TB and 3) those with frequent TB contact. RESULTS: The antigen presentation ability of monocytes of persons in the frequent contact group was significantly higher than that of the active TB and healed TB groups. There was no difference between patients with active and healed TB. In addition, 1,25(OH)2D3 increased the presentation of mycobacterial antigens by monocytes from participants with frequent TB contact, but not those with active or healed TB. CONCLUSION: Patients with active and healed TB exhibit defective M. tuberculosis presentation in monocytes. The administration of vitamin D did not correct this defect in monocytes from participants with active or healed TB, but could increase antigen presentation by monocytes in participants with frequent TB contact. PMID- 23928172 TI - Simultaneous detection of Mycobacterium bovis and M. tuberculosis in an apparently immunocompetent patient. PMID- 23928173 TI - Clinical experience of using clofazimine to treat multidrug-resistant tuberculosis [Correspondence]. PMID- 23928174 TI - Treating pyrazinamide mono-resistant pulmonary tuberculosis. PMID- 23928175 TI - Sociodemographic basis of tuberculosis knowledge in Bolivia. PMID- 23928176 TI - Homocysteine, depression and cognitive function in older adults. AB - BACKGROUND: Depression and high total plasma homocysteine (tHcy) are independently associated with cognitive impairment in older adults. We designed this study to determine if high tHcy is a mediator of cognitive performance in older adults with major depression. METHODS: We recruited 358 community-dwelling older adults experiencing depressive symptoms, 236 (65.9%) of who met DSM-IV-TR criteria for major depression. Assessment included the Montgomery Asberg Depression Rating Scale (MADRS), fasting tHcy and the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery. RESULTS: Individuals with major depression and high tHcy had significantly worse immediate verbal and delayed visual recall. Non-depressed participants with high tHcy had lower MMSE, immediate and delayed recall scores than those with normal tHcy. The odds of cognitive inefficiency for those with high tHcy was nearly doubled for the MMSE (OR 1.9, 95%CI 1.1-3.3), immediate (OR 1.9, 95%CI 1.1-3.5) and delayed (OR 1.9, 95%CI 1.1-3.4) word recall after adjusting for age, gender, IHD and MADRS score. LIMITATIONS: The presence of sub-syndromal depressive symptoms in our non depressed group and exclusion of participants with established cognitive impairment may limit the generalizability of this study. CONCLUSIONS: Elevated tHcy was associated with weaker performance in tests of immediate and delayed memory and global cognitive performance when compared to those with normal tHcy independent of the presence of major depression or the severity of depressive symptoms. Homocysteine lowering B-vitamin supplementation may offer a potential therapeutic target to try and mitigate the often-disabling impact of cognitive deficits found in this population. PMID- 23928178 TI - Emergency ultrasound: a prospective study on sufficient adequate training for military doctors. AB - PURPOSE: To evaluate the feasibility of "accelerated" training for military doctors in front line ultrasound. To establish the number of ultrasounds required to validate the doctor's training. To assess the average acquisition time for each ultrasound target. MATERIALS AND METHODS: Prospective study on 10 novice generalist military doctors to assess training for five urgent ultrasound targets: focused assessment with sonography in trauma (FAST), pleura, bladder, abdominal aorta and gallbladder. Each student received theoretical and practical training on "healthy" people and then performed 10 timed ultrasounds in an emergency situation, the result of which was either confirmed or rejected by a nationally qualified ultrasound expert. RESULTS: Some targets were easier to acquire (bladder, aorta and pleura) with excellent diagnostic performance after 10 ultrasounds on healthy people (sensitivity = 100%; specificity = 100%). The overall number of ultrasound errors fell over time. The median investigation time also fell significantly for all targets, reaching a plateau. Twenty ultrasounds including 10 "real life" appear to be needed for FAST. A minimum number of 30 ultrasounds is required to diagnose acute cholecystitis. CONCLUSION: "Accelerated" training for generalist military doctors in front line ultrasound is achievable. The recommended number of 25 ultrasounds per target is not appropriate for all ultrasound targets. PMID- 23928177 TI - Efficient preloading of the ventricles by a properly timed atrial contraction underlies stroke work improvement in the acute response to cardiac resynchronization therapy. AB - BACKGROUND: The acute response to cardiac resynchronization therapy (CRT) has been shown to be due to 3 mechanisms: resynchronization of ventricular contraction, efficient preloading of the ventricles by a properly timed atrial contraction, and mitral regurgitation reduction. However, the contribution of each of the 3 mechanisms to the acute response to CRT, specifically stroke work improvement, has not been quantified. OBJECTIVE: To use a magnetic resonance image-based anatomically accurate 3-dimensional model of failing canine ventricular electromechanics to quantify the contribution of each of the 3 mechanisms to stroke work improvement and identify the predominant mechanisms. METHODS: An MRI-based electromechanical model of the failing canine ventricles assembled previously by our group was further developed and modified. Three different protocols were used to dissect the contribution of each of the 3 mechanisms to stroke work improvement. RESULTS: Resynchronization of ventricular contraction did not lead to a significant stroke work improvement. Efficient preloading of the ventricles by a properly timed atrial contraction was the predominant mechanism underlying stroke work improvement. Stroke work improvement peaked at an intermediate atrioventricular delay, as it allowed ventricular filling by atrial contraction to occur at a low diastolic left ventricular pressure but also provided adequate time for ventricular filling before ventricular contraction. Reduction of mitral regurgitation by CRT led to stroke work worsening instead of improvement. CONCLUSION: Efficient preloading of the ventricles by a properly timed atrial contraction is responsible for a significant stroke work improvement in the acute CRT response. PMID- 23928179 TI - Efficacy and consumer preferences for different approaches to calorie labeling on menus. AB - OBJECTIVE: To evaluate the efficacy and consumer preferences of calorie labeling on menus. DESIGN: Between-group experiment. Participants were randomized to view menu items according to 1 of 4 experimental conditions: no calorie information, calorie-only information, calorie plus health statement (HS), and calorie plus the Physical Activity Scale. Participants selected a snack and then rated menus from all conditions on the level of understanding and perceived effectiveness. SETTING: University of Waterloo, Canada. PARTICIPANTS: A total of 213 undergraduate university students recruited from classrooms. MAIN OUTCOME MEASURES: The calorie amount of menu selection and ratings of understandability and perceived effectiveness. ANALYSIS: Linear regression models and chi-square tests. RESULTS: Participants who selected items from menus without calorie information selected snacks with higher calorie amounts than participants in the calorie-only condition (P = .002) and the calorie plus HS condition (P = .001). The calorie plus HS menu was perceived as most understandable and the calorie plus calorie plus Physical Activity Scale menu was perceived as most effective in helping to promote healthy eating. CONCLUSIONS AND IMPLICATIONS: Calorie labeling on menus may assist consumers in making healthier choices, with consumer preference for menus that include contextual health statements. PMID- 23928180 TI - E-ADA activity in erythrocytes of lambs experimentally infected with Haemonchus contortus and its possible functional correlations with anemia. AB - The aim of this study was to evaluate the ecto-adenosine deaminase (E-ADA) activity in erythrocytes of lambs experimentally infected with Haemonchus contortus, correlating it with the degrees of anemia of the experimental animals. A total of 14 healthy lambs, with negative fecal exam for parasites, were to carry out the present study. They were divided into two groups, composed by seven animals: Group A represented the healthy animals (uninfected), while in Group B the animals were infected with 15,000 larvae of H. contortus. Blood was drawn on the days 15, 45 and 75 post-infection (PI) in order to perform the hematological analysis, as well as the mensuration of E-ADA activity in erythrocytes. Parasitological stool exam were performed on the same days mentioned above to follow up the evolution of the infection, as well to determine the number of eggs per gram of feces (EPG). On day 15PI, the animals presented negative EPG and there was not significant (P>0.05) difference between groups in relation to E-ADA activity and hematologic parameters. Animals in Group B had positive EPG for helminths on days 45 and 75 PI, accompanied by varying degrees of anemia, when compared to Group A. At the same periods E-ADA activity was significantly (P<0.05) increased in the erythrocytes of animals of Group B when compared with the not-infected ones. Statistically, there was a negative correlation (P<0.01) between activity E-ADA in erythrocytes and hematocrit on days 45 (r = -0.76) and 75 (r = -0.85)PI. Based on these results and in the scientific literature, it is possible to conclude that the E-ADA may participate on mechanisms related with the pathogenesis and host response against anemia caused by H. contortus. PMID- 23928181 TI - Identification of weakly haemolytic Brachyspira isolates recovered from pigs with diarrhoea in Spain and Portugal and comparison with results from other countries. AB - Weakly haemolytic anaerobic intestinal spirochaetes of the genus Brachyspira are commonly identified based on species-specific gene sequences. Apart from the pathogenic Brachyspira pilosicoli, the distribution and disease associations of the other weakly haemolytic Brachyspira species in pigs have not been comprehensively investigated. In this study weakly haemolytic Brachyspira isolates (n=67) from Spanish and Portuguese pigs with diarrhoea, negative in a routine diagnostic PCR for B. pilosicoli, were identified by sequencing their NADH oxidase genes (nox). Nearly half the isolates were identified as Brachyspira murdochii (n=31; 46.3%). The others were Brachyspira innocens (n=26; 38.8%), Brachyspira intermedia (n=7; 10.4%), "Brachyspira pulli" (n=1; 1.5%) and a potentially novel Brachyspira species (n=2; 3%). Multilocus sequence typing (MLST) on a subset of 18 isolates confirmed their species designations, including the potential new species, and identified similarities to strains from other countries. PMID- 23928182 TI - An overview of the diagnostic tools. AB - Prions are unconventional infectious agents that cause fatal neurological illnesses such as Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy, and scrapie. Variant CJD can occur via blood transfusions. However, as no screening assay is available, uncertainties remain over the prevalence of vCJD in asymptomatic blood donors. Development of a diagnostic assay is therefore a primary objective. Little is known about the nature, distribution and level of infectivity in human blood and we have to rely on assumptions made from animal models. Ideally, two types of assays are required: a rapid high-throughput assay to routinely screen all blood donations and a confirmatory assay to ensure that all positive results from initial screening are true positives. Key event in prion disease is thought to be the conversion of normal cellular prion protein PrPc to a misfolded aggregated form termed PrP(TSE). This specific characteristic has been exploited to develop some tests. PMID- 23928183 TI - UK approach to assessing assays and filters designed to reduce the risk of transfusion-transmitted vCJD. AB - Three cases of vCJD transmission by blood transfusion have been reported in the UK, and a fourth case discovered at post-mortem. Modelling has been conducted to predict the number of cases that may occur in the future through transfusion, based on estimates of prevalence, infectivity and susceptibility, and a number of steps have been taken to reduce the risk of transmission. These include deferral of previously transfused donors, leucocyte depletion of all components, importation of plasma for certain patient groups and for fractionation, and the collection of the majority of platelets from single donors (by apheresis). However, even with these interventions, some future cases are still predicted. The UK-wide Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) considers the evidence for clinical and cost-effectiveness of any proposed intervention, such as prion assays and filters, and makes recommendations to the governments of the UK. The development of prion assays is challenging as prions do not generate an immune response, do not have nucleic acid and are present in blood in very low concentrations against a high background of normal prion protein. It is critically important that prion assays show high levels of sensitivity and - especially -specificity for a healthy blood donor population. Assessment is impacted by the very short supply of positive human samples, necessitating the use of animal models. Filters that are capable of removing prions from blood components have been developed and CE marked, but it is again necessary to use animal models to study their efficacy. Guidelines have been produced for the assessment of the quality of red cells filtered through these devices, and a clinical safety study has recently been completed. In conclusion, the evaluation of screening assays and prion filters is challenging, time consuming and costly, but these evaluations are critical to policy making. PMID- 23928184 TI - Symposium on prions and transfusion safety. PMID- 23928185 TI - A multicenter study to standardize reporting and analyses of fluorescence activated cell-sorted murine intestinal epithelial cells. AB - Fluorescence-activated cell sorting (FACS) is an essential tool for studies requiring isolation of distinct intestinal epithelial cell populations. Inconsistent or lack of reporting of the critical parameters associated with FACS methodologies has complicated interpretation, comparison, and reproduction of important findings. To address this problem a comprehensive multicenter study was designed to develop guidelines that limit experimental and data reporting variability and provide a foundation for accurate comparison of data between studies. Common methodologies and data reporting protocols for tissue dissociation, cell yield, cell viability, FACS, and postsort purity were established. Seven centers tested the standardized methods by FACS-isolating a specific crypt-based epithelial population (EpCAM+/CD44+) from murine small intestine. Genetic biomarkers for stem/progenitor (Lgr5 and Atoh 1) and differentiated cell lineages (lysozyme, mucin2, chromogranin A, and sucrase isomaltase) were interrogated in target and control populations to assess intra- and intercenter variability. Wilcoxon's rank sum test on gene expression levels showed limited intracenter variability between biological replicates. Principal component analysis demonstrated significant intercenter reproducibility among four centers. Analysis of data collected by standardized cell isolation methods and data reporting requirements readily identified methodological problems, indicating that standard reporting parameters facilitate post hoc error identification. These results indicate that the complexity of FACS isolation of target intestinal epithelial populations can be highly reproducible between biological replicates and different institutions by adherence to common cell isolation methods and FACS gating strategies. This study can be considered a foundation for continued method development and a starting point for investigators that are developing cell isolation expertise to study physiology and pathophysiology of the intestinal epithelium. PMID- 23928186 TI - Comparison of ELISA measurements of anti-Abeta concentrations and percentages of specific binding to Abeta between unfractionated intravenous immunoglobulin products and their purified anti-Abeta antibodies. AB - Intravenous immunoglobulin (IVIG) products are being investigated as possible therapeutic agents for mild cognitive impairment and Alzheimer's disease (AD). Anti-Abeta antibodies have been measured by ELISA in unfractionated IVIG products and in affinity-purified antibodies from these products, but it is unclear if similar results are obtained with these two approaches. Measurements of anti Abeta antibodies in unfractionated IVIG may be confounded by the presence of polyvalent antibodies which can bind to multiple antigens, including those on ELISA plates; whether this is an issue when measuring anti-Abeta antibodies in purified antibody eluates from IVIG is also unknown. The objective of this study was to clarify these issues. The concentrations of specific antibodies to Abeta1 42 monomer and the percentages of specific binding to it were compared via ELISA between three unfractionated IVIG products (Gamunex [Talecris], Gammagard [Baxter], and Flebogamma [Grifols]) and their affinity-purified anti-Abeta antibodies. The concentrations of anti-Abeta antibodies in unfractionated IVIG products were higher than in their respective purified anti-Abeta eluates, and the rank order of the IVIG products with respect to their anti-Abeta concentrations differed between the two types of samples. The percentages of specific binding to Abeta were lower for unfractionated IVIG than for purified anti-Abeta eluates. These findings indicate that ELISA measurements of specific anti-Abeta antibodies and percentages of specific binding to Abeta produce different results depending upon whether these measurements are made in unfractionated IVIG products or their purified anti-Abeta antibodies. Polyvalent binding occurs even with purified anti-Abeta antibodies eluated from IVIG products, but it is less extensive than with unfractionated IVIG. PMID- 23928187 TI - Differential regulation of CYP3A4 promoter activity by a new class of natural product derivatives binding to pregnane X receptor. AB - The pregnane X receptor (PXR) regulates drug metabolism by regulating the expression of drug-metabolizing enzymes such as cytochrome P450 3A4 (CYP3A4), which is involved in the metabolism of >50% of clinically prescribed drugs. The activity of PXR can be controlled by the binding of small molecule agonists or antagonists. Because of its unique ligand binding pocket, PXR binds promiscuously to structurally diverse chemicals. To study the structure-activity relationship, novel modulators for PXR are needed. Here we report the virtual screening of ~25,000 natural product derivatives from the ZINC database using the Molecular Operating Environment docking software tool against the PXR-rifampicin complex X ray crystal structure. Our screening resulted in identification of compounds based on the lowest S score, which measures Gibbs free energy. Interestingly, we found that the compounds that bind directly to PXR, as revealed in an intrinsic tryptophan fluorescence assay, modulate CYP3A4 promoter activity differentially in HepG2 cells. Mutational analysis and docking studies showed that these compounds bind broadly in the ligand binding pocket but interact with different amino acid residues. We further investigated the mechanism of binding by analyzing the functional groups that are important for distinguishing agonists from antagonists. The approach we used to identify novel modulators that bind to PXR can be useful for finding novel modulators of PXR. PMID- 23928188 TI - The focal adhesion kinase inhibitor PF-562,271 impairs primary CD4+ T cell activation. AB - The focal adhesion kinase inhibitor, PF-562,271, is currently in clinical development for cancer, however it is not known how PF-562,271 affects T cell function. Here, we demonstrate inhibitory effects of PF-562,271 on the activation of primary human and mouse T cells. PF-562,271 inhibits T cell receptor signaling induced T cell adhesion to intercellular adhesion molecule-1 and T cell interactions with antigen-presenting cells. An additional focal adhesion kinase inhibitor, PF-573,228, and genetic depletion of focal adhesion kinase also impair T cell conjugation with antigen-presenting cells. PF-562,271 blocks phosphorylation of the signaling molecules zeta chain associate protein of 70 kDa, linker of activated T cells, and extracellular signal-regulated kinase, and impairs T cell proliferation. The effects observed on T cell proliferation cannot solely be attributed to focal adhesion kinase inhibition, as genetic depletion did not alter proliferation. The effect of PF-562,271 on T cell proliferation is not rescued when proximal T cell receptor signaling is bypassed by stimulation with phorbol-12-myristate-13-acetate and ionomycin. Taken together, our findings demonstrate that focal adhesion kinase regulates integrin-mediated T cell adhesion following T cell receptor activation. Moreover, our findings suggest that PF-562,271 may have immunomodulatory effects that could impact its therapeutic applications. PMID- 23928189 TI - Trapidil, a platelet-derived growth factor antagonist, inhibits osteoclastogenesis by down-regulating NFATc1 and suppresses bone loss in mice. AB - Trapidil, a platelet-derived growth factor antagonist, was originally developed as a vasodilator and anti-platelet agent and has been used to treat patients with ischemic coronary heart, liver, and kidney disease. In this study, we investigated the effects of trapidil on osteoclastogenesis and elucidated the possible mechanism of action of trapidil. Trapidil strongly inhibited osteoclast formation in co-cultures of bone marrow cells and osteoblasts without affecting receptor activator of NF-kappaB ligand (RANKL) or osteoprotegerin expression in osteoblasts. In addition, trapidil suppressed RANKL-induced osteoclast formation from osteoclast precursors. Trapidil reduced RANKL-induced expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a master transcription factor for osteoclastogenesis, without affecting the expression of c-Fos that functions as a key upstream activator of NFATc1 during osteoclastogenesis. Ectopic expression of a constitutively active form of NFATc1 reversed the anti osteoclastogenic effect of trapidil, indicating that NFATc1 is a critical target of the anti-osteoclastogenic action of trapidil. RANKL-induced calcium oscillation and Pim-1 expression, which are required for NFATc1 induction and osteoclastogenesis, were abrogated by trapidil. Consistent with the in vitro results, trapidil had a potent inhibitory effect on osteoclast formation and bone resorption induced by interleukin-1 in an animal model. Taken together, our data demonstrate that trapidil abrogates RANKL-induced calcium oscillation and Pim-1 expression required for NFATc1 induction, thereby inhibiting osteoclastogenesis. PMID- 23928191 TI - Differential activation of the human farnesoid X receptor depends on the pattern of expressed isoforms and the bile acid pool composition. AB - The farnesoid X receptor (FXR) is a key sensor in bile acid homeostasis. Although four human FXR isoforms have been identified, the physiological role of this diversity is poorly understood. Here we investigated their subcellular localization, agonist sensitivity and response of target genes. Measurement of mRNA revealed that liver predominantly expressed FXRalpha1(+/-), whereas FXRalpha2(+/-) were the most abundant isoforms in kidney and intestine. In all cases, the proportion of FXRalpha(1/2)(+) and FXRalpha(1/2)(-) isoforms, i.e., with and without a 12bp insert, respectively, was approximately 50%. When FXR was expressed in liver and intestinal cells the magnitude of the response to GW4064 and bile acids differs among FXR isoforms. In both cell types the strongest response was that of FXRalpha1(-). Different efficacy of bile acids species to activate FXR was found. The four FXR isoforms shared the order of sensitivity to bile acids species. When in FXR-deficient cells FXR was transfected, unconjugated, but not taurine- and glycine-amidated bile acids, were able to activate FXR. In contrast, human hepatocytes and cell lines showing an endogenous expression of FXR were sensitive to both unconjugated and conjugated bile acids. This suggests that to activate FXR conjugated, but not unconjugated, bile acids require additional component(s) of the intracellular machinery not related with uptake processes, which are missing in some tumor cells. In conclusion, cell specific pattern of FXR isoforms determine the overall tissue sensitivity to FXR agonists and may be involved in the differential response of FXR target genes to FXR activation. PMID- 23928190 TI - Complex relationships of nicotinic receptor actions and cognitive functions. AB - Nicotine has been shown in a variety of studies to improve cognitive function including learning, memory and attention. Nicotine both stimulates and desensitizes nicotinic receptors, thus acting both as an agonist and a net antagonist. The relative roles of these two actions for nicotine-induced cognitive improvement have not yet been fully determined. We and others have found that acute nicotinic antagonist treatment can improve learning and attention. Nicotine acts on a variety of nicotinic receptor subtypes. The relative role and interactions of neuronal nicotinic receptor subtypes for cognition also needs to be better characterized. Nicotine acts on nicotinic receptors in a wide variety of brain areas. The role of some of these areas such as the hippocampus has been relatively well studied but other areas like the thalamus, which has the densest nicotinic receptor concentration are still only partially characterized. In a series of studies we characterized nicotinic receptor actions, anatomic localization and circuit interactions, which are critical to nicotine effects on the cognitive functions of learning, memory and attention. The relative role of increases and decreases in nicotinic receptor activation by nicotine were determined in regionally specific studies of the hippocampus, the amygdala, the frontal cortex and the mediodorsal thalamic nucleus with local infusions of antagonists of nicotinic receptor subtypes (alpha7 and alpha4beta2). The understanding of the functional neural bases of cognitive function is fundamental to the more effective development of nicotinic drugs for treating cognitive dysfunction. PMID- 23928192 TI - Antiproliferative and apoptosis inducing activity of Markhamia tomentosa leaf extract on HeLa cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Markhamia tomentosa (Benth) K. Schum ex. Engl. (Bignoniaceae), a tree widely dispersed in West Tropical Africa, is used traditionally to treat various diseases as it possesses antimicrobial, antioxidant, analgesic, anticancer and anti-inflammatory activities. MATERIALS AND METHODS: This study evaluates the cytotoxic effect and underlying mechanisms of the ethanolic extract of Markhamia tomentosa on HeLa and MCF-7 cancer cell lines and non-cancerous Vero cell line. Brine shrimp lethality test was used for preliminary screening. Cytotoxicity was determined using the MTT assay and IC50 was calculated. Effect of Markhamia tomentosa on the cell cycle was monitored by flow cytometry and the apoptosis-induction capability confirmed by exposure of phosphatidylserine to the outer leaflet of the plasma membrane. Loss of mitochondrial membrane potential was analysed by flow cytometry using JC-1. RESULTS: Markhamia tomentosa was toxic to brine shrimps with LD50 of 31.62ug/ml. Cell viability and growth of HeLa cells was inhibited by the extract with an IC50 of 189.1+/-1.76ug/ml at 24h post treatment. However, no cytotoxic effect was observed in MCF-7 and Vero cell lines. The extract induced cell cycle arrest in HeLa cells in the G0/G1 phase resulting in cell death after 24h exposure. Induction of apoptosis in HeLa cells was substantiated by Annexin V-FITC/PI double staining showing phosphatidylserine translocation and depolarisation of the mitochondrial membrane potential by flow cytometry of JC-1 stained cells. CONCLUSION: The ethanolic extract of Markhamia tomentosa induces G0/G1 in HeLa cells followed by induction of the intrinsic pathway of apoptosis. PMID- 23928193 TI - Rhythmic ictal nonclonic hand (RINCH) motions in temporal lobe epilepsy: invasive EEG findings, incidence, and lateralizing value. AB - The main purpose of this retrospective analysis was to evaluate the incidence and lateralization value of rhythmic ictal nonclonic hand (RINCH) motions in patients with temporal lobe epilepsy (TLE), who were classified as Engel I at least 2 years after epilepsy surgery. We analyzed the distribution of ictal activity at the time of RINCH appearance in patients in whom RINCH motions were present during invasive EEG monitoring. A group of 120 patients was included in this study. In total, we reviewed 491 seizures: 277 seizures in patients with temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (TLE-HS group) and 214 in TLE caused by other lesions (TLE-OTH group). We analyzed 29 patients (79 of the seizures) during invasive EEG monitoring. Fisher's exact test and binomial test were used for the statistical analysis. RINCH motions were observed in 24 out of 120 patients (20%) and in 48 out of 491 seizures (9.8%). There was no significant difference between the occurrence of RINCH motions in patients with TLE-HS and in patients with TLE-OTH, or between gender, right/left-sided TLE, and language dominant/nondominant TLE. RINCH motions were contralateral to the seizure onset in 83.3% of patients and 91.7% of seizures (p=0.0015; p<0.001, respectively). There were no differences in the lateralizing value of RINCH motions in patients with TLE-HS or TLE-OTH. We analyzed RINCH motions in 5 patients/7 seizures during invasive EEG. In all 7 seizures with RINCH motions, we observed the widespread activation of the temporal lobe (mesial and lateral, opercular and polar regions) contralateral to the side of RINCH motions. In all 7 seizures, we observed that at the time of RINCH motion onset, at least 1 explored region of the frontal lobe was affected by the ictal activity. In 3 seizures, we observed time-locked epileptic activation associated with the appearance of RINCH motions, i.e., in the orbitofrontal cortex in 2 seizures and in both the orbitofrontal cortex and anterior cingulate gyrus in 1 seizure. RINCH motions are a relatively frequent ictal sign in patients with TLE. They have a high lateralizing value in these patients, occurring contralateral to the ictal onset. RINCH motions usually occur after the spread of ictal activity beyond the temporal lobe, and their appearance is usually associated with the presence of ictal activity in various regions of the contralateral frontal lobe, mainly the orbitofrontal cortex and anterior cingulate gyrus. This is the first study analysing this phenomenon during invasive EEG recording. PMID- 23928194 TI - Brain proton magnetic resonance spectroscopy: introduction and overview. AB - Magnetic resonance (MR) spectroscopy offers a noninvasive means of assessing in vivo brain metabolites that shed light on cellular concentrations, cell function and dysfunction, cellular energetics, presence of ischemia, and presence of necrosis, among others. Studies obtained at higher field strengths are evolving toward sampling of smaller tissue volumes, greater signal-to-noise ratio, and higher metabolic spatial resolution. This article discusses the usefulness, from the clinical standpoint, of MR spectroscopy in various disorders. However, to be valid and significant the results of MR spectroscopy should always be correlated with their imaging counterparts. PMID- 23928197 TI - The use of magnetic resonance spectroscopy in the evaluation of epilepsy. AB - Magnetic resonance spectroscopy (MRS) is indicated in the imaging protocol of the patient with epilepsy to screen for metabolic derangements such as inborn errors of metabolism and to characterize masses that may be equivocal on conventional magnetic resonance imaging for dysplasia versus neoplasia. Single-voxel MRS with echo time of 35 milliseconds may be used for this purpose as a quick screening tool in the epilepsy imaging protocol. MRS is useful in the evaluation of both focal and generalized epilepsy. PMID- 23928195 TI - Proton magnetic resonance spectroscopy: technique for the neuroradiologist. AB - Magnetic resonance spectroscopy (MRS) provides information on neuronal and axonal viability, energetics of cellular structures, and status of cellular membranes. Proton MRS appeals to clinicians and scientists because its application in the clinical setting can increase the specificity of MR imaging. The objective of this article is to provide descriptive concepts of the technique and its application in vivo for a variety of patient populations. When appropriately incorporating MRS into the neuroradiologic evaluation, this technique produces relevant information to radiologists and clinicians for their understanding of adult and pediatric neurologically based disease processes. PMID- 23928198 TI - Magnetic resonance spectroscopy in metabolic disorders. AB - Magnetic resonance spectroscopy (MRS) is a powerful clinical tool for investigating the metabolic characteristics of neurologic diseases. Proton ((1)H) MRS is the most commonly used and widely available method. In this article, a brief introduction regarding technical issues of (1)H-MRS applied to the study of metabolic diseases is followed by a description of findings in some of the most common entities in this large, heterogeneous group of neurologic disorders. The aim was to provide a focused representation of the most common applications of (1)H-MRS to metabolic disorders in a routine clinical setting. PMID- 23928199 TI - Hypoxic-ischemic injuries: the role of magnetic resonance spectroscopy. AB - Hypoxic ischemic injuries are a very common clinical situation in the pediatric population. This article focuses on the metabolic signature of hypoxic ischemic injuries and metabolic indicators of prognosis. PMID- 23928196 TI - Magnetic resonance spectroscopy in common dementias. AB - Neurodegenerative dementias are characterized by elevated myoinositol and decreased N-acetylaspartate (NAA) levels. The increase in myoinositol seems to precede decreasing NAA levels in Alzheimer's diseases. NAA/myo-inositol ratio in the posterior cingulate gyri decreases with increasing burden of Alzheimer's disease pathologic conditions. Proton magnetic resonance spectroscopy ((1)H MRS) is sensitive to the pathophysiologic processes associated with the risk of dementia in patients with mild cognitive impairment. Although significant progress has been made in improving the acquisition and analysis techniques in (1)H MRS, translation of these technical developments to clinical practice have not been effective because of the lack of standardization for multisite applications and normative data and an insufficient understanding of the pathologic basis of (1)H MRS metabolite changes. PMID- 23928200 TI - 1H magnetic resonance spectroscopy in multiple sclerosis and related disorders. AB - Proton magnetic resonance spectroscopy ((1)H-MRS) is an unconventional technique that allows noninvasive characterization of metabolic abnormalities in the central nervous system. (1)H-MRS provides important insights into the chemical pathologic changes that occur in patients with multiple sclerosis (MS). In this review article we present the main brain and spinal cord (1)H-MRS features in MS, their diagnostic value in differentiating pseudotumoral demyelinating lesions from primary brain tumors, and their relationship with clinical variables. Last, some data related to the use of (1)H-MRS in therapeutic trials is presented. PMID- 23928201 TI - MR spectroscopy in brain infections. AB - Infection of the central nervous system can be life-threatening and hence requires early diagnostic support for its optimal management. Routine definitive laboratory diagnostic tests can be time-consuming and delay definitive therapy. Noninvasive imaging modalities have established themselves in the diagnosis of various neurologic diseases. In this article, a pragmatic review of the current role of magnetic resonance spectroscopy in the diagnosis and management of intracranial infections is addressed. PMID- 23928202 TI - Pediatric brain tumors. AB - Pediatric brain tumors are the most common solid tumor of childhood. This article focuses on the metabolic signature of common pediatric brain tumors using MR spectroscopic analyses. PMID- 23928203 TI - Adult brain tumors: clinical applications of magnetic resonance spectroscopy. AB - Proton magnetic resonance spectroscopy (H-MRS) may be helpful in suggesting tumor histology and tumor grade and may better define tumor extension and the ideal site for biopsy compared with conventional magnetic resonance (MR) imaging. A multifunctional approach with diffusion-weighted imaging, perfusion-weighted imaging, and permeability maps, along with H-MRS, may enhance the accuracy of the diagnosis and characterization of brain tumors and estimation of therapeutic response. Integration of advanced imaging techniques with conventional MR imaging and the clinical history help to improve the accuracy, sensitivity, and specificity in differentiating tumors and nonneoplastic lesions. PMID- 23928204 TI - Neuroimaging Clinics of North America. MR spectroscopy of the brain. Foreword. PMID- 23928205 TI - Neuroimaging Clinics of North America. MR spectroscopy of the brain. Preface. PMID- 23928206 TI - Body weight and mortality in type 2 diabetes: weighing up the evidence. PMID- 23928207 TI - Enlightening epilepsy. PMID- 23928208 TI - Microalgae for high-value compounds and biofuels production: a review with focus on cultivation under stress conditions. AB - Microalgal biomass as feedstock for biofuel production is an attracting alternative to terrestrial plant utilization for biofuels production. However, today the microalgal cultivation systems for energy production purposes seem not yet to be economically feasible. Microalgae, though cultivated under stress conditions, such as nutrient starvation, high salinity, high temperature etc. accumulate considerable amounts (up to 60-65% of dry weight) of lipids or carbohydrates along with several secondary metabolites. Especially some of the latter are valuable compounds with an enormous range of industrial applications. The simultaneous production of lipids or carbohydrates for biofuel production and of secondary metabolites in a biorefinery concept might allow the microalgal production to be economically feasible. This paper aims to provide a review on the available literature about the cultivation of microalgae for the accumulation of high-value compounds along with lipids or carbohydrates focusing on stress cultivation conditions. PMID- 23928209 TI - Fairness for all. PMID- 23928210 TI - Making existential meaning in transition to motherhood--a scoping review. AB - OBJECTIVE: to provide a thematic overview of the existing literature on existential meaning-making related to transition to motherhood among mothers of full term born babies in Western oriented countries and to discuss the themes from a existential psychology perspective. DESIGN: the review follows the approach of a scoping review. Systematic searches in the electronic databases PubMed, CINAHL and PsycINFO were combined with manual and electronic searches for related references. Studies published between 1990 and 2010 examining dimensions of existential meaning-making in transition to motherhood were selected. Eleven papers were included in the synthesis, all using qualitative interviews. The following data were extracted from each study: (a) author(s), year of publication, study location, (b) aims of the study, (c) participants, (d) research design, (e) data collection method, (f) outcome measures, and (g) results. MEASUREMENTS: the studies were synthesised in a thematisation on the basis of the existential psychotherapist and philosopher Emmy van Deurzen's concepts of four interwoven life dimensions, through which we experience, interpret, and act in the world: Umwelt, Mitwelt, Eigenwelt, and Uberwelt. KEY CONCLUSIONS: the findings in this review suggest that transition to motherhood is considered a pivotal and paradoxical life event. Through the lens of existential psychology it can be interpreted as an existentially changing event, reorganising values and what makes life worth living, and to some women also being interpreted as a spiritual experience. However, in present maternity services there is a predominant focus on biomedical issues, which sets the arena for motherhood transition, and the issues related to potentially existentially changing experiences, are not considered important. Without an integrative approach, where personal meaning-making issues are discussed, the potential for growth during existential authenticity is not utilised. Transition to motherhood raises existential questions about mortality and meaning of life, and we should explore this field in research and in clinical work. PMID- 23928211 TI - Professional attitudes towards normal childbirth in a shared care unit. AB - OBJECTIVE: to identify and compare obstetricians', midwives' and, assistant personnel's attitudes towards Clinical Practice Guidelines (CPG) for normal birth of The National Health System. DESIGN: quantitative methodology using a self completed questionnaire regarding the recommendations of the CPG for normal birth with two five-point Likert scales that measured the degree of agreement and the level of applicability. SETTING: a Labour Ward: Catalonia, Spain. PARTICIPANTS: a total sample of 96 professionals (obstetricians=32, midwives=44 and assistant personnel=20) answered the questionnaire. FINDINGS: midwives and obstetricians often have significantly divergent levels of agreement on key recommendations. Assistant personnel have more similar opinions to midwives', even though they are a more diverse group. Midwives are more in line with the recommendations of CPG for normal birth than obstetricians and assistant personnel. Concerning the applicability, obstetricians showed greater degree of applicability, followed by the other two groups. CONCLUSIONS: given that there is divergence in opinion on agreement and applicability between professional groups it is necessary to identify areas of accordance, disagreement or ambiguity of knowledge and practice among all care providers, so that midwives can facilitate normal childbirth in a shared-model unit. PMID- 23928212 TI - Validation of Chinese version of the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) in patients with schizophrenia spectrum disorders. AB - There is a lack of validated instruments assessing the decision-making capacity to consent to clinical research of patients with schizophrenia spectrum disorders who speak Chinese. This study aimed to determine the validity and reliability of the Chinese version of MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR). The MacCAT-CR using a hypothetical study, the Positive and Negative Syndrome Scale (PANSS), the Mini-Mental State Examination (MMSE) assessed 139 patients with schizophrenia or schizoaffective disorder. The Cronbach's alpha coefficient was 0.74. The intra-class coefficients for understanding, appreciation, and reasoning scores ranged from 0.53 to 0.81. Regarding validity, the understanding, appreciation and reasoning scores were negatively correlated with the PANSS (r ranged from -0.27 to -0.33), and the negative subscale score (r ranged from -0.31 to -0.37) as well as positively correlated with the MMSE (r ranged from 0.26 to 0.43). All pvalues were less than 0.01. The factor analysis explained 57.6 % of the total variance; specifically, Components 1 and 2 contributed 44.5% and 13.1 % of the variance respectively. These findings indicate that the Chinese version of the MacCAT-CR is a reliable and valid instrument to assess the decision-making capacity to consent to clinical research of patients with schizophrenia spectrum disorders. PMID- 23928213 TI - Anticipatory pleasure and approach motivation in schizophrenia-like negative symptoms. AB - Previous research of negative symptoms in schizophrenia has emphasized an anticipatory pleasure deficit, yet the relationship of this deficit to patients' motivation in everyday life is poorly understood. This study tested the link between anticipatory pleasure and two broad motivational systems that are said to regulate the intensity of approach and avoidance behavior, the Behavioral Inhibition system (BIS) and the Behavioral Activation System (BAS). It was hypothesized that high vulnerability for negative symptoms would be associated with low reward responsiveness and that this association will be mediated by the amount of anticipated pleasure. Students (n=171) with varying vulnerability for negative symptoms (assessed by the Community Assessment of Psychic Experiences) completed questionnaires regarding (a) anticipatory and consummatory pleasure, and (b) responsiveness to threat and reward. As hypothesized, anticipatory pleasure correlated significantly negatively with subclinical negative symptoms (r=-0.21) and significantly positively with BAS (r=0.55). Furthermore, evidence for a partial mediation effect was found. The findings support the notion of a close association between negative symptoms, the ability to anticipate pleasure and approach motivation that is evident even in healthy persons. It is suggested that the behavioral deficits immanent to negative symptoms reflect difficulties in the ability to translate emotions into motivation. PMID- 23928215 TI - Dengue virus capsid protein and very low density lipoproteins. PMID- 23928214 TI - Phospholipid-modified polyethylenimine-based nanopreparations for siRNA-mediated gene silencing: implications for transfection and the role of lipid components. AB - The clinical application of gene silencing mediated by small interfering RNA (siRNA) has been limited by the lack of efficient and safe carriers. Phospholipid modification of low molecular weight polyethylenimine (PEI 1.8 kDa) dramatically increased its gene down-regulation capacity while keeping cytotoxicity levels low. The silencing efficacy was highly dependent on the nature of the lipid grafted to PEI and the polymer/siRNA ratio employed. Phosphoethanolamine (DOPE and DPPE) and phosphocholine (PC) conjugation did not change the physicochemical properties and siRNA binding capacity of PEI complexes but had a large impact on their transfection and ability to down-regulate Green Fluorescent Protein (GFP) expression (60%, 30% and 5% decrease of GFP expression respectively). We found that the micelle-forming structure of DOPE and DPPE-PEI dramatically changed PEI's interaction with cell membranes and played a key role in promoting PEI 1.8 kDa transfection, completely ineffective in the absence of the lipid modification. FROM THE CLINICAL EDITOR: While siRNA-based gene silencing methods could have numerous clinical applications, efficient delivery remains a major challenge. This team reports that DOPE-PEI and DPPE-PEI based micelle-forming nanostructures may be able to provide an efficient vector for siRNA transfection. PMID- 23928216 TI - High efficacy gold-KDEL peptide-siRNA nanoconstruct-mediated transfection in C2C12 myoblasts and myotubes. AB - Gold nanoparticles (AuNP) were conjugated with cysteine terminated KDEL (Lys-Asp Glu-Leu) peptide and siRNA directed against NADPH Oxidase 4 (Nox4). Fluorescence microscopy analysis provided evidence of cytocellular retrograde transport pathways and sub-cellular colocalization of AuNP nanoconstructs in both undifferentiated C2C12 myoblasts and differentiated C2C12 myotubes. The cellular trafficking of AuNP nanoconstructs in undifferentiated myoblasts suggests stable and efficient transfection of siRNA as demonstrated by colocalization of AuNP delivered KDEL and siRNA. The cellular uptake of AuNP nanoconstructs was more efficient than Lipofectamine mediated transfection in differentiated myotubes (P<0.05) compared to undifferentiated myoblasts, suggesting that AuNP nanoconstructs provide an efficient platform for siRNA delivery to differentiated myotubes. The localization of these nanoconstructs in undifferentiated myoblasts suggests that most of the siRNA was localized in the endoplasmic reticulum (ER) with a minimal distribution in the Golgi bodies suggesting that the ER is a primary localization site for AuNP-KDEL mediated delivery of nanoconstructs. FROM THE CLINICAL EDITOR: This team of investigators demonstrate that a delivery system composed of gold nanoparticle and KDEL based siRNA is superior to lipofectamine in delivering siRNA in differentiated myoblasts, paving the way to gene silencing methods in these cells for future therapeutic exploitation. PMID- 23928217 TI - Co-expression pattern of dopamine beta-hydroxylase (DbetaH) and neuropeptide Y (NPY) within sympathetic innervation of ovary and umbilical cord of the European bison (Bison bonasus L.). AB - Co-expression of dopamine beta-hydroxylase (DbetaH) and neuropeptide Y (NPY) has never been examined in ovary (OV) and umbilical cord (UC) of the European bison (Eb), the endangered wild species. The OV and UC samples were harvested from seasonally eliminated Eb females (45-120 days post coitum). Frozen histological sections were examined by double fluorescent immunohistochemistry (dF-IHC), using the primary mouse anti-DbetaH monoclonals and rabbit anti-NPY polyclonals and then the immunocomplexes were visualized with FITC and CY3 fluorophores, respectively. Numerous DbetaH immunoreactive nerve fibers (DbetaH-IRs) and a little less frequent NPY-IRs were found in the bundle-like structures, innervating mainly perivascular regions of the OV. The NPY-IRs constantly co expressed DbetaH, while some DbetaH-IRs did not express NPY. This specific pattern of innervation was observed both in the stromal and cortical regions of the OV. The simultaneous co-expression of DbetaH and NPY were also detected in the UC, in which specific single or bundle-like structures ran along the smooth muscles of blood vessels. The spatial-specific co-expression of DbetaH and NPY in OV and UC, may suggest that these markers are involved in the control of vascularization that regulates nourishing blood circulation required for proper pregnancy maintenance and efficient embryo/fetus development in the Eb. PMID- 23928218 TI - An immunohistochemical study of somatostatin in the stomach and the small intestine of the African ostrich (Struthio camelus). AB - The aim of the present study was to clarify the distribution and relative frequencies of somatostatin (SST)-producing cells in the stomach and the small intestine of the ostrich by using immunohistochemistry. The results indicated that somatostatin-immunoreactive (SST-IR) cells were distributed in mucosal layers of the proventriculus, duodenum, jejunum and ileum. However, no immunoreactivity was observed in the gizzard. SST-IR cells were found at the lower part of glandular lobule in the proventriculus, which were oval and round generally. SST-IR cells were present in the mucous membrane of entire small intestine of the ostrich. SST-IR cells had round and spherical shapes (closed type cells), or spindle and pyriform shapes (open-type cells) in the small intestine. SST-positive cells were localized preferentially in the proventriculus of the 60-day-old ostrich. These results indicated that SST might be involved in functional and developmental regulation of gastrointestinal tract of the ostrich. PMID- 23928219 TI - Investigation of telomere length dynamics in induced pluripotent stem cells using quantitative fluorescence in situ hybridization. AB - Here we attempted to clarify telomere metabolism in parental cells and their derived clonal human induced pluripotent stem cells (iPSCs) at different passages using quantitative fluorescence in situ hybridization (Q-FISH). Our methodology involved estimation of the individual telomere lengths of chromosomal arms in individual cells within each clone in relation to telomere fluorescence units (TFUs) determined by Q-FISH. TFUs were very variable within the same metaphase spread and within the same cell. TFUs of the established iPSCs derived from human amnion (hAM933 iPSCs), expressed as mean values of the median TFUs of 20 karyotypes, were significantly longer than those of the parental cells, although the telomere extension rates varied quite significantly among the clones. Twenty metaphase spreads from hAM933 iPSCs demonstrated no chromosomal instability. The iPSCs established from fetal lung fibroblasts (MRC-5) did not exhibit telomere shortening and chromosomal instability as the number of passages increased. However, the telomeres of other iPSCs derived from MRC-5 became shorter as the number of passages increased, and one (5%) of 20 metaphase spreads showed chromosomal abnormalities including X trisomy at an early stage and all 20 showed abnormalities including X and 12 trisomies at the late stage. PMID- 23928220 TI - A novel insight on chronic AlCl3 neurotoxicity through IL-6 and GFAP expressions: modulating effect of functional food fenugreek seeds. AB - OBJECTIVE: This study was designed to review the effect of chronic aluminium exposure on interleukin-6 (IL-6) secretion in the posterior brain and test the putative modulating effect of fenugreek seeds. METHODS: Female Wistar rats were divided into four groups: control; AlCl3 during 5 months (500 mg/kg body weight, intragastric for 1 month then 1600 ppm via the drinking water); AlCl3 plus fenugreek seed powder (FSP) (5%) during the last 2 months and FSP alone. RESULTS: Oral administration of aluminium chloride during 5 months caused hypoproduction of IL-6 together with a decrease in GFAP reactivity and an alteration of antioxidant status in the posterior brain. On the other hand, fenugreek seeds supplementation was able to enhance IL-6 expression, re-increase GFAP reactivity, and modulate the pro-oxidant-related effect. DISCUSSION: In the context of recent researches, IL-6 hypoproduction in the posterior brain could be a novel mechanism of Al chronic toxicity with a direct effect on glial cells. Using FSP as a diet supplement could offer a neuroprotective effect against Al toxicity. This could be mediated by astroglial cells protection, antioxidant and immunomodulatory actions. PMID- 23928221 TI - Serotonin and dopamine in the hypothalamus of control and malnourished mother rats during pregnancy and lactation and body composition of their offspring. AB - OBJECTIVE: To determine concentrations of serotonin and dopamine in the hypothalamus of undernourished rats and controls during pregnancy and lactation and body composition of their offspring. METHODS: Malnourished rats along with control rats were used during pregnancy and lactation. At birth of their offspring, control mothers nursed their young and malnourished rats and the undernourished mothers nursed their offspring and control pups. On days 5, 10, 15, and 21 of lactation (at the beginning and end of a feeding), L-tryptophan (L Trp)-free, bound and total, plasma prolactin (PRL) and milk composition were determined. Serotonin and dopamine were measured in the hypothalamus. Body composition of offspring was determined. RESULTS: Increase of free L-Trp was confirmed in undernourished mothers. Furthermore, hypothalamic serotonin was elevated at the start of suckling and decreased at termination. There was also a decrease in dopamine in the hypothalamus at the beginning and end of suckling followed by an increase of plasma PRL that was greater in control mothers who breastfed malnourished offspring. Interestingly, undernourished offspring consumed more milk and showed a clear recovery of body composition with accumulation of body fat. DISCUSSION: Changes observed in hypothalamic neurotransmitters appear to be closely related to nutritional status and to the response and control of PRL production, possibly to adapt the offspring to the metabolic changes. It was also confirmed that on-demand feeding of undernourished offspring is the main factor involved in nutritional recovery and a predisposition to overweight in the recovered undernourished animals. PMID- 23928222 TI - Improved rolling circle amplification (RCA) of hepatitis B virus (HBV) relaxed circular serum DNA (RC-DNA). AB - For functional analysis of HBV isolates, epidemiological studies and correct identification of recombinant genomes, the amplification of complete genomes is necessary. A method for completely in vitro amplification of full-length HBV genomes starting from serum RC-DNA is described. This uses in vitro completion/ligation of plus-strand HBV RC-DNA and amplification using Rolling Circle Amplification, eventually followed by a genomic PCR. The method can amplify complete HBV genomes from sera with viral loads ranging from >1.0E+8 IU/ml down to 1.0E+3 IU/ml. The method can be applied to archived sera that have undergone long-term storage or to archived DNA serum extracts. The genomes can easily be cloned. HBV genotypes A-G can all be amplified with no apparent problems. A recombinant subgenotype A3/genotype E genome was identified and fully sequenced. PMID- 23928223 TI - Development of a peptide ELISA for discrimination between serological responses to equine herpesvirus type 1 and 4. AB - A peptide-based enzyme-linked immunosorbent assay (ELISA) for discrimination between serological responses to equine herpesvirus type 1 (EHV-1) and 4 (EHV-4) was developed. Three and four peptides for EHV-1 and EHV-4, respectively, were designed and studied initially in the ELISA using sera from foals infected experimentally. The most promising peptide pair, derived from EHV-1 glycoprotein E and EHV-4 glycoprotein G, was evaluated further using acute and convalescent sera from horses infected experimentally and naturally as well as a panel of horse field sera. Ten pre- and post-vaccination serum pairs were similarly tested in the type-specific ELISA. The peptide ELISA was able to identify horses which had been infected with EHV-1 or EHV-4 as derived from the results using acute and convalescent sera collected from natural outbreaks. When applied to a set of field samples, the assay proved robust with respect to determining the EHV-1 and EHV-4 antibody status. Also, the peptide ELISA was able to detect type-specific seroconversion for EHV-1 in vaccinated animals. With further validation, the EHV 1/EHV-4 peptide ELISA described in this study could serve as a reliable and cost effective alternative to current methods for serological EHV-1 and EHV-4 diagnosis. PMID- 23928224 TI - In vitro lymphocyte stimulation by recombinant hepatitis B surface antigen: a tool to detect the persistence of cellular immunity after vaccination. AB - The study of the human immune response to hepatitis B virus (HBV) has been hampered by the lack of an adequate model to evaluate the hepatitis B surface antigen (HBsAg) specific cell response. Thus, this study was conducted to perform an in vitro analysis of the antigenic properties of recombinant HBsAg and demonstrate the influence of variables such as culture time, antigen concentration and cell density on lymphocyte proliferation. Peripheral blood mononuclear cells (PBMCs) were isolated from the venous blood of vaccinated individuals, and in vitro cellular immune responses were evaluated using an HBsAg specific proliferation assay. Lymphoproliferative responses were detected in culture systems, despite the lack of serum antibodies. Optimal results were obtained when lymphocytes were stimulated at a seeding density of 4*10(6) cells/mL, with 50 ng/mL of recombinant HBsAg protein vaccine for 3 days. Data from the present study may contribute to the development of an adequate system to evaluate the cellular immune responses to HBsAg in vaccine recipients. PMID- 23928225 TI - Optimization of fixed-permeabilized cell monolayers for high throughput micro neutralizing antibody assays: application to the zebrafish/viral hemorrhagic septicemia virus (vhsv) model. AB - A new high throughput centrifugation-free method to estimate viral neutralizing antibody levels in low volumes and large numbers of plasma blood samples is described. Cell monolayers were, (i) plated on poly-d-Lys coated 96-wells, (ii) infected with viruses previously incubated with fish plasma containing antibodies, (iii) fixed with formaldehyde to increase cell recovery and avoid centrifugation steps, (iv) permeabilized with Saponin, (v) immunostained in the presence of Saponin by using a monoclonal antibody (MAb) to viral protein, (vi) digested with trypsin to detach cells from the monolayer, in the absence of Saponin to reduce damage of intracellular MAb-antigen complexes, and (vii) gated by flow cytometry using automatic 96-well batch analysis. The method was applied to the determination of plasma neutralizing antibodies from zebrafish (Danio rerio) surviving infections with viral hemorrhagic septicemia virus (VHSV) (an important rhabdovirus of salmonids). This semi-automatic, rapid and practical assay detected anti-VHSV neutralizing antibodies in the plasma (~3 MUl per fish) of 95.1% of the zebrafish surviving VHSV infections. The fixed-permeabilized monolayer (FIXPERM) micro-neutralization method might help to analyze sera/plasma from small fish under standarized high throughput conditions. PMID- 23928226 TI - Genetically engineered bone marrow mesenchymal stem cells improve functional outcome in a rat model of epilepsy. AB - Bone marrow mesenchymal stem cells (BMSCs) hold a great promising approach for the treatment of epilepsy owing to their distinctive characteristics and multi potency. However, there is little research focusing on the multi-potency of BMSCs in the treatment of epilepsy, the present study was designed to examine the influence of genetically engineered BMSCs (GE-BMSCs) on the functional outcome in a rat model of epilepsy. First, Hes1 gene of BMSCs was genetically engineered by RNA interference (RNAi), and then the GABAergic differentiation of GE-BMSCs was tested in vitro. Second, the lithium chloride-pilocarpine induced epileptic rats were administrated with the GE-BMSCs, the behavioral observation and electroencephalography (EEG) monitoring was employed to analyze the functional outcome on the epileptic model at different time points (day 7, day 14, day 21 and day 28), followed by histological verification. In vitro test showed that Hes1 silencing could promote BMSCs to differentiate into GABAergic neuron-like cells. In vivo test showed that GE-BMSCs graft could further improve the functional recovery of the epileptic rats, and the GABAergic differentiation of grafted GE-BMSCs was correlated with the functional recovery. Taken together, these data suggest that GE-BMSCs can improve the functional outcome in a rat model of epilepsy. PMID- 23928227 TI - Investigation of six novel susceptibility loci for male androgenetic alopecia in women with female pattern hair loss. PMID- 23928228 TI - Pregnancy in postpartum estrus induces inflammatory milk production and catagen specific pup skin inflammation in interleukin-10 deficient mice. AB - BACKGROUND: The interleukin 10 deficient mice (IL-10(-/-)) showed high incidence of pup alopecia compared to other strains, and pup alopecia was caused by skin inflammation and was recoverable. Pup alopecia of B6.IL-10(-/-) might be related with maternal factor and interleukin-10 deficient phenotype. OBJECTIVE: The objectives of this study were elucidating of maternal factors for inflammatory milk production and characterization of pup alopecia in IL-10(-/-) mice. METHODS: Incidences of pup alopecia were analyzed with 13 breeding cases. Comparison between control and alopecia pups and its dams, were conducted with histological examination (H&E, TUNEL assay, immunohistochemistry for F4/80, iNOS, CD206, Gr-1, CD4, CD8, CD11c and CD326), fostering test, forced weaning test, qPCR for tyrosine hydroxylase, flow cytometry, IL-10 inhibition test, BMDM stimulation test and LC/MS analysis. RESULTS: Presence of pregnancy in postpartum estrus showed significant correlation with inflammatory milk production and mammary gland involution in B6.IL-10(-/-) mice. There were no different mass in inflammatory milk, but different ionization intensity was detected. Inflammatory milk directly induced hepatocyte steatosis, catagen stage specific hair breaking and alopeicia in pups. Histologically, hypertropy of outer root sheath and macrophage/neutrophil infiltration were typical. CONCLUSION: B6.IL-10(-/-) dam with stress such as PPE could produce untimely mammary gland involution and inflammatory milk production. Interleukin 10 is important for maternal stress regulation and protecting inflammatory milk production, also influence severity of pup skin inflammation and alopecia. Remarkably, inflammatory milk induced hepatocyte steatosis, and it could indicate there is abnormal lipid metabolism. This was first report for catagen specific alopecia in mouse. PMID- 23928229 TI - Epithelial to mesenchymal transition markers are associated with an increased metastatic risk in primary cutaneous squamous cell carcinomas but are attenuated in lymph node metastases. AB - BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in humans and approximately 5% metastasize, usually to regional lymph nodes. Epithelial to mesenchymal transition (EMT) is a process involving loss of intercellular adhesion, acquisition of a mesenchymal phenotype and enhanced migratory potential; epithelial markers, such as E-cadherin, are down-regulated and mesenchymal proteins (Vimentin), increased. OBJECTIVE: To investigate the expression of EMT markers in metastatic SCC (MSCC) and their corresponding metastases, and to correlate them with clinico-pathological factors associated with an increased risk of metastasis. METHODS: We performed a retrospective study that included 146 cSCC samples (51 primary non-metastatic, 56 primary metastatic, 39 lymphatic metastases). Immunohistochemistry for E-cadherin, Vimentin, Snail, beta-catenin, Twist, Zeb1 and Podoplanin was performed. RESULTS: Loss of membranous E-cadherin was observed in 77% cSCCs, with no differences between MSCC and non-MSCC. Among the transcriptional factors controlling EMT, no significant Snail1 expression was detected. Twist, Zeb1, Vimentin, beta-catenin and Podoplanin were significantly overexpressed in MSCCs. Twist ectopic expression in SCC13 cells induced Zeb1, Vimentin and Podoplanin expression and E-cadherin delocalization. These changes resulted in a scattered migration pattern in vitro. Expression of EMT markers was decreased in the metastases when compared with the corresponding primary tumors. CONCLUSION: These results suggest that a partial EMT, characterized by the expression of Twist but without a total E-cadherin depletion, is involved in the acquisition of invasive traits by cSCC, but the process is downregulated in lymph node metastases. PMID- 23928230 TI - Occupational trichloroethylene hypersensitivity syndrome: human herpesvirus 6 reactivation and rash phenotypes. AB - BACKGROUND: Trichloroethylene (TCE) is an industrial solvent which can cause severe generalized dermatitis, i.e., occupational TCE hypersensitivity syndrome. Reactivation of latent human herpesvirus 6 (HHV6) can occur in such patients, which has made TCE known as a causative chemical of drug-induced hypersensitivity syndrome (DIHS). OBJECTIVE: This study aimed to clarify HHV6 status, cytokine profiles and their association with rash phenotypes in patients with TCE hypersensitivity syndrome. METHODS: HHV6 DNA copy numbers, anti-HHV6 antibody titers, and cytokines were measured in blood prospectively sampled 5-7 times from 28 hospitalized patients with the disease. RESULTS: The patients (19 had exfoliative dermatitis (ED) and 9 had non-ED type rash) generally met the diagnostic criteria for DIHS. Viral reactivation defined as increases in either HHV6 DNA (>=100 genomic copies/10(6) peripheral blood mononuclear cells) or antibody titers was identified in 24 (89%) patients. HHV6 DNA, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-5, IL-6 and IL-10 concentrations were remarkably higher in the patients than in the healthy workers (p<0.01). Positive correlations between HHV6 DNA, TNF-alpha, IFN-gamma, IL-6 and IL-10 were significant (p<0.05) except for that between HHV6 DNA and IFN-gamma. An increase in HHV6 DNA was positively associated with an increase in TNF-alpha on admission (p<0.01). HHV6 DNA, the antibody titers, TNF-alpha and IL-10 concentrations were significantly higher in ED than in the non-ED type (p<0.05). CONCLUSION: Reactivated HHV6 and the increased cytokines could be biomarkers of TCE hypersensitivity syndrome. The higher-level reactivation and stronger humoral responses were associated with ED-type rash. PMID- 23928231 TI - Prospective comparative evaluation of quantitative-elastosonography (Q elastography) and contrast-enhanced ultrasound for the evaluation of thyroid nodules: preliminary experience. AB - PURPOSE: To assess the effectiveness of semiquantitative elastosonography (Q elastography) compared with contrast-enhanced ultrasound (CEUS) in differentiating the nature of thyroid nodules. METHODS AND MATERIALS: Forty-eight consecutive patients (35 males, 13 females, range: 34-69 years, mean: 49.4 years), candidate to surgery, previously detected at color-Doppler ultrasound (CDUS), were prospectively examined with elastosonography with dedicated semiquantitative software (Q-Elastography, Toshiba XG) and CEUS (Technos Mylab 70 Gold X, and Toshiba XG) before surgery. CEUS and elastosonography were evaluated by two investigators in consensus. Comparison between the CEUS pattern and elastonographic strain ratio observed and expected frequencies for the diagnoses was evaluated with chi(2) test or with Fisher exact test. RESULTS: Fifty-three nodules (19 papillary carcinoma, 32 hyperplasia, and 2 follicular adenoma) in 48 patients were available for analysis. Regarding echogenicity score, sensitivity, specificity, PPV and NPV of conventional US were 81%, 50%, 56%, 77%; according to Q-elastography, sensitivity, specificity, PPV and NPV were 95%, 88%, 97% and 91% respectively; whereas concerning CEUS, sensitivity specificity PPV and NPV were 79%, 91%, 83% and 89% respectively. Both CEUS and Q-elastography were more specific than US (p<0.01), with not statistical significant difference with regard to sensitivity. CONCLUSIONS: The results of the present study suggest that Q-elastography is a valuable tool in the characterization of thyroid nodules and it seems to be more sensitive than CEUS. PMID- 23928232 TI - Effect of radiation dose and iterative reconstruction on lung lesion conspicuity at MDCT: does one size fit all? AB - OBJECTIVE: To evaluate the effect of different acquisition parameters and reconstruction algorithms in lung lesions conspicuity in chest MDCT. METHODS: An anthropomorphic chest phantom containing 6 models of lung disease (ground glass opacity, bronchial polyp, solid nodule, ground glass nodule, emphysema and tree in-bud) was scanned using 80, 100 and 120 kVp, with fixed mAs ranging from 10 to 110. The scans were reconstructed using filtered back projection (FBP) and iterative reconstruction (IR) algorithms. Three blinded thoracic radiologists reviewed the images and scored lesions conspicuity and overall image quality. Image noise and radiation dose parameters were recorded. RESULTS: All acquisitions with 120 kVp received a score of 3 (acceptable) or higher for overall image quality. There was no significant difference between IR and FBP within each setting for overall image quality (p>0.05), even though image noise was significantly lower using IR (p<0.0001). When comparing specific lower radiation acquisition parameters 100 kVp/10 mAs [Effective Dose (ED): 0.238 mSv] vs 120 kVp/10 mAs (ED: 0.406 mSv) vs 80 kVp/40 mAs (ED: 0.434 mSv), we observed significant difference in lesions conspicuity (p<0.02), as well as significant difference in overall image quality, independent of the reconstruction algorithm (p<0.02), with higher scores on the 120 kV/10 mAs setting. Tree-in-bud pattern, ground glass nodule and ground glass opacity required lower radiation doses to get a diagnostic score using IR when compared to FBP. CONCLUSION: Designing protocols for specific lung pathologies using lower dose acquisition parameters is feasible, and by applying iterative reconstruction, radiologists may have better diagnostic confidence to evaluate some lesions in very low dose settings, preserving acceptable image quality. PMID- 23928233 TI - Time resolved imaging of contrast kinetics (TRICKS) MR angiography of arteriovenous malformations of head and neck. AB - PURPOSE: To evaluate vasculature of arteriovenous malformations (AVMs) of head and neck with time resolved imaging of contrast kinetics (TRICKS) MR angiography (MRA). MATERIAL AND METHODS: Prospective study was conducted upon 19 patients (age range, 12-29 years; mean age 18 years; 10 males and 9 females) with AVM of head and neck. TRICKS-MRA of head and neck was performed during injection of contrast medium. Post processing with reconstruction of the images was done. Two independent readers assessed the overall TRICKS-MRA image quality score using a 5 point scale and depiction of the main arterial feeders, nidus, and venous drainage using 3 points scale. The Kappa test for interobserver agreement was done. The AVMs were evaluated morphologically in terms of number and origin of the main arterial feeders, the location and size of nidus either small (>2 cm) or large (>2 cm) and the draining veins into the superficial or deep venous drainage. RESULTS: The average TRICKS-MRA image quality score as judged by reader 1 was 3.89 +/- 1.15 and that as judged by reader 2 was 3.89 +/- 0.10, which yielded excellent interobserver agreement (k=0.77, 95% CI=0.53-0.98, r=0.78, P=0.001). The interobserver agreement of both readers was excellent for the arterial feeders (k=0.81, 95% CI=0.57-1.00, r=0.83, P=0.001), excellent for the nidus (k=0.91, 95% CI=0.75-1.00, r=0.92, P=0.001), and good for the venous drainage (k=0.77, 95% CI=0.53-0.98, r=0.78, P=0.001). The arterial feeders were single (n=14) or multiple (n=5), the nidus was large (n=16) or small (n=3) and the venous drainage was into the internal jugular (n=17) or the external jugular (n=2) veins. Three patients with small nidus and single arterial feeder were treated with sclerotherapy. Eleven patients with large nidus and single arterial feeder were referred for embolization. Combined embolization and surgery were done for five patients with large nidus and multiple arterial feeders. CONCLUSION: We concluded that TRICKS-MRA is a reliable non invasive tool for evaluation of the feeding arteries, the nidus and the draining veins of AVMs of head and neck. TRICKS-MRA can be used for evaluation and treatment planning of AVMs of head and neck. PMID- 23928234 TI - Three-dimensional reconstructions for asymptomatic and cerebral palsy children's lower limbs using a biplanar X-ray system: a feasibility study. AB - The aim of this study is to explore the feasibility of 3D subject-specific skeletal reconstructions of lower limb in children using stereoradiography, and to assess uncertainty of clinical and anatomical parameters for children with cerebral palsy and for healthy children. The stereoradiography technique, using the EOS((r)) system (Eos-imaging((r))), is based on the acquisition of two simultaneous digital anteroposterior and lateral X-rays, from head to feet in standing position and at low radiation dose. This technique allows subject specific skeletal 3D reconstructions. Five children with cerebral palsy (CP) and 5 typically developing children (TD) were included in the study. Two operators performed the lower limb reconstructions twice. Tridimensional reconstructions were feasible for children over the age of 5 years. The study of reproducibility of anatomical parameters defining skeletal alignment showed uncertainties under 3 degrees for the neck shaft angle, the femoral mechanical angle, and for the femoral and tibial torsions. The maximum degree of uncertainty was obtained for the femoral tibial rotation (4 degrees for healthy children and 3.5 degrees for children with CP). PMID- 23928235 TI - COL2A1 mutation as a cause of premature osteoarthritis in a 13-year-old child. AB - Diagnostic assessment of osteoarthritis in children and adolescents is difficult. Here, we report the sixth family with a COL2A1 mutation R275C. The index patient, her mother and her three brothers had severe coxarthrosis, in some cases requiring surgery. Only the mother was hard of hearing, and only her children had brachydactyly of the fourth digit. The index patient suffered a femoral neck fracture after minor trauma at a time when osteoarthritis was not yet radiologically detectable. Hip fracture or osteoarthritis of unclear origin in childhood should prompt genetic work-up for the purposes of correct classification and genetic counseling. PMID- 23928236 TI - The learning curve of nurses for the assessment of swollen and tender joints in rheumatoid arthritis. AB - OBJECTIVES: In rheumatoid arthritis (RA), nurses are now increasingly involved in joint count assessment but training is not standardized. The aim was to evaluate and describe the learning curve of nurses for the assessment of swollen and tender joints in RA. METHOD: Twenty nurses from university rheumatology centres inexperienced with joint counts were allocated to a rheumatologist from their centre (teacher). Acquisition of skills consisted of Phase 1: (training), a centralized 4hour training session, with (a) lecture and demonstration, and (b) practical sessions on patients with their teachers, followed by Phase 2: (practice) involving further practice on 20 patients in their own hospitals. Primary outcome was achievement of adequate swollen joint agreement between nurse and their teacher ("gold standard") at the "joint" level defined by prevalence adjusted biased adjusted kappa (PABAK)>0.60. Agreement at the "patient" level of swollen joint count (SJC), tender joint count (TJC) as well as DAS28 between nurse and their teacher were assessed with intra-class correlation coefficients (ICC). RESULTS: During the training phase, 75% of nurses achieved a swollen joint PABAK>0.60 when compared with their teachers, which further improved to 89% after the 20 practice patients (Phase 2). Median swollen joint PABAK improved from 0.64 (Q1:Q3 0.55,0.86) to 0.83 (Q1:Q3 0.77,1) by the end of Phase 2. At the "patient" level, SJC agreement remained globally stable (ICC, 0.52 to 0.66), while TJC and DAS28 agreement remained excellent throughout. CONCLUSION: Nurses inexperienced in joint counts were able to achieve excellent agreement with their teachers in assessment of tender and swollen joints through a short training session; practice further enhanced this agreement. Larger longitudinal studies are required to assess skills retention. PMID- 23928237 TI - Myositis in a patient with familial Mediterranean fever and spondyloarthritis successfully treated with anakinra. AB - Familial Mediterranean fever is an autosomal-recessive autoinflammatory disorder more commonly observed in Mediterranean populations and characterized by recurrent episodes of fever, serositis, myalgia and arthritis. There is rarely any association with spondyloarthritis. The most important long-term complication is progressive systemic type AA amyloidosis. Treatment with colchicine is effective in reducing the frequency of attacks and prevents the development of amyloidosis. However, 5% of cases are considered resistant to colchicine. We here describe the case of a 39-year-old man, with a history of arthritis, arthralgias, and sacroiliitis in the course of a familial Mediterranean fever. He is homozygous for the M694I mutation in the MEFV gene. He subsequently developed myositis of the right quadriceps muscle confirmed by magnetic resonance imaging, electromyography and histology. He had frequent and severe arthralgias, despite colchicine, then etanercept and adalimumab, impairing his quality of life. The patient was successfully treated with the IL-1 receptor antagonist anakinra with a dramatic improvement of muscular and articular symptoms. To our knowledge, our patient is the first patient with coexisting FMF, spondyloarthritis and myositis responding to anakinra treatment. Moreover this is the second case in the literature of myositis associated with familial Mediterranean fever. PMID- 23928238 TI - Breast magnetic resonance imaging technique at 1.5 T and 3 T: requirements for quality imaging and American College of Radiology accreditation. AB - Although there are multiple variations in acquisition protocols for breast magnetic resonance (MR) imaging, there is agreement that components of high quality technique include a bilateral acquisition obtained with a dedicated breast coil. Further, key pulse sequences should be included and spatial and temporal resolution should be sufficiently high to assess lesion morphology and kinetics. Artifacts must be recognized and avoided. The American College of Radiology Breast MRI Accreditation Program requirements provide minimum standards to guide facilities in technique. MR imaging at 3 T is increasingly available and offers signal-to-noise ratio advantages over 1.5 T but also some technical challenges. PMID- 23928239 TI - Updates and revisions to the BI-RADS magnetic resonance imaging lexicon. AB - This article summarizes the updates and revisions to the second edition of the BI RADS MRI lexicon. A new feature in the lexicon is background parenchymal enhancement and its descriptors. Another major focus is on revised terminology for masses and non-mass enhancement. A section on breast implants and associated lexicon terms has also been added. Because diagnostic breast imaging increasingly includes multimodality evaluation, the new edition of the lexicon also contains revised recommendations for combined reporting with mammography and ultrasound if these modalities are included as comparison, and clarification on the use of final assessment categories in MR imaging. PMID- 23928240 TI - Screening MR imaging versus screening ultrasound: pros and cons. AB - Data support greater sensitivity of MR imaging compared with mammography and ultrasound in high-risk populations, in particular BRCA 1 and BRCA 2 carriers. Screening ultrasound improves cancer yield versus mammography alone in high-risk patients and in patients with dense breasts and is less expensive. Drawbacks include low positive predictive value, operator dependence, and significant physician time expenditure. Advances, such as refinement of automated whole breast ultrasound, new outcomes data from ultrasound-detected masses in BI-RADS 3 and 4a categories, and development of new MR imaging sequences that allow rapid screening, potentially without use of contrast, will likely reveal the most appropriate tool over time. PMID- 23928241 TI - Breast magnetic resonance imaging for screening high-risk women. AB - Mammography is the only imaging modality that has been validated by multiple randomized clinical trials and meta-analyses to reduce mortality from breast cancer. Although it is demonstrated to be effective in reducing mortality from breast cancer, mammography has its limitations, especially in young high-risk women with dense breasts. Other imaging modalities have been pursued as an adjunct screening modality in this population. Of these, the most widely accepted is contrast-enhanced breast magnetic resonance (MR) imaging. This article reviews current recommendations and limitations of using MR imaging of the breast to screen asymptomatic women at high risk for breast cancer. PMID- 23928242 TI - Breast MR imaging for extent of disease assessment in patients with newly diagnosed breast cancer. AB - Breast cancer staging and surgical planning are affected by the burden of pathologically proven cancer detected on clinical examination and/or imaging. Magnetic resonance (MR) imaging has superior sensitivity and accuracy for the detection of invasive and in situ breast cancer as compared with physical examination, mammography, and ultrasound but can be limited in specificity. The use of preoperative breast MR imaging for evaluating the extent of disease remains controversial at present because studies have not definitively shown it to improve overall survival, decrease re-excision rates, or to decrease the cost of care. PMID- 23928243 TI - Breast magnetic resonance imaging for monitoring response to therapy. AB - There is no difference in disease-free or overall survival in patients who undergo adjuvant versus neoadjuvant chemotherapy. Thus, neoadjuvant chemotherapy is recommended in patients with locally advanced breast cancer who would like to consider breast conservation, and is also the primary treatment in patients with inflammatory breast cancer. Magnetic resonance has emerged as the most sensitive imaging modality to assess the response of tumor to neoadjuvant chemotherapy. PMID- 23928244 TI - Evaluation of breast silicone implants. AB - While clinical evaluation of breast implants and their complications can identify capsule contracture and rupture of saline implants, the identification of silicone implant failure is best accomplished by silicone specific protocols for MRI with orthogonal acquisition. Such imaging can also help resolve other clinical problems. Following a brief overview of the history and development of commercial use of silicone implants and alternatives, this article outlines the approach toward optimal imaging and expected results. PMID- 23928245 TI - BI-RADS 3 for magnetic resonance imaging. AB - A BI-RADS (Breast Imaging Reporting and Data System) 3, or probably benign, assessment is given in approximately 7% to 12% of breast magnetic resonance (MR) images. However, the imaging features of probably benign lesions on MR imaging have not been well defined. As with mammography and ultrasonography, a BI-RADS 3 assessment should be used only when there is a less than 2% likelihood of malignancy. The use of BI-RADS 3 for classically benign findings should be avoided. Certain masses, foci, and areas of nonmass enhancement may be categorized as probably benign on baseline MR imaging. PMID- 23928246 TI - Magnetic resonance imaging-guided biopsy of the breast: fundamentals and finer points. AB - Magnetic resonance (MR) imaging is now an accepted component of standard breast imaging practice. This article reviews the fundamentals of performing an MR imaging-guided biopsy using a grid localization system, and discusses many of the finer points and nuances of the procedure. Tips and tricks found useful at the authors' institution are included, although multiple variations also exist. Performing effective and efficient MR imaging-guided biopsy depends both on deliberate preparation (of the proceduralist, the patient, and the equipment) and on deliberate positioning (of the patient and the sampling device). PMID- 23928247 TI - Radiologic-pathologic correlation at breast MR imaging: what is the appropriate management for high-risk lesions? AB - Breast magnetic resonance (MR) imaging is increasingly performed for a variety of indications, most commonly with the goal of detecting breast cancer. Percutaneous biopsy (usually under MR guidance or ultrasound if there is a correlating finding) is commonly used to evaluate suspicious imaging findings detected on MR imaging with the goal of identifying malignancy. It is important to be familiar with the characteristics and management of high-risk lesions detected or biopsied under MR guidance. This review focuses on the appearance of a variety of breast lesions detected on MR imaging that require excision with focus on pathologic correlation. PMID- 23928249 TI - Magnetic resonance spectroscopy of the breast: current status. AB - In vivo magnetic resonance spectroscopy (MRS) of the breast can be used to measure the level of choline-containing compounds, which is a biomarker of malignancy. In the diagnostic setting, MRS can provide high specificity for distinguishing benign from malignant lesions. MRS also can be used as an early response indicator in patients undergoing neoadjuvant chemotherapy. This article describes the acquisition and analysis methods used for measuring total choline levels in the breast using MRS, reviews the findings from clinical studies of diagnosis and treatment response, and discusses problems, limitations, and future developments for this promising clinical technology. PMID- 23928250 TI - Breast MRI. PMID- 23928248 TI - Diffusion weighted magnetic resonance imaging of the breast: protocol optimization, interpretation, and clinical applications. AB - Diffusion-weighted magnetic resonance (MR) imaging (DWI) has shown promise for improving the positive predictive value of breast MR imaging for detection of breast cancer, evaluating tumor response to neoadjuvant chemotherapy, and as a noncontrast alternative to MR imaging in screening for breast cancer. However, data quality varies widely. Before implementing DWI into clinical practice, one must understand the pertinent technical considerations and current evidence regarding clinical applications of breast DWI. This article provides an overview of basic principles of DWI, optimization of breast DWI protocols, imaging features of benign and malignant breast lesions, promising clinical applications, and potential future directions. PMID- 23928251 TI - Breast imaging. PMID- 23928252 TI - [Computer-assisted navigation in orthognathic surgery. Application to Le Fort I osteotomy.] AB - Computer-assisted navigation is a tool that allows the surgeon to reach intraoperatively a previously defined target. This technique can be applied to the positioning of bone fragments in orthognathic surgery. It is not used routinely yet because there are no specifically dedicated systems available on the market for this kind of surgery. The goal of our study was to describe the various systems that could be used in orthognathic surgery and to report our experience of computer-assisted surgery in the positioning of the maxilla during maxillomandibular osteotomies. PMID- 23928253 TI - [Guided maxillofacial surgery: Simulation and surgery aided by stereolithographic guides and custom-made miniplates.] AB - We present a new model of guided surgery, exclusively using computer assistance, from the preoperative planning of osteotomies to the actual surgery with the aid of stereolithographic cutting guides and osteosynthetic miniplates designed and made preoperatively, using custom-made titanium miniplates thanks to direct metal laser sintering. We describe the principles that guide the designing and industrial manufacturing of this new type of osteosynthesis miniplates. The surgical procedure is described step-by-step using several representative cases of dento-maxillofacial dysmorphosis. The encouraging short-term results demonstrate the wide range of application of this new technology for cranio maxillofacial surgery, whatever the type of osteotomy performed, and for plastic reconstructive surgery. PMID- 23928254 TI - [Stereomodel-assisted fibula free flap harvest and mandibular reconstruction: A technical note. Literature review of CAS and CAM applied to mandibular reconstruction.] AB - PURPOSE: Mandibular reconstruction with fibula free flap harvest is currently the reference technique. Various preoperative processes have been developed to optimize this reconstruction. We report our experience with a simple, inexpensive, preoperative technique requiring a 3D printer, a device for maintaining mandibular reduction, a paper-cutting guide. TECHNICAL NOTE: Stereomodels of the mandible were obtained from computed tomography scan data and printed 3D in ABS. It allowed planning mandibular osteotomies, determine the angle between two bone fragments, and preoperatively modeling the osteosynthesis plate. A paper-cutting guide, and a simple device for maintaining mandibular reduction were also built. Two patients were operated on with this technique, with follow-up at 6 and 8 months. Reconstructions were successful with good clinical outcome in terms of mandibular contour and reconstructed segments positions. DISCUSSION: Preoperative planning of reconstruction may be used for mandibular osteotomies, fibular osteotomies, maintaining mandibular reduction, osteosynthesis, or placing implants for dental rehabilitation. The most complex procedures can virtually plan all these steps, but they are expensive and long to implement. Nevertheless, such procedures are quite expansive and require time not always compatible with carcinoma. Using a mandibular stereomodel is fast, easy, and cheap. PMID- 23928255 TI - Use of fish farms to assess river contamination: combining biomarker responses, active biomonitoring, and chemical analysis. AB - Here we addressed the possible effects of trace levels of contaminants on fish by means of a combination of biomarker responses, active biomonitoring (ABM), and chemical analysis. In environmental studies, cytochromes P4501A (Cyp1A) and Cyp3A and related enzyme activities (7-ethoxyresorufin-O-deethylase, EROD, and benzyloxy-4-[trifluoromethyl]-coumarin-O-debenzyloxylase, BFCOD, respectively) are commonly used as biomarkers for evidencing exposure to a variety of contaminants. In a rainbow trout (Oncorhynchus mykiss) fish farm that is routinely sampled to obtain references regarding normal levels of such enzyme activities in freshwater fish, we observed a strong and punctual increase in these activities at the end of 2011. In order to shed light on the causes of this induction, we transferred some fish to a fish farm with controlled conditions and examined them using an active biomonitoring (ABM) approach. EROD activity showed a decrease of 80% from the original values after 7 days in the control farm, while BFCOD activity was also reduced after 15 days. Although not significant, a decrease in cyp1A and cyp3A mRNA levels was also observed. To determine the presence of pollutants, water and sediment samples from the river feeding the fish farm were analyzed by two-dimensional gas chromatography-time-of-flight mass spectrometry (GC*GC-TOF-MS). The screening study reflected a weak inflow of pollutants in the monitored area, which is located far from any industrial activity or densely populated cities. Trace levels of polyaromatic hydrocarbons (PAHs) and personal care products (the polycyclic musk fragrance HHCB, and triclosan) were detected in sediments, at concentrations ranging from 0.01 to 38 ng/g dry weight, and in water from 4 to 441 ng/L. The approach followed in this study proved useful as a biomonitoring technique for the early detection of trace contaminants. PMID- 23928256 TI - The status of public reporting of clinical outcomes in assisted reproductive technology. PMID- 23928257 TI - Reply of the authors. PMID- 23928258 TI - Human monoclonal ScFv specific to NS1 protein inhibits replication of influenza viruses across types and subtypes. AB - Currently, there is a need of new anti-influenza agents that target influenza virus proteins other than ion channel M2 and neuraminidase. Non-structural protein-1 (NS1) is a highly conserved multifunctional protein which is indispensable for the virus replication cycle. In this study, fully human single chain antibody fragments (HuScFv) that bound specifically to recombinant and native NS1 were produced from three huscfv-phagemid transformed Escherichia coli clones (nos. 3, 10 and 11) selected from a human ScFv phage display library. Western blot analysis, mimotope searching/epitope identification, homology modeling/molecular docking and phage mimotope ELISA inhibition indicated that HuScFv of clone no. 3 reacted with NS1 R domain important for host innate immunity suppression; HuScFv of clone nos. 10 and 11 bound to E domain sites necessary for NS1 binding to the host eIF4GI and CPSF30, respectively. The HuScFv of all clones could enter the influenza virus infected cells and interfered with the NS1 activities leading to replication inhibition of viruses belonging to various heterologous A subtypes and type B by 2-64-fold as semi-quantified by hemagglutination assay. Influenza virus infected cells treated with representative HuScFv (clone 10) had up-expression of IRF3 and IFN-beta genes by 14.75 and 4.95-fold, respectively, in comparison with the controls, indicating that the antibodies could restore the host innate immune response. The fully human single chain antibodies have high potential for developing further as a safe (adjunctive) therapeutic agent for mitigating, if not abrogating, severe symptoms of influenza. PMID- 23928259 TI - Approved and experimental countermeasures against pestiviral diseases: Bovine viral diarrhea, classical swine fever and border disease. AB - The pestiviruses, bovine viral diarrhea virus (BVDV), classical swine fever (CSFV) and border disease virus, are important livestock pathogens in many countries, but current vaccines do not completely prevent the spread of infection. Control of pestiviral diseases is especially difficult due to the constant viremia and viral shedding of persistently infected (PI) animals, which must be identified and eliminated to prevent disease transmission. Existing vaccines are limited by the delay between vaccination and the onset of protection, the difficulty of differentiating serologically between vaccinated and naturally infected animals and the need for broad vaccine cross-protection against diverse virus strains. Antiviral therapy could potentially supplement vaccination by providing immediate protection in the case of an outbreak. Numerous compounds with in vitro antiviral activity against BVDV have been identified through its role as a surrogate for hepatitis C virus. Fewer drugs active against CSFV have been identified, but many compounds that are effective against BVDV will likely inhibit CSFV, given their similar genomic sequences. While in vitro research has been promising, the paucity of efficacy studies in animals has hindered the commercial development of effective antiviral drugs against the pestiviruses. In this article, we summarize the clinical syndromes and routes of transmission of BVD, CSF and border disease, discuss currently approved vaccines, review efforts to develop antiviral therapies for use in outbreak control and suggest promising directions for future research. PMID- 23928260 TI - Review of transplantation of neural stem/progenitor cells for spinal cord injury. AB - Spinal cord injury (SCI) is a debilitating condition often resulting in paralysis, yet currently there is no effective treatment. Stem cell transplantation is a promising therapeutic strategy for promoting tissue repair after SCI. Stem cells offer a renewable source of cells with inherent plasticity for tissue regeneration. Neural stem/progenitor cells (NSPCs) are multipotent cells that self-renew and are committed to the neural lineage, and thus, they are especially suited to SCI repair. NSPCs may differentiate into neural cells after transplantation into the injured spinal cord, replacing lost or damaged cells, providing trophic support, restoring connectivity, and facilitating regeneration. Here, we review experimental studies and considerations for clinical translation of NSPC transplantation for SCI. PMID- 23928261 TI - Mycoplasma hyopneumoniae-derived lipid-associated membrane proteins induce apoptosis in porcine alveolar macrophage via increasing nitric oxide production, oxidative stress, and caspase-3 activation. AB - Mycoplasma hyopneumoniae is the primary etiological agent of enzootic pneumonia in swine. Lipid-associated membrane proteins (LAMP) of mycoplasma are the main pathogenicity factors in mycoplasma diseases. In this study, we investigated the effects of M. hyopneumoniae LAMP on porcine alveolar macrophage (PAM) 3D4/21 cell line. Apoptotic features, such as chromatin condensation and apoptotic bodies, were observed in LAMP-treated PAM 3D4/21 cells. Moreover, LAMP significantly increased the number of TUNEL positive apoptotic cells in PAM 3D4/21 cells compared with the untreated control. In addition, flow cytometric analysis using dual staining with annexin-V-FITC and propidium iodide (PI) showed that LAMP of M. hyopneumoniae induced a time-dependent apoptosis in PAM 3D4/21 cells. Moreover, increased levels of superoxide anion production and activated caspase-3 in PAM 3D4/21 cells were observed after exposure to LAMP. Increased production of nitric oxide (NO) was also confirmed in the cell supernatants. Besides, apoptotic rates increase and caspase-3 activation were suppressed by NOS inhibitor or antioxidant. It is suggested that LAMP of M. hyopneumoniae induced apoptosis in porcine alveolar macrophage via NO production, superoxide anion production, and caspase-3 activation. PMID- 23928262 TI - Development of a modified BODE index as a mortality risk measure among older adults with and without chronic obstructive pulmonary disease. AB - The BODE index was developed as a prognostic mortality risk tool for persons with chronic obstructive pulmonary disease (COPD). It incorporates 4 measures: body mass index, lung obstruction, dyspnea, and exercise capacity. The intent of this study was to examine how well a BODE-like index constructed using a simpler lung function measure, peak expiratory flow, in combination with physical functioning and symptom information more readily found in survey data (a quasi-BODE index), performs in identifying persons at higher risk of mortality and whether it may be extended as an assessment of mortality risk to persons without diagnosed COPD. Using US national survey data from the Health Retirement Study for 2006-2010, each unit increase in the quasi-BODE index score was associated with a multiplicative 50% increase in mortality risk (odds ratio = 1.50, 95% confidence interval: 1.41, 1.59). The quasi-BODE index is a multidimensional health status instrument based on the BODE index, which is a good predictor of mortality. The quasi-BODE index was compiled using simple measures of physical and respiratory function. It is a potentially useful prognostic instrument for older adult populations with or without COPD, including those with severe physical limitations, particularly when combined with demographic factors and comorbid conditions. PMID- 23928264 TI - Resonance tracking and vibration stablilization for high power ultrasonic transducers. AB - Resonant frequency shift and electrical impedance variation are common phenomena in the application of high power ultrasonic transducers, e.g. in focused ultrasound surgery and in cutting. They result in low power efficiency and unstable vibration amplitude. To solve this problem, a driving and measurement system has been developed to track the resonance of high power transducers and to stabilise their vibration velocity. This has the ability to monitor the operating and performance parameters of the ultrasonic transducers in real time. The configuration of the system, with its control algorithm implemented in LabVIEW (National Instruments, Newbury, UK), ensures flexibility to suit different transducers and load conditions. In addition, with different programs, it can be utilised as a high power impedance analyser or an instantaneous electrical power measurement system for frequencies in the MHz range. The effectiveness of this system has been demonstrated in detailed studies. With it, high transducer performance at high power can be achieved and monitored in real time. PMID- 23928263 TI - Null association between histology of first and second primary malignancies in men with bilateral testicular germ cell tumors. AB - Testicular germ cell tumors (TGCTs), the most common neoplasms of young men, are categorized histologically as either seminomas or nonseminomas/mixed germ cell tumors. These subtypes differ by age at diagnosis and clinical course, but little is known about etiological distinctions. To test the hypothesis that histological subtypes have distinct sets of unrecognized etiological factors, we used a recently described approach, estimating the association between histological types of first and second tumors of men with 2 primary TGCTs. The study population of 488 men each with 2 primary TGCTs was ascertained through population-based cancer registries in the United States between 1972 and 2006. Univariate logistic regression analysis revealed that the histology of second primary TGCTs was associated with the histology of first TGCTs (odds ratio = 1.70, 95% confidence interval: 1.14, 2.52); however, the association did not persist in analyses adjusted for age at diagnosis of first TGCT (odds ratio = 1.09, 95% confidence interval: 0.71, 1.70). These results would be expected if the subtypes share etiology but experience different rates of progression to diagnosis or if the histological fate of TGCTs is influenced by age-related processes. Men with 2 primary TGCTs provide novel opportunities to learn whether histological subtypes are likely to share etiology, so results may inform research designed to identify causes. PMID- 23928265 TI - Frequency and clinical correlates of bipolar features in acute coronary syndrome patients. AB - BACKGROUND: Depression and acute coronary syndrome (ACS) are both extremely prevalent diseases. Studies aimed at evaluating whether depression is an independent risk factor for cardiac events provided no definitive results. In most of these studies, depression has been broadly defined with no differentiation between unipolar (MDD) versus bipolar forms (BD). The aim of this study was to evaluate the frequency of DSM-IV BD (bipolar I and bipolar II subtypes, cyclothymia), as well as temperamental or isolated bipolar features in a sample of 171 patients hospitalized for ACS. We also explored whether these psychopathological conditions were associated with some clinical characteristics of ACS. METHODS: Patients with ACS admitted to three neighboring Cardiac Intensive Care Units (CICUs) in a 12-month continuative period of time were eligible for inclusion if they met the criteria for either acute myocardial infarct with or without ST-segment elevation or unstable angina, verified by standard ACS criteria. All patients underwent standardized cardiological and psychopathological evaluations. RESULTS: Of the 171 ACS patients enrolled, 37 patients (21.7%) were found to have a DSM-IV mood disorder. Of these, 20 (11.7%) had bipolar type I or type II or cyclothymia, while 17 (10%) were the cases of MDD. Rapid mood switches ranged from 11% of ACS patients with no mood disorders, to 47% of those with MDD to 55% of those with BD. Linear regression analysis showed that a diagnosis of BD (p=.023), but not that of MDD (p=.721), was associated with a significant younger age at the index episode of ACS. A history of previous coronary events was more frequent in ACS patients with BD than in those with MDD. CONCLUSIONS: Our data indicate that bipolar features and diagnosis are frequent in ACS patients. Bipolar disorder has a negative impact on cardiac symptomatology. Further research in this area is warranted. PMID- 23928266 TI - Initial evidence for sex-specific effects of early emotional abuse on affective processing in bipolar disorder. AB - PURPOSE: This study investigates the effect of sex and childhood trauma on affective processing in bipolar disorder (BPD) patients. METHODS: In a sample of fifty-six BPD patients, we administered the Childhood Trauma Questionnaire (CTQ), and the Iowa Gambling Task (IGT) and the Affective Go/No-Go (AGNG) to measure affective processing. Analysis of Variance (ANOVA) was used to evaluate the effect of sex and childhood trauma on IGT; Repeated-Measures ANOVAs to measure accuracy and bias measures across conditions on the AGNG. RESULTS: In the context of childhood abuse, females evidenced a more conservative cognitive style than males by selecting fewer cards from the disadvantageous decks [F(1, 49)=14.218; P<0.001] and showed an improvement throughout the task, as noted in a normal learning curve [F(1.49)=4.385; P=0.041)]. For the AGNG, an interaction specific to the negative valence stimuli on response bias measures was found. Abused females scored higher (mean=8.38; SD=6.39) than abused males (mean=0.69; SD=1.19) [F(1.46)=6.348; P=0.015]. CONCLUSION: Severity of childhood trauma was significantly different between sexes. In the context of a history of emotional abuse, male bipolar patients tended toward a more risk-taking behavior compared to female. Further investigations are needed to elucidate potential pathophysiological mechanisms underlying this interaction. PMID- 23928267 TI - Effect of COMT Val158Met polymorphism on personality traits and educational attainment in a longitudinal population representative study. AB - The COMT Val158Met polymorphism has been associated with anxiety and affective disorders, but its effect on anxiety-related personality traits varies between studies. Our purpose was to investigate the effect of COMT Val158Met on personality traits from adolescence to young adulthood in a population representative Caucasian birth cohort. Also its association with educational attainment and anxiety and mood disorders by the age 25 were examined. This analysis is based on the older cohort of the Estonian Children Personality Behavior and Health Study (original number of subjects 593). The personality traits were assessed when the participants were 15, 18 and 25 years old. COMT Val158Met had an effect on Neuroticism in females by age 25 (p=0.001, Bonferroni corrected for five traits), whereas female Val homozygotes scored the highest. In addition, the Conscientiousness scores of subjects with Val/Val genotype were decreasing in time, being the lowest by the age 25 (p=0.006, Bonferroni-corrected for five traits). By the age 25, males with the Val/Met genotype had mainly secondary or vocational education, whereas female heterozygotes mostly had obtained or were obtaining university education. COMT Val158Met was not associated with anxiety or mood disorders in either gender. These results suggest that genes affecting dopamine system are involved in the development of personality traits and contribute to educational attainment. PMID- 23928268 TI - Impact of Bacillus Calmette-Guerin Moreau vaccine on lung remodeling in experimental asthma. AB - We analyzed the effects of different administration routes and application times of the BCG-Moreau strain on airway and lung inflammation and remodeling in a murine model of allergic asthma. BALB/c mice (n=168) were divided into two groups. The first group received BCG-Moreau strain while the second group received saline using the same protocol. BCG or saline were intradermally or intranasally injected one or two months before the induction of asthma. Mice were further sensitized and challenged with ovalbumin or received saline. Twenty-four hours after the last challenge, BCG prevented the triggering of pro-inflammatory cytokines, probably by increasing Foxp3 and interleukin (IL)-10, modulating eosinophil infiltration and collagen fiber deposition, thus reducing airway hyperresponsiveness. In conclusion, BCG-Moreau prevented lung remodeling in the present model of allergic asthma, regardless of administration route and time of vaccination. These beneficial effects may be related to the increase in regulatory T cells and to IL-10 production in tandem with decreased Th2 cytokines (IL-4, IL-5, and IL-13). PMID- 23928269 TI - Efficient collection and cryopreservation of embryos in F344 strain inbred rats. AB - In rats, it is now possible to produce genetically engineered strains, not only as transgenic animals but also using gene knockout techniques. Reproductive technologies have been used as indispensable tools to produce and maintain these novel valuable strains. Although studies for collecting and cryopreserving embryos have been reported using outbred rats, efficient methods have not been established in inbred strains. The F344 inbred strain is important in rat breeding and has been used for the production of transgenic/knockout strains and for genome sequencing. Here we studied the optimal conditions for oocyte collection by induction of superovulation, and the development of embryos after cryopreservation in F344 rats. The response to pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) was examined by injection of 150 IU/kg PMSG + 75 IU/kg hCG or 300 IU/kg PMSG + 300 IU/kg hCG. Superovulation was achieved at high efficiency by an injection of 150 IU/kg PMSG + 75 IU/kg hCG. Furthermore, superovulation in this strain showed similar high response as Wistar rats. Of 2-cell embryos cryopreserved by vitrification in a solution containing 10% propylene glycol, 30% ethylene glycol, 20% Percoll and 0.3 M sucrose, more than 90% survived after warming and 32% developed to offspring. However, the freezability of pronuclear stage embryos was extremely low. This study demonstrated that sufficient unfertilized oocytes and embryos can be collected from F344 rats by the induction of superovulation with 150 IU/kg PMSG + 75 IU/kg hCG. Furthermore, cryopreservation of 2-cell embryos using this vitrification protocol can now be applied to maintaining valuable rat strains derived from the F344 inbred strain as genetic resources. PMID- 23928270 TI - Application of cetylpyridinium chloride and sodium chloride decontamination method for recovery of Mycobacterium tuberculosis from clinically suspected cases of pulmonary tuberculosis. AB - The study was designed to compare the efficacy of cetylpyridinium chloride (CPC) and sodium chloride (NaCl) decontamination method with N-acetyl L-Cystine (NALC) and sodium hydroxide (NaOH) decontamination (the reference method) method for the recovery of Mycobacterium tuberculosis (MTB) from clinically suspected cases of pulmonary tuberculosis. To evaluate CPC-NaCl and NALC-NaOH decontamination methods, sputum specimens (n = 796) were studied (culturing on Lowenstein-Jensen medium), and the performances were compared. The CPC-NaCl decontamination method demonstrated a sensitivity, specificity, negative predictive value, and positive predictive value of 97.99%, 87.53%, 70.19%, and 99.32%, respectively, when compared to NALC-NaOH decontamination method. In summary, CPC-NaCl decontamination method effectively detected significantly higher number of MTB cases (n = 208) than NALC-NaOH decontamination method (n = 149) particularly in sputum with scanty bacilli and smear-negative cases, indicating the potential of CPC-NaCl decontamination method to preserve paucibacillary cases more efficient than NALC-NaOH decontamination method. PMID- 23928271 TI - 'I saw the words right from your mouth': An unusual case of synaesthesia. PMID- 23928272 TI - Olanzapine long-acting injection: When and for how long is oral supplementation required? PMID- 23928273 TI - Selection bias in the economic evaluation of crisis accommodation for patients with severe mental illness. PMID- 23928274 TI - Choosing an SSRI in pregnancy: Clinical context versus statistical significance. PMID- 23928275 TI - Cognitive deconstruction of parenting in schizophrenia: the role of theory of mind. AB - OBJECTIVE: Schizophrenia patients experience impairments across various functional roles. Emotional unresponsiveness and an inability to foster intimacy and display affection may lead to impairments in parenting. A comprehensive cognitive understanding of parenting abilities in schizophrenia has the potential to guide newer treatment strategies. As part of a larger study on functional ability in schizophrenia patients, we attempted a cognitive deconstruction of their parenting ability. METHODS: Sixty-nine of the 170 patients who participated in a study on social cognition in remitted schizophrenia were parents (mean age of their children: 11.8 +/- 6.2 years). They underwent comprehensive assessments for neurocognition, social cognition (theory of mind, emotion processing, social perception and attributional bias), motivation and insight. A rater blind to their cognitive status assessed their social functioning using the Groningen Social Disabilities Schedule. We examined the association of their functional ability (active involvement and affective relationship) in the parental role with their cognitive performance as well as with their level of insight and motivation. RESULTS: Deficits in first- and second-order theory of mind (t = 2.57, p = 0.01; t = 3.2, p = 0.002, respectively), speed of processing (t = 2.37, p = 0.02), cognitive flexibility (t = 2.26, p = 0.02) and motivation (t = 2.64, p = 0.01) had significant association with parental role dysfunction. On logistic regression, second-order theory of mind emerged as a specific predictor of parental role, even after controlling for overall functioning scores sans parental role. CONCLUSIONS: Second-order theory of mind deficits are specifically associated with parental role dysfunction of patients with schizophrenia. Novel treatment strategies targeting theory of mind may improve parenting abilities in individuals with schizophrenia. PMID- 23928276 TI - Psychotic patients and other social deviants. PMID- 23928278 TI - Left ventricular non-compaction: troubles and traps of current imaging techniques. PMID- 23928277 TI - Abortion and mental health: A response to Romans and Steinberg. PMID- 23928279 TI - Multichannel surface electrodes increase the sensitivity of diagnosis of neuropathy in diabetic patients. AB - This prospective study investigated the diagnostic sensitivity of a novel multichannel surface electrode for detecting electrophysiologic changes in symptomatic diabetic neuropathy. We recruited healthy subjects without neuropathic complaints and diabetic patients with distal symmetric sensory symptoms who had normal nerve conduction studies (NCS). Eight compound muscle action potentials (CMAPs) were recorded using a multichannel electrode from each subject's abductor pollicis brevis muscle by stimulating the median nerve at the wrist. Latency- and amplitude-related variables were obtained and analyzed to compare the two groups. We used the Classification and Regression Tree (CART) algorithm to determine the cut-off values for selected predictors of diabetic neuropathy. All of the variables related to CMAP latency showed statistically significant differences between the median values for the diabetic group and the healthy control group. For example, the median value of the maximum latency and standard deviation of the eight CMAP onset latencies in diabetic patients (3.82ms and 0.15ms, respectively) were significantly larger than those in controls (3.26ms and p<0.001; 0.09ms and p<0.001, respectively). The CART analysis revealed that these variables were the most sensitive and specific variables for discriminating between patients with diabetic neuropathy and normal subjects. The multichannel surface electrode demonstrated both high sensitivity and specificity in detecting neurophysiologic abnormality of diabetic neuropathy, even when conventional NCS did not detect the abnormality. PMID- 23928280 TI - Comparison of erector spinae and hamstring muscle activities and lumbar motion during standing knee flexion in subjects with and without lumbar extension rotation syndrome. AB - The aim of this study was to compare the activity of the erector spinae (ES) and hamstring muscles and the amount and onset of lumbar motion during standing knee flexion between individuals with and without lumbar extension rotation syndrome. Sixteen subjects with lumbar extension rotation syndrome (10 males, 6 females) and 14 healthy subjects (8 males, 6 females) participated in this study. During the standing knee flexion, surface electromyography (EMG) was used to measure muscle activity, and surface EMG electrodes were attached to both the ES and hamstring (medial and lateral) muscles. A three-dimensional motion analysis system was used to measure kinematic data of the lumbar spine. An independent-t test was conducted for the statistical analysis. The group suffering from lumbar extension rotation syndrome exhibited asymmetric muscle activation of the ES and decreased hamstring activity. Additionally, the group with lumbar extension rotation syndrome showed greater and earlier lumbar extension and rotation during standing knee flexion compared to the control group. These data suggest that asymmetric ES muscle activation and a greater amount of and earlier lumbar motion in the sagittal and transverse plane during standing knee flexion may be an important factor contributing to low back pain. PMID- 23928281 TI - Changes in electromyographic activity after botulinum toxin injection of the rectus femoris in patients with hemiparesis walking with a stiff-knee gait. AB - PURPOSE: This study was designed to evaluate the effects of botulinum toxin type A (BoNTA) injection of the rectus femoris (RF) muscle on the electromyographic activity of the knee flexor and extensor and on knee and hip kinematics during gait in patients with hemiparesis exhibiting a stiff-knee gait. METHOD: Two gait analyses were performed on fourteen patients: before and four weeks after BoNTA injection. Spatiotemporal, kinematic and electromyographic parameters were quantified for the paretic limb. RESULTS: BoNTA treatment improved gait velocity, stride length and cadence with an increase of knee angular velocity at toe-off and maximal knee flexion in the swing phase. Amplitude and activation time of the RF and co-activation duration between the RF and biceps femoris were significantly decreased. The instantaneous mean frequency of RF was predominantly lower in the pre-swing phase. CONCLUSIONS: The results clearly show that BoNTA modified the EMG amplitude and frequency of the injected muscle (RF) but not of the synergist and antagonist muscles. The reduction in RF activation frequency could be related to increased activity of slow fibers. The frequency analysis of EMG signals during gait appears to be a relevant method for the evaluation of the effects of BoNTA in the injected muscle. PMID- 23928282 TI - A systematic review of circulating markers in primary chronic venous insufficiency. AB - OBJECTIVES: The etiology of primary chronic venous insufficiency is poorly understood. This systematic review aimed to summarize published evidence assessing the association of circulating markers with primary chronic venous insufficiency. METHODS: A search was undertaken through the PubMed database using the terms "venous insufficiency" and "biological marker" or "plasma" or "serum". Search limits included English language, human subjects and studies with publication dates from 1994. Studies which classified patients using the Clinical Etiology-Anatomy-Pathophysiology system of venous disease were analyzed. RESULTS: Seventeen studies were included, which have examined > 60 different biomarkers. A total of 13 markers were assessed in >1 study with the number of primary chronic venous insufficiency cases ranging from 41 to 244 and the number of controls ranging from 30 to 144 in these studies. Circulating estradiol, homocysteine and vascular endothelial growth factor were the most consistently associated with primary chronic venous insufficiency. CONCLUSIONS: Whilst a number of studies have examined biomarkers associated with primary chronic venous insufficiency, further studies are required using improved and standardized approaches on larger populations. Biomarker research may increase pathogenic knowledge and result in opportunities to decrease chronic venous insufficiency burden. PMID- 23928283 TI - A bidirectional stapling technique for laparoscopic small bowel anastomosis. AB - BACKGROUND: Small bowel anastomoses can present a technical challenge during laparoscopic procedures, particularly gastric bypass procedures. Early small bowel obstruction (SBO) rates associated with such procedures occur in .7%-5.2% of patients. Herein, we describe how a bidirectional stapling technique moves the enterotomy to the center of the anastomosis, decreasing the chances of an afferent limb obstruction. METHODS: A prospectively collected cohort of 2263 consecutive patients who underwent laparoscopic Roux-en-Y gastric bypass with bidirectional stapling of the small bowel anastomosis was evaluated for early SBO. All patients met the National Institutes of Health criteria for bariatric surgery. RESULTS: Overall, 3 patients' perioperative courses were complicated by perioperative, early SBO (.13%). These instances were all attributable to intraluminal blood clots and not from inadvertent narrowing of the afferent limb. One was diagnosed on postoperative day 1 by upper gastrointestinal study (UGI); 2 were diagnosed on postoperative day 2 by computed tomography (CT) scan with oral contrast. All 3 patients' complications were managed with a laparoscopic operation. CONCLUSION: The bidirectional stapling technique for small bowel anastomoses, with our modifications, is a rapid, well-tolerated, and effective technique that offers potential advantages over standard laparoscopic anastomotic techniques by reducing perioperative SBO complications. PMID- 23928284 TI - The Spanish Society of Nuclear Medicine and Molecular Imaging, a a solid and growing society. PMID- 23928285 TI - Antibacterial potency of V.A.C. GranuFoam Silver((r)) Dressing. AB - INTRODUCTION: V.A.C.((r)) GranuFoamTM therapy is regularly used in the surgical therapy of infected wounds and soft tissue injuries. Silver nanoparticles can destroy bacterial cell walls and inhibit enzymes for cell replication. Silver dressings are therefore successfully used for many indications in wound therapy. In this study, we investigated the antimicrobial potency of ionic silver released from the silver-coated V.A.C.((r)) GranuFoamTM during vacuum therapy. Silver dressing was exposed to agar plates populated with bacteria to measure silver release. MATERIALS AND METHODS: A total of 15 agar plates colonised with either Staphylococcus aureus populations or with Staphylococcus epidermidis, were loaded with V.A.C. GranuFoam Silver((r)) Dressing polyurethane foam (KCI, San Antonio, Texas). Each of 13 pieces of silver-coated foam was applied to an agar plate. Two plates were loaded with conventional black foam without any coating. After connecting to a vacuum pump, the vacuum therapy of the 15 plates lasted 5 days. The zone of inhibition of bacterial growth around the foam was measured daily. Silver release was also determined as a function of time. RESULTS: At each time point, there was evidence of silver in the agar independent of bacterial colonisation. The S. aureus agar showed a consecutive increase in silver concentration from baseline upon 48 h after exposure to the negative pressure of V.A.C. therapy. An increasing mean silver level after 48, 72 and 96 h was measured under V.A.C. therapy with a peak value after 120 h. In contrast, the results from the S. epidermidis plates did not follow a linear pattern. At the beginning of vacuum therapy, we documented a rise in silver concentration. After 48-96h, the silver levels fluctuated. A maximum zone of inhibition in both bacterial colonised plates (S. aureus and S. epidermidis) was found 39 h after the start of the V.A.C. GranuFoam Silver((r)) therapy. CONCLUSION: From our results, we confirmed the antimicrobial effect of the silver ions against S. aureus and S. epidermidis under continuous V.A.C. GranuFoam((r)) Silver therapy with a negative pressure of 25 mmHg. Furthermore we could quantify the amounts of silver, which were released from the foam under negative pressure as a function of time. PMID- 23928287 TI - C-reactive protein predicts fatigue independently of depression in breast cancer patients prior to chemotherapy. AB - Heightened inflammatory activity has been proposed as a mechanism for the development of cancer-related fatigue (CRF), a common and distressing condition that can negatively affect quality of life. Inflammation is also implicated in the pathogenesis of depression, and depression is a strong predictor of CRF. Thus, the role of the pro-inflammatory cytokine network in CRF may be mediated by depression or both conditions may share similar underlying physiological processes. The current study investigated associations between fatigue, depression and inflammatory cytokine (IFN-gamma, IL-6, TNF-alpha) and CRP concentrations, as well as kynurenine pathway (KP) activation, in 61 breast cancer patients prior to chemotherapy. Changes in inflammatory markers and KP activation over time were also explored, and associations with changes in fatigue and depression were examined. Higher levels of CRP were significantly correlated with fatigue and depression before chemotherapy; nevertheless, CRP predicted fatigue independently of depression. Although greater kynurenine concentrations were associated with increased immune activation, there was no evidence that the KP played a role in fatigue or depression. Furthermore, no relationships emerged between either fatigue or depression and IFN-gamma, IL-6, or TNF-alpha before chemotherapy. Nevertheless, kynurenine levels pre- and post-treatment significantly predicted changes in depression, suggesting that heightened KP activation may contribute to depressive symptoms in patients treated for cancer. In addition, IL-6 significantly covaried with fatigue. These preliminary findings provide some support for the idea that low-grade inflammation contributes to the development of CRF, independently of depression; however, there was no evidence that this is mediated by KP activity. PMID- 23928286 TI - Moderate aerobic exercise alters migration patterns of antigen specific T helper cells within an asthmatic lung. AB - Studies have indicated increased incidence and severity of allergic asthma due to western lifestyle and increased sedentary activity. Investigations also indicate that exercise reduces the severity of asthma; however, a mechanism of action has not been elucidated. Additional work implicates re-distribution of T helper (Th) cells in mediating alterations of the immune system as a result of moderate aerobic exercise in vivo. We have previously reported that exercise decreases T helper 2 (Th2) responses within the lungs of an ovalbumin (OVA)-sensitized murine allergic asthma model. Therefore, we hypothesized that exercise alters the migration of OVA-specific Th cells in an OVA-challenged lung. To test this hypothesis, wildtype mice received OVA-specific Th cells expressing a luciferase reporter construct and were OVA-sensitized and exercised. OVA-specific Th cell migration was decreased in OVA-challenged lungs of exercised mice when compared to their sedentary controls. Surface expression levels of lung-homing chemokine receptors, CCR4 and CCR8, on Th cells and their cognate lung-homing chemokine gradients revealed no difference between exercised and sedentary OVA-sensitized mice. However, transwell migration experiments demonstrated that lung-derived Th cells from exercised OVA-sensitized mice exhibited decreased migratory function versus controls. These data suggest that Th cells from exercised mice are less responsive to lung-homing chemokine. Together, these studies demonstrate that moderate aerobic exercise training can reduce the accumulation of antigen specific Th cell migration into an asthmatic lung by decreasing chemokine receptor function. PMID- 23928288 TI - Exogenous phage recombinase-independent inactivation of chromosomal genes in Yersinia enterocolitica. AB - Characterization of newly identified genes is necessary to understand their functions. Phenotypic characterization of isogenic mutants provides good understanding of the functions of the genes in wild type strains. In the present study, we report the use of linear dsDNA as a substrate for homologous recombination in Yersinia enterocolitica. A double-stranded linear recombinant DNA (LRD) containing an antibiotic resistance gene flanked by homologous regions to the target gene was created. Transformation of this LRD into Y. enterocolitica led to the replacement of targeted loci with antibiotic resistance gene. Using this strategy, two chromosomal genes namely urease C (ureC) and hemophore A (hasA) were disrupted in three strains of Y. enterocolitica. These recombinations were independent of the EPR functions. This is the first report of EPR independent inactivation of chromosomal genes in Y. enterocolitica strains. PMID- 23928289 TI - Cancer drug discovery by repurposing: teaching new tricks to old dogs. AB - Progressively increasing failure rates, high cost, poor bioavailability, poor safety, limited efficacy, and a lengthy design and testing process associated with cancer drug development have necessitated alternative approaches to drug discovery. Exploring established non-cancer drugs for anticancer activity provides an opportunity rapidly to advance therapeutic strategies into clinical trials. The impetus for development of cancer therapeutics from non-cancer drugs stems from the fact that different diseases share common molecular pathways and targets in the cell. Common molecular origins of diverse diseases have been discovered through advancements in genomics, proteomics, and informatics technologies, as well as through the development of analytical tools that allow researchers simultaneously to screen large numbers of existing drugs against a particular disease target. Thus, drugs originally identified as antitussive, sedative, analgesic, antipyretic, antiarthritic, anesthetic, antidiabetic, muscle relaxant, immunosuppressant, antibiotic, antiepileptic, cardioprotective, antihypertensive, erectile function enhancing, or angina relieving are being repurposed for cancer. This review describes the repurposing of these drugs for cancer treatment. PMID- 23928291 TI - A systematic review of the prevalence of mucosal and cutaneous human papillomavirus types. AB - Systematic reviews of the prevalence of different types of Human Papillomavirus (HPV) across a broad range of disease grades from normal to cancer are essential to gain basic knowledge of how widespread infections with the different HPV types are, and to provide information on the possible carcinogenicity of different HPV types. For HPV types that infect human mucosa, of which 12 are established causes of cervical cancer, we present the results of a systematic review and meta analysis of 47 HPV types in cervical samples across the entire range of cervical diagnoses from normal to cervical cancer, restricted to studies using a number of well characterized PCR assays. For the cutaneous HPV types, which have been linked to the development of squamous cell carcinoma of the skin, their presence has been measured in a variety of different sample types and by assays with variable performance. Therefore, we restricted a systematic review of their prevalence to studies that assayed for cutaneous HPV infection in a case-control format. PMID- 23928292 TI - Mortalin antibody-conjugated quantum dot transfer from human mesenchymal stromal cells to breast cancer cells requires cell-cell interaction. AB - The role of tumor stroma in regulation of breast cancer growth has been widely studied. However, the details on the type of heterocellular cross-talk between stromal and breast cancer cells (BCCs) are still poorly known. In the present study, in order to investigate the intercellular communication between human mesenchymal stromal cells (hMSCs) and breast cancer cells (BCCs, MDA-MB-231), we recruited cell-internalizing quantum dots (i-QD) generated by conjugation of cell internalizing anti-mortalin antibody and quantum dots (QD). Co-culture of illuminated and color-coded hMSCs (QD655) and BCCs (QD585) revealed the intercellular transfer of QD655 signal from hMSCs to BCCs. The amount of QD double positive BCCs increased gradually within 48h of co-culture. We found prominent intercellular transfer of QD655 in hanging drop co-culture system and it was non-existent when hMSCs and BBCs cells were co-cultured in trans-well system lacking imminent cell-cell contact. Fluorescent and electron microscope analyses also supported that the direct cell-to-cell interactions may be required for the intercellular transfer of QD655 from hMSCs to BCCs. To the best of our knowledge, the study provides a first demonstration of transcellular crosstalk between stromal cells and BCCs that involve direct contact and may also include a transfer of mortalin, an anti-apoptotic and growth-promoting factor enriched in cancer cells. PMID- 23928293 TI - Cytoplasmic-targeted parvalbumin blocks the proliferation of multipotent mesenchymal stromal cells in prophase. AB - INTRODUCTION: Multipotent mesenchymal stromal cells (MSCs) have gained considerable interest because of their potential use in the treatment of a variety of diseases and injuries. Although remarkable advancements have been made in clinical studies, substantial concerns still regard the safety of MSCs. Some evidence suggests that MSCs can spontaneously generate a population of cells with tumorigenic potential. Thus, studying the molecular mechanisms that control the proliferation of MSCs may be a necessary step toward the development of strategies for safe clinical practice. Ca(2+) is a second messenger that mediates a wide range of cellular responses, including the regulation of cell proliferation, but little is known about its function in MSCs. The aim of this study was to investigate the effects of targeted Ca(2+) buffering on MSCs proliferation in vitro. METHODS: Here, we used an adenoviral (Ad) vector encoding the Ca(2+) chelator protein parvalbumin (PV) fused to a nuclear exclusion signal (NES) and the Discosoma red fluorescent protein (DsRed) to investigate the function of cytoplasmic Ca(2+) signals on MSC proliferation. Confocal microscopy was used to demonstrate that PV-NES-DsRed was expressed in the cytoplasm. Ca(2+) signaling was monitored by using Fluo-4-AM. Fluorescence-activated cell sorting (FACS) analysis of cells that were stained with propidium iodide was used as a quantitative measure of cell death. The mitotic index was assessed by immunofluorescence, and the expression of cyclins was examined with Western blot. RESULTS: Our results show that the Ad-PV-NES-DsRed fusion protein decreased serum induced Ca(2+) signaling and blocked the proliferation of rat adipose-derived MSCs (AT-MSCs) in prophase. FACS analysis revealed that Ad-PV-NES-DsRed did not induce cell death in AT-MSCs. Furthermore, Western blot analysis demonstrated that Ad-PV-NES-DsRed reduced extracellular signal-regulated kinase (Erk1/2) phosphorylation and cyclin B1 expression. Buffering cytosolic Ca(2+) did not alter the expression of cyclins A/D1/D2/D3/E and E2. CONCLUSIONS: Our results show that cytoplasmic Ca(2+) signals are important for AT-MSCs progression beyond prophase because of their effects on Erk phosphorylation and cyclin B1 expression. PMID- 23928294 TI - 5-HT3 receptor influences the washing phenotype and visual organization in obsessive-compulsive disorder supporting 5-HT3 receptor antagonists as novel treatment option. AB - A role of the HTR3A-E genes in obsessive-compulsive disorder (OCD) can be expected based on promising effects of 5-HT3 receptor antagonists as adjunctive treatment of OCD. We therefore genotyped six common coding or promoter variants within the HTR3A-E genes in a case-control-sample consisting of N=236 OCD patients and N=310 control subjects and in N=58 parent-child-trios. Given the heterogeneous OCD phenotype, we also investigated OCD symptom dimensions and cognitive endophenotypes in subsamples. OCD patients scoring high for the washing subtype were significantly more likely to carry the c.256G-allele of the HTR3E variant rs7627615 (p=0.0001) as compared to OCD patients low for this symptom dimension. Visual organization was impaired in OCD patients and unaffected relatives as compared to healthy control subjects and carriers of the HTR3E c.256G/c.256G-genotype performed significantly worse (p=0.007). The case-control analyses revealed a nominal significant association of the HTR3D variant rs1000592 (p.H52R) with OCD (p=0.029) which was also evident after combination of the case-control and the trio-results (p=0.024). In male subjects, the variant rs6766410 (p.N163K) located in the HTR3C was significantly associated with OCD (p=0.007). The association findings of the HTR3C and the HTR3E remained significant after correction for the number of variants investigated. These findings indicate a role of common variants of the HTR3A-E genes in OCD and OCD related phenotypes and further support the use of 5-HT3 receptor antagonists as novel treatment options. The HTR3E gene is a novel candidate gene impacting on the individual expression of OC symptoms and OCD-related cognitive dysfunction. PMID- 23928295 TI - The endocannabinoid system and emotional processing: a pharmacological fMRI study with ?9-tetrahydrocannabinol. AB - Various psychiatric disorders such as major depression are associated with abnormalities in emotional processing. Evidence indicating involvement of the endocannabinoid system in emotional processing, and thus potentially in related abnormalities, is increasing. In the present study, we examined the role of the endocannabinoid system in processing of stimuli with a positive and negative emotional content in healthy volunteers. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross over design, investigating effects of the endocannabinoid agonist ?9 tetrahydrocannabinol (THC) on brain function related to emotional processing in 11 healthy subjects. Performance and brain activity during matching of stimuli with a negative ('fearful faces') or a positive content ('happy faces') were assessed after placebo and THC administration. After THC administration, performance accuracy was decreased for stimuli with a negative but not for stimuli with a positive emotional content. Our task activated a network of brain regions including amygdala, orbital frontal gyrus, hippocampus, parietal gyrus, prefrontal cortex, and regions in the occipital cortex. THC interacted with emotional content, as activity in this network was reduced for negative content, while activity for positive content was increased. These results indicate that THC administration reduces the negative bias in emotional processing. This adds human evidence to support the hypothesis that the endocannabinoid system is involved in modulation of emotional processing. Our findings also suggest a possible role for the endocannabinoid system in abnormal emotional processing, and may thus be relevant for psychiatric disorders such as major depression. PMID- 23928296 TI - The cardiovascular safety profile of escitalopram. AB - The cardiovascular effects of escitalopram were examined in a large group of participants in double-blind, randomized, placebo-controlled studies. Escitalopram (n=3298) was administered at doses between 5 and 20mg/day. Patients were treated in acute (8-12 weeks) and long-term (24 weeks) studies. Assessment of cardiovascular safety included heart rate, blood pressure (BP), treatment emergent adverse events (TEAEs) and electrocardiograms (ECGs). In the short-term, there was a small, but statistically significant 2 beats per minute decrease in heart rate with escitalopram compared with placebo. The difference compared to placebo in systolic or diastolic BP was not clinically or statistically significant. Valid ECG assessments at both baseline and last assessment were available for 2407 escitalopram patients and 1952 placebo patients. Escitalopram placebo differences in mean changes in ECG values were not clinically meaningful. The mean difference to placebo in the corrected QT [Fridericia's (QTcF)] interval was 3.5 ms (all escitalopram doses); 1.3 ms (escitalopram 10mg) and 1.7 ms (escitalopram 20mg) (p=0.2836 for 10 versus 20 mg). One out of 2407 escitalopram patients had a QTcF interval >500 ms and a change from baseline >60 ms. The incidence and types of cardiac-associated adverse events were similar between patients treated for 8-12 weeks with placebo (2.2%) or escitalopram (1.9%) and for 24 weeks with placebo (2.7%) or escitalopram (2.3%). Analyses of data from long-term studies and studies of the elderly showed similar results. In conclusion, these data demonstrate that escitalopram, like other SSRIs, has a statistically significant effect on heart rate and no clinically meaningful effect on ECG values, BP, with a placebo-level incidence of cardiac-associated adverse events. PMID- 23928297 TI - President's page: the mandate for quality. An invitation to be part of the solution. PMID- 23928298 TI - Calibrated bioresorbable microspheres: a preliminary study on the level of occlusion and arterial distribution in a rabbit kidney model. AB - PURPOSE: To assess the level of occlusion and arterial distribution of calibrated bioresorbable microspheres (BRMS-I and BRMS-II) compared with tris-acryl gelatin microspheres (TGMS) after renal embolization. MATERIALS AND METHODS: Six rabbits underwent renal embolization with 100-300 um BRMS-I and TGMS; three rabbits received partial occlusion (group 1, n = 3), and three rabbits received total occlusion (group 2, n = 3). Four other rabbits received 100-300 um BRMS-II (with higher cross-linking density than BRMS-I) in the left kidneys reaching total occlusion (group 3, n = 4). Coronal sections of the kidneys were histologically analyzed. Ease of injection, microsphere deformation, vessel sizes, and arterial distribution were assessed. RESULTS: The injection of BRMS-I, BRMS-II, and TGMS through microcatheters went smoothly without any clogging. In group 1, BRMS identification was easier than TGMS. In group 2, both BRMS-I and TGMS were observed in all three arterial levels (interlobar, arcuate, and interlobular arteries) without a significant difference (P = .84). BRMS-I were not significantly different from TGMS in the mean diameter of vessels occluded (197 um +/- 23 vs 158 um +/- 21, P = .25) or the microsphere deformation (8.85% +/- 0.53% vs 11.80% +/- 0.64%, P = .071). In group 3, the arterial distribution of BRMS-II was significantly different from BRMS-I and TGMS (P < .0001). CONCLUSIONS: In occluding arteries, 100-300 um BRMS-I were not significantly different from 100-300 um TGMS. Arterial distribution of BRMS can be influenced by their cross-linking density. PMID- 23928299 TI - Recent applications of ATR FTIR spectroscopy and imaging to proteins. AB - Attenuated Total Reflection (ATR) Fourier Transform Infrared (FTIR) spectroscopy is a label-free, non-destructive analytical technique that can be used extensively to study a wide variety of different molecules in a range of different conditions. The aim of this review is to discuss and highlight the recent advances in the applications of ATR FTIR spectroscopic imaging to proteins. It briefly covers the basic principles of ATR FTIR spectroscopy and ATR FTIR spectroscopic imaging as well as their advantages to the study of proteins compared to other techniques and other forms of FTIR spectroscopy. It will then go on to examine the advances that have been made within the field over the last several years, particularly the use of ATR FTIR spectroscopy for the understanding and development of protein interaction with surfaces. Additionally, the growing potential of Surface Enhanced Infrared Spectroscopy (SEIRAS) within this area of applications will be discussed. The review includes the applications of ATR FTIR imaging to protein crystallisation and for high-throughput studies, highlighting the future potential of the technology within the field of protein structural studies and beyond. PMID- 23928300 TI - REM sleep behavior disorder and motor dysfunction in Parkinson's disease--a longitudinal study. AB - OBJECTIVES: Longitudinal assessment of a Parkinson's disease (PD) cohort, to investigate the evolution or REM sleep behavior symptoms (RBD) over time and to test the relation between RBD at onset and motor dysfunction progression. METHODS: An early stage PD cohort (n = 61) was assessed at two time points, separated by a two years interval. Diagnostic criteria for RBD were: violent behavior during sleep and body movements or vocalization indicative of dream enacting and at least six affirmative answers in the REM sleep behavior disorder screening questionnaire. Motor function assessment was performed with the Unified Parkinson's Disease Scale part II and III (total and partial scores for tremor, bradykinesia, rigidity, gait/postural instability and dysarthria). RESULTS: 25 Patients had RBD at baseline, vs. 35 at follow-up. Three RBD changed to non-RBD at follow-up, while 10 non-RBD patients developed RBD at follow-up (annual incidence of 12.5%). RBD and non-RBD patients did not differ significantly at baseline or follow-up. The presence of RBD at baseline was significantly related to an increase in UPDRS total and bradykinesia scores over time. DISCUSSION: RBD symptoms can vary over time and have a tendency to increase during the early stages of disease. The presence of RBD symptoms could be a risk factor for motor function deterioration and particularly for bradykinesia worsening. PMID- 23928301 TI - Partitioning of the nuclear and mitochondrial tRNA 3'-end processing activities between two different proteins in Schizosaccharomyces pombe. AB - tRNase Z is an essential endonuclease responsible for tRNA 3'-end maturation. tRNase Z exists in a short form (tRNase Z(S)) and a long form (tRNase Z(L)). Prokaryotes have only tRNase Z(S), whereas eukaryotes can have both forms of tRNase Z. Most eukaryotes characterized thus far, including Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and humans, contain only one tRNase Z(L) gene encoding both nuclear and mitochondrial forms of tRNase Z(L). In contrast, Schizosaccharomyces pombe contains two essential tRNase Z(L) genes (trz1 and trz2) encoding two tRNase Z(L) proteins, which are targeted to the nucleus and mitochondria, respectively. Trz1 protein levels are notably higher than Trz2 protein levels. Here, using temperature-sensitive mutants of trz1 and trz2, we provide in vivo evidence that trz1 and trz2 are involved in nuclear and mitochondrial tRNA 3'-end processing, respectively. In addition, trz2 is also involved in generation of the 5'-ends of other mitochondrial RNAs, whose 5'-ends coincide with the 3'-end of tRNA. Thus, our results provide a rare example showing partitioning of the nuclear and mitochondrial tRNase Z(L) activities between two different proteins in S. pombe. The evolution of two tRNase Z(L) genes and their differential expression in fission yeast may avoid toxic off-target effects. PMID- 23928302 TI - The Upf factor complex interacts with aberrant products derived from mRNAs containing a premature termination codon and facilitates their proteasomal degradation. AB - Up-frameshift (Upf) factors eliminate aberrant mRNAs containing a specific premature termination codon (PTC). Here, we show that Upf complex facilitates the ubiquitin-dependent degradation of products derived from mRNA containing specific PTCs in Saccharomyces cerevisiae. The efficiency of recruitment of the Upf complex to a PTC product was correlated with the decay of the PTC product. Upf factors promoted the degradation of the human von Hippel-Lindau (VHL) protein, which is an unfolded protein in yeast cells, in a manner that depends on the presence of a faux 3'-UTR. Mass spectrometric analysis and Western blot analysis revealed that Hsp70 was associated with the PTC product. These findings suggest that the Upf complex may be recruited to ribosomes in a faux 3'-UTR-dependent manner and then associates with aberrant products to facilitate their degradation by the proteasome. PMID- 23928303 TI - Role of aldose reductase in the metabolism and detoxification of carnosine acrolein conjugates. AB - Oxidation of unsaturated lipids generates reactive aldehydes that accumulate in tissues during inflammation, ischemia, or aging. These aldehydes form covalent adducts with histidine-containing dipeptides such as carnosine and anserine, which are present in high concentration in skeletal muscle, heart, and brain. The metabolic pathways involved in the detoxification and elimination of these conjugates are, however, poorly defined, and their significance in regulating oxidative stress is unclear. Here we report that conjugates of carnosine with aldehydes such as acrolein are produced during normal metabolism and excreted in the urine of mice and adult human non-smokers as carnosine-propanols. Our studies show that the reduction of carnosine-propanals is catalyzed by the enzyme aldose reductase (AR). Carnosine-propanals were converted to carnosine-propanols in the lysates of heart, skeletal muscle, and brain tissue from wild-type (WT) but not AR-null mice. In comparison with WT mice, the urinary excretion of carnosine propanols was decreased in AR-null mice. Carnosine-propanals formed covalent adducts with nucleophilic amino acids leading to the generation of carnosinylated proteins. Deletion of AR increased the abundance of proteins bound to carnosine in skeletal muscle, brain, and heart of aged mice and promoted the accumulation of carnosinylated proteins in hearts subjected to global ischemia ex vivo. Perfusion with carnosine promoted post-ischemic functional recovery in WT but not in AR-null mouse hearts. Collectively, these findings reveal a previously unknown metabolic pathway for the removal of carnosine-propanal conjugates and suggest a new role of AR as a critical regulator of protein carnosinylation and carnosine mediated tissue protection. PMID- 23928304 TI - Autoregulation of the mechanistic target of rapamycin (mTOR) complex 2 integrity is controlled by an ATP-dependent mechanism. AB - Nutrients are essential for living organisms because they fuel biological processes in cells. Cells monitor nutrient abundance and coordinate a ratio of anabolic and catabolic reactions. Mechanistic target of rapamycin (mTOR) signaling is the essential nutrient-sensing pathway that controls anabolic processes in cells. The central component of this pathway is mTOR, a highly conserved and essential protein kinase that exists in two distinct functional complexes. The nutrient-sensitive mTOR complex 1 (mTORC1) controls cell growth and cell size by phosphorylation of the regulators of protein synthesis S6K1 and 4EBP1, whereas its second complex, mTORC2, regulates cell proliferation by functioning as the regulatory kinase of Akt and other members of the AGC kinase family. The regulation of mTORC2 remains poorly characterized. Our study shows that the cellular ATP balance controls a basal kinase activity of mTORC2 that maintains the integrity of mTORC2 and phosphorylation of Akt on the turn motif Thr-450 site. We found that mTOR stabilizes SIN1 by phosphorylation of its hydrophobic and conserved Ser-260 site to maintain the integrity of mTORC2. The optimal kinase activity of mTORC2 requires a concentration of ATP above 1.2 mM and makes this kinase complex highly sensitive to ATP depletion. We found that not amino acid but glucose deprivation of cells or acute ATP depletion prevented the mTOR-dependent phosphorylation of SIN1 on Ser-260 and Akt on Thr-450. In a low glucose medium, the cells carrying a substitution of SIN1 with its phosphomimetic mutant show an increased rate of cell proliferation related to a higher abundance of mTORC2 and phosphorylation of Akt. Thus, the homeostatic ATP sensor mTOR controls the integrity of mTORC2 and phosphorylation of Akt on the turn motif site. PMID- 23928305 TI - The malignant brain tumor (MBT) domain protein SFMBT1 is an integral histone reader subunit of the LSD1 demethylase complex for chromatin association and epithelial-to-mesenchymal transition. AB - Chromatin readers decipher the functional readouts of histone modifications by recruiting specific effector complexes for subsequent epigenetic reprogramming. The LSD1 (also known as KDM1A) histone demethylase complex modifies chromatin and represses transcription in part by catalyzing demethylation of dimethylated histone H3 lysine 4 (H3K4me2), a mark for active transcription. However, none of its currently known subunits recognizes methylated histones. The Snai1 family transcription factors are central drivers of epithelial-to-mesenchymal transition (EMT) by which epithelial cells acquire enhanced invasiveness. Snai1-mediated transcriptional repression of epithelial genes depends on its recruitment of the LSD1 complex and ensuing demethylation of H3K4me2 at its target genes. Through biochemical purification, we identified the MBT domain-containing protein SFMBT1 as a novel component of the LSD1 complex associated with Snai1. Unlike other mammalian MBT domain proteins characterized to date that selectively recognize mono- and dimethylated lysines, SFMBT1 binds di- and trimethyl H3K4, both of which are enriched at active promoters. We show that SFMBT1 is essential for Snai1-dependent recruitment of LSD1 to chromatin, demethylation of H3K4me2, transcriptional repression of epithelial markers, and induction of EMT by TGFbeta. Carcinogenic metal nickel is a widespread environmental and occupational pollutant. Nickel alters gene expression and induces EMT. We demonstrate the nickel-initiated effects are dependent on LSD1-SFMBT1-mediated chromatin modification. Furthermore, in human cancer, expression of SFMBT1 is associated with mesenchymal markers and unfavorable prognosis. These results highlight a critical role of SFMBT1 in epigenetic regulation, EMT, and cancer. PMID- 23928306 TI - YidC protein, a molecular chaperone for LacY protein folding via the SecYEG protein machinery. AB - To understand how YidC and SecYEG function together in membrane protein topogenesis, insertion and folding of the lactose permease of Escherichia coli (LacY), a 12-transmembrane helix protein LacY that catalyzes symport of a galactoside and an H(+), was studied. Although both the SecYEG machinery and signal recognition particle are required for insertion of LacY into the membrane, YidC is not required for translocation of the six periplasmic loops in LacY. Rather, YidC acts as a chaperone, facilitating LacY folding. Upon YidC depletion, the conformation of LacY is perturbed, as judged by monoclonal antibody binding studies and by in vivo cross-linking between introduced Cys pairs. Disulfide cross-linking also demonstrates that YidC interacts with multiple transmembrane segments of LacY during membrane biogenesis. Moreover, YidC is strictly required for insertion of M13 procoat protein fused into the middle cytoplasmic loop of LacY. In contrast, the loops preceding and following the inserted procoat domain are dependent on SecYEG for insertion. These studies demonstrate close cooperation between the two complexes in membrane biogenesis and that YidC functions primarily as a foldase for LacY. PMID- 23928307 TI - Complement-mediated opsonization of invasive group A Streptococcus pyogenes strain AP53 is regulated by the bacterial two-component cluster of virulence responder/sensor (CovRS) system. AB - Group A Streptococcus pyogenes (GAS) strain AP53 is a primary isolate from a patient with necrotizing fasciitis. These AP53 cells contain an inactivating mutation in the sensor component of the cluster of virulence (cov) responder (R)/sensor (S) two-component gene regulatory system (covRS), which enhances the virulence of the primary strain, AP53/covR(+)S(-). However, specific mechanisms by which the covRS system regulates the survival of GAS in humans are incomplete. Here, we show a key role for covRS in the regulation of opsonophagocytosis of AP53 by human neutrophils. AP53/covR(+)S(-) cells displayed potent binding of host complement inhibitors of C3 convertase, viz. Factor H (FH) and C4-binding protein (C4BP), which concomitantly led to minimal C3b deposition on AP53 cells, further showing that these plasma protein inhibitors are active on GAS cells. This resulted in weak killing of the bacteria by human neutrophils and a corresponding high death rate of mice after injection of these cells. After targeted allelic alteration of covS(-) to wild-type covS (covS(+)), a dramatic loss of FH and C4BP binding to the AP53/covR(+)S(+) cells was observed. This resulted in elevated C3b deposition on AP53/covR(+)S(+) cells, a high level of opsonophagocytosis by human neutrophils, and a very low death rate of mice infected with AP53/covR(+)S(+). We show that covRS is a critical transcriptional regulator of genes directing AP53 killing by neutrophils and regulates the levels of the receptors for FH and C4BP, which we identify as the products of the fba and enn genes, respectively. PMID- 23928308 TI - Intramolecular dynamics within the N-Cap-SH3-SH2 regulatory unit of the c-Abl tyrosine kinase reveal targeting to the cellular membrane. AB - c-Abl is a key regulator of cell signaling and is under strict control via intramolecular interactions. In this study, we address changes in the intramolecular dynamics coupling within the c-Abl regulatory unit by presenting its N-terminal segment (N-Cap) with an alternative function in the cell as c-Abl becomes activated. Using small angle x-ray scattering, nuclear magnetic resonance, and confocal microscopy, we demonstrate that the N-Cap and the Src homology (SH) 3 domain acquire MUs-ms motions upon N-Cap association with the SH2 L domain, revealing a stabilizing synergy between these segments. The N-Cap myristoyl tether likely triggers the protein to anchor to the membrane because of these flip-flop dynamics, which occur in the MUs-ms time range. This segment not only presents the myristate during c-Abl inhibition but may also trigger protein localization inside the cell in a functional and stability-dependent mechanism that is lost in Bcr-Abl(+) cells, which underlie chronic myeloid leukemia. This loss of intramolecular dynamics and binding to the cellular membrane is a potential therapeutic target. PMID- 23928309 TI - RanBPM protein acts as a negative regulator of BLT2 receptor to attenuate BLT2 mediated cell motility. AB - BLT2, a low affinity receptor for leukotriene B4 (LTB4), is a member of the G protein-coupled receptor family and is involved in many signal transduction pathways associated with various cellular phenotypes, including chemotactic motility. However, the regulatory mechanism for BLT2 has not yet been demonstrated. To understand the regulatory mechanism of BLT2, we screened and identified the proteins that bind to BLT2. Using a yeast two-hybrid assay with the BLT2 C-terminal domain as bait, we found that RanBPM, a previously proposed scaffold protein, interacts with BLT2. We demonstrated the specific interaction between BLT2 and RanBPM by GST pulldown assay and co-immunoprecipitation assay. To elucidate the biological function of the RanBPM-BLT2 interaction, we evaluated the effects of RanBPM overexpression or knockdown. We found that BLT2-mediated motility was severely attenuated by RanBPM overexpression and that knockdown of endogenous RanBPM by shRNA strongly promoted BLT2-mediated motility, suggesting a negative regulatory function of RanBPM toward BLT2. Furthermore, we observed that the addition of BLT2 ligands caused the dissociation of BLT2 and RanBPM, thus releasing the negative regulatory effect of RanBPM. Finally, we propose that Akt induced BLT2 phosphorylation at residue Thr(355), which occurs after the addition of BLT2 ligands, is a potential mechanism by which BLT2 dissociates from RanBPM, resulting in stimulation of BLT2 signaling. Taken together, our results suggest that RanBPM acts as a negative regulator of BLT2 signaling to attenuate BLT2 mediated cell motility. PMID- 23928310 TI - Heme-based globin-coupled oxygen sensors: linking oxygen binding to functional regulation of diguanylate cyclase, histidine kinase, and methyl-accepting chemotaxis. AB - An emerging class of novel heme-based oxygen sensors containing a globin fold binds and senses environmental O2 via a heme iron complex. Structure-function relationships of oxygen sensors containing a heme-bound globin fold are different from those containing heme-bound PAS and GAF folds. It is thus worth reconsidering from an evolutionary perspective how heme-bound proteins with a globin fold similar to that of hemoglobin and myoglobin could act as O2 sensors. Here, we summarize the molecular mechanisms of heme-based oxygen sensors containing a globin fold in an effort to shed light on the O2-sensing properties and O2-stimulated catalytic enhancement observed for these proteins. PMID- 23928312 TI - Transradial intervention for unprotected left main PCI--balancing can and should. PMID- 23928311 TI - Dioxygenases catalyze O-demethylation and O,O-demethylenation with widespread roles in benzylisoquinoline alkaloid metabolism in opium poppy. AB - In opium poppy, the antepenultimate and final steps in morphine biosynthesis are catalyzed by the 2-oxoglutarate/Fe(II)-dependent dioxygenases, thebaine 6-O demethylase (T6ODM) and codeine O-demethylase (CODM). Further investigation into the biochemical functions of CODM and T6ODM revealed extensive and unexpected roles for such enzymes in the metabolism of protopine, benzo[c]phenanthridine, and rhoeadine alkaloids. When assayed with a wide range of benzylisoquinoline alkaloids, CODM, T6ODM, and the functionally unassigned paralog DIOX2, renamed protopine O-dealkylase, showed novel and efficient dealkylation activities, including regio- and substrate-specific O-demethylation and O,O-demethylenation. Enzymes catalyzing O,O-demethylenation, which cleave a methylenedioxy bridge leaving two hydroxyl groups, have previously not been reported in plants. Similar cleavage of methylenedioxy bridges on substituted amphetamines is catalyzed by heme-dependent cytochromes P450 in mammals. Preferred substrates for O,O demethylenation by CODM and protopine O-dealkylase were protopine alkaloids that serve as intermediates in the biosynthesis of benzo[c]phenanthridine and rhoeadine derivatives. Virus-induced gene silencing used to suppress the abundance of CODM and/or T6ODM transcripts indicated a direct physiological role for these enzymes in the metabolism of protopine alkaloids, and they revealed their indirect involvement in the formation of the antimicrobial benzo[c]phenanthridine sanguinarine and certain rhoeadine alkaloids in opium poppy. PMID- 23928313 TI - Direct stent puncture technique for intraluminal stent recanalization in the superficial femoral and popliteal arteries in-stent occlusion: outcomes from a prospective clinical analysis of diabetics with critical limb ischemia. AB - PURPOSE: To evaluate the efficacy and safety of "Direct Stent Puncture" technique for intraluminal stent recanalization in the femoro-popliteal segments. METHODS AND MATERIALS: A cohort of diabetics who had symptomatic in-stent occlusion of the superficial femoral or popliteal arteries underwent endovascular recanalization. After antegrade failure, direct stent puncture technique was performed. The primary end-point was to efficacy assessment, intended as technical success and clinical improvement. The secondary end-point was safety assessment, intended as free of complication rate. RESULTS: Fifty-four patients (37 men; 73.6+/-8.5 years) underwent direct stent puncture technique, after several unsuccessful antegrade attempts to cross the occluded stent. Technical success for intraluminal stent recanalization was achieved in 53/54 (98.2%) of cases and failed in 1/54 (1.8%). Clinical improvement was obtained in 51/54 (94.4%) of cases, with regression of the clinical symptoms and improvement of the TcPO2, from 3+/-18 mmHg to 43+/-11 mmHg after 15 days (p<0.001). Free of complications rate was 92.5%. In 2/54 (3.7%) of cases distal embolization occurred, in 1/54 (1.9%) case a sudden vessel thrombosis was diagnosed after 12 hours and in 1/54 (1.9%) case hematoma at the stent puncture site was observed. CONCLUSIONS: Direct Stent Puncture technique is an efficacy and safety option for intraluminal stent recanalization in the femoro-popliteal segment in-stent occlusion. PMID- 23928314 TI - Sympathetic renal denervation: hypertension beyond SYMPLICITY. AB - Despite a wide range of drug treatment for hypertension, resistant hypertension rates remain high. The SymplicityTM Renal Denervation System (Medtronic, Santa Rosa, CA), which creates renal nerve denervation, has shown initial success in lowering blood pressure among patients with resistant hypertension. Given the enormous market for this treatment approach, an estimated two dozen other companies are pursuing technologies with alternative approaches. Despite this fact, very little has been published on preclinical and clinical experience with these new devices. The current review summarizes the most prominent technologies in the pipeline and provides insight into the mechanism of action, preclinical, and clinical experience with these new devices. PMID- 23928315 TI - Percutaneous transcatheter closure of infarct related ventricular septal defects assisted with portable miniaturized extracorporeal membrane oxygenation: a case series. AB - Infarct associated ventricular septal defects (VSDs) are associated with considerable morbidity and mortality and are typically treated via an open surgical approach with the assistance of full mechanical bypass support in the setting of cardiogenic shock. We present two patients with infarct related VSDs and cardiogenic shock (CS) following acute ST segment elevation myocardial infarction (STEMI) and a review of the literature. Each patient successfully underwent percutaneous transcatheter closure of infarct related VSDs and initiation of extracorporeal membrane oxygenation (ECMO) via a portable miniaturized system that resulted in improvement in the patients' hemodynamics. PMID- 23928316 TI - Use of extracorporeal membrane oxygenation in tracheal surgery: a case series. AB - OBJECTIVES: To review our experience of extracorporeal membrane oxygenation in airway management during tracheal surgery. METHODS: A retrospective, observational study was conducted to evaluate the effectiveness of extracorporeal membrane oxygenation in tracheal surgery in Shanghai Chest Hospital between 2008 and 2012. RESULTS: In all 91 tracheal surgeries, 7 high-risk cases used extracorporeal membrane oxygenation. The duration of extracorporeal membrane oxygenation support ranged from 10 min to 31 min. All extracorporeal membrane oxygenation patients underwent surgical procedures safely and there was no hospital mortality. CONCLUSIONS: Although various advanced anesthesia techniques can ensure a safe airway in tracheal surgery in most cases, extracorporeal circulation plays an important role in high-risk cases. PMID- 23928318 TI - Risk stratification of nonvalvular atrial fibrillation: the possible role of blood cells. PMID- 23928317 TI - Bisphenol A inhibits cultured mouse ovarian follicle growth partially via the aryl hydrocarbon receptor signaling pathway. AB - Bisphenol A (BPA) is an endocrine disruptor that inhibits growth of mouse ovarian follicles and disrupts steroidogenesis at a dose of 438MUM. However, the effects of lower doses of BPA and its mechanism of action in ovarian follicles are unknown. We hypothesized that low doses of BPA inhibit follicular growth and decrease estradiol levels through the aryl hydrocarbon receptor (AHR) pathway. Antral follicles from wild-type and Ahr knock-out (AhrKO) mice were cultured for 96h. Follicle diameters and estradiol levels then were compared in wild-type and AhrKO follicles +/- BPA (0.004-438MUM). BPA inhibited follicle growth (110 438MUM) and decreased estradiol levels (43.8-438MUM) in wild-type and AhrKO follicles. However, at BPA 110MUM, inhibition of growth in AhrKO follicles was attenuated compared to wild-type follicles. These data suggest that BPA may inhibit follicle growth partially via the AHR pathway, whereas its effects on estradiol synthesis likely involve other mechanisms. PMID- 23928319 TI - Autograft versus nonirradiated allograft tissue for anterior cruciate ligament reconstruction: a systematic review. AB - BACKGROUND: An autograft has traditionally been the gold standard for anterior cruciate ligament reconstruction (ACLR), but the use of allograft tissue has increased in recent years. While numerous studies have demonstrated that irradiated allografts are associated with increased failure rates, some report excellent results after ACLR with nonirradiated allografts. The purpose of this systematic review was to determine whether the use of nonirradiated allograft tissue is associated with poorer outcomes when compared with autografts. HYPOTHESIS: Patients undergoing ACLR with autografts versus nonirradiated allografts will demonstrate no significant differences in graft failure risk, laxity on postoperative physical examination, or differences in patient-oriented outcome scores. STUDY DESIGN: Systematic review. METHODS: A systematic review was performed to identify prospective or retrospective comparative studies (evidence level 1, 2, or 3) of autografts versus nonirradiated allografts for ACLR. Outcome data included graft failure based on clinical findings and instrumented laxity, postoperative laxity on physical examination, and patient-reported outcome scores. Studies were excluded if they did not specify whether the allograft had been irradiated. Quality assessment and data extraction were performed by 2 examiners. RESULTS: Nine studies comparing autografts and nonirradiated allografts were included. Six of the 9 studies compared bone-patellar tendon-bone (BPTB) autografts with BPTB allografts. Two studies compared hamstring tendon autografts to hamstring tendon allografts, and 1 study compared hamstring tendon autografts to tibialis anterior allografts. The mean patient age in 7 of 9 studies ranged from 24.5 to 32 years, with 1 study including only patients older than 40 years and another not reporting patient age. The mean follow-up duration was 24 to 94 months. Six of 9 studies reported clinical graft failure rates, 8 of 9 reported postoperative instrumented laxity measurements, 7 of 9 reported postoperative physical examination findings, and all studies reported patient reported outcome scores. This review demonstrated no statistically significant difference between autografts and nonirradiated allografts in any outcome measure. CONCLUSION: No significant differences were found in graft failure rate, postoperative laxity, or patient-reported outcome scores when comparing ACLR with autografts to nonirradiated allografts in this systematic review. These findings apply to patients in their late 20s and early 30s. Caution is advised when considering extrapolation of these findings to younger, more active cohorts. PMID- 23928320 TI - Passive anterior tibial subluxation in anterior cruciate ligament-deficient knees. AB - BACKGROUND: Abnormal anterior-posterior and rotational motion secondary to anterior cruciate ligament (ACL) insufficiency is typically described in terms of dynamic laxity. An original description of the abnormal tibiofemoral relationship in the setting of ACL insufficiency has highlighted the presence of a fixed anterior tibial subluxation in this population of failed ACL reconstruction (ACLR); however, no study has quantified the degree of tibial subluxation in both the medial and lateral compartments. PURPOSE: To measure and compare the amount of anterior tibial subluxation among various states of ACL competency, including (1) intact ACL, (2) acute ACL disruption, and (3) failed ACLR (ie, patients requiring revision ACLR). We hypothesized that anterior tibial displacement would be greater in the lateral compartment and in cases of failed ACLR compared with intact and acute ACL injured states. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Using sagittal magnetic resonance imaging (MRI) and a standardized measurement technique, we determined the amount of anterior tibial subluxation relative to a constant posterior condylar reference point. Measurements were performed in both the medial and the lateral compartments and were compared with 1-way analysis of variance. The presence of meniscal tears along with meniscal volume loss and chondral damage was correlated with the amount of subluxation in each group. RESULTS: Compared with the intact ACL state, the medial tibial plateau was positioned more anteriorly relative to the femur in both acute ACL injured knees (mean 1.0 mm) and those that failed ACLR (mean 1.8 mm) (P = .072). In the lateral compartment, there was 0.8 mm of mean anterior tibial displacement after acute ACL injury and 3.9 mm of mean anterior subluxation in patients who failed ACLR (P < .001). Mean anterior displacement of the lateral plateau in patients who failed ACLR was almost 5 times greater than the amount observed in patients with acute ACL injuries. There was no correlation between meniscal/chondral injury and the amount of subluxation. CONCLUSION: Patients who require revision ACLR have an abnormal tibiofemoral relationship noted on MRI that is most pronounced in the lateral compartment and should be taken into account during revision surgery. These observations may explain the suboptimal clinical results seen in some patients who undergo revision ACLR. PMID- 23928321 TI - Results of arthroscopic labral reconstruction of the hip in elite athletes. AB - BACKGROUND: Femoroacetabular impingement (FAI) has been well characterized as a cause of hip pain and resultant damage to the acetabular labrum. It has become increasingly clear that an intact labrum is essential for normal joint mechanics, hip stability, and preservation of the articular cartilage. Elite athletes with a hypoplastic or irreparable labrum present a difficult clinical challenge. PURPOSE: To assess clinical outcomes and determine if elite athletes are able to return to a high level of function and sport after labral reconstruction. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A retrospective review of a prospectively collected registry identified 21 elite athletes (23 hips) with an average age of 28.0 years (range, 19-41 years) who underwent an arthroscopic iliotibial band labral reconstruction. Concomitant procedures included femoral and acetabular osteoplasty in all patients and microfracture in 9 of 23 hips. Clinical outcomes were assessed with the modified Harris Hip Score (MHHS), the Hip Outcome Score (HOS), the Short Form-12 (SF-12), and patient satisfaction (on a scale from 1-10). Return to play was determined, as well as level of return to play, based on sport-specific statistics. RESULTS: Two patients progressed to arthroplasty. There were 2 revisions in this group of patients, both for lysis of capsulolabral adhesions in which the graft was found to be well integrated at the time of surgery. The rate of return to play was 85.7% (18/21), with 81% (17/21) returning to a similar level. Subjective follow-up was obtained from 17 of the remaining 19 patients (89%), with an average follow-up of 41.4 months (range, 20 74 months). The average MHHS improved from 67 to 84 (P = .026) and the average HOS Sport subscore from 56 to 77 (P = .009). The overall median patient satisfaction with outcome was 8.2 (range, 3-10). CONCLUSION: Arthroscopic labral reconstruction using an ipsilateral iliotibial band autograft provides good short term clinical outcomes, high patient satisfaction, and a satisfactory level of return to play in a select group of elite athletes. PMID- 23928322 TI - The JOINT model of nurse absenteeism and turnover: a systematic review. AB - BACKGROUND: Absenteeism and turnover among healthcare workers have a significant impact on overall healthcare system performance. The literature captures variables from different levels of measurement and analysis as being associated with attendance behavior among nurses. Yet, it remains unclear how variables from different contextual levels interact to impact nurses' attendance behaviors. OBJECTIVES: The purpose of this review is to develop an integrative multilevel framework that optimizes our understanding of absenteeism and turnover among nurses in hospital settings. METHODS: We therefore systematically examine English only studies retrieved from two major databases, PubMed and CINAHL Plus and published between January, 2007 and January, 2013 (inclusive). FINDINGS: Our review led to the identification of 7619 articles out of which 41 matched the inclusion criteria. The analysis yielded a total of 91 antecedent variables and 12 outcome variables for turnover, and 29 antecedent variables and 9 outcome variables for absenteeism. The various manifested variables were analyzed using content analysis and grouped into 11 categories, and further into five main factors: Job, Organization, Individual, National and inTerpersonal (JOINT). Thus, we propose the JOINT multilevel conceptual model for investigating absenteeism and turnover among nurses. CONCLUSIONS: The JOINT model can be adapted by researchers for fitting their hypothesized multilevel relationships. It can also be used by nursing managers as a lens for holistically managing nurses' attendance behaviors. PMID- 23928323 TI - The impact of the Bologna process on nursing higher education in Europe: a review. AB - BACKGROUND: Changes are occurring in global higher education. Nursing is not exempt from these changes, and must adapt in order to be competitive in a global market. The Bologna process has been integral in the last decade in modernizing European higher education. However, modernization does not occur without challenges. This paper addresses the Bologna process and the challenges it presents to nursing higher education in Europe. OBJECTIVE: To describe the Bologna Process as it relates to European nursing education. DESIGN AND METHODOLOGY: Literature review via searches of the following electronic databases: Academic Search Premier, MEDLINE, PubMed, ERIC, and CINAHL. Search criteria included Bologna process, European higher education, nursing education, quality assurance, and ECTS. RESULTS: Twenty-four peer-reviewed articles were included as well as one peer-reviewed presentation, one commission report, and one book. CONCLUSION: Further investigation is required to address the complexities of the Bologna process and its evolutionary changes as it relates to nursing education in Europe. Change is not always easy, and is often complex, especially as it relates to cross-border education that involves governmental regulation. Bologna-member countries need to adapt to the ever-changing higher education environment or fall behind. PMID- 23928324 TI - Improving the interface between informal carers and formal health and social services: a qualitative study. AB - BACKGROUND: Reports about the impact of caring vary widely, but a consistent finding is that the role is influenced (for better or worse) by how formal services respond to, and work with informal carers and of course the cared for person. OBJECTIVE: We aimed to explore the connection between informal and formal cares and identify how a positive connection or interface might be developed and maintained. DESIGN: We undertook a qualitative descriptive study with focus groups and individual interviews with informal carers, formal care service providers and representatives from carer advocacy groups. Content analysis was used to identify key factors impacting on the interface between informal and formal carers and propose specific recommendations for service development. SETTING: Community setting including urban and rural areas of New Zealand. PARTICIPANTS AND METHODS: Seventy participants (the majority informal carers) took part in 13 focus groups and 22 individual interviews. RESULTS: Four key themes were derived: Quality of care for the care recipient; Knowledge exchange (valuing carer perspectives); One size does not fit all (creating flexible services); and A constant struggle (reducing the burden services add). An optimum interface to address these key areas was proposed. CONCLUSION: In addition to ensuring quality care for the care recipient, specific structures and processes to support a more positive interface appear warranted if informal carers and services are to work well together. An approach recognising the caring context and carer expertise may decrease the additional burden services contribute, and reduce conflicting information and resultant confusion and/or frustration many carers experience. PMID- 23928325 TI - Neuroprotective action of synthetic steroids with oxygen bridge. Activity on GABAA receptor. AB - Allopregnanolone (A) and pregnanolone (P) are able to modify neural activities acting through the GABAA receptor complex. This capacity makes them useful as anticonvulsant, anxiolytic, or anti-stress compounds. In this study, the performance of seven synthetic steroids (SS) analogous of A or P containing an intramolecular oxygen bridge was evaluated using different assays. Competition assays showed that compounds 1, 5, 6 and 7 affected the binding of specific ligands for the GABAA receptor in a way similar to that of A and P, whereas compounds 3 and 4 stimulated [(3)H]-flunitrazepam and reduced [(35)S]-TBPS binding. The enzyme 3beta-hydroxysteroid dehydrogenase (3beta-HSD) produces the precursor for A and P, and its activity is regulated by steroids. The action of several SS on 3beta-HSD activity was tested in different tissues. All SS analyzed inhibit its activity, but compound 5 was the least effective. Finally, the neuroprotective role of two SS was evaluated in cerebral cortex and hippocampus cultures subjected to hypoxia. Glial fibrillary acidic protein (GFAP) increase was prevented by A, P, and compounds 3 and 5. Only A, P and compound 5 prevented neurofilament (NF160/200) decrease in hippocampus cultures, whereas A and compound 5 partially prevented NF200 and NF160 decreases respectively in cerebral cortex cultures. A prevented microtubule associated protein (MAP 2b) decrease in cerebral cortex cultures, while in hippocampus cultures only compounds 3 and 5 had effect. All steroids prevented MAP 2c decrease in both brain regions. PMID- 23928326 TI - Copper and cadmium effects on growth and extracellular exudation of the marine toxic dinoflagellate Alexandrium catenella: 3D-fluorescence spectroscopy approach. AB - In this study, metal contamination experiments were conducted to investigate the effects of copper and cadmium on the growth of the marine toxic dinoflagellate Alexandrium catenella and on the production of dissolved organic matter (Dissolved Organic Carbon: DOC; Fluorescent Dissolved Organic Matter: FDOM). This species was exposed to increasing concentrations of Cu(2+) (9.93 * 10(-10)-1.00 * 10(-7)M) or Cd(2+) (1.30 * 10(-8)-4.38 * 10(-7)M), to simulate polluted environments. The drastic effects were observed at pCu(2+)=7.96 (Cu(2+): 1.08 * 10(-8)M) and pCd(2+)=7.28 (Cd(2+): 5.19 * 10(-8)M), where cyst formation occurred. Lower levels of Cu(2+) (pCu(2+)>9.00) and Cd(2+) (pCd(2+)>7.28) had no effect on growth. However, when levels of Cu(2+) and Cd(2+) were beyond 10(-7)M, the growth was totally inhibited. The DOC released per cell (DOC/Cell) was different depending on the exposure time and the metal contamination, with higher DOC/Cell values in response to Cu(2+) and Cd(2+), comparatively to the control. Samples were also analyzed by 3D-fluorescence spectroscopy, using the Parallel Factor Analysis (PARAFAC) algorithm to characterize the FDOM. The PARAFAC analytical treatment revealed four components (C1, C2, C3 and C4) that could be associated with two contributions: one, related to the biological activity; the other, linked to the decomposition of organic matter. The C1 component combined a tryptophan peak and a characteristic humic substances response, and the C2 component was considered as a tryptophan protein fluorophore. The C3 and C4 components were associated to marine organic matter production. PMID- 23928327 TI - A comparison of bilevel and continuous positive airway pressure noninvasive ventilation in acute cardiogenic pulmonary edema. AB - BACKGROUND: Whether bilevel positive airway pressure (BiPAP) is advantageous compared with continuous positive airway pressure (CPAP) in acute cardiogenic pulmonary edema (ACPO) remains uncertain. The aim of the meta-analysis was to assess potential beneficial and adverse effects of CPAP compared with BiPAP in patients with ACPO. METHODS: Randomized controlled trials comparing the treatment effects of BiPAP with CPAP were identified from electronic databases and reference lists from January 1966 to December 2012. Two reviewers independently assessed study quality. In trials that fulfilled inclusion criteria, we critically evaluate the evidence for the use of noninvasive ventilation on rates of hospital mortality, endotracheal intubation, myocardial infarction, and the length of hospital stay. Data were combined using Review Manager 4.3 (The Cochrane Collaboration, Oxford, UK). Both pooled effects and 95% confidence intervals (CIs) were calculated. RESULTS: Twelve randomized controlled trials with a total of 1433 patients with ACPO were included. The hospital mortality (relative risk [RR], 0.86; 95% CI, 0.65-1.14; P = .46; I(2) = 0%) and need for requiring invasive ventilation (RR, 0.89; 95% CI, 0.57-1.38; P = .64; I(2) = 0%) were not significantly different between patients treated with CPAP and those treated with BiPAP. The occurrence of new cases of myocardial infarction (RR, 0.95; 95% CI, 0.77-1.17; P = .53, I(2) = 0%) and length of hospital stay (RR, 1.01; 95% CI, -0.40 to 2.41; P = .98; I(2) = 0%) were also not significantly different between the 2 groups. CONCLUSIONS: There are no significant differences in clinical outcomes when comparing CPAP vs BiPAP. Based on the limited data available, our results suggest that there are no significant differences in clinical outcomes when comparing CPAP with BiPAP. PMID- 23928328 TI - Late diagnosis of an outbreak of leanness-enhancing agent-related food poisoning. AB - INTRODUCTION: Ractopamine is a leanness-enhancing agent approved in the United States and 26 other countries to reduce body fat content, increase muscle mass, and improve growth rate of certain food-producing animals. Other beta-agonists with stronger pharmacologic effects, especially clenbuterol, had been illegally used as leanness-enhancing agents in the United States, China, and the European Union, and foodborne poisonings related to clenbuterol residue in meat or liver were rarely reported in the European Union and China. We describe an unusual outbreak of leanness-enhancing agent-related food poisoning in Taiwan and its associated diagnostic challenge. REPORT OF THE OUTBREAK: Twelve patients presented to the emergency department of a regional hospital after having dinner together. Their clinical manifestations included nausea, vomiting, palpitation, facial flush, trunk or limb numbness, tremor, headache, weakness, chill, and dyspnea. Laboratory workup revealed the presence of hypokalemia, leukocytosis, and hyperglycemia. Poisoning attributable to beta-agonists was suspected; however, the diagnosis of leanness-enhancing agent poisoning was delayed because there was no leftover meat for analysis and because the veterinary medicine was illegal in Taiwan. Clenbuterol and salbutamol were eventually detected in 10 patients' urine sample by using liquid chromatography-tandem mass spectrometry, and the concentrations ranged from 54 to 806 MUg/L and from 0 to 4052 MUg/L, respectively. CONCLUSION: beta-Agonist leanness-enhancing agent-related food poisonings are rarely encountered, especially in those countries where relevant veterinary medicines are banned, and may thus pose diagnostic challenge to both emergency physicians and clinical toxicologists. PMID- 23928329 TI - Safety and efficacy of intravenous combination sedatives in the ED. AB - OBJECTIVE: The objective of the study is to determine the safety of intravenously administered combination sedatives in the emergency department (ED). METHODS: This was a retrospective study of alcohol-intoxicated patients in the ED. We examined the incidence of adverse events in agitated patients who received combination sedatives intravenously and compared the efficacy of combination sedatives and single-agent sedatives. RESULTS: Of 1300 patient visits, there was a single adverse event, a dystonic reaction, in the combination sedative group, for an adverse event rate of less than 1%. Patients who received combination sedatives were less likely to require a second dose of sedative medication than patients who received a single-agent sedative (21% vs 44%). CONCLUSIONS: Combination sedatives appear to be safe when administered intravenously in the ED. Combination sedatives may be more effective than single-agent sedatives in agitated alcohol-intoxicated patients. PMID- 23928330 TI - Highly efficient differentiation of neural precursors from human embryonic stem cells and benefits of transplantation after ischemic stroke in mice. AB - INTRODUCTION: Ischemic stroke is a leading cause of death and disability, but treatment options are severely limited. Cell therapy offers an attractive strategy for regenerating lost tissues and enhancing the endogenous healing process. In this study, we investigated the use of human embryonic stem cell derived neural precursors as a cell therapy in a murine stroke model. METHODS: Neural precursors were derived from human embryonic stem cells by using a fully adherent SMAD inhibition protocol employing small molecules. The efficiency of neural induction and the ability of these cells to further differentiate into neurons were assessed by using immunocytochemistry. Whole-cell patch-clamp recording was used to demonstrate the electrophysiological activity of human embryonic stem cell-derived neurons. Neural precursors were transplanted into the core and penumbra regions of a focal ischemic stroke in the barrel cortex of mice. Animals received injections of bromodeoxyuridine to track regeneration. Neural differentiation of the transplanted cells and regenerative markers were measured by using immunohistochemistry. The adhesive removal test was used to determine functional improvement after stroke and intervention. RESULTS: After 11 days of neural induction by using the small-molecule protocol, over 95% of human embryonic stem-derived cells expressed at least one neural marker. Further in vitro differentiation yielded cells that stained for mature neuronal markers and exhibited high-amplitude, repetitive action potentials in response to depolarization. Neuronal differentiation also occurred after transplantation into the ischemic cortex. A greater level of bromodeoxyuridine co-localization with neurons was observed in the penumbra region of animals receiving cell transplantation. Transplantation also improved sensory recovery in transplant animals over that in control animals. CONCLUSIONS: Human embryonic stem cell derived neural precursors derived by using a highly efficient small-molecule SMAD inhibition protocol can differentiate into electrophysiologically functional neurons in vitro. These cells also differentiate into neurons in vivo, enhance regenerative activities, and improve sensory recovery after ischemic stroke. PMID- 23928331 TI - Improved method for expression and isolation of the Mycoplasma hominis arginine deiminase from the recombinant strain of Escherichia coli. AB - Arginine deiminase is a promising anticancer drug active against melanoma, hepatocarcinoma and other tumors. Recombinant strains of Escherichia coli that express arginine deiminase from pathogenic bacteria Mycoplasma have been developed. However, production costs of heterologous arginine deiminase are high due to use of an expensive inducer and extraction buffer, as well as using diluted culture for enzyme induction. We report on a new advanced protocol for Mycoplasma hominis arginine deiminase expression, extraction and renaturation. The main improvements include manipulation with dense suspensions of E. coli, use of lactose instead of isopropyl beta-D-1-thiogalactopyranoside as an inducer and a cheaper but not less efficient buffer for solubilization of arginine deiminase inclusion bodies. In addition, supplementation of the storage culture medium with glucose and substrate (arginine) significantly stabilized the recombinant arginine deiminase producer. Homogenous preparations of recombinant arginine deiminase were obtained using anion-exchange and hydrophobic chromatography. The purified enzyme retained a specific activity of 30-34 U/mg for 12 months when stored at 4 degrees C in 20 mM sodium phosphate buffer pH 7.2 containing 1 M NaCl. PMID- 23928332 TI - Collagen hydrogels incorporated with surface-aminated mesoporous nanobioactive glass: Improvement of physicochemical stability and mechanical properties is effective for hard tissue engineering. AB - Collagen (Col) hydrogels have poor physicochemical and mechanical properties and are susceptible to substantial shrinkage during cell culture, which limits their potential applications in hard tissue engineering. Here, we developed novel nanocomposite hydrogels made of collagen and mesoporous bioactive glass nanoparticles (mBGns) with surface amination, and addressed the effects of mBGn addition (Col:mBG = 2:1, 1:1 and 1:2) and its surface amination on the physicochemical and mechanical properties of the hydrogels. The amination of mBGn was shown to enable chemical bonding with collagen molecules. As a result, the nanocomposite hydrogels exhibited a significantly improved physicochemical and mechanical stability. The hydrolytic and enzymatic degradation of the Col-mBGn hydrogels were slowed down due to the incorporation of mBGn and its surface amination. The mechanical properties of the hydrogels, specifically the resistance to loading as well as the stiffness, significantly increased with the addition of mBGn and its aminated form, as assessed by a dynamic mechanical analysis. Mesenchymal stem cells cultivated within the Col-mBGn hydrogels were highly viable, with enhanced cytoskeletal extensions, due to the addition of surface aminated mBGn. While the Col hydrogel showed extensive shrinkage (down to ~20% of initial size) during a few days of culture, the shrinkage of the mBGn added hydrogel was substantially reduced, and the aminated mBGn-added hydrogel had no observable shrinkage over 21 days. Results demonstrated the effective roles of aminated mBGn in significantly improving the physicochemical and mechanical properties of Col hydrogel, which are ultimately favorable for applications in stem cell culture for bone tissue engineering. PMID- 23928333 TI - The importance of size-exclusion characteristics of type I collagen in bonding to dentin matrices. AB - The mineral phase of dentin is located primarily within collagen fibrils. During development, bone or dentin collagen fibrils are formed first and then water within the fibril is replaced with apatite crystallites. Mineralized collagen contains very little water. During dentin bonding, acid-etching of mineralized dentin solubilizes the mineral crystallites and replaces them with water. During the infiltration phase of dentin bonding, adhesive comonomers are supposed to replace all of the collagen water with adhesive monomers that are then polymerized into copolymers. The authors of a recently published review suggested that dental monomers were too large to enter and displace water from collagen fibrils. If that were true, the endogenous proteases bound to dentin collagen could be responsible for unimpeded collagen degradation that is responsible for the poor durability of resin-dentin bonds. The current work studied the size exclusion characteristics of dentin collagen, using a gel-filtration-like column chromatography technique, using dentin powder instead of Sephadex. The elution volumes of test molecules, including adhesive monomers, revealed that adhesive monomers smaller than ~1000 Da can freely diffuse into collagen water, while molecules of 10,000 Da begin to be excluded, and bovine serum albumin (66,000 Da) was fully excluded. These results validate the concept that dental monomers can permeate between collagen molecules during infiltration by etch-and-rinse adhesives in water-saturated matrices. PMID- 23928334 TI - Screening on binary Zr-1X (X = Ti, Nb, Mo, Cu, Au, Pd, Ag, Ru, Hf and Bi) alloys with good in vitro cytocompatibility and magnetic resonance imaging compatibility. AB - In this study, the microstructures, mechanical properties, corrosion behaviors, in vitro cytocompatibility and magnetic susceptibility of Zr-1X alloys with various alloying elements, including Ti, Nb, Mo, Cu, Au, Pd, Ag, Ru, Hf and Bi, were systematically investigated to explore their potential use in biomedical applications. The experimental results indicated that annealed Zr-1X alloys consisted entirely or primarily of alpha phase. The alloying elements significantly increased the strength and hardness of pure Zr and had a relatively slight influence on elastic modulus. Ru was the most effective enhancing element and Zr-1Ru alloy had the largest elongation. The results of electrochemical corrosion indicated that adding various elements to Zr improved its corrosion resistance, as indicated by the reduced corrosion current density. The extracts of the studied Zr-1X alloys produced no significant deleterious effects on osteoblast-like cells (MG 63), indicating good in vitro cytocompatibility. All except for Zr-1Ag alloy showed decreased magnetic susceptibility compared to pure Zr, and Zr-1Ru alloy had the lowest magnetic susceptibility value, being comparable to that of alpha' phase Zr-Mo alloy and Zr-Nb alloy and far lower than that of Co-Cr alloy and Ti-6Al-4V alloy. Among the experimental Zr-1X alloys, Zr 1Ru alloy possessing high strength coupled with good ductility, good in vitro cytocompatibility and low magnetic susceptibility may be a good candidate alloy for medical devices within a magnetic resonance imaging environment. PMID- 23928335 TI - Mass spectrometry evidence for formation of estrogen-homocysteine conjugates: estrogens can regulate homocysteine levels. AB - Homocysteine (HCys), a sulfur-containing amino acid, is formed during the metabolism of methionine. An imbalance between the rate of production and the use of HCys during methionine metabolism can result in an increase in the plasma and urinary levels of HCys. HCys has been shown to be toxic to vascular endothelial cells through several pathways. Many earlier clinical studies have revealed an association between plasma HCys and cardiovascular and other diseases. In contrast, estrogens are suggested to lower the risk of cardiovascular disease. Several studies indicate that estrogen metabolites could be responsible for cardiovascular protection. It has been demonstrated that electrophilic estrogen quinones, E1(E2)-2,3-Q and E1(E2)-3,4-Q, can alkylate DNA as well as form conjugates with glutathione. I hypothesize that estrogen quinones generated in situ by oxidative enzymes, metal ions, or molecular oxygen can interact with HCys to form conjugates. This in turn could lower the levels of toxic HCys as well as quenching the reactive estrogen quinones, resulting in cardiovascular protective effects. To test the feasibility of a protective estrogen-HCys pathway, estrogen quinones were treated with HCys. Tandem mass spectrometry analysis of the assay mixture shows the formation of estrogen-HCys conjugates. Furthermore, incubation of catechol estrogens with myeloperoxidase (MPO) in the presence of HCys resulted in the formation of respective estrogen-HCys conjugates. The identities of estrogen-HCys conjugates in MPO assay extracts were confirmed by comparing them to pure synthesized estrogen-HCys standards. I propose that through conjugation estrogens could chemically regulate HCys levels; moreover these conjugates could be used as potential biomarkers in determining health. PMID- 23928336 TI - Illusory contours: a window onto the neurophysiology of constructing perception. AB - Seeing seems effortless, despite the need to segregate and integrate visual information that varies in quality, quantity, and location. The extent to which seeing passively recapitulates the external world is challenged by phenomena such as illusory contours, an example of visual completion whereby borders are perceived despite their physical absence in the image. Instead, visual completion and seeing are increasingly conceived as active processes, dependent on information exchange across neural populations. How this is instantiated in the brain remains controversial. Divergent models emanate from single-unit and population-level electrophysiology, neuroimaging, and neurostimulation studies. We reconcile discrepant findings from different methods and disciplines, and underscore the importance of taking into account spatiotemporal brain dynamics in generating models of brain function and perception. PMID- 23928337 TI - Anaphylaxis mediated myocardial infarction in a coronary graft: a new variant of Kounis syndrome (a case report). PMID- 23928338 TI - The beneficial effects of statins in patients undergoing hemodialysis. AB - BACKGROUND: The beneficial effects of statins in patients undergoing hemodialysis are controversial. Our study aimed to investigate the use of statins and the subsequent risk of cardiovascular morbidity and mortality in patients undergoing hemodialysis. METHODS: We conducted a cohort study using data from the Taiwan National Health Insurance Research Database. Cox regressions were performed to determine the hazard ratio (HR) of cardiovascular morbidity and mortality in the HD patients taking statins (statin cohort) compared with a propensity-matched comparison cohort. RESULTS: The statin cohort included a total of 4074 patients who received statin treatment while also undergoing hemodialysis (mean age 53.3 +/- 13.5 years, male 34.9%). The comparison cohort included 8148 propensity matched hemodialysis patients who were not using statins. During the three years of follow-up, the statin cohort had lower incidence of ischemic stroke (p < 0.001), hospitalizations due to unstable angina (p < 0.001), deep vein thrombosis (p < 0.001), cardiovascular mortality (p < 0.001), and all-cause mortality (p < 0.001). After Cox regression analysis, statin use was independently associated with lower risk of future ischemic stroke (HR, 0.49; 95% confidence interval [CI], 0.39-0.63), hospitalization for unstable angina (HR, 0.57; 95% CI, 0.47 0.70), deep vein thrombosis (HR, 0.11; 95% CI, 0.05-0.27), cardiovascular mortality (HR, 0.29; 95% CI, 0.18-0.46), and all-cause mortality (HR, 0.49; 95% CI, 0.41-0.58). CONCLUSION: Statin use was associated with a lower incidence of cardiovascular morbidity and mortality in patients undergoing hemodialysis. PMID- 23928339 TI - Impact of transseptal puncture site on acute and mid-term outcomes during cryoballoon ablation: a comparison between anterior, medial and posterior transatrial access. AB - BACKGROUND: Cryoballoon ablation (CBA) (Arctic Front, Medtronic, USA) has proven very effective in achieving pulmonary vein isolation (PVI). Different transseptal (TS) puncture sites might influence CBA procedure. The aim of the present study was to analyze the influence of different TS puncture sites (anterior, medial and posterior) on the acute and midterm outcomes of CBA in a series of patients undergoing PVI for drug resistant AF. METHODS AND RESULTS: A total 103 patients (78 males, mean age: 57 +/- 13 years) formed the study group. Transseptal punctures were performed in the anterior, medial and posterior portion of the FO in 41 (39.8%), 35 (34%) and 27 (26.2%) patients respectively. We found no statistical significant difference between the various sites of TS puncture in 1) the grade of PV occlusion (p = ns), the rate of PV isolation (p = ns), freedom from AF at a mean 12 month follow-up (p = ns) and complication rates (p = ns). Mean grade of occlusion was slightly lower in the RIPV when puncturing in the posterior FO but did not reach statistical significance. Mean procedural and fluoroscopy times were significantly lower when using the inner lumen mapping catheter (ILMC) (Achieve, Medtronic, USA) than the circular mapping catheter (CMC) (Lasso, Biosense Webster, California, USA) (107.24 mn vs 97.74 (p <= 0.001) and 25.7 mn vs 19.2 mn (p <= 0.001)). CONCLUSION: Different sites of TS puncture on the horizontal axis of the FO (anterior, medial and posterior) did not influence grades of PV occlusion, rates of isolation, mid-term outcome and rates of complications during CB ablation. PMID- 23928340 TI - Inappropriate left ventricular mass independently predicts cardiovascular mortality in patients with type 2 diabetes. PMID- 23928341 TI - Prevalence and clinical meaning of isolated increase of QRS voltages in hypertrophic cardiomyopathy versus athlete's heart: relevance to athletic screening. PMID- 23928342 TI - The enigma of 's' in the English language. PMID- 23928343 TI - Intravascular optical coherence tomographic (OCT) findings late after intracoronary beta brachytherapy. PMID- 23928344 TI - Presence of anti-viral and anti-parasitic antibodies and cardiovascular mortality: insights from NHANES III. PMID- 23928345 TI - Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. AB - BACKGROUND: As all anticoagulants, apixaban exposes to a bleeding risk, thus an effective way to reverse its effects is needed. Objectives were to study efficacy and safety of recombinant activated factor VII (rFVIIa), prothrombin complex concentrate (PCC), and fibrinogen concentrate (Fib) to reverse apixaban in a rabbit model of bleeding and thrombosis. METHODS: After a dose-ranging study to assess the minimal amount of apixaban increasing bleeding, 63 anaesthetized rabbits were randomized into 5 groups: control (saline), apixaban (apixaban and saline), rFVIIa (apixaban and rFVIIa), PCC (apixaban and PCC) and fibrinogen (apixaban and Fib). The Folts model was applied: a stenosis and an injury were carried out on the carotid artery, inducing thrombosis detected as cyclic flow reductions (CFRs) within 20 min. A number of parameters were recorded through ear immersion bleeding time (BT), clotting times (CT), thrombelastography, and thrombin generation time (TGT). Ultimately, a hepatosplenic section was performed to evaluate as primary endpoint the blood loss in 15 min. RESULTS: Apixaban increased blood loss (11.6 +/- 3 g vs. 8.3 +/- 3 g for control, p < 0.0003), lengthened BT, the prothrombin time (PT), thrombelastographic CT and decreased thrombin generation. Only rFVIIa reduced BT yet failed to improve blood loss. PCC and rFVIIa both shortened the PT, CT in thrombelastographic, and lag time in TGT. Fib improved clot firmness, enhanced thrombin generation but increased bleeding. Regarding safety, neither rFVIIa, PCC, nor Fib increased CFRs. CONCLUSION: rFVIIa, PCC, and Fib failed to reverse apixaban-induced bleeding. They only improved several laboratory parameters. PMID- 23928347 TI - Trends in stroke survival incidence rates in older Australians in the new millennium and forecasts into the future. AB - AIMS: The objective of this study is (i) to evaluate trends in the incidence rates of stroke survivors aged 60 years and older over a 11-year period in the Australian Capital Territory (ACT) and (ii) to forecast future trends in Australia until 2051. METHODS: Analysis of age- and sex-specific standardized incidence rates of older first-ever stroke survivors in ACT from 1999-2000 to 2009-2010 and projections of number of stroke survivors (NSS) in 2021 and 2051 using 2 models based only on (i) demographic changes and (ii) assuming changing of both incidence rates and demography. RESULTS: In the ACT in the first decade of the 21st century, the absolute numbers and age-adjusted standardized incidence rates of stroke survivors (measured as a function of age and period) increased among both men and women aged 60 years or older. The trend toward increased survival rates in both sexes was driven mainly by population aging, whereas the effect of stroke year was more pronounced in men compared with women. The absolute NSS (and the financial burden to the society) in Australia is predicted to increase by 35.5%-59.3% in 2021 compared with 2011 and by 1.6- to 4.6-fold in 2051 if current only demographic (first number) or both demographic and incidence trends (second number) continue. CONCLUSIONS: Our study demonstrates favorable trends in stroke survivor rates in Australia in the first decade of the new millennium and projects in the foreseeable future significant increases in the absolute numbers of older stroke survivors, especially among those aged 70 years or older and men. PMID- 23928348 TI - On the causal paths underlying the relation between atmospheric temperature and acute stroke. PMID- 23928349 TI - Identification of antimony resistance markers in Leishmania tropica field isolates through a cDNA-AFLP approach. AB - Pentavalent antimonial compounds have been the first line therapy for leishmaniasis; unfortunately the rate of treatment failure of anthroponotic cutaneous leishmaniasis (ACL) is increasing due to emerging of drug resistance. Elucidation of the molecular mechanisms operating in antimony resistance is critical for development of new strategies for treatment. Here, we used a cDNA AFLP approach to identify gene(s) which are differentially expressed in resistant and sensitive Leishmania tropica field isolates. We identified five genes, aquaglyceroporin (AQP1) acts in drug uptake, ATP-binding cassette (ABC) transporter (MRPA) involved in sequestration of drug, phosphoglycerate kinase (PGK) implicated in glycolysis metabolism, mitogen activated protein kinase (MAPK) and protein tyrosine phosphatase (PTP) responsible for phosphorylation pathway. The results were confirmed using real time RT-PCR which revealed an upregulation of MRPA, PTP and PGK genes and downregulation of AQP1 and MAPK genes in resistant isolate. To our knowledge, this is the first report of identification of PTP and PGK genes potentially implicated in resistance to antimonials. Our findings support the idea that distinct biomolecules might be involved in antimony resistance in L. tropica field isolates. PMID- 23928350 TI - The westernmost tarsier: a new genus and species from the Miocene of Pakistan. AB - As the closest living sister group of anthropoids, tarsiers (Family Tarsiidae) are an important group in primate evolution. However, their fossil record is poor: only four species have been described, two from the Eocene of China and two from the Miocene of Thailand. All are from outside the range of the living species, which occur only on islands off Southeast Asia. Here, we describe a new fossil tarsier from Pakistan, a significant range extension. This record consists of two lower molars, an upper molar, and a lower premolar found in the Miocene Manchar Formation (~18-16 Ma [millions of years ago]) of Sindh Province, southern Pakistan. The Pakistani tarsier is morphologically distinct from all living and fossil tarsiers, but most similar to the middle Miocene Thai species Tarsius thailandicus. Though living tarsiers have traditionally been classified in a single genus, a recent revision proposed a division into three genera, which is strongly supported by molecular data. The Pakistani species is not referable to any of these genera, and we create for it and T. thailandicus a new tarsiid genus. This discovery broadens our understanding of the geographic range and morphological diversity of Miocene tarsiers and helps to put the living tarsiers into their evolutionary context. PMID- 23928351 TI - Muscle force production during bent-knee, bent-hip walking in humans. AB - Researchers have long debated the locomotor posture used by the earliest bipeds. While many agree that by 3-4 Ma (millions of years ago), hominins walked with an extended-limb human style of bipedalism, researchers are still divided over whether the earliest bipeds walked like modern humans, or walked with a more bent knee, bent-hip (BKBH) ape-like form of locomotion. Since more flexed postures are associated with higher energy costs, reconstructing early bipedal mechanics has implications for the selection pressures that led to upright walking. The purpose of this study is to determine how modern human anatomy functions in BKBH walking to clarify the links between morphology and energy costs in different mechanical regimes. Using inverse dynamics, we calculated muscle force production at the major limb joints in humans walking in two modes, both with extended limbs and BKBH. We found that in BKBH walking, humans must produce large muscle forces at the knee to support body weight, leading to higher estimated energy costs. However, muscle forces at the hip remained similar in BKBH and extended limb walking, suggesting that anatomical adaptations for hip extension in humans do not necessarily diminish the effective mechanical advantage at the hip in more flexed postures. We conclude that the key adaptations for economical walking, regardless of joint posture, seem to center on maintaining low muscle forces at the hip, primarily by keeping low external moments at the hip. We explore the implications of these results for interpreting locomotor energetics in early hominins, including australopithecines and Ardipithecus ramidus. PMID- 23928352 TI - Regional behaviour among late Neanderthal groups in Western Europe: a comparative assessment of late Middle Palaeolithic bifacial tool variability. AB - Population dynamics between and within Pleistocene groups are vital to understanding wider behavioural processes like social transmission and cultural variation. The late Middle Palaeolithic (MIS 5d-3, ca. 115,000-35,000 BP [years before present]) permits a novel, data-driven assessment of these concepts through a unique record: bifacial tools made by classic Neanderthals. Previously, studies of late Middle Palaeolithic bifacial tools were hampered by a convoluted plethora of competing terms, types and regional entities. This paper presents a large-scale intercomparison of this tool type, and bridges typo-technological and spatio-temporal data from across Western Europe (Britain, Belgium, the Netherlands, France and Germany). Results indicate a high level of variation among individual bifacial tools and assemblages. Each bifacial tool concept is correlated with various methods of production, resulting in large degrees of morphological variation. Despite such variation, a distinct three-fold, macro regional pattern was identified: the Mousterian of Acheulean Tradition (MTA) in the southwest dominated by handaxes, the Keilmessergruppen (KMG) in the northeast typified by backed and leaf-shaped bifacial tools, and, finally a new unit, the Mousterian with Bifacial Tools (MBT), geographically situated between these two major entities, and characterised by a wider variety of bifacial tools. Differing local conditions, such as raw material or function, are not sufficient to explain this observed macro-regional tripartite. Instead, the MTA and KMG can be viewed as two distinct cultural traditions, where the production of a specific bifacial tool concept was passed on over generations. Conversely, the MBT is interpreted as a border zone where highly mobile groups of Neanderthals from both the east (KMG) and west (MTA) interacted. Principally, this study presents an archaeological contribution to behavioural concepts such as regionality, culture, social transmission and population dynamics. It illustrates the interpretive potential of large-scale lithic studies, and more specifically the presence of regionalised cultural behaviour amongst late Neanderthal groups in Western Europe. PMID- 23928353 TI - Automatic intraocular lens segmentation and detection in optical coherence tomography images. AB - We present a new algorithm for automatic segmentation and detection of an accommodative intraocular lens implanted in a biomechanical eye model. We extracted lens curvature and position. The algorithm contains denoising and fan correction by a multi-level calibration routine. The segmentation is realized by an adapted canny edge detection algorithm followed by a detection of lens surface with an automatic region of interest search to suppress non-optical surfaces like the lens haptic. The optical distortion of lens back surface is corrected by inverse raytracing. Lens geometry was extracted by a spherical fit. We implemented and demonstrated a powerful algorithm for automatic segmentation, detection and surface analysis of intraocular lenses in vitro. The achieved accuracy is within the expected range determined by previous studies. Future improvements will include the transfer to clinical anterior segment OCT devices. PMID- 23928354 TI - What is the role of online support from the perspective of facilitators of face to-face support groups? A multi-method study of the use of breast cancer online communities. AB - OBJECTIVE: To explore the role of online communities from the perspective of breast cancer survivors who are facilitators of face-to-face support groups. METHODS: Seventy-three attendees (73% response rate) of a Canadian support group training program completed a questionnaire examining when and why they used online communities. A purposive sample of 12 respondents was interviewed on how they used them in comparison to traditional supportive care. Survey responses were analyzed using descriptive statistics, and interview transcripts using a descriptive interpretive approach. RESULTS: Online communities were used by 31.5%, mostly during treatment (73.9%), daily or weekly (91.3%), primarily for information (91.3%) and symptom management (69.6%) and less for emotional support (47.8%). Reasons for non-use were lack of need (48.0%), self-efficacy (30.0%), trust (24.0%), and awareness (20.0%). Respondents used online communities to address unmet needs during periods of stress and uncertainty. A multi-theory framework helps to explain the conditions influencing their use. CONCLUSION: Online communities have the potential to fill gaps in supportive care by addressing the unmet needs of a subgroup of breast cancer survivors. Further research is required among typical cancer survivors. PRACTICE IMPLICATIONS: Online communities could play an important role as a supplemental resource for a sub-group of breast cancer survivors. PMID- 23928355 TI - Effect of the velopharynx on intraluminal pressures in reconstructed pharynges derived from individuals with and without sleep apnea. AB - The most collapsible part of the upper airway in the majority of individuals is the velopharynx which is the segment positioned behind the soft palate. As such it is an important morphological region for consideration in elucidating the pathogenesis of obstructive sleep apnea (OSA). This study compared steady flow properties during inspiration in the pharynges of nine male subjects with OSA and nine body-mass index (BMI)- and age-matched control male subjects without OSA. The k-omegaSST turbulence model was used to simulate the flow field in subject specific pharyngeal geometric models reconstructed from anatomical optical coherence tomography (aOCT) data. While analysis of the geometry of reconstructed pharynges revealed narrowing at velopharyngeal level in subjects with OSA, it was not possible to clearly distinguish them from subjects without OSA on the basis of pharyngeal size and shape alone. By contrast, flow simulations demonstrated that pressure fields within the narrowed airway segments were sensitive to small differences in geometry and could lead to significantly different intraluminal pressure characteristics between subjects. The ratio between velopharyngeal and total pharyngeal pressure drops emerged as a relevant flow-based criterion by which subjects with OSA could be differentiated from those without. PMID- 23928356 TI - Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38. AB - SN38 (7-ethyl-10-hydroxy camptothecin) is a prominent and efficacious anticancer agent. It is poorly soluble in both water and pharmaceutically approved solvents; therefore, the direct formulation of SN38 in solution form is limited. Currently, the water soluble prodrug of SN38, irinotecan (CPT-11), is formulated as a low pH solution and is approved for chemotherapy. However, CPT-11, along with most other water-soluble prodrugs shows unpredictable inter-patient conversion to SN38 in vivo, instability in the physiological environment and variable dose-related toxicities. More recently, macromolecular prodrugs (i.e. EZN-2208, IMMU-130) and nanomedicine formulations (i.e. nanoemulsions, polymeric micelles, lipid nanocapsule/nanoparticle, and liposomes) of SN38 have been investigated for improved delivery to cancer cells and tissues. Specifically, these carriers can take advantage of the EPR effect to direct drug preferentially to tumour tissues, thereby substantially improving efficacy and minimising side effects. Furthermore, oral delivery has been shown to be possible in preclinical results using nanomedicine formulations (i.e. dendrimers, lipid nanocapsules, polymeric micelles). This review summarizes the recent advances for the delivery of SN38 with a focus on macromolecular prodrugs and nanomedicines. PMID- 23928357 TI - A depot-forming glucagon-like peptide-1 fusion protein reduces blood glucose for five days with a single injection. AB - Peptide drugs are an exciting class of pharmaceuticals for the treatment of a variety of diseases; however, their short half-life dictates multiple and frequent injections causing undesirable side effects. Herein, we describe a novel peptide delivery system that seeks to combine the attractive features of prolonged circulation time with a prolonged release formulation. This system consists of glucagon-like peptide-1, a type-2 diabetes drug fused to a thermally responsive, elastin-like-polypeptide (ELP) that undergoes a soluble-insoluble phase transition between room temperature and body temperature, thereby forming an injectable depot. We synthesized a set of GLP-1-ELP fusions and verified their proteolytic stability and potency in vitro. Significantly, a single injection of depot forming GLP-1-ELP fusions reduced blood glucose levels in mice for up to 5 days, 120 times longer than an injection of the native peptide. These findings demonstrate the unique advantages of using ELPs to release peptide-ELP fusions from a depot combined with enhanced systemic circulation to create a tunable peptide delivery system. PMID- 23928359 TI - Dosing of cytotoxic chemotherapy: impact of renal function estimates on dose. AB - BACKGROUND: Oncology clinicians are now routinely provided with an estimated glomerular filtration rate on pathology reports whenever serum creatinine is requested. The utility of using this for the dose determination of renally excreted drugs compared with other existing methods is needed to inform practice. PATIENTS AND METHODS: Renal function was determined by [Tc(99m)]DTPA clearance in adult patients presenting for chemotherapy. Renal function was calculated using the 4-variable Modification of Diet in Renal Disease (4v-MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Cockcroft and Gault (CG), Wright and Martin formulae. Doses for renal excreted cytotoxic drugs, including carboplatin, were calculated. RESULTS: The concordance of the renal function estimates according to the CKD classification with measured Tc(99m)DPTA clearance in 455 adults (median age 64.0 years: range 17-87 years) for the 4v-MDRD, CKD EPI, CG, Martin and Wright formulae was 47.7%, 56.3%, 46.2%, 56.5% and 60.2%, respectively. Concordance for chemotherapy dose for these formulae was 89.0%, 89.5%, 85.1%, 89.9% and 89.9%, respectively. Concordance for carboplatin dose specifically was 66.4%, 71.4%, 64.0%, 73.8% and 73.2%. CONCLUSION: All bedside formulae provide similar levels of concordance in dosage selection for the renal excreted chemotherapy drugs when compared with the use of a direct measure of renal function. PMID- 23928358 TI - VKORC1L1, an enzyme rescuing the vitamin K 2,3-epoxide reductase activity in some extrahepatic tissues during anticoagulation therapy. AB - Vitamin K is involved in the gamma-carboxylation of the vitamin K-dependent proteins, and vitamin K epoxide is a by-product of this reaction. Due to the limited intake of vitamin K, its regeneration is necessary and involves vitamin K 2,3-epoxide reductase (VKOR) activity. This activity is known to be supported by VKORC1 protein, but recently a second gene, VKORC1L1, appears to be able to support this activity when the encoded protein is expressed in HEK293T cells. Nevertheless, this protein was described as being responsible for driving the vitamin K-mediated antioxidation pathways. In this paper we precisely analyzed the catalytic properties of VKORC1L1 when expressed in Pichia pastoris and more particularly its susceptibility to vitamin K antagonists. Vitamin K antagonists are also inhibitors of VKORC1L1, but this enzyme appears to be 50-fold more resistant to vitamin K antagonists than VKORC1. The expression of Vkorc1l1 mRNA was observed in all tissues assayed, i.e. in C57BL/6 wild type and VKORC1 deficient mouse liver, lung, and testis and rat liver, lung, brain, kidney, testis, and osteoblastic cells. The characterization of VKOR activity in extrahepatic tissues demonstrated that a part of the VKOR activity, more or less important according to the tissue, may be supported by VKORC1L1 enzyme especially in testis, lung, and osteoblasts. Therefore, the involvement of VKORC1L1 in VKOR activity partly explains the low susceptibility of some extrahepatic tissues to vitamin K antagonists and the lack of effects of vitamin K antagonists on the functionality of the vitamin K-dependent protein produced by extrahepatic tissues such as matrix Gla protein or osteocalcin. PMID- 23928360 TI - GCN2 and TOR converge on aging. PMID- 23928361 TI - Effects of corticosterone and amyloid-beta on proteins essential for synaptic function: implications for depression and Alzheimer's disease. AB - The relationship between Alzheimer's disease (AD) and depression has been well established in terms of epidemiological and clinical observations. Depression has been considered to be both a symptom and risk factor of AD. Several genetic and neurobiological mechanisms have been described to underlie these two disorders. Despite the accumulating knowledge on this topic, the precise neuropathological mechanisms remain to be elucidated. In this study, we propose that synaptic degeneration plays an important role in the disease progression of depression and AD. Using primary culture of hippocampal neurons treated with oligomeric Abeta and corticosterone as model agents for AD and depression, respectively, we found significant changes in the pre-synaptic vesicle proteins synaptophysin and synaptotagmin. We further investigated whether the observed protein changes affected synaptic functions. By using FM((r))4-64 fluorescent probe, we showed that synaptic functions were compromised in treated neurons. Our findings led us to investigate the involvement of protein degradation mechanisms in mediating the observed synaptic protein abnormalities, namely, the ubiquitin-proteasome system and autophagy. We found up-regulation of ubiquitin-mediated protein degradation, and the preferential signaling for the autophagic-lysosomal degradation pathway. Lastly, we investigated the neuroprotective role of different classes of antidepressants. Our findings demonstrated that the antidepressants Imipramine and Escitalopram were able to rescue the observed synaptic protein damage. In conclusion, our study shows that synaptic degeneration is an important common denominator underlying depression and AD, and alleviation of this pathology by antidepressants may be therapeutically beneficial. PMID- 23928363 TI - Epidemiology and classification of post-traumatic headache: what do we know and how do we move forward? Comment on Lucas et al., "Prevalence and characterization of headache following mild TBI". PMID- 23928362 TI - Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts. AB - Lipin-1 deficiency is associated with massive rhabdomyolysis episodes in humans, precipitated by febrile illnesses. Despite well-known roles of lipin-1 in lipid biosynthesis and transcriptional regulation, the pathogenic mechanisms leading to rhabdomyolysis remain unknown. Here we show that primary myoblasts from lipin-1 deficient patients exhibit a dramatic decrease in LPIN1 expression and phosphatidic acid phosphatase 1 activity, and a significant accumulation of lipid droplets (LD). The expression levels of LPIN1-target genes [peroxisome proliferator-activated receptors delta and alpha (PPARdelta, PPARalpha), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC 1alpha), acyl-coenzyme A dehydrogenase, very long (ACADVL), carnitine palmitoyltransferase IB and 2 (CPT1B and CPT2)] were not affected while lipin-2 protein level, a closely related member of the family, was increased. Microarray analysis of patients' myotubes identified 19 down-regulated and 51 up-regulated genes, indicating pleiotropic effects of lipin-1 deficiency. Special attention was paid to the up-regulated ACACB (acetyl-CoA carboxylase beta), a key enzyme in the fatty acid synthesis/oxidation balance. We demonstrated that overexpression of ACACB was associated with free fatty acid accumulation in patients' myoblasts whereas malonyl-carnitine (as a measure of malonyl-CoA) and CPT1 activity were in the normal range in basal conditions accordingly to the normal daily activity reported by the patients. Remarkably ACACB invalidation in patients' myoblasts decreased LD number and size while LPIN1 invalidation in controls induced LD accumulation. Further, pro-inflammatory treatments tumor necrosis factor alpha+Interleukin-1beta(TNF1alpha+IL-1beta) designed to mimic febrile illness, resulted in increased malonyl-carnitine levels, reduced CPT1 activity and enhanced LD accumulation, a phenomenon reversed by dexamethasone and TNFalpha or IL-1beta inhibitors. Our data suggest that the pathogenic mechanism of rhabdomyolysis in lipin-1-deficient patients combines the predisposing constitutive impairment of lipid metabolism and its exacerbation by pro inflammatory cytokines. PMID- 23928364 TI - PPAR signaling pathway is a key modulator of liver proteome in pups born to vitamin B(12) deficient rats. AB - Maternal nutritional deficiency in-utero is known to predict risk of complex disorders like cardiovascular disease, diabetes and many neurological disorders in the offspring and vitamin B12 is one such critical micronutrient. Here we performed 2D-DIGE followed by MALDI TOF/TOF analysis to identify proteins that are differentially expressed in liver of pups born to mothers fed vitamin B12 deficient diet vis-a-vis control diet. To further establish causality, we analyzed the effect of B12 rehabilitation at parturition on the protein levels and the phenotype in pups. We identified 38 differentially expressed proteins that were enriched in pathways involved in the regulation of amino acid, lipid and carbohydrate metabolism. Further, three enzymes in the beta-oxidation pathway (hydroxyacyl-coenzyme A dehydrogenase, medium-chain specific acyl-CoA dehydrogenase, 3-ketoacyl-CoA thiolase) were down-regulated in pups born to mothers fed vitamin B12 deficient diet. We observed age-dependent differential expression of peroxisome proliferator activated-receptor (PPAR) alpha and gamma in the deficient pups. Interestingly, expression of 27 proteins that were differentially expressed was restored to the control levels after rehabilitation of female rats with vitamin B12 from parturition. Our study thus provides the first evidence that maternal vitamin B12 deficiency influences lipid and other micronutrient metabolism in pups through regulation of PPAR signaling pathway. BIOLOGICAL SIGNIFICANCE: Maternal vitamin B12 deficiency has been shown to predict the onset of complex disorders like atherosclerosis, type II diabetes etc. in the next generation during their adulthood. We have shown earlier that pups born to female rats fed with vitamin B12 deficient diet were obese and developed high levels of other intermediate traits such as triglycerides, cholesterol etc. that are related to the risk of diabetes and cardiovascular disorders. In this piece of work using differential proteomic approach we have identified the altered metabolic processes in the liver of vitamin B12 deficient pups. We have also documented that the proteins involved in beta-oxidation pathway are down-regulated. Further, differential expression of PPARalpha and PPARgamma was evidently documented as the master regulator for the alteration of lipid, amino acid and carbohydrate metabolism during maternal vitamin B12 deficiency. PMID- 23928365 TI - Rose bengal staining as an assessment of ocular surface damage and recovery in dry eye disease-a review. AB - PURPOSE: To review the use of ophthalmic rose bengal to assess the ocular surface, especially considering the grading scales used. METHODS: A literature search was undertaken to identify reports where either rose bengal or lissamine green had been used as a 'vital' stain, with a special interest in identifying studies that provided data before and after treatment for dry eye and also considered the mechanism of action of these two chemicals. RESULTS: Between 1985 and 2006, numerous clinical studies used a consistent grading scheme (that attributed to Van Bijsterveld) to assess the outcome of artificial tear treatments on dry eye patients. With such consistency, including the adoption of a treatment period of 1 month, comparisons can be made to indicate the efficacy of rose bengal staining to assess reduction in ocular surface desiccation. However, in the following years, several alternative grading schemes have been used for both rose bengal and lissamine green and assessment periods have been variable so making inter-study comparisons considerably more difficult to undertake. An attribute of rose bengal appears to be its ability to stain the nuclei of cells, but whether this also occurs for lissamine green is unclear. CONCLUSIONS: Ophthalmic rose bengal has been successfully adopted for use to assess the ocular surface over many years as a vital stain. More research is needed to assess whether lissamine green ocular surface staining can simply be substituted for rose bengal in evaluation of dry eye treatments. PMID- 23928366 TI - Effects of social environment on baseline glucocorticoid levels in a communally breeding rodent, the colonial tuco-tuco (Ctenomys sociabilis). AB - The social environment in which an animal lives can profoundly impact its physiology, including glucocorticoid (GC) responses to external stressors. In social, group-living species, individuals may face stressors arising from regular interactions with conspecifics as well as those associated with basic life history needs such as acquiring food or shelter. To explore the relative contributions of these two types of stressors on glucocorticoid physiology in a communally breeding mammal, we characterized baseline GC levels in female colonial tuco-tucos (Ctenomys sociabilis), which are subterranean rodents endemic to southwestern Argentina. Long-term field studies have revealed that while about half of all yearling female C. sociabilis live and breed alone, the remainder live and breed within their natal group. We assessed the effects of this intraspecific variation in social environment on GC physiology by comparing concentrations of baseline fecal corticosterone metabolite (fCM) for (1) lone and group-living yearling females in a free-living population of C. sociabilis and (2) captive yearling female C. sociabilis that had been experimentally assigned to live alone or with conspecifics. In both cases, lone females displayed significantly higher mean baseline fCM concentrations. Data from free-living animals indicated that this outcome arose from differences in circadian patterns of GC production. fCM concentrations for group-living animals declined in the afternoon while fCM in lone individuals did not. These findings suggest that for C. sociabilis, stressors associated with basic life history functions present greater challenges than those arising from interactions with conspecifics. Our study is one of the first to examine GC levels in a plural-breeding mammal in which the effects of group-living are not confounded by differences in reproductive or dominance status, thereby generating important insights into the endocrine consequences of group-living. PMID- 23928367 TI - Bifid cardiac apex in a 25-year-old male with sudden cardiac death. AB - Although a bifid cardiac apex is common in certain marine animals, it is an uncommon finding in humans. When present, bifid cardiac apex is usually associated with other congenital heart anomalies. We present a case of bifid cardiac apex that was an incidental finding in a 25-year-old male with sudden cardiac death from combined drug toxicity. On gross examination, there was a bifid cardiac apex with a 2-cm long cleft. There were no other significant gross or microscopic abnormalities. This case represents the very rare occurrence of a bifid cardiac apex as an isolated cardiac anomaly. PMID- 23928368 TI - Granulomatous myocarditis in severe heart failure patients undergoing implantation of a left ventricular assist device. AB - BACKGROUND: Granulomatous myocarditis may develop into cardiomyopathy and severe congestive heart failure that requires implantation of a left ventricular assist device (LVAD). METHODS: Left ventricular (LV) core samples were collected from 177 patients with severe heart failure at the time of LVAD implantation, and samples were histologically examined and graded for severity of hypertrophy and fibrosis. Granulomatous myocarditis incidentally seen in a subset of samples was characterized by staining and culturing for mycobacteria and fungi. Various clinical parameters in these patients were analyzed. RESULTS: Of the 177 LV core samples examined, 6 (3.4%) showed nonnecrotizing granulomatous inflammation in the myocardial wall. Stains and cultures for mycobacteria and fungi were negative. All six patients [three women, three men; five African American, one Asian; mean age, 52+/-9 years (range, 41-61 years)] had arrhythmias and required an automatic implantable cardioverter defibrillator. Before LVAD implantation, the patients' mean cardiac index was 1.8+/-0.4 l/min/m(2); cardiac output, 2.9+/ 0.6 l/min; and ejection fraction, 20+/-2%. One year after LVAD implantation, one patient had undergone heart transplantation. At 2 years, a second patient was transplanted, and one died. At 3 years, a third patient was transplanted and died postoperatively; two patients remained on support. No clinical evidence indicated involvement of other organs or recurrence in the transplanted patients. CONCLUSION: The incidental diagnosis of granulomatous myocarditis in our patients indicates that histological study of LV core samples in patients who undergo LVAD implantation may contribute to the diagnosis and be a consideration in the management of the underlying cause of heart failure. PMID- 23928369 TI - Simultaneous analysis of urinary phthalate metabolites of residents in Korea using isotope dilution gas chromatography-mass spectrometry. AB - Phthalates are used in industry products, household items, and medical tools as plasticizers. Human exposure to phthalates has raised concern about its toxicity. In the present study, optimization was conducted for the simultaneous analysis of eight kinds of phthalate metabolites using gas chromatography-mass spectrometry (GC-MS): MEP, MiBP, MnBP, MBzP, MiNP, MEHP, MEOHP, and MEHHP. In order to minimize the matrix effect and to do quantitative analysis, isotope dilution and LLE-GC-MS methods were performed. Urine samples were enzymatically hydrolyzed, extracted with a mixture of n-hexane and ethyl ether (8:2; v:v), and subsequently derivatized with trimethylsilylation. All eight kinds of analytes showed clear resolution and high reproducibility in GC-MS results. The method detection limit ranged from 0.05 ng/mL to 0.2 ng/mL. Calibration curves were found to be linear from 0.2 to 100 ng/mL with -(2)>0.992. The relative standard deviation of the intraday precision using water and urine ranged from 2.1% to 16.3%. The analysis was performed with urine samples that were collected from adults residing in the Republic of Korea. The analyzed concentration results were compared according to gender and region. As a result, DEHP metabolites showed the highest detected concentration (75.92 MUg/g creatinine, 100%), and MiNP, a metabolite of DiNP, showed the lowest detected concentration (0.42 MUg/g creatinine, 22.5%). On average, female urine (200.76 MUg/g creatinine) had a higher detected concentration of ?8 phthalate metabolites than male urine. Samples from rural regions (211.96 MUg/g creatinine) had higher levels than samples from urban regions. PMID- 23928370 TI - Future water resources for food production in five South Asian river basins and potential for adaptation--a modeling study. AB - The Indian subcontinent faces a population increase from 1.6 billion in 2000 towards 2 billion around 2050. Therefore, expansion of agricultural area combined with increases in productivity will be necessary to produce the food needed in the future. However, with pressure on water resources already being high, and potential effects of climate change still uncertain, the question rises whether there will be enough water resources available to sustain this production. The objective of this study is to make a spatially explicit quantitative analysis of water requirements and availability for current and future food production in five South Asian basins (Indus, Ganges, Brahmaputra, Godavari and Krishna), in the absence or presence of two different adaptation strategies: an overall improvement in irrigation efficiency, and an increase of reservoir storage capacity. The analysis is performed by using the coupled hydrology and crop production model LPJmL. It is found that the Godavari and Krishna basins will benefit most from an increased storage capacity, whereas in the Ganges and the Indus water scarcity mainly takes place in areas where this additional storage would not provide additional utility. Increasing the irrigation efficiency will be beneficial in all basins, but most in the Indus and Ganges, as it decreases the pressure on groundwater resources and decreases the fraction of food production that would become at risk because of water shortage. A combination of both options seems to be the best strategy in all basins. The large-scale model used in this study is suitable to identify hotspot areas and support the first step in the policy process, but the final design and implementation of adaptation options requires supporting studies at finer scales. PMID- 23928371 TI - Predicting reductive debromination of polybrominated diphenyl ethers by nanoscale zerovalent iron and its implications for environmental risk assessment. AB - The reductive debromination of polybrominated diphenyl ethers (PBDEs) by nanoscale zerovalent iron (nZVI) has proven to be a successful remediation approach. This study simulates the congener profiles and overall ecotoxicological impact of PBDE debromination by nZVI. The relationship between the calculated redox potential values and PBDE debromination rates was sufficiently strong to generate a satisfactory predictive capacity, which was further used to develop a quantitative structure-activity relationship (QSAR) model for the determination of the PBDE debromination patterns and dominant pathways. The predicted results of deca-BDE debromination showed that it would completely disappear within 30 days, but its lower brominated products, particularly tri- to penta-homologues, could exist in the environment even after 5 years. Formation and accumulation of more toxic, low brominated congeners through deca-BDE debromination suggest that deca-BDE may pose prolonged environmental risks. Changes in the toxic equivalent (TEQ) values during deca-BDE debromination parallel the occurrence and transformation of specific low brominated congeners with dioxin-like potency. PMID- 23928372 TI - Genetic deficiency of anti-aging gene klotho exacerbates early nephropathy in STZ induced diabetes in male mice. AB - Klotho is a recently discovered anti-aging gene and is primarily expressed in kidneys. In humans, the klotho level decreases with age whereas the prevalence of chronic kidney disease (CKD) increases with age. Diabetic nephropathy is the most common form of CKD, which leads to end-stage renal disease. A decrease in klotho has been found in kidneys of patients with diabetic nephropathy. The purpose of this study is to assess whether klotho gene deficiency affects early diabetic nephropathy in a mouse of model of type 1 diabetes induced by streptozotocin (STZ). Male KL(+/-) mutant and wild-type mice (6-8 weeks) were injected with multiple low doses of STZ. Renal functions and renal blood flow were assessed. Kidneys were collected for histological examination and molecular assays of TGFbeta1 and mammalian targets of rapamycin (mTOR) signaling. Klotho deficiency in KL(+/-) mutant mice exacerbated STZ-induced increases in urine albumin, blood urea nitrogen, expansion of mesangial matrix in renal glomeruli, and kidney hypertrophy, suggesting a protective role of klotho in kidney function and structure. Klotho deficiency did not affect renal blood flow. Notably, klotho deficiency significantly increased phosphorylation of Smad2, indicating enhanced TGFbeta1 signaling in kidneys. Klotho deficiency also increased phosphorylation of mTOR and S6 (a downstream effector of mTOR), indicating enhanced mTOR signaling in kidneys of early diabetic mice. Thus, klotho gene deficiency may make kidneys more susceptible to diabetic injury. Klotho gene deficiency exacerbated early diabetic nephropathy via enhancing both TGFbeta1 and mTOR signaling in kidneys. PMID- 23928373 TI - Activation of neurokinin 3 receptors stimulates GnRH release in a location dependent but kisspeptin-independent manner in adult mice. AB - GnRH neurons form the final common pathway for the central control of reproduction. GnRH release occurs from terminals in the external layer of the median eminence (ME) for neuroendocrine control of the pituitary, and near GnRH GnRH fiber appositions within the preoptic area (POA). Whether or not control of GnRH secretion by neuromodulators is different in these 2 areas is unknown. Mutations in neurokinin B (NKB) or the neurokinin-3 receptor (NK3R) are linked to hypogonadotropic hypogonadism in humans, suggesting that NKB may regulate GnRH secretion. Using fast scan cyclic voltammetry through carbon-fiber microelectrodes, we examined real-time GnRH release in response to the NK3R agonist senktide in the ME and POA. Coronal brain slices were acutely prepared from adult gonad-intact GnRH-green fluorescent protein male mice, and carbon fiber microelectrodes were placed either within green fluorescent protein positive terminal fields of the ME or near GnRH-GnRH fiber appositions in the POA. Senktide induced GnRH release consistently in the ME but not the POA, indicating that GnRH release is differentially regulated by NKB in a location dependent manner. Senktide also induced GnRH secretion in the ME of kisspeptin knockout (Kiss1 knockout) mice. Interestingly, release amplitude was lower compared with wild-type mice. These data indicate regulation of GnRH release by NK3R agonists is site specific and suggest that kisspeptin is not a required mediator between NK3R activation and GnRH secretion in the ME. This information will be useful for informing future models of afferent regulation of GnRH release. PMID- 23928374 TI - Vitamin D deficiency-induced muscle wasting occurs through the ubiquitin proteasome pathway and is partially corrected by calcium in male rats. AB - Vitamin D deficiency leads to muscle wasting in both animals and humans. A vitamin D-deficient rat model was created using Sprague Dawley male rats. We studied the involvement of the ubiquitin proteasome and other proteolytic pathways in vitamin D deficiency-induced muscle atrophy. To delineate the effect of hypocalcemia that accompanies D deficiency, a group of deficient rats was supplemented with high calcium alone. Total protein degradation in muscle was assessed by release of tyrosine; proteasomal, lysosomal, and calpain enzyme activities were studied using specific substrates by fluorometry, and E2 enzyme expression was assessed by Western blot analysis. Muscle histology was done by myosin ATPase staining method, whereas 3-methylhistidine in the urine was estimated using HPLC. Muscle gene expression was measured by semiquantitative RT PCR. Total protein degradation in muscle and the level of 3-methylhistidine in urine were increased in the deficient group compared with the control group. Proteasomal enzyme activities, expression of the E2 ubiquitin conjugating enzyme, and ubiquitin conjugates were increased in the deficient group compared with controls. On the other hand, lysosomal and calpain activities were not altered. Type II fiber area, a marker for muscle atrophy, was decreased in the deficient muscle compared with control muscle. Muscle atrophy marker genes and proteasomal subunit genes were up-regulated, whereas myogenic genes were down-regulated in D deficient muscle. From the results it appears that the ubiquitin proteasome pathway is the major pathway involved in vitamin D deficiency-induced muscle protein degradation and that calcium supplementation alone in the absence of vitamin D partially corrects the changes. PMID- 23928375 TI - Evidence that orphanin FQ mediates progesterone negative feedback in the ewe. AB - Orphanin FQ (OFQ), a member of the opioid family, is found in many areas of the hypothalamus and, when given centrally OFQ inhibits episodic LH secretion in rodents and sheep. Because GnRH neurons are devoid of the appropriate receptors to mediate steroid negative feedback directly, neurons that release OFQ may be involved. Using immunocytochemistry, we first determined that most OFQ neurons in the arcuate nucleus (ARC) and other hypothalamic regions of luteal phase ewes contained both estrogen receptor alpha and progesterone (P) receptor. Given a similar high degree of steroid receptor colocalization in other ARC subpopulations, we examined whether OFQ neurons of the ARC contained those other neuropeptides and neurotransmitters. OFQ did not colocalize with kisspeptin, tyrosine hydroxylase, or agouti-related peptide, but all ARC OFQ neurons coexpressed proopiomelanocortin. To test for a role for endogenous OFQ, we examined the effects of an OFQ receptor antagonist, [Nphe1,Arg14,Lys15]Nociceptin NH2 (UFP-101) (30 nmol intracerebroventricular/h), on LH secretion in steroid treated ewes in the breeding season and ovary-intact ewes in anestrus. Ovariectomized ewes with luteal phase concentrations of P and estradiol showed a significant increase in LH pulse frequency during infusion of UFP-101 (4.5 +/- 0.5 pulses/6 h) compared with saline infusion (2.6 +/- 0.4 pulses/6 h), whereas ewes implanted with only estradiol did not. Ovary-intact anestrous ewes displayed no significant differences in LH pulse amplitude or frequency during infusion of UFP-101. Therefore, we conclude that OFQ mediates, at least in part, the negative feedback action of P on GnRH/LH pulse frequency in sheep. PMID- 23928377 TI - Late-onset exercise in female rat offspring ameliorates the detrimental metabolic impact of maternal obesity. AB - Rising rates of maternal obesity/overweight bring the need for effective interventions in offspring. We observed beneficial effects of postweaning exercise, but the question of whether late-onset exercise might benefit offspring exposed to maternal obesity is unanswered. Thus we examined effects of voluntary exercise implemented in adulthood on adiposity, hormone profiles, and genes involved in regulating appetite and metabolism in female offspring. Female Sprague Dawley rats were fed either normal chow or high-fat diet (HFD) ad libitum for 5 weeks before mating and throughout gestation/lactation. At weaning, female littermates received either chow or HFD and, after 7 weeks, half were exercised (running wheels) for 5 weeks. Tissues were collected at 15 weeks. Maternal obesity was associated with increased hypothalamic inflammatory markers, including suppressor of cytokine signaling 3, TNF-alpha, IL-1beta, and IL-6 expression in the arcuate nucleus. In the paraventricular nucleus (PVN), Y1 receptor, melanocortin 4 receptor, and TNF-alpha mRNA were elevated. In the hippocampus, maternal obesity was associated with up-regulated fat mass and obesity-associated gene and TNF-alpha mRNA. We observed significant hypophagia across all exercise groups. In female offspring of lean dams, the reduction in food intake by exercise could be related to altered signaling at the PVN melanocortin 4 receptor whereas in offspring of obese dams, this may be related to up-regulated TNF-alpha. Late-onset exercise ameliorated the effects of maternal obesity and postweaning HFD in reducing body weight, adiposity, plasma leptin, insulin, triglycerides, and glucose intolerance, with greater beneficial effects in offspring of obese dams. Overall, hypothalamic inflammation was increased by maternal obesity or current HFD, and the effect of exercise was dependent on maternal diet. In conclusion, even after a significant sedentary period, many of the negative impacts of maternal obesity could be improved by voluntary exercise and healthy diet. PMID- 23928376 TI - Morpholino-mediated knockdown of ERalpha, ERbetaa, and ERbetab mRNAs in zebrafish (Danio rerio) embryos reveals differential regulation of estrogen-inducible genes. AB - Genetically distinct estrogen receptor (ER) subtypes (ERalpha and ERbeta) play a major role in mediating estrogen actions in vertebrates, but their unique and overlapping functions are not entirely clear. Although mammals have 1 gene of each subtype (ESR1 and ESR2), teleost fish have a single esr1 (ERalpha) and 2 esr2 (ERbetaa and ERbetab) genes. To determine the in vivo role of different ER isoforms in regulating estrogen-inducible transcription targets, zebrafish (Danio rerio) embryos were microinjected with esr-specific morpholino (MO) oligonucleotides to disrupt splicing of the exon III/intron III junction in the DNA-binding domain. Each MO knocked down its respective normal transcript and increased production of variants with a retained intron III (esr1 MO) or a deleted or mis-spliced exon III (esr2a and esr2b MOs). Both esr1 and esr2b MOs blocked estradiol induction of vitellogenin and ERalpha mRNAs, predominant hepatic genes, but esr2b was the only MO that blocked induction of cytochrome P450 aromatase B mRNA, a predominant brain gene. Knockdown of ERbetaa with the esr2a MO had no effect on estrogen induction of the 3 mRNAs but, when coinjected with esr1 MO, attenuated the effect of ERalpha knockdown. Results indicate that ERalpha and ERbetab, acting separately or cooperatively on specific gene targets, are positive transcriptional regulators of estrogen action, but the role of ERbetaa, if any, is unclear. We conclude that MO technology in zebrafish embryos is an advantageous approach for investigating the interplay of ER subtypes in a true physiological context. PMID- 23928378 TI - Organizational readiness for change in community-based addiction treatment programs and adherence in implementing evidence-based practices: a national study. AB - Prior studies by the authors identified that clinical staff who reported that their treatment unit had lower levels of organizational readiness to change experienced higher levels of barriers in implementing an evidence-based practice (EBP). The current study examined whether clinical staff perceptions of their treatment unit's organizational readiness to change were also associated with their adherence to EBP protocols during EBP implementation. Adherence was examined through a variable measuring the extent to which staff modified EBP standards and manuals when implementing a new EBP. Multivariate regression analyses identified that clinical staff who had five or more years of addiction counseling experience, who rated staff in their organization as having higher levels of influence, who less frequently implemented new counseling interventions and who reported higher levels of barriers when implementing a newly funded EBP also reported that their program made more modifications to the EBP in the implementation process. Finally, staff who implemented MI compared to any other EBP reported lower levels of EBP modifications. IMPLICATIONS: Continued federal funding is needed to enhance treatment unit organizational resources in order to reduce barriers and promote adherence to EBPs. Also, funders of treatment need to continue to provide ongoing technical assistance and training opportunities to promote implementation of EBPs with fidelity. PMID- 23928379 TI - Antimicrobial activity of quinoxaline 1,4-dioxide with 2- and 3-substituted derivatives. AB - Quinoxaline is a chemical compound that presents a structure that is similar to quinolone antibiotics. The present work reports the study of the antimicrobial activity of quinoxaline N,N-dioxide and some derivatives against bacterial and yeast strains. The compounds studied were quinoxaline-1,4-dioxide (QNX), 2 methylquinoxaline-1,4-dioxide (2MQNX), 2-methyl-3-benzoylquinoxaline-1,4-dioxide (2M3BenzoylQNX), 2-methyl-3-benzylquinoxaline-1,4-dioxide (2M3BQNX), 2-amino-3 cyanoquinoxaline-1,4-dioxide (2A3CQNX), 3-methyl-2-quinoxalinecarboxamide-1,4 dioxide (3M2QNXC), 2-hydroxyphenazine-N,N-dioxide (2HF) and 3-methyl-N-(2 methylphenyl)quinoxalinecarboxamide-1,4-dioxide (3MN(2MF)QNXC). The prokaryotic strains used were Staphylococcus aureus ATCC 6538, S. aureus ATCC 6538P, S. aureus ATCC 29213, Escherichia coli ATCC 25922, E. coli S3R9, E. coli S3R22, E. coli TEM-1 CTX-M9, E. coli TEM-1, E. coli AmpC Mox-2, E. coli CTX-M2 e E. coli CTX-M9. The Candida albicans ATCC 10231 and Saccharomyces cerevisiae PYCC 4072 were used as eukaryotic strains. For the compounds that presented activity using the disk diffusion method, the minimum inhibitory concentration (MIC) was determined. The alterations of cellular viability were evaluated in a time-course assay. Death curves for bacteria and growth curves for S. cerevisiae PYCC 4072 were also accessed. The results obtained suggest potential new drugs for antimicrobial activity chemotherapy since the MIC's determined present low values and cellular viability tests show the complete elimination of the bacterial strain. Also, the cellular viability tests for the eukaryotic model, S. cerevisiae, indicate low toxicity for the compounds tested. PMID- 23928380 TI - Detoxification of aflatoxin B1 by an aqueous extract from leaves of Adhatoda vasica Nees. AB - The effectiveness of aqueous extracts of various medicinal plants in detoxification of aflatoxin B1 (AFB1) was tested in vitro by thin-layer chromatography and enzyme-linked immunosorbent assay (ELISA). Among the different plant extracts, the leaf extract of Vasaka (Adhatoda vasica Nees) showed the maximum degradation of AFB1 (>= 98%) after incubation for 24h at 37 degrees C. The aflatoxin detoxifying activity of the A. vasica leaf extract was significantly reduced by heating to 100 degrees C for 10 min or autoclaving at 121 degrees C for 20 min. Dialysis had no effect on aflatoxin detoxifying ability of A. vasica extract and the dialyzed extract showed similar level of detoxification of AFB1 as that of the untreated extract. A time course study of aflatoxin detoxification by A. vasica extract showed that 69% of the toxin was degraded within 6h and >= 95% degradation was observed after 24h of incubation. Detoxification of AFB1 by A. vasica extract was further confirmed by liquid chromatography-mass spectrometry (LC-MS) analysis. Phytochemical analysis revealed the presence of alkaloids in methanolic extract of A. vasica leaves. A partially purified alkaloid from A. vasica leaves by preparative TLC exhibited strong AFB1 detoxification activity. PMID- 23928382 TI - Pregnancy and kidney disease: crossroads no more. PMID- 23928381 TI - Role of collagen matrix in tumor angiogenesis and glioblastoma multiforme progression. AB - Glioblastoma is a highly vascularized brain tumor, and antiangiogenic therapy improves its progression-free survival. However, current antiangiogenic therapy induces serious adverse effects including neuronal cytotoxicity and tumor invasiveness and resistance to therapy. Although it has been suggested that the physical microenvironment has a key role in tumor angiogenesis and progression, the mechanism by which physical properties of extracellular matrix control tumor angiogenesis and glioblastoma progression is not completely understood. Herein we show that physical compaction (the process in which cells gather and pack together and cause associated changes in cell shape and size) of human glioblastoma cell lines U87MG, U251, and LN229 induces expression of collagen types IV and VI and the collagen crosslinking enzyme lysyl oxidase and up regulates in vitro expression of the angiogenic factor vascular endothelial growth factor. The lysyl oxidase inhibitor beta-aminopropionitrile disrupts collagen structure in the tumor and inhibits tumor angiogenesis and glioblastoma multiforme growth in a mouse orthotopic brain tumor model. Similarly, d penicillamine, which inhibits lysyl oxidase enzymatic activity by depleting intracerebral copper, also exhibits antiangiogenic effects on brain tumor growth in mice. These findings suggest that tumor microenvironment controlled by collagen structure is important in tumor angiogenesis and brain tumor progression. PMID- 23928383 TI - Pregnancy and kidney disease-the miracle continues against all odds. PMID- 23928384 TI - Renal physiology of pregnancy. AB - Pregnancy involves remarkable orchestration of physiologic changes. The kidneys are central players in the evolving hormonal milieu of pregnancy, responding and contributing to the changes in the environment for the pregnant woman and fetus. The functional impact of pregnancy on kidney physiology is widespread, involving practically all aspects of kidney function. The glomerular filtration rate increases 50% with subsequent decrease in serum creatinine, urea, and uric acid values. The threshold for thirst and antidiuretic hormone secretion are depressed, resulting in lower osmolality and serum sodium levels. Blood pressure drops approximately 10 mmHg by the second trimester despite a gain in intravascular volume of 30% to 50%. The drop in systemic vascular resistance is multifactorial, attributed in part to insensitivity to vasoactive hormones, and leads to activation of the renin-aldosterone-angiostensin system. A rise in serum aldosterone results in a net gain of approximately 1000 mg of sodium. A parallel rise in progesterone protects the pregnant woman from hypokalemia. The kidneys increase in length and volume, and physiologic hydronephrosis occurs in up to 80% of women. This review will provide an understanding of these important changes in kidney physiology during pregnancy, which is fundamental in caring for the pregnant patient. PMID- 23928385 TI - Acute kidney injury in pregnancy-current status. AB - Pregnancy-related acute kidney injury (PR-AKI) causes significant maternal and fetal morbidity and mortality. Management of PR-AKI warrants a thorough understanding of the physiologic adaptations in the kidney and the urinary tract. Categorization of etiologies of PR-AKI is similar to that of acute kidney injury (AKI) in the nonpregnant population. The causes differ between developed and developing countries, with thrombotic microangiopathies (TMAs) being common in the former and septic abortion and puerperal sepsis in the latter. The incidence of PR-AKI is reported to be on a decline, but there is no consensus on the exact definition of the condition. The physiologic changes in pregnancy make diagnosis of PR-AKI difficult. Newer biomarkers are being studied extensively but are not yet available for clinical use. Early and accurate diagnosis is necessary to improve maternal and fetal outcomes. Timely identification of "at-risk" individuals and treatment of underlying conditions such as sepsis, preeclampsia, and TMAs remain the cornerstone of management. Questions regarding renal replacement therapy such as modality, optimal prescription, and timing of initiation in PR-AKI remain unclear. There is a need to systematically explore these variables to improve care of women with PR-AKI. PMID- 23928386 TI - Pregnancy in chronic kidney disease. AB - Despite vast improvements in fetal outcomes, pregnancy in women with CKD is fraught with hazards; worsening of renal function and complications like preeclampsia and premature delivery are common. To date, there is no accurate formula to calculate glomerular filtration rate (GFR). Also, whether the current CKD classification is better than the older classification at predicting outcomes in pregnant women with CKD is unknown. Women with an estimated GFR >=1.4 mg/dL are at increased risk of progressive worsening of renal function regardless of the cause of the underlying kidney disease. Preeclampsia is difficult to diagnose in pregnant women with underlying CKD, and serum markers such as soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PIGF) may lead the way for definitive diagnosis. New-onset lupus or lupus flare is an indication for kidney biopsy during pregnancy; cyclosporine is safe and is the most effective agent that can be used during pregnancy. Women with adult polycystic kidney disease are at increased risk of hypertension and preeclampsia during pregnancy, as well as hepatic cysts later in life, the latter occurring with multiple pregnancies. Strict blood pressure control is important in pregnant women with diabetic nephropathy. A multidisciplinary team that includes nephrologists and obstetricians who deal with high-risk pregnancies should be involved in the care of pregnant women with CKD for successful pregnancy outcomes. PMID- 23928388 TI - Changes in fertility and hormone replacement therapy in kidney disease. AB - Infertility is common among men and women with CKD and fertility is usually restored with successful kidney transplantation. There are many causes of infertility in those on dialysis, including sexual dysfunction and impaired spermatogenesis and ovulation resulting from an altered hormonal milieu. There is little information about infertility in CKD, but it is clear that ESRD results in low rates of pregnancy in women. Early reports of increased pregnancy rates in women on nocturnal hemodialysis suggest that this modality may improve the abnormal reproductive hormonal milieu of ESRD; small studies of men on dialysis also suggest this. Just as the specific causes of infertility in men and women with CKD/ESRD are unknown, we also lack information about the appropriateness of hormone replacement in these patients. This paper reviews these linked issues, pointing out the lack of data upon which to base clinical decision-making about these quality-of-life issues in our CKD/ESRD patients. PMID- 23928387 TI - The management of hypertension in pregnancy. AB - Hypertensive pregnancy disorders complicate 6% to 8% of pregnancies and cause significant maternal and fetal morbidity and mortality. The goal of treatment is to prevent significant cerebrovascular and cardiovascular events in the mother without compromising fetal well-being. Current guidelines differentiate between the treatment of women with acute hypertensive syndromes of pregnancy and women with preexisting chronic hypertension in pregnancy. This review will address the management of hypertension in pregnancy, review the various pharmacologic therapies, and discuss the future directions in this field. PMID- 23928389 TI - End-stage renal disease and pregnancy. AB - Pregnancy in patients with ESRD is rare and remains especially challenging. Because endocrine abnormalities and sexual dysfunction decrease fertility, conception rates have been remarkably low in this patient population. Moreover, when pregnancy does occur, hypertension, preeclampsia, anemia, intrauterine growth restriction, preterm delivery, stillbirth, and other complications can decrease the rate of a successful outcome. However, recent experiences with intensive hemodialysis managed by a multidisciplinary team are encouraging with respect to better overall outcomes for mothers and infants. In this article, we discuss the main causes of decreased fertility in dialysis-dependent women, review outcomes and complications of pregnancy among dialysis patients with a special focus on recent intensive hemodialysis data, and summarize the current best strategy to manage pregnant women on dialysis. PMID- 23928390 TI - Pregnancy in renal transplant recipients. AB - Fertility in women with kidney failure is restored by transplantation. It requires careful planning and is only advisable in women with good kidney function, controlled blood pressure, and general good health. Immunosuppressive drugs carry risks for the fetus, but the risks of prednisone, azathioprine, cyclosporine, and tacrolimus are surprisingly low. Mycophenolate is teratogenic. The success rate for pregnancy in kidney transplant recipients is lower than in the general population with 70% to 80% of pregnancies resulting in surviving infants. Prematurity, intrauterine growth restriction, and preeclampsia are all increased. Complications are higher and outcomes are worse for women with serum creatinine levels over 1.3 mg/dL. Ten to 15% of women have a temporary or permanent decline in kidney function, particularly if prepregnancy creatinine is high. Transplant-related infections can be serious for the mother and fetus. A multidisciplinary team should coordinate care. PMID- 23928391 TI - Kidney stones and pregnancy. AB - Kidney stones are common and do not spare the pregnant population. Although a simple stone event is usually straightforward in the general population, it is complex during pregnancy. Acute nephrolithiasis is associated with a unique set of complications during pregnancy and, because of imaging limitations, diagnosis is challenging. Multidisciplinary care is the key in proper management decisions. The pathophysiology of kidney stone formation in the pregnant state is also unique. Herein, we discuss the complexity of kidney stones and pregnancy. PMID- 23928393 TI - Emerging new biomarkers of preeclampsia. AB - Preeclampsia continues to plague some of the most vulnerable women and fetuses. It is surprisingly prevalent in developing and developed nations. According to the World Health Organization, hypertension during pregnancy is a leading cause of maternal mortality in industrialized countries at 16% and up to 25% in developing countries. As the pathogenesis of this disease is being unraveled, we are afforded new opportunities to develop novel biomarkers for early identification and prevention of disease. The angiogenic markers including soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin have demonstrated to be the most promising, perhaps in conjunction with traditional markers such as plasma protein-13 and uterine artery Doppler studies. There is also increasing evidence that the podocyte is shed during the course of preeclampsia, which may be useful for diagnosis. Systems biology approaches to biomarker discovery such as proteomics and metabolomics are also gaining more attention and will most certainly open new avenues of research. In this review, we present the best studied biomarkers of preeclampsia to date. PMID- 23928392 TI - New developments in the pathogenesis of preeclampsia. AB - Preeclampsia affects 3% to 5% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality worldwide. This disorder is characterized by a constellation of signs and symptoms, most notably new-onset hypertension and proteinuria during the last trimester of pregnancy. In this review, the molecular mechanisms of preeclampsia with an emphasis on the role of circulating antiangiogenic proteins in the pathogenesis of preeclampsia and its complications will be discussed. PMID- 23928394 TI - Preeclampsia: a "nephrocentric" view. AB - To the obstetrician, preeclampsia is a placental syndrome becoming clinically apparent in later pregnancy and presenting with maternal hypertension, proteinuria, and in some cases liver and central nervous system dysfunction, which, if not addressed in a timely fashion can lead to significant maternal and fetal morbidity and mortality. As such, the only satisfactory cure is delivery of the fetus, after which most, if not all, of the manifestations disappear. The nephrologist, who often is consulted only when patients develop more serious manifestations such as accelerating hypertension, acute kidney injury, and microangiopathic features, often has a different perspective. She/he sees a woman with hypertension and proteinuric kidney disease with mildly reduced glomerular filtration rate. Exciting discoveries regarding the pathogenesis of this syndrome have helped to reconcile these two views; however, much remains unknown. This review focuses on the hypertension and kidney manifestations of the disease, acknowledging that complex placental pathogenic alterations are clearly an important, if not the most important, initiator of the later maternal signs and symptoms. PMID- 23928395 TI - Preeclampsia: an obstetrician's perspective. AB - Preeclampsia is a pregnancy-specific syndrome that usually develops after 20 weeks gestation. The exact pathogenic mechanisms remain uncertain and are likely multifactorial. Preeclampsia is a heterogeneous condition with potentially maternal and fetal consequences. As part of the spectrum of hypertensive disorders of pregnancy, preeclampsia may progress rapidly and is a leading cause of maternal and perinatal morbidity and mortality worldwide. In the United States, the incidence of preeclampsia has increased. Clinical manifestations are highly variable and may occur antepartum, intrapartum, or postpartum. Hypertension and proteinuria are the traditional hallmarks for the diagnosis of preeclampsia. These signs may occur with or without multisystem dysfunction and fetal involvement. Risk factors have been identified for the development of preeclampsia; however, ideal methods for prevention, screening, and treatment remain elusive. Preeclampsia resolves after delivery of the fetus, but patients may still have hypertension postpartum. Women and fetuses affected by preeclampsia are at higher risk of developing long-term health issues. There appear to be risk factors common to hypertensive disorders of pregnancy and cardiovascular disease seen later in adulthood. Physicians providing healthcare to women are urged to recognize potential risk factors that arise from patient obstetric histories so that optimal long-term health surveillance is provided. PMID- 23928396 TI - Comparing group dehumanization and intra-sexual competition among normally ovulating women and hormonal contraceptive users. AB - Two studies address the role of hormonal shift across menstrual cycle in female dehumanization of other women. In Study 1, normally ovulating women (NOW) and women who use hormonal contraceptives (HCW) are compared in terms of how much they dehumanize other women and two other control targets (men and elderly people). In NOW, the level of dehumanization of other women, but not of men and elderly people, increases as the conception risk is enhanced. HCW do not show this pattern of results. In Study 2, we investigate the level of dehumanization of other women and of intra-sexual competition. Findings concerning dehumanization replicate those of Study 1. Intra-sexual competition increases with the rise of conception risk only in NOW. In addition, dehumanization is significantly associated with intra-sexual competition in NOW but not in HCW. Together, these studies demonstrate that dehumanization of women is elicited by menstrual cycle-related processes and associated with women's mate-attraction goals. PMID- 23928397 TI - Back to the future: nostalgia increases optimism. AB - This research examined the proposition that nostalgia is not simply a past oriented emotion, but its scope extends into the future, and, in particular, a positive future. We adopted a convergent validation approach, using multiple methods to assess the relation between nostalgia and optimism. Study 1 tested whether nostalgic narratives entail traces of optimism; indeed, nostalgic (compared with ordinary) narratives contained more expressions of optimism. Study 2 manipulated nostalgia through the recollection of nostalgic (vs. ordinary) events, and showed that nostalgia boosts optimism. Study 3 demonstrated that the effect of nostalgia (induced with nomothetically relevant songs) on optimism is mediated by self-esteem. Finally, Study 4 established that nostalgia (induced with idiographically relevant lyrics) fosters social connectedness, which subsequently increases self-esteem, which then boosts optimism. The nostalgic experience is inherently optimistic and paints a subjectively rosier future. PMID- 23928398 TI - The motivational dynamics of retrieval-induced forgetting: a test of cognitive energetics theory. AB - Two experiments addressed the phenomenon of retrieval-induced forgetting (RIF) from the standpoint of cognitive energetics theory (CET). Consistent with the inhibitory account of RIF and with the notion that inhibition can be demanding and resource dependent, we found that where the inhibitory activity was difficult (vs. easy), defining a high restraining force according to the CET, RIF occurred only in the presence of a high driving force combining an elevated motivation to inhibit with the availability of high resources. Overall, the current work highlights the crucial role of motivation in producing the RIF and the way in which this phenomenon abides by the general principles of motivated cognition. PMID- 23928399 TI - Does cultural exposure partially explain the association between personality and political orientation? AB - Differences in political orientation are partly rooted in personality, with liberalism predicted by Openness to Experience and conservatism by Conscientiousness. Since Openness is positively associated with intellectual and creative activities, these may help shape political orientation. We examined whether exposure to cultural activities and historical knowledge mediates the relationship between personality and political orientation. Specifically, we examined the mediational role of print exposure (Study 1), film exposure (Study 2), and knowledge of American history (Study 3). Studies 1 and 2 found that print and film exposure mediated the relationships Openness to Experience and Conscientiousness have with political orientation. In Study 3, knowledge of American history mediated the relationship between Openness and political orientation, but not the association between Conscientiousness and political orientation. Exposure to culture, and a corollary of this exposure in the form of acquiring knowledge, can therefore partially explain the associations between personality and political orientation. PMID- 23928400 TI - Caspase 8 differentially controls hepatocytes and non-parenchymal liver cells during chronic cholestatic liver injury in mice. AB - BACKGROUND & AIMS: Receptor mediated cell death through the activation of caspases has been identified as an important mechanism to control life and death in various tissues and is thus crucial for the maintenance of liver tissue homeostasis. Here we investigated how caspase 8 (Casp8) differentially regulates immune-mediated liver injury and regeneration in distinct liver cell types during chronic liver injury. METHODS: Conditional knockout mice with hepatocellular (Casp8(Deltahepa)) and ubiquitous deletion of Casp8 (Casp8(DeltaMx)) were used in models of cholestatic hepatitis [(DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine) treatment, bile duct ligation (BDL) and choline deficient diet with ethionine supplementation (CDE)]. RESULTS: Mice with a hepatocellular deletion of Casp8 (Casp8(Deltahepa)) were protected after DDC-treatment. Animals with a ubiquitous conditional Casp8 knockout (Casp8(DeltaMx)) displayed a significantly enhanced liver injury in various models of cholestatic liver injury. This was associated with higher transaminases, bilirubin levels and finally more liver fibrosis. However, caspase 3 (Casp3) activity was reduced in both knockout strains, suggesting additionally mechanisms contributing to the phenotype. Casp8(DeltaMx) mice displayed a stronger infiltration of mononuclear immune cells and more proliferation of liver-parenchymal cells in periportal areas. Further analysis confirmed that these infiltrating immune cells are resistant against extrinsic apoptosis. Bone-marrow-transplantation (BMT) experiments demonstrated that Casp8 deficient bone marrow derived cells are responsible for increased liver injury in DDC fed mice. CONCLUSIONS: Our results demonstrate that cell-type specific differences in apoptosis resistance mediated by Casp8 deletion are of significant relevance for the outcome of chronic liver injury. PMID- 23928401 TI - Delayed liver regeneration after partial hepatectomy in adipose differentiation related protein-null mice. AB - BACKGROUND & AIMS: Adult hepatocytes undergo cell cycle progression and proliferation in response to partial hepatectomy (PH). Transient lipid accumulation within hepatocytes preceding the peak proliferative phase is a characteristic feature of regenerating livers. However, the molecular mediators and mechanisms responsible for lipid accumulation in regenerating livers are not well understood. Adipose differentiation related protein (ADRP; Plin2) regulates hepatic triglyceride storage and Plin2-deficient (Plin2(-/-)) mice have significantly reduced triglyceride (TG) content in the liver. We sought to determine the functional significance of PLIN2 in liver regeneration in response to PH and toxic liver injury and examined whether absence of Plin2 expression modulates hepatocyte proliferation and liver regeneration. METHODS: We subjected wild-type (WT) and Plin2(-/-) mice to 70% PH or acute carbon tetrachloride (CCL4) treatment and examined the hepatic lipid content, the expression profile of lipid metabolism-related genes, the rate of cellular proliferation and the dynamics of liver regeneration in the treated animals. RESULTS: In response to PH, Plin2(-/-) mice showed decreased hepatic triglyceride accumulation and delayed cell cycle progression, which was associated with impaired liver regeneration. Fatty acid (FA) synthesis and lipid transfer gene expression profile were comparable between Plin2(-/-) and wild-type mice, while VLDL secretion rate was higher in the Plin2( /-) mice. Downregulated beta-oxidation and reduced cytosolic FA level in Plin2(-/ ) mice may have contributed to the attenuation of the liver regeneration capacity in these animals. In parallel experiments, we also observed attenuated hepatic lipid accumulation and proliferation in response to CCl4-mediated acute toxic liver injury in Plin2(-/-) mice. CONCLUSIONS: We conclude that PLIN2-mediated lipid accumulation and utilization by the liver is important for efficient liver regeneration in response to PH and toxic liver injury. PMID- 23928402 TI - HCV core-mediated activation of latent TGF-beta via thrombospondin drives the crosstalk between hepatocytes and stromal environment. AB - BACKGROUND & AIMS: The mechanisms by which fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) develop during chronic hepatitis C virus (HCV) infection are not fully understood. We previously observed that HCV core protein induced a TGF-beta-dependent epithelial mesenchymal transition, a process contributing to the promotion of cell invasion and metastasis by impacting TGF beta1 signalling. Here we investigated HCV core capacity to drive increased expression of the active form of TGF-beta1n transgenic mice and hepatoma cell lines. METHODS: We used an in vivo model of HCV core expressing transgenic mice. RESULTS: We observed that about 50% of genes deregulated by core protein expression were TGF-beta1 target genes. Active TGF-beta levels were increased in HCV core transgenic mouse livers. Overexpression of core protein in hepatoma cells increased active TGF-beta levels in culture supernatants and induced Smad2/3 phosphorylation, thus reflecting activation of the TGF-beta signaling pathway. Moreover, our data showed the implication of thrombospondin-1 in core dependent TGF-beta activation. Finally, hepatoma cells expressing HCV core could activate stellate cells in co-culture and this activation was TGF-beta dependent. CONCLUSIONS: Collectively, these data delineate a novel paradigm where HCV may be related to liver pathogenesis through its ability to induce a local, intrahepatic TGF-beta activation. They argue for a dual impact of HCV core on liver fibrosis and liver carcinogenesis: HCV core could act both as autocrine and paracrine factor modulating TGF-beta responses within hepatocytes and in stromal environment through TGF-beta activation. PMID- 23928403 TI - Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma. AB - BACKGROUND & AIMS: Sorafenib is the only therapy shown to improve overall survival in advanced hepatocellular carcinoma (HCC). Combination therapy targeting multiple signaling pathways may improve outcomes. This phase I study was designed to determine the maximum tolerated dose (MTD) of everolimus given with sorafenib 400mg twice daily in patients with advanced HCC of Child-Pugh class A liver function who were naive to systemic therapy. METHODS: Everolimus was initiated at 2.5mg once daily and increased per a Bayesian sequential dose escalation scheme based on the dose-limiting toxicities experienced within the first 28 days of treatment. Adverse events were assessed continuously. Efficacy was evaluated using the best overall response rate per RECIST. RESULTS: Thirty patients were enrolled; 25 were evaluable for MTD determination. One out of 12 patients treated with everolimus 2.5mg once daily and 6 out of 13 patients treated with everolimus 5.0mg once daily experienced a dose-limiting toxicity, most commonly thrombocytopenia (n=5). All patients experienced 1 adverse event, most commonly diarrhea (66.7%), hand-foot skin reaction (66.7%), and thrombocytopenia (50.0%). Best overall response was stable disease (62.5% and 42.9% in the 2.5-mg and 5.0-mg cohorts, respectively). Median time to progression and overall survival in the 2.5-mg cohort were 4.5 months and 7.4 months, respectively, and 1.8 months and 11.7 months, respectively, in the 5.0-mg cohort. CONCLUSIONS: In patients with advanced HCC, the everolimus MTD in combination with standard-dose sorafenib was 2.5mg once daily. The inability to achieve a biologically effective everolimus concentration at the MTD precluded phase II study of this combination. PMID- 23928404 TI - Adipose tissue and liver expression of SIRT1, 3, and 6 increase after extensive weight loss in morbid obesity. AB - BACKGROUND & AIMS: Severe obesity is associated with a state of chronic inflammation. Sirtuins (SIRT) are a family of conserved enzymes which are able to affect many metabolic and inflammatory pathways thereby potentially improving health and increasing lifespan. METHODS: We investigated the effect of weight loss on subcutaneous adipose tissue and liver mRNA and immunohistochemical expression of SIRT1, SIRT3, and SIRT6. Twenty-nine severely obese patients undergoing laparoscopic adjustable gastric banding (LAGB) were studied. Tissue samples were collected before and 6months after LAGB surgery. Tissue mRNA expression levels of SIRT1, SIRT3, and SIRT6 were correlated with clinical, biochemical, and histological parameters. In vitro, we studied sirtuin expression in native and stimulated monocytes, adipocytes, and hepatocytes. RESULTS: SIRT1, SIRT3, and SIRT6 mRNA expression was higher in the subcutaneous adipose tissue than in the liver. Weight loss resulted in a significant induction of SIRT1, SIRT3, and SIRT6 expression in the subcutaneous adipose tissue. In the liver, a significant increase after weight loss was observed, particularly for SIRT3 and SIRT6 mRNA expression; immunohistochemically, SIRT1 and SIRT3 expression was upregulated. Endotoxin and tumor necrosis factor-alpha suppressed SIRT1, SIRT3, and SIRT6 expression in human monocytes. The same stimuli suppressed total sirtuin deacetylase activity again, mainly in monocytes and less in adipocytes and hepatocytes. CONCLUSIONS: The relative abundance of adipose tissue mRNA expression of certain sirtuins exceeds its expression in the liver. Extensive weight loss increases sirtuin expression significantly both in adipose tissue and liver, probably as a consequence of reduced inflammation. PMID- 23928405 TI - Reply to: "Uncovering the molecular events associated with increased intestinal permeability in liver cirrhosis: The pivotal role of enterocyte tight junctions and future perspectives". PMID- 23928406 TI - Towards new tools for refined management of patients with advanced hepatocellular carcinoma under systemic therapy: some enthusiasm with a word of caution. PMID- 23928407 TI - ESM-1 expression in stromal cells is predictive of recurrence after radiofrequency ablation in early hepatocellular carcinoma. AB - BACKGROUND & AIMS: The prognosis of hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA) is mainly linked to tumor recurrence. So far, no tissue biomarker of recurrence has been validated in biopsy samples. We aimed at investigating the prognostic value of tissue biomarkers in HCC biopsy samples of patients treated with RFA. METHODS: All consecutive naive patients from 3 university hospitals, with compensated cirrhosis, early-stage (BCLC 0/A) uninodular HCC treated with RFA, and available tumor biopsy, were included. Edmondson's grade, and the expression of cytokeratin 19, glutamine synthase, beta catenin, epithelial cell adhesion molecule (EpCAM), and endothelial cell-specific molecule 1 (ESM-1) were assessed. Main clinical end points were overall and early recurrence. Statistical analyses were performed using Kaplan Meier, Log-rank test, and Cox models. RESULTS: 150 patients were included. Recurrence, death or liver transplantation occurred in 85, 51, and 12 patients, respectively. Median follow-up was 27months. ESM-1 expression by HCC stromal endothelial cells was observed in 58 patients (40%) and was associated with higher serum AFP levels, larger tumor, and more frequent expression of EpCAM and surrogate markers of activation of the Wnt-beta-catenin pathway. The 2 independent predictive factors of overall recurrence were serum AFP (HR 1.11 [1.002; 1.22], p=0.045) and ESM-1 expression (HR 1.56 [1.004; 2.43], p=0.048). ESM-1 expression was also an independent predictive factor of early recurrence (HR 1.81 [1.02; 3.21], p=0.042). CONCLUSIONS: ESM-1 expression by stromal endothelial cells, in tumor biopsy samples, has an independent predictive value of early recurrence after RFA. PMID- 23928408 TI - ABO-incompatible living donor liver transplantation is suitable in patients without ABO-matched donor. AB - BACKGROUND & AIMS: ABO-incompatible liver transplantation is usually contraindicated because of the risk of antibody-mediated humoral rejection of the graft. We describe 22 successful cases of patients who had living donor liver transplantation (LDLT) from ABO-incompatible donors. METHODS: The immunosuppressive protocol consisted of rituximab and plasmapheresis prior to LDLT. Plasmapheresis was planned for up to 2 weeks after LDLT aiming at maintaining levels of anti-ABO titers below 1:32. RESULTS: The median age of recipients was 54 years and the median MELD score was 13. The initial range of isoagglutinin IgM and IgG titers were 1:8-1:1024 and 1:2-1:1024, respectively. Preoperative isoagglutinin IgM and IgG titers were achieved less than or equal to 1:8 by performing therapeutic plasma exchange (TPE). While the median number of TPE was 4 (range, 2-18) in all patients, it was 4 (range, 2-8) in the initial low titer group (<1:256) and 8 (range, 6-18) in the high titer group (>= 1:256). There were no statistically significant differences for liver function tests in the first 2 weeks after transplantation between the groups having high MELD score (>= 20) vs. low MELD score (<20), local graft infusion vs. systemic infusion, or high initial isoagglutinin titer (>= 1:256) vs. low initial isoagglutinin titer (<1:256). Patient and graft survival was 100% and there was no acute humoral rejection in recipients at a mean follow-up of 10months (range, 3-21). CONCLUSIONS: ABO-incompatible LDLT can be safely performed when rituximab and TPE are used, and may be proposed when ABO-compatible donors are not available. PMID- 23928409 TI - MicroRNA profiles in graft preservation solution are predictive of ischemic-type biliary lesions after liver transplantation. AB - BACKGROUND & AIMS: Ischemic-type biliary lesions (ITBL) are the second most common cause of graft loss after liver transplantation. Though the exact pathophysiology of ITBL is unknown, bile duct injury during graft preservation is considered to be a major cause. Here we investigated whether the release of cholangiocyte-derived microRNAs (CDmiRs) during graft preservation is predictive of the development of ITBL after liver transplantation. METHODS: Graft preservation solutions (perfusates) and paired liver biopsies collected at the end of cold ischemia were analysed by RT-qPCR for CDmiR-30e, CDmiR-222, and CDmiR 296 and hepatocyte-derived miRNAs (HDmiRs) HDmiR-122 and HDmiR-148a. MicroRNAs in perfusates were evaluated on their stability by incubation and fractionation experiments. MicroRNA profiles in perfusates from grafts that developed ITBL (n=20) and grafts without biliary strictures (n=37) were compared. RESULTS: MicroRNAs in perfusates were proven to be stable and protected against degradation by interacting proteins. Ratios between HDmiRs/CDmiRs were significantly higher in perfusates obtained from grafts that developed ITBL (p<0.01) and were identified as an independent risk factor by multivariate analysis (p<0.01, HR: 6.89). The discriminative power of HDmiRs/CDmiRs in perfusates was validated by analysis of separate brain death- (DBD) and cardiac death donors (DBD; p <= 0.016) and was superior to expression in liver biopsies (C=0.77 in perfusates vs. C<0.50 in biopsies). CONCLUSIONS: This study demonstrates that differential release of CDmiRs during graft preservation is predictive of the development of ITBL after liver transplantation. This provides new evidence for the link between graft-related bile duct injury and the risk for later development of ITBL. PMID- 23928410 TI - Uncovering the molecular events associated with increased intestinal permeability in liver cirrhosis: the pivotal role of enterocyte tight junctions and future perspectives. PMID- 23928411 TI - Enhanced interpretation of adsorption data generated by liquid chromatography and by modern biosensors. AB - In this study we demonstrate the importance of proper data processing in adsorption isotherm estimations. This was done by investigating and reprocessing data from five cases on two closely related platforms: liquid chromatography (LC) and biosensors. The previously acquired adsorption data were reevaluated and reprocessed using a three-step numerical procedure: (i) preprocessing of adsorption data, (ii) adsorption data analysis and (iii) final rival model fit. For each case, we will discuss what we really measure and what additional information can be obtained by numerical processing of the data. These cases clearly demonstrate that numerical processing of LC and biosensor data can be used to gain deeper understanding of molecular interactions with adsorption media. This is important because adsorption data, especially from biosensors, is often processed using old and simplified methods. PMID- 23928413 TI - Determination of benzothiazole and benzotriazole derivates in tire and clothing textile samples by high performance liquid chromatography-electrospray ionization tandem mass spectrometry. AB - A high performance liquid chromatography-tandem mass spectrometry method utilizing electrospray ionization in positive and negative mode has been developed for the separation and detection of benzothiazole and benzotriazole derivates. Ultra-sonication assisted solvent extraction of these compounds has also been developed and the overall method demonstrated on a selected clothing textile and an automobile tire sample. Matrix effects and extraction recoveries, as well as linearity and limits of detection have been evaluated. The calibration curves spanned over more than two orders of magnitude with coefficients of correlation R(2)>0.99 and the limits of detection and the limits of quantification were in the range 1.7-58pg injected and 18-140pg/g, respectively. The extraction recoveries ranged between 69% and 102% and the matrix effects between 75% and 101%. Benzothiazole and benzotriazole derivates were determined in the textile sample and benzothiazole derivatives determined in the tire sample with good analytical performance. PMID- 23928412 TI - Large volume injection of aqueous peptide samples on a monolithic silica based zwitterionic-hydrophilic interaction liquid chromatography system for characterization of posttranslational modifications. AB - Zwitterionic-hydrophilic interaction liquid chromatography (HILIC) has been found very appropriate for separation of polar compounds and peptides with post translational modifications (PTMs) such as phosphorylation and glycosylation. In this study, a column switching system based on zwitterionic-HILIC silica based monolith columns was used for enrichment and separation of peptides and characterization of N-linked glycosylation by higher-energy collisional dissociation (HCD) Orbitrap mass spectrometry (MS). Peptides were found to be retained on a zwitterionic-HILIC precolumn, even in an aqueous buffer due to electrostatic interactions. Thus, a novel approach of using a zwitterionic-HILIC precolumn, for introduction of an aqueous sample such as a tryptic digest, followed by HILIC separation of the peptides is presented. The repeatability and loadability of the zwitterionic-HILIC-zwitterionic-HILIC column switching system were explored using a tryptic digest of transferrin and a mixture of six proteins. The column switching system was furthermore used to enrich and separate a tryptic digested rat liver extract gel fraction, where in total 48 peptides corresponding to 14 proteins were identified. N-linked glycoforms were also identified, both in the standard test proteins (transferrin and six protein mixture digest) and the rat liver extract fraction. In all cases, the identified N-linked glycoforms were identified at the end of the gradient, at high aqueous buffer content in the mobile phase, showing the suitability of the developed method for characterization of glycosylated peptides in aqueous samples. PMID- 23928415 TI - Fusarium euwallaceae sp. nov.--a symbiotic fungus of Euwallacea sp., an invasive ambrosia beetle in Israel and California. AB - The invasive Asian ambrosia beetle Euwallacea sp. (Coleoptera, Scolytinae, Xyleborini) and a novel Fusarium sp. that it farms in its galleries as a source of nutrition causes serious damage to more than 20 species of live trees and pose a serious threat to avocado production (Persea americana) in Israel and California. Adult female beetles are equipped with mandibular mycangia in which its fungal symbiont is transported within and from the natal galleries. Damage caused to the xylem is associated with disease symptoms that include sugar or gum exudates, dieback, wilt and ultimately host tree mortality. In 2012 the beetle was recorded on more than 200 and 20 different urban landscape species in southern California and Israel respectively. Euwallacea sp. and its symbiont are closely related to the tea shot-hole borer (E. fornicatus) and its obligate symbiont, F. ambrosium occurring in Sri Lanka and India. To distinguish these beetles, hereafter the unnamed xyleborine in Israel and California will be referred to as Euwallacea sp. IS/CA. Both fusaria exhibit distinctive ecologies and produce clavate macroconidia, which we think might represent an adaption to the species-specific beetle partner. Both fusaria comprise a genealogically exclusive lineage within Clade 3 of the Fusarium solani species complex (FSSC) that can be differentiated with arbitrarily primed PCR. Currently these fusaria can be distinguished only phenotypically by the abundant production of blue to brownish macroconidia in the symbiont of Euwallacea sp. IS/CA and their rarity or absence in F. ambrosium. We speculate that obligate symbiosis of Euwallacea and Fusarium, might have driven ecological speciation in these mutualists. Thus, the purpose of this paper is to describe and illustrate the novel, economically destructive avocado pathogen as Fusarium euwallaceae sp. nov. S. Freeman et al. PMID- 23928414 TI - Genomewide annotation and comparative genomics of cytochrome P450 monooxygenases (P450s) in the polypore species Bjerkandera adusta, Ganoderma sp. and Phlebia brevispora. AB - Genomewide annotation of cytochrome P450 monooxygenases (P450s) in three white rot species of the fungal order Polyporales, namely Bjerkandera adusta, Ganoderma sp. and Phlebia brevispora, revealed a large contingent of P450 genes (P450ome) in their genomes. A total of 199 P450 genes in B. adusta and 209 P450 genes each in Ganoderma sp. and P. brevispora were identified. These P450omes were classified into families and subfamilies as follows: B. adusta (39 families, 86 subfamilies), Ganoderma sp. (41 families, 105 subfamilies) and P. brevispora (42 families, 111 subfamilies). Of note, the B. adusta genome lacked the CYP505 family (P450foxy), a group of P450-CPR fusion proteins. The three polypore species revealed differential enrichment of individual P450 families in their genomes. The largest CYP families in the three genomes were CYP5144 (67 P450s), CYP5359 (46 P450s) and CYP5344 (43 P450s) in B. adusta, Ganoderma sp. and P. brevispora, respectively. Our analyses showed that tandem gene duplications led to expansions in certain P450 families. An estimated 33% (72 P450s), 28% (55 P450s) and 23% (49 P450s) of P450ome genes were duplicated in P. brevispora, B. adusta and Ganoderma sp., respectively. Family-wise comparative analysis revealed that 22 CYP families are common across the three Polypore species. Comparative P450ome analysis with Ganoderma lucidum revealed the presence of 143 orthologs and 56 paralogs in Ganoderma sp. Multiple P450s were found near the characteristic biosynthetic genes for secondary metabolites, namely polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS), terpene cyclase and terpene synthase in the three genomes, suggesting a likely role of these P450s in secondary metabolism in these Polyporales. Overall, the three species had a richer P450 diversity both in terms of the P450 genes and P450 subfamilies as compared to the model white-rot and brown-rot polypore species Phanerochaete chrysosporium and Postia placenta. PMID- 23928416 TI - Comparative genomics and evolutionary analysis of hydrophobins from three species of wood-degrading fungi. AB - Hydrophobins are small, secreted proteins playing important roles at different stages of fungal life cycles. Their characteristic feature is the presence of eight highly conserved cysteine residues. Here we present an inventory and evolutionary analysis of hydrophobin genes from three wood-degrading basidiomycetes, Phlebia brevispora, Ganoderma sp. and Bjerkandera adusta. The genomes of the three analyzed species are characterized by the presence of high copy numbers of hydrophobin genes. Results of the phylogenetic analysis of the identified proteins revealed that many of them share a high degree of sequence similarity and probably originated from a series of duplication events. The presence of several clusters of adjacent copies of the hydrophobin gene in a particular location in the genome further supports the interpretation that gene duplication has played a role in the evolution of hydrophobins in the analyzed species. PMID- 23928417 TI - Consolidating the legacy of J.-F. Manier: new species and records of trichomycetes from France. AB - New data about trichomycetes (arthropod-gut endosymbionts) from southern France is documented, including the description of two Harpellales, Legeriosimilis cebennensis from mayfly nymphs (Heptageniidae) and Smittium manierei from Chironomidae larvae. New geographical records from France are provided, including Bojamyces transfuga, Genistellospora homothallica, Lancisporomyces vernalis, Legeriomyces rarus, Orphella catalaunica, O. helicospora, Stachylina pedifer, Smittium hecatei, S. pseudodimorphum and Tectimyces leptophlebiidarum. Most of these records include species with a Mediterranean distribution, reported before from neighboring countries, and a few others are subcosmopolitan. PMID- 23928418 TI - Polyporales genomes reveal the genetic architecture underlying tetrapolar and bipolar mating systems. AB - The process of mating in Basidiomycota is regulated by homeodomain-encoding genes (HD) and pheromones and G protein-coupled pheromone receptor genes (P/R). Whether these genes are actually involved in determining mating type distinguishes mating systems that are considered tetrapolar (two locus) from bipolar (one locus). Polyporales are a diverse group of wood-decay basidiomycetes displaying high variability in mating and decay systems. Many of the bipolar species appear to be brown-rot fungi, and it has been hypothesized that there is a functional basis for this correlation. Here we characterize mating genes in recently sequenced Polyporales and other Agaricomycete genomes. All Agaricomycete genomes encode HD and pheromone receptor genes regardless of whether they are bipolar or tetrapolar. The HD genes are organized into a MAT-HD locus with a high degree of gene order conservation among neighboring genes, with the gene encoding mitochondrial intermediate peptidase consistently syntenic but no linkage to the P/R genes. To have a complete dataset of species with known mating systems we determined that Wolfiporia cocos appears to be bipolar, using the criterion that DNA polymorphism of MAT genes should be extreme. Testing the correlation of mating and decay systems while controlling for phylogenetic relatedness failed to identify a statistical association, likely due to the small number of taxa employed. Using a phylogenetic analysis of Ste3 proteins, we identified clades of sequences that contain no known mating type-specific receptors and therefore might have evolved novel functions. The data are consistent with multiple origins of bipolarity within the Agaricomycetes and Polyporales, although the alternative hypothesis that tetrapolarity and bipolarity are reversible states needs better testing. PMID- 23928419 TI - Dispersal of ectomycorrhizal basidiospores: the long and short of it. PMID- 23928420 TI - Phylogenetic and phenotypic characterization of Fomes fasciatus and Fomes fomentarius in the United States. AB - The wood-decay fungi Fomes fasciatus and F. fomentarius share many morphological characters that historically have made species delimitation challenging. We examined morphological, molecular and physiological characters of basidiomata and pure cultures of F. fasciatus and F. fomentarius sampled from multiple plant hosts and geographic regions in the United States to determine whether they support separation of the two species. We find that mean basidiospore size is significantly larger in F. fomentarius and represents the most informative morphological character for delineating the species. Basidiomata and pore-surface shape provided additional resolution of the species, but these characters often overlap and are more variable than basidiospore size. Phylogenetic analyses of ITS and RPB2 sequences suggest that F. fasciatus and F. fomentarius represent distinct evolutionary lineages. The two species share less than 88% maximum identity for the ITS region. Limited intraspecific sequence variation at each locus also was observed. In vitro experiments of hyphal-growth response to a wide range of temperatures support differences in physiology between the two species. PMID- 23928421 TI - Diversity and evolution of ABC proteins in basidiomycetes. AB - ABC proteins constitute one of the largest families of proteins. They are implicated in wide variety of cellular processes ranging from ribosome biogenesis to multidrug resistance. With the advance of fungal genomics, the number of known fungal ABC proteins increases rapidly but the information on their biological functions remains scarce. In this work we extended the previous analysis of fungal ABC proteins to include recently sequenced species of basidiomycetes. We performed an identification and initial cataloging of ABC proteins from 23 fungal species representing 10 orders within class Agaricomycotina. We identified more than 1000 genes coding for ABC proteins. Comparison of sets of ABC proteins present in basidiomycetes and ascomycetes revealed the existence of two groups of ABC proteins specific for basidiomycetes. Results of survey should contribute to the better understanding of evolution of ABC proteins in fungi and support further experimental work on their characterization. PMID- 23928422 TI - Toward genome-enabled mycology. AB - Genome-enabled mycology is a rapidly expanding field that is characterized by the pervasive use of genome-scale data and associated computational tools in all aspects of fungal biology. Genome-enabled mycology is integrative and often requires teams of researchers with diverse skills in organismal mycology, bioinformatics and molecular biology. This issue of Mycologia presents the first complete fungal genomes in the history of the journal, reflecting the ongoing transformation of mycology into a genome-enabled science. Here, we consider the prospects for genome-enabled mycology and the technical and social challenges that will need to be overcome to grow the database of complete fungal genomes and enable all fungal biologists to make use of the new data. PMID- 23928423 TI - Evolutionary consequences of putative intra-and interspecific hybridization in agaric fungi. AB - Agaric fungi of the southern Appalachian Mountains including Great Smoky Mountains National Park are often heterozygous for the rDNA internal transcribed spacer region (ITS) with >42% of collections showing some heterozygosity for indels and/or base-pair substitutions. For these collections, intra-individual haplotype divergence is typically less than 2%, but for 3% of these collections intra-individual haplotype divergence exceeds that figure. We hypothesize that high intra-individual haplotype divergence is due to hybridization between agaric fungi with divergent haplotypes, possibly migrants from geographically isolated glacial refugia. Four species with relatively high haplotype divergence were examined: Armillaria mellea, Amanita citrina f. lavendula, Gymnopus dichrous and the Hygrocybe flavescens/chlorophana complex. The ITS region was sequenced, haplotypes of heterozygotes were resolved through cloning, and phylogenetic analyses were used to determine the outcome of hybridization events. Within Armillaria mellea and Amanita citrina f. lavendula, we found evidence of interbreeding and recombination. Within G. dichrous and H. flavescens/chlorophana, hybrids were identified but there was no evidence for F2 or higher progeny in natural populations suggesting that the hybrid fruitbodies might be an evolutionary dead end and that the genetically divergent Mendelian populations from which they were derived are, in fact, different species. The association between ITS haplotype divergence of less than 5% (Armillaria mellea = 2.6% excluding gaps; Amanita citrina f. lavendula = 3.3%) with the presence of putative recombinants and greater than 5% (Gymnopus dichrous = 5.7%; Hygrocybe flavescens/chlorophana = 14.1%) with apparent failure of F1 hybrids to produce F2 or higher progeny in populations may suggest a correlation between genetic distance and reproductive isolation. PMID- 23928424 TI - Evolution of RNA interference proteins dicer and argonaute in Basidiomycota. AB - RNA interference (RNAi) refers to a mechanism in which cells control gene expression, protect the genome against mobile repetitive DNA sequences, retro elements and transposons, and defend themselves against viruses. Two core components, dicer and argonaute, are central in the RNAi machinery. In this study the evolution of argonaute and dicer genes were analyzed with 43 fungal genomes, with the focus on Basidiomycota. Argonaute and dicer genes are widely represented in Basidiomycota as well as in other fungal groups, but the number of copies of them vary. However, in certain lineages, argonaute or dicer is missing. Our results suggest an ancient duplication of dicer and argonaute genes concurrently with early diversification of the Basidiomycota followed by additional species specific duplications and losses of more recent origin. Several distinct RNAi pathways exist in fungi, based on structural similarity and phylogenetic relationship, our results indicate that quelling possibly exists in most Basidiomycota, while we could not find any evidence for the MSUD (meiotic silencing) pathway in Basidiomycota. RNAi has been developed to be an important tool for reverse genetics studies. Because both argonaute and dicer are present in almost all Basidiomycota our results indicate that it should be possible to develop RNAi as a tool for functional studies of genes in most Basidiomycota species. PMID- 23928425 TI - Distribution and bioinformatic analysis of the cerato-platanin protein family in Dikarya. AB - The cerato-platanin family is a group of small cysteine-rich fungal proteins new to science. They usually are abundantly secreted extracellularly and are involved in fungus-host interactions. With the advance of available fungal genome sequences, we performed a genomewide study of the distribution of this family in fungi and analyzed the common characteristics of the protein sequences. A total of 55 fungal genomes, including 27 from Ascomycota and 28 from Basidiomycota, were used. A total of 130 cerato-platanin homolog protein sequences were obtained and analyzed. Our results showed that cerato-platanin homologs existed in both Ascomycota and Basidiomycota but were lost in early branches of jelly fungi as well as in some groups with yeast or yeast-like forms in their life cycle. Homolog numbers varied considerably between Ascomycota and Basidiomycota. Phylogenetic analysis suggested that the ancestor of the Dikarya possessed multiple copies of cerato-platanins, which sorted differently in Ascomycota and Basidiomycota, and that this gene family might have expanded in the Basidiomycota. Almost all homologs contained signal peptide sequences, and the length of mature proteins were mainly 105-134 amino acids. Four cysteines involved in forming two disulfide bridges and signature sequences (CSD or CSN) were highly conserved in most homologs. These results indicated a higher diversity of the cerato-platanin family in Basidiomycota than Ascomycota. PMID- 23928427 TI - Helping a grieving patient. PMID- 23928426 TI - Management paradigms along a histologic spectrum of pineal cell tumors. PMID- 23928428 TI - Continuing education holds the key to minimally invasive biomimetic dental successes. PMID- 23928429 TI - Mounted diagnostic casts: the entry into comprehensive care. PMID- 23928430 TI - An introduction to forensic dentistry. PMID- 23928431 TI - What's wrong with this picture? PMID- 23928432 TI - Parental presence. PMID- 23928433 TI - Minimally invasive dentistry and its impact on esthetic restorative dentistry. PMID- 23928434 TI - Pyogenic granuloma on the tongue: a pediatric case report. AB - Pyogenic granuloma (PG) is a rare, benign, vascular, hyperplasic, soft tissue lesion caused by diverse factors, including traumatic injuries. This article presents a case involving the surgical removal of PG on the tongue of a 4-year old boy who had difficulty with speech and eating because of the tongue lesion. The parents reported that the child had the habit of nibbling on and sucking his tongue. The lesion was excised and histopathological analysis confirmed the diagnosis of PG; however, because the child continued to nibble and suck on his tongue, the lesion recurred. A second surgery was performed with the same histopathological diagnosis. At a one-year follow-up, the child had ceased his tongue habits, and no recurrence was seen. PMID- 23928435 TI - Using a dental operating microscope for endodontic management of a mandibular central incisor with 3 root canals. AB - Endodontic management of teeth with aberrant root canal morphology can be challenging. This article presents a case in which multiple angulated radiographs and a dental operating microscope clearly revealed the presence of 3 root canals in a right mandibular central incisor with 2 different canal patterns. This case report emphasizes the importance of utilizing a dental operating microscope to understand unusual root canal morphology. PMID- 23928436 TI - Bisphosphonate-related osteonecrosis of the jaws: a potential alternative to drug holidays. AB - In 2011, the American Dental Association Council on Scientific Affairs released an update by their expert panel on managing the care of patients receiving antiresorptive therapy for the prevention and treatment of osteoporosis. In this report, the panel found no study results that confirmed the effectiveness of drug holidays to prevent antiresorptive agent-induced osteonecrosis of the jaws without increasing the risks of low bone mass. The purpose of this article is to provide suggestions for a pattern of patient care for individuals who desire or require an invasive surgical procedure of the jaws, but who also have a skeleton that is at risk for osteoporotic fracture. The authors reviewed pertinent literature related to basic bone histology, the pharmacokinetics of the aminobisphosphonates (nBP), diagnostic criteria for osteopenia/osteoporosis, and clinical applications of the antiresorptive agents. The skeletal system demonstrates a mixture of resting surfaces (osteocytes, 85%), resorbing surfaces (osteoclasts, 2%), and forming surfaces (osteoblasts, 10%-12%). Deposition of nBP is not uniform, and is highly concentrated in areas of bone remodeling. A full understanding of bone remodeling and the pharmacokinetics of nBP allow for the modification of the antiresorptive therapy and the timing of the oral surgical procedure in a manner that minimizes the prevalence of osteonecrosis while at the same time continuing to protect the patient's skeleton from osteoporotic fracture. The lack of support for drug holidays by the ADA's expert panel is strongly consistent with the science behind bone remodeling and nBP pharmacokinetics. In spite of this, creative interdisciplinary patient care has the potential to dramatically reduce the prevalence of bisphosphonate-related osteonecrosis (BRON), while at the same time continuing to protect the skeleton of the osteoporotic patient. Creative interdisciplinary patient care may prove to be an effective intervention to reduce the prevalence of BRON of the jaws. PMID- 23928437 TI - Different ultrasonic vibration protocols and their effects on retention of post and-core to root canal. AB - This study evaluated the effect of different ultrasonic vibration protocols on custom cast post-and-cores' retention to the root canal. Post holes were placed in the root canals of human maxillary canines, and post-and-core sets were luted, using zinc phosphate cement. The samples were divided into 5 groups (n = 8). Group 1 (control) received no ultrasonic vibration. For the other samples, the tip of the ultrasonic device was positioned either over the incisal face of the core (Group 2), over the lateral core surfaces and close to the incisal edge (Group 3), over the lateral face of the core but close to the line of cementation (Group 4), or over the lateral face of the core but with the end of the mouth mirror handle positioned on the opposite surface of the core (Group 5). After a tensile test, data were submitted to 2-way ANOVA and Tukey's tests (P < 0.05). The control group showed higher values than all of the groups that were submitted to ultrasonic vibration. Bond strength was similar for Groups 2 and 3. Bond strength was lower in Groups 4 and 5; no statistical difference was observed between these 2 groups. Based on these results, both positioning the tip of the ultrasonic device near the cement line and placing a mouth mirror handle on the opposite surface of the core, are effective ways to reduce the retention of a cast post-and-core within a root canal. PMID- 23928438 TI - Using spiral computed tomography for endodontic management of a mandibular first molar with a middle mesial canal: a case report. AB - The root canal anatomy of a permanent mandibular first molar has been traditionally described as 2 roots--1 mesial and 1 distal--with 2 canals in the mesial root and 1 or 2 canals in the distal root. Nonetheless, other possibilities exist. The presence of a third canal in the mesial root has been reported to have an incidence of 0%-17%. Conventional radiographs are routinely used to determine root canal anatomy; however, these are 2-dimensional representations of a 3-dimensional object. Advanced diagnostic methods that can provide 3-dimensional data, such as spiral computed tomography (SCT), is very helpful in determining complex morphology. This case report presents the management of a mandibular first molar with 3 mesial and 2 distal canals, confirmed with the aid of both SCT and conventional radiographic methods. PMID- 23928439 TI - Coronal reconstruction following anterior teeth traumatism: multidisciplinary treatment. AB - This study describes how periodontology, endodontology, and dentistry were integrated for the coronal reconstruction of anterior teeth extensively destroyed by dental trauma. A 15-year-old girl suffered a bicycle accident that resulted in the fracture of teeth No. 8 and 9. Clinical and radiographic examinations confirmed coronal fracture in both teeth, in addition to compromised pulp vitality, invasion of the biologic periodontal space, and loss of coronal space due to mesialization of the neighboring teeth. The protocol consisted of endodontic treatment for the fractured teeth, periodontal surgery to augment the clinical crown and gingival recontouring, intracanal cementation of esthetic glass fiber posts, and coronal reconstruction with resin composite. At a longitudinal follow-up visit 1 year later, clinical and radiographic examinations revealed successful rehabilitation of the fractured teeth. PMID- 23928440 TI - Salivary thiol levels and periodontal parameters assessed with a chromogenic strip. AB - Periodontitis tends to be associated with bacteria that use sulfate as an energy source and produce thiol compounds that contain sulfhydryl (-SH) groups. This study used a chromogenic thiol-detecting strip to investigate whole saliva -SH concentration (SS) in subjects with and without periodontal disease. Ninety-six subjects were enrolled; all underwent periodontal evaluations, including plaque index (PI), gingival index (GI), probing depth measurements (PD), and attachment levels (AL). Subjects were divided into 3 groups: those who were periodontally healthy (n = 17), those with gingivitis (n = 54), and those with periodontitis (n = 25). Of the 96 subjects, 33% (n = 32) were cigarette smokers. A chromogenic strip was used to collect a whole saliva sample from the mouth. Color reaction was scored based on a color chart. Good-to-moderate correlations were found between SS scores and PI (r = 0.47, P = 0.0001), GI (r = 0.45, P = 0.0001), PD (r = 0.42, P = 0.0001), and AL (r = 0.30, P = 0.002). Analysis of variance showed significant differences in SS scores among the 3 study groups (P = 0.0001); post hoc analysis showed higher SS scores in subjects with periodontitis than in those without (P = 0.05). Logistic regression, adjusting for smoking, showed the odds ratio of periodontitis increased by a factor of 12.76 for each increase of one unit of measure of SS. These results indicate that assessing whole saliva thiol levels with a chromogenic strip could be used as a screening test for periodontal diseases. PMID- 23928441 TI - Modified frenectomy: a review of 3 cases with concerns for esthetics. AB - The maxillary labial frenum is a normal anatomical structure in the oral cavity. An abnormal labial frenum causes localized gingival recession and midline diastema, both of which can interfere with oral hygiene procedures, and eventually affect esthetics. When the frenum maintains its high papillary attachment, frenectomy is the treatment of choice. Though this technique has undergone many modifications, the zone of attachment and esthetics in the anterior maxillary region have been neglected. This article highlights a new frenectomy technique that results in good esthetics, excellent color match, gain in attached gingiva, and healing by primary intention at the site of thick, extensive abnormal frena. PMID- 23928442 TI - An evaluation and adjustment method for natural proximal contacts of crowns using diamond dental strips: a case report. AB - The best way to adjust proximal contacts of newly fabricated indirect restorations has been a long-standing unresolved issue in dentistry. Excessively tight contacts cause incomplete seating of indirect restorations and intrusion of adjacent teeth, which leads to patient discomfort, hypersensitivity, and recurrent dental caries at the crown margins. When seating indirect restorations, interproximal relief should be restored as it exists in natural dentition. This article presents an innovative method of crown seating using diamond strips. This simple, consistent, method makes it easier for clinicians to provide comfortable and long-lasting restorations with minimal time and effort. Laboratory technicians utilize diamond strips to provide properly fitting indirect restorations that require minimal adjustment upon clinical delivery. Diamond strips also allow for accurate determination of heavier proximal contacts, allowing dentists to adjust the proximal contact properly in the patients' mouths. Clinically, restoring natural proximal contacts is a critical factor to the success of indirect restorations. Using this method standardizes proper proximal contact adjustments of laboratory-fabricated indirect restorations between dental labs and dental offices. The method also helps to limit or eliminate the lingering proximal contact issue between clinicians and laboratory technicians. PMID- 23928443 TI - Rehabilitation of the edentulous maxilla complicated by combination syndrome with an implant overdenture: a case report. AB - The treatment of the edentulous jaws with complete dentures is determined individually and often is unpredictable. Implant-assisted overdentures are a significant improvement over conventional complete dentures in terms of patient comfort and function. Combination syndrome refers to a dramatic exaggeration of maxillary alveolar resorption leading to a more complicated rehabilitation. This article reviews how the edentulous maxilla can be rehabilitated with an implant assisted overdenture. A case report is presented which utilizes a computer-aided design/computer-aided manufactured milled titanium connecting bar to retain a chrome-cobalt based, precision attachment, palateless prosthesis. PMID- 23928444 TI - Evaluating complications of local anesthesia administration and reversal with phentolamine mesylate in a portable pediatric dental clinic. AB - This study sought to identify and quantify complications with local anesthetic administration and reversal on consecutive patients seen for comprehensive dental care in a school-based, portable dental clinic, and includes data on the patients seen by the participating portable dental providers. In 923 dental visits where local anesthetic was administered, a standardized form was used to gain further information and identify any complications; this was accompanied by a questionnaire for the student's teacher, in order to quantify the student's distraction and disruption ratings following the dental visit. After statistical analysis of the 923 consecutive cases, the overall complication rate was 5.3%. All of the complications were considered to be mild or moderate, and there were no severe event reports. The complications encountered most frequently (n = 49) were associated with self-inflicted soft tissue injury. The results of this study indicate that comprehensive care with local anesthesia delivered by a school based portable dental clinic has a low risk of complications. Whereas safe administration of dental care is achievable with or without phentolamine mesylate as a local anesthetic reversal agent, its use was determined to improve safety outcomes. Three factors appeared to directly increase the incidence of complications: the administration of an inferior alveolar nerve block, attention deficit disorder, and obesity. Teacher evaluations demonstrated that children receiving care by a portable dental team were able to reorient back to classwork and were not disruptive to classmates. PMID- 23928445 TI - Bluish discoloration of alveolar ridge. Minocycline staining. PMID- 23928446 TI - A conservative treatment approach using direct composite resins for anterior teeth eroded by lemon sucking. AB - An excessively acidic diet results in the progressive deterioration of dental health, with functional, esthetic, and biological consequences. Previously, rehabilitation required placing numerous full crowns and root canal treatments; however, with improved adhesive techniques, a more conservative approach may be utilized to preserve tooth structure. This article describes 2 cases that utilized conservative dental treatments (involving direct composite resins with minimal preparation of the tooth structure) to treat eroded dentition induced by lemon sucking. PMID- 23928447 TI - Non-drug induced gingival enlargement. AB - Gingival enlargement refers to an increase in the size of the gingival tissue. The etiology varies, and often is multifactorial; however, local and systemic conditions, disease, and idiopathic factors may contribute to gingival enlargement. Tissue consistency can vary from soft and spongy to dense, typically appearing darker in shade compared to the drug-induced gingival enlargement. Treatment modalities usually involve surgical removal of excess tissue, non surgical debridement, use of chemotherapeutic agents, and/or elimination or mitigation of contributing factors and conditions. PMID- 23928448 TI - Optimal depth of cure for nanohybrid resin composite using quartz tungsten halogen and new high intensity light-emitting diode curing units. AB - This study sought to evaluate the effects of quartz tungsten halogen (QTH) and light-emitting diode (LED) photocuring units on the degree of conversion (DC) and surface microhardness of a resin composite that had been cured for optimal depth of cure (DoC) assessment. Two hundred and forty cylindrical specimens (4.0 mm in diameter, 2.0-4.0 mm thick) of shade A2 resin composite were prepared and cured with either a QTH or an LED. The DC and top and bottom surface hardness were recorded, and data were analyzed using 2-way ANOVA, Tukey's test, t-test (alpha = 0.05) and linear regression analysis. The results showed that surface microhardness values and DC were affected by light intensity (P < 0.01), and resin composite thickness (2, 3, and 4 mm) (P < 0.01). Resin composite polymerized by the QTH had an optimal DoC of 3 mm, compared to 4 mm for the LED. PMID- 23928449 TI - Microleakage of 3 single-bottle self-etch adhesives having different solvents. AB - This study compared the microleakage from 3 single-bottle self-etch adhesives (SEAs) with a conventional etch and rinse (ER) system. Class V cavities were prepared on buccal and lingual surfaces at the cementoenamel junction of 40 extracted human third molars. The cavities were allocated into 4 groups (n = 20). The groups were treated with either a combination of composite resin and 1 of 3 SEAs, or with a conventional ER system. Dye penetration of the samples was performed by placing them in a fresh solution of India ink for 48 hours. After rinsing and sectioning, the samples were placed under a light microscope and evaluated for microleakage along occlusal (enamel) and gingival (dentin) margins. The data were analyzed statistically. Microleakage scores of the adhesives exhibited significant differences (P < 0.05). All 3 single-bottle SEAs tested exhibited more microleakage than the ER system. There was no difference in terms of microleakage between the enamel and dentin margins in the SEA-bonded specimens (P > 0.05). The ER system was more successful in sealing enamel than dentin. PMID- 23928450 TI - The effect of baking soda when applied to bleached enamel prior to restorative treatment. AB - This in vitro study evaluated the effect of 10% baking soda solution and sodium bicarbonate powder (applied with jets) when applied to bleached enamel prior to restorative treatment. The surfaces of 40 bovine incisors were flattened and divided into 5 groups (n = 8): Group B (bleached and restored, negative control), Group W (bleached, stored in distilled water for 7 days, and restored), Group BSJ (bleached, abraded with baking soda jet for 1 min, and restored), Group BSS (bleached, application of 10% baking soda solution for 5 min, and restored), and Group R (restored, without bleaching, positive control). The samples were bleached in 1 session with 3 applications of 35% HP-based gel and activated with a LED appliance for 9 min each. Resin composite cylinders (2 mm height and 0.8 mm diameter) were made on the enamel surface after the acid etching and a conventional 1-step single vial adhesive application was performed. After storage in distilled water (37 +/- 1 degrees C, 24 hr), the microshear bond test was performed (1 mm/min). ANOVA and Tukey tests were applied to compare the results. The mean results of these tests showed that Groups W, BBS, and R were not statistically different. These groups also indicated a higher bond strength when compared with Groups B and BSJ. The application of 10% baking soda solution for 5 min may be an alternative pre-restorative treatment for bleached enamel, but further studies are needed to consider whether or not this treatment may be effectively used in clinical practice. PMID- 23928452 TI - Mobile teledermatopathology: using a tablet PC as a novel and cost-efficient method to remotely diagnose dermatopathology cases. AB - : Dermatopathology has relatively few studies regarding teledermatopathology and none have addressed the use of new technologies, such as the tablet PC. We hypothesized that the combination of our existing dynamic nonrobotic system with a tablet PC could provide a novel and cost-efficient method to remotely diagnose dermatopathology cases. 93 cases diagnosed by conventional light microscopy at least 5 months earlier by the participating dermatopathologist were retrieved by an electronic pathology database search. A high-resolution video camera (Nikon DS L2, version 4.4) mounted on a microscope was used to transmit digital video of a slide to an Apple iPAD2 (Apple Inc, Cupertino, CA) at the pathologist's remote location via live streaming at an interval time of 500 ms and a resolution of 1280/960 pixels. Concordance to the original diagnosis and the seconds elapsed to reaching the diagnosis were recorded. 24.7% (23/93) of cases were melanocytic, 70.9% (66/93) were nonmelanocytic, and 4.4% (4/93) were inflammatory. About 92.5% (86/93) of cases were diagnosed on immediate viewing (<5 seconds), with the average time to diagnosis at 40.2 seconds (range: 10-218 seconds). Of the cases diagnosed immediately, 98.8% (85/86) of the telediagnoses were concordant with the original. Telepathology performed via a tablet PC may serve as a reliable and rapid technique for the diagnosis of routine cases with some diagnostic caveats in mind. Our study established a novel and cost-efficient solution for those institutions that may not have the capital to purchase either a dynamic robotic system or a virtual slide system. PMID- 23928453 TI - Mantle cell lymphoma of blastoid variant with skin lesion and rapid progression: a case report and literature review. AB - Mantle cell lymphoma (MCL) is a type of aggressive mature B-cell neoplasm. Skin involvement of MCL is extremely rare, with only 21 cases reported so far. We report a case of MCL with blastoid variant, presenting as skin lesion initially. A 53-year-old man presented with increasing petechiae and ecchymosis after slight hit. Biopsy of skin showed tumor cells densely infiltrated dermal and subcutis with blastoid cytological features and numerous mitotic figures. Immunohistochemistry study showed tumor cells were positive for CD20, CD79a, BCL2, CyclinD1, and MUM1 but lost CD5 expression. Fluorescence in situ hybridization (FISH) studies demonstrated t(11;14). Although received chemotherapy after the diagnosis established, the patient deteriorated rapidly and died 5 weeks after presenting with skin lesions. PMID- 23928451 TI - Therapeutic and space radiation exposure of mouse brain causes impaired DNA repair response and premature senescence by chronic oxidant production. AB - Despite recent epidemiological evidences linking radiation exposure and a number of human ailments including cancer, mechanistic understanding of how radiation inflicts long-term changes in cerebral cortex, which regulates important neuronal functions, remains obscure. The current study dissects molecular events relevant to pathology in cerebral cortex of 6 to 8 weeks old female C57BL/6J mice two and twelve months after exposure to a gamma radiation dose (2 Gy) commonly employed in fractionated radiotherapy. For a comparative study, effects of 1.6 Gy heavy ion 56Fe radiation on cerebral cortex were also investigated, which has implications for space exploration. Radiation exposure was associated with increased chronic oxidative stress, oxidative DNA damage, lipid peroxidation, and apoptosis. These results when considered with decreased cortical thickness, activation of cell-cycle arrest pathway, and inhibition of DNA double strand break repair factors led us to conclude to our knowledge for the first time that radiation caused aging-like pathology in cerebral cortical cells and changes after heavy ion radiation were more pronounced than gamma radiation. PMID- 23928454 TI - Trichodysplasia spinulosa associated with lupus. AB - Trichodysplasia spinulosa (TS) is a unique clinical and histological entity described in immunosuppressed patients. The recent discovery of genomic DNA from a new Polyomavirus named trichodysplasia spinulosa-associated Polyomavirus in TS lesions and good clinical response to cidofovir strengthens the hypothesis of a viral etiology for the disease. The authors report a case of TS associated with lupus erythematosus in a 26-year-old woman with no history of transplant, hemopathy, or cyclosporine treatment. The patient developed a progressive worsening eruption composed of confluent papules and spiky filiform excrescences concentrated in the midfacial area. Pathological features were characterized by aberrant distended and abnormally maturated hair follicles with sheets of eosinophilic cells containing large purple granules, and the presence of trichodysplasia spinulosa-associated Polyomavirus DNA was confirmed by polymerase chain reaction. This case is the first description in a nontransplanted lupus patient without underlying hemopathy. PMID- 23928455 TI - Josef jadassohn--an appreciation on the occasion of his 150th birthday. AB - Josef Jadassohn was a pioneering dermatologist who influenced the development of his specialty in many ways. He introduced the patch test for detection of hypersensitivity reactions, gave original descriptions of several entities, such as nevus sebaceous, granulosis rubra nasi, and pachyonychia congenita, and edited the Handbuch der Haut- und Geschlechtskrankheiten, the most comprehensive textbook of dermatology ever published. Moreover, Jadassohn left a phalanx of distinguished students, including Felix Lewandowsky, Wilhelm Lutz, Max Jessner, Hans Biberstein, Hermann Pinkus, and Marion B. Sulzberger. PMID- 23928456 TI - Declines in sugar-sweetened beverage consumption among children in Los Angeles County, 2007 and 2011. AB - This study assessed changes in consumption of sugar-sweetened beverages (SSBs) among children (aged<=17 years) in Los Angeles County. We analyzed children's data from the 2007 (n=5,595) and 2011 (n=5,934) Los Angeles County Health Survey. The percentage of children who consumed 1 or more SSB per day decreased from 43.3% in 2007 to 38.3% in 2011 (P<.001); this decrease was seen across most sociodemographic subgroups. Despite measurable progress in reducing SSB consumption among children in Los Angeles County, consumption remains high, highlighting the need for additional policy and programmatic interventions. PMID- 23928457 TI - Radon control activities for lung cancer prevention in national comprehensive cancer control program plans, 2005-2011. AB - INTRODUCTION: Radon is the second leading cause of lung cancer among smokers and the leading cause among nonsmokers. The US Environmental Protection Agency recommends that every home be tested for radon. Comprehensive Cancer Control (CCC) programs develop cancer coalitions that coordinate funding and resources to focus on cancer activities that are recorded in cancer plans. Radon tests, remediation, and radon mitigation techniques are relatively inexpensive, but it is unclear whether coalitions recognize radon as an important carcinogen. METHODS: We reviewed 65 cancer plans created from 2005 through 2011 for the terms "radon," "radiation," or "lung." Plan activities were categorized as radon awareness, home testing, remediation, supporting radon policy activities, or policy evaluation. We also reviewed each CCC program's most recent progress report. Cancer plan content was reviewed to assess alignment with existing radon specific policies in each state. RESULTS: Twenty-seven of the plans reviewed (42%) had radon-specific terminology. Improving awareness of radon was included in all 27 plans; also included were home testing (n=21), remediation (n=11), support radon policy activities (n=13), and policy evaluation (n=1). Three plans noted current engagement in radon activities. Thirty states had radon-specific laws; most (n=21) were related to radon professional licensure. Eleven states had cancer plan activities that aligned with existing state radon laws. CONCLUSION: Although several states have radon-specific policies, approximately half of cancer coalitions may not be aware of radon as a public health issue. CCC developed cancer coalitions and plans should prioritize tobacco control to address lung cancer but should consider addressing radon through partnership with existing radon control programs. PMID- 23928458 TI - Raising awareness of sleep as a healthy behavior. PMID- 23928459 TI - Assessing public policies and assets that affect obesity risk while building new public health partnerships, New Hampshire, 2011. AB - The New Hampshire Obesity Prevention Program and the 9 New Hampshire regional planning commissions assessed the state's obesity-related policies and assets by using community measures recommended by the Centers for Disease Control and Prevention. A self-administered questionnaire that focused on policies and assets that promote healthful eating, physical activity, and breast-feeding was sent to 234 municipalities; 59% responded (representing 73% of the state's population). Of the municipalities that responded, 52% had sidewalks, 22% had bicycle lanes, none had nutrition standards, and 4% had a policy supporting breastfeeding. Through collaboration, we gathered baseline information that can be used to set priorities and assess progress over time. PMID- 23928460 TI - The virulence-related rhoptry protein 5 (ROP5) of Toxoplasma Gondii is a novel vaccine candidate against toxoplasmosis in mice. AB - Infections with the intracellular protozoan parasite Toxoplasma gondii pose a serious public health problem and are of great economic importance worldwide. The parasite rhoptry protein 5 (ROP5) has been implicated as a major virulence factor that reduces the accumulation of immunity-related GTPases (IRG) in parasitophorous vacuole membrane (PVM), which maintains PVM integrity and evades IFNgamma-mediated killing by intracellular parasites. To study the immunoprotective value of ROP5, BALB/c mice were immunized with a recombinant form of the protein administered alone or in combination with another promising vaccine antigen, rSAG1. All mice vaccinated with the recombinant antigens developed a high level of specific antibody responses against soluble tachyzoite antigens (STAg), a statistically significant increase of the splenocyte proliferation response, and significant levels of IFN-gamma and IL-2 production. In contrast to rSAG1, which only stimulated the release of IFN-gamma and IL-2, rROP5 induced the specific production of IL-10, the Th2-type cytokine, in addition to IFN-gamma and IL-2. These results demonstrated that rROP5 could induce significant cellular and humoral (Th1/Th2) immune responses. Moreover, mice immunized with rROP5 displayed a prolonged survival time against a lethal challenge with the T. gondii RH strain. Additionally, vaccination with the mixture of rROP5+rSAG1 resulted in higher levels of T. gondii-specific IgG antibodies and lymphocyte proliferative responses and conferred more efficient protection against T. gondii challenge compared to immunization with rROP5 or rSAG1 alone. Our studies show that recombinant ROP5 antigen may be a promising vaccine candidate against toxoplasmosis. To our knowledge, this is the first report to evaluate the immunoprotective value of ROP5. PMID- 23928461 TI - Trends and disparity in zoster vaccine uptake in a managed care population. AB - OBJECTIVES: Zoster vaccine is recommended for prevention of herpes zoster among adults aged 60 years and older. We examined the zoster vaccination rates during 2007-2011 and assessed association with age, sex, race/ethnicity, neighborhood income and education attainment in eligible adults at Kaiser Permanente Southern California, a managed care organization in the US. METHODS: We calculated annual zoster vaccination rate among members >=60 years without documented contraindications. Multivariable logistic regression was performed to examine factors associated with zoster vaccine uptake in an open cohort of 819,466 adults. RESULTS: The zoster vaccination rates increased annually in all groups and the overall rate reached 21.7% in 2011 (P-trend<0.001). Coverage was highest among individuals aged 65-74 years, who were female and non-Hispanic White. In the adjusted analysis, odds of vaccination decreased by age. Females (odds ratio [OR]=1.19, 95% confidence interval [CI]=1.17-1.20) and those who lived in neighborhoods with higher education attainment were more likely to be vaccinated (>75% vs. <50% adults with some college education: OR=1.76, 95% CI=1.73-1.80). Compared to Whites, non-Hispanic Blacks and Hispanics were less likely to receive the vaccine (non-Hispanic Blacks: OR=0.56, 95% CI=0.55-0.58; Hispanics: OR=0.59, 95% CI=0.58-0.60). CONCLUSION: The zoster vaccine coverage is higher in this insured population than previously reported in the US general population, but it remains low. Significant racial/ethnic disparity was observed and worsened even among individuals with relatively equal access to zoster vaccination. PMID- 23928462 TI - Attenuation and immunogenicity of host-range extended modified vaccinia virus Ankara recombinants. AB - Modified vaccinia virus Ankara (MVA) is being widely investigated as a safe smallpox vaccine and as an expression vector to produce vaccines against other infectious diseases and cancer. MVA was isolated following more than 500 passages in chick embryo fibroblasts and suffered several major deletions and numerous small mutations resulting in replication defects in human and most other mammalian cells as well as severe attenuation of pathogenicity. Due to the host range restriction, primary chick embryo fibroblasts are routinely used for production of MVA-based vaccines. While a replication defect undoubtedly contributes to safety of MVA, it is worth considering whether host range and attenuation are partially separable properties. Marker rescue transfection experiments resulted in the creation of recombinant MVAs with extended mammalian cell host range. Here, we characterize two host-range extended rMVAs and show that they (i) have acquired the ability to stably replicate in Vero cells, which are frequently used as a cell substrate for vaccine manufacture, (ii) are severely attenuated in immunocompetent and immunodeficient mouse strains following intranasal infection, (iii) are more pathogenic than MVA but less pathogenic than the ACAM2000 vaccine strain at high intracranial doses, (iv) do not form lesions upon tail scratch in mice in contrast to ACAM2000 and (v) induce protective humoral and cell-mediated immune responses similar to MVA. The extended host range of rMVAs may be useful for vaccine production. PMID- 23928463 TI - Generation of CTL responses against pancreatic cancer in vitro using dendritic cells co-transfected with MUC4 and survivin RNA. AB - Pancreatic cancer (PC) is one of the most devastating human malignancies without effective therapies. Tumor vaccine based on RNA-transfected dendritic cells (DCs) has emerged as an alternative therapeutic approach for a variety of human cancers including advanced PC. In the present study we compared the cytotoxic T lymphocyte (CTL) responses against PC cells in vitro, which were induced by DCs co-transfected with two mRNAs of tumor associated-antigens (TAA) MUC4 and survivin, versus DCs transfected with a single mRNA encoding either MUC4 or survivin. DCs co-transfected with two TAA mRNAs were found to induce stronger CTL responses against PC target cells in vitro, compared with the DCs transfected with a single mRNA. Moreover, the antigen-specific CTL responses were MHC class I restricted. These results provide an experimental foundation for further clinical investigations of DC vaccines encoding multiple TAA epitopes for metastatic PC. PMID- 23928464 TI - Carrier protein influences immunodominance of a known epitope: implication in peptide vaccine design. AB - We investigated how the processing of a given antigen by antigen presenting cells (APC) is dictated by the conformation of the antigen and how this governs the immunodominance hierarchy. To address the question, a known immunodominant sequence of bacteriophage lambda repressor N-terminal sequence 12-26 [lambdaR(12 26)] was engineered at the N and C termini of a heterologous leishmanial protein, Kinetoplastid membrane protein-11 (KMP-11); the resulting proteins were defined as N-KMP-11 and C-KMP-11 respectively. The presence of lambdaR(12-26) in N-KMP-11 and C-KMP-11 was established by western blot analysis with antibody to lambdaR(12 26) peptide. N-KMP-11 but not C-KMP-11 could stimulate the anti lambdaR(12-26) T cell clonal population very efficiently in the presence of APCs. Priming of BALB/c mice with N-KMP-11 or C-KMP-11 generated similar levels of anti-KMP-11 IgG, but anti-lambdaR(12-26) specific IgG was observed only upon priming with N KMP-11. Interestingly, uptake of both N-KMP-11 and C-KMP-11 by APCs was similar but catabolism of N-KMP-11 but not C-KMP-11 was biphasic and fast at the initial time point. Kratky plots of small angle X-ray scattering showed that while N-KMP 11 adopts flexible Gaussian type of topology, C-KMP-11 prefers Globular nature. To show that KMP-11 is not unique as a carrier protein, an epitope (SPITBTNLBTMBK) of Plasmodium yoelii (PY) apical membrane protein 1[AMA-1 (136 148)], is placed at the C and N terminals of a dominant T-cell epitope of ovalbumin protein OVA(323-339) and the resulting peptides are defined as PY-OVA and OVA-PY respectively. Interestingly, only OVA-PY could stimulate anti-OVA T cells and produce IgG response upon priming of BALB/c mice with it. Thus for rational design of peptide vaccine it is important to place the dominant epitope appropriately in the context of the carrier protein. PMID- 23928465 TI - Enhancement of antigen-specific CD8 T cell responses by co-delivery of Fc-fused CXCL11. AB - Chemokines have been known to play an important role in eliciting adaptive immune responses by, selectively attracting the innate cellular components to the site of antigen presentation. In this study, we demonstrated that all three CXCR3 ligands, CXCL9, CXCL10, and CXCL11, could act as a strong, genetic adjuvant. Among them, CXCL11 increased vaccine antigen-specific CD8 T cells, including, several cytokine secretions (IFN-gamma and TNF-alpha) to a greater degree than the other two CXCR3 ligands. Fc-fusion of CXCL11 (CXCL11-Fc) induced similar but slightly higher CD8 T cell response, which, appeared to be antigen- (ovalbumin (OVA) vs. human papillomavirus 16 (HPV16) E7) and vaccine, type- (adenovirus vs. DNA vaccine) independent. In addition, the adjuvant effect of CXCL11-Fc was, further confirmed by suppressing tumor growth and extension of survival rates in a therapeutic tumor, model, which was correlated with enhanced antigen-specific CD8 T cell responses. Interestingly, the, enhanced antigen-specific CD8 T cell responses by co-delivery of CXCL11-Fc were associated with CD8, T cell proliferation, followed by increased total and effector memory T cell frequencies. Taken together, our findings provide a novel role of CXCL11 as a strong genetic adjuvant which might be used to, increase antigen-specific CD8 T cell immunity elicited by vaccination. PMID- 23928466 TI - Serotype prevalence and antibiotic resistance in Streptococcus pneumoniae clinical isolates among global populations. AB - Streptococcus pneumoniae remains a leading cause of disease in children and adults. Serotypes differ in invasiveness, virulence, and antibiotic resistance; therefore, serotype surveillance is necessary to monitor the burden of pneumococcal disease, especially in the setting of pneumococcal vaccination programs. The Tigecycline Evaluation Surveillance Trial, (TEST), is an on-going global antibiotic susceptibility surveillance program. Serotypes and antibiotic susceptibilities of 2173 invasive S. pneumoniae in this existing database during 2004-2008 were evaluated. Worldwide, serotypes 19A (28%), 19F (10%) and 14 (9%) were the most common in children under 5 years. In adults over 16 years, 19A (13%), 3, 6A and 7F (all 7%) were most common. Serotypes 19A, 6A, 19F, 6B, 15A, 9V, and 14 exhibited significantly higher levels of erythromycin resistance (P<0.05), while 19A, 19F, 35B, 6A, 6B, 23A, 9V, 15A, and 14 demonstrated higher rates of penicillin resistance (P<0.05). This analysis of an existing pathogen database provides a snapshot of global serotype data and describes the consequential issue of antibiotic resistance in specific serotypes, many of which are increasingly common causes of invasive pneumococcal disease. PMID- 23928467 TI - Association of high post-transplant soluble CD30 serum levels with chronic allograft nephropathy. AB - The purpose of this study was to evaluate the association of post-transplant soluble CD30 (sCD30) levels, isolated or in combination with of anti-HLA class II antibodies and of serum creatinine levels, with kidney graft loss due to chronic allograft nephropathy (CAN), and type of lesions in graft biopsies for cause. The study comprised 511 first kidney graft recipients, transplanted at a single center, with a graft functioning for at least 2.8 years. A single blood sample was collected from each patient. sCD30 levels were determined by ELISA, and HLA antibodies by Luminex assay. The minimum follow-up after testing was 9.3 years. High sCD30 levels, set at sCD30 >= 34.15 ng/mL, the presence of HLA class II antibodies, and serum creatinine >= 1.9 mg/dL were independently associated with CAN-graft loss (P values <0.0001, 0.05, <0.0001, respectively), and the combined hazard ratio for CAN-graft loss was 20.2. Analyses of 166 biopsies for cause showed that high sCD30 levels and creatinine were independently associated with interstitial lesions. Post-transplant sCD30 serum levels, especially in conjunction with information regarding HLA class II antibodies and serum creatinine levels, provide valuable information regarding graft outcome and could be useful for the management of kidney transplant recipients. PMID- 23928468 TI - Supratrochlear and supraorbital nerves: an anatomical study and applications in the head and neck area. AB - BACKGROUND: This article elucidates the anatomical details of the course and territory of the supraorbital (SO) and supratrochlear (ST) nerves. Possible applications of the SO and ST nerves for sensory nerve transfer are also examined. METHODS: The dissection of 3 fresh cadaver heads (6 hemifaces) was performed. In each hemiface, the ST and SO nerves were identified. The following data were recorded: 1) number of branches, 2) skin boundaries, 3) communicative branches, and 4) branch length. The feasibility of specific nerve-transfer procedures was also examined. RESULTS: In 4 hemifaces the SO nerve exited from the SO notch and in 2 hemifaces from the SO foramen. The position was lateral to the midline, with a mean distance of 1.93 cm. In all dissections, a maximum of 4 SO branches (range 2-4) were identified. The ST nerve exited the orbital rim medial to the SO nerve, and lateral to the midline with a mean distance of 0.866 cm. The mean distance between the SO and ST nerves at the level of the SO rim was 1.06 cm. In 5 of 6 hemifaces, several sub-branches emerged from the main trunk of the ST nerve. In 1 hemiface the ST nerve was divided in 2 main branches. CONCLUSIONS: The data presented in the current study are in agreement with previous anatomical studies. Both ST and SO nerves can be used as sensory nerve donors in the head and neck area for numerous expanding applications. PMID- 23928469 TI - ATM is required for the repair of Topotecan-induced replication-associated double strand breaks. AB - PURPOSE: DNA replication is a promising target for anti-cancer therapies. Therefore, the understanding of replication-associated DNA repair mechanisms is of great interest. One key factor of DNA double-strand break (DSB) repair is the PIK kinase Ataxia-Telangiectasia Mutated (ATM) but it is still unclear whether ATM is involved in the repair of replication-associated DSBs. Here, we focused on the involvement of ATM in homology-directed repair (HDR) of indirect DSBs associated with replication. MATERIAL AND METHODS: Experiments were performed using ATM-deficient and -proficient human cells. Replication-associated DSBs were induced with Topotecan (TPT) and compared with gamma-irradiation (IR). Cell survival was measured by clonogenic assay. Overall DSB repair and HDR were evaluated by detecting residual gammaH2AX/53BP1 and Rad51 foci, respectively. Cell cycle distribution was analysed by flow cytometry and protein expression by Western blot. RESULTS: ATM-deficiency leads to enhanced numbers of residual DSBs, resulting in a pronounced S/G2-block and decreased survival upon TPT-treatment. In common with IR, persisting Rad51 foci were detected following TPT-treatment. CONCLUSIONS: These results demonstrate that ATM is essentially required for the completion of HR-mediated repair of TPT-induced DSBs formed indirectly at replication forks. PMID- 23928470 TI - Life changes itself via genetic engineering: comment on "How life changes itself: the Read-Write (RW) genome" by James Shapiro. PMID- 23928471 TI - Theories, frameworks and aesthetics: comment on "From everyday emotions to aesthetic emotions: towards a unified theory of musical emotions" by Patrik Juslin. PMID- 23928472 TI - What is special about musical emotion? PMID- 23928473 TI - Determinants of carbon nanotube toxicity. AB - In the last few years questions have been raised regarding the potential toxicity of carbon nanotubes (CNTs) to humans and environment. It is believed that the physico-chemical characteristics of these materials are key determinants of CNT interaction with living organisms, and hence determine their toxicity. As for other nanomaterials, the most important of these characteristics are the length, diameter, surface area, tendency to agglomerate, bio-durability, presence and nature of catalyst residues as well as chemical functionalization of the CNT. This review highlights the recent advancements in the understanding of the CNT properties which are essential in determining CNT toxicity. Hence the focus is on CNT dimensions, surface properties, bio-durability and corona formation as these fields have evolved greatly in recent years. A deeper understanding of these events and their underlying mechanisms could provide a molecular explanation of the biological and physiological responses following CNT administration and therefore help in the development of safe by design materials. PMID- 23928474 TI - Stroke prediction with an adjusted R-CHA2DS2VASc score in a cohort of patients with a Myocardial Infarction. AB - INTRODUCTION: A new risk stratification scheme incorporating the original CHADS2 score and renal function, entitled R(2)CHADS(2), was validated in the ROCKET-AF and ATRIA study cohorts. AIMS: Adjusting and validating a modified R-CHA2DS2VASc score as a predictor of ischaemic stroke and all-cause mortality in patients discharged following admission for a Myocardial Infarction (MI). MATERIALS AND METHODS: Observational retrospective single-centre cohort study including 1711 patients admitted with MI and discharged alive. We tested the prognostic performance of R-CHA2DS2VASc, based on the original CHA2DS2VASc score with few modifications (addition of renal function parameters [glomerular filtration rate and urea], performance of a revascularization procedure and history of atrial fibrillation). R-CHA2DS2VASc was evaluated for its discriminative performance and calibration in the prediction of ischaemic stroke (primary endpoint), all-cause mortality and a composite endpoint of ischemic stroke plus all-cause mortality (secondary outcomes) during follow-up. RESULTS: R-CHA2DS2VASc score's areas under the curve (AUC) for the occurrence of primary and secondary outcomes were: Ischaemic stroke: AUC 0.717 +/- 0.031, p<0.001 (vs. 0.681 +/- 0.043 for CHA2DS2VASc, p=0.290); all-cause mortality during follow-up: AUC 0.811 +/- 0.014, p<0.001 (vs. 0.782 +/- 0.019 for GRACE, p=0.245); composite endpoint: AUC 0.803 +/- 0.014, p<0.001. The integrated discrimination improvement index (IDI) and relative IDI for the primary endpoint were 0.015 and 28.2%, respectively, while the IDI and relative IDI for all-cause mortality were 0.13 and 72.1%, suggesting a large improvement in risk stratification. An R-CHA2DS2VASc score below 3 had a negative predictive value of 98.6% for the occurrence of ischaemic stroke. CONCLUSIONS: The modified R-CHA2DS2VASc score has shown good calibration and high discriminative performance in the prediction of post-discharge ischaemic stroke and all-cause mortality. The inclusion of renal function in thromboembolic risk predicting schemes seems warranted. PMID- 23928475 TI - Comparison of 24-hour urinary protein and protein-to-creatinine ratio in women with preeclampsia. AB - OBJECTIVE: To compare the spot urine protein-to-creatinine (P/C) ratio and 24 hour urine protein excretion in pregnant women with preeclampsia and also to determine the best discriminator values of the spot P/C ratios for 300 mg and 2000 mg protein per 24h. STUDY DESIGN: Prospective study of 200 pregnant women with new onset hypertension at or greater than 140/90 mmHg after 20 weeks of gestation. Women were instructed to collect urine during a 24-hour period, and after the 24-hour urine sample collection was completed a mid-stream urine specimen was obtained for P/C ratio determination. The correlation between 24 hour urine protein excretion and spot urine P/C ratio was calculated. The receiver operating characteristic (ROC) curve was used to identify the cut-off values of the spot P/C ratios for 300 mg and 2000 mg protein per 24h. Areas under ROC curves were calculated. RESULTS: There was a significant correlation between 24-hour protein excretion and the urine P/C ratio (r=0.828, p<0.0001). The cut off P/C ratio for 300 mg per 24h was 0.28: sensitivity and specificity were 60.4% and 77.9%, respectively. The positive predictive value (PPV) was 77.5% and negative predictive value (NPV) was 60.9%. The cut-off P/C ratio for 2000 mg per 24h was 0.77: sensitivity and specificity were 96.8% and 98.6%, respectively. The PPV was 96.8% and NPV was 98.6%. Area under ROC curves for 24-hour urine total protein of 300-2000 mg/day and >2000 mg/day were 0.74 (95% CI 0.66-0.80) and 0.99 (95% CI 0.95-0.99), respectively. CONCLUSIONS: Spot P/C ratio is a poor predictor of 24-hour proteinuria but can predict proteinuria >2000 mg better than 300-2000 mg. PMID- 23928476 TI - Psychological impact of single and multiple courses of assisted reproductive treatments in couples: a comparative study. AB - OBJECTIVE: To analyze the psychological impact on levels of anxiety and depression in couples who, confronted with the diagnosis of infertility, propose to carry out ART; to evaluate and compare state-trait anxiety and depression levels in couples undergoing ART treatments for the first time and repeatedly, and to verify gender differences. STUDY DESIGN: In this prospective study in the Medically Assisted Reproduction Unit of the Centro Hospitalar de Sao Joao, Porto, Portugal, 89 couples diagnosed with infertility were divided into two groups: (1) couples starting ART for the first time (43), and (2) couples pursuing ART repeatedly (46). Participants completed the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory-Form Y (STAI-Y), prior to their first or subsequent treatment cycle. RESULTS: Couples pursuing ART for the first time show higher levels of state-anxiety compared to couples who repeatedly carry out ART (p < 0.05). Levels of depression are higher in couples who repeatedly carry out ART (p < 0.05). In both study groups, women and men have higher levels of state anxiety compared to trait-anxiety (p < 0.05). With respect to depression, there are significant differences between genders in both groups, showing higher values in women compared to men (p < 0.01). CONCLUSIONS: The results show that there is room to tailor psychological interventions for the specific story of each couple, but we emphasize the importance and need for more studies to support these findings. PMID- 23928477 TI - Familial predisposition to pelvic floor dysfunction: prolapse and incontinence surgery among family members and its relationship with age or parity in a Swedish population. AB - OBJECTIVE: To estimate the relationship between heredity and proband's age/parity on the risk of undergoing surgery for pelvic organ prolapse and stress incontinence. STUDY DESIGN: Swedish population based study. Data from two national Swedish registers were used: the Hospital Discharge Register, National Board of Health and Welfare, containing information on all in-patient surgical procedures on Swedish hospitals, and the Multi-Generation Register, Statistics Sweden, containing information on individuals belonging to the same family. Women who had a surgical procedure for urinary incontinence or genital organ prolapse between the years 1987 and 2002 were identified (probands). Mothers and sisters of the probands were identified and information on incontinence or prolapse operations was linked to those relatives from the Hospital Discharge file, after which adjusted analyses were performed. RESULTS: Sisters to probands had a relative risk (RR) of 4.69 (95% confidence intervals (CI) 4.49-48.9) and mothers a RR of 2.17 (95% CI 2.07-2.27) for pelvic floor surgery. For sisters the risk decreased with increasing age and parity of the proband. CONCLUSION: Sisters and mothers of women operated for urinary incontinence/urogenital prolapse had a higher risk of surgery for pelvic floor conditions, in particular sisters of women operated at a young age (<50) and with a low parity. This suggests that heredity plays a lesser role for the development of pelvic floor dysfunction at older age and with increasing parity. PMID- 23928478 TI - Statistical significance of paracetamol administration in fetal and maternal body temperatures. PMID- 23928479 TI - Duplicated uterus and hemivaginal or hemicervical atresia with ipsilateral renal agenesis: an institutional clinical series of 52 cases. AB - OBJECTIVES: To retrospectively review cases of unilateral vaginal or cervical atresia with ipsilateral renal agenesis at our institution and to analyze the clinical presentation, diagnostic pitfalls, management, and embryological implications for the vaginal origin that arise from this syndrome. STUDY DESIGN: A retrospective observational study that included 52 patients diagnosed with this syndrome between 1998 and 2008 at Peking Union Medical College Hospital. RESULTS: The median age at diagnosis was 21.5 years, and the median time between the first onset of symptoms and diagnosis was 12 months. The most common presenting complaints were dysmenorrhea, purulent discharge and irregular spotting, despite the wide spectrum of symptoms at referral. Patients with and without a communication between the two hemivaginas or hemiuteri had different clinical characteristics. Of the patients, 59.6% had an obstruction on the right side. Of patients who had received a check-up prior to referral, 92.9% (n=28) had been misdiagnosed, and 53.9% had received inappropriate surgery as therapy. The pathology of the resected septum showed squamous epithelium in 13 samples, while 5 samples had epithelium with paramesonephric characteristics. CONCLUSION: Knowledge of the origins and clinical presentation of this syndrome is the foundation for correct and timely diagnosis and treatment. Moreover, this unique anomaly may offer essential clues for determining the embryological origins of the vagina and cervix. PMID- 23928480 TI - Maternal and fetal factors which affect fetometry: use of in vitro fertilization and birth register data. AB - BACKGROUND: Fetometry dating of gestational age is the gold standard in most developed countries but may have some inborn errors. Dating pregnancies after in vitro fertilization can be used for the evaluation of fetometric studies and for studies of variables which may affect them. METHODS: We compared the actual gestational age of 9543 singleton and 869 twin pregnancies with estimates based on second-trimester fetometry. Mean gestational age, percentage of births classified as preterm, and skewness of the distribution of differences between actual and estimated gestational age were studied. Subanalyses were made of data on singletons for males and females, for infants born to overweight or obese women or to smoking women, for infants judged to be small or large for gestational age, and on twins. RESULTS: In the majority of cases, good agreement was found between actual and estimated gestational age but in singletons there was an excess of positive differences resulting in a moderate over-estimate of the rate of preterm births (8%), more marked for females (11%) than for males (6%) and increased for infants born to overweight (7%) or obese (16%) mothers. Singleton infants born small for gestational age also showed an excess of positive differences (3%). These differences were less marked for twins. CONCLUSIONS: In most IVF pregnancies, routine fetometry correctly predicts gestational age but deviations exist which indicate that ultrasound underestimates the age of fetuses that will be born small for gestational age and when the woman is obese. The differences between actual age and estimates based on fetometry seem to be smaller than those between estimates based on last menstrual period and fetometry. PMID- 23928481 TI - Preparation of tumor antigen-loaded mature dendritic cells for immunotherapy. AB - While clinical studies have established that antigen-loaded DC vaccines are safe and promising therapy for tumors, their clinical efficacy remains to be established. The method described below, prepared in accordance with Good Manufacturing Process (GMP) guidelines, is an optimization of the most common ex vivo preparation method for generating large numbers of DCs for clinical studies. Our method utilizes the synthetic TLR 3 agonist Polyinosinic-Polycytidylic Acid poly-L-lysine Carboxymethylcellulose (Poly-ICLC) to stimulate the DCs. Our previous study established that Poly-ICLC is the most potent individual maturation stimulus for human DCs as assessed by an upregulation of CD83 and CD86, induction of interleukin-12 (IL-12), tumor necrosis factor (TNF), interferon gamma-induced protein 10 (IP-10), interleukmin 1 (IL-1), and type I interferons (IFN), and minimal interleukin 10 (IL-10) production. DCs are differentiated from frozen peripheral blood mononuclear cells (PBMCs) obtained by leukapheresis. PBMCs are isolated by Ficoll gradient centrifugation and frozen in aliquots. On Day 1, PBMCs are thawed and plated onto tissue culture flasks to select for monocytes which adhere to the plastic surface after 1-2 hr incubation at 37 degrees C in the tissue culture incubator. After incubation, the lymphocytes are washed off and the adherent monocytes are cultured for 5 days in the presence of interleukin-4 (IL-4) and granulocyte macrophage-colony stimulating factor (GM-CSF) to differentiate to immature DCs. On Day 6, immature DCs are pulsed with the keyhole limpet hemocyanin (KLH) protein which serves as a control for the quality of the vaccine and may boost the immunogenicity of the vaccine. The DCs are stimulated to mature, loaded with peptide antigens, and incubated overnight. On Day 7, the cells are washed, and frozen in 1 ml aliquots containing 4-20 x 10(6) cells using a controlled-rate freezer. Lot release testing for the batches of DCs is performed and must meet minimum specifications before they are injected into patients. PMID- 23928482 TI - Radiological assessment of response to neoadjuvant transcatheter hepatic therapy with irinotecan-eluting beads (DEBIRI((r))) for colorectal liver metastases does not predict tumour destruction or long-term outcome. AB - INTRODUCTION: Transcatheter hepatic therapy with irinotecan-eluting beads (DEBIRI((r))) allows targeted delivery of irinotecan direct to liver tissue and colorectal liver metastases (CRLM). Accurate assessment of tumour response to therapy is vital to guide optimal treatment. Preliminary work has suggested existing criteria for radiological response may not reflect pathological response after neoadjuvant DEBIRI. This study assessed the relationship between existing and novel radiological response criteria and pathological tumour response as well as long-term outcome. METHODS: Patients with easily resectable CRLM were treated with DEBIRI 4 weeks prior to resection and pathological tumour response graded using a validated system. Radiological response was assessed using RECIST and novel morphological response criteria. RESULTS: Twenty-two patients with 37 lesions were treated with DEBIRI. Median residual tumour was 20% (range 0-80), median necrosis 45% (10-100) and median fibrosis 10% (10-70). Twenty patients (91%) demonstrated stable disease by RECIST, with 11 (50%) demonstrating partial morphological response. Neither radiological response criteria correlated with pathological response. Overall median disease free survival (DFS) was 13.6 months (95% CI 4.7-22.5). Radiological response was not associated with DFS. CONCLUSION: Existing criteria reporting short-term radiological response to DEBIRI do not accurately predict pathological tumour response or long-term outcome. Further work is necessary to define the optimum timing and method of assessing response to DEBIRI. PMID- 23928483 TI - Thermodynamic analysis and fluorescence imaging of homochiral amino acid-amino acid interactions at the air/water interface. AB - Surface pressure-molecular area (Pi-A) isotherms and fluorescence microscopy were used to investigate the interactions between N-stearoyl-glutamic acid (l- and d-) and l-arginine at the air/water interface. N-stearoyl-glutamic acids (C18-Glu) with different chirality (l- and d-) were spread at the air-water interface onto subphases containing varied concentrations of l-arginine at pH 5. The apparent binding affinity of C18-Glu to l-arginine was obtained by fitting the plots of the change in mean molecular area of C18-Glu vs. l-arginine concentration. The thermodynamic properties of the binding events such as binding constant and Gibbs free energy were estimated from the binding curves. We found that N-stearoyl-l glutamic acid (C18-l-Glu) had a stronger binding affinity to l-arginine as compared to N-stearoyl-d-glutamic acid (C18-d-Glu) at low to moderate surface pressures (below ~22mN/m). The C18-d-Glu had stronger binding to l-arginine at higher surface pressure. Domains with different shapes in C18-l-Glu and C18-d-Glu monolayers were observed under a fluorescence microscope in situ at the air/water interface. Herein, we present a mechanism for C18-l-Glu and C18-d-Glu interacting with l-arginine at the air/water interface. PMID- 23928484 TI - Photovoltaic performance of bithiazole-bridged dyes-sensitized solar cells employing semiconducting quantum dot CuInS2 as barrier layer material. AB - In this work, the quantum dot CuInS2 layer was deposited on TiO2 film using successive ionic layer absorption and reaction (SILAR) method, and then two bithiazole-bridged dyes (BTF and BTB) were sensitized on the CuInS2/TiO2 films to form dye/CuInS2/TiO2 photoanodes for DSSCs. It was found that the quantum dots CuInS2 as an energy barrier layer not only could effectively improve open-circuit voltage (Voc) of solar cell, but also increase short-circuit photocurrent (Jsc) compared to the large decrease in Jsc of ZnO as energy barrier layer. The electrochemical impedance spectroscopy (EIS) measurement showed that the CuInS2 formed a barrier layer to suppress the recombination from injection electron to the electrolyte and improve open-circuit voltage. Finally, the open-circuit voltage increased about 22 and 27mV for BTF and BTB-/CuInS2/TiO2-based cells, the overall conversion efficiencies also reached to 7.20% and 6.74%, respectively. PMID- 23928485 TI - Controlling nanostructure and lattice parameter of the inverse bicontinuous cubic phases in functionalised phytantriol dispersions. AB - The preparation and phase behavior of dispersed liquid crystalline particles comprised of phytantriol and various functionalised lipids are reported. These inverse bicontinuous cubic phase colloidal dispersions have been sterically stabilized with a triblock copolymer, Pluronic F127. The influence of added negatively charged amphiphiles oleic acid and sodium dodecylsulfate, the positively charged hexadecyltrimethylammonium bromide, and monoolein a neutral amphiphile, on phase behavior and cubic phase structure was examined by synchrotron small angle X-ray scattering (SAXS). Functionality was also introduced through ligand specific lipids monosialoganglioside-GM1 and 1,2 distearoyl-sn-glycero-3-phosphoethanolamine-N-[biotinyl(polyethylene glycol) 2000]. SAXS measurements showed that all of the additives affected the long-range order of the inverse cubic phase observed through either phase behavior changes or alteration in lattice parameter. PMID- 23928486 TI - NO reduction by CO over Rh/Al2O3 and Rh/AlPO4 catalysts: Metal-support interaction and thermal aging. AB - Rhodium was impregnated on gamma-Al2O3 and AlPO4 followed by treating in a wet air at 1050 degrees C for 5h. The catalytic activities of the catalysts were evaluated by temperature-programmed reactions in a stoichiometric mixture of NO and CO. The fresh Rh/Al2O3 and Rh/AlPO4 catalysts exhibit similar catalytic activities. After the hydrothermal aging, Rh/Al2O3 experiences a significant deactivation, whereas Rh/AlPO4 shows even higher activity than the fresh sample. A series of structural and surface characterizations were performed to explore different aging mechanisms of these two catalysts. The fresh Rh/AlPO4 catalyst shows superior low-temperature redox property, but its NOx adsorption is weakened due to the acidic nature of the support. Thus, two fresh catalysts present similar catalytic activities. The hydrothermal aging at high temperature leads to the formation of inert Al5Rh2 alloy. Contrarily, no such strong interaction occurs between rhodium and AlPO4. Furthermore, large Rh particles, which facilitate the dissociation of NO, are formed on the aged Rh/AlPO4 catalyst. Thus, a superior high activity for NO-CO is achieved over the aged Rh/AlPO4. PMID- 23928487 TI - Charged microcapsules for controlled release of hydrophobic actives Part II: surface modification by LbL adsorption and lipid bilayer formation on properly anchored dispersant layers. AB - Charge microcapsules with a dodecane core and a poly(methyl methacrylate) (PMMA) shell have been prepared via the internal phase separation method using ionic dispersants. The microcapsules have subsequently been surface modified with polyelectrolyte multilayers and lipid bilayers. Two types of ionic dispersant systems have been investigated: a small set of ionic amphiphilic block copolymers of poly(methyl methacrylate)-block-poly(sodium (meth)acrylate) type and an oil soluble anionic surfactant, sodium 1,5-dioxo-1,5-bis(3,5,5-trimethylhexyloxy)-3 ((3,5,5trimethylhexyloxy)carbonyl)pentane-2-sulfonate, in combination with a water-soluble polycation, poly(diallyldimethylammonium chloride). The Layer-by Layer adsorption of the polyelectrolyte pair poly(diallydimethylammonium chloride) (350,000 g/mol) and poly(sodium methacrylate) (15,000 g/mol) was successfully made on both microcapsule systems with the formation of very thin multilayers as indicated with quartz crystal microbalance with dissipation monitoring (QCM-D) measurements on model surfaces. Formation of a lipid bilayer on the surface of the microcapsules from liposomes with a charge opposite that of the capsule surface was also proven to be successful as indicated by the zeta potential of the microcapsules, the characteristic frequency shift as measured with QCM-D and fluorescence recovery after photobleaching (FRAP) on model systems. However, the proper anchorage of the dispersants in the underlying PMMA surface was key for the successful surface modification. PMID- 23928488 TI - Water evaporation in silica colloidal deposits. AB - The results of an experimental study on the evaporation and boiling of water confined in the pores of deposits made of mono-dispersed silica colloidal micro spheres are reported. The deposits are studied using scanning electron microscopy, adsorption of nitrogen, and adsorption of water through attenuated total reflection-infrared spectroscopy. The evaporation is characterized using differential scanning calorimetry and thermal gravimetric analysis. Optical microscopy is used to observe the patterns on the deposits after evaporation. When heating at a constant rate and above boiling temperature, the release of water out of the deposits is a two step process. The first step is due to the evaporation and boiling of the surrounding and bulk water and the second is due to the desorption of water from the pores. Additional experiments on the evaporation of water from membranes having cylindrical pores and of heptane from silica deposits suggest that the second step is due to the morphology of the deposits. PMID- 23928489 TI - Grafting of poly-L-lysine dendrigrafts onto polypropylene surface using plasma activation for ATP immobilization - Nanomaterial for potential applications in biotechnology. AB - The present work describes a new environmental friendly strategy for the development of surfaces with high amine density via the grafting of native or modified poly-L-lysine dendrigraft (DGL G3) onto plasma activated polypropylene (PP), polystyrene (PS), polyimide, and polytetrafluoroethylene (PTFE) surface. Modified DGL G3 was prepared by replacement of few peripheral amines by various functionalities. Grafting efficiency was determined by wettability measurements, IRTF, XPS, AFM, and by colorimetry using optimized Coomassie Brilliant Blue method tailored for surface analysis. It was shown that a 4-7nm DGL G3 monolayer with 4*10(14)aminecm(-)(2) was covalently grafted onto various surfaces. Immobilization of adenosine triphosphate on the DGL-g-PP material from dilute solution was studied by bioluminescence and proved the ability of the material to interact with polyanionic biological compounds: 1 ATP complex with 5 amine groups. So, this material has a potential use in diagnostic and more widely for biotechnology due to its high capacity for biomolecule immobilization. PMID- 23928490 TI - Magnetic nanomaterial derived from graphene oxide/layered double hydroxide hybrid for efficient removal of methyl orange from aqueous solution. AB - Magnetic hybrid nanomaterials composed of reduced graphene oxide, zero-valent nickel, and NiAl-mixed metal oxides (rGO/Ni/MMO) have been synthesized by calcining graphene oxide (GO)/layered double hydroxide (LDH) hybrid in nitrogen atmosphere. Structural characterizations demonstrate that with the presence of GO substrate, NiAl-LDHs can be reduced into zero-valent Ni and NiAl-MMOs during calcination. Transmission electron microscopy (TEM) is used to investigate the morphology of the as-prepared hybrid nanomaterials, demonstrating that the introduction of GO substrate prevents the aggregation of LDHs. Magnetism characterization proves the ferromagnetic property of rGO/Ni/MMO hybrid. This magnetic hybrid nanomaterial exhibits excellent adsorption ability toward methyl orange (MO) in aqueous solutions. The kinetics of the adsorption process and the adsorption isotherm are investigated. The MO removal process is found to obey the Redlich-Peterson isotherm model, and its kinetics follows pseudo-second-order rate equation. In addition, the magnetic hybrid also exhibits good recycle ability for MO removal. This novel magnetic hybrid nanomaterial derived from GO/LDH hybrid demonstrates great potential in the applications of water treatment. PMID- 23928491 TI - Amine-functionalized monodispersed porous silica microspheres with enhanced CO2 adsorption performance and good cyclic stability. AB - Carbon dioxide capture using solid adsorbent has caused more and more attention in the world. Herein, amine-functionalized monodispersed porous silica microspheres (MPSM) were prepared by the hydrolysis and condensation of tetraethoxysilane (TEOS) in a water-ethanol-dodecylamine mixed solution, then calcined at 600 degrees C, and finally functionalized with tetraethylenepentamine (TEA). The CO2 adsorption performance of the prepared samples was measured using a Chemisorb 2720 pulse chemisorption system (Micromeritics, USA). The results showed that the specific surface area and pore volume of the 600 degrees C calcined SiO2 microspheres reached 921m(2)/g and 0.48cm(3)/g, respectively. All the TEA-functionalized samples exhibited good CO2 adsorption performance, which were related to the amount of loaded TEA, adsorption temperatures, and the specific surface areas of the prepared samples. An optimal TEA loading amount (34wt%) and adsorption temperature (75 degrees C) were determined. The maximum CO2 adsorption amount (4.27mmolg(-1) adsorbent) was achieved on the 600 degrees C calcined SiO2 microsphere sample with TEA loading of 34wt%. Repeated adsorption/desorption cycle experiments revealed that the TEA-functionalized SiO2 microspheres were good CO2 adsorbents exhibiting excellent cyclic stability. PMID- 23928492 TI - Validity of web-based self-reported weight and height: results of the Nutrinet Sante study. AB - BACKGROUND: With the growing scientific appeal of e-epidemiology, concerns arise regarding validity and reliability of Web-based self-reported data. OBJECTIVE: The objectives of the present study were to assess the validity of Web-based self reported weight, height, and resulting body mass index (BMI) compared with standardized clinical measurements and to evaluate the concordance between Web based self-reported anthropometrics and face-to-face declarations. METHODS: A total of 2513 participants of the NutriNet-Sante study in France completed a Web based anthropometric questionnaire 3 days before a clinical examination (validation sample) of whom 815 participants also responded to a face-to-face anthropometric interview (concordance sample). Several indicators were computed to compare data: paired t test of the difference, intraclass correlation coefficient (ICC), and Bland-Altman limits of agreement for weight, height, and BMI as continuous variables; and kappa statistics and percent agreement for validity, sensitivity, and specificity of BMI categories (normal, overweight, obese). RESULTS: Compared with clinical data, validity was high with ICC ranging from 0.94 for height to 0.99 for weight. BMI classification was correct in 93% of cases; kappa was 0.89. Of 2513 participants, 23.5% were classified overweight (BMI>=25) with Web-based self-report vs 25.7% with measured data, leading to a sensitivity of 88% and a specificity of 99%. For obesity, 9.1% vs 10.7% were classified obese (BMI>=30), respectively, leading to sensitivity and specificity of 83% and 100%. However, the Web-based self-report exhibited slight underreporting of weight and overreporting of height leading to significant underreporting of BMI (P<.05) for both men and women: -0.32 kg/m2 (SD 0.66) and 0.34 kg/m2 (SD 1.67), respectively. Mean BMI underreporting was -0.16, -0.36, and -0.63 kg/m2 in the normal, overweight, and obese categories, respectively. Almost perfect agreement (ie, concordance) was observed between Web-based and face-to face report (ICC ranged from 0.96 to 1.00, classification agreement was 98.5%, and kappa 0.97). CONCLUSIONS: Web-based self-reported weight and height data from the NutriNet-Sante study can be considered as valid enough to be used when studying associations of nutritional factors with anthropometrics and health outcomes. Although self-reported anthropometrics are inherently prone to biases, the magnitude of such biases can be considered comparable to face-to-face interview. Web-based self-reported data appear to be an accurate and useful tool to assess anthropometric data. PMID- 23928493 TI - A flow cytometric method for the analysis of macrophages in the vascular wall. AB - Macrophages accumulate in the vascular wall during conditions such as hypertension and hypercholesterolemia and contribute to vascular remodelling. Here we describe a method for the isolation and subsequent flow cytometric analysis of macrophages from aortas of mice. Cell suspensions were prepared from thoracic aortas of male C57BL/6J mice by a combination of manual disruption, incubation in enzymatic digestion medium, and passage through a 70 MUm cell strainer. Flow cytometric analysis of these suspensions revealed a high content of cells with strong light scattering properties (i.e. SSC(hi)) compared with suspensions derived from mouse blood, spleen, thymus or kidney. Unstained aortic cell suspensions also displayed a preponderance of autofluorescence in the B670, V560, V460, B525 and V610 channels of the flow cytometer, suggesting that these channels should be avoided for subsequent flow cytometric analyses, at least for initial gating steps. Thus, aortic preparations were labelled with an APC-Cy7 conjugated antibody against the pan-leukocyte marker, CD45, as well as an APC conjugated antibody against the macrophage-specific antigen, F4/80, as these fluorochromes emit in channels that displayed relatively low levels of auto fluorescence in our initial studies (i.e. R780 and R660). Flow cytometric analysis of labelled aortic preparations revealed a distinct population of CD45(+)F4/80(+) cells. Importantly, back-gating on this CD45(+)F4/80(+) cell population showed it to be now virtually devoid of autofluorescence in all remaining open channels, and hence an appropriate foundation for further detailed analysis of macrophage polarization using multiple intra- and extra-cellular markers. Furthermore, we demonstrated that angiotensin II-induced hypertension in C57BL6/J mice, and hypercholesterolemia in apolipoprotein E-deficient mice, each resulted in an approximate doubling of CD45(+)F4/80(+) cells in the aortic wall, highlighting the utility of our new protocol for studying the impact of disease on macrophage accumulation in the vascular wall. PMID- 23928494 TI - Differential representation of B cell subsets in mixed bone marrow chimera mice due to expression of allelic variants of CD45 (CD45.1/CD45.2). AB - The CD45 congenic marker system is a highly utilized technique to track hematopoietic cells following bone marrow transplantation (BMT), with CD45.1 and CD45.2 being efficiently distinguished by flow cytometry. During the analysis of control mixed BM chimera mice in which lethally irradiated recipients were transplanted with an equal number of BM cells from WT CD45.1 and WT CD45.2 mice, we observed an unequal reconstitution of specific B cell subsets in the bone marrow (BM), lymph node (LN) and spleen. Specifically, in the BM and LN, there was an increase in the percentage of CD45.2 mature B cells. In the spleen, an increase in the percentage of CD45.2 transitional (T) 1 and T2 cells was observed. In contrast, the percentage of splenic CD45.1 marginal zone (MZ) B cells was significantly increased. When we compared the percentage of B cell subsets in unmanipulated WT CD45.1 and WT CD45.2 mice, we found that WT CD45.2 mice had significantly more LN B cells while WT CD45.1 mice exhibited an increase in MZ B cells. These data indicate that the alteration in the ratio of CD45.1 and CD45.2 B cell subsets in mixed chimera mice is a cell-intrinsic effect. Thus whenever the CD45 congenic system is used to track two genetically distinct populations of immune cells WT chimeras must be generated to allow normalization of the experimental data to avoid the reporting of unintentionally skewed data. PMID- 23928495 TI - Development of transgenic mice expressing a coronavirus-specific public CD4 T cell receptor. AB - Mice that are transgenic (Tg) for T cell receptor (TCR) expression are used extensively to analyze longitudinal T cell responses during effector and memory phases of the T cell response. Generation of TCR Tg mice generally requires T cell stimulation and cloning in vitro prior to amplification, processes which introduce biases into selection of the TCR that is ultimately chosen for TCR Tg mouse generation. Here we describe an alternative approach that involves no T cell stimulation or propagation in vitro. We generated mice that were transgenic for a TCR responding to a CD4 T cell epitope (epitope M133) that is immunodominant in mice infected with a neurotropic coronavirus, the JHM strain of mouse hepatitis virus. The CD4 T cell response to epitope M133 is of particular interest because it may be pathogenic, protective or regulatory, depending upon the physiological setting. We applied an iterative process in which we identified a TCR-beta chain expressed by all mice that were examined ('public sequence'). This TCR-beta chain was introduced into bone marrow cells with a lentivirus vector, generating TCR-beta retrogenic mice. A TCR-alpha chain that paired with this TCR-beta was then identified and used to generate a second set of TCR (alpha/beta) retrogenic mice. After demonstrating that these cells were functional and responded to epitope M133, these TCR chains were used to generate an epitope M133-specific TCR Tg mouse. This method should be generally useful for engineering TCR Tg mice without introduction of bias caused by in vitro manipulation and propagation. PMID- 23928496 TI - Effects of aging and divided attention on episodic feeling-of-knowing accuracy. AB - This research investigated the effect of aging on episodic feeling-of-knowing (FOK) using a divided attention (DA) paradigm in order to examine whether DA in younger adults mimics the effects of aging when decreasing either memory encoding or monitoring processes. To that end, four groups of participants were tested on the FOK task: young adults (control group), young adults under DA at encoding, young adults under DA when making FOK judgments, and older adults. Our results showed that DA at encoding in young adults mimicked the effect of aging on memory performance, and also on FOK magnitude and accuracy, supporting the memory constraint hypothesis (Hertzog et al., 2010). However, our results do not completely contradict the monitoring-deficit hypothesis, as DA during FOK judgments also affected FOK accuracy, but to a lesser extent than the aging effect or DA during encoding. We suggest that the age-related FOK deficit may be due to a lower level of deep encoding, leading to difficulty retrieving target related contextual details enabling accurate prediction of subsequent recognition. PMID- 23928497 TI - Testing a word is not a test of word learning. AB - Although vocabulary acquisition requires children learn names for multiple things, many investigations of word learning mechanisms teach children the name for only one of the objects presented. This is problematic because it is unclear whether children's performance reflects recall of the correct name-object association or simply selection of the only object that was singled out by being the only object named. Children introduced to one novel name may perform at ceiling as they are not required to discriminate on the basis of the name per se, and appear to rapidly learn words following minimal exposure to a single word. We introduced children to four novel objects. For half the children, only one of the objects was named and for the other children, all four objects were named. Only children introduced to one word reliably selected the target object at test. This demonstration highlights the over-simplicity of one-word learning paradigms and the need for a shift in word learning paradigms where more than one word is taught to ensure children disambiguate objects on the basis of their names rather than their degree of salience. PMID- 23928499 TI - Analysis of GSH and GSSG after derivatization with N-ethylmaleimide. AB - This protocol describes a procedure for determining glutathione (GSH) and glutathione disulfide (GSSG) concentrations in blood and other tissues. Artifactual oxidation to GSSG of 5-15% of the GSH found in a sample can occur during deproteination of biological samples with any of the commonly used acids, with consequent marked overestimation of GSSG. This can be prevented by derivatizing GSH with the alkylating agent N-ethylmaleimide (NEM) to form GS-NEM before acid deproteination, followed by back-extraction of excess NEM from the deproteinized samples with dichloromethane. GSSG concentration is then measured by spectrophotometry with the GSH recycling method, on the basis of conversion of GSSG to GSH by glutathione reductase and NADPH and reaction with 5,5'-dithiobis (2-nitrobenzoic acid). GSH concentration is instead measured by either of two methods: by analysis of GS-NEM conjugates by HPLC in the same sample that is used to measure GSSG or, alternatively, by analysis of GSH by spectrophotometry (GSH recycling method) on one additional sample aliquot that has not been derivatized with NEM. The procedure can assay GSH and GSSG in blood and other tissues in 30 min or less. PMID- 23928498 TI - Fabrication of pRNA nanoparticles to deliver therapeutic RNAs and bioactive compounds into tumor cells. AB - RNA nanotechnology is a term that refers to the design, fabrication and use of nanoparticles that are mainly composed of RNAs via bottom-up self-assembly. The packaging RNA (pRNA) of the bacteriophage phi29 DNA packaging motor has been developed into a nanodelivery platform. This protocol describes the synthesis, assembly and functionalization of pRNA nanoparticles on the basis of three 'toolkits' derived from pRNA structural features: interlocking loops for hand-in hand interactions, palindrome sequences for foot-to-foot interactions and an RNA three-way junction for branch extension. siRNAs, ribozymes, aptamers, chemical ligands, fluorophores and other functionalities can also be fused to the pRNA before the assembly of the nanoparticles, so as to ensure the production of homogeneous nanoparticles and the retention of appropriate folding and function of the incorporated modules. The resulting self-assembled multivalent pRNA nanoparticles are thermodynamically and chemically stable, and they remain intact at ultralow concentrations. Gene-silencing effects are progressively enhanced with increasing numbers of siRNAs in each pRNA nanoparticle. Systemic injection of the pRNA nanoparticles into xenograft-bearing mice has revealed strong binding to tumors without accumulation in vital organs or tissues. The pRNA-based nanodelivery scaffold paves a new way for nanotechnological application of pRNA based nanoparticles for disease detection and treatment. The time required for completing one round of this protocol is 3-4 weeks when including in vitro functional assays, or 2-3 months when including in vivo studies. PMID- 23928500 TI - Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells. AB - Forebrain gamma-aminobutyric acid (GABA) interneurons have crucial roles in high order brain function via modulating network activities and plasticity, and they are implicated in many psychiatric disorders. Availability of enriched functional human forebrain GABA interneurons, especially those from people affected by GABA interneuron deficit disease, will be instrumental to the investigation of disease pathogenesis and development of therapeutics. We describe a protocol for directed differentiation of forebrain GABA interneurons from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in a chemically defined system. In this protocol, human PSCs are first induced to primitive neuroepithelial cells over 10 d, and then patterned to NKX2.1-expressing medial ganglionic eminence progenitors by simple treatment with sonic hedgehog or its agonist purmorphamine over the next 2 weeks. These progenitors generate a nearly pure population of forebrain GABA interneurons by the sixth week. This simple and efficient protocol does not require transgenic modification or cell sorting, and it has been replicated with multiple human ESC and iPSC lines. PMID- 23928501 TI - Isolation and expansion of human and mouse brain microvascular endothelial cells. AB - Brain microvascular endothelial cells (BMVECs) have an important role in the constitution of the blood-brain barrier (BBB). The BBB is involved in the disease processes of a number of neurological disorders in which its permeability increases. Isolation of BMVECs could elucidate the mechanism involved in these processes. This protocol describes how to isolate and expand human and mouse BMVECs. The procedure covers brain-tissue dissociation, digestion and cell selection. Cells are selected on the basis of time-responsive differential adhesiveness to a collagen type I-precoated surface. The protocol also describes immunophenotypic characterization, cord formation and functional assays to confirm that these cells in endothelial proliferation medium (EndoPM) have an endothelial origin. The entire technique requires ~7 h of active time. Endothelial cell clusters are readily visible after 48 h, and expansion of BMVECs occurs over the course of ~60 d. PMID- 23928502 TI - Design and use of synthetic regulatory small RNAs to control gene expression in Escherichia coli. AB - Gene knockout experiments are often essential in functional genomics and metabolic engineering studies. However, repeated multiple gene knockout experiments are laborious, time consuming and sometimes impossible to perform for those genes that are essential for cell function. Small regulatory RNAs (sRNAs) are short noncoding RNAs in prokaryotes that can finely control the expression of target genes in trans at the post-transcriptional level. Here we describe the protocol for synthetic sRNA-based gene expression control, including sRNA design principles. Customized synthetic sRNAs consist of a scaffold and a target-binding sequence, and they can be created by simply replacing an existing target-binding sequence with one that is complementary to the target mRNA to be repressed, while retaining the scaffold. Our plasmid-based synthetic sRNA system does not require chromosomal modifications, and it enables one to perform high-throughput studies on the effects of knockdowns on host cell physiology, and it further allows the simultaneous screening of target genes in different Escherichia coli strains for applications in metabolic engineering and synthetic biology. Once an sRNA scaffold-harboring plasmid is constructed, customized synthetic sRNAs can be made within 3-4 d; after this time, the synthetic sRNAs can be applied to the desired experiments. PMID- 23928503 TI - Homogenization of sample absorption for the imaging of large and dense fossils with synchrotron microtomography. AB - Propagation phase-contrast synchrotron radiation microtomography (PPC-SRMUCT) has proved to be very successful for examining fossils. Because fossils range widely in taphonomic preservation, size, shape and density, X-ray computed tomography protocols are constantly being developed and refined. Here we present a 1-h procedure that combines a filtered high-energy polychromatic beam with long distance PPC-SRMUCT (sample to detector: 4-16 m) and an attenuation protocol normalizing the absorption profile (tested on 13-cm-thick and 5.242 g cm(-3) locally dense samples but applicable to 20-cm-thick samples). This approach provides high-quality imaging results, which show marked improvement relative to results from images obtained without the attenuation protocol in apparent transmission, contrast and signal-to-noise ratio. The attenuation protocol involves immersing samples in a tube filled with aluminum or glass balls in association with a U-shaped aluminum profiler. This technique therefore provides access to a larger dynamic range of the detector used for tomographic reconstruction. This protocol homogenizes beam-hardening artifacts, thereby rendering it effective for use with conventional MUCT scanners. PMID- 23928504 TI - Explaining the road accident risk: weather effects. AB - This research aims to highlight the link between weather conditions and road accident risk at an aggregate level and on a monthly basis, in order to improve road safety monitoring at a national level. It is based on some case studies carried out in Work Package 7 on "Data analysis and synthesis" of the EU-FP6 project "SafetyNet-Building the European Road Safety Observatory", which illustrate the use of weather variables for analysing changes in the number of road injury accidents. Time series analysis models with explanatory variables that measure the weather quantitatively were used and applied to aggregate datasets of injury accidents for France, the Netherlands and the Athens region, over periods of more than 20 years. The main results reveal significant correlations on a monthly basis between weather variables and the aggregate number of injury accidents, but the magnitude and even the sign of these correlations vary according to the type of road (motorways, rural roads or urban roads). Moreover, in the case of the interurban network in France, it appears that the rainfall effect is mainly direct on motorways--exposure being unchanged, and partly indirect on main roads--as a result of changes in exposure. Additional results obtained on a daily basis for the Athens region indicate that capturing the within-the-month variability of the weather variables and including it in a monthly model highlights the effects of extreme weather. Such findings are consistent with previous results obtained for France using a similar approach, with the exception of the negative correlation between precipitation and the number of injury accidents found for the Athens region, which is further investigated. The outlook for the approach and its added value are discussed in the conclusion. PMID- 23928505 TI - Sauchinone, a lignan from Saururus chinensis, attenuates neutrophil pro inflammatory activity and acute lung injury. AB - Previous studies have shown that sauchinone modulates the expression of inflammatory mediators through mitogen-activated protein kinase (MAPK) pathways in various cell types. However, little information exists about the effect of sauchinone on neutrophils, which play a crucial role in inflammatory process such as acute lung injury (ALI). We found that sauchinone decreased the phosphorylation of p38 MAPK in lipopolysaccharide (LPS)-stimulated murine bone marrow neutrophils, but not ERK1/2 and JNK. Exposure of LPS-stimulated neutrophils to sauchinone or SB203580, a p38 inhibitor, diminished production of tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2 compared to neutrophils cultured with LPS. Treatment with sauchinone decreased the level of phosphorylated ribosomal protein S6 (rpS6) in LPS-stimulated neutrophils. Systemic administration of sauchinone to mice led to reduced levels of phosphorylation of p38 and rpS6 in mice lungs given LPS, decreased TNF-alpha and MIP-2 production in bronchoalveolar lavage fluid, and also diminished the severity of LPS-induced lung injury, as determined by reduced neutrophil accumulation in the lungs, wet/dry weight ratio, and histological analysis. These results suggest that sauchinone diminishes LPS-induced neutrophil activation and ALI. PMID- 23928506 TI - Astragalin suppresses inflammatory responses via down-regulation of NF-kappaB signaling pathway in lipopolysaccharide-induced mastitis in a murine model. AB - Mastitis is a prevalent and economic disease around the world and defined as infection and inflammation of the mammary gland. Astragalin, a bioactive component isolated from persimmon or Rosa agrestis, has been reported to have anti-inflammatory properties. To investigate the potential therapeutic effect of astragalin in mastitis, a murine model of mastitis was induced by administration of LPS in mammary gland. Astragalin was applied 1h before and 12h after LPS treatment. The results showed that astragalin attenuated the infiltration of inflammatory cells, the activity of myeloperoxidase (MPO) and the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin 1beta (IL-1beta) in a dose-dependent manner. Additionally, Western blotting results showed that astragalin efficiently blunt decreased nuclear factor-kappaB (NF-kappaB) activation by inhibiting the degradation and phosphorylation of IkappaBalpha and the nuclear translocation of p65. These results suggested that astragalin exerts anti-inflammatory properties in LPS-mediated mastitis, possibly through inhibiting inhibition of the NF-kappaB signaling pathway, which mediates the expression of pro-inflammatory cytokines. Astragalin may be a potential therapeutic agent against mastitis. PMID- 23928507 TI - Is green tea a potential trigger for autoimmune hepatitis? AB - A case of autoimmune liver hepatitis is reported: the onset was triggered by consumption of green tea infusion in a patient taking oral contraceptives and irbesartan. We hypothesize that our patient, carrying genetic variant of hepatic metabolism making her particularly susceptible to oxidative stress, developed an abnormal response to a mild toxic insult, afforded by a combination of agents (oral contraceptives+irbesartan+green tea) that normally would not be able to cause damage. Her particular hepatic metabolism further increased the drugs' concentration, favoring the haptenization of liver proteins, eventually leading to the development of an autoimmune hepatitis. PMID- 23928509 TI - Early cochlear response and ICAM-1 expression to cochlear implantation. AB - AIM: To examine the early cochlear response and intercellular cell adhesion molecule-1 (ICAM-1) expression to implantation of a cochlear electrode into the scala tympani. BACKGROUND: Understanding the early response of the cochlea to implantation may inform the duration which drug therapies should be delivered to protect hearing. METHODS: Guinea pigs were implanted with a cochlear electrode and survived 1, 2, or 7 days before they were euthanized, cochleae harvested, processed, and cryosectioned for light microscopy or ICAM-1 immunohistochemistry. RESULTS: On hematoxylin and eosin staining, scala tympani was characterized by the presence of fibrin and blood clot at 1 to 2 days after surgery, with a leukocytic infiltrate, primarily of neutrophils and macrophage-like cells. By 7 days after surgery, fibroblasts had infiltrated the clot, and the numbers of red blood cells (RBCs) and neutrophils had diminished. ICAM-1 expression was greatest in the lateral cochlear wall with highest expression found in the basal turn in the region of the electrode at 24 hours postimplantation. CONCLUSION: The cochlear vasculature is maximally primed to recruit cells from the circulation, as evidenced by ICAM-1 expression levels, at 24 hours after cochlear implantation. This response is similar to that seen after other types of injury. Where cochlear implantation differs is the predominance of fibrin and clot early after electrode insertion before infiltration by fibroblasts by the end of the first postoperative week. These results suggest that anti-inflammatory drugs aimed at reducing the extravasation of immunecompetent cells into the cochlea must be effective over the first few days after surgery. Whether this can be achieved through preoperative treatment alone, or whether therapy will need to continue postoperatively, awaits further experimentation. PMID- 23928508 TI - A novel flavonoid C-glucoside from Ulmus wallichiana preserves bone mineral density, microarchitecture and biomechanical properties in the presence of glucocorticoid by promoting osteoblast survival: a comparative study with human parathyroid hormone. AB - PURPOSE: 6-C-beta-D-glucopyranosyl-(2S,3S)-(+)-5,7,3',4' tetrahydroxydihydroflavonol (GTDF) is a novel compound isolated from Ulmus wallichiana, reported to have bone anabolic action in ovariectomized rats. Here, we studied the effect of GTDF in glucocorticoid (GC)-induced bone loss and its mode of action. METHODS: Osteoblasts were cultured from rat calvaria or bone marrow to study apoptosis and differentiation by dexamethasone (Dex), methylprednisolone (MP), GTDF, quercetin and rutin. Female Sprague Dawley rats were treated with Dex or MP with or without GTDF or PTH. Efficacy was evaluated by bone microarchitecture using microcomputed tomography, determination of new bone formation by fluorescent labeling of bone and osteoblast apoptosis by co labeling bone sections with Runx-2 and TUNEL. Serum osteocalcin was determined by ELISA. RESULTS: GTDF preserved trabecular and cortical bones in the presence of Dex and MP and mitigated the MP-mediated suppression of serum osteocalcin. Co administration of GTDF to MP rats increased mineral apposition, bone formation rates, bone biomechanical strength, reduced osteoblast apoptosis and increased osteogenic differentiation of bone marrow stromal cells compared to MP group, suggesting in vivo osteogenic effect of GTDF. These effects of GTDF were to a great extent comparable to PTH. GTDF prevented GC-induced osteoblast apoptosis by inhibiting p53 expression and acetylation, and activation of AKT but did not influence transactivation of GC receptor (GR). CONCLUSIONS: GTDF protects against GC-induced bone loss by promoting osteoblast survival through p53 inhibition and activation of AKT pathways but not as a GR antagonist. GTDF has the potential in the management of GC-induced osteopenia. PMID- 23928510 TI - The effect of increased stiffness of the incudostapedial joint on the transmission of air-conducted sound by the human middle ear. AB - OBJECTIVE: To study the possible effects of increased stiffness at the incudostapedial joint (ISJ) on sound transmission in the human middle ear. BACKGROUND: The physiologic role played by the IS joint in the mechanics of human middle ear function is unclear. It is also unclear how fixation of this joint might manifest itself and what the implications are of fixing this joint during surgical reconstruction. HYPOTHESIS: Increased stiffness of the ISJ will affect sound transmission through the middle ear. METHODS: Cyanoacrylate adhesive was instilled around the ISJ joint in 5 fresh human cadaveric temporal bones to increase ISJ stiffness. Laser Doppler vibrometry measurements of sound-induced peak-to-peak displacement of the umbo and stapes footplate were made before and after stiffening the ISJ. RESULTS: At baseline, the measurements at the stapes footplate followed those at the umbo but were approximately 12 dB lower in the speech frequencies. We found that stiffening the ISJ produced an almost equal decrease in peak-to-peak displacement at both the umbo and the stapes footplate, with little change in their relative motion, consistent with an increase in ossicular impedance. The decrease was mainly between 400 and 1,000 Hz with a statistically significant mean magnitude loss of 6 dB at 740 Hz. CONCLUSION: Increased stiffness at the ISJ results in a small, probably clinically insignificant decrease of 3 to 6 dB in middle ear sound transmission in the lower frequencies between 400 and 1,000 Hz. PMID- 23928511 TI - Bilateral fallopian canal arachnoid cysts in a patient with spontaneous cerebrospinal fluid otorrhea. PMID- 23928512 TI - A guinea pig model of selective severe high-frequency hearing loss. AB - HYPOTHESIS: Using an appropriate dose of an aminoglycoside antibiotic cotreated with a loop diuretic a guinea pig model of high-frequency loss can be obtained mimicking cochlear implant candidates with low-frequency residual hearing. We examined the stability of this model over time. BACKGROUND: A well-established method to create an animal model for profound deafness is cotreatment with an aminoglycoside antibiotic and a loop diuretic. Recent data indicated that reduction of the aminoglycoside dose might yield selective high-frequency hearing loss. Such a model is relevant for studies related to hybrid cochlear implant devices, for example, with respect to preservation of residual hearing. METHODS: Guinea pigs received an electrode for chronic recording of compound action potentials to tones to assess thresholds. They were treated with a coadministration of kanamycin (200 mg/kg) and furosemide (100 mg/kg), after which, the animals were sacrificed for histologic analysis at 2, 4, or 7 weeks. RESULTS: After 2 to 7 weeks threshold shifts were greater than 50 dB for 8 to 16 kHz in 15 of 17 animals, whereas threshold shifts at 2 kHz or lower were less than 50 dB in 13 animals. Major threshold shifts occurred the first 2 to 4 days; subsequently, some spontaneous recovery occurred and, after 2-3 weeks thresholds, remained stable. Inner hair cell loss still progressed between 2 and 4 weeks in the most basal cochlear region; thereafter, hair cell loss was stable. CONCLUSION: An appropriate animal model for selective severe high-frequency hearing loss was obtained, which is stable at 4 weeks after ototoxic treatment. PMID- 23928513 TI - Canal conversion between anterior and posterior semicircular canal in benign paroxysmal positional vertigo. AB - OBJECTIVE: To investigate the characteristics of canal conversion between the anterior and posterior semicircular canals in benign paroxysmal positional vertigo (BPPV). STUDY DESIGN: Retrospective chart review. SETTING: Secondary referral center. PATIENTS: A total of 709 patients who were treated with the Epley maneuver for BPPV of the anterior or posterior semicircular canal. INTERVENTIONS: Vestibular examinations with videonystagmography and the canalith repositioning procedure (CRP) to treat BPPV. RESULTS: Canal conversion between the anterior and posterior semicircular canals was observed in 18 (2.9%) patients who underwent CRP. In 13 (2.3%) of 564 patients initially diagnosed with posterior canal BPPV (PC-BPPV), switch to anterior canal BPPV (AC-BPPV) was observed at a follow-up visit. In 5 (12.1%) of 41 patients who presented with AC BPPV, canal switch to PC-BPPV occurred more frequently (p = 0.005). The average number of CRPs before nystagmus resolution was 3.6 in conversion cases versus 1.6 in the nonconversion group (p < 0.001). CONCLUSION: Canal conversion between the anterior and posterior semicircular canals can occur during treatment. The possibility of canal conversions should be considered for appropriate management of BPPV of the vertical semicircular canals. PMID- 23928514 TI - Natural compounds as potential treatments of NF2-deficient schwannoma and meningioma: cucurbitacin D and goyazensolide. AB - HYPOTHESIS: Cucurbitacin D and goyazensolide, 2 plant-derived natural compounds, possess potent growth-inhibitory activity in schwannoma and meningioma cells. BACKGROUND: Currently, no FDA-approved drugs are available for neurofibromatosis type 2 (NF2)-associated schwannomas and meningiomas. Selected natural compounds with antineoplastic activity, such as cucurbitacin D and goyazensolide, may be developed as potential treatments for these tumors. METHODS: The Nf2-deficient mouse schwannoma Sch10545 and human benign meningioma Ben-Men-1 cells were treated with various concentrations of cucurbitacin D and goyazensolide. The effect on cell proliferation was determined using resazurin assays. Flow cytometry was used to assess the cell cycle profiles. Western blot analysis was performed to investigate the expression of various signaling molecules related to the cell cycle and the AKT pathway. RESULTS: Cucurbitacin D inhibited proliferation of Sch10545 cells (IC50 ~ 0.75 MUM) and Ben-Men-1 cells (IC50 ~0.2 MUM). Goyazensolide also reduced cell proliferation of Sch10545 cells (IC50 ~0.9 MUM) and Ben-Men-1 cells (IC50 ~1 MUM). The G2/M population increased in both Sch10545 and Ben-Men-1 cells treated with cucurbitacin D or goyazensolide around the IC50. Cucurbitacin and goyazensolide substantially reduced the levels of cyclins E and A in treated Sch10545 and Ben-Men-1 cells. Cucurbitacin D also inhibited cyclin B, phospho-AKT and phospho-PRAS40 expression. In addition, goyazensolide reduced the levels of phospho-AKT and NFkappaB and increased the expression of pro-apoptotic Bim in Sch10545 and Ben-Men-1 cells. CONCLUSION: Both cucurbitacin D and goyazensolide effectively inhibit proliferation of NF2 deficient schwannoma and meningioma cells, suggesting that these natural compounds should be further evaluated as potential treatments for NF2-related tumors. PMID- 23928515 TI - Normative data of incus and stapes displacement during middle ear surgery using laser Doppler vibrometry. AB - OBJECTIVES: To report normative data for incus and stapes motion using laser Doppler vibrometry (LDV) during middle ear surgery and to discuss possible limitations of the procedure. STUDY DESIGN: Institutional review board-approved, retrospective study of data from patients undergoing the Envoy Esteem implantable device at 3 institutions. SETTING: Quaternary referral health system. PATIENTS: ELIGIBILITY CRITERIA: patients sucsessfully implanted with an Esteem device. METHODS: Data from 70 patients undergoing the Envoy Esteem procedure were reviewed. Sound at 100 dB and 50 frequencies ranging from 125 to 8,000 Hz were used during the procedure. LDV was performed to measure the displacment of the body of the incus and the posterior crus of the stapes to assess whether there was sufficient ossicular mobility to allow for implantation. RESULTS: The average displacement of the ossicles for all 70 patients was collected and analyzed. The trend was an average displacement around 100 nm from 125 to 500 Hz for both the incus and stapes with a linear decline starting at 1,000 Hz for the incus and 500 Hz for the stapes, with slightly greater displacement of the stapes at higher frequencies. CONCLUSION: This is the first article to report in vivo measures of ossicular mobility. These data help to understand the micromechanics of ossicular motion as well as the use and limitations of LDV. This information may lead to a prescreening process for implanted middle ear devices that function by overdriving the stapes. PMID- 23928516 TI - Evaluation of the increased use of partial resection of large vestibular schwanommas: facial nerve outcomes and recurrence/regrowth rates. AB - OBJECTIVE: To determine whether partial tumor removal in large vestibular schwannoma improves facial nerve outcomes while maintaining a low risk of tumor regrowth/recurrence. STUDY DESIGN: Retrospective chart review and prospective database. SETTING: Tertiary neurotologic referral center. PATIENTS: Four hundred patients with a vestibular schwannoma of 2.5 cm or greater in maximum diameter undergoing translabyrinthine microsurgical resection from 2001 to 2011. There were 325 gross total resections (GTR), 44 near total resections (NTR), and 31 subtotal resections (STR), with an overall mean tumor size of 3.2 cm (standard deviation, 0.7). INTERVENTION(S): Translabyrinthine surgical tumor resection. MAIN OUTCOME MEASURES: House-Brackmann (H-B) facial nerve grade postoperatively and at 1 year, tumor regrowth/recurrence (>=2 mm), additional treatment, and complications. RESULTS: Higher rates of H-B facial nerve Grades I and II were achieved at both the postoperative and 1-year follow-ups in the NTR (78%, 97%) and STR (71%, 96%) groups compared with GTR (53%, 77%) (p <= 0.001). Eye treatment, medical or surgical, was required more often in GTR (28.0%) than NTR and STR (8% and 21%, respectively, p <= 0.04), with no other differences in complications. The NTR and STR groups had a significantly higher rate of regrowth than GTR resection (21% and 22% versus 3%) (p <= 0.001) at average follow-up times of 3.7, 3.7, and 5.1 years, respectively, and need for further treatment occurred at a higher rate, although infrequently, in NTR and STR (2% and 10% versus 0%) (p <= 0.001). CONCLUSION: Near total and subtotal removal in large tumors are viable treatment options to maintain facial nerve function. During the follow-up period examined in this study, there was a low risk of need for further treatment. Longer-term follow-up is needed to better assess the need for retreatment in patients treated with NTR and STR. PMID- 23928517 TI - Effect of hyperinsulinism on sensorineural hearing impairment in Meniere's disease: a cohort study. AB - OBJECTIVE: To compare the degree of sensorineural hearing loss in patients with Meniere's disease (MD) with and without hyperinsulinism by different methods of assessment. STUDY DESIGN: Historical cohort study. SETTING: Meniere's Disease Care and Research Clinics of Hospital de Clinicas de Porto Alegre, a tertiary care university hospital in Southern Brazil. PATIENTS: Patients with a definite diagnosis of MD based on the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guidelines. INTERVENTION: Patients were assessed by glucose overload tests (5-h glucose and insulin curves) and under baseline physiological conditions (Homeostasis Model Assessment/Insulin Resistance [HOMA-IR], Quantitative Insulin Sensitivity Check Index [QUICKI], and glucose/insulin ratio). These patients underwent annual pure-tone audiometry and were analyzed using 4-tone average (FTA), that is, arithmetic mean of 500, 1,000, 2,000, and 3,000 Hz, during the third, fourth, and fifth years of disease progression. MAIN OUTCOME MEASURE: Hearing loss assessed by FTA and classified in Stages I to IV (AAO-HNS). RESULTS: Forty-nine (76.6%) patients were defined as hyperinsulinemic and 15 (23.4%) as normoinsulinemic. Impairment on FTA was higher in the hyperinsulinemic group (52.04 +/- 17.5 versus 39.75 +/- 9.20, p = 0.027) when assessed by the 5-hour insulin curve. Hyperinsulinemic subjects were 3.5 times more likely to develop hearing damage greater than 40 dB (i.e., Stages III and IV) than normoinsulinemic subjects (OR = 3.52; 95% CI, 1.05-11.76). A moderate correlation between the insulin curve and the HOMA-IR was found (r = 0.524, p = 0.001). CONCLUSION: Hyperinsulinism in MD is associated with greater clinical hearing damage. PMID- 23928518 TI - Trigeminal and taste sensations of the tongue after middle ear surgery. AB - OBJECTIVE: To establish clinical tests for measurement of trigeminal sensitivity on the human tongue and objectively assess changes in oral trigeminal sensitivity and taste ability after chorda tympani nerve (CTN) injury. STUDY DESIGN: Prospective study. SETTING: University hospital. PATIENTS: One-hundred and twenty six patients with unilateral middle ear diseases who underwent primary middle ear surgery. MAIN OUTCOMES AND MEASURES: Trigeminal sensation was measured each operated side as well as nonoperated side both before and 14 days after surgery using 3 kinds of tests: Semmes-Weinstein sensory test (SW test), 2-point discrimination test, and the electrostimulator test. Taste function was assessed with electrogustometry (EGM) similarly. RESULTS: The patients which the CTN was not touched (n = 6) showed no differences between preoperative and postoperative thresholds in any tests. In the patients with sectioned CTN (n=30), postoperative thresholds on the operated side were significantly higher than preoperative thresholds on the electrostimulator test, 2-point discrimination test, and EGM. In the patients with manipulated but not sectioned CTN (n = 90), postoperative thresholds were significantly higher than preoperative thresholds on the electrostimulator test and EGM. The patients with manipulated but not sectioned CTN and abnormal EGM postoperative thresholds (n = 48) showed that postoperative thresholds were significantly higher than preoperative thresholds in all tests. CONCLUSION: These findings suggest that the electrostimulator test was most useful to objectively assess small changes of trigeminal sensation among the 3 tests. The finding that trigeminal sensitivity of the tongue deteriorated on the operated side after CTN injury suggests that CTN function affected both taste sensation and trigeminal sensation of the tongue. PMID- 23928519 TI - The pathologic basis of facial nerve stimulation in otosclerosis and multi channel cochlear implantation. AB - HYPOTHESIS: Unintentional electrical stimulation of the facial nerve by cochlear implants occurs when advanced otosclerosis invades the endosteum of both the upper basal turn of the cochlea (UBTC) and the facial nerve canal (FNC) and all the bone between these 2 structures. BACKGROUND: A complication of cochlear implantation is facial nerve stimulation (FNS) known to be more common in otosclerosis. Otosclerotic involvement of the enchondral bone of the otic capsule results in areas of bone resorption, new bone formation, vascular proliferation, and a connective tissue stroma. This may reduce impedance, shunting current to the facial nerve. The cause of FNS has not been fully elucidated, and remarkable differences in FNS rates have been reported using different types of electrode arrays. METHODS: Thirteen implanted temporal bones from 11 patients with otosclerosis, 10 with straight, and 3 with perimodiolar electrodes, were histologically processed after death. The data were analyzed using Fisher's exact test. RESULTS: In the straight electrode group (n = 10), only those subjects with temporal bones showing involvement by otosclerosis of the UBTC and of FNC endosteum and the bone between these 2 structures (n = 4; 40%) showed FNS during life (p = 0.005), which was consistent with the location of problematic electrodes during life. None of the cases in the perimodiolar group had FNS even with endosteal involvement by otosclerosis. CONCLUSION: FNS is a common complication of cochlear implantation in patients with otosclerosis and occurs most commonly with straight electrode implants where the endosteum of both UBTC and FNC and the intervening bone are otosclerotic. PMID- 23928520 TI - Histopathology of the inner ear in patients with xeroderma pigmentosum and neurologic degeneration. AB - INTRODUCTION: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations resulting in defective repair of DNA damage. XP patients have a markedly increased risk of ultraviolet-induced neoplasms and premature aging of sun-exposed tissue. Approximately 25% of XP patients in the United States have neurologic abnormalities including progressive sensorineural hearing loss (SNHL). OBJECTIVE: To describe the temporal bone histopathology in 2 individuals with XP (XPA and XPD) with neurologic degeneration and to discuss the possible causes of deafness in these patients. METHODS: Temporal bones were removed at autopsy and studied using light microscopy. RESULTS: In the case with XPD, the organ of Corti was missing throughout the cochlea, whereas the case with XPA demonstrated scattered presence of sensory cells in the middle and apical turns. In both cases, there was moderate-to-severe patchy atrophy of the stria vascularis in all turns, and cochlear neurons were severely atrophied compared with age-matched controls, with loss of both peripheral dendrites and central axons. There was severe degeneration of Scarpa's ganglion in the case with XPA. CONCLUSION: Two cases of XP with neurologic degeneration are reported. The case with XPD demonstrated a more severe audiologic phenotype than XPA, although both had similar findings such as atrophy of the organ of Corti, stria vascularis, and spiral ganglia leading to severe or profound SNHL by the third decade of life. It is not clear if the neuronal degeneration in the inner ear was primary or secondary to loss of neuroepithelial cells. PMID- 23928521 TI - Aplasia of the cochlea: radiologic assessment and options for hearing rehabilitation. AB - OBJECTIVE: Hearing rehabilitation of patients with severe inner ear malformations remains controversial. Our objective was to describe the radiologic findings of aplasia of the cochlea (AC) and evaluate the existing therapeutic options in such patients. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: Pediatric and adult patients with AC evaluated at our institution from 1995 to 2010. INTERVENTIONS: The precise radiologic findings were identified using high-resolution computed tomography (HRCT) and magnetic resonance imaging (MRI) scans of the inner ear. In cases of auditory implantation on the AC side, the achieved outcome was recorded using categories of auditory performance (CAP). Related surgical aspects were analyzed. RESULTS: Twenty-three patients (28 ears) with AC were found. In 5 patients AC was bilateral. The remaining unilateral cases had contralateral normal ears (2 patients), cochlea hypoplasia (5 patients), common cavity (6 patients), incomplete partition Type I (4 patients), and atresia of the internal auditory canal (1 patient). Four patients (3 bilateral, 1 unilateral ACs) were treated with cochlear implants in ears with AC, and 1 patient underwent auditory brainstem implantation. All implanted patients achieved speech perception with limited vocabulary (CAP scores between 4 and 5). CONCLUSION: AC is defined as the total absence of the cochlea, with a present, although malformed, vestibule. Although a distinct auditory nerve was not seen in these cases of AC, results following cochlear implantation suggest functional cochlear nerve fibers in the remaining dysplastic inner ear structures. In selected cases, cochlear implantation may be a reasonable option for the habilitation of deafness associated with AC. PMID- 23928522 TI - Head shaking during Dix-Hallpike exam increases the diagnostic yield of posterior semicircular canal BPPV. AB - OBJECTIVES: To examine whether shaking the head during the DH exam (HSDH) may improve diagnosis of posterior semicircular canal benign paroxysmal positional vertigo (pBPPV) in patients with a negative Dix-Hallpike (DH) examination. STUDY DESIGN: A prospective cohort clinical study on consecutive patients with dizziness, who were seen by 2 experienced neurotologists. Patients underwent a complete neurotology examination, including positioning testing with roll test and DH. Patients with a negative DH underwent a HSDH. Patients with a positive DH (Group 1) or only with a positive HSDH (Group 2) underwent a particle reposition maneuver (PRM), which was a modification of the Epley maneuver. Variables including sex, age, the duration of symptoms until diagnosis, and the number of visits required until cure were examined in each group. SETTING: A tertiary dizziness clinic and in 2 private clinics. SUBJECTS AND METHODS: All patients diagnosed with pBPPV. MAIN OUTCOME MEASURES: DH test after head shaking and comparison of variables between the 2 study groups. RESULTS: Sixty nine patients were diagnosed with pBPPV (Group 1). Twelve additional patients were negative on DH but were found positive on HSDH (Group 2), improving the diagnostic yield by 14.8%. There was no statistical relation between the 2 groups and the variables examined; however, there was a trend for longer duration of symptoms (44.3 versus 64 d) and less visits until cure (1.5 versus 1.7 visits) in Group 2. CONCLUSION: Patients with a negative DH should undergo a HSDH. Patients only diagnosed as pBPPV by a positive HSDH may represent a subgroup with a milder form of disease. PMID- 23928523 TI - Head impulse test abnormalities and influence on gait speed and falls in older individuals. AB - OBJECTIVE: To assess the prevalence of vestibular dysfunction in older adults using the head impulse test (HIT) and to assess the independent influence of HIT abnormalities on gait speed and fall risk in older individuals. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary care academic medical center. PATIENTS: Fifty community-dwelling individuals age 70 and older. INTERVENTIONS: HIT (abnormal HIT defined as right or left HIT abnormality), visual acuity, monofilament testing, and grip strength. MAIN OUTCOME MEASURES: Gait speed on a 4 meter walk and a history of falls (including number of falls) in the last 1 and 5 years. RESULTS: The participants' mean age was 77 years (range, 70-95 yr); 52% were female subjects. Fifty percent of participants had an abnormal HIT. An abnormal HIT was significantly associated with a 0.23 m/s reduction in gait speed (p = 0.042), 0.44 more falls in the last 1 year (p = 0.047), and a 5-fold increase in the odds of falling in the last 5 years (p = 0.024) in multivariate analyses adjusted for age, sex, and other balance and fall risk factors. CONCLUSION: We observed that half of the community-dwelling older individuals in our study had evidence of vestibular dysfunction, which was significantly associated with gait speed and fall risk in adjusted analyses. Screening for vestibular impairment using the simple HIT and directing targeted vestibular therapy may be important to reduce gait impairment and fall risk in older individuals. PMID- 23928524 TI - Recovery of bilateral vestibular loss in Cogan's syndrome--a case report. AB - OBJECTIVE: To show that both hearing and vestibular loss can be reversible and quantified in Cogan's syndrome. PATIENT AND METHODS: Immunosuppressive medication was continued for more than 6 years in a young woman with Cogan's syndrome. Standard pure tone audiometry (PTA) and speech discrimination score (SDS) for hearing, motorized head impulse test (MHIT) for horizontal, angular vestibulo ocular reflex, and erythrocyte sedimentation rate were followed serially. RESULTS: The PTA before medication was 59/74 dB, and it stabilized to 13/46 dB in 2 years. The initial SDS of 92/72% improved later to 100/100%, respectively. The gain of the vestibulo-ocular reflex was asymmetric (32%) and decreased to 0.48/0.25 at the beginning. Two years after the treatment, both the asymmetry (7%) and the gain (0.95/0.82) were recovered within normal limits. Erythrocyte sedimentation rate improved from 40 to 5 mm/h. CONCLUSION: Our case report of Cogan's syndrome demonstrates objective, simultaneous deterioration of hearing and vestibular function, which improved and stabilized after the introduction of immunosuppressive medication. The efficacy of immunosuppressive medication on vestibular function may be followed repetitively using MHIT in patients with Cogan's syndrome. PMID- 23928525 TI - [Standardization of pathologic diagnosis of lymphomas]. PMID- 23928526 TI - [Towards standardization of lymphoma diagnosis]. PMID- 23928527 TI - [Immunohistochemical patterns of follicular dendritic cell meshwork and Ki-67 in small B-cell lymphomas]. AB - OBJECTIVE: To identify the immunohistochemical patterns of follicular dendritic cell (FDC) meshwork and Ki-67 labeling index in small B-cell lymphomas (SBLs) and their significance in differential diagnosis. METHODS: Sixty-eight cases of SBLs were included collected from November 2008 to June 2012. The patterns of FDCs and Ki-67 expression were studied on paraffin sections by CD21, CD23 and Ki-67 immunohistochemistry. The characteristic staining patterns of FDCs and Ki-67 expression among different SBLs were analyzed statistically. RESULTS: The age of SBL patients ranged from 28 to 85 years with a mean of 55.2 years. The male to female ratio was 1.2:1. Fifty-five cases involved only lymph nodes (80.9%), and the remaining cases involved multiple extra-nodal sites. Histological classification of the cases was made according to the 2008 WHO lymphoma classification criteria: 22 were low-grade follicular lymphomas (FLs, including grade 1 and grade 2), 19 marginal zone lymphomas (MZLs), 17 mantle cell lymphomas (MCLs), and 10 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLLs). FDC meshwork limited to the central part of neoplastic follicles was characteristic for FL (90.9%, 20/22). The germinal center FDC meshwork was destroyed primarily at periphery in MZL (14/19). The absence or scattered FDC clusters were typical of SLL/ CLL. Irregular FDC was seen in 7/17 of MCL, while 7/17 MCL displayed FDC pattern similar to that of CLL/SLLs. The pattern of FDCs was a significantly diagnostic feature in distinguishing the four types of SBLs (P < 0.01). Ki-67 was also a statistically significant parameter (P < 0.05) with decreasing labeling index as the following: MCL, FL, SLL and MZL. Ki-67 showed scattered pattern in germinal centers with loss of polarity in FLs. MZL presented uniformly scattered positive pattern in interfollicullar areas. Ki-67 staining was uniform in MCL, but its labeling index varied from 5% to 90%. The Ki-67 index was higher in the morphological "proliferation centers" of all CLL/SLLs. CONCLUSION: Immunohistochemical staining patterns of FDC meshworks and Ki-67 labeling index offer a significant discriminatory power in the differential diagnoses among SBLs. PMID- 23928528 TI - [CD16 expression is an independent prognostic factor for extranodal NK/T cell lymphoma of nasal type]. AB - OBJECTIVE: To analyze the clinicopathologic features of extranodal NK/T cell lymphoma, nasal type (ENKTCL-N), to explore the expression of NK cell-associated receptors in ENKTCL-N and the relationship with prognosis, and to establish a prognostic model. METHODS: One hundred and twenty-six cases of ENKTCL-N were selected from the files of the Department of Pathology, West China Hospital of Sichuan University. The relevant clinical and follow-up data were collected, and the histopathology was reviewed. All specimens were stained immunohistochemically for CD16, ICAM-1 and LFA-1. RT-PCR was used to detect the expression of CD94, NKG2 and KIR. The relationship between the prognosis of ENKTCL-N, clinical features, histopathological characteristics and expression of these markers were also analyzed. RESULTS: ENKTCL-N mainly occurred in middle-age and young patients (median age, 41 years). The male to female ratio was 3.2:1. Sites more commonly involved were the nose and upper aerodigestive tract whereas those for the non nasal type were the skin and gut. Only six cases involved two or more extranodal sites. Most (86.5%, 109/126) of the patients were in clinical stages I/II. The tumors showed predominately medium-sized tumor cells and large-sized tumor cells accounted for only 9.5% (12/126). Coagulative necrosis was present in all cases. The expression rates of CD56, CD16, CD94, LFA-1 and ICAM-1 were 82.6% (95/115), 15.1% (19/126), 55.4% (41/74), 40.5% (51/126) and 0, respectively. The expression rate of NKG2 receptor was 90.5% (67/74) overall. NKG2 receptor expression was independent of CD94. The overall expression rate of KIR receptor was 33.8% (25/74) and KIR receptor restriction was not detected in 20.8% (5/24) of the cases. Follow-up data was available in all patients, with median and average survival time being 15 months and 20.2 months, respectively. Survival analysis showed that prognostic factors included the gender, age, disease type, extranodal involvement, stage, the expression of CD16, LFA-1 and CD94. Cox's proportional hazard regression analysis revealed four factors, age, involved site, stage and CD16 expression, were independent prognostic factors. CONCLUSIONS: The age, disease type, stage and CD16 expression are independent prognostic factors. Establishment of a prognostic model based on the above four factors can be more accurate in the prognostication of ENKTCL-N. The differences in the clinical features, prognosis, and expression of NK cell-associated receptors are obvious between nasal NK-cell lymphoma and non-nasal NK-cell lymphoma. PMID- 23928529 TI - [Clinicopathologic features and differential diagnosis of splenic B-cell marginal zone lymphoma involving bone marrow]. AB - OBJECTIVE: To study the clinicopathologic features and differential diagnosis of splenic B-cell marginal zone lymphoma (SMZL) involving bone marrow. METHODS: The clinical and pathologic features of 22 patients with SMZL were retrospectively studied. Immunophenotypic analysis was carried out by flow cytometry and immunohistochemistry. Immunoglobulin heavy chain rearrangement study was performed using polymerase chain reaction-based method. RESULTS: Villous lymphocytes were found in peripheral blood smears of 11/18 of the patients. In bone marrow aspirates, lymphocytosis (> 20%) was demonstrated in 15 cases (15/18) and villous lymphocytes in 6 cases (6/18). Flow cytometry showed CD19(+) CD20(+) FMC7(+) CD22(+) CD10(-) CD2(-) CD3(-) CD7(-) in 18 cases. Bone marrow biopsies of all the 22 patients revealed various degrees and patterns of neoplastic infiltration, as follows: mild (4 cases, 18.2%), moderate (11 cases, 50.0%) or severe (7 cases, 31.8%); intrasinusoidal (16 cases, 72.7%), interstitial (14 cases, 63.6%), nodular (11 cases, 50.0%) or diffuse (1 case, 4.5%). Reactive germinal center formation (CD23(+) bcl-2(-)) was found in 2 cases (91.0%). Immunohistochemical study showed the following results: CD20(+) PAX5(+) CD3(-) CD5(-) CD10(-) cyclin D1(-) CD23(-) CD43(-) Annexin A1(-) CD11C(-) CD25(-) in all the 22 cases, CD38(+) in 2 cases (9.1%) and CD138(+) in 2 cases (9.1%). CONCLUSIONS: Different and overlapping patterns of bone marrow involvement are observed in SMZL. As the histologic and immunophenotypic features are not specific to SMZL, distinction from other types of mature B-cell lymphomas is necessary. PMID- 23928530 TI - [Epstein-Barr virus infection and expression of latent membrane protein 2A in Hodgkin's lymphoma of Uygur patients]. AB - OBJECTIVE: To investigate Epstein-Barr virus(EBV) infection in Hodgkin's lymphoma (HL) of Uygur patients and related clinicopathological characteristics. METHODS: EBV-encoded small RNA (EBER) was detected in 40 cases of HL and 20 cases of lymphoid reactive hyperplasia by in-situ hybridization. Expression of LMP2A in HL was investigated by immunohistochemistry. RESULTS: EBV was detected in 26/40 (65.0%) of HL and 5/20 of lymphoid reactive hyperplasia (P < 0.05). The expression level of EBER showed significant difference among various histological subtypes of HL (P < 0.05) and between patients with and without B symptom (P = 0.02). However, no difference was found in relation to gender, clinical stage and tumor burden. The expression of LMP2A in the mixed cellularity and nodular sclerosis classical HL associated with EBV infection was 57.7% (15/26). Expression of LMP2A was not detected in lymphoid reactive hyperplasia cases. CONCLUSION: Uyghur patients with Hodgkin's lymphoma have a high infection rate of EBV and distinct clinicopathologic characteristics. PMID- 23928531 TI - [Clinicopathologic features of intestinal natural killer/T-cell lymphoma]. AB - OBJECTIVE: To study the clinicopathologic features, diagnosis and differential diagnosis of intestinal natural killer (NK)/T-cell lymphoma. METHODS: The clinical features, histopathology, immunohistochemical findings and follow-up data of 14 cases of intestinal NK/T-cell lymphoma were retrospectively reviewed. RESULTS: The male-to-female ratio was 9:5. The medium age of patients was 45 years. The sites of involvement included small intestine (6 cases), colon (6 cases) or both (2 cases). The main clinical manifestations were an abdominal mass, other gastrointestinal symptoms such as abdominal pain, as well as systemic symptoms such as fever and cachexia. Intestinal perforation complicated by acute peritonitis might occur in advanced disease. Histologically, the intestinal wall showed full-thickness infiltration by medium-sized atypical lymphoid cells with pleomorphic nuclei, prominent inflammatory background, angiocentric/angiodestructive growth pattern and coagulative necrosis. Immunohistochemical study showed that the tumor cells were positive for CD3epsilon, CD43, CD56, granzyme B and perforin. They were negative for CD20, CD79alpha and MPO. In-situ hybridization for Epstein-Barr virus encoded RNA (EBER) showed negative signals. A high proliferative index was demonstrated by Ki 67 immunostaining. Follow-up data of 8 cases were available, with duration of follow up ranging from 0.5 to 36 months. Five patients died within 20 months. CONCLUSIONS: Extranodal NK/T-cell lymphoma, nasal-type primarily involving intestine is rare and tends to carry an aggressive clinical course. The relatively non-specific clinical manifestations of intestinal NK/T-cell lymphoma may result in misdiagnosis in some cases. A comprehensive evaluation of clinical manifestations, pathologic features and immunohistochemical findings is essential for definitive diagnosis. PMID- 23928532 TI - [Intraductal tubulopapillary neoplasm of the pancreas: a clinicopathologic study of 6 cases]. AB - OBJECTIVE: To study the pathologic features, diagnosis, differential diagnosis and molecular characteristics of intraductal tubulopapillary neoplasm of the pancreas (ITPN). METHODS: The clinical findings, morphologic features, immunophenotype (by EnVision method) and KRAS gene alterations (by reverse transcriptase-polymerase chain reaction) of 6 cases of ITPN encountered during the period from January, 2001 to June, 2010 were analyzed. RESULTS: There were altogether 2 males and 4 females. The mean age of the patients was 64 years. Gross examination showed that the tumors were located in large pancreatic ducts and appeared as polypoid nodules with ductal obstruction. Solid tumor nodules associated with adjoining dilated ducts were identified in one case. Histologically, the tumors were characterized by tubulopapillary growth pattern without luminal mucin. The tumor cells showed high-grade nuclear atypia with scanty intracytoplasmic mucin. Intraductal necrotic foci were frequently observed. Immunohistochemical study showed that the tumor cells expressed CK7 and CK19. Focal positivity for MUC5AC was demonstrated. Two cases expressed MUC1. The staining for MUC2 was negative. KRAS gene mutations were identified in 2 cases, with a single-amino-acid substitution in codon 12 (35G > A and 35G > T/34G > A). CONCLUSIONS: ITPN is a newly described pancreatic intraductal neoplasm and different from intraductal papillary mucinous neoplasm. ITPN is characterized by intraductal tubulopapillary growth pattern, severe cytologic atypia and scanty mucin secretion. PMID- 23928533 TI - [Detection of EML4-ALK fusion gene in non-small cell lung cancer and its clinicopathologic correlation]. AB - OBJECTIVE: To investigate the frequency of EML4-ALK fusion gene in non-small-cell lung cancer (NSCLC) patients, and its correlation with clinicopathologic features. METHODS: Real-time PCR was used to detect the presence of EML4-ALK fusion gene in 268 cases of NSCLCs using paraffin-embedded tissue samples(among which 164 samples were re-validated by Sanger sequencing). Related clinicopathological correlation was analyzed. RESULTS: EML4-ALK fusion gene was found in 4.1% (11/268) of the cases. One hundred and sixty four samples were verified by Sanger sequencing, and the overall coincidence of the results of two methods (Sanger sequencing and Real-time PCR) was 100%. Female patients (5.9%, 5/85), <= 60 years of age (4.3%, 6/140), non-smokers (6.8%, 8/118) and adenocarcinomas (7.6%, 10/132) had a higher mutation rate than that in male patients (3.3%, 6/183), > 60 years of age (4.0%, 5/124), smokers (1.6%, 2/132) and squamous cell carcinomas (1.3%, 1/79), although no statistical significance in age (P = 0.918), gender (P = 0.503), smoking history (P = 0.092) and histological type (P = 0.094). CONCLUSIONS: Chinese NSCLC patients have a 4.1% detection rate of EML4-ALK fusion gene in the tumor tissues. Female, non-smoker and adenocarcinoma histological subtype tend to be associated with a higher rate of EML4-ALK gene fusion. PMID- 23928534 TI - [Expression of fatty acid synthase and its association with HER2 in invasive ductal carcinoma of breast]. AB - OBJECTIVE: To investigate the expression of fatty acid synthase (FAS) in adenosis, atypical ductal epithelial hyperplasia, ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) of breast, and the correlation of FAS expression with HER2 gene amplification in IDC. METHODS: Immunohistochemical EnVision method staining for FAS was performed in 100 cases of breast lesions and 10 normal breast tissues. HER2 gene amplification was detected with FISH in 60 cases of IDC. RESULTS: The cohort included 10 cases of adenosis, 10 atypical ductal epithelial hyperplasia, 20 DCIS (8 high-grade, 9 intermediated-grade and 3 low-grade), and 60 cases of IDC (5 grade 1, 40 grade 2 and 15 grade 3). FAS expression was negative in all 10 normal breast tissues; in the 10 cases of adenosis, strongly positive FAS expression was detected in one case, positive in 2, weakly positive in 4, and negative in 3; in the 10 cases of atypical ductal epithelial hyperplasia, FAS immunohistochemistry showed that 1 was strongly positive, 4 positive, 4 weakly positive, and 1 negative; in the 20 cases of DCIS, FAS immunostaining showed that 12 were strongly positive, 5 positive, 1 weakly positive, and 2 negative; FAS expression showed a clear increasing trend from normal breast tissue, atypical ductal epithelial hyperplasia to DCIS (chi(2) = 42.02, P < 0.01). Likewise, the increasing trend was also demonstrated from adenosis to DCIS (chi(2) = 34.69, P < 0.01). There was also a positive correlation between FAS expression and extent of lesion among normal breast tissue, adenosis, atypical ductal epithelial hyperplasia and DCIS (chi(2) = 86.02, P < 0.01; r = 0.568, P < 0.01). FAS expression was not correlated with the grade of DCIS (chi(2) = 9.12, P = 0.16). In the five cases of grade 1 IDC, FAS immunostaining showed that 4 cases were strongly positive and 1 positive; in the 40 cases of grade 2 IDC, FAS immunostaining showed that 27 strongly positive, 12 positive, and 1 negative; in the 15 cases of grade 3 IDC, FAS immunostaining showed that 6 were strongly positive, 5 positive, 3 weakly positive, and 1 negative; FAS expression was stronger and more extensive in DCIS, IDC grades 1 and 2 than that in other groups. However, FAS expression was weaker in the IDC grade 3 (chi(2) = 11.26, P = 0.01). The positive expression rate of FAS in IDC was generally higher than that in benign breast lesions (chi(2) = 47.19, P < 0.01). In the 60 cases of IDC, FISH showed HER2 gene amplification in 22 cases, but not in the remaining 38 cases. FAS expression in IDC was highly correlated with HER2 gene amplification (r = 0.44, P < 0.01). The expression of FAS had significant correlation with status of ER and PR and tumor size (P < 0.05). There was no significant correlation with age, immunohistochemical HER2 expression, lymph node metastasis and clinical stage (P > 0.05). CONCLUSIONS: FAS may be closely related to the carcinogenesis of breast IDC. FAS expression is closely associated with HER2 gene amplification in IDC. PMID- 23928535 TI - [Down-regulation of Smoothened gene expression inhibits proliferation of breast cancer stem cells]. AB - OBJECTIVE: To investigate the influence of down-regulating Smoothened (SMO) gene expression through short hairpin RNA (shRNA) on the proliferation of breast cancer stem cells. METHODS: Human SMO shRNA was designed, synthesized chemically, and transfected into MCF-7 cells to down-regulate SMO gene. By using G418, stable cells with down-regulated SMO were selected. In vitro proliferation of these cells was measured by CCK8 assay. The proportion of CD44(+)/CD24(-) cells was detected by flow cytometry and the mammospheres formation was determined by suspension sphere culture. The expression of SMO, GLI1 and Oct4 was detected by Western blot. In vivo, the volume of tumor was measured every 3 days and the expression of SMO, GLI1 and Oct4 detected by Western blot. RESULTS: In vitro, the cells were transfected with SMO-shRNA and selected by G418 after 21 days. SMO shRNA effectively down-regulated the expression of SMO gene and protein, and inhibited the proliferation of MCF-7 and markedly reduced the proportion of CD44(+)/CD24(-) cells and mammospheres. In vivo, SMO-shRNA treatment of MCF-7 significantly inhibited the volume of tumor. The positive rate of SMO in negative control and SMO-shRNA group was 5/5 and 2/5, respectively. The expression of SMO, GLI1 and Oct4 in different groups were 0.72 +/- 0.17 and 0.21 +/- 0.09, 1.21 +/- 0.21 and 0.47 +/- 0.12, 0.83 +/- 0.13 and 0.25 +/- 0.07. SMO, GLI1 and Oct4 down regulation significantly suppressed at protein levels (P < 0.05). CONCLUSION: The shRNA by chemical synthesis can effectively down-regulate SMO gene expression and inhibit the proliferation of breast cancer stem cells. PMID- 23928536 TI - [Expression of CERS2 in invasive breast cancer tissues and its clinical significance]. PMID- 23928537 TI - [Comparison of liquid-based and conventional preparations in cytologic diagnosis of pancreatobiliary lesions]. PMID- 23928538 TI - [Slide drying after staining is the culprit of poor hematoxylin-eosin staining]. PMID- 23928539 TI - [Right cervical lymph node enlargement]. PMID- 23928540 TI - [Placental mesenchymal dysplasia: reports of two cases]. PMID- 23928541 TI - [Wolman disease: report of a case]. PMID- 23928542 TI - [Intimal sarcoma of pulmonary artery: report of a case]. PMID- 23928543 TI - [Small non-coding RNA and RNA activation]. PMID- 23928544 TI - Red cell distribution width is independently related to endothelial dysfunction in patients with chronic kidney disease. AB - BACKGROUND: Red cell distribution width (RDW) is a measure of erythrocyte size variability and has been shown as an independent predictor of mortality. The aim of this article was to evaluate the association of RDW with endothelial dysfunction in patients with chronic kidney disease (CKD). METHODS: Patients with 1 to 5 stages of CKD were included in the study. Endothelial function was assessed with flow-mediated dilatation (FMD). Estimated glomerular filtration rate (eGFR) and carotid intima media thickness (CIMT) were determined. Clinicodemographic characteristics, biochemical values, complete blood counts, ferritin, C-reactive protein (CRP) and cholesterol levels were recorded. Spearman's correlation was used to determine correlates of RDW. Multivariate linear regression model was used to assess independent associates of FMD. RESULTS: Overall, 367 patients with CKD 1 to 5 were included in the study. RDW showed a significant increase from stage 1 to stage 5 CKD. Median RDW was 13.5. Patients with RDW values higher than median had significantly lower hemoglobin, eGFR and FMD values and higher CIMT and CRP values compared with patients who had RDW values below median. RDW showed a significant positive correlation with the presence of diabetes mellitus, CIMT and CRP, whereas a significant negative correlation with eGFR, ferritin and FMD. Multivariate analysis showed independent predictors of FMD as RDW, presence of diabetes, hemoglobin, eGFR, CRP, and serum albumin. CONCLUSIONS: Multivariate regression model revealed RDW as a significant predictor of FMD independent of major confounding factors, such as diabetes, inflammation, anemia and kidney function in CKD. PMID- 23928545 TI - Decreased femoral cartilage thickness in patients with systemic sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc), or scleroderma, is a severe connective tissue disease. Although musculoskeletal involvement is frequent and causes significant functional disability in patients with SSc, articular cartilage thickness has not been previously investigated. The aim of this study was to compare the femoral cartilage thickness (FCT) in patients with SSc with that of controls who were matched for age, body mass index and osteoarthritis prevalence. METHODS: The thickness of femoral articular cartilage was measured by ultrasonography in patients and controls. Three midpoint measurements were taken from each knee: lateral femoral condyle (LFC), femoral intercondylar area and medial femoral condyle (MFC). RESULTS: Forty female patients with SSc and 85 female controls were included. In patients with SSc, 18 (45.0%) had diffuse SSc, 18 (45.0%) had limited SSc, 1 (2.5%) had overlap (polymyositis) and 3 (7.5%) had SSc sine scleroderma. The mean FCT measurements of patients with SSc at MFC of the right and left knees (1.86 and 1.84 mm, respectively) and LFC of the left knee (1.93 mm) were statistically lower than in the controls (right and left MFC, 2.23 and 2.25 mm, respectively, P < 0.0001, and left LFC 2.15 mm, P = 0.026). CONCLUSIONS: Patients with SSc had thinner femoral cartilage compared with controls. The underlying possible mechanisms of thin FCT may be multifactorial, and there may be many influencing factors like immune activation, vasculopathy, oxidative stress and synovial fibrosis or markers of cartilage degradation. The possible factors influencing the change in cartilage thickness or metabolism in patients with SSc require further research. PMID- 23928546 TI - Histoplasma infection of aortofemoral bypass graft. AB - Histoplasma infection of vascular grafts is extremely rare. To our knowledge, there are only 4 cases reported with Histoplasma capsulatum infection of the aortic graft. All had previous disseminated histoplasmosis and atherosclerotic peripheral vascular disease. They were treated surgically with explantation of the infected graft and reimplantation of new graft in extra-anatomic uninfected site. The authors present a new case of H capsulatum infection of aortofemoral bypass graft, but unlike the other cases, this case was managed without surgical intervention. PMID- 23928547 TI - Clinical characteristics and prognosis of nonleukemic myeloid sarcoma. AB - Myeloid sarcoma (MS) is an extramedullary mass that is composed of immature myeloid cells. The objectives of this study was to describe the frequency, clinical characteristics and the prognostic factors of patients with nonleukemic MS. Twenty-three cases of nonleukemic MS were recorded in the authors' institution between April 2006 and March 2012. Most of the patients received systemic antiacute myeloid leukemia chemotherapy and the overall response rate was 91.3%, and 56.5% patients experienced complete remission. The anticipated 3 year progression-free survival and overall survival rates are 23% and 41%, respectively. The prognostic impact of nonleukemic MS is unclear. The cytogenetic and molecular abnormalities of malignant cells may be the most important prognostic factor because these are not always available because of cost and technical reason. In this case, the remission state, Ki67 score of tumor cells and number and size of the lesions might act as independent prognostic factors; this finding requires further confirmation. PMID- 23928553 TI - Ni(II) and Cu(II) N(4)-ethylmorpholine citronellalthiosemicarbazonate: a comparative analysis of cytotoxic effects in malignant human cancer cell lines. AB - In this paper we report a study conducted with two analogous complexes, bis(N(4) ethylmorpholine citronellalthiosemicarbazonate) nickel(II) and -copper(II) on four tumour cell lines (U937, HL60, SK-N-MC and HT29). All cell lines appear to be sensitive to both metal complexes, but while in U937, HL60 and SK-N-MC, apoptosis is the main mode through which cell death occurs, HT29 cells undergo necrosis. Among the cell lines which undergo apoptosis, SK-N-MC response is characterized by the intrinsic pathway, whereas U937 and HL60 involve both the intrinsic and the extrinsic pathways. The redox activity of the two complexes provides experimental evidence that they can modulate reactive oxygen species (ROS) production as a function of both the metal and the cell line used. Among the four cell lines, HL60 does not seem to give a significant response to exposure to both compounds. In the case of the nickel derivative, ROS generation is a relatively early event, and ROS could be the mediator leading to cellular damage. HT29 shows a remarkable and rapid ROS increase and a significant induction of membrane peroxidation that could be correlated to the onset of necrosis. PMID- 23928554 TI - Special issue: biomolecular systems under extreme environmental conditions. PMID- 23928555 TI - Temperature dependent absorption cross-sections of O2-O2 collision pairs between 340 and 630 nm and at atmospherically relevant pressure. AB - The collisions between two oxygen molecules give rise to O4 absorption in the Earth atmosphere. O4 absorption is relevant to atmospheric transmission and Earth's radiation budget. O4 is further used as a reference gas in Differential Optical Absorption Spectroscopy (DOAS) applications to infer properties of clouds and aerosols. The O4 absorption cross section spectrum of bands centered at 343, 360, 380, 446, 477, 532, 577 and 630 nm is investigated in dry air and oxygen as a function of temperature (203-295 K), and at 820 mbar pressure. We characterize the temperature dependent O4 line shape and provide high precision O4 absorption cross section reference spectra that are suitable for atmospheric O4 measurements. The peak absorption cross-section is found to increase at lower temperatures due to a corresponding narrowing of the spectral band width, while the integrated cross-section remains constant (within <3%, the uncertainty of our measurements). The enthalpy of formation is determined to be DeltaH(250) = -0.12 +/- 0.12 kJ mol(-1), which is essentially zero, and supports previous assignments of O4 as collision induced absorption (CIA). At 203 K, van der Waals complexes (O(2-dimer)) contribute less than 0.14% to the O4 absorption in air. We conclude that O(2-dimer) is not observable in the Earth atmosphere, and as a consequence the atmospheric O4 distribution is for all practical means and purposes independent of temperature, and can be predicted with an accuracy of better than 10(-3) from knowledge of the oxygen concentration profile. PMID- 23928556 TI - Generation of recombinant arenavirus for vaccine development in FDA-approved Vero cells. AB - The development and implementation of arenavirus reverse genetics represents a significant breakthrough in the arenavirus field. The use of cell-based arenavirus minigenome systems together with the ability to generate recombinant infectious arenaviruses with predetermined mutations in their genomes has facilitated the investigation of the contribution of viral determinants to the different steps of the arenavirus life cycle, as well as virus-host interactions and mechanisms of arenavirus pathogenesis. In addition, the development of trisegmented arenaviruses has permitted the use of the arenavirus genome to express additional foreign genes of interest, thus opening the possibility of arenavirus-based vaccine vector applications. Likewise, the development of single cycle infectious arenaviruses capable of expressing reporter genes provides a new experimental tool to improve the safety of research involving highly pathogenic human arenaviruses. The generation of recombinant arenaviruses using plasmid based reverse genetics techniques has so far relied on the use of rodent cell lines, which poses some barriers for the development of Food and Drug Administration (FDA)-licensed vaccine or vaccine vectors. To overcome this obstacle, we describe here the efficient generation of recombinant arenaviruses in FDA-approved Vero cells. PMID- 23928558 TI - Dectin-2 is predominately macrophage restricted and exhibits conspicuous expression during Aspergillus fumigatus invasion in human lung. AB - We investigated the features of Dectin-2 expression both at transcriptional and translational levels during Aspergillus fumigatus infection in human lung. Simultaneously, the expression of CD206 was assayed as an activated marker of alveolar macrophages. The characteristic of Dectin-2 expression were then confirmed in Monocyte-derived macrophages (MDM) after A. fumigatus stimulation by Flow Cytometry. We found that the expression of Dectin-2 was low in normal lung, while it revealed a markedly up-regulation during A. fumigatus invasion. Dectin-2 expression was predominantly restricted to CD206 positive cells. There was salient positive correlation between Dectin-2 expression and CD206. We conclude that Dectin-2 expression is largely restricted to alveolar macrophages in human lung. The conspicuous expression of Dectin-2 during A. fumigatus invasion suggests its notable contribution to antifungal defenses in pulmonary aspergillosis. PMID- 23928559 TI - Group marginalization: extending research on interpersonal rejection to small groups. AB - An extensive research literature has examined the reactions of individuals facing interpersonal rejection. Small groups can also be rejected, but current research tells us little about the experiences of groups and their members directly. We integrate findings from various literatures to gain insight into shared rejection experiences and their outcomes. Of most practical importance, we argue that groups can be expected to react with more hostility than individuals when rejected. Four existing models that account for how group processes might alter such reactions are examined: a need-threat model, a rejection-identification model, a multimotive model, and a dual attitudes model. Aspects of these models are then integrated into a unifying framework that is useful for understanding hostile reactions to group marginalization. Implications for natural groups such as terrorist cells, school cliques, racial and ethnic minorities, and gangs are discussed. PMID- 23928557 TI - ADAMTS-7 forms a positive feedback loop with TNF-alpha in the pathogenesis of osteoarthritis. AB - OBJECTIVE: To examine the expression of ADAMTS-7 during the progression of osteoarthritis (OA), defining its role in the pathogenesis of OA, and elucidating the molecular events involved. METHODS: ADAMTS-7 expression in cartilage of a rat OA model was assayed using immunohistochemistry. Cartilage-specific ADAMTS-7 transgenic mice and ADAMTS-7 small interfering (si)RNA knockdown mice were generated and used to analyse OA progression in both spontaneous and surgically induced OA models. Cartilage degradation and OA was evaluated using Safranin-O staining, immunohistochemistry, ELISA and western blotting. In addition, mRNA expression of tumour necrosis factor (TNF)-alpha and metalloproteinases known to be involved in cartilage degeneration in OA was analysed. Furthermore, the transactivation of ADAMTS-7 by TNF-alpha and its downstream NF-kappaB signalling was measured using reporter gene assay. RESULTS: ADAMTS-7 expression was elevated during disease progression in the surgically induced rat OA model. Targeted overexpression of ADAMTS-7 in chondrocytes led to chondrodysplasia characterised by short-limbed dwarfism and a delay in endochondral ossification in 'young mice' and a spontaneous OA-like phenotype in 'aged' mice. In addition, overexpression of ADAMTS-7 led to exaggerated breakdown of cartilage and accelerated OA progression, while knockdown of ADAMTS-7 attenuated degradation of cartilage matrix and protected against OA development, in surgically induced OA models. ADAMTS-7 upregulated TNF-alpha and metalloproteinases associated with OA; in addition, TNF-alpha induced ADAMTS-7 through NF-kappaB signalling. CONCLUSIONS: ADAMTS-7 and TNF-alpha form a positive feedback loop in the regulation of cartilage degradation and OA progression, making them potential molecular targets for prevention and treatment of joint degenerative diseases, including OA. PMID- 23928560 TI - Programming microbes using pulse width modulation of optical signals. AB - Cells transmit and receive information via signalling pathways. A number of studies have revealed that information is encoded in the temporal dynamics of these pathways and has highlighted how pathway architecture can influence the propagation of signals in time and space. The functional properties of pathway architecture can also be exploited by synthetic biologists to enable precise control of cellular physiology. Here, we characterised the response of a bacterial light-responsive, two-component system to oscillating signals of varying frequencies. We found that the system acted as a low-pass filter, able to respond to low-frequency oscillations and unable to respond to high-frequency oscillations. We then demonstrate that the low-pass filtering behavior can be exploited to enable precise control of gene expression using a strategy termed pulse width modulation (PWM). PWM is a common strategy used in electronics for information encoding that converts a series of digital input signals to an analog response. We further show how the PWM strategy extends the utility of bacterial optogenetic control, allowing the fine-tuning of expression levels, programming of temporal dynamics, and control of microbial physiology via manipulation of a metabolic enzyme. PMID- 23928561 TI - Building a genome analysis pipeline to predict disease risk and prevent disease. AB - Reduced costs and increased speed and accuracy of sequencing can bring the genome based evaluation of individual disease risk to the bedside. While past efforts have identified a number of actionable mutations, the bulk of genetic risk remains hidden in sequence data. The biggest challenge facing genomic medicine today is the development of new techniques to predict the specifics of a given human phenome (set of all expressed phenotypes) encoded by each individual variome (full set of genome variants) in the context of the given environment. Numerous tools exist for the computational identification of the functional effects of a single variant. However, the pipelines taking advantage of full genomic, exomic, transcriptomic (and other) sequences have only recently become a reality. This review looks at the building of methodologies for predicting "variome"-defined disease risk. It also discusses some of the challenges for incorporating such a pipeline into everyday medical practice. PMID- 23928562 TI - Risk of thyroid cancer in relatives of patients with medullary thyroid carcinoma by age at diagnosis. AB - The familial risk of medullary thyroid carcinoma (MTC alone or as part of multiple endocrine neoplasms, MEN2A/MEN2B) is high, so we aimed to answer open questions about the lifetime cumulative risk of thyroid cancer (LCRTC at 0-79 years) among relatives of MTC patients by age and sex. For this nationwide study, a cohort of 3217 first-/second-degree relatives (FDRs/SDRs) of 389 MTC patients diagnosed in 1958-2010 in the Swedish Family-Cancer Database was followed for the incidence of thyroid cancer. The LCRTC in female relatives of patients with early onset MEN2B (diagnosis age <25 years) was 44-57%, representing 140-520 times increase over the risk in their peers without a family history of endocrine tumors (men: LCRTC=22-52%, 320-750 times) depending on the number of affected FDRs/SDRs. The LCRTC in female relatives of patients with late-onset MEN2B (diagnosis age >=25 years) was about 15-43% (men=24%). The LCRTC among relatives of early-onset MTC-alone patients was 3-20%. The LCRTC among relatives of late onset MTC-alone patients was 5-26%. The LCRTC in female relatives of MEN2A patients was 16-63% (men=52%). The relatives of patients with early-onset MTC exhibited a high tendency to develop early-onset thyroid cancer. Simply available data on the number of FDRs and even SDRs affected with MTC and their age at diagnosis were quite informative for the estimation of the risk of thyroid cancer in probands. In settings where genetic testing is not available or affordable for all, evidence-based cumulative risks reported in this nationwide study may help physicians to identify very high-risk individuals. PMID- 23928563 TI - Temporal resolution of figures and grounds. AB - Recent studies have demonstrated that establishing figure-ground organization influences other perceptual processes. Specifically, figures undergo perceptual processing earlier than ground regions (Lester, Hecht, & Vecera, 2009), and they are processed for longer durations relative to ground regions (Hecht & Vecera, 2011). One potential consequence of figures' extended processing is degraded temporal resolution compared to ground regions. To test this hypothesis, observers completed a modified flicker-fusion task while viewing either displays that contained well-defined figures and grounds or displays that were ambiguous. As evidenced by increased sensitivity for flickering targets on the ground regions, the current results support the claim that figures have poorer temporal resolution than ground regions. PMID- 23928564 TI - Asymmetries in visuomotor recalibration of time perception: does causal binding distort the window of integration? AB - The recalibration of perceived visuomotor simultaneity to vision-lead and movement-lead temporal discrepancies is marked by an underlying causal asymmetry, if the movement (button press) is voluntary and self-initiated; a visual stimulus lagging the button press may be interpreted as causally linked sensory feedback (intentional or causal binding), a leading visual stimulus not. Here, we test whether this underlying causal asymmetry leads to directional asymmetries in the temporal recalibration of visuomotor time perception, using an interval estimation paradigm. Participants were trained to the presence of one of three temporal discrepancies between a motor action (button press) and a visual stimulus (flashed disk): 100 ms vision-lead, simultaneity, and 100 ms movement lead. By adjusting a point on a visual scale, participants then estimated the interval between the visual stimulus and the button press over a range of discrepancies. Comparing the results across conditions, we found that temporal recalibration appears to be implemented nearly exclusively on the movement-lead side of the range of discrepancies by a uni-lateral lengthening or shortening of the window of temporal integration. Interestingly, this marked asymmetry does not lead to a significantly asymmetrical recalibration of the point of subjective simultaneity or to significant differences in discriminability. This seeming contradiction (symmetrical recalibration of subjective simultaneity and asymmetrical recalibration of interval estimation) poses a challenge to common models of temporal order perception that assume an underlying time measurement process with Gaussian noise. Using a two-criterion model of the window of temporal integration, we illustrate that a compressive bias around perceived simultaneity (temporal integration) even prior to perceptual decisions about temporal order would be very hard to detect given the sensitivity of the psychophysical procedures commonly used. PMID- 23928565 TI - Type 2 diabetes risk prediction--do biomarkers increase detection? PMID- 23928566 TI - Rebuttal to the letter 'Meta-analysis of biodegradable versus durable polymer drug eluting stents in coronary artery disease: the reality?' of Kwong et al. PMID- 23928567 TI - Efficacy of exercise training in symptomatic patients with hypertrophic cardiomyopathy: results of a structured exercise training program in a cardiac rehabilitation center. AB - BACKGROUND: Recent data suggest that exercise training (ET) confers significant symptomatic and functional improvements in patients with diastolic dysfunction, and thus may be beneficial in patients with hypertrophic cardiomyopathy (HCM). However, there are no data regarding the safety or efficacy of ET in HCM patients. DESIGN: A prospective non-randomized intervention design was used. METHODS: We enrolled 20 patients with symptomatic HCM, significantly limited in everyday activity, into a supervised cardiac rehabilitation exercise program. RESULTS: Patients were 62 +/- 13 years old, in New York Heart Association (NYHA) functional class II (35%) or III (65%), had a mean interventricular septum dimension of 17 +/- 5 mm and left ventricular ejection fraction (LVEF) of 53 +/- 15%. Left ventricular outflow gradient was present at rest in nine patients (mean 51 +/- 24 mm Hg) and six patients had an implantable defibrillator. Exercise prescription was based on heart rate reserve (HRR) determined from a symptom limited graded exercise stress test. Exercise intensity was gradually increased from 50% to 85% of the HRR over the training period. Patients completed an average of 41 +/- 8 hours of aerobic ET. No adverse events or sustained ventricular arrhythmias occurred during the training program. Functional capacity, assessed by a graded exercise test, improved from 4.7 +/- 2.2 to 7.2 +/ 2.8 metabolic equivalents (METs) (p = 0.01). NYHA functional class improved from baseline by >= 1 grade in 10 patients (50%) and none experiencing deterioration during follow-up. CONCLUSIONS: The present study suggests that patients with HCM who remain symptomatic despite medical therapy may achieve considerable functional improvement through a supervised ET program. PMID- 23928568 TI - RETRACTED: Nut consumption with risk of hypertension and type 2 diabetes mellitus: A meta-analysis of prospective cohort studies. AB - BACKGROUND: The consumption of nuts was reported to be associated with risk of hypertension and type 2 diabetes mellitus (T2DM), but the results were inconclusive. The aim of this study was to systematically examine longitudinal studies investigating nut intake in relation to risk of hypertension and T2DM. METHODS: A systematic search of the PubMed and EMBASE databases to 31 March 2013 was performed. Reference lists of retrieved articles were also screened. Summary relative risks (SRRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Q and I2 statistics were used to examine between-study heterogeneity. RESULTS: A total of nine prospective cohort studies (three for hypertension and six for T2DM) were identified. Using random effects models, we found that based on the highest vs lowest analysis, nut consumption were inversely associated with risk of hypertension (SRR = 0.84, 95% CI: 0.76-0.93, pheterogeneity = 0.831, I2 = 0%). Dose-response analyses indicated that nut consumption at more than two servings/wk, but not ne serving/wk, had a preventative role in the hypertension. In addition, nut consumption was not associated with risk of T2DM (SRRs = 0.98, 95% CI: 0.84-1.15; pheterogeneity = 0.008, I2 = 67.7%) on the basis of the highest vs lowest analysis. This null association was also shown in the dose-response analysis. CONCLUSION: In our meta analysis, nut consumption is found to be inversely associated with hypertension risk but is not associated with the risk of T2DM. PMID- 23928569 TI - Downward trends in acute myocardial infarction incidence: how do migrants fare with the majority population? Results from a nationwide study. AB - AIMS: In previous decades, a steep decline in acute myocardial infarction (AMI) incidence occurred in Western countries. We assessed whether this decline was also present in migrant groups living in the Netherlands. METHODS AND RESULTS: Nationwide registers were linked between 1998 and 2007. Poisson regression analyses were used to calculate the biannual percentage change in AMI incidence within major non-Western migrant groups, and the differences in these changes with the Dutch majority population. Within the Dutch majority population, AMI incidence significantly declined in men (-12%) and women (-9.5%). Incidence also declined among most migrant groups under study, ranging from -12 to -4.0% in men, and from -16 to -9.5% in women. Only in Turkish women and Moroccan men the AMI incidence remained stable over time (-0.3 and 2.8%, respectively). There were no statistically significant trend differences between the Dutch majority population and the migrant groups under study. The higher AMI incidence in Turkish men and Surinamese men and women, and the lower AMI incidence in Moroccan men persisted over time. CONCLUSIONS: There was a declining AMI incidence rate within the Dutch majority population as well as within most of the major migrant groups living in the Netherlands, except in Turkish women and Moroccan men. Trend patterns among migrant groups did not significantly differ from the Dutch majority population. To reduce ethnic inequalities, primary preventive strategies should be targeted at those migrant groups with a persisting higher incidence. PMID- 23928570 TI - FOLFIRI in patients with locally advanced or metastatic pancreatic or biliary tract carcinoma: a monoinstitutional experience. AB - Pancreatic and biliary tract carcinomas are very chemoresistant. After a first line treatment with a gemcitabine-based regimen, no second-line scheme is consolidated in clinical practice. The aim of this study was to evaluate the toxicity and the activity of the FOLFIRI regimen as first-line or second-line chemotherapy in patients with pancreatic or biliary tract tumors. Fifty-four patients (30 with pancreatic tumor, nine with gallbladder tumor, and 15 with biliary tract tumor) were treated with FOLFIRI (irinotecan 180 mg/m2, day 1; leucovorin 100 mg/m2 intravenously, days 1 and 2; 5-fluorouracil 400 mg/m2 intravenous bolus, days 1 and 2; and 600 mg/m2 in 22 h intravenously, continuous infusion days 1 and 2; every 14 days). Toxicity was recorded at each cycle according to the NCI-CTC V3.0 criteria, the response rate was verified each four cycles according to the RECIST criteria, and the progression-free survival rates as well as the overall survival rates were calculated according to the Kaplan Meier method. Overall, the toxicity was mild. Grade 3-4 neutropenia occurred in 42.6% of patients. Grade 3-4 gastrointestinal toxicity was rare. FOLFIRI as a first-line treatment produced a response rate of 25%. In the second-line group, 9/21 patients (42.9%) obtained a stable disease as best response. In the entire population, the median progression-free survival rates were 3.1 months [95% confidence interval (CI), 1.9-4.4] and 3.5 months (95% CI, 2.6-4.4), respectively, in the first-line and the second-line cohort of patients. The median overall survival rates were 14.5 months (95% CI, 7.0-22.1) and 6.2 months (95% CI, 5.4-7.0), respectively, in the first-line and the second-line cohort of patients. FOLFIRI is feasible and well tolerated in patients with pancreatic or biliary tract tumors; it has a good activity in first line and mostly in patients with pancreatic cancer. PMID- 23928571 TI - Coadministration of lapatinib increases exposure to docetaxel but not doxorubicin in the small intestine of mice. AB - Combination therapy is increasingly being utilized for the treatment of metastatic breast cancer. However, coadministration of drugs, particularly agents that are substrates for or inhibitors of p-glycoprotein, can result in increased tissue toxicity. Unfortunately, determination of levels of chemotherapeutics in human tissues is challenging, and plasma drug concentrations are not always indicative of tissue toxicokinetics or toxicodynamics, especially when tissue penetration is altered. The aim of the present work was to determine whether concomitant administration of compounds currently being combined in clinical trials for metastatic breast cancer treatment alters plasma and tissue pharmacokinetics in mice if both agents are p-glycoprotein substrates and/or inhibitors. Accordingly, we investigated the pharmacokinetic interactions of the classic cytotoxics and p-glycoprotein substrates docetaxel and doxorubicin when administered concurrently with the targeted agent and p-glycoprotein inhibitor lapatinib. Our time-course plasma and tissue distribution studies showed that coadministration of lapatinib with doxorubicin did not appreciably alter the pharmacokinetics of this anthracycline in the plasma or six tissues evaluated in mice, presumably because, at doses relevant to human exposure, lapatinib inhibition of p-glycoprotein did not significantly alter doxorubicin transport out of these tissue compartments. However, combining lapatinib with docetaxel significantly increased intestinal exposure to this chemotherapeutic, which has clinical implications for enhancing gastrointestinal toxicity. The significant lapatinib-docetaxel interaction is likely CYP3A4-mediated, suggesting that caution should be exercised when this combination is administered, particularly to patients with compromised CYP3A activity, and recipients should be monitored closely for enhanced toxicity, particularly for adverse effects on the intestine. PMID- 23928572 TI - Evolution: A gutsy defence of the skin. PMID- 23928574 TI - Mucosal immunology: What memories are made of. PMID- 23928575 TI - Microscopic properties of liquid water from combined ab initio molecular dynamics and energy decomposition studies. AB - The application of newly developed first-principle modeling techniques to liquid water deepens our understanding of the microscopic origins of its unusual macroscopic properties and behaviour. Here, we review two novel ab initio computational methods: second-generation Car-Parrinello molecular dynamics and decomposition analysis based on absolutely localized molecular orbitals. We show that these two methods in combination not only enable ab initio molecular dynamics simulations on previously inaccessible time and length scales, but also provide unprecedented insights into the nature of hydrogen bonding between water molecules. We discuss recent applications of these methods to water clusters and bulk water. PMID- 23928576 TI - European urology: quality, impact, online. AB - European Urology provides contemporary, cutting-edge urologic research, guidance, and discussion. The journal continues to invite collaborative reviews, to invest in rapid but fair peer review, to seek the best research, and to serve the needs of readers and patients. PMID- 23928577 TI - Liquid-liquid extraction assisted by a carbon nanoparticles interface. Electrophoretic determination of atrazine in environmental samples. AB - A novel method for the determination of atrazine, using liquid-liquid extraction assisted by a nanoparticles film formed in situ and composed of organic solvent stabilized-carbon nanoparticles, is described. The presence of nanoparticles located at the liquid-liquid interface reinforced the extraction of analyte from matrix prior to capillary electrophoresis (CE) analysis. Some influential experimental variables were optimized in order to enhance the extraction efficiency. The developed procedure confirmed that carbon nanoparticles, especially multi-walled carbon nanotubes, are suitable to be used in sample treatment processes introducing new mechanisms of interaction with the analyte. The application of the proposed preconcentration method followed by CE detection enabled the determination of atrazine in spiked river water providing acceptable RSD values (11.6%) and good recoveries (about 87.0-92.0%). Additionally, a similar extraction scheme was tested in soil matrices with a view to further applications in real soil samples. PMID- 23928578 TI - A rationally designed CuFe2O4-mesoporous Al2O3 composite towards stable performance of high temperature water-gas shift reaction. AB - High temperature water-gas shift reaction was demonstrated for the first time on a CuFe2O4-mesoporous alumina nanocomposite between 350 and 550 degrees C with 70 80% CO-conversion using simulated waste derived syngas under realistic conditions. Despite high Al-content, the catalyst exhibited stable activity, which was attributed to the nano-architectured robust porous nature of alumina integrated with surrounding CuFe2O4. PMID- 23928573 TI - Scavenger receptors in homeostasis and immunity. AB - Scavenger receptors were originally identified by their ability to recognize and to remove modified lipoproteins; however, it is now appreciated that they carry out a striking range of functions, including pathogen clearance, lipid transport, the transport of cargo within the cell and even functioning as taste receptors. The large repertoire of ligands recognized by scavenger receptors and their broad range of functions are not only due to the wide range of receptors that constitute this family but also to their ability to partner with various co receptors. The ability of individual scavenger receptors to associate with different co-receptors makes their responsiveness extremely versatile. This Review highlights recent insights into the structural features that determine the function of scavenger receptors and the emerging role that these receptors have in immune responses, notably in macrophage polarization and in the pathogenesis of diseases such as atherosclerosis and Alzheimer's disease. PMID- 23928580 TI - The Members have spoken... PMID- 23928581 TI - Treating the whole patient. PMID- 23928579 TI - Real-time control of walking using recordings from dorsal root ganglia. AB - OBJECTIVE: The goal of this study was to decode sensory information from the dorsal root ganglia (DRG) in real time, and to use this information to adapt the control of unilateral stepping with a state-based control algorithm consisting of both feed-forward and feedback components. APPROACH: In five anesthetized cats, hind limb stepping on a walkway or treadmill was produced by patterned electrical stimulation of the spinal cord through implanted microwire arrays, while neuronal activity was recorded from the DRG. Different parameters, including distance and tilt of the vector between hip and limb endpoint, integrated gyroscope and ground reaction force were modelled from recorded neural firing rates. These models were then used for closed-loop feedback. MAIN RESULTS: Overall, firing-rate-based predictions of kinematic sensors (limb endpoint, integrated gyroscope) were the most accurate with variance accounted for >60% on average. Force prediction had the lowest prediction accuracy (48 +/- 13%) but produced the greatest percentage of successful rule activations (96.3%) for stepping under closed-loop feedback control. The prediction of all sensor modalities degraded over time, with the exception of tilt. SIGNIFICANCE: Sensory feedback from moving limbs would be a desirable component of any neuroprosthetic device designed to restore walking in people after a spinal cord injury. This study provides a proof-of-principle that real-time feedback from the DRG is possible and could form part of a fully implantable neuroprosthetic device with further development. PMID- 23928582 TI - Anticoagulant update. PMID- 23928583 TI - Scant evidence. PMID- 23928584 TI - Proofless pudding. PMID- 23928585 TI - Bleeding sockets. PMID- 23928586 TI - Pejorative statement. PMID- 23928587 TI - Bizarre metal splint. PMID- 23928588 TI - Not an IANB. PMID- 23928589 TI - Entertainment vs. education. PMID- 23928590 TI - Together we are stronger. PMID- 23928592 TI - Child protection course adds dental stream. PMID- 23928598 TI - Seaweed harvesting threatens impression material. PMID- 23928599 TI - Managing the phase-down of amalgam: Part I. Educational and training issues. AB - Following the recently agreed Minamata Convention, a phase-down in the use of dental amalgam will become a priority for the profession. With a lead-in period of a number of years, important changes in the mind-set of the profession are required to ensure that patient safety is not compromised. Posterior composites have been a viable, and in many cases preferable, alternative to amalgam for many years. However, notwithstanding considerable developments in dental school teaching on the application and placement of posterior composites, growing evidence to support the use of composites in the restoration of posterior teeth and advances in composite systems, many practitioners remain reluctant to place composite rather than amalgam. This paper considers the present and future use of posterior composites and highlights ways in which dental school teaching and continuing professional development (CPD) may contribute to the successful phase down, and now inevitable discontinuation, in the use of dental amalgam. PMID- 23928600 TI - Practitioner evaluation of a novel online integrated oral health and risk assessment tool: a practice pilot. AB - AIM: To report the development and evaluation of an evidence-based, online, patient assessment tool, capable of measuring oral health status, future disease risk and capitation fee guidance. METHODS: An online integrated oral health and risk assessment tool called DEPPA was developed, incorporating 1) PreViser(TM) risk scores for periodontal disease, caries, non-carious tooth surface loss and oral cancer, 2) revised versions of Denplan Excel's Oral Health Score and 3) capitation fee guidance score. DEPPA was piloted by 25 dentists who provided quantitative and qualitative feedback. RESULTS: Six hundred and forty assessments were performed. There was strong agreement on the need for such a tool, that it constituted a comprehensive assessment and supported good patient communication. The validity of the system was perceived as sound and the revised capitation fee guidance broadly welcomed. While some deemed the caries risk scoring algorithm to be too sensitive, the 30% high/very high risk rating is consistent with current rates of active caries in UK adults. CONCLUSIONS: A viable online oral health and risk-assessment tool has been developed (DEPPA) that will allow dental teams to measure oral health status, future disease risk and receive ongoing guidance on capitation fee setting. The indications are that DEPPA could be a valuable audit, care planning and patient communication tool. PMID- 23928606 TI - Summary of: Communicating new policy on antibiotic prophylaxis with patients: a randomised controlled trial. PMID- 23928607 TI - Clinician and simulated patient scoring - the psychometrics of a national programme recruiting dentists to DF1 training posts. AB - INTRODUCTION: In 2012 a national, standardised approach was taken to UK Dental Foundation 1 recruitment. Prior to that recruitment method was at the discretion of individual Deaneries. The new national system is interactive, including simulated patients to see how applicants perform in a clinical communication context. A question was whether simulated patient scores could/should be awarded as well as clinicians' scores. This paper presents score data collected in the first round of national DF1 recruitment centres, with focus on how clinical examiners and trained simulated patients rated applicants. METHOD: At the live recruitment events across four national centres score data were collected from observing clinical assessors and simulated patients on the communication station. On this occasion only the clinician awarded scores 'counted', but all simulated patients completed marking sheets to enable the process to be evaluated. Data were retrospectively analysed to test the hypotheses that there would be no significant scoring differences between centres and that inter-rater reliability, by applicant, between paired clinicians, and between clinicians and simulated patients would be strong. RESULTS: Results showed encouraging consistency between assessors, with some differences between centres. Clinicians were more likely to offer a borderline score. In communication analyses empathy had the weakest correlation with the overall score, while professional attitude had the strongest correlation. Data supported the hypothesis that trained simulated patients can be considered as assessors. Their future inclusion offers candidates a dual perspective (clinical and non-clinical) on performance, and saves clinical time.Discussion Simulated patients scored consistently and value can be added by including different perspectives in interactive assessment. Robust training is needed in all assessor training. CONCLUSION: Simulated patients can usefully contribute to scoring in national dental recruitment centres. Lessons learned here can inform other dental assessments where stakeholders are already using, or considering using, simulated patients as assessors or co-assessors. PMID- 23928608 TI - Patient satisfaction with oral urgent treatment (OUT) in North West Tanzania. AB - AIM: A pilot questionnaire survey was carried out to determine levels of patient satisfaction with oral urgent treatment (OUT) provided by rural clinical officers who had been trained by the charity Bridge2Aid in North West Tanzania. METHOD: The survey was carried out over a five-day period, among adult patients who had received oral urgent treatment from a trained clinical officer. A satisfaction questionnaire was administered by a team of English-speaking dental students and Swahili-speaking college students under supervision. RESULTS: A total of 140 questionnaires were completed. The overall satisfaction with the OUT service provided by the clinical officers was high, with 93.6% being very satisfied or satisfied. However, some areas were highlighted where improvements could be made: providing a clearer explanation of treatment, improved pain control and reducing costs of treatment. PMID- 23928610 TI - What is quality primary dental care? AB - In the first paper of a series exploring quality in primary dental care a definition for quality in dentistry is sought. There is a little agreement in academic literature as to what quality really means in primary dental care and without a true understanding it is difficult to measure and improve quality in a systematic way. 'Quality' of healthcare in dentistry will mean different things to practitioners, policy makers and patients but a framework could be modelled on other definitions within different healthcare sectors, with focus on access, equity and overall healthcare experience. PMID- 23928611 TI - Oral anatomy in the sixteenth century: Juan Valverde de Amusco. AB - In 1554 Juan Valverde de Amusco, a Spanish anatomist, wrote the History of the composition of the human body, a complete anatomical treatise that took as its model the Vesalius school of thought (La fabrica of Vesalius). Considered one of the most complete anatomical treatises of the Renaissance and one of the most widely read books of the sixteenth century, it was translated into four languages in its day. The first chapter, devoted to bones, provides a meticulously detailed analysis of the bones of the facial structures and of the teeth, their supporting structures, vascularisation and innervation. Juan Valverde de Amusco even describes techniques for reducing mandibular luxations. Even with the imprecise observations typical of the time the treatise must be considered an exceptional document. PMID- 23928630 TI - Communicating new policy on antibiotic prophylaxis with patients: a randomised controlled trial. AB - OBJECTIVES: This trial aimed to assess the effectiveness of two different communication tools on the levels of anxiety and concern when a change in patients' treatment was introduced. METHOD: Patients previously advised to have antibiotic prophylaxis before their dental treatments were randomised to receive information about the new policy either through a video accompanied by a written leaflet or just the leaflet. All patients completed a questionnaire to assess anxiety and concern as well as intentions regarding accepting dental treatment without antibiotic prophylaxis at enrolment point, after intervention and after meeting the cardiologist. RESULTS: Ninety questionnaires were analysed (45 in each group). The mean level of anxiety and concern scores were significantly reduced after the intervention point (p <0.05). The ANOVA model revealed a significant reduction in the levels of anxiety and concern during the trial (p <0.001). However, the main effect of group (intervention versus control) and the interaction term were not significant. At the end of trial there was no difference in the number of patients accepting dental treatment without cover in the two groups. CONCLUSION: Patients appear more likely to accept a change if it is communicated directly to them by their practitioners via face to face consultation compared with video or leaflet. When there is a lack of time for in depth consultation, video could be a more effective method than leaflet alone. PMID- 23928631 TI - [Applications of ecological niche models in risk predictions of infectious diseases]. PMID- 23928632 TI - [Relationship between environmental endocrine-disrupting chemicals and obesity epidemic]. PMID- 23928633 TI - [Current status and urban-rural comparison of clinical agency of detection, management, and health insurance for hypertensive patients in communities of five provinces in China in 2010]. AB - OBJECTIVE: To investigate the status of the clinical agency of detection, management, and health insurance for hypertensive patients in urban and rural communities of five provinces in China in 2010, in order to provide fundamental data for implementation and evaluation of community health management of hypertensive patients in basic public health service. METHODS: From Jiangsu, Shandong, Hebei, Sichuan and Gansu provinces, cities and districts (counties) were selected according to economic development level and 10 survey sites were finally determined. In each survey site, 3-4 communities or townships were selected by cluster sampling methods in 2010. A total of 8326 eligible hypertensive patients (4363 in urban and 3963 in rural) were included. The urban rural difference of clinical agency and health insurance was compared for hypertensive patients. RESULTS: In urban areas, 43.74% (1867/4268) hypertensive patients were first diagnosed at hospitals of district level or above, 25.07% (1070/4268) at community health service centers (CHSC), and 20.20% (862/4268) at community health service stations (CHSS), respectively; 30.72% (1274/4147) and 31.11% (1290/4147) patients chose CHSC and CHSS for their follow-up visiting, respectively; 60.23% (3073/5102) antihypertensive medication was obtained from pharmacies. In rural areas, 54.58% (2133/3908) hypertensive patients were first diagnosed at village clinics, 22.36% (874/3908) at township hospitals, and 18.86% (737/3908) at hospitals of county level or above; 70.49% (2695/3823) patients chose village clinics for their follow-up visiting; 46.23% (2116/4577) antihypertensive medication was obtained from village clinics, and 36.29% (1661/4577) from pharmacies. The main reasons for choosing clinical agency for both urban and rural patients were convenience (45.79%, 6276/13 706) and low cost (11.78%, 1614/13 706). The proportions of reimbursements for hospitalization expenses and total medical expenses for hypertensive patients in urban in the past year were 66.67% and 34.78%, respectively, which were much higher than those in rural (35.71% and 9.50%) (Z value was -12.13 and -17.56, P < 0.01). CONCLUSION: Community-based hypertension detection and routine blood pressure measurement during clinical visiting should be further strengthened to improve early diagnosis of hypertension. The development of community-based clinical agency should be able to provide convenient and low cost health service for hypertensive patients to improve treatment, follow-up and control of hypertension. PMID- 23928634 TI - [The tendency of prevalence of hypertension in two countries in Gansu province from 1990 to 2012]. AB - OBJECTIVE: To study the variation tendency of hypertension in two rural areas in Gansu, and provide epidemiological evidence to evaluate the hypertension of rural residents. METHODS: Using equidistant random sampling method and cross-sectional sentinel monitoring, two remote natural villages, Yangzhuang and Xiangming, at Yellow river and Yangtze river valley were selected as hypertension monitoring site. From 1990 to 2012, clinical examination to the resident above 18 years old was carried out continuously for 23 years, 11 164 cases were included. RESULTS: Hypertension prevalence of tested cases increased with years, Yangzhuang monitoring site increased from 6.9% (16/232) in 1990 to 36.7% (216/597) in 2012 with an increase of 29.8%, and Xiangming monitoring site increased from 3.4% (16/474) in 1995 to 20.6% (120/582) in 2011 with an increase of 17.2%. Total prevalence of Yangzhuang (24.1%, 1505/6240) was significantly higher than Xiangming (11.4%, 578/4924) (chi(2) = 277.9, P < 0.01). Total hypertension prevalence of 18 - 35 years old group was 9.9% (292/2944) in Yangzhuang and 4.2% (63/1495) in Xiangming, Yangzhuang was higher than Xiangming (chi(2) = 43.7, P < 0.01). Total hypertension prevalence of above 35 years old group was 36.8% (1213/3296) in Yangzhuang and 14.1% (515/3429) in Xiangming, Yangzhuang was higher than Xiangming (chi(2) = 417.7, P < 0.01). The growth rates of hypertension prevalence in 18 - 35 years old group of both areas (Yangzhuang: 823.5%, Xiangming: 614.3%) were higher than 35 years old group (Yangzhuang:310.5%, Xiangming: 368.0%), but the hypertension prevalence of above 35 years old group was higher than 18 - 35 years old group. Hypertension prevalence of male was 25.4% (761/2992) in Yangzhuang and 11.7% (238/2047) in Xiangming, Yangzhuang was higher than Xiangming (chi(2) = 145.8, P < 0.01), hypertension prevalence of female was 22.7% (738/3248) in Yangzhuang and 11.2% (340/2877)in Xiangming, Yangzhuang was higher than Xiangming (chi(2) = 125.1, P < 0.01). While the difference between male and female had no statistical significance in both areas. CONCLUSION: Hypertension of the two monitoring points was in high epidemic trend, but with different epidemic trend. From different region and environment research to discuss the cause of hypertension can provide scientific evidence for prevention and control. PMID- 23928635 TI - [Relationship between physical activity and the incidence of metabolic syndrome in Chinese adults: a prospective cohort study]. AB - OBJECTIVE: To investigate the association between physical activity (PA) and the incidence of metabolic syndrome (MS) in Chinese adults. METHODS: Data on PA and other variables were obtained at the baseline examination of China Multi-center study of Cardiovascular Epidemiology in 1998 and of International Collaborative study of Cardiovascular Disease in Asia(InterASIA) during 2000 - 2001. Follow-up study was conducted in 2007 - 2008. A total of 11 512 Chinese adults aged 35 - 74 years (5563 men and 5949 women) were included in the final data analysis. Information on demographics, PA, smoking and alcohol consumption were obtained and components of MS were examined. Participants were divided into four groups according to quartile of total metabolic equivalent (MET) values per day. In addition, subjects were grouped into the following categories according to occupational PA: inactive, light, moderate and vigorous. Binary logistic model was used to examine the association between PA and the incidence of MS. RESULTS: A total of 2527 cases with MS were documented during an average following up of 8.1 years. The annual incidence rate of MS was 2.71% (2527/93 178.68). After multivariate logistic regression analysis, compared with participants with total PA volume < 32.0 MET*h*d(-1) (annual incidence rate was 3.19% (697/21 830.74)), the RR (95%CI) value of participants with total PA volume during 32.00 - 37.85, 37.86 - 52.29, and >= 52.30 MET*h*d(-1) was 1.05(0.92 - 1.19), 0.98(0.86 - 1.12), and 0.68(0.59 - 0.80), respectively (chi(2)trend = 34.23, P < 0.05), with corresponding annual incidence rates of 2.82% (690/24 504.25), 2.73% (661/24 179.36) and 2.11% (479/22 664.33). In addition, compared to inactive occupational PA (annual incidence rate was 2.76% (402/14 588.33)), the corresponding RR (95%CI) value was 0.80 (0.69 - 0.92), 0.70 (0.59 - 0.82), and 0.54 (0.45 - 0.65) (chi(2)trend = 42.34, P < 0.05), and the annual incidence rates were 2.86% (648/22 663.41), 2.40% (455/18 956.14) and 1.89% (344/18 173.86) in participants with light, moderate and vigorous occupational PA, respectively. CONCLUSION: Both increased total PA volume and occupational PA intensity are significantly associated with decreased risk of incidence of MS. PMID- 23928636 TI - [Path analysis of lifestyle habits to the metabolic syndrome]. AB - OBJECTIVE: To evaluate the relationship between lifestyle habits and the components of metabolic syndrome (MS). METHODS: Based on the routine health check up system in a certain Center for Health Management of Shandong Province, a longitudinal surveillance health check-up cohort from 2005 to 2010 was set up. There were 13 225 urban workers in Jinan included in the analysis. The content of the survey included demographic information, medical history, lifestyle habits, body mass index (BMI) and the level of blood pressure, fasting blood-glucose, and blood lipid, etc. The distribution of BMI, blood pressure, fasting blood-glucose, blood lipid and lifestyle habits between MS patients and non-MS population was compared, latent variables were extracted by exploratory factor analysis to determine the structure model, and then a partial least squares path model was constructed between lifestyle habits and the components of MS. RESULTS: Participants'age was (46.62 +/- 12.16) years old. The overall prevalence of the MS was 22.43% (2967/13 225), 26.49% (2535/9570) in males and 11.82% (432/3655) in females. The prevalence of the MS was statistically different between males and females (chi(2) = 327.08, P < 0.01). Between MS patients and non-MS population, the difference of dietary habits was statistically significant (chi(2) = 166.31, P < 0.01) in MS patients, the rate of vegetarian, mixed and animal food was 23.39% (694/2967), 42.50% (1261/2967) and 34.11% (1012/2967) respectively, while in non-MS population was 30.80% (3159/10 258), 46.37% (4757/10 258), 22.83% (2342/10 258) respectively. Their alcohol consumption has statistical difference (chi(2) = 374.22, P < 0.01) in MS patients, the rate of never or past, occasional and regular drinking was 27.37% (812/2967), 24.71% (733/2967), 47.93% (1422/2967) respectively, and in non-MS population was 39.60% (4062/10 258), 31.36% (3217/10 258), 29.04% (2979/10 258) respectively. The difference of their smoking status was statistically significant (chi(2) = 115.86, P < 0.01) in MS patients, the rate of never or past, occasional and regular smoking was 59.72% (1772/2967), 6.24% (185/2967), 34.04% (1010/2967) respectively, while in non-MS population was 70.03% (7184/10 258), 5.35% (549/10 258), 24.61% (2525/10 258) respectively. Both lifestyle habits and the components of MS were attributable to only one latent variable. After adjustment for age and gender, the path coefficient between the latent component of lifestyle habits and the latent component of MS was 0.22 with statistical significance (t = 6.46, P < 0.01) through bootstrap test. Reliability and validity of the model:the lifestyle latent variable: average variance extracted was 0.53, composite reliability was 0.77 and Cronbach's a was 0.57. The MS latent variable: average variance extracted was 0.45, composite reliability was 0.76 and Cronbach's a was 0.59. CONCLUSION: Unhealthy lifestyle habits are closely related to MS. Meat diet, excessive drinking and smoking are risk factors for MS. PMID- 23928637 TI - [A cohort study on the relationship between cerebrovascular hemodynamic changing and risk of stroke]. AB - OBJECTIVE: To study the role of cerebrovascular hemodynamic indexes (CVHI) changing in stroke and to provide reference for stroke prevention and risk factor study. METHODS: From 2003 to 2004, participants aged 40 years and above in two communities in Fengxian district were recruited by cluster sampling. Risk factors of stroke and CVHI were investigated and checked during baseline investigation. A total of 10 565 individuals completed the survey and met the inclusion criterion. After baseline investigation, the cohort was followed up for stroke occurrence. Relative risk (RR) of CVHI and common risk factors were estimated by cohort study design. RESULTS: Age of the cohort was (56.2 +/- 11.4) years. 4444 (42.1%) were males and 6121 (57.9%) were females. Total follow-up duration was 67 885.7 person years. A total of 195 stroke cases occurred and incidence density of stroke was 287.2 per 100 000 person-years. Stroke incidence in exposure groups of hypertension, heart disease and alcohol drinking was 3.47% (108/3118), 2.96% (21/710) and 2.50% (47/1882), respectively. The incidence in corresponding non exposure group was 1.17% (87/7448), 1.77% (174/9855) and 1.70% (148/8683) respectively. There was significant difference between 2 groups (chi(2) value was 62.72, 4.56 and 4.94, respectively, P < 0.05). Stroke incidence in CVHI score < 25, 25 - 49, 50 - 74 and >= 75 groups was 9.12% (59/647), 5.68% (44/775), 2.52% (39/1545) and 0.72% (53/7403)(chi(2)trend = 273.57, P < 0.05), respectively. Incidence of stroke in 40 - 49, 50 - 59, 60 - 69, >= 70 years age group was 0.22% (8/3565), 1.28% (43/3357), 2.71% (50/1848) and 5.88% (94/1600) (chi(2)trend = 181.48, P < 0.05), respectively. Multiple Cox regression analysis indicated that RR (95%CI) value of hypertension and cigarette smoking was 1.40(1.02 - 1.92) and 1.59(1.19 - 2.12), respectively when comparing with non-exposure group. RR (95%CI) value in CVHI score < 25, 25 - 49 and 50 - 74 points group were 6.15 (4.08 - 9.26), 4.55 (2.98 - 6.96) and 2.68 (1.75 - 4.09), respectively when comparing with the score >= 75 points group. RR (95%CI) value in age 50 - 59, 60 69 and >= 70 years group was 4.61 (2.16 - 9.82), 7.81 (3.67 - 16.60) and 13.49(6.44 - 28.24), respectively when comparing with below 40 years group. CONCLUSION: CVHI score is the strong independent predictive factor and hypertension, cigarette smoking and age are the independent risk factors of stroke. PMID- 23928638 TI - [Analysis of reported infectious diarrhea (other than cholera, dysentery, typhoid and paratyphoid) in China in 2011]. AB - OBJECTIVE: To analysis the etiological and epidemiological characteristics of the reported infectious diarrhea (other than cholera, dysentery, typhoid and paratyphoid) cases in China in 2011. METHODS: A total of 836 591 reported infectious diarrhea cases were collected from "China Information System for Disease Prevention and Control" since first week to fifty-second weeks in 2011, 59 929 out of which were laboratory-confirmed. The information of thirty public health emergencies relevant with infectious diarrhea was collected from "Emergency Public Reporting System" between first week and fifty-second weeks in 2011. The epidemiological characteristics of reported cases, confirmed cases and outbreaks, and the pathogenic spectrum of confirmed cases were then analyzed. RESULTS: In 2011, 836 591 infectious diarrhea cases (other than cholera, dysentery, typhoid and paratyphoid) were reported, and the incidence rate was 62.39/100 000. More than half patients were children aged under 5 year-old, accounting for 52.13% (436 098/836 591) and the incidence rate was 447.06/100 000 (436 098 cases). Most of the ill children were scattered, accounting for 50.53% (422 752/836 591). Reported cases showed two incidence peaks, with a summer peak from twenty-third weeks to thirty-fifth weeks, accounting for 34.33% (287 231/836 591) and a winter peak from forty-third weeks to fifty-second weeks, accounting for 23.54% (196 939/836 591). Cases distributed all over China, the incidence in Beijing (253.00/100 000 (49 619 cases)), Tianjin (244.34/100 000 (31 614 cases)), Zhejiang (204.42/100 000 (111 257 cases)), Ningxia (132.16/100 000 (9328 cases)) and Guangdong (127.40/100 000 (132 880 cases)) ranked the top five. Among the 30 public health emergencies, 5 outbreaks had lab tested pathogenic results, including 4 were norovirus-induced. Laboratory-confirmed cases accounted for 7.16% (59 929/836 591) of the case reported, including 56 687 viral cases and 3242 bacterial cases. Rotavirus cases took the highest proportion of viral cases, at 97.35% (53 612/55 185); and 97.15% (53 612/55 185) of which were children aged under 5 year-old. 82.42% (45 480/55 185) of the cases distributed in Guangdong and Zhejiang province, with the incidence peak from fiftieth weeks to fifty-first weeks, accounting for 15.42% (8508/55 185) of the whole year cases. The main pathogens of bacterial diarrhea were Salmonella, Vibrio parahaemolyticus and Escherichia coli, accounting for 48.43% (1570/3242), 32.20% (1044/3242) and 8.57% (278/3242) respectively, with the incidence peak from thirty-first weeks to thirty-fifth weeks, accounting for 23.01% (746/3242). Salmonella infection patients were mainly from Shanghai, Guangdong and Zhejiang province (91.59% (1438/1570)), Vibrio parahaemolyticus patients were mainly from Shanghai (80.94% (845/1044)), and Escherichia coli patients were mainly from Guangdong province (84.17% (234/278)). Salmonella patients were concentrated in 0-9 years group, accounting for 42.36% (665/1570), while Vibrio parahaemolyticus patients in 20-39 years group, accounting for 81.99% (856/1044), and Escherichia coli patients in under 1 year old and 20-39 years group, accounting for 63.67% (177/278). CONCLUSION: In China, children aged under 5 year-old should be the priority population in surveillance of infectious diarrhea. Rotavirus is the main pathogen causing infectious diarrhea. The lab-testing and case-reporting capabilities differed greatly among areas. PMID- 23928639 TI - [Analysis of clinical features and early warning indicators of death from hand, foot and mouth disease in Shandong province]. AB - OBJECTIVE: To understand the clinical features of death from hand, foot and mouth disease (HFMD) and to explore the early warning index of HFMD death. METHODS: A total of 41 HFMD death cases were collected as case group in Shandong province between 2009 and 2011, and another 123 serious HFMD cases were selected as control group according to the similar gender, place of origin and hospital level, with the ratio at 1:3. We investigated the general situation, clinical treatment, past medical history, clinical symptoms and signs of the ill children, and applied the conditional logistic regression to explore early warning index of HFMD death. RESULTS: The rate of patients who had symptoms in nervous system, digestive system, circulatory system and respiratory system were separately 90.2% (37/41), 58.5% (24/41), 53.7% (22/41) and 90.2% (37/41) in case group; and the proportions were 44.7% (55/123), 13.8% (17/123), 10.6% (13/123) and 12.2% (15/123) respectively in control group. The difference between the two groups showed statistical significance (chi(2) = 25.881, 32.791, 34.011, 86.505, P < 0.05). In case group, 37 patients had neurogenic pulmonary edema, 26 patients got encephalitis, 15 patients had respiratory and circulatory failure, 7 patients got pulmonary hemorrhage, 4 patients had multiple organ failure, 4 patients got myocarditis and 1 patient had cerebral hernia. According to multi-factor logistic regression analysis, the early warning indicators of HFMD death included neck resistance (case group: 34.1% (14/41), control group: 4.1% (5/123); OR = 7.145, 95%CI: 1.748 - 29.204), vomiting (case group: 58.5% (24/41), control group: 13.8% (17/123); OR = 5.632, 95%CI: 1.793 - 17.685) and increase of heart rate (case group: 53.7% (22/41), control group: 10.6% (14/123), OR = 6.370, 95%CI: 1.517 - 26.743). CONCLUSION: In the process of clinical treatment and care, we should interfere the serious HFMD patients with neck resistance, vomiting and increase of heart rate, and thereby reduce the death from HFMD. PMID- 23928640 TI - [Sero-conversion of HIV sero-negative partners among discordant couples in a city of Henan province]. AB - OBJECTIVE: To understand the overall HIV sero-conversion rate and its trend and risk factors of uninfected partners in sero-discordant couples. METHODS: A total of 3088 uninfected partners, whose HIV positive partners infected via former plasma donation or blood transfusion from July, 2006 to December 2010, were chosen as a fix cohort. They were tested for HIV antibodies twice a year using ELISA by local CDC from July, 2006 to December, 2010. Data regarding demographic, sexual behavior information of uninfected partners and infection, serologic characteristics of positive partners were retrospectively surveyed and collected to analyze possible risky factors. RESULTS: A total of 132 in 3088 uninfected partners were sero-converted, with a sero-conversion rate of 1.17/100 person years (95%CI: 0.99/100 person years -1.39/100 person years). Sero-conversion rate reached the peak (0.82%) in the following interval of January and June in 2008 and have a bottom conversion rate (0.13%) in the same month interval in 2010. Conversion rate outcome showed a downward trend in following(chi(2)trend = 8.907, P < 0.05). In the survey, 56.6% (1513/2673) uninfected partners were males, 56.2% (1501/2673) were with lower education level. Among uninfected partners, as reported by themselves, having sex in recently 6 months accounted for a proportion of 81.4% (2176/2673), sex frequency of less than 4 times per month accounted for 45.7% (1169/2558) and consistent using of condom accounted for 94.5% (2418/2558). The proportion of the index partners' most recently CD4 cell count less than 200 cells per ul was 17.4% (437/2505). Results from multivariate of Cox regression showed that male negative partners (RR = 1.58, 95%CI: 1.02 - 2.43), negative partners with lower education level(RR = 2.77, 95%CI: 1.68 - 4.57), having sexual activity in latest one year(RR = 4.39, 95%CI: 1.53 - 12.56) and CD4 count less than 200 cells per ul (RR = 2.36, 95%CI: 1.42 - 3.93) were associated with increased risk of HIV sero-conversion, while intercourse frequency less than 4 times per month(RR = 0.18, 95%CI: 0.10 - 0.32), consistent using of condom(RR = 0.07, 95%CI: 0.05 - 0.12) decreased the risk of conversion. CONCLUSION: In this city, the conversion rate of negative partners whose positive partner infected via former plasma donation or blood transfusion is relatively low and behave a downward trend. Serologic surveillance, education and intervention based on couple are needed to be enhanced. PMID- 23928641 TI - [Analysis of molecular subtypes and microflora structure of Neisseria meningitidis strains isolated in Jiangxi province]. AB - OBJECTIVE: To study the molecular subtypes and microflora structure of Neisseria meningitidis (Nm) strains isolated in Jiangxi province. METHODS: A total of 123 Nm strains separately isolated from patients, close contacts and health people in 1976-1987 and 2005-2008 were investigated by multilocus sequence typing (MLST) and PorA subtyping, to test the characteristics of gene Nm and sequence porA. Minimum spanning tree was constructed by using BioNumerics software based on data of MLST; and the microflora structure was then analyzed. RESULTS: The serogroups of 67 Nm strains isolated in 1976-1987 included group A (43 strains), group B (18 strains), group C (1 strains) and group W135 (5 strains); while the serogroups of 56 Nm strains isolated in 2005-2008 included group A (3 strains), group B (7 strains), group C (45 strains) and 1 ungrouped strain. The total 123 Nm strains could be divided into 40 MLST types; while the 46 strains in group A could be divided into 14 MLST types, 29 out of which belonged to ST-3 type, accounting for 63.0% (29/46) as the dominant type. All of the 29 strains were isolated between 1976 and 1987, while 14 strains were isolated from patients, 9 were from close contacts and 6 were from health people. The 46 strains in group C could be divided into 5 MLST types, 41 out of which belonged to ST-4821 type, accounting for 89.1% (41/46). All of the strains were isolated between 2005 and 2008, 6 strains were isolated from patients, 6 were from close contacts and 29 were from health people. The porA gene of the total 123 Nm strains were classified to 32 different types, including 24 different VR1 types and 22 different VR2 types. The dominant PorA type of the prevalent strain (ST-3 type, group A) between 1976 and 1987 was P1.7-1, 10, accounting for 39.1% (18/46) of the strains in group A; while the 18 strains were isolated from 11 patients, 4 close contacts and 3 health people. The dominant PorA type of the prevalent strain (ST-4821 type, group C) between 2005 and 2008 was P1.20, 9, accounting for 46.3% (19/41) of the ST-4821 strains in group C; while the 19 strains were isolated from 1 close contacts and 18 health people. P1.7-2, 14 dominated since 2006, including 22 strains, accounting for 53.7% (22/41) of the ST-4821 strains in group C, isolated from 6 patients, 5 close contacts and 11 health people. There were no dominant PorA type found in group B and all the 5 strains in group W135 belonged to ST-174 and the PorA type was P1.21, 16, isolating from 3 close contacts and 2 health people between 1979 and 1980. CONCLUSION: Nm isolated in Jiangxi province showed significant gene polymorphism, as well as predominant lineages existing. In different periods, the prevalent lineages varied a lot, as translating from serogroup A: ST-3:P1.7-1, 10 to serogroup C: ST-4821:P1.7-2, 14 nowadays. PMID- 23928642 TI - [Status of household disaster preparedness and affecting factors among the general public of four counties in Shaanxi]. AB - OBJECTIVE: To investigate the status of household disaster preparedness in 4 counties of Shaanxi province and explore the affecting factors. METHODS: During the period from September to October in 2008, multi-stage sampling was used to select subjects from urban and rural residents in Xincheng district, Hantai district, Fuping county and Xunyang county of Shaanxi province. Questionnaire survey was conducted among 1945 subjects aged 18-88 years to investigate their experience and expectation of disaster events, preparedness knowledge, activities and emergency supplies. Logistic regression was used to analyze the factors influencing household disaster preparedness. RESULTS: The average age of the 1945 subjects was (43.55 +/- 12.76) years old. A total of 7.12% (138/1939) of respondents never experienced disaster. Earthquake and fire (57.35% (1175/2049), 19.81% (406/2049), respectively) were rated as the two disasters most likely to occur. The awareness rate of knowledge about household disaster preparedness was 51.43% (989/1923), and 23.41% (454/1939) discussed how to prepare for disaster with their family, only 9.27% (179/1932) attended evacuation drill. The rates of preparing household emergency supplies were 23.64% (230/973), 30.56% (55/180), 31.19% (141/452) and 54.49% (97/178) for urban residents, subjects with junior college or above education, subjects having frequent family discussions of disaster preparedness and subjects participating in emergency rescue drills, respectively. For subjects with junior high school, senior high school and junior college or higher education, the likelihood of preparing household emergency supplies was 5.02 (95%CI: 1.12 - 22.42), 5.74 (95%CI: 1.27 - 26.04) and 6.84 (95%CI: 1.44 - 32.39) times as that of illiterate, respectively. Urban residents, subjects who often discussed disaster preparedness with their family, and who participated in emergency rescue drills were more likely to prepare emergency supplies than rural residents (OR = 4.38, 95%CI: 2.74 - 7.00), those who never discussed (OR = 4.99, 95%CI: 2.52 - 9.91), and who didn't participate (OR = 5.72, 95%CI: 3.84 - 8.51). CONCLUSION: The residents in 4 counties of Shaanxi lack comprehensive knowledge and appropriate activities of disaster preparedness, the rate of preparing household emergency supplies is low. Higher education, living in urban area, frequent family discussions of disaster preparedness and participating in emergency rescue drills are facilitating factors of preparing household emergency supplies. PMID- 23928643 TI - [Gene expression patterns of offsprings' hepatocytes induced by prenatal Benzo[a]pyrene exposure]. AB - OBJECTIVE: To study the gene expression patterns in livers of infant rats after Benzo[a]pyrene (BaP) exposure during pregnancy and explore the important gene and signaling pathways in the toxic mechanism of BaP. METHODS: Thirty-two pregnant SD rats were randomly divided into four groups: vehicle control (corn oil) and treatment groups (0.75, 1.50 and 3.00 mg/kg BaP in corn oil). BaP solutions were given by gastric infusion from the 3rd to the 17th day of pregnancy. After delivery the offspring's liver were taken to detect the gene expression by RatRef 12 gene chip. The stability of gene chip was tested by repeated experiments. RESULTS: After prenatal BaP exposure 1232 genes with different expression variations in hepatocytes of offsprings were identified. Three expression patterns of genes related to the dose of prenatal BaP exposure were identified with significant difference (P < 0.05). As the dose of prenatal BaP exposure increased, the gene expression patterns were downregulated, upregulated, and fluctuated. Twenty-six signaling pathways with differently expressed genes mainly focused on: growth and development, toxicant metabolism and inflammation (P < 0.05). The data from gene network analysis demonstrated that CYP2C13, GSTO1, Rela, MAPK8 and Plcg1 were the key genes in the gene network. CONCLUSION: Gene expression patterns of offsprings' hepatocytes were influenced by prenatal BaP exposure. Some key genes and signal pathways were also found. The study provides an important clue for the toxicity and mechanisms of the prenatal BaP exposure on the growth and development of offspring. PMID- 23928644 TI - [A meta-analysis on overweight, obesity and the risk of breast cancer in Chinese female population]. AB - OBJECTIVE: To estimate the association between overweight, obesity and the risk of breast cancer in Chinese female population. METHODS: Literatures published in China and abroad about overweight, obesity and breast cancer risk among Chinese females were searched. We used "breast cancer", "overweight", "obesity", "weight", "body mass index" and "risk factors" as keywords, to retrieve papers in Chinese literature databases including CNKI, Wanfang and Weipu database. The same strategy was used to retrieve English papers in English literature database including Embase database, PubMed, Science Direct, Elsevier and Cochrane database, supplemented by literature tracing method. Time range was from the founding of each database to April 2012. A total of 124 research papers were collected. Using Stata11.2 software, meta-analysis was conducted, combined odds ratio (OR) and 95% confidence interval (CI) were calculated to estimate the associations between overweight, obesity and the risk of breast cancer in Chinese female population. RESULTS: Eighteen studies were included in meta-analysis, among them 12 studies were in Chinese and 6 were in English, with a number of 7217 cases and 81 605 controls. Results showed a 7.7% increased risk of breast cancer among overweight or obesity women (OR = 1.08, 95%CI: 1.04 - 1.12). Compared with normal BMI women, the OR (95%CI) of overweight or obesity women were 1.07 (1.03 - 1.11) and 1.56 (1.29 - 1.84) before and after the adjustment of menopausal status. CONCLUSION: Overweight, obesity may be important risk factors of breast cancer in Chinese female population. The intervention and control activities may reduce the risk of breast cancer at population level. PMID- 23928645 TI - [Establishment and preliminary application of dengue virus envelope domain III IgG antibody capture enzyme-linked immuno-absorbent assay]. AB - OBJECTIVE: To establish a highly sensitive and specific assay to detect dengue virus (DENV) envelope protein domain III (EDIII) IgG antibody, and to explore its value in the diagnosis and seroepidemiological survey of dengue. METHODS: The DENV EDIII IgG antibody capture ELISA was developed using the recombinant full length DENV EDIII, which was prepared by Pichia yeast expression system as the capture antigen. The serum samples were collected from the same group of 35 DENV 1 patients of primary infection during disease period in 2006 and their follow-up phase in 2010; and the sensitivity of the assay was compared to that of the commercial Panbio DENV IgG ELISA. RESULTS: The sensitivity of DENV EDIII IgG ELISA in detecting the serum samples from disease period and follow-up phase was 87% (20/23) and 94% (33/35), respectively; whereas the sensitivity of Panbio DENV IgG ELISA was 71% (25/35) and 0, respectively. The sensitivity of DENV EDIII IgG ELISA in detecting the serum samples from both periods was similar, without statistical significance (chi(2) = 0.946, P = 0.331). For serum samples from disease period, the sensitivity of DENV EDIII IgG ELISA was comparable with that of Panbio DENV IgG ELISA (chi(2) = 1.924, P = 0.165). However, DENV EDIII IgG ELISA demonstrated a significantly higher sensitivity than Panbio DENV IgG ELISA in detecting the serum samples from follow-up phase (chi(2) = 62.432, P = 0.000). CONCLUSION: DENV EDIII IgG capture ELISA is highly sensitive in detecting IgG in the serum samples from either disease period or follow-up phase. This method might be a promising alternative for diagnosis and seroepidemiologic survey of dengue. PMID- 23928646 TI - [Comparison of direct immune-fluorescent assay and real-time quantitative PCR in detecting the Hantavirus]. AB - OBJECTIVE: To compare the differences between the direct immuno-fluorescent assay (DFA) and real-time quantitative PCR in detecting the Hantavirus (HV) in rat lungs. METHODS: From April to October in 2012, a total of 479 rats were caught by mouse-trap in residential or wild areas in Huxian, Jingyang, and Meixian of Shaanxi province, where haemorrhagic fever with renal syndrome (HFRS) was highly prevalent. The rats were dissected to take the two lungs, one was frozen and applied immuno-fluorescent assay to detect HV antigen while the other one was extracted its RNA and detected HV nucleic acid by real-time quantitative PCR. Then we compared the positive rate of the two methods. RESULTS: Out of the 479 rats, 105 were caught from residential areas and the other 374 were caught from wild areas. Among the 105 rats caught from residential areas, no HV were detected out neither by DFA nor by real-time quantitative PCR. Among the 374 wild rats, 13.1% (49/374) were detected HV positive by DFA and 14.7% (55/374) were detected HV positive by real-time quantitative PCR. The difference showed no statistical significance (chi(2) = 0.402, P = 0.526). When detecting each lung sample, the HV positive rate was 10.2% (49/479) under the detection by DFA while the HV positive rate was 11.5% (55/479) under the detection by real-time quantitative PCR. The difference had no statistical significance (chi(2) = 1.286, P = 0.257) and the consistency coefficient was 68.2% under the paired chi-square test analysis, which showed high consistency (u = 11.759, P < 0.05). The sensitivity of real time quantitative PCR to detect HV was 77.6% (38/49) comparing with DFA as standard, and the specificity was 96.1% (413/430). Out of the 9 suspected HV positive sample detected by DFA, 6 were confirmed positive by real-time quantitative PCR and 3 were denied. CONCLUSION: Compared with the DFA, real-time quantitative PCR could also be used to detect the infection of HV in rats, and the result might be more stable. PMID- 23928647 TI - Evaluating cough assessment tools: a systematic review. AB - BACKGROUND: Little is known about the comparative validity, reliability, or responsiveness of instruments for assessing cough frequency or impact, where the term impact encompasses both cough severity and the impact of cough on health related quality of life. METHODS: We conducted a systematic review to evaluate instruments that assess cough frequency or impact in adults, adolescents, and children with acute or chronic cough. RESULTS: Seventy-eight studies were included, of which eight were randomized controlled trials and 70 were observational studies. In all age groups, audio and video electronic recording devices had good reliability compared with other methods of assessing cough frequency but had variable correlation with other cough assessments, such as visual analog scale scores, quality-of-life questionnaires, cough diaries, and tussigenic challenges. Among adult and adolescent patients, the Leicester Cough Questionnaire (LCQ) and the Cough-Specific Quality-of-Life Questionnaire (CQLQ) were valid and reliable, showing high intraclass and test-retest correlations. Among children, the Parent Cough-Specific Quality of Life Questionnaire and Pediatric Cough Questionnaire were valid and reliable. CONCLUSIONS: Electronic recording devices can be valid assessments of cough frequency. The LCQ and CQLQ for adults and the Parent Cough-Specific Quality of Life questionnaire for children are valid instruments for assessing cough impact. There is limited but insufficient evidence to determine the reliability or concurrent validity of the different types of cough diaries or visual analog scale scores. There are also limited data to support the responsiveness of recording devices. There is good responsiveness data for the LCQ and CQLQ, but more evidence is needed. PMID- 23928648 TI - Tissue transglutaminase antibody levels predict IgA deficiency. AB - OBJECTIVE: Measuring serum tissue transglutaminase immunoglobulin A (tTG IgA) levels is the most widely used screening test for coeliac disease. However, given an increased prevalence of IgA deficiency among coeliac patients there is a risk of false negative results. Hence, in addition to specific serum tTG IgA, screening tests frequently include total IgA levels. The objective of this study was to determine whether tTG IgA antibody levels might be used to predict IgA deficiency and hence avoid unnecessary testing of total IgA levels in all individuals. DESIGN: Retrospective analysis of 9429 serum tTG IgA and corresponding total IgA levels obtained from children and young adults in the East of England between 2007 and 2011. RESULTS: The overall prevalence of IgA deficiency was found to be very low with only 0.9% of individuals affected. Using receiver operating characteristic curve analysis we identified a cut-off value for tTG IgA of >=0.10 MU/mL to be predictive for the absence of total IgA deficiency (IgA<0.06 g/L). Specifically, using this cut-off value, total IgA deficiency could be excluded with a sensitivity of 0.92 and specificity of 0.84. In our cohort, only 16.4% of our patient sample would have needed total IgA measurement to rule out a false negative result due to IgA deficiency. CONCLUSIONS: Our data provide a simple means of avoiding unnecessary total IgA measurements in the assessment of coeliac disease. By using tTG IgA value quantitatively, only values <0.10 MU/mL require total IgA measurements to rule out IgA deficiency and hence a potentially false negative screening result. PMID- 23928649 TI - Do we really need continuous vancomycin infusion in neonates? PMID- 23928650 TI - Heart rate: a prognostic factor and therapeutic target in chronic heart failure. The distinct roles of drugs with heart rate-lowering properties. AB - Heart rate not only predicts outcome but may also be a therapeutic target in patients with chronic heart failure. Several classes of pharmacological agents can be used to modulate heart rate, including beta-blockers, ivabradine, digoxin, amiodarone, and verapamil. Choice of agent will depend on heart rhythm, co morbidities, and disease phenotype. Beneficial and harmful interactions may also exist. The aim of this paper is to summarize the current body of knowledge regarding the relevance of heart rate as a prognostic factor (risk marker) and particularly as a therapeutic target (risk factor) in patients with chronic heart failure, with a special focus on ivabradine, a novel agent that is currently the only available purely bradycardic agent. PMID- 23928652 TI - Identification of a novel spinal dorsal horn astroglial D-amino acid oxidase hydrogen peroxide pathway involved in morphine antinociceptive tolerance. AB - BACKGROUND: D-Amino acid oxidase (DAAO) is a flavin adenine dinucleotide dependent peroxisomal flavoenzyme which is almost exclusively expressed within astrocytes in the spinal cord. DAAO catalyzes oxidation of D-amino acids to hydrogen peroxide, which is a stable and less active reactive oxygen species, and may represent a final form of reactive oxygen species. This study tested the hypothesis that the spinal astroglial DAAO-hydrogen peroxide pathway plays an important role in the development of morphine antinociceptive tolerance. METHODS: Rat and mouse formalin, hot-plate, and tail-flick tests were used, and spinal DAAO expression and hydrogen peroxide level were measured. Sample size of animals was six in each study group. RESULTS: Subcutaneous and intrathecal DAAO inhibitors, including 5-chloro-benzo[d]isoxazol-3-ol, AS057278, and sodium benzoate, completely prevented and reversed morphine antinociceptive tolerance in the formalin, hot-plate, and tail-immersion tests, with a positive correlation to their DAAO inhibitory activities. Intrathecal gene silencers, small interfering RNA/DAAO and small hairpin RNA/DAAO, almost completely prevented morphine tolerance. Intrathecal 5-chloro-benzo[d]isoxazol-3-ol and small interfering RNA/DAAO completely prevented increased spinal hydrogen peroxide levels after chronic morphine treatment. Intrathecal nonselective hydrogen peroxide scavenger phenyl-tert-N-butyl nitrone and the specific hydrogen peroxide catalyst catalase also abolished established morphine tolerance. Spinal dorsal horn astrocytes specifically expressed DAAO was significantly up-regulated, accompanying astrocyte hypertrophy after chronic morphine treatment. CONCLUSIONS: For the first time, the authors' result identify a novel spinal astroglial DAAO-hydrogen peroxide pathway that is critically involved in the initiation and maintenance of morphine antinociceptive tolerance, and suggest that this pathway is of potential utility for the management of morphine tolerance and chronic pain. PMID- 23928653 TI - Genome-wide identification and analysis of membrane-bound O-acyltransferase (MBOAT) gene family in plants. AB - Membrane bound O-acyl transferase (MBOAT) family is composed of gene members encoding a variety of acyltransferase enzymes, which play important roles in plant acyl lipid metabolism. Here, we present the first genome-enabled identification and analysis of MBOAT gene models in plants. In total, we identified 136 plant MBOAT sequences from 14 plant species with complete genomes. Phylogenetic relationship analyses suggested the plant MBOAT gene models fell into four major groups, two of which likely encode enzymes of diacylglycerol acyltransferase 1 (DGAT1) and lysophospholipid acyltransferase (LPLAT), respectively, with one-three copies of paralogs present in each of the most plant species. A group of gene sequences, which are homologous to Saccharomyces cerevisiae glycerol uptake proteins (GUP), was identified in plants; copy numbers were conserved, with only one copy represented in each of the most plant species; analyses showed that residues essential for acyltransferases were more prone to be conserved than vertebrate orthologs. Among four groups, one was inferred to emerge in land plants and experience a rapid expansion in genomes of angiosperms, which suggested their important roles in adaptation of plants in lands. Sequence and phylogeny analyses indicated that genes in all four groups encode enzymes with acyltransferases. Comprehensive sequence identification of MBOAT family members and investigation into classification provide a complete picture of the MBOAT gene family in plants, and could shed light into enzymatic functions of different MBOAT genes in plants. PMID- 23928654 TI - Conversion of membrane lipid acyl groups to triacylglycerol and formation of lipid bodies upon nitrogen starvation in biofuel green algae Chlorella UTEX29. AB - Algal lipids are ideal biofuel sources. Our objective was to determine the contributors to triacylglycerol (TAG) accumulation and lipid body formation in Chlorella UTEX29 under nitrogen (N) deprivation. A fivefold increase in intracellular lipids following N starvation for 24 h confirmed the oleaginous characteristics of UTEX29. Ultrastructural studies revealed increased number of lipid bodies and decreased starch granules in N-starved cells compared to N replete cells. Lipid bodies were observed as early as 3 h after N removal and plastids collapsed after 48 h of stress. Moreover, the identification of intracellular pyrenoids and differences in the expected nutritional requirements for Chlorella protothecoides (as UTEX29 is currently classified) led us to conduct a phylogenetic study using 18S and actin cDNA sequences. This indicated UTEX29 to be more phylogenetically related to Chlorella vulgaris. To investigate the fate of different lipids after N starvation, radiolabeling using 14C-acetate was used. A significant decrease in 14C-galactolipids and phospholipids matched the increase in 14C-TAG starting at 3 h of N starvation, consistent with acyl groups from structural lipids as sources for TAG under N starvation. These results have important implications for the identification of key steps controlling oil accumulation in N-starved biofuel algae and demonstrate membrane recycling during lipid body formation. PMID- 23928655 TI - Decision maker based on nanoscale photo-excitation transfer. AB - Decision-making is one of the most important intellectual abilities of the human brain. Here we propose an efficient decision-making system which uses optical energy transfer between quantum dots (QDs) mediated by optical near-field interactions occurring at scales far below the wavelength of light. The simulation results indicate that our system outperforms the softmax rule, which is known as the best-fitting algorithm for human decision-making behaviour. This suggests that we can produce a nano-system which makes decisions efficiently and adaptively by exploiting the intrinsic spatiotemporal dynamics involving QDs mediated by optical near-field interactions. PMID- 23928656 TI - Comparison of aggregating agents for the surface-enhanced Raman analysis of benzodiazepines. AB - Benzodiazepines are among the most prescribed compounds and are commonly present in many toxicological screens. They are also of concern forensically in cases of drug facilitated sexual assault. Currently these compounds are predominantly analyzed using immunoassay techniques; however more specific screening methods are needed. This paper demonstrates the applicability of surface enhanced Raman spectroscopy as a method for the analysis and detection of benzodiazepines. The procedure involves mixing urine extracts with gold nanoparticles and appropriate aggregating agents for trace detection of these compounds and their metabolites. In this paper we will discuss the optimization of various parameters of this technique as well as its application to screening urine samples. Eleven different benzodiazepines and metabolites were examined, including 1,2-triazolo benzodiazepines and 1,4-benzodiazpines. Experiments were performed using four different chloride salts, MgCl2, CaCl2, KCl, and NaCl, as aggregating agents for the colloidal gold nanoparticles. Overall it was found that each aggregating agent produced different levels of signal enhancement for each drug. MgCl2 provided the lowest limit of detection at 2.5 ng mL(-1), and linearity over a wide range of concentrations for a variety of drugs chosen. It was also determined that the optimum MgCl2 concentration was 1.67 M. This method has shown the applicability of SERS for the detection of trace quantities of benzodiazepines in aqueous solutions as well as the optimization of the technique over a wide range of compounds. This technique can be utilized in the detection of trace benzodiazepines in toxicological samples following extraction of the analyte. PMID- 23928658 TI - Assemblies of polyvinylpyrrolidone-capped tetrahedral and spherical Pt nanoparticles in polyelectrolytes: hydrogen underpotential deposition and electrochemical characterization. AB - Polyvinylpyrrolidone (PVP)-capped Pt nanoparticles (NPs) were synthesized in mostly tetrahedral (TH-Pt, [edge] = 4.3 +/- 0.7 nm) or spherical (S-Pt, [d] = 3.4 +/- 0.8 nm) shapes and assembled layer-by-layer in poly(diallyldimethylammonium) chloride on electrodes driven by electrostatic and hydrophobic interactions. The nanostructured Pt electrodes were characterized using hydrogen underpotential deposition (H(upd)) in 1 M H2SO4. The H(upd) charge increased linearly with the PDDA-Pt NP adsorption cycle measured up to 10 cycles revealing a linear incorporation of Pt NPs per cycle, indicative of reproducible surface charge reversal despite the submonolayer NP coverage imaged by TEM on a PDDA layer, and showing the feasibility of charge and mass transport in the thickness of the films. H(upd) at both PVP-TH-Pt and PVP-S-Pt occurred in two states, a major weak adsorption H(W) peak, and a minor strong-adsorption state H(S) appearing as a shoulder. H(upd) features and other electrochemical processes at assemblies of PVP-Pt NP in PDDA were compared to assemblies of 2.5 nm polyacrylate-capped Pt NPs in PDDA and to polycrystalline Pt. Results indicated that H(W) adsorption likely occurs on a PVP-modified Pt NP surface without being accompanied by PVP desorption, while H(S) occurs on free (100) sites. The PVP-Pt NPs were resistant to surface oxidation and were stable against usual surface restructuring when scanned into the Pt-oxide potential region as they remained modified with PVP. O2 evolution was also suppressed by PVP-capping compared to PAC-Pt NPs and polycryst Pt, but the assemblies were electrocatalytic for hydrogen evolution, hydrogen oxidation, and oxygen reduction. Increasing anodic polarization increased the H(W) charge but without causing a potential shift, indicating absence of PVP decapping or Pt surface restructuring, but possibly some structural polymer rearrangement increasing the accessibility of buried sites for H-adsorption. PMID- 23928657 TI - Traumatic injuries to the craniovertebral junction: a review of rare events. AB - The craniovertebral junction is a specific region of the spine with unique anatomical and biomechanical properties that yields a wide variety of injury patterns. Junctional traumatic fractures and/or dislocations are widely reported in clinical practice, but we could identify only a subgroup of upper cervical spine traumatic injuries with very few cases reported in the literature, and for this reason may be considered rare. In some of these cases, the absence of spinal biomechanical instability, in association with moderate clinical symptoms (neck stiffness and pain) and the difficulty in fracture identification through standard cervical radiographs, leads to a high percentage of missed injuries. In other cases, traumatic events have been commonly described only in autopsy series due to the high degree of spinal biomechanical instability. Herein, we have summarized all the relevant literature concerning this issue and also included our cases, with the aim of emphasizing prompt diagnosis and correct management. We provide a guide for correctly identifying "rare" craniovertebral junction traumatic injuries. PMID- 23928659 TI - Antitumour activity of abiraterone and diethylstilboestrol when administered sequentially to men with castration-resistant prostate cancer. AB - BACKGROUND: Abiraterone is a standard treatment for men with castration-resistant prostate cancer (CRPC). We evaluated the antitumour activity of abiraterone following the synthetic oestrogen diethylstilboestrol (DES). METHODS: Castration resistant prostate cancer patients treated with abiraterone were identified. Demographics, response variables and survival data were recorded. RESULTS: Two hundred and seventy-four patients received abiraterone, 114 (41.6%) after DES. Pre-chemotherapy abiraterone resulted in >=50% PSA declines in 35/41 (85.4%) DES naive and 20/27 (74.1%) DES-treated patients. Post-docetaxel abiraterone resulted in >=50% PSA declines in 40/113 (35.4%) DES-naive and 23/81 (28.4%) DES-treated patients. Time to PSA progression was similar regardless of prior DES. CONCLUSION: Abiraterone has important antitumour activity in men with CRPC even after DES exposure. PMID- 23928660 TI - The role of Mediterranean diet on the risk of pancreatic cancer. AB - BACKGROUND: The Mediterranean diet has been shown to have a beneficial role on various neoplasms, but data are scanty on pancreatic cancer. METHODS: We analysed data from two case-control studies conducted in Italy between 1983 and 2008, including 362 and 326 pancreatic cancer cases and 1552 and 652 hospital-controls, respectively. A Mediterranean Diet Score (MDS) summarising major characteristics of the Mediterranean diet was used in the two studies separately and overall. Two further scores of adherence to the Mediterranean diet were applied in the second study only, the Mediterranean Dietary Pattern Adherence Index (MDP) and the Mediterranean Adequacy Index (MAI). RESULTS: Odds ratios (ORs) for increasing levels of the scores (i.e., increasing adherence) were estimated using multiple logistic regression models. Odds ratio for a MDS score >=6 compared with <3 was 0.57 (95% confidence interval (CI) 0.34-0.95) in the first study, 0.51 (95% CI 0.29-0.92) in the second study, and 0.48 (95% CI 0.35-0.67) overall. A trend of decreasing risk was observed also for the MDP and MAI the ORs for the highest vs the lowest quintile being 0.44 (95% CI 0.27-0.73) for MDP and 0.68 (95% CI 0.42 1.11) for the MAI. The results were consistent across strata of age, sex, education, body mass index, alcohol drinking, tobacco smoking, and diabetes. CONCLUSION: Our study provides evidence that a priori-defined scores measuring adherence to the Mediterranean diet are favourably associated with pancreatic cancer risk. PMID- 23928661 TI - Critical weight loss is a major prognostic indicator for disease-specific survival in patients with head and neck cancer receiving radiotherapy. AB - BACKGROUND: Pre-treatment weight loss (WL) is a prognostic indicator for overall survival (OS) in head and neck cancer (HNC) patients. This study investigates the association between WL before or during radiotherapy and disease-specific survival (DSS) in HNC patients. METHODS: In 1340 newly diagnosed HNC patients, weight change was collected before and during (adjuvant) radiotherapy with curative intent. Critical WL during radiotherapy was defined as >5% WL during radiotherapy or >7.5% WL until week 12. Differences in 5-year OS and DSS between WL groups were analysed by Cox's regression with adjustments for important socio demographic and tumour-related confounders. RESULTS: Before radiotherapy, 70% of patients had no WL, 16% had <=5% WL, 9% had >5-10% WL, and 5% had >10% WL. Five year OS and DSS rates for these groups were 71%, 59%, 47%, and 42% (P<0.001), and 86%, 86%, 81%, and 71%, respectively (P<0.001). After adjustment for potential confounders, >10% WL before radiotherapy remained significantly associated with a worse OS (HR 1.7; 95% CI 1.2-2.5; P=0.002) and DSS (HR 2.1; 95% CI 1.2-3.5; P=0.007).The 5-year OS and DSS rates for patients with critical WL during radiotherapy were 62% and 82%, compared with 70% and 89% for patients without critical WL (P=0.01; P=0.001). After adjustment, critical WL during radiotherapy remained significantly associated with a worse DSS (HR 1.7; 95% CI 1.2-2.4; P=0.004). CONCLUSION: Weight loss both before and during radiotherapy are important prognostic indicators for 5-year DSS in HNC patients. Randomised studies into the prognostic effect of nutritional intervention are needed. PMID- 23928662 TI - Exploring inequalities in access to care and the provision of choice to women seeking breast reconstruction surgery: a qualitative study. AB - BACKGROUND: Breast reconstruction (BR) may improve psychosocial and cosmetic outcomes after mastectomy for breast cancer but currently, few women opt for surgery. Reasons for this are unclear. The aim of this qualitative study was to explore access to care and the provision of procedure choice to women seeking reconstructive surgery. METHODS: Semi-structured interviews with a purposive sample of patients who had undergone BR and professionals providing specialist care explored participants' experiences of information provision before BR. Interviews were transcribed verbatim and analysed using the constant comparative technique of grounded theory. Sampling, data collection and analysis were performed concurrently and iteratively until data saturation was achieved. RESULTS: Both patients and professionals expressed concerns about the provision of adequate procedure choice and access to care. Lack of information and/or time, involvement in decision making and issues relating to the evolution and organisation of reconstructive services, emerged as potential explanations for the inequalities seen. Interventions to improve cross-speciality collaboration were proposed to address these issues. CONCLUSION: Inequalities in the provision of choice in BR exist, which may be explained by a lack of integration between surgical specialities. Pathway restructuring, service reorganisation and standardisation of training may enhance cross-speciality collaboration and improve the patient experience. PMID- 23928663 TI - Detecting bladder fullness through the ensemble activity patterns of the spinal cord unit population in a somatovisceral convergence environment. AB - OBJECTIVE: Chronic monitoring of the state of the bladder can be used to notify patients with urinary dysfunction when the bladder should be voided. Given that many spinal neurons respond both to somatic and visceral inputs, it is necessary to extract bladder information selectively from the spinal cord. Here, we hypothesize that sensory information with distinct modalities should be represented by the distinct ensemble activity patterns within the neuronal population and, therefore, analyzing the activity patterns of the neuronal population could distinguish bladder fullness from somatic stimuli. APPROACH: We simultaneously recorded 26-27 single unit activities in response to bladder distension or tactile stimuli in the dorsal spinal cord of each Sprague-Dawley rat. In order to discriminate between bladder fullness and tactile stimulus inputs, we analyzed the ensemble activity patterns of the entire neuronal population. A support vector machine (SVM) was employed as a classifier, and discrimination performance was measured by k-fold cross-validation tests. MAIN RESULTS: Most of the units responding to bladder fullness also responded to the tactile stimuli (88.9-100%). The SVM classifier precisely distinguished the bladder fullness from the somatic input (100%), indicating that the ensemble activity patterns of the unit population in the spinal cord are distinct enough to identify the current input modality. Moreover, our ensemble activity pattern based classifier showed high robustness against random losses of signals. SIGNIFICANCE: This study is the first to demonstrate that the two main issues of electroneurographic monitoring of bladder fullness, low signals and selectiveness, can be solved by an ensemble activity pattern-based approach, improving the feasibility of chronic monitoring of bladder fullness by neural recording. PMID- 23928664 TI - Intranasal insulin reduces olfactory sensitivity in normosmic humans. AB - CONTEXT: High densities of insulin receptors are found throughout the human brain, including the olfactory bulb, an essential brain area for odor processing. This brain region is the phylogenetically oldest part of the olfactory central nervous system. OBJECTIVE: We hypothesized that enhanced brain insulin signaling would modulate olfactory processing in humans. DESIGN: We applied a double-blind, placebo-controlled, balanced within-subject design. SETTING: This study was conducted in the research unit of a university hospital. INTERVENTIONS/PARTICIPANTS/MAIN OUTCOME MEASURES: A single dose of either insulin (40 IU) or placebo was intranasally administered to 17 normal-weight normosmic participants (7 women). Subjects' olfactory abilities were examined by means of an olfactory threshold test (odorant n-butanol) and an olfactory discrimination test. In addition, circulating concentrations of glucose, insulin, and cortisol levels were measured. RESULTS: After intranasal insulin administration, subjects' sensitivity for the odorant n-butanol was significantly decreased compared with that for the placebo condition (-13%; P = .025), whereas olfactory discrimination ability was not (P = .841). While serum insulin and serum cortisol were not altered after intranasal insulin administration, there was a small but significant drop in plasma glucose levels. Importantly, a correlational analysis demonstrated that this treatment-induced drop in plasma glucose was not related to the effects of intranasal insulin on olfactory sensitivity. CONCLUSIONS: These findings suggest that intranasal insulin impairs olfactory sensitivity for a nonfood odorant, whereas no such effects were found for olfactory discrimination. Thus, variations in brain insulin signaling most likely have implications for the olfactory threshold of normosmic humans. Bearing in mind the fact that insulin acts as an anorexigenic signal in the human brain, further studies are needed to test whether intranasal insulin also impairs the ability of humans to perceive food-related odors. PMID- 23928665 TI - S100A11 overexpression contributes to the malignant phenotype of papillary thyroid carcinoma. AB - CONTEXT: Papillary thyroid carcinoma (PTC) is the most frequent thyroid tumor and is responsible for the overall increase in thyroid cancer incidence. S100A11 (calgizzarin), a member of the S100 Ca(2+)-binding protein family, is involved in several different biological processes. S100A11 has been found up-regulated in PTC, both at the mRNA and protein levels. OBJECTIVE: Through a combination of expression analysis and functional in vitro and in vivo studies, we have attempted to gain insight into the relevance of S100A11 overexpression in PTC biology. DESIGN: The expression of the S100A11 gene in PTC was investigated in several gene expression data sets. The effect of S100A11 silencing on the hallmarks of the malignant phenotype of several PTC-derived cell lines was investigated. In NIH3T3 cells, the cooperation of S100A11 with the different PTC specific oncogenes was assessed. RESULTS: We found that the S100A11 gene expression is frequently up-regulated in PTC, anaplastic thyroid carcinoma, but not in follicular thyroid carcinoma. S100A11 overexpression was also detected in PTC-derived cell lines, which were then used for functional studies. S100A11 silencing in PTC-derived cell lines did not affect cell proliferation, whereas it reduced the loss of contact inhibition, anchorage-independent growth, and resistance to anoikis. Cotransfection experiments in NIH3T3 cells showed that overexpression of the S100A11 gene was able to enhance the transforming capabilities of the different PTC-associated oncogenes by affecting the loss of contact inhibition, anchorage-independent growth, and in vivo tumor formation. CONCLUSION: Our data indicate that S100A11 overexpression exerts a protumoral functional role in PTC pathogenesis. PMID- 23928666 TI - Changes in circulating microRNAs are associated with childhood obesity. AB - CONTEXT: Circulating microRNAs (miRNAs) are valuable biomarkers of metabolic diseases and potential therapeutic targets in this field. OBJECTIVE: Our objective was to define the circulating pattern of miRNAs in childhood obesity. DESIGN, SETTINGS, AND MAIN OUTCOME MEASURE: The genome-wide circulating miRNA profile was assessed by RT-PCR in 10 boys (5 lean and 5 obese children). The most relevant miRNAs were cross-sectionally validated in 85 lean versus 40 obese children (63 boys and 62 girls) and longitudinally evaluated in samples from the same children when they were ~ 7 and ~ 10 years old (23 boys and 22 girls). RESULTS: The cross-sectional validation study disclosed that 15 specific circulating miRNAs were significantly deregulated in prepubertal obesity, including the decreased miR-221 and miR-28-3p and increased concentrations in plasma of miR-486-5p, miR-486-3p, miR-142-3p, miR-130b, and miR-423-5p (all P < .0001). The circulating concentration of these miRNAs was significantly associated with body mass index and other measures of obesity such as percent fat mass, waist, regional fat distribution and with laboratory parameters such as homeostasis model assessment of insulin resistance, high-molecular-weight adiponectin, C-reactive protein, and circulating lipids in concordance with anthropometric associations. Plasma concentrations of 10 of these circulating miRNAs changed significantly and differently during the 3-year follow-up in children who increased or decreased their normalized weight. CONCLUSION: This study provides the first evidence that circulating miRNAs are deregulated in prepubertal obese children. Thus, the very early detection of an abnormal circulating miRNA profile may be a promising strategy to identify obese children who may suffer from metabolic abnormalities. PMID- 23928667 TI - Pulsatile interleukin-6 leads CRH secretion and is associated with myometrial contractility during the active phase of term human labor. AB - OBJECTIVE: Our objective was to investigate IL-6 and CRH secretion during the active phase of human labor and to define their potential involvement in myometrial contractility. STUDY DESIGN: Twenty-two primigravid women were studied for 90 minutes during the active phase of term labor by serial plasma sampling every 3 minutes for measurement of IL-6 and CRH concentrations. Uterine contractions, measured by cardiotocograph, were evaluated in Montevideo units. Basic, quantitative, pulsatility, and time cross-correlation statistical analyses were performed. RESULTS: By linear regression analysis, a positive correlation was observed between IL-6 and CRH total mean area under the curve above 0 (r = 0.76184, P = .006). Mean number of pulses was 2.00 +/- 0.70 and 3.33 +/- 1.29 for IL-6 and CRH, respectively. There was a significant positive correlation between IL-6 and CRH over time, peaking at the 12-minute interval, with IL-6 leading CRH. Also, there was a significant positive correlation between myometrial contractility expressed in Montevideo units and IL-6 concentrations over time, starting at +51 minutes and ending at +57 minutes with myometrial contractility leading IL-6. No significant correlation was found between myometrial contractility and CRH concentrations over time. CONCLUSION: IL-6 and CRH are both secreted in a pulsatile fashion during the active phase of human labor. The time integrated concentrations of the two hormones are positively correlated, with IL 6 leading CRH secretion. It appears, thus, that proinflammatory mediators may be direct and/or indirect promoters of placental CRH release. Furthermore, the secretion of IL-6, which is a myokine, seems to be associated positively with uterine contractility. Additional studies are needed to elucidate the combined effect of inflammation, placental CRH release, and/or the receptors of the latter in parturition. PMID- 23928668 TI - Central diabetes insipidus: a previously unreported side effect of temozolomide. AB - CONTEXT: Temozolomide (TMZ) is an alkylating agent primarily used to treat tumors of the central nervous system. We describe 2 patients with apparent TMZ-induced central diabetes insipidus. Using our institution's Research Patient Database Registry, we identified 3 additional potential cases of TMZ-induced diabetes insipidus among a group of 1545 patients treated with TMZ. CASE PRESENTATIONS: A 53-year-old male with an oligoastrocytoma and a 38-year-old male with an oligodendroglioma each developed symptoms of polydipsia and polyuria approximately 2 months after the initiation of TMZ. Laboratory analyses demonstrated hypernatremia and urinary concentrating defects, consistent with the presence of diabetes insipidus, and the patients were successfully treated with desmopressin acetate. Desmopressin acetate was withdrawn after the discontinuation of TMZ, and diabetes insipidus did not recur. Magnetic resonance imaging of the pituitary and hypothalamus was unremarkable apart from the absence of a posterior pituitary bright spot in both of the cases. Anterior pituitary function tests were normal in both cases. Using the Research Patient Database Registry database, we identified the 2 index cases and 3 additional potential cases of diabetes insipidus for an estimated prevalence of 0.3% (5 cases of diabetes insipidus per 1545 patients prescribed TMZ). CONCLUSIONS: Central diabetes insipidus is a rare but reversible side effect of treatment with TMZ. PMID- 23928669 TI - Parallel variations of insulin-like peptide 3 (INSL3) and antimullerian hormone (AMH) in women with the polycystic ovary syndrome according to menstrual cycle pattern. AB - CONTEXT: Antimullerian hormone (AMH) and insulin-like factor 3 (INSL3) represent ovarian functional markers of granulosa and theca cells, respectively. OBJECTIVE: We conducted a prospective study to investigate AMH and INSL3 plasma levels in 3 groups of women with polycystic ovary syndrome (PCOS) classified according to menstrual cyclicity pattern and their relationship with ovarian morphology and hormonal levels. DESIGN AND PARTICIPANTS: AMH and INSL3 were measured in a cohort of 57 patients with PCOS, divided into 3 groups according to menstrual status: eumenorrheic (PCOS-E, n = 15), oligomenorrheic (PCOS-O, n = 25), and amenorrheic (PCOS-A, n = 17). Clinical and endocrine characteristics and ovarian morphology were compared among the groups. Twenty-seven age- and weight-matched women without hyperandrogenism were included as controls. RESULTS: According to the menstrual pattern, the women with PCOS-A and PCOS-O had higher INSL3 levels with respect to the control women (P = .025 and P = .004, respectively) and higher but not significant INSL3 levels compared with those of the women with PCOS-E. AMH levels were significantly higher in women with PCOS-A and PCOS-O with respect to those in women with PCOS-E (P < .001 and P < .001, respectively) and control women (P < .001 and P < .001, respectively). Interestingly, a significant positive correlation was found between INSL3 and AMH blood levels in all women with PCOS (R = 0.43; P = .002) and across the groups (R = 0.41; P < .001). CONCLUSIONS: INSL3 and AMH levels are significantly correlated with each other in women with PCOS, and they are significantly increased, particularly in the presence of amenorrhea and oligomenorrhea. INSL3 and AMH may reflect a dysfunction of PCOS thecal and granulosa cells, which are responsible for the increased androgen production and chronic anovulation of this condition. PMID- 23928670 TI - Bloom syndrome in short children born small for gestational age: a challenging diagnosis. AB - BACKGROUND: GH treatment has become a frequently applied growth-promoting therapy in short children born small for gestational age (SGA). In some disorders GH treatment is contraindicated, eg, chromosomal breakage syndromes. Bloom syndrome is a rare chromosomal breakage syndrome characterized by severe pre- and postnatal growth deficiency, a photosensitive facial erythema, immunodeficiency, mental retardation or learning disabilities, endocrinopathies, and a predisposition to develop a wide variety of cancers. OBJECTIVE: We report 2 patients with Bloom syndrome illustrating the variety in clinical manifestations. They were initially diagnosed with short stature after SGA birth and Silver Russell syndrome and treated with GH. CASES: Both patients presented with pre- and postnatal growth failure but no clear other characteristic features associated with Bloom syndrome. Photosensitive skin lesions developed only at a pubertal age and were minimal. Also, both children showed normal immunoglobulin levels, normal development, and no signs of endocrinopathies at start of GH. Dysmorphic features resembling Silver Russell syndrome were observed in both patients. Remarkably, during GH treatment IGF-1 levels increased to values greater than 3.5 SD score, with normal IGF binding protein-3 levels. CONCLUSION: Short children born SGA comprise a heterogeneous group. Bloom syndrome should be tested for in children with consanguineous parents, dysmorphic features (particularly resembling Silver Russell syndrome), skin abnormalities, and/or IGF 1 levels greater than 2.5 SD score during standard GH treatment with normal IGF binding protein-3 levels. PMID- 23928671 TI - Whole-transcriptome profiling of thyroid nodules identifies expression-based signatures for accurate thyroid cancer diagnosis. AB - PURPOSE: Due to the limitations of fine-needle aspiration biopsy (FNAB) cytopathology, many individuals who present with thyroid nodules eventually undergo thyroid surgery to diagnose thyroid cancer. The objective of this study was to use whole-transcriptome profiling to develop and validate a genomic classifier that significantly improves the accuracy of preoperative thyroid cancer diagnosis. MATERIALS AND METHODS: Nucleic acids were extracted and amplified for microarray expression analysis on the Affymetrix Human Exon 1.0 ST GeneChips from 1-mm-diameter formalin-fixed and paraffin-embedded thyroid tumor tissue cores. A training group of 60 thyroidectomy specimens (30 cancers and 30 benign lesions) were used to assess differential expression and for subsequent generation of a genomic classifier. The classifier was validated in a blinded fashion on a group of 31 formalin-fixed and paraffin-embedded thyroid FNAB specimens. RESULTS: Expression profiles of the 57 thyroidectomy training and 31 FNAB validation specimens that passed a series of quality control steps were analyzed. A genomic classifier composed of 249 markers that corresponded to 154 genes, had an overall validated accuracy of 90.0% in the 31 patient FNAB specimens and had positive and negative predictive values of 100% and 85.7%, respectively. The majority of the identified markers that made up the classifier represented non-protein-encoding RNAs. CONCLUSIONS: Whole-transcriptome profiling of thyroid nodule surgical specimens allowed for the development of a genomic classifier that improved the accuracy of preoperative thyroid cancer FNAB diagnosis. PMID- 23928672 TI - PTH: a new target in arteriosclerosis? AB - CONTEXT: Growing evidence demonstrates that hyperparathyroidism is associated with an increased risk of cardiovascular morbidity and mortality. However, little is known about the relation between serum PTH levels within the normal range and cardiovascular diseases (CVD). OBJECTIVE: In this study the relationship of serum PTH levels within the normal range with CVD and abdominal aortic calcifications was investigated. DESIGN: A cross-sectional, population-based study was performed using data of the Longitudinal Aging Study Amsterdam, including 558 men and 537 women, aged 65-88 years. Models were controlled for sex, age, body mass index, hypertension, diabetes mellitus, high-density lipoprotein cholesterol, total cholesterol, smoking, physical activity, alcohol consumption, glomerular filtration rate, season of blood collection, calcium or diuretic use, and serum 25-hydroxyvitamin D and osteocalcin levels when these variables were found to be relevant confounders. RESULTS: Multivariate models showed that subjects in the highest quintile of serum PTH had a significantly higher risk of CVD as compared with subjects in the lowest quintile (odds ratio 2.22, confidence interval 1.39 3.56). The relationship between PTH and abdominal aortic calcifications was observed only in men, which remained significant after adjusting for confounders (odds ratio 4.03, confidence interval 1.50-10.83). CONCLUSIONS: This study demonstrated that in older persons the presence of serum PTH levels within the upper normal range is highly related to CVD. In men, this association may partly be explained by calcifications of the abdominal aorta. Because CVD poses an important health risk, further elucidation of the role of serum PTH in CVD and arteriosclerosis is relevant. PMID- 23928673 TI - Recurrent thrombotic obstruction of a mechanical prosthetic valve in tricuspid position. Value of cinefluoroscopy in diagnosis and follow-up of thrombolytic treatment. PMID- 23928674 TI - Diagnostic and therapeutic challenges. PMID- 23928675 TI - Topical nepafenac after intravitreal injection: a prospective double-masked randomized controlled trial. AB - PURPOSE: To evaluate if a single drop of nepafenac can reduce the ocular discomfort after intravitreal injections compared with placebo. METHODS: One hundred and twenty patients undergoing intravitreal injections of bevacizumab or ranibizumab received a drop of nepafenac or placebo (Systane Ultra) after the injection in a prospective, double-masked, randomized controlled design. Patients rated their pain levels from 0 to 3 (no pain, mild pain, moderate pain, severe pain) at 1 hour, 6 hours, and 24 hours after the procedure. RESULTS: Statistically significant reduction of postinjection pain with nepafenac was noted 6 hours after the injection when compared with placebo (0.8 +/- 0.6 [standard deviation] vs. 1.3 +/- 0.8, P < 0.001) with similar trends at 1 hour (1.1 +/- 0.7 vs. 1.3 +/- 0.7, P = 0.12) and 24 hours (0.3 +/- 0.5 vs. 0.5 +/- 0.6, P = 0.15). CONCLUSION: A single drop of nepafenac is effective in reducing discomfort after intravitreal injections. PMID- 23928676 TI - Adaptive optics imaging of parafoveal cones in type 1 diabetes. AB - PURPOSE: To evaluate the parafoveal cone density in patients with Type 1 diabetes mellitus (DM1). METHODS: Adaptive optics retinal images of the photoreceptor mosaic were acquired from 11 DM1 patients (study group) and 11 age-matched healthy subjects (control group). Cone density was analyzed, along the horizontal and vertical meridian, at 230-um, 350-um, and 460-um eccentricity from the fovea. Central retinal thickness was measured using a Spectralis spectral-domain optical coherence tomography. A multiple regression model was performed to determine the relationships between the explanatory variables (age, glycohemoglobin level, presence of diabetic retinopathy, duration of diabetes, and central retinal thickness) and cone density. RESULTS: Patients had a diagnosis of DM1 in the past 9 years to 21 years. Of these, five patients had a diagnosis of no diabetic retinopathy and six had mild nonproliferative diabetic retinopathy. On average, cone density was 10% lower in the study than in the control group at each retinal eccentricity along the horizontal and vertical meridians (analysis of variance, P < 0.001). The central retinal thickness was thicker in DM1 eyes than in the control eyes (278 +/- 20 um and 260 +/- 13 um; P < 0.05). The model explained 61% (P < 0.01) of the variance of cone density in the population, with the variables representing an abnormal glucose metabolism, that is, a higher glycohemoglobin level, the presence of diabetic retinopathy, and a chronic diabetes, having the highest influence on cone density decline. CONCLUSION: A subtle decrease of parafoveal cone density was found in DM1 patients in comparison with age-matched control subjects via high-resolution adaptive optics retinal imaging. The cone density decline was moderately associated with a disturbance in the glucose metabolism. PMID- 23928677 TI - Clinical course of vitreomacular adhesion managed by initial observation. AB - PURPOSE: The purpose of the study was to investigate the clinical course of patients with idiopathic vitreomacular adhesion (VMA). METHODS: A noncomparative case series of patients who had clinical symptoms and spectral-domain optical coherence tomography findings consistent with VMA. The VMA was graded based on the optical coherence tomography findings at initial and follow-up examinations. Grade 1 was incomplete cortical vitreous separation with attachment at the fovea, Grade 2 was the Grade 1 findings and any intraretinal cysts or clefts, and Grade 3 was the Grade 2 findings and the presence of subretinal fluid. RESULTS: One hundred and six eyes of 81 patients were identified as having VMA by spectral domain optical coherence tomography at 3 retina clinics. The mean age was 73 years and the mean time of follow-up was 23 months. Forty-three eyes (41%) had Grade 1 VMA, 56 eyes (52%) had Grade 2 VMA, and 7 eyes (7%) had Grade 3 VMA. By the last follow-up, spontaneous release of VMA occurred in 34 eyes (32%), and pars plana vitrectomy was performed in 5 eyes (4.7%). Mean best-corrected visual acuity was 0.269 logarithm of the minimum angle of resolution or 20/37 at baseline (range, 20/20-20/200) and logarithm of the minimum angle of resolution 0.251 or 20/35 at the last examination (range, 20/20-20/400). CONCLUSION: In this selected patient cohort with mild symptoms, the clinical course of patients with VMA managed by initial observation was generally favorable. PMID- 23928678 TI - Focal chorioretinitis in Thailand. AB - PURPOSE: To report the clinical features of patients with focal chorioretinitis (FCR), as well as toxoplasma serology. METHODS: We included 25 (4%) consecutive patients with FCR of 593 with uveitis. Controls consisted of 127 patients with posterior and panuveitis and clinical features other than FCR. Results of enzyme linked immunosorbent assay for anti-Toxoplasma gondii immunoglobulin G (IgG) and IgM, demographic data, and clinical features of patients were registered. RESULTS: Positive anti-T. gondii IgG levels were observed in 21 of 25 patients (84%) with FCR in contrast to 14 of 127 patients (11%) with non-FCR (P < 0.001, Fisher test). The IgG levels >600 IU were found in 19 of 25 patients (76%) with FCR and in none of the patients with non-FCR (P < 0.001). All cases had unilateral involvement. Ocular features consisting of FCR and vitritis were present in all patients, but associated chorioretinal atrophic scars were not commonly seen (7/25 eyes; 28%). Retinal vasculitis was found in 9 of 25 eyes (36%) and affected solely the arteries. CONCLUSION: The majority of patients with FCR in Thailand exhibit highly positive anti-T. gondii IgG levels suggesting the presence of active systemic infection, which is also consistent with the absence of old scars. The absence of old scars and retinal arteritis were the features distinct from typical ocular toxoplasmosis lesions reported in the European and the U.S. series. PMID- 23928681 TI - Effects of surfactants on electrochemically prepared Ag nanostructures. AB - The morphology and corrosion behavior of electrochemically prepared Ag nanostructures (NSs) have been examined in the absence and presence of potassium citrate, polyvinylpyrrolidone (PVP) and polyoxyethylene(20) sorbitan monolaurate (Tween-20). These additives give rise to morphologically distinct Ag NSs. The presence of citrate increases the dissolution of Ag and creates finer nanostructured Ag surfaces with more cavities, while Tween-20 protects the Ag surface against corrosion in alkaline solution and generates spherical non-packed nanofeatured Ag surfaces. PMID- 23928680 TI - Stepwise acetyltransferase association and histone acetylation at the Myod1 locus during myogenic differentiation. AB - While chromatin modifications can offer a useful readout for enhancer activities, it is less clear whether these modification marks are a cause or consequence of transcription factor occupancy and enhancer activation. We have examined in details the temporal events of acetyltransferase associations and histone acetylations at different regulatory regions of the Myod1 locus. Our studies demonstrate that the histone acetyltransferase (HAT) p300 is stepwise enriched at distinct Myod1 regulatory regions during myogenic differentiation. This enrichment of p300 is associated with increased histone acetylation in a discrete pattern. Inhibition of p300 HAT activity impedes myogenic differentiation, which is coupled with decreased histone acetylation at specific Myod1 regulatory regions. We show for the first time that p300 is directly involved in the early regulation of Myod1 enhancer, and provide molecular insights into how p300 HAT activity and histone acetylation are related to enhancer activation and, consequently, gene transcription. PMID- 23928682 TI - Vegetarian diets in cardiovascular prevention. AB - OPINION STATEMENT: There is growing evidence that consumption of a vegetarian diet as well as specific components of a vegetarian diet lower the incidence of cardiovascular disease (CVD) and death. Vegetarian diets lower the probability of developing CVD, are effective in altering serum lipids, are beneficial in reducing blood pressure, improve glycemic control and insulin sensitivity, reduce weight, and lower mortality. Vascular effects of a vegetarian diet include a thinner carotid IMT and lower brachial artery resistance. Health care providers should be aware of the types of vegetarian diets and their risks and benefits in order to guide patients' dietary habits with the ultimate goal of reducing their CVD risk. While a patient does not have to become a complete vegetarian to reduce their CVD risk, they can make simple changes in their diet that are effective in risk reduction. PMID- 23928683 TI - Encoding of the amplitude modulation of pulsatile electrical stimulation in the feline cochlear nucleus by neurons in the inferior colliculus; effects of stimulus pulse rate. AB - OBJECTIVES: Persons without a functional auditory nerve cannot benefit from cochlear implants, but some hearing can be restored by an auditory brainstem implant (ABI) with stimulating electrodes implanted on the surface of the cochlear nucleus (CN). Most users benefit from their ABI, but speech recognition tends to be poorer than for users of cochlear implants. Psychophysical studies suggest that poor modulation detection may contribute to the limited performance of ABI users. In a cat model, we determined how the pulse rate of the electrical stimulus applied within or on the CN affects temporal and rate encoding of amplitude modulation (AM) by neurons in the central nucleus of the inferior colliculus (ICC). APPROACH: Stimulating microelectrodes were implanted chronically in and on the cats' CN, and multi-site recording microelectrodes were implanted chronically into the ICC. Encoding of AM pulse trains by neurons in the ICC was characterized as vector strength (VS), the synchrony of neural activity with the AM, and as the mean rate of neuronal action potentials (neuronal spike rate (NSR)). MAIN RESULTS: For intranuclear microstimulation, encoding of AM as VS was up to 3 dB greater when stimulus pulse rate was increased from 250 to 500 pps, but only for neuronal units with low best acoustic frequencies, and when the electrical stimulation was modulated at low frequencies (10-20 Hz). For stimulation on the surface of the CN, VS was similar at 250 and 500 pps, and the dynamic range of the VS was reduced for pulse rates greater than 250 pps. Modulation depth was encoded strongly as VS when the maximum stimulus amplitude was held constant across a range of modulation depth. This 'constant maximum' protocol allows enhancement of modulation depth while preserving overall dynamic range. However, modulation depth was not encoded as strongly as NSR. SIGNIFICANCE: The findings have implications for improved sound processors for present and future ABIs. The performance of ABIs may benefit from using pulse rates greater than those presently used in most ABIs, and by sound processing strategies that enhance the modulation depth of the electrical stimulus while preserving dynamic range. PMID- 23928684 TI - Effectiveness and safety of doxorubicin loaded beads in hepatocellular carcinoma. AB - BACKGROUND: Transarterial chemoembolization using microspheres is a new treatment option for patients with hepatocellular carcinoma. OBJECTIVE: To assess the effectiveness of this technique, in terms of tumor response and overall survival rates, and to assess the procedure's safety. SETTING: A General University Hospital in Spain. METHODS: Single-center retrospective observational study. The cohort included all patients treated between October 2006 and April 2010. Effectiveness was determined by the tumor response rate (using modified RECIST and EASL criteria) and overall survival. Safety was assessed according to the Common Terminology Criteria for Adverse Events. MAIN OUTCOME MEASURE: Tumor response rate, overall survival and safety of transarterial chemoembolization in patients with hepatocellular carcinoma. RESULTS: 53 patients were treated (81.1 % men, median age 65). Baseline characteristics 98.1 % had cirrhosis, 75.5 % Child Pugh Class A, 71.7 % Okuda I, and 94.3 % were ECOG 0. 43.4 % were waiting for a liver transplant and 56.6 % were given the treatment as a palliative measure. Eighty-one procedures were carried out, with a median of 1 per patient [1-5]. Four weeks after treatment, the objective response rate was 87.5 % and the complete response rate was 62.5 %. Median survival was 735 days (CI 95 %: 351.9 1118.1). The 1, 2 and 3-year overall survival rates were 65.4, 50.9 and 42.5 %, respectively. 71.7 % of patients experienced post-embolization syndrome, with grade 1 abdominal pain as the most frequent symptom (37.7 %). CONCLUSION: This study provides new evidence of the safety and effectiveness of transarterial chemoembolization using doxorubicin-loaded microspheres for the treatment of hepatocellular carcinoma in patients who are not eligible for other treatments, or as a bridging treatment in patients on the liver transplant waiting list. PMID- 23928686 TI - Environmentally friendly ionic liquid-in-water microemulsions for extraction of hydrophilic and lipophilic components from Flos Chrysanthemi. AB - Ionic liquids (ILs) have numerous chemical applications as environmentally green solvents that are extending into microemulsion applications. In this work, a novel benign IL-in-water microemulsion system modified by an IL surfactant has been proposed for simultaneous extraction of hydrophilic and lipophilic constituents from Flos Chrysanthemi (Chrysanthemum morifolium). Constituents were analyzed by rapid-resolution liquid chromatography coupled with quadrupole time of-flight mass spectrometry. A mixture-design approach was used to optimize the IL surfactant and the IL oil phase in the microemulsion system. Microemulsions consisting of 6.0% 1-dodecyl-3-methylimidazolium hydrogen sulfate, 0.1% 1-vinyl-3 methylimidazolium hexafluorophosphate and 93.9% water offered the acceptable extract efficiency that are comparable to or even better than conventional volatile organic solvents. This assay was fully validated with respect to the linearity of response (r(2) > 0.999 over two orders of magnitude), precision (intra-RSD < 0.49 and inter-day RSD < 2.21), and accuracy (recoveries ranging from 93.73% to 101.84%). The proposed IL-in-water microemulsion method provided an environmentally friendly alternative for efficient extraction of compounds from Flos Chrysanthemi and could be extended to complex environmental and pharmaceutical samples. PMID- 23928687 TI - [Anesthesiological management of Gitelman syndrome : Teaching example on physiology and pathophysiology of electrolyte balance]. AB - Gitelman syndrome is a rare autosomal recessive inherited disease that affects the thiazide-sensitive sodium chloride cotransport channels and the magnesium channels of the distal renal tubuli. Characteristic features are hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria. This case report presents the anesthesiological management of the Gitelman syndrome. The article demonstrates the pathophysiology, symptoms, diagnosis and therapy of this disease from the anesthesiologists point of view. PMID- 23928688 TI - Distance dependence of hole transfer rates from G radical cations to GGG traps in DNA. AB - Relative reaction rates for hole transfer between G radical cations and GGG triplets in DNA, through different bridges of varying lengths, are numerically calculated and the obtained results are compared with corresponding experimental observations [Giese et al., 2001, Nature, 412, 318; Angew. Chem., Int. Ed., 1999, 38, 996]. Hole donors and acceptors are separated either by (T-A)n bridges or by N repeated barriers consisting of (T-A,T-A) double base-pairs which are connected through single G-C base-pairs. In the former case, hole transfer rates show a strong exponential decrease with the length of the bridge for short bridges, while a switching to weak distance dependence has been observed for longer bridges. In the latter case, a power law seems to better describe the distance dependence of charge transfer rates. All these experimental observations are qualitatively reproduced by our simulations without any adjustable parameter, considering only tunneling as the charge transfer mechanism. Physical insights into the mechanism providing the switching behavior in the case of (T-A)n bridges are presented through an analysis of the eigenfunctions of the system. PMID- 23928689 TI - Stereoselective metal-free catalytic synthesis of chiral trifluoromethyl aryl and alkyl amines. AB - The enantioselective organocatalytic reduction of trifluoromethyl aryl and alkyl ketoimines afforded the corresponding fluorinated amines with high chemical and stereochemical efficiency. The Lewis base catalyzed reaction with trichlorosilane led to chiral products with a trifluoromethyl group directly linked to the newly generated stereocenter typically in >90% yield and up to 98% e.e. PMID- 23928690 TI - Nickel-catalyzed hydrogenolysis of unactivated carbon-cyano bonds. AB - Selective hydrogenolysis of C-CN bonds can allow chemists to take advantage of ortho-directing ability, alpha-C-H acidity and electron withdrawing ability of the cyano group for synthetic manipulations. We have discovered hydrogenolysis of aryl and aliphatic cyanides under just 1 bar of hydrogen by using a nickel catalyst. This protocol was applied in the aryl cyanide directed functionalization reaction and alpha-substitution of benzyl cyanides. PMID- 23928691 TI - Chronic treatment with coenzyme Q10 reverses restraint stress-induced anhedonia and enhances brain mitochondrial respiratory chain and creatine kinase activities in rats. AB - Several recent studies suggest a close link between mitochondrial dysfunction and depression. Coenzyme Q10 (CoQ10) is a mobile electron carrier in the mitochondrial respiratory chain (MRC) with antioxidant and potential neuroprotective activities. This study investigated the effect of chronic administration of CoQ10 (50, 100, and 200 mg/kg/day, intraperitoneally, for 4 weeks) on anhedonia and on the activities of MRC complexes and creatine kinase in the frontal cortex and hippocampus of Wistar rats subjected to chronic restraint stress (CRS, 6 h * 28 days). Exposure to CRS-induced anhedonic-like behavior (decreased sucrose preference), reduced body weight gain and food intake, increased adrenal gland weight, and altered the activity of the MRC complexes in the brain areas tested. CoQ10 dose-dependently antagonized CRS-induced depressive behavior by increasing sucrose preference (reversal of anhedonia), body weight, and food intake and reducing adrenal gland weight. CoQ10 also enhanced the activities of MRC complexes (I-IV) and creatine kinase in the frontal cortex and hippocampus. Thus, the reversal of CRS-induced anhedonia may be partially mediated by amelioration of brain mitochondrial function. The findings also support the hypothesis that brain energy impairment is involved in the pathophysiology of depression and enhancing mitochondrial function could provide an opportunity for development of a potentially more efficient drug therapy for depression. PMID- 23928692 TI - Contribution of NMDA glutamate and nicotinic acetylcholine receptor mechanisms in the discrimination of ethanol-nicotine mixtures. AB - Ethanol and nicotine are commonly coabused drugs, and the incidence of codependence is greater than would be expected on the basis of the summed probability of dependence on each drug alone. Previous findings from our laboratory and others suggest that interactive mechanisms at the level of discriminative stimulus (S(D)) effects may contribute to this coabuse phenomenon. Specifically, ethanol overshadows the nicotine S(D) whereas nicotine potentiates the stimulus salience of ethanol when the two drugs are conditioned as a drug mixture. The goal of the current study was to begin to delineate the pharmacological bases of these ethanol-nicotine interactions. Three groups of C57BL/6J mice were trained to discriminate 0.8 mg/kg nicotine + 0.5 g/kg ethanol (0.8 N + 0.5 E), 0.8 N + 1.0 E, or 0.8 N + 2.0 E. An NMDA receptor antagonist (MK 801) and three nACh receptor ligands were tested for their ability to generalize from or antagonize, respectively, the drug mixtures. MK-801 fully generalized from the 0.8 N + 1.0 E and 0.8 N + 2.0 E mixtures and partially generalized from 0.8 N + 0.5 E. In contrast, nACh receptor ligands had minimal influence in blocking the perception of 0.8 N + 1.0 E and 0.8 N + 2.0 E mixtures, and only mecamylamine partially blocked 0.8 N+0.5 E. Reduced and enhanced contributions of nACh and NMDA receptors, respectively, in the discrimination of ethanol-nicotine mixtures may contribute to the overshadowing and potentiation phenomena observed previously. PMID- 23928693 TI - Phencyclidine decreases tickling-induced 50-kHz ultrasound vocalizations in juvenile rats: a putative model of the negative symptoms of schizophrenia? AB - The objective of the present study was to examine the idea that the decrease in 50-kHz ultrasonic vocalizations elicited by tickling in juvenile rats following the administration of the psychotomimetic drug phencyclidine (PCP) may represent a valid model of the negative symptoms of schizophrenia. Fifty-kilohertz calls in rodents have been suggested to represent an archaic model of human laughter. Our results showed that daily tickling sessions produced a gradual increase in 50-kHz vocalizations, an effect that reached statistical significance from day 3. Administration of PCP (1 mg/kg, intraperitoneally) attenuated the 50-kHz calls induced by 4 consecutive days of tickling. The ability of several clinically effective or potential antipsychotics to reverse the effects of PCP was investigated. The 5-HT1A receptor partial agonist, buspirone (0.3 and 1 mg/kg, intraperitoneally), the dual D2/5-HT1A receptor ligand, SSR181507 (0.5-0.75 mg/kg, intraperitoneally), but not the atypical antipsychotic, aripiprazole (0.1 1 mg/kg, intraperitoneally), the 5-HT2A receptor antagonist, eplivanserin (0.3-3 mg/kg, intraperitoneally), and the GlyT1 inhibitor, SSR103800 (0.3-3 mg/kg, intraperitoneally) significantly attenuated the effects of PCP on 50-kHz calls. Importantly, in animals not treated with PCP, none of the drugs affected 50-kHz calls elicited by a first handling-tickling session, indicating that the action of buspirone and SSR181507 cannot be explained by an intrinsic effect. To investigate further the specificity of these drug effects, we tested the anxiolytic and antidepressant agents, diazepam (0.1-1 mg/kg, intraperitoneally) and fluoxetine (1-10 mg/kg, intraperitoneally), respectively, in this procedure. Neither drug affected tickling-induced 50-kHz calls in naive or PCP-treated rats. In conclusion, the results of the present study confirm that 50-kHz calls elicited by several tickling sessions in rats can be reduced by acute administration of PCP, and that this effect can be reversed by previous administration of compounds with 5-HT1A receptor agonist properties. As evidence for clinical efficacy of both agents on the negative symptoms of schizophrenia is weak or lacking, the current findings do not allow a definite conclusion to be drawn on the validity of this procedure as a model of this aspect of schizophrenia. PMID- 23928694 TI - Early methyl donor deficiency may induce persistent brain defects by reducing Stat3 signaling targeted by miR-124. AB - The methyl donors folate (vitamin B9) and vitamin B12 are centrepieces of the one carbon metabolism that has a key role in transmethylation reactions, and thus in epigenetic and epigenomic regulations. Low dietary intakes of folate and vitamin B12 are frequent, especially in pregnant women and in the elderly, and deficiency constitutes a risk factor for various diseases, including neurological and developmental disorders. In this respect, both vitamins are essential for normal brain development, and have a role in neuroplasticity and in the maintenance of neuronal integrity. The consequences of a methyl donor deficiency (MDD) were studied both in vivo in rats exposed in utero, and in vitro in hippocampal progenitors (H19-7 cell line). Deficiency was associated with growth retardation at embryonic day 20 (E20) and postnatally with long-term brain defects in selective areas. mRNA and protein levels of the transcription factor Stat3 were found to be decreased in the brains of deprived fetuses and in differentiating progenitors (62 and 48% for total Stat3 protein, respectively), along with a strong reduction in its phosphorylation at both Tyr705 and Ser727 residues. Vitamin shortage also affected upstream kinases of Stat3 signaling pathway (phospho-Erk1/2, phospho-Src, phospho-JNK, and phospho-p38) as well as downstream target gene products (Bcl-2 and Bcl-xL), thus promoting apoptosis. Conversely, the expression of the Stat3 regulator miR-124 was upregulated in deficiency conditions (>=65%), and its silencing by using siRNA partly restored Stat3 signaling in hippocampal neurons by increasing specifically the phosphorylation of Erk1/2 and Src kinases. Furthermore, miR-124 siRNA improved the phenotype of deprived cells, with enhanced neurite outgrowth. Taken together, our data suggest that downregulation of Stat3 signaling by miR-124 would be a key factor in the deleterious effects of MDD on brain development. PMID- 23928695 TI - Concurrent inhibition of enzymatic activity and NF-Y-mediated transcription of Topoisomerase-IIalpha by bis-DemethoxyCurcumin in cancer cells. AB - Topoisomerases-IIalpha (TOP2A) enzyme is essential for cell viability due to its fundamental role in DNA metabolism and in chromatin organization during interphase and mitosis. TOP2A expression is finely regulated at the transcriptional level through the binding of the CCAAT-transcription factor NF-Y to its promoter. Overexpression and/or amplification of TOP2A have been observed in many types of cancers. For this reason, TOP2A is the target of the most widely successful drugs in cancer chemotherapy, such as TOP2A poisons, which stabilize TOP2A-DNA cleavage complexes and create DSBs, leading to chromosome damage and cell death. We previously reported that the Curcumin-derivative bis DemethoxyCurcumin (bDMC) is an anti-proliferative agent that inhibits cell growth by concomitant G1/S and G2/M arrest. Here we showed that bDMC irreversibly induces DSBs in cancer cells, but not in normal cells, by targeting TOP2A activity and expression. TOP2A ablation by siRNA corroborates its contribution to apoptosis induced by bDMC. Short-term exposure to bDMC induces retention of TOP2A DNA intermediates, while longer exposure inhibits TOP2A transcription by affecting expression and sub-cellular localization of NF-Y subunits. ChIP analysis highlighted reduced recruitment of NF-Y to TOP2A regulatory regions, concomitantly to histone deacetylation and decreased gene transcription. Our findings suggest that the dual activity of bDMC on TOP2A represents a novel therapeutic strategy to induce persistent apoptosis in cancer cells and identify NF-Y regulation as a promising approach in anti-cancer therapy. PMID- 23928696 TI - BRCC2 inhibits breast cancer cell growth and metastasis in vitro and in vivo via downregulating AKT pathway. AB - In our previous study, we demonstrated that the BRCC2 (breast cancer cell 2) gene is a proapoptotic molecule that interacts with Bcl-X(L). BRCC2 downregulation is associated with poor disease-free and overall survival in breast cancer. In this study, we aimed to investigate the role of BRCC2 in tumor suppression in breast cancer. In clinical breast cancer samples, we found that BRCC2 expression was significantly downregulated in cancer lesions compared with paired normal breast tissues. By silencing or overexpressing BRCC2 in breast cancer cells, we found that BRCC2 could inhibit cell growth and metastasis in vitro. An in vivo assay showed that BRCC2 not only dramatically inhibited breast cancer cell xenograft formation and growth but also inhibited breast cancer cell metastasis in a lung metastasis model. Moreover, we demonstrated that BRCC2 inhibited breast cancer metastasis via regulation of the Akt pathway. Thus, our study provided evidence that BRCC2 functions as a novel tumor suppressor in breast cancer and may be a potential therapeutic target for breast cancer management. PMID- 23928697 TI - Differential regulation of cell death programs in males and females by Poly (ADP Ribose) Polymerase-1 and 17beta estradiol. AB - Cell death can be divided into the anti-inflammatory process of apoptosis and the pro-inflammatory process of necrosis. Necrosis, as apoptosis, is a regulated form of cell death, and Poly-(ADP-Ribose) Polymerase-1 (PARP-1) and Receptor Interacting Protein (RIP) 1/3 are major mediators. We previously showed that absence or inhibition of PARP-1 protects mice from nephritis, however only the male mice. We therefore hypothesized that there is an inherent difference in the cell death program between the sexes. We show here that in an immune-mediated nephritis model, female mice show increased apoptosis compared to male mice. Treatment of the male mice with estrogens induced apoptosis to levels similar to that in female mice and inhibited necrosis. Although PARP-1 was activated in both male and female mice, PARP-1 inhibition reduced necrosis only in the male mice. We also show that deletion of RIP-3 did not have a sex bias. We demonstrate here that male and female mice are prone to different types of cell death. Our data also suggest that estrogens and PARP-1 are two of the mediators of the sex-bias in cell death. We therefore propose that targeting cell death based on sex will lead to tailored and better treatments for each gender. PMID- 23928698 TI - Skp-cullin-F box E3 ligase component FBXL2 ubiquitinates Aurora B to inhibit tumorigenesis. AB - Aurora B kinase is an integral regulator of cytokinesis, as it stabilizes the intercellular canal within the midbody to ensure proper chromosomal segregation during cell division. Here we identified that the ubiquitin E3 ligase complex SCF(FBXL2) mediates Aurora B ubiquitination and degradation within the midbody, which is sufficient to induce mitotic arrest and apoptosis. Three molecular acceptor sites (K102, K103 and K207) within Aurora B protein were identified as important sites for its ubiquitination. A triple Lys mutant of Aurora B (K102/103/(207R)) exhibited optimal resistance to SCF(FBXL2)-directed polyubiquitination, and overexpression of this variant resulted in a significant delay in anaphase onset, resulting in apoptosis. A unique small molecule F box/LRR-repeat protein 2 (FBXL2) activator, BC-1258, stabilized and increased levels of FBXL2 protein that promoted Aurora B degradation, resulting in tetraploidy, mitotic arrest and apoptosis of tumorigenic cells, and profoundly inhibiting tumor formation in athymic nude mice. These findings uncover a new proteolytic mechanism targeting a key regulator of cell replication that may serve as a basis for chemotherapeutic intervention in neoplasia. PMID- 23928699 TI - OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway. AB - Octamer-binding transcription factor 4 (OCT4) is a key regulatory gene that maintains the pluripotency and self-renewal properties of embryonic stem cells. Although there is emerging evidence that it can function as oncogene in several cancers, the role in mediating cervical cancer remains unexplored. Here we found that OCT4 protein expression showed a pattern of gradual increase from normal cervix to cervical carcinoma in situ and then to invasive cervical cancer. Overexpression of OCT4 in two types of cervical cancer cells promotes the carcinogenesis, and inhibits cancer cell apoptosis. OCT4 induces upregulation of miR-125b through directly binding to the promoter of miR-125b-1 confirmed by chromatin immunoprecipitation analysis. MiRNA-125b overexpression suppressed apoptosis and expression of BAK1 protein. In contrast, miR-125b sponge impaired the anti-apoptotic effect of OCT4, along with the upregulated expression of BAK1. Significantly, Luciferase assay showed that the activity of the wild-type BAK1 3' untranslated region reporter was suppressed and this suppression was diminished when the miR-125b response element was mutated or deleted. In addition, we observed negative correlation between levels of BAK1 and OCT4, and positive between OCT4 and miR-125b in primary cervical cancers. These findings suggest an undescribed regulatory pathway in cervical cancer, by which OCT4 directly induces expression of miR-125b, which inhibits its direct target BAK1, leading to suppression of cervical cancer cell apoptosis. PMID- 23928700 TI - Marchantin M: a novel inhibitor of proteasome induces autophagic cell death in prostate cancer cells. AB - We previously reported that marchantin M (Mar) is an active agent to induce apoptosis in human prostate cancer (PCa), but the molecular mechanisms of action remain largely unknown. Here, we demonstrate that Mar potently inhibited chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing activities of 20S proteasome both in in vitro and intracellular systems and significantly induced the accumulation of polyubiquitinated proteins in PCa cells. The computational modeling analysis suggested that Mar non-covalently bound to active sites of proteasome beta5 and beta1 subunits, resulting in a non-competitive inhibition. Proteasome inhibition by Mar subsequently resulted in endoplasmic reticulum (ER) stress, as evidenced by elevated glucose-regulated protein 78 and CHOP, increased phospho-eukaryotic translation initiation factor 2alpha (eIF(2alpha)), splicing of X-box-binding protein-1 and dilation of the ER. However, Mar-mediated cell death was not completely impaired by a pan inhibitor of caspases. Further studies revealed that the Mar-induced cell death was greatly associated with the activation of autophagy, as indicated by the significant induction of microtubule associated protein-1 light chain-3 beta (LC3B) expression and conversion. Electron microscopic and green fluorescent protein-tagged LC3B analyses further demonstrated the ability of autophagy induction by Mar. Time kinetic studies revealed that Mar induced a rapid and highly sustained processing of LC3B in treated cells and simultaneously decreased the expression of p62/SQSTM1. Pharmacological blockade or knockdown of LC3B and Atg5 attenuated Mar-mediated cell death. The autophagic response triggered by Mar required the activation of RNA-dependent protein kinase-like ER kinase/eIF(2alpha) and suppression of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin axis via preventing activation and expression of Akt. Our results identified a novel mechanism for the cytotoxic effect of Mar, which strengthens it as a potential agent in cancer chemotherapy. PMID- 23928701 TI - Malaria parasite liver stages render host hepatocytes susceptible to mitochondria initiated apoptosis. AB - Intracellular eukaryotic parasites and their host cells constitute complex, coevolved cellular interaction systems that frequently cause disease. Among them, Plasmodium parasites cause a significant health burden in humans, killing up to one million people annually. To succeed in the mammalian host after transmission by mosquitoes, Plasmodium parasites must complete intracellular replication within hepatocytes and then release new infectious forms into the blood. Using Plasmodium yoelii rodent malaria parasites, we show that some liver stage (LS) infected hepatocytes undergo apoptosis without external triggers, but the majority of infected cells do not, and can also resist Fas-mediated apoptosis. In contrast, apoptosis is dramatically increased in hepatocytes infected with attenuated parasites. Furthermore, we find that blocking total or mitochondria initiated host cell apoptosis increases LS parasite burden in mice, suggesting that an anti-apoptotic host environment fosters parasite survival. Strikingly, although LS infection confers strong resistance to extrinsic host hepatocyte apoptosis, infected hepatocytes lose their ability to resist apoptosis when anti apoptotic mitochondrial proteins are inhibited. This is demonstrated by our finding that B-cell lymphoma 2 family inhibitors preferentially induce apoptosis in LS-infected hepatocytes and significantly reduce LS parasite burden in mice. Thus, targeting critical points of susceptibility in the LS-infected host cell might provide new avenues for malaria prophylaxis. PMID- 23928702 TI - Brimonidine promotes axon growth after optic nerve injury through Erk phosphorylation. AB - It is well known that axons of the adult mammalian central nervous system have a very limited ability to regenerate after injury. Therefore, the neurodegenerative process of glaucoma results in irreversible functional deficits, such as blindness. Brimonidine (BMD) is an alpha2-adrenergic receptor agonist that is used commonly to lower intraocular pressure in glaucoma. Although it has been suggested that BMD has neuroprotective effects, the underlying mechanism remains unknown. In this study, we explored the molecular mechanism underlying the neuroprotective effect of BMD in an optic nerve injury (ONI) model. BMD treatment promoted optic nerve regeneration by inducing Erk1/2 phosphorylation after ONI. In addition, an Erk1/2 antagonist suppressed BMD-mediated axonal regeneration. A gene expression analysis revealed that the expression of the neurotrophin receptor gene p75 was increased and that the expression of the tropomyosin receptor kinase B (TrkB) gene was decreased after ONI. BMD treatment abrogated the changes in the expression of these genes. These results indicate that BMD promotes optic nerve regeneration via the activation of Erk1/2. PMID- 23928704 TI - Mammalian ncRNA-disease repository: a global view of ncRNA-mediated disease network. PMID- 23928703 TI - Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling. AB - Despite androgen deprivation therapy (ADT) suppression of prostate cancer (PCa) growth, its overall effects on PCa metastasis remain unclear. Using human (C4 2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells-macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion. In contrast, the AR degradation enhancer, ASC-J9, suppressed both macrophage migration and subsequent PCa cell invasion. Mechanism dissection showed that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression and enhanced the pSTAT3-CCL2 pathway. Addition of CCR2 antagonist reversed the Casodex/MDV3100-induced macrophage migration and PCa cell invasion. In contrast, ASC-J9 could regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation. These findings were confirmed in the in vivo mouse model with orthotopically injected TRAMP-C1 cells. Together, these results may raise the potential concern about the currently used ADT with anti-androgens that promotes PCa metastasis and may provide some new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage. PMID- 23928705 TI - Insulin concentration is critical in culturing human neural stem cells and neurons. AB - Cell culture of human-derived neural stem cells (NSCs) is a useful tool that contributes to our understanding of human brain development and allows for the development of therapies for intractable human brain disorders. Human NSC (hNSC) cultures, however, are not commonly used, mainly because of difficulty with consistently maintaining the cells in a healthy state. In this study, we show that hNSC cultures, unlike NSCs of rodent origins, are extremely sensitive to insulin, an indispensable culture supplement, and that the previously reported difficulty in culturing hNSCs is likely because of a lack of understanding of this relationship. Like other neural cell cultures, insulin is required for hNSC growth, as withdrawal of insulin supplementation results in massive cell death and delayed cell growth. However, severe apoptotic cell death was also detected in insulin concentrations optimized to rodent NSC cultures. Thus, healthy hNSC cultures were only produced in a narrow range of relatively low insulin concentrations. Insulin-mediated cell death manifested not only in all human NSCs tested, regardless of origin, but also in differentiated human neurons. The underlying cell death mechanism at high insulin concentrations was similar to insulin resistance, where cells became less responsive to insulin, resulting in a reduction in the activation of the PI3K/Akt pathway critical to cell survival signaling. PMID- 23928706 TI - Risk factors for and outcomes of detention of patients with TB in New York City: an update: 2002-2009. AB - BACKGROUND: One of the most controversial aspects of New York City's highly effective TB control program is the use of public health law and court-ordered detention to treat persistently recalcitrant patients with active TB. We now report on characteristics and outcomes of patients undergoing detention for completion of TB treatment due to nonadherence in New York City from 2002 through 2009. METHODS: A retrospective cohort study was designed to compare patients undergoing court-ordered detention (n = 79) and time-matched control subjects undergoing TB treatment in outpatient directly observed therapy (DOT) at Bellevue Hospital in New York City. RESULTS: From January 1, 2002, through December 31, 2009, 79 patients underwent court-ordered detention for TB treatment. Compared with patients completing treatment in DOT, univariate analysis found that detainees were younger; more likely to be of minority race/ethnicity; to have a history of substance abuse, tobacco use, homelessness, incarceration, HIV infection; and to be born in the United States. Multivariate analysis adjusting for other variables found smear positivity (OR = 3.93; 95% CI, 1.05-14.75; P = .04), mental illness (OR = 5.80; 95% CI, 1.18-28.51; P = .03), and substance abuse (OR = 9.25; 95% CI, 2.81-30.39; P < .01) to be the strongest independent predictors of likelihood of detention. Of those initially detained, 46 (58%) completed treatment during inpatient detention, 29(37%) completed treatment under outpatient court-ordered DOT, and four died during their hospitalization. CONCLUSIONS: The majority of patients undergoing court-ordered detention for TB treatment (95%) successfully completed therapy. Likelihood of detention was most strongly associated with factors expected to be associated with poor adherence, including mental illness and substance abuse. PMID- 23928708 TI - Editorial: our enthusiasm for "related research". PMID- 23928707 TI - Single-injection or continuous femoral nerve block for total knee arthroplasty? AB - BACKGROUND: The ideal local anesthetic regime for femoral nerve block that balances analgesia with mobility after total knee arthroplasty (TKA) remains undefined. QUESTIONS/PURPOSES: We compared two volumes and concentrations of a fixed dose of ropivacaine for continuous femoral nerve block after TKA to a single injection femoral nerve block with ropivacaine to determine (1) time to discharge readiness; (2) early pain scores and analgesic consumption; and (3) functional outcomes, including range of motion and WOMAC scores at the time of recovery. METHODS: Ninety-nine patients were allocated to one of three continuous femoral nerve block groups for this randomized, placebo-controlled, double-blind trial: a high concentration group (ropivacaine 0.2% infusion), a low concentration group (ropivacaine 0.1% infusion), or a placebo infusion group (saline 0.9% infusion). Infusions were discontinued on postoperative Day (POD) 2. The primary outcome was time to discharge readiness. Secondary outcomes included opioid consumption, pain, and functional outcomes. Ninety-three patients completed the study protocol; the study was halted early because of unanticipated changes to pain protocols at the host institution, by which time only 61% of the required number of patients had been enrolled. RESULTS: With the numbers available, the mean time to discharge readiness was not different between groups (high concentration group, 62 hours [95% confidence interval [CI], 51-72 hours]; low concentration group, 73 hours [95% CI, 63-83 hours]; placebo infusion group 65 hours [95% CI, 56-75 hours]; p = 0.27). Patients in the low concentration group consumed significantly less morphine during the period of infusion (POD 1, high concentration group, 56 mg [95% CI, 42-70 mg]; low concentration group, 35 mg [95% CI, 27-43 mg]; placebo infusion group, 48 mg [95% CI, 38-59 mg], p = 0.02; POD 2, high concentration group, 50 mg [95% CI, 41-60 mg]; low concentration group, 33 mg [95% CI, 24-42 mg]; placebo infusion group, 39 mg [95% CI, 30-48 mg], p = 0.04); however, there were no important differences in pain scores or opioid-related side effects with the numbers available. Likewise, there were no important differences in functional outcomes between groups. CONCLUSIONS: Based on this study, which was terminated prematurely before the desired sample size could be achieved, we were unable to demonstrate that varying the concentration and volume of a fixed-dose ropivacaine infusion for continuous femoral nerve block influences time to discharge readiness when compared with a conventional single-injection femoral nerve block after TKA. A low concentration of ropivacaine infusion can reduce postoperative opioid consumption but without any important differences in pain scores, side effects, or functional outcomes. These pilot data may be used to inform the statistical power of future randomized trials. LEVEL OF EVIDENCE: Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23928709 TI - Editor's spotlight/take 5: longitudinal urban-rural discrepancies in the US orthopaedic surgeon workforce. Interview by Seth S. Leopold. PMID- 23928710 TI - CORR Insights (r): Bariatric orthopaedics: total knee arthroplasty in super-obese patients (BMI > 50 kg/m2). Survivorship and complications. PMID- 23928711 TI - Unplanned hip arthroplasty imposes clinical and cost burdens on treating institutions. AB - BACKGROUND: Emergent surgery has been shown to be a risk factor for perioperative complications. Studies suggest that patient morbidity is greater with an unplanned hip arthroplasty, although it is controversial whether unplanned procedures also result in higher patient mortality. The financial impact of these procedures is not fully understood, as the costs of unplanned primary hip arthroplasties have not been studied previously. QUESTIONS/PURPOSES: We asked: (1) What are the institutional costs associated with unplanned hip arthroplasties (primary THA, hemiarthroplasty, revision arthroplasty, including treatment of periprosthetic fractures, dislocations, and infections)? (2) Does timing of surgery (urgent/unplanned versus elective) influence perioperative outcomes such as mortality, length of stay, or need for advanced care? (3) What diagnoses are associated with unplanned surgery and are treated urgently most often? (4) Do demographics and insurance status differ between admission types (unplanned versus elective hip arthroplasty)? METHODS: We prospectively followed all 419 patients who were admitted to our Level I trauma center in 2011 for procedures including primary THA, hemiarthroplasty, and revision arthroplasty, including the treatment of periprosthetic fractures, dislocations, and infections. Fifty-seven patients who were treated urgently on an unplanned basis were compared with 362 patients who were treated electively. Demographics, admission diagnoses, complications, and costs were recorded and analyzed statistically. RESULTS: Median total costs were 24% greater for patients admitted for unplanned hip arthroplasties (USD 18,206 [USD 15,261-27,491] versus USD 14,644 [USD 13,511 16,309]; p < 0.0001) for patients admitted for elective arthroplasties. Patients with unplanned admissions had a 67% longer median hospital stay (5 days [range, 4 9 days] versus 3 days [range, 3-4 days]; p < 0.0001) for patients with elective admissions. Mortality rates were equivalent between groups (p = 1.0). Femoral fracture (p < 0.0001), periprosthetic fracture (p = 0.01), prosthetic infection (p = 0.005), and prosthetic dislocation (p < 0.0001) were observed at higher rates in the patients with unplanned admissions. These patients were older (p = 0.04), less likely to have commercial insurance (p < 0.0001), more likely to be transferred from another institution (p < 0.0001), and more likely to undergo a revision procedure (p < 0.0001). CONCLUSIONS: Unplanned arthroplasty and urgent surgery are associated with increased financial and clinical burdens, which must be accounted for when considering bundled quality and reimbursement measures for these procedures. PMID- 23928712 TI - Imaging for suspected colorectal cancer in frail and elderly patients. PMID- 23928713 TI - Quantum corrections crossover and ferromagnetism in magnetic topological insulators. AB - Revelation of emerging exotic states of topological insulators (TIs) for future quantum computing applications relies on breaking time-reversal symmetry and opening a surface energy gap. Here, we report on the transport response of Bi2Te3 TI thin films in the presence of varying Cr dopants. By tracking the magnetoconductance (MC) in a low doping regime we observed a progressive crossover from weak antilocalization (WAL) to weak localization (WL) as the Cr concentration increases. In a high doping regime, however, increasing Cr concentration yields a monotonically enhanced anomalous Hall effect (AHE) accompanied by an increasing carrier density. Our results demonstrate a possibility of manipulating bulk ferromagnetism and quantum transport in magnetic TI, thus providing an alternative way for experimentally realizing exotic quantum states required by spintronic applications. PMID- 23928714 TI - Perioperative complications and mortality after spinal fusions: analysis of trends and risk factors. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To analyze the trends in complications and mortality after spinal fusions. SUMMARY OF BACKGROUND DATA: Utilization of spinal fusions has been increasing during the past decade. It is essential to evaluate surgical outcomes to better identify patients who benefit most from surgical intervention. Integration of empiric evidence from large administrative databases into clinical decision making is instrumental in providing higher-quality, evidence-based, patient-centered care. METHODS: This study used Nationwide Inpatient Sample data from 2001 through 2010. Patients who underwent spinal fusions were identified using the CCS (Clinical Classifications Software) and ICD-9 (International Classification of Diseases, 9th Revision) codes. Data on patient comorbidities, primary diagnosis, and postoperative complications were obtained via ICD-9 diagnosis codes and via CCS categories. National estimates were calculated using weights provided as part of the database. Time trend analysis for average length of stay, total charges, mortality, and comorbidity burden was performed. Univariate and multivariate models were constructed to identify predictors of mortality and postoperative complications. RESULTS: An estimated 3,552,873 spinal fusions were performed in the United States between 2001 and 2010. The national bill for spinal fusions increased from $10 billion to $46.8 billion. Today, patients are older and have a greater comorbidity burden than 10 years ago. Mortality remained relatively constant at 0.46%, 1.2%, and 0.14% for cervical, thoracic, and lumbar fusions, respectively. Morbidity rates showed an increasing trend at all levels. Multivariate analysis of 19 procedures and patient-related risk factors and 9 perioperative complications identified 85 statistically significant (P< 0.01) interactions. CONCLUSION: The data on perioperative risks and risk factors for postoperative complications of spinal fusions presented in this study is pivotal to appropriate surgical patient selection and well-informed risk-benefit evaluation of surgical intervention. LEVEL OF EVIDENCE: N/A. PMID- 23928715 TI - Effectiveness of rocker sole shoes in the management of chronic low back pain: a randomized clinical trial. AB - STUDY DESIGN: Multicenter, assessor-blind, randomized, clinical trial. OBJECTIVE: To compare the effectiveness of rocker sole footwear to traditional flat sole footwear as part of the management for people with low back pain (LBP). SUMMARY OF BACKGROUND DATA: During the past decade, persistent advertising has claimed that footwear constructed with a rocker sole will reduce LBP. However, there is no robust evidence to support these claims. METHODS: One hundred fifteen people with chronic LBP were randomized to wear rocker sole shoes or flat sole shoes for a minimum of 2 hours each day while standing and walking. Primary outcome was the Roland Morris Disability Questionnaire (RMDQ). In addition, participants attended an exercise and education program once a week for 4 weeks and wore their assigned shoes during these sessions. Participants were assessed without their knowledge of group allocation prerandomization, and at 6 weeks, 6 months, and 1 year (main outcome point). Analysis was by intention-to-treat method. RESULTS: At 12 months, data from 44 of 58 (77.2%) of the rocker sole group and 49 of 57 (84.5%) of the flat sole group were available for analysis. In the rocker sole group, mean reduction in RMDQ was -3.1 (95% CI [confidence interval], -4.5 to -1.6), and in the flat sole group, it was -4.4 (95% CI, -5.8 to -3.1) (a greater negative value represents a greater reduction in disability). At 6 months, more people wearing flat shoes compared with those wearing rocker shoes demonstrated a minimal clinically important improvement in disability (53.2% and 31.1%, respectively; P = 0.03). Between-group differences were not significant for RMDQ or any secondary outcomes (e.g., pain) at any time. People reporting pain when standing and walking at baseline (n = 59) reported a greater reduction in RMDQ at 12 months in the flat sole group (-4.4 [95% CI, -6.0 to -2.8], n = 29) than the rocker sole group (-2.0 [95% CI, -3.6 to -0.4], n = 30) (P < 0.05). CONCLUSION: Rocker sole shoes seem to be no more beneficial than flat sole shoes in affecting disability and pain outcomes in people with chronic LBP. Flat shoes are more beneficial for LBP aggravated by standing or walking. LEVEL OF EVIDENCE: N/A. PMID- 23928716 TI - Early versus late initiation of rehabilitation after lumbar spinal fusion: economic evaluation alongside a randomized controlled trial. AB - STUDY DESIGN: Economic evaluation conducted alongside a randomized controlled trial with 1-year follow-up. OBJECTIVE: To examine the cost-effectiveness of initiating rehabilitation 6 weeks after surgery as opposed to 12 weeks after surgery. SUMMARY OF BACKGROUND DATA: In a previously reported randomized controlled trial, we assessed the impact of timing of rehabilitation after a lumbar spinal fusion and found that a fast-track strategy led to poorer functional ability. Before making recommendations, it seems relevant to address the societal perspective including return to work, quality of life, and costs. METHODS: A cost-effectiveness analysis and a cost-utility analysis were conducted. Eighty-two patients undergoing instrumented lumbar spinal fusion due to degenerative disc disease or spondylolisthesis (grade I or II) were randomized to an identical protocol of 4 sessions of group-based rehabilitation and were instructed in home exercises focusing on active stability training. Outcome parameters included functional disability (Oswestry Disability Index) and quality adjusted life years. Health care and productivity costs were estimated from national registries and reported in euros. Costs and effects were transformed into net benefit. Bootstrapping was used to estimate 95% confidence intervals (95% CI). RESULTS: The fast-track strategy tended to be costlier by ?6869 (95% CI, -4640 to 18,378) while at the same time leading to significantly poorer outcomes of functional disability by -9 points (95% CI, -18 to -3) and a tendency for a reduced gain in quality-adjusted life years by -0.04 (95% CI, -0.13 to 0.01). The overall probability for the fast-track strategy being cost-effective does not reach 10% at conventional thresholds for cost-effectiveness. CONCLUSION: Initiating rehabilitation at 6 weeks as opposed to 12 weeks after surgery is on average more costly and less effective. The uncertainty of this result did not seem to be sensitive to methodological issues, and clinical managements who have already adapted fast-track rehabilitation strategies have reason to reconsider their choice. . PMID- 23928717 TI - Suprachoroidal electrical stimulation: effects of stimulus pulse parameters on visual cortical responses. AB - OBJECTIVE: Neural responses to biphasic constant current pulses depend on stimulus pulse parameters such as polarity, duration, amplitude and interphase gap. The objective of this study was to systematically evaluate and optimize stimulus pulse parameters for a suprachoroidal retinal prosthesis. APPROACH: Normally sighted cats were acutely implanted with platinum electrode arrays in the suprachoroidal space. Monopolar stimulation comprised of monophasic and biphasic constant current pulses with varying polarity, pulse duration and interphase gap. Multiunit responses to electrical stimulation were recorded in the visual cortex. MAIN RESULTS: Anodal stimulation elicited cortical responses with shorter latencies and required lower charge per phase than cathodal stimulation. Clinically relevant retinal stimulation required relatively larger charge per phase compared with other neural prostheses. Increasing the interphase gap of biphasic pulses reduced the threshold of activation; however, the benefits of using an interphase gap need to be considered in light of the pulse duration and polarity used and other stimulation constraints. Based on our results, anodal first biphasic pulses between 300-1200 us are recommended for suprachoroidal retinal stimulation. SIGNIFICANCE: These results provide insights into the efficacy of different pulse parameters for suprachoroidal retinal stimulation and have implications for the design of safe and clinically relevant stimulators for retinal prostheses. PMID- 23928718 TI - Single, double or multiple-injection techniques for non-ultrasound guided axillary brachial plexus block in adults undergoing surgery of the lower arm. AB - BACKGROUND: Regional anaesthesia comprising axillary block of the brachial plexus is a common anaesthetic technique for distal upper limb surgery. This is an update of a review first published in 2006 and updated in 2011. OBJECTIVES: To compare the relative effects (benefits and harms) of three injection techniques (single, double and multiple) of axillary block of the brachial plexus for distal upper extremity surgery. We considered these effects primarily in terms of anaesthetic effectiveness; the complication rate (neurological and vascular); and pain and discomfort caused by performance of the block. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE and reference lists of trials. We contacted trial authors. The date of the last search was March 2013 (updated from March 2011). SELECTION CRITERIA: We included randomized controlled trials that compared double with single-injection techniques, multiple with single-injection techniques, or multiple with double-injection techniques for axillary block in adults undergoing surgery of the distal upper limb. We excluded trials using ultrasound-guided techniques. DATA COLLECTION AND ANALYSIS: Independent study selection, risk of bias assessment and data extraction were performed by at least two investigators. We undertook meta-analysis. MAIN RESULTS: The 21 included trials involved a total of 2148 participants who received regional anaesthesia for hand, wrist, forearm or elbow surgery. Risk of bias assessment indicated that trial design and conduct were generally adequate; the most common areas of weakness were in blinding and allocation concealment.Eight trials comparing double versus single injections showed a statistically significant decrease in primary anaesthesia failure (risk ratio (RR 0.51), 95% confidence interval (CI) 0.30 to 0.85). Subgroup analysis by method of nerve location showed that the effect size was greater when neurostimulation was used rather than the transarterial technique.Eight trials comparing multiple with single injections showed a statistically significant decrease in primary anaesthesia failure (RR 0.25, 95% CI 0.14 to 0.44) and of incomplete motor block (RR 0.61, 95% CI 0.39 to 0.96) in the multiple injection group.Eleven trials comparing multiple with double injections showed a statistically significant decrease in primary anaesthesia failure (RR 0.28, 95% CI 0.20 to 0.40) and of incomplete motor block (RR 0.55, 95% CI 0.36 to 0.85) in the multiple injection group.Tourniquet pain was significantly reduced with multiple injections compared with double injections (RR 0.53, 95% CI 0.33 to 0.84). Otherwise there were no statistically significant differences between groups in any of the three comparisons on secondary analgesia failure, complications and patient discomfort. The time for block performance was significantly shorter for single and double injections compared with multiple injections. AUTHORS' CONCLUSIONS: This review provides evidence that multiple-injection techniques using nerve stimulation for axillary plexus block produce more effective anaesthesia than either double or single injection techniques. However, there was insufficient evidence for a significant difference in other outcomes, including safety. PMID- 23928719 TI - Interaction of free-living marine nematodes in the artificial mangrove environment (Southeast Coast of India). AB - Free-living marine nematode diversity was analyzed between Avicennia marina and Rhizophora mucronata mangrove covers of the Vellar Estuary (southeast coast of India). A total of 4,976 specimens of free-living marine nematodes were collected in 56 species. Comparatively, a higher species richness was obtained for A. marina (52 species) than for R. mucronata (44 species), whereas 40 species commonly existed in both mangrove covers. A higher density of nematodes was found in sediments of sandy nature, whereas there was lower total organic carbon compared to silt/clay composition; epigrowth feeders were dominant over the other feeding groups based on organic enrichment in surface sediments. Principal component analysis clearly explained the relationship between the environmental parameters of various months. Higher R values of analysis of similarities revealed significant differences in nematode assemblages between months, and it was quite evident by non-metric multidimensional scaling. Diversity indices showed higher values in the dry months. RELATE analysis explained serial changes in nematode species composition between months, and a relationship between biotic and abiotic variables was clarified using the BIO-ENV procedure. Viscosia spp., Metachromadora spp., Theristus spp., and Sphaerolaimus spp. were candidate species of A. marina leaf interaction by observation. PMID- 23928721 TI - Bi-functional RuO2-Co3O4 core-shell nanofibers as a multi-component one dimensional water oxidation catalyst. AB - The core-shell structure of RuO2-Co3O4 fibers comprising the inner region of highly conductive RuO2 and the outer region of catalytic Co3O4 provided a fast and effective transport pathway for holes to O2-evolving sites, leading to a highly efficient water oxidation performance. PMID- 23928722 TI - Water-gas shift on gold catalysts: catalyst systems and fundamental studies. AB - Since the pioneering finding by Haruta et al. that small gold nanoparticles on reducible supports can be highly active for low-temperature CO oxidation, the synthesis, characterization, and application of supported gold catalysts have attracted much attention. The water-gas shift reaction (WGSR: CO + H2O = CO2 + H2) is important for removing CO and upgrading the purity of H2 for fuel cell applications, ammonia synthesis, and selective hydrogenation processes. In recent years, much attention has been paid to exploration the possibility of using supported gold nanocatalysts for WGSR and understanding the fundamental aspects related to catalyst deactivation mechanisms, nature of active sites, and reaction mechanisms. Here we summarize recent advances in the development of supported gold catalysts for this reaction and fundamental insights that can be gained, and furnish our assessment on the status of research progress. PMID- 23928723 TI - Characterization of two naturally truncated, Ssb-like proteins from the nitrogen fixing cyanobacterium, Anabaena sp. PCC7120. AB - Single-stranded (ss) DNA-binding (Ssb) proteins are vital for all DNA metabolic processes and are characterized by an N-terminal OB-fold followed by P/G-rich spacer region and a C-terminal tail. In the genome of the heterocystous, nitrogen fixing cyanobacterium, Anabaena sp. strain PCC 7120, two genes alr0088 and alr7579 are annotated as ssb, but the corresponding proteins have only the N terminal OB-fold and no P/G-rich region or acidic tail, thereby rendering them unable to interact with genome maintenance proteins. Both the proteins were expressed under normal growth conditions in Anabaena PCC7120 and regulated differentially under abiotic stresses which induce DNA damage, indicating that these are functional genes. Constitutive overexpression of Alr0088 in Anabaena enhanced the tolerance to DNA-damaging stresses which caused formation of DNA adducts such as UV and MitomycinC, but significantly decreased the tolerance to gamma-irradiation, which causes single- and double-stranded DNA breaks. On the other hand, overexpression of Alr7579 had no significant effect on normal growth or stress tolerance of Anabaena. Thus, of the two truncated Ssb-like proteins, Alr0088 may be involved in protection of ssDNA from damage, but due to the absence of acidic tail, it may not aid in repair of damaged DNA. These two proteins are present across cyanobacterial genera and unique to them. These initial studies pave the way to the understanding of DNA repair in cyanobacteria, which is not very well documented. PMID- 23928724 TI - [Update dyslipidemia]. AB - The treatment of dyslipidemia is a cornerstone of atherosclerosis prevention. Statin-based reduction of LDL cholesterol plays a central role in this context. Whether and to what extent other lipids such as triglycerides, HDL-cholesterol, lipoprotein(a) should also be addressed is still under discussion. However, in the treatment of hypertriglyceridemia and combined hyperlipoproteinemia, life style modification plays a significant role. Important issues are correct classification of the dyslipidemia, a LDL-cholesterol target based on the absolute risk of the patient, and a therapeutic strategy that also includes treatment of other risk factors. If statin therapy not sufficient to reach the treatment target, combination therapy with ezetimibe, bile acid binding substances, fibrates or omega-3 fatty acids should be discussed, considering the lipid profile, the overall risk, and potential side effects. Patients with severe LDL hypercholesterolemia or greatly elevated lipoprotein(a) levels should be considered for regular lipid apheresis if the cardiovascular disease is progressing. PMID- 23928725 TI - Magnetic solid-phase extraction based on tetrabenzyl modified Fe3O4 nanoparticles for the analysis of trace polycyclic aromatic hydrocarbons in environmental water samples. AB - A novel sorbent for magnetic solid-phase extraction, 1,4,7,10-tetrabenzyl 1,4,7,10-tetraazacyclododecane (TBCD) modified magnetic nanoparticles, was synthesized in this work. The four benzyl groups of TBCD provide the Fe3O4-TBCD nanoparticles with strong adsorption capacity for polycyclic aromatic hydrocarbons (PAHs) due to their pi-pi stacking interaction, which increases selectivity of the synthesized material to target analytes. The prepared material was characterized by scanning electron microscopy, X-ray diffraction patterns, Fourier transform infrared spectroscopy and vibrating sample magnetometry. The results indicated that the Fe3O4-TBCD nanoparticles were successfully prepared, and the particles were homogeneous nanospheres with excellent magnetic properties. Based on the optimized extraction conditions, a rapid and effective method was developed for the pre-concentration of PAHs from environmental water samples by combination with high performance liquid chromatography (HPLC). Satisfactory precision and accuracy of the developed method were obtained in a low concentration range of 0.3 ng L(-1) to 1.2 * 10(3) ng L(-1). This method produced lower limits of detection in the range of 3.0 * 10(-2) ng L(-1) to 1.2 ng L(-1). The high pre-concentration rate and efficiency of the method ensure its successful application in extraction of trace PAHs from large volumes of environmental water samples. The extraction recoveries in environmental water samples ranged from 81.1% to 115.5% with the relative standard deviations (n = 5) less than 10%. PMID- 23928726 TI - The stem cell markers Oct4A, Nanog and c-Myc are expressed in ascites cells and tumor tissue of ovarian cancer patients. AB - PURPOSE: The aim of this study was to examine the expression of established stem cell markers in ascites and tumor tissue obtained from ovarian cancer patients. METHODS: Mononuclear cells present in ascites were collected by density gradient centrifugation. Intracellular flowcytometry was used to assess the putative presence of stem cell markers. RT-PCR was used to detect full length Oct4A, a splice variant Oct4B, implicated in glioma and breast cancer, Oct4 pseudogenes and c-Myc. Genes were cloned and sequenced to determine putative mutations. Confocal laser scanning microscopy was performed to localize the markers in ascites cells as well as in tumor tissue. Material from carcinomas other than epithelial ovarian carcinoma served as control. RESULTS: A small quantity of cells in ascites and in tumor tissue of ovarian cancer patients was detected that expresses c-Myc, Oct4A and Nanog. Besides Oct4A, present in the nucleus, also the cytoplasmic resident Oct4B splice variant was detected. Remarkably, c-Myc was found partially in the cytoplasm. Since no mutations in c-Myc were found that could explain the cytoplasmic localization, we hypothesize that this is due an IL 6 induced c-Myc shuttle factor. CONCLUSIONS: The expression of stem cell genes was detected in a small proportion of tumor cells present in ascites as well as in tumor tissue. IL-6 plays an important role in the induction of c-Myc. PMID- 23928727 TI - Perioperative management of antiplatelet therapy in patients with a coronary stent who need noncardiac surgery: a systematic review of clinical practice guidelines. AB - BACKGROUND: It is unclear how to appropriately manage discontinuation and resumption of antiplatelet therapy in patients with coronary stents who need noncardiac surgery. We undertook a systematic review of the literature to identify practice guideline statements regarding antiplatelet therapy in patients with coronary stents undergoing noncardiac surgery. METHODS: We used six search strategies to identify practice guideline statements that comment on perioperative antiplatelet management for patients with coronary stents undergoing noncardiac surgery. Two independent reviewers assessed study eligibility, abstracted data, and completed quality assessment. RESULTS: We identified 11 practice guidelines that met the eligibility criteria; these were included in the review. These guidelines advised that elective noncardiac surgery be delayed for at least 4 weeks after bare-metal stent implantation and at least 6 months after drug-eluting stent implantation. For elective surgery, all guidelines advised continuing acetylsalicylic acid (ASA) therapy whenever possible. If interruption of antiplatelet therapy was required, four guidelines advised to discontinue ASA/clopidogrel at least 5 days before surgery, while two guidelines advised to discontinue 7 to 10 days before surgery. Five guidelines provided varying guidance for the use of perioperative bridging during antiplatelet therapy interruption. CONCLUSIONS: Most current recommendations are based on expert opinion. This review highlights the need for well-designed prospective studies to identify optimal management strategies in patients with coronary stents who are on antiplatelet therapy and who need noncardiac surgery. PMID- 23928728 TI - The Ponseti method for the treatment of congenital club foot: review of the current literature and treatment recommendations. AB - The Ponseti method has become the gold standard of care for the treatment of congenital club foot. Despite numerous articles in MEDLINE reporting results from around the globe there are still crucial details of the Ponseti method which seem to be less commonly known or considered. The Ponseti method is not only a detailed method of manipulation and casting but also of preventing and treating relapse. Recommendations on how to correct complex club foot have resulted in an almost 100 % initial correction rate. The foot abduction brace is crucial for preventing relapse and is still a challenge for families and sometimes doctors alike. Experience and knowledge on how to support the parents, how to set and apply the brace in the best possible way and how to solve problems that can be encountered during the bracing period are essential to ensure compliance. Regular follow-up visits are necessary to be able to detect early signs of recurrence and prevent full relapse by enforcing abduction bracing, recasting or performing tibialis anterior tendon transfer. Recent midterm outcome studies have shown that by following the Ponseti treatment regime in all aspects it is possible to prevent open joint surgery in almost all cases. The body of literature of the last decade has evaluated many steps and aspects of the Ponseti method and gives valuable answers to questions encountered in daily practice. This review of the current literature and recommendations on the different aspects of the Ponseti method aims to promote understanding of the treatment regime and its' details. PMID- 23928729 TI - Individual intake of free-choice mineral mix by grazing beef cows may be less than typical formulation assumptions and form of selenium in mineral mix affects blood Se concentrations of cows and their suckling calves. AB - The objectives of this study were to determine (1) the individual ad libitum intake of mineral mix by beef cows managed under a year-long, fall-calving, forage-based production regimen and (2) if Se form in the mineral mix affected the blood Se concentrations of cows and suckling calves. Twenty-four late gestation (6 to 8 months) Angus-cross cows (2.7 +/- 0.8 years; body weight [BW] = 585 +/- 58 kg) were blocked by BW and randomly assigned (n = 8) to a mineral supplement treatment (TRT) containing 35 ppm Se as either inorganic (ISe; sodium selenite), organic (OSe; Sel-Plex(r)), or a 1:1 combination of ISe/OSe (MIX). Cows commonly grazed a 10.1-ha predominately tall fescue pasture and had individual ad libitum access to TRT using in-pasture Calan gates. Cows calved from August to November and calves had common ad libitum access to creep feed and a mineral supplement that lacked Se. Cow jugular blood was taken at 28-day intervals (13 periods) and calf blood was taken with cows from birth through weaning. Individual cow mineral mix (mean = 54.0 +/- 7.0 g/day, range = 97.3 to 27.9 +/- 7.4 g/day) and Se (mean = 1.82 +/- 0.25 mg/day, range = 3.31 to 0.95 +/- 0.25 mg/day) intakes were affected by period (P < 0.0001), but not by cow Se TRT (P > 0.30). Cow blood Se (0.109 to 0.229 +/- 0.01 MUg/mL) was affected (P < 0.002) by period, Se form, and their interaction, with ISe < MIX for periods 8 and 11, ISe < OSe for all periods except period 1, and MIX < OSe for periods 2 to 4, 7, 8, 10, and 12. Calf blood Se (in micrograms Se per milliliter) was correlated with cow blood Se and affected (P < 0.0001) by cow Se TRT, with ISe (0.07 to 0.11) < MIX (0.10 to 0.15) = OSe (0.16 to 0.19). These data reveal that (1) mean supplemental ad libitum cow mineral intake was 36% less than the typical formulation intake expectations (85 g/day) and, correspondingly, mean supplemental Se intake was 33% less than that allowed by the FDA and (2) cow Se TRT differentially affected both cow and calf blood Se concentrations, resulting in adequate concentrations for all cows but inadequate concentrations for ISe calves. PMID- 23928730 TI - The effects of radiation on antitumor efficacy of an oncolytic adenovirus vector in the Syrian hamster model. AB - We report that radiation enhances the antitumor efficacy of the oncolytic adenovirus vector VRX-007 in Syrian hamster tumors. We used tumor-specific irradiation of subcutaneous tumors and compared treatment options of radiation alone or combined with VRX-007 and cyclophosphamide (CP). Radiation therapy further augmented the VRX-007-mediated inhibition of tumor growth, in both CP treated and non-CP-treated hamsters, even though radiation did not lead to increased viral replication in tumors when compared with those treated with VRX 007 alone. Moreover, tumor growth inhibition was similar in tumors irradiated either 1 week before or after injection with VRX-007, which suggests that radiation exerts its antitumor effect independently from vector therapy. Thus, our results demonstrate that these two therapies do not have to be provided simultaneously to enhance their combined effectiveness against subcutaneous hamster tumors. PMID- 23928731 TI - The role of cyclophosphamide in enhancing antitumor efficacy of an adenovirus oncolytic vector in subcutaneous Syrian hamster tumors. AB - We have previously reported that intratumoral injection of VRX-007--an Ad5 (a species C adenovirus)-based vector overexpressing adenovirus death protein--can suppress the growth of subcutaneous HaK (hamster renal cancer) tumors. VRX-007 replication and tumor growth inhibition are enhanced when the hamsters are immunosuppressed by a high dose of cyclophosphamide (CP), an immunosuppressive and chemotherapeutic agent. Here, we report that continuous immunosuppression with CP was not required for increased oncolytic activity of VRX-007 because short-term dosing or continuous dosing with the drug yielded similar antitumor results. Prolonged viral replication was found only in animals on continuous CP treatment. We used 007-Luc, a replication-competent, luciferase-expressing vector similar to VRX-007, to investigate the replication of the vector over time. Tumor growth inhibition was similar in hamsters given CP treatment either 1 week before or 1 week after 007-Luc injection, which suggests that CP exerts its antitumor efficacy independently of vector therapy. 007-Luc did not spread far from the inoculation site, even in immunosuppressed, CP-treated animals. Our results indicate that the enhanced effectiveness that is produced by the combination of VRX-007 and CP therapies is due to their two independent mechanisms and that they do not have to be given simultaneously for the improved outcome. PMID- 23928732 TI - Mst1 overexpression inhibited the growth of human non-small cell lung cancer in vitro and in vivo. AB - Mammalian STE20-like kinase 1 (Mst1) ubiquitously encodes serine threonine kinase, which is a 59-kDa class II GC kinase that shares 76% identity in amino acid sequence with MST2, and is the closest mammalian homolog of Drosophila Hippo protein kinase, a major inhibitor of cell proliferation in Drosophila. Recent studies have shown that Mst1 and Mst2 perform tumor-suppressor function in a redundant manner and were originally identified as pro-apoptotic cytoplasmic kinases important for controlling cell growth, proliferation, apoptosis and organ size. We used recombinant eukaryotic expression vector containing human wild-type Mst1 gene to transfect human non-small cell lung cancer (NSCLC) A549 cells in vitro and in vivo. The results showed that Mst1 overexpression inhibited cell proliferation and induced apoptosis of A549 cells, promoted Yes-associated protein (YAP) (Ser127) phosphorylation and downregulated the transcriptional level of Cystein-rich protein connective tissue growth factor (CTGF), amphiregulin (AREG) and Survivin. In human NSCLC-cell-A549-xenograft models, Mst1 gene or cisplatin alone suppressed the growth of tumors and increased the cytoplasm-positive expression levels of YAP and Phospho-YAP (Ser127) proteins; however, their combination had the strongest anticancer effects. Overall, Mst1 has an important role in inhibiting the growth of NSCLC in vitro and in vivo; its antiproliferative effect is associated with induction of apoptosis through promotion of the cytoplasmic localization and phosphorylation of YAP protein at Ser127 site, indicating that Mst1 may be developed as a promising therapeutic target for NSCLC. PMID- 23928733 TI - Augmented adenovirus transduction of murine T lymphocytes utilizing a bi-specific protein targeting murine interleukin 2 receptor. AB - Adenoviruses are currently used in a variety of bench and bedside applications. However, their employment in gene delivery to lymphocyte lineages is hampered by the lack of coxsackie virus and adenovirus receptor (CAR) on the cell surface. Exploitation of an alternative receptor on the surface of T lymphocytes can allow for utilization of adenovirus in a variety of T lymphocyte-based diseases and therapies. Here, we describe how resistance to infection can be overcome by the utilization of a bi-specific fusion protein, soluble CAR murine interleukin 2 (sCAR-mIL-2), that retargets adenovirus to the murine IL-2 receptor (IL-2R). Infection of a murine T-cell line, CTLL-2, with a sCAR-mIL-2/Adenovirus conjugate provided a ninefold increase in both green fluorescence protein-positive cells and luciferase expression. In addition, this increase in infection was also seen in isolated primary murine T lymphocytes. In this context, the sCAR-mIL-2 adapter provided a fourfold gene transduction increase in activated primary murine T lymphocytes. Our results show that recombinant sCAR-mIL-2 fusion protein promotes IL-2R-targeted gene transfer to murine T lymphocytes and that alternative targeting can abrogate their native resistance to infection. PMID- 23928734 TI - Prevention of pacemaker infections with perioperative antimicrobial treatment: an in vitro study. AB - AIMS: The antimicrobial treatment of pacemaker casings with antiseptics (povidone iodine or octenidine dihydrochloride) or antibiotics (vancomycin, daptomycin, cefuroxime, Tazobac, or nebacetin) was analysed in vitro for its biocompatibility and efficacy in preventing the bacterial adhesion of Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli to cardiac implantable electrophysiological devices (CIEDs). METHODS AND RESULTS: Titan platelets (0.4 cm²) cut from pacemaker casings were impregnated with seven different antimicrobial solutions: two antiseptics and five antibiotics. Subsequently, they were challenged with bacterial contamination by four test strains over a 24 h incubation period. Bacterial adherence was quantified using the colony-forming-unit method after cell recovery with sonication and examined with confocal laser scanning electron microscopy. Simultaneously, the biocompatibility of the antimicrobial impregnation was assessed using pre-treated titan platelets in a culture of human fibroblasts, skeletal myoblasts, and microvascular endothelial cells. After a 48 h incubation, cell vitality was measured using the 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4 disulfophenyl)-2H/tetrazolium monosodium (WST-8) assay. The immersion of pacemaker casings in antiseptic or antibiotic solutions applies an antimicrobial coating that can significantly reduce bacterial adhesion. The studied impregnations differed in their antimicrobial efficacy and toxicity. CONCLUSION: Compared with the two antiseptics and the other tested antibiotics, nebacetin showed the best ratio of efficacy to toxicity. Nebacetin showed good in vitro antibacterial activity against both Gram-positive and Gram-negative pathogens without impairing human cell vitality. It is a safe and effective candidate for CIED impregnation. PMID- 23928735 TI - The use of an integrated electroanatomic mapping system and intracardiac echocardiography to reduce radiation exposure in children and young adults undergoing ablation of supraventricular tachycardia. AB - AIMS: Non-fluoroscopic imaging (NFI) devices are increasingly used in ablations. The objective was to determine the utility of intracardiac echocardiography (ICE) in ablating paediatric supraventricular tachycardias (SVTs) and assess whether its integrated use with electroanatomic mapping (EAM) resulted in lower radiation exposure than use of EAM alone. METHODS AND RESULTS: Prospective, controlled, single-centre study of patients (pts) age >=10 years, weight >=35 kg, with SVT and normal cardiac anatomy. Patients were randomized to ICE + EAM (ICE) or EAM only (no ICE). Both had access to fluoroscopy as needed. Eighty-four pts were enroled (42 ICE, 42 no ICE). Median age was 15 years (range 10.4-23.7 years); 57% had accessory pathways, 42% atrioventricular nodal reentry tachycardia. There was no difference in radiation dose (9 mGy ICE vs. 23 mGy no ICE, P = 0.37) or fluoroscopy time (1.1 min ICE vs. 1.5 min no ICE, P = 0.38). Transseptal punctures were performed in 25 pts (16 ICE, 9 no ICE), with ICE reducing radiation (8 mGy ICE vs. 62 mGy no ICE, P = 0.002) and fluoroscopy time (1.1 min ICE vs. 4.5 min no ICE, P = 0.01). Zero fluoroscopy was achieved in 13 pts (15% of total, 5 ICE, 8 no ICE), and low-dose cases (<50 mGy) in 57 pts (68% of total, 33 ICE, 24 no ICE). Acute success was 95% for ICE, 88% for no ICE. CONCLUSION: Use of an integrated EAM/ICE system was no better than EAM alone in limiting radiation, but can be helpful for transseptal punctures. Given the low dose savings, use of ICE may be weighed against its financial cost. Low-fluoroscopy cases are performed in most NFI procedures. PMID- 23928736 TI - Eastern Association for the Surgery of Trauma: management of the open abdomen, part III-review of abdominal wall reconstruction. PMID- 23928738 TI - A comprehensive review of blood product use in civilian mass casualty events. PMID- 23928737 TI - Autologous bone marrow mononuclear cells therapy attenuates activated microglial/macrophage response and improves spatial learning after traumatic brain injury. AB - BACKGROUND: Autologous bone marrow-derived mononuclear cells (AMNCs) have shown therapeutic promise for central nervous system insults such as stroke and traumatic brain injury (TBI). We hypothesized that intravenous injection of AMNC provides neuroprotection, which leads to cognitive improvement after TBI. METHODS: A controlled cortical impact (CCI) rodent TBI model was used to examine blood-brain barrier (BBB) permeability, neuronal and glial apoptosis, as well as cognitive behavior. Two groups of rats underwent CCI with AMNC treatment (CCI autologous) or without AMNC treatment (CCI-alone), consisting of 2 million AMNC per kilogram body weight harvested from the tibia and intravenously injected 72 hours after injury. CCI-alone animals underwent sham harvests and received vehicle injections. RESULTS: Ninety-six hours after injury, AMNC significantly reduced the BBB permeability in injured animals, and there was an increase in apoptosis of proinflammatory activated microglia in the ipsilateral hippocampus. At 4 weeks after injury, we observed significant improvement in probe testing of CCI-Autologous group in comparison to CCI-Alone in the Morris Water Maze paradigm. CONCLUSION: Our data demonstrate that the intravenous injection of AMNC after TBI leads to neuroprotection by preserving early BBB integrity, increasing activated microglial apoptosis and improving cognitive function. PMID- 23928739 TI - Western Trauma Association critical decisions in trauma: evaluation and management of peripheral vascular injury, part II. AB - This is a position article from members of the Western Trauma Association (WTA). Because there are no prospective randomized trials on the evaluation and management of peripheral vascular trauma, the algorithm is based on the expert opinion of the WTA members and published observational studies. It may not be applicable at all hospitals caring for injured patients. The algorithm contains letters that correspond to lettered text that is intentionally concise. This Part II algorithm focuses on operative techniques, while the Part I algorithm (J Trauma 2011;70: 1551-1556) emphasized evaluation, diagnosis, and need for operation versus a therapeutic procedure performed in an interventional suite. PMID- 23928740 TI - Embolization for pediatric blunt splenic injury is an alternative to splenectomy when observation fails. AB - BACKGROUND: Management of splenic injury has shifted from operative to nonoperative management in both children and adults with reports of high success rates. Benefits of splenic conservation include decreased hospital stay, blood transfusion, and mortality, as well as avoidance of infectious complications. Angiography with embolization is an innovative adjunct to nonoperative management and has resulted in increased splenic salvage in adults; however, data in the pediatric population are scant. METHODS: A retrospective comparative study of a single-hospital trauma registry reviewed from 1999 to 2009. Patients 18 years and younger admitted with injury to the spleen were included. Children with penetrating injury were excluded. Children were divided into three categories by initial treatment: observation, embolization, or splenectomy. Data recorded include age, radiographic grade of injury, and Injury Severity Score (ISS). Groups were analyzed for success of initial treatment, requirement for transfusion of packed red blood cells, splenic salvage, and mortality. RESULTS: Registry review identified 259 children with blunt splenic injury. Initial treatment was observation in 227, embolization in 15, and splenectomy in 17. In the observation group, 9 (4%) of 227 children failed initial treatment; 8 of these underwent embolization, while 1 unerwent splenectomy. In the embolization group, 1 (7%) of 15 failed initial treatment and underwent splenectomy. Blood transfusion was required by 38 (17%) of 227 in the observation group, 6 (40%) of 15 (p = 0.02) in the embolization group, and 15 (88%) of 17 (p < 0.01) in the splenectomy group. Overall splenic salvage rate was 237 (92%) of 259. Three children died in the observation group, and four children died in the splenectomy group. There was no death in the embolization group. CONCLUSION: Splenic artery embolization for blunt trauma in children is associated with a higher blood transfusion rate compared with observation but offers a safe, intermediate alternative to splenectomy when observation fails. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 23928741 TI - Topical negative-pressure therapy for small bowel leakage in a frozen abdomen: a technical report. PMID- 23928742 TI - Outcomes following "rescue" superselective angioembolization for gastrointestinal hemorrhage in hemodynamically unstable patients. AB - BACKGROUND: Therapeutic angioembolization is a relatively new "rescue treatment" modality for gastrointestinal hemorrhage (GIH) for unstable patients who fail primary treatment approaches; however, the effectiveness of this treatment and the incidence of ischemic necrosis following embolization for acute GIH are poorly described. The purpose of this study was to evaluate the effectiveness and safety of "rescue" transcatheter superselective angioembolization (SSAE) for the treatment of hemodynamically unstable patients with GIH. METHODS: A 10-year retrospective review of all hemodynamically unstable patients (systolic blood pressure < 90 mm Hg and ongoing transfusion requirement) who underwent "rescue" SSAE for GIH after failed endoscopic management was performed. All patients with evidence of active contrast extravasation were included. Data were collected on demographics, comorbidities, clinical presentation, and type of intravascular angioembolic agent used. Outcomes included technical success (cessation of extravasation), clinical success (no rebleeding requiring intervention within 30 days), and incidence of ischemic complications. RESULTS: Ninety-eight patients underwent SSAE for GIH during the study period; 47 were excluded owing to lack of active contrast extravasation. Of the remaining 51 patients, 22 (43%) presented with a lower GIH and 29 (57%) with upper GIH. The majority underwent embolization with a permanent agent (71%), while the remaining patients received either a temporary agent (16%) or a combination (14%). The overall technical and clinical success rates were 98% and 71%, respectively. Of the 14 patients with technical success but clinical failure (rebleeding within 30 days) and the 1 patient with technical failure, 4 were managed successfully with reembolization, while 2 underwent successful endoscopic therapy, and 9 had surgical resections. Only one patient had an ischemic complication (small bowel necrosis) requiring resection. CONCLUSION: SSAE, with reembolization if necessary, is an effective rescue treatment modality for hemodynamically unstable patients with active GIH. Of the patients, 20% will fail SSAE and require additional intervention. Ischemic complications are extremely rare. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 23928743 TI - Hyperosmolar reconstituted lyophilized plasma is an effective low-volume hemostatic resuscitation fluid for trauma. AB - BACKGROUND: We performed this study to optimize reconstituted lyophilized plasma (LP) into a minimal volume fluid that provides effective hemostatic resuscitation for trauma while minimizing logistical limitations. METHODS: We performed a prospective, blinded animal study. Plasma was lyophilized following whole blood collection from anesthetized swine. The minimal volume needed for reconstitution was determined, and this solution was evaluated for safe infusion into the swine. Reconstituted LP was analyzed for electrolyte content, osmolarity, and coagulation factor activity. Twenty swine were anesthetized and subjected to a validated model of polytrauma and hemorrhagic shock (including a Grade V liver injury), then randomized to resuscitation with LP reconstituted to either 100% of the original plasma volume (100%LP) or the minimal volume LP fluid. Physiologic data were monitored, and blood loss and hematocrit were measured. Coagulation status was evaluated using thrombelastography. RESULTS: The minimal volume of reconstituted LP safe for infusion in swine was 50% of the original plasma volume (50%LP). The 50%LP had higher electrolyte concentrations, osmolarity, and increased coagulation factor activity levels by volume compared with 100%LP (p < 0.05). Blood loss, hematocrit, mean arterial pressure, and heart rate did not differ between animals receiving 100%LP (n = 10) or 50%LP (n = 10) at any time point (p > 0.05). International normalized ratio and thrombelastography parameters were not different between groups (R time, alpha angle, or maximal amplitude, p > 0.05). CONCLUSION: Resuscitation with 50%LP fluid was well tolerated and equally effective compared with 100%LP, with respect to physiologic and hemostatic properties. The smaller volume of fluid necessary to reconstitute hypertonic LP makes it logistically superior to 100%LP for first responders and may reduce adverse effects of large-volume resuscitation. PMID- 23928744 TI - Effects of leading mortality risk factors among trauma patients vary by age. AB - BACKGROUND: Patient age is well recognized as a factor that contributes to increased mortality risk among trauma patients. Less well recognized is the potential that the strength of the effects of other risk factors that increase mortality risk may depend on a patient's age. This study examines whether the statistical relationship between trauma patient survival and key mortality risk factors varies significantly by patient age in years, across mechanisms of injury. METHODS: The statistical interaction between age and values of key risk factors included in the Trauma Quality Improvement Program mortality risk adjustment model is assessed using patient data included in the 2008 National Trauma Data Bank National Sample Program. Multivariable logistic regression analysis is used to assess the statistical significance of the interaction effect on patient morality risk for key mortality risk factors and patient age in years, across mechanisms of injury. RESULTS: Statistically significant interactions (p < 0.01) occurred between age and each of the selected risk factors, for each common mechanism of injury. Differences also occurred in the direction of the interactions between age and selected risk factors, across mechanism of injury. CONCLUSION: The effects of key risk factors included in trauma patient mortality risk adjustment models vary depending on patient age in years, for each commonly occurring mechanism of injury. Statistical models assessing patient mortality risk could be meaningfully improved by accounting for these interaction effects. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 23928745 TI - Damage-control laparotomy in nontrauma patients: review of indications and outcomes. AB - BACKGROUND: The principle of damage-control laparotomy (DCL) in trauma is well established. The DCL concept can be applied in emergency general surgery when an abbreviated laparotomy is performed at the initial stage. Subsequent definitive management and abdominal closure are achieved when the patient is stabilized. In this study, we report our experience with DCL in acute general surgical nontrauma patients. METHODS: A retrospective review was performed of all nontrauma patients who underwent DCL at Auckland City Hospital from January 2008 to December 2010. Data including indications and outcome were collected and analyzed. RESULTS: Forty-two nontrauma patients underwent DCL in the 3-year period. The median age was 66 years. There were 22 males and 20 females. The most common primary indications for DCL were bowel ischemia (13 patients), bleeding (13 patients), and peritonitis (10 patients). Majority of patients had an American Society of Anesthesiologists score of 3 or 4. Overall, 24 patients (57%) underwent closure of the fascia within 7 days, 7 patients were closed after more than 7 days, and 11 patients could not undergo primary closure at all. The main complications after DCL were sepsis (14 patients) and intra-abdominal collections (10 patients). There were significantly fewer postoperative complications in patients undergoing early closure. The medium length of stay in intensive care as well as in hospital was significantly less in the early closure group. However, postoperative respiratory failure was more common in those with early closure (5 vs. 0). The mortality rate overall was 19%, with no significant difference regarding timing of abdominal closure. CONCLUSION: The DCL principle is often applied to the critically ill surgical patients in the nontrauma setting. This group of critical surgical patients has a high morbidity and mortality. However, early abdominal closure should be performed where possible to prevent complications. It is unclear whether patients with early closure were going to have a better outcome regardless, and prospective studies are needed to address. LEVEL OF EVIDENCE: Therapeutic/care management, level V. PMID- 23928746 TI - Functional genomics suggest neurogenesis in the adult human olfactory bulb. AB - The human olfactory bulb displays high morphologic dynamics changing its volume with olfactory function, which has been explained by active neurogenetic processes. Discussion continues whether the human olfactory bulb hosts a continuous turnover of neurons. We analyzed the transcriptome via RNA quantification of adult human olfactory bulbs and intersected the set of expressed transcriptomic genes with independently available proteomic expression data. To obtain a functional genomic perspective, this intersection was analyzed for higher-level organization of gene products into biological pathways established in the gene ontology database. We report that a fifth of genes expressed in adult human olfactory bulbs serve functions of nervous system or neuron development, half of them functionally converging to axonogenesis but no other non-neurogenetic biological processes. Other genes were expectedly involved in signal transmission and response to chemical stimuli. This provides a novel, functional genomics perspective supporting the existence of neurogenesis in the adult human olfactory bulb. PMID- 23928748 TI - Impact of COMT genotype on serotonin-1A receptor binding investigated with PET. AB - Alterations of the inhibitory serotonin-1A receptor (5-HT1A) constitute a solid finding in neuropsychiatric research, particularly in the field of mood and anxiety disorders. Manifold factors influencing the density of this receptor have been identified, e.g., steroid hormones, sunlight exposure and genetic variants of serotonin-related genes. Given the close interactions between serotonergic and dopaminergic neurotransmission, we investigated whether a common single nucleotide-polymorphism of the catechol-O-methyltransferase (COMT) gene (VAL158MET or rs4680) coding for a key enzyme of the dopamine network that is associated with the pathogenesis of mood disorders and antidepressant treatment response, directly affects 5-HT1A receptor binding potential. Fifty-two healthy individuals (38 female, mean age +/- standard deviation = 40.48 +/- 14.87) were measured via positron emission tomography using the radioligand [carbonyl (11)C]WAY-100635. Genotyping for rs4680 was performed using DNA isolated from whole blood with the MassARRAY platform of the software SEQUENOM((r)). Whole brain voxel-wise ANOVA resulted in a main effect of genotype on 5-HT1A binding. Compared to A carriers (AA + AG) of rs4680, homozygote G subjects showed higher 5 HT1A binding potential in the posterior cingulate cortex (F (2,49) = 17.7, p = 0.05, FWE corrected), the orbitofrontal cortex, the anterior cingulate cortex, the insula, the amygdala and the hippocampus (voxel-level: p < 0.01 uncorrected, t > 2.4; cluster-level: p < 0.05 FWE corrected). In light of the frequently reported alterations of 5-HT1A binding in anxiety and mood disorders, this study proposes a potential implication of the COMT genotype, more specifically the VAL158MET polymorphism, via modulation of the serotonergic neurotransmission. PMID- 23928747 TI - Multi-region hemispheric specialization differentiates human from nonhuman primate brain function. AB - The human behavioral repertoire greatly exceeds that of nonhuman primates. Anatomical specializations of the human brain include an enlarged neocortex and prefrontal cortex (Semendeferi et al. in Am J Phys Anthropol 114:224-241, 2001), but regional enlargements alone cannot account for these vast functional differences. Hemispheric specialization has long believed to be a major contributing factor to such distinctive human characteristics as motor dominance, attentional control and language. Yet structural cerebral asymmetries, documented in both humans and some nonhuman primate species, are relatively minor compared to behavioral lateralization. Identifying the mechanisms that underlie these functional differences remains a goal of considerable interest. Here, we investigate the intrinsic connectivity networks in four primate species (humans, chimpanzees, baboons, and capuchin monkeys) using resting-state fMRI to evaluate the intra- and inter- hemispheric coherences of spontaneous BOLD fluctuation. All three nonhuman primate species displayed lateralized functional networks that were strikingly similar to those observed in humans. However, only humans had multi-region lateralized networks, which provide fronto-parietal connectivity. Our results indicate that this pattern of within-hemisphere connectivity distinguishes humans from nonhuman primates. PMID- 23928749 TI - Mediation and moderation effects of an in-home family intervention: the "in control: no alcohol!" pilot study. AB - The aim of this study was to examine the effect of a theory-based in-home family intervention (In control: No alcohol!) on adolescent alcohol cognitions via its putative mediators using a randomized controlled design. In the South Holland region of the Netherlands, a total of 213 children (11-12 years) and their mothers were randomly assigned to the prevention program (108 dyads) and the control condition (105 dyads). Mediation effects were analyzed using pretest and two follow-up measurements (5 and 12 months after baseline). A path model was estimated (using Mplus) to examine the effect of the intervention on the putative mediators (frequency- and quality of mother-child communication, rules about alcohol, establishing a nondrinking agreement, and parental monitoring of the child's whereabouts). Outcomes were adolescents' perceived harmfulness of drinking and intention to drink. Multigroup analyses were performed to examine potential differences across gender. The program led to an increase in frequency of alcohol-specific communication, nondrinking agreements, and parental monitoring. Moreover, adolescents in the experimental condition perceived drinking to be more harmful and had less intention to drink compared to adolescents in the control condition. The effect of the program on adolescent alcohol cognitions was significantly mediated through having more frequent conversations about alcohol, yet only among boys. Although results on actual drinking need to be added, findings indicate that this relatively inexpensive, easy-to-administer home intervention is promising. PMID- 23928751 TI - Enhanced performance of inverted organic photovoltaic cells using CNTs-TiO(X) nanocomposites as electron injection layer. AB - In this study, we fabricated inverted organic photovoltaic cells with the structure ITO/carbon nanotubes (CNTs)-TiO(X)/P3HT:PCBM/MoO3/Al by spin casting CNTs-TiO(X) nanocomposite (CNTs-TiO(X)) as the electron injection layer onto ITO/glass substrates. The power conversion efficiency (PCE) of the 0.1 wt% single walled nanotubes (SWNTs)-TiO(X) nanocomposite device was almost doubled compared with the TiO(X) device, but with increasing concentration of the incorporated SWNTs in the TiO(X) film, the performance of the devices appeared to decrease rapidly. Devices with multi-walled NTs in the TiO(X) film have a similar trend. This phenomenon mainly depends on the inherent physical and chemical characteristics of CNTs such as their high surface area, their electron-accepting properties and their excellent carrier mobility. However, with increasing concentration of CNTs, CNTs-TiO(X) current leakage pathways emerged and also a recombination of charges at the interfaces. In addition, there was a significant discovery. The incorporated CNTs were highly conducive to enhancing the degree of crystallinity and the ordered arrangement of the P3HT in the active layers, due to the intermolecular pi-pi stacking interactions between CNTs and P3HT. PMID- 23928750 TI - Pre-college matriculation risk profiles and alcohol consumption patterns during the first semesters of college. AB - Excessive alcohol consumption represents a significant concern on U.S. college campuses, and there is a need to identify students who may be at risk for engaging in risky alcohol use. The current study examined how variables measured prior to college matriculation, specifically alcohol-related decision-making variables drawn from the Theory of Reasoned Action (i.e., alcohol expectancies, attitudes, and normative beliefs), were associated with patterns of alcohol use prior to and throughout the first semesters of college. Participants were 392 undergraduate students (56% female) from a large Northeastern U.S. university. Decision-making variables were assessed prior to college matriculation, and alcohol use was measured with five assessments before and throughout freshman and sophomore semesters. Latent profile analysis was used to identify types of students with distinct patterns of decision-making variables. These decision making profiles were subsequently linked to distinct patterns of alcohol use using latent transition analysis. Four distinct decision-making profiles were found and were labeled "Anti-Drinking," "Unfavorable," "Mixed," and "Risky." Five drinking patterns were observed and included participants who reported consistently low, moderate, or high rates of alcohol use. Two patterns described low or non-drinking at the pre-college baseline with drinking escalation during the measurement period. Students' likelihood of following the various drinking patterns varied according to their decision-making. Findings suggest the early identification of at-risk students may be improved by assessing decision-making variables in addition to alcohol use. The findings also have implications for the design of early identification assessments to identify at-risk college students and for the targeting of alcohol prevention efforts to students based on their alcohol-related attitudes and beliefs. PMID- 23928759 TI - Q&A: Eric Winer on neoadjuvant clinical trials. AB - Eric Winer, MD, professor of medicine at Harvard Medical School and director of the Breast Oncology Center at Dana-Farber Cancer Institute, discusses presurgical trials for breast cancer and the roles such trials may eventually play in drug approvals. PMID- 23928760 TI - Seeking value as cancer drug costs soar. AB - As significant increases in the costs of cancer drugs cause financial difficulties for many U.S. patients, some oncologists suggest that changes in pricing policies at the federal and state levels are inevitable. PMID- 23928771 TI - Targeting BRAF in multiple myeloma. AB - In multiple myeloma, it is believed that multiple mutations in different pathways deregulate the intrinsic biology of the plasma cell, resulting in a genetically complex heterogeneous disease. Mutations in the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway have been identified and represent potential targets for therapy in this disease. BRAF, a serine/threonine kinase, has received considerable attention given the success of targeted therapy in malignant melanoma. Andrulis and colleagues report, for the first time, successful treatment of multiple myeloma with vemurafenib, a BRAF inhibitor, in a patient with a BRAF mutation. PMID- 23928772 TI - Energizing the search to target LKB1-mutant tumors. AB - SUMMARY: LKB1 is the third most frequently mutated gene in non-small cell lung cancer and serves as a master regulator of cell metabolism and polarity across a variety of model organisms. Recent studies are beginning to identify therapeutics that exploit defects associated with LKB1 loss. The work presented here by Liu and colleagues shows that deoxythymidylate kinase is a new potential target in LKB1-deficient tumors and highlights the possibility of a new therapeutic option for this subset of patients with cancer. PMID- 23928773 TI - Myeloid TGF-beta responsiveness promotes metastases. AB - Tumor-induced immune suppression is a major impediment to many potentially effective cancer therapies. TGF-beta has previously been described as having both tumor-promoting and tumor-suppressive characteristics. In this issue of Cancer Discovery, Pang and colleagues show that myeloid-specific TGF-beta signaling is a critical mediator in tumor metastasis. These findings point to a more specific means to reduce cancer immunosuppression, prevent metastasis, and minimize treatment-related adverse events. PMID- 23928793 TI - The brain microenvironment negatively regulates miRNA-768-3p to promote K-ras expression and lung cancer metastasis. AB - The brain microenvironment promotes metastasis through mechanisms that remain elusive. Co-culture of lung cancer cells with astrocytes - the most abundant cell type within the metastatic brain niche - lead to downregulation of miRNA-768-3p which drives K-ras expression and key signaling pathways, enhances cell viability and promotes chemotherapeutic resistance. Vector-based forced expression of miRNA 768-3p complementary sequence or a chemically-engineered miRNA-768-3p inhibitor recapitulated the astrocyte effect to increase tumor cell viability. The miRNA 768-3p inhibitor targeted the K-ras 3'-UTR as demonstrated by increased luminescence from a luciferase reporter and strikingly increased the K-ras protein and the downstream effectors ERK1/2 and B-Raf. miRNA-768-3p was reduced in patient brain metastases compared to normal brain tissue and was lower in patient tissue from brain metastases compared to same-patient primary tumour tissue. The brain microenvironment negatively regulates miRNA-768-3p to enhance K ras and promote metastasis. We propose that therapeutic replacement of the metastasis suppressor miRNA-768-3p holds clinical promise. PMID- 23928794 TI - An n->pi* interaction reduces the electrophilicity of the acceptor carbonyl group. AB - Carbonyl-carbonyl (C=O...C'=O') interactions are ubiquitous in both small and large molecular systems. This interaction involves delocalization of a lone pair (n) of a donor oxygen into the antibonding orbital (pi*) of an acceptor carbonyl group. Analyses of high-resolution protein structures suggest that these carbonyl carbonyl interactions prefer to occur in pairs, that is, one donor per acceptor. Here, the reluctance of the acceptor carbonyl group (C'=O') to engage in more than one n->pi* electron delocalization is probed using imidazolidine-based model systems with one acceptor carbonyl group and two equivalent donor carbonyl groups. The data indicate that the electrophilicity of the acceptor carbonyl group is reduced when it engages in n->pi* electron delocalization. This diminished electrophilicity discourages a second n->pi* interaction with the acceptor carbonyl group. PMID- 23928795 TI - Multicellular aggregates: a model system for tissue rheology. AB - Morphogenetic processes involve cell flows. The mechanical response of a tissue to active forces is linked to its effective viscosity. In order to decouple this mechanical response from the complex genetic changes occurring in a developing organism, we perform rheometry experiments on multicellular aggregates, which are good models for tissues. We observe a cell softening behavior when submitting to stresses. As our technique is very sensitive, we were able to get access to the measurement of a yield point above which a creep regime is observed obtained for strains above 12%. To explain our rheological curves we propose a model for the cytoskeleton that we represent as a dynamic network of parallel springs, which will break under stress and reattach at null strain. Such a simple model is able to reproduce most of the important behavior of cells under strain. We highlight here the importance of considering cells as complex fluids whose properties will vary with time according to the history of applied stress. PMID- 23928796 TI - Increased Th22 cells are independently associated with Th17 cells in type 1 diabetes. AB - Type 1 diabetes (T1D) is perceived as an autoimmune disease caused by T cell mediated destruction of the insulin-producing pancreatic beta cells. However, the number of inflammatory T cells in blood, as well as the relative importance of each cell type is unclear. Forty-two patients with T1D and 30 controls were enrolled. Circulating primary CD4(+) or CD8(+) T cells were quantified with 5 color flow cytometry. Serum IL-22 and IL-17 levels were examined by ELISA. Serum autoantibodies were measured by radio-binding assays, using (35)S-labeled glutamic acid decarboxylase-65 (GAD65), protein tyrosine phosphatase-2 (IA-2), and zinc transporter 8 (ZnT8). Th17-Th22 and Tc1-Tc17 were significantly elevated in patients with T1D compared to control subjects, while there were no significant differences in Th1 cells. The levels of these T cells in different stages of T1D were investigated. Th22 cells showed a positive correlation with Th17 cells in T1D patients. However, we did not find any correlation between IL 17 and IL-22 in sera. Autoantibodies were not significantly different between patients with early T1D and those who have had it for a longer duration. This study indicates that Th22 may contribute to the pathogenesis of T1D. Blockade of Th22 cells might be of clinical profit in T1D patients. PMID- 23928797 TI - [Cost analysis of emergency room patients in the German diagnosis-related groups system. A practice relevant depiction subject to clinical parameters]. AB - BACKGROUND: Since the implementation of the diagnosis-related system there has been a continuous lack of finances in the treatment of multiple injured patients. The current investigation summarizes consecutive patients from a level I trauma centre and tests the hypothesis that an injury severity score (ISS) based reimbursement would be an improvement in the cost-effectiveness of this patient population. METHODS: The study is based on multiple injured patients admitted to the emergency department in 2009. The ISS, intensive care unit (ICU) stay and cost data were recorded for every patient and two subgroups were formed: group I ISS < 16 and group II ISS >= 16. RESULTS: A total of 442 patients with an average age of 40.5 +/- 9.1 years (ISS 12) were included. The average amount of coverage during an average length of stay of 13.15 +/- 6.3 was -2,752 per patient. Patients in group I (n = 296, ISS 6.3) showed a value of -1,163 with an average length of stay of 8 +/- 4.6 days. In group II (n = 146, ISS 23.6) the average amount of coverage was -5,973 during an average hospital stay of 23 +/- 8.7 days. CONCLUSION: Improvements have been made with the recent adjustment of the reimbursement within the last year. Nevertheless, several factors identified in this study require additional adjustment: the ISS, the requirement of blood transfusion and the presence of additional chest trauma should be weighted in the calculation of reimbursement. PMID- 23928798 TI - Efficacy and tolerability of treatments for chronic cough: a systematic review and meta-analysis. AB - BACKGROUND: Understanding the comparative effectiveness of treatments for patients with unexplained or refractory cough is important to increase awareness of proven therapies and their potential adverse effects in this unique population. METHODS: We performed a literature search for English-language studies published up to June 2012 that compared symptomatic therapies for chronic cough. Two investigators screened each abstract and full-text article for inclusion, abstracted data, and rated quality. Meta-analysis with random-effects models was used to summarize effects of treatments. RESULTS: We identified 49 studies (3,067 patients) comprising 68 therapeutic comparisons. Of the studied agents, opioid and certain nonopioid and nonanesthetic antitussives had demonstrated efficacy for chronic cough in adults. Compared with placebo, effect sizes (standardized mean differences for cough severity and rate ratios for cough frequency) for opioids were 0.55 (95% CI, 0.38-0.72; P < .0001) and 0.57 (95% CI, 0.36-0.91; P = .0260), respectively. For dextromethorphan, effect sizes were 0.37 (95% CI, 0.19-0.56; P = .0008) and 0.40 (95% CI, 0.18-0.85; P = .0248), respectively. The overall strength of evidence was limited by inconsistency and imprecision of results and by small numbers of direct comparisons. Nonpharmacologic therapies and the management of cough in children were infrequently studied. CONCLUSIONS: Although evidence is limited, opioid and certain nonopioid and nonanesthetic antitussives demonstrated efficacy for treating chronic cough in adults. There is a need for further studies in patients with unexplained or refractory cough as well as for more systematic study designs, assessment of patient-centered outcomes, and reporting. PMID- 23928799 TI - Optimization of microfluidic PET tracer synthesis with Cerenkov imaging. AB - Microfluidic technologies provide an attractive platform for the synthesis of radiolabeled compounds. Visualization of radioisotopes on chip is critical for synthesis optimization and technological development. With Cerenkov imaging, beta particle emitting isotopes can be localized with a sensitive CCD camera. In order for Cerenkov imaging to also serve as a quantitative tool, it is necessary to understand how material properties relevant to Cerenkov emission, namely, index of refraction and beta particle stopping power, affect Cerenkov light output. In this report, we investigate the fundamental physical characteristics of Cerenkov photon yield at different stages of [(18)F]FDG synthesis on the electrowetting on dielectric (EWOD) microfluidic platform. We also demonstrate how Cerenkov imaging has enabled synthesis optimization. Geant4, a Monte Carlo program applied extensively in high energy physics, is used to simulate Cerenkov photon yield from (18)F beta particles traversing materials of interest during [(18)F]FDG synthesis on chip. Our simulations show that the majority (approximately two thirds) of the (18)F beta particle energy available to produce Cerenkov photons is deposited on the glass plates of the EWOD chip. This result suggests the possibility of using a single calibration factor to convert Cerenkov signal to radioactivity, independent of droplet composition. We validate our simulations with a controlled measurement examining varying ratios of [(18)O]H2O, dimethyl sulfoxide (DMSO), and acetonitrile (MeCN), and find a consistent calibration independent of solvent composition. However, the calibration factor may underestimate the radioactivity in actual synthesis due to discoloration of the droplet during certain steps of probe synthesis. In addition to the attractive quantitative potential of Cerenkov imaging, this imaging strategy provides indispensable qualitative data to guide synthesis optimization. We are able to use this imaging technique to optimize the mixing protocol as well as identify and correct for loss of radioactivity due to the migration of radioactive vapor outside of the EWOD heater, enabling an overall increase in the crude radiochemical yield from 50 +/- 3% (n = 3) to 72 +/- 13% (n = 5). PMID- 23928800 TI - One hundred years since the birth of academician Dimitar Arsov, founder and nestor of the modern internal medicine in the Republic of Macedonia. AB - Dimitar Arsov was born in Kriva Palanka on September 28, 1908 and died on July 2, 1974 in Skopje; he had finished elementary education in Kriva Palanka, high school (1922-1926) in Kumanovo, Macedonia and Col-lege of Medicine (1926-1932), Ph. D. University of Paris, Sorbone, France, 1936. He returned to Macedonia in 1937. In 1947 he was elected and Assistant Professor and in 1950 a Docent at the Faculty of Medicine in Skopje. He was appointed Director of the Clinic of Medicine and Head of the Chair of Internal Medicine, who served at those positions in the period 1952-74. In 1958 he was elected Professor of Internal Medicine. The first habilitation of the Medical Faculty in Skopje was defended by D. Arsov in 1954, titled: "The Effects of the Intravenous Epinephrine on the Hypersplenism of Malaria and Cala-Azar". On August 18, 1967, D. Arsov was elected Full Member and also the first member in the field of medicine of the Macedonian Academy of Sciences and Arts. The excellent experience in the work with the patients, precise observation of the symptoms and syndromes of the diseases in each patient, knowing the most advanced therapy at that time enabled D. Arsov to make conclusion for possibility of new therapy and gave him the material for writing scientific papers. In the first half of the 50s, during his regular work, Arsov discovers a new, internationally recognized therapy for rheumatism. Patients of both Cala-Azar and inflammatory rheumatism were treated with small doses of adrenaline therapy and they felt drastic decrease in rheumatism inflammation within one week. This therapy was used a couple of years in several countries around the world. He participated in the undergraduate and graduate studies. He contributed to the development of 2,240 graduated doctors and under his management over 300 doctors specialized in internal medicine and became specialists internists. Under his management, numerous habilitations and dissertations in internal medicine were finished. He contributed also to the development of 25 assistants, 5 docents, 5 full-time professors in internal medicine at the Medical Faculty in Skopje. He has published more than 200 papers from different areas of internal medicine, of which 36 are on the PubMed. He has published 5 books on internal medicine for students and doctors. He was a President and member of several Macedonian medical associations, as well as of medical associations of former Yugoslavia. He was awarded with the highest awards of former Yugoslavia and Macedonia. He was also awarded with international awards, such as: Doctor Honoris Causa by the University in Besancon and Honor and Medal from the City Assembly of Besancon (France). During his management of the Internal clinic the University Internal clinic developed eight different sub specialist departments: Cardiology, Pneumology, Rheumatology, Nephrology, Hematology, Gastroenterology and Endocrinology with metabolism and Clinical biochemical laboratory. The fast development of subspecialties has led to development of separate clinics for each subspecialty in 1975, so only the Chair of Internal Medicine remained as a connection between the subspecialties for education and scientific research. He was a prolific scientist who after World War II wrote the first scientific and specialist papers and books in the field of internal medicine in Macedonia. He created a school of internal medicine. The scientific and uncompromised attitude towards the expert truth are weaved in the unforgettable face of the Academician Prof. D-r. Dimitar Arsov, scientist, teacher, and doctor. With his vast work in healing the sick and preventing the diseases in the Republic of Macedonia, he became the cornerstone of modern medicine in the Republic of Macedonia. Thus, he truly deserves to be the doyen of internal medicine, one of the leading, most important persons in medicine of the 20th century in our country. Today, his honorary name appears on: Clinic of Rheumatology at the Medical Faculty in Skopje, Medical Center in Kriva Palanka, Scientific Club of the student organization of the Medical Faculty in Skopje. PMID- 23928801 TI - University Clinic of Toxicology--historical note and present work. AB - The University Clinic of Toxicology (UCT) in Skopje was founded as the Clinic for Toxicology and Emergency Internal Medicine on January 15th 1976. Today UCT has a modern building with office space of 1,300 m2 on 4 floors, 40 hospital beds and 72 employees including 18 doctors. UCT works in accordance with the public healthcare services in the Republic of Macedonia through the use of specialist/consultative and hospital healthcare for people over the age of 14 years. The Clinic also provides services in the field of emergency internal medicine, acute poisoning with medications, pesticides, corrosives, poisonous gases and mushrooms, heavy metals and other chemicals. The Clinic takes an active part in the detoxification programme for users of opiates and psychotropic substances, protocols for enteral and parenteral nutrition and guides for home treatment. Yearly there are more than 14,000 ambulance admissions, over 1,400 hospitalized patients, over 4,000 urgent EHO checks, more than 1,000 urgent upper endoscopies and over 700 other toxicological analyses and other interventions. The educational services and activities are realized through the chair for internal medicine. The Clinic offers undergraduate and graduate level education for medical students and dentists, for medical nurses, radiology technicians, speech therapists and physiotherapists. Over 300 papers and reports have been published to date by the medical staff at the UCT in the form of abstracts and integrated projects in the Republic of Macedonia and aboard. 8 doctorates have been successfully completed by employees from the Clinic as well as 4 master's theses and 1 in-depth project. UCT employees are the authors of some textbooks and monographs. UCT have undertaken some scientific projects. Employees from the Clinic of Toxicology are members taking an active part in many domestic and international associations. PMID- 23928802 TI - Six decades of the chair of Internal Medicine at the Medical Faculty in Skopje. AB - The chair of internal medicine in Republic of Macedonia was created in 1947. The Department of Internal Medicine (CIM) is the most numerous at Skopje's medical faculty (currently 56 members). According to the archive material from the first session of the Scientific Teaching Council of the Faculty of Medicine (17.03.1947), Mr Mario Krmpotic (Professor of Internal Medicine) was proposed as the first Director of the Internal Clinic (1947). For reasons unknown, Mr Krmpotic never came to Skopje to accept the post. As a consequence of this fact, the real founder of the CIM was the Russian Professor Alexandar Ignjatovski (1875 1955). Mr Ignjatovski was elected as the first Director of the Clinic for Internal Medicine in 1948 for a period of 4 years (1948-1952). At the same time, he was the first Chief of the CIM in Skopje (Macedonia). Dr D. Arsov was elected as the first Assistant Professor of Medicine in 1947, and second (and last) Director of the Clinic for Internal Medicine (1952-1974). For the same period (22 years) he was Head of the CIM. Dr D. Arsov sequentially and successively became first associated and then ordinary professor of medicine in the years 1951 and 1958. The regular activities of the CIM are as follows: 1) Undergraduate education for students (Clinical Investigation, Internal Medicine, Clinical Pharmacy) in general medicine, dentistry, geriatrics, urgent and family medicine (ECKTS); Undergraduate educationfor nurses, speech therapists, physiotherapists, radiologists (high /three year/ nurses School, ECKTS); 2) Postgraduate education (candidates for specialisation in internal medicine, infectology, anaesthesiology, neurology and surgery; 3) Continual medical education (a traditional morning scientific meeting on Thursdays, 08 h; weekly meetings of all internal medicine subspecialists); Scientific meetings, symposiums, congresses of former internal medicine associations (cardiology, pulmoallergology, gastroenterology, nephrology, haematology, rheumathology, endocriniology and toxicology); 4) Publishing activities in the national journals (Macedonian Medical Review, Journal of Macedonian Medical Science, Acta Physiologica, Medicus); 5) Decision-making: the Head of CIM regularly collaborates with the subspecialities of internal medicine by means of a coordinated body for all questions related to educational purposes in clinical investigation and internal medicine. PMID- 23928803 TI - Perindopril treatment in streptozotocin induced diabetic nephropaty. AB - Diabetic nephropathy (DN) is one of the most common causes of terminal stadium damage to the kidneys. The angiotensin-converting enzyme (ACE) represents a significant risk factor for the progression of DN. ACE inhibitors are medications of particular interest knowing the role of angiotensin II in the development of DN. This study aimed to examine the effects of ACE inhibitor treatment perindopril (PER), administered to rats with streptozotocin (STZ) induced DN, that developed albuminuria, renal hypertrophy and mild glomerulussclerosis. DN was induced by a STZ (60 mg/kg ip) single injection to normotensive Wistar rats. The administration of STZ caused diabetes mellitus (DM) with symptoms and signs of DN including poor general condition, body-weight loss, kidney weight increase as well as increased values of BUN and serum creatinine, accompanied by increased diuresis as well as distinct albuminuria. The majority of these symptoms were manifested 4 weeks after, and even more distinctly 8 and 12 weeks after administering STZ. The perindopril treatment (6 mg/kg BW), starting 4 weeks after administering STZ, resulted in a significant improvement of all symptoms and signs of DN, significantly lowering the values of BUN and serum creatinine, albuminuria and diuresis. The histopathological examination of the renal samples at 8 and 12 weeks after the beginning of the study have shown that perindopril significantly lowers the progression of glomerulopathy, and significantly improves the glomerulosclerotic index, as well as the progression of renal histological abnormalities induced with STZ. Thus perindopril treatment ameliorates STZ-induced nephropathic changes in DM rats. PMID- 23928804 TI - Risk assessment of cardiovascular mortality in Macedonia type 2 diabetes patients based on decode model. AB - AIM: To estimate the absolute risk (%) of 5- and 10-years cardiovascular mortality in Macedonian type 2 diabetes patients based on DECODE model, and the gender difference of the estimated risk. METHODS AND MATERIALS: Observational, cross-sectional study including a cohort of 1,404 type 2 diabetes patients; inclusion criteria: aged 25 to 65 years, absence of confirmed arterial disease, history of ischaemic heart disease, cerebrovascular disease or peripheral arterial disease; and absence of life-threatening conditions, such as cancer; at the time of risk assessment. Absolute risk was assessed based on the following risk factors: gender, age, known diabetes, smoking status, systolic blood pressure and total cholesterol. RESULTS: From the study cohort, 884 were identified as eligible for analysis, 503 (56.9%) of these were women. The estimated absolute risk (%) of 5- and 10-year cardiovascular mortality, based on DECODE model, was 1.1+/-1.3% and 5.5+/-6.1%, respectively; significantly higher absolute risk was estimated in men (1.7+/-1.6 vs 0.6+/-0.8, p<0.001 and 8.9+/-7.6 vs 2.9+/-2.5, p<0.001, for 5- and 10-years absolute risk, respectively). DISCUSSION AND CONCLUSION: This study is a first assessment of cardiovascular mortality in the Macedonian type 2 diabetic population based on DECODE model. It would be of both clinical and scientific interest to assess the risk prediction accuracy of the model, and to compare it with other diabetes-specific and diabetes non-specific models. PMID- 23928805 TI - Correlation of serum leptin with anthropometric parameters and abdominal fat depots determined by ultrasonography in overweight and obese women. AB - Leptin is an adipocytokine that has an important role in energy homeostasis and therefore in the patho-physiology of obesity. Leptin levels are influenced by many factors such as gender, race, energy intake, fat mass, etc. The aim of our study is to investigate the relationship of circulating leptin levels to anthropometric parameters and to the subcutaneous and visceral fat tissue determined by ultrasonography in healthy overweight and obese women. The study included 50 healthy women, with body mass index (BMI) above 25 kg/m2. Measurements of anthropometric parameters were performed with a standardized technique. The subcutaneous and visceral fat tissue was measured with ultrasound 1 cm above the umbilicus. Leptin was determined by radioimmunoassay. The serum leptin levels presented a positive correlation between the levels of leptin and BMI (r-0.73, p<0.05) waist circumference (r-0.73, p<0.05) hip circumference (r 0.74, p<0.05), thigh circumference (r-0.56, p<0.05) and abdominal subcutaneous fat tissue (r- 0.46, p<0.05). There was no correlation between leptin and visceral fat tissue, waist to hip and waist to thigh ratio. The results of our study confirmed the correlation between leptin and BMI. The correlation between leptin and all measured circumferences cannot be attributed to a particular fat depot, but rather reflect the correlation between this adipocytokine and the total body fat. The subcutaneous fat depot determined by ultrasound showed a correlation with leptin, while this kind of connection was not established for the visceral fat tissue. PMID- 23928806 TI - The need for regular screening of postpartum depression. AB - AIM: The aim of this study was to examine the level of depression during the first week of the postpartum period in a sample of women hospitalized for childbirth at the University Obstetric Clinic in Skopje and correlate it with some demographic characteristics. METHOD AND SAMPLE: The sample comprised 150 randomly selected women with a mean age of 29.23 years (SD+/-5.11). As a psychometric test the Beck Depression Inventory was used. It is a multiple choice, self-report inventory for measuring the severity of depression. For statistic evaluation (descriptive analysis and correlations) software Statistica 7 was used. RESULTS: The random study showed that 68% of postpartum women have minimal, 25% mild and 5% moderate depression. Fortunately only 2% manifested severe depression. Our findings showed that depression is negatively correlated with the level of education (r=-0.17), as well as with age (r=-0.15). The comparison of the level of depression with a group of chronic dialyzed patients showed that PPD is not so serious a problem. However, this study shows that PPD is under diagnosed. CONCLUSION: As a common mental health problem PPD is not systematically screened in our country. The study showed the presence of minimal (68%) and mild (25%) depression in the examined women. The age of the woman is important for PPD; younger women are more susceptible to depressive reactions. The level of education is negatively correlated with depression. It was pointed out that PPD must be recognized, treated and followed for a long period because it is a risk not only to the mental health of the mother but also for the development of child. PMID- 23928807 TI - Principles of biological therapy in psoriasis. AB - Psoriasis is a chronic, systemic T-cell mediated autoimmune skin disease, potentially associated with arthritis. The new understanding of immunopathogenesis and inflammatory cytokine pathways was actually the rationale for developing and introducing biological drugs in the treatment of moderate to severe psoriasis and psoriatic arthritis. Different from the traditional systemic drugs that impact the entire immune system, bio-logics target only specific points of the immune system. This review focuses on five biologics which target either T-cells (alefacept) or TNF-alpha (etanercept, adalimumab and infliximab) or interleukin IL-12/IL-23 (ustekinumab)--their efficacy, safety, patient monitoring and recommended dosage. The purpose of the treatment guidelines presented here is to provide a high standard of continuing care of psoriasis and psoriatic arthritis patients. PMID- 23928808 TI - Assessing natural and anthropogenic variability in wetland structure for two hydrogeomorphic riverine wetland subclasses. AB - The hydrogeomorphic approach (HGM) to wetland classification and functional assessment has been applied regionally throughout the United States, but the ability of HGM functional assessment models to reflect wetland condition has limited verification. Our objective was to determine how variability derived from anthropogenic effects and natural variability impacted site assessment variables within regional wetland subclasses in central Oklahoma. We collected data for nine potential assessment variables including vegetation physiognomy (e.g., tree basal area, herbaceous cover, canopy cover, etc.) and soil organic matter at wetlands of two HGM riverine subclasses (oxbow and riparian) in May and June, 2010. Using Akaike Information Criteria, we identified limited relationships between landscape disturbance metrics and assessment variables within subclasses. The high degree of natural variability from climatic and hydrologic factors within both subclasses may be masking the impact of landscape disturbance on the other measured assessment variables. Precipitation had significant effects on assessment variables within each of the subclasses. To reduce natural climatic variability, the reference domain may need to be further subdivided. The approach used in this study provides fairly rapid and quantitative methods for evaluating the effectiveness of using HGM assessment variables in assessing wetland condition regionally. PMID- 23928810 TI - Oxidation-state dependent electrocatalytic activity of iridium nanoparticles supported on graphene nanosheets. AB - Nanocomposites of iridium nanoparticles (Ir NPs), supported on graphene nanosheets, are synthesized and their electrocatalytic acitivities in the oxygen reduction reaction (ORR) are studied depending on their Ir oxidation state. Graphene functionalized with poly(vinyl pyrrolidone) (pRGO) is a suitable support for Ir NPs, producing well-monodispersed Ir NPs anchored strongly on the pRGO surface (Ir NP/pRGO) with a very high density. This was confirmed by scanning electron microscopy and transmission electron microscopy. The ORR activity of the Ir NP/pRGO nanocomposites in 0.5 M H2SO4 solution was observed to be dependent on the oxidation state of the immobilized Ir NPs. In fact, the nanocomposite composed of Ir(0) metal NPs, rather than Ir oxide (IrOx) NPs, exhibits higher ORR activity, such as more positive onset potential, higher and flatter limiting current density, a greater n value, and a sharper curve shape in the rotating disk electrode voltammetry experiments. Higher ORR activity of Ir is ascribed to the stronger adsorption of oxygen on the surface of Ir compared to IrOx. The practical stability of the Ir NP/pRGO composite was also confirmed under O2 saturated/acidic conditions. PMID- 23928809 TI - Prevalence and prognosis of congestive heart failure in Saudi patients admitted with acute coronary syndrome (from SPACE registry). AB - OBJECTIVES: The aim of this study was to assess the prevalence, clinical features, and in-hospital outcomes of heart failure in patients with acute coronary syndrome (ACS). MATERIALS AND METHODS: The Saudi Project for Assessment of Coronary Events recruited patients admitted with ACS from 17 hospitals in Saudi Arabia from 2005 to 2007. The outcomes of ACS patients with congestive heart failure (CHF) compared with those without CHF were analyzed. RESULTS: A total of 4523 patients with ACS were identified, of whom 905 (20%) had CHF. Compared with no CHF, patients with CHF were older (62+/-13.1 vs. 57+/-12.9 years; P=0.001), less likely to be men (70 vs. 79%; P=0.001), likely to present with non-ST-segment elevation myocardial infarction (48 vs. 36%; P=0.001), likely to have diabetes (71 vs. 54%; P=0.001), hypertension (64 vs. 54%; P=0.001) and previous history of coronary artery disease (53 vs. 43%; P=0.001), and likely to have significant left ventricular systolic dysfunction (left ventricular ejection fraction <35%) (56 vs. 30%; P=0.001). Patients with CHF were less likely to receive in-hospital beta-blockers (74 vs. 86%; P=0.001) and a percutaneous coronary intervention (19 vs. 50%; P=0.001). Adjusted in-hospital mortality and cardiogenic shock were higher in the CHF group (odds ratio 4.43, 95% confidence interval 2.52-7.78; and odds ratio 3.51, 95% confidence interval 2.23-5.52), respectively. CONCLUSION: ACS patients with CHF in the Saudi Project for Assessment of Coronary Events were older, more likely to have more cardiac risk factors, and less likely to be treated with optimum medical treatment on admission. These findings were associated with higher incidence of their in hospital adverse outcomes. More aggressive treatment is warranted to improve prognosis. PMID- 23928811 TI - STAT3 promotes corticospinal remodelling and functional recovery after spinal cord injury. AB - If and how neurons remodel their connections after CNS injury critically influences recovery of function. Here, we investigate the role of the growth initiating transcription factor STAT3 during remodelling of the injured corticospinal tract (CST). Endogenous STAT3 expression in lesioned cortical projection neurons is transient but can be sustained by viral gene transfer. Sustained activation of STAT3 enhances remodelling of lesioned CST fibres and induces de novo formation of collaterals from unlesioned CST fibres. In a unilateral pyramidotomy paradigm, this recruitment of unlesioned fibres leads to the formation of midline crossing circuits that establish ipsilateral forelimb activation and functional recovery. PMID- 23928812 TI - Sirtuins and ageing--new findings. PMID- 23928813 TI - A cautionary tale. PMID- 23928814 TI - A customized method for palatal crib fabrication. PMID- 23928815 TI - Drs. S.J. "Jack" Burrow and William R. Proffit on the efficacy of self-ligating brackets. PMID- 23928816 TI - Early Class III treatment with a facemask anchored by fixed appliances. PMID- 23928817 TI - Single-tooth intrusion with a cross tube and a cantilever spring. PMID- 23928818 TI - Orthodontic extrusion with a thermoformed appliance. PMID- 23928819 TI - Preprosthetic molar uprighting using skeletal anchorage. PMID- 23928820 TI - Physical activity and quality of life among university students: exploring self efficacy, self-esteem, and affect as potential mediators. AB - PURPOSE: Physical activity (PA) has been shown to enhance quality of life (QOL) in older adults. Findings from these studies indicate that the relationship between PA and QOL is indirect and likely mediated by variables such as physical self-esteem, exercise self-efficacy, and affect. As PA varies greatly by age, the purpose of the current study is to extend this area of research to young adults and explore the complex relationship between PA and QOL in this target population. METHODS: Data were collected via anonymous questionnaire from N = 590 undergraduate students. PA was assessed with the Godin Leisure Time Exercise Questionnaire, and QOL was assessed by the Satisfaction with Life Scale. Path analysis was used to test the relationship between PA and QOL, with mediators of exercise self-efficacy, physical self-esteem, and affect. RESULTS: The PA model (RMSEA = .03, CFI = .99) accounted for 25 % of the variance in QOL. PA had positive direct effects on exercise self-efficacy (beta = .28, P < .001), physical self-esteem (beta = .10, P < .001), positive affect (beta = .10, P < .05), and negative affect (beta = .08, P < .05). Physical self-esteem was found to be the most powerful mediating variable on QOL (beta = .30, P < .001), followed by positive affect (beta = .27, P < .001) and negative affect (beta = .14, P < .001). CONCLUSION: Physical self-esteem and, to a lesser extent, positive affect emerged as integral components in the link between PA and QOL. Findings suggest that health education programs designed to promote regular PA and increase physical self-esteem may be effective in improving QOL in young adults. PMID- 23928823 TI - Microwave effect on catalytic enantioselective Claisen rearrangement. AB - Catalytic enantioselective Claisen rearrangement was drastically enhanced under microwave irradiation conditions without any loss of the enantioselectivity. Based on Arrhenius plots it was revealed that enantioselectivity decreased as the internal reaction temperature increased. Therefore, this reaction acceleration would NOT be caused by only a simple thermal effect. PMID- 23928822 TI - Evidence for the contribution of muscle stem cells to nonhypertrophic skeletal muscle remodeling in humans. AB - The purpose of this study was to explore the possible role of muscle stem cells, also referred to as satellite cells (SCs), in adaptation and remodeling following a nonhypertrophic stimulus in humans. Muscle biopsies were obtained from the vastus lateralis of previously untrained women (n=15; age: 27+/-8 yr, BMI: 29+/-6 kg/m(2)) before and after 6 wk of aerobic interval training. The fiber type specific SC response to training was analyzed using immunofluorescent microscopy of muscle cross sections. Following training, the number of SCs associated with fibers expressing myosin heavy-chain type I and II isoforms (hybrid fibers) increased (pre: 0.062+/-0.035 SC/hybrid fiber; post: 0.38+/-0.063 SC/hybrid fiber; P<0.01). In addition, there was a greater number of MyoD(+)/Pax7(-) SCs, indicative of differentiating SCs, associated with hybrid fibers (0.18+/-0.096 MyoD(+)/Pax7(-) SC/hybrid fiber) compared to type I (0.015+/-0.00615 MyoD(+)/Pax7(-) SC/type I fiber) or II (0.012+/-0.00454 MyoD(+)/Pax7(-) SC/type II fiber) fibers (P<0.05). There was also a training-induced increase in the number of hybrid fibers containing centrally located nuclei (15.1%) compared to either type I (3.4%) or II fibers (3.6%) (P<0.01). These data are consistent with the hypothesis that SCs contribute to the remodeling of muscle fibers even in the absence of hypertrophy. PMID- 23928824 TI - A brief history of the changing occupations and demographics of coleopterists from the 18th through the 20th century. AB - Systematic entomology flourished as a branch of Natural History from the 1750s to the end of the nineteenth century. During this interval, the "era of Heroic Entomology," the majority of workers in the field were dedicated amateurs. This article traces the demographic and occupational shifts in entomology through this 150-year interval and into the early twentieth century. The survey is based on entomologists who studied beetles (Coleoptera), and who named sufficient numbers of species to have their own names abbreviated by subsequent taxonomists. In the eighteenth century, 27 entomologists achieved this level of prominence, of whom 37% were academics, 19% were doctors, 11% had private incomes, 19% were clergymen, and 8% were government officials. Many of those with private incomes were members of the European aristocracy, and all but one were European men. The nineteenth century list included 192 entomologists, of whom 17% were academics, 16% were museum curators, 2% were school teachers, 15% were doctors, 6% were military men, 7% were merchants, 2% were government entomologists, 6% had private incomes, 5% were clergymen, 5% were government officials, and 4% were lawyers. The demographics of entomology shifted dramatically in the nineteenth century. Whereas many of the noteworthy entomologists of the eighteenth century were German, Swedish, or French, in the nineteenth century, many more European countries are represented, and almost one-fifth of the noteworthy entomologists were from the United States. The nineteenth century list, like the eighteenth century list, contains no women. By the twentieth century, 63% of 178 noteworthy systematic entomologists were paid professionals, teaching entomology courses in universities, or studying insect taxonomy in museums and government-sponsored laboratories. Only one person on the twentieth century list had a private income, but women (ten individuals) were included on the list for the first time. PMID- 23928826 TI - Spatial frequency filtering and the direct control of fixation durations during scene viewing. AB - The present study employed a saccade-contingent change paradigm to investigate the effect of spatial frequency filtering on fixation durations during scene viewing. Subjects viewed grayscale scenes while encoding them for a later memory test. During randomly chosen saccades, the scene was replaced with an alternate version that remained throughout the critical fixation that followed. In Experiment 1, during the critical fixation, the scene could be changed to high pass and low-pass spatial frequency filtered versions. Under both conditions, fixation durations increased, and the low-pass condition produced a greater effect than the high-pass condition. In subsequent experiments, we manipulated the familiarity of scene information during the critical fixation by flipping the filtered scenes upside down or horizontally. Under these conditions, we observed lengthening of fixation durations but no difference between the high-pass and low pass conditions, suggesting that the filtering effect is related to the mismatch between information extracted within the critical fixation and the ongoing scene representation in memory. We also conducted control experiments that tested the effect of changes to scene orientation (Experiment 2a) and the addition of color to a grayscale scene (Experiment 2b). Fixation distribution analysis suggested two effects on the distribution fixation durations: a fast-acting effect that was sensitive to all transsaccadic changes tested and a later effect in the tail of the distribution that was likely tied to the processing of scene information. These findings are discussed in the context of theories of oculomotor control during scene viewing. PMID- 23928825 TI - Genome-wide identification and characterisation of F-box family in maize. AB - F-box-containing proteins, as the key components of the protein degradation machinery, are widely distributed in higher plants and are considered as one of the largest known families of regulatory proteins. The F-box protein family plays a crucial role in plant growth and development and in response to biotic and abiotic stresses. However, systematic analysis of the F-box family in maize (Zea mays) has not been reported yet. In this paper, we identified and characterised the maize F-box genes in a genome-wide scale, including phylogenetic analysis, chromosome distribution, gene structure, promoter analysis and gene expression profiles. A total of 359 F-box genes were identified and divided into 15 subgroups by phylogenetic analysis. The F-box domain was relatively conserved, whereas additional motifs outside the F-box domain may indicate the functional diversification of maize F-box genes. These genes were unevenly distributed in ten maize chromosomes, suggesting that they expanded in the maize genome because of tandem and segmental duplication events. The expression profiles suggested that the maize F-box genes had temporal and spatial expression patterns. Putative cis-acting regulatory DNA elements involved in abiotic stresses were observed in maize F-box gene promoters. The gene expression profiles under abiotic stresses also suggested that some genes participated in stress responsive pathways. Furthermore, ten genes were chosen for quantitative real-time PCR analysis under drought stress and the results were consistent with the microarray data. This study has produced a comparative genomics analysis of the maize ZmFBX gene family that can be used in further studies to uncover their roles in maize growth and development. PMID- 23928827 TI - The impact of memantine in combination with acetylcholinesterase inhibitors on admission of patients with Alzheimer's disease to nursing homes: cost effectiveness analysis in France. AB - The costs associated with the care of Alzheimer's disease patients are very high, particularly those associated with nursing home placement. The combination of a cholinesterase inhibitor (ChEI) and memantine has been shown to significantly delay admission to nursing homes as compared to treatment with a ChEI alone. The objective of this cost-effectiveness analysis was to evaluate the economic impact of the concomitant use of memantine and ChEI compared to ChEI alone. Markov modelling was used in order to simulate transitions over time among three discrete health states (non-institutionalised, institutionalised and deceased). Transition probabilities were obtained from observational studies and French national statistics, utilities from a previous US survey and costs from French national statistics. The analysis was conducted from societal and healthcare system perspectives. Mean time to nursing home admission was 4.57 years for ChEIs alone and 5.54 years for combination therapy, corresponding to 0.98 additional years, corresponding to a gain in quality adjusted life years (QALYs) of 0.25. From a healthcare system perspective, overall costs were ?98,609 for ChEIs alone and ?90,268 for combination therapy, representing cost savings of ?8,341. From a societal perspective, overall costs were ?122,039 and ?118,721, respectively, representing cost savings of ?3,318. Deterministic and probabilistic (Monte Carlo simulations) sensitivity analyses indicated that combination therapy would be the dominant strategy in most scenarios. In conclusion, combination therapy with memantine and a ChEI is a cost-saving alternative compared to ChEI alone as it is associated with lower cost and increased QALYs from both a societal and a healthcare perspective. PMID- 23928828 TI - One-step spray processing of high power all-solid-state supercapacitors. AB - Aqueous suspensions of multi-wall carbon nanotubes (MWNTs) in dilute H2SO4 were sprayed onto both sides of a Nafion membrane and dried to fabricate flexible solid-state supercapacitors. A single cell with MWNT-only electrodes had a capacitance of 57 F g(-1) per electrode at 2 mV s(-1) and 44 F g(-1) at 150 mV s( 1) but with low H(+) mobility. Cells with MWNT + ionomer hybrid electrodes showed higher H(+) mobility, and the electric double layer (EDL) capacitance increased to 145 F g(-1) at 2 mV s(-1) and 91 F g(-1) at 150 mV s(-1). The energy and power densities of one electrode charged to 1 V at 1 A g(-1) were 12.9 Wh kg(-1) and 3.3 kW kg(-1) respectively. Three solid-state supercapacitor cells connected in series charged to 3 V at 1 and 2 A g(-1) provided a device power density of 8.9 kW kg(-1) at 1 A g(-1) and 9.4 kW kg(-1) at 2 A g(-1), the highest for all-solid state EDL supercapacitors. PMID- 23928829 TI - Chemopreventive effects of aloin against 1,2-dimethylhydrazine-induced preneoplastic lesions in the colon of Wistar rats. AB - Chemoprevention opens new window in the prevention of all types of cancers including colon cancer. Aloin, an anthracycline in plant pigment, can be utilized as a protective agent in cancer induction. In the present study, we have evaluated the chemopreventive efficacy of aloin against 1,2-dimethylhydrazine (DMH)-induced preneoplastic lesions in the colon of Wistar rats. DMH-induced aberrant crypt foci (ACF) and mucin-depleted foci (MDF) have been used as biomarkers of colon cancer. Efficacy of aloin against the colon toxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, lipid peroxidation, ACF, MDF, histopathological changes, and expression levels of molecular markers of inflammation and tumor promotion. Aloin pretreatment ameliorates the damaging effects induced by DMH through a protective mechanism that involved reduction in increased oxidative stress enzymes (p < 0.001), ACF, MDF, cyclooxygenase-2, inducible nitric oxide synthase, interleukin-6, proliferating cell nuclear antigen protein expression, and tumor necrosis factor alpha (p < 0.001) release. From the results, it could be concluded that aloin clearly protects against chemically induced colon toxicity and acts reasonably by inducing antioxidant level, anti-inflammatory and antiproliferative markers. PMID- 23928830 TI - Quercetin protects rat hepatocytes from oxidative damage induced by ethanol and iron by maintaining intercellular liable iron pool. AB - Accumulating evidence has shown that ethanol-induced iron overload plays a crucial role in the development and progression of alcoholic liver disease. We designed the present study to investigate the potential protective effect of quercetin, a naturally occurring iron-chelating antioxidant on alcoholic iron overload and oxidative stress. Ethanol-incubated (100 mmol/L) rat primary hepatocytes were co-treated by quercetin (100 umol/L) and different dose of ferric nitrilotriacetate (Fe-NTA) for 24 h. When the hepatic enzyme releases in the culture medium, redox status of hepatocytes and the intercellular labile iron pool (LIP) level were assayed. Our data showed that Fe-NTA dose dependently induced cellular leakage of aspartate transaminase and lactate dehydrogenase, glutathione depletion, superoxide dismutase inactivation, and overproduction of malondialdehyde) and reactive oxygen species (ROS) of intact and especially ethanol-incubated hepatocytes. The oxidative damage resulted from ethanol, Fe NTA, and especially their combined treatment was substantially alleviated by quercetin, accompanying the corresponding normalization of intercellular LIP level. Iron in excess, thus, may aggravate ethanol hepatotoxicity through Fenton active LIP, and quercetin attenuated ethanol-induced iron and oxidative stress. To maintain intercellular LIP contributes to the hepatoprotective effect of quercetin besides its direct ROS-quenching activity. PMID- 23928831 TI - In vivo ozone exposure does not increase DNA single-strand breaks in human peripheral lymphocytes. AB - In this randomized parallel study, we examined whether an acute ozone (O3) exposure leads to increased DNA strand breaks in human lymphocytes. The groups were exposed to 0.21 ppm O3 or filtered air for two hours. 30min and 4.5 h after exposure, DNA damage was determined in isolated lymphocytes using the Fast Micromethod. There was no detectable effect after O3 exposure. We conclude that an acute O3 exposure at the tested concentration does not lead to persistent DNA damage. PMID- 23928832 TI - The effect of lead exposure on tracheal responsiveness to methacholine and ovalbumin, total and differential white blood cells count, and serum levels of immunoglobulin E, histamine, and cytokines in guinea pigs. AB - The effect of exposure to inhaled lead acetate in guinea pigs was evaluated. The present study comprised of five groups of guinea pigs including control (C), sensitized to ovalbumin (OA; S) and three groups exposed to 0.1, 0.2, and 0.4 M inhaled lead (Pb; n = 6 for each group). Tracheal responsiveness to methacholine and OA, total and differential white blood cells (WBCs) count in lung lavage, serum levels of cytokines (interferon gamma (IFN-gamma) and interleukin 4 (IL 4)), histamines, and immunoglobulin E (IgE), and Pb concentration in lung were measured. Tracheal responsiveness to methacholine, OA, total and differential WBC types as well as IL-4, IFN-gamma, histamine, and IgE were significantly increased but IFN-gamma/IL-4 were significantly decreased in sensitized animals as well as those exposed to high Pb concentrations when compared with the control group (from p < 0.05 to p < 0.001). In addition, there was not a significant difference in most measured values between animals exposed to high Pb concentration and group S. The Pb concentration in lung tissues of animals exposed to all three Pb concentrations was significantly higher than that of group C (p < 0.001 for all cases).These results showed that inhaled lead acetate exposure can induce lung inflammatory changes similar to sensitized animals. Therefore, exposure to environmental Pb pollution may cause asthma-like changes. PMID- 23928833 TI - Initial experience with stereotactic body radiation therapy for localized prostate cancer using helical tomotherapy. AB - PURPOSE: Single-institution single-arm prospective study. Endpoint: To assess whether there are more than 5 % of men having grade 3 GU or any grade 3 GI acute toxicity during stereotactic body radiation therapy (SBRT) for prostate cancer using helical tomotherapy. METHODS: Since May 2012, 17 prostate cancer patients were treated with helical tomotherapy. The exclusion criteria used are the following: Gleason score >=8, PSA >20 ng/ml, cT3b-4, IPSS >=20 and history of acute urinary retention. CTV included the prostate gland and 1 cm of seminal vesicles in the low-risk group (LR) or the seminal vesicles completely in the intermediate (IR) and high-risk (HR) NCCN groups. CTV margins ranged from 2 to 8 mm, while PTV margins were 2 to 9 mm. Patients received eight fractions of 5.48 Gy (LR) or 5.65 Gy (IR, HR) on alternate days. Total equivalent doses at 2 Gy per fraction are 87.4 for LR and 92.3 Gy for IR-HR using an alpha/beta value of 1.5. Correspondent figures for a alpha/beta of 3 are 74.3 Gy and 78.2 Gy, respectively. Megavoltage CT (MVCT) for on-line correction was taken before every fraction. RESULTS: The patient distribution by risk group is 29, 47 and 24 % for LR, IR and HR, respectively. 82 % received neoadjuvant-concomitant hormonal therapy. Acute GU toxicity grade 1, 2 and 3 was found in 70, 6 and 0 % of men. GI toxicity was observed in 50, 0 and 0. After 136 MVCT, the standard deviation of the mean individual corrections in the anterior-posterior direction was 2.5 mm. CONCLUSION: SBRT for prostate cancer using helical tomotherapy is feasible. Initial results show an early toxicity profile no worse than SBRT delivered with robotic radiosurgery or conventionally fractionated radiotherapy. PMID- 23928834 TI - Targeting dexamethasone to macrophages in a porcine endotoxemic model. AB - OBJECTIVES: Macrophages are important cells in immunity and the main producers of pro-inflammatory cytokines. The main objective was to evaluate if specific delivery of glucocorticoid to the macrophage receptor CD163 is superior to systemic glucocorticoid therapy in dampening the cytokine response to lipopolysaccharide infusion in pigs. DESIGN: Two randomized, placebo-controlled trials. SETTING: University hospital laboratory. SUBJECTS: Female farm-bred pigs (26-31 kg). DESIGN: A humanized antibody that binds to pig and human CD163 was produced, characterized, and conjugated with dexamethasone. In the first study (total n = 12), pigs were randomly assigned to four groups: 1) saline; 2) dexamethasone (1.0 mg/kg); 3) dexamethasone (0.02 mg/kg); and 4) anti-CD163 conjugated dexamethasone (0.02 mg/kg). In the second study (total n = 36), two additional groups were included in addition to the four original groups: 5) anti CD163-conjugated dexamethasone (0.005 mg/kg); 6) unconjugated anti-CD163. Treatments were given 20 hours prior to infusion of lipopolysaccharide (1 ug * kg * h) for 5 hours. Blood samples were analyzed for cytokines, cortisol, and adrenocorticotropic hormone. RESULTS: In the saline group, lipopolysaccharide increased cytokine and plasma cortisol levels. In both studies, dexamethasone (1 mg/kg) and anti-CD163 dexamethasone (0.02 mg/kg) uniformly attenuated tumor necrosis factor-alpha peak levels (both p < 0.05) compared with low-dose dexamethasone (0.02 mg/kg). However, dexamethasone 1 mg/kg significantly suppressed plasma cortisol and adrenocorticotropic hormone levels compared with anti-CD163 dexamethasone (0.02 mg/kg; p < 0.05). No significant hemodynamic difference existed between groups. The anti-CD163 dexamethasone drug conjugate exhibited a fast plasma clearance, with a half-life of approximately 5-8 minutes. CONCLUSION: Targeted delivery of dexamethasone to macrophages using a humanized CD163 antibody as carrier exhibits anti-inflammatory effects comparable with 50 times higher concentrations of free dexamethasone and does not inhibit endogenous cortisol production. This antibody-drug complex showing similar affinity and specificity for human CD163 is, therefore, a promising drug candidate in this novel type of anti-inflammatory therapy. PMID- 23928835 TI - National surgical quality improvement program underestimates the risk associated with mild and moderate postoperative acute kidney injury. AB - OBJECTIVES: In a single-center cohort of surgical patients, we assessed the association between postoperative change in serum creatinine and adverse outcomes and compared the American College of Surgeons National Surgical Quality Improvement Program's definition for acute kidney injury with consensus risk, injury, failure, loss, and end-stage kidney and Kidney Disease: Improving Global Outcomes definitions. DESIGN: Retrospective single-center cohort. SETTING: Academic tertiary medical center. PATIENTS: Twenty-seven thousand eight hundred forty-one adult patients with no previous history of chronic kidney disease undergoing major surgery. INTERVENTIONS: Risk, injury, failure, loss, and end stage kidney defines acute kidney injury as change in serum creatinine greater than or equal to 50% while Kidney Disease: Improving Global Outcomes uses 0.3 mg/dL change from the reference serum creatinine. Since National Surgical Quality Improvement Program defines acute kidney injury as serum creatinine change greater than 2 mg/dL, it may underestimate the risk associated with less severe acute kidney injury. MEASUREMENTS AND MAIN RESULTS: The optimal discrimination limits for both percent and absolute serum creatinine changes were calculated by maximizing sensitivity and specificity along the receiver operating characteristic curves for postoperative complications and mortality. Although prevalence of risk, injury, failure, loss, and end-stage kidney-acute kidney injury was 37%, only 7% of risk, injury, failure, loss, and end-stage kidney acute kidney injury patients would be diagnosed with acute kidney injury using the National Surgical Quality Improvement Program definition. In multivariable logistic models, patients with risk, injury, failure, loss, and end-stage kidney or Kidney Disease: Improving Global Outcomes-acute kidney injury had a 10 times higher odds of dying compared to patients without acute kidney injury. The optimal discrimination limits for change in serum creatinine associated with adverse postoperative outcomes were as low as 0.2 mg/dL while the National Surgical Quality Improvement Program discrimination limit of 2.0 mg/dL had low sensitivity (0.05-0.28). CONCLUSIONS: Current American College of Surgeons National Surgical Quality Improvement Program definition underestimates the risk associated with mild and moderate acute kidney injury otherwise captured by the consensus risk, injury, failure, loss, and end-stage kidney and Kidney Disease: Improving Global Outcomes criteria. PMID- 23928836 TI - Doxycycline reduces cardiac matrix metalloproteinase-2 activity but does not ameliorate myocardial dysfunction during reperfusion in coronary artery bypass patients undergoing cardiopulmonary bypass. AB - OBJECTIVES: Matrix metalloproteinase-2 proteolyzes intracellular proteins in the heart and induces acute myocardial contractile dysfunction in ischemia reperfusion injury. Doxycycline, a matrix metalloproteinase inhibitor, prevented matrix metalloproteinase-2-induced troponin I cleavage in rat hearts and improved contractile function following ischemia-reperfusion. In patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass, increased atrial matrix metalloproteinase-2 activity was inversely correlated with cardiac mechanical function at 3 hours reperfusion. We performed a study in patients with coronary artery disease undergoing primary elective coronary artery bypass graft surgery with cardiopulmonary bypass to determine whether doxycycline reduces cardiac mechanical dysfunction, matrix metalloproteinase activity, and troponin I degradation after reperfusion. DESIGN: Randomized, double-blinded, placebo controlled study. SETTING: University of Alberta Hospital. PATIENTS: Forty-two patients with coronary artery disease undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. INTERVENTIONS: Patients were randomized to receive either oral administration of 20 mg of doxycycline or matching placebo pill twice a day at least 2 days prior to surgery, on the day of surgery, and for the first 3 postoperative days. MEASUREMENTS AND MAIN RESULTS: Left ventricular stroke work index was examined prior to cardiopulmonary bypass and at 24 hours reperfusion. Right atrial biopsies were collected before cardiopulmonary bypass and 10 minutes after aortic cross-clamp release to determine matrix metalloproteinase-2 activity and troponin I level. Blood was collected to determine matrix metalloproteinase activity and interleukin-6, C-reactive protein, and troponin I levels. Cardiac 72-kDa matrix metalloproteinase-2 activity was lower upon reperfusion in biopsies from the doxycycline group (p = 0.01), and the increase of matrix metalloproteinase-2 activity in the placebo group due to reperfusion did not appear in the doxycycline group (p = 0.05). Doxycycline, however, did not ameliorate cardiac mechanical dysfunction following reperfusion or the cardiopulmonary bypass-coronary artery bypass graft-induced increased plasma matrix metalloproteinase-9, interleukin-6, and C-reactive protein levels. Cardiopulmonary bypass-coronary artery bypass graft or doxycycline did not change tissue or plasma troponin I levels at 10 minutes reperfusion. CONCLUSIONS: Although doxycycline did not improve myocardial stunning following coronary artery bypass graft surgery with cardiopulmonary bypass, it reduced cardiac matrix metalloproteinase-2 activity in these patients. A larger trial and/or higher dose of doxycycline may yet be warranted. PMID- 23928837 TI - The landscape for diabetes education: results of the 2012 AADE National Diabetes Education Practice Survey. AB - PURPOSE: The National Member Practice Survey (NPS) of the American Association of Diabetes Educators (AADE) is conducted biannually to describe the current diabetes education practice in the United States and identify trends, opportunities, and areas for improvement. METHODS: The 2012 NPS contained 49 questions about diabetes education providers, patients, and programs. The survey, sent electronically to approximately 13,000 AADE members, was completed by 3644 members. Testing was completed using a significance level of .05 or 95% confidence. RESULTS: While nurses and dietitians continued to comprise the majority of diabetes educators in 2012, a significant increase from 2010 occurred in the respondents identified as pharmacists (5% vs. 4%). Individuals holding the certified diabetes educator (CDE) credential decreased slightly in 2012 from 2010. Practice settings for diabetes education increased significantly in 2012 versus 2010 for hospital outpatient/clinic (44% vs. 37%) and hospital inpatient (20% vs. 15%) settings. Prediabetes education was provided by 78% of respondents. Nearly 53% of educators indicated they devoted more than 4 hours per week to data entry, significantly higher than any other amount of time. Collection of clinical and behavioral outcomes increased significantly in 2012 from 2010. CONCLUSIONS: Results of the 2012 NPS provide evidence that the practice of diabetes education is continuing to adapt to evolving models of health care in the United States by expanding the mix of practitioners providing education, engaging in necessary system support activities, and broadening the range of patients seen to include individuals at risk of developing diabetes. PMID- 23928838 TI - State-to-state quantum dynamics of the F + HCl (vi = 0, ji = 0) -> HF(vf, jf) + Cl reaction on the ground state potential energy surface. AB - The state-to-state reaction dynamics of the title reaction is investigated on the ground electronic state potential energy surface using two quantum dynamical methods. The results obtained using the Chebyshev real wave packet method are in excellent agreement with those obtained using the time-independent method, except at low translational energies. It is shown that this exothermic hydrogen abstraction reaction is direct, resulting in a strong back-scattered bias in the product angular distribution. The HF product is highly excited internally. Agreement with available experimental data is only qualitative. We discuss several possible causes of disagreement with experiment. PMID- 23928839 TI - Poor correlation between the removal or deposition of pollen grains and frequency of pollinator contact with sex organs. AB - Pollinators deposit pollen grains on stigmas and remove pollen grains from anthers. The mechanics of these transfers can now be quantified with the use of high-speed video. We videoed hawkmoths, carpenter bees, and swallowtail butterflies pollinating Clerodendrum trichotomum. The number of grains deposited on stigmas did not vary significantly with the number of times pollinators contacted stigmas. In contrast, pollen removal from the anthers increased significantly with the number of contacts to anthers. Pollen removal varied among the three types of pollinators. Also, the three types carried pollen on different parts of their bodies. In hawkmoths and carpenter bees, a large number of contacted body part with anthers differed significantly from the body part that attached a large number of pollen grains. Our results indicate that a large number of contacts by pollinators does not increase either the male or female reproductive success of plants compared to a small number of contacts during a visit. PMID- 23928840 TI - High beta-glucosidase secretion in Saccharomyces cerevisiae improves the efficiency of cellulase hydrolysis and ethanol production in simultaneous saccharification and fermentation. AB - Bioethanol production from lignocellulose is considered as a sustainable biofuel supply. However, the low cellulose hydrolysis efficiency limits the cellulosic ethanol production. The cellulase is strongly inhibited by the major end product cellobiose, which can be relieved by the addition of beta-glucosidase. In this study, three beta-glucosidases from different organisms were respectively expressed in Saccharomyces cerevisiae and the beta-glucosidase from Saccharomycopsis fibuligera showed the best activity (5.2 U/ml). The recombinant strain with S. fibuligera beta-glucosidase could metabolize cellobiose with a specific growth rate similar to the control strain in glucose. This recombinant strain showed higher hydrolysis efficiency in the cellulose simultaneous saccharification and fermentation, when using the Trichoderma reesei cellulase, which is short of the beta-glucosidase activity. The final ethanol concentration was 110% (using Avicel) and 89% (using acid-pretreated corncob) higher than the control strain. These results demonstrated the effect of beta-glucosidase secretion in the recombinant S. cerevisiae for enhancing cellulosic ethanol conversion. PMID- 23928841 TI - Targeting acetate kinase: inhibitors as potential bacteriostatics. AB - Despite the importance of acetate kinase in the metabolism of bacteria, limited structural studies have been carried out on this enzyme. In this study, a three dimensional structure of the Escherichia coli acetate kinase was constructed by use of molecular modeling methods. In the next stage, by considering the structure of the catalytic intermediate, trifluoroethanol (TFE) and trifluoroethyl butyrate were proposed as potential inhibitors of the enzyme. The putative binding mode of these compounds was studied with the use of a docking program, which revealed that they can fit well into the enzyme. To study the role of these potential enzyme inhibitors in the metabolic pathway of E. coli, their effects on the growth of this bacterium were studied. The results showed that growth was considerably reduced in the presence of these inhibitors. Changes in the profile of the metabolic products were studied by proton nuclear magnetic resonance spectroscopy. Remarkable changes were observed in the quantity of acetate, but other products were less altered. In this study, inhibition of growth by the two inhibitors as reflected by a change in the metabolism of E. coli suggests the potential use of these compounds (particularly TFE) as bacteriostatic agents. PMID- 23928842 TI - Application of scale-up criterion of constant oxygen mass transfer coefficient (kLa) for production of itaconic acid in a 50 L pilot-scale fermentor by fungal cells of Aspergillus terreus. AB - The scale-up criterion of constant oxygen mass transfer coefficient (kLa) was applied for the production of itaconic acid (IA) in a 50 L pilot-scale fermentor by the fungal cells of Aspergillus terreus. Various operating conditions were examined to collect as many kLa data as possible by adjusting the stirring speed and aeration rate in both 5 L and 50 L fermentor systems. In the fermentations performed with the 5 L fermentor, the highest IA production was obtained under the operating conditions of 200 rpm and 1.5 vvm. Accordingly, we intended to find out parallel agitation and aeration rates in the 50 L fermentor system, under which the kLa value measured was almost identical to that (0.02 sec(-1)) of the 5 L system. The conditions of 180 rpm and 0.5 vvm in the 50 L system turned out to be optimal for providing almost the same volumetric amount of dissolved oxygen (DO) into the fermentor, without causing shear damage to the producing cells due to excessive agitation. Practically identical fermentation physiologies were observed in both fermentations performed under those respective operating conditions, as demonstrated by nearly the same values of volumetric (Qp) and specific (qp) IA production rates, IA production yield (Yp/s), and specific growth rate (MU). Specifically, the negligible difference of the specific growth rate (MU) between the two cultures (i.e., 0.029 h(-1) vs. 0.031 h(-1)) was notable, considering the fact that MU normally has a significant influence on qp in the biosynthesis of secondary metabolites such as itaconic acid. PMID- 23928843 TI - Extracellular novel metalloprotease from Xenorhabdus indica and its potential as an insecticidal agent. AB - Proteases produced by Xenorhabdus are known to play a significant role in virulence leading to insect mortality. The present study was undertaken to purify and characterize protease from Xenorhabdus indica, an endosymbiont of nematode Steinernema thermophilum, and to decipher its role in insect mortality and its efficacy to control Helicoverpa armigera. A set of 10 strains of Xenorhabdus isolated from different regions of India were screened for protease activity on the basis of zone of clearing on gelatin agar plates. One potent strain of Xenorhabdus indica was selected for the production of protease, and the highest production (1,552 U/ml) was observed at 15-18 h of incubation at 28 degrees C in soya casein digest broth. The extracellular protease was purified from culture supernatant using ammonium sulfate precipitation and ion-exchange chromatography. The enzyme was further characterized by SDS-PAGE and zymography, which confirmed the purity of the protein and its molecular mass was found to be ~52 kDa. Further MALDI-TOF/TOF analysis and effect of metal chelating agent 1,10-phenanthrolin study revealed the nature of the purified protease as a secreted alkaline metalloprotease. The bioefficacy of the purified protease was also tested against cotton bollworm (Helicoverpa armigera) and resulted in 67.9 +/- 0.64% mortality within one week. This purified protease has the potential to be developed as a natural insecticidal agent against a broad range of agriculturally important insects. PMID- 23928844 TI - A novel radiation-resistant strain of Filobasidium sp. isolated from the West Sea of Korea. AB - A novel radiation-resistant Filobasidium sp. yeast strain was isolated from seawater. Along with this strain, a total of 656 yeast isolates were purified from seawater samples collected from three locations in the West Sea of Korea and assessed for their radiation tolerance. Among these isolates, five were found to survive a 5 kGy radiation dose. The most radiationresistant strain was classified as Filobasidium sp. based on 18S rDNA sequence analysis and hence was named Filobasidium RRY1 (Radiation-Resistant Yeast 1). RRY1 differed from F. elegans, which is closely related to RRY1, in terms of the optimal growth temperature and radiation resistance, and was resistant to high doses of gamma-ionizing radiation (D10: 6-7 kGy). When exposed to a high dose of 3 kGy irradiation, the RRY1 cells remained intact and undistorted, with negligible cell death. When these irradiated cells were allowed to recover, the cells fully repaired their genomic DNA within 3 h of growth recovery. This is the first report in which a radiation resistant response has been investigated at the physiological, morphological, and molecular levels in a strain of Filobasidium sp. PMID- 23928845 TI - Insight into norfloxacin resistance of Acinetobacter oleivorans DR1: target gene mutation, persister, and RNA-Seq analyses. AB - Antibiotic resistance of soilborne Acinetobacter species has been poorly explored. In this study, norfloxacin resistance of a soil bacterium, Acinetobacter oleivorans DR1, was investigated. The frequencies of mutant appearance of all tested non-pathogenic Acinetobacter strains were lower than those of pathogenic strains under minimum inhibitory concentration (MIC). When the quinolone-resistance-determining region of the gyrA gene was examined, only one mutant (His78Asn) out of 10 resistant variants had a mutation. Whole transcriptome analysis using a RNA-Seq demonstrated that genes involved in SOS response and DNA repair were significantly up-regulated by norfloxacin. Determining the MICs of survival cells after norfloxacin treatment confirmed some of those cells were indeed persister cells. Ten colonies, randomly selected from among those that survived in the presence of norfloxacin, did not exhibit increased MIC. Thus, both the low mutation frequency of the target gene and SOS response under norfloxacin suggested that persister formation might contribute to the resistance of DR1 against norfloxacin. The persister frequency increased without a change in MIC when stationary phase cells, low growth rates conditions, and growth-deficient dnaJ mutant were used. Taken together, our comprehensive approach, which included mutational analysis of the target gene, persister formation assays, and RNA sequencing, indicated that DR1 survival when exposed to norfloxacin is related not only to target gene mutation but also to persister formation, possibly through up-regulation of the SOS response and DNA repair genes. PMID- 23928846 TI - Enhanced biodegradation of lindane using oil-in-water bio-microemulsion stabilized by biosurfactant produced by a new yeast strain, Pseudozyma VITJzN01. AB - Organochlorine pesticide residues continue to remain as a major environmental threat worldwide. Lindane is an organochlorine pesticide widely used as an acaricide in medicine and agriculture. In the present study, a new lindane degrading yeast strain, Pseudozyma VITJzN01, was identified as a copious producer of glycolipid biosurfactant. The glycolipid structure and type were elucidated by FTIR, NMR spectroscopy, and GC-MS analysis. The surface activity and stability of the glycolipid was analyzed. The glycolipids, characterized as mannosylerythritol lipids (MELs), exhibited excellent surface active properties and the surface tension of water was reduced to 29 mN/m. The glycolipid was stable over a wide range of pH, temperature, and salinity, showing a very low CMC of 25 mg/l. Bio microemulsion of olive oil-in-water (O/W) was prepared using the purified biosurfactant without addition of any synthetic cosurfactants, for lindane solubilization and enhanced degradation assay in liquid and soil slurry. The O/W bio-microemulsions enhanced the solubility of lindane up to 40-folds. Degradation of lindane (700 mg/l) by VITJzN01 in liquid medium amended with bio microemulsions was found to be enhanced by 36% in 2 days, compared with degradation in 12 days in the absence of bio-microemulsions. Lindane-spiked soil slurry incubated with bio-microemulsions also showed 20-40% enhanced degradation compared with the treatment with glycolipids or yeast alone. This is the first report on lindane degradation by Pseudozyma sp., and application of bio microemulsions for enhanced lindane degradation. MEL-stabilized bio microemulsions can serve as a potential tool for enhanced remediation of diverse lindanecontaminated environments. PMID- 23928847 TI - Rv3168 phosphotransferase activity mediates kanamycin resistance in Mycobacterium tuberculosis. AB - Tuberculosis is a worldwide epidemic disease caused by Mycobacterium tuberculosis, with an estimated one-third of the human population currently affected. Treatment of this disease with aminoglycoside antibiotics has become less effective owing to antibiotic resistance. Recent determination of the crystal structure of the M. tuberculosis Rv3168 protein suggests a structure similar to that of Enterococcus faecalis APH(3')-IIIa, and that this protein may be an aminoglycoside phosphotransferase. To determine whether Rv3168 confers antibiotic resistance against kanamycin, we performed dose-response antibiotic resistance experiments using kanamycin. Expression of the Rv3168 protein in Escherichia coli conferred antibiotic resistance against 100 MUM kanamycin, a concentration that effected cell growth arrest in the parental E. coli strain and an E. coli strain expressing the Rv3168(D249A) mutant, in which the catalytic Asp249 residue was mutated to alanine. Furthermore, we detected phosphotransferase activity of Rv3168 against kanamycin as a substrate. Moreover, docking simulation of kanamycin into the Rv3168 structure suggests that kanamycin fits well into the substrate binding pocket of the protein, and that the phosphorylation-hydroxyl-group of kanamycin was located at a position similar to that in E. faecalis APH(3')-IIIa. On the basis of these results, we suggest that the Rv3168 mediates kanamycin resistance in M. tuberculosis, likely through phosphotransferase targeting of kanamycin. PMID- 23928848 TI - The influence of the N-terminal region of antimicrobial peptide pleurocidin on fungal apoptosis. AB - In our previous study, the 25-mer antimicrobial peptide pleurocidin (Ple) had been thought to induce apoptosis in Candida albicans. This study demonstrated that reactive oxygen species (ROS) production was a major cause of Ple-induced apoptosis. Four truncated analogs were synthesized to understand the functional roles in the N- and C-terminal regions of Ple on the apoptosis. Ple, Ple (4-25), Ple (1-22), and Ple (1-19) produced ROS, including hydroxyl radicals, on the order of [Ple > Ple (1-22) > Ple (4-25) > Ple (1-19)], whereas Ple (7-25) did not induce any ROS production. The results suggested that the N-terminal deletion affected the ROS-inducing activities much more than that of the C-terminal deletion, and net hydrophobicity [Ple > Ple (1-22) > Ple (4-25) > Ple (1-19) > Ple (7-25)] was related to ROS generation rather than other primary factors like net charge. Hence, we focused on the N-terminal-truncated peptides, Ple (4-25) and Ple (7-25), and examined other apoptotic features, including mitochondrial membrane depolarization, caspase activation, phosphatidylserine externalization, and DNA and nuclear fragmentation. The results also confirmed the disappearance of apoptotic activity of Ple (7-25) by the truncation of the N-terminal region (1 6) and the specific activity patterns between Ple and analogs. In conclusion, the N-terminal region of Ple played an important role in apoptosis. PMID- 23928849 TI - Central nervous system prophylaxis with intrathecal liposomal cytarabine in diffuse large B-cell lymphomas. AB - INTRODUCTION: Central nervous system (CNS) involvement is a serious and potentially fatal complication in patients with lymphoma because it is associated with a particularly poor prognosis (median progression-free survival [PFS] of 4-6 months). Although CNS prophylaxis is considered necessary, there are no clear guidelines on identifying high-risk patients or selecting treatment regimen. OBJECTIVES: The aim of the study was to assess the safety and efficacy of CNS prophylaxis with intrathecal liposomal cytarabine. PATIENTS AND METHODS: We analyzed the data of 79 patients (46 men and 33 women; median age, 48.5 years [20 79]) with diffuse large B-cell lymphoma (83.5% of the patients) and primary mediastinal large B-cell lymphoma (16.5%). Patients were treated in the departments of hematology in Krakow and Wroclaw, Poland, between the years 2009 2012. They were considered to be at a high risk of developing CNS involvement associated with a lymphoma. RESULTS: Adverse reactions after intrathecal liposomal cytarabine were reported in 59 patients (74.7%); in 7 cases, the reactions were severe. The most common side effect was headache (67.1%). During antilymphoma therapy and prophylaxis, the functional status assessed by the Karnofsky score improved in 56 patients (70.9%) and remained unchanged in the remaining cases. A median follow-up time did not exceed 28 months (range, 1.4 52.1); during follow-up, neither median overall survival (OS) nor PFS were reached (projected OS and PFS at 48 months are 86.1% and 90.1%, respectively). CONCLUSIONS: Our results encourage the use of intrathecal liposomal cytarabine in CNS prophylaxis in patients with lymphoma. PMID- 23928850 TI - Disturbed intestinal integrity in patients with COPD: effects of activities of daily living. AB - BACKGROUND: COPD is accepted to be a multicomponent disease with various comorbidities. To our knowledge, the contribution of the GI tract to the systemic manifestation of COPD has never been investigated. This metabolically active organ may experience recurring local oxygen deficits during daily life, leading to disturbed intestinal integrity in patients with COPD. METHODS: Eighteen patients with moderate COPD (mean FEV1, 55 +/- 3% predicted) and 14 matched healthy control subjects were tested on two occasions: a baseline measurement at rest and, on another day, during the performance of activities of daily living (ADLs). To assess enterocyte damage, plasma intestinal fatty acid binding protein (IFABP) levels were determined, whereas urinary excretion of orally ingested sugar probes was measured using liquid chromatography and mass spectrometry to assess GI permeability. RESULTS: Plasma IFABP concentrations were not different between patients with COPD and healthy control subjects at rest. In contrast, 0- to 3-h urinary lactulose to rhamnose and sucralose to erythritol ratios and 5- to 24-h urinary sucralose to erythritol ratios were significantly higher in patients with COPD compared with control subjects, indicating increased permeability of the small intestine and colon. Furthermore, the performance of ADLs led to significantly increased plasma IFABP concentrations in patients with COPD but not in control subjects. Similarly, the intestinal permeability difference between patients and control subjects was intensified. CONCLUSIONS: Besides an altered intestinal permeability in patients with COPD when at rest, performing ADLs led to enterocyte damage in addition to intestinal hyperpermeability in patients with COPD but not in control subjects, indicating functional alteration in the GI tract. Hence, intestinal compromise should be considered as a new component of the multisystem disorder COPD. TRIAL REGISTRY: ISRCTN Register; No.: ISRCTN33686980; URL: www.controlled-trials.com. PMID- 23928851 TI - Metabolically healthy obesity: definitions, determinants and clinical implications. AB - Obesity is associated with increased risk of developing metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) leading to higher all-cause mortality. However accumulating evidence suggests that not all obese subjects are at increased cardiometabolic risk and that the "metabolically healthy obese" (MHO) phenotype may exist in the absence of metabolic abnormalities. Despite the knowledge of the existence of obese metabolic phenotypes for some time now there is no standard set of criteria to define metabolic health, thus impacting on the accurate estimation of the prevalence of the MHO phenotype and making comparability between studies difficult. Furthermore prospective studies tracking the development of cardiometabolic disease and mortality in MHO have also produced conflicting results. Limited data regards the determinants of the MHO phenotype exist, particularly in relation to dietary and lifestyle behaviours. In light of the current obesity epidemic it is clear that current "one size fits all" approaches to tackle obesity are largely unsuccessful. Whether dietary, lifestyle and/or therapeutic interventions based on stratification of obese individuals according to their metabolic health phenotype are more effective remains to be seen, with limited and conflicting data available so far. This review will present the current state of the art including the epidemiology of MHO and its definitions, what factors may be important in determining metabolic health status and finally, some potential implications of the MHO phenotype in the context of obesity diagnosis, interventions and treatment. PMID- 23928852 TI - Takotsubo cardiomyopathy. AB - Takotsubo cardiomyopathy (TC) is characterized by transient left ventricular apical wall motion abnormalities, chest pain with electrocardiographic changes, and modest myocardial enzymatic release mimicking acute coronary syndrome, but without significant coronary artery disease. TC is an increasingly recognized type of acquired cardiomyopathy occurring commonly after a recent stressful event, in particular emotional stress, and is relatively common in middle-aged and older women. The pathogenetic mechanism remains unknown. Catecholamine surge related to emotional distress seems to play a major role in the pathogenesis of this cardiomyopathy, rendering TC a type of neurocardiological disorder that manifests as acute but reversible heart failure. Clinicians should consider this syndrome in the differential diagnosis of patients presenting with clinical findings suggestive of acute coronary syndrome, especially in postmenopausal women with a recent history of acute emotional or physical stress. PMID- 23928853 TI - Tuning universality far from equilibrium. AB - Possible universal dynamics of a many-body system far from thermal equilibrium are explored. A focus is set on meta-stable non-thermal states exhibiting critical properties such as self-similarity and independence of the details of how the respective state has been reached. It is proposed that universal dynamics far from equilibrium can be tuned to exhibit a dynamical transition where these critical properties change qualitatively. This is demonstrated for the case of a superfluid two-component Bose gas exhibiting different types of long-lived but non-thermal critical order. Scaling exponents controlled by the ratio of experimentally tuneable coupling parameters offer themselves as natural smoking guns. The results shed light on the wealth of universal phenomena expected to exist in the far-from-equilibrium realm. PMID- 23928854 TI - A functional variant of pre-miRNA-196a2 confers risk for Behcet's disease but not for Vogt-Koyanagi-Harada syndrome or AAU in ankylosing spondylitis. AB - This study aimed to investigate the predisposition of common pre-miRNA SNPs with Behcet's disease (BD), Vogt-Koyanagi-Harada (VKH) syndrome and acute anterior uveitis (AAU) associated with ankylosing spondylitis (AS). A two-stage association study was carried out in 859 BD, 400 VKH syndrome, 209 AAU(+)AS(+) patients and 1,685 controls all belonging to a Chinese Han population. Genotyping, the expression of miR-196a and Bach1 (the target gene of miR-196a), cell proliferation, cytokine production were examined by PCR-RFLP, real-time PCR, CCK8 and ELISA. In the first stage study, the results showed significantly increased frequencies of the miR-196a2/rs11614913 TT genotype and T allele in BD patients (adjusted P(c) = 0.024, OR = 1.63; adjusted P(c) = 5.4 * 10(-3), OR = 1.45, respectively). However, no significant association of the tested SNPs with VKH and AAU(+)AS(+) patients was observed. The second stage and combined studies confirmed the association of rs11614913 with BD (TT genotype: adjusted P(c) = 6*10(-5), OR = 1.53; T allele: adjusted P(c) = 8*10(-6), OR = 1.35; CC genotype: adjusted P(c) = 0.024, OR = 0.68). A stratified analysis showed an association of the rs11614913 TT genotype and T allele with the arthritis subgroup of BD (P(c) = 5.3 * 10(-3), OR = 1.89; P(c) = 0.015, OR = 1.56, respectively). Functional experiments showed a decreased miR-196a expression, an increased Bach1 expression and an increased production of IL-1beta and MCP-1 in TT cases compared to CC cases (P = 0.023, P = 0.0073, P = 0.012, P = 0.002, respectively). This study shows that a functional variant of miR-196a2 confers risk for BD but not for VKH syndrome or AAU(+)AS(+) by modulating the miR-196a gene expression and by regulating pro-inflammatory IL-1beta and MCP-1 production. PMID- 23928855 TI - TDAG51 deficiency promotes oxidative stress-induced apoptosis through the generation of reactive oxygen species in mouse embryonic fibroblasts. AB - Apoptosis has an important role in maintaining tissue homeostasis in cellular stress responses such as inflammation, endoplasmic reticulum stress, and oxidative stress. T-cell death-associated gene 51 (TDAG51) is a member of the pleckstrin homology-like domain family and was first identified as a pro apoptotic gene in T-cell receptor-mediated cell death. However, its pro-apoptotic function remains controversial. In this study, we investigated the role of TDAG51 in oxidative stress-induced apoptotic cell death in mouse embryonic fibroblasts (MEFs). TDAG51 expression was highly increased by oxidative stress responses. In response to oxidative stress, the production of intracellular reactive oxygen species was significantly enhanced in TDAG51-deficient MEFs, resulting in the activation of caspase-3. Thus, TDAG51 deficiency promotes apoptotic cell death in MEFs, and these results indicate that TDAG51 has a protective role in oxidative stress-induced cell death in MEFs. PMID- 23928856 TI - Seamless correction of the sickle cell disease mutation of the HBB gene in human induced pluripotent stem cells using TALENs. AB - Sickle cell disease (SCD) is the most common human genetic disease which is caused by a single mutation of human beta-globin (HBB) gene. The lack of long term treatment makes the development of reliable cell and gene therapies highly desirable. Disease-specific patient-derived human induced pluripotent stem cells (hiPSCs) have great potential for developing novel cell and gene therapies. With the disease-causing mutations corrected in situ, patient-derived hiPSCs can restore normal cell functions and serve as a renewable autologous cell source for the treatment of genetic disorders. Here we successfully utilized transcription activator-like effector nucleases (TALENs), a recently emerged novel genome editing tool, to correct the SCD mutation in patient-derived hiPSCs. The TALENs we have engineered are highly specific and generate minimal off-target effects. In combination with piggyBac transposon, TALEN-mediated gene targeting leaves no residual ectopic sequences at the site of correction and the corrected hiPSCs retain full pluripotency and a normal karyotype. Our study demonstrates an important first step of using TALENs for the treatment of genetic diseases such as SCD, which represents a significant advance toward hiPSC-based cell and gene therapies. PMID- 23928857 TI - Feasibility of clofarabine cytoreduction followed by haploidentical hematopoietic stem cell transplantation in patients with relapsed or refractory advanced acute leukemia. AB - Clofarabine is a novel purine nucleoside analogue with immunosuppressive and anti leukemic activity in acute lymphoblastic and myeloid leukemia (AML, ALL). This retrospective study was performed to evaluate the feasibility and anti-leukemic activity of a sequential therapy using clofarabine for cytoreduction followed by conditioning for haploidentical hematopoietic stem cell transplantation (HSCT) in patients with non-remission acute leukemia. Patients received clofarabine (5 * 30 mg/m2 IV) followed by a T cell replete haploidentical transplantation for AML (n = 15) or ALL (n = 3). Conditioning consisted of fludarabine, cyclophosphamide plus either melphalan, total body irradiation or treosulfan/etoposide. High-dose cyclophosphamide was administered for post-grafting immunosuppression. Neutrophil engraftment was achieved in 83 % and complete remission in 78% at day +30. The rate of acute graft versus host disease (GvHD) grade II-IV was 22%, while chronic GvHD occured in five patients (28%). Non-relapse mortality (NRM) after 1 year was 23%. At a median follow-up of 19 months, estimated overall survival and relapse free survival at 1 year from haploidentical HSCT were 56 and 39%, respectively. Non-hematological regimen-related grade III-IV toxicity was observed in ten patients (56%) and included most commonly transient elevation of liver enzymes (44%), mucositis (40%), and skin reactions including hand-foot syndrome (17%), creatinine elevation (17%), and nausea/vomiting (17%). The concept of a sequential therapy using clofarabine for cytoreduction followed by haploidentical HSCT proved to be feasible and allows successful engraftment, while providing an acceptable toxicity profile and anti-leukemic efficacy in patients with advanced acute leukemia. NRM and rate of GvHD were comparable to results after HSCT from HLA-matched donors. PMID- 23928858 TI - Non-ideal effects in indentation testing of soft tissues. AB - Indentation has several advantages as a loading mode for determining constitutive behavior of soft, biological tissues. However, indentation induces a complex, spatially heterogeneous deformation field that creates analytical challenges for the calculation of constitutive parameters. As a result, investigators commonly assume small indentation depths and large sample thicknesses to simplify analysis and then restrict indentation depth and sample geometry to satisfy these assumptions. These restrictions limit experimental resolution in some fields, such as brain biomechanics. However, recent experimental evidence suggests that conventionally applied limits are in fact excessively conservative. We conducted a parametric study of indentation loading with various indenter geometries, surface interface conditions, sample compressibility, sample geometry and indentation depth to quantitatively describe the deviation from previous treatments that results from violation of the assumptions of small indentation depth and large sample thickness. We found that the classical solution was surprisingly robust to violation of the assumption of small strain but highly sensitive to violation of the assumption of large sample thickness, particularly if the indenter was cylindrical. The ramifications of these findings for design of indentation experiments are discussed and correction factors are presented to allow future investigators to account for these effects without recreating our finite element models. PMID- 23928859 TI - Executive control influences linguistic representations. AB - Although it is known that words acquire their meanings partly from the contexts in which they are used, we proposed that the way in which words are processed can also influence their representation. We further propose that individual differences in the way that words are processed can consequently lead to individual differences in the way that they are represented. Specifically, we showed that executive control influences linguistic representations by influencing the coactivation of competing and reinforcing terms. Consequently, people with poorer executive control perceive the meanings of homonymous terms as being more similar to one another, and those of polysemous terms as being less similar to one another, than do people with better executive control. We also showed that bilinguals with poorer executive control experience greater cross linguistic interference than do bilinguals with better executive control. These results have implications for theories of linguistic representation and language organization. PMID- 23928860 TI - Approach to the functionalized cyclopentane core of marine prostanoids by applying a radical cyclization of beta-disubstituted acrylates. AB - A synthetic approach to highly functionalized cyclopentanes that incorporate adjacent secondary and tertiary alcohols is described. These systems, prepared in one step by a ketyl radical cyclization of beta-disubstituted acrylates, represent the core of the marine prostanoid family of natural products. PMID- 23928862 TI - Laryngeal chondrosarcoma. AB - Laryngeal chondrosarcoma is a rare tumor requiring clinical, histologic, and radiographic correlation for definitive diagnosis. Although it typically presents with low-grade histology, even high-grade histology has a fairly indolent progression in this location, with a relatively low-likelihood for metastatic potential or recurrence. Because of this, conservative surgical excision with negative margins is recommended. We present a case of a laryngeal chondrosarcoma arising from the cricoid cartilage in a patient who presented with hoarseness, dysphagia, and odynophagia with subsequent head and neck computed tomography scan suggestive of the diagnosis. The patient was treated with hemicricoidectomy. PMID- 23928861 TI - Genetic variation of six desaturase genes in flax and their impact on fatty acid composition. AB - Flax (Linum usitatissimum L.) is one of the richest plant sources of omega-3 fatty acids praised for their health benefits. In this study, the extent of the genetic variability of genes encoding stearoyl-ACP desaturase (SAD), and fatty acid desaturase 2 (FAD2) and 3 (FAD3) was determined by sequencing the six paralogous genes from 120 flax accessions representing a broad range of germplasm including some EMS mutant lines. A total of 6 alleles for sad1 and sad2, 21 for fad2a, 5 for fad2b, 15 for fad3a and 18 for fad3b were identified. Deduced amino acid sequences of the alleles predicted 4, 2, 3, 4, 6 and 7 isoforms, respectively. Allele frequencies varied greatly across genes. Fad3a, with 110 SNPs and 19 indels, and fad3b, with 50 SNPs and 5 indels, showed the highest levels of genetic variations. While most of the SNPs and all the indels were silent mutations, both genes carried nonsense SNP mutations resulting in premature stop codons, a feature not observed in sad and fad2 genes. Some alleles and isoforms discovered in induced mutant lines were absent in the natural germplasm. Correlation of these genotypic data with fatty acid composition data of 120 flax accessions phenotyped in six field experiments revealed statistically significant effects of some of the SAD and FAD isoforms on fatty acid composition, oil content and iodine value. The novel allelic variants and isoforms identified for the six desaturases will be a resource for the development of oilseed flax with unique and useful fatty acid profiles. PMID- 23928863 TI - Sirolimus stimulates vascular stem/progenitor cell migration and differentiation into smooth muscle cells via epidermal growth factor receptor/extracellular signal-regulated kinase/beta-catenin signaling pathway. AB - OBJECTIVE: Sirolimus-eluting stent therapy has achieved considerable success in overcoming coronary artery restenosis. However, there remain a large number of patients presenting with restenosis after the treatment, and the source of its persistence remains unclarified. Although recent evidence supports the contribution of vascular stem/progenitor cells in restenosis formation, their functional and molecular responses to sirolimus are largely unknown. APPROACH AND RESULTS: Using an established technique, vascular progenitor cells were isolated from adventitial tissues of mouse vessel grafts and purified with microbeads specific for stem cell antigen-1. We provide evidence that vascular progenitor cells treated with sirolimus resulted in an induction of their migration in both transwell and wound healing models, clearly mediated by CXCR4 activation. We confirmed the sirolimus-mediated increase of migration from the adventitial into the intima side using an ex vivo decellularized vessel scaffold, where they form neointima-like lesions that expressed high levels of smooth muscle cell (SMC) markers (SM-22alpha and calponin). Subsequent in vitro studies confirmed that sirolimus can induce SMC but not endothelial cell differentiation of progenitor cells. Mechanistically, we showed that sirolimus-induced progenitor-SMC differentiation was mediated via epidermal growth factor receptor and extracellular signal-regulated kinase 1/2 activation that lead to beta-catenin nuclear translocation. The ablation of epidermal growth factor receptor, extracellular signal-regulated kinase 1/2, or beta-catenin attenuated sirolimus induced SM-22alpha promoter activation and SMC differentiation. CONCLUSIONS: These findings provide direct evidence of sirolimus-induced progenitor cell migration and differentiation into SMC via CXCR4 and epidermal growth factor receptor/extracellular signal-regulated kinase/beta-catenin signal pathways, thus implicating a novel mechanism of restenosis formation after sirolimus-eluting stent treatment. PMID- 23928864 TI - Hypoxia inhibits cellular senescence to restore the therapeutic potential of old human endothelial progenitor cells via the hypoxia-inducible factor-1alpha-TWIST p21 axis. AB - OBJECTIVE: Endothelial progenitor cells (EPCs) can significantly improve tissue repair by providing regeneration potential within injured cardiovascular tissue; however, it is challenging to obtain a sufficient amount of functional EPCs from aged patients for autologous stem cell therapy. To overcome this issue, we aimed to establish adequate ex vivo expansion protocols and identify repair modulators of cellular senescence. The senescence repair circuit of hypoxia-preconditioned senescent EPCs (hyp-old EPCs) was examined in an effort to enhance their regenerative potential. APPROACH AND RESULTS: Long-term culturing of EPCs in normoxic conditions markedly induced the expression of p21, whereas siRNA targeting of p21 in old EPCs significantly enhanced the proliferation potential of cells. Hyp-old EPCs displayed increased hypoxia-inducible factor-1alpha and TWIST expression. siRNA inhibition of TWIST, a target molecule of the hypoxia inducible factor-1alpha, markedly upregulated the expression of p21 in hyp-old EPCs by reprogramming cell-cycle regulatory proteins. In a hindlimb model of ischemia, the transplantation of hyp-old EPCs enhanced the blood flow ratio and capillary density, improved cellular proliferation and cell survival at ischemic sites, and augmented the secretion of pivotal tissue angiogenic cytokines. It has been previously demonstrated that the restoration of old EPCs from a senescent state by hypoxia preconditioning is tightly mediated by the downregulation of p21 via the hypoxia-inducible factor-1alpha-TWIST axis. CONCLUSIONS: This study introduces ex vivo expansion protocols involving hypoxic preconditioning that are suitable for efficiently expanding old EPCs without senescence through modulation of the hypoxia-induced hypoxia-inducible factor-1alpha-TWIST-p21 axis. In addition, the expanded cells are shown to be useful for therapeutic vasculogenesis. PMID- 23928865 TI - Endoplasmic reticulum stress participates in aortic valve calcification in hypercholesterolemic animals. AB - OBJECTIVES: Aortic valve (AV) calcification occurs via a pathophysiological process that includes lipoprotein deposition, inflammation, and osteoblastic differentiation of valvular interstitial cells. Here, we investigated the association between endoplasmic reticulum (ER) stress and AV calcification. APPROACH AND RESULTS: We identified ER stress activation in AV of patients with calcified AV stenosis. We generated an AV calcification model in hypercholesterolemic rabbits and mice, respectively, and found marked AV ER stress induction. Classical ER stress inhibitor, tauroursodeoxycholic acid, administration markedly prevented AV calcification, and attenuated AV osteoblastic differentiation and inflammation in both rabbit and mouse models of AV calcification via inhibition of ER stress. In cultured valvular interstitial cells (VICs), we found that oxidized low density lipoprotein (oxLDL) caused ER stress in a cytosolic [Ca](2+)i-dependent manner. OxLDL promoted osteoblastic differentiation via ER stress-mediated protein kinase-like ER kinase/activating transcription factor 4/osteocalcin and inositol-requiring transmembrane kinase and endonuclease-1alpha (IRE1alpha)/spliced X-box-binding protein 1/Runx2 pathway, and induced inflammatory responses through IRE1alpha/c-Jun N-terminal kinase and IRE1alpha/nuclear factor kappa-light-chain-enhancer of activated B cells signaling in VICs. Inhibition of ER stress by either tauroursodeoxycholic acid or 4-phenyl butyric acid could both suppress oxLDL-induced osteoblastic differentiation and inflammatory responses in VICs. CONCLUSIONS: These data provide novel evidence that ER stress participates in AV calcification development, and suggest that ER stress may be a novel target for AV calcification prevention and treatment. PMID- 23928866 TI - A comprehensive strategy to boost the quantum yield of luminescence of europium complexes. AB - Lanthanide luminescence has many important applications in anion sensing, protein recognition, nanosized phosphorescent devices, optoelectronic devices, immunoassays, etc. Luminescent europium complexes, in particular, act as light conversion molecular devices by absorbing ultraviolet (UV) light and by emitting light in the red visible spectral region. The quantum yield of luminescence is defined as the ratio of the number of photons emitted over the number of UV photons absorbed. The higher the quantum yield of luminescence, the higher the sensitivity of the application. Here we advance a conjecture that allows the design of europium complexes with higher values of quantum yields by simply increasing the diversity of good ligands coordinated to the lanthanide ion. Indeed, for the studied cases, the percent boost obtained on the quantum yield proved to be strong: of up to 81%, accompanied by faster radiative rate constants, since the emission becomes less forbidden. PMID- 23928867 TI - Metformin added to intensive insulin therapy reduces plasma levels of glycated but not oxidized low-density lipoprotein in young patients with type 1 diabetes and obesity in comparison with insulin alone: a pilot study. AB - INTRODUCTION: There are scarce data about the effect of metformin on lipid profile in patients with type 1 diabetes. OBJECTIVES: The present study is the first prospective clinical trial evaluating the effect of combined therapy of metformin and insulin on the pool of oxidized and glycated low-density lipoproteins (LDL) in young patients with type 1 diabetes and concomitant obesity. PATIENTS AND METHODS: A total of 33 obese patients with type 1 diabetes treated with intensive insulin therapy were randomized into a group where metformin was added. The remaining 19 patients continued to receive intensive insulin therapy (control group). In all patients, lipid profile and glycemia were assessed using routine laboratory tests. Oxidized and glycated LDL were measured using commercially available kits. Laboratory tests were performed at baseline and at a control visit after 6 months of treatment. RESULTS: A significant decrease in the levels of glycated hemoglobin, fasting plasma glucose, postprandial glucose, average glucose, triglycerides, glycated LDL, and body mass index was observed in the group receiving combined therapy. A similar decrease was not observed in the control group. The remaining lipid parameters were not changed during follow-up in any of the groups. CONCLUSIONS: Addition of metformin to intensive insulin therapy in young obese patients with type 1 diabetes results in a significant reduction of glycated LDL levels. This can be possibly explained by better glucose control, which improved insulin sensitivity of the peripheral tissues and reduced body mass in this patient group. PMID- 23928868 TI - Novel oral anticoagulants: pharmacology, coagulation measures, and considerations for reversal. AB - Novel oral anticoagulants (NOAC) provide an effective and, in some cases, superior alternative to traditional, oral vitamin K antagonists such as warfarin. These drugs differ in their pharmacokinetic and pharmacodynamics profiles, which is important for selecting the right drug for the right patient. A concern among clinicians is a virtual absence of guidance from clinical trials for reversing the anticoagulant effects of these drugs in clinical settings such as life threatening bleeding or a need for emergent procedures that carry bleeding risk. In this review, we discuss NOAC, the role of coagulation assays to assess their systemic anticoagulants effects, and the available data supporting strategies designed to reverse or attenuate these effects. PMID- 23928869 TI - Preprocedural TIMI flow and infarct size in STEMI undergoing primary angioplasty. AB - Despite optimal epicardial recanalization, primary angioplasty for STEMI is still associated with suboptimal reperfusion in a relatively large proportion of patients. The aim the current study was to evaluate the impact of preprocedural TIMI flow on myocardial scintigraphic infarct size among STEMI undergoing primary angioplasty. Our population is represented by 793 STEMI patients undergoing primary PCI. Infarct size was evaluated at 30 days by technetium-99m-sestamibi. Poor preprocedural TIMI flow (TIMI 0-1) was observed in 645 patients (81.3%). Poor preprocedural TIMI flow was associated with more hypercholesterolemia (p = 0.012), and a trend in lower prevalence of diabetes (p = 0.081). Preprocedural TIMI flow significantly affected scintigraphic and enzymatic infarct size. Similar findings were observed in the analysis restricted to patients with postprocedural TIMI 3 flow. The impact of preprocedural TIMI flow on scintigraphic infarct size was confirmed when the analysis was performed according to the percentage of patients above the median (p < 0.001) and after adjustment for baseline confounding factors (Hypercholesterolemia and diabetes) [adjusted OR (95% CI) for pre preprocedural TIMI 3 flow = 0.59 (0.46-0.75), p < 0.001]. This study shows that among patients with STEMI undergoing primary angioplasty, poor preprocedural TIMI flow is independently associated with larger infarct size. PMID- 23928871 TI - Polymer-grafted nanoparticles prepared by surface-initiated polymerization: the characterization of polymer chain conformation, grafting density and polydispersity correlated to the grafting surface curvature. AB - The polymer-grafted nanoparticles prepared by the surface-initiated polymerization induced from the spherical surface is studied by coarse-grained molecular dynamics simulations combined with the stochastic reaction model. The coupling effect of the initiator density and the grafting surface curvature is mainly investigated. The confinement degree greatly changes with the grafting surface curvature, thus the initiation efficiency, the grafted chain polydispersity, as well as the chain mass distribution show great dependence on the surface curvature. The results reveal that preparing the nanoparticle with desired size (i.e., grafting surface curvature) is crucial for control of the grafted chain polydispersity and even its dispersion in the polymer matrix. Our studies shed light on better design of grafted nanoparticles and better control of dispersion in polymer matrices for improving the performance of polymer nanocomposite materials. PMID- 23928870 TI - Nutri-pharmacogenomics of warfarin anticoagulation therapy: VKORC1 genotype dependent influence of dietary vitamin K intake. AB - Warfarin is the most widely prescribed oral anticoagulant, but large interindividual variations exist in the dose required to achieve comparable therapeutic effects. Several clinical and genetic variables have been identified that influence warfarin dosing. However, interactions between genotype and nutrition remain uncertain in terms of dietary vitamin K intake. To investigate genotype-nutrient interactions in warfarin anticoagulation therapy, 202 consecutive outpatients (M/F = 142/60, mean age, 69 years) undergoing treatment with warfarin were enrolled. Prevalent single nucleotide polymorphisms in VKORC1 and CYP2C9 were genotyped, and dietary vitamin K intake during the week preceding the blood sampling was quantitatively estimated by a dietitian-assisted questionnaire. Patients were classified according to low, medium, or high vitamin K intake. The mean daily warfarin dose in subjects with a VKORC1-1639 A/A genotype was significantly smaller than that with a -1639A/G genotype (2.74 vs. 3.91 mg/day, respectively, p < 0.0001). Dose requirements did not differ between subjects with a CYP2C9 *1/*3 genotype versus a CYP2C9 *1/*1 genotype. In subjects with a variant VKORC1-1639 G allele, the mean daily warfarin dose was significantly attenuated by low vitamin K intake compared with medium and high intake after adjustment for covariates (3.4 vs. 5.0 vs. 4.0 mg/day, respectively, p = 0.028). No such genotype effects were observed in homozygous patients for the VKORC1-1639 A allele. The results of the present study suggest that the capacity of dietary vitamin K intake to influence warfarin dose requirements during anticoagulation therapy is VKORC1 genotype-dependent, at least in part. PMID- 23928872 TI - Extension and application of the "enzyme test bench" for oxygen consuming enzyme reactions. AB - Within industrial process development, powerful screening techniques are required to select the optimal biocatalyst regarding such process characteristics as cost effectiveness, turnover number or space time yield. Conventional measurement of the initial enzyme activity, which is the established high throughput screening technique, disregards the long-term stability of an enzyme. A new model based technique called "enzyme test bench" was recently presented before by our group which addresses this issue. It combines the high throughput screening approach with an extensive enzyme characterization, focusing especially on the long-term stability. The technique is based on modeling enzyme activation and deactivation as temperature dependent reactions in accordance with the Arrhenius law. Controlling these reactions by tailor made temperature profiles, the slow long term deactivation effects are accelerated and characterizing models are parameterized. Thus, the process properties of an enzyme can be predicted and included into the screening procedure. Moreover, the optimum process temperature as function of the envisaged operation time can be found by these means. In this work, the technique is extended to the important class of oxygen consuming reactions. For this aim, a suitable assay and a defined oxygen supply were established. This extended technique was applied to characterize and to optimize a complex, multi-stage laccase-mediator system (LMS). For the variation and optimization of the enzyme to mediator to substrate ratio, experiments in microtiter plates were performed. Predictions from this high throughput characterization were compared to long-term experiments in a RAMOS device (Respiration Activity Monitoring System), a technique for on-line monitoring of the oxygen transfer rate in shake flasks. Within the limits of the model validity, the enzyme test bench predictions are in good agreement with the long term experiments. PMID- 23928873 TI - Objectively measured vs self-reported compliance during oral appliance therapy for sleep-disordered breathing. AB - BACKGROUND: Assessment of the overall therapeutic effectiveness of oral appliance therapy can only be realized through objectively measured compliance. The aims of this study were to assess objectively measured compliance during oral appliance therapy at 1-year follow-up and to compare these data with self-reported use. METHODS: Fifty-one eligible patients were enrolled in this 1-year prospective clinical study (men, 61%; mean age, 49 +/- 10 years; apnea-hypopnea index, 18.0 +/- 11.9 events/h sleep; BMI, 26.6 +/- 4.1 kg/m2). Objective compliance during oral appliance therapy at 1-year follow-up was assessed with a microsensor thermometer. Subjective compliance was assessed by self-report. Patients with a mean objectively measured use of >= 4 h/night on 70% of nights monitored were considered regular users. The mean disease alleviation was calculated as a measure of overall therapeutic effectiveness. RESULTS: High agreement between objective and subjective compliance data at 1-year follow-up was reported (intraclass correlation coefficient, 0.8; 95% CI, 0.5-0.9), showing a mean subjective overestimation of 30 min (95% CI, -3.1 to 1.9; P = .02). The discontinuation rate at 1-year follow-up was 9.8%. The objective mean use rate was 6.4 +/- 1.7 h/night at 1-year follow-up in continuing users, with a regular use rate of 83%. The mean disease alleviation was 54.9%. CONCLUSIONS: This study is the first to our knowledge to report the 1-year results of objectively measured compliance during oral appliance therapy. In addition, a high agreement between objective and subjective compliance data were reported, with a mean subjective overestimation of 30 min. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01284881; URL: www.clinicaltrials.gov. PMID- 23928874 TI - Aryl hydrocarbon receptor and colitis. AB - The aryl hydrocarbon receptor (AhR), a transcription factor activated by a large variety of natural and synthetic ligands, has recently become the object of great interest among researchers since it represents an important link between environment and immune-mediated pathologies. In this context, evidence has been accumulated to show that AhR is necessary for the maintenance/expansion of intraepithelial lymphocytes and interleukin-22-producing innate lymphoid cells in the gut and that defects in AhR-delivered signals may contribute to amplify gut tissue destructive immune-inflammatory reactions. We here review the available data supporting the role of AhR in the control of immune homeostasis in the gut and discuss whether and how AhR activators can help dampen inflammatory processes. PMID- 23928875 TI - High mobility group box 1 (HMGB1) mediates high-glucose-induced calcification in vascular smooth muscle cells of saphenous veins. AB - Diabetes accelerates saphenous vein grafts calcification after years of coronary artery bypass grafting (CABG) surgery. Vascular smooth muscle cells (VSMC) undergoing a phenotypic switch to osteoblast-like cells play a key role in this process. The receptor for advanced glycation and products (RAGE) and toll-like receptors (TLRs) are all involved in various cardiovascular calcification processes. Therefore, the role of their common ligand, high mobility group box 1 (HMGB1), in high-glucose-induced calcification in VSMC of saphenous vein was investigated. In this study, VSMC were cultured from saphenous vein of patients arranged for CABG. We first demonstrated high-glucose-induced HMGB1 translocation from nucleus to cytosol, and this translocation was induced through a NADPH oxidase and PKC-dependent pathway. We next found high glucose also increased TLR2, TLR4, and RAGE expression. Then, we revealed downregulating HMGB1 expression abolished high-glucose-induced calcification accompanied by NFkappaB inactivation and low expression of bone morphogenetic protein-2 (BMP-2). We further demonstrated NFkappaB activation was necessary in high-glucose-induced BMP-2 expression and calcification. Finally, by using a chromatin immunoprecipitation assay, we demonstrated NFkappaB transcriptional regulation of BMP-2 promoter was induced by NFkappaB binding to its kappaB element on the BMP-2 promoter. Our findings thus suggest HMGB1 plays an important role in mediating the calcification process induced by high glucose through NFkappaB activation and BMP-2 expression in VSMC of saphenous vein. PMID- 23928876 TI - Hyperleptinemia: implications on the inflammatory state and vascular protection in obese adolescents submitted to an interdisciplinary therapy. AB - The low-grade systemic inflammation seen in obesity may affect the actions of some adipose tissue-derived adipokines that are involved in the regulation of vascular function. We sought to verify whether hyperleptinemia may influence the inflammatory and atherogenic responses in obese adolescents undergoing interdisciplinary therapy. Thirty-four obese adolescents underwent interdisciplinary therapy for 1 year. Subjects were considered hyperleptinemic if they had baseline values of leptin above 20 ng/mL for boys and 24 ng/mL for girls. Both groups showed an improvement in body composition and a reduction in carotid intima-media thickness. However, only subjects in the non-hyperleptinemic group showed an increase in adiponectin concentration after therapy. Moreover, leptin concentration was positively correlated with adiponectin and inversely correlated with PAI-1 in this group. Hyperleptinemic state may impair the attenuation of inflammation in obese adolescents undergoing interdisciplinary therapy, particularly by impeding the increase in adiponectin concentration, which is directly involved in vascular protection. PMID- 23928877 TI - Elevated cell proliferation and VEGF production by high-glucose conditions in Muller cells involve XIAP. AB - PURPOSE: Muller cells have important roles in the pathogenesis of diabetic retinopathy by promoting cell proliferation and inducing the production of vascular endothelial growth factor (VEGF) under hyperglycemic conditions. The objective of this study was to determine the potential mechanism of Muller cell proliferation and VEGF production due to high-glucose conditions. METHODS: Primary cultured rat Muller cells were incubated with medium containing variable concentrations of glucose and/or embelin, a specific inhibitor of X-linked inhibitor of apoptosis protein (XIAP), for 72 h. The proliferation of Muller cells was assessed by the MTT assay. The expression and/or phosphorylation of 146 proteins were assessed using protein pathway array. RESULTS: High concentrations of glucose-induced Muller cell proliferation and altered expression and/or phosphorylation of 47 proteins that have been identified to have key roles in several important signaling pathways (XIAP, VEGF, HIF1alpha, NFkappaB, etc) and are involved in the regulation of cell survival, proliferation, or apoptosis. However, Muller cell alterations induced by high-glucose conditions were counteracted by the XIAP inhibitor embelin, and 26 proteins/phosphorylations (out of 47) were restored to their normal levels. Nine proteins, including NFkappaB p65, p-p38, tumor necrosis factor-alpha, urokinase-type plasminogen activator, CREB, IL-1beta, HCAM, estrogen receptor-alpha, and p-Stat3, were involved in regulatory networks between XIAP and VEGF. CONCLUSIONS: The current study suggests that XIAP may be a potential regulator that can mediate a series of pathological changes induced by high-glucose conditions in Muller cells. Therefore, embelin could be a potential agent for the prevention and treatment of diabetic retinopathy. PMID- 23928878 TI - Swept-source optical coherence tomography identifies connection between vitreous cavity and retrobulbar subarachnoid space in patient with optic disc pit. PMID- 23928879 TI - Influence of stereopsis and abnormal binocular vision on ocular and systemic discomfort while watching 3D television. AB - PURPOSE: To evaluate the degree of three-dimensional (3D) perception and ocular and systemic discomfort in patients with abnormal binocular vision (ABV), and their relationship to stereoacuity while watching a 3D television (TV). METHODS: Patients with strabismus, amblyopia, or anisometropia older than 9 years were recruited for the ABV group (98 subjects). Normal volunteers were enrolled in the control group (32 subjects). Best-corrected visual acuity, refractive errors, angle of strabismus, and stereoacuity were measured. After watching 3D TV for 20 min, a survey was conducted to evaluate the degree of 3D perception, and ocular and systemic discomfort while watching 3D TV. RESULTS: One hundred and thirty subjects were enrolled in this study. The ABV group included 49 patients with strabismus, 22 with amblyopia, and 27 with anisometropia. The ABV group showed worse stereoacuity at near and distant fixation (P<0.001). Ocular and systemic discomfort was, however, not different between the two groups. Fifty-three subjects in the ABV group and all subjects in the control group showed good stereopsis (60 s of arc or better at near), and they reported more dizziness, headache, eye fatigue, and pain (P<0.05) than the other 45 subjects with decreased stereopsis. The subjects with good stereopsis in the ABV group felt more eye fatigue than those in the control group (P=0.031). The subjects with decreased stereopsis showed more difficulty with 3D perception (P<0.001). CONCLUSIONS: The subjects with abnormal stereopsis showed decreased 3D perception while watching 3D TV. However, ocular and systemic discomfort was more closely related to better stereopsis. PMID- 23928880 TI - Improvement in patients' quality-of-life following strabismus surgery: evaluation of postoperative outcomes using the Adult Strabismus 20 (AS-20) score. AB - INTRODUCTION: Quantification of the psychosocial effects of manifest strabismus has been made possible by the introduction of the Adult Strabismus 20 (AS-20) questionnaire. We investigated the effects of strabismus surgery and patient demographics on the pre- and postoperative AS-20 scores. METHODS: A prospective, cohort study of adult patients undergoing strabismus surgery. Full pre- and postoperative orthoptic measurements were analysed and compared with the AS-20 total scores and its subscales (psychosocial and functional). Any relationship between: gender; direction; and size of preoperative deviation and the changes in AS-20 score was investigated. RESULTS: Eighty-six patients were included with a follow-up of 91 days following surgery. Median deviation preoperatively was 30.5 prism diopters (PD) and the median preoperative AS-20 score was 45. Postoperatively, the median deviation was 8 PD and the AS-20 score was significantly (Z=-7.83, P<0.0001) higher at 73.1. Females have a lower preoperative AS-20 score (P=0.01) but show a greater improvement in scores following surgery compared with males (P=0.058). There is a close correlation between change in AS-20 score and change in deviation size (r=0.291, P=0.006). CONCLUSION: Strabismus surgery gives a highly significant improvement in quality of-life scores. Females gain more benefit from surgery and there is a greater improvement in the score with larger changes in deviation size. The smaller the postoperative angle, the larger the final AS-20 score. PMID- 23928881 TI - Capsular blockage syndrome in a child: a case report. PMID- 23928882 TI - 2013 awards for Journal of Plant Research publications. PMID- 23928883 TI - Spatial and seasonal distribution of trace metal concentrations in mussel (Mytilus galloprovincialis) and sediment of Bosphorus and Golden Horn. AB - The Golden Horn Estuary and Bosphorus Strait are two major marine environments of metropolitan Istanbul which have been exposed to intensive industrial discharges for more than 50 years. In the present study, concentrations of cadmium (Cd), chromium (Cr), copper (Cu), lead (Pb) and zinc (Zn) were measured in mussel tissue and sediment samples by using inductively coupled plasma-atomic emission spectroscopy to assess the current status of metal pollution in the Golden Horn and Bosphorus Strait. Ranges of Cd, Cr, Cu, Pb and Zn concentrations in soft parts of the mussels were BDL-2.59; BDL-7.35; 3.96-20.90; BDL-10.0; and 124.8 293.2 MUg g(-1) dry weight (dw), respectively, while the ranges of Cd, Cr, Cu, Pb and Zn in <63 MUm sediment fractions were BDL, 19.5-300.3, 16.9-724.7, 10.5 260.9, and 39.3-793.1 MUg g(-1) dw, respectively. Ranges of Cd, Cr, Cu, Pb and Zn in >63 MUm sediment fractions were BDL, 4.73-52.81, 3.45-481.87, 3.13-174.67 and 10.7-241.2 MUg g(-1) dw, respectively. Trace metal concentrations found in sediment of the Golden Horn were 5-10 times higher than average literature values obtained in Mediterranean marine environment, whereas those of the Bosphorus Strait were consistent with or slightly higher than average literature values. PMID- 23928884 TI - Isolated intramedullary cervical dermoid cyst. PMID- 23928885 TI - Progressive bilateral medial medullary infarction. PMID- 23928886 TI - A calixarene based metal organic material, calixMOM, that binds potassium cations. AB - A porous calixarene-based metal organic material, calixMOM-1, has been prepared by using a custom designed tetradentate thiacalixarene which links manganese molecular building blocks. Potassium ions were introduced into the cavity of the thiacalixarene to afford calixMOM-2. Gas sorption properties of both compounds were studied. PMID- 23928887 TI - First synthesis of antitumoral dasyscyphin B. AB - The first synthesis of dasyscyphin B, an antitumoral metabolite obtained from the ascomycete Dasyscyphus niveus, has been achieved starting from commercial abietic acid. The key steps of the synthetic sequence are the diastereoselective alpha methylation of a ketoaldehyde, followed by an intramolecular aldol condensation and the further Diels-Alder cycloaddition of a dienol ester. The procedure reported will allow the synthesis of related metabolites functionalized in the A ring. PMID- 23928888 TI - Nitrogen dynamics in arctic tundra soils of varying age: differential responses to fertilization and warming. AB - In the foothills of the Brooks Range, Alaska, different glaciation histories have created landscapes with varying soil age. Productivity of most of these landscapes is generally N limited, but varies widely, as do plant species composition and soil properties (e.g., pH). We hypothesized that the projected changes in productivity and vegetation composition under a warmer climate might be mediated through differential changes in N availability across soil age. We compared readily available [water-soluble NH4 (+), NO3 (-), and amino acids (AA)], moderately available (soluble proteins), hydrolyzable, and total N pools across three tussock-tundra landscapes with soil ages ranging from 11.5k to 300k years. The effects of fertilization and warming on these N pools were also compared for the two younger sites. Readily available N was highest at the oldest site, and AA accounted for 80-89 % of this N. At the youngest site, inorganic N constituted the majority (80-97 %) of total readily available N. This variation reflected the large differences in plant functional group composition and soil chemical properties. Long-term (8-16 years) fertilization increased the soluble inorganic N by 20- to 100-fold at the intermediate-age site, but only by twofold to threefold at the youngest site. Warming caused small and inconsistent changes in the soil C:N ratio and AA, but only in soils beneath Eriophorum vaginatum, the dominant tussock-forming sedge. These differential responses suggest that the ecological consequences of warmer climates on these tundra ecosystems are more complex than simply elevated N-mineralization rates, and that the responses of landscapes might be impacted by soil age, or time since deglaciation. PMID- 23928889 TI - Growth and carbon isotopes of Mediterranean trees reveal contrasting responses to increased carbon dioxide and drought. AB - Forest dynamics will depend upon the physiological performance of individual tree species under more stressful conditions caused by climate change. In order to compare the idiosyncratic responses of Mediterranean tree species (Quercus faginea, Pinus nigra, Juniperus thurifera) coexisting in forests of central Spain, we evaluated the temporal changes in secondary growth (basal area increment; BAI) and intrinsic water-use efficiency (iWUE) during the last four decades, determined how coexisting species are responding to increases in atmospheric CO2 concentrations (C(a)) and drought stress, and assessed the relationship among iWUE and growth during climatically contrasting years. All species increased their iWUE (ca. +15 to +21%) between the 1970s and the 2000s. This increase was positively related to C(a) for J. thurifera and to higher C(a) and drought for Q. faginea and P. nigra. During climatically favourable years the study species either increased or maintained their growth at rising iWUE, suggesting a higher CO2 uptake. However, during unfavourable climatic years Q. faginea and especially P. nigra showed sharp declines in growth at enhanced iWUE, likely caused by a reduced stomatal conductance to save water under stressful dry conditions. In contrast, J. thurifera showed enhanced growth also during unfavourable years at increased iWUE, denoting a beneficial effect of C(a) even under climatically harsh conditions. Our results reveal significant inter specific differences in growth driven by alternative physiological responses to increasing drought stress. Thus, forest composition in the Mediterranean region might be altered due to contrasting capacities of coexisting tree species to withstand increasingly stressful conditions. PMID- 23928890 TI - Differences between height- and light-dependent changes in shoot traits in five deciduous tree species. AB - The effects of tree height on shoot traits may in some cases differ in magnitude and direction from the effects of light. Nevertheless, general patterns of change in shoot traits in relation to variations in height and light have not so far been revealed. A comprehensive analysis of the differences between the effects of height and light on a range of leaf and shoot traits is important for the scaling of these traits to individual trees. We investigated the biomass allocation and structure of current-year shoots at the top of the crowns of five deciduous tree species in Japan. Height effect was investigated by comparing shoot traits among trees of different heights growing under a high light environment. The effects of light were examined by comparing saplings growing in high- and low-light environments. The effects of light were significant for most traits, while those of height were not significant for some traits. The magnitudes of the effects of light were larger than those of height for most traits related to biomass allocation. There was an extreme difference between the effects of height and light in the direction of change in the length of current-year shoots and in the number of standing leaves. The measures of both parameters increased with the increase in light, but decreased with the increase in tree height. Thus, the effects of height and light on diverse traits at the level of current-year shoots were not always similar. These results suggest that great care must be taken when scaling shoot traits from small trees to tall trees because the effects of height and light can be complex. PMID- 23928891 TI - Humanlike robot hands controlled by brain activity arouse illusion of ownership in operators. AB - Operators of a pair of robotic hands report ownership for those hands when they hold image of a grasp motion and watch the robot perform it. We present a novel body ownership illusion that is induced by merely watching and controlling robot's motions through a brain machine interface. In past studies, body ownership illusions were induced by correlation of such sensory inputs as vision, touch and proprioception. However, in the presented illusion none of the mentioned sensations are integrated except vision. Our results show that during BMI-operation of robotic hands, the interaction between motor commands and visual feedback of the intended motions is adequate to incorporate the non-body limbs into one's own body. Our discussion focuses on the role of proprioceptive information in the mechanism of agency-driven illusions. We believe that our findings will contribute to improvement of tele-presence systems in which operators incorporate BMI-operated robots into their body representations. PMID- 23928892 TI - Narrow-band imaging and white-light endoscopy for detection of colorectal polyps: a randomized study. AB - INTRODUCTION: Narrow-band imaging (NBI) is a new, promising technique that might be helpful in the detection of colorectal polyps during colonoscopy. OBJECTIVES: The aim of the study was to compare the usefulness of NBI with white-light endoscopy (WLE) for the detection of polyps as well as to determine the distribution of missed polyps. PATIENTS AND METHODS: This was a randomized controlled trial. A total of 253 patients were included, in whom colonoscopy was performed twice: 126 patients underwent 2 procedures using white light, while in 127 patients NBI was used for the second procedure. The number and location of colorectal polyps identified during the second colonoscopy were recorded. RESULTS: No significant differences were observed in the rates of detected polyps, adenomas, and hyperplastic polyps between the WLE and NBI groups (38 vs. 48, P <0.2051; 11 vs. 19, P < 0.12; 27 vs. 29, P <0.4647, respectively). A half of all missed adenomas (n = 15) were found in the cecum and the ascending colon. CONCLUSIONS: WLE and NBI seem to be equally effective in identifying missed adenomas and hyperplastic polyps during colonoscopy. Repeated endoscopy of the cecum and ascending colon may significantly increase the number of detected adenomas. PMID- 23928894 TI - Photoinduced charge transport over branched conjugation pathways: donor-acceptor substituted 1,1-diphenylethene and 2,3-diphenylbutadiene. AB - Photoinduced charge transport in 1,1-diphenylethene and 2,3-diphenylbutadiene functionalized with an electron donating dimethylamino group and an electron accepting cyano group is reported. UV-spectroscopy reveals that in these compounds, which incorporate a cross-conjugated spacer, a direct charge transfer transition is possible. It is shown by application of the generalized Mulliken Hush approach that introduction of an additional branching point in the pi electron spacer (i.e., when going from the 1,1-diphenylethene to the 2,3 diphenylbutadiene) leads to only a moderate reduction (68-92%) of the electronic coupling between the ground and the charge separated state. The sigma-electron system is however likely to be dominant in the photoinduced charge separation process. PMID- 23928896 TI - Physical activity in daily life of patients with fibrotic idiopathic interstitial pneumonia. AB - BACKGROUND: The 6-min walk test (6MWT) is commonly used to assess exercise capacity in patients with fibrotic idiopathic interstitial pneumonia (f-IIP). However, it is not known whether patients with f-IIP have reduced levels of physical activity in daily life (DLPA) or whether pulmonary function tests and the 6MWT correlate with their DLPA. METHODS: The aim of this study was to measure DLPA in patients with f-IIP and to determine the relationships between DLPA and the 6MWT, pulmonary functional parameters, and anxiety and depression scores. Fifty patients with f-IIP and 25 sex- and age-matched healthy control subjects were enrolled. Markers of DLPA were assessed with a physical activity monitor for 4 consecutive days. Hospital Anxiety and Depression Scale (HADS) scores were evaluated. RESULTS: DLPA parameters were significantly reduced in patients with f IIP compared with control subjects (all P < .001). The mean number of steps per day correlated strongly with diffusing capacity of the lung for carbon monoxide (Dlco), FVC, the 6MWT distance, and the 6MWT lowest oxygen saturation as measured by pulse oximetry (Spo2). DLPA was unrelated to HADS scores. Multivariate analysis showed that Dlco and 6MWT distance explained only 31% of the variance in the number of steps per day. Dlco, 6MWT distance, 6MWT lowest Spo2, and DLPA were significant predictors of mortality, but only Dlco and 6MWT distance were independent predictors. CONCLUSIONS: Quantitation of DLPA is a novel patient centered approach to assess function in f-IIP and may be a useful tool for clinical care and assessing response to therapy. PMID- 23928897 TI - Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis. AB - PURPOSE: Erythropoiesis stimulating agents (ESAs) are used to treat anemia in critically ill patients. This indication is off-label, because it is not licensed by regulatory authorities. Recently ESAs were suspected to harm critically ill patients. Our objective was to assess the safety of ESAs in off-label indications in critically ill patients. METHODS: Eleven databases were searched up to April 2012. We considered randomized controlled trials (RCTs) and controlled observational studies in any language that compared off-label ESAs treatment with other effective interventions, placebo or no treatment in critically ill patients. Two authors independently screened and evaluated retrieved records, extracted data and assessed risk of bias and quality of reporting. RESULTS: We used frequentist and Bayesian models to combine studies, and performed sensitivity and subgroup analyses. From 12,888 citations, we included 48 studies (34 RCTs; 14 observational), involving 944,856 participants. Harm reporting was of medium to low quality. There was no statistically significant increased risk of adverse events in general, serious adverse events, the most frequently reported adverse events, and death in critically ill patients treated with ESAs. These results were robust against risk of bias and analysis methods. There is evidence that ESAs increase the risk of clinically relevant thrombotic vascular events, and there is some less certain evidence that ESAs might increase the risk for venous thromboembolism. CONCLUSIONS: In critically ill patients, administration of ESAs is associated with a significant increase in clinically relevant thrombotic vascular events but not with other frequently reported adverse events and death. PMID- 23928899 TI - Hydrogenation of nitroarenes using defined iron-phosphine catalysts. AB - A novel iron-catalyzed hydrogenation of nitroarenes to the corresponding amines is reported. An in situ combination of Fe(BF4)2.6H2O and phosphine allows for highly selective hydrogenation of a broad range of aromatic and nitroarenes tolerating different functional groups. PMID- 23928898 TI - Potentially harmful effects of inspiratory synchronization during pressure preset ventilation. AB - PURPOSE: Pressure preset ventilation (PPV) modes with set inspiratory time can be classified according to their ability to synchronize pressure delivery with patient's inspiratory efforts (i-synchronization). Non-i-synchronized (like airway pressure release ventilation, APRV), partially i-synchronized (like biphasic airway pressure), and fully i-synchronized modes (like assist-pressure control) can be distinguished. Under identical ventilatory settings across PPV modes, the degree of i-synchronization may affect tidal volume (VT), transpulmonary pressure (PTP), and their variability. We performed bench and clinical studies. METHODS: In the bench study, all the PPV modes of five ventilators were tested with an active lung simulator. Spontaneous efforts of -10 cmH2O at rates of 20 and 30 breaths/min were simulated. Ventilator settings were high pressure 30 cmH2O, positive end-expiratory pressure (PEEP) 15 cmH2O, frequency 15 breaths/min, and inspiratory to expiratory ratios (I:E) 1:3 and 3:1. In the clinical studies, data from eight intubated patients suffering from acute respiratory distress syndrome (ARDS) and ventilated with APRV were compared to the bench tests. In four additional ARDS patients, each of the PPV modes was compared. RESULTS: As the degree of i-synchronization among the different PPV modes increased, mean VT and PTP swings markedly increased while breathing variability decreased. This was consistent with clinical comparison in four ARDS patients. Observational results in eight ARDS patients show low VT and a high variability with APRV. CONCLUSION: Despite identical ventilator settings, the different PPV modes lead to substantial differences in VT, PTP, and breathing variability in the presence spontaneous efforts. Clinicians should be aware of the possible harmful effects of i-synchronization especially when high VT is undesirable. PMID- 23928900 TI - Strong two-photon absorption enhancement in a unique bis-porphyrin bearing a diketopyrrolopyrrole unit. AB - A pi-extended bis-porphyrin bridged via a diketopyrrolopyrrole unit was prepared in 5 steps. This fully conjugated pi-system displays strongly distorted linear absorption, while its two-photon absorption cross-section reaches 2500-3000 GM at 940 nm. LC-like behaviour, easy orientation and low viscosity are, according to XRD, POM and DSC measurements, due to formation of plastic rather than a liquid crystal. PMID- 23928901 TI - Engineering of Saccharomyces cerevisiae for the synthesis of short chain fatty acids. AB - Carbon feedstocks from fossilized sources are being rapidly depleted due to rising demand for industrial and commercial applications. Many petroleum-derived chemicals can be directly or functionally substituted with chemicals derived from renewable feedstocks. Several short chain organic acids may fulfill this role using their functional groups as a target for chemical catalysis. Saccharomyces cerevisiae was engineered to produce short chain carboxylic acids (C6 to C10 ) from glucose using the heterologous Homo sapiens type I fatty acid synthase (hFAS). This synthase was activated by phosphopantetheine transfereases AcpS and Sfp from Escherichia coli and Bacillus subtilis, respectively, both in vitro and in vivo. hFAS was produced in the holo-form and produced carboxylic acids in vitro, confirmed by NADPH and ADIFAB assays. Overexpression of hFAS in a yeast FAS2 knockout strain, deficient in de novo fatty acid synthesis, demonstrated the full functional replacement of the native fungal FAS by hFAS. Two active heterologous short chain thioesterases (TEs) from Cuphea palustris (CpFatB1) and Rattus norvegicus (TEII) were evaluated for short chain fatty acid (SCFA) synthesis in vitro and in vivo. Three hFAS mutants were constructed: a mutant deficient in the native TE domain, a mutant with a linked CpFatB1 TE and a mutant with a linked TEII TE. Using the native yeast fatty acid synthase for growth, the overexpression of the hFAS mutants and the short-chain TEs (linked or plasmid based) increased in vivo caprylic acid and total SCFA production up to 64-fold (63 mg/L) and 52-fold (68 mg/L), respectively, over the native yeast levels. Combined over-expression of the phosphopantetheine transferase with the hFAS mutant resulted in C8 titers of up to 82 mg/L and total SCFA titers of up to 111 mg/L. PMID- 23928902 TI - Recombinant trivalent influenza vaccine (flublok((r))): a review of its use in the prevention of seasonal influenza in adults. AB - Flublok((r)) is a trivalent influenza vaccine manufactured using the baculovirus insect cell system, which has a number of differences compared with the traditional embryonated chicken egg system. Flublok((r)) is the first vaccine containing recombinant protein to be approved for the prevention of seasonal influenza, and is indicated in the USA in adults aged 18-49 years. In a large, placebo-controlled, phase III trial in individuals aged 18-49 years, Flublok((r)) met the US FDA requirements for immunogenicity, effectiveness and safety, despite a high incidence of antigenic mismatch between confirmed cases of influenza and the vaccine component strains. Flublok((r)) was also compared with Fluzone((r)) in two noninferiority trials in older adults aged 50-64 or >=65 years; although noninferiority was shown for a number of endpoints in these trials, Flublok((r)) is not currently approved in these age groups. Flublok((r)) is a useful and generally well-tolerated vaccination option for the prevention of seasonal influenza in adults aged 18-49 years, including those with egg allergy. PMID- 23928904 TI - Isoindigo-based small molecules for high-performance solution-processed organic photovoltaic devices: the electron donating effect of the donor group on photo physical properties and device performance. AB - Five solution processable isoindigo-based donor-acceptor-donor (D-A-D) small molecules with different electron donating strengths have been designed and synthesized. The variation in the electron donating strength of the donor group strongly affected the optical, thermal, electrochemical and photovoltaic device performances of the isoindigo organic materials. The highest power conversion efficiency of ~3.2% was achieved in the bulk heterojunction photovoltaic device consisting of ID3T as the donor and PC70BM as the acceptor. This work demonstrates the potential of isoindigo moieties as electron-deficient units and presents guidelines for the synthesis of D-A-D small molecules for producing highly efficient, solution-processed organic photovoltaic devices. PMID- 23928903 TI - Enhancement of gamma-aminobutyric acid production in recombinant Corynebacterium glutamicum by co-expressing two glutamate decarboxylase genes from Lactobacillus brevis. AB - gamma-Aminobutyric acid (GABA), a non-protein amino acid, is a bioactive component in the food, feed and pharmaceutical fields. To establish an effective single-step production system for GABA, a recombinant Corynebacterium glutamicum strain co-expressing two glutamate decarboxylase (GAD) genes (gadB1 and gadB2) derived from Lactobacillus brevis Lb85 was constructed. Compared with the GABA production of the gadB1 or gadB2 single-expressing strains, GABA production by the gadB1-gadB2 co-expressing strain increased more than twofold. By optimising urea supplementation, the total production of L-glutamate and GABA increased from 22.57 +/- 1.24 to 30.18 +/- 1.33 g L-1, and GABA production increased from 4.02 +/- 0.95 to 18.66 +/- 2.11 g L-1 after 84-h cultivation. Under optimal urea supplementation, L-glutamate continued to be consumed, GABA continued to accumulate after 36 h of fermentation, and the pH level fluctuated. GABA production increased to a maximum level of 27.13 +/- 0.54 g L-1 after 120-h flask cultivation and 26.32 g L-1 after 60-h fed-batch fermentation. The conversion ratio of L-glutamate to GABA reached 0.60-0.74 mol mol-1. By co-expressing gadB1 and gadB2 and optimising the urea addition method, C. glutamicum was genetically improved for de novo biosynthesis of GABA from its own accumulated L-glutamate. PMID- 23928905 TI - Potassium loss from chlorhexidine-treated bacterial pathogens is time- and concentration-dependent and variable between species. AB - The membrane-active antimicrobial agent chlorhexidine is used extensively as an antiseptic during infection prophylaxis and treatment. Whilst known to induce membrane damage that results in loss of internal solutes from bacteria, the present study sought to determine the rate and extent of cytoplasmic potassium loss and whether any species-specific differences exist. Direct measurement of potassium was achieved using flame emission spectrophotometry. Exposure of selected species to minimum inhibitory (MIC) or minimum bactericidal concentration (MBC) resulted in solute loss that was both concentration and time dependent. Within 5-min treatment with MIC levels, losses of 3 % from P. aeruginosa, 9 % from E. coli, and 15 % from S. aureus were recorded, whilst at 5 % w/v chlorhexidine, elevated loss of 20, 28, and 41 % occurred, respectively. Nonlinear potassium release was evident from all species when treated with 5 % chlorhexidine over a 60-min period. After this contact time, potassium loss from E. coli and S. aureus rose to 93 or 90 %, respectively; in contrast, P. aeruginosa retained 62 % intracellular potassium. Results confirm lethal concentrations of chlorhexidine induce rapid and substantial loss of cytoplasmic potassium from common pathogens. However, bacterial responses vary between species and should be borne in mind when considering mechanism of action. PMID- 23928906 TI - Retrograde fluorescent labeling allows for targeted extracellular single-unit recording from identified neurons in vivo. AB - The overall goal of this method is to record single-unit responses from an identified population of neurons. In vivo electrophysiological recordings from individual neurons are critical for understanding how neural circuits function under natural conditions. Traditionally, these recordings have been performed 'blind', meaning the identity of the recorded cell is unknown at the start of the recording. Cellular identity can be subsequently determined via intracellular(1), juxtacellular(2) or loose-patch(3) iontophoresis of dye, but these recordings cannot be pre-targeted to specific neurons in regions with functionally heterogeneous cell types. Fluorescent proteins can be expressed in a cell-type specific manner permitting visually-guided single-cell electrophysiology(4-6). However, there are many model systems for which these genetic tools are not available. Even in genetically accessible model systems, the desired promoter may be unknown or genetically homogenous neurons may have varying projection patterns. Similarly, viral vectors have been used to label specific subgroups of projection neurons(7), but use of this method is limited by toxicity and lack of trans-synaptic specificity. Thus, additional techniques that offer specific pre visualization to record from identified single neurons in vivo are needed. Pre visualization of the target neuron is particularly useful for challenging recording conditions, for which classical single-cell recordings are often prohibitively difficult(8-11). The novel technique described in this paper uses retrograde transport of a fluorescent dye applied using tungsten needles to rapidly and selectively label a specific subset of cells within a particular brain region based on their unique axonal projections, thereby providing a visual cue to obtain targeted electrophysiological recordings from identified neurons in an intact circuit within a vertebrate CNS. The most significant novel advancement of our method is the use of fluorescent labeling to target specific cell types in a non-genetically accessible model system. Weakly electric fish are an excellent model system for studying neural circuits in awake, behaving animals(12). We utilized this technique to study sensory processing by "small cells" in the anterior exterolateral nucleus (ELa) of weakly electric mormyrid fish. "Small cells" are hypothesized to be time comparator neurons important for detecting submillisecond differences in the arrival times of presynaptic spikes(13). However, anatomical features such as dense myelin, engulfing synapses, and small cell bodies have made it extremely difficult to record from these cells using traditional methods(11, 14). Here we demonstrate that our novel method selectively labels these cells in 28% of preparations, allowing for reliable, robust recordings and characterization of responses to electrosensory stimulation. PMID- 23928908 TI - Racial disparities in paediatric kidney transplantation. AB - BACKGROUND: Transplantation is the preferred treatment for children with end stage kidney disease (ESKD). Pre-emptive transplants, those from live donors and with few human leukocyte antigen (HLA) mismatches provide the best outcomes. Studies into disparities in paediatric transplantation to date have not adequately disentangled different transplant types. METHODS: We studied a retrospective cohort of 823 patients aged <18 years who started renal replacement therapy (RRT) in Australia 1990-2011, using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). The primary outcomes were time to first kidney transplant and kidney donor type (deceased or living), analysed using competing risk regression. RESULTS: Caucasian patients were most likely to receive any transplant, due largely to disparities in live donor transplantation. No Indigenous patients received a pre-emptive transplant. Indigenous patients were least likely to receive a transplant from a live donor (sub-hazard ratio 0.41, 95 % confidence interval 0.20-0.82, compared to Caucasians). Caucasian recipients had fewer HLA mismatches, were less sensitised and were more likely to have kidney diseases that could be diagnosed early or progress slowly. CONCLUSIONS: Caucasian paediatric patients are more likely to receive optimum treatment--a transplant from a living donor and fewer HLA mismatches. Further work is required to identify and address barriers to live donor transplantation among minority racial groups. PMID- 23928910 TI - Simulation study optimizing the number of photodetection faces for the X'tal cube PET detector with separated crystal segments. AB - We are developing a novel PET detector with 3D isotropic resolution called a crystal (X'tal) cube. The X'tal cube detector consists of a crystal block all 6 surfaces of which are covered with silicon photomultipliers (SiPMs). We have developed a prototype detector with 3D isotropic 1 mm resolution. On the other hand, when the X'tal cubes are arranged to form a PET scanner, insensitive inter detector gaps made by the SiPM arrays should not be too wide, or, better yet, they should be removed. Reduction of the number of SiPMs will also be reflected in the production costs. Therefore, reducing the number of faces to be connected to the SiPMs has become our top priority. In this study, we evaluated the effect of reducing the number of SiPMs on the positioning accuracy through numerical simulations. Simulations were performed with the X'tal cube, which was composed of a 6 * 6 * 6 array of Lu2x Gd2(1-x)SiO5:Ce crystal elements with dimensions of (3.0 mm)(3). Each surface of the crystal block was covered with a 4 * 4 array of SiPMs, each of which had a (3.0 mm)(2) active area. For material between crystal elements, we compared two: optical glue and an air gap. The air gap showed a better crystal identification performance than did the optical glue, although a good crystal identification performance was obtained even with optical glue for the 6-face photodetection. In conclusion, the number of photodetection faces could be reduced to two when the gap material was air. PMID- 23928911 TI - Low-temperature selective catalytic reduction of NO with NH3 over nanoflaky MnOx on carbon nanotubes in situ prepared via a chemical bath deposition route. AB - Nanoflaky MnO(x) on carbon nanotubes (nf-MnO(x)@CNTs) was in situ synthesized by a facile chemical bath deposition route for low-temperature selective catalytic reduction (SCR) of NO with NH3. This catalyst was mainly characterized by the techniques of X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), N2 adsorption-desorption analysis, X-ray photoelectron spectroscopy (XPS), H2 temperature-programmed reduction (H2-TPR) and NH3 temperature-programmed desorption (NH3-TPD). The SEM, TEM, XRD results and N2 adsorption-desorption analysis indicated that the CNTs were surrounded by nanoflaky MnO(x) and the obtained catalyst exhibited a large surface area as well. Compared with the MnO(x)/CNT and MnO(x)/TiO2 catalysts prepared by an impregnation method, the nf-MnO(x)@CNTs presented better NH3-SCR activity at low temperature and a more extensive operating temperature window. The XPS results showed that a higher atomic concentration of Mn(4+) and more chemisorbed oxygen species existed on the surface of CNTs for nf-MnO(x)@CNTs. The H2-TPR and NH3-TPD results demonstrated that the nf-MnO(x)@CNTs possessed stronger reducing ability, more acid sites and stronger acid strength than the other two catalysts. Based on the above mentioned favourable properties, the nf-MnO(x)@CNT catalyst has an excellent performance in the low-temperature SCR of NO to N2 with NH3. In addition, the nf-MnO(x)@CNT catalyst also presented favourable stability and H2O resistance. PMID- 23928912 TI - Frequency of Prader-Willi syndrome in births conceived via assisted reproductive technology. AB - PURPOSE: Prader-Willi syndrome is an imprinting disorder characterized by typical facial, physical, and cognitive/behavioral features, resulting from lack of paternally expressed genes on chromosome 15q11.2-q13. Studies have suggested an increased risk of other imprinting disorders in children conceived by assisted reproductive techniques. This study was designed to determine the association between assisted reproductive technology and Prader-Willi syndrome. METHODS: Data on individuals with Prader-Willi syndrome were collected from three distinct sources and the proportion of assisted reproductive technology births analyzed. RESULTS: The proportions of assisted reproductive technology births in the Prader Willi Syndrome Association (USA), Rare Diseases Clinical Research Network, and University of California, Irvine Medical Center populations were 1.0% (18/1,736), 1.0% (1/98), and 2.0% (1/50), respectively (overall 1.1%; population frequency for the United States was 1.0%). Of note, 2.4% (45/1,898) of participants were co twins (11 born after assisted reproductive technology procedures); US twin frequency is 1.6% (P = 0.007). The proportion of individuals with maternal disomy 15/imprinting defects born after assisted reproductive technology was higher than that in the total sample, 55.6% (10/18) and 34.5% (431/1,250), respectively. CONCLUSION: This study found no association between assisted reproductive technology and Prader-Willi syndrome. There was an increased frequency of twinning. The number of individuals with maternal disomy 15/imprinting defect was nearly double in the assisted reproductive technology group as compared with the total Prader-Willi syndrome participants. PMID- 23928913 TI - The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders. AB - PURPOSE: The purpose of this study was to assess the diagnostic yield of the traditional, comprehensive clinical evaluation and targeted genetic testing, within a general genetics clinic. These data are critically needed to develop clinically and economically grounded diagnostic algorithms that consider presenting phenotype, traditional genetics testing, and the emerging role of next generation sequencing (whole-exome/genome sequencing). METHODS: We retrospectively analyzed a cohort of 500 unselected consecutive patients who received traditional genetic diagnostic evaluations at a tertiary medical center. We calculated the diagnosis rate, number of visits to diagnosis, genetic tests, and the cost of testing. RESULTS: Thirty-nine patients were determined to not have a genetic disorder; 212 of the remaining 461 (46%) received a genetic diagnosis, and 72% of these were diagnosed on the first visit. The cost per subsequent successful genetic diagnosis was estimated at $25,000. CONCLUSION: Almost half of the patients were diagnosed using the traditional approach, most at the initial visit. For those remaining undiagnosed, next-generation sequencing may be clinically and economically beneficial. Estimating a 50% success rate for next-generation sequencing in undiagnosed genetic disorders, its application after the first clinical visit could result in a higher rate of genetic diagnosis at a considerable cost savings per successful diagnosis. PMID- 23928914 TI - The EGAPP initiative: lessons learned. AB - The Evaluation of Genomic Applications in Practice and Prevention Working Group was first convened in 2005 to develop and test evidence-based methods for the evaluation of genomic tests in transition from research to clinical and public health practice. Over the ensuing years, the Working Group has met 26 times, publishing eight recommendation statements, two methods papers, and one outcomes paper, as well as planning and serving as technical experts on numerous associated systematic reviews. Evaluation of Genomic Applications in Practice and Prevention methods have evolved to address implications of the proliferation of genome-wide association studies and are currently expanding to face challenges expected from clinical implementation of whole-genome sequencing tests. In this article, we review the work of the Evaluation of Genomic Applications in Practice and Prevention Working Group over the first 8 years of its existence with an emphasis on lessons learned throughout the process. It is hoped that in addition to the published methods of the Working Group, the lessons we have learned along the way will be informative to others who are producers and consumers of evidence based guidelines in the field of genomic medicine. PMID- 23928915 TI - Laser flash photolysis study of photocatalytic properties of pillared interlayered clays and Fe,Al-silica mesoporous catalysts. AB - Laser flash photolysis was applied to determine the primary photochemical processes over iron-containing clay (montmorillonite KSF), pillared interlayered clays (PILCs) and mesoporous mesophase iron silicate materials (MMMs). For KSF, the homogeneous photochemical reaction of Fe(III) leached from the clay material resulted in the formation of OH radicals, which were monitored by means of their reaction with methyl viologen dication (MV(2+)). For PILCs and MMMs, no leaching of Fe(III) to the solution nor hydroxyl radical formation were observed. Nevertheless, these catalysts were found to exhibit a sufficient effect on phenol photoionization. The increase in quantum yields of PhO radicals is caused by the effect of PILCs and MMMs and is explained by heterogeneous processes on the surface of catalyst particles. PMID- 23928916 TI - Modeling interactions between voltage-gated Ca (2+) channels and KCa1.1 channels. AB - High voltage-activated (HVA) Cav channels form complexes with KCa1.1 channels, allowing reliable activation of KCa1.1 current through a nanodomain interaction. We recently found that low voltage-activated Cav3 calcium channels also create KCa1.1-Cav3 complexes. While coimmunoprecipitation studies again supported a nanodomain interaction, the sensitivity to calcium chelating agents was instead consistent with a microdomain interaction. A computational model of the KCa1.1 Cav3 complex suggested that multiple Cav3 channels were necessary to activate KCa1.1 channels, potentially causing the KCa1.1-Cav3 complex to be more susceptible to calcium chelators. Here, we expanded the model and compared it to a KCa1.1-Cav2.2 model to examine the role of Cav channel conductance and kinetics on KCa1.1 activation. As found for direct recordings, the voltage-dependent and kinetic properties of Cav3 channels were reflected in the activation of KCa1.1 current, including transient activation from lower voltages than other KCa1.1-Cav complexes. Substantial activation of KCa1.1 channels required the concerted activity of several Cav3.2 channels. Combined with the effect of EGTA, these results suggest that the Ca (2+) domains of several KCa1.1-Cav3 complexes need to cooperate to generate sufficient [Ca (2+)]i, despite the physical association between KCa1.1 and Cav3 channels. By comparison, Cav2.2 channels were twice as effective at activating KCa1.1 channels and a single KCa1.1-Cav2.2 complex would be self-sufficient. However, even though Cav3 channels generate small, transient currents, the regulation of KCa1.1 activity by Cav3 channels is possible if multiple complexes cooperate through microdomain interactions. PMID- 23928917 TI - X-linked inhibitor of apoptosis protein negatively regulates neuronal differentiation through interaction with cRAF and Trk. AB - X-linked Inhibitor of apoptosis protein (XIAP) has been classically identified as a cell death regulator. Here, we demonstrate a novel function of XIAP as a regulator of neurite outgrowth in neuronal cells. In PC12 cells, XIAP overexpression prevents NGF-induced neuronal differentiation, whereas NGF treatment induces a reduction of endogenous XIAP levels concomitant with the induction of neuronal differentiation. Accordingly, downregulation of endogenous XIAP protein levels strongly increases neurite outgrowth in PC12 cells as well as axonal and dendritic length in primary cortical neurons. The effects of XIAP are mediated by the mitogen-activated protein kinase (MEK)/extracellular signal regulated kinases (ERKs) pathway since blocking this pathway completely prevents the neuritogenesis mediated by XIAP downregulation. In addition, we found that XIAP binds to cRaf and Trk receptors. Our results demonstrate that XIAP plays a new role as a negative regulator of neurotrophin-induced neurite outgrowth and neuronal differentiation in developing neurons. PMID- 23928918 TI - 'Adiposopathy' and cardiovascular disease: the benefits of bariatric surgery. AB - PURPOSE OF REVIEW: Obesity is an independent risk factor for cardiovascular disease (CVD) and promotes CVD risk factors. Bariatric surgery has gained much favor because it ameliorates CVD. This review examines the current evidence for the mechanism behind this, which is currently thought to occur in part by reduction of adiposopathy, or dysfunctional adipose tissue, through modulation of adipokine secretion. RECENT FINDINGS: Increased visceral fat in obesity leads to adiposopathy, due to the chronic inflammation present in this tissue. Bariatric surgery causes weight loss as well as reduction in insulin resistance, hypertension, dyslipidemia, cardiac hypertrophy, and mortality. It also causes changes in the adipokines adiponectin, leptin, and C-reactive protein, but not in tumor necrosis factor-alpha. These changes contribute to improved CVD risk, possibly through decrease of chronic inflammation. SUMMARY: The modulations in adipokine secretion that occur after bariatric surgery are involved with reduction in CVD risk factors, CVD, and CV mortality. On the basis of the known anti-inflammatory effects of adiponectin and the pro-inflammatory effects of leptin and CRP, reduction in chronic inflammation associated with less visceral fat after surgery may contribute to the reduction in CVD. This may promote improvement of endothelial dysfunction and insulin resistance. Further work is necessary to explore these relationships. PMID- 23928920 TI - Statins for primary prevention of cardiovascular disease: the benefits outweigh the risks. AB - PURPOSE OF REVIEW: Statins significantly reduce cardiovascular morbidity and mortality in patients with and without coronary heart disease. Recently, much debate has focused on use of statins for primary prevention following a class wide safety label change by the US Food and Drug Administration amidst concerns of worsened hyperglycemia. Here, we review the evidence for statins in primary prevention and offer guidance for their appropriate use. RECENT FINDINGS: Two meta-analyses published since 2012 unequivocally support statins for primary prevention. Data from the Cholesterol Treatment Trialists' Collaborators demonstrated a 9% [relative risk (RR) 0.91, 95% confidence interval (CI) 0.85 0.97] reduction in all-cause mortality and a 25% (RR 0.75, 95% CI 0.70-0.80) reduction in major vascular events per 1.0 mmol/l reduction in low-density lipoprotein cholesterol, even among low-risk patients. A 2013 Cochrane review corroborated these findings including a 14% (OR 0.86, 95% CI 0.79-0.94) reduction in all-cause mortality and a 25% (RR 0.75, 95% CI 0.70-0.81) reduction in cardiovascular disease events with statin therapy despite an 18% (RR 1.18, 95% CI 1.01-1.39) increase in incident diabetes. SUMMARY: Statins effectively lower atherogenic lipoproteins and result in clinically significant reductions in cardiovascular morbidity and mortality. When well tolerated, the cardiovascular benefits of statins for primary prevention generally far outweigh the reported harms. PMID- 23928919 TI - Importance of engaging obstetrician/gynecologists in cardiovascular disease prevention. AB - PURPOSE OF REVIEW: To review recent evidence regarding traditional and sex specific factors identified among women during their reproductive years and their importance in lifetime risk for cardiovascular disease (CVD). RECENT FINDINGS: Longitudinal studies demonstrated a woman's burden of risk during her reproductive years is associated with future risk of CVD. Similarly, women with a healthy lifestyle are relatively protected and have the lowest lifetime risk. Some primary prevention strategies, when implemented during this age window, were cost-effective. The link between pregnancy outcome and future CVD risk is now better understood, and evidence now relates pregnancy-associated hypertension and diabetes, as well as a preterm delivery or a low birth weight delivery, to excess risk. Gaps in preventive healthcare for women in this age group included low rates of treatment initiation for hypertension and failure to follow guidelines for diabetes surveillance among women with a history of gestational diabetes. Knowledge gaps for standard CVD prevention, as well as the link between pregnancy complications and future CVD risk, were identified among both primary care providers and obstetrician/gynecologists. SUMMARY: Traditional and sex-specific risk factors for CVD present during women's reproductive years. Engaging the obstetrician/gynecologist provides a strategy to enhance prevention. PMID- 23928921 TI - When to prevent cardiovascular disease? As early as possible: lessons from prospective cohorts beginning in childhood. AB - PURPOSE OF REVIEW: To detail recent developments linking modifiable youth risk factors with preclinical markers of cardiovascular disease such as carotid artery intima-media thickness, pulse-wave velocity (PVW) and large artery stiffness, brachial artery flow-mediated dilatation, left ventricular geometry, and coronary artery calcification in adulthood. RECENT FINDINGS: Population-based data from prospective cohort studies beginning in youth with follow-up into adulthood have shown that the modifiable youth risk factors of elevated blood lipids, blood pressure, and adiposity, smoking (active and passive), metabolic disorders, physical inactivity, low cardiorespiratory fitness, and diet associate with preclinical markers of cardiovascular disease in adulthood. The data suggest that, in some instances, those who amend their trajectory by not maintaining these risk factors into adulthood experience reductions in preclinical markers to levels associated with never having had the risk factor. SUMMARY: Though avoidance of risk factors in youth is ideal, there is still a window for intervention where long-lasting cardiovascular effects might be avoided. Health enhancing changes in the rates of active and passive smoking, adiposity, increased physical activity, accentuated fitness, modified diet, and socioeconomic position in the transition from youth to adulthood might be important in modifying an individual's trajectory from high risk in youth to low risk in adulthood. PMID- 23928922 TI - Parental smoking produces long-term damage to vascular function in their children. AB - PURPOSE OF REVIEW: This review provides an overview of recent findings concerning the cardiovascular effects of childhood exposure to environmental tobacco smoke (ETS). RECENT FINDINGS: Epidemiological studies have shown that childhood ETS exposure is associated with increased occurrence of several cardiovascular risk factors, including obesity, elevated blood pressure, dyslipidemia and metabolic syndrome. Several cross-sectional analyses have found that ETS adversely affects arterial structure (increased intima-media thickness) and function (decreased elasticity and endothelial function). In addition, recent findings suggest that individuals exposed in childhood have significantly reduced brachial artery endothelial function 20 years later in adulthood. Importantly, this effect could not be explained by adult risk factor levels or smoking behaviors. So far, results from intervention studies to promote parental smoking cessation have been disappointing, with an average success rate of less than 25% in intervention studies. SUMMARY: Childhood ETS exposure is strongly associated with both cardiovascular risk factors and subclinical markers of atherosclerosis. As present, intervention strategies for parental smoking cessation seem inadequate; there is an urgent need for innovative intervention strategies to protect children from the detrimental effects of ETS. PMID- 23928923 TI - Physical activity and risk of cardiovascular disease: what does the new epidemiological evidence show? AB - PURPOSE OF REVIEW: Abundant evidence has documented inverse associations of physical activity and the risk of cardiovascular disease (CVD). However, the effects of different types of physical activity (e.g., leisure time and occupational physical activity) are still poorly understood. RECENT FINDINGS: Drawing on recommended and established guidelines for study selection, we identified and included 23 prospective epidemiological studies published during the last 2 years. These studies included a total of more than 790 000 adults at baseline with some 22 000 incident cases occurring during follow-up. Our findings suggest that moderate and high levels of leisure time physical activity are associated with a moderately reduced risk of CVD. In contrast, moderate and high levels of occupational physical activity showed weak positive associations, that is, a slightly increased risk of CVD. SUMMARY: This updated meta-analysis supports the notion of primary prevention of CVD through engagement in leisure time physical activity. The role of occupational physical activity in CVD prevention is questionable. PMID- 23928924 TI - Drug treatment of obesity in the cardiovascular patient. AB - PURPOSE OF REVIEW: The incidence of obesity and its associated comorbidities have significantly increased over the years with adverse health and financial consequences for society. Lifestyle changes are essential for the prevention and treatment of obesity but their benefit appears limited as inadequate and nonsustained weight loss results have been reported. Pharmacotherapy is frequently advocated as part of a weight loss strategy. In this review, we will discuss the antiobesity drugs with Food and Drug Administration approval and their cardiovascular implications. RECENT FINDINGS: Orlistat (Xenical) remains the single monotherapy that has approval in Europe. Topiramate (Topamax) and phentermine have long been approved in the United States, whereas lorcaserin and the extended release combination of phentermine with topiramate have recently gained approval. The development of single peptides targeting gut hormones or other host signals related to obesity may represent promising therapeutic options. SUMMARY: Despite the recent failures of a number of antiobesity drugs, the pharmacotherapy of obesity is progressing rapidly. Treating the obese cardiovascular patient has proven challenging. Efficacy, safety and the sustainability of weight loss are key areas of focus in drug development strategies. PMID- 23928925 TI - Current world literature. Imaging and echocardiography. Prevention. PMID- 23928927 TI - Renal epithelioid angiomyolipoma: a rare variant with unusual behavior. AB - PURPOSE: To compare the clinical, pathological and oncological outcome of EAML with classic angiomyolipoma (AML). METHODS: A retrospective review of patients' files with a diagnosis of AML was conducted. Both classic and epithelioid AML were compared as regard the patients' demographics, mode of presentation, tumor features and follow-up data. The accuracy of preoperative radiological diagnosis of EAML and the postoperative pathological data were evaluated. RESULTS: Between November 1988 and July 2012, 1,502 renal masses were treated. Forty-two patients (2.8 %) had renal AML of whom 12 patients (28.6 %) had epithelioid morphology. All the patients with EAML were symptomatic on presentation compared to 16.7 % asymptomatic patients with classic AML. Specific diagnosis of EAML was not suggested based on preoperative radiological evaluation. In one patient, there was a venous tumor extension into the right renal vein; another patient had a solitary pulmonary nodule. Pathological data of EAML patients showed wide areas of necrosis (4 patients), atypia (6 patients), increased mitotic figures (2 patients), nuclear anaplasia, enlarged nuclei and prominent nucleoli (3 patients), and multilobulated multinucleated giant cells (5 patients). At a median follow-up period of 12 and 9 months for EAML and classic AML groups, respectively, one patient with EAML had evidence of both local recurrence and distant metastasis 3 months following open radical nephrectomy. CONCLUSION: Epithelioid AML is potentially aggressive and usually present as a symptomatic renal mass. It may be misdiagnosed as malignant renal mass on preoperative radiological evaluation. PMID- 23928928 TI - Association between environmental tobacco smoke exposure and lung cancer susceptibility: modification by antioxidant enzyme genetic polymorphisms. AB - BACKGROUND: Environmental tobacco smoke (ETS) is the primary etiologic factor responsible for lung cancer. However, only 10-15 % of smokers develop lung cancer, suggesting a genetic role in modifying individual susceptibility to lung cancer. Antioxidant enzymes and genetic polymorphisms should be considered. AIM: The present study aimed to evaluate the role of antioxidant enzyme activity and genetic polymorphisms in modifying the susceptibility to lung cancer among individuals exposed to ETS. SUBJECTS AND METHODS: A total of 150 male subjects were divided into three groups: 50 lung cancer patients, 50 chronic smokers, and 50 passive smokers. Genotyping of microsomal epoxide hydrolase (mEH) exon 3 (Tyr(113)Hist) and exon 4 (Hist(139)Arg) polymorphisms were done by the polymerase chain reaction-restriction fragment length polymorphism technique. MnSOD (Val(16)Ala) polymorphism was detected by the real time-TaqMan assay. Erythrocyte MnSOD activity was measured spectrophotometrically. RESULTS: ETS exposed individuals (both active and passive smokers) who carried the His allele of mEH exon3 have a 2.9-fold increased risk of lung cancer (odds ratio [OR] 2.9, P < 0.001). In addition, ETS-exposed carriers of the Arg allele of mEH exon 4 have a 2.1-fold increased risk of lung cancer (OR 2.1, P = 0.024). However, no association between the MnSOD Val(16)Ala polymorphism and lung cancer was detected among ETS-exposed individuals (OR 1.6, P = 0.147), although the lung cancer group had significantly lower MnSOD activity than the chronic or passive smoker groups (P = 0.03). CONCLUSIONS: Exons 3 and 4 polymorphisms of the mEH gene may contribute to lung cancer susceptibility through disturbed antioxidant balance. However, this was not the case with the MnSOD Val(16)Ala single nucleotid polymorphism. Antioxidant enzymes may modulate the influence of ETS exposure on lung cancer risk. PMID- 23928929 TI - Intra-operative results and radiological outcome of conventional and patient specific surgery in total knee arthroplasty: a multicentre, randomised controlled trial. AB - PURPOSE: This prospective, double-blind, randomised controlled trial was designed to address the following research questions: firstly, is there a significant difference in outliers in alignment in the frontal and sagittal plane between PSG TKA and conventional TKA. Secondly, is there a significant difference in operation time, blood loss and length of hospital stay between the two techniques. We hypothesise that there will be fewer outliers with PSG TKA and that operation time, blood loss and length of hospital stay can be significantly reduced with PSG. METHODS: A total of 180 patients were randomised for PSG TKA (group 1) or conventional TKA (group 2) in two centres. Patients were stratified per hospital. Alignment of the mechanical axis of the leg and flexion/extension and varus/valgus of the individual prosthesis components were measured on digital, standing, long-leg and standard lateral radiographs by two independent outcome assessors in both centres. Percentages of outliers (>3 degrees ) were determined. We compared blood loss, operation time and length of hospital stay. RESULTS: There was no statistically significant difference in mean mechanical axis or outliers in mechanical axis between groups. No statistically significant difference was found for the alignment of the individual components in the frontal plane nor for the percentages of outliers. There was a statistically significant difference in outliers for the femoral component in the sagittal plane, with a higher percentage of outliers in the group 1 (p = 0.017). No such significant result was found for the tibial component in that plane. All interclass correlation coefficients were good. Blood loss was 100 mL less in group 1 (p < 0.001). Operation time was 5 min shorter in group 1 (p < 0.001). Length of hospital stay was identical with a mean of 3.6 days (p = 0.657). CONCLUSIONS: The results in terms of obtaining a neutral mechanical axis and a correct position of the prosthesis components did not differ between groups. A small reduction in operation time and blood loss was found with the PSG system. Future research should especially focus on cost-effectiveness analysis and functional outcome of PSG TKA. LEVEL OF EVIDENCE: I. PMID- 23928931 TI - Subxiphoid pericardial window to exclude occult cardiac injury after penetrating thoracoabdominal trauma. AB - BACKGROUND: An occult cardiac injury may be present in patients with an acute abdomen after penetrating thoracoabdominal trauma. This study assessed the use of a subxiphoid pericardial window (SPW) as a diagnostic manoeuvre in this setting. METHODS: This was a retrospective review of a trauma database (2001-2009). Patients presenting with a penetrating thoracoabdominal injury with an acute abdomen, and in whom there was concern about a potential cardiac injury from the site or tract of the injury, were included. RESULTS: Fifty patients with an indication for emergency laparotomy underwent a SPW for a possible cardiac injury. An occult haemopericardium was present at SPW in 14 patients (28 per cent) mandating, median sternotomy. Nine cardiac injuries (18 per cent) were identified including five tangential injuries and four perforations. The specific complication rate relating to the SPW was 2 per cent. CONCLUSION: The SPW is a useful technique at laparotomy to identify cardiac injuries in patients with penetrating thoracoabdominal injuries. PMID- 23928933 TI - Robot-assisted radiofrequency ablation of primary and secondary liver tumours: early experience. AB - OBJECTIVE: Computed tomography (CT)-compatible robots, both commercial and research-based, have been developed with the intention of increasing the accuracy of needle placement and potentially improving the outcomes of therapies in addition to reducing clinical staff and patient exposure to radiation during CT fluoroscopy. In the case of highly inaccessible lesions that require multiple plane angulations, robotically assisted needles may improve biopsy access and targeted drug delivery therapy by avoidance of the straight line path of normal linear needles. METHODS: We report our preliminary experience of performing radiofrequency ablation of the liver using a robotic-assisted CT guidance system on 11 patients (17 lesions). RESULTS/CONCLUSION: Robotic-assisted planning and needle placement appears to have high accuracy, is technically easier than the non-robotic-assisted procedure, and involves a significantly lower radiation dose to both patient and support staff. KEY POINTS: * An early experience of robotic assisted radiofrequency ablation is reported * Robotic-assisted RFA improves accuracy of hepatic lesion targeting * Robotic-assisted RFA makes the procedure technically easier with significant lower radiation dose. PMID- 23928932 TI - Magnetic resonance elastography for the detection and staging of liver fibrosis in chronic hepatitis B. AB - OBJECTIVES: We measured the accuracy of magnetic resonance elastography (MRE) for the detection and staging of liver fibrosis in chronic hepatitis B (CHB) and compared it with serum fibrosis markers. METHODS: Prospective comparison of MRE and routine serum fibrosis markers, namely serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), ALT/AST ratio (AAR), AST to platelet ratio index (APRI) and prothrombin index (PI), was performed in 63 consecutive CHB patients who underwent MRE and histological confirmation of liver fibrosis within a 6-month interval. Diagnostic performance of MRE and serum markers for staging fibrosis (>=F1), significant fibrosis (>=F2), advanced fibrosis (>=F3) and cirrhosis (F4) was compared. RESULTS: The study group comprised 63 patients (19 female; mean age +/- SD, 50 +/- 11.9 years). MRE (rho = 0.94, P < 0.0001), APRI (rho = 0.42, P = 0.0006), PI (rho = 0.42, P = 0.0006) and AST (rho = 0.28, P = 0.028) results correlated significantly with fibrosis stage. MRE was significantly more accurate than serum fibrosis markers for the detection of significant fibrosis (0.99 vs. 0.55-0.73) and cirrhosis (0.98 vs. 0.53-0.77). Sensitivity, specificity, positive predictive and negative predictive values for MRE for significant fibrosis and cirrhosis were 97.4 %, 100 %, 100 % and 96 %, and 100 %, 95.2 %, 91.3 % and 100 %, respectively. CONCLUSION: MRE is an accurate non-invasive technique for the detection and staging of liver fibrosis in CHB. KEY POINTS: * Magnetic resonance elastography is accurate for liver fibrosis detection and staging. * MR elastography is more accurate than serum tests for staging liver fibrosis. * MR elastography can potentially replace liver biopsy in chronic hepatitis B. PMID- 23928934 TI - Pneumococcal urinary antigen positivity in healthy colonized children: is it age dependent? AB - BACKGROUND: Pneumococcal urinary antigen test is a valuable tool for diagnosing pneumococcal pneumonia and meningitis in adults. Its use in children is generally not accepted because of nonspecificity at this age. It is frequently positive in asymptomatic nasopharyngeal carriers. The aim of our study was to assess the age limit from which the test is no longer positive in asymptomatic healthy carriers. METHODS: A total of 197 children aged 36-83 months attending 9 day care centers in Prague were enrolled during February and March 2010. Nasopharyngeal swab specimens were collected from each participant and selectively cultivated. The presence of pneumococcal antigen in urine was detected by BinaxNOW(r) S. pneumoniae kit. RESULTS: Streptococcus pneumoniae was cultivated in 53.3 % of healthy children with the highest colonization rate (59.3 %) in children aged 48 59 months. The most frequently colonizing serotypes were: 19F, 23F, 3, 19A, 6B and 4. The presence of pneumococcal antigen in urine decreased with age from 39.0 % in 36-47 months to 17.9 % in 72-83 months old (p = 0.031). The antigen positivity was serotype-dependent and more frequent in nonvaccinated children. CONCLUSION: We demonstrated age-dependent linear decrease of pneumococcal antigen excretion into urine in healthy children. The positivity rate of the test in children aged 72-83 months was similar to that referred in healthy adults, irrespective of colonization. To confirm this age limit for use of this test in diagnostics of pneumococcal diseases, further study in school-age children is justified. PMID- 23928935 TI - Expression of beta-catenin and cyclin D1 in Merkel cell carcinomas of the head and neck. AB - BACKGROUND: Merkel cell carcinomas (MCC) are very aggressive tumors of the sun exposed skin with a high potential to metastasize. Little is known about the genesis of MCC and very few prognostic markers have been detected so far. The Wnt pathway protein beta-catenin and the cell cycle protein cyclin D1 are two promotors of tumor growth and are expressed in a variety of malignant neoplasms such as lymphomas, thyroid, breast cancer, and many others. PATIENTS AND METHODS: Tissue samples of 27 patients with MCC were immunohistochemically stained for beta-catenin and cyclin D1 and correlated with overall survival of patients. In addition, western blot analysis was carried out in the two MCC cell lines MCC-13 and MCC-26. RESULTS: beta-catenin showed a cytoplasmatic expression of 10-30 % in 11 samples and an expression lower than 10 % in eight samples. Nuclear staining was visible in two samples. None of the 27 samples expressed cyclin D1. CONCLUSION: Neither cyclin D1 nor beta-catenin was expressed in a statistically significant manner, concluding that the development of MCCs is independent of beta-catenin and cyclin D1 expression and these proteins are not suitable as prognostic markers. We could describe the expression pattern of cyclin D1 for the first time. PMID- 23928936 TI - In-hospital cardiac arrest: can we change something? AB - Cardiac arrest is classified as 'in-hospital' if it occurs in a hospitalised patient who had a pulse at the time of admission. A probability of patient's survival until hospital discharge is very low. The reasons for this are old age, multiple co-morbidity of patients, late recognition of cardiac arrest, poor knowledge about basic life support algorithm, insufficient equipment, absence of qualified resuscitation teams (RTs) and poor organization.The aim of this study was to demonstrate characteristics of in-hospital cardiac arrests and resuscitation measures in University Hospital Osijek. We analysed retrospectively all resuscitation procedures data where anaesthesiology RTs provided cardiopulmonary resuscitation (CPR) during 5-year period.We analysed 309 in hospital resuscitation attempts with complete documentation. Victims of cardiac arrest were principally elderly patients, neurological (30.4 %), surgical (25.24 %) and neurosurgical patients (15.2 %) with many associated severe diseases. In 85.6 % of the cases, resuscitation was initiated by ward personnel and RTs arrived within 5 min in 67 % of the cases. However, in 14.6 % of the cases resuscitation measures had not been started before RT arrival. We found statistical correlation between lower initial survival rates and length of hospital stay (p = 0.001), presence of cerebral ischemia (p = 0.026) or cardiomyopathy (p = 0.004) and duration of CPR (p = 0.041). Initial survival was very low (14.6 %), and full recovery was accomplished in only eight patients out of 309 (2.59 %).Identification of terminal chronic patients in which the CPR is not reasonable, a better organisation and ward personnel education can contribute to better overall success. PMID- 23928938 TI - Upper urothelium carcinomas in Croatian endemic area. AB - BACKGROUND/AIMS: Endemic nephropathy (EN) is a chronic tubulointerstitial disease. Strong association between EN and urothelial carcinoma was noted as early as 40-50 ago. The aim of the study was to determine and compare specific mortality and morbidity of renal pelvis and ureter (upper urothelium) carcinoma (UUC) among Croatia as a whole, Brod-Posavina County, and Croatian endemic area. METHODS: Data on UUC mortality and morbidity were analyzed. Indirect standardization was employed on data comparison by calculating standardized mortality ratio and morbidity ratio. RESULTS: Our study results showed the specific mortality rate in the endemic area to be 26.3-fold and 7.3-fold the rate recorded in Croatia and Brod-Posavina County, respectively. The mean standardized mortality ratio obtained by indirect standardization yielded an 8-fold and 32 fold risk of death from UUC in the endemic area vs. Brod-Posavina County and Croatia as a whole, respectively. These data revealed the specific morbidity in the Croatian endemic area and Brod-Posavina County to be 13.95-fold and 3.78-fold the morbidity recorded at the national level, respectively. The standardized morbidity ratio also showed the risk of developing UUC in the Croatian endemic area to be 3.75-fold the risk in Brod-Posavina County and 16.4-fold the risk in Croatia. CONCLUSIONS: These results showed that specific mortality and morbidity as well as standardized morbidity ratio and standardized mortality ratio were higher in Croatian endemic area than in Brod-Posavina County and Croatia. PMID- 23928939 TI - Stereoselective copper-catalyzed Chan-Lam-Evans N-arylation of glucosamines with arylboronic acids at room temperature. AB - An efficient and practical N-arylation of glycosylamines with substituted aryl boronic acids has been established. Using Cu(OAc)2 and pyridine at room temperature under air atmosphere, the protocol proved to be general, and a variety of aryl N-glycosides have been prepared in good to excellent yields with exclusive beta selectivity. PMID- 23928940 TI - Construction of a preclinical multimodality phantom using tissue-mimicking materials for quality assurance in tumor size measurement. AB - World Health Organization (WHO) and the Response Evaluation Criteria in Solid Tumors (RECIST) working groups advocated standardized criteria for radiologic assessment of solid tumors in response to anti-tumor drug therapy in the 1980s and 1990s, respectively. WHO criteria measure solid tumors in two-dimensions, whereas RECIST measurements use only one-dimension which is considered to be more reproducible (1, 2, 3,4,5). These criteria have been widely used as the only imaging biomarker approved by the United States Food and Drug Administration (FDA) (6). In order to measure tumor response to anti-tumor drugs on images with accuracy, therefore, a robust quality assurance (QA) procedures and corresponding QA phantom are needed. To address this need, the authors constructed a preclinical multimodality (for ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI)) phantom using tissue-mimicking (TM) materials based on the limited number of target lesions required by RECIST by revising a Gammex US commercial phantom (7). The Appendix in Lee et al. demonstrates the procedures of phantom fabrication (7). In this article, all protocols are introduced in a step-by-step fashion beginning with procedures for preparing the silicone molds for casting tumor-simulating test objects in the phantom, followed by preparation of TM materials for multimodality imaging, and finally construction of the preclinical multimodality QA phantom. The primary purpose of this paper is to provide the protocols to allow anyone interested in independently constructing a phantom for their own projects. QA procedures for tumor size measurement, and RECIST, WHO and volume measurement results of test objects made at multiple institutions using this QA phantom are shown in detail in Lee et al. (8). PMID- 23928941 TI - Enantiotopic discrimination and director organization in the twist-bend nematic phase. AB - Extending a molecular field model for the orientational order in the nematic phase, we calculate the (2)H-NMR splittings for the achiral solute 8CB-d2 in the twist-bend nematic phase formed by the achiral liquid crystal dimer CB7CB. We give an explanation for the enantiotopic discrimination observed in the spectra and comparison with experimental data allows us to provide quantitative estimates of the order parameters (pitch and conical angle) that characterize the director modulation of the twist-bend nematic phase. PMID- 23928942 TI - Spectral domain optical coherence tomography study of macular microhole morphology and its correlation with vitreomacular interface abnormalities. AB - To describe the demographic, clinical and optical coherence tomography (OCT) characteristics of macular microholes and to determine if the size or character of the microholes has any correlation with vitreomacular interface abnormalities. Case records of 46 eyes of 39 consecutive patients with diagnosed macular microholes were reviewed as a non-interventional retrospective case study. Demographic and clinical features were noted from the detailed case records. Spectral domain OCT images were analysed for microhole and retinal characteristics. SPSS 16.0 was used for statistical analysis. Main outcome measure was the presence of vitreomacular interface abnormalities in large and small macular microholes. Of 39 patients, 21 were male and 18 were female. Most of these patients (56.4 %) presented with visual complaints. Clinically, the commonest feature was a 'red spot' at the fovea on indirect ophthalmoscopy (25 of 44 eyes; 54.3 %). Mean logMAR vision was 0.117 (+/-SD 0.21). 34 (76.08 %) eyes exhibited a photoreceptor loss, 38 eyes (82.6 %) had lamellar tissue defects involving layers posterior to the outer nuclear layer. The difference between means of the groups with and without vitreomacular interface abnormalities was analysed using the unpaired t test. The presence of vitreomacular interface abnormalities was significantly associated with the size of the microhole, with larger microholes being more likely to have vitreomacular interface abnormalities than smaller ones (p < 0.05). We concluded that there was a positive correlation between the size of the microhole and the presence of vitreomacular interface abnormalities. Visual acuity had no correlation with the size of the microhole; functional vision was generally well preserved in the affected eyes. PMID- 23928943 TI - Confocal microscopy in a case of crystalline keratopathy in a patient with smouldering multiple myeloma. AB - We report the clinical and confocal microscopic findings of the cornea in a patient with smouldering multiple myeloma (SMM) using in vivo scanning laser confocal microscopy. A 72-year-old female underwent a complete ophthalmological examination including slit-lamp biomicroscopy with digital photography, HRT II laser scanning in vivo confocal microscopy and haematological laboratory assessment. Corneal biomicroscopy revealed the presence of bilateral diffuse microgranular tiny grey opacities. In vivo confocal microscopy showed randomly oriented hyper-reflective needle-shaped crystals throughout all levels of the stroma, sparing epithelium and endothelium. In vivo confocal microscopy was very helpful in the differential diagnosis by allowing the nature of the corneal deposits to be established, revealing the typical aspect of the crystals, and excluding granular dystrophy, leading to a suspected diagnosis of SMM. Crystalline corneal deposits may easily be confused as crumb-like opacities typical of granular dystrophy on slit-lamp examination even by experienced ophthalmologists. PMID- 23928944 TI - Chronic conjunctivitis due to Mycobacterium tuberculosis. AB - To report the clinical characteristics and treatment outcome in six patients with chronic conjunctivitis due to Mycobacterium tuberculosis. In this retrospective observational case series, all patients with a diagnosis of conjunctival tuberculosis seen in our clinics between January 2000 and January 2010 were reviewed. The clinical presentation, diagnostic investigations and response to medical therapy and outcomes were analyzed. Six patients (age range 15-47 years) were diagnosed with conjunctival tuberculosis. The mean duration from onset of symptoms to diagnosis was 6.5 months (range 1-12 months). Of the six patients, two had ulceration, one had a nodulo-ulcerative lesion, one had bilateral nodular epibulbar masses, and one had a hypertrophied papillary lesion. Systemic signs of tuberculosis were noted in two patients--pleural effusion in one and preauricular and submandibular lymph node involvement in the other. All patients had resolution of symptoms after treatment with four-drug anti-tuberculosis therapy (ATT). None had ocular or systemic recurrences after completion of ATT. Tuberculosis of the conjunctiva can have varied clinical presentation. Although a rare entity, it should be suspected in non-responding chronic conjunctivitis. A high index of suspicion and clinical examination aided by appropriate microbiological and histopathological testing can help in early diagnosis and management. PMID- 23928945 TI - Scleral fixation of dexamethasone intravitreal implant (OZURDEX(r)) in a case of angle-supported lens implantation. AB - OZURDEX((r)) is a biodegradable drug delivery system which has been reported to be an effective treatment in cases of macular edema. However, migration of the implant into the anterior chamber with elevation of intraocular pressure and corneal decompensation might occur in some cases. We report a case of an 80-year old male who underwent intravitreal scleral fixation of OZURDEX((r)) due to postoperative macular edema secondary to complicated cataract surgery. He had a previous angle-supported lens implantation with superior Nd:YAG laser iridotomy. During surgery, the dexamethasone implant was introduced into the vitreous cavity and sutured to the sclera using a 10-0 non-absorbable polypropylene suture to prevent the risk of anterior complications in case of migration into the anterior chamber. After 6 months of follow-up, the macular edema had disappeared completely, the drug delivery system was not observed in the posterior segment and best-corrected visual acuity improved from 20/125 to 20/40 (Snellen equivalent). Neither anterior nor posterior segment complications were reported during the follow-up period. Intravitreal scleral fixation of the OZURDEX((r)) to the pars plana could be recommended as an alternative technique to avoid anterior migration of the device in a patient with an anterior chamber intraocular lens, which may lead to corneal decompensation and increased intraocular pressure. PMID- 23928946 TI - Heat-related mortality risk model for climate change impact projection. AB - OBJECTIVES: We previously developed a model for projection of heat-related mortality attributable to climate change. The objective of this paper is to improve the fit and precision of and examine the robustness of the model. METHODS: We obtained daily data for number of deaths and maximum temperature from respective governmental organizations of Japan, Korea, Taiwan, the USA, and European countries. For future projection, we used the Bergen climate model 2 (BCM2) general circulation model, the Special Report on Emissions Scenarios (SRES) A1B socioeconomic scenario, and the mortality projection for the 65+-year old age group developed by the World Health Organization (WHO). The heat-related excess mortality was defined as follows: The temperature-mortality relation forms a V-shaped curve, and the temperature at which mortality becomes lowest is called the optimum temperature (OT). The difference in mortality between the OT and a temperature beyond the OT is the excess mortality. To develop the model for projection, we used Japanese 47-prefecture data from 1972 to 2008. Using a distributed lag nonlinear model (two-dimensional nonparametric regression of temperature and its lag effect), we included the lag effect of temperature up to 15 days, and created a risk function curve on which the projection is based. As an example, we perform a future projection using the above-mentioned risk function. In the projection, we used 1961-1990 temperature as the baseline, and temperatures in the 2030s and 2050s were projected using the BCM2 global circulation model, SRES A1B scenario, and WHO-provided annual mortality. Here, we used the "counterfactual method" to evaluate the climate change impact; For example, baseline temperature and 2030 mortality were used to determine the baseline excess, and compared with the 2030 excess, for which we used 2030 temperature and 2030 mortality. In terms of adaptation to warmer climate, we assumed 0 % adaptation when the OT as of the current climate is used and 100 % adaptation when the OT as of the future climate is used. The midpoint of the OTs of the two types of adaptation was set to be the OT for 50 % adaptation. RESULTS: We calculated heat-related excess mortality for 2030 and 2050. CONCLUSIONS: Our new model is considered to be better fit, and more precise and robust compared with the previous model. PMID- 23928947 TI - Growth in rice cells requires de novo purine biosynthesis by the blast fungus Magnaporthe oryzae. AB - Increasing incidences of human disease, crop destruction and ecosystem perturbations are attributable to fungi and threaten socioeconomic progress and food security on a global scale. The blast fungus Magnaporthe oryzae is the most devastating pathogen of cultivated rice, but its metabolic requirements in the host are unclear. Here we report that a purine-requiring mutant of M. oryzae could develop functional appressoria, penetrate host cells and undergo the morphogenetic transition to elaborate bulbous invasive hyphae from primary hyphae, but further in planta growth was aborted. Invasive hyphal growth following rice cell ingress is thus dependent on de novo purine biosynthesis by the pathogen and, moreover, plant sources of purines are neither available to the mutant nor required by the wild type during the early biotrophic phase of infection. This work provides new knowledge about the metabolic interface between fungus and host that might be applicable to other important intracellular fungal pathogens. PMID- 23928948 TI - Vitreous and Aqueous Penetration of Orally Administered Trimethoprim Sulfamethoxazole Combination in Humans. AB - PURPOSE: To determine the penetration of orally administered trimethoprim (TMP) sulfamethoxazole (SMX) into the aqueous and vitreous cavity of noninflamed human eyes. METHODS: Nine adult patients undergoing cataract surgery and 10 adult patients undergoing pars plana vitrectomy were given 3 doses of oral TMP-SMX every 12 hours before the surgery. Aqueous and blood samples were collected from patients undergoing cataract surgery; vitreous and blood samples were collected from patients undergoing vitrectomy. The levels of TMP and SMX were analyzed using high-performance liquid chromatography and were compared with the mean minimum inhibitory concentrations (MIC) of potential ocular pathogens. RESULTS: TMP-SMX was present in all samples. Among eyes undergoing cataract surgery, the mean concentrations of TMP in aqueous and blood were 0.341 +/- 0.141 MUg/mL (mean +/- SD) and 1.501 +/- 0.433 MUg/mL and of SMX were 5.259 +/- 0.929 MUg/mL and 11.835 +/- 2.100 MUg/mL, respectively. Among eyes undergoing vitrectomy, the mean concentrations of TMP in vitreous and blood were 1.864 +/- 0.807 MUg/mL and 4.591 +/- 2.979 MUg/mL and of SMX were 5.910 +/- 2.705 MUg/mL and 39.289 +/- 15.469 MUg/mL, respectively. MIC levels were achieved against many bacterial pathogens, including methicillin-resistant Staphylococcus aureus. CONCLUSIONS: TMP-SMX penetrates both the aqueous and vitreous cavities when given orally. The components reach therapeutic inhibitory concentrations in the ocular cavity against many potential pathogens. PMID- 23928949 TI - Epithelial downgrowth after penetrating keratoplasty: imaging by high-resolution optical coherence tomography and in vivo confocal microscopy. AB - PURPOSE: To report the clinical utility of high-resolution anterior segment optical coherence tomography (AS-OCT) combined with in vivo confocal microscopy (IVCM) to diagnose and follow the effectiveness of treatment of 2 cases of epithelial downgrowth after penetrating keratoplasty. METHODS: A retrospective case review was performed on 2 eyes of 2 patients with a history of multiple penetrating keratoplasties that developed epithelial downgrowth 4 and 6 months after the most recent penetrating graft. At various time points, high-resolution AS-OCT images were obtained using the Spectralis (Heidelberg Engineering GmbH), and IVCM images were obtained using the Heidelberg Retina Tomograph III Rostock Cornea Module (Heidelberg Engineering GmbH). In 1 case, the diagnosis was confirmed by histopathologic evaluation. RESULTS: Two patients developed epithelial downgrowth after penetrating keratoplasty. In case 1, a 48-year-old man with a history of Acanthamoeba keratitis developed epithelial downgrowth after undergoing 2 therapeutic grafts over a 1-year period. In case 2, a 40-year old man with a history of a corneal laceration complicated by fungal keratitis was diagnosed with epithelial downgrowth after undergoing 3 penetrating grafts, the placement of a glaucoma drainage device, and a pars plana vitrectomy over a 3 year period. In both cases, at the level of the endothelium, AS-OCT identified a highly reflective layer and IVCM revealed round hyperreflective nuclei consistent with epithelium. CONCLUSIONS: Epithelial downgrowth is an uncommon complication after penetrating keratoplasty. High-resolution AS-OCT and IVCM are noninvasive imaging modalities that may potentially be more sensitive in identifying and monitoring epithelial downgrowth than routine light biomicroscopy and may obviate the need for invasive diagnostic measures. PMID- 23928950 TI - Fellow Eye Comparison of Descemet Membrane Endothelial Keratoplasty and Penetrating Keratoplasty. AB - PURPOSE: To compare the visual outcomes and postoperative complications in patients undergoing penetrating keratoplasty (PKP) in 1 eye followed by Descemet membrane endothelial keratoplasty (DMEK) in their fellow eye. METHODS: A retrospective analysis of 11 patients, who underwent a PKP procedure first in 1 eye and then a DMEK surgery in their fellow eye, was performed. Intraoperative and postoperative complications were recorded. Visual and refractive outcomes were also evaluated, including higher-order aberrations (HOAs) and contrast thresholds. A subjective questionnaire was used to evaluate patient satisfaction. RESULTS: Both uncorrected and best-corrected visual acuities were significantly better in the case of DMEK when compared with that in the case of PKP (0.82 vs. 0.37 logMAR, P = 0.005; 0.61 vs. 0.21 logMAR, P = 0.011, respectively). Postkeratoplasty astigmatism, mean spherical equivalent, and HOAs were also significantly lower in eyes after undergoing DMEK than after undergoing PKP (3.90 vs. 0.89 diopters, P = 0.005; -3.90 vs. -0.68 diopters, P = 0.005; 6.81 vs. 1.71 um, P = 0.043, respectively). Visual outcome and patient satisfaction were significantly better in those who underwent DMEK (2.91 vs. 4.45, P = 0.011; 3.27 vs. 5.64, P = 0.016, respectively). The estimated time for recovery and rehabilitation was significantly shorter after DMEK (64.0 vs. 9.3 days, P = 0.012). Contrast threshold was better after the DMEK. Ten of 11 patients preferred DMEK procedure. CONCLUSIONS: The Patients preferred DMEK to PKP. The reasons for better patient satisfaction after DMEK included better uncorrected visual acuity, better best-corrected visual acuity, avoidance of surgery-induced astigmatism, and lower HOA. PMID- 23928951 TI - A donor cornea with metastatic cells from a cutaneous malignant melanoma. AB - PURPOSE: To describe the case of a donor cornea that showed hematogenous metastatic spread of cutaneous melanoma to the sclerocorneal limbus. METHODS: Corneal tissue obtained from a donor with cutaneous malignant melanoma was evaluated for endothelial cell density, corneal transparency, and epithelial morphology. Subsequently, hematoxylin and eosin staining and immunohistochemical characterization using S100, HMB45, Melan-A, and CD34 antibodies were performed on the corneal sections. RESULTS: The corneal tissue was transparent with high endothelial cell density; it was graded as being suitable for transplantation according to the current eye bank criteria. However, the aggressiveness of the donor's cancer and the diffuse melanosis of the sclera led to the suspicion of malignant melanoma metastasis to the cornea. Histochemical analysis of the corneoscleral rim showed small aggregates rich in pigmented cells that were localized in cleft-like structures in the sclera, at the sclerocorneal interface and in the peripheral avascular portion of the cornea. The aggregates were positive for the melanocytic tumor markers S100, HMB45, and Melan-A; the rims of the clefts expressed the panvascular CD34 antigen, which was suggestive of neovascularization. CONCLUSIONS: Corneal tissue from a donor with malignant cutaneous melanoma displayed neoplastic lesions of melanocytic origin that had spread from a primitive melanoma through hematogenous routes to the sclerocorneal limbus. On the basis of this finding, we believe that having a metastatic cutaneous malignant melanoma could in some cases be reviewed as an exclusionary criterion for undergoing cornea transplantation. PMID- 23928952 TI - Immune response to 1 and 2 dose regimens of measles vaccine in Pakistani children. AB - Measles is a significant problem in Pakistan despite vaccine coverage rates reported at 80%. The purpose of this study was to determine the serologic response in children after one dose of measles vaccine at 9 mo versus two doses at 9 and 15 mo of age. From March through December 2006, children were enrolled from immunization clinics and squatter settlements in Karachi. Blood samples were taken from children in Group A at 9-10 mo of age prior to measles vaccine and 8 to 11 weeks later; from children in Group B at 16-17 mo of age after receiving 2 doses of measles vaccine; and from children in Group C who had received at least one dose of measles vaccine by 5 y of age. After the first dose of measles vaccine, 107/147 (73%) of children in Group A were seropositive, 157/180 (87%) of children in Group B were seropositive after two doses and 126/200 (63%) of children in Group C were seropositive at 5 y of age. The post-vaccination geometric mean antibody concentrations were higher in females than males in groups A (irrespective of pre-vaccination antibody levels) and B. The serologic response to one and two doses of measles vaccine was lower in children in Karachi than has been reported in many other countries. Two doses of vaccine were significantly better than one dose. An in-depth investigation is needed to determine the reason for the lower-than-expected protection rates. Differences in immunogenicity between genders need to be further studied. Recent introduction of supplemental measles vaccine doses should help control measles in Pakistan. PMID- 23928953 TI - Where to for pelvic organ prolapse treatment after the FDA pronouncements? Comment. PMID- 23928954 TI - Where to for pelvic organ prolapse treatment after the FDA pronouncements? Reply to Pelikan. PMID- 23928955 TI - Combined spinal and general anesthesia vs general anesthesia for robotic sacrocervicopexy: a randomized controlled trial. AB - INTRODUCTION AND HYPOTHESIS: Gynecologic laparoscopic surgery is frequently accompanied by early postoperative pain. This study assessed the effect of combined general and spinal anesthesia on postoperative pain score, analgesic use, and patient satisfaction following robotic surgeries. METHODS: This was a randomized controlled trial. Thirty-eight consecutive women who underwent robotic surgeries for pelvic organ prolapse (sacrocolpopexy with or without subtotal hysterectomy) were randomly assigned to receive general anesthesia (control group, n = 20) or combined general with spinal anesthesia (study group, n = 18). Pain scores were assessed at rest and while coughing using a visual analog scale (VAS) 0-10. Dosage of analgesic medication consumption was retrieved from patients' charts. RESULTS: There were no statistically significant differences between the two groups with respect to demographic data and intraoperative hemodynamic parameters. In the postanesthesia care unit (PACU) mean total IV morphine and meperidine dosages were significantly lower for the study than the control group (0.33 vs 7.59 mg, 1.39 vs 27.89 mg, respectively, P < 0.003, <0.001, respectively). In addition, a significantly lower percentage of patients belonging to the study group demanded analgesic medications while in the PACU (33 vs 53 %, P = 0.042). Pain scores in the PACU and during postoperative day 1 were significantly lower in the study group than in the control group (delta VAS 1.9 vs 3.0, P = 0.04). Satisfaction with pain treatment among both patients and nurses was significantly higher in the study group. CONCLUSIONS: Reported levels of pain and analgesic use during the first 24 h following robotic gynecologic surgery were significantly lower following general and spinal anesthesia compared to general anesthesia alone. PMID- 23928956 TI - Good quality sleep is associated with better academic performance among university students in Ethiopia. AB - PURPOSE: This study assessed the association of sleep quality with academic performance among university students in Ethiopia. METHODS: This cross-sectional study of 2,173 college students (471 female and 1,672 male) was conducted in two universities in Ethiopia. Students were selected into the study using a multistage sampling procedure, and data were collected through a self administered questionnaire. Sleep quality was assessed using Pittsburgh Sleep Quality Index, and academic performance was based on self-reported cumulative grade point average. The Student's "t" test, analysis of variance, and multiple linear regression were used to evaluate associations. RESULTS: We found that students with better sleep quality score achieved better on their academic performance (P value = 0.001), while sleep duration was not associated with academic performance in the final model. CONCLUSION: Our study underscores the importance of sleep quality on better academic performance. Future studies need to identify the possible factors which influence sleep quality other than the academic environment repeatedly reported by other literature. It is imperative to design and implement appropriate interventions to improve sleep quality in light of the current body of evidence to enhance academic success in the study setting. PMID- 23928957 TI - Influencing factors on the effect of mandibular advancement device in obstructive sleep apnea patients: analysis on cephalometric and polysomnographic parameters. AB - BACKGROUND: The purposes of this study were to evaluate clinical outcome of mandibular advancement device (MAD) for obstructive sleep apnea (OSA) patients and to estimate influencing factors on MAD effect. METHODS: From the patients who were diagnosed as OSA by polysomnography at Seoul National University Bundang Hospital from January 2007 to February 2009, the patients who chose MAD as initial treatment option were included. All the patients' data were collected by reviewing and analyzing medical record and radiograph retrospectively. RESULTS: Eighty-six patients (76 males and 10 females; mean age of 51.5 +/- 9.8 years) with OSA were included in this study. Total success rate of MAD treatment was 47.7% (41/86 patients). Among cephalometric parameters, lower facial height (35.61 +/- 4.26 vs. 38.19 +/- 4.89) showed significant difference between success group and non-success group. From the polysomnographic parameters, apnea index (19.79 +/- 17.32 vs. 30.08 +/- 23.28), average oxygen saturation (95.03 +/- 1.42 vs. 94.32 +/- 1.56), lowest oxygen saturation (81.44 +/- 6.64 vs. 76.87 +/- 7.98), oxygen saturation under 90% (4.47 +/- 5.90 vs. 9.01 +/- 9.29), and oxygen desaturation index (23.58 +/- 17.46 vs. 37.16 +/- 22.35) showed significant difference between groups. CONCLUSIONS: From the results, it was proved that MAD was an effective treatment option for the OSA patients. Some cephalometric and polysomnographic parameters including posterior lower facial height, apnea index, average oxygen saturation, lowest oxygen saturation, oxygen saturation under 90 %, and oxygen desaturation index could be influencing factors on MAD effect. PMID- 23928959 TI - 2013 ACTERIA Prize winners: get to know them. PMID- 23928961 TI - Eberhard Wecker (1923-2013). PMID- 23928962 TI - Functional development of gammadelta T cells. AB - The thymus generates T cells that are generally functionally immature and thus require peripheral activation for differentiation into effector lymphocytes. Notable exceptions to this rule are murine gammadelta T cells, many of which have been shown to acquire their functional potential during thymic development from late embryonic stages. Here, we review the underlying ontogenic processes and molecular differentiation mechanisms of murine gammadelta T cells, focusing on the transcriptional control of IFN-gamma and IL-17 expression. We propose that functional commitment of gammadelta T cells occurs in "developmental windows" defined by the molecular composition of the thymic microenvironment, such as T cell receptor (TCR), TCR coreceptor ligands, and cytokines. We further discuss the similarities and particularities of functional development of gammadelta T cells in mice and humans, while highlighting some key unresolved issues for future investigation. PMID- 23928963 TI - The immunopathogenesis of the HIV tuberculosis immune reconstitution inflammatory syndrome. AB - HIV-1 patients co-infected with some pathogens are at risk of developing the immune reconstitution inflammatory syndrome (IRIS) when initiating antiretroviral therapy (ART). IRIS is characterized by inflammation leading to the clinical worsening of a treated infection or the unmasking of a previously undiagnosed condition or infection. It is commonly associated with tuberculosis (TB), 8-43% of the HIV-TB co-infected patients prescribed with antitubercular treatment and ART develop TB-IRIS. Although IRIS has been recognized for over 20 years, relatively little was known until recently about its pathogenesis. Despite these advances in understanding IRIS, there remains no immune biomarker for diagnostic or prognostic purposes. Here, we review the risk factors associated with TB-IRIS, the challenges in studying this syndrome, and how T lymphocytes, dysregulated cytokine responses, and innate immunity may contribute to the development of TB IRIS. PMID- 23928964 TI - Damage control: management of cellular stress by the NLRP3 inflammasome. AB - The NLRP3 inflammasome plays a critical role in regulating inflammatory and cell death pathways in response to a diverse array of stimuli. Activation of the NLRP3 inflammasome results in activation of the cysteine protease caspase-1 and the subsequent processing and secretion of the proinflammatory cytokines IL-1beta and IL-18. In this issue of the European Journal of Immunology, Licandro et al. [Eur. J. Immunol. 2013. 43, 2126-2137] show that the NLRP3 inflammasome contributes to oxidative DNA damage. In addition, activation of the NLRP3 inflammasome modulates a number of pathways involved in DNA damage repair, cell cycle, and apoptosis, suggesting a novel role for the NLRP3 inflammasome in DNA damage responses following cellular stress. PMID- 23928965 TI - Endocytosis-free DNA sensing by cell surface TLR9 in neutrophils: rapid defense with autoimmune risks. AB - TLR9 senses microbial DNA, but may also respond to self-DNA. To prevent the initiation of innate immune responses to self-DNA, TLR9 is thought to sense microbial DNA in endolysosomes, and not at the cell surface. A report by Lindau et al. in this issue of the European Journal of Immunology [Eur. J. Immunol. 2013. 43: 2101-2113] shows that TLR9 is expressed on the surface of human and mouse neutrophils and, furthermore, shows that cell surface TLR9, instead of endosomal TLR9, senses DNA in neutrophils. These findings demonstrate that DNA sensing by TLR9 in neutrophils is quite distinct from that in DCs or macrophages. The unique DNA sensing by cell surface TLR9 in neutrophils may reflect their role in inducing rapid inflammation by degranulation with a minimal role in engulfing microbial products for antigen presentation. PMID- 23928980 TI - 131I sodium-iodide versus 56Fe surgical steel. Which is better for lateral lymph node metastases in differentiated thyroid cancer patients? PMID- 23928981 TI - Distant metastatic lesions in patients with differentiated thyroid carcinoma. Clinical implications of radioiodine and FDG uptake. AB - AIM: Many investigators have reported an inverse relationship between iodine and glucose utilization of differentiated thyroid carcinoma (DTC) according to its degree of differentiation; however, not every DTC is compatible with this phenomenon. This study was conducted to evaluate the clinical implication of iodine and glucose uptake at distant metastatic lesions in DTC patients. PATIENTS, METHODS: 64 DTC patients (women 47; mean age 49.9 +/- 16.4 years) with distant metastasis who underwent post (131)I treatment whole-body scan (RxWBS) and FDG PET/CT were included in the study. Radioiodine (RAI) and FDG uptake of metastatic lesions were evaluated. TSH stimulated serum thyroglobulin (s-Tg) were obtained. RESULTS: 53 of 64 patients (82.8%) were RAI(+) group, and 37 patients (57.8%) were FDG(+) group. Patients in the RAI(-) group showed a higher rate of FDG uptake than RAI(+) group (100.0% vs. 49.1%, p = 0.002). Patients in the FDG( ) group showed a higher rate of RAI uptake than FDG(+) group (100.0% vs. 70.3%, p = 0.002). Patients with s-Tg < 100 ng/ml were frequently observed in the FDG( )/RAI(+) group and the FDG(+)/RAI(-) group (p = 0.023). And patients with s-Tg >= 500 ng/ml were more frequently observed in the FDG(+)/RAI(+) group, compared with the FDG(+)/RAI(-) group (p = 0.036). Reduced disease-specific survival (DSS) was observed in patients with RAI(-) (p = 0.003), FDG(+) (p = 0.006), SUVmax > 3.6 (p<0.001), and s-Tg > 75.8 ng/ml (p = 0.009). In multivariate analysis, only a SUVmax > 3.6 was significantly predictive of DSS (p = 0.006). CONCLUSION: An inverse relationship between RAI and FDG uptake, flip-flop phenomenon, was observed in patients with metastatic lesions of DTC. Reduced disease-specific survival was observed in patients with FDG(+), RAI(-) in metastatic lesions, or high s-Tg value. PMID- 23928982 TI - Interim PET response criteria in paediatric non-Hodgkin's lymphoma. Results from a retrospective multicenter reading. AB - AIM: To evaluate the use and reliability of the PET-based response criteria for interim PET (iPET) in terms of interobserver variability in pediatric and adolescent patients suffering from non-Hodgkin's lymphoma (NHL). Particular attention was given to the identification of visual cutoff to separate patients with a favourable outcome. PATIENTS, METHODS: Retrospective analysis of PET datasets of 18 children and adolescents suffering from NHL who underwent iPET after two cycles of chemotherapy for response assessment. Datasets were evaluated and rated in three independent review centers (RC) (blinded-read, intra-center consensus) using a visual 5-point response scale. Ratings were compared to clinical outcome. Pairwise interobserver agreement was analysed with Cohen's kappa-test (kappa). Overall agreement (between attended RCs) was assessed with Fleiss' kappa-test. RESULTS: Four patients suffered relapse (early, n = 2; late, n = 2). Per region analyses on interobserver variability revealed a "substantial" agreement (Fleiss' kappa = 0.618). Per patient analyses revealed concordant iPET ratings in eight patients: iPET-negative (iPET-), n = 5; iPET-positive (iPET+), n = 2; iPET-inconclusive (iPET+/-), n = 1. Discordant ratings were found in the remaining patients. Patients with early relapse were concordantly identified using mediastinal blood pool structures (MBPS, score >= 3) as visual cutoff between iPET+ or iPET-, respectively. However, patients with late relapse were not concordantly identified taking the MBPS as visual cutoff. CONCLUSION: The iPET interpretation using a dedicated PET-based response scale assured a low interobserver variability in per-region but not in per-patient analyses in a multicenter read. Using a sensitive read out (iPET+, score >= 3) a reliable identification of patients suffering relapse was limited to those with early relapse. PMID- 23928983 TI - Relationship between the number of cytomegalovirus in anterior chamber and severity of anterior segment inflammation. AB - PURPOSE: To characterize the cytomegalovirus-associated anterior segment inflammation and to determine whether the number of cytomegalovirus is significantly correlated with the disease characteristics. METHODS: Retrospective consecutive case series. Seventy-three patients with refractory anterior segment inflammation due to iridocyclitis, corneal endotheliitis and keratouveitis were studied. All the patients were suspected to have cytomegalovirus infection and had undergone real-time PCR of the aqueous humor to determine the amount of cytomegalovirus DNA. RESULTS: Cytomegalovirus DNA was detected in 24 of the 73 cases. The cytomegalovirus copy number was significantly correlated with the number of recurrent episodes and glaucoma treatment levels, but was not significantly correlated with the disease type. A high cytomegalovirus copy number was a significant risk factor for IOP elevation [Odds ratio (OR) per logarithm CMV amount: 2.5 (95 % confidence interval (CI) 1.1-5.4), presence of coin-shaped lesions (2.3 (1.3-4.0)), recurrent inflammation (2.1 (1.3-3.5)), and reduction of endothelial cell densities (1.7 (1.2-2.5))]. An IOP elevation [OR 18.2 (95 % CI 2.2-153.0)], reduction of endothelial cell densities [13.2 (2.9 60.0)], and recurrent inflammations [11.9 (2.5-56.6)], but not the disease type, were significant predictors of the presence of >10(3) copies/ml cytomegalovirus in the aqueous. CONCLUSIONS: Measurements of the cytomegalovirus DNA amount is useful for evaluating the severity of the anterior segment inflammation. PMID- 23928984 TI - Diagnostic accuracy and safety of semirigid thoracoscopy in exudative pleural effusions: a meta-analysis. AB - BACKGROUND: The usefulness of semirigid thoracoscopy in undiagnosed exudative pleural effusions (EPEs) has been variably reported in different studies. Herein, we perform a systematic review and meta-analysis to estimate the overall diagnostic yield and safety of semirigid thoracoscopy in EPE. METHODS: We searched the PubMed and EMBASE databases for studies reporting the outcomes of semirigid thoracoscopy in EPE. The quality of studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The yield of semirigid thoracoscopy was analyzed by calculating the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic OR (DOR) for each study and pooling the study results using a random effects model. Heterogeneity and publication bias were assessed for individual outcomes. Sensitivity analysis was performed to explore the potential causes of heterogeneity. RESULTS: Our search yielded 17 studies (755 patients with undiagnosed EPE). The sensitivity, specificity, PLR, NLR, and DOR of semirigid thoracoscopy was 91%, 100%, 4.92, 0.08, and 102.28, respectively. The area under the curve for the summary receiver operating characteristic curve was 0.93. There were negligible complications and no mortality. There was evidence of heterogeneity, which significantly decreased on sensitivity analysis after exclusion of smaller (< 25 participants) studies. There was no evidence of publication bias. CONCLUSIONS: Semirigid thoracoscopy is an efficacious and safe procedure in diagnosis of EPE. Because of the small sample size, larger well designed trials are required to confirm the results of this study. There is also a need for head-to-head comparison of semirigid and rigid thoracoscopy. PMID- 23928985 TI - 'Are you still on that stupid diet?': women's experiences of societal pressure and support regarding weight loss, and attitudes towards health policy intervention. AB - This study investigated how people's attitudes and motivations towards losing weight are influenced by societal pressures surrounding weight loss, their interaction with the obesogenic environment and individuals' attitudes and motivations towards weight. Semi-structured qualitative interviews were conducted with 10 women currently attending commercial weight-loss programmes. Participants experienced conflicting messages regarding weight norms, with the media portraying powerful social norms relating to thinness and beauty, and changes to the food environment and interactions with family and friends commonly undermining weight-loss activities and promoting increased consumption. Providing social and environmental support for the behaviours needed to produce weight loss may need to be a primary focus for obesity policy. PMID- 23928986 TI - Cancer in full-colour: use of a graphic novel to identify distress in women with breast cancer. AB - The graphic novel Cancer Vixen about breast cancer was used as an example to examine whether reading of graphic novels may enhance insight into illness experiences. Content analysis showed that the graphic novel depicts the full range of distress, by portraying practical, social, emotional, religious/spiritual and physical problems. Findings were illustrated with descriptions from the book. The results indicate that--from a content perspective -this graphic novel may be of value in medical education and health psychology settings to teach students and patients about the human side of being ill. PMID- 23928987 TI - Relationships among factual and perceived knowledge of harms of waterpipe tobacco, perceived risk, and desire to quit among college users. AB - Waterpipe tobacco smoking is increasing in the United States among college students. Through a web-based survey, we explored associations among factual and perceived knowledge, perceived risks and worry about harm and addiction, and desire to quit among 316 college waterpipe tobacco smoking users. Overall, factual knowledge of the harm of waterpipe tobacco smoking was poor, factual and perceived knowledge was weakly correlated, both forms of knowledge were related inconsistently to perceived risks and worry, and neither form of knowledge was associated with the desire to quit. Findings provide preliminary insights as to why knowledge gaps may not predict cessation among waterpipe users. PMID- 23928988 TI - The influence of time perspective on cervical cancer screening among Latinas in the United States. AB - To develop effective interventions to increase cervical cancer screening among Latinas, we should understand the role of cultural factors, such as time perspective, in the decision to be screened. We examined the relation between present time orientation, future time orientation, and self-reported cervical cancer screening among Latinas. A group of 206 Latinas completed a survey measuring factors associated with screening. Logistic regression analyses revealed that future time orientation was significantly associated with self reported screening. Understanding the influence of time orientation on cervical cancer screening will assist us in developing interventions that effectively target time perspective and screening. PMID- 23928989 TI - An empirical test of the Theory of Planned Behaviour applied to contraceptive use in rural Uganda. AB - There is a high unmet need for contraceptives in developing countries such as Uganda, with high population growth, where efforts are needed to promote family planning and contraceptive use. Despite this high need, little research has investigated applications of health-behaviour-change theories to contraceptive use among this population. This study tested the Theory of Planned Behaviour's ability to predict contraceptive-use-related behaviours among post-partum women in rural Uganda. Results gave modest support to the theory's application and suggest an urgent need for improved theory-based interventions to promote contraceptive use in the populations of developing countries. PMID- 23928990 TI - Downregulation of microRNA-515-5p by the estrogen receptor modulates sphingosine kinase 1 and breast cancer cell proliferation. AB - Sphingosine kinase 1 (SK1) plays an important role in estrogen-dependent breast tumorigenesis, but its regulation is poorly understood. A subset of microRNAs (miRNA, miR) is regulated by estrogen and contributes to cellular proliferation and cancer progression. Here, we describe that miR-515-5p is transcriptionally repressed by estrogen receptor alpha (ERalpha) and functions as a tumor suppressor in breast cancer. Its downregulation enhances cell proliferation and estrogen-dependent SK1 activity, mediated by a reduction of miR-515-5p posttranscriptional repression. Enforced expression of miR-515-5p in breast cancer cells causes a reduction in SK1 activity, reduced cell proliferation, and the induction of caspase-dependent apoptosis. Conversely, opposing effects occur with miR-515-5p inhibition and by SK1 silencing. Notably, we show that estradiol (E2) treatment downregulates miR-515-5p levels, whereas the antiestrogen tamoxifen causes a decrease in SK1, which is rescued by silencing miR-515-5p. Analysis of chromatin immunoprecipitation sequencing (ChIP-Seq) data reveals that miR-515-5p suppression is mediated by a direct interaction of ERalpha within its promoter. RNA-sequencing (RNA-Seq) analysis of breast cancer cells after overexpressing miR-515-5p indicates that it partly modulates cell proliferation by regulating the Wnt pathway. The clinical implications of this novel regulatory system are shown as miR-515-5p is significantly downregulated in ER-positive (n = 146) compared with ER-negative (n = 98) breast cancers. Overall, we identify a new link between ERalpha, miR-515-5p, proliferation, and apoptosis in breast cancer tumorigenesis. PMID- 23928991 TI - Constitutive beta-catenin activation induces male-specific tumorigenesis in the bladder urothelium. AB - The incidence for bladder urothelial carcinoma, a common malignancy of the urinary tract, is about three times higher in men than in women. Although this gender difference has been primarily attributed to differential exposures, it is likely that underlying biologic causes contribute to the gender inequality. In this study, we report a transgenic mouse bladder tumor model upon induction of constitutively activated beta-catenin signaling in the adult urothelium. We showed that the histopathology of the tumors observed in our model closely resembled that of the human low-grade urothelial carcinoma. In addition, we provided evidence supporting the KRT5-positive;KRT7-negative (KRT5(+); KRT7(-)) basal cells as the putative cells-of-origin for beta-catenin-induced luminal tumor. Intriguingly, the tumorigenesis in this model showed a marked difference between opposite sexes; 40% of males developed macroscopically detectable luminal tumors in 12 weeks, whereas only 3% of females developed tumors. We investigated the mechanisms underlying this sexual dimorphism in pathogenesis and showed that nuclear translocation of the androgen receptor (AR) in the urothelial cells is a critical mechanism contributing to tumor development in male mice. Finally, we carried out global gene profiling experiments and defined the molecular signature for the beta-catenin-induced tumorigenesis in males. Altogether, we have established a model for investigating sexual dimorphism in urothelial carcinoma development, and implicated synergy between beta-catenin signaling and androgen/AR signaling in carcinogenesis of the basal urothelial cells. PMID- 23928992 TI - Cyclin D1-dependent induction of luminal inflammatory breast tumors by activated notch3. AB - Accumulating evidence suggests that Notch3 (N3) is involved in breast cancer development, but its precise contributions are not well understood. Here, we report that pregnant mice expressing an activated intracellular form of N3 (N3(IC)) exhibit a cyclin D1-dependent expansion of premalignant CD24(+) CD29(low) luminal progenitors with enhanced differentiation potential in vitro and in vivo. Parous mice developed luminal mammary tumors in a cyclin D1 dependent manner. Notably, mice expressing higher levels of N3(IC) exhibited tumors resembling inflammatory breast cancer that frequently metastasized. N3(IC) induced tumors contained a large percentage of tumor-initiating cells, but these were reduced significantly in tumors derived from N3(IC) transgenic mice that were heterozygous for cyclin D1. After transplantation in the presence of normal mammary cells, N3(IC)-expressing tumor cells became less malignant, differentiating into CK6(+) CK18(+) CK5(-) alveolar-like structures akin to expanded luminal progenitors from which they were likely derived. Taken together, our results argue that activated N3 signaling primarily affects luminal progenitors among mammary cell subsets, with more pronounced levels of activation influencing tumor type, and provide a novel model of inflammatory breast cancer. PMID- 23928993 TI - An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. AB - HER2/HER3 dimerization resulting from overexpression of HER2 or neuregulin (NRG1) in cancer leads to HER3-mediated oncogenic activation of phosphoinositide 3 kinase (PI3K) signaling. Although ligand-blocking HER3 antibodies inhibit NRG1 driven tumor growth, they are ineffective against HER2-driven tumor growth because HER2 activates HER3 in a ligand-independent manner. In this study, we describe a novel HER3 monoclonal antibody (LJM716) that can neutralize multiple modes of HER3 activation, making it a superior candidate for clinical translation as a therapeutic candidate. LJM716 was a potent inhibitor of HER3/AKT phosphorylation and proliferation in HER2-amplified and NRG1-expressing cancer cells, and it displayed single-agent efficacy in tumor xenograft models. Combining LJM716 with agents that target HER2 or EGFR produced synergistic antitumor activity in vitro and in vivo. In particular, combining LJM716 with trastuzumab produced a more potent inhibition of signaling and cell proliferation than trastuzumab/pertuzumab combinations with similar activity in vivo. To elucidate its mechanism of action, we solved the structure of LJM716 bound to HER3, finding that LJM716 bound to an epitope, within domains 2 and 4, that traps HER3 in an inactive conformation. Taken together, our findings establish that LJM716 possesses a novel mechanism of action that, in combination with HER2- or EGFR-targeted agents, may leverage their clinical efficacy in ErbB-driven cancers. PMID- 23928994 TI - Telomere length in peripheral blood lymphocytes contributes to the development of HPV-associated oropharyngeal carcinoma. AB - Sexual transmission of human papillomavirus (HPV), particularly HPV16, has been associated with an increasing incidence of oropharyngeal squamous cell carcinoma (OPC). Telomere shortening results in chromosomal instability, subsequently leading to cancer development. Given that HPV16 can affect telomerase activity and telomere length, we conjectured that telomere length in peripheral blood lymphocytes (PBL) might affect the risk of HPV16-associated OPC and tumor HPV16 status in patients. Telomere length in PBLs and HPV16 serologic status were measured in peripheral blood samples in 188 patients with OPC, 137 patients with oral cavity cancer (OCC) and 335 controls of non-Hispanic Whites. Tumor HPV status was determined in 349 OPC cases. ORs and 95% confidence intervals were calculated in univariate and multivariable logistic regression models. Overall, as compared with the long telomere length, short telomere length was significantly associated with a moderately increased risk of OPC but not with increased risk of OCC. When we stratified the data by HPV16 serologic status, using long telomere length and HPV16 seronegativity as the reference group, we found that the risk associated with HPV16 seropositivity was higher among patients with OPC with short telomere length. Notably, such risk was particularly pronounced in never smokers, never drinkers, and those more than 50 years of age. Furthermore, short telomere length was also associated significantly with tumor HPV-positive OPC. Together, our findings suggest that telomere length in PBLs may be associated with higher risk of HPV16-associated OPC and tumor HPV16 status, particularly in certain patient subgroups. Larger studies are needed to validate these findings. PMID- 23928996 TI - Diffusion tensor magnetic resonance imaging in the analysis of neurodegenerative diseases. AB - Diffusion tensor imaging (DTI) techniques provide information on the microstructural processes of the cerebral white matter (WM) in vivo. The present applications are designed to investigate differences of WM involvement patterns in different brain diseases, especially neurodegenerative disorders, by use of different DTI analyses in comparison with matched controls. DTI data analysis is performed in a variate fashion, i.e. voxelwise comparison of regional diffusion direction-based metrics such as fractional anisotropy (FA), together with fiber tracking (FT) accompanied by tractwise fractional anisotropy statistics (TFAS) at the group level in order to identify differences in FA along WM structures, aiming at the definition of regional patterns of WM alterations at the group level. Transformation into a stereotaxic standard space is a prerequisite for group studies and requires thorough data processing to preserve directional inter dependencies. The present applications show optimized technical approaches for this preservation of quantitative and directional information during spatial normalization in data analyses at the group level. On this basis, FT techniques can be applied to group averaged data in order to quantify metrics information as defined by FT. Additionally, application of DTI methods, i.e. differences in FA maps after stereotaxic alignment, in a longitudinal analysis at an individual subject basis reveal information about the progression of neurological disorders. Further quality improvement of DTI based results can be obtained during preprocessing by application of a controlled elimination of gradient directions with high noise levels. In summary, DTI is used to define a distinct WM pathoanatomy of different brain diseases by the combination of whole brain-based and tract-based DTI analysis. PMID- 23928995 TI - Breast tumor kinase (Brk/PTK6) is a mediator of hypoxia-associated breast cancer progression. AB - Basal-type triple-negative breast cancers (TNBC) are aggressive and difficult to treat relative to luminal-type breast cancers. TNBC often express abundant Met receptors and are enriched for transcriptional targets regulated by hypoxia inducible factor-1alpha (HIF-1alpha), which independently predict cancer relapse and increased risk of metastasis. Brk/PTK6 is a critical downstream effector of Met signaling and is required for hepatocyte growth factor (HGF)-induced cell migration. Herein, we examined the regulation of Brk by HIFs in TNBC in vitro and in vivo. Brk mRNA and protein levels are upregulated strongly in vitro by hypoxia, low glucose, and reactive oxygen species. In HIF-silenced cells, Brk expression relied upon both HIF-1alpha and HIF-2alpha, which we found to regulate BRK transcription directly. HIF-1alpha/2alpha silencing in MDA-MB-231 cells diminished xenograft growth and Brk reexpression reversed this effect. These findings were pursued in vivo by crossing WAP-Brk (FVB) transgenic mice into the MET(Mut) knockin (FVB) model. In this setting, Brk expression augmented MET(Mut) induced mammary tumor formation and metastasis. Unexpectedly, tumors arising in either MET(Mut) or WAP-Brk * MET(Mut) mice expressed abundant levels of Sik, the mouse homolog of Brk, which conferred increased tumor formation and decreased survival. Taken together, our results identify HIF-1alpha/2alpha as novel regulators of Brk expression and suggest that Brk is a key mediator of hypoxia induced breast cancer progression. Targeting Brk expression or activity may provide an effective means to block the progression of aggressive breast cancers. PMID- 23928997 TI - An ENDOR and DFT analysis of hindered methyl group rotations in frozen solutions of bis(acetylacetonato)-copper(II). AB - ENDOR spectroscopy and DFT calculations have been used to thoroughly investigate the ligand hyperfine couplings for the bis(acetylacetonato)-copper(ii) complex [Cu(acac)2] in frozen solution. Solutions of [Cu(acac)2] were prepared under anhydrous conditions, and EPR revealed that the g and (Cu)A values were affected by traces of water present in the solvent. The ligand (H)Ai hyperfine couplings were subsequently investigated by CW and pulsed ENDOR spectroscopy. Anisotropic hyperfine couplings to the methine protons ((H)Ai = 1.35, -1.62, -2.12 MHz; a(iso) = -0.80 MHz) and smaller couplings to the fully averaged methyl group protons ((H)Ai = -0.65, 1.658, -0.9 MHz; a(iso) = 0.036 MHz) were identified by simulation of the angular selective ENDOR spectra and confirmed by DFT. Since the barrier to methyl group rotation was estimated to be ca. 5 kJ mol(-1) by DFT, rapid rotation of these -CH3 groups, even at 10 K, leads to an averaged value of (H)Ai. However, variable temperature X-band Mims ENDOR revealed an additional set of hyperfine couplings which showed a pronounced temperature dependency. Using CW Q-band ENDOR, these additional couplings were characterised by the hyperfine parameters (H)Ai = 3.45, 2.9, 2.62 MHz, a(iso) = 2.99 MHz and assigned to a hindered methyl group rotation. This hindered rotation of a sub-set of methyl groups occurs in 120 degrees jumps, such that a large A(dip) and a(iso) component is always observed. Whilst the majority of the methyl groups undergo free rotation, a sub-set of methyl groups experience hindered rotation in frozen solution, through proton tunnelling. This hindered rotation appears to be caused by weak outer-sphere solvent interactions with the complex. PMID- 23928998 TI - Atomic structures of silicene layers grown on Ag(111): scanning tunneling microscopy and noncontact atomic force microscopy observations. AB - Silicene, the considered equivalent of graphene for silicon, has been recently synthesized on Ag(111) surfaces. Following the tremendous success of graphene, silicene might further widen the horizon of two-dimensional materials with new allotropes artificially created. Due to stronger spin-orbit coupling, lower group symmetry and different chemistry compared to graphene, silicene presents many new interesting features. Here, we focus on very important aspects of silicene layers on Ag(111): First, we present scanning tunneling microscopy (STM) and non-contact Atomic Force Microscopy (nc-AFM) observations of the major structures of single layer and bi-layer silicene in epitaxy with Ag(111). For the (3 * 3) reconstructed first silicene layer nc-AFM represents the same lateral arrangement of silicene atoms as STM and therefore provides a timely experimental confirmation of the current picture of the atomic silicene structure. Furthermore, both nc-AFM and STM give a unifying interpretation of the second layer (?3 * ?3)R +/- 30 degrees structure. Finally, we give support to the conjectured possible existence of less stable, ~2% stressed, (?7 * ?7)R +/- 19.1 degrees rotated silicene domains in the first layer. PMID- 23929000 TI - Autophagy, a new target for disease treatment. PMID- 23928999 TI - Newfound compassion after prostate cancer: a psychometric evaluation of additional items in the Posttraumatic Growth Inventory. AB - PURPOSE: The most widely used measure of posttraumatic growth (PTG) is the Posttraumatic Growth Inventory (PTGI). Qualitative research indicates the importance of increased compassion as a result of struggling with challenges presented by cancer and treatments. However, current PTG measures may not adequately assess compassion. METHODS: A cross-sectional survey of 514 prostate cancer survivors assessed the PTGI and Dispositional Positive Emotional Scale (DPES). Five additional PTG items were derived from previous qualitative research to assess increased compassion. RESULTS: After removing eight items with complex loadings, a principal components analysis with oblimin rotation revealed a six component structure. A clear delineation was seen between components relating to compassion, new possibilities, relating to others, personal strength, appreciation of life and spiritual change. Compassion accounted for 48.9 % of variance in data, with the overall model accounting for 79.9 % of variance. Strong factorability was demonstrated through Kaiser-Meyer-Olkin (0.92) and Bartlett's test of sphericity (approximate chi (2) = 5,791.85, df 153, p < 0.001). The six-component structure was validated with a confirmatory factor analysis. Strong internal consistency was evidenced through Cronbach's alpha coefficients ranging from 0.74 to 0.90 for subscales, and item-to-total correlations and inter-item correlations exceeded accepted thresholds of 0.50 and 0.30, respectively. Convergent validity was acceptable between the PTGI compassion subscale and DPES (r = 0.50). CONCLUSIONS: Compassion is a highly salient PTG domain after prostate cancer. Further studies can explore this construct with more heterogeneous samples of cancer types and gender. PMID- 23929002 TI - Atomic force microscopy imaging of live mammalian cells. AB - Atomic force microscopy (AFM) was used to examine the morphology of live mammalian adherent and suspended cells. Time-lapse AFM was used to record the locomotion dynamics of MCF-7 and Neuro-2a cells. When a MCF-7 cell retracted, many small sawtooth-like filopodia formed and reorganized, and the thickness of cellular lamellipodium increased as the retraction progressed. In elongated Neuro 2a cells, the cytoskeleton reorganized from an irregular to a parallel, linear morphology. Suspended mammalian cells were immobilized by method combining polydimethylsiloxane-fabricated wells with poly-L-lysine electrostatic adsorption. In this way, the morphology of a single live lymphoma cell was imaged by AFM. The experimental results can improve our understanding of cell locomotion and may lead to improved immobilization strategies. PMID- 23929001 TI - Zacopride selectively activates the Kir2.1 channel via a PKA signaling pathway in rat cardiomyocytes. AB - We recently reported that zacopride is a selective inward rectifier potassium current (I K1) channel agonist, suppressing ventricular arrhythmias without affecting atrial arrhythmias. The present study aimed to investigate the unique pharmacological properties of zacopride. The whole-cell patch-clamp technique was used to study I K1 currents in rat atrial myocytes and Kir2.x currents in human embryonic kidney (HEK)-293 cells transfected with inward rectifier potassium channel (Kir)2.1, Kir2.2, Kir2.3, or mutated Kir2.1 (at phosphorylation site S425L). Western immunoblots were performed to estimate the relative protein expression levels of Kir2.x in rat atria and ventricles. Results showed that zacopride did not affect the IK1 and transmembrane potential of atrial myocytes. In HEK293 cells, zacopride increased Kir2.1 homomeric channels by 40.7%+/-9.7% at -50 mV, but did not affect Kir2.2 and Kir2.3 homomeric channels, and Kir2.1 Kir2.2, Kir2.1-Kir2.3 and Kir2.2-Kir2.3 heteromeric channels. Western immunoblots showed that similar levels of Kir2.3 protein were expressed in rat atria and ventricles, but atrial Kir2.1 protein level was only 25% of that measured in the ventricle. In addition, 5-hydroxytryptamine (5-HT)3 receptor was undetectable, whereas 5-HT4 receptor was weakly expressed in HEK293 cells. The Kir2.1 activating effect of zacopride in these cells was abolished by inhibition of protein kinase A (PKA), but not PKC or PKG. Furthermore, zacopride did not activate the mutant Kir2.1 channel in HEK293 cells but selectively activated the Kir2.1 homomeric channel via a PKA-dependent pathway, independent to that of the 5-HT receptor. PMID- 23929003 TI - Effects of external stimuli on the pacemaker function of the sinoatrial node in sodium channel gene mutations models. AB - Loss of function and gain of function mutations of the sodium channel were investigated using an intact two-dimensional rabbit sinoatrial node (SAN) and atrial cell model. The effects of three external stimuli (acetylcholine secretion by the vagal nerve, acid-base concentration, and tissue temperature) on cardiac pacemaker function and conduction were studied. Our results show that these two groups of mutations have different effects on pacemaker function and conduction. Furthermore, we found that the negative effects of these mutations could be altered by external stimuli. The bradycardic effects of mutations were magnified by an increase in acetylcholine level. Changes in acid-base concentration and tissue temperature increased the ability of the SAN to recover its pacemaker function. The results of this study increase our understanding of sodium channel disorders, and help to advance research on the treatment of these conditions. PMID- 23929004 TI - Development of the Osteoporosis Assessment Questionnaire--physical Function (OPAQ PF): an osteoporosis-targeted, patient-reported outcomes (PRO) measure of physical function. AB - We have developed a short, patient-reported outcome questionnaire--the Osteoporosis Assessment Questionnaire--Physical Function (OPAQ-PF)--that assesses the impact of osteoporosis on physical function. OPAQ-PF contains 15 items in three domains (mobility, physical positions, and transfers) and has content validity in osteoporosis patients with and without a history of fracture. INTRODUCTION: This paper describes the development of the Osteoporosis Assessment Questionnaire--Physical Function (OPAQ-PF), a patient-reported outcome (PRO) questionnaire based on OPAQ v.2.0 (60 items, 14 domains) that assesses the impact of osteoporosis on physical function. METHODS: OPAQ v.2.0 was administered to patients with osteoporosis. Item response theory methodology and clinical judgment were used to retain/eliminate items. The resulting instrument was modified during two sets of concept elicitation and cognitive debriefing interviews with osteoporosis patients. RESULTS: Item response theory-based analysis of OPAQ v.2.0 (n = 1,478) coupled with clinician input resulted in the generation of a 21-item, six-domain instrument with a frequency response format. Interview data from 32 participants were used to modify this version and led to generation of the final instrument, OPAQ-PF. This final version has a severity response format and contains 15 items in three domains (mobility, physical positions, and transfers) that group together to provide an overall assessment of physical function in patients with osteoporosis. Twenty-two of the 32 interview participants (69 %) had previously sustained a fracture. Symptoms occurred primarily in these patients. CONCLUSIONS: OPAQ-PF represents a brief, focused, PRO instrument that assesses physical function in patients with osteoporosis, specifically related to mobility, physical positions, and transfers. This questionnaire has content validity in osteoporosis patients who have, and have not, sustained a prior fracture. PMID- 23929005 TI - Maternal intrusiveness, family financial means, and anxiety across childhood in a large multiphase sample of community youth. AB - Intrusive parenting has been positively associated with child anxiety, although examinations of this relationship to date have been largely confined to middle to upper middle class families and have rarely used longitudinal designs. With several leading interventions for child anxiety emphasizing the reduction of parental intrusiveness, it is critical to determine whether the links between parental intrusiveness and child anxiety broadly apply to families of all financial means, and whether parental intrusiveness prospectively predicts the development of child anxiety. This study employed latent growth curve analysis to evaluate the interactive effects of maternal intrusiveness and financial means on the developmental trajectory of child anxiety from 1st grade to age 15 in 1,121 children (50.7 % male) and their parents from the NICHD SECCYD. The overall model was found to provide good fit, revealing that early maternal intrusiveness and financial means did not impact individual trajectories of change in child anxiety, which were stable from 1st to 5th grade, and then decrease from 5th grade to age 15. Cross-sectional analyses also examined whether family financial means moderated contemporaneous relationships between maternal intrusiveness and child anxiety in 3rd and 5th grades. The relationship between maternal intrusiveness and child anxiety was moderated by family financial means for 1st graders, with stronger links found among children of lower family financial means, but not for 3rd and 5th graders. Neither maternal intrusiveness nor financial means in 1st grade predicted subsequent changes in anxiety across childhood. Findings help elucidate for whom and when maternal intrusiveness has the greatest link with child anxiety and can inform targeted treatment efforts. PMID- 23929006 TI - Prediction of preschool aggression from DRD4 risk, parental ADHD symptoms, and home chaos. AB - This study investigated the influence of a child's DRD4 risk, parental levels of ADHD symptoms, and the interactive influence of these factors on the development of preschool aggression. Additionally, the study investigated the role of home chaos as a mediator between parental ADHD symptoms and child aggression. The sample consisted of 84 4.5-year-old children and their parents. Children were genotyped for the DRD4 polymorphism. ADHD symptoms were self-reported by parents when the child was 2 to 6 months old. Parental reports of home chaos and the child's aggression were collected 4 years later. Child's DRD4 risk and parental ADHD symptoms significantly contributed to the prediction of preschool aggression. However, contrary to our hypotheses, no interactions were found between the child's DRD4 risk and the levels of parental ADHD symptoms. Home chaos played a mediating role in the relation between paternal ADHD symptoms and the child's aggression. The relation between maternal ADHD symptoms and the child's aggression was not significantly mediated through the level of home chaos. The current study emphasizes the importance of longitudinally investigating the contribution of parental ADHD symptoms to child aggression, while also exploring the differential contribution of maternal/paternal inattention and hyperactivity-impulsivity symptoms. Moreover, home chaos was found to be a significant environmental mechanism through which paternal ADHD symptoms affect children's aggression in the preschool years. PMID- 23929007 TI - alphaB-crystallin/HspB5 regulates endothelial-leukocyte interactions by enhancing NF-kappaB-induced up-regulation of adhesion molecules ICAM-1, VCAM-1 and E selectin. AB - alphaB-crystallin is a small heat shock protein, which has pro-angiogenic properties by increasing survival of endothelial cells and secretion of vascular endothelial growth factor A. Here we demonstrate an additional role of alphaB crystallin in regulating vascular function, through enhancing tumor necrosis factor alpha (TNF-alpha) induced expression of endothelial adhesion molecules involved in leukocyte recruitment. Ectopic expression of alphaB-crystallin in endothelial cells increases the level of E-selectin expression in response to TNF alpha, and enhances leukocyte-endothelial interaction in vitro. Conversely, TNF alpha-induced expression of intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and E-selectin is markedly inhibited in endothelial cells isolated from alphaB-crystallin-deficient mice. This is associated with elevated levels of IkappaB in alphaB-crystallin deficient cells and incomplete degradation upon TNF-alpha stimulation. Consistent with this, endothelial adhesion molecule expression is reduced in inflamed vessels of alphaB-crystallin deficient mice, and leukocyte rolling velocity is increased. Our data identify alphaB-crystallin as a new regulator of leukocyte recruitment, by enhancing pro-inflammatory nuclear factor kappa B-signaling and endothelial adhesion molecule expression during endothelial activation. PMID- 23929009 TI - Mesenteric/mesorectal fat and lymph node retrieval: to clear or not to clear? PMID- 23929008 TI - Silencing of S100A4, a metastasis-associated protein, in endothelial cells inhibits tumor angiogenesis and growth. AB - Endothelial cells express S100A4, a metastasis-associated protein, but its role in angiogenesis remains to be elucidated. Here we show that knockdown of S100A4 in mouse endothelial MSS31 cells by murine specific small interference RNA (mS100A4 siRNA) markedly suppressed capillary-like tube formation in vitro, in early stage after the treatment, along with down- and up-regulation of some of the pro-angiogenic and anti-angiogenic gene expression, respectively. Of particular note is that intra-tumor administration of the mS100A4 siRNA in a human prostate cancer xenograft significantly reduced tumor vascularity and resulted in the inhibition of tumor growth. These findings show that S100A4 in endothelial cells is involved in tube formation, and suggest its potential as a molecular target for inhibiting tumor angiogenesis, which warrants further development of endothelial S100A4-based strategies for cancer treatment. PMID- 23929010 TI - Practice parameters for the management of pilonidal disease. PMID- 23929011 TI - Impact of Schwartz enhanced visualization solution on staging colorectal cancer and clinicopathological features associated with lymph node count. AB - BACKGROUND: Stage-specific survival for colon cancer improves when more lymph nodes are reported in the surgical specimen. This has led to a minimum standard of identifying 12 lymph nodes as a quality indicator. OBJECTIVE: The aim of this study was to determine whether the addition of Schwartz solution increases node yield and impacts pathologic staging. DESIGN: This is a prospective cohort study. SETTING: The study was conducted in an academic medical center. PATIENTS: Included were 104 consecutive patients with colorectal cancer. MAIN OUTCOME MEASURES: Lymph node counts before and after specimen treatment with Schwartz solution and incidence of upstaging were measured. RESULTS: An additional 20 minutes (interquartile range, 15-40 minutes) was spent searching for lymph nodes, increasing the median number of nodes from 22.5 to 29.0 nodes. However, only 1 patient was upstaged. Schwartz solution decreased the number of specimens with less than 12 lymph nodes from 15 to 6. The following factors were associated with Schwartz solution leading to the detection of additional nodes: number of nodes detected initially with formalin only (p < 0.000), mesenteric fat volume (p < 0.000), mesenteric fat weight (p < 0.000), length of specimen (p < 0.016), tumor greatest dimension (p < 0.016), patient body surface area (p < 0.034), and patient age (p < 0.003). LIMITATIONS: Clinical data for this study were obtained retrospectively and were not available for all of the patients. CONCLUSIONS: Although Schwartz solution increased the number of nodes detected in 95% of patients and improved compliance with the 12-node standard for colon resection, there was minimal impact on cancer staging. Upstaging is unlikely to explain the increase in overall survival in patients with higher lymph node counts, casting doubt on the validity of this process measure as a meaningful quality indicator. Rather, the lymph node count may be a reflection of inherent tumor biology or host-related factors. PMID- 23929012 TI - The prognostic significance of pretreatment leukocytosis in patients with anal cancer treated with radical chemoradiotherapy or radiotherapy. AB - BACKGROUND: There are emerging data showing the prognostic significance of pretreatment leukocytosis in patients with cervical cancer; it is generally associated with adverse outcome. However, the prognostic impact of leukocytosis in patients with anal cancer has not been previously reported. OBJECTIVE: The purpose of this study was to assess the relationship between pretreatment leukocytosis and clinical outcomes in patients with anal cancer treated with radical chemoradiotherapy or radiotherapy. DESIGN: This is a retrospective cohort study. SETTING AND PATIENTS: One hundred twenty-six patients with invasive anal canal cancer, treated with radical chemoradiotherapy or radiotherapy between 2000 and 2008 at 2 major tertiary cancer centers, were evaluated. MAIN OUTCOME MEASURES: The primary outcomes were disease-free and overall survival. RESULTS: Median follow-up was 24 months. Pretreatment leukocytosis (white blood cell count >10 * 10/L) was identified in 15.9% (20/126) of patients. After adjusting for sex, tumor size, and stage in a multivariate analysis, leukocytosis remained significantly associated with worse disease-free survival (HR, 2.2; 95% CI, 1.1 4.8; p = 0.045) and worse overall survival (HR, 2.9; 95% CI, 1.1-7.9; p = 0.036). Patients with both leukocytosis and anemia (pretreatment hemoglobin <125 g/L) had the worst prognosis: 2-year disease-free survival 42.1% versus 72.9% for patients without these factors (HR, 2.7; 95% CI, 1.1-6.8; p = 0.033); 2-year overall survival 60.9% versus 89.8% (HR, 4.5; 95% CI, 1.5-13.2; p = 0.006). LIMITATIONS: The study was limited by its retrospective nature and lack of patients with multiple hematologic abnormalities (ie, both anemia and leukocytosis). HIV status was unable to be evaluated. CONCLUSIONS: Pretreatment leukocytosis in patients with anal cancer is associated with significantly worse disease-free and overall survival, which appears to be exacerbated with the presence of pretreatment anemia. PMID- 23929013 TI - Distribution of human papillomavirus genotypes in anal cytological and histological specimens from HIV-infected men who have sex with men and men who have sex with women. AB - BACKGROUND: Anal cancer is caused by human papillomavirus (HPV). Moreover, human immunodeficiency virus (HIV) is an additional risk factor for anal cancer. Therefore, when designing preventive protocols for HIV-infected men, it is important to detect high-risk (HR) oncogenic HPV genotypes present in their anal canals. However, most studies have focused only on men who have sex with men (MSM). OBJECTIVE: To estimate the prevalence of HPV and describe its genotype distribution using anal cytology and histology specimens from HIV-infected populations of MSM and men who have sex with women (MSW). DESIGN: Crosssectional study of the CARH.MEN cohort. SETTING: Single-center prospective cohort of HIV infected men attending the Outpatient HIV Clinic of Hospital Germans Trias i Pujol (Spain), where they undergo annual screening for HPV infection of the anus, penis and mouth. PATIENTS: Four hundred eighty-three HIV-infected men (341 MSM, 142 MSW) with no current or previous history of anal condylomata. MAIN OUTCOME MEASURES: HPV genotypes detected (multiplex-PCR), cytology results (Papanicolaou test) and histology results (biopsy-based). RESULTS: Cytological abnormalities were detected in 40% of MSM (129/321; 95%CI, 35-46) and 20% of MSW (26/131; 95%CI, 13-28) (OR=2.7; 95%CI, 1.7-4.4). All high-grade squamous intraepithelial lesions (HSIL) were positive for HR-HPV in both groups. High-resolution anoscopy was performed in 146 patients (120 MSM, 26 MSW) with abnormal cytological diagnoses. Lesions were visualized in 80 MSM (67%) and 14 MSW (54%) (OR=1.7 [95%CI, 0.7-4.0]). Histological diagnosis was anal intraepithelial neoplasia (AIN)-1 in 51 MSM (64%) and 6 MSW (43%), AIN-2 in 9 MSM (11%) and 3 MSW (21%), AIN-3 in 7 MSM (9%) and 1 MSW (7%), and normal in 13 MSM (16%) and 4 MSW (29%). HPV16 was the most prevalent HR genotype. LIMITATIONS: Study limitations include its crosssectional design. CONCLUSIONS: Anal cancer screening should be offered to all HIV-infected men, regardless of their sexual orientation. PMID- 23929014 TI - Hospital readmissions and emergency department visits following laparoscopic and open colon resection for cancer. AB - BACKGROUND: Laparoscopic colectomy for the treatment of colon cancer has been widely adopted in community practice, in part, because of shorter hospitalizations. The benefits of a shorter hospital stay are only realized if readmissions and emergency department visits, collectively termed revisits, do not increase after discharge. We conducted a population-based analysis to determine whether hospitals with higher laparoscopic colectomy rates have higher revisit rates. OBJECTIVE: The aim of this study was to determine whether hospital utilization after discharge is increased for patients undergoing laparoscopic colectomy for cancer. DESIGN: This is a retrospective cohort study. SETTINGS: Data were gathered from the Healthcare Cost and Utilization Project's inpatient and emergency department databases for California. These databases include data from all nonfederal hospitals in the State of California. PATIENTS: Patients who underwent elective colectomy for cancer from 2008 to 2009 were included. INTERVENTIONS: The primary intervention was elective colectomy with the use of the open or laparoscopic approach. MAIN OUTCOME MEASURES: The correlation between hospital laparoscopy rates and hospital readmission rates, emergency department visit rates, and revisit rates was calculated. RESULTS: Overall, 6760 patients were treated at 176 hospitals. For every 100 patients discharged, there were 14.0 readmissions and 9.2 emergency department encounters. At the hospital level, laparoscopy rates varied considerably (median = 45.7%, range = 2.2%-88.9%), as did the risk-standardized readmission (12.1%, 8.6%-16.5%), emergency department encounter (7.8%, 4.1%-18.0%), and revisit rates (17.9%, 13.0%-26.4%). A hospital's laparoscopy rate was not significantly correlated with its risk standardized readmission (weighted correlation coefficient = 0.05, p = 0.50), emergency department encounter (-0.11, p = 0.16), or revisit (-0.03, p = 0.70) rates. LIMITATIONS: There are inherent limitations when using administrative data. CONCLUSIONS: Hospitals where a greater proportion of colon resections for cancer are approached laparoscopically do not have higher 30-day, risk standardized readmission, emergency department encounter, or revisit rates. PMID- 23929015 TI - Payer status and access to laparoscopic subtotal colectomy for ulcerative colitis. AB - BACKGROUND: Medicaid populations have been shown to have inferior surgical outcomes, but less is known about their access to advanced surgical procedures. OBJECTIVE: The aim of this study was to evaluate if patients with Medicaid and ulcerative colitis who presented for subtotal colectomy would have reduced access to the laparoscopic approach in comparison with a similar population with private insurance. DESIGN/SETTINGS/PATIENTS: Using the Nationwide Inpatient Sample database from 2008 to 2010, we identified all patients who underwent subtotal colectomy for ulcerative colitis. The chi test and multivariable logistic regression were used to identify predictors for laparoscopic subtotal colectomy for ulcerative colitis. MAIN OUTCOME MEASURES: The primary end point was the use of open or laparoscopic subtotal colectomy. Secondary end points included hospital length of stay and surgical outcomes. RESULTS: We identified a total of 2589 subtotal colectomy hospitalizations for ulcerative colitis (435 with Medicaid and 2154 with private insurance). The private insurance and Medicaid groups did not have significantly different mean age, sex, or Charlson scores (p > 0.05). Although 43% of the private insurance cohort received laparoscopic subtotal colectomy during their hospitalization, only 23% of the Medicaid population received equivalent care (p < 0.001). In a multivariate analysis that included age, sex, emergency status, hospital location, hospital size, teaching status, income, and Charlson score, urban teaching hospital status (p < 0.01), emergency status (p = 0.045), age <40 (p < 0.01), northeast location (p = 0.01), and private insurance status (p < 0.01) were independent predictors of the laparoscopic approach. LIMITATIONS: Administrative data have the potential for unrecognized miscoding or incomplete risk adjustment. Disease severity is not accounted for in the Nationwide Inpatient Sample database. CONCLUSION: Medicaid payer status was associated with reduced use of laparoscopic subtotal colectomy for ulcerative colitis. Although this finding may be due in part to physician preference or patient characteristics, health system factors appear to contribute to selection of the surgical approach. PMID- 23929016 TI - A single nucleotide polymorphism in the STAT5 gene favors colonic as opposed to small-bowel inflammation in Crohn's disease. AB - BACKGROUND: Crohn's disease is a chronic inflammatory ailment that can affect the colon and/or small intestine. A genetic basis for disease distribution is being sought, although the available data are seminal. The STAT5 gene is known to influence colonic permeability, mucosal regeneration, and interleukin 2 production, although its role in the distribution of Crohn's disease is unclear. OBJECTIVE: The aim of this study was identification of single nucleotide polymorphisms associated with Crohn's distribution, with the goal of distinguishing disease subcategories and differing pathophysiologies. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted in a single tertiary referral center. PATIENTS: A total of 173 patients with Crohn's disease who were identified from our biobank were segregated by disease distribution (colitis, n = 28; ileocolic disease, n = 116; enteritis, n = 29) and were genotyped for 258 Crohn's-associated single nucleotide polymorphisms. Patients with ulcerative colitis (n = 119) were also genotyped to confirm the association of identified single nucleotide polymorphisms with small-bowel sparing, colonic pathology. MAIN OUTCOME MEASURES: We investigated an association between single nucleotide polymorphisms and Crohn's disease distribution. RESULTS: Single nucleotide polymorphism rs16967637 in the STAT5 gene was associated with small-bowel sparing Crohn's disease when the enteritis group was compared with either a combined colitis/ileocolic group (p = 0.025) or those with only ileocolic disease (p = 0.04). Homozygosity for the at-risk allele (C) was present in 59% of patients with sparing of the small bowel. The association of this single nucleotide polymorphism with small-bowel sparing disease persisted when patients with ulcerative colitis were compared with the group with Crohn's enteritis (p = 0.036), as well as after combining patients with ulcerative colitis with both the Crohn's colitis group (p = 0.009) and the Crohn's ileocolitis/colitis group (p = 0.00008). LIMITATIONS: This study was limited by the small numbers of study subjects with isolated enteritis or colitis. CONCLUSIONS: Single nucleotide polymorphism rs16967637 in the STAT5 gene was the only single nucleotide polymorphism associated with Crohn's disease without enteritis. Homozygosity for the at-risk allele demonstrated the strongest association with this phenotype. These results suggest a role for this single nucleotide polymorphism in the development of inflammatory bowel disease of the large intestine. PMID- 23929017 TI - Bilateral transcutaneous posterior tibial nerve stimulation for the treatment of fecal incontinence. AB - BACKGROUND: Unilateral posterior tibial nerve stimulation has been shown to improve fecal incontinence in the short term. Posterior tibial nerve stimulation is believed to work by stimulation of the ascending afferent spinal pathways. Bilateral stimulation may activate more of these pathways. This may lead to an improved therapeutic effect. OBJECTIVE: The aim of this study was to assess the efficacy of bilateral transcutaneous posterior tibial nerve stimulation for fecal incontinence. DESIGN: This was a single-group pilot prospective study. SETTING: The study was conducted from June 2012 to September 2012 at the authors' institution. PATIENTS: Twenty patients with fecal incontinence were recruited consecutively. Conservative therapy had failed to improve the fecal incontinence in all 20 patients. INTERVENTION: All patients received 30 minutes of daily bilateral stimulation for 6 weeks. The bilateral stimulation was administered by each patient at home. No further stimulation was given after 6 weeks, and the patients were followed up until their symptoms returned to the prestimulation state (baseline). MAIN OUTCOME MEASURE: The primary outcome measure was a change in the frequency of incontinent episodes per week. RESULTS: Seventeen patients completed 6 weeks of treatment. Two patients achieved complete continence. Ten (59%) achieved a >=50% reduction in frequency of incontinent episodes. Overall, there was a significant reduction in median (interquartile range) frequency of incontinent episodes per week of 6 (8.25) to 2 (7.25) (p = 0.03). There was a significant improvement in the ability to defer defecation from 3 (4) to 5 (8) minutes (p = 0.03). There was no change in the St Mark's incontinence score. One domain of the Rockwood fecal incontinence quality-of-life score and of the Medical Outcomes Study Short Form 36 score improved significantly. LIMITATIONS: This study was limited by its small size and its lack of blinding and control. CONCLUSIONS: Bilateral transcutaneous posterior tibial nerve stimulation appears to be a cheap and effective treatment for fecal incontinence. It can easily be used by the patient at home. PMID- 23929018 TI - Prevalence correlates and impact of fecal incontinence among older women. AB - BACKGROUND: Fecal incontinence is a common problem that has been associated with anatomic, physiological, and medical conditions. There are very few data on the factors associated with fecal incontinence in elderly women. OBJECTIVES: We aimed to determine the factors associated with fecal incontinence via a population based survey in a large cohort of elderly Australian women. DESIGN AND SETTING: Data from a large longitudinal population-based study of elderly Australian women aged 82 to 87 years were analyzed. PATIENTS: Participants were 5560 women (aged 82-87 years) who participated in the Australian Longitudinal Study on Women's Health; 4815 women responded to questions relating to fecal incontinence. MAIN OUTCOME MEASURES: Fecal incontinence was defined as leakage of liquid and/or solid stool at least once per month over the past 12 months. Self-reported medical conditions and lifestyle factors as well as demographic factors were recorded. RESULTS: The prevalence of fecal incontinence was 10.4% (95% CI, 9.6 11.3) (n = 510). The prevalence was significantly higher among institutional- versus community-dwelling women (14.1% vs 9.7%; p = 0.0002). Univariately, lifestyle factors including fruit intake and fluid intake, along with a range of comorbidities, were associated. However, independent factors for fecal incontinence among community-dwelling women included diabetes mellitus (OR, 1.51; 95% CI, 1.14-2.01; p = 0.004), depression (OR, 1.84; 95% CI, 1.30-2.62; p = 0.001), urinary incontinence (OR, 2.29; 95% CI, 1.83-2.86; p < 0.0001), and osteoarthritis (OR, 0.73; 95% CI, 0.57-0.94; p = 0.013). Among institutional dwelling women, however, we found urinary incontinence (OR, 4.43; 95% CI, 2.83 6.93; p < 0.0001) and poorer general health (OR, 0.98; 95% CI, 0.97-0.99; p = 0.003) to be independently associated. LIMITATIONS: This is a cross-sectional study, which prevents making conclusions about the cause and effect of observed correlations. CONCLUSIONS: The independent factors associated with fecal incontinence in this population do not appear readily modifiable, and many previously identified risk factors may not be important in the elderly women with fecal incontinence. PMID- 23929019 TI - Readmission after colorectal surgery is related to preoperative clinical conditions and major complications. AB - BACKGROUND: Hospital readmission is increasingly perceived as a marker of quality and is poorly investigated in patients receiving colorectal surgery. OBJECTIVE: The objective of this study was to describe patterns and etiology of readmission, to determine the rate of readmission, and to identify risk factors for readmission after colorectal surgery. DESIGN: This study is a retrospective medical chart review. Significant (p < 0.1) preoperative and perioperative factors associated with readmission on univariate analysis were examined in a multivariable model. SETTING: The investigation was conducted in a tertiary care hospital. PATIENTS: Patients included adults undergoing major colorectal operations by colorectal surgeons at the University of Minnesota in 2008-2009. MAIN OUTCOME MEASURES: The primary outcome measure was hospital readmission at 60 days. RESULTS: The study included 220 patients. Common surgical indications were inflammatory bowel disease (21%), colorectal cancer (39%), and diverticular disease (13%), and 11% were emergencies. Readmissions at 60 days occurred in 25% (n = 54), mostly because of major complications (57%), nonspecific nausea, vomiting and/or pain (18%), dehydration (11%), and wound infections (11%). Predictors of readmission in multivariable analysis were major complications (OR, 13.0), female sex (OR, 5.9), prednisone use (OR, 4.3), BMI >=30 (OR, 2.6), and preoperative weight loss (OR, 3.4). Age and comorbidity (Charlson score) were not predictors. LIMITATIONS: This was a retrospective study at a single institution, with a small sample size. CONCLUSIONS: Predictors of readmission were major complications and immediate preoperative condition of the patients. Comorbidity profiling does not capture readmission risk. Because most readmissions relate to complications, further efforts to prevent these will improve readmission rates. PMID- 23929020 TI - Prognostic significance of partial tumor regression after preoperative chemoradiotherapy for rectal cancer: a meta-analysis. AB - BACKGROUND: Complete tumor regression after preoperative chemoradiotherapy for rectal cancer has been associated with better disease-free and overall survival. The survival experience for patients with partial tumor regression is less clear. OBJECTIVE: The aim of this meta-analysis was to evaluate the prognostic significance of partial response after preoperative chemotherapy on disease-free survival in rectal cancer patients. DATA SOURCES: Relevant studies were identified by a search of MEDLINE and EMBASE databases with no restrictions to October 31, 2012. STUDY SELECTION: We included long-course radiotherapy that reported the association between degree of tumor regression and disease-free survival of rectal cancer. INTERVENTIONS: Direct, indirect, and graph methods were used to extract HRs. MAIN OUTCOME MEASURES: Study-specific HRs on the disease-free survival were pooled using a random-effects model. Eleven articles in total were selected. Analysis was performed first among the 6 studies that separated partial response from the complete response and later among all 11 of the studies. RESULTS: Pooled HR was 0.49 (95% CI, 0.28-0.85) for the 6 studies that compared partial response with poor response. It was 0.41 (95% CI, 0.25 0.67) when all 11 of the studies were analyzed together. LIMITATIONS: The studies were limited by not being prospective, randomized trials, and the tumor regression grades were not uniform. CONCLUSIONS: Partial tumor response is associated with a 50% improvement in disease-free survival and should be considered as a favorable prognostic factor. PMID- 23929021 TI - Uterus and extralevator abdominoperineal excision: a technique. AB - BACKGROUND: Perineal hernia is well described after standard abdominoperineal excision of rectum. There appears to be an increasing incidence of perineal hernia following extralevator abdominoperineal excision of the rectum. Currently, there is no standard for the prevention of perineal wound herniation and its potential sequelae. Techniques have been described to prevent perineal hernia, including the use of mesh, muscle flaps, or simple layered closure. OBJECTIVE: This technique describes the use of the uterus in postmenopausal women as a "natural packing material" to prevent the small bowel from entering the lower pelvis, and subsequent perineal herniation. PROCEDURE: The procedure involves retroverting the uterus and securing it to the bony pelvis with the use of nonabsorbable suture material. This can be achieved via the abdominal route as well as the perineal wound. LIMITATIONS: This procedure is only applicable in women with uterus in situ. Dyspareunia may be a side effect. Caution is advised in premenopausal women, because positional menstruation may be an issue. Subsequent hysteroscopy and hysterectomy may be difficult. Care should be taken to avoid damage to the presacral venous plexus and sacral nerves. CONCLUSION: Uterine interposition is a practical, low-risk, inexpensive solution to this problem in a selected group of patients. It avoids the cost and complications of prosthetic mesh and myoplastic reconstruction procedures. PMID- 23929022 TI - Canadian Association of General Surgeons, the American College of Surgeons, the Canadian Society of Colorectal Surgeons and the American Society of Colorectal Surgeons evidence based reviews in surgery - colorectal surgery. PMID- 23929023 TI - The management of patients with T1 adenocarcinoma of the low rectum: are you certain? PMID- 23929025 TI - DNA persistence after treatment of Lyme borreliosis. AB - One hundred twenty-four patients-53 with neuroborreliosis, 48 with erythema migrans, and 23 with Lyme arthritis-were tested in a prospective study for the presence of the DNA of Borrelia burgdorferi sensu lato in plasma, cerebrospinal fluid (CSF), urine, and synovial fluid by nested polymerase chain reaction (PCR). Specific DNA was detected using five amplification systems simultaneously: three targeted chromosomal genes encoding 16S rDNA, flagellin, and p66; and two plasmid sequences of OspA and OspC. Patients were examined clinically and by PCR before and after treatment and again after 3 and 6 months. Before treatment, the specific DNA was detected in 78 patients (62.9 %). Forty-one neuroborreliosis patients were DNA-positive (77.4 %), with CSF positivity in 26 patients, urine in 25, and plasma in 16. Twenty-six erythema migrans patients were DNA-positive (54.2 %), with plasma positivity in 18 cases and urine in 14. Eleven Lyme arthritis cases (47.8 %) were DNA positive (six in urine, five in plasma, and four in synovial fluid). The frequency of PCR positives was comparable in CSF and urine, and it was lower by approximately 50 % in plasma. Specific DNA was also found in a significant number of patients in later testing periods: 48 patients after treatment, 29 patients after 3 months, and 6 patients after 6 months. The prolonged PCR positivity was not explainable by persistent infection according to the clinical manifestations of the disease. Possible explanations of the problem are discussed. PMID- 23929026 TI - Body mass index and in-hospital mortality in anorexia nervosa: data from the Japanese Diagnosis Procedure Combination database. AB - One of the main purposes of admission for anorexia nervosa is to manage acute medical conditions related to this condition. Factors associated with in-hospital mortality in anorexia nervosa remain unclear. This study describes the clinical features of anorexia nervosa patients requiring hospitalization in Japan. We analyzed the association between in-hospital mortality and body mass index upon admission using a currently available, nationwide hospital-based database. We identified 669 eligible patients with anorexia nervosa (BMI <= 16.5) from 229 hospitals between July and December, 2010. More than 90 % of the patients were female and 100 patients were admitted involuntarily. The average body mass index was 13.1, and the in-hospital mortality rate was 0.7 %. Five patients who died had a BMI under 11, indicating that patients with an extremely low BMI may be likely to die, despite admission. PMID- 23929027 TI - Reply to sontheimer. PMID- 23929028 TI - Six new 3d-4f heterometallic coordination polymers constructed from pyrazole bridged Cu(II)Ln(III) dinuclear units. AB - Reactions of lanthanide chlorides, copper hydroxycarbonate and 3,5-pyrazole dicarboxylic acid (H3pdc) under hydrothermal conditions result in six new 3d-4f heterometallic coordination polymers with two types of structures. Compounds [CuLn2(pdc)2(Hpdc)(H2O)4].2H2O (Ln = Tb (1), Dy (2), Er (3), and Y (4) exhibit a layered porous structure, made up of Cu(II)Ln(III) di-nuclear units which are connected by protonated Hpdc(2-) ligand, while the others [Cu3Ln4(pdc)6(H2O)8] (Ln = Eu (5), Gd (6)) display a three-dimensional (3-D) framework structure, in which six Cu(II)Ln(III) di-nuclear units are cross-linked by two coordinated lanthanide atoms. The catalytic properties of 3 are investigated showing its activity and recyclability in the reaction of cyclopropanation of styrene. PMID- 23929029 TI - Medicare payment for chronic care delivered in a patient-centered medical home. PMID- 23929030 TI - WebRASP: a server for computing energy scores to assess the accuracy and stability of RNA 3D structures. AB - SUMMARY: The understanding of the biological role of RNA molecules has changed. Although it is widely accepted that RNAs play important regulatory roles without necessarily coding for proteins, the functions of many of these non-coding RNAs are unknown. Thus, determining or modeling the 3D structure of RNA molecules as well as assessing their accuracy and stability has become of great importance for characterizing their functional activity. Here, we introduce a new web application, WebRASP, that uses knowledge-based potentials for scoring RNA structures based on distance-dependent pairwise atomic interactions. This web server allows the users to upload a structure in PDB format, select several options to visualize the structure and calculate the energy profile. The server contains online help, tutorials and links to other related resources. We believe this server will be a useful tool for predicting and assessing the quality of RNA 3D structures. AVAILABILITY AND IMPLEMENTATION: The web server is available at http://melolab.org/webrasp. It has been tested on the most popular web browsers and requires Java plugin for Jmol visualization. PMID- 23929031 TI - PARSEC: PAtteRn SEarch and Contextualization. AB - SUMMARY: We present PARSEC (PAtteRn Search and Contextualization), a new open source platform for guided discovery, allowing localization and biological characterization of short genomic sites in entire eukaryotic genomes. PARSEC can search for a sequence or a degenerated pattern. The retrieved set of genomic sites can be characterized in terms of (i) conservation in model organisms, (ii) genomic context (proximity to genes) and (iii) function of neighboring genes. These modules allow the user to explore, visualize, filter and extract biological knowledge from a set of short genomic regions such as transcription factor binding sites. AVAILABILITY: Web site implemented in Java, JavaScript and C++, with all major browsers supported. Freely available at lbgi.fr/parsec. Source code is freely available at sourceforge.net/projects/genomicparsec. PMID- 23929032 TI - ASPeak: an abundance sensitive peak detection algorithm for RIP-Seq. AB - SUMMARY: Unlike DNA, RNA abundances can vary over several orders of magnitude. Thus, identification of RNA-protein binding sites from high-throughput sequencing data presents unique challenges. Although peak identification in ChIP-Seq data has been extensively explored, there are few bioinformatics tools tailored for peak calling on analogous datasets for RNA-binding proteins. Here we describe ASPeak (abundance sensitive peak detection algorithm), an implementation of an algorithm that we previously applied to detect peaks in exon junction complex RNA immunoprecipitation in tandem experiments. Our peak detection algorithm yields stringent and robust target sets enabling sensitive motif finding and downstream functional analyses. AVAILABILITY: ASPeak is implemented in Perl as a complete pipeline that takes bedGraph files as input. ASPeak implementation is freely available at https://sourceforge.net/projects/as-peak under the GNU General Public License. ASPeak can be run on a personal computer, yet is designed to be easily parallelizable. ASPeak can also run on high performance computing clusters providing efficient speedup. The documentation and user manual can be obtained from http://master.dl.sourceforge.net/project/as-peak/manual.pdf. PMID- 23929033 TI - On representative and illustrative comparisons with real data in bioinformatics: response to the letter to the editor by Smith et al. PMID- 23929034 TI - Female sex workers in three cities in Russia: HIV prevalence, risk factors and experience with targeted HIV prevention. AB - Within Eastern Europe/Central Asia's expanding HIV epidemic, relatively little is known about female sex workers (FSWs). Using mixed methods, we report on sex work context, HIV prevalence and contextual risk factors, and exposure to FSW-targeted prevention services among FSWs in Kazan, Krasnoyarsk, and Tomsk, Russia. Following a qualitative phase, FSWs (n = 754) were recruited via respondent driven sampling for a cross-sectional survey with HIV screening in 2011. HIV was prevalent (3.9 %). In adjusted analyses, significant risk factors included injection drug use (IDU; AOR 5.85, 95 % CI 2.47, 14.43), client-perpetrated physical violence (AOR 2.52, 95 % CI 1.41, 4.51), and client-perpetrated sexual violence (vaginal AOR 3.77, 95 % CI 1.73, 8.22; anal AOR 4.80, 95 % CI 1.89, 12.19). FSW-targeted programming (reported by 75 %) was described as highly valuable, providing free, anonymous, and non-stigmatizing care. Findings confirm FSWs as a core HIV risk population in Russia, and demonstrate the need to support FSW-oriented HIV services. Such efforts should address violence against FSWs. PMID- 23929036 TI - Genetic modification of corneal neovascularization in Dstn (corn1) mice. AB - Mutations in the gene for destrin (Dstn), an actin depolymerizing factor, lead to corneal abnormalities in mice. A null mutation in Dstn, termed Dstn (corn1) , isolated and maintained in the A.BY background (A.BY Dstn (corn1) ), results in corneal epithelial hyperproliferation, inflammation, and neovascularization. We previously reported that neovascularization in the cornea of Dstn (corn1) mice on the C57BL/6 background (B6.A.BY-Dstn (corn1) ) is significantly reduced when compared to A.BY Dstn (corn1) mice, suggesting the existence of genetic modifier(s). The purpose of this study is to identify the genetic basis of the difference in corneal neovascularization between A.BY Dstn (corn1) and B6.A.BY Dstn (corn1) mice. We generated N2 mice for a whole-genome scan by backcrossing F1 progeny (A.BY Dstn (corn1) * B6.A.BY-Dstn (corn1) ) to B6.A.BY-Dstn (corn1) mice. N2 progeny were quantitatively phenotyped for the extent of corneal neovascularization and genotyped for markers across the mouse genome. We identified significant association of variability in corneal neovascularization with a locus on chromosome 3 (Chr3). The validity of the identified quantitative trait locus (QTL) was tested using B6 consomic mice carrying Chr3 from A/J mice. Dstn (corn1) mice from F1 and F2 intercrosses (B6.A.BY-Dstn (corn1) * C57BL/6J Chr3(A/J)/NaJ) were phenotyped for the extent of corneal neovascularization. This analysis showed that mice carrying the A/J allele at the QTL show significantly increased neovascularization. Our results indicate the existence of a modifier that genetically interacts with the Dstn gene. This modifier demonstrates allelic differences between C57BL6 and A.BY or A/J. The modifier is sufficient to increase neovascularization in Dstn (corn1) mice. PMID- 23929037 TI - Lens density tracking in mice by Scheimpflug imaging. AB - Scheimpflug imaging has recently been established for in vivo imaging of the anterior eye segment and quantitative determination of lens transparency in the mouse. This enables more effective investigations of cataract formation with the mouse model, including longitudinal studies. In order to enable recognition of disease-associated irregularities, we performed Scheimpflug measurements with the common laboratory inbred lines C57BL/6J, C3HeB/FeJ, FVB/NCrl, BALB/cByJ, and 129/SvJ in a period between 2 and 12 months of age. C57BL/6J mice showed lowest mean lens densities during the test period. Progressive cortical lens opacification was generally observed, with the earliest onset in C57BBL/6J, C3HeB/FeJ, and 129/SvJ, between 2 and 6 months after birth. Moreover, lenses of these inbred lines developed nuclear opacities. Calculated mean lens density significantly increased between 6 and 12 months of age in all inbred strains except 129/SvJ. Lens densities (and the corresponding standard deviations) of FVB/NCrl and 129/SvJ increased most likely because of differences in the genetic background. Albinism as confounder might be excluded since the albino Balb/cByJ mice are more similar to the C57BL/6J or C3Heb/FeJ mice. We further identified strain-specific anterior lens opacities (C57BL/6J) and cloudy corneal lesions (C57BL/6J, FVB/NCrl, and BALB/cByJ) at later stages. In conclusion, our results indicate that there are lifelong opacification processes in the mouse lens. The highest lens transparency and a dark coat color, which prevents interference from light reflections, make mice with the C57BL/6J background most suitable for cataract research by Scheimpflug imaging. We show that lens densitometry by Scheimpflug imaging in mouse eyes can resolve differences of less than 1 %, making it possible to detect differences in cataract development in different mouse strains, even if they are small. PMID- 23929035 TI - Helicobacter pylori infection does not promote hepatocellular cancer in a transgenic mouse model of hepatitis C virus pathogenesis. AB - Helicobacter pylori (H. pylori) and hepatitis C virus (HCV) infect millions of people and can induce cancer. We investigated if H. pylori infection promoted HCV associated liver cancer. Helicobacter-free C3B6F1 wild-type (WT) and C3B6F1 Tg(Alb1-HCVN)35Sml (HT) male and female mice were orally inoculated with H. pylori SS1 or sterile media. Mice were euthanized at ~12 mo postinoculation and samples were collected for analyses. There were no significant differences in hepatocellular tumor promotion between WT and HT mice; however, HT female mice developed significantly larger livers with more hepatic steatosis than WT female mice. H. pylori did not colonize the liver nor promote hepatocellular tumors in WT or HT mice. In the stomach, H. pylori induced more corpus lesions in WT and HT female mice than in WT and HT male mice, respectively. The increased corpus pathology in WT and HT female mice was associated with decreased gastric H. pylori colonization, increased gastric and hepatic interferon gamma expression, and increased serum Th1 immune responses against H. pylori. HT male mice appeared to be protected from H. pylori-induced corpus lesions. Furthermore, during gastric H. pylori infection, HT male mice were protected from gastric antral lesions and hepatic steatosis relative to WT male mice and these effects were associated with increased serum TNF-alpha. Our findings indicate that H. pylori is a gastric pathogen that does not promote hepatocellular cancer and suggest that the HCV transgene is associated with amelioration of specific liver and gastric lesions observed during concurrent H. pylori infection in mice. PMID- 23929038 TI - Development of a 3D origami multiplex electrochemical immunodevice using a nanoporous silver-paper electrode and metal ion functionalized nanoporous gold chitosan. AB - A simple and sensitive 3D microfluidic origami multiplex electrochemical immunodevice was developed for the first time using a novel nanoporous silver modified paper working electrode as a sensor platform and different metal ion functionalized nanoporous gold-chitosan as a tracer. PMID- 23929040 TI - A culture of patient safety in military medicine. PMID- 23929041 TI - When will acupuncture become a first-line treatment for acute pain management? PMID- 23929042 TI - Testing a resilience model among Canadian Forces recruits. AB - Evidence suggests that personal characteristics serve as resilience factors, and may protect military personnel against the development of psychological distress, even during stressful conditions. Structural equation modeling analyses were conducted on data from Canadian Forces candidates undertaking their basic training (N = 200) to test the fit of a model of resilience that is comprised of several individual characteristics, such as personality, hardiness, and coping. The most parsimonious model of resilience with the best fit to the data was identified. This model consisted of neuroticism, military hardiness, and problem solving coping. The results of the study were consistent with previous research, showing that personality, military hardiness, and coping are important predictors of life satisfaction and health. The proposed resilience model offers a useful approach for the development of training programs to enhance readiness and recovery in the military context. PMID- 23929039 TI - Paracrine activation of hepatic stellate cells in platelet-derived growth factor C transgenic mice: evidence for stromal induction of hepatocellular carcinoma. AB - Cirrhosis is the primary risk factor for the development of hepatocellular carcinoma (HCC), yet the mechanisms by which cirrhosis predisposes to carcinogenesis are poorly understood. Using a mouse model that recapitulates many aspects of the pathophysiology of human liver disease, we explored the mechanisms by which changes in the liver microenvironment induce dysplasia and HCC. Hepatic expression of platelet-derived growth factor C (PDGF-C) induces progressive fibrosis, chronic inflammation, neoangiogenesis and sinusoidal congestion, as well as global changes in gene expression. Using reporter mice, immunofluorescence, immunohistochemistry and liver cell isolation, we demonstrate that receptors for PDGF-CC are localized on hepatic stellate cells (HSCs), which proliferate, and transform into myofibroblast-like cells that deposit extracellular matrix and lead to production of growth factors and cytokines. We demonstrate induction of cytokine genes at 2 months, and stromal cell-derived hepatocyte growth factors that coincide with the onset of dysplasia at 4 months. Our results support a paracrine signaling model wherein hepatocyte-derived PDGF-C stimulates widespread HSC activation throughout the liver leading to chronic inflammation, liver injury and architectural changes. These complex changes to the liver microenvironment precede the development of HCC. Further, increased PDGF-CC levels were observed in livers of patients with nonalcoholic fatty steatohepatitis and correlate with the stage of disease, suggesting a role for this growth factor in chronic liver disease in humans. PDGF-C transgenic mice provide a unique model for the in vivo study of tumor-stromal interactions in the liver. PMID- 23929043 TI - Psychological health of military children: longitudinal evaluation of a family centered prevention program to enhance family resilience. AB - Family-centered preventive interventions have been proposed as relevant to mitigating psychological health risk and promoting resilience in military families facing wartime deployment and reintegration. This study evaluates the impact of a family-centered prevention program, Families OverComing Under Stress Family Resilience Training (FOCUS), on the psychological adjustment of military children. Two primary goals include (1) understanding the relationships of distress among family members using a longitudinal path model to assess relations at the child and family level and (2) determining pathways of program impact on child adjustment. Multilevel data analysis using structural equation modeling was conducted with deidentified service delivery data from 280 families (505 children aged 3-17) in two follow-up assessments. Standardized measures included service member and civilian parental distress (Brief Symptom Inventory, PTSD Checklist Military), child adjustment (Strengths and Difficulties Questionnaire), and family functioning (McMaster Family Assessment Device). Distress was significantly related among the service member parent, civilian parent, and children. FOCUS improved family functioning, which in turn significantly reduced child distress at follow-up. Salient components of improved family functioning in reducing child distress mirrored resilience processes targeted by FOCUS. These findings underscore the public health potential of family-centered prevention for military families and suggest areas for future research. PMID- 23929044 TI - Changes in stigma and barriers to care over time in U.K. Armed Forces deployed to Afghanistan and Iraq between 2008 and 2011. AB - Stigmatizing beliefs about seeking help for mental health conditions and perceived barriers to care (BTC) may influence the decision to seek support and treatment in U.K. military personnel. Many coalition partners, including the U.K. Armed Forces (UKAF), have made considerable efforts to reduce stigma/BTC although the impact of these efforts over time has not been assessed. We surveyed a total of 23,101 UKAF personnel who deployed to Afghanistan and Iraq between 2008 and 2011 and examined whether stigma/BTC levels changed during this time. The results suggested that stigma, including the fear of being treated differently by commanders and loss of trust among peers, was greater than perceived BTC. The likelihood of reporting stigma/BTC, although significantly greater during deployment than postdeployment, reduced significantly over the survey period. A similar reduction was less apparent during postdeployment phase. These findings support the notion that UKAF's anti-stigma campaigns may have had some positive effects, particularly among deployed personnel. However, we suggest that stigma still plays a part in inhibiting help-seeking, particularly during deployment when stigma rates are higher, and that a careful balance must be struck between encouraging help-seeking and maintaining the operational effectiveness of deployed personnel. PMID- 23929045 TI - A yoga program for the symptoms of post-traumatic stress disorder in veterans. AB - The purpose of this pilot study was to evaluate the feasibility and effectiveness of a yoga program as an adjunctive therapy for improving post-traumatic stress disorder (PTSD) symptoms in Veterans with military-related PTSD. Veterans (n = 12) participated in a 6 week yoga intervention held twice a week. There was significant improvement in PTSD hyperarousal symptoms and overall sleep quality as well as daytime dysfunction related to sleep. There were no significant improvements in the total PTSD, anger, or quality of life outcome scores. These results suggest that this yoga program may be an effective adjunctive therapy for improving hyperarousal symptoms of PTSD including sleep quality. This study demonstrates that the yoga program is acceptable, feasible, and that there is good adherence in a Veteran population. PMID- 23929046 TI - Interaction, action, and reflection: how medics learn medical care in the Swedish Armed Forces. AB - The objective of this study is to examine how medics within the Swedish Armed Forces perceive their learning outcome following military prehospital training. A qualitative study with a phenomenographic approach was used to investigate how learning is perceived among military medics. At meta level, the results can be viewed as an interaction, i.e., being able to collaborate in the medical platoon, including the ability to interact within the group and being able to lead; an action, i.e., being able to assess and treat casualties, including the ability to communicate with the casualty, to prioritize, and to be able to act; and a reflection, i.e., having confidence in one's own ability in first aid, including being prepared and feeling confident. Interaction during the period of education is important for learning. Action, being able to act in the field, is based on a drill in which the subject progresses from simple to complex procedures. Reflection, learning to help others, is important for confidence, which in turn creates preparedness, thereby making the knowledge meaningful. PMID- 23929047 TI - Auricular acupuncture: a brief introduction for military providers. AB - Injured veterans returning from Operation Iraqi Freedom and Operation Enduring Freedom often require long-term medical management for a variety of complex physical and mental health conditions. These conditions can be challenging to treat with conventional Western medicine practices alone. Recently, complementary and alternative medicine practices have been used within military settings, and have been well received by veterans. Auricular acupuncture is a practice that has provided veterans with a new approach to manage symptoms associated with a wide range of health conditions. This treatment has become an attractive treatment option because of its low cost, portability, minimal side effect profile, and ease of use in clinical and operational settings. Although formally trained Oriental medicine practitioners have historically performed these treatments, military health care providers are now receiving education and training to administer these treatments. This education and training allows military health care providers to expand their knowledge of acupuncture and provide this treatment to veterans across the continuum of care. The purpose of this article is to provide a fundamental description of auricular acupuncture and increase awareness of this treatment and its relevance to military settings. PMID- 23929048 TI - Assessing psychosocial differences in stages of change: an analysis of military healthcare system patients with type 2 diabetes. AB - INTRODUCTION: Provider advice is considered key to behavioral change for a healthier lifestyle. However, a healthcare professional simply telling an individual to change does not prompt behavior change. This study intends to link patient knowledge, attitudes, and beliefs to the stages of change. By incorporating a stages-of-change assessment and tailoring interventions to patient with diabetes, outcomes can improve. METHODS: This study is a secondary data analysis of a single-site, prospective intervention study promoting walking in patients with type 2 diabetes (n = 111) in an Army community hospital. RESULTS: Analysis of variance provided evidence of significant knowledge and attitude differences between precontemplation and contemplation groups, and for significant self-efficacy and social norms differences across the stages of change. DISCUSSION: Results here provided evidence for the application of stages of change in promoting exercise to patient with type 2 diabetes. Specifically, this study makes message recommendations for patients in the various stages of change. PMID- 23929049 TI - Military maternal weight trends and perinatal outcomes. AB - OBJECTIVE: Obesity is epidemic in the United States and the prevalence is increasing. We sought to determine if the prevalence of obesity in women eligible for health care at military treatment facilities, specifically, active duty (AD) women, is increasing similar to national trends. METHODS: Our retrospective cohort study evaluated selected outcomes in women delivering in 1999 and 2006. Women delivering living, singleton, term, nonanomalous neonates in 1999 and 2006 were eligible. Prepregnancy weight and weight gain during pregnancy were compared between the two populations, and data were stratified by AD status, age, and ethnicity. Obstetric outcomes were evaluated based on body mass index (BMI). RESULTS: There were 1,543 and 1,745 mother-infant pairs available, respectively, for analysis. Prepregnancy BMI for all women evaluated increased significantly from 1999 to 2006 (25.0 vs. 25.6, p < 0.05). Prepregnancy BMI increased significantly for AD women between 1999 and 2006 (24.3 vs. 25.4, p < 0.05). The prevalence of overweight and obese women increased from 1999 to 2006 in the population evaluated (41.2% vs.46.2%, respectively), and this was demonstrated among all ethnicities. Obesity was associated with increased adverse obstetric outcomes. CONCLUSION: We demonstrated increasing maternal obesity in a military population over time and associated adverse perinatal outcomes. PMID- 23929050 TI - Origins of the physical profile. AB - This article examines how the U.S. Army came to adopt the physical profile. In 1945, the Army adopted the physical profile system that has, with some changes, survived to this day. Although the profile system does not always work smoothly, it replaced a system that was failing completely to deliver physically fit men to combat units. The World War II problems were the outgrowth of two World War I systems that had been adopted to speed mobilization by (1) accepting physically substandard men and (2) matching men to a noncombat job by their skills. By simply identifying a soldier as "General Service" or "Limited Service" it did not provide enough information about his limitations. In addition, the Army used an intelligence test to grade manpower, but because it lacked information on a man's physical abilities/limitations, that data were misused to allot manpower. These policies interacted with a societal disdain for the "handicapped" and "substandard" and made it hard to use Limited Service men. Adding detail to the information on physical abilities was the Army's solution. PMID- 23929051 TI - Evaluating effects of self-reported domestic physical activity on pregnancy and neonatal outcomes in "stay at home" military wives. AB - OBJECTIVE: To determine if an association exists between daily physical activity, and pregnancy/neonatal outcomes in stay at home military wives. METHODS: This is a prospective observational study of pregnant military wives who do not work outside the home. Participants completed a validated questionnaire of their daily activity from which the average energy expenditure per day (kcal/day) was calculated. Participants were grouped, according to their energy expenditure and assessed for antepartum, intrapartum, and neonatal outcomes. RESULTS: There were 55 women (group 1) who expended <= 2,200 kcal/day, 77 expended 2,201 to 3,000 kcal/day, and 58 expended >= 3,001 kcal/day. Group 1 had the lowest maternal weight at first visit (p < 0.001) and delivery (p < 0.001) and highest percentage of primigravidas (p = 0.002). After adjusting for key maternal characteristics, women in group 1 were more likely to develop gestational diabetes. Although not significant, the women in group 1 had more intrauterine growth restriction and preterm labor whereas group 3 had a greater risk of antepartum hemorrhage. CONCLUSIONS: Primigravida women of low weight not working are most likely to use the least energy compared to the heaviest women who use the most calories and are more likely to develop gestational diabetes. PMID- 23929052 TI - Ergonomic assessment of future methods of ballistic neck protection. AB - INTRODUCTION: Neck injuries from explosively propelled fragments are present in 11% of injured U.K. soldiers and result in significant mortality and long-term morbidity. U.S. forces in contrast sustain only neck wounds in 3 to 4% of those injured, which is believed to be because of their greater acceptance in the wearing of issued neck protection. METHOD: A three-piece neck collar, two-piece neck collar, a nape pad, a ballistic scarf, and an enhanced protection under body armor shirt (EP-UBACS) reinforced at the collar were objectively compared during a treadmill test using physiological measurements. Designs were subjectively compared regarding their effect on soldier performance using representative military tasks. RESULTS: Both neck collars and the EP-UBACS prototype demonstrated 90% acceptability in terms of military task performance. No statistical difference in tympanic temperature and heart rate was found between prototypes. The statistically significant higher skin temperatures found for prototypes lying close to the skin (EP-UBACS and ballistic scarf) were unrelated to perceived comfort. DISCUSSION: Neck collars remain the most successful design in terms of military performance, comfort, and potential levels of ballistic protection. However the EP-UBACS concept should also be developed further, with future iterations potentially removing the zip and increasing skin standoff. PMID- 23929053 TI - Pityriasis versicolor: avoiding pitfalls in disease diagnosis and therapy. AB - Pityriasis versicolor is common among young active duty members with overactive sweat glands working in humid environments and results in pigmentary changes that can be profound in those with darker skin. This article addresses several issues related to making the correct diagnosis and providing appropriate treatment, as well as the specific challenges military providers may face in these cases. PMID- 23929054 TI - Management of seizure disorders in the deployed environment: a treatment guide for the non-neurologist in theater. AB - Patients with seizures can present a common and challenging problem for medical providers in the deployed environment. Unfortunately, there is a paucity of controlled clinical trial data that can be used to formulate evidence-based guidelines for management. In an attempt to aid the non-neurologist deployed provider in the care of patients presenting with seizures, the authors describe two cases illustrative of common presentations. Thereafter, the authors address many facets of the management questions commonly raised by such cases and offer suggestions regarding such issues as initial pharmacologic management, the need for admission and evacuation, seizure precautions, differentiation from syncope and nonepileptic seizures, addressing patient and command concerns regarding evaluation and duty restrictions, and obtaining online management assistance. PMID- 23929055 TI - Update: Community-acquired methicillin-resistant Staphylococcus aureus skin and soft tissue infection surveillance among active duty military personnel at Fort Benning GA, 2008-2010. AB - BACKGROUND: Increasing numbers of Staphylococcus aureus infections demonstrate antibiotic resistance. Military populations experiencing crowding are at increased risk of community-acquired methicillin-resistant S. aureus (CA-MRSA) infection. High prevalence of CA-MRSA infection among Army personnel was previously documented at Fort Benning, GA from 2002 to 2007. PURPOSE: To ascertain recent CA-MRSA trends at Fort Benning regarding antibiotic susceptibility, infection rates, and treatment regimens among Army personnel. METHODS: Incident CA-MRSA cases among active duty members/trainees from January 2008 to December 2010 were identified using active surveillance and laboratory data. RESULTS: In total, 2,171 infections were identified, representing 5,794 CA MRSA-related clinic visits. Annual rates decreased from 33 to 27 infections per 1,000 soldiers from 2008 to 2010. Approximately 78% of isolates were from training units. Approximately 4% of infections required hospitalization. Most infections (97%) were treated with antibiotics (36% received antibiotics and wound drainage). Antibiotic susceptibility patterns remained comparable to previous assessments. CONCLUSION: The observed decline in CA-MRSA rates and associated hospitalizations, coupled with stable antibiotic susceptibility patterns, is encouraging. Passive surveillance using laboratory records proved useful in identifying infection and could enhance detection across training sites. Given the continued high CA-MRSA prevalence among trainees, providers/public health personnel should remain vigilant to bolster prevention, detection, and treatment efforts. PMID- 23929056 TI - United States military service members and their tattoos: a descriptive study. AB - To explore the characteristics of military service tattoos a descriptive study was conducted at Walter Reed Army Medical Center to collect information from a convenience sample. An investigator-developed questionnaire provided the data for this study. Over the ensuing 12 month-period the researchers collected 126 questionnaires. Typical respondents were enlisted men with at least one deployment to an area of combat operations. Among the respondents, 57% acquired their tattoos before their deployment. One-quarter of the respondents reported only one tattoo, leaving the majority with multiple tattoos. Men received their first tattoo at an earlier age than women. The most common tattoo listed a person's name. Respondents did not regret their tattoos and rarely acquired the body art under the influence of alcohol or drugs. Little evidence was found to support a connection between tattoos and deployment. Few regretted their decisions and most all approached the tattoo experience free of any mind-altering substance. All this seems to suggest that military tattoos are a well-accepted means of self-expression. PMID- 23929057 TI - Comparison of methods for estimating Wet-Bulb Globe Temperature index from standard meteorological measurements. AB - Environmental heat illness and injuries are a serious concern for the Army and Marines. Currently, the Wet-Bulb Globe Temperature (WBGT) index is used to evaluate heat injury risk. The index is a weighted average of dry-bulb temperature (Tdb), black globe temperature (Tbg), and natural wet-bulb temperature (Tnwb). The WBGT index would be more widely used if it could be determined using standard weather instruments. This study compares models developed by Liljegren at Argonne National Laboratory and by Matthew at the U.S. Army Institute of Environmental Medicine that calculate WBGT using standard meteorological measurements. Both models use air temperature (Ta), relative humidity, wind speed, and global solar radiation (RG) to calculate Tnwb and Tbg. The WBGT and meteorological data used for model validation were collected at Griffin, Georgia and Yuma Proving Ground (YPG), Arizona. Liljegren (YPG: R(2) = 0.709, p < 0.01; Griffin: R(2) = 0.854, p < 0.01) showed closer agreement between calculated and actual WBGT than Matthew (YPG: R(2) = 0.630, p < 0.01; Griffin: R(2) = 0.677, p < 0.01). Compared to actual WBGT heat categorization, the Matthew model tended to underpredict compared to Liljegren's classification. Results indicate Liljegren is an acceptable alternative to direct WBGT measurement, but verification under other environmental conditions is needed. PMID- 23929059 TI - A comparison of deployed occupational tasks performed by different types of military battalions and resulting low back pain. AB - With deployment Soldiers must now wear body armor and additional equipment while performing occupational tasks, representing a large demand that has not been considered when studying military occupations. The purpose of this study was to: (1) describe tasks required by different occupational battalions within a Brigade Combat Team; (2) establish the incidence of low back pain (LBP) in each battalion and; (3) determine which tasks predict LBP within the different battalions. This was a prospective cohort study investigating 805 Soldiers in a Brigade Combat Team deployed to Afghanistan for 1 year. Demographic, occupational, and fitness variables were recorded. There was no difference in time spent on fitness training between the battalions. Occupational tasks performed by deployed Soldiers vary in the level of physical demand between battalions. Infantry had the highest fitness score (257); wore the heaviest equipment (70 lb.); spent the most time wearing body armor (49 hours/week), performing dismounted patrol (29 hours/week), and lifting objects (35 hours/week); spent the least amount of time working at a desk (14 hours/week); but had a similar incidence of LBP (77%) compared to other battalions. History of LBP and time spent wearing body armor were the two most consistent predictors of LBP across battalion types. PMID- 23929060 TI - Field-based PCR for rapid diagnosis of cutaneous anthrax in the deployed setting using the joint biological agent identification and diagnostic system. AB - Anthrax is occasionally encountered by U.S. military physicians in the deployed setting, where limited resources make it difficult to obtain laboratory confirmation. We present a case of cutaneous anthrax diagnosed using a ruggedized polymerase chain reaction device in austere combat conditions. PMID- 23929061 TI - An inexpensive workplace initiative to motivate high-risk individual health improvement. AB - Unhealthy lifestyles cost businesses, governmental organizations, and the U.S. military billions of dollars every year, not to mention intangible costs associated with increased mortality. This study implemented a low-cost cognitive behavioral motivational intervention to effect behavioral change in high-risk civilian employees working for a U.S. military organization, with accompanying improvement in certain health indicators after 120 days compared with a control group. Our analysis of these results led to two conclusions: first, low-cost cognitive-behavioral motivational treatments can improve both behavior and health, and second, tentative results indicate a fully mediated relationship may exist among the cognitive variables of locus of control and self-efficacy, vice the predicted parallel relationship. Overall, we assert that effective implementation of an intervention like the one used in this study might lower the U.S. Air Force's health care bill by as much as $40 million, improve employee efficiency and mission capability, enable healthier lives, and prevent premature death. PMID- 23929062 TI - Ovarian dysgerminoma: a case report and literature review. AB - A 27-year-old nulligravida active duty U.S. Navy chief petty officer presented with right flank pain and recurrent urinary tract infections without any history of nocturnal sweating or unexplained weight loss. Her physical examination was remarkable for mild right costovertebral angle tenderness and urinalysis showed hematuria. Subsequent computed tomography urolithiasis protocol revealed a 5 * 13 * 7 cm right pelvic mass. Further evaluation of the mass with magnetic resonance imaging revealed a solid, enhancing right ovarian mass and para-aortic lymphadenopathy; additional samples were drawn demonstrating elevated serum lactate dehydrogenase, suggestive of malignancy. Dysgerminoma was suspected and subsequent salpingo-oophorectomy and lymph node biopsies confirmed the diagnosis. The prevalence, common presentation, diagnosis, clinical course, and prognosis- with specific attention to cooperative management of this patient in many aspects of military medicine: primary care, gynecology, oncology, and radiology--were explored. PMID- 23929063 TI - Intra-articular synovial sarcoma treated with a transfemoral amputation: a case report and review of the literature. AB - A case of monophasic intra-articular synovial sarcoma in the right knee of a 39 year-old active duty serviceman treated with a transfemoral amputation is presented. The patient was evaluated for right knee pain and fullness. After further workup, the patient underwent computed tomography guided biopsy, with the tissue specimen consistent with intra-articular synovial sarcoma. The patient elected for a transfemoral amputation rather than limb or joint-sparing surgery. The gross specimen measured 3.5 * 3.0 * 1.7 cm in the posteromedial knee. No metastatic lesions were seen on positron emission tomography-computed tomography. Chemotherapy and radiation therapy have not been utilized. The transfemoral amputation adds to the uniqueness of this report and is discussed with a review of the multimodality treatment toward intra-articular synovial sarcoma in prior published literature. PMID- 23929064 TI - Novel Pseudomonas fluorescens septic sacroiliitis in a healthy soldier. AB - Septic sacroiliitis is an uncommon infection of immunocompetent patients, typically caused by gram-positive bacteria, with fewer gram-negative cases, and only 5% attributed to Pseudomonas species. We present a healthy soldier with the first reported case of Pseudomonas fluorescens septic sacroiliitis and discuss unique diagnostic and management issues. Because of its rare incidence and nonspecific presentation, septic sacroiliitis is often unrecognized, and its diagnosis is often delayed. Increased awareness of septic sacroiliitis as a potential disease process in the differential diagnosis of troops presenting with a combination of fever, low-back pain, and weight-bearing difficulty is important. As the young age and trauma exposure of the military population represent a prime demographic for this often unrecognized infection, delayed diagnosis can negatively impact a soldier's military readiness. P. fluorescens is itself a rare pathogen and often misidentified in the laboratory. Enhanced microbiological diagnostic techniques beyond routine culture and susceptibility testing should also be considered to account for less commonly seen pathogens. Although optimal antimicrobial treatment duration for infectious sacroiliitis is not well established, this case shows the early efficacy of oral antibiotics. PMID- 23929065 TI - The median arcuate ligament syndrome: a mimicker of mesenteric vasculitis. AB - The median arcuate ligament syndrome is an uncommon condition characterized by the triad of postprandial abdominal pain, unintentional weight loss, and an epigastric bruit. This condition is diagnostically challenging and patients often undergo extensive laboratory, radiographic, and invasive evaluations before it is identified. Physicians should consider this syndrome in the differential diagnoses of chronic abdominal pain and mesenteric vasculitis. Once diagnosed, treatment is generally surgical with known predictors of favorable and unfavorable outcomes. Surgical candidates should be selected carefully. We describe the cases of two young active duty patients diagnosed with median arcuate ligament syndrome after suffering from chronic abdominal pain. Both were referred to our rheumatology department to evaluate for mesenteric vasculitis. Each had a different therapeutic outcome. PMID- 23929068 TI - Effect of mass disorder on the lattice thermal conductivity of MgO periclase under pressure. AB - Thermal conductivity of mantle materials controlling the heat balance and thermal evolution of the Earth remains poorly constrained as the available experimental and theoretical techniques are limited in probing minerals under the relevant conditions. We report measurements of thermal conductivity of MgO at high pressure up to 60 GPa and 300 K via diamond anvil cells using the time-domain thermoreflectance technique. These measurements are complemented by model calculations which take into account the effect of temperature and mass disorder of materials within the Earth. Our model calculations agree with the experimental pressure dependencies at 300 and 2000 K for MgO. Furthermore, they predict substantially smaller pressure dependence for mass disordered materials as the mechanism of scattering changes. The calculated thermal conductivity at the core mantle boundary is smaller than the majority of previous predictions resulting in an estimated total heat flux of 10.4 TW, which is consistent with modern geomodeling estimates. PMID- 23929066 TI - Current recommendations for Helicobacter pylori therapies in a world of evolving resistance. AB - Occurrence of resistance, especially to clarithromycin, renders the standard triple therapy used to cure Helicobacter pylori infection ineffective. This review presents the bacteriological and pharmacological basis for H. pylori therapy and the current recommendations. The third-line treatment must be based on clarithromycin susceptibility testing. If the bacteria are still susceptible, failure may come from problems of compliance, hyperacidity or high bacterial load which can be overcome. If the bacteria are resistant, different regimens must be considered, including bismuth and non-bismuth-based quadruple therapies (sequential or concomitant), as well as triple therapies where amoxicillin is administered several times a day to obtain an optimal concentration at the gastric mucosal level. The treatments are becoming more and more complex and ecologically unsatisfactory, waiting for new agents or vaccines. PMID- 23929067 TI - Transcriptional network analysis for the regulation of left ventricular hypertrophy and microvascular remodeling. AB - Hypertension and cardiomyopathies share maladaptive changes of cardiac morphology, eventually leading to heart failure. These include left ventricular hypertrophy (LVH), myocardial fibrosis, and structural remodeling of coronary microcirculation, which is the morphologic hallmark of coronary microvascular dysfunction. To pinpoint the complex molecular mechanisms and pathways underlying LVH-associated cardiac remodeling independent of blood pressure effects, we employed gene network approaches to the rat heart. We used the Spontaneously Hypertensive Rat model showing many features of human hypertensive cardiomyopathy, for which we collected histological and histomorphometric data of the heart and coronary vasculature, and genome-wide cardiac gene expression. Here, we provide a large catalogue of gene co-expression networks in the heart that are significantly associated with quantitative variation in LVH, microvascular remodeling, and fibrosis-related traits. Many of these networks were significantly conserved to human idiopathic and/or ischemic cardiomyopathy patients, suggesting a potential role for these co-expressed genes in human heart disease. PMID- 23929071 TI - Whole cell patch clamp for investigating the mechanisms of infrared neural stimulation. AB - It has been demonstrated in recent years that pulsed, infrared laser light can be used to elicit electrical responses in neural tissue, independent of any further modification of the target tissue. Infrared neural stimulation has been reported in a variety of peripheral and sensory neural tissue in vivo, with particular interest shown in stimulation of neurons in the auditory nerve. However, while INS has been shown to work in these settings, the mechanism (or mechanisms) by which infrared light causes neural excitation is currently not well understood. The protocol presented here describes a whole cell patch clamp method designed to facilitate the investigation of infrared neural stimulation in cultured primary auditory neurons. By thoroughly characterizing the response of these cells to infrared laser illumination in vitro under controlled conditions, it may be possible to gain an improved understanding of the fundamental physical and biochemical processes underlying infrared neural stimulation. PMID- 23929069 TI - Long-term efficacy and emergence of multidrug resistance in patients with lamivudine-refractory chronic hepatitis B treated by combination therapy with adefovir plus lamivudine. AB - BACKGROUND: Few studies have investigated the emergence of multidrug resistance to adefovir dipivoxil (ADV) plus lamivudine (LAM) combination therapy for patients with LAM-refractory chronic hepatitis B (CHB). In this retrospective study, we investigated the long-term clinical course of these patients with or without multidrug resistance mutations. METHODS: We analyzed 406 Japanese patients with LAM-refractory CHB treated with combination therapy with follow-up for a median of 5.4 (0.5-9.5) years. Multidrug resistance of hepatitis B virus (HBV) DNA was analyzed using direct sequencing or cloning methods at baseline and viral breakthrough or insufficient decline during combination therapy. RESULTS: Ratio of patients with undetectable serum HBV DNA levels (<2.6 log copies/mL) during combination therapy was 63, 72, 75, 79, 82, 80 and 85 % at years 1 through 7, respectively. Substitutions associated with multidrug resistance were identified in 11 patients (2.7 %) at baseline, and in 12 patients (3 %) during therapy. HBV DNA levels of patients with rtA181S mutation at baseline and emergence of rtA181T + rtN236T double mutation or a wide variety of mutations during combination therapy could not be suppressed. Moreover, using ultra-deep sequencing, rtA181T/V mutations were detected at baseline in 7 of 10 patients with emergent multidrug resistance during combination therapy, although 6 of these 7 patients had very low frequency (<1 %) variants. CONCLUSION: Long-term ADV plus LAM combination therapy is effective in LAM-refractory patients. However, HBV DNA levels of the patients with multidrug resistance at baseline or during combination therapy sometimes could not achieve complete suppression or were re-elevated after a decrease. PMID- 23929072 TI - [Experimental study of new material for biocompatibility as orbital implant]. AB - PURPOSE: To evaluate the resin FullCure 720(r) biocompatibility as orbital implant. Clinical response and signs of systemic toxicity to the resin were evaluated, local biocompatibility and microscopic analysis regarding chronic local inflammatory response to the implant. The animals were weighted, biochemical exams and inflammatory response were evaluated. All animals were eviscerated and implantation of the spheres was carried out. Animals were followed for 60 days. Clinical behavior of animals and local signals of inflammation had been observed. After this period animals underwent euthanasia followed by enucleation. Macroscopic and histomorphometric analysis were performed. The results showed normal behavior of the animals, without implant exposure, extrusion, death or systemic toxicity. Capsule tissue formation was observed between the sclera and the implant. Normal inflammatory response to the foreign material in contact with the rabbit soft tissue was observed. The resin FullCure 720(r), demonstrated to be biocompatible as an orbital implant in this study. PMID- 23929073 TI - [Positioning of intraocular lens haptics intentionally implanted in the ciliary sulcus by ultrasound biomicroscopy]. AB - PURPOSE: To evaluate the position of haptics of intraocular lens intentionally implanted in the ciliary sulcus in eyes undergoing cataract surgery complication associated with intraoperative posterior capsule rupture, as well as to correlate the findings with clinical changes observed in ophthalmic examination, utilizing ultrasound biomicroscopy. METHODS: Eleven eyes (11 patients) who had posterior capsule rupture during cataract surgery with intentional implantation of the haptics in the ciliary sulcus, underwent complete ophthalmic examination and ultrasound biomicroscopy. Ultrasound biomicroscopy evaluated the parameters: positioning of the distal portion of the haptics, tilt and decentration of the intraocular lens. Ophthalmic examination was aimed to evaluate the presence of flare and cells in the anterior chamber, deposits on the lens and iris transillumination defects. Intraocular pressure was measured, pigmentation of the trabecular meshwork was determined, and a fundoscopic evaluation was needed to rule out peripheral retinal rupture and macular edema. RESULTS: Mean postoperative time for the examinations: 103.09 +/- 32.93 days. Asymmetry of the haptics positioning was observed in 3 eyes (27.2%) that had one haptic in the ciliary sulcus, the second haptic was placed in the pars plana in 2 eyes, associated to intraocular lens tilt and decentration; or in the ciliary body (1 eye). Ophthalmic examination observed: 5 (45.5%) eyes with iris transillumination defects, 2 (18.1%) with intraocular lens decentration; 1 eye (9%) presented ocular hypertension. In all cases trabecular hyperpigmentation was observed at gonioscopy. No cases of peripheral retinal rupture and/or macular edema were reported. CONCLUSIONS: Ultrasound biomicroscopy was able to locate the intraocular lens haptics intentionally implanted in the ciliary sulcus during complicated cataract surgery, and could demonstrate the relation of intraocular lens decentration to assymetric haptic implantation. PMID- 23929074 TI - New adjustable suture technique for trabeculectomy. AB - PURPOSE: To describe an adjustable suture (AS) experimental model that allows for tightening, loosening and retightening of the suture tension in trabeculectomy. METHODS: Standard trabeculectomy was performed in fifteen pig eyeballs. All pig eyes were tested twice: one test with conventional suture in both flap's corners (conventional suture group) and another test with a conventional suture at one corner and an adjustable suture in the other corner (AS group). The order in which each test was performed was defined by randomization. Intraocular pressure was measured at three time points: T1) when the knots were tightened; T2) when the AS was loosened or the conventional knot was removed; and T3) when the AS was retightened in the AS group or five minutes after the knot removal in the conventional suture group. RESULTS: The mean Intraocular pressure was similar between the two groups at time point 1 (p=0.97). However, significant Intraocular pressure differences were found between eyes in the conventional and adjustable suture groups at time points 2 (12.6 +/- 4.2 vs 16.3 +/- 2.3 cmH2O, respectively, p=0.006) and 3 (12.2 +/- 4.0 vs 26.4 +/- 1.7 cmH2O, respectively; p=0.001). While the conventional technique allowed only Intraocular pressure reduction (following the knot removal; T2 and T3), the AS technique allowed both Intraocular pressure reduction (T2) and elevation (T3) through the management (loosening and retightening) of the suture. CONCLUSION: This experimental model provides an effective noninvasive postoperative mechanism of suture tension adjustment. PMID- 23929075 TI - Corneal thickness changes during corneal collagen cross-linking with UV-A irradiation and hypo-osmolar riboflavin in thin corneas. AB - PURPOSE: To evaluate the thinnest corneal thickness changes during and after corneal collagen cross-linking treatment with ultraviolet-A irradiation, using hypo-osmolar riboflavin solution in thin corneas. METHODS: Eighteen eyes of 18 patients were included in this study. After epithelium removal, iso-osmolar 0.1% riboflavin solution was instilled to the cornea every 3 minutes for 30 minutes. Hypo-osmolar 0.1% riboflavin solution was then applied every 20 seconds for 5 minutes or until the thinnest corneal thickness reached 400 um. Ultraviolet-A irradiation was performed for 30 minutes. During irradiation, iso-osmolar 0.1% riboflavin drops were applied every 5 minutes. Ultrasound pachymetry was performed at approximately the thinnest point of the cornea preoperatively, after epithelial removal, after iso-osmolar riboflavin instillation, after hypo-osmolar riboflavin instillation, after ultraviolet-A irradiation, and at 1, 6 and 12 months after treatment. RESULTS: Mean preoperative thinnest corneal thickness was 380 +/- 11 um. After epithelial removal it decreased to 341 +/- 11 um, and after 30 minutes of iso-osmolar 0.1% riboflavin drops, to 330 +/- 7.6 um. After hypo osmolar 0.1% riboflavin drops, mean thinnest corneal thickness increased to 418 +/- 11 um. After UVA irradiation, it was 384 +/- 10 um. At 1, 6 and 12 months after treatment, it was 372 +/- 10 um, 381 +/- 12.7, and 379 +/- 15 um, respectively. No intraoperative, early postoperative, or late postoperative complications were noted. CONCLUSIONS: Hypo-osmolar 0.1% riboflavin solution seems to be effective for swelling thin corneas. The swelling effect is transient and short acting. Corneal thickness should be monitored throughout the procedure. Larger sample sizes and longer follow-up are required in order to make meaningful conclusions regarding safety. PMID- 23929076 TI - [Vitrectomy and gas-fluid exchange for the treatment of serous macular detachment due to optic disc pit: long-term evaluation]. AB - PURPOSE: To evaluate 5 patients with serous macular detachment due to optic disc pit that were submitted to pars plana vitrectomy and were followed for at least 7 years. METHODS: Patients were submitted to pars plana vitrectomy, posterior hyaloid removal, autologous serum injection and gas-fluid exchange, without laser photocoagulation, and were evaluated pre and post-operatively with visual acuity and Amsler grid testing, retinography, and recently, with autofluorescence imaging and high resolution OCT. RESULTS: All 5 eyes improved visual acuity significantly following the surgical procedure maintaining good vision throughout the follow-up period. Mean pre-operative visual acuity was 20/400 and final visual acuity was 20/27 with a mean follow-up time of 13.6 years. No recurrences of serous detachments were observed. OCT examinations demonstrated an attached retina up to the margin of the pit. CONCLUSION: Serous macular detachments due to optic disc pits were adequately treated with pars plana vitrectomy and gas fluid exchange, without the need for laser photocoagulation, maintaining excellent visual results for a long period of time. PMID- 23929077 TI - Level of agreement among Latin American glaucoma subspecialists on the diagnosis and treatment of glaucoma: results of an online survey. AB - PURPOSE: The aim of this research was to assess the level of agreement among glaucoma experts in Latin America on key practices related to treatment and diagnosis of glaucoma. METHODS: An online questionnaire was sent to a multinational panel of glaucoma experts. The questionnaire contained 107 statements on the medical treatment (Part 1) and diagnosis (Part 2) of glaucoma, and was developed in Spanish and translated into English. Agreement was defined as >70% of respondents. RESULTS: Fifty participants from 14 countries completed the questionnaire. For the medical treatment of glaucoma, nearly all respondents (98% or greater) confirmed that medical treatment as first-line therapy is preferred to surgery, prostaglandin analogs are the medication of first choice for primary open-angle glaucoma (POAG), longitudinal monitoring of efficacy should include intraocular pressure, structural and functional status, as well as if patients' quality of life is impaired by the high cost of medication. For the diagnosis of glaucoma section, all respondents confirmed that, after initial examination, gonioscopy should be repeated over time, standard automated perimetry is the most important functional examination for diagnosis and monitoring of primary open-angle glaucoma, central corneal thickness is important in assessment of glaucoma, and computerized imaging tests help in clinical evaluation of optic disc. CONCLUSIONS: This survey shows a high level of agreement on most aspects of glaucoma diagnosis and treatment among Latin American glaucoma experts. Areas of disagreement highlight the need for further evidence or education. These findings will be useful for guiding future efforts to optimize glaucoma practice by clinicians in Latin America. PMID- 23929078 TI - Sensitivity and specificity of machine learning classifiers for glaucoma diagnosis using Spectral Domain OCT and standard automated perimetry. AB - PURPOSE: To evaluate the sensitivity and specificity of machine learning classifiers (MLCs) for glaucoma diagnosis using Spectral Domain OCT (SD-OCT) and standard automated perimetry (SAP). METHODS: Observational cross-sectional study. Sixty two glaucoma patients and 48 healthy individuals were included. All patients underwent a complete ophthalmologic examination, achromatic standard automated perimetry (SAP) and retinal nerve fiber layer (RNFL) imaging with SD OCT (Cirrus HD-OCT; Carl Zeiss Meditec Inc., Dublin, California). Receiver operating characteristic (ROC) curves were obtained for all SD-OCT parameters and global indices of SAP. Subsequently, the following MLCs were tested using parameters from the SD-OCT and SAP: Bagging (BAG), Naive-Bayes (NB), Multilayer Perceptron (MLP), Radial Basis Function (RBF), Random Forest (RAN), Ensemble Selection (ENS), Classification Tree (CTREE), Ada Boost M1(ADA),Support Vector Machine Linear (SVML) and Support Vector Machine Gaussian (SVMG). Areas under the receiver operating characteristic curves (aROC) obtained for isolated SAP and OCT parameters were compared with MLCs using OCT+SAP data. RESULTS: Combining OCT and SAP data, MLCs' aROCs varied from 0.777(CTREE) to 0.946 (RAN).The best OCT+SAP aROC obtained with RAN (0.946) was significantly larger the best single OCT parameter (p<0.05), but was not significantly different from the aROC obtained with the best single SAP parameter (p=0.19). CONCLUSION: Machine learning classifiers trained on OCT and SAP data can successfully discriminate between healthy and glaucomatous eyes. The combination of OCT and SAP measurements improved the diagnostic accuracy compared with OCT data alone. PMID- 23929079 TI - Clinical characteristics and outcomes of patients admitted with presumed microbial keratitis to a tertiary medical center in Israel. AB - PURPOSES: Microbial keratitis is commonly diagnosed worldwide, and continues to cause significant ocular morbidity, requiring prompt and appropriate treatment. The objective of this study is to describe the clinical characteristics and outcomes of patients with presumed microbial keratitis admitted to The Goldschleger Eye Institute, Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel. METHODS: A cross-sectional study was conducted, in which the medical records of patients with presumed microbial keratitis admitted during a period of 3 years were reviewed. RESULTS: Keratitis was diagnosed in 276 patients (51% males and 48.9% females). The mean age was 39.29 +/- 22.30 years. The hospital length of stay ranged from 1 to 65 days (mean 5.69 +/- 5.508). Fortified antibiotics were still used at discharge in 72% of the cases. Overall visual acuity improved significantly from the time of admission to the 1st-week follow up visit showing a p<0.001 on the Wilcoxon signed ranks test. Contact lens wearing was present in 36.1% of the patients, although there was no significant relation with severity of the presentation and visual outcome (p>0.05). The degree of hypopyon and cells in the anterior chamber was significantly related to the hospital length of stay (r Spearman=0.31; p<0.001 and r Spearman=0.21; p<.001, respectively) as well as to a worse visual outcome (r Spearman=0.32; p<0.01 and r Spearman=0.18; p=0.01, respectively). Of all patients, 2.3% required an urgent therapeutic penetrating keratoplasty, and 1% underwent evisceration. There was no enucleation. CONCLUSION: Treating keratitis aggressively and assuring patient compliance is imperative for a good final visual outcome. Inpatient treatment may have a positive impact on this outcome. PMID- 23929080 TI - Intravitreal bevacizumab combined with infliximab in the treatment of choroidal neovascularization secondary to age-related macular degeneration: case report series. AB - PURPOSE: To evaluate the feasibility of the combined use of bevacizumab (Avastin(r)) and combined with infliximab (Remicade(r)) in the treatment of naive choroidal neovascularization due to age-related macular degeneration eyes. METHODS: Intravitreal injections of bevacizumab combined with infliximab in 6 neovascular age-related macular degeneration eyes. All patients underwent complete ophthalmologic examination on the initial visit and at days 1, 30, 60, 90, 120, 150 and 180 following the first injection. Optical coherence tomography and fluorescein angiography were performed during at initial visit and monthly during the 6 months follow-up period. Electroretinography was performed before and 30 days after initial injection, in order to evaluate retinal toxicity induced by such treatment. RESULTS: Thirty days after the first injection, 5 eyes (83%) shown decrease in macular thickness. No change was seen in electroretinogram in any eyes compared to initially performed electroretinogram. All phakic eyes developed cataract. One patient developed vitritis and was submitted to medical treatment successfully. At the end of the 6 months follow-up period, 4 patients showed significant improvement in the exudative process of choroidal neovascularization. One eye had mild persistent submacular fluid without active choroidal neovascularization, and another eye had persistent amount of intraretinal fluid due to active choroidal neovascularization. CONCLUSION: The combined use of bevacizumab with infliximab in eyes with neovascular age-related macular degeneration was effective in reducing leakage and improving the macular thickness. However, it is not possible to assert that the results were related to synergic effects of the combination therapy. A controlled study with more cases is necessary to precisely define the complication rates; however the dosage and/or association of drugs studied in this research should not be recommended in clinical practice due to cataract as well as inflammatory reaction. PMID- 23929081 TI - Persistent fetal vasculature: ocular features, management of cataract and outcomes. AB - PURPOSES: To describe ocular features, management of cataract and functional outcomes in patients with persistent fetal vasculature. METHODS: Retrospective, descriptive case series of patients with persistent fetal vasculature. Data were recorded from the Congenital Cataract Section of Federal University of Sao Paulo, Brazil from 2001 to 2012. All patients were evaluated for sex, age at diagnosis, systemic findings, laterality, age at surgery, and initial and final follow-up visual acuities. Follow-up and complications after cataract surgery were recorded. Ultrasound was performed in all cases and ocular eco-Doppler was performed in most. RESULTS: The study comprised 53 eyes from 46 patients. Age at diagnosis ranged from 5 days of life to 10 years-old (mean 22.7 months). Twenty seven patients were male (58.7%). Persistent fetal vasculature was bilateral in 7 patients (15.2%). Forty-two eyes (79.2%) had combined (anterior and posterior forms) PFV presentation, 5 eyes (9.4%) had only anterior persistent fetal vasculature presentation and 6 eyes (11.3%) had posterior persistent fetal vasculature presentation. Thirty-eight eyes (71.7%) were submitted to cataract surgery. Lensectomy combined with anterior vitrectomy was performed in 18 eyes (47.4%). Phacoaspiration with intraocular lens implantation was performed in 15 eyes (39.5%), and without lens implantation in 5 eyes (13.2%). Mean follow-up after surgery was 44 months. Postoperative complications were posterior synechiae (3 cases), retinal detachment (2 cases), phthisis (3 cases), posterior capsular opacification (8 cases), inflammatory pupillary membrane (5 cases), glaucoma (4 cases), intraocular lens implantation displacement (1 case) and vitreous hemorrhage (2 cases). Complications were identified in 19 (50%) of the 38 operated eyes. Visual acuity improved after cataract surgery in 83% of the eyes. CONCLUSIONS: Patients with persistent fetal vasculature have variable clinical presentation. There is an association of persistent fetal vasculature with congenital cataract. Severe complications are related to cataract surgery in patients with persistent fetal vasculature, but 83% of the operated eyes improved visual acuity. PMID- 23929082 TI - Enhanced depth imaging optical coherence tomography and fundus autofluorescence findings in bilateral choroidal osteoma: a case report. AB - The authors present enhanced depth imaging optical coherence tomography (EDI OCT) and fundus autofluorescence (FAF) characteristics of a patient with bilateral choroidal osteoma and try to make a correlation between two imaging techniques. Two eyes of a patient with choroidal osteoma underwent complete ophthalmic examination. Enhanced depth imaging optical coherence tomography revealed a cage like pattern, which corresponded to the calcified region of the tumor. Fundus autofluorescence imaging of the same area showed slight hyperautofluorescence. Three different reflectivity patterns in the decalcified area were defined. In the areas of subretinal fluid, outer segment elongations similar to central serous chorioretinopathy were observed. Hyperautofluorescent spots were evident in fundus autofluorescence in the same area. Calcified and decalcified portions of choroidal osteoma as well as the atrophy of choriocapillaris demonstrated different patterns with enhanced depth imaging and fundus autofluorescence imaging. Both techniques were found to be beneficial in the diagnosis and follow up of choroidal osteoma. PMID- 23929083 TI - Unilateral central retinal artery occlusion as the sole presenting sign of Susac syndrome in a young man: case report. AB - We report the case of a 24-year-old man presenting with sudden visual loss in the left eye from a central retinal artery occlusion. An extensive clinical investigation revealed no etiology. Three weeks later, however, the patient developed hearing loss followed by encephalopathy and multiple branch retinal artery occlusions in the right eye. Fluorescein angiography confirmed retinal vascular occlusions with no sign of vasculitis. The neurological examination revealed a diffuse encephalopathy while the MRI scan disclosed several small areas of infarcts in the brain. Bilateral sensorineural hearing loss was confirmed on audiometry. The patient was diagnosed with Susac syndrome and treated with methylprednisolone and cyclophosphamide, resulting in slight improvement and stabilization. This case shows that Susac syndrome may be diagnosed late due to the absence at onset of one or more of the symptoms of the classic triad (encephalopathy, multiple branch retinal artery occlusions and hearing loss). This case also serves to emphasize that Susac syndrome should be considered in the differential diagnosis of central retinal artery occlusion, even in apparently healthy young men. PMID- 23929084 TI - Keratoconus and corneal stability after radial keratectomy in the fellow eye: case report. AB - Keratoconus has usually been described as bilateral but asymmetric disease. Corneal ectasia is one of the long-term complications of modern refractive surgery, especially those submitted to laser in situ keratomileusis (LASIK). We describe a patient with keratoconus in the right eye that was submitted to radial keratectomy (RK) in the left eye 19 years ago with no progression of the ectatic cornea and no complications related to the refractive surgery. Because unilateral keratoconus is rare, we believe that RK was performed on an already ectatic cornea (not clinically detected) or with fruste keratoconus. However, neither corneal ectasia progressed, nor ectasia was induced by RK in the fellow eye. PMID- 23929085 TI - [Asymmetric recession of the horizontal rectus muscles for correction of alphabetical incomitance: case report]. AB - The authors report a case of 21-year-old man with divergent noncomitant strabismus, "V" pattern anisotropy, right inferior oblique muscle overaction and right superior oblique muscle hypofunction, which was performed under topical anesthesia an asymmetrical recession of the horizontal rectus muscles fibers to correct alphabetical incomitance. The immediate surgical outcome was considered very good (orthotropic, no "V" or "A" pattern), since the success was not obtained through conventional surgical technique. PMID- 23929086 TI - Retinal vasoproliferative tumor. AB - Retinal vasoproliferative tumor is a rare disease that has capillary hemangioma as the most frequent diferential diagnosis. The tumor is considered to be of reactive nature. It can be idiophatic or secondary to other ocular diseases such as: uveitis, retinitis pigmentosa, sickle cell disease, previous surgery and retinopathy of prematurity. Lesions with no exsudation or visual decrease can be observed. Lesions that need treatment can be managed by on or more modalities such as cryotherapy, a variety of lasers, surgical excision, radiation, and antiangiogenic intravitreal injections. PMID- 23929087 TI - Fine prints at the bottom of the page. PMID- 23929088 TI - Cell biology of unique anammox bacteria that contain an energy conserving prokaryotic organelle. AB - Anammox bacteria obtain their energy for growth from the anaerobic oxidation of ammonium with nitrite to dinitrogen gas. This property has made anammox bacteria very valuable for industry where they are applied for the removal of nitrogen compounds from industrial and domestic wastewaters. Anammox bacteria are also important in nature where they contribute significantly to oceanic nitrogen loss. Further, anammox bacteria have similarities to both Archaea and Eukarya, making them extremely interesting from a cell biological perspective. The anammox cell does not conform to the typical prokaryotic cell plan: single bilayer membranes divide the anammox cell into three distinct cellular compartments that possibly also have distinct cellular functions. The innermost and largest compartment, the anammoxosome, is the location of the energy metabolism. The middle compartment, the riboplasm, contains the nucleoid and ribosomes and thus has a genetic, information processing function. Finally, the outermost compartment, the paryphoplasm, has an as yet unknown function. In addition, anammox bacteria are proposed to have an atypical cell wall devoid of both peptidoglycan and a typical outer membrane. Here, I review the current knowledge on the cell biology of this enigmatic group of bacteria. PMID- 23929089 TI - Characterization of a planctomycete associated with the marine dinoflagellate Prorocentrum micans Her. AB - During attempts to obtain axenic the cultures of the marine dinoflagellate Prorocentrum micans, a microorganism with peculiar features was isolated. This contaminant resisted the physical and antibiotic treatments performed. Subsequent characterization showed that in agar plates this microorganism develops round granular pink colonies. It is a salt-dependent mesophilic and chemoheterotrophic Gram negative bacterium with a rod to ovoid shape, presenting cell motility in young cultures. Cell division occurs by cell budding. The bacterium forms aggregates with a variable number of cells that are stacked by fibrillar glycoproteic material, the holdfast. A tuft of numerous short glycoproteic fimbriae emerges from one pole of the cell. Preeminent granular inclusions, also of glycoproteic nature, are present in the cytoplasm. Several structural and compositional aspects of the cell envelope and cytoplasm are provided. The production of fibrillar material and the existence of the polar appendages suggest that this microorganism should occur in aquatic environments bound to substrates and could be associated with P. micans in natural marine habitats. Based on the characteristics displayed, this microorganism is a member of the Planctomycetes, order Planctomycetales. PMID- 23929091 TI - Borate-templated self-assembly of multinuclear nickel(II)-containing POMs. AB - Two unprecedented nickel-boron cluster-containing POMs have been isolated through a facile approach by the reactions of trivacant [A-alpha-SiW9O34](10-) and Ni(2+) in borate buffer. The {BO3} and {B2O4(OH)2} units enclosed in the Ni8 cluster of 1 and the Ni12 cluster of 2 play important templating roles in the assembly of the target compounds. PMID- 23929090 TI - Serum uric acid levels and long-term outcomes in chronic kidney disease. AB - Hyperuricemia is common in chronic kidney disease (CKD), but data regarding the relationship between serum uric acid levels and the long-term outcomes of CKD patients have been limited. The present study evaluated the associations between baseline serum uric acid levels with mortality and end-stage renal disease (ESRD). The subjects of this study were 551 stage 2-4 CKD patients. Cox proportional hazards models were used to evaluate the relationship between serum uric acid tertiles and all-cause mortality, cardiovascular disease (CVD) mortality, 50 % reduction in estimated glomerular filtration rate (eGFR), and development of ESRD, initially without adjustment, and then after adjusting for several groups of covariates. The mean age of the study subjects was 58.5 years, 59.3 % were men, and 10.0 % had diabetes. The mean eGFR was 42.02 +/- 18.52 ml/min/1.73 m(2). In all subjects, the mean serum uric acid level was 6.57 +/- 1.35 mg/dl, and 52.2 % of study subjects were on hypouricemic therapy (allopurinol; 48.3 %) at baseline. Thirty-one patients (6.1 %) died during a follow-up period of approximately 6 years. There was no significant association between serum uric acid level and all-cause mortality, CVD mortality, development of ESRD and 50 % reduction in eGFR in the unadjusted Cox models. In the adjusted models, hyperuricemia was found to be associated with all-cause mortality and CVD mortality after adjustment with CVD risk factors, kidney disease factors, and allopurinol, but not associated with development of ESRD and 50 % reduction in eGFR. The results of this study showed that hyperuricemia but not serum uric acid levels were associated with all-cause mortality, CVD mortality after adjustments with CVD risk factors, kidney disease factors, and allopurinol in stage 2-4 CKD patients. PMID- 23929092 TI - Response to learned threat: An FMRI study in adolescent and adult anxiety. AB - OBJECTIVE: Poor threat-safety discrimination reflects prefrontal cortex dysfunction in adult anxiety disorders. While adolescent anxiety disorders are impairing and predict high risk for adult anxiety disorders, the neural correlates of threat-safety discrimination have not been investigated in this population. The authors compared prefrontal cortex function in anxious and healthy adolescents and adults following conditioning and extinction, processes requiring threat-safety learning. METHOD: Anxious and healthy adolescents and adults (N=114) completed fear conditioning and extinction in the clinic. The conditioned stimuli (CS+) were neutral faces, paired with an aversive scream. Physiological and subjective data were acquired. Three weeks later, 82 participants viewed the CS+ and morphed images resembling the CS+ in an MRI scanner. During scanning, participants made difficult threat-safety discriminations while appraising threat and explicit memory of the CS+. RESULTS: During conditioning and extinction, the anxious groups reported more fear than the healthy groups, but the anxious adolescent and adult groups did not differ on physiological measures. During imaging, both anxious adolescents and adults exhibited lower activation in the subgenual anterior cingulate cortex than their healthy counterparts, specifically when appraising threat. Compared with their age-matched counterpart groups, anxious adults exhibited reduced activation in the ventromedial prefrontal cortex when appraising threat, whereas anxious adolescents exhibited a U-shaped pattern of activation, with greater activation in response to the most extreme CS+ and CS-. CONCLUSIONS: Two regions of the prefrontal cortex are involved in anxiety disorders. Reduced subgenual anterior cingulate cortex engagement is a shared feature in adult and adolescent anxiety disorders, but ventromedial prefrontal cortex dysfunction is age-specific. The unique U-shaped pattern of activation in the ventromedial prefrontal cortex in many anxious adolescents may reflect heightened sensitivity to threat and safety conditions. How variations in the pattern relate to later risk for adult illness remains to be determined. PMID- 23929093 TI - Cell senescence culturing methods. AB - Development of therapeutic approaches that slow or ablate the adverse physiological and pathological changes associated with aging has been considered as an important goal for gerontological research. As cellular senescence is characterized as the basis for aging in organisms, culturing and subculturing of normal human diploid fibroblasts to mimic the in vivo aging processes have been developed as major methods to investigate molecular events involved in aging. It has been established that normal human diploid fibroblasts can proliferate in culture for only finite periods of time. There are many ways to study aging in vitro. In this chapter, we will discuss some of the basic laboratory procedures for cell senescence culturing methods. PMID- 23929094 TI - Digital image analysis of cells stained with the senescence-associated beta galactosidase assay. AB - Cellular senescence plays important roles in the aging process of complex organisms, in response to stress and in tumor suppression. Several markers can be used to identify senescent cells, of which the most widely used is the senescence associated beta-galactosidase (SABG) activity. Here we describe a procedure for digital image analysis of cells stained by the SABG staining technique at pH 6 or at pH 4. This analysis is highly reproducible and sensitive to subtle differences in staining intensities resulting from diverse cellular senescence pathways in culture. PMID- 23929096 TI - Cell sorting of young and senescent cells. AB - Cellular senescence is the irreversible loss of proliferative potential and is accompanied by a number of phenotypic changes. First described by Hayflick and Moorhead in 1961, it has since become a popular model to study cellular aging. The replicative lifespan of human fibroblasts is heterogeneous even in clonal populations, with the fraction of senescent cells increasing with each population doubling (PD). Thus, the study of individual cells in mass culture is necessary in order to properly understand senescence and its associated phenotype. Cell sorting is a process that allows the physical separation of cells based on different characteristics which can be measured by flow cytometry. Here, we describe various methods by which senescent cells can be sorted from mixed cultures and discuss how different methods impact on the posterior analysis of sorted populations. PMID- 23929095 TI - Analysis of biomarkers of caloric restriction in aging cells. AB - Caloric restriction (CR) has been extensively documented for its profound role in effectively extending maximum lifespan in many different species. However, the accurate mechanisms, especially at the cellular level, for CR-induced aging delay are still under intense investigation. An emerging technique, recently explored in our laboratory, provides precisely controllable caloric intake in a cultured cellular system that allows real-time observation and quantitative analysis of the impact of CR on the molecular cellular level during the aging processes. This in vitro method allows investigation of the molecular mechanisms pertaining to how CR influences aging processes leading to life extension in human cellular systems. It will provide important clinical implications for future preventive approaches for aging and aging-related degeneration diseases in humans. Hence, we will discuss the detailed procedures of this novel technique as well as the analysis of relevant aging biomarkers and its broad application in the field. PMID- 23929097 TI - Studying the replicative life span of yeast cells. AB - The budding yeast Saccharomyces cerevisiae is a useful model for elucidating the pathways that control life span and the influence of environmental factors, such as calorie restriction (CR). For 75 years, CR has been studied for its ability to delay diseases of aging in mammals, from cancer to cardiovascular disease (McCay et al., Nutr Rev 33:241-243, 1975). In many other species, reducing calorie intake extends life span, including unicellular organisms (Jiang et al., FASEB J 14:2135-2137, 2000; Lin et al., Science 289:2126-2128, 2000), invertebrates (Rogina and Helfand, Proc Natl Acad Sci U S A 101:15998-16003, 2004), and rodents (Martin-Montalvo et al., Oncogene 30:505-520, 2011). Here we describe how to calorically restrict yeast cells, the methods used to determine the replicative life span (RLS) of budding yeast cells, how to selectively kill daughter cells using the mother enrichment program (MEP), how to measure recombination frequency at the rDNA locus, how to isolate large quantities of old cells, and how to analyze the circular forms of DNA known as extrachromosomal rDNA circles (ERCs), a cause of aging in S. cerevisiae (Petes, Cell 19:765-774, 1980; Sinclair and Guarente, Cell 91:1033-1042, 1997; Defossez et al., Mol Cell 3:447-455, 1999). PMID- 23929098 TI - Methods for creating mutations in C. elegans that extend lifespan. AB - The principle of commonly used methods to create mutations in the nematode Caenorhabditis elegans (C. elegans) is straightforward. In general, worms are exposed to a dose of mutagen resulting in DNA damages and mutations. Screening the progeny of the mutagenized animals for a certain phenotype is the regular forward genetic approach in C. elegans. A mutant selected from such a population is stabilized to recover a pure homozygous strain. In this chapter, we categorize the protocol into mutagenesis, phenotype screen, and outcross and provide time tested procedures for their implementation to create long-lived worm mutants. PMID- 23929099 TI - Aging studies in Drosophila melanogaster. AB - Drosophila is a genetically tractable system ideal for investigating the mechanisms of aging and developing interventions for promoting healthy aging. Here we describe methods commonly used in Drosophila aging research. These include basic approaches for preparation of diets and measurements of lifespan, food intake, and reproductive output. We also describe some commonly used assays to measure changes in physiological and behavioral functions of Drosophila in aging, such as stress resistance and locomotor activity. PMID- 23929100 TI - The use of calorie restriction mimetics to study aging. AB - Calorie restriction (CR) has a variety of effects on extending lifespan and delaying the onset of age-related diseases, and it is accepted as the only established experimental antiaging intervention. Several pharmacological agents that can replicate the beneficial effects of CR, called calorie restriction mimetics (CRMs), have been identified. The nutrient-sensing pathways including those involving sirtuins (especially SIRT1) and mammalian target of rapamycin (mTOR) may regulate the physiology of CR, and candidate CRMs that modulate these specific pathways have been identified and investigated using animal models. In this chapter, we focus on candidate CRMs including sirtuin-activating compounds (STACs) and mTOR inhibitors, their slowing of aging, and methods for evaluation of lifespan and metabolic disorders. PMID- 23929101 TI - Using somatic-cell nuclear transfer to study aging. AB - In mammals, a diploid genome following fertilization of haploid cells, an egg, and a spermatozoon is unique and irreproducible. This implies that the generated unique diploid genome is doomed with the individual's inevitable demise. Since it was first reported in 1997 that Dolly the sheep had been cloned, many mammalian species have been cloned successfully using somatic-cell nuclear transfer (SCNT). The success of SCNT in mammals enables us not only to reproduce offspring without germ cells, that is, to "passage" a unique diploid genome, but also to address valuable biological questions on development, nuclear reprogramming, and epigenetic memory. Successful cloning can also support epigenetic reprogramming where the aging clock is reset or reversed. Recent work using iPS cell technology has explored the practicality and led to the recapitulation of premature aging with iPSCs from progeroid laminopathies. As a result, reprogramming tools are also expected to contribute to studying biological age. However, the efficiency of animal cloning is still low in most cases and the mechanism of reprogramming in cloned embryos is still largely unclear. Here, based on recent advances, we describe an improved, more efficient mouse cloning protocol using histone deacetylase inhibitors (HDACis) and latrunculin A, which increases the success rates of producing cloned mice or establishing ES cells fivefold. This improved method of cloning will provide a strong tool to address many issues including biological aging more easily and with lower cost. PMID- 23929102 TI - Induction of cellular senescence by oncogenic RAS. AB - Cellular senescence is a state of permanent cell cycle arrest, which has been shown to prevent neoplastic transformation. Oncogenes are pro-proliferative genes that promote survival and proliferation of cancer cells. Paradoxically, introduction of an activated oncogene leads to activation of a state similar to cellular senescence, which is referred to as oncogene-induced senescence. Studies have shown that oncogene-induced senescence function as a barrier to neoplastic transformation. Here, we describe a protocol for inducing cellular senescence by oncogenic RAS in primary human fibroblast. The approach that we describe here is of general utility and can be applied to study senescence induction by other defined genetic elements, for example, other activated oncogenes. PMID- 23929103 TI - Methods of cellular senescence induction using oxidative stress. AB - Normal somatic cells do not divide indefinitely and have their finite replicative lifespan. This property leads to an eventual arrest of cell division termed cell senescence. Human diploid fibroblasts offer a typical model for studying cell senescence in vitro. Various approaches to evoke oxidative stresses, such as the exposures of cells to ultraviolet light, ethanol, tert-butyl hydroperoxide (t BHP), and peroxide hydrogen (H2O2), have been used to study the onset of cellular senescence. The early onset of cellular senescence induced by these stresses is termed stress-induced premature senescence (SIPS). In this manuscript, we will mainly summarize the basic knowledge and experimental approaches important for the induction of SIPS by H2O2, since H2O2 is the most commonly used inducer of SIPS in vitro and an endogenous source of cellular oxidative stress. Several assays methods generally used for testifying cell senescence are introduced. PMID- 23929104 TI - Methods of testing pharmacological drugs effects on aging and life span in mice. AB - The methodology of testing antiaging drugs in laboratory mice is presented. It is based on more than 40-year-long authors' experience in the field and includes the selection of mouse strain, sex, age at start of treatment, housing conditions, design of the long-term study, some noninvasive methods of assessment of biomarkers of aging, life-span parameters, pathology examination, and statistical treatment of the results. PMID- 23929105 TI - Mitochondria-targeted antiaging gene therapy with adeno-associated viral vectors. AB - Transgenic expression of catalase in mitochondria using a transgenic strategy extends life span and prevents aging-related pathology in mice. However, transgenic overexpression is not suitable for a clinical application. Adeno associated virus (AAV) is the most promising gene delivery vehicle. Here we outline strategies on the generation of an AAV vector expressing the mitochondria targeted catalase gene (AV.RSV.MCAT). We also describe methods for evaluating physiological impact of AV.RSV.MCAT on muscle contractility and running performance in mice. PMID- 23929106 TI - Real-time bioluminescence functional imaging for monitoring tissue formation and regeneration. AB - Real-time bioluminescence functional imaging holds great promise for regenerative medicine because it improves the researcher's ability to analyze and understand the healing process. Using transgenic mice coupled with gene-modified cells, one can employ this method to monitor host and graft activity in various models of tissue regeneration. We implemented real-time bioluminescence functional imaging to analyze bone formation by following a unique protocol in which the luciferase reporter gene, driven by an osteocalcin promoter, is used to visualize host and graft activity during bone formation. Real-time bioluminescence functional imaging can be used to assess the "host reaction" in transgenic mice models; it can also be used to assess "graft activity" in other animals in which genetically labeled stem cells have been implanted or direct gene delivery has been applied. The suggested imaging protocol requires 25 min per sample. However, special attention must be given to the layout of the experimental design, which determines the specific activity that will be analyzed. PMID- 23929107 TI - Exometabolomic mapping of Caenorhabditis elegans: a tool to noninvasively investigate aging. AB - Metabolomic analyses can provide valuable information about the internal metabolism of an organism; however, these studies can become quickly complicated by the large number of metabolites that are often detected. Overcoming this limitation requires high-resolution analytical separation techniques, coupled with high-power deconvolution software. Additionally, much care must be taken in metabolomic sample preparation to quench active enzymes and avoid artifactual changes in the metabolome. Here we present a relatively simple and straightforward technique, exometabolome mapping, which bypasses each of these concerns, is noninvasive, and provides a concise summary of the key metabolic processes operative in an organism. We illustrate our method using the nematode C. elegans, an organism which has been widely exploited in aging studies; however, with only minimal modification, our technique is extendible to other sample types, and indeed we have successfully used it both to perform yeast footprinting and to study the excreted metabolic end products of human kidney cancer cell lines. PMID- 23929108 TI - Detecting polymorphisms in human longevity studies: HLA typing and SNP genotyping by amplicon sequencing. AB - Life expectancy has always been associated to several determinants, such as environmental and genetic factors. Studies have related human lifespan as being 25-32 % due to genetic polymorphisms between individuals associated to longevity and aging. Nonetheless, no single gene will convey a phenotype like longevity. Aging is a process that occurs from changes in various levels of the cell, from genes to functions. Longevity is the ability to cope and repair the damage that results from these changes. It has been described as the result of an optimal performance of immune system and as an overexpression of anti-inflammatory sequence variants of immune/inflammatory genes.Longevity gene candidates can be separated into the following categories: inflammatory and immune-related, stress response elements, mediators of glucose and lipid metabolism, DNA repair components and cellular proliferation, and DNA haplogroups.Studies have related lifespan with Common Single-Nucleotide Polymorphisms (SNPs); polygenic effects can explain an important part of how genetics influence it. In this chapter we describe how to sequence Class I HLA allele polymorphism, as well as SNP sequencing, two methodologies most frequently used in polymorphism detection. PMID- 23929109 TI - Gel electrophoresis-based proteomics of senescent tissues. AB - Cellular aging is a fundamental biological process, and mass spectrometry-based proteomics has been widely used for the global identification of age-related changes in a variety of tissues. The proteomic profiling of senescent skeletal muscles has revealed a variety of alterations in proteins associated with the contractile apparatus, cell signaling, ion homeostasis, metabolism, and the cellular stress response. Here, we outline the two-dimensional gel electrophoretic separation and fluorescent labeling of the urea-soluble protein complement from aged diaphragm muscle. This chapter describes the various experimental steps involved in gel electrophoresis-based proteomics, including protein extraction, isoelectric focusing, slab gel electrophoresis, fluorescence labeling, image analysis, protein digestion, mass spectrometric identification of proteins and immunoblotting. PMID- 23929110 TI - Single-cell semiconductor sequencing. AB - RNA-seq or transcriptome analysis of individual cells and small-cell populations is essential for virtually any biomedical field. It is especially critical for developmental, aging, and cancer biology as well as neuroscience where the enormous heterogeneity of cells present a significant methodological and conceptual challenge. Here we present two methods that allow for fast and cost efficient transcriptome sequencing from ultra-small amounts of tissue or even from individual cells using semiconductor sequencing technology (Ion Torrent, Life Technologies). The first method is a reduced representation sequencing which maximizes capture of RNAs and preserves transcripts' directionality. The second, a template-switch protocol, is designed for small mammalian neurons. Both protocols, from cell/tissue isolation to final sequence data, take up to 4 days. The efficiency of these protocols has been validated with single hippocampal neurons and various invertebrate tissues including individually identified neurons within a simpler memory-forming circuit of Aplysia californica and early (1-, 2-, 4-, 8-cells) embryonic and developmental stages from basal metazoans. PMID- 23929111 TI - Application of DNA microarray technology to gerontological studies. AB - Gene expression patterns change dramatically in aging and age-related events. The DNA microarray is now recognized as a useful device in molecular biology and widely used to identify the molecular mechanisms of aging and the biological effects of drugs for therapeutic purpose in age-related diseases. Recently, numerous technological advantages have led to the evolution of DNA microarrays and microarray-based techniques, revealing the genomic modification and all transcriptional activity. Here, we show the step-by-step methods currently used in our lab to handling the oligonucleotide microarray and miRNA microarray. Moreover, we introduce the protocols of ribonucleoprotein [RNP] immunoprecipitation followed by microarray analysis (RIP-chip) which reveal the target mRNA of age-related RNA-binding proteins. PMID- 23929112 TI - Epigenetic biomarker to determine replicative senescence of cultured cells. AB - Somatic cells change continuously during culture expansion-long-term culture evokes increasing cell size, declining differentiation potential, and ultimate cell cycle arrest upon senescence. These changes are of particular relevance for cellular therapy which necessitates standardized products and reliable quality control. Recently, replicative senescence has been shown to be associated with highly reproducible epigenetic modifications. Here, we describe a simple method to track the state of senescence in mesenchymal stromal cells (MSCs) or fibroblasts by monitoring continuous DNA methylation (DNAm) changes at specific sites in the genome. Six CpG sites have been identified which reveal either linear hypermethylation or hypomethylation with respect to the number of cumulative population doublings (cPDs). Conversely, the DNAm level at these CpG sites can be analyzed-for example, by pyrosequencing of bisulfite-converted DNA and then used for linear regression models to predict cPDs. Our method provides an epigenetic biomarker to determine the state of senescence in cell preparations. PMID- 23929114 TI - Changes in delivery methods at specialty care hospitals in the United States between 2006 and 2010. AB - OBJECTIVE: Given the increasing rates of labor induction and cesarean delivery, and efforts to reduce early term births, we examined recent trends in methods and timing of delivery. STUDY DESIGN: We identified delivery methods and medical indications for delivery from administrative hospital discharge data for 231 691 deliveries in 2006 and 213 710 deliveries in 2010 from 47 specialty care member hospitals of the National Perinatal Information Center/Quality Analytic Services. In a subset of 17 hospitals, we examined trends by gestational age. RESULT: From 2006 to 2010, there was an 11% increase in labor induction and a 6% increase in cesarean delivery, largely due to repeat cesareans. There was a 4 per 100 reduction in early term births (37 to 38 weeks), mostly due to a decline in non medically indicated interventional deliveries. CONCLUSION: We report a shift in deliveries at 38 weeks, which we believe may be attributed to efforts to actively limit non-medically indicated early term deliveries. PMID- 23929113 TI - Single-neuron transcriptome and methylome sequencing for epigenomic analysis of aging. AB - Enormous heterogeneity in transcription and signaling is the feature that slows down progress in our understanding of the mechanisms of normal aging and age related diseases. This is critical for neurobiology of aging where the enormous diversity of neuronal populations presents a significant challenge in experimental design. Here, we introduce Aplysia as a model for genomic analysis of aging at the single-cell level and provide protocols for integrated transcriptome and methylome profiling of individually identified neurons during the aging process. These single-cell RNA-seq and DNA methylation assays (methyl capture/methyl enrichment) are compatible with all major next generation sequencing platforms (we used Roche/454 and SOLiD/Life Technologies as illustrative examples) and can be used to integrate an epigenetic signature with transcriptional output. The described sequencing library construction protocol provides both quantitative and directional information from transcriptional profiling of individual cells. Our results also confirm that different copies of DNA in polyploid Aplysia neurons behave similarly with respect to their DNA methylation. PMID- 23929115 TI - Note from the editors: Eurosurveillance special issue on leishmaniasis painting a picture of the situation in Europe. PMID- 23929116 TI - Ongoing outbreak of visceral leishmaniasis in Bologna Province, Italy, November 2012 to May 2013. AB - An increased number of autochthonous visceral leishmaniasis (VL) cases has recently been reported in Bologna Province in northern Italy. Over six months from November 2012 to May 2013, 14 cases occurred, whereas the average number of cases per year was 2.6 (range: 0-8) in 2008 to 2012. VL was diagnosed in a median of 40 days (range: 15-120) from disease onset. This delay in diagnosis shows the need for heightened awareness of clinicians for autochthonous VL in Europe. PMID- 23929117 TI - Geographical distribution and epidemiological characteristics of visceral leishmaniasis in Bulgaria, 1988 to 2012. AB - Visceral leishmaniasis is a sporadic illness in Bulgaria. However, cases in humans are registered nearly every year. This study describes the geographical distribution of the disease in Bulgaria from 1988 to 2012, over a period of 25 years. Cases were analysed according to age, sex, and place of residence. A total of 122 cases were registered in 25 years, 118 of which were autochthonous and four of which were imported from endemic countries in southern Europe. The average annual incidence for the study period was 0.06 per 100,000 population, or an average of five cases per year (maximum 15 in 1989; no cases notified in 1991, 1995, 1996 and 2008). Cases of visceral leishmaniasis were recorded in 13 out of 28 regions in Bulgaria, mainly in the southern part of the country. The highest number of cases were registered in the regions of Blagoevgrad (n=36) and Stara Zagora (n=34). Data presented in this study show that there is ongoing transmission of visceral leishmaniasis in Bulgaria with a high mortality rate (1:7), affecting mostly children. PMID- 23929118 TI - Epidemiology of human leishmaniasis in Greece, 1981-2011. AB - Leishmaniasis is endemic and mandatorily notifiable in Greece. Epidemiological surveillance data for leishmaniasis in Greece between 1981 and 2011 are presented. In 1998, the notification system began distinguishing between visceral and cutaneous leishmaniasis. The mean annual incidence of reported leishmaniasis cases between 1998 and 2011 was 0.36 per 100,000 population. Of a total 563 leishmaniasis cases reported after 1998, 523 (93%) were visceral leishmaniasis cases. Incidence of reported visceral leishmaniasis cases fluctuated during this period, generally decreasing after 2007, with a small re-increase in 2011. The mean annual incidence rate of reported visceral leishmaniasis cases was significantly higher in less than four year-olds (p <0.001). Leishmaniasis cases occurred both in the country mainland and islands. Between 1998 and 2011, Attica concentrated almost half of the reported visceral leishmaniasis cases, with incidence rates in western Attica and western Athens above 12.00 per 100,000 population. Compared to visceral leishmaniasis, cutaneous leishmaniasis had a rather sporadic distribution, with many prefectures appearing free of cases. From 2004, the notification also included risk factors and of 287 cases with known immune status, 44 (15%) were immunocompromised. Moreover having a dog at home was reported by 209 of 312 leishmaniasis cases (67%), whereas 229 of 307 cases (75%) reported the presence of stray dogs near their residence. Linking clinical surveillance data with laboratory data and improving collaboration with the veterinary public health sector are some of the future challenges for leishmaniasis surveillance in Greece. PMID- 23929119 TI - Asymptomatic Leishmania infantum infections in humans living in endemic and non endemic areas of Croatia, 2007 to 2009. AB - The prevalence of asymptomatic leishmaniasis in the general population of Croatia has not been studied to date. To assess the prevalence of Leishmania infantum specific IgG antibodies among immunocompetent residents of Croatia, sera from 2,035 persons (eastern coast of Adriatic Sea, n=1,186; Adriatic islands, n=653; mainland, n=196), were tested by an enzyme immunoassay. A total of 231 (11.4%) persons had anti-Leishmania antibodies. Multivariate analysis revealed that seropositivity was associated with geographic location and age. Residents of coastal areas and islands were significantly more seropositive than mainland residents (odds ratios (OR) 20.37 to 28.51). Moderate to high anti-Leishmania seroprevalence was found throughout the eastern Adriatic coast and islands (4.0% to 22.2%) including the sites previously considered non-endemic. A highly endemic focus was identified in central coastal Dalmatia (seroprevalence 22.2%; OR: 1.72; 95% confidence interval (CI): 1.33-2.22). Regarding age, children aged 0-9 years were the most vulnerable group for asymptomatic Leishmania infection (OR: 2.19; 95% CI: 1.16-4.14). PMID- 23929120 TI - The burden of visceral leishmaniasis in Italy from 1982 to 2012: a retrospective analysis of the multi-annual epidemic that occurred from 1989 to 2009. AB - Starting from 1989 Italy experienced an increase of visceral leishmaniasis (VL) cases over a baseline of 10 to 30 cases reported annually. The number of cases peaked in 2000 and 2004 with more than 200 cases/year, and subsequently declined to reach on average one third of the 2000 peak value in the period after 2010. A retrospective analysis from 1982 to 2012 showed that the multi-annual epidemic consisted of major components including (i) an outbreak involving infants and immunocompetent adults in parts of the Campania region (southern peninsular Italy) and that appears to have declined naturally, (ii) a second outbreak affecting human immunodeficiency virus (HIV)-infected individuals throughout the country, that declined owing to the use of highly active antiretroviral therapies (HAART), (iii) a generalised increase of VL cases in immunocompetent individuals and patients affected by associated conditions other than HIV from endemic regions of peninsular and insular Italy (other than Campania), which was due to a geographical spreading of VL foci, with no major case-clusters or outbreak features. A minor component consisted in the appearance of a few autochthonous cases in formerly non-endemic areas, starting from the early 1990s. Epidemic determinants and reasons for VL decline in the Campania region remain largely unexplained, despite the information available on canine reservoir and phlebotomine vectors in Italy. PMID- 23929121 TI - Surveillance of leishmaniases in France, 1999 to 2012. AB - Leishmaniasis is endemic in the south of France, where autochthonous disease is caused by Leishmania infantum, and affects both humans and dogs. The prevalence of canine leishmaniasis is between 3 and 66% depending on the region and the methods used. Human leishmaniases are also imported into France, mainly from French Guiana and North Africa. The surveillance of autochthonous and imported human leishmaniases is based on passive notification to the National Reference Centre for Leishmaniases (NRCL) created in 1998. Between 1999 and 2012, 317 autochthonous and 1,154 imported cases were notified to the NRCL. The average number of autochthonous cases notified per year was 22.6, mainly cases of visceral leishmaniasis (84.5%). All cases were infected in the south of France. Leishmaniasis incidence is 0.22 per 100,000 inhabitants in the endemic area. Imported cases were more frequent (annual mean of 82.4 cases) and consisted predominantly in cutaneous leishmaniasis (CL) cases (91%), essentially L. major CL imported from Maghreb and Sub-Saharan Africa, and L. guyanensis CL from French Guiana. This national notification system allowed a better understanding of the incidence and distribution of the disease; it is also useful to assess the temporal-spatial evolution of the disease in France, which appears relatively stable. PMID- 23929122 TI - Subclonal evolution of a classical Hodgkin lymphoma from a germinal center B-cell derived mantle cell lymphoma. AB - Composite lymphomas (CL) represent the occurrence of two distinct lymphomas in the same patient. Often, CL share a common cellular origin, thus representing a unique model to investigate the multistep genetic path leading to lymphomagenesis in general and to the specific development of each distinct lymphoma component in particular. Here, we present the molecular analysis of a case consisting of an unusual Hodgkin lymphoma (HL) and a mantle cell lymphoma (MCL), intimately admixed within one another in lymph nodes and bone marrow yet phenotypically distinct, in a patient who first presented with splenic/leukemic MCL two years earlier. MCL and Hodgkin and Reed/Sternberg (HRS) cells harbored identical immunoglobulin (Ig) VH gene rearrangements with shared somatic mutations, proving their common clonal origin from a (post-)germinal center (GC) B cell. This also demonstrates the (post-)GC origin of MCL with mutated IgV genes. Both lymphomas carried the same CCND1/IGH translocation and, unexpectedly for HL, expressed cyclin D1 and OCT2. Thus, HRS cells are able to preserve IGH locus activity (otherwise usually silenced in HL) to promote expression of an oncogene translocated into this locus. Both lymphoma populations further showed an identical TP53 function-impairing mutation, and later acquired a TP53 heterozygous deletion independently from one another (convergent evolution). The surprisingly close genetic relationship of the lymphomas, together with their histological intermingling and the clinical history of the patient, suggests subclonal evolution of HL from MCL as a plausible pathway in alternative to that so far described in CL, i.e. separate development from a common precursor. PMID- 23929123 TI - MRI and ultrasound evaluation of invasive lobular carcinoma of the breast after primary systemic therapy. AB - AIM: To assess magnetic resonance imaging (MRI) and ultrasound (US) evaluation of invasive lobular carcinoma after primary systemic therapy compared to the primary surgery group. METHODS: A total of 218 breasts with invasive lobular carcinoma (ILC), which were diagnosed by core needle biopsy and underwent surgery between 2004 and 2010 in St. Luke's International Hospital, were reviewed. Of these, 44 breasts received primary systemic therapy (PST) and the residual 174 breasts underwent surgery first. Before surgery, MRI and second-look US were performed. Patients whose extent of lesion from MRI and US was over 90 degrees were recommended to receive total mastectomy. Diagnostic image evaluation was categorized from the final pathology. A negative margin of breast-conserving surgery (BCS) and mastectomy which has over 90 degrees tumor extent in pathology were regarded as "appropriate". A positive margin of BCS was regarded as "underestimated". "Overestimation" was determined when the pathological extension was small enough for BCS although MRI and US diagnosis was over 90 degrees . RESULTS: Of 44 breasts which received PST, 26 breasts received BCS as initial surgery. Of these, 14 (53.8 %) breasts were "underestimated". Of these 14, 5 breasts received additional total mastectomy. Of 174 breasts that received surgery first, 121 (69.5 %) breasts received BCS as the initial surgery. Of these, 46 (38.0 %) breasts were "underestimated" and 6 breast of these 46 received additional total mastectomy. "Underestimated" rate was similar in the two groups, but the additional total mastectomy rate was significantly higher in the PST group (p = 0.025). There were no "overestimations". The "appropriate" rate was similar between the PST (68.2 %) and surgery-first groups (73.6 %). CONCLUSIONS: Although 68.2 % of ILC patients were evaluated "appropriately" even after PST, higher additional total mastectomy rates should be considered when selecting the surgical procedure. PMID- 23929124 TI - On parsing the neural code in the prefrontal cortex of primates using principal dynamic modes. AB - Nonlinear modeling of multi-input multi-output (MIMO) neuronal systems using Principal Dynamic Modes (PDMs) provides a novel method for analyzing the functional connectivity between neuronal groups. This paper presents the PDM based modeling methodology and initial results from actual multi-unit recordings in the prefrontal cortex of non-human primates. We used the PDMs to analyze the dynamic transformations of spike train activity from Layer 2 (input) to Layer 5 (output) of the prefrontal cortex in primates performing a Delayed-Match-to Sample task. The PDM-based models reduce the complexity of representing large scale neural MIMO systems that involve large numbers of neurons, and also offer the prospect of improved biological/physiological interpretation of the obtained models. PDM analysis of neuronal connectivity in this system revealed "input output channels of communication" corresponding to specific bands of neural rhythms that quantify the relative importance of these frequency-specific PDMs across a variety of different tasks. We found that behavioral performance during the Delayed-Match-to-Sample task (correct vs. incorrect outcome) was associated with differential activation of frequency-specific PDMs in the prefrontal cortex. PMID- 23929125 TI - Subdural hematoma following labor analgesia utilizing an intrathecal catheter. PMID- 23929126 TI - The bronchoscopy model LM-092 has educational benefits. PMID- 23929127 TI - Heterogeneous junction engineering on core-shell nanocatalysts boosts the dye sensitized solar cell. AB - In this study, we successfully manipulate the heterogeneous junction at Co3O4-Pt core-shell cathodic nanocatalysts (C/P CNCs) by controlling the core/shell ratios. Our results indicate the cobalt core atoms would inject their valence charge to the surface Pt atoms due to the presence of extensive lattice strain in the shell region. This charge injection accelerates the redox kinetics at the catalysts surface. Consequently, compared with that using Pt nanoparticle cathode, the C/P CNCs at an optimal Pt/Co atomic ratio of 1, improves the current density and the photovoltaic efficiency of dye-sensitized soar cell (DSSC) by ~36.3% and ~22.9%, respectively. By combining structure and electrochemical analysis, we systematically elucidate the effects of Pt/Co (shell/core) ratios, the interplay of Co atoms on the shell structures, and the redox activity of C/P CNCs on the DSSC performance. Hereby, this study provide mechanistic insights in developing electrocatalysts for DSSC with programmable performance and reduced Pt utilization. PMID- 23929129 TI - Association of telomere shortening in myocardium with heart weight gain and cause of death. AB - We attempted to clarify myocardial telomere dynamics using samples from 530 autopsied patients using Southern blot analysis. Overall regression analysis demonstrated yearly telomere reduction rate of 20 base pairs in the myocardium. There was a significant correlation between myocardial telomere and aging. Moreover, regression analyses of telomere and heart weight yielded a telomere reduction rate of 3 base pairs per gram, and a small but significant correlation between telomere reduction and heart weight was demonstrated. Hearts of autopsied patients who had died of heart disease were significantly heavier than those of patients who had died of cancer or other diseases, and heart disease was significantly more correlated with myocardial telomere shortening than cancer or other diseases. Here we show that telomeres in myocardial tissue become shortened with aging and heart disease, and that heart disease was associated with a gain of heart weight and telomere shortening in the myocardium. PMID- 23929130 TI - Acid-cleavable thiomaleamic acid linker for homogeneous antibody-drug conjugation. AB - In this communication we describe a novel acid-cleavable linker strategy for antibody-drug conjugation. Functional disulfide bridging of the single interchain disulfide bond of a trastuzumab Fab fragment yields a homogeneous antibody-drug conjugate bearing a thiomaleamic acid linker. This linker is stable at physiological pH and temperature, but quantitatively cleaves at lysosomal pH to release the drug payload. PMID- 23929131 TI - Live cell imaging of early autophagy events: omegasomes and beyond. AB - Autophagy is a cellular response triggered by the lack of nutrients, especially the absence of amino acids. Autophagy is defined by the formation of double membrane structures, called autophagosomes, that sequester cytoplasm, long-lived proteins and protein aggregates, defective organelles, and even viruses or bacteria. Autophagosomes eventually fuse with lysosomes leading to bulk degradation of their content, with the produced nutrients being recycled back to the cytoplasm. Therefore, autophagy is crucial for cell homeostasis, and dysregulation of autophagy can lead to disease, most notably neurodegeneration, ageing and cancer. Autophagosome formation is a very elaborate process, for which cells have allocated a specific group of proteins, called the core autophagy machinery. The core autophagy machinery is functionally complemented by additional proteins involved in diverse cellular processes, e.g. in membrane trafficking, in mitochondrial and lysosomal biology. Coordination of these proteins for the formation and degradation of autophagosomes constitutes the highly dynamic and sophisticated response of autophagy. Live cell imaging allows one to follow the molecular contribution of each autophagy-related protein down to the level of a single autophagosome formation event and in real time, therefore this technique offers a high temporal and spatial resolution. Here we use a cell line stably expressing GFP-DFCP1, to establish a spatial and temporal context for our analysis. DFCP1 marks omegasomes, which are precursor structures leading to autophagosomes formation. A protein of interest (POI) can be marked with either a red or cyan fluorescent tag. Different organelles, like the ER, mitochondria and lysosomes, are all involved in different steps of autophagosome formation, and can be marked using a specific tracker dye. Time-lapse microscopy of autophagy in this experimental set up, allows information to be extracted about the fourth dimension, i.e. time. Hence we can follow the contribution of the POI to autophagy in space and time. PMID- 23929134 TI - Editorial on trigonocephaly. PMID- 23929133 TI - Alcohol and smoking and subsequent risk of prostate cancer in Japanese men: the Japan Public Health Center-based prospective study. AB - Although alcohol and smoking have not been established as risk factors for prostate cancer, they are important risk factors for other human cancers and potentially major avoidable factors. Alcohol drinkers and smokers might be less likely to get screening, which might lead to attenuation of the positive association. Here, we investigated the association of alcohol drinking and smoking and prostate cancer according to stage, as well as prostate cancer detected by subjective symptoms, in a large prospective study among Japanese men. The Japan Public Health Center-based prospective study (JPHC study) was established in 1990 for Cohort I and in 1993 for Cohort II. Subjects were 48,218 men aged 40-69 years who completed a questionnaire, which included their alcohol and smoking habits at baseline, and who were followed until the end of 2010. During 16 years of follow-up, 913 men were newly diagnosed with prostate cancer; of whom 248 had advanced cases, 635 were organ-localized and 30 were of an undetermined stage. Alcohol consumption was dose-dependently associated with advanced prostate cancer [nondrinkers: reference, 0-150 g/week: hazard ratio (HR) = 1.23, 95% confidence interval (CI) = 0.83-1.82; 150-300 g/week: HR = 1.51, 95% CI = 1.04-2.19; >= 300 g/week: HR = 1.41, 95% CI = 0.97-2.05, p for trend = 0.02]. The positive association was not substantially changed among cancers detected by subjective symptoms. Smoking was inversely associated with prostate cancer among total subjects, but tended to increase the risk of advanced prostate cancer detected by subjective symptoms. In conclusion, abstinence from alcohol and prohibition of smoking might be important factors in the prevention of advanced prostate cancer. PMID- 23929132 TI - Differential effects of estrogen and testosterone on auditory sensory gating in rats. AB - RATIONALE: Estrogen has been shown to have beneficial effects in patients with schizophrenia. However, the mechanisms involved in this protective effect are unclear. Schizophrenia is associated with deficits in sensory gating, a filtering mechanism which normally prevents sensory overload. In rodent models, acute treatment with drugs such as the dopamine D1/D2 receptor agonist, apomorphine; the dopamine releaser, amphetamine; and the glutamate NMDA receptor antagonists, phencyclidine or MK-801, can induce a phenotype similar to that seen in schizophrenia. OBJECTIVES: Given the putative protective action of estrogen in schizophrenia, here we investigated the effect of ovariectomy (OVX) and estrogen replacement in female rats on drug-induced auditory gating deficits. For comparison, we also assessed the effects of castration (CAST) and dihydrotestosterone (DHT) replacement in male rats. METHODS: Rats were instrumented with cortical surface electrodes. Test sessions comprised of 150 presentations of paired clicks, 500 ms apart (S1 and S2). RESULTS: Administration of all drugs increased the ratio of responses to S2/S1 in sham-operated female and male rats. OVX reduced event-related potential amplitudes but did not alter S2/S1 ratio or drug effects. In OVX rats with 17beta-estradiol implants, the effect of apomorphine was abolished, but there was no change in that of amphetamine and phencyclidine. There were no effects of CAST or DHT replacement in male rats. CONCLUSIONS: Chronic estrogen replacement in OVX rats protected against sensory gating deficits caused by direct dopamine D1/D2 receptor stimulation. These data could indicate a possible mechanism by which estrogen exerts a protective action in schizophrenia. PMID- 23929135 TI - New amine-functionalized cobalt cluster-based frameworks with open metal sites and suitable pore sizes: multipoint interactions enhanced CO2 sorption. AB - By employing the mixed-linker synthetic strategy, two new cobalt(II) cluster based frameworks, [Co(2.5)(btc)(atz)2(Hatz)(DMF)].2DMF (1) and [Co(2.5)(btc)(Hbtc)0.5(atz)(CH3CN)(H2O)].H2O (2), constructed from the same initial materials Co(NO3)2, 1,3,5-benzenetricarboxylic acid (H3btc) and 3-amino 1,2,4-triazole (Hatz), have been synthesized by solvothermal reactions. Crystal structure analyses demonstrated that 1 and 2 are three-dimensional (3D) porous frameworks based on Co-triazolate chain/layer and tricarboxylate pillars. Thermogravimetric analysis (TGA) and power X-ray diffraction (PXRD) measurements showed that both of them have high thermal stability and good water stability. Remarkably, both the structures of desolvated 1 and 2 contain suitable pore sizes and highly polar channel systems functionalized by amino groups, open metal sites, carbonyl or free carboxylic acid sites and uncoordinated triazolate nitrogen atoms on the pore surfaces, exhibiting multipoint interactions between CO2 molecules and frameworks, resulting in high CO2 uptake and selectivity for CO2 over N2. PMID- 23929137 TI - Septoplasty in children: problem or solution? PMID- 23929138 TI - Propolis and its emerging anti-neoplastic effects: beyond its role in oral dysplasia. PMID- 23929139 TI - Does Epstein-Barr virus infection have an influence on the development of laryngeal carcinoma? Detection of EBV by Real-Time Polymerase Chain Reaction in tumour tissues of patients with laryngeal carcinoma. AB - Epstein-Barr virus (EBV) is a well-known carcinogenic virus, and the association of EBV with some tumours suggests that there may also be an association between laryngeal carcinoma and EBV. OBJECTIVE: The aim of this study is to determine the role of EBV in the aetiology of laryngeal carcinoma. METHOD: Prospective investigation the EBV with real time polymerase chain reaction in tumour tissues of 25 patients with laryngeal carcinoma and 17 patients with benign laryngeal lesions, and investigation of the relationship between the presence of viral DNA and patients' smoking habits, alcohol consumption, localization and differentiation of the tumour. RESULTS: There was no significant difference between the control group and patient group in terms of EBV polymerase chain reaction positivity (p > 0.05). Also we couldn't find a statistically significant relationship between EBV positivity and differentiation of the tumour, localization of the tumour, smoking and alcohol consumption habits (p > 0.05). CONCLUSION: Our results suggest that, although EBV is present in some of the squamous cell laryngeal carcinomas, its presence has no effect on the pathogenesis of laryngeal carcinomas. PMID- 23929140 TI - Mastication and deglutition changes in children with tonsillar hypertrophy. AB - The changes in mastication and deglutition in children with adenotonsillar hypertrophy need to be better characterized. OBJECTIVE: To evaluate the frequency of parent-reported myofunctional changes and to determine if there are differences in the alteration patterns of children with adenotonsillar hypertrophy and subjects with adenoid hypertrophy. METHOD: Questionnaire and assessment by a speech therapist of children aged between three and six years with tonsillar hypertrophy. The data reported by the parents were compared to the data obtained from the speech therapist's evaluation; additionally, data from children with adenotonsillar hypertrophy were compared to findings from subjects with adenoid hypertrophy. STUDY DESIGN: cross-sectional cohort. RESULTS: The myofunctional changes observed by the speech therapist were more frequent than the alterations reported by the parents, and there was no correlation between the two findings. The children with adenoid hypertrophy and the individuals with adenotonsillar hypertrophy had the same pattern of myofunctional alteration. CONCLUSION: Parents cannot clearly correlate tonsillar hypertrophy with changes in mastication and deglutition. The cause of the respiratory obstruction does not seem to interfere in the pattern of myofunctional change. PMID- 23929141 TI - Prevalence of auditory neuropathy spectrum disorder in an auditory health care service. AB - Auditory neuropathy spectrum disorder (ANSD) is characterized by impairment of the auditory nerve associated with preservation of outer hair cell function. OBJECTIVE: To establish the prevalence of ANSD in subjects with sensorineural hearing loss (SNHL). METHOD: This retrospective study was carried out between 2010 and 2012 and included the charts of 2,292 individuals with SNHL. Data from otolaryngological and audiological examinations based on pure-tone and speech audiometry, impedance tests, otoacoustic emissions (OAEs), and brainstem auditory evoked potentials (BAEPs) were collected. INCLUSION CRITERIA: presence of OAEs and/or cochlear microphonic (CM); absent or altered BAEPs, and normal MRI scans of the brain. RESULTS: Twenty-seven (1.2%) of the 2,292 subjects with SNHL had ANSD (37% males; 63% females). Mild SNHL was seen in 29.6% of the individuals with ANSD; 55.5% had moderate SNHL; 7.4% had severe SNHL; and 7.5% had profound SNHL. In terms of age, 14.8% were aged between zero and 20 years, 44.1% were 41 to 60 years old, and 7.4% were above the age of 60. CONCLUSION: ANSD was seen in 1.2% of the individuals with SNHL included in this study. PMID- 23929142 TI - Clinical diagnosis and histological analysis of vocal nodules and polyps. AB - Recent studies emphasize the importance of the clinical-histology correlation in laryngeal pathologies. OBJECTIVE: To compare the ENT diagnosis with the pathology diagnosis one of 132 surgical specimens, from 119 patients with vocal nodules and polyps. METHOD: Retrospective study. We investigated the paraffin blocks corresponding to the lesions of the operated patients. We made new histology cross-sections, totaling 396 new slides, divided into three groups: hematoxylin and eosin, Gomori trichrome and PAS. We analyzed the following histological parameters: epithelium, lamina propria, basement membrane, vascular changes. We compared the laryngological and pathological diagnoses, and we did the statistical analysis, checking the predominant histological aspects in each lesion. RESULTS: There was an agreement between the clinical and pathological diagnoses in 123 (93.18%) of 132 lesions analyzed (42.42% nodules and 50.76% polyps). In the histological parameters we found: epithelial changes such as nodules hyperplasia (82.14%) and polyp atrophy (31.34%). Lamina propria: edema in polyps (71.43%), fibrosis in the nodules (57.14%). Basement membrane: thickened nodules (100%), thin/no change in polyps (100%). There was a predominance of vascular changes in the polyps. CONCLUSION: We found a high correlation between the ENT diagnosis and the pathology report. Histopathologically, the nodules presented with predominantly epithelial changes, lamina propria and basement membrane fibrosis, while the polyps by changes strictly on the lamina propria and vascular aspects. PMID- 23929143 TI - Facial nerve grafting and end-to-end anastomosis in the middle ear: tympanic cavity and mastoid. AB - Sectioned facial nerves can be repaired with grafting or end-to-end anastomosis. OBJECTIVE: To discuss these repair procedures and what can be expected of them. METHOD: Seven patients with sectioned facial nerves were included in the study. Four underwent grafting and three were offered end-to-end anastomosis. Facial nerve palsy was iatrogenic in five patients and was caused by bullet wounds in two. Assessment of motor function recovery was based on Janssen's scale. RESULTS: Mean motor recovery was rated at 72.5% for subjects offered grafting and 73.3% for patients submitted to anastomosis. CONCLUSION: 1. Grafting and anastomosis are proper solutions to repair sectioned facial nerves; complete recovery is never attained; synkinesis may occur. 2. In principle anastomosis is the procedure of choice, but when there is minimal traction in the facial nerve stump grafting is preferred. 3. Both procedures yielded mean motor recovery rates above 70% (72.5% for grafting and 73.3% for anastomosis). PMID- 23929144 TI - Mastoid surface area-to-volume ratios in adult Brazilian individuals. AB - Computed tomography-based measurements of mastoid surface area and volume have not been described for adult Brazilian individuals. These measurements add to the understanding of middle ear physiology, related diseases, and their impact on mastoid pneumatization. OBJECTIVE: To check the ratio between mastoid surface area and volume. METHOD: This contemporary cross-sectional cohort study included 28 patients submitted to CT imaging of the mastoid. Measurements of surface area and volume were made based on serial CT scans and produced with the aid of software package Image Pro Plus. RESULTS: Mastoid volumes ranged from 5.5 to 72.4 cm3. Surface areas ranged from 43.9 to 525.2 cm2. Surface areas varied linearly with volumes. CONCLUSION: Mastoid surface areas and volumes of adult Brazilian subjects followed a linear correlation, as also described in studies carried out in other countries. Mean surface areas and volumes were higher than previously published, unlike surface area-to-volume ratios, which were lower. Further studies with larger populations will provide evidence as to whether Brazilian subjects have larger surface areas and volumes than other populations. PMID- 23929145 TI - The impact of Metzembaum septoplasty on nasal and facial growth in children. AB - Several studies have investigated the effects of septoplasty on facial growth in children, with conflicting results. However, just handful of those employed objective measures or evaluated patients after facial growth completion. OBJECTIVE: This study assesses the effects of the Metzenbaum septoplasty, which preserves the perichondrium and growth-related areas on nasal and facial growth in children. METHOD: We included those children submitted to surgery before the age of 14 and who had 16 years or years of follow up. Sixteen patients were selected. We evaluated the following parameters: clinical satisfaction (nasal patency and aesthetics), anthropometric measurements and cephalometry. Scientific design: cross-sectional historical cohort. RESULTS: The mean age at surgery was 13 years, children were assessed on average 4.3 years after surgery. Only one patient had anthropometric and cephalometric values below normal, but no aesthetics or patency complaints. Four other patients complained about their nasal aesthetics and three had patency complaints. CONCLUSION: The Metzenbaum septoplasty appears to be a safe technique to correct caudal septum deviations. This technique had no significant impact on facial growth of the patients assessed. PMID- 23929146 TI - Oropharyngeal dysphagia in patients with multiple sclerosis: do the disease classification scales reflect dysphagia severity? AB - Multiple sclerosis is a neurological disease that involves swallowing disorders. Many studies have shown an association between neurological and swallowing performance, but results have been conflicting. OBJECTIVE: To identify the frequency of dysphagia in patients with multiple sclerosis and neurological indicators that can represent the performance of swallowing. METHOD: In this study (cross-sectional) 120 Multiple Sclerosis patients underwent Functional Assessment of Swallowing by flexible nasal-pharyngo-laryngoscopy and the results were compared with the scores of the rating scales: (Clinical Evolving Forms of Disease, Functional Disability Scale for and Scale Systems Extended Functional Disability [Kurtzke Expanded Disability Status Scale]). RESULTS: Dysphagia was found in 90% of patients. Among the clinical forms of the disease, the progressive forms (primary progressive and secondary progressive) were more frequently associated with severe dysphagia, while the relapsing-remitting form presented more often mild and moderate dysphagia. Regarding the Disability Scale for Functional Systems, cerebellar function, brainstem function and mental health were associated with dysphagia, especially in the severe form. Regarding the Extended Functional Disability Scale, higher scores were associated with severe dysphagia. CONCLUSION: Dysphagia is common in MS patients, especially in those with greater impairment of neurological functions. PMID- 23929147 TI - Prognostic factors in sudden sensorineural hearing loss: a retrospective study using interaction effects. AB - The prognostic significance of vertigo in patients with idiopathic sudden sensorineural hearing loss (SSNHL) remains a matter of debate. OBJECTIVE: This paper aims to verify the difference between a group with vertigo and a group without vertigo, and to analyze vertigo's validation as a prognostic factor in patients with SSNHL. METHOD: This study involved 183 patients with SSNHL. A t test was used to compare group A (SSNHL with vertigo, n = 31) and group B (SSNHL without vertigo, n = 152). Also we want to verify the interaction effects between vertigo and other prognostic factors using multiple regression analysis. RESULTS: There was a significant difference between group A and group B: the initial hearing level of group A was lower than group B, and their treatment onset was also shorter. In addition, vertigo itself didn't affect hearing improvement, but the interaction variable between vertigo and initial hearing level did affect hearing improvement significantly. CONCLUSION: The clinical characteristics of patients with vertigo did not directly affect hearing improvement with SSNHL; however, vertigo had an influence on SSNHL though its interaction with the initial hearing levels. PMID- 23929148 TI - Septoplasty with or without postoperative nasal packing? Prospective study. AB - Anterior nasal packing is carried out in a number of nasal surgeries, especially in septoplasty. However, it is not an innocuous procedure and for this its benefit has been challenged. OBJECTIVE: To assess the need for anterior nasal packing and the quality of life of patients submitted to septoplasty. METHOD: Patients submitted to septoplasty with or without inferior turbinoplasty were randomized to receive or not anterior nasal packing postoperatively. We recorded and compared postoperative data (pain and bleeding). Quality of life was assessed before and after surgery. This is a randomized prospective study. RESULTS: We had 73 patients (37 packed and 36 who did not receive a nasal packing) with a minimum follow-up of 3 months. Patients with nasal packing complained more of nasal pain and headache in the immediate postoperative period. Of these patients, 75.7% reported moderate/intense pain upon nasal packing removal. Bleeding was more frequent in those patients who did not receive a nasal packing, and only 1 patient required packing. All the patients enjoyed an improvement in quality of life. CONCLUSION: Septoplasty improves the quality of life of patients with septal deviation and nasal obstruction. Routine use of anterior nasal packing should be challenged for not presenting proven benefit. PMID- 23929149 TI - Tomographic evaluation of the contralateral ear in patients with severe chronic otitis media. AB - Some studies indicate a bilateral tendency of chronic otitis media. It is believed that the contralateral ear can provide evidences of the route of formation of ear disease in the most affected, be a parameter of Eustachian tube function and predict successful treatment. The CT scan is an excellent test to evaluate the structures of the temporal bone and the changes resulting from otitis media. OBJECTIVE: To evaluate Temporal Bone Computed Tomography of patients with chronic otitis media and describe abnormalities in the contralateral ear. METHOD: Cross-sectional study. Evaluation of CT scans of 75 patients with chronic otitis media from a tertiary referral hospital in Brazil by a neuroradiologist. RESULTS: Population was consisted of 50.6% males with a mean age of 36 years. We found 54.7% of changes in contralateral ear clearly associated with chronic otitis media. CONCLUSION: The prevalence of radiographic changes in the contralateral ears of patients with chronic otitis media corroborates with clinical, histopathological and functional resources developed by the same group that this disease has a bilateral feature. PMID- 23929150 TI - Nasal endoscopic and CT scan alterations of the paranasal sinuses as predictors of severity in patients with cystic fibrosis. AB - Cystic Fibrosis (CF) results from mutation in the transmembrane conductance regulator gene, responsible for controlling secretory processes. The upper airways (UA) are usually involved in the form of chronic pansinusitis. OBJECTIVE: To evaluate UA changes in patients with CF and to establish the correlations between sinonasal CT and endoscopic endonasal findings and disease severity. METHOD: Cross-sectional and prospective study with 20 patients older than 5 years with CF, assessing the Shwachman-Kulczycki (S-K) score, paranasal sinus tomography (CT) (Lund-Mackay score) and nasal endoscopy (Meltzer score). RESULTS: CT scan alterations were observed in 94% of cases. Endoscopic alterations findings in the upper airways were found in 10 patients. Nasal polyps were found in 3 patients (15%). There was a correlation between the intensity of changes on the CT and S-K score (p = 0.0097), and between endoscopic findings and S-K score (p = 0.0318). There was a positive correlation between the presence of chronic colonization and endoscopic findings (p = 0.0325), which was not observed on the CT (p = 0.2941). CONCLUSION: There is an inverse correlation between the S-K clinical score and nasal endoscopy and CT findings. Therefore, patients who are clinically more severe according to the S-K score have greater UA involvement. PMID- 23929151 TI - Analysis of theoretical knowledge and the practice of science among Brazilian otorhinolaryngologists. AB - Physicians from all medical specialties are required to understand the principles of science and to interpret medical literature. Yet, the levels of theoretical and practical knowledge held by Brazilian otorhinolaryngologists has not been evaluated to date. OBJECTIVE: To assess the background and level of scientific knowledge of Brazilian otorhinolaryngologists. METHOD: Participants of two national ENT meetings were invited to answer a questionnaire to assess scientific practice and knowledge. RESULTS AND CONCLUSION: This study included 73 medical doctors (52% otorhinolaryngologists and 38% residents) aged between 18 and 65 years. About two-thirds have been involved in some form of scientific activity during undergraduate education and/or reported to have written at least one scientific paper. Physicians who took part in research projects felt better prepared to interpret scientific papers and carry out research projects (p = 0.0103 and p = 0.0240, respectively). Respondents who claimed to have participated in research or to have written papers had higher scores on theoretical scientific concepts (p = 0.0101 and p = 0.0103, respectively). However, the overall rate of right answers on questions regarding scientific knowledge was 46.1%. Therefore, a deficiency was observed in the scientific education of Brazilian otorhinolaryngologists. Such deficiency may be mitigated through participation in research. PMID- 23929152 TI - Intraoperative PTH cutoff definition to predict successful parathyroidectomy in secondary and tertiary hyperparathyroidism. AB - In order to improve success rates in surgery of renal hyperparathyroidism, we evaluated intraoperative PTH (IOPTH) measurement utility. METHOD: 86 patients underwent total parathyroidectomy with intramuscular presternal autotransplantation from 04/2000 to 10/2009 and were followed for 26.5 months on average (prospective cohort). Patients were divided in secondary (SHPT) and tertiary hyperparathyroidism (THPT). SHPT group was composed by patients under dialysis treatment, THPT group included renal grafted ones. IOPTH (Elecsys-PTH Immunoassay/Roche) was measured at anesthesia induction (IOPTH-0') and 20 minutes (IOPTH-20') after parathyroidectomy. RESULTS: 80.2% (69/86) presented with 80% decrease or more in the IOPTH-20' and all were cured. In 11/86 patients (12.7%), a lower IOPTH-20' drop (70-79%) was observed, and 2 of them (18.1%) failed to cure. 6/86 (6.9%) patients presented IO-PTH-20' decrease of less than 70%: two were cured, in three a supernumerary/ectopic parathyroid was found and removed, and in one of these six patients, surgery was finished after 4-gland excision and the patient failure to cure. CONCLUSION: IOPTH-20' decrease of 80% or more compared to IOPTH-0' predicts cure in all renal patients throughout follow-up. A decay of less than 70% points to missed or hyperfunctioning supernumerary gland and is predictive of surgical failure in 66.6%. A marginal IOPTH drop of 70-79% leaves the decision whether or not surgery should be continued up to the experienced surgeon. PMID- 23929153 TI - Epidemiological assessment and therapeutic response in hypopharyngeal cancer. AB - Despite the low incidence, diagnostic and therapeutic advances, hypopharyngeal cancer still has high mortality. OBJECTIVE: To evaluate retrospectively the epidemiological profile and response to surgery and radiation/chemotherapy of patients with hypopharyngeal cancer. METHOD: We reviewed the medical records of 114 patients treated between 2002 and 2009 in a tertiary hospital with histopathological diagnosis of squamous cell carcinoma. RESULTS: The mean age of the patients was 57 years, 94.7% were males and 5.3% females, 98.2% were smokers and 92% consumed alcohol; 72% are illiterate or did not complete first grade schooling. The main complaints were: neck node (28%), pain and dysphagia (22%), odynophagia (12.2%), dysphonia (7.8%). The clinical staging was: I (1.7%), II (3.5%), III (18.4%), IV (76.3%). The treatment was carried out with radiotherapy and chemotherapy alone in 35%, with mean 2-year survival of 20% and 5-year survival of 18%; surgery followed by radiotherapy and chemotherapy in 22.8% with 2-year survival of 60.0% and 5 years of 55.0%; chemotherapy alone in 2.6%, and 39.4% without treatment. CONCLUSION: Most patients already had advanced clinical stages and independent of the treatment option, had a low survival rate, confirming the poor prognosis of this neoplasm. PMID- 23929154 TI - The impact of endoscopy on the treatment of cholesteatomas. AB - Recurrent cholesteatoma is relatively uncommon. Residual middle ear cholesteatomas account for most of the cases of recurrent disease. The limited role of microscopy in the visualization of tridimensional anatomic alterations of the temporal bone led to the use of endoscopic examination as an additional tool in the realm of ear surgery. Endoscopy has significantly aided in the management of chronic cholesteatomatous otitis media and in the prevention of recurrent disease. OBJECTIVE: To review the literature and assess the relevance of endoscopy in the surgical treatment of cholesteatomas and in the prevention of relapsing lesions. METHOD: Searches on databases MedLine and LILACS were carried out between March and June of 2011 to select studies in which endoscopy was used in the management of cholesteatomas. RESULTS: Three studies comparing surgery aided by endoscopy and surgery performed with the aid of a microscope met the inclusion criteria. CONCLUSION: Endoscopy has positively impacted the management of cholesteatomas and should be used in cholesteatoma surgery. PMID- 23929155 TI - Applicability of the P300 frequency pattern test to assess auditory processing. AB - Temporal ordering and auditory attention are important skills in information processing, being evaluated by a behavioral test, as the frequency pattern test (FPT) in temporal ordering (TO) and electrophysiological testing, as the P300 in auditory attention. OBJECTIVE: To analyze the applicability of FPT and P300 as testing for auditory processing. METHOD: We performed an integrative literature review, with papers that met the inclusion criteria, using the MedLine, LILACS and SciELO databases, with the keywords: hearing attention, P300 evoked potential, P300 and electrophysiology, temporal ordering, processing and FPT. We found 13 papers concerning the use of the TPF and 16 regarding the use of P300. RESULTS: The TPF was the most used test in the evaluation of TO, presented in a diotic way in individuals with language disorders, musicians, blind people, rural workers and different age groups. The P300 is used in the frequency of 1000 Hz in the frequent stimulus and 2000 Hz for the rare stimulus, applicable in individuals of both genders, different age groups, and in patients with Down syndrome, liver cirrhosis, AIDS and Sleep Apnea Syndrome. CONCLUSION: The FPT and P300 are efficient instruments used to assess the intended skills. PMID- 23929156 TI - Unusual congenital malformation of the larynx. PMID- 23929157 TI - Unilateral hearing loss: CROS fitting. PMID- 23929158 TI - Endovascular treatment of a linguofacial trunk pseudoaneurysm after tonsillectomy. PMID- 23929159 TI - Parapharyngeal space emphysema by temporal bone fracture resulting from mandibular trauma. PMID- 23929160 TI - [Hydroxyethyl starch: Statement of the Presidents of DGAI and the BDA and the President of the DAAF]. PMID- 23929162 TI - [Propofol up2date]. AB - Propofol is a common hypnotic agent in anaesthesiology and intensive care medicine and for procedural sedation as well. Despite the intensive usage the full potential, pharmacokinetic and -dynamic abilities, interactions and side effects of the substance may not be realized by all providers. Additionally there is dispute and unwarranted myth about the substance. Propofol is a highly potent hypnotic with a wide range of (un)desired effects. This article is reviewing the diversity of the substance in clinical practice. PMID- 23929163 TI - [Hemostasis and antifibrinolytic therapy in major pediatric surgery]. AB - More than 30 years ago the pioneering work of Andrew and co-workers showed that the coagulation system of children is different than from adult. They have introduced the term of "developmental hemostasis" to describe this phenomenon. They were able to show that the concentration of coagulation factors and inhibitors are age-dependent and therefore reference limits from adult practice cannot be transferred to children one to one. Numerous studies showed that the perioperative loss of blood, and thus the use of homologous blood could be limited by administering antifibrinolytic substances such as aprotinin. Other antifibrinolytics acting substances like Epsilon-aminocaproic acid (EACA) or tranexamic acid (TXA) tended to be misfits in routine clinical practice. In 2006, the publication of a retrospective study carried out by Mangano et al, in which considerable safety concerns were expressed with regard to aprotinin led to a significant rethinking of its clinical use. Two years later the results of the BART (Blood Conservation using antifibrinolytics in a Randomized Trial) study confirmed that there was an increased postoperative mortality associated with the use of aprotinin compared to TXA and EACA. In a few adult studies so far tranexamic acid was found to be comparably as effective as aprotinin. Although TXA is a long known drug available on the market for more than 50 years, the studies connecting factors of indication, dosage regimen and safety are limited especially in children and infants. This article highlights the differences in the coagulation system in children compared to adult as well as indication, dosage regimens and possible side effects of antifibrinolytic agents in children. PMID- 23929164 TI - [Emergency medicine interventions for psycho-social crisis]. AB - Psycho-social crisis intervention has emerged to be a routine treatment application in the pre-hospital emergency medical system in Germany. It is applied to both patients with psychiatric disorders and in psycho-social crises. For the latter, a psycho-physiological reaction is typical that can be treated with the BELLA concept. Psycho-social crisis intervention for the emergency physician must be regarded as psychological first-aid and is characterised by an immediate start, a limited time frame, consideration of security aspects, flexibility and a determination to pre-set goals and their achievements. We recommend to adequately document this complex service. PMID- 23929165 TI - [Pssst ... AINS Secrets! - Today in ophthalmology]. PMID- 23929166 TI - [The Helsinki Declaration for Patient Safety in Anaesthesiology - Post operative care including pain management]. AB - Primary aspects of post operative care should include decisive and adequate treatment of pain. Accordingly, schemes based on international guidelines and in consensus with other departments of the university hospital were developed. Successful therapy includes resolute action on three levels: Instruction of physicians, including supervision. standardized approach based on a readily available algorithm. adherence to fundamental implications of pain therapy such as pain assessment, repeated consultations and observation of complications. Based on this concept, patient safety in anesthesia can be increased. PMID- 23929167 TI - [Anesthesia in urology - Current aspects and developments]. PMID- 23929168 TI - [Status quo in radical prostate surgery]. AB - Radical prostatectomy (RP) is a treatment option with an excellent cure rate in patients with localized prostate cancer but is accompanied by increased side effects. Particularly laparoscopic techniques developed in the last decade and are widespread. The operation techniques (retropubic(RRP), laparoscopic (LRP) and robot assisted laparoscopic (RALP) radical prostatectomy) and the comparative literature available are presented. RALP shows less blood loss compared to RRP and a lower transfusion rate compared to RRP and LRP. RALP may obtain better 12 months continence and potency rates. However, due to short follow-up and methodic weaknesses no conclusions can be drawn at this time. At present RALP seems not to be usable in an economically reasonable way. RRP, LRP and RALP show similar oncologic outcomes and comparable side effects. RP is the gold standard in the treatment of localized prostate cancer. PMID- 23929169 TI - [Anaesthesia for urological surgery - Anaesthesia for robotic assisted prostatectomies]. AB - Because of excellent results, high patient satisfaction, and extraordinary surgical conditions robotic assisted prostatectomies have found a wide spread acceptance. Trendelenburg positioning, CO2-Insufflation, and installation of the robot system cause moderate hemodynamic and respiratory changes. Respiration can be compromised by significantly reduced pulmonary compliance during surgery and a marked CO2 load. Therefore, arterial blood gas controls during surgery can be recommended. Over hours edema of head and neck including the upper airways and an increase of the intraocular pressure can develop. There are no restrictions in the choice of the anesthetics. Careful positioning of the patient and critical intravenous fluid management are important determinants of a successful anesthetic management. PMID- 23929170 TI - [Current strategies to minimize of blood loss during radical prostatectomy]. AB - Prostate cancer is a frequently diagnosed cancer in men with a high incidence. Despite enhancements of surgical techniques in prostatectomyperioperative blood loss is still the most frequent complication. Controlled hypotension (MAP 60 70mmHg) consisting of thoracal epidural anaesthesia und restrictive fluid management is a safe method to minimize blood loss. 25 degrees Trendelenburg position supports the multimodal treatment of controlled hypotension. Tranexamic acid is a safe drug to treat hyperfibrinolysis during prostate resection. PMID- 23929174 TI - C-QUALITY: cost and quality-of-life pharmacoeconomic analysis of antidepressants in major depressive disorder in Italy. AB - INTRODUCTION: Major depressive disorder (MDD) is a common and disabling condition across the world. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) are the most commonly used antidepressants. The objective of this study was to assess the cost-effectiveness [? per quality-adjusted life year (QALY)] of all SSRIs and all SNRIs for the treatment of MDD in Italy. METHODS: A decision analytic model was adapted from the Swedish Dental and Pharmaceutical Benefits agency model to reflect current clinical practice in the treatment of MDD in the largest Italian regions. This adaptation was possible thanks to the collaboration of an expert panel of Italian psychiatrists and health economists. The model evaluated patients with a first diagnosis of MDD and initiating an SSRI or an SNRI for the first time. The time horizon was 12 months. Efficacy and utility data for the model were retrieved from the literature and validated by the expert panel. Local data were considered for resource utilization and for treatment costs based on each regional health service perspective. Population-weighted regional data were used to define a national model. Scenario simulations, one-way sensitivity analyses, and Monte Carlo simulations were performed to test the robustness of the model. RESULTS: The base case analysis showed that escitalopram was associated with a lower total cost (? 1,562) and a larger health gain (QALYs) at 1 year (0.732) per patient and dominated the other treatment strategies since more QALYs were achieved at a lower total cost. Sensitivity analyses support the robustness of the model. CONCLUSION: The results indicate that escitalopram is the most cost-effective pharmacological treatment strategy for the Italian health service compared with other SSRIs and all SNRIs used in the first-line treatment of MDD. PMID- 23929175 TI - The hotel study: multimorbidity in a community sample living in marginal housing. AB - OBJECTIVE: The health of people living in marginal housing is not well characterized, particularly from the perspective of multimorbid illness. The authors investigated this population in a community sample. METHOD: A prospective community sample (N=293) of adults living in single-room occupancy hotels was followed for a median of 23.7 months. Assessment included psychiatric and neurological evaluation, multimodal MRI, and viral testing. RESULTS: Previous homelessness was described in 66.6% of participants. Fifteen deaths occurred during 552 person-years of follow-up. The standardized mortality ratio was 4.83 (95% CI=2.91-8.01). Substance dependence was ubiquitous (95.2%), with 61.7% injection drug use. Psychosis was the most common mental illness (47.4%). A neurological disorder was present in 45.8% of participants, with definite MRI findings in 28.0%. HIV serology was positive in 18.4% of participants, and hepatitis C virus serology in 70.3%. The median number of multimorbid illnesses (from a list of 12) was three. Burden of multimorbidity was significantly correlated with lower role functioning score. Comorbid addiction or physical illness significantly decreased the likelihood of treatment for psychosis but not the likelihood of treatment for opioid dependence or HIV disease. Participants who died during follow-up appeared to have profiles of multimorbidity similar to those of the overall sample. CONCLUSIONS: This marginally housed cohort had greater than expected mortality and high levels of multimorbidity with adverse associations with role function and likelihood of treatment for psychosis. These findings may guide the development of effective health care delivery in the setting of marginal housing. PMID- 23929176 TI - Epidemiological surveillance of leishmaniasis in the European Union: operational and research challenges. PMID- 23929177 TI - Re-emergence of leishmaniasis in Spain: community outbreak in Madrid, Spain, 2009 to 2012. AB - Since July 2009, there has been a community outbreak of leishmaniasis in the south-west area of the Madrid autonomous community, Spain, affecting residents from four towns that are geographically close together and share extensive park areas. As of December 2012, 446 cases were reported (6 in 2009, 97 in 2010, 196 in 2011 and 147 in 2012), a mean incidence rate of 22.2 per 100,000 inhabitants during July 2009 and December 2012. The mean age was 44 years (range: 2 months to 95 years); 61.0% were male. A total of 68 (15.2%) had immunosuppressive conditions; 160 (35.9%) had visceral leishmaniasis and 286 (64.1%) cutaneous. A total of 421 (94.4%) cases were confirmed. Leishmania infantum was identified as the agent. Monitoring revealed high densities of the vector Phlebotomus perniciosus. The surveillance system for canine leishmaniasis did not detect any increase in prevalence during the period. Environmental control measures have been taken, such as improvements in sanitation and disinsection in the risk areas and control of the overpopulation of Leporidae, as xenodiagnosis studies have shown that hares play a role as active reservoirs. This is the largest reported community outbreak of leishmaniasis in Europe. The discovery of the new reservoir stands out in the multifactorial aetiology of the outbreak. Epidemiological research and environmental intervention measures are continuing. PMID- 23929178 TI - Imported leishmaniasis in the Netherlands from 2005 to 2012: epidemiology, diagnostic techniques and sequence-based species typing from 195 patients. AB - Leishmaniasis is an imported disease in the Netherlands. We report data for the period between 2005 and 2012, on clinical presentation, country where leishmaniasis was acquired, and causative species, for 195 civilian and military patients who had travelled abroad. Most patients were affected by cutaneous leishmaniasis (CL) (n=185 patients), while visceral leishmaniasis (VL) (n=8 patients) and mucocutaneous leishmaniasis (n=2 patients) were less frequently observed. All VL patients had been infected in Europe. CL was mainly acquired in Afghanistan, Surinam, Morocco and Spain. The majority of CL patients consisted of military personnel (55%, 102/185), 78 of whom had been infected during an outbreak in Afghanistan. Parasitological diagnosis was made by a combination of polymerase chain reaction (PCR), microscopy and culture. Compared to a standard of parasitological proof by any method other than the one under consideration, sensitivities of the individual methods ranged from 73% to 98%. Microscopy was least sensitive, but is fast and cheap. Mini-exon repeat PCR combines high sensitivity and specificity, and allows differentiation between species by sequencing of the PCR product. Eight different species or species complexes were identified, allowing species-specific therapy. Four patients proved infected with Leishmania naiffi, a hitherto rarely described cause of leishmaniasis. In comparison to previous decennia, an increase in cutaneous leishmaniasis was observed in our hospital, both in civilian and military patients who had travelled abroad. This calls for increased awareness among clinicians, availability of diagnostic tests and species-specific treatment guidelines in non endemic countries. PMID- 23929179 TI - Molecular typing of Leishmania infantum isolates from a leishmaniasis outbreak in Madrid, Spain, 2009 to 2012. AB - Leishmaniasis is endemic in south-west Europe. Recent data point to the spread and (re-)emergence of this disease in previously endemic and non-endemic European countries. A recent example is the urban community outbreak of cutaneous and visceral leishmaniasis in the south-west of Madrid autonomous community, Spain, which began on 1 July 2009. A total of 446 cases associated to this outbreak were reported up to 31 December 2012. We show molecular typing data for 73 Leishmania infantum isolates obtained from January 2008 to July 2012 from different areas of Madrid, including those affected by the outbreak. Seven different genotypes were identified by combining data from two targets: the ribosomal internal transcribed spacers (ITS)-1 and -2 and the haspb (k26) gene. The results contribute to a better understanding of the parasite population circulating in the region, and indicate that most of the outbreak-associated isolates (22/31) were infected by parasites with the same combined genotype. Additional data from 82 L. infantum isolates typed as either MON-1 or MON-24 by isoenzyme analysis indicate that far from concluding that the outbreak was caused by a 'new' emerging genotype, further molecular typing-based surveillance studies are required to better understand the epidemiology of leishmaniasis in the region. PMID- 23929180 TI - Leishmania infantum in free-ranging hares, Spain, 2004-2010. AB - Iberian hares (Lepus granatensis) were recently deemed responsible for an outbreak of human leishmaniasis affecting metropolitan Madrid, Spain. However, the reservoir potential of hares in Europe is poorly known. We report a retrospective survey on Leishmania infantum, the causal agent of zoonotic endemic leishmaniasis in the Mediterranean basin, infection status of Iberian, European (Le. europaeus) and Broom (Le. castroviejoi) hares in Spain. Spleen samples from 94 hares were tested by polymerase chain reaction. Sequencing and restriction fragment length polymorphism (RFLP) assays were performed on positive samples and RFLP patterns compared with those of strains reported in the scientific literature. DNA prevalence in hare spleen samples was 43.6% (95% confidence interval: 33.6-53.6). In all six regions studied at least one positive sample was found. RFLP revealed existence of specific hare strains of L. infantum differing from those reported in wild carnivores in Spain. The widespread presence of L. infantum in the most abundant Spanish hare species and the recent evidence of the ability of naturally infected hares to transmit the pathogen to Phlebotomus perniciosus, its main vector in the western Mediterranean, suggest that hares may have an unexpected role in the epidemiology of L. infantum in Spain. PMID- 23929181 TI - Heat-shock protein 70 gene sequencing for Leishmania species typing in European tropical infectious disease clinics. AB - We describe Leishmania species determination on clinical samples on the basis of partial sequencing of the heat-shock protein 70 gene (hsp70), without the need for parasite isolation. The method is especially suited for use in non-endemic infectious disease clinics dealing with relatively few cases on an annual basis, for which no fast high throughput diagnostic tests are needed. We show that the results obtained from this gene are in nearly perfect agreement with those from multilocus enzyme electrophoresis, which is still considered by many clinicians and the World Health Organization (WHO) as the gold standard in Leishmania species typing. Currently, 203 sequences are available that cover the entire hsp70 gene region analysed here, originating from a total of 41 leishmaniasis endemic countries, and representing 15 species and sub-species causing human disease. We also provide a detailed laboratory protocol that includes a step-by step procedure of the typing methodology, to facilitate implementation in diagnostic laboratories. PMID- 23929182 TI - Leishmaniasis in the era of tumor necrosis factor alpha antagonist therapy--a research agenda for Europe. AB - A number of published case reports suggest an association of tumor necrosis factor (TNF) alpha antagonist use and manifest leishmaniasis. Despite increasing popularity of antagonising TNF alpha for the treatment of autoimmune disorders, systematic research on the risk of opportunistic leishmaniasis in patients receiving these drugs is lacking. This perspective identifies areas of uncertainty regarding the safety profile of TNF alpha antagonist drugs and their clinical use in patients at risk of leishmaniasis. Then, we reflect on how current pharmacovigilance activities in Europe could be enhanced to help reduce these uncertainties. Our aim is to stimulate a debate about this important drug safety issue with potential consequences for patients receiving TNF alpha antagonists living in or travelling to areas endemic for leishmaniasis. PMID- 23929183 TI - The role of indigenous phlebotomine sandflies and mammals in the spreading of leishmaniasis agents in the Mediterranean region. AB - An updated view of the establishment and spread of the leishmaniases in Europe is presented, mostly with respect to newly emerging and re-emerging foci and the incrimination of neglected as well as new reservoir hosts. At the same time, a concept of specific versus permissive vectors reassesses the potential role of various sandfly species in Leishmania transmission and considers the risk of introduction of exotic Leishmania species in Europe. The leishmaniases are dynamic diseases and the circumstances of transmission are continually changing in relation to environmental, demographic and human behavioural factors. Changes in the habitat of the natural hosts and vectors, immunosuppressive conditions (like infection with human immunodeficiency virus (HIV) or organ transplantation associated therapies in humans) and the consequences of war, all contribute to the transformation of the epidemiology of leishmaniasis. Such changes should be considered when studying the spread of the disease throughout Europe for targeted control measures to safeguard public health. PMID- 23929184 TI - LeishMan: harmonising diagnostic and clinical management of leishmaniasis in Europe. PMID- 23929186 TI - Letter to the editor, reply to "commentary on meta-analysis of prospective randomized studies comparing single-incision laparoscopic cholecystectomy (SILC) and conventional multiport laparoscopic cholecystectomy (CMLC)" by Pisanu et al. (J Gastrointest Surg 2012; 16:1790-1801). PMID- 23929187 TI - Laparoscopic intussuscepting pancreaticojejunostomy. AB - Perhaps the greatest barrier to adoption of laparoscopic pancreaticoduodenectomy by experienced pancreatic surgeons is the technical challenge of constructing the pancreaticojejunostomy (PJ). The authors present a less demanding PJ technique they have developed that creates an end-to-end intussuscepting anastomosis using a running monofilament suture. This method reduces technical complexity and operative time while producing acceptably comparable outcomes. PMID- 23929188 TI - Irreversible electroporation of locally advanced pancreatic head adenocarcinoma. AB - Irreversible electroporation of locally advanced pancreatic adenocarcinoma has been used to palliate appropriate patients with locally advanced pancreatic adenocarcinoma. The setting was at a university tertiary care center. Subjects are patients with locally advanced pancreatic adenocarcinoma who have undergone appropriate induction chemotherapy for at least 3 to 4 months in duration. Technique of open irreversible electroporation of locally advanced pancreatic adenocarcinoma is described. The technique of open irreversible electroporation with continuous intraoperative ultrasound imaging and consideration of intraoperative navigational system is described. Irreversible electroporation of locally advanced pancreatic adenocarcinoma is feasible for locally advanced unresectable pancreatic cancer. PMID- 23929189 TI - Detecting orbital angular momentum through division-of-amplitude interference with a circular plasmonic lens. AB - We demonstrate a novel detection scheme for the orbital angular momentum (OAM) of light using circular plasmonic lens. Owing to a division-of-amplitude interference phenomenon between the surface plasmon waves and directly transmitted light, specific intensity distributions are formed near the plasmonic lens surface under different OAM excitations. Due to different phase behaviors of the evanescent surface plasmon wave and the direct transmission, interference patterns rotate as the observation plane moves away from the lens surface. The rotation direction is a direct measure of the sign of OAM, while the amount of rotation is linked to the absolute value of the OAM. This OAM detection scheme is validated experimentally and numerically. Analytical expressions are derived to provide insights and explanations of this detection scheme. This work forms the basis for the realization of a compact and integrated OAM detection architect that may significantly benefit optical information processing with OAM states. PMID- 23929190 TI - Review of stationary phases for microelectromechanical systems in gas chromatography: feasibility and separations. AB - This review covers the recent development of stationary phases for chip-based gas chromatography (GC). Portable systems for rapid and reliable analysis are urgently needed. One way to achieve this is to miniaturize the entire analysis. Because the column is the central component of the GC system and determines the feasibility and quality of separation, this review focuses on stationary phases reported in the literature and their use in different fields during the last two decades, with emphasis on different methods for introducing the stationary phase into the GC column. PMID- 23929192 TI - [Not Available]. PMID- 23929191 TI - Fast quantification of amino acids by microchip electrophoresis-mass spectrometry. AB - A fast microchip electrophoresis-nano-electrospray ionization-mass spectrometric method (MCE-nanoESI-MS) was developed for analysis of amino acids in biological samples. A glass/poly(dimethylsiloxane) hybrid microchip with a monolithic nanoESI emitter was used in the platform. The proposed MCE-nanoESI-MS analytical method showed high separation efficiency for amino acids. Baseline separation of an amino acid mixture containing Lys, Arg, Val, Tyr, and Glu was completed within 120 s with theoretical plate numbers of >7,500. The method was applied to study cellular release of excitatory amino acids (i.e., aspartic acid (Asp) and glutamic acid (Glu)) under chemical stimulations. Linear calibration curves were obtained for both Asp and Glu in a concentration range from 1.00 to 150.0 MUM. Limits of detection were found to be 0.37 MUM for Asp and 0.33 MUM for Glu (S/N = 3). Assay repeatability (relative standard deviation, n = 6) was 4.2 and 4.5%, for Asp and Glu at 5.0 MUM, respectively. In the study of cellular release, PC-12 nerve cells were incubated with alcohol at various concentrations for 1 h. Both extra- and intracellular levels of Asp and Glu were measured by the proposed method. The results clearly indicated that ethanol promoted the release of both Asp and Glu from the cells. PMID- 23929194 TI - The first enantiopure lanthanoid cryptate. AB - The first enantiomerically pure 2,2'-bipyridine-based cryptand is reported. Complexation of this macrobicyclic ligand with the trivalent lanthanoid cations Yb and Lu produces enantiomerically and diastereomerically pure cryptates in solution. The Yb cryptate shows near-IR photoluminescence with lifetimes of up to tau = 29.8 MUs in CD3OD. PMID- 23929195 TI - [Gender identity disorders: what the gynecologist must know about transsexualism]. PMID- 23929193 TI - [Gender aspects of malnutrition and associated sequelae. Prevention and therapy]. AB - Malnutrition is related to a range of secondary complications. The prevalence of many of these sequelae is higher in elderly women than in men, thus resulting in a higher level of impairment and reduced quality of life. Multiple factors lead to the development of malnutrition and socioeconomic causes, such as poverty among the elderly and isolation, are more common in elderly women. The age associated loss of muscle mass is more pronounced in women than in men and the risk of developing sarcopenia and frailty is increased. The prevalence of sarcopenic obesity is higher in women than in men. Malnutrition increases the risk of osteoporosis and about 80 % of all osteoporosis patients are women. Furthermore, low serum levels of vitamin D correlate more closely to a poorer cognitive outcome in elderly women than they do in men. The prevention, early diagnosis and therapy of malnutrition is of great clinical importance, particularly to preserve physical functional capacity and thus quality of life in elderly women. PMID- 23929196 TI - Accuracy of sonography and hysteroscopy in the diagnosis of premalignant and malignant polyps in postmenopausal women. AB - PURPOSE: To evaluate the accuracy of sonographic endometrial thickness and hysteroscopic characteristics in predicting malignancy in postmenopausal women undergoing surgical resection of endometrial polyps. METHODS: Five hundred twenty one (521) postmenopausal women undergoing hysteroscopic resection of endometrial polyps between January 1998 and December 2008 were studied. For each value of sonographic endometrial thickness and polyp size on hysteroscopy, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated in relation to the histologic diagnosis of malignancy. The best values of sensitivity and specificity for the diagnosis of malignancy were determined by the Receiver Operating Characteristic (ROC) curve. RESULTS: Histologic diagnosis identified the presence of premalignancy or malignancy in 4.1% of cases. Sonographic measurement revealed a greater endometrial thickness in cases of malignant polyps when compared to benign and premalignant polyps. On surgical hysteroscopy, malignant endometrial polyps were also larger. An endometrial thickness of 13 mm showed a sensitivity of 69.6%, specificity of 68.5%, PPV of 9.3%, and NPV of 98% in predicting malignancy in endometrial polyps. Polyp measurement by hysteroscopy showed that for polyps 30 mm in size, the sensitivity was 47.8%, specificity was 66.1%, PPV was 6.1%, and NPV was 96.5% for predicting cancer. CONCLUSIONS: Sonographic endometrial thickness showed a higher level of accuracy than hysteroscopic measurement in predicting malignancy in endometrial polyps. Despite this, both techniques showed low accuracy for predicting malignancy in endometrial polyps in postmenopausal women. In suspected cases, histologic evaluation is necessary to exclude malignancy. PMID- 23929197 TI - [Clinical manifestations, biochemical, ultrasonographic and metabolic of polycystic ovary syndrome in adolescents]. AB - PURPOSE: To evaluate the clinical, ultrasonographic, biochemical and metabolic alterations of adolescents with polycystic ovary syndrome (PCOS). METHODS: Retrospective observational study conducted on 44 adolescents aged 12 to 19 years, diagnosed with PCOS according to the Rotterdam Consensus. Metabolic changes were assessed according to the recommendations of the International Diabetes Federation, considering: waist circumference (WC) >90th percentile (10 15 years of age) or >80 cm (age >16 years), fasting glucose >100 mg/dL, triglycerides >150 mg/dL, HDL <40 mg/dL, and blood pressure >Hg 130/85 mm. RESULTS: Mean age was 16.7 +/- 2.2 years and age at menarche was 11.8 +/- 1.4 years. The menstrual irregularity most frequently observed was amenorrhea (72.7%) followed by oligomenorrhea (27.3%); hirsutism was observed in 86.4% and acne in 56.8%. Polycystic ovaries were observed by ultrasound only in 27.3%. Mean BMI was 30.3 +/- 6.6 kg/m2. According to BMI, 52.3% of adolescents were obese, 13.6% were overweight and 6.8% had a healthy weight. Increased waist circumference (63.6%, 28/44) and the reduction of HDL-C (34.1%, 15/44) were the metabolic changes most frequently observed. Increased triglycerides were observed in 27.3% (12/44) and increased blood pressure and impaired fasting glucose were found in 9.1% (4/44) and 4.5% (2/44) of cases, respectively. Acanthosis nigricans was observed in 52.3% and insulin resistance in 62.8% of the adolescents with PCOS. Metabolic syndrome was identified in six children (13.6%), all of them obese or overweight. CONCLUSION: In the adolescents with PCOS studied here, menstrual irregularity and hirsutism were the most common clinical manifestations, while the sonographic findings consistent with polycystic ovaries were less prevalent. Obesity associated with insulin resistance predisposes these adolescents to a higher frequency of metabolic disorders. PMID- 23929198 TI - [Stress of men and women seeking treatment for infertility]. AB - PURPOSE: To evaluate the level of stress in men and women seeking treatment for infertility and to identify the associated variables. METHODS: A cross-sectional study with 101 men and 101 women consulting for the first time at the Human Reproduction Unit. Participants completed the Brazilian version of the Fertility Problem Inventory (FPI) based on four domains: "social relationships", "life without children"; "marital relationship/sexual" and "maternity/paternity" and a structured questionnaire with socioeconomic and reproductive variables. Bivariate analysis was performed using the Chi-square and Fisher exact tests, considering p<0.05. Afterwards the multivariate correspondence analysis was done with variables with p<0.20. RESULTS: Overall, the participants presented a high level of stress in all domains, except in the "life without children" domain. Multivariate analysis of correspondence showed that variables associated with a high level of stress in the "social relationships" domains were: to be a woman, to have the infertility problem, and to consider the quality of the marital relationship to be regular. In the "life without children" domain the variables that approached the high stress were: to be woman, age between 18 and 24 years, and to have the infertility problem. To be a man, to consider adoption, parents/in-laws and other people knowing about the difficulty to become pregnant, and to consider the quality of the marital relationship to be excellent were the variables associated with high level of stress in "marital/sexual relationship" domain. For "maternity/paternity" domain the variables associated were to be women, consider marital relationship quality regular, age between 25 and 35 years, be evangelical or protestant were the variables associated with a high level of stress. CONCLUSION: Men and women seeking treatment for infertility present a high level of stress and it can be suggested that psychosocial support is important and should be different for men and women. PMID- 23929199 TI - [Correlation between serum Ca-125 levels and surgical findings in women with symptoms evocative of endometriosis]. AB - PURPOSE: To correlate preoperative serum cancer antigen 125 (Ca-125) levels and laparoscopic findings in women with pelvic pain symptoms suggestive of endometriosis. METHODS: A retrospective study was conducted including all women with pelvic pain symptoms suspected for endometriosis operated by laparoscopy from January 2010 to March 2013. Patients were divided into 2 groups according to preoperative Ca-125 level (<35 U/mL and >= 35 U/mL). Subsequently, patients with ovarian endometriomas were excluded and a further analysis was conducted again according to the preoperative Ca-125 level. The following parameters were compared between groups: presence of ovarian endometrioma, presence and number of deep infiltrating endometriosis (DIE) lesions and American Society for Reproductive Medicine score. The statistical analysis was performed with Statistica version 8.0, using the Fisher exact test, Student's t-test and Mann Whitney test, when needed. A p value of <0.05 was considered to be statistically significant. RESULTS: During the study period, a total of 350 women were submitted to laparoscopic treatment of endometriosis. One hundred thirty patients (37.1%) had Ca-125 >= 35 U/mL and 220 (62.9%) had Ca-12<35 U/mL. The presence of ovarian endometriomas (47.7 versus 15.9%), DIE lesions (99.6 versus 78.6%) and intestinal DIE lesions (60 versus 30.9%) was more frequent, and the AFSr score was higher (34 versus 6) in the former group. In the second analysis, excluding the patients with ovarian endometriomas (>= 35 U/mL=68 patients and <35 U/mL=185 patients), similar results were obtained. The presence of DIE lesions (91.2 versus 76.2%), intestinal DIE lesions (63.2 versus 25.4%), bladder DIE lesions (20.6 versus 4.8%) and ureteral DIE lesions (7.3 versus 1.6%) was more frequent, and the AFSr score was higher (10 versus 6) in the Ca-125 >= 35 U/mL group. CONCLUSIONS: Investigation for DIE is mandatory in women with pelvic pain symptoms suggestive of endometriosis with a preoperative Ca-125 level >= 35 U/mL, especially when an ovarian endometrioma is not present. PMID- 23929200 TI - [Anthropometric characteristics of HIV/AIDS: pregnants and birth weight of theirs newborns]. AB - PURPOSE: To describe the anthropometric and pregnancy characteristics of women with HIV/AIDS, assisted by the Brazilian National Health System and the birth weight of their newborns. METHODS: The participants were women assisted at public STD/AIDS clinics of the Municipal Health system of Sao Paulo. The anthropometric characteristics were evaluated by trained nutritionists and other information was obtained from the medical records. For comparison of the survey data to those of the general population, secondary maternal and pregnancy data were obtained from live birth certificates through the Live Birth Information System. Continuous variables were summarized as mean and standard deviation or as the 25th, 50th and 75th percentiles and minimum and maximum values. The other variables are presented as percentages. Means were compared by the Student's t-test or Kruskal Wallis test depending on the fulfillment of assumptions, with the decision based on the p value. RESULTS: We found the presence of inadequate maternal nutrition according to triceps skinfold (60.9%). The BMI/gestational age showed the presence of underweight (18.5%) and overweight or obesity (40%). There was no association between disease status (HIV or AIDS) and weight, height, and lean or fat mass. Mean newborn birth weight was lower than the value for the general population without infection or disease. The results of this study indicate the need to develop adapted curves to allow a more accurate nutritional assessment of this population group. PMID- 23929201 TI - [Perinatal and pediatric follow up of children with increased nuchal translucency and normal karyotype]. AB - PURPOSE: To analyze the perinatal and pediatric outcome of fetuses that showed nuchal translucency (NT) above the 95th percentile (P95) and a normal karyotype in order to obtain data allowing better maternal prenatal counseling. METHODS: fetuses from a tertiary obstetric service with an NT above P95 and a normal karyotype were analyzed between 2005 and 2011. We analyzed gestational ultrasound follow-up, fetal and postnatal echocardiography (ECHO), weight, length and Apgar score at birth, and neuropsychomotor development by the Ages and Stages Questionnaire (ASQ) up to July 2012. RESULTS: During this period, there were 116 cases of nuchal translucency above the 95th percentile, and the fetal karyotype was determined in 79 of them (68%). Forty-three analyses were normal (54.4%) and 36 were altered (45.6%). Among the fetuses with a normal karyotype, one was miscarried at 15 weeks of gestation with Cantrel pentalogy and one died at 24 weeks with several structural abnormalities. There was one neonatal death of unknown cause and two cases of intraventricular communication (IVC) detected by fetal ECHO. Postnatal echocardiography revealed the persistence of IVC in one case and one case of atrial septal defect (ASD) and patent ductus arteriosus (PDA). Of the 40 surviving children, only 1 showed delayed speech development and another presented autism. The remaining cases resulted in normal neurodevelopment. CONCLUSION: During the monitoring of fetuses with increased NT and a normal karyotype, parents can be best advised that when a 2nd trimester morphological-echocardiography ultrasound study is normal, the probability of the child being born alive and well is high (93.5%). PMID- 23929202 TI - [Preference in the process of parturition: a comparison between primiparous and nulliparous women]. AB - PURPOSE: It was to describe and compare the preference of nulliparous and primiparous women for a particular mode of delivery and to determine whether the previous experience of childbirth influences the delivery process. METHODS: We conducted a prospective cross-sectional study. One-hundred interviews were held with 56 nulliparous and 44 primiparous women using previously prepared questionnaires. The quantitative and categorical data were evaluated by the chi square or Fisher's Exact Test. RESULTS: 60.7% of nulliparous women and 70.5% of primiparous women reported to prefer vaginal delivery. When analyzing the answers about receiving sufficient information about the type of delivery, the presence or absence of influence on the choice of route of delivery and the preferred route of delivery by the partner, there were no statistically significant differences between the two groups. The level of significance used for the tests was 0.05. CONCLUSIONS: This study permitted us to conclude that the previous experience of delivery does not influence the expectation of the delivery process or the choice for a specific mode of delivery. When choosing the route of delivery, women seek to ensure the health of mother and neonate, as well as to avoid the process of pain and suffering. PMID- 23929203 TI - Stereotaxic microinjection of viral vectors expressing Cre recombinase to study the role of target genes in cocaine conditioned place preference. AB - Microinjecting recombinant adenoassociated viral (rAAV) vectors expressing Cre recombinase into distinct mouse brain regions to selectively knockout genes of interest allows for enhanced temporally- and regionally-specific control of gene deletion, compared to existing methods. While conditional deletion can also be achieved by mating mice that express Cre recombinase under the control of specific gene promoters with mice carrying a floxed gene, stereotaxic microinjection allows for targeting of discrete brain areas at experimenter determined time points of interest. In the context of cocaine conditioned place preference, and other cocaine behavioral paradigms such as self-administration or psychomotor sensitization that can involve withdrawal, extinction and/or reinstatement phases, this technique is particularly useful in exploring the unique contribution of target genes to these distinct phases of behavioral models of cocaine-induced plasticity. Specifically, this technique allows for selective ablation of target genes during discrete phases of a behavior to test their contribution to the behavior across time. Ultimately, this understanding allows for more targeted therapeutics that are best able to address the most potent risk factors that present themselves during each phase of addictive behavior. PMID- 23929204 TI - Paralimbic cortical thickness in first-episode depression: evidence for trait related differences in mood regulation. AB - OBJECTIVE: Impaired mood regulation is a key deficit of major depressive disorder that is primarily mediated by an interaction between the paralimbic cortex (i.e., orbitofrontal, cingulate, insular, parahippocampal, and temporopolar cortices) and limbic regions. The authors investigated whether depressed patients and healthy comparison subjects have differences in cortical thickness in the paralimbic cortex and whether potential differences are evident only during a depressive state or are trait related. METHOD: Forty patients with a first episode of major depressive disorder participated: 20 medication-naive currently depressed patients and 20 medication-free recovered patients. The patients and 31 matched healthy comparison subjects underwent structural magnetic resonance imaging. Group differences in mean cortical thickness of the paralimbic cortex were measured by using FreeSurfer software, with adjustment for age, sex, and intracranial volume, and subgroup analyses were performed to assess state and trait effects. RESULTS: The medial orbitofrontal cortex was thinner in the depressed patients than in the comparison subjects. Greater thickness was present in the temporal pole and the caudal anterior and posterior cingulate cortex. All changes were trait related. CONCLUSIONS: The data provide evidence that even early in the course of depression brain regions involved in mood regulation show trait-related differences in cortical thickness. PMID- 23929206 TI - The prognostic value of transient ischemic dilatation with otherwise normal SPECT myocardial perfusion imaging: a cautionary note in patients with diabetes and coronary artery disease. AB - BACKGROUND: The prognostic implications of transient ischemic dilatation (TID) of the left ventricle with otherwise normal single-photon emission computed tomography myocardial perfusion imaging (MPI) remain controversial. Whether this finding may have prognostic implications only in high-risk populations, such as patients with diabetes or manifest coronary artery disease (CAD), is uncertain. METHODS: We conducted a prospective cohort study of 1,236 consecutive patients with normal (99m)Tc-sestamibi MPI, defined as normal perfusion (summed stress score = 0) and normal left ventricle volume and function. TID was defined as >2 standard deviations above the mean of patients with low likelihood of CAD. RESULTS: The study subjects were followed for 27 +/- 9 months. The 76 (6%) patients with TID had a greater rate of cardiac death or myocardial infarction (MI) [4 (5.3%) vs 11 (0.6%), P = .003] independent of covariates [hazard ratio = 6.4, P = .004]. This finding was entirely derived from the subgroup of 294 patients with diabetes or CAD [4 (13.3%) with TID vs 1 (0.4%) without TID, P = .001] independent of covariates. However, TID was not predictive of cardiac death or MI among the 941 patients without diabetes or CAD. Furthermore, TID was not predictive of coronary revascularization. CONCLUSIONS: This study confirms a benign prognosis of TID with otherwise normal MPI in patients without diabetes or CAD, but cautions against extending this conclusion to high-risk individuals, particularly those with diabetes or CAD. PMID- 23929207 TI - The changing face of graduate medical education: what is the impact on nuclear cardiology? PMID- 23929205 TI - Mechanistic links between aging and lung fibrosis. AB - Our understanding of the biology of aging has advanced significantly in recent years. This has resulted in the recent formulation of the "hallmarks of aging" that include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that results from the accumulation of scar tissue in the lungs of affected individuals. IPF is a disease of aging that most commonly affects human subjects older than 60 years of age. While progress has been made in elucidating key pathological processes in IPF, the relationship of these processes to those that occur during aging are not well defined. In this review, we explore existing and emerging paradigms in the pathogenesis of IPF in light of the recently defined hallmarks of aging. PMID- 23929208 TI - Nonclassical hedgehog-GLI signaling and its clinical implications. AB - Hedgehog (Hh) signaling regulates embryonic patterning and organ morphogenesis. It is also involved in regeneration and repair of tissues. Aberrant Hh pathway activation is a feature of many human malignancies. Classical Hh signaling is activated by Hh ligands that can signal in an autocrine or paracrine manner generating a tumor-stromal crosstalk. In contrast to canonical Hh signaling that culminates in the activation of GLI transcription factors, "noncanonical" Hh signaling does not involve GLI transcriptional activity. Several Hh pathway inhibitors have progressed to clinical trials, where the outcomes have not been very encouraging in many solid tumors. Here we discuss the likely role of "nonclassical" Hh-GLI signaling that is activated by growth factors and cytokines from the tumor and/or its microenvironment; these uncouple Hh signaling from the vital regulatory protein Smoothened, and result in the activation of GLI. While efforts are being made to target tumor-intrinsic Hh targets, it is imperative to acknowledge the role of the complex molecular networks and crosstalk between different components of the tumor microenvironment that can result in the emergence of resistance to conventional Hh therapy. These considerations have an important bearing on appreciating the need to mitigate the effects of tumor microenvironment to combat resistance to Hh inhibitors. PMID- 23929209 TI - [The new S2k AWMF guideline for the treatment of obstructive sialadenitis in commented short form]. AB - A new and interdisciplinary S2k AWMF guideline for the treatment of obstructive sialadenitis has been published. There have been several technical achievements, for instance in the field of ultrasonography, via sialendoscopy, or by MR sialography, that have increased the possibilities for diagnosis and treatment of patients with obstructive sialadenitis. In the past, the treatment of choice in case of unsuccessful medical treatment was a complete extirpation of the affected salivary gland. Nowadays, using a variety of modern treatment options (like sialendoscopy, or extracorporeal shock-waves lithotripsy sometimes combined with salivary duct incision), it is possible in most patients, especially in cases of sialolithiasis, to preserve the affected gland. A functional recovery after gland sparing surgery is described but more data is needed to finally evaluate the long time results. The new guideline describes all relevant steps to diagnose an obstructive sialadenitis and values all diagnostic tools critically. Finally, all recommendable therapy options are described and valued, too. PMID- 23929210 TI - [Management of T1a vocal fold carcinoma]. AB - About 2/3 of the larynx carcinomas affect the vocal chords. The main risk factor is smoking. Carcinomas in this localisation often arise from leukoplakias with dysplasia. A typical symptom is dysphonia. Arrest of vibration in microlaryngostroboscopy is a hint that a carcinoma could be present. Transoral laser cordectomy or radiotherapy show equivalent oncological results and results in quality of voice in the treatment of vocal fold carcinoma (T1a). As lymph node and distant metastasis are very rare, follow-up can concentrate on microlaryngoscopy. In case of a suspicious area on the vocal fold, biopsy of the affected tissue is needed to plan correct treatment. The prognosis of the T1 vocal chord carcinoma is quite good with a 5-year survival rate of almost 100%. PMID- 23929211 TI - [Gonosomal trisomy syndrome. Five case reports and review of literature]. AB - Gonosomal trisomies (GT) or so called sex chromosome trisomies (SCTs) are the most common chromosomal abnormalities in humans. The addition of extra X and/or Y chromosomes leads to neurodevelopmental differences, with increased risk for developmental delays, cognitive impairments, executive dysfunction, and behavioural and psychological disorders. Attentional problems, hyperactivity, autistic spectrum disorders and impulsivity are commonly described. Rates of language and communication problems are high in all 3 trisomies. Especially in cases of language impairment ENT specialists may be the main contact to rule out hearing loss. Here, we present 5 patients with SCT. In 2 boys and a young man, SCT was already known (47,XXY; 47,XYY; 47,XYY), in 2 cases we initiated genetic investigation (47,XXX; 47,XXY). Main symptom of the 4 children was a language delay; the young man reported had a history of mild language and motor coordination delay, too. Main complaints of the adult patient were problems with speech-in-noise perception. Furthermore 2 of the patients had mild facial dysmorphic features. The prognosis of the development in patients with SCT is variable, depending on severity of the manifestations and on quality and timing of treatment. Furthermore, in children with motor development/language delay a chromosomal analysis may be initiated at least at the request of the parents to clarify the etiology of developmental abnormalities. If the suspicion of hearing impairment as the cause of problems is not confirmed in a patient, ENT specialists should also consider SCA as a possible cause in the differential diagnosis. PMID- 23929212 TI - Noise induced oscillations and coherence resonance in a generic model of the nonisothermal chemical oscillator. AB - Oscillating chemical reactions are common in biological systems and they also occur in artificial non-biological systems. Generally, these reactions are subject to random fluctuations in environmental conditions which translate into fluctuations in the values of physical variables, for example, temperature. We formulate a mathematical model for a nonisothermal minimal chemical oscillator containing a single negative feedback loop and study numerically the effects of stochastic fluctuations in temperature in the absence of any deterministic limit cycle or periodic forcing. We show that noise in temperature can induce sustained limit cycle oscillations with a relatively narrow frequency distribution and some characteristic frequency. These properties differ significantly depending on the noise correlation. Here, we have explored white and colored (correlated) noise. A plot of the characteristic frequency of the noise induced oscillations as a function of the correlation exponent shows a maximum, therefore indicating the existence of autonomous stochastic resonance, i.e. coherence resonance. PMID- 23929213 TI - Circulating adiponectin levels and the risk of breast cancer: a meta-analysis. AB - Adiponectin is an important adipokine exclusively secreted from adipose tissue. Growing evidence suggests that adiponectin inhibits the growth of cancer cells and reduces cancer risk. Many studies have examined the association between circulating adiponectin levels and the risk of breast cancer. However, the results of numerous epidemiological studies have been inconsistent. The aim of the present study was to conduct a systematic review and a meta-analysis on the association between circulating adiponectin levels and the risk of breast cancer. PubMed, MEDLINE, EMBASE, and ISI Web of Science were searched to identify all observational studies that examined the relationship between circulating adiponectin and breast cancer. Standard mean difference (SMD) values and 95% confidence intervals (CIs) were estimated and pooled using the meta-analysis methodology. Summary effect estimates were derived using a random effects meta analysis model. The analysis included eight studies that met the study criteria and described the relationship between circulating adiponectin levels and breast cancer. A total of 1803 participants and 885 cases of breast cancer were included in this meta-analysis. Serum total adiponectin concentrations were lower in patients with breast cancer, with a pooled SMD of -0.39 MUg/ml (95% CI -0.618 to 0.161, P=0.001). However, adiponectin levels were not associated with the risk of breast cancer in premenopausal women [four studies, random effects SMD=0.02 MUg/ml (95% CI -0.164 to 0.204, P=0.829)]. These results collectively suggest that lower adiponectin levels are associated with a higher risk of breast cancer in postmenopausal women. PMID- 23929214 TI - Characterization of porous glass fiber-reinforced composite (FRC) implant structures: porosity and mechanical properties. AB - The aim of this study was to characterize the microstructure and mechanical properties of porous fiber-reinforced composites (FRC). Implants made of the FRC structures are intended for cranial applications. The FRC specimens were prepared by impregnating E-glass fiber sheet with non-resorbable bifunctional bis-phenyl glycidyl dimethacrylate and triethylene glycol dimethacrylate resin matrix. Four groups of porous FRC specimens were prepared with a different amount of resin matrix. Control group contained specimens of fibers, which were bound together with sizing only. Microstructure of the specimens was analyzed using a micro computed tomography (micro-CT) based method. Mechanical properties of the specimens were measured with a tensile test. The amount of resin matrix in the specimens had an effect on the microstructure. Total porosity was 59.5 % (median) in the group with the lowest resin content and 11.2 % (median) in the group with the highest resin content. In control group, total porosity was 94.2 % (median). Correlations with resin content were obtained for all micro-CT based parameters except TbPf. The tensile strength of the composites was 21.3 MPa (median) in the group with the highest resin content and 43.4 MPa (median) in the group with the highest resin content. The tensile strength in control group was 18.9 MPa (median). There were strong correlations between the tensile strength of the specimens and most of the micro-CT based parameters. This experiment suggests that porous FRC structures may have the potential for use in implants for cranial bone reconstructions, provided further relevant in vitro and in vivo tests are performed. PMID- 23929215 TI - BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms. AB - Small molecule inhibition of the BET family of proteins, which bind acetylated lysines within histones, has been shown to have a marked therapeutic benefit in pre-clinical models of mixed lineage leukemia (MLL) fusion protein-driven leukemias. Here, we report that I-BET151, a highly specific BET family bromodomain inhibitor, leads to growth inhibition in a human erythroleukemic (HEL) cell line as well as in erythroid precursors isolated from polycythemia vera patients. One of the genes most highly downregulated by I-BET151 was LMO2, an important oncogenic regulator of hematopoietic stem cell development and erythropoiesis. We previously reported that LMO2 transcription is dependent upon Janus kinase 2 (JAK2) kinase activity in HEL cells. Here, we show that the transcriptional changes induced by a JAK2 inhibitor (TG101209) and I-BET151 in HEL cells are significantly over-lapping, suggesting a common pathway of action. We generated JAK2 inhibitor resistant HEL cells and showed that these retain sensitivity to I-BET151. These data highlight I-BET151 as a potential alternative treatment against myeloproliferative neoplasms driven by constitutively active JAK2 kinase. PMID- 23929216 TI - Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis. PMID- 23929218 TI - Body-Mass Index and All-Cause Mortality in US Adults With and Without Diabetes. AB - BACKGROUND: Previous studies found normal weight compared to overweight/obese adults with type 2 diabetes had a higher mortality risk, and body-mass index (BMI)-mortality studies do not typically account for baseline diabetes status. OBJECTIVE: To determine if diabetes influences the BMI-mortality relationship. DESIGN: Using a prospective study design, we analyzed data from a nationally representative sample of US adults participating in the National Health Interview Survey from 1997 to 2002, and followed for mortality through 2006. PARTICIPANTS: Excluding those with heart disease or cancer, our final analytic sample included 74,710 (34,805 never smoker) adults. MAIN MEASURES: BMI was calculated from self reported height and weight. Diabetes status was based on self-reported diagnosis from a health professional. We used direct age standardization to calculate all cause mortality rates and adjusted Cox models for all-cause mortality hazard ratios by BMI quintile; this was done separately for adults with diabetes and without diabetes. KEY RESULTS: Among never smokers, mean age was 50.1 years and 43 % were men. Mean BMI was 27.4 kg/m(2), 26 % were obese, and 2,035 (5 %) reported diagnosed diabetes. After 9 years, there were 4,355 deaths (754 of 4,740 with diabetes; 3,601 of 69,970 without) among 74,710 participants, and 1,238 (247 of 2,035 with diabetes; 991 of 32,770 without) among 34,805 never smokers. We observed a qualitative interaction with diabetes on the BMI-mortality relationship (p = 0.002). Death rates were substantially higher among participants with diabetes compared to those without diabetes across all BMI quintiles. However, death rates in participants with diabetes fell with increasing BMI quintile, while rates followed a J-shaped curve among those without diabetes. In adjusted Cox models, BMI was positively associated with mortality in adults without diabetes, but inversely associated with mortality among participants with diabetes. CONCLUSIONS: Mortality increased with increasing BMI in adults without diabetes, but decreased with increasing BMI among their counterparts with diabetes. Future studies need to be better designed to answer the question of whether normal weight adults with diabetes have a higher risk of mortality, by minimizing the possibility of reverse causation. Future studies should also account for prevalent diabetes in all investigations of the BMI-mortality relationship. PMID- 23929220 TI - The long bone deformity of osteogenesis imperfecta III: analysis of structural changes carried out with scanning electron microscopic morphometry. AB - The wedges of the mid-diaphyseal osteotomies carried out to correct the femoral and/or tibial native deformity in type III osteogenesis imperfecta (OI III) were used to study the remodeling patterns and lamellar organization at the level of the major deformity. Histology and scanning electron microscopy (SEM) morphology showed abnormal cortical remodeling characterized by the failure to form a cylinder of compact bone with a regular marrow canal. Atypical, flattened, and large resorption lacunae with a wide resorption front on one side and systems of parallel lamellae on the opposite side were observed, resembling those formerly reported as drifting osteons. SEM morphometry documented a higher percentage of nonossified vascular/resorption area (44.3 %) in OI than in controls (13.6 %), a lower density of secondary osteons, and lower values for the parameters expressing the individual osteon size. The mean osteon total area, the mean central canal area, and the mean osteon bone area of two selected, randomized populations of secondary osteons were significantly higher (p < 0.001, p = 0.028, and p < 0.001, respectively) in control bones than in OI. The mean ossified matrix area was not significantly different, but the mean secondary osteon number and mean density were higher in controls (both p < 0.001). Osteon wedges were carried out to correct the native deformity of OI III and morphologic analysis suggested that the abnormal remodeling pattern (with "drifting osteons") may result from the altered load and tensile stresses on the deformed tubular bones. PMID- 23929219 TI - Sustainability of quality improvement following removal of pay-for-performance incentives. AB - BACKGROUND: Although pay-for-performance (P4P) has become a central strategy for improving quality in US healthcare, questions persist about the effectiveness of these programs. A key question is whether quality improvement that occurs as a result of P4P programs is sustainable, particularly if incentives are removed. OBJECTIVE: To investigate sustainability of performance levels following removal of performance-based incentives. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study that capitalized on a P4P program within the Veterans Health Administration (VA) that included adoption and subsequent removal of performance based incentives for selected inpatient quality measures. The study sample comprised 128 acute care VA hospitals where performance was assessed between 2004 and 2010. INTERVENTION: VA system managers set annual performance goals in consultation with clinical leaders, and report performance scores to medical centers on a quarterly basis. These scores inform performance-based incentives for facilities and their managers. Bonuses are distributed based on the attainment of these performance goals. MEASUREMENTS: Seven quality of care measures for acute coronary syndrome, heart failure, and pneumonia linked to performance-based incentives. RESULTS: Significant improvements in performance were observed for six of seven quality of care measures following adoption of performance-based incentives and were maintained up to the removal of the incentive; subsequently, the observed performance levels were sustained. LIMITATIONS: This is a quasi-experimental study without a comparison group; causal conclusions are limited. CONCLUSION: The maintenance of performance levels after removal of a performance-based incentive has implications for the implementation of Medicare's value-based purchasing initiative and other P4P programs. Additional research is needed to better understand human and system level factors that mediate sustainability of performance-based incentives. PMID- 23929217 TI - Integration of cytogenetic and molecular alterations in risk stratification of 318 patients with de novo non-M3 acute myeloid leukemia. AB - Conventionally, acute myeloid leukemia (AML) patients are categorized into good-, intermediate- and poor-risk groups according to cytogenetic changes. However, patients with intermediate-risk cytogenetics represent a largely heterogeneous population regarding treatment response and clinical outcome. In this study, we integrated cytogenetics and molecular mutations in the analysis of 318 patients with de novo non-M3 AML who received standard chemotherapy. According to the mutation status of eight genes, including NPM1, CEBPA, IDH2, RUNX1, WT1, ASXL1, DNMT3A and FLT3, that had prognostic significance, 229 patients with intermediate risk cytogenetics could be refinedly stratified into three groups with distinct prognosis (P<0.001); patients with good-risk genotypes had a favorable outcome (overall survival, OS, not reached) similar to those with good-risk cytogenetics, whereas those with poor-risk genotypes had an unfavorable prognosis (OS, 10 months) similar to those with poor-risk cytogenetics (OS, 13.5 months), and the remaining patients with other genotypes had an intermediate outcome (OS, 25 months). Integration of cytogenetic and molecular profiling could thus reduce the number of intermediate-risk AML patients from around three-fourth to one-fourth. In conclusion, integration of cytogenetic and molecular changes improves the prognostic stratification of AML patients, especially those with intermediate risk cytogenetics, and may lead to better decision on therapeutic strategy. PMID- 23929222 TI - Scanning-probe single-electron capacitance spectroscopy. AB - The integration of low-temperature scanning-probe techniques and single-electron capacitance spectroscopy represents a powerful tool to study the electronic quantum structure of small systems - including individual atomic dopants in semiconductors. Here we present a capacitance-based method, known as Subsurface Charge Accumulation (SCA) imaging, which is capable of resolving single-electron charging while achieving sufficient spatial resolution to image individual atomic dopants. The use of a capacitance technique enables observation of subsurface features, such as dopants buried many nanometers beneath the surface of a semiconductor material(1,2,3). In principle, this technique can be applied to any system to resolve electron motion below an insulating surface. As in other electric-field-sensitive scanned-probe techniques(4), the lateral spatial resolution of the measurement depends in part on the radius of curvature of the probe tip. Using tips with a small radius of curvature can enable spatial resolution of a few tens of nanometers. This fine spatial resolution allows investigations of small numbers (down to one) of subsurface dopants(1,2). The charge resolution depends greatly on the sensitivity of the charge detection circuitry; using high electron mobility transistors (HEMT) in such circuits at cryogenic temperatures enables a sensitivity of approximately 0.01 electrons/Hz(1/2) at 0.3 K(5). PMID- 23929221 TI - Detection and perceptual impact of side-to-side facial movement asymmetry. AB - IMPORTANCE: In this study, we examined whether specific facial movements have different time-delay detection thresholds, and to what extent such side-to-side facial movement asymmetry affects subjective ratings of movement naturalness. Ratings of dynamic asymmetry in experimentally manipulated video recordings demonstrate that there are different side-to-side time-delay thresholds for distinct regions of the face, with a strong inverse correlation between naturalness rating and the length-of-time delay. These findings will be helpful for counseling patients with unilateral facial paralysis and guide the design of neural interfaces for facial reanimation. OBJECTIVE: To determine the detection threshold of side-to-side facial movement timing asymmetry and measure its effect on perceived movement naturalness. DESIGN, SETTING, AND PARTICIPANTS: Videos of 5 symmetrical facial movements (eye blink, rapid eyebrow raising, slow eyebrow raising, smiling, and lip depression) were edited to introduce 6 levels of side to-side timing asymmetry, ranging from 33 to 267 milliseconds. Participants (N = 58) viewed video clips through an online survey service, indicating whether they noticed side-to-side asymmetry and judging movement naturalness on a 5-point scale. RESULTS: There was a significant difference among facial movements in asymmetry detection threshold. There was a strong correlation between naturalness ratings and amount of delay across movements (R = 0.823), with greater asymmetry being judged as progressively less natural. Blink was judged as less natural at 33, 67, 100, and 133 milliseconds of side-to-side delay compared with all other movements (P < .005). CONCLUSIONS AND RELEVANCE: Side-to-side asymmetry in blink timing is detected sooner and viewed as less natural compared with asymmetry of the eyebrow and lips. At 100 milliseconds of delay, nearly all movements are detected as asymmetric, although blink is judged as the least natural. These findings will help set timing goals for facial pacing technologies treating unilateral paralysis. LEVEL OF EVIDENCE: NA. PMID- 23929223 TI - SAD and the not-so-single photoreceptors. AB - Research in the last century has demonstrated that light is a critical regulator of physiology in animals. More recent research has exposed the influence of light on human behavior, including the phenomenon of seasonal affective disorder (SAD). Repeated studies have shown that light treatment is effective in this disorder. The molecular mechanism by which the body absorbs the light that has energizing and antidepressant effects is still uncertain. This review presents evidence regarding the role of rod and cone photoreceptors, as well as the role of recently discovered nonvisual neuronal melanopsin-containing photoreceptors. The authors discuss an evolutionary-based theoretical model of humoral phototransduction. This model postulates that tetrapyrrole pigments, including hemoglobin and bilirubin, are blood-borne photoreceptors, regulating gasotransmitters such as carbon monoxide when exposed to light in the eye. Recent studies in an animal model for seasonality provide data consistent with this model. Understanding the molecular mechanisms by which light affects physiology may guide the development of therapies for SAD and other pathologies of circadian and circannual regulation. PMID- 23929225 TI - Programmed functionalization of SURMOFs via liquid phase heteroepitaxial growth and post-synthetic modification. AB - Heterostructured surface mounted metal-organic frameworks (SURMOFs) [Cu2(NH2 bdc)2(dabco)] (B) on top of [Cu2(bdc)2(dabco)] (A) were deposited on pyridyl terminated Au covered QCM substrate using a step-by-step liquid phase epitaxial growth method. Sequentially, the pore size of the top layer [Cu2(NH2 bdc)2(dabco)] (B) was modified by targeting the installed amino moiety with tert butyl isothiocyanate (tBITC). The adsorption properties of the programmed functionalized SURMOFs studied using an environment controlled quartz crystal microbalance (QCM) instrument exhibited the possibility to achieve high selectivity and capacity by heteroepitaxial growth and post-synthetic modification. PMID- 23929224 TI - Antioxidant properties of aqueous and ethanolic extracts of tara (Caesalpinia spinosa) pods in vitro and in model food emulsions. AB - BACKGROUND: The successful replacement of some synthetic food antioxidants by safe natural antioxidants has fostered intensive search for new vegetable sources of antioxidants. In our study the phenol and flavonoid content of extracts of tara pods was determined. The antioxidant activity was also studied by three different analytical assays: the measurement of scavenging capacity against a radical ABTS+ , the oxygen radical absorbance capacity (ORAC) and the ferric reducing antioxidant power (FRAP). RESULTS: All analyzed samples showed a good antioxidant capacity, but the use of a solution of ethanol 75% in a 1 h ultrasonic process allowed achieving the greatest quantity of phenolics (0.464 mg gallic acid equivalent (GAE) g-1 dry weight (DW) ) and the highest antioxidant activity measured by the ABTS+ and ORAC methods (10.17 and 4.29 mmol L-1 Trolox equivalents (TE) g-1 DW, respectively). The best method for efficient extraction of flavonoids (3.08 mg catechin equivalent (CE) g-1 DW) was a 24 h maceration in cold water. Two extracts obtained with ethanol 75% and water were added to a model food system (oil-in-water emulsion) and the oxidative stability was studied during storage at 38 degrees C. Oxidation was monitored by determination of the peroxide value. The addition of 48 ug mL-1 ethanol extract to the emulsion delayed oxidation to the same extent as 17.8 ug mL-1 of Trolox, while water extract was only effective in the early stages of the oxidation process. CONCLUSION: The results of this study indicate that ethanolic tara extracts may be suitable for use in food, cosmetic and nutraceutical applications. PMID- 23929226 TI - Outbreak of NDM-1-producing Acinetobacter baumannii in France, January to May 2013. AB - We report the first outbreak of carbapenem-resistant NDM-1-producing Acinetobacter baumannii in Europe, in a French intensive-care unit in January to May 2013. The index patient was transferred from Algeria and led to the infection/colonisation of five additional patients. Concurrently, another imported case from Algeria was identified. The seven isolates were genetically indistinguishable, belonging to ST85. The bla(NDM-1) carbapenemase gene was part of the chromosomally located composite transposon Tn125. This report underscores the growing concern about the spread of NDM-1-producing A. baumannii in Europe. PMID- 23929227 TI - First report of IMI-1-producing colistin-resistant Enterobacter clinical isolate in Ireland, March 2013. AB - We report the first case in Ireland of an IMI-1 carbapenemase-producing Enterobacter asburiae, which was resistant to both colistin and fosfomycin. The circumstances under which this isolate was acquired were unclear. Several reports of IMI-producing Enterobacter spp. have emerged in recent years, and colistin resistance in Enterobacteriaceae is also increasingly reported. Laboratories should be aware of the unusual antibiograms of IMI-producing isolates. PMID- 23929228 TI - Intercontinental spread of OXA-48 beta-lactamase-producing Enterobacteriaceae over a 11-year period, 2001 to 2011. AB - OXA-48 beta-lactamase producers are emerging as an important threat mostly in the Mediterranean area. We report here the molecular epidemiology of a collection of OXA-48 beta-lactamase-positive enterobacterial isolates (n=107) recovered from European and north-African countries between January 2001 and December 2011. This collection included 67 Klebsiella pneumoniae, 24 Escherichia coli and 10 Enterobacter cloacae. Using the EUCAST breakpoints, ninety-eight isolates (91.6%) were of intermediate susceptibility or resistant to ertapenem, whereas 66% remained susceptible to imipenem. Seventy-five per cent of the isolates co produced an extended-spectrum beta-lactamase, most frequently CTX-M-15 (77.5%). Susceptibility testing to non-beta-lactam antibiotics showed that colistin, tigecycline, amikacin, and fosfomycin remain active against most of the isolates. Multilocus sequence typing indicated that the most common sequence types (ST) were ST101 and ST38 for K. pneumoniae and E. coli, respectively. The bla(OXA-48) gene was located on a 62 kb IncL/M plasmid in 92.5% of the isolates, indicating that a single plasmid was mainly responsible for the spread of that gene. In addition, this study identified multiple cases of importation of OXA-48 beta lactamase producers at least in Europe, and spread of OXA-48 beta-lactamase producers giving rise to an endemic situation, at least in France. PMID- 23929229 TI - Silent hepatitis E virus infection in Dutch blood donors, 2011 to 2012. AB - In Europe, the dynamics of endemic hepatitis E virus (HEV) infection remain enigmatic. We studied the presence of silent HEV infection among Dutch blood donors. Using donations collected throughout the Netherlands in 2011 and 2012, 40,176 donations were tested for HEV RNA in 459 pools of 48 or 480 donations. Deconstruction of the reactive pools identified 13 viraemic donors. In addition, 5,239 donors were tested for presence of anti-HEV IgG and IgM and for HEV RNA when IgM-positive. Of the 5,239 donations, 1,401 (27%) tested repeat-positive for HEV IgG, of which 49 (3.5%) also tested positive for anti-HEV IgM. Four of the HEV IgM-positive donors tested positive for HEV RNA. HEV IgG seroprevalence ranged from 13% among donors younger than 30 years to 43% in donors older than 60 years. The finding of 17 HEV RNA-positive donations among 45,415 donations corresponds to one HEV-positive blood donation per day in the Netherlands. For 16 of the 17 HEV RNA-positive donors, genotyping succeeded, revealing HEV genotype 3, which is circulating among Dutch pigs. Apparently, silent HEV infection is common in the Netherlands, which possibly applies to larger parts of Europe. PMID- 23929231 TI - Bovine papillomavirus: opening new trends for comparative pathology. AB - For many years, research on bovine papillomavirus (BPV) has contributed to the understanding of papillomavirus-induced pathology in humans and animals. The present review shows how recent studies on BPV keep providing evidence concerning key points in viral infection, such as the expression of viral proteins in lymphocytes and the occurrence of productive infections of the placenta. Studies on BPV-induced tumours also provide important information concerning the mechanisms of oncogenesis and immune evasion, as in the cases of connexin 43 down regulation with loss of intercellular gap junctions and Toll-like receptor 4 (TLR4) down-regulation in equine sarcoids. The biological functions of viral proteins are also being further clarified, as in the case of E2, which was recently shown to load BPV genomes into host chromosomes during the S phase, a process mediated by the ChlR1 protein. In the near future, the ongoing efforts to characterize and classify additional emerging BPV types are likely to broaden even further the possibilities for research. PMID- 23929232 TI - Development of real-time RT-PCR for detection of human metapneumovirus and genetic analysis of circulating strains (2009-2011) in Pune, India. AB - Human metapneumovirus (HMPV) is an important respiratory virus implicated in respiratory infections. The purpose of this study was to develop a one-step real time RT-PCR assay that can detect all four lineages of HMPV and to identify the HMPV lineages circulating in Pune, India. Conserved regions of the nucleoprotein gene were used to design real-time primers and a probe. A total of 224 clinical samples that were positive for different respiratory viruses (including 51 samples that were positive for HMPV) were tested using the real time RT-PCR assay, and the specificity of the assay was observed to be 100 %. Using in vitro synthesized RNA, the sensitivity of the assay was ascertained to be 100 copies of the target gene per reaction. Phylogenetic analysis of the nucleoprotein (N) and attachment glycoprotein (G) genes confirmed that this assay detected all lineages of HMPV. A2, B1 and B2 strains were observed during the study period. Our assay is highly sensitive and specific for all known lineages of HMPV, making it a valuable tool for rapid detection of the virus. A2 and B2 were the predominant subtypes circulating in Pune, Western India. PMID- 23929233 TI - Existence of feline morbillivirus infection in Japanese cat populations. AB - Feline morbillivirus (FmoPV) is a member of a new virus species that has only been found in the Hong Kong cat population. For the first time, however, we have now detected nucleotide sequences similar to FmoPV in samples from Japanese cat populations. The positive rates for urine and blood samples from Japanese cats were 6.1 % (5/82) and 10 % (1/10), respectively. These sequences are similar to the previously reported FmoPV, with 92-94 % identity, and substantially different from all other morbilliviruses. Phylogenetic analysis of the identified Japanese FmoPVs and other morbilliviruses demonstrated a pattern similar to those previously published for the FmoPV viruses isolated in Hong Kong. FmoPV RNA was also detected from formalin-fixed paraffin-embedded (FFPE) kidney tissues of cats with nephritis, with a positive rate of 40 % (4/10). By using nested-set primers based on the FmoPV sequence and RNA from FFPE tissues, we demonstrated the existence of FmoPV infection in Japanese cats and established the method for detection of the FmoPV RNA from kidney tissues prepared for pathology examinations, which is useful for studies on the pathogenicity of the virus. PMID- 23929234 TI - Specific biomolecule corona is associated with ring-shaped organization of silver nanoparticles in cells. AB - We correlate the localization of silver nanoparticles inside cells with respect to the cellular architecture with the molecular information in the vicinity of the particle surface by combining nanoscale 3D cryo-soft X-ray tomography (cryo SXT) with surface-enhanced Raman scattering (SERS). The interaction of the silver nanoparticle surface with small molecules and biopolymers was monitored by SERS in vitro over time in living cells. The spectra indicate a stable, time independent surface composition of silver nanoparticles, despite the changing environment in the endosomal structure. Cryo-SXT reveals a characteristic ring shaped organization of the silver nanoparticles in endosomes of different cell types. The ring-like structures inside the endosomes suggest a strong association among silver particles and with membrane structures. The comparison of the data with those obtained with gold nanoparticles suggests that the interactions between the nanoparticles and with the endosomal component are influenced by the molecular composition of the corona. PMID- 23929236 TI - [Early diagnosis of Alzheimer disease: the role of Positron Emission Tomography (PET)]. PMID- 23929237 TI - [Therapy of anxiety: pills or talking? Elderly mostly chose psychotherapy]. PMID- 23929238 TI - [Vaccination recommendations of the Commission for Pharmacotherapy of the German Society of Rheumatology]. PMID- 23929239 TI - [Vaccination in adult patients with chronic inflammatory rheumatic diseases]. AB - Patients with chronic inflammatory rheumatic diseases often have an intrinsic and therapy associated increased susceptibility to infections which substantially contributes to morbidity and mortality of the patients. A large proportion of these infections are preventable by vaccination. For this reason in 2005 the standing vaccination committee (STIKO) recommended for patients with immunosuppression vaccination against pneumococcus, influenza, Haemophilus influenza b and meningococcus in addition to standard vaccinations, independent of age. Every patient should therefore be informed about a possible increase in susceptibility to infections and the recommended prevention by vaccination before implementation of immunosuppressive therapy. PMID- 23929240 TI - [Common variable immunodeficiency: a clinical challenge]. AB - Common variable immunodeficiency (CVID) represents the most common clinically relevant form of primary immunodeficiency. This heterogeneous antibody deficiency syndrome is characterized not only by susceptibility to bacterial respiratory tract infections but displays additional signs of immune dysregulation, such as autoimmunity, chronic inflammation and lymphoproliferation in more than 30 % of the patients. Due to poor awareness the diagnosis is often delayed by 4-6 years. A close collaboration in patient care with a center specialized in primary immunodeficiency is recommended. Regular follow-up visits include assessment of adequate immunoglobulin replacement therapy and screening for manifestation of secondary complications. Regular substitution with intravenous or subcutaneous immunoglobulins has more or less normalized life expectancy of patients with isolated susceptibility to bacterial infections. Therefore, the current core task in the management of CVID patients is the elaboration of more effective and safer forms of prophylaxis and treatment of sequelae of immune dysregulation in the lungs, intestines and liver of affected patients. PMID- 23929241 TI - [Screening investigations during intensified immunosuppression in children and adolescents. Part 1]. AB - The increasing use of combination therapies, including disease-modifying antirheumatic drugs (DMARD) and biologicals has improved the outcome for children and adolescents in several rheumatic diseases. However, this strategy has increased the risk of drug-specific side-effects, such as an increased risk of infections. Furthermore, the underlying rheumatic disease itself often includes an increased risk of infections and some patients additionally present with immunological or organic comorbidities (e.g. complement deficiency and interstitial pulmonary disease) further increasing the susceptibility to infections. The presented review is based on an analysis of the currently available literature proposing a checklist of diagnostic procedures and immunological laboratory tests specific for the detection of patients prone to infections. The combined stratification of the underlying disease, comorbidities and the immunological mechanisms of the medication enables (1) an individual risk stratification of planned immunosuppressive therapy and (2) a prediction of the risks of infection for the patient. PMID- 23929242 TI - [Medicinal prophylaxis during intensified immunosuppression in children and adolescents : part 2]. AB - The goal of modern antirheumatic therapy is to achieve an optimized disease control. This is individually achieved by an intensified immunosuppression (IS) frequently combining different immunosuppressive agents. Intensified IS should be accompanied by a standardized protocol to monitor immunological changes in the patient. This should include checklists (see Part 1 Screening during intensified IS in children and adolescents). An individual risk stratification according to the planned IS allows a prediction of infectious disease risks for the patient and, thus, individual infection prophylaxis. In addition, standardized management of patients with fever while receiving intensified IS may prevent further complications. PMID- 23929243 TI - Treatment of ankylosing spondylitis with biologics and targeted physical therapy: positive effect on chest pain, diminished chest mobility, and respiratory function. AB - OBJECTIVE: Biologics are highly effective in ankylosing spondylitis (AS). In this self-controlled study, we assessed the additive value of complex physiotherapy in decreasing chest pain and tenderness and improving respiratory function in AS patients treated with tumor necrosis factor alpha (TNF-alpha) inhibitors. PATIENTS AND METHODS: The trial consisted of 2 parts. In study I, clinical data of AS patients with (n=55) or without biological therapy (n=20) were retrospectively analyzed and compared. Anthropometrical data, duration since diagnosis and patient assessment of disease activity, pain intensity, tender points, sacroiliac joint involvement determined by X-ray, functional condition, and physical activity level were recorded. Subjective, functional, and physical tests were performed. In study II, 10 voluntary patients (6 men and 4 women, age 52.4 +/- 13.6 years) with definite AS and receiving anti-TNF therapy were recruited. It was a prospective, non-randomized physiotherapeutic trial. BASFI (Bath Ankylosing Spondylitis Functional Index), BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), modified Schober Index, occiput-to-wall distance, and fingertip-to-floor distance were evaluated. Forced vital capacity, forced 1-s expiratory volume, peak expiratory flow, and maximum voluntary ventilation were recorded. Furthermore, typical tender points were recorded. A targeted physiotherapy program was conducted twice a week for 12 weeks and all above parameters were recorded at baseline and after 12 weeks. RESULTS: Differences in patient assessment of disease activity (p=0.019) and pain intensity (p=0.017) were found in study I. Pain and tenderness of the thoracic spine were observed in both groups. Back pain without biologic therapy was slightly higher than other group. In study II, we found that patient assessment of disease activity and pain intensity significantly improved after the physical therapy program (p=0.002 and p<0.001). BASFI and BASDAI increased after treatment (p=0.004 and p<0.001). The finger-to-floor distance, chest expansion, and modified Schober index increased (p=0.008, p<0.001, and p=0.031, respectively). The respiratory functional parameters showed a tendency towards improvement. CONCLUSION: AS patients already receiving biological therapy may benefit from additional targeted physiotherapy. Physical therapy may be of important additive value in AS patients being treated with biological. The exercise program presented here showed an improvement in functional parameters as well as spine and chest mobility, thereby enhancing the favorable effects of biological therapy. PMID- 23929244 TI - Structure-activity relationship study of biflavonoids on the Dengue virus polymerase DENV-NS5 RdRp. AB - Dengue virus is the world's most prevalent human pathogenic arbovirus. There is currently no treatment or vaccine, and solutions are urgently needed. We previously demonstrated that biflavonoids from Dacrydium balansae, an endemic gymnosperm from New Caledonia, are potent inhibitors of the Dengue virus NS5 RNA dependent RNA polymerase. Herein we describe the structure-activity relationship study of 23 compounds: biflavonoids from D. balansae (1-4) and from D. araucarioides (5-10), hexamethyl-amentoflavone (11), cupressuflavone (12), and apigenin derivatives (13-23). We conclude that 1) over the four different biflavonoid skeletons tested, amentoflavone (1) and robustaflavone (5) are the most promising ones for antidengue drug development, 2) the number and position of methyl groups on the biflavonoid moiety modulate their inhibition of Dengue virus NS5 RNA-dependent RNA polymerase, and 3) the degree of oxygenation of flavonoid monomers influences their antidengue potential. Sotetsuflavone (8), with an IC50 = 0.16 uM, is the most active compound of this series and is the strongest inhibitor of the Dengue virus NS5 RNA-dependent RNA polymerase described in the literature. PMID- 23929245 TI - Diterpenes and phenylpropanoids from Clerodendrum splendens. AB - Four new clerodane diterpenes (1-4) and one new phenylpropanoid (5) have been isolated from Clerodendrum splendens aerial parts, together with nine known compounds. Their structures were determined by spectroscopic and spectrometric analysis and chemical methods. The absolute configuration of the 15,16-diol moiety in 4 was determined by Snatzke's method. Antiproliferative activity of diterpenes in HeLa cells was also evaluated. The IC50 values were 98 +/- 11 uM for 3 and 101 +/- 8 uM for 1, respectively. PMID- 23929246 TI - Antiprotozoal screening of 60 South African plants, and the identification of the antitrypanosomal germacranolides schkuhrin I and II. AB - Two hundred and seven extracts were prepared from sixty plants from South Africa and screened for in vitro activity against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum. For the 21 extracts which inhibited the growth of one or more parasites with more than 95 % at 10 ug/mL, the IC50 values against all four protozoal parasites and cytotoxic IC50 values against L6 myoblasts were determined. Amongst the most notable results are the activities of Psoralea pinnata (IC50 of 0.15 ug/mL), Schkuhria pinnata (2.04 ug/mL), and Vernonia mespilifolia (1.01 ug/mL) against Trypansoma brucei rhodesiense. HPLC-based activity profiling was used to identify the active constituents in the extracts, and the germacranolide sesquiterpene lactones schkuhrin I and II from S. pinnata, and cynaropicrin from V. mespilifolia were identified, with IC50 values of 0.9, 1.5, and 0.23 uM, respectively. PMID- 23929247 TI - 2-(2-phenylethyl)chromone derivatives in Chinese agarwood "Qi-Nan" from Aquilaria sinensis. AB - Five new 2-(2-phenylethyl)chromone derivatives, qinanones A-E (1-5), together with eight known 2-(2-phenylethyl)chromone derivatives (6-13), were isolated from the Et2O extract of high-quality Chinese agarwood "Qi-Nan" originating from Aquilaria sinensis. The structures of the new 2-(2-phenylethyl)chromones were elucidated by spectroscopic techniques (UV, IR, 1D and 2D NMR) and MS analyses. In the bioassay for acetylcholinesterase inhibitors, compounds 1-6, 10, and 12 exhibited weak inhibitory activities (inhibition percentage ranged from 10 % to 24 % at the concentration of 50 ug/mL). Compared with other agarwoods, "Qi-Nan" was different in containing 2-(2-phenylethyl)chromones with unsubstituted chromone rings. PMID- 23929248 TI - Clematichinenoside attenuates myocardial infarction in ischemia/reperfusion injury both in vivo and in vitro. AB - Clematichinenoside is a triterpenoid saponin isolated from the roots of Clematis chinensis. Oxidative stress and excessive nitric oxide production are thought to play considerable roles in ischemia/reperfusion injury that impairs cardiac function. The present study investigated the protective effect of clematichinenoside on regional and global ischemia/reperfusion injury and ventricular myocytes. In vivo, regional myocardial ischemia/reperfusion injury of rats was induced by the occlusion of the left anterior descending coronary artery, and isolated guinea pigs heart using Langendorff apparatus served as a global ischemia/reperfusion injury model ex vivo. Primary cultured neonatal ventricular myocytes were further applied to explore the anti ischemia/reperfusion injury property in vitro. Infarct size was measured with TTC stain; enzyme activities such as lactate dehydrogenase, creatine kinase, superoxide dismutase, malondialdehyde, and nitric oxide were analyzed with assay kits; inducible nitric oxide synthase and endothelial nitric oxide synthase expressions were determined by Western blot. Clematichinenoside attenuated infarct size, decreased lactate dehydrogenase, creatine kinase, and malondialdehyde levels and enhanced superoxide dismutase activity. Clematichinenoside improved hemodynamics indexes, such as left ventricular developed pressure, maximum left ventricular developed pressure, and increase/decrease rate (+/- dp/dtmax) in the isolated guinea pig heart after reperfusion. Clematichinenoside also inhibited excessive production of nitric oxide through downregulating inducible nitric oxide synthase as well as upregulating endothelial nitric oxide synthase during ischemia/reperfusion injury. Clematichinenoside attenuates ischemia/reperfusion injury in vivo, ex vivo, and in vitro via an antioxidant effect and by restoring the balance between inducible nitric oxide synthase and endothelial nitric oxide synthase. PMID- 23929249 TI - Helicobacter pylori CagA and VacA genotypes and gastric phenotype: a meta analysis. AB - BACKGROUND: CagA+ and vacuolizing cytotoxin (VacA)-specific strains of Helicobacter pylori have been associated with different risks for developing gastric lesions. We aim to summarize a possible association between these genotypes and the risk for developing different gastric phenotypes. MATERIALS AND METHODS: A MEDLINE database (PubMed) search was performed and a meta-analysis conducted. RESULTS: Forty-four studies were retrieved, all with either a case control (n=13) or cross-sectional (n=31) design, including 17 374 patients. CagA positivity was associated with an increased risk for gastric cancer [odds ratio (OR) 2.09 (95% confidence interval (CI), 1.48-2.94)] compared with that in individuals without gastric lesions [OR 2.44 (95% CI 1.27-4.70)] and in those with previously identified gastritis. In addition, there was an increased risk for peptic ulcer disease [OR 1.69 (95% CI 1.12-2.55)]. Individuals harboring the H. pylori strains VacA s1 (vs. s2), m1 (vs. m2), s1m1 (vs. s1m2), and s1m1 (vs. s2m2) had an increased risk for development of cancer [OR of 5.32 (95% CI 2.76 10.26), 2.50 (95% CI 1.67-3.750), 2.58 (95% CI 1.24-5.38), and 4.36 (95% CI 2.08 9.10), respectively]. s1m1 strains (vs. s2m2) were also associated with peptic ulcer disease [OR 2.04 (1.01-4.13)]. CONCLUSION: Our results indicate that individuals infected with CagA+ H. pylori strains and those infected with VacA s1 and m1 strains have an increased risk for gastric cancer. Cohort studies are welcome to integrate this information in the management of at-risk individuals such as those with precancerous cancer conditions and/or a family history of gastric cancer. PMID- 23929250 TI - Human papillomavirus prevalence and type distribution in invasive cervical cancer in sub-Saharan Africa. AB - In sub-Saharan Africa, invasive cervical cancer (ICC) incidence and mortality are among the highest in the world. This cross-sectional epidemiological study assessed human papillomavirus (HPV) prevalence and type distribution in women with ICC in Ghana, Nigeria, and South Africa. Cervical biopsy specimens were obtained from women aged >= 21 years with lesions clinically suggestive of ICC. Histopathological diagnosis of ICC was determined by light microscopy examination of hematoxylin and eosin stained sections of paraffin-embedded cervical specimens; samples with a confirmed histopathological diagnosis underwent HPV DNA testing by polymerase chain reaction. HPV-positive specimens were typed by reverse hybridization line probe assay. Between October 2007 and March 2010, cervical specimens from 659 women were collected (167 in Ghana, 192 in Nigeria and 300 in South Africa); 570 cases were histologically confirmed as ICC. The tumor type was identified in 551/570 women with ICC; squamous cell carcinoma was observed in 476/570 (83.5%) cases. The HPV-positivity rate in ICC cases was 90.4% (515/570). In ICC cases with single HPV infection (447/515 [86.8%]), the most commonly detected HPV types were HPV16 (51.2%), HPV18 (17.2%), HPV35 (8.7%), HPV45 (7.4%), HPV33 (4.0%) and HPV52 (2.2%). The prevalence of single and multiple HPV infections seemed higher among HIV-positive women and HPV type distribution appeared to differ according to tumor type and HIV status. In conclusion, HPV16, 18, 45 and 35 were the most common HPV types in sub-Saharan African women with ICC and HPV infections were more common in HIV-positive women. PMID- 23929251 TI - Paget's disease of the nipple. AB - Paget's disease of the breast is a disorder of the nipple-areola complex that, while rare, is often associated with an underlying carcinoma. It is characterized by eczematoid changes of the nipple. Two theories have been proposed to explain the pathogenesis of Paget's disease. The Epidermotropic, which is the most accepted theory, suggests that Paget's cells originate from ductal cancer cells that had migrated from the underlying breast parenchyma. It is supported by the predominance of breast cancer markers found in Paget's disease. This article provides an overview of Paget's disease of the breast with special attention to immunohistochemistry and raises the question of new therapeutic approaches. PMID- 23929252 TI - Mesenchymal stem cells in the treatment of pediatric diseases. AB - BACKGROUND: In recent years, the incredible interests in mesenchymal stem cells have boosted the expectations of both patients and physicians. Unlike embryonic stem cells, neither their procurement nor their use is deemed controversial. Moreover, their immunomodulatory capacity coupled with low immunogenicity has opened up their allogenic use, consequently broadening the possibilities for their application. In May 2012, Canadian health regulators approved Prochymal, the first mesenchymal stem cells-based drug, for acute graft-versus-host diseases in children who have failed to respond to steroid treatment. The aim of this article is to review the recent advances in mesenchymal stem cells for pediatric diseases. DATA SOURCES: A literature review was performed on PubMed from 1966 to 2013 using the MeSH terms "mesenchymal stem cells", "clinical trials" and "children". Additional articles were identified by a hand search of the references list in the initial search. RESULTS: The following categories are described: general properties, mechanisms of action, graft-versus-host diseases, cardiovascular diseases, liver diseases, inflammatory bowel diseases, osteoarticular diseases, autoimmune diseases, type 1 diabetes, and lung diseases. CONCLUSIONS: Mesenchymal stem cells, owing to their availability, immunomodulatory properties, low immunogenicity, and therapeutic potential, have become one of the most attractive options for the treatment of a wide range of diseases. It is expected to see more and more clinical trials and applications of mesenchymal stem cells for pediatric diseases in the near future. PMID- 23929253 TI - Treatment of children with chronic viral hepatitis: what is available and what is in store. AB - BACKGROUND: At present, therapy of children with chronic hepatitis B and C is still based on few drugs, all burdened by a series of side-effects, unsatisfactory serum conversion rates, and/or drug-resistance. Moreover, selection of subjects to treat with conventional therapies is not univocal, especially during the pediatric age when the disease course is often mild with significant spontaneous seroconversion rate. Our review deals with pros and cons points when a physician decides to design a drug therapy for a child with chronic viral hepatitis, and different possible therapeutic opportunities. METHODS: A literature search was performed through PubMed. The newest articles, reviews, systematic reviews, and guidelines were included in this review. RESULTS: The management of children with viral hepatitis is still controversial over whom and when to treat and the use of drug(s). Novel therapeutic strategies have been evaluated only in clinical and preclinical trials involving, for instance, "therapeutic" vaccines. The data on safety and effectiveness of new drugs are also reviewed. CONCLUSION: The results of reported studies confirmed that at least some of the new drugs, with greater efficacy and/or minor side-effects, will be used clinically. PMID- 23929254 TI - Beta-blockers versus corticosteroids in the treatment of infantile hemangioma: an evidence-based systematic review. AB - BACKGROUND: The efficacy and safety of beta-blockers versus corticosteroids in the treatment of infantile hemangiomas (IHs) is controversial. This study aimed to summarize evidence described in the literature and to assess the quality of studies involving beta-blockers and corticosteroids for the treatment of cutaneous IHs. METHODS: Comparative studies were collected from 15 online electronic databases, including OVID Medline, PubMed, ISI Web of Science, CENTRAL, CNKI, ChiCTR, JPCTR, CTRIndia, IranCTR, SLCTR, ISRCTRN, NLCTR, GCTR, ANCTR, ClinicalTrial. gov, and associated references. Studies without a control group were excluded, and the remaining studies were assessed by two reviewers independently using the Downs & Black scale for reported quality. The main areas assessed in the included studies were volume changes, overall improvement in appearance, eye function, and adverse events. RESULTS: Ten comparative studies were included with a total of 419 children. A meta-analysis was not performed due to the considerable heterogeneity across studies. Some evidence showed that beta blockers are superior to steroids in reducing volume and improving the overall appearance of IHs, such as lightening of the color and flattening of the surface. Conclusions regarding improved eye function and adverse events were divided, and no consensus has been reached on the superiority of one treatment over another. No episodes of severe-onset asthma, hypotension, or bradycardia occurred in the beta-blocker treatment due to the rigorous exclusion of patients with contraindications. CONCLUSIONS: Available studies indicate that beta-blockers are an alternative option to corticosteroids for IH treatment with respect to volume shrinkage and improvement in appearance. No evidence has shown a significant difference in improved eye function and adverse events between beta-blockers and corticosteroids in the treatment of IH; indeed, there is a lack of well-designed, high-quality randomized control trials. PMID- 23929255 TI - Psycho-behavioral changes in children with type 1 diabetes mellitus. AB - BACKGROUND: Type 1 diabetes mellitus (T1DM) is the most common type of diabetes in children. This study aimed to investigate psycho-behavioral changes in Chinese children with T1DM and to provide some advices for nurses, parents and other persons. METHODS: Forty-five patients with T1DM (26 boys and 19 girls with a mean age of 10.40+/-3.01 years) were enrolled. According to the glycosylated hemoglobin levels recommended by the American Diabetes Association, the patients were subdivided into a well-controlled group and a poorly-controlled group. Fifty three healthy children served as a control group. Psycho-behavioral changes were investigated by using Achenbach's Child Behavior Check List. RESULTS: Compared with the control group, the patients with T1DM had significantly higher mean scores for withdrawal, anxiety/depression, attention problems, delinquent behavior, aggressive behavior, externalizing problems, and internalizing problems (P<0.017). Moreover, the mean scores for somatic complaints in the poorly controlled subgroup were significantly higher than those in the well-controlled subgroup (t=3.582, P=0.001). Compared with the control group, the well-controlled subgroup had higher scores for withdrawal, anxiety/depression, and internalizing problems (P<0.017). But the poorly-controlled subgroup had higher scores for withdrawal, somatic complaint, anxiety/depression, delinquent behavior, aggressive behavior, externalizing and internalizing problems (P<0.017). CONCLUSIONS: Children with T1DM may have some psycho-behavioral problems. Timely nursing interventions must be conducted to solve these problems. PMID- 23929256 TI - Hepatic CYP3A expression and activity in low birth weight developing female rats. AB - BACKGROUND: We aimed to investigate the effects of low birth weight (LBW) on the hepatic expression of cytochrome P-450 3A (CYP3A) in developing female rats. METHODS: Pregnant rats were divided into two groups, a nourished group and an under-nourished group. The offspring of the nourished rats were defined as a normal weight, normal diet group (NN group). The offspring of the under-nourished rats were designated as a LBW, normal diet group (LN group). CYP3A mRNA expression, protein expression, protein localization and activity were determined. RESULTS: The CYP3A1 mRNA expression levels of the LN group on days 3, 21, and 56 were significantly higher than those of the same age in the NN group (P<=0.01). The mRNA expression of CYP3A2 in the LN group on day 21 was higher than in rats of the same age in the NN group (P<0.01). The staining intensity and frequency of CYP3A1-positive hepatocytes were significantly lower on days 7 and 21 in the LN group than those of rats of the same age in the NN group (P<0.05). The staining intensity and frequency of CYP3A2-positive hepatocytes on days 14 and 21 were higher in the LN group than those on the same days in the NN group (P<0.05). The mean CYP3A activity of the LN group on day 3 was significantly higher than that of the NN group (P<0.001). CONCLUSIONS: We found the effect of LBW on CYP3A activity was most prominent during the early days of life in rats. Investigators and clinicians should consider the effect of LBW on CYP3A in both pharmacokinetic study design and data interpretation, when prescribing drugs to LBW infants. PMID- 23929257 TI - The HHEX gene is not related to congenital heart disease in 296 Chinese patients. AB - BACKGROUND: The hematopoietically expressed homeobox (HHEX) gene is an important determinant of mammalian heart development. This study aimed to identify the potential mutations of the gene in Chinese patients with congenital heart disease (CHD). METHODS: We collected 296 CHD patients and 200 controls, and classified the cardiac deformities. Then we conducted sequence analyses of the HHEX gene in those patients. RESULTS: In all the CHD patients, we did not find any causative mutations in the coding region of the HHEX gene. CONCLUSION: To our knowledge, this is the first study to examine the HHEX gene in non-symptomatic CHD cases, and this has expanded our knowledge about its etiology. PMID- 23929258 TI - Isolation of a Mn(IV) acylperoxo complex and its monooxidation ability. AB - The first example of monooxygenation by a high-valent Mn(IV) complex with a peroxide is described. A key Mn(IV) acylperoxo intermediate, which uses m chloroperoxybenzoic acid as the oxygen donor, is directly observed by electro spray ionization mass spectrometry and resonance Raman spectroscopy. PMID- 23929260 TI - Effect of dietary advanced glycation end products on postprandial appetite, inflammation, and endothelial activation in healthy overweight individuals. AB - PURPOSE: Advanced glycation end products (AGEs) formed in food during high-heat cooking may induce overeating and inflammation. We investigated whether AGE contents in a single meal affect postprandial appetite and markers of inflammation, endothelial activation, and oxidative stress. METHODS: In total, 19 healthy overweight individuals completed a crossover meal test with two meals of identical ingredients prepared by roasting (H-AGE) or steaming (L-AGE), respectively. Postprandial blood samples were analysed for N(epsilon) carboxymethyl-lysine (CML), appetite-regulating gut hormones, glucose, insulin, triacylglycerol, and markers of inflammation and endothelial activation. Subjective appetite ratings and subsequent food intake were also assessed, and urine was analysed for CML, methylglyoxal-derived hydroimidazolone (MG-H1), and F2-isoprostanes. RESULTS: CML content of the H- and L-AGE meals was 5.0 and 2.8 mg, respectively. Plasma CML and urinary CML and MG-H1 tended to be higher after the H-AGE meal. There was no change in subsequent food intake, appetite sensations, or appetite hormone responses between meals, except for the overall ghrelin response, which was higher after the H-AGE meal compared with the L-AGE meal (p = 0.016). There was an increased glycaemic response to the H-AGE meal (p = 0.027) compared with the L-AGE meal. Inflammatory and endothelial activation markers did not differ between meals, but there was an overall effect on endothelial activation (p = 0.021) and on the oxidative marker, F2-isoprostanes, in urine (p = 0.013). CONCLUSION: The present study did not show any pronounced effects of AGEs on appetite and markers of inflammation, but did indicate that AGEs may affect postprandial ghrelin, oxidative stress, and glucose responses. PMID- 23929261 TI - Abdominal pain in ulcerative colitis. AB - BACKGROUND: Chronic pain is common in patients with inflammatory bowel disease and often attributed to inflammation. However, many patients with inflammatory bowel disease without evidence of active disease continue to experience pain. This study was undertaken to determine the prevalence of pain in patients with ulcerative colitis (UC) and examine the role of inflammation and psychiatric comorbidities in patients with UC with pain. METHODS: We performed a retrospective cross-sectional analysis of adult patients with UC seen at a tertiary referral inflammatory bowel disease center. Age, gender, disease duration and extent, abdominal pain rating, quality of life, physician global assessment, endoscopic and histological rating of disease severity, C reactive protein, and erythrocyte sedimentation rate were abstracted. RESULTS: A total of 1268 patients were identified using billing codes for colitis. Five hundred and two patients (48.2% women) met all inclusion criteria. Two hundred and sixty-two individuals (52.2%) complained of abdominal pain, with 108 individuals (21.5%) describing more frequent pain ("some of the time or more"). Of those with quiescent disease (n = 326), 33 patients (10%) complained of more frequent pain. Physician global assessment, endoscopic and histological severity rating, erythrocyte sedimentation rate, and C reactive protein significantly correlated with pain ratings. The best predictors of pain were physician global assessment, C reactive protein and erythrocyte sedimentation rate, female gender, and coexisting mood disorders. CONCLUSIONS: Abdominal pain affects more than 50% of patients with UC. Although inflammation is important, the skewed gender distribution and correlation with mood disorders highlight parallels with functional bowel disorders and suggest a significant role for central mechanisms. Management strategies should thus go beyond a focus on inflammation and also include interventions that target psychological mechanisms of pain. PMID- 23929259 TI - Signalling mechanisms involved in renal pathological changes during cisplatin induced nephropathy. AB - CONTEXT: Cisplatin, a coordination platinum complex, is used as a potential anti neoplastic agent, having well recognized DNA-damaging property that triggers cell cycle arrest and cell death in cancer therapy. Beneficial chemotherapeutic actions of cisplatin can be detrimental for kidneys. BACKGROUND: Unbound cisplatin gets accumulated in renal tubular cells, leading to cell injury and death. This liable action of cisplatin on kidneys is mediated by altered intracellular signalling pathways such as mitogen-activated protein kinase (MAPK), extracellular regulated kinase (ERK), or C- Jun N terminal kinase/stress activated protein kinase (JNK/SAPK). Further, these signalling alterations are responsible for release and activation of tumour necrosis factor (TNF-alpha), mitochondrial dysfunction, and apoptosis, which ultimately cause the renal pathogenic process. Cisplatin itself enhances the generation of reactive oxygen species (ROS) and activation of nuclear factor-kappaB (NF-kappaB), inflammation, and mitochondrial dysfunction, which further leads to renal apoptosis. Cisplatin induced nephropathy is also mediated through the p53 and protein kinase-Cdelta (PKCdelta) signalling pathways. OBJECTIVE: This review explores these signalling alterations and their possible role in the pathogenesis of cisplatin-induced renal injury. PMID- 23929262 TI - Treatment of an initial infection with clostridium difficile in patients with inflammatory bowel disease. AB - : Although the incidence of Clostridium difficile-associated diarrhea in the general population has increased dramatically over the past decade, an even greater rate of infection exists in patients with inflammatory bowel disease. Susceptibility in this population is likely inherent to the pathophysiology and treatment of these diseases. C. difficile infection can cause serious complications and death. Consequently, early diagnosis and initiation of effective antibacterial therapy is imperative. This article evaluates treatment recommendations for an initial episode of C. difficile infection in patients with inflammatory bowel disease based on the current guidelines and a Cochrane systematic review. PMID- 23929263 TI - Diffusion-weighted MR imaging of benign and malignant breast lesions before and after contrast enhancement. AB - PURPOSE: Many publications describe the use of diffusion-weighted imaging (DWI) in breast MRI. This article addresses the question of when to apply the DWI sequence in the course of the scan protocol. The effect of T1-shortening contrast media (CM) on the ADC values of breast lesions is investigated. MATERIALS AND METHODS: Data were acquired on a 1.5 T scanner. 60 patients with 79 lesions (20 benign, 59 malignant) were included. The DWI sequence (4 mm slice thickness, b values: 50, 400, 800) was applied before and after CM administration. Before calculating the ADC map, the b50, b400 and b800 series were analyzed concerning lesion displacement. ADC values before and after CM application were compared. RESULTS: The mean lesion size was 1.5 +/- 0.8 cm. On the basis of the b50 and b400 measurements, the mean ADC value of benign lesions was 1.89 +/- 0.30 * 10-3 mm2/s before and 1.85 +/- 0.28 *10-3 mm2/s after CM administration. The consecutive values for two pure mucinous carcinomas were 1.88 * 10-3 mm2/s and 1.81 * 103 mm2/s and for the remaining malignant lesions 1.00 +/- 0.18 * 10-3 mm2/s and 0.88 +/- 0.21 * 10-3 mm2. On the basis of the b50, b400 and b800 measurements, the mean ADC value of benign lesions was 1.99 +/- 0.37 * 10-3 mm2/s before and 1.97 +/- 0.30 * 10-3 mm2/s after CM application, whereas the mean ADC value of the malignant lesions was 0.90 +/- 0.14 * 10-3 mm2/s before and 0.80 +/- 0.14 * 10-3 mm2/s after CM application. While there was no significant change for benign lesions, the ADC value decrease in post-contrast malignant lesions was highly significant. CONCLUSION: DWI after CM is possible and even leads to slightly better lesion discrimination between benign and malignant. However, further studies need to be performed to verify this. Citation Format: * Janka R, Hammon M, Geppert C et al. Diffusion-Weighted MR Imaging of Benign and Malignant Breast Lesions Before and After Contrast Enhancement. Fortschr Rontgenstr 2014; 186: 130 - 135. PMID- 23929264 TI - Bridging the language barrier in health awareness. PMID- 23929265 TI - Diagnostic utility of SOX10 to distinguish malignant peripheral nerve sheath tumor from synovial sarcoma, including intraneural synovial sarcoma. AB - Synovial sarcoma and malignant peripheral nerve sheath tumor pose a significant diagnostic challenge given similar histomorphology. The distinction is further complicated by similar immunophenotype and especially by occasional synovial sarcomas that present as intraneural tumors. Although the presence of a t(X;18) rearrangement or expression of TLE1 can help confirm the diagnosis of synovial sarcoma, negative results for these tests are not diagnostic of malignant peripheral nerve sheath tumor. The SOX10 transcription factor, a putative marker of neural crest differentiation, may have diagnostic utility in this differential, but immunohistochemical data are limited. The goal of the present study was to determine the diagnostic utility of SOX10 to discriminate between synovial sarcoma and malignant peripheral nerve sheath tumor. Forty-eight cases of malignant peripheral nerve sheath tumor, all from patients with documented neurofibromatosis, and 97 cases of genetically confirmed synovial sarcoma, including 4 intraneural synovial sarcomas, were immunohistochemically stained for SOX10. The stain was scored for intensity and fraction of cells staining. Thirty two of 48 malignant peripheral nerve sheath tumors (67%) were SOX10-positive. The majority of malignant peripheral nerve sheath tumors showed >=2+ staining, but staining did not correlate with grade. By contrast, only 7/97 (7%) synovial sarcomas were SOX10-positive. Only three synovial sarcomas showed >=2+ staining but, importantly, two of these were intraneural synovial sarcoma. Therefore, SOX10 is a specific (93%), albeit not very sensitive (67%), diagnostic marker to support a diagnosis of malignant peripheral nerve sheath tumor over synovial sarcoma. Furthermore, the stain needs to be interpreted with caution in intraneural tumors in order to avoid a potential diagnostic pitfall. It remains to be determined whether SOX10-positive cells in intraneural synovial sarcoma represent entrapped Schwann cells, synovial sarcoma cells or both. PMID- 23929266 TI - Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer. AB - Treatment of triple-negative invasive breast cancers, defined by the absence of estrogen and progesterone receptors and c-erbB2 expression, remains challenging. Androgen receptor, a member of the nuclear receptor superfamily that is involved in signaling pathways regulating cell proliferation, has been implicated in breast tumorigenesis. We immunohistochemically examined the expression of androgen receptor, basal markers (CK14, 34betaE12) and EGFR in 699 triple negative invasive breast cancers in tissue microarrays using the streptavidin biotin method, and correlated the findings with clinical outcome. Positive androgen receptor expression was defined as staining of 1% or more of tumor cell nuclei. Survival outcomes were estimated with the Kaplan-Meier method and compared between groups with log-rank statistics. Cox proportional hazards models were used to determine the effect of androgen receptor on survival outcomes. Immunohistochemical positivity was observed in 38% of tumors, with the proportion of stained tumor cells ranging from 1 to 95% (mean 29%, median 10%). Androgen receptor expression was inversely associated with histologic grade and mitotic score. CK14, 34betaE12 and EGFR confirmed 85% of cases to be basal-like, without significant association of basal-like phenotype with androgen receptor expression. Disease-free survival was significantly better in androgen receptor positive triple-negative breast cancer, with a trend for improved overall survival. Decreased recurrence likelihood in both triple-negative and basal-like tumors (hazard ratio, 0.704; 95% confidence intervals, 0.498-0.994; P=0.0464; and hazard ratio, 0.675; 95% confidence intervals, 0.468-0.974; P=0.0355, respectively) was noted within 5 years of diagnosis but not thereafter. Our study suggests that loss of androgen receptor in triple-negative breast cancers augurs a worse prognosis, including those with basal-like features. More work in elucidating its relationship with mechanisms of progression, as well as trials of targeted treatment for androgen receptor-expressing triple-negative tumors, needs to be performed. PMID- 23929267 TI - Hepatitis C virus-related lymphoproliferative disorders encompass a broader clinical and morphological spectrum than previously recognized: a clinicopathological study. AB - We describe a retrospective series of B-cell lymphoproliferative disorders associated with hepatitis C virus infection. In addition to splenic marginal zone lymphoma, follicular lymphoma and diffuse large B-cell lymphoma, all of which showed some specific features, we found two poorly described groups of cases. The first featured disseminated marginal zone lymphoma without splenic marginal zone lymphoma features, defying the current marginal zone lymphoma classification; the other consisted of monoclonal B lymphocytes in the peripheral blood, bone marrow or other tissues, with no clinical or histological evidence of lymphoma, and exhibiting a pattern that requires proper identification in order to avoid the misdiagnosis of the lymphoma. Diagnosis of hepatitis C virus infection-associated lymphoproliferative disorders requires the integration of clinical, pathological and molecular findings to establish an adequate diagnosis and decide the appropriate therapy to be applied. PMID- 23929268 TI - Tissue IgG4-positive plasma cells in inflammatory bowel disease: a study of 88 treatment-naive biopsies of inflammatory bowel disease. AB - The distinction of Crohn's disease from ulcerative colitis is based on clinical, endoscopic, radiological, and histological findings, a paradigm that remains unchanged despite the advent of new understanding of the immunological and genetic basis of inflammatory bowel disease. There is a strong correlation between inflammatory bowel disease, predominantly ulcerative colitis, and autoimmune pancreatitis. We hypothesized that colonic biopsies from patients with inflammatory bowel disease would demonstrate increased numbers of IgG4-positive plasma cells and that this elevation might be restricted to ulcerative colitis. We examined a cohort of 78 cases of inflammatory bowel disease: 50 ulcerative colitis and 38 Crohn's disease. We identified treatment-naive biopsies. Additionally, four cases of inflammatory bowel disease associated with autoimmune pancreatitis and 15 cases of lymphocytic/collagenous colitis were also identified. Immunohistochemical stains for IgG4 were performed. Biopsies from patients with ulcerative colitis showed significantly higher numbers of IgG4 bearing plasma cells than those with Crohn's disease (mean IgG4 counts per high power field (hpf) 9.8 vs 2.8, P=0.001). Samples from 19 (38%) ulcerative colitis patients had IgG4 counts >10/hpf, compared with only two (5%) patients with Crohn's disease; the sensitivity and specificity of a cutoff at 10 IgG4-positive plasma cells per hpf was 38 and 95%, respectively. Among individuals <18 years, there were no statistically differences in the IgG4 counts between the two subforms of inflammatory bowel disease. Among adult patients, a cutoff of 5 IgG4+ plasma cells distinguished ulcerative colitis from Crohn's disease with a sensitivity of 53% and specificity of 83%. In comparison to inflammatory bowel disease, patients with lymphocytic/collagenous colitis showed significantly lower numbers of IgG4-positive plasma cells (P=0.0001). Ulcerative colitis with pancolitis showed higher numbers of IgG4-bearing plasma cells (mean IgG4 12.8 vs 5.8 per hpf; P=0.09). An immunohistochemical stain for IgG4 may aid in making the distinction between ulcerative colitis and Crohn's disease (with exclusion of the pediatric cases), albeit with a relatively low sensitivity. This study also provides additional support to the hypothesis that a subset of ulcerative colitis cases is associated with a Th2 response. PMID- 23929270 TI - Development of the CAT-ANX: a computerized adaptive test for anxiety. AB - OBJECTIVE: The authors developed a computerized adaptive test for anxiety that decreases patient and clinician burden and increases measurement precision. METHOD: A total of 1,614 individuals with and without generalized anxiety disorder from a psychiatric clinic and community mental health center were recruited. The focus of the present study was the development of the Computerized Adaptive Testing-Anxiety Inventory (CAT-ANX). The Structured Clinical Interview for DSM-IV was used to obtain diagnostic classifications of generalized anxiety disorder and major depressive disorder. RESULTS: An average of 12 items per subject was required to achieve a 0.3 standard error in the anxiety severity estimate and maintain a correlation of 0.94 with the total 431-item test score. CAT-ANX scores were strongly related to the probability of a generalized anxiety disorder diagnosis. Using both the Computerized Adaptive Testing-Depression Inventory and the CAT-ANX, comorbid major depressive disorder and generalized anxiety disorder can be accurately predicted. CONCLUSIONS: Traditional measurement fixes the number of items but allows measurement uncertainty to vary. Computerized adaptive testing fixes measurement uncertainty and allows the number and content of items to vary, leading to a dramatic decrease in the number of items required for a fixed level of measurement uncertainty. Potential applications for inexpensive, efficient, and accurate screening of anxiety in primary care settings, clinical trials, psychiatric epidemiology, molecular genetics, children, and other cultures are discussed. PMID- 23929269 TI - Direct comparison of eight national FRAX(r) tools for fracture prediction and treatment qualification in Canadian women. AB - SUMMARY: We compared the calibration of FRAX tools from Canada, the US (white), UK, Sweden, France, Australia, New Zealand, and China when used to assess fracture risk in 36,730 Canadian women. Our data underscores the importance of applying country-specific FRAX tools that are based upon high-quality national fracture epidemiology. PURPOSE: A FRAX(r) model for Canada was constructed for prediction of hip fracture and major osteoporotic fracture (MOF) using national hip fracture and mortality data. We examined the calibration of this model in Canadian women and compared it with seven other FRAX tools. METHODS: In women aged >=50 years with baseline bone mineral density (BMD) measures identified from the Manitoba Bone Density Program, Canada (n = 36,730), 10-year fracture probabilities were calculated with and without BMD using selected country specific FRAX tools. FRAX risk estimates were compared with observed fractures <=10 years (506 hip, 2,380 MOF). Ten-year fracture risk was compared with predicted probabilities, and proportions exceeding specific treatment thresholds contrasted. RESULTS: For hip fracture prediction, good calibration was observed for FRAX Canada and most other country-specific FRAX tools, excepting Sweden (risk overestimated) and China (risk underestimated). For MOF prediction, greater between-country differences were seen; FRAX Sweden and FRAX China showed the largest over- and underestimation in this Canadian population. Relative to treatment qualification based upon FRAX Canada, treatment of high-hip fracture probability (>=3%) was greater by FRAX Sweden (ratio 1.41 without and 1.55 with BMD), and markedly less by FRAX China (ratio 0.09 without and 0.11 with BMD). Greater between-country differences were observed for treatment of high MOF (>=20%); FRAX Sweden again greatly increased (ratio 1.76 without and 1.83 with BMD), and FRAX China severely reduced treatment qualification (ratio 0.00 without and 0.01 with BMD). CONCLUSIONS: The use of country-specific FRAX tools, accurately calibrated to the target population, is essential. Relatively small calibration differences can have large effects on high-risk categorization and treatment qualification. PMID- 23929271 TI - Alleviation of exogenous 6-benzyladenine on two genotypes of eggplant (Solanum melongena Mill.) growth under salt stress. AB - Cytokinins were recently shown to control plant adaptation to environmental stresses. To characterize the roles of cytokinins in the tolerance of eggplant (Solanum melongena Mill.) to salt stress, the protective effects of 6 benzyladenine (6-BA) on the growth, photosynthesis, and antioxidant capacity in the leaves of two eggplant cultivars Huqie12 (salt-sensitive) and Huqie4 (salt tolerant) were investigated. Under 90 mM NaCl stress, Huqie4 showed higher biomass accumulation and less oxidative damage compared to the Huqie12. Application of exogenous 10 MUM 6-BA significantly alleviated the growth suppression caused by salt stress in two eggplant genotypes. In parallel with the growth, 6-BA application in salt-stressed plants resulted in enhanced chlorophyll contents, as well as photosynthetic parameters such as net CO2 assimilation rate (P n), stomatal conductance (g s), transpiration rate (E), and intercellular CO2 concentration (C i). Furthermore, exogenous 6-BA also significantly reduced the O2 (-) production rate and malondialdehyde content and markedly increased the antioxidant enzymes superoxide dismutase and peroxidase, the antioxidant metabolites ascorbate and reduced glutathione (GSH), and proline in both genotypes under salt stress. The results indicate that exogenous 6-BA is useful to improve the salt resistance of eggplant, which is most likely related to the increase in photosynthesis and antioxidant capacity. PMID- 23929272 TI - Direct correlation of consecutive C'-N groups in proteins: a method for the assignment of intrinsically disordered proteins. AB - Two novel 3D (13)C-detected experiments, hNcocaNCO and hnCOcaNCO, are proposed to facilitate the resonance assignment of intrinsically disordered proteins. The experiments correlate the (15)N and (13)C' chemical shifts of two consecutive amide moieties without involving other nuclei, thus taking advantage of the good dispersion shown by the (15)N-(13)C' correlations, even for proteins that lack a well defined tertiary structure. The new pulse sequences were successfully tested using Nupr1, an intrinsically disordered protein of 93 residues. PMID- 23929273 TI - Separation and phase transition investigation of Yb3+/Er3+ co-doped NaYF4 nanoparticles. AB - Density gradient ultracentrifuge separation was employed to study the phase transition of Yb(3+)/Er(3+) co-doped NaYF4 from alpha-phase to beta-phase. It was found that the cubic alpha-phased NaYF4 was rich in Y, exhibited predominantly red luminescence, whilst the newly formed hexagonal beta-phased NaYF4 had relatively higher Yb and Er atomic ratios, exhibited green luminescence most strongly. PMID- 23929274 TI - Characterization of the volatile profiles of beer using headspace solid-phase microextraction and gas chromatography-mass spectrometry. AB - BACKGROUND: The objective of this study was a multivariate characterization of the volatile profile of beers. Such a characterization is timely considering the increasing worldwide consumption of beer, the continuous growth of microbreweries and the importance of volatile compounds to beer flavour. A method employing solid-phase microextraction and gas chromatography-mass spectrometry (SPME-GC-MS) was optimized and then applied to a sample set of 36 industrial and craft beers of various styles and fermentation types. RESULTS: The volatile profiles of different beer styles is described, with particular attention paid to the volatile compounds characteristic of a spontaneously fermented lambic raspberry framboise beer. Furthermore, it was also possible to identify which specific volatile compounds are principally responsible for the differences in the volatile profiles of top- and bottom-fermented beers. Moreover, a volatile fingerprint of the craft top-fermented Italian beers was defined, as they show a very similar volatile profile. Finally, the volatile compounds that are characteristic of the bock-style beers are described. CONCLUSIONS: The SPME-GC-MS analytical method optimized in this study is suitable for characterizing the volatile fingerprint of different beers, especially on the basis of the kind of fermentation (top, bottom or spontaneous), the method of production and the style of the beer. PMID- 23929275 TI - Ionic liquids are compatible with on-water catalysis. AB - A major limitation of on-water catalysis has been the need for liquid reactants to enable emulsification. We demonstrate that ionic liquids are compatible with on-water catalysis, enabling on-water catalysed reactions for otherwise unreactive solid-solid systems. The unique solvation properties of ionic liquids dramatically expands the scope of on-water catalysis. PMID- 23929276 TI - Fabrication and characterization of disordered polymer optical fibers for transverse Anderson localization of light. AB - We develop and characterize a disordered polymer optical fiber that uses transverse Anderson localization as a novel waveguiding mechanism. The developed polymer optical fiber is composed of 80,000 strands of poly (methyl methacrylate) (PMMA) and polystyrene (PS) that are randomly mixed and drawn into a square cross section optical fiber with a side width of 250 MUm. Initially, each strand is 200 MUm in diameter and 8-inches long. During the mixing process of the original fiber strands, the fibers cross over each other; however, a large draw ratio guarantees that the refractive index profile is invariant along the length of the fiber for several tens of centimeters. The large refractive index difference of 0.1 between the disordered sites results in a small localized beam radius that is comparable to the beam radius of conventional optical fibers. The input light is launched from a standard single mode optical fiber using the butt-coupling method and the near-field output beam from the disordered fiber is imaged using a 40X objective and a CCD camera. The output beam diameter agrees well with the expected results from the numerical simulations. The disordered optical fiber presented in this work is the first device-level implementation of 2D Anderson localization, and can potentially be used for image transport and short-haul optical communication systems. PMID- 23929277 TI - Carcinoma gallbladder in a patient with choledochal cyst, cysto-hepatolithiasis, and simple liver cyst. PMID- 23929279 TI - ZnO nanowires as effective luminescent sensing materials for nitroaromatic derivatives. AB - We report on the efficient room-temperature photoluminescence (PL) quenching of ZnO in the presence of 2,4-dinitrotoluene (DNT) vapor and for concentration as low as 180 ppb. Compared to ZnO thin films, ZnO nanowires exhibit a strong (95%) and fast (41 s) quenching of the PL intensity in the presence of DNT vapor. Assuming that the PL quenching is due to a trapping of the ZnO excitons by adsorbed DNT molecules, Monte-Carlo calculations show that the nanometric dimensions as well as the better crystallographic quality (longer mean free path) of the ZnO nanowires result in an enhanced trapping process at the origin of the improved sensing properties of the nanowires. The results demonstrate the importance of nanostructures in improving the sensitivity of ZnO. The study also reveals the sensing capability of ZnO nanowires and paves the path towards the potential realization of low-cost sub-ppb nitroaromatic derivative sensors. PMID- 23929278 TI - Case-control study of lifetime alcohol consumption and endometrial cancer risk. AB - PURPOSE: Alcohol consumption is hypothesized to increase the risk of endometrial cancer by increasing circulating estrogen levels. This study sought to investigate the association between lifetime alcohol consumption and endometrial cancer risk. METHODS: We recruited 514 incident endometrial cancer cases and 962 frequency age-matched controls in this population-based case-control study in Alberta, Canada, from 2002 to 2006. Participants completed in-person interviews querying lifetime alcohol consumption and other relevant health and lifestyle factors. Participants reported the usual number of drinks of beer, wine, and liquor consumed; this information was compiled for each drinking pattern reported over the lifetime to estimate average lifetime exposure to alcohol. RESULTS: Lifetime average alcohol consumption was relatively low (median intake: 3.9 g/day for cases, 4.9 g/day for controls). Compared with lifetime abstainers, women consuming >2.68 and <=8.04 g/day alcohol and >8.04 g/day alcohol on average over the lifetime showed 38 and 35 % lower risks of endometrial cancer, respectively (p trend = 0.023). In addition, average lifetime consumption of all types of alcohol was associated with decreased risks. There was no evidence for effect modification by body mass index, physical activity, menopausal status, and hormone replacement therapy use combined and effects did not differ by type of endometrial cancer (type I or II). CONCLUSION: This study provides epidemiologic evidence for an inverse association between relatively modest lifetime average alcohol consumption (approximately 1/4 to 1/2 drink/day) and endometrial cancer risk. The direction of this relation is consistent with previous studies that examined similar levels of alcohol intake. PMID- 23929280 TI - The best in the world. PMID- 23929281 TI - Legionella bacteria in water supply systems. PMID- 23929282 TI - [Genetic self-tests]. PMID- 23929283 TI - [Carelessness in the original article]. PMID- 23929284 TI - [E. Hem replies]. PMID- 23929285 TI - Children in the blind zone. PMID- 23929286 TI - [Should we boycott academic cooperation with China?]. PMID- 23929287 TI - [Can the physician prevent traffic accidents?]. PMID- 23929288 TI - [The doctorate trial lecture has a too narrow topic selection]. PMID- 23929292 TI - [Alzheimer's disease and genetics]. AB - BACKGROUND: Alzheimer's disease is the most frequent cause of dementia. Recent knowledge reveals several new risk genes. We wish to summarise the knowledge of genetic factors related to Alzheimer's disease. METHOD: This article is based on findings in Alzgene, a database that summarises genetic association studies in Alzheimer's disease, a literature search in PubMed and the authors' own experience in dementia research. RESULTS: Several mutations of the genes APP, PSEN1 and PSEN2 are described. These cause around half of all cases of the rare early onset autosomal dominant form of Alzheimer's disease. Heritability, or how much of the development of the disease in an individual that is explained by genetics, is between 60 and 80% in the most common late onset form of Alzheimer's disease. APOE epsilon4 is the most robust risk gene for the development of this form of the disease, but recently ten new genes that increase the risk of developing Alzheimer's disease were identified by applying genome-wide association studies. These genes code for proteins that are central in the metabolism of cholesterol, activation of the immune system and synaptic cell membrane processes. INTERPRETATION: New hypotheses on the disease mechanisms for Alzheimer's disease are suggested based on the identification of new risk genes. These hypotheses partly replace and partly supplement the previously dominant amyloid pathway hypothesis. The new risk genes point to the potential for new biomarkers for specific disease processes and to possible new targets for future disease modifying therapies. PMID- 23929291 TI - Legionella pneumophila in Norwegian naval vessels. AB - BACKGROUND: Little is known about the occurrence of Legionella pneumophila in water supply systems on board ships. Our aim was to study the occurrence of L. pneumophila in the water supply system on board Norwegian naval vessels as the basis for framing preventive strategies against Legionella infection. MATERIAL AND METHOD: Water samples were collected from technical installations and from the water distribution network on board 41 vessels and from ten water filling (bunkering) stations, the sampling taking place in two rounds separated by a one year interval. The samples were subjected to analysis, including serotyping and genotyping, with a view to identifying the presence of L. pneumophila and of free living amoebae. RESULTS: L. pneumophila was found in 20 out of a total of 41 vessels in the first round of sampling, and live L. pneumophila serogroup 1 was isolated in seven of the 20 vessels. Free-living amoebae were found in the water supply system in most of the vessels, including all the vessels with L. pneumophila. The same genotype of L. pneumophila was identified in the water in bunkering stations and in the water on board the vessels. INTERPRETATION: L. pneumophila was not present in all the vessels, but all the vessels where the bacterium was found were also contaminated with free-living amoebae. We have demonstrated the probability of the fresh water from bunkering stations being the source of the contamination. In framing preventive strategies, importance should therefore be attached to identifying the source of contamination and the presence of free-living amoebae, as a premise for the establishment and growth of L. pneumophila in onboard water supply systems. PMID- 23929294 TI - [Malignant cerebral infarction]. PMID- 23929293 TI - [Atrial fibrillation and stroke]. AB - BACKGROUND: More than 70,000 Norwegians have atrial fibrillation, which is a major risk factor for ischemic stroke. A large proportion of ischemic strokes caused by atrial fibrillation could be prevented if patients receive optimal prophylactic treatment. This article describes the risk for ischemic stroke in patients with atrial fibrillation, and discusses who should receive prophylactic treatment and which therapy provides the best prevention. METHOD: The article is based on recently published European, American and Canadian guidelines, a search in PubMed and the authors' own clinical experience. RESULTS: The new risk score CHA2DS2-VASc is better than the CHADS2 score for identifying patients with atrial fibrillation who have a truly low risk of ischemic stroke and are not in need of antithrombotic treatment. Oral anticoagulation therapy is recommended for patients with two or more risk factors for thromboembolism in addition to atrial fibrillation (CHA2DS2-VASc >= 2). Patients with atrial fibrillation and a single additional risk factor (CHA2DS2-VASc =1) an individual assessment should be made as to who should receive oral anticoagulants, and for patients with CHA2DS2-VASc = 0 antithrombotic treatment is not recommended. New oral anticoagulants are at least as effective as warfarin for preventing ischemic stroke in patients with nonvalvular atrial fibrillation, they carry a lower risk of cerebral haemorrhage, especially intracranial haemorrhage and are more practical in use. Platelet inhibitors have a minimal role in stroke prevention in patients with atrial fibrillation. INTERPRETATION: Risks stratifying patients using the CHA2DS2-VASc score is a better method for assessing which patients with atrial fibrillation who should receive oral anticoagulation. The introduction of new oral anticoagulants will simplify preventive treatment and hopefully lead to a more efficient anticoagulation treatment in a larger number of patients with atrial fibrillation. PMID- 23929295 TI - Three siblings with progressive respiratory distress as infants. PMID- 23929296 TI - [Are cytostatics harmful for the brain?]. PMID- 23929297 TI - When diagnosis makes us blind. PMID- 23929298 TI - 20 years of efforts for human rights. PMID- 23929299 TI - [Bacteria and other microorganisms]. PMID- 23929302 TI - Glioma-derived galectin-1 regulates innate and adaptive antitumor immunity. AB - Galectin-1 is a glycan-binding protein, which is involved in the aggressiveness of glioblastoma (GBM) in part by stimulating angiogenesis. In different cancer models, galectin-1 has also been demonstrated to play a pivotal role in tumor mediated immune evasion especially by modulating cells of the adaptive immune system. It is yet unknown whether the absence or presence of galectin-1 within the glioma microenvironment also causes qualitative or quantitative differences in innate and/or adaptive antitumor immune responses. All experiments were performed in the orthotopic GL261 mouse high-grade glioma model. Stable galectin 1 knockdown was achieved via transduction of parental GL261 tumor cells with a lentiviral vector encoding a galectin-1-targeting miRNA. We demonstrated that the absence of tumor-derived but not of host-derived galectin-1 significantly prolonged the survival of glioma-bearing mice as such and in combination with dendritic cell (DC)-based immunotherapy. Both flow cytometric and pathological analysis revealed that the silencing of glioma-derived galectin-1 significantly decreased the amount of brain-infiltrating macrophages and myeloid-derived suppressor cells (MDSC) in tumor-bearing mice. Additionally, we revealed a pro angiogenic role for galectin-1 within the glioma microenvironment. The data provided in this study reveal a pivotal role for glioma-derived galectin-1 in the regulation of myeloid cell accumulation within the glioma microenvironment, the most abundant immune cell population in high-grade gliomas. Furthermore, the prolonged survival observed in untreated and DC-vaccinated glioma-bearing mice upon the silencing of tumor-derived galectin-1 strongly suggest that the in vivo targeting of tumor-derived galectin-1 might offer a promising and realistic adjuvant treatment modality in patients diagnosed with GBM. PMID- 23929303 TI - Bernard-Soulier syndrome: an update. AB - Bernard-Soulier syndrome (BSS) is a rare inherited platelet bleeding disorder characterized by low platelet count and abnormally large platelets (macrothrombocytopenia). Platelets from BSS patients are typically defective in surface expression of glycoprotein (GP)Ib-IX-V, a platelet-specific adhesion signaling complex, composed of GPIbalpha disulfide linked to GPIbbeta, and noncovalently associated with GPIX and GPV. The major ligand-binding subunit, GPIbalpha, binds the adhesive ligands von Willebrand factor (VWF) or thrombospondin, counterreceptors on activated endothelial cells (P-selectin) or activated leukocytes (integrin alphaMbeta2), and coagulation factors (thrombin, factors XI and XII, high-molecular-weight kininogen). The cytoplasmic domain of GPIb-IX-V interacts with the cytoskeletal protein, filamin-A via a binding site within the GPIbalpha cytoplasmic tail, and with structural-signaling proteins including calmodulin, 14-3-3zeta and the p85 subunit of phosphoinositide 3 kinase. GPIbalpha is physically/functionally co-associated on the platelet surface with the major platelet collagen receptor, GPVI. As such, it is easy to see how genetic defects impacting GPIb-IX-V expression or function can have significant consequences on normal platelet size, adhesion to VWF/collagen and/or stable thrombus formation, and why BSS is often associated with clinical bleeding. Furthermore, the rarity, multiple genetic causes, and variable clinical phenotype of BSS can complicate routine diagnosis. Here, we discuss how studies of BSS have contributed to platelet biology and recent studies to improve diagnosis and treatment. PMID- 23929304 TI - Congenital factor XI deficiency: an update. AB - Severe factor XI (FXI) deficiency is an injury-related bleeding disorder, common in Ashkenazi Jews (with two mutations prevailing), but rare worldwide (with heterogeneous mutations). In the past two decades, more than 220 mutations in the FXI gene have been reported in patients with FXI deficiency, of which 7 showed a founder effect. Inhibitors to FXI were described in patients with null-allele mutations, following exposure to plasma, FXI concentrates, or anti-RhD immunoglobulin. Treatment of patients with severe FXI deficiency remains challenging because factors influencing bleeding risks are still unknown. The use of lower doses of recombinant activated factor VII in comparison with the doses commonly applied in hemophilia A or B seems promising also when assessed in vitro by thrombin generation test. Recently, FXI has been shown to have a separate role in hemostasis and in thrombosis. In animal models, targeting FXI by knocking out the gene or by using FXI-neutralizing antibodies, antisense oligonucleotides, and peptidomimetic inhibitors, prevents arterial and vein thrombosis. The homology between human and murine FXI and the significant antithrombotic effect of FXI deficiency in animal models resulted in the development of a novel approach of targeting FXI for prevention of thrombosis without impairing hemostasis in high risk patients. The acceptance of FXI as a risk factor for thrombosis is a new concept, and patients with severe FXI deficiency might gain profit during life course. PMID- 23929306 TI - Occurrence of thrombosis in rare bleeding disorders. AB - Paradoxically, there are reports of thrombotic events for some rare bleeding disorders associated with significant bleeding tendency. Afibrinogenemia, factor (F) VII, or FXI deficiencies are those most commonly associated with venous or arterial thrombosis. Pathogenesis is multifactorial and the main conditions associated with this complication relate to the coexistence of inherited or acquired thrombotic risk factors linked to certain specific characteristics of the underlying defect. Patients with afibrinogenemia can develop severe, spontaneous, or recurrent thromboembolic disease. Up to 20% of congenital dysfibrinogenemia patients show predisposition to thrombosis. Thrombotic episodes, particularly deep vein thrombosis, have been reported in 3 to 4% FVII deficient patients, even those who were severely affected. These events have been reported either after infusion of plasma derived FXI concentrate or recombinant activated FVII in FXI deficient patients. So, in addition to factor level, replacement therapy must be individualized and should take into account past personal or family history of bleeding and thrombosis, and other prothrombotic risk factors. Treatment of thrombosis represents a challenge. For mild factor deficiencies, antithrombotic prophylaxis must be considered with or without concomitant use of replacement therapy. For all patients, it is also recommended to control known cardiovascular disease risk factors. PMID- 23929307 TI - Factor XIII deficiency: an update. AB - Confirmation of suspected congenital factor XIII (FXIII) deficiency still represents a diagnostic challenge in the field of rare bleeding disorders. Because of the lack of awareness and difficulties associated with timing of blood sampling, FXIII laboratory assays, and interpretation of laboratory results, diagnoses of FXIII deficiency are still missed all over the world with potentially fatal consequences from severe bleeding complications. Better knowledge of FXIII biochemical properties and function and understanding of the principles and limitations of FXIII laboratory assays can prevent missed diagnoses, and patients will benefit from better care. This review gives a detailed overview and update about congenital FXIII deficiency, its epidemiology, and molecular genetics. It highlights the importance of newer specific FXIII assays and their principles to avoid any missed diagnosis of FXIII deficiency. This review also gives an update on the therapeutic options for patients suffering from this rare but life-threatening disease. PMID- 23929305 TI - Glanzmann thrombasthenia: state of the art and future directions. AB - Glanzmann thrombasthenia (GT) is the principal inherited disease of platelets and the most commonly encountered disorder of an integrin. GT is characterized by spontaneous mucocutaneous bleeding and an exaggerated response to trauma caused by platelets that fail to aggregate when stimulated by physiologic agonists. GT is caused by quantitative or qualitative deficiencies of alphaIIbbeta3, an integrin coded by the ITGA2B and ITGB3 genes and which by binding fibrinogen and other adhesive proteins joins platelets together in the aggregate. Widespread genotyping has revealed that mutations spread across both genes, yet the reason for the extensive variation in both the severity and intensity of bleeding between affected individuals remains poorly understood. Furthermore, although genetic defects of ITGB3 affect other tissues with beta3 present as alphavbeta3 (the vitronectin receptor), the bleeding phenotype continues to dominate. Here, we look in detail at mutations that affect (i) the beta-propeller region of the alphaIIb head domain and (ii) the membrane proximal disulfide-rich epidermal growth factor (EGF) domains of beta3 and which often result in spontaneous integrin activation. We also examine deep vein thrombosis as an unexpected complication of GT and look at curative procedures for the diseases, including allogeneic stem cell transfer and the potential for gene therapy. PMID- 23929309 TI - Different antivascular endothelial growth factor treatments and regimens and their outcomes in neovascular age-related macular degeneration: a literature review. AB - Antivascular endothelial growth factor (anti-VEGF) therapy has revolutionised the treatment of wet age-related macular degeneration (wAMD). Recent research has focused on evaluating competing agents and alternative dosage regimens, providing evidence to help determine optimal treatment strategies. We therefore conducted a review of clinical research studies in wAMD published since 2008 that compared anti-VEGF dosing regimens and therapies; seven studies met our inclusion criteria. Data on baseline disease characteristics, disease outcomes, safety (ocular and systemic) and treatment burden (injection and visit frequencies) were extracted on patients treated with ranibizumab 0.5 mg, bevacizumab 1.25 mg or aflibercept 2.0 mg for up to 2 years. For ranibizumab and bevacizumab, visual and anatomical outcomes at 1 and 2 years were superior using scheduled monthly (or 4 weekly (q4w)) compared with as needed or scheduled quarterly dosing regimens. Treatment outcomes were generally better for both drugs when more aggressive retreatment criteria were used, which resulted in more frequent injections. Bevacizumab, however, was associated with a 30-35% elevated rate of serious systemic adverse events compared with ranibizumab, regardless of dosing interval; further study in larger patient populations will be required to determine the validity of this finding. Intravitreal aflibercept injection every 8 weeks was non-inferior to ranibizumab q4w on all visual and anatomical endpoints at week 52, had a similar safety profile and required five fewer anti-VEGF injections. PMID- 23929310 TI - TiO2 supported Pd@Ag as highly selective catalysts for hydrogenation of acetylene in excess ethylene. AB - A novel TiO2 supported core-shell (Pd@Ag) bimetallic catalyst was fabricated via the sequential photodeposition method. The Ag shell effectively blocks the high coordination sites on the Pd core, and therefore pronouncedly enhances the ethylene selectivity for the catalytic hydrogenation of acetylene in excess ethylene. PMID- 23929311 TI - Structure and function: how to connect? AB - INTRODUCTION: The majority, but not all, of very preterm-born infants have difficulties with a variety of cognitive functions as children. It is critical to be able to predict as early as possible those who will have difficulties, to be able to direct appropriate interventions. METHODS: We are conducting multimodal structural and functional MRI studies in very preterm-born infants and following them with behavioural and neuroimaging assessments until 4 years of age. We are also completing structural and more complex functional imaging in school-aged very preterm-born children. RESULTS: A number of MRI measures between preterm and term age correlate with outcome at 2 years of age. Functional and structural differences are also seen at school age; examples from these various studies are presented. CONCLUSION: Structural and functional studies in preterm-born versus term-born infants and children, particularly if completed longitudinally, provide important information on the evolution of brain-behaviour correlates and can help predict outcome in this high-risk population. PMID- 23929313 TI - Single-incision laparoscopic cholecystectomy and overweight patients. AB - BACKGROUND: Modifications of minimally invasive laparoscopic cholecystectomy have been achieved, including single-incision laparoscopic cholecystectomy (SILC). In the current literature, the effects of high body mass index (BMI) on the results of the surgical therapy have not been sufficiently investigated after SILC. We evaluated perioperative outcomes and postoperative complications of overweight patients who underwent SILC. METHODS: Two hundred two patients who underwent SILC were retrospectively evaluated. The data included demographics and outcomes such as postoperative complications and postoperative hospitalization were obtained. For the outcome analyses, patients were divided into two group according to their BMI (<30 vs >= 30 kg/m(2)). RESULTS: Of the 202 patients, 157 patients were in normal weight group and 45 patients were in overweight group. Mean operative time was 31.67 +/- 6.4 min in overweight group and 26.6 +/- 5.3 min in normal weight group. The wound infection rate for overweight and normal weight patients was 13.3 and 7.6 %, respectively. Eleven of the 202 patients (5.4 %) experienced port site hernia (PSH). CONCLUSIONS: This retrospective study comparing overweight and normal weight patient in SILC demonstrates that SILC is associated with the prolonged operative time, high additional port requirement, and increased wound complication rate. PSH occurrence rate was high after SILC irrespective of the body weight. PMID- 23929312 TI - Pre-conditioning with synthetic CpG-oligonucleotides attenuates myocardial ischemia/reperfusion injury via IL-10 up-regulation. AB - The aim of the study was to investigate whether pre-conditioning with CpG oligodeoxynucleotides (CpG-ODN) may change cardiac ischemia/reperfusion (I/R) dependent inflammation and modulates infarct size and cardiac performance. WT and TLR9-deficient mice were pre-treated with 1668-, 1612- and H154-thioate or D-Gal as control. Priming with 1668-thioate significantly induced inflammatory mediators in the serum and a concomitant increase of immune cells in the blood and spleen of WT mice. Furthermore, it induced myocardial pattern recognition receptors and pro-inflammatory cytokines peaking 2 h after priming and a continuous increase of IL-10. 16 h after pre-conditioning, myocardial ischemia was induced for 1 h. Infarct size determined after 24 h of I/R was reduced by 75 % due to pre-conditioning with 1668-thioate but not in the other groups. During reperfusion, cytokine expression in 1668-thioate primed mice increased further with IL-10 exceeding the other mediators by far. These changes were observed neither in animals pre-treated with 1612- or H154-thioate nor in TLR9-deficient mice. The 1668-thioate-dependent increase of IL-10 was further supported by results of a micro-array analysis 3 h after begin of reperfusion. Block of IL-10 signaling increased I/R size and prevented influence of priming. In the group pre treated with 1668-thioate, cardiac function was preserved 24 h, 14 days and 28 days after I/R, whereas animals without pre-conditioning exhibited impaired heart function 24 h and 14 days after I/R. The excessive 1668-thioate-dependent IL-10 up-regulation during pre-conditioning and after I/R seems to be the key factor for reducing infarct size and improving cardiac function. This is in agreement with the finding that IL-10 block prevents cardioprotection by pre-conditioning. PMID- 23929314 TI - Letter to editor: "Gastric fistula after laparoscopic sleeve gastrectomy: don't forget to treat for Candida". PMID- 23929315 TI - Irreversible blindness following intravenous streptokinase. PMID- 23929316 TI - Acute lymphoblastic leukemia with pancytopenia at presentation: clinical correlates, prognostic impact, and association with survival. AB - Acute lymphoblastic leukemia has a wide variety of presentations. There is paucity of any data addressing pancytopenia at presentation in acute lymphoblastic leukemia. In this study we assessed 84 patients with pancytopenia at presentation. They had a significantly lower incidence of bulky disease at presentation. A significantly higher fraction of these patients (n=66, 78.57%) opted for therapy (P=0.005) as compared with the rest. The estimated mean survival in patients presenting with pancytopenia (67.2+/-17.2 mo) was significantly higher (P=0.031, log-rank test) as compared with that of other patients (47.2+/-7.4 mo). Pancytopenia was an independent predictor of better survival (P=0.043) in multivariate analysis. PMID- 23929318 TI - Propranolol for infantile hemangioma (PINCH): an open-label trial to assess the efficacy of propranolol for treating infantile hemangiomas and for determining the decline in heart rate to predict response to propranolol. AB - BACKGROUND: Propranolol has emerged as front-line therapy for infantile hemangiomas (IHs). However, a well-defined protocol for administering and predicting response to propranolol is unavailable. METHODS: In this open-label trial, 31 children with IH (median age=5 mo; range,1 mo to 9 y) were administered propranolol (2 mg/kg/d) for a median duration of 28 weeks (12 to 50 wk). They were compared with 14 historical controls with IH who did not receive any treatment. An image-based scoring system was used to assess involution. RESULTS: Propranolol (28/31, 90.3%) produced better and faster response compared with control treatment (4/14, 28.6%). With propranolol, 65% to 80% involution was obtained in the first 8 weeks, with an additional 2% to 10% involution until 20 weeks. After 20 weeks, the changes in IH were insignificant. Response was more pronounced among infants <=6 months of age who attained a peak involution score of 1.86, suggesting >80% involution of IH. The similar score in the cohort aged 6 to 36 months was 3.31. The heart rate (HR) decline after propranolol treatment was significantly higher among patients whose hemangioma responded to propranolol than in those who did not respond (P=0.0006). Decline in HR by >20%, 2 weeks after propranolol administration, was predictive of IH involution (relative risk=0.11; 95% confidence interval, 0.02-0.51; P=0.036). CONCLUSIONS: Propranolol is efficacious in patients with IH. The most pronounced response is seen in the first 8 weeks and in infants aged 6 months or younger. A decline in HR >20% is an early marker of response to propranolol. PMID- 23929317 TI - Risk factors for human herpesvirus 6 reactivation and its relationship with syndrome of inappropriate antidiuretic hormone secretion after stem cell transplantation in pediatric patients. AB - There have been several reports on the reactivation of human herpesvirus 6 (HHV6) after stem cell transplantation (SCT) in adults, which sometimes induces severe illness. Few reports exist on pediatric patients; therefore, we retrospectively examined HHV6 reactivation after SCT in children. We reviewed 80 patients with a median age of 6 years. We analyzed HHV6 DNA serum samples from the patients before SCT and at 20 and 40 days after SCT using polymerase chain reaction. We also analyzed the relationship between HHV6 reactivation and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). At 20 days after SCT, 35.0% of serum samples were positive for HHV6 DNA. The median viral load was 3.1*10 copies/mL serum. Multivariate analysis showed cord blood transplantation as the only risk factor for HHV6 reactivation. HHV6 reactivation occurs in 59.4% of 32 patients who underwent cord blood transplantation and in 18.8% of 48 patients who underwent SCT from other sources. Among the 14 patients with SIADH, 78.6% experienced HHV6 reactivation. Among the 66 patients without SIADH, only 25.8% had HHV6 reactivation. This result was statistically significant (P<0.001). This analysis revealed that HHV6 reactivation occurs in many children. In addition, HHV6 reactivation plus SIADH should prompt evaluation for central nervous system disease. PMID- 23929319 TI - Osteosarcoma after bone marrow transplantation: still a challenge. PMID- 23929320 TI - Open to interpretation. PMID- 23929321 TI - Myriad decision aftershocks ripple through biotech. PMID- 23929325 TI - Melanoma combination therapies ward off tumor resistance. PMID- 23929328 TI - Volunteer GM wheat, mischief or carelessness? PMID- 23929331 TI - SARS-like virus reignites ownership feuds. PMID- 23929332 TI - 2Q13--an IPO revival. PMID- 23929333 TI - Spreading biotech dollars around Washington. PMID- 23929334 TI - Stock options and beyond. PMID- 23929335 TI - Startups on the menu. PMID- 23929336 TI - Heritable gene targeting in the mouse and rat using a CRISPR-Cas system. PMID- 23929337 TI - Simultaneous generation and germline transmission of multiple gene mutations in rat using CRISPR-Cas systems. PMID- 23929338 TI - Targeted genome modification of crop plants using a CRISPR-Cas system. PMID- 23929339 TI - Multiplex and homologous recombination-mediated genome editing in Arabidopsis and Nicotiana benthamiana using guide RNA and Cas9. PMID- 23929340 TI - Targeted mutagenesis in the model plant Nicotiana benthamiana using Cas9 RNA guided endonuclease. PMID- 23929342 TI - The rarest of bounties. PMID- 23929341 TI - Chinese hamster genome sequenced from sorted chromosomes. PMID- 23929343 TI - Public biotech 2012--the numbers. PMID- 23929344 TI - The European BRCA patent oppositions and appeals: coloring inside the lines. PMID- 23929346 TI - From embryonic stem cells to mature photoreceptors. PMID- 23929347 TI - Network cleanup. PMID- 23929348 TI - Taking the fish out of fish oil. PMID- 23929349 TI - A caffeine fix for human nuclear transfer? PMID- 23929351 TI - Second-quarter biotech job picture. PMID- 23929353 TI - Cytogenetic study of secondary malignancy in giant cell tumor. PMID- 23929354 TI - Transfection in the third dimension. AB - An understanding of parameters that modulate gene transfer in 3-D will assist in the formation of gene delivery systems and scaffolds, which can mediate efficient non-viral delivery for guiding in vivo tissue regeneration and therapy. We have previously demonstrated the cell area and length, integrin expression, and RhoGTPase mediated signalling to be pivotal parameters that guide gene transfer to mouse mesenchymal stem cells (mMSCs) cultured in 2-D and are modulated by ECM proteins. In this study, we were interested in determining if cationic polymer mediated gene transfer to cells seeded in 3-D would occur through different mechanisms as compared to those seeded in 2-D. In particular, we examined the endocytosis pathways used to internalize polyplexes, and the role of cytoskeletal dynamics and RhoGTPases in non-viral gene transfer for cells seeded in 2-D and 3 D. Inhibition of clathrin- and caveolae-mediated endocytosis resulted in a more drastic decrease in overall transgene expression for cells seeded in 3-D than for those in 2-D. In addition, polyplex internalization was only significantly decreased in 3-D when clathrin-mediated endocytosis was inhibited, while caveolae mediated endocytosis inhibition for cells seeded in 2-D resulted in the strongest polyplex internalization inhibition. Actin and microtubule polymerization affected 2-D and 3-D transfection differently. Microtubule depolymerization enhanced transgene expression in 2-D, but inhibited transgene expression in 3-D. Lastly, inhibition of RhoGTPases also affected 2-D and 3-D transfection differently. The inhibition of ROCK effectors resulted in a decrease of transgene expression and internalization for cells seeded in 3-D, but not in 2-D, and the inhibition of the effector PAK1 resulted in an increase of transgene expression for both 2-D and 3-D. Overall, our study suggests that the process of gene transfer occurs through different mechanisms for cells seeded in 2-D compared to those seeded in 3-D. PMID- 23929355 TI - Assisting Social Security Disability Insurance beneficiaries with schizophrenia, bipolar disorder, or major depression in returning to work. AB - OBJECTIVE: People with psychiatric impairments (primarily schizophrenia or a mood disorder) are the largest and fastest-growing group of Social Security Disability Insurance (SSDI) beneficiaries. The authors investigated whether evidence-based supported employment and mental health treatments can improve vocational and mental health recovery for this population. METHOD: Using a randomized controlled trial design, the authors tested a multifaceted intervention: team-based supported employment, systematic medication management, and other behavioral health services, along with elimination of barriers by providing complete health insurance coverage (with no out-of-pocket expenses) and suspending disability reviews. The control group received usual services. Paid employment was the primary outcome measure, and overall mental health and quality of life were secondary outcome measures. RESULTS: Overall, 2,059 SSDI beneficiaries with schizophrenia, bipolar disorder, or depression in 23 cities participated in the 2 year intervention. The teams implemented the intervention package with acceptable fidelity. The intervention group experienced more paid employment (60.3% compared with 40.2%) and reported better mental health and quality of life than the control group. CONCLUSIONS: Implementation of the complex intervention in routine mental health treatment settings was feasible, and the intervention was effective in assisting individuals disabled by schizophrenia or depression to return to work and improve their mental health and quality of life. PMID- 23929356 TI - Fast micro-iontophoresis of glutamate and GABA: a useful tool to investigate synaptic integration. AB - One of the fundamental interests in neuroscience is to understand the integration of excitatory and inhibitory inputs along the very complex structure of the dendritic tree, which eventually leads to neuronal output of action potentials at the axon. The influence of diverse spatial and temporal parameters of specific synaptic input on neuronal output is currently under investigation, e.g. the distance-dependent attenuation of dendritic inputs, the location-dependent interaction of spatially segregated inputs, the influence of GABAergig inhibition on excitatory integration, linear and non-linear integration modes, and many more. With fast micro-iontophoresis of glutamate and GABA it is possible to precisely investigate the spatial and temporal integration of glutamatergic excitation and GABAergic inhibition. Critical technical requirements are either a triggered fluorescent lamp, light-emitting diode (LED), or a two-photon scanning microscope to visualize dendritic branches without introducing significant photo damage of the tissue. Furthermore, it is very important to have a micro iontophoresis amplifier that allows for fast capacitance compensation of high resistance pipettes. Another crucial point is that no transmitter is involuntarily released by the pipette during the experiment. Once established, this technique will give reliable and reproducible signals with a high neurotransmitter and location specificity. Compared to glutamate and GABA uncaging, fast iontophoresis allows using both transmitters at the same time but at very distant locations without limitation to the field of view. There are also advantages compared to focal electrical stimulation of axons: with micro iontophoresis the location of the input site is definitely known and it is sure that only the neurotransmitter of interest is released. However it has to be considered that with micro-iontophoresis only the postsynapse is activated and presynaptic aspects of neurotransmitter release are not resolved. In this article we demonstrate how to set up micro-iontophoresis in brain slice experiments. PMID- 23929357 TI - Comparison of image quality between filtered back-projection and the adaptive statistical and novel model-based iterative reconstruction techniques in abdominal CT for renal calculi. AB - OBJECTIVES: To compare image quality on computed tomographic (CT) images acquired with filtered back-projection (FBP), adaptive statistical iterative reconstruction (ASIR) and model-based iterative reconstruction (MBIR) techniques in CT kidney/ureter/bladder (KUB) examination. METHODS: Eighteen patients underwent standard protocol CT KUB at our institution. The same raw data were reconstructed using FBP, ASIR and MBIR. Objective [mean image noise, contrast-to noise ratio (CNR) for kidney and mean attenuation values of subcutaneous fat] and subjective image parameters (image noise, image contrast, overall visibility of kidneys/ureters/bladder, visibility of small structures, and overall diagnostic confidence) were assessed using a scoring system from 1 (best) to 5 (worst). RESULTS: Objective image measurements revealed significantly less image noise and higher CNR and the same fat attenuation values for the MBIR technique (P < 0.05). MBIR scored best in all the subjective image parameters (P < 0.001) with averages ranging between 2.05-2.73 for MBIR, 2.95-3.10 for ASIR and 3.08-3.31 for FBP. No significant difference was observed between FBP and ASIR (P > 0.05), while there was a significant difference between ASIR vs. MBIR (P < 0.05). The mean effective dose was 3 mSv. CONCLUSION: MBIR shows superior reduction in noise and improved image quality (both objective and subjective analysis) compared with ASIR and FBP CT KUB examinations. MAIN MESSAGES: * There are many reconstruction options in CT. * Novel model-based iterative reconstruction (MBIR) showed the least noise and optimal image quality. * For CT of the kidneys/ureters/bladder, MBIR should be utilised, if available. * Further studies to reduce the dose while maintaining image quality should be pursued. PMID- 23929358 TI - Unprecedented infinite lanthanide hydroxide ribbons [Ln3(MU3-OH)3]n(6n+) in a 3-D metal-organic framework. AB - Unprecedented infinite lanthanide hydroxide ribbons interconnected by Pra2biim(2 ) (H2Pra2biim = 1'-di(propionic acid)-2,2'-biimidazole) into 3-D [Ln3(MU3 OH)3(Pra2biim)3 (H2O)2]n.4nH2O (Ln = Nd, Pr and La) have been achieved by utilizing the unique H2Pra2biim-Ln(3+) hydrolysis system. The Ln...Ln antiferromagnetic coupling with magnetic anisotropy has been observed. PMID- 23929359 TI - Interleukin-17A stimulates migration of periodontal ligament fibroblasts via p38 MAPK/NF-kappaB -dependent MMP-1 expression. AB - Interleukin-17 (IL-17) is a cytokine secreted predominantly by Th17 cells. Although IL-17 is primarily associated with the induction of tissue inflammation, the other biological functions of IL-17, including its wound-healing functions, have yet to be thoroughly explored. Fibroblast proliferation and migration play essential roles in periodontal wound-healing responses. In this study, we report that IL-17A can increase the migration and expression of matrix metalloproteinase (MMP)-1 in human periodontal ligament (PDL) fibroblasts but has no effect on PDL fibroblast proliferation. IL-17A-induced MMP-1 expression led to cell migration, which was attenuated by pre-treatment with IL-17 receptor neutralizing antibody and small interfering RNA (siRNA) for MMP-1. The IL-17A-induced cell migration was also attenuated by its tissue inhibitor of matrix metalloproteinase (TIMP)-1. In addition, a p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580) inhibited IL-17A-induced increase of the migration and MMP-1 upregulation of PDL fibroblasts. The involvement of p38 MAPK in IL-17A-induced MMP-1 expression and cell migration was further confirmed by transfection of p38alpha siRNA. A nuclear factor kappaB (NF-kappaB) inhibitor (pyrrolidine dithiocarbamate) also suppressed the cell migration and MMP-1 expression enhanced by IL-17A. Moreover, transfection with p38alpha siRNA inhibited IL-17A-induced NF-kappaB nuclear translocation as well as NF-kappaB binding activity. Our results suggest that IL 17A enhances the migration of PDL fibroblasts by increasing MMP-1 expression through the IL-17 receptor, p38 MAPK, and NF-kappaB signal transduction pathways. PMID- 23929360 TI - A review of the confirmation algorithm and related timing cycles of St. Jude ICDs. AB - The confirmation algorithm of implantable cardioverter-defibrillators (ICDs) functioning in the uncommitted mode verifies the presence of a continuing tachyarrhythmia during or following charging of the capacitor. Confirmation is usually applied in relation to the first shock. The details of the normal reconfirmation process of St. Jude ICDs and its role in delayed shock delivery or other abnormalities have received relatively little attention. This review describes the confirmation process of St. Jude ICDs and provides an illustrative clinical example of delayed shock as a result of a pacing or sensing lead fracture. The fundamental timing cycles of St. Jude ICDs are also reviewed to facilitate understanding of the problems related to the confirmation process. PMID- 23929361 TI - Light curing through glass ceramics: effect of curing mode on micromechanical properties of dual-curing resin cements. AB - OBJECTIVES: The aim of this study was to investigate micromechanical properties of five dual-curing resin cements after different curing modes including light curing through glass ceramic materials. MATERIALS AND METHODS: Vickers hardness (VH) and indentation modulus (Y HU) of Panavia F2.0, RelyX Unicem 2 Automix, SpeedCEM, BisCem, and BeautiCem SA were measured after 1 week of storage (37 degrees C, 100 % humidity). The resin cements were tested following self-curing or light curing with the second-generation light-emitting diode (LED) curing unit Elipar FreeLight 2 in Standard Mode (1,545 mW/cm(2)) or with the third-generation LED curing unit VALO in High Power Mode (1,869 mW/cm(2)) or in XtraPower Mode (3,505 mW/cm(2)). Light curing was performed directly or through glass ceramic discs of 1.5 or 3 mm thickness of IPS Empress CAD or IPS e.max CAD. VH and Y HU were analysed with Kruskal-Wallis tests followed by pairwise Wilcoxon rank sum tests (alpha = 0.05). RESULTS: RelyX Unicem 2 Automix resulted in the highest VH and Y HU followed by BeautiCem SA, BisCem, SpeedCEM, and finally Panavia F2.0. Self-curing of RelyX Unicem 2 Automix and SpeedCEM lowered VH and Y HU compared to light curing whereas self-curing of Panavia F2.0, BisCem, and BeautiCem SA led to similar or significantly higher VH and Y HU compared to light curing. Generally, direct light curing resulted in similar or lower VH and Y HU compared to light curing through 1.5-mm-thick ceramic discs. Light curing through 3-mm thick discs of IPS e.max CAD generally reduced VH and Y HU for all resin cements except SpeedCEM, which was the least affected by light curing through ceramic discs. CONCLUSIONS: The resin cements responded heterogeneously to changes in curing mode. The applied irradiances and light curing times adequately cured the resin cements even through 1.5-mm-thick ceramic discs. CLINICAL RELEVANCE: When light curing resin cements through thick glass ceramic restorations, clinicians should consider to prolong the light curing times even with LED curing units providing high irradiances. PMID- 23929362 TI - Non-erosive reflux disease patients are more complex than the sole endoscopy tells us. PMID- 23929363 TI - Response to Ottonello et al.: Non-erosive reflux disease patients are more complex than the sole endoscopy tells us. PMID- 23929364 TI - Response to a letter to the editor addressing the publication "Effect of nonsurgical periodontal therapy and strict plaque control on preterm/low birth weight: a randomized controlled clinical trial". PMID- 23929367 TI - Posterior maxillary segmental osteotomy for the implant reconstruction of a vertically deficient ridge: a 3-year clinical report. AB - A vertically deficient posterior maxillary edentulous ridge in conjunction with sinus pneumatization or extensive horizontal bone resorption presents significant challenges for implant placement and restoration with an implant-supported fixed prosthesis. Various surgical techniques have been reported for the reconstruction of the vertically deficient posterior maxilla: guided bone regeneration, sinus elevation, block and/or particulate grafting with barrier membranes, and distraction osteogenesis. This clinical report describes the technique, the management of intrasurgical complications, and the 3-year follow-up results of augmenting the vertically deficient posterior maxilla with a segmental osteotomy prior to rehabilitation with an implant-supported fixed prosthesis. PMID- 23929365 TI - Fatty acid composition, physicochemical properties, antioxidant and cytotoxic activity of apple seed oil obtained from apple pomace. AB - BACKGROUND: Apple pomace is generated in huge quantities in juice-processing industries the world over and continuous efforts are being made for its inclusive utilization. In this study, apple seeds separated from industrial pomace were used for extraction of oil. The fatty acid composition, physicochemical and antioxidant as well as in vitro anticancer properties of extracted oil were studied to assess its suitability in food and therapeutic applications. RESULTS: The fatty acid composition of seed oil revealed the dominance of oleic (46.50%) and linoleic acid (43.81%). It had high iodine (121.8 g I 100 g-1) and saponification value (184.91 mg KOH g-1 oil). The acid value, refractive index and relative density were 4.28 mg KOH g-1, 1.47 and 0.97 mg mL-1, respectively. The antioxidant potential (IC50) of apple seed oil was 40.06 ug mL-1. Cytotoxicity of apple seed oil against CHOK1, SiHa and A549 cancer cell lines ranged between 0.5 +/- 0.06% and 88.6 +/- 0.3%. CONCLUSION: The physicochemical properties of apple seed oil were comparable with edible food oil, indicating its better stability and broad application in the food and pharmaceutical industries. Apple seed oil could be a good source of natural antioxidants. Also, the in vitro cytotoxic activity against specific cell lines exhibited its potential as an anticancer agent. PMID- 23929368 TI - Patient satisfaction survey of mandibular two-implant-retained overdentures in a predoctoral program. AB - STATEMENT OF PROBLEM: In response to the Commission of Dental Accreditation (CODA) mandate of a competency in the "replacement of teeth including fixed, removable and implant" prostheses, a predoctoral implant curriculum was implemented at New York University College of Dentistry. The assessment of the success or failure of a program should include an assessment of patient satisfaction with the treatment received in the predoctoral clinics. PURPOSE: The purpose of this study was to measure patient satisfaction with the mandibular 2 implant-retained overdenture therapy received in the predoctoral program at New York University College of Dentistry. MATERIAL AND METHODS: A telephone survey of patients who received an implant-retained overdenture in the predoctoral clinics at New York University, College of Dentistry (n=101) was conducted. Two of the authors contacted patients for participation in the survey and, using a prepared script, asked about their satisfaction with items such as function, comfort, and esthetics in addition to their overall satisfaction with the treatment they received. Data were analyzed with descriptive statistics. RESULTS: The study revealed that 79% of participants were satisfied with their masticatory ability, 84% were satisfied with the comfort of the prosthesis, and 89% were satisfied with the esthetics of their new prosthesis. Additionally, 85% of participants reported satisfaction with the overall treatment experience, and 90% would recommend that a friend receive the same treatment. CONCLUSIONS: The results of this study support the incorporation of treatment with an implant-retained mandibular overdenture as part of the routine care provided in the predoctoral education program to meet the mandates of CODA. PMID- 23929366 TI - Renal effects of levosimendan: a consensus report. AB - Renal dysfunction is common in clinical settings in which cardiac function is compromised such as heart failure, cardiac surgery or sepsis, and is associated with high morbidity and mortality. Levosimendan is a calcium sensitizer and potassium channel opener used in the treatment of acute heart failure. This review describes the effects of the inodilator levosimendan on renal function. A panel of 25 scientists and clinicians from 15 European countries (Austria, Finland, France, Hungary, Germany, Greece, Italy, Portugal, the Netherlands, Slovenia, Spain, Sweden, Turkey, the United Kingdom, and Ukraine) convened and reached a consensus on the current interpretation of the renal effects of levosimendan described both in non-clinical research and in clinical study reports. Most reports on the effect of levosimendan indicate an improvement of renal function in heart failure, sepsis and cardiac surgery settings. However, caution should be applied as study designs differed from randomized, controlled studies to uncontrolled ones. Importantly, in the largest HF study (REVIVE I and II) no significant changes in the renal function were detected. As it regards the mechanism of action, the opening of mitochondrial KATP channels by levosimendan is involved through a preconditioning effect. There is a strong rationale for randomized controlled trials seeking beneficial renal effects of levosimendan. As an example, a study is shortly to commence to assess the role of levosimendan for the prevention of acute organ dysfunction in sepsis (LeoPARDS). PMID- 23929369 TI - Proposed shade guide for human facial skin and lip: a pilot study. AB - STATEMENT OF PROBLEM: Currently, no commercially available facial shade guide exists in the United States for the fabrication of facial prostheses. PURPOSE: The purpose of this study was to measure facial skin and lip color in a human population sample stratified by age, gender, and race. Clustering analysis was used to determine optimal color coordinates for a proposed facial shade guide. MATERIAL AND METHODS: Participants (n=119) were recruited from 4 racial/ethnic groups, 5 age groups, and both genders. Reflectance measurements of participants' noses and lower lips were made by using a spectroradiometer and xenon arc lamp with a 45/0 optical configuration. Repeated measures ANOVA (alpha=.05), to identify skin and lip color differences, resulting from race, age, gender, and location, and a hierarchical clustering analysis, to identify clusters of skin colors) were used. RESULTS: Significant contributors to L*a*b* facial color were race and facial location (P<.01). b* affected all factors (P<.05). Age affected only b* (P<.001), while gender affected only L* (P<.05) and b* (P<.05). Analyses identified 5 clusters of skin color. CONCLUSIONS: The study showed that skin color caused by age and gender primarily occurred within the yellow-blue axis. A significant lightness difference between gender groups was also found. Clustering analysis identified 5 distinct skin shade tabs. PMID- 23929370 TI - An in vitro comparison of the accuracy of implant impressions with coded healing abutments and different implant angulations. AB - STATEMENT OF PROBLEM: Fabricating implant definitive casts with CAD/CAM technology (Robocasts) from coded healing abutment impressions represents a simpler and innovative alternative to conventional implant impression techniques. However, information about the accuracy of the impressions and the resultant definitive casts is limited. PURPOSE: The purpose of the study was to evaluate the accuracy of the Robocasts and compare them to those definitive casts fabricated with conventional implant impression techniques (open tray with splinted impression copings technique). MATERIAL AND METHODS: A reference epoxy resin cast was fabricated and shaped to simulate a dental arch. Two regular platform implant replicas (Biomet 3i Certain, 4.1 mm diameter and 15 mm length) with internal connections were placed 10 mm apart with a 10-degree convergence for one side of the reference resin cast and a 30-degree convergence for the other. Coded healing abutments (Encode) were placed at 3 different heights above the level of the soft tissue replication material (approximately 1, 2, and 4 mm) and served as test groups (E1, E2, and E4), and open trays with splinted impression copings (OTSC) served as a control group. The control group was compared to the impressions of the coded healing abutments by using a standardized measurement protocol. Impressions were made for each group (n=18) and poured with vacuum mixed (100 g powder/20 mL water) Type IV dental stone. The vertical discrepancy (Z axis) between 2 prefabricated passively fitting titanium reference frameworks and the platforms of the implant replicas was measured with an optical comparator applying the 1 screw test. Data were analyzed with Kruskal Wallis and post-hoc Mann-Whitney U tests, as well as the Wilcoxon signed-rank tests. The Bonferroni correction was used to account for multiple comparisons. The significance level (alpha) used in a given set of tests was equal to .05 divided by the number of tests performed in that set. RESULTS: The median vertical discrepancy of each coded healing abutment impression group was higher than the corresponding median of the control group (OTSC) for every combination of angulation and position. Kruskal-Wallis tests indicated a statistically significant difference (P<.001) between groups for each angulation/position combination. All post hoc Mann-Whitney U tests indicated statistically significant differences (all P<=.002) between OTSC and the other groups. Differences between the angulations and positions were not statistically significant when accounting for multiple comparisons. CONCLUSIONS: The implant definitive casts fabricated from the coded healing abutment impressions were found to be less accurate than those fabricated from the open tray with splinted impression copings technique for restoring 2 paired (10 or 30 degrees) convergent internal connection implants with nonengaging screw-retained splinted 2-unit implant restorations. Accuracy of fit was not influenced by the implant angulation or position for either impression technique or by the Encode healing abutment height for the Encode impression technique. PMID- 23929371 TI - Withdrawn. Duplicate: Effect of gold sputtering on the adhesion of porcelain to cast and machined titanium. AB - STATEMENT OF PROBLEM: The bond strength of porcelain to titanium is insufficient to provide a clinically acceptable alternative to existing alloys for metal ceramic restorations. PURPOSE: The purpose of the study was to investigate the effect of gold coating on the adhesion of porcelain to titanium. MATERIAL AND METHODS: Forty titanium plates (25 * 8 * 1 mm) were prepared by casting and machining procedures to make 2 groups of each type (n=10). All plates were subjected to airborne-particle abrasion with alumina powder. One of each of the cast and machined groups was gold sputtered. A layer of porcelain was built up onto the titanium plates of all groups with a conventional technique. A precrack was created at the center of the specimen. Specimens were then subjected to a 4 point bending test with a universal testing machine. The load recorded from the test was used to determine adhesion in terms of the strain energy release rate (G value). The data were analyzed with ANOVA and post hoc testing (alpha=.05). The interfacial area of the tested specimen was then examined with scanning electron microscopy. RESULTS: The G values of the gold-sputtered groups were significantly higher than those of the uncoated groups for both cast and machined groups (P<.05). No significant differences were noted within the groups. CONCLUSIONS: The adhesion between porcelain and titanium was significantly improved when titanium was sputter coated with gold in both the cast and machined groups. PMID- 23929372 TI - Antibacterial activity, surface roughness, flexural strength, and solubility of conventional luting cements containing chlorhexidine diacetate/cetrimide mixtures. AB - STATEMENT OF PROBLEM: The failure of fixed dental restorations is commonly associated with caries. The use of conventional luting cements containing antibacterial agents may overcome this problem. PURPOSE: The purpose of this study was to evaluate the antibacterial activity (ABA), surface roughness (Ra), flexural strength (FS), and solubility (SL) patterns of the conventional dental luting cements zinc phosphate (ZP), zinc polycarboxylate (PC), and glass ionomer (GIC) after the addition of 5% chlorhexidine diacetate/cetrimide (CHX+CT). MATERIAL AND METHODS: Antibacterial agents with a total concentration of 5% (2.5% CHX+2.5% CT) were added to antibacterial agent-free conventional luting cement powders (ZPC, PCC, and GICC) and designated as experimental groups (ZPE, PCE, and GICE). ABA against Streptococcus mutans (SM) and Lactobacillus casei (LB) was examined by using the agar diffusion test method. Ra, FS, and SL values were obtained after storage in distilled water at 37 degrees C for 24 hours. The Kruskal-Wallis and Mann Whitney U with Bonferroni correction tests were used to test for agar diffusion (alpha=.05) and 2-way ANOVA and Fisher Least Significant Difference (LSD) test were used to measure Ra, FS, and SL (alpha=.05). RESULTS: The control groups exhibited limited ABA. With the exception of PCE>PCC on day 1 for SM, all experimental groups showed significantly greater and longer-lasting protection against SM and LB bacteria for up to 180 days than their controls (P<.05). Ra values decreased (ZPC>ZPE; P>.05, PCC>PCE; P<.05) except that GICE>GICC (P>.05) when compared with their individual controls. Control groups exhibited higher FS values than did the experimental groups (ZPC>ZPE; P<.05, PCC>PCE; P<.05, GICC>GICE; P>.05). The experimental groups exhibited higher solubilities than did their controls in the ZPC (P>.05) and GICC groups (P<.05) but were lower in PCC group (P<.05). CONCLUSIONS: Incorporating a 5% CHX+CT mixture into conventional dental luting cements and altering their Ra, FS, and SL values may provide greater antibacterial protection against SM and LB. PMID- 23929373 TI - Influence of alveolar bone loss, post type, and ferrule presence on the biomechanical behavior of endodontically treated maxillary canines: strain measurement and stress distribution. AB - STATEMENT OF PROBLEM: Teeth restored with posts are more frequently associated with bone loss, but there is no evidence to suggest that the post type and the presence of bone loss influence biomechanical behavior. PURPOSE: The purpose of this study was to evaluate the effect of alveolar bone loss, post type, and ferrule presence on the biomechanical behavior of endodontically treated maxillary canines. MATERIAL AND METHODS: For the experimental analysis, 40 human canine teeth were selected and divided into 8 experimental groups (n=5) according to 3 treatment variations: with or without 5.0 mm of bone loss (bl), with or without a ferrule, and restored with cast post and cores or glass fiber post. The restored canines were loaded at 15 degrees, and deformation was measured with strain gauges placed on the buccal and proximal root surfaces. Strain results were analyzed by 3-way analysis of variance (ANOVA) and the Tukey HSD tests (alpha=.05). For the finite element analysis, eight 3D models were created by following the same variations of the experimental analysis. The models were analyzed by using the maximum principal stress criteria for stress distribution analysis. RESULTS: The absence of a ferrule significantly increased the buccal and proximal strain values. The post type influenced the stress distribution, mainly at the interface of post and dentin. The bone loss significantly increased the stress concentration and strain values, mainly on root dentin and surrounding cortical bone. CONCLUSIONS: The presence of a ferrule improved the mechanical behavior. The 5.0 mm of bone loss significantly increased the stress concentration and the strain on the root dentin. PMID- 23929374 TI - Fracture resistance of endodontically treated teeth restored with glass fiber reinforced posts and cast gold post and cores cemented with three cements. AB - STATEMENT OF PROBLEM: Dental fractures can occur in endodontically treated teeth restored with glass fiber reinforced posts and cast gold posts. PURPOSE: The objective of this study was to record the fracture strength of endodontically treated teeth restored with glass fiber reinforced or cast gold post and cores cemented with 3 cements. MATERIAL AND METHODS: Forty-two single-rooted premolars with standardized weakened roots were endodontically treated and allocated to 6 experimental groups (n=7) defined by the 2 factors investigated: post system and cement. Three groups were restored with glass fiber posts and resin-modified glass ionomer cement, dual-polymerizing resin cement, or chemically active autopolymerizing resin cement. The other 3 groups were restored with cast gold post and cores and the same 3 cements. The cores of the glass fiber post groups were fabricated with composite resin core material. Metal crowns were cemented on the cores in the 6 groups. The entire system was subjected to continuous compression in a universal testing machine, and fracture limit and location (cervical third, middle third, or apical third) were noted. Two-way ANOVA and the Scheffe test were used to analyze the data and compare the groups (alpha=.05). RESULTS: Two-way ANOVA showed significant differences in the post type (P<.001) and the cements (P<.001). The interaction between them (P<.001) was statistically significant in the fracture resistance of the endodontically treated teeth. The greatest interaction between post and cement was the glass fiber post with resin modified glass ionomer cement, followed by the cast gold post and core with resin modified glass ionomer cement. CONCLUSIONS: The use of a glass fiber reinforced post and resin-modified glass ionomer cement increased the fracture resistance of endodontically treated teeth. PMID- 23929376 TI - A technique to correct incisal plane error in maxillary immediate denture therapy. AB - This article describes a predictable technique for rectifying an asymmetrical incisal plane after the placement of a maxillary immediate denture. The inability to have a wax trial placement precludes an esthetic evaluation of the maxillary anterior teeth, which may lead to esthetic errors. After correction of the incisal plane, a rebase procedure and a clinical remount follow after appropriate healing time for the patient after extraction. PMID- 23929375 TI - Push-out bond strengths of different dental cements used to cement glass fiber posts. AB - STATEMENT OF PROBLEM: Since the introduction of glass fiber posts, irreversible vertical root fractures have become a rare occurrence; however, adhesive failure has become the primary failure mode. PURPOSE: The purpose of this study was to evaluate the push-out bond strength of glass fiber posts cemented with different luting agents on 3 segments of the root. MATERIAL AND METHODS: Eighty human maxillary canines with similar root lengths were randomly divided into 8 groups (n=10) according to the cement assessed (Rely X luting, Luting and Lining, Ketac Cem, Rely X ARC, Biscem, Duo-link, Rely X U100, and Variolink II). After standardized post space preparation, the root dentin was pretreated for dual polymerizing resin cements and untreated for the other cements. The mixed luting cement paste was inserted into post spaces with a spiral file and applied to the post surface that was seated into the canal. After 7 days, the teeth were sectioned perpendicular to their long axis into 1-mm-thick sections. The push-out test was performed at a speed of 0.5 mm/min until extrusion of the post occurred. The results were evaluated by 2-way ANOVA and the all pairwise multiple comparison procedures (Tukey test) (alpha=.05). RESULTS: ANOVA showed that the type of interaction between cement and root location significantly influenced the push-out strength (P<.05). The highest push-out strength results with root location were obtained with Luting and Lining (S3) (19.5 +/-4.9 MPa), Ketac Cem (S2) (18.6 +/-5.5 MPa), and Luting and Lining (S1) (18.0 +/-7.6 MPa). The lowest mean values were recorded with Variolink II (S1) (4.6 +/-4.0 MPa), Variolink II (S2) (1.6 +/-1.5 MPa), and Rely X ARC (S3) (0.9 +/-1.1 MPa). CONCLUSIONS: Self adhesive cements and glass ionomer cements showed significantly higher values compared to dual-polymerizing resin cements. In all root segments, dual polymerizing resin cements provided significantly lower bond strength. Significant differences among root segments were found only for Duo-link cement. PMID- 23929377 TI - Fabrication of a fixed multipurpose template retained by existing dental implants. AB - This report describes the use of a multipurpose template stabilized with existing implants to provide accurate information for immediate implant placement, to facilitate impression making, and to record maxillomandibular relationships for the fabrication of an interim immediate implant-supported fixed prosthesis. PMID- 23929378 TI - Contrast-enhanced ultrasound in renal transplants: applications and future directions. PMID- 23929379 TI - [Diagnosis and therapy of fetal arrhythmia part 2--Fetal tachyarrhythmias and their intrauterine treatment]. PMID- 23929380 TI - Hepatocellular carcinoma presenting as a wandering abdominal lump with atypical CEUS. PMID- 23929381 TI - Hydrogels in Healthcare: From Static to Dynamic Material Microenvironments. AB - Advances in hydrogel design have revolutionized the way biomaterials are applied to address biomedical needs. Hydrogels were introduced in medicine over 50 years ago and have evolved from static, bioinert materials to dynamic, bioactive microenvironments, which can be used to direct specific biological responses such as cellular ingrowth in wound healing or on-demand delivery of therapeutics. Two general classes of mechanisms, those defined by the user and those dictated by the endogenous cells and tissues, can control dynamic hydrogel microenvironments. These highly tunable materials have provided bioengineers and biological scientists with new ways to not only treat patients in the clinic but to study the fundamental cellular responses to engineered microenvironments as well. Here, we provide a brief history of hydrogels in medicine and follow with a discussion of the synthesis and implementation of dynamic hydrogel microenvironments for healthcare-related applications. PMID- 23929382 TI - Paracentral acute middle maculopathy: a new variant of acute macular neuroretinopathy associated with retinal capillary ischemia. AB - IMPORTANCE: With the advent of more sophisticated imaging systems, such as spectral domain optical coherence tomography (SD-OCT), disruption of the inner segment/outer segment (IS/OS) band, and thinning of the outer nuclear layer (ONL) have been identified in association with acute macular neuroretinopathy (AMN). OBJECTIVES: To characterize a new SD-OCT presentation of AMN as a paracentral acute middle maculopathy and to describe multimodal imaging findings that implicate an underlying pathogenesis related to retinal capillary ischemia. DESIGN, SETTING, AND PARTICIPANTS: Retrospective observational case series (January 1, 2012, to January 1, 2013) reviewing clinical and imaging data from 9 patients (11 eyes) with AMN at 6 tertiary referral centers. Lesions were classified as type 1 or 2 in relation to the SD-OCT location of the lesion above (type 1) or below (type 2) the outer plexiform layer (OPL) at 6 tertiary referral centers. RESULTS: Of the 9 patients, 5 were female and 4 were male (mean age, 47.6 years; range, 21-65 years). All patients presented with an acute paracentral scotoma and demonstrated a classic dark gray paracentral lesion with near infrared imaging. Visual acuity ranged from 20/15 to 20/30. Six eyes (5 patients) had type 1 SD-OCT lesions, also referred to as paracentral acute middle maculopathy, and 5 eyes (4 patients) had type 2 SD-OCT lesions. Although type 1 lesions lead to inner nuclear layer (INL) thinning, type 2 lesions resulted in ONL thinning. Type 2 lesions were always associated with significant outer macular defects, including disruption of the inner segment/outer segment and outer segment/retinal pigment epithelium bands, whereas type 1 lesions spared the outer macula. CONCLUSIONS AND RELEVANCE: Paracentral acute middle maculopathy may represent a novel variant of AMN that affects the middle layers of the macula above the OPL as diagnosed with SD-OCT imaging. Two types of AMN lesions may be seen with SD-OCT occurring above and below the OPL. Type 1 refers to hyperreflective bands in the OPL/INL region with subsequent INL thinning. Type 2 is hyperreflective bands in the OPL/ONL region with subsequent ONL thinning. Type 2 lesions may be associated with concomitant defects of the inner segment/outer segment layer. We propose that each of these lesions may be explained by occlusion of either the superficial capillary plexus (type 1) or deep capillary plexus (type 2) located in the innermost and outermost portion of the INL, respectively, immediately adjacent to each corresponding lesion type. PMID- 23929383 TI - Toxicity of triphenyltin hydroxide to fish. AB - Triphenyltin (TPhT) is used worldwide in pesticide formulas for agriculture. Toxic effects of this compound to aquatic life have been reported; however, the biochemical response of fish exposed to different concentrations of TPhT hydroxide (TPhTH) was investigated for the first time in this study. The lethal concentration (LC50) of TPhTH to silver catfish, Rhamdia quelen, was calculated from an acute-exposure experiment (96 h). In addition, acethylcholinesterase (AChE) activity in brain and muscle-as well as glucose, glycogen, lactate, total protein, ammonia, and free amino acids in liver and muscle-were evaluated in a chronic-exposure experiment (15-day exposure). Speciation analysis of tin (Sn) was performed in fish tissues at the end of both experiments using gas chromatography coupled to a pulsed-flame photometric detector (GC-PFPD). Concentrations of TPhT, diphenyltin, and monophenyltin (reported as Sn) were lower than limits of quantification (10sigma criteria). Waterborne TPhTH concentration used through the experiment was also evaluated by GC-PFPD, and no degradation of this species was observed. The LC50 value for silver catfish juveniles was 9.73 MUg L(-1) (as Sn). Decreased brain and muscle AChE activities were observed in fish exposed to TPhTH in relation to unexposed fish (control). Liver glycogen and lactate levels were significantly higher in fish kept at the highest waterborne TPhTH concentration compared with the control. Liver and muscle glucose levels of fish exposed to all TPhTH concentrations were significantly lower than those of control fish. Silver catfish exposed to all TPhTH concentrations showed lower total protein values and higher total free amino acids levels in liver and muscle compared with controls. Total ammonia levels in liver and muscle were significantly higher for the highest TPhTH concentration compared with controls. In conclusion, TPhTH caused metabolic alterations in silver catfish juveniles, and the analyzed parameters can also be used as bioindicators for TPhTH contamination. PMID- 23929384 TI - Toxicity of degradation products of the antifouling biocide pyridine triphenylborane to marine organisms. AB - We evaluated the acute toxicities of the main degradation products of pyridine triphenylborane (PTPB), namely, diphenylborane hydroxide (DPB), phenylborane dihydroxide (MPB), phenol, and biphenyl, to the alga Skeletonema costatum, the crustacean Tigriopus japonicus, and two teleosts, the red sea bream Pagrus major and the mummichog Fundulus heteroclitus. DPB was the most toxic of the degradation products to all four organisms. The acute toxicity values of DPB for S. costatum, T. japonicus, red sea bream, and mummichog were 55, 70, 100, and 200 310 MUg/L, respectively. The degradation products were less toxic than PTPB to S. costatum and T. japonicus; however, the toxicities of DPB and PTPB to the fish species were similar. We also examined changes in the inhibition of growth rate of S. costatum as well as the percentage of immobilization of T. japonicus as end points of toxicity of PTPB after irradiation of PTPB with 432 +/- 45 W/m(2) of 290-700 nm wavelength light. After 7 days of irradiation with this light, the concentration of PTPB in the test solutions decreased markedly. A decrease in toxic effects closely coincided with the decrease in the concentration of PTPB caused by the irradiation. PTPB probably accounted for most of the toxicity in the irradiation test solutions. Because the concentrations of PTPB that were acutely toxic to S. costatum and T. japonicus were <10 % of the corresponding concentrations of its degradation products, PTPB probably accounted for most of the toxicity in the irradiation test solutions. PMID- 23929385 TI - Assessment of nonlethal methods for predicting muscle tissue mercury concentrations in coastal marine fishes. AB - Caudal fin clips and dorsolateral scales were analyzed as a potential nonlethal approach for predicting muscle tissue mercury (Hg) concentrations in marine fish. Target fish were collected from the Narragansett Bay (Rhode Island, USA) and included black sea bass Centropristis striata [n = 54, 14-55 cm total length (TL)], bluefish Pomatomus saltatrix (n = 113, 31-73 cm TL), striped bass Morone saxatilis (n = 40, 34-102 cm TL), summer flounder Paralichthys dentatus (n = 64, 18-55 cm TL), and tautog Tautoga onitis (n = 102, 27-61 cm TL). For all fish species, Hg concentrations were greatest in muscle tissue [mean muscle Hg = 0.47 1.18 mg/kg dry weight (dw)] followed by fin clips (0.03-0.09 mg/kg dw) and scales (0.01-0.07 mg/kg dw). The coefficient of determination (R (2)) derived from power regressions of intraspecies muscle Hg against fin and scale Hg ranged between 0.35 and 0.78 (mean R (2) = 0.57) and 0.14-0.37 (mean R (2) = 0.30), respectively. The inclusion of fish body size interaction effects in the regression models improved the predictive ability of fins (R (2) = 0.63-0.80; mean = 0.71) and scales (R (2) = 0.33-0.71; mean = 0.53). According to the high level of uncertainty within the regression models (R (2) values) and confidence interval widths, scale analysis was deemed an ineffective tool for estimating muscle tissue Hg concentrations in the target species. In contrast, the examination of fin clips as predictors of muscle Hg had value as a cursory screening tool; however, this method should not be the foundation for developing human consumption advisories. It is also noteworthy that the efficacy of these nonlethal techniques was highly variable across fishes and likely depends on species-specific life-history characteristics. PMID- 23929386 TI - Antimicrobial effect of bayberry leaf extract for the preservation of large yellow croaker (Pseudosciaena crocea). AB - BACKGROUND: Chemical preservatives have been widely used to keep large yellow croaker fresh. However, the potential harm to human health cannot be ignored. This study was undertaken to investigate the antimicrobial effect of bayberry leaf extract and to evaluate the efficacy of this natural product on the preservation of large yellow croaker. RESULTS: The minimum inhibitory concentration (MIC) values of bayberry leaf extract against bacteria were 1.0 mg mL-1 for Micrococcus luteus, 0.5 mg mL-1 for Staphylococcus aureus, 0.25 mg mL-1 for Escherichia coli, 0.5 mg mL-1 for Pseudomonas aeruginosa, 0.0625 mg mL-1 for Vibrio parahaemolyticus, and 0.03125 mg mL-1 for Listeria monocytogenes, respectively. This result was confirmed by the diameters of inhibition zone (DIZ) assay. Further studies showed that the bacterial growth was significantly retarded when large yellow croaker was pretreated with bayberry leaf extract (2 g L-1) compared to that in the control group. Moreover, the generation of total volatile basic nitrogenous compounds (TVB-N), ATP degradation products (K-value) and thiobarbituric acid-reactive substances (TBARS) were significantly reduced compared to that in the control group. CONCLUSION: Our results demonstrated that the shelf life of large yellow croaker can be extended when supplemented with bayberry leaf extract, which might have implications for natural preservatives. PMID- 23929387 TI - Incidence, clinical features and possible etiology of early onset (<=40 years) colorectal neoplasms. AB - The aim of the study was to investigate the clinical features, including survival, of patients with colorectal malignancies developed at a very early age (<=40 years), together with possible factors involved in the pathogenesis of these rare neoplasms. The study took advantage of the existence of a specialized colorectal cancer Registry active from 1984. 57 patients met the criteria of early onset cancer; main epidemiological data, morphology, stage, familial aggregation, possible role of inheritance and survival were analyzed. Despite the relevant increase over time of all registered patients, joiningpoint analysis of crude incidence rate of early onset colorectal neoplasms revealed a certain stability of these tumors (EAPC: 2.4, CI 14-22) with a constant prevalence of the male sex. Stage at diagnosis did not show significant variations between early onset and maturity onset colorectal neoplasms. Hereditary as well as familial cases were significantly (P < 0.005 and 0.03) more frequent among patients with early onset tumors, although in the majority of them no specific etiological factor could be identified. Survival was more favorable in patients with early onset tumors, though this had to be attributed to the higher presence of some histological types in early onset cases. Survival was significantly more favorable for patients of all ages registered in the last decade. Incidence of early onset colorectal cancer was relatively stable between 1984 and 2008. A male preponderance was evident through the registration period. Hereditary and familial cases were significantly more frequent among early onset case. A well defined etiology could be observed in 16% of the cases (versus 2-3% in older individuals). Five-year survival showed a significant improvement over time. PMID- 23929388 TI - Cardio pump reloaded: in-hospital resuscitation during transport. AB - High-quality chest compressions are crucial during resuscitation if a positive outcome is to be achieved. Sometimes a patient must be transported within the hospital while chest compressions are being performed. We compared different chest compression devices [animax mono (AM), AutoPulse((r)) (AP) and LUCAS2TM (L2)] with manual chest compression using a manikin during transport from a fifth floor ward to the cardiac catheterization laboratory in the basement. Chest compressions were interrupted for 10.7 s to set up the AM, 15.3 s for the L2 and 23.5 s for the AP. The use of a mechanical device reduced transport times from 144.5 s when manual compressions were underway, to 126.8, 111.1 and 98.5 s with the AM, L2 and AP, respectively (p < 0.05). Transfer to the laboratory gurney required little or no interruption in chest compressions with the L2 (0.8 s) and AP (no interruption), compared with 10.3 s with the AP and 3.3 s for manual compressions. Manual compression frequency was 124 min(-1), compared with 100.4 min(-1) for the AM, 99.9 min(-1) for the L2 and 79.7 min(-1) for the AP. Compression depth did not change during transport in any group. Mechanical compression devices are suitable for use during transport, but are not clearly superior to manual compressions. Devices maintain the same compression depth, but fell short of current guidelines, as did manual compressions. Some interruptions occurred while the devices were set up. Further, patient studies are necessary to determine the clinical utility of these devices. PMID- 23929389 TI - Prolonged PT and aPTT in a patient with severe proteinuria. PMID- 23929390 TI - Radiotherapy for gastric cancer: a systematic review and meta-analysis. AB - There have been many trials trying to prove the benefit of radiotherapy for gastric cancer; however, the results were either inclusive or controversial. The purpose of the study was to elucidate the effect of radiotherapy on gastric cancer delivered as perioperative or palliative treatment. We conducted systematic searches for trials exploring the effect of radiotherapy on gastric cancer. In the subgroup of patients receiving preoperative radiotherapy for gastric cancer, a significant benefit was found on 10-year overall survival with a hazard ratio (HR) of 0.75 (95% confidence interval (CI), 0.61 to 0.91); however, the benefit on 5-year overall survival was not proven (HR, 0.68; 95%CI, 0.45 to 1.01). There are also no significant differences in resection rate and radical resection rate between group of patients receiving radiotherapy and control group with a relative risk (RR) of 1.06 (95%CI, 0.99 to 1.13) and 1.12 (95%CI 0.93 to 1.36), respectively. In the subgroup of patients receiving postoperative radiotherapy for gastric cancer, survival benefits were found on 3- and 5-year progression-free survival with HR of 0.69 (95%CI, 0.53 to 0.90) and HR of 0.70 (95%CI, 0.61 to 0.80), respectively. Survival benefits of adjuvant radiotherapy on 3- and 5-year progression-free survival were also found; nonetheless, there was no evidence of significant difference in 3-year overall survival (HR, 0.70; 95%CI, 0.61 to 1.01). The effect of radiotherapy on 5-year overall survival was also quite controversial. In short, gastric cancer patients could benefit from radiotherapy both in the form of preoperative radiotherapy and postoperative radiotherapy. PMID- 23929391 TI - Glucose-regulated protein 94 modulates the therapeutic efficacy to taxane in cervical cancer cells. AB - Cervical cancer is an important health issue for women worldwide, and the endoplasmic reticulum stress pathway is important for determining the chemotherapeutic response to cancer. However, the role of glucose-regulated protein 94 (GRP94) in taxane therapy for cervical cancer remains unclear. In this study, we generated GRP94 knockdown (GRP94-KD) Hela cells using short hairpin RNAs and found that GRP94-KD cells were resistant to taxane treatment in an MTT assay. Scrambled control cells demonstrated higher levels of apoptosis when treated with taxanes in comparison to GRP94-KD cells, as determined by cell cycle profiling, 4',6-diamidino-2-phenylindole staining, and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. Caspase 3 and caspase 7 activity was also higher in scrambled control cells treated with taxane in comparison to GRP94-KD cells. Moreover, we found that depletion of GRP94 altered the levels of the apoptosis-related proteins Bcl2 and Bad, leading to sensitivity to taxane. Exposure to taxane also induced the expression of Bad in scrambled cells but not in GRP94-KD cells. In addition, the expression of Bcl2 was increased dramatically in GRP94-KD cells, whereas only a small increase was observed in scrambled cells. Therefore, we conclude that silencing GRP94 may increase resistance to taxane treatment in cervical cancer cells by altering the activation of the apoptosis pathway. In addition, GRP94 may represent a key biomarker for determining the therapeutic efficacy of taxane treatment in cervical cancer patients. PMID- 23929392 TI - Low expression of cyclic AMP response element modulator-1 can increase the migration and invasion of esophageal squamous cell carcinoma. AB - Cyclic AMP response element-binding protein (CREB) family can regulate biological functions of various types of cells and has relation with esophageal cancer cell migration and invasion. Cyclic AMP response element modulator-1 (CREM-1) is one member of the family with limited acquaintance. This study was conducted to investigate the effect of CREM-1 on migration and invasion in human esophageal squamous cell carcinoma (ESCC). The expression of CREM-1 protein in ESCC tissues with or without lymph nodes metastasis was determined by western blot. Immunohistochemical analysis of CREM-1 expression were carried out in paraffin embedded sections of ESCC and correlated with clinical features. The roles of CREM-1 in migration and invasion were studied in TE1 cells through knocking CREM 1 down with siRNA or overexpression of CREM-1 in ECA109 cells. The regulations of CREM-1 on invasion and migration were determined by transwell and wounding healing assay. The effect of CREM-1 on chemotherapy drug was analyzed by Cell counting kit-8 assay. We found that the expression of CREM-1 was significantly downregulated in ESCC tissues with lymph nodes metastasis compared with the tissues without lymph nodes metastasis and was correlated with the clinical features of pathological grade, tumor stage and lymph node metastasis. Moreover, knocking CREM-1 down with siRNA increased cell migration and invasion in human ESCC cell lines TE1 while upregulation of CREM-1 inhibited the motility. Our data suggested that CREM-1 might play an important role in the regulation of tumor metastasis and invasion and serve as a tumor suppressor in human ESCC. We proposed that CREM-1 might be used as a potential therapeutic agent for human ESCC. PMID- 23929393 TI - Elevated expression of hyaluronic acid binding protein 1 (HABP1)/P32/C1QBP is a novel indicator for lymph node and peritoneal metastasis of epithelial ovarian cancer patients. AB - The present study aims to clarify whether hyaluronan binding protein 1 (HABP1/p32/C1QBP) is an indicator of peritoneal and lymph node metastasis in epithelial ovarian cancer (EOC), which to the authors' knowledge is not previously reported by others. Western blot analysis demonstrated that HABP1 was highly overexpressed in most metastatic lesions. Of 89 patients whose primary tumors showed high HABP1 expression on immunohistochemical staining, 85 (95.5%) presented peritoneal metastases and 43 (48.3%) had lymph node metastases. Univariate and multivariate logistic regression analyses revealed that HABP1 overexpression correlated with peritoneal dissemination and lymph node metastasis in EOC. The specificity and positive predictive value of HABP1 staining were shown to be better for peritoneal metastasis, while the negative and sensitivity predictive value of HABP1 staining were better for lymph node metastasis. The odds ratio of high versus low staining for peritoneal spread was 9.236 (95% confidence interval (CI), 2.705, 19.316), and that for lymph node metastasis was 8.614 (95% CI, 2.507, 21.039). Furthermore, HABP1 protein may potentially be used alone or in combination with other markers as a predictive marker of EOC patients with lymph node metastasis and/or peritoneal dissemination. PMID- 23929394 TI - A PDMS/paper/glass hybrid microfluidic biochip integrated with aptamer functionalized graphene oxide nano-biosensors for one-step multiplexed pathogen detection. AB - Infectious pathogens often cause serious public health concerns throughout the world. There is an increasing demand for simple, rapid and sensitive approaches for multiplexed pathogen detection. In this paper we have developed a polydimethylsiloxane (PDMS)/paper/glass hybrid microfluidic system integrated with aptamer-functionalized graphene oxide (GO) nano-biosensors for simple, one step, multiplexed pathogen detection. The paper substrate used in this hybrid microfluidic system facilitated the integration of aptamer biosensors on the microfluidic biochip, and avoided complicated surface treatment and aptamer probe immobilization in a PDMS or glass-only microfluidic system. Lactobacillus acidophilus was used as a bacterium model to develop the microfluidic platform with a detection limit of 11.0 cfu mL(-1). We have also successfully extended this method to the simultaneous detection of two infectious pathogens - Staphylococcus aureus and Salmonella enterica. This method is simple and fast. The one-step 'turn on' pathogen assay in a ready-to-use microfluidic device only takes ~10 min to complete on the biochip. Furthermore, this microfluidic device has great potential in rapid detection of a wide variety of different other bacterial and viral pathogens. PMID- 23929395 TI - The factor structure of the Liebowitz Social Anxiety Scale for Children and Adolescents: development of a brief version. AB - The Liebowitz Social Anxiety Scale for Children and Adolescents (LSAS-CA-SR) is a validated instrument for the assessment of social anxiety in youth. The three main objectives of the present study were to (a) examine the factor structure of the LSAS-CA-SR; (b) to validate the factors against relevant personality measures, and (c) to create a brief and reliable version of the questionnaire. A total of 1,362 adolescents completed self-report measures of social anxiety, temperament, character and personality traits. The factor structure was examined using a combination of confirmatory and exploratory factor analysis. The analysis was conducted on both the anxiety and avoidance sub-scales, and identical items for both sub-scales were maintained. Two factors emerged: social interaction and school performance. These factors demonstrated high internal consistency and a significant correlation with relevant self-report measures. A brief version comprised of 14 items was highly correlated (0.96) with the full version. The new factor structure represents advancement over the previous efforts, and holds promise for efficient utilization of the LSAS-CA. PMID- 23929396 TI - Reversibility of anodic lithium in rechargeable lithium-oxygen batteries. AB - Non-aqueous lithium-air batteries represent the next-generation energy storage devices with very high theoretical capacity. The benefit of lithium-air batteries is based on the assumption that the anodic lithium is completely reversible during the discharge-charge process. Here we report our investigation on the reversibility of the anodic lithium inside of an operating lithium-air battery using spatially and temporally resolved synchrotron X-ray diffraction and three dimensional micro-tomography technique. A combined electrochemical process is found, consisting of a partial recovery of lithium metal during the charging cycle and a constant accumulation of lithium hydroxide under both charging and discharging conditions. A lithium hydroxide layer forms on the anode separating the lithium metal from the separator. However, numerous microscopic 'tunnels' are also found within the hydroxide layer that provide a pathway to connect the metallic lithium with the electrolyte, enabling sustained ion-transport and battery operation until the total consumption of lithium. PMID- 23929397 TI - Treatment outcomes in elderly with advanced-stage non-small cell lung cancer. AB - PURPOSE: Lung cancer remains the top cause of cancer morbidity and mortality in the world. Although the identification of epidermal growth factor receptor (EGFR) gene mutations could predict efficacy of tyrosine kinase inhibitor (TKI), testing for predictive biomarkers are not always possible due to tissue availability. The overall therapeutic decision remains a clinical one for a significant proportion of elderly patients with advanced stage lung cancer but no known EGFR mutation status. The purpose of this study was to compare the outcome of drug treatment modalities in progression-free survival (PFS) and overall survival (OS) for elderly with advanced-stage non-small cell lung cancer (NSCLC) and to identify clinical parameters that could predict treatment outcome. METHODS: Clinical records of patients aged 70 years or older with advanced-stage NSCLC who have received treatment were reviewed. A group of gender- and histology-matched subjects younger than age 70 years were identified as controls. RESULTS: Fifty six elderly patients were included. The median age at diagnosis was 73 years; 60.7 % received only one line of treatment. Baseline performance status (PS) was the only predictor of improved PFS (p = 0.042) and OS (p = 0.002). There was no difference in survival between the upfront chemotherapy and the TKI groups CONCLUSIONS: In elderly with advanced-stage NSCLC without known EGFR mutation status, use of EGFR-TKI and chemotherapy resulted in comparable survival benefits. Age was not predictive of worse treatment outcome. The baseline PS should be taken into consideration in the therapeutic decision in elderly with NSCLC where the EGFR mutation status is not known. PMID- 23929398 TI - Multiple medication adherence and its effect on clinical outcomes among patients with comorbid type 2 diabetes and hypertension. AB - OBJECTIVE: To investigate multiple medication adherence (MMA) and its impact on microvascular and macrovascular complications using instrumental variables (IVs). RESEARCH DESIGN: A retrospective observational study was conducted using administrative claims and electronic medical records from a large physician group in Southern California (N=2334). SUBJECTS: We identified individuals between January 2006 and June 2009 newly starting oral diabetes (DM) or hypertension (HTN) medications with preexisting comorbid HTN or DM prescription history. MEASURES: MMA was defined as a proportion of days covered where both DM and HTN medications were simultaneously available over a 33-month follow-up period. Microvascular or macrovascular complications included myocardial infarction, stroke, renal failure, and diabetic retinopathy. Multivariable logistic regressions and an IV estimation using physician-related variables were implemented. RESULTS: MMA was supoptimal as the mean (SD) proportion of days covered was 0.53 (0.32). Patients were more adherent to medications for a preexisting condition in comparison with those for the newer disease. Older age, number of index medications [OR (95% CI)=1.36 (1.22-1.52)], receiving care from a physician who prescribed statin more frequently [OR (95% CI)=2.63 (1.67-4.14)], and receiving care from the same physician for both DM and HTN [OR (95% CI)=1.57 (1.08-2.27)] were significant factors of being adherent. Using physician-related IVs, MMA reduced microvascular and macrovascular complications. The increase in MMA from 50% to 80% reduced the average predicted probability of microvascular or macrovascular complication rate by 29.5%. CONCLUSIONS: Adherence to medications for DM and HTN were differed and higher MMA reduced microvascular or macrovascular complications when controlling for endogeneity bias. PMID- 23929399 TI - Transgender patient perceptions of stigma in health care contexts. AB - OBJECTIVES: Transgender individuals, or those who cross or transcend sex categories, commonly experience stigma and discrimination. Anecdotal evidence indicates that this transphobia manifests in health care settings, but few studies address the forms of mistreatment experienced in this context. This study was designed to explore transgender patients' experiences with health care. This brief report focuses on their negative experiences. METHODS: A total of 152 transgender adults were recruited to complete an online questionnaire about their health care. Participants were asked if and how they had been mistreated, and responses were analyzed by qualitative content analysis. RESULTS: Participants' descriptions of mistreatment coalesced around 6 themes: gender insensitivity, displays of discomfort, denied services, substandard care, verbal abuse, and forced care. CONCLUSIONS: These findings provide insight into transgender patients' perceptions of and sensitivity to mistreatment in health care contexts. This information might be used to increase providers' cultural competency and inform their interactions with transgender patients. PMID- 23929400 TI - Outcomes of cardiac surgery: associations with physician characteristics, institutional characteristics, and transfers of care. AB - BACKGROUND: Although there are several studies of the human and system factors that influence the outcomes of cardiac surgery, it remains difficult to draw conclusions because many do not simultaneously adjust for the characteristics of patients, physicians, and institutions. The current study explores the associations between these factors and inhospital mortality, with a particular focus on whether patients had the same operating and attending physician. METHOD AND RESULTS: This is a retrospective observational study of 114,751 hospitalizations from 2003 to 2009 in Pennsylvania that included a coronary artery bypass graft, valve surgery, or both. The study included 70 teaching and nonteaching hospitals, 289 operating physicians who were also the attending physicians for 75% of the hospitalizations, and 2654 attending physicians for the remaining hospitalizations. After adjustment, there was a 38.4% decrease (95% CI, 20.3%-56.5%) in mortality when the operating and attending physician were the same. For the operator, each procedure performed was associated with a 0.05% (95% CI, 0.04%-0.06%) decrease in mortality and each year since medical school was associated with a 0.9% (95% CI, 0.02%-1.8%) increase in mortality. For the attending, each year since medical school was associated with a 0.67% (95% CI, 0.01%-1.4%) decrease in patient mortality. CONCLUSIONS: The findings indicated that an increase in the log odds of mortality was associated with the transfer of care between an attending and operating physician. Better patient outcomes were associated with an operator with higher volume who was closer to medical school graduation and an attending physician with more clinical experience. PMID- 23929401 TI - The revolving hospital door: hospital readmissions among patients who are homeless. AB - BACKGROUND: National attention is increasingly focused on hospital readmissions. Little prior research has examined readmissions among patients who are homeless. OBJECTIVE: The aim of the study was to determine 30-day hospital readmission rates among patients who are homeless and examine factors associated with hospital readmissions in this population. METHODS: We conducted a retrospective chart review of patients who were homeless and hospitalized at a single urban hospital from May-August 2012. Homelessness was identified by an electronic medical record flag and confirmed by manual chart review. The primary outcome was all-cause hospital readmission to the study hospital within 30 days of hospital discharge. Patient-level and hospitalization-level factors associated with risk for readmission were examined using generalized estimating equations. RESULTS: There were 113 unique patients who were homeless and admitted to the hospital a total of 266 times during the study period. The mean age was 49 years, 27.4% of patients were women, and 75.2% had Medicaid. Half (50.8%) of all hospitalizations resulted in a 30-day hospital inpatient readmission and 70.3% resulted in either an inpatient readmission, observation status stay, or emergency department visit within 30 days of hospital discharge. Most readmissions occurred early after hospital discharge (53.9% within 1 week, 74.8% within 2 weeks). Discharge to the streets or shelter versus other living situations was associated with increased risk for readmission in multivariable analyses. CONCLUSIONS: Patients who were homeless had strikingly high 30-day hospital readmission rates. These findings suggest the urgent need for further research and interventions to improve postdischarge care for patients who are homeless. PMID- 23929402 TI - Euthanasia and assisted suicide in selected European countries and US states: systematic literature review. AB - BACKGROUND: Legal in some European countries and US states, physician-assisted suicide and voluntary active euthanasia remain under debate in these and other countries. OBJECTIVES: The aim of the study was to examine numbers, characteristics, and trends over time for assisted dying in regions where these practices are legal: Belgium, Luxembourg, the Netherlands, Switzerland, Oregon, Washington, and Montana. DESIGN: This was a systematic review of journal articles and official reports. Medline and Embase databases were searched for relevant studies, from inception to end of 2012. We searched the websites of the health authorities of all eligible countries and states for reports on physician assisted suicide or euthanasia and included publications that reported on cases of physician-assisted suicide or euthanasia. We extracted information on the total number of assisted deaths, its proportion in relation to all deaths, and socio-demographic and clinical characteristics of individuals assisted to die. RESULTS: A total of 1043 publications were identified; 25 articles and reports were retained, including series of reported cases, physician surveys, and reviews of death certificates. The percentage of physician-assisted deaths among all deaths ranged from 0.1%-0.2% in the US states and Luxembourg to 1.8%-2.9% in the Netherlands. Percentages of cases reported to the authorities increased in most countries over time. The typical person who died with assistance was a well educated male cancer patient, aged 60-85 years. CONCLUSIONS: Despite some common characteristics between countries, we found wide variation in the extent and specific characteristics of those who died an assisted death. PMID- 23929403 TI - Validation of Case Finding Algorithms for Hepatocellular Cancer From Administrative Data and Electronic Health Records Using Natural Language Processing. AB - BACKGROUND: Accurate identification of hepatocellular cancer (HCC) cases from automated data is needed for efficient and valid quality improvement initiatives and research. We validated HCC International Classification of Diseases, 9th Revision (ICD-9) codes, and evaluated whether natural language processing by the Automated Retrieval Console (ARC) for document classification improves HCC identification. METHODS: We identified a cohort of patients with ICD-9 codes for HCC during 2005-2010 from Veterans Affairs administrative data. Pathology and radiology reports were reviewed to confirm HCC. The positive predictive value (PPV), sensitivity, and specificity of ICD-9 codes were calculated. A split validation study of pathology and radiology reports was performed to develop and validate ARC algorithms. Reports were manually classified as diagnostic of HCC or not. ARC generated document classification algorithms using the Clinical Text Analysis and Knowledge Extraction System. ARC performance was compared with manual classification. PPV, sensitivity, and specificity of ARC were calculated. RESULTS: A total of 1138 patients with HCC were identified by ICD-9 codes. On the basis of manual review, 773 had HCC. The HCC ICD-9 code algorithm had a PPV of 0.67, sensitivity of 0.95, and specificity of 0.93. For a random subset of 619 patients, we identified 471 pathology reports for 323 patients and 943 radiology reports for 557 patients. The pathology ARC algorithm had PPV of 0.96, sensitivity of 0.96, and specificity of 0.97. The radiology ARC algorithm had PPV of 0.75, sensitivity of 0.94, and specificity of 0.68. CONCLUSIONS: A combined approach of ICD-9 codes and natural language processing of pathology and radiology reports improves HCC case identification in automated data. PMID- 23929404 TI - Validation of a Medicare Claims-based Algorithm for Identifying Breast Cancers Detected at Screening Mammography. AB - BACKGROUND: The breast cancer detection rate is a benchmark measure of screening mammography quality, but its computation requires linkage of mammography interpretive performance information with cancer incidence data. A Medicare claims-based measure of detected breast cancers could simplify measurement of this benchmark and facilitate mammography quality assessment and research. OBJECTIVES: To validate a claims-based algorithm that can identify with high positive predictive value (PPV) incident breast cancers that were detected at screening mammography. RESEARCH DESIGN: Development of a claims-derived algorithm using classification and regression tree analyses within a random half-sample of Medicare screening mammography claims followed by validation of the algorithm in the remaining half-sample using clinical data on mammography results and cancer incidence from the Breast Cancer Surveillance Consortium (BCSC). SUBJECTS: Female fee-for-service Medicare enrollees aged 68 years and older who underwent screening mammography from 2001 to 2005 within BCSC registries in 4 states (CA, NC, NH, and VT), enabling linkage of claims and BCSC mammography data (N=233,044 mammograms obtained by 104,997 women). MEASURES: Sensitivity, specificity, and PPV of algorithmic identification of incident breast cancers that were detected by radiologists relative to a reference standard based on BCSC mammography and cancer incidence data. RESULTS: An algorithm based on subsequent codes for breast cancer diagnoses and treatments and follow-up mammography identified incident screen-detected breast cancers with 92.9% sensitivity [95% confidence interval (CI), 91.0%-94.8%], 99.9% specificity (95% CI, 99.9%-99.9%), and a PPV of 88.0% (95% CI, 85.7%-90.4%). CONCLUSIONS: A simple claims-based algorithm can accurately identify incident breast cancers detected at screening mammography among Medicare enrollees. The algorithm may enable mammography quality assessment using Medicare claims alone. PMID- 23929406 TI - Acute decompensation of noncommunicating hydrocephalus caused by dilated Virchow Robin spaces type III in a woman treated by endoscopic third ventriculostomy: a case report and review of the literature. AB - BACKGROUND AND IMPORTANCE: Even though dilated Virchow-Robin spaces (VRS) are a very rare entity, they can compel the clinician to start immediate intervention in the case of acute onset of symptoms. To allow a well-balanced management decision, we compiled a summary of all cases published in the literature and discuss the different methods and indications for neurosurgical intervention in relation to dilated VRS. CLINICAL PRESENTATION: We report a case of a 43-year-old female patient who came to admission after syncope with a history of unspecific neck pain, fatigue, diplopia, and dizziness. Dilated VRS type III causing a noncommunicating hydrocephalus were found to be responsible. Although the patient was initially awake, within 72 hours after admission, a deterioration of consciousness and repeated vomiting were observed. The patient underwent an urgent endoscopic third ventriculostomy (ETV) and was discharged in a good condition. CONCLUSION: To the best of our knowledge, the case presented here is the first case of acute decompensation of a noncommunicating hydrocephalus caused by dilated VRS. Neurosurgical intervention is required in cases of noncommunicating hydrocephalus caused by giant tumefactive VRS. The treatment options are mono- or biventricular shunt surgery or ETV. Because ETV provides the possibility of cyst fenestration and membrane sampling, it appears to be the most advantageous treatment option. PMID- 23929405 TI - Seeing is believing: visualizing transcriptional dynamics in single cells. AB - For a gene to be expressed, the functions of multiple molecular machines must be coordinated at the site of transcription. To understand the role of nuclear organization in transcription, it is necessary to visualize the dynamic interactions of regulatory factors with chromatin and RNA. It is currently possible to localize individual transcription sites in single living mammalian cells by engineering reporter gene constructs to include sequence elements which permit the visualization of nucleic acids in vivo. Upon stable integration, these transgenes form chromatinized arrays, which can be imaged during activation to obtain high-resolution quantitative information about transcriptional dynamics. Modeling can suggest new hypotheses about gene regulation, which can be tested both in the single-cell imaging system and at endogenous genes. This gene specific imaging strategy has the potential to reveal regulatory mechanisms, which would be difficult to imagine outside of single living cells. PMID- 23929407 TI - Intracerebellar hemorrhage caused by developmental venous anomaly, from diagnosis to treatment. AB - BACKGROUND: Developmental venous anomaly (DVA) is considered a benign and asymptomatic cerebrovascular malformation, and only isolated cases of symptomatic DVAs are described in the literature. Even more rarely will these symptoms come from an intraparenchymal hemorrhage caused by the DVA. METHODS AND RESULTS: We present two symptomatic DVAs by intracerebellar hemorrhage. CONCLUSION: The diagnostic steps regarding the pathophysiology of DVA hemorrhage and the treatment options are discussed. PMID- 23929408 TI - Practical use of a simple technique, insertion of wet cotton pledgets into the tumor resection cavity in transsphenoidal surgery of pituitary tumors, for a better comparison between pre- and intraoperative high-field magnetic resonance images. AB - BACKGROUND: Intraoperative high-field magnetic resonance imaging (iMRI) is a useful modality for immediate intraoperative quality control. With iMRI, a surgeon can confirm whether tumor remnants exist during surgery; which makes it possible to add further resection, obtain a higher resection rate, and improve the cure rate. It is sometimes difficult to evaluate the existence of tumor remnants when the tumor resection cavity is collapsed. In this study, we reported a simple technique for comparing pre- and intraoperative MR images. PATIENTS AND METHODS: Thirty-five consecutive patients with pituitary adenoma underwent endoscopic endonasal transsphenoidal surgery using iMRI. Twenty-six patients had adenomas with suprasellar extension, and 9 had intrasellar adenomas. Nine adenomas had cavernous sinus invasion. Eight patients had endocrine-active, and 27 endocrine-inactive tumors. The simple technique included wet cotton pledgets inserted into the resection cavity to easily and precisely compare pre- and intraoperative MR images. Furthermore, we evaluated the efficacy of iMRI using our method on determining the extent of tumor resection in this study. RESULTS: The first iMRI scan showed that 12 of 35 patients had some tumor remnants, and 23 patients did not. Eight of these 12 patients with tumor remnants had cavernous sinus invasion. Three cases received further tumor resection after iMRI and had a gross total removal. CONCLUSIONS: We presented our initial results after using a simple method in high-field iMRI during endoscopic transnasal transsphenoidal pituitary surgery. This procedure allowed us to obtain valuable information to determine the extent of tumor resection and to precisely visualize the parasellar structures. PMID- 23929409 TI - Evaluation of sciatic nerve function after ultrasonic and electrocautery muscle dissection: an electromyographic study. AB - BACKGROUND: Minimally invasive surgery has been developed with various innovative surgical tools. Ultrasonic (US) blades have been introduced as an alternative to conventional electrocautery (EC) monopolar device. The purpose of the present study was to evaluate the effects of surgical devices used for muscle dissection close to peripheral nerves on motor nerve function using electromyographic (EMG) recordings. MATERIALS AND METHODS: A total of 24 rats were used in this study. The rats were assigned to the following three groups: Control (n = 8), EC (n = 8), and US (n = 8). A stimulus electrode was placed under the sciatic nerve at a sciatic notch. A pair of recording electrodes was implanted into the midbelly regions of the gastrocnemius muscle. To evoke compound muscle action potentials (CMAPs), 3-V stimuli with 0.3-ms duration were applied to the sciatic nerve at a frequency of 1 Hz. After the recording of the baseline, a monopolar surgical device (EC or US) was applied to cut the muscle 10 mm in length and 2 mm away on both sides of the sciatic nerve. Amplitude and latency of the evoked CMAPs were measured. CMAPs were monitored until 3 hours after the device application. RESULTS: The EC device caused a marked drop in the amplitude of CMAP with no recovery at the end of the experiment. In the US group, the amplitude of CMAP was stable and constant CMAP over 3 hours, similar to the control group could be measured. In all three groups, the latency of CMAP showed no significant changes through the experiment. CONCLUSION: The study showed that the EC device resulted in injury to several motor units in the sciatic nerve. The US device may be a safe tool for muscle dissection around peripheral nerves. PMID- 23929410 TI - Open thoracic cordotomy as a treatment option for severe, debilitating pain. AB - OBJECTIVE: The treatment of patients with debilitating lower extremity or medically refractory quadrant pain presents a challenge for management. Contemporary neuromodulatory therapies may not be affordable or practical, especially in patients with limited life expectancy or from countries with limited resources. We present a small retrospective series to evaluate the role of open thoracic cordotomy as a practice option in the treatment of patients with severe, unilateral, medically refractory pain of the lower abdominal quadrant, hip, or leg. Technical aspects of the procedure, anatomic pathways within the spinal cord, and intraoperative maneuvers are described. METHODS: The medical records of 9 patients (7 men, 2 women; median age, 57 years) treated between 1998 and 2010 were reviewed. Each patient underwent open thoracic cordotomy after 1998 for severe lower quadrant or lower extremity pain refractory to multiple other treatment modalities. The indications for surgery included cancer-related pain (4 of 9), postherpetic neuralgia (2 of 9), post-spinal cord injury pain (2 of 9), and multiple sclerosis (1 of 9). RESULTS: Six of nine patients reported improvement in their postoperative level of pain after a median follow-up of 31 weeks. Complications included ipsilateral lower extremity weakness, urinary incontinence, and the development of new postcordotomy pain. A higher incidence of complications, including ipsilateral motor weakness, was observed in this series than with previous reports of percutaneous cervical cordotomy (PCC). CONCLUSIONS: Although open thoracic cordotomy may be cautiously recommended as a treatment option in certain settings, this procedure should be viewed only as a second-line treatment option in settings where the technology and expertise to perform PCC are available. PMID- 23929411 TI - Comparative results of standard open and mini open, KnifeLight instrument assisted carpal tunnel release. AB - PURPOSE: The purpose of our study was to compare the results of standard open and mini open (approximately 1.5-cm incision), KnifeLight instrument (Stryker Instruments, Kalamazoo, Michigan, USA) assisted carpal tunnel release (CTR) concerning symptomatic, functional, and electrophysiological aspects, as well as complications during early and late postoperative follow-up. PATIENTS AND METHOD: Seventy-five patients who did not improve with nonsurgical methods and were planned to undergo surgery were separated into two groups. Patients in the first group (n = 37) underwent surgery with standard open CTR (Group A); patients in the second group (n = 38) underwent surgery with mini open KnifeLight instrument assisted CTR (Group B). Preoperative and 6-month postoperative electrophysiological values and functional utilization of the operated hand of both groups were compared. Nerve conduction studies were used for electrophysiological evaluation, visual analog scale (VAS) was used for pain evaluation, symptom severity scale (SSS) was used for symptomatic evaluation, and functional status scale (FSS) was used to evaluate hand functions that are the part of the Boston Carpal Tunnel Questionnaire. All evaluations were done preoperatively and repeated at postoperative month 6. Also, to determine early effects of surgical procedures, SSS and FSS scales were repeated at postoperative week 2 and month 3. Groups were also compared for complications and need for reoperation. RESULTS: No significant difference was detected between the two groups at postoperative month 6 on VAS and electrophysiological values. Postoperative week 2 FSS and SSS scores of Group B were significantly lower than Group A. Although scores were lower in Group B at month 3, there was no statistically significant difference. Six months after surgery, no significant difference was detected between the two groups in mean SSS and FSS scores. Postoperative complications and reoperation rates were lower in Group B but the difference was not statistically significant. CONCLUSION: After 6 months the results of both techniques for CTR are comparable. Mini open KnifeLight instrument assisted CTR is easy to perform and is superior to standard open CTR in the early post-operative period. PMID- 23929412 TI - Electrode materials for biphenyl-based rectification devices. AB - An ab initio approach was utilized to explore the electronic transport properties of 4'-thiolate-biphenyl-4-dithiocarboxylate (TBDT) sandwiched between two electrodes made of various materials X (X = Cu, Ag, and Au). Analysis of current voltage (I-V) characteristics, rectification performance, transmission functions, and the projected density of states (PDOS) under various external voltage biases showed that the transport properties of these constructed systems are markedly impacted by the choice of electrode materials. Further, Cu electrodes yield the best rectifying behavior, followed by Ag and then Au electrodes. Interestingly, the rectification effects can be tuned by changing the torsion angle between the two phenyl rings, as well as by stretching the contact distances between the end group and the electrodes. For Cu, the maximum rectifying ratio increases by 37 % as the contact distance changes from 1.7 A to 1.9 A. This is due to an increase in coupling strength asymmetry between the molecule and the electrodes. Our findings are compared with the results reported for other systems. The present calculations are helpful not only for predicting the optimal electrode material for practical applications but also for achieving better control over rectifying performance in molecular devices. PMID- 23929413 TI - A DFT study of adsorption and decomposition of hexahydro-1,3,5-trinitro-1,3,5 triazine on Mg(0001) surface. AB - The adsorption and decomposition of hexogen (RDX) molecule on the Mg(0001) surface were investigated by the generalized gradient approximation (GGA) of density functional theory (DFT). The calculations employed a supercell (4 * 4 * 4) slab model and three-dimensional periodic boundary conditions. The strong attractive forces between RDX molecule and magnesium atoms induce the RDX's N - O bond breaking. Subsequently, the dissociated oxygen atoms and radical fragment of RDX oxidize the Mg surface. The largest adsorption energy is -2104.0 kJ mol(-1). We also investigated the decomposition mechanism of RDX molecule on the Mg(0001) surface. The activation energy for the dissociation step of configuration V4 is as small as 2.5 kJ mol(-1), while activation energies of other configurations are much larger, in the range of 964.9-1375.1 kJ mol(-1). Mg powder is more active than Al powder, and Mg powder performs better in increasing the combustion exothermicity of RDX as well. PMID- 23929414 TI - Temporal trends in sleep apnea surgery: 1993-2010. AB - OBJECTIVES/HYPOTHESIS: Growing evidence supports the use of multilevel surgery to effectively address obstructive sleep apnea (OSA). We sought to characterize changes in the patterns of surgical sleep care over time. STUDY DESIGN: Repeated cross-sectional study. METHODS: Discharge data from the US Nationwide Inpatient Sample for 232,470 patients who underwent nasal, palatal, or hypopharyngeal procedures for sleep disordered breathing or OSA from 1993 to 2010 were analyzed using cross-tabulations and multivariate regression modeling. RESULTS: Inpatient sleep surgical procedures increased from 97,363 performed in 1993-2000 to 135,107 in 2001-2010. Sleep surgery in 2001-2010 was associated with increased hypopharyngeal surgery (relative risk ratio [RRR] = 3.6, 95% confidence interval [CI] = 2.6-4.9, P < .001), tongue radiofrequency/midline glossectomy (RRR = 5.1, 95% CI = 3.4-7.5, P < .001), hyoid suspension (RRR = 6.8, 95% CI = 3.8-12.5, P < .001), nasal surgery (RRR = 1.3, 95% CI = 1.1-1.5, P = 0.002), and multilevel surgery (RRR = 5.6, 95% CI = 3.8-9.4, P < .001) and decreased tracheostomy (RRR = 0.58, 95% CI = 0.49-0.68, P < .001) compared to 1993-2000. Patients undergoing sleep surgery in 2001-2010 were more likely to have an OSA diagnosis (RRR = 1.9, 95% CI = 1.4-2.5, P < .001), obesity (RRR = 1.5, 95% CI = 1.4-1.7, P < .001), and advanced comorbidity (RRR = 2.4, 95% CI = 2.0-2.8, P < .001). In 2001-2010, surgeons (>23 cases/yr) in the top-volume quintile were more likely to perform hypopharyngeal procedures (RRR = 2.4, 95% CI = 1.7-3.4, P < .001,) and to be associated with teaching hospitals (RRR = 1.5, 95% CI = 1.0-2.2, P = 0.034) and less likely to perform tracheostomy (RRR = 0.27, 95% CI = 0.18-0.40, P < .001). However, they represented only 17% of surgeons performing sleep surgery in contrast to surgeons in the bottom-volume quintile, who performed 35% of cases. CONCLUSIONS: These data reflect changing trends in the surgical management of OSA, with meaningful differences in the type of surgical care provided by high volume surgeons and a significant increase in surgical sleep procedures, particularly nasal and hypopharyngeal surgery. PMID- 23929415 TI - Despite an overall decline in U.S. infant mortality rates, the Black/White disparity persists: recent trends and future projections. AB - This paper has two objectives. First, we examine the Black-White disparity in the U.S. infant mortality rate (IMR) between 1995 and 2009, and explore the influence of socioeconomic characteristics (e.g., marital status, education, and prenatal care) on this racial gap. Second, we calculate projected IMRs and compare these results to the objectives of the Healthy People 2020 program. Descriptive statistics were calculated and linear regression models were conducted using data from the Centers for Disease Control and Prevention's linked birth and infant death files. Between 1995 and 2009, the IMR declined by 11.9 % for White mothers and 15.3 % for Black mothers. Among unmarried mothers, there was a 19.6 % decline for Whites and a 15.2 % reduction for Blacks. In comparison, among married mothers, there was a 19.3 % decline for Whites and an 18.1 % reduction for Blacks. For both Blacks and Whites, the largest percent declines occurred among women with the lowest and highest levels of education. For both racial groups, those with no prenatal care had the highest IMRs. Despite these significant declines, educated White women are the only group predicted to reach the Healthy People 2020 objective of an IMR lower than 6.0 infant deaths per 1,000 live births. The predicted IMR for highly educated Black women in 2020 is 10.6, and the projected rates for Black mothers with low education levels are even higher. Although the IMR has declined since 1995, the racial disparity between Blacks and Whites will most likely persist through 2020. Whereas educated White mothers are projected to meet the Healthy People 2020 IMR goal, other groups will fall short. The racial disparity persists even when mothers are grouped by marital status, educational attainment, and access to care. Future policies and prevention programs should address these racial disparities. PMID- 23929416 TI - Early-onset foveal involvement in retinitis punctata albescens with mutations in RLBP1. AB - IMPORTANCE: Retinitis punctata albescens (RPA) is an autosomal recessive form of retinitis pigmentosa characterized by white dotlike deposits in the fundus, in most cases caused by mutations in RLBP1. OBJECTIVE: To study disease progression and visual function in RPA. DESIGN: We performed clinical and molecular investigations in patients with RPA at various ages, from November 5, 2003, through June 20, 2012, with no planned patient follow-up. SETTING: The National Reference Center for Genetic Sensory Diseases (Montpellier). PARTICIPANTS: Eleven patients with RPA (mean age, 24 [range, 3-39] years) from 7 families and 11 control subjects undergoing evaluation. EXPOSURE: Optical coherence tomography measurements. MAIN OUTCOMES AND MEASURES: Screening for mutations by polymerase chain reaction sequencing of the 9 RLBP1 exons. Patients underwent standard ophthalmic examination, fundus imaging, autofluorescence testing, Goldmann visual field measurement, optical coherence tomography, adaptive optics-based infrared fundus ophthalmoscopy, dark adaptometry, and electroretinography. RESULTS: We found 2 novel RLBP1 mutations (p.Tyr111X and p.Arg9Cys), and 8 patients from Morocco were homozygous for the recurrent 7.36-kilobase RLBP1 deletion of exons 7 through 9. All patients had night blindness (before age 6 years in 10). The dotlike deposits were generally dense but could be rare, appearing in adaptive optics as elongated structures with variable orientation and no foveal involvement. We found no specific refractive error, and visual acuity varied widely from normal (1.2) to counting fingers. Variable degrees of visual field impairment were present, and all patients had severely decreased electroretinographic responses with predominant rod impairment. No correlation between visual acuity (P = .27) or visual field and age (P = .08) was present. On optical coherence tomography, the mean (SD) central foveal (122 [23] vs 187 [30] um in controls) and foveal (147 [19] vs 217 [17] um) thicknesses were significantly (P < .01) decreased, independently of age, whereas the retinal thickness at the 3- and 6-mm rings around the fovea progressively decreased with age. Mean (SD) cone number was normal in 1 patient aged 13 years (21,000/mm2 [2000/mm2]) but dropped to 10,500/mm2 (5244/mm2), 8667/mm2 (2944/mm2), and 5833/mm2 (983/mm2) in 3 other patients aged 39, 32, and 29 years, respectively. CONCLUSIONS AND RELEVANCE: Patients with RPA show variable degrees of foveal cone death, even at an early stage. This finding has implications for future treatment. PMID- 23929417 TI - Evaluation on the compliance with secondary prevention and influence factors of ischemic stroke in Hainan province, China. AB - Survivors of ischemic stroke are still at a significant risk for recurrence. Numerous effective strategies for the secondary prevention of ischemic stroke have now been established; however, these guidelines are not widely known. In this retrospective, a multicenter study was conducted from January 2011 to February 2012 in 10 general hospitals, which included 1300 elderly patients who had previously been diagnosed with ischemic stroke and re-admitted to hospitals. Logistic regression models were fitted to determine the relationship between compliance with secondary prevention therapy and each variable of interest. The treatment rates of antihypertensive, antiplatelet and lipid-lowering therapy were only 56.3%, 48.9% and 19.6%, respectively. Multivariate analysis presented that cardiovascular risk factors would motivate patients with hypertension and hyperlipidemia to receive corresponding treatments. However, it is worth noting that they did not influence the use of antiplatelet therapy. In addition, high education, health education and insurance promote the use of secondary prevention in patients. In conclusion, the importance of antiplatelet therapy should not be ignored any more. Besides, health education will raise patients' attention to ischemic stroke. PMID- 23929418 TI - Causes of recurrent lower limb varicose veins after surgical interventions in 141 limbs - five-year retrospective analysis of two centers. AB - AIM: The purpose of this study was to explore the causes of recurrent lower limb varicose veins after surgical interventions. METHODS: A retrospective five-year survey was conducted on patients who underwent second surgery due to recurrent lower limb varicose veins after surgical interventions. A total of 141 limbs (112 cases), including 72 cases of left lower limbs, 47 of right lower limbs and 22 of both limbs, were involved in the study. All patients underwent lower limb venography (141 limbs were anterograde and 28 cases were retrograde), and then examined with color-Doppler ultrasound. RESULTS: The major causes that urged patients to undergo second surgery are clinical changes graded above CEAP IV (93.6%), limb edema without changes on skin (5%), and single varicosity (1.4%). Up to 127 (83%) limbs exhibited perforating venous reflux, 67 (47.5%) limbs had varied degrees of deep venous insufficiency and 68 (48.2%) limbs had through or above-the-knee great saphenous vein trunk residual. CONCLUSIONS: Preoperative venography before operation is indispensible in confirming the diagnosis and operation strategies. Patients with severe primary deep venous reflux and symptoms up to C3 may need simultaneous repair of the deep venous valves. PMID- 23929419 TI - Recent trends in publications of US vascular surgery program directors. AB - AIM: We reviewed the number of vascular publications listed in PubMed from 2001 to 2009 for US program directors in vascular surgery and suggest that this can be used as a benchmark. METHODS: PubMed listed 3284 citations published during this time period. The average number of citations in PubMed per program director was 3.68 per year. The top third produced 67% of the publications. Journal of Vascular Surgery publications made up 37%. No statistical differences could be ascertained between the regions of the country and the number of publications. RESULTS: Compared to the first six years, the number of citations decreased during the last three years (13%). During the first period, there were no programs with no publications and seven with no Journal of Vascular Surgery publication. During the last three years, there were seven programs with no publications and 19 programs with no Journal of Vascular Surgery publications. The number of aortic-endovascular citations peaked in 2002 and 2003, while the number of open and basic science citations decreased. Imaging citations peaked in 2003-2005, and carotid-endovascular, vein-endovascular, and thoracic aortic endovascular citations climbed. CONCLUSIONS: The decrease in the number of citations/program/year raises concern about the level of academic activity in vascular surgery. Overall, the annual distribution of the topic of these citations represents a continued shift from open to endovascular cases and decreasing basic science citations. PMID- 23929420 TI - Popliteal artery pseudoaneurysm associated with solitary osteochondromatosis. AB - Osteochondroma is the most common benign tumor of the bone, seen mostly during adolescence. In the current study, we report a 19-year-old male patient with a two-week history of pain and swelling of the medial side of his right thigh just above the knee without any trauma. CT angiography revealed a popliteal artery pseudoaneurysm and its close relationship with a femoral osteochondroma. Surgical repair consisted of repair of pseudoaneurysm and removal of osteochondroma. In young patients, a non-traumatic pseudoaneurysm of distal femoral artery may be a complication of an osteochondroma and this treatable pathology should be looked for to prevent recurrence. PMID- 23929421 TI - Treatment of temporal artery pseudoaneurysms. AB - PURPOSE: To give an overview of the etiology and diagnostic process of superficial temporal artery pseudoaneurysms and to evaluate different treatment modalities. BASIC METHODS: PubMed was used for searching multiple databases for relevant clinical studies. PRINCIPAL FINDINGS: A total of 62 studies were included, harboring 82 patients. Surgical excision is the most frequently described treatment, but less invasive treatment modalities as coiling and thrombin injections are gaining popularity. Surgical treatment was successful in all cases (67/67). Endovascular treatment was successful in 69% (9/13); the five cases treated with thrombin injection were all successful. Complementary, a description of our experience with thrombin injection is given. CONCLUSIONS: Limited evidence of minimal invasive treatment for superficial temporal artery pseudoaneurysm is available. Based on this review combined with our limited experience, we suggest thrombin injections to be considered as the future primary treatment modality. In the case of unsuccessful exclusion of the aneurysm, surgical excision can be performed. PMID- 23929422 TI - Spontaneous bilateral carotid artery dissection in a patient with bovine aortic arch. AB - Carotid artery dissections are commonly associated with trauma or various connective tissue disorders. Dissection of the cerebrovascular arteries can result in ischemic stroke and is a frequent stroke etiology in younger patients. Anatomical variants of aortic arch branching, such as the 'bovine' aortic arch, are assumed to have little or no physiological consequence. To the best of our knowledge, we present for the first time a case of spontaneous dissection of the common origin of the innominate and left common carotid artery in a bovine aortic arch, resulting in bilateral dissection of the carotid arteries. PMID- 23929423 TI - Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in Chinese patients with atrial fibrillation. AB - This study assessed the effects and safety of rivaroxaban versus warfarin in Chinese patients with atrial fibrillation. In this double-blind clinical trial, a total of 353 consecutive patients with atrial fibrillation who were at risk of stroke or systemic embolism were enrolled to receive either rivaroxaban or warfarin. The primary effect endpoint occurred in five patients in the rivaroxaban group (2.29% per year) and in seven patients in the warfarin group (2.91% per year) (hazard ratio with warfarin, 0.76, 95% CI, 0.64-0.91; p = 0.03). Major and non-major clinically relevant bleeding occurred in 38 patients (14.3% per year) in the rivaroxaban group and in 36 patients (13.7% per year) in the warfarin group (hazard ratio rivaroxaban versus warfarin, 1.07; 95% CI, 0.93 1.14; p = 0.39). Adverse events were similar between these two arms (p > 0.05). In conclusion, oral administration of rivaroxaban reduced the risk of stroke or systemic embolism without significantly increasing the safety concern. PMID- 23929424 TI - Staged hybrid open and endovascular exclusion of a symptomatic thoracoabdominal aortic aneurysm in a high-risk patient. AB - Thoracoabdominal aortic aneurysms have a higher prevalence in the elderly, who are often poor surgical candidates. These extensive aneurysms may be lethal if left untreated. Conventional open repair has proven to be a major task, involving cardiopulmonary bypass, aortic cross-clamping and expeditious repair of an inaccessible structure involving two body cavities. Endovascular repair has become a viable option to treat isolated descending thoracic aneurysms and infrarenal abdominal aortic aneurysms. However, endovascular techniques alone have been less applicable for treating complex aortic aneurysms, including those involving visceral vessels. Therefore, a hybrid open and endovascular approach with visceral debranching has become an increasingly favorable alternative for patients with these complex conditions. We report a case in which a staged hybrid approach was used for successful exclusion of an extensive thoracoabdominal aortic aneurysm in a symptomatic, high-risk patient who would not have been an appropriate candidate for open surgical repair. PMID- 23929425 TI - Hypercholesterolemia in pregnant mice increases the susceptibility to atherosclerosis in adult life. AB - PURPOSE: To determine the effects of hypercholesterolemia in pregnant mice on the susceptibility to atherosclerosis in adult life through a new animal modeling approach. METHODS: Male offspring from apoE-/- mice fed with regular (R) or high (H) cholesterol chow during pregnancy were randomly subjected to regular (Groups R-R and H-R, n = 10) or high cholesterol diet (Groups R-H and H-H, n = 10) for 14 weeks. Plasma lipid profiles were determined in all rats. The abdominal aorta was examined for the severity of atherosclerotic lesions in offspring. RESULTS: Lipids significantly increased while high-density lipoprotein-cholesterol/low density lipoprotein-cholesterol decreased in mothers fed high cholesterol chow after delivery compared with before pregnancy (p < 0.01). Groups R-H and H-R indicated dyslipidemia and significant atherosclerotic lesions. Group H-H demonstrated the highest lipids, lowest high-density lipoprotein-cholesterol/low density lipoprotein-cholesterol, highest incidence (90%), plaque area to luminal area ratio (0.78 +/- 0.02) and intima to media ratio (1.57 +/- 0.05). CONCLUSION: Hypercholesterolemia in pregnant mice may increase susceptibility to atherosclerosis in their adult offspring. PMID- 23929426 TI - Amyloidosis and spontaneous hepatic bleeding, transcatheter therapy for hepatic parenchymal bleeding with massive intraperitoneal hemorrhage: a case report and review of the literature. AB - Hepatic hemorrhage can be devastating, especially in patients with underlying hepatic pathology. This is a case report of a 50-year-old man who presented to the emergency room with Stage 3 shock as evidenced by a systolic blood pressure of 90 mmHg, a heart rate of 125 beats per minute, respiration of 32, with delayed capillary refill and agitation. At this time, he was found to have a massive spontaneous intra-abdominal hemorrhage with an advanced stage of amyloidosis with multiple organ malfunctions. The initial diagnosis was based on an abdominal computed tomography scan and the patient was taken expeditiously to a hybrid angiography suite for a celiac angiogram. An intraoperative diagnosis of extravasation from amyloid related vasculopathy was made based on the angiographic appearance of hepatic circulation. Coil embolization of the feeding branch of the bleeder was achieved using the interlock coil system and a completion angiogram was done showing complete cessation of active bleeding. The postoperative phase was uneventful and the patient was discharged home on postoperative day three. His postoperative visit at five months later was unremarkable. PMID- 23929427 TI - Cause of a rare acute renal insufficiency: rupture aortocaval fistula. AB - INTRODUCTION: Abdominal aortic aneurysms can be complicated by some conditions and aortocaval fistula is one of them. Aortocaval fistula is an unusual entity. CASE REPORT: A male patient was admitted to the hospital for abdominal pain and leg oedema of three days duration. In addition, severe anuria was also noted. We determined a fistula from the right lateral wall of aneurysm to the distal of vena cava inferior. The aortocaval fistula was closed with pledged-reinforced 4/0 polypropylene suture in the aneurysmal wall. At the postoperative 10th day, he was discharged with normal renal function. DISCUSSION: After a long-term untreated fistula, right-sided heart failure, acute renal and hepatic insufficiency, deep vein thrombosis and pulmonary thrombo-embolism can be seen in these patients. Increased venous pressure should be the reason for decreased arterial flow results in renal insufficiency. Emergency intervention in these patients saves the patient's life as well as prevents irreversible organ failure. PMID- 23929428 TI - Treatment paradigms for ductus arteriosus aneurysms in adults. AB - We report two symptomatic cases of ductus arteriosus aneurysm (DDA) in adults treated in our department over a 5-years period. One patient underwent an open off-pump surgical procedure, while the second one was treated with partial aortic arch debranching and endovascular stent-grafting. DDA in adults is an uncommon condition and can present with rupture, hoarseness or symptoms of airway obstruction. Although indications for intervention are not clearly established, most authors advocate that DDAs should be treated regardless of their size, to avoid the risk of rupture, while others reserve intervention for symptomatic patients. We report on the management of these patients and provide an updated review of the current literature. PMID- 23929429 TI - Advanced treatment of acute femoropopliteal bypass graft occlusion with Fogarty catheter guidance. AB - PURPOSE: The guiding role of the Fogarty catheter was investigated among patients suffering from limb ischemia due to acute femoropopliteal bypass graft occlusion. METHODS: A total of 27 patients with a history of femoropopliteal bypass operation who was admitted with acute limb ischemia were enrolled in this retrospective study. In cases in which the Fogarty catheter could not be passed through the popliteal anastomosis, the popliteal region was explored and a new bypass or patch plasty was performed for the distal anastomosis. The cases in which the blood circulation was observed in the graft, but in which the Fogarty catheter balloon was stuck in the native vessels on the proximal and distal side of the graft and the balloon could be withdrawn by deflation, were referred to conventional angiography. The stenosis observed in native vessels was managed by endovascular stent grafting and/or balloon dilatation. FINDINGS: Graft patency was achieved in all patients. In 11 patients, conventional angiography was implemented following embolectomy. In these patients, all the occlusions found as significant on angiography were removed by percutaneous transluminal angioplasty. CONCLUSION: Effective use of Fogarty catheter is safe in acute femoropopliteal bypass graft occlusions and in particular, in the planning of further treatment following thrombectomy. PMID- 23929430 TI - Use of duplex guided stent graft placement to prevent bleeding from previously thrombosed pseudo-aneurysms during thrombolytic therapy for acute popliteal artery occlusion. AB - We present a 68-year-old female who developed multiple pseudo-aneurysms (PSAs) following cardiac catheterization via the right groin. During subsequent thrombin injection of PSAs, the patient developed acute occlusion of the popliteal artery. A covered stent was placed to obliterate the PSAs and allow for successful endovascular treatment of the occlusion without hemorrhage from the previous arteriotomy sites. This report demonstrates a safe and successful method to treating high surgical risk patients with recent PSA's and a necessity for thrombolysis. PMID- 23929431 TI - Sequential (18)F-FDG PET/CT for early prediction of complete pathological response in breast and axilla during neoadjuvant chemotherapy. AB - PURPOSE: To investigate the value of response monitoring in both the primary tumour and axillary nodes on sequential PET/CT scans during neoadjuvant chemotherapy (NAC) for predicting complete pathological response (pCR), taking the breast cancer subtype into account. METHODS: In 107 consecutive patients 290 PET/CT scans were performed at baseline (PET/CT1, 107 patients), after 2 - 3 weeks of chemotherapy (PET/CT2, 85 patients), and after 6 - 8 weeks (PET/CT3, 98 patients). The relative changes in SUVmax (from baseline) of the tumour and the lymph nodes and in both combined (after logistic regression), and the changes in the highest SUVmax between scans (either tumour or lymph node) were determined and their associations with pCR of the tumour and lymph nodes after completion of NAC were assessed using receiver operating characteristic (ROC) analysis. RESULTS: A pCR was seen in 17 HER2-positive tumours (65 %), 1 ER-positive/HER2 negative tumour (2 %), and 16 triple-negative tumours (52 %). The areas under the ROC curves (ROC-AUC) for the prediction of pCR in HER2-positive tumours after 3 weeks were 0.61 for the relative change in tumours, 0.67 for the combined change in tumour and nodes, and 0.72 for the changes in the highest SUVmax between scans. After 8 weeks equivalent values were 0.59, 0.42 and 0.64, respectively. In triple-negative tumours the ROC-AUCs were 0.76, 0.84 and 0.76 after 2 weeks, and 0.87, 0.93 and 0.88 after 6 weeks, respectively. CONCLUSION: In triple-negative tumours a PET/CT scan after 6 weeks (three cycles) appears to be optimally predictive of pCR. In HER2-positive tumours neither a PET/CT scan after 3 weeks nor after 8 weeks seems to be useful. The changes in SUVmax of both the tumour and axillary nodes combined correlates best with pCR. PMID- 23929432 TI - Reduced cardiac 123I-metaiodobenzylguanidine uptake in patients with spinocerebellar ataxia type 2: a comparative study with Parkinson's disease. AB - PURPOSE: Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia, supranuclear ophthalmoplegia, and peripheral neuropathy. Autonomic nervous system dysfunction is often present. This study evaluated the cardiac sympathetic function in patients with SCA2 using (123)I-metaiodobenzylguanidine (MIBG) in comparison with patients with Parkinson's disease (PD) and control subjects. METHODS: Nine patients with SCA2, nine patients with PD, and nine control subjects underwent (123)I-MIBG imaging studies from which early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates were calculated. RESULTS: Early (F = 12.3, p < 0.0001) and late (F = 16.8, p < 0.0001) H/M ratios were significantly different among groups. In controls, early and late H/M ratios (2.2 +/- 0.12 and 2.1 +/- 0.20) were significantly higher than in patients with SCA2 (1.9 +/- 0.23 and 1.8 +/- 0.20, both p < 0.05) and with patients with PD (1.7 +/- 0.29 and 1.4 +/- 0.35, both p < 0.001). There was also a significant difference in washout rates among groups (F = 11.7, p < 0.0001). In controls the washout rate (19.9 +/- 9.6%) was significantly lower (p < 0.005) than in patients with PD (51.0 +/- 23.7%), but not different from that in SCA2 patients (19.5 +/- 9.4%). In SCA2 patients, in a multivariable linear regression analysis only the Scale for the Assessment and Rating of Ataxia score was independently associated with early H/M ratio (beta = -0.12, p < 0.05). CONCLUSION: (123)I-MIBG myocardial scintigraphy demonstrated an impairment of cardiac sympathetic function in patients with SCA2, which was less marked than in PD patients. These results suggest that (123)I-MIBG cardiac imaging could become a useful tool for analysing the pathophysiology of SCA2. PMID- 23929433 TI - miR-23a inhibits E-cadherin expression and is regulated by AP-1 and NFAT4 complex during Fas-induced EMT in gastrointestinal cancer. AB - Fas signaling has been shown to induce the epithelial-mesenchymal transition (EMT) to promote gastrointestinal (GI) cancer metastasis, but the involvement of microRNA in this mechanism remains unknown. We found that Fas ligand (FasL) treatment inhibited E-cadherin expression and promoted cell invasion by upregulation of miR-23a, but overexpression of the miR-23a inhibitor could partially block this activity. FasL-induced extracellular signal-regulated kinase/mitogen-activated protein kinase signaling activated the activator protein 1 (AP-1) complex and repressed glycogen synthase kinase-3beta activity, which contributed to nuclear translocation of AP-1 and nuclear factor of activated T cells (NFAT4). Nuclear accumulation and interaction of AP-1 and NFAT4 and subsequent binding to the miR-23a promoter led to increased miR-23a expression. Inhibition of Fas signaling by downregulation of the Fas receptor led to a decrease in miR-23a expression and cell invasion ability in vivo and in vitro, as well as an increase in E-cadherin. Evaluation of human GI precancerous and cancer specimens showed that the expression of FasL and miR-23a increased, whereas the expression of E-cadherin decreased during GI cancer progression. A significant correlation was noted between any two of these three molecules. An EMT phenotype was shown to correlate with an advanced cancer stage and worse prognosis. Taken together, our results show that miR-23a participates in the mechanism of the FasL induced EMT process and may serve as a potential therapeutic target for cancer metastasis. PMID- 23929434 TI - The highly prevalent BRCA2 mutation c.2808_2811del (3036delACAA) is located in a mutational hotspot and has multiple origins. AB - BRCA2-c.2808_2811del (3036delACAA) is one of the most reported germ line mutations in non-Ashkenazi breast cancer patients. We investigated its genetic origin in 51 Spanish carrier families that were genotyped with 11 13q polymorphic markers. Three independent associated haplotypes were clearly distinguished accounting for 23 [west Castilla y Leon (WCL)], 20 [east Castilla y Leon (ECL)] and 6 (South of Spain) families. Mutation age was estimated with the Disequilibrium Mapping using Likelihood Estimation software in a range of 45-68 and 45-71 generations for WCL and ECL haplotypes, respectively. The most prevalent variants, c.2808_2811del and c.2803G > A, were located in a double hairpin loop structure (c.2794-c.2825) predicted by Quikfold that was proposed as a mutational hotspot. To check this hypothesis, random mutagenesis was performed over a 923 bp fragment of BRCA2, and 86 DNA variants were characterized. Interestingly, three mutations reported in the mutation databases (c.2680G > A, c.2944del and c.2957dup) were replicated and 20 affected the same position with different nucleotide changes. Moreover, five variants were placed in the same hairpin loop of c.2808_2811del, and one affected the same position (c.2808A > G). In conclusion, our results support that at least three different mutational events occurred to generate c.2808_2811del. Other highly prevalent DNA variants, such as BRCA1-c.68_69delAG, BRCA2-c.5946delT and c.8537delAG, are concentrated in hairpin loops, suggesting that these structures may represent mutational hotspots. PMID- 23929435 TI - An exploration of pathways involved in lung carcinoid progression using gene expression profiling. AB - Pulmonary carcinoids comprise a well-differentiated subset of neuroendocrine tumors usually associated with a favorable prognosis, but mechanisms underlying disease progression are poorly understood. In an explorative approach to identify pathways associated with progression, we compared gene expression profiles of tumors from five patients with a favorable and five with a poor disease outcome. Differentially expressed genes were validated using quantitative real-time PCR on 65 carcinoid tumors, in combination with survival analysis. One of the identified pathways was further examined using immunohistochemistry. As compared with other chromosomal locations, a significantly higher number of genes downregulated in carcinoids with a poor prognosis were located at chromosome 11q (P = 0.00017), a region known to be frequently lost in carcinoids. In addition, a number of upregulated genes were found involved in the mitotic spindle checkpoint, the chromosomal passenger complex (CPC), mitotic kinase CDC2 activity and the BRCA Fanconi anemia pathway. At the individual gene level, BIRC5 (survivin), BUB1, CD44, IL20RA, KLK12 and OTP were independent predictors of patient outcome. For survivin, the number of positive nuclei was also related to poor prognosis within the group of carcinoids. Aurora B kinase and survivin, major components of the CPC, were particularly upregulated in high-grade carcinomas and may therefore comprise therapeutic targets for these tumors. To our knowledge, this is the first expression profiling study focusing specifically on pulmonary carcinoids and progression. We have identified novel pathways underlying malignant progression and validated several genes as being strong prognostic indicators, some of which could serve as putative therapeutic targets. PMID- 23929436 TI - O6-methylguanine-DNA methyltransferase in the defense against N-nitroso compounds and colorectal cancer. AB - Colorectal cancer (CRC) is among the leading causes of cancer death worldwide, involving multiple dietary and non-dietary risk factors. A growing body of evidence suggests that N-nitroso compounds (NOC) play a pivotal role in the etiology of CRC. NOC are present in food and are also formed endogenously in the large intestine. Upon metabolic activation and also spontaneously, they form electrophilic species that methylate the DNA, producing N-methylated purines and O(6)-methylguanine, the latter of which bears high mutagenic and carcinogenic potential. Methylated DNA bases are removed by base excision repair initiated by the alkyladenine-DNA glycosylase, the family of AlkB homologs proteins, and the suicide enzyme O(6)-methylguanine-DNA methyltransferase (MGMT), which is the main focus of this review. We present animal models with a deficiency of MGMT that display a tremendously enhanced sensitivity toward alkylation-induced colorectal carcinogenesis, highlighting its role in the protection against the cytotoxic and mutagenic effects of alkylating agents. In line with these studies, MGMT was linked to the formation of human sporadic CRC. Colorectal tumors and precursor lesions frequently display epigenetic inactivation of MGMT resulting from promoter hypermethylation, which is tightly associated with the occurrence of G:C to A:T transition mutations in the KRAS oncogene. We also discuss clinical data, which identified the MGMT status of CRC patients as promising parameter for the treatment of metastasized CRC using alkylating anticancer drugs such as temozolomide. PMID- 23929437 TI - The EDA-containing cellular fibronectin induces epithelial-mesenchymal transition in lung cancer cells through integrin alpha9beta1-mediated activation of PI3 K/AKT and Erk1/2. AB - Cellular fibronectin (cFN) is one of the main components of tissue extracellular matrices and is involved in multiple physiologic and pathologic processes such as embryogenesis, wound healing, inflammation and tumor progression. The function of fibronectin in regulating normal cell adhesion and migration is well documented, but its function in cancer progression is only partially unraveled. We have reported previously that fibronectin stimulates the proliferation and survival of non-small lung carcinoma cells through upregulation of pro-oncogenic signals related to cyclooxygenase-2/phosphatidylinositol-3-kinase/protein kinase B (COX 2/PI3-K/AKT)/mammalian target of rapamycin triggered by activation of the integrin alpha5beta1. Here, we extend these studies by showing that fibronectin promotes epithelial-mesenchymal transition (EMT) in lung cancer cells. We found that cFN, but not plasma fibronectin or type 1 collagen, induces lung carcinoma cell scattering in vitro, promotes cell migration and invasion of Matrigel and stimulates the expression of the mesenchymal marker alpha-smooth muscle actin while decreasing the expression of the epithelial marker E-cadherin through PI3-K and Erk pathways. Interestingly, the extra domain A (EDA) within cFN was found to be crucial for this process, as confirmed by testing cells overexpressing EDA or cells exposed to EDA-containing matrices. We found that the integrin alpha9, but not alpha5, mediated cFN-induced EMT as silencing integrin alpha9 neutralized cFN induced EMT. Overall, our findings show that the EDA domain within cFN induces EMT in lung carcinoma cells through integrin alpha9-mediated activation of PI3-K and Erk. PMID- 23929439 TI - Bases for time-resolved probing of transient carrier dynamics by optical pump probe scanning tunneling microscopy. AB - The tangled mechanism that produces optical pump-probe scanning tunneling microscopy spectra from semiconductors was analyzed by comparing model simulation data with experimental data. The nonlinearities reflected in the spectra, namely, the excitations generated by paired laser pulses with a delay time, the logarithmic relationship between carrier density and surface photovoltage (SPV), and the effect of the change in tunneling barrier height depending on SPV, were examined along with the delay-time-dependent integration process used in measurement. The optimum conditions required to realize reliable measurement, as well as the validity of the microscopy technique, were demonstrated for the first time. PMID- 23929440 TI - Sub-bandgap absorption in organic solar cells: experiment and theory. AB - Most high-performance organic solar cells involve bulk-heterojunctions in order to increase the active donor-acceptor interface area. The power conversion efficiency depends critically on the nano-morphology of the blend and the interface. Spectroscopy of the sub-bandgap region, i.e., below the bulk absorption of the individual components, provides unique opportunities to study interface-related properties. We present absorption measurements in the sub bandgap region of bulk heterojunctions made of poly(3-hexylthiophene-2,5-diyl) as an electron donor and [6,6]-phenyl-C61-butyric acid methyl ester (P3HT:PCBM) as an electron acceptor and compare them with quantum-chemical calculations and recently published data on the external quantum efficiency (EQE). The very weak absorption of the deep sub-bandgap region measured by the ultra-sensitive Photothermal Deflection Spectroscopy (PDS) features Urbach tails, polaronic transitions, conventional excitons, and possibly charge-transfer states. The quantum-chemical calculations allow characterizing some of the unsettled spectral features. PMID- 23929438 TI - Dihydroartemisinin inhibits the mammalian target of rapamycin-mediated signaling pathways in tumor cells. AB - Dihydroartemisinin (DHA), an antimalarial drug, has previously unrecognized anticancer activity, and is in clinical trials as a new anticancer agent for skin, lung, colon and breast cancer treatment. However, the anticancer mechanism is not well understood. Here, we show that DHA inhibited proliferation and induced apoptosis in rhabdomyosarcoma (Rh30 and RD) cells, and concurrently inhibited the signaling pathways mediated by the mammalian target of rapamycin (mTOR), a central controller for cell proliferation and survival, at concentrations (<3 MUM) that are pharmacologically achievable. Of interest, in contrast to the effects of conventional mTOR inhibitors (rapalogs), DHA potently inhibited mTORC1-mediated phosphorylation of p70 S6 kinase 1 and eukaryotic initiation factor 4E binding protein 1 but did not obviously affect mTORC2 mediated phosphorylation of Akt. The results suggest that DHA may represent a novel class of mTORC1 inhibitor and may execute its anticancer activity primarily by blocking mTORC1-mediated signaling pathways in the tumor cells. PMID- 23929441 TI - Impact of a 2-year multimodal intervention for disruptive 6-year-olds on substance use in adolescence: randomised controlled trial. AB - BACKGROUND: Adolescent substance use is associated with both earlier childhood behavioural problems and serious lifetime addiction problems later in life. AIMS: To examine whether, and through which mechanisms, targeting risk factors in early childhood prevents substance use across adolescence. METHOD: Disruptive kindergarten boys (n = 172) living in Montreal were randomly allocated to a preventive intervention and a control condition. The intervention was delivered over 2 years (7-9 years of age) with two main components: (a) social and problem solving skills training for the boys; and (b) training for parents on effective child-rearing skills. RESULTS: Adolescent substance use, up to 8 years post intervention, was reduced in those who received the intervention (d = 0.48-0.70). Of most interest, the intervention effects were explained partly by reductions in impulsivity, antisocial behaviour and affiliation with less deviant peers during pre-adolescence (11-13 years). CONCLUSIONS: Adolescent substance use may be indirectly prevented by selectively targeting childhood risk factors that disrupt the developmental cascade of adolescent risk factors for substance use. PMID- 23929442 TI - Anxiety and mortality risk in community-dwelling elderly people. AB - BACKGROUND: There are conflicting data on the role of anxiety in predicting mortality. AIMS: To evaluate the 10-year mortality risk associated with anxiety in community-dwelling elderly people. METHOD: Using data from 718 men and 1046 women aged 65 years and over, gender-stratified associations of anxiety symptoms (Spielberger State-Trait Anxiety Inventory, third tertile) and current DSM-IV anxiety disorder including generalised anxiety disorder (GAD) and phobia with all cause and cardiovascular mortality were determined. RESULTS: In women, mortality risk was increased for anxiety disorder and GAD in multivariate Cox models (hazard ratio (HR) = 1.53, 95% CI 1.02-2.27 and HR = 2.04, 95% CI 1.08-3.86 respectively), whereas for phobia it was nearly significant (HR = 1.52, 95% CI 0.94-2.47). Anxiety trait symptoms became non-significant as a result of the confounding effect of depressive symptoms. Anxiety disorder was associated with cardiovascular mortality in univariate analysis (HR = 2.42, 95% CI 1.16-5.07). No significant associations were found in men. CONCLUSIONS: Our study suggests a gender-specific association of anxiety and mortality. PMID- 23929443 TI - Comparative mortality risks of antipsychotic medications in community-dwelling older adults. AB - BACKGROUND: All antipsychotic medications carry warnings of increased mortality for older adults, but little is known about comparative mortality risks between individual agents. AIMS: To estimate the comparative mortality risks of commonly prescribed antipsychotic agents in older people living in the community. METHOD: A retrospective, claims-based cohort study was conducted of people over 65 years old living in the community who had been newly prescribed risperidone, olanzapine, quetiapine, haloperidol, aripiprazole or ziprasidone (n = 136 393). Propensity score-adjusted Cox proportional hazards models assessed the 180-day mortality risk of each antipsychotic compared with risperidone. RESULTS: Risperidone, olanzapine and haloperidol showed a dose-response relation in mortality risk. After controlling for propensity score and dose, mortality risk was found to be increased for haloperidol (hazard ratio (HR) = 1.18, 95% CI 1.06 1.33) and decreased for quetiapine (HR = 0.81, 95% CI 0.73-0.89) and olanzapine (HR = 0.82, 95% CI 0.74-0.90). CONCLUSIONS: Significant variation in mortality risk across commonly prescribed antipsychotics suggests that antipsychotic selection and dosing may affect survival of older people living in the community. PMID- 23929444 TI - Efficacy and pharmacokinetic/pharmacodynamic study of 1,1'-methylenebis{4 [(hydroxyimino)methyl] pyridinium} dimethanesulfonate in guinea pigs and rhesus macaques exposed to cyclosarin. AB - Male Hartley guinea pigs and male rhesus macaques were used to determine an efficacious dose of 1,1'-methylenebis{4-[(hydroxyimino)methyl] pyridinium} dimethanesulfonate (MMB4 DMS) that would result in 80% survival, 24 hours following a single exposure to cyclosarin (GF). The pharmacokinetic/pharmacodynamic relationship between acetylcholinesterase activity and MMB4 plasma concentrations relative to survival was evaluated. Guinea pigs and non-human primates (NHPs) were concurrently administered MMB4 DMS (guinea pigs: 0, 10, 30, or 40 mg/kg, intramuscular [IM] and NHPs: 0.1, 1, 5, 10, or 20 mg/kg, IM), atropine, and diazepam following a 3 * median lethal dose (LD50) GF challenge. Clinical observations were evaluated using a quality-of-life (QOL) scoring system. All GF-exposed animals exhibited typical signs of nerve agent poisoning immediately following challenge. In guinea pigs, 24-hour survival was 0%, 50%, 90%, and 90% for 0, 10, 30, and 40 mg/kg MMB4 DMS groups, respectively. In addition, nearly all animals surviving to 24 hours were clinically normal, with many in the 30 and 40 mg/kg MMB4 DMS dose group observed as normal by 4 hours post-challenge. In NHPs, survival was 100% for all treatment groups, with all animals noted as clinically normal by 48 hours. Following treatment with atropine/MMB4 DMS/diazepam, NHPs exhibited dose- and temporal related decreases in incidence and duration of the clinical signs of toxicity. The QOL scores improved with increasing MMB4 DMS dose in both species. The estimated ED80s were 25.5 mg/kg MMB4 DMS (human equivalent dose [HED] of 5.5 mg/kg) and <= 0.1 mg/kg (HED of 0.03 mg/kg) in guinea pigs and NHPs, respectively. PMID- 23929445 TI - MMB4 DMS nanoparticle suspension formulation with enhanced stability for the treatment of nerve agent intoxication. AB - Various oximes are currently fielded or under investigation in the United States and other countries as a component of autoinjector emergency treatment systems for organophosphate nerve agent chemical weapons. Bis-pyridinium oximes in general have greater efficacy against a broad spectrum of nerve agents, but they have poor stability due to hydrolytic degradation at elevated temperatures. 1,1' Methylenebis-4-[(hydroxyimino)methyl]pyridinium dimethanesulfonate (MMB4 DMS) is a leading candidate for next-generation nerve agent treatment systems, because it is more stable than other bis-pyridinium oximes, but it still degrades quickly at temperatures often encountered during storage and field use. The primary goal is to increase the stability and shelf life of MMB4 while maintaining the desirable pharmacokinetic (PK) properties of the aqueous formulation. We have developed a formulation to be used in a phase 1 clinical trial consisting of MMB4 micro/nanoparticles suspended in cottonseed oil, a biocompatible vegetable oil. Through various milling techniques, the average particle size can be controlled from approximately 200 to 6000 nm to produce non-Newtonian formulations that are viscous enough to resist rapid particle sedimentation while remaining injectable at a range of concentrations from 5 to 400 mg/mL. The preliminary accelerated stability test shows that MMB4 in these formulations is stable for at least 2 years at temperatures up to 80 degrees C. Preliminary preclinical in vivo studies have demonstrated that all concentrations and particle sizes have desirable PK properties, including high bioavailability and rapid absorption, which is critical to combat potent and fast-acting nerve agents. PMID- 23929446 TI - Good manufacturing practice: manufacturing of a nerve agent antidote nanoparticle suspension. AB - We have established a current good manufacturing practice (GMP) manufacturing process to produce a nanoparticle suspension of 1,1'-methylenebis-4 [(hydroxyimino)methyl]pyridinium dimethanesulfonate (MMB4 DMS) in cottonseed oil (CSO) as a nerve agent antidote for a Phase 1 clinical trial. Bis-pyridinium oximes such as MMB4 were previously developed for emergency treatment of organophosphate nerve agent intoxication. Many of these compounds offer efficacy superior to monopyridinium oximes, but they have poor thermal stability due to hydrolytic cleavage in aqueous solution. We previously developed a nonaqueous nanoparticle suspension to improve the hydrothermal stability, termed Enhanced Formulation (EF). An example of this formulation technology is a suspension of MMB4 DMS nanoparticles in CSO. Due to the profound effect of particle size distribution on product quality and performance, particle size must be controlled during the manufacturing process. Therefore, a particle size analysis method for MMB4 DMS in CSO was developed and validated to use in support of good laboratory practice/GMP development and production activities. Manufacturing of EF was accomplished by milling MMB4 DMS with CSO and zirconia beads in an agitator bead mill. The resulting bulk material was filled into 5-mL glass vials at a sterile fill facility and terminally sterilized by gamma irradiation. The clinical lot was tested and released, a Certificate of Analysis was issued, and a 3-year International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) stability study started. The drug product was placed in storage for Phase 1 clinical trial distribution. A dose delivery uniformity study was undertaken to ensure that the correct doses were delivered to the patients in the clinic. PMID- 23929447 TI - Pharmacokinetics of MMB4 DMS in rats, rabbits, and dogs following a single IV administration. AB - Organophosphorus (OP) nerve agents pose tremendous threats to both military and civilian populations. The substance 1,1'-methylenebis[4-[(hydroxyimino)methyl] pyridinium] (MMB4) is being developed as a replacement for the currently fielded 2-pyridine aldoxime, or pralidoxime (2-PAM) as a treatment for OP nerve agent induced toxicity. The present study characterized pharmacokinetic (PK) profiles of MMB4 in male and female Sprague-Dawley rats, New Zealand White rabbits, and beagle dogs given a single intravenous (IV) administration of MMB4 dimethanesulfonate (DMS) at 55, 25, and 15 mg/kg dose, respectively. The plasma MMB4 concentration versus time profiles were biphasic for all species tested and fit a 2-compartment model with first-order elimination. There were no overt sex related differences in the calculated PK parameters. For the rat, rabbit, and dog, the average systemic exposure parameters predicted Cmax (ug/mL) and AUCinfinity (ug.h/mL) were 273 and 71.0, 115 and 48.1, and 87.4 and 39.6; the average volume of distribution (mL/kg) values to the central and peripheral compartments were 207 and 143, 242 and 172, and 198 and 213; and the average elimination half-life (hour) and clearance (mL/h/kg) values were 0.18 and 778, 0.29 and 577, and 0.32 and 430, respectively, when the PK parameters for males and females were combined. The current study revealed a similarity in the volume of distribution to the central compartment for MMB4 among the 3 species tested while demonstrating species-related differences in the elimination half-life and clearance of MMB4. PMID- 23929448 TI - Comparative toxicokinetics of MMB4 DMS in rats, rabbits, dogs, and monkeys following single and repeated intramuscular administration. AB - 1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Time courses of MMB4 concentrations in plasma were characterized following 7-day repeated intramuscular (IM) administrations of MMB4 DMS to male and female Sprague-Dawley rats, New Zealand White rabbits, beagle dogs (single dose only), and rhesus monkeys at drug dose levels used in earlier toxicology studies. In general, there were no significant differences in MMB4 toxicokinetic (TK) parameters between males and females for all the species tested in these studies. After a single IM administration to rats, rabbits, dogs, and monkeys, MMB4 DMS was rapidly absorbed, resulting in average T max values ranging from 5 to 30 minutes. Although C max values did not increase dose proportionally, the overall exposure to MMB4 in these preclinical species, as indicated by area under the curve (AUC) extrapolated to the infinity (AUCinfinity) values, increased in an approximately dose-proportional manner. The MMB4 DMS was extensively absorbed into the systemic circulation after IM administration as demonstrated by greater than 80% absolute bioavailability values for rats, rabbits, and dogs. Repeated administrations of MMB4 DMS for 7 days did not overtly alter TK parameters for MMB4 in rats, rabbits, and monkeys (150 and 300 mg/kg/d dose groups only). However, C max and AUC values decreased in monkeys given 450 and 600 mg/kg IM doses of MMB4 DMS following repeated administrations for 7 days. Based on the TK results obtained from the current study and published investigations, it was found that the apparent volume of distribution and clearance values were similar among various preclinical species, except for the rat. PMID- 23929449 TI - International Journal of Toxicology special edition volume of MMB4 DMS. PMID- 23929450 TI - MMB4 DMS: cardiovascular and pulmonary effects on dogs and neurobehavioral effects on rats. AB - The objectives of these studies were to determine the cardiopulmonary effects of a single intramuscular administration of 1,1'-methylenebis[4 [(hydroxyimino)methyl]-pyridinium] dimethanesulfonate (MMB4 DMS) on dogs and on the central nervous system in rats. On days 1, 8, 15, and 22, male and female dogs received either vehicle (water for injection/0.5% benzyl alcohol/methane sulfonic acid) or MMB4 DMS (20, 50, or 100 mg/kg). Pulmonary function was evaluated for the first 5 hours after concurrent dosing with cardiovascular monitoring; then cardiovascular monitoring continued for 72 hours after dosing. Rats were dosed once by intramuscular injection with vehicle (water for injection/0.5% benzyl alcohol/methane sulfonic acid) or MMB4 DMS (60, 170, or 340 mg/kg). In dogs, 100 mg/kg MMB4 DMS resulted in increased blood pressure, slightly increased heart rate, slightly prolonged corrected QT, and moderately increased respiratory rate. There were no toxicological effects of MMB4 DMS on neurobehavioral function in rats administered up to 340 mg/kg MMB4 DMS. PMID- 23929451 TI - Comparative toxicology studies in Sprague-Dawley rats, rhesus monkeys, and New Zealand White rabbits to determine a no observed adverse effect level for 1,1' methylenebis[4-[(hydroxyimino)methyl]-pyridinium] dimethanesulfonate. AB - Studies were conducted in Sprague-Dawley rats, New Zealand White (NZW) rabbits, and rhesus monkeys to characterize the toxicity of 1,1'-methylenebis[4 [(hydroxyimino)methyl]-pyridinium] dimethanesulfonate (MMB4 DMS) following intramuscular administration. Rats received MMB4 DMS once daily for 7 days at 100, 200, 400, and 800 mg/kg/d; rabbits received a range of dose levels in 3 separate 7-day studies from 3 to 800 mg/kg/d and in a single-dose study from 50 to 200 mg/kg; and monkeys received MMB4 DMS at 150 to 600 mg/kg/d. Mortality was noted in rats and rabbits administered >= 200 mg/kg. All monkeys survived until scheduled termination. Adverse clinical observations were noted in the rats at >= 400 mg/kg/d and in rabbits administered >= 200 mg/kg; no adverse findings were noted in the monkeys. Clinical pathology changes were noted in the rabbit related to cardiac and renal function. In the rabbit and monkey, elevations in myoglobin, alanine aminotransferase/aspartate aminotransferase, platelets, creatine kinase, and coagulation factors were related to local inflammation at the intramuscular administration site. Light microscopic examination at the injection sites revealed acute skeletal muscle necrosis in vehicle control and treated groups. Target tissues in the rabbit studies were identified as kidney, heart, and lungs at >= 100 mg/kg/d. All changes noted in all the species demonstrated partial to complete recovery comparable to control values or to a clinically irrelevant level of effect. The NZW rabbit was the most sensitive species, and the no observed adverse effect level (NOAEL) was determined as 50 mg/kg/d; the NOAEL in the rat was 100 mg/kg/d; and the NOAEL in rhesus monkeys was >600 mg/kg/d. PMID- 23929452 TI - Evaluations of in vitro metabolism, drug-drug interactions mediated by reversible and time-dependent inhibition of CYPs, and plasma protein binding of MMB4 DMS. AB - 1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Drug metabolism and plasma protein binding for MMB4 DMS were examined using various techniques and a wide range of species. When (14)C-MMB4 DMS was incubated in liver microsomes, 4-pyridine aldoxime (4-PA) and an additional metabolite were detected in all species tested. Identity of the additional metabolite was postulated to be isonicotinic acid (INA) based on liquid chromatography with a tandem mass spectrometry analysis, which was confirmed by comparison with authentic INA. Formation of INA was dependent on species, with the highest level found in monkey liver microsomes. The MMB4 DMS exhibited reversible inhibition in a concentration dependent manner toward cytochrome P450 1A2 (CYP1A2), CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human liver microsomes showing the highest inhibition for CYP2D6. Human recombinant CYPs were used to evaluate inhibitory curves more adequately and determine detailed kinetic constants for reversible inhibition and potential time-dependent inhibition (TDI). The MMB4 DMS exhibited reversible inhibition toward human-recombinant CYP2D6 with an inhibition constant (K i) value of 66.6 umol/L. Based on the k inact/K I values, MMB4 DMS was found to exhibit the most potent TDI toward CYP2D6. The MMB4 DMS at 5 different concentrations was incubated in plasma for 5 hours using an equilibrium dialysis device. For all species tested, there were no concentration-dependent changes in plasma protein binding, ranging from 10% to 17%. These results suggest that MMB4 was not extensively bound to plasma protein, and there were no overt species-related differences in the extent of MMB4 bound to plasma protein. PMID- 23929453 TI - Absorption, distribution, metabolism, and excretion of 14C-MMB4 DMS administered intramuscularly to Sprague-Dawley rats and New Zealand White rabbits. AB - 1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] dimethanesulfonate (MMB4 DMS) is currently under development for the treatment of chemical warfare organophosphorus nerve agent poisoning. The present study evaluates the absorption, distribution, metabolism, and excretion of (14)C-MMB4 DMS administered intramuscularly to rats and rabbits. The formulated mixture of radiolabeled and nonradiolabeled MMB4 DMS was administered as a single or 7-day repeated dose. Rat doses were 55 or 220 mg/kg (100 uCi/kg), and rabbit doses were 25 or 100 mg/kg (31.25 and 62.5 uCi/kg, respectively). Urine, bile (rats only), feces, blood, and tissues were collected for up to 72 hours. Metabolic profiling using high-performance liquid chromatography with radiodetection was performed on selected urine samples. For both animal species, the majority of the total radioactivity was excreted in the urine (74%-94%) by 72 hours after dosing with greater than 90% of the radioactivity measured in the urine within 8 to 12 hours after dosing. There were no apparent species or dose differences in the urine excretion pattern. The distribution of (14)C-MMB4 DMS-derived radioactivity was rapid and generally reached the highest concentration by the first collection time point (0.25 hours). The tissue-blood concentration ratios were highest at the injection sites and in the kidneys and gastrointestinal tract contents for both the species. Two metabolites of MMB4 DMS were detected in rat and rabbit urine; their structure was confirmed by liquid chromatography with tandem mass spectrometry as 4-pyridine aldoxime and isonicotinic acid (pyridine-4-carboxylic acid). PMID- 23929454 TI - In vivo acetylcholinesterase reactivation in male guinea pigs and rhesus macaques following cyclosarin exposure and treatment with 1,1'-methylenebis{4 [(hydroxyimino)methyl] pyridinium} dimethanesulfonate. AB - Acetylcholinesterase (AChE) reactivation studies were conducted in guinea pigs (GPs) and nonhuman primates (NHPs) to determine the 1,1'-methylenebis{4 [(hydroxyimino)methyl] pyridinium} dimethanesulfonate (MMB4 DMS) dose that reactivated at least 20% of blood AChE within 15 minutes following cyclosarin (GF) dosing (used as the criterion for efficacy). Male GPs and male rhesus macaques (NHPs) were pretreated with atropine 15 minutes prior to GF administration (1 * median lethal dose [LD50]) and MMB4 DMS 15 minutes following GF administration. The GP survival was 5 of 8, 8 of 8, 8 of 8, and 6 of 8 for the 0.75, 3.0, 6.0, or 12.0 mg/kg MMB4 DMS treatment groups, respectively. In NHPs, survival was 6 of 6 at 0.5, 1.2, 3.0, or 9.3 mg/kg MMB4 DMS, respectively, 24 hours post-challenge, with the majority of animals noted as clinically normal by 24 hours. Pharmacokinetic/pharmacodynamic modeling revealed that 1.8 mg/kg in GPs or 0.013 mg/kg in NHPs would result in an average 20% reactivation; human equivalent doses were calculated as 0.39 mg/kg (based on GP data) and 0.004 mg/kg (based on NHP data). The model suggested that MMB4 plasma concentrations of 1000 ng/mL and AChE reactivation of 80% would be most effective. Although a 0.5 mg/kg MMB4 DMS dose in NHPs resulted in 100% survival and an average of 78% AChE reactivation, adverse effects associated with GF administration were still observed 24 hours post-challenge (tremors, mydriasis, and weakness were observed in 3 of 6 animals). In comparison, 6 of 6 animals treated with 1.2 mg/kg MMB4 DMS were observed as clinically normal 24 hours post-challenge. PMID- 23929455 TI - Inhibition of stearoyl-CoA desaturase 1 reduces lipogenesis in primary bovine adipocytes. AB - The objectives were to determine the effect of stearoyl-CoA desaturase (SCD1) inhibition on adipocyte proliferation, differentiation and cellular lipid metabolism in bovine primary adipocytes. Inhibition of SCD1 activity by sterculic acid (SA) or conjugated linoleic acid, trans-10 cis-12 isomer, (t10, c12-CLA) did not alter adipocyte cellular proliferation, viability or differentiation. In 1,2 [(13)C]-acetate supplemented cells, the mass isotopomer distribution analysis showed that the fractional synthesis rate of [(13)C]-16:0 was reduced (P < 0.01) in SA and t10, c12-CLA treatments compared to control. Of the lipogenic genes, t10, c12-CLA treatment decreased (P < 0.05) the expression of SCD1, acetyl-CoA carboxylase (ACC), fatty acid synthase; whereas SA supplementation decreased (P < 0.05) the expression of ACC. Both SA and t10, c12-CLA increased (P < 0.05) the expression of hormone-sensitive lipase and carnitine palmitoyl transferase involved in lipolysis and oxidation. Inhibition of SCD1 in bovine adipocytes decreases de novo fatty acid synthesis by down-regulating genes involved in lipogenesis and up-regulating genes involved in lipolysis and oxidation. PMID- 23929456 TI - Traditional foods for health: screening of the antioxidant capacity and phenolic content of selected Black Sea area local foods. AB - BACKGROUND: The nutritional characteristics of the Black Sea area (BSA) traditional foods are almost unknown, and they could be interesting sources of antioxidant compounds. In this study, carried out within the BaSeFood project, the in vitro total antioxidant capacity (TAC) and phenolic content of 39 BSA traditional foods were determined using different assays. RESULTS: An ample range of TAC and phenolics content was detected in the examined foods that were ranked according to their scavenging activity expressed per weight unit and per serving size. Based on serving size, the highest TAC was in the order blueberries > nettle soup > sunflower seeds, and the fruits/fruit-based foods group was the one having the highest activity. Correlation analysis evidenced that the TAC is highly dependent on total phenolic content, while hydroxycinnamic acids and compounds having o-diphenolic structure did not show specific prominent effects. Finally, correlations between the two methods used for measuring the TAC suggest that they are both suitable in a wide range of foods. CONCLUSION: Our data represent the first contribution to further research on the health effects of BSA traditional foods. This could enhance the interest of consumers, with potential benefits to stakeholders at all levels of the production chain. PMID- 23929457 TI - Correlating the amount of urea, creatinine, and glucose in urine from patients with diabetes mellitus and hypertension with the risk of developing renal lesions by means of Raman spectroscopy and principal component analysis. AB - Patients with diabetes mellitus and hypertension (HT) diseases are predisposed to kidney diseases. The objective of this study was to identify potential biomarkers in the urine of diabetic and hypertensive patients through Raman spectroscopy in order to predict the evolution to complications and kidney failure. Urine samples were collected from control subjects (CTR) and patients with diabetes and HT with no complications (lower risk, LR), high degree of complications (higher risk, HR), and doing blood dialysis (DI). Urine samples were stored frozen (-20 degrees C) before spectral analysis. Raman spectra were obtained using a dispersive spectrometer (830-nm, 300-mW power, and 20-s accumulation). Spectra were then submitted to principal component analysis (PCA) followed by discriminant analysis. The first PCA loading vectors revealed spectral features of urea, creatinine, and glucose. It has been found that the amounts of urea and creatinine decreased as disease evoluted from CTR to LR/HR and DI (PC1, p<0.05), and the amount of glucose increased in the urine of LR/HR compared to CTR (PC3, p<0.05). The discriminating model showed better overall classification rate of 70%. These results could lead to diagnostic information of possible complications and a better disease prognosis. PMID- 23929459 TI - Local perceptions of changes in traditional ecological knowledge: a case study from Malekula island, Vanuatu. AB - Traditional ecological knowledge (TEK) is a critical global resource that may be eroding amid social and environmental change. Here, we present data on local perceptions of TEK change from three communities on Malekula Island in Vanuatu. Utilizing a structured interview (n = 120), we find a common perception of TEK loss. Participants defined two key periods of TEK erosion (roughly 1940-1960 and 1980-present), and noted that TEK decline was driven both external (e.g., church) and internal (e.g., shifting values) processes. Erosion was perceived to more comprehensive in the worldview domain than in aspects of ethnobiological knowledge and practice. These data indicate the perceived fragility of TEK systems and the complexity of TEK change. TEK systems are critical to natural resource management, and data such as these will assist in designing nuanced responses to the ongoing loss of cultural knowledge and practice. PMID- 23929460 TI - Response to Dissociation between severity of takotsubo cardiomyopathy and presentation with shock or hypotension. PMID- 23929461 TI - Antiepileptic and neuroprotective effects of human umbilical cord blood mononuclear cells in a pilocarpine-induced epilepsy model. AB - Status epilepticus (SE) is a condition of persistent seizure that leads to brain damage and, frequently, to the establishment of chronic epilepsy. Cord blood is an important source of adult stem cells for the treatment of neurological disorders. The present study aimed to evaluate the effects of human umbilical cord blood mononuclear cells (HUCBC) transplanted into rats after induction of SE by the administration of lithium and pilocarpine chloride. Transplantation of HUCBC into epileptic rats protected against neuronal loss in the hippocampal subfields CA1, CA3 and in the hilus of the dentate gyrus, up to 300 days after SE induction. Moreover, transplanted rats had reduced frequency and duration of spontaneous recurrent seizures (SRS) 15, 120 and 300 days after the SE. Our study shows that HUCBC provide prominent antiepileptic and neuroprotective effects in the experimental model of epilepsy and reinforces that early interventions can protect the brain against the establishment of epilepsy. PMID- 23929462 TI - Expression of biomineralisation genes in tissues and cultured cells of the abalone Haliotis tuberculata. AB - Mollusc shell biomineralisation involves a variety of organic macromolecules (matrix proteins and enzymes) that control calcium carbonate (CaCO3) deposition, growth of crystals, the selection of polymorph, and the microstructure of the shell. Since the mantle and the hemocytes play an important role in the control of shell formation, primary cell cultures have been developed to study the expression of three biomineralisation genes recently identified in the abalone Haliotis tuberculata: a matrix protein, Lustrin A, and two carbonic anhydrase enzymes. Mantle cells and hemocytes were successfully maintained in primary cultures and were evaluated for their viability and proliferation over time using a semi-automated assay (XTT). PCR and densitometric analysis were used to semi quantify the gene expression and compare the level of expression in native tissues and cultured cells. The results demonstrated that the three genes of interest were being expressed in abalone tissues, with expression highest in the mantle and much lower in the hemocytes and the gills. Biomineralisation genes were also expressed significantly in mantle cells, confirming that primary cultures of target tissues are suitable models for in vitro investigation of matrix protein secretion. PMID- 23929463 TI - A reconfigurable plasmofluidic lens. AB - Plasmonics provides an unparalleled method for manipulating light beyond the diffraction limit, making it a promising technology for the development of ultra small, ultra-fast and power-efficient optical devices. To date, the majority of plasmonic devices are in the solid state and have limited tunability or configurability. Moreover, individual solid-state plasmonic devices lack the ability to deliver multiple functionalities. Here we utilize laser-induced surface bubbles on a metal film to demonstrate, for the first time, a plasmonic lens in a microfluidic environment. Our 'plasmofluidic lens' is dynamically tunable and reconfigurable. We record divergence, collimation and focusing of surface plasmon polaritons using this device. The plasmofluidic lens requires no sophisticated nanofabrication and utilizes only a single low-cost diode laser. Our results show that the integration of plasmonics and microfluidics allows for new opportunities in developing complex plasmonic elements with multiple functionalities, high-sensitivity and high-throughput biomedical detection systems, as well as on-chip, all-optical information processing techniques. PMID- 23929464 TI - Draft Genome Sequence of Euryhalocaulis caribicus Strain JL2009T, a New Member of the Family Hyphomonadaceae Isolated from the Caribbean Sea. AB - Euryhalocaulis caribicus strain JL2009(T) is a novel genus and species of the family Hyphomonadaceae and was first isolated from surface water in the Caribbean Sea. Here, we report the first draft genome from this genus. Its genome contains genes encoding proteins that are involved in organic acid metabolism and probable low-affinity inorganic phosphate transporters, which suggests its competence in oligotrophic oceans. PMID- 23929465 TI - Draft Genome Sequence of Helicobacter fennelliae Strain MRY12-0050, Isolated from a Bacteremia Patient. AB - Helicobacter fennelliae, a human enterohepatic pathogen, causes bacteremia and colitis. We isolated H. fennelliae strain MRY12-0050 from a female patient; this strain was isolated from 2 other patients from the same hospital during the same period, suggesting human-to-human transmission. This is the first report of an H. fennelliae genome sequence. PMID- 23929466 TI - Whole-Genome Sequence of Fish-Pathogenic Mycobacterium sp. Strain 012931, Isolated from Yellowtail (Seriola quinqueradiata). AB - The genus Mycobacterium comprises a large number of well-characterized species, several of which are human and animal pathogens. Here, we report the whole-genome sequence of Mycobacterium sp. strain 012931, a fish pathogen responsible for huge losses in aquaculture farms in Japan. The strain was isolated from a marine fish, yellowtail (Seriola quinqueradiata). PMID- 23929467 TI - Draft Genome Sequence of D-Branched-Chain Amino Acid Producer Lactobacillus otakiensis JCM 15040T, Isolated from a Traditional Japanese Pickle. AB - Lactobacillus otakiensis strain JCM 15040(T) was isolated from an unsalted pickling solution used in the production of sunki, a traditional Japanese pickle. Here, we prepared a draft genome sequence for this strain consisting of 40 contigs containing a total of 2,347,132 bp, 2,310 predicted coding sequences, and a G+C content of 42.4%. PMID- 23929468 TI - Complete Genome Sequences of Novel Reassortant H1N2 Swine Influenza Viruses Isolated from Pigs in the Republic of Korea. AB - Novel reassortant swine H1N2 influenza viruses were isolated from pigs in a commercial slaughterhouse in the Republic of Korea. Genome sequence analyses revealed that these isolates contain segments from Eurasian avian-like swine (hemagglutinin [HA]), Korean swine H1N2 (neuraminidase [NA]), and North American H3N2pM-like (remaining genes) viruses. Further characterization is needed to gauge the potential threats of these viruses to public health. PMID- 23929469 TI - Genome Sequence of Staphylococcus massiliensis Strain S46, Isolated from the Surface of Healthy Human Skin. AB - Staphylococcus massiliensis strain S46 was isolated from the surface of healthy human skin. Here, we report the draft genome sequence of S. massiliensis S46 (2,447,110 bp, with a G+C content of 36.3%). PMID- 23929470 TI - Complete Genome Sequence of Porcine Epidemic Diarrhea Virus Strain USA/Colorado/2013 from the United States. AB - Porcine epidemic diarrhea virus (PEDV) is newly emerging in the United States. PEDV strain USA/Colorado/2013 (CO/13) was obtained from a 7-day-old piglet with severe diarrhea, and the complete genome was sequenced to further study the PEDV outbreak in the United States. PMID- 23929471 TI - Identification of a Novel Circular DNA Virus in New Zealand Fur Seal (Arctocephalus forsteri) Fecal Matter. AB - Fur seal feces-associated circular DNA virus (FSfaCV) is a novel virus isolated from the fecal matter of New Zealand fur seals. FSfaCV has two main open reading frames in its 2,925-nucleotide (nt) genome. The replication-associated protein (Rep) of FSfaCV has similarity to Rep-like sequences in the Giardia intestinalis genome. PMID- 23929472 TI - Discovery of Sclerotinia sclerotiorum Hypovirulence-Associated Virus-1 in Urban River Sediments of Heathcote and Styx Rivers in Christchurch City, New Zealand. AB - In samples of benthic and bank river sediments of two urban rivers in Christchurch city (New Zealand), we identified and recovered isolates of Sclerotinia sclerotiorum hypovirulence-associated virus-1 (SsHADV-1), a fungus infecting circular single-stranded DNA virus. This is the first report of SsHADV 1 outside of China and in environmental samples. PMID- 23929473 TI - Complete Genome Sequence of Tick-Borne Encephalitis Virus Strain A104 Isolated from a Yellow-Necked Mouse (Apodemus flavicollis) in Austria. AB - Tick-borne encephalitis virus (TBEV) strain A104 was isolated from the brain of a yellow-necked mouse in Austria in 1990. The complete genome sequence was 11,097 nucleotides long. Comparison with TBEV prototype strain Neudoerfl showed 32 amino acid exchanges and the absence of an internal poly(A) stretch within the 3' noncoding region. PMID- 23929474 TI - Genome Sequence of Bovine Viral Diarrhea Virus Strain 10JJ-SKR, Belonging to Genotype 1d. AB - Here, we report the complete genome sequence of a bovine viral diarrhea virus (BVDV) belonging to genotype 1d, strain 10JJ-SKR, which was isolated from cattle. The complete genome is 12,267 nucleotides (nt) in length, with a single large open reading frame. This is the first report of a BVDV belonging to genotype 1d and will enable further study of the molecular and epidemiological characteristics of this virus. PMID- 23929475 TI - Complete Genome Sequence of a Variant of the Methicillin-Resistant Staphylococcus aureus ST239 Lineage, Strain BMB9393, Displaying Superior Ability To Accumulate ica-Independent Biofilm. AB - Biofilm is considered an important virulence factor in nosocomial infections. Herein, we report the complete genome sequence of a variant of methicillin resistant Staphylococcus aureus, strain BMB9393, which is highly disseminated in Brazil. This strain belongs to the lineage ST239 and displays increased ability to accumulate ica-independent biofilm and to invade human epithelial cells. PMID- 23929476 TI - Whole-Genome Sequence of the Purple Photosynthetic Bacterium Rhodovulum sulfidophilum Strain W4. AB - We report the draft genome sequence of the purple photosynthetic bacterium Rhodovulum sulfidophilum. The photosynthesis gene cluster comprises two segments a unique feature among photosynthesis gene clusters of purple bacteria. The genome information will be useful for further analysis of bacterial photosynthesis. PMID- 23929477 TI - Draft Genome Sequence of Streptomyces rapamycinicus Strain NRRL 5491, the Producer of the Immunosuppressant Rapamycin. AB - Streptomyces rapamycinicus strain NRRL 5491 produces the important drug rapamycin. It has a large genome of 12.7 Mb, of which over 3 Mb consists of 48 secondary metabolite biosynthesis clusters. PMID- 23929478 TI - Draft Genome Sequence of Pseudomonas stutzeri Strain B1SMN1, a Nitrogen-Fixing and Naphthalene-Degrading Strain Isolated from Wastewater. AB - Pseudomonas stutzeri strain B1SMN1 is a naphthalene-degrading and simultaneously nitrogen-fixing strain isolated from a wastewater sample taken at a lagooning treatment plant in Menorca (Balearic Islands, Spain). Here we report the draft genome sequence of P. stutzeri B1SMN1. It is composed of a chromosome of an estimated size of 5.2 Mb and two plasmids of 44,324 bp and 56,118 bp. PMID- 23929479 TI - Draft Genome Sequence of Pseudomonas plecoglossicida Strain NB2011, the Causative Agent of White Nodules in Large Yellow Croaker (Larimichthys crocea). AB - We describe the draft genome sequence of Pseudomonas plecoglossicida strain NB2011, the causative agent of white nodules in cultured large yellow croaker (Larimichthys crocea) in China. The draft genome sequence of the bacterium consists of 5.41 million bp, with a G+C content of 62.8%. A total of 4,952 genes were identified. PMID- 23929480 TI - Genome Sequence of Klebsiella pneumoniae Strain ATCC 25955, an Oxygen-Insensitive Producer of 1,3-Propanediol. AB - Klebsiella pneumoniae strain ATCC 25955 is a 1,3-propanediol-producing bacterium that is insensitive to oxygen. Here, we present a 5.29-Mb assembly of its genome sequence. We have annotated 10 coding sequences (CDSs) for 1,3-propanediol fermentation and 18 CDSs for glycerol uptake. The CDSs related to virulence and by-product formation were also annotated. PMID- 23929481 TI - Draft Genome Sequence of Strain SA_ST125_MupR of Methicillin-Resistant Staphylococcus aureus ST125, a Major Clone in Spain. AB - Here, we report the draft genome sequence of a methicillin-resistant Staphylococcus aureus (MRSA) strain with high-level mupirocin resistance (SA_ST125_MupR), isolated from a patient with recurrent bacteremia. This strain belonged to sequence type ST125, which was responsible for more than 50% of the health care-associated infections caused by MRSA in Spain. PMID- 23929482 TI - Draft Genome Sequence of the Fast-Growing Marine Bacterium Vibrio natriegens Strain ATCC 14048. AB - Vibrio natriegens bacteria are Gram-negative aquatic microorganisms that are found primarily in coastal seawater and sediments and are perhaps best known for their high growth rates (generation time of <10 min). In this study, we report the first sequenced genome of this species, that of the type strain Vibrio natriegens ATCC 14048, a salt marsh mud isolate from Sapelo Island, GA. PMID- 23929483 TI - Junonia coenia Densovirus (JcDNV) Genome Structure. AB - The sequence of Junonia coenia densovirus was the first densovirus genome sequence published, but the first published sequence contained incomplete inverted terminal repeats and ambiguous nucleotides or indels leading to an incorrect map of the open reading frames. Our sequencing of clones of the complete genome demonstrated that this virus is closely related to other viruses in the Densovirus genus. PMID- 23929484 TI - Genome Sequence of Serratia plymuthica Strain S13, an Endophyte with Germination- and Plant-Growth-Promoting Activity from the Flower of Styrian Oil Pumpkin. AB - The bacterium Serratia plymuthica strain S13 was demonstrated to colonize various plant-associated microhabitats and to suppress damping-off diseases. The completed genome sequence has a size of 5.5 Mb, containing 4,957 putative protein encoding regions, and will be used to identify genetic determinants enabling the bacterium to escort a plant's entire life cycle. PMID- 23929485 TI - Draft Genome Sequence of Exiguobacterium pavilionensis Strain RW-2, with Wide Thermal, Salinity, and pH Tolerance, Isolated from Modern Freshwater Microbialites. AB - We report the draft genome sequence of Exiguobacterium pavilionensis strain RW-2, isolated from a cold thrombolytic microbialite. The isolate grows at temperatures from 4 to 50 degrees C, at pH levels from 5 to 11, and in media without added NaCl or KCl or with 7% added NaCl. PMID- 23929486 TI - The Draft Genome Sequence of Sphingomonas paucimobilis Strain HER1398 (Proteobacteria), Host to the Giant PAU Phage, Indicates That It Is a Member of the Genus Sphingobacterium (Bacteroidetes). AB - The draft genome sequence of Sphingomonas paucimobilis host index number (HER) 1398, host of the giant PAU phage isolated from silk moths (Bombyx mori), indicates that this isolate belongs within the genus Sphingobacterium. We suggest that Sphingomonas paucimobilis strain HER1398 be reclassified as Sphingobacterium paucimobilis strain HER1398. PMID- 23929487 TI - Draft Genome Sequence of Lactococcus lactis subsp. lactis Strain YF11. AB - Lactococcus lactis subsp. lactis strain YF11 is a food preservative bacterium with a high capacity to produce nisin. Here, we announce the draft genome sequence of Lactococcus lactis subsp. lactis YF11 (2,527,433 bp with a G+C content of 34.81%). PMID- 23929488 TI - Genome Sequence of the 2,4,5-Trichlorophenoxyacetate-Degrading Bacterium Burkholderia phenoliruptrix Strain AC1100. AB - Burkholderia phenoliruptrix strain AC1100 (ATCC 53867) degrades a variety of recalcitrant xenobiotics, including 2,4,5-trichlorophenoxyacetate. The molecular mechanism of 2,4,5-trichlorophenoxyacetate degradation has been extensively studied. Here we present a 7.8-Mb assembly of the genome sequence of this 2,4,5 trichlorophenoxyacetate-degrading strain, which may provide useful information related to the degradation of chlorinated aromatic compounds. PMID- 23929489 TI - Genome Sequence of the Cheese-Starter Strain Lactobacillus delbrueckii subsp. lactis CRL 581. AB - We report the genome sequence of Lactobacillus delbrueckii subsp. lactis CRL 581 (1,911,137 bp, GC 49.7%), a proteolytic strain isolated from a homemade Argentinian hard cheese which has a key role in bacterial nutrition and releases bioactive health-beneficial peptides from milk proteins. PMID- 23929490 TI - Whole-Genome Sequence of a Novel Species, Mycobacterium yongonense DSM 45126T. AB - Here, we report the complete genome sequence of Mycobacterium yongonense DSM 45126(T), genetically closely related to the INT5 genotype of M. intracellulare. PMID- 23929491 TI - Complete Genome Sequence of Clostridium sp. Strain DL-VIII, a Novel Solventogenic Clostridium Species Isolated from Anaerobic Sludge. AB - We report the genome sequence of Clostridium sp. strain DL-VIII, a novel Gram positive, endospore-forming, solventogenic bacterium isolated from activated anaerobic sludge of a wastewater treatment plant. Aside from a complete sol operon, the 6,477,357-bp genome of DL-VIII reveals genes for several unique enzymes with applications in lignocellulose degradation, including two phenolic acid decarboxylases. PMID- 23929492 TI - Whole-Genome Sequence of the Potentially Hypertransmissible Multidrug-Resistant Mycobacterium tuberculosis Beijing Strain OM-V02_005. AB - We report the draft genome sequence of Mycobacterium tuberculosis Beijing strain OM-V02_005, which exhibits possible hypertransmissible characteristics among the population of patients with multidrug-resistant tuberculosis in Osaka Prefecture, the largest urban area in western Japan. PMID- 23929494 TI - Multivariate frailty models for two types of recurrent events with a dependent terminal event: application to breast cancer data. AB - Individuals may experience more than one type of recurrent event and a terminal event during the life course of a disease. Follow-up may be interrupted for several reasons, including the end of a study, or patients lost to follow-up, which are non informative censoring events. Death could also stop the follow-up, hence, it is considered as a dependent terminal event. We propose a multivariate frailty model that jointly analyzes two types of recurrent events with a dependent terminal event. Two estimation methods are proposed: a semiparametrical approach using penalized likelihood estimation where baseline hazard functions are approximated by M-s plines, and another one with piecewise constant baseline hazard functions. Finally, we derived martingale residuals to check the goodness of-fit. We illustrate our proposals with a real dataset on breast cancer. The main objective was to model the dependency between the two types of recurrent events (locoregional and metastatic) and the terminal event (death) after a breast cancer. PMID- 23929493 TI - The Arabidopsis CAP-D proteins are required for correct chromatin organisation, growth and fertility. AB - In plants as in other eukaryotes, the structural maintenance of chromosome (SMC) protein complexes cohesin, condensin and SMC5/6 are essential for sister chromatid cohesion, chromosome condensation, DNA repair and recombination. The presence of paralogous genes for various components of the different SMC complexes suggests the diversification of their biological functions during the evolution of higher plants. In Arabidopsis thaliana, we identified two candidate genes (Cap-D2 and Cap-D3) which may express conserved proteins presumably associated with condensin. In silico analyses using public databases suggest that both genes are controlled by factors acting in a cell cycle-dependent manner. Cap D2 is essential because homozygous T-DNA insertion mutants were not viable. The heterozygous mutant showed wild-type growth habit but reduced fertility. For Cap D3, we selected two homozygous mutants expressing truncated transcripts which are obviously not fully functional. Both mutants show reduced pollen fertility and seed set (one of them also reduced plant vigour), a lower chromatin density and frequent (peri)centromere association in interphase nuclei. Sister chromatid cohesion was impaired compared to wild-type in the cap-D3 mutants but not in the heterozygous cap-D2 mutant. At superresolution (Structured Illumination Microscopy), we found no alteration of chromatin substructure for both cap-D mutants. Chromosome-associated polypeptide (CAP)-D3 and the cohesin subunit SMC3 form similar but positionally non-overlapping reticulate structures in 2C-16C nuclei, suggesting their importance for interphase chromatin architecture in differentiated nuclei. Thus, we presume that CAP-D proteins are required for fertility, growth, chromatin organisation, sister chromatid cohesion and in a process preventing the association of centromeric repeats. PMID- 23929495 TI - Reversible control over molecular recognition in surface-bound photoswitchable hydrogen-bonding receptors: towards read-write-erase molecular printboards. AB - The synthesis of an anthracene-bearing photoactive barbituric acid receptor and its subsequent grafting onto azide-terminated alkanethiol/Au self-assembled monolayers by using an Cu(I) -catalyzed azide-alkyne reaction is reported. Monolayer characterization using contact-angle measurements, electrochemistry, and spectroscopic ellipsometry indicate that the monolayer conversion is fast and complete. Irradiation of the receptor leads to photodimerization of the anthracenes, which induces the open-to-closed gating of the receptor by blocking access to the binding site. The process is thermally reversible, and polarization modulated IR reflection-absorption spectroscopy indicates that photochemical closure and thermal opening of the surface-bound receptors occur in 70 and 100 % conversion, respectively. Affinity of the open and closed surface-bound receptor was characterized by using force spectroscopy with a barbituric-acid-modified atomic force microscope tip. PMID- 23929496 TI - Emerging roles of microRNA in modulating cell-death processes in malignant glioma. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. In mammals, their function mainly represses the mRNA transcripts via imperfect complementary sequences in the 3'UTR of target mRNAs. Several miRNAs have been recently reported to be involved in modulation of different genes in tumors, including glioblastoma, the most frequent brain tumor in adults. Despite the improvements in treatments, survival of patients remains poor, and glioblastoma is one of the most lethal form of human cancer. To define novel strategies against this tumor, emerging research investigated miRNAs involvement in glioblastoma. In particular, this review is focused on miRNAs involved on the two principal programmed cell death, apoptosis and autophagy, recently described from the literature. Moreover, the discovery of miRNAs role in glioma cell-death pathways has also revealed a new category of therapeutic targets, fundamental for this kind of tumor. PMID- 23929497 TI - Totally laparoscopic abdominal wall reconstruction: lessons learned and results of a short-term follow-up. AB - PURPOSE: Totally Laparoscopic Abdominal Wall Reconstruction (TLAWR) combines the laparoscopic component separation and the laparoscopic ventral hernia repair, with the purpose of further increasing the benefits of a minimally invasive procedure. However, neither the patient selection criteria nor the long-term results of this technique have been reported. Our objective is to discuss our experience with five patients who received a TLAWR. METHODS: All patients with a midline incisional hernia who underwent a TLAWR from September 2008 to October 2009 were retrospectively reviewed for early and late postoperative complications. RESULTS: A total of five patients underwent the procedure, with a mean age of 48.6 +/- 7.9 years. The mean length of stay was 9.2 +/- 5.4 days, and follow-up was 12.3 +/- 6.8 months. The mean defect size was 175.8 +/- 56.2 cm(2). There were no early or late wound complications. Two patients had an early respiratory complication, and one patient developed a port site hernia and small bowel obstruction early after procedure, which required a re-operation. Three patients (60 %) experienced a recurrence. Possible risk factors for recurrence include previous failed hernia repair, loss of domain, large hernias and close proximity to bony structures. CONCLUSIONS: Although TLAWR is feasible and improves wound complications, it may be associated with higher recurrence. Appropriate patient selection is imperative in order for the patient to benefit from this technique. PMID- 23929498 TI - A rare case of a groin hernia: the Hesselbach's hernia. AB - A 61-year-old woman presented with pain in the left groin. The pain radiated from the groin to the knee. At physical examination, a non-reducible swelling was found lateral to the femoral vessels. A CT-scan showed herniation of fatty tissue through the lacuna musculorum. A laparoscopic repair was carried out. A large adipose structure was found herniating through the lacuna musculorum and originating from the Bogros area. It ran along the iliopsoas muscle, suppressing the femoral cutaneous nerve. The tissue was reduced and excised, and a polypropylene mesh was placed to cover the defect. Inguinal hernias are categorized as medial, lateral or femoral hernias. We describe a case in which a hernia through the lacuna musculorum was found, which is very rare and referred to as a Hesselbach's hernia. PMID- 23929499 TI - Role of orchiectomy in severe testicular pain after inguinal hernia surgery: audit of the Finnish Patient Insurance Centre. AB - PURPOSE: Testicular ischemia and necrosis are uncommon complications after inguinal hernioplasty. Our aim was to evaluate the incidence of severe urological complications related to adult inguinal hernia surgery in Finland with special reference to orchiectomy in relieving intractable chronic testicular pain. METHODS: All urological complications related to inguinal hernia surgery during 2003-2010 were analysed from the Finnish Patient Insurance Centre. The patients with intractable chronic scrotal or testicular pain that resulted in orchiectomy were re-evaluated after a median follow-up of 7 years (range 2-15 years). The operative factors related to chronic testicular pain and atrophy were analysed using multiple regression analysis. RESULTS: Altogether 62 urological complications (from 335 litigations) were recorded from 92,000 inguinal hernia operations. The distribution of claimed urological complications consisted of 34 testicular injuries, ten bladder perforations, seven massive scrotal haemorrhage or 11 miscellaneous injuries. Seventeen atrophic testes were left in situ and 17 (six early < 7 days, 11 late > 8 days) orchiectomies were performed due to necrosis or chronic testicular pain syndrome. In the conservative group of moderate scrotal or testicular pain (n = 17), all patients had late pain symptoms (>8 days), but pain was not so severe that orchiectomy was attempted. Using a multivariate analysis, postoperative infections were associated with chronic testicular or scrotal pain and atrophy, but hospital status, surgeon's training level, laparoscopic or open operation, type of hernia or use of mesh did not correlate with testicular injuries. During follow-up, 11/17 (65%) patients with orchiectomy were free of testicular pain. CONCLUSION: Urological injuries form one-fifth of the major complications after inguinal hernioplasty. Orchiectomy appears to help the majority of patients with severe testicular pain syndrome. PMID- 23929500 TI - Local extension of HMGB1 in atherosclerotic lesions of human main cerebral and carotid arteries. AB - High mobility group box 1 protein (HMGB1) is a non-histone chromosomal protein which is highly conserved, ubiquitous, and widely distributed. HMGB1 has multiple functions in the nucleus, including the maintenance of nucleosome structure, the regulation of gene transcription, and involvement in DNA recombination. HMBG1 is currently recognized to have a wide range of potential functions and pathological relevance. HMGB1 is released into the extracellular space from necrotic cells and from activated macrophages. HMGB1 binds to the receptor for advanced glycation end products, resulting in the induction of inflammatory cytokines, and to endothelial cell thrombomodulin. HMGB1 neutralization may also reduce the development of atherosclerosis and ameliorate brain infarction. We investigated the immunolocalization of HMGB1 in atherosclerotic lesions of human cerebral and carotid arteries using a specific antibody, and confirmed the detailed expression and cell type localization using double immunofluorolabeling. In the main cerebral arteries, this anti-HMGB1 antibody intensely immunolabeled both normal morphological vascular smooth muscle cells (VSMCs) within the tunica media and infiltrating VSMCs within the intima of thickened fibrous cap plaques. Endothelial cells were also positive for HMGB1. In carotid plaques, HMGB1-like immunoreactivity (IR) was intense in macrophages, although this IR decreased with increasing cell size. Medium-sized foam cells (50-150 MUm) were the most intensely stained. This IR was also observed in the nuclei of foam cells and VSMCs. These findings may provide a basis for understanding the association of HMGB1 with atherosclerotic lesions of the cerebral and carotid arteries, and for constructing strategies to counteract atherosclerosis with anti-HMGB1 antibody. PMID- 23929501 TI - ADA perceived disability claims: a decision-tree analysis. AB - INTRODUCTION: The purpose of this study is to examine the possible interactions of predictor variables pertaining to perceived disability claims contained in a large governmental database. Specifically, it is a retrospective analysis of US Equal Employment Opportunity Commission (EEOC) data for the entire population of workplace discrimination claims based on the "regarded as disabled" prong of the Americans with Disabilities Act (ADA) definition of disability. METHODS: The study utilized records extracted from a "master database" of over two million charges of workplace discrimination in the Integrated Mission System of the EEOC. This database includes all ADA-related discrimination allegations filed from July 26, 1992 through December 31, 2008. Chi squared automatic interaction detection (CHAID) was employed to analyze interaction effects of relevant variables, such as issue (grievance) and industry type. The research question addressed by CHAID is: What combination of factors are associated with merit outcomes for people making ADA EEOC allegations who are "regarded as" having disabilities? RESULTS: The CHAID analysis shows how merit outcome is predicted by the interaction of relevant variables. Issue was found to be the most prominent variable in determining merit outcome, followed by industry type, but the picture is made more complex by qualifications regarding age and race data. Although discharge was the most frequent grievance among charging parties in the perceived disability group, its merit outcome was significantly less than that for the leading factor of hiring. PMID- 23929502 TI - Prognostic factors for return to work, sickness benefits, and transitions between these states: a 4-year follow-up after work-related rehabilitation. AB - PURPOSE: The aim of this study was to examine if age, gender, medical diagnosis, occupation, and previous sick leave predicted different probabilities for being at work and for registered sickness benefits, and differences in the transitions between any of these states, for individuals that had participated in an interdisciplinary work-related rehabilitation program. METHODS: 584 individuals on long-term sickness benefits (mean 9.3 months, SD = 3.4) were followed with official register data over a 4-year period after a rehabilitation program. 66 % were female, and mean age was 44 years (SD = 9.3). The majority had a mental (47 %) or a musculoskeletal (46 %) diagnosis. 7 % had other diagnoses. Proportional hazards regression models were used to analyze prognostic factors for the probability of being on, and the intensity of transitions between, any of the following seven states during follow-up; working, partial sick leave, full sick leave, medical rehabilitation, vocational rehabilitation, partial disability pension (DP), and full DP. RESULTS: In a fully adjusted model; women, those with diagnoses other than mental and musculoskeletal, blue-collar workers, and those with previous long-term sick leave, had a lower probability for being at work and a higher probability for full DP during follow-up. DP was also associated with high age. Mental diagnoses gave higher probability for being on full sick leave, but not for transitions to full sick leave. Regression models based on transition intensities showed that risk factors for entering a given state (work or receiving sickness benefits) were slightly different from risk factors for leaving the same state. CONCLUSIONS: The probabilities for working and for receiving sickness benefits and DP were dependent on gender, diagnoses, type of work and previous history of sick leave, as expected. The use of novel statistical methods to analyze factors predicting transition intensities have improved our understanding of how the processes to and from work, and to and from sickness benefits may differ between groups. Further research is required to understand more about differences in prognosis for return to work after intensive work-related rehabilitation efforts. PMID- 23929503 TI - Predictors of clinical outcome after tracheotomy in critically ill obese patients. AB - OBJECTIVES/HYPOTHESIS: To identify patient factors associated with outcomes in critically ill obese patients requiring tracheotomy. STUDY DESIGN: Single institution, retrospective cohort study. METHODS: Charts were reviewed for inpatients admitted to an intensive care unit from 2007 to 2010 with International Classification of Diseases, 9th Revision codes of obesity or morbid obesity and tracheotomy. Variables collected in the dataset include subject age, ethnicity, gender, body mass index, tracheotomy type, patient outcome, chief diagnosis, and medical comorbid conditions. The primary outcomes of interest were tracheotomy type and patient outcome at the time of hospital discharge. Logistic regression models were developed for the probability of each patient outcome using univariate and multivariate models. RESULTS: One hundred two patients met inclusion criteria. The most common outcome was tracheostomy dependence (49%). Increased mortality was independently significantly associated with pulmonary hypertension (P = .019) and African American ethnicity (P = .045). Increased tracheostomy dependence was significantly associated with obstructive sleep apnea (P = .030). Increased decannulation was significantly associated with percutaneous tracheotomy (P = .016) and Caucasian ethnicity (P < .001). CONCLUSIONS: Obese patients in the intensive care unit who undergo tracheotomy have a high likelihood of remaining tracheostomy dependent at the time of discharge from the hospital. The factors most commonly found to be significantly associated with poor outcomes were open tracheotomy, African American ethnicity, obstructive sleep apnea, and pulmonary hypertension. PMID- 23929504 TI - Value-based insurance design: aligning incentives and evidence in pulmonary medicine. AB - When consumers are required to pay the same out-of-pocket amount for pulmonary services for which clinical benefits depend on patient characteristics, clinical indication, and provider choice, there is an enormous potential for both underutilization and overutilization. Unlike most current one-size-fits-all health plan designs, value-based insurance design (V-BID) explicitly acknowledges clinical heterogeneity across the continuum of care. By adding clinical nuance to benefit design, V-BID seeks to align consumer and provider incentives with value, encouraging the use of high-value services and discouraging the use of low-value interventions. This article describes the concept of V-BID; creates a framework for its development in pulmonary medicine; and outlines how this concept aligns with research, care delivery, and payment reform initiatives. PMID- 23929505 TI - CXCR4 prevents dispersion of granule neuron precursors in the adult dentate gyrus. AB - Neurogenesis in the adult dentate gyrus (DG) generates new granule neurons that differentiate in the inner one-third of the granule cell layer (GCL). The migrating precursors of these neurons arise from neural stem cells (NSCs) in the subgranular zone (SGZ). Although it is established that pathological conditions, including epilepsy and stroke, cause dispersion of granule neuron precursors, little is known about the factors that regulate their normal placement. Based on the high expression of the chemokine CXCL12 in the adult GCL and its role in guiding neuronal migration in development, we addressed the function of the CXCL12 receptor CXCR4 in adult neurogenesis. Using transgenic reporter mice, we detected Cxcr4-GFP expression in NSCs, neuronal-committed progenitors, and immature neurons of adult and aged mice. Analyses of hippocampal NSC cultures and hippocampal tissue by immunoblot and immunohistochemistry provided evidence for CXCL12-promoted phosphorylation/activation of CXCR4 receptors in NSCs in vivo and in vitro. Cxcr4 deletion in NSCs of the postnatal or mature DG using Cre technology reduced neurogenesis. Fifty days after Cxcr4 ablation in the mature DG, the SGZ showed a severe reduction of Sox2-positive neural stem/early progenitor cells, NeuroD-positive neuronal-committed progenitors, and DCX positive immature neurons. Many immature neurons were ectopically placed in the hilus and inner molecular layer, and some developed an aberrant dendritic morphology. Only few misplaced cells survived permanently as ectopic neurons. Thus, CXCR4 signaling maintains the NSC pool in the DG and specifies the inner one-third of the GCL as differentiation area for immature granule neurons. PMID- 23929506 TI - Syntheses and structures of an "alumole" and its dianion. AB - Base free: An alumole was synthesized and treatment with lithium afforded the lithium salt of the alumole dianion. The structures of these two molecules were then investigated. The C-C bond lengths of the AlC4 ring in the dianion are nearly equal. DFT calculations revealed that the 3p(Al)-pi* conjugation lowers the LUMO level of the alumole and that coordination of two lithium cations to the alumole dianion results in a planar AlC4 ring. PMID- 23929507 TI - An in vitro study reveals nutraceutical properties of Ananas comosus (L.) Merr. var. Mauritius fruit residue beneficial to diabetes. AB - BACKGROUND: Rapid urbanisation and nutritional transition is fuelling the increased global incidence of type 2 diabetes. Pineapple fruit residue was explored for its nutraceutical properties as an alternative or adjunct to currently available treatment regime. Ethyl acetate and methanolic extracts of pineapple fruit residue were evaluated for anti-diabetic activity in cell free and cell based systems. Specifically, we assessed: (1) antioxidant potential, (2) anti-glycation potential, (3) carbohydrate digestive enzyme inhibition, and (4) lipid accumulation and glycerol-3-phosphate dehydrogenase activity in differentiating 3T3-L1 cells. RESULTS: The active components in the ethyl acetate and methanolic extracts were identified as sinapic acid, daucosterol, 2 methylpropanoate, 2,5-dimethyl-4-hydroxy-3(2H)-furanone, methyl 2-methylbutanoate and triterpenoid ergosterol using DART/HRMS and ESI/HRMS. Micronutrient analysis revealed the presence of magnesium, potassium and calcium. Adipogenic potential, anti-glycation property of the ethyl acetate extract, and DNA damage protection capacity of the methanolic extract are promising. CONCLUSION: Results from this study clearly indicate that pineapple fruit residue could be utilised as a nutraceutical against diabetes and related complications. PMID- 23929508 TI - Predicting the posttransplant prognosis of patients with hepatocellular carcinoma: what lies beneath alpha-fetoprotein? PMID- 23929509 TI - Outcome after modified Putti-Platt procedure for recurrent traumatic anterior shoulder dislocations. AB - Most recent studies on procedures for stabilizing the glenohumeral joint focus on arthroscopic techniques. A relatively simple open procedure is the modified Putti Platt procedure. The aim of these retrospective case series was to evaluate the functional outcome, patient satisfaction, and quality of life of patients who underwent this procedure. After a median follow-up time of 4.7 (P25-P75 1.7-6.8) years, fifty-one patients could be enrolled with a mean age of 25 (21-39) years. Five patients (10 %) reported re-dislocations. The median Constant score for the affected side was 84 (P25-P75 75-91). Median loss of motion in abduction, elevation, external rotation, and external rotation in 90 degrees of abduction did not exceed 10 degrees when compared to the healthy shoulder. A median Rowe score of 92 (P25-P75 75-95) was measured. The WOSI score and SF-36 showed excellent quality of life. The VAS proved high patient satisfaction with the outcome; 7.9 (6.8-9.5). We concluded that the modified Putti-Platt procedure leads to excellent outcome scores and only marginal restriction in range of motion combined with a high patient satisfaction. Our data prove that excellent results can be obtained with a relatively simple open procedure. PMID- 23929510 TI - iTRAQ-based quantitative proteomic analysis reveals new metabolic pathways of wheat seedling growth under hydrogen peroxide stress. AB - As an abundant ROS, hydrogen peroxide (H2 O2 ) plays pivotal roles in plant growth and development. In this work, we conducted for the first time an iTRAQ based quantitative proteomic analysis of wheat seedling growth under different exogenous H2 O2 treatments. The growth of seedlings and roots was significantly restrained by increased H2 O2 concentration stress. Malondialdehyde, soluble sugar, and proline contents as well as peroxidase activity increased with increasing H2 O2 levels. A total of 3,425 proteins were identified by iTRAQ, of which 157 showed differential expression and 44 were newly identified H2 O2 responsive proteins. H2 O2 -responsive proteins were mainly involved in stress/defense/detoxification, signal transduction, and carbohydrate metabolism. It is clear that up-regulated expression of signal transduction and stress/defence/detoxification-related proteins under H2 O2 stress, such as plasma membrane intrinsic protein 1, fasciclin-like arabinogalactan protein, and superoxide dismutase, could contribute to H2 O2 tolerance of wheat seedlings. Increased gluconeogenesis (phosphoenol-pyruvate carboxykinase) and decreased pyruvate kinase proteins are potentially related to the higher H2 O2 tolerance of wheat seedlings. A metabolic pathway of wheat seedling growth under H2 O2 stress is presented. PMID- 23929512 TI - Herpes simplex virus conjunctival ulceration. PMID- 23929513 TI - Fluorescein angiography of a closing funnel retinal detachment in familial exudative vitreoretinopathy. PMID- 23929514 TI - Pressure-induced stromal keratopathy as a result of ocular trauma after laser in situ keratomileusis. AB - IMPORTANCE: Pressure-induced stromal keratopathy is a rare kind of complication of laser in situ keratomileusis (LASIK) that may cause vision loss in affected eyes. Herein, we described the clinical features and treatment of 2 cases of pressure-induced stromal keratopathy due to traumatic hyphema in post-LASIK eyes. OBSERVATIONS: Two patients sought treatment for painful vision loss after blunt trauma on post-LASIK eyes. On examination, high intraocular pressure was found in the injured eyes. Hyphema was seen in the anterior chamber. High-resolution slitlamp biomicroscopy demonstrated interface hyperreflection, which resembled interface keratitis. However, an isolated pocket of fluid was clearly demonstrated at the level of the LASIK flap interface in the anterior segment optical coherence tomographic images. After topical corticosteroid and antiglaucoma medication, the hyphema and the hyperreflection in the cornea resolved in several days. The intraocular pressure and visual acuity returned to normal levels. Repeated anterior segment optical coherence tomographic examinations revealed completed resolution of the interface fluid. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first report of pressure-induced stromal keratopathy caused by traumatic hyphema. Anterior segment optical coherence tomography plays a unique role in revealing occult interface fluid in post-LASIK eyes, which may masquerade as interface keratitis during slitlamp examination. PMID- 23929515 TI - Leiomyoma of the lower eyelid. PMID- 23929516 TI - "Lines across my vision". Posterior ophthalmomyiasis interna. PMID- 23929517 TI - Differences in clinical outcomes in keratitis due to fungus and bacteria. PMID- 23929519 TI - Serpiginous choroiditis secondary to Bartonella henselae? PMID- 23929521 TI - Comparative effects of emotion management training and social skills training in Korean children with ADHD. AB - OBJECTIVE: ADHD is associated with social and emotional impairment that goes beyond the core symptoms of hyperactivity, impulsivity, and attention deficits. This study evaluates the comparative efficacy of emotional management training (EMT) with social skills training (SST) and no treatment in children with ADHD. METHOD: A randomized, controlled treatment outcome study was conducted with 32 boys and 40 girls (aged 10-12 years). The Child Behavior Checklist, Emotion Expression Scale for Children, Child Depression Inventory, and State-Trait Anxiety Inventory for children were completed before and after the intervention. RESULTS: The EMT group exhibited a significant improvement in emotion recognition and expressive reluctance. Therefore, focusing on emotion identification and expression in social cognitive processes (i.e., EMT), instead of merely focusing on social skills (SST), enhances treatment efficacy. CONCLUSION: These results support the hypothesis that focusing on the identification and expression of emotional information processes, instead of merely focusing on social skills (SST) enhances treatment efficacy. PMID- 23929522 TI - Overweight, mortality and survival. PMID- 23929523 TI - A single-blind randomized controlled trial to evaluate the effect of 6 months of progressive aerobic exercise training in patients with uraemic restless legs syndrome. AB - BACKGROUND: Uraemic restless legs syndrome (RLS) affects a significant proportion of patients receiving haemodialysis (HD) therapy. Exercise training has been shown to improve RLS symptoms in uraemic RLS patients; however, the mechanism of exercise-induced changes in RLS severity is still unknown. The aim of the current randomized controlled exercise trial was to investigate whether the reduction of RLS severity, often seen after training, is due to expected systemic exercise adaptations or it is mainly due to the relief that leg movements confer during exercise training on a cycle ergometer. This is the first randomized controlled exercise study in uraemic RLS patients. METHODS: Twenty-four RLS HD patients were randomly assigned to two groups: the progressive exercise training group (n = 12) and the control exercise with no resistance group (n = 12). The exercise session in both groups included intradialytic cycling for 45 min at 50 rpm. However, only in the progressive exercise training group was resistance applied, at 60-65% of maximum exercise capacity, which was reassessed every 4 weeks to account for the patients' improvement. The severity of RLS symptoms was evaluated using the IRLSSG severity scale, functional capacity by a battery of tests, while sleep quality, depression levels and daily sleepiness status were assessed via validated questionnaires, before and after the intervention period. RESULTS: All patients completed the exercise programme with no adverse effects. RLS symptom severity declined by 58% (P = 0.003) in the progressive exercise training group, while a no statistically significant decline was observed in the control group (17% change, P = 0.124). Exercise training was also effective in terms of improving functional capacity (P = 0.04), sleep quality (P = 0.038) and depression score (P = 0.000) in HD patients, while no significant changes were observed in the control group. After 6 months of the intervention, RLS severity (P = 0.017), depression score (P = 0.002) and daily sleepiness status (P = 0.05) appeared to be significantly better in the progressive exercise group compared with the control group. CONCLUSION: A 6-month intradialytic progressive exercise training programme appears to be a safe and effective approach in reducing RLS symptom severity in HD patients. It seems that exercise-induced adaptations to the whole body are mostly responsible for the reduction in RLS severity score, since the exercise with no applied resistance protocol failed to improve the RLS severity status of the patients. PMID- 23929524 TI - Early growth response 1 is an early signal inducing Cav3.2 T-type calcium channels during cardiac hypertrophy. AB - AIMS: The Cav3.2 T-channel plays a pivotal role in inducing calcineurin/nuclear factor of activated T cell (NFAT) signalling during cardiac hypertrophy. Because calcineurin/NFAT signalling is induced early after pressure overload, we hypothesized that Cav3.2 is induced by an early signal. Our aim is to investigate when and how Cav3.2 is induced during cardiac hypertrophy. METHODS AND RESULTS: The evolutionary conserved promoter Cav3.2-3500 from mouse genome was validated to express the reporter gene as endogenous Cav3.2 in cell lines and transgenic (Tg; Cav3.2-3500-Luc) mice. The early induction of luciferase in Tg mice and Cav3.2 mRNA in wild-type mice after transverse aortic banding (TAB) surgery supported our hypothesis that Cav3.2 is induced early during cardiac hypertrophy. The TAB-responding element [-81 to -41 bp upstream of the transcription start site (TSS) of mouse Cav3.2] was identified by in vivo gene transfer by injecting reporter constructs into the left ventricle followed by TAB surgery. Electrophoresis mobility shift assay and chromatin immunoprecipitation assays revealed that Egr1 bound to the TAB-responding element of Cav3.2. Egr1 level was increased with increased Cav3.2 mRNA level at 3 days after TAB. To demonstrate that Egr1 indeed regulates Cav3.2 expression after hypertrophic stimulation, knockdown of Egr1 with short hairpin RNA prevented the phenylephrine-induced up regulation of Cav3.2 expression and cellular hypertrophy in neonatal rat ventricular myocytes (NRVMs) and H9c2 cells. Furthermore, overexpression of Cav3.2 in Egr1-knockdown cells restored the phenylephrine-induced hypertrophy. CONCLUSION: Cav3.2 is induced early by Egr1 during cardiac hypertrophy and Cav3.2 is an important mediator of Egr1 in regulating cardiac hypertrophy. PMID- 23929525 TI - Super-resolution fluorescence microscopy of the cardiac connexome reveals plakophilin-2 inside the connexin43 plaque. AB - AIMS: Cell function requires formation of molecular clusters localized to discrete subdomains. The composition of these interactomes, and their spatial organization, cannot be discerned by conventional microscopy given the resolution constraints imposed by the diffraction limit of light (~200-300 nm). Our aims were (i) Implement single-molecule imaging and analysis tools to resolve the nano scale architecture of cardiac myocytes. (ii) Using these tools, to map two molecules classically defined as components 'of the desmosome' and 'of the gap junction', and defined their spatial organization. METHODS AND RESULTS: We built a set-up on a conventional inverted microscope using commercially available optics. Laser illumination, reducing, and oxygen scavenging conditions were used to manipulate the blinking behaviour of individual fluorescent reporters. Movies of blinking fluorophores were reconstructed to generate subdiffraction images at ~20 nm resolution. With this method, we characterized clusters of connexin43 (Cx43) and of 'the desmosomal protein' plakophilin-2 (PKP2). In about half of Cx43 clusters, we observed overlay of Cx43 and PKP2 at the Cx43 plaque edge. SiRNA-mediated loss of Ankyrin-G expression yielded larger Cx43 clusters, of less regular shape, and larger Cx43-PKP2 subdomains. The Cx43-PKP2 subdomain was validated by a proximity ligation assay (PLA) and by Monte-Carlo simulations indicating an attraction between PKP2 and Cx43. CONCLUSIONS: (i) Super-resolution fluorescence microscopy, complemented with Monte-Carlo simulations and PLAs, allows the study of the nanoscale organization of an interactome in cardiomyocytes. (ii) PKP2 and Cx43 share a common hub that permits direct physical interaction. Its relevance to excitability, electrical coupling, and arrhythmogenic right ventricular cardiomyopathy, is discussed. PMID- 23929526 TI - Polymeric pseudo-crown ether for cation recognition via cation template-assisted cyclopolymerization. AB - Cyclopolymerization is a chain polymerization of bifunctional monomers via alternating processes of intramolecular cyclization and intermolecular addition, to give soluble linear polymers consisting of in-chain cyclic structures. Though cyclopolymers comprising in-chain multiple large rings potentially show unique functionality, they generally require the elaborate design of bifunctional monomers. Here we report cation template-assisted cyclopolymerization of poly(ethylene glycol) dimethacrylates as an efficient strategy directly yielding polymeric pseudo-crown ethers with large in-chain cavities (up to 30-membered rings) for selective molecular recognition. The key is to select a size-fit metal cation for the spacer unit of the divinyl monomers to form a pseudo-cyclic conformation, where the two vinyl groups are suitably positioned for intramolecular cyclization. The marriage of supramolecular chemistry and polymer chemistry affords efficient, one-pot chemical transformation from common chemical reagents with simple templates to functional cyclopolymers. PMID- 23929527 TI - Diverse antimicrobial interactions of halophilic archaea and bacteria extend over geographical distances and cross the domain barrier. AB - The significance of antimicrobial substances, halocins, produced by halophilic archaea and bacteria thriving in hypersaline environments is relatively unknown. It is suggested that their production might increase species diversity and give transient competitive advances to the producer strain. Halocin production is considered to be common among halophilic archaea, but there is a lack of information about halocins produced by bacteria in highly saline environments. We studied the antimicrobial activity of 68 halophilic archaea and 22 bacteria isolated from numerous geographically distant hypersaline environments. Altogether 144 antimicrobial interactions were found between the strains and aside haloarchaea, halophilic bacteria from various genera were identified as halocin producers. Close to 80% of the interactions were detected between microorganisms from different genera and in few cases, even across the domain boundary. Several of the strains produced halocins with a wide inhibitory spectrum as has been observed before. Most of the antimicrobial interactions were found between strains from distant sampling sites indicating that hypersaline environments around the world have similar microorganisms with the potential to produce wide activity range antimicrobials. PMID- 23929528 TI - Extreme thermal noxious stimuli induce pain responses in zebrafish larvae. AB - Exposing tissues to extreme high or low temperature leads to burns. Burned animals sustain several types of damage, from the disruption of the tissue to degeneration of axons projecting through muscle and skin. Such damage causes pain due to both inflammation and axonal degeneration (neuropathic-like pain). Thus, the approach to cure and alleviate the symptoms of burns must be twofold: rebuilding the tissue that has been destroyed and alleviating the pain derived from the burns. While tissue regeneration techniques have been developed, less is known on the treatment of the induced pain. Thus, appropriate animal models are necessary for the development of the best treatment for pain induced in burned tissues. We have developed a methodology in the zebrafish aimed to produce a new animal model for the study of pain induced by burns. Here, we show that two events linked to the onset of burn-induced inflammation and neuropathic-like pain in mammals, degeneration of axons innervating the affected tissues and over expression of specific genes in sensory tissues, are conserved from zebrafish to mammals. PMID- 23929530 TI - Ethnic identity and mental health in American Indian youth: examining mediation pathways through self-esteem, and future optimism. AB - Mental health functioning in American Indian youth is an understudied topic. Given the increased rates of depression and anxiety in this population, further research is needed. Using multiple group structural equation modeling, the current study illuminates the effect of ethnic identity on anxiety symptoms, depressive symptoms, and externalizing behavior in a group of Lumbee adolescents and a group of Caucasian, African American, and Latino/Hispanic adolescents. This study examined two possible pathways (i.e., future optimism and self-esteem) through which ethnic identity is associated with adolescent mental health. The sample (N = 4,714) is 28.53% American Indian (Lumbee) and 51.38% female. The study findings indicate that self-esteem significantly mediated the relationships between ethnic identity and anxiety symptoms, depressive symptoms, and externalizing behavior for all racial/ethnic groups (i.e., the total sample). Future optimism significantly mediated the relationship between ethnic identity and externalizing behavior for all racial/ethnic groups and was a significant mediator between ethnic identity and depressive symptoms for American Indian youth only. Fostering ethnic identity in all youth serves to enhance mental health functioning, but is especially important for American Indian youth due to the collective nature of their culture. PMID- 23929529 TI - The metabolic syndrome and neuropathy: therapeutic challenges and opportunities. AB - The metabolic syndrome and neuropathy are common conditions, especially in the elderly, that are associated with significant morbidity. Furthermore, the metabolic syndrome is reaching epidemic proportions across the world. Current evidence supports the association of the metabolic syndrome and its individual components with neuropathy. Several clinical trials have demonstrated that treating hyperglycemia, a component of the metabolic syndrome, has a significant effect on reducing the incidence of neuropathy in those with type 1 diabetes. However, glucose control has only a marginal effect on preventing neuropathy in those with type 2 diabetes, suggesting that other factors may be driving nerve injury in these patients. Emerging evidence supports the metabolic syndrome as including risk factors for neuropathy. Interventions exist for treatment of all of the metabolic syndrome components, but only glucose control has strong evidence to support its use and is widely employed. Our understanding of the biology of metabolic nerve injury has rapidly expanded over the past several years. Mechanisms of injury include fatty deposition in nerves, extracellular protein glycation, mitochondrial dysfunction, and oxidative stress. Additionally, the activation of counter-regulatory signaling pathways leads to chronic metabolic inflammation. Medications that target these signaling pathways are being used for a variety of diseases and are intriguing therapeutic agents for future neuropathy clinical trials. As we move forward, we need to expand our understanding of the association between the metabolic syndrome and neuropathy by addressing limitations of previous studies. Just as importantly, we must continue to investigate the pathophysiology of metabolically induced nerve injury. PMID- 23929531 TI - The development of moral emotions and decision-making from adolescence to early adulthood: a 6-year longitudinal study. AB - Adolescents' emotions in the context of moral decision-making repeatedly have been shown to predict actual behaviour. However, little systematic information on developmental change regarding these emotion expectancies has been available thus far. This longitudinal study investigated anticipated moral emotions and decision making between the ages of 15 and 21 in a representative sample of Swiss adolescents (N = 1,258; 54 % female; M = 15.30 years). Anticipated moral emotions and decision-making were assessed through a semi-structured interview procedure. Using Bernoulli hierarchical linear modeling, it was found that positive feelings after a moral transgression (i.e., "happy victimizer" responses) decreased over time, whereas positive feelings after a moral decision (i.e., "happy moralist" responses) increased. However, this pattern was contingent upon the moral scenario presented. Systematic relationships between anticipated moral emotions and moral personality characteristics of sympathy, conscientiousness, and agreeableness were found, even when controlling for socio-demographic characteristics and cognitive ability. Overall, this study demonstrates that the development of anticipated moral emotions is not limited to childhood. Furthermore, our findings suggest that moral emotions serve as an important link between moral personality development and decision-making processes that are more proximal to everyday moral behavior. PMID- 23929532 TI - Vocal group signatures in the goitred gazelle Gazella subgutturosa. AB - The potential for vocal modification in mammals has recently been of great interest. This study focuses on the potential for vocal matching in juvenile and adolescent goitred gazelles Gazella subgutturosa that were group housed as part of an animal management programme. Two groups of animals (16 and 19 unrelated individuals, respectively) were recorded at two different ages, juvenile and adolescent, regarding 20-25 calls per individual per age; each group was evaluated in a separate year. Vocal similarity of group members compared to non members was prominent in both ages, but higher in juveniles. Individual identity was prominent in both ages and higher in adolescents. The more prominent vocal indicators of group membership in juveniles could be related to their higher social dependence compared to adolescents. The more individualized calls of adolescents could be a mechanistic consequence of more stable growth at older age. Our results suggest vocal plasticity of goitred gazelles under social influences. These data add to recent evidence about domestic goat kids Capra hircus, suggesting that vocalizations of species that are not capable of imitation are more flexible than previously thought. PMID- 23929533 TI - Association between fetal position at onset of labor and mode of delivery: a prospective cohort study. AB - OBJECTIVES: To determine the association between fetal position at onset of labor and mode of delivery, specifically left occipito-anterior (LOA) fetal position and spontaneous vaginal delivery (SVD). METHODS: All nulliparous women who were booked at the Birmingham Women's NHS Foundation Trust over an 18-month period from April 2007 to September 2008 with a singleton live fetus without structural anomalies at term gestation were invited to take part in the study. Women recruited to the study underwent a transabdominal ultrasound scan to determine fetal occiput position at the onset of labor. They were then followed up until birth to determine outcome. The primary outcome measure was mode of delivery, categorized into SVD, instrumental delivery and Cesarean section. RESULTS: Of 1647 eligible women, 1250 had valid scans at onset of labor; 155 of the 1250 (12.4%) had fetuses in the LOA position. Analysis showed no evidence of difference in odds ratio (OR) of SVD for fetuses in the LOA position compared with all other positions (OR 0.864 (95% CI, 0.617-1.209); P = 0.394). No difference remained with adjustment for confounding effects of variables known to influence mode of delivery (OR 0.837 (95% CI, 0.551-1.272); P = 0.405). No other occipital position showed significant association with SVD. There was no evidence of the LOA position being associated with Cesarean section, ventouse or forceps delivery. CONCLUSION: There is no evidence of an association between the fetal LOA position at onset of labor and SVD. This finding challenges the conventional theory that LOA is the optimum fetal position at onset of labor, and suggests that antenatal practices encouraging adoption of the LOA position through maternal posturing are unnecessary. PMID- 23929534 TI - Decreased functional magnetic resonance imaging activity in the hippocampus in favor of the caudate nucleus in older adults tested in a virtual navigation task. AB - The neuroimaging literature has shown consistent decreases in functional magnetic resonance imaging (fMRI) activity in the hippocampus of healthy older adults engaged in a navigation task. However, navigation in a virtual maze relies on spatial or response strategies known to depend on the hippocampus and caudate nucleus, respectively. Therefore, since the proportion of people using spatial strategies decreases with normal aging, we hypothesized that it was responsible for the observed decreases in fMRI activity in the hippocampus reported in the literature. The aim of this study was to examine the effects of aging on the hippocampus and caudate nucleus during navigation while taking into account individual navigational strategies. Young (N = 23) and older adults (N = 29) were tested using fMRI on the Concurrent Spatial Discrimination Learning Task, a radial task that dissociates between spatial and response strategies (in Stage 2) after participants reached criteria (in Stage 1). Success on Stage 2 requires that participants have encoded the spatial relationship between the target object and environmental landmarks, that is, the spatial strategy. While older adults required more trials, all participants reached criterion. fMRI results showed that, as a group, young adults had significant activity in the hippocampus as opposed to older adults who instead had significant activity in the caudate nucleus. Importantly, individual differences showed that the older participants who used a spatial strategy to solve the task had significant activity in the hippocampus. These findings suggest that the aging process involves a shift from using the hippocampus toward the caudate nucleus during navigation but that activity in the hippocampus is sustained in a subset of healthy older adults engaged in spatial strategies. PMID- 23929535 TI - Respiratory viral infection in the chronic persistent phase of chronic rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: The role of respiratory viral infection in the pathogenesis of chronic rhinosinusitis (CRS) has been rarely studied and remains controversial. The aim of this study was to explore the prevalence of respiratory viruses in the chronic status of CRS. STUDY DESIGN: A case-control prospective study. METHODS: Fifty-three control subjects, and 67 CRS with nasal polyp (CRSwNP) and 61 CRS without nasal polyp (CRSsNP) patients without signs of acute viral infection were enrolled. Epithelial cells scraped from the middle nasal meatus were tested for the nucleic acid of nine common respiratory viruses using polymerase chain reaction assay. The clinical disease severity was compared between subjects with and without viral infection. RESULTS: The overall detection rate of viral infection was 75.47%, 68.66%, and 73.77% in controls, CRSwNP, and CRSsNP, respectively, and no significant difference among studied groups was observed. There was no significant difference in detection rate of any specific individual virus or multiple viruses among the groups studied either. Visual analog scale scores of symptoms, computed tomography scores, or endoscope scores did not show obvious difference between subjects with and without viral infection. CONCLUSIONS: Although a high frequency of viral infection could be observed in the middle nasal meatus, no increase of frequency of viral infection could be demonstrated in chronic persistent phase of CRSsNP and CRSwNP. The contribution of the interaction between viral infection and host immunity to the pathogenesis of CRS remains to be determined. LEVEL OF EVIDENCE: 3b. Laryngoscope, 124:832-837, 2014. PMID- 23929536 TI - Bioactive stilbenes from Vitis vinifera grapevine shoots extracts. AB - BACKGROUND: Viticultural residues from commercial viticultural activities represent a potentially important source of bioactive stilbenes such as resveratrol. The main aim of the present study was therefore to isolate, identify and perform biological assays against amyloid-beta peptide aggregation of original stilbenes from Vitis vinifera shoots. RESULTS: A new resveratrol oligomer, (Z)-cis-miyabenol C (3), was isolated from Vitis vinifera grapevine shoots together with two newly reported oligostilbenes from Vitis vinifera shoots, vitisinol C (1) and (E)-cis-miyabenol C (2), and six known compounds: piceatannol, resveratrol, (E)-epsilon-viniferin (trans-epsilon-viniferin), omega viniferin, vitisinol C and (E)-miyabenol C. The structures of these resveratrol derivatives were established on the basis of detailed spectroscopic analysis including nuclear magnetic resonance experiments. All the newly reported compounds were tested for their anti-aggregative activity against amyloid-beta fibril formation. Vitisinol C was found to exert a significant activity against amyloid-beta aggregation. CONCLUSION: Vitis vinifera grapevine shoots are potentially interesting as a source of new bioactive stilbenes, such as vitisinol C. PMID- 23929537 TI - Latent cytomegalovirus infection and innate immune function following a 75 km cycling time trial. AB - PURPOSE: This study compared the acute immune response, inflammation, and lipid peroxidation to a 75 km cycling time trial in male athletes testing positive or negative for latent cytomegalovirus (CMV) infection. DESIGN: Trained cyclists (N = 20) were tested for CMV serostatus, and cycled 75 km on a mountainous course using indoor trainers with continuous workload monitoring. Pre-, post-, and 1 h post-exercise blood samples were analyzed for total blood leukocyte counts, blood granulocyte (GR) and monocyte (MO) phagocytosis (PHAG) and oxidative burst activity (OBA), four plasma cytokines, and plasma F2-isoprostanes. RESULTS: Forty percent of the subjects tested positive for CMV. No differences in subject characteristics were found between CMVpos and CMVneg groups. Mean power (57.3 +/- 1.6, 59.4 +/- 1.8 % maximal Watts, p = 0.803), heart rate (87.0 +/- 1.0, 86.5 +/- 1.3 % maximal heart rate, p = 0.376), and total time (2.56 +/- 0.08, 2.60 +/- 0.08 h, p = 0.744) to complete the 75 km cycling time trial did not differ between CMVpos and CMVneg groups. Whereas exercise induced significant changes in total blood leukocyte counts, GR and MO-PHAG, four plasma cytokines, and plasma F2-isoprostanes (p < 0.05, omega(2) > 0.03), these exercise-induced changes did not differ between CMVpos and CMVneg groups (p > 0.05, omega(2) < 0.01). CONCLUSIONS: CMV serostatus does not appear to influence these innate immune responses or markers of inflammation and lipid peroxidation in response to a single bout of heavy exertion. PMID- 23929538 TI - Sleep-disordered breathing in Ehlers-Danlos syndrome: a genetic model of OSA. AB - OBJECTIVES: The objective of this study was to investigate the presence of sleep disordered breathing (SDB) in patients with Ehlers-Danlos syndrome. Ehlers-Danlos syndrome is a genetic disorder characterized by cartilaginous defects, including nasal-maxillary cartilages. METHODS: A retrospective series of 34 patients with Ehlers-Danlos syndrome and complaints of fatigue and poor sleep were evaluated by clinical history, physical examination, polysomnography (PSG), and, in some cases, anterior rhinomanometry. Additionally, a prospective clinical investigation of nine patients with Ehlers-Danlos syndrome was performed in a specialized Ehlers-Danlos syndrome clinic. RESULTS: All patients with Ehlers Danlos syndrome evaluated had SDB on PSG. In addition to apneas and hypopneas, SDB included flow limitation. With increasing age, flow limitation decreased in favor of apnea and hypopnea events, but clinical complaints were similar independent of the type of PSG finding. In the subgroup of patients who underwent nasal rhinomanometry, increased nasal resistance was increased relative to normative values. Nasal CPAP improved symptoms. Patients with Ehlers-Danlos syndrome presenting to the medical clinic had symptoms and clinical signs of SDB, but they were never referred for evaluation of SDB. CONCLUSIONS: In patients with Ehlers-Danlos syndrome, abnormal breathing during sleep is commonly unrecognized and is responsible for daytime fatigue and poor sleep. These patients are at particular risk for SDB because of genetically related cartilage defects that lead to the development of facial structures known to cause SDB. Ehlers-Danlos syndrome may be a genetic model for OSA because of abnormalities in oral-facial growth. Early recognition of SDB may allow treatment with orthodontics and myofacial reeducation. PMID- 23929539 TI - The potential for PCR based testing to improve diagnosis and treatment of sepsis. AB - Early and appropriate antibiotic use is critical for the treatment of sepsis. In practice, however, early antibiotic administration is hampered by diagnostic uncertainty with regard to both early diagnosis of disease and delayed or absent microbiological results. The diagnostic uncertainty often persists into the later stages of sepsis when clinical response to antibiotic treatment is assessed. Blood culture, the current "gold standard" test for diagnosis of sepsis, is inadequate due to low sensitivity and delayed results. However, despite this, the technology remains entrenched in microbiology laboratories due to decades of accumulated experience with the technique. However, in recent years there has been increasing experience with testing based on polymerase chain reaction (PCR). As the technology continues to improve, PCR testing is becoming faster and more sensitive. Moreover, PCR technologies that quantify bacterial load may enable monitoring of response to treatment and susceptibility testing. PMID- 23929540 TI - Proteomics analysis in Caenorhabditis elegans to elucidate the response induced by tyrosol, an olive phenol that stimulates longevity and stress resistance. AB - Tyrosol (TYR, 2-(4-hydroxyphenyl)ethanol), one of the main phenols in olive oil and olive fruit, significantly strengthens resistance to thermal and oxidative stress in the nematode Caenorhabditis elegans and extends its lifespan. To elucidate the cellular functions regulated by TYR, we have used a proteomic procedure based on 2DE coupled with MS with the aim to identify the proteins differentially expressed in nematodes grown in a medium containing 250 MUM TYR. After the comparison of the protein profiles from 250 MUM TYR and from control, 28 protein spots were found to be altered in abundance (>=twofold). Analysis by MALDI-TOF/TOF and PMF allowed the unambiguous identification of 17 spots, corresponding to 13 different proteins. These proteins were as follows: vitellogenin-5, vitellogenin-2, bifunctional glyoxylate cycle protein, acyl CoA dehydrogenase-3, alcohol dehydrogenase 1, adenosylhomocysteinase, elongation factor 2, GTP-binding nuclear protein ran-1, HSP-4, protein ENPL-1 isoform b, vacuolar H ATPase 12, vacuolar H ATPase 13, GST 4. Western-blot analysis of yolk protein 170, ras-related nuclear protein, elongation factor 2, and vacuolar H ATPase H subunit supported the proteome evidence. PMID- 23929541 TI - Synthesis of an imidazolium phosphanide zwitterion and its conversion into anionic imidazol-2-ylidene derivatives. AB - Matter of opinion: The novel zwitterion 1 has been synthesized and studied theoretically and also converted into anionic NHCs 2. The former can also be described as a phosphinidene adduct of an abnormal N-heterocyclic carbene (1') and, in the same vein, the latter represents a phosphinidene adduct of an anionic N-heterocyclic dicarbene (2'). PMID- 23929542 TI - Left untreated: the natural course of a thoracic aortic aneurysm. PMID- 23929543 TI - Bypass graft aneurysm. PMID- 23929544 TI - Assessment of satiety depends on the energy density and portion size of the test meal. AB - OBJECTIVE: Foods that enhance satiety can reduce overconsumption, but the availability of large portions of energy-dense foods may counter their benefits. The influence on meal energy intake of varying the energy density and portion size of food consumed after a preload shown to promote satiety was tested. DESIGN AND METHODS: In a crossover design, 46 women were served lunch on six days. On four days they ate a compulsory salad (300 g, 0.33 kcal/g). Unlike previous studies, instead of varying the preload, the subsequent test meal of pasta was varied between standard and increased levels of both energy density (1.25 or 1.66 kcal/g) and portion size (450 or 600 g). On two control days a salad was not served. RESULTS: Following the salad, the energy density and portion size of the test meal independently affected meal energy intake (both P < 0.02). Serving the higher-energy-dense pasta increased test meal intake by 153 +/- 19 kcal and serving the larger portion of pasta increased test meal intake by 40 +/- 16 kcal. Compared to having no salad, consuming the salad decreased test meal intake by 123 +/- 18 kcal. CONCLUSIONS: The effect of satiety-enhancing foods can be influenced by the energy density and portion size of other foods at the meal. PMID- 23929545 TI - Abnormalities in white matter microstructure associated with chronic ketamine use. AB - Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has been found to induce schizophrenia-type symptoms in humans and is a potent and fast acting antidepressant. It is also a relatively widespread drug of abuse, particularly in China and the UK. Acute administration has been well characterized, but the effect of extended periods of ketamine use-on brain structure in humans-remains poorly understood. We measured indices of white matter microstructural integrity and connectivity in the brain of 16 ketamine users and 16 poly-drug-using controls, and we used probabilistic tractography to quantify changes in corticosubcortical connectivity associated with ketamine use. We found a reduction in the axial diffusivity profile of white matter in a right hemisphere network of white matter regions in ketamine users compared with controls. Within the ketamine-user group, we found a significant positive association between the connectivity profile between the caudate nucleus and the lateral prefrontal cortex and dissociative experiences. These findings suggest that chronic ketamine use may be associated with widespread disruption of white matter integrity, and white matter pathways between subcortical and prefrontal cortical areas may in part predict individual differences in dissociative experiences due to ketamine use. PMID- 23929546 TI - Altered resting-state functional connectivity of basolateral and centromedial amygdala complexes in posttraumatic stress disorder. AB - The amygdala is a major structure that orchestrates defensive reactions to environmental threats and is implicated in hypervigilance and symptoms of heightened arousal in posttraumatic stress disorder (PTSD). The basolateral and centromedial amygdala (CMA) complexes are functionally heterogeneous, with distinct roles in learning and expressing fear behaviors. PTSD differences in amygdala-complex function and functional connectivity with cortical and subcortical structures remain unclear. Recent military veterans with PTSD (n=20) and matched trauma-exposed controls (n=22) underwent a resting-state fMRI scan to measure task-free synchronous blood-oxygen level dependent activity. Whole-brain voxel-wise functional connectivity of basolateral and CMA seeds was compared between groups. The PTSD group had stronger functional connectivity of the basolateral amygdala (BLA) complex with the pregenual anterior cingulate cortex (ACC), dorsomedial prefrontal cortex, and dorsal ACC than the trauma-exposed control group (p<0.05; corrected). The trauma-exposed control group had stronger functional connectivity of the BLA complex with the left inferior frontal gyrus than the PTSD group (p<0.05; corrected). The CMA complex lacked connectivity differences between groups. We found PTSD modulates BLA complex connectivity with prefrontal cortical targets implicated in cognitive control of emotional information, which are central to explanations of core PTSD symptoms. PTSD differences in resting-state connectivity of BLA complex could be biasing processes in target regions that support behaviors central to prevailing laboratory models of PTSD such as associative fear learning. Further research is needed to investigate how differences in functional connectivity of amygdala complexes affect target regions that govern behavior, cognition, and affect in PTSD. PMID- 23929548 TI - The rat model of femur fracture for bone and mineral research: An improved description of expected comminution, quantity of soft callus and incidence of complications. AB - OBJECTIVES: One commonly used rat fracture model for bone and mineral research is a closed mid-shaft femur fracture as described by Bonnarens in 1984. Initially, this model was believed to create very reproducible fractures. However, there have been frequent reports of comminution and varying rates of complication. Given the importance of precise anticipation of those characteristics in laboratory research, we aimed to precisely estimate the rate of comminution, its importance and its effect on the amount of soft callus created. Furthermore, we aimed to precisely report the rate of complications such as death and infection. METHODS: We tested a rat model of femoral fracture on 84 rats based on Bonnarens' original description. We used a proximal approach with trochanterotomy to insert the pin, a drop tower to create the fracture and a high-resolution fluoroscopic imager to detect the comminution. We weighed the soft callus on day seven and compared the soft callus parameters with the comminution status. RESULTS: The mean operating time was 34.8 minutes (sd 9.8). The fracture was usable (transverse, mid-shaft, without significant comminution and with displacement < 1 mm) in 74 animals (88%). Of these 74 usable fractures, slight comminution was detected in 47 (63%). In 50 animals who underwent callus manipulation, slight comminution (n = 32) was statistically correlated to the amount of early callus created (r = 0.35, p = 0.015). Two complications occurred: one death and one deep infection. CONCLUSIONS: We propose an accurate description of comminution and complications in order to improve experiments on rat femur fracture model in the field of laboratory research. Cite this article: Bone Joint Res 2013;2:149-54. PMID- 23929547 TI - Antenatal glucocorticoid treatment induces adaptations in adult midbrain dopamine neurons, which underpin sexually dimorphic behavioral resilience. AB - We demonstrated previously that antenatal glucocorticoid treatment (AGT, gestational days 16-19) altered the size and organization of the adult rat midbrain dopaminergic (DA) populations. Here we investigated the consequences of these AGT-induced cytoarchitectural disturbances on indices of DA function in adult rats. We show that in adulthood, enrichment of striatal DA fiber density paralleled AGT-induced increases in the numbers of midbrain DA neurons, which retained normal basal electrophysiological properties. This was co-incident with changes in (i) striatal D2-type receptor levels (increased, both sexes); (ii) D1 type receptor levels (males decreased; females increased); (iii) DA transporter levels (males increased; females decreased) in striatal regions; and (iv) amphetamine-induced mesolimbic DA release (males increased; females decreased). However, despite these profound, sexually dimorphic changes in markers of DA neurotransmission, in-utero glucocorticoid overexposure had a modest or no effect on a range of conditioned and unconditioned appetitive behaviors known to depend on mesolimbic DA activity. These findings provide empirical evidence for enduring AGT-induced adaptive mechanisms within the midbrain DA circuitry, which preserve some, but not all, functions, thereby casting further light on the vulnerability of these systems to environmental perturbations. Furthermore, they demonstrate these effects are achieved by different, often opponent, adaptive mechanisms in males and females, with translational implications for sex biases commonly found in midbrain DA-associated disorders. PMID- 23929549 TI - Silent embolism after stent-assisted coiling of cerebral aneurysms: diffusion weighted MRI study of 75 cases. AB - PURPOSE: New ischemic brain lesions are common findings after cerebral diagnostic angiography and endovascular therapy. Diffusion-weighted MRI (DWI) can be used for detection of these lesions. The aim of the present study was to investigate the incidence of DWI lesions after stent-assisted coiling and the evaluation of possible risk factors. METHODS: The study included a total of 75 consecutive patients treated with stent-assisted coiling. Post-procedural DWI of the brain was performed to detect ischemic lesions. Demographic data, aneurysm characteristics and angiographic parameters were correlated with properties of DWI lesions. RESULTS: In post-procedural DWI, 48 of the 75 patients (64%) had 163 DWI lesions in a pattern consistent with embolic events. The number of patients with DWI lesions was significantly increased in older patients (>=55 years) and longer intervention times (>=120 min). The ischemic brain volume was significantly increased in older patients (>=55 years) as well as in patients who were implanted with a shorter stent (<20 mm). CONCLUSIONS: Thromboembolic events are common after stent-assisted coiling with an incidence comparable to DWI studies after coiling alone. Despite several devices and low operator experience, stent-assisted coiling for intracranial aneurysms has a very low risk of permanent neurologic disability. Further studies are necessary to improve the safety of stent-assisted coiling for patients in conditions with increased risk potential (age, procedure time, stent length). PMID- 23929550 TI - Wall shear stress association with rupture status in volume matched sidewall aneurysms. AB - OBJECTIVE: Flow induced tangential wall shear stress (WSS) is thought to be involved in aneurysm formation, growth, and rupture. Low WSS was previously associated with rupture, but definitive quantitative analyses remain scant as larger aneurysms are associated with lower WSS regardless of rupture status, and ruptured aneurysms are larger than unruptured aneurysms. Here, the intra-dome WSS was evaluated on 18 internal carotid artery aneurysms, volume matched as ruptured/unruptured pairs in order to remove the confounding effect of size dependence. METHODS: Computational fluid dynamic simulations were performed and WSS was evaluated at peak systole, end diastole, and as time averaged over the cardiac cycle. WSS logarithmic scaling was applied to refine value discrimination at extrema. Ruptured/unruptured lesions were statistically evaluated using pairwise t test analysis. The effect of size on WSS was evaluated in parametric models. RESULTS: In parametric data, there was a statistically significant negative correlation between volume and WSS values. In patient data, mean WSS was not statistically significant but low range WSS values were significantly lower for ruptured aneurysms, regardless of WSS evaluation (time averaged, peak systole, end diastole). Statistically, logarithmic WSS performed better than WSS, with minimum logarithmic WSS at end diastole being the best rupture status discriminator (p=0.001, area under the curve=0.98). Higher range and maximal WSS were not significantly significant. CONCLUSIONS: Aneurysm size is a confounding factor to WSS rupture discrimination, and volume matched analysis is necessary for unbiased evaluation. While these results lend support to the hypothesis that lower WSS induces wall changes which may be associated with rupture, it raises questions regarding the extent of this association, which requires further exploration. PMID- 23929551 TI - E and M circadian pacemaker neurons use different PDF receptor signalosome components in drosophila. AB - We used real-time imaging to detect cAMP levels in neurons of intact fly brains to study the mechanisms of circadian pacemaker synchronization by the neuropeptide pigment dispersing factor (PDF) in Drosophila. PDF receptor (PDF-R) is expressed by both M (sLNv) and E (LNd) pacemaker subclasses and is coupled to G(salpha) in both cases. We previously reported that PDF-R in M pacemakers elevates cAMP levels by activating the ortholog of mammalian adenylate cyclase 3 (AC3) but that AC3 disruptions had no effect on E pacemaker sensitivity to PDF. Here, we show that PDF-R in E pacemakers activates a different AC isoform, AC78C, an ortholog of mammalian AC8. Knockdown of AC78C by transgenic RNAi substantially reduces, but does not completely abrogate, PDF responses in these E pacemakers. The knockdown effect is intact when restricted to mature stages, suggesting a physiological and not a development role for AC78C in E pacemakers. The AC78C phenotype is rescued by the overexpression of AC78C but not by overexpression of the rutabaga AC. AC78C overexpression does not disrupt PDF responses in these E pacemakers, and neither AC78C knockdown nor its overexpression disrupted locomotor rhythms. Finally, knockdown of 2 AKAPs, nervy and AKAP200, partially reduces LNd PDF responses. These findings begin to identify the components of E pacemaker PDF-R signalosomes and indicate that they are distinct from PDF-R signalosomes in M pacemakers: we propose they contain AC78C and at least 1 other AC. PMID- 23929552 TI - Period gene expression in the brain of a dual-phasing rodent, the Octodon degus. AB - Clock gene expression is not only confined to the master circadian clock in the suprachiasmatic nucleus (SCN) but is also found in many other brain regions. The phase relationship between SCN and extra-SCN oscillators may contribute to known differences in chronotypes. The Octodon degus is a diurnal rodent that can shift its activity-phase preference from diurnal to nocturnal when running wheels become available. To understand better the relationship between brain clock gene activity and chronotype, we studied the day-night expression of the Period genes, Per1 and Per2, in the SCN and extra-SCN brain areas in diurnal and nocturnal degus. Since negative masking to light and entrainment to the dark phase are involved in the nocturnalism of this species, we also compare, for the first time, Per expression between entrained (EN) and masked nocturnal (MN) degus. The brains of diurnal, MN, and EN degus housed with wheels were collected during the light (ZT4) and dark (ZT16) phases. Per1 and Per2 mRNA levels were analyzed by in situ hybridization. Within the SCN, signals for Per1 and Per2 were higher at ZT4 irrespective of chronotype. However, outside of the SCN, Per1 expression in the hippocampus of EN degus was out of phase (higher values at ZT16) with SCN values. Although a similar trend was seen in MN animals, this day-night difference in Per1 expression was not significant. Interestingly, daily differences in Per1 expression were not seen in the hippocampus of diurnal degus. For other putative brain areas analyzed (cortices, striatum, arcuate, ventromedial hypothalamus), no differences in Per1 levels were found between chronotypes. Both in diurnal and nocturnal degus, Per2 levels in the hippocampus and in the cingulate and piriform cortices were in phase with their activity rhythms. Thus, diurnal degus showed higher Per2 levels at ZT4, whereas in both types of nocturnal degus, Per2 expression was reversed, peaking at ZT16. Together, the present study supports the hypothesis that the mechanisms underlying activity-phase preference in diurnal and nocturnal mammals reside downstream from the SCN, but our data also indicate that there are fundamental differences between nocturnal masked and entrained degus. PMID- 23929553 TI - Dim light at night disrupts molecular circadian rhythms and increases body weight. AB - With the exception of high latitudes, life has evolved under bright days and dark nights. Most organisms have developed endogenously driven circadian rhythms that are synchronized to this daily light/dark cycle. In recent years, humans have shifted away from the naturally occurring solar light cycle in favor of artificial and sometimes irregular light schedules produced by electric lighting. Exposure to unnatural light cycles is increasingly associated with obesity and metabolic syndrome; however, the means by which environmental lighting alters metabolism are poorly understood. Thus, we exposed mice to dim light at night and investigated changes in the circadian system and metabolism. Here we report that exposure to ecologically relevant levels of dim (5 lux) light at night altered core circadian clock rhythms in the hypothalamus at both the gene and protein level. Circadian rhythms in clock expression persisted during light at night; however, the amplitude of Per1 and Per2 rhythms was attenuated in the hypothalamus. Circadian oscillations were also altered in peripheral tissues critical for metabolic regulation. Exposure to dimly illuminated, as compared to dark, nights decreased the rhythmic expression in all but one of the core circadian clock genes assessed in the liver. Additionally, mice exposed to dim light at night attenuated Rev-Erb expression in the liver and adipose tissue. Changes in the circadian clock were associated with temporal alterations in feeding behavior and increased weight gain. These results are significant because they provide evidence that mild changes in environmental lighting can alter circadian and metabolic function. Detailed analysis of temporal changes induced by nighttime light exposure may provide insight into the onset and progression of obesity and metabolic syndrome, as well as other disorders involving sleep and circadian rhythm disruption. PMID- 23929554 TI - Environmental circadian disruption elevates the IL-6 response to lipopolysaccharide in blood. AB - The immune system is regulated by circadian clocks within the brain and immune cells. Environmental circadian disruption (ECD), consisting of a 6-h phase advance of the light:dark cycle once a week for 4 weeks, elevates the inflammatory response to lipopolysaccharide (LPS) both in vivo and in vitro. This indicates that circadian disruption adversely affects immune function; however, it remains unclear how the circadian system regulates this response under ECD conditions. Here, we develop an assay using ex vivo whole-blood LPS challenge to investigate the circadian regulation of immune responses in mice and to determine the effects of ECD on these rhythms. LPS-induced IL-6 release in whole blood was regulated in a circadian manner, peaking during subjective day under both entrained and free-running conditions. This LPS-induced IL-6 release rhythm was associated with daily variation in both white blood cell counts and immune cell responsiveness. ECD increased the overall level of LPS-induced IL-6 release by increasing immune cell responsiveness and not by affecting immune cell number or the circadian regulation of this rhythm. This indicates that ECD produces pathological immune responses by increasing the proinflammatory responses of immune cells. Also, this newly developed whole blood assay can provide a noninvasive longitudinal method to quantify potential health consequences of circadian disruption in humans. PMID- 23929555 TI - Photoperiod can entrain circannual rhythms in pinealectomized European hamsters. AB - In mammals, the pineal hormone melatonin is thought to be essential to process environmental photoperiodic information. In this study, we demonstrate in a circannual species, the European hamster Cricetus cricetus, the existence of a melatonin-independent second pathway. In 4 physiological parameters (reproduction, body weight, activity pattern, body temperature), a large majority of pinealectomized European hamsters were entrained to an accelerated photoperiodic regime. It compressed the natural variations in the photoperiod to a 6-month cycle, which allowed us to record up to 6 complete physiological cycles during the life span of the individuals. We show further that whether a pinealectomized animal is able to entrain to changes in the photoperiod is influenced by the season of pinealectomy. The results do not disprove that melatonin is capable of entraining a circannual rhythm, but they show clearly that melatonin is not necessary, demonstrating another melatonin-independent pathway for circannual entrainment by the photoperiod. In view of these new insights, a revision of the original literature revealed that probably the melatonin-independent pathway plays an important role in most circannual mammals but only a minor role in photoperiodic species. Thus, the present work provides also the first evidence for different synchronization mechanisms in photoperiodic and circannual species. PMID- 23929556 TI - Photic phase-response curve in 2 strains of mice with impaired responsiveness to estrogens. AB - Steroid hormones including estrogens modulate the expression of daily activity and circadian rhythms, including free-running period, phase angle of activity onset, and response to light. The mechanisms underlying these effects, however, are not fully understood. We tested the hypothesis that estrogen signaling is required for photic responsiveness of the circadian timing system. We used estrogen receptor subtype 1 (ESR1) knock-out mice (ERKO) and nonclassic estrogen receptor knock-in mice (NERKI). ERKO animals are unable to respond to estrogen at ESR1, and NERKI animals lack the ability to respond to estrogens via estrogen response element-mediated transcription but still respond via nonclassical mechanisms. We analyzed behavioral shifts in activity onset in response to 1-h light pulses given across the subjective 24-h day in gonadally intact male and female NERKI, ERKO, and wild-type (WT) littermates. We also examined Fos protein expression in the suprachiasmatic nucleus, the site of the master circadian pacemaker, at 2 times of day. We found a significant effect of genotype on phase shifts in response to light pulses given in the subjective night. Female WT mice had a significantly larger phase response than ERKO females during the early subjective night (phase shift of 98 min and 58 min, respectively; p < 0.05). NERKI females were intermediate to WT and ERKO females, suggesting a contribution of nonclassical estrogen signaling on circadian timekeeping functions. This genotype effect is not observed in males; they did not have a difference in phase shifts following a light pulse at any time point. WT males, however, shifted an average of 47 min less than did females at zeitgeber time (ZT) 16 (ZT 0 lights-on and ZT 12 lights-off). These data indicate that estrogens modify the response of the circadian timekeeping system to light via classical and nonclassical signaling pathways. PMID- 23929558 TI - Findings of long-term depression up to 8 years post infection from West Nile virus. AB - OBJECTIVE: To examine the psychological sequelae following West Nile virus (WNV) infection among a large cohort of participants over an 8-year period. DESIGN: We conducted a longitudinal study to assess mental health outcomes among a cohort of 171 WNV-positive participants in Houston, Texas. RESULTS: We found 35% of participants met the Center for Epidemiologic Studies Depression scale definition for new onset clinical depression. Multivariate analysis found that severe depression was significantly associated with gender and physical disability (Barthel index score <100) at 5 years post-WNV infection. CONCLUSIONS: Practitioners should be aware of depression as a possible outcome in patients who were infected with WNV and include this as a part of their routine assessment. PMID- 23929559 TI - Restricting state part C eligibility policy is associated with lower early intervention utilization. AB - To examine if state differences in early intervention (EI) utilization can be explained by recent restrictions on EI state eligibility policy. The sample (n = 923), derived from the 2009/10 National Survey of Children with Special Health Care Needs, included CSHCN who were ages 0-3 with a developmental delay or disability that affected their function. Multi-level logistic modeling was used to describe state differences in EI utilization and to determine if narrower state eligibility policy explained these differences. EI utilization ranged from 6 to 87 % across states. Having a severe condition (beta = 0.99, SE = 0.28) and a usual source of care (beta = 0.01, SE = 0.001) was associated with higher odds of utilizing EI. Compared to a diagnosed disability, having a developmental delay (beta = -0.61, SE = 0.20) was associated with lower odds of utilizing EI. Living in a state with narrow and narrower state eligibility policy (beta = -0.18, SE = 0.06) was significantly associated with lower odds of EI utilization, and this effect was strongest for children with the most severe functional impairments. Significant state variation in EI rates exists that can be explained, in part, by the restrictiveness of state eligibility criteria. Children with the most severe functional impairments appear to be least likely to utilize EI in states with the most restrictive eligibility policies. PMID- 23929557 TI - Helminths and their implication in sepsis - a new branch of their immunomodulatory behaviour? AB - The prevalence of autoimmune and allergic disorders has dramatically increased in developed countries, and it is believed that our 'cleaner living' reduces exposure to certain microorganisms and leads to deviated and/or reduced regulation of the immune system. In substantiation of this health hygiene hypothesis, multiple epidemiological studies and animal models have characterized the protective immune responses induced by helminths during auto-inflammatory disorders. The beneficial effects of such helminths, like schistosomes and filariae, are thought to lie in their immunomodulatory capacity, which can be induced by different life-cycle stages or components thereof. In addition to suppressing autoimmunity recent evidence indicates that concurrent helminth infections also counterbalance exacerbated pro-inflammatory immune responses that occur during sepsis, improving survival. As with allergy, epidemiological studies have observed a steady rise in severe sepsis cases and although this may have resulted from several factors (immunosuppressive drugs, chemotherapy, transplantation, increased awareness and increased surgical procedures), it is tempting to hypothesize that the lack of helminth infections in Western countries may have contributed to this phenomenon. This review summarizes how helminths modulate host immunity during sepsis, such as manipulating macrophage activation and provides an overview about the possible implications that may arise during overwhelming bacterial co-infections. PMID- 23929560 TI - The latent symptom structure of the Beck depression inventory: second edition in Latina pregnant women. AB - Pregnancy represents a unique period of time when women are at an increased risk of developing depression. Although the Beck Depression Inventory-Second Edition (BDI-II) is one of the most widely used self-report measures of depression symptomology, its psychometric properties and underlying factor structures have not been determined for antenatal women and among Latinas. The current study evaluated the latent symptom structure of the BDI-II in a community-based sample of Latina pregnant women (N = 217) identified to be at high risk for depression. Exploratory factor analyses were used to identify underlying salient individual item loadings for two- and three-factor models. Confirmatory factor analyses then examined several different indices to determine the best model fit. Examination of exploratory and confirmatory factor analyses supports a three-factor oblique structure of the BDI-II composed of Cognitive-Affective, Somatic, and Pregnancy Symptoms. The three-factor model provides clinicians with the ability to target specific constellations of depressive symptoms instead of relying on the BDI-II total score that represents the overall severity of depression in this population. PMID- 23929561 TI - Mediterranean diet: Relationship with anxiety and depression. Reply. PMID- 23929562 TI - Effects of low-intensity laser therapy over mini-implants success rate in pigs. AB - The success rate of miniscrews when used as temporary orthodontic anchorage is relatively high, but some factors could affect its clinical success such as inflammation around the miniscrew. Low-intensity laser therapy has been widely used for biostimulation of tissue and wound healing specially for its anti inflammatory effects. The purpose of this study was to evaluate the effect of low intensity laser therapy over the miniscrew success rate. Five Landrace's pigs received 50 miniscrews on the buccal side of the mandible and on the palate of the maxilla. All the miniscrews were immediately loaded with 250 gf. The laser group were irradiated with a 780-nm diode laser with 70 mWs for 1 min (dose = 34 J/cm(2)); the contralateral side was used as the control group. The miniscrews were photographed and analyzed clinically every week to determine their stability and presence of local inflammation. After 3 weeks, histological analysis and fluorescent microscopy were performed to compare the laser and the control side. Clinical results showed a success rate of 60% for the control group and 80% for the laser-treated group. The histological analysis and fluorescent microscopy demonstrated that the laser group had less inflammatory cells than the control group and the bone neoformation around the miniscrew was more intense. Low intensity laser therapy increased the success rate of orthodontic miniscrews, probably due to anti-inflammatory effect and bone stimulation. PMID- 23929563 TI - Effects of increased low-level diode laser irradiation time on extraction socket healing in rats. AB - In our previous studies, we confirmed that low-level laser therapy (LLLT) with a 980-nm gallium-aluminum-arsenide diode laser was beneficial for the healing of the alveolar bone in rats with systemic disease. However, many factors can affect the biostimulatory effects of LLLT. Thus, we attempted to investigate the effects of irradiation time on the healing of extraction sockets by evaluating the expressions of genes and proteins related to bone healing. The left and right first maxillary molars of 24 rats were extracted. Rats were randomly divided into four groups in which extraction sockets were irradiated for 0, 1, 2, or 5 min each day for 3 or 7 days. Specimens containing the sockets were examined using quantitative real-time reverse transcription polymerase chain reaction and western blotting. LLLT increased the expressions of all tested genes, Runx2, collagen type 1, osteocalcin, platelet-derived growth factor-B, and vascular endothelial growth factor, in a time-dependent manner. The highest levels of gene expressions were in the 5-min group after 7 days. Five minutes of irradiation caused prominent increases of the expression of all tested proteins after both 3 and 7 days. The expression level of each protein in group 4 was higher by almost twofold compared with group 1 after 7 days. Laser irradiation for 5 min caused the highest expressions of genes and proteins related to bone healing. In conclusion, LLLT had positive effects on the early stages of bone healing of extraction sockets in rats, which were irradiation time-dependent. PMID- 23929565 TI - Demographic and cultural changes: impact on dental education. PMID- 23929564 TI - Effect of Er:YAG laser pretreatment on bond strength of a composite core build-up material to fiber posts. AB - The study evaluated the micro push-out bond strength of resin material (Multicore Flow) to two types of fiber posts (FP), namely fiber-reinforced composite (FRC) Postec and Radix Fiber posts using Er:YAG laser pretreatment. FP were divided into four groups, two being control groups. Before the core build-up procedure, representative specimens from each group were chosen to determine the surface roughness (Ra) at three different areas using a contact profilometer, while after the procedure, 1.5-mm-thick discs were sectioned and the micro push-out method was used to assess the bond strength of the core build-up material to the fiber post in each group. Two-way analysis of variance was used for statistical analysis with the level of significance set at p < 0.05. Scanning electron microscopy was used to analyze the post surfaces after Er:YAG laser pretreatment and to classify the failure mode after loading. The type of pretreatment (p < 0.001) and an interaction between the pretreatment and type of post (p < 0.001) had a significant effect on the bond strength, while the type of post did not (p = 0.965). The mean bond strength in the Er:YAG laser pretreatment group was significantly lower compared to the FRC Postec posts control group (p < 0.001), while there was no significant difference between the Radix Fiber posts groups (p = 0.680). Mean Ra values from the Er:YAG laser pretreatment groups were significantly higher compared to control groups (p < 0.001). Er:YAG laser pretreatment at tested parameters negatively affected the bond strength of Multicore to FP and cannot be recommended as a standard procedure. PMID- 23929566 TI - Alfred Owre: revisiting the thought of a distinguished, though controversial, early twentieth-century dental educator. AB - Many in dental education are unfamiliar with the professional life and thought of Dr. Alfred Owre, a distinguished though controversial dental educator in the early twentieth century. Owre served as dean of dentistry at both the University of Minnesota, 1905-27, and Columbia University, 1927-33. He was also a member of the Carnegie Foundation's commission that developed the report Dental Education in the United States and Canada, written by Dr. William J. Gies. Owre was a controversial leader due to his creative and original ideas that challenged dental education and the profession. His assessment and critique of the problems of dental education in his era can readily be applied to contemporary dental education and the profession, just as his vision for transformative change resonates with ideas that continue to be advocated by some individuals today. This article also documents his tumultuous relationship with Gies. PMID- 23929567 TI - Dental students' reflections on their experiences with a diverse patient population. AB - Recent developments, including national reports and new accreditation standards, have emphasized the need for dental students to be prepared to address the needs of a diverse patient population. The purpose of this study was to explore students' descriptions of and reflections on their day-to-day interactions with a diverse patient population in the clinical setting, using a qualitative approach. All dental students (sixty-six) enrolled in the third year of the D.M.D. program at a Midwestern dental school were required to write a paper reflecting on their experiences working with a diverse patient population in the general dental clinic of the school as part of a behavioral sciences course. All third-year dental students were invited to participate in the study. The students' papers were deidentified prior to data analysis. Forty-two students' papers describing a total of 126 patient-student interactions were reviewed. Data analysis resulted in identification of three key themes: 1) development of cultural awareness and recognition of the need to understand each patient as a unique individual, 2) desire to build rapport with all patients, and 3) realization that the development of cultural competence is a lifelong learning process requiring ongoing experiences working with a diverse patient population. Review of student reflection papers is valuable in providing faculty with an understanding of students' degree of development of cultural competence. A greater understanding of students' day-to-day experiences with a diverse patient population can provide insights for dental educators who develop cultural competence curricula. PMID- 23929568 TI - A tool for assessing cultural competence training in dental education. AB - Policies exist to promote fairness and equal access to opportunities and services that address basic human needs of all U.S. citizens. Nonetheless, health disparities continue to persist among certain subpopulations, including those of racial, ethnic, geographic, socioeconomic, and other cultural identity groups. The Commission on Dental Accreditation (CODA) has added standards to address this concern. According to the most recent standards, adopted in 2010 for implementation in July 2013, CODA stipulates that "students should learn about factors and practices associated with disparities in health." Thus, it is imperative that dental schools develop strategies to comply with this addition. One key strategy for compliance is the inclusion of cultural competence training in the dental curriculum. A survey, the Dental Tool for Assessing Cultural Competence Training (D-TACCT), based on the Association of American Medical Colleges' Tool for Assessing Cultural Competence Training (TACCT), was sent to the academic deans at seventy-one U.S. and Canadian dental schools to determine best practices for cultural competence training. The survey was completed by thirty-seven individuals, for a 52 percent response rate. This article describes the use of this survey as a guide for developing culturally competent strategies and enhancing cultural competence training in dental schools. PMID- 23929569 TI - The knowledge, efficacy, and practices instrument for oral health providers: a validity study with dental students. AB - Valid and reliable instruments to measure and assess cultural competence for oral health care providers are scarce in the literature, and most published scales have been contested due to a lack of item analysis and internal estimates of reliability. The purposes of this study were, first, to develop a standardized instrument to measure dental students' knowledge of diversity, skills in culturally competent patient-centered communication, and use of culture-centered practices in patient care and, second, to provide preliminary validity support for this instrument. The initial instrument used in this study was a thirty-six item Likert-scale survey entitled the Knowledge, Efficacy, and Practices Instrument for Oral Health Providers (KEPI-OHP). This instrument is an adaption of an initially thirty-three-item version of the Multicultural Awareness, Knowledge, and Skills Scale-Counselor Edition (MAKSS-CE), a scale that assesses factors related to social justice, cultural differences among clients, and cross cultural client management. After the authors conducted cognitive and expert interviews, focus groups, pilot testing, and item analysis, their initial instrument was reduced to twenty-eight items. The KEPI-OHP was then distributed to 916 dental students (response rate=48.6 percent) across the United States to measure its reliability and assess its validity. Both exploratory and confirmatory factor analyses were conducted to test the scale's validity. The modification of the survey into a sensible instrument with a relatively clear factor structure using factor analysis resulted in twenty items. A scree test suggested three expressive factors, which were retained for rotation. Bentler's comparative fit and Bentler and Bonnett's non-normed indices were 0.95 and 0.92, respectively. A three-factor solution, including efficacy of assessment, knowledge of diversity, and culture-centered practice subscales, comprised of twenty-items was identified. The KEPI-OHP was found to have reasonable internal consistency reliability to warrant its use for baseline and repeated measures in assessing changes in dental students' growth in cultural competence across four year dental curricula. PMID- 23929570 TI - Early performance in a humanistic medicine course as a predictor of dental students' later clinical performance. AB - The purpose of this study was to test the hypothesis that dental students' early ability to demonstrate a humanistic approach with patients is associated with later clinical performance. A first-year humanistic medicine course, Patient Doctor I (PDI), at Harvard School of Dental Medicine combines training in conducting the medical interview with human values, placing a high value on strengthening relationships with patients and emphasizing empowerment, respect, and strong communication skills. Retrospective data were collected in the following domains: PDI course evaluations, admissions information, National Board Dental Examination Parts I and II scores, and Promotions Committee and faculty evaluation scores for hand skills and humanistic and interactive patient-student skills. Planned linear contrasts comparisons were performed for each clinical outcome variable. Tests to support the a priori hypothesis of linear relationships between PDI evaluation ratings and clinical performance, defined as hand skills and humanistic and interactive patient-student skills scores, were significant, both at p=0.03. This study demonstrated the feasibility of measuring dental students' humanistic qualities during the first year. Humanistic qualities (PDI performance) during the first year were found to be associated with clinical performance in the third year of dental school. PMID- 23929571 TI - Pharmacology education in North American dental schools: the basic science survey series. AB - As part of the Basic Science Survey Series (BSSS) for Dentistry, members of the American Dental Education Association (ADEA) Physiology, Pharmacology, and Therapeutics Section surveyed course directors of basic pharmacology courses in North American dental schools. The survey was designed to assess, among other things, faculty affiliation and experience of course directors, teaching methods, general course content and emphasis, extent of interdisciplinary (shared) instruction, and impact of recent curricular changes. Responses were received from forty-nine of sixty-seven (73.1 percent) U.S. and Canadian dental schools. The findings suggest the following: 1) substantial variation exists in instructional hours, faculty affiliation, placement within curriculum, class size, and interdisciplinary nature of pharmacology courses; 2) pharmacology course content emphasis is similar among schools; 3) the number of contact hours in pharmacology has remained stable over the past three decades; 4) recent curricular changes were often directed towards enhancing the integrative and clinically relevant aspects of pharmacology instruction; and 5) a trend toward innovative content delivery, such as use of computer-assisted instruction applications, is evident. Data, derived from this study, may be useful to pharmacology course directors, curriculum committees, and other dental educators with an interest in integrative and interprofessional education. PMID- 23929572 TI - Consensus training: an effective tool to minimize variations in periodontal diagnosis and treatment planning among dental faculty and students. AB - Considerable disagreements and variations exist in diagnosis and treatment planning of periodontal disease. Achieving high interrater periodontal diagnosis can prove challenging. The objectives of this study were to measure variations in periodontal diagnosis and treatment planning among predoctoral periodontics faculty members after consensus training and to compare such variation with those identified in third- and fourth-year dental students. Nine electronically stored case vignettes and survey instruments were made available to eighteen faculty members and twenty dental students under standardized conditions. A chi-square test was used to compare responses between groups, and multirater kappa tests were used to evaluate interrater agreement/reliability. Of the nine cases, only one differed between groups significantly in terms of treatment. Also, third-year students differed from fourth-year students on the diagnosis of aggressive periodontitis versus chronic periodontitis. Most respondents were able to distinguish clearly among diagnoses of chronic periodontitis, aggressive periodontitis, and gingivitis. This study established a baseline assessment of the current status of consensus after training. We will reassess variations after addressing the specific challenges identified. Programs designed and implemented to help decrease the variation in periodontal diagnosis and treatment planning among faculty members may ultimately translate into better agreement and better standardization of dental instruction. PMID- 23929573 TI - An office-based emergencies course for third-year dental students. AB - Although uncommon, medical emergencies do occur in the dental office setting. This article describes the development and implementation of an office-based emergencies course for third-year dental students. The course reviews the basic management of selected medical emergencies. Background information is provided that further highlights the importance of proper training to manage medical emergencies in the dental office. Details regarding course development, implementation, logistics, and teaching points are highlighted. The article provides a starting point from which dental educators can modify and adapt this course and its objectives to fit their needs or resources. This is a timely topic that should benefit both dental students and dental educators. PMID- 23929574 TI - Cultivating professional responsibility in a dental hygiene curriculum. AB - To prepare dental hygienists for future roles in the health care system, dental hygiene education must prepare graduates with skills, ethics, and values that align with professional responsibility. The objective of this study was to determine the effectiveness of curricular changes designed to develop professional identity and responsibility over the entire span of the dental hygiene curriculum. Twenty-four dental hygiene students at the University of Minnesota were surveyed about their attitudes toward access to dental care, society's and health professionals' responsibility to care for the underserved, and their personal efficacy to provide care for the underserved. Surveys were conducted at three time points in the curriculum. The Attitudes Toward Health Care instrument adapted by Holtzman for dental use was used to survey the students. The findings indicate that this institution's curricular changes were effective in cultivating professional responsibility among these students. Their attitude scores increased across the six-semester curriculum, and students in their last semester of the program believed that all individuals have a right to dental care and that society has an obligation to provide dental care. These students' sense of obligation to care for the needy became stronger and their perceptions of their own ability to impact the community and act as an agent of change also increased. PMID- 23929575 TI - Perceptions and practices of U.S. dental schools regarding curriculum integrated format and traditional format licensure exams. AB - The dental licensure exam in the United States has evolved over the past ten years, and two formats-the traditional format and curriculum integrated format are now available for students to satisfy licensure requirements. The objective of this study was to examine the differences and relative merits of the two formats. A twenty-five-question survey was distributed to the fifty-seven U.S. dental schools at the time. The survey included both quantitative and discrete variables and followed a strategic sequential order. The first set of questions sought to determine what type of board preparatory/mock exam each dental school offered, and the next set of questions asked which licensure exam each school formally offered. The final questions were qualitative in nature and aimed to determine the school representatives' opinions about the curriculum integrated format versus traditional format. Of the fifty-seven schools contacted, thirty seven agreed to participate (response rate=64.9 percent). Fourteen schools reported that they administer the traditional format only and twelve administer the curriculum integrated format only, while eleven offer both. Thirty-two schools offered mock board exams to their graduating students, and twenty-four of those said their mock exams were identical in format to the actual qualifying clinical exams offered at their institution. The respondents reported no significant advantage to preparing for the curriculum integrated format examination as compared to the traditional format examination with regards to number of clock hours taken from regular curriculum time. In reporting on this study, this article provides an overview of the relative advantages and disadvantages of the two examination formats used for the dental licensure process in the United States. PMID- 23929576 TI - Effect of an enrichment program on DAT scores of potential dental students from disadvantaged backgrounds. AB - The objectives of this study were to explore whether Dental Admission Test (DAT) training in an enrichment program for potential dental students increases the participants' Perceptual Achievement Test (PAT) and academic average (AA) scores and whether the length of the program and personal factors such as the number of disadvantages correlate with the DAT scores. Data were collected from 361 students in the summer enrichment program at one dental school between 1994 and 2011. Their baseline, midpoint, and end of program PAT and AA DAT scores were collected. Seventy students self-reported official scores. These students' PAT scores increased from 14.40 at baseline to 17.09 at midpoint to 17.84 at program end (p<0.001), and their AA scores increased from 13.53 to 14.09 to 15.12 (p<0.001). Their official scores were higher than the beginning scores (PAT: 14.42 vs. 16.15; p<0.001; AA: 13.61 vs. 16.23; p<0.001). The longer the program, the more the students improved their official scores (PAT: r=0.35; p=0.003; AA: r=0.24; p=0.044). The more disadvantages the students self-reported, the better their official test scores were (PAT: r=0.40; p<0.001; AA: r=0.43; p<0.001). This study found that the DAT training during summer enrichment programs for students from disadvantaged backgrounds led to significant improvements in their DAT scores. The longer the programs, the more the students improved; and the more disadvantages the students had, the more they benefitted. PMID- 23929577 TI - Assessment of tobacco dependence curricula in Italian dental hygiene schools. AB - The aim of this study was to assess the level of tobacco dependence education offered by Italian dental hygiene programs. A fifty-question survey was mailed to the thirty-one active public and private dental hygiene programs in Italy during the 2008-09 academic year. The survey assessed faculty confidence in teaching tobacco treatment, which courses contained tobacco dependence content, the number of minutes spent on specific content areas, and the level of clinical competence that dental hygiene graduates should be able to demonstrate. Surveys were returned by sixteen programs for a response rate of 52 percent. Respondents indicated tobacco dependence education was included in clinic or clinic seminar (56 percent), periodontics (44 percent), oral pathology (31 percent), and prevention (19 percent). All programs reported including the effects of tobacco on general and oral diseases in courses. However, more in-depth topics received less curriculum time; these included tobacco treatment strategies (63 percent) and discussion of cessation medications (31 percent). Interestingly, 62 percent of the respondents indicated they expected dental hygiene graduates to demonstrate a tobacco treatment competency level of a moderate intervention or higher (counseling, discussion of medications, follow-up) rather than a brief intervention in which patients are advised to quit then referred to a quitline. The results of this study indicated that Italian dental hygiene students are not currently receiving adequate instruction in tobacco treatment techniques nor are they being adequately assessed. This unique overview of Italian dental hygiene tobacco dependence education provides a basis for further discussion towards a national competency-based curriculum. PMID- 23929578 TI - Critical appraisal-based learning in a dental college in India: a randomized control study. AB - This study examined the effect of critical appraisal exercises on the quality of preclinical tooth preparation skills and the confidence level of undergraduate dental students at a dental college in India. Forty-two student volunteers were randomly divided into critical appraisal (CA; n=19) and control (C; n=23) groups. Both groups were given conventional lecture and video demonstration; the CA group was also given critical appraisal exercises. Four evaluators assessed the incisor, canine, premolar, and molar preparations made by all students. The mean overall scores (reported as mean+/-SD) assigned to the CA group by all evaluators were significantly higher (independent t-test, p<0.05) than the C group for incisor (CA: 6.19+/-1.47, C: 5.09+/-1.52), canine (CA: 5.64+/-1.36, C: 4.50+/ 1.35), premolar (CA: 5.88+/-1.03, C: 4.88+/-1.18), and molar (CA: 5.98+/-1.16, C: 5.20+/-0.71) teeth. The CA group also demonstrated a significant increase in self confidence over that of the C group (repeated measures general linear model F=8.554, p=0.006). In this study, the critical appraisal exercises significantly improved the preclinical incisor, canine, premolar, and molar tooth preparation skills and the confidence level of the undergraduate dental students. PMID- 23929579 TI - Performance of experienced dentists in Switzerland after an e-learning program on ICDAS occlusal caries detection. AB - This study aimed to evaluate the effect of an e-learning program on the validity and reproducibility of the International Caries Detection and Assessment System (ICDAS) in detecting occlusal caries. For the study, 170 permanent molars were selected. Four dentists in Switzerland who had no previous contact with ICDAS examined the teeth before and after the e-learning program and scored the sites according to ICDAS. Teeth were histologically prepared and assessed for caries extension. The significance level was set at 0.05. Sensitivity before and after the e-learning program was 0.80 and 0.77 (D1), 0.72 and 0.63 (D2), and 0.74 and 0.67 (D3,4), respectively. Specificity was 0.64 and 0.69 (D1), 0.70 and 0.81 (D2), and 0.81 and 0.87 (D3,4). A McNemar test did not show any difference between the values of sensitivity, specificity, accuracy, and area under the ROC curve (AUC) before and after the e-learning program. The averages of wK values for interexaminer reproducibility were 0.61 (before) and 0.66 (after). Correlation with histology presented wK values of 0.62 (before) and 0.63 (after). A Wilcoxon test showed a statistically significant difference between before and after the e-learning program. In conclusion, even though ICDAS performed well in detecting occlusal caries, the e-learning program did not have any statistically significant effect on its performance by these experienced dentists. PMID- 23929580 TI - Communication skills course in an Indian undergraduate dental curriculum: a randomized controlled trial. AB - This study assessed the impact of a course on communication skills for third-year undergraduate dental students at a dental institute in India. A randomized pretest, posttest controlled trial was conducted with all the students from four cohorts of third-year dental undergraduate students, divided into an intervention group (n=30) and a control group (n=30). The course was developed using Kern's six-step approach to curriculum development. Needs assessment was ascertained, and readings, lectures, and role-plays with real and simulated patients were implemented. Encounters of students during two patient interviews (simulated and real) were rated by two raters using a twenty-seven-item dental consultation communication checklist with a rating scale 0 to 3. Students completed a questionnaire regarding their acceptance of the course. A 2*2 (group * time) ANOVA with group as a between-subjects factor (control vs. experimental) and time as a within-subjects factor (pre vs. post) was performed. The two groups did not differ at pretest but differed significantly at posttest. This study showed that simply attending to patients during a clinical course did not improve professional communication skills. In contrast, the implementation of a course on communication skills did improve the students' dentist-patient interactions. Integrating the teaching and development of a relevant, outcome-based course on communication skills provided clear evidence of communication skills acquisition among these dental students. The course could be introduced in other Indian dental schools. PMID- 23929581 TI - Modulation of multiple memory systems: from neurotransmitters to metabolic substrates. AB - This article reviews evidence showing that neurochemical modulators can regulate the relative participation of the hippocampus and striatum in learning and memory tasks. For example, relative release of acetylcholine increases in the hippocampus and striatum reflects the relative engagement of these brain systems during learning of place and response tasks. Acetylcholine release is regulated in part by available brain glucose levels, which themselves are dynamically modified during learning. Recent findings suggest that glucose acts through astrocytes to deliver lactate to neurons. Brain glycogen is contained in astrocytes and provides a capacity to deliver energy substrates to neurons when needed, a need that can be generated by training on tasks that target hippocampal and striatal processing mechanisms. These results integrate an increase in blood glucose after epinephrine release from the adrenal medulla with provision of brain energy substrates, including lactate released from astrocytes. Together, the availability of peripheral and central energy substrates regulate the processing of learning and memory within and across multiple neural systems. Dysfunctions of the physiological steps that modulate memory--from hormones to neurotransmitters to metabolic substrates--may contribute importantly to some of the cognitive impairments seen during normal aging and during neurodegenerative diseases. PMID- 23929582 TI - Supramolecular hydrogel capsules based on PEG: a step toward degradable biomaterials with rational design. AB - Supramolecular microgel capsules based on polyethylene glycol (PEG) are a promising class of soft particulate scaffolds with tailored properties. An approach to fabricate such particles with exquisite control by droplet-based microfluidics is presented. Linear PEG precursor polymers that carry bipyridine moieties on both chain termini are gelled by complexation to iron(II) ions. To investigate the biocompatibility of the microgels, living mammalian cells are encapsulated within them. The microgel elasticity is controlled by using PEG precursors of different molecular weights at different concentrations and the influence of these parameters on the cell viabilities, which can be optimized to exceed 90% is studied. Reversion of the supramolecular polymer cross-linking allows the microcapsules to be degraded at mild conditions with no effect on the viability of the encapsulated and released cells. PMID- 23929583 TI - Breeding for seedless grapes using Chinese wild Vitis spp. II. In vitro embryo rescue and plant development. AB - BACKGROUND: Since 1982, the embryo rescue technique has been widely applied to embryo germination of stenospermic grapes in cross-breeding programmes. This project aimed to: (1) use embryos to breed new seedless cultivars of Vitis vinifera as the female parents utilising wild Chinese Vitis spp. as the male parents; and (2) develop an efficient method for in vitro embryo rescue and plant development. RESULTS: Among the different genotypes, the productions of hybrid plants were significantly different, ranged from 21.1% ('Ruby Seedless' * 'Beichun') to only 1.1% ('Pink Seedless' * 'Beichun'), except for the combinations from which no surviving seedlings were obtained. We collected hybridisation fruits from 28 June to 3 August, and obtained their best sampling times described within days after flowering. The highest rates of embryo formation (24.3%) and plant development (91.4%) were found when ovules of 'Ruby Seedless' were cultured in MM4 + 500 mg L(-1) mashed banana. CONCLUSION: Seven new hybrids of V. vinifera with wild Chinese Vitis spp. were obtained. As a result of early nuclear-free character identification, 17 seedless grape lines were obtained. An efficient system of seedless grape breeding through embryo rescue was also established. PMID- 23929585 TI - An extensive proteome map of tomato (Solanum lycopersicum) fruit pericarp. AB - Tomato (Solanum lycopersicum) is the model species for studying fleshy fruit development. An extensive proteome map of the fruit pericarp is described in light of the high-quality genome sequence. The proteomes of fruit pericarp from 12 tomato genotypes at two developmental stages (cell expansion and orange-red) were analyzed. The 2DE reference map included 506 spots identified by nano-LC/MS and the International Tomato Annotation Group Database searching. A total of 425 spots corresponded to unique proteins. Thirty-four spots resulted from the transcription of genes belonging to multigene families involving two to six genes. A total of 47 spots corresponded to a mixture of different proteins. The whole protein set was classified according to Gene Ontology annotation. The quantitative protein variation was analyzed in relation to genotype and developmental stage. This tomato fruit proteome dataset is currently the largest available and constitutes a valuable tool for comparative genetic studies of tomato genome expression at the protein level. All MS data have been deposited in the ProteomeXchange with identifier PXD000105. PMID- 23929586 TI - Strong intermolecular interactions shaping a small piano-stool complex. PMID- 23929584 TI - Genetic susceptibility to chronic otitis media with effusion: candidate gene single nucleotide polymorphisms. AB - OBJECTIVES/HYPOTHESIS: The genetic factors leading to a predisposition to otitis media are not well understood. The objective of the current study was to develop a tag-single nucleotide polymorphism (SNP) panel to determine if there is an association between candidate gene polymorphisms and the development of chronic otitis media with effusion. STUDY DESIGN: A 1:1 case/control design of 100 cases and 100 controls was used. The study was limited to the chronic otitis media with effusion phenotype to increase the population homogeneity. METHODS: A panel of 192 tag-SNPs was selected. Saliva for DNA extraction was collected from 100 chronic otitis media with effusion cases and 100 controls. After quality control, 100 case and 79 control samples were available for hybridization. Genomic DNA from each subject was hybridized to the SNP probes, and genotypes were generated. Quality control across all samples and SNPs reduced the final SNPs used for analysis to 170. Each SNP was then analyzed for statistical association with chronic otitis media with effusion. RESULTS: Eight SNPs from four genes had an unadjusted P value of <.05 for association with the chronic otitis media with effusion phenotype (TLR4, MUC5B, SMAD2, SMAD4); five of these polymorphisms were in the TLR4 gene. CONCLUSIONS: Even though these results need to be replicated in a novel population, the presence of five SNPs in the TLR4 gene having association with chronic otitis media with effusion in our study population lends evidence for the possible role of this gene in the susceptibility to otitis media. PMID- 23929587 TI - Bariatric surgery influences the number and quality of oocytes in patients submitted to assisted reproduction techniques. AB - OBJECTIVE: To determine differences in follicle stimulation, oocyte retrieval, maturation, and fertilization among patients who underwent bariatric surgery, obese patients, and patients with 18 < BMI < 30 kg/m2 submitted to assisted reproduction techniques and check that these patients may have some impairment in ovarian response. METHODS: The study comprised three groups: GI: 29 patients who had undergone restrictive and/or malabsorptive bariatric surgery; GII: 57 obese patients (BMI > 30 kg/m2); and GIII: 94 patients (18 < BMI < 30 kg/m2) with infertility due to a male factor. BMI, weight loss until oocyte retrieval, vitamin supplementation, and anemia were evaluated. Data were compared with the number of follicles observed, the number of oocytes retrieved, and the maturation status of these oocytes. Results were analyzed statistically. RESULTS: A statistically significant difference in the number of follicles observed by ultrasound (P < 0.01), the number of oocytes retrieved (P = 0.013), and the number of metaphase II oocytes (P < 0.01) between the patients with prior bariatric surgery and both GII and GIII group was found. CONCLUSIONS: The weight loss resulting from bariatric surgery can be very beneficial to the overall health of the woman, but the reproductive process can be impaired. Bariatric surgery appears to have an important impact on the formation of follicles and oocytes. PMID- 23929588 TI - Two cases of placental T21 mosaicism: challenging the detection limits of non invasive prenatal testing. PMID- 23929589 TI - Replacing tracheostomy with overnight intubation to manage the airway in head and neck oncology patients: towards an improved recovery. AB - In maxillofacial head and neck oncology, tracheostomy is often used to secure the airway, but not without risk. This study compared the existing practice of two units: one where tracheostomy was routinely done with one where overnight intubation was used. From both units we retrospectively analysed 50 consecutive patients who had intraoral resection, neck dissection, and microvascular reconstruction for head and neck cancer. When compared with tracheostomy, overnight intubation resulted in a shorter mean stay in the intensive therapy unit (ITU) (1.4 compared with 3.7 days), a shorter overall hospital stay (12.9 compared with 18.0 days), less time to first oral intake (8.9 compared with 12.8 days), and a lower rate of lower respiratory tract infection (LRTI) (10% compared with 38%). This study supports the discontinuation of routine tracheostomy and the adoption of a more selective practice to improve recovery. PMID- 23929590 TI - The relationship between subjective experiences during first use of tobacco and cannabis and the effect of the substance experienced first. AB - INTRODUCTION: We examined the positive and negative subjective feelings associated with initial tobacco and cannabis use as well as the role of these experiences in regular use. Additionally, we investigated the effect of the first substance experienced on initial subjective experiences and later regular use. METHODS: Baseline data from a representative sample of young Swiss men were obtained from an ongoing Cohort Study on Substance Use Risk Factors, which includes 2,321 lifetime tobacco and cannabis users. We assessed the age of first tobacco and cannabis use along with the subjective experiences associated with initial use. Additionally, subjective experiences related to regular use of both substances were analyzed. RESULTS: The initial subjective experiences were divided into positive and negative for each substance, and we found that the feelings associated with first use of tobacco and cannabis were similar. Moreover, the participants who used cannabis before tobacco reported fewer negative experiences associated with first tobacco use, whereas the participants who initially used tobacco reported more negative experiences related to first cannabis use. Also, we identified that regular use was encouraged by positive experiences and that negative experiences were more adverse for regular use of cannabis compared with tobacco. CONCLUSIONS: Taken together, these results indicate that similar subjective experiences were associated with the first use of tobacco and cannabis. Also, the use of cannabis before tobacco, which occurred in only a minority of users, had the potential to enhance the effects of initial tobacco use. PMID- 23929591 TI - Role of the Listeria monocytogenes 2-Cys peroxiredoxin homologue in protection against oxidative and nitrosative stress and in virulence. AB - Peroxiredoxins contribute to protection of some bacteria against reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates (RNIs). Listeria monocytogenes, a facultative intracellular bacterial pathogen, interacts with ROIs and RNIs during infection. In this study, we investigated the involvement of the 2-Cys peroxiredoxin (Prx) homologue in L. monocytogenes in the protection against ROIs and RNIs and in virulence through the construction of an in-frame prx deletion mutant. The Deltaprx mutant had increased sensitivity to hydrogen peroxide and cumene hydroperoxide compared to the wild-type strain. The mutant also exhibited an increased susceptibility to the nitric oxide-generating compound S-nitroso-N-acetylpenicillamine (SNAP) and 3-morpholinosydnonimine hydrochloride (SIN-1), a peroxynitrite donor. Furthermore, a diminished virulence of the Deltaprx mutant relative to the wild-type was observed in C57BL/6 mice, but not in inducible nitric oxide synthase-deficient mice. The results suggest that Prx protects L. monocytogenes against oxidative and nitrosative stress in vitro and in vivo and that the prx-encoded polypeptide thereby is involved in L. monocytogenes virulence. PMID- 23929592 TI - Bevacizumab for refractory adverse radiation effects after stereotactic radiosurgery. AB - To retrospectively evaluate the clinical benefit and imaging response of bevacizumab when used to treat refractory adverse radiation effects (ARE) after stereotactic radiosurgery. Twenty-nine patients with brain tumors or vascular malformations developed clinical and/or imaging evidence of ARE after SRS and were treated using bevacizumab. Patients received an average dose of 7.4 mg/kg over a mean of 5.7 weeks at a median of 16 months following SRS. Initial diagnosis, SRS dose, bevacizumab treatment protocols, magnetic resonance imaging T2/FLAIR and T1 paramagnetic contrast enhanced edema volumes were compared before and after bevacizumab administration. Ninety percent (18/20) with clinically symptomatic ARE had neurological improvement after bevacizumab therapy. Twenty six patients had a decrease of 62 % of T2/FLAIR volumes and a 50 % decrease in magnetic resonance imaging intravenous contrast enhancement volumes. Two patients showed progression of the T2/FLAIR and contrast enhancement volumes. One patient had progression of post-Gd-enhancement but regression of T2/FLAIR volume. Symptoms recurred in 11 of the 20 patients after discontinuing therapy. Patients who experienced a return of enhancement received a lower marginal dose during SRS. Our experience provides additional evidence that bevacizumab reduces both symptoms and reactive imaging changes in patients with ARE. After SRS, refractory ARE unresponsive to initial corticosteroids or other agents may benefit from a bevacizumab trial. The necessary duration and optimum dose of therapy is unknown and provides a further impetus to conduct a prospective trial. PMID- 23929593 TI - Mediterranean diet: Relationship with anxiety and depression. PMID- 23929594 TI - Hippocampus and striatum: dynamics and interaction during acquisition and sleep related motor sequence memory consolidation. AB - While several models of memory consolidation have previously associated hippocampal activity with declarative memory, there is now increasing evidence that the hippocampus also plays a crucial role in procedural memory. Here, we review recent human functional neuroimaging studies demonstrating that the hippocampus is involved in the acquisition and sleep-related consolidation of procedural memories, and motor sequence-based skills in particular. More specifically, we present evidence that hippocampal activity and its functional interactions with other brain structures, particularly competition with the striatum, contribute to initial learning of sequential motor behavior. Interestingly, these early cerebral representations in the hippocampus and striatum, which may interact through the prefrontal cortex, can even predict subsequent sleep-related memory consolidation processes. We propose that sleep can reorganize the activity within, as well as the functional interactions between, these structures, ultimately favoring overnight performance enhancement. Finally, we conclude by offering insights into the respective roles of these structures in procedural memory consolidation processes. We argue that, in the context of motor sequence memory consolidation, the hippocampal system triggers subsequent sleep-dependent performance enhancement whereas the striatal system is involved in the maintenance of the motor behavior over time. PMID- 23929595 TI - Botryoid-shaped reactive nanoparticles through spontaneous structural reorganization of terpolymer micelles. AB - Botryoid-shaped reactive terpolymer nanoparticles, whose aldehyde-functional living domains are miniaturized into small-sized discrete "grapes" and attached onto the outwardly-branched scaffolds of fluorinated segments, are reported. These nanostructures can be fabricated by spontaneous structural reorganization of core-shell terpolymer micelles simply by manipulating drying conditions. The miniaturized discrete living domains are stabilized by outwardly-branched scaffolds and exhibit excellent accessibility to solution media, thus can effectively respond to solution media, which is desired in sensor-related applications. PMID- 23929596 TI - A synthesis of the chlorosulfolipid mytilipin A via a longest linear sequence of seven steps. AB - Magnificent seven: The chlorosulfolipid mytilipin A was synthesized in racemic form in seven steps and in enantioenriched form in eight steps. Key transformations include a highly diastereoselective bromoallylation of a sensitive alpha,beta-dichloroaldehyde, a kinetic resolution of a vinyl epoxide, a convergent and highly Z-selective alkene cross-metathesis, and a chemoselective and diastereoselective dichlorination of a complex diene. PMID- 23929597 TI - Functional regeneration of laryngeal muscle using bone marrow-derived stromal cells. AB - OBJECTIVES/HYPOTHESIS: To investigate the functional efficiency of skeletal muscles regenerated by transplantation of bone marrow-derived stromal cells (BSCs) or induced-muscle progenitor cells (IMCs) as assessed in the canine posterior cricoarytenoid (PCA) muscle injury model. STUDY DESIGN: Prospective animal experiment with control. METHODS: We performed BSC/IMC transplantation into injured canine PCA muscles. We investigated the capability of auto- and allo BSC/IMC transplantation using a gelatin sponge scaffold to promote functional regeneration of PCA muscles. Transplantation was assessed by fiberscopic analysis of vocal fold movement. We also examined the histologic changes of the transplanted regions. As a control, a gelatin sponge scaffold without additional cells was transplanted into the injured area. RESULTS: Auto-BSC/IMC transplantation effectively restored vocal fold movement, whereas scaffold alone or allo-BSC/IMC transplantation did not. Histologic examination revealed that (in cases of good recovery) muscle regeneration occurred in the area of cell transplantation, and scar formation without muscle regeneration was observed under control conditions. The dogs with autologous transplantation of BSC had faster functional recovery than did dogs treated with autologous transplantation of IMC. CONCLUSIONS: Functional efficiency was shown in skeletal muscles regenerated using BSCs and IMPs. Motor function recovery was observed using autologous transplantation of BSCs and IMCs. Minimal functional recovery was observed using allogeneic transplantation of these cells. PMID- 23929598 TI - The nasopharyngeal tube: a simple and effective tool to indicate the need for uvulopalatopharyngoplasty. AB - OBJECTIVES/HYPOTHESIS: To compare polysomnography (PSG) data after nasopharyngeal tube (NPT) insertion and uvulopalatopharyngoplasty (UPPP), and explore the possibility of predicting UPPP outcomes with NPT-PSG. STUDY DESIGN: Prospective nonrandomized study. METHODS: PSG was performed after NPT insertion in 73 inpatients with obstructive sleep apnea-hypopnea syndrome (OSAHS). All patients accepted UPPP surgery. PSG was repeated after 12 months of UPPP to assess curative effects. Data were then compared to correlate NPT-PSG with the efficacy of UPPP. RESULTS: NPT insertion decreased the overall apnea-hypopnea index (AHI) and increased the lowest oxygen saturation (LaSO2 ). NPT-PSG results correlated well with surgical outcomes 12 months post-UPPP. The correlation coefficient for AHI and LaSO2 were 0.571 (P < .001) and 0.268 (P = .033), respectively. Next, enrolled patients were divided into two groups based on NPT-PSG results: group A, AHI <15 times/hr, 50 cases; group B, AHI >=15 times/hr, 23 cases. The UPPP surgery success rates of the two groups were 86.0% and 39.1%, respectively. CONCLUSIONS: NPT-PSG data are closely correlated with UPPP efficacy and may assist in the selection of appropriate OSAHS patients for UPPP. An AHI >=15 times/hr after NPT insertion indicates glossopharyngeal obstruction and suggests the need for appropriate intervention. LEVEL OF EVIDENCE: 4. PMID- 23929600 TI - School lunch debit card payment systems are associated with lower nutrition and higher calories. AB - OBJECTIVE: Debit card payment systems are known to induce more frivolous purchases in adults, but their impact on children is unknown. DESIGN AND METHODS: Using a national survey of 2,314 public school students in the United States, food purchases in schools with debit-only systems to those in schools with both debit and cash options are compared. RESULTS: Students in debit and cash schools purchase more fresh fruit and vegetables and fewer total calories. CONCLUSIONS: Payment systems with cash options have a lower purchase incidence of less healthy foods and higher purchase incidence of more healthy foods. PMID- 23929599 TI - Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia. AB - FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL 3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan-Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients. PMID- 23929601 TI - Who bought the drinks? Juror perceptions of intoxication in a rape trial. AB - In this study, the perceptions of victim intoxication and the drinking context (i.e., who purchased the drinks) were investigated. Men and women mock jurors (N = 158) read a rape trial summary in which the victim was intoxicated or sober, and either the victim or the perpetrator purchased the drinks. Overall, participants who perceived a victim as intoxicated were less likely to render guilty verdicts and made lower ratings of victim credibility. In addition, when the perpetrator purchased the drinks, participants were more likely to render guilty verdicts and made more negative judgments about the defendant than when the victim bought the drinks. Mediation analyses explained the relationship between the independent variables and verdict. The results are discussed in terms of the factors that influence juror perceptions of rape cases in court. PMID- 23929602 TI - Victimization experiences, substance misuse, and mental health problems in relation to risk for lethality among African American and African Caribbean women. AB - The purpose of this study was to investigate the association of intimate partner victimization experiences, mental health (MH), and substance misuse problems with the risk for lethality among women of African descent. Data for this cross sectional study were derived from a large case-control study examining the relationship between abuse status and health consequences. Women were recruited from primary care, prenatal, or family planning clinics in Baltimore and the U.S. Virgin Islands. Logistic regression was used to generate the study findings. Among 543 abused women, physical and psychological abuse by intimate partners, comorbid posttraumatic stress disorder (PTSD) and depression symptoms, and PTSD only problems significantly increased the likelihood of lethality risk. However, victims' substance misuse and depression-only problems were not associated with the risk for lethality. In addition, PTSD symptoms mediated the relationship between severe victimization experiences and risk for lethality. Practitioners should pay attention to victimization experiences and MH issues when developing treatment and safety plans. Policies to fund integrated services for African American and African Caribbean women with victimization and related MH issues, and training of providers to identify at-risk women may help reduce the risk for lethality in intimate partner relationships. PMID- 23929603 TI - Evaluation of liver disease progression in the German hepatitis C virus (1b) contaminated anti-D cohort at 35 years after infection. AB - The natural course of HCV infection remains controversial. The German HCV (1b) contaminated anti-D cohort provides an ideal population to investigate the natural course of HCV infection in a large, homogenous cohort of young women from the date of HCV inoculation. Our previous follow-up studies at 20 and 25 years after infection suggested slow fibrosis progression rates in this unique cohort. The aim of our prospective, community-based, multicenter study was to reevaluate the liver disease progression in 718 patients of the original anti-D cohort at 35 years after infection. Patients with self-limited HCV infection (n = 189) were compared to those who failed to eliminate the virus spontaneously (n = 529), comprising patients who were treatment naive (n = 197) or achieved a sustained virological response (SVR; n = 149), respectively, failed to clear the virus (non SVR; n = 183) after antiviral therapy. In the overall cohort, 9.3% of patients showed clinical signs of liver cirrhosis at 35 years after infection. Liver disease progression largely depended on HCV infection status. The highest proportion of patients with clinical signs of end-stage liver disease was observed in the non-SVR group (15.3%), whereas decreased cirrhosis rates were detected in the SVR group (6%) and in patients with self-limited HCV infection (1.1%; P = 6.2 * 10(-6)). Overall survival was significantly enhanced after SVR, compared to treatment-naive patients or non-SVR (P = 0.027). CONCLUSION: The present study provides further evidence for a mild, but significant, disease progression at 35 years after infection in the German HCV (1b)-contaminated anti D cohort. Patients with self-limited HCV infection or SVR after antiviral treatment were protected from progressive liver disease and showed the best clinical long-term outcome. PMID- 23929604 TI - Mycobacterium tuberculosis escapes from the phagosomes of infected human osteoclasts reprograms osteoclast development via dysregulation of cytokines and chemokines. AB - Spinal tuberculosis is a condition characterized by massive resorption of the spinal vertebrae due to the infection with Mycobacterium tuberculosis (Mtb). However, the pathogenesis of spinal tuberculosis has not been established because it was almost completely eradicated by the establishment of antibiotic treatment in the mid-20th century. In this study, we investigated the inflammatory responses of human multinucleated osteoclasts infected with virulent Mtb strain. We found that the intracellular Mtb infection of multinuclear osteoclasts resulted in the rapid growth of Mtb and an osteolytic response, rather than inflammation. In response to Mtb infection, the mononuclear osteoclast precursors produced proinflammatory cytokines including tumor necrosis factor (TNF)-alpha, an intrinsic characteristic they share with macrophages. In contrast, highly fused multinucleated osteoclasts incapacitated the production of these cytokines. Instead, the intracellular Mtb inside multinuclear osteoclasts escaped from the endosome/phagosome, leading to a different pattern of osteoclast activation, with the production of chemokines such as CCL5, CCL17, CCL20, CCL22, CCL24, and CCL25. Moreover, intracellular infection with an avirulent Mtb strain resulted in diminished production of these chemokines. These findings indicate that intracellular Mtb infection in multinuclear osteoclasts reprograms osteoclast development via the dysregulation of cytokines and chemokines. PMID- 23929605 TI - Empty scrotum: undescended testis or ectopic? AB - This case of ectopic testis highlights the importance of a thorough first newborn examination followed by senior review when appropriate, and the expertise required to interpret neonatal ultrasounds. Following a provisional diagnosis of unilateral undescended testicle in a newborn, an ultrasound scan was unable to correctly identify the condition, resulting in a delay in diagnosis. The condition was later recognised incidentally, which led to a successful surgical correction. The early clinical examination and recognition of ectopic testis allows a timely surgical intervention preventing potential complications. PMID- 23929606 TI - Avulsion fracture of the anterior cruciate ligament in a 9-year-old child. PMID- 23929607 TI - Fatal migration of an endobronchial stent into the pulmonary artery. PMID- 23929608 TI - Peripheral osteoma of the body of mandible. AB - Osteoma is a benign osteogenic neoplasm microscopically consisting of proliferation of cancellous or compact bone. Peripheral osteomas (PO) arise from the periosteum and are quite uncommon in the jaw bones. POs of mandible are considered as rare entity and very few cases have been reported in the literature. The pathogenesis of PO is unclear. Some investigators consider it a true neoplasm, while others believe it as a developmental anomaly, a reactive mechanism due to trauma or infection. The purpose of this article is to present the clinical, radiographic, surgical and histological features of a solitary peripheral osteoma of the mandible in a 43-year-old woman and to review the literature for PO located in the mandible. PMID- 23929609 TI - Preoperative L1 and L2 paravertebral block is an effective postoperative analgesia for hip arthroscopy in a multimodal analgesic regimen. AB - We describe the case of a 30-year-old woman with chronic hip pain secondary to avascular necrosis. She received preoperative L1-L2 paravertebral block for postoperative pain control after arthroscopic hip surgery. Preoperative paravertebral block at the level of L1-L2 provided an effective postoperative analgesia for hip arthroscopy when used in a multimodal approach. PMID- 23929610 TI - The 'gap' in the 'plasma osmolar gap'. AB - Ethylene glycol poisoning is a medical emergency that presents challenges for clinicians and clinical laboratories. If left untreated, it may cause morbidity and death, but effective therapy is available if diagnosed in time. The diagnosis of ethylene glycol poisoning is not always straightforward and the commonly quoted 'plasma osmolar gap' is not sufficiently sensitive to exclude a small ingestion and has been reported to be normal in a number of serious exposures. The 'plasma osmolar gap' cannot distinguish among ethanol, isopropyl alcohol, methanol or ethylene glycol. Thus, the measurement of serum ethylene glycol and, ideally, glycolic acid, its major toxic metabolite in serum, is definitive. This also holds true for methanol and its metabolite formic acid. Ethylene glycol metabolites target the kidney and lead to reversible oliguric or anuric injury, which in turn slows the elimination of ethylene glycol. The therapeutic options include reversal of metabolic acidosis, inhibition of alcohol dehydrogenase and early haemodialysis. PMID- 23929611 TI - Tattoo pigment in axillary lymph node mimicking calcification of breast cancer. AB - A tattoo is defined as the intentional or accidental deposit of pigment into the skin. The phenomenon of skin tattooing is on the rise worldwide and complications of tattooing are increasingly being recognised in diagnostic and clinical medicine. We describe a case of calcification-like changes on mammography resembling that of breast malignancy as a result of tattoo pigment deposition in an axillary lymph node. Recognition of such changes in routine breast screening is crucial to avoid further unnecessary invasive investigations and surgery in such patients. PMID- 23929612 TI - Immeasurable glycosylated haemoglobin: a marker for severe haemolysis. AB - Glycosylated haemoglobin (HbA1c) is a measurement commonly performed in patients with diabetes. Factors causing a change in the life span of the red blood cell (RBC) can affect the measurement of HbA1c. Thus haemolysis is an important factor that may affect the HbA1c level determination. Haemolysis has been shown to cause a falsely low HbA1c. A 62-year-old man with a history of autoimmune haemolytic anaemia was admitted for severe haemolytic anaemia and an Hb of 2.9 g/dL. HbA1c tested during hospitalisation was unrecordable due to the extremely low Hb. The patient was treated with intravenous steroids, immunoglobulin, fluids and RBC transfusions but continued to haemolyse and eventually expired. We emphasise that an extremely low HbA1c level can serve as a marker of haemolysis and an unrecordable HbA1c level may point towards fatal haemolysis. PMID- 23929613 TI - Solitary plasmocytoma of the skull. AB - A 63-year-old man presented with a 4-month history of a slowly growing soft mass at his right parieto-occipital region. Neuroradiological examinations revealed an osteolytic extradural tumour of the skull vault. The outer and inner tables of the skull were partially destroyed by the tumour, but the dura was not involved. The tumour and the invaded bone were totally removed and the skull defect was reconstructed using the outer table of the adjacent intact skull. Histopathological examination confirmed plasmocytoma. Laboratory investigations revealed no systemic myelomatosis. It is very important to differentiate solitary plasmocytoma from systemic myelomatosis since their treatment and prognosis are different. Although the prognosis of solitary plasmocytoma is good, regular follow-up examinations are required for any possibility to progress to systemic myelomatosis. PMID- 23929614 TI - Should anyone still be taking simvastatin 80 mg? AB - A 64-year-old woman who previously suffered myalgia with lower dose simvastatin was given just one high dose of simvastatin and developed rhabdomyolysis. This was a potentially life-threatening complication. Fortunately she recovered with conservative management and did not require haemofiltration. This case reminds us of the risks of statins and the caution that needs to be exercised when prescribing these medications to patients with a history of intolerances. PMID- 23929615 TI - Socioeconomic position and incidence of gastric cancer: a systematic review and meta-analysis. AB - BACKGROUND: Low socioeconomic position (SEP) has been associated with increased risks of morbidity and mortality from many diseases. We investigated the associations between gastric cancer incidence and education, occupation and income as indicators for SEP. METHODS: We searched the PubMed and EMBASE databases for studies on SEP and gastric cancer incidence published from 1966 through February 2013. We used a random-effect model to pool the risk estimates from the individual studies. The relative indexes of inequality (RIIs) with their 95% CIs were used as summary estimates. We stratified the analysis by SEP indicators, sex, country's income group, geographical area, level of adjustment for an established risk factor, publication year, study design, type of control and length of follow-up. RESULTS: Of 1549 citations, 36 studies met our inclusion criteria. We observed an increased risk of gastric cancer among the lowest SEP categories in education (RII=2.97; 95% CI 1.923 to 4.58), occupation (RII=4.33; 95% CI 2.57 to 7.29) and combined SEP (RII=2.64; 95% CI 1.05 to 6.63) compared with the highest SEP categories. Although the association between the incidence of gastric cancer and the level of income is evident, it did not reach a statistically significant level (RII=1.25; 95% CI 0.93 to 1.68). CONCLUSIONS: We found that the risk of gastric cancer incidence is higher among low SEP groups. PMID- 23929616 TI - Economic analysis of the health impacts of housing improvement studies: a systematic review. AB - BACKGROUND: Economic evaluation of public policies has been advocated but rarely performed. Studies from a systematic review of the health impacts of housing improvement included data on costs and some economic analysis. Examination of these data provides an opportunity to explore the difficulties and the potential for economic evaluation of housing. METHODS: Data were extracted from all studies included in the systematic review of housing improvement which had reported costs and economic analysis (n=29/45). The reported data were assessed for their suitability to economic evaluation. Where an economic analysis was reported the analysis was described according to pre-set definitions of various types of economic analysis used in the field of health economics. RESULTS: 25 studies reported cost data on the intervention and/or benefits to the recipients. Of these, 11 studies reported data which was considered amenable to economic evaluation. A further four studies reported conducting an economic evaluation. Three of these studies presented a hybrid 'balance sheet' approach and indicated a net economic benefit associated with the intervention. One cost-effectiveness evaluation was identified but the data were unclearly reported; the cost effectiveness plane suggested that the intervention was more costly and less effective than the status quo. CONCLUSIONS: Future studies planning an economic evaluation need to (i) make best use of available data and (ii) ensure that all relevant data are collected. To facilitate this, economic evaluations should be planned alongside the intervention with input from health economists from the outset of the study. When undertaken appropriately, economic evaluation provides the potential to make significant contributions to housing policy. PMID- 23929617 TI - Healthcare utilisation and empowerment among women in Liberia. AB - BACKGROUND: Many efforts have been undertaken to improve access to healthcare services in low-income settings; nevertheless, underutilisation persists. Women's lack of empowerment may be a central reason for underutilisation, but empirical literature establishing this relationship is sparse. METHODS: We conducted a cross-sectional study using data from the 2007 Liberia Demographic and Health Survey. Our sample included all non-pregnant women who were currently married or living with a partner (N=3925 unweighted). We used multivariate logistic regression to assess the associations between constructs derived from the Theory of Gender and Power (TGP) and healthcare utilisation. RESULTS: Two-thirds of women (65.6%) had been to a healthcare facility for herself or her children in the past 12 months. Constructs from the three major theoretical structures were associated with healthcare utilisation. Women with no education, compared with women with some education, were less likely to have been to a healthcare facility (OR=0.76; 95% CI 0.62 to 0.93) as were women who had experienced sexual abuse (OR=0.65; 95% CI 0.45 to 0.95) and women who were married (OR=0.69, 95% CI 0.54 to 0.88). Women in higher wealth quintiles, compared with women in the next lower wealth quintile, and women with more decision-making power had greater odds of having been to a healthcare facility (OR=1.22; 95% CI 1.10 to 1.36 and OR=1.10; 95% CI 1.01 to 1.20; respectively). CONCLUSIONS: Strong associations exist between healthcare utilisation and empowerment among women in Liberia, and gender imbalances are prevalent. This fundamental issue likely needs to be addressed before large-scale improvement in health service utilisation can be expected. PMID- 23929618 TI - Explaining the social patterning of lung function in adulthood at different ages: the roles of childhood precursors, health behaviours and environmental factors. AB - BACKGROUND: Lung function successfully predicts subsequent health. Although lung function is known to decline over age, little is known about changes in association with socioeconomic status (SES) throughout life, and whether explanatory factors for association vary with age or patterns for non smokers. METHODS: Analyses were based on data on 24 500 participants aged >=18 years from the 1995, 1998 and 2003 Scottish Health Surveys who were invited to provide 1 s forced expiratory volume (FEV1) and forced vital capacity (FVC) lung measurements. Sex-stratified multiple linear regression assessed lung function SES (occupational social class) associations and attenuation by covariates in three age groups (2003 data (n=7928)). RESULTS: The FEV1-SES patterns were clear (p<0.001) and constant over time. Relative to the least disadvantaged, FEV1 in the most disadvantaged was lower by 0.28 L in men and 0.20 L in women under 40 years compared with differences of 0.51 L in men and 0.25 L in women over 64 years (p(interaction)<0.001 men, p(interaction)=0.004 women). The greatest attenuation of these results was seen by height, parental social class and smoking, especially among the under 65s. Second-hand smoke exposure and urban/rural residence had some impact among older groups. Adjusting for physical activity and weight had little effect generally. Similar patterns were seen for FVC and among never smokers. CONCLUSIONS: We found cross-sectional evidence that SES disparity in lung function increases with age, especially for men. Our findings indicate that early-life factors may predict inequity during younger adulthood, with environmental factors becoming more important at older ages. PMID- 23929619 TI - The fruits of Maclura pomifera extracts inhibits glioma stem-like cell growth and invasion. AB - Glioma is the most common primary intracranial tumour. Recently, growing evidence showed that glioma possesses stem-like cells, which are thought to be chemo- and radio-resistant and believed to contribute to the poor clinical outcomes of these tumours. In this study, we found that stem-like glioma cells (CD133+) were significantly increased in neurosphere cells, which are highly invasive and resistant to multiple chemotherapeutic agents. From our natural products library, we screened 48 natural products and found one compound, Pomiferin, which was of particular interest. Our results showed that Pomiferin could inhibit cell viability, CD133+ cell population, sphere formation, and invasion ability of glioma neurosphere cells. We also found that multiple stemness-associated genes (BIM1, Nestin, and Nanog) were down-regulated by Pomiferin treatment of glioma neurosphere cells. Taken together, our results suggest that Pomiferin could kill the cancer stem-like cells in glioma and may serve as a potential therapeutic agent in the future. PMID- 23929621 TI - Dextran-based self-healing hydrogels formed by reversible diels-alder reaction under physiological conditions. AB - A dextran-based self-healing hydrogel is prepared by reversible Diels-Alder reaction under physiological conditions. Cytocompatible fulvene-modified dextran as main polymer chains and dichloromaleic-acid-modified poly(ethylene glycol) as cross-linkers are used. Both macro- and microscopic observation as well as the rheological recovery test confirm the self-healing property of the dextran-l poly(ethylene glycol) hydrogels ("l" means "linked-by"). In addition, scanning electrochemical microscopy is used to qualitatively and quantitatively in situ track the self-healing process of the hydrogel for the first time. It is found that the longitudinal depth of scratch on hydrogel surface almost completely healed at 37 degrees C after 7 h. This work represents a facile approach for fabrication of polysaccharide self-healing hydrogel, which can be potentially used in several biomedical fields. PMID- 23929620 TI - Splicing biomarkers of disease severity in myotonic dystrophy. AB - OBJECTIVE: To develop RNA splicing biomarkers of disease severity and therapeutic response in myotonic dystrophy type 1 (DM1) and type 2 (DM2). METHODS: In a discovery cohort, we used microarrays to perform global analysis of alternative splicing in DM1 and DM2. The newly identified splicing changes were combined with previous data to create a panel of 50 putative splicing defects. In a validation cohort of 50 DM1 subjects, we measured the strength of ankle dorsiflexion (ADF) and then obtained a needle biopsy of tibialis anterior (TA) to analyze splice events in muscle RNA. The specificity of DM-associated splicing defects was assessed in disease controls. The CTG expansion size in muscle tissue was determined by Southern blot. The reversibility of splicing defects was assessed in transgenic mice by using antisense oligonucleotides to reduce levels of toxic RNA. RESULTS: Forty-two splicing defects were confirmed in TA muscle in the validation cohort. Among these, 20 events showed graded changes that correlated with ADF weakness. Five other splice events were strongly affected in DM1 subjects with normal ADF strength. Comparison to disease controls and mouse models indicated that splicing changes were DM-specific, mainly attributable to MBNL1 sequestration, and reversible in mice by targeted knockdown of toxic RNA. Splicing defects and weakness were not correlated with CTG expansion size in muscle tissue. INTERPRETATION: Alternative splicing changes in skeletal muscle may serve as biomarkers of disease severity and therapeutic response in myotonic dystrophy. PMID- 23929622 TI - Circuit mechanisms of GluA1-dependent spatial working memory. AB - Spatial working memory (SWM), the ability to process and manipulate spatial information over a relatively short period of time, requires an intact hippocampus, but also involves other forebrain nuclei in both in rodents and humans. Previous studies in mice showed that the molecular mechanism of SWM includes activation of AMPA receptors containing the GluA1 subunit (encoded by gria1) as GluA1 deletion in the whole brain (gria1(-/-)) results in strong SWM deficit. However, since these mice globally lack GluA1, the circuit mechanisms of GluA1 contribution to SWM remain unknown. In this study, by targeted expression of GluA1 containing AMPA receptors in the forebrain of gria1(-/-) mice or by removing GluA1 selectively from hippocampus of mice with "floxed" GluA1 alleles (gria1(fl/fl) ), we show that SWM requires GluA1 action in cortical circuits but is only partially dependent on GluA1-containing AMPA receptors in hippocampus. We further show that hippocampal GluA1 contribution to SWM is temporally restricted and becomes prominent at longer retention intervals (>= 30 s). These findings provide a novel insight into the neural circuits required for SWM processing and argue that AMPA mediated signaling across forebrain and hippocampus differentially contribute to encoding of SWM. PMID- 23929623 TI - Autologous myoblasts attenuate atrophy and improve tongue force in a denervated tongue model: a pilot study. AB - OBJECTIVES/HYPOTHESIS: Autologous muscle-derived stem cell (MdSC) therapy is a promising treatment to restore function. No group has evaluated MdSC therapy in a denervated tongue model. The purpose of this pilot investigation was to determine the extent of autologous MdSC survival, effects on tongue muscle atrophy, maximal contractile force, and lingual pressure in a denervated ovine tongue model. STUDY DESIGN: Pilot animal experiment. METHODS: Bilateral implantable cuff electrodes were placed around the hypoglossal nerves in two Dorper cross ewes. Tensometer and high-resolution manometry (HRM) testing were performed during supermaximum hypoglossal nerve stimulation to assess baseline tongue strength. Sternocleidomastoid muscle biopsies were acquired to create autologous MdSC cultures. At 1 month, 5 * 10(8) green fluorescent protein (GFP)-labeled autologous MdSCs were injected into the partially denervated tongue. Two-months postinjection, lingual tensometer testing, HRM, and postmortem histological assessment were performed. RESULTS: GFP+ myofibers were identified in denervated tongue specimens indicating MdSC survival. Muscle fiber diameter was larger in GFP+ fibers for both tongue specimens, suggesting attenuation of muscle atrophy. Myofiber diameter was larger in GFP+ myofibers than preinjury diameters, providing evidence of new muscle formation. These myogenic changes led to a 27% increase in maximal tongue contractile force and a 54% increase in maximum base of tongue pressure in one animal. CONCLUSIONS: Autologous MdSC therapy may be a viable treatment for the partially denervated tongue, with current findings demonstrating that injected MdSCs survived and fused with tongue myofibers, with a resultant increase in myofiber diameter and an increase in tongue strength. LEVEL OF EVIDENCE: N/A. PMID- 23929624 TI - Structure-guided rational design of alpha/beta-peptide foldamers with high affinity for BCL-2 family prosurvival proteins. AB - We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported alpha/beta peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-x(L) but weakly to Mcl-1. The crystal structure of the Puma derived alpha/beta-peptide complexed to Bcl-x(L) was used as the basis for computational design of variants intended to display improved binding to Mcl-1. Molecular modelling suggested modification of three alpha residues of the original alpha/beta backbone. Individually, each substitution caused only a modest (4- to 15-fold) gain in affinity; however, together the three substitutions led to a 250-fold increase in binding to Mcl-1. These modifications had very little effect on affinity for Bcl-x(L). Crystal structures of a number of the new alpha/beta-peptides bound to either Mcl-1 or Bcl-x(L) validated the selection of each substitution. Overall, our findings demonstrate that structure guided rational design can be used to improve affinity and alter partner selectivity of peptidic ligands with unnatural backbones that bind to specific protein partners. PMID- 23929625 TI - Regulation of flavivirus RNA synthesis and capping. AB - RNA viruses, such as flaviviruses, are able to efficiently replicate and cap their RNA genomes in vertebrate and invertebrate cells. Flaviviruses use several specialized proteins to first make an uncapped negative strand copy of the viral genome that is used as a template for the synthesis of large numbers of capped genomic RNAs. Despite using relatively simple mechanisms to replicate their RNA genomes, there are significant gaps in our understanding of how flaviviruses switch between negative and positive strand RNA synthesis and how RNA capping is regulated. Recent work has begun to provide a conceptual framework for flavivirus RNA replication and capping and shown some surprising roles for genomic RNA during replication and pathogenesis. PMID- 23929626 TI - Obesity susceptibility loci and uncontrolled eating, emotional eating and cognitive restraint behaviors in men and women. AB - OBJECTIVE: Many confirmed genetic loci for obesity are expressed in regions of the brain that regulate energy intake and reward-seeking behavior. Whether these loci contribute to the development of specific eating behaviors has not been investigated. The relationship between a genetic susceptibility to obesity and cognitive restraint, uncontrolled and emotional eating was examined. METHODS: Eating behavior and body mass index (BMI) were determined by questionnaires for 1471 men and 2381 women from two US cohorts. Genotypes were extracted from genome wide scans and a genetic-risk score (GRS) derived from 32 obesity-loci was calculated. RESULTS: The GRS was positively associated with emotional and uncontrolled eating (P<0.002). In exploratory analysis, BMI-increasing variants of MTCH2, TNNI3K, and ZC3H4 were positively associated with emotional eating and those of TNNI3K and ZC3H4 were positively associated with uncontrolled eating. The BMI-increasing variant of FTO was positively and those of LRP1B and TFAP2B were inversely associated with cognitive restraint. These associations for single SNPs were independent of BMI but were not significant after multiple-testing correction. CONCLUSIONS: An overall genetic susceptibility to obesity may also extend to eating behaviors. The link between specific loci and obesity may be mediated by eating behavior but larger studies are warranted to confirm these results. PMID- 23929628 TI - Advances and challenges in treatment and prevention of ischemic stroke. AB - We review recent advances in the treatment and prevention of acute ischemic stroke, including the current state of endovascular therapy, in light of 5 randomized controlled trials published this past year. Although no benefit of endovascular therapy over intravenous (IV) recombinant tissue plasminogen activator (rt-PA) has been demonstrated, endovascular therapy is an appropriate treatment for acute ischemic stroke patients within the t-PA window who are ineligible for IV t-PA but have a large vascular occlusion. These trials reveal promises and current limitations of endovascular therapy, and comparison of reperfusion therapies remains an important area of research. One common theme is the strong association between a faster time to reperfusion, improved outcome, and reduced mortality. Primary and secondary stroke prevention trials emphasize the importance of aggressive management of medical risk factors as part of any preventative strategy. New oral anticoagulants, for example, offer cost-effective risk reduction in patients with atrial fibrillation, and may represent an opportunity for those with cryptogenic stroke. We highlight areas of unmet need and promising research in stroke, including the need to deliver proven therapies to more patients, and the need to recruit patients into clinical trials that better define the role of endovascular and other stroke therapies. Finally, improvement in strategies to recover speech, cognition, and motor function has the potential to benefit far more stroke patients than any acute stroke therapy, and represents the greatest opportunity for research in the coming century. PMID- 23929627 TI - Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression. AB - Despite activating similar signaling cascades, the type I and type III interferons (IFNs) differ in their ability to antagonize virus replication. However, it is not clear whether these cytokines induce unique antiviral states, particularly in the liver, where the clinically important hepatitis B and C viruses cause persistent infection. Here, clustering and promoter analyses of microarray-based gene expression profiling were combined with mechanistic studies of signaling pathways to dynamically characterize the transcriptional responses induced by these cytokines in Huh7 hepatoma cells and primary human hepatocytes. Type I and III IFNs differed greatly in their level of interferon-stimulated gene (ISG) induction with a clearly detectable hierarchy (IFN-beta > IFN-alpha > IFN lambda3 > IFN-lambda1 > IFN-lambda2). Notably, although the hierarchy identified varying numbers of differentially expressed genes when quantified using common statistical thresholds, further analysis of gene expression over multiple timepoints indicated that the individual IFNs do not in fact regulate unique sets of genes. The kinetic profiles of IFN-induced gene expression were also qualitatively similar with the important exception of IFN-alpha. While stimulation with either IFN-beta or IFN-lambdas resulted in a similar long lasting ISG induction, IFN-alpha signaling peaked early after stimulation then declined due to a negative feedback mechanism. The quantitative expression hierarchy and unique kinetics of IFN-alpha reveal potential specific roles for individual IFNs in the immune response, and elucidate the mechanism behind previously observed differences in IFN antiviral activity. While current clinical trials are focused on IFN-lambda1 as a potential antiviral therapy, the finding that IFN-lambda3 invariably possesses the highest activity among type III IFNs suggests that this cytokine may have superior clinical activity. PMID- 23929629 TI - Time-dependent inhibition of CYP3A4 by sertraline, a selective serotonin reuptake inhibitor. AB - Drug-drug interactions associated with selective serotonin reuptake inhibitors (SSRIs) are widely known. A major interaction by SSRIs is the inhibition of cytochrome P450 (P450)-mediated hepatic drug metabolism. The SSRI, sertraline, is also reported to increase the blood concentration of co-administered drugs. The potency of sertraline directly to inhibit hepatic drug metabolism is relatively weak compared with the other SSRIs, implying that additional mechanisms are involved in the interactions. The study examined whether sertraline produces time dependent inhibition of CYP3A4 and/or other P450 enzymes. Incubation of human liver microsomes with sertraline in the presence of NADPH resulted in marked decreases in testosterone 6beta-hydroxylation activities, indicating that sertraline metabolism leads to CYP3A4 inactivation. This inactivation required NADPH and was not protected by glutathione. No significant inactivation was observed for other P450 enzymes. Spectroscopic evaluation revealed that microsomes with and without sertraline in the presence of NADPH gave a Soret peak at 455 nm, suggesting the formation of metabolic intermediate (MI) complexes of sertraline metabolite(s) with the reduced form of P450. This is the first report indicating that sertraline produced time-dependent inhibition of CYP3A4, which may be associated with MI complex formation. PMID- 23929630 TI - Alterations in TLRs as new molecular markers of congenital infections with Human cytomegalovirus? AB - Toll-like receptors (TLRs) play a crucial role in non-specific immunity against various infections. The most common intrauterine infection, caused by Human cytomegalovirus (HCMV), results in perinatal morbidity and mortality of primary infected fetuses. The induction of immune response by TLRs was observed in HCMV infections in murine models and cell lines cultured in vitro. Studies reported an immunological response in pregnant women with primary HCMV infection and TLR2 activity in collecting of HCMV particles in placental syncytiotrophoblasts (STs) in vivo and cultured ST, and in stimulation of tumor necrosis factor (TNF)-alpha expression and damage of villous trophoblast. Expression levels of TLRs are associated with cell type, stage of pregnancy and response to microorganisms. We show the effect of HCMV infection on the development of pregnancy as well as the effect of TLR single-nucleotide polymorphisms on the occurrence and course of infectious diseases, immune response and diseases of pregnancy. We report the impact of TLRs on the function of miRNAs and the altered expression levels of these molecules, as observed in HCMV infections. We suggest that the methylation status of TLR gene promoter regions as epigenetic modifications may be significant in the immune response to HCMV infections. We conclude that it is important to study in detail the molecular mechanisms of TLR function in the immune response to HCMV infections in pregnancy. PMID- 23929632 TI - Getting from point A to point B ...the diverse routes for germ-line determination. PMID- 23929631 TI - Inhibition of human alpha-methylacyl CoA racemase (AMACR): a target for prostate cancer. AB - The enzyme alpha-methylacyl CoA racemase (AMACR) is involved in the metabolism of branched-chain fatty acids and has been identified as a promising therapeutic target for prostate cancer. By using the recently available human AMACR from HEK293 kidney cell cultures, we tested a series of new rationally designed inhibitors to determine the structural requirements in the acyl component. An N methylthiocarbamate (Ki=98 nM), designed to mimic the proposed enzyme-bound enolate, was found to be the most potent AMACR inhibitor reported to date. PMID- 23929633 TI - Ligand-dependent upregulation of ribosomal shunting. PMID- 23929634 TI - Spermine-alt-poly(ethylene glycol) polyspermine as a safe and efficient aerosol gene carrier for lung cancer therapy. AB - The clinical success of gene therapy critically depends upon the safety and efficiency of delivery system used. Although polyethylenimine (PEI) has been commonly used as an efficient cationic polymeric gene carrier due to its high transfection efficiency, its cytotoxicity and nondegradability limit the polymer's therapeutic applications in clinical trials. In this study, biocompatible polyspermine based on spermine (SPE) and poly(ethylene glycol) (PEG) diacrylate (SPE-alt-PEG) was synthesized using a Michael-type addition reaction, and its ability as an alternative gene carrier for lung cancer therapy was evaluated. SPE-alt-PEG polyspermine was complexed with plasmid DNA, and the resulting complexes were characterized by particle size and surface charge by dynamic light scattering, complex formation and DNA protection ability by gel retardation, and complex shape by energy-filtering transmission electron microscopy. The SPE-alt-PEG copolymer showed low cytotoxicity, and SPE-alt PEG/DNA complexes showed efficacious transfection efficiency compared with 25 kDa PEI (PEI 25K). Also SPE-alt-PEG/GFP complexes were efficiently transferred into the lungs after aerosol administration without toxicity, and delivery of Pdcd4 gene as a therapeutic gene with SPE-alt-PEG polyspermine greatly reduced tumor size as well as tumor numbers in K-ras(LA1) lung cancer model mice compared relative to the effect observed for PEI 25K. These results suggest that SPE-alt PEG has potential as a gene carrier for lung cancer gene therapy. PMID- 23929635 TI - Psychotropic medication use in adolescents with intellectual disability living in the community. AB - PURPOSE: Information on the use of psychotropic medications in adolescents with intellectual disability is scant. Such information can guide interventions to improve psychotropic medication use in this population. We investigated the prevalence of, and factors associated with, psychotropic medication use in adolescents with intellectual disability in Australia who live in the community. METHODS: Cross-sectional data were obtained from adolescents with intellectual disability living in the community in South East Queensland, Australia, between February 2007 and September 2010. Self-reported information on medication use was extracted from a health screening tool. Demographic and medical data were collected through parent/caregiver surveys. Medications were classified according to the Anatomical Therapeutic Chemical classification system. Psychopathology was assessed using the Developmental Behaviour Checklist Short Form. Logistic regression analysis was used to assess the association of demographic and medical characteristics with psychotropic medication use. RESULTS: There were 176 participants (median age = 16 years, range = 11-19 years; 55% male). Psychotropics were used by 20% of participants. Psychostimulants were the commonest psychotropic class, used by 9% of participants. Multipsychotropic prescribing was not common with only seven participants using more than one psychotropic agent. After adjusting for potentially confounding variables, use of psychotropic medications was significantly associated with male gender (adjusted odds ratio = 3.6; 95% confidence interval = 1.3-9.5) and having major behaviour problems (3.1; 1.1-8.9). CONCLUSIONS: Adolescents with intellectual disability use a wide range of psychotropic medications. Being male and having major behaviour problems are associated with the use of psychotropic medications. Research examining the rationale for psychotropic prescribing in this population is needed. PMID- 23929636 TI - Cervical pregnancy with massive bleeding after treatment with methotrexate. AB - This report describes a catastrophic bleeding following methotrexate treatment of cervical pregnancy and dramatic response to Bakri surgical obstetric silicone (SOS) balloon tamponade in controlling massive bleeding. A 42-year-old woman was diagnosed for cervical pregnancy with a viable fetus at 12 weeks by transvaginal ultrasound. Conservative treatment with intrafetal potassium chloride injection and systemic methotrexate were instituted. On the sixth day of therapy, catastrophic bleeding lead to hypovolemic shock. After resuscitation and blood transfusion, we attempt to control the bleeding with evacuation and curettage but was unsuccessful. Bakri SOS balloon tamponade was applied with immediate and effective response. Nevertheless, total abdominal hysterectomy was performed. In conclusion, conservative treatment of cervical pregnancy with systemic methotrexate could be catastrophic in some patients. Control of active bleeding with Bakri SOS balloon tamponade may possibly be helpful in case of uncontrolled bleeding in selected cases. PMID- 23929638 TI - Changes in Farr radioimmunoassay and EliA fluorescence immunoassay anti-dsDNA in relation to exacerbation of SLE. AB - Measuring anti-dsDNA levels could support treatment adjustment during follow-up of patients with systemic lupus erythematosus (SLE). We investigated whether patients with exacerbations of SLE showed changes in anti-double-stranded DNA (anti-dsDNA) levels prior to the exacerbation using the Farr and EliA assay and examined which assay showed highest specificity and predictive value for exacerbations. Changes in anti-dsDNA of >= 25% prior to exacerbation were considered of clinical significance. Exacerbations were retrospectively abstracted from medical records. Eighteen of 48 patients showed one or more exacerbations. We found 22 exacerbations with complete lab work-up, all accompanied by >= 25% change in anti-dsDNA in one or both assays. Only 10 exacerbations showed concordant changes in anti-dsDNA in both assays. Changes in anti-dsDNA had a low predictive value for exacerbations of SLE, but the specificity of anti-dsDNA changes for patients with exacerbations was higher for EliA than Farr. We conclude that despite the limited relation between anti-dsDNA changes and exacerbations of SLE, anti-dsDNA testing could still support clinical decision making when used in the correct setting. We conclude that EliA is preferable over Farr for assaying anti-dsDNA during follow-up of patients with SLE because of higher specificity, less "hands-on" time and absence of radioactivity. PMID- 23929637 TI - Childbearing is not associated with young women's long-term obesity risk. AB - OBJECTIVE: Contemporary childbearing is associated with greater gestational weight gain and postpartum weight retention than in previous decades, potentially leading to a more pronounced effect of childbearing on women's long-term obesity risk. Previous work on the association of childbearing with women's long-term obesity risk mostly examined births in the 1970s and 1980s and produced mixed results. The association of childbearing and obesity incidence in a diverse, contemporary sample of 2731 US women was estimated. METHODS: Propensity-score (PS) matching was used for confounding control when estimating the effect of incident parity (1996-2001) on 7-year incident obesity (BMI>=30 kg/m(2) ) (2001 2008). RESULTS: In the sample, 19.3% of parous women became obese, whereas 16.1% of unmatched nulliparous women did. After PS matching without and with replacement, the differences in obesity incidence were, respectively, 0.0 percentage points (ppts) (95% CI: -4.7 to 4.7) and 0.9 ppts (95% CI: -4.9 to 6.7). Results were similar in analyses of prevalent parity and obesity in 2008 (n = 6601) conducted to explore possible selection bias. CONCLUSIONS: These results imply that, in contemporary US parous women in their late 20s and early 30s, childbearing may not increase obesity incidence. PMID- 23929639 TI - The clinical manifestations and survival of systemic lupus erythematosus patients in Turkey: report from two centers. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a variety of clinical features. Survival has become longer as a result of better treatment modalities and better supportive care. There is no information on survival of SLE patients in Turkey. We evaluated clinical features and survival in SLE patients in two rheumatology departments. METHODS: All SLE patients being followed up by the Department of Rheumatology, Trakya University Medical Faculty, and the Department of Rheumatology, Marmara University Medical Faculty, over the 1996-2012 period were included. Patients were diagnosed with SLE if they fulfilled at least four American College of Rheumatology (ACR) criteria. The clinical and laboratory features, mortality data were obtained from medical charts. RESULTS: We had 428 SLE patients, and women (399 patients, 93.2%) far outnumbered men (29 patients, 6.8%). The mean age at the time of SLE diagnosis was 40.3 +/- 12.4 years. The most frequent clinical manifestations were arthritis (76.9%) and photosensitivity (70.1%). Renal disease was present in 32.9% of patients and neurological involvement in 12.9% of patients. After a median follow-up of 60 months, 19 patients died. The most frequent causes of death were ischemic heart disease, chronic renal failure and sepsis. The rate of five-year survival was 96%; 10-year survival, 92%; and 15-year survival, 88.8%. Multivariate Cox analysis showed that serositis at the time of diagnosis, SLE disease activity index (SLEDAI) score 6, and autoimmune hemolytic anemia were independent prognostic factors. CONCLUSIONS: Data from two centers in Northwestern Turkey show that the mortality rate for SLE is similar to the rate in Western countries. PMID- 23929640 TI - Preface to the Supplement introducing a new innovative desensitising mouthrinse: "Can a potassium oxalate mouthrinse successfully prevent and treat dentine sensitivity?". PMID- 23929641 TI - A novel potassium oxalate-containing tooth-desensitising mouthrinse: a comparative in vitro study. AB - OBJECTIVE: To compare the efficacy of a new potassium oxalate (KO)-containing mouthrinse [Listerine(r) Advanced Defence Sensitive (LADS)] in reducing dentine permeability and occluding open dentinal tubules versus other desensitising products. METHODS: The permeability of acid-etched dentine disks was measured by hydraulic conductance; dentine surfaces were examined by scanning electron microscopy and energy-dispersive X-ray spectroscopy. The KO concentration was optimised for tubule occlusion by screening formulations containing 0.0-2.0% KO (n=5 disks per concentration). The optimal formulation was compared with five commercial products with non-oxalate occlusion technologies. After establishing the baseline permeability of acid-etched dentine disks, disks (n=6 per product) were randomly treated with the desensitising products (12 treatments, each 60 s, alternated with distilled-water rinses) and permeability was measured at intervals. Occluded disks were acid challenged. All experiments were conducted at room temperature. An unpooled, two-tailed t test was performed to assess between treatment differences in relative residual permeability. RESULTS: The optimal concentration of KO in LADS was 1.4%, which provided ~ 100% reduction in dentine permeability after nine treatments. Only LADS reduced permeability to zero and was significantly more effective in reducing dentine permeability than the other products (p <= 0.033 vs all other test products). All products partially occluded dentine. The occlusion associated with LADS was substantially more stable in resisting acid challenge versus Colgate(r) Sensitive Pro-Relief mouthrinse (p=0.054) and significantly more stable versus all other test products (p <= 0.045), as determined by dentine permeability. CONCLUSION: LADS was significantly more effective in occluding open dentinal tubules versus other desensitising products. CLINICAL SIGNIFICANCE: LADS provides fast, complete and stable intratubular occlusion of patent dentinal tubules. PMID- 23929642 TI - Interactions of dentine desensitisers with human dentine: morphology and composition. AB - OBJECTIVE: To evaluate the effect of desensitising agents on human dentine morphology and composition. METHODS: Randomly assigned human coronal-dentine specimens were subjected to: (a) no treatment (smear-layer control, n=4); (b) acid etching with 6% citric acid (demineralised control, n=4); (c) treatment with desensitising agents (12 cycles of 60 s treatment with 60 s between-treatment rinsing, n=6 per agent); and (d) exposure to acidic challenge (pH 5.0 for 90 s, n=6 per agent). The tested products were: Listerine(r) Advanced Defence Sensitive (LADS; 1.4% potassium oxalate) mouthrinse, Colgate(r) Sensitive Pro-ReliefTM mouthrinse, and toothpaste slurries (paste/water 1:2 wt/wt ratio) of Colgate(r) Sensitive Pro-ReliefTM paste, Crest(r) Sensitive paste and Sensodyne(r) Repair and Protect paste. All dentine surfaces were studied by attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, Raman microscopy and high vacuum scanning electron microscopy with energy-dispersive X-ray microanalysis (HV-SEM/EDX). RESULTS: Desensitising slurry treatments occluded tubule orifices of acid-etched dentine, creating a randomly distributed surface pattern of particle aggregates. The greatest intratubular penetration of occluding particles was found in dentine treated with LADS. The atomic ratios of Ca/N and Ca/P, and the mineral/matrix ratios increased after toothpaste-slurry treatments compared with the acid-etched dentine. However, the acidic challenge removed most surface precipitates and further demineralised these substrates. Before the acidic challenge, the surface features were least affected in specimens treated with Sensodyne(r) Repair and Protect. After the acidic challenge, the sub-surface occlusion features were least affected in specimens treated with LADS. CLINICAL SIGNIFICANCE: Although most tested products achieved occlusion of dentinal tubules and provided evidence of mineral deposits, the deposit formed by LADS demonstrated the greatest resistance to acidic challenge, which simulates intra-oral demineralisation phases. PMID- 23929643 TI - Dentine sensitivity: past, present and future. AB - OBJECTIVE: This review defines dentine sensitivity (DS), its prevalence, its aetiology, the mechanism(s) responsible for DS, its diagnosis and its treatment. The review then examines the modes of action of various treatments for DS including potassium salts, strontium salts, bioglasses, arginine/calcium carbonate and professional treatments such as adhesives and oxalates. The methods used to evaluate the various treatment modalities are discussed, including laboratory studies and randomised controlled clinical trials. DATA SOURCES AND STUDY SELECTION: A literature search was conducted using PubMed, Ovid Medline and Cochrane reviews for information on DS and its treatments, as well as laboratory and clinical studies used to evaluate the efficacy of various DS treatments. With regard to efficacy of treatments for DS only reports of clinical studies that were randomised, controlled and blinded were reviewed. The authors offer new insights into the shortcomings of the recent systematic review of the use of oxalates for DS. CONCLUSION: The authors introduce the concept of a novel desensitising mouthrinse containing 1.4% potassium oxalate: Listerine(r) Advanced Defence Sensitive mouthrinse. Readers of this supplement issue of the Journal of Dentistry are invited to review the significance of managing the clinical problem of DS. They are also invited to assess data from laboratory and randomised controlled clinical studies in order to understand the advantages offered by regular use of 1.4% potassium oxalate-containing mouthrinse, Listerine Advanced Defence Sensitive, in particular its resistance to daily erosive and/or abrasive challenges. PMID- 23929644 TI - Randomised clinical efficacy trial of potassium oxalate mouthrinse in relieving dentinal sensitivity. AB - OBJECTIVE: The study aimed to determine the efficacy in relieving dentinal sensitivity of 4 weeks' treatment with an alcohol-free mouthrinse comprising 1.4% potassium oxalate (KO) (Listerine(r) Advanced Defence Sensitive; LADS), compared with negative and positive controls. METHODS: Subjects were randomised to one of three treatments: LADS mouthrinse - twice-daily toothbrushing with Crest(r) Cavity Protection Regular toothpaste, rinsing with water and then 10 mL LADS mouthrinse, followed by expectoration; negative control (twice-daily brushing with Crest Cavity Protection Regular toothpaste); or positive control (twice daily brushing with Sensodyne(r) Original desensitising toothpaste). Dentine sensitivity was assessed at baseline and after 2 and 4 weeks by Yeaple probe (tactile pressure; patient-reported discomfort by visual analogue scale [VAS]), air blast (VAS) and global subjective sensitivity (VAS). Oral tolerance was monitored throughout the study. RESULTS: At 2 weeks, subjects treated with the positive control and LADS mouthrinse showed significant reductions (p<0.05) in sensitivity scores versus the negative control. At 4 weeks, sensitivity decreased by 110% in the positive-control subjects versus negative-control subjects (p<0.001); sensitivity decreased by 80% in subjects receiving LADS mouthrinse versus negative-control subjects (p<0.05). No serious treatment-related oral adverse events were reported. CONCLUSIONS: The positive control (Sensodyne Original) significantly reduced sensitivity compared with the negative control (Crest toothpaste alone), thus validating the study. The LADS mouthrinse (1.4% KO mouthrinse) significantly reduced sensitivity compared with the negative control, suggesting that LADS mouthrinse was responsible for the clinical effect observed. The treatments were well tolerated. CLINICAL SIGNIFICANCE: To our knowledge, this is the first randomised clinical study to demonstrate the efficacy of a KO containing mouthrinse (LADS) in relieving dentinal sensitivity. PMID- 23929645 TI - How can sensitive dentine become hypersensitive and can it be reversed? AB - This paper reviews a number of studies in oral biology and endodontics that deal with the reactivity of the pulpo-dentine complex in response to mechanical and immunological stimuli. It can be hypothesized that these reactions could also apply to changes in dentine sensitivity following periodontal procedures. Some of these changes involve neurogenic inflammation of the pulp under exposed open tubules; this increases the rate of outward fluid flow through the tubules, making the overlying exposed dentine more sensitive. Other changes may be due to inflammation-related nerve sprouting of pulpal nerves, which can lead to innervation of more tubules than normal. Changes may also involve upregulation of new, more sensitive ion channels in the membranes of these nerves. The goal of the paper is to increase awareness of the complex issues involved in dentine sensitivity, so that future investigators may develop agents or techniques to stimulate mechanisms that mitigate dentine sensitivity, or to block mechanisms that aggravate the condition, for therapeutic effect. PMID- 23929652 TI - Juvenile nasopharyngeal angiofibroma: vascular determinates for operative complications and tumor recurrence. AB - OBJECTIVES/HYPOTHESIS: Operative complications and tumor recurrence in juvenile nasopharyngeal angiofibroma (JNA) are measurable and meaningful outcomes. This study aimed to assess the association of these two outcomes to various clinical indices and in particular, vascular determinates. STUDY DESIGN: Retrospective cohort study. METHODS: An 18-year retrospective chart review of an academic tertiary center was undertaken. Data from clinical notes, imaging studies, and arteriograms were analyzed. RESULTS: Thirty-seven male (mean age, 14.4 years) patients were included in the study. Tumor stages included: IA (three), IB (three), IIA (14), IIB (three), IIC (five), IIIA (five), and IIIB (four). Four complications (cerebrospinal fluid leak, cerebral vascular accident, and two transient ocular defects) occurred. Eight recurrences occurred within 24 months following surgery. Complications were associated with estimated intraoperative blood loss (EBL) (P = .045). Tumor recurrence was associated with feeding vessels from the contralateral internal carotid artery (ICA) (P = .017). EBL was significantly associated with surgical technique used. EBL, tumor stage, and tumor vascular supply were significantly associated with each other. CONCLUSIONS: Vascular factors were associated with JNA complication and tumor recurrence. EBL might affect complications, and contralateral ICA as a feeding vessel might affect recurrence. EBL was influenced by procedure choice and was interrelated to size and vascular supply of the tumor. This study bolsters the need to decrease intraoperative blood loss by preoperative embolization and use of endoscopic removal techniques. Furthermore, when branches of the ICA are found to be feeding vessels, greater surgical attention for a dry surgical field is encouraged. PMID- 23929653 TI - RNA interference against cancer/testis genes identifies dual specificity phosphatase 21 as a potential therapeutic target in human hepatocellular carcinoma. AB - Cancer/testis (CT) antigens have been considered therapeutic targets for treating cancers. However, a central question is whether their expression contributes to tumorigenesis or if they are functionally irrelevant by-products derived from the process of cellular transformation. In any case, these CT antigens are essential for cancer cell survival and may serve as potential therapeutic targets. Recently, the cell-based RNA interference (RNAi) screen has proven to be a powerful approach for identifying potential therapeutic targets. In this study we sought to identify new CT antigens as potential therapeutic targets for human hepatocellular carcinoma (HCC), and 179 potential CT genes on the X chromosome were screened through a bioinformatics analysis of gene expression profiles. Then an RNAi screen against these potential CT genes identified nine that were required for sustaining the survival of Focus and PLC/PRF/5 cells. Among the nine genes, the physiologically testis-restricted dual specificity phosphatase 21 (DUSP21) encoding a dual specificity phosphatase was up-regulated in 39 (33%) of 118 human HCC specimens. Ectopic DUSP21 had no obvious impact on proliferation and colony formation in HCC cells. However, DUSP21 silencing significantly suppressed cell proliferation, colony formation, and in vivo tumorigenicity in HCC cells. The administration of adenovirus-mediated RNAi and an atelocollagen/siRNA mixture against endogenous DUSP21 significantly suppressed xenograft HCC tumors in mice. Further investigations showed that DUSP21 knockdown led to arrest of the cell cycle in G1 phase, cell senescence, and expression changes of some factors with functions in the cell cycle and/or senescence. Furthermore, the antiproliferative role of DUSP21 knockdown is through activation of p38 mitogen-activated protein kinase in HCC. CONCLUSION: DUSP21 plays an important role in sustaining HCC cell proliferation and may thus act as a potential therapeutic target in HCC treatment. PMID- 23929655 TI - The regulation of seasonal flowering in the Rosaceae. AB - Molecular mechanisms regulating the flowering process have been extensively studied in model annual plants; in perennials, however, understanding of the molecular mechanisms controlling flowering has just started to emerge. Here we review the current state of flowering research in perennial plants of the rose family (Rosaceae), which is one of the most economically important families of horticultural plants. Strawberry (Fragaria spp.), raspberry (Rubus spp.), rose (Rosa spp.), and apple (Malus spp.) are used to illustrate how photoperiod and temperature control seasonal flowering in rosaceous crops. We highlight recent molecular studies which have revealed homologues of terminal flower1 (TFL1) to be major regulators of both the juvenile to adult, and the vegetative to reproductive transitions in various rosaceous species. Additionally, recent advances in understanding of the regulation of TFL1 are discussed. PMID- 23929654 TI - Functional delineation of rice MADS29 reveals its role in embryo and endosperm development by affecting hormone homeostasis. AB - Rice MADS29 has recently been reported to cause programmed cell death of maternal tissues, the nucellus, and the nucellar projection during early stages of seed development. However, analyses involving OsMADS29 protein expression domains and characterization of OsMADS29 gain-of-function and knockdown phenotypes revealed novel aspects of its function in maintaining hormone homeostasis, which may have a role in the development of embryo and plastid differentiation and starch filling in endosperm cells. The MADS29 transcripts accumulated to high levels soon after fertilization; however, protein accumulation was found to be delayed by at least 4 days. Immunolocalization studies revealed that the protein accumulated initially in the dorsal-vascular trace and the outer layers of endosperm, and subsequently in the embryo and aleurone and subaleurone layers of the endosperm. Ectopic expression of MADS29 resulted in a severely dwarfed phenotype, exhibiting elevated levels of cytokinin, thereby suggesting that cytokinin biosynthesis pathway could be one of the major targets of OsMADS29. Overexpression of OsMADS29 in heterologous BY2 cells was found to mimic the effects of exogenous application of cytokinins that causes differentiation of proplastids to starch-containing amyloplasts and activation of genes involved in the starch biosynthesis pathway. Suppression of MADS29 expression by RNAi severely affected seed set. The surviving seeds were smaller in size, with developmental abnormalities in the embryo and reduced size of endosperm cells, which also contained loosely packed starch granules. Microarray analysis of overexpression and knockdown lines exhibited altered expression of genes involved in plastid biogenesis, starch biosynthesis, cytokinin signalling and biosynthesis. PMID- 23929656 TI - Identification of immunoreactive proteins of Streptococcus agalactiae isolated from cultured tilapia in China. AB - Streptococcus agalactiae (Group B streptococcus, GBS) is an important zoonotic pathogen that can cause lethal infections in humans and animals, including aquatic species. Immunoreactive proteins of the S. agalactiae strain, GD201008 001, isolated from cultured tilapia in China, were screened by immunoproteomics using hyperimmune sera, convalescent guinea pig sera and GD201008-001-infected tilapia antisera as primary detection antibodies. A total of 16 different proteins were identified including 13 novel immunoreactive proteins of S. agalactiae. Four proteins, serine-rich repeat glycoprotein 1, branched-chain alpha-keto acid dehydrogenase (BKD) subunit E2, 5'-nucleotidase family protein and ornithine carbamoyltransferase, were shown to react with the three types of sera and thus were considered to represent novel S. agalactiae vaccine candidate antigens. Our findings represent the basis for vaccine development for piscine S. agalactiae and are necessary for understanding virulence factors and immunogenicity of S. agalactiae with different hosts. PMID- 23929657 TI - All-metal clusters that mimic the chemistry of halogens. AB - Owing to their s(2)p(5) electronic configuration, halogen atoms are highly electronegative and constitute the anionic components of salts. Whereas clusters that contain no halogen atoms, such as AlH(4), mimic the chemistry of halogens and readily form salts (e.g., Na(+)(AlH(4))(-)), clusters that are solely composed of metal atoms and yet behave in the same manner as a halogen are rare. Because coinage-metal atoms (Cu, Ag, and Au) only have one valence electron in their outermost electronic shell, as in H, we examined the possibility that, on interacting with Al, in particular as AlX(4) (X=Cu, Ag, Au), these metal atoms may exhibit halogen-like properties. By using density functional theory, we show that AlAu(4) not only mimics the chemistry of halogens, but also, with a vertical detachment energy (VDE) of 3.98 eV in its anionic form, is a superhalogen. Similarly, analogous to XHX superhalogens (X=F, Cl, Br), XAuX species with VDEs of 4.65, 4.50, and 4.34 eV in their anionic form, respectively, also form superhalogens. In addition, Au can also form hyperhalogens, a recently discovered species that show electron affinities (EAs) that are even higher than those of their corresponding superhalogen building blocks. For example, the VDEs of M(AlAu(4))(2)(-) (M=Na and K) and anionic (FAuF)?Au?(FAuF) range from 4.06 to 5.70 eV. Au-based superhalogen anions, such as AlAu(4)(-) and AuF(2)(-), have the additional advantage that they exhibit wider optical absorption ranges than their H-based analogues, AlH(4)(-) and HF(2)(-). Because of the catalytic properties and the biocompatibility of Au, Au-based superhalogens may be multifunctional. However, similar studies that were carried out for Cu and Ag atoms have shown that, unlike AlAu(4), AlX(4) (X=Cu, Ag) clusters are not superhalogens, a property that can be attributed to the large EA of the Au atom. PMID- 23929658 TI - De novo 15q13.3 microdeletion with cryptogenic West syndrome. AB - West syndrome is a well-recognized form of epilepsy, defined by a triad of infantile spasms, hypsarrhythmia and developmental arrest. West syndrome is heterogenous, caused by mutations of genes ARX, STXBP1, KCNT1 among others; 16p13.11 and 17q21.31 microdeletions are less frequent, usually associated with intellectual disability and facial dysmorphism. So-called "idiopathic" West syndrome is of better prognostic, without prior intellectual deficiency and usually responsive to anti-epileptic treatment. We report on a boy falling within the scope of idiopathic West syndrome, with no dysmorphic features and normal development before the beginning of West syndrome, with a good resolution after treatment, bearing a de novo 15q13.3 microdeletion. Six genes are located in the deleted region, including CHRNA7, which encodes a subunit of a nicotinic acetylcholine receptor, and is frequently associated with epilepsy. Exploration of the 15q13.3 region should be proposed in idiopathic West syndrome. PMID- 23929659 TI - Clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban, an oral direct factor Xa inhibitor, in healthy Caucasian and Japanese subjects. AB - BACKGROUND: Darexaban (YM150) is a potent direct factor Xa (FXa) inhibitor developed for the prophylaxis of venous and arterial thromboembolic disease. This drug is rapidly and extensively metabolized to darexaban glucuronide (YM-222714), which is a pharmacologically active metabolite. The objective of the present study was to evaluate the clinical pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of ascending multiple oral doses of darexaban in healthy non-elderly Caucasian and Japanese subjects. METHODS: A randomized, double-blind, placebo-controlled, single and multiple dose-escalating study of healthy Caucasian and Japanese male and female subjects was performed. The tested doses were 20, 60, 120 and 240 mg of darexaban. RESULTS: Plasma concentrations of darexaban glucuronide increased with dose, and Cmax and AUC increased dose dependently after both single and repeated doses in both Caucasians and Japanese. Cmax was about 17%-19% lower in Caucasians than in Japanese, although AUC appeared to be similar. The time-profiles of prothrombin time reported as the international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) and FXa activity closely followed the time-concentration profile of darexaban glucuronide, and no clear differences were observed in ethnicity. Overall, 38 of the 82 enrolled subjects reported a total of 57 treatment-emergent adverse events (TEAEs). Fifty-five TEAEs were of mild intensity and two were of moderate intensity. CONCLUSION: It is concluded that single and multiple doses of darexaban are safe and well tolerated up to 240 mg with predictable PK and PD profiles in both Caucasians and Japanese, and that ethnicity does not affect its PK, PD or tolerability. PMID- 23929660 TI - Modifying influence of dietary sugar in the relationship between cortisol and visceral adipose tissue in minority youth. AB - OBJECTIVE: Cortisol has been associated with preferential visceral adipose tissue (VAT) deposition; however, findings in humans are mixed, which may be clarified when diet is considered. DESIGN AND METHODS: Participants included 165 African American and Latino, overweight adolescents (BMI% 97.2+/-3.2%, ages 13-18, 67% Latino, 66% female). Body composition was determined by dual energy X-ray absorptiometry, abdominal fat depots [VAT, subcutaneous (SAT)] by multiple-slice MRI, time-controlled serum sample to measure cortisol, and 2-day multi-pass 24 hour dietary recall. Linear regression analysis examined the cross-sectional relationship between cortisol, and the interaction of diet and cortisol on adiposity measures. Sex, race, age, and total body fat were a priori covariates. RESULTS: There was a significant interaction between cortisol and sugar (total and added) in the prediction of VAT (P(interaction) <= 0.05). Amongst participants with high total or added-sugar intake, cortisol was significantly associated with VAT (beta = 0.031 P < 0.001; beta = 0.026 P < 0.001), with no relationship in low consumers of total or added-sugar. CONCLUSION: Dietary sugar may play an important role in modifying the relationship between cortisol and VAT, such that cortisol is significantly associated with elevated VAT under conditions of high sugar intake. PMID- 23929661 TI - Narrow-band imaging in the endoscopic evaluation of hereditary hemorrhagic telangiectasia patients. PMID- 23929662 TI - Celiac artery compression syndrome: a changing clinical entity To the Editor. PMID- 23929663 TI - Antismooth muscle and antiactin antibodies are indirect markers of histological and biochemical activity of autoimmune hepatitis. AB - Reactivity and titers of autoantibodies vary during the course of autoimmune hepatitis (AIH), and some autoantibodies have been associated with disease activity and adverse outcomes after treatment. The aim of this study was to assess the autoantibody behavior in AIH and its significance as predictors of biochemical and histological remission. A total of 117 patients with AIH (mean age 18.6 [4-69] years) were evaluated and tested for autoantibodies at disease onset and successively (mean 3.2 [2-6] times) after a mean follow-up evaluation of 70 [20-185] months. Antismooth muscle (ASMA), antiliver kidney microsome type 1 (anti-LKM1), antiliver cytosol type 1 (anti-LC1), antimitochondrial, antinuclear (ANA), and antiactin antibodies (AAA) were determined at disease onset and 379 other times during the follow-up evaluation through indirect immunofluorescence in rodent tissues, HEp-2 cells, and human fibroblasts. Anti SLA/LP were assessed 45 times in the follow-up evaluation of 19 patients using enzyme-linked immunosorbent assay (ELISA). Upon admission, AIH types 1 and 2 were observed in 95 and 17 patients, respectively. Five subjects had AIH with anti SLA/LP as the sole markers. Patients initially negative for AAA did not develop these antibodies thereafter. ANA were detected de novo in six and three subjects with AIH types 1 and 2, respectively. After treatment, only ASMA (>1:80) and AAA (>1:40) were significantly associated with biochemical (76.9% and 79.8%) and histological features (100% and 100%) of disease activity (P < 0.001). CONCLUSION: With the exception of ANA, the autoantibody profile does not markedly vary in the course of AIH. The persistence of high titers of ASMA and/or AAA in patients with AIH is associated with disease activity. PMID- 23929664 TI - Acceptance of home-based telehealth problem-solving therapy for depressed, low income homebound older adults: qualitative interviews with the participants and aging-service case managers. AB - PURPOSE: To report low-income homebound older adults' experience of telehealth problem-solving therapy (tele-PST) and aging-service case managers' (CMs') experience/perception of client-level personal barriers to accessing psychotherapy in general and PST specifically. DESIGN AND METHODS: The study sample consisted of 42 homebound older adults who participated in the feasibility and efficacy trial of tele-PST and completed 36-week follow-up assessments and 12 CMs of a large home-delivered meals program who referred their clients to the tele-PST trial. In-depth interviews with the older adults and written feedback and focus group discussions with the CMs provided the data. RESULTS: Older adults reported a high rate of approval of PST procedures and acknowledged its positive treatment effect. Tele-PST participants were satisfied with videoconferenced sessions because they were convenient and allowed them to see their therapist. However, CMs reported that only about 10%-20% of potentially eligible older adults gave oral consent for PST. Significant treatment engagement barriers were the older adults' lack of motivation, denial of depression, perceived stigma, and other personal attitudinal factors. IMPLICATIONS: The real-world implementation of tele-PST or other psychotherapies needs to include educating and motivating depressed homebound elders to recognize their depression and accept treatment. PMID- 23929665 TI - Rational design of resorcylic acid lactone analogues as covalent MNK1/2 kinase inhibitors by tuning the reactivity of an enamide Michael acceptor. AB - Recent biological and computational advances in drug design have led to renewed interest in targeted covalent inhibition as an efficient and practical approach for the development of new drugs. As part of our continuing efforts in the exploration of the therapeutic potential of resorcylic acid lactones (RALs), we report herein the design, synthesis, and biological evaluation of conveniently accessible RAL enamide analogues as novel covalent inhibitors of MAP kinase interacting kinases (MNKs). In this study, we have successfully demonstrated that the covalent binding ability of RAL enamides can be tuned by attaching an electron-withdrawing motif, such as an acyl group, to enhance its reactivity toward the cysteine residues at the MNK1/2 binding sites. We have also shown that 1H NMR spectroscopy is a convenient and effective tool for screening the covalent binding activities of enamides using cysteamine as a mimic of the key cysteine residue in the enzyme, whereas mass spectrometric analysis confirms covalent modification of the kinases. Preliminary optimization of the initial hit led to the discovery of enamides with low micromolar activity in MNK assays. Cancer cell line assays have identified RAL enamides that inhibit the growth of cancer cells with similar potency to the natural product L-783,277. PMID- 23929666 TI - Inhaled versus systemic corticosteroids for acute asthma in children. A systematic review. AB - OBJECTIVE: To compare the effects of inhaled corticosteroids (ICS) against systemic corticosteroids (SC) in children consulting in emergency department (ED) or equivalent for asthma exacerbation. METHODS: Electronic search in MEDLINE, CENTRAL, CINAHL, and LILACS databases and other sources. Study selection criteria: children 2-18 years of age, consulting in ED or equivalent for asthma exacerbation, comparison between ICS and SC, randomized controlled trials. PRIMARY OUTCOMES: hospital admission rate, unscheduled visits for asthma symptoms, need of additional course of SC. SECONDARY OUTCOMES: improvement of lung function, length of stay in ED, clinical scores, and adverse effects. RESULTS: Eight studies met inclusion criteria (N = 797), published between 1995 and 2006. All used prednisolone as SC and budesonide, fluticasone, dexamethasone, and flunisolide were administered as ICS. No significant difference between ICS versus SC was found in terms of hospital admission (RR: 1.02; 95% CI: 0.41-2.57), unscheduled visits for asthma symptoms (RR: 9.55; 95% CI: 0.53-170.52) nor for need of additional course of SC (RR: 1.45; 95% CI: 0.28-7.62). The change in % of predicted FEV1 at fourth hour was significantly higher for SC group, but there was no significant difference between both groups after this time. There was insufficient data to perform meta-analysis of length of stay during first consult in ED and of symptom scores. Vomiting was similar among both groups. CONCLUSIONS: There is no evidence of a difference between ICS and SC in terms of hospital admission rates, unscheduled visits for asthma symptoms and need of additional course of SC in children consulting for asthma exacerbations. PMID- 23929667 TI - Probing rapidly-ionizing super-atom molecular orbitals in C60: a computational and femtosecond photoelectron spectroscopy study. AB - Super-atom molecular orbitals (SAMOs) are diffuse hydrogen-like orbitals defined by the shallow potential at the centre of hollow molecules such as fullerenes. The SAMO excited states differ from the Rydberg states by the significant electronic density present inside the carbon cage. We provide a detailed computational study of SAMO and Rydberg states and an experimental characterization of SAMO excited electronic states for gas-phase C(60) molecules by photoelectron spectroscopy. A large band of 500 excited states was computed using time-dependent density functional theory. We show that due to their diffuse character, the photoionization widths of the SAMO and Rydberg states are orders of magnitude larger than those of the isoenergetic non-SAMO excited states. Moreover, in the range of kinetic energies experimentally measured, only the SAMO states photoionize significantly on the timescale of the femtosecond laser experiments. Single photon ionization of the SAMO states dominates the photoelectron spectrum for relatively low laser intensities. The computed photoelectron spectra and photoelectron angular distributions are in good agreement with the experimental results. PMID- 23929669 TI - Commentary: assessing FRET using spectral techniques. PMID- 23929668 TI - Stk31 is dispensable for embryonic development and spermatogenesis in mice. PMID- 23929670 TI - Obesity status of middle school students in Xiangtan and its relationship with Internet addiction. AB - OBJECTIVE: To investigate the state of middle school students' obesity in Xiangtan, China and to study the influence of Internet addiction on obesity. SUBJECTS: 1,150 junior and senior middle school students in Xiangtan, China. DESIGN AND METHODS: The research subjects were select randomly for the study. The height and body weight of human body were measured and the obesity state was judged according to BMI value and the Working Group on Obesity in China (WGOC) standard. The questionnaire for the survey of middle school students' basic situation was designed and a survey of the respondents' personal information and the contributory factors to obesity was conducted. The Middle School Students' Internet Addiction Diagnosis Scale was adopted for measuring and judging the Internet addiction of the research subjects. RESULTS: (1) The total detection rate of obesity was 23.57%. (2) The overall detection rate of Internet addiction was 21.23%. (3) The detection rate of obesity in middle school students with Internet addiction (32.92%) was significantly higher than that without Internet addiction (21.06%). Logistic regression showed that Internet addiction was an independent risk factor of obesity. CONCLUSION: Internet addiction is related to obesity of middle school students. PMID- 23929672 TI - Ultrasound-guided core needle biopsy of salivary gland lesions: a systematic review and meta-analysis. AB - OBJECTIVES/HYPOTHESIS: To obtain summary estimates of the sensitivity and specificity of core needle biopsy for assessment of salivary gland lesions and to investigate sources of variation in accuracy between study locations. STUDY DESIGN: Data sources were PubMed, Embase, CAB Abstracts, CINAHL, BIOSIS, LILACS, PakMediNet, Trip Database, and the National Guideline Clearinghouse. Scopus was used to perform forward (citation) and backward (reference) searches of all potentially relevant studies. METHODS: Screening, data extraction, and quality assessment were independently performed by two different assessors. Meta-analysis was performed using bivariate mixed-effects binary regression as implemented in Stata 12. Quality assessment was performed using the QUADAS-2. RESULTS: The summary estimates of sensitivity and specificity of core needle biopsy for diagnosis of malignancy were 96% (95% confidence interval [CI] = 87-99) and 100% (95% CI = 84-100), respectively. There was no significant heterogeneity in accuracy between studies. The quality of included studies was high, with low risk of verification bias. The risk of hematoma was 1.6% per procedure. CONCLUSIONS: Core needle biopsy has high sensitivity and specificity, and has low risk of complications. There is no significant variation in accuracy between study locations. PMID- 23929671 TI - MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast. AB - We report three families presenting with hypertrophic cardiomyopathy, lactic acidosis, and multiple defects of mitochondrial respiratory chain (MRC) activities. By direct sequencing of the candidate gene MTO1, encoding the mitochondrial-tRNA modifier 1, or whole exome sequencing analysis, we identified novel missense mutations. All MTO1 mutations were predicted to be deleterious on MTO1 function. Their pathogenic role was experimentally validated in a recombinant yeast model, by assessing oxidative growth, respiratory activity, mitochondrial protein synthesis, and complex IV activity. In one case, we also demonstrated that expression of wt MTO1 could rescue the respiratory defect in mutant fibroblasts. The severity of the yeast respiratory phenotypes partly correlated with the different clinical presentations observed in MTO1 mutant patients, although the clinical outcome was highly variable in patients with the same mutation and seemed also to depend on timely start of pharmacological treatment, centered on the control of lactic acidosis by dichloroacetate. Our results indicate that MTO1 mutations are commonly associated with a presentation of hypertrophic cardiomyopathy, lactic acidosis, and MRC deficiency, and that ad hoc recombinant yeast models represent a useful system to test the pathogenic potential of uncommon variants, and provide insight into their effects on the expression of a biochemical phenotype. PMID- 23929673 TI - Diagnosis and management of an asymptomatic intraneural fibular cyst. PMID- 23929674 TI - Impulsive frotteurism: a case report. AB - Frotteurism is a perverted sexual behaviour wherein the person tends to rub or bring about physical contact between his genitals and an unrelated female or male to derive sexual pleasure. Moreover, frotteurism is a common phenomenon among the general population which usually goes unnoticed or overlooked. Nevertheless, public frottage has legal implications in almost all countries over the world. But, when frotteurism manifests on the backdrop of psychiatric illness or as a developmental abnormality then it is worth discussing what the legal liability would be. The present case report is based on hypersexual frotteuristic behaviour manifested on the background of a concealed psychiatric illness, featuring depression and obsessive compulsive disease. The hypersexual behaviour manifested in the form of masturbation with features of frotteurism and subsequent development of depression. Nevertheless, compulsive manifestation of frotteuristic behaviour and subsequent development of morbid depression is rare. This paper describes a 12-year-old boy having unrestrained impulsive frotteurism with his peers, school mates and with his younger brother. He was conscious of the fact and feeling guilty of what he was doing but unable to restrain himself. It was followed by the development of symptoms of depression which was treated with Sertraline. Concurrent psychiatric counseling and rehabilitation measures were taken too. There was complete remission of the symptoms 6 months after the onset of treatment and without relapse thereafter. The paper discusses the differential diagnosis and management of hypersexual behaviour. PMID- 23929675 TI - Use of non-human DNA analysis in forensic science: a mini review. AB - Analysis of non-human DNA in forensic science, first reported about two decades ago, is now commonplace. Results have been used as evidence in court in a variety of cases ranging from abduction and murder to patent infringement and dog attack. DNA from diverse species, including commonly encountered pets such as dogs and cats, to plants, viruses and bacteria has been used and the sheer potential offered by such analyses has been proven. In this review, using case examples throughout, we detail the considerable literature in this field. PMID- 23929676 TI - Suspension without a knot in the noose. AB - Most deaths by hanging are due to self-suspension. This may be carried out by a wide variety of methods, but a typical method of self-suspension is to attach a thin rope to a high point such as a ceiling beam. A 35-year-old woman committed suicide by hanging, where the ligature employed was not a typical knotted noose but instead an open iron chain anchored to the ceiling above. PMID- 23929677 TI - Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice. AB - Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for nonalcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the major cause of liver disease worldwide. Although caffeine is known to stimulate hepatic fat oxidation, its mechanism of action on lipid metabolism is still not clear. Here, we show that caffeine surprisingly is a potent stimulator of hepatic autophagic flux. Using genetic, pharmacological, and metabolomic approaches, we demonstrate that caffeine reduces intrahepatic lipid content and stimulates beta oxidation in hepatic cells and liver by an autophagy-lysosomal pathway. Furthermore, caffeine-induced autophagy involved down-regulation of mammalian target of rapamycin signaling and alteration in hepatic amino acids and sphingolipid levels. In mice fed a high-fat diet, caffeine markedly reduces hepatosteatosis and concomitantly increases autophagy and lipid uptake in lysosomes. CONCLUSION: These results provide novel insight into caffeine's lipolytic actions through autophagy in mammalian liver and its potential beneficial effects in NAFLD. PMID- 23929678 TI - Report of wood decay fungus Inonotus tropicalis (phylum Basidiomycota) from a dog with a granulomatous mediastinal mass. AB - A 75.9-kg, 3.5-year-old male Irish Wolfhound dog with a 2-3-week history of gagging and eating difficulties was referred to the University of Florida Veterinary Medical Hospital (Gainesville, Florida) for evaluation of a large cranial mediastinal mass suspected to be a thymoma or lymphosarcoma. The patient had 4 months of nearly 10 kg progressive weight loss with severe flank sensitivity and radiographically apparent lumbar vertebral changes interpreted as discospondylitis. Lab work revealed hyperglobulinemia, mild proteinuria, normal T4, negative Brucella canis titer, and negative blood and urine bacterial cultures. A thoracotomy revealed a nonresectable, destructive, space-occupying mediastinal mass resulting in euthanasia without surgical recovery. Biopsies from the mass were collected during surgery for histology. Microscopic examination revealed extensive granulomatous cellulitis and lymphadenitis characterized by central cavitated necrotic areas containing debris and degenerate neutrophils, intermediate zones of fibrovascular proliferation with marked mixed inflammation, peripheral fibrosis, frequent multinucleated macrophages, and scattered mineralization. The necrotic material contained dense mats of 2 um wide by 8-15 um long fungal hyphae with parallel walls, acute angle branching, frequent septae, and occasional bulb-like dilations. DNA sequencing and phylogenetic analysis of the internal transcribed spacer region confirmed the presence of a fungus in the Inonotus tropicalis group. Inonotus tropicalis is primarily a wood decay fungus that is found on dead wood from angiosperms in tropical and subtropical habitats. Isolates of the I. tropicalis group have been detected a few times from immunosuppressed human beings with X-linked granulomatous disease. PMID- 23929679 TI - CONFECT: conformations from an expert collection of torsion patterns. AB - The generation of sets of low-energy conformations for a given molecule is a central task in drug design. Herein we present a new conformation generator called CONFECT that builds on our previously published library of torsion patterns. Conformations are generated as well as ranked by means of normalized frequency distributions derived from the Cambridge Structural Database (CSD). Following an incremental construction approach, conformations are selected from a systematic enumeration within energetic boundaries. The new tool is benchmarked in several different ways, indicating that it allows the efficient generation of high-quality conformation ensembles. These ensembles are smaller than those produced by state-of-the-art tools, yet they effectively cover conformational space. PMID- 23929680 TI - Differential effects of route of T-2 toxin exposure on hepatic oxidative damage in mice. AB - T-2 toxin is the most toxic among mycotoxins and poses a potential health hazard for both humans and animals. At high doses, T-2 toxin can cause shock-like syndrome that can result in death. We evaluated the effect of time course and route of exposure on hepatic oxidative damage in mice and it is only such study so far to compare the effects of dermal and subcutaneous exposure of T-2 toxin. Mice were exposed to 1 LD50 of T-2 toxin either by percutaneous (5.94 mg/kg body weight) or subcutaneous (1.54 mg/kg body weight) route and sacrificed at 0, 1, 3, and 7 days postexposure. Analysis of a number of serum biochemical variables, antioxidant enzymes activity, gene and protein expression by immunoblot assay showed time and route dependent effects of T-2 induced hepatic oxidative damage. Time dependent increase in protein carbonyl content and protein oxidation was seen in serum and liver. Results of our study may provide possible mechanism for developing medical countermeasures against T-2 toxin. PMID- 23929681 TI - Effects of Maya ancestry and environmental variables on knee height and body proportionality in growing individuals in Merida, Yucatan. AB - OBJECTIVE: Identify the biological, social, and economic conditions influencing the knee height/stature index (KHSI) in growing individuals of Maya ancestry in the city of Merida, Yucatan, Mexico. METHODS: The hypothesis was that KHSI values would be lower in subjects with two Maya surnames. This was tested by analyzing the effect of a series of environmental, biological, and socioeconomic variables on stature and knee height (KH). Data were collected from 2008 to 2009 from 841 individuals (444 girls), 9 to 17 years of age, in Merida, Yucatan, Mexico. Ancestry was used as a proxy for genetics, and based on number of Maya surnames (2, 1, or none). The KHSI was calculated for all individuals. Multiple regression models were run to identify the variables that best explained variation in stature, KH, and KHSI. RESULTS: Ancestry negatively (P < 0.05) affected stature, but birth weight, crowding index, and mother's education level (MEL) were more significant (P < 0.01). Ancestry had no effect on KH and KHSI values, but birth weight and MEL had a significant effect. Individuals who had grown up in an adverse environment, in terms of MEL, had higher KHSI values. Apparently, lower leg length was proportionally longer than thigh length in the sample. CONCLUSIONS: Growth measurements were more responsive to the studied environmental variables than to ancestry-related genetic conditions. Genetic predisposition is, therefore, not the primary cause of short stature in this sample of Yucatec Mayas. PMID- 23929682 TI - Effects of landfill leachate treatment on hepatopancreas of Armadillidium vulgare (Crustacea, Isopoda). AB - The major environmental impact of landfills is emission of pollutants via the leachate and gas pathways. The hepatopancreas of the terrestrial isopod Armadillidium vulgare (Isopoda, Crustacea, Latreille 1804) plays an important role in the bioaccumulation of contaminants, such as heavy metals. To evaluate the effects of landfill leachate treatment, 2 different approaches were applied: 1) the detection of accumulation of trace elements (As, Cd, Cr, Cu, Sb, Zn, Pb, Ni, V) in hepatopancreatic cells, and 2) the evaluation of biological effect of contaminants on fresh hepatopancreatic cells by flow-cytometric analyses. The presence of 2 different cell types (herein referred to as "small" [S] cells and "big" [B] cells, in agreement with the literature based on morphological examinations) was detected for the first time by flow cytometry, which also highlighted their different response to stress stimuli. In particular, B cells appeared more sensitive to landfill leachate treatment, being more damaged in the short term, while S cells seemed more adaptive. Furthermore, S cells could represent a pool from which they are able to differentiate into B cells. These findings were also confirmed by principal component analyses, underlining that S SYBR Green I bright cells correlate with specific chemicals (Ca, Cu, Co), confirming their resistance to stress stimuli, and suggesting that the decrease of specific cell types may prime other elements to replace them in a homeostasis preservation framework. PMID- 23929683 TI - Increased expression of intrinsic antiviral genes in HLA-B*57-positive individuals. AB - The genetic background of HIV-1-infected subjects, particularly the HLA class I haplotype, appears to be critical in determining disease progression rates, thought to be a result of the role of HIV-1-specific CD8(+) T cell responses. The HLA-B*57 allele is strongly associated with viremic suppression and slower disease progression. However, there is considerable heterogeneity in HIV-1 disease progression rates among HLA-B*57-positive subjects, suggesting that additional factors may help to contain viral replication. In this report, we investigated the association between host restriction factors, other established immunological parameters, and HLA type in HIV-1-seronegative individuals. Our results demonstrate that healthy, uninfected HLA-B*57-positive individuals exhibit significantly higher gene-expression levels of host restriction factors, such as APOBEC3A, APOBEC3B, BST-2/tetherin, and ISG15. Interestingly, HLA-B*57 individuals have significantly lower CD4(+) T cell frequencies but harbor slightly more activated CD4(+) T cells compared with their HLA-B*35 counterparts. We detected significant correlations between CD4(+) T cell activation and expression of several APOBEC3 family members, BST-2/tetherin, SAMHD1, and TRIM5alpha in HLA-B*57-positive individuals. To our knowledge, this is the first report showing distinct associations between host restriction factors and HLA class I genotype. Our results provide insights into natural protection mechanisms and immunity against HIV-1 that fall outside of classical HLA-mediated effects. PMID- 23929684 TI - Assessing FRET using spectral techniques. AB - Forster resonance energy transfer (FRET) techniques have proven invaluable for probing the complex nature of protein-protein interactions, protein folding, and intracellular signaling events. These techniques have traditionally been implemented with the use of one or more fluorescence band-pass filters, either as fluorescence microscopy filter cubes, or as dichroic mirrors and band-pass filters in flow cytometry. In addition, new approaches for measuring FRET, such as fluorescence lifetime and acceptor photobleaching, have been developed. Hyperspectral techniques for imaging and flow cytometry have also shown to be promising for performing FRET measurements. In this study, we have compared traditional (filter-based) FRET approaches to three spectral-based approaches: the ratio of acceptor-to-donor peak emission, linear spectral unmixing, and linear spectral unmixing with a correction for direct acceptor excitation. All methods are estimates of FRET efficiency, except for one-filter set and three filter set FRET indices, which are included for consistency with prior literature. In the first part of this study, spectrofluorimetric data were collected from a CFP-Epac-YFP FRET probe that has been used for intracellular cAMP measurements. All comparisons were performed using the same spectrofluorimetric datasets as input data, to provide a relevant comparison. Linear spectral unmixing resulted in measurements with the lowest coefficient of variation (0.10) as well as accurate fits using the Hill equation. FRET efficiency methods produced coefficients of variation of less than 0.20, while FRET indices produced coefficients of variation greater than 8.00. These results demonstrate that spectral FRET measurements provide improved response over standard, filter-based measurements. Using spectral approaches, single-cell measurements were conducted through hyperspectral confocal microscopy, linear unmixing, and cell segmentation with quantitative image analysis. Results from these studies confirmed that spectral imaging is effective for measuring subcellular, time-dependent FRET dynamics and that additional fluorescent signals can be readily separated from FRET signals, enabling multilabel studies of molecular interactions. (c) 2013 International Society for Advancement of Cytometry. PMID- 23929685 TI - Time series analyses of the effect of FDA communications on use of prescription weight loss medications. AB - OBJECTIVE: To determine the impact of FDA safety communications regarding the weight loss medications sibutramine and orlistat. METHODS: The 2008 to 2011 pharmacy claims data from CVS Caremark were used to determine the effect of the relevant FDA warnings on (1) use of sibutramine and orlistat, (2) their rates of discontinuation, and (3) substitution to an alternate weight loss medication in the 3-month period following discontinuation. RESULTS: The use of sibutramine, orlistat, or phentermine declined from 45 users per 100,000 Caremark enrollees in May 2008 to 24 users per 100,000 enrollees in December 2010. In the time series analyses of overall use of medications, a very small decline in the trend of use of sibutramine after the FDA communication (0.000002% per month decline after the communication; P < 0.001) was found. However, rates of discontinuation of sibutramine and orlistat were similar before and after relevant FDA communications (all P values >0.1 for both level and trend changes post-warning). Patients discontinuing sibutramine post-communication increased use of phentermine at a rate of 0.004% per month after discontinuation (P = 0.01). CONCLUSION: From 2008 to 2010, use of prescription weight loss medications was low and declined over time. FDA communications regarding the safety of these medications had limited effect on use. PMID- 23929687 TI - Olfactory training is helpful in postinfectious olfactory loss: a randomized, controlled, multicenter study. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to evaluate the effects of olfactory training (OT) on olfactory function in patients with persistent postinfectious olfactory dysfunction (PIOD). STUDY DESIGN: Randomized, single blind, controlled, multicenter crossover study. METHODS: Twelve tertiary university medical centers participated. Investigations were performed at three visits (baseline, after 18 weeks, and after 36 weeks), including only subjects with PIOD of <24-months duration. At each visit, participants received detailed assessment of olfactory function. Seventy subjects trained with high concentrations of four odors for 18 weeks; the other half (n = 74) trained with low concentrations of odors. For the following 18 weeks this regimen was switched. RESULTS: After 18 weeks, olfactory function improved in the high training group in 18 of 70 participants (26%), whereas only 11/74 improved in the low-training group (15%). In subjects with a duration of olfactory dysfunction of <12 months, olfactory function improved in 15/24 participants (63%) of the high training group and in 6/31 participants (19%) of the low-training group (P = .03). CONCLUSIONS: OT improves PIOD, and the use of odors at higher concentrations is beneficial to improvement. OT is a safe procedure and appears to be particularly useful in patients who start OT within 12 months after the onset of the disorder. OT is the first successful therapy regime in patients with PIOD. LEVEL OF EVIDENCE: 1b. PMID- 23929688 TI - Novel gamma-sarcoglycan-mutation affects cardiac function and N-terminal dystrophin expression. PMID- 23929686 TI - Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients. AB - De novo germline variants in several components of the SWI/SNF-like BAF complex can cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD powered databases to facilitate further genotype-phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation. PMID- 23929689 TI - Kupffer cell-derived IL-10 plays a key role in maintaining humoral immune tolerance in hepatitis B virus-persistent mice. AB - The liver is considered as a unique lymphoid organ favoring the induction of immune tolerance, rather than immunity. Biologists and clinicians alike have a long-standing interest in how the liver induces systemic immune tolerance, but the mechanism has not yet been well elucidated. Here, we employed hepatitis B virus (HBV)-carrier mice generated by hydrodynamically injecting phosphor-adeno associated virus/HBV1.2 plasmid as a model for adult chronic HBV infection, which we found were unable to respond to hepatitis B surface antigen vaccination. Humoral tolerance induced in HBV-carrier mice could be transferred into Rag1(-/-) mice, because anti-HBV immunity in immunologically reconstituted Rag1(-/-) mice was inhibited by adoptive transfer of splenocytes from HBV-carrier mice. Humoral tolerance needed at least 7 days for induction and persisted to 3 months after a single HBV plasmid injection. Kupffer cell (KC) depletion or interleukin (IL-10) deficiency broke this humoral tolerance, and exogenous injection of IL-10 could effectively induce this tolerance. CONCLUSION: KCs in HBV-carrier mice expressed more IL-10 and mediated the systemic tolerance induction in an IL-10-dependent manner. This previously undescribed humoral tolerance regarding HBV infection will help to explore new approaches to reverse liver-sustained systemic immune tolerance in liver disease. PMID- 23929690 TI - Evaluating prodrug strategies for esterase-triggered release of alcohols. AB - Prodrugs are effective tools in overcoming drawbacks typically associated with drug formulation and delivery. Those employing esterase-triggered functional groups are frequently utilized to mask polar carboxylic acids and phenols, increasing drug-like properties such as lipophilicity. Herein we detail a comprehensive assessment for strategies that effectively release hydroxy and phenolic moieties in the presence of an esterase. Matrix metalloproteinases (MMPs) serve as our proof-of-concept target. Three distinct ester-responsive protecting groups are incorporated into MMP proinhibitors containing hydroxy moieties. Analytical evaluation of the proinhibitors demonstrates that the use of a benzyl ether group appended to the esterase trigger leads to considerably faster kinetics of conversion and enhanced aqueous stability when compared with more conventional approaches where the trigger is directly attached to the inhibitor. Biological assays confirm that all protecting groups effectively cleave in the presence of esterase to generate the active inhibitor. The superior reaction-based prodrug strategies presented here should serve as a platform for esterase-responsive prodrug design in the future. PMID- 23929691 TI - Triclosan exhibits a tendency to accumulate in the epididymis and shows sperm toxicity in male Sprague-Dawley rats. AB - Triclosan (TCS) is considered a potent endocrine disruptor that causes reproductive toxicity in non-mammals, but it is still unclear exactly whether TCS has adverse effects on the sperm or reproductive organs in mammals. In this study, we aimed to evaluate the distribution status of TCS in male reproductive organs of rats, and seek the correlation with the TCS-induced sperm toxicity or reproductive organ damage. Male rats were intragastrically administered with TCS at a dose of 50 mg/kg, the kinetics of TCS in the plasma and reproductive organs were investigated. TCS in testes and prostates both showed a lower-level distribution compared to that in the plasma, which indicates it has no tendency to accumulate in those organs. However, TCS in the epididymides showed a longer elimination half-life (t1/2 z), a longer the mean retention time (MRT), and a lower clearance (CLZ /F) compared with those in the plasma. Besides, the ratios of mean area under the concentration-time curve (AUC)(0-96 h(epididymides/plasma)) and AUC(0-infinity(epididymides/plasma)) were 1.13 and 1.51, respectively. These kinetic parameters suggest TCS has an accumulation tendency in the epididymides. Based on this, we investigated the TCS-induced sperm toxicity and histopathological changes of reproductive organs in rats. TCS was given intragastrically at doses of 10, 50, and 200 mg/kg for 8 weeks. Rats treated with the high dose (200 mg/kg) of TCS showed a significant decrease in daily sperm production (DSP), changes in sperm morphology and epididymal histopathology. Considering the histopathological change in the epididymides, TCS may induce the epididymal damage due to the epididymal accumulation of that. PMID- 23929692 TI - Error augmentation enhancing arm recovery in individuals with chronic stroke: a randomized crossover design. AB - BACKGROUND: Neurorehabilitation studies suggest that manipulation of error signals during practice can stimulate improvement in coordination after stroke. OBJECTIVE: To test visual display and robotic technology that delivers augmented error signals during training, in participants with stroke. METHODS: A total of 26 participants with chronic hemiparesis were trained with haptic (via robot rendered forces) and graphic (via a virtual environment) distortions to amplify upper-extremity (UE) tracking error. In a randomized crossover design, the intervention was compared with an equivalent amount of practice without error augmentation (EA). Interventions involved three 45-minute sessions per week for 2 weeks, then 1 week of no treatment, and then 2 additional weeks of the alternate treatment. A therapist provided a visual cursor using a tracking device, and participants were instructed to match it with their hand. Haptic and visual EA was used with blinding of participant, therapist, technician-operator, and evaluator. Clinical measures of impairment were obtained at the beginning and end of each 2-week treatment phase as well as at 1 week and at 45 days after the last treatment. RESULTS: Outcomes showed a small, but significant benefit to EA training over simple repetitive practice, with a mean 2-week improvement in Fugl Meyer UE motor score of 2.08 and Wolf Motor Function Test of timed tasks of 1.48 s. CONCLUSIONS: This interactive technology may improve UE motor recovery of stroke-related hemiparesis. PMID- 23929693 TI - Interval cancer: nightmare of colonoscopists. PMID- 23929694 TI - A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. AB - The cholinergic anti-inflammatory pathway (CAIP) has been proposed as a key mechanism by which the brain, through the vagus nerve, modulates the immune system in the spleen. Vagus nerve stimulation (VNS) reduces intestinal inflammation and improves postoperative ileus. We investigated the neural pathway involved and the cells mediating the anti-inflammatory effect of VNS in the gut. The effect of VNS on intestinal inflammation and transit was investigated in wild type, splenic denervated and Rag-1 knockout mice. To define the possible role of alpha7 nicotinic acetylcholine receptor (alpha7nAChR), we used knockout and bone marrow chimaera mice. Anterograde tracing of vagal efferents, cell sorting and Ca(2+) imaging were used to reveal the intestinal cells targeted by the vagus nerve. VNS attenuates surgery-induced intestinal inflammation and improves postoperative intestinal transit in wild-type, splenic denervated and T-cell deficient mice. In contrast, VNS is ineffective in alpha7nAChR knockout mice and alpha7nAChR-deficient bone marrow chimaera mice. Anterograde labelling fails to detect vagal efferents contacting resident macrophages, but shows close contacts between cholinergic myenteric neurons and resident macrophages expressing alpha7nAChR. Finally, alpha7nAChR activation modulates ATP-induced Ca(2+) response in small intestine resident macrophages. We show that the anti inflammatory effect of the VNS in the intestine is independent of the spleen and T cells. Instead, the vagus nerve interacts with cholinergic myenteric neurons in close contact with the muscularis macrophages. Our data suggest that intestinal muscularis resident macrophages expressing alpha7nAChR are most likely the ultimate target of the gastrointestinal CAIP. PMID- 23929695 TI - Newly diagnosed diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis. AB - BACKGROUND: Diabetes mellitus (DM) is common in the general population and it poses a heavy burden to society in the form of long-term disability, healthcare use and costs. The pancreas is a key player in glucose homeostasis, but the occurrence of newly diagnosed DM after acute pancreatitis (AP), the most frequent disease of the pancreas, has never been assessed systematically. The aim of this study was to conduct a systematic literature review to determine the prevalence and time course of DM and related conditions after the first attack of AP as well as the impact of covariates. METHODS: Relevant literature cited in three electronic databases (Scopus, EMBASE and MEDLINE) was reviewed independently by two authors. The main outcome measures studied were newly diagnosed prediabetes, DM, or DM treated with insulin. Pooled prevalence and 95% CIs were calculated for all outcomes. RESULTS: A total of 24 prospective clinical studies, involving 1102 patients with first episode of AP, met all the eligibility criteria. Prediabetes and/or DM was observed in 37% (95% CI 30% to 45%) individuals after AP. The pooled prevalence of prediabetes, DM and treatment with insulin after AP was 16% (95% CI 9% to 24%), 23% (95% CI 16% to 31%), and 15% (95% CI 9% to 21%), respectively. Newly diagnosed DM developed in 15% of individuals within 12 months after first episode of AP and the risk increased significantly at 5 years (relative risk 2.7 (95% CI 1.9 to 3.8)). A similar trend was observed with regard to treatment with insulin. The severity of AP, its aetiology, individuals' age and gender had minimal effect on the studied outcomes. CONCLUSIONS: Patients with AP often develop prediabetes and/or DM after discharge from hospital, and have a greater than twofold increased risk of DM over 5 years. Further studies are warranted to determine the optimal strategy for its detection and whether the risk of developing DM after AP can be reduced. PMID- 23929696 TI - Comparison of MRI with liver-specific contrast agents and multidetector row CT for the detection of hepatocellular carcinoma: a meta-analysis of 15 direct comparative studies. PMID- 23929698 TI - Value of HIV patients with regular follow-up as in-house internal controls of flow cytometry measurement of lymphocyte subsets. AB - BACKGROUND: Quality assessment in flow cytometry cannot obey the same rules as those applicable to the measurement of chemical analytes. However, regular follow up of known patients may provide a robust in-house control of cell subsets evaluation. METHODS: Sequential blood samples assessed for 32 HIV patients over several years and showing good stability were retrospectively assessed to establish coefficient of variations of the percentages of CD3+, CD4+, CD8+ cells, and CD4+ absolute counts (ACs). RESULTS: Mean relative standard variations for the whole cohort were of 0.04, 0.14, 0.08, and 0.18 for CD3%, CD4%, CD8%, and CD4 ACs, respectively. DISCUSSION: In-house follow-up of regularly checked compliant patients is a good alternative to traditional and costly repeatability and reproducibility studies for the validation of routine flow cytometry. (c) 2013 International Clinical Cytometry Society. PMID- 23929697 TI - Plasma dihydroceramide species associate with waist circumference in Mexican American families. AB - OBJECTIVE: Waist circumference (WC), the clinical marker of central obesity, is gaining popularity as a screening tool for type 2 diabetes (T2D). While there is epidemiologic evidence favoring the WC-T2D association, its biological substantiation is generally weak. Our objective was to determine the independent association of plasma lipid repertoire with WC. METHODS: Samples and data from the San Antonio Family Heart Study of 1208 Mexican Americans from 42 extended families were used. Association of plasma lipidomic profiles with the cross sectionally assessed WC was determined. Plasma lipidomic profiling entailed liquid chromatography with mass spectrometry. Statistical analyses included multivariable polygenic regression models and bivariate trait analyses using the SOLAR software. RESULTS: After adjusting for age and sex interactions, body mass index, homeostasis model of assessment-insulin resistance, total cholesterol, triglycerides, high density lipoproteins and use of lipid lowering drugs, dihydroceramides as a class were associated with WC. Dihydroceramide species 18:0, 20:0, 22:0, and 24:1 were significantly associated and genetically correlated with WC. Two sphingomyelin species (31:1 and 41:1) were also associated with WC. CONCLUSIONS: Plasma dihydroceramide levels independently associate with WC. Thus, high resolution plasma lipidomic studies can provide further credence to the biological underpinnings of the association of WC with T2D. PMID- 23929699 TI - The role of indeterminate fine-needle biopsy in the diagnosis of parotid malignancy. AB - OBJECTIVES/HYPOTHESIS: To examine the significance of indeterminate fine needle aspiration biopsy in the diagnosis of parotid gland malignancy. STUDY DESIGN: Retrospective case series, academic tertiary referral center. METHODS: A total of 559 parotidectomies performed between the years of 2005 and 2010 were reviewed, with 56.7% (N = 317) meeting investigation eligibility criteria: primary parotid tumor, availability of fine-needle aspiration biopsy, intraoperative frozen section, and final pathologic diagnosis. One-hundred fifteen (n = 115, 36.3%) of the 317 parotid biopsies were interpreted as indeterminate. Clinical history, physical examination, operative findings, and histopathologic characteristics were analyzed. Multiple logistic regression, with deviation from means coding, was used to estimate the odds of malignancy in the indeterminate group and provide a comparison with reference to the average odds of malignancy over the overall sample. RESULTS: Overall final pathologic distribution of parotid masses (N = 317) was 82.3% benign and 17.7% malignant. Overall final pathologic distribution of parotid masses in the indeterminate group (n = 115) was 31.3% malignant and 68.7% benign. In comparison, the overall group (N = 317) had a decreased comparative percentage of malignant specimens at 17.7%. Interestingly, in the instance of an indeterminate biopsy, the odds of having a malignancy was estimated to increase by 1.98-fold compared to overall mean odds of malignancy in the sample. Other statistically significant clinical predictors of parotid malignancy included history of prior malignancy, current tobacco user, locally invasive characteristics intraoperatively, and facial nerve involvement intraoperatively. CONCLUSIONS: In the context of an indeterminate fine-needle aspiration biopsy, an elevated index of suspicion for parotid malignancy may be warranted. PMID- 23929700 TI - Robot-assisted selective neck dissection combined with facelift parotidectomy in parotid cancer. AB - BACKGROUND: Robot-assisted neck dissection in patients with head and neck cancer has been demonstrated to be feasible. We conceived a surgical technique of surgery for parotid cancer with the robotic system via a gasless modified facelift (MFL) approach. A detailed surgical technique is provided. METHODS: In a 28-year-old female patient with parotid cancer, the disease was treated with primary tumor resection with robotic selective neck dissection I to III via an MFL incision. RESULTS: Robot-assisted selective neck dissection I to III combined with primary tumor resection was successfully conducted without any significant intraoperative complication, applying additional incision, or conversion to open conventional neck dissection. Videographic demonstration of the robotic-assisted neck dissection is included. CONCLUSION: Robot-assisted surgery via the MFL approach is a feasible and useful method with excellent cosmetic results for the surgical treatment in selected cases of parotid gland cancer. PMID- 23929701 TI - Multicenter trial of the proficiency of smart quantitative sensation tests. AB - INTRODUCTION: We assessed proficiency (accuracy and intra- and intertest reproducibility) of smart quantitative sensation tests (smart QSTs) in subjects without and with diabetic sensorimotor polyneuropathy (DSPN). METHODS: Technologists from 3 medical centers using different but identical QSTs independently assessed 6 modalities of sensation of the foot (or leg) twice in patients without (n = 6) and with (n = 6) DSPN using smart computer assisted QSTs. RESULTS: Low rates of test abnormalities were observed in health and high rates in DSPN. Very high intraclass correlations were obtained between continuous measures of QSTs and neuropathy signs, symptoms, or nerve conductions (NCs). No significant intra- or intertest differences were observed. CONCLUSIONS: These results provide proof of concept that smart QSTs provide accurate assessment of sensation loss without intra- or intertest differences useful for multicenter trials. Smart technology makes possible efficient testing of body surface area sensation loss in symmetric length-dependent sensorimotor polyneuropathies. PMID- 23929702 TI - Geochemical and ecotoxicological assessment of iron- and steel-making slags for potential use in environmental applications. AB - Prior to the productive use of iron- and steel-making slags as environmental amendments, a risk assessment supported by material characterization concomitant with leaching and ecotoxicological testing is necessary. Five iron- and steel making slags were characterized geochemically, and the leachability of their elemental constituents was assessed. The toxicity of slag leachate to microalgae (Chlorella sp.), cladocerans (Ceriodaphnia dubia), and bacteria (Vibrio fischeri) was related to elemental composition. Slag leachates with the highest concentrations of dissolved elements were the most toxic (10% effective concentration [EC10] ~1%), whereas those with the lowest concentrations of elements were the least toxic (EC10 63-85%). It was not possible to determine which elements caused the observed toxicity; however, comparisons with contaminant guidelines and published toxicity data identified several elements of potential environmental concern. Low to moderate activities were measured for radionuclides in the U and Th decay chains in slags. Based on these data, some of the slags examined herein are potentially suitable for use as environmental amendments following >=10 times dilution to ameliorate potential toxic effects because of leachate pH. PMID- 23929704 TI - Alterations of tau and VASP during microcystin-LR-induced cytoskeletal reorganization in a human liver cell line. AB - Previously, we have reported alterations to HSP27 during Microcystin-LR (MC-LR) induced cytoskeletal reorganization in the human liver cell line HL7702. To further elucidate the detailed mechanism of MC-LR-induced cytoskeletal assembly, we focused on two cytoskeletal-related proteins, Tau and VASP. These two proteins phosphorylated status influences their ability to bind and stabilize cytoskeleton. We found that MC-LR markedly increased the level of Tau phosphorylation with the dissociation of phosphorylated Tau from the cytoskeleton. Furthermore, the phosphorylation of Tau induced by MC-LR was suppressed by an activator of PP2A and by an inhibitor of p38 MAPK. VASP was also hyperphosphorylated upon MC-LR exposure; however, its phosphorylation appeared to regulate its cellular localization rather than cytoskeletal dynamics, and its phosphorylation was unaffected by the PP2A activator. These data suggest that phosphorylated Tau is regulated by p38 MAPK, possibly as a consequence of PP2A inhibition. Tau hyperphosphorylation is likely an important factor leading to the cytoskeletal destabilization triggered by MC-LR and the role of VASP alteration upon MC-LR exposure needs to be studied further. To our knowledge, the finding that Tau is implicated in cytoskeletal destabilization in MC-LR-treated hepatocytes and MC-LR-induced VASP's alteration has not been reported previously. PMID- 23929703 TI - Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo. AB - Hepatocellular carcinoma (HCC) occurs predominantly in patients with liver cirrhosis. Here we show an innovative RNA-based targeted approach to enhance endogenous albumin production while reducing liver tumor burden. We designed short-activating RNAs (saRNA) to enhance expression of C/EBPalpha (CCAAT/enhancer binding protein-alpha), a transcriptional regulator and activator of albumin gene expression. Increased levels of both C/EBPalpha and albumin mRNA in addition to a 3-fold increase in albumin secretion and 50% decrease in cell proliferation was observed in C/EBPalpha-saRNA transfected HepG2 cells. Intravenous injection of C/EBPalpha-saRNA in a cirrhotic rat model with multifocal liver tumors increased circulating serum albumin by over 30%, showing evidence of improved liver function. Tumor burden decreased by 80% (P = 0.003) with a 40% reduction in a marker of preneoplastic transformation. Since C/EBPalpha has known antiproliferative activities by way of retinoblastoma, p21, and cyclins, we used messenger RNA (mRNA) expression liver cancer-specific microarray in C/EBPalpha saRNA-transfected HepG2 cells to confirm down-regulation of genes strongly enriched for negative regulation of apoptosis, angiogenesis, and metastasis. Up regulated genes were enriched for tumor suppressors and positive regulators of cell differentiation. A quantitative polymerase chain reaction (PCR) and western blot analysis of C/EBPalpha-saRNA-transfected cells suggested that in addition to the known antiproliferative targets of C/EBPalpha, we also observed suppression of interleukin (IL)6R, c-Myc, and reduced STAT3 phosphorylation. CONCLUSION: A novel injectable saRNA-oligonucleotide that enhances C/EBPalpha expression successfully reduces tumor burden and simultaneously improves liver function in a clinically relevant liver cirrhosis/HCC model. PMID- 23929705 TI - In silico optimization of a fragment-based hit yields biologically active, high efficiency inhibitors for glutamate racemase. AB - A novel lead compound for inhibition of the antibacterial drug target, glutamate racemase (GR), was optimized for both ligand efficiency and lipophilic efficiency. A previously developed hybrid molecular dynamics-docking and scoring scheme, FERM-SMD, was used to predict relative potencies of potential derivatives prior to chemical synthesis. This scheme was successful in distinguishing between high- and low-affinity binders with minimal experimental structural information, saving time and resources in the process. In vitro potency was increased approximately fourfold against GR from the model organism, B. subtilis. Lead derivatives show two- to fourfold increased antimicrobial potency over the parent scaffold. In addition, specificity toward B. subtilis over E. coli and S. aureus depends on the substituent added to the parent scaffold. Finally, insight was gained into the capacity for these compounds to reach the target enzyme in vivo using a bacterial cell wall lysis assay. The outcome of this study is a novel small-molecule inhibitor of GR with the following characteristics: Ki=2.5 MUM, LE=0.45 kcal mol(-1) atom(-1), LiPE=6.0, MIC50=260 MUg mL(-1) against B. subtilis, EC50, lysis=520 MUg mL(-1) against B. subtilis. PMID- 23929706 TI - Progesterone reduces the expression of spinal cyclooxygenase-2 and inducible nitric oxide synthase and prevents allodynia in a rat model of central neuropathic pain. AB - BACKGROUND: Spinal cord injury (SCI) results in the development of chronic pain that is refractory to conventional treatment. Progesterone, a neuroprotective steroid, may offer a promising perspective in pain modulation after central injury. Here, we explore the impact of progesterone administration on the post injury inflammatory cascade involving the enzymes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) at the spinal cord level. We also analyse pain behaviours, the profile of glial cell activation, and IkappaB-alpha mRNA levels, as an index of NF-kappaB transactivation. METHODS: We used biochemical, immunohistochemical and molecular techniques, as well as behavioural studies, to investigate the effects of progesterone in a well-characterized model of central neuropathic pain. RESULTS: Injured animals receiving progesterone presented reduced mRNA levels of the proinflammatory enzymes, as well as decreased COX-2 activity and nitrite levels, as compared to vehicle-treated injured rats. Further, animals receiving the steroid exhibited lower levels of IkappaB-alpha mRNA, suggesting decreased NF-kappaB transactivation. Progesterone administration also attenuated the injury-induced increase in the number of glial fibrillary acidic protein and OX-42 positive cells both at early and late time points after injury, and prevented the development of mechanical and thermal allodynia. Further, when injured rats received early progesterone administration for a critical period of time after injury, they did not display allodynic behaviours even after the treatment had stopped. CONCLUSIONS: Our results suggest that progesterone, by modulating early neuroinflammatory events triggered after SCI, may represent a useful strategy to prevent the development of central chronic pain. PMID- 23929709 TI - Differential reward response to palatable food cues in past and current dieters: a fMRI study. AB - OBJECTIVE: Prior neuroimaging research has shown that restrained and unrestrained eaters demonstrate differential brain activation in response to food cues that parallels their food intake in lab studies. These findings were extended by comparing brain activation in response to food cues in normal weight nondieters, historical dieters, and current dieters under the conditions that mimicked past lab studies. METHODS: Participants (N = 30) were shown pictures of highly and moderately palatable food and neutral cues while being scanned in an fMRI BOLD paradigm following an 8-h fast and again after a liquid meal. RESULTS: In the Fed state, historical dieters showed elevated reward circuitry activation in response to highly palatable food, as compared to nondieters and current dieters. In contrast, current dieters did not show the same pattern of activation as historical dieters, despite their shared history of frequent weight-loss dieting. CONCLUSIONS: The parallels between eating behavior and regional brain activation across groups suggest that (1) a neurophysiological response which could represent a vulnerability to overeat exists in some normal weight young women that may increase susceptibility to weight gain in the long term, and (2) current dieting temporarily reverses this vulnerability. PMID- 23929707 TI - Mesenchymal stem cells alleviate bacteria-induced liver injury in mice by inducing regulatory dendritic cells. AB - Fulminant hepatic failure (FHF) is a clinical syndrome characterized by sudden and severe impairment of liver function. Mesenchymal stem cells (MSCs) have been proposed as a promising therapeutic approach for FHF. In this study we used Propionibacterium acnes (P. acnes)-primed, lipopolysaccharide (LPS)-induced liver injury in mice as an animal model of human FHF. We demonstrated that administration of MSCs significantly ameliorated liver injury and improved the survival rates of mice subjected to P. acnes plus LPS-induced FHF. Allogeneic MSCs showed similar treatment efficacy as autologous MSCs did in FHF. Treatment efficacy of MSCs could be attributed to decreased infiltration and activation of CD4(+) T cells in the liver, inhibition of T helper 1 cells, and induction of regulatory T cells (Tregs). Moreover, decreased DNA copies of P. acnes were detected in the liver of MSC-treated mice. Intriguingly, a distinct liver population of CD11c(+) MHCII(hi) CD80(lo) CD86(lo) regulatory dendritic cells (DCs) was induced by MSCs. Moreover, these DCs induced Treg differentiation through transforming growth factor-beta production. Further mechanistic studies demonstrated that MSC-derived prostaglandin E2 and one of its receptors, EP4, played essential roles in the differentiation of CD11c(+) B220(-) DC precursors into regulatory DCs in a phosphoinositide 3-kinase-dependent manner. CONCLUSION: MSCs induce regulatory DCs from CD11c(+) B220(-) DC precursors. This study elucidates an immunoregulatory mechanism of MSCs and lays a foundation for application of MSCs in FHF therapy. PMID- 23929711 TI - Root-to-Shoot transfer and distribution of endosulfan in the wetland macrophyte Bidens laevis L. AB - Endosulfan is genotoxic in somatic cells of Bidens laevis, and reproduction could be affected if translocated from roots to flower buds. Hydroponic experiments were conducted to quantify this transfer. While the root uptake of [(14) C] endosulfan and its transfer to aboveground tissues was relatively low, the resulting average flower bud concentration (1.01 +/- 0.76 ng/g) after 30 d of exposure to an aqueous concentration of 5 MUg/L could still represent a genotoxic risk for germ cells. PMID- 23929710 TI - Systematic test of neurotoxin dose and volume on muscle function in a rat model. AB - INTRODUCTION: Onabotulinum toxin serotype A (BT-A) is used for a variety of motor and sensory disorders related to abnormal muscle activity. METHODS: We developed a high-resolution rodent model to allow precise determination of the effect of BT A dose (measured in units) and injectate volume (measured in MUl) on the efficacy of the injection and systemic side effects. Dorsiflexion is the best indicator of injected and contralateral muscle function. RESULTS: One month after injection, dorsiflexion torque of BT-A-injected limbs was decreased significantly in all experimental groups compared with saline controls (P < 0.05). Torque was also compared among the BT-A groups, which demonstrated a significant effect of dose (P < 0.001), but no effect of volume (P > 0.2) and no dose * volume interaction (P > 0.3). Similar results were observed for other parameters measured. CONCLUSIONS: These data demonstrate that injection dose and not volume or concentration is the primary determinant of neurotoxin efficacy in a rodent model. PMID- 23929712 TI - Postural stability in vestibular neuritis: age, disease duration, and residual vestibular function. AB - OBJECTIVES/HYPOTHESIS: To assess the influence of factors that can affect postural instability in vestibular neuritis (VN). STUDY DESIGN: Retrospective data collection study. METHODS: Foam posturography was performed in 58 VN patients. We examined six variables: the velocity of movement of the center of pressure and the envelopment area in eyes closed/foam rubber condition, Romberg's ratios of velocity and area with foam rubber, and the foam ratios of velocity and area with eyes closed. Multiple regression analyses were performed to explore the relationship between these variables and the following independent variables: gender, age, canal paresis (CP) percentage, and disease duration. RESULTS: All six variables were positively associated with age, CP percentage, and a disease duration of 10 days or less (P < .05) except for Romberg's ratio of velocity with foam rubber, which was positively associated with CP percentage and a disease duration of 10 days or less (P < .05), but not with age (P > .05). CONCLUSIONS: VN patients show poor postural performance, which is affected by age, residual vestibular function, and disease duration. Once a VN patient passes the acute phase of the vertigo attack, it is likely that age and residual vestibular function make a greater contribution to postural control. LEVEL OF EVIDENCE: 3b. PMID- 23929713 TI - Electrochemical characteristics of discrete, uniform, and monodispersed hollow mesoporous carbon spheres in double-layered supercapacitors. AB - Core-shell-structured mesoporous silica spheres were prepared by using n octadecyltrimethoxysilane (C18TMS) as the surfactant. Hollow mesoporous carbon spheres with controllable diameters were fabricated from core-shell-structured mesoporous silica sphere templates by chemical vapor deposition (CVD). By controlling the thickness of the silica shell, hollow carbon spheres (HCSs) with different diameters can be obtained. The use of ethylene as the carbon precursor in the CVD process produces the materials in a single step without the need to remove the surfactant. The mechanism of formation and the role played by the surfactant, C18TMS, are investigated. The materials have large potential in double-layer supercapacitors, and their electrochemical properties were determined. HCSs with thicker mesoporous shells possess a larger surface area, which in turn increases their electrochemical capacitance. The samples prepared at a lower temperature also exhibit increased capacitance as a result of the Brunauer-Emmett-Teller (BET) area and larger pore size. PMID- 23929714 TI - Connective tissue growth factor is a new ligand of epidermal growth factor receptor. AB - Chronic kidney disease is reaching epidemic proportions worldwide and there is no effective treatment. Connective tissue growth factor (CCN2) has been suggested as a risk biomarker and a potential therapeutic target for renal diseases, but its specific receptor has not been identified. Epidermal growth factor receptor (EGFR) participates in kidney damage, but whether CCN2 activates the EGFR pathway is unknown. Here, we show that CCN2 is a novel EGFR ligand. CCN2 binding to EGFR extracellular domain was demonstrated by surface plasmon resonance. CCN2 contains four distinct structural modules. The carboxyl-terminal module (CCN2(IV)) showed a clear interaction with soluble EGFR, suggesting that EGFR-binding site is located in this module. Injection of CCN2(IV) in mice increased EGFR phosphorylation in the kidney, mainly in tubular epithelial cells. EGFR kinase inhibition decreased CCN2(IV)-induced renal changes (ERK activation and inflammation). Studies in cultured tubular epithelial cells showed that CCN2(IV) binds to EGFR leading to ERK activation and proinflammatory factors overexpression. CCN2 interacts with the neurotrophin receptor TrkA, and EGFR/TrkA receptor crosstalk was found in response to CCN2(IV) stimulation. Moreover, endogenous CCN2 blockade inhibited TGF-beta-induced EGFR activation. These findings indicate that CCN2 is a novel EGFR ligand that contributes to renal damage through EGFR signalling. PMID- 23929715 TI - Isolation of adult human spermatogonial progenitors using novel markers. PMID- 23929716 TI - miRNA-214 is related to invasiveness of human non-small cell lung cancer and directly regulates alpha protein kinase 2 expression. AB - The prognosis of non-small cell lung cancer (NSCLC) is poor, since it has often metastasized to distant organs by the time of diagnosis. Therefore, biomarkers predicting metastasis are crucial. miRNAs play important roles in the regulation of different tumor cell processes, including metastasis. We recently showed that miRNA-214 is linked to a radioresistant phenotype of NSCLC. miRNA-214 has been linked to metastasis in other tumor types. Therefore, we examined the role of miRNA-214 in the metastatic potential of NSCLC. We showed that downregulation of miRNA-214 increased invasive potential, and conversely, overexpression of miRNA 214 decreased invasiveness of NSCLC cells in vitro. Gene expression and bioinformatic analyses of NSCLC cells with ablated miRNA-214, identified a number of metastasis-related target genes, including pregnancy-associated plasma protein A (PAPP-A), alpha protein kinase 2 (ALPK2), cyclin-dependent kinase 6 (CDK6) and tumor necrosis-factor alpha-induced protein 3 (TNFAIP3). These were validated on mRNA and protein level to be regulated by miRNA-214. Through immunoprecipitation we showed that only ALPK2 is directly regulated by miRNA-214. We also examined the protein expression of these four genes in NSCLC tumors with respect to metastatic potential. These results showed that NSCLC tumors express these proteins at moderate-high levels in the nucleus, cytoplasm and/or plasma membrane although with no significant correlation to the overall survival or the metastatic potential of the patients. However, we also showed that the membrane localized PAPP-A had a higher expression level compared to the cytoplasm localized. In conclusion, we show that low miRNA-214 expression is linked to a higher invasive potential of NSCLC cells. PMID- 23929717 TI - Dose and time-dependent effects of cyanide on thiosulfate sulfurtransferase, 3 mercaptopyruvate sulfurtransferase, and cystathionine lambda-lyase activities. AB - We assessed the dose-dependent effect of potassium cyanide (KCN) on thiosulfate sulfurtransferase (TST), 3-mercaptopyruvate sulfurtransferase (3-MPST), and cystathionine lambda-lyase (CST) activities in mice. The time-dependent effect of 0.5 LD50 KCN on cyanide level and cytochrome c oxidase (CCO), TST, 3-MPST, and CST activities was also examined. Furthermore, TST, 3-MPST, and CST activities were measured in stored mice cadavers. Hepatic and renal TST activity increased by 0.5 LD50 KCN but diminished by >=2.0 LD50. After 0.5 LD50 KCN, the elevated hepatic cyanide level was accompanied by increased TST, 3-MPST, and CST activities, and CCO inhibition. Elevated renal cyanide level was only accompanied by increased 3-MPST activity. No appreciable change in enzyme activities was observed in mice cadavers. The study concludes that high doses of cyanide exert saturating effects on its detoxification enzymes, indicating their exogenous use during cyanide poisoning. Also, these enzymes are not reliable markers of cyanide poisoning in autopsied samples. PMID- 23929718 TI - Elevated serum ferritin and mercury concentrations are associated with hypertension; analysis of the fourth and fifth Korea national health and nutrition examination survey (KNHANES IV-2, 3, 2008-2009 and V-1, 2010). AB - The impact of simultaneously elevated serum ferritin and mercury concentrations on hypertension in the general population is not known. To determine the association of serum ferritin and mercury concentrations with hypertension, 6213 subjects (3060 men and 3153 women) over 20 years of age from 2008 to 2010 Korea National Health and Nutrition Examination Survey were divided into tertiles according to serum ferritin and mercury concentrations in each gender. Serum ferritin (258.2 vs. 94.8 pmol/L) and mercury concentrations (28.4 vs. 19.9 nmol/L) were higher in men than in women. Serum ferritin (men; P = 0.029, women; P < 0.001) and mercury (men; P < 0.001, women; P = 0.003) concentrations were significantly associated with the prevalence of hypertension. In addition, significant correlation between serum ferritin and mercury concentrations in both men (r = 0.193, P < 0.001) and women (r = 0.145, P < 0.001) were found. Also, the increase of serum ferritin concentrations were more prominent in men (P < 0.001) than in women (P = 0.017) as the serum mercury tertiles increased after proper adjustments. Furthermore, significantly higher odds ratios of hypertension were found in the second (OR = 1.86, 95% CI; 1.05-3.30), and third (OR = 1.84, 95% CI; 1.01-3.36) tertiles of serum ferritin with the top tertile of serum mercury in men. The current study indicate that serum ferritin and mercury concentrations are associated with the prevalence of hypertension and that simultaneously elevated serum ferritin and mercury concentrations are related to the risk for hypertension in men. PMID- 23929719 TI - Quantitative proteomics identifies the membrane-associated peroxidase GPx8 as a cellular substrate of the hepatitis C virus NS3-4A protease. AB - The hepatitis C virus (HCV) NS3-4A protease is not only an essential component of the viral replication complex and a prime target for antiviral intervention but also a key player in the persistence and pathogenesis of HCV. It cleaves and thereby inactivates two crucial adaptor proteins in viral RNA sensing and innate immunity, mitochondrial antiviral signaling protein (MAVS) and TRIF, a phosphatase involved in growth factor signaling, T-cell protein tyrosine phosphatase (TC-PTP), and the E3 ubiquitin ligase component UV-damaged DNA binding protein 1 (DDB1). Here we explored quantitative proteomics to identify novel cellular substrates of the NS3-4A protease. Cell lines inducibly expressing the NS3-4A protease were analyzed by stable isotopic labeling using amino acids in cell culture (SILAC) coupled with protein separation and mass spectrometry. This approach identified the membrane-associated peroxidase GPx8 as a bona fide cellular substrate of the HCV NS3-4A protease. Cleavage by NS3-4A occurs at Cys 11, removing the cytosolic tip of GPx8, and was observed in different experimental systems as well as in liver biopsies from patients with chronic HCV. Overexpression and RNA silencing studies revealed that GPx8 is involved in viral particle production but not in HCV entry or RNA replication. CONCLUSION: We provide proof-of-concept for the use of quantitative proteomics to identify cellular substrates of a viral protease and describe GPx8 as a novel proviral host factor targeted by the HCV NS3-4A protease. PMID- 23929720 TI - Abscisic acid regulates axillary bud outgrowth responses to the ratio of red to far-red light. AB - Low red light/far-red light ratio (R:FR) serves as an indicator of impending competition and has been demonstrated to suppress branch development. The regulation of Arabidopsis (Arabidopsis thaliana) rosette bud outgrowth by the R:FR and the associated mechanisms were investigated at several levels. Growth under low R:FR suppressed outgrowth of the third from topmost bud (bud n-2) but not that of the topmost bud. Subsequently increasing the R:FR near the time of anthesis promoted bud n-2 outgrowth and reduced topmost bud growth. Buds from specific rosette positions, exhibiting divergent fates to increased R:FR, were harvested 3 h after modifying the R:FR and were used to conduct ATH1 microarray based transcriptome profiling. Differentially expressed genes showed enrichment of light signaling and hormone-related Gene Ontology terms and promoter motifs, most notably those associated with abscisic acid (ABA). Genes associated with ABA biosynthesis, including the key biosynthetic gene NINE-CIS-EPOXYCAROTENOID DIOXYGENASE3 (NCED3), and with ABA signaling were expressed at higher levels in the responsive bud n-2, and increasing the R:FR decreased their expression only in bud n-2. ABA abundance in responsive buds decreased within 12 h of increasing the R:FR, while indole-3-acetic acid levels did not change. A role for ABA in repressing bud outgrowth from lower positions under low R:FR was demonstrated using the nced3-2 and aba2-1 ABA biosynthesis mutants, which showed enhanced branching and a defective bud n-2 outgrowth response to low R:FR. The results provide evidence that ABA regulates bud outgrowth responses to the R:FR and thus extend the known hormonal pathways associated with the regulation of branching and shade avoidance. PMID- 23929722 TI - Nonivamide, a capsaicin analog, increases dopamine and serotonin release in SH SY5Y cells via a TRPV1-independent pathway. AB - SCOPE: Dietary intake of capsaicin has been shown to reduce body weight by increasing energy expenditure, and to enhance alertness and mood by stimulating the brain's reward system. Binding of capsaicin to the vanilloid receptor 1 (transient receptor potential cation channel subfamily V member 1 (TRPV1)) is one of the major cellular mechanisms responsible for these effects. However, strong TRPV1 agonists like capsaicin elicit a sharp, burning pain that limits their dietary intake. The present study aimed to investigate the effect of the less pungent capsaicin-analog nonivamide on dopamine and serotonin release in neural SH-SY5Y cells. METHODS AND RESULTS: Nonivamide (1 MUM) stimulated the Ca(2+) dependent release of serotonin (272 +/- 115%) and dopamine (646 +/- 48%) in SH SY5Y cells compared to nontreated cells (100%) to a similar extent as capsaicin. qRT-PCR analysis of 1 MUM nonivamide-treated SH-SY5Y cells revealed gene regulation of the receptors dopamine D1 and D2, serotonin HTR1A, 1B and 2A, cannabinoid 1, and TRPV1. Co-incubation experiments of SH-SY5Y cells with the TRPV1 inhibitors trans-tert-butylcyclohexanol and capsazepine demonstrated that capsaicin, but not nonivamide, induces serotonin and dopamine release through TRPV1 activation. CONCLUSION: The results indicate a TRPV1-independent signaling pathway for nonivamide that might allow dietary administration of higher doses of nonivamide compared to capsaicin. PMID- 23929721 TI - A regulatory network-based approach dissects late maturation processes related to the acquisition of desiccation tolerance and longevity of Medicago truncatula seeds. AB - In seeds, desiccation tolerance (DT) and the ability to survive the dry state for prolonged periods of time (longevity) are two essential traits for seed quality that are consecutively acquired during maturation. Using transcriptomic and metabolomic profiling together with a conditional-dependent network of global transcription interactions, we dissected the maturation events from the end of seed filling to final maturation drying during the last 3 weeks of seed development in Medicago truncatula. The network revealed distinct coexpression modules related to the acquisition of DT, longevity, and pod abscission. The acquisition of DT and dormancy module was associated with abiotic stress response genes, including late embryogenesis abundant (LEA) genes. The longevity module was enriched in genes involved in RNA processing and translation. Concomitantly, LEA polypeptides accumulated, displaying an 18-d delayed accumulation compared with transcripts. During maturation, gulose and stachyose levels increased and correlated with longevity. A seed-specific network identified known and putative transcriptional regulators of DT, including ABSCISIC ACID-INSENSITIVE3 (MtABI3), MtABI4, MtABI5, and APETALA2/ ETHYLENE RESPONSE ELEMENT BINDING PROTEIN (AtAP2/EREBP) transcription factor as major hubs. These transcriptional activators were highly connected to LEA genes. Longevity genes were highly connected to two MtAP2/EREBP and two basic leucine zipper transcription factors. A heat shock factor was found at the transition of DT and longevity modules, connecting to both gene sets. Gain- and loss-of-function approaches of MtABI3 confirmed 80% of its predicted targets, thereby experimentally validating the network. This study captures the coordinated regulation of seed maturation and identifies distinct regulatory networks underlying the preparation for the dry and quiescent states. PMID- 23929723 TI - Atomic force microscopy study of the effects of water-soluble fullerenes on the elasticity of living plant cells. AB - In this work, atomic force microscopy (AFM) was employed to characterize the elastic properties of a living suspension of Nicotiana tabacum L. cv. Bright Yellow (BY-2) cells and to investigate the changes in plant-cell elasticity that were induced by water-soluble C70 fullerene derivatives. The results revealed different effects of the three fullerene derivatives that had different numbers of carboxylic groups on the cell elasticity. BY-2 cells that were repressed by dimalonic-acid-modified C70 fullerenes (DiF70) and trimalonic-acid-modified C70 fullerenes (TriF70) showed a clear decrease in their Young's modulus. However, the Young's modulus of cells that were treated with tetramalonic-acid-modified C70 fullerenes (TetraF70) increased. Disruption of the actin cytoskeleton arrangement was observed following treatment with DiF70 and TriF70, but not with TetraF70. Moreover, the fullerene-induced cell-elasticity change was consistent with the change in cell-proliferation rate. This work provides a new approach and valuable information for the study of the biological effect of nanomaterials on plant cells. PMID- 23929724 TI - Patient-perceived outcome after sialendoscopy using the glasgow benefit inventory. AB - OBJECTIVES/HYPOTHESIS: Sialendoscopy is a technique for investigating and managing obstructive salivary disease that avoids risks associated with the more invasive sialoadenectomy and other open surgery techniques. To date, surgeon based outcomes have been reported, but only one report of patient-oriented outcomes has appeared in the literature. The objective of this study was to review our experience after introducing sialendoscopy to New Zealand and report the patient-perceived benefit. STUDY DESIGN: A prospective observational study of all sialendoscopic procedures performed in the only sialendoscopy-practicing center in New Zealand between June 2010 and June 2012. METHODS: Clinical and epidemiological data of all patients were recorded. Sialendoscopic findings, complications, and outcomes were noted. The Glasgow Benefit Inventory questionnaire was administered to the patients at their follow-up. RESULTS: Fifty four patients underwent a total of 66 sialendoscopic procedures, involving 44 parotid and 22 submandibular glands. There was a complete symptom resolution in 54 procedures (82%). Sialolith removal was successful in 67% of cases, with postsialendoscopy symptom resolution in 86% of sialolithiasis cases. Symptoms resolved in 81% of cases with ductal stenosis. The overall mean Glasgow Benefit Inventory score was +31, which compares very favorably with other otolaryngology procedures. CONCLUSIONS: This study shows a substantial positive patient perceived benefit of sialendoscopy for both sialolith- and stenosis-based pathology. The overall rate of symptom resolution is comparable to international literature. LEVEL OF EVIDENCE: 4. PMID- 23929725 TI - Local translation in neuronal processes--in vivo tests of a "heretical hypothesis". AB - Intracellular trafficking and localization of mRNA is a fundamental feature of living cells, suggesting that localized mRNA translation should enable subcellular regulation of the proteome. Such localized regulation may be of particular importance in highly polarized cells such as neurons, where the requirement for a specific protein can be at a site far distant from the nucleus. Although dendritic and synaptic protein syntheses are well-established phenomena, the apparent paucity of ribosomes in early studies on mature vertebrate axons generated significant skepticism regarding the possibility of protein synthesis within axons. Here, we summarize recent findings in genetically engineered mouse models that support a role for local translation in axonal expression of beta actin and importin beta1 in injured adult sensory neurons in vivo. These definitive confirmations of mammalian axonal protein synthesis in both transgenic and subcellular knockout models should direct further attention to the diverse roles suggested for local protein synthesis in axonal physiology. PMID- 23929726 TI - Whole-genome paired-end analysis confirms remarkable genomic stability of atypical teratoid/rhabdoid tumors. PMID- 23929728 TI - Novel mutation of the mitofusin 2 gene in a family with Charcot-Marie-Tooth disease type 2. PMID- 23929727 TI - Assessing intrarenal nonperfusion and vascular leakage in acute kidney injury with multinuclear (1) H/(19) F MRI and perfluorocarbon nanoparticles. AB - PURPOSE: We sought to develop a unique sensor-reporter approach for functional kidney imaging that employs circulating perfluorocarbon nanoparticles and multinuclear (1) H/(19) F MRI. METHODS: (19) F spin density weighted and T1 weighted images were used to generate quantitative functional mappings of both healthy and ischemia-reperfusion (acute kidney injury) injured mouse kidneys. (1) H blood-oxygenation-level-dependent (BOLD) MRI was also employed as a supplementary approach to facilitate the comprehensive analysis of renal circulation and its pathological changes in acute kidney injury. RESULTS: Heterogeneous blood volume distributions and intrarenal oxygenation gradients were confirmed in healthy kidneys by (19) F MRI. In a mouse model of acute kidney injury, (19) F MRI, in conjunction with blood-oxygenation-level-dependent MRI, sensitively delineated renal vascular damage and recovery. In the cortico medullary junction region, we observed 25% lower (19) F signal (P < 0.05) and 70% longer (1) H T2* (P < 0.01) in injured kidneys compared with contralateral kidneys at 24 h after initial ischemia-reperfusion injury. We also detected 71% higher (19) F signal (P < 0.01) and 40% lower (1) H T2* (P < 0.05) in the renal medulla region of injured kidneys compared with contralateral uninjured kidneys. CONCLUSION: Integrated (1) H/(19) F MRI using perfluorocarbon nanoparticles provides a multiparametric readout of regional perfusion defects in acutely injured kidneys. PMID- 23929729 TI - Pilot study assessing a seven-day continuous intrathecal topotecan infusion for recurrent or progressive leptomeningeal metastatic cancer. AB - OBJECTIVE: To determine the feasibility and toxicity profile of topotecan administered as a seven-day continuous intrathecal infusion for patients with leptomeningeal metastasis secondary to recurrent or progressive central nervous system cancer. STUDY DESIGN: Two patients with central nervous system leptomeningeal metastasis were treated with a seven-day continuous infusion of topotecan (0.2 mg/day) administered via continuous intrathecal/intraventricular infusion at a rate of 0.6 mL/h, totaling 1.4 mg/course. CSF and plasma concentrations of topotecan closed lactone (the active metabolite) were quantified at various points during topotecan infusion. Patients were monitored for neurologic and systemic toxicities according to NCI common toxicity criteria. RESULTS: Both patients tolerated the seven-day continuous topotecan without any significant adverse events. One patient received a second course 21 days after treatment initiation. CSF concentration of topotecan closed lactone ranged from 3.73 to 312 ng/mL (median = 131 ng/mL) and plasma topotecan closed lactone ranged from 0.44 to 1.78 ng/mL (median = 0.92 ng/mL). The median CSF topotecan concentration was greater than the median serum topotecan concentration by a 44 fold magnitude when samples were obtained at the same time point. None of the patients experienced any grade 3 or higher hematological toxicities or signs of arachnoiditis. CONCLUSION: A seven-day continuous intrathecal infusion of topotecan is well tolerated and has the potential of maximizing central nervous system drug exposure. PMID- 23929730 TI - Sunitinib-induced reversible purpuric rash in a patient with gastrointestinal stromal tumor. AB - Sunitinib which is used in the treatment of kidney cancer, gastrointestinal stromal tumor, and advanced pancreatic neuroendocrine tumor is a multi-targeted tyrosine kinase inhibitor. Although sunitinib is associated with some side effects, it is generally well tolerated. In the present case, the diagnosis of gastrointestinal stromal tumor was four years ago. The patient had multiple liver metastases at the time of diagnosis. Sunitinib was initiated with a dose of 50 mg daily for four weeks and two weeks off, because of resistance of imatinib. The patient was admitted to the hospital with purpuric rash on her arms and body in the eighth week of treatment. No other disorders or drugs which may cause purpuric rash were detected in the patient. Purpuric rash disappeared two weeks after sunitinib discontinuation without any further intervention. PMID- 23929731 TI - Examining factors that influence the effectiveness of cleaning antineoplastic drugs from drug preparation surfaces: a pilot study. AB - Occupational exposure to antineoplastic drugs has been documented to result in various adverse health effects. Despite the implementation of control measures to minimize exposure, detectable levels of drug residual are still found on hospital work surfaces. Cleaning these surfaces is considered as one means to minimize the exposure potential. However, there are no consistent guiding principles related to cleaning of contaminated surfaces resulting in hospitals to adopt varying practices. As such, this pilot study sought to evaluate current cleaning protocols and identify those factors that were most effective in reducing contamination on drug preparation surfaces. Three cleaning variables were examined: (1) type of cleaning agent (CaviCide(r), Phenokil IITM, bleach and chlorhexidine), (2) application method of cleaning agent (directly onto surface or indirectly onto a wipe) and (3) use of isopropyl alcohol after cleaning agent application. Known concentrations of antineoplastic drugs (either methotrexate or cyclophosphamide) were placed on a stainless steel swatch and then, systematically, each of the three cleaning variables was tested. Surface wipes were collected and quantified using high-performance liquid chromatography-tandem mass spectrometry to determine the percent residual of drug remaining (with 100% being complete elimination of the drug). No one single cleaning agent proved to be effective in completely eliminating all drug contamination. The method of application had minimal effect on the amount of drug residual. In general, application of isopropyl alcohol after the use of cleaning agent further reduced the level of drug contamination although measureable levels of drug were still found in some cases. PMID- 23929733 TI - Assessing the performance of the photo-acoustic infrared gas monitor for measuring CO(2), N(2)O, and CH(4) fluxes in two major cereal rotations. AB - Rapid, precise, and globally comparable methods for monitoring greenhouse gas (GHG) fluxes are required for accurate GHG inventories from different cropping systems and management practices. Manual gas sampling followed by gas chromatography (GC) is widely used for measuring GHG fluxes in agricultural fields, but is laborious and time-consuming. The photo-acoustic infrared gas monitoring system (PAS) with on-line gas sampling is an attractive option, although it has not been evaluated for measuring GHG fluxes in cereals in general and rice in particular. We compared N2 O, CO2 , and CH4 fluxes measured by GC and PAS from agricultural fields under the rice-wheat and maize-wheat systems during the wheat (winter), and maize/rice (monsoon) seasons in Haryana, India. All the PAS readings were corrected for baseline drifts over time and PAS-CH4 (PCH4 ) readings in flooded rice were corrected for water vapor interferences. The PCH4 readings in ambient air increased by 2.3 ppm for every 1000 mg cm(-3) increase in water vapor. The daily CO2 , N2 O, and CH4 fluxes measured by GC and PAS from the same chamber were not different in 93-98% of all the measurements made but the PAS exhibited greater precision for estimates of CO2 and N2 O fluxes in wheat and maize, and lower precision for CH4 flux in rice, than GC. The seasonal GC- and PAS-N2 O (PN2 O) fluxes in wheat and maize were not different but the PAS-CO2 (PCO2 ) flux in wheat was 14-39% higher than that of GC. In flooded rice, the seasonal PCH4 and PN2 O fluxes across N levels were higher than those of GC-CH4 and GC-N2 O fluxes by about 2- and 4fold, respectively. The PAS (i) proved to be a suitable alternative to GC for N2 O and CO2 flux measurements in wheat, and (ii) showed potential for obtaining accurate measurements of CH4 fluxes in flooded rice after making correction for changes in humidity. PMID- 23929732 TI - Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. AB - Nonalcoholic fatty liver disease (NAFLD), hepatic insulin resistance, and type 2 diabetes are all strongly associated and are all reaching epidemic proportions. Whether there is a causal link between NAFLD and hepatic insulin resistance is controversial. This review will discuss recent studies in both humans and animal models of NAFLD that have implicated increases in hepatic diacylglycerol (DAG) content leading to activation of novel protein kinase Cepsilon (PKCepsilon) resulting in decreased insulin signaling in the pathogenesis of NAFLD-associated hepatic insulin resistance and type 2 diabetes. The DAG-PKCepsilon hypothesis can explain the occurrence of hepatic insulin resistance observed in most cases of NAFLD associated with obesity, lipodystrophy, and type 2 diabetes. PMID- 23929734 TI - 1,25(OH)2-vitamin D3 enhances the stimulating effect of leucine and insulin on protein synthesis rate through Akt/PKB and mTOR mediated pathways in murine C2C12 skeletal myotubes. AB - SCOPE: In recent years, there has been a growing body of evidence pointing to an effect of vitamin D on muscle mass and function. Our aim was to investigate the combined effect of 1,25(OH)2-vitamin D3 (1,25(OH)2D3) with anabolic factors insulin and leucine on protein fractional synthesis rate (FSR) and regulation in the mouse C2C12 myotube. METHODS AND RESULTS: After differentiation, myotubes were cultured in 1,25(OH)2D3 solutions at 0, 1, or 10 nM for 72 h. Cells were treated by L-[1-(13) C]valine and puromycin in presence or not of leucine and insulin, and protein FSR was determined by measuring tracer enrichments and puromycin incorporation in proteins, respectively. Protein expression and phosphorylation state of insulin receptor (IR), Akt, GSK3, mTOR, p70 S6 kinase, rpS6, and 4EBP1 were measured by Western blot. Transcript levels of IR and 1,25(OH)2D3 receptor (VDR) were determined by qPCR. 1,25(OH)2D3 (10 nM) with leucine and insulin increased protein FSR in C2C12 myotubes (14-16%). IR and VDR mRNA expression was increased with 1,25(OH)2D3 treatment. The Akt/mTOR-dependent pathway was activated by insulin and leucine and further enhanced by 1,25(OH)2D3. CONCLUSION: 1,25(OH)2D3 sensitizes the Akt/mTOR-dependant pathway to the stimulating effect of leucine and insulin, resulting in a further activation of protein synthesis in murine C2C12 skeletal myotubes. PMID- 23929735 TI - Investigation of steric influences on hydrogen-bonding motifs in cyclic ureas by using X-ray, neutron, and computational methods. AB - A series of urea-derived heterocycles, 5N-substituted hexahydro-1,3,5-triazin-2 ones, has been prepared and their structures have been determined for the first time. This family of compounds only differ in their substituent at the 5-position (which is derived from the corresponding primary amine), that is, methyl (1), ethyl (2), isopropyl (3), tert-butyl (4), benzyl (5), N,N-(diethyl)ethylamine (6), and 2-hydroxyethyl (7). The common heterocyclic core of these molecules is a cyclic urea, which has the potential to form a hydrogen-bonding tape motif that consists of self-associative R22(8) dimers. The results from X-ray crystallography and, where possible, Laue neutron crystallography show that the hydrogen-bonding motifs that are observed and the planarity of the hydrogen bonds appear to depend on the steric hindrance at the alpha-carbon atom of the N substituent. With the less-hindered substituents, methyl and ethyl, the anticipated tape motif is observed. When additional methyl groups are added onto the alpha-carbon atom, as in the isopropyl and tert-butyl derivatives, a different 2D hydrogen-bonding motif is observed. Despite the bulkiness of the substituents, the benzyl and N,N-(diethyl)ethylamine derivatives have methylene units at the alpha-carbon atom and, therefore, display the tape motif. The introduction of a competing hydrogen-bond donor/acceptor in the 2-hydroxyethyl derivative disrupts the tape motif, with a hydroxy group interrupting the N H...O=C interactions. The geometry around the hydrogen-bearing nitrogen atoms, whether planar or non-planar, has been confirmed for compounds 2 and 5 by using Laue neutron diffraction and rationalized by using computational methods, thus demonstrating that distortion of O-C-N-H torsion angles occurs to maintain almost linear hydrogen-bonding interactions. PMID- 23929736 TI - Quality-of-life scores compared to objective measures of swallowing after oropharyngeal chemoradiation. AB - OBJECTIVES/HYPOTHESIS: To compare objective measures of swallowing function with patient reports of swallowing-related quality of life 1 year after treatment of oropharyngeal cancer with chemoradiation therapy. STUDY DESIGN: Patients seen for follow-up at least 1 year after treatment of oropharyngeal carcinoma with chemoradiation therapy were sequentially approached and asked to participate in the study. METHODS: Maximum pharyngeal constriction, hyoid elevation, upper esophageal sphincter opening size, and bolus pharyngeal transit time were measured from modified barium swallowing studies in a group of 31 patients at least 1 year after chemoradiation therapy for the treatment of oropharyngeal carcinoma. Measures were made for a liquid 1-mL, 3-mL, and 20-mL bolus. Objective measure results were compared to scores from the MD Anderson Dysphagia Inventory and The University of Washington Swallowing Quality of Life Questionnaire results from the same patients. RESULTS: No strong correlation was identified between any of the objective measures of swallowing physiology and quality-of-life scores. CONCLUSIONS: Patient perception of the impact of swallowing function on quality of life does not correlate well with actual physiologic functioning. PMID- 23929737 TI - Calcium binding protein expression in the optic tectum of Alligator during development. AB - The onset and distribution of the calcium binding proteins, calretinin, calbindin, and parvalbumin, were examined in the optic tectum of Alligator mississipiensis embryos between Stages 18 and 26-28. The immunoreactivity of each calcium binding protein correlated well with the results from the Western blot experiments. In terms of onset and distribution, calretinin expressison was the most widespread of the three calcium binding proteins that were examined, and was also the earliest to be visualized. Calbindin expression occurred next, whereas parvalbumin expression was the most limited and appeared last. For small calretinin (+) neurons, the pattern of immunoreactivity during development was from inside to outside, whereas for the larger cells, it was from outside to inside. For calbindin immunoreactive cells in the superficial zone, the pattern was from outside to inside. The distribution of the parvalbumin immunopositive neurons did not change significantly over the time period examined. Similar data on other amniotes is limited. However, the pattern in Alligator shares some similarities with kittens in regards to the distribution of calbindin and parvalbumin in the developing superior colliculus. PMID- 23929739 TI - Changes of microRNA profile and microRNA-mRNA regulatory network in bones of ovariectomized mice. AB - Growing evidence shows the possibility of a role of microRNAs (miRNA) in regulating bone mass. We investigated the change of miRNAs and mRNA expression profiles in bone tissue in an ovariectomized mice model and evaluated the regulatory mechanism of bone mass mediated by miRNAs in an estrogen-deficiency state. Eight-week-old female C3H/HeJ mice underwent ovariectomy (OVX) or sham operation (Sham-op), and their femur and tibia were harvested to extract total bone RNAs after 4 weeks for microarray analysis. Eight miRNAs (miR-127, -133a, 133a*, -133b, -136, -206, -378, -378*) were identified to be upregulated after OVX, whereas one miRNA (miR-204) was downregulated. Concomitant analysis of mRNA microarray revealed that 658 genes were differentially expressed between OVX and Sham-op mice. Target prediction of differentially expressed miRNAs identified potential targets, and integrative analysis using the mRNA microarray results showed that PPARgamma and CREB pathways are activated in skeletal tissues after ovariectomy. Among the potential candidates of miRNA, we further studied the role of miR-127 in vitro, which exhibited the greatest changes after OVX. We also studied the effects of miR-136, which has not been studied in the context of bone mass regulation. Transfection of miR-127 inhibitor has enhanced osteoblastic differentiation in UAMS-32 cells as measured by alkaline phosphatase activities and mRNA expression of osteoblast-specific genes, whereas miR-136 precursor has inhibited osteoblastic differentiation. Furthermore, transfection of both miR-127 and miR-136 inhibitors enhanced the osteocyte-like morphological changes and survival in MLO-Y4 cells, whereas precursors of miR-127 and -136 have aggravated dexamethasone-induced cell death. Both of the precursors enhanced osteoclastic differentiation in bone marrow macrophages, indicating that both miR-127 and -136 are negatively regulating bone mass. Taken together, these results suggest a novel insight into the association between distinct miRNAs expression and their possible role through regulatory network with mRNAs in the pathogenesis of estrogen deficiency-induced osteoporosis. PMID- 23929740 TI - Hepatocytes as a source of cholangiocytes in injured liver. PMID- 23929738 TI - Common chromosome fragile sites in human and murine epithelial cells and FHIT/FRA3B loss-induced global genome instability. AB - Chromosomal positions of common fragile sites differ in lymphoblasts and fibroblasts, with positions dependent on the epigenetically determined density of replication origins at these loci. Because rearrangement of fragile loci and associated loss of fragile gene products are hallmarks of cancers, we aimed to map common fragile sites in epithelial cells, from which most cancers derive. Among the five most frequently activated sites in human epithelial cells were chromosome bands 2q33 and Xq22.1, which are not among top fragile sites identified in lymphoblasts or fibroblasts. FRA16D at 16q23 was among the top three fragile sites in the human epithelial cells examined, as it is in lymphoblasts and fibroblasts, while FRA3B at 3p14.2, the top fragile locus in lymphoblasts, was not fragile in most epithelial cell lines tested. Epithelial cells exhibited varying hierarchies of fragile sites; some frequent epithelial cell fragile sites are apparently not frequently altered in epithelial cancers and sites that are frequently deleted in epithelial cancers are not necessarily among the most fragile. Since we have reported that loss of expression of the FRA3B-encoded FHIT protein causes increased replication stress-induced DNA damage, we also examined the effect of FHIT-deficiency on markers of genome instability in epithelial cells. FHIT-deficient cells exhibited increases in fragile breaks and in gammaH2AX and 53BP1 foci in G1 phase cells, confirming in epithelial cells that the FHIT gene and encompassing FRA3B, is a "caretaker gene" necessary for maintenance of genome stability. PMID- 23929741 TI - Phosphorylation of Dpsyl2 (CRMP2) and Dpsyl3 (CRMP4) is required for positioning of caudal primary motor neurons in the zebrafish spinal cord. AB - Dpysls (CRMPs) that were initially identified as mediator proteins of Semaphorin3a (Sema3a) signaling are involved in neuronal polarity and axon elongation in cultured neurons. Previous studies have shown that knockdown of neuropilin1a, one of the sema3a receptors, exhibited ectopic primary motor neurons (PMNs) outside of the spinal cord in zebrafish. However, downstream molecules of sema3a signaling involved in the positioning of motor neurons are largely unknown. Here, we addressed the role of Dpysl2 (CRMP2) and Dpysl3 (CRMP4) in the positioning of PMNs in the zebrafish spinal cord. We found that the knockdown of dpysls by antisense morpholino oligonucleotides (AMO) causes abnormal positioning of caudal primary (CaP) motor neurons outside the spinal cord. The knockdown of cdk5 and dyrk2 by AMO also caused similar phenotype in the positioning of CaP motor neurons, and this phenotype was rescued by co-injection of phosphorylation-mimic type dpysl2 mRNA. These results suggest that the phosphorylation of Dpysl2 and Dpysl3 by Cdk5 and Dyrk2 is required for correct positioning of CaP motor neurons in the zebrafish spinal cord. PMID- 23929742 TI - Kinetics of sulforaphane in mice after consumption of sulforaphane-enriched broccoli sprout preparation. AB - SCOPE: Sulforaphane (SF) is a natural isothiocyanate in broccoli sprouts with cancer chemopreventive activity. This study is aimed to use different methods to develop broccoli sprout preparations to compare their ability to deliver SF to the mice and to evaluate the kinetics and biodistribution of SF. METHODS AND RESULTS: The SF-enriched sprout preparation generated by two-step procedure (quick-steaming followed by myrosinase treatment) contained the highest level of SF, which was 11 and 5 times higher than the freeze-dried fresh broccoli sprouts and the quick-steamed, freeze-dried broccoli sprouts, respectively. After oral administration of 2.5 mg/g body weight of the broccoli sprout preparations, SF was quickly absorbed and distributed throughout the tissues. The SF-rich preparation resulted in the highest exposure, with peak plasma SF concentration of 337 ng/mL, which is 6.0 times and 2.6 times higher compared to the other two preparations. A whole body physiologically based pharmacokinetic model (developed with ADAPT 5 software) suggests that distribution of SF is perfusion-limited in all organs. CONCLUSION: This study provides a broccoli sprout preparation that can serve as a good source of SF, and the model can be utilized to guide the dose designed for the use of broccoli sprout preparation in chemoprevention. PMID- 23929744 TI - Incidence of venous thromboembolism in the wake of the Clots in Legs Or sTockings after Stroke (CLOTS) study. AB - BACKGROUND AND PURPOSE: In the United Kingdom, compressive stockings were standard care in all stroke units until the publication of the Clots in Legs Or sTockings after Stroke (CLOTS) trial results in May 2009, which concluded that stockings were ineffective. The aim of this audit was to assess whether this change in practice was associated with any change in venous thromboembolism incidence in routine clinical practice. METHOD: All stroke register entries at the University Hospital of North Staffordshire from 2 years before the publication of the CLOTS trial results to 2 years after were identified and included in this audit. The hospital radiology reporting system was then cross checked for evidence of venous thromboembolism on computed tomography pulmonary angiogram, ventilation/perfusion lung scan, and leg Doppler reports. RESULTS: There were 773 patients in the before cohort and 861 in the after cohort (mean age, 74/74 years; men, 47%/45%; and ischemic stroke, 87%/85%, respectively). Symptomatic venous thromboembolism incidence was the same in both cohorts, 21 (2.7%) in the before cohort and 26 (3.0%) in the after cohort (P=0.8). There was a trend toward more deep vein thrombosis (9 [1.2%] versus 19 [2.2%]; P=0.1) and fewer pulmonary embolisms (12 [1.6%] versus 6 [0.7%]; P=0.2) in the after cohort. CONCLUSIONS: Discontinuation of compressive stockings did not increase venous thromboembolism incidence. There was a trend toward more deep vein thrombosis and fewer PEs after CLOTS, which might be because of increased clinical vigilance in the diagnosis of deep vein thrombosis, but a chance variation cannot be excluded. PMID- 23929743 TI - Genome-wide analysis of blood pressure variability and ischemic stroke. AB - BACKGROUND AND PURPOSE: Visit-to-visit variability in blood pressure (vBP) is associated with ischemic stroke. We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke. METHODS: A Genome Wide Association Study (GWAS) for loci influencing BP variability was undertaken in 3802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, in which long-term visit-to-visit and within-visit BP measures were available. Because BP variability is strongly associated with ischemic stroke, we genotyped the sentinel single nucleotide polymorphism in an independent ischemic stroke population comprising 8624 cases and 12 722 controls and in 3900 additional (Scandinavian) participants from the ASCOT study to replicate our findings. RESULTS: The ASCOT discovery GWAS identified a cluster of 17 correlated single nucleotide polymorphisms within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 (P=1.4*10(-8)). Conditional analysis of rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in patients with ischemic stroke found no association for overall stroke (odds ratio, 1.02; 95% CI, 0.97-1.07; P=0.52) or its subtypes: cardioembolic (odds ratio, 1.07; 95% CI, 0.97-1.16; P=0.17), large vessel disease (odds ratio, 0.98; 95% CI, 0.89-1.07; P=0.60), and small vessel disease (odds ratio, 1.07; 95% CI, 0.97-1.17; P=0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants (P=0.18). CONCLUSIONS: We identified a cluster of single nucleotide polymorphisms at the NLGN1 locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes. PMID- 23929746 TI - Letter by Radecki regarding article, "safety of thrombolysis in stroke mimics: results from a multicenter cohort study". PMID- 23929745 TI - Serum brain-derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury: Framingham Study. AB - BACKGROUND AND PURPOSE: Brain-derived neurotrophic factor (BDNF), a major neurotrophin and vascular endothelial growth factor (VEGF) have a documented role in neurogenesis, angiogenesis, and neuronal survival. In animal experiments, they impact infarct size and functional motor recovery after an ischemic brain lesion. We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample. METHODS: In 3440 Framingham Study participants (mean age, 65+/-11 years; 56% women) who were free of stroke/transient ischemic attack (TIA), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological tests available (n=1863 and 2104, respectively; mean age, 61+/-9 years, 55% women, in each), we related baseline BDNF and logVEGF to log-white matter hyperintensity volume on brain MRI, and to visuospatial memory and executive function tests. RESULTS: During a median follow up of 10 years, 193 participants experienced incident stroke/TIA. In multivariable analyses adjusted for age, sex, and traditional stroke risk factors, lower BDNF and higher logVEGF levels were associated with an increased risk of incident stroke/TIA (hazard ratio comparing BDNF Q1 versus Q2-Q4, 1.47; 95% confidence interval, 1.09-2.00; P=0.012 and hazard ratio/SD increase in logVEGF, 1.21; 95% confidence interval, 1.04-1.40; P=0.012). Persons with higher BDNF levels had less log-white matter hyperintensity volume (beta+/-SE=-0.05+/ 0.02; P=0.025), and better visual memory (beta+/-SE=0.18+/-0.07; P=0.005). CONCLUSIONS: Lower serum BDNF and higher VEGF concentrations were associated with increased risk of incident stroke/TIA. Higher levels of BDNF were also associated with less white matter hyperintensity and better visual memory. Our findings suggest that circulating BDNF and VEGF levels modify risk of clinical and subclinical vascular brain injury. PMID- 23929747 TI - Longitudinal cortical volume changes correlate with motor recovery in patients after acute local subcortical infarction. AB - BACKGROUND AND PURPOSE: Secondary changes in the volume of motor-related cortical regions and the relationship with functional recovery during the acute stage after cerebral infarction have not been determined. In the present study, we quantified changes in gray matter (GM) volume in motor-related cortical regions and analyzed their correlations to clinical scores in patients with focal cerebral infarct. METHODS: Fifteen patients with acute subcortical infarct underwent longitudinal high-resolution structural MRI and clinical assessment 3 times during a 12-week period (weeks 1, 4, and 12). Fourteen age- and sex-matched controls underwent MRI examination. Voxel-based morphometry was used to quantify changes in global GM volume; in addition, relationships between GM volume changes in volumes of interest and clinical scores were analyzed. RESULTS: In patients with cerebral infarction, GM volumes detected by voxel-based morphometry both decreased and increased significantly in diffuse cortical regions during the observation period (P<0.001). GM volumes within volumes of interest decreased significantly in the ipsilateral supplementary motor area and contralateral insula, but they increased in the contralateral supplementary motor area over time (all P<0.017). The changes of GM volumes in the ipsilesional and contralesional supplementary motor area correlated with the changes in the Fugl Meyer scale scores (ipsilesional, rs=0.52; P=0.048; contralesional, rs=0.74; P=0.002) and Barthel Index (ipsilesional, rs=0.56; P=0.030; contralesional, rs=0.65; P=0.009). CONCLUSIONS: These results suggest that secondary GM changes occur in diffuse areas and structural changes in some specific motor-related cortex may inhibit or promote functional recovery after an acute subcortical cerebral infarct. PMID- 23929749 TI - Geometric, hemodynamic, and pathological study of a distal internal carotid artery aneurysm model in dogs. AB - BACKGROUND AND PURPOSE: We created a distal internal carotid artery side-wall aneurysm model in dogs and compared its geometric, hemodynamic, and histological similarities with human models. METHODS: Eight distal internal carotid artery shaped devices were constructed using rapid prototyping, and 8 aneurysms were created via surgical reconstruction and elastase incubation. The geometric and hemodynamic parameters of the aneurysm and the parent artery of the dog and human models were compared, and histological response was evaluated at 12 weeks. RESULTS: Eight aneurysms were successfully created with good geometric simulation of the arteries between the dog and human models. Hemodynamic analysis revealed similar changes in the hemodynamic parameters both in the aneurysm sac and in the parent artery of the dog and human models. Histological analysis revealed internal elastic lamina discontinuity, elastic fiber disruption, a thinner muscular layer, increased smooth muscle cell proliferation rate, increased inflammation cell infiltration, and higher matrix metalloproteinase-2 and matrix metalloproteinase-9 expression indices in the medial aneurysm wall. CONCLUSIONS: The distal internal carotid artery aneurysm model in dogs is feasible and exhibited considerable geometric, hemodynamic, and histological similarities with the original human models. PMID- 23929748 TI - Optimizing prediction scores for poor outcome after intra-arterial therapy in anterior circulation acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Intra-arterial therapy (IAT) promotes recanalization of large artery occlusions in acute ischemic stroke. Despite high recanalization rates, poor clinical outcomes are common. We attempted to optimize a score that combines clinical and imaging variables to more accurately predict poor outcome after IAT in anterior circulation occlusions. METHODS: Patients with acute ischemic stroke undergoing IAT at University of Texas (UT) Houston for large artery occlusions (middle cerebral artery or internal carotid artery) were reviewed. Independent predictors of poor outcome (modified Rankin Scale, 4-6) were studied. External validation was performed on IAT-treated patients at Emory University. RESULTS: A total of 163 patients were identified at UT Houston. Independent predictors of poor outcome (P<=0.2) were identified as score variables using sensitivity analysis and logistic regression. Houston Intra Arterial Therapy 2 (HIAT2) score ranges 0 to 10: age (<=59=0, 60-79=2, >=80 years=4), glucose (<150=0, >=150=1), National Institute Health Stroke Scale (<=10=0, 11-20=1, >=21=2), the Alberta Stroke Program Early CT Score (8-10=0, <=7=3). Patients with HIAT2>=5 were more likely to have poor outcomes at discharge (odds ratio, 6.43; 95% confidence interval, 2.75-15.02; P<0.001). After adjusting for reperfusion (Thrombolysis in Cerebral Infarction score>=2b) and time from symptom onset to recanalization, HIAT2>=5 remained an independent predictor of poor outcome (odds ratio, 5.88; 95% confidence interval, 1.96-17.64; P=0.02). Results from the cohort of Emory (198 patients) were consistent; patients with HIAT2 score>=5 had 6* greater odds of poor outcome at discharge and at 90 days. HIAT2 outperformed other previously published predictive scores. CONCLUSIONS: The HIAT2 score, which combines clinical and imaging variables, performed better than all previous scores in predicting poor outcome after IAT for anterior circulation large artery occlusions. PMID- 23929750 TI - Letter by Schlachetzki et al regarding article, "endovascular stroke therapy: tirofiban is associated with risk of fatal intracerebral hemorrhage and poor outcome". PMID- 23929751 TI - Response to letter regarding article, "endovascular stroke therapy: tirofiban is associated with risk of fatal intracerebral hemorrhage and poor outcome". PMID- 23929753 TI - Response to letter regarding article, "safety of thrombolysis in stroke mimics: results from a multicenter cohort study". PMID- 23929752 TI - Validation of the DRAGON score in 12 stroke centers in anterior and posterior circulation. AB - BACKGROUND AND PURPOSE: The DRAGON score predicts functional outcome in the hyperacute phase of intravenous thrombolysis treatment of ischemic stroke patients. We aimed to validate the score in a large multicenter cohort in anterior and posterior circulation. METHODS: Prospectively collected data of consecutive ischemic stroke patients who received intravenous thrombolysis in 12 stroke centers were merged (n=5471). We excluded patients lacking data necessary to calculate the score and patients with missing 3-month modified Rankin scale scores. The final cohort comprised 4519 eligible patients. We assessed the performance of the DRAGON score with area under the receiver operating characteristic curve in the whole cohort for both good (modified Rankin scale score, 0-2) and miserable (modified Rankin scale score, 5-6) outcomes. RESULTS: Area under the receiver operating characteristic curve was 0.84 (0.82-0.85) for miserable outcome and 0.82 (0.80-0.83) for good outcome. Proportions of patients with good outcome were 96%, 93%, 78%, and 0% for 0 to 1, 2, 3, and 8 to 10 score points, respectively. Proportions of patients with miserable outcome were 0%, 2%, 4%, 89%, and 97% for 0 to 1, 2, 3, 8, and 9 to 10 points, respectively. When tested separately for anterior and posterior circulation, there was no difference in performance (P=0.55); areas under the receiver operating characteristic curve were 0.84 (0.83-0.86) and 0.82 (0.78-0.87), respectively. No sex-related difference in performance was observed (P=0.25). CONCLUSIONS: The DRAGON score showed very good performance in the large merged cohort in both anterior and posterior circulation strokes. The DRAGON score provides rapid estimation of patient prognosis and supports clinical decision-making in the hyperacute phase of stroke care (eg, when invasive add-on strategies are considered). PMID- 23929754 TI - Hydrothermal synthesis of nickel oxide nanosheets for lithium-ion batteries and supercapacitors with excellent performance. AB - Nickel oxide nanosheets have been successfully synthesized by a facile ethylene glycol mediated hydrothermal method. The morphology and crystal structure of the nickel oxide nanosheets were characterized by X-ray diffraction, field-emission SEM, and TEM. When applied as electrode materials for lithium-ion batteries and supercapacitors, nickel oxide nanosheets exhibited a high, reversible lithium storage capacity of 1193 mA h g(-1) at a current density of 500 mA g(-1), an enhanced rate capability, and good cycling stability. Nickel oxide nanosheets also demonstrated a superior specific capacitance of 999 F g(-1) at a current density of 20 A g(-1) in supercapacitors. PMID- 23929755 TI - Withdrawal reflexes in the upper limb adapt to arm posture and stimulus location. AB - INTRODUCTION: Withdrawal reflexes in the leg adapt in a context-appropriate manner to remove the limb from noxious stimuli, but the extent to which withdrawal reflexes adapt in the arm remains unknown. METHODS: We examined the adaptability of withdrawal reflexes in response to nociceptive stimuli applied in different arm postures and to different digits. Reflexes were elicited at rest, and kinetic and electromyographic responses were recorded under isometric conditions, thereby allowing motorneuron pool excitability to be controlled. RESULTS: Endpoint force changed from a posterior-lateral direction in a flexed posture to predominantly a posterior direction in a more extended posture [change in force angle (mean +/- standard deviation) 35.6 +/- 5.0 degrees ], and the force direction changed similarly with digit I stimulation compared with digit V (change = 22.9 +/- 2.9 degrees ). CONCLUSIONS: The withdrawal reflex in the human upper limb adapts in a functionally relevant manner when elicited at rest. PMID- 23929756 TI - PCDH10 promoter hypermethylation is frequent in most histologic subtypes of mature lymphoid malignancies and occurs early in lymphomagenesis. AB - PCDH10 is epigenetically inactivated in multiple tumor types; however, studies in mature lymphoid malignancies are limited. Here, we have investigated the presence of promoter hypermethylation of the PCDH10 gene in a large cohort of well characterized subsets of lymphomas. PCDH10 promoter hypermethylation was identified by methylation-specific PCR in 57 to 100% of both primary B- and T cell lymphoma specimens and cell lines. These findings were further validated by Sequenom Mass-array analysis. Promoter hypermethylation was also identified in 28.6% cases of reactive follicular hyperplasia, more commonly occurring in states of immune deregulation and associated with rare presence of clonal karyotypic aberrations, suggesting that PCDH10 methylation occurs early in lymphomagenesis. PCDH10 expression was down regulated via promoter hypermethylation in T- and B cell lymphoma cell lines. The transcriptional down-regulation resulting from PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases in cell lines. Both T- and B-cell lymphoma cell lines harboring methylation-mediated inactivation of PCDH10 were resistant to doxorubicin treatment, suggesting that hypermethylation of this gene might contribute to chemotherapy response. PMID- 23929757 TI - Contribution of the pharyngeal plexus to vocal cord adduction. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to elucidate whether the pharyngeal plexus (PP) contributes to vocal cord adduction in the porcine model. STUDY DESIGN: Experimental study. METHODS: Thyroarytenoid (TA) muscle contraction was recorded electromyographically with electrical stimulation of the internal branch of the superior laryngeal nerve (iSLN) and PP in seven pigs. RESULTS: Glottic closure reflex (GCR) was detected with stimulation of the iSLN in all subjects. Electrical stimulation of the PP elicited a response from the TA in six of the seven pigs. In one subject, TA electromyography (EMG) mean latency was noted to be 18.8 msec, approximating that of GCR elicited by iSLN stimulation. Antidromic nerve pulses generated the responses from the TA with a medium latency (mean, 6.32 msec) in three of the seven pigs. TA EMG with a short latency (mean, 1.8 msec) was identified in two of the seven pigs. CONCLUSIONS: Electrical stimulation of both central and distal ends of the PP elicited vocal cord adduction. These results support the promise of future rehabilitative uses of the PP to treat dysfunctions of the iSLN or as a means of addressing many age-related or metabolic causes of protective laryngeal paresis. LEVEL OF EVIDENCE: NA. PMID- 23929758 TI - Comparison of laser ablation using multidirectional and forward-firing fiber in human thyroid gland: experimental study. AB - The aim of this study is to evaluate the differences between forward-firing and multidirectional lasers and to evaluate the effects of exposure times and power on laser ablation of thyroid tissue. This is an experimental, ex vivo study. The experiments were conducted on 3 thyroid glands using 2 power levels (3 and 5 W) and exposure times (3 and 5 minutes) with forward-firing and multidirectional lasers. The length and width of the demarcated zone were measured to assess the size of thermal effect. NADPH staining was performed to determine tissue viability. Thermal transformation caused by the forward-firing laser produced oval necrotic zones, whereas thermal transformation caused by the multidirectional-firing laser produced clear round necrotic zones, which clearly demarcated in both hematoxylin and eosin staining and NADH staining. PMID- 23929759 TI - Synthesis of a silylium zwitterion. PMID- 23929760 TI - The impact of acute kidney injury with temporary dialysis on the risk of fracture. AB - Acute kidney injury (AKI) has a negative impact on long-term renal function and prognosis. However, the association between acute renal dysfunction and long-term effects on bone disorders has not yet been characterized. Using a population based cohort study, we aimed to evaluate associations between AKI and long-term effects on bone fractures. We identified relevant data of all hospitalized patients aged >18 years with histories of dialysis-requiring AKI, with subsequent recovery and discharge, from the claim records of the Taiwan National Health Insurance database between 2000 and 2008. We determined long-term de novo bone fracture and all-cause mortality after patients' index-hospitalization discharge using propensity score-adjusted Cox proportional hazard model. Varying-time models were used to adjust for long-term effects of end-stage renal disease (ESRD) on main outcomes. Among 448 AKI patients who had dialysis and survived 90 days after index-hospitalization discharge without reentering dialysis, 273 were male (60.9%) with a mean age of 61.4 +/- 16.6 years. Controls included 1792 hospitalized patients without AKI, dialysis, or bone fracture history. In the AKI recovery group, bone fracture incidence was 320 per 10,000 person-years and hazard ratio (HR) of long-term bone fracture was 1.25 (p = 0.049) compared with the control group, independent of subsequent ESRD status (HR = 1.55; p = 0.01). Both AKI recovery status (HR = 2.31; p < 0.001) and time varying factor of bone fracture (HR = 1.43; p < 0.001) were independent predictors of mortality compared with controls. In conclusion, AKI requiring temporary dialysis independently increases long-term risk of bone fracture, regardless of subsequent progression to ESRD. Long-term bone fractures may negatively impact patient mortality. PMID- 23929761 TI - Constitutive NLRP3 activation: too much of a bad thing. PMID- 23929763 TI - Predictors of 30-day readmission in patients hospitalized with decompensated heart failure. AB - BACKGROUND: Heart failure (HF) is the leading cause of hospitalizations and readmissions in the United States. Approximately one-third of patients admitted for HF are readmitted within 3 months; however, there are few markers that can identify those at highest risk for readmission. The purpose of this study was to identify clinical and laboratory markers associated with hospital readmission in decompensated HF. HYPOTHESIS: Clinical and laboratory markers are associated with readmission rates in decompensated HF. METHODS: Clinical and laboratory data from 412 patients admitted with HF were analyzed using a multivariable logistic regression analysis to find predictors of HF readmission by 30 days. RESULTS: HF readmission rates at 30 days were lowest in those with at least 2 of the following discharge criteria: net fluid reduction >1.3 L (odds ratio [OR]: 0.27, P = 0.019), serum sodium level >135 (OR: 0.46, P = 0.034), and N-terminal brain natriuretic peptide level reduction >23% (OR: 0.11, P = 0.048). In multivariate analysis, those patients meeting >=2 criteria had a very low risk of 30-day readmission (OR: 0.10, 95% confidence interval: 0.01-0.68, P = 0.019) compared to patients who failed to meet 2 criteria. CONCLUSIONS: A negative fluid balance, normal serum sodium, and net reduction in N-terminal brain natriuretic peptide level during hospitalization may be important indices to target to help reduce the likelihood of HF readmission within 30 days. PMID- 23929762 TI - The human tongue slows down to speak: muscle fibers of the human tongue. AB - Little is known about the specializations of human tongue muscles. In this study, myofibrillar adenosine triphosphatase (mATPase) histochemical staining was used to study the percentage and distribution of slow twitch muscle fibers (slow MFs) within tongue muscles of four neurologically normal human adults and specimens from a 2-year-old human, a newborn human, an adult with idiopathic Parkinson's disease (IPD), and a macaque monkey. The average percentage of slow MFs in adult and the 2-year-old muscle specimens was 54%, the IPD was 45%, while the neonatal human (32%) and macaque monkey (28%) had markedly fewer slow MFs. In contrast, the tongue muscles of the rat and cat have been reported to have no slow MFs. There was a marked spatial gradient in the distribution of slow MFs with the highest percentages found medially and posteriorly. Normal adult tongue muscles were found to have a variety of uniquely specialized features including MF-type grouping (usually found in neuromuscular disorders), large amounts of loose connective tissue, and short branching MFs. In summary, normal adult human tongue muscles have by far the highest proportion of slow MFs of any mammalian tongue studied to date. Moreover, adult human tongue muscles have multiple unique anatomic features. As the tongue shape changes that are seen during speech articulation are unique to humans, we hypothesize that the large proportion of slow MFs and the anatomical specializations observed in the adult human tongue have evolved to perform these movements. PMID- 23929764 TI - The effect of early-life stress on memory systems supporting instrumental behavior. AB - People experiencing early-life stress (ELS) exhibit increased incidence of behaviors that lead to addiction and obesity as adults. Many of these behaviors may be viewed as resulting from an overreliance on habits as opposed to goal directed instrumental behavior. This increased habitization may result from alterations in the interactions between dorsolateral striatum-dependent and hippocampus-dependent learning systems. As an initial examination of this idea, we investigated the effect of ELS on instrumental learning and extinction. In Experiment 1, we examined the effect of ELS in two groups of people, one trained on a continuous reinforcement schedule and one trained on a partial reinforcement schedule. We found that people who experienced ELS had a diminished effect of the partial reinforcement schedule on extinction. In Experiment 2, we again manipulated reinforcement schedule and also challenged declarative memory by requiring subjects to perform a concurrent task. We found that the declarative challenge did not affect extinction responding in the non-ELS group. In a moderate-ELS group, we observed a diminished sensitivity to the reinforcement schedule during extinction only under divided attention. In the high-ELS group, we observed a reduced sensitivity to reinforcement schedule even in the absence of the declarative memory challenge, consistent with Experiment 1. Our results suggest that ELS reduces the tendency to use declarative, hippocampus-dependent memory in instrumental tasks in favor of habits. ELS may affect hippocampal development, thus altering the interaction between memory systems and potentially contributing to poor health outcomes. PMID- 23929765 TI - Multifunctional Co(0.85)Se-Fe(3)O(4) nanocomposites: controlled synthesis and their enhanced performances for efficient hydrogenation of p-nitrophenol and adsorbents. AB - A new kind of multifunctional Co0.85 Se-Fe3 O4 nanocomposites is synthesized by loading Fe3 O4 nanoparticles (NPs) with a size of about 5 nm on the surface of Co0.85 Se nanosheets under hydrothermal conditions without using any surfactant or structure-directing agents. The Co0.85 Se-Fe3 O4 nanocomposite exhibits remarkable catalytic performance for hydrogenation of p-nitrophenol (4-NP) at room temperature and good adsorption behavior for methylene blue trihydrate in water. This nanocomposite also shows a high specific surface area and magnetic separation capability for recyclable utilization. The enhanced performances both in catalysis and adsorption are better than either individual component of Co0.85 Se nanosheets or Fe3 O4 nanoparticles, demonstrating the possibility for designing new multifunctional nanocomposites with improved performances for catalysis, adsorbents, and other applications. PMID- 23929766 TI - Targeted disruption of Shp2 in chondrocytes leads to metachondromatosis with multiple cartilaginous protrusions. AB - Metachondromatosis is a benign bone disease predominantly observed in the hands and feet of children or young adults demonstrating two different manifestations: a cartilage-capped bony outgrowth on the surface of the bone called exostosis and ectopic cartilaginous nodules inside the bone called enchondroma. Recently, it has been reported that loss-of-function mutations of the SHP2 gene, which encodes the SHP2 protein tyrosine phosphatase, are associated with metachondromatosis. The purpose of this study was to investigate the role of SHP2 in postnatal cartilage development, which is largely unknown. We disrupted Shp2 during the postnatal stage of mouse development in a chondrocyte-specific manner using a tamoxifen-inducible system. We found tumor-like nodules on the hands and feet within a month after the initial induction. The SHP2-deficient mice demonstrated an exostosis-like and enchondroma-like phenotype in multiple bones of the hands, feet, and ribs as assessed by X-ray and micro-computed tomography (CT). Histological assessment revealed the disorganization of the growth plate cartilage, a cartilaginous protrusion from the epiphyseal bone, and ectopic cartilage nodules within the bones, which is consistent with the pathological features of metachondromatosis in humans (ie, both exostosis and enchondroma). At molecular levels, we observed an abundant expression of Indian hedgehog protein (IHH) and fibroblast growth factor 2 (FGF2) and impaired expression of mitogen activated protein kinases (MAPK) in the affected cartilage nodules in the SHP2 deficient mice. In summary, we have generated a mouse model of metachondromatosis that includes manifestations of exostosis and enchondroma. This study provides a novel model for the investigation of the pathophysiology of the disease and advances the understanding of metachondromatosis. This model will be useful to identify molecular mechanisms for the disease cause and progression as well as to develop new therapeutic strategies in the future. PMID- 23929767 TI - Oxygenation of ruthenium carbene complexes containing naphthothiophene or naphthofuran: spectroscopic and DFT studies. AB - The aryl propargylic alcohol 1-[2-(thiophen-3-yl)phenyl]prop-2-yn-1-ol (1a) is readily prepared from 2-(thiophen-3-yl)benzaldehyde. In the presence of visible light, treatment of 1a with one-half mole equivalent of [Ru]Cl ([Ru]=Cp(dppe)Ru) (dppe=1,2-bis(diphenylphosphino)ethane) and NH4PF6 in O2 affords the naphtha[2,1 b]thiophene-4-carbaldehyde (4a) in high yields. The cyclization reaction of 1a proceeds through the formation of the carbene complex 2a that contains the naphtha[2,1-b]thiophene ring, which is isolated in a 1:1 stoichiometric reaction. The C-C bond formation between the inner carbon of the terminal triple bond and the heterocyclic ring is confirmed by structure determination of 2a using single crystal X-ray diffraction analysis. Facile oxygenation of 2a by O2 yields the aldehyde product 4a accompanied by the formation of phosphine oxide of dppe. Oxygen is most likely activated by coordination to the ruthenium center when one PPh2 unit of the dppe ligand dissociates. This dissociated PPh2 unit then reacts with the coordinated oxygen nearby to generate half-oxidized dppe ligand and an unobserved oxo-carbene intermediate. Coupling of the oxo/carbene ligands followed by demetalation then yields 4a. Presumably the resulting complex with the half oxidized dppe ligand continuously promotes cyclization/oxygenation of 1a to yield the second aldehyde molecule. In alcohol such as MeOH or EtOH, the oxygenation reaction affords a mixture of 4a and the corresponding esters 5a or 5a'. Four other aryl propargylic alcohols 1b-e, which contain thiophen-2-yl, isopropenyl, fur-3-yl, and fur-2-yl, respectively, on the aryl ring are also prepared. Analogous aldehydes 4b-e are similarly prepared from 1b-e, respectively. For oxygenations of 1b, 1d, and 1e in alcohol, mixtures of aldehyde 4, ester 5, and acetal 8 are obtained. The carbene complex 2b obtained from 1b was also characterized by single-crystal X-ray diffraction analysis. The UV/Vis spectra of 2a and 2b consist of absorption bands with a high extinction coefficient. From DFT calculations on 2a and 2b, the visible light is found to populate the LUMO antibonding orbital of mainly Ru=C bonds, thereby weakening the Ru=C bond and promoting the oxygenation/demetalation reactions of 2. PMID- 23929768 TI - Polymerized microgel colloidal crystals: photonic hydrogels with tunable band gaps and fast response rates. AB - Into and out of the blue: The highly ordered structure of a PNIPAM microgel colloidal crystal (MCC) is stabilized by photopolymerization of its surface-bound vinyl groups. The resulting polymerized MCCs can respond reversibly and quickly to external stimuli, including temperature and ionic strength of the surrounding media, allowing the color and band gap to be finely tuned in the whole visible range. PMID- 23929769 TI - Disease progression during advanced fibrosis: IL28B genotype or HCV RNA levels? PMID- 23929770 TI - Active vitamin D treatment for reduction of residual proteinuria: a systematic review. AB - Despite renin-angiotensin-aldosterone system blockade, which retards progression of CKD by reducing proteinuria, many patients with CKD have residual proteinuria, an independent risk factor for disease progression. We aimed to address whether active vitamin D analogs reduce residual proteinuria. We systematically searched for trials published between 1950 and September of 2012 in the Medline, Embase, and Cochrane Library databases. All randomized controlled trials of vitamin D analogs in patients with CKD that reported an effect on proteinuria with sample size>=50 were selected. Mean differences of proteinuria change over time and odds ratios for reaching >=15% proteinuria decrease from baseline to last measurement were synthesized under a random effects model. From 907 citations retrieved, six studies (four studies with paricalcitol and two studies with calcitriol) providing data for 688 patients were included in the meta-analysis. Most patients (84%) used an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker throughout the study. Active vitamin D analogs reduced proteinuria (weighted mean difference from baseline to last measurement was -16% [95% CI, 13% to -18%]) compared with controls (+6% [95% CI, 0% to +12%]; P<0.001). Proteinuria reduction was achieved more commonly in patients treated with an active vitamin D analog (204/390 patients) than control patients (86/298 patients; OR, 2.72 [95% CI, 1.82 to 4.07]; P<0.001). Thus, active vitamin D analogs may further reduce proteinuria in CKD patients in addition to current regimens. Future studies should address whether vitamin D therapy also retards progressive renal functional decline. PMID- 23929771 TI - The pathogenesis of lupus nephritis. AB - Lupus nephritis is an immune complex GN that develops as a frequent complication of SLE. The pathogenesis of lupus nephritis involves a variety of pathogenic mechanisms. The extrarenal etiology of systemic lupus is based on multiple combinations of genetic variants that compromise those mechanisms normally assuring immune tolerance to nuclear autoantigens. This loss of tolerance becomes clinically detectable by the presence of antinuclear antibodies. In addition, nucleic acids released from netting or apoptotic neutrophils activate innate and adaptive immunity via viral nucleic acid-specific Toll-like receptors. Therefore, many clinical manifestations of systemic lupus resemble those of viral infection. In lupus, endogenous nuclear particles trigger IFN-alpha signaling just like viral particles during viral infection. As such, dendritic cells, T helper cells, B cells, and plasma cells all contribute to the aberrant polyclonal autoimmunity. The intrarenal etiology of lupus nephritis involves antibody binding to multiple intrarenal autoantigens rather than the deposition of circulating immune complexes. Tertiary lymphoid tissue formation and local antibody production add to intrarenal complement activation as renal immunopathology progresses. Here we provide an update on the pathogenic mechanisms that lead to lupus nephritis and provide the rationale for the latest and novel treatment strategies. PMID- 23929772 TI - Genetic deletion of cell division autoantigen 1 retards diabetes-associated renal injury. AB - Cell division autoantigen 1 (CDA1) enhances TGF-beta signaling in renal and vascular cells, and renal expression of CDA1 is elevated in animal models of diabetes. In this study, we investigated the genetic deletion of Tspyl2, the gene encoding CDA1, in C57BL6 and ApoE knockout mice. The increased renal expression of TGF-beta1, TGF-beta type I and II receptors, and phosphorylated Smad3 associated with diabetes in wild-type mice was attenuated in diabetic CDA1 knockout mice. Notably, CDA1 deletion significantly reduced diabetes-associated renal matrix accumulation and immunohistochemical staining for collagens III and IV and attenuated glomerular and tubulointerstitial injury indices, despite the presence of persistent hyperglycemia, polyuria, renal hypertrophy, and hyperfiltration. Furthermore, CDA1 deletion reduced gene expression of TGF-beta1 receptors in the kidney, resulting in a functionally attenuated response to exogenous TGF-beta, including reduced levels of phosphorylated Smad3 and ERK1/2, in primary kidney cells from CDA1 knockout animals. Taken together, these data suggest that CDA1 deletion reduces but does not block renal TGF-beta signaling. Because direct antagonism of TGF-beta or its receptors has unwanted effects, CDA1 may be a potential therapeutic target for retarding DN and perhaps, other kidney diseases associated with TGF-beta-mediated fibrogenesis. PMID- 23929773 TI - Nephrologist caseload and hemodialysis patient survival in an urban cohort. AB - Physician caseload may be a predictor of patient outcomes associated with various medical conditions and procedures, but the association between patient-physician ratio and mortality among patients undergoing hemodialysis has not been determined. We examined whether a higher patient-nephrologist ratio affects patient mortality risk using de-identified data from DaVita dialysis clinics and the U.S. Renal Data System. A total of 41 nephrologists with a caseload of 50-200 hemodialysis patients from an urban California region were retrospectively ranked according to their hemodialysis patient mortality rate during a 6-year period between 2001 and 2007. We calculated all-cause mortality hazard ratios for each nephrologist and compared patient- and provider-level characteristics between the 10 nephrologists with the highest patient mortality rates and the 10 nephrologists with the lowest patient mortality rates. Nephrologists with the lowest patient mortality rates had significantly lower patient caseloads than nephrologists with the highest mortality rates (median [interquartile range], 65 [55-76] versus 103 [78-144] patients per nephrologist, respectively; P<0.001). Additionally, patients treated by nephrologists with the lowest patient mortality rates received higher dialysis doses, had longer sessions, and received more kidney transplants. In demographic characteristic-adjusted analyses, each 50 patient increase in caseload was associated with a 2% increase in patient mortality risk (hazard ratio, 1.02; 95% confidence interval, 1.00 to 1.04; P<0.001). Hence, these results suggest that nephrologist caseload influences hemodialysis patient outcomes, and future research should focus on identifying the factors underlying this association. PMID- 23929774 TI - Microscopic clusters of sensory neurons in C1 spinal nerve roots and in the C1 level of the spinal accessory nerve in adult humans. AB - This study examined C1 spinal nerve roots and their anastomotic connections with the spinal accessory nerve for histological evidence of sensory neurons in adult humans. C1 spinal nerves and roots with the adjacent segments of the spinal accessory nerve and the spinal cord were dissected en bloc from cadaveric specimens, and prepared for histological study. Results show that in 39.3% of specimens studied, no sensory component to the C1 spinal nerve could be identified. The C1 dorsal root was present 35.7% of the time, and when present it always contained neuronal cell bodies. In the remaining specimens, the sensory contribution to the C1 spinal nerve came through an anastomotic connection with the spinal accessory nerve. The investigators were able to identify clusters of neuronal cell bodies along the spinal accessory nerve at the level of C1 in 100% of the specimens examined. PMID- 23929775 TI - MHC class I molecules are preferentially ubiquitinated on endoplasmic reticulum luminal residues during HRD1 ubiquitin E3 ligase-mediated dislocation. AB - Misfolded MHC class I heavy chains (MHC I HCs) are targeted for endoplasmic reticulum (ER)-associated degradation (ERAD) by the ubiquitin E3 ligase HRD1, and E2 ubiquitin conjugating enzyme UBE2J1, and represent one of the few known endogenous ERAD substrates. The mechanism by which misfolded proteins are dislocated across the ER membrane into the cytosol is unclear. Here, we investigate the requirements for MHC I ubiquitination and degradation and show that endogenous misfolded MHC I HCs are recognized in the ER lumen by EDEM1 in a glycan-dependent manner and targeted to the core SEL1L/HRD1/UBE2J1 complex. A soluble MHC I HC lacking its transmembrane domain and cytosolic tail uses the same ERAD components and is degraded as efficiently as wild-type MHC I. Unexpectedly, HRD1-dependent polyubiquitination is preferentially targeted to the ER luminal domain of full-length MHC I HCs, despite the presence of an exposed cytosolic C-terminal tail. MHC I luminal domain ubiquitination occurs before p97 ATPase-mediated extraction from the ER membrane and can be targeted to nonlysine, as well as lysine, residues. A subset of integral membrane proteins, therefore, requires an early dislocation event to expose part of their luminal domain to the cytosol, before HRD1-mediated polyubiquitination and dislocation. PMID- 23929776 TI - Probing the mechanisms of proton transfer in liquid water. PMID- 23929778 TI - Crystal structure of sialylated IgG Fc: implications for the mechanism of intravenous immunoglobulin therapy. PMID- 23929777 TI - UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling. AB - At our body surface, the epidermis absorbs UV radiation. UV overexposure leads to sunburn with tissue injury and pain. To understand how, we focus on TRPV4, a nonselective cation channel highly expressed in epithelial skin cells and known to function in sensory transduction, a property shared with other transient receptor potential channels. We show that following UVB exposure mice with induced Trpv4 deletions, specifically in keratinocytes, are less sensitive to noxious thermal and mechanical stimuli than control animals. Exploring the mechanism, we find that epidermal TRPV4 orchestrates UVB-evoked skin tissue damage and increased expression of the proalgesic/algogenic mediator endothelin 1. In culture, UVB causes a direct, TRPV4-dependent Ca(2+) response in keratinocytes. In mice, topical treatment with a TRPV4-selective inhibitor decreases UVB-evoked pain behavior, epidermal tissue damage, and endothelin-1 expression. In humans, sunburn enhances epidermal expression of TRPV4 and endothelin-1, underscoring the potential of keratinocyte-derived TRPV4 as a therapeutic target for UVB-induced sunburn, in particular pain. PMID- 23929779 TI - Recent diversification of a marine genus (Tursiops spp.) tracks habitat preference and environmental change. AB - Understanding the evolution of diversity and the resulting systematics in marine systems is confounded by the lack of clear boundaries in oceanic habitats, especially for highly mobile species like marine mammals. Dolphin populations and sibling species often show differentiation between coastal and offshore habitats, similar to the pelagic/littoral or benthic differentiation seen for some species of fish. Here we test the hypothesis that lineages within the polytypic genus Tursiops track past changes in the environment reflecting ecological drivers of evolution facilitated by habitat release. We used a known recent time point for calibration (the opening of the Bosphorus) and whole mitochondrial genome (mitogenome) sequences for high phylogenetic resolution. The pattern of lineage formation suggested an origin in Australasia and several early divisions involving forms currently inhabiting coastal habitats. Radiation in pelagic environments was relatively recent, and was likely followed by a return to coastal habitat in some regions. The timing of some nodes defining different ecotypes within the genus clustered near the two most recent interglacial transitions. A signal for an increase in diversification was also seen for dates after the last glacial maximum. Together these data suggest the tracking of habitat preference during geographic expansions, followed by transition points reflecting habitat shifts, which were likely associated with periods of environmental change. PMID- 23929780 TI - Stress and the engagement of multiple memory systems: integration of animal and human studies. AB - Learning and memory can be controlled by distinct memory systems. How these systems are coordinated to optimize learning and behavior has long been unclear. Accumulating evidence indicates that stress may modulate the engagement of multiple memory systems. In particular, rodent and human studies demonstrate that stress facilitates dorsal striatum-dependent "habit" memory, at the expense of hippocampus-dependent "cognitive" memory. Based on these data, a model is proposed which states that the impact of stress on the relative use of multiple memory systems is due to (i) differential effects of hormones and neurotransmitters that are released during stressful events on hippocampal and dorsal striatal memory systems, thus changing the relative strength of and the interactions between these systems, and (ii) a modulatory influence of the amygdala which biases learning toward dorsal striatum-based memory after stress. This shift to habit memory after stress can be adaptive with respect to current performance but might contribute to psychopathology in vulnerable individuals. PMID- 23929782 TI - Concurrent extraction, clean-up, and analysis of polybrominated diphenyl ethers, hexabromocyclododecane isomers, and tetrabromobisphenol A in human milk and serum. AB - A method has been developed and validated for the concurrent extraction, clean up, and analysis of polybrominated diphenyl ethers (PBDEs), alpha-, beta-, and gamma-hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA) in human milk and serum. Milk and serum samples were extracted using accelerated solvent extraction with acetone/hexane 1:1, v/v and liquid-liquid extraction with methyl tert-butyl ether/hexane 1:1, v/v, respectively. The removal of co-extracted biogenic materials was achieved by gel permeation chromatography followed by sulfuric acid treatment. The fractionation of the PBDEs and HBCD/TBBPA was performed using a Supelco LC-Si SPE cartridge. The detection of the PBDEs was then performed by GC-MS and that of the HBCDs and the TBBPA was performed using UPLC-MS/MS. The pretreatment procedure was optimized, and the characteristic ions and fragmentation of the analytes were studied by MS or MS/MS. A recovery test was performed using a matrix spiking test at concentrations of 0.05-10 ng/g. The recoveries ranged from 78.6-108.8% with RSDs equal to or lower than 14.04%. The LODs were 1.8-60 pg/g. The usefulness of the developed method was tested by the analysis of real human samples, and several brominated flame retardants in different samples were detected and analyzed. PMID- 23929781 TI - Anemia and associated clinical outcomes in patients with heart failure due to reduced left ventricular systolic function. AB - BACKGROUND: Anemia is associated with decreased functional capacity, reduced quality of life, and worsened outcomes among patients with heart failure (HF) due to reduced left ventricular ejection fraction (HFREF). We sought to evaluate the independent effect of anemia on clinical outcomes among those with HFREF. HYPOTHESIS: Anemia is associated with cardiovascular events in patients with heart failure. METHODS: The HF-ACTION trial was a prospective, randomized trial of exercise therapy vs usual care in 2331 patients with HFREF. Patients with New York Heart Association class II to IV HF and left ventricular ejection fractions of <= 35% were recruited. Hemoglobin (Hb) was measured up to 1 year prior to entry and was stratified by quintile. Anemia was defined as baseline Hb <13 g/dL and <12 g/dL in men and women, respectively. Hemoglobin was assessed in 2 models: a global prediction model that had been previously developed, and a modified model including variables associated with anemia and the studied outcomes. RESULTS: Hemoglobin was available at baseline in 1763 subjects (76% of total study population); their median age was 59.0 years, 73% were male, and 62% were Caucasian. The prevalence of anemia was 515/1763 (29%). Older age, female sex, African American race, diabetes, hypertension, and lower estimated glomerular filtration rates were all more frequent in lower Hb quintiles. Over a median follow-up of 30 months, the primary outcome of all-cause mortality or all-cause hospitalization occurred in 78% of those with anemia and 64% in those without (P < 0.001). The secondary outcomes of all-cause mortality alone,cardiovascular (CV) mortality or CV hospitalization, and CV mortality or HF hospitalization occurred in 23% vs 15%, 67% vs 54%, and 44 vs 29%, respectively (P < 0.001). Heart failure hospitalizations occurred in 36% vs 22%, and urgent outpatient visits for HF exacerbations occurred in 67% and 55%, respectively (P < 0.001). For the global model, there was an association observed for anemia and all-cause mortality or hospitalization (adjusted hazard ratio [HR]: 1.15, 95% confidence interval [CI]: 1.01-1.32, P = 0.04), but other outcomes were not significant at P < 0.05. In the modified model, the adjusted HR for anemia and the primary outcome of all-cause mortality or all-cause hospitalization was 1.25 (95% CI: 1.10-1.42, P < 0.001). There were independent associations between anemia and all-cause death (HR: 1.11, 95% CI: 0.87-1.42, P = 0.38), CV death or CV hospitalization (HR: 1.16, 95% CI: 1.01-1.33, P = 0.035), and CV death and HF hospitalization (HR: 1.27, 95% CI: 1.06-1.51, P = 0.008). CONCLUSIONS: Anemia modestly is associated with increased rates of death, hospitalization, and HF exacerbation in patients with chronic HFREF. After adjusting for other important covariates, anemia is independently associated with an excess hazard for all-cause mortality and all-cause hospitalization. Anemia is also associated with combinations of CV death and CV/HF hospitalizations as composite endpoints. PMID- 23929783 TI - Efficient dye-sensitized solar cells using a tetramethylthiourea redox mediator. AB - An organic redox couple tetramethylthiourea/tetramethylformaminium disulfide (TMTU/TMFDS(2+) ) is evaluated in dye-sensitized solar cells in conjunction with a series of indoline and ruthenium-based dyes. Of these, devices with indoline dye D205 show the best performance, with an optimized power conversion efficiency of 7.6 % under AM 1.5G 1 sun illumination. Charge collection and injection are highly efficient in all TMTU-based DSCs studied. Regeneration of indoline dyes is highly efficient, whereas regeneration of ruthenium dyes by TMTU is less efficient, accounting for their inferior performance. Impedance spectroscopy results reveal that using an optimized TMTU/TMFDS(2+) electrolyte solution, the TiO2 conduction band edge is 300-400 meV lower than when an optimized I3 (-) /I( ) electrolyte is used. The would-be loss in open-circuit voltage caused by the downward conduction band shift is mostly compensated by approximately the 200 meV lower redox level of the TMTU/TMFDS(2+) electrolyte and up to 1000 times slower recombination rates. This makes TMTU/TMFDS(2+) a promising redox couple in the development of highly efficient solar energy conversion devices. PMID- 23929785 TI - Catalytic asymmetric beta,gamma activation of alpha,beta-unsaturated gamma butyrolactams: direct approach to beta,gamma-functionalized dihydropyranopyrrolidin-2-ones. AB - Skeleton in the closet: The title reaction enables the development of the first catalytic beta,gamma-selective Diels-Alder [4+2] annulation of alpha,beta unsaturated gamma-butyrolactams (see scheme; Boc=tert-butoxycarbonyl, Ts=4 toluenesulfonyl). This process provides a direct method for the enantioselective construction of bi- or tricyclic dihydropyranopyrrolidin-2-one skeletons in only one step. PMID- 23929784 TI - Bone loss after bariatric surgery: discordant results between DXA and QCT bone density. AB - Several studies, using dual-energy X-ray absorptiometry (DXA), have reported substantial bone loss after bariatric surgery. However, profound weight loss may cause artifactual changes in DXA areal bone mineral density (aBMD) results. Assessment of volumetric bone mineral density (vBMD) by quantitative computed tomography (QCT) may be less susceptible to such artifacts. We assessed changes in BMD of the lumbar spine and proximal femur prospectively for 1 year using DXA and QCT in 30 morbidly obese adults undergoing Roux-en-Y gastric bypass surgery and 20 obese nonsurgical controls. At 1 year, subjects who underwent gastric bypass surgery lost 37 +/- 2 kg compared with 3 +/- 2 kg lost in the nonsurgical controls (p < 0.0001). Spine BMD declined more in the surgical group than in the nonsurgical group whether assessed by DXA (-3.3 versus -1.1%, p = 0.034) or by QCT (-3.4 versus 0.2%, p = 0.010). Total hip and femoral neck aBMD declined significantly in the surgical group when assessed by DXA (-8.9 versus -1.1%, p < 0.0001 for the total hip and -6.1 versus -2.0%, p = 0.002 for the femoral neck), but no changes in hip vBMD were noted using QCT. Within the surgical group, serum P1NP and CTX levels increased by 82% +/- 10% and by 220% +/- 22%, respectively, by 6 months and remained elevated over 12 months (p < 0.0001 for all). Serum calcium, vitamin D, and PTH levels remained stable in both groups. We conclude that moderate vertebral bone loss occurs in the first year after gastric bypass surgery. However, striking declines in DXA aBMD at the proximal femur were not confirmed with QCT vBMD measurements. These discordant results suggest that artifacts induced by large changes in body weight after bariatric surgery affect DXA and/or QCT measurements of bone, particularly at the hip. PMID- 23929786 TI - Beta-blockers in cirrhosis patients with refractory ascites. PMID- 23929787 TI - More is less: pitch discrimination and language delays in children with optimal outcomes from autism. AB - The autism spectrum disorders (ASD) are neurodevelopmental disorders diagnosed behaviorally but associated with differences in brain development. Individuals with ASD exhibit superior auditory perceptual skills, which may correlate with ASD symptomatology, particularly language skills. We describe findings from individuals diagnosed with ASD before age five, who now have no symptoms (e.g., having optimal outcomes). Unlike an ASD group, which shows heightened pitch discrimination, the Optimal Outcome group's abilities do not differ from those of typically developing controls. Furthermore, pitch discrimination is associated with both current autism symptomatology and early-language milestones. Findings illuminate processes associated with resolution of autism. We also discuss a specific mechanism by which heightened auditory discrimination leads to language delays in ASD. PMID- 23929789 TI - Early NT-proBNP decrease with ivabradine in ambulatory patients with systolic heart failure. AB - BACKGROUND: Heart rate (HR) reduction in patients with systolic heart failure (HF) is a cornerstone of current therapy. The aim of this study was to evaluate the short-term effect of the HR reduction with ivabradine on N-terminal pro-brain natriuretic peptide (NT-proBNP) in outpatients with systolic HF. HYPOTHESIS: Ivabradine improves survival and promotes left ventricle remodelling by reducing resting heart rate. Nt-ProBNP absolute and trends predict prognosis. We hypothesized a possible association between heart rate decrease and Nt-ProBNP values. METHODS: We included 25 outpatients with systolic HF on optimized medical therapy (80% on angiotensin-converting enzyme inhibitors, 56% on spironolactone, and 88% on beta-blocker therapy), left ventricle ejection fraction <40%, and sinus rhythm and HR >70/bpm. After a 1 month running-out period, to establish the clinical and NT-proBNP stability, patients were started on ivabradine for 3 months. RESULTS: Ivabradine decreased NT-proBNP (P = 0.002) from a median of 2850 pg/mL to 1802 pg/mL, corresponding to a median absolute and percent decrease of 964 pg/mL and 44.5%, respectively. The baseline HR correlated significantly with the baseline NT-proBNP (rs = 0.411, P = 0.041). The absolute and percent HR decrease correlated with the absolute NT-proBNP decrease (rs = 0.442, P = 0.027; rs = 0.395, P = 0.05). The greater the NT-proBNP absolute decrease tertile, the greater the baseline HR (P = 0.023) and the absolute (P = 0.028) and percent (P = 0.064) HR variation. CONCLUSIONS: In outpatients with systolic HF, the NT-proBNP reduction obtained by short-term ivabradine treatment correlates closely with the degree of HR reduction. PMID- 23929790 TI - The yin and the yang of immunosuppression with inhaled corticosteroids. PMID- 23929791 TI - Comparison of microwave-assisted and conventional extraction of mangiferin from mango (Mangifera indica L.) leaves. AB - Mangiferin is the main bioactive component in mango leaves, which possesses anti inflammatory, antioxidative, antidiabetic, immunomodulatory, and antitumor activities. In the present study, a microwave-assisted extraction method was developed for the extraction of mangiferin from mango leaves. Some parameters such as ethanol concentration, liquid-to-solid ratio, microwave power, and extraction time were optimized by single-factor experiments and response surface methodology. The optimal extraction conditions were 45% ethanol, liquid-to-solid ratio of 30:1 (mL/g), and extraction time of 123 s under microwave irradiation of 474 W. Under optimal conditions, the yield of mangiferin was 36.10 +/- 0.72 mg/g, significantly higher than that of conventional extraction. The results obtained are beneficial for the full utilization of mango leaves and also indicate that microwave-assisted extraction is a very useful method for extracting mangiferin from plant materials. PMID- 23929792 TI - Three-dimensional superwetting mesh film based on graphene assembly for liquid transportation and selective absorption. AB - Superwetting membranes or porous absorbent materials have recently attracted considerable interest from both commercial and academic communities due to their excellent performance for separation or selective absorption of organic compounds and oils from water, which shows great potential for addressing environmental issues. Herein, the first example of engineering a commercially available stainless-steel grid based on the assembly of graphene for the fabrication of superwetting mesh films (SMFs) is reported. An excellent surface wettability of the SMFs, which exhibit a unique adhesion force to liquids, is observed; this makes it possible to transfer small quantities of liquid samples to perform microsample analysis. A three-dimensional SMF shows unprecedented performance in the separation, transportation, and selective absorption of organic compounds or oils from water. The performance is considerably improved in comparison to traditional separation/absorption technologies and may useful for a wide range of applications such as purification, water treatment, or oil-spill cleanup. PMID- 23929788 TI - Homeostatic regulation of memory systems and adaptive decisions. AB - While it is clear that many brain areas process mnemonic information, understanding how their interactions result in continuously adaptive behaviors has been a challenge. A homeostatic-regulated prediction model of memory is presented that considers the existence of a single memory system that is based on a multilevel coordinated and integrated network (from cells to neural systems) that determines the extent to which events and outcomes occur as predicted. The "multiple memory systems of the brain" have in common output that signals errors in the prediction of events and/or their outcomes, although these signals differ in terms of what the error signal represents (e.g., hippocampus: context prediction errors vs. midbrain/striatum: reward prediction errors). The prefrontal cortex likely plays a pivotal role in the coordination of prediction analysis within and across prediction brain areas. By virtue of its widespread control and influence, and intrinsic working memory mechanisms. Thus, the prefrontal cortex supports the flexible processing needed to generate adaptive behaviors and predict future outcomes. It is proposed that prefrontal cortex continually and automatically produces adaptive responses according to homeostatic regulatory principles: prefrontal cortex may serve as a controller that is intrinsically driven to maintain in prediction areas an experience dependent firing rate set point that ensures adaptive temporally and spatially resolved neural responses to future prediction errors. This same drive by prefrontal cortex may also restore set point firing rates after deviations (i.e. prediction errors) are detected. In this way, prefrontal cortex contributes to reducing uncertainty in prediction systems. An emergent outcome of this homeostatic view may be the flexible and adaptive control that prefrontal cortex is known to implement (i.e. working memory) in the most challenging of situations. Compromise to any of the prediction circuits should result in rigid and suboptimal decision making and memory as seen in addiction and neurological disease. PMID- 23929793 TI - Deletion of a single beta-catenin allele in osteocytes abolishes the bone anabolic response to loading. AB - The Wnt/beta-catenin signaling pathway is essential for bone cell viability and function and for skeletal integrity. To determine if beta-catenin in osteocytes plays a role in the bone anabolic response to mechanical loading, 18- to 24-week old osteocyte beta-catenin haploinsufficient mice (Dmp1-Cre * beta-catenin fl/ + ; HET cKO) were compared with their beta-catenin fl/fl (control) littermates. Trabecular bone volume (BV/TV) was significantly less (58.3%) in HET cKO females versus controls, whereas male HET cKO and control mice were not significantly different. Trabecular number was significantly less in HET cKO mice compared with controls for both genders, and trabecular separation was greater in female HET cKO mice. Osteoclast surface was significantly greater in female HET cKO mice. Cortical bone parameters in males and females showed subtle or no differences between HET cKO and controls. The right ulnas were loaded in vivo at 100 cycles, 2 Hz, 2500 uepsilon, 3 days per week for 3 weeks, and the left ulnas served as nonloaded controls. Calcein and alizarin complexone dihydrate were injected 10 days and 3 days before euthanization, respectively. Micro-computed tomography (uCT) analysis detected an 8.7% and 7.1% increase in cortical thickness in the loaded right ulnas of male and female control mice, respectively, compared with their nonloaded left ulnas. No significant increase in new cortical bone formation was observed in the HET cKO mice. Histomorphometric analysis of control mice showed a significant increase in endocortical and periosteal mineral apposition rate (MAR), bone-formation rate/bone surface (BFR/BS), BFR/BV, and BFR/TV in response to loading, but no significant increases were detected in the loaded HET cKO mice. These data show that deleting a single copy of beta-catenin in osteocytes abolishes the anabolic response to loading, that trabecular bone in females is more severely affected and suggest that a critical threshold of beta catenin is required for bone formation in response to mechanical loading. PMID- 23929794 TI - Maelstrom promotes hepatocellular carcinoma metastasis by inducing epithelial mesenchymal transition by way of Akt/GSK-3beta/Snail signaling. AB - Amplification of 1q is one of the most frequent chromosomal alterations in human hepatocellular carcinoma (HCC). In this study we identified and characterized a novel oncogene, Maelstrom (MAEL), at 1q24. Amplification and overexpression of MAEL was frequently detected in HCCs and significantly associated with HCC recurrence (P = 0.031) and poor outcome (P = 0.001). Functional study demonstrated that MAEL promoted cell growth, cell migration, and tumor formation in nude mice, all of which were effectively inhibited when MAEL was silenced with short hairpin RNA (shRNAs). Further study found that MAEL enhanced AKT activity with subsequent GSK-3beta phosphorylation and Snail stabilization, finally inducing epithelial-mesenchymal transition (EMT) and promoting tumor invasion and metastasis. In addition, MAEL up-regulated various stemness-related genes, multidrug resistance genes, and cancer stem cell (CSC) surface markers at the messenger RNA (mRNA) level. Functional study demonstrated that overexpression of MAEL increased self-renewal, chemoresistance, and tumor metastasis. CONCLUSION: MAEL is an oncogene that plays an important role in the development and progression of HCC by inducing EMT and enhancing the stemness of HCC. PMID- 23929795 TI - How does a specific learning and memory system in the mammalian brain gain control of behavior? AB - This review addresses a fundamental, yet poorly understood set of issues in systems neuroscience. The issues revolve around conceptualizations of the organization of learning and memory in the mammalian brain. One intriguing, and somewhat popular, conceptualization is the idea that there are multiple learning and memory systems in the mammalian brain and they interact in different ways to influence and/or control behavior. This approach has generated interesting empirical and theoretical work supporting this view. One issue that needs to be addressed is how these systems influence or gain control of voluntary behavior. To address this issue, we clearly specify what we mean by a learning and memory system. We then review two types of processes that might influence which memory system gains control of behavior. One set of processes are external factors that can affect which system controls behavior in a given situation including task parameters like the kind of information available to the subject, types of training experience, and amount of training. The second set of processes are brain mechanisms that might influence what memory system controls behavior in a given situation including executive functions mediated by the prefrontal cortex; switching mechanisms mediated by ascending neurotransmitter systems, the unique role of the hippocampus during learning. The issue of trait differences in control of different learning and memory systems will also be considered in which trait differences in learning and memory function are thought to potentially emerge from differences in level of prefrontal influence, differences in plasticity processes, differences in ascending neurotransmitter control, differential access to effector systems like motivational and motor systems. Finally, we present scenarios in which different mechanisms might interact. This review was conceived to become a jumping off point for new work directed at understanding these issues. The outcome of this work, in combination with other approaches, might improve understanding of the mechanisms of volition in human and non-human animals. PMID- 23929796 TI - Octahedral noble-metal nanoparticles and their electrocatalytic properties. AB - Octahedrally shaped noble-metal nanocrystals are fascinating for their unique properties, such as electrocatalytic, catalytic, plasmonic, and optical behavior, owing to their exclusively exposed {111} facets; Oh symmetric structure; and close-packed surface atoms in low-index surface categories, which are normally stable in a reaction. A series of protocols in the preparation of noble-metal nano-octahedra through a wet-chemical synthetic strategy have been developed in recent years. Herein, advances in synthetic approaches and mechanistic studies of noble-metal nano-octahedra are systematically discussed and key factors, including reduction kinetics, selective capping, and epitaxial growth, are outlined. Their unique performance as advanced electrocatalysts towards fuel-cell reactions is highlighted as well. PMID- 23929797 TI - Analysis of the magnetic properties of nitrogenase FeMo cofactor by single crystal EPR spectroscopy. AB - The catalytic center of nitrogenase, the [Mo:7Fe:9S:C]:homocitrate FeMo cofactor, is a S=3/2 system with a rhombic magnetic g tensor. Single-crystal EPR spectroscopy in combination with X-ray diffraction were used to determine the relative orientation of the g tensor with respect to the cluster structure. The protein environment influences the electronic structure of the FeMo cofactor, dictating preferred orientations of possible functional relevance. PMID- 23929798 TI - Clinical utility of a novel coronary heart disease risk-assessment test to further classify intermediate-risk patients. AB - BACKGROUND: Current coronary heart disease (CHD) risk assessments inadequately assess intermediate-risk patients, leaving many undertreated and vulnerable to heart attacks. A novel CHD risk-assessment (CHDRA) tool was developed for intermediate-risk stratification using biomarkers and established risk factors to significantly improve CHD risk discrimination. HYPOTHESIS: Physicians will change their treatment plan in response to more information about a patient's CHD risk level provided by the CHDRA test. METHODS: A Web-based survey of cardiology, internal medicine, family practice, and obstetrics/gynecology physicians (n = 206) was conducted to assess the CHDRA clinical impact. Each physician was shown 3 clinical vignettes representing community-based cohort participants randomly selected from 8 total vignettes. For each, the physicians assessed the individual's CHD risk and selected preferred therapies based on the individual's comorbidities, physical examination, and laboratory results. The individual's CHDRA score was then provided and the physicians were queried for changes to their initial treatment plans. RESULTS: After obtaining the CHDRA result, 70% of the physician responses indicated a change to the patient's treatment plan. The revised lipid-management plans agreed more often (74.6% of the time) with the current Adult Treatment Panel III guidelines than did the original plans (57.6% of the time). Most physicians (71.3%) agreed with the statement that the CHDRA result provided information that would impact their current treatment decisions. CONCLUSIONS: The CHDRA test provided additional information to which physicians responded by more often applying appropriate therapy and actions aligned with guidelines, thus demonstrating the clinical utility of the test. PMID- 23929799 TI - Imaging of inflammation by PET, conventional scintigraphy, and other imaging techniques. AB - Nuclear medicine imaging procedures play an important role in the assessment of inflammatory diseases. With the advent of 3-dimensional anatomic imaging, there has been a tendency to replace traditional planar scintigraphy by CT or MRI. Furthermore, scintigraphic techniques may have to be combined with other imaging modalities to achieve high sensitivity and specificity, and some may require time consuming labeling procedures. On the other hand, new developments such as combined SPECT/CT increase the diagnostic power of scintigraphy. Also, the advent of PET had a considerable impact on the use of nuclear medicine imaging techniques. In this review, we aim to provide nuclear medicine specialists and clinicians with the relevant information on rational and efficient use of nuclear medicine imaging techniques in the assessment of patients with osteomyelitis, infected vascular prostheses, metastatic infectious disease, rheumatoid arthritis, vasculitis, inflammatory bowel disease, sarcoidosis, and fever of unknown origin. PMID- 23929800 TI - Scintigraphic techniques for early detection of cancer treatment-induced cardiotoxicity. AB - New antitumor agents have resulted in significant survival benefits for cancer patients. However, several agents may have serious cardiovascular side effects. Left ventricular ejection fraction measurement by (99m)Tc multigated radionuclide angiography is regarded as the gold standard to measure cardiotoxicity in adult patients. It identifies left ventricular dysfunction with high reproducibility and low interobserver variability. A decrease in left ventricular ejection fraction, however, is a relatively late manifestation of myocardial damage. Nuclear cardiologic techniques that visualize pathophysiologic processes at the tissue level could detect myocardial injury at an earlier stage. These techniques may give the opportunity for timely intervention to prevent further damage and could provide insights into the mechanisms and pathophysiology of cardiotoxicity caused by anticancer agents. This review provides an overview of past, current, and promising newly developed radiopharmaceuticals and describes the role and recent advances of scintigraphic techniques to measure cardiotoxicity. Both first order functional imaging techniques (visualizing mechanical [pump] function), such as (99m)Tc multigated radionuclide angiography and (99m)Tc gated blood-pool SPECT, and third-order functional imaging techniques (visualizing pathophysiologic and neurophysiologic processes at the tissue level) are discussed. Third-order functional imaging techniques comprise (123)I metaiodobenzylguanidine scintigraphy, which images the efferent sympathetic nervous innervations; sympathetic neuronal PET, with its wide range of tracers; (111)In-antimyosin, which is a specific marker for myocardial cell injury and necrosis; (99m)Tc-annexin V scintigraphy, which visualizes apoptosis and cell death; fatty-acid-use scintigraphy, which visualizes the storage of free fatty acids in the lipid pool of the cytosol (which can be impaired by cardiotoxic agents); and (111)In-trastuzumab imaging, to study trastuzumab targeting to the myocardium. To define the prognostic importance and clinical value of each of these functional imaging techniques, prospective clinical trials are warranted. PMID- 23929806 TI - A unique family of rigid analogues of the GFP chromophore with tunable two-photon action cross-sections for biological imaging. AB - Conformationally restricted analogues of the GFP chromophore have been synthesized. The spectroscopic properties of GCTPOC, a unique family with tunable two-photon action cross-sections, were investigated. GCTPOC could be used as a robust two-photon platform for development of a two-photon fluorescent thiol sensor, which could stain endogenous thiols both in vitro and in vivo. PMID- 23929805 TI - Self-assembly in nature: using the principles of nature to create complex nanobiomaterials. AB - Self-assembly is a ubiquitous process in biology where it plays numerous important roles and underlies the formation of a wide variety of complex biological structures. Over the past two decades, materials scientists have aspired to exploit nature's assembly principles to create artificial materials, with hierarchical structures and tailored properties, for the fabrication of functional devices. Toward this goal, both biological and synthetic building blocks have been subject of extensive research in self-assembly. In fact, molecular self-assembly is becoming increasingly important for the fabrication of biomaterials because it offers a great platform for constructing materials with high level of precision and complexity, integrating order and dynamics, to achieve functions such as stimuli-responsiveness, adaptation, recognition, transport, and catalysis. The importance of peptide self-assembling building blocks has been recognized in the last years, as demonstrated by the literature available on the topic. The simple structure of peptides, as well as their facile synthesis, makes peptides an excellent family of structural units for the bottom up fabrication of complex nanobiomaterials. Additionally, peptides offer a great diversity of biochemical (specificity, intrinsic bioactivity, biodegradability) and physical (small size, conformation) properties to form self-assembled structures with different molecular configurations. The motivation of this review is to provide an overview on the design principles for peptide self-assembly and to illustrate how these principles have been applied to manipulate their self assembly across the scales. Applications of self-assembling peptides as nanobiomaterials, including carriers for drug delivery, hydrogels for cell culture and tissue repair are also described. PMID- 23929807 TI - The hard Test Your Memory. Evaluation of a short cognitive test to detect mild Alzheimer's disease and amnestic mild cognitive impairment. AB - OBJECTIVE: The aim of this study is the evaluation of a novel cognitive test, the hard Test Your Memory (H-TYM), in the detection of mild Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). METHODS: This paper uses a prospective study in an outpatient memory clinic. We recruited 97 patients with a diagnosis of mild AD or aMCI aged between 50 and 80 years. All scored 20 or more on the mini mental state examination (MMSE). We recruited 200 controls from a similar background. The patients were given a novel short cognitive test (H-TYM) designed to test recall of newly learnt visual and verbal material together with the Addenbrooke's Cognitive Assessment Revised, MMSE, and TYM test. RESULTS: Alzheimer's disease/aMCI patients completed the H-TYM with an average recall score of 6.69 (SD 3.45); control participants scored an average of 20.4 (SD 4.54). The H-TYM detected 95% of cases of mild AD/aMCI on the basis of an optimum cutoff point. The area under the receiver operating characteristic for the H-TYM ratio was calculated to be 0.989 with a 95% confidence interval of 0.980-0.997. CONCLUSIONS: The H-TYM test has an excellent ability to discriminate between AD/aMCI cases and healthy controls. The H-TYM is a useful tool for the detection of mild AD/aMCI, and it detects AD/aMCI in the majority of patients who "pass" the MMSE and Addenbrooke's Cognitive Assessment Revised. PMID- 23929809 TI - Factors that influence the relative use of multiple memory systems. AB - Neurobehavioral evidence supports the existence of at least two anatomically distinct "memory systems" in the mammalian brain that mediate dissociable types of learning and memory; a "cognitive" memory system dependent upon the hippocampus and a "stimulus-response/habit" memory system dependent upon the dorsolateral striatum. Several findings indicate that despite their anatomical and functional distinctiveness, hippocampal- and dorsolateral striatal-dependent memory systems may potentially interact and that, depending on the learning situation, this interaction may be cooperative or competitive. One approach to examining the neural mechanisms underlying these interactions is to consider how various factors influence the relative use of multiple memory systems. The present review examines several such factors, including information compatibility, temporal sequence of training, the visual sensory environment, reinforcement parameters, emotional arousal, and memory modulatory systems. Altering these parameters can lead to selective enhancements of either hippocampal-dependent or dorsolateral striatal-dependent memory, and bias animals toward the use of either cognitive or habit memory in dual-solution tasks that may be solved adequately with either memory system. In many learning situations, the influence of such experimental factors on the relative use of memory systems likely reflects a competitive interaction between the systems. Research examining how various factors influence the relative use of multiple memory systems may be a useful method for investigating how these systems interact with one another. PMID- 23929808 TI - Steroid use in acute liver failure. AB - Drug-induced and indeterminate acute liver failure (ALF) might be due to an autoimmune-like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune hepatitis, drug-induced, or indeterminate ALF, and whether this benefit varies according to the severity of illness. We conducted a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF patients in the Acute Liver Failure Study Group from 1998-2007. The primary endpoints were overall and spontaneous survival (SS, survival without transplant). In all, 361 ALF patients were studied, 66 with autoimmune (25 steroids, 41 no steroids), 164 with indeterminate (21 steroids, 143 no steroids), and 131 with drug-induced (16 steroids, 115 no steroids) ALF. Steroid use was not associated with improved overall survival (61% versus 66%, P = 0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including those with the highest quartile of the Model for Endstage Liver Disease (MELD) (>40, survival 30% versus 57%, P = 0.03). In multivariate analysis controlling for steroid use and diagnosis, age (odds ratio [OR] 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07), and pH < 7.4 (OR 3.09) were significantly associated with mortality. Although steroid use was associated with a marginal benefit in SS overall (35% versus 23%, P = 0.047), this benefit did not persistent in multivariate analysis; mechanical ventilation (OR 0.24), MELD (OR 0.93), and alanine aminotransferase (1.02) were the only significant predictors of SS. CONCLUSION: Corticosteroids did not improve overall survival or SS in drug-induced, indeterminate, or autoimmune ALF and were associated with lower survival in patients with the highest MELD scores. PMID- 23929810 TI - Au@Pd core-shell nanobricks with concave structures and their catalysis of ethanol oxidation. AB - Au@Pd core-shell nanobricks (CNBs) with concave surfaces and Pd shells with a thickness of approximately 5 nm were synthesized by co-reduction of HAuCl4 and H2 PdCl4 in the presence of Au seeds and Ag ions. These as-synthesized concave CNBs exhibit significantly enhanced catalytic activity for the electrooxidation of ethanol in alkaline media compared to the commercially-used Pd black. The improved performance of the Au@Pd CNBs can be attributed to the exposed stepped surfaces, high-index facets, and the synergistic effects of the core and shell metals. PMID- 23929811 TI - Reply: To PMID 23585361. PMID- 23929812 TI - Flavoured, non-cigarette tobacco for sale in the USA: an inventory analysis of Internet retailers. PMID- 23929813 TI - Fluorinated dendrimers as imaging agents for 19F MRI. AB - 19F is the second most sensitive stable nucleus for magnetic resonance imaging (MRI). Because there is no endogenous 19F signal, 19F MRI is much more suited for quantification and tracking than 1H MRI. However, 19F MRI is not in clinical use because in spite of more than three decades of research, there are no approved 19F imaging agents. New approaches and new methodologies are needed to move the field forward. Water-soluble fluorinated dendrimers present a promising alternative to conventional perfluorocarbon emulsions. This article outlines recent development of fluorinated dendrimers as 19F imaging agents. This is not meant to be a comprehensive review of 19F imaging agents, for which there is an excellent recent review by Knight et al. Rather, the article aims to give an insider's account on research efforts in this exciting and challenging field. PMID- 23929814 TI - pH-Switchable ampholytic supramolecular copolymers. AB - beta-sheet-encoded anionic and cationic dendritic peptide amphiphiles form supramolecular copolymers when self-assembled in a 1:1 feed ratio of the monomers. These ampholytic materials have been designed for on-off polymerization in response to pH triggers. The cooperative supramolecular self-assembly process is switched on at a physiologically relevant pH value and can be switched off by increasing or decreasing the pH value. PMID- 23929819 TI - Parallel processing of information about location in the amygdala, entorhinal cortex and hippocampus. AB - The conditioned cue preference paradigm was used to study how rats use extra-maze cues to discriminate between 2 adjacent arms on an 8-arm radial maze, a situation in which most of the same cues can be seen from both arms but only one arm contains food. Since the food-restricted rats eat while passively confined on the food-paired arm no responses are reinforced, so the discrimination is due to Pavlovian stimulus-reward (or outcome) learning. Consistent with other evidence that rats must move around in an environment to acquire a spatial map, we found that learning the adjacent arms CCP (ACCP) required a minimum amount of active exploration of the maze with no reinforcers present prior to passive pairing of the extra-maze cues with the food reinforcer, an instance of latent learning. Temporary inactivation of the hippocampus during the pre-exposure sessions had no effect on ACCP learning, confirming other evidence that the hippocampus is not involved in latent learning. A series of experiments indentified a circuit involving fimbria-fornix and dorsal entorhinal cortex as the neural basis of latent learning in this situation. In contrast, temporary inactivation of the entorhinal cortex or hippocampus during passive training or during testing blocked ACCP learning and expression, respectively, suggesting that these two structures co-operate in using spatial information to learn the location of food on the maze during passive pairing and to express this combined information during testing. In parallel with these processes we found that the amygdala processes information leading to an equal tendency to enter both adjacent arms (even though only one was paired with food) suggesting that the stimulus information available to this structure is not sufficiently precise to discriminate between the ambiguous cues visible from the adjacent arms. Expression of the ACCP in normal rats depends on hippocampus-based learning to avoid the unpaired arm which competes with the amygdala-based tendency to enter that arm. In contrast, there is cooperation between amygdala- and hippocampus based tendencies to enter the food-paired arm. These independent forms of learning contribute to the rat's ability to discriminate among spatial locations using ambiguous extra-maze cues. PMID- 23929820 TI - Erythropoietin in patients with acute myocardial infarction: no proof of effectiveness or proof of no effectiveness? PMID- 23929821 TI - Resiliency of the plasma membrane and actin cortex to large-scale deformation. AB - The tight coupling between the plasma membrane and actin cortex allows cells to rapidly change shape in response to mechanical cues and during physiological processes. Mechanical properties of the membrane are critical for organizing the actin cortex, which ultimately governs the conversion of mechanical information into signaling. The cortex has been shown to rapidly remodel on timescales of seconds to minutes, facilitating localized deformations and bundling dynamics that arise during the exertion of mechanical forces and cellular deformations. Here, we directly visualized and quantified the time-dependent deformation and recovery of the membrane and actin cortex of HeLa cells in response to externally applied loads both on- and off-nucleus using simultaneous confocal and atomic force microscopy. The local creep-like deformation of the membrane and actin cortex depends on both load magnitude and duration and does not appear to depend on cell confluency. The membrane and actin cortex rapidly recover their initial shape after prolonged loading (up to 10 min) with large forces (up to 20 nN) and high aspect ratio deformations. Cytoplasmic regions surrounding the nucleus are shown to be more resistant to long-term creep than nuclear regions. These dynamics are highly regulated by actomyosin contractility and an intact actin cytoskeleton. Results suggest that in response to local deformations, the nucleus does not appear to provide significant resistance or play a major role in cell shape recovery. The membrane and actin cortex clearly possess remarkable mechanical stability, critical for the transduction of mechanical deformation into long term biochemical signals and cellular remodeling. PMID- 23929822 TI - Genetic inactivation of the allograft inflammatory factor-1 locus. AB - Allograft inflammatory factor-1 (Aif-1) is a 17 kDa EF hand motif-bearing protein expressed primarily in developing spermatids and cells of monocyte/macrophage lineage. Increased Aif-1 expression has been identified in clinically important conditions, including rheumatoid arthritis, systemic sclerosis, endometriosis, and transplant-associated arteriosclerosis. Largely similar gene products arising from the same locus are known as ionized Ca(2+) binding adapter-1 (Iba1), microglial response factor-1 (MRF1), and daintain; Iba1 in particular has emerged as a histologic marker of microglia and their activation in pathologic CNS conditions, including the response to facial nerve axotomy and stroke, uveitis, and experimental autoimmune neuritis and encephalomyelitis. Nevertheless, how aif 1 gene products affect cellular function is only partly understood, and the physiologic significance of these products for male fertility, immune system development, and inflammation has not been described. To permit such investigations, we generated a mouse line with targeted deletion of the coding regions of the aif-1 gene. Here we report that mice lacking Aif-1 breed well and show normal post-natal growth, but show resistance to disease in a model of collagen-induced arthritis. We anticipate that these mice will be useful for studies of Aif-1 function in a variety of immune and inflammatory disease models. PMID- 23929823 TI - A high-resolution structure that provides insight into coiled-coil thiodepsipeptide dynamic chemistry. AB - Stable and reactive: A crystal structure at 1.35 A of a thioester coiled-coil protein reveals high similarity to all-peptide-bond proteins. In these assemblies, the thioester bonds are kept reactive towards thiol molecules in the mixture. This enables efficient domain exchange between proteins in response to changes in folding conditions or introduction of external templates. PMID- 23929824 TI - Comparative biodistribution and radiation dosimetry of 68Ga-DOTATOC and 68Ga DOTATATE in patients with neuroendocrine tumors. AB - (68)Ga-DOTATOC and (68)Ga-DOTATATE are 2 radiolabeled somatostatin analogs for in vivo diagnosis of neuroendocrine tumors with PET. The aim of the present work was to measure their comparative biodistribution and radiation dosimetry. METHODS: Ten patients diagnosed with neuroendocrine tumors were included. Each patient underwent a 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 3 h after injection of each tracer on consecutive days. Absorbed doses were calculated using OLINDA/EXM 1.1. RESULTS: Data from 9 patients could be included in the analysis. Of the major organs, the highest uptake at 1, 2, and 3 h after injection was observed in the spleen, followed by kidneys and liver. For both tracers, the highest absorbed organ doses were seen in the spleen and urinary bladder wall, followed by kidney, adrenals, and liver. The absorbed doses to the liver and gallbladder wall were slightly but significantly higher for (68)Ga DOTATATE. The total effective dose was 0.021 +/- 0.003 mSv/MBq for both tracers. CONCLUSION: The effective dose for a typical 100-MBq administration of (68)Ga DOTATATE and (68)Ga-DOTATOC is 2.1 mSv for both tracers. Therefore, from a radiation dosimetry point of view, there is no preference for either tracer for PET/CT evaluation of somatostatin receptor-expressing tumors. PMID- 23929825 TI - Surveillance of cancer patients with imaging: self-evident or evidence-based? PMID- 23929826 TI - A designed 5-fluorouracil-based bridged silsesquioxane as an autonomous acid triggered drug-delivery system. AB - Two new prodrugs, bearing two and three 5-fluorouracil (5-FU) units, respectively, have been synthesized and were shown to efficiently treat human breast cancer cells. In addition to 5-FU, they were intended to form complexes through H-bonds to an organo-bridged silane prior to hydrolysis-condensation through sol-gel processes to construct acid-responsive bridged silsesquioxanes (BS). Whereas 5-FU itself and the prodrug bearing two 5-FU units completely leached out from the corresponding materials, the prodrug bearing three 5-FU units was successfully maintained in the resulting BS. Solid-state NMR ((29) Si and (13) C) spectroscopy show that the organic fragments of the organo-bridged silane are retained in the hybrid through covalent bonding and the (1) H NMR spectroscopic analysis provides evidence for the hydrogen-bonding interactions between the prodrug bearing three 5-FU units and the triazine-based hybrid matrix. The complex in the BS is not affected under neutral medium and operates under acidic conditions even under pH as high as 5 to deliver the drug as demonstrated by HPLC analysis and confirmed by FTIR and (13) C NMR spectroscopic studies. Such functional BS are promising materials as carriers to avoid the side effects of the anticancer drug 5-FU thanks to a controlled and targeted drug delivery. PMID- 23929827 TI - Predictors of short-term outcome to exercise and manual therapy for people with hip osteoarthritis. AB - BACKGROUND: Physical therapy for hip osteoarthritis (OA) has shown short-term effects but limited long-term benefit. There has been limited research, with inconsistent results, in identifying prognostic factors associated with a positive response to physical therapy. OBJECTIVES: The purpose of this study was to identify potential predictors of response to physical therapy (exercise therapy [ET] with or without adjunctive manual therapy [MT]) for hip OA based on baseline patient-specific and clinical characteristics. DESIGN: A prognostic study was conducted. METHODS: Secondary analysis of data from a multicenter randomized controlled trial (RCT) (N=131) that evaluated the effectiveness of ET and ET+MT for hip OA was undertaken. Treatment response was defined using OMERACT/OARSI responder criteria. Ten baseline measures were used as predictor variables. Regression analyses were undertaken to identify predictors of outcome. Discriminative ability (sensitivity, specificity, and likelihood ratios) of significant variables was calculated. RESULTS: The RCT results showed no significant difference in most outcomes between ET and ET+MT at 9 and 18 weeks posttreatment. Forty-six patients were classified as responders at 9 weeks, and 36 patients were classified as responders at 18 weeks. Four baseline variables were predictive of a positive outcome at 9 weeks: male sex, pain with activity (<6/10), Western Ontario and McMaster Universities Osteoarthritis Index physical function subscale score (<34/68), and psychological health (Hospital Anxiety and Depression Scale score <9/42). No predictor variables were identified at the 18 week follow-up. Prognostic accuracy was fair for all 4 variables (sensitivity=0.5 0.58, specificity=0.57-0.72, likelihood ratios=1.25-1.77), indicating fair discriminative ability at predicting treatment response. LIMITATIONS: The short term follow-up limits the interpretation of results, and the low number of identified responders may have resulted in possible overfitting of the predictor model. CONCLUSIONS: The authors were unable to identify baseline variables in patients with hip OA that indicate those most likely to respond to treatment due to low discriminative ability. Further validation studies are needed to definitively define the best predictors of response to physical therapy in people with hip OA. PMID- 23929828 TI - Locomotor requirements for bipedal locomotion: a Delphi survey. AB - BACKGROUND: Bipedal locomotor control requirements may be useful as classifications for walking dysfunction because they go beyond gait analysis to address all issues contributing to walking dysfunction. OBJECTIVE: The objective of this study was to determine whether locomotor experts could achieve consensus about the requirements for bipedal locomotion. DESIGN AND METHODS: Locomotor experts from physical therapy and other related professions participated in an electronic mail Delphi survey. Experts recommended additions, deletions, rewording, and merges for 15 proposed locomotor requirements in round 1. In rounds 2 and 3, panelists commented on and rated the validity, mutual exclusiveness, and understandability of each requirement. Consensus was defined a priori as: (1) 75% or more panelists agree or strongly agree that a requirement is valid, mutually exclusive, and understandable in round 3; (2) no difference between round 2 and 3 ratings with kappa coefficients >=.60; and (3) a reduction in panelists who commented and convergence of comments between rounds 1 and 3. Content analysis and nonparametric statistics were used. RESULTS: Fifty-eight panelists reached full consensus on 5 locomotor requirements (Initiation, Termination, Anticipatory Dynamic Balance, Multi-Task Capacity, and Walking Confidence) and partial consensus for 7 other requirements. There were no significant differences in ratings between rounds 2 and 3, and there was a decrease in the percentage of panelists who commented between rounds 1 and 3. LIMITATIONS: The study's 6-month time frame may have contributed to panelist attrition. CONCLUSIONS: Locomotor experts achieved consensus on several bipedal locomotor requirements. With validation, these requirements can provide the framework for a clinically feasible and systematic diagnostic tool for physical therapists to categorize locomotor problems and standardize intervention for walking dysfunction. PMID- 23929829 TI - Polymeric microtubules that breathe: CO2 -driven polymer controlled-self-assembly and shape transformation. AB - Tubular breathing motion: Polymer tubules self-assembled from a gas-sensitive triblock copolymer can undergo shape evolution. A sequence from microtubes through submicroscopic vesicles to nanosized spherical micelles is modulated by CO2 stimulation levels. PMID- 23929830 TI - Abnormality in face scanning by children with autism spectrum disorder is limited to the eye region: evidence from multi-method analyses of eye tracking data. AB - There has been considerable controversy regarding whether children with autism spectrum disorder (ASD) and typically developing children (TD) show different eye movement patterns when processing faces. We investigated ASD and age- and IQ matched TD children's scanning of faces using a novel multi-method approach. We found that ASD children spent less time looking at the whole face generally. After controlling for this difference, ASD children's fixations of the other face parts, except for the eye region, and their scanning paths between face parts were comparable either to the age-matched or IQ-matched TD groups. In contrast, in the eye region, ASD children's scanning differed significantly from that of both TD groups: (a) ASD children fixated significantly less on the right eye (from the observer's view); (b) ASD children's fixations were more biased towards the left eye region; and (c) ASD children fixated below the left eye, whereas TD children fixated on the pupil region of the eye. Thus, ASD children do not have a general abnormality in face scanning. Rather, their abnormality is limited to the eye region, likely due to their strong tendency to avoid eye contact. PMID- 23929831 TI - The effect of inoculum dose on the genetic diversity detected within Helicoverpa armigera nucleopolyhedrovirus populations. AB - Environmental and infection variables may affect the genetic diversity of baculovirus populations. In this study, Helicoverpa armigera nucleopolyhedrovirus (HearNPV) was used as a model system for studying the effects of a key infection variable, inoculum dose, on the genetic diversity within nucleopolyhedrovirus populations. Diversity and equitability indices were calculated from DNA polymerase-specific denaturing gradient gel electrophoresis profiles obtained from individual H. armigera neonate larvae inoculated with either an LD5 or LD95 of HearNPV. Although the genetic diversity detected in larvae treated with an LD95 was not statistically different from the diversity detected in the HearNPV inoculum samples, there was a statistically significant difference in the genetic diversity detected in the LD5-inoculated larvae compared with the genetic diversity detected in the HearNPV samples used for the inoculations. The study suggests that inoculum dose needs to be considered carefully in experiments that evaluate HearNPV genetic diversity or in studies where differences in genetic diversity may have phenotypic consequences. PMID- 23929833 TI - Long-range control of T-cell development. AB - In this issue of Blood, Li et al reveal the genetic elements that control the activity of Bcl11b, a critical regulator of T-cell development. Lineage-defining transcription factors (TFs), such as Bcl11b, control key steps in cellular differentiation throughout development, and understanding how these TFs are themselves regulated represents a major challenge. PMID- 23929832 TI - Genetic engineering of T-cell receptors: TCR takes to titin. AB - In this issue of Blood, Linette et al report a cautionary tale-a lethal off target toxicity following T-cell receptor (TCR) optimization to enhance affinity against a tumor-associated antigen, MAGE-A3. PMID- 23929834 TI - Defects in DBA: more than meets the eye. AB - In this issue of Blood, Garcon et al describe successful derivation of induced pluripotent stem cells (iPSs) from fibroblasts of Diamond Blackfan anemia (DBA) patients with 2 distinct ribosomal defects. Using these cells, the authors showed that they not only exhibit defective erythropoiesis but also globally impaired hematopoiesis affecting multipotent progenitors. PMID- 23929835 TI - Inhibiting inhibitory pathways in human gammadelta T cells. AB - In this issue of Blood, Gertner-Dardenne et al show that B- and T-lymphocyte attenuator (BTLA) functions as an inhibitory receptor on gd T cells and suggest that disruption of this inhibitory pathway in tumor-reactive gd T cells may result in enhanced antitumor responses. PMID- 23929836 TI - Ideal donors, imperfect results in sickle cell disease. AB - In this issue of Blood, Chou et al report findings from an observational study of alloimmunization in patients with sickle cell disease (SCD) receiving blood transfusions from ethnically matched donors. PMID- 23929837 TI - Hemoglobin disorders: a look to the future. AB - In this issue of Blood, Locatelli et al compare the results of histocompatible family donor bone marrow and cord blood transplants (BMT and CBT) for severe beta thalassemia (SBT) and sickle cell disease (SCD) as experienced by the Eurocord and European Blood and Marrow Transplantation group and collaborating centers in the United States, Hong Kong, and Israel between 1994 and 2005. Obviously, many changes in medical care and particularly MHC typing occurred over that decade, so this retrospective represents a moving target, but some firm points can be made for which we are indebted to this excellent group. PMID- 23929838 TI - Immune responses against the mutated region of cytoplasmatic NPM1 might contribute to the favorable clinical outcome of AML patients with NPM1 mutations (NPM1mut). PMID- 23929839 TI - Minimal residual disease testing in multiple myeloma by flow cytometry: major heterogeneity. PMID- 23929840 TI - Detection of an NRAS mutation in Erdheim-Chester disease. PMID- 23929841 TI - Lactate dehydrogenase and hemolysis in sickle cell disease. PMID- 23929843 TI - Anisotropic elliptic PDEs for feature classification. AB - The extraction and classification of multitype (point, curve, patch) features on manifolds are extremely challenging, due to the lack of rigorous definition for diverse feature forms. This paper seeks a novel solution of multitype features in a mathematically rigorous way and proposes an efficient method for feature classification on manifolds. We tackle this challenge by exploring a quasi harmonic field (QHF) generated by elliptic PDEs, which is the stable state of heat diffusion governed by anisotropic diffusion tensor. Diffusion tensor locally encodes shape geometry and controls velocity and direction of the diffusion process. The global QHF weaves points into smooth regions separated by ridges and has superior performance in combating noise/holes. Our method's originality is highlighted by the integration of locally defined diffusion tensor and globally defined elliptic PDEs in an anisotropic manner. At the computational front, the heat diffusion PDE becomes a linear system with Dirichlet condition at heat sources (called seeds). Our new algorithms afford automatic seed selection, enhanced by a fast update procedure in a high-dimensional space. By employing diffusion probability, our method can handle both manufactured parts and organic objects. Various experiments demonstrate the flexibility and high performance of our method. PMID- 23929844 TI - A spherical Gaussian framework for Bayesian Monte Carlo rendering of glossy surfaces. AB - The Monte Carlo method has proved to be very powerful to cope with global illumination problems but it remains costly in terms of sampling operations. In various applications, previous work has shown that Bayesian Monte Carlo can significantly outperform importance sampling Monte Carlo thanks to a more effective use of the prior knowledge and of the information brought by the samples set. These good results have been confirmed in the context of global illumination but strictly limited to the perfect diffuse case. Our main goal in this paper is to propose a more general Bayesian Monte Carlo solution that allows dealing with nondiffuse BRDFs thanks to a spherical Gaussian-based framework. We also propose a fast hyperparameters determination method that avoids learning the hyperparameters for each BRDF. These contributions represent two major steps toward generalizing Bayesian Monte Carlo for global illumination rendering. We show that we achieve substantial quality improvements over importance sampling at comparable computational cost. PMID- 23929842 TI - Differential regulation of hepatic organic cation transporter 1, organic anion transporting polypeptide 1a4, bile-salt export pump, and multidrug resistance associated protein 2 transporter expression in lymphocyte-deficient mice associates with interleukin-6 production. AB - Cholestasis results from interrupted bile flow and is associated with immune mediated liver diseases. It is unclear how inflammation contributes to cholestasis. The aim of this study was to determine whether T and B cells contribute to hepatic transporter expression under basal and inflammatory conditions. C57BL/6J wild-type mice or strains lacking T, B, or both T and B cells were exposed to lipopolysaccharide (LPS) or saline, and livers were collected 16 hours later. Branched DNA signal amplification was used to assess mRNA levels of organic anion-transporting polypeptides (Oatp) 1a1, 1a4, and 1b2; organic cation transporter (Oct) 1; canalicular bile-salt export pump (Bsep); multidrug resistance-associated proteins (Mrp) 2 and 3; and sodium-taurocholate cotransporting polypeptide (Ntcp). Real-time polymerase chain reaction analysis was used to correlate changes of transporter expression with interleukin-1b (IL 1b), IL-6, IL-17A, IL-17F, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma expression in the liver. LPS treatment inhibited Bsep and Oct1 mRNA expression, and this was abrogated with a loss of T cells, but not B cells. In addition, the absence of T cells increased Mrp2 mRNA expression, whereas B cell deficiency attenuated Oatp1a4 mRNA in LPS-treated mice. Oatp1a1, Oatp1b2, Ntcp, and Mrp3 were largely unaffected by T or B cell deficiency. Lymphocyte deficiency altered basal and inflammatory IL-6, but not TNF-alpha or IL-1b, mRNA expression. Taken together, these data implicate lymphocytes as regulators of basal and inflammatory hepatic transporter expression and suggest that IL-6 signaling may play a critical role. PMID- 23929845 TI - Boundary-aware multidomain subspace deformation. AB - In this paper, we propose a novel framework for multidomain subspace deformation using node-wise corotational elasticity. With the proper construction of subspaces based on the knowledge of the boundary deformation, we can use the Lagrange multiplier technique to impose coupling constraints at the boundary without overconstraining. In our deformation algorithm, the number of constraint equations to couple two neighboring domains is not related to the number of the nodes on the boundary but is the same as the number of the selected boundary deformation modes. The crack artifact is not present in our simulation result, and the domain decomposition with loops can be easily handled. Experimental results show that the single-core implementation of our algorithm can achieve real-time performance in simulating deformable objects with around quarter million tetrahedral elements. PMID- 23929846 TI - Compact video synopsis via global spatiotemporal optimization. AB - Video synopsis aims at providing condensed representations of video data sets that can be easily captured from digital cameras nowadays, especially for daily surveillance videos. Previous work in video synopsis usually moves active objects along the time axis, which inevitably causes collisions among the moving objects if compressed much. In this paper, we propose a novel approach for compact video synopsis using a unified spatiotemporal optimization. Our approach globally shifts moving objects in both spatial and temporal domains, which shifting objects temporally to reduce the length of the video and shifting colliding objects spatially to avoid visible collision artifacts. Furthermore, using a multilevel patch relocation (MPR) method, the moving space of the original video is expanded into a compact background based on environmental content to fit with the shifted objects. The shifted objects are finally composited with the expanded moving space to obtain the high-quality video synopsis, which is more condensed while remaining free of collision artifacts. Our experimental results have shown that the compact video synopsis we produced can be browsed quickly, preserves relative spatiotemporal relationships, and avoids motion collisions. PMID- 23929847 TI - Content-aware video retargeting using object-preserving warping. AB - A novel content-aware warping approach is introduced for video retargeting. The key to this technique is adapting videos to fit displays with various aspect ratios and sizes while preserving both visually salient content and temporal coherence. Most previous studies solve this spatiotemporal problem by consistently resizing content in frames. This strategy significantly improves the retargeting results, but does not fully consider object preservation, sometimes causing apparent distortions on visually salient objects. We propose an object preserving warping scheme with object-based significance estimation to reduce this unpleasant distortion. In the proposed scheme, visually salient objects in 3D space-time space are forced to undergo as-rigid-as-possible warping, while low significance contents are warped as close as possible to linear rescaling. These strategies enable our method to consistently preserve both the spatial shapes and temporal motions of visually salient objects and avoid overdeformations on low significance objects, yielding a pleasing motion-aware video retargeting. Qualitative and quantitative analyses, including a user study and experiments on complex videos containing diverse cameras and dynamic motions, show a clear superiority of our method over related video retargeting methods. PMID- 23929848 TI - Cubic gradient-based material interfaces. AB - Multifluid simulations often create volume fraction data, representing fluid volumes per region or cell of a fluid data set. Accurate and visually realistic extraction of fluid boundaries is a challenging and essential task for efficient analysis of multifluid data. In this work, we present a new material interface reconstruction method for such volume fraction data. Within each cell of the data set, our method utilizes a gradient field approximation based on trilinearly blended Coons-patches to generate a volume fraction function, representing the change in volume fractions over the cells. A continuously varying isovalue field is applied to this function to produce a smooth interface that preserves the given volume fractions well. Further, the method allows user-controlled balance between volume accuracy and physical plausibility of the interface. The method works on two- and three-dimensional Cartesian grids, and handles multiple materials. Calculations are performed locally and utilize only the one-ring of cells surrounding a given cell, allowing visualizations of the material interfaces to be easily generated on a GPU or in a large-scale distributed parallel environment. Our results demonstrate the robustness, accuracy, and flexibility of the developed algorithms. PMID- 23929849 TI - Cylinder detection in large-scale point cloud of pipeline plant. AB - The huge number of points scanned from pipeline plants make the plant reconstruction very difficult. Traditional cylinder detection methods cannot be applied directly due to the high computational complexity. In this paper, we explore the structural characteristics of point cloud in pipeline plants and define a structure feature. Based on the structure feature, we propose a hierarchical structure detection and decomposition method that reduces the difficult pipeline-plant reconstruction problem in IR3 into a set of simple circle detection problems in IR2. Experiments with industrial applications are presented, which demonstrate the efficiency of the proposed structure detection method. PMID- 23929850 TI - Flow field modulation. AB - The nonlinear and nonstationary nature of Navier-Stokes equations produces fluid flows that can be noticeably different in appearance with subtle changes. In this paper, we introduce a method that can analyze the intrinsic multiscale features of flow fields from a decomposition point of view, by using the Hilbert-Huang transform method on 3D fluid simulation. We show how this method can provide insights to flow styles and help modulate the fluid simulation with its internal physical information. We provide easy-to-implement algorithms that can be integrated with standard grid-based fluid simulation methods and demonstrate how this approach can modulate the flow field and guide the simulation with different flow styles. The modulation is straightforward and relates directly to the flow's visual effect, with moderate computational overhead. PMID- 23929851 TI - Image-based modeling of unwrappable facades. AB - In this paper, we propose an unwrappable representation for image-based facade modeling from multiple registered images. An unwrappable facade is represented by the mutually orthogonal baseline and profile. We first reconstruct semidense 3D points from images, then the baseline and profile are extracted from the point cloud to construct the base shape and compose the textures of the building from the images. Through our unwrapping process, the reconstructed 3D points and composed textures are further mapped to an unwrapped space that is parameterized by the baseline and profile. In doing so, the unwrapped space becomes equivalent to the planar space in which planar facade modeling techniques can be used to reconstruct the details of the buildings. Finally, the augmented details can be wrapped back to the original 3D space to generate the final model. This newly introduced unwrappable representation extends the state-of-the-art modeling for planar facades to a more general class of facades. We demonstrate the power of the unwrappable representation with a few examples in which the facade is not planar. PMID- 23929852 TI - Perceptually driven visibility optimization for categorical data visualization. AB - Visualization techniques often use color to present categorical differences to a user. When selecting a color palette, the perceptual qualities of color need careful consideration. Large coherent groups visually suppress smaller groups and are often visually dominant in images. This paper introduces the concept of class visibility used to quantitatively measure the utility of a color palette to present coherent categorical structure to the user. We present a color optimization algorithm based on our class visibility metric to make categorical differences clearly visible to the user. We performed two user experiments on user preference and visual search to validate our visibility measure over a range of color palettes. The results indicate that visibility is a robust measure, and our color optimization can increase the effectiveness of categorical data visualizations. PMID- 23929853 TI - Temporal coherence in image-based visual hull rendering. AB - Image-based visual hull rendering is a method for generating depth maps of a desired viewpoint from a set of silhouette images captured by calibrated cameras. It does not compute a view-independent data representation, such as a voxel grid or a mesh, which makes it particularly efficient for dynamic scenes. When users are captured, the scene is usually dynamic, but does not change rapidly because people move smoothly within a subsecond time frame. Exploiting this temporal coherence to avoid redundant calculations is challenging because of the lack of an explicit data representation. This paper analyzes the image-based visual hull algorithm to find intermediate information that stays valid over time and is, therefore, worth to make explicit. We then derive methods that exploit this information to improve the rendering performance. Our methods reduce the execution time by up to 25 percent. When the user's motions are very slow, reductions of up to 50 percent are achieved. PMID- 23929854 TI - The generalized sensitivity scatterplot. AB - Scatterplots remain a powerful tool to visualize multidimensional data. However, accurately understanding the shape of multidimensional points from 2D projections remains challenging due to overlap. Consequently, there are a lot of variations on the scatterplot as a visual metaphor for this limitation. An important aspect often overlooked in scatterplots is the issue of sensitivity or local trend, which may help in identifying the type of relationship between two variables. However, it is not well known how or what factors influence the perception of trends from 2D scatterplots. To shed light on this aspect, we conducted an experiment where we asked people to directly draw the perceived trends on a 2D scatterplot. We found that augmenting scatterplots with local sensitivity helps to fill the gaps in visual perception while retaining the simplicity and readability of a 2D scatterplot. We call this augmentation the generalized sensitivity scatterplot (GSS). In a GSS, sensitivity coefficients are visually depicted as flow lines, which give a sense of continuity and orientation of the data that provide cues about the way data points are scattered in a higher dimensional space. We introduce a series of glyphs and operations that facilitate the analysis of multidimensional data sets using GSS, and validate with a number of well-known data sets for both regression and classification tasks. PMID- 23929856 TI - Genetically coupled receptor-ligand pair NKp80-AICL enables autonomous control of human NK cell responses. AB - NKp80 is a C-type lectin-like receptor broadly expressed on human natural killer (NK) cells, triggering cytotoxicity via an atypical cytoplasmic hemi immunoreceptor tyrosine-based activation motif. As with other lectin-like NK receptors, NKp80 is encoded in the natural killer gene complex, but unlike most of these, adjacent to its ligand, ie, activation-induced C-type lectin (AICL). The reasons for the tight genetic linkage of this receptor-ligand pair remain elusive. Previous studies showed that NKp80 augments NK cell responses toward malignant and nonmalignant myeloid cells. Here, we report that resting human NK cells not only express NKp80 but also contain intracellular stores of AICL colocalizing with the Golgi complex. Domain-swapping experiments revealed that intracellular localization of AICL is determined by its C-type lectin-like ectodomain. Exposure of NK cells to monokines associated with conversion into memorylike cells induces substantial AICL cell surface expression, whereas NKp80 is downregulated, and NK cells become refractory to NKp80-mediated stimulation. AICL on monokine-exposed NK cells elicits NKp80-dependent effector responses by autologous NK cells and, hence, renders monokine-activated NK cells susceptible to NKp80-mediated cytolysis. Altogether, our data report a previously unrecognized regulatory circuit enabling autonomous control of human NK cell responses via the NKp80-AICL axis. PMID- 23929855 TI - DOCK8 is critical for the survival and function of NKT cells. AB - Patients with the dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome suffer from recurrent viral and bacterial infections, hyper-immunoglobulin E levels, eczema, and greater susceptibility to cancer. Because natural killer T (NKT) cells have been implicated in these diseases, we asked if these cells were affected by DOCK8 deficiency. Using a mouse model, we found that DOCK8 deficiency resulted in impaired NKT cell development, principally affecting the formation and survival of long-lived, differentiated NKT cells. In the thymus, DOCK8 deficient mice lack a terminally differentiated subset of NK1.1(+) NKT cells expressing the integrin CD103, whereas in the liver, DOCK8-deficient NKT cells express reduced levels of the prosurvival factor B-cell lymphoma 2 and the integrin lymphocyte function-associated antigen 1. Although the initial NKT cell response to antigen is intact in the absence of DOCK8, their ongoing proliferative and cytokine responses are impaired. Importantly, a similar defect in NKT cell numbers was detected in DOCK8-deficient humans, highlighting the relevance of the mouse model. In conclusion, our data demonstrate that DOCK8 is required for the development and survival of mature NKT cells, consistent with the idea that DOCK8 mediates survival signals within a specialized niche. Accordingly, impaired NKT cell numbers and function are likely to contribute to the susceptibility of DOCK8-deficient patients to recurrent infections and malignant disease. PMID- 23929857 TI - Chain-RNA: a comparative ncRNA search tool based on the two-dimensional chain algorithm. AB - Noncoding RNA (ncRNA) identification is highly important to modern biology. The state-of-the-art method for ncRNA identification is based on comparative genomics, in which evolutionary conservations of sequences and secondary structures provide important evidence for ncRNA search. For ncRNAs with low sequence conservation but high structural similarity, conventional local alignment tools such as BLAST yield low sensitivity. Thus, there is a need for ncRNA search methods that can incorporate both sequence and structural similarities. We introduce chain-RNA, a pairwise structural alignment tool that can effectively locate cross-species conserved RNA elements with low sequence similarity. In chain-RNA, stem-loop structures are extracted from dot plots generated by an efficient local-folding algorithm. Then, we formulate stem alignment as an extended 2D chain problem and employ existing chain algorithms. Chain-RNA is tested on a data set containing annotated ncRNA homologs and is applied to novel ncRNA search in a transcriptomic data set. The experimental results show that chain-RNA has better tradeoff between sensitivity and false positive rate in ncRNA prediction than conventional sequence similarity search tools and is more time efficient than structural alignment tools. The source codes of chain-RNA can be downloaded at http://sourceforge.net/projects/chain rna/ or at http://www.cse.msu.edu/~leijikai/chain-rna/. PMID- 23929858 TI - Curvature analysis of cardiac excitation wavefronts. AB - We present the Spiral Classification Algorithm (SCA), a fast and accurate algorithm for classifying electrical spiral waves and their associated breakup in cardiac tissues. The classification performed by SCA is an essential component of the detection and analysis of various cardiac arrhythmic disorders, including ventricular tachycardia and fibrillation. Given a digitized frame of a propagating wave, SCA constructs a highly accurate representation of the front and the back of the wave, piecewise interpolates this representation with cubic splines, and subjects the result to an accurate curvature analysis. This analysis is more comprehensive than methods based on spiral-tip tracking, as it considers the entire wave front and back. To increase the smoothness of the resulting symbolic representation, the SCA uses weighted overlapping of adjacent segments which increases the smoothness at join points. SCA has been applied to a number of representative types of spiral waves, and, for each type, a distinct curvature evolution in time (signature) has been identified. Distinct signatures have also been identified for spiral breakup. These results represent a significant first step in automatically determining parameter ranges for which a computational cardiac-cell network accurately reproduces a particular kind of cardiac arrhythmia, such as ventricular fibrillation. PMID- 23929859 TI - A graph-theoretical approach to the selection of the minimum tiling path from a physical map. AB - The problem of computing the minimum tiling path (MTP) from a set of clones arranged in a physical map is a cornerstone of hierarchical (clone-by-clone) genome sequencing projects. We formulate this problem in a graph theoretical framework, and then solve by a combination of minimum hitting set and minimum spanning tree algorithms. The tool implementing this strategy, called FMTP, shows improved performance compared to the widely used software FPC. When we execute FMTP and FPC on the same physical map, the MTP produced by FMTP covers a higher portion of the genome, and uses a smaller number of clones. For instance, on the rice genome the MTP produced by our tool would reduce by about 11 percent the cost of a clone-by-clone sequencing project. Source code, benchmark data sets, and documentation of FMTP are freely available at >http://code.google.com/p/fingerprint-based-minimal-tiling-path/ under MIT license. PMID- 23929860 TI - Evaluation of breast cancer susceptibility using improved genetic algorithms to generate genotype SNP barcodes. AB - Genetic association is a challenging task for the identification and characterization of genes that increase the susceptibility to common complex multifactorial diseases. To fully execute genetic studies of complex diseases, modern geneticists face the challenge of detecting interactions between loci. A genetic algorithm (GA) is developed to detect the association of genotype frequencies of cancer cases and noncancer cases based on statistical analysis. An improved genetic algorithm (IGA) is proposed to improve the reliability of the GA method for high-dimensional SNP-SNP interactions. The strategy offers the top five results to the random population process, in which they guide the GA toward a significant search course. The IGA increases the likelihood of quickly detecting the maximum ratio difference between cancer cases and noncancer cases. The study systematically evaluates the joint effect of 23 SNP combinations of six steroid hormone metabolisms, and signaling-related genes involved in breast carcinogenesis pathways were systematically evaluated, with IGA successfully detecting significant ratio differences between breast cancer cases and noncancer cases. The possible breast cancer risks were subsequently analyzed by odds-ratio (OR) and risk-ratio analysis. The estimated OR of the best SNP barcode is significantly higher than 1 (between 1.15 and 7.01) for specific combinations of two to 13 SNPs. Analysis results support that the IGA provides higher ratio difference values than the GA between breast cancer cases and noncancer cases over 3-SNP to 13-SNP interactions. A more specific SNP-SNP interaction profile for the risk of breast cancer is also provided. PMID- 23929861 TI - FNphasing: a novel fast heuristic algorithm for haplotype phasing based on flow network model. AB - An enormous amount of sequence data has been generated with the development of new DNA sequencing technologies, which presents great challenges for computational biology problems such as haplotype phasing. Although arduous efforts have been made to address this problem, the current methods still cannot efficiently deal with the incoming flood of large-scale data. In this paper, we propose a flow network model to tackle haplotype phasing problem, and explain some classical haplotype phasing rules based on this model. By incorporating the heuristic knowledge obtained from these classical rules, we design an algorithm FNphasing based on the flow network model. Theoretically, the time complexity of our algorithm is (O(n(2)m+m(2)), which is better than that of 2SNP, one of the most efficient algorithms currently. After testing the performance of FNphasing with several simulated data sets, the experimental results show that when applied on large-scale data sets, our algorithm is significantly faster than the state-of the-art Beagle algorithm. FNphasing also achieves an equal or superior accuracy compared with other approaches. PMID- 23929862 TI - GENESHIFT: a nonparametric approach for integrating microarray gene expression data based on the inner product as a distance measure between the distributions of genes. AB - The potential of microarray gene expression (MAGE) data is only partially explored due to the limited number of samples in individual studies. This limitation can be surmounted by merging or integrating data sets originating from independent MAGE experiments, which are designed to study the same biological problem. However, this process is hindered by batch effects that are study dependent and result in random data distortion; therefore numerical transformations are needed to render the integration of different data sets accurate and meaningful. Our contribution in this paper is two-fold. First we propose GENESHIFT, a new nonparametric batch effect removal method based on two key elements from statistics: empirical density estimation and the inner product as a distance measure between two probability density functions; second we introduce a new validation index of batch effect removal methods based on the observation that samples from two independent studies drawn from a same population should exhibit similar probability density functions. We evaluated and compared the GENESHIFT method with four other state-of-the-art methods for batch effect removal: Batch-mean centering, empirical Bayes or COMBAT, distance weighted discrimination, and cross-platform normalization. Several validation indices providing complementary information about the efficiency of batch effect removal methods have been employed in our validation framework. The results show that none of the methods clearly outperforms the others. More than that, most of the methods used for comparison perform very well with respect to some validation indices while performing very poor with respect to others. GENESHIFT exhibits robust performances and its average rank is the highest among the average ranks of all methods used for comparison. PMID- 23929863 TI - Gene regulation networks in early phase of Duchenne muscular dystrophy. AB - The aim of this study was to analyze previously published gene expression data of skeletal muscle biopsies of Duchenne muscular dystrophy (DMD) patients and controls (gene expression omnibus database, accession #GSE6011) using systems biology approaches. We applied an unsupervised method to discriminate patient and control populations, based on principal component analysis, using the gene expressions as units and patients as variables. The genes having the highest absolute scores in the discrimination between the groups, were then analyzed in terms of gene expression networks, on the basis of their mutual correlation in the two groups. The correlation network structures suggest two different modes of gene regulation in the two groups, reminiscent of important aspects of DMD pathogenesis. PMID- 23929864 TI - How many clusters: a validation index for arbitrary-shaped clusters. AB - Clustering validation indexes are intended to assess the goodness of clustering results. Many methods used to estimate the number of clusters rely on a validation index as a key element to find the correct answer. This paper presents a new validation index based on graph concepts, which has been designed to find arbitrary shaped clusters by exploiting the spatial layout of the patterns and their clustering label. This new clustering index is combined with a solid statistical detection framework, the gap statistic. The resulting method is able to find the right number of arbitrary-shaped clusters in diverse situations, as we show with examples where this information is available. A comparison with several relevant validation methods is carried out using artificial and gene expression data sets. The results are very encouraging, showing that the underlying structure in the data can be more accurately detected with the new clustering index. Our gene expression data results also indicate that this new index is stable under perturbation of the input data. PMID- 23929865 TI - Mining featured patterns of MiRNA interaction based on sequence and structure similarity. AB - MicroRNA (miRNA) is an endogenous small noncoding RNA that plays an important role in gene expression through the post-transcriptional gene regulation pathways. There are many literature works focusing on predicting miRNA targets and exploring gene regulatory networks of miRNA families. We suggest, however, the study to identify the interaction between miRNAs is insufficient. This paper presents a framework to identify relationships between miRNAs using joint entropy, to investigate the regulatory features of miRNAs. Both the sequence and secondary structure are taken into consideration to make our method more relevant from the biological viewpoint. Further, joint entropy is applied to identify correlated miRNAs, which are more desirable from the perspective of the gene regulatory network. A data set including Drosophila melanogaster and Anopheles gambiae is used in the experiment. The results demonstrate that our approach is able to identify known miRNA interaction and uncover novel patterns of miRNA regulatory network. PMID- 23929866 TI - Mining quasi-bicliques from HIV-1-human protein interaction network: a multiobjective biclustering approach. AB - In this work, we model the problem of mining quasi-bicliques from weighted viral host protein-protein interaction network as a biclustering problem for identifying strong interaction modules. In this regard, a multiobjective genetic algorithm-based biclustering technique is proposed that simultaneously optimizes three objective functions to obtain dense biclusters having high mean interaction strengths. The performance of the proposed technique has been compared with that of other existing biclustering methods on an artificial data. Subsequently, the proposed biclustering method is applied on the records of biologically validated and predicted interactions between a set of HIV-1 proteins and a set of human proteins to identify strong interaction modules. For this, the entire interaction information is realized as a bipartite graph. We have further investigated the biological significance of the obtained biclusters. The human proteins involved in the strong interaction module have been found to share common biological properties and they are identified as the gateways of viral infection leading to various diseases. These human proteins can be potential drug targets for developing anti-HIV drugs. PMID- 23929867 TI - Multilabel learning via random label selection for protein subcellular multilocations prediction. AB - Prediction of protein subcellular localization is an important but challenging problem, particularly when proteins may simultaneously exist at, or move between, two or more different subcellular location sites. Most of the existing protein subcellular localization methods are only used to deal with the single-location proteins. In the past few years, only a few methods have been proposed to tackle proteins with multiple locations. However, they only adopt a simple strategy, that is, transforming the multilocation proteins to multiple proteins with single location, which does not take correlations among different subcellular locations into account. In this paper, a novel method named random label selection (RALS) (multilabel learning via RALS), which extends the simple binary relevance (BR) method, is proposed to learn from multilocation proteins in an effective and efficient way. RALS does not explicitly find the correlations among labels, but rather implicitly attempts to learn the label correlations from data by augmenting original feature space with randomly selected labels as its additional input features. Through the fivefold cross-validation test on a benchmark data set, we demonstrate our proposed method with consideration of label correlations obviously outperforms the baseline BR method without consideration of label correlations, indicating correlations among different subcellular locations really exist and contribute to improvement of prediction performance. Experimental results on two benchmark data sets also show that our proposed methods achieve significantly higher performance than some other state-of-the-art methods in predicting subcellular multilocations of proteins. The prediction web server is available at >http://levis.tongji.edu.cn:8080/bioinfo/MLPred-Euk/ for the public usage. PMID- 23929868 TI - Nonnegative least-squares methods for the classification of high-dimensional biological data. AB - Microarray data can be used to detect diseases and predict responses to therapies through classification models. However, the high dimensionality and low sample size of such data result in many computational problems such as reduced prediction accuracy and slow classification speed. In this paper, we propose a novel family of nonnegative least-squares classifiers for high-dimensional microarray gene expression and comparative genomic hybridization data. Our approaches are based on combining the advantages of using local learning, transductive learning, and ensemble learning, for better prediction performance. To study the performances of our methods, we performed computational experiments on 17 well-known data sets with diverse characteristics. We have also performed statistical comparisons with many classification techniques including the well performing SVM approach and two related but recent methods proposed in literature. Experimental results show that our approaches are faster and achieve generally a better prediction performance over compared methods. PMID- 23929869 TI - Normalized feature vectors: a novel alignment-free sequence comparison method based on the numbers of adjacent amino acids. AB - Based on all kinds of adjacent amino acids (AAA), we map each protein primary sequence into a 400 by ((L-1)) matrix (M). In addition, we further derive a normalized 400-tuple mathematical descriptors (D), which is extracted from the primary protein sequences via singular values decomposition (SVD) of the matrix. The obtained 400-D normalized feature vectors (NFVs) further facilitate our quantitative analysis of protein sequences. Using the normalized representation of the primary protein sequences, we analyze the similarity for different sequences upon two data sets: 1) ND5 sequences from nine species and 2) transferrin sequences of 24 vertebrates. We also compared the results in this study with those from other related works. These two experiments illustrate that our proposed NFV-AAA approach does perform well in the field of similarity analysis of sequence. PMID- 23929870 TI - On the increase in network robustness and decrease in network response ability during the aging process: a systems biology approach via microarray data. AB - Aging, an extremely complex and system-level process, has attracted much attention in medical research, especially since chronic diseases are quite prevalent in the elderly population. These may be the result of both gene mutations that lead to intrinsic perturbations and environmental changes that may stimulate signaling in the body. Therefore, analysis of network robustness to tolerate intrinsic perturbations and network response ability of gene networks to respond to external stimuli during the aging process may provide insight into the systematic changes caused by aging. We first propose novel methods to estimate network robustness and measure network response ability of gene regulatory networks by using their corresponding microarray data in the aging process. Then, we find that an aging-related gene network is more robust to intrinsic perturbations in the elderly than the young, and therefore is less responsive to external stimuli. Finally, we find that the response abilities of individual genes, especially FOXOs, NF-IoB, and p53, are significantly different in the young versus the aged subjects. These observations are consistent with experimental findings in the aged population, e.g., elevated incidence of tumorigenesis and diminished resistance to oxidative stress. The proposed method can also be used for exploring and analyzing the dynamic properties of other biological processes via corresponding microarray data to provide useful information on clinical strategy and drug target selection. PMID- 23929871 TI - Pareto optimal pairwise sequence alignment. AB - Sequence alignment using evolutionary profiles is a commonly employed tool when investigating a protein. Many profile-profile scoring functions have been developed for use in such alignments, but there has not yet been a comprehensive study of Pareto optimal pairwise alignments for combining multiple such functions. We show that the problem of generating Pareto optimal pairwise alignments has an optimal substructure property, and develop an efficient algorithm for generating Pareto optimal frontiers of pairwise alignments. All possible sets of two, three, and four profile scoring functions are used from a pool of 11 functions and applied to 588 pairs of proteins in the ce_ref data set. The performance of the best objective combinations on ce_ref is also evaluated on an independent set of 913 protein pairs extracted from the BAliBASE RV11 data set. Our dynamic-programming-based heuristic approach produces approximated Pareto optimal frontiers of pairwise alignments that contain comparable alignments to those on the exact frontier, but on average in less than 1/58th the time in the case of four objectives. Our results show that the Pareto frontiers contain alignments whose quality is better than the alignments obtained by single objectives. However, the task of identifying a single high-quality alignment among those in the Pareto frontier remains challenging. PMID- 23929872 TI - Profile-Based LC-MS data alignment--a Bayesian approach. AB - A Bayesian alignment model (BAM) is proposed for alignment of liquid chromatography-mass spectrometry (LC-MS) data. BAM belongs to the category of profile-based approaches, which are composed of two major components: a prototype function and a set of mapping functions. Appropriate estimation of these functions is crucial for good alignment results. BAM uses Markov chain Monte Carlo (MCMC) methods to draw inference on the model parameters and improves on existing MCMC-based alignment methods through 1) the implementation of an efficient MCMC sampler and 2) an adaptive selection of knots. A block Metropolis Hastings algorithm that mitigates the problem of the MCMC sampler getting stuck at local modes of the posterior distribution is used for the update of the mapping function coefficients. In addition, a stochastic search variable selection (SSVS) methodology is used to determine the number and positions of knots. We applied BAM to a simulated data set, an LC-MS proteomic data set, and two LC-MS metabolomic data sets, and compared its performance with the Bayesian hierarchical curve registration (BHCR) model, the dynamic time-warping (DTW) model, and the continuous profile model (CPM). The advantage of applying appropriate profile-based retention time correction prior to performing a feature based approach is also demonstrated through the metabolomic data sets. PMID- 23929873 TI - RANGI: a fast list-colored graph motif finding algorithm. AB - Given a multiset of colors as the query and a list-colored graph, i.e., an undirected graph with a set of colors assigned to each of its vertices, in the NP hard list-colored graph motif problem the goal is to find the largest connected subgraph such that one can select a color from the set of colors assigned to each of its vertices to obtain a subset of the query. This problem was introduced to find functional motifs in biological networks. We present a branch-and-bound algorithm named RANGI for finding and enumerating list-colored graph motifs. As our experimental results show, RANGI's pruning methods and heuristics make it quite fast in practice compared to the algorithms presented in the literature. We also present a parallel version of RANGI that achieves acceptable scalability. PMID- 23929874 TI - Reconstruction of signaling network from protein interactions based on function annotations. AB - The directionality of protein interactions is the prerequisite of forming various signaling networks, and the construction of signaling networks is a critical issue in the discovering the mechanism of the life process. In this paper, we proposed a novel method to infer the directionality in protein-protein interaction networks and furthermore construct signaling networks. Based on the functional annotations of proteins, we proposed a novel parameter GODS and established the prediction model. This method shows high sensitivity and specificity to predict the directionality of protein interactions, evaluated by fivefold cross validation. By taking the threshold value of GODS as 2, we achieved accuracy 95.56 percent and coverage 74.69 percent in the human test set. Also, this method was successfully applied to reconstruct the classical signaling pathways in human. This study not only provided an effective method to unravel the unknown signaling pathways, but also the deeper understanding for the signaling networks, from the aspect of protein function. PMID- 23929875 TI - Unrooted tree reconciliation: a unified approach. AB - Tree comparison functions are widely used in phylogenetics for comparing evolutionary trees. Unrooted trees can be compared with rooted trees by identifying all rootings of the unrooted tree that minimize some provided comparison function between two rooted trees. The plateau property is satisfied by the provided function, if all optimal rootings form a subtree, or plateau, in the unrooted tree, from which the rootings along every path toward a leaf have monotonically increasing costs. This property is sufficient for the linear-time identification of all optimal rootings and rooting costs. However, the plateau property has only been proven for a few rooted comparison functions, requiring individual proofs for each function without benefitting from inherent structural features of such functions. Here, we introduce the consistency condition that is sufficient for a general function to satisfy the plateau property. For consistent functions, we introduce general linear-time solutions that identify optimal rootings and all rooting costs. Further, we identify novel relationships between consistent functions in terms of plateaus, especially the plateau of the well studied duplication-loss function is part of a plateau of every other consistent function. We introduce a novel approach for identifying consistent cost functions by defining a formal language of Boolean costs. Formulas in this language can be interpreted as cost functions. Finally, we demonstrate the performance of our general linear-time solutions in practice using empirical and simulation studies. PMID- 23929876 TI - Parameter estimation of biological phenomena: an unscented Kalman filter approach. AB - Recent advances in high-throughput technologies for biological data acquisition have spurred a broad interest in the construction of mathematical models for biological phenomena. The development of such mathematical models relies on the estimation of unknown parameters of the system using the time-course profiles of different metabolites in the system. One of the main challenges in the parameter estimation of biological phenomena is the fact that the number of unknown parameters is much more than the number of metabolites in the system. Moreover, the available metabolite measurements are corrupted by noise. In this paper, a new parameter estimation algorithm is developed based on the stochastic estimation framework for nonlinear systems, namely the unscented Kalman filter (UKF). A new iterative UKF algorithm with covariance resetting is developed in which the UKF algorithm is applied iteratively to the available noisy time profiles of the metabolites. The proposed estimation algorithm is applied to noisy time-course data synthetically produced from a generic branched pathway as well as real time-course profile for the Cad system of E. coli. The simulation results demonstrate the effectiveness of the proposed scheme. PMID- 23929877 TI - Implementing health in all policies post Helsinki 2013: why, what, who and how. PMID- 23929878 TI - The importance of repeated measurements of the sFlt-1/PlGF ratio for the prediction of preeclampsia and intrauterine growth restriction. AB - AIMS: The sFlt-1/PlGF ratio has been evaluated as a diagnostic marker for preeclampsia (PE). The aim of this study was to explore the use of the sFlt 1/PlGF ratio as an aid in prediction for PE. METHODS: 150 patients with a high risk for PE were enrolled in this prospective study. Groups were compared according to the pregnancy outcome: controls (n=114), intrauterine growth restriction (IUGR) (n=14) and PE (n=22) with subclassification early PE<34 weeks (n=6). Measurements of sFlt-1 and PlGF were performed on the automated Elecsys system. Statistical comparison of the sFlt-1/PlGF ratio in different outcome groups and a mixed model analysis using random intercept models were performed. RESULTS: The sFlt-1/PlGF ratio was significantly higher in pregnancies complicated by PE up to 4 weeks before clinical diagnosis compared to controls (106.7 +/- 47.7 vs. 21.0 +/- 4.1; P=0.02). Levels of the sFlt-1/PlGF ratio were higher throughout pregnancy in women with IUGR compared to PE/control patients (intercept 1.57 vs. 1.30/0.67; P<0.05). The slope for the sFlt-1/PlGF ratio was significantly higher in PE and IUGR pregnancies compared to controls, indicating that a steep increase of the sFlt-1/PlGF ratio correlates with pathologic pregnancy outcomes. CONCLUSION: The sFlt-1/PlGF ratio can identify pathologic pregnancy outcomes such as IUGR and PE before clinical diagnosis. Repeated measurements are necessary to assess the dynamics in serum values. The time dependent slope of the sFlt-1/PlGF ratio is predictive for future pregnancy outcome and risk of developing preeclampsia. PMID- 23929879 TI - Does carbon monoxide inhibit proinflammatory cytokine production by fetal membranes? AB - AIM: Infection-induced inflammation is a common cause of preterm birth. Pharmacologic inhibition of proinflammatory cytokines improves pregnancy outcome in animal models but there are no universally effective therapies for preterm birth in women. Carbon monoxide (CO) has anti-inflammatory properties at low concentrations but its effects on reproductive tissues is unclear. Therefore, we studied the effect of supplemental CO on the production of cytokines associated with preterm birth by fetal membranes. METHODS: Cross-sections of whole fetal membranes, isolated choriodecidua, and isolated amnion were prepared using tissues collected from women who had normal vaginal deliveries at term. Tissues were placed in an organ explant culture system and stimulated with up to 10(8) CFU/mL Escherichia coli. Cultures were incubated under room air or room air+250 ppm CO for 18 h and cytokine concentrations in conditioned medium were quantified by ELISA. RESULTS: CO inhibited IL-1beta and TNF-alpha (P<=0.001) production by cultures stimulated with 10(7) CFU/mL bacteria but had no detectable effect on IL 10 by full-thickness membranes. Although CO also tended to reduce TNF-alpha production (P=0.053), no effect of CO was detected for IL-10 or IL-1beta for membranes stimulated with 10(8) CFU/mL E. coli. TNF-alpha, but not IL-1beta or IL 10 production, was inhibited by CO for choriodecidual cultures stimulated with 10(7) or 10(8) CFU/mL E. coli (P<0.001). IL-1beta production was significantly inhibited by CO for amnion cultures stimulated with 10(7) (P=0.002) and 10(8) (P=0.017) CFU/mL E. coli. Exposure to bacteria had no effect on TNF-alpha or IL 10 production but CO tended to increase IL-10 production by amnion cultures stimulated with 10(8) CFU/mL E. coli (P=0.037). CONCLUSIONS: These results suggest that CO may help promote an anti-inflammatory environment during intrauterine infections by inhibiting TNF-alpha and IL-1beta production. PMID- 23929880 TI - Double exposure to intra-amniotic lipopolysaccharide and maternal betamethasone induces sustained increase of neutrophils in the lungs and disrupts alveolarization in newborn rats. AB - AIM: We investigated the combined effects of intra-amniotic lipopolysaccharide (LPS) and maternal betamethasone (BMZ) on alveolarization using a newborn rat model. METHODS: LPS (1.0 MUg/sac) or vehicle was injected into the amniotic sacs of pregnant rats and BMZ (170 MUg/kg) or vehicle was injected intramuscularly into the pregnant rats twice at 8-h intervals on gestation day 20. The rat pups were delivered spontaneously after 2-2.5 days and raised until the measurements were taken. Bronchoalveolar lavage was performed on days 2 and 5, and morphometric analyses of the lungs were performed on days 5 and 14. RESULTS: Intra-amniotic LPS significantly increased the neutrophils in the bronchoalveolar lavage fluid (BALF) on day 2, but double exposure to LPS and BMZ significantly alleviated the neutrophil increase in the BALF. On day 5, while the neutrophils in the BALF decreased in the animals exposed to LPS alone, the neutrophil numbers in the BALF were steady in the animals exposed to both LPS and BMZ. Morphometric analyses on days 5 and 14 revealed a significant disruption of alveolarization only in the animals exposed to both LPS and BMZ. CONCLUSIONS: Our results suggested that double exposure to maternal BMZ and intra-amniotic LPS induces sustained increase of neutrophils in the lungs and disrupts alveolarization. PMID- 23929881 TI - Enzyme-substrate complexes of the quinate/shikimate dehydrogenase from Corynebacterium glutamicum enable new insights in substrate and cofactor binding, specificity, and discrimination. AB - Quinate dehydrogenase (QDH) catalyzes the reversible oxidation of quinate to 3 dehydroquinate by nicotineamide adenine dinucleotide (NADH) and is involved in the catabolic quinate metabolism required for the degradation of lignin. The enzyme is a member of the family of shikimate/quinate dehydrogenases (SDH/QDH) occurring in bacteria and plants. We characterized the dual-substrate quinate/shikimate dehydrogenase (QSDH) from Corynebacterium glutamicum (CglQSDH) kinetically and revealed a clear substrate preference of CglQSDH for quinate compared with shikimate both at the pH optimum and in a physiological pH range, which is a remarkable contrast to closely related SDH/QDH enzymes. With respect to the cosubstrate, CglQSDH is strictly NAD(H) dependent. These substrate and cosubstrate profiles correlate well with the details of three atomic resolution crystal structures of CglQSDH in different functional states we report here: with bound NAD+ (binary complex) and as ternary complexes with NADH plus either shikimate or quinate. The CglQSDH-NADH-quinate structure is the first complex structure of any member of the SDH/QDH family with quinate. Based on this novel structural information and systematic sequence and structure comparisons with closely related enzymes, we can explain the strict NAD(H) dependency of CglQSDH as well as its discrimination between shikimate and quinate. PMID- 23929882 TI - Contribution of distinct platelet integrins to binding, unfolding, and assembly of fibronectin. AB - Fibronectin (FN) fibrillogenesis depends on the binding of FN to cellular receptors and subsequent unfolding of bound FN. Integrins alphaIIbbeta3, alphavbeta3, and alpha5beta1 are known to assemble FN fibrils on platelets. In our study, we examined the contribution of these integrins to FN binding, unfolding, and assembly on platelets in suspension and adherent platelets in the presence or absence of agonists. Phorbol 12-myristate 13-acetate (PMA), but not adenosine diphosphate (ADP), induced binding of FN to platelets in suspension. In contrast, adherent platelets were able to deposit FN on their surfaces in the absence of agonists. beta3 integrins had a major impact on the interaction of FN on platelets. alphavbeta3 showed a similar contribution to the binding of FN as alphaIIbbeta3 on PMA-stimulated platelets in suspension but had a lesser contribution to unfolding and deposition of FN on adherent platelets. alpha5beta1 also participated in the interaction of FN with platelets by mediating the unfolding and assembly of FN, but to a lesser extent than beta3 integrins. None of the distinct antibodies directed against one of the three integrins caused a complete inhibition of binding, unfolding, and assembly of FN by platelets. Thus, it is likely that alphaIIbbeta3, alphavbeta3, and alpha5beta1 or another still unknown receptor can be substituted. PMID- 23929883 TI - Structural comparison of the transport units of type V secretion systems. AB - Pathogenic gram-negative bacteria have evolved several secretion mechanisms to translocate adhesins, enzymes, toxins, and other virulence factors across the inner and outer membranes. Currently, eight different secretion systems, type I type VIII (T1SS-T8SS) plus the chaperone-usher (CU) pathway, have been identified, which act in one-step or two-step mechanisms to traverse both membrane barriers. The type V secretion system (T5SS) is dependent first on the Sec translocon within the inner membrane. The periplasmic intermediates are then secreted through aqueous pores formed by beta-barrels in the outer membrane. Until now, transport across the outer membrane has not been understood on a molecular level. With respect to special characteristics revealed by crystal structure analysis, bioinformatic and biochemical data, five subgroups of T5SS were defined. Here, we compare the transport moieties of members of four subgroups based on X-ray crystal structures. For the fifth subgroup, which was identified only recently, no structures have thus far been reported. We also discuss different models for the translocation process across the outer membrane with respect to recent findings. PMID- 23929884 TI - The addition of MESNA in vitro prolongs prothrombin time similar to N-acetyl cysteine. PMID- 23929885 TI - The use of financial incentives to help improve health outcomes: is the quality and outcomes framework fit for purpose? A systematic review. AB - BACKGROUND: The quality and outcomes framework (QOF) is one of the world's largest pay-for-performance schemes, rewarding general practitioners for the quality of care they provide. This review examines the evidence on the efficacy of the scheme for improving health outcomes, its impact on non-incentivized activities and the robustness of the clinical targets adopted in the scheme. METHODS: The review was conducted using six electronic databases, six sources of grey literature and bibliography searches from relevant publications. Studies were identified using a comprehensive search strategy based on MeSH terms and keyword searches. A total of 21,543 references were identified of which 32 met the eligibility criteria with 11 studies selected for the review. RESULTS: Findings provide strong evidence that the QOF initially improved health outcomes for a limited number of conditions but subsequently fell to the pre-existing trend. There was limited impact on non-incentivized activities with adverse effects for some sub-population groups. CONCLUSION: The QOF has limited impact on improving health outcomes due to its focus on process-based indicators and the indicators' ceiling thresholds. Further research is required to strengthen the quality of evidence available on the QOF's impact on population health to ensure that the incentive scheme is both clinically and cost-effective. PMID- 23929886 TI - Alcohol imagery on popularly viewed television in the UK. AB - BACKGROUND: Exposure to alcohol consumption and product imagery in films is associated with increased alcohol consumption among young people, but the extent to which exposure also occurs through television is not clear. We have measured the occurrence of alcohol imagery in prime-time broadcasting on UK free-to-air television channels. METHODS: Occurrence of alcohol imagery (actual use, implied use, brand appearances or other reference to alcohol) was measured in all broadcasting on the five most popular UK television stations between 6 and 10 p.m. during 3 weeks in 2010, by 1-min interval coding. RESULTS: Alcohol imagery occurred in over 40% of broadcasts, most commonly soap operas, feature films, sport and comedies, and was equally frequent before and after the 9 p.m. watershed. Brand appearances occurred in 21% of programmes, and over half of all sports programmes, a third of soap operas and comedies and a fifth of advertising/trailers. Three brands, Heineken, Budweiser and Carlsberg together accounted for ~40% of all brand depictions. CONCLUSIONS: Young people are exposed to frequent alcohol imagery, including branding, in UK prime-time television. It is likely that this exposure has an important effect on alcohol consumption in young people. PMID- 23929888 TI - Reply to Bruns et al. PMID- 23929887 TI - Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance. AB - Rapamycin extends lifespan in mice, but can have a number of undesirable effects that may ultimately limit its utility in humans. The canonical target of rapamycin, and the one thought to account for its effects on lifespan, is the mammalian/mechanistic target of rapamycin, complex 1 (mTORC1). We have previously shown that at least some of the detrimental side effects of rapamycin are due to "off target" disruption of mTORC2, suggesting they could be avoided by more specific targeting of mTORC1. However, mTORC1 inhibitionper se can reduce the mRNA expression of mitochondrial genes and compromise the function of mitochondria in cultured muscle cells, implying that defects in bioenergetics might be an unavoidable consequence of targeting mTORC1 in vivo. Therefore, we tested whether rapamycin, at the same doses used to extend lifespan, affects mitochondrial function in skeletal muscle. While mitochondrial transcripts were decreased, particularly in the highly oxidative soleus muscle, we found no consistent change in mitochondrial DNA or protein levels. In agreement with the lack of change in mitochondrial components, rapamycin-treated mice had endurance equivalent to that of untreated controls, and isolated, permeabilized muscle fibers displayed similar rates of oxygen consumption. We conclude that the doses of rapamycin required to extend life do not cause overt mitochondrial dysfunction in skeletal muscle. PMID- 23929889 TI - Impact of an evidence-based bundle intervention in the quality-of-care management and outcome of Staphylococcus aureus bacteremia. AB - BACKGROUND: Staphylococcus aureus bacteremia (SAB) is associated with significant morbidity and mortality. Several aspects of clinical management have been shown to have significant impact on prognosis. The objective of the study was to identify evidence-based quality-of-care indicators (QCIs) for the management of SAB, and to evaluate the impact of a QCI-based bundle on the management and prognosis of SAB. METHODS: A systematic review of the literature to identify QCIs in the management of SAB was performed. Then, the impact of a bundle including selected QCIs was evaluated in a quasi-experimental study in 12 tertiary Spanish hospitals. The main and secondary outcome variables were adherence to QCIs and mortality. Specific structured individualized written recommendations on 6 selected evidence-based QCIs for the management of SAB were provided. RESULTS: A total of 287 and 221 patients were included in the preintervention and intervention periods, respectively. After controlling for potential confounders, the intervention was independently associated with improved adherence to follow up blood cultures (odds ratio [OR], 2.83; 95% confidence interval [CI], 1.78 4.49), early source control (OR, 4.56; 95% CI, 2.12-9.79), early intravenous cloxacillin for methicillin-susceptible isolates (OR, 1.79; 95% CI, 1.15-2.78), and appropriate duration of therapy (OR, 2.13; 95% CI, 1.24-3.64). The intervention was independently associated with a decrease in 14-day and 30-day mortality (OR, 0.47; 95% CI, .26-.85 and OR, 0.56; 95% CI, .34-.93, respectively). CONCLUSIONS: A bundle orientated to improving adherence to evidence-based QCIs improved the management of patients with SAB and was associated with reduced mortality. PMID- 23929890 TI - Editorial commentary: a quality-of-care bundle for treatment of Staphylococcus aureus bacteremia: ready for prime time? PMID- 23929891 TI - Long-term survival in community-acquired pneumonia caused by other bacteria than pneumococci is impaired more than in pneumococcal pneumonia: effect of underlying disease? PMID- 23929892 TI - Identification and quantification of AKT isoforms and phosphoforms in breast cancer using a novel nanofluidic immunoassay. AB - Breast cancer subtype-specific molecular variations can dramatically affect patient responses to existing therapies. It is thought that differentially phosphorylated protein isoforms might be a useful prognostic biomarker of drug response in the clinic. However, the accurate detection and quantitative analysis of cancer-related protein isoforms and phospho-isoforms in tumors are limited by current technologies. Using a novel, fully automated nanocapillary electrophoresis immunoassay (NanoPro(TM) 1000) designed to separate protein molecules based on their isoelectric point, we developed a reliable and highly sensitive assay for the detection and quantitation of AKT isoforms and phosphoforms in breast cancer. This assay enabled the measurement of activated AKT1/2/3 in breast cancer cells using protein produced from as few as 56 cells. Importantly, we were able to assign an identity for the phosphorylated S473 phosphoform of AKT1, the major form of activated AKT involved in multiple cancers, including breast, and a current focus in clinical trials for targeted intervention. The ability of our AKT assay to detect and measure AKT phosphorylation from very low amounts of total protein will allow the accurate evaluation of patient response to drugs targeting activated PI3K-AKT using scarce clinical specimens. Moreover, the capacity of this assay to detect and measure all three AKT isoforms using one single pan-specific antibody enables the study of the multiple and variable roles that these isoforms play in AKT tumorigenesis. PMID- 23929893 TI - Lipid-induced hepatic insulin resistance. PMID- 23929895 TI - The impact of the workplace on health. PMID- 23929896 TI - Probiotics do not prevent diarrhoea caused by antibiotics in older people, study finds. PMID- 23929897 TI - Above average glucose level may boost dementia risk in people without diabetes. PMID- 23929894 TI - Perceived job insecurity as a risk factor for incident coronary heart disease: systematic review and meta-analysis. AB - OBJECTIVE: To determine the association between self reported job insecurity and incident coronary heart disease. DESIGN: A meta-analysis combining individual level data from a collaborative consortium and published studies identified by a systematic review. DATA SOURCES: We obtained individual level data from 13 cohort studies participating in the Individual-Participant-Data Meta-analysis in Working Populations Consortium. Four published prospective cohort studies were identified by searches of Medline (to August 2012) and Embase databases (to October 2012), supplemented by manual searches. REVIEW METHODS: Prospective cohort studies that reported risk estimates for clinically verified incident coronary heart disease by the level of self reported job insecurity. Two independent reviewers extracted published data. Summary estimates of association were obtained using random effects models. RESULTS: The literature search yielded four cohort studies. Together with 13 cohort studies with individual participant data, the meta analysis comprised up to 174,438 participants with a mean follow-up of 9.7 years and 1892 incident cases of coronary heart disease. Age adjusted relative risk of high versus low job insecurity was 1.32 (95% confidence interval 1.09 to 1.59). The relative risk of job insecurity adjusted for sociodemographic and risk factors was 1.19 (1.00 to 1.42). There was no evidence of significant differences in this association by sex, age (<50 v >= 50 years), national unemployment rate, welfare regime, or job insecurity measure. CONCLUSIONS: The modest association between perceived job insecurity and incident coronary heart disease is partly attributable to poorer socioeconomic circumstances and less favourable risk factor profiles among people with job insecurity. PMID- 23929898 TI - Relation of regional fat distribution to left ventricular structure and function. AB - BACKGROUND: The relation of body fat distribution to left ventricular (LV) structure and function is poorly defined. METHODS AND RESULTS: A total of 2710 participants without heart failure or LV dysfunction in the Dallas Heart Study underwent dual energy x-ray absorptiometry and MRI assessment of fat distribution, LV morphology, and hemodynamics. Cross-sectional associations of fat distribution with LV structure and function were examined after adjustment for age, sex, race, comorbidities, and lean mass. Mean age was 44 years with 55% women; 48% blacks; and 44% obese. After multivariable adjustment, visceral adipose tissue was associated with concentric remodeling characterized by lower LV end-diastolic volume (beta=-0.21), higher concentricity (beta=0.20), and wall thickness (beta=0.09; P<0.0001 for all). In contrast, lower body subcutaneous fat was associated with higher LV end-diastolic volume (beta=0.48), reduced concentricity (beta=-0.50), and wall thickness (beta=-0.28, P<0.0001 for all). Visceral adipose tissue was also associated with lower cardiac output (beta= 0.10, P<0.05) and higher systemic vascular resistance (beta=0.08, P<0.05), whereas lower body subcutaneous fat associated with higher cardiac output (beta=0.20, P<0.0001) and lower systemic vascular resistance (beta=-0.18, P<0.0001). Abdominal subcutaneous fat showed weaker associations with concentric remodeling and was not associated with hemodynamics. Among the subset of obese participants, visceral adipose tissue, but not abdominal subcutaneous fat, was significantly associated with concentric remodeling. CONCLUSIONS: Visceral adipose tissue, a marker of central adiposity, was independently associated with concentric LV remodeling and adverse hemodynamics. In contrast, lower body subcutaneous fat was associated with eccentric remodeling. The impact of body fat distribution on heart failure risk requires prospective study. PMID- 23929899 TI - Inferior vena caval and right atrial thrombus complicating amoebic liver abscess. AB - We present the result of right atrial thrombectomy in a paediatric patient suffering from a right atrial thrombus due to amoebic liver abscess under total circulatory arrest. A 2-year old boy with amoebic liver abscess complicated by inferior vena cava (IVC) thrombus extending up to the right atrium (RA) was operated on in our institute. During the surgery, the thrombus was removed from the IVC and the RA under deep hypothermic circulatory arrest. After chest closure, open drainage of the abscess was performed. Metronidazole was given postoperatively for 2 weeks. The postoperative period was uneventful. There was rapid convalescence with complete resolution of the abscess. Anticoagulation with warfarin was started on the day following surgery and continued for 6 weeks. There was no recurrence of thrombosis or embolic events in the follow-up period. Extension of thrombus into the right atrium mandates an aggressive surgical approach which may prove life saving. It is crucial in the prevention of pulmonary embolism or Budd-Chiari syndrome, which may have an overall poor outcome. PMID- 23929900 TI - Which is the best tissue valve used in the pulmonary position, late after previous repair of tetralogy of Fallot? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: which is the best tissue valve for use in the pulmonary position, late after previous repair of tetralogy of Fallot? Altogether 141 papers were found using the reported search, of which 13 represented the best evidence to answer the clinical question. In addition to this, 1 paper was found by searching the reference lists of the relevant papers. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude from the best evidence available that homograft valves function well in the pulmonary position late after Tetralogy of Fallot (TOF) repair. This is particularly evident in the larger studies where the patients were only treated with homografts. It has been suggested that Homografts are better than xenografts and this has not been statistically shown. Two articles have suggested that xenografts outperform homografts however, in both studies these results were not statistically significant. Furthermore, early indications suggest that porcine valves may be better than bovine pericardial valves but a better longer term follow-up is certainly required to demonstrate this. It is important to realize also that when comparing the effectiveness of these valves in the pulmonary position, one cannot ignore confounding factors. The most important of these include timing of operation, age of patient, valve size, immunological factors, operative complexity and also postoperative valvular gradients. The timing of these operations has always been an area of great controversy illustrated by varied guidelines. There is no general consensus regarding whether there is even a role of pulmonary valve replacement late after TOF repair. Further weakening any conclusions that may be drawn based on current best evidence is the lack of strong follow-up data (transvalvular gradients and right ventricular (RV) volumetric data). New research is required with comparisons using objective clinical parameters in order to more effectively answer our clinical question. PMID- 23929901 TI - Alkaline phosphatases contribute to uterine receptivity, implantation, decidualization, and defense against bacterial endotoxin in hamsters. AB - Alkaline phosphatase (AP) activity has been demonstrated in the uterus of several species, but its importance in the uterus, in general and during pregnancy, is yet to be revealed. In this study, we focused on identifying AP isozyme types and their hormonal regulation, cell type, and event-specific expression and possible functions in the hamster uterus during the cycle and early pregnancy. Our RT-PCR and in situ hybridization studies demonstrated that among the known Akp2, Akp3, Akp5, and Akp6 murine AP isozyme genes, hamster uteri express only Akp2 and Akp6; both genes are co-expressed in luminal epithelial cells. Studies in cyclic and ovariectomized hamsters established that while progesterone (P4) is the major uterine Akp2 inducer, both P4 and estrogen are strong Akp6 regulators. Studies in preimplantation uteri showed induction of both genes and the activity of their encoded isozymes in luminal epithelial cells during uterine receptivity. However, at the beginning of implantation, Akp2 showed reduced expression in luminal epithelial cells surrounding the implanted embryo. By contrast, expression of Akp6 and its isozyme was maintained in luminal epithelial cells adjacent to, but not away from, the implanted embryo. Following implantation, stromal transformation to decidua was associated with induced expressions of only Akp2 and its isozyme. We next demonstrated that uterine APs dephosphorylate and detoxify endotoxin lipopolysaccharide at their sites of production and activity. Taken together, our findings suggest that uterine APs contribute to uterine receptivity, implantation, and decidualization in addition to their role in protection of the uterus and pregnancy against bacterial infection. PMID- 23929903 TI - The dynamics of the primordial follicle reserve. AB - The female germline comprises a reserve population of primordial (non-growing) follicles containing diplotene oocytes arrested in the first meiotic prophase. By convention, the reserve is established when all individual oocytes are enclosed by granulosa cells. This commonly occurs prior to or around birth, according to species. Histologically, the 'reserve' is the number of primordial follicles in the ovary at any given age and is ultimately depleted by degeneration and progression through folliculogenesis until exhausted. How and when the reserve reaches its peak number of follicles is determined by ovarian morphogenesis and germ cell dynamics involving i) oogonial proliferation and entry into meiosis producing an oversupply of oocytes and ii) large-scale germ cell death resulting in markedly reduced numbers surviving as the primordial follicle reserve. Our understanding of the processes maintaining the reserve comes primarily from genetically engineered mouse models, experimental activation or destruction of oocytes, and quantitative histological analysis. As the source of ovulated oocytes in postnatal life, the primordial follicle reserve requires regulation of i) its survival or maintenance, ii) suppression of development (dormancy), and iii) activation for growth and entry into folliculogenesis. The mechanisms influencing these alternate and complex inter-related phenomena remain to be fully elucidated. Drawing upon direct and indirect evidence, we discuss the controversial concept of postnatal oogenesis. This posits a rare population of oogonial stem cells that contribute new oocytes to partially compensate for the age-related decline in the primordial follicle reserve. PMID- 23929904 TI - Caregivers' confidence in performing child safety seat installations: what matters most? AB - BACKGROUND: Although effective when used correctly, child restraint systems (CRS) are commonly misused. Caregivers must make accurate judgements about the quality of their CRS installations, but there is little research on the psychological, technological, or contextual factors that might influence these judgements. METHODS: Seventy-five caregivers were observed installing a CRS into a vehicle and completed self-report surveys measuring risk appraisals, previous utilisation of CRS resources, task difficulty, and confidence that the CRS was installed correctly. RESULTS: Approximately 30% of caregivers installed the CRS inaccurately and insecurely, but reported that it was correctly installed. Predictors of confidence were ease of use (beta=0.47) and exposure to CRS resources (beta=-0.34). Installation errors and CRS security were unrelated to caregivers' confidence. CONCLUSIONS: An interdisciplinary approach is needed to understand factors influencing caregivers' judgements about their installations, optimise channels to connect caregivers to CRS resources, and to design safety technologies in light of these findings. PMID- 23929905 TI - Financial gain is driving referrals for specialist prostate radiotherapy, says report. PMID- 23929902 TI - Regulatory T cells and the immune pathogenesis of prenatal infection. AB - Pregnancy in placental mammals offers exceptional comprehensive benefits of in utero protection, nutrition, and metabolic waste elimination for the developing fetus. However, these benefits also require durable strategies to mitigate maternal rejection of fetal tissues expressing foreign paternal antigens. Since the initial postulate of expanded maternal immune tolerance by Sir Peter Medawar 60 years ago, an amazingly elaborate assortment of molecular and cellular modifications acting both locally at the maternal-placental interface and systemically have been shown to silence potentially detrimental maternal immune responses. In turn, simultaneously maintaining host defense against the infinite array of potential pathogens during pregnancy is equally important. Fortunately, resistance against most infections is preserved seamlessly throughout gestation. On the other hand, recent studies on pathogens with unique predisposition for prenatal infections have uncovered distinctive holes in host defense associated with the reproductive process. Using these infections to probe the response during pregnancy, the immune suppressive regulatory subset of maternal CD4 T cells has been increasingly shown to dictate the inter-workings between prenatal infection susceptibility and pathogenesis of ensuing pregnancy complications. Herein, the recent literature suggesting a necessity for maternal regulatory T cells (Tregs) in pregnancy-induced immunological shifts that sustain fetal tolerance is reviewed. Additional discussion is focused on how expansion of maternal Treg suppression may become exploited by pathogens that cause prenatal infections and the perilous potential of infection-induced immune activation that may mitigate fetal tolerance and inadvertently inject hostility into the protective in utero environment. PMID- 23929906 TI - Obesity rates dip slightly among some poor children in the US. PMID- 23929907 TI - L500m fund for emergency services will not fix longstanding problems, say doctors. PMID- 23929908 TI - What we can learn from twins: congenital heart disease in the danish twin registry. PMID- 23929909 TI - Increased prevalence of congenital heart defects in monozygotic and dizygotic twins. AB - BACKGROUND: Smaller studies and many case series reports indicate that congenital heart defects may be more common in monochorionic twins than in dichorionic twins and singletons. METHODS AND RESULTS: We investigated congenital heart defect occurrence in all twins and 5% of all singletons born in Denmark in 1977-2001 and followed through 2006 by linking the Danish Twin Registry and Statistics Denmark registers including the National Medical Birth Register and the Danish National Patient Register. Among 41 525 twin individuals, a total of 584 twins (1.4%) had a congenital heart defect registered in the Danish National Patient Register, whereas the corresponding numbers for singletons were 648 of 74 473 (0.87%; P<0.001; ie, a 63% [95% confidence interval, 45-82%] increased risk for congenital heart defect for twins). Patent ductus arteriosus and coarctation of aorta occurred >3 times as often in twins as in singletons, at 3.9 (95% confidence interval, 2.6-5.8) and 3.1 (95% confidence interval, 1.5-6.4), respectively. The increased occurrence in twins was also found in sensitivity analyses including only inpatients or only surgically treated cases regardless of whether preterm patent ductus arteriosus was included. We were not able to demonstrate a higher risk for congenital heart defect among monozygotic twins compared with dizygotic twins, and the congenital heart defect occurrence was also increased in dizygotic twins, who are all dichorionic. CONCLUSIONS: Congenital heart defect is more common in twins than in singletons, and the increased occurrence is not restricted to monochorionic twins. Intrauterine surveillance and a postnatal comprehensive cardiac assessment for both twins may be considered regardless of chorionicity and zygosity. PMID- 23929910 TI - The next steps in developing clinical practice guidelines for prevention. PMID- 23929911 TI - Low frequency of GITR+ T cells in ex vivo and in vitro expanded Treg cells from type 1 diabetic patients. AB - Reported alterations in T(reg) cells from type 1 diabetes (T1D) patients led us to a revision of their phenotypical features compared with controls. A fine cytometric analysis was designed for their characterization, using a panel of markers including FOXP3, CTLA4, glucocorticoid-induced TNFR family related (GITR) and CD127. The frequency of peripheral CD4(+)CD25(hi) T(reg) cells was similar between samples. However, the yield of sorted T(reg) cells was significantly lower in patients than in controls. When comparing the T(reg)-cell phenotype between samples, the only difference concerned the expression of GITR. A significant decrease of GITR(+) cells and GITR mean fluorescence intensity within the T(reg)-cell population, and to a lesser extent in the effector population, was observed in T1D compared with controls. Moreover, GITR expression was analyzed in several conditions of T-cell activation and differences were only observed in T1D T(reg) cells versus controls when responding to sub-optimal stimulation, that is, soluble anti-CD3 or medium alone but not in the presence of anti-CD3-/anti-CD28-coated beads. However, expanded T1D T(reg)-cell-mediated suppression was as efficient as that mediated by their control counterparts, showing no association between their regulatory capacity and the reduced GITR. Our results show a higher susceptibility to apoptosis in patients' versus controls' T(reg) cells, suggesting that GITR is a T(reg)-cell marker that would be primarily involved in T(reg)-cell survival rather than in their suppressor function. PMID- 23929912 TI - TGF-beta type II receptor expression in thymic epithelial cells inhibits the development of Hassall's corpuscles in mice. AB - Hassall's corpuscles are concentric clusters of keratinized epithelial cells located within the thymic medulla of humans and guinea pigs but are scant in mouse and rat. They are considered to be the terminally differentiated stages of medullary thymic epithelial cells (mTECs) but the mechanisms of their origin are unclear. We have previously deleted the TGF-beta type II receptor (TGFbetaRII) specifically in mouse TECs and reported that these mice have mitigated thymic involution and exhibit earlier reconstitution post-irradiation. In this study, we analyzed the differentiation of mTECs in the TGFbetaRII-knockout mice. Interestingly, the TGFbetaRII-knockout mice display enhanced development of Hassall's corpuscles. The expression of Aire, stromal-cell-derived factor 1 and thymic stromal lymphopoietin in the thymi of the TGFbetaRII-knockout mice was similar to that previously reported for the human thymus. In addition, the putative epithelial progenitor markers MTS20 and MTS24 labeled Hassall's corpuscles in normal mice, but the extent and intensity of this staining were greatly enhanced in Hassall's corpuscles of the TGFbetaRII-knockout mice. The phosphorylated forms of ERK and JNK were also found in Hassall's corpuscles of the TGFbetaRII-knockout mice. Taken together, we suggest that TGFbetaRII-mediated signaling in TECs inhibits their development into Hassall's corpuscles in mice. PMID- 23929913 TI - Benchmarking French regions according to their prevalence of healthcare associated infections. AB - OBJECTIVE: To propose an original method of benchmarking regions based on their prevalence of healthcare-associated infections (HAIs) and to identify regions with unusual results. DESIGN: To study between-region variability with a three level hierarchical logistic regression model and a Bayesian non-parametric method. SETTING: French 2006 national HAIs point prevalence survey. PARTICIPANTS: A total of 336 858 patients from 2289 healthcare facilities in 27 regions. Patients with an imported HAI (1% of the data, 20.7% of infected patients), facilities with <5 patients and patients who had at least one missing value for the variables taken into account were excluded (5.0% of patients). MAIN OUTCOME MEASURE: Binary outcome variable indicates whether a given patient was infected. RESULTS: Two clusters of regions were identified: one cluster of five regions had a lower adjusted prevalence than the other one of 22 regions, while no region with unusually high prevalence could be identified. Nevertheless, the degree of heterogeneity of odds ratios between facilities for facility-specific effects of use of invasive devices was more important in some regions than in others. CONCLUSIONS: The adjusted regional prevalence of HAIs can serve as an adequate benchmark to identify regions with concerning results. Although no outlier regions were identified, the proposed approach could be applied to the data of the 2012 national survey to benchmark regional healthcare policies. The estimation of facility-specific effects of use of invasive devices may orient future regional action plans. PMID- 23929914 TI - Consent for the use of human biological samples for biomedical research: a mixed methods study exploring the UK public's preferences. AB - OBJECTIVE: A mixed-methods study exploring the UK general public's views towards consent for the use of biosamples for biomedical research. SETTING: Cross sectional population-based focus groups followed by an online survey. PARTICIPANTS: 12 focus groups (81 participants) selectively sampled to reflect a range of demographic groups; 1110 survey responders recruited through a stratified sampling method with quotas set on sex, age, geographical location, socioeconomic group and ethnicity. MAIN OUTCOME MEASURES: (1) Views on the importance of consent when donating residual biosamples for medical research; (2) preferences for opt-in or opt-out consent approaches and (3) preferences for different consent models. RESULTS: Participants believed obtaining consent for use of residual biosamples was important as it was 'morally correct' to ask, and enabled people to make an active choice and retain control over their biosamples. Survey responders preferred opt-in consent (55%); the strongest predictor was being from a low socioeconomic group (OR 2.22, 95% CI 1.41 to 3.57, p=0.001) and having a religious affiliation (OR 1.36, 95% CI 1.01 to 1.81, p=0.04). Focus group participants had a slight preference for opt-out consent because by using this approach more biosamples would be available and facilitate research. Concerning preferred models of consent for research use of biosamples, survey responders preferred specific consent with recontact for each study for which their biosamples are eligible. Focus group participants preferred generic consent as it provided 'flexibility for researchers' and reduced the likelihood that biosamples would be wasted. The strongest predictor for preferring specific consent was preferring opt-in consent (OR 4.58, 95% CI 3.30 to 6.35, p=0.015) followed by non-'White' ethnicity (OR 2.94, 95% CI 1.23 to 7.14, p<0.001). CONCLUSIONS: There is a preference among the UK public for ongoing choice and control over donated biosamples; however, increased knowledge and opportunity for discussion is associated with acceptance of less restrictive consent models for some people. PMID- 23929916 TI - Correction. PMID- 23929915 TI - Public views on the donation and use of human biological samples in biomedical research: a mixed methods study. AB - OBJECTIVE: A mixed methods study exploring the UK general public's willingness to donate human biosamples (HBSs) for biomedical research. SETTING: Cross-sectional focus groups followed by an online survey. PARTICIPANTS: Twelve focus groups (81 participants) selectively sampled to reflect a range of demographic groups; 1110 survey responders recruited through a stratified sampling method with quotas set on sex, age, geographical location, socioeconomic group and ethnicity. MAIN OUTCOME MEASURES: (1) Identify participants' willingness to donate HBSs for biomedical research, (2) explore acceptability towards donating different types of HBSs in various settings and (3) explore preferences regarding use and access to HBSs. RESULTS: 87% of survey participants thought donation of HBSs was important and 75% wanted to be asked to donate in general. Responders who self reported having some or good knowledge of the medical research process were significantly more likely to want to donate (p<0.001). Reasons why focus group participants saw donation as important included: it was a good way of reciprocating for the medical treatment received; it was an important way of developing drugs and treatments; residual tissue would otherwise go to waste and they or their family members might benefit. The most controversial types of HBSs to donate included: brain post mortem (29% would donate), eyes post mortem (35%), embryos (44%), spare eggs (48%) and sperm (58%). Regarding the use of samples, there were concerns over animal research (34%), research conducted outside the UK (35%), and research conducted by pharmaceutical companies (56%), although education and discussion were found to alleviate such concerns. CONCLUSIONS: There is a high level of public support and willingness to donate HBSs for biomedical research. Underlying concerns exist regarding the use of certain types of HBSs and conditions under which they are used. Improved education and more controlled forms of consent for sensitive samples may mitigate such concerns. PMID- 23929917 TI - Clinical and imaging services for TIA and minor stroke: results of two surveys of practice across the UK. AB - OBJECTIVES: Transient ischaemic attack (TIA) is a medical emergency requiring rapid access to effective, organised, stroke prevention. There are about 90 000 TIAs per year in the UK. We assessed whether stroke-prevention services in the UK meet Government targets. DESIGN: Cross-sectional survey. SETTING: All UK clinical and imaging stroke-prevention services. INTERVENTION: Electronic structured survey delivered over the web with automatic recording of responses into a database; reminders to non-respondents. The survey sought information on clinic frequency, staff, case-mix, details of brain and carotid artery imaging, medical and surgical treatments. RESULTS: 114 stroke clinical and 146 imaging surveys were completed (both response rates 45%). Stroke-prevention services were available in most (97%) centres but only 31% operated 7 days/week. Half of the clinic referrals were TIA mimics, most patients (75%) were prescribed secondary prevention prior to clinic referral, and nurses performed the medical assessment in 28% of centres. CT was the most common and fastest first-line investigation; MR, used in 51% of centres, mostly after CT, was delayed up to 2 weeks in 26%; 51% of centres omitted blood-sensitive (GRE/T2*) MR sequences. Carotid imaging was with ultrasound in 95% of centres and 59% performed endarterectomy within 1 week of deciding to operate. CONCLUSIONS: Stroke-prevention services are widely available in the UK. Delays to MRI, its use in addition to CT while omitting key sequences to diagnose haemorrhage, limit the potential benefit of MRI in stroke prevention, but inflate costs. Assessing TIA mimics requires clinical neurology expertise yet nurses run 28% of clinics. Further improvements are still required for optimal stroke prevention. PMID- 23929918 TI - Quality and safety in transitional care of the elderly: the study protocol of a case study research design (phase 1). AB - INTRODUCTION: Although international studies have documented that patients' transitions between care providers are associated with the risk of adverse events and uncoordinated care, research directed towards the quality and safety of transitional care between primary and secondary health and care services, especially for the elderly receiving care from multiple healthcare providers due to complex health problems, is lacking. This study investigates how different aspects of transitional care can explain the quality and safety of elderly healthcare services in Norway. The overall aim of the study was to explore different aspects of transitional care of the elderly, in different contexts and how they might explain the quality and safety of care. METHODS AND ANALYSIS: The study applies a case study design. Two cases are chosen: one city-based hospital and one rural hospital with associated nursing homes and home-based nursing services. Admission and discharge to/from hospital to/from nursing homes or home based nursing services constitute the main focal areas of the study, including the patient, next-of-kin and the professional perspective. The qualitative methods employed include participant observation, individual interviews and document analysis. To ensure trustworthiness in the data analysis, we will apply analyst triangulation and member checks. A total impression of the data material will first be created in a systematic text condensation approach. Second, the qualitative data analysis will involve in-depth analyses of two specific themes: the risk perspective and the patient perspective in transitional care. ETHICS AND DISSEMINATION: The study is approved by the Norwegian Regional Committees for Medical and Health Research Ethics. The study is based on informed written consent, and informants can withdraw from the study at any point in time. Interview and observation data material will be managed confidentially. RESULTS: It will be disseminated at research conferences, in peer-reviewed journals and through public presentations to people outside the academic community. PMID- 23929919 TI - A Protocol for the Pharmacokinetics of Enteric Coated Mycophenolate Sodium in Lupus Nephritis (POEMSLUN): an open-label, randomised controlled trial. AB - INTRODUCTION: Mycophenolate sodium, an enteric-coated tablet (EC-MPS), is as effective and safe as mycophenolate mofetil (MMF) in preventing transplant rejection. EC-MPS and MMF improve the outcome of severe lupus nephritis (LN) and have fewer side effects than pulsed intravenous cyclophosphamide. Blood concentrations of mycophenolic acid (MPA), the active metabolite of EC-MPS, vary between participants despite fixed dosing. Interpatient variability has been studied in transplantation, but not well documented in LN. The relationship between MPA concentration and its clinical effect on LN has not been described. METHODS AND ANALYSIS: This is a prospective, open-label, randomised controlled trial. -32 participants with LN who meet the inclusion and exclusion criteria will be randomised into two groups: one receiving a fixed dose of EC-MPS and the second, a dosing regimen that is titrated with therapeutic drug monitoring. Included participants will have blood sampled over a period of 8-12 h on three different occasions. Pharmacokinetic parameters will be calculated using non compartmental methods. ETHICS AND DISSEMINATION: The Human Research and Ethics Committee of the Royal Brisbane Women's Hospital have approved this study. The study is registered with Australian and New Zealand Clinical Trials Registry ACTRN12611000798965 We planned to present the de-identified information at conferences and publish the results in medical journals. TRIAL REGISTRATION: ACTRN12611000798965. PMID- 23929921 TI - Correction. PMID- 23929920 TI - A mixed-methods study of the Care Needs of individuals with idiopathic Pulmonary fibrosis and their carers--CaNoPy: a study protocol. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive, life threatening illness of unknown aetiology, with no proven pharmacological treatments. There is a limited evidence base indicating that the disease negatively affects quality of life, leading to increased dependence, restrictions on daily activities and fatigue. However, there is a paucity of in-depth information on disease impact across its trajectory, particularly in relation to unmet needs, outcomes of importance to patients and the experiences of carers. Furthermore, little is known about the support and information needs of individuals and their carers, or at what point individual need should trigger a referral to palliative care services. METHODS AND ANALYSIS: A mixed-methods study is proposed recruiting individuals with IPF at different stages of the disease and their carers from three respiratory centres in England and Wales. In-depth interviews will be undertaken with participants, adopting an Interpretative Phenomenological Analysis approach. The study will also use validated questionnaires to explore quality of life (EQ-5D), depression (Hospital Anxiety and Depression Scale), breathlessness (Borg dyspnoea scale) and cough (Leicester Cough Questionnaire, Cough Symptom Score). ETHICS AND DISSEMINATION: Ethical approvals were gained in April 2012. Palliative care research is a developing field, but there has been limited focus on IPF. We anticipate that the results of the study will enable healthcare professionals to provide appropriate palliative care across the trajectory for individuals with the disease, and their carers, and we therefore aim to disseminate via relevant respiratory and palliative care journals and conferences. We will also support the lay representative involved in the project to disseminate the findings to patient groups. PMID- 23929922 TI - The Scleroderma Patient-centered Intervention Network (SPIN) Cohort: protocol for a cohort multiple randomised controlled trial (cmRCT) design to support trials of psychosocial and rehabilitation interventions in a rare disease context. AB - INTRODUCTION: Psychosocial and rehabilitation interventions are increasingly used to attenuate disability and improve health-related quality of life (HRQL) in chronic diseases, but are typically not available for patients with rare diseases. Conducting rigorous, adequately powered trials of these interventions for patients with rare diseases is difficult. The Scleroderma Patient-centered Intervention Network (SPIN) is an international collaboration of patient organisations, clinicians and researchers. The aim of SPIN is to develop a research infrastructure to test accessible, low-cost self-guided online interventions to reduce disability and improve HRQL for people living with the rare disease systemic sclerosis (SSc or scleroderma). Once tested, effective interventions will be made accessible through patient organisations partnering with SPIN. METHODS AND ANALYSIS: SPIN will employ the cohort multiple randomised controlled trial (cmRCT) design, in which patients consent to participate in a cohort for ongoing data collection. The aim is to recruit 1500-2000 patients from centres across the world within a period of 5 years (2013-2018). Eligible participants are persons >=18 years of age with a diagnosis of SSc. In addition to baseline medical data, participants will complete patient-reported outcome measures every 3 months. Upon enrolment in the cohort, patients will consent to be contacted in the future to participate in intervention research and to allow their data to be used for comparison purposes for interventions tested with other cohort participants. Once interventions are developed, patients from the cohort will be randomly selected and offered interventions as part of pragmatic RCTs. Outcomes from patients offered interventions will be compared with outcomes from trial-eligible patients who are not offered the interventions. ETHICS AND DISSEMINATION: The use of the cmRCT design, the development of self-guided online interventions and partnerships with patient organisations will allow SPIN to develop, rigourously test and effectively disseminate psychosocial and rehabilitation interventions for people with SSc. PMID- 23929923 TI - Regional variation in the incidence of dialysis-requiring AKI in the United States. AB - BACKGROUND AND OBJECTIVES: Little is known about geographic differences in the incidence of AKI. The objective of this study was to determine if regional variation exists in the population incidence of dialysis-requiring AKI in the United States. DESIGN, SETTING, PARTICIPANTS, & METHODS: Data from the Nationwide Inpatient Sample, a US nationally representative sample of hospitalizations, were used to determine the incidence rates of dialysis-requiring AKI between 2007 and 2009 among the four US Census-designated regions. Cases were identified using validated discharge codes. Poisson regression models were used to estimate overall regional rates, accounting for the data's sampling scheme. RESULTS: In 2007-2009, the population incidence rates of dialysis-requiring AKI differed across the four Census-designated regions (P=0.04). Incidence was highest in the Midwest (523 cases/million person-yr, 95% confidence interval=483 to 568) and lowest in the Northeast (457 cases/million person-yr, 95% confidence interval=426 to 492). The pattern of regional variation in the incidence of dialysis-requiring AKI was not the same as the pattern of regional variation in the incidence of renal replacement therapy-requiring ESRD (obtained from the US Renal Data System). In-hospital mortality associated with dialysis-requiring AKI differed across the four regions, with the highest case fatality in the Northeast (25.9%) and the lowest case fatality in the Midwest (19.4%). CONCLUSIONS: Significant regional variation exists in the population incidence of dialysis-requiring AKI in the United States, and additional investigation is warranted to uncover potential causes behind these geographic differences. PMID- 23929924 TI - Determinants and changes associated with aldosterone breakthrough after angiotensin II receptor blockade in patients with type 2 diabetes with overt nephropathy. AB - BACKGROUND AND OBJECTIVES: Inhibition of the renin-angiotensin-aldosterone system decreases proteinuria and slows estimated GFR decline in patients with type 2 diabetes mellitus with overt nephropathy. Serum aldosterone levels may increase during renin-angiotensin-aldosterone system blockade. The determinants and consequences of this aldosterone breakthrough remain unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study examined the incidence, determinants, and changes associated with aldosterone breakthrough in a posthoc analysis of a randomized study that compared the effect of two angiotensin II receptor blockers in patients with type 2 diabetes mellitus with overt nephropathy. RESULTS: Of 567 of 860 participants included in this posthoc analysis, 28% of participants developed aldosterone breakthrough, which was defined by an increase greater than 10% over baseline values of serum aldosterone levels after 1 year of angiotensin II receptor blocker treatment. Factors independently associated with aldosterone breakthrough at 1 year were lower serum aldosterone and potassium levels at baseline, higher decreases in sodium intake, systolic BP, and estimated GFR from baseline to 1 year, and use of losartan versus telmisartan. Aldosterone breakthrough at 6 months was not sustained at 1 year in 69% of cases, and it did not predict estimated GFR decrease and proteinuria increase between 6 months and 1 year. CONCLUSIONS: Aldosterone breakthrough is a frequent event 1 year after initiating renin-angiotensin-aldosterone system blockade, particularly in participants exposed to intensive lowering of BP with sodium depletion and short acting angiotensin II receptor blockers. Short-term serum aldosterone level increases at 6 months are not associated with negative kidney outcomes between 6 months and 1 year. PMID- 23929925 TI - Cardiorenal syndrome: new developments in the understanding and pharmacologic management. AB - Cardiorenal syndromes (CRSs) with bidirectional heart-kidney signaling are increasingly being recognized for their association with increased morbidity and mortality. In acute CRS, recognition of the importance of worsening kidney function complicating management of acute decompensated heart failure has led to the examination of this specific outcome in the context of acute heart failure clinical trials. In particular, the role of fluid overload and venous congestion has focused interest in the most effective use of diuretic therapy to relieve symptoms of heart failure while at the same time preserving kidney function. Additionally, many novel vasoactive therapies have been studied in recent years with the hopes of augmenting cardiac function, improving symptoms and patient outcomes, while maintaining or improving kidney function. Similarly, recent advances in our understanding of the pathophysiology of chronic CRS have led to reanalysis of kidney outcomes in pivotal trials in chronic congestive heart failure, and newer trials are including changes in kidney function as well as kidney injury biomarkers as prospectively monitored and adjudicated outcomes. This paper provides an overview of some new developments in the pharmacologic management of acute and chronic CRS, examines several reports that illustrate a key management principle for each subtype, and discusses opportunities for future research. PMID- 23929926 TI - Aldosterone breakthrough during angiotensin receptor blocker use: more questions than answers? PMID- 23929927 TI - Short-term changes after a weight reduction intervention in advanced diabetic nephropathy. AB - BACKGROUND AND OBJECTIVES: Obesity precedes and is strongly linked to the development of type 2 diabetic nephropathy in most patients, yet little is known about the effects of weight reduction on this disease. This study aimed to establish proof of concept for the hypothesis that weight reduction ameliorates diabetic nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Six obese individuals with advanced diabetic nephropathy (estimated GFR <40 ml/min per 1.73 m(2), urine albumin excretion >30 mg/d) currently taking a renin-aldosterone axis inhibitor underwent a 12-week very low calorie ketogenic weight reduction diet with encouragement of exercise between March and September 2012. Albuminuria and other parameters of kidney health were the main outcome measures. RESULTS: There was a 12% reduction in weight (median 118.5 versus 104.3 kg, P=0.03). The intervention was associated with a 36% reduction in albuminuria that did not reach statistical significance (2124 versus 1366 mg/24 h, P=0.08) and significant reductions in the filtration markers serum creatinine (3.54 versus 3.13 mg/dl, P<0.05) and cystatin C (2.79 versus 2.46 mg/l, P<0.05). Improvements were also noted for the diabetes markers fasting glucose (166 versus 131 mg/dl, P<0.05), fasting insulin (26.9 versus 10.4 MUU/ml, P<0.05), and insulin resistance (9.6 versus 4.2, P=0.03). Physical function, general health, and the number of diabetes medications also showed statistically significant signs of improvement. CONCLUSIONS: After a short-term intensive weight reduction intervention in patients with advanced diabetic nephropathy, improvements were observed in markers of glomerular filtration, diabetes status, and risk factors for kidney disease progression, as well as other general indicators of health and well being. PMID- 23929928 TI - Randomized controlled trial of febuxostat versus allopurinol or placebo in individuals with higher urinary uric acid excretion and calcium stones. AB - BACKGROUND AND OBJECTIVES: Higher urinary uric acid excretion is a suspected risk factor for calcium oxalate stone formation. Febuxostat, a xanthine oxidoreductase inhibitor, is effective in lowering serum urate concentration and urinary uric acid excretion in healthy volunteers and people with gout. This work studied whether febuxostat, compared with allopurinol and placebo, would reduce 24-hour urinary uric acid excretion and prevent stone growth or new stone formation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this 6-month, double-blind, multicenter, randomized controlled trial, hyperuricosuric participants with a recent history of calcium stones and one or more radio-opaque calcium stone >= 3 mm (as seen by multidetector computed tomography) received daily febuxostat at 80 mg, allopurinol at 300 mg, or placebo. The primary end point was percent change from baseline to month 6 in 24-hour urinary uric acid. Secondary end points included percent change from baseline to month 6 in size of index stone and change from baseline in the mean number of stones and 24-hour creatinine clearance. RESULTS: Of 99 enrolled participants, 86 participants completed the study. Febuxostat led to significantly greater reduction in 24-hour urinary uric acid (-58.6%) than either allopurinol (-36.4%; P=0.003) or placebo (-12.7%; P<0.001). Percent change from baseline in the size of the largest calcium stone was not different with febuxostat compared with allopurinol or placebo. There was no change in stone size, stone number, or renal function. No new safety concerns were noted for either drug. CONCLUSIONS: Febuxostat (80 mg) lowered 24-hour urinary uric acid significantly more than allopurinol (300 mg) in stone formers with higher urinary uric acid excretion after 6 months of treatment. There was no change in stone size or number over the 6-month period. PMID- 23929929 TI - Association of cholesterol levels with mortality and cardiovascular events among patients with CKD and different amounts of proteinuria. AB - BACKGROUND AND OBJECTIVES: Malnutrition and/or inflammation may modify the risk relationship of total cholesterol with cardiovascular disease in CKD patients. However, it is unclear whether the relationship of total cholesterol with cardiovascular events and mortality varies by proteinuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study enrolled 3303 patients with CKD stages 3 5 from a medical center and a regional hospital between November of 2002 and May of 2009 and followed the patients until July of 2010. RESULTS: During a median 2.8-year follow-up, there were 471 (14.3%) deaths and 545 (16.5%) cardiovascular events. In an adjusted Cox model, the two highest quartiles of total cholesterol (hazard ratio, 1.90; 95% confidence interval, 1.16 to 3.13 and hazard ratio, 2.00; 95% confidence interval, 1.18 to 3.39 versus quartile 1, respectively) were associated with a significant higher risk of all-cause mortality in patients with urine protein-to-creatinine ratio<1 g/g (n=1535), but this higher risk was not seen in those patients with urine protein-to-creatinine ratio >= 1 g/g (n=1768; hazard ratio, 0.75; 95% confidence interval, 0.53 to 1.07 and hazard ratio, 0.70; 95% confidence interval, 0.49 to 1.02 versus quartile 1, respectively). The interaction between total cholesterol and proteinuria with all-cause mortality was significant (interaction, P=0.05). However, the relationship between total cholesterol and cardiovascular events did not significantly differ by proteinuria (interaction, P=0.91). CONCLUSIONS: The association between cholesterol and mortality is different among patients with different levels of proteinuria. Large scale clinical trials to evaluate the mortality benefit should specifically target lowering hypercholesterolemia in CKD patients with different levels of proteinuria. PMID- 23929930 TI - Dietary sodium restriction and association with urinary marinobufagenin, blood pressure, and aortic stiffness. AB - BACKGROUND AND OBJECTIVES: Systolic BP and large elastic artery stiffness both increase with age and are reduced by dietary sodium restriction. Production of the natriuretic hormone marinobufagenin, an endogenous alpha1 Na+,K+-ATPase inhibitor, is increased in salt-sensitive hypertension and contributes to the rise in systolic BP during sodium loading. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The hypothesis was that dietary sodium restriction performed in middle-aged/older adults (eight men and three women; 60 +/- 2 years) with moderately elevated systolic BP (139 +/- 2/83 +/- 2 mmHg) would reduce urinary marinobufagenin excretion as well as systolic BP and aortic pulse-wave velocity (randomized, placebo-controlled, and crossover design). This study also explored the associations among marinobufagenin excretion with systolic BP and aortic pulse-wave velocity across conditions of 5 weeks of a low-sodium (77 +/- 9 mmol/d) and 5 weeks of a normal-sodium (144 +/- 7 mmol/d) diet. RESULTS: Urinary marinobufagenin excretion (weekly measurements; 25.4 +/- 1.8 versus 30.7 +/- 2.1 pmol/kg per day), systolic BP (127 +/- 3 versus 138 +/- 5 mmHg), and aortic pulse wave velocity (700 +/- 40 versus 843 +/- 36 cm/s) were lower during the low- versus normal-sodium condition (all P<0.05). Across all weeks, marinobufagenin excretion was related with systolic BP (slope=0.61, P<0.001) and sodium excretion (slope=0.46, P<0.001). These associations persisted during the normal- but not the low-sodium condition (both P<0.005). Marinobufagenin excretion also was associated with aortic pulse-wave velocity (slope=0.70, P=0.02) and endothelial cell expression of NAD(P)H oxidase-p47phox (slope=0.64, P=0.006). CONCLUSIONS: These results show, for the first time in humans, that dietary sodium restriction reduces urinary marinobufagenin excretion and that urinary marinobufagenin excretion is positively associated with systolic BP, aortic stiffness (aortic pulse-wave velocity), and endothelial cell expression of the oxidant enzyme NAD(P)H oxidase. Importantly, marinobufagenin excretion is positively related to systolic BP over ranges of sodium intake typical of an American diet, extending previous observations in rodents and humans fed experimentally high-sodium diets. PMID- 23929931 TI - Clinical factors and the decision to transfuse chronic dialysis patients. AB - BACKGROUND AND OBJECTIVES: Red blood cell transfusion was previously the principle therapy for anemia in CKD but became less prevalent after the introduction of erythropoiesis-stimulating agents. This study used adaptive choice-based conjoint analysis to identify preferences and predictors of transfusion decision-making in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A computerized adaptive choice-based conjoint survey was administered between June and August of 2012 to nephrologists, internists, and hospitalists listed in the American Medical Association Masterfile. The survey quantified the relative importance of 10 patient attributes, including hemoglobin levels, age, occult blood in stool, severity of illness, eligibility for transplant, iron indices, erythropoiesis-stimulating agents, cardiovascular disease, and functional status. Triggers of transfusions in common dialysis scenarios were studied, and based on adaptive choice-based conjoint-derived preferences, relative importance by performing multivariable regression to identify predictors of transfusion preferences was assessed. RESULTS: A total of 350 providers completed the survey (n=305 nephrologists; mean age=46 years; 21% women). Of 10 attributes assessed, absolute hemoglobin level was the most important driver of transfusions, accounting for 29% of decision-making, followed by functional status (16%) and cardiovascular comorbidities (12%); 92% of providers transfused when hemoglobin was 7.5 g/dl, independent of other factors. In multivariable regression, Veterans Administration providers were more likely to transfuse at 8.0 g/dl (odds ratio, 5.9; 95% confidence interval, 1.9 to 18.4). Although transplant eligibility explained only 5% of decision-making, nephrologists were five times more likely to value it as important compared with non-nephrologists (odds ratio, 5.2; 95% confidence interval, 2.4 to 11.1). CONCLUSIONS: Adaptive choice-based conjoint analysis was useful in predicting influences on transfusion decisions. Hemoglobin level, functional status, and cardiovascular comorbidities most strongly influenced transfusion decision making, but preference variations were observed among subgroups. PMID- 23929932 TI - Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria. AB - BACKGROUND AND OBJECTIVES: Soluble Klotho is an anti-aging phosphaturic protein associated with vascular-renal protection. In vitro and in vivo studies have demonstrated that renin-angiotensin system (RAS) blockade increases soluble Klotho levels. The effect of RAS blockers on soluble Klotho in patients with diabetic kidney disease (DKD) is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma-soluble Klotho was measured in a secondary analysis of a randomized controlled clinical trial performed at a single university hospital center (ClinicalTrials.gov number NCT001715, from March 2003 to September 2006). Seventy-six patients with type 2 diabetes and DKD (all with albuminuria and serum creatinine <1.7 mg/dl) were studied at baseline and at 24 weeks (study end) after randomization to valsartan/hydrochlorothiazide (n=37) or amlodipine (n=39) treatment. Aortic-pulse wave velocity by applanation tonometry and albuminuria (from three timed urine collections) were also measured at baseline and 24 weeks. RESULTS: Valsartan/hydrochlorothiazide treatment significantly increased mean (+/ SD) soluble Klotho (from 432.7 +/- 179 to 506.4 +/- 226.8 pg/ml; P=0.01) and reduced serum phosphate (from 3.25 +/- 1.18 to 2.60 +/- 0.96 mg/dl; P=0.04) compared with amlodipine (from 430.1 +/- 145.8 to 411.9 +/- 157.6 pg/ml and from 2.94 +/- 0.56 to 2.69 +/- 1.52 mg/dl, respectively). There was a significant difference between treatment groups in soluble Klotho (mean 91.9 pg/ml; 95% confidence interval, 19.9 to 162) and serum phosphate levels (mean -0.68 mg/dl; 95% confidence interval, -0.15 to -1.33) with valsartan/hydrochlorothiazide treatment (P=0.03 and P=0.04, respectively). Attained BP was similar in the two groups and levels of soluble Klotho were not associated with aortic-pulse wave velocity and albuminuria, variables that fell significantly only with valsartan/hydrochlorothiazide. CONCLUSIONS: Treatment with a RAS blocker, valsartan, is associated with an increase in soluble Klotho, which may contribute to the BP-independent cardiorenal benefits of these drugs in DKD. PMID- 23929933 TI - Fibroblast growth factor 23 and cardiovascular mortality after kidney transplantation. AB - BACKGROUND AND OBJECTIVES: Circulating fibroblast growth factor 23 (FGF23) is associated with adverse cardiovascular outcomes in CKD. Whether FGF23 predicts cardiovascular mortality after kidney transplantation, independent of measures of mineral metabolism and cardiovascular risk factors, is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The association between plasma C-terminal FGF23 and cardiovascular mortality was analyzed in a single-center prospective cohort of 593 stable kidney transplant recipients (mean age +/- SD, 52 +/- 12 years; 54% male; estimated GFR, 47 +/- 16 ml/min per 1.73 m(2)), at a median of 6.1 (interquartile range, 2.7-11.7) years after transplantation. Multivariate Cox regression models were built, adjusting for measures of renal function and mineral metabolism; Framingham risk factors; the left ventricular wall strain markers midregional fragment of pro-A-type natriuretic peptide (MR-proANP) and N terminal-pro brain natriuretic peptide (NT-proBNP); and copeptin, the stable C terminal portion of the precursor of vasopressin. RESULTS: In multivariate linear regression analysis, MR-proANP (beta=0.20, P<0.001), NT-proBNP (beta=0.18, P<0.001), and copeptin (beta=0.26, P<0.001) were independently associated with FGF23. During follow-up for 7.0 (interquartile range, 6.2-7.5) years, 128 patients (22%) died, of whom 66 (11%) died due to cardiovascular disease; 54 (9%) had graft failure. FGF23 was associated with an higher risk of cardiovascular mortality in a fully adjusted multivariate Cox regression model (hazard ratio [HR], 1.88 [95% confidence interval (CI), 1.11 to 3.19]; P=0.02). FGF23 was also independently associated with all-cause mortality (full model HR, 1.86 [95% CI, 1.27 to 2.73]; P=0.001). Net reclassification improved for both cardiovascular mortality (HR, 0.07 [95% CI, 0.01 to 0.14]; P<0.05) and all-cause mortality (HR, 0.11 [95% CI, 0.05 to 0.18]; P<0.001). CONCLUSIONS: Plasma FGF23 is independently associated with cardiovascular and all-cause mortality after kidney transplantation. The association remained significant after adjustment for measures of mineral metabolism and cardiovascular risk factors. PMID- 23929934 TI - Decreased cord-blood phospholipids in young age-at-onset type 1 diabetes. AB - Children developing type 1 diabetes may have risk markers already in their umbilical cord blood. It is hypothesized that the risk for type 1 diabetes at an early age may be increased by a pathogenic pregnancy and be reflected in altered cord-blood composition. This study used metabolomics to test if the cord-blood lipidome was affected in children diagnosed with type 1 diabetes before 8 years of age. The present case-control study of 76 index children diagnosed with type 1 diabetes before 8 years of age and 76 healthy control subjects matched for HLA risk, sex, and date of birth, as well as the mother's age and gestational age, revealed that cord-blood phosphatidylcholines and phosphatidylethanolamines were significantly decreased in children diagnosed with type 1 diabetes before 4 years of age. Reduced levels of triglycerides correlated to gestational age in index and control children and to age at diagnosis only in the index children. Finally, gestational infection during the first trimester was associated with lower cord blood total lysophosphatidylcholines in index and control children. In conclusion, metabolomics of umbilical cord blood may identify children at increased risk for type 1 diabetes. Low phospholipid levels at birth may represent key mediators of the immune system and contribute to early induction of islet autoimmunity. PMID- 23929935 TI - Age-dependent labeling and imaging of insulin secretory granules. AB - Insulin is stored within the secretory granules of pancreatic beta-cells, and impairment of its release is the hallmark of type 2 diabetes. Preferential exocytosis of newly synthesized insulin suggests that granule aging is a key factor influencing insulin secretion. Here, we illustrate a technology that enables the study of granule aging in insulinoma cells and beta-cells of knock-in mice through the conditional and unequivocal labeling of insulin fused to the SNAP tag. This approach, which overcomes the limits encountered with previous strategies based on radiolabeling or fluorescence timer proteins, allowed us to formally demonstrate the preferential release of newly synthesized insulin and reveal that the motility of cortical granules significantly changes over time. Exploitation of this approach may enable the identification of molecular signatures associated with granule aging and unravel possible alterations of granule turnover in diabetic beta-cells. Furthermore, the method is of general interest for the study of membrane traffic and aging. PMID- 23929936 TI - Pitavastatin as an in vivo probe for studying hepatic organic anion transporting polypeptide-mediated drug-drug interactions in cynomolgus monkeys. AB - Drug-drug interactions (DDIs) caused by the inhibition of hepatic uptake transporters such as organic anion transporting polypeptide (OATP) can affect therapeutic efficacy and cause adverse reactions. We investigated the potential utility of pitavastatin as an in vivo probe substrate for preclinically studying OATP-mediated DDIs using cynomolgus monkeys. Cyclosporine A (CsA) and rifampicin (RIF), typical OATP inhibitors, inhibited active uptake of pitavastatin into monkey hepatocytes with half-maximal inhibitory concentration values comparable with those in human hepatocytes. CsA and RIF increased the area under the plasma concentration-time curve (AUC) of intravenously administered pitavastatin in cynomolgus monkeys by 3.2- and 3.6-fold, respectively. In addition, there was no apparent prolongation of the elimination half-life of pitavastatin due to the decrease in both hepatic clearance and volume of distribution. These findings suggest that DDIs were caused by the inhibition of hepatic uptake of pitavastatin. CsA and RIF increased the AUC of orally administered pitavastatin by 10.6- and 14.8-fold, respectively, which was additionally caused by the effect of the CsA and RIF in the gastrointestinal tract. Hepatic contribution to the overall DDI for oral pitavastatin with CsA was calculated from the changes in hepatic availability and clearance, and it was shown that the magnitude of hepatic DDI was comparable between the present study and the clinical study. In conclusion, pharmacokinetic studies using pitavastatin as a probe in combination with drug candidates in cynomolgus monkeys are useful to support the assessment of potential clinical DDIs involving hepatic uptake transporters. PMID- 23929937 TI - Why so few case reports--why (systematic) reviews instead? PMID- 23929938 TI - Strong anion-exchange fast performance liquid chromatography as a versatile tool for preparation and purification of RNA produced by in vitro transcription. AB - Here we demonstrate the use of strong anion-exchange fast performance liquid chromatography (FPLC) as a simple, fast, and robust method for RNA production by in vitro transcription. With this technique, we have purified different transcription templates from unreacted reagents in large quantities. The same buffer system could be used to readily remove nuclease contamination from the overexpressed pyrophosphatase, the important reagent for in vitro transcription. In addition, the method can be used to monitor in vitro transcription reactions to enable facile optimization of reaction conditions, and we have compared the separation performance between strong and weak anion-exchange FPLC for various transcribed RNAs, including the Diels-Alder ribozyme, the hammerhead ribozyme tRNA, and 4.5S RNA. The functionality of the purified tRNA(Cys) has been confirmed by the aminoacylation assay. Only the purification by strong anion exchange FPLC has led to the enrichment of the functional tRNA from run-off transcripts as revealed by both enzymatic and electrophoretic analysis. PMID- 23929940 TI - Cardiac fibrosis in mice expressing an inducible myocardial-specific Cre driver. AB - Tamoxifen-inducible Cre-mediated manipulation of animal genomes has achieved wide acceptance over the last decade, with numerous important studies heavily relying on this technique. Recently, a number of groups have reported transient complications of using this protocol in the heart. In the present study we observed a previously unreported focal fibrosis and depressed left-ventricular function in tamoxifen-treated alphaMHC-MerCreMer-positive animals in a Tbeta4shRNAflox * alphaMHC-MerCreMer cross at 6-7 weeks following standard tamoxifen treatment, regardless of the presence of the floxed transgene. The phenotype was reproduced by treating mice from the original alphaMHC-MerCreMer strain with tamoxifen. In the acute phase after tamoxifen treatment, cell infiltration into the myocardium was accompanied by increased expression of pro inflammatory cytokines (IL-1beta, IL-6, TNFalpha, IFNgamma, Ccl2) and markers of hypertrophy (ANF, BNP, Col3a1). These observations highlight the requirement for including tamoxifen-treated MerCreMer littermate controls to avert misinterpretation of conditional mutant phenotypes. A survey of the field as well as the protocols presented here suggests that controlling the parameters of tamoxifen delivery is important in avoiding the chronic MerCreMer-mediated cardiac phenotype reported here. PMID- 23929941 TI - Moderate and high amounts of tamoxifen in alphaMHC-MerCreMer mice induce a DNA damage response, leading to heart failure and death. AB - Numerous mouse models have utilized Cre-loxP technology to modify gene expression. Adverse effects of Cre recombinase activity have been reported, including in the heart. However, the mechanisms associated with cardiac Cre toxicity are largely unknown. Here, we show that expression of Cre in cardiomyocytes induces a DNA damage response, resulting in cardiomyocyte apoptosis, cardiac fibrosis and cardiac dysfunction. In an effort to increase the recombination efficiency of a widely used tamoxifen-sensitive Cre transgene under control of the alpha-myosin-heavy-chain promoter (alphaMHC-MerCreMer), we observed myocardial dysfunction and decreased survival, which were dependent on the dose of tamoxifen injected. After excluding a Cre-independent contribution by tamoxifen, we found that Cre induced myocardial fibrosis, activation of pro fibrotic genes and cardiomyocyte apoptosis. Examination of the molecular mechanisms showed activation of DNA damage response signaling and p53 stabilization in the absence of loxP sites, suggesting that Cre induced illegitimate DNA breaks. Cardiomyocyte apoptosis was also induced by expressing Cre using adenoviral transduction, indicating that the effect was not dependent on genomic integration of the transgene. Cre-mediated homologous recombination at loxP sites was dose-dependent and had a ceiling effect at ~80% of cardiomyocytes showing recombination. By titrating the amount of tamoxifen to maximize recombination while minimizing animal lethality, we determined that 30 MUg tamoxifen/g body weight/day injected on three consecutive days is the optimal condition for the alphaMHC-MerCreMer system to induce recombination in the Rosa26 lacZ strain. Our results further highlight the importance of experimental design, including the use of appropriate genetic controls for Cre expression. PMID- 23929942 TI - Epigenetic basis of regeneration: analysis of genomic DNA methylation profiles in the MRL/MpJ mouse. AB - Epigenetic regulation plays essential role in cell differentiation and dedifferentiation, which are the intrinsic processes involved in regeneration. To investigate the epigenetic basis of regeneration capacity, we choose DNA methylation as one of the most important epigenetic mechanisms and the MRL/MpJ mouse as a model of mammalian regeneration known to exhibit enhanced regeneration response in different organs. We report the comparative analysis of genomic DNA methylation profiles of the MRL/MpJ and the control C57BL/6J mouse. Methylated DNA immunoprecipitation followed by microarray analysis using the Nimblegen '3 * 720 K CpG Island Plus RefSeq Promoter' platform was applied in order to carry out genome-wide DNA methylation profiling covering 20 404 promoter regions. We identified hundreds of hypo- and hypermethylated genes and CpG islands in the heart, liver, and spleen, and 37 of them in the three tissues. Decreased inter tissue diversification and the shift of DNA methylation balance upstream the genes distinguish the genomic methylation patterns of the MRL/MpJ mouse from the C57BL/6J. Homeobox genes and a number of other genes involved in embryonic morphogenesis are significantly overrepresented among the genes hypomethylated in the MRL/MpJ mouse. These findings indicate that epigenetic patterning might be a likely molecular basis of regeneration capability in the MRL/MpJ mouse. PMID- 23929939 TI - Modeling human neurodevelopmental disorders in the Xenopus tadpole: from mechanisms to therapeutic targets. AB - The Xenopus tadpole model offers many advantages for studying the molecular, cellular and network mechanisms underlying neurodevelopmental disorders. Essentially every stage of normal neural circuit development, from axon outgrowth and guidance to activity-dependent homeostasis and refinement, has been studied in the frog tadpole, making it an ideal model to determine what happens when any of these stages are compromised. Recently, the tadpole model has been used to explore the mechanisms of epilepsy and autism, and there is mounting evidence to suggest that diseases of the nervous system involve deficits in the most fundamental aspects of nervous system function and development. In this Review, we provide an update on how tadpole models are being used to study three distinct types of neurodevelopmental disorders: diseases caused by exposure to environmental toxicants, epilepsy and seizure disorders, and autism. PMID- 23929943 TI - The neural basis of unwanted thoughts during resting state. AB - Human beings are constantly engaged in thought. Sometimes thoughts occur repetitively and can become distressing. Up to now the neural bases of these intrusive or unwanted thoughts is largely unexplored. To study the neural correlates of unwanted thoughts, we acquired resting-state fMRI data of 41 female healthy subjects and assessed the self-reported amount of unwanted thoughts during measurement. We analyzed local connectivity by means of regional homogeneity (ReHo) and functional connectivity of a seed region. More unwanted thoughts (state) were associated with lower ReHo in right dorsolateral prefrontal cortex (DLPFC) and higher ReHo in left striatum (putamen). Additional seed-based analysis revealed higher functional connectivity of the left striatum with left inferior frontal gyrus (IFG) in participants reporting more unwanted thoughts. The state-dependent higher connectivty in left striatum was positively correlated with rumination assessed with a dedicated questionnaire focussing on trait aspects. Unwanted thoughts are associated with activity in the fronto-striatal brain circuitry. The reduction of local connectivity in DLPFC could reflect deficiencies in thought suppression processes, whereas the hightened activity in left striatum could imply an imbalance of gating mechanisms housed in basal ganglia. Its functional connectivity to left IFG is discussed as the result of thought-related speech processes. PMID- 23929944 TI - Empathic arousal and social understanding in individuals with autism: evidence from fMRI and ERP measurements. AB - Lack of empathy is a hallmark of social impairments in individuals with autism spectrum disorder (ASD). However, the concept empathy encompasses several socio emotional and behavioral components underpinned by interacting brain circuits. This study examined empathic arousal and social understanding in individuals with ASD and matched controls by combining pressure pain thresholds (PPT) with functional magnetic resonance imaging (study 1) and electroencephalography/event related potentials and eye-tracking responses (study 2) to empathy-eliciting stimuli depicting physical bodily injuries. Results indicate that participants with ASD had lower PPT than controls. When viewing body parts being accidentally injured, increased hemodynamic responses in the somatosensory cortex (SI/SII) but decreased responses in the anterior mid-cingulate and anterior insula as well as heightened N2 but preserved late-positive potentials (LPP) were detected in ASD participants. When viewing a person intentionally hurting another, decreased hemodynamic responses in the medial prefrontal cortex and reduced LPP were observed in the ASD group. PPT was a mediator for the SI/SII response in predicting subjective unpleasantness ratings to others' pain. Both ASD and control groups had comparable mu suppression, indicative of typical sensorimotor resonance. The findings demonstrate that, in addition to reduced pain thresholds, individuals with ASD exhibit heightened empathic arousal but impaired social understanding when perceiving others' distress. PMID- 23929946 TI - Molecular mechanism for plant steroid receptor activation by somatic embryogenesis co-receptor kinases. AB - Brassinosteroids, which control plant growth and development, are sensed by the leucine-rich repeat (LRR) domain of the membrane receptor kinase BRASSINOSTEROID INSENSITIVE 1 (BRI1), but it is unknown how steroid binding at the cell surface activates the cytoplasmic kinase domain of the receptor. A family of somatic embryogenesis receptor kinases (SERKs) has been genetically implicated in mediating early brassinosteroid signaling events. We found a direct and steroid dependent interaction between the BRI1 and SERK1 LRR domains by analysis of their complex crystal structure at 3.3 angstrom resolution. We show that the SERK1 LRR domain is involved in steroid sensing and, through receptor-co-receptor heteromerization, in the activation of the BRI1 signaling pathway. Our work reveals how known missense mutations in BRI1 and in SERKs modulate brassinosteroid signaling and the targeting mechanism of BRI1 receptor antagonists. PMID- 23929947 TI - Mapping tectonic deformation in the crust and upper mantle beneath Europe and the North Atlantic Ocean. AB - We constructed a three-dimensional azimuthally anisotropic model of Europe and the North Atlantic Ocean based on adjoint seismic tomography. Several features are well correlated with historical tectonic events in this region, such as extension along the North Atlantic Ridge, trench retreat in the Mediterranean, and counterclockwise rotation of the Anatolian Plate. Beneath northeastern Europe, the direction of the fast anisotropic axis follows trends of ancient rift systems older than 350 million years, suggesting "frozen-in" anisotropy related to the formation of the craton. Local anisotropic strength profiles identify the brittle-ductile transitions in lithospheric strength. In continental regions, these profiles also identify the lower crust, characterized by ductile flow. The observed anisotropic fabric is generally consistent with the current surface strain rate measured by geodetic surveys. PMID- 23929945 TI - Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. AB - Retroviruses, including HIV, can activate innate immune responses, but the host sensors for retroviruses are largely unknown. Here we show that HIV infection activates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) to produce cGAMP, which binds to and activates the adaptor protein STING to induce type I interferons and other cytokines. Inhibitors of HIV reverse transcriptase, but not integrase, abrogated interferon-beta induction by the virus, suggesting that the reverse-transcribed HIV DNA triggers the innate immune response. Knockout or knockdown of cGAS in mouse or human cell lines blocked cytokine induction by HIV, murine leukemia virus, and simian immunodeficiency virus. These results indicate that cGAS is an innate immune sensor of HIV and other retroviruses. PMID- 23929948 TI - Enhanced seasonal exchange of CO2 by northern ecosystems since 1960. AB - Seasonal variations of atmospheric carbon dioxide (CO2) in the Northern Hemisphere have increased since the 1950s, but sparse observations have prevented a clear assessment of the patterns of long-term change and the underlying mechanisms. We compare recent aircraft-based observations of CO2 above the North Pacific and Arctic Oceans to earlier data from 1958 to 1961 and find that the seasonal amplitude at altitudes of 3 to 6 km increased by 50% for 45 degrees to 90 degrees N but by less than 25% for 10 degrees to 45 degrees N. An increase of 30 to 60% in the seasonal exchange of CO2 by northern extratropical land ecosystems, focused on boreal forests, is implicated, substantially more than simulated by current land ecosystem models. The observations appear to signal large ecological changes in northern forests and a major shift in the global carbon cycle. PMID- 23929951 TI - Preparing for disasters. PMID- 23929950 TI - SGK196 is a glycosylation-specific O-mannose kinase required for dystroglycan function. AB - Phosphorylated O-mannosyl trisaccharide [N-acetylgalactosamine-beta3-N acetylglucosamine-beta4-(phosphate-6-)mannose] is required for dystroglycan to bind laminin-G domain-containing extracellular proteins with high affinity in muscle and brain. However, the enzymes that produce this structure have not been fully elucidated. We found that glycosyltransferase-like domain-containing 2 (GTDC2) is a protein O-linked mannose beta 1,4-N-acetylglucosaminyltransferase whose product could be extended by beta 1,3-N-acetylgalactosaminyltransferase2 (B3GALNT2) to form the O-mannosyl trisaccharide. Furthermore, we identified SGK196 as an atypical kinase that phosphorylated the 6-position of O-mannose, specifically after the mannose had been modified by both GTDC2 and B3GALNT2. These findings suggest how mutations in GTDC2, B3GALNT2, and SGK196 disrupt dystroglycan receptor function and lead to congenital muscular dystrophy. PMID- 23929949 TI - Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. AB - Consistent, high-level, vaccine-induced protection against human malaria has only been achieved by inoculation of Plasmodium falciparum (Pf) sporozoites (SPZ) by mosquito bites. We report that the PfSPZ Vaccine--composed of attenuated, aseptic, purified, cryopreserved PfSPZ--was safe and well tolerated when administered four to six times intravenously (IV) to 40 adults. Zero of six subjects receiving five doses and three of nine subjects receiving four doses of 1.35 * 10(5) PfSPZ Vaccine and five of six nonvaccinated controls developed malaria after controlled human malaria infection (P = 0.015 in the five-dose group and P = 0.028 for overall, both versus controls). PfSPZ-specific antibody and T cell responses were dose-dependent. These data indicate that there is a dose-dependent immunological threshold for establishing high-level protection against malaria that can be achieved with IV administration of a vaccine that is safe and meets regulatory standards. PMID- 23929956 TI - Scientific community. Embezzlement casts harsh light on China's grant system. PMID- 23929958 TI - U.S. science policy. France Cordova brings management expertise to NSF. PMID- 23929957 TI - Paleoclimatology. How to make a great ice age, again and again and again. PMID- 23929959 TI - Food science. Lab burger adds sizzle to bid for research funds. PMID- 23929960 TI - Scientific community. Grim day for Turkish science as six academics get long prison terms. PMID- 23929961 TI - Environmental policy. House subpoena revives battle over air pollution studies. PMID- 23929962 TI - Infectious diseases. Unconventional vaccine shows promise against malaria. PMID- 23929963 TI - The Web's faceless judges. PMID- 23929964 TI - Wildfire science. Computing a better fire forecast. PMID- 23929965 TI - Gain-of-function experiments on H7N9. PMID- 23929967 TI - Technical comment on "The placental mammal ancestor and the post-K-Pg radiation of placentals". AB - O'Leary et al. (Research Article, 8 February 2013, p. 662) examined mammalian relationships and divergence times and concluded that a single placental ancestor crossed the Cretaceous-Paleogene (K-Pg) boundary. This conclusion relies on phylogenetic analyses that fail to discriminate between homology and homoplasy and further implies virus-like rates of nucleotide substitution in early Paleocene placentals. PMID- 23929968 TI - Response to comment on "The placental mammal ancestor and the post-K-Pg radiation of placentals". AB - Tree-building with diverse data maximizes explanatory power. Application of molecular clock models to ancient speciation events risks a bias against detection of fast radiations subsequent to the Cretaceous-Paleogene (K-Pg) event. Contrary to Springer et al., post-K-Pg placental diversification does not require "virus-like" substitution rates. Even constraining clade ages to their model, the explosive model best explains placental evolution. PMID- 23929969 TI - Science priorities. Who will pay for public access to research data? PMID- 23929970 TI - Geophysics. Buildings as weapons of mass destruction. PMID- 23929971 TI - Applied physics. Graphene for terahertz applications. PMID- 23929972 TI - Transcription. Flashing a light on the spatial organization of transcription. PMID- 23929973 TI - Physiology. Lymphatics are in my veins. PMID- 23929974 TI - Chemistry. Copper's contribution to amination catalysis. PMID- 23929975 TI - Genetics. The maturing brain methylome. PMID- 23929976 TI - A quantum many-body spin system in an optical lattice clock. AB - Strongly interacting quantum many-body systems arise in many areas of physics, but their complexity generally precludes exact solutions to their dynamics. We explored a strongly interacting two-level system formed by the clock states in (87)Sr as a laboratory for the study of quantum many-body effects. Our collective spin measurements reveal signatures of the development of many-body correlations during the dynamical evolution. We derived a many-body Hamiltonian that describes the experimental observation of atomic spin coherence decay, density-dependent frequency shifts, severely distorted lineshapes, and correlated spin noise. These investigations open the door to further explorations of quantum many-body effects and entanglement through use of highly coherent and precisely controlled optical lattice clocks. PMID- 23929977 TI - Writing and deleting single magnetic skyrmions. AB - Topologically nontrivial spin textures have recently been investigated for spintronic applications. Here, we report on an ultrathin magnetic film in which individual skyrmions can be written and deleted in a controlled fashion with local spin-polarized currents from a scanning tunneling microscope. An external magnetic field is used to tune the energy landscape, and the temperature is adjusted to prevent thermally activated switching between topologically distinct states. Switching rate and direction can then be controlled by the parameters used for current injection. The creation and annihilation of individual magnetic skyrmions demonstrates the potential for topological charge in future information storage concepts. PMID- 23929978 TI - A semi-floating gate transistor for low-voltage ultrafast memory and sensing operation. AB - As the semiconductor devices of integrated circuits approach the physical limitations of scaling, alternative transistor and memory designs are needed to achieve improvements in speed, density, and power consumption. We report on a transistor that uses an embedded tunneling field-effect transistor for charging and discharging the semi-floating gate. This transistor operates at low voltages (<=2.0 volts), with a large threshold voltage window of 3.1 volts, and can achieve ultra-high-speed writing operations (on time scales of ~1 nanosecond). A linear dependence of drain current on light intensity was observed when the transistor was exposed to light, so possible applications include image sensing with high density and performance. PMID- 23929979 TI - Active atmosphere-ecosystem exchange of the vast majority of detected volatile organic compounds. AB - Numerous volatile organic compounds (VOCs) exist in Earth's atmosphere, most of which originate from biogenic emissions. Despite VOCs' critical role in tropospheric chemistry, studies for evaluating their atmosphere-ecosystem exchange (emission and deposition) have been limited to a few dominant compounds owing to a lack of appropriate measurement techniques. Using a high-mass resolution proton transfer reaction-time of flight-mass spectrometer and an absolute value eddy-covariance method, we directly measured 186 organic ions with net deposition, and 494 that have bidirectional flux. This observation of active atmosphere-ecosystem exchange of the vast majority of detected VOCs poses a challenge to current emission, air quality, and global climate models, which do not account for this extremely large range of compounds. This observation also provides new insight for understanding the atmospheric VOC budget. PMID- 23929980 TI - Social influence bias: a randomized experiment. AB - Our society is increasingly relying on the digitized, aggregated opinions of others to make decisions. We therefore designed and analyzed a large-scale randomized experiment on a social news aggregation Web site to investigate whether knowledge of such aggregates distorts decision-making. Prior ratings created significant bias in individual rating behavior, and positive and negative social influences created asymmetric herding effects. Whereas negative social influence inspired users to correct manipulated ratings, positive social influence increased the likelihood of positive ratings by 32% and created accumulating positive herding that increased final ratings by 25% on average. This positive herding was topic-dependent and affected by whether individuals were viewing the opinions of friends or enemies. A mixture of changing opinion and greater turnout under both manipulations together with a natural tendency to up-vote on the site combined to create the herding effects. Such findings will help interpret collective judgment accurately and avoid social influence bias in collective intelligence in the future. PMID- 23929981 TI - Spatial dynamics of chromosome translocations in living cells. AB - Chromosome translocations are a hallmark of cancer cells. We have developed an experimental system to visualize the formation of translocations in living cells and apply it to characterize the spatial and dynamic properties of translocation formation. We demonstrate that translocations form within hours of the occurrence of double-strand breaks (DSBs) and that their formation is cell cycle independent. Translocations form preferentially between prepositioned genome elements, and perturbation of key factors of the DNA repair machinery uncouples DSB pairing from translocation formation. These observations generate a spatiotemporal framework for the formation of translocations in living cells. PMID- 23929982 TI - Sequence-controlled polymers. AB - Sequence-controlled polymers are macromolecules in which monomer units of different chemical nature are arranged in an ordered fashion. The most prominent examples are biological and have been studied and used primarily by molecular biologists and biochemists. However, recent progress in protein- and DNA-based nanotechnologies has shown the relevance of sequence-controlled polymers to nonbiological applications, including data storage, nanoelectronics, and catalysis. In addition, synthetic polymer chemistry has provided interesting routes for preparing nonnatural sequence-controlled polymers. Although these synthetic macromolecules do not yet compare in functional scope with their natural counterparts, they open up opportunities for controlling the structure, self-assembly, and macroscopic properties of polymer materials. PMID- 23929983 TI - Introductory Chemistry: A Molar Relaxivity Experiment in the High School Classroom. AB - Dotarem and Magnevist, two clinically available magnetic resonance imaging (MRI) contrast agents, were assessed in a high school science classroom with respect to which is the better contrast agent. Magnevist, the more efficacious contrast agent, has negative side effects because its gadolinium center can escape from its ligand. However, Dotarem, though a less efficacious contrast agent, is a safer drug choice. After the experiment, students are confronted with the FDA warning on Magnevist, which enabled a discussion of drug efficacy versus safety. We describe a laboratory experiment in which NMR spin lattice relaxation rate measurements are used to quantify the relaxivities of the active ingredients of Dotarem and Magnevist. The spin lattice relaxation rate gives the average amount of time it takes the excited nucleus to relax back to the original state. Students learn by constructing molar relaxivity curves based on inversion recovery data sets that Magnevist is more relaxive than Dotarem. This experiment is suitable for any analytical chemistry laboratory with access to NMR. PMID- 23929985 TI - Sustainable harvesting of medicinal plants: Some thoughts in search for solutions. PMID- 23929984 TI - Towards the chemoenzymatic synthesis of heparan sulfate oligosaccharides: Oxidative cleavage of p-nitrophenyl group with ceric ammonium salts. AB - We have developed an efficient chemoenzymatic synthesis of heparan sulfate oligosaccharides employing the para-nitrophenyl (p-NP) beta-glucuronide as an acceptor compatible with enzymatic elongation and one that significantly simplifies oligosaccharide purification on C-18 resin. Employing ceric ammonium nitrate as oxidative reagent to remove the p-NP group unexpectedly also removed the glucuronic acid residue at the reducing-end, affording a smaller oligosaccharide. The application of ceric ammonium sulfate allowed the removal of the p-NP without concomitant loss of the adjacent glucuronic acid offering a route to longer heparin sulfate oligosaccharide products. PMID- 23929986 TI - Botanical identity of plant sources of Dasamula drugs through an analysis of published literature. AB - BACKGROUND: Dasamula (DM) is a top-traded group of medicinal plants used by the Ayurvedic industry. Through literature survey and analysis, this article has enlisted the botanical sources of DM, as correlated by several scholars. Such a list is not available from any single, earlier publication. It brings to light the confusion that exists in terms of botanical sources correlated to Ayurvedic entities. There is quite a bit of difference in the botanical correlation, parts, and substitutes reported in the different scholarly works, particularly for Prsniparni, and Agnimantha. For e.g., is Uraria picta the original intended Prsniparni, as the Ayurvedic Formulary of India (AFI) stipulates or is it U. lagopoidiodes or Desmodium gangeticum as other scholars report? While AFI provides two botanical correlations to Agnimantha in its two editions, namely Premna integrifolia and Clerodendrum phlomidis, other scholars correlate it to other Premna and Clerodendrum species. Why has AFI provided stem bark and whole plant as substitutes for roots of DM? Are substitutes recommended by AFI only for ecological or practical convenience or is there an Ayurvedic or pharmacological explanation for the same? AIM: There are many species used in the name of Dasamula,, in this article all the species are listed out to find the differences in the usage of the drugs. MATERIALS AND METHODS: Ayurveda texts and lexicons along with the texts which have done correlation work were considered to arrive at a list of various species used as Dasmula. RESULTS AND CONCLUSION: Since neither the methodology nor the logic behind the correlation have been discussed in these scholarly works, including the AFI, the same is not available for analysis or scrutiny. Such a list as provided in this article can form an essential base for a much needed systematic approach at etymological analysis, botanical correlation, and further scientific work to establish legitimacy of substitutes prescribed. PMID- 23929987 TI - Study of Brahmi Ghrta and piracetam in amnesia. AB - OBJECTIVE: To compare the effect of Brahmi Ghrta with piracetam (a reference standard chemical) in amnesia. MATERIALS AND METHODS: Brahmi Ghrta contained Brahmi (Bacopa monneri), Vaca (Acorus calamus), Kustha (Sassurea lappa), Sankhapuspi (Convolvulos pluricalis), and Purana Ghrta, prepared as per snehapaka process. Antiamnesic activity of Brahmi Ghrta (400 and 800 mg/kg, p.o.) was evaluated in scopolamine (1 mg/kg, s.c.) induced amnesia in Charles Foster rats using elevated plus maze, passive avoidance, and active avoidance tests. Piracetam (500 mg/kg, p.o.) was used as standard drug. This effect was compared with standard chemical used in experimental study. RESULTS: Brahmi Ghrta - (in both doses) and piracetam-treated rats significantly reversed the effect of scopolamine in modified elevated plus maze, passive avoidance, and active avoidance tests. But there were no significant differences observed in antiamnesic activity of Brahmi Ghrta and standard drug. CONCLUSION: Brahmi Ghrta and piracetam produced significant beneficial effect on scopolamine-induced amnesic effect, but no significant difference was observed in between them. PMID- 23929988 TI - Identity and pharmacognosy of Ruta graveolens Linn. AB - Ruta graveolens L., is a odoriferous herb belonging to the family Rutaceae. It is the source of Rue or Rue oil, called as Sadab or Satab in Hindi. It is distributed throughout the world and cultivated as a medicinal and ornamental herb. The ancient Greeks and Romans, held the plant in high esteem. It is used in Ayurveda, Homoeopathy and Unani. Phytochemical constituents and pharmacological properties were studied in depth. In 14 species of genus Ruta, R. graveolens and R. chalepensis are available in India and also cultivated in gardens. Taxonomical characters to identify the Indian plants are very clear with fringed and or non fringed petals. However, references to it are confused in the traditional literature. Due to sharing of regional language name, its identity is confused with Euphorbia dracunculoides. Morphological and anatomical characters were described. Pharmacognostic studies with microscopic characters were also published. Upon reviewing the anatomical characters and pharmacognostic characters one finds that it is highly confused and conflicting. The characters described are opposite of each other and authenticity of the market sample of R. graveolens cannot be guaranteed and able to be differentiated from R. chalepensis. Present work is to describe the pharmacognostic characters of R. graveolens to differentiate it from R. chalepensis. It is concluded that morphologically, R. graveolens can be identified with its non-fringed petals and blunted apices of fruit lobes. Whereas, in R. chalepensis petals are fringed or ciliated and apices of the fruit lobes are sharp and projected. Microscopically, in stem of R. graveolens pericyclic fibers have wide lumen. Whereas, in R. chalepensis, it is narrow. The published pharmacognosy reports do not pertain to authentic plant or some of the characteristic features like glandular trichomes are not observed in our samples. PMID- 23929989 TI - A comparative antibacterial evaluation of raw and processed Gunja (Abrus precatorius Linn.) seeds. AB - BACKGROUND: Seed of Gunja (Abrus precatorius Linn.), a known poisonous drug, is used extensively in various ayurvedic formulations with great therapeutic significance. Ayurveda recommends the administration of Gunja in diseases like Indralupta (alopecia), Sotha (edema), Krmi (helminthes), Kustha (skin diseases), Kandu (itching), Prameha (urinary disorders) etc., after being treated with specific Sodhana (purification) procedures. OBJECTIVE: To assess the antimicrobial action of of raw and Shodhita (Processed) Gunja seeds. METHODS: Gunja seeds after being processed with Godugdha (cow's milk), Nimbu swarasa (Lemon juice), Kanji (Sour gruel) and water, as the media, were evaluated for its antibacterial effect against clinically important bacterial strains using agar well diffusion method. RESULTS: Aqueous extracts of raw seeds of Gunja exert its antibacterial effect on both Gram positive, as well as Gram negative bacteria but none of the Sodhita Gunja seeds showed any bactericidal effect on any bacterial strains. Chloroform extracts of all the Sodhita Gunja seed extracts could inhibit bacterial growth but with variations. CONCLUSION: The study displayed that chloroform extracts of raw and sodhita samples for bacterial study were much sensitive than the aqueous extracts. PMID- 23929990 TI - Evaluation of in vitro antioxidant capacity and reducing potential of polyherbal drug- Bharangyadi. AB - BACKGROUND: Present work was designed to investigate antioxidant activity of polyherbal formulation in search for new, safe and inexpensive antioxidant. Clerodendrum serratum, Hedychium spicatum and Inula racemosa, were extensively used in ayurvedic medicine and were investigated together in the form of polyherbal compound (Bharangyadi) for their antioxidant potential. MATERIALS AND METHODS: Hydroalcoholic extract was prepared from the above samples and was tested for total reducing power and in vitro antioxidant activity by ABTS(+) assay, Superoxide anion scavenging activity assay and lipid per-oxidation assay. RESULT: Reducing power shows dose depended increase in concentration maximum absorption of 0.677 +/- 0.017 at 1000 MUg/ml compared with standard Quercetin 0.856+/-0.020. ABTS(+) assay shows maximum inhibition of 64.2 +/- 0.86 with EC50 675.31 +/- 4.24. Superoxide free radical shows maximum scavenging activity of 62.45 +/- 1.86 with EC50 774.70 +/- 5.45. Anti-lipidperoxidation free radicals scavenge maximum absorption of 67.25+/- 1.89 with EC50 is 700.08 +/- 6.81. Ascorbic acid was used as standard with IC50 value is 4.6 MUg/ml. The result suggests polyherbal formulation to be a good potential for antioxidant activity. Oxidative stress results from imbalance between free radical-generation and radical scavenging systems. This will lead to tissue damage and oxidative stress. CONCLUSION: In conclusion, we strongly suggest that Polyherbal compounds are source of potential antioxidant for radical scavenging. The highly positive correlation of antiradical scavenging activity and total polyphenolic content in Polyherbal compounds indicates that polyphenols are important components which could be used for the free radical scavenging activity. Further study is needed for isolation and characterization of the active moiety responsible for biological activity and to treat in various stress condition. PMID- 23929991 TI - Microscopic characterization of Scoparia dulcis Linn.(Scrophulariaceae). AB - This manuscript covers a detailed pharmacognostic evaluation of Scoparia dulcis Linn. whole plant (Scrophulariaceae), including morphology, microscopy, physicochemical, and phytochemical screening. Microscopy of different plant part was done by performing transverse sections and longitudinal sections, which were identified by the different staining reagents and dyes. Physicochemical constants were done for whole plant; it includes ash value, extractive value and moisture content. Phytochemical screening was done for aqueous and methanolic extract in maceration and soxhletion, results revealed the presence of alkaloids, glycosides, carbohydrates, phenolic compound, flavonoids, saponins, proteins, and amino acids. These study includes parameters to establish the authenticity of S. dulcis and can possibly help to differentiate the drug from its other species. PMID- 23929992 TI - Development of a chewable tablet from Dugdhamalakyadi Yoga: An Ayurvedic preparation. AB - BACKGROUND: Amalaki (Embelica officinalis Gaertn.) is one of the most celebrated herbs in the Indian system of traditional medicine. It is one of the best Rasayana-s (health promoting) drug. In Dugdhamalakyadi yoga, Amalaki (Embelica officinalis Gaertn.) powder is administered along with milk in case of svarabhanga (hoarseness of voice). Here an attempt is made to convert this formulation into chewable tablet without altering its property to improve its palatability, shelf life and fixation of proper therapeutic dose. METHODOLOGY: Chewable tablets were prepared by wet granulation method. Here, Amalaki powder was prepared initially and it was mixed with additives and preservatives. Granules were prepared from this mixture by adding binding agent, finally compressed in to tablets. RESULTS AND CONCLUSION: The physico-chemical analysis of Amalaki standard are: Foreign Matter-Nil, Acid insoluble Ash-0.51%w/w, Water soluble Ash-2.01% w/w, Alcoholic Extractives-44.48%, Aqueous Extractives 67.52%, pH-3.1, Moisture content-8.19%. Quality control test for chewable tablet was carried out and found satisfactory with general characteristics of tablet viz. hardness 1.8, disintegration time 15-20 min, friability 0.5%, weight variation +/ 3%. The TLC of Amalaki powder showed 3 spots with Rf value 0.14, 0.4, and 0.73 and the chewable tablets showed 2 spots with Rf value 0.31 and 0.89 under 254 nm. The adaptation of modern techniques or methods to convert the Ayurvedic formulations without altering its therapeutic property is necessary to made them suitable for the present trends of newer drug delivery dosage forms. PMID- 23929993 TI - Standardization of the finished product: Habbe Irqun Nisa - A Unani anti inflammatory formulation. AB - BACKGROUND: Habb (Pill) is one of the important dosage forms of Unani system of medicine. A number of effective formulations are manufactured in form of Habb because of its various advantages. Out of these, Habbe Irqun Nisa (HI) is a popular anti-inflammatory formulation used in the treatment of Warame Mafasil (arthritis) and Irqun Nisa (sciatica). Nowadays, with increased incidence of these diseases many non-steroidal anti-inflammatory drugs (NSAIDs) are being used in their treatment. Owing to the adverse effects of these drugs, the use of herbal medicines is seen as a better alternative. The basic requirement for the development of Unani system of Medicine is the standardization of single and compound drugs. HI is mentioned in National Formulary of Unani Medicne and selected for the present study. MATERIALS AND METHODS: HI was prepared manually with the powder of crude drugs, passed through sieve no. 100 and mixed with 1% w/w of gum acacia in mucilage form. It was then dried at 60 degrees C for 90 min and then tested for its standardization on different physicochemical parameters, e.g. organoleptic properties, pH values, moisture content, ash values, friability, hardness, weight variation, disintegration time, and thin layer chromatography (TLC). RESULTS AND CONCLUSION: The data evolved from this study will make it a validated product and will help in the quality control of other finished products in future research. PMID- 23929994 TI - Physico-chemical analysis of Mayurapuccha Bhasma prepared by two methods. AB - BACKGROUND: Mayurapuccha Bhasma (Calx of peacock feather) is an Ayurvedic animal product prepared from peacock feathers by employing two different methods as mentioned in Siddhayogasangraha and Bhaisajya samhita. It is mainly indicated in vomiting, hiccough, and respiratory disorder. MATERIALS AND METHODS: In the present study, Mayurapuccha Bhasma was prepared by two classical procedures, one by burning on ghee flame and the other by giving Gajaputa (burning the peacock feathers at about 1000 degrees C by using a thousand cow dung cakes). The products so obtained were subjected to various physico-chemical studies to find out ash value, pH value, specific gravity, moisture content, preliminary organic analysis, gravimetric analysis, chemical components, and to lay-down the pharmacopeial standards for standardization of Mayurapuccha Bhasma. RESULTS AND CONCLUSION: Both the Bhasmas exhibited marked difference in color, moisture content, and percentage of inorganic compounds. The Bhasma prepared by Gajaputa method contains essential and beneficial inorganic elements, electrolytes in larger quantity, and lower moisture content. PMID- 23929995 TI - Performance in attentional tasks following meditative focusing and focusing without meditation. AB - BACKGROUND/AIMS: Ancient Indian yoga texts have described four mental states. These are caicalata (random thinking), ekagrata (focusing without meditation), dharana (meditative focusing), and dhyana (defocused meditative expansiveness). A previous study compared the performance in a cancellation task at the beginning and end of each of the four mental states (practiced for 20 minutes each, on four separate days) showed an increase in the scores after dharana Hence, the present study was designed to assess the effects of dharana (meditative focusing) and ekagrata (focusing without meditation) on two attention tasks (i) d2 test of attention and (ii) digit symbol substitution test. MATERIALS AND METHODS: Sixty normal healthy male volunteers with ages ranging from 17 to 38 years (group mean age +/- S.D., 24.87 +/- 4.95) were studied. Assessments were made before and after the practice of ekagrata and dharana on two separate days. RESULTS: After both types of focusing, there was a significant improvement in all measures of the d2 test of attention (TN, E, TN-E, E%, and CP). However, the performance in the digit symbol substitution test was better after dharana but did not change after ekagrata. CONCLUSIONS: Hence, in summary, dharana (meditative focusing) and ekagrata (focusing without meditation) produce nearly comparable results though dharana (meditative focusing) results in better incidental learning and better accuracy (as assessed by the substitution task). PMID- 23929996 TI - Efficacy of Ayurvedic treatment using Pancakarma combined with balance exercises for disability and balance in progressive supranuclear palsy. AB - A 55-year-old female presented at Department of Pancakarma with diagnosis of progressive supranuclear palsy (PSP). For assessing disability, progressive supranuclear palsy rating scale (PSPRS) was used and balance was assessed by using Tetrax Interactive Balance System (IBS) posturography. Ayurvedic treatment was given along with Pancakarma and balance exercises for 3 months. As part of Ayurvedic treatment, first Virecana karma was done with classical method and then Matra basti, Sirobasti, and other palliative treatment was given for 3 months. Amanatidine was not continued during Virecana karma but started thereafter. On comparison with pre-intervention scores, there was a significant improvement in the patient post-treatment. The features which mainly showed improvement were: Eye movements, spontaneous episodes of laughing, dysphagia, dysarthria, double vision, and neck rigidity. Balance showed significant improvement and there was a remarkable decrease in the postural sway. This case study may present new possibilities for treatment of neurodegenerative diseases by Ayurveda. PMID- 23929997 TI - Challenge of infertility: How protective the yoga therapy is? PMID- 23929998 TI - The European Academy of Ayurveda: 20 years of Ayurvedic education in Germany. PMID- 23929999 TI - Immunomodulatory and anti-tumor effects of Nigella glandulifera freyn and sint seeds on ehrlich ascites carcinoma in mouse model. AB - AIM: This study investigated the immunomodulatory and anti-tumor effects of Nigella glandulifera Freyn and Sint seeds (NGS) on Ehrlich ascites carcinoma in a mouse model. MATERIALS AND METHODS: Kunming mice with transplanted Ehrlich ascites tumor cells (EAC) were treated with NGS by oral administration. On the 11(th) day after the EAC implant, mouse thymus, liver, spleen and kidney tumors were removed for histopathological analysis. Blood samples were taken for hematological and biochemical analyses. RESULTS: The results indicate that NGS treatment leads to an increase in TNF-alpha, IL-1beta, and IL-2 blood serum levels. Absence of viable EAC and presence of necrotic cells were observed in the tumor tissue of the NGS-treated animals. CONCLUSIONS: The study results indicated that a water extract of NGS had the highest anti-tumor effect. Moreover, NGS treatment also showed an increase in the immune system activity. PMID- 23930000 TI - Orthogonal test design for optimizing the extraction of total flavonoids from Inula helenium. AB - BACKGROUND: Inula helenium, which belongs to thecomposite family, is an important crude drug in traditional Chinese medicine. MATERIALS AND METHODS: The effects of ethanol concentration, liquid to solid ratio, extraction temperature, and duration of microwave irradiation on the flavonoid extraction yield were studied through a single-factor experiment. An orthogonal array (L9(3(4))) was then constructed to achieve the best extraction conditions. RESULTS: Variance analysis revealed that ethanol concentration significantly affected the extraction yield. The optimal conditions were as follows: ethanol concentration, 50% (v/v); liquid to solid ratio, 15:1; duration of microwave irradiation, 240 s; and extraction temperature, 60 degrees C. CONCLUSION: Under these optimal conditions, the total flavonoid yield was 18.34 +/- 0.64 mg/g. The use of a microwave-assisted process dramatically reduced the time needed for extraction of flavonoids from I. helenium. PMID- 23930001 TI - Interaction of lobed kudzuvine root, rhizoma chuanxiong with both acetylcholinesterase and beta-amyloid (Abeta1-42). AB - BACKGROUND: Lobed kudzuvine root and rhizoma chuanxiong are effective drugs in traditional Chinese medicine. OBJECTIVE: Extracts of the two medicines were investigated for their in vitro of beta-amyloid (Abeta1-42)-aggregation-and acetylcholinesterase (AChE)-inhibitory activities. MATERIALS AND METHODS: The interaction of lobed kudzuvine root, rhizoma chuanxiong with both acetylcholinesterase and beta-amyloid (Abeta1-42) were studied by Michaelis Menten equations, Thioflavin T (ThT) fluorescence analysis and transmission electron microscope (TEM). RESULTS: Inhibition of acetylcholinesterase showed that 1-butanol fraction of the two medicines were noncompetitive inhibition, apparent inhibition constants were 9.947 and 7.1523. ThT fluorescence analysis and TEM results indicated that inhibition of the water fraction and 1-butanol fraction (both lobed kudzuvine root and rhizoma chuanxiong) was better. CONCLUSION: The result supported further research on chemical constituents and pharmacological mechanisms. PMID- 23930002 TI - Comparison of the protective effects of ferulic acid and its drug-containing plasma on primary cultured neonatal rat cardiomyocytes with hypoxia/reoxygenation injury. AB - BACKGROUND: To simulate the ischemia-reperfusion injury in vivo, hypoxia/reoxygenation injury model was established in vitro and primary cultured neonatal rat cardiomyocytes were underwent hypoxia with hydrosulfite (Na2S2O4) for 1 h followed by 1 h reoxygenation. MATERIALS AND METHODS: Determination the cell viability by MTT colorimetric assay. We use kit to detect the activity of lactate dehydrogenase (LDH), Na(+)-K(+)-ATPase and Ca(2+)-ATPase. Do research on the effect which ferulic acid and its drug-containing plasma have to self discipline, conductivity, action potential duration and other electrophysiological phenomena of myocardial cells by direct observation using a microscope and recording method of intracellular action potential. RESULTS: The experimental datum showed that both can reduce the damage hydrosulfite to myocardial cell damage and improve myocardial viability, reduce the amount of LDH leak, increase activity of Na(+)-K(+)-ATPase, Ca(2+)-ATPase, and increase APA (Action potential amplitude), Vmax (Maximum rate of depolarization) and MPD (Maximum potential diastolic). CONCLUSION: Taken together, therefore, we can get the conclusion that ferulic acid drug-containing plasma has better protective effect injured myocardial cell than ferulic acid. PMID- 23930003 TI - Response surface modeling and optimization of ultrasound-assisted extraction of three flavonoids from tartary buckwheat (Fagopyrum tataricum). AB - BACKGROUND: Buckwheat (Fagopyrum spp., Polygonaceae) is a widely planted food crop. Flavonoids, including quercetin, rutin, and kaempferol, are the main bioactive components in tartary buckwheat (Fagopyrum tataricum (L.) Gaertn). From the nutriological and pharmacological perspectives, flavonoids have great value in controlling blood glucose and blood pressure levels, and they also have antioxidant properties. OBJECTIVE: To optimize the conditions for extraction of quercetin, rutin, and kaempferol from F. tataricum. MATERIALS AND METHODS: A combination of ultrasound-assisted extraction (UAE) and response surface methodology (RSM) was used for flavonoid extraction and yield assessment. The RSM was based on a three-level, three-variable Box-Behnken design. RESULTS: Flavonoids were optimally extracted from F. tataricum by using 72% methanol, at 60 degrees C, for 21 minutes. Under these conditions, the obtained extraction yield of the total flavonoids was 3.94%. CONCLUSION: The results indicated that the UAE method was effective for extraction of flavonoids from tartary buckwheat. PMID- 23930004 TI - Simultaneous determination of four bioactive compounds in Glechoma longituba extracts by high performance liquid chromatography. AB - BACKGROUND: Glechoma longituba, one of the long-practiced traditional Chinese medicines in history, is still commonly used nowadays in oriental countries. Previous study indicates that phenolic acid and flavonoids have considerable bioactivities, thus, chlorogenic acid, caffeic acid, apigenin-7-O-glucoside and rosmarinic acid were chosen as the marker components for the simultaneous determination to evaluate the intrinsic quality of G. longituba, and related high performance liquid chromatographic method was urgent to established. MATERIALS AND METHODS: A HPLC method was established for simultaneous determination of four major active components in G. longituba, three batches which collected from different suppliers in Zhejiang, Anhui and Jiangsu Provinces were determined. RESULTS: The contents of chlorogenic acid, caffeic acid, apigenin-7-O-glucoside and rosmarinic acid in G. longituba samples analyzed were 0.00225-0.00234%, 0.0238-0.0242%, 0.00271-0.00313%, 0.830-0.896%, respectively. CONCLUSION: The developed method can be applied to the intrinsic quality control of G. longituba. PMID- 23930005 TI - Effects of honeybee (Apis mellifera) venom on keratinocyte migration in vitro. AB - BACKGROUND: Since the ancient times the skin aging application of honeybee venom (BV) is practiced and persisted until nowadays. The present study evaluated the effect of the honeybee venom (BV) on keratinocyte migration in wound healing model in vitro. OBJECTIVE: To access BV further as a cosmetic ingredient and a potential external application for topical uses, we performed studies to investigate the biologic effect of BV treatment on keratinocyte proliferation and migration in vitro. MATERIAL AND METHODS: BV cytotoxicity was assessed by using a 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl tetrazolium bromide (MTT) assay over 24 h. To assess BV genotoxicity, damage to human epidermal keratinocyte (HEK) was evaluated using the Comet assay. HEK migration was evaluated using a commercial wound healing kit. The skin pro-inflammatory cytokines interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha were examined to evaluate the pro-inflammatory response to BV. RESULTS: It was found that BV (<100 MUg/ml) was not cytotoxic and stimulated more HEK proliferation and migration compared to negative control, and did not induce DNA damage. There were also decreases in IL-8 and TNF-alpha expression levels in HEK at all time points. CONCLUSION: These findings highlight the potential of topical application of BV for promoting cell regeneration and wound treatment. PMID- 23930006 TI - Inhibitory effects of Cyrtomium fortunei J. Smith root extract on melanogenesis. AB - BACKGROUND: Recently, a great deal of attention has been directed toward the use of crude extracts from natural products for cosmetic applications. Thus, we performed a series of experiments to investigate skin depigmenting properties of a crude extract that was derived from a traditional Korean medicinal plant. MATERIALS AND METHODS: In this study, the depigmentational potency of Cyrtomium fortunei J. Smith was investigated. The inhibitory effects of the root of Cyrtomium fortunei J. Smith extract on melanin production were evaluated by assessing its tyrosinase inhibitory effects, melanin production-inhibitory properties in melan-a cells and depigmenting ability in brown guinea pig skin. RESULTS: The methanolic extract of the root of Cyrtomium fortunei J. Smith appeared to inhibit tyrosinase activity and melanin production in melan-a cells. In addition, this extract exhibited depigmenting ability on Ultra violet-induced hyper pigmentation in brown guinea pig skin. CONCLUSION: These results suggested that root of Cyrtomium fortunei J. Smith might prove useful in treating skin hyperpigmentation associated with excess sun-exposure. PMID- 23930007 TI - Antiproliferative and apoptotic effects of spanish honeys. AB - BACKGROUND: Current evidence supports that consumption of polyphenols has beneficial effects against numerous diseases mostly associated with their antioxidant activity. Honey is a good source of antioxidants since it contains a great variety of phenolic compounds. OBJECTIVE: The main objective of this work was to investigate the antiproliferative and apoptotic effects of three crude commercial honeys of different floral origin (heather, rosemary and polyfloral honey) from Madrid Autonomic Community (Spain) as well as of an artificial honey in human peripheral blood promyelocytic leukemia cells (HL-60). MATERIAL AND METHODS: HL-60 cells were cultured in the presence of honeys at various concentrations for up to 72 hours and the percentage of cell viability was evaluated by MTT assay. Apoptotic cells were identified by chromatin condensation and flow cytometry analysis. ROS production was determined using 2',7' dichlorodihydrofluorescein diacetate (H2DCFDA). RESULTS: The three types of crude commercial honey induced apoptosis in a concentration and time dependent-manner. In addition, honeys with the higher phenolic content, heather and polyfloral, were the most effective to induce apoptosis in HL-60 cells. However, honeys did not generate reactive oxygen species (ROS) and N-acetyl-L-cysteine (NAC) could not block honeys-induced apoptosis in HL-60 cells. CONCLUSION: These data support that honeys induced apoptosis in HL-60 cells through a ROS-independent cell death pathway. Moreover, our findings indicate that the antiproliferative and apoptotic effects of honey varied according to the floral origin and the phenolic content. PMID- 23930008 TI - Fingerprint analysis of Hibiscus mutabilis L. leaves based on ultra performance liquid chromatography with photodiode array detector combined with similarity analysis and hierarchical clustering analysis methods. AB - BACKGROUND: A method for chemical fingerprint analysis of Hibiscus mutabilis L. leaves was developed based on ultra performance liquid chromatography with photodiode array detector (UPLC-PAD) combined with similarity analysis (SA) and hierarchical clustering analysis (HCA). MATERIALS AND METHODS: 10 batches of Hibiscus mutabilis L. leaves samples were collected from different regions of China. UPLC-PAD was employed to collect chemical fingerprints of Hibiscus mutabilis L. leaves. RESULTS: The relative standard deviations (RSDs) of the relative retention times (RRT) and relative peak areas (RPA) of 10 characteristic peaks (one of them was identified as rutin) in precision, repeatability and stability test were less than 3%, and the method of fingerprint analysis was validated to be suitable for the Hibiscus mutabilis L. leaves. CONCLUSIONS: The chromatographic fingerprints showed abundant diversity of chemical constituents qualitatively in the 10 batches of Hibiscus mutabilis L. leaves samples from different locations by similarity analysis on basis of calculating the correlation coefficients between each two fingerprints. Moreover, the HCA method clustered the samples into four classes, and the HCA dendrogram showed the close or distant relations among the 10 samples, which was consistent to the SA result to some extent. PMID- 23930010 TI - New ionic liquid-based preparative method for diosgenin from Rhizoma dioscoreae nipponicae. AB - BACKGROUND: Rhizoma dioscoreae nipponicae is a perennial herb and its roots have been widely used in Traditional Chinese Medicine (TCM). OBJECTIVE: To develop and optimize the extraction and hydrolysis technology of diosgenin from Rhizoma dioscoreae nipponicae. MATERIALS AND METHODS: 1-methyl-3-(3-sulfopropyl) imidazolium hydrogen sulfate ([PSMIM]HSO4), as a kind of functional ionic liquid, replaced inorganic acid, and was used in a one-step ultrasonic extraction and hydrolysis for the preparation of diosgenin (the aglycone of dioscin and an important precursor chemical in the pharmaceutical industry) from Rhizoma dioscoreae nipponicae, for the first time. The effects of various factors were evaluated. The obtained product was studied using high performance liquid chromatography (HPLC). RESULTS: About 6.35 mg of diosgenin could be obtained from 2.0 g of raw material. Reusability and recycling of the ionic liquid were validated with fairly good results. The ionic liquid solution was reused four times, and the final extraction efficiency only decreased by 5%. CONCLUSION: In virtue of the obvious advantages of the green extraction and catalytic solvent, with further study, it is believed that this new one-step preparative method promises to replace the traditional methods. PMID- 23930009 TI - Anti-microorganism, anti-tumor, and immune activities of a novel polysaccharide isolated from Tricholoma matsutake. AB - BACKGROUND: Many more fungal polysaccharides have been reported to exhibit a variety of biological activities, including anti-tumor, immunostimulation, anti oxidation, and so on. The non-starch polysaccharides have emerged as an important class of bioactive natural products. OBJECTIVE: To investigate the anti microorganism, anti-tumor, and immune activities of a novel polysaccharide (TMP A) isolated from Tricholoma matsutake. MATERIALS AND METHODS: The anti microorganism activity of purified polysaccharides (TMP-A) was evaluated by the inhibition zone diameter, the anti-tumor activity was evaluated by the S180 tumor cells that were implanted subcutaneously into the Kunming strain male mice in vivo, and the immune activity was evaluated by lymphocyte proliferation and macrophage stimulation, respectively. RESULTS: In this study, the most susceptible bacteria of TMP-A at a concentration of 20 mg/ml was Micrococcus lysodeikticus (inhibition zone diameter 24.38 +/- 1.19 mm) and the TMP-A did not show any antifungal activity for the tested stains of the fungi. In addition, the inhibitory rate in mice treated with 80 mg/kg TMP-A could reach 68.422%, being the highest in the three doses, which might be comparable to mannatide. The anti tumor activity of the TMP-A was usually believed to be a consequence of the stimulation of the cell-mediated immune response, because it could significantly promote the lymphocyte and macrophage cells in the dose range of 50-200 MUg/mL and in the dose range of 100 - 400 MUg/mL in vitro, respectively. DISCUSSION AND CONCLUSION: The results obtained in the present study indicate that the purification polysaccharide of Tricholoma matsutake is a potential source of natural broad-spectrum, anti-microorganism, anti-tumor, and immunomodulation. PMID- 23930012 TI - Evaluation of the hypolipidemic activity of 6,7-dimethoxycoumarin on placental tissue factor mRNA expression in experimental anti-phospholipid syndrome. AB - BACKGROUND: Anti-phospholipid syndrome is a thrombogenic and systemic autoimmune disorder that influences fetal life throughout gestation period. Over expression of tissue factor on the surface of monocyte(s) is reported to be a major causative agent in inducing anti-phospholipid antibody-mediated placental thrombosis and fetal loss in pregnant women. The over expression of tissue factor is proposed to be due to high levels of blood cholesterol and oxidized lipoproteins. OBJECTIVE: In this study, we report the lipid-lowering property and anti-tissue factor activity of one of the naturally occurring coumarin derivates 6,7-dimethoxycoumarin, found aplenty in Chinese medicinal plant Artemisia scoparia, and its effect on tissue factor mRNA expression in experimental anti phospholipid syndrome. MATERIALS AND METHODS: Adult female mice were immunized with cardiolipin and beta-2-glycoprotein-1 to induce experimental anti phospholipid syndrome. Female mice with high titer of aCL were allowed to mate with male, and the female mice were treated with 6,7-dimethoxycoumarin on a daily dose of 5 mg/kg body weight from day 3 to day 15 of gestation. On day 18 of pregnancy, all the animals were dissected to measure biochemical parameters in blood, and TF mRNA expression levels were measured in placenta. RESULTS: Treatment with 6,7-dimethoxycoumarin significantly reduced the levels of cholesterol and plasma lipids by its potent hypolipidemic property, which eventually reduced the over-expression tissue factor at mRNA levels in placenta. We believe that further studies in animal model would reveal the potential therapeutic properties of 6,7-dimethoxycoumarin against anti-phospholipid syndrome. CONCLUSION: The 6,7-dimethoxycoumarin is capable to reduce the expression of TF in placenta at the mRNA level and thrombus generation indirectly by its potent anti-TF and anti-oxidant activities. PMID- 23930011 TI - Identification of ethnomedicinal plants (Rauvolfioideae: Apocynaceae) through DNA barcoding from northeast India. AB - BACKGROUND: DNA barcode-based molecular characterization is in practice for plants, but yet lacks total agreement considering the selection of marker. Plant species of subfamily Rauvolfioideae have long been used as herbal medicine by the majority of tribal people in Northeast (NE) India and at present holds mass effect on the society. Hence, there is an urgent need of correct taxonomic inventorization vis-a-vis species level molecular characterization of important medicinal plants. OBJECTIVE: To test the efficiency of matK in species delineation like DNA barcoding in Rauvolfiadae (Apocynaceae). MATERIALS AND METHODS: In this study, the core DNA barcode matK and trnH-psbA sequences are examined for differentiation of selected ethnomedicinal plants of Apocynaceae. DNA from young leaves of selected species was isolated, and matK gene (~800 bp) and trnH-psbA spacer (~450 bp) of Chloroplast DNA was amplified for species level identification. RESULTS: The ~758 bp matK sequence in comparison to the trnH-psbA showed easy amplification, alignment, and high level of discrimination value among the medicinal Rauvolfioidae species. Intergenic spacer trnH-psbA is also exhibited persistent problem in obtaining constant bidirectional sequences. Partial matK sequences exhibited 3 indels in multiple of 3 at 5 end. Evidently, generated matK sequences are clustered cohesively, with their conspecific Genbank sequences. However, repeat structures with AT-rich regions, possessing indels in multiple of 3, could be utilized as qualitative molecular markers in further studies both at the intra-specific and shallow inter-specific levels like the intergenic spacers of CpDNA. CONCLUSION: matK sequence information could help in correct species identification for medicinal plants of Rauvolfioideae. PMID- 23930013 TI - Qualitative and quantitative analysis of nine major compounds in the Bozhougyiqi Tang using a high-performance liquid chromatography coupled with a diode array detector and electrospray ionization mass spectrometer. AB - BACKGROUND: Bozhougyiqi-Tang (BZYQT) is of traditional herbal medicine used for enhancement of digestive capacity. OBJECTIVE: An accurate and reliable simultaneous determination using a HPLC-DAD and ESI-MS was developed and validated for the qualitative and quantitative analysis of 9 major compounds, ferulic acid (1), naringin (2), hesperidin (3), decursinol (4), glycyrrhizin (5), saikosaponin A (6), 6-gingerol (7), ginsenoside Rg3 (8), decursin (9), in traditional herbal medicine 'Bozhougyiqi-Tang.' MATERIALS AND METHODS: The chromatographic separation of 9 compounds was performed on a SHISEIDO C18 column (250 mm * 4.6 mm i.d., S-5 MUm) using gradient elution with 0.1% trifluoroacetic acid and acetonitrile at a flow rate of 1.0 ml/min. The 9 compounds were identified based on peak retention time and UV spectrum and MS data of these compounds. RESULTS: This developed method showed good linearity (R(2) > 0.999). The LOD and LOQ of the major compounds were less than 0.09 and 0.28 MUg/ml, respectively. The intra - day and inter - day RSD values were within 2.06% and 1.64%, respectively. The mean recoveries were from 92.10% to 108.56% with less than 1.88%. The results indicated that established method had good precision and accuracy. CONCLUSION: The new method was successfully applied to the simultaneous analysis of 9 compounds in Bozhougyiqi-Tangs samples. PMID- 23930015 TI - Molecule of the month: miRNA and Human Prion brain disease. PMID- 23930016 TI - Sitagliptin does not inhibit the M1 alanyl aminopeptidase from Plasmodium falciparum. PMID- 23930017 TI - Workflow management systems for gene sequence analysis and evolutionary studies - A Review. AB - Post 'omic' era has resulted in the development of many primary, secondary and derived databases. Many analytical and visualization bioinformatics tools have been developed to manage and analyze the data available through large sequencing projects. Availability of heterogeneous databases and tools make it difficult for researchers to access information from varied sources and run different bioinformatics tools to get desired analysis done. Building integrated bioinformatics platforms is one of the most challenging tasks that bioinformatics community is facing. Integration of various databases, tools and algorithm is a challenging problem to deal with. This article describes the bioinformatics analysis workflow management systems that are developed in the area of gene sequence analysis and phylogeny. This article will be useful for biotechnologists, molecular biologists, computer scientists and statisticians engaged in computational biology and bioinformatics research. PMID- 23930018 TI - Molecular distribution of amino acid substitutions on neuraminidase from the 2009 (H1N1) human influenza pandemic virus. AB - The pandemic influenza AH1N1 (2009) caused an outbreak of human infection that spread to the world. Neuraminidase (NA) is an antigenic surface glycoprotein, which is essential to the influenza infection process, and is the target of anti flu drugs oseltamivir and zanamivir. Currently, NA inhibitors are the pillar pharmacological strategy against seasonal and global influenza. Although mutations observed after NA-inhibitor treatment are characterized by changes in conserved amino acids of the enzyme catalytic site, it is possible that specific amino acid substitutions (AASs) distant from the active site such as H274Y, could confer oseltamivir or zanamivir resistance. To better understand the molecular distribution pattern of NA AASs, we analyzed NA AASs from all available reported pandemic AH1N1 NA sequences, including those reported from America, Africa, Asia, Europe, Oceania, and specifically from Mexico. The molecular distributions of the AASs were obtained at the secondary structure domain level for both the active and catalytic sites, and compared between geographic regions. Our results showed that NA AASs from America, Asia, Europe, Oceania and Mexico followed similar molecular distribution patterns. The compiled data of this study showed that highly conserved amino acids from the NA active site and catalytic site are indeed being affected by mutations. The reported NA AASs follow a similar molecular distribution pattern worldwide. Although most AASs are distributed distantly from the active site, this study shows the emergence of mutations affecting the previously conserved active and catalytic site. A significant number of unique AASs were reported simultaneously on different continents. PMID- 23930019 TI - Insight from the structural molecular model of cytidylate kinase from Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis is a gram-positive bacterium causes tuberculosis in human. H37Rv strain is a pathogenic strain utilized for tuberculosis research. The cytidylate mono-phosphate (CMP) kinase of Mycobacterium tuberculosis belongs to the family nucleoside mono-phosphate kinase (NMK), this enzyme is required for the bacterial growth. Therefore, it is important to study the structural and functional features of this enzyme in the control of the disease. Hence, we developed the structural molecular model of the CMP kinase protein from Mycobacterium tuberculosis by homology modeling using the software MODELLER (9v10). Based on sequence similarity with protein of known structure (template) of Mycobacterium smegmatis (PDB ID: 3R20) was chosen from protein databank (PDB) by using BLASTp. The energy of constructed models was minimized and the qualities of the models were evaluated by PROCHECK and VERRIFY-3D. Resulted Ramachandran plot analysis showed that conformations for 100.00% of amino acids residues are within the most favored regions. A possible homologous deep cleft active site was identified in the Model using CASTp program. Amino acid composition and polarity of that protein was observed by CLC-Protein Workbench tool. Expasy's Prot-param server and CYC_REC tool were used for physiochemical and functional characterization of the protein. Studied of secondary structure of that protein was carried out by computational program, ProFunc. The structure is finally submitted in Protein Model Database. The predicted model permits initial inferences about the unexplored 3D structure of the CMP kinase and may be promote in relational designing of molecules for structure-function studies. PMID- 23930020 TI - Insights from the docking and molecular dynamics simulation of the Phosphopantetheinyl transferase (PptT) structural model from Mycobacterium tuberculosis. AB - A great challenge is posed to the treatment of tuberculosis due to the evolution of multidrug-resistant (MDR) and extensively drugresistant (XDR) strains of Mycobacterium tuberculosis in recent times. The complex cell envelope of the bacterium contains unusual structures of lipids which protects the bacterium from host enzymes and escape immune response. To overcome the drug resistance, targeting "drug targets" which have a critical role in growth and virulence factor is a novel approach for better tuberculosis treatment. The enzyme Phosphopantetheinyl transferase (PptT) is an attractive drug target as it is primarily involved in post translational modification of various types-I polyketide synthases and assembly of mycobactin, which is required for lipid virulence factors. Our in silico studies reported that the structural model of M.tuberculosis PptT characterizes the structure-function activity. The refinement of the model was carried out with molecular dynamics simulations and was analyzed with root mean square deviation (RMSD), and radius of gyration (Rg). This confirmed the structural behavior of PptT in dynamic system. Molecular docking with substrate coenzyme A (CoA) identified the binding pocket and key residues His93, Asp114 and Arg169 involved in PptT-CoA binding. In conclusion, our results show that the M.tuberculosis PptT model and critical CoA binding pocket initiate the inhibitor design of PptT towards tuberculosis treatment. PMID- 23930021 TI - Isolation, purification and characterization of Cardiolipin synthase from Mycobacterium phlei {PRIVATE}. AB - It has been observed that mycobacterial species has high content of cardiolipin (CL) in their cell membranes more so pathogenic mycobacteria and in bacteria CL activates polymerases, gyrases by removing the bound ADP. Therefore, in the present study cardiolipin synthase (cls) which catalyses the formation of CL was isolated purified and characterized from the cell membrane of Mycobacterium phlei. The purified cls obtained from C-18 RP-HPLC column had a molecular weight of 58 kDa with an isoelectric point of 4.5. The enzyme activity (11.5+0.15 uM of CL phosphorous. ml-1 minute-1 for PG as substrate and 14+0.35uM of CL phosphorous. ml-1 minute-1 for CDP-DG as substrate) was optimal at pH 4.8 and showed KM values of 55+0.05uM and 2.56+0.04uM for phosphatidyl glycerol and CDP diacylglycerol, respectively, with an absolute requirement of Mg(2+) and Mn(2+) ions for its activity however, Ca(2+) ions inhibited the activity of the cls. The partial amino acid sequence of cls showed significant homology with pgsA3 gene of M. tuberculosis and in this organism the CL biosynthesis is very high having three genes coding for PLs biosynthesis therefore, enzymes involved in CL biosynthesis may be an attractive drug target in the development of new antimycobacterial drugs. PMID- 23930022 TI - Molecular dynamics simulation of complex Histones Deacetylase (HDAC) Class II Homo Sapiens with suberoylanilide hydroxamic acid (SAHA) and its derivatives as inhibitors of cervical cancer. AB - Cervical cancer is second most common cancer in woman worldwide. Cervical cancer caused by human papillomavirus (HPV) oncogene. Inhibition of histone deacetylase (HDAC) activity has been known as a potential strategy for cancer therapy. SAHA is an HDAC inhibitor that has been used in cancer therapy but still has side effects. SAHA modification proposed to minimize side effects. Triazole attachment on the chain of SAHA has been known to enhance the inhibition ability of SAHA and less toxic. In this study, it will be carried out with molecular dynamic simulations of SAHA modifications consisting ligand 1a, 2a and, 2c to interact with six HDAC in hydrated conditions. To all six HDAC Class II, performed docking with SAHA and a modified inhibitor. The docking results were then carried out molecular dynamics simulations to determine the inhibitor affinities in hydrated conditions. The molecular dynamic simulations results show better affinities of ligand 2c with HDAC 4, 6, and 7 than SAHA itself, and good affinity was also shown by ligand 2a and 1c on HDAC 5 and 9. The results of this study can be a reference to obtain better inhibitors. PMID- 23930023 TI - in-silico analysis suggests alterations in the function of XisA protein as a possible mechanism of butachlor toxicity in the nitrogen fixing cyanobacterium Anabaena sp. PCC 7120. AB - Butachlor, a commonly used herbicide adversely affects the nitrogen fixing capability of Anabaena, an acclaimed nitrogen fixer in the Indian paddy fields. The nitrogen fixation in Anabaena is triggered by the excision of nifD element by xisA gene leading to rearrangement of nifD forming nifHDK operon in the heterocyst of Anabaena sp. PCC7120. Functional elucidation adjudged through in silico analysis revealed that xisA belongs to integrase family of tyrosine recombinase. The predicted functional partners with XisA protein that have shown cooccurence with this protein in a network are mainly hypothetical proteins with unknown functions except psaK1 whose exact function in photosystem I is not yet known. The focus of this study was to find out the relation between XisA and butachlor using in-silico approaches. The XisA protein was modeled and its active sites were identified. Docking studies revealed that butachlor binds at the active site of XisA protein hampering its excision ability vis-a-vis nif genes in Anabaena sp. PCC7120. This study reveals that butachlor is not directly involved in hampering the nitrogen fixing ability of Anabaena sp. PCC7120 but by arresting the excision ability of XisA protein necessary for the functioning of nif gene and nitrogen fixation. PMID- 23930024 TI - PROcEED: Probabilistic reverse dosimetry approaches for estimating exposure distributions. AB - As increasing amounts of biomonitoring survey data become available, a new discipline focused on converting such data into estimates of chemical exposures has developed. Reverse dosimetry uses a pharmacokinetic model along with measured biomarker concentrations to determine the plausible exposure concentrations-- a critical step to incorporate ground-truthing experimental data into a distribution of probable exposures that reduces model uncertainty and variability. At the population level, probabilistic reverse dosimetry can utilize a distribution of measured biomarker concentrations to identify the most likely exposure concentrations (or intake doses) experienced by the study participants. PROcEED is software that provides access to probabilistic reverse dosimetry approaches for estimating exposure distributions via a simple user interface. AVAILABILITY: PROcEED along with installation instructions is freely available for download from http://www.epa.gov/heasd/products/proceed/proceed.html. PMID- 23930025 TI - Bridging the mind-body divide. PMID- 23930027 TI - A comparative study of the effects of asan, pranayama and asan-pranayama training on neurological and neuromuscular functions of Pondicherry police trainees. AB - BACKGROUND: Though neurological benefits of yoga training have been reported, lacunae still exists in understanding neurophysiological effects of such training. Hence, the present study was conducted to find the effect of yogasanas and pranayams on neurological and neuromuscular functions in healthy human volunteers and also determined differential effects of training in asan, pranayama and their combination. MATERIALS AND METHODS: Eighty male trainees from Pondicherry Police Training School were randomly divided into asan, pranayama, and asan-pranayama groups who received a training of 4 days a week for 6 months and a control group. Electroencephalogram (EEG), nerve conduction (NC), electromyogram (EMG), visual evoked potentials (VEP), and auditory reaction time (ART) were recorded before and after the study period. NC, EMG, and VEP data were obtained from 28 subjects; EEG data from 48 subjects; and RT from 67 subjects. Intergroup differences were assessed by AVOVA/Kruskal-Wallis and intragroup differences by Student's t-test. RESULTS AND DISCUSSION: Police trainees showed beneficial effects of yoga training, although they were undergoing intensive police training and the yoga training was relatively less intense. Alpha, theta, and total power of EEG increased as a result of asan training. A shortening of visual reaction time and a decrease in red-green discriminatory reaction time signifies an improved and faster processing of visual input. They also showed a decrease in resting EMG voltage, signifying better muscular relaxation following pranayama training. Beta, theta and total power of EEG increased. ART and red green discriminatory reaction times decreased in the trainees, signifying a more alert state as well as improved central neural processing. A combination of asan and pranayama training for 6 months produced an improvement in motor and sensory nerve conduction. Total power of EEG, alpha and theta power as well as delta % increased, while reaction time decreased signifying an alert and yet relaxed state of the neuromuscular system. SUMMARY AND CONCLUSION: The present study has shown that 6 months training in asan, pranayama as well as their combination is effective in improving physiological functions of police trainees. They showed beneficial effects of yoga training, although they were undergoing intensive police training and the yoga training was relatively less intense. Hence, we recommend that yoga training be introduced in police training curricula. PMID- 23930026 TI - Male reproductive health and yoga. AB - Now-a-days reproductive health problems along with infertility in male is very often observed. Various Assisted Reproductive Technologies have been introduced to solve the problem, but common people cannot afford the cost of such procedures. Various ayurvedic and other alternative medicines, along with regular yoga practice are proven to be not only effective to enhance the reproductive health in men to produce a successful pregnancy, but also to regulate sexual desire in men who practice celibacy. Yoga is reported to reduce stress and anxiety, improve autonomic functions by triggering neurohormonal mechanisms by the suppression of sympathetic activity, and even, today, several reports suggested regular yoga practice from childhood is beneficial for reproductive health. In this regard the present review is aimed to provide all the necessary information regarding the effectiveness of yoga practice to have a better reproductive health and to prevent infertility. PMID- 23930028 TI - Effect of fast and slow pranayama on perceived stress and cardiovascular parameters in young health-care students. AB - CONTEXT: Perceived stress is higher for students in various healthcare courses. Previous studies have shown that pranayama practice is beneficial for combating stress and improve cardiovascular functions but both fast and slow pranayama practice produce different physiological responses. AIM: Present study was conducted to compare the effects of commonly practiced slow and fast pranayama on perceived stress and cardiovascular functions in young health-care students. MATERIALS AND METHODS: Present study was carried out in Departments of Physiology and Advanced Centre for Yoga Therapy Education and Research, JIPMER, Pondicherry. Ninety subjects (age 18-25 years) were randomized to fast pranayama (Group 1), slow pranayama (Group 2) and control group (Group 3). Group 1 subjects practiced Kapalabhati, Bhastrika and Kukkuriya Pranayama while Group 2 subjects practiced Nadishodhana, Savitri and Pranav Paranayama. Supervised pranayama training was given for 30 min, 3 times a week for the duration of 12 weeks to Groups 1 and 2 subjects by certified yoga trainer. Following parameters were recorded at the baseline and after 12 weeks of training; perceived stress scale (PSS), heart rate (HR), respiratory rate, systolic blood pressure and diastolic blood pressure (DBP), mean arterial pressure (MAP), rate pressure product (RPP), and double product (Do P). RESULTS: There was a significant decrease in PSS scores in both Group 1 and Group 2 subjects but percentage decrease was comparable in these groups. Significant decrease in HR, DBP, RPP, and Do P was seen in only Group 2 subjects. CONCLUSION: This study demonstrates that both types of pranayama practice are beneficial in reducing PSS in the healthy subjects but beneficial effect on cardiovascular parameters occurred only after practicing slow pranayama. PMID- 23930029 TI - Mindfulness-based stress reduction program in coronary heart disease: A randomized control trial. AB - BACKGROUND: Psychological risk factors such as anxiety and depression have been associated with coronary heart disease (CHD). Stress can have an impact on the risk factors for the disease, such as high blood pressure (BP), physical inactivity and being overweight. AIMS: Examine the effect of the Mindfulness Based Stress Reduction (MBSR) program on symptoms of anxiety and depression, perceived stress, BP and body mass index (BMI) in patients with CHD. SETTINGS AND DESIGN: Intervention was carried out at an Outpatient clinic. Parallel group - MBSR group; and treatment-as-usual group (TAU) - randomized control design with pre- (baseline), post-intervention and follow-up assessments was adopted. MATERIALS AND METHODS: Thirty male patients, age range (30-65 years) with CHD were randomly allocated to either group. The therapeutic program comprised of eight weekly sessions of structured MBSR intervention for the MBSR group and one health education session for the TAU group. Regular medical intervention and monthly consultations with the cardiologist were consistent for both groups. The main outcome measures were: Hospital Anxiety and Depression Scale, Perceived Stress Scale (perceived stress), BP and BMI. STATISTICAL ANALYSIS: Independent sample t-tests, chi square test and paired sample t-test were used. RESULTS: All patients completed intervention in the MBSR group. Significant reduction was observed in symptoms of anxiety and depression, perceived stress, BP and BMI in patients of the MBSR group after the completion of intervention assessment. At 3 month follow-up, therapeutic gains were maintained in patients of the MBSR group. CONCLUSION: The MBSR program is effective in reducing symptoms of anxiety and depression, perceived stress, BP and BMI in patients with CHD. PMID- 23930030 TI - Efficacy of certain yogic and naturopathic procedures in premature ejaculation: A pilot study. AB - CONTEXT: Premature ejaculation (PE) is the most common sexual disorder of young males. Even though there are number of treatment options available for PE, patient's satisfaction and drug side effects remain to be a problem. Non pharmacological treatment options like Yoga and Naturopathy have been implicated in sexual fulfillment, pleasure and efficacy of some of these approaches has been established in previous studies. AIM: To assess the efficacy of certain yogic and naturopathic procedures in the management of PE. MATERIALS AND METHODS: A total of 12 patients with PE satisfying the DSM IV TR diagnostic criteria were selected and allotted into two groups, Yoga group and Naturopathic group by following the randomization method. In the Yoga group, various asanas, mudra, bandha and pranayama were practiced 1 hour daily for 21 days. In the Naturopathy group, lower abdomen massage and steam bath, hip bath and lingasnana, mud pack on lower abdomen, and acupressure were done 1 hour daily for 21 days. Criteria of assessment were based on the scoring of Premature Ejaculation Severity Index (PESI). Statistical analysis was done by using paired and unpaired "t" tests. RESULTS: In the Yoga group (n = 6), 7.3% relief was observed (P < 0.01) and in the Naturopathy group (n = 6), 2.4% of relief was observed (P > 0.05) on the total score of PESI. There was no significant difference (P > 0.05) found in between the two groups. CONCLUSION: Both Yoga and Naturopathic procedures didn't provide relief (<25%) on total score of PESI. PMID- 23930031 TI - Additional effect of iyengar yoga and EMG biofeedback on pain and functional disability in chronic unilateral knee osteoarthritis. AB - BACKGROUND: There are limited data about Iyengar Yoga and EMG biofeedback in knee OA, although the efficacy of EMG biofeedback in the rehabilitation of patients with quadriceps muscle weakness secondary to immobilization, contracture, and joint surgery has been well established. MATERIALS AND METHODS: Thirty subjects who have fulfilled inclusion and exclusion criteria were selected and divided into two groups (Group A and B). Both the groups were treated with EMG biofeedback, knee muscle strengthening exercises, and TENS. Group A received additionally Iyengar Yoga for 8 weeks. Both groups were evaluated by Visual Analog Scale and Modified WOMAC-Western Ontario McMaster Universities Scale. RESULTS: Patients in both groups experienced significant reduction in pain and improvement in functional ability. In VAS scale Group A showed reduction of 56.83% (P = 0.001) when compared with Group B 38.15% (P <= 0.001). In modified WOMAC Scale, Group A showed reduction of 59.21% (P = 0.001) when compared with Group B 34.08% (P = 0.001). CONCLUSION: Adding Iyengar Yoga along with conventional therapy provides better results in chronic unilateral knee osteoarthritis in terms of pain and functional disability. PMID- 23930032 TI - Effect of kapalabhati on performance of six-letter cancellation and digit letter substitution task in adults. AB - BACKGROUND: Attention and concentration are valuable skills for all fields of human activity. Training to improve these skills is described in ancient hatha yoga texts. AIMS: To study the effect of 1-min Kapalabhati (KB1) and 5-min Kapalabhati (KB5) practice of the Yoga rapid breathing exercise, Kapalabhati (KB), on psychomotor performance, as measured by the six-letter cancellation task (SLCT) and digit-letter substitution task (DLST). MATERIALS AND METHODS: Thirty six subjects, 21 male (mean age 25.71 years, SD 2.10), 15 female (mean age 24.13 years, SD 2.23) participated in the study. All were participating in a 3-month pranayama training program, part of residential degree courses at Swami Vivekananda Yoga Anusandhana Samsthana, Yoga University. The subjects were divided into two groups, and assessed on the SLCT and DLST, immediately before and after KB on two successive days. The first group did KB1 on day 1, and KB5 on day 2. For the second group, the order was reversed. RESULTS: There were no significant differences on SLCT and DLST on Total and Net Scores between sessions for the same group, and between groups for the same session i.e. the effects of KB1 and KB5 were not distinguishable. However, both groups made more errors on DLST after the interventions, 525% after KB1 and 562.5% after KB5, P < 0.018 and P < 0.041, respectively (Wilcoxon Signed Rank Test). In contrast, scores on SLCT remained completely unchanged. CONCLUSIONS: Both KB1 and KB5 found no change on both SLCT and DLST. But, this kind of breathing practices leads to increases error score. PMID- 23930033 TI - Can yoga be used to treat gastroesophageal reflux disease? AB - Yoga methods including Pranayama are the best ways to prevent many diseases and their progression. Even though, Yoga is widely practiced, its effects on certain medical conditions have not been studied or reported. Gastroesophageal reflux disease (GERD) is one of them. GERD is extremely common condition requiring frequent consumption of over-the-counter or prescribed proton pump inhibitors (PPI). In severe symptoms of GERD and in the presence of multiple etiologies, PPIs are insufficient to relieve the symptoms of gastric reflux. Regular and proper use of the Yoga along with PPI can control the severe symptoms of GERD and can avoid or delay the necessity of invasive procedures. This evidence-based case report focuses on the effects of Yoga on GERD. Our case report showed that regular practice of Kapalbhati and Agnisar kriya along with PPI, patients with hiatal hernia had improvement in severe symptoms of GERD, which were initially refractory to PPI alone. PMID- 23930034 TI - Yoga therapy and schizophrenia. PMID- 23930035 TI - Author's reply. PMID- 23930036 TI - Time for evidence-based Ayurveda: A clarion call for action. PMID- 23930038 TI - Analysis of repeated measurement data in the clinical trials. AB - Statistics is an integral part of Clinical Trials. Elements of statistics span Clinical Trial design, data monitoring, analyses and reporting. A solid understanding of statistical concepts by clinicians improves the comprehension and the resulting quality of Clinical Trials. In biomedical research it has been seen that researcher frequently use t-test and ANOVA to compare means between the groups of interest irrespective of the nature of the data. In Clinical Trials we record the data on the patients more than two times. In such a situation using the standard ANOVA procedures is not appropriate as it does not consider dependencies between observations within subjects in the analysis. To deal with such types of study data Repeated Measure ANOVA should be used. In this article the application of One-way Repeated Measure ANOVA has been demonstrated by using the software SPSS (Statistical Package for Social Sciences) Version 15.0 on the data collected at four time points 0 day, 15(th) day, 30(th) day, and 45(th) day of multicentre clinical trial conducted on Pandu Roga (~Iron Deficiency Anemia) with an Ayurvedic formulation Dhatrilauha. PMID- 23930037 TI - Reliability studies of diagnostic methods in Indian traditional Ayurveda medicine: An overview. AB - Recently, a need to develop supportive new scientific evidence for contemporary Ayurveda has emerged. One of the research objectives is an assessment of the reliability of diagnoses and treatment. Reliability is a quantitative measure of consistency. It is a crucial issue in classification (such as prakriti classification), method development (pulse diagnosis), quality assurance for diagnosis and treatment and in the conduct of clinical studies. Several reliability studies are conducted in western medicine. The investigation of the reliability of traditional Chinese, Japanese and Sasang medicine diagnoses is in the formative stage. However, reliability studies in Ayurveda are in the preliminary stage. In this paper, examples are provided to illustrate relevant concepts of reliability studies of diagnostic methods and their implication in practice, education, and training. An introduction to reliability estimates and different study designs and statistical analysis is given for future studies in Ayurveda. PMID- 23930039 TI - Effective detoxification of Abrus precatorius Linn. seeds by Shodhana. AB - Ayurveda, which is one of the traditional systems of medicine of India, reports the seeds of Abrus precatorius (family: Fabaceae) can be used therapeutically after shodhana process, which removes the toxin. The main objective was to scientifically study the shodhana process by evaluating the safety and efficacy of A. precatorius seeds. Aqueous extract (A1) and detoxified extract (A2) of the seeds were prepared by a process described in Ayurvedic pharmacopoeia. Thin-layer chromatography (TLC) method was developed for the two extracts using different solvent systems. Identical spots were obtained in A1 with reference values (Rf) 0.27, 0.47, and 0.79, whereas A2 showed the absence of spot having Rf value 0.47, which could possibly be the toxin found in the intact seed. A1 and A2 were evaluated for their safety and efficacy. The acute toxicity studies for A1 and A2 revealed that A1 was toxic, whereas A2 was safe at the dose of 2 g/kg. Absence of toxicity in the detoxified extract suggests removal of toxic material in processed seeds. The results obtained for hair growth activity of both the extracts were comparable to that of the standard. However, A2 showed better results in comparison to A1. Thus, the shodhana process described in Ayurveda helps in removing the toxin, while retaining the efficacy at the same time. The statistical analysis was done using one-way analysis of variance. PMID- 23930040 TI - Evaluation of anti-inflammatory potential of the multidrug herbomineral formulation in male Wistar rats against rheumatoid arthritis. AB - BACKGROUND: Immunological and inflammatory mechanisms, which may play a role in a number of disorders like rheumatoid arthritis (RA). Ancient ayurvedic physicians had developed certain dietary and therapeutic measures to arrest or prevent these disorders. OBJECTIVE: Rheuma off gold (RG) is a herbomineral formulation recommended by ayurvedic medical practitioners for treatment of RA. This study was carried out to lend scientific evidence to the efficacy claim for RG in the management of RA in folklore medicine. MATERIALS AND METHODS: Arthritis was induced by complete Freund's adjuvant. Treatment with formulation 100 mg/kg and dexamethasone 2 mg/kg was given to rats intragastrically once a day from day 1 to day 21 and after which estimation of physical, biochemical, and hematological parameters were carried out. RESULTS: Treatment of formulation to adjuvant induced arthritic animal showed statistically significant (P < 0.05) improvement in physical parameters like arthritic index, paw edema, paw thickness as well as reduction of inflammatory markers like C-reactive protein, serum rheumatoid factor, erythrocyte sedimentation rate. The treatment also produced statistically significant (P < 0.05) increase in hemoglobin percent and improvement in splenomegaly and thymus index. In the histopathological examination, ameliorative effect of formulation was observed in hyperplasia of synovium, pannus formation, and destruction of the joint space. CONCLUSION: The results obtained in experiments indicated that the formulation significantly inhibited the adjuvant induced arthritis which was comparable to dexamethasone and had preferable anti inflammatory effect without significant side effect. Thus, the formulation may be a potential preventive or therapeutic candidate for the treatment of chronic inflammation and arthritis. PMID- 23930041 TI - Reproductive effects of lipid soluble components of Syzygium aromaticum flower bud in male mice. AB - BACKGROUND: The flower buds of Syzygium aromaticum (clove) have been used in indigenous medicines for the treatment of male sexual disorders in Indian subcontinent. OBJECTIVE: To evaluate the effect of Syzygium aromaticum flower bud on male reproduction, using Parkes (P) strain mice as animal model. MATERIALS AND METHODS: Mice were orally administered lipid soluble components of Syzygium aromaticum flower bud in doses of 15, 30, and 60 mg/kg body weight for 35 days, and several male reproductive endpoints were evaluated. RESULTS: Treatment with lower dose (15 mg) of Syzygium increased the motility of sperm and stimulated the secretory activities of epididymis and seminal vesicle, while higher doses (30 and 60 mg) had adverse effects on sperm dynamics of cauda epididymidis and on the secretory activities of epididymis and seminal vesicle. Libido was not affected in treated males; however, a significant decrease in litter in females sired by males treated with higher doses of Syzygium was recorded. CONCLUSION: Treatment with Syzygium aromaticum flower bud causes dose-dependent biphasic effect on male reproductive indices in P mice; lower dose of Syzygium appears stimulatory, while the higher doses have adverse effect on male reproduction. The results suggest that the lower dose of Syzygium may have androgenic effect, but further studies are needed to support this contention. PMID- 23930042 TI - Antidiabetic and antihyperlipidemic activity of hydroalcoholic extract of Withania coagulans Dunal dried fruit in experimental rat models. AB - OBJECTIVE: Evaluation of antidiabetic potential of the hydroalcoholic extract of Withania coagulans Dunal dried fruit (WCDF) alone and in combination with glipizide, in streptozotocin-induced diabetes, and evaluation of possible antihyperlipidemic activity of the same extract in high-cholesterol diet-induced hyperlipidemia, in albino rats. MATERIALS AND METHODS: Experimental diabetes was induced in 30 albino rats with intraperitoneal injection of streptozotocin (55 mg/kg). The rats were divided into five groups receiving the following treatments orally for 4 weeks: Vehicle, glipizide (2.5 mg/kg), WCDF extract (1000 mg/kg), WCDF extract (1000 mg/kg) plus glipizide (1 mg/kg) and WCDF extract (1000 mg/kg) plus glipizide (2.5 mg/kg). Fasting and postprandial blood glucose levels were measured every week for 4 weeks. Endocrine pancreas histopathology was done at the end. In a separate set of experiment, five groups of six albino rats each, received orally for 4 weeks, vehicle, cholesterol (25 mg/kg/day), cholesterol (25 mg/kg/day) plus atorvastatin (7.2 mg/kg/day), cholesterol (25 mg/kg/day) plus WCDF extract (1000 mg/kg/day) and no treatment, respectively. Estimation of serum lipid profile and liver histopathology was done at the end of 4 weeks. STATISTICAL ANALYSIS: Between-group and within-group comparisons were respectively done by analysis of variance (ANOVA) and repeated measures ANOVA, followed by post hoc Tukey's test, with a significance level of P < 0.05. RESULTS AND CONCLUSIONS: The 4-week treatment with WCDF extract significantly reversed hyperglycemia in streptozotocin-induced diabetes that was comparable to glipizide. When combined with glipizide (2.5 mg/kg), WCDF extract produced a synergistic antihyperglycemic effect as well as improvement in pancreatic histopathology. Moreover, hydroalcoholic extract of WCDF was effective and comparable to atorvastatin in controlling the high-cholesterol diet-induced hyperlipidemia in rats. PMID- 23930043 TI - Trividha Snehapaka of Panchagavya Ghrita: A critical comparative evaluation. AB - BACKGORUND: The three stages of Snehapaka formulations namely Mridu, Madhyama and Khara Paka have been characteristically advocated for different routes of administration-Nasya, Pana/Basti and Abhyanga, respectively. Guidelines or established method for post-formulation characterization for the same is hardly available. OBJECTIVE: The present communication is the comparative study of Mridu, Madhyama and Khara Paka of Panchagavya ghrita (PGG). MATERIALS AND METHODS: Laboratory prepared samples of PGG following classical method were analyzed for different physicochemical, spectroscopic, chromatographic parameters, and antioxidant activity. RESULTS: No significant difference was found among Mridu, Madhyama and Khara Paka in physicochemical parameters as well as chromatographic profiles. The ratio of absorbance at 240 and 294 nm showed steady increase from Mridu to Madhyama to Khara Paka in the ultraviolet (UV) visible spectra of unsaponifiable matter. The high performance thin layer chromatography (HPTLC)-2,2 Diphenyl-1-picryl hydrazil (DPPH) bioautography assay revealed presence of two antioxidant compounds in low concentration in all the samples. This was further supported by estimation of total reducing power and DPPH assay. No significant difference was found among the three samples. CONCLUSION: Comparison of various physicochemical parameters, chromatographic profiles, and in vitro antioxidant activity determination is of little help in establishing any significant difference among the samples. However, spectrophotometric analysis of unsaponifiable matter reveals some encouraging characteristic findings which will be useful in establishing difference among the three stages of processing of PGG as well as Snehapaka in general. PMID- 23930044 TI - Management of postaxial polydactyly by "Ksharsutra": A minimally invasive Ayurvedic parasurgical procedure. AB - Polydactyly is a most common congenital hand defects in which the hand has one or more extra fingers, commonly seen postaxial, that is, on the small finger side. It is usually treated by surgically removing the extra finger typically, when the child is between 1 and 2 years old. Prognosis after removal of extra digit is good if it occurs in isolation though not devoid of complications like scar formation, stiffness, instability, and late deformity which may need additional reconstructive surgery to recover full function and improve the hand's appearance. I have used "Ksharsutra," an Ayurvedic-medicated thread coated with herbal alkaline drugs having simultaneous cutting and healing property, to remove extra finger in a child, whose parents were not willing to undergo surgery and asked for alternative treatment. "Ksahrsutra ligation" showed excellent result in postaxial polydactyly. The extra finger started necrosing within 24 hours and sloughed out in just 9 days with minimal scar formation. After observing the prognosis, I believe that more cases should be done to establish and promote this unique parasurgical procedure, "Ksharsutra" in the management of polydactyly. PMID- 23930045 TI - Linking Ayurveda and Western medicine by integrative analysis. AB - In this article, we discuss our recent work in elucidating the mode-of-action of compounds used in traditional medicine including Ayurvedic medicine. Using computational ('in silico') approach, we predict potential targets for Ayurvedic anti-cancer compounds, obtained from the Indian Plant Anticancer Database given its chemical structure. In our analysis, we observed that: (i) the targets predicted can be connected to cancer pathogenesis i.e. steroid-5-alpha reductase 1 and 2 and estrogen receptor-beta, and (ii) predominantly hormone-dependent cancer targets were predicted for the anti-cancer compounds. Through the use of our in silico target prediction, we conclude that understanding how traditional medicine such as Ayurveda work through linking with the 'western' understanding of chemistry and protein targets can be a fruitful avenue in addition to bridging the gap between the two different schools of thinking. Given that compounds used in Ayurveda have been tested and used for thousands of years (although not in the same approach as Western medicine), they can potentially be developed into potential new drugs. Hence, to further advance the case of Ayurvedic medicine, we put forward some suggestions namely: (a) employing and integrating novel analytical methods given the advancements of 'omics' and (b) sharing experimental data and clinical results on studies done on Ayurvedic compounds in an easy and accessible way. PMID- 23930047 TI - Conference report. PMID- 23930046 TI - Patanjali Yogpeeth, Haridwar: An Ayurveda center which includes treatment, research, and education. PMID- 23930048 TI - Future event. PMID- 23930049 TI - Technology in Treatment: Are Adolescents and Counselors Interested in Online Relapse Prevention? AB - BACKGROUND: Approximately 75% of adolescents who receive substance abuse treatment relapse within one year; therefore, it is important to have effective, easily accessible aftercare resources to support them while they are in recovery. OBJECTIVE: The goal of this study was twofold: 1) to find out from adolescents and counselors if an online relapse prevention program was feasible and of interest and 2) to solicit ideas for content for this program regarding peer relationships during early recovery. METHODS: Sixteen counselors were interviewed about peer relationship-related content and features this program should include then asked to sort and rate the responses using an online concept mapping program. The development of an interactive prototype of the proposed program was informed by these results. This prototype was shown to the 16 counselors and 24 adolescents in substance abuse treatment (M age=15.8 years) for feedback. Then the adolescents participated in focus groups in which they discussed their use of technology and peer relationship-related challenges in recovery. RESULTS: The concepts that were rated highest by counselors were Setting Boundaries in Peer Relationships (M = 4.38), How to Follow Through with Decisions (M = 4.23), and Figuring Out What You Really Want (M = 4.18). Pre-established criteria for satisfaction were exceeded with both adolescents (M = 84%) and counselors (M = 86%). In the focus groups, adolescents said that they would be interested in using technology to meet challenges in recovery. CONCLUSIONS: The online relapse prevention program concept has feasibility according to these key stakeholders. PMID- 23930050 TI - The impact of the European financial crisis on clinical research within the European union or "when life gives you lemons, make lemonade". AB - The European Union (EU) and the world are faced with unprecedented economic challenges, which if allowed to persist could threaten its continued existence in its current form as a union. Furthermore, these same financial challenges can easily translate into societal hardship. The biomedical and pharmaceutical industries of the U.S. and Europe have been in the midst of severe financial constraints over the last few years, which will worsen in the coming years. A critical factor is a financial crisis that appears to be spreading like wildfire through Europe, with 3 of its oldest members (Greece, Ireland, Portugal) already having enlisted the aid of the International Monetary Fund (IMF) to avoid bankruptcy, and with the possibility of others to follow (Italy, Spain). Adding to this the increasing cost of introducing new medications and devices, and conducting clinical research, as well as the tightening regulatory pressures and the drying pharmaceutical pipelines, cost cutting pressures are mounting on pharmaceutical industries and the biomedical sector, whether in academia or in industry. This paper will attempt to highlight some of the problems that clinical research in Europe may be facing, as well as discuss some of the potential solutions. Although this will by no means be an exhaustive analysis, the goal is to show that times of financial hardship, such as the current one, may also provide the impetus for constructive change. PMID- 23930051 TI - Recent medical devices for tonsillectomy. AB - The most frequent and probably the earliest described surgical intervention of ENT field is tonsillectomy. Various methods were described and devices were invented up to now in order to increase safety and decrease time consumption and complications. All new created devices promises lower intraoperative blood loss, intraoperative time, postoperative pain and bleeding. But with their widely use it is seen that they cannot fulfill what they promise. Debate also continues as to which technique yields the best outcome. This study reports a summary for common medical devices which were previously used in tonsillectomy. PMID- 23930052 TI - Diagnosis of chronic obstructive pulmonary disease in the primary care setting. AB - Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality with increasing rates during the last decades. Due to the progressive nature of the disease, underestimation of symptoms by the patients, lack of knowledge and underuse of spirometry by the Primary Care providers the disease remains under-diagnosed in about half of the cases. Patients with a smoking history of >=20 pack-years and relevant symptoms (e.g. dyspnea, chronic cough and sputum production) are considered a high risk group. Measurement of spirometric parameters after administration of a short acting bronchodilator confirms the presence of irreversible airflow obstruction and establishes the diagnosis. However in the primary care spirometry is usually not available and differential diagnosis with other obstructive pulmonary diseases (e.g. asthma, bronchiectasis) is not always easy. General Practitioners (GPs) need simple screening tools to decide if a patient belong to a high risk group and pulmonary consultation is necessary. Early and accurate diagnosis of COPD in the primary care setting allowing for a timely and effective management which reduces the rate of decline in lung function improves survival of patients, their quality of life and reduces health-care utilization. The aim of the present review is to provide the existing information about COPD diagnosis and the related problems in the Primary Care. Also we reviewed numerous simple COPD diagnosis questionnaires as well as the use of hand-held flow meters which could be used as effective screening tools. PMID- 23930053 TI - Prognostic analysis of carcinoma of the ampulla of Vater: pancreaticoduodenectomy versus local resection. AB - BACKGROUND AND AIM: Pancreaticoduodenectomy (PD) is considered to be the optimal treatment for carcinoma of the ampulla of Vater, but the trauma caused by PD is often severe and extensive. Local resection (LR) for ampullary tumors has been performed for a century but remains controversial. The use of this procedure for benign conditions is clear, but its place, if any, in the management of ampullary carcinoma is debated. The aim of this study was to investigate the outcomes and analyse the prognostic factors of LR of carcinoma of the ampulla of Vater by comparison with PD. PATIENTS AND METHODS: A retrospective analysis of 71 patients of carcinoma of the ampulla of Vater was conducted at Zhejiang Cancer Hospital from January 1995 to December 2005. We investigated the differences of the baseline characteristics and the intra- and postoperative data of patients who underwent PD and LR. Prognostic factors for recurrence and survival of carcinoma of the ampulla of Vater between PD and LR was also analysed. RESULTS: Among the 71 patients of ampullary carcinoma who underwent surgical resection, a PD was performed in 46 (64.8%) patients while a LR was performed in 25 (35.2%) patients. The 30-day mortality rate associated with PD (6.5%) was not different from that with LR (0%; p=0.547) while the morbidity following PD (30.4%) and LR (8.0%) was statistically different (p=0.031). The complications were also significantly higher in the PD group than the LR group (34.8% vs 6.5%; p=0.013). In a univariate Cox regression analysis of survival, there were significant differences in tumor size (p=0.031), TNM (Tumor Node Metastasis) stage (p=0.000), pT (pathologic Tumor) stage (p=0.010), pN (pathologic Node) stage (p=0.000), differentiation (p=0.026), and surgical margin (p=0.031). Multivariate Cox regression analysis showed that TNM stage (HR=3.640, 95% CI 1.428~9.282; p=0.007), pT stage (HR=3.090, 95% CI 1.230~7.762; p=0.016), and pN stage (HR=4.479, 95% CI 1.524~013.161; p=0.005) remained as independent predictors of survival rates. According to the method of Kaplan-Meier, the five-year survival rate in the PD group was 53.5% and that in the LR group was 48.0%, no significant differences were found between the two groups in overall survival rates (p=0.540). Compared with the PD, the 5-year survival of patients with the TNM stage-III/IV who undergoing LR was statistically lower (11.1% vs 38.1%; p=0.040). As expected, the overall survival were signicant differences between the two groups in pT stage-T3/T4 (47.4% vs 18.2%, p=0.018) and pN stage-N1 (36.8% vs 11.1%, p=0.004), respectively. Tumor recurrence was diagnosed in 10/43 (23.3%) patients after PD and 12/25 (48.0%) patients after LR (p=0.035). Logistic regression analysis of recurrence showed that TNM stage-III/IV (p=0.004), pT stage-T3/T4 (p=0.034), and pN stage-N1 (p=0.007) were associated with a 2.444, 1.943, and 2.111-fold increased risk of recurrence, respectively. CONCLUSIONS: PD is the preferred operation for carcinoma of the ampulla of Vater. LR is less mortal and morbid than PD, which is a suitable treatment in patients with a low risk cancer in stages I/II or pT1/T2 N0 with a maximum diameter of 2 cm or less. TNM stage, pT stage, and pN stage remained as independent predictors of survival rates. PMID- 23930054 TI - Dermoscopic features in the diagnosis of different types of basal cell carcinoma: a prospective analysis. AB - BACKGROUND: There is limited data on dermoscopic features of basal cell carcinomas (BCCs). We evaluated the presence of dermoscopic features in superficial (sBCCs), nodular (nBCCs), pigmented and non-pigmented BCCs in order to evaluate the role of dermoscopy in the diagnosis of different subtypes of BCCs. PATIENTS AND METHODS: We conducted a retrospective study to evaluate the presence of dermoscopic features in superficial, nodular, pigmented and non - pigmented BCCs. One hundred thirty eight lesions (42 superficial, 96 nodular, 102 pigmented and 36 non-pigmented) were assessed by dermoscopy. RESULTS: The most significant features in all categories, were a scattered vascular pattern, featureless areas, atypical red vessels, arborizing vessels, comma vessels, background of white-red structureless areas and telangiectasias. Haemorrhage ulceration, hypopigmented areas and blue-grey ovoid nests were all more likely to be observed in sBCCs, than in nBCCs (p < 0.0001). Arborizing and atypical red vessels in addition to featureless areas, were more frequent in nodular than in sBCCs (p < 0.0001). Telangectasias, white-red structureless areas, red dots and red globules were more common in non- pigmented than in pigmented BCCs (p <0.0001). In addition, a significant difference of arborizing vessels was detected in pigmented lesions in comparison to non-pigmented (p<0.0001). CONCLUSIONS: There is limited data on dermoscopic features of basal cell carcinomas (BCCs). We evaluated the presence of dermoscopic features in superficial (sBCCs), nodular (nBCCs), pigmented and non-pigmented BCCs in order to evaluate the role of dermoscopy in the diagnosis of different subtypes of BCCs. PMID- 23930055 TI - Gender and morphogenetic variability of patients with spina bifida occulta and spina bifida aperta: prospective population-genetic study. AB - BACKGROUND: Aim of our study was to evaluate degree of genetic homozygosity in male and female gender of spina bifida (SB) occulta and SB aperta patients. PATIENTS AND METHODS: We evaluated 95 patients with SB occulta and 51 with SB aperta. Degree of genetic homozygosity was evaluated by direct observation of 15 homozygously recessive characteristics (HRC) by HRC-test separately for SB occulta and SB aperta participants. Additionally 370 individuals without SB from Serbia were randomly selected and evaluated as control group. Male and female gender was separately evaluated for assessing degree of genetic homozygosity. RESULTS: There was no significant difference in mean values of HRC between male and female gender in control group (male gender -3.9+/-1.2, female gender -4.0+/ 1.4, z=0.39; p>0.05), SB occulta (male gender -4.1+/-1.5, female gender -4.7+/ 1.4, z=1.87, p>0.05) and SB aperta patients (male gender -4.3+/-1.6, female gender -4.5+/-1.4, z=0.66, p>0.05), while there was significantly increased recessive homozygosity in female SB occulta group versus control female group (Females: SB occulta -4.7+/-1.4, Control group -4.0+/-1.4, z=3.16, p<0.01) and female SB aperta group versus control female group (Females: SB aperta -4.5+/ 1.4, Control group -4.0+/-1.4, z=2.05, p<0.05). CONCLUSION: There is increased recessive homozygosity in tested female SB occulta and female SB aperta individuals versus SB male participants and significantly increased recessive homozygosity in female groups of SB patients versus control female group. These findings could lead to the possible assumption that different genes in different degree might be expressed in SB occulta and SB aperta patients. PMID- 23930056 TI - Radioiodine-induced kidney damage and protective effect of amifostine: An experimental study. AB - BACKGROUND: Ablative radioiodine-131 ((131)I) therapy is used in the standart treatment procedure of thyroid carcinoma and procedures using (131)I represent the majority of Nuclear Medicine therapeutic procedures. The principal route of (131)I excretion after the administration of (131)I is the urine. Amifostine is an organic thiophosphate ester prodrug and the kidney concentrations of the active metabolite WR-1065 are about 100 times higher than tumour concentrations. To our knowledge, there is no published data in literature presenting acute effect of radioiodine on renal tissue during high dose I-131 radioiodine treatment (RIT). Additionally, it is not known whether amifostine takes role in this process. MATERIALS AND METHODS: In this study, 50 healthy female Wistar albino rats, weighing 200-250 g and averaging 16 weeks old were utilised. The rats were randomly divided into ten groups. 1- Sham group (n=5), 2- Amifostine group (n=5): rats pretreated with 1 cc amifostine (200 mg/kg) by intraperitoneal injection, 3- Radioactive iodine first day group (RI-1) (n=5): rats treated with 1 cc oral 185 MBq radioactive iodine-131 and sacrification performed after 1(st) day, 4- Amifostine + Radioactive iodine first day group (A+RI-1) (n=5): rats pretreated with amifostine (200 mg/kg) by intraperitoneal injection and rats treated with 5mCi radioactive iodine-131 and sacrification performed after 1(st) day. 5- Radioactive iodine third day group (RI-3) (n=5), 6- Amifostine + Radioactive iodine third day group (A+RI-3) (n=5), 7- Radioactive iodine fifth day group (RI-5) (n=5), 8- Amifostine + Radioactive iodine fifth day group (A+RI 5) (n=5), 9- Radioactive iodine seventh day group (RI-7) (n=5) and 10- Amifostine + Radioactive iodine seventh day group (A+RI-7) (n=5). The renal cast formation and tubular damage are evaluated by a pathologist in a blinded manner. RESULTS: Ablative radioiodine-131 therapy induced renal tubular damage was significantly higher in the radioactive iodine fifth day group (RI-5) when compared with the Sham group (p=0.01) and Amifostine group (p=0.01). CONCLUSIONS: A marked ablative radioiodine-131 induced renal toxicity was seen at fifth day of the therapy after a single RIT application and the main histopathological change was tubular damage. Amifostine have protective effects against ablative radioiodine-131 therapy and this effect is significant at fifth day of the therapy. PMID- 23930057 TI - Effects of diet and exercise in 337 overweight/obese adults. AB - BACKGROUND AND AIMS: The purpose of the study was to determine for the first time the effects of a weight loss diet with or without exercise on body fat levels and other anthropometrical characteristics in overweight and obese Cypriot adults. METHODS: Three hundred and thirty seven overweight and obese subjects were assigned randomly to either a diet only (DO) or diet and exercise group (DE) for an 18-week period. Both groups received an energy reduced diet of 1500 +/- 200 Kcal. Furthermore, the DE group received specific dietary and activity guidelines involving a moderate intensity activity level included any of the following 3 criteria of ACSM guidelines and behavior modification consultation. All data analyses were performed by using the SPSS(v. 16.5) and the level of statistical significance was set at p < 0.05. RESULTS: No significant differences were observed in both DO and DE groups during baseline period. During the intervention period weight, BMI and WC decreased significantly in DO group (p<0.001). In addition, body fat levels were found to be significantly reduced (p<0.001) in the DE group compared with the DO group. In multiple regression analysis Body fat levels were independently associated with weight (Beta: 0.569, 95%CI: 0.157 1.296, P<0.001) BMI (Beta: 0.295, 95%CI:0.088-1.214, P<0.01) and WC (Beta:0.206, 95%CI:0.095-0.954, P<0.001) after adjustment of age and gender. CONCLUSIONS: Despite the reduced effects of diet alone on body weight, BMI and WC, combining a reduced diet with exercise improves also BF levels which may have important benefits on several diseases later in life. PMID- 23930058 TI - Stereotactic coordinates for intracerebroventricular infusion after permanent focal cerebral ischemia in Wistar rats. AB - BACKGROUND: Intracerebroventricular (ICV) experimental route is highly promising due to immediate approach of a "therapy" to the cerebrospinal compartment. Ischemic edema causes structural dislocations and stereotaxia alterations after temporary Middle Cerebral Artery Occlusion (t-MCAO), while there is no similar study for intracerebroventricular (ICV) invasion after permanent MCAO (p-MCAO). METHODS: Male Wistar rats were subjected to right p-MCAO and clinically evaluated 6 and 18 hours post-occlusion, using the modified Neurological Stroke Scale (mNSS) and modified Bederson's Scale (mBS). Infarction volume, hemispheric edema, middle line dislocation and stereotaxia of the lateral ventricles were studied at the same time-points. RESULTS: P-MCAO induced mild but significant changes in the stereotaxia of the infarcted (ipsilateral) lateral ventricle on 18- (P<0.05), though not 6-hours (P>0.05) post-occlusion. These changes correlated with the mNSS and mBS scores (P<0.01) and allowed the expression of linear mathematical equations (stereotaxic coordinate = b0 + b1*mNSS; calculated by regression analysis) predicting the new ventricular position in each individual animal. The contralateral ventricular system was structurally unaffected on both time-points. Verification experiments indicated that the new coordinates were necessary on 18 hours post-occlusion for successful ICV invasion in all p-MCAO rats (Number Needed to Treat 2.28), compared to 56.25% success when using the classical coordinates for normal rats. CONCLUSION: P-MCAO causes relatively late but predictable stereotaxia shifts for ICV invasion, which are different compared to t-MCAO. PMID- 23930059 TI - Cancer in elderly: A study of hospital-based cancer registry in the Western Turkey. AB - AIM: The aim of the study is to evaluate the data of cases who were 65 years and older among cancer records from the data of Izmir Cancer Registry (ICR), in Izmir Ataturk Research Training Hospital (IAEAH), according to topography, histology, sex and having multiple tumors and to compare them with the data of cases younger than 65 years. MATERIAL AND METHODS: Twenty thousands eight hundred and thirty (20,830) cases (7148 cases are >=65 years) recorded during the period of 1993 2005 by office of ICR, located in IAEAH, were analyzed. Assessment of data was carried out by SPSS 10.0 for Windows package program. For statistical analysis Pearson's Chi-Square Test and Yates 'corrections were performed. RESULTS: Of 20,830 cases with cancer, recorded in the hospital data-base during 1993-2005, 34.3% were diagnosed at the age of 65 years and older. The most frequent tumor localizations in the cases younger than 65 years were breast, larynx, digestive system, skin and hematopoietic-reticuloendothelial system whereas the tumors in the, skin, digestive system and the urogenital system were more common in cases older than 65 years. When histological diagnoses were taken into consideration, basal cell carcinomas and squamous and transitional cell carcinoma were seen more frequent in the group of cases 65 years or older. The incidence of synchronous and metachronous tumors were not different in the cases younger or older than 65 years. CONCLUSION: There is a strong need to establish a communication between national and international database systems, which would yield an opportunity in the comparison of the incidence of the diseases. PMID- 23930060 TI - Fatty liver disease in an autopsy series of children and adolescents. AB - BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents. Obesity is a major risk factor for NAFLD; however, it has been shown that NAFLD is not rare in non-obese adults. The aim of this study was to determine the prevalence of NAFLD in obese and non obese children and adolescents. METHODS: The medical records of 340 subjects (aged 2-20 years) in whom autopsy was performed were retrospectively reviewed. Of those, 10 subjects were excluded due to insufficient data. The remaining 330 subjects were included in the study, of whom 264 were normal weight and 66 were obese. All liver biopsy sections were evaluated by two pathologists in a blinded fashion. RESULTS: The prevalence of fatty liver was 6% among all the subjects and was higher in the overweight group than in the normal-weight group (10.6% vs 4.9%; p<0.001). The prevalence of NAFLD increased concomitant with age. There was no significant difference between sexes in cases with NAFLD. Simple steatosis was detected in 7 subjects. Steatohepatitis was determined as type 1 in 5 subjects, type 2 in 7 subjects, and as overlap in 1 subject. CONCLUSIONS: This study demonstrated that NAFLD is an important public health problem not only in obese but also in non-obese children and adolescents. This suggests that whereas obesity may be a risk factor, other pathogenic factors may exist that could contribute to the NAFLD. PMID- 23930061 TI - Prolonged lymphopenia following anti-thymocyte globulin induction is associated with decreased long-term graft survival in liver transplant recipients. AB - BACKGROUND AND AIM: Induction with anti-thymocyte globulin (ATG) during solid organ transplantation is associated with an improved clinical course and leads to prolonged lymphopenia. This study aims to investigate whether prolonged lymphopenia, caused by ATG induction, has an impact on patient and graft survival following liver and kidney transplantation. PATIENTS AND METHODS: This was a single-center, retrospective study. A total of 292 liver and 417 kidney transplants were performed with ATG induction (6 mg/kgr, divided into four doses), and the transplant recipients were followed for at least three months. The average lymphocyte count for the first 30 days after the operation was calculated, and the cut-off value for defining lymphopenia was arbitrarily set to <= 500 cells/mm(3). RESULTS: There were 210 liver transplant recipients (71.9%) who achieved prolonged lymphopenia, whereas the remaining 82 recipients (28.1%) did not. The mean survival time of these patient groups was 10.27 and 12.71 years, respectively (p = 0.1217), and the mean graft survival time was 8.98 and 12.25 years, respectively (p = 0.0147). Of the kidney transplant patients, 330 (79.1%) recipients achieved prolonged lymphopenia, whereas the remaining 87 (20.9%) did not. The mean survival time of these patient groups was 13.94 and 14.59 years, respectively, (p = 0.4490), and the mean graft survival time was 11.84 and 11.54 years, respectively (p = 0.7410). CONCLUSION: The efficacy and safety of ATG induction partially depend on decreased total lymphocyte counts. Following ATG induction in liver transplant recipients, a reasonable average lymphocyte count during the first postoperative month would be above 500 cells/mm(3). PMID- 23930062 TI - Pancreatic pseudocyst in a child due to blunt andominal trauma during a football game. AB - Pancreatic pseudocyst in children due to abdominal trauma is a rare entity. We report a 14-year-old boy suffering from acute pancreatitis due to blunt abdominal trauma that occurred during a football game, and resulted in a large pseudocyst formation. The child was treated conservatively for the post traumatic acute pancreatitis for 4 weeks and thereafter he was followed up for another 2 weeks. At the end of the 6 weeks after the first insult, the child underwent an open cystgastrostomy. Postoperative course was uneventful and the child was discharged on the 6(th) postoperative day. PMID- 23930063 TI - Basaloid squamous cell carcinoma of the tonsil. AB - Basaloid squamous cell carcinoma (BSCC) is a rare and aggressive variant of squamous cell carcinoma that mainly arises in the upper aerodigestive tract. The tonsil is a rare site of BSCC development and only fourteen cases have been reported in the international literature. We report here on the case of a 56-year old man who presented with mild dysphagia. Computed tomography and examination of the oropharynx revealed a suspicious-looking, bulky mass on the right tonsil. Histopathological examination confirmed the presence of BSCC. The patient had cervical lymph node metastases and pulmonary metastases and was treated with chemotherapy and concurrent radiation. Despite the metastases the patient is still alive 3 years after the initial diagnosis. PMID- 23930064 TI - Arthroscopic removal of impinging cement after unicompartmental knee arthroplasty. AB - Complications following unicompartmental knee arthroplasty (UKA) include aseptic loosening, polyethylene wear, arthritis progression and periprothetic fractures. We report on a patient with a firmly fixed, sizeable cement extrusion into the posteromedial aspect of the knee after a UKA causing impingement and pain in full extension. Cement extrusion is an extremely rare but potentially disabling complication that may occur despite care to remove all cement following implantation of the prosthesis. Removing a cement fragment, especially when this is firmly fixed to difficult-to-visualise and access parts of the prosthesis, is challenging. We believe the patient we report is the first one where a firmly fixed, sizeable cement extrusion was removed arthroscopically from the posterior aspect of the knee. This was achieved via an anterolateral portal with trans notch view, combined with a posteromedial portal used both for viewing and instrument insertion. Arthroscopic removal of the impinging cement with the technique described above is a safe and effective option for the treatment of this difficult albeit rare problem. PMID- 23930065 TI - A case of an acromegalic patient resistant to the recommended maximum GH receptor antagonist dosage. AB - BACKGROUND: The competitive GH receptor antagonist pegvisomant is reported to normalise IGF-1 levels in up to 97 % of acromegalic patients at a maximum dosage of 40 mg/d. Description of Case: We present an acromegalic patient resistant to the recommended maximum GH receptor antagonist dosage. The 60-year-old male patient presenting with typical clinical signs of acromegaly has underwent multiple transsphenoidal surgeries and pituitary irradiation, while currently available pharmacological therapies for acromegaly have been exhausted. RESULTS: Biochemical control of the disease could only be achieved until uptitration of pegvisomant to 60 mg/d which was tolerated well. CONCLUSIONS: The current treatment algorithm for acromegaly should be modified to treat cases of persistent and uncontrolled disease. PMID- 23930066 TI - Trimethylaminuria (fish malodour syndrome) in chronic renal failure. AB - Trimethylaminuria (fish malodour syndrome) is a rare genetic metabolic disorder presented with a body odour which smells like a decaying fish. This odour is highly objectionable, that can be destructive for the social, and work life of the patient. Trimethylamine is derived from the intestinal bacterial degradation of foods that are rich of choline and carnitine. Trimethylamine is normally oxidised by the liver to odourless trimethylamine N-oxide which is excreted in the urine, so, uremia may worsen the condition. Uremia itself may cause more or less unpleasant odour. Poor uremic control may worsen the odour. We reported this case because Trimethylaminuria is not usually considered in the differential diagnosis of malodour in chronic renal failure and it is the first case that shown the association with Trimethylaminuria and chronic renal failure in the literature. PMID- 23930067 TI - Primary prostatic lymphoma with components of both diffuse large B-cell lymphoma (DLBCL) and MALT lymphoma. AB - Although lymphomas involving the prostate gland are rare, they should always be considered in the differential diagnosis. We report a case of primary prostatic NHL in a 70-year-old man presented with hematuria and urinary obstructive symptoms. Routine laboratory tests were within normal limits and prostate specific antigen (PSA) was 0,01 ng/ml. The patient underwent radical prostatectomy. Histologically, two different coexisting patterns of non-Hodgkin lymphoma, infiltrating the prostatic tissue, were identified. The diagnosis of diffuse large B-cell lymphoma (DLBCL) presenting with an associated low-grade lymphoma of MALT-type was confirmed by immunohistochemistry. The patient received chemotherapy without any complication and has been followed-up for 2 years since surgical resection with no recurrence. The clinicopathologic characteristics of prostatic lymphomas are discussed, while reviewing the current English-language literature. PMID- 23930068 TI - Non catheter-related bacteremia caused by Pseudomonas oryzihabitans in an adolescent with chronic renal failure undergoing peritoneal dialysis. AB - A Pseudomonas oryzihabitans clinical isolate was recovered from a blood sample. The patient, a 14-year-old-adolescent underwent parathyroidectomy due to secondary hyperparathyroidism. The patient had been going peritoneal dialysis because of chronic renal failure. According to the susceptibility testing conducted with phenotypic methods the microorganism was sensitive to the vast majority of the antibiotics. The isolation of this rare species of Pseudomonas combined with the patient's medical history stimulated as to focus on the causes of the bacteremia, which was non catheter-related. PMID- 23930069 TI - Superiorly displaced flap tear of the medial meniscus. PMID- 23930070 TI - Successful surgical management of severe mediastinitis caused by a perforating esophageal foreign body. PMID- 23930071 TI - D-penicillamine induced membranous glomerulonephritis in a child with Wilson's disease. PMID- 23930072 TI - Multifocal cutaneous protothecosis in a patient with myelodysplastic syndrome. PMID- 23930073 TI - Mycobacterium marinum: a potential immunotherapy for Mycobacterium tuberculosis infection. AB - PURPOSE: The aim of the present study was to investigate the immune response induced by Mycobacterium marinum infection in vitro and the potential of M. marinum as an immunotherapy for M. tuberculosis infection. METHODS: The potential human immune response to certain bacillus infections was investigated in an immune cell-bacillus coculture system in vitro. As a potential novel immunotherapy, M. marinum was studied and compared with two other bacilli, Bacillus Calmette-Guerin (BCG) and live attenuated M. tuberculosis. We examined the changes in both the bacilli and immune cells, especially the time course of the viability of mycobacteria in the coculture system and host immune responses including multinuclear giant cell formation by Wright-Giemsa modified staining, macrophage polarization by cell surface antigen expression, and cytokines/chemokine production by both mRNA expression and protein secretion. RESULTS: The M. marinum stimulated coculture group showed more expression of CD209, CD68, CD80, and CD86 than the BCG and M. tuberculosis (an attenuated strain, H37Ra) groups, although the differences were not statistically significant. Moreover, the M. marinum group expressed more interleukin (IL)-1B and IL-12p40 on day 3 (IL-1B: P = 0.003 and 0.004, respectively; IL-12p40: P = 0.001 and 0.011, respectively), a higher level of CXCL10 on day 1 (P = 0.006 and 0.026, respectively), and higher levels of chemokine (C-X-C motif) ligand (CXCL) 8 and chemokine (C motif) ligand (XCL) 1 on day 3 (CXCL8: P = 0.012 and 0.014, respectively; XCL1: P = 0.000 and 0.000, respectively). The M. marinum stimulated coculture group also secreted more tumor necrosis factor (TNF)-alpha, IL-1beta, and IL-10 on day 1 (TNF-alpha: P = 0.000 and 0.000, respectively; IL-1beta: P = 0.000 and 0.000, respectively; IL-10: P = 0.002 and 0.019, respectively) and day 3 (TNF-alpha: P = 0.000 and 0.000, respectively; IL-1beta: P = 0.000 and 0.001, respectively; IL-10: P = 0.000 and 0.000, respectively). In addition, the colony forming units (an index of viability) of M. marinum in the M. marinum stimulated coculture group was significantly less than that of BCG and H37Ra in their corresponding bacillus stimulated groups (P = 0.037 and 0.013, respectively). CONCLUSION: Our results indicated that M. marinum could be a potentially safe and effective immunotherapy. PMID- 23930074 TI - Comparative heart failure profile over a 3-year period in a Romanian general hospital. AB - BACKGROUND: Heart failure (HF) has become an increasingly significant public health problem, associated with repeated hospitalizations, high costs, low quality of life, and decreased survival rate. The progress of the disease may be slowed if treatment is administered in accordance with current guidelines. OBJECTIVES: To compare the clinical profile of HF patients in a Romanian general hospital over a 3-year period. METHODS AND RESULTS: We studied two cohorts of patients admitted in the cardiology department of a rehabilitation hospital with a diagnosis of chronic HF New York Heart Association class II-IV The first, in 2006, included 415 patients, 67.08 +/- 10.59 years; the second, in 2009, included 500 patients, 67.31 +/- 11.27 years. Considering all patients, the left ventricle ejection fraction (LVEF) was not statistically different in the two cohorts. Compared to the 2006 cohort, the 2009 female cohort had higher LVEF (60.49% +/- 13.41% vs 64.42% +/- 13.79%, P < 0.05), while males over 65 years of age had lower LVEF (52.75% +/- 15.02% vs 54.37% +/- 15.23%, P = NS). For females, the probability of having LVEF <45% was higher in 2006 (odds ratio = 1.573). HF with preserved LVEF was more common in females, both in 2006 (78.2% vs 54.2%) and 2009 (87.2% vs 57.3%). In the 2009 cohort, LVEF was higher both in young patients (59.08% +/- 14.22% vs 55.35% +/- 14.92%) and patients >= than 75 years of age (62.28% +/- 13.81% vs 56.79% +/- 14.81%) compared to the 2006 cohort. Ischemic heart disease was the main underlying cause for HF in both cohorts. CONCLUSION: HF appeared to have the same clinical profile over a 3-year period. Females diagnosed with HF showed higher rates of preserved LVEF. PMID- 23930075 TI - Relationship between antibiotic resistance and sickle cell anemia: preliminary evidence from a pediatric carriage study in Ghana. AB - BACKGROUND: Antibiotics are frequently used among people with sickle cell anemia (homozygous SS or HbSS disease), especially for prophylaxis. However, the relationship between antibiotic resistance and people with HbSS disease has not been adequately studied, especially in the developing world. The objectives of the study were (1) to compare antibiotic resistance patterns of nasal Staphylococcus aureus between children with HbSS disease and children without HbSS disease (healthy children) and (2) to evaluate nasopharyngeal carriage of antibiotic-resistant Streptococcus pneumoniae among children with HbSS disease. METHODS: This was a prospective cross-sectional study, and the subjects were children under 12 years old. Nasal swabs were collected from 50 children with HbSS disease and 50 children without HbSS disease. Nasopharyngeal swabs were collected from another group of 92 children with HbSS disease. The nasal and nasopharyngeal swabs were cultured for S. aureus and S. pneumoniae, respectively. Susceptibility testing was carried out on the S. aureus and S. pneumoniae isolates for various antibiotics, including penicillin, ampicillin, cefuroxime, erythromycin, cloxacillin, and cotrimoxazole. RESULTS: The carriage rates of S. aureus among pediatric subjects with HbSS disease and those without HbSS disease were 48% and 50%, respectively (P > 0.05). S. pneumoniae carriage among the pediatric subjects with HbSS disease was 10%. Antibiotic resistance patterns of S. aureus carried by children with HbSS disease and children without HbSS disease were similar, and the S. aureus resistance rates were >40% for the various antibiotics, with the exception of erythromycin and cloxacillin. Low levels of S. pneumoniae resistance (0%-11%) were observed for the various antibiotics tested except cotrimoxazole, which showed an extremely high-percentage resistance (100%). CONCLUSION: Sickling status is not a risk factor for carriage of S. aureus. In this cohort of Ghanaian children with HbSS disease, S. aureus is higher in carriage and more antibiotic-resistant, compared to S. pneumoniae. PMID- 23930076 TI - Role of leukotrienes in exercise-induced bronchoconstriction before and after a pilot rehabilitation training program. AB - BACKGROUND: Whatever the initial stimulus for the exercise-induced bronchoconstriction (EIB) observed in asthmatic patients after exercise, the final effect is release of bronchoactive mediators, especially cysteinyl leukotrienes. Exercise rehabilitation training programs have been reported to protect against EIB. The exact mechanism(s) involved are not well understood. However, this protective effect may be related to adaptation and better coordination during exercise, depletion of cysteinyl leukotrienes, and/or a sluggish cysteinyl leukotriene response to exercise. The aim of the present work was to test the hypothesis that improvement in the incidence and severity of post exercise bronchoconstriction after a rehabilitation training program is related to a change in leukotriene levels in response to exercise. METHODS: Twenty asthmatic children aged 6-12 years and known to develop EIB were enrolled in an exercise training program for 12 weeks. The severity and incidence of EIB before and after training was assessed. Baseline and post-exercise sputum cysteinyl leukotriene levels were assessed before and after the training program. RESULTS: The training program offered significant protection against EIB with a concomitant decrease in sputum cysteinyl leukotriene levels in response to exercise. CONCLUSION: A training program can result in depletion and/or a sluggish cysteinyl leukotriene response to exercise and may be responsible for the protective effect of training programs on EIB. It is recommended to use an exercise rehabilitation training program as a complementary tool in the management of bronchial asthma, especially EIB. PMID- 23930077 TI - The hospital educational environment and performance of residents in the General Medicine In-Training Examination: a multicenter study in Japan. AB - BACKGROUND: It is believed that the type of educational environment in teaching hospitals may affect the performance of medical knowledge base among residents, but this has not yet been proven. OBJECTIVE: We aimed to investigate the association between the hospital educational environment and the performance of the medical knowledge base among resident physicians in Japanese teaching hospitals. METHODS: To assess the knowledge base of medicine, we conducted the General Medicine InTraining Examination (GM-ITE) for second-year residents in the last month of their residency. The items of the exam were developed based on the outcomes designated by the Japanese Ministry of Health, Labor, and Welfare. The educational environment was evaluated using the Postgraduate Hospital Educational Environment Measure (PHEEM) score, which was assessed by a mailed survey 2 years prior to the exam. A mixed-effects linear regression model was employed for the analysis of variables associated with a higher score. RESULTS: Twenty-one teaching hospitals participated in the study and a total of 206 residents (67 women) participated and completed the exam. There were no residents who declined to participate in the exam. The mean GM-ITE score was 58 (standard deviation 8.4). The mixed-effects linear regression analysis showed that a higher PHEEM score was associated with a higher GM-ITE score (P = 0.02). Having a department of general medicine, and hospital location in a provincial community (versus an urban setting), were also shown to have a significant relationship with the higher score (P = 0.03, and P = 0.02, respectively). CONCLUSION: We found that the performance of the medical knowledge base of resident physicians was significantly associated with the educational environment of their hospitals. Improvement of the educational environment in teaching hospitals might be crucial for enhancing the performance of resident physicians in Japan. PMID- 23930078 TI - Use and cardiovascular safety of transdermal and other granisetron preparations in cancer management. AB - 5-HT3 antagonists have been available as oral and intravenous preparations for decades. The availability more recently of transdermal granisetron and the anticipated availability of a subcutaneous granisetron preparation have provided helpful alternatives to patients, and these preparations have been shown to have less potential to prolong QT than other drugs in the class. PMID- 23930079 TI - A proposal for a drug information database and text templates for generating package inserts. AB - To prevent prescription errors caused by information systems, a database to store complete and accurate drug information in a user-friendly format is needed. In previous studies, the primary method for obtaining data stored in a database is to extract drug information from package inserts by employing pattern matching or more sophisticated methods such as text mining. However, it is difficult to obtain a complete database because there is no strict rule concerning expressions used to describe drug information in package inserts. The authors' strategy was to first build a database and then automatically generate package inserts by embedding data in the database using templates. To create this database, the support of pharmaceutical companies to input accurate data is required. It is expected that this system will work, because these companies can earn merit for newly developed drugs to decrease the effort to create package inserts from scratch. This study designed the table schemata for the database and text templates to generate the package inserts. To handle the variety of drug-specific information in the package inserts, this information in drug composition descriptions was replaced with labels and the replacement descriptions utilizing cluster analysis were analyzed. To improve the method by which frequently repeated ingredient information and/or supplementary information are stored, the method was modified by introducing repeat tags in the templates to indicate repetition and improving the insertion of data into the database. The validity of this method was confirmed by inputting the drug information described in existing package inserts and checking that the method could regenerate the descriptions in the original package insert. In future research, the table schemata and text templates will be extended to regenerate other information in the package inserts. PMID- 23930080 TI - Pediatric palliative care for youth with HIV/AIDS: systematic review of the literature. AB - Improvement in treatment has led to decreased death in youth with human immunodeficiency virus (HIV) in developed countries. Despite this, youth with HIV are still at risk for increased mortality and morbidity compared with their uninfected counterparts. In developing countries, high numbers of youth die from acquired immune deficiency syndrome (AIDS)-related illnesses due to lack of access to consistent antiretroviral treatment. As a result, pediatric palliative care is a relevant topic for those providing care to youth with HIV. A systematic review was conducted to gather information regarding the status of the literature related to pediatric palliative care and medical decision-making for youth with HIV. The relevant literature published between January 2002 and June 2012 was identified through searches conducted using PubMed, CINAHL, Scopus, and PSYCInfo databases and a series of key words. Articles were reviewed by thematic analysis using the pillars of palliative care set out by the National Consensus Project. Twenty-one articles were retained after review and are summarized by theme. In general, few empirically based studies evaluating palliative care and medical decision-making in youth with HIV were identified. Articles identified focused primarily on physical aspects of care, with less attention paid to psychological, social, ethical, and cultural aspects of care. We recommend that future research focuses on broadening the evaluation of pediatric palliative care among youth with HIV by directly evaluating the psychological, social, ethical, and cultural aspects of care and investigating the needs of all involved stakeholders. PMID- 23930081 TI - What do foreign neighbors say about the mental lexicon? AB - A corpus analysis of phonological word-forms shows that English words have few phonological neighbors that are Spanish words. Concomitantly, Spanish words have few phonological neighbors that are English words. These observations appear to undermine certain accounts of bilingual language processing, and have significant implications for the processing and representation of word-forms in bilinguals. PMID- 23930083 TI - Journal of the Medical Library Association readership survey. PMID- 23930082 TI - Synthesis of N6 ,N6-Dialkyl Adenine Nucleosides With In Situ Formed Hexaalkylphosphorus Triamides. AB - Reactions between secondary amines and phosphorus trichloride (PCl3) leads to the formation of the corresponding tris(dialkylamino)phosphines or hexaalkylphosphorus triamides [HAPT: (R2N)3P]. Reaction of silyl-protected 2' deoxyinosine and acetyl-protected inosine with the in situ formed HAPT and iodine (I2) leads to the formation of N6,N6-dialkyl adenosine and 2'-deoxyadenosine. In some cases the stoichiometry of the amine is important as also the use of a tertiary amine base. The effect of amine stoichiometry on the reaction of HAPT with I2 has been studied by 31P{1H} NMR. PMID- 23930084 TI - Creating brand love for libraries: can we be a kind of paradise. PMID- 23930085 TI - Dixie A. Jones, AHIP Medical Library Association President, 2013-2014. PMID- 23930086 TI - Increasing the efficiency of medical research article searching for the public and experts by "shepardizing": a lesson from legal research databases. PMID- 23930087 TI - Spaces that support redefined roles of academic health sciences librarians. PMID- 23930088 TI - The effect of a clinical medical librarian on in-patient care outcomes. AB - OBJECTIVE: The research sought to determine the effect of a clinical medical librarian (CML) on outcomes of in-patients on the internal medicine service. METHODS: A prospective study was performed with two internal medicine in-patient teams. Team 1 included a CML who accompanied the team on daily rounds. The CML answered questions posed at the point of care immediately or in emails post rounds. Patients on Team 2, which did not include a CML, as well as patients who did not require consultation by the CML on Team 1, served as the control population. Numerous clinical and library metrics were gathered on each question. RESULTS: Patients on Team 1 who required an answer to a clinical question were more ill and had a longer length of stay, higher costs, and higher readmission rates compared to those in the control group. Using a matched pair analysis, we showed no difference in clinical outcomes between the intervention group and the control group. CONCLUSIONS: This study is the largest attempt to prospectively measure changes in patient outcomes when physicians were accompanied by a CML on rounds. This approach may serve as a model for further studies to define when and how CMLs are most effective. PMID- 23930089 TI - Making the Critical Appraisal for Summaries of Evidence (CASE) for evidence-based medicine (EBM): critical appraisal of summaries of evidence. AB - OBJECTIVES: Standards for evaluating evidence-based medicine (EBM) point-of-care (POC) summaries of research are lacking. The authors developed a "Critical Appraisal for Summaries of Evidence" (CASE) worksheet to help assess the evidence in these tools. The authors then evaluated the reliability of the worksheet. METHODS: The CASE worksheet was developed with 10 questions covering specificity, authorship, reviewers, methods, grading, clarity, citations, currency, bias, and relevancy. Two reviewers independently assessed a random selection of 384 EBM POC summaries using the worksheet. The responses of the raters were then compared using a kappa score. RESULTS: The kappa statistic demonstrated an overall moderate agreement (kappa = 0.44) between the reviewers using the CASE worksheet for the 384 summaries. The 3 categories of evaluation questions in which the reviewers disagreed most often were citations (kappa = 0), bias (kappa = 0.11), and currency (kappa = -0.18). CONCLUSIONS: The CASE worksheet provided an effective checklist for critically analyzing a treatment summary. While the reviewers agreed on worksheet responses for most questions, variation occurred in how the raters navigated the tool and interpreted some of the questions. Further validation of the form by other groups of users should be investigated. PMID- 23930090 TI - Mapping the literature of health care chaplaincy. AB - OBJECTIVE: This study examined citation patterns and indexing coverage from 2008 to 2010 to determine (1) the core literature of health care chaplaincy and (2) the resources providing optimum coverage for the literature. METHODS: Citations from three source journals (2008-2010 inclusive) were collected and analyzed according to the protocol created for the Mapping the Literature of Allied Health Professions Project. An analysis of indexing coverage by five databases was conducted. A secondary analysis of self-citations by source journals was also conducted. RESULTS: The 3 source journals--Chaplaincy Today, the Journal of Health Care Chaplaincy, and the Journal of Pastoral Care and Counseling--ranked as the top 3 journals in Zone 1 and provided the highest number of most frequently cited articles for health care chaplaincy. Additional journals that appeared in this highly productive zone covered the disciplines of medicine, psychology, nursing, and religion, which were also represented in the Zones 2 and 3 journals. None of the databases provided complete coverage for the core journals; however, MEDLINE provided the most comprehensive coverage for journals in Zones 1 and 2, followed by Academic Search Complete, CINAHL, PsycINFO, and ATLA. Self-citations for the source journals ranged from 9% to 16%. CONCLUSIONS: Health care chaplaincy draws from a diverse body of inter-professional literature. Libraries wishing to provide access to journal literature to support health care chaplaincy at their institutions will be best able to do this by subscribing to databases and journals that cover medical, psychological, nursing, and religion- or spirituality-focused disciplines. PMID- 23930092 TI - The impact of library instruction: do first-year medical students use library resources specifically highlighted during instructional sessions? AB - OBJECTIVES: The research sought to determine if first-year medical students consulted and cited resources specifically highlighted during library instructional sessions. METHODS: Students attended a library resources instructional session. Resources that pertained to the students' assignment were demonstrated and discussed. The students created a report including citations from relevant literature. The citations were analyzed and categorized as: a resource discussed at the instructional session, a resource found on the course LibGuide, a library resource, course material, or some other resource. All citations were subcategorized as print or electronic. RESULTS: Three years (2008 2011) of data analyzing 2,983 citations showed that 49.55% of all citations were from resources discussed during library instructional sessions; 21.86% came from resources with links on the course LibGuide; 77.51% were from library resources; and 90.68% came from electronic resources. CONCLUSION: Students cited resources specifically highlighted during library instructional sessions for their assignments. The percentage of all citations coming from resources highlighted during the instructional sessions or found on the course LibGuide indicates that library instruction had an impact on the students' work. PMID- 23930091 TI - Access of primary and secondary literature by health personnel in an academic health center: implications for open access. AB - PURPOSE: The research sought to ascertain the types and quantity of research evidence accessed by health personnel through PubMed and UpToDate in a university medical center over the course of a year in order to better estimate the impact that increasing levels of open access to biomedical research can be expected to have on clinical practice in the years ahead. METHODS: Web log data were gathered from the 5,042 health personnel working in the Stanford University Hospitals (SUH) during 2011. Data were analyzed for access to the primary literature (abstracts and full-text) through PubMed and UpToDate and to the secondary literature, represented by UpToDate (research summaries), to establish the frequency and nature of literature consulted. RESULTS: In 2011, SUH health personnel accessed 81,851 primary literature articles and visited UpToDate 110,336 times. Almost a third of the articles (24,529) accessed were reviews. Twenty percent (16,187) of the articles viewed were published in 2011. CONCLUSION: When it is available, health personnel in a clinical care setting frequently access the primary literature. While further studies are needed, this preliminary finding speaks to the value of the National Institutes of Health public access policy and the need for medical librarians and educators to prepare health personnel for increasing public access to medical research. PMID- 23930093 TI - Are proposals by politicians for health care reform based on evidence? PMID- 23930094 TI - Implementing a tablet circulation program on a shoestring. PMID- 23930095 TI - Collaborating to develop and test an enhanced text messaging system to encourage health information seeking. PMID- 23930096 TI - Using library search service metrics to demonstrate library value and manage workload. PMID- 23930097 TI - A SPECIAL MEETING REVIEW EDITION: Advances in the Treatment of Hepatitis C Virus Infection From EASL 2013: The 48th Annual Meeting of the European Association for the Study of the LiverApril 24-28, 2013 * Amsterdam, The NetherlandsSpecial Reporting on:* Simeprevir Plus Peginterferon/Ribavirin Is Associated with a High SVR12 Rate in Treatment-Naive Patients with Genotype 1 Hepatitis C Virus Infection* Addition of Simeprevir to Peginterferon/Ribavirin Is Associated with Faster Resolution of Fatigue in Treatment-Naive Patients* Sofosbuvir Plus Ribavirin Demonstrates Significant Efficacy in Multiple HCV Genotype 2/3 Populations* Daclatasvir Plus Sofosbuvir with or without Ribavirin Yields 100% SVR24 Rate in Genotype 1 Patients Who Fail Telaprevir or Boceprevir* Addition of TG4040 Vaccine to Peginterferon/Ribavirin Increases Sustained Virologic Response Rate at 24 Weeks in Genotype 1 Hepatitis C InfectionPLUS Meeting Abstract Summaries With Expert Commentary by: Ira M. Jacobson, MDJoan Sanford I. Weill Medical College at Cornell UniversityNew York, New York. PMID- 23930098 TI - Extreme sensitivity and the practical implications of risk assessment thresholds. AB - Traditional risk-assessment theory assumes the existence of a threshold for non cancer health effects. However, a recent trend in environmental regulation rejects this assumption in favor of non-threshold linearity for these endpoints. This trend is driven largely by two related concepts: (1) a theoretical assumption of wide-ranging human sensitivity, and (2) inability to detect thresholds in epidemiologic models. Wide-ranging sensitivity assumes a subpopulation with extreme background vulnerability, so that even trivial environmental exposures are hazardous to someone somewhere. We use examples from the real world of clinical medicine to show that this theoretical assumption is inconsistent with the biology of mammalian systems and the realities of patient care. Using examples from particulate-matter air-pollution research, we further show that failure to reject linearity is usually driven by statistical rather than biological considerations, and that nonlinear/threshold models often have a similar or better fit than their linear counterparts. This evidence suggests the existence of practical, real-world thresholds for most chemical exposures. PMID- 23930099 TI - Insects, insecticides and hormesis: evidence and considerations for study. AB - Insects are ubiquitous, crucial components of almost all terrestrial and fresh water ecosystems. In agricultural settings they are subjected to, intentionally or unintentionally, an array of synthetic pesticides and other chemical stressors. These ecological underpinnings, the amenability of insects to laboratory and field experiments, and our strong knowledgebase in insecticide toxicology, make the insect-insecticide model an excellent one to study many questions surrounding hormesis. Moreover, there is practical importance for agriculture with evidence of pest population growth being accelerated by insecticide hormesis. Nevertheless, insects have been underutilized in studies of hormesis. Where hormesis hypotheses have been tested, results clearly demonstrate stimulatory effects on multiple taxa as measured through several biological endpoints, both at individual and population levels. However, many basic questions are outstanding given the myriad of chemicals, responses, and ecological interactions that are likely to occur. PMID- 23930100 TI - Theoretical and experimental models of hormetic fusion tubulogenesis. AB - Hormetic morphogens are morphogens such as transforming growth factor beta (TGF beta) in mammals and auxin in plants that induce hormetic responses. For example, in vitro, TGF-beta stimulates and inhibits cell proliferation at low and high concentrations respectively. I developed a model of hormetic morphogen gradient control of the morphogenesis of the fusion of bilateral aortic precursors (Anlagen) that form the aorta during development; and validated the model with findings obtained by Daucus Carota fusion experiments. Theoretically, radial concentration gradients of a hormetic morphogen can form hollow (vessels) or solid (Carota) tubular structures. In arteries, blood flow and pressure can shape mural gradients and determine wall curvature and thereby vessel diameter. As Anlagen grow they form a temporary common wall that is subsequently removed, which results in fusion of the Anlagen lumina and an aorta with a lumen diameter that accommodates the combined blood flow to the iliac arteries. Carota seedlings grown close together exhibited proximally fused root cones, serial cross-sections of which exhibited coaxial fusion patterns that closely resembled the predicted vascular fusion patterns, thus validating a role for hormesis and hormetic morphogens in the morphogenesis of the aorta and possibly the morphogenesis of other human midline structures. PMID- 23930101 TI - Computational modeling of cellular effects post-irradiation with low- and high let particles and different absorbed doses. AB - The use of computational methods to improve the understanding of biological responses to various types of radiation is an approach where multiple parameters can be modelled and a variety of data is generated. This study compares cellular effects modelled for low absorbed doses against high absorbed doses. The authors hypothesized that low and high absorbed doses would contribute to cell killing via different mechanisms, potentially impacting on targeted tumour radiotherapy outcomes. Cellular kinetics following irradiation with selective low- and high linear energy transfer (LET) particles were investigated using the Virtual Cell (VC) radiobiology algorithm. Two different cell types were assessed using the VC radiobiology algorithm: human fibroblasts and human crypt cells. The results showed that at lower doses (0.01 to 0.2 Gy), all radiation sources used were equally able to induce cell death (p>0.05, ANOVA). On the other hand, at higher doses (1.0 to 8.0 Gy), the radiation response was LET and dose dependent (p<0.05, ANOVA). The data obtained suggests that the computational methods used might provide some insight into the cellular effects following irradiation. The results also suggest that it may be necessary to re-evaluate cellular radiation-induced effects, particularly at low doses that could affect therapeutic effectiveness. PMID- 23930102 TI - Incorporating Low-dose Epidemiology Data in a Chlorpyrifos Risk Assessment. AB - USEPA assessed whether epidemiology data suggest that fetal or early-life chlorpyrifos exposure causes neurodevelopmental effects and, if so, whether they occur at exposures below those causing the current most sensitive endpoint, 10% inhibition of blood acetylcholinesterase (AChE). We previously conducted a hypothesis-based weight-of-evidence analysis and found that a proposed causal association between chlorpyrifos exposure and neurodevelopmental effects in the absence of AChE inhibition does not have a substantial basis in existing animal or in vitro studies, and there is no plausible basis for invoking such effects in humans at their far lower exposure levels. The epidemiology studies fail to show consistent patterns; the few associations are likely attributable to alternative explanations. Human data are inappropriate for a dose-response assessment because biomarkers were only measured at one time point, may reflect exposure to other pesticides, and many values are at or below limits of quantification. When considered with pharmacokinetic data, however, these biomarkers provide information on exposure levels relative to those in experimental studies and indicate a margin of exposure of at least 1,000. Because animal data take into account the most sensitive lifestages, the use of AChE inhibition as a regulatory endpoint is protective of adverse effects in sensitive populations. PMID- 23930103 TI - Dual Effects of Bilirubin on the Proliferation of Rat Renal NRK52E Cells and ITS Association with Gap Junctions. AB - OBJECTIVE: The effect of bilirubin on renal pathophysiology is controversial. This study aimed to observe the effects of bilirubin on the proliferation of normal rat renal tubular epithelial cell line (NRK52E) and its potential interplay with gap junction function. METHODS: Cultured NRK52E cells, seeded respectively at high- or low- densities, were treated with varying concentrations of bilirubin for 24 hours. Cell injury was assessed by measuring cell viability and proliferation, and gap junction function was assessed by Parachute dye coupling assay. Connexin 43 protein was assessed by Western blotting. RESULTS: At doses from 17.1 to 513MUmol/L, bilirubin dose-dependently enhanced cell viability and colony-formation rates when cells were seeded at either high- or low- densities (all p<0.05 vs. solvent group) accompanied with enhanced intercellular fluorescence transmission and increased Cx43 protein expression in high-density cells. However, the above effects of BR were gradually reversed when its concentration increased from 684 to 1026MUmol/L. In high-density cells, gap junction inhibitor 12-O-tetradecanoylphorbol 13-acetate attenuated bilirubin induced enhancement of colony-formation and fluorescence transmission. However, in the presence of high concentration bilirubin (1026MUmol/L), activation of gap junction with retinoid acid decreased colony-formation rates. CONCLUSION: Bilirubin can confer biphasic effects on renal NRK52E cell proliferation potentially by differentially affecting gap junction functions. PMID- 23930105 TI - Quantitative structure activity relationships (QSAR) for binary mixtures at non equitoxic ratios based on toxic ratios-effects curves. AB - The present study proposed a QSAR model to predict joint effects at non-equitoxic ratios for binary mixtures containing reactive toxicants, cyanogenic compounds and aldehydes. Toxicity of single and binary mixtures was measured by quantifying the decrease in light emission from the Photobacterium phosphoreum for 15 min. The joint effects of binary mixtures (TU sum) can thus be obtained. The results showed that the relationships between toxic ratios of the individual chemicals and their joint effects can be described by normal distribution function. Based on normal distribution equations, the joint effects of binary mixtures at non equitoxic ratios ( [Formula: see text]) can be predicted quantitatively using the joint effects at equitoxic ratios ( [Formula: see text]). Combined with a QSAR model of [Formula: see text]in our previous work, a novel QSAR model can be proposed to predict the joint effects of mixtures at non-equitoxic ratios ( [Formula: see text]). The proposed model has been validated using additional mixtures other than the one used for the development of the model. Predicted and observed results were similar (p>0.05). This study provides an approach to the prediction of joint effects for binary mixtures at non-equitoxic ratios. PMID- 23930104 TI - Hormesis, cell death, and regenerative medicine for neurode-generative diseases. AB - Although the adult human brain has a small number of neural stem cells, they are insufficient to repair the damaged brain to achieve significant functional recovery for neurodegenerative diseases and stroke. Stem cell therapy, by either enhancing endogenous neurogenesis, or transplanting stem cells, has been regarded as a promising solution. However, the harsh environment of the diseased brain posts a severe threat to the survival and correct differentiation of those new stem cells. Hormesis (or preconditioning, stress adaptation) is an adaptation mechanism by which cells or organisms are potentiated to survive an otherwise lethal condition, such as the harsh oxidative stress in the stroke brain. Stem cells treated by low levels of chemical, physical, or pharmacological stimuli have been shown to survive better in the neurodegenerative brain. Thus combining hormesis and stem cell therapy might improve the outcome for treatment of these diseases. In addition, since the cell death patterns and their underlying molecular mechanism may vary in different neurodegenerative diseases, even in different progression stages of the same disease, it is essential to design a suitable and optimum hormetic strategy that is tailored to the individual patient. PMID- 23930106 TI - Effects of Low Concentrations of Rotenone upon Mitohormesis in SH-SY5Y Cells. AB - The mitochondrial toxin rotenone exerts cytotoxicity via overproduction of reactive oxygen species (ROS) and depolarization of the mitochondrial membrane. We investigated the effects of rotenone (12.5, 25, 50, 100 nmol/L) on mitochondrial biogenesis and the potential roles of ROS production in SH-SY5Y cells. Mitochondrial biogenesis was assessed by counting the number of mitochondria, determining protein expression of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC1-alpha) and its regulator, SIRT1, and oxygen consumption. ROS production and levels of reduced glutathione (GSH) and oxidized glutathione (GSSG) were also determined. Compared with controls, rotenone (12.5 nmol/L) significantly increased the quantity of mitochondria and amount of oxygen consumption, whereas rotenone at >12.5 nmol/L decreased the quantity of mitochondria and amount of oxygen consumption. GSH contents and GSH/GSSG were also significantly enhanced by rotenone at 12.5 nmol/L and decreased by rotenone at >12.5 nmol/L. Except for ROS production and SIRT1 protein expression, all concentration-response relationships showed a typical inverted-U shape. ROS production was continually increased in cells treated with rotenone. These data indicate that low concentrations of rotenone can induce mitohormesis, which may be attributed to ROS production. PMID- 23930107 TI - Increased Radioresistance to Lethal Doses of Gamma Rays in Mice and Rats after Exposure to Microwave Radiation Emitted by a GSM Mobile Phone Simulator. AB - The aim of this study was to investigate the effect of pre-irradiation with microwaves on the induction of radioadaptive response. In the 1(st) phase of the study, 110 male mice were divided into 8 groups. The animals in these groups were exposed/sham-exposed to microwave, low dose rate gamma or both for 5 days. On day six, the animals were exposed to a lethal dose (LD). In the 2(nd) phase, 30 male rats were divided into 2 groups of 15 animals. The 1(st) group received microwave exposure. The 2(nd) group (controls) received the same LD but there was no treatment before the LD. On day 5, all animals were whole-body irradiated with the LD. Statistically significant differences between the survival rate of the mice only exposed to lethal dose of gamma radiation before irradiation with a lethal dose of gamma radiation with those of the animals pre-exposed to either microwave (p=0.02), low dose rate gamma (p=0.001) or both of these physical adapting doses (p=0.003) were observed. Likewise, a statistically significant difference between survival rates of the rats in control and test groups was observed. Altogether, these experiments showed that exposure to microwave radiation may induce a significant survival adaptive response. PMID- 23930108 TI - Window theory in non-ionizing radiation-induced adaptive responses. PMID- 23930109 TI - A Microfluidic Passive Pumping Coulter Counter. AB - A microfluidic device using on-chip passive pumping was characterized for use as a particle counter. Flow occurred due to a Young-Laplace pressure gradient between two 1.2 mm diameter inlets and a 4 mm diameter reservoir when 0.5MU L fluid droplets were applied to the inlets using a micropipette. Polystyrene particles (10MUm diameter) were enumerated using the resistive pulse technique. Particle counts using passive pumping were within 13% of counts from a device using syringe pumping. All pumping methods produced particle counts that were within 16% of those obtained with a hemocytometer. The effect of intermediate wash steps on particle counts within the passive pumping device was determined. Zero, one, or two wash droplets were loaded after the first of two sample droplets. No statistical difference was detected in the mean particle counts among the loading patterns (p > 0.05). Hydrodynamic focusing using passive pumping was also demonstrated. PMID- 23930110 TI - Comparing the efficacy of preemptive intravenous paracetamol on the reducing effect of opioid usage in cholecystectomy. AB - BACKGROUND: The purpose of the present study was to determine the post-operative analgesic effects of preemptive intravenous (iv) paracetamol and the amount of reduction in tramadol (Contramal((r))) consumption. MATERIALS AND METHODS: Following local research ethics committee approval, ASAI-II, 300 patients were assigned in a randomized manner into three groups: Group I (preemptive) received iv paracetamol 1 g/100 mL 10 min before skin inscision and 100 mL of saline solution at the end of the operation, Group II (post-operative) received 100 mL of saline solution 10 min before skin inscision and iv paracetamol 1 g/100 mL at the end of the operation and Group III (placebo) received 100 mL of saline solution 10 min before skin insicision and 100 mL of saline solution at the end of the operation as well. The time to first analgesic requirement use and 24 h total analgesic consumption were recorded. Visual analog scale (VAS) pain scores were obtained from all patients at 15, 30, min 1, 2, 4, 6, 8, 12 and 24 h after the end of the operation. RESULTS: Time to first analgesic requirement was significantly longer in Group I and Group II, compared to Group III (P < 0.05). Time to first analgesic requirement was significantly longer in Group I compared to Group II (P < 0.05). Total analgesic consumption and postoperative VAS pain scores recorded were significantly lower in Group I and II, compared to Group III. Total analgesic consumption and postoperative VAS pain scores recorded were significantly lower in Group I compared to Group II (P < 0.05). CONCLUSION: In conclusion, preemptive iv paracetamol provided effective and reliable pain control after cholecystectomy surgeries and reduced post-operative pain scores, the need for and use of supplementary opioids and the time to first request of analgesics. PMID- 23930111 TI - Kidney function in obese adolescents with or without metabolic syndrome in a nationally-representative sample of pediatric population: First report from the Middle East and North Africa: The CASPIAN-III Study: A Case-Control Study. AB - BACKGROUND: Obesity in accordance with metabolic syndrome (MetS) confronts populations at the higher risk of morbidity and mortality of chronic diseases including, chronic kidney diseases (CKD). The renal complication of obesity and MetS has been less debated in young adolescents. The objective of this study was to assess the kidney function in obese adolescents with or without MetS. MATERIALS AND METHODS: The data used in this study were collected as part of a national study entitled Childhood and Adolescence Surveillance and Prevention of Adult Non-communicable disease Study. The present study was conducted on a sub sample of 113 obese adolescents (body mass index >95(th) percentile) aged between 10 years and 16 years selected by convenient sampling from the whole population studied. Anthropometric indexes and blood pressure were examined. A 12-h fasting serum was obtained for each participant to measure blood glucose, lipid profile, quantitative C-reactive protein (hs-CRP), Cystatin-c, urea, and creatinine. Fasting spot urine was collected to determine microalbumin and creatinine. Based on the study findings, participants were assigned into two groups with and without MetS. RESULTS: The mean of microalbuminuria was in similar ranges in two groups and while the mean glomerular filtration rate (GFR) calculated by Bokenkamp's, updated and combined Schwartz's formulas were significantly lower in MetS + obese group in comparison with obese group. The similar result was not achieved by Filler's formula. Among MetS components, waist circumference had a correlation with hs-CRP (P = 0.04; r = 0.15). GFR was calculated based on the Schwartz formula and Cystatin-c formulas had no significant correlation with any MetS components. CONCLUSION: Our findings suggest that MetS can increase the risk of kidney dysfunction in obese adolescents. More studies are suggested in this regard in the pediatric population. PMID- 23930112 TI - Effect of sesame on sperm quality of infertile men. AB - BACKGROUND: High level of semen reactive oxygen species is considered as an important factor in male infertility. Sesame has antioxidant properties, which could be effective on improvement of semen parameters. This study was designed to determine the effects of sesame on sperm quality. MATERIALS AND METHODS: Twenty five infertile men entered this clinical trial. They were treated with a 3-months course of taking 0.5 mg/kg sesame. The pre intervention sperm analysis (sperm count, motile sperm percentage and normal morphology sperm percentage) was compared with post treatment sperm analysis. Based on the post intervention seamen analysis, patients were advised to undergo either IVF or ICSI to assess their fertility status. RESULTS: There was significant improvement in the sperm count (10.56 +/- 5.25 vs. 22.71 +/- 30.14 million per ml) and motility (15.32 +/- 13.58 vs. 23.32 +/- 20.61 percent) after treatment with sesame (P value: 0.04 and <0.0001 respectively), but there was no significant improvement in sperm morphology after the treatment (10.72 +/- 6.66 vs. 13.20 +/- 11.14 percent, P value: 0.10). Three patients (12%) underwent IUI, which resulted in 1 successful pregnancy. Two patients (8%) underwent ICSI, which was not successful; however 2 (8%) patients had spontaneous pregnancy. Fortunately, all pregnancies led to live birth. Except 1 case of diarrhea, no other major side effect was reported. CONCLUSION: Sesame improved sperm count and motility, and can be prescribed as an effective and safe method for male factor infertility. PMID- 23930113 TI - Evaluation of the relation between triceps surae H-reflex, M-response latencies and thigh length in normal population. AB - BACKGROUND: The H-reflex is a useful electrophysiological procedure for evaluating the status of the peripheral nervous system, especially at the proximal segment of the peripheral nerve. The purpose of this study is to investigate the relation between triceps surae H-reflex and M- response latencies and thigh length in normal population, in order to determine if there is any regression equation between them. MATERIALS AND METHODS: After screening 75 volunteers by considering inclusion and exclusion criteria, 72 of them were selected to enroll into our study (34 men and 38 women with the mean age of 36.04 +/- 7.7 years). In all of the subjects H-reflex and M-response latencies were recorded by standard electrophysiological techniques and thigh length was measured. Finally, our data was analyzed for its relations with respect to ages in both sexes by appropriate statistical and mathematical methods. RESULTS: Mean +/- SD for H-reflex latency was 27.94 +/- 1.6 ms. We found a significant correlation between H-reflex latency and M-latency (r = 0.28), no significant correlation was found between H-reflex latency and thigh length (r = -0.051). Finally based on our findings we introduce a new formula in this paper. CONCLUSION: We found a significant correlation among of M-response latency and other variables (H-reflex latency and thigh length). Despite this it was eliminated from our formula. The relationship between H-reflex latency and age was significant. Further studies are required to delineate the clinical usage and interpretation of the formula, which we found in this study. PMID- 23930114 TI - The relation between Vitamin D status with fatigue and depressive symptoms of multiple sclerosis. AB - BACKGROUND: The relation between Vitamin D deficiency with depressive and fatigue symptoms in both Multiple sclerosis (MS) patients and healthy population have been reported. To represent our regional achievement in this field we investigated the relation between Vitamin D status with fatigue and depressive symptoms in MS patients. MATERIALS AND METHODS: In two hundred MS patients, depressive symptoms and fatigue were measured using Beck PC (BDI-PC) and FFS scale, respectively. Venous blood sample was obtained from all participants and serum 25-hydroxy Vitamin D was measured by radioimmunoassay (RIA) method. Mean score of FSS, BDI-PC and EDSS were compared in patients with normal and low level of Vitamin D. The relation between FSS, BDI-PC score, EDSS and low Vitamin D status was determined. RESULTS: There was a moderate significant correlation between MS disability evaluated by EDSS and fatigue (r = 0.37, P < 0.001) and depression (r = 0.26, P < 0.001). The prevalence of low Vitamin D status was 48.5%. Low Vitamin D status was inversely associated with depressive symptoms of patients with MS (P = 0.02 rs = -0.16), but there was not significant correlation between Vitamin D and fatigue symptoms (P = 0.2). CONCLUSION: More interventional studies for determining the role of Vitamin D supplements in this regard is recommended. PMID- 23930115 TI - Perceived stress and self-rated health of Haitian and African Americans with and without Type 2 diabetes. AB - BACKGROUND: Blacks have a higher incidence of diabetes and its related complications. Self-rated health (SRH) and perceived stress indicators are associated with chronic diseases. The aim of this study was to examine the associations between SRH, perceived stress and diabetes status among two Black ethnicities. MATERIALS AND METHODS: The cross-sectional study included 258 Haitian Americans and 249 African Americans with (n = 240) and without type 2 diabetes (n = 267) (n = 507). Recruitment was performed by community outreach. RESULTS: Haitian-Americans were less likely to report 'fair to poor' health as compared to African Americans [OR = 0.58 (95% CI: 0.35, 0.95), P = 0.032]; yet, Haitian Americans had greater perceived stress than African Americans (P = 0.002). Having diabetes was associated with 'fair to poor' SRH [OR = 3.14 (95% CI: 2.09, 4.72), P < 0.001] but not perceived stress (P = 0.072). Haitian Americans (P = 0.023), females (P = 0.003) and those participants having 'poor or fair' SRH (P < 0.001) were positively associated with perceived stress (Nagelkerke R(2) = 0.151). CONCLUSION: Perceived stress associated with 'poor or fair' SRH suggests that screening for perceived stress should be considered part of routine medical care; albeit, further studies are required to confirm our results. The findings support the need for treatment plans that are patient centered and culturally relevant and that address psychosocial issues. PMID- 23930116 TI - Urotensin-II and endothelin-I levels after contrast media administration in patients undergoing percutaneous coronary interventions. AB - BACKGROUND: Contrast induced kidney injury is an acute renal dysfunction that is secondary to the administration of radio contrast media. The purpose of this study was to evaluate the levels of urotensin-II (UT-II) and endothelin-I (ET-I) after contrast media administration in patients undergoing percutaneous coronary interventions. MATERIALS AND METHODS: In this prospective cohort study, we evaluated 78 patients with coronary artery disease who were scheduled for and ultimately underwent percutaneous coronary interventions. As a contrast material, nonionic contrast media was used in various amounts (70-480 mL). Blood and urine samples were obtained to measure U-II, ET-I just before and at the twenty-fourth hour of percutaneous coronary interventions. RESULTS: Compared to baseline, twenty-fourth hour creatinine levels were significantly increased (P < 0.001). The twenty-fourth hour serum and urine levels of both UT-II and ET-I were also significantly increased compared to baseline (P < 0.001 for all) and 24(th) hour serum and urine UT-II (r = 0.322, P = 0.004; r = 0.302, P = 0.007 respectively), ET-I (r = 0.511, P < 0.001; r = 0.266, P = 0.019 respectively) levels were significantly correlated with the amount of contrast media. CONCLUSION: Our study indicates that; increased UT-II and ET-I levels seem to be a consequence of hazardous effects of contrast media on blood vessels and the kidney. PMID- 23930117 TI - The status of lead and cadmium in soils of high prevalenct gastrointestinal cancer region of Isfahan. AB - BACKGROUND: Cadmium and lead compounds are classified as human carcinogens by several regulatory agencies. Twenty five percent of all cancer-related deaths are attributed to gastrointestinal cancers (GI Ca). We investigated the levels of 2 different heavy metals (Cd and Pb) in the soils of the Lenjanat region, Isfahan province, Central Iran where intensive agriculture is surrounded by different industries like steel and cement-making factories and mining and gastrointestinal cancers are very common in this province. MATERIALS AND METHODS: Two hundred topsoil samples (0-20 cm depth) were collected from agricultural and non agricultural soils of the region and were analyzed for heavy metals. The metal contents were determined by flame atomic absorption spectrometry. RESULTS: The findings of this study showed that frequency of gastrointestinal cancers in the study area have been increased in the recent years. Results of soil samples in this region showed that the mean concentration of Pb and Cd were more than 16 and 1 mg kg(-1), respectively. The total Cd concentration in most of the samples exceeded the suggested Swiss thresholds (0.8 mg kg(-1)) but the mean value of Pb concentration in soil was less than the threshold of 50 mg kg(-1) set by Swiss Federal Office of Environmental, Forest and Landscape. Compared to the threshold values for heavy metals (Cd and Pb) in soils, data showed that the studied fields were contaminated especially by Cd. CONCLUSION: High heavy metals content in the soils seems to play an important etiological role in the carcinogenesis. Excessive accumulation of heavy metals in agricultural soils may not only result in soil contamination, but also lead to elevated heavy metal uptake by crops, and thus affect food quality and safety. Thus, analyzing heavy metals content in crops, water and dust could provide us a better insight to solve the problem. PMID- 23930118 TI - Antinociceptive and antitumor activity of novel synthetic mononuclear Ruthenium (II) compounds. AB - BACKGROUND: From the thousands of years, metal compounds have been used in medicine for treatment of various diseases including various types of cancers. Ruthenium was seen as a promising metal due to its similar kinetics to platinum and its lower toxicity. Therefore, we aimed to evaluate the newer mononuclear ruthenium (II) compounds for antinociceptive and antitumor activities. MATERIALS AND METHODS: Ruthenium (II) compounds were evaluated for antinociceptive and antitumor activity using the various in vitro and in vivo models. The compounds were injected to mice at concentrations of 1 and 2 mg kg(-1) intraperitoneally and were screened for antinociceptive activity, and the antiproliferative effect was evaluated against murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa) using MTT assay. RESULTS: The results for antitumor activity clearly indicated that compound R1 was potent cytotoxic agent than R2 with IC50 values ranging from 4-6 MUM for R1, whereas IC50 values for compound R2 ranging from 65-103 MUM. The compounds have shown a significant anti-inflammatory effect in carrageenan and dextran models but do not having the central analgesic activity, this indicating that the antinociceptive activity is related to the peripheral nervous system. The results for 5 Lipoxygenase (5-LOX) activity showed that both R1 and R2 compounds were found to be significant 5-LOX inhibitory activity with IC50 values of 14.35 MUg ml(-1) and 29.24 MUg ml(-1) respectively. CONCLUSION: These findings concluded that the new ruthenium compounds might be the promising antiproliferative agents as these compounds showing significant 5-LOX inhibitory activity and potential agents in the management of pain related disorders. PMID- 23930119 TI - The comparison of retinal blood flow after scleral buckling surgery with or without encircling procedure. AB - AIM: We aimed to compare peak systolic velocity of central retinal artery (PSV.CRA) and peak systolic velocity of ophthalmic artery (PSV.OA) between patients with retinal detachment who were treated with segmental scleral bucking and scleral buckling with encircling procedure. MATERIALS AND METHODS: This study was a descriptive-analytic cross sectional study that was performed in Isfahan university referral centers since April 2010 to April 2011. Of the patients who have undergone scleral buckling surgery, 20 patients belonging to two groups were randomly selected to enroll in the study. Study groups were, patients who have undergone segmental scleral buckling and the other group were patients who have undergone scleral buckling with encircling procedure. Patients were invited to perform color Doppler imaging. PSV-RA and PSV-OA were measured and documented in both operated and unoperated eyes. All of the Doppler's performed at least three months after ophthalmic surgery. RESULTS: We found significant decrease in PSV.CRA among patients in both groups. In patients who had undergone scleral buckling with encircling procedure PSV.CRA was 11.03 +/- 3.04 (cm/sec) and 14.83 +/- 4.80 in operated and unoperated eye respectively (P = 0.03). In other hand, who treated with segmental scleral buckling these parameters were 11.02 +/- 2.48 and 14.45 +/- 4.69 (P = 0.03). PSV.OA did not change significantly in each method. The difference between mean PSV.CRA and PSV.OA in operated eye between two study groups was not significant. CONCLUSION: PSV.CRA reduced significantly in both surgery methods and PSV.OA changes was not significant. However, the mean PSV.CRA and PSV.OA changes did not show statistically significant difference between surgery methods. PMID- 23930120 TI - Serum gastrin 17, pepsinogen I and pepsinogen II in atrophic gastritis patients living in North-East of Iran. AB - BACKGROUND: Gastric carcinoma is the second most common cause of cancer-related death in Iran. It is well-known that atrophic gastritis is a major risk factor for gastric cancer, which leads to variations in the serum levels of gastrin 17 (G-17), pepsinogen I (P-I), and pepsinogen II (P-II). The aim of this study was to investigate the diagnostic accuracy of these serum biomarkers in the early detection of atrophic gastritis. MATERIALS AND METHODS: A total of 132 dyspeptic patients underwent upper endoscopy and biopsies were taken. The biopsy specimens were evaluated as the gold standard according to operative link for gastritis assessment staging system. Serum levels of G-17, P-I, and P-II were investigated using enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) analysis was used to calculate the diagnostic indices and optimal cut-off values using Statistical Package for the Social Sciences SPSS statistical software. RESULTS: A total of 67 men and 65 women were analyzed, among which 48 (36.4%) had atrophic gastritis. The mean age was 45.8 (+/-15.8) years. ROC curve analysis demonstrated that the biomarkers (including pepsinogen I/II [P-I/II] ratio), except for P-I, are diagnostically significant in detecting gastric atrophy. The area under the curve (95% confidence interval [CI]) for G-17, P-I, P-II, and P I/II ratio were 0.65 (0.55-0.76), 0.42 (0.32-0.53), 0.62 (0.52-0.72), and 0.61 (0.50-0.72), respectively. However, the diagnostic indices were low (sensitivity <50%, specificity < 90%). The prevalence of Helicobacter pylori infection was significantly higher in patients with atrophy against those without atrophy (75.0% vs. 57.4%, P value < 0.0001). CONCLUSION: In the studied population, the serum biomarkers of atrophic gastritis are not useful screening tests due to their low sensitivity. PMID- 23930121 TI - Effect of Ramadan fasting on acute upper gastrointestinal bleeding. AB - BACKGROUND: Prolonged fasting may precipitate or exacerbate gastrointestinal complaints. The aim of this study was to evaluate the relation between Ramadan fasting and acute upper gastrointestinal bleeding (AUGIB), and to assess characteristics of those occurred in the holly month. MATERIALS AND METHODS: Retrospective analysis was conducted for all patients, who underwent endoscopy for AUGIB in Ramadan (R) and the month before Ramadan (BR). Epidemiological, clinical and etiological characteristics and outcome of patients having AUGIB were compared between the two periods from 2001 to 2010. RESULTS: Two hundred and ninety-one patients had endoscopy for AUGIB during the two periods study. There was an increasing trend in the overall number of patients in Ramadan period (n = 132, 45.4% versus n = 159, 54.6%), especially with duodenal ulcer (n = 48, 37.2% versus n = 81, 62.8%). The most frequent etiology was peptic ulcer but it was more observed in group R than in group BR (46.2% versus 57.9%, P = 0.04), especially duodenal ulcer (36.4% versus 50.3%, P = 0.01); this finding persisted in multivariable modeling (adjusted odds ratio: 1.67; 95% confidence interval, 1.03-2.69, P = 0.03). In contrast, there was a decreasing trend in rate of variceal bleeding from BR period (26.5%) to R period (18.9%; P = 0.11). Regarding the outcome, there were no significant differences between the two periods of the study: Recurrent bleeding (10.6% versus 7.5%, P = 0.36) and mortality rate (5.3% versus 4.4%, P = 0.7). CONCLUSION: The most frequent etiology of AUGIB was peptic ulcer during Ramadan. However, Ramadan fasting did not influence the outcome of the patients. Prophylactic measures should be taken for people with risk factors for peptic ulcer disease. PMID- 23930122 TI - Serum cryoglobulins and disease activity in systematic lupus erythematosus. AB - BACKGROUND: To determine the prevalence of cryoglobulins in Iranian patients with systemic lupus erythematosus (SLE) and evaluate the correlation of cryoglobulins with disease activity in these patients. MATERIALS AND METHODS: In a cross sectional study, we investigated 80 consecutive women who fulfilled the 1982 revised criteria of the American College of Rheumatology for the classification of SLE. All the patients had undergone a medical interview and general physical examination by a rheumatologist for clinical and serologic characteristics of SLE. For the determination of cryoglobulins, sera were collected by a standard protocol at 37 degrees C, and after incubation at 4 degrees C for seven days, the level of cryoglobulins was estimated for each patient. RESULTS: Cryoglobulins were detected in the sera of 39 (48.8%) patients. All of these patients had cryocrit over 5%. Disease was active in 30 patients [SLEDAI >=6 (DAI: disease activity index)] and inactive in 50 (SLEDAI <6). There was no significant difference between active and inactive patients for the presence of serum cryoglobulins (r = 0.086, P = 0.56). A significant positive correlation was observed between antinuclear antibody (ANA), anti-dsDNA (dsDNA: Double-stranded deoxyribonucleic acid), CH50 (CH50: total hemolytic complement assay), and C reactive protein (CRP) (r = 0.21, P = 0.004, r = 0.65, P = 0.001, r = 0.45, P = 0.023, r = 0.38, P = 0.036, respectively). Hepatitis C virus (HCV) infection was not detected in any of the SLE patients. CONCLUSION: Although the presence of cryoglobulins in the SLE patients correlated with positive anti-ds DNA and low CH50, it could not be predict activity of the disease. PMID- 23930123 TI - Deoxyribonucleic acid damage in Iranian veterans 25 years after wartime exposure to sulfur mustard. AB - BACKGROUND: More than 100,000 Iranian veterans and civilians still suffer from various long-term complications due to their exposure to sulfur mustard (SM) during the Iran-Iraq war in 1983-88. The aim of the study was to investigate DNA damage of SM in veterans who were exposed to SM, 23-27 years prior to this study. MATERIALS AND METHODS: Blood samples were obtained from the veterans and healthy volunteers as negative controls. Lymphocytes were isolated from blood samples and DNA breaks were measured using single-cell microgel electrophoresis technique under alkaline conditions (comet assay). Single cells were analyzed with "Tri Tek Comet Score version 1.5" software and DNA break was measured based on the percentage of tail DNA alone, or in the presence of H2O2 (25 MUM) as a positive control. RESULTS: A total of 25 SM exposed male veterans and 25 male healthy volunteers with similar ages (44.66 +/- 6.2 and 42.12 +/- 5.75 years, respectively) were studied. Percentage of the lymphocyte DNA damage was significantly (P < 0.01) higher in the SM-exposed individuals than in the controls (6.47 +/- 0.52 and 1.31 +/- 0.35, respectively). Percentages of DNA damage in the different age groups of 35-39, 40-44, 45-49, and 50-54 years in SM exposed veterans (5.48 +/- 0.17, 6.7 3 +/- 1.58, 6.42 +/- 0.22, and 7.27 +/- 0.38, respectively) were all significantly (P < 0.05) higher than the controls (1.18 +/- 0.25, 1.53 +/- 0.22, 1.27 +/- 0.20, and 1.42 +/- 0.10, respectively). The lymphocytes incubated with H2O2 had much higher DNA damage as expected. The average of tail DNA is 42.12 +/- 2.75% for control cells + H2O2 and 18.48 +/- 2.14% for patients cells + H2O2; P < 0.001. CONCLUSION: SM exposure of the veterans revealed DNA damage as judged by the comet assay. PMID- 23930124 TI - Student seminar on smoking: A novel way to introduce different perspectives on smoking to medical students. AB - BACKGROUND: The respiratory module at Shifa College of Medicine (SCM) is delivered in third year with emphasis on respiratory pathophysiology and respiratory medicine. Smoking as a topic was introduced to emphasize the preventive aspects of respiratory illnesses. An innovative approach to involve students in their learning was developed. To determine whether this innovation would be well received and effective for students' learning about smoking, we carried out this study. MATERIALS AND METHODS: This is a one group post-test quasi-experiment. Two days were assigned for a smoking seminar. The class of 106 students was divided into 10 batches, and each batch was assigned a theme related to smoking. These themes were developed by the faculty, and each theme was related to a different perspective on smoking. A post-test questionnaire was distributed at the end of the seminar for feedback to see what aspects of students' learning were highlighted and what needed to be improved upon. Questions related to the usefulness of the activity were incorporated into the questionnaire and the students were asked to agree or disagree on a five-point Likert scale. RESULTS: Most (68.3%) students agreed that this activity improved their knowledge regarding smoking, and 54.8% agreed that it also helped in application of this knowledge. Improvement in presentation and counseling skills (59.8%), evidence-based medicine (47.6%), and softer skills, such as teamwork (72%) and creativity (63.4%), were also reported to be enhanced. CONCLUSION: Seminars led by the students have shown to be effective in breaking the monotony and generating an interest of the topic. Such an activity serves as a small step to make our graduates more empathic, humane, competent, and skilful. PMID- 23930125 TI - Diagnostic value of serum adenosine deaminase level in pulmonary tuberculosis. AB - BACKGROUND: In some studies, the level of adenosine deaminase (ADA) in sputum and effusion liquids was used for the diagnosis of tuberculosis (TB). But it is not always possible to access these materials. The goal of this study is to assess the diagnostic value of serum ADA levels in pulmonary TB patients. MATERIALS AND METHODS: In this study, 40 sputum smear-positive TB patients who were hospitalized and 40 non-TB patients who referred for surgeries were selected. A serum sample was collected and serum ADA level was measured by ADA kit. RESULTS: The average (SD) of serum ADA in TB and non-TB patients were 20.88 (+/-5.97) and 10.69 (+/-2.98) U/L, respectively (P value < 0.05). The best cut-off point was 14 U/L. The calculated area under the receiver operating characteristic (ROC) curve was 0.955 (95% CI, 0.914-0.995); sensitivity was 92.7% (95% CI, 84.7-100) and specificity was 88.1% (95% CI, 78.3-97.8) (P < 0.001). CONCLUSION: Serum ADA level may be proposed as a proper index for TB diagnosis. PMID- 23930126 TI - Pulmonary thromboembolism in pregnancy: Diagnostic imaging and related consideration. AB - Pulmonary thromboembolism (PTE) in pregnancy as a common cause of maternal death has been a challenge for both clinicians and radiologists. Choosing the appropriate modality in each case has been under question and there are also related imaging pitfalls and hesitancy about radiation exposure and using contrast media for a pregnant mother. The aim of this article is to review the imaging modalities used to investigate PTE in pregnancy, related pitfalls, and recommendations for optimizing them. PMID- 23930127 TI - Infectious endocardial intracardiac defibrillator lead, infectious pericarditis, and delayed constrictive pericarditis. AB - The usage of Implantable Cardiac Defibrillator (ICD) since 1980s is becoming more popular these days. The rate of both, endocarditis and constrictive pericarditis are low but it still needs attention. We are reporting a rare case of ICD endocarditis as a result of toe infection in a diabetic patient. This was followed by infectious pericarditis after device removal by open heart surgery and then delayed constrictive pericarditis. PMID- 23930128 TI - Osteoid osteoma of distal phalanx: A rare disorder and review of literature. AB - Osteoid osteomata are rarely found in the distal phalanges of the hand. The usual presenting features are chronic pain, nail enlargement and increase in size of the terminal part of the digit. Diagnosis is difficult but surgical excision is effective for treating the patients' pain. We reported this tumor in distal phalanx of the middle finger. PMID- 23930129 TI - Commentary on: Is uric acid an indicator of metabolic syndrome in the first degree relatives of patients with type 2 diabetes? PMID- 23930130 TI - New pathogenic variations of mitochondrial DNA in Alzheimer disease!! PMID- 23930131 TI - Low intensity pulsed ultrasound therapy: A potential adjuvant treatment for osteonecrosis of alveolar bone grafting. PMID- 23930132 TI - Direct medical care costs associated with patients diagnosed with chronic HCV. AB - BACKGROUND: HCV virus (HCV) is a significant global problem with wide-ranging socio-economic impacts. Because of the high morbidity and mortality associated with end-stage liver disease, cirrhosis, and hepatocellular carcinoma (HCC), the economic burden of HCV infection is substantial. OBJECTIVES: This study aimed to estimate the direct medical care costs of chronic HCV infection. PATIENTS AND METHODS: For this cross-sectional study, 365 courses of HCV treatment were extracted from medical records of 284 patients being referred to Tehran HCV clinic, a clinical clinic of Baqiyatallah Research Center for Gastroenterology and Liver diseases, from 2005 to 2010. All the patients had been diagnosed with HCV. Direct medical care costs for each course of HCV treatment have been calculated based on Purchasing Power Parity Dollar (PPP$). RESULTS: Average direct medical costs for the courses treated with conventional interferon plus ribavirin (INF-RBV) were 4,403 PPP$, and 20,010 PPP$ for peg-interferon plus ribavirin (PEG-RBV) courses. There was an increase of the direct costs in both courses of treatment to achieve Sustain Viral Response (SVR). The costs amounted to 10,072 PPP$ in (INF-RBV) treatment and 34,035 PPP$ in (PEG-RBV). The significant difference between the costs of these two courses of treatment is attributable to high cost of Peg-interferon. This indicates that the medication costs are the dominant costs. CONCLUSIONS: According to the results, total direct medical costs for HCV patients in Iran exceeded 12 billion PPP$ in (INF-RBV) treatment and 55 billion PPP$ in (PEG-RBV). PMID- 23930133 TI - The effect of pioglitazone and metformin on liver function tests, insulin resistance, and liver fat content in nonalcoholic Fatty liver disease: a randomized double blinded clinical trial. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of insulin resistance (IR) syndrome. The effect of insulin sensitizers on liver function tests and metabolic indices in NAFLD patients is a matter of debate. OBJECTIVES: The aim of study was to compare the effects of two different insulin sensitizers, pioglitazone, and metformin, on liver function tests (LFT), lipid profile, homeostasis model assessment-IR (HOMA-IR) index, and liver fat content (LFC) in NAFLD patients. MATERIALS AND METHODS: This double blind clinical trial was performed on patients who were referred to a gastroenterology clinic with evidence of fatty liver in ultrasonography. After excluding other causes, participants with persistent elevated alanine aminotransferase (ALT) levels and "NAFLD liver fat score" greater than -0.64 were presumed to have NAFLD and were enrolled. They were randomly assigned to take metformin (1 g/day) or pioglitazone (30 mg/day) for four months. Fasting serum glucose (FSG), ALT, aspartate aminotransferase (AST), alkaline phosphatase (ALP), triglyceride, cholesterol (CHOL), high and low density lipoprotein (HDL, LDL), HOMA-IR, and LFC were checked at the baseline, two and four months post treatment. LFC was measured by a validated formula. RESULTS: Eighty patients (68 males) with mean age of 35.27 (+/- 7.98) were included. After 2 months, LFT was improved significantly in the pioglitazone group and did not change in the metformin group. After four months, both medications significantly decreased serum levels of LFT, FSG, CHOL, LDL, HOMA-IR, and LFC, and increased serum level of HDL. No statistically significant differences were seen between the two treatment groups with regard to the changes of laboratory parameters and LFC from baseline to four months post-treatment. CONCLUSIONS: During the four months, the use of metformin (1 g/day) and pioglitazone (30 mg/day) were safe and might have equally affected LFT, HOMA-IR, lipid profile, and LFC in NAFLD patients. PMID- 23930134 TI - Bacteria-surface interactions. AB - The interaction of bacteria with surfaces has important implications in a range of areas, including bioenergy, biofouling, biofilm formation, and the infection of plants and animals. Many of the interactions of bacteria with surfaces produce changes in the expression of genes that influence cell morphology and behavior, including genes essential for motility and surface attachment. Despite the attention that these phenotypes have garnered, the bacterial systems used for sensing and responding to surfaces are still not well understood. An understanding of these mechanisms will guide the development of new classes of materials that inhibit and promote cell growth, and complement studies of the physiology of bacteria in contact with surfaces. Recent studies from a range of fields in science and engineering are poised to guide future investigations in this area. This review summarizes recent studies on bacteria-surface interactions, discusses mechanisms of surface sensing and consequences of cell attachment, provides an overview of surfaces that have been used in bacterial studies, and highlights unanswered questions in this field. PMID- 23930135 TI - The multi-faceted role of the actin cap in cellular mechanosensation and mechanotransduction. AB - The perinuclear actin cap (or actin cap) is a recently characterized cytoskeletal organelle composed of thick, parallel, and highly contractile acto-myosin filaments that are specifically anchored to the apical surface of the interphase nucleus. The actin cap is present in a wide range of adherent eukaryotic cells, but is disrupted in several human diseases, including laminopathies and cancer. Through its large terminating focal adhesions and anchorage to the nuclear lamina and nuclear envelope through LINC complexes, the perinuclear actin cap plays a critical role both in mechanosensation and mechanotransduction, the ability of cells to sense changes in matrix compliance and to respond to mechanical forces, respectively. PMID- 23930136 TI - Tunable and dynamic soft materials for three-dimensional cell culture. AB - The human body is complex and hierarchically structured, composed of cells residing within the extracellular matrix (ECM) of tissues that are assembled into organs, all working together to complete a given function. One goal of current biomaterials research is to capture some of this complexity outside of the body for understanding the underlying biology of development, repair, and disease and to devise new strategies for regenerative medicine or disease treatment. Polymeric materials have arisen as powerful tools to mimic the native ECM, giving experimenters a way to capture key aspects of the native cellular environment outside of the body. In particular, dynamic materials allow changes in the properties of these ECM mimics during an experiment, affording an additional degree of control for the experimenter. In this tutorial review, the basic cellular processes of cell migration, proliferation, and differentiation will be overviewed to motivate design considerations for polymeric ECM mimics, and examples will be given of how classes of dynamic materials are being used to study each cellular process. PMID- 23930137 TI - The relationship between air pollution and low birth weight: effects by mother's age, infant sex, co-pollutants, and pre-term births. AB - Previously we identified associations between the mother's air pollution exposure and birth weight for births in Connecticut and Massachusetts from 1999-2002. Other studies also found effects, though results are inconsistent. We explored potential uncertainties in earlier work and further explored associations between air pollution and birth weight for PM10, PM2.5, CO, NO2, and SO2. Specifically we investigated: (1) whether infants of younger (<=24 years) and older (>=40 years) mothers are particularly susceptible to air pollution's effects on birth weight; (2) whether the relationship between air pollution and birth weight differed by infant sex; (3) confounding by co-pollutants and differences in pollutants' measurement frequencies; and (4) whether observed associations were influenced by inclusion of pre-term births. Findings did not indicate higher susceptibility to the relationship between air pollution and birth weight based on the mother's age or the infant's sex. Results were robust to exclusion of pre-term infants and co pollutant adjustment, although sample size decreased for some pollutant pairs. These findings provide additional evidence for the relationship between air pollution and birth weight, and do not identify susceptible sub-populations based on infant sex or mother's age. We conclude with discussion of key challenges in research on air pollution and pregnancy outcomes. PMID- 23930138 TI - METABOLIC SPATIAL VARIABILITY IN ELECTRODE-RESPIRING GEOBACTER SULFURREDUCENS BIOFILMS. AB - In this study, we quantified electron transfer rates, depth profiles of electron donor, and biofilm structure of Geobacter sulfurreducens biofilms using an electrochemical-nuclear magnetic resonance microimaging biofilm reactor. Our goal was to determine whether electron donor limitations existed in electron transfer processes of electrode-respiring G. sulfurreducens biofilms. Cells near the top of the biofilms consumed acetate and were metabolically active; however, acetate concentration decreased to below detection within the top 100 microns of the biofilms. Additionally, porosity in the biofilms fell below 10% near the electrode surface, exacerbating exclusion of acetate from the lower regions. The dense biofilm matrix in the acetate-depleted zone acted as an electrical conduit passing electrons generated at the top of the biofilm to the electrode. To verify the distribution of cell metabolic activity, we used uranium as a redox-active probe for localizing electron transfer activity and X-ray absorption spectroscopy to determine the uranium oxidation state. Cells near the top reduced UVI more actively than the cells near the base. High-resolution transmission electron microscopy images showed intact, healthy cells near the top and plasmolyzed cells near the base. Contrary to models proposed in the literature, which hypothesize that cells nearest the electrode surface are the most metabolically active because of a lower electron transfer resistance, our results suggest that electrical resistance through the biofilm does not restrict long-range electron transfer. Cells far from the electrode can respire across metabolically inactive cells, taking advantage of their extracellular infrastructure produced during the initial biofilm formation. PMID- 23930139 TI - Endoplasmic reticulum stress, the unfolded protein response, and gene network modeling in antiestrogen resistant breast cancer. AB - Lack of understanding of endocrine resistance remains one of the major challenges for breast cancer researchers, clinicians, and patients. Current reductionist approaches to understanding the molecular signaling driving resistance have offered mostly incremental progress over the past 10 years. As the field of systems biology has begun to mature, the approaches and network modeling tools being developed and applied therein offer a different way to think about how molecular signaling and the regulation of critical cellular functions are integrated. To gain novel insights, we first describe some of the key challenges facing network modeling of endocrine resistance, many of which arise from the properties of the data spaces being studied. We then use activation of the unfolded protein response (UPR) following induction of endoplasmic reticulum stress in breast cancer cells by antiestrogens, to illustrate our approaches to computational modeling. Activation of UPR is a key determinant of cell fate decision making and regulation of autophagy and apoptosis. These initial studies provide insight into a small subnetwork topology obtained using differential dependency network analysis and focused on the UPR gene XBP1. The XBP1 subnetwork topology incorporates BCAR3, BCL2, BIK, NFkappaB, and other genes as nodes; the connecting edges represent the dependency structures amongst these nodes. As data from ongoing cellular and molecular studies become available, we will build detailed mathematical models of this XBP1-UPR network. PMID- 23930141 TI - Using a Multidisciplinary Approach for a Multi-faceted Public Health Problem. PMID- 23930140 TI - Biological sex and mechanisms of ischemic brain injury. AB - Cerebrovascular disease is a leading cause of death-from-disease and of disability worldwide, affecting some 15 million people. The incidence of stroke or "brain attack" is unlikely to recede for a decade at minimum by most predictions, despite large public health initiatives in stroke prevention. It has been well established that stroke is also one of the most strikingly sex-specific diseases in its epidemiology, and in some cases, in patient outcomes. For example, women sustain lower rates of ischemic stroke relative to men, even beyond their menopausal years. In contrast, outcomes are worse in women in many clinical studies. The biological basis for this sexual dimorphism is a compelling story, and both hormone-dependent and hormone-independent factors are involved, the latter of which is the subject of this brief review. Understanding the molecular and cell-based mechanisms underlying sex differences in ischemic brain injury is an important step toward personalized medicine and effective therapeutic interventions in patients of both sexes. PMID- 23930142 TI - Prevalence of Exposure to Risk Factors for Violence among Young Adults Seen in an Inner-City Emergency Department. AB - INTRODUCTION: To assess the prevalence of risk factors for violent injury among young adults treated at an urban emergency department (ED). METHODS: This study is a cross-sectional analysis of data collected as part of a longitudinal study. Enrollment took place in an urban ED in a Level 1 trauma center, June through December 2010. All patients aged 18-24 years were eligible. Patients were excluded if they were incarcerated, critically ill, or unable to read English. Study participants completed a 10-minute multiple-choice questionnaire using previously validated scales: a) aggression, b) perceived likelihood of violence, c) recent violent behavior, d) peer behavior, and e) community exposure to violence. RESULTS: 403 eligible patients were approached, of whom 365 (90.1%) consented to participate. Average age was 21.1 (95% confidence interval: 20.9, 21.3) years, and participants were 57.2% female, 85.7% African American, and 82.2% were educated at the high school level or beyond. Among study participants, rates of high-risk exposure to individual risk factors ranged from 7.4% (recent violent behavior) to 24.5% (exposure to community violence), with 32.3% of patients showing high exposure to at least one risk factor. When comparing participants by ethnicity, no significant differences were found between White, African-American, and Hispanic participants. Males and females differed significantly only on 1 of the scales - community violence, (20.4% of males vs. 30.3% of females, p= 0.03). Self-reported hostile/aggressive feelings were independently associated with initial presentation for injury-associated complaint after controlling for age, sex, and race (odds ratio 3.48 (1.49-8.13). CONCLUSION: Over 30% of young adults presenting to an urban ED reported high exposure to risk factors for violent injury. The high prevalence of these risk factors among ED patients highlights the potential benefit of a survey instrument to identify youth who might benefit from a targeted, ED-based violence prevention program. PMID- 23930143 TI - Screening for Elder Mistreatment among Older Adults Seeking Legal Assistance Services. AB - INTRODUCTION: The aging population is a rapidly growing demographic in the United States. Isolation, limited autonomy, and declining physical and mental health render many older adults vulnerable to elder mistreatment (EM). The purpose of this study was to assess the prevalence and correlates of EM among a sample of older adults using legal assistance services in Atlanta, Georgia. METHODS: Researchers administered surveys to consenting older adults (aged 60+) in 5 metro Atlanta community centers that hosted legal assistance information sessions as part of the Elderly Legal Assistance Program. The surveys screened for risk factors and prevalence of EM risk using valid and reliable measures and included additional questions regarding demographics characteristics and healthcare use behaviors. RESULTS: Surveys were completed by 112 participants. Findings reveal that 32 (28.6%) respondents met the criteria for elder abuse / neglect risk; 17 (15.2%) respondents met criteria for depression; and 105 (93.7%) had visited a healthcare provider during the past 6 months. CONCLUSION: The rates of EM risk in this sample were higher than those previously reported in research. Findings support continued examination of unique risks that may be present among older adults who may be possibly facing legal issues. Additionally, the reported frequency of healthcare visits among participants reveals a promising opportunity to examine development of a more widespread EM screening approach to be conducted in non-emergency settings. Interdisciplinary collaboration is required to inform screening approaches that account for complexities that EM cases present. PMID- 23930144 TI - Dyadic, Partner, and Social Network Influences on Intimate Partner Violence among Male-Male Couples. AB - INTRODUCTION: Despite a recent focus on intimate partner violence (IPV) among men who have sex with men (MSM), the male-male couple is largely absent from the IPV literature. Specifically, research on dyadic factors shaping IPV in male-male couples is lacking. METHODS: We took a subsample of 403 gay/bisexual men with main partners from a 2011 survey of approximately 1,000 gay and bisexual men from Atlanta. Logistic regression models of recent (<12 month) experience and perpetration of physical and sexual IPV examined dyadic factors, including racial differences, age differences, and social network characteristics of couples as key covariates shaping the reporting of IPV. RESULTS: Findings indicate that men were more likely to report perpetration of physical violence if they were a different race to their main partner, whereas main partner age was associated with decreased reporting of physical violence. Having social networks that contained more gay friends was associated with significant reductions in the reporting of IPV, whereas having social networks comprised of sex partners or closeted gay friends was associated with increased reporting of IPV victimization and perpetration. CONCLUSION: The results point to several unique factors shaping the reporting of IPV within male-male couples and highlight the need for intervention efforts and prevention programs that focus on male couples, a group largely absent from both research and prevention efforts. PMID- 23930145 TI - An examination of bullying in georgia schools: demographic and school climate factors associated with willingness to intervene in bullying situations. AB - INTRODUCTION: Research dedicated to identification of precursors to cases of aggravated bullying in schools has led to enhanced knowledge of risk factors for both victimization and perpetration. However, characteristics among those who are more likely to intervene in such situations are less understood. The purpose of this study is to examine the associations between demographic characteristics, school climate and psychosocial factors, and willingness to intervene in a bullying situation among middle and high school students in Georgia. METHODS: We computed analyses using cross-sectional data from the Georgia Student Health Survey II (GSHS 2006) administered to public school students in grades 6, 8, 10, and 12 (n=175,311). We used logistic regression analyses to determine the demographic, school climate and psychosocial factors associated with a willingness to intervene in a bullying situation. RESULTS: Students who were white and who were girls were most likely to report willingness to intervene in bullying situations. Several school-climate factors, such as feeling safe at school, liking school, feeling successful at school and perceiving clear rules at school, were associated with willingness to intervene, while youth who reported binge drinking were less willing to intervene. CONCLUSION: These findings, while preliminary, indicate that girls, students who are white, and students who experience a relatively positive school climate and adaptive psychosocial factors are more likely to report that they would intervene in bullying situations. These findings may guide how bullying is addressed in schools and underscore the importance of safe school climates. PMID- 23930146 TI - Sexual Violence Perpetration by Adolescents in Dating versus Same-Sex Peer Relationships: Differences in Associated Risk and Protective Factors. AB - INTRODUCTION: Little is known about the risk and protective factors for youth sexual violence (SV) perpetration across different types of relationships. This study examined factors associated with perpetrating SV against a dating partner and a same-sex peer. METHODS: Analyses were based on data from a survey conducted in 2004 with public school boys and girls in grades 7, 9, 11, and 12 (N = 4,131) in a high-risk, urban school district in the United States. SV perpetration was defined broadly to include forcing someone, about the same age and of the same or opposite sex as the respondent, to have sex or to do something sexual that they did not want to do. Analyses examined the associations between risk and protective factors and SV perpetration, adjusting for SV victimization and demographic characteristics. RESULTS: Findings revealed that 2.1% of respondents reported perpetration against a same-sex peer and 3.2% reported perpetration against a date during the past 12 months. Victims of SV for each relationship type were more likely than non-victims to perpetrate SV. A combination of factors across the individual, relationship, and community level were significantly associated with SV perpetration and there were both shared and unique factors across the relationship types. CONCLUSION: Data suggest that programs to prevent SV perpetration for both relationship types should start when students are young, with particular focus on middle school boys. Prevention efforts should have slightly different foci to address these 2 types of SV perpetration. PMID- 23930147 TI - Co-Occurring Physical Fighting and Suicide Attempts among U.S. High School Students: Examining Patterns of Early Alcohol Use Initiation and Current Binge Drinking. AB - INTRODUCTION: A growing body of empirical research documents a significant co occurrence of suicide attempts and interpersonal violence among youth. However, the potential role of early alcohol use initiation and current heavy alcohol use as correlates of this comorbidity has not been examined in a nationally representative sample of high school students. METHODS: We based our analyses on cross-sectional data from the 2009 Youth Risk Behavior Survey, which includes a nationally representative sample (n=16,410) of high school students in grades 9 through 12 in the United States. Multinomial logistic regression analyses were conducted to test the associations between measures of alcohol use (early alcohol use initiation and heavy drinking) and comorbid suicidal and violent behavior while controlling for potential confounders. RESULTS: Among high school students, 3.6% reported comorbid physical fighting and suicide attempt in the past year. Early alcohol use (prior to age 13) and heavy drinking (5 or more drinks in a row) were strongly associated with comorbid reports of physical fighting and suicide attempts (Adj. odds ratio [OR]=3.12; 95% confidence interval [CI]:2.49 3.89) and (Adj. OR=3.45; 95%CI:2.63-4.52). CONCLUSION: These findings underscore the importance of both early alcohol use initiation and heavy drinking as statistically significant correlates of comorbid fighting and suicide attempts among youth. While future research is needed to determine the temporal ordering between problem drinking and violent or suicidal behaviors, existing prevention programs may benefit from including components aimed at reducing and delaying alcohol use. PMID- 23930148 TI - The economic burden of intimate partner violence in ecuador: setting the agenda for future research and violence prevention policies. AB - INTRODUCTION: Intimate partner violence (IPV) is a widespread social structural problem that affects a great proportion of Ecuadorian women. IPV is a sexually, psychologically, or physically coercive act against an adult or adolescent woman by a current or former intimate partner. Not-for-profit groups in Ecuador report that 70% of women experience 1 of the forms of IPV sometime during their lifetime, but population-based surveys suggest that 41% of Ecuadorian women are exposed to emotional violence, 31% physical violence, and 12% sexual violence by their spouse or partner over their lifetime. Despite the high prevalence, the response of the Ecuadorian government has been insufficient to reduce the number of victims and to provide adequate legal and health services for the prevention and treatment of IPV. Given the power of economic data to influence policy making, the goal of this study is to produce the first estimate of the economic impact of IPV in Ecuador and to identify the policy paths in which these estimates would have the greatest impact for Ecuador. METHODS: Using a bottom-up method for estimating the economic burden of IPV and a national prevalence of IPV based on a population-based survey in the 2003-2004 year, the total economic burden is estimated at approximately $109 million adjusted to the 2012 United States (U.S.) currency rate. RESULTS: Based on a prevalence of 255,267 women who were victims of IPV in the 2003-2004 year, the total economic burden is estimated at approximately $109 million adjusted to the 2012 the U.S. currency rate. The largest cost category contributing to the economic burden was the costs of healthcare services to treat injuries associated with IPV events. CONCLUSION: The asymmetry between the economic burden of IPV and the amount of government resources devoted to IPV prevention efforts suggests the need for a greater role to be played by the government and other factors in society in the area of IPV prevention. PMID- 23930149 TI - Gay and Bisexual Men's Perceptions of Police Helpfulness in Response to Male-Male Intimate Partner Violence. AB - Introduction Despite several recent studies documenting high rates of intimate partner violence (IPV) among gay and bisexual men (GBM), the literature is silent regarding GBM's perceptions of IPV within their community. We examine GBM's perceptions of same-sex IPV: its commonness, its severity, and the helpfulness of a hypothetical police response to a GBM experiencing IPV. METHODS: We drew data from a 2011 survey of venue-recruited GBM (n=989). Respondents were asked to describe the commonness of IPV, severity of IPV, and helpfulness of a hypothetical police response to IPV among GBM and among heterosexual women. We fitted a logistic model for the outcome of viewing the police response to a gay/bisexual IPV victim as less helpful than for a female heterosexual IPV victim. The regression model controlled for age, race/ethnicity, education, sexual orientation, employment status, and recent receipt of physical, emotional, and sexual IPV, with key covariates being internalized homophobia and experiences of homophobic discrimination. RESULTS: The majority of respondents viewed IPV among GBM as common (54.9%) and problematic (63.8%). While most respondents had identical perceptions of the commonness (82.7%) and severity (84.1%) of IPV in GBM compared to heterosexual women, the majority of the sample (59.1%) reported perceiving that contacting the police would be less helpful for a GBM IPV victim than for a heterosexual female IPV victim. In regression, respondents who reported more lifetime experiences of homophobic discrimination were more likely to have this comparatively negative perception (odds ratio: 1.11, 95% confidence interval: 1.06, 1.17). CONCLUSION: The results support a minority stress hypothesis to understand GBM's perceptions of police helpfulness in response to IPV. While IPV was viewed as both common and problematic among GBM, their previous experiences of homophobia were correlated with a learned anticipation of rejection and stigma from law enforcement. As the response to same-sex IPV grows, legal and health practitioners should ensure that laws and policies afford all protections to GBM IPV victims that are afforded to female IPV victims, and should consider methods to minimize the negative impact that homophobic stigma has upon GBM's access of police assistance. PMID- 23930150 TI - Who sends the email? Using electronic surveys in violence research. AB - INTRODUCTION: Students aged 16-24 years are at greatest risk for interpersonal violence and the resulting short and long-term health consequences. Electronic survey methodology is well suited for research related to interpersonal violence. Yet methodological questions remain about best practices in using electronic surveys. While researchers often indicate that potential participants receive multiple emails as reminders to complete the survey, little mention is made of the sender of the recruitment email. The purpose of this analysis is to describe the response rates from three violence-focused research studies when the recruitment emails are sent from a campus office, researcher or survey sampling firm. METHODS: Three violence-focused studies were conducted about interpersonal violence among college students in the United States. Seven universities and a survey sampling firm were used to recruit potential participants to complete an electronic survey. The sender of the recruitment emails varied within and across the each of the studies depending on institutional review boards and university protocols. RESULTS: An overall response rate of 30% was noted for the 3 studies. Universities in which researcher-initiated recruitment emails were used had higher response rates compared to universities where campus officials sent the recruitment emails. Researchers found lower response rates to electronic surveys at Historically Black Colleges or Universities and that other methods were needed to improve response rates. CONCLUSION: The sender of recruitment emails for electronic surveys may be an important factor in response rates for violence focused research. For researchers identification of best practices for survey methodology is needed to promote accurate disclosure and increase response rates. PMID- 23930151 TI - Sexualized and dangerous relationships: listening to the voices of low-income african american girls placed at risk for sexual exploitation. AB - INTRODUCTION: Youth from low-income, urban backgrounds face significant challenges to maintaining a positive developmental trajectory. Dangerous neighborhoods and stressed relationships are common in these settings and threaten adaptation by weakening the natural assets that undergird resilience. African American girls in these contexts face specific, multiple risks, including gender stereotyping, violence, and sexual exploitation. The commercial sexual exploitation of children (CSEC) is a multibillion-dollar industry victimizing over 1 million children around the globe. The typical victim in 1 city in the southeastern United States is an African American girl 12-14 years old. There has been little research investigating the characteristics of girls placed at risk for CSEC and even less research on the personal perspectives of these girls. METHODS: Over 3 school terms we provided preventive intervention groups for 36 African American middle school girls who were placed at risk because they lived in neighborhoods with high rates of interpersonal violence and CSEC. Two group leaders and a process recorder took detailed notes on each group session. Our focus on group conversations over a period of weeks increased the probability of recording spontaneous, open comments by the children and is a promising method with this population. The data were analyzed qualitatively and resulted in an account of the girls' own views of the environmental challenges and personal experiences that may influence their development. RESULTS: The girls' language during the group sessions contained 4 themes: difficulty forming trusting relationships, frequent peer aggression, familiarity with adult prostitution, and sexuality as a commodity. CONCLUSION: Our research shows how girls placed at risk for CSEC view their own lives. These children described violence and sexual exploitation and cited limited supports to protect them from these risks. Understanding the perspectives of these girls should generate future research and intervention strategies to support their coping and resilience. PMID- 23930152 TI - SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti Viral Activity. AB - It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein we report structure-activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4 phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC50 of 1 nM, and viral replication of VSV and WSN-Influenza with an EC50 of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogs of brequinar. PMID- 23930153 TI - Advancement of Imidazo[1,2-a]pyridines with Improved Pharmacokinetics and Nanomolar Activity Against Mycobacterium tuberculosis. AB - A set of fourteen imidazo[1,2-a]pyridine-3-carboxamides was synthesized and screened against Mycobacterium tuberculosis H37Rv. The minimum inhibitory concentrations of twelve of these agents were <= 1 MUM against replicating bacteria and five compounds (9, 12, 16, 17 and 18) had MIC values <= 0.006 MUM. Compounds 13 and 18 were screened against a panel of MDR and XDR drug resistant clinical Mtb strains with the potency of 18 surpassing that of clinical candidate PA-824 by nearly 10 fold. The in vivo pharmacokinetics of compounds 13 and 18 were evaluated in male mice by oral (PO) and intravenous (IV) routes. These results indicate that readily synthesized imidazo[1,2-a]pyridine-3-carboxamides are an exciting new class of potent, selective anti-TB agents that merit additional development opportunities. PMID- 23930155 TI - The malQ gene is essential for starch metabolism in Streptococcus mutans. AB - BACKGROUND: The malQ and glgP genes, respectively, annotated as putative 4-alpha glucanotransferase and putative glycogen phosphorylase are located with a 29 nucleotide overlap on the Streptococcus mutans genome. We found that the glgP gene of this organism was induced with maltose, and the gene likely constituted an operon with the upstream gene malQ. This putative operon was negatively regulated with the malR gene located upstream from the malQ gene and a MalR binding consensus sequence was found upstream of the malQ gene. S. mutans is not able to catabolize starch. However, this organism utilizes maltose degraded from starch in the presence of saliva amylase. Therefore, we hypothesized that the MalQ/GlgP system may participate in the metabolism of starch-degradation products. METHODS: A DNA fragment amplified from the malQ or glgP gene overexpressed His-tagged proteins with the plasmid pBAD/HisA. S. mutans malQ and/or glgP mutants were also constructed. Purified proteins were assayed for glucose-releasing and phosphorylase activities with appropriate buffers containing maltose, maltotriose, maltodextrin, or amylodextrin as a substrate, and were photometrically assayed with a glucose-6-phosphate dehydrogenase-NADP system. RESULTS: Purified MalQ protein released glucose from maltose and maltotriose but did not from either maltodextrin or amylodextrin. The purified GlgP protein did not exhibit a phosphorylase reaction with maltose or maltotriose but generated glucose-1-phosphate from maltodextrin and amylodextrin. However, the GlgP protein released glucose-1-phosphate from maltose and maltotriose in the presence of the MalQ protein. In addition, the MalQ enzyme activity with maltose released not only glucose but also produced maltooligosaccharides as substrates for the GlgP protein. CONCLUSION: These results suggest that the malQ gene encodes 4-alpha-glucanotransferase but not alpha-1,4-glucosidase activity. The malQ mutant could not grow in the presence of maltose as a carbon source, which suggests that the malQ gene is essential for the utilization of starch degradation products. PMID- 23930156 TI - Bioaerosol sampling for airborne bacteria in a small animal veterinary teaching hospital. AB - BACKGROUND: Airborne microorganisms within the hospital environment can potentially cause infection in susceptible patients. The objectives of this study were to identify, quantify, and determine the nosocomial potential of common airborne microorganisms present within a small animal teaching hospital. METHODS: Bioaerosol sampling was done initially in all 11 rooms and, subsequently, weekly samples were taken from selected rooms over a 9-week period. Samples were collected twice (morning and afternoon) at each site on each sampling day. The rooms were divided into two groups: Group 1, in which morning sampling was post cleaning and afternoon sampling was during activity, and Group 2, in which morning sampling was pre-cleaning and afternoon sampling was post-cleaning. The total aerobic bacterial plate counts per m(3) and bacterial identification were done using standard microbiological methods. RESULTS: A total of 14 bacterial genera were isolated with the most frequent being Micrococcus spp. followed by species of Corynebacterium, Bacillus, and Staphylococcus. There was a significant interaction between location and time for rooms in Group 1 (p=0.0028) but not in Group 2 (p>0.05). Microbial counts for rooms in Group 2 were significantly greater in the mornings than in the afternoon (p=0.0049). The microbial counts were also significantly different between some rooms (p=0.0333). CONCLUSION: The detection of significantly higher airborne microbial loads in different rooms at different times of the day suggests that the probability of acquiring nosocomial infections is higher at these times and locations. PMID- 23930154 TI - Labeling Cytosolic Targets in Live Cells with Blinking Probes. AB - With the advent of superresolution imaging methods, fast dynamic imaging of biological processes in live cells remains a challenge. A subset of these methods requires the cellular targets to be labeled with spontaneously blinking probes. The delivery and specific targeting of cytosolic targets and the control of the probes' blinking properties are reviewed for three types of blinking probes: quantum dots, synthetic dyes, and fluorescent proteins. PMID- 23930157 TI - Habitat, wildlife, and one health: Arcanobacterium pyogenes in Maryland and Upper Eastern Shore white-tailed deer populations. AB - BACKGROUND: Understanding the distribution of disease in wildlife is key to predicting the impact of emerging zoonotic one health concerns, especially for wildlife species with extensive human and livestock interfaces. The widespread distribution and complex interactions of white-tailed deer (Odocoileus virginianus) with humans suggest deer population health and management may have implications beyond stewardship of the animals. The intracranial abscessation suppurative meningitis (IASM) disease complex in deer has been linked to Arcanobacterium pyogenes, an under-diagnosed and often misdiagnosed organism considered commensal in domestic livestock but associated with serious disease in numerous species, including humans. METHODS: Our study used standard bacterial culture techniques to assess A. pyogenes prevalence among male deer sampled across six physiogeographic regions in Maryland and male and female deer in the Upper Eastern Shore under Traditional Deer Management (TDM) and Quality Deer Management (QDM), a management protocol that alters population demographics in favor of older male deer. Samples were collected from antler pedicles for males, the top of the head where pedicles would be if present for females, or the whole dorsal frontal area of the head for neonates. We collected nasal samples from all animals by swabbing the nasopharyngeal membranes. A gram stain and catalase test were conducted, and aerobic bacteria were identified to genus and species when possible. We evaluated the effect of region on whether deer carried A. pyogenes using Pearson's chi-square test with Yates' continuity correction. For the white tailed deer management study, we tested whether site, age class and sex predisposed animals to carrying A. pyogenes using binary logistic regression. RESULTS: A. pyogenes was detected on deer in three of the six regions studied, and was common in only one region, the Upper Eastern Shore. In the Upper Eastern Shore, 45% and 66% of antler and nasal swabs from deer were positive for A. pyogenes, respectively. On the Upper Eastern Shore, prevalence of A. pyogenes cultured from deer did not differ between management areas, and was abundant among both sexes and across all age classes. No A. pyogenes was cultured from a small sample of neonates. CONCLUSION: Our study indicates A. pyogenes may be carried widely among white-tailed deer regardless of sex or age class, but we found no evidence the pathogen is acquired in utero. The distribution of A. pyogenes across regions and concentration in a region with low livestock levels suggests the potential for localized endemicity of the organism and the possibility that deer may serve as a maintenance reservoir for an emerging one health concern. PMID- 23930158 TI - Vitamin d: shining a light on clinical and sex specific effects in multiple sclerosis? PMID- 23930159 TI - Antibiotics for the treatment of leptospirosis: systematic review and meta analysis of controlled trials. AB - Leptospirosis is a zoonotic disease prevalent mainly in developing countries and is associated with high case fatality. Antibiotics especially penicillin are the mainstay of treatment for a suspected or confirm case of leptospirosis but role of Penicillin has not been evaluated systematically in the light of current evidence. The present systematic review and meta-analysis is done to evaluate the role of antibiotics in the treatment of leptospirosis. Parallel group clinical trials involving use of penicillin in treatment of leptospirosis were searched from all available sources. Ten clinical trials were found suitable as per laid inclusion criteria eligible for present systematic review and five clinical trials were included in meta-analysis. Clinical trials included for meta-analysis were compared on the basis of mortality, fever days, numbers of patients presenting with oliguria, and number of patients undergoing need-based dialysis. Analysis was done by comprehensive meta-analysis software 2. Qualitative outcomes are summarized as odds ratio and quantitative outcomes are summarized as standard mean difference with 95% confidence interval. Random and fixed models are used for analysis. There was no significant difference between penicillin group and controlled group for mortality (Odds ratio 1.59 (95% CI 0.59-4.29), P = 0.35), fever days (std difference in mean = -0.223 (95% CI 0.394-0.995), P = 0.358), number of patients presenting with oliguria (Odds ratio 1.795 (95% CI 0.325 9.929), P = 0.502), and number of patients who underwent need based dialysis (Odds ratio 1.587 (95% CI 0.919-2.731), P = 0.098). Role of various antibiotics in treatment of leptospirosis is uncertain, and can be attributed to nonavailability of adequate clinical trials. Role of penicillin in the treatment of leptospirosis can be debated. PMID- 23930160 TI - Durability of effect of massage therapy on blood pressure. AB - BACKGROUND: Pre-hypertension is considered as a cardiovascular disease predicator. Management of pre-hypertension is an appropriate objective for clinicians in a wide range of medical centers. Treatment of pre-hypertension is primarily non-pharmacological, one of which is massage therapy that is used to control the BP. This study aimed to evaluate the survival effect of Swedish massage (face, neck, shoulders, and chest) on BP of the women with pre hypertension. METHODS: This was a single-blind clinical trial study. Fifty pre hypertensive women selected by simple random sampling which divided into control and test groups. The test group (25 patients) received Swedish massage 10-15 min, 3 times a week for 10 sessions and the control groups (25 patients) also were relaxed at the same environment with receiving no massage. Their BP was measured before and after each session and 72 h after finishing the massage therapy. Analyzing the data was done using descriptive and inferential statistical methods (Chi- square, Mann-Whitney, paired t-test and Student t-test) through SPSS software. RESULTS: The results indicated that mean systolic and diastolic BP in the massage group was significantly lower in comparison with the control group (P < 0.001). Evaluation of durability of the massage effects on BP also indicated that 72 h after finishing the study, still there was a significant difference between the test and control groups in systolic and diastolic BP (P < 0.001). CONCLUSIONS: Findings of the study indicated that massage therapy was a safe, effective, applicable and cost-effective intervention in controlling BP of the pre-hypertension women and it can be used in the health care centers and even at home. PMID- 23930161 TI - Association of polymorphism of ser311cys paraoxonase-2 gene with type 2 diabetes mellitus in iran. AB - BACKGROUND: It is believed that paraoxonase-2 gene polymorphism is associated with type 2 diabetes. This study is aimed to investigate the association between paraoxonase-2 gene polymorphism and type 2 diabetes in an Iranian population. METHODS: This study was performed on 200 individuals including 100 diabetics and 100 healthy subjects. Genomic DNA was extracted from peripheral blood leukocytes, and PCR-RFLP was carried out. Palindromic sequence in PON2 gene was recognized by Dde1 restriction endonuclease. In order to visualize restriction products, electrophoresis was carried out using polyacrylamide gel (8%) and ethidium bromide staining. RESULTS: The expected PCR product of 331 bp was obtained. Digestion of this product with DdeI showed four Ser homozygotes, three Cys homozygotes, and five Ser311 Cys heterozygotes. The gene frequency of Cys (C) in diabetic subjects was significantly higher than in healthy subjects. CONCLUSIONS: This study suggests that an association exists between Ser311 Cys polymorphism and type 2 diabetes mellitus. PMID- 23930162 TI - Underweight, overweight and obesity among zaboli adolescents: a comparison between international and iranians' national criteria. AB - BACKGROUND: Obesity and overweight are the major health problems in Iran. The aim of this study was to determine the prevalence of overweight and obesity among adolescents living in Zabol settled in Sistan va Baluchistan, one of economically underprivileged provinces in South Eastern of Iran, based on four different definitions. METHODS: This cross-sectional study was accomplished among a sample of 837 Zaboli adolescents (483 males; 354 females) aged 11-15 years. Anthropometric measurements including weight and height were measured and body mass index (BMI) was calculated. Sex-specific BMI-for-age reference data of the Iranian national data, Centers for Disease Control data (CDC 2000), International Obesity Task Force data (IOTF) and recent World Health Organization (WHO) data was used to define overweight and obesity. RESULTS: Mean age of the studied population was 13.14 year. Underweight was prevalent among almost 18.7% and 18.4% of adolescents by the use of WHO 2007 and CDC 2000 cut-off points. The prevalence rates reached 25.8% and 27.2% by IOTF and Iranian national criteria, respectively. The highest prevalence of overweight was obtained by IOTF cut points (10.8%) followed by CDC 2000 criteria (9.4%), WHO 2007 (8.8%) while national Iranian cut-points resulted in the lowest prevalence (2.4%). 7.5% of the studied population were found to be obese by WHO 2007 definition, while this rate was 2.2%, 3.4% and 1.5% by IOTF, CDC 2000 and national Iranian cut-points. CONCLUSIONS: Almost all definitions revealed coexistence of underweight, overweight, and obesity among Zaboli adolescents. Huge differences exist between different criteria. To understand the best appropriate criteria for Iranian adolescents, future studies should focus on the predictability of obesity-related co-morbidities by these criteria. PMID- 23930163 TI - Effect of a Probiotic and Metformin on Liver Aminotransferases in Non-alcoholic Steatohepatitis: A Double Blind Randomized Clinical Trial. AB - BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a clinicopathological entity that is being recognized more frequently in recent years. This study aimed to evaluate the effects of Metformin, with and without a probiotic supplement on liver aminotransferases in patients with NASH. METHODS: Sixty four patients 18-75 years with NASH confirmed by biopsy and histological assessment were enrolled to study. Patients were randomized to one of the following treatments for 6 months: Group I, probiotic (Protexin two tablets per day) plus Metformin 500 mg two tablets per day (Met/Pro), or group II, Metformin 500 mg two tablets per day plus two placebo tablet (Met/P). After 6 month alanine aminotransferase (ALT), aspartate aminotransferase, and ultrasound grading of NASH were assessed. RESULTS: IN GROUP I, SERUM ALANINE AMINOTRANSFERASE (ALT: 133.7 +/- 70 vs. 45.2 +/- 32.5; P < 0.00), and aspartate aminotransferase activity (AST: 123.1 +/- 72 vs. 44.2 +/- 33.9; P < 0.001), and ultrasound grading of NASH (P < 0.001) all decreased significantly by the end of the treatment period. In group II, while serum alanine aminotransferase (ALT) was not significantly reduced (118.4 +/- 67.9 vs. 112.5 +/- 68.7; P < 0.064), aspartate aminotransferase activity (AST: 125.3 +/- 71 vs. 113.4 +/- 71; P < 0.001), and ultrasound grading of NASH did fall significantly (P < 0.01). Body mass index (BMI), fasting blood sugar (FBS), cholesterol, and triglyceride fell significantly in both groups. CONCLUSIONS: Probiotic combination with Metformin improves liver aminotransferases better than metformin alone in patients with NASH. PMID- 23930164 TI - Evaluation of the effect of noise on the rate of errors and speed of work by the ergonomic test of two-hand co-ordination. AB - BACKGROUND: Among the most important and effective factors affecting the efficiency of the human workforce are accuracy, promptness, and ability. In the context of promoting levels and quality of productivity, the aim of this study was to investigate the effects of exposure to noise on the rate of errors, speed of work, and capability in performing manual activities. METHODS: This experimental study was conducted on 96 students (52 female and 44 male) of the Isfahan Medical Science University with the average and standard deviations of age, height, and weight of 22.81 (3.04) years, 171.67 (8.51) cm, and 65.05 (13.13) kg, respectively. Sampling was conducted with a randomized block design. Along with controlling for intervening factors, a combination of sound pressure levels [65 dB (A), 85 dB (A), and 95 dB (A)] and exposure times (0, 20, and 40) were used for evaluation of precision and speed of action of the participants, in the ergonomic test of two-hand coordination. Data was analyzed by SPSS18 software using a descriptive and analytical statistical method by analysis of covariance (ANCOVA) repeated measures. RESULTS: The results of this study showed that increasing sound pressure level from 65 to 95 dB in network 'A' increased the speed of work (P < 0.05). Increase in the exposure time (0 to 40 min of exposure) and gender showed no significant differences statistically in speed of work (P > 0.05). Male participants got annoyed from the noise more than females. Also, increase in sound pressure level increased the rate of error (P < 0.05). CONCLUSIONS: According to the results of this research, increasing the sound pressure level decreased efficiency and increased the errors and in exposure to sounds less than 85 dB in the beginning, the efficiency decreased initially and then increased in a mild slope. PMID- 23930165 TI - Association of proteinuria with various clinical findings and morphologic variables of oxford classification in immunoglobulin a nephropathy patients. AB - BACKGROUND: Immunoglobulin A nephropathy (IgAN) with nephrotic syndrome is an uncommon form of IgAN. Clinical and morphological characteristics of proteinuria in IgAN, especially when is in nephrotic range have not yet been fully examined. This study was aimed to correlate morphologic variables of the Oxford classification, and various clinical data with proteinuria in IgAN patients. We also aimed to demonstrate the significance of prevention of proteinuria as one of the important factors in progression of this disease. METHODS: In an observational study conducted on IgAN patients, total of 114 biopsies were entered in the study. IgAN was diagnosed by light and immunofluorescence study. RESULTS: Of 114 patients 70.2% were male. Mean age of patients was 37.7 +/- 13.6 years. The mean of proteinuria was 1742 +/- 1324 mg/day. Also mean of serum creatinine (Cr) was 1.6 +/- 1.5 mg/dL. Of 114 patients, 11(9.6%) had nephrotic range proteinuria. In this study, there was a positive correlation between proteinuria and serum Cr, peri-glomerular fibrosis or interstitial fibrosis. There was a positive association between proteinuria and totally sclerotic glomeruli too. There was also a positive association between the amount of fibrous crescents and the level of proteinuria. Nephrotic proteinuria could just be seen in male patients. Also, nephrotic syndrome had a positive association with the number of crescents. CONCLUSIONS: Our findings firstly support the prognostic value of crescent due to its association with proteinuria and secondly imply the importance of treatment of proteinuria to prevent progression of IgAN. PMID- 23930166 TI - Can selection of mechanical ventilation mode prevent increased intra-abdominal pressure in patients admitted to the intensive care unit? AB - BACKGROUND: Increased intra-abdominal pressure (IAP) results in dysfunction of vital organs. The aim of the present study was to evaluate the effect of mechanical ventilation mode on IAP. METHODS: In a cohort study, a total of 60 patients aged 20-70 years who were admitted to the ICU and underwent mechanical ventilation were recruited. Mechanical ventilation included one of the three modes: Biphasic positive airway pressure (BIPAP) group, synchronize intermittent mandatory ventilation (SIMV) group, or continuous positive airway pressure (CPAP) group. For each patient, mechanical ventilation mode and its parameters, blood pressure, SpO2, and status of tube feeding and IAP were recorded. RESULTS: Our findings indicate that the study groups were not significantly different in terms of anthropometric characteristics including age (64.5 +/- 4, P = 0.1), gender (male/female 31/29, P = 0.63), and body mass index (24 +/- 1.2, P = 0.11). Increase IAP was related to the type of respiratory mode with the more increased IAP observed in SIMV mode, followed by BIPAP and CPAP modes (P = 0.01). There were significant correlations between increased IAP and respiratory variables including respiratory rate, pressure support ventilation, and inspiratory pressure (P < 0.05). Tube feeding tolerance through NG-tube was lower in SIMV group, followed by BIPAP and CPAP groups (P < 0.05). CONCLUSIONS: There is a significant relationship between respiratory modes and IAP; therefore, it is better to utilize those types of mechanical ventilation like CPAP and BIPAP mode in patients who are prone to Intra-abdominal hypertension. PMID- 23930167 TI - Cigarette smoking, knowledge, attitude and prediction of smoking between male students, teachers and clergymen in tehran, iran, 2009. AB - BACKGROUND: Students, clergymen and teachers as role models can be very important in encouragement or prevention of cigarette smoking in young people. The aim of this study was to compare prevalence of smoking in 3 male groups of teachers, clergymen and university students. Also, study their knowledge and attitude towards it and the prediction of their future consumption. METHODS: In a cross sectional study in 2009 in Tehran, Iran, 1,271 male students, 549 clergymen and 551 teachers were randomly enrolled. Each participant completed the global adult tobacco survey questionnaire. Knowledge, attitude and prediction of smoking for the next 5 years were questioned in these 3 groups. Chi-squared test and logistic regression were used for analysis. P < 0.05 was considered significant. RESULTS: Prevalence of cigarette smoking was 31.1%, 21.9% and 27.2% among students, clergymen and teachers, respectively. Smoking in students was not associated with poor knowledge but were in teachers and clergymen. The odds ratio of smoking in students, clergymen and teachers was higher among those with having inappropriate attitude towards it (OR = 1.6, 6.1 and 4.5). Those with poor knowledge had an inappropriate attitude and predicted higher chance of cigarette consumption in the next 5 years (P < 0.0001). Inappropriate attitude in all 3 groups resulted in higher prediction of future smoking (P = 0.008). CONCLUSIONS: This study revealed that the prevalence of smoking among male students and teachers was higher than general population and clergymen who equally smoked. Also, level of knowledge and attitude of students were lower than teachers and clergymen. PMID- 23930169 TI - Diabetes distress and its association with depression in patients with type 2 diabetes in iran. AB - BACKGROUND: Patients with diabetes experience some level of emotional distress varying from disease-specific distress to general symptoms of anxiety and depression. Since empirical data about symptom distress in relation to diabetes are sparse in Iran, this study was designed to assess the diabetes-specific distress in Iranian population. METHODS: Persian version of Diabetes Distress Scale (DDS) questionnaire was completed by volunteer outpatients on a consecutive basis between February 2009 and July 2010, in Endocrine Research Center (Firouzgar Hospital). Then, scheduled appointments were made with a psychiatrist in the same week following completion of the questionnaire. The psychiatrist was not aware about the results of this questionnaire and patients were interviewed based on DSM-IV criteria. RESULTS: One hundred and eighty-five patients completed the questionnaire and were interviewed by a psychiatrist. Fifty-two percent of the patients were females. The mean age was 56.06 (SD=9.5) years and the mean of duration of diabetes was 9.7 (SD=7.3) years. Sixty-five (35%) had distress. Among the patients with distress, 55% were females and 64% had lower grade of education. Eighty patients were diagnosed as having Major Depressive Disorder. There was a relation between Emotional Burden subscale and age (P=0.004), employment status (P=0.03), and also diabetes duration (P=0.02). The physician related distress subscale was also related to the type of medication (P=0.009) and marital status (P=0.01). It has been shown that the regimen-related distress subscale was also related to age (P=0.003) and duration of diabetes (P=0.005). CONCLUSIONS: High prevalence rate of distress in the study highlights the significance of the need for identifying distress and also other mental health conditions in patients with diabetes in order to take collaborative care approaches. PMID- 23930168 TI - The Combating Obesity in Maori and Pasifika Adolescent School-Children Study: COMPASS Methodology and Study Protocol. AB - BACKGROUND: Lifestyle modifications including, physical activity can reduce obesity-related morbidity and subsequent cardiovascular disease in youth. This study will investigate the efficacy of a culturally-sensitive, non-contact, boxing-orientated training program on obesity and related cardio-metabolic conditions in Maori and Pasifika adolescents. Details of the methodological aspects of recruitment, inclusion criteria, randomization, cultural sensitivity, intervention program, assessments, process evaluation, and statistical analyses are described. METHODS: This study will be a community based, New Zealand, randomized control trial (RCT). Male and female obese (body mass index >95(th) percentile) Maori and Pasifika adolescents aged 14-16 years will be recruited and the sample size will be confirmed through a feasibility study. Combating Obesity in Maori and Pasifika Adolescent School-children Study (COMPASS) is a 6-month, theory-based program, conducted 3-times/week in a culturally appropriate setting. Each session includes 40 min boxing-orientated training and 30 min resistance training. Assessments will be made at baseline, 3-months, 6-months, 12-months, and 24-months. Main outcomes include abdominal obesity, endothelial function, and insulin resistance. Other outcomes include arterial stiffness, lipid profile, inflammatory biomarkers, well-being, and aerobic fitness. Control measures include physical activity, sleep behavior, and dietary intake. RESULTS: As a protocol paper there are no specific results to present, our purpose is to share our RCT design with the scientific community. CONCLUSIONS: COMPASS will be used to provide direction for exercise prescription policy in at-risk Maori and Pasifika adolescents. PMID- 23930170 TI - Vitamin d3 concentration correlates with the severity of multiple sclerosis. AB - BACKGROUND: To investigate the possible association between serum 25(OH) vitamin D3 concentration and the severity of disease in Iranian patients with multiple sclerosis (MS) and to compare this concentration with a matched control group. METHODS: This was an analytical cross-sectional study performed at Jondishapour Neurology Clinic in Tehran, Iran. Patients with relapsing-remitting MS were categorized by disease severity: mild [0<= Expanded Disability Status Scale (EDSS) <=3], moderate (3.5<=EDSS<=5.5), and severe (6<=EDSS). Serum concentrations of 25(OH) vitamin D3, calcium, phosphorus, magnesium, and parathyroid hormone were measured in 98 MS patients and 17 healthy age- and sex matched controls. Fisher's exact, Kruskal-Wallis, Mann-Whitney U test, and independent t and Spearman rank correlation tests were used. RESULTS: Serum 25(OH) vitamin D3 concentration was significantly lower in patients with MS, especially in the severe MS subgroup, compared with healthy controls (P=0.047). There was a statistically significant inverse correlation between 25(OH) vitamin D3 concentration and EDSS score (P=0.049, R=-0.168 by Spearman rank correlation test), which was observed in women only (P=0.044, R=-0.199). CONCLUSIONS: Our findings not only further disclose the lower level of vitamin D in MS patients in comparison with healthy controls, but also support the association between vitamin D and disease severity in MS. PMID- 23930171 TI - Clinical risk assessment in intensive care unit. AB - BACKGROUND: Clinical risk management focuses on improving the quality and safety of health care services by identifying the circumstances and opportunities that put patients at risk of harm and acting to prevent or control those risks. The goal of this study is to identify and assess the failure modes in the ICU of Qazvin's Social Security Hospital (Razi Hospital) through Failure Mode and Effect Analysis (FMEA). METHODS: This was a qualitative-quantitative research by Focus Discussion Group (FDG) performed in Qazvin Province, Iran during 2011. The study population included all individuals and owners who are familiar with the process in ICU. Sampling method was purposeful and the FDG group members were selected by the researcher. The research instrument was standard worksheet that has been used by several researchers. Data was analyzed by FMEA technique. RESULTS: Forty eight clinical errors and failure modes identified, results showed that the highest risk probability number (RPN) was in respiratory care "Ventilator's alarm malfunction (no alarm)" with the score 288, and the lowest was in gastrointestinal "not washing the NG-Tube" with the score 8. CONCLUSIONS: Many of the identified errors can be prevented by group members. Clinical risk assessment and management is the key to delivery of effective health care. PMID- 23930172 TI - Bird Fancier's Disease Due to Exposure to Birds Via a Desert Cooler. AB - Hypersensitivity pneumonitis (HP) is an immunologically mediated pulmonary disease caused by various organic particles and some non-organic chemicals. HP is mostly associated with some occupations such as farming and bird breeding. We report a case of hypersensitivity pneumonitis in a housewife without any prior history of occupational exposures. The disease was developed due to indirect exposure of the patient to doves antigens via a desert cooler ducts. PMID- 23930173 TI - Poor dental hygiene in pregnancy leading to submandibular cellulitis and intrauterine fetal demise: case report and literature review. AB - Ludwig's angina is an infectious process involving submandibular, sublingual, and submental spaces that can rapidly progress to hemodynamic instability and airway obstruction. A 38-year-old unbooked multipara of low socioeconomic status with a poor oral and dental hygiene presented with bilateral submandibular cellulitis and intrauterine fetal demise. She delivered vaginally, and subsequently drainage was done for cellulitis. The report highlights the importance of dental hygiene during pregnancy, lest life-threatening complications like Ludwig's angina occur, complicating the course of pregnancy. PMID- 23930174 TI - Comparing the outcomes of physiologic delivery with non-physiologic delivery group. AB - BACKGROUND: The main purpose of physiologic delivery is to rely on mother's body for childbirth. In physiologic delivery method pregnant women attend delivery preparation classes and they learn how to overcome fear and pain. This study compares delivery outcomes among women who participated in physiologic delivery with those who had undergone non-physiologic delivery. METHODS: All patients referred for physiologic delivery were assessed. Exclusion criteria were lack of PROM, post date, cephalopelvic disproportion, multi-fetal pregnancy, Meconium stain, blood pressure above 90/140, placenta previa and previous record of cesarean. Data was entered in SPSS 16 software and Fisher and Chi-square tests were used to compare vaginal laceration, episiotomy and Apgar score between two groups. RESULTS: Twelve out of 73 pregnant women (16.4%) in physiologic delivery group and 27 out of 69 pregnant women (39.1%) in non-physiologic delivery group needed episiotomy (P = 0.002). Ten patients (13.7%) in physiologic delivery group and seven persons (10.1%) in the non-physiologic delivery group were suffering from vaginal laceration (P = 0.51). There was no significant statistical difference between newborns' Apgar score in two groups. CONCLUSIONS: Physiologic delivery can reduce the need for episiotomy without any further complications. PMID- 23930175 TI - Risk of Contamination of Different Areas of Dentist's Face During Dental Practices. AB - BACKGROUND: Dental practice presents opportunities for cross-contamination. The dentist's face is at high-risk of infection transmission. The purpose of this study was to evaluate the risk of contamination in different areas of dentist's face during dental practices. METHODS: The visible splashes of materials that accumulated on cellulose face shields during 144 prosthetics and periodontal procedures were evaluated. The splashes were detected on 14 areas (each 1 cm(2)) of the dentist's face including around nose, mouth, eyes, and zygoma by a magnifier (*2). One way Analysis of variance, Duncan and t-test were used for data analysis (alpha = 0.05). RESULTS: Contamination of different areas of dentist's face was significantly different (P < 0.05). The areas around nose and the inner corner of eyes were the most contaminated areas. Zygoma was the least contaminated area. The contaminated areas during periodontal treatments were significantly more than prosthetic treatments (P < 0.05). There was no significant difference between contamination on left and right sides of the face. CONCLUSIONS: During dental practice, central areas of the face such as inner part of the eyes and around the nose were most contaminated areas. These parts are the important areas for transmission of infection. It is recommended to use protective means like glasses, mask, and protective shield, which have more protection field in these areas. PMID- 23930176 TI - Multilevel approach to intimate partner violence research and prevention. PMID- 23930177 TI - Commentary on: Effects of Cinnamon Consumption on Glycemic Status, Lipid Profile and Body Composition in Type 2 Diabetic Patients. PMID- 23930178 TI - Socio-economic health inequalities: ever-lasting facts or amenable to change? PMID- 23930179 TI - The Laboratory Rat: Relating Its Age With Human's. AB - By late 18(th) or early 19(th) century, albino rats became the most commonly used experimental animals in numerous biomedical researches, as they have been recognized as the preeminent model mammalian system. But, the precise correlation between age of laboratory rats and human is still a subject of debate. A number of studies have tried to detect these correlations in various ways, But, have not successfully provided any proper association. Thus, the current review attempts to compare rat and human age at different phases of their life. The overall findings indicate that rats grow rapidly during their childhood and become sexually mature at about the sixth week, but attain social maturity 5-6 months later. In adulthood, every day of the animal is approximately equivalent to 34.8 human days (i.e., one rat month is comparable to three human years). Numerous researchers performed experimental investigations in albino rats and estimated, in general, while considering their entire life span, that a human month resembles every-day life of a laboratory rat. These differences signify the variations in their anatomy, physiology and developmental processes, which must be taken into consideration while analyzing the results or selecting the dose of any research in rats when age is a crucial factor. PMID- 23930180 TI - Validation of a questionnaire for heat strain evaluation in women workers. AB - INTRODUCTION: Physiological, anthropometrical and thermal perceptual are the most important factors affecting thermoregulation of men and women in workplaces. The purpose of this study was determining the validity of a questionnaire method for assessing women's heat strain in workplaces. METHODS: This cross-sectional study was carried out on 96 healthy women. Data were continuously collected over a period of 3 months (July-September) in 2012. Mean +/- (SD) of age was found to be 31.5 +/- 7.48 years, of height 1.61 +/- 0.05 m, of weight 61.55 +/- 10.35 kg, and of body mass index 23.52 +/- 3.75 kg/m(2) in different workplaces. Heart rate and oral temperature were measured by heart rate monitoring and a medical digital thermometer, respectively. Subjects completed a draft questionnaire about the effective factors in the onset of heat strain. After collecting the questionnaires, the data were analyzed by applying Cronbach'sa calculation, factor analysis method, Pearson correlation and receiver operator characteristic curves using the SPSS 18 software. RESULTS: The value for Cronbach's alpha was found to be 0.68. The factor analysis method on items of draft questionnaire extracted three subscale (16 variables) which they explained 63.6% of the variance. According to the results of receiver operator characteristic curve analysis, the cut-off questionnaire score for separating people with heat strain from people with no heat strain was obtained to be 17. CONCLUSIONS: The results of this research indicated that this quantitative questionnaire has an acceptable reliability and validity, and a cut-off point. Therefore it could be used in the preliminary screening of heat strain in women in warm workplaces, when other heat stress evaluation methods are not available. PMID- 23930181 TI - Prediction of elders' general health based on positive and negative perfectionism and type-d personality. AB - BACKGROUND: Multiple factors such as retirement, work disability, social rejection, physical illness and etc., have an impact on general health of the elders. One factor among others is the role of psychological variables. The study is intended to assess the effect of positive and negative perfectionism and type D personality (distressed) on general health of the elders. METHODS: In this descriptive-correlation study, 80 people (47 male and 33 female) were selected from residents of Nursing Home in Hamadan and Malayer using non-probability (accessible) sampling method. They responded to the questionnaires of type-D Personality, Goldberg and Hillier's General Health and Positive and Negative Perfectionism of Terry-Short et al. RESULTS: Positive perfectionism (r = 0.30) and type-D personality (r = 0.32) had significant correlation with general health. Multiple regression analysis revealed that positive perfectionism and type-D personality could explain at least 49% of the variance in general health. Concerning the variables of negative affectivity, social inhibition and social function, the females' mean was higher than that of males and considering the variables of positive perfectionism, and social functioning, the males' mean was higher than that of females. CONCLUSIONS: Positive perfectionism decreases mental disorder of the elders by creating optimistic attitudes and enhancing social functions. On the other hand, type-D personality, unlike positive perfectionism, makes elders susceptible to physical illness and mental disorder. PMID- 23930182 TI - Protective role of recombinant human erythropoietin in kidney and lung injury following renal bilateral ischemia-reperfusion in rat model. AB - BACKGROUND: Acute kidney injury (AKI) has been recognized as one of the most complex clinical complications in modern medicine, and ischemia/reperfusion (I/R) injury is well-known as a main reason of AKI. In addition, AKI leads to important systemic consequences such as acute lung injury. This study was designed to investigate the role of erythropoietin (EPO) on kidney function makers and tissue damage; and lung endothelial permeability and lung water content (LWC) in bilateral renal I/R injury model in rats. METHODS: Male Wistar rats were randomly divided into three groups of sham, I/R, and I/R treated with EPO (I/R + EPO) groups. The I/R and I/R + EPO groups were subjected to bilateral renal I/R injury; however, only the I/R + EPO group received EPO (500 IU/kg, i.p.) 2 h before ischemia surgery, and the same dose was continued once a day for 3 days after ischemia. The sham group underwent a surgical procedure without ischemia process. RESULTS: The blood urea nitrogen (BUN) and serum creatinine (Cr) levels, kidney tissue damage score (KTDS), and kidney weight (KW) per 100 g body weight significantly increased in I/R group (P < 0.05). EPO administration decreased levels of BUN and Cr significantly (P < 0.05), and KTDS and KW insignificantly (P = 0.1). No significant differences in kidney and serum levels of malondialdehyde, and lung vascular permeability and LWC were observed between the groups. The serum and kidney levels of nitrite were not significantly different between I/R and sham groups; however, administration of EPO increased the renal level of nitrite (P < 0.05). CONCLUSIONS: EPO protected the kidney against I/R injury; however, it may not protect the lung tissue from the damage induced by renal I/R injury in rats. PMID- 23930183 TI - Road traffic fatalities in oman from 1995 to 2009: evidence from police reports. AB - BACKGROUND: Fatalities from road traffic crashes (RTCs) are a public health challenge for low- and middle-income countries, especially those experiencing epidemiological transition. This paper aims to describe demographics and trend analysis of fatalities of RTCs in Oman from 1995 to 2009. METHODS: The RTC data from 1995 to 2009 were obtained from the published reports of the Royal Oman Police (ROP). Data were extracted on the distribution of deaths by age, sex, nationality, mode of travel (driver, passenger, pedestrians), and type of vehicle (four- vs. two-wheelers). Trend analyses were carried out using the Chi-square for the percentages of deaths and linear regression for rates. RESULTS: A total of 9,616 deaths from RTCs were reported from 1995 to 2009. Of 9,616 fatalities, 4,666 (48.5%) were aged 26-50 years, 7,927 (82.4%) were males, 7,215 (75.0%) were Omanis, and 2,278 (23.8%) were pedestrians. Overall, mortality increased by around 50% from 479 deaths during 1995 to 953 deaths during 2009. There was a significant increase in the proportion of deaths (P < 0.05) and death rates (P < 0.05) among individuals aged 26-50 years, males, Omani nationals, and drivers. The number and rate of RTC fatalities due to overspeeding was also increased (P < 0.05). CONCLUSIONS: Fatalities due to RTCs in Oman are increasing, especially among those aged 26-50 years, males, drivers, and Omani nationals with overspeeding as a major cause of road traffic fatalities. There is a need for more research in understanding the risk-taking behaviors of young drivers, and sociocultural factors, especially among Omani nationals to target interventions. PMID- 23930184 TI - Factors Influencing H1N1 Vaccination Among Primary Health Care Workers: A Cross Sectional Study. AB - BACKGROUND: Primary health care workers (PHCW) are the front-liners in any infectious disease outbreaks. The recent outbreak of H1N1 influenza demonstrated that uptake of H1N1 vaccination remained low amongst PCHW despite its proven effectiveness. This trend is worrying as PHCW are the first point of contact in any emerging outbreak of future influenza epidemic. To investigate factors influencing willingness of H1N1 vaccination amongst PHCW. METHODS: A cross sectional survey using self-reported questionnaire assessing perception and practice towards H1N1 Influenza A vaccination. A score of 34/50 was used as a cut off score that divide good and poor perception. Logistic regression analysis used to explore the association between acceptance to be vaccinated and chosen variables. RESULTS: The mean age was 33.91 (SD: 8.20) with mean year of service of 9.23 (SD: 8.0). Acceptance of H1N1 vaccination was 86.3%. A total of 85.9% perceived the vaccination can prevent serious disease. Willingness to be vaccinated influenced by perception at risk of having illness (OR: 10.182, CI: 1.64-63.23, P 0.013) and need for vaccination (OR: 11.35, CI: 4.67-27.56, P < 0.0001). CONCLUSIONS: PCHW were generally willing to be vaccinated should H1N1 Influenza epidemic emerges in the future. However, acceptance of vaccination was influenced by factors of benefit to prevent illness and reduction of spread of the illness. Fear of side-effects remained a barrier toward acceptance which should be taken into account in planning of preparation for future wave of outbreak. PMID- 23930185 TI - Socioeconomic Inequality of Non-Communicable Risk Factors among People Living in Kurdistan Province, Islamic Republic of Iran. AB - BACKGROUND: The most fundamental way to decrease the burden of noncommunicable diseases (NCDs) is to identify and control their related risk factors. The goal of this study is to determine socioeconomic inequalities in risk factors for NCDs using concentration index based on Non-Communicable Disease Surveillance Survey (NCDSS) data in Kurdistan province, Islamic Republic of Iran in 2005 and 2009. METHODS: The required data for this study are taken from two NCDSSs in Kurdistan province in 2005 and 2009. A total of 2,494 persons in 2005 and 997 persons in 2009 were assessed. Concentration index was used to determine socioeconomic inequality. To assess the relationship between the prevalence of each risk factor and socioeconomic status (SES), logistic regression was used and odds ratio (OR) was calculated for each group, compared with the poorest group. RESULTS: The concentration index for hypertension was -0.095 (-0.158, -0.032) in 2005 and 0.080 (-0.156, -0.003) in 2009. The concentration index for insufficient consumption of fruits and vegetables was -0.117 (-0.153, -0.082) in 2005 and 0.100 (-0.153, -0.082) in 2009. The concentration index for the consumption of unhealthy fat and oil was -0.034 (-0.049, -0.019) in 2005 and -0.108 (-0.165, 0.051) in 2009. The concentration index for insufficient consumption of fish was 0.070 (-0.096, -0.044) in 2005. The concentration index for physical inactivity was 0.008 (-0.057, 0.075) in 2005 and 0.139 (0.063, 0.215) in 2009. In all the cases, the OR of the richest group to the poorest group was significant. CONCLUSION: Hypertension, insufficient consumption of fruits and vegetables, consumption of unhealthy fat and oil, and insufficient consumption of fish are more prevalent among poor groups. There was no significant socioeconomic inequality in the distribution of smoking, excess weight, and hypercholesterolemia. Physical inactivity was more prevalent among the rich groups of society in 2009. The reduction of socioeconomic inequalities must become a main goal in health-care policies. PMID- 23930186 TI - Body Esteem and Self-examination in British Men and Women. AB - BACKGROUND: Breast and testicular cancers affect a substantial and increasing proportion of the global population. Self-examination encourages early detection and treatment of these cancers, which positively impacts on patient quality of life and survival. METHODS: The present study investigated the role of body esteem in breast and testicular self-examination. Men (N = 60) and women (N = 90) recruited from a British University completed the body esteem scale and either the testicular self-examination or breast self-examination questionnaire. RESULTS: Logistic regression models revealed that body esteem predicted women's intention to engage in breast self-examination. Women with higher levels of sexual attractiveness and those with lower levels of weight concern were more likely to report that they would regularly self-examine in the future. Body esteem did not however, distinguish between those women that did or did not currently self-examine or predict men's current or intended testicular self examination. CONCLUSION: The findings have implications for the promotion of self examination and highlight an emerging area of preventive health research. PMID- 23930187 TI - The coexistence of dual form of malnutrition in a sample of rural malaysia. AB - BACKGROUND: The coexistence of under and over nutrition might be influenced by a marked shift in dietary and lifestyle practices of people in developing countries. This study aims to identify factors associated with the occurrence of dual form of malnutrition in the same households in a rural district in Peninsular Malaysia. METHODS: A cross sectional study was conducted on a 223 mother-child pairs based on several inclusion criteria such as; non-pregnant, non lactating mothers and having youngest children aged from 2 to 12 years old. Anthropometric indices of Weight-for-age Z score (WAZ) <= 1SD was used to classify underweight status in children and body mass index (BMI) >=25kg/m(2) was used to measure overweight status among mothers. A pre-tested questionnaire was used to collect socio-demographic data, whereas food frequency questionnaire was used to assess the diet diversity. RESULTS: The results showed that the prevalence of overweight mother/underweight child (OWM/UWC) pairs was 29.6%, whereas the prevalence of normal weight mother/normal weight child (NWM/NWC) pairs was 15.2%. Out of mother-child pairs measured, 61.0% of the children were underweight and 61.4% were stunted, whereas the prevalence of overweight and obesity in women were 35.0% and 17.0%, respectively. The study did not report any association between the dual burden of malnutrition and household size, number of children, educational level of the mother, total income, income per capita, and food expenditure, except with household type (OR:5.01;95% CI:1.63,15.34; P = 0.005). In general, the total diet diversity score of both types of mother-child pairs was low. CONCLUSIONS: Dual forms of malnutrition in the same household exists in Malaysian households. This phenomenon will be a big challenge especially for food intervention programs to be implemented in the future. PMID- 23930188 TI - The effects of gluten-free diet on hypertransaminasemia in patients with celiac disease. AB - BACKGROUND: Celiac disease (CD) is an immune mediated condition that leads to small bowel atrophy and improve with a gluten free diet (GFD). Extra-intestinal manifestations of CD include hypertransaminasemia. In this study, the effects of a GFD on hypertransaminasemia in patients with newly diagnosed CD were studied. METHODS: Ninety eight new diagnosed consecutive patients with CD 40 males and 58 females) with mean age of 32 +/- 17.1 were studied. All patients with CD were treated with a GFD. Patients with hypertransaminasemia, at diagnosis, had a cirrhosis screen performed. Patients with a negative cirrhosis screen were reviewed, 6 months after the introduction of a GFD, and serum levels of liver transaminases were measured again. RESULTS: Nine patients had hypertransaminasemia. One patient was Hepatitis B surface antigen positive and was excluded from this study. The 8 remaining patients had no obvious cause for the hypertransaminasemia. Mean (+/- SD) of baseline aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were 42.6 +/- 16.5 IU/L (range: 16-66 IU/L) and 69.3 +/- 9.3 IU/L (range: 52-81 IU/L). Six months after treatment with a GFD, mean AST and ALT levels decreased to 24.5 +/- 5.1 IU/L (range: 18-31 IU/L) (P: 0.04) and 24.6 +/- 6 IU/L (range: 17-32 IU/L) (P: 0.01), respectively. In 7 patients the hypertransaminasemia, at diagnosis had resolved. CONCLUSIONS: This study provides further evidence that some patients with CD have a reversible hypertransaminasemia that resolves with a GFD. PMID- 23930189 TI - Visual fitness of public vehicle drivers in southeast of iran. AB - BACKGROUND: Although visual impairment of drivers is a very important risk factor for car accident, a few published papers have explored this issue in Iran. This study aims to evaluate the visual fitness of public vehicle drivers in Kerman province, southeast of Iran. METHODS: A total of 4,003 public vehicle drivers were examined by one ophthalmologist for visual fitness in Kerman province between January 2009 and June 2010. Data are presented as Mean+/-SD or percentage, and with 95% confidence intervals (CIs). Pearson Chi-square and McNemmar tests along with crude odds ratio (OR) were used to compare vision deficit between groups. RESULTS: Almost 361 drivers (9.0%; 95% CI: 8.1-9.9) had insufficient vision to drive public vehicles before the refractive errors (RE) correction and this number, was reduced to 68 drivers (1.7%; 95% CI: 1.3-2.1) after the correction. A number of them including 200 drivers (5.0%; 95% CI: 4.3 5.7) had insufficient vision to drive personal vehicles before the correction and this was reduced to 30 thereafter (0.8%; 95% CI: 0.5-1.0). We also found out that the vision status got worse with aging, and RE was the most prevalent cause of sight defects. CONCLUSION: It seems that visual fitness of public vehicle drivers is a point of real concerns which might somewhat explain the high rate of car accidents in Iran. PMID- 23930190 TI - Estimation and comparison of levels of salivary nitric oxide in patients with oral lichen planus and controls. AB - BACKGROUND: Normal salivary function is considered to be critical for the maintenance of healthy oral mucosa. Oral fluids provide an easily available, non invasive medium for the diagnosis of wide range of diseases and clinical situations. The objective of this study was to estimate and compare salivary nitric oxide levels in patients with oral lichen planus and healthy individuals. METHODS: Saliva was collected by spitting method. Unstimulated whole saliva thus collected was refrigerated at 4 degrees C, and processed within 24 h for the estimation of nitric oxide levels which was done using Griess reaction. The results were analyzed using Student's "t" test. RESULTS: There was statistically significant difference in the levels of salivary nitric oxide between the study and control groups. CONCLUSIONS: The present study clearly indicates a significant increase in salivary nitric oxide levels in oral lichen planus patients as compared to controls. PMID- 23930191 TI - Close contact precautions could prevent an outbreak of crimean-congo hemorrhagic Fever: a case series report from southern part of tehran. AB - Between the end of June and the middle of July 2011, an outbreak of Crimean-Congo Hemorrhagic Fever occurred in southern part of Tehran, Iran. This study reports clinical, laboratory findings and outcome of six cases, who were all consanguine. Index case who was livestock-worker died with hemorrhagic manifestations; thereafter his pregnant wife, three brothers, mother-in-law and his pregnant sister-in-law were admitted and except for the latter, ribavirin was administered. The brother with close contact with body fluids and blood of index case, died with hemorrhage. Low platelet, high aminotransferases and elevated PT, PTT were detected in this case. Skin manifestations were present in five cases. Only in one case RT-PCR and IgM serology were reported as positive for CCHF virus by reference laboratory. In endemic areas, high index of suspicion should be kept in mind in successfully finding and treating cases in early phase of the disease. PMID- 23930192 TI - Wandering ascaris coming out through the abdominal wall. AB - A rare case of ascaris coming out through the anterior abdominal wall is reported here. A 40-year-old female had undergone dilatation and curettage by a quack. On the second day she presented with presented with features of peritonitis. She was explored. Resection anastomosis of the ileum was done for multiple perforations of the ileum. Patient developed a fistula in the anterior abdominal wall which was draining bile-colored fluid. On the 12(th) postoperative day a 10-cm-long worm was seen coming out through the fistulous tract which was found to be Ascaris lumbricoids. Ascaris lumbricoids can lead to many complications ranging from worm colic to intestinal obstruction, volvulus, peritonitis, pancreatitis, cholangiohepatitis, liver abscess and many more. Worm has been reported to come out through mouth, nostrils, abdominal drains, T-tubes etc. But ascaris coming out through the anterior abdominal wall is very rare hence reported here. PMID- 23930193 TI - Epidemiologic characteristics of occupational burns in yazd, iran. AB - OBJECTIVE: Occupational burns are among the important causes of work-related fatalities and absenteeism. Epidemiologic assessment of these injuries is important to define high-risk jobs. We designed this study to evaluate the epidemiology of occupational burns in Yazd, an industrial province in Iran. METHODS: This is a prospective study on work-related burns in a 1-year period (2008-2009). A questionnaire was completed for them about the characteristics of the burn injury. RESULTS: Three Hundred and Thirty Eight patients with occupational burns were identified. Their mean age was 29.64 years. Most burn victims were male workers in the metal industry. The most common job was smelting. Most burns were happened in the morning. Thermal burns were observed more than chemical and electrical burns. Mean total body surface area burned was 6.5%. The most common cause of burn was hot fluid, followed by hot object and flame. There was no any significant relationship between burn type, and burn degree or burned body surface. CONCLUSIONS: The highest incidence of occupational burns was in 21-30 year-old workers. There was a male preponderance in work related burns. Metal industry had the most injured workers and among them, smelters were more frequently injured. PMID- 23930194 TI - Cardiovascular disorders risk factors in different industries of iran. AB - BACKGROUND: Disorders of cardiovascular system can cause disability or death, screening is necessary specially in workers who maybe had risk factors. Hypertension, hyperlipidemia, obesity, smoking, genetic, exposure to chemicals, fumes, solvents, coldness are non occupational and occupational risk factors. Objective was comparison of cardiovascular disorders risk factors between workers in different industries of Iran. METHODS: In a cross-sectional study, workers of automobile, food industries and light works had been selected and cardiovascular disorders risk factors had been gathered then data analyzed in SPSS with one-way ANOVA, Chi-2 and multi nominal logistic regression with P < 0.05. RESULTS: 875 workers had been participated in the study, all of the cardiovascular disorders risk factors were in the normal range. Mean of high density lipoprotein (HDL) in food industry workers was 63.83 +/- 17.42 mg/dl and it was protective, but in workers who work in automobile industry was 38.97 +/- 11.08 mg/dl and the lowest, Also hypertension and hypertriglyceridemia were more prominent in this industry and after regression with P < 0.05, the differences were significant. CONCLUSIONS: Screening of cardiovascular disorders risk factors were important and helpful in industries specially automobile industry, that might be preventive method for these disorders in the future. PMID- 23930195 TI - Comment on: The Protective Role of Silymarin and Deferoxamine Against Iron Dextran-Induced Renal Iron Deposition in Male Rats. PMID- 23930196 TI - Emerging and Re-emerging Infectious Diseases: Public Health Perspective. PMID- 23930197 TI - Does surge in research papers symbolize good publication practice? - a preliminary report from India. PMID- 23930198 TI - Small molecules aimed at type III secretion systems to inhibit bacterial virulence. PMID- 23930199 TI - Indole/triazole conjugates are selective inhibitors and inducers of bacterial biofilms. AB - Herein is described a method of accessing indole/triazole and benzothiophene/triazole analogues that selectively promote or inhibit biofilm formation by Gram-positive and Gram-negative bacteria. Structure/function studies revealed that the addition of a bromine atom at the 2-position of the indole/triazole scaffold altered activity against both Gram-negative and Gram positive bacteria and could transform a biofilm inhibitor into a biofilm inducer. Isosteric replacement of the indole core by a benzothiophene significantly impaired anti-biofilm activity. A competition assay exposing Escherichia coli to the most potent biofilm inducer and an inhibitor of E. coli biofilm formation was performed. The inducer exhibited the ability to mute the effect of the anti biofilm compound for this targeted bacterial population. PMID- 23930200 TI - The use of 111Ag as a tool for studying biological distribution of silver-based antimicrobials. AB - Recently, there has been an emergence of significant interest in silver-based antimicrobials. Our goal was to develop a radioactive tracer for investigating the biological fate of such compounds. Purified 111Ag was incorporated into the methylated caffeine analogue, IC1 to yield the silver carbene complex designated as [111Ag]SCC1 and investigated in biodistribution studies. PMID- 23930201 TI - Ab initio calculations and validation of the pH-dependent structures of the His37 Trp41 quartet, the heart of acid activation and proton conductance in the M2 protein of Influenza A virus. AB - The M2 protein of Influenza A virus forms a homotetrameric proton channel activated by low pH. The His37-Trp41 quartet is the heart of acid activation and proton conductance, but the functional mechanism is still controversial. We carried out ab initio calculations to model the pH-dependent structures of the His37-Trp41 quartet. In our model at neutral pH, the four His37 residues are configured into a pair of dimers; in each dimer, a proton is shared between Ndelta1 on one residue and Nepsilon2 on the other, and, under the restraint of the backbone, the two imidazole rings are nearly parallel, in contrast to a perpendicular arrangement for a free imidazole-imidazolium dimer. Within each dimer the +1 charge is highly delocalized, contributing to its stabilization in a low dielectric environment. The Ndelta1-H-Nepsilon2 strong hydrogen bonds result in significantly downfield shifted Ndelta1 and Nepsilon2 chemical shifts (at 169.7 and 167.6 ppm, respectively), in good agreement with experiments. In our model at acidic pH (where the channel becomes activated), a third proton binds to an imidazole-imidazolium dimer; the imidazole rings rotate away (each by ~55 degrees ) from each other, destroying the dimer structure. The two imidazoliums are stabilized by hydrogen bonds with water molecules and a cation-pi interaction with Trp41. The Raman spectra calculated for the His37-Trp41 quartet at neutral and acidic pH are in agreement with experiments. Our calculations support an activation and conductance mechanism in which a hydronium ion from the N-terminal side passes a proton to an imidazole-imidazolium dimer; when the Trp41 gate is open, relaying of a proton onto a water molecule from the C-terminal side then allows the imidazole-imidazolium dimer to reform and be ready for the next round of proton conductance. PMID- 23930202 TI - DNA strands with alternating incorporations of LNA and 2'-O-(pyren-1 yl)methyluridine: SNP-discriminating RNA detection probes. AB - Detection of nucleic acids using fluorophore-modified oligonucleotides forms the basis of many important applications in molecular biology, genetics and medical diagnostics. Here we demonstrate that DNA strands with central segments of alternating locked nucleic acid (LNA) and 2'-O-(pyren-1-yl)methyluridine monomers display very large and highly mismatch-sensitive increases in fluorescence emission upon RNA hybridization, whereas corresponding "LNA-free" controls do not. Absorbance spectra strongly suggest that LNA-induced conformational tuning of flanking 2'-O-(pyren-1-yl)methyluridine monomers places the reporter group in the minor groove upon RNA binding, whereby pyrene-nucleobase interactions leading to quenching of fluorescence are minimized. Accordingly, these easy-to-synthesize probes are promising SNP-discriminating RNA detection probes. PMID- 23930203 TI - Hybrid liposomes inhibit tumor growth and lung metastasis of murine osteosarcoma cells. AB - Antitumor effects of hybrid liposomes (HL) composed of l-alpha dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene(23) dodecyl ether (C12(EO)23) on the metastatic growth of murine osteosarcoma (LM8) cells were investigated in vitro and in vivo. Remarkable inhibitory effects of HL-23 on the growth of LM8 cells were obtained through the induction of apoptotic cell death in vitro. It was also indicated that HL-23 should dramatically suppress the invasion of LM8 cells and the formation of filopodia on the cell surface in vitro. Furthermore, significantly high therapeutic effects were observed in the homograft mouse models of LM8 cells with lung metastasis after the treatment with HL-23 in vivo. That is, the histological analysis demonstrated that the primary tumor growth of LM8 cells implanted subcutaneously into the mice was inhibited along with the induction of apoptosis. In addition, it was found that HL-23 significantly decreased the lung metastasis of LM8 cells in the mouse models through the inhibition of primary tumor invasion. These results suggest that HL 23 could be a novel agent for the chemotherapy of osteosarcoma. PMID- 23930204 TI - Prognostic impact and the relevance of PTEN copy number alterations in patients with advanced colorectal cancer (CRC) receiving bevacizumab. AB - Loss of phosphatase and tensin homologue (PTEN) expression may be prognostic in colorectal cancer (CRC) and may have a correlation with vascular endothelial growth factor (VEGF) expression via hypoxia-inducible factor 1 (HIF-1) alpha, and the PI3K/mTOR pathways. We therefore have explored the prognostic association of PTEN loss and the potential that PTEN loss may be predictive of outcome with bevacizumab. Patients enrolled in the AGITG MAX trial, a randomized Phase III trial of capecitabine (C) +/- bevacizumab (B) (+/- mitomycin C [M]) with available tissues were analyzed for PTEN expression (loss vs. no loss) as assessed using a Taqman(r) copy number assay (CNA). Of the original 471 patients enrolled, tissues from 302 (64.1%) patients were analyzed. PTEN loss was observed in 38.7% of patients. There was no relationship between PTEN loss and KRAS or BRAF mutation. PTEN status was not prognostic for progression-free survival (PFS) or overall survival (OS) in multivariate analyses adjusting for other baseline factors; loss versus no loss PFS hazard ratio (HR) 0.9 (0.7-1.16), OS HR 1.04 (0.79-1.38). PTEN was not prognostic when assessed by KRAS and BRAF status. By using the comparison of C versus CB+CBM, PTEN status was not significantly predictive of the effectiveness of B for PFS or OS. PTEN status was not prognostic for survival in advanced colorectal cancer, irrespective of KRAS or BRAF status. PTEN status did not significantly predict different benefit with bevacizumb therapy. PMID- 23930205 TI - Combination therapy with gefitinib and doxorubicin inhibits tumor growth in transgenic mice with adrenal neuroblastoma. AB - Highly relevant mouse models of human neuroblastoma (NB) are needed to evaluate new therapeutic strategies against NB. In this study, we characterized transgenic mice with bilateral adrenal tumors. On the basis of information from the tumoral gene expression profiles, we examined the antitumor effects of unencapsulated and liposomal doxorubicin (DXR), alone and in combination with gefitinib, on adrenal NB. We showed that intravenous injection of unencapsulated or liposomal DXR alone inhibited tumor growth in a dose-dependent manner, as assessed by magnetic resonance imaging (MRI). However, liposomal DXR did not exhibit greater antitumor effect than unencapsulated DXR. Immunohistochemical analysis revealed that the adrenal tumor vasculature with abundant pericyte coverage was a less leaky structure for liposomes. Combination therapy with unencapsulated or liposomal DXR plus gefitinib strongly suppressed tumor growth and delayed tumor regrowth than treatment with unencapsulated or liposomal DXR alone, even at a lower dose of DXR. Dynamic contrast-enhanced MRI analysis revealed that gefitinib treatment increased blood flow in the tumor, indicating that gefitinib treatment changes the tumor vascular environment in a manner that may increase the antitumor effect of DXR. In conclusion, the combination of gefitinib and DXR induces growth inhibition of adrenal NBs in transgenic mice. These findings will provide helpful insights into new treatments for NB. PMID- 23930206 TI - EGFR, KRAS, BRAF, and HER-2 molecular status in brain metastases from 77 NSCLC patients. AB - The aim of this study was to determine the frequency of EGFR, KRAS, BRAF, and HER 2 mutations in brain metastases from non-small cell lung carcinomas (BM-NSCLC). A total of 77 samples of BM-NSCLC were included and 19 samples of BM from breast, kidney, and colorectal tumors were also studied as controls. These samples were collected from patients followed between 2008 and 2011 at Poitiers and Nice University Hospitals in France. The frequencies of EGFR, KRAS, BRAF, and HER-2 mutations in BM-NSCLC were 2.6, 38.5, 0, and 0% respectively. The incidence of KRAS mutation was significantly higher in female and younger patients (P < 0.05). No mutations of the four genes were found in BM from breast or kidney. However, among six BM from colorectal tumors, we identified KRAS mutations in three cases and BRAF mutations in two other cases. This study is the largest analysis on genetic alterations in BM-NSCLC performed to date. Our results suggest a low frequency of EGFR mutations in BM-NSCLC whereas KRAS mutations are as frequent in BM-NSCLC as in primitive NSCLC. These results raise the question of the variability of the brain metastatic potential of NSCLC cells in relation to the mutation pattern. PMID- 23930207 TI - Aromatase in human liver and its diseases. AB - Estrogens play important roles in the cell proliferation and invasion of estrogen dependent human neoplasms. Aromatase overexpression has been also reported in hepatitis and hepatocellular carcinoma (HCC) compared with normal liver but its details in these hepatic disorders have remained unclear. Therefore, in this study, we first immunolocalized aromatase using immunohistochemistry in patients with liver cirrhosis, steatosis, hepatitis, HCC, and metastasis liver carcinoma (MLC) in order to study the detailed status of intrahepatic aromatase. Aromatase immunoreactivity was predominantly detected in nonneoplastic hepatocytes around tumor cells. We then evaluated the effects of an interaction between hepatocytes and carcinoma cells upon aromatase mRNA expression, using HepG2 as a substitute model of hepatocytes by coculture systems. Aromatase mRNA levels in HepG2 were significantly increased by coculture with all carcinoma cell lines examined. We also evaluated alternative splicing of aromatase exon 1 but the same splicing variant was used in HepG2 cells regardless of carcinoma cell lines employed in the coculture system. These findings obtained in HepG2 indicated that carcinoma cells, whether metastatic or primary, induced aromatase expression in adjacent normal hepatocytes possibly through the soluble aromatase inducible factors in human hepatic microenvironments. PMID- 23930208 TI - A phase I study of ABT-510 plus bevacizumab in advanced solid tumors. AB - Targeting multiple regulators of tumor angiogenesis have the potential to improve treatment efficacy. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor and ABT-510 is a synthetic analog of thrombospondin, an endogenous angiogenesis inhibitor. Dual inhibition may result in additional benefit. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus ABT-510 in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. Thirty-four evaluable subjects were enrolled and received study drug. Therapy was well tolerated; minimal treatment-related grade 3/4 toxicity was observed. One patient treated at dose level 1 had a partial response and five other patients treated at the recommended phase II dose had prolonged stable disease for more than 1 year. Biomarker evaluation revealed increased levels of D dimer, von Willebrand factor, placental growth factor, and stromal-derived factor 1 in response to treatment with the combination of bevacizumab and ABT-510. Data suggest that continued evaluation of combination antiangiogenesis therapies may be clinically useful. PMID- 23930209 TI - Phase I study of everolimus and mitomycin C for patients with metastatic esophagogastric adenocarcinoma. AB - This study aimed at determining the recommended dose of the mammalian target of rapamycin inhibitor everolimus in combination with mitomycin C (MMC) in patients with previously treated metastatic esophagogastric cancer. In this phase I trial, patients received escalated doses of oral everolimus (5, 7.5, and 10 mg/day) in combination with intravenous MMC 5 mg/m2 every 3 weeks. Endpoints were the dose limiting toxicity (DLT), safety, and response rates. Tumor tissues were tested for HER2-status and mutations in the PTEN, PIK3CA, AKT1, CTNNB1, and E-cadherin type 1 genes. Sixteen patients (12 male, four female) with gastric/gastroesophageal junction cancer were included. All patients were previously treated with a platinum-based chemotherapy. Treatment cohorts were: 5 mg/day, three patients; 7.5 mg/day, three patients; and 10 mg/day, 10 patients. No DLTs occurred during dose escalation. Most frequent grade 3 toxicities were leukopenia (18.8%) and neutropenia (18.8%). All other grade 3 toxicities were below 10%. No grade 4 toxicities occurred. Three (18.8%) patients experienced partial responses and four patients had stable disease (SD). Antitumor activity according to Response Evaluation Criteria In Solid Tumors (RECIST)-criteria was highest in the 10 mg/day cohort. No associations between HER2-status or detected mutations and response were observed. The recommended dose of everolimus combined with MMC is 10 mg/day. Encouraging signs of antitumor activity were seen (http://www.ClinicalTrials.gov; CLINICAL TRIAL REGISTRATION NUMBER: NCT01042782). PMID- 23930210 TI - A contemporary analysis of morbidity and outcomes in cytoreduction/hyperthermic intraperitoneal chemoperfusion. AB - The risks and benefits of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CS/HIPEC) continue to be debated by the oncology community. A retrospective analysis of contemporary data (2003-2011) was performed to provide objective information regarding surgical morbidity, mortality, and survival for patients undergoing CS/HIPEC at a comprehensive cancer center. While procedure-associated morbidity was comparable to other major surgical oncology procedures, there was no operative or 30-day mortality and 60 day mortality was 2.7%. Increasing numbers of bowel resections were found to correlate to an increased incidence of deep surgical site infections (including abscess and enterocutaneous fistula) and need for reoperation which was in turn associated with a decreased overall survival (OS) and progression-free survival (PFS). Five-year OS rates varied by site of tumor origin and histology (disseminated peritoneal adenomucinosis [91.3%], Mesothelioma [80.8%], Appendiceal Adenocarcinoma [38.7%], and Colorectal Adenocarcinoma [38.2%]). With an acceptable morbidity and mortality rate, CS/HIPEC should be included as an effective treatment modality in the multidisciplinary care of select patients with peritoneal metastases. PMID- 23930211 TI - Breast cancer molecular subtypes and survival in a hospital-based sample in Puerto Rico. AB - Information on the impact of hormone receptor status subtypes in breast cancer (BC) prognosis is still limited for Hispanics. We aimed to evaluate the association of BC molecular subtypes and other clinical factors with survival in a hospital-based female population of BC cases in Puerto Rico. We analyzed 663 cases of invasive BC diagnosed between 2002 and 2005. Information on HER-2/neu (HER-2) overexpression, estrogen (ER), and progesterone (PR) receptor status and clinical characteristics were retrieved from hospitals cancer registries and record review. Survival probabilities by covariates of interest were described using the Kaplan-Meier estimators. Cox proportional hazards models were employed to assess factors associated with risk of BC death. Overall, 17.3% of BC cases were triple-negative (TN), 61.8% were Luminal-A, 13.3% were Luminal-B, and 7.5% were HER-2 overexpressed. In the multivariate Cox model, among patients with localized stage, women with TN BC had higher risk of death (adjusted hazard ratio [HR]: 2.57, 95% confidence interval [CI]: 1.29-5.12) as compared to those with Luminal-A status, after adjusting for age at diagnosis. In addition, among women with regional/distant stage at diagnosis, those with TN BC (HR: 5.48, 95% CI: 2.63-11.47) and those HER-2+, including HER-2 overexpressed and Luminal-B, (HR: 2.73, 95% CI:1.30-5.75) had a higher mortality. This is the most comprehensive epidemiological study to date on the impact of hormone receptor expression subtypes in BC survival in Puerto Rico. Consistent to results in other populations, the TN subtype and HER-2+ tumors were associated with decreased survival. PMID- 23930212 TI - Phase II study of TAS-106 in patients with platinum-failure recurrent or metastatic head and neck cancer and nasopharyngeal cancer. AB - TAS-106, a RNA polymerase inhibitor, was studied in solid tumors with potential clinical benefit and reasonable tolerability. We conducted a multicenter, international phase II trial of TAS-106 in salvage metastatic or recurrent head and neck squamous cell cancer (HNSCC) and nasopharyngeal cancer (NPC) patients. TAS-106 monotherapy was given at 6.5 mg/m(2) over 24-h continuous infusion every 3 weeks. Translational studies for blood and tissue were included. Twenty-seven enrolled patients experienced the most common drug-related adverse events of neutropenia, fatigue, non-neutropenic fever, injection site reaction, and skin rash/dermatitis. The greater than or equal to grade 3 adverse events included neutropenia (14.8%), febrile neutropenia (7.4%), pneumonia (7.4%), and peripheral neuropathy (3.7%). The overall response rate was 0% in both subgroups; five HNSCC patients had stable disease (median duration 99 days) and four NPC patients had stable disease (median duration of 92.5 days). Median progression-free survival (PFS) for HNSCC patients was 52 days (95% CI 43.0-99.0 days) and 48 days (95% CI 41.0-83.0 days) for NPC. Median overall survival (OS) for HNSCC patients was 175 days (95% CI 92.0-234.0 days) and 280 days (95% CI 107.0-462.0 days) for NPC. The TAS-106 plasma levels were equivalent between Asian and Caucasian patients. There was no significant correlation of tumor UCK2 protein expression levels to TAS-106 efficacy. TAS-106 was reasonably tolerated in patients with platinum-failure HNSCC and NPC. The administration schedule of 24-h continuous infusion prevented neurologic toxicity, but had myelosuppression as its main toxicity. There was no anti-tumor efficacy seen with TAS-106 monotherapy. Future studies will focus on TAS-106 combinations and mechanisms of drug resistance. PMID- 23930213 TI - A potential new enriching trial design for selecting non-small-cell lung cancer patients with no predictive biomarker for trials based on both histology and early tumor response: further analysis of a thalidomide trial. AB - There are few predictive biomarkers for antiangiogenic trials in lung cancer. We examine a potential treatment strategy in which a patient group is enriched using both histology and an early assessment of response during standard chemotherapy, and where a new agent is given for the remainder of chemotherapy and as maintenance. We performed a retrospective analysis of 722 stage IIIB/IV non-small cell lung cancer patients from a double-blind placebo-controlled trial of thalidomide or placebo 100-200 mg/day, combined with gemcitabine/carboplatin (for up to four cycles), then given as single agent maintenance therapy. There was a significant statistical interaction between treatment and histology, with a possible benefit among squamous cell cancer (SCC) patients. We examined 150 SCC patients who were "nonprogressors" (stable disease or complete/partial response) after completing the second chemotherapy cycle. Endpoints were progression-free survival (PFS) and overall survival (OS). Among the 150 patients nonprogressors after cycle 2 (thalidomide, n = 72; placebo, n = 78; baseline characteristics were similar), the hazard ratios (HRs) were: OS = 0.76 (95% CI: 0.54-1.07) and PFS = 0.69 (95% CI: 0.50-0.97). In 57 patients who had a complete/partial response, the HRs were: OS = 0.63 (95% CI: 0.34-1.15) and PFS = 0.50 (95% CI: 0.28-0.88). SCC patients who were nonprogressors after 2 cycles of standard chemotherapy showed evidence of a benefit from thalidomide when taken for the remainder of chemotherapy and as maintenance. This strategy based on histology and, importantly, early assessment of tumor response, as a means of patient enrichment, could be examined in other lung cancer studies. Such an approach might be suitable for trials where there are no predictive biomarkers. PMID- 23930214 TI - Comparison of the accuracy of Hybrid Capture II and polymerase chain reaction in detecting clinically important cervical dysplasia: a systematic review and meta analysis. AB - The effectiveness of screening programs for cervical cancer has benefited from the inclusion of Human papillomavirus (HPV) DNA assays; which assay to choose, however, is not clear based on previous reviews. Our review addressed test accuracy of Hybrid Capture II (HCII) and polymerase chain reaction (PCR) assays based on studies with stronger designs and with more clinically relevant outcomes. We searched OvidMedline, PubMed, and the Cochrane Library for English language studies comparing both tests, published 1985-2012, with cervical dysplasia defined by the Bethesda classification. Meta-analysis provided pooled sensitivity, specificity, and 95% confidence intervals (CIs); meta-regression identified sources of heterogeneity. From 29 reports, we found that the pooled sensitivity and specificity to detect high-grade squamous intraepithelial lesion (HSIL) was higher for HCII than PCR (0.89 [CI: 0.89-0.90] and 0.85 [CI: 0.84 0.86] vs. 0.73 [CI: 0.73-0.74] and 0.62 [CI: 0.62-0.64]). Both assays had higher accuracy to detect cervical dysplasia in Europe than in Asia-Pacific or North America (diagnostic odd ratio - dOR = 4.08 [CI: 1.39-11.91] and 4.56 [CI: 1.86 11.17] for HCII vs. 2.66 [CI: 1.16-6.53] and 3.78 [CI: 1.50-9.51] for PCR) and accuracy to detect HSIL than atypical squamous cells of undetermined significance (ASCUS)/ low-grade squamous intraepithelial lesion (LSIL) (HCII-dOR = 9.04 [CI: 4.12-19.86] and PCR-dOR = 5.60 [CI: 2.87-10.94]). For HCII, using histology as a gold standard results in higher accuracy than using cytology (dOR = 2.87 [CI: 1.31-6.29]). Based on higher test accuracy, our results support the use of HCII in cervical cancer screening programs. The role of HPV type distribution should be explored to determine the worldwide comparability of HPV test accuracy. PMID- 23930215 TI - Adenoma detection in patients undergoing a comprehensive colonoscopy screening. AB - Measures shown to improve the adenoma detection during colonoscopy (excellent bowel preparation, cecal intubation, cap fitted colonoscope to examine behind folds, patient position change to optimize colon distention, trained endoscopy team focusing on detection of subtle flat lesions, and incorporation of optimum endoscopic examination with adequate withdrawal time) are applicable to clinical practice and, if incorporated are projected to facilitate comprehensive colonoscopy screening program for colon cancer prevention. To determine adenoma and serrated polyp detection rate under conditions designed to optimize quality parameters for comprehensive screening colonoscopy. Retrospective analysis of data obtained from a comprehensive colon cancer screening program designed to optimize quality parameters. Academic medical center. Three hundred and forty three patients between the ages of 50 years and 75 years who underwent first screening colonoscopy between 2009 and 2011 among 535 consecutive patients undergoing colonoscopy. Comprehensive colonoscopy screening program was utilized to screen all patients. Cecal intubation was successful in 98.8% of patients. The Boston Bowel Preparation Scale for quality of colonoscopy was 8.97 (95% confidence interval [CI]; 8.94, 9.00). The rate of adenoma detection was 60% and serrated lesion (defined as serrated adenomas or hyperplastic polyps proximal to the splenic flexure) detection was 23%. The rate of precancerous lesion detection (adenomas and serrated lesions) was 66%. The mean number of adenomas per screening procedure was 1.4 (1.2, 1.6) and the mean number of precancerous lesions (adenomas or serrated lesions) per screening procedure was 1.6 (1.4, 1.8). Retrospective study and single endoscopist experience. A comprehensive colonoscopy screening program results in high-quality screening with high detection of adenomas, advanced adenomas, serrated adenomas, and multiple adenomas. PMID- 23930216 TI - Cancer survival disparities by health insurance status. AB - Previous studies found that uninsured and Medicaid insured cancer patients have poorer outcomes than cancer patients with private insurance. We examined the association between health insurance status and survival of New Jersey patients 18-64 diagnosed with seven common cancers during 1999-2004. Hazard ratios (HRs) with 95% confidence intervals for 5-year cause-specific survival were calculated from Cox proportional hazards regression models; health insurance status was the primary predictor with adjustment for other significant factors in univariate chi square or Kaplan-Meier survival log-rank tests. Two diagnosis periods by health insurance status were compared using Kaplan-Meier survival log-rank tests. For breast, colorectal, lung, non-Hodgkin lymphoma (NHL), and prostate cancer, uninsured and Medicaid insured patients had significantly higher risks of death than privately insured patients. For bladder cancer, uninsured patients had a significantly higher risk of death than privately insured patients. Survival improved between the two diagnosis periods for privately insured patients with breast, colorectal, or lung cancer and NHL, for Medicaid insured patients with NHL, and not at all for uninsured patients. Survival from cancer appears to be related to a complex set of demographic and clinical factors of which insurance status is a part. While ensuring that everyone has adequate health insurance is an important step, additional measures must be taken to address cancer survival disparities. PMID- 23930217 TI - IKZF1 deletion is associated with a poor outcome in pediatric B-cell precursor acute lymphoblastic leukemia in Japan. AB - Genetic alterations of Ikaros family zinc finger protein 1 (IKZF1), point mutations in Janus kinase 2 (JAK2), and overexpression of cytokine receptor-like factor 2 (CRLF2) were recently reported to be associated with poor outcomes in pediatric B-cell precursor (BCP)-ALL. Herein, we conducted genetic analyses of IKZF1 deletion, point mutation of JAK2 exon 16, 17, and 21, CRLF2 expression, the presence of P2RY8-CRLF2 fusion and F232C mutation in CRLF2 in 202 pediatric BCP ALL patients newly diagnosed and registered in Japan Childhood Leukemia Study ALL02 protocol to find out if alterations in these genes are determinants of poor outcome. All patients showed good response to initial prednisolone (PSL) treatment. Ph+, infantile, and Down syndrome-associated ALL were excluded. Deletion of IKZF1 occurred in 19/202 patients (9.4%) and CRLF2 overexpression occurred in 16/107 (15.0%), which are similar to previous reports. Patients with IKZF1 deletion had reduced event-free survival (EFS) and overall survival (OS) compared to those in patients without IKZF1 deletion (5-year EFS, 62.7% vs. 88.8%, 5-year OS, 71.8% vs. 90.2%). Our data also showed significantly inferior 5 year EFS (48.6% vs. 84.7%, log rank P = 0.0003) and 5-year OS (62.3% vs. 85.4%, log rank P = 0.009) in NCI-HR patients (n = 97). JAK2 mutations and P2RY8-CRLF2 fusion were rarely detected. IKZF1 deletion was identified as adverse prognostic factor even in pediatric BCP-ALL in NCI-HR showing good response to PSL. PMID- 23930220 TI - Changes in lipid density induce membrane curvature. AB - Highly curved bilayer lipid membranes make up the shell of many intra- and extracellular compartments, including organelles and vesicles. Using all-atom molecular dynamics simulations, we show that increasing the density of lipids in the bilayer membrane can induce the membrane to form a curved shape. PMID- 23930219 TI - Array of Biodegradable Microraftsfor Isolation and Implantation of Living, Adherent Cells. AB - A new strategy for efficient sorting and implantation of viable adherent cells into animals is described. An array of biodegradable micro-structures (microrafts) was fabricated using a polydimethylsiloxane substrate for micromolding poly(lactic-co-glycolic acid) (PLGA). Screening various forms of PLGA determined that the suitability of PLGA for microraft manufacture, biocompatibility and in vitro degradation was dependent on molecular weight and lactic/glycolic ratio. Cells plated on the array selectively attached to the microrafts and could be identified by their fluorescence, morphology or other criteria. The cells were efficiently dislodged and collected from the array using a microneedle device. The platform was used to isolate specific cells from a mixed population establishing the ability to sort target cells for direct implantation. As a proof of concept, fluorescently conjugated microrafts carrying tumor cells stably expressing luciferase were isolated from an array and implanted subcutaneously into mice. In vivo bio-luminescence imaging confirmed the growth of a tumor in the recipient animals. Imaging of tissue sections from the tumors demonstrated in vivo degradation of the implanted microrafts. The process is a new strategy for isolating and delivering a small number of adherent cells for animal implantation with potential applications in tissue repair, tumor induction, in vivo differentiation of stem cells and other biomedical research. PMID- 23930221 TI - O2-Protected Diazeniumdiolate-Modified Silica Nanoparticles for Extended Nitric Oxide Release from Dental Composites. AB - O2-protected N-diazeniumdiolate-based silanes were grafted onto mesoporous silica nanoparticles to yield a scaffold with an NO payload of 2.4 MUmol NO/mg and NO release half-life of 23 d. Reduced (3-log) Streptococcus mutans viable adhesion was observed for NO-releasing dental restorative materials modified with these particles relative to controls. PMID- 23930222 TI - How to Optimize Binding of Coated Nanoparticles: Coupling of Physical Interactions, Molecular Organization and Chemical State. AB - One of the key challenges in the development of nano carriers for drug delivery and imaging is the design of a system that selectively binds to target cells. A common strategy is to coat the delivery device with specific ligands that bind strongly to overexpressed receptors. However such devices are usually unable to discriminate between receptors found on benign and malignant cells. We demonstrate, theoretically, how one can achieve enhanced binding to target cells by using multiple physical and chemical interactions. We study the effective interactions between a polymer decorated nano micelle or nanoparticle with three types of model lipid membranes that differ in the composition of their outer leaflet. They are: i) lipid membranes with overexpressed receptors, ii) membranes with a given fraction of negatively charged lipids and iii) membranes with both overexpressed receptors and negatively charged lipids. The coating contains a mixtures of two short polymers, one neutral for protection and the other a polybase with a functional end-group to optimize specific binding with the overexpressed receptors and electrostatic interactions with charged lipid head groups. The strength of the binding for the combined system is much larger than the sum of the independent electrostatic or specific interactions binding. We find a range of distances where the addition of two effective repulsive interactions become an attraction in the combined case. The changes in the strength and shape of the effective interaction are due to the coupling that exists between molecular organization, physical interactions and chemical state, e.g., protonation. The predictions provide guidelines for the design of carrier devices for targeted drug and nanoparticle delivery and give insight in the competing and highly non-additive nature of the different effective interactions in nanoscale systems in constrained environments that are ubiquitous in synthetic and biological systems. PMID- 23930223 TI - Cellular resolution models for even skipped regulation in the entire Drosophila embryo. AB - Transcriptional control ensures genes are expressed in the right amounts at the correct times and locations. Understanding quantitatively how regulatory systems convert input signals to appropriate outputs remains a challenge. For the first time, we successfully model even skipped (eve) stripes 2 and 3+7 across the entire fly embryo at cellular resolution. A straightforward statistical relationship explains how transcription factor (TF) concentrations define eve's complex spatial expression, without the need for pairwise interactions or cross regulatory dynamics. Simulating thousands of TF combinations, we recover known regulators and suggest new candidates. Finally, we accurately predict the intricate effects of perturbations including TF mutations and misexpression. Our approach imposes minimal assumptions about regulatory function; instead we infer underlying mechanisms from models that best fit the data, like the lack of TF specific thresholds and the positional value of homotypic interactions. Our study provides a general and quantitative method for elucidating the regulation of diverse biological systems. DOI:http://dx.doi.org/10.7554/eLife.00522.001. PMID- 23930224 TI - Single molecule imaging reveals a major role for diffusion in the exploration of ciliary space by signaling receptors. AB - The dynamic organization of signaling cascades inside primary cilia is key to signal propagation. Yet little is known about the dynamics of ciliary membrane proteins besides a possible role for motor-driven Intraflagellar Transport (IFT). To characterize these dynamics, we imaged single molecules of Somatostatin Receptor 3 (SSTR3, a GPCR) and Smoothened (Smo, a Hedgehog signal transducer) in the ciliary membrane. While IFT trains moved processively from one end of the cilium to the other, single SSTR3 and Smo underwent mostly diffusive behavior interspersed with short periods of directional movements. Statistical subtraction of instant velocities revealed that SSTR3 and Smo spent less than a third of their time undergoing active transport. Finally, SSTR3 and IFT movements could be uncoupled by perturbing either membrane protein diffusion or active transport. Thus ciliary membrane proteins move predominantly by diffusion, and attachment to IFT trains is transient and stochastic rather than processive or spatially determined. DOI:http://dx.doi.org/10.7554/eLife.00654.001. PMID- 23930226 TI - Computing away the magic? AB - Computer simulations and quantitative imaging of Drosophila embryos have been used to recreate the dynamic activities of a complex transcriptional enhancer. PMID- 23930225 TI - The ER-Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. AB - Autophagy is a catabolic process for bulk degradation of cytosolic materials mediated by double-membraned autophagosomes. The membrane determinant to initiate the formation of autophagosomes remains elusive. Here, we establish a cell-free assay based on LC3 lipidation to define the organelle membrane supporting early autophagosome formation. In vitro LC3 lipidation requires energy and is subject to regulation by the pathways modulating autophagy in vivo. We developed a systematic membrane isolation scheme to identify the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) as a primary membrane source both necessary and sufficient to trigger LC3 lipidation in vitro. Functional studies demonstrate that the ERGIC is required for autophagosome biogenesis in vivo. Moreover, we find that the ERGIC acts by recruiting the early autophagosome marker ATG14, a critical step for the generation of preautophagosomal membranes. DOI:http://dx.doi.org/10.7554/eLife.00947.001. PMID- 23930228 TI - Are "bath salts" on your differential list? A case report of delirium and agitation after use of illicit bath salts. PMID- 23930227 TI - Using stimulants for attention-deficit/hyperactivity disorder: clinical approaches and challenges. PMID- 23930229 TI - Relationship between rages and criminal behavior in an internal medicine outpatient sample. PMID- 23930230 TI - "K2/Spice": have you updated your differentials? A case report. PMID- 23930231 TI - A case of amelioration of venlafaxine-discontinuation "brain shivers" with atomoxetine. PMID- 23930232 TI - Psychiatric features in high-functioning adult brothers with fragile x spectrum disorders. PMID- 23930233 TI - A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer's disease. AB - OBJECTIVE: To examine the role of butyrylcholinesterase (BuChE) in cholinergic signaling and neurologic conditions, such as Alzheimer's disease (AD). The rationale for inhibiting cholinesterases in the management of AD, including clinical evidence supporting use of the dual acetylcholinesterase (AChE) and BuChE inhibitor rivastigmine, is discussed. DATA SOURCES: PubMed searches were performed using butyrylcholinesterase as a keyword. English-language articles referenced in PubMed as of September 2011 were included. Study Selection and Data Synthesis: English-language articles related to BuChE considered to be of clinical relevance to physicians were included. English-language articles specifically related to AChE were not included, as the role of AChE in cholinergic signaling and the underlying pathology of AD is well documented. Reference lists of included publications were used to supplement the search. RESULTS: AChE and BuChE play a role in cholinergic signaling; BuChE can hydrolyze acetylcholine and compensate for AChE when levels are depleted. In the AD brain, AChE levels decrease, while BuChE levels are reportedly increased or unchanged, with changes becoming more pronounced during the disease course. Furthermore, BuChE genotype may influence AD risk and rate of disease progression. Strategies that increase acetylcholine levels (eg, cholinesterase inhibitors) demonstrate symptomatic efficacy in AD. Rivastigmine has proven cognitive efficacy in clinical trials, and data suggest that its action is mediated, in part, by inhibition of BuChE. Retrospective analyses of clinical trials provide evidence that BuChE genotype may also influence treatment response. CONCLUSIONS: AChE selective inhibitors and a dual AChE and BuChE inhibitor demonstrate symptomatic efficacy in AD. Mounting preclinical and clinical evidence for a role of BuChE in maintaining normal cholinergic function and the pathology of AD provides a rationale for further studies investigating use of rivastigmine in AD and the influence of BuChE genotype on observed efficacy. PMID- 23930235 TI - Psychiatric disorders and quality of life in patients with implantable cardioverter defibrillators: a systematic review. AB - OBJECTIVE: To systematically review the literature with regard to psychiatric disorders and quality of life in patients with an implantable cardioverter defibrillator. DATA SOURCES: Research was conducted in 3 databases (ISI Web of Science, PubMed, and PsycINFO) using the terms implantable, cardioverter, defibrillator, quality of life, psych *, anxiety, and depression. STUDY SELECTION: The search yielded 1,399 references. Non-English and repeated references were excluded. After abstract analysis, 42 references were recovered for full-text reading, and 25 articles were selected for this review. DATA EXTRACTION: Research took place in April 2012, and no time restriction was placed on any of the database searches. Review or theoretical articles were excluded, and only clinical trials and epidemiologic studies were selected for this review. RESULTS: A systematic review of the literature revealed mostly observational prospective cohort studies followed by cross-sectional observational studies and randomized clinical trials. Few studies included in the review were observational retrospective cohort or case-control studies. There are prominent signs and symptoms of anxiety and depression in patients with an implantable cardioverter defibrillator. Disorders include phobic anxiety, posttraumatic stress disorder, panic disorder, somatoform disorder, agoraphobia, and depression. Quality of life in the physical, social, and psychological domains is affected and is related to the intensity and the frequency of the device's electrical discharge. CONCLUSIONS: Work regarding psychiatric comorbidity in patients with an implantable cardioverter defibrillator has shown that anxiety and depression are common. The patients and their families should be informed by their doctors that the presence of the device minimizes risk of sudden death and allows them to have a normal life. PMID- 23930234 TI - A review of antidepressant therapy in primary care: current practices and future directions. AB - OBJECTIVE: To provide general practitioners with a comparison of major depressive disorder treatments received in primary care and psychiatric clinic settings, a focus on treatment outcomes related to currently prescribed antidepressants, and a review of new and emerging therapeutic strategies. DATA SOURCES: English language evidence-based guidelines and peer-reviewed literature published between January 1, 2005, and December 31, 2011, were identified using PubMed, MEDLINE, and EMBASE. All searches contained the terms major depressive disorder and unipolar depression, and excluded the terms bipolar disorder/manic depressive disorder. The following search terms were also included: naturalistic study, antidepressant, relapse, recurrence, residual symptoms, response, remission, sequential medication trials, and treatment-resistant depression. STUDY SELECTION: Meta-analyses, systematic reviews, and practice guidelines were included. Bibliographies were used to identify additional articles of interest. DATA EXTRACTION: Abstracts and articles were screened for relevance to primary care practice. Population-based studies and those involving patients treated in primary care were used whenever possible. DATA SYNTHESIS: Achieving remission from a major depressive episode is important to improve functional outcomes and to reduce relapse and recurrence. Despite the availability of numerous antidepressants, as many as 50% of patients require treatment modifications beyond first-line therapy. Among remitters, 90% report residual symptoms that may interfere with function. Patients treated in primary care often have chronic depression (symptom duration >= 24 months at presentation) and medical comorbidities. These are clinical predictors of worse outcomes and require individualized attention when treatment is initiated. Antidepressants differ in efficacy, tolerability, and side effects-factors that may affect adherence to treatment. CONCLUSIONS: Major depressive disorder is highly prevalent in primary care and is among the most common causes of loss of disability-adjusted life years worldwide. There are few differences in clinical profiles between depressed patients in primary care and those in specialist clinics, although differences in symptoms and comorbid conditions among individual depressed patients present a challenge for the physician providing individualized treatment. The goal of treatment is remission with good functional and psychosocial outcomes. Physicians in primary care should have expertise in working with a number of current antidepressant approaches and an awareness of new and emerging treatments. PMID- 23930237 TI - As time goes by. PMID- 23930236 TI - Depression and chronic diseases: it is time for a synergistic mental health and primary care approach. AB - OBJECTIVE: To identify the growing significance of depression as a global leading cause of years lost to disability and its role as a major independent risk factor in many chronic illnesses. The distinct effects of depression on morbidity and mortality in cancer, diabetes, heart disease, and stroke are investigated, including behavioral factors and plausible biological mechanisms (psychoneuroimmunology of depression). DATA SOURCES: PubMed articles in English were searched from 1992 to 2012 (20-year span) using the following search criteria: psychoneuroimmunology of depression, immune-mediated inflammation, depression treatment recommendations, depression screening, years lost to disability, underserved populations and depression, chronic illnesses and depression, and selective serotonin reuptake inhibitors and immune system. DATA SYNTHESIS: Evidence of the robust bidirectional relationship between depression and individual chronic diseases is presented and discussed. A brief overview of currently recommended psychotherapeutic and psychopharmacologic treatment approaches in regard to depression in chronic diseases is provided. RESULTS: Discordance between mental health and primary care within the US public health system is a systematic problem that must be addressed. This situation leads to a potentially high hidden prevalence of underdiagnosed and undertreated depression, especially in the underserved populations. CONCLUSION: Measures must be implemented across the communities of mental health and primary care practitioners in order to achieve a synergistic approach to depression. PMID- 23930238 TI - Revisiting the role of a palliative care psychiatrist. PMID- 23930239 TI - Chromothripsis in a Case of TP53-Deficient Chronic Lymphocytic Leukemia. AB - We describe genomic findings in a case of CLL with del(17p13.1) by FISH, in which SNP array analysis revealed chromothripsis, a phenomenon by which regions of the cancer genome are shattered and recombined to generate frequent oscillations between two DNA copy number states. The findings illustrate the value of SNP arrays for precise whole genome profiling in CLL and for the detection of alterations that would be overlooked with a standard FISH panel. This second report of chromothripsis in CLL indicates that this phenomenon is a recurrent change in this disease. PMID- 23930240 TI - Etiology and management of esophageal impaction in children: A review of 11 years. AB - INTRODUCTION: Esophageal impaction in children is a medical emergency that needs an immediate medical attention. In the last years multiple objects have been detected and were removed endoscopically. In the last decade, Eosinophilic Esophagitis (EoE) has been associated with esophageal stenosis, leading to esophageal impaction with various objects including toys, food, coins and other. AIM: To determine the various objects and symptoms associated with impactions and to develop algorithm that guides Emergency Department Physicians and Primary care Providers when facing such problem in pediatric patient. MATERIAL AND METHODS: A retrospective chart review of all children referred to the pediatric gastroenterology service at Marshall University for FB impaction between 2000 and 2010 was performed. Foreign bodies treated by other specialties were excluded from this review. Clinical and demographic data were retrieved. RESULTS: A total of 291 charts with the diagnosis of foreign body reviewed of which only 126 met the inclusion criteria and considered for final calculation. Male/Female ratio and mean age were 1.17:1.0, and 3.65 +/- 0.75 years, respectively. Time of impaction before ER evaluation was: < 24hrs in 75 patients, >24hrs in 17 and in 34 the time of ingestion was not known. Radiology was performed in 118 patients, of whom 1 had pneumo-mediastinum and 1 had pneumothorax. Endoscopic localization of the objects showed: 81- proximal, 23- middle esophagus, and 22- in the distal esophagus. The esophageal mucosa showed non-specific changes in 37 patients, 5 with EoE features, 1 patient with hiatal hernia, 1 patient with candidiasis, and in 5 pts had no mucosal description. CONCLUSION: Children with foreign body in the esophagus are commonly seen in our Hospital ER. Those children may harbor undiagnosed medical conditions that will need future therapy. Careful endoscopic assessment with mucosal biopsies is needed to diagnose those conditions earlier. Referral to a GI specialist may be warranted. PMID- 23930242 TI - Posterior tracheal wall leading to life-threatening obstruction of tracheostomy tube. AB - This is a case report of a 28-year-old male patient with severe traumatic brain injury and Glasgow coma scale score = 8: E2 M5 VT, who required a tracheotomy for airway protection. On day 5, a surgical tracheotomy was performed with size 8 tracheotomy tube (TT). On the 4(th) day of post-tracheostomy, he developed a sudden onset respiratory distress while on T-piece. Immediate fiber optic bronchoscopy revealed almost a complete closure of TT due to posterior tracheal wall indrawing into the TT with every inspiratory effort. PMID- 23930243 TI - Intermittent left bundle branch block caused by coronary vasospasm. AB - Intermittent left bundle branch block (LBBB) has been reported in the literature following certain conditions such as cardiac blunt trauma, myocardial infarction (MI) or exercise induced LBBB. In the majority of cases, the patients usually have underlying coronary arteries disease. LBBB often prevents the electrocardiographic diagnosis of acute MI; therefore, new LBBB in the setting of chest pain is usually treated as transmural MI. We describe a case of patient who presented with intermittent LBBB associated with chest pain, and subsequently the patient was taken to the catheterization laboratory for emergency coronary angiogram, which revealed 80% spasm in left anterior descending artery, which was totally relieved by nitroglycerin infusion. No other significant CAD was noted. PMID- 23930241 TI - Idiopathic CD4 Lymphocytopenia: Spectrum of opportunistic infections, malignancies, and autoimmune diseases. AB - Idiopathic CD4 lymphocytopenia (ICL) was first defined in 1992 by the US Centers for Disease Control and Prevention (CDC) as the repeated presence of a CD4+ T lymphocyte count of fewer than 300 cells per cubic millimeter or of less than 20% of total T cells with no evidence of human immunodeficiency virus (HIV) infection and no condition that might cause depressed CD4 counts. Most of our knowledge about ICL comes from scattered case reports. The aim of this study was to collect comprehensive data from the previously published cases to understand the characteristics of this rare condition. We searched the PubMed database and Science Direct for case reports since 1989 for Idiopathic CD4 lymphocytopenia cases. We found 258 cases diagnosed with ICL in 143 published papers. We collected data about age, sex, pathogens, site of infections, CD4 count, CD8 count, CD4:CD8 ratio, presence of HIV risk factors, malignancies, autoimmune diseases and whether the patients survived or died. The mean age at diagnosis of first opportunistic infection (or ICL if no opportunistic infection reported) was 40.7 +/- 19.2 years (standard deviation), with a range of 1 to 85. One-sixty (62%) patients were males, 91 (35.2%) were females, and 7 (2.7%) patients were not identified whether males or females. Risk factors for HIV were documented in 36 (13.9%) patients. The mean initial CD4 count was 142.6 +/- 103.9/mm(3) (standard deviation). The mean initial CD8 count was 295 +/- 273.6/mm(3) (standard deviation). The mean initial CD4:CD8 ratio was 0.6 +/- 0.7 (standard deviation). The mean lowest CD4 count was 115.4 +/- 87.1/mm(3) (standard deviation). The majority of patients 226 (87.6%) had at least one infection. Cryptococcal infections were the most prevalent infections in ICL patients (26.6%), followed by mycobacterial infections (17%), candidal infections (16.2%), and VZV infections (13.1%). Malignancies were reported in 47 (18.1%) patients. Autoimmune diseases were reported in 37 (14.2%) patients. PMID- 23930244 TI - Alcoholic leukopenic pneumococcal sepsis. AB - Alcohol abuse has been associated with an increased mortality and morbidity due to increased aspiration, delirium tremens, and seizures. The association of pneumococcal lung infections and leukopenia in the setting of alcohol abuse are rarely reported; however, when present, severe lung infections can happen with severe lung injury and poor response to conventional therapy and ultimately, death. We are reporting a case of 55-year-old-man presented with shortness of breath, cough and altered mental status and eventually found with severe pneumococcal lung infection in the setting of leukopenia and long-term alcohol abuse representing alcoholic leukopenic pneumococcal sepsis syndrome. PMID- 23930245 TI - Telenovela: an innovative colorectal cancer screening health messaging tool. AB - BACKGROUND: Alaska Native people have nearly twice the rate of colorectal cancer (CRC) incidence and mortality as the US White population. OBJECTIVE: Building upon storytelling as a culturally respectful way to share information among Alaska Native people, a 25-minute telenovela-style movie, What's the Big Deal?, was developed to increase CRC screening awareness and knowledge, role-model CRC conversations, and support wellness choices. DESIGN: Alaska Native cultural values of family, community, storytelling, and humor were woven into seven, 3-4 minute movie vignettes. Written post-movie viewing evaluations completed by 71.3% of viewers (305/428) were collected at several venues, including the premiere of the movie in the urban city of Anchorage at a local movie theater, seven rural Alaska community movie nights, and five cancer education trainings with Community Health Workers. Paper and pencil evaluations included check box and open-ended questions to learn participants' response to a telenovela-style movie. RESULTS: On written-post movie viewing evaluations, viewers reported an increase in CRC knowledge and comfort with talking about recommended CRC screening exams. Notably, 81.6% of respondents (249/305) wrote positive intent to change behavior. Multiple responses included: 65% talking with family and friends about colon screening (162), 24% talking with their provider about colon screening (59), 31% having a colon screening (76), and 44% increasing physical activity (110). CONCLUSIONS: Written evaluations revealed the telenovela genre to be an innovative way to communicate colorectal cancer health messages with Alaska Native, American Indian, and Caucasian people both in an urban and rural setting to empower conversations and action related to colorectal cancer screening. Telenovela is a promising health communication tool to shift community norms by generating enthusiasm and conversations about the importance of having recommended colorectal cancer screening exams. PMID- 23930246 TI - The influence of ureteral orifice configuration on the success rate of endoscopic treatment of vesicoureteral reflux. AB - BACKGROUND: To investigate the effect of polyacrylate polyalcohol copolymer (Vantris) injection for the correction of VUR in children according to ureteral orifice shape and VUR grade. MATERIALS AND METHODS: Forty children (29 girls and 11 boys) with 61 renal refluxing units (RRU) and primary VUR underwent endoscopic correction of their reflux, using Vantris. Under general anesthesia, routine cystoscopy was performed and ureteral orifice configuration and dynamic hydro distention grade were determined. The injection technique was STING, HIT or a combination of them. Ultrasound scan was performed one and 3 months after injection and radionuclide cystography (RNC) was performed 3 months after the operation. RESULTS: The mean volume of injected Vantris was 0.62 cc. Reflux was corrected in 52 (85.2%) of the 61 RRU after single injection and this equates reflux correction in 37 of the 40 patients. No significant correlation was observed between ureteral orifice shape and VUR correction rate. CONCLUSIONS: Our results showed that there was no correlation between the ureteral orifice configuration and the success rate of endoscopic surgery for VUR in short term. PMID- 23930247 TI - Comparison between examination with naked eye, curretage and dermoscopy in determining tumor extension before Mohs micrographic surgery. AB - Mohs micrographic surgery (MMS) is a technique for the treatment of cutaneous malignancies. Subtle determination of tumor margin would end to fewer stages of surgery. Our aim was to compare these three ways for determining tumor extension before initiation of MMS, examination with the naked eye, dermoscopy and curettage. Sixty patients who had basal cell carcinoma (BCC) in head and neck area were randomized in three groups (curettage, dermoscopy and examination with the naked eye). Each group encompassed twenty patients. The total number of resection stages in MMS was recorded for each patient. Demographic data of the patients and the total number of resection stages in MMS were statistically analyzed. Based on analysis of variance (ANOVA) test results, there was no significant difference for total number of stages in statistical point of view between three groups (P value = 0.1). In this research, the Pearson correlation coefficient showed that there is a direct relation between the age and resection stages (r = 0.19, P value = 0.04). The Chi-square test showed no differences between three groups in age, residence and radiotherapy history. PMID- 23930248 TI - Prostate cancer: Relationship between vascular diameter, shape and density and Gleason score in needle biopsy specimens. AB - BACKGROUND: Tumor growth requires expansion and development of vascular network. An increase in Gleason score is representative of an increase in tumor invasion and extent. In this study, the relationship between Gleason score and vascular characteristics of needle biopsy samples in prostate cancer patients has been evaluated. MATERIALS AND METHODS: We evaluated vascular characteristics including density and size of vessels; and percentage of vessels with irregular shape in 62 cancer-positive samples obtained by prostate needle biopsy under ultrasound guide, and compared them to Gleason score. RESULT: Gleason scores of 23 patients were <=6; Gleason scores of 18 patients were 7 and 21 patients had their Gleason score from 8 to 10. An increase in Gleason score was associated with increased vascular density (P < 0.0001), increased percentage of vessels with irregular shape (P < 0.02) and decreased average vascular diameter (P < 0.015), from which the relationship with vascular density was clearer and more evident. CONCLUSION: Vascular morphological characteristics can be representative of angiogenic potential of prostate cancer which is required for tumor progression. As Gleason score can prognosticate the behavioral characteristics of prostate cancer in future, vascular characteristics may also be able to express tumor behavior. With attention to vascular characteristics in biopsy samples and apart from Gleason score, we may also be able to divide patients into other subtypes in a way being helpful for the establishment of treatment plan. PMID- 23930249 TI - Early versus delayed initiation of nasal continuous positive airway pressure for treatment of respiratory distress syndrome in premature newborns: A randomized clinical trial. AB - BACKGROUND: This prospective study was performed to identify whether the early use of nasal continuous positive airway pressure (n CPAP) would reduce the rate of endotracheal intubation, mechanical ventilation and surfactant administration. MATERIALS AND METHODS: This study was conducted from June 2009 to September 2010 in the Shahid Beheshti University Hospital, Isfahan-Iran. A total of 72 preterm infants with 25-30 weeks gestation who needed respiratory support at 5 min after birth entered the study. Infants were randomly assigned to the very early CPAP (initiated 5 min after birth) or to the late CPAP (initiated 30 min after birth) treatment groups. The primary outcomes were need for intubation and mechanical ventilation during the first 48 h after birth and secondary outcomes were death, pneumothorax, intraventricular hemorrhage, duration of mechanical ventilation and bronchopulmonary dysplasia. RESULTS: There were no significant differences between the two groups with regard to mortality rate, bronchopulmonary dysplasia and patent ductus arteriosus. The need for surfactant administration was significantly reduced in the early CPAP group (P = 0.04). Infants in the early CPAP group less frequently required intubation and mechanical ventilation. CONCLUSIONS: Early n CPAP is more effective than late n CPAP for the treatment of respiratory distress syndrome. In addition, the early use of n CPAP would reduce the need for some invasive procedures such as intubation and mechanical ventilation. PMID- 23930250 TI - Sensorineural hearing loss in patients with coronary artery bypass surgery. AB - BACKGROUND: This study is planned to obtain a better understanding of the correlation between sudden sensorineural hearing loss and cardiopulmonary bypass. There are many causes for sudden hearing loss which include infectious, circulatory, inner ear problems like meniere's disease, neoplastic, traumatic, metabolic, neurologic, immunologic, toxic, cochlear, idiopathic (unknown cause) and other causes. One of the less common cause is surgery include cardiopulmonary bypass procedures. MATERIALS AND METHODS: This study is a self controlled clinical trial on 105 patients that was carried out in chamran Hospital, Esfahan, Iran. Participants were including all those patients undergoing coronary artery bypass surgery in the hospital who fell under the criteria for inclusion. Patients underwent audiometric testing at our hospital on three or two different occasions during the course of this study, Initially before the procedure to test the baseline hearing capacity; then two week after the procedure to assess any changes in hearing ability following the surgery. Data analysis performed by co variance analysis. RESULTS: In our study the changes in the threshold of hearing in frequency of 1000 in right ear and in frequencies of 2000 and 4000 in left ear were significant, but this changes were about 2-3 db and were not noticeable. The difference in degree of SNHL, before and after surgery in different frequencies were been shown. CONCLUSION: As loss of the patients with symptomatic sensory neural hearing loss in this study, It isn't commanded the routin auditory assessment pre and post surgery was been done. PMID- 23930252 TI - A new multiplex polymerase chain reaction assay for the identification a panel of bacteria involved in bacteremia. AB - BACKGROUND: Throughout the world, bloodstream infections (BSIs) are associated with high rates of morbidity and mortality. Rapid pathogens identification is central significance for the outcome of the patient than culture techniques for microbial identification. To develop an end point multiplex PCR to identify a group of bacteria including Enterococcus spp., Pseudomons aeruginosa, Staphylococcus spp., Acinetobacter baumannii, 16S rDNA, and Drosophila Melanogaster were used as internal control (IC). MATERIALS AND METHODS: Design of primers was done using Mega4, Allel ID6, Oligo6 and Oligo analyzer softwares. Genetic targets for primer designing and identification of genus Enterococcus spp., Staphylococcus spp., and species of Acinetobacter baumannii, Pseudomons aeruginosa, included the rpoB, rpoB and gyrA, sss respectively. Then PCR and multiplex PCR were performed. RESULTS: The intended specificity was obtained for the bacteria, which used in this study and there wasn't seen any unspecific amplification by the multiplex PCR. The test showed a sensitivity ranging from 1 to 100 target copies per reaction depending on the bacterial species. CONCLUSIONS: The presented multiplex PCR offers a rapid and accurate molecular diagnostic tool for simultaneous detection of some pathogenic microorganisms. The IC exists in the multiplex PCR accompanied by other primers in the system, can serve as a simple, cost- effective internal control for the multiplex PCR assay. PMID- 23930251 TI - An insight into genetics of non-syndromic cleft palate. AB - Our proband is a 29-year-old man, who is affected with soft cleft palate and hypernasality. A study of about six generations of this family pedigree shows that cleft palate has repeatedly occurred in males, with probably a X-linked recessive pattern of inheritance. Interestingly, the sister of the proband is affected with hypernasality and she has an affected son. This is the first report of X-linked inheritance pattern of cleft palate in Iran. PMID- 23930253 TI - Progesterone therapy in women with intractable catamenial epilepsy. AB - BACKGROUND: Catamenial epilepsy is a kind of epilepsy, known in this name, when the periodicity of the exacerbation of the seizure is in association with menstural cycle. The present study examined the progesterone effectiveness as a complementary treatment in women with intractable catamenial epilepsy. MATERIALS AND METHODS: The present study was conducted as a double-blind randomized controlled trial on 38 women with intractable catamenial epilepsy. Patients were assessed in two groups: The case group received in addition to AEDs, two (Mejestrol) 40 mg progesterone tablets in the second half of the cycle from 15(th) to 25(th) day. And the control group received in addition to AEDs, two placebo tablets daily. Age, BMI, epilepsy duration, types of the drugs used, progesterone level, and the number of the seizures in 3 months before and after the study were compared. RESULTS: Based on the results of which there was no statistically significant difference in regard to age, BMI, epilepsy duration, types of the drugs used, progesterone level between the case and the control groups (P-value > 0.05). The number of the seizures after treatment has significantly decreased compared to before-treatment state. The degree of decreasing in the case group receiving the progesterone was higher than in the control group receiving the placebo. The difference, thus, is significant, based on statistical tests (P-value = 0.024). CONCLUSION: Based on the findings of this study using progesterone in women with intractable catamenial epilepsy has a significant effect on the degree of decreasing in the number of the seizures. PMID- 23930254 TI - Preemptive analgesia with intra-articular pethidine reduces pain after arthroscopic knee surgery. AB - BACKGROUND: Postoperative pain relief is important in procedures of the lower extremity. Several previous studies have evaluated the efficacy of intra articular (IA) pethidine as a compound, which has local anesthetic and opioid agonist properties, on postoperative pain relief in arthroscopic knee surgery (AKS). This study compared the postoperative analgesic effect of pre- and post surgical IA pethidine administration in AKS. MATERIALS AND METHODS: Seventy-five patients of American Society of Anesthesiologists (ASA) I and II undergoing AKS with general anesthesia were enrolled in this double-blind study. Patients were randomized in three equal groups to receive either 50 mg IA pethidine before surgical incision incision and saline after skin closure (PS), saline before surgical incision and pethedine after skin closure (SP), and only saline at two different times (SS). In each patient with operated knee joint, pain at rest and joint movement was evaluated at 1, 2, 6, 12, and 24 h after surgery completion using Visual Analog Scale (VAS). Data were analyzed using analysis of variance (ANOVA)-repeated measure, t-paired, and Chi-square tests. RESULTS: Postoperative pain score at rest and joint movement in PS group was significantly lower than those in other groups. The time (Mean +/- SD) between completion of operation and patient's request for morphine, total morphine consumption (Mean +/- SD) in postoperative 24 h, and the numbers of patients requesting analgesic in PS, SP, SS, groups were: 5.2 +/- 1.3, 3.3 +/- 1.5, and 2 +/- 1.3 h (P < 0.05); 4.4 +/- 2.4, 8.7 +/- 2, and 11.6 +/- 4.4 mg (P < 0.05); 11, 18, and 21 persons (P < 0.05), respectively. CONCLUSION: The present study shows that preemptive intra articular pethidine 50 mg injection is more effective than preventive injection for postoperative pain relief at rest and joint movement in arthroscopic knee surgery. PMID- 23930255 TI - Effect of aromatherapy with orange essential oil on salivary cortisol and pulse rate in children during dental treatment: A randomized controlled clinical trial. AB - BACKGROUND: Essential oils have been used as an alternative and complementary treatment in medicine. Citrus fragrance has been used by aromatherapists for the treatment of anxiety symptoms. Based on this claim, the aim of present study was to investigate the effect of aromatherapy with essential oil of orange on child anxiety during dental treatment. MATERIALS AND METHODS: Thirty children (10 boys, 20 girls) aged 6-9 years participated in a crossover intervention study, according to the inclusion criteria, among patients who attended the pediatric department of Isfahan Dental School in 2011. Every child underwent two dental treatment appointments including dental prophylaxis and fissure-sealant therapy under orange aroma in one session (intervention) and without any aroma (control) in another one. Child anxiety level was measured using salivary cortisol and pulse rate before and after treatment in each visit. The data were analyzed using t-test by SPSS software version 18. RESULTS: The mean +/- SD and mean difference of salivary cortisol levels and pulse rate were calculated in each group before and completion of treatment in each visit. The difference in means of salivary cortisol and pulse rate between treatment under orange odor and treatment without aroma was 1.047 +/- 2.198 nmol/l and 6.73 +/- 12.3 (in minutes), which was statistically significant using paired t-test (P = 0.014, P = 0.005, respectively). CONCLUSION: It seems that the use of aromatherapy with natural essential oil of orange could reduce salivary cortisol and pulse rate due to child anxiety state. PMID- 23930256 TI - Effects of gamma irradiation on microbial load and quality characteristics of veal. AB - BACKGROUND: Veal is a rich nutrient medium that provides a suitable environment for proliferation of veal spoiling microorganisms and common food-borne pathogens. In this study, the effects of irradiation on the veal microbiological quality and half life of minced beef during chilled storage was investigated. MATERIALS AND METHODS: Twenty samples of minced veal were irradiated with doses of 2, 5, 7, and 10 kGy (Cobalt-60, gamma cell 220) and evaluated for their microbiological quality up to 10 days. RESULTS: The results showed that gamma irradiation reduced the number of microorganisms in all the irradiated minced veal samples, with 2, 5, 7, and 10 kGy (P < 0.01). Moreover, the half life of the samples were increased considerably (P < 0.01). In addition, the results indicated that there was a significant difference in the number of coliformes between untreated and irradiated samples (P < 0.05). While, Staphylococcus aureus could not be detected in the irradiated samples with doses of 7 and 10 kGy. CONCLUSION: These results indicated that irradiation could be employed as an effective mean to inactivate common food-borne pathogens namely S. aureus and increases the half life of veal. PMID- 23930257 TI - Pre emptive analgesia for reducing pain after cholecystectomy: Oral tramadol vs. acetaminophen codeine. AB - BACKGROUND: Considering that protocols of postoperative pain management would be planned regarding the facilities of each center or region and the importance of its proper management to reduce its related complication and improve patient's satisfaction, in this study we compared the effect of orally administrated tramadol and acetaminophen-codeine in this regard. MATERIALS AND METHODS: In this prospective randomized double-blind clinical trial, 136 (68 in tramadol and 68 in acetaminophen codeine groups) ASA I and II patients scheduled for open cholecystectomy under general anaesthesia were enrolled. They randomly allocated to receive oral tramadol (50 mg capsule) or acetaminophen-codeine (325/10 mg) 1 hour before surgery. After surgery they evaluated for postoperative pain using VAS score, analgesic consumption and vomiting. RESULTS: Mean of postoperative pain score during 24 hours after surgery was 2.1 +/- 1.0 and 3.8 +/- 2.0 in tramadol and acetaminophen-codeine groups, respectively (P < 0.05). Mean of analgesic consumption (morphine) during 24 hours after surgery was 6.2 +/- 4.4 mg and 12.9 +/- 5.7 mg in tramadol and acetaminophen-codeine groups, respectively (P < 0.05). Mean of vomiting during 24 hours after surgery was 1.2 +/-0.9 and 0.4 +/ 0.5 in tramadol and acetaminophen-codeine groups, respectively (P < 0.05). CONCLUSION: The findings of current study indicated that in lower dose of tramadol (50 mg) and acetaminophen/codeine (325 mg/10 mg) the analgesic effect of tramadol is better and its side effects are higher than acetaminophen/codeine, which limit its use for mentioned purpose. It seems that administration of each of studied agents it depends on patients' tolerance and decision of the physician. PMID- 23930258 TI - The comparison of Staphylococcus aureus types 5 and 8 with respect to methicillin resistance in patients admitted to Al-Zahra Hospital by PCR. AB - BACKGROUND: Staphylococcus aureus is a common human pathogen in community- and hospital-acquired infection, and its capsule is involved in pathogenesis. The predominance of 2 capsular polysaccharides types 5 and 8, on the surface of clinical isolates, led to the development of conjugate vaccine (Staph VAX) based on capsular polysacchrides types 5 and 8 conjugated to a carrier protein. The aim of this study was to determine the prevalence of capsular polysaccharides types 5 and 8 Staphylococcus aureus strains among isolates and their comparison with respect to methicillin resistance. MATERIALS AND METHODS: We studied the capsular genotypes of 193 isolates that encompassed both hospital- and community-acquired infection in Al-Zahra Hospital of Isfahan city from 2008 to 2009. Cap5 and 8 genes were detected by PCR method. Methicillin resistance was determined by PCR (mecA) and disk diffusion methods as well. RESULT: In this population (193 cases), most of the clinical isolates (73%) expressed capsular polysaccharide type 5 (24%) and 8 (49%), whereas 27% were non-typeable. The prevalence of MRSA in type 8 was 67.9%, whereas MRSA isolates in the capsular genotype 5 were 22.2%. CONCLUSION: This study Staphylococcus aureus confirms that the prevalence of capsular polysaccharide types (5 and 8) are predominant, and Staphylococcus aureus type 8 is more resistant to methicillin compared to type 5. PMID- 23930259 TI - Evaluation the treatment outcomes of intracapsular femoral neck fractures with closed or open reduction and internal fixation by screw in 18-50-year-old patients in Isfahan from Nov 2010 to Nov 2011. AB - BACKGROUND: There is conflict of interest in the treatment of intracapsular femoral neck fractures and the outcomes. The aim of this study was evaluation the treatment outcomes of closed and open reduction and internal fixation with screw in 18-50-year-old patients. MATERIALS AND METHODS: This clinical randomized study was conducted in Ayatollah Kashani Center in Isfahan from Nov 2010 to Nov 2011. In 42 patients selected in a randomized manner, fractures were reduced by closed reduction or open if necessary and C-ARM was controlled in AP and lateral plans. Movement range and femur pain severity were evaluated according to Visual analogue Scale (VAS) score at 3 and 6 months after surgery. Data were analyzed by SPSS 18. Chi-square, t-test, one-way analysis of variance (ANOVA), and descriptive statistics such as frequency distribution, mean, and mean deviation were used. RESULTS: Forty-two patients with femoral neck fracture were treated by open [31 patients (73.8%)] or closed reduction [11 patients (26.2%)] and also osteosynthesis. Their mean age was 47.3 +/- 9.8 years; 29 of them were males and 13 were females. Twelve patients had bad range of motion (ROM) (28.6%), 16 had intermediate ROM (38%), and 14 had good ROM (33.4%). After 6 months, 12 patients (28.6%) had bad ROM, 10 (23.8%) had intermediate ROM, and 20 (47.6%) had good ROM. There were 11 cases of non-union (35.5%) in the open reduction group and 4 in the closed group. CONCLUSION: This study showed that femoral neck fracture is associated with several complications, especially if open reduction was necessary. So, the surgical method and necessary equipments such as radiolucent bed, C-ARM machine, and implant cannulated screw set should be considered. PMID- 23930260 TI - A morphological study to note the variable patterns of cutaneous innervation on the dorsum of foot in south Indian human foetuses and its clinical implications. AB - BACKGROUND: Cutaneous nerves on the dorsum of foot are at risk for iatrogenic damage while performing arthroscopy, local anaesthetic block, surgical approach to the fibula, open reduction and internal fixation of lateral malleolar fractures, application of external fixators, elevation of a fasciocutaneous or fibular flaps for grafting, surgical decompression of neurovascular structures, or miscellaneous surgery on leg, foot and ankle. Hence the present study was undertaken to classify the different patterns of cutaneous innervation on the dorsum of foot of foetuses which will help in minimizing iatrogenic damage to the nerves. MATERIALS AND METHODS: A total of 40 lower limbs from 20 foetuses were dissected and the branching patterns of nerves were noted and specimens were photographed. RESULTS: Four distinct patterns of innervation with additional subtypes were identified and designated as Type 1 a-g; 2 a-d; 3; 4 a-c. CONCLUSION: Detailed knowledge about the pattern of cutaneous innervation of dorsum of foot may decrease the damage to these nerves during operative procedures near the foot and ankle. PMID- 23930261 TI - Berlin questionnaire study in surgical patient in Alzahra Hospital in year 2010. AB - BACKGROUND: To examine the prevalence of high-risk subjects of obstructive sleep apnea (OSA) and its predictive factors in patients undergoing elective surgery by using the Berlin Questionnaire. MATERIALS AND METHODS: 300 surgical ASA physical status I, II, III, and IV patients were surveyed. Patients were screened with the Berlin questionnaire for obstructive sleep apnea. Data of sex, age, BMI and HTN also evaluated. Data were analyzed by Chi-square test and P < 0.05 was meaningful. RESULTS: The Berlin questionnaire identified 25.3% (76/300) of patients as being at high risk of sleep apnea (95% confidence interval, 20%-28%). This group consisted of 195 (65%) males and 105 (35%) females. The prevalence of high-risk subjects in men were more significantly than women (P = 0.001). High risk subjects also were increasing with age (P = 0.000) and increasing with obesity (P = 0.000) and arterial hypertension (P = 0.000). CONCLUSIONS: Predictors of high risk for OSA-related symptoms were female sex, age more than 50 years, and body mass index. PMID- 23930262 TI - Comparison of effectiveness and safety of Iranian-made vs. Indian-made imatinib in treatment of chronic myeloid leukemia. AB - BACKGROUND: Currently, imatinib is the drug of choice for initiation of medical treatment of chronic myeloid leukemia (CML) in the chronic phase. The current study was carried out to compare effectiveness and safety of Iranian vs. Indian imatinib. MATERIALS AND METHODS: The clinical study was performed on newly diagnosed CML patients in Seyyed-oShohada Hospital (Isfahan) and Khansari Hospital (Arak) from January to June 2011. The control group consisted of CML patients who received Indian imatinib previously. The drug was initiated with the dose of 400 mg daily. The patients were followed for six months, and the treatment outcomes (WBC <10(4)) and molecular response. Finally, the two groups were compared in these respects. RESULT: We evaluated 43 patients in each group. The hematological and molecular responses for the Iranian Imatinib were respectively 86.0% and 46.5%, while the rates were respectively 86.0 and 44.2% for the Indian imatinib. The two groups were similar with regard to the treatment outcome. The two groups were not significantly different with regard to the drug adverse effects. CONCLUSION: According to the findings, the Iranian imatinib is not different from the Indian drug in the hematological and molecular responses in treatment of the chronic phase of CML patients. Furthermore, the adverse effects of the two kinds were not significantly different. Compared with the results of other studies, the effectiveness of Iranian imatinib is equivalent to the Indian drug can be employed for treatment of CML patients in the chronic phase. PMID- 23930263 TI - Phenotypic characterization and PCR-Ribotypic profile of Pseudomonas aeruginosa isolated from cystic fibrosis patients in Iran. AB - BACKGROUND: Pseudomonas aeruginosa, is the most common pathogen in patients with cystic fibrosis (CF) that shows various resistance to antibiotics, acquires mucoidity and multiple genotypes. This survey was performed to study phenotypic and genotypic variations among P. aeruginosa isolates in CF patients at Alzahra Hospital in Isfahan, Iran. MATERIALS AND METHODS: The isolates of Pseudomonas aeruginosa from CF patients at Alzahra Hospital was identified by appropriate biochemical and microscopic tests, then performed antibiotic resistance tests and mucoid colony morphotyping. The genum of isolates extracted and confirmed on 16S rDNA-based PCR assay and typed on 16S rDNA-23SrDNA spacer, restricted with Hinf1 restriction enzyme. RESULTS: P. aeruginosa was isolated from 21 of the 59 CF patients (35.5%), Out of 21 isolates 9 (42.8%) strains were revealed mucoid morphotype. 81.8% isolates of mucoid strains were resistance to at least one of four antibiotics (GM, AN, PIP and CP). Most of the isolates (86%) showed resistance to ceftazidime. Ribotyping revealed two patterns (P1, P5). CONCLUSION: The isolates of P. aeruginosa showed meaningful difference between drug resistance to antibiotics. The majority of P. aeruginosa isolated from CF patients showed pattern1 of PCR-Ribotyping. PMID- 23930264 TI - Comparing two methods of plastination and glycerin preservation to study skeletal system after Alizarin red-Alcian blue double staining. AB - BACKGROUND: Plastination is a new method of preserving tissue samples for a long time. This study aimed to compare the new plastination technique with the conventional preservative method in glycerin for fetus skeleton tissues and young rats dyed by Alizarin red- Alcian blue double staining. MATERIALS AND METHODS: In this study, 4 groups of 1-day, 3-day, 12-day and mature rats were selected and, after being anesthetized and slaughtered, their skin was completely removed. In Alizarin red- Alcian blue double staining method, first the samples were fixed in 95% ethanol and then their cartilages were dyed by 0.225% Alcian blue solution; after that, they were cleared in 1% KOH. Then, the bones were dyed in 0.003% Alizarin red solution and finally the tissue was decolorized in 95% ethanol. In each group, half of the samples were preserved by the conventional method in a glycerin container and the other half were plastinated. RESULTS: In the present study, the samples preserved by plastination technique were dry, odorless, indecomposable and tangible. Quality of coloring had an inverse relationship with rats' age. Transparency of the plastinated samples had also an inverse relationship with rats' age. Therefore, skeletal tissue of younger rats had higher quality and transparency in both preservation methods (glycerin and plastination). CONCLUSION: This study showed that plastination technique was an appropriate method in comparison with glycerin preservation, which conserved skeletal tissue of fetus and young rats colored by Alizarin red- Alcian blue double staining. And the final result was that plastination technique can generate dry, odorless, indecomposable and tangible samples. PMID- 23930265 TI - Emergency peripartum hysterectomy in Isfahan; maternal mortality and morbidity rates among the women who underwent peripartum hysterectomy. AB - BACKGROUND: Peripartum hysterectomy is associated with significant morbidity and mortality. We determined the factors leading to and maternal mortality and morbidity rates among the women whose underwent peripartum hysterectomy in Iran. MATERIALS AND METHODS: This case-series study was conducted from March 2004 to March 2009 in the Department of Gynecology and Obstetrics at two central university hospitals (Azahra hospital and Shahid Beheshti Hospital) in Isfahan. Forty one women among 29,444 deliveries underwent peripartum hysterectomy. Women who had delivery before 24 weeks and a hysterectomy for other reasons like sterilizations were excluded. Incidence, indications and maternal complications including maternal death and urological, infectious and wound complications were evaluated after operation. RESULTS: During the study period, the incidence of peripartum hysterectomy estimated about 1.39 per 1,000 deliveries. The maternal mortality rate was 17.07%. There was no statistical difference in mortality rates between referrals and non-referrals women (P = 0.6). Post-operative complications included infection (22%), bladder injuries (7.3%), urine retention (4.8%) and wound dehiscence (4.87%). The main indication was placenta accreta 28 (68.3%). CONCLUSION: This study indicated the high rate of mortality among patients underwent peripartum hysterectomy. Evaluation of management during referring the patients and designing more studies to evaluate the mortality and morbidities are warranted. PMID- 23930266 TI - The authors respond. PMID- 23930267 TI - The authors respond. PMID- 23930268 TI - Author response-vitamin D deficiency and systemic inflammation in bronchiectasis. PMID- 23930269 TI - Genetic variants in pre-eclampsia should be interpreted with caution. PMID- 23930270 TI - [Influenza vaccination for healthcare workers who work with the elderly]. PMID- 23930271 TI - A web-based intervention to improve and prevent low back pain among office workers: a randomized controlled trial. AB - OBJECTIVES: To test the feasibility, safety, and efficacy of a web-based multidisciplinary intervention for office workers with subacute, nonspecific low back pain. METHODS: The randomized controlled trial included 100 office workers with subacute low back pain. The intervention group had access to both the study intervention and standard care. The control group had access to standard care only. Standard care was defined as all existing non-web-based interventions offered by the University of Extremadura's Preventive Medicine Service. The web based program was offered via the Preventive Medicine Service website. The participants in the intervention group were asked to engage in the web-based program at their work site for 11 minutes each day, 5 days a week. Primary outcomes were functional disability, as measured by the Roland-Morris Disability Questionnarie, and health-related quality of life, as measured by the European Quality of Life-5 Dimensions-3 Levels. Secondary outcomes were the number of episodes of low back pain and trunk muscles endurance. Outcomes were measured before and after the 9-month intervention period. RESULTS: Over the 9-month study, the score on the Roland-Morris Disability Questionnaire for the participants in the web-based intervention group improved by a mean of -7.36 points (95% confidence interval [CI]:-8.41, -6.31) compared to a worsening of 1.89 points (95% CI: 0.71, 2.65) in the control group. The between-group difference in change on the Roland-Morris Disability Questionnarie over the study period was -9.25 points (95% CI:-10.57, -7.89). Similarly, over the compared to the control group. CONCLUSIONS: A 9 month web-based intervention is feasible and effective to improve function and health-related quality of life and to decrease episodes of low back pain among office workers with a history of subacute, nonspecific low back pain. PMID- 23930272 TI - [News from the European Agency for Health and Safety at Work]. PMID- 23930273 TI - [News from the National Institute of Safety and Hygiene at Work]. PMID- 23930274 TI - Cardiovascular risks with azithromycin. PMID- 23930275 TI - Reply to K. Orendi et al. PMID- 23930276 TI - Reply to M.L. Friedlander et al. PMID- 23930277 TI - Reply to M.L. Friedlander et al. PMID- 23930278 TI - Data-sharing: Everything on display. PMID- 23930280 TI - Handle with care. PMID- 23930279 TI - An essential requirement for the licensing of new antibiotics is the provision of data on efficacy and safety obtained from clinical trials in which patients are randomized to receive either the experimental drug or a comparator antibiotic regarded as a standard treatment option. Preface. PMID- 23930281 TI - Blood ties. PMID- 23930282 TI - New CMS guidelines suggest changes in advance directive policies. PMID- 23930283 TI - ASCs must prepare to meet latest CMS infection control expectations. PMID- 23930285 TI - [Mobbing: bullying or just "workplace acceptability"?]. PMID- 23930284 TI - [Disability and disability insurance in the private: issues in the assessment]. PMID- 23930286 TI - [Doctor's error in the treatment of functional and somatoform disorders]. PMID- 23930290 TI - Part 2: a troubled state. What can we learn from Iowa's experience? PMID- 23930291 TI - Case study: connecting patients to social services. PMID- 23930292 TI - Case study: shaping up Seniors in Washington State. PMID- 23930293 TI - Do retirement savings policies increase total retirement saving? PMID- 23930295 TI - The revenue demands of public employee pension promises. PMID- 23930294 TI - Behavioral hazard in health insurance. PMID- 23930296 TI - What makes annuitization more appealing? PMID- 23930297 TI - The prevalence and economic consequences of disability. PMID- 23930298 TI - Seven tricks to boost your energy. PMID- 23930299 TI - Surprising ways to cut your drug costs: even with insurance you might be paying too much. PMID- 23930300 TI - Your safer-surgery survival guide: our ratings of 2,463 U.S. hospitals can help you find the right one. PMID- 23930301 TI - Are the mechanical properties of zirconia abutments sufficient for clinical use? PMID- 23930302 TI - Building a business case for evidence-based medicine. PMID- 23930303 TI - VE debate. PMID- 23930304 TI - Simple answers. PMID- 23930306 TI - Government announces changes to workplace laws. PMID- 23930305 TI - Overcoming disability. PMID- 23930307 TI - Panacea for the ageing nurse. PMID- 23930308 TI - Moral distress. PMID- 23930309 TI - Access to global health. PMID- 23930310 TI - The Coroner's Court and nursing practice. PMID- 23930311 TI - The impact of workplace bullying in nursing. PMID- 23930312 TI - Debriefing to make a difference: a nursing lecturer's experience. PMID- 23930313 TI - Working life. PMID- 23930314 TI - Magnesium sulphate for the prevention of cerebral palsy in Australia and New Zealand. PMID- 23930315 TI - 'Precovery': a proactive version of recovery in perinatal mental health. PMID- 23930316 TI - Team effort to provide more convenient care. PMID- 23930317 TI - Introducing hearing assessment into diabetes care. PMID- 23930318 TI - My role as a chronic illness management nurse. PMID- 23930319 TI - Aboriginal and Torres Strait Islanders tobacco smoking: tackling the challenge. PMID- 23930320 TI - Obstructive sleep apnoea. PMID- 23930321 TI - Are you looking after yourself? PMID- 23930322 TI - The people of Alpha Omega: delivered at the 2011 International Convention. PMID- 23930323 TI - Is it better to give than receive? PMID- 23930324 TI - Evolving settings for dental services for individuals with special health needs. PMID- 23930325 TI - Lessons from the great molasses flood of Boston. PMID- 23930326 TI - Would you believe that about 1-in-5 U.S. children has a disability? AB - A review of a series of federation reports documents the numbers of youngsters with a variety of special health care needs who are residents in our communities and are dependent upon local dentists for needed services. The increased costs for health care and complexities of access to this care are emphasized. While dental schools have introduced changes in their curricula to improve the preparation of new graduates to provide services for patients with special health care needs, the challenge is to provide current practitioners with programs to ensure the treatment of youngsters (and the not so young) with disabilities. PMID- 23930327 TI - More than 71 million seniors (including 26 million with disabilities) will reside in the United States in 2030. AB - In the coming years the United States will experience a burgeoning number of senior residents, including those with disabilities. A review of these developments and the dental and medical concerns in the delivery of dental services is presented. PMID- 23930328 TI - Dental health of children with autism spectrum disorders: a population-based study. AB - Data from the 2007 National Survey of Children's Health were used to investigate how autism spectrum disorder (ASD) symptom severity and comorbidity are associated with the dental health needs of children. The results of this study help provide insights into the greater oral needs of the increasing population of children with ASD that reside in our communities and their dependency upon local practitioners for treatment. PMID- 23930329 TI - Hispanic health and social inequalities: an inventory. PMID- 23930330 TI - What is Special Olympic Special Smiles? PMID- 23930331 TI - Stem cell therapy for bone regeneration: present and future strategies. AB - Alveolar bone atrophy may occur due to trauma, malignancy and periodontal disease. Restoring the lost bone is crucial for the rehabilitation of the patient's functioning, phonetics and aesthetics. Currently the methods available for vertical bone augmentation prior to dental implant placement are rather limited. This paper describes present and future concepts of utilizing mesenchymal stem cells (MSC) as well as endothelial progenitor cells (EPC) for enhancing bone growth in severe atrophic cases. Stem/progenitor cell-based regenerative therapy may prove to be the best option to meet individual patient needs and open new horizons in periodontal, maxillofacial and implant surgery. PMID- 23930332 TI - Zinc status in South Asian populations--an update. AB - This article attempts to highlight the prevalence of zinc deficiency and its health and economic consequences in South Asian developing countries and to shed light on possible approaches to combating zinc deficiency. A computer-based search was performed on PubMed, Google, and ScienceDirect.com to retrieve relevant scientific literature published between 2000 and 2012. The search yielded 194 articles, of which 71 were culled. Studies were further screened on the basis of population groups, age and sex, pregnancy, and lactation. The most relevant articles were included in the review. Cutoffs for serum zinc concentration defined for zinc deficiency were 65 microg/dL for males and females aged < 10 years, 66 microg/dL for non-pregnant females, and 70 microg/dL for males aged > or = 10 years. Population segments from rural and urban areas of South Asian developing countries were included in the analysis. They comprised pregnant and lactating women, preschool and school children. The analysis reveals that zinc deficiency is high among children, pregnant and lactating women in India, Pakistan, Bangladesh, Sri Lanka, and Nepal. Diarrhoea has been established as a leading cause to intensify zinc deficiency in Bangladesh. Little has been done in Sri Lanka and Nepal to estimate the prevalence of zinc deficiency precisely. A substantial population segment of the South Asian developing countries is predisposed to zinc deficiency which is further provoked by increased requirements for zinc under certain physiological conditions. Supplementation, fortification, and dietary diversification are the most viable strategies to enhancing zinc status among various population groups. PMID- 23930334 TI - Coverage and awareness of and compliance with mass drug administration for elimination of lymphatic filariasis in Burdwan District, West Bengal, India. AB - India adopted WHO's strategy of repeated rounds of mass drug administration (MDA) with diethylcarbamazine to eliminate lymphatic filariasis. The present study attempted to assess the coverage and awareness of and compliance with MDA for elimination of lymphatic filariasis in Burdwan district of India, following MDA round in July 2010. A cross-sectional study was conducted among the four randomly selected clusters in the district of Burdwan, West Bengal, India, covering 603 individuals from 154 households, using a predesigned pretested schedule. The drug distribution coverage, compliance, and effective coverage were 48.76%, 70.07%, and 34.16% respectively. Only 41.4% of the study population was aware of the MDA activity. This evaluation study noted that MDA is restricted to tablet distribution only. There is an urgent need to improve compliance with drug intake through strengthening of the awareness programme involving both government health workers and community volunteers. PMID- 23930333 TI - Socioeconomic factors in adherence to HIV therapy in low- and middle-income countries. AB - It is not clear what effect socioeconomic factors have on adherence to antiretroviral therapy (ART) among patients in low- and middle-income countries. We performed a systematic review of the association of socioeconomic status (SES) with adherence to treatment of patients with HIV/AIDS in low- and middle-income countries. We searched electronic databases to identify studies concerning SES and HIV/AIDS and collected data on the association between various determinants of SES (income, education, occupation) and adherence to ART in low- and middle income countries. From 252 potentially-relevant articles initially identified, 62 original studies were reviewed in detail, which contained data evaluating the association between SES and adherence to treatment of patients with HIV/AIDS. Income, level of education, and employment/occupational status were significantly and positively associated with the level of adherence in 15 studies (41.7%), 10 studies (20.4%), and 3 studies (11.1%) respectively out of 36, 49, and 27 studies reviewed. One study for income, four studies for education, and two studies for employment found a negative and significant association with adherence to ART. However, the aforementioned SES determinants were not found to be significantly associated with adherence in relation to 20 income-related (55.6%), 35 education related (71.4%), 23 employment/occupational status-related (81.5%), and 2 SES related (100%) studies. The systematic review of the available evidence does not provide conclusive support for the existence of a clear association between SES and adherence to ART among adult patients infected with HIV/ AIDS in low- and middle-income countries. There seems to be a positive trend among components of SES (income, education, employment status) and adherence to antiretroviral therapy in many of the reviewed studies. PMID- 23930335 TI - Molecular characterization of the circulating strains of Vibrio cholerae during 2010 cholera outbreak in Nigeria. AB - This study aimed at characterizing the phenotypic and toxigenic status of circulating strains of cholera during outbreaks in Nigeria, employing molecular typing techniques. Two hundred and one samples of rectal swabs, stool, vomitus, water (from the well, borehole, sachet, stream, and tap) and disinfectants (sodium hypochlorite) were collected from three states in the country. The samples were inoculated on thiosulphate-citrate bile salt-sucrose (TCBS), Cary Blair transport medium and smeared on glass slides for direct examination. The Vibrio cholerae isolates were serotyped, biotyped, and characterized using PCR of the cytotoxin gene A (ctxA), wbeO1, and wbfO139 gene primer. Of the 201 samples screened, 96 were positive for V cholerae O1 (48%), with 69 (72%) positive for ctxA gene. The results from this study showed that the circulating strains of cholera in Nigeria were of Ogawa serotype, also observed in other outbreaks in Nigeria (1991, 1992, and 1996). However, the strains were of the Classical biotype and were mainly (72%) ctxA gene-positive. This current investigation has confirmed the production of cholera toxin by the circulating strains, and this could be harnessed for possible cholera vaccine production in Nigeria. PMID- 23930337 TI - Nutritional knowledge, attitude, and practices among HIV-positive individuals in India. AB - This descriptive study investigated the nutrition-related knowledge, attitude, and practices (KAP) among people living with HIV/AIDS (PLHIV) in India. Data relating to nutritional KAP and sociodemographic profile were gathered from a sample of 400 PLHIV from New Delhi, India, using preset multiple-choice questionnaire. The knowledge on HIV/AIDS was low; nutritional knowledge was moderate as 80% of respondents could answer 4 out of 7 questions correctly. The attitude toward disease and food was positive but the application of nutritional knowledge was lacking as indicated by the moderate practice score of 8.1 +/- 2.3 out of a total score of 15. There were no significant differences in scores between genders. The PLHIV had knowledge about importance of nutrition during infection, had positive attitude toward the disease and the importance of nutrition during the course of the disease but translation of this knowledge into practice was low. Thus, there is a need for continuous interventions primarily aiming at behaviour change to convert knowledge into healthy dietary practices. PMID- 23930336 TI - Prevalence and correlates of prenatal vitamin A deficiency in rural Sidama, Southern Ethiopia. AB - A cross-sectional study was conducted to assess the prevalence and correlates of prenatal vitamin A deficiency (VAD) in rural Sidama, Southern Ethiopia. Seven hundred randomly-selected pregnant women took part in the study. Serum retinol concentration was determined using high-performance liquid chromatography. Data were analyzed by logistic and linear regression. Interpretation of data was made using adjusted odds ratio (AOR) and adjusted linear regression coefficient. The prevalence of VAD (serum retinol < 0.7 micromol/L) was 37.9%. Advanced gestational age and elevated C-reactive protein (CRP > or = 5 mg/dL) were negatively associated with retinol concentration (p < 0.05). The odds of VAD was significantly higher among the women with no education and those devoid of self income. Women aged 35-49 years had 2.23 (95% CI 1.31-3.81) times higher odds compared to those aged 15-24 years. The lower the dietary diversity score in the preceding day of the survey, the higher were the odds of VAD. With reference to nulliparas, grand multiparas had 1.92 (95% CI 1.02-3.64) times increased odds of VAD. VAD and zinc deficiency (serum zinc <8.6 pmol/L during the first trimester, or <7.6 pmol/L during the second or third trimester) were significantly associated with AOR of 1.80 (95% CI 1.28-2.53). VAD has major public-health significance in the area. Accordingly, it should be combated through enhancement of diet diversity, birth control, and socioeconomic empowerment of women. PMID- 23930338 TI - Major dietary patterns in relation to stunting among children in Tehran, Iran. AB - To the best of our knowledge, no information is available to link major dietary patterns to stunting during childhood, although dietary patterns are associated with chronic diseases. This study was conducted to determine the relationship between major dietary patterns and stunting in the first grade pupils of Tehran in 2009. In this case-control study, 86 stunted children (defined as height-for age of less than the 5th percentile of CDC2000 cutoff points) were enrolled from among 3,147 first grade pupils of Tehran, selected using a multistage cluster random-sampling method. Participants for the control group (n=308) were selected randomly from non-stunted children (height-for-age more than the 5th percentile of CDC2000 cutoff points), after matching for age, sex, and area of residence. Dietary data were collected using two 24-hour dietary recalls through face-to face interview with mothers. Factor analysis was used for identifying major dietary patterns. Mean consumption of dairy products (308 +/- 167 vs 382 +/- 232 g/day, p < 0.05), dried fruits and nuts (2.5819 vs 7.15 +/- 26 g/day, p < 0.05) were significantly lower among stunted children than those in the control group. Three major dietary patterns were identified: 'traditional dietary pattern' that was dominated by bread, potato, fats, eggs, flavours, vegetables other than leafy ones, sugar, drinks, and fast food; 'mixed dietary pattern' that was dominated by leafy vegetables, fast foods, nuts, fats, cereals other than bread, fruits, legumes, visceral meats, sugars, eggs, and vegetables other than leafy vegetables; and 'carbohydrate-protein pattern' that was dominated by sweets and desserts, poultry, dairy, fruits, legumes, and visceral meats. No significant relationships were found between traditional and mixed dietary patterns and stunting. Individuals in the third quartile of carbohydrate-protein dietary pattern were less likely to be stunted compared to those in the bottom quartile (OR: 0.31, 95% CI 0.13-0.78, p < 0.05). Adherence to dietary patterns high in protein (e.g. dairy, legumes, and meat products) and carbohydrates (e.g. fruits, sweets, and desserts) might be associated with reduced odds of being stunted among children. PMID- 23930339 TI - Introduction of new vaccines: decision-making process in Bangladesh. AB - The understanding of the decision-making process in the introduction of new vaccines helps establish why vaccines are adopted or not. It also contributes to building a sustainable demand for vaccines in a country. The purpose of the study was to map and analyze the formal decision-making process in relation to the introduction of new vaccines within the context of health policy and health systems and identify the ways of making decisions to introduce new vaccines in Bangladesh. During February-April 2011, a qualitative assessment was made at the national level to evaluate the decision-making process around the adoption of new vaccines in Bangladesh. The study population included: policy-level people, programme heads or associates, and key decision-makers of the Government, private sector, non-governmental organizations, and international agencies at the national level. In total, 13 key informants were purposively selected. Data were collected by interviewing key informants and reviewing documents. Data were analyzed thematically. The findings revealed that the actors from different sectors at the policy level were involved in the decision-making process in the introduction of new vaccines. They included policy-makers from the ministries of health and family welfare, finance, and local government and rural development; academicians; researchers; representatives from professional associations; development partners; and members of different committees on EPI. They contributed to the introduction of new vaccines in their own capacity. The burden of disease, research findings on vaccine-preventable diseases, political issues relating to outbreaks of certain diseases, initiatives of international and local stakeholders, pressure of development partners, the Global Alliance for Vaccines and Immunization (GAVI) support, and financial matters were the key factors in the introduction of new vaccines in Bangladesh. The slow introduction and uptake of new vaccines is a concern in the country. Rapid action on the application of GAVI support and less time taken by the Government in processing the implementation and administrative work may expedite the introduction of new vaccines in future in this country. PMID- 23930340 TI - Clinical manifestations, laboratory findings, and therapeutic regimen in hospitalized children with brucellosis in an Iranian Referral Children Medical Centre. AB - Brucellosis is considered a known widespread zoonotic disease and is endemic in Mediterranean region, like Iran. This study reviewed the clinical manifestations, laboratory findings, and therapeutic regimen in childhood brucellosis in Iran. In this retrospective study, we reviewed hospital-records of 34 consecutive children with a confirmed diagnosis of brucellosis among a total number of 10,864 patients admitted to Children's Medical Center, Tehran, Iran, between 2002 and 2010. Among the patients diagnosed with brucellosis, 22 (65%) were admitted during spring and summer. Clinical findings of these patients at admission were arthritis, splenomegaly, hepatomegaly, lymphadenopathy, maculopapular skin rashes, and fever. Anaemia (53%) and leukopenia (33%) were the most common findings in the children. Only one patient had presented with leukocytosis. Four children (12%) were thrombocytopenic, and none of patients had pancytopenia. Blood cultures were positive in 5 patients (23%). Only one patient underwent bone-marrow aspiration and had positive culture for Brucella spp. Positive titres were found in 33 cases (97%) in Wright test, 23 cases (96%) in Coombs test, and 16 patients (72.7%) in 2ME (2-Mercaptoethanol) test. In one case, Wright and Coombs test titres were below 1:80 while Brucella spp. were isolated from blood at the same time. It is concluded, prolonged fever with joint involvement and organomegaly may increase possibility of infection with Brucella spp. Appropriate treatment regimen by more tolerable oral drugs, with a duration of at least 8 weeks, is recommended. PMID- 23930341 TI - Comparison of accessibility among Vision-impaired patients visiting mobile and stationary hospitals in rural Bangladesh. AB - The aim of this study is to compare accessibility of vision-impaired (VI) patients to other eyecare centres before attending the mobile and stationary hospitals. Under a cross-sectional study design, VI patients were consecutively enrolled if they visited one of the three Impact Foundation Hospitals--one mobile and two stationary hospitals. The cost and service output of all hospitals were also reviewed; 27.7% of patients at the mobile and 36.8% at the two stationary hospitals had sought eyecare at other health facilities in the past. Mobile hospital patients lived closer to the hospital but spent more time in travelling, bore less direct cost, needed less extra support, and had a higher level of satisfaction on the service. They also identified more barriers to access eyecare in the past. The mobile hospital had a higher percentage of patients with accessibility problems and should continue to help the remote population in overcoming these problems. PMID- 23930342 TI - Evaluation of academic detailing programme on childhood diarrhoea management by primary healthcare providers in Banke district of Nepal. AB - Academic detailing is rarely practised in developing countries. A randomized control trial on healthcare service was conducted to evaluate the impact of academic detailing programme on the adherence of primary healthcare providers in Banke district, Nepal, to childhood diarrhoea treatment guidelines recommended by World Health Organization/United Nations Children's Fund (WHO/UNICEF). The participants (N=209) were systematically divided into control and intervention groups. Four different academic detailing sessions on childhood diarrhoea management were given to participants in the intervention group. At baseline, 6% of the participants in the control and 8.3% in the intervention group were adhering to the treatment guidelines which significantly (p < 0.05) increased among participants in the intervention (65.1%) than in the control group (16.0%) at the first follow-up. At the second follow-up, 69.7% of participants in the intervention group were adhering to the guidelines, which was significantly (p < 0.05) greater than those in the control group (19.0%). Data also showed significant improvement in prescribing pattern of the participants in the intervention group compared to the control group. Therefore, academic detailing can be used for promoting adherence to treatment guidelines in developing countries, like Nepal. PMID- 23930343 TI - Sleeping under insecticide-treated nets to prevent malaria in Nigeria: what do we know? AB - Malaria remains a public-health concern in Nigeria despite huge global investments in the production and distribution of insecticide-treated bednets (ITNs) to protect people from Plasmodium falciparum parasite. Information on the use of ITNs is needed for designing strategies for its effective use. Focus group discussions (FGDs) were conducted in communities from 3 geopolitical zones of Nigeria. The people had poor knowledge of malaria and mosquito bites, which resulted in wrong perception and misuse of the nets as door and window blinds to "protect entire household" since only two nets were given per household. The use of community structures (traditional leaders/village heads, youths, churches, and mosques) was suggested to ensure effective distribution of nets, sensitize, and monitor net-use in the communities. Health education would dispel misconceptions that ITNs could kill, curtail human fertility, and that local gin (Kai-Kai) would induce sleep and make one oblivious of mosquito nuisance. PMID- 23930344 TI - White rice consumption and CVD risk factors among Iranian population. AB - Association between white rice intake and risk factors of cardiovascular diseases remained uncertain. Most of the previous published studies have been done in western countries with different lifestyles, and scant data are available from the Middle East region, including Iran. This cross-sectional study was conducted in the structure of Isfahan Healthy Heart Program (IHHP) to assess the association between white rice consumption and risk factors of cardiovascular diseases. In the present study, 3,006 men were included from three counties of Isfahan, Najafabad, and Arak by multistage cluster random-sampling method. Dietary intake was assessed with a 49-item food frequency questionnaire (FFQ). Laboratory assessment was done in a standardized central laboratory. Outcome variables were fasting blood glucose, serum lipid levels, and anthropometric variables. Socioeconomic and demographic data, physical activity, and body mass index (BMI) were considered covariates and were adjusted in analysis. In this study, Student's t-test, chi-square test, and logistic regression were used for statistical analyses. Means of BMI among those subjects who consumed white rice less than 7 times per week and people who consumed 7-14 times per week were almost similar--24.8 +/- 4.3 vs 24.5 +/- 4.7 kg/m2. There was no significant association between white rice consumption and risk factors of cardiovascular diseases, such as fasting blood sugar arid serum lipid profiles. Although whole grain consumption has undeniable effect on preventing cardiovascular disease risk, white rice consumption was not associated with cardiovascular risks among Iranian men in the present study. Further prospective studies with a semi quantitative FFQ or dietary record questionnaire, representing type and portion size of rice intake as well as cooking methods and other foods consumed with rice that affect glycaemic index (GI) of rice, are required to support our finding and to illustrate the probable mechanism. PMID- 23930345 TI - Identifying factors associated with maternal deaths in Jharkhand, India: a verbal autopsy study. AB - Maternal mortality has been identified as a priority issue in health policy and research in India. The country, with an annual decrease of maternal mortality rate by 4.9% since 1990, now records 63,000 maternal deaths a year. India tops the list of countries with high maternal mortality. Based on a verbal autopsy study of 403 maternal deaths, conducted in 2008, this paper explores the missed opportunities to save maternal lives, besides probing into the socioeconomic factors contributing to maternal deaths in Jharkhand, India. This cross-sectional study was carried out in two phases, and a multistage sampling design was used in selecting deaths for verbal autopsy. Informed consent was taken into consideration before verbal autopsy. The analytical approach includes bivariate analysis using SPSS 15, besides triangulation of qualitative and quantitative findings. Most of the deceased were poor (89%), non-literates (85%), and housewives (74%). Again, 80% died in the community/at home, 28% died during pregnancy while another 26% died during delivery. Any antenatal care was received by merely 28% women, and only 20% of the deliveries were conducted by skilled birth attendants (doctors and midwives). Delays in decision-making, travel, and treatment compounded by ignorance of obstetric complications, inadequate use of maternal healthcare services, poor healthcare infrastructure, and harmful rituals are the major contributing factors of maternal deaths in India. PMID- 23930346 TI - Review of twin pregnancies in a tertiary hospital in Abuja, Nigeria. AB - Studies on twin pregnancy are uniquely important to Africa and particularly Nigeria where the highest incidence in the world exists. This study was designed to determine the trend, rate, and obstetric outcomes of twin deliveries in the University of Abuja Teaching Hospital, Gwagwalada. This was a retrospective study of twin deliveries in the hospital over a period of 10 years. During the study period, there were 349 twin births out of 10,739 deliveries, giving an overall twining rate of 32.5 per 1,000 deliveries. Preterm delivery occurred in 39.7% cases and was, therefore, the most common complication. Mode of delivery was vaginal in 72.7% while 27.3% were delivered by caesarean section. Emergency caesarean section for delivery of both the babies was carried out in 22.3% while elective caesarean section for both the babies accounted for 1.0%. Combined vaginal and abdominal delivery occurred in 4.0% of deliveries. The stillbirth rate was 102 per 1,000 births. There were 24 (8.0%) and 37 (12.3%) stillbirths among the first and the second baby respectively. The mean foetal weight was 2.395 +/- 0.63 kg while the female-to-male ratio was 1:1.1. The rate of twin deliveries in our centre is high. Successful vaginal delivery of twins is high when the mothers are booked and the presentations of the twins are favourable. The use of antenatal care services and good intrapartum management will help improve outcome in twin pregnancies. PMID- 23930347 TI - Daughter preference and contraceptive-use in matrilineal tribal societies in Meghalaya, India. AB - Although son preference in patrilineal society is an established fact, daughter preference in matrilineal society is not thoroughly examined. Very few studies have been carried out on the issue. This paper attempts to explore the daughter preference and contraceptive-use in matrilineal tribal societies in Meghalaya, India. Data from the National Family Health Survey 1998-1999 have been used in this study because, among the large-scale surveys, only this dataset allows identification of matrilineal sample. Mean, percentage, and standard deviation are computed in the present study. Further, the data have been cross-tabulated, and logistic regression has been run through SPSS (version 15). Among the ever married matrilineal women, 17% desired more sons than daughters but 18.2% desired more daughters than sons. About 11% of ever-married women could achieve their desired sex composition of children. However, a very striking finding suggests that, even after achieving desired sex composition of children, as high as 61.8% of women were still not using contraception mainly because of programme factors while one-fourth were still depending on temporary methods. The rest 13.2% adopted terminal method of contraception, which calls for immediate attention of planners. With the increase in the number of sons but without daughter, contraceptive-use drastically decreased. The most desired sex composition of children seems to be two daughters and a son. Absence of daughter with increase in the total number of sons increased the desire for additional children. Every woman with two or more sons but without daughter wanted the next child to be a daughter. Thus, there are ample evidences to draw the conclusion that there is, in fact, a daughter preference in the matrilineal tribal societies in Meghalaya, India. Policy-makers may, thus, target the women who have achieved fertility and should ensure that daughter preference does not lead to the negligence to sons. PMID- 23930348 TI - Prevalence of giardiasis in children attending semi-urban daycare centres in Guatemala and comparison of 3 giardia detection tests. AB - Giardia intestinalis is an intestinal parasite widely prevalent in children attending daycare centres worldwide and has been associated with undernutrition. Stool samples from 48 Guatemalan children (aged 1.5-7 years) attending participating daycare centres were analyzed over five weeks for presence of Giardia intestinalis using light microscopy, ELISA, and rapid dipstick test. Giardia prevalence rates were 43.7% at Week 0 and 44.7% at Week 4, based on ELISA. Intensity, but not prevalence, of infection showed a trend toward decreased weight-for-age (1-tailed p = 0.08). We believe that ELISA analysis of stool samples may be further adapted for measuring the intensity of infection in humans. PMID- 23930349 TI - Post-kala-azar dermal leishmaniasis with mucosal involvement: an unusual case presentation including successful treatment with miltefosine. AB - Post-kala-azar dermal leishmaniasis (PKDL) is a dermatologic manifestation that usually occurs after visceral leishmaniasis (VL) caused by Leishmania donovani. It is characterized by hypopigmented patches, a macular or maculopapular rash and nodular skin lesions on the body surface. Involvement of the mucosae is very rare and unusual in PKDL. We report a case of PKDL that presented with polymorphic skin lesions, along with involvement of peri-oral mucosa and tongue from an endemic area for kala-azar in Bangladesh. In the absence of a definite past history of kala-azar, a clinical suspicion for PKDL was confirmed by positive rapid serological tests against two recombinant (rK39 and rK28) leishmanial antigens, demonstration of Leishmania donovani (LD) body in the slit skin smear, and isolation of promastigotes by culture from a nodular lesion. The patient was treated with oral Miltefosine for three consecutive months and showed significant clinical improvement as demonstrated by a negative slit skin smear at two months after initiation of therapy. We report this case as an unusual presentation of mucosal involvement in PKDL and subsequent treatment success with Miltefosine. PMID- 23930350 TI - Louis A. Duhring, MD (1845-1913): the centennial of his death. PMID- 23930351 TI - Dyslipidemia in skin disease: now we know more and should do more. PMID- 23930352 TI - A clinicoepidemiological study of pityriasis rosea in South India. AB - Pityriasis rosea is an acute self-limiting papulosquamous skin disorder of unknown etiology. Although pityriasis rosea is a common dermatologic disorder, information regarding the epidemiology of the disease in India is limited because of inadequate studies. The incidence and presentation of pityriasis rosea varies from one geographical region to another. The objective was to study the various clinical patterns of the disease and epidemiologic factors influencing its occurrence. A cross-sectional study on the clinicoepidemiologic pattern of pityriasis rosea was conducted. A detailed history of illness regarding onset, evolution, duration, symptoms, systemic features, recurrence, history of contact, and associated factors such as socioeconomic status, history of drug intake, and use of new clothing, along with epidemiologic data, was recorded in the performa. The age of the patients ranged from 3 to 47 (mean 20.32) years. Incidence of pityriasis rosea was highest among patients aged 11 to 20 years followed by those 21 to 30 years. There was a male preponderance. Seasonal variation was not evident. History of using new garments or old garments, unwashed for an extended period was elicited in 23% of cases. The average interval of onset of lesions and presentation to physician was 14.45 days. Pruritus was a common symptom (70%). Of 73 patients, 67 had herald patch. The clinical features of most of the cases were in accordance with the classical pattern of pityriasis rosea. PMID- 23930353 TI - Severity of acne and its impact on quality of life. AB - Acne is a chronic disease that is especially common among adolescents. It can have a considerable psychological and social impact that is not always correlated with clinical severity. The aim of this paper was to evaluate clinical severity and alteration of quality of life in acne patients, and to investigate a possible correlation between the two. A total of 82 patients with juvenile acne were included in this study. The clinical severity of acne was evaluated using the Echelle de Cotation des Lesions d'Acne (ECLA) scale. The Cardiff Acne Disability Index (CADI) was used to assess acne-related quality of life. Acne was mild to moderate in 61% of patients (ECLA < or = 12). A considerable alteration of quality of life was present in 51% of cases. There was a positive correlation between overall scores on the ECLA and CADI scales (P = .012) before and after treatment. Additionally, CADI score improved after effective treatment of acne. Acne may have an important impact on teenagers' psychological and social life. An objective assessment of this impact seems to be necessary. ECLA and CADI scores appear to be objective and simple instruments that may be used in acne management. PMID- 23930354 TI - Cutaneous mucormycosis. AB - Mucormycosis is an invasive fungal infection caused by fungi of the order Mucorales, mainly affecting immunocompromised patients. Cutaneous mucormycosis is the third most common clinical form of the disease, after pulmonary and rhino cerebral. The usual factors predisposing to this infection are hematological malignancies and diabetes mellitus, but a significant proportion of patients are immunocompetent. The agents of mucormycosis are ubiquitous in nature and are transmitted to the skin by direct inoculation, as a result of various types of trauma. These include needle sticks, stings and bites by animals, motor vehicle accidents, natural disasters, and burn injuries. The typical presentation of mucormycosis is the necrotic eschar, but it can present with various other signs. The infection can be locally invasive and penetrate into the adjacent fat, muscle, fascia, and bone, or become disseminated. Diagnosis is difficult because of the nonspecific findings of mucormycosis. Biopsy and culture should be performed. The treatment of mucormycosis is multimodal and consists of surgical debridement, use of antifungal drugs (amphotericin B and posaconazole), and reversal of underlying risk factors, when possible. Mortality rates, although lower than in other forms of the disease, are significant, ranging from 4% to 10% when the infection is localized. PMID- 23930355 TI - Lichen planopilaris: update on pathogenesis and treatment. AB - Lichen planopilaris (LPP) is considered to be a follicular variant of lichen planus. Clinical variants include classic LPP, frontal fibrosing alopecia, and the Graham-Little-Piccardi-Lassueur syndrome. The pathogenesis of LPP remains to be fully elucidated, but like other cicatricial alopecias involves the irreversible destruction of hair follicle stem cells and loss of a hair follicle's capacity to regenerate itself In the early stages of LPP, patients may have scalp pruritus, burning, tenderness, and increased hair shedding. A scalp biopsy shows a lymphocytic infiltrate involving the isthmus and infundibulum. Apoptotic cells present in the external root sheath and concentric fibrosis surrounds the hair follicle. Treatment is prescribed with the goal to alleviate patient symptoms and to halt the progression of hair loss. Treatment involves use of potent topical corticosteroids and/or intralesional corticosteroids. Options for systemic treatment include anti-inflammatory agents such as hydroxychloroquine, tetracyclines, pioglitazones, and immunosuppressive medications such as cyclosporine, mycophenolate mofetil, or systemic corticosteroids. Hair transplantation may also be an option if the disease has been in clinical remission. The management of LPP can sometimes be challenging and additional research is needed to improve outcomes for patients. PMID- 23930356 TI - Anonymous dermatopathologists: a socioeconomic solution to a medical problem. PMID- 23930357 TI - Sklice (ivermectin) lotion for the treatment of head lice. PMID- 23930358 TI - Pancreatic panniculitis following endoscopic retrograde cholangiopancreatography. PMID- 23930359 TI - Sporadic progressive mucinous histiocytosis in a Mexican patient. AB - A 33 year-old woman presented with numerous 3- to 5-mm red-brown and yellow-brown dome-shaped nodules, primarily located on the scalp, dorsal aspects of the forearms, and lower extremities (Figure 1 and Figure 2). Her lesions started to appear 5 years prior to her consultation with increasing number and without spontaneous regression. Findings from a previous biopsy revealed epithelioid dermatofibroma. The remainder of the physical examination was unremarkable. There were no familial cases of this condition (both the mother and two older sisters were examined). PMID- 23930360 TI - Giant metastatic Merkel cell carcinoma. AB - A 68-year-old man presented with a rapidly growing, asymptomatic mass on his left mid-back for the past 3 months. The patient's medical history revealed an intentional 60-pound weight loss over the previous 2 years along with smoking approximately 1 pack of cigarettes per day. On physical examination, a fungating, 11-cm red tumor with palpable broader underlying extension (23 cm total) was present on the left mid-back with distinct red dermal nodules in a dermatomal distribution. In close proximity were two ulcerated nodules, proven histologically to be basal cell carcinomas. In the left groin was massive, fixed lymphadenopathy. A punch biopsy of the tumor was performed, which showed a dense infiltrate of small, round hyperchromatic blue cells that stained positive for CD 56 and pancytokeratin in a perinuclear dot pattern. Tumor cells were negative for CK20, TTF, CK7, and LCA. PMID- 23930361 TI - Oral squamous cell carcinoma of the mandibular region presenting as multiple discharging sinuses: imperative of magnetic resonance imaging and computerized tomography. AB - A 40-year-old woman presented with red swelling of the right mandibular region of the face. She had several painful, progressive, ulcerative, raised serosanguinous discharging sinuses. The presence of granules and bony contents were not reported. She was an habitual tobacco and betel chewer for the past 20 years. There was no history of injury/trauma over the site in the past. Progressive loss of appetite and body weight was prominent. She was nonambulatory and denied treatment. PMID- 23930362 TI - Vesiculobullous dermatomyositis with sensory motor neuropathy. AB - A 74-year-old man presented with muscle weakness in both legs for a duration of 2 months. Physical examination revealed periorbital edema and erythema, erythema on the neck and chest, erythematous papules on the proximal-distal interphalangeal and metocarpophalangeal joints, crusted plaque lesions on the thighs and around the knees, and bullous and ulcerated lesions in the antecubital and popliteal fossae (Figure 1A and 1B). Some bullous lesions were intact and some were ulcerated. There was severe edema especially in the upper extremities. He had a history of 15-kg weight loss for 4 months. Laboratory findings were remarkable for a white blood cell count of 16.0 K/UL (4.60-10.20 K/UL), a C-reactive protein of 6.93 mg/dL (0-0.5 mg/dL), an erythrocyte sedimentation rate of 50 mm/h (8-15 mm/h), an aspartate aminotransferase level of 213 U/L (10-40 U/L), a lactate dehydrogenase of 447 U/L (< 225 U/L), and a creatine kinase level of 1733 U/L (29 200 U/L). Results from antinuclear antibody at 1:320 titers and anti-smooth muscle antibody were positive. Results from anti-SS A/SS B antibodies, anti Jo-1 antibody, U1-snRNP antibody, and anti-ds DNA antibody tests were negative. A skin biopsy specimen obtained from the right antecubital fossa showed minimal orthokeratosis and subepidermal detachments. There was marked edema in the dermis and lymphocyte infiltration around the skin appendages (Figure 2). Direct immunofluorescence studies demonstrated scattered staining for C3 and IgM at the basal membrane zone. Results for IgG, IgA, and fibrin staining were negative. Muscle biopsy from left deltoid muscle was performed and some muscle fibers were demonstrated to be atrophied. There was remarkable difference between muscle fiber diameters. With Masson staining, there was increased connective tissue and no inflammation. Electromyography (EMG) showed a myogenic pattern. Nerve conduction studies showed tibial, median, ulnar, peroneal motor neuropathy, and median, ulnar, and sural sensory neuropathy. Based on these findings, diagnosis of vesiculo-bullous dermatomyositis (DM) was made. Further investigation of esophagogastroduodenoscopy with biopsy revealed ulcerated lesions on antrum and corpus and these were assessed as Helicobacter pylori-negative atrophic chronic gastritis. No pathologic findings were described on chest, abdomen, and pelvic tomography. Levels of tumor markers were within normal ranges. Overall, no sign of malignancy was detected. Methyl prednisolone treatment of 1 mg/kg/d was started; however, new bullous lesions erupted while the original lesions were healing. PMID- 23930363 TI - Congenital triangular alopecia: an imitator of alopecia areata. PMID- 23930364 TI - Celecoxib-induced bullous pemphigoid. PMID- 23930365 TI - Living with uncertainty Implementing the Affordable Care Act in Tennessee. PMID- 23930366 TI - In memory of John Brown Thomison, MD. PMID- 23930367 TI - Split prescriptions; tax ID numbers? PMID- 23930368 TI - State doctor shopping law conflicts with federal law. PMID- 23930369 TI - TMA partners with MCAG--get your share of the VISA/MasterCard settlement! PMID- 23930370 TI - New laws affecting physicians. PMID- 23930371 TI - Are you a "top 50" prescriber? PMID- 23930372 TI - Paying for health care. PMID- 23930373 TI - What will ACA insurance mandates mean to my practice as an employer? PMID- 23930374 TI - Dr. Dossett a natural leader, dedicated to the TMA. PMID- 23930375 TI - Case report and review of literature: coronary artery fistulae. AB - Coronary artery fistula (CAF) is a rare disease. In more than 90 percent of cases, a single fistula drains into the right heart chambers or into the pulmonary artery. Fistulae draining into the left ventricle are uncommon; further, multiple CAF involving the three major coronary artery vessels are very rare. This report will describe two rare cases of CAF, one of multiple CAF, and the other of single CAF, all of which drained into the left ventricular chamber. PMID- 23930376 TI - Microbubble transmission during cardiotomy infusion of a hardshell venous reservoir with integrated cardiotomy versus a softshell venous reservoir with separated cardiotomy: an in vitro comparison. AB - An important mechanism for postoperative cognitive impairment after cardiac surgery using cardiopulmonary bypass (CPB) is microemboli. One component of the CPB circuit-the cardiotomy-is a major source of gaseous microemboli because it aspirates significant volumes of air with blood from the operative field and intracardiac chambers. Cardiotomies are either integrated within an open hardshell venous reservoir (IC-HSVR) or are a separate canister attached to a softshell collapsible venous reservoir bag (SC-SSVR). The purpose of this study was to compare the Medtronic IC-HSVR (Affinity NT CVR) with Medtronic's SC-SSVR (CB 1351, CBMVR 1600) in terms of relative microbubble transmission during cardiotomy infusion. A recirculating in vitro circuit primed with blood was used to compare the two cardiotomy-reservoir systems with the venous reservoir in the SC-SSVR further assessed in a fully closed or partially open state (SC-SSVR closed; SC-SSVR-open). Microbubbles were detected using a GAMPT BC100 Doppler system in the outflow line of the venous reservoir. Measurements were taken before (baseline) and after aerated prime was pumped into the cardiotomy while altering pump flow rates (3 L/min; 5 L/min) and reservoir prime volumes (400 mL; 900 mL). Infusing cardiotomy blood into the venous reservoir was associated with an increase in microbubbles and bubble volume transmitted by both cardiotomy reservoir systems with the magnitude rising with reduced prime volumes. The effect was markedly greater with the IC-HSVR. The IC-HSVR also transmitted larger bubbles, particularly with reduced prime volumes. There was no significant difference in microbubble transmission seen between the SC-SSVR-closed and SC SSVR-open. The SC-SSVR transmits fewer microbubbles than the IC-HSVR during cardiotomy infusion and should be considered as the preferential system. Because both cardiotomy-reservoir systems transmitted microbubbles during cardiotomy infusion, particularly at the lower venous reservoir volume, it is important to use strategies to minimize cardiotomy microbubble infusion. PMID- 23930378 TI - The effects of pressure on gases in solution: possible insights to improve microbubble filtration for extracorporeal circulation. AB - Improvements in micropore arterial line filter designs used for extracorporeal circulation are still needed because microbubbles larger than the rated pore sizes are being detected beyond the filter outlet. Linked to principles governing the function of micropore filters, fluid pressures contained in extracorporeal circuits also influence the behavior of gas bubbles and the extent to which they are carried in a fluid flow. To better understand the relationship between pressure and microbubble behavior, two ex vivo test circuits with and without inline resistance were designed to assess changes in microbubble load with changes in pressure. Ultrasound Doppler probes were used to measure and compare the quality and quantity of microbubbles generated in each test circuit. Analysis of microbubble load was separated into two distinct phases, the time periods during and immediately after bubble generation. Although microbubble number decreased similarly in both test circuits, changes in microbubble volume were significant only in the test circuit with inline resistance. The test circuit with inline resistance also showed a decrease in the rate of volume transferred across each ultrasound Doppler probe and the microbubble number and size range measured in the postbubble generation period. The present research proposes that fluid pressures contained in extracorporeal circuits may be used to affect gases in solution as a possible method to improve microbubble filtration during extracorporeal circulation. PMID- 23930377 TI - Brachial arterial temperature as an indicator of core temperature: proof of concept and potential applications. AB - There is potential for heat loss and hypothermia during anesthesia and also for hyperthermia if heat conservation and active warming measures are not accurately titrated. Accurate temperature monitoring is particularly important in procedures in which the patient is actively cooled and then rewarmed such as during cardiopulmonary bypass surgery (CPB). We simultaneously measured core, nasopharyngeal, and brachial artery temperatures to investigate the last named as a potential peripheral temperature monitoring site. Ten patients undergoing hypothermic CPB were instrumented for simultaneous monitoring of temperatures in the pulmonary artery (PA), aortic arterial inflow (AI), nasopharynx (NP), and brachial artery (BA). Core temperature was defined as PA temperature before and after CPB and the AI temperature during CPB. Mean deviations of BA and NP temperatures from core temperature were calculated for three steady-state periods (before, during, and after CPB). Mean deviation of BA and NP temperatures from AI temperature was also calculated during active rewarming. A total of 1862 measurements were obtained and logged from eight patients. Mean BA and NP deviations from core temperature across the steady-state periods (before, during, and after CBP) were, respectively: .23 +/- .25, -.26 +/- .3, and -.09 +/- .05 degrees C (BA), and .11 +/- .19, -.1 +/- .47, and -.04 +/- .3 degrees C (NP). During steady-state periods, there was no evidence of a difference between the mean BA and NP deviation. During active rewarming, the mean difference between the BA and AI temperatures was .14 +/- .36 degrees C. During this period, NP temperature lagged behind AI and BA temperatures by up to 41 minutes and was up to 5.3 degres C lower than BA (mean difference between BA and NP temperatures was 1.22 +/- .58 degrees C). The BA temperature is an adequate surrogate for core temperature. It also accurately tracks the changing AI temperature during rewarming and is therefore potentially useful in detecting a hyperthermic perfusate, which might cause cerebral hyperthermia. PMID- 23930379 TI - Cryoprecipitate and platelet administration during modified ultrafiltration in children less than 10 kg undergoing cardiac surgery. AB - The timing of blood product administration after cardiopulmonary bypass (CPB) may influence the amount of postoperative transfusion and chest tube output. We performed a retrospective study of a novel technique of administering blood products during modified ultrafiltration (MUF) in congenital cardiac surgery. A Control Group (CG; n = 55) received cryoprecipitate and platelets after modified ultrafiltration. The Treatment Group (TG; n = 59) received cryoprecipitate and platelets during MUF. Volumes of blood products transfused in the operating room, initial coagulation parameters in the cardiac intensive care unit, and first 24 hour chest tube output were recorded. Age (116 +/- 198 versus 84 +/- 91 days), weight (4.6 +/- 1.8 versus 4.5 +/- 1.4 kg), duration of bypass (121 +/- 50 versus 139 +/- 57 minutes), and Aristotle scoring (9.3 +/- 2.7 versus 9.1 +/- 3.1) were not significantly different when comparing the control and treatment groups, respectively. Intraoperative packed red blood cells (74.4 +/- 34.8 versus 79.3 +/ 58.0 mL/kg, p = .710), fresh-frozen plasma (58.3 +/- 27.1 versus 59.1 +/- 27.2 mL/kg, p = .849), cryoprecipitate (7.3 +/- 5.1 versus 8.6 +/- 5.9 mL/kg, p = .109), and platelet (19.0 +/- 14.6 versus 23.7 +/- 20.8 mL/kg, p = .176) administration were the same in the control and treatment groups, respectively. However, fibrinogen levels on arrival in the coronary intensive care unit were significantly higher (305 +/- 80 versus 255 +/- 40 mg/dL, p < .001) in the CG compared with the TG. Twenty-four-hour chest tube output was not significantly different but the CG (17.76 +/- 9.34 mL/kg/24 hours) was trending lower than the TG (19.52 +/- 10.94 mL/kg/24 hours, p = .357). In an attempt to minimize CPB associated bleeding and transfusions, we changed our practice by adjusting the timing of blood product administration after patient separation from CPB. The goals of the change in practice were not measurably different in terms of shorter intraoperative times, fewer blood transfusions, or less chest tube output at our institution. KEYWORDS: congenital heart disease, modified ultrafiltration, cryoprecipitate, platelets, cardiopulmonary bypass. PMID- 23930380 TI - Has the new USP assay for heparin affected dosage for patients undergoing cardiopulmonary bypass? AB - In October 2009, the U.S. Pharmacopoeia (USP) changed the monograph for heparin to bring USP units in line with international units for heparin. The result was a 10% decrease in potency as measured by in vitro laboratory tests. This decrease led to questions regarding dosing guidelines. There existed a need for an in vivo study to determine the practical changes that may need to be implemented in regard to heparin administration for cardiopulmonary bypass in the clinical setting. A retrospective study was conducted to determine the heparin dose administered and the corresponding effect on patients undergoing coronary artery bypass grafting surgery using cardiopulmonary bypass. The study compared the heparin dose requirements and activated clotting time (ACT) results using the heparin before and after the USP changes. An analysis of the data was performed to determine the increased heparin dose required to achieve the same effect as before the USP change. This new heparin dosing protocol was instituted at Concord Hospital, Concord, NH. A prospective study was then preformed to verify the effects of the dosing change. In the new heparin group, the postheparin ACT fell by 9.1% (p = .028) and the patients achieving an ACT > 479 seconds fell by 12.8% as compared with the old heparin group. After adjustment of the loading dose calculation for heparin, the prospective study demonstrated the postheparin ACT (p = .684) and the percentage of patients achieving an ACT > 479 seconds (p = 1.000) to be similar to the values obtained before the USP change. An increase of the loading dose of approximately 12% is needed to achieve the patient effects seen before the UPS change. PMID- 23930381 TI - Brain protection during cardiac surgery: circa 2012. AB - Brain injury during cardiac surgery can cause a potentially disabling syndrome consisting mainly of cognitive dysfunction but can manifest itself as symptoms and signs indistinguishable from frank stroke. The cause of the damage is mainly the result of emboli consisting of solid material such as clots or atherosclerotic plaque, fat, and/or gas. These emboli enter the cerebral circulation from the cardiopulmonary bypass machine, break off the aorta during manipulation, and enter the circulation from cardiac chambers. This damage can be prevented or at least minimized by avoiding aortic manipulation, filtering aortic inflow from the pump, preventing air from entering the pump plus careful deairing of the heart. Shed blood from the cardiotomy suction should be processed by a cell saver whenever possible. By doing these maneuvers, inflammation of the brain can be avoided. Long-term neurocognitive damage has been largely prevented in large series of patients having high-risk surgery, which makes these preventive measures worthwhile. PMID- 23930382 TI - Vacuum-assisted venous drainage, angel or demon: PRO? AB - Vacuum-assisted venous drainage (VAVD) was proposed to optimize venous drainage during bypass through femoral venous cannulation. It is currently used in both adult and pediatric surgery when siphon gravity venous drainage is suboptimal. In pediatric surgery, the major advantages of VAVD are a significant decrease in cardiopulmonary bypass prime volume and an improved drainage with all collateral benefits. To limit gravity drainage, we use a two-level heart-lung machine dedicated to pediatric perfusion. The top level of the cardiotomy reservoir is positioned at the patient atrial level, making it possible to downsize the length and diameter of venous and arterial lines. Since 2008, a negative pressure of approximately -30 mmHg has been used for all patients. Initiation of bypass is performed in a classical way with a cardiotomy reservoir open; vacuum is added as soon as the maximal gravity drainage is reached. During bypass, when the blood level in the reservoir decreases to the safety limit level, a small increase in negative pressure is used to improve venous drainage. For weaning from bypass, the negative pressure is gradually decreased to zero, then the reservoir is opened and the venous line progressively closed. Prime volumes were significantly reduced to 100 mL for small neonates, 125 mL for infants, and 175 mL for older children with flow up to 1.5 L/min(-1). A low prime volume is expected to improve blood conservation and decrease donor exposure, prevent drawbacks of transfusion (immunomodulation, infection), increase the incidence of blood-free surgery in smaller babies, and decrease whole body systemic inflammation by decreasing surface of foreign material in contact with blood and inflammation associated with blood transfusion. The main drawbacks described have been retrograde flow in the venous line with cerebral air embolus and an increased incidence of gaseous microemboli. These drawbacks are avoidable through appropriate training of perfusionists. When negative pressure is "reasonable," complications are more theoretical than significant in clinical practice. A technique with a benefit/drawback ratio of 1:0 is utopian, but the advantages of VAVD far outweigh any potential drawbacks when applied properly. PMID- 23930383 TI - Vacuum assist: angel or demon CON. AB - Vacuum-assisted venous drainage (VAVD) to enhance venous return during cardiopulmonary bypass (CPB) was described as early as 1958 but was not widely used until the late 1990s. VAVD was initially used to facilitate the use of smaller cannulas with ministernotomy but was increasingly used to allow reduction in CPB circuit size while maintaining CPB flow rates. This innovation was made without planned consideration to CPB circuit design, most critically that of the venous reservoir. Clinical reports of prime reduction facilitated by VAVD in both adult and pediatric CPB were associated with reduced nadir hematocrit and rates of transfusion that encouraged the proliferation of VAVD in CPB. Concomitantly, investigators have reported both in vitro and in vivo significantly increased arterial emboli associated with the use of VAVD, mostly related to accelerated venous air entrainment. In vitro studies continue to confirm this association and likely underestimate the resulting embolic load as a result of flawed study design. While the evidence for VAVD is equivocal, our understanding of the clinical impact of gaseous microemboli in CPB is similarly limited, most likely confined to blood-brain barrier disruption. It is only after two decades that CPB component design is receiving serious attention in terms of air handling. The ethics of innovation in the field of CPB warrant careful consideration. The application of VAVD is not without consequence. PMID- 23930384 TI - The Thoratec CentriMag for pediatric right ventricular failure. AB - Acute right ventricular failure post heart transplantation in the pediatric population has not been well documented. Treatment using medical therapies including inotropes and nitric oxide are often inefficient for pediatric patients. Extracorporeal membrane oxygenation has been traditionally used in children until a long-term decision can be made. As a result of the emergence of smaller assist devices, pediatric practitioners now have more options available to treat this patient population. We describe the successful use of the Thoratec CentriMag in a pediatric patient posttransplantation with acute right ventricular failure. PMID- 23930385 TI - A novel method for percutaneous insertion of a right ventricular assist device. AB - Right heart failure is a rare but often fatal complication both in the pre- and postoperative setting. Right heart support with a ventricular assist device inserted in the operating room through median sternotomy can be a time-consuming procedure that requires a reoperation for removal. In cases of urgent need of right heart support, a percutaneous technique option may be of benefit. We present our initial experience with a percutaneously inserted right ventricular assist device (RVAD) in an elderly patient with severe right heart failure. An 81 year-old female patient underwent combined aortic and mitral valve replacement at our institution. During the first postoperative evening, the patient sustained sudden cardiovascular collapse and a bedside transesophageal echocardiogram revealed severe right heart failure. A coronary angiogram showed thrombosis of the right coronary artery, which was cleared with a suction device. As a result of the patient's critical condition, it was decided that an RVAD was needed as a bridge to recovery. The patient's condition improved significantly almost immediately. Her right heart function recovered over the next few days and the RVAD was removed at the bedside. She made a complete recovery and was discharged home. This patient is a prime example that a totally RVAD can be inserted in urgent situations easily and safely under fluoroscopic and echocardiographic guidance. More clinical experience with percutaneous RVADs is required to establish this technique as an alternative equivalent to the traditional open method. Right heart failure complicates many heart diseases both in the pre- and the postoperative setting. In cases of urgent need of right heart support, a percutaneous technique of a RVAD is needed for a successful outcome. We present our initial experience with a percutaneously inserted RVAD in an elderly patient with severe postoperative right heart failure. PMID- 23930387 TI - Improved environmental impact with diversion of perfusion bypass circuit to municipal solid waste. AB - The project goal was to reduce waste disposal volume, costs and minimize the negative impact that regulated waste treatment and disposal has on the environment. This was accomplished by diverting bypass circuits from the traditional regulated medical waste (RMW) to clear bag waste, or municipal solid waste (MSW). To qualify circuits to be disposed of through MSW stream, the circuits needed to be void of any free-flowing blood and be "responsibly clear." Traditionally the perfusion bypass circuit was emptied through the cardioplegia pump starting shortly after decannulation and heparin reversal. Up to 2000 mL of additional prime solution was added until the bypass circuit was rinsed clear. Three hundred sixty of 400 procedures (90%) had a complete circuit rinse and successful diversion to MSW. An additional 240 mL of processed cell salvage blood was available for transfusion. No additional time was spent in the operating room as a result of this procedure. Based on our procedure case volume and circuit weight of 15 pounds, almost 15,000 pounds (7.5 tons) of trash will be diverted from RMW. This technique represents another way for perfusionists to participate in sustainability efforts. Diverting the bypass circuit to clear bag waste results in a reduced environmental impact and annual cost savings. The treatment of RMW is associated with various environmental implications. MSW, or clear bag waste, on the other hand can now be disposed of in waste-to-energy facilities. This process not only releases a significantly less amount of carbon dioxide into the environment, but also helps generate renewable energy. Therefore, the bypass circuit diversion pilot project effectively demonstrates decreases in the carbon footprint of our organization and overall operating costs. PMID- 23930386 TI - Custodiol HTK cardioplegia use in robotic mitral valve. AB - Robotic surgery is a growing subspecialty in cardiac surgery. Custodiol HTK cardioplegia offers long-term myocardial protection, decreased metabolism, and eliminates multiple cardioplegia dosing. This article reviews the technique, strategy, and considerations for use of Custodiol HTK for myocardial protection in robotic mitral valve surgery. PMID- 23930388 TI - Facts and fallacies: why isn't Pennsylvania the worst state? PMID- 23930389 TI - National Children's Dental Health Month achieves gold in Pennsylvania. PMID- 23930390 TI - What the non-covered services law means for you. PMID- 23930391 TI - Why am I a dental educator? PMID- 23930392 TI - Why should you teach part-time? PMID- 23930393 TI - Bring in the closer. PMID- 23930394 TI - "...Sometimes life gets in the way!". PMID- 23930395 TI - Maintaining compliance in a 21st century dental practice: electronic communications and HIPAA compliance. PMID- 23930396 TI - Mandated dental screenings: what state governments consider (Part 2 of 2). PMID- 23930397 TI - [What ails the young athlete? Osteoid osteoma, lumbar spine]. PMID- 23930398 TI - [Not into the supermarket with a growling stomach!]. PMID- 23930400 TI - [Medical service for men: billing pitfalls in many practices]. PMID- 23930399 TI - [Which M-III or M-IV service can I claim with IGeL?]. PMID- 23930401 TI - [Minimal hepatic encephalopathy and driving ability. Can your liver patient still drive safely?]. PMID- 23930402 TI - [Sex specific manifestations in type 2 diabetes. Women become depressive, men impotent]. PMID- 23930403 TI - [Initiative helps physicians in managing employed asthmatic patients]. PMID- 23930404 TI - [Strategies to prevent sarcopenia. The price of aging can be diminished]. PMID- 23930405 TI - [Causes and therapy of acne tarda. Acne of mature skin: how to deal with it? (interview by Dr. Elke Oberhofer)]. PMID- 23930406 TI - [Irritable bowel syndrome. Why it should be properly evaluated]. PMID- 23930407 TI - [A successful scar]. PMID- 23930408 TI - [The 3 pill misunderstanding]. PMID- 23930409 TI - [When physicians travel. Emergencies on the aircraft and in the airport]. PMID- 23930410 TI - [Not Available]. PMID- 23930412 TI - [Not Available]. PMID- 23930413 TI - [Not Available]. PMID- 23930414 TI - [Not Available]. PMID- 23930415 TI - [Not Available]. PMID- 23930416 TI - [Not Available]. PMID- 23930417 TI - [Not Available]. PMID- 23930418 TI - [Tonsillectomy and otoplasty--no routine surgery]. PMID- 23930419 TI - [Indications and methods of tonsil surgery]. PMID- 23930421 TI - [Sexual medicine in the family doctor's office]. PMID- 23930420 TI - [Prominent ears--when and how to do surgery?]. PMID- 23930422 TI - [Fishy vaginal odour--just a nuisance or a serious matter?]. PMID- 23930423 TI - [Prevention of falls in the frail elderly]. PMID- 23930424 TI - [Emergency checklist: shoulder dislocation]. PMID- 23930425 TI - [Review and basics of frequently used wound dressings]. PMID- 23930426 TI - [NSAIDs and painkiller in sport]. PMID- 23930427 TI - Poised for progress. Hospitals continue on path to sustainability. Interview by Jeff Ferenc. PMID- 23930428 TI - Shades of green. Slow but steady progress on road to sustainability. PMID- 23930429 TI - Making connections. Managing the medical equipment integration process. PMID- 23930431 TI - New vision. Security surveillance installations in the digital age. PMID- 23930430 TI - Eight ambulatory trends. Designing facilities for health care's growth segment. PMID- 23930432 TI - Mind and body. Design elements to address cancer patient needs. PMID- 23930433 TI - Joplin tornado offers response lessons. PMID- 23930434 TI - HCAHPS improvement strategies for ES. PMID- 23930435 TI - Always on. What it takes to generate fail-safe emergency power. PMID- 23930436 TI - The diagnosis and treatment of peripheral lymphedema: 2013 Consensus Document of the International Society of Lymphology. AB - This International Society of Lymphology (ISL) Consensus Document is the current revision of the 1995 Document for the evaluation and management of peripheral lymphedema (1) for discussion at the XXIV International Congress of Lymphology. It is based upon modifications: [A] suggested and published following the 1997 XVI International Congress of Lymphology (ICL) in Madrid, Spain (2) discussed at the 1999 XVII ICL in Chennai, India (3) and considered/ confirmed at the 2000 (ISL) Executive Committee meeting in Hinterzarten, Germany (4); [B] derived from integration of discussions and written comments obtained during and following the 2001 XVIII ICL in Genoa, Italy as modified at the 2003 ISL Executive Committee meeting in Cordoba, Argentina (5); [C] suggested from comments, criticisms, and rebuttals as published in the December 2004 issue of Lymphology (6); [D] discussed in both the 2005 XX ICL in Salvador, Brazil and the 2007 XXI ICL in Shanghai, China and modified at the 2008 Executive Committee Meeting in Naples, Italy (7,8); and [E] modified from discussions and written comments from the 2009 XXII ICL in Sydney, Australia, the 2011 XXIII ICL in Malmo, Sweden and 2012 Executive Committee Meetings. The document attempts to amalgamate the broad spectrum of protocols advocated worldwide for the diagnosis and treatment of peripheral lymphedema into a coordinated proclamation representing a "Consensus" of the international community. The document is not meant to override individual clinical considerations for problematic patients nor to stifle progress. It is also not meant to be a legal formulation from which variations define medical malpractice. The Society understands that in some clinics the method of treatment derives from national standards while in others access to medical equipment and supplies is limited, and therefore the suggested treatments are impractical. Adaptability and inclusiveness does come at the price that members can rightly be critical of what they see as vagueness or imprecision in definitions, qualifiers in the choice of words (e.g., the use of "may... perhaps... unclear", etc.) and mention (albeit without endorsement) of treatment options supported by limited hard data. Most members are frustrated by the reality that NO treatment method has really undergone a satisfactory meta-analysis (let alone rigorous, randomized, stratified, long-term, controlled study). With this understanding, the absence of definitive answers and optimally conducted clinical trials, and with emerging technologies and new approaches and discoveries on the horizon, some degree of uncertainty, ambiguity, and flexibility along with dissatisfaction with current lymphedema evaluation and management is appropriate and to be expected. We continue to struggle to keep the document concise while balancing the need for depth and details. With these considerations in mind, we believe that this latest version presents a Consensus that embraces the entire ISL membership, rises above national standards, identifies and stimulates promising areas for future research and represents the best judgment of the ISL membership on how to approach patients with peripheral lymphedema as of 2013. Therefore the document has been, and should continue to be, challenged and debated in the pages of Lymphology (e.g., as Letters to the Editor), and ideally will remain a continued focal point for robust discussion at local, national and international conferences in lymphology and related disciplines. We further anticipate as experience evolves and new ideas and technologies emerge that this "living document" will undergo further periodic revision and refinement as the practice and theories of medicine and specifically lymphology change and advance. PMID- 23930437 TI - Alterations of lymph flow after lymphadenectomy in rats revealed by real time fluorescence imaging system. AB - Secondary lymphedema is one of the sequella of cancer treatment that in inadequately understood. The purpose of the present study is to investigate lymphedema formation and to explore the escape routes for excess interstitial fluid using lymphadenectomy in a rat model. In twelve Wistar rats, lymph nodes in the right inguinal and popliteal fossas were completely removed and lymph vessels carefully ligated. After operation, treated hind limbs were evaluated by indocyanine green lymphography and circumferential measurement. Both evaluations were performed from day 3 to ten weeks. Approximately 2 to 3 weeks after operation, a network-like pattern of the fluorescent signal appeared around the surgical site which then transitioned into a linear pattern in the lower abdomen. Videorecordings identified fluorescent flow moving from the lower abdomen to the ipsilateral axillary lymph node and in some rats, the network-like pattern was also observed to pass transversely over the suprapubic region to the contralateral inguinal lymph nodes. The network-like pattern on the lower abdomen and the linear pattern to the axillary fossa were seen continuously to the end of observation. Circumferential measurements of the treated hind limbs increased initially and then declined over time. This imaging system may be useful to detect early changes in lymphatic flow before swelling occurs and further study is needed. PMID- 23930438 TI - Surgical prevention and treatment of lymphedema after lymph node dissection in patients with cutaneous melanoma. AB - Despite the development of minimal access dissection techniques, use of superficial groin dissection alone, and other recommendations to reduce morbidity in melanoma treatment, the incidence of lymphedema is still significant. The purpose of the current study was to assess the efficacy of microsurgical methods to limit the morbidity of inguinal lymphadenectomy. We conducted a retrospective review of patients who underwent groin dissection for melanoma treatment from February 2006 to April 2009. A total of 59 melanoma patients with positive groin lymph nodes comprised 18 patients (T-group) with melanoma in the trunk and 41 patients (E-group) who had melanoma in an extremity and currently have lymphedema. The T-group patients underwent primary prevention of lymphedema with microsurgical lymphatic-venous anastomoses (LVA) performed simultaneously with groin dissection. The E-group patients underwent LVA to treat the secondary lymphedema after an accurate oncological and lymphological assessment. Limb volume measurements and lymphoscintigraphy were performed pre- and postoperatively to assess short and long term outcome. No lymphedema occurred after microsurgical primary preventive approach in the T- group. Significant (average 80% reduction of pre-op excess volume) reduction of lymphedema resulted after microsurgical treatment for secondary leg lymphedema. Post-operative lymphoscintigraphy in 35 patients demonstrated patency of microsurgical anastomoses in all cases with an average follow-up of 42 months. Study results demonstrate that microsurgical LVA primary prevention prevented lymphedema after inguinal lymphadenectomy in the T-group patients. In addition, lymphatic-venous multiple anastomoses proved to be a successful treatment for clinical lymphedema with particular success if treated at the early stages. PMID- 23930439 TI - A systematic review of care delivery models and economic analyses in lymphedema: health policy impact (2004-2011). AB - A project of the American Lymphedema Framework Project (ALFP), this review seeks to examine the policy and economic impact of caring for patients with lymphedema, a common side effect of cancer treatment. This review is the first of its kind undertaken to investigate, coordinate, and streamline lymphedema policy initiatives in the United States with potential applicability worldwide. As part of a large scale literature review aiming to systematically evaluate the level of evidence of contemporary peer-reviewed lymphedema literature (2004 to 2011), publications on care delivery models, health policy, and economic impact were retrieved, summarized, and evaluated by a team of investigators and clinical experts. The review substantiates lymphedema education models and clinical models implemented at the community, health care provider, and individual level that improve delivery of care. The review exposes the lack of economic analysis related to lymphedema. Despite a dearth of evidence, efforts towards policy initiatives at the federal and state level are underway. These initiatives and the evidence to support them are examined and recommendations for translating these findings into clinical practice are made. Medical and community-based disease management interventions, taking on a public approach, are effective delivery models for lymphedema care and demonstrate great potential to improve cancer survivorship care. Efforts to create policy at the federal, state, and local level should target implementation of these models. More research is needed to identify costs associated with the treatment of lymphedema and to model the cost outlays and potential cost savings associated with comprehensive management of chronic lymphedema. PMID- 23930440 TI - A meta-analysis of the relationship between lymphatic microvessel density and the survival of patient with colorectal cancer. AB - Colorectal cancer (CRC) is a frequently observed malignant neoplasm that is a leading cause of cancer death despite recent advances in treatment and research. The role of lymphangiogenesis in CRC development is a source of controversy in current research. We undertook this study to examine the relationship between lymphatic microvessel density (LMVD) and the overall survival (OS) or disease free survival (DFS) of CRC using meta-analysis of recent studies. PubMed and Embase databeases were searched and nine relevant studies including 799 total patients were included. Six studies including 575 patients focused on overall survival (OS) and 3 studies with 224 patients focused on disease free survival (DFS). We performed a meta-analysis to estimate the prognostic role of lymphatic microvessel density by combining separately estimated hazard ratios. A remarkable correlation between LMVD and DFS was observed in pooled analyses using a fixed effect model (HR 2.29; 95% CI 1.11, 3.48). LMVD and OS showed a pooled HR value of 1.02 (95% CI 0.71,1.33), indicating no significant correlation between LMVD and OS. There was no evidence for significant heterogeneity or publishing bias in both DFS and OS (I2 = 0.0%, P = 0.861; I2 = 48.1%, P = 0.086, respectively). A close relationship was observed between LMVD and DFS, though no correlation between LMVD and OS was apparent. The current meta-analysis suggests that LMVD may be a poor prognostic factor for CRC patients. However, these results should be regarded cautiously and future confirmatory studies are necessary. PMID- 23930441 TI - Disarming the patient through therapeutic communication. PMID- 23930442 TI - Successful intermittent self-catheterization teaching: one nurse's strategy of how and what to teach. AB - Learning how to perform intermittent self-catheterization (ISC) can be a daunting task for the patient with a newly diagnosed voiding dysfunction. The nurse can facilitate this learning process by working with the patient until knowledge and confidence is gained to successfully perform self-catheterization. Teaching ISC requires a knowledgeable and skilled nurse who can recognize the patient's physical and psychological readiness; instruct the patient in anatomy, physiology, and the disease process, as well as guide the patient through the procedure. With a comprehensive teaching program, the patient is empowered to care for his or her own urologic health and accomplish an important step in regaining independence. This article describes one nurse's strategy for teaching patients to become confident and competent in performing ISC. PMID- 23930443 TI - General clinical practice getting the intermittent catheter the patient needs: considerations in coding, coverage, and documentation. AB - Nurses with knowledge of catheter features, the Healthcare Common Procedural Coding System (HCPCS), reimbursement guidelines, and proper documentation will have the essential information needed to ensure that patients performing intermittent self-catheterization receive the right products. PMID- 23930444 TI - Effects of an online support group for prostate cancer survivors: a randomized trial. AB - This longitudinal study evaluated the effect a prostate cancer-specific online support group had for self-assessed quality of life. Participants (N = 40) were randomly assigned to an online support group or the control group. Data consisted of four previously validated quality-of-life measurements. Analysis determined that over time, quality of life improved for those in the online group and decreased for those in the control group, but returned to baseline at eight weeks. Providing support using online methods is effective; the length of time this intervention should be provided to patients will require further research. PMID- 23930445 TI - Adding to the evidence base: effects of an online support group for prostate cancer survivors: a randomized trial. PMID- 23930446 TI - The risk of radiation exposure to assisting staff in urological procedures: a literature review. AB - Fluoroscopy is an integral part of urology and is used for various procedures, such as extra-corporeal shock wave lithotripsy, percutaneous nephrolithotomy, uretero-renoscopy, and ureteral stenting. This technique exposes the urologist and assistants to radiation, which is known to have deleterious effects. Although there have been studies that determine the amount of exposure and the risks to the operating urologist, the risk to the assisting staff remains largely undetermined. A literature review was conducted to determine the risk of radiation exposure during urological procedures, with emphasis on data concerning assisting staff. Data from nine major studies is presented in this article. PMID- 23930448 TI - President's message. PMID- 23930447 TI - A one-day couple group intervention to enhance sexual recovery for surgically treated men with prostate cancer and their partners: a pilot study. AB - Researchers evaluated the acceptance and effectiveness of a group intervention that provided education about post-prostatectomy sexual recovery and peer support for couples. Couples valued the intervention and retained the information. Partners became accepting of erectile dysfunction and communicated more openly about upsetting topics. PMID- 23930449 TI - Texas legislature began its 83rd legislative session. PMID- 23930450 TI - Oral and maxillofacial pathology. Case of the month. Diagnosis: Necrotizing sialometaplasia. PMID- 23930451 TI - Missed canal systems are the most likely basis for endodontic retreatment of molars. AB - Unfortunately, a small percentage of endodontically treated teeth do not respond favorably to non-surgical root canal treatment. Failure to cate and treat an additional nal system is cited as the principle basis for endodontic retreatment. The aim of this retrospective clinical study was to identify the incidence of additional or missed canal systems in molar retreatment cases in a private practice setting. Missed canals were identified in 64 of the 133 previously treated teeth (48%). Of the total missed canals, 11% involved a maxillary second molar and 44% involved a maxillary first molar. For the maxillary first molars, 93% of all missed canal were identified in the mesiobuccal root. In the mandibular second molars, 29% of missed canals were identified in the distal and 71% were identified in the mesial root. In the mandibular first molars, 86% of missed canals were identified in the distal and 14% were identified in the mesial root. The results of the current study support the findings of previous studies and confirm the importance of locating, instrumenting and obturating the endodontic treatment. Given that failure to locate all canal systems of a tooth contributes significantly to unsuccessful endodontic treatment, all measures available to the clinician to maximize canal identification should be used. PMID- 23930452 TI - CAD/CAM and lithium disilicate: an anterior esthetic case study. AB - Digital technology has brought a new and exciting dimension to dental esthetics. Innovative ways to take impressions and create chair-side restorations are continuing to expand and new dental materials specifically made for CAD/CAM are allowing for extremely esthetic restorations. Lithium disilicate is one such material that is efficiently milled, has a favorable flexural strength, and provides highly esthetic chair-side restorations. The following is a case study that utilizes lithium disilicate for esthetic full coverage crowns on teeth #7, 8, 9, and 10. PMID- 23930454 TI - Ethics is a choice. PMID- 23930453 TI - Oral appliance therapy and CPAP demonstrate similar improvements in mild to moderate obstructive sleep apnea (UT CAT# 2334). PMID- 23930455 TI - Value for your profession. Studying numbers before opening a new office is critical. PMID- 23930456 TI - Rational prescribing. PMID- 23930457 TI - Medicine and business. PMID- 23930458 TI - Article misses important point. PMID- 23930459 TI - More on morale. PMID- 23930460 TI - The medicine of addiction. PMID- 23930461 TI - Diversion detective. PMID- 23930462 TI - Stopping doctor-shoppers. PMID- 23930463 TI - The opioid crisis: combating misuse through better prescribing. PMID- 23930464 TI - A few minutes with ... Rep. Jim Abeler, clinician and legislator. PMID- 23930465 TI - Where there's smoke ... raise the price. PMID- 23930466 TI - Moving addiction treatment into the 21st century. Our treatment system needs an overhaul. PMID- 23930467 TI - Why doctors prescribe opioids to known opioid abusers. How cultural attitudes and financial disincentives affect the prescribing habits of physicians. PMID- 23930468 TI - The rampant abuse of prescription pain medications. AB - Opioid abuse has become a national and state public health crisis. This article reviews the extent of the problem in Minnesota, the relationship between prescription opioids and heroin, and the nature of addiction. It also describes what every physician can do to help remedy the situation. PMID- 23930469 TI - Opioid use and abuse: a pain clinic perspective. AB - Prescription opioid abuse has become the biggest drug problem facing the United States, surpassing abuse of cocaine, methamphetamines and heroin combined. For physicians treating patients with chronic pain, deciding whether to prescribe opioids, especially long-term, can be a challenge. This article describes the history of the opioid abuse problem in the United States, new agents that are effective but less prone to abuse, and tools physicians can use to evaluate whether a patient is a candidate for prescription opioids or other options for pain control. PMID- 23930470 TI - A comprehensive response to the opioid epidemic: Hazelden's approach. AB - For years, treatment professionals have debated the virtues of medication maintenance versus psychosocial therapies for treating opioid addiction. In its response to the opioid crisis, Hazelden is attempting to bridge the difference by using a treatment protocol that involves both the conservative use of safe medications and psychosocial therapies while maintaining the ultimate goal of abstinence. This article discusses the recent and precipitous rise in opioid use, abuse, dependence and overdoses in the United States; the physician's role in creating and solving the problem; and Hazelden's unique approach to caring for people with opioid addiction. PMID- 23930471 TI - Neonatal drug withdrawal. AB - In recent years, the number of babies exposed to both illegal and prescribed drugs during pregnancy has increased. This has led to an increase in the number of babies born with addiction. This article describes the signs of neonatal drug withdrawal and suggests a comprehensive approach to preventing and treating it. PMID- 23930472 TI - Finding a feasible solution. States employ different legislative strategies to curb misuse. PMID- 23930473 TI - Pattern, clinical presentations and management of thyroid diseases in national endocrine referral clinics, Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. AB - BACKGROUND: Thyroid diseases are common endocrine abnormalities affecting the cellular metabolism of the body. There are limited recent studies addressing the different aspects of thyroid diseases in Ethiopia. OBJECTIVES: To assess the pattern, clinical presentations, management and associated illnesses of thyroid diseases in endocrine referral clinics of Tikur Anbessa Specialized Tertiary Hospital (TASH). METHODS: A cross-sectional study was conducted on consecutive thyroid patient attending endocrine referral clinics of TASH from Nov 2009 to March 2010. Patients with thyroid diseases, 14 years of age and above, thyroid patients with other endocrine diseases were included in the study. Data were collected by trained nurses and physicians using pre-constructed questionnaires. Review of charts for patients, presenting manifestations, date of diagnosis, laboratory investigation results, treatment and other pertinent information was conducted. RESULTS: Among 376 patients with thyroid diseases, females were 337 (90%) and males were 39 (10.4%). The mean (SD) age of female participants was 43.1 +/- 15.2 males was 37.3 +/- 17.3. Age 40 and above accounted for 59%. The prevalence of Hyperthyroidism and hypothyroidism in 376 patients were 233 (61.7%) and 129 (34.3%) respectively. Toxic Multinodular Goiter occurred in 135 (35.9%), Toxic nodules in 32 (8.5%) and of Graves' disease in 65 (17.3%), Seven patients progressed from Graves' disease to Hashimoto's thyroiditis. Subclinical hypothyroidism occurred in 5(1.32%), and secondary hypothyroidism in 4 patients. Palpitation (96%), goiter (99%) and hot intolerance (81.9%) were the commonest presentations of thyrotoxicosis, whereas hypothyroidism patients presented mostly with cold intolerance (50.4%) and goiter (38%). Autoimmune polyglandular syndrome occurred in 16 (4.3%) patients. 26 (7.0%) had history of pregnancy, 82 (22.2%) had family history of thyroid diseases and seven patients had history of alcohol intake. Thyrotoxicosis was treated with Propylthiouracil (96.8%) with or with out beta blockers, thyroidectomy was done in 16 (6.8%), few received radioiodine therapy. Hypothyroidism patients were treated with thyroxin. CONCLUSION: Thyroid diseases were more common in females and more prevalent in age group of 40-49. Toxic Multinodular Goiter, Graves' disease and Toxic Nodular Goiter were causes of thyrotoxicosis. The most common presenting feature of thyrotoxicosis was palpitation, and hypothyroidism was cold intolerance. A few Graves' disease cases were progressed to hypothyroidism. Autoimmune Polyglandular Syndrome was an important associated disease. There was limited access for radioiodine treatment. RECOMMENDATION: To conduct further studies in different aspects of thyroid disease, strengthening access for radioiodine therapy and introduce anti thyroid antibody tests. PMID- 23930474 TI - Magnitude and pattern of osteoporotic fractures among adults in Tigiray, Ethiopia; a retrospective hospital based study. AB - INTRODUCTION: Osteoporotic fractures are devastating public health problems due to significant morbidity, mortality, and the socioeconomic burden. h2 Ethiopia, the weight of such fractures is often underestimated due to lack of epidemiological data. OBJECTIVE: To assess the magnitude and pattern of osteoporotic fractures among adults admitted to zonal hospitals in Tigrai, North Ethiopia. METHODS: Two years retrospective hospital based medical-record review was employed. All fractures that occurred from September, 01, 2009 to August, 31, 2011 where the source population and osteoporosis related fracture cases were extracted. A total of 1173 charts was retrieved for further characterization of the cases with osteoporotic fractures. The sample size was proportionally distributed to the six hospitals, the cards were selected using a systematic random sampling technique and descriptive analysis was done using SPSS version 19.0. RESULT: A total of 24.672 (15.402 males and 9,270 females) fractures of all types were extracted from medical records of the six zonal hospitals in the region (September 2009-August 2011), among which 2,294 (1,465 males and 829 females) were cases with osteoporotic fractures. The overall prevalence of osteoporotic fractures was 9.3 % and the sex specific prevalence rate was 9.5 and 8.9% for males and females respectively. Characterization in terms of the fracture site, cause, residence, age, and gender was done for 1173 patient charts with osteoporotic fracture. Eight hundred twenty nine (70.9%) of the cases were males. The mean age was 50 (+/- 12) with median age of 45 years. The highest proportion 441 (37.7%) of osteoporotic fractures were of the proximal femur; with higher proportion among males than females. The majority of the fractures, 688 (58.9%) were observed between the age group 40-49. CONCLUSION: Osteoporotic fractures are not infrequent in Tigrai, Ethiopia. Clinicians and other health care providers should be more aware of osteoporosis as the predominant underlying cause of fragility fractures in the region. PMID- 23930475 TI - Epidemiology of skeletal fluorosis in Wonji Shoa Sugar Estate, Wonji, Ethiopia: a community based survey. AB - INTRODUCTION: Endemic skeletal fluorosis is a form of chronic fluoride intoxication resulting from ingestion of excessive quantities of fluoride through drinking water. It is an important public health problem in parts of several developing countries including Ethiopia. OBJECTIVE: The aim of this study is assess the magnitude of the problem at the community level. MATERIALS AND METHODS: This community based, cross-sectional study was undertaken in Wonji-Shoa Sugar Estate. (WSSE). A base line census of the adult population of WSSE was carried out at the beginning of the study. A total of 578 subjects were selected by simple random sampling using a sampling frame which was prepared from the census results. For each study participant, information on socio-demographic characteristics, possible risk factors gathered and X-ray of the forearm PA and Lateral were taken using standard x-ray techniques. RESULTS: The overall prevalence of skeletal fluorosis is 65.7%, with male to female prevalence ratio of 79.3% vs. 53%. The crude analysis of factors associated with skeletal fluorosis shows that, males than females and manual workers than others had significantly higher risk (Crude OR = 3.39, 95% CI = 2.31-4.95 and OR = 3.22, 95% CI = 2.20-4.72 respectively). On logistic regression, only sex, age and camp of residence remained significantly associated with skeletal fluorosis. Adjusted for other factors, males were more likely (about 2.5 times to be at risk than females and older people of age 55 years and above had about 20 times higher risk than young adults of age 15-24. CONCLUSION: The finding of very high prevalence of radiological skeletal fluorosis (SKF) in this study highlights the importance of endemic SKF as a public health problem. Therefore, prompt measures are required to provide the community with safe drinking water to prevent development of crippling skeletal fluorosis. PMID- 23930477 TI - A two years prospective follow up and outcome of patients operated for carotid body tumors: experience from Ethiopia. AB - OBJECTIVE: We aimed to describe the patterns of patient presentation, management and prospective two-year follow up at the Tikur Anbessa Hospital. INTRODUCTION: Carotid body tumors (CBTs) constitute about 80% of paragangliomas and they occur frequently in Ethiopia. METHODOLOGY: This is a two years prospective study, involving all patients operated from September 2007-August 2009 (over a two year period) at the Tikur Anbessa Hospital, Addis Ababa, Ethiopia for CBTs. Routine patient characteristics along with details of presentation, diagnostic tools employed, preoperative and post operative management, intra-operative staging and postoperative complications were recorded. All patients were followed post operatively for an average of 13 months. Data was prospectively collected and analysis done. RESULTS: A total of 19 patients were admitted and operated. All patients presented with a painless slowly growing neck mass. The tumor was situated in the left side in 12 (63.2%) and was bilateral in only 1 (5.2%). The preoperative diagnosis was suspected by clinical examination in all patients and confirmation done with fine needle aspiration cytology (FNAC) in 18 (94.7%) and doppler ultrasound in 12 (57.9). No patient required vascular bypass or deliberate resection and reconstruction of the carotid artery during surgery. Staging of the tumor showed 5 (26.3%) were Shamblin I, 10 (52.6%) were Shamblin II and 4 (21.1%) were Shamblin III. Five (26.3%) of the patients had evidence of temporary nerve injury. Malignancy was not diagnosed in any of the patient. Nine (47.4%) of the procedures were complicated by bleeding in excess of 500 ml and mortality was 0%. CONCLUSION: The experience in carotid body tumor excision at our center is encouraging and our surgical management of carotid body tumors had good long term outcome and low complication rates. PMID- 23930476 TI - Malaria microscopy performance in self-presenting febrile patients at four health facilities in Fentale district of East Shewa, Ethiopia. AB - BACKGROUND: Correct and reliable microscopic examination results are vital in appropriate treatment of malaria in endemic areas, mainly where Plasmodiumn falciparum and P. vivax co-exist in Ethiopia. Thus, evaluation of regular malaria microscopy performance is needed. OBJECTIVES: To evaluate the performance of regular malaria microscopy and antimalarial drug prescription practices for self presenting febrile patients at health facilities located in malaria endemic areas of upper Awash Valley, eastern central Ethiopia. METHODS: A cross sectional study design was used to recruit 260 febrile patients at four health facilities in Fentale district. All slides collected at health facilities were rechecked in reference laboratories and Kappa score was calculated to see the slide reading agreement. RESULTS: Malaria parasites from clinical cases were found in 19.6% (51/260) of the total febrile patients of which 82.4% (42/51) were infected with P. vivax and 17.6% (9/51) with P. falciparum. Overall sensitivity, specificity, positive and negative predictive values of regular malaria microscopy readings were 92.2%, 83.7%, 58% and 97.8%, respectively. Artemether-lumefantrine over prescription rates was 50.8% by the regular microscopy and 53.6% by reference microscopy. There was only a moderate agreement between regular malaria microscopy and reference microscopy with the Kappa value of 0.52. CONCLUSION: The overall reading agreement and agreement on species identification of the regular and reference microscopy were low. There was variability in performance in the different health facilities. Sensitivity, specificity, and positive predictive value of regular malaria microscopy need to be improved for accurate diagnosis and prompt treatment of malaria cases in Fentale district health facilities. There should be rational use of antimalarials especially on slide negative subjects. PMID- 23930478 TI - Schistosomiasis mansoni focus in Mekele City, northern Ethiopia. AB - BACKGROUND: Intestinal schistosomiasis due to Schistosoma mansoni is prevalent and widely distributed in Ethiopia. The disease continues to spread to previously non-endemic areas mainly in connection with water resource development and population movement. OBJECTIVES: To assess the transmission and magnitude of Schistosoma mansoni infection among school children in Addisalem and Lachi Primary Schools in Mekele City, northern Ethiopia. METHODS: A cross-sectional study was carried out in two primary schools in Mekele City in March 2011. Stool specimens were collected and processed for quantitative microscopic examination using Kato-Katz technique and ova were quantified Search for intermediate snail hosts was carried out in Elala stream and collected snails were examined for trematode infection by shedding after they were individually exposed to electric light for about one to two hours. RESULT: The overall prevalence of S. mansoni infection was 26.3% and for those infected with S. mansoni the mean intensity of infection was 50 egg per gram of stool (epg). About 1.9%, 20.8% and 77.4% of the positive children for S. mansoni had heavy, moderate and light infection, respectively. All collected snails were identified to be Biomphalaria pfeifferi, intermediate host for S. mansoni, and 2 of them shed cercariae, accounting for 2.5% (2/80) infection rate of the snails. CONCLUSION: The present study showed that transmission of intestinal schistosomiasis is taking place in Ellala stream. The finding of infected children with S. mansoni, the presence of infected snails in the stream as well as the prevalence of S. mansoni being above 5% all confirm the endemicity of the area for S. mansoni infection. Preventive and control measures should be instituted to reduce on-going transmission and morbidity of the disease in the area. PMID- 23930479 TI - Clinical and neuroimaging profile of HIV-1 encephalopathy in infancy and childhood in a sub-Saharan African country. AB - BACKGROUND: Neurological dysfunction in AIDS is common, occurring in as many as eighty percent of children. Thus, it is important to recognize the central nervous system imaging appearance of HIV, in particular those of HIV encephalopathy, as this is an AIDS defining illness and with distinct neuro imaging features essential for early diagnosis and timely therapeutic intervention AIM: To identify the clinical features in HIV-1 infection of the central nervous system and their associated neuroradiological correlates. METHODS: Retrospective review of the records of all children with HIV-1 encephalopathy identified among children with neurological and developmental problems and who were on follow up at a child development and neurology clinic in an African city. RESULTS: A total of 22 children (10 male and 12 female) with HIV 1 encephalopathy were identified among 2382 children with various forms of neurological and developmental problems and who were on follow up at a child development and neurology clinic for a little bit over eight years period. All the children acquired the infection vertically. The age range of these children was between 10 months to 14 years. The median age was 5.6 years. The mean duration of symptom was 3.2 years. Global delay or regression in development along with signs of pyramidal tract involvement and seizures were the commonest clinical signs observed in these children. Neuro-behavioral problems were commonly observed among preschool and school aged children. In older children and preadolescents focal seizures with or with out neurologic deficit and neuroradiological findings were common. Nonhemorrhagic stroke was rare and occurred in one child and another child had cortical blindness. Three children had no neurological deficit. Rapid progression of the disease carried grave prognosis. Opportunistic infections and tumors of the central nervous system were also uncommon among these children. Brain volume loss with dilatation of the lateral ventricle, bilateral symmetrical or asymmetrical calcification of the basal ganglia and periventricular involvement of the white matter were the commonest neuro-radiological findings observed in these children. CONCLUSION: Atrophy of the brain with dilatation of the lateral ventricles and calcification of the basal ganglia and peri-ventricular involvement of the white matter were the commonest neuro-radiological findings in children with HIV-1 encephalopathy. Similarly global delay or regression in development along with pyramidal tract signs and seizures were the commonest neurological findings. Behavioral problems were common in preschool and school aged children. Focal seizures were common in older children and preadolescents. Rapid progression of the disease carried grave prognosis. PMID- 23930480 TI - Improved detection of acid-fast bacilli in sputum by the bleach-concentration techinique at Gondar University Teaching Hospital, northwest Ethiopia. AB - BACKGROUND: Direct sputum smear microscopy remains the most widespread method for the diagnosis and followup of patients with tuberculosis despite its limited sensitivity. OBJECTIVE: Our aim was to investigate whether sputum smears prepared using liquefaction with household bleach and concentration by centrifugation was more sensitive for the detection and quantification of acid-fast bacilli as compared to smears processed directly from sputum. METHODS: A cross-sectional study was conducted among patients with a clinical presentation suggestive of pulmonary tuberculosis at Gondar University Hospital, Northwest Ethiopia in April 2008. Three consecutive sputum samples were collected from the study participants and examined for acid fast bacilli using the standard direct microscopy as well as the household bleach-concentration technique. RESULTS: Out of 264 samples examined, 33 (12.5 %) were smear positive by direct microscopy and 61 samples (23.2 %) were smear positive by the bleach-concentration method (OR 2.1, 95% CI 1.3-3.4, p < 0.010). There was an absolute increase in the number of acid fast bacilli per slide using the bleach-concentration technique compared to the direct method. The detection of acid fast bacilli was superior in early morning sputum followed by overnight spot samples. CONCLUSION: The bleach-concentration method for sputum smear samples significantly increased the detection rate of smear positive patients compared to the direct method Thus, a shift from direct sputum microscopy to the bleach-concentration technique should be considered. PMID- 23930481 TI - Adherence to antiretroviral therapy and its associated factors among people living with HIV/AIDS in Addis Ababa, Ethiopia. AB - BACKGROUND: HIV/AIDS became a chronic illness since the introduction of Anti Retroviral-Therapy which needs ongoing assessment for adherence to prevent treatment failure. OBJECTIVE: The objective of this study was to assess antiretroviral therapy adherence and its associated factors. METHODS: A cross sectional quantitative study was conducted on 420 People Living With HIV/AIDS (PLWHA) who were attending Anti-Retroviral-Therapy clinic at Tikur Anbessa, Zewditu and St Paul's Hospitals from March to April 2009. Systematic random sampling technique was used to select the participants from their document. Then Data were collected, checked, categorized, coded and analyzed using SPSS 15.0 statistical package. RESULT: From the total 420 respondents, 244 (58.1%) were women. Among the respondents, 308 (73.3%) had adhered to Anti-Retroviral-Therapy (ART). Respondents who had good relationship with health care provider had 3.15 times more likely to adhere to ART compared to those who had poor relationship. Those who stated stigma and discrimination as a major problem were 81% less likely to adhere to ART compared to those who stated stigma and discrimination not to be a problem at all. CONCLUSION: The findings of the study indicate that ART adherence rate to be low. The study also showed that Stigma and discrimination, and poor relationship with health care provider to be associated with low adherence. Based on the finding, keep away from stigmatization and discrimination, and enhancing good relationship need to be given attention for improving ART adherence. PMID- 23930482 TI - Current and future role of voluntary surgical contraception in increasing access to and utilization of family planning services in Africa. AB - BACKGROUND: Voluntary surgical contraception is the most widely utilized method of contraception in the world. High effectiveness, low complication rates and reduced cost in the long term make them the ideal contraceptive choice to diverse group of clients including clients from low resource settings. OBJECTIVE: To assess the current status of utilization and effectiveness of voluntary surgical contraception in Africa and suggest possible future roles in contraceptive method choice. METHODS: A review of available literature on voluntary surgical contraception and synthesis of information under relevant headings. RESULTS: Despite very high total fertility rates in most countries of Africa, surgical contraceptives still contribute to a very small proportion ofcontraceptive method choice in the continent. Client profile and acceptability studies indicate a large unmet need for permanent contraception in the continent. Lack of information, misconceptions and weak health systems (particularly surgical care) are the major impediments to increasing availability of surgical contraception. Lack of knowledge and low levels of motivation among health care providers may also be significant barriers to access. CONCLUSIONS: Ihcreasing availability of information on the safety and effectiveness of these methods to both health care providers and the general population can increase demand and acceptability. Delegating service provision to appropriately trained non-physician providers at primary care settings can assist in increasing accessibility of these important family planning methods. PMID- 23930483 TI - Oral expulsion of taenia worm by a pregnant lady. AB - The case of a pregnant lady who expelled a tapeworm orally is discussed and a brief review on Taeniasis is also presented. PMID- 23930484 TI - Young male patient with advanced breast cancer: a case report. AB - Breast cancer in male is a rare disease, accounting for less than 1% all breast cancer cases. The incidence of male breast carcinoma increases with advancing patient age. This is the case report of a young man with a breast mass, which turned out to be malignant. PMID- 23930485 TI - Had "Meles" Zenawi been a physician. . . . PMID- 23930486 TI - Fertility desires predictors among people living with HIV/AIDS at art care centers of two teaching hospitals in Addis Ababa. AB - BACKGROUND: Studies from different contexts worldwide in both developed and developing countries in the era of wide access to antiretroviral drugs indicate that many HIV positive individuals continue to exhibit high risk sexual behaviors, fertility intentions being one of the many characteristics. OBJECTIVE: Identify the level and determinants of fertility desire among people living with HIV/AIDS (PLWHAs) at antiretroviral treatment (ART) centers. METHODS: A cross sectional study was conducted on randomly sampled, 396 PLWHAs. Odds ratio along with 95% confidence intervals were used to measure the association of the study variables with the outcome variable. RESULTS: The majority of respondents were females, 330 (83.3%), and 224 (56.6%) were in the age category of 25-35 years with the mean age of 33.5 +/- 6.61 years. From a total of 396 study subjects interviewed, 172 (43.3%) desired to have children in the future, out of which 123 (71.5%) stated positively that they intended to give birth in the near future, and of these 33 (26.8%) had taken action and are currently pregnant. CD4 count above 350/mm3, partner's desire to have a child, life time history of not having live births and number of alive children are the most important predictors of fertility desire reported in this survey. CONCLUSION: Fertility desire remains to be high. This will pose serious challenges in areas of high HIV prevalence, like Ethiopia, on the implementation of the PMTCT programs. The strong predictors of fertility desire found in our study on the other hand can be used by policy makers, planners, and health service providers in the planning and implementation of the PMTCT programs. We suggest a large scale studies to be undertaken in the future. PMID- 23930487 TI - Polysubstance use and its linkage with risky sexual behavior in university students: significance for policy makers and parents. AB - BACKGROUND: Despite the high prevalence of polysubstance use in low income countries, little has been done to investigate the linkage between polysubstance use and risky sexual behaviors. OBJECTIVE: To assess the association of polysubstance use with risky sexual behaviors, economic, educational and geographic factors. METHODS: A cross-sectional study on aspects of risky behavior towards HIV-infection was conducted on a sample of 1220 university students. Logistic regression analysis was applied to examine the linkage between polysubstance use and risky sexual behavior--having sex with multiple partners, commercial sex workers and failure to use condom. RESULTS: About one fourth of study participants reported to use one or more types of substance (mainly cigarette, alcohol and khat) in one year period. Of these students, more than three-fifths started using the substance before joining university and more than two-fifths were polysubstance users. Students from urban areas were more likely to be polysubstance users and to engage in sexual practice. Logistic regression analysis demonstrated a strong association of polysubstance use with male gender, being born and growing up in urban areas, good income, taught in private school, academically senior and born to more educated parents (P < 0.05 each). The majority (42%) of polysubstance users was also practicing sex with multiple partners and commercial sex workers, had sex without condoms and developed active sexually transmitted infection (STI) symptoms (P < 0.0001 for each). CONCLUSION: This analysis unveils the strong association of polysubstance use with better socioeconomic circumstances, better education and risky sexual behaviors. Primary prevention strategies should target students in elementary and secondary schools, mainly in the urban setting, and preferably by involving their parents. PMID- 23930488 TI - Clinical characteristics of patients with hematological malignancies at gondar university hospital, North West Ethiopia. AB - BACKGROUND: Hematological malignancies are primary cancers of the blood and blood forming organs (bone marrow and lymphoid tissues), which includes leukemia, lymphoma and plasma cell dyscrasia. The overall incidence of hematological malignancies appears to be rising in United States of America and Europe, and estimated to be rising in Africa. This study was conducted as there is scarcity of information regarding clinical characteristics of hematological malignancies in Ethiopia. OBJECTIVE: The study aims to determine the distribution and spectrum of various hematological malignancies encountered in the locality. METHOD: This is a retrospective descriptive study done in Gondar University Hospital, North West Ethiopia from January 2008 to December 2011 in those admitted with the diagnosis of hematological malignancies. RESULTS: Sixty-seven patients were admitted with the diagnosis of hematological malignancies during the study period The mean and median ages of patients with hematological malignancies were 42 yrs and 45 yrs respectively. Non-Hodgkin's lymphoma (NHL) comprised 22/67 (32.8%) of all hematological malignancies, followed by 17/67 (25.4%) chronic myeloid leukemia (CML) and 13/67 (19.4%) chronic lymphocytic leukemia (CLL). Majority of patients with NHL presented with advanced disease (77%), high-grade type (73%) with B-symptoms (68%), reflecting aggressive nature of the disease. Patients with acute leukemia, especially acute lymphoblastic leukemia (ALL), presented with features of cytopenia (fatigue, fever and bleeding tendency), while chronic leukemia (CML and CLL) cases had fatigue, weight loss and organomegally on admission. Among patients with CML, 12/17 (71%) were in chronic phase, 4/17 (23%) in accelerated phase and 1/17 (6%) in blast phase on admission. Majority of CLL patients had advanced disease on admission with 9/13 (69%) Binet C and 10/13 (76%) (Rai stage III and IV). CONCLUSION: The distribution and spectrum of various hematological malignancies in this study is grossly similar to the pattern reported in other African countries. PMID- 23930489 TI - Assessment of antibacterial drug exposure patterns of patient encounters seen by different categories of prescribers at health institutions in Bahir Dar, Ethiopia. AB - BACKGROUND: Understanding of existing antibacterial drug prescribing patterns is a pre-requisite for further investigation of potential determinants of irrational prescribing, if any, thereby looking for solutions would be easier. OBJECTIVE: This study was conducted to assess antibacterial prescription patterns of different health professionals working at general outpatient clinics of different health institutions. METHODS: In this cross-sectional study, a total of 1558 prescriptions of patient encounters, were collected from four clusters of prescribers randomly selected from 11 public and 15 private health institutions in Bahir Dar town and its environs, North West Ethiopia. RESULTS: A significant proportion of patient encounters were exposed to at least one antibacterial drug with percentage of encounters to whom antibacterial(s) prescribed was 64.5%. Multiple antibacterial drug exposure was minimal (7.8%) with a maximum of 3 antibacterial drugs per encounter. The study showed that patients at pediatric age group were more likely to receive an antibacterial drug than adult counter parts (70.3% vs 62.8%, p = 0.038, OR = 1.33). On the other hand, there were no statistically significant differences in the antibacterial exposure patterns of patients seen by prescribers of shorter pre-service training (health assistants and nurses) and those with longer duration (health officers and general practitioners) and also between patients seen at public and private health institutions. CONCLUSIONS: This study indicates that a significant proportion of patient encounters were exposed to antibacterial drugs. The actual determinants of the existing patterns should be further investigated in order to arrive at clear and feasible strategies to promote rational antibacterial drug prescribing practices. PMID- 23930490 TI - Nasal and hand carriage rate of methicillin resistant Staphylococcus aureus (MRSA) among health care workers in Mekelle Hospital, North Ethiopia. AB - BACKGROUND: Methicillin resistant Staphylococcus aureus (MRSA) is significant major pathogen responsible for hospital and community based infections. OBJECTIVE: The aim of this study was to assess the nasal and hand carriage of methicillin resistant Staphylococcus aureus in health care workers of Mekelle Hospital METHODS: The study was carried out during November 2010 to January 2011. Swab samples from both anterior nares and hands were taken. The samples were cultured on mannitol salt agar and incubated aerobically at 37 degrees C for 48 hours. Staphylococcus aureus was identified as nmannitol fermenter and coagulase test positive. Antimicrobial susceptibility test for MRSA was done by disk diffusion method using oxacillin disks. Data were analysed using SPSS version 16 software. RESULTS: Out of the 177 health care workers screened, 36 (20.3%) of them were methicillin resistant Staphylococcus aureus carriers in their hand and anterior nares. More females, 25(14.1%) were colonized by methicillin resistant Staphylococcus aureus than males 11 (6.2%) (P = 0.044). Nasal carriage of MRSA of 25 (14.1%) was higher than hand carriage 11 (6.2%) (p < 0.05). Nurses and medical doctors had methicillin resistant Staphylococcus aureus carriage rates of 26 (13.6%) and 4 (2.3%), respectively. The isolated MRSA were resistant to multiple antibiotics. The highest resistance was observed for ampicillin (88.9%) and tetracycline (86.1%). Two (5.6%) of the nasal isolates were vancomycin resistant. CONCLUSION: Methicillin resistant Staphylococcus aureus carriage among health care workers in this study was high. The carriage rate was higher among nurses and doctors. The MRSA isolates were multi drug resistant to other antibiotics. So, the result of this study emphasizes the need of regular surveillance of health care workers. It also calls a need for an effective infection prevention and control program. PMID- 23930491 TI - Diagnostic performance of transvesical ultrasound in clinically suspected ectopic pregnancy in a public and tertiary hospital setup. AB - BACKGROUND: Ectopic pregnancy consists 1.2 to 1.4% of all reported pregnancies and an increasing accordance has been documented in many parts of the world OBJECTIVE: To evaluate the performance of transvesical ultrasound (TVS) in the diagnosis of ectopic pregnancy in the public hospital setup. METHODS: Review of medical records of 117 patients who were admitted to St Paul's Hospital with the diagnosis of ectopic pregnancy between the years 2005 and 2008 was made. Data on demographic & clinical information, and laboratory investigations done and transvesical ultrasound records were collected. Outcomes after Laparatomy were used as confirmations or gold standard for final diagnosis. RESULTS: Of the 117 admitted patients for ectopic pregnancy, 99 (84.6%) had transvesical ultrasound done & in 65 (65.9%) of those 99 patients, it suggested diagnosis of ectopic pregnancy. Sixty-four (55%) had pervaginal bleeding and lower abdominal pain as presenting complaint. Documentation of uterine, adnexal & cul-de-sac findings fall the three diagnostic variables) was noted in 71/99 (71.7%) two of the three and only one of the three diagnostic variables were seen 20.2% and 8.1% of the sonographic studies respectively. Of patients whose ultrasound report suggested ectopic pregnancy, in 46 (70.8%) a complex adnexal mass and in 33 (50.8%) moderate to large amount of cul-de-sac fluid, and in 9 (19.8%) patients fluid in the uterine cavity were detected The overall sensitivity and specificity of transvesical ultrasound study in the diagnosis of ectopic pregnancy were 83.3% and 33.3% respectively, with positive & negative predictive values of 73.5% and 47.4% respectively and accuracy of 68%. CONCLUSION: About 83.3% of admitted patients were diagnosed sonographically to have ectopic gestation prior to surgery. Quality of the ultrasound report with respect to completeness in number of sonographic diagnostic variables has a statistically significant (P < 0.05) role in enhancing the accuracy of transvesical ultrasonography in the diagnosis and exclusion of ectopic pregnancy. PMID- 23930492 TI - A review of a five (5) years experience (Sept. 2004-Aug. 2009) with hepatic resections at Gondar University Hospital (GUH). AB - Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Many patients with benign and malignant hepatobiliary disease have been referred to the surgical outpatient department (OPD) of GUH. Hepatic resection is appropriate treatment for a variety of benign or malignant primary or secondary liver tumors. However, hepatobiliary neoplasms present a surgical management challenge and experience in the effective surgical management of these conditions has been generally lacking in the country. Few patients have been offered resection for liver tumors at GUH. The resections reported here represent the first set of cases from GUH and probably from any other institution in Ethiopia. This review summarizes a five year experience in hepatic resection procedures at GUH. Patients' charts and operating room logbooks, as well as the follow up notes of the senior surgeons were reviewed. Nine tumor resections (major, minor and enucleations) were done. There were two deaths; one from sepsis and the other from an acute cardiopulmonary event. We believe that in carefully selected patients hepatic resection is possible in facilities such as GUH and generally offers the best opportunity for long-term palliation and survival. At laparotomy general abdominal examination is a crucial step and should be routinely undertaken prior to hepatic resection. PMID- 23930493 TI - Life with anotner cornea: impact of corneal transplantation and eye banking in Ethiopia. AB - PURPOSE: Although clinical success of corneal transplantation is encouraging, its impact on the lives of beneficiaries is overlooked. We tried to understand how visually impaired people perceive the effect of a recently introduced corneal transplantation and eye banking service. METHODS: In-depth interviews were conducted among 20 patients with corneal visual impairment. All had transplantation surgery at Minilik II Hospital, mostly with corneas harvested and processed by Eye Bank of Ethiopia. The qualitative data focused on their experiences regarding changes in quality of life, visual outcome, and attitude toward corneal donation. Data were analyzed using the thematic framework approach. RESULTS: Before the transplantation, patients suffered from disability and low self-esteem but remained hopeful. After the transplantation, they felt satisfied with whatever visual gain they got and described the process as 'a miracle'. They believed their life had somewhat changed for the better as they became independent and capable again. They also felt extremely grateful to donors and became advocates for corneal donation. CONCLUSION: The availability of a corneal harvesting and transplantation service is making positive impacts on the lives of visually impaired individuals in Ethiopia. However, the extent of this service should be widened to have a significant effect on the magnitude of corneal blindness across the country. PMID- 23930494 TI - A case report of left sided IVC with retroaortic right renal vein and hemiazygos continuation. AB - A case report of a left sided IVC with hemiazygos continuation and retro aortic right renal vein in a 45 year old female is described here with discussion of embryogenesis of this anomaly and its clinical importance. The anomaly was first observed on computer tomographic images performed for a different purpose. Doppler ultrasound done afterwards then showed absence of hepatic segment of the IVC and a retro aortic right renal vein. As far as our search is concerned this is the first report of its kind in Ethiopia. PMID- 23930495 TI - CT and color Doppler diagnosis of the vein of Galen malformations with hydrocephalus: a case series report of rare intracranial vascular malformations. AB - Arteriovenous malformations are uncommonly occurring congenital conditions and great vein of Galen malformations are rare form of arteriovenous malformations. Aneurysmal dilatation of the median prosencephalic vein of Markowski is responsible for the clinical presentation of patients and most children manifest the disease during infancy. We present three cases of great vein of Galen malformations, presenting to Tikur Anbessa hospital, one with thrombosis and communicating hydrocephalus; the other two with obstructive hydrocephalus and no thrombosis. All patients have markedly dilated intracranial veins with vascular enhancement pattern in venous phase of brain CT scan. Physicians should be aware of different radiological presentations of vein of Galen malformations and different clinical presentation of these cases. Very rarely the vein of Galen malformation can have thromboses and obliteration of itself The clinicians should also know that CT scan and MRI are the corner stones for the diagnosis of vein of Galen malformations but more fetuses are diagnosed with VGM in the uterus by ultrasound during ANC. PMID- 23930496 TI - A 52-year-old lady with post operative reversible blindness and hemiparesis. AB - A 52-year-old lady developed cortical blindness followed by left sided hemiparesis after cholecystectomy, both of which resolved remarkably. A diagnosis of posterior reversible encephalopathy syndrome (PRES) was made based on characteristic clinical and MRI features. PMID- 23930497 TI - [Establishment of a 3D finite element model of human thoracic cage and biomechanical analysis]. AB - OBJECTIVE: To establish a 3D finite element model of the complete human thoracic cage, and to perform a biomechanical analysis. METHODS: The multislice computed tomography (MSCT) images of human thorax were obtained and used to develop a 3D reconstruction and a finite element model of the thoracic cage by finite element modeling software. The right hypochondrium area of the model was simulated to sustain the frontal impacts by a blunt impactor with velocities of 4, 6 and 8 m/s, and the distribution of stress and strain after the impact of the model was analyzed. RESULTS: A highly anatomically simulated finite element model of human thoracic cage was successfully developed with a fine element mean quality which was above 0.7. The biomechanical analysis showed that the thoracic cage revealed both local bending and overall deformation after the impact. Stress and strain arose from the initial impact area of the ribs, and then spread along the ribs to both sides, at last concentrated in the posterior side of the ribs and near the sternum. Impacts with velocities of 6 m/s and 8 m/s were predicted to cause rib fractures when the strain of the ribs were beyond the threshold values. CONCLUSION: The finite element modeling software is capable of establishing a highly simulated 3D finite element model of human thoracic cage. And the established model could be applicable to analyze stress and strain distribution of the thoracic cage under forces and to provide a new method for the forensic identification of chest injury. PMID- 23930498 TI - [Expression of BNP in rat myocardial tissue after acute cardiac dysfunction]. AB - OBJECTIVE: To investigate the expression of brain natriuretic peptide (BNP) in rat myocardial tissue after acute cardiac dysfunction and to explore the role of BNP in diagnosis of cardiac dysfunction in forensic practice. METHODS: Rat models of acute cardiac dysfunction were established. The expression of BNP protein and BNP mRNA in myocardial tissue after cardiac dysfunction were detected by immunohistochemistry, Western blotting and real-time RT-PCR. RESULTS: The extent of positive staining of BNP increased over the time course during cardiac dysfunction. The expression of BNP showed mild positive in cardiomyocytes from 1 h to 2 h. From 4 h to 6 h, the expression was moderate positive. From 10 h to 12 h, the BNP showed a strongest positive expression. The expression of BNP presented a significant raise with the increasing time of cardiac dysfunction by Western blotting and real-time RT-PCR. The expression of BNP mRNA increased significantly 1 h after cardiac dysfunction. CONCLUSION: Investigating the expression of BNP protein and BNP mRNA in myocardial tissue may provide a new approach to evaluate the cardiac function for forensic pathologists. PMID- 23930499 TI - [Relation between expression of cerebral beta-APP in the chronic alcoholism rats and death caused by TSAH]. AB - OBJECTIVE: By observing the cerebral beta-amyloid precursor protein (beta-APP) expression in the chronic alcoholism rats with slight cerebral injury, to discuss the correlation of chronic alcoholism and death caused by traumatic subarachnoid haemorrhage (TSAH). METHODS: Sixty male SD rats were randomly divided into watering group, watering group with strike, alcoholism group and alcoholism group with strike. Among them, the alcohol was used for continuous 4 weeks in alcoholism groups and the concussion was made in groups with strike. In each group, HE staining and immunohistochemical staining of the cerebral tissues were done and the results were analyzed by the histopathologic image system. RESULTS: In watering group, there was no abnormal. In watering group with strike, mild neuronic congestion was found. In alcoholism group, vascular texture on cerebral surface was found. And the neurons arranged in disorder with dilated intercellular space. In alcoholism group with strike, diffuse congestion on cerebral surface was found. And there was TSAH with thick-layer patches around brainstem following irregular axonotmesis. The quantity of beta-APP IOD in alcoholism group was significantly higher in the frontal lobe, hippocampus, cerebellum, brainstem than those in watering group with strike and alcoholism group with strike. CONCLUSION: The cerebral tissues with chronic alcoholism, due to the decreasing tolerance, could cause fatal TSAH and pathological changes in cerebral tissues of rats under slight cerebral injury. PMID- 23930500 TI - [Correlativity between projected visual chart vision and contrast vision]. AB - OBJECTIVE: To study the correlativity between the projected visual chart vision ("projector vision" in this paper) and the measured values of contrast vision, and to explore the application of contrast vision in identifying visual impairment after eye injury in the clinical forensic medicine. METHODS: One hundred and twenty nine eyes of seventy-nine young volunteers were collected for examination both of projector vision and contrast vision. In the examination of contrast vision, the contrast of optotypes were set to 100%, 25% and 10%, respectively. The correlativity of both collected experimental data were statistically analyzed. RESULTS: Projector vision was consistent with 100% contrast vision. There was a close and positive correlation between the contrast of optotypes and measured vision values. Under the same contrast of optotypes, projector vision presented a linear correlation with the average value of contrast vision. CONCLUSION: There is a close correlation between projector vision and contrast vision. The contrast vision can be applied to judicial identification in the clinical forensic medicine. PMID- 23930501 TI - [Development of competency to stand trial rating scale in offenders with mental disorders]. AB - OBJECTIVE: According with Chinese legal system, to develop a competency to stand trial rating scale in offenders with mental disorders. METHODS: Proceeding from the juristical elements, 15 items were extracted and formulated a preliminary instrument named the competency to stand trial rating scale in offenders with mental disorders. The item analysis included six aspects, which were critical ratio, item-total correlation, corrected item-total correlation, alpha value if item deleted, communalities of items, and factor loading. The Logistic regression equation and cut-off score of ROC curve were used to explore the diagnostic efficiency. RESULTS: The data of critical ratio of extreme group were 18.390 46.763; item-total correlation, 0.639-0.952; corrected item-total correlation, 0.582-0.944; communalities of items, 0.377-0.916; and factor loadings, 0.614 0.957. Seven items were included in the regression equation and the accuracy of back substitution test was 96.0%. The score of 33 was ascertained as the cut-off score by ROC fitting curve, the overlapping ratio compared with the expertise was 95.8%. The sensibility and the specificity were 0.938 and 0.966, respectively, while the positive and negative likelihood ratios were 27.67 and 0.06, respectively. CONCLUSION: With all items satisfied the requirement of homogeneity test, the rating scale has a reasonable construct and excellent diagnostic efficiency. PMID- 23930502 TI - [Genotyping and parental related methylation of SNRPN gene rs220030]. AB - OBJECTIVE: To establish two methods by denaturing gradient gel electrophoresis (DGGE) and pyrosequencing for genotyping rs220030 (a SNP in the promoter region of small nuclear ribonucleoprotein polypeptide N, SNRPN). To establish an analytical technique for detecting CpG methylation status by pyrosequencing and to further investigate the feasibility of applying rs220030 to the determination of parental origin allele. METHODS: The rs220030 of 97 blood samples from individuals of Shanghai Han population were genotyped by DGGE, meanwhile the rs220030 of 25 blood samples of them were genotyped by pyrosequencing to compare the two methods in genotyping SNP. Pyrosequencing united bisulfite conversion method was applied to detect CpG methylation status of region upstream rs220030 of two random blood genealogical samples and investigate whether the methylation status was parental related. RESULTS: The rs220030 genotyping results of 97 blood samples detected by DGGE were 20 C homozygote, 29 T homozygote, and 48 C/T heterozygote. Twenty-five blood samples genotyped by pyrosequencing showed the same result with DGGE. The CpG methylation status of region upstream rs220030 of the child was similar to the mother. CONCLUSION: Compared with DGGE, pyrosequencing is more accurate, convenient, and suitable for large samples and high throughput SNP genotyping. Pyrosequencing united bisulfite conversion can be used to detect CpG methylation status precisely. It is feasible to apply rs220030 to parental origin allele determination. PMID- 23930503 TI - [Correlation between genetic polymorphisms of -855 G/C and -1140 G/A in GRIN1 gene and paranoid schizophrenia]. AB - OBJECTIVE: To investigate the single nucleotide polymorphisms (SNP) of -855 G/C and -1140 G/A in promoter regions of GRIN1 gene and find their genetic correlation to paranoid schizophrenia as well as their applicable values in forensic medicine. METHODS: The genetic polymorphisms of -855 G/C and -1140 G/A at the 5' end of GRIN1 gene were detected by PCR restriction fragment length polymorphism and PAGE in 183 healthy unrelated individuals of northern Chinese Han population and 172 patients of paranoid schizophrenia, respectively. The chi2 test was used to identify Hardy-Weinberg equilibrium of the genotype distribution. The differences of genotypes and allelic frequency distributions were compared between the two groups. RESULTS: Distributions of the genotypic frequencies satisfied Hardy-Weinberg equilibrium in both groups. The difference of genotypes was statistically significant between female patient group and female control group in -855 G/C distribution (P < 0.05). The differences of genotypes and allelic frequencies were statistically significant not only between the patient group and the control group but also between female patient group and female control group in -1140 G/A distribution (P < 0.05). CONCLUSION: The SNP of -1140 G/A in promoter regions of GRIN1 gene might positively correlate to paranoid schizophrenia. The genetic factor of schizophrenia is involved in gender tendency. And it could be useful in forensic identification of schizophrenia. PMID- 23930504 TI - Method development and validation for determining 1,3-butadiene in human blood by gas chromatography-mass spectrometry and head-space gas chromatography. AB - To develop a simple, validated method for identifying and quantifying 1,3 butadiene (BD) in human blood by gas chromatography-mass spectrometry (GC-MS) and head-space gas chromatography (HS-GC). BD was identified by GC-MS and HS-GC, and quantified by HS-GC. The method showed that BD had a good linearity from 50 to 500 microg/mL (r > 0.99). The limits of detection and quantification were 10 microg/mL and 50 microg/mL, respectively. Both the intra-day precision and inter day precision were < 6.08%, and the accuracy was 96.98%-103.81%. The method was applied to an actual case, and the concentration of BD in the case was 242 microg/mL in human blood. This simple method is found to be useful for the routine forensic analysis of acute exposure to BD. PMID- 23930505 TI - [Forensic psychiatric cases of 534 mental disorders caused by traumatic brain injury]. AB - OBJECTIVE: To analyze the types of mental disorders caused by traumatic brain injury and the optimal time for forensic psychiatric appraisal. To explore the relationship between the degree of traumatic brain injury, the time of appraisal and the grade of intellectual deficiency. METHODS: Five hundred and thirty-four forensic psychiatric cases of mental disorders caused by traumatic brain injury were retrospectively analyzed. RESULTS: In the types of mental disorders caused by traumatic brain injury, the most cases were diagnosed as organic mood disorders (51.1%), following organic neurosis-like syndrome (24.0%) and organic intellectual deficiency (18.0%). For the disability grades, the most cases were the level VIII and IX disability grades, 219 cases (41.0%) and 177 cases (33.1%), respectively. The degree of brain injury and the degree of intelligence defection according to WAIS-RC were higher in intellectual deficiency group compared with non-intellectual deficiency group (P < 0.05). The grade of disability correlated with the degree of brain injury, the result of WAIS-RC, the result of cerebral CT scanning, and the grade of brain electrical activity mapping (BEAM) abnormality (P < 0.05). Nevertheless, the degree of intellectual deficiency did not correlate with appraisal time and the degree of brain injury (P > 0.05). CONCLUSION: The factors influencing intellectual deficiency are complex. The findings of objective examination including cerebral CT scanning, BEAM, WAIS-RC and others should be considered as important indexes for disability evaluation. PMID- 23930506 TI - [Reappraisals of mental disabilities due to traffic accidents: a retrospective analysis of 51 cases]. AB - OBJECTIVE: To discuss the causes for changes of opinions in reappraisals of mental disabilities due to traffic accidents. METHODS: Fifty-one reappraisals of mental disorders due to traffic accidents from October 2009 to October 2011 in the Institute of Forensic Science, Shaoxing Seventh People's Hospital, were retrospectively analyzed. RESULTS: In the reappraisals, the opinions about disability grade changed in 30 cases (58.82%), including 8 cases increased and 22 cases decreased. According to the causes of changing the opinions, there were 8, 10 and 2 cases related to different understandings of appraisers in the severities of mental disorders, subjective judgements and certain psychiatric symptoms, respectively. Also, there were 10 cases related to different appraisal time. CONCLUSION: Appraisals of mental disabilities should grasp the appraisal time, decrease the changes of opinions due to the differences of appraisers and correctly understand the orders of rules and clauses. PMID- 23930507 TI - [A retrospective analysis of 97 drunk driving cases]. AB - OBJECTIVE: Based on a retrospective analysis of the drunk driving cases, to explore the drunk drivers' personnel composition, occurrence time and psychology. METHODS: As a result of punishment of the drunk driving by criminal law for one year from May 1st, 2011 to April 30th, 2012, 91 drunk driving cases were statistically analyzed the easy-happening time of drunk driving, the drunk drivers' age, gender, occupational characteristics, domicile and psychological factors. RESULTS: In 97 drunk driving cases, 26-40 years old, non-local domiciled and non-professional male drivers were prone to drunk driving at night from 22:00 to 5:00. CONCLUSION: The behavior of drunk driving is relevant to time, age, genders and occupation. The psychological characteristics of most drivers are fluky, making-life-easy, competitive and peacockish. PMID- 23930508 TI - [Influences of cycle index and volume on sensitivity of DNA detection]. AB - OBJECTIVE: To explore the feasibility of improving the sensitivity of DNA detection by increasing the PCR cycle index and decreasing the volume of amplifying system. METHODS: The DNA of semen were collected from 10 healthy irrelevant volunteers, and were quantified to 50, 40, 30, 25, 20, 15, 10 pg/microL, separately. All samples were then amplified in 10, 5, 3 microL volume and at 28, 30, 32, 34, 36 cycles, respectively. 3130 genetic analyzer was used to detect 15 autosomal STR loci. RESULTS: Under the situation of 28 cycles and 3 microL volume, samples which achieved > 40 pg/microL could be correctly typed. Under the situation of 10, 5, 3 microL volume, samples which achieved > 20 pg/microL could be correctly typed at 34 cycles. When increasing the index to 36 cycles, they could not be correctly typed because of the non-specific band. CONCLUSION: DNA detecting sensitivity can be improved to a certain extent by increasing the cycle index and decreasing the volume of amplifying system. PMID- 23930509 TI - [DNA extraction from bones and teeth using AutoMate Express forensic DNA extraction system]. AB - OBJECTIVE: To explore a new method in order to extract DNA from bones and teeth automatically. METHODS: Samples of 33 bones and 15 teeth were acquired by freeze mill method and manual method, respectively. DNA materials were extracted and quantified from the triturated samples by AutoMate Express forensic DNA extraction system. RESULTS: DNA extraction from bones and teeth were completed in 3 hours using the AutoMate Express forensic DNA extraction system. There was no statistical difference between the two methods in the DNA concentration of bones. Both bones and teeth got the good STR typing by freeze-mill method, and the DNA concentration of teeth was higher than those by manual method. CONCLUSION: AutoMate Express forensic DNA extraction system is a new method to extract DNA from bones and teeth, which can be applied in forensic practice. PMID- 23930510 TI - [Progress in thin layer CT scan technology in estimating skeletal age of sternal end of clavicle]. AB - It is practical value for determination the teenagers whether the age is full of the legal responsibility age of 18 years old or not by estimating skeletal age of sternal end of clavicle. The traditional methods mainly based on X-ray radiography. However, sternal end of clavicle and adjacent lung, bronchus, sternum, rib, transverse process of thoracic vertebra are overlapped each other. As a result of overlapping, there will be obtained false negative or positive film reading results when according to X-ray observation of epiphyseal growth of sternal end of clavicle, which directly affect the scientificalness and accuracy of estimating of skeletal age. In recent years, the scholars at home and abroad have started to use thin layer CT scan technology to estimate skeletal age of the sternal end of clavicle. With the 2D and 3D CT recombination technology, the accuracy of the film reading distinctly improves by making the shape, size and position of epiphysis displayed clearly. This article reviews the application and research progress of thin layer CT scanning technology in estimating skeletal age of sternal end of clavicle at home and abroad, analyzes the superiority and value of thin layer CT scan technology, which applied to skeletal age of sternal end of clavicle. PMID- 23930511 TI - [Progress in InDel as a new generation of genetic marker]. AB - As forensic DNA typing experienced three generations of genetic marker researching stage, short tandem repeat (STR) has been widely used in forensic identification as a mature tool. Further exploration of the human genome led to the discovery of polymorphism markers of single nucleotide polymorphism (SNP) and Insertion/Deletion (InDel). InDel, which combines the desirable characteristics of previous genetic markers as a new type of genetic marker, has got extensive concern in fields like medical molecular biology and forensic biology. This paper generally reviews the history of research and the corresponding results of InDel along the line of time axis as well as the different aims of these research focusing on the progress in the multiple amplification system with several InDel as the genetic marker (autosomal or X chromosome) in forensic biology and anthropology. Finally, the direction of research in this field and the problems to be solved have been put forward. PMID- 23930512 TI - [Progress in myofibroblast and its application in forensic medicine]. AB - The myofibroblasts have dual characteristics of smooth muscle cells and fibroblasts. In repairing tissular wound, myofibroblasts are involved in fibrogenesis and remodeling the extracellular matrix of the fibrotic cascades reaction. The review describes the morphological characteristics and biological behaviors of myofibroblasts and the application of skin wound age determination, which may provide reference for research in forensic medicine. PMID- 23930513 TI - Transitional care: looking for the right shoes to fit older adult patients. AB - Potentially avoidable hospitalizations are associated with high costs and an increased risk for iatrogenic conditions in older adult patients. Although care managers may be aware of the common potential pitfalls that may arise in the transfer of patients to and from the hospital defining best practice models has been difficult. Many current models of geriatric care have had little or no impact on lowering the rates of hospitalizations and rehospitalizations when formally studied. Health care reform legislation mandates initiatives involving new models of coordinated or guided care such as the medical home model and the accountable care organization. These new models too will face significant challenges in their attempt to provide the financial incentives and systematic changes needed to successfully address transitional care in older adults. PMID- 23930514 TI - Integrating behavioral and physical health services and organizational merger. AB - This article describes the process of the merger of two mental health agencies with a primary care physical health provider to establish within the merged structure an integrated behavioral and physical health delivery system. The purpose of this article is to share our experience with those administrators and staff of agencies planning an integration initiative of behavioral and physical health services. PMID- 23930515 TI - A cross-national comparison of perceptions of aging and older adults discussion of comparative analysis and findings of the five countries: Part 2. AB - This international comparative study on perceptions of aging and older people focusing on the predictor variables of Age, Gender, Marital Status, and Income Level has demonstrated that there are similarities and differences among how the participants in the countries view aging and older people. This study is exploratory with the intent to demonstrate that there is much to be gained from investigating the similarities and differences in perceptions of aging among countries. PMID- 23930516 TI - Social withdrawal of persons with vascular dementia associated with disturbance of basic daily activities, apathy, and impaired social judgment. AB - Patients with vascular dementia (VaD) are often isolated, withdrawn from society because of negative symptoms and functional disabilities. The aim of this study was to detect factors associated with social withdrawal in patients with VaD. The participants were 36 institutionalized patients with VaD. Social withdrawal was assessed with the social withdrawal of the Multidimensional Observation Scale for Elderly Subjects (MOSES). Possible explanatory variables were the MOSES items depression and self-care, Cognitive Abilities Screening Instrument (CASI), apathy evaluation scale (AES), and Behavioral Pathology in Alzheimer's Disease Frequency Weighted Severity Scale (BEHAVE-AD-FW). Multiple regression analyses were conducted for two groups: Analysis 1 was performed in all patients (N = 36) and Analysis 2 was performed in the patients with the ability to move by themselves (i.e., independent walking or independent movement with a cane or a wheelchair; n = 28). In Analysis 1, MOSES item social withdrawal was correlated with AES and MOSES item self-care. In Analysis 2, MOSES item social withdrawal was correlated with AES and CASI domain abstraction and judgment. Decreased social activities of VaD were not related to general cognitive function or depression. Disturbed activities of daily living (ADLs) for self-care may involve decreased frontal lobe function, indicating that comprehensive rehabilitation for both ADL and dementia are needed to improve the social activities of patients with VaD. PMID- 23930517 TI - Verna Green Smith, PhD: born on the prairie, 1919. Interview by Marian Brickner. PMID- 23930518 TI - Government public housing health needs assessment: focus on race, ethnicity, and the older adult: background, methods, and demographics. AB - St. Vincent's Catholic Medical Centers of New York initiated a study in 2009 to assess the health needs of residents of New York City (NYC) municipal housing at the Robert Fulton public housing complex in Manhattan. The aim of this project was to provide valid data on perceived health services needs of the residents of a NYC housing project. These data may also be used to support hospital and community collaborative strategic decisions for developing resident-appropriate health and social services and would be valuable for use in formulating policies and programs by other interested nonprofit health and social services organizations and government. We designed a 28-item instrument and pilot tested it with our research team and members of the population under study. The English and Spanish surveys were designed as an in-person surveyor-administered instruments addressing four domains: demographics, access and barriers to health care services, risk behaviors, and perceived health needs. The sampling was an apartment-level stratified random sampling. A 20%, 188 apartment sample was drawn from the population of 944 housing units. Our response rate was 92% (173/188 apartments). Background methods, and demographic results are reported in this article. A second article will report on the needs assessment results. PMID- 23930519 TI - NYC Department for the Aging Annual Plan Summary: April 1, 2013-March 31, 2014. PMID- 23930520 TI - Nurses' public health role is underestimated. PMID- 23930521 TI - RCN demands urgent talks with ministers over staffing numbers. PMID- 23930522 TI - Training should focus on shift to community care, report urges. PMID- 23930523 TI - Watchdog's inspection standards chime with aims of care campaign. PMID- 23930524 TI - Mid Staffs performance improves but police review is unsettling. PMID- 23930525 TI - Surge in A&E attendances caused by public confusion about services. PMID- 23930526 TI - Think tank blames the working classes again. PMID- 23930527 TI - Nursing a nation back to health. AB - England's top nurse for public health Viv Bennett discusses new opportunities for nurses and the benefits of moving responsibility for services to local government. Nurses' contribution to public health has been overlooked for too long, she says. PMID- 23930529 TI - Changes bring opportunities. PMID- 23930528 TI - Every nurse's new role. AB - All nurses and midwives should be making use of their routine contacts with patients to improve public health, argue a senior nurse and midwife who will be presenting a new model of public health nursing at a major conference next week. Front line nurses explain how they are extending their traditional roles. PMID- 23930530 TI - Appendicitis: a case study. AB - The presentation of patients with abdominal pain is a common occurrence in emergency departments. Since there are many potential causes of abdominal pain, diagnosis may be challenging. Accurate history taking and appropriate physical examination are essential to identify potentially life-threatening conditions, such as appendicitis, and ensure prompt treatment. This article presents a case study of a patient presenting with right lower quadrant abdominal pain. Assessment, differential diagnosis and management of the patient are discussed. PMID- 23930531 TI - Hypoglycaemia: causes, risk factors and pathophysiology. AB - This article examines the prevalence, symptoms, risk factors, management and prevention of hypoglycaemia in adults. Relevant research and government policies are discussed, and recent guidelines on the management of hypoglycaemia are presented. Standard 7 of the National Service Framework for Diabetes focuses on the need for improved knowledge and skills of healthcare professionals when dealing with diabetic emergencies. Healthcare professionals should be aware that tight glycaemic control may increase the risk of hypoglycaemia. Ongoing education about the recognition and treatment of hypoglycaemic episodes, particularly in patients being treated with insulin and sulfonylureas, is an important component of the nursing role. PMID- 23930532 TI - Safe and effective application of topical treatments to the skin. AB - Skin conditions are common in all age ranges, and can significantly affect an individual's quality of life. Nurses prescribing or applying topical treatments should have a comprehensive understanding of skin barrier function and the effects this has on the absorption of medication through the skin. This article focuses on the therapeutic options available to treat skin conditions with particular emphasis on topical treatments, including emollients and topical corticosteroids. The principles of skin barrier function and the way in which therapies applied to the skin work are also discussed. PMID- 23930533 TI - Bone metastases. PMID- 23930534 TI - My aim is to improve care. PMID- 23930536 TI - Be open to criticism and ideas. PMID- 23930535 TI - Specialists prove their worth. PMID- 23930537 TI - The learning partnership. PMID- 23930538 TI - C. H. McCloy Lecture: symbols, conventions, games, Eleanor Metheny, and the evolution of human intelligence. AB - In this essay I argue that Eleanor Metheny was ahead of her time when she argued that nonverbal physical activities carry symbolic meanings and are, for that reason and others, intellectually impressive. I compare her theories on the symbolic process with something that might be called the "conventional process." I will show why conventional logic rather than symbolic reasoning tells us more about the way intelligence evolved and the potentially impressive role played by games in the advance of human civilization. PMID- 23930539 TI - Perceived success, auditory feedback, and mental imagery: what best predicts improved efficacy and motor performance? AB - PURPOSE: Performance enhancement techniques can improve self-efficacy (SE) and task performance. The focus of this study was to determine which techniques could best achieve this with three novel tasks. METHOD: Participants (n = 98) were counterbalanced across tasks and conditions (48 participants assigned to each condition in each task) and completed two trials of putting (imagery vs. no imagery), throwing (easy vs. difficult), and kicking (verbal feedback vs. no feedback) tasks, and SE and performance scores were recorded. RESULTS: The results revealed that the auditory feedback condition had the greatest impact as it significantly explained both SE and performance scores, with a greater effect recorded for SE scores. Use of imagery or allocation to the easy-to-score condition did not improve performance or SE scores more than did the control conditions. CONCLUSIONS: These findings were unexpected as successful past performance is often cited as the main determinant of SE change. Further empirical investigation is required to determine if these findings are repeatable and if they generalize to sporting settings. PMID- 23930540 TI - The representation of physically active girls in children's picture books. AB - PURPOSE: Borrowing from Tuchman's (1978) concept of symbolic annihilation, the purpose of this study was to explore the ways in which physically active females were represented in children's picture books. METHOD: Employing a qualitative content analysis methodology (Hsieh & Shannon, 2005), the written and pictorial portrayals of girls' physical activities were analyzed in 10 children's picture books. A directed approach to content analysis (Hsieh & Shannon, 2005) was employed in which the researchers began with predetermined categories that were used to code the text and images. RESULTS: The findings indicated that the majority of the primary female characters were illustrated wearing appropriate athletic attire that would allow for physical movement. Although all of the primary female characters were depicted as excited about being physically active, 6 of the books described the movement of the primary female characters using action-oriented descriptors. The parents of the primary female characters were identified as the primary source of encouragement and peers were found to be the primary source of discouragement toward the primary female characters' physical activity or sport involvement. The physical abilities of the primary female characters were compared to male peers in 3 of the books. CONCLUSIONS: Although the 10 books studied provide young girls with imagery and text that encourage female physicality, it is apparent that more books are needed that focus on girls' involvement in sport and physical activity. Meaningful forms of literature that encourage physical activity and sport involvement for girls are needed. PMID- 23930541 TI - Understanding the contexts of adolescent female participation in sport and physical activity. AB - PURPOSE: Participation in physical activity (PA) is reported to decline in adolescence, particularly for girls. However, we do not know if this decline in PA is consistent across modes and settings or whether there are transfers of participation between modes and settings. Nor do we understand the changes in specific types of PA or the interaction between types of participation and different modes/settings. This study investigated contexts of PA participation for female adolescents at two life transition points. METHOD: A survey of 489 Year 7 and 243 Year 11 adolescent girls was conducted, incorporating a measure of overall PA level and participation rates in seven modes/settings and in specific types of sport and PA. RESULTS: Less than half of the respondents met or exceeded the recommended level of moderate or vigorous PA--60 min or more--on the previous day, and there was no statistically significant difference in the proportions in Years 7 and 11 (39.5% vs. 45.9%; p > .05). However, older adolescents shifted their participation away from organized, competitive modes and settings toward nonorganized and noncompetitive modes and settings and individual types of PA. CONCLUSIONS: An understanding of the changes in PA modes and settings identified here can inform the planning of policies and implementation of programs for the promotion of PA by adolescent girls. PMID- 23930542 TI - Psychological predictors of children' s recess physical activity motivation and behavior. AB - PURPOSE: This study explored the relationship between children's basic psychological needs satisfaction at recess, level of recess physical activity motivation (RPAM), and recess physical activity (RPA). METHOD: Fifth-grade children (N = 203; 50.2% boys; 71.7% healthy-weight) completed measures of age, gender, basic psychological need satisfaction, and level of self-determined motivation for RPA. Children also wore pedometers during six consecutive 30-min mid-school-day recesses. RESULTS: Multiple regression analyses indicated unique significant predictors of RPAM and RPA according to gender and weight status. RPAM was significantly predicted by all three basic psychological needs for boys and only competence need satisfaction for girls and healthy-weight children. RPA was predicted by RPAM for girls, competence need satisfaction for overweight children, and autonomy need satisfaction for boys and healthy-weight children. CONCLUSIONS: Findings support self-determination theory and provide important insight into the variations in psychological predictors of motivation for RPA and actual physical activity behavior based on gender and weight status. PMID- 23930543 TI - Association between accelerometer-assessed physical activity and tinnitus, NHANES 2005-2006. AB - PURPOSE: Internet-based claims suggest that physical activity may help to relieve tinnitus symptoms. The purpose of this study was to empirically investigate the association between accelerometer-assessed physical activity and tinnitus (i.e., ringing, roaring, or buzzing in the ears). METHOD: Data were obtained from the 2005-2006 National Health and Nutrition Examination Survey on 963 adolescents (aged 12-19 years old) and 473 older adults (aged 70-85 years old). Physical activity was measured using an accelerometer, and participants were asked several tinnitus-related questions. RESULTS: The weighted prevalence of tinnitus was 8.9% and 25.3% for adolescents and older adults, respectively. For every 1-min increase in moderate-to-vigorous physical activity, adolescents were 4% less likely to have tinnitus lasting more than 3 months compared with less than 3 months (OR = 0.96, 95% CI [0.93, 0.99]). For older adults with hypertension, for every 60-min increase in light-intensity physical activity, they were 21% less likely to have tinnitus zcompared with not having tinnitus (OR = 0.790, 95% CI [0.649, 0.963]). CONCLUSION: Overall, we conclude that physical activity was associated with tinnitus status in a nationally representative sample of adolescents and older adults. If additional studies confirm these findings, then audiologists and other hearing specialists are encouraged to promote physical activity among their patients to help treat and prevent tinnitus. PMID- 23930544 TI - Stepping from Belgium to the United States and back: the conceptualization and impact of the Harvard Step Test, 1942-2012. AB - PURPOSE: This article examines the contribution of the Belgian-American exercise physiologist Lucien Brouha in developing the Harvard Step Test (HST) at the'pioneering Harvard Fatigue Laboratory (HFL) during the Second World War and provides a better understanding of the importance of transnational relations concerning scientific progress. METHOD: Analysis of sources in the University Archives of the State University in Liege (Belgium), the Archives and Documentation Centre of the Sportimonium at Hofstade (Belgium), the Harvard Business School Archives at Baker Library (Cambridge, MA), the Harvard Medical School Archives at Countway Library (Cambridge, MA), and the Brouha and Shaler private family archives (Sutton, VT). RESULTS: The outbreak of the Second World War shifted research at the interdisciplinary HFL toward the field of military physiology and resulted in the transfer of Brouha from Belgium to the HFL. Brouha's personal and academic experiences made him the right man in the right place to develop the HST in 1942. The HST--which has celebrated its 70th anniversary--was of immediate academic and practical significance during and after the war. CONCLUSIONS: Brouha' s case demonstrates the importance of personal experiences, transnational relations, and interdisciplinary research settings for the establishment of scientific (sub)disciplines. Studying internal scientific evolutions in relation to personal and work experiences of "mobile" and therefore often "forgotten" researchers like Brouha is necessary to better understand and interpret evolutions in science and corresponding processes of academic and social mobility. PMID- 23930545 TI - Testing the validity of the Halverson developmental sequences for skipping. AB - PURPOSE: The purpose of this study was to test the validity of developmental sequences hypothesized by Halverson (Roberton & Halverson, 1984) for the arm and leg action in skipping. METHOD: Children's skipping movements were categorized into the Halverson sequences using (a) cross-sectional video data collected on one hundred and fifty 5- to 12-year-olds, and (b) longitudinal film data collected on 7 children followed from age 3 through high school. Both data sets were graphed separately across age to see if the sequence levels rose and fell in accordance with developmental theory. RESULTS: The longitudinal data indicated tentative validity of the sequences although study of younger children will be needed to validate the earliest levels of arm and leg action. In contrast to the children in the longitudinal study, relatively few children in the cross sectional study had reached the most advanced levels of the skip by 12 years of age. Supporting the findings of Loovis and Butterfield (2000), the cross sectional skipping data showed no gender differences (p >or= .05). CONCLUSION: Future studies should continue the validation process as well as further examine questions related to gender differences in skipping and to the amount of practice needed to acquire advanced movement in this task. PMID- 23930546 TI - The effect of a picture activity schedule on performance of the MABC-2 for children with autism spectrum disorder. AB - PURPOSE: The purpose of this study was to examine the impact of an assessment protocol utilizing a picture activity schedule on the performance of the Movement Assessment Battery for Children-Second Edition (MABC-2) by children with autism spectrum disorder (ASD). METHOD: Twenty-five children (ages 3-16 years; 20 boys, 5 girls) performed the MABC-2 under two different protocols (i.e., traditional protocol and picture activity schedule protocol). In the traditional protocol condition, each child received detailed verbal descriptions and demonstrations prior to the motor skill performance. During the picture activity schedule protocol, a picture of each task was presented to the children and the verbal instructions were minimized to emphasize visual supports. MABC-2 percentile scores were analyzed using a within-subjects repeated-measures analysis of variance. RESULTS: All children were delayed or at risk for delay in both fine and gross motor skill performance during the administration of the traditional protocol. However, when the picture activity schedule protocol was utilized, children showed a significantly higher MABC-2 percentile score (12.4) compared with that of the traditional protocol (1.1), F(1, 24)= 24.143, p < .001. CONCLUSIONS: The findings indicated that the picture activity schedule protocol may elicit better motor skill performance on the MABC-2 by children with ASD. We suggest researchers and practitioners incorporate a picture activity schedule into the MABC-2 assessment protocol when examining the fine and gross motor performance of children with ASD. PMID- 23930547 TI - Running on a lower-body positive pressure treadmill: VO2max, respiratory response, and vertical ground reaction force. AB - PURPOSE: This study investigated maximal oxygen consumption (VO2max) and time to exhaustion while running on a lower-body positive pressure treadmill (LBPPT) at normal body weight (BW) as well as how BW support affects respiratory responses, ground reaction forces, and stride characteristics. METHOD: Twelve runners performed VO2max tests on a regular treadmill and an LBPPT. Furthermore, they performed steady-state running (10km/hr, 14 km/hr, and 18 km/hr) and high-speed running (20km/hr and 22 km/hr) at four different BWs on the LBPPT. VO2, heart rate, ventilation, and breathing frequency as well as vertical ground reaction force (vGRF) and stride characteristics were measured. RESULTS: VO2max could be obtained on both treadmills, although time to exhaustion was 34.5% longer on the LBPPT. VO2, ventilation, and heart rate decreased linearly with increasing BW support at steady-state running, while breathing rate remained unaffected by increasing BW support. Ground reaction force was markedly reduced with increasing BW support. The contact time decreased and flight time increased with increasing BW support. The step frequency decreased and step length increased to some extent with increasing BW support. CONCLUSIONS: VO2max can be achieved on an LBPPT at 100% BW with an incline-running protocol. The LBPPT is a suitable training device for athletes and allows training at high running speeds and high aerobic stimuli with the benefit of low vGRF and a near-normal movement pattern, although manipulation of gravitational weight causes some adaptations in locomotion. PMID- 23930549 TI - The relationships among critical power determined from a 3-min all-out test, respiratory compensation point, gas exchange threshold, and ventilatory threshold. AB - PURPOSE: Critical power (CP) from the 3-min test was compared to the power outputs associated with thresholds determined from gas exchange parameters that have been used to demarcate the exercise-intensity domains including the respiratory compensation point (RCP), gas exchange threshold (GET), and ventilatory threshold (VT). METHOD: Twenty-eight participants performed an incremental-cycle ergometer test to exhaustion. The VT was determined from the relationship between the ventilatory equivalent for oxygen uptake (VE/VO2) versus VO2 and the GET was determined using the V-slope method (VCO2 vs. VO2). The RCP was identified from the VE-versus-VCO2 relationship. CP was the average power output during the last 30 s of the 3-min all-out test. Linear regression was used to determine the power outputs associated with the RCP, GET, and VT, as well as the VO2 associated with CP. Mean differences among the associated power outputs, percent VO2 peak, and percent peak power output for the GET, VT, RCP, and CP were analyzed using separate one-way repeated-measures analyses of variance. RESULTS: There were no significant differences between CP (187 +/- 47W) and the power output associated with RCP (190 +/- 49W) or between the power outputs associated with GET (139 +/- 37W) and VT (145 +/- 37W). The power outputs associated with GET and VT, however, were significantly less than were those at CP and associated with RCRP. CONCLUSIONS: These findings suggest CP and RCP demarcate the heavy from severe exercise-intensity domain and result from a different mechanism of fatigue than that of GET and VT, possibly hyperkalemia. PMID- 23930548 TI - Test-retest reliability and minimum detectable change using the K4b2: oxygen consumption, gait efficiency, and heart rate for healthy adults during submaximal walking. AB - PURPOSE: Oxygen consumption (VO2; mLO2/kg/min), gait efficiency (GE; mlO2/kg/m) and heart rate (HR; beats per minute) are measures of physiological gait performance. However, the collection device, procedures for data normalization, and biological factors can affect measurement variability. The purpose of this study was to determine the test-retest reliability and minimum detectable change (MDC) for VO2, GE, and HR with the K4b2 at submaximal walking speeds in healthy young adults. A second purpose was to determine if net measures improved reproducibility. METHOD: Twenty-two participants completed 2 identical treadmill tests on separate days at submaximal walking speeds from 0.71 m/s to 1.65 m/s. RESULTS: Intraclass correlation coefficient (ICC) values for gross VO2, gross GE, and HR were greater than .85 for all walking speeds. Associated MDC values were approximately 7% to 10% for gross VO2 and GE, and approximately 9% to 12% for HR. ICC values for resting VO2 were lower, with MDC values approaching 25%. Subtracting out resting values to derive net VO2 and GE values produced ICC values below .76 for the 2 slowest speeds but ICC values greater than .83 for the faster speeds. MDC values for net VO2 and GE were up to 20% for the slowest speeds. CONCLUSIONS: The results demonstrate metabolic cost can be assessed reliably using the K4b2 during submaximal walking and that gross measures are more reliable than net measures. Furthermore, changes at self-selected speeds exceeding 1.0 mLO2/kg/min in gross VO2 and 0.01 mLO2/kg/m in gross GE can be considered a true change in walking performance. PMID- 23930550 TI - Age and gender differences in adolescent and adult overarm throwing. AB - PURPOSE: The purposes of this study were to examine age and gender differences in throwing performance across an underexplored portion of the lifespan: middle adolescents (14-17 years old), young adults (18-25 years old), and adults (35-55 years old). METHOD: Throwing performance was assessed using the body component levels from Roberton's developmental sequences for force and ball velocity that were recorded by a radar gun. Participants in each age group performed between 5 to 10 forceful overhand throws toward a target approximately 15m to 20m from the thrower. A Wilcoxon-Mann-Whitney Test was used to determine gender differences and a Wilcoxon-Signed Ranks Test was used to determine age-group differences for each component. Gender and age-group differences in ball speed were determined by a 3 (age group) x 2 (gender) factorial analysis of variance with follow-up post hoc tests. RESULTS: Young-adult men had higher body component levels and ball speed compared with the adolescent boys and adult men. Female age-group differences existed only for humerus action between young-adult and adult groups and for ball speed between young-adult and adolescent groups. Gender differences (p < .01) existed in component levels for the adolescent and young-adult groups, but not the adult groups. Gender differences in ball speed (p < .001) existed within each age group. CONCLUSION: Although these data were cross-sectional, the regressive developmental changes observed and the narrowing gender gap may eventually provide insight related to the relationships among motor skill competence, physical fitness, and physical activity across the lifespan. PMID- 23930551 TI - Effects of supplemental GAKIC ingestion on resistance training performance in trained men. AB - PURPOSE: Glycine-arginine-alpha-ketoisocaproic acid (GAKIC) is a relatively new supplement that athletes and fitness enthusiasts ingest to enhance performance during anaerobic exercise. Therefore, the purpose of this study was to investigate the potential ergogenic effects of GAKIC ingestion during multiple bouts of resistance exercise. METHOD: Seven resistance-trained men participated in a randomized, counterbalanced, double-blind study. Participants were randomly assigned to placebo or GAKIC (10.2 g) and performed 5 sets of 75% of 1-repetition maximum leg press to failure. Total load volume was calculated by multiplying the 75% of 1-repetition maximum mass lifted by the sum of repetitions to failure. One week later, participants ingested the other supplement (placebo or GAKIC) and the same exercise protocol was performed (i.e., crossover). Blood lactate, glucose, and heart rate were determined preexercise and immediately postexercise. RESULTS: GAKIC supplementation significantly increased leg-press total load volume (GAKIC = 31,564 +/- 9,132 kg; placebo = 25,763 +/- 6,595 kg, p < .05). Heart rate and blood lactate were significantly increased (p < .05) postexercise compared with preexercise but were not significantly different between GAKIC and placebo. No significant changes (p > .05) were detected for one-repetition maximum and blood glucose. CONCLUSIONS: These novel findings suggest that GAKIC increases total work performed during repeated bouts of lower-body resistance exercise. Thus, our data suggest that GAKIC ingestion before weight training may increase the training volume of athletes and resistance-trained individuals. PMID- 23930552 TI - Guiding attention aids the acquisition of anticipatory skill in novice soccer goalkeepers. AB - PURPOSE: The ability to anticipate the actions of opponents can be enhanced through perceptual-skill training, though there is doubt regarding the most effective form of doing so. We sought to evaluate whether perceptual-skill learning would be enhanced when supplemented with guiding visual information. METHOD: Twenty-eight participants without soccer-playing experience were assigned to a guided perceptual-training group (n = 9), an unguided perceptual-training group (n = 10), or a control group (n = 9). The guided perceptual-training group received half of their trials with color cueing that highlighted either the key kinematic changes in the kicker's action or the known visual search strategy of expert goalkeepers. The unguided perceptual-training group undertook an equal number of trials of practice, but all trials were without guidance. The control group undertook no training intervention. All participants completed an anticipation test immediately before and after the 7-day training intervention, as well as a 24-hr retention test. RESULTS: The guided perceptual-training group significantly improved their response accuracy for anticipating the direction of soccer penalty kicks from preintervention to postintervention, whereas no change in performance was evident at posttest for either the unguided perceptual training group or the control group. The superior performance of the guided perceptual-training group was preserved in the retention test and was confirmed when relative changes in response time were controlled using a covariate analysis. CONCLUSIONS: Perceptual training supplemented with guiding information provides a level of improvement in perceptual anticipatory skill that is not seen without guidance. PMID- 23930553 TI - Do coaches orchestrate? The working practices of elite Portuguese coaches. AB - PURPOSE: Although the concept of orchestration has resonated well with coaches and students of coaching, it remains quite an immature theorization lacking empirical evidence. Consequently, the purpose of this study was to explore the practice of expert Portuguese coaches from the perspective of orchestration. The specific objectives related to examining if and how coaches manipulate contexts and relationships toward desired ends, if and how they steer and/or stage-manage events, and precisely what informs their actions. METHODS: Data were gathered through a series of semi-structured interviews with 5 top-level Portuguese coaches from a variety of sports. The coaches were selected through purposive sampling. The interviews were taped and transcribed verbatim so that an accurate record of the data gathered was obtained. The data were subject to both inductive and deductive examination through a process of thematic analysis. RESULTS: The categorical themes resulting from the process of data analysis included (a) the need amongst the coaches "for stakeholder buy-in," (b) "generating an illusion of empowerment" among both staff and athletes to ensure compliance, (c) "scaffolding the context to create a controlled instability" and (d) "detailed noticing to inform action." CONCLUSION: The coaches featured in this study were found to carefully and strategically consider their actions and behaviors; particularly concerning the generation of others' compliance and respect. Consequently, in giving further credence to the notions of power, social obligation, and the flexible scaffolding of learning, the findings support the notion that the concept of orchestration deserves further exploration and development in order to better understand the coach's role. PMID- 23930554 TI - Improving access to healthcare and the impact of medical practice in West Virginia. PMID- 23930555 TI - Behavioral change in rural practice: improving patient motivation in primary care. AB - As the disparities in rural healthcare have become better understood, the need to adjust and compensate for these unique challenges becomes a priority. This manuscript suggests three constructs that can be readily integrated into rural care providers' daily work to improve treatment outcomes. Autonomy support, relational support, and competence support are among the motivational constructs discussed with a special consideration for the unique cultural and environmental influences of rural West Virginia residents. The overall objective of this review is to renew the basic tenants of shared decision making as they related to successful behavioral change in primary care. PMID- 23930556 TI - Assessing moderate to vigorous physical activity in rural West Virginia elementary school physical education classes. AB - BACKGROUND: Physical education (PE) provides a natural opportunity for students to be physically active during the school day; however, the amount and intensity of this activity varies. The Centers for Disease Control and Prevention recommends that students engage in MVPA for at least 50% of their PE class period. The purpose of the present study was to quantify the amount of MVPA that occurs during elementary school PE. METHODS: Accelerometer data were collected from 203 students (100 2nd grade; 103 5th grade) in 10 West Virginia elementary schools. At each school, PE teachers identified three 2nd grade classes and three 5th grade classes in which to collect the physical activity data. For each selected class, the teachers identified the first 4 students on their alphabetic roll to wear the accelerometers. PE teachers recorded the date and time of the class and the gender of the students wearing the accelerometers. RESULTS: Using 5 second epochs and Puyau's cut-offs, results indicated that, on average, students engaged in MVPA for 27% of their PE class. No significant differences were observed in MVPA between 2nd and 5th grade students or between males and females. Male and female students spent equal amounts of PE class in MVPA. CONCLUSION: Findings support policy to increase the required minimum amount of MVPA during each PE class. PMID- 23930558 TI - Rural healthcare disparities: challenges and solutions for the pregnant opioid dependent population. AB - Substance abuse among pregnant women is a significant public health problem affecting both maternal and fetal health. Access to both obstetrical care and substance abuse treatment is a challenge for women in rural West Virginia. A multi-disciplinary collaborative treatment approach for this population is necessary to reach and retain women in treatment. Through such collaboration, a positive impact on access to treatment for women from rural communities and reduced barriers to both prenatal care and substance abuse treatment can be achieved in order to improve outcomes for both mother and infant. PMID- 23930557 TI - HIV/AIDS patient migration in North-Central West Virginia. AB - INTRODUCTION: Many HIV/AIDS patients rely on the Ryan White CARE Act, a federally funded program to cover the costs of their medical care. The dispersal of this funding is dependent on a complex algorithm, which factors in the number of people that test positive for HIV in each state. However, demographic and migration studies have suggested that HIV/AIDS patients in rural America are first diagnosed in urban areas and then later moved to more rural areas. METHODS: The participant pool was identified from adult patients who have received care from the West Virginia University (WVU) Positive Health Clinic from January 1, 2004 to July 26, 2012 and knew the location where they had initially tested positive for HIV. RESULTS: The place of initial HIV diagnosis could be determined for 398 out of 433 patients and fewer than half (48%) were initially diagnosed in West Virginia. CONCLUSIONS: Because over half of the patients who are treated at WVU were initially tested outside of West Virginia, this could negatively impact the federal funding opportunities for our state through the Ryan White CARE Act using the current algorithm. PMID- 23930559 TI - Bedside ultrasound: advanced technology to improve rural healthcare. PMID- 23930560 TI - Rural practice realities. PMID- 23930561 TI - Expanding models for rural primary care in West Virginia. AB - This review paper outlines current and newer rural healthcare organizational models to improve availability and access to healthcare services for our state's large rural population. Included in the review are several suggested models for addressing rural healthcare needs: (a) the rural interdisciplinary medical home model; (b) the spoke and wheel model; (c) medical center/community linkages; (d) technology-based outreach modalities, such as tele-health; (e) part-time physician care and (f) expanding the role of health education centers to improve rural primary care. The overall goal is to stimulate exploration, funding and adoption of some of these models and advocate novel methods of addressing and reducing healthcare disparities in rural West Virginia. PMID- 23930562 TI - Inter-hospital transfers from rural hospitals to an academic medical center. AB - INTRODUCTION: The need for inter-hospital patient transfers from rural hospitals, especially Critical Access Hospitals, to larger, more urban hospitals is predictable considering the limited resources at rural hospitals. No systematic study of the inter-hospital transfers themselves has been published. The aim of this retrospective descriptive chart review was to provide a preliminary look at inter-hospital transfers from rural hospitals to a more urban, academic medical center in West Virginia. Ultimately, the creation of an agenda for further research was in view. METHODS: A list of study participants was generated from the academic center's electronic health record database. Study participants were patients who had been transferred for acute care, from November 2011 through June 2012, to the receiving hospital from another acute care hospital and had been under the care of the family medicine teaching service. RESULTS: One hundred and thirty-eight patient transfers were included. Medicare was the most common source of health insurance coverage but over a third of the patients were uninsured. Only five of the twenty-four referring hospitals were Critical Access Hospitals. Four institutions alone initiated 49.3% of transfers. Nineteen specialty services were sought with critical care and neurology accounting for 53.9% of requests. Stroke or stroke-like presentation was the most common transfer diagnosis. 24.6% of transfers were transferred for services that were available at the transferring facility. CONCLUSIONS: This study has suggested an agenda for further research that includes replication and analysis of the data with larger study samples as well as qualitative research into the transferring physicians' decision-making process. PMID- 23930563 TI - Cost-savings analysis of telemedicine use for ophthalmic screening in a rural Appalachian health clinic. AB - Life in mountainous, rural areas poses unique obstacles for ophthalmic care- notably, a lack of access to ophthalmologists and cost of care. Using telemedicine as a screening tool addresses both issues for diabetic retinopathy (DR) screening, as fundus photography has been determined to be sensitive and specific when screening for DR. The American Diabetes Association places a Grade E recommendation on fundus photography as a screening tool. We analyze the financial impact of ophthalmic telemedicine in a mountainous, rural health clinic in West Virginia over a seven year period from 2003-2009. At-risk patients are screened with a fundus camera during routine clinic visits, and the image is interpreted off-site by an ophthalmologist. Patients are either advised to follow up yearly or receive an immediate opthalmic referral. Considering the number of patients screened, travel costs, work missed, overhead, and billing considerations yields a savings of $153.43 per patient visit. PMID- 23930564 TI - Thinking outside the city: treating patients with disordered eating in rural West Virginia. PMID- 23930565 TI - Dr. Who? Providing stability to recruiting and retaining health care professionals in West Virginia. AB - Primary care physicians comprise less than 15% of the United States outpatient work force, yet they perform 23% of the visits that Americans make to their physicians each year. In rural areas, an even greater proportion or about 42% of these visits are to family physician's offices. The country's rural areas have been medically underserved for decades. United States census data has determined that about 21% of the United States population lives in rural areas. Sparse population, extreme poverty, high proportions of racial and ethnic minorities and lack of cultural amenities characterize rural communities most likely to suffer from a shortage of physicians. This persistent, intractable shortage of physicians in rural communities means that many communities struggle continuously to recruit and retain physicians. The Division of Rural Health and Recruitment, located within the Office of Community Health Systems and Health Promotion, Bureau for Public Health, works diligently to alleviate some of those shortages and to strengthen the health care safety net in West Virginia. The Division of Rural Health and Recruitment utilizes the most up-to-date and relevant provider recruitment and retention strategies available. PMID- 23930566 TI - Physical education in West Virginia schools: are we doing enough to generate peak bone mass and promote skeletal health? AB - Peak bone mass (PBM) is attained at 25-35 years of age, followed by a lifelong decline in bone strength. The most rapid increase in bone mass occurs between the ages of 12-17. Daily school physical education (PE) programs have been shown to produce measurable increases in PBM, but are not federally mandated. Increases in PBM can decrease the lifelong risk of osteoporosis and fractures; critical for West Virginia prevention programs. Nationally only 1 in 6 schools require PE three days per week, with 4% of elementary schools, 8% of middle schools and 2% of high schools providing daily PE. In 2005, West Virginia passed the Healthy Lifestyles Act that returned physical education to the K-12 curriculum. This law requires only one credit of PE from grades 9-12 and provides only 35% of the recommended PE for grades K-12. This article highlights the relationship of PE to PBM and discusses the potential impact on West Virginia skeletal health. PMID- 23930567 TI - Extending the university into the community to address healthcare disparities. AB - Healthcare disparities in rural areas contribute to poor health outcomes, but health outcomes are also affected by social determinants of health and lifestyle behaviors. There is a compelling need to promote physical, mental, and financial health through community-based programs that lead to behavior change. The objective of this article is to disseminate information about West Virginia University Extension Service programming as it relates to health issues in rural communities. There is a WVU Extension office in each county with one or more faculty and staff members. They deliver research-based educational programs that promote diabetes self-management, moderate physical activity, healthier food choices, stress management, fall prevention, and financial competency. Healthcare providers are encouraged to refer clients to their local Extension office for educational programs that put knowledge to work. PMID- 23930569 TI - Recruitable Community Program. A plan of action for community involvement and revitalization. PMID- 23930570 TI - Liability update for physicians at youth sporting events. PMID- 23930568 TI - Appalachian women and heart health: current prevention strategies and future directions. AB - BACKGROUND: Heart disease claims the lives of 25% of women in the United States. Only about half of women recognize it as the number one cause of adult female mortality, indicating a gap in the public's knowledge base. In West Virginia, women often face barriers such as social isolation, lack of healthy lifestyle options and fewer physician visits. METHODS: Literature review focused on successful efforts to remedy barriers in Appalachian women with strategies such as community outreach, group, and individual education. RESULTS: Primary care doctors can get involved by providing personalized information on heart health risk and utilizing appointments as opportunities for preventative heart health treatment. CONCLUSIONS: Future initiatives should highlight the need for brief, accurate risk assessments and continued encouragement to decrease cardiac risk factors. An ongoing West Virginia Rural Scholars project is aimed at achieving those two aforementioned goals: increasing awareness and reducing risk factors for women's heart health. PMID- 23930571 TI - Seen your insurance agent lately? PMID- 23930572 TI - IDS 2013--don't lose touch with reality. PMID- 23930573 TI - CAD/CAM single retainer zirconia-ceramic resin-bonded fixed dental prostheses: clinical outcome after 5 years. AB - PURPOSE: This study evaluated the clinical outcome of CAD/CAM zirconia-ceramic resin-bonded fixed dental prostheses (RBFDPs) with a cantilevered single-retainer design. MATERIALS AND METHODS: Thirty anterior zirconia-ceramic RBFDPs fabricated with the Cerec CAD/CAM system were inserted using either a phosphate monomer containing resin (Panavia 21 TC; N = 16) or an adhesive bonding system with a phosphoric acid acrylate primer (Multilink-Automix with Metal/Zirconia primer; N = 14). RESULTS: During a mean observation time of 64.2 months, one debonding occurred in each group. Both RBFDPs could be rebonded successfully resulting in a five-year survival rate of 100%. CONCLUSION: Independent of the bonding system, cantilevered zirconia-ceramic RBFDPs showed promising results during the first five years. (ClinicalTrials.gov Identifier: NCT01411592). CLINICAL SIGNIFICANCE: Single-retainer zirconia ceramic RBFDPs present an alternative treatment option offering good esthetics, a minimally invasive preparation, a high biocompatibility and can even be used to treat juvenile patients who do not yet come into consideration for implant placement. No significant influence of the bonding system used has been detected so far. PMID- 23930574 TI - Surface EMG of the masticatory muscles (Part 3): Impact of changes to the dynamic occlusion. AB - The third part of this literature review on the clinical relevance of surface electromyography (EMG) of the masticatory muscles summarizes the results of clinical studies in patients with temporomandibular disorders (TMD), preferably randomized controlled trials, examining the impact of changes to the dynamic occlusion. Clenching in left and right laterotrusive positions results in decrease in EMG activity of masseter and temporalis muscles on both working and non-working side. Masseter muscle exhibits largely uniform bilateral activity in laterotrusive positions, independent of canine guidance or group function with and without non-working side contacts. There is a dominance of temporalis muscle activity on the working side and, in case of posterior contacts and balancing contacts, temporalis muscle activity increases and changes from an unilateral to a symmetrical pattern. PMID- 23930575 TI - CAD/CAM-based implant abutments. AB - This article presents two novel options for lithium-disilicate restorations supported by single-tooth implants. By using a Ti-Base connector, hybrid abutments and hybrid abutment crowns can be fabricated for different implant systems. The latter option in particular is an interesting new process that yields economical and esthetic restorations supported by single-tooth implants. Further studies are urgently needed to validate the usefulness of this system. PMID- 23930576 TI - Intraoral optical impression systems--an overview. PMID- 23930577 TI - Current technologies for functional diagnostics and CAD/CAM. PMID- 23930578 TI - New CAD/CAM materials and blocks for chairside procedures. PMID- 23930580 TI - Antibodies directed to RNA/DNA hybrids: an electrochemical immunosensor for microRNAs detection using graphene-composite electrodes. AB - We report a simple and sensitive label-free immunosensor for detection of microRNAs (miRNA) based on a conducting polymer/reduced graphene oxide-modified electrode to detect miR-29b-1 and miR-141. Square wave voltammetry is used to record the redox signal. Current increases upon hybridization (signal on) from 1 fM to 1 nM of target miRNA. The limit of quantification is ca. 5 fM. The sensor exhibits high selectivity as it distinguishes mismatch. To double-check its selectivity, two specific RNA-DNA antibodies recognizing miRNA-DNA heteroduplexes, antipoly(A)-poly(dT) and anti-S9.6, were used. The antibody complexation with the hybrid leads to a current decrease that confirms the presence of miRNA, down to a concentration of 8 fM. The antibody-hybrid complex can be then dissociated by adding miRNA-DNA hybrids in solution, causing a shift back on the signal, i.e., an increase in the current density (signal-on). This On Off-On detection sequence was used as a triple verification to increase the reliability of the results. PMID- 23930582 TI - Occupational therapy research priorities in mental health. AB - This study used a Delphi survey method to identify research priorities of occupational therapists working in mental health. Twenty-two subjects were initially surveyed for their suggestions regarding research topics they thought were important. These 22 subjects represent a random sample of 12.4% of national OT-Australia membership of occupational therapists working in mental health. After three "rounds" of the Delphi methodology, consensus research priorities were obtained in six areas: research of value to clients (5 topics); research of value to occupational therapists working in mental health (4 topics); research related to providing community care for clients (2 topics); research that facilitates health promotion and disease prevention (6 topics); research that is of value to the profession of occupational therapy (6 topics); and research that is of value to occupational therapy education (4 topics). Implications for occupational therapy practice and re search are discussed. PMID- 23930581 TI - Enhancement of 4-acetylantroquinonol B production by supplementation of its precursor during submerged fermentation of Antrodia cinnamomea. AB - The antiproliferation activity of the ethanol extract of A. cinnamomea mycelium on hepatocellular cancer cells HepG2 was found to be associated with aroma intensity of the broth during fermentation. We hypothesized that some of the volatile compounds are the precursors of the key bioactive component 4 acetylantroquinonol B of this fungus. The major volatile compounds of A. cinnamomea were identified by GC/MS, and they are oct-1-en-3-ol, linalool, methyl phenylacetate, nerolidol, gamma-cadinene and 2,4,5-trimethoxybenzaldehyde (TMBA). TMBA and nerolidol were further selected and used as supplements during fermentation. It was found that both of them could increase the production of 4 acetylantroquinonol B and enhance the antiproliferation activity of the fungus. In addition, the TMBA was identified as the most promising supplement for increasing the bioactivity of A. cinnamomea during cultivation. PMID- 23930583 TI - Online learning: perspectives of students and faculty in two disciplines occupational therapy and teacher education. AB - Computer technology and the Internet are creating revolutionary changes in higher education. New methods for teaching and learning using these technologies need to be evaluated. Researchers from two disciplines collaborated to assess the efficiency, effectiveness, and satisfaction with online learning. The mixed methods study gathered quantitative data from pretest and posttest questionnaires and qualitative data from focus groups and faculty interviews. Students found the online learning experience to be efficient, effective, and satisfying, but limited computer skills and difficulties using technology reduced efficiency. Self-efficacy in word processing, electronic mail, and Internet technologies increased significantly over the course of the semester. Qualitative analysis resulted in nine assertions about online learning that have implications for faculty designing online learning. PMID- 23930584 TI - Chat Rooms and Level II Fieldwork. AB - Integration of technology within the academic setting has brought about new opportunities for the classroom and clinical portions of the occupational therapy curriculum. Web-based instruction (WBI) is an innovative approach for delivering instruction to a remote audience. Level II fieldwork experiences thus provide a fertile ground to incorporate a Web-based instructional approach, particularly an Internet communication tool, such as chat rooms. Text-based distance communication through chat rooms enrich the learning opportunities and enhance communication between the sites, the Academic Fieldwork Coordinator and the students, and among the students themselves. This article will describe such an experience utilized at the Medical College of Georgia. PMID- 23930585 TI - Doing does it. AB - Lecturing is probably the most common teaching method used in higher education. However, it does not involve the student in the learning process. Student achievement is improved when students are involved in active rather than passive learning. This article focuses on how the Five-Step Lesson Guide was used by the author to move from the traditional lecture format to a more active mode of teaching in her Introduction to Occupational Therapy class. PMID- 23930586 TI - Genetics, human genome project and occupational therapy practice. AB - The Human Genome Project (HGP) has enabled rapid advances in healthcare practice. Medical genetics, once largely confined to relatively rare diseases seen by only a few specialists, is now becoming a central component in our understanding of most major diseases. Occupational therapy practice, without a doubt, will be changed significantly by the explosion of genetic knowledge. This article provides the basic concepts of genes and their relationship to our health. Four types of genetic disorders are introduced. The HGP and its expected gains and limitations are described. Ethical, legal and social implications (ELSI) of advances in genetics are discussed with an example of an ethical dilemma. Finally, this article also provides information on genetic counseling to assist occupational therapists in identifying the need for a referral to genetic counseling. PMID- 23930587 TI - Duchenne muscular dystrophy in females: a rare genetic disorder and occupational therapy perspectives. AB - As genetic technology rapidly advances, its effects on healthcare will inevitably change the way occupational therapists serve their clients. This change will include how the needs and goals of clients are met and achieved. It is, therefore, necessary that occupational therapists become educated and remain current in the field of genetics. Duchenne muscular dystrophy (DMD) is an X linked genetic disorder known as the most common form of muscular dystrophy in males. The majority of the available literature on DMD focuses on males, as the disorder is clinically very rare in females. This article reviews the basics of genetics and explains the etiology of DMD in females. A case example of a young girl with DMD is provided to illustratethe occupational therapy implications of this rare genetic disorder. PMID- 23930588 TI - The effects of serial casting on spasticity: a literature review. AB - This article is a literature review of the research regarding the use of serial casting in the treatment of spasticity. Spasticity has serious consequences, which impact activities of daily living and the quality of life. Classical studies in physiology indicate that muscle tissue immobilized in the shortened position can be physiologically changed through prolonged stretch. Serial casting has proven effective in improving such factors as range of motion and clinical measures of spasticity in spastic limbs. Further research is needed to determine the most effective uses of serial casts in the treatment of spasticity. PMID- 23930590 TI - Reprogramming and transdifferentiation shift the landscape of regenerative medicine. AB - Regenerative medicine is a new interdisciplinary field in biomedical science, which aims at the repair or replacement of the defective tissue or organ by congenital defects, age, injury, or disease. Various cell-related techniques such as stem cell-based biotherapy are a hot topic in the current press, and stem cell research can help us to expand our understanding of development as well as the pathogenesis of disease. In addition, new technology such as reprogramming or dedifferentiation and transdifferentiation open a new area for regenerative medicine. Here we review new approaches of these technologies used for cell-based therapy and discuss future directions and challenges in the field of regeneration. PMID- 23930591 TI - Characterization and expression analysis of common carp Cyprinus carpio TLR5M. AB - TLR5 is responsible for the recognition of bacterial flagellin in vertebrates. In this study, we cloned the TLR5M gene of common carp using the rapid amplification of cDNA ends (RACE) method. The TLR5M cDNA was 3182 bp in length and contained a 2658-bp open reading frame, which encoded a protein of 885 amino acids (aa). The entire coding region of the TLR5M gene was successfully amplified from genomic DNA and contained a single exon. The aa sequence of carp TLR5M showed the highest similarity (84.46%) to Cirrhinus mrigala. Tissue-specific expression analysis of the TLR5M gene by quantitative real-time polymerase chain reaction revealed its broad distribution in various organs and tissues; however, the highest level of TLR5M expression was noted in the liver. TLR5M gene expression was examined after flagellin stimulation and showed highly significant (p<0.01) induction in the spleen, heart, liver and kidney. The induction of TLR5M was analyzed in various organs infected with Aeromonas hydrophila. TLR5M gene expression in the kidney and spleen was significantly (p<0.01) increased. Concurrently, modulation of TLR5M gene expression and the induction of IFN-gamma, IL-1beta, IL-10 and TNF alpha4 were analyzed in peripheral blood leucocytes after lipopolysaccharide, concanavalin A, and flagellin stimulation. In the treated group, significant induction of these genes was noted, although the intensity varied between the tissues. These findings may indicate a crucial role for TLR5M in the innate immunity of common carp in response to pathogenic invasion. PMID- 23930592 TI - Genotype variability and haplotype frequency of MDR1 (ABCB1) gene polymorphism in Morocco. AB - The multidrug resistance gene (MDR1) plays an important role in the transport of a wide range of drugs and elimination of xenobiotics from the body. Identification of polymorphisms and haplotypes in the MDR1 gene might not only help understand pharmacokinetics and pharmacodynamics of drugs, but also can help in the prediction of drug responses, toxicity, and side effects, especially, in the era of personalized medicine. We have analyzed the genotypic and haplotypic frequencies of the three most common single-nucleotide polymorphisms in the MDR1 gene in a sample of 100 unrelated healthy Moroccan subjects by polymerase chain reaction-restrictive fragment length polymorphism. The observed genotype frequencies were 43% for 1236CC, 49% for 1236CT, and 8% for 1236TT in exon 12; 49% for 2677GG, 47% for 2677GT, and 4% for 2677TT in exon 21; 39% for 3435CC, 51% 3435CT for 3435TT, and 10% for 3435TT in exon 26, respectively. We found that all polymorphisms were in Hardy-Weinberg equilibrium. Moderate linkage disequilibrium (LD) was observed between the three polymorphisms, the strongest LD in our study has been observed between C1236T and G2677T (D'=0.76; r(2)=0.45). We identified eight haplotypes, the most frequent were 1236C-2677G-3435C (53%), 1236T-2677T 3435T (21%), and 1236C-2677G-3435T (10%), respectively. Our findings might facilitate future studies on pharmacokinetics of P-glycoprotein substrate drugs and interindividual variability to drugs in Moroccan patients. PMID- 23930593 TI - Mixed phenotype acute leukaemia with Burkitt-like cells and positive peroxidase cytochemistry. PMID- 23930594 TI - Site-specific chemistry on the microtubule polymer. AB - Microtubules are hollow tube-like biological polymers required for transport in diverse cellular contexts and are important drug targets. Microtubule function depends on interactions with associated proteins and post-translational modifications at specific sites located on its interior and exterior surfaces. However, we lack strategies to selectively perturb or probe these basic biochemical mechanisms. In this work, by combining amber suppression-mediated non natural amino acid incorporation and tubulin overexpression in budding yeast, we demonstrate, for the first time, a general strategy for site-specific chemistry on microtubules. Probes and labels targeted to precise sites on the interior and exterior surfaces of microtubules will allow analysis and modulation of interactions with proteins and drugs, and elucidation of the functions of post translational modifications. PMID- 23930597 TI - Can parkin be a target for future treatment of Parkinson's disease? AB - INTRODUCTION: Parkinson's disease (PD) is one of the most common neurodegenerative diseases affecting an increasing number of people worldwide with the ageing society. Although the etiology of PD remains largely unknown, it is now clear that genetic factors contribute to the pathogenesis of the disease. Recently, several causative genes have been identified in mendelian forms of PD. Growing evidence indicates that their gene products play important roles in oxidative stress response, mitochondrial function, and the ubiquitin-proteasome system, which are also implicated in idiopathic PD, suggesting that these gene products share a common pathway to nigral degeneration in both familial and idiopathic PD. However, treatment options are currently limited. AREAS COVERED: Recently, a possible role of parkin, a gene product of PARK2-liked PD, in neuroprotection has been suggested. To this regard, several investigations have focused on the possible contribution of parkin in neurotoxic insults. In this article, the role of parkin in the pathogenesis of PD and the potential of parkin as a therapeutic target in PD will be discussed. EXPERT OPINION: There is an urgent need to develop novel therapeutic options to better manage patients with PD. The data discussed in this article provide rationale for parkin as a therapeutic target. PMID- 23930595 TI - Fronto-limbic-striatal dysfunction in pediatric and adult patients with bipolar disorder: impact of face emotion and attentional demands. AB - BACKGROUND: Research in bipolar disorder (BD) implicates fronto-limbic-striatal dysfunction during face emotion processing but it is unknown how such dysfunction varies by task demands, face emotion and patient age. METHOD: During functional magnetic resonance imaging (fMRI), 181 participants, including 62 BD (36 children and 26 adults) and 119 healthy comparison (HC) subjects (57 children and 62 adults), engaged in constrained and unconstrained processing of emotional (angry, fearful, happy) and non-emotional (neutral) faces. During constrained processing, subjects answered questions focusing their attention on the face; this was processed either implicitly (nose width rating) or explicitly (hostility; subjective fear ratings). Unconstrained processing consisted of passive viewing. RESULTS: Pediatric BD rated neutral faces as more hostile than did other groups. In BD patients, family-wise error (FWE)-corrected region of interest (ROI) analyses revealed dysfunction in the amygdala, inferior frontal gyrus (IFG), anterior cingulate cortex (ACC) and putamen. Patients with BD showed amygdala hyperactivation during explicit processing (hostility ratings) of fearful faces and passive viewing of angry and neutral faces but IFG hypoactivation during implicit processing of neutral and happy faces. In the ACC and striatum, the direction of dysfunction varied by task demand: BD demonstrated hyperactivation during unconstrained processing of angry or neutral faces but hypoactivation during constrained processing (implicit or explicit) of angry, neutral or happy faces. CONCLUSIONS: Findings suggest amygdala hyperactivation in BD while processing negatively valenced and neutral faces, regardless of attentional condition, and BD IFG hypoactivation during implicit processing. In the cognitive control circuit involving the ACC and putamen, BD neural dysfunction was sensitive to task demands. PMID- 23930598 TI - Brain-derived neurotrophic factor interacts with astrocytes and neurons to control respiration. AB - Respiratory rhythm is generated and modulated in the brainstem. Neuronal involvement in respiratory control and rhythmogenesis is now clearly established. However, glial cells have also been shown to modulate the activity of brainstem respiratory groups. Although the potential involvement of other glial cell type(s) cannot be excluded, astrocytes are clearly involved in this modulation. In parallel, brain-derived neurotrophic factor (BDNF) also modulates respiratory rhythm. The currently available data on the respective roles of astrocytes and BDNF in respiratory control and rhythmogenesis lead us to hypothesize that there is BDNF-mediated control of the communication between neurons and astrocytes in the maintenance of a proper neuronal network capable of generating a stable respiratory rhythm. According to this hypothesis, progression of Rett syndrome, an autism spectrum disease with disordered breathing, can be stabilized in mouse models by re-expressing the normal gene pattern in astrocytes or microglia, as well as by stimulating the BDNF signaling pathway. These results illustrate how the signaling mechanisms by which glia exerts its effects in brainstem respiratory groups is of great interest for pathologies associated with neurological respiratory disorders. PMID- 23930599 TI - Transmitral resection of a left ventricular apical papillary fibroelastoma using video-assisted thoracoscopy. AB - Papillary fibroelastomas (PFEs) are rare benign tumors usually found on cardiac valves, and do not commonly originate from the left ventricle (LV). We report a 74-year-old female with a PFE in the LV apex. We performed complete resection of the tumor through a transmitral approach using video-assisted thoracoscopy. PMID- 23930600 TI - What factors in rural and remote extended clinical placements may contribute to preparedness for practice from the perspective of students and clinicians? AB - BACKGROUND: Community-based rural education opportunities have expanded in Australia, attracting more medical students to placements in rural and remote settings. AIM: To identify the factors in an integrated, community-engaged rural placement that may contribute to preparedness for practice (P4P) from the perspective of students and clinicians. METHOD: Forty-two semi-structured interviews with medical students, supervisors and clinicians analysed thematically. RESULTS: Opportunities for clinical learning, personal and professional development and cultural awareness were reported by students and clinicians as key factors that contribute to P4P. Potential barriers in rural and remote settings included geographical and academic isolation, perceived educational risk and differing degrees of program engagement. CONCLUSIONS: A longitudinal clinical placement in a rural setting may enable development of enhanced competencies leading to P4P. A rural setting can provide a unique experience through hands-on learning, enhanced personal and professional development opportunities and observation of the cultural and contextual impact on health. PMID- 23930601 TI - Solid-phase microextraction (SPME) with stable isotope calibration for measuring bioavailability of hydrophobic organic contaminants. AB - Solid-phase microextraction (SPME) is a biomimetic tool ideally suited for measuring bioavailability of hydrophobic organic compounds (HOCs) in sediment and soil matrices. However, conventional SPME sampling requires the attainment of equilibrium between the fiber and sample matrix, which may take weeks or months, greatly limiting its applicability. In this study, we explored the preloading of polydimethylsiloxane fiber with stable isotope labeled analogs (SI-SPME) to circumvent the need for long sampling time, and evaluated the performance of SI SPME against the conventional equilibrium SPME (Eq-SPME) using a range of sediments and conditions. Desorption of stable isotope-labeled analogs and absorption of PCB-52, PCB-153, bifenthrin and cis-permethrin were isotropic, validating the assumption for SI-SPME. Highly reproducible preloading was achieved using acetone-water (1:4, v/v) as the carrier. Compared to Eq-SPME that required weeks or even months, the fiber concentrations (Cf) under equilibrium could be reliably estimated by SI-SPME in 1 day under agitated conditions or 20 days under static conditions in spiked sediments. The Cf values predicted by SI SPME were statistically identical to those determined by Eq-SPME. The SI-SPME method was further applied successfully to field sediments contaminated with PCB 52, PCB 153, and bifenthrin. The increasing availability of stable isotope labeled standards and mass spectrometry nowadays makes SI-SPME highly feasible, allowing the use of SPME under nonequilibrium conditions with much shorter or flexible sampling time. PMID- 23930602 TI - A systematic review of evaluation methods for neonatal brachial plexus palsy: a review. AB - OBJECT: Neonatal brachial plexus palsy (NBPP) affects 0.4-2.6 newborns per 1000 live births in the US. Many infants recover spontaneously, but for those without spontaneous recovery, nerve and/or secondary musculoskeletal reconstruction can restore function to the affected arm. This condition not only manifests in a paretic/paralyzed arm, but also affects the overall health and psychosocial condition of the children and their parents. Currently, measurement instruments for NBPP focus primarily on physical ability, with limited information regarding the effect of the disablement on activities of daily living and the child's psychosocial well-being. It is also difficult to assess and compare overall treatment efficacy among medical (conservative) or surgical management strategies without consistent use of evaluation instruments. The purpose of this study is to review the reported measurement evaluation methods for NBPP in an attempt to provide recommendations for future measurement usage and development. METHODS: The authors systematically reviewed the literature published between January 1980 and February 2012 using multiple databases to search the keywords "brachial plexus" and "obstetric" or "pediatrics" or "neonatal" or "congenital." Original articles with primary patient outcomes were included in the data summary. Four types of evaluation methods (classification, diagnostics, physical assessment, and functional outcome) were distinguished among treatment management groups. Descriptive statistics and 1-way ANOVA were applied to compare the data summaries among specific groups. RESULTS: Of 2836 articles initially identified, 307 were included in the analysis, with 198 articles (9646 patients) reporting results after surgical treatment, 70 articles (4434 patients) reporting results after medical treatment, and 39 articles (4247 patients) reporting results after combined surgical and medical treatment. Among medical practitioners who treat NBPP, there was equivalence in usage of classification, diagnostic, and physical assessment tools (that focused on the Body Function and Structures measure of the International Classification of Functioning, Disability, and Health [ICF]). However, there was discordance in the functional outcome measures that focus on ICF levels of Activity and Participation. Of the 126 reported evaluation methods, only a few (the Active Movement Scale, Toronto Scale Score, Mallet Scale, Assisting Hand Assessment, and Pediatric Outcomes Data Collection Instrument) are specifically validated for evaluating the NBPP population. CONCLUSIONS: In this review, the authors demonstrate disparities in the use of NBPP evaluation instruments in the current literature. Additionally, valid and reliable evaluation instruments specifically for the NBPP population are significantly lacking, manifesting in difficulties with evaluating the overall impact and effectiveness of clinical treatments in a consistent and comparative manner, extending across the various subspecialties that are involved in the treatment of patients with NBPP. The authors suggest that all ICF domains should be considered, and future efforts should include consideration of spontaneous (not practitioner-elicited) use of the affected arm in activities of daily living with attention to the psychosocial impact of the disablement. PMID- 23930603 TI - My week at the AUA meeting. PMID- 23930604 TI - Legends in urology. PMID- 23930605 TI - Vitamin D and benign prostatic hyperplasia -- a review. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) is a more common form of lower urinary tract symptoms (LUTS). BPH is due to the excessive growth of both stromal and epithelial cells of the prostate. Fifty percent of men over the age of 50 will have this disease, along with the probability that 90% of men at the age of 80 will have an enlarged prostate. The prevalence of vitamin D deficiency in the male urological population may represent a connection between BPH and vitamin D. MATERIAL AND METHODS: This review is geared to provide the most relevant data on the correlation between vitamin D and BPH. A comprehensive review was conducted on all studies on the specific topic and compiled into a complete article. RESULTS: Data suggests that vitamin D has an inhibitory effect on the RhoA/ROCK pathway, along with cyclooxygenase-2 expression and prostaglandin E2 production in BPH stromal cells. Increasing intake of vitamin D from diet and supplements has shown a correlation with decreased BPH prevalence. Vitamin D analogues of up to 6000 IU/day have shown to decrease prostate volume in BPH patients. Pre clinical trials have shown vitamin D to not only decrease BPH cell and prostate cell proliferation alone, but also when induced by known growth promoting molecules such as IL-8, Des (1-3) IGF-1, testosterone and dihydrotestosterone. Among all the studies there has not been any side effects or negative implications with increased vitamin D intake. CONCLUSION: The impact of vitamin D on prostate volume and BPH has shown promising results, thus proposing further studies on vitamin D and BPH be conducted. PMID- 23930606 TI - Morbidity and mortality of octogenarians following open radical cystectomy using a standardized reporting system. AB - INTRODUCTION: Recent evidence suggests that radical cystectomy may be underutilized in elderly patients, despite literature supporting acceptable morbidity/mortality in this population. However, there is a paucity of literature reporting complications in a standardized manner. Therefore, we evaluated the morbidity and mortality of octogenarians treated with radical cystectomy using the modified Clavien complication reporting system. MATERIALS AND METHODS: We retrospectively reviewed 443 consecutive patients undergoing radical cystectomy at our institution between January 2000 and April 2010. Patients who underwent cystectomy for benign conditions were excluded, leaving 359 for analysis. Baseline demographic and perioperative data were reviewed and all complications were graded. We compared the outcomes of our octogenarian population (n = 43) against our younger population (n = 316). RESULTS: There was no difference between octogenarians and the younger cohort for overall complication rates (86% versus 83%, p = 0.91), or major (33% versus 30%, p = 0.93) or minor (81% versus 80%, p = 0.91) complications. The younger group was more likely to encounter a late complication (41.5% versus 23.3%, p = 0.03). Those 80 years and older trended toward more intraoperative complications (21% versus 10%, p = 0.07). The older group also had a greater propensity for neurological complications (26% versus 11%, p = 0.02), but there was no difference in CVA (2% versus 3%, p = 0.22). There was no difference in mortality rates between the older and younger cohort (2.3% versus 0.9%, p = 0.95). CONCLUSIONS: Radical cystectomy is a morbid procedure regardless of patient age. Age alone should not preclude radical cystectomy in the elderly. PMID- 23930607 TI - Balancing disease and risk in octogenarians undergoing radical cystectomy. PMID- 23930608 TI - Simplified approach to estimating renal function based on computerized tomography. AB - INTRODUCTION: To determine whether a simplified approach to estimate renal function based on preoperative computerized tomography (CT) imaging correlates with nuclear renography (NR) following surgical treatment of ureteropelvic junction obstruction (UPJO). MATERIALS AND METHODS: We reviewed the charts of 47 patients who underwent robotic assisted laparoscopic pyeloplasty (RALP) for UPJO who had performed preoperative and postoperative NR and preoperative CT imaging. Twenty patients satisfied our inclusion criteria. We calculated differential renal function by measuring parenchymal thickness at the upper pole, midpole and lower pole regions of the kidney on the preoperative CT. Distances were measured from the edge of the collecting system to the capsule at the midpoint of the kidney in the coronal plane. After parenchymal thickness measurements were calculated bilaterally, a differential parenchymal thickness was obtained, and the ratio of parenchymal area was compared to the observed function on NR. Measurements were taken by three blinded observers and compared to preop and postop differential renal function as measured by NR to assess if preoperative CT renal parenchymal thickness correlates well with differential function of the affected and contralateral kidneys. RESULTS: Estimated renal function was predicted with excellent accuracy and minimal interobserver variability. Pearson correlation coefficients for Observers 1, 2 and 3 were 0.89, 0.88 and 0.91, respectively when compared to the postoperative differential function on NR. The interclass correlation coefficient between the three observers was 0.957, which indicates an almost perfect correlation and reproducibility of the formula. CONCLUSIONS: Estimating differential renal function based on renal parenchymal thickness on preoperative CT imaging correlates very well with observed postoperative differential renal function on NR following RALP. PMID- 23930609 TI - The utility of abdominal ultrasound during percutaneous suprapubic catheter placement. AB - INTRODUCTION: To evaluate the use of ultrasound (US) at the time of percutaneous suprapubic catheter (SPC) placement. US has been recommended as a way to minimize complications, such as bowel injury, during percutaneous SPC placement, yet there is limited data supporting this recommendation. MATERIALS AND METHODS: A retrospective chart review was performed on patients undergoing percutaneous SPC placement from 2002 to 2011. The method of percutaneous SPC placement (cystoscopic and/or ultrasound guidance, blind) was recorded and patients were subdivided into groups based on the use of US. The need to modify the approach based on US findings and complications such as bleeding or bowel injury were noted and compared between groups. RESULTS: A total of 307 percutaneous SPCs were placed: cystoscopy alone was used in 190 (62%) patients, cystoscopy + US in 86 (28%) patients, US alone in 6 (2%) patients, and 25 (8%) patients had the SPC placed blindly. Previous lower abdominal surgery was noted in 41/92 (45%) of patients with and 32/215 (15%) of patients without US usage. US identified intervening loops of bowel in 5/92 cases (5%), all of whom had a history of lower abdominal surgery. The approach was modified in 2/5 and abandoned in 3/5 based on US findings. Postoperative bleeding occurred in 1/215 (0.5%) of patients with and 1/92 (1%) of patients without US usage. No bowel injuries occurred. CONCLUSIONS: While US may not be needed in most patients, particularly when cystoscopy is used, it may help to avoid bowel injury in patients with a history of lower abdominal surgery. PMID- 23930610 TI - Viberect penile vibratory stimulation system: evaluation of its erectogenic efficacy. AB - INTRODUCTION: Current non-surgical strategies employed to treat erectile dysfunction (ED) target the vascular component of erection physiology. The Viberect handheld device (Reflexonic, LLC, Chambersburg, PA, USA) is a new FDA cleared ED treatment, which exploits vibratory stimulation of genital afferent nerves for provoking erections. The aim of this study was to evaluate the clinical feasibility of the Viberect device for the achievement of penile erection and rigidity. MATERIALS AND METHODS: Subjects for this study were five healthy men (mean age 26.4 years) with normal erectile function as measured by responses to the IIEF-EF. The Viberect treatment at 75 Hz with ventral stimulation was initiated without any external visual sexual stimulation. Both objective Rigiscan measurements of rigidity and subjective Erection Hardness Score (EHS) responses were recorded and correlated. Toleration and safety were monitored. RESULTS: Rigiscan demonstrated that 4/5 subjects achieved tumescence episodes beyond 60% total rigidity (considered the minimum required to achieve a non-buckling erection capable of vaginal intromission). According to EHS, the Viberect treatment yielded scores of 4/4 (penis is completely hard and fully rigid) in 2 subjects, 3/4 (penis hard enough for penetration but not completely hard) in 2 and 2/4 (penis is hard but not enough for penetration) in 1. There were no complications, and all subjects felt that Viberect would be a reasonable, practical ED treatment. CONCLUSION: This study provides evidence that Viberect produces a non-invasive, well-tolerated erectogenic effect. These results indicate that penile vibratory stimulation provokes erections via neurostimulatory principles and support further study of this modality in treating men with ED. PMID- 23930611 TI - Length of prostate biopsy cores: does it impact cancer detection? AB - INTRODUCTION: The detection of prostate carcinoma relies on adequate sampling. We aimed to evaluate whether core length is a significant biopsy parameter in the detection of cancer, especially in the low risk cancer category group. MATERIALS AND METHODS: We retrospectively analyzed pathology reports of 197 patients (2196 biopsy cores) undergoing initial transrectal ultrasound guided biopsy. A multivariate analysis of age, total prostate-specific antigen (PSA) concentration, prostate gland volume, total number of cores and length of biopsy cores was performed. Secondary analyses included stratification by Gleason score. Single core analysis was done to calculate a workable cut off value for core length with optimal sensitivity and specificity in carcinoma detection. RESULTS: Mean age, PSA, prostate volume, and total number of cores were 66.9 years, 12.6 ng/mL, 47.2 cc and 11.1 cores, respectively. Whereas detection of cancer was significantly associated with advanced age (p < 0.01) and smaller prostate volumes (p < 0.001), PSA levels (p = 0.40) and number of cores (p = 0.20) were not significant predictive factors. Assessment of biopsy core lengths showed that cores harboring cancer (n = 307, average length 14.1 mm) were significantly longer than benign cores (n = 1889, average length = 13.2 mm) (p < 0.001). Core length analysis yielded 13 mm cores have an optimal sensitivity (42.8%) and specificity (76.5%) for detection of carcinoma (odds ratio: 2.43). Secondary analyses of Gleason score did not show any difference with respect to core length. CONCLUSION: This study suggests that core length is a biopsy parameter that affects detection of cancer and is an essential parameter for core biopsy quality. PMID- 23930612 TI - Length matters in prostate cancer. PMID- 23930613 TI - Magnetic resonance imaging for intratesticular and extratesticular scrotal lesions. AB - INTRODUCTION: To evaluate magnetic resonance imaging (MRI) utility in intratesticular and extratesticular scrotal diseases. MATERIALS AND METHODS: Two radiologists retrospectively reviewed images of patients who underwent ultrasound followed by MRI, categorizing them as intratesticular or extratesticular and malignant, benign, indeterminate, or inadequate study. For patients who underwent surgical excision, pathologic results were also correlated to the presurgical ultrasound and MRI diagnoses. RESULTS: Of 69 cases, 38 were intratesticular lesions and 31 were extratesticular lesions. MRI and ultrasound diagnoses were discordant in 21 (55.32%) intratesticular and 19 (61.3%) extratesticular lesions. MRI diagnosis was malignant after an indeterminate ultrasound in 0 and 4 (12.9%) intratesticular and extratesticular lesions, respectively. MRI diagnosis was benign after an indeterminate ultrasound in 18 (47.43%) and 14 (45.2%) intratesticular and extratesticular lesions, respectively. A malignant ultrasound diagnosis was reversed to benign MRI diagnosis in one (2.6%) intratesticular and one (3.2%) extratesticular lesion. In no case was a benign lesion on ultrasound read as malignant on MRI in either group. The cohort of patients with intratesticular lesions received a mean clinical and radiographic follow up of 2.49 +/- 1.97 and 1.85 +/- 1.46 years, respectively. The patients with extratesticular lesions received a mean clinical and radiographic follow up of 1.30 +/- 1.08 and 2.00 +/- 1.28 years, respectively. In no case did repeat imaging change the diagnosis after initial MRI and ultrasound evaluation. CONCLUSIONS: MRI was effective at characterizing both intratesticular and extratesticular lesions in the majority of cases. PMID- 23930614 TI - Clinically atypical seminomas with yolk sac tumor features. AB - INTRODUCTION: A small subset of young men die from seminoma. Studying these high risk, clinically atypical seminomas (CASs)-aggressive tumors with visceral metastases and chemotherapy resistance-may provide clues to the nature of drug resistance and the origin of testicular cancers. We explored the possibility that these seminomas are a unique clinical and biologic entity with intrinsic yolk sac tumor (YST) features. MATERIALS AND METHODS: We assayed available archived tissue samples (n = 22) for chemotherapy-resistance markers found in YSTs. Specifically, we analyzed tissues and clinical histories from patients with CASs (those who had visceral metastases and recurrent disease), classical seminomas, and mixed germ cell tumors containing YST. By using immunohistochemical testing, we evaluated the expression of bone morphogenetic protein 2, alpha fetoprotein, and glutathione S-transferase (pi) [GST (pi)]. RESULTS: GST (pi) expression significantly predicted for overall survival (p = .036). In addition, according to the results of GST (pi) immunohistochemical staining, the CASs appeared to resemble YSTs more than they did classical seminomas (p = 0.043). Less-advanced tumors, both those that expressed GST (pi) and those that were negative for GST (pi), were more amenable to local therapies, and the patients who had those tumors had better clinical outcomes. CONCLUSIONS: Results from this exploratory study suggest that certain CASs that express GST (pi) are more similar to YST than they are to classical seminomas, and that GST (pi) expression may be able to be used as a prognosticator of disease-specific survival. Such CASs thus may have a unique biologic origin that differs from that of classical seminomas. Additional studies are needed to determine the natural history and therapeutic implications of these CASs. PMID- 23930615 TI - New-onset psychosis following androgen deprivation therapy for prostate cancer. AB - Androgen deprivation therapy (ADT) is commonly used in the treatment of prostate cancer and is associated with several side effects including psychiatric disorders. We present an unusual case of a 62-year-old man with high risk prostate cancer that developed de novo psychosis after starting luteinizing hormone-releasing hormone (LHRH) agonists and discuss possible mechanisms to explain such findings. This case report highlights the importance of continuing assessment and monitoring of potential emotional and behavioral symptoms in prostate cancer patients treated with ADT. PMID- 23930616 TI - An uncommon cause of gross hematuria: two cases of ureteroarterial fistula. AB - Ureteroarterial fistula (UAF) is a rare but potentially fatal cause of hematuria seen in patients with prolonged ureteral stenting in the setting of surgery or abdominal radiation. It presents as episodic, transfusion-dependent hematuria with formation of clots. There is no current consensus for the optimal way to diagnose or treat UAF. We report two cases of UAF that required repeated studies and provocative testing to confirm the diagnosis. Both were successfully managed by endovascular stenting. Clinicians must recognize the diagnostic difficulties involved and maintain a high index of suspicion for UAF in stented patients with intermittent, severe hematuria. PMID- 23930618 TI - International Young Urological Association: a global platform network for young urologists. AB - Despite the growth of the digital era, rapid spread of information, and real-time communication, there are several urologists throughout the world who do not have access to urological scientific programs, academic training programs, or memberships to well-established urological organizations, associations, and societies. The International Young Urological Association (IYUA) is a non-profit organization that was created to specifically address and facilitate access for urologists that for geopolitical, economical, or other reasons would not otherwise have these opportunities available to them. The IYUA's non-competitive nature allows for urologists to use the IYUA as an initial platform to network with globally established organizations to deliver scientific training programs, courses, and meetings in less common locations. It is our objective to demonstrate the IYUA's mission and facets that may contribute to the increased academic and scientific education of professionals in Urology where the access to these resources can be challenging. PMID- 23930617 TI - Crossed testicular ectopia with preoperative ultrasound. AB - Crossed testicular ectopia/transverse testicular ectopia is a rare congenital anomaly. It is most commonly identified intraoperatively in the setting of inguinal hernia repair with contralateral cryptorchidism. We report a case of crossed testicular ectopia identified in a 3-month-old male who presented with right cryptorchidism. Preoperative ultrasound revealed no testicle on the right and two testicles on the left - one within the left hemiscrotum and one within the left inguinal canal. Laparoscopy at 7 months of age revealed a closed right external ring and right ectopic testicle at the left external ring. Bilateral orchiopexy was performed. PMID- 23930619 TI - Abstracts presented at the 1st International UroAnatomy Congress June 14 to 16, 2013 in Izmir, Turkey. PMID- 23930620 TI - Exploring how Australian occupational therapists and physiotherapists understand each other's professional values: implications for interprofessional education and practice. AB - This article provides insight into the values Australian occupational therapists and physiotherapists consider essential for their practice and the values that they perceive as important for each other. Findings from a study that employed the Delphi technique to identify the values occupational therapists and physiotherapists consider essential for their practice were compared with interview results that provide insight into how these professionals perceive one another's values. The results from this comparison indicate that occupational therapy and physiotherapy participants have limited knowledge of each other's values. This is evidenced by participants only identifying a minority of the values considered essential within the other profession and not identifying many of the values that guide daily practice within the other profession. The results hold implications for interprofessional education and practice, where knowledge of the values of other professions in the team is essential. To enable interprofessional collaboration, professions need to make their values explicit and provide their students, practitioners and educators with opportunities to learn about their own values and the values of other professions. PMID- 23930621 TI - Heterogeneity of tumor endothelial cells. AB - Tumor blood vessels play important roles in tumor progression and metastasis. Thus, targeting tumor blood vessels is an important strategy for cancer therapy. Tumor endothelial cells (TECs) are the main targets of anti-angiogenic therapy. Although tumor blood vessels generally sprout from pre-existing vessels and have been thought to be genetically normal, they display a markedly abnormal phenotype, including morphological changes. The degree of angiogenesis is determined by the balance between the positive and negative regulating molecules that are released by tumor and host cells in the microenvironment. Reportedly, tumor blood vessels are heterogeneous with TECs differing from normal endothelial cells (in contrast to the conventional view). We recently compared characteristics of different TECs isolated from highly and low metastatic tumors. We found TECs from highly metastatic tumors had more proangiogenic phenotypes than those from low metastatic tumors. Elucidating the variety of TEC phenotypes and identifying TEC molecular signatures should lead to more complete understanding of the mechanisms of tumor progression, discovery of new therapeutic targets, and development of biomarkers. This review considers current studies on TEC heterogeneity and discusses the therapeutic implications of these findings. PMID- 23930622 TI - Molecular dynamics simulation of chemokine receptors in lipid bilayer: a case study on C-C chemokine receptor type 2. AB - Chemokine receptors belong to the membrane proteins that are included in many physiological phenomena. However, the mechanism of their action is unknown at the atomistic level in different aspects. In this study, a computational pipeline is exploited to investigate the molecular basis of how the structure of C-C chemokine receptor type 2, a prototypical chemokine receptor, is affected by lipid bilayer and an antagonist (INCB3344). This study includes homology modeling, molecular dynamics simulation in lipid bilayer, and docking. A detailed mechanism of INCB3344 has been described. Tyr 49, Trp 98, Tyr 120, His 121, and Glu 291 are proved to play important roles in binding. Integrating results obtained in this study and experimental data help us to suggest a two-step ligand binding mechanism. The N-terminus of protein first sticks out from the extracellular domain suitable for the contact with the antagonist. Binding of ligand to this segment leads to the geometrical changes to facilitate the ligand interactions with extracellular loop 2 of C-C chemokine receptor type 2. Finally, the interactions occurring between extracellular loop 2 and ligand induce conformational changes in C-C chemokine receptor type 2 structure. These changes bring the ligand closer to the binding pocket, allowing the interaction between INCB3344 and the residues of active site. PMID- 23930624 TI - The risk of acquiring bacterial meningitis following surgery in Denmark, 1996 2009: a nationwide retrospective cohort study with emphasis on ear, nose and throat (ENT) and neurosurgery. AB - SUMMARY: This paper estimates the risk of bacterial meningitis following surgery between 1996 and 2009 in Denmark. We conducted two retrospective nationwide cohort studies; first by linking notified bacterial meningitis cases to the National Patient Registry to see how many had undergone a surgical procedure; second, we scrutinized notified bacterial meningitis cases to see if the clinician suspected a surgical procedure to be the aetiology. We found that ear, nose and throat surgery had an 11-fold, and neurosurgery a sevenfold, increased risk compared to the reference group in the first 10 days following surgery. Streptococcus pneumoniae was the pathogen most often involved. Operation procedures involving penetration of dura mater was associated with increased risk for post-operative bacterial meningitis. In absolute numbers we found few bacterial meningitis cases after surgery; however, patients undergoing certain surgical procedures are at-risk and should be considered when national vaccination guidelines are revised. PMID- 23930623 TI - Increased cigarette tax is associated with reductions in alcohol consumption in a longitudinal U.S. sample. AB - BACKGROUND: Cigarette taxation has been recognized as one of the most significant policy instruments to reduce smoking. Smoking and drinking are highly comorbid behaviors, and the public health benefits of cigarette taxation may extend beyond smoking-related outcomes to impact alcohol consumption. The current study is the first to test whether increases in cigarette taxes are associated with reductions in alcohol consumption among smokers using a large, prospective U.S. sample. METHODS: Our sample included 21,473 alcohol consumers from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). Multiple linear regression analyses were conducted to evaluate whether increases in cigarette taxes between Waves 1 (2001 to 2002) and 2 (2004 to 2005) were associated with reductions in quantity and frequency of alcohol consumption, adjusting for demographics, baseline alcohol consumption, and alcohol price. Stratified analyses were conducted by sex, hazardous drinking status, and age and income group. RESULTS: Increases in cigarette taxes were associated with modest reductions in typical quantity of alcohol consumption and frequency of binge drinking among smokers. Cigarette taxation was not associated with changes in alcohol consumption among nonsmokers. In analyses stratified by sex, the inverse associations of cigarette taxes with typical quantity and binge drinking frequency were found only for male smokers. Further, the inverse association of cigarette taxation and alcohol consumption was stronger among hazardous drinkers (translating into approximately 1/2 a drink less alcohol consumption per episode), young adult smokers, and smokers in the lowest income category. CONCLUSIONS: Findings from this longitudinal, epidemiological study suggest increases in cigarette taxes are associated with modest to moderate reductions in alcohol consumption among vulnerable groups. Additional research is needed to further quantify the public health benefits of cigarette taxation on alcohol consumption and to evaluate the potential broader crossover effects of cigarette taxation on other health behaviors. PMID- 23930626 TI - The reverse quad helix expander: easy access for bone graft manipulation in the cleft maxilla. AB - Cleft-affected patients are characterized by a normal/almost normal posterior maxillary width and a severe anterior constriction of the maxilla in the mixed dentition period. The purposes of this paper were to present: two cases of unilateral cleft-affected patients treated with a reverse quad-helix appliance; and a new method for differential expansion of the premaxillary area of the palatal cleft using a reverse quad-helix expander, thus enabling improved access for the surgeons during secondary bone graft procedures. /// Orthodontic and Craniofacial Department, School of Graduate Dentistry, Rambam Health Care Campus and Bruce Rappaport Faculty of Medicine-Technion, Israel Institute of Technology, Haifa, Israel. aizenbud@ortho.co.il PMID- 23930625 TI - Autogenous tooth transplants for the pediatric dental patient: report of three cases. AB - There are select instances where autogenous tooth transplantation should be considered as part of the overall management of the developing occlusion in the child patient. These circumstances occur when there are missing mandibular premolars in Class II malocclusions with good faces, unevenly distributed agenesis, missing or lost incisors, and ectopic teeth. The purposes of this paper were to educate pediatric dentists about the autogenous tooth transplantation technique, its success, its potential advantages and disadvantages and to report on three cases treated with autogenesis tooth transplantation. PMID- 23930627 TI - An improved interim therapeutic restoration technique for management of anterior early childhood caries: report of two cases. AB - Early childhood caries presents unique treatment challenges that often require advanced behavior management techniques, such as general anesthesia or procedural sedation. In some cases, use of these pharmacologic adjuncts is undesirable or not possible. The interim therapeutic restoration is a treatment method that, while sometimes employed in such cases, can often produce unsatisfactory results in primary anterior teeth. This is often due to insufficient bulk of material and lack of retention. The purpose of this report was to describe a simple alternative technique (resin modified glass ionomer strip crowns) that may be employed to deliver esthetic anterior restorations to marginally cooperative children in the dental clinic setting and to report on two cases in which it was successfully used. ???Department of Pediatric Dentistry, University of Washington, Seattle, Wash., USA. tmnelson@uw.edu PMID- 23930628 TI - Table thirteen and top-down solutions. PMID- 23930629 TI - The bonding of glass ionomer cements to caries-affected primary tooth dentin. AB - PURPOSE: The purpose of this study was to evaluate the bonding of glass ionomer cements (GICs) to sound and caries-affected dentin by microtensile bond strength (MUTBS) and nanoleakage (NL) tests. METHODS: Occlusal cavity preparations were made in 36 sound primary molars. Half of the specimens were submitted to a pH cycling model to create simulated caries-affected dentin. Teeth were randomly restored with one of the three materials: (1) resin-modified GIC with nanoparticles (Ketac N100; KN); (2) resin-modified GIC (Vitremer; VI); and (3) high-viscosity GIC (Ketac Molar Easy Mix; KM). Specimens were tested using a microtensile test (1 mm/minute). One specimen from each tooth was immersed in ammoniacal silver nitrate for 24 hours and revealed after eight hours to assess interfacial NL. The MUTBS means were analyzed by 2-way analysis of variance and Tukey's post hoc test. For NL, Kruskal-Wallis and Mann-Whitney tests were used (P<.05). RESULTS: No difference was found between sound and caries-affected dentin (P>.05). KM showed the lowest GIC-dentin MUTBS values, while VI and KN showed higher values. Infiltration of ammoniacal silver nitrate into the adhesive interface was not affected by sound or caries-affected dentin. CONCLUSION: Caries affected dentin does not jeopardize the bonding of glass ionomer cements to primary tooth dentin. PMID- 23930630 TI - Inter-relations between infraocclusion of primary mandibular molars, tipping of adjacent teeth, and alveolar bone height. AB - PURPOSE: The purpose of this study was to examine inter-relations between infraocclusion of primary mandibular molars, tipping of adjacent teeth, and alveolar bone height of infraoccluded teeth. METHODS: A total of 402 periapical radiographs of infraoccluded primary mandibular molars were reviewed. Infraocclusion, alveolar bone height, and tipping of adjacent teeth were measured. RESULTS: Infraocclusion was most prevalent among primary mandibular first molars. The amount of infraocclusion was most profound among primary mandibular second molars (2.79+/-1.25). The shortest distal alveolar crest (reflected by the highest distance between the cementoenamel junction and bone crest) was observed among infraoccluded primary mandibular first molars (0.9+/ 0.92). The permanent mandibular first molar and the primary mandibular first molar demonstrated the maximum tipping mesially and distally. CONCLUSIONS: Infraocclusion of primary mandibular molars, tipping of adjacent teeth, and alveolar bone height of the infraoccluded teeth are inter-related. PMID- 23930631 TI - Sodium hypochlorite vs formocresol as pulpotomy medicaments in primary molars: 1 year follow-up. AB - PURPOSE: The study evaluated the effects of 3 percent sodium hypochlorite (NaOCl) and formocresol (FC) as pulp dressing agents in pulpotomized primary molars. METHODS: One hundred children between three and six years each with at least one primary mandibular second molar requiring pulpotomy were randomly allocated to two groups (of 50 each). All the teeth received stainless steel crown after conventional pulpotomy procedure with either NaOCI (applied for 15 second) or FC (applied for one minute). Clinical and radiographic signs/symptoms were blindly recorded at zero, six. and 12 months. The differences were statistically analyzed using the Fisher's exact test. RESULTS: At six months, 100 percent clinical success was found with both NaOCl, and FC. Radiographic success rates for NaOCl were 98 percent and 92 percent at 6- and 12-month recalls respectively. FC group showed 94 percent and 93 percent radiographic success rates at the same periods respectively. There was no statistically significant difference between the groups. CONCLUSION: NaOCl can be suggested as a pulpotomy agent for primary teeth pulpotomies. However further clinical studies with long-term follow-ups are needed to test the efficacy of NaOCl as a pulpotomy medicament in primary teeth. PMID- 23930632 TI - The influence of location of local anesthesia and complexity/duration of restorative treatment on children's behavior during dental treatment. AB - PURPOSE: The purpose of this study was to investigate whether the region of local anesthetic injection and the complexity and duration of restorative treatment were associated with children's behavior during and immediately after dental treatment. METHODS: This study examined 90 children, divided into two age groups (2-3.5 years old and >3.5-5.5 years old), who underwent dental treatment while lightly sedated. The region of local anesthesia (maxillary infiltration or mandibular block), complexity and duration of treatment, and behavior during and after treatment were assessed. RESULTS: Children's behavior during and after dental treatment, within and between age groups, was not found to be associated with the region of local anesthesia or complexity of treatment. For both age groups, more children exhibited negative behaviors during treatment when procedures exceeded 30 minutes. For younger children, more negative behaviors were also observed after longer vs shorter procedures. CONCLUSION: Treatment duration, not the region of local anesthesia or complexity of treatment, was associated with children's behavior during and after dental procedures. PMID- 23930633 TI - Assessment of restorative treatment of patients with amelogenesis imperfecta. AB - PURPOSE: The purpose of this study was to assess restorative treatment outcomes in the mixed dentition of amelogenesis imperfecta (AI) patients and determine the postrehabilitation oral health status and satisfaction of the patients. METHODS: Clinical and radiographic examinations were performed on eight AI patients, who had 74 restorations placed in permanent incisors and molars, to allow evaluation of the integrity of the restorations and periodontal status post-treatment. Subjects completed a survey regarding esthetics, function, and sensitivity. RESULTS: Among the 74 restorations evaluated, seven were lost; of the remaining restorations, 31 were posterior, and 36 were anterior. Ten were rated clinically unacceptable. Teeth with stainless steel crowns had a moderate gingival index (mean=2.3) and plaque index (mean=2.0) scores. Widening of the periodontal ligament and pulp canal obliteration were common radiographic findings. Subject's recall of satisfaction regarding esthetics (P=.002) and sensitivity (brushing P=.03; eating-P=.01) showed a statically significant difference before and after treatment. CONCLUSIONS: During mixed dentition, teeth with amelogenesis imperfecta may be restored with conventional treatment modalities. Direct restorations should be considered "interim" with multiple repairs anticipated. Post-treatment, gingival inflammation and plaque accumulation were observed. Subjects were satisfied with their appearance and reported a decrease of hypersensitivity. PMID- 23930634 TI - Pediatric dentists' job satisfaction: results of a national survey. AB - PURPOSE: The purpose of this study was to determine pediatric dentists' level of job satisfaction and to explore which factors (demographic and practice/work/patient characteristics) are related to their satisfaction. METHODS: Data were collected with mailed surveys from 385 and with web-based surveys from 966 pediatric dentists in the United States. Professional satisfaction was measured with the Professional Satisfaction Scale and the Dentists' Satisfaction Scale. RESULTS: Most respondents would choose dentistry (89 percent) and pediatric dentistry (92 percent) again and would recommend dentistry (85 percent) and pediatric dentistry (83 percent) to their child as a career. Male respondents were more satisfied with income, personal and professional time, staff, and practice management aspects, and female respondents were more satisfied with patient relations. The older the dentists were, the more satisfied they were. Respondents in academia were less stressed and less satisfied with their income than respondents in nonacademic settings. The more time spent in the operatory and the less administrative work, the more satisfied the respondents were. The fewer patients from a lower socioeconomic background they treated, the more satisfied they were. CONCLUSIONS: Overall, pediatric dentists have a high level of job satisfaction. Demographic factors and practice/work/patient characteristic are related to job satisfaction. PMID- 23930635 TI - Effectiveness of a self-etching adhesive on sealant retention in primary teeth. AB - PURPOSE: The purpose of this study was to conduct a clinical evaluation of fissure sealant retention in primary teeth using self-etching adhesive Adper Prompt L-Pop or a conventional phosphoric acid-etching technique. METHODS: A total of 90 primary second molars indicated for sealants were selected from 45 healthy 4- to 6-year-olds. A randomized, split-mouth design was applied using bilateral primary second molars. Sealant retention was evaluated, using the Color Coverage Caries sealant evaluation system, and blindly checked by the same examiner at six and 12 months. RESULTS: There was no statistically significant difference in the retention of sealant using self-etching adhesives vs the conventional acid-etching technique. Statistically significant lower retention rates were found with both techniques after evaluating at 12 months vs six months. CONCLUSIONS: Replacing phosphoric acid-etching with self-etching adhesive Adper Prompt L-Pop does not compromise sealant retention in primary teeth after a 1-year period. PMID- 23930636 TI - Regenerative endodontic treatment of an immature permanent canine following infant oral mutilation. AB - Extracting primary canine tooth buds is a ritual ceremony that prevails in some African countries. This procedure is considered infant oral mutilation (IOM) and may damage the permanent successor and adjacent primary and permanent teeth, resulting in dysplastic or deformed teeth. The purpose of this report was to describe regenerative endodontic treatment of a permanent mandibular canine with extensive coronal hypoplasia, immature root, and a periapical radiolucency following damage to the permanent canine that was probably a result of infant oral mutilation. Regenerative endodontic treatment was initiated by irrigating the root canal, followed by applying triple antibiotic paste dressing over three weeks and creating a blood clot scaffold covered with mineral trioxide aggregate. A 4-year clinical and radiographic follow-up demonstrated healing of the periapical radiolucency. This treatment may serve as a substitute for traditional apexification with calcium hydroxide or creation of an artificial apical barrier with mineral trioxide aggregate. PMID- 23930637 TI - Localized juvenile spongiotic gingival hyperplasia: a report of 3 cases. AB - Localized juvenile spongiotic gingival hyperplasia (LJSGH) is a recently described benign condition that affects the gingiva of children and young adults. Clinically distinctive, LJSGH presents as a localized area of erythema on the attached gingiva, with a subtly papillary surface architecture. The lesions are generally biopsied because of the lack of resolution with conservative oral hygiene therapeutic measures and esthetic concerns. The histopathology has a characteristic appearance of subtle papillary epithelial hyperplasia, acute inflammation, and numerous engorged capillary vascular spaces in the lamina propria, although clinical correlation is necessary to make the diagnosis. The purposes of this paper were to: introduce localized juvenile spongiotic gingival hyperplasia to the pediatric dental community; document its clinical and histologic features and treatment and the follow-up of three cases; and discuss the most common clinical differential diagnoses. PMID- 23930639 TI - Influence of age and vertical facial type on the location of the mandibular foramen. AB - PURPOSE: A successful inferior alveolar nerve block anesthesia necessitates knowledge of the exact location of the mandibular foramen. The aim of this study was to determine whether the location of the mandibular foramen is related to the age or the vertical facial morphology of the patient. METHODS: Lateral cephalometric radiographs from 145 patients (average age 10.4 years; range 6.3 to 14.6 years) were collected. The position of the mandibular foramen was investigated both antero-posteriorely and vertically in relation to the occlusal plane. Pearson's correlation and multiple regression analysis were performed between the variables under study. RESULTS: The mandibular foramen was horizontally located at 60 percent of the ramus width from its anterior border. The vertical distance of the mandibular foramen from the occlusal plane was significantly correlated to all examined variables, especially to the patient's age (r=0.69, P<0.001), the inter-maxillary angle (r=-0.60, P<0.001), and the lower facial anterior soft tissue ratio (r=-0.76, P<0.001). Multiple regression analysis explained more than 70 percent of the variation of the vertical position of the mandibular foramen. CONCLUSIONS: Taking into consideration the age and the facial morphology of the patient may help better locate the mandibular foramen, which is a prerequisite for a successful and safe inferior alveolar nerve block. PMID- 23930638 TI - Management of impacted incisors following surgery to remove obstacles to eruption: a prospective clinical trial. AB - PURPOSE: The purpose of this study was to assess the effectiveness of rapid maxillary expansion (RME) vs simply monitoring the eruption of permanent maxillary incisors following the surgical removal of obstacles to their eruption (supernumerary teeth, odontomas). METHODS: Following surgical removal of the obstacles to incisor eruption (T1), 62 patients were randomly assigned to either the group to undergo RME (34 subjects; mean age 8 years, 11 months +/- 11 months) or the group that was monitored without further treatment (28 subjects; mean age=9 years, 1 month +/- 1 year). At T2 (1 year after T1), the prevalence rate of erupted incisors was recorded. Also, the time of eruption of the incisors and the amount of space loss were analyzed. RESULTS: At T2, eruption of impacted incisors occurred in approximately 82 percent of the RME group cases vs approximately 39 percent of the monitored group cases (chi-square=10.43, P<.001). Time of eruption was significantly faster in the RME group, and anterior space loss significantly smaller. CONCLUSIONS: Rapid maxillary expansion treatment following surgical removal of the obstacles to the eruption of permanent maxillary incisors appears to be an efficient interceptive approach leading to eruption of the incisors in four out of five cases within seven months. PMID- 23930640 TI - Varicella vaccine uptake and associated factors in children in Hong Kong. AB - Varicella is a common and highly contagious childhood disease which impacts the public worldwide. Hong Kong children can only be vaccinated against the disease in private practice. The varicella vaccination rate of local children in preschool is uncertain. Therefore a cross-sectional kindergarten-based parent administered questionnaire survey was conducted in Hong Kong during 2012. Twelve kindergartens were randomly selected from a complete school list from the Education Bureau of Hong Kong. In total, 1285/1538 (83.6%) parents consented to join the study and completed the questionnaires. The overall varicella infection rate was 19.5% and the uptake of varicella vaccination rate was 57.6%. Barriers against varicella vaccination were mostly due to parental uncertainties about the effectiveness of vaccine, lack of recommendations from doctors or government, and adverse side-effects of the vaccine. The government and healthcare professional bodies are strongly recommended to further enhance health education among healthcare professionals, encouraging their active promotion of varicella vaccination for their patients. Furthermore, health education through various stakeholders is crucial to enhance parental awareness of varicella, as well as the effectiveness and safety of varicella vaccine. PMID- 23930641 TI - Non-extractable polyphenols, a major dietary antioxidant: occurrence, metabolic fate and health effects. AB - Current research on dietary antioxidants misses the so-called non-extractable polyphenols (NEPP), which are not significantly released from the food matrix either by mastication, acid pH in the stomach or action of digestive enzymes, reaching the colon nearly intact. NEPP, not detected by the usual analytical procedures, are made up of macromolecules and single phenolic compounds associated with macromolecules. Therefore, NEPP are not included in food and dietary intake data nor in bioavailability, intervention or observational studies. The present paper aims to provide an overview of dietary NEPP - nature, occurrence in diet, metabolic fate and possible health effects. NEPP are a relevant fraction of dietary polyphenols exerting their main biological action in the colon, where they are extensively fermented by the action of microbiota, giving place to absorbable metabolites. NEPP exhibit different potential health related properties, in particular in relation to gastrointestinal health, such as increases in antioxidant and antiproliferative capacities, reduction of intestinal tumorigenesis and modification of gene expression, as observed in different animal models. Further research into NEPP may provide a better understanding of the health effects of dietary antioxidants. PMID- 23930642 TI - Resilience in patients with amputation because of Complex Regional Pain Syndrome type I. AB - PURPOSE: Although controversial, an amputation for longstanding and therapy resistant Complex Regional Pain Syndrome Type I (CRPS-I) may improve quality of life and pain intensity. Resilience, the way people deal with adversity in a positive way may be related to these positive outcomes. This study focused on the relationship between resilience and post-amputation outcomes, i.e. quality of life, pain and recurrence of CRPS-I and psychological distress. METHOD: Twenty six patients with an amputation related to CRPS-I filled in the Connor-Davidson Resilience Scale (CD-RISC), World Health Organisation -- Quality of life Assessment (WHOQOL-Bref) and the Symptom Checklist-90 Revised (SCL-90-R). An interview was conducted and a physical examination performed. Results were compared with reference groups from literature and a control group from the outpatient rehabilitation clinic at our medical center. RESULTS: Resilience correlated significantly with all domains of the WHOQOL-Bref (rho ranged from 0.41 to 0.72) and negatively with all domains of the SCL-90-R (rho ranged from 0.39 to -0.68). Patients with an amputation because of CRPS-I have higher scores on resilience and quality of life than the control group. Resilience was lower in patients who reported CRPS-I symptoms compared to those who did not. CONCLUSIONS: The results confirmed our hypothesis that patients with an amputation because of CRPS-I who have a higher resilience also have a higher quality of life and experience lower psychological distress. The prognostic value of resilience in this patient group requires further research. Implications for Rehabilitation Until characteristics of patients with positive quality of life outcome have been further unraveled, amputation for CRPS-I should only be performed in expertise centers. Resilience, the process of adapting well in the face of adversity, should be further explored in Rehabilitation Medicine research in general. Measurement of resilience should be a standard procedure when patients with CRPS I request an amputation. Improving resilience of patients in in- and outpatient rehabilitation clinics might be an additional treatment in rehabilitation care. PMID- 23930643 TI - Content comparison of self-reported disability measures for the elderly according to the international classification of functioning, disability and health. AB - PURPOSE: To identify self-reported disability measures developed for older adults by performing a systematic literature review and to compare the contents of all identified measures based on the International Classification of Functioning, Disability and Health (ICF). METHOD: A broad systematic literature search was performed in March 2012 in the following databases: MEDLINE, EMBASE, CINAHL, PsycINFO and PROQOLID. Each item in the identified measures was extracted and linked to the ICF categories. A content comparison between measures was performed. The content density and diversity of each measure were assessed by calculating the content density ratio (the number of meaningful concepts divided by the number of items in each questionnaire) and content diversity ratio (the number of different ICF categories divided by the number of linked meaningful concepts), respectively. RESULTS: We reviewed 5622 published articles and identified 13 eligible measures. In total, 293 meaningful concepts from 265 items were extracted, of which, 270 concepts were linked to the ICF. A total of 62 different ICF categories were addressed. EARRS, FHS and SF-LLFDI had the highest content density ratio, while FHS and KI had the highest content diversity ratio. Different measures differed considerably in content. CONCLUSIONS: The ICF can be used as a conceptual framework not only for assessing measures but also for developing new measures. According to this ICF-based content comparison, the contents of currently available measures for disability in older adults vary significantly from one another. Our study may provide useful information for the selection of suitable measures for a particular purpose, as well as the development of new measures. PMID- 23930644 TI - Communicating with individuals receiving home mechanical ventilation: the experiences of key communication partners. AB - PURPOSE: The aim of the study was to explore the communication experiences of key communications partners (CPs) of individuals receiving home mechanical ventilation (HMV), with particular emphasis on the possibilities, difficulties and limitations CPs experienced in communication, possible support given to facilitate communication and exploring what made a skilled communicator. METHOD: A qualitative research design using interviews was used. The participants included 19 key CPs of individuals receiving HMV. RESULTS: The analysis resulted in five themes: Encountering communication limitations, Functional communication strategies, Being a communication facilitator, Role insecurity and Emotional reactions and coping. The findings revealed that CPs needed to develop partly new reference frames for communication. In particular, participants emphasised the need to understand and interpret subtle details in the communicative interaction. CONCLUSIONS: The findings are discussed in the light of previous research, in particular an earlier study exploring another perspective; the ventilator supported individuals' experiences of communication. Issues relating to the educational needs of CPs of individuals receiving HMV are discussed. The results are intended to enhance understanding of the challenges that individuals receiving HMV and their CPs face with communication, which should be of relevance not only to speech therapists, but for all healthcare practitioners in the field of HMV. PMID- 23930645 TI - Predictors of changes in suicidality in multiple sclerosis over time. AB - PURPOSE: Studies show that suicidality is greater in persons with multiple sclerosis (MS) than in the general population. In this study, we evaluated the consistency of suicidality over time in patients with MS. METHOD: Participants were patients (n = 344) at an outpatient clinic at a large medical center in New Jersey. Longitudinal data was collected as part of an ongoing research project. Binary logistic regression examined the effect of gender, age, depression and disability on level of suicidality at Time 1 versus Time 2. RESULTS: Baseline depression and change in level of depression significantly predicted level of suicidality at Time 2, while demographic variables, baseline disability, change in level of disability, and the interaction between change in depression and change in disability over time did not. CONCLUSIONS: Interventions aimed at evaluating and monitoring depression over time should be considered in order to reduce the risk of suicidality. Implications for Rehabilitation Due to the inconsistency and unpredictability of MS, depression should be assessed routinely. Given the high prevalence of depression and suicidality in MS, mental health services should be available and encouraged by healthcare providers treating individuals with MS. PMID- 23930646 TI - A comparative review of measurement instruments to inform and evaluate effectiveness of disability inclusive development. AB - PURPOSE: A review of existing measurement instruments was conducted to examine their suitability to measure disability prevalence and assess quality of life, protection of disability rights and community participation by people with disabilities, specifically within the context of development programs in low and middle-income countries. METHODS: From a search of PubMed and the grey literature, potentially relevant measurement instruments were identified and examined for their content and psychometric properties, where possible. Criteria for inclusion were: based on the WHO's International Classification of Functioning Disability and Health (ICF), used quantitative methods, suitable for population-based studies of disability inclusive development in English and published after 1990. Characteristics of existing instruments were analysed according to components of the ICF and quality of life domains. RESULTS: Ten instruments were identified and reviewed according to the criteria listed above. Each version of instruments was analysed separately. Only three instruments included a component on quality of life. Domains from the ICF that were addressed by some but not all instruments included the environment, technology and communication. CONCLUSION: The measurement instruments reviewed covered the range of elements required to measure disability-inclusion within development contexts. However no single measurement instrument has the capacity to measure both disability prevalence and changes in quality of life according to contemporary disability paradigms. The review of measurement instruments supports the need for developing an instrument specifically intended to measure disability inclusive practice within development programs. Implications for Rehabilitation Surveys and tools are needed to plan disability inclusive development. Existing measurement tools to determine prevalence of disability, wellbeing, rights and access to the community were reviewed. No single validated tool exists for population-based studies, uses quantitative methods and the components of the ICF to measure prevalence of disability, well-being of people with disability and their access to their communities. A measurement tool that reflects the UNCRPD and addresses all components of the ICF is needed to assist in disability inclusive development, especially in low and mid resource countries. PMID- 23930648 TI - Practitioner perspectives: effective intraprofessional relationships in occupational therapy. AB - OBJECTIVE: This qualitative study examined OTR and COTA perspectives regarding the effectiveness of these intraprofessional relationships and their understanding of these two distinct roles in occupational therapy. METHOD: Twenty two pairs of OTR/COTA teams that work together in Pennsylvania, Ohio, and West Virginia were interviewed. Themes relating to effective intraprofessional relationships were synthesized from this convenience sample and considered within the context of current settings and relevant literature in the health professions. RESULTS: Three primary themes emerged from the data as having a significant impact on these OTR/COTA relationships. The themes include effective two-way communication, the need for mutual respect, and the importance of professionalism. The presence or absence of these three factors were perceived to impact the overall quality of these OTR/COTA relationships. CONCLUSION: It was determined that these factors influenced participants' perceptions about their work in occupational therapy. Both OTRs and COTAs expressed that effective intraprofessional relationships enhance the quality of occupational therapy services provided and strengthen their desire to practice in the field. PMID- 23930647 TI - Positive parenting for positive parents: HIV/AIDS, poverty, caregiver depression, child behavior, and parenting in South Africa. AB - Families affected by HIV/AIDS in the developing world experience higher risks of psychosocial problems than nonaffected families. Positive parenting behavior may buffer against the negative impact of child AIDS-orphanhood and caregiver AIDS sickness on child well-being. Although there is substantial literature regarding the predictors of parenting behavior in Western populations, there is insufficient evidence on HIV/AIDS as a risk factor for poor parenting in low- and middle-income countries. This paper examines the relationship between HIV/AIDS and positive parenting by comparing HIV/AIDS-affected and nonaffected caregiver child dyads (n=2477) from a cross-sectional survey in KwaZulu-Natal, South Africa (27.7% AIDS-ill caregivers; 7.4% child AIDS-orphanhood). Multiple mediation analyses tested an ecological model with poverty, caregiver depression, perceived social support, and child behavior problems as potential mediators of the association of HIV/AIDS with positive parenting. Results indicate that familial HIV/AIDS's association to reduced positive parenting was consistent with mediation by poverty, caregiver depression, and child behavior problems. Parenting interventions that situate positive parenting within a wider ecological framework by improving child behavior problems and caregiver depression may buffer against risks for poor child mental and physical health outcomes in families affected by HIV/AIDS and poverty. PMID- 23930649 TI - A team approach to health promotion of community elders: the microwave project. AB - An occupational therapy program and an agency that addresses the needs of community elderly collaborated to resolve a problem of the homebound people who receive Meals-on-Wheels. Staff of the agency realized that many elders were unable to safely and comfortably reheat their delivered meals. Risk factors of malnutrition, bacterial infection, functional decline and reduced quality of life are the sequelae. To solve this complex problem, an interdisciplinary team formed to clarify the nature of the problem and implement a plan of action. The result is "The Microwave Project," designed to enhance nutrition and function of elderly people who are homebound. PMID- 23930650 TI - Comparison of Final Exam Test Scores of Neuroscience Students Who Experienced Traditional Methodologies versus Problem-Based Learning Methodologies. AB - Faculty members in the Occupational Therapy Department at Belmont University needed to determine if an alternative teaching method, consisting of lecture and problem-based learning (PBL), was more effective than a traditional lecture method in maximizing student achievement in neuroscience. This study was undertaken to determine if students who participated in an alternative methodology (experimental group) would perform differently on a comprehensive final exam than students who experienced a traditional lecture approach (control group). A second purpose was to determine if the experimental group achieved a greater score on higher-level thinking test questions than the control group. There were two research questions for this study. First, "Will there be a significant difference in the mean final unit test score of the experimental group in comparison with the control group?" Second, "Will there be a significant increase in the mean final unit test score on higher-level thinking items between the experimental and control groups? For research question one, a two-tailed independent samples t-test was used to compare mean test scores of the two groups. Based on a P value of. 846, it was determined that there was not a significant difference in total test scores between the two groups. For research question two, a one-tailed independent samples t-test resulted in a P value of. 491; therefore, it was determined that there was not a significant difference on higher-level thinking test scores between the two groups. However, a bi-modal distribution of the scores for the experimental group suggests that some performed well under PBL conditions while some did not. Potential implications of this bimodal distribution are discussed to assist OT educators in choosing appropriate instructional methodologies. The findings suggest that faculty should continue to explore variables that may affect performance under PBL conditions and achievement in neuroscience. PMID- 23930651 TI - Factors affecting the retention of occupational therapists in rural services. AB - Failure to retain health professionals in rural areas contributes to the poor health status of these communities through an inability to deliver reliable and consistent services. Considerable attention has focused on factors affecting recruitment of health professionals. Far less is known about factors affecting the retention of occupational therapists. In this study ethnographic interviews were conducted with 10 occupational therapists to explore their experiences related to leaving rural practice. Six themes emerged from the participants' experiences and gave rise to a framework that suggests retention can be improved by addressing the imbalance between incentives to leave and to stay in rural practice. The findings can be used by occupational therapists contemplating rural practice, as well as by health services managers responsible for service delivery in rural areas. PMID- 23930652 TI - The utilization of spirituality in occupational therapy: beliefs, practices, and perceived barriers. AB - Spirituality has become an increasingly important topic in healthcare and specifically in occupational therapy. This study utilized a survey design to examine occupational therapists' current beliefs and practices regarding spirituality, and to identify barriers to the use of spirituality in OT treatment. No statistically significant relationship was found between the use of spirituality and different practice settings or therapists' demographics However the participants' response indicated that the beliefs and practices regarding spirituality in occupational therapy may be changing Therapists reported discussing spiritual issues with clients more frequently than in previous studies. Lack of education or experience in taking a spiritual history was reported as the major barrier impeding the therapists' ability to incorporate spirituality into OT practice. PMID- 23930653 TI - A critical review of assessment tools related to home adaptation issues. AB - For several decades now, occupational therapists have dealt with eliminating architectural barriers confronting persons using wheelchairs. The occupational therapist is usually a key resource person in the home care assessment team, but faces a penury of evaluation tools to carry out the task. Being often obliged to develop homemade instruments, the process tends to lack structure, uniformity and objectivity. A review of writings about assessment tools for occupational therapists has demonstrated the need for a specific tool dealing with the various factors involved in the home adaptation issue. PMID- 23930654 TI - Clinical reasoning, looking back. AB - Expert clinical reasoning is a vital skill for occupational therapists, particularly in today's rapidly changing health care environment. Clinical reasoning may be the strongest building block of the profession as it diversifies and grows to meet the challenges of the new millennium. Therefore, it is a critical time to continue the research to understand, further develop, and expand occupational therapy's knowledge of clinical reasoning. This article describes the development of the occupational therapy clinical reasoning process and compares it to that of medicine and nursing. PMID- 23930656 TI - Stereoselective total synthesis of hainanolidol and harringtonolide via oxidopyrylium-based [5 + 2] cycloaddition. AB - The tetracyclic carbon skeleton of hainanolidol and harringtonolide was efficiently constructed by an intramolecular oxidopyrylium-based [5 + 2] cycloaddition. An anionic ring-opening strategy was developed for the cleavage of the ether bridge in 8-oxabicyclo[3.2.1]octenes derived from the [5 + 2] cycloaddition. Conversion of cycloheptadiene to tropone was realized by a sequential [4 + 2] cycloaddition, Kornblum-DeLaMare rearrangement, and double elimination. The biomimetic synthesis of harringtonolide from hainanolidol was also confirmed. PMID- 23930657 TI - Case management: the occupational and environmental health nurse role. PMID- 23930658 TI - Evaluation of a stretching program to increase worker flexibility. AB - This article describes the evaluation of a stretching program intended to increase worker flexibility. PMID- 23930659 TI - Job and life satisfaction of nonstandard workers in South Korea. AB - Since the South Korean financial crisis of the late 1990s, the number of nonstandard workers in South Korea has increased rapidly. With such a drastic change, it has been difficult to establish national welfare systems (e.g., accident insurance or support for families with dependent children) for nonstandard workers and identify critical aspects of their health. To evaluate job and life satisfaction among nonstandard workers, this study used a representative sample of South Koreans. Using data from the 2008 Korean Labor and Income Panel Study, the sample size totaled 4,340 observations, of which 1,344 (31.0%) involved nonstandard workers. Significant differences in job and life satisfaction between nonstandard workers and standard workers were found. The results also indicate discrimination in the welfare and fringe benefit systems in South Korea. Occupational health nurses must address the physical and psychological health issues, personal problems, and everyday life concerns of nonstandard workers. Given that the employment status of nonstandard workers in companies is generally unstable, it is difficult for these workers to report poor working conditions to employers or other authorities. Accordingly, occupational health nurses should advocate for nonstandard workers by notifying employers of the many problems they face. PMID- 23930660 TI - Leveraging best practices to promote health, safety, sustainability, and stewardship. AB - Strategically leveraging health and safety initiatives with sustainability and stewardship helps organizations improve profitability and positively impact team member and customer attachment to the organization. Collective efficacy enhances the triple bottom line: healthy people, healthy planet, and healthy profits. The HS(3)TM Best Practice Exchanges group demonstrated that collective efficacy can leverage the social cohesion, communication channels, and activities within workplaces to promote a healthy, sustainable work culture. This in turn (1) protects the health and safety of workers, (2) preserves the natural environment, and (3) increases attachment to the organization. Community-based participatory research using the Attach21 survey assessed the progress of these companies in their efforts to integrate health, safety, sustainability, and stewardship. Monthly Best Practice Exchanges promoted collective efficacy by providing support, encouragement, and motivation to share and adopt new ideas. PMID- 23930662 TI - Reducing sodium consumption. AB - Occupational and environmental health nurses can educate workers on the dangers of excess sodium and how to make better food choices. PMID- 23930663 TI - Anthocyanins from Chinese bayberry extract activate transcription factor Nrf2 in beta cells and negatively regulate oxidative stress-induced autophagy. AB - Islet replacement is a promising cure for insulin-dependent diabetes but is limited by a massive early cell death following transplantation. Overburden oxidative stress is one of the major factors causing cell damage. We have shown previously that anthocyanins in Chinese bayberry extract protected beta cells (INS-1) from hydrogen peroxide (H2O2)-induced apoptosis and decreased grafts' apoptosis after transplantation partially through heme oxygenase-1 (HO-1) up regulation. In the present study, we observed that H2O2 stimulation induced autophagy in beta cells. Inhibition of autophagy increased cell viability and decreased cell death. Anthocyanin pretreatment attenuated oxidative stress mediated autophagic cell death. Anthocyanins activated antioxidant transcription factor Nrf2 in INS-1 cells, and Nrf2/HO-1 negatively regulated autophagy process. Furthermore, we here demonstrate that autophagy also took place in beta cell grafts during the early post-transplantation phase. beta Cells pretreated with anthocyanins displayed decreased extent of autophagy after transplantation. Taken together, these findings further supported the conclusion that anthocyanins could serve as a protective agent of beta cells and suggested that autophagy might play a role in beta cells during transplantation. PMID- 23930664 TI - 15N-cholamine--a smart isotope tag for combining NMR- and MS-based metabolite profiling. AB - Recently, the enhanced resolution and sensitivity offered by chemoselective isotope tags have enabled new and enhanced methods for detecting hundreds of quantifiable metabolites in biofluids using nuclear magnetic resonance (NMR) spectroscopy or mass spectrometry. However, the inability to effectively detect the same metabolites using both complementary analytical techniques has hindered the correlation of data derived from the two powerful platforms and thereby the maximization of their combined strengths for applications such as biomarker discovery and the identification of unknown metabolites. With the goal of alleviating this bottleneck, we describe a smart isotope tag, (15)N-cholamine, which possesses two important properties: an NMR sensitive isotope and a permanent charge for MS sensitivity. Using this tag, we demonstrate the detection of carboxyl group containing metabolites in both human serum and urine. By combining the individual strengths of the (15)N label and permanent charge, the smart isotope tag facilitates effective detection of the carboxyl-containing metabolome by both analytical methods. This study demonstrates a unique approach to exploit the combined strength of MS and NMR in the field of metabolomics. PMID- 23930665 TI - New analyses of the National Institute of Mental Health Treatment of Depression Collaborative Research Program: do different treatments reflect different processes? AB - To determine whether or not different therapies have distinct patterns of change, it is useful to investigate not only the end result of psychotherapy (outcome) but also the processes by which outcomes are attained. The present study subjected data from the National Institute of Mental Health Treatment of Depression Collaborative Research Program to survival analyses to examine whether the process of psychotherapy, as conceptualized by the phase model, differed between psychotherapy treatment approaches. Few differences in terms of progression through phases of psychotherapy were identified between cognitive behavior therapy and interpersonal therapy. Additionally, results indicate that phases of psychotherapy may not represent discrete, sequentially invariant processes. PMID- 23930667 TI - Assessment of socioemotional processes facilitates the distinction between frontotemporal lobar degeneration and Alzheimer's disease. AB - We explored the value of a battery of socioemotional tasks for differentiating between frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Patients with FTLD (n = 13) or AD (n = 13) and healthy controls (n = 26) underwent a neuropsychological assessment and the socioemotional battery (an empathy questionnaire, an emotion recognition task, and theory of mind tasks). Socioemotional processes were markedly impaired in FTLD but relatively unaffected in mild AD. The computed Socioemotional Index discriminated more accurately between FTLD from AD than behavioral and executive assessments did. Furthermore, impairments in socioemotional processes were correlated with indifference to others. PMID- 23930668 TI - Nutritional strategies to counteract muscle atrophy caused by disuse and to improve recovery. AB - Periods of immobilisation are often associated with pathologies and/or ageing. These periods of muscle disuse induce muscle atrophy which could worsen the pathology or elderly frailty. If muscle mass loss has positive effects in the short term, a sustained/uncontrolled muscle mass loss is deleterious for health. Muscle mass recovery following immobilisation-induced atrophy could be critical, particularly when it is uncompleted as observed during ageing. Exercise, the best way to recover muscle mass, is not always applicable. So, other approaches such as nutritional strategies are needed to limit muscle wasting and to improve muscle mass recovery in such situations. The present review discusses mechanisms involved in muscle atrophy following disuse and during recovery and emphasises the effect of age in these mechanisms. In addition, the efficiency of nutritional strategies proposed to limit muscle mass loss during disuse and to improve protein gain during recovery (leucine supplementation, whey proteins, antioxidants and anti-inflammatory compounds, energy intake) is also discussed. PMID- 23930669 TI - Pharmacogenetic labyrinth of neovascular age-related macular degeneration therapy: how to escape and move forward? PMID- 23930666 TI - The DNA helicase-primase complex as a target for herpes viral infection. AB - INTRODUCTION: The Herpesviridae are responsible for debilitating acute and chronic infections, and some members of this family are associated with human cancers. Conventional anti-herpesviral therapy targets the viral DNA polymerase and has been extremely successful; however, the emergence of drug-resistant virus strains, especially in neonates and immunocompromised patients, underscores the need for continued development of anti-herpes drugs. In this article, we explore an alternative target for antiviral therapy, the HSV helicase/primase complex. AREAS COVERED: This review addresses the current state of knowledge of HSV DNA replication and the important roles played by the herpesvirus helicase- primase complex. In the last 10 years several helicase/primase inhibitors (HPIs) have been described, and in this article, we discuss and contrast these new agents with established inhibitors. EXPERT OPINION: The outstanding safety profile of existing nucleoside analogues for alpha-herpesvirus infection make the development of new therapeutic agents a challenge. Currently used nucleoside analogues exhibit few side effects and have low occurrence of clinically relevant resistance. For HCMV, however, existing drugs have significant toxicity issues and the frequency of drug resistance is high, and no antiviral therapies are available for EBV and KSHV. The development of new anti-herpesvirus drugs is thus well worth pursuing especially for immunocompromised patients and those who develop drug-resistant infections. Although the HPIs are promising, limitations to their development into a successful drug strategy remain. PMID- 23930670 TI - Cancer heterogeneity and signaling network-based drug target. PMID- 23930673 TI - DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis. AB - AIM: In the present study we conducted a systematic review and meta-analysis of published data to quantify the impact of the DPYD IVS14+1G>A and 2846A>T variants on the risk of fluoropyrimidine-related toxicities and to determine sensitivity and specificity testing for DPYD variants. METHODS: Relevant studies were identified through PubMed and Web of Knowledge databases, studies included were those published up until to May 2012. Study quality was assessed according to the HuGENET guidelines and Strengthening the Reporting of Genetic Association (STREGA) recommendations. RESULTS: Random-effects meta-analysis provided evidence that carriers of DPYD IVS14+1G>A are at higher risk of >=3 degrees of overall grade toxicity, hematological toxicity, mucositis and diarrhea. In addition, a strong association was also found between carriers of the DPYD 2846T allele and overall grade >=3 toxicity or grade >=3 diarrhea. An inverse linear relationship was found in prospective studies between the odds ratio of DPYD IVS14+1G>A and the incidence of overall grade >=3 toxicity, indicating an higher impact in cohorts in which the incidence of severe toxicity was lower. CONCLUSION: The results of this meta-analysis confirm clinical validity of DPYD IVS14+1G>A and 2846A>T as risk factors for the development of severe toxicities following fluoropyrimidine treatment. Furthermore, the sensitivity and specificity estimates obtained could be useful in establishing the cost-effectiveness of testing for DPYD variants. PMID- 23930674 TI - Role of ethnicity in antipsychotic-induced weight gain and tardive dyskinesia: genes or environment? AB - AIM: This study explored the role of self-reported ethnicity and genetic ancestry on antipsychotic (AP)-induced weight gain and tardive dyskinesia (TD) in schizophrenia. PATIENTS & METHODS: Ethnicity was determined by self-report as well as Structure analysis of 190 SNPs selected from HapMap3, genotyped using a customized Illumina BeadChip. Age, gender, baseline weight and AP response using Brief Psychiatric Rating Scale were assessed. Multivariate regression models for AP-induced weight gain and TD, based on the Abnormal Involuntary Movement Scale were constructed. RESULTS: African-American ethnicity (self-report, p = 0.021 and Structure analysis, p = 0.042) predicted AP-induced weight gain but not TD (self report, p = 0.408 and Structure analysis, p = 0.714). CONCLUSION: Self-reported African-American ethnicity seemed to better predict AP-induced weight gain in schizophrenia compared with genetic ancestry, suggesting a possible role of environmental in addition to genetic factors. Future larger studies are needed to clarify specific gene-environment mechanisms mediating the effect of ethnicity on AP-induced weight gain. PMID- 23930675 TI - Effects of polymorphisms in ABCG2, SLCO1B1, SLC10A1 and CYP2C9/19 on plasma concentrations of rosuvastatin and lipid response in Chinese patients. AB - AIM: This study examined whether the ABCG2 421C>A polymorphism and variants in other genes potentially related to the pharmacokinetics of rosuvastatin influenced the plasma concentration of rosuvastatin in Chinese patients with hypercholesterolemia. PATIENTS & METHODS: Overnight fasting blood samples were collected from 291 patients who had received a rosuvastatin 10 mg night-time dose for at least 4 weeks. Plasma concentrations of rosuvastatin and N-desmethyl rosuvastatin were quantified using liquid chromatography tandem mass spectrometry. RESULTS: In subjects with the ABCG2 421AA genotype (n = 39), the mean plasma concentrations of rosuvastatin and its metabolite were 63 and 41% greater than the values in those with the 421CA genotype (n = 108) and 120 and 99% greater than in those with the 421CC genotype (n = 129). The plasma concentrations of rosuvastatin were associated (r = -0.194; p = 0.001) with the percentage reduction in low-density lipoprotein cholesterol with rosuvastatin, but the association was not significant after adjusting for the ABCG2 421C>A polymorphism. The SLCO1B1 521T>C polymorphism was associated with increased plasma concentrations of rosuvastatin and impaired N-demethylation of rosuvastatin, but had no impact on its lipid-lowering effect. Polymorphisms in CYP2C9, CYP2C19 and SLC10A1 had minimal effects. CONCLUSION: These findings suggest that the increased plasma concentrations of rosuvastatin in Chinese patients are associated with increased lipid-lowering effects and lower doses of rosuvastatin should be effective in subjects with the ABCG2 421C>A variant. PMID- 23930676 TI - Genetic variation in the PPARA gene is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study. AB - AIM: Recently, minor alleles of two strongly linked polymorphisms in the PPARA gene, rs4253728 G>A and rs4823613 A>G, were related to decreased CYP3A4 expression and activity. We studied whether they were associated with the cholesterol-lowering effect of simvastatin. MATERIALS & METHODS: We identified 123 incident users with cholesterol measurements before and after starting statin therapy in a prospective population-based cohort study. Associations between PPARA polymorphisms and change in total and low-density lipoprotein (LDL) cholesterol levels were analyzed using linear regression. RESULTS: The minor G allele of the rs4823613 A>G polymorphism was associated with a 0.258 mmol/l (95% CI: -0.470 to -0.046) and a 0.294 mmol/l (95% CI: -0.495 to -0.093) larger reduction in total and LDL-cholesterol, respectively, after starting simvastatin therapy. Results were similar for the rs4253728 G>A polymorphism. CONCLUSION: The minor alleles of the PPARA rs4253728 and rs4823613 polymorphisms are associated with a better total and LDL-cholesterol-lowering response to simvastatin, possibly through influence on CYP3A4. PMID- 23930677 TI - Triptolide, a Chinese herbal extract, enhances drug sensitivity of resistant myeloid leukemia cell lines through downregulation of HIF-1alpha and Nrf2. AB - AIM: To explore whether triptolide (TPL) can enhance drug sensitivity of resistant myeloid leukemia cell lines through downregulation of HIF-1alpha and Nrf2. MATERIALS & METHODS: HL60/A and K562/G cells were subjected to different treatments and thereafter an methyl thiazole tetrazolium bromide assay, flow cytometry, western blot and real-time PCR were used to determine IC50, apoptotic status and expression of Nrf2, HIF-1alpha and their target genes. RESULTS: Doxorubicin- or imatinib-induced apoptosis was enhanced when anticancer agents were used in combination with TPL. When combined with TPL, both doxorubicin and imatinib downregulate Nrf2 and HIF-1alpha expression at protein and mRNA levels. Genes downstream of Nrf2, for example, NQO1, GSR and HO-1, as well as target genes of HIF-1alpha, for example, BNIP3, VEGF and CAIX are also downregulated at the mRNA level. CONCLUSION: TPL is able to enhance drug sensitivity of resistant myeloid leukemia cell lines through downregulation of HIF-1alpha and Nrf2. PMID- 23930678 TI - Pharmacogenetics of olanzapine metabolism. AB - The pharmacokinetics of the atypical antipsychotic, olanzapine, display large interindividual variation leading to multiple-fold differences in drug exposure between patients at a given dose. This variation in turn gives rise to the need for individualized dosing in order to avoid concentration-dependent adverse effects or therapeutic failure. Genetically determined differences in olanzapine metabolism represent a less studied source of variability in comparison to environmental and physiological factors. In this review, we summarize available in vitro and in vivo data addressing the influence of polymorphisms in drug metabolizing enzymes on olanzapine serum exposure. The polymorphic CYP2D6 enzyme appears to have no significant influence on olanzapine steady-state serum concentrations. The formation of the various olanzapine metabolites is influenced by polymorphisms in the genes coding for CYP1A2, CYP1A expression regulator AHR, UGT1A4 and UGT2B10, as well as FMO3. An impact on steady-state olanzapine serum concentrations has been suggested for variants of CYP1A2 and UGT1A4, with somewhat conflicting findings. The potential involvement of FMO1 and CYP3A43 in olanzapine disposition has also been suggested but needs future validation. PMID- 23930679 TI - Current approaches for TYMS polymorphisms and their importance in molecular epidemiology and pharmacogenetics. AB - TS is critical for providing the requisite nucleotide precursors in order to maintain DNA synthesis and repair. Furthermore, it is an important target for several drugs such as 5-fluorouracil and methotrexate. However, several mechanisms of resistance to TS inhibitors have been explained as linked to TYMS overexpression. Some authors have described the relationship between genetic polymorphisms on TYMS, in particular rs34743033, rs2853542 and rs34489327, with the development of several diseases and with the clinical response to drug therapy and/or survival. Nevertheless, the obtained results described in the literature are controversial, which has lead to a search strategy to understand the impact of these polymorphisms on molecular epidemiology and pharmacogenetics. With the progress of these scientific areas, early identification of individuals at risk of disease along with improvement in the prediction of patients' outcome will offer a powerful tool for the translation of TYMS polymorphisms into clinical practice and individualization of treatments. PMID- 23930680 TI - Implications of the incidentalome for clinical pharmacogenomics. AB - Incidental findings have long posed challenges for healthcare providers, but the scope and scale of these challenges have increased with the introduction of new technologies. This article assesses the impact of incidental findings on the introduction of prospective pharmacogenomic testing into clinical use. Focusing on the challenges of the incidentalome, the large set of incidental findings potentially generated through genotyping, the paper argues that provisional approaches to managing incidental findings may be implemented if necessary to allow benefits of pharmacogenomic testing to be realized in the clinical setting. In the longer term, approaches to returning incidental findings may need to focus on limiting the number of incidental findings to a number that can be addressed by patients and providers. PMID- 23930682 TI - Assessing the scale of resource recovery for centralized and satellite wastewater treatment. AB - Wastewater treatment to recover water, energy, and other resources is largely carried out at centralized treatment facilities. An alternative is local treatment at satellite facilities where wastewater is removed from a collection system, resources are recovered locally, and the residuals are returned to the collection system. Satellite systems decrease the pipe and energy required for delivery of treated water and may decrease cost. But decisions regarding the geographic scale of resource recovery require consideration of many criteria. In this study, we rank water and energy recovery options for a simplified test case at three scale configurations: a centralized configuration and two hybrid configurations. We first choose criteria for decision-making. Quantitative performance metrics are defined for each criterion, weighted, and computed for each configuration. We then rank configurations. Rankings depend upon the decision-making strategy. For our test case, though, several strategies yield the same top-ranked configuration: a hybrid where communities close to the centralized facility use centralized resource recovery; communities far from the centralized facility use satellite resource recovery. Our ranking is sensitive to initial investment cost for satellite treatment. The results underscore the importance of cost-effective treatment systems and of an accurate and comprehensive analysis of design components. PMID- 23930683 TI - Future learning environments. Introduction. PMID- 23930684 TI - "Living museums": is it time to reconsider the learning landscape for professional and interprofessional education? PMID- 23930685 TI - The disconnections between space, place and learning in interprofessional education: an overview of key issues. AB - This article explores and discusses current conceptual and empirical dimensions of the study of space, place, education and interprofessional education (IPE) within a health professions context. This article addresses defining elements of the concepts, their use in nursing and medical literature and their positioning within educational theories. It outlines a series of ideas and approaches for future research aimed at investigating the intersections and relationships amongst these concepts. Importantly, this article argues that the conceptualization of space and place in IPE can potentially impact how educational space, places and curricular are (re)conducted and utilized. PMID- 23930686 TI - The dislocation of medical dominance: making space for interprofessional care. AB - The historical transition of modern medicine from an autonomous profession to a team-based interprofessional practice can be described in terms of space rather than time, with "place" as the unit of analysis. Imagining modern medicine spatially was instigated by Foucault, who described medical dominance as a territorializing of both individual body spaces and public spaces--the former through the diagnostic medical gaze, the latter in a gaze of health surveillance. However, much has happened since Foucault's (1963) analysis. The diagnostic gaze has been dispersed to develop a collaborative gaze including patients and healthcare professionals; political interests have appropriated the public health gaze; and the medical profession is subject to democratic processes of accountability. Medicine has lost its territorial imperative as new "liquid" and "nomadic" work practices emerge, making space for interprofessional care. Such dislocation of medical dominance and its multiple relocations are poorly theorised. Deleuze and Guattari distinguish between "striated" and "smooth" spaces. Striated space is associated with hierarchies and boundaries, where smooth space includes boundary crossing and democratic collaboration. Smooth or liminal spaces in hospitals, such as corridors, can paradoxically act as catalysts for collaboration or assembly democracy, affording opportunities for improvised interprofessional encounters. Such encounters can act as an antidote to planned protocols or imperatives for interprofessional collaboration. PMID- 23930688 TI - Strategic planning for future learning environments: an exploration of interpersonal, interprofessional and political factors. AB - This article, written from the stance of a public planner and a policy maker, explores the challenges and potential in creating future learning environments through the concept of a new learning landscape. It is based on the belief that physical planning can support the strategic goals of universities. In Denmark, a political focus on education as a mean to improve national capacity for innovation and growth are redefining the universities role in society. This is in turn changing the circumstances for the physical planning. Drawing on examples of physical initiatives in three different scales--city, building and room scale, the paper highlights how space and place matters on an interpersonal, an interprofessional and a political level. The article suggests that a wider understanding of how new learning landscapes are created--both as a material reality and a political discourse--can help frame an emerging community of practice. This involves university leaders, faculty and students, architects, designers and urban planners, citizens and policy makers with the common goal of creating future learning environments today. PMID- 23930687 TI - Evaluating learning environments for interprofessional care. AB - Many institutions have invested considerably in the provision of student facilities--lecture halls, tutorial rooms and classrooms--spaces we call collectively learning environments. In expending resources on such facilities, we have assumed that we have needed to create this range of spaces for such activities. However, how do we know we have invested wisely in support of learning for interprofessional care? In this article I review the literature to identify evidence in a range of fields, including health care, to consider the issues and difficulties of employing established approaches from practices of evidence-based design. Central in this article is the role of evidence in the assessment of learning environments. In particular, I argue that the evidence must include qualitative dimensions of the learning experience. To address the qualitative outcomes from education, with particular attention to the concerns of interprofessional education, a model is proposed to examine different levels of outcomes. By developing an interpretation of Kirkpatrick's model, four levels are described for the effective evaluation of interprofessional learning environments. PMID- 23930689 TI - Encouraging choice, serendipity and experimentation: experiences from Griffith University library (G11) extension and Gumurrii Centre. AB - The refurbishment and extension of existing university buildings is a critical consideration for many universities. This article details an architect's perspective of an innovative and collaborative design approach to transforming an existing library into a futuristic and student-centric interactive learning environment. The design is responsive to people, place, the community and the environment, due, in part, to the enhanced physical permeability of the building. Associated user-group forums comprised the end user client, the university's facilities body, the builder, lead architectural consultants, the Centre for Indigenous Students (Gumurrii Centre) and architectural sub-consultants. This article discusses five key design moves--"triangulate", "unique geometries and spaces", "learning aviary", "sky lounge" and "understanding flexibility". It goes on to discuss these elements in relation to designing spaces to enhance interprofessional education and collaboration. In summary, this article identifies how it is possible to maximise the value and characteristics of an existing library whilst creating a series of innovative spaces that offer choice, encourage serendipity and embrace experimentation. PMID- 23930690 TI - Reflecting on interprofessional education in the design of space and place: lessons from Namibia. AB - Education at the University of Namibia, School of Medicine and School of Pharmacy relies on a community-centred curriculum. The aim is to nurture "7-star" doctors and pharmacists that will address the current social and health needs within the country. A sound understanding of the interplay between learning and the learning environment is said to improve interprofessional educational activities. This relationship is dependent on constrictive alignment of not only the aspects of pedagogy, but also that of educational leadership in context of the current and social health needs. In this report, we reflect on the interprofessional-learning environment that was created out of necessity within a Namibian context. PMID- 23930691 TI - Future learning environments: the advent of a "spatial turn"? PMID- 23930693 TI - Mg2+ tunes the wettability of liquid precursors of CaCO3: toward controlling mineralization sites in hybrid materials. AB - Amorphous and liquid precursors of calcium carbonate are believed to be central species of biomineralization, which serves as an important inspiration for materials chemists in the quest for new and improved organic-inorganic hybrid materials. It has become increasingly clear that magnesium ions exhibit an important function through kinetic stabilization of the metastable precursors. We show that they additionally tune the wettability of liquid precursors of CaCO3, which is a crucial requirement for successful mineralization of proteinaceous organic matrices. Moreover, tunable wettability offers straightforward means to control mineralization sites in organic-inorganic hybrids. PMID- 23930694 TI - Distribution of antimicrobial-resistant lactic acid bacteria in natural cheese in Japan. AB - To determine and compare the extent of contamination caused by antimicrobial resistant lactic acid bacteria (LAB) in imported and domestic natural cheeses on the Japanese market, LAB were isolated using deMan, Rogosa and Sharpe (MRS) agar and MRS agar supplemented with six antimicrobials. From 38 imported and 24 Japanese cheeses, 409 LAB isolates were obtained and their antimicrobial resistance was tested. The percentage of LAB resistant to dihydrostreptomycin, erythromycin, and/or oxytetracycline isolated from imported cheeses (42.1%) was significantly higher than that of LAB resistant to dihydrostreptomycin or oxytetracycline from cheeses produced in Japan (16.7%; P=0.04). Antimicrobial resistance genes were detected in Enterococcus faecalis (tetL, tetM, and ermB; tetL and ermB; tetM) E. faecium (tetM), Lactococcus lactis (tetS), Lactobacillus (Lb.), casei/paracasei (tetM or tetW), and Lb. rhamnosus (ermB) isolated from seven imported cheeses. Moreover, these E. faecalis isolates were able to transfer antimicrobial resistance gene(s). Although antimicrobial resistance genes were not detected in any LAB isolates from Japanese cheeses, Lb. casei/paracasei and Lb. coryniformis isolates from a Japanese farm-made cheese were resistant to oxytetracycline (minimal inhibitory concentration [MIC], 32 ug/mL). Leuconostoc isolates from three Japanese farm-made cheeses were also resistant to dihydrostreptomycin (MIC, 32 to >512 ug/mL). In conclusion, the present study demonstrated contamination with antimicrobial-resistant LAB in imported and Japanese farm-made cheeses on the Japanese market, but not in Japanese commercial cheeses. PMID- 23930695 TI - Characterizing gender differences in treatment seekers. AB - BACKGROUND: Available evidence suggests women may be more vulnerable to the effects of chronic alcohol consumption than men. The few investigations of gender differences in treatment-seeking populations have often involved study samples restricted by selection criteria (e.g., age, education). The current study examined gender differences in a heterogeneous sample of individuals seeking treatment for a substance use disorder. We examined alcohol drinking levels, age at drinking milestones (e.g., first drink, first intoxication), and progression from milestones to alcohol problems or treatment. Additionally, family history, spousal alcoholism, and nicotine use were analyzed. METHODS: Participants included men (n = 274) and women (n = 257) in substance abuse treatment facilities. Participants completed inventories quantifying affect, intellectual ability, and drinking consequences. A family tree for substance use and personal histories for alcohol and nicotine use, including chronicity, frequency, and regularity, were collected. RESULTS: Telescoping was not observed when progression from drinking milestones to alcoholism or alcohol problems was compared between men and women. In contrast, when considered as progression to treatment, marked telescoping effects were detected, with women entering treatment more rapidly by approximately 4 years. Familial differences included a greater proportion of women reporting alcoholic parents (73% women; 61% men) and alcoholic spouses (58% women; 38% men). Smoking behaviors were similar between genders; however, men reporting higher levels of alcohol consumption reported greater intensity of chronic smoking. Smoking and drinking behaviors were correlated among men, but not women. Rates of pretreatment drug problems were equivalent between genders. CONCLUSIONS: When contrasted with the available literature, our data were only partially supportive of gender-contingent telescoping. While women did not experience alcohol problems or alcoholism earlier than men, they progressed to treatment more quickly. These results highlight the importance of carefully considering the sample and specific outcome variables when interpreting gender differences. PMID- 23930696 TI - Waldestrom macroglobulinaemia relapsing with focal bone disease and achieving major response with single-agent zoledronic acid. PMID- 23930697 TI - Newly developed strategies for improving sensitivity to radiation by targeting signal pathways in cancer therapy. AB - Inherent and acquired resistance of cancer cells is increasingly recognized as a significant impediment to effective radiation cancer treatment. As important intracellular factors, aberrant tumor transmembrane signal transduction pathways, which include the prosurvival cascades (PI3K/Akt, MAPK/ERK and JAK/STAT) and the proapoptosis pathways (Wnt, p53 and TNF-alpha/NF-kappaB), have been proved to be crucial determinants of the probability of cell sensitivity to radiation in malignant lesions. There is increasing evidence that targeting the abnormal pathways that can regulate the activity of the DNA damage response and further influence the response of tumor cells to radiation may be suitable for improving radiation sensitization. Preclinical and clinical evidence suggest that agents targeting aberrant tumor signals can effectively improve the therapeutic effect of ionizing radiation. Therefore, in this review, we discuss the intricate interplay between tumor responses to radiation with the aberrant signal pathways, and the potential druggable targets within the pathways to sensitize tumors without significant collateral damage to normal tissues. The application of novel targeting compounds to manipulate the aberrant signal of tumor cells in clinical treatments is also addressed. PMID- 23930698 TI - Maximized song learning of juvenile male zebra finches following BDNF expression in the HVC. AB - During song learning, vocal patterns are matched to an auditory memory acquired from a tutor, a process involving sensorimotor feedback. Song sensorimotor learning and song production of birds is controlled by a set of interconnected brain nuclei, the song control system. In male zebra finches, the beginning of the sensorimotor phase of song learning parallels an increase of the brain derived neurotrophic factor (BDNF) in just one part of the song control system, the forebrain nucleus HVC. We report here that transient BDNF-mRNA upregulation in the HVC results in a maximized copying of song syllables. Each treated bird shows motor learning to an extent similar to that of the selected best learners among untreated zebra finches. Because this result was not found following BDNF overexpression in the target areas of HVC within the song system, HVC-anchored mechanisms are limiting sensorimotor vocal learning. PMID- 23930699 TI - Repair of aorto-left ventricular and aorto-right ventricular fistulas following prosthetic valve endocarditis. AB - We report a case of a 77-year-old male who presented with an aorto-left ventricular fistula and an aorto-right ventricular fistula secondary to prosthetic valve endocarditis. PMID- 23930700 TI - Recall initiation strategies must be controlled in training studies that use immediate free recall tasks to measure the components of working memory capacity across time. AB - There has been great interest in using working memory (WM) training regimens as an alternative treatment for ADHD, but it has recently been concluded that existing training regimens may not be optimally designed because they target the primary memory component but not the secondary component of WM capacity. This conclusion requires the ability to accurately measure changes in primary and secondary memory abilities over time. The immediate free recall task has been used in previous studies to measure these changes; however, one concern with these tasks is that the recall order required on training exercises may influence the recall strategy used during free recall, which may in turn influence the relative number of items recalled from primary and secondary memory. To address this issue, previous training studies have explicitly controlled recall strategy before and after training. However, the necessity of controlling for recall strategies has not been explicitly tested. The present study investigated the effects of forward-serial-order training on free recall performance under conditions in which recall strategy was not controlled using a sample of adolescents with ADHD. Unlike when recall order was controlled, the main findings showed selective improvement of the secondary memory component (as opposed to the primary memory component) when recall order was uncontrolled. This finding advances our understanding of WM training by highlighting the importance of controlling for recall strategies when free recall tasks are used to measure changes in the primary and secondary components of WM across time. PMID- 23930701 TI - Integrating simulations and experiments to predict sheet resistance and optical transmittance in nanowire films for transparent conductors. AB - Metal nanowire films are among the most promising alternatives for next generation flexible, solution-processed transparent conductors. Breakthroughs in nanowire synthesis and processing have reported low sheet resistance (Rs <= 100 Omega/sq) and high optical transparency (%T > 90%). Comparing the merits of the various nanowires and fabrication methods is inexact, because Rs and %T depend on a variety of independent parameters including nanowire length, nanowire diameter, areal density of the nanowires and contact resistance between nanowires. In an effort to account for these fundamental parameters of nanowire thin films, this paper integrates simulations and experimental results to build a quantitatively predictive model. First, by fitting the results from simulations of quasi-2D rod networks to experimental data from well-defined nanowire films, we obtain an effective average contact resistance, which is indicative of the nanowire chemistry and processing methods. Second, this effective contact resistance is used to simulate how the sheet resistance depends on the aspect ratio (L/D) and areal density of monodisperse rods, as well as the effect of mixtures of short and long nanowires on the sheet resistance. Third, by combining our simulations of sheet resistance and an empirical diameter-dependent expression for the optical transmittance, we produced a fully calculated plot of optical transmittance versus sheet resistance. Our predictions for silver nanowires are validated by experimental results for silver nanowire films, where nanowires of L/D > 400 are required for high performance transparent conductors. In contrast to a widely used approach that employs a single percolative figure of merit, our method integrates simulation and experimental results to enable researchers to independently explore the importance of contact resistance between nanowires, as well as nanowire area fraction and arbitrary distributions in nanowire sizes. To become competitive, metal nanowire systems require a predictive tool to accelerate their design and adoption for specific applications. PMID- 23930703 TI - Toward the use of endometrial and menstrual blood mesenchymal stem cells for cell based therapies. AB - INTRODUCTION: Bone marrow is a widely used source of mesenchymal stem cells (MSCs) for cell-based therapies. Recently, endometrium - the highly regenerative lining of the uterus - and menstrual blood have been identified as more accessible sources of MSCs. These uterine MSCs include two related cell types: endometrial MSCs (eMSCs) and endometrial regenerative cells (ERCs). AREAS COVERED: The properties of eMSCs and ERCs and their application in preclinical in vitro and in vivo studies for pelvic organ prolapse, heart disorders and ischemic conditions are reviewed. Details of the first clinical Phase I and Phase II studies will be provided. EXPERT OPINION: The authors report that eMSCs and ERCs are a readily available source of adult stem cells. Both eMSCs and ERCs fulfill the key MSC criteria and have been successfully used in preclinical models to treat various diseases. Data on clinical trials are sparse. More research is needed to determine the mechanism of action of eMSCs and ERCs in these regenerative medicine models and to determine the long-term benefits and any adverse effects after their administration. PMID- 23930704 TI - Ethical decision-making challenges in clinical practice. AB - Today's health care environment requires professionals to pay increasing attention to efficiencies and functional outcomes. Today's patients are hospitalized for short stays, and those needing rehabilitation often have multiple diagnoses and goals. Cost effective strategies support fast paced occupational therapy programs and professionals who are adept multi-task specialists and problem solvers. Practitioners have multiple resources and strategies for clinical reasoning and decision-making; however, ethical decision making requires use of additional resources and strategies. This paper provides strategies to examine everyday ethical problems and dilemmas, including application of The American Occupational Therapy's Code of Ethics, to support ethical decision-making in practice settings (American Occupational Therapy Association, 2000a). PMID- 23930702 TI - The validity of clinic-based samples in approximating out-of-care HIV-infected populations. AB - Tremendous strides have been made in the diagnosis and treatment of human immunodeficiency virus (HIV); perhaps now the largest barrier to controlling HIV is retaining those diagnosed in care. Data on out-of-care populations are needed to develop effective retention methods, yet obtaining these remains methodologically challenging due to inherent difficulties in sampling. The purpose of this study was to evaluate whether individuals identified by two sampling methods commonly used to approximate out-of-care populations were significantly different from a sample of newly identified out-of-care persons. We compared medical records of 345 out-of-care persons identified by a novel population-based health information exchange who had not received CD4 or viral load monitoring in >1 year with: medical records from a randomly selected, time matched sample of 488 HIV-infected persons with at least one HIV care visit in the past 5 years, and interviews with 382 participants from a time-matched clinic based convenience sample. Newly identified out-of-care persons were significantly different from both proxies with respect to demographic, clinical, and utilization characteristics, suggesting that samples of in-care proxy persons are inadequate to describe those not engaged in care. Novel approaches to sampling out-of care populations are urgently needed in order to better understand these populations and ways to improve retention and slow the HIV/AIDS epidemic. PMID- 23930705 TI - Visual motor skills in homeless children. AB - OBJECTIVE: Identify the visual motor, visual perceptual and motor coordination skills of homeless pre-school and school-aged children living in an emergency shelter for homeless families. METHOD: All three subtests of the Developmental Test of Visual Motor Integration-4th Edition, Revised (VMI) were administered to 33 children living in a family homeless shelter. RESULTS: Homeless children did not display significant deficits in visual motor, visual perceptual or motor coordination skills. However, participants performed significantly better on the motor coordination subtest than on the visual motor and visual perceptual subtests. CONCLUSIONS: Previous literature had identified visual motor deficits in pre-school homeless children. This finding was not supported in this investigation. The significant difference in performance on the various subtests suggests that these children may benefit from external structure for paper/pencil tasks. Implications for occupational therapy services are made with suggestions for further investigations. PMID- 23930706 TI - Assistive technology for children with disabilities. AB - Through The Rehabilitation Act, the Technology Related Assistance for Individuals with Disabilities Act (The Tech Act), the Individuals with Disabilities Education Act (IDEA), and the Americans with Disabilities Act (ADA) of 1990, the federal government broadened the states' roles in increasing awareness and accessibility of assistive technology (AT) devices and services to children with disabilities. As a member of the AT team, the occupational therapy practitioner plays an integral role in selecting the most appropriate device, and working with parents and other professionals to integrate the device into a child's daily routines. This literature review presents a summary of available information on AT materials and strategies that assist infants, toddlers, and school-aged children with disabilities. We begin with a brief look at legislation affecting the provision of AT. Issues concerning the use of Electronic Aides of Daily Living (EADL), and strategies for successful manipulation are presented; followed by a discussion of play and leisure, mobility, and communication devices. Finally, we conclude with a discussion concerning the importance of measuring the effectiveness of AT devices and services. PMID- 23930707 TI - Infant massage programs may assist in decreasing parental perceived stress levels in new parents. AB - A qualitative study was conducted to determine whether there is a relationship between the perceived stress levels of new parents in interacting with their infant and the parental implementation of infant massage techniques. A sample of four new parents demonstrated decreased perceived stress levels following involvement in a month long infant massage program, indicating an enhanced perception of their individual parenting abilities. The results of the study indicate that infant massage training is an effective tool to be used in assisting parents/caregivers in the acquisition of the parenting role and the development of role related skills. PMID- 23930708 TI - The community practicum: an opportunity to synthesize learning for emerging practices. PMID- 23930710 TI - MetIDB: a publicly accessible database of predicted and experimental 1H NMR spectra of flavonoids. AB - Identification of natural compounds, especially secondary metabolites, has been hampered by the lack of easy to use and accessible reference databases. Nuclear magnetic resonance (NMR) spectroscopy is the most selective technique for identification of unknown metabolites. High quality (1)H NMR (proton nuclear magnetic resonance) spectra combined with elemental composition obtained from mass spectrometry (MS) are essential for the identification process. Here, we present MetIDB, a reference database of experimental and predicted (1)H NMR spectra of 6000 flavonoids. By incorporating the stereochemistry, intramolecular interactions, and solvent effects into the prediction model, chemical shifts and couplings were predicted with great accuracy. A user-friendly web-based interface for MetIDB has been established providing various interfaces to the data and data mining possibilities. For each compound, additional information is available comprising compound annotation, a (1)H NMR spectrum, 2D and 3D structure with correct stereochemistry, and monoisotopic mass as well as links to other web resources. The combination of chemical formula and (1)H NMR chemical shifts proved to be very efficient in metabolite identification, especially for isobaric compounds. Using this database, the process of flavonoid identification can then be significantly shortened by avoiding repetitive elucidation of already described compounds. PMID- 23930711 TI - In praise of the humanities in academic medicine. Values, metrics, and ethics in uncertain times. PMID- 23930712 TI - Effect of diet composition and lysine supply on growth and body composition in juvenile turbot (Psetta maxima). AB - A 10-week feeding trial was conducted to study the effect of feeding level and dietary lysine concentration on growth, protein and lysine retention, and body composition in juvenile turbot. Maintenance requirement for lysine and the efficiency of lysine utilisation were determined as well. Two experimental diets were formulated based on fishmeal or wheat gluten as main protein sources, containing 6.4 g (Diet A, control) and 4.5 g lysine per 100 g CP (Diet B), respectively. Diets were fed once daily at six feeding levels (per day 0.3%, 0.6%, 0.9%, 1.2%, and 1.5% of body weight [BW] and ad libitum) to a total of 432 fish of 48 g initial BW. No differences in the growth parameters were observed between diets at the same feeding level, except a lower feed to gain ratio (p < 0.05) at the highest feeding level at Diet B. Whole-body composition was not affected by diet, whereas muscle protein concentration was significantly lower for fish fed Diet B. Amino acid concentration in whole-body protein was affected by dietary treatment and fish fed Diet B showed lower concentrations of all essential amino acids. In fish muscle protein, lysine, methionine, leucine, isoleucine, and valine concentrations were significantly lower in Diet B. Efficiency of lysine utilisation for growth (klys) was determined by linear regression analysis and amounted for 0.69 for Diet B. The maintenance lysine requirement defined at zero lysine retention was 6.5 mg . kg(-0.8) . d(-1). Lysine intakes at zero protein retention were 13.0 mg and 12.9 mg . kg(-0.8) . d( 1) for Diet A and B, respectively. Growth and nutrient retention were similar for both diets and, therefore, a lysine deficiency in Diet B did not occur. In conclusion, a proportion of 330 g wheat gluten per kg feed did not influence growth performance and maintenance requirement for lysine in juvenile turbot. However, the effect of diet composition on the amino acid profile of body protein might be relevant for the derivation of the amino acid requirement from protein retention. PMID- 23930713 TI - Comparative metabolomics in Glycine max and Glycine soja under salt stress to reveal the phenotypes of their offspring. AB - Metabolomics is developing as an important functional genomics tool for understanding plant systems' response to genetic and environmental changes. Here, we characterized the metabolic changes of cultivated soybean C08 (Glycine max L. Merr) and wild soybean W05 (Glycine soja Sieb.et Zucc.) under salt stress using MS-based metabolomics, in order to reveal the phenotypes of their eight hybrid offspring (9H0086, 9H0124, 9H0391, 9H0736, 9H0380, 9H0400, 9H0434, and 9H0590). Total small molecule extracts of soybean seedling leaves were profiled by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-Fourier transform mass spectrometry (LC-FT/MS). We found that wild soybean contained higher amounts of disaccharides, sugar alcohols, and acetylated amino acids than cultivated soybean, but with lower amounts of monosaccharides, carboxylic acids, and unsaturated fatty acids. Further investigations demonstrated that the ability of soybean to tolerate salt was mainly based on synthesis of compatible solutes, induction of reactive oxygen species (ROS) scavengers, cell membrane modifications, and induction of plant hormones. On the basis of metabolic phenotype, the salt-tolerance abilities of 9H0086, 9H0124, 9H0391, 9H0736, 9H0380, 9H0400, 9H0434, and 9H0590 were discriminated. Our results demonstrated that MS-based metabolomics provides a fast and powerful approach to discriminate the salt-tolerance characteristics of soybeans. PMID- 23930714 TI - Evaluation of Coptidis Rhizoma-Euodiae Fructus couple and Zuojin products based on HPLC fingerprint chromatogram and simultaneous determination of main bioactive constituents. AB - CONTEXT: Coptidis Rhizoma-Euodiae Fructus couple (CEC) is a classic traditional Chinese medicine preparation consisting of Coptidis Rhizoma and Euodiae Fructus at the ratio of 6:1, and used to treat gastro-intestinal disorders. Alkaloids are the main bioactive component. This research provides comprehensive analysis information for the quality control of CEC. OBJECTIVE: To develop a high performance liquid chromatography-diode array detection fingerprint for chemical composition characteristics of CEC and its products. MATERIALS AND METHODS: The samples were separated with a Gemini C18 column by using gradient elution with water-formic acid (100:0.03) and acetonitrile as mobile phase. Flow rate was 1.0 mL/min and detection wavelength was 250 nm. Similarity analysis and principal component analysis (PCA) were employed to evaluate quality consistencies of analytes. Mean chromatograms and correlation coefficients of analytes were calculated by the software "Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine". RESULTS: Fingerprint chromatogram comparison determined 20 representative general fingerprint peaks, and the fingerprint chromatogram resemblances are all better than 0.988. Consistent results were obtained to show that CEC and its related samples could be successfully divided into three groups. Contribution plots generated by PCA were performed to interpret differences among the sample groups while peaks which significantly contributed to classification were identified. Seven bioactive constituents in the samples were verified by quantitative analysis. DISCUSSION AND CONCLUSION: The chromatographic fingerprint with similarity evaluation and PCA assay combined with quantification of seven compounds could be utilized as a quality control method for the herbal couple. PMID- 23930715 TI - Subphrenic hematoma after thoracoscopic discectomy: description of a very rare adverse event and review of the literature on complications: case report. AB - The authors describe a very rare and previously unreported complication of thoracoscopic discectomy. Endoscopic spine surgery has evolved as a safe and effective treatment, and thoracoscopic discectomy, in particular, provides several advantages over open approaches, although it can be associated with intraoperative or postoperative complications. The most frequently observed adverse events are intercostal neuralgia, retained disc fragments, durotomies, atelectasis, extensive bleeding, and emergency conversion to open thoracotomy for vascular injuries. Even rare complications, such as chylorrhea or brain hemorrhagic infarction, have been reported. Nonetheless, a literature review did not reveal any case of postoperative intraabdominal hematoma following thoracoscopic discectomy. A 43-year-old woman, with no history of hematological or vascular disorders or thoracic surgery, underwent a right-sided thoracoscopic discectomy for T11-12 disc herniation. No apparent surgical technique-related complications were encountered, but intermittently repeated difficulties with single-lung ventilation occurred. The resultant dysventilation allowed partial right lung reexpansion, along with increased abdominal pressure. The latter induced an upward ballooning of the right diaphragm with consequent obstruction of the surgical field of view, requiring constant and continuous pressure applied to the thoracic surface of the diaphragm via a metal fan retractor and thus counteracting the increased abdominal pressure. Postoperatively, a large subdiaphragmatic hematoma originating from a bleeding right inferior phrenic artery was diagnosed and required urgent endovascular occlusion. The patient made an uneventful recovery with conservative treatment. A very rare and previously unreported complication-that is, early subdiaphragmatic hematoma after thoracoscopic discectomy-is described here. The authors submit that conversion to an open approach is safer when persistent anesthesia-related complications are encountered in thoracoscopic discectomy. PMID- 23930716 TI - Letter to the Editor: Acute motor-sensory axonal neuropathy and Helicobacter pylori infections. PMID- 23930717 TI - Sagittal plane correction in pedicle subtraction osteotomy using the Xia 3 SUK Direct Vertebral Rotation System: technical note. AB - The Xia 3 SUK Direct Vertebral Rotation (DVR) System was developed for performing the vertebral derotation maneuver in scoliosis surgery. The author applied this device to sagittal plane correction in pedicle subtraction osteotomy for adult spinal deformity. The surgical procedure included 1) preparing secure proximal and distal foundations for correction using mutisegmental pedicle screw-rod fixation (to avoid stress concentration to a specific screw-bone interface), 2) decancellating only the posterior two-thirds of the vertebral column, 3) providing supplemental interbody fusion above and below the osteotomy site (the anterior one-third of the vertebral column and interbody cages serve as an anterior column support and a pivot of correction), 4) closing the osteotomy by gradual approximation of SUK tubes secured to the proximal- and distal-most screw heads, and 5) connecting rods between the proximal and distal screw-rod constructs. Eight consecutive patients with fixed sagittal imbalance were treated using this surgical procedure. No patient required distal fixation points extending to the sacrum and/or pelvis. The sagittal plane correction was 43 degrees . The mean anterior deviation of the C-7 plumb line was improved from 12.7 cm to 4.0 cm immediately after surgery, and it was 6.0 cm at the final follow-up. A pedicle subtraction osteotomy using the Xia 3 SUK DVR System ensures a safe and secure sagittal plane correction in adult spinal deformity. PMID- 23930718 TI - Efficacy of anterior cervical decompression and fusion procedures for monomelic amyotrophy treatment: a prospective randomized controlled trial: clinical article. AB - OBJECT: Monomelic amyotrophy (MMA) is a benign, self-limiting lower motor neuron disease. Optimal surgical strategies-discectomy decompression and fusion (DDF) or corpectomy decompression and fusion (CDF)-for patients with aggravated symptoms (within 6 months of presentation) are controversial, particularly in those who are ineligible for conventional treatment. These 2 methods of anterior cervical decompression and fusion for MMA in patients unwilling or unable to wear a conventional cervical collar long term were evaluated. METHODS: Anterior cervical decompression and fusion were performed in 48 male patients with MMA between September 2007 and September 2010. Patients were randomly treated with anterior cervical discectomy decompression with autologous iliac crest bone grafting and internal plate fixation (DDF group: 24 patients) or anterior cervical corpectomy, posterior longitudinal ligament resection, autologous iliac crest bone grafting, and internal plate fixation (CDF group: 24 patients). Subjective symptom assessments and electromyography (EMG) examinations were conducted both preoperatively and postoperatively. RESULTS: Subjective assessments and EMG studies (mean follow-up duration 25.9 months) indicated improvement in 64.6% and 60% of patients, respectively. No significant correlations between the effectiveness of surgery and age at symptom onset, preoperative symptom duration, or postoperative follow-up time were found. CONCLUSIONS: The lack of a significant difference in effectiveness between DDF and CDF favors DDF as more clinically applicable because of its lower procedural risks. As a second-line alternative to cervical collar treatment, surgical anterior cervical decompression and fusion via DDF or CDF may prevent further deterioration and produce good short-term therapeutic effects in patients with MMA; however, cervical collar treatment is recommended for eligible patients because of its lower associated risks. PMID- 23930719 TI - Biocatalysis in organic chemistry and biotechnology: past, present, and future. AB - Enzymes as catalysts in synthetic organic chemistry gained importance in the latter half of the 20th century, but nevertheless suffered from two major limitations. First, many enzymes were not accessible in large enough quantities for practical applications. The advent of recombinant DNA technology changed this dramatically in the late 1970s. Second, many enzymes showed a narrow substrate scope, often poor stereo- and/or regioselectivity and/or insufficient stability under operating conditions. With the development of directed evolution beginning in the 1990s and continuing to the present day, all of these problems can be addressed and generally solved. The present Perspective focuses on these and other developments which have popularized enzymes as part of the toolkit of synthetic organic chemists and biotechnologists. Included is a discussion of the scope and limitation of cascade reactions using enzyme mixtures in vitro and of metabolic engineering of pathways in cells as factories for the production of simple compounds such as biofuels and complex natural products. Future trends and problems are also highlighted, as is the discussion concerning biocatalysis versus nonbiological catalysis in synthetic organic chemistry. This Perspective does not constitute a comprehensive review, and therefore the author apologizes to those researchers whose work is not specifically treated here. PMID- 23930721 TI - Comparative advantage strategy for rapid pollution mitigation in China. AB - Due to its sheer size and growth trend, no other country is facing more daunting challenges than China in reducing its pollutant emissions. A critical but inadequately addressed question is how rapidly China could feasibly achieve such mitigation. The stake is high not only about how much worse China's environmental quality could become but also about how the world can prevent catastrophic climate change. Through examining sulfur dioxide (SO2) mitigation in coal-fired power plants and wind energy development for carbon dioxide (CO2) mitigation, this article proposes a comparative advantage strategy for overcoming high barriers to fast pollution mitigation. On the demand side, China could first make progress in the deployment of more pollution control facilities and then improve their operational performance. The resulting low technological market entry barriers could help to build enough industrial capacity to meet the huge demand with prices under control. The strategy in the current practice could be improved to establish not only a large supply industry but also a strong one to enable other countries to move more rapidly in pollution mitigation. PMID- 23930722 TI - The aetiology of acute gastro-enteritis in infants and young children. PMID- 23930723 TI - Parents' satisfaction with repair of paediatric cleft lip/palate in Honduras. PMID- 23930724 TI - Childhood acute non-traumatic coma: aetiology and challenges in management in resource-poor countries of Africa and Asia. AB - OBJECTIVE: This review examines the best available evidence on the aetiology of childhood acute non-traumatic coma in resource-poor countries (RPCs), discusses the challenges associated with management, and explores strategies to address them. METHODS: Publications in English and French which reported on studies on the aetiology of childhood non-traumatic coma in RPCs are reviewed. Primarily, the MEDLINE database was searched using the keywords coma, unconsciousness, causality, aetiology, child, malaria cerebral, meningitis, encephalitis, Africa, Asia, and developing countries. RESULTS: 14 records were identified for inclusion in the review. Cerebral malaria (CM) was the commonest cause of childhood coma in most of the studies conducted in Africa. Acute bacterial meningitis (ABM) was the second most common known cause of coma in seven of the African studies. Of the studies in Asia, encephalitides were the commonest cause of coma in two studies in India, and ABM was the commonest cause of coma in Pakistan. Streptococcus pneumoniae was the most commonly isolated organism in ABM. Japanese encephalitis, dengue fever and enteroviruses were the viral agents most commonly isolated. CONCLUSION: Accurate diagnosis of the aetiology of childhood coma in RPCs is complicated by overlap in clinical presentation, limited diagnostic resources, disease endemicity and co-morbidity. For improved outcomes, studies are needed to further elucidate the aetiology of childhood coma in RPCs, explore simple and practical diagnostic tools, and investigate the most appropriate specific and supportive interventions to manage and prevent infectious encephalopathies. PMID- 23930725 TI - Community-acquired infectious diarrhoea in children under 5 years of age in Dakar, Senegal. AB - BACKGROUND: In sub-Saharan Africa, infectious diarrhoea is a major cause of childhood morbidity and mortality. A cross-sectional study was undertaken to document the pathogens potentially involved in community-acquired childhood diarrhoea in Dakar, the capital of Senegal. METHODS: Between September 2007 and March 2008, 176 children aged 1 month to 5 years were recruited consecutively from a primary health care institution in an urban area. Clinical data were recorded and stool samples were collected. Bacterial pathogens were identified using conventional methods and/or PCR assays. Rotaviruses and adenoviruses were detected by a rapid immunochromatographic test. Intestinal parasites were diagnosed by microscopy. RESULTS: Rotavirus was the most common enteric pathogen, detected in 27% of patients, followed by Shigella (12%), diarrhoeagenic Escherichia coli (8%), enteric adenovirus (8%), Salmonella (4%), Campylobacter jejuni (3%) and Plesiomonas shigelloides (2%). Mixed bacterial/viral infections were detected in 6% of cases. Parasites, mostly protozoa, were detected in 14% of children. Using ipaH PCR, 30% of samples were positive for Shigella/entero invasive E. coli. Detection of rotavirus was more frequently associated with younger age groups (<24 months), whereas bacterial diarrhoea was isolated more often in children over 1 year of age. Detection of bacterial pathogens was significantly associated with malnutrition. Antibiotics were prescribed for 77% of children who attended for consultation. No pathogen was found in 36% of them, whereas a virus was detected without any other associated bacterial or parasitic pathogen in 23% of patients. CONCLUSION: In developing countries, there is a need to develop reliable, easy-to-use, inexpensive rapid diagnostic tests to guide the management of diarrhoea in infants and children and thereby prevent over-use of antimicrobial agents. PMID- 23930726 TI - A randomized controlled trial of chelated zinc for prevention of the common cold in Thai school children. AB - BACKGROUND: The common cold is responsible for the largest proportion of school and work absenteeism and is a huge economic burden. None of the currently available interventions is clearly effective for prevention or treatment. OBJECTIVE: To assess the efficacy of 15-mg chelated zinc (zinc bis-glycinate) given once a day for 3 months during the winter season to healthy school children aged 8-13 years to prevent symptoms of the common cold. METHODS: In a double blind randomized controlled trial, zinc bis-glycinate 15 mg or matching placebo once a day for 3 months was administered to healthy school children aged 8-13 years. Primary outcomes were any symptom of cold (fever, cough, rhinorrhoea) during the study period, and secondary outcomes were vomiting, diarrhoea, use of antibiotics, school absence for any reason, school absence because of a cold and duration of all symptoms. RESULTS: Of 50 children in each group, 42 (84%) in the zinc group and 41 (82%) in the placebo group (P = 1.00) developed at least one symptom of a cold. There was no difference in the incidence of fever, cough, rhinorrhoea, school absence and school absence related to the common cold compared with children in the placebo group. However, duration of cough [median (IQR) 1.0 (0.0-6.0) vs 6.0 (0.0-13.3) days], rhinorrhoea [median (IQR) 2.0 (0.0 7.0) vs 5.5 (1.0-15.3) days] and the frequency of having two or more symptoms of the common cold [median (IQR) 0.0 (0.0-1.0) vs 1.0 (0.0-5.3) days] were reduced significantly in the intervention group (P<0.01). CONCLUSIONS: Zinc bis-glycinate given in a dose of 15 mg once a day for 3 months failed to reduce the incidence of the common cold in 8 to 13-year-old school children, but decreased the number of days on which children suffered from cough, rhinorrhoea and the likelihood of having two or more symptoms of the common cold. PMID- 23930728 TI - Static skinfold thickness in African newborns as an index of fetal nutritional assessment. AB - BACKGROUND: Fetal malnutrition (FM) has grave implications for the neonate and is reliably assessed by the CANSCORE which is time-consuming. Static skinfold thickness, a measure of adiposity, is a validated method of assessing malnutrition in older children. AIM: To establish if static skinfold measurements in neonates can serve as a reliable measure of FM. OBJECTIVE: To compare static skinfold thickness measurements in neonates using the CANSCORE for the identification of FM. METHOD: 252 consecutive term neonates delivered at University College Hospital, Ibadan, Nigeria had their CANSCOREs and static skinfold thickness measured within 24 hours of delivery. Using correlation and linear regression analysis, static skinfold thickness cut-off points for FM were determined using a reference CANSCORE of <25. RESULTS: Prevalence of FM was 20.2% and 26.2% using the CANSCORE and the sum of five skinfold thickness measurements, respectively. The mean (SD) skinfold thicknesses were triceps 3.91 mm (0.74), biceps 2.84 mm (0.55), subscapular 3.79 mm (0.91), supra-iliac 2.64 mm (0.62), quadriceps 4.43 mm (1) and the sum of all measurements 17.61 mm (3.16). All the skinfold thickness measurements correlated significantly with the CANSCORE, but the sum of the five had the best correlation. The quadriceps had the highest specificity of 85.6% and lowest sensitivity of 54.9%, while the sum of all had a sensitivity of 66.7% and specificity of 84.0%. CONCLUSION: The sum of all five skinfold measurements might be a useful screening tool for FM in view of its objectivity, convenience and simplicity, but it is not sufficiently sensitive or specific to replace the CANSCORE in the identification of FM in neonates. PMID- 23930727 TI - Anaemia and malnutrition in children aged 0-59 months on the Bijagos Archipelago, Guinea-Bissau, West Africa: a cross-sectional, population-based study. AB - BACKGROUND: Childhood malnutrition is the leading risk factor for the global burden of disease. Guinea-Bissau is a politically unstable country with high levels of childhood malnutrition and mortality. AIM: To determine the nutritional status of children on three remote islands of the Bijagos Archipelago, Bubaque, Rubane and Soga, and to identify factors associated with malnutrition and anaemia in this population in order to provide a baseline for future public health interventions. METHODS: A cross-sectional, population-based, door-to-door household survey of randomly selected households was undertaken to collect data on children aged 0-59 months (n = 872). Dietary information was collected using a validated questionnaire. Anthropometric measurements were collected using World Health Organization techniques. Capillary blood samples were analysed using a Hemocue(r), with anaemia defined as Hb<11 g/dl. RESULTS: The prevalences of stunted, wasted and underweight children were 21.8%, 9.4% and 3.7%, respectively. These figures indicate moderate chronic malnutrition. The significant predictor variables for stunting were: age in months (OR 1.03), rural residence (OR 2.32), anaemia (OR 3.55) and residence on Soga island (OR 0.44). Stunting was more prevalent in males (25.4%) than in females (18.6%) (P = 0.03). The prevalence of anaemia was 80.2%. Age (OR 0.96), male gender (OR 1.81) and stunting (OR 2.87) were significant predictors. The Minimum Acceptable Diet was achieved by only 8.7% of children. CONCLUSION: The prevalence of malnutrition on the Bijagos Archipelago is less than half that on the mainland. This study is the first to determine the prevalence of anaemia in Guinea-Bissau, which, at 80.2%, is of severe public health concern. Future research should focus on the aetiology of stunting and anaemia, especially the contribution of infectious diseases and mother-child interaction. Iron supplementation should be strongly considered in this population. PMID- 23930729 TI - A comparative study of rectal tympanic and axillary thermometry in febrile children under 5 years of age in Nigeria. AB - BACKGROUND: Fever alone accounts for over 25% of paediatric emergency room consultations. Accurate determination of temperature is critical for the management of sick children by both parents and health care-providers. AIMS AND OBJECTIVES: To compare simultaneous measurements of temperature measured by the rectal, axillary, and tympanic routes in children under 5 admitted to the University of Ilorin Teaching Hospital. METHODS: 400 children under 5 years of age with a rectal temperature of >= 38.0 degrees C were recruited consecutively into the study. Rectal and axillary temperatures were measured using digital thermometers. Tympanic measurements were undertaken with an infrared tympanic thermometer. All measurements were made simultaneously and compared. RESULTS: Mean (SD) rectal temperature was 38.8 (0.7) degrees C, and mean (SD) tympanic and axillary temperatures were 38.7 (0.7) degrees C and 38.1 (0.7) degrees C, respectively. There was no significant difference between rectal and tympanic temperatures (P = 0.14), and a strong correlation was identified between values from these two sites (r = 0.91). At 91.5%, the sensitivity of tympanic thermometry in determining fever was higher than that of axillary measurements (54.0%). A mathematical relationship was demonstrated between rectal/tympanic temperatures and between rectal/axillary temperatures as follows: Rectal temperature ( degrees C) = 6.03+0.85 * Mean tympanic temperature ( degrees C) Rectal temperature ( degrees C) = 11.7+0.71 * Axillary temperature ( degrees C) Conclusion: In febrile children, tympanic temperature better reflects rectal temperature than does axillary temperature; tympanic temperature should therefore be measured when there are no contra-indications for its use. PMID- 23930730 TI - Parents' satisfaction with repair of paediatric cleft lip/cleft palate in Honduras. AB - BACKGROUND: Operation Smile is a non-profit organization that provides free cleft lip and cleft palate repair to impoverished children worldwide. To date, no longitudinal studies of satisfaction among these patients or their families have been published. OBJECTIVES: In a cohort of parents of children receiving cleft lip/cleft palate repair, to assess parental satisfaction and fulfillment of expectations. METHODS: A prospective cohort study with pre-operative and 6-month post-operative interviews of parents of 45 patients of the Operation Smile mission in Tegucigalpa, Honduras, 2007 was undertaken. Patients were recruited from a total of 96 who underwent surgery, with follow-up data available for 22 of them (49% of participants). Pre-operative interviews concerned expectations regarding surgery, and post-operative interviews addressed surgical outcomes and satisfaction. RESULTS: Mean patient age was 4 years (range 3 months to 17 years); 51% underwent isolated cleft lip repair, and 49% cleft palate repair. This was the first surgery for 53%, the remainder having had previous surgery on one to six occasions. Pre-operatively, parents expressed expectations that speech (n = 26), appearance (n = 21) or feeding (n = 17) would improve. Among the 22 re interviewed 6 months after surgery, two had experienced minor and one major post operative complications. Only 14 of 22 had all their pre-operative expectations fulfilled. All except one parent reported satisfaction with the surgery. CONCLUSION: Despite unmet expectations, parents of children who received medical mission surgery for cleft lip or cleft palate express satisfaction with outcomes. Other factors are likely to influence expressions of satisfaction in this setting. PMID- 23930731 TI - Clinical spectrum of incomplete Kawasaki disease in Thailand. AB - BACKGROUND: Inadequate diagnostic criteria in incomplete Kawasaki disease (KD) patients may lead to misdiagnosis and delayed treatment. However, the risk of coronary artery aneurysm in these patients remains uncertain. AIM: To investigate differences in clinical, laboratory and echocardiographic variables between patients with incomplete KD and classic KD. METHOD: The medical records of 208 KD patients treated between January 2001 and December 2009 in the Department of Pediatrics, Chiang Mai University Hospital were reviewed retrospectively. Patients with three or fewer major criteria were defined as having incomplete KD. RESULTS: Of the 208 KD patients, 61 (29%) had incomplete KD. In those with incomplete KD, a significantly higher proportion were male (73.8% vs 59.2%, P = 0.03), the diagnosis was made later [mean (SD) day 9.0 (4.2) vs 7.2 (2.5), P = 0.003], there was a higher rate of delayed diagnosis (>10 days, 21% vs 10%, P = 0.02) and the presence of five major criteria was less common. The proportion of associated symptoms (irritability, upper respiratory tract symptoms, diarrhoea, vomiting and reactivation of BCG) and laboratory findings (pyuria, haemoglobin level, white blood count, polymorphonuclear cells, platelet count, erythrocyte sedimentation rate and serum albumin) were comparable in patients with incomplete KD and classic KD. The incomplete KD group tended to have a higher proportion of coronary artery abnormalities but the difference was not statistically significant (38% vs 25%, P = 0.09). However, a significantly greater proportion of the group with incomplete KD had large aneurysms (10% vs 1%, P = 0.009). CONCLUSIONS: Incomplete KD and classic KD have the same disease spectrum. Owing to the absence of some major criteria, incomplete KD can be more difficult to diagnose, which can result in delayed diagnosis and a greater risk of large coronary aneurysms. PMID- 23930733 TI - Isolated tuberculous liver abscess in a 3-year-old immunocompetent child. AB - Tuberculous liver abscess without active pulmonary or miliary tuberculosis or other clinical evidence of tuberculosis, is very rare. A 3-year-old immunocompetent boy with isolated tuberculous liver abscess recovered completely on systemic anti-tuberculous drugs. PMID- 23930732 TI - How well do mothers in Ghana understand why their newborn is hospitalized? AB - BACKGROUND: Maternal knowledge about serious infant illnesses has significant implications for care after discharge, particularly in countries with high infant mortality rates. No existing studies on this topic in low-income countries were identified. The study sought to identify the level of maternal understanding about why a newborn was hospitalized and how mothers in Ghana attributed blame for the illness. METHODS: The project team conducted semi-structured interviews with mothers aged 18 and older who had infants hospitalized in a tertiary care facility in Kumasi, Ghana, and collected data on demographics, pregnancy and delivery, and beliefs about their infant's illness. Infant charts were abstracted to identify medical reasons for hospitalization for comparison with the mother's understanding, and levels of understanding were coded as 'none', 'partial' or 'full'. RESULTS: 153 mothers were interviewed and their average age was 28. For 27%, this was their first pregnancy. Forty per cent of mothers had no understanding of why their infant was in the hospital and 28% had only partial understanding. One-third of the women reported blaming themselves for the child's illness. In multivariable analysis, demographic factors including maternal age, education, primiparous status, and urban vs rural residence did not predict maternal understanding or self-blame. CONCLUSIONS: Sick newborns in low-income countries are at very high risk of adverse outcomes. Mothers who lack a clear understanding of why their infant is in the hospital might have difficulty communicating preferences about care, understanding the type of care that is being given, and recognizing future warning signs of illness. Such gaps in understanding could put the discharged infant at significant risk. PMID- 23930734 TI - Co-existence of acute transverse myelitis and Guillain-Barre syndrome associated with Bartonella henselae infection. AB - Cat scratch disease (CSD) is a benign, self-limiting condition associated with Bartonella henselae. Neurological manifestations are uncommon. Acute transverse myelitis and Guillain-Barre syndrome have been reported rarely with CSD. This report describes a 12-year-old boy with acute transverse myelitis and Guillain Barre syndrome associated with CSD. PMID- 23930735 TI - Shewanella putrefaciens bacteraemia associated with terminal ileitis. AB - Shewanella putrefaciens has a wide geographical distribution, including sea- and fresh water, fish and soil, but it is an unusual pathogen in humans. A previously healthy boy without known immunodeficiency presented with fever, abdominal pain and diarrhoea, and a mass in the right lower quadrant. Terminal ileitis was confirmed by MRI and Shewanella putrefaciens was isolated from two separate blood cultures. This is the first report of terminal ileitis associated with Shewanella putrefaciens septicaemia. PMID- 23930736 TI - Bayley-II or Bayley-III: what do the scores tell us? PMID- 23930737 TI - Unusual cause of intraoperative hemoptysis. AB - We present a rare complication of sternotomy wire removal in a patient with history of coronary artery bypass graft four years prior now undergoing redo sternotomy for aortic valve replacement. Upon removal of the third sternotomy wire the patient experienced hemoptysis from intrapulmonary hemorrhage, requiring that the procedure be aborted; careful review of preoperative computed tomography (CT) demonstrated this sternotomy wire to be traversing through lung parenchyma. PMID- 23930738 TI - Responsive multidomain free-standing films of gold nanoparticles assembled by DNA directed layer-by-layer approach. AB - Responsive free-standing films of gold nanoparticles are fabricated by a new approach combining the programmable DNA-directed self-assembly and the layer-by layer (LbL) thin film fabrication technique. This approach allows for the assembly of multidomain nanoparticle films with each domain possessing distinct properties in response to external stimuli, which is essential for the formation of dynamic nanostructures. Large area free-standing films of DNA-modified gold particles are fabricated by the selective melting of a sacrificial nanoparticle domain, taking advantage of the unique sharp melting transition of DNA-modified gold nanoparticles. Furthermore, we show that released multidomain films can be designed to further split into multiple intact daughter films in a precisely controlled manner, demonstrating that this new approach provides a powerful means to fabricate free-standing nanoparticle films that are capable of programmable transformation. PMID- 23930739 TI - Left ventricular mass and hypertrophy by echocardiography and cardiac magnetic resonance: the multi-ethnic study of atherosclerosis. AB - BACKGROUND: Left ventricular mass (LVM) and hypertrophy (LVH) are important parameters, but their use is surrounded by controversies. We compare LVM by echocardiography and cardiac magnetic resonance (CMR), investigating reproducibility aspects and the effect of echocardiography image quality. We also compare indexing methods within and between imaging modalities for classification of LVH and cardiovascular risk. METHODS: Multi-Ethnic Study of Atherosclerosis enrolled 880 participants in Baltimore city, 146 had echocardiograms and CMR on the same day. LVM was then assessed using standard techniques. Echocardiography image quality was rated (good/limited) according to the parasternal view. LVH was defined after indexing LVM to body surface area, height(1.7) , height(2.7) , or by the predicted LVM from a reference group. Participants were classified for cardiovascular risk according to Framingham score. Pearson's correlation, Bland Altman plots, percent agreement, and kappa coefficient assessed agreement within and between modalities. RESULTS: Left ventricular mass by echocardiography (140 +/- 40 g) and by CMR were correlated (r = 0.8, P < 0.001) regardless of the echocardiography image quality. The reproducibility profile had strong correlations and agreement for both modalities. Image quality groups had similar characteristics; those with good images compared to CMR slightly superiorly. The prevalence of LVH tended to be higher with higher cardiovascular risk. The agreement for LVH between imaging modalities ranged from 77% to 98% and the kappa coefficient from 0.10 to 0.76. CONCLUSIONS: Echocardiography has a reliable performance for LVM assessment and classification of LVH, with limited influence of image quality. Echocardiography and CMR differ in the assessment of LVH, and additional differences rise from the indexing methods. PMID- 23930741 TI - Proximal bacterial lysis and detection in nanoliter wells using electrochemistry. AB - Rapid and direct genetic analysis of low numbers of bacteria using chip-based sensors is limited by the slow diffusion of mRNA molecules. Long incubation times are required in dilute solutions in order to collect a sufficient number of molecules at the sensor surface to generate a detectable signal. To overcome this barrier here we present an integrated device that leverages electrochemistry driven lysis less than 50 MUm away from electrochemical nucleic acid sensors to overcome this barrier. Released intracellular mRNA can diffuse the short distance to the sensors within minutes, enabling rapid and sensitive detection. We validate this strategy through direct lysis and detection of E. coli mRNA at concentrations as low as 0.4 CFU/MUL in 2 min, a clinically relevant combination of speed and sensitivity for a sample-to-answer molecular analysis approach. PMID- 23930740 TI - Long-term depression of synaptic transmission in the adult mouse insular cortex in vitro. AB - The insular cortex (IC) is known to play important roles in higher brain functions such as memory and pain. Activity-dependent long-term depression (LTD) is a major form of synaptic plasticity related to memory and chronic pain. Previous studies of LTD have mainly focused on the hippocampus, and no study in the IC has been reported. In this study, using a 64-channel recording system, we show for the first time that repetitive low-frequency stimulation (LFS) can elicit frequency-dependent LTD of glutamate receptor-mediated excitatory synaptic transmission in both superficial and deep layers of the IC of adult mice. The induction of LTD in the IC required activation of the N-methyl-d-aspartate (NMDA) receptor, metabotropic glutamate receptor (mGluR)5, and L-type voltage-gated calcium channel. Protein phosphatase 1/2A and endocannabinoid signaling are also critical for the induction of LTD. In contrast, inhibiting protein kinase C, protein kinase A, protein kinase Mzeta or calcium/calmodulin-dependent protein kinase II did not affect LFS-evoked LTD in the IC. Bath application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine produced another form of LTD in the IC, which was NMDA receptor-independent and could not be occluded by LFS induced LTD. Our studies have characterised the basic mechanisms of LTD in the IC at the network level, and suggest that two different forms of LTD may co-exist in the same population of IC synapses. PMID- 23930742 TI - Evolving research in the geriatric neuropsychiatry of stroke. PMID- 23930743 TI - Prevention of poststroke apathy using escitalopram or problem-solving therapy. AB - OBJECTIVE: Apathy occurs frequently following stroke and prior studies have demonstrated the negative effect of apathy on recovery from stroke. This study was a secondary analysis examining the efficacy of escitalopram, problem-solving therapy (PST), or placebo administered for 1 year to prevent the onset of apathy among patients with recent stroke. METHODS: Patients within 3 months of an index stroke who did not meet DSM-IV diagnostic criteria for major or minor depression and who did not have a serious comorbid physical illness were enrolled. Patients were recruited from three sites: University of Iowa, University of Chicago, and Burke Rehabilitation Hospital. One hundred fifty-four patients without evidence of apathy at initial evaluation were included in the randomized controlled trial using escitalopram (10 mg patients <=65 years; 5 mg patients >65 years) (N = 51) or placebo (N = 47) or non-blinded PST (12 total sessions) (N = 56) over 1 year. At 3, 6, 9, and 12 months, patients were assessed for diagnosis and severity of apathy using the Apathy Scale. RESULTS: Using a Cox proportional hazards model of time to onset of apathy, participants given placebo were 3.47 times more likely to develop apathy than patients given escitalopram and 1.84 times more likely to develop apathy than patients given PST after controlling for age, sex, cognitive impairment, and diabetes mellitus status (adjusted hazard ratio: 3.47, 95% CI: 1.79-6.73 [escitalopram group]; adjusted hazard ratio: 1.84, 95% CI: 1.21-2.80 [PST group]). CONCLUSION: Escitalopram or PST was significantly more effective in preventing new onset of apathy following stroke compared with placebo. PMID- 23930744 TI - Economic costs and quality of life in chronic inflammatory neuropathies in southeast England. AB - BACKGROUND AND PURPOSE: Cost-of-illness studies and health-related quality of life (HRQoL) measurements are needed to assess the effects of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN) and paraproteinaemic demyelinating neuropathy (PDN) on society. METHODS: This study was conducted in 2008 in a southeast England population of 3,557,352 people. Data on service use and treatment were collected with a client service receipt inventory and service costs were calculated by combining these data with national unit costs. The EuroQol was used to calculate utility scores, a measurement of HRQoL. RESULTS: The total annual cost-of-illness per patient was L22,085 for CIDP, L22,812 for MMN and L7566 for PDN. The annual total cost per patient was L49,430 for individuals on intravenous immunoglobulin (IVIg) and L9046 for those not on IVIg (P < 0.01). The mean (SD) utility scores were 0.62 (0.23) for CIDP, 0.63 (0.22) for PDN and 0.72 (0.14) for MMN (P = 0.52). The mean (SD) utility score for those on IVIg was 0.65 (0.16) and those not on IVIg 0.63 (0.23) (P = 0.77). CONCLUSION: The use of IVIg was the most important determinant of cost in all three diseases and the higher frequency of its use in CIDP and MMN accounted for the much greater average cost per patient in these diseases. There was no significant difference in HRQoL amongst the three diseases or between those receiving or not receiving IVIg. PMID- 23930745 TI - Syntheses and structural characterizations of inorganic ansa-metallocene analogues: ansa-ferratricarbadecaboranes. AB - New linked cyclopentadienyl-tricarbadecaboranyl and bis-tricarbadecaboranyl dianions have been used to form the first examples of ansa metallatricarbadecaboranyl complexes. The hybrid cyclopentadienyl tricarbadecaboranyl dianion, Li2(+)[6-C5H4-(CH2)2-nido-5,6,9-C3B7H9](2-) (1), was produced by an initial carbon-insertion reaction of a nitrile-substituted cyclopentadiene with the arachno-4,6-C2B7H12(-) anion, followed by deprotonation to the dianion with LiH. The linked-cage bis-tricarbadecaboranyl dianion, Li2(+)[6,6'-(CH2)2-nido-(5,6,9-C3B7H9)2](2-) (2), was produced by a similar carbon-insertion route involving the reaction of two equivalents of arachno-4,6 C2B7H12(-) with succinonitrile. The reaction of 1 with an equivalent of FeCl2 produced the hybrid complex, ansa-(2-(CH2)2)-(1-eta(5)-C5H4-closo-1,2,3,4 C3B7H9)Fe (3), with a crystallographic determination confirming the formation of a sandwich structure where the ring and cage are linked by the ansa -CH2CH2- group with attachment to the cage at the C2 carbon. The reaction of 2 with FeCl2 produced three isomeric ansa-(CH2)2-ferrabistricarbadecaboranyl sandwich complexes, ansa-(CH2)2-(closo-C3B7H9)2Fe (4, 5 and 6). Crystallographic determinations showed that in 4, the two tricarbadecaboranyl ligands are linked by the ansa-CH2CH2- group at the C2 and C2' cage carbons, whereas in 5 and 6 they are linked at their C2 and C4' carbons, with the structures of 5 and 6 differing in the relative positions of the C4' carbons in the two cages of each complex. The structural determinations also showed that, depending upon the linking position of the ansa-tether, constraints in cage-orientation, such as observed in 4, produce unfavorable intercage steric interactions. However, the cage fragments in these complexes can readily undergo a cage-carbon migration that moves one carbon and its tether linkage to the more favorable 4-position. This isomerization reduces the cage steric interactions and produces configurations, such as those found for 5 and 6, where the iron cage bonding is enhanced as a result of the binding effect of the tether. PMID- 23930746 TI - Predictors of sun-related behaviors among young women: comparisons between outdoor tanners, fake tanners, and tan avoiders. AB - OBJECTIVE: Skin cancer incidence continues to rise as a tanned appearance remains desirable, particularly among young women. Fake tanning provides a tanned appearance without exposure to ultraviolet radiation. In order to advance our understanding of the factors that contribute to long-term behavior change, this study explores determinants associated with different types of tanning. PARTICIPANTS: The sample included 162 female students from the University of Adelaide, Australia, aged 18-26 years. Data were collected in July 2010. METHODS: The current study measured differences in skin type, skin cancer knowledge, unrealistic optimism, appearance motivation, and sun-protective and sun exposure behaviors amongst outdoor tanners, fake tanners, and tan avoiders through an online survey. RESULTS: Differences were observed for skin type, skin cancer knowledge, unrealistic optimism, sun protection, and sun exposure. CONCLUSIONS: A "one-size-fits-all" approach to skin cancer prevention may not be appropriate; type of tanning behavior may need to be considered in health promotion work. PMID- 23930747 TI - The slope of change: an environmental management approach to reduce drinking on a day of celebration at a US college. AB - OBJECTIVE: This research extends the literature on event-specific environmental management with a case study evaluation of an intervention designed to reduce student drinking at a university's year-end celebration. PARTICIPANTS: Cornell University undergraduates were surveyed each May from 2001 through 2009. Sample sizes ranged from 322 to 1,973. METHODS: Randomly sampled surveys were conducted after a large, annual spring campus celebration. An environmental management plan was initiated in 2003 that included increased enforcement of the minimum legal drinking age (MLDA) law. RESULTS: In the short term, drinking at the campus celebration decreased while drinking before the event increased. Over time, the intervention significantly reduced high-risk drinking on the day of the event, especially among those under the age of 21. CONCLUSION: These findings are contrary to the argument that enforcement of MLDA laws simply leads to increased high-risk drinking, and therefore have implications for how colleges approach the challenge of student alcohol misuse. PMID- 23930748 TI - Human papillomavirus vaccine stages of change among male and female university students: ready or not? AB - OBJECTIVE: To examine gender differences in human papillomavirus (HPV) vaccine stages of change following the recommendations for permissive use of HPV vaccine in males. PARTICIPANTS: Students aged 18-26 attending a large, public, Midwest university in April 2010. METHODS: Participants completed a self-administered, online questionnaire. HPV vaccine stage of change was assessed according to core constructs of the Transtheoretical Model of Behavior Change. Logistic regression was used to identify associations of HPV-related beliefs and attitudes with stage of change. RESULTS: Although most (80.5%) of the 4,019 participants had at least contemplated HPV vaccination, more females had taken observable steps towards vaccination. Significant differences between genders in HPV-related beliefs and attitudes were observed, particularly perceived parental or perceived health care provider approval of HPV vaccination. CONCLUSIONS: University students generally agreed with the benefits of HPV vaccination, both for themselves and for society, and these attitudes were significantly associated with having at least contemplated vaccination. PMID- 23930750 TI - Knowledge and attitudes toward hookah usage among university students. AB - OBJECTIVE: Hookah smoking is a popular form of tobacco use on university campuses. This study documented use, attitudes, and knowledge of hookah smoking among college students. PARTICIPANTS: The sample included 943 university students recruited between February 2009 and January 2010. Respondents (M age = 20.02) included 376 males, 533 females, and 34 who did not report sex. METHODS: An anonymous online questionnaire was completed by respondents. RESULTS: In this sample, 42.9% of college students had tried hookah, and 40% of those individuals had used it in the past 30 days. Students perceived fewer negative consequences of hookah smoking compared with cigarette smoking. Age, sex, racial background, marijuana/cigarette use, and perceptions of side effects were significantly associated with hookah use. CONCLUSIONS: University students are misinformed regarding the health consequences of hookah smoking. Programs aimed at education, prevention, and intervention for hookah use are needed to address this growing public health concern. PMID- 23930749 TI - Examining the efficacy of a brief mindfulness-based stress reduction (Brief MBSR) program on psychological health. AB - OBJECTIVE: The purpose of the study was to examine potential psychological health benefits of participating in a brief (5-week) mindfulness-based stress reduction (brief MBSR) program integrated into an academic course. PARTICIPANTS: Participants were 119 undergraduate students (treatment: n = 72; control: n = 47) enrolled in elective academic courses on addictive behaviors, between January 2010 and May 2012. METHODS: This study employed a quasi-experimental pretest/posttest design comparing changes in psychological health between brief MBSR treatment and parallel control groups. Baseline and follow-up data were collected synchronously across semesters for both groups. RESULTS: Analysis of covariance revealed significant improvements in psychological health, measured by mindfulness (Philadelphia Mindfulness Scale: p <= .001; Kentucky Inventory of Mindfulness Scale: p <= .001) and self-compassion (Self-compassion Scale: p <= .001), among brief MBSR participants compared with the parallel control cohort. Significant reductions in trait anxiety were not evident. CONCLUSIONS: Brief MBSR programs can improve psychological health; however, longer MBSR programs may be needed to improve psychological distress, such as trait anxiety. PMID- 23930751 TI - Mindfulness and alcohol problems in college students: the mediating effects of stress. AB - OBJECTIVE: To examine the relationship between mindfulness and alcohol problems in college students, as well as the role of stress as a mediator in this relationship. PARTICIPANTS: Participants were 310 students from a small, private college in the Northeast. METHODS: Students completed self-report measures, including the Perceived Stress Scale, the Five Facet Mindfulness Questionnaire, and the Rutgers Alcohol Problems Index. RESULTS: Mindfulness was negatively correlated with alcohol problems and stress, whereas stress positively correlated with alcohol problems. Results implicated stress as fully mediating the relationship between mindfulness and alcohol problems. Alcohol problems were negatively correlated with the Acting With Awareness and Describing Experience facets of mindfulness. CONCLUSION: Mindfulness-based stress reduction or other mindfulness programs may be useful in decreasing alcohol problems on college campuses via the effects on stress. PMID- 23930752 TI - ACHS Guidelines. Standards for student health insurance coverage. PMID- 23930753 TI - Infection of chickens with antimicrobial-resistant Salmonella enterica Typhimurium DT193 and monophasic Salmonella Typhimurium-like variants: an emerging risk to the poultry industry? AB - Antimicrobial-resistant Salmonella enterica poses a particular risk to public health, and in particular isolates belonging to clonal lineages such as Salmonella Typhimurium DT104 cause epidemics across species including poultry. In recent years, antimicrobial-resistant S. Typhimurium DT193 and specifically the monophasic S. Typhimurium-like variants of this phage type, serotypes 4,12:i:- and 4,5,12:i:-, have become an increasing risk to public health in Europe and the USA and now account for nearly one-half of human S. Typhimurium infections in the UK. Unlike S. Typhimurium that possesses two forms of flagella which can vary between phase 1 and phase 2 during infection, monophasic variants possess only phase 1 flagella. These monophasic antimicrobial-resistant variants have become a major problem in pig production but human cases have also been associated with poultry consumption and have been found in UK flocks through surveillance schemes since 2010. In this study we determined the ability of antimicrobial-resistant DT193 serotype 4,12:i:- and 4,5,12:i:- isolates from pigs to infect chickens. All isolates were found to colonize the caeca and liver. All but one isolate of serotype 4,5,12:i:- also infected the spleen. Levels of infection and pathology were comparable with those found with the virulent S. Typhimurium isolate 4/74. These findings indicate that both S. Typhimurium DT193 and monophasic variants of this phage type usually associated with pigs are capable of colonizing the chicken. This shows that both S. Typhimurium DT193 and monophasic variants represent a significant and potential emerging threat to poultry production from "spill-over" of these isolates from the pig industry or other sources. PMID- 23930754 TI - Targeted therapy for NSCLC with driver mutations. AB - INTRODUCTION: Activating mutations of the epidermal growth factor receptor (EGFR) gene and rearrangement of anaplastic lymphoma kinase (ALK) gene best illustrate the therapeutic relevance of molecular characterization in non-small cell lung cancer (NSCLC) patients. Several genetic aberrations with a potential prognostic or predictive role have been identified, mainly in adenocarcinoma subtype, including ROS1, RET, MET, HER2, BRAF and KRAS. More recently oncogenic drivers, such as DDR2, FGFR1 and PI3KCA, have been characterized in squamous cell lung carcinoma (SCC) and target agents are currently under evaluation. The aim of this review is to summarize the growing scenario of new targetable oncogenes in NSCLC. AREAS COVERED: For this review article all published data on NSCLC genomic alterations, including the techniques employed for oncogenic drivers identification, the prevalence of each one in lung cancer subtypes, the preclinical data corroborating their role in tumorigenesis and the potential biological tailored agents tested and under evaluation were collected and analyzed using PubMed. EXPERT OPINION: Oncogenic products represent reliable targets for drug therapy and the expanding knowledge of molecular pathways involved in lung tumorigenesis is resulting in a dramatic change of treatment strategies leading to an improvement in disease and symptom control, extending life duration and improving quality of life. PMID- 23930755 TI - Cardiovascular and electroencephalographic responses to purposeful versus nonpurposeful activities in children. AB - To discern effects of purposefulness on cardiovascular and neural responses, heart rate and electroencephalographic recordings were taken in 31 children performing purposeful and nonpurposeful activities of equal duration and cardiopulmonary workload. Heart rate increased from resting levels during both purposeful (p = .001) and nonpurposeful (p = .01) activities, but the level of increase was the same for both (p = .30). Similarities in heart rate during purposeful and nonpurposeful activities suggest that purposefulness might not influence heart rate response in children. Encephalographic recordings did not show a higher beta-wave activity quotient during purposeful activity (p = .33). PMID- 23930756 TI - Cardiovascular and Electroencephalographic Response to Purposeful vs. Nonpurposeful Activity in Adults (?). AB - eEffects of purposefulness on heart rate, blood pressure, and electroencephalographic recordings were examined in 32 adults performing purposeful and nonpurposeful activities of equal cardiopulmonary workload. Blood pressure increased from resting during purposeful and nonpurposeful activity (all p < .02); the level of increase was similar for purposeful and nonpurposeful activity [systolic (p = .44); diastolic (p = .25)]. No significant differences in heart rate (p = .42) or electroencephalographic beta wave activity (p = .39) were noted between purposeful and nonpurposeful activities. These findings suggest that the degree of purposefulness of the activity did not influence the cardiovascular response. PMID- 23930757 TI - Using journal clubs to promote skills for evidence-based practice. AB - Occupational therapy students in Pittsburgh, Pennsylvania, participated in a 9 week journal club experience within an evidence-based practice course. Working in groups of seven, students were provided with an overall framework to develop and conduct weekly journal club sessions. They determined the focus and direction for their journal club section, decided on the number, type, and focus of research articles that were discussed each week, created methods for evaluating individual and group performance, and determined the effect of the journal club experience on their knowledge and professional behavior. Students completed a weekly reflective journal and at the conclusion of the course, results were uniformly positive. Review of the reflexive journals indicated substantive changes in the students' professional development, commitment to evidence-based practice, and perceived responsibility to demonstrate leadership in this area. PMID- 23930758 TI - To assert or not to assert: conflict management and occupational therapy students. AB - As occupational therapists prepare to fulfill the vision of the profession and face the challenges of this century, asserting themselves professionally and effectively collaborating with others is of critical importance. The conflict resolution behaviors used to manage current and future practice environments have significant implications for job retention, work climate, patient care and the development of professional relationships. The literature suggests that occupational therapy students tend to use unassertive forms of conflict management. In an effort to identify potential inconsistencies between students' tendencies and professional demands, this study examined the conflict resolution behaviors that graduate, traditional, and nontraditional occupational therapy students, are likely to use (n = 145). The design of the study was descriptive and correlational. The Thomas Kilmann's MODE instrument and a Conflict Case questionnaire were used as measures of the conflict resolution styles. Results indicated that traditional students favored collaborating while nontraditional students preferred competing and avoiding. The management strategies used by the two groups differed based on the outcome focus and the power relationship between disputants. Findings are relevant for occupational therapy education and continuing professional development. Training in conflict management strategies that would strengthen students' assertiveness and interpersonal skills would be helpful in fostering the leadership needed for fulfilling the profession's vision. PMID- 23930760 TI - Jewish perspectives on theology and the human experience of disability. PMID- 23930761 TI - Atlas of anatomy: general anatomy and musculoskeletal system. PMID- 23930762 TI - Developing occupation-centered programs for the community. PMID- 23930765 TI - Kinesiology for occupational therapy. PMID- 23930766 TI - Occupational Therapy with Children: Understanding Children's Occupations and Enabling Participation. PMID- 23930767 TI - Enhancing human occupation through hippotherapy: a guide for occupational therapy. PMID- 23930768 TI - Driver rehabilitation and community mobility principles and practice. PMID- 23930769 TI - Occupations and activities from clay to computers: theory and practice. PMID- 23930771 TI - A systematic review of vitamin D status in populations worldwide. AB - Vitamin D deficiency is associated with osteoporosis and is thought to increase the risk of cancer and CVD. Despite these numerous potential health effects, data on vitamin D status at the population level and within key subgroups are limited. The aims of the present study were to examine patterns of 25-hydroxyvitamin D (25(OH)D) levels worldwide and to assess differences by age, sex and region. In a systematic literature review using the Medline and EMBASE databases, we identified 195 studies conducted in forty-four countries involving more than 168 000 participants. Mean population-level 25(OH)D values varied considerably across the studies (range 4.9-136.2 nmol/l), with 37.3 % of the studies reporting mean values below 50 nmol/l. The highest 25(OH)D values were observed in North America. Although age-related differences were observed in the Asia/Pacific and Middle East/Africa regions, they were not observed elsewhere and sex-related differences were not observed in any region. Substantial heterogeneity between the studies precluded drawing conclusions on overall vitamin D status at the population level. Exploratory analyses, however, suggested that newborns and institutionalised elderly from several regions worldwide appeared to be at a generally higher risk of exhibiting lower 25(OH)D values. Substantial details on worldwide patterns of vitamin D status at the population level and within key subgroups are needed to inform public health policy development to reduce risk for potential health consequences of an inadequate vitamin D status. PMID- 23930772 TI - Cross-sectional neck response of a total human body FE model during simulated frontal and side automobile impacts. AB - Human body finite element (FE) models are beginning to play a more prevalent role in the advancement of automotive safety. A methodology has been developed to evaluate neck response at multiple levels in a human body FE model during simulated automotive impacts. Three different impact scenarios were simulated: a frontal impact of a belted driver with airbag deployment, a frontal impact of a belted passenger without airbag deployment and an unbelted side impact sled test. Cross sections were created at each vertebral level of the cervical spine to calculate the force and moment contributions of different anatomical components of the neck. Adjacent level axial force ratios varied between 0.74 and 1.11 and adjacent level bending moment ratios between 0.55 and 1.15. The present technique is ideal for comparing neck forces and moments to existing injury threshold values, calculating injury criteria and for better understanding the biomechanical mechanisms of neck injury and load sharing during sub-injurious and injurious loading. PMID- 23930773 TI - Step-scan IR spectroelectrochemistry with ultramicroelectrodes: nonsurface enhanced detection of near femtomole quantities using synchrotron radiation. AB - The result of interfacing step-scan spectroelectrochemistry with an IR microscope and synchrotron infrared (SIR) radiation is provided here. An external reflectance cell containing a 25 MUm gold ultramicroelectrode is employed to achieve an electrochemical time constant less than one microsecond. The use of a prototypical electrochemical system, i.e., the mass-transport controlled reduction of ferricyanide, allows for a proof of principle evaluation of the viability of SIR for step-scan spectroelectrochemistry. An analysis of the importance of accounting for synchrotron source variation over the prolonged duration of a step-scan experiment is provided. Modeling of the material flux in the restricted diffusion space afforded by the external reflectance cell allows the quantitative IR results to be compared to theoretical predictions. The results indicate that only at very short times does linear diffusion within the cavity dominate the electrode response and the majority of the transient signal operates under conditions of quasi-hemispherical diffusion. The analytical information provided by the IR signal is found to be considerably less than that derived from the current response due the latter's pronounced edge effects. The results provide a detection limit of 36 fmol for step-scan SIR measurements of ferrocyanide. Implications for future IR spectroelectrochemical studies in the microsecond domain are discussed. PMID- 23930774 TI - On first reading Emmanuel Levinas. PMID- 23930775 TI - A novel bioactivity of andrographolide from Andrographis paniculata on cerebral ischemia/reperfusion-induced brain injury through induction of cerebral endothelial cell apoptosis. AB - CONTEXT: Andrographolide, extracted from the leaves of Andrographis paniculata (Burm. f.) Nees (Acanthaceae), is a labdane diterpene lactone. It is widely reported to possess anti-inflammatory and antitumorigenic activities. Cerebral endothelial cells (CECs) play a crucial role in supporting the integrity and the function of the blood-brain barrier (BBB). However, no data are available concerning the effects of andrographolide in CECs. The aim of this study was to examine the detailed mechanisms of andrographolide on CECs. OBJECTIVE: This study investigated a novel bioactivity of andrographolide on cerebral ischemia/reperfusion-induced brain injury. MATERIALS AND METHODS: CECs were treated with andrographolide (20-100 uMU) for the indicated times (0-24 h). After the reactions, cell survival rate and cytotoxicity were tested by the MTT assay and the lactate dehydrogenase (LDH) test, respectively. Western blotting was used to detect caspase-3 expression. In addition, analysis of cell cycle and apoptosis using PI staining and annexin V-FITC/PI labeling, respectively, was performed by flow cytometry. We also investigated the effect of andrographolide on middle cerebral artery occlusion (MCAO)/reperfusion-induced brain injury in a rat model. RESULTS: In the present study, we found that andrographolide (50-100 uMU) markedly inhibited CEC growth according to an MTT assay and caused CEC damage according to a LDH test. Our data also revealed that andrographolide (50 uM) induced CEC apoptosis and caspase-3 activation as respectively detected by PI/annexin-V double staining and western blotting. Moreover, andrographolide arrested the CEC cell cycle at the G0/G1 phase by PI staining. In addition, andrographolide (5 mg/kg) caused deterioration of MCAO/reperfusion-induced brain injury in a rat model. CONCLUSIONS: These data suggest that andrographolide may disrupt BBB integrity, thereby deteriorating MCAO/reperfusion-induced brain injury, which are, in part, associated with its capacity to arrest cell-cycle and induce CEC apoptosis. PMID- 23930776 TI - Metallo-supramolecular cyclic polymers. AB - Cyclic brush polymers represent an exciting new macromolecular topology. For the first time, this new topology has been combined with metallo-supramolecular interactions to construct novel cyclic brush polymers. Here, ring-expansion metathesis polymerization was used to synthesize a universal cyclic template with a polynorbornene backbone, which was further modified with the metal-chelating synthon terpyridine. The terpyridine side chains served as the key supramolecular unit for the creation of cyclic polymer brushes and gels. This metallo supramolecular functionality allowed direct visualization of the cyclic brush polymers by transmission electron microscopy for the first time. This demonstration should open a new area in which supramolecular interactions are used to build an array of novel cyclic brush copolymers as well as other cyclic polymer-based architectures generating new materials. PMID- 23930777 TI - Alternative to the bentall procedure for elderly patients with aortic root aneurysms. AB - We describe an alternative technique to the Bentall procedure for elderly patients with aortic root aneurysms. It is the subcoronary implantation of a Freestyle (Medtronic, Minneapolis, MN) aortic bioprosthesis with interposition of a graft material between the upper part of the Freestyle bioprosthesis and the distal aorta. The technique described avoids the proximal anastomosis of the graft and avoids the coronary reimplantations of the Bentall procedure which are still a potential risk of bleeding particularly in elderly patients. PMID- 23930778 TI - The journal clarifies a policy. PMID- 23930779 TI - Incidence, risk factors, and consequences of amniotic fluid embolism. AB - BACKGROUND: Amniotic fluid embolism (AFE) is a rare but serious cause of maternal mortality whose aetiology remains obscure. Previous population-based studies have reported associations with labour induction and caesarean delivery. METHODS: We updated a previous analysis based on the US Nationwide Inpatient Sample from 1999 to 2008. We adapted a diagnostic validation algorithm to minimise false-positive diagnoses, along with statistical methods that account for the stratified random sampling design. RESULTS: Of the 8 571 209 deliveries recorded in the database, 276 met our case definition of AFE, of which 62 (22.9% of the 274 with known vital status) were fatal. Significant associations with AFE were observed for medical induction {adjusted odds ratio [aOR] = 1.7 [95% confidence interval (CI) 1.2, 2.5]}, caesarean delivery [aOR = 15.0; 95% CI 9.4, 23.9], instrumental vaginal delivery [aOR = 6.6; 95% CI 4.0, 11.1], and cervical/uterine trauma [aOR = 7.4; 95% CI 3.6, 14.9]. AFE was associated with increases in risk of stillbirth, hysterectomy, maternal death, and prolonged maternal length of delivery hospital stay. CONCLUSIONS: AFE remains an extremely serious obstetric complication with high risks of maternal and fetal mortality. The increased risks of AFE associated with labour induction and caesarean delivery have implications for elective use of these interventions. PMID- 23930780 TI - Obstetrical interventions for term first deliveries in the US. AB - BACKGROUND: Labour induction and caesarean are increasingly done without clinical indication. However, little is known about the prevalence of such interventions, or the characteristics of women who receive them. We used the 2003 revision of the US birth certificates to summarise recorded interventions and to characterise maternal profiles associated with such interventions. METHODS: We carried out a retrospective study of 2.35 million primiparous women delivering singleton live births at 37-44 weeks in the US from 2005 to 2008. We used the 2003 revision of the birth certificate to define delivery categories: 'indicated' were those with induced labour or pre-labour caesarean for hypertension, diabetes, chorioamnionitis, failed cephalic version at >=40 weeks, growth restriction (<3rd centile), or post-term (>=42 weeks); those with pre-labour caesarean with breech at >=39 weeks; or those with caesarean with labour lasting >=12 h, failed trial of labour, vacuum/forceps extraction, or fetal intolerance to labour. Remaining deliveries with induction/caesarean were classified as 'non-indicated' and all other deliveries 'spontaneous'. RESULTS: Half of all term first births (50%) were delivered after intervention, and half of interventions were non-indicated (26% of all deliveries). Women with interventions were more likely to deliver on a weekday. Non-indicated interventions were more common among socially advantaged women. CONCLUSIONS: Nearly a quarter of US term first deliveries had an indicated intervention, and another quarter received intervention without a recorded clinical indication. Both numbers are probably underestimates. PMID- 23930781 TI - What do we know about the natural outcomes of preterm labour? A systematic review and meta-analysis of women without tocolysis in preterm labour. AB - BACKGROUND: Current knowledge of the natural outcomes of untreated women in preterm labour is both incomplete and outcomes vary significantly between the available studies. The aim of this study was to systematically review outcomes of preterm labour without tocolysis and determine if outcome variation could be accounted for by differences in study populations. Such data could potentially assist in the interpretation of intervention trials that do not include a no treatment arm. METHODS: Included studies reported outcomes of women in clinically diagnosed preterm labour without tocolytic treatment between 1950 and 2011. Studies that were limited to preterm prelabour rupture of membranes, recurrent preterm labour or in which the women without tocolysis represented a potentially biased subgroup, or were not tocolysed because of contraindications were excluded. Study quality, design, and population characteristics were abstracted. Outcomes included pregnancy prolongation and the proportion of women undelivered at 48-72 h, 7 days, and term. Study characteristics associated with differing odds of preterm birth were explored through logistic regression. RESULTS: Three hundred and eighty-five citations were initially identified, of which 26 were included encompassing 1383 women. The percentage of patients who were undelivered at 48-72 hours was 62.8%, at 7 days 53.4% and 40.4% delivered at term, though the range was very wide. Characteristics associated with decreased odds of delivery were not consistent among reported outcome measures. CONCLUSIONS: Most women without tocolysis do not deliver within 7 days, although the range is very wide. The majority of this variation is unrelated to reported differences in study design or reported population characteristics. PMID- 23930782 TI - Maternal weight status, cord blood leptin and fetal growth: a prospective mother child cohort study (Rhea study). AB - BACKGROUND: Leptin is an adipocyte-secreted hormone that regulates energy homeostasis, while its role in fetal programming remains poorly understood. We aimed to evaluate the effect of maternal weight status on cord blood leptin levels and their combined effect on fetal growth. METHODS: We included 638 mother child pairs from the prospective mother-child cohort 'Rhea' study in Crete, Greece with singleton pregnancies, providing cord blood serum samples for leptin analysis and complete data on birth outcomes. Multivariable logistic and linear regression models were used adjusting for confounders. Generalised additive models were used to explore the form of the relationship between cord leptin and continuous birth outcomes. RESULTS: Log cord leptin was positively associated with birthweight {beta-coef: 176.5 [95% confidence interval (CI): 133.0, 220.0] }, ponderal index (beta-coef: 1.0 [95% CI: 0.6, 1.4] ) and gestational age (beta coef: 0.7 [95% CI: 0.5, 0.8] ). Excessive weight gain during pregnancy was associated with a threefold increased risk for cord hyperleptinaemia {relative risk (RR): 3.0, [95% CI: 1.5, 6.3] }. Maternal pre-pregnancy overweight/obesity [body mass index (BMI) >=25 kg/m(2) ] increased the risk of giving birth to a hyperleptinaemic neonate (RR: 2.1 [95% CI: 1.4, 3.2] and the effect of log leptin on birthweight (beta-coef: 219.1 [95% CI: 152.3, 285.9] compared with women with a BMI <25 kg/m(2) (beta-coef: 150.5 [95% CI: 93.1, 207.9]. CONCLUSIONS: Higher cord blood leptin levels are associated with increased size at birth and gestational age, while maternal pre-pregnancy BMI and weight gain during pregnancy represent significant indicators of cord blood leptin. PMID- 23930783 TI - Maternal birthweight is associated with subsequent risk of vitamin D deficiency in early pregnancy. AB - BACKGROUND: Maternal low birthweight and vitamin D deficiency in pregnancy are associated with a similar spectrum of adverse pregnancy outcomes including pre eclampsia and gestational diabetes. However, the relationship between maternal birthweight and subsequent vitamin D concentrations in early pregnancy is largely unknown. METHODS: We assessed whether self-reported maternal birthweight was associated with risk of early pregnancy vitamin D deficiency (<=20 ng/mL) among a pregnancy cohort (n = 658). Serum 25-hydroxyvitamin D [25(OH)D] was measured using liquid chromatography-tandem mass spectroscopy. RESULTS: Adjusting for maternal characteristics and month of blood draw, a 100-g higher maternal birthweight was associated with a 5.7% decreased risk of early pregnancy 25(OH)D deficiency [odds ratio (OR) = 0.94; 95% confidence interval (CI) 0.90, 0.99]. Low birthweight (<2500 g) women were 3.7 times as likely to have early pregnancy 25(OH)D deficiency compared with normal-birthweight women [OR = 3.69; 95% CI 1.63, 8.34]. These relationships were not modified by either pre-pregnancy overweight status [body mass index (BMI) >=25 kg/m(2)] or adulthood weight trajectory (BMI change >=2 kg/m(2) from age 18 to pre-pregnancy). CONCLUSIONS: Further research on shared developmental mechanisms that determine birthweight and vitamin D homeostasis may help identify targets and related preventative measures for adverse pregnancy and birth outcomes. PMID- 23930784 TI - Re-conceptualising prenatal life stressors in predicting post-partum depression: cumulative-, specific-, and domain-specific approaches to calculating risk. AB - BACKGROUND: Prenatal life stress predicts post-partum depression (PPD); however, studies generally examine individual stressors (a specific approach) or the summation of such exposure (a cumulative approach) and their associations with PPD. Such approaches may oversimplify prenatal life stress as a risk factor for PPD. We evaluated approaches in assessing prenatal life stress as a predictor of PPD diagnosis, including a domain-specific approach that captures cumulative life stress while accounting for stress across different life stress domains: financial, relational, and physical health. METHODS: The Pregnancy Risk Assessment Monitoring System, a population-based survey, was used to analyse the association of prenatal life stressors with PPD diagnoses among 3566 New York City post-partum women. RESULTS: Specific stressors were not associated with PPD diagnosis after controlling for sociodemographic variables. Exposure to a greater number of stressors was associated with PPD diagnosis, even after adjusting for both sociodemographic variables and specific stressors [odds ratio (OR) = 3.1, 95% confidence interval (CI) = 1.5, 6.7]. Individuals reporting a moderate-to high number of financial problems along with a moderate-to-high number of physical problems were at greater odds of PPD (OR = 4.2, 95% CI = 1.2, 15.3); those with a moderate-to-high number of problems in all three domains were at over fivefold increased odds of PPD (OR = 5.5, CI = 1.1, 28.5). CONCLUSIONS: In assessing prenatal stress, clinicians should consider the extent to which stressors occur across different life domains; this association appears stronger with PPD diagnosis than simple assessments of individual stressors, which typically overestimate risk or cumulative exposures. PMID- 23930785 TI - Accuracy loss due to selection bias in cohort studies with left truncation. AB - BACKGROUND: Selection is a common problem in paediatric and perinatal epidemiology, and truncation can be thought of as missing person time that can result in selection bias. Left truncation, also known as late or staggered entry, may induce selection bias and/or adversely affect precision. There are two kinds of left truncation: fixed left truncation where the start of follow-up is initiated at a set time, and variable left truncation where follow-up begins at a stochastically varying time-point. METHODS: Using data from a time-to-pregnancy study, augmented by a simulation study, we demonstrate the effects of fixed and variable truncation on estimates of the hazard ratio. RESULTS: First, fixed or variable non-differential left truncation results in a loss of precision. Fixed or variable differential left truncation results in a bias either towards or away from the null as well as a loss of precision. The extent and direction of this bias is a function of the size and direction of the association between exposure and outcome, and occurs in common scenarios and under a wide range of conditions. CONCLUSIONS: As demonstrated in simulation studies, selection bias due to left truncation could have a serious impact on inferences, especially in the case of fixed or variable differential left truncation. When present in epidemiologic studies, proper accounting for left truncation is just as important as proper accounting for right censoring. PMID- 23930786 TI - Letter to the editor from Ahrens and Schisterman. PMID- 23930787 TI - Response to Ahrens and Schisterman. PMID- 23930788 TI - Clinical efficacy of florfenicol administered in the drinking water against Ornithobacterium rhinotracheale in turkeys housed in different environmental conditions: a pharmacokinetic/pharmacodynamic approach. AB - In poultry rearing, medicated drinking water is a commonly used administration route, but drug uptake can be affected by many factors. In this study, the influence of two important parameters, the photoperiod and feeding schemes, on florfenicol uptake in turkeys was tested. First, the uptake was determined as the pharmacokinetic/pharmacodynamic profile of florfenicol; and second, we evaluated the clinical efficacy of florfenicol against Ornithobacterium rhinotracheale. Both experiments were conducted during a 5-day treatment of 30 mg/kg body weight florfenicol administered via drinking water and considering different photoperiods and feeding schemes (group 20/4L: photoperiod of 20 h, fed ad libitum; group 16/8L: photoperiod of 16 h, fed ad libitum; group 16/8R: photoperiod of 16 h, fed ad libitum but feed was withdrawn during the dark period and replaced 1 h after lighting). On day 1 of treatment, all groups showed plasma concentrations above the minimum inhibitory concentration (both MIC50 and MIC90, 1 mg/l) of 37.7%, 63.5% and 53.1% of a 24-h interval for 20/4L, 16/8L and 16/8R, respectively. Only in the 16/8L and 16/8R groups was the MIC also exceeded on day 5 (47.9% and 21.5% of a 24-h interval, respectively). In all groups, a clinical improvement could be noticed, resulting in reduction of the clinical score. However, only the 16/8L and 16/8R groups showed significant differences from the control group. The results demonstrated an important influence of the photoperiod on the pharmacokinetics of florfenicol as well as the clinical outcome in an infection model. It can be advised that the photoperiod should be <20 h to have sufficient drug intake. Nevertheless, there was no effect between fed and fasted turkeys for both the pharmacokinetics and the clinical outcome. PMID- 23930789 TI - Nitrogen stable isotopes in primary uptake compartments across streams differing in nutrient availability. AB - High variability in the natural abundance of nitrogen stable isotopes (delta(15)N) has been reported for primary uptake compartments (PUCs; e.g., epilithon, filamentous algae, bryophytes, macrophytes) in human-impacted aquatic ecosystems, but the origin of this variability is not yet well understood. We examined how delta(15)N of different PUC types relate to delta(15)N of dissolved inorganic nitrogen (DIN) species (nitrate and ammonium) and to the stream nutrient concentrations in which they grow. We selected 25 reaches located across the fluvial network of La Tordera catchment (NE Spain, 868.5 km(2)), encompassing a gradient of human pressures from headwaters to the river valley. delta(15)N-PUC variability was mostly explained by location within the fluvial network and was strongly related to the delta(15)N of DIN species, especially of ammonium. Models were stronger for PUCs growing within the stream channel and thus using streamwater as their main source of nutrients. Regression models including nutrient concentrations improved the prediction power for delta(15)N-PUCs, suggesting that nutrient concentrations and stoichiometry cannot be ignored in explaining the natural abundance of nitrogen isotopes in PUCs. These results provide insights into what controls variability in delta(15)N of PUCs within a stream network, with implications for the application of stables isotopes as an ecological tool. PMID- 23930790 TI - From reactive "level of concern" to proactive on lead. PMID- 23930792 TI - Survey on radiation safety management (RSM) among Korean radiation workers who operate radiation generators or handle radioactive isotopes. AB - This study examined the knowledge, attitudes, and behaviors of radiation workers to radiation safety management (RSM) using survey questionnaires. Radiation workers are those who handle radiation generators, radioactive isotopes, and other radioactive materials for industrial uses. The survey was distributed to 861 radiation workers between 1 August to 5 September 2011. A knowledge of, awareness of, attitude toward, and behaviors related to RSM were analyzed by comparing the means and standard deviations. Both the knowledge and awareness of RSM among radiation workers were high. Although all questions about the awareness of RSM were answered correctly, there were also many negative responses. All questions regarding the attitude of radiation workers toward RSM were answered correctly, and their attitude toward and awareness of RSM were high. Overall, the results demonstrated that safety management is not taken seriously in many cases, highlighting the need for proper education in the future to raise awareness among radiation workers. Furthermore, it is important to establish a foundation for the efficient use of radiation based on the continuous management of radiation workers. PMID- 23930793 TI - Employment type, workplace interpersonal conflict, and insomnia: a cross sectional study of 37,646 employees in Japan. AB - This study explored whether workplace interpersonal conflict (WIC) is associated with insomnia, and whether the relationship between WIC and insomnia differs across different employment groups. A total of 37,646 Japanese full-time employees participated in a cross-sectional survey. Employment types included permanent employment and 2 forms of temporary employment: direct-hire and temporary work agent (TWA). Insomnia symptoms, including difficulty initiating sleep, difficulty maintaining sleep, and early morning awakening were measured. Insomnia was defined as having experienced 1 or more of these symptoms on >=3 nights per week over the past 12 months. Results showed that WIC was significantly associated with an increased risk of insomnia (odds ratio OR = 1.63; 95% confidence interval CI = 1.55-1.71), controlling for confounders. However, the relationship between WIC and the risk of insomnia was significantly stronger for TWAs than for permanent employees (OR = 1.97; 95% CI = 1.13-3.45). A frequent exposure to WIC may increase the risk of insomnia, particularly for TWAs. PMID- 23930791 TI - Agricultural workers and urinary bladder cancer risk in Egypt. AB - The authors examined the associations between farming and the risk for squamous cell (SCC) or urothelial cell (UC) carcinoma of the urinary bladder among Egyptians. The authors used data from a multicenter case-control study (1,525 male and 315 female cases, and 2,069 male and 547 female age- and residence matched, population-based controls) to calculate adjusted odds ratios (AORs) and 95% confidence intervals (CIs). Men in farming and who never smoked had increased risk for either SCC or UC (AOR [95% CI]: 4.65 [2.59-8.36] and 6.22 [3.82-10.15], respectively). If they ever smoked, their risks were 2.27 (1.75-2.95) and 1.93 (1.58-2.35), respectively. Women in farmer households were at increased risk for SCC (1.40 [0.93-2.09] and UC [1.25 (0.82-1.89]), although not statistically significant. Occupational and environmental exposures to farming increased the risk for bladder cancer among Egyptians. PMID- 23930794 TI - Physical therapists versus nurses in a rehabilitation hospital: comparing prevalence of work-related musculoskeletal complaints and working conditions. AB - The objective of this study was to investigate the prevalence and work avoidance of work-related musculoskeletal complaints and to compare patient handling tasks and psychosocial factors of physical therapists (PTs) and nurses in a rehabilitation hospital. Cross-sectional observational study was carried out using questionnaires relating to basic demographics, prevalence of musculoskeletal morbidity, workload, and job satisfaction. Comparing 26 PTs and 54 nurses, all females, lower back pain was significantly more prevalent in PTs, even after adjusting for the confounding demographic factors; PTs performed full and partial manual patient transfer, as well as trunk bending and walking assistance more frequently than the nurses and were significantly more satisfied. Unique physical load could be the main factor for the high prevalence of lower back pain in PTs. They should urgently initiate a "no-lift policy" in treatment. PMID- 23930795 TI - The role of chemical interactions between thorium, cerium, and lanthanum in lymphocyte toxicity. AB - Thorium, cerium, and lanthanum are metals present in several types of minerals, the most common of which is monazite. Cerium and lanthanum are elements in the lanthanides series. Thorium, an actinide metal, is a hazardous element due to its radioactive characteristics. There is a lack of information describing the possible chemical interactions among these elements and the effects they may have on humans. Toxicological analyses were performed using cell viability, cell death, and DNA damage assays. Chemical interactions were evaluated based on the Loewe additivity model. The results indicate that thorium and cerium individually have no toxic effects on lymphocytes. However, thorium associated with lanthanum increases the toxicity of this element, thereby reducing the viability of lymphocytes at low concentrations of metals in the mixture. PMID- 23930796 TI - Associations between hair manganese levels and cognitive, language, and motor development in preschool children from Montevideo, Uruguay. AB - Environmental manganese (Mn) exposure in childhood has been associated with developmental deficits. This study investigated associations between low-level Mn exposure and developmental scores in children aged 14-45 months. Children's hair samples (n = 60) were analyzed for Mn and lead (Pb) using inductively coupled plasma mass spectrometry (ICP-MS). Children were assessed with the Bayley Scales of Infant Development III (BSID). Mean hair Mn and Pb concentrations were 0.98 +/ 0.74 and 10.1 +/- 10.5 MUg/g, respectively. Unadjusted inverse associations were seen between Mn and BSID subscales, with girls having lower scores related to Mn than boys. No significant associations remained in covariate-adjusted models, although when stratified by sex boys had a positive association between hair Mn levels and language scores. This study does not show clear evidence of an association between hair Mn concentrations and children's developmental scores in a region of low-level Mn exposure. PMID- 23930797 TI - Effect of shift work on the development of metabolic syndrome after 3 years in Japanese male workers. AB - A 3-year follow-up study of an occupational cohort was conducted to clarify the effect of the type of shift work on the risk of development of metabolic syndrome (MetS). The subjects were 1,677 Japanese male employees aged 36 to 57. Age, each component of MetS, serum uric acid, serum insulin, lifestyle factors, and occupational position were used for the analyses. The odds ratios (95% confidence intervals) of 2-shift work (n = 686) and 3-shift work (n = 99) against daytime work (n = 868) for the development of MetS, as defined by the National Cholesterol Education Program, were 1.43 (1.05, 1.95) and 0.72 (0.37, 1.41), respectively. When Japanese criteria were adopted for defining MetS, the corresponding odds ratios (95% confidence intervals) were 1.88 (1.29, 2.74) and 0.87 (0.39, 1.97), respectively. The results of the analyses suggested that 2 shift work was a risk factor for the development of metabolic syndrome. PMID- 23930799 TI - Toxicity and poisoning: the example of lead. PMID- 23930800 TI - Immune alterations in malignant melanoma and current immunotherapy concepts. AB - INTRODUCTION: Malignant melanoma is a highly aggressive, immunogenic tumor that has the ability to modulate the immune system to its own advantage. Patients with melanoma present numerous cellular immune defects and cytokine abnormalities, all leading to suppression of the host anti-tumor immune response. Innovative treatment strategies can be achieved through employing our knowledge of the melanoma-induced immune alterations. AREAS COVERED: The authors review comprehensively the immune abnormalities in individuals with melanoma, and provide a summary of currently available melanoma immunotherapy agents that are currently on the market or undergoing clinical trials. EXPERT OPINION: Ipilimumab, a monoclonal antibody directed against the CTLA-4, is one of the current forefront treatment strategies in malignant melanoma. Novel immunomodulating agents have shown clear activity in patients with malignant melanoma. These include anti-PD-1 and anti-PD-1 ligand antibodies that may soon become important items in the anti-melanoma armamentarium. Combinations of different immunotherapy agents, between themselves or with other agents, are currently being studied in an attempt to further enhance the antineoplastic effect in patients with malignant melanoma. PMID- 23930801 TI - Compensation of in-plane rigid motion for in vivo intracoronary ultrasound image sequence. AB - Intracoronary ultrasound (ICUS) is an interventional imaging modality that is used to acquire a series of tomographic images from the vascular lumen, for diagnosis and treatment of coronary artery diseases in clinical settings. Motion artifacts caused by cardiac dynamics and the pulsatile blood flow within the vascular lumen, during continuous pullback (non-gated) ICUS image acquisition, hinder visualization of longitudinal cuts, assessment of arterial morphology and hemodynamics, and three-dimensional (3-D) vessel reconstruction. The aim of this study is to develop a method to compensate for in-plane rigid motion in non-gated in vivo ICUS sequences. The signals associated with cardiac motion are first detected from the gray-scale image sequence. They are represented with rigid motion parameters between luminal contours extracted from successive slices. Subsequently, the signals were filtered to separate the dynamic components caused by cardiac motion from those caused by the irregular morphology of the vascular lumen. Dynamic components were then compensated by performing a back transformation of related pixels within the vessel region in each frame. The method is validated by computer-simulation and using real ICUS image data. Possible sources of error are discussed based on the experimental results. PMID- 23930802 TI - Elastic image registration using hierarchical spatially based mean shift. AB - In this paper, a novel estimation technique for corresponding points using a hierarchical, spatially based mean shift algorithm is proposed. We proposed a spatially based probability estimation using different spatial masks. For a given point on reference image, its corresponding register point is found along the search trajectory generated by optimizing Bhattacharyya coefficient between two windows centered at the points on the register and reference images. The outliers are further eliminated by analyzing statistical information on the displacements of the candidate register points. Experiments on various monomodal medical images show that the proposed method is feasible and fast. PMID- 23930803 TI - Simulation of a pulsatile non-Newtonian flow past a stenosed 2D artery with atherosclerosis. AB - Atherosclerotic plaque can cause severe stenosis in the artery lumen. Blood flow through a substantially narrowed artery may have different flow characteristics and produce different forces acting on the plaque surface and artery wall. The disturbed flow and force fields in the lumen may have serious implications on vascular endothelial cells, smooth muscle cells, and circulating blood cells. In this work a simplified model is used to simulate a pulsatile non-Newtonian blood flow past a stenosed artery caused by atherosclerotic plaques of different severity. The focus is on a systematic parameter study of the effects of plaque size/geometry, flow Reynolds number, shear-rate dependent viscosity and flow pulsatility on the fluid wall shear stress and its gradient, fluid wall normal stress, and flow shear rate. The computational results obtained from this idealized model may shed light on the flow and force characteristics of more realistic blood flow through an atherosclerotic vessel. PMID- 23930804 TI - Contractions of the whole and longitudinally cut rat's portal vein. AB - To investigate the role of lateral interactions, we quantified spontaneous contractions of whole and longitudinally cut rat's portal vein in vitro. The disruption of the wall had no effect on basic frequency determined from spectra and complexity index (CI) calculated by multiscale entropy analysis. Endothelium was disrupted and nonfunctional in all samples. Considering amplitude, frequency and CI we identified two modes of contractions. Neither mode of contractions nor the effect of aminopyridine (4-AP) depended on the integrity of the wall. We concluded that contractions in vitro originate in smooth muscle cells without involvement of the endothelium and lateral interactions. PMID- 23930805 TI - Multi-stage filtering for improving confidence level and determining dominant clusters in clustering algorithms of gene expression data. AB - A drastic improvement in the analysis of gene expression has lead to new discoveries in bioinformatics research. In order to analyse the gene expression data, fuzzy clustering algorithms are widely used. However, the resulting analyses from these specific types of algorithms may lead to confusion in hypotheses with regard to the suggestion of dominant function for genes of interest. Besides that, the current fuzzy clustering algorithms do not conduct a thorough analysis of genes with low membership values. Therefore, we present a novel computational framework called the "multi-stage filtering-Clustering Functional Annotation" (msf-CluFA) for clustering gene expression data. The framework consists of four components: fuzzy c-means clustering (msf-CluFA-0), achieving dominant cluster (msf-CluFA-1), improving confidence level (msf-CluFA 2) and combination of msf-CluFA-0, msf-CluFA-1 and msf-CluFA-2 (msf-CluFA-3). By employing double filtering in msf-CluFA-1 and apriori algorithms in msf-CluFA-2, our new framework is capable of determining the dominant clusters and improving the confidence level of genes with lower membership values by means of which the unknown genes can be predicted. PMID- 23930806 TI - Blood flow vectoring control in aortic arch using full and partial clamps. AB - BACKGROUND: Early diagnosis and treatment of aneurysm plays an important role in reducing the mortality risk of rupture. The aneurysm is a complex phenomenon and caused by different reasons, such as arteriosclerosis and heredity. In addition, pressure and Wall Shear Stress are two known factors influencing the establishment of an aneurysm. The aim of this study is to investigate the effect of using a full or partial clamp to control the blood flow streamlines and hence the location of stress concentration in a clean configuration of aorta. The main question is how to control the stresses distribution in order to reduce the possibility of aneurysm growth with less negative effects on the other sides. METHODS AND RESULTS: A simple form of aortic arch with three branches is considered to simulate the effect of changing blood flow streamlines directions. A parameter study has been performed on the main characteristics of clamp, i.e. size, location, and the percentage of coverage. The Shear Stress Transport model is employed to simulate steady-state Newtonian blood flow when the Reynolds number is about 6500. Simulations are conducted using the commercial CFD solver ANSYS Fluent. The obtained results show that the location of clamp is more effective than the size. It is also found that increasing the depth of clamp has a negative impact on mean velocity field and hence on stress concentration. CONCLUSION: The present results demonstrate that the Blood Flow Vectoring Control (BFVC) can change the main form of flow streamlines and consequently the distributions of pressure and Wall Shear Stress. A partial clamp leads to better results. PMID- 23930807 TI - Semi-computational simulation of magneto-hemodynamic flow in a semi-porous channel using optimal homotopy and differential transform methods. AB - In this paper, the semi-numerical techniques known as the optimal homotopy analysis method (HAM) and Differential Transform Method (DTM) are applied to study the magneto-hemodynamic laminar viscous flow of a conducting physiological fluid in a semi-porous channel under a transverse magnetic field. The two dimensional momentum conservation partial differential equations are reduced to ordinary form incorporating Lorentizian magnetohydrodynamic body force terms. These ordinary differential equations are solved by the homotopy analysis method, the differential transform method and also a numerical method (fourth-order Runge Kutta quadrature with a shooting method), under physically realistic boundary conditions. The homotopy analysis method contains the auxiliary parameter h, which provides us with a simple way to adjust and control the convergence region of solution series. The differential transform method (DTM) does not require an auxiliary parameter and is employed to compute an approximation to the solution of the system of nonlinear differential equations governing the problem. The influence of Hartmann number (Ha) and transpiration Reynolds number (mass transfer parameter, Re) on the velocity profiles in the channel are studied in detail. Interesting fluid dynamic characteristics are revealed and addressed. The HAM and DTM solutions are shown to both correlate well with numerical quadrature solutions, testifying to the accuracy of both HAM and DTM in nonlinear magneto hemodynamics problems. Both these semi-numerical techniques hold excellent potential in modeling nonlinear viscous flows in biological systems. PMID- 23930808 TI - Path length entropy analysis of diastolic heart sounds. AB - Early detection of coronary artery disease (CAD) using the acoustic approach, a noninvasive and cost-effective method, would greatly improve the outcome of CAD patients. To detect CAD, we analyze diastolic sounds for possible CAD murmurs. We observed diastolic sounds to exhibit 1/f structure and developed a new method, path length entropy (PLE) and a scaled version (SPLE), to characterize this structure to improve CAD detection. We compare SPLE results to Hurst exponent, Sample entropy and Multiscale entropy for distinguishing between normal and CAD patients. SPLE achieved a sensitivity-specificity of 80%-81%, the best of the tested methods. However, PLE and SPLE are not sufficient to prove nonlinearity, and evaluation using surrogate data suggests that our cardiovascular sound recordings do not contain significant nonlinear properties. PMID- 23930809 TI - Evaluation of an artificial neural network to ascertain why there is a high incidence of hepatitis B in the Chinese population after vaccination. AB - OBJECTIVE: The purpose of the study was to understand why there is a high incidence of hepatitis B, including acute and chronic infections, after vaccination. METHODS: All data were obtained from the published information. The incidence of hepatitis B, life expectancy, and positive rates of hepatitis B surface antigen (HBsAg) and the antibody to HBsAg (anti-HBs) in a specific observation year was depicted. The relationships between the HBsAg-positive rate, anti-HBs-positive rate, life expectancy and incidence of hepatitis B were assessed by Pearson's correlation. The quantitative effects of HBsAg-positive rate, anti-HBs-positive rate and life expectancy on hepatitis B incidence were assessed by SPSS 18.0 software with a neural network. RESULTS: There was no correlation between hepatitis B incidence and the rates of HBsAg or anti-HBs (r= 0.334 for HBsAg, r=0.247 for anti-HBs, p>0.05 for both indicators). A clear correlation was observed between incidence and life expectancy (r=0.841, p<0.05). The standardized percentage of affect of life expectancy on hepatitis B incidence (100%) was much higher than that of either the rates of HBsAg (59.0%) or anti-HBs (45.7%). CONCLUSION: An increase in life expectancy and an improved quality of life may be associated with a higher incidence of hepatitis B. Because hepatitis B is caused by the host immune response, a stronger immune response in individuals with an improved quality of life could contribute to that higher incidence. PMID- 23930810 TI - NGSPE: A pipeline for end-to-end analysis of DNA sequencing data and comparison between different platforms. AB - We present NGSPE, a pipeline for variation discovery and genotyping of pair-ended Illumina next generation sequencing (NGS) data (http://ngspeanalysis.sourceforge.net/). This pipeline not only describes a set of sequential analytical steps, such as short reads alignment, genotype calling and functional variation annotation that can be conducted using open-source software tools, but also provides users a set of scripts to install the dependent software and resources and implement the pipeline on their data. A sample summary report including the concordance rate between data generated by this pipeline and different resources as well as the comparison between replication samples of two commercial platforms from Illumina and Complete Genomics is also provided. Furthermore, some of the mutations identified by the pipeline were verified using Sanger sequencing. PMID- 23930811 TI - In silico identification of Gram-negative bacterial secreted proteins from primary sequence. AB - In this study, we focus on different types of Gram-negative bacterial secreted proteins, and try to analyze the relationships and differences among them. Through an extensive literature search, 1612 secreted proteins have been collected as a standard data set from three data sources, including Swiss-Prot, TrEMBL and RefSeq. To explore the relationships among different types of secreted proteins, we model this data set as a sequence similarity network. Finally, a multi-classifier named SecretP is proposed to distinguish different types of secreted proteins, and yields a high total sensitivity of 90.12% for the test set. When performed on another public independent dataset for further evaluation, a promising prediction result is obtained. Predictions can be implemented freely online at http://cic.scu.edu.cn/bioinformatics/secretPv2_1/index.htm. PMID- 23930812 TI - FRAN and RBF-PSO as two components of a hyper framework to recognize protein folds. AB - In this paper, an intelligent hyper framework is proposed to recognize protein folds from its amino acid sequence which is a fundamental problem in bioinformatics. This framework includes some statistical and intelligent algorithms for proteins classification. The main components of the proposed framework are the Fuzzy Resource-Allocating Network (FRAN) and the Radial Bases Function based on Particle Swarm Optimization (RBF-PSO). FRAN applies a dynamic method to tune up the RBF network parameters. Due to the patterns complexity captured in protein dataset, FRAN classifies the proteins under fuzzy conditions. Also, RBF-PSO applies PSO to tune up the RBF classifier. Experimental results demonstrate that FRAN improves prediction accuracy up to 51% and achieves acceptable multi-class results for protein fold prediction. Although RBF-PSO provides reasonable results for protein fold recognition up to 48%, it is weaker than FRAN in some cases. However the proposed hyper framework provides an opportunity to use a great range of intelligent methods and can learn from previous experiences. Thus it can avoid the weakness of some intelligent methods in terms of memory, computational time and static structure. Furthermore, the performance of this system can be enhanced throughout the system life-cycle. PMID- 23930813 TI - Discrimination of malignant neutrophils of chronic myelogenous leukemia from normal neutrophils by support vector machine. AB - Malignant neutrophils of chronic myelogenous leukemia (CML) have similar antigen expression patterns compared to their normal counterparts, thus making the cells difficult to distinguish by clinical flow cytometry. In this study, we applied the support vector machine method to build a malignant neutrophil prediction model based on nine CML patients and nine healthy donors. This approach effectively differentiated between malignant and normal neutrophils with high specificity and sensitivity (<=95.80% and <=95.30%, respectively). This approach may broaden the application of flow cytometry for differentiation between CML and normal neutrophils and become an important diagnostic tool in CML. PMID- 23930814 TI - Improving protein complex classification accuracy using amino acid composition profile. AB - Protein complex prediction approaches are based on the assumptions that complexes have dense protein-protein interactions and high functional similarity between their subunits. We investigated those assumptions by studying the subunits' interaction topology, sequence similarity and molecular function for human and yeast protein complexes. Inclusion of amino acids' physicochemical properties can provide better understanding of protein complex properties. Principal component analysis is carried out to determine the major features. Adopting amino acid composition profile information with the SVM classifier serves as an effective post-processing step for complexes classification. Improvement is based on primary sequence information only, which is easy to obtain. PMID- 23930815 TI - Noise/spike detection in phonocardiogram signal as a cyclic random process with non-stationary period interval. AB - The major aim of this study is to describe a unified procedure for detecting noisy segments and spikes in transduced signals with a cyclic but non-stationary periodic nature. According to this procedure, the cycles of the signal (onset and offset locations) are detected. Then, the cycles are clustered into a finite number of groups based on appropriate geometrical- and frequency-based time series. Next, the median template of each time series of each cluster is calculated. Afterwards, a correlation-based technique is devised for making a comparison between a test cycle feature and the associated time series of each cluster. Finally, by applying a suitably chosen threshold for the calculated correlation values, a segment is prescribed to be either clean or noisy. As a key merit of this research, the procedure can introduce a decision support for choosing accurately orthogonal-expansion-based filtering or to remove noisy segments. In this paper, the application procedure of the proposed method is comprehensively described by applying it to phonocardiogram (PCG) signals for finding noisy cycles. The database consists of 126 records from several patients of a domestic research station acquired by a 3M Littmann((r)) 3200, 4KHz sampling frequency electronic stethoscope. By implementing the noisy segments detection algorithm with this database, a sensitivity of Se=91.41% and a positive predictive value, PPV=92.86% were obtained based on physicians assessments. PMID- 23930816 TI - Estimation of the reliability of all-ceramic crowns using finite element models and the stress-strength interference theory. AB - The reliability of all-ceramic crowns is of concern to both patients and doctors. This study introduces a new methodology for quantifying the reliability of all ceramic crowns based on the stress-strength interference theory and finite element models. The variables selected for the reliability analysis include the magnitude of the occlusal contact area, the occlusal load and the residual thermal stress. The calculated reliabilities of crowns under different loading conditions showed that too small occlusal contact areas or too great a difference of the thermal coefficient between veneer and core layer led to high failure possibilities. There results were consistent with many previous reports. Therefore, the methodology is shown to be a valuable method for analyzing the reliabilities of the restorations in the complicated oral environment. PMID- 23930817 TI - Analytical cone-beam SPECT reconstruction algorithm with non-uniform attenuation for general non-circular orbit. AB - In single photon emission computed tomography (SPECT), due to the attenuation of gamma photons, the analytical reconstruction is complicated, where attenuation should be compensated to obtain quantitative results. We know that the resolution of SPECT is low. The cone-beam SPECT reconstruction can improve the photon density and spatial resolution of the reconstructed image. In practice, to minimize the effect of distance-dependent resolution variation (DDRV), the detector should be set as close as possible to the patient. Therefore it would be more efficacious for the orbit of the detector to be elliptical or another shape. In this paper, based on the Novikov's reconstruction formula and our Ray-driven Technology, we present an analytical cone-beam SPECT reconstruction algorithm for general non-circular orbit. The simulation results demonstrate the accuracy and robustness of our method. PMID- 23930818 TI - Effects of degenerated intervertebral discs on intersegmental rotations, intradiscal pressures, and facet joint forces of the whole lumbar spine. AB - The effects of intervertebral disc (IVD) degeneration on biomechanics of the lumbar spine were analyzed. Finite element models of the lumbar spine with various degrees of IVD degeneration at the L4-L5 functional spinal unit (FSU) were developed and validated. With progression of degeneration, intersegmental rotation at the degenerated FSU decreased in flexion-extension and left-right lateral bending, intradiscal pressure at the adjacent FSUs increased in flexion and lateral bending, and facet joint forces at the degenerated FSU increased in lateral bending and axial rotation. These results could provide fundamental information for understanding the mechanism of injuries caused by IVD degeneration. PMID- 23930820 TI - Identification and analysis of the regulatory network of Myc and microRNAs from high-throughput experimental data. AB - As a transcription factor, c-Myc exerts significant influence in cancer development by regulating transcription of a large number of target genes including microRNAs. However, details of regulatory networks composed of Myc, microRNAs, and microRNA target genes are still unclear. Here, at system level, we built a comprehensive Myc-regulated miRNAs (Myc-miRNAs) regulatory network through the integration of experimentally validated high-throughput data and computational predictions. Using miRNA genomic information with ChIP-PET, we identified 30 Myc-miRNAs and found most of these Myc-miRNAs target genes were significantly enriched in cell cycle, apoptosis, cell proliferation GO terms and Myc-regulated signaling pathways, using gene sets enrichment analysis. We found most Myc-miRNAs involved in Myc-related cancer pathways expressed abnormally in Myc-associated tumors through the integration of diverse types of experimental data. Based upon Myc target genes identified by ChIP-chip assays, we identified that 1031 Myc-miRNAs feed-forward loops (FFLs) were significantly different from those obtained by chance; also, 11 high-quality FFLs were extracted from experimentally validated interactions. Finally, we built the miRNA-protein interaction network of experimentally validated Myc-miRNAs and discussed the more complex network composed of several FFLs networks. As shown in this study, we performed comprehensive analysis of the Myc-miRNAs regulatory network and provided potential Myc-miRNAs target genes which were involved in Myc pathway and cancer-related biological processes. PMID- 23930819 TI - Synergistic combination of clinical and imaging features predicts abnormal imaging patterns of pulmonary infections. AB - We designed and tested a novel hybrid statistical model that accepts radiologic image features and clinical variables, and integrates this information in order to automatically predict abnormalities in chest computed-tomography (CT) scans and identify potentially important infectious disease biomarkers. In 200 patients, 160 with various pulmonary infections and 40 healthy controls, we extracted 34 clinical variables from laboratory tests and 25 textural features from CT images. From the CT scans, pleural effusion (PE), linear opacity (or thickening) (LT), tree-in-bud (TIB), pulmonary nodules, ground glass opacity (GGO), and consolidation abnormality patterns were analyzed and predicted through clinical, textural (imaging), or combined attributes. The presence and severity of each abnormality pattern was validated by visual analysis of the CT scans. The proposed biomarker identification system included two important steps: (i) a coarse identification of an abnormal imaging pattern by adaptively selected features (AmRMR), and (ii) a fine selection of the most important features from the previous step, and assigning them as biomarkers, depending on the prediction accuracy. Selected biomarkers were used to classify normal and abnormal patterns by using a boosted decision tree (BDT) classifier. For all abnormal imaging patterns, an average prediction accuracy of 76.15% was obtained. Experimental results demonstrated that our proposed biomarker identification approach is promising and may advance the data processing in clinical pulmonary infection research and diagnostic techniques. PMID- 23930821 TI - Inter- and intra-observer variability analysis of completely automated cIMT measurement software (AtheroEdgeTM) and its benchmarking against commercial ultrasound scanner and expert Readers. AB - The purpose of this study was to evaluate the measurement error and inter- and intra-observer variability of completely off-line automated and semi-automated carotid intima-media thickness (cIMT) measurement software (AtheroEdgeTM). Two hundred carotid ultrasound images from 50 asymptomatic women were analyzed. AtheroEdgeTM was benchmarked against a commercial system (Syngo, Siemens) using automated and semi-automated modes. The measurement error and inter- and intra observer variability of AtheroEdgeTM were tested using three readings. The measurement error of AtheroEdgeTM compared to the commercial software was 0.002+/ 0.019mm (r=0.99) in the automated mode and -0.001+/-0.004mm in the semi-automated mode (r=0.99). The measurement error of AtheroEdgeTM compared to the mean value of the three expert Readers (cIMT bias) for the automated and semi-automated methods was -0.0004+/-0.158mm and -0.008+/-0.157mm, respectively. The Figure-of Merit was 99.8% and 99.9% when compared to the commercial ultrasound scanner (using the automated and semi-automated method, respectively) and was 99.9% and 98.9% when compared to the mean value of the three expert Readers. Regarding inter- and intra-observer variability, the intra-class correlation coefficient of the three independent users using the semi-automated AtheroEdgeTM was 0.98. AtheroEdgeTM showed a measurement performance comparable to the commercial ultrasound scanner software and the expert Readers' tracings. AtheroEdgeTM belongs to a class of automated systems that could find application in processing large datasets for common carotid arteries, avoiding subjectivity in cIMT measurements. PMID- 23930823 TI - Statistical evaluation of coherence estimated from optimally beamformed signals. AB - In this paper we investigate a situation where we want to perform a coherence analysis of two signal sources, one of which is measured directly, and the other is measured through a sensor array affected by noise. To extract the latter signal, we suggest the use of the optimal beamforming with reference. We note, however, that this approach results in a coherence estimate that is noticeably biased, and cannot be evaluated by the known statistical tests. We therefore derive a new statistical test, that allows the evaluation of the biased coherence estimate. We illustrate the applicability of our methodology on the coherence analysis of EEG and EMG signals. We note that the suggested approach has several advantages over the surface Laplacian, which is a spatial filter commonly used in the EEG-EMG coherence analysis. PMID- 23930822 TI - Structurally-motivated characterization of the passive pseudo-elastic response of esophagus and its layers. AB - This paper reports on the implementation of microstructurally-motivated models for material characterization of the passive esophagus and its layers. The principal findings afforded herewith were that the comprehensive model with two- and four-fiber family terms for elastin and collagen fitted more accurately the inflation/extension data of healthy rabbit esophagus than traditional phenomenological models. An analysis of material constant behavior was also performed from which concise, specific models were derived, neither missing essential collagen and elastin structures in mucosa, submucosa, and muscle layers nor being over-parameterized, while providing equally-accurate fits with all the advantages of computational economy and material constant interpretability. PMID- 23930824 TI - Low incidence of Pneumocystis jirovecii pneumonia in an unprophylaxed liver transplant cohort. AB - BACKGROUND: Liver transplant recipients are managed with a range of immunosuppressive regimens that place them at heightened risk of life-threatening opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP). No routine PJP prophylaxis is used at out institution. We reviewed the incidence of PJP in this cohort of unprophylaxed liver transplant recipients. METHODS: We examined all liver transplants performed between January 2000 and January 2012 in Ireland's National Liver Transplant Centre, St. Vincent's University Hospital, Dublin. Cases were identified through a computerized database and through the histopathology and microbiology registration system. The diagnosis of PJP was confirmed by identification of Pneumocystis cysts in bronchoalveolar lavage (BAL) fluid or on autopsy specimens using Grocott-Gomori methenamine-silver nitrate or modified Wright-Giemsa staining methods. RESULTS: During the study period, 687 liver transplants were performed. We found 7 cases of PJP with an incidence rate of 0.84 per 1000 person transplant years. Five cases occurred within 12 months of transplant with 2 cases occurring at 56 and 60 months, respectively. Two cases were diagnosed at postmortem; 1 previously had negative cytology from BAL, while the other could not be bronchoscoped because of rapid deterioration in the clinical condition. Three of the 5 treated patients died. CONCLUSIONS: The incidence of PJP in this cohort was very low, but the case fatality rate was high. Two cases occurred well after the usual recommended period of prophylaxis. In institutions with a very low risk of infection, targeted rather than universal prophylaxis may be reasonable. PMID- 23930825 TI - Tissue-compliant neural implants from microfabricated carbon nanotube multilayer composite. AB - Current neural prosthetic devices (NPDs) induce chronic inflammation due to complex mechanical and biological reactions related, in part, to staggering discrepancies of mechanical properties with neural tissue. Relatively large size of the implants and traumas to blood-brain barrier contribute to inflammation reactions, as well. Mitigation of these problems and the realization of long-term brain interface require a new generation of NPDs fabricated from flexible materials compliant with the brain tissue. However, such materials will need to display hard-to-combine mechanical and electrical properties which are not available in the toolbox of classical neurotechnology. Moreover, these new materials will concomitantly demand different methods of (a) device micromanufacturing and (b) surgical implantation in brains because currently used processes take advantage of high stiffness of the devices. Carbon nanotubes (CNTs) serve as a promising foundation for such materials because of their record mechanical and electrical properties, but CNT-based tissue-compliant devices have not been realized yet. In this study, we formalize the mechanical requirements to tissue-compliant implants based on critical rupture strength of brain tissue and demonstrate that miniature CNT-based devices can satisfy these requirements. We fabricated them using MEMS-like technology and miniaturized them so that at least two dimensions of the electrodes would be comparable to brain tissue cells. The nanocomposite-based flexible neural electrodes were implanted into the rat motor cortex using a surgical procedure specifically designed for soft tissue-compliant implants. The post-surgery implant localization in the motor cortex was successfully visualized with magnetic resonance and photoacoustic imaging. In vivo functionality was demonstrated by successful registration of the low frequency neural recording in the live brain of anesthetized rats. Investigation of inflammation processes around these electrodes will be required to establish their prospects as long-term neural electrodes. PMID- 23930826 TI - Intrinsic electronic transport properties of high-quality monolayer and bilayer MoS2. AB - We report electronic transport measurements of devices based on monolayers and bilayers of the transition-metal dichalcogenide MoS2. Through a combination of in situ vacuum annealing and electrostatic gating we obtained ohmic contact to the MoS2 down to 4 K at high carrier densities. At lower carrier densities, low temperature four probe transport measurements show a metal-insulator transition in both monolayer and bilayer samples. In the metallic regime, the high temperature behavior of the mobility showed strong temperature dependence consistent with phonon-dominated transport. At low temperature, intrinsic field effect mobilities approaching 1000 cm(2)/(V.s) were observed for both monolayer and bilayer devices. Mobilities extracted from Hall effect measurements were several times lower and showed a strong dependence on density, likely caused by screening of charged impurity scattering at higher densities. PMID- 23930827 TI - Bihemispheric stimulation over left and right inferior frontal region enhances recovery from apraxia of speech in chronic aphasia. AB - Several studies have already shown that transcranial direct current stimulation (tDCS) is a useful tool for enhancing recovery in aphasia. However, all tDCS studies have previously investigated the effects using unihemisperic stimulation. No reports to date have examined the role of bihemispheric tDCS on aphasia recovery. Here, eight aphasic persons with apraxia of speech underwent intensive language therapy in two different conditions: real bihemispheric anodic ipsilesional stimulation over the left Broca's area and cathodic contralesional stimulation over the right homologue of Broca's area, and a sham condition. In both conditions, patients underwent concurrent language therapy for their apraxia of speech. The language treatment lasted 10 days (Monday to Friday, then weekend off, then Monday to Friday). There was a 14-day intersession interval between the real and the sham conditions. In all patients, language measures were collected before (T0), at the end of (T10) and 1 week after the end of (F/U) treatment. Results showed that after simultaneous excitatory stimulation to the left frontal hemisphere and inhibitory stimulation to the right frontal hemisphere regions, patients exhibited a significant recovery not only in terms of better accuracy and speed in articulating the treated stimuli but also in other language tasks (picture description, noun and verb naming, word repetition, word reading) which persisted in the follow-up session. Taken together, these data suggest that bihemispheric anodic ipsilesional and cathodic contralesional stimulation in chronic aphasia patients may affect the treated function, resulting in a positive influence on different language tasks. PMID- 23930828 TI - Cognitive Functional Evaluation (CFE) Process for Individuals with Suspected Cognitive Disabilities. AB - The purpose of this paper is to conceptualize the evaluation process for individuals with suspected cognitive disabilities. The Cognitive Functional Evaluation (CFE) process yields a comprehensive profile of the clients' cognitive strengths and weaknesses in occupational performance. The components of the CFE are outlined in six stages as a decision tree with examples of standardized instruments from which to choose the assessments for each client evaluated: (1) interview and background information; (2) cognitive screening and baseline status tests; (3) general measures of cognition and executive functions in occupation; (4) cognitive tests for specific domains; (5) measures of specific cognitive domains in occupations; and (6) environmental assessment. The first three stages are required to ascertain basic cognitive abilities underlying occupational performance. Tests for each stage can be chosen from the ones listed according to the client characteristics and the theory utilized, there is no need to use all of them. Once this data is available a further decision is made whether a more in depth assessment is needed (stages (4) and (5)). The environmental component is evaluated in all instances with at least one of the assessments. The CFE process for individuals with suspected cognitive disabilities is recommended to be used by occupational therapists as a common ground for evaluation, documentation, and communicating information. PMID- 23930829 TI - Fall-prevention pilot: hazard survey and responses to recommendations. AB - This work reports a partial inventory of fall hazards for community-dwelling elders and characterizes older adult responses to fall prevention. Thirty-five seniors living in their homes participated in a fall-prevention initiative designed to identify hazards and make recommendations. Fifteen external hazards were identified and operationalized, and between one and four changes were reported per home in 18 of 22 homes, consistent with recommendations; however, most of the recommendations were unrelated to the cause of later participant falls. Considering the varied circumstances of falls in the community, we question the wisdom of designating specific risk posed by individual hazards and encourage future investigation on the merits of multifaceted evaluation and intervention including the consideration of combinations and interactions of hazards as well as raising caution and awareness. PMID- 23930830 TI - The Framework of Occupational Gradation (FOG) to Treat Upper Extremity Impairments in Persons With Central Nervous System Impairments. AB - Occupational therapists providing treatment of persons with central nervous system (CNS) impairments now embrace a motor control approach based on principles of strength training and practice of meaningful occupations. This paper describes the Framework of Occupational Gradation (FOG), which was developed to assist occupational therapists to systematically challenge upper extremity function by manipulating the degrees of freedom of active motion in a person's extremity. Clients may be able to perform occupations under several or all levels within the framework. However, the person, task, or object properties and the environment can also be manipulated by the occupational therapist to optimize or challenge a person's performance at each level. Application of the FOG is presented through case studies. PMID- 23930831 TI - Choice, knowledge, and utilization of a practice theory: a national study of occupational therapists who use the model of human occupation. AB - Objective. To identify how therapists choose and use the Model of Human Occupation (MOHO). Method. A systematic random sample of 1,000 occupational therapists was surveyed as to whether they used MOHO in their practice. Those who were using MOHO were then sent a detailed questionnaire; 259 therapists responded to the survey questionnaire, forming a response rate of 60.2 percent. Results. A total of 80.7% of therapists indicated that they had used MOHO in their practice. A number of factors influenced therapists' choice to use MOHO. The most frequently cited factors were therapists' judgment that MOHO fit their own practice philosophy and their clients' needs. Most therapists used multiple means of learning about MOHO, and the number of means they used was related to both self-reported levels of knowledge and utilization of this model. Many therapists are also actively engaged in sharing their knowledge and utilization of this model. Conclusion. Multiple factors contribute to therapists' choice and use of MOHO. Therapists actively make a decision to use MOHO in practice and put forth substantial efforts to learn and share their knowledge of MOHO. PMID- 23930832 TI - From the internet editor. PMID- 23930833 TI - A Review of: "Evidence-based Rehabilitation: A Guide to Practice, 2nd edition (2008)". PMID- 23930834 TI - A Review of: "Occupational Therapy Evidence in Practice for Mental Health (2006)". PMID- 23930835 TI - A Review of: "Ariadne's Thread-case Studies in the Therapeutic Relationship (2005)". PMID- 23930836 TI - A Review of: "Model of Human Occupation: Theory and Application, 4th edition (2008)". PMID- 23930838 TI - A Review of: "Occupational Therapy for Physical Dysfunction 6th Edition (2008)". PMID- 23930839 TI - A Review of: "Occupational Therapy: Performance, Participation, and Well-being (2005)". PMID- 23930840 TI - A Review of: "Crafts and Creative Media in Therapy, 3rd edition (2007)". PMID- 23930841 TI - Erratum. PMID- 23930842 TI - Corrigendum. PMID- 23930843 TI - Fruit juice drinks prevent endogenous antioxidant response to high-fat meal ingestion. AB - High-fat meals (HFM) induce metabolic stress, leading to the activation of protective mechanisms, including inflammation and endogenous antioxidant defences. In the present study, we investigated the effects of antioxidant-rich fruit juice drinks on the endogenous antioxidant response induced by HFM. In a double-blind, cross-over design (10 d washout), fourteen overweight volunteers were randomly assigned to one of the following interventions: HFM+500 ml placebo beverage (HFM-PB, free from fruit); HFM+500 ml antioxidant beverage 1 (HFM-AB1; apple, grape, blueberry and pomegranate juices and grape skin, grape seed and green tea extracts); HFM+500 ml antioxidant beverage 2 (HFM-AB2; pineapple, black currant and plum juices). HFM-PB consumption increased the plasma levels of thiols (SH) (4 h, P< 0.001) and uric acid (UA) (2 h, P< 0.01) and total radical trapping antioxidant parameter (TRAP) (4 h, P< 0.01). Following the consumption of drinks, UA production was significantly reduced with respect to placebo beverage consumption 8 h after HFM-AB2 consumption (P< 0.05). SH levels were reduced 0.5 (P< 0.05), 1 (P< 0.05) and 2 h (P< 0.01) after HFM-AB1 consumption and 2, 4 and 8 h (P< 0.05) after HFM-AB2 consumption. Plasma TRAP (2 h, P< 0.001) and urinary ferric reducing antioxidant power (0-8 h, P< 0.01) were increased by HFM-AB1 consumption, the drink with the highest in vitro antioxidant capacity, but not by HFM-AB2 consumption. In urine, UA levels were significantly increased from basal levels after the consumption of HFM-PB and HFM-AB2. However, neither of the beverages increased the urinary excretion of UA with respect to the placebo beverage. In conclusion, the increase in UA and SH levels induced by HFM as part of an endogenous antioxidant response to postprandial stress can be prevented by the concomitant ingestion of antioxidant-rich fruit juice drinks. PMID- 23930844 TI - Determinants of functional mitral regurgitation severity in patients with ischemic cardiomyopathy versus nonischemic dilated cardiomyopathy. AB - AIMS: Functional mitral regurgitation (MR) is prevalent among patients with left ventricular (LV) dysfunction and is associated with a poorer prognosis. Our aim was to assess the primary determinants of MR severity in patients with ischemic cardiomyopathy (ICM) and nonischemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: Patients with functional MR secondary to ICM (n = 55) and DCM (n = 48) were prospectively enrolled. Effective regurgitant orifice (ERO) area, global LV remodeling, regional wall-motion abnormalities, and mitral apparatus deformity indices were assessed utilizing conventional and tissue Doppler echocardiography. ICM patients had more severe MR compared with DCM patients despite similar ejection fraction and functional status (ERO = 0.16 +/- 0.08 cm(2) vs. ERO = 0.12 +/- 0.70 cm(2) , respectively, P = 0.002). Regional myocardial systolic velocities in mid-inferior and mid-lateral wall were negatively correlated with ERO in ICM and DCM patients, respectively. Multivariate analysis identified coaptation height as the only independent determinant of ERO in both groups. In a subset of ICM patients (n = 9) with relatively high ERO despite low coaptation height, a higher prevalence of left bundle branch block was detected (88.9% vs. 46.7%, P = 0.02). CONCLUSIONS: Functional MR severity was chiefly determined by the extent of mitral apparatus deformity, and coaptation height can provide a rapid estimation of MR severity in heart failure patients. Additional contributory mechanisms in ICM patients include depressed myocardial systolic velocities in posteromedial papillary muscle attaching site and evidence of global LV dyssynchrony. PMID- 23930845 TI - Sciatic nerve lipomatosis and knee osteochondroma. PMID- 23930846 TI - Functional mapping. PMID- 23930847 TI - Deep brain stimulation. PMID- 23930848 TI - Unilateral versus bilateral deep brain stimulation. PMID- 23930849 TI - Methylation markers of malignant potential in meningiomas. AB - OBJECT: Although most meningiomas are benign, about 20% are atypical (Grade II or III) and have increased mortality and morbidity. Identifying tumors with greater malignant potential can have significant clinical value. This validated genome wide methylation study comparing Grade I with Grade II and III meningiomas aims to discover genes that are aberrantly methylated in atypical meningiomas. METHODS: Patients with newly diagnosed meningioma were identified as part of the Ohio Brain Tumor Study. The Infinium HumanMethylation27 BeadChip (Illumina, Inc.) was used to interrogate 27,578 CpG sites in 14,000 genes per sample for a discovery set of 33 samples (3 atypical). To verify the results, the Infinium HumanMethylation450 BeadChip (Illumina, Inc.) was used to interrogate 450,000 cytosines at CpG loci throughout the genome for a verification set containing 7 replicates (3 atypical), as well as 12 independent samples (6 atypical). A nonparametric Wilcoxon exact test was used to test for difference in methylation between benign and atypical meningiomas in both sets. Heat maps were generated for each set. Methylation results were validated for the 2 probes with the largest difference in methylation intensity by performing Western blot analysis on a set of 20 (10 atypical) samples, including 11 replicates. RESULTS: The discovery array identified 95 probes with differential methylation between benign and atypical meningiomas, creating 2 distinguishable groups corresponding to tumor grade when visually examined on a heat map. The validation array evaluated 87 different probes and showed that 9 probes were differentially methylated. On heat map examination the results of this array also suggested the existence of 2 major groups that corresponded to histological grade. IGF2BP1 and PDCD1, 2 proteins that can increase the malignant potential of tumors, were the 2 probes with the largest difference in intensity, and for both of these the atypical meningiomas had a decreased median production of protein, though this was not statistically significant (p = 0.970 for IGF2BP1 and p = 1 for PDCD1). CONCLUSIONS: A genome-wide methylation analysis of benign and atypical meningiomas identified 9 genes that were reliably differentially methylated, with the strongest difference in IGF2BP1 and PDCD1. The mechanism why increased methylation of these sites is associated with an aggressive phenotype is not evident. Future research may investigate this mechanism, as well as the utility of IGF2BP1 as a marker for pathogenicity in otherwise benign-appearing meningiomas. PMID- 23930850 TI - Results of gamma knife surgery for Cushing's disease. AB - OBJECT: Cushing's disease is a challenging neuroendocrine disorder. Although resection remains the primary treatment option for most patients, the disease persists if there is residual or recurrent tumor. Stereotactic radiosurgery has been used to treat patients with persistent Cushing's disease after a prior resection. The authors report on the long-term risks and benefits of radiosurgery for Cushing's disease. METHODS: A retrospective review of a prospectively collected database of radiosurgery patients was undertaken at the University of Virginia. All patients with Cushing's disease treated with Gamma Knife surgery (GKS) were identified. Those without at least 12 months of clinical and radiological follow-up were excluded from this analysis. Rates of endocrine remission, tumor control, and adverse events were assessed. Statistical methods were used to identify favorable and unfavorable prognostic factors. RESULTS: Ninety-six patients with the required follow-up data were identified. The mean tumor margin dose was 22 Gy. The median follow-up was 48 months (range 12-209.8 months). At the last follow-up, remission of Cushing's disease occurred in 70% of patients. The median time to remission among all patients was 16.6 months (range 1-165.7 months). The median time to remission in those who had temporarily stopped taking ketoconazole at the time of GKS was 12.6 months, whereas it was 21.8 months in those who continued to receive ketoconazole (p < 0.012). Tumor control was achieved in 98% of patients. New loss of pituitary function occurred in 36% of patients. New or worsening cranial neuropathies developed in 5 patients after GKS, with the most common involving cranial nerves II and III. CONCLUSIONS: Gamma Knife surgery offers a high rate of tumor control and a reasonable rate of endocrine remission in patients with Cushing's disease. The cessation of cortisol lowering medications around the time of GKS appears to result in a more rapid rate of remission. Delayed hypopituitarism and endocrine recurrence develop in a minority of patients and underscore the need for long-term multidisciplinary follow-up. PMID- 23930851 TI - Shaving. PMID- 23930852 TI - Normal pressure hydrocephalus. PMID- 23930853 TI - Overdrainage shunt complications in idiopathic normal-pressure hydrocephalus and lumbar puncture opening pressure. AB - OBJECT: Management of idiopathic normal-pressure hydrocephalus (iNPH) is hard because the diagnosis is difficult and shunt surgery has high complication rates. An important complication is overdrainage, which often can be treated with adjustable-shunt valve manipulations but also may result in the need for subdural hematoma evacuation. The authors evaluated shunt surgery overdrainage complications in iNPH and their relationship to lumbar puncture opening pressure (LPOP). METHODS: The authors reviewed the charts of 164 consecutive patients with iNPH who underwent shunt surgery at their institution from 2005 to 2011. They noted age, sex, presenting symptoms, symptom duration, hypertension, body mass index (BMI), imaging findings of atrophy, white matter changes, entrapped sulci, LPOP, valve opening pressure (VOP) setting, number of valve adjustments, serious overdrainage (subdural hematoma requiring surgery), radiological overdrainage (subdural hematomas or hygroma seen on postoperative imaging), clinical overdrainage (sustained or postural headache), other complications, and improvements in gait, urine control, and memory. RESULTS: Eight patients (5%) developed subdural hematomas requiring surgery. All had an LPOP of greater than 160 mm H2O and an LPOP-VOP of greater than 40 mm H2O. Radiological overdrainage was more common in those with an LPOP of greater than 160 mm H2O than in those with an LPOP of less than 160 mm H2O (38% vs. 21%, respectively; p = 0.024). The BMI was also significantly higher in those with an LPOP of greater than 160 mm H2O (median 30.2 vs. 27.0, respectively; p = 0.005). CONCLUSIONS: Serious overdrainage that caused subdural hematomas and also required surgery after shunting was related to LPOP and LPOP-VOP, which in turn were related to BMI. If this can be replicated, individuals with a high LPOP should have their VOP set close to the LPOP, or even higher. In doing this, perhaps overdrainage complications can be reduced. PMID- 23930855 TI - Velocity and pressure gradients of cerebrospinal fluid assessed with magnetic resonance imaging. AB - OBJECT: New approaches for understanding CSF motion in healthy individuals and patients with hydrocephalus and Chiari malformation are presented. The velocity and the pressure gradient of CSF motion were determined using phase contrast (PC) MRI. METHODS: The authors examined 11 healthy control subjects and 2 patients (1 with hydrocephalus and 1 with Chiari malformation), using 4-dimensional PC (4D PC) MRI and a newly developed computer analysis method that includes calculation of the pressure gradient from the velocity field. Sagittal slices including the center of the skull and coronal slices of the foramen of Monro and the third ventricle were used. RESULTS: In the ventricular system, mixing and swirling of the CSF was observed in the third ventricle. The velocity images showed that the CSF was pushed up and back down to the adjacent ventricle and then returned again to the third ventricle. The CSF traveled bidirectionally in the foramen of Monro and sylvian aqueduct. Around the choroid plexus in the lateral ventricle, the CSF motion was stagnant and the CSF pressure gradient was lower than at the other locations. An elevated pressure gradient was observed in the basal cistern of the subarachnoid space. Sagittal imaging showed that the more prominent pressure gradients originated around the cisterna magna and were transmitted in an upward direction. The coronal image showed a pressure gradient traveling from the central to the peripheral subarachnoid spaces that diminished markedly in the convexity of the cerebrum. The 2 patients, 1 with secondary hydrocephalus and 1 with Chiari malformation, were also examined. CONCLUSIONS: The observed velocity and pressure gradient fields delineated the characteristics of the CSF motion and its similarities and differences among the healthy individuals and between them and the 2 patients. Although the present results did not provide general knowledge of CSF motion, the authors' method more comprehensively described the physiological properties of the CSF in the skull than conventional approaches that do not include measurements of pressure gradient fields. PMID- 23930856 TI - Cerebrovascular complications and granuloma formation after wrapping or coating of intracranial aneurysms with cotton gauze and human fibrin adhesives: results from a single-center patient series over a 5-year period. AB - OBJECT: Reinforcement of intracranial aneurysms (IAs) by wrapping or coating is a well-established therapeutic approach to those IAs not amenable to any other definitive treatment, but has been associated with complications such as parent artery narrowing, granuloma formation, and ischemic stroke. The goal of this study was to systematically investigate cerebrovascular complications following this procedure. METHODS: The authors' hospital database was searched for all patients who underwent wrapping or coating of IAs with cotton gauze and human fibrin adhesives between October 2006 and October 2011. The follow-up records of these patients were extracted, including regular clinical visits and vascular imaging. RESULTS: Five hundred sixty-seven patients were treated for IAs over the 5-year period: 303 patients underwent endovascular strategies and 264 underwent craniotomies. Wrapping or coating of IAs was performed in 20 patients (3.5%). Parent artery narrowing occurred in 5 (25%) of the 20 patients and was associated with major ischemic strokes in 4 patients and severe headache in another. Ischemic strokes were associated with parent artery narrowing, which occurred early postoperatively in 2 patients or was a consequence of granuloma formation in 2 patients 1 and 2 months after the procedure, respectively. CONCLUSIONS: These data should add to the awareness of significant cerebrovascular complications following wrapping or coating of IAs with cotton gauze and human fibrin adhesives and indicate that major ischemic strokes need to be included in the risk/benefit considerations during decision making for such treatment strategies. Patients who receive IA wrapping should be monitored and followed up closely for arterial narrowing and granuloma formation. PMID- 23930857 TI - Cushing's disease and stereotactic radiosurgery. PMID- 23930858 TI - Right parietal cortex and calculation processing: intraoperative functional mapping of multiplication and addition in patients affected by a brain tumor. AB - OBJECT: The role of parietal areas in number processing is well known. The significance of intraoperative functional mapping of these areas has been only partially explored, however, and only a few discordant data are available in the surgical literature with regard to the right parietal lobe. The purpose of this study was to evaluate the clinical impact of simple calculation in cortical electrostimulation of right-handed patients affected by a right parietal brain tumor. METHODS: Calculation mapping in awake surgery was performed in 3 right handed patients affected by high-grade gliomas located in the right parietal lobe. Preoperatively, none of the patients presented with calculation deficits. In all 3 cases, after sensorimotor and language mapping, cortical and intraparietal sulcus areas involved in single-digit multiplication and addition calculations were mapped using bipolar electrostimulation. RESULTS: In all patients, different sites of the right parietal cortex, mainly in the inferior lobule, were detected as being specifically related to calculation (multiplication or addition). In 2 patients the intraparietal sulcus was functionally specific for multiplication. No functional sites for language were detected. All sites functional for calculation were spared during tumor resection, which was complete in all cases without postoperative neurological deficits. CONCLUSIONS: These findings provide intraoperative data in support of an anatomofunctional organization for multiplication and addition within the right parietal area. Furthermore, the study shows the potential clinical relevance of intraoperative mapping of calculation in patients undergoing surgery in the right parietal area. Further and larger studies are needed to confirm these data and assess whether mapped areas are effectively essential for function. PMID- 23930859 TI - Radiosurgery for parasagittal and parafalcine meningiomas. PMID- 23930860 TI - Recurrent glioma. PMID- 23930861 TI - Radiosurgery for parasagittal and parafalcine meningiomas. AB - OBJECT: Parasagittal and parafalcine (PSPF) meningiomas represent the second most common location for intracranial meningiomas. Involvement of the superior sagittal sinus or deep draining veins may prevent gross-total resection of these tumors without significant morbidity. The authors review their results for treatment of PSPF meningiomas with radiosurgery. METHODS: The authors retrospectively reviewed the institutional review board-approved University of Virginia Gamma Knife database and identified 65 patients with 90 WHO Grade I parasagittal (59%) and parafalcine (41%) meningiomas who had a mean MRI follow-up of 56.6 months. The patients' mean age was 57 years, the median preradiosurgery Karnofsky Performance Status score was 80, and the median initial tumor and treatment volumes were 3 and 3.7 cm(3), respectively. The median prescription dose was 15 Gy, isodose line was 40%, and the number of isocenters was 5. Kaplan Meier analysis was used to determine progression-free survival (PFS). Univariate and multivariate Cox regression analyses were used to identify factors associated with PFS. RESULTS: The median overall PFS was 75.6 months. The actuarial tumor control rate was 85% at 3 years and 70% at 5 years. Parasagittal location, no prior resection, and younger age were found to be independent predictors of tumor PFS. For the 49 patients with clinical follow-up (mean 70.8 months), the median postradiosurgery Karnofsky Performance Status score was 90. Symptomatic postradiosurgery peritumoral edema was observed in 4 patients (8.2%); this group comprised 3 patients (6.1%) with temporary and 1 patient (2%) with permanent clinical sequelae. Two patients (4.1%) died of tumor progression. CONCLUSIONS: Radiosurgery offers a minimally invasive treatment option for PSPF meningiomas, with a good tumor control rate and an acceptable complication rate comparable to most surgical series. PMID- 23930862 TI - Wrong-site craniotomy. PMID- 23930863 TI - Exploring the desumoylation process of SENP1: a study combined MD simulations with QM/MM calculations on SENP1-SUMO1-RanGAP1. AB - The small ubiquitin-related modifier (SUMO)-specific protease (SENP) processes SUMOs to mature forms and deconjugates them from various modified substrates. Loss of the equilibrium from desumoylation catalyzed by abnormal SENP1 is associated with cancers and transcription factor activity. In spite of the significant role of SENP1, the molecular basis of its desumoylation remains unclear. Here, MD simulations and QM/MM methods are combined to investigate the catalytic mechanism of desumoylation. The results showed that substrate SUMO1 RanGAP1 fitted into the catalytic pocket of SENP1 by the break of internal hydrophobic interactions and the isomerization of isopeptide from trans to cis. After that, the nucleophilic sulfur anion of Cys603 in SENP1 attacked the carbonyl carbon of Gly97 of SUMO1 to trigger the reaction, and then a tetrahedral intermediate and an acyl-enzyme intermediate were generated in turn, leading to the final release of enzyme SENP1 and two products, free SUMO1 and RanGAP1. In the process, nucleophilic attack was identified as the rate-determining step with a potential energy barrier of 20.2 kcal/mol. These results are in agreement with experimental data from mutagenesis and other experiments. Our findings elucidate the catalytic mechanism of SENP1 with its substrate and may provide a better understanding of SENP desumoylation. In particular, we have identified key residues in SENP1 needed for desumoylation that might be beneficial for the design of novel inhibitors of SENP1-related diseases. PMID- 23930864 TI - Sex differences associated with intermittent swim stress. AB - Various animal models of depression have been used to seek a greater understanding of stress-related disorders. However, there is still a great need for novel research in this area, as many individuals suffering from depression are resistant to current treatment methods. Women have a higher rate of depression, highlighting the need to investigate mechanisms of sex differences. Therefore, we employed a new animal model to assess symptoms of depression, known as intermittent swim stress (ISS). In this model, the animal experiences 100 trials of cold water swim stress. ISS has already been shown to cause signs of behavioral depression in males, but has yet to be assessed in females. Following ISS exposure, we looked at sex differences in the Morris water maze and forced swim test. The results indicated a spatial learning effect only in the hidden platform task between male and female controls, and stressed and control males. A consistent spatial memory effect was only seen for males exposed to ISS. In the forced swim test, both sexes exposed to ISS exhibited greater immobility, and the same males and females also showed attenuated climbing and swimming, respectively. The sex differences could be due to different neural substrates for males and females. The goal of this study was to provide the first behavioral examination of sex differences following ISS exposure, so the stage of estrous cycle was not assessed for the females. This is a necessary future direction for subsequent experiments. The current article highlights the importance of sex differences in response to stress. PMID- 23930865 TI - Collaboration between family medicine and emergency medicine for integrated care in Pakistan. PMID- 23930866 TI - Efficacy of pre-incisional peritonsillar infiltration of ketamine for post tonsillectomy analgesia in children. AB - OBJECTIVE: To assess the efficacy of pre-incisional peritonsillar infiltration of two doses of ketamine on postoperative analgesia compared with peritonsillar normal saline in children undergoing tonsillectomy. STUDY DESIGN: Double blind, randomized controlled trial. PLACE AND DURATION OF STUDY: Department of Anaesthesiology, Surgical Intensive Care and Pain Management, Civil Hospital, Karachi, Dow University of Health Sciences, from August 2008 to January 2009. METHODOLOGY: Seventy-five ASA physical status one patients, aged 5 - 12 years scheduled for tonsillectomy were enrolled in this study. Patients were divided into three groups of 25 each. Group-A received normal saline, Group-B, ketamine 0.5 mg/kg while group-C ketamine 1 mg/kg respectively. All medications were 2 ml and were applied 1 ml per tonsil; 3 minutes before tonsillectomy incision. Anaesthesia was induced and maintained with standard technique. All patients were monitored throughout surgery. The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and Wilson sedation scale were used to evaluate pain levels and sedation respectively after operation. RESULTS: Mean duration of analgesia was significantly higher in group-C (17.28 +/- 5.33 hours) as compared to group-B (11.36 +/- 4.15 hours) and A (3.2 +/- 0.71 hours) as well as group-B was also significantly higher than group-A (p < 0.05). Group-A had significantly higher pain scores than group-B and group-C. Both B and C groups had comparable pain scores, which were statistically significant at 6 and 8 hours. CONCLUSION: Single 0.5 or 1 mg/kg injection of ketamine given before surgical incision by peritonsillar infiltration provides efficient pain relief during postoperative period without significant side-effects in children undergoing tonsillectomy. PMID- 23930867 TI - Frequency of diabetic cardiomyopathy among type-2 diabetics presenting as heart failure. AB - OBJECTIVE: To determine the frequency of diabetic cardiomyopathy among patients with type-2 diabetes presenting with overt heart failure. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Department of Cardiology, Mayo Hospital, Lahore, from April 2008 to July 2009. METHODOLOGY: One hundred patients with type 2 diabetes mellitus having symptoms and signs of heart failure were enrolled. Anthropometric parameters were recorded and all patients had investigations including complete blood count, blood glucose (fasting and random), serum creatinine, fasting lipid profile, haemoglobin A1c, chest X-ray, electrocardiogram and Doppler echocardiography. After stabilization, every patient underwent coronary angiography. The data was entered in a structured proforma. RESULTS: Sixty (60%) patients were males and 40 (40%) were females. Duration of diabetes was > 10 years in all. Eighty (80%) were on oral hypoglycemic and 20 (20%) were on insulin. Diabetic cardiomyopathy was found in 40 patients (40%) of the total study patients. Forty percent (40%) patients had marked left ventricular (LV) systolic dysfunction (ejection fraction < 30%). Three (5%) patients died during hospitalization. CONCLUSION: Diabetic cardiomyopathy is a fairly common cause of heart failure in the native population with type-2 diabetes mellitus and results in high morbidity and mortality. PMID- 23930868 TI - Congenital heart disease screening: which referral factors are most important? AB - OBJECTIVE: To identify the referral factors for fetal echocardiography which are associated with congenital cardiac defects in the fetus. STUDY DESIGN: Cross sectional descriptive study. PLACE AND DURATION OF STUDY: Radiology Department, CMH, Rawalpindi, from January 2007 to November 2010. METHODOLOGY: All patients referred for fetal echocardiography with one or more risk factors for the development of congenital heart disease, and those patients with incidental discovery of congenital heart disease on antenatal ultrasound were evaluated. Patients with no risk factors who were found to have normal fetal echocardiography were excluded from the study. Univariate logistic regression analysis was carried out for each variable. The variables with statistical significance of less than 0.05 were subjected to multivariate logistic regression. Fetal echocardiographic diagnosis was taken as the dependent variable and all other variables were the independent variables. RESULTS: Two hundred and sixty four patients were evaluated by fetal echocardiography for congenital heart disease. The statistically significant factor was detection of congenital heart disease on routine ultrasound examination. CONCLUSION: A routine obstetric scan should include evaluation of the heart with four-chamber and base-of-heart views to exclude cardiac anomalies. A cardiac anomaly picked up on routine ultrasound scan is the most important indication for referral for fetal echocardiography. Fetal arrhythmias and echogenic focus in the left ventricle do not have a significant association with structural cardiac malformation. PMID- 23930869 TI - Ultrasound based evaluation of hepatic steatosis and fibrosis in hepatitis C non responders. AB - OBJECTIVE: To determine the accuracy of ultrasound in the diagnosis and grading of steatosis and fibrosis in Hepatitis C (HCV) patients not responding to ribavarin-interferon therapy. STUDY DESIGN: A cross-sectional, analytical study. PLACE AND DURATION OF STUDY: Radiology Department, Civil Hospital, Karachi, from March 2008 to August 2010. METHODOLOGY: Patients with positive HCV RNA despite 24 weeks ribavarin-interferon therapy (non-responders) were subjected to ultrasound and biopsy prior to institution of pegylated interferon therapy for detection and grading of steatosis and fibrosis. Using histopathology as the gold standard, sensitivity, specificity, negative and positive predictive values for ultrasound were determined. RESULTS: The sensitivity of ultrasound for hepatic steatosis was 90.9% for no steatosis (NS), 100% for moderate and gross steatosis and 84.4% for mild steatosis with 100% specificity. The sensitivity for fibrosis was 25% for no fibrosis, 100% for mild fibrosis, 89.74% for moderate fibrosis and 100% for gross fibrosis. The overall accuracy for detection of steatosis was 95.39% and that for fibrosis was 98.02%. Hepatic vein showed increased dampening of flow with advancing grades of steatosis and fibrosis. CONCLUSION: Ultrasound has a high accuracy in the diagnosis and grading of steatosis and fibrosis in HCV nonresponders. Mild fibrosis may confound the diagnosis of mild steatosis. PMID- 23930870 TI - Role of genetic counselling in prenatal diagnosis of beta-thalassaemia in Pakistan. AB - OBJECTIVE: To compare the response towards prenatal diagnosis (PND) of b thalassaemia, in individuals who had not received genetic counselling and a genetically counselled population. STUDY DESIGN: Cross-sectional survey. PLACE AND DURATION OF STUDY: Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from March 2009 to December 2010. METHODOLOGY: Using non-probability consecutive sampling, a total of 176 individuals having thalassaemic children, were interviewed regarding PND of thalassaemia, by using a structured questionnaire. Forty two individuals were taken as controls as they had received genetic counselling for PND, whereas the remaining 134 were taken as cases. Responses towards PND were compared using chi-square test. Odds ratio was also calculated for subsequent PND utilization. RESULTS: Seventy (52.2%) cases and 42 (100%) controls were aware of the availability of PND in Pakistan. This difference in awareness was statistically significant (p < 0.001). In the controls, 40 (95.3%) individuals were aware of the appropriate timing of the test, in contrast to 52 (39%) cases (p < 0.001). PND was used in subsequent pregnancies by 50 (37.3%) cases and 32 (80%) controls (p < 0.001). The calculated odds ratio for subsequent PND utilization was 5.37. CONCLUSION: The study reflects a very positive attitude of genetically counselled thalassaemia affected families towards PND. For better utilization of PND, genetic counselling services should be available at all health strata. PMID- 23930871 TI - Wound healing without drains in posterior spinal fusion in idiopathic scoliosis. AB - OBJECTIVE: To determine the frequency of wound infection and neurological injuries in patients with idiopathic scoliosis who underwent posterior spinal fusion without use of drains. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Department of Orthopaedics, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia, from February 2007 to June 2010. METHODOLOGY: Patients who underwent similar technique of posterior spinal fusion instrumentation for the correction of scoliosis without use of drain were included. Wound Demographics, wound healing, complications and duration of hospital stay were considered and described as frequency and mean values. RESULTS: The average age at the time of surgery was 12.80 +/- 1.30 years, duration of surgery was 3.80 +/- 0.86 hours, hospital stay was 3.84 +/- 0.78 days and patients were followed-up over the last 30 months. There was no incidence of any neurological complication and deep infection. However, only 2 (4.16%) cases with superficial skin infection were treated with dressing and antibiotics with full recovery. CONCLUSION: The wound healing is adequate without using drain for patients with idiopathic scoliosis who underwent posterior spinal fusion and instrumentation when good wash, watertight closure technique and appropriate antibiotics coverage is provided. PMID- 23930872 TI - Effect of early release of tourniquet in total knee arthroplasty. AB - OBJECTIVE: To evaluate whether tourniquet release intraoperatively is better than postoperative release in reducing overall blood loss, duration of surgery, duration of tourniquet, length of hospital stay, wound related complications and transfusion requirement. STUDY DESIGN: Comparative study. PLACE AND DURATION OF STUDY: Department of Surgery, The Aga Khan University Hospital, Karachi, from January 2004 to June 2007. METHODOLOGY: One hundred and thirty patient files were reviewed retrospectively. Patients were divided into two groups. Group-A consisted of 65 patients with early deflation of tourniquet and group-B comprised of 65 patients with the release of tourniquet after applying compressive dressing. Total blood loss (determined by Gross method) and other study variables were noted as per objective and computed. RESULTS: There were 22 males and 108 females with comparable BMI. All had undergone posterior stabilized cemented total knee replacement. Calculated blood loss was 1.208 L and 1.108 L in group-A and B respectively (p = 0.27). Significant increase in duration of surgery was noted in group-A patients. Four patients in group-B showed complication related to wound with 3 being minor and 1 requiring additional operation room visit. Mean length of hospital stay was 9 days. Transfusion frequency was higher in group-B despite comparable postoperative haemoglobin values. CONCLUSION: Intraoperative tourniquet release does not reduce overall blood loss with no effect in conserving blood after total knee replacement, however, this group had relatively shorter hospital stay. PMID- 23930873 TI - Clinical course of retinoblastoma. AB - OBJECTIVE: To determine the clinical manifestations and results of current treatment for patients with retinoblastoma (Rb) in a tertiary care eye hospital in the north west of Pakistan. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan, from January 2006 and December 2009. METHODOLOGY: The data of 139 patients diagnosed as having retinoblastoma was collected. Gender, age at diagnosis, laterality, presenting sign, classification of tumour, treatment modality and outcome were noted. RESULTS: The mean age of presentation in this patients ranged from 6 to 50 months (mean: 24.05 +/- 10.74 months). The most common presenting sign was leucocoria in 78 eyes (44.1%). One hundred and one (72.7%) patients had unilateral retinoblastoma. Using the International Classification of Retinoblastoma (ICRB), 135 (76.3%) eyes were placed in group-E. one hundred and twenty four (77.5%) eyes were enucleated or exenterated while globe preservation was achieved by chemoreduction and/or focal therapy in the rest of the treated eyes (n = 36, 22.5%). Twenty three (16.5%) cases were lost to follow-up before one year. Ninety two (66.2%) patients survived, being free of tumour, at least one year after the completion of treatment. CONCLUSION: Most children with Rb showed an advanced stage of tumour at the time of diagnosis. Measures to improve the rate of globe preservation and patient survival by early diagnosis and intervention are the need of the hour. PMID- 23930874 TI - Severe combined immune deficiency syndrome. AB - OBJECTIVE: To determine the clinico-demographic features and laboratory parameters of children with severe combined immunodeficiency (SCID). STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Department of Paediatrics and Child Health, the Aga Khan University, Karachi, from July 2006 to July 2011. METHODOLOGY: Thirteen infants who were discharged with a diagnosis of SCID were inducted in the study. Their clinicodemographic features and laboratory parameters were determined. Descriptive statistics has been used for computing frequency and percentage. RESULTS: The median age at diagnosis was five months; 5 infants presented within 3 months of life. Three-fourth (77%) were males. Most of the infants were severely malnourished (85%) at the time of presentation. More than two-thirds (69%) were products of consanguineous marriages. All subjects had severe lymphopenia {absolute lymphocyte count (ALC) ranging between 170 - 2280} and low T and B lymphocyte counts. CONCLUSION: SCID should be considered in infants presenting with severe and recurrent infections. Low ALC (< 2500/mm3), is a reliable diagnostic feature of SCID. These infants should be promptly referred to a facility where stem cell transplant can be done. PMID- 23930875 TI - An overview of the predictors of depression among adult Pakistani women. AB - Diseases of women that are due to their gender specific roles and responsibilities result from cultural and social factors prevalent in the environs. World Health Organization has put special emphasis on research need regarding gender related factors for diseases disproportionately affecting women in developing countries. The objective of this write up was to determine the prevalence of depression and the associated risk factors among adult women in Pakistan. PubMed was searched using key words depression, risk factors, women and Pakistan. Out of 20 initially retrieved articles, 12 were directly related to depression and its risk factors among Pakistani women within Pakistani geographical context. Women in Pakistan are vulnerable to poor mental health due to marriage related issues, domestic violence, verbal or physical abuse by in laws, stressful life and poor social conditions. Women in their perinatal period are more at risk of depression due to pregnancy related concerns. PMID- 23930876 TI - Double-lock technique: a simple method to secure abdominal wall closure. AB - Secure closure of a laparotomy incision remains an important aspect of any abdominal operation with the aim to avoid the postoperative morbidity and hasten the patient's recovery. Depending on the operator's preference and experience, it may be done by the continuous or the interrupted methods either using a non absorbable or delayed-absorbable suture. We describe a simple, secure and quick technique of abdominal wall closure which involves continuous suture inter-locked doubly after every third bite. This simple and easy to use mass closure technique can be easily mastered by any member of the surgical team and does not need any assistant. It amalgamates the advantages of both, the continuous and the interrupted methods of closures. To our knowledge, such a technique has not been reported in the literature. PMID- 23930877 TI - Airway management in a patient with bullous pemphigoid. AB - Airway management in patients with pemphigoid lesions has anaesthetic implications. We report a case of a 23 years old female with bullous pemphigoid who presented with laryngeal stenosis and critical airway narrowing. The airway was initially managed with jet ventilation. Anaesthesia was maintained with propofol infusion and ventilation was performed by introducing a size 10 French gauge suction catheter through the stenotic laryngeal orifice. Thirty minutes into anaesthesia, she developed subcutaneous emphysema and decreased air entry on right side of the chest but remained hemodynamically stable. The airway was further managed by tracheostomy. This case report highlights complications that can occur during the anaesthetic management of such cases. PMID- 23930878 TI - Zosteriform cutaneous leiomyoma: a rare cutaneous neoplasm. AB - Cutaneous leiomyomas are firm, round to oval, skin-coloured to brownish papules and nodules that may present as a solitary, few discrete or multiple clustered lesions. Different uncommon patterns of multiple leiomyoma distribution have been noted as bilateral, symmetrical, linear, zosteriform, or dermatomal-like arrangement. One such rare presentation was seen in a 23-year-old patient who presented with zosteriform skin coloured, occasionally painful cutaneous lesions over left shoulder region. Histopathology confirmed the diagnosis of cutaneous leiomyoma. He was symptomatically managed with non-steroidal anti-inflammatory agents and topical capcicum cream. Case is reported here due to rare occurrence of this benign cutaneous neoplasm in an atypical pattern and on uncommon site. PMID- 23930879 TI - Multiple disseminated pyogenic granulomas. AB - Pyogenic granulomas (Granuloma telengiectaticum) or lobular capillary haemangioma are classically described as solitary lesions, occurring in young individuals, usually at the site of previous trauma, with a tendency to recur after treatment. We describe an unusual case of multiple disseminated pyogenic granulomas in an elderly male caucasoid of Pakistani origin in whom more than 400 lesions occurred de novo without any antecedent history of trauma or skin disease, responded well to treatment and showed no tendency for recurrence. Multiple eruptive pyogenic granulomas are probably a rare subset of the disease, which can occur at any age, arise de novo or in association with a skin or systemic disease and do not exhibit a tendency to recur after treatment. PMID- 23930880 TI - Discrepancy in ABO blood grouping. AB - Discrepancies in blood typing is one of the major reasons in eliciting a transfusion reaction. These discrepancies can be avoided through detailed analysis for the blood typing. Here, we report a subgroup of blood group type-B in the ABO system. Donor's blood was analyzed by employing commercial antisera for blood grouping. The results of forward (known antisera) and reverse (known antigen) reaction were not complimentary. A detailed analysis using the standard protocols by American Association of Blood Banking revealed the blood type as a variant of blood group-B instead of blood group-O. This is suggestive of the fact that blood group typing should be performed with extreme care and any divergence, if identified, should be properly resolved to avoid transfusion reactions. Moreover, a major study to determine the blood group variants in Pakistani population is needed. PMID- 23930881 TI - Periocular infantile haemangioma and the role of propranolol. AB - This case of a four and a half-month-old girl describes periocular infantile haemangioma which was treated successfully with propranolol. She developed a red coloured lesion around the left upper eye lid at one week of age. A gradual increase was noticed in the size of the lesion and by the age of four and a half months, the swelling had increased enough to cover her visual axis, completely occluding her left eye. Oral propranolol therapy was initiated with a daily dosage of 1 mg/kg body weight. The dose was increased gradually, and there was an excellent response to propranolol treatment. A complete eye opening was observed 8 months after the initiation of this treatment. PMID- 23930882 TI - A 7-month-old infant with Cushing's disease. AB - Cushing's disease in children is not rare but in infants it is quite rare and an important medical condition needing proper line of investigations and management options. Craniopharyngioma as a cause of Cushing's disease is well reported and practical inference of the condition is of clinical importance. Craniopharyngioma generally affects children at 5 - 10 years of age and is rarely seen in infancy. It usually manifests as endocrinological deficits such as short stature, delayed puberty, and obesity. We report the case of a 7 months old infant who presented with obesity and Cushing's disease associated with craniopharyngioma. PMID- 23930883 TI - Necrotizing enterocolitis in a newborn following intravenous immunoglobulin treatment for haemolytic disease. AB - ABO iso-immunization is the most frequent haemolytic disease of the newborn. Treatment depends on the total serum bilirubin level, which may increase very rapidly in the first 48 hours of life in cases of haemolytic disease of the newborn. Phototherapy and, in severe cases, exchange transfusion are used to prevent hyperbilirubinaemic encephalopathy. Intravenous immunoglobulins (IVIG) are used to reduce exchange transfusion. Herein, we present a female newborn who was admitted to the NICU because of ABO immune haemolytic disease. After two courses of 1 g/kg of IVIG infusion, she developed necrotizing enterocolitis (NEC). Administration of IVIG to newborns with significant hyperbilirubinaemia due to ABO haemolytic disease should be cautiously administered and followed for complications. PMID- 23930884 TI - A double toe-to-hand transfer in a young girl. AB - A 14 years old girl lost all the fingers of her right hand except the thumb in a Toka (fodder chopping machine) 4 months ago. The fingers had been amputated at the level of the metacarpophalangeal joint. A double toe transfer was done using the second and third toes of her right foot to reconstruct the second and third digits of her right hand using microvascular technique. Bones were fixed with K wires, corresponding tendons and nerves were attached, the dorsalis pedis artery was anastamosed end-to-side to the radial artery and the vein was anastamosed to the cephalic vein. The patient recovered well. K-wires were removed at 6 weeks and physiotherapy was started. After 4 months, the patient was able to use the hand for normal hand function and could make a tripod pinch. PMID- 23930885 TI - Illuminating the dark side--vitamin D status in different localities of Karachi. AB - This study was conducted to determine the association between place of residence (grouped into neighbourhoods), and 25-hydroxy D (25[OH]D) levels of individuals of Karachi. Addresses of 4788 individuals tested for 25[OH]D at the clinical laboratory of the Aga Khan University (AKU), Karachi, from January 2007 to June 2008 were reviewed. The neighbourhoods were categorized into ten, based on locality attributes. A high overall prevalence (74%) of vitamin D deficiency (VDD) was observed. There was a significant difference (p-value < 0.01) between mean log 25[OH]D levels amongst neighbourhoods grouped according to distinct housing structure attributes and localities. A high frequency of VDD in all the studied localities of an urban city warrant dietary vitamin D supplementation and food fortification. PMID- 23930886 TI - Convergence of technologies: the print, web and multimedia united to deliver an integrated basic medical sciences course in a resource limited setting. AB - This mixed methodology study was conducted at Shifa College of Medicine to see if study guide, module website and multimedia compact disk can be used to deliver an integrated basic sciences course while introducing the concepts of evidence based medicine and how it translates in students' performance. The study guide focused on the management of learning, activities and provision of information. The website was used to introduce evidence based medicine while the multimedia disc provided pictures, videos and animations for organs of special senses. Feedback questionnaire and end of module result were used to evaluate the module and its learning tools. The students agreed that the study guide, module website and multimedia compact disc facilitated their learning experience. PMID- 23930887 TI - Diets in liver diseases. PMID- 23930888 TI - Cancer registration in Pakistan. PMID- 23930889 TI - Tradition or change? Sources of body procurement for the Anatomical Institute of the University of Cologne in the Third Reich. AB - While it is known that all German anatomical institutes that have been examined made use of the bodies of victims of the National Socialist (NS) regime for teaching and research between 1933 and 1945, detailed investigations on many institutions are still missing. Among these is the anatomical institute of the University of Cologne. This university was the first university to voluntarily self-align with the policies of the new regime and was therefore often called a 'model NS university'. In addition, Cologne was the site of a NS special court and a central place for executions. Based on archival sources, this study investigates the interaction between the anatomical institute of the University of Cologne with the NS authorities and the origin of the body supply for dissection and research. The documents reveal that the institute continued to receive bodies from traditional sources like the public morgue and hospitals, but with the beginning of World War II (WWII) an increasing amount of bodies of victims of the NS regime became available. Thus, the anatomical institute of Cologne collaborated and benefited from the policies of the NS regime, especially during WWII, like all other already explored anatomical institutes in Germany to varying degrees. PMID- 23930890 TI - The mechanism of borane-amine dehydrocoupling with bifunctional ruthenium catalysts. AB - Borane-amine adducts have received considerable attention, both as vectors for chemical hydrogen storage and as precursors for the synthesis of inorganic materials. Transition metal-catalyzed ammonia-borane (H3N-BH3, AB) dehydrocoupling offers, in principle, the possibility of large gravimetric hydrogen release at high rates and the formation of B-N polymers with well defined microstructure. Several different homogeneous catalysts were reported in the literature. The current mechanistic picture implies that the release of aminoborane (e.g., Ni carbenes and Shvo's catalyst) results in formation of borazine and 2 equiv of H2, while 1 equiv of H2 and polyaminoborane are obtained with catalysts that also couple the dehydroproducts (e.g., Ir and Rh diphosphine and pincer catalysts). However, in comparison with the rapidly growing number of catalysts, the amount of experimental studies that deal with mechanistic details is still limited. Here, we present a comprehensive experimental and theoretical study about the mechanism of AB dehydrocoupling to polyaminoborane with ruthenium amine/amido catalysts, which exhibit particularly high activity. On the basis of kinetics, trapping experiments, polymer characterization by (11)B MQMAS solid state NMR, spectroscopic experiments with model substrates, and density functional theory (DFT) calculations, we propose for the amine catalyst [Ru(H)2PMe3{HN(CH2CH2PtBu2)2}] two mechanistically connected catalytic cycles that account for both metal-mediated substrate dehydrogenation to aminoborane and catalyzed polymer enchainment by formal aminoborane insertion into a H-NH2BH3 bond. Kinetic results and polymer characterization also indicate that amido catalyst [Ru(H)PMe3{N(CH2CH2PtBu2)2}] does not undergo the same mechanism as was previously proposed in a theoretical study. PMID- 23930891 TI - A novel approach to determine solid fraction using a laser-based direct volume measurement device. AB - Material properties play a significant role in pharmaceutical processing. In the present study, a novel approach is used to determine solid fraction (SF) based on a direct measurement (DM) of the apparent volume of a sample. The sample was scanned with low intensity laser beams that integrate the sample thickness across the surface (area) and quantitate the apparent volume. The SF by DM method was compared against that obtained by volume displacement (VD) and manual measurement methods. SF was determined by all three methods for formulations of Avicel DG, lactose and a 1:1 mixture of the two. The results from DM method and variability were comparable to that obtained by VD method. The manual method provided lower and more variable results. The DM method was able to differentiate between SF of different ribbon and tablet formulations and at varying force levels. Tracking SF of compacts during tablet development can help in setting acceptable specifications and to understand material deformation behavior during compression. Further, the results of the study indicate that the DM method using laser scan technique was suitable for routine testing of SF of roller compacted ribbons and compressed tablets. PMID- 23930893 TI - Paternal fibrillin-1 mutation transmitted to an affected son with neonatal marfan syndrome: the importance of early recognition. AB - We describe a case of neonatal Marfan syndrome diagnosed because of a family history, dysmorphic features, and cardiac abnormality. The echocardiogram showed aortic root dilatation. Molecular genetic studies showed a mutation in exon 31 of the FBN1 gene in the infant and father. The infant was treated with losartan, which significantly slowed the rate of enlargement of the aorta. PMID- 23930894 TI - Mechanistic analysis of the pump cycle of the KdpFABC P-type ATPase. AB - The high-affinity potassium uptake system KdpFABC is a unique type Ia P-type ATPase, because it separates the sites of ATP hydrolysis and ion transport on two different subunits. KdpFABC was expressed in Escherichia coli. It was then isolated and purified to homogeneity to obtain a detergent-solubilized enzyme complex that allowed the analysis of ion binding properties. The electrogenicity and binding affinities of the ion pump for K(+) and H(+) were determined in detergent-solubilized complexes by means of the electrochromic styryl dye RH421. Half-saturating K(+) concentrations and pK values for H(+) binding could be obtained in both the unphosphorylated and phosphorylated conformations of KdpFABC. The interaction of both ions with KdpFABC was studied in detail, and the presence of independent binding sites was ascertained. It is proposed that KdpFABC reconstituted in vesicles translocates protons at a low efficiency opposite from the well-established import of K(+) into the bacteria. On the basis of our results, various mechanistic pump cycle models were derived from the general Post-Albers scheme of P-type ATPases and discussed in the framework of the experimental evidence to propose a possible molecular pump cycle for KdpFABC. PMID- 23930896 TI - Factors associated with HIV-testing history among Black men who have sex with men (BMSM) in Los Angeles County. AB - Black men who have sex with men (BMSM) are disproportionately affected with HIV, and nearly half are unaware of their status. Those unaware of their status are more likely to engage in risky behavior; thus, HIV-testing uptake is crucial. This study explored correlates of past-two-year HIV-testing history. BMSM (n = 102) completed self-administered questionnaires. Fisher exact test indicated that BMSM at clubs/bars and Gay Pride events had higher rates of being tested within the past two years (86%-65%) than did participants who responded to online advertisements (44%, p < .001). Among those untested for HIV, slightly half reported receptive anal sex without a condom (48%, p = .033), used the Internet seeking sex (54%, p < .001), low HIV knowledge (52%, p = .005), and less education. Literacy and tailored online interventions might be worth considering to increase HIV-testing uptake. PMID- 23930897 TI - Investigating self-reported health behaviors in Australian adults with mental illness. AB - To investigate self-reported health behaviors among Australian adults with mental illness, 1,935 Australian adults completed an online survey including the Kessler Psychological Distress Scale and instruments assessing health behaviors in October 2011. Participants with moderate or higher psychological distress reported significantly lower weekly physical activity levels ( p = .024), daily fruit ( p = .001) and vegetable ( p < .001) intakes, and greater regularity of consuming six or more drinks on one occasion ( p = .002) and of smoking within 30 minutes of waking ( p = .001), Participants with very high psychological distress had significantly increased odds ratios for insufficient weekly physical activity (2.38, 95% CI 1.42-4.00), insufficient daily fruit and vegetable intake (1.72, 95% CI 1.03-2.88), and smoking (2.27, 95% CI 1.12-4.60). Australian adults with current mental illness demonstrate significantly poorer health behaviors than those without mental illness. PMID- 23930898 TI - Understanding cervical cancer screening intentions among Latinas using an expanded theory of planned behavior model. AB - We examined the utility of an expanded theory of planned behavior (TPB) model in predicting cervical cancer screening intentions among Latinas. The model included acculturation and past cervical cancer screening behavior along with attitude, subjective norms, and perceived behavioral control. This cross-sectional study included a sample of 206 Latinas who responded to a self-administered survey. Structural equation modeling was employed to test the expanded TPB model. Acculturation (p = .025) and past screening behavior (p = .001) along with attitude (p = .019), subjective norms (p = .028), and perceived behavioral control (p = .014) predicted the intention to be screened for cervical cancer. Our findings suggest that the TPB is a useful model for understanding cervical cancer screening intentions among Latinas when both past behavior and culture are included. This research highlights the importance of culture on behavior and indicates a need to develop culturally sensitive, theory-based interventions to encourage screening and reduce cervical cancer-related health disparities in Latinas. PMID- 23930899 TI - A preliminary study of cigarette smoking in female orofacial pain patients. AB - The relationship between behavior (eg, diet, exercise, substance use) and the functioning of chronic-pain patients, including orofacial-pain patients, is poorly understood. This preliminary study examined cigarette smoking and both pain-related and psychological functioning in female orofacial-pain patients. Correlates of intentions to quit smoking were also explored. There were 48 participants in this cross-sectional study. Smokers reported significantly less self-control over pain (d = .66), lower general activity levels (d = .52), more fatigue (d = .80), and poorer sleep quality (d = .53) than non-smokers. The mean effect size for all dependent variables was .49 (range, .33-.80) with the smallest and largest effect found for negative mood and fatigue, respectively. More positive attitudes toward smoking cessation independently predicted stronger intentions to quit (beta = .52, p = .03). Findings suggest smoking is significantly associated with pain-related and psychological functioning in female orofacial-pain patients. Smoking-cessation treatment for these patients should include motivational interviewing techniques directed toward attitudinal change. PMID- 23930900 TI - Depression impacts the course of recovery in patients with acute low-back pain. AB - Little is known about the course of recovery of acute low back pain (LBP) patients as a function of depression. In a prospective study, 286 acute LBP patients were assessed at baseline and followed up over 6 months. Recovery was defined as improvement in the Oswestry Disability Index (ODI). Repeated-measures analysis of covariance was employed with ODI as repeated factor, age, sex, and body mass index as covariates, depression and all other potential prognostic factors as between-subject factors. Of study participants, 18% were classified as depressive (>33 points on the Zung Self-Rating Depression Scale). Of 286 participants, 135 were lost to follow-up. In the longitudinal sample of 151 patients the course of recovery was slower in depressive patients. Depression was associated with LBP especially after 6 weeks and should therefore be included in screening instruments for acute LBP patients to identify those at risk of delayed recovery at an early stage. PMID- 23930901 TI - Assessing self-efficacy and self-help methods in women with and without Polycystic Ovary Syndrome. AB - Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder in women strongly associated with obesity and psychological dysfunction. It is crucial to assess the contributions of psychological parameters to obesity and weight management. This survey based cross-sectional study assessed self-efficacy, health attitudes and beliefs, response to illness and adult health history in women with (n = 74) and without PCOS (n = 90). There were no significant differences in self efficacy, health attitudes and beliefs between groups. Women with PCOS reported less engagement in self-help methods compared to women without (p = 0.003). Women with PCOS reported poorer overall (p < 0.001) and recent health history (p = 0.02), greater prevalence (p < 0.001) and impact of a chronic illness (p < 0.001). It is crucial that women recognize that PCOS is a chronic condition requiring on-going lifestyle management; to encourage active engagement in their management, enhance participation in screening for complications and uptake of lifestyle recommendations. PMID- 23930902 TI - Anatomical repair of aortopulmonary window with anomalous origin of the right coronary artery from the pulmonary artery. AB - Aortopulmonary window (APW) with an anomalous origin of a coronary artery is extremely rare. We report surgical management of a four-week-old infant with the association of a distal type of APW and an anomalous origin of the right coronary artery (RCA) from the pulmonary artery. Complete anatomical correction comprising division of the great arteries and transferring the RCA as an autologous flap to the aortic defect was successfully performed. PMID- 23930906 TI - Gastrointestinal complications of pelvic radiotherapy: medical and surgical management strategies. PMID- 23930907 TI - Chronic subdural hematoma infected by Campylobacter fetus. PMID- 23930903 TI - Graphene synthesis via magnetic inductive heating of copper substrates. AB - Scaling graphene growth using an oven to heat large substrates becomes less energy efficient as system size is increased. We report a route to graphene synthesis in which radio frequency (RF) magnetic fields inductively heat metal foils, yielding graphene of quality comparable to or higher than that of current chemical vapor deposition techniques. RF induction heating allows for rapid temperature ramp up/down, with great potential for large scale and rapid manufacturing of graphene with much better energy efficiency. Back-gated field effect transistors on a SiO2/Si substrate showed carrier mobility up to ~14 000 cm(2) V(-1) s(-1) measured under ambient conditions. Many advantages of RF heating are outlined, and some fundamental aspects of this approach are discussed. PMID- 23930908 TI - Barium peritonitis. PMID- 23930909 TI - Effect of gentamicin-containing collagen sponges on surgical site infection after hand-assisted laparoscopic donor nephrectomy. AB - BACKGROUND: Postoperative surgical site infection (SSI) can be considered a frequent complication of hand-assisted laparoscopic donor nephrectomy (HALDN). Since 2007, our center used routinely a gentamicin-containing collagen sponge (GCCS) when closing the wound. The effect of GCCS on SSI is not elucidated clearly. In this retrospective cohort study, we assessed the effects of GCCS on SSI after HALDN. METHODS: Between December 2004 and November 2007, we treated 100 patients without GCCS, and from November 2007 to July 2010, there were 100 patients with GCCS placed after HALDN. A SSI was defined as an incisional infection that required an intervention such as opening of the site or antibiotic treatment within 90 days after surgery. RESULTS: Implantation of a GCCS resulted in a statistically significant reduction in the SSI rate, from 6% to 0 (p=0.01). All infections occurred in the Pfannenstiel incision site. There was no significant difference between the groups in the creatinine concentration after three months. CONCLUSIONS: The use of gentamicin-containing collagen sponges reduces the risk of SSI significantly after HALDN without compromising kidney function. PMID- 23930910 TI - Tubercular temporalis abscess with skull and dural invasion. AB - BACKGROUND: Mycobacterium tuberculosis infection rarely penetrates both skull and dura with temporalis muscle abscess formation. METHODS: Case report and review of the literature. RESULTS: A non-immunocompromised female patient with a right temporal mass underwent surgical resection. The tubercular abscess extended from the temporalis muscle to the skull and through the dura and subdural space with dissemination of the granuloma over the arachnoid membrane. CONCLUSION: Adequate debridement with a full course of antituberculous medication is necessary for complete treatment of these lesions. PMID- 23930911 TI - Photophysical behavior of 8-anilino-1-naphthalenesulfonate in vesicles of pulmonary surfactant dipalmitoylphosphatidylcholine (DPPC) and its sensitivity toward the bile salt-vesicle interaction. AB - The photophysical behavior of 8-anilino-1-naphthalenesulphonate (ANS) in vesicles of dipalmitoylphosphatidylcholine (DPPC), a pulmonary surfactant, has been carried out in a detailed manner. ANS shows notable variations in fluorescence intensity, lifetime, and anisotropy parameters as it gets into the vesicle. It was found that ANS partitions well into the DPPC bilayer membrane with an estimated partition coefficient of ~2.0 * 10(5). Among the various fluorescence parameters of ANS, fluorescence anisotropy was found to be most responsive to the temperature induced phase change of the bilayer membrane. These interesting fluorescence parameters of ANS were then used to study the hydration of lipid bilayer membrane by submicellar concentration of bile salts. From the steady state fluorescence intensity and dynamic fluorescence lifetime analyses it is clear that ANS is able to probe the submicellar concentration (<=1 mM) of bile salt induced hydration of lipid bilayer membrane that accompanies expulsion of ANS from the bilayer to the aqueous bulk phase. Lower-temperature shift in the phase transition of DPPC bilayer indicates that fluorescence anisotropy of ANS is sensitive enough to the bile salt induced perturbation in the packed acyl chains of DPPC bilayer and modification in the membrane fluidity. In presence of sodium deoxycholate (NaDC) and sodium cholate (NaC) in DPPC vesicles, ANS experiences restriction in rotational mobility which is evident from the variation in steady state fluorescence anisotropy and fluorescence anisotropy decay parameters. PMID- 23930912 TI - Global and regional right ventricular dysfunction in pulmonary hypertension. AB - BACKGROUND: Pulmonary hypertension (PH) is known to affect the right ventricular (RV) function. AIMS: To assess the extent of global and regional RV dysfunction in PH patients. METHODS: We performed a cross-sectional study on 20 controls (age 62 +/- 15 years, 7 males) and 35 patients (age 67 +/- 12 years, 13 males) with PH of mixed etiologies and assessed RV inflow and outflow tracts (OTs) function, using speckle tracking echocardiography (STE) based myocardial deformation and its time relations. RV inlet and OT dimensions (2D), inlet myocardial velocities (TDI), myocardial strain and strain rate (SR), TAPSE (M-mode), ejection and filling times (pulsed-wave [PW] Doppler), and pulmonary artery acceleration (PAc) were measured. RESULTS: RV inlet and OT were dilated (P < 0.001 for both) and TAPSE (P < 0.001), inlet velocities (P < 0.001), basal and mid-cavity strain, SR and longitudinal displacement reduced (P < 0.001 for all). The time to peak systolic SR at basal, mid-cavity (P < 0.001 for both), and RVOT (P = 0.007) was short as was that to peak displacement (P < 0.001 for all). The time to peak pulmonary ejection correlated with time to peak SR at RVOT (r = 0.7, P < 0.001) in controls, but with that of the mid-cavity in patients (r = 0.71, P < 0.001). PAc was faster (P = 0.001) and RV filling time shorter in patients (P = 0.03) with respect to controls. CONCLUSIONS: PH has drastic effects on RV structure and intrinsic myocardial function, significantly disturbing its ejection time relations and overall pump performance. Increased RV afterload results in RV configuration changes with the inflow tract determining peak ejection rather than OT. PMID- 23930913 TI - Solar photothermochemical reaction and supercritical CO2 work up for a fully green process of preparation of pure p-nitrobenzyl bromide. AB - It has been reported by us recently that p-nitrobenzyl bromide (PNBBr) can be synthesized from p-nitrotoluene (PNT) in high isolated yield with respect to available bromine in 2:1 Br(-)-BrO3(-) employed as brominating reagent. The reaction was conducted in ethylene dichloride (EDC) and the substrate was taken in excess to suppress dibromo impurity formation. The product was "cold crystallized" from the reaction mass and the mother liquor was recycled in the subsequent batch thereby eliminating organic discharge. The present work attempts to further advance the synthesis of this commercially important molecule employed in protection-deprotection strategies. Herein its successful synthesis employing neat substrate and solar radiation as the sole energy source to drive this photothermochemical reaction is reported. Further, 100% pure PNBBr could be isolated from the solid reaction mass in 87% yield by leaching out the excess substrate through supercritical CO2 (Sc-CO2) extraction. The reaction was therefore accomplished cleanly in all respects and with low carbon footprint. PMID- 23930914 TI - Transport and trapping in two-dimensional nanoscale plasmonic optical lattice. AB - We report the transport and trapping behavior of 100 and 500 nm diameter nanospheres in a plasmon-enhanced two-dimensional optical lattice. An optical potential is created by a two-dimensional square lattice of gold nanostructures, illuminated by a Gaussian beam to excite plasmon resonance. The nanoparticles can be guided, trapped, and arranged using this optical potential. Stacking of 500 nm nanospheres into a predominantly hexagonal closed pack crystalline structure under such a potential is also reported. PMID- 23930915 TI - Development of long-acting recombinant FVIII and FIX Fc fusion proteins for the management of hemophilia. AB - INTRODUCTION: Prophylactic treatment with replacement clotting factor is the recommended regimen for patients with severe hemophilia to prevent bleeding episodes. However, currently available replacement clotting factors are limited by their relatively short half-lives and require intravenous injections up to three times weekly to maintain protective levels, which can impact compliance and, thus, patient outcomes. AREAS COVERED: The potential advantages of long acting coagulation factors, including reduced injection frequency, increased treatment adherence, and improved clinical outcomes, are discussed. Fragment crystallizable (Fc) fusion technology is introduced and the development of long acting recombinant factor VIII Fc (rFVIIIFc) and recombinant factor IX Fc (rFIXFc) fusion proteins for the treatment of hemophilia A and B, respectively, are described. Preclinical and clinical studies of rFVIIIFc and rFIXFc showing improved pharmacokinetics over currently available products are reviewed. EXPERT OPINION: Long-acting coagulation factors, including rFVIIIFc and rFIXFc, have the potential to change current paradigms of care for hemophilia A and B, respectively. Less frequent infusions may provide prolonged protection from bleeding and bleed resolution with fewer injections. In addition, long-acting coagulation factors provide an opportunity for improved individualized treatment for hemophilia. PMID- 23930916 TI - Adalimumab in the treatment of plaque-type psoriasis and psoriatic arthritis. AB - INTRODUCTION: Psoriasis and psoriatic arthritis (PsA) are chronic immune-mediated diseases, and TNF-alpha (tumor necrosis factor) is a pro-inflammatory cytokine that plays a critical role in the pathogenesis of these conditions. Adalimumab is an anti-TNF-alpha drug widely used for the treatment of both psoriasis and PsA. Controlled clinical trials demonstrated that adalimumab is characterized by a high degree of clinical response. The aim of this review is to report the safety, efficacy, and recent findings in the treatment of psoriasis and PsA with adalimumab. AREAS COVERED: This article reviews the results of Phase II, III, controlled, and observational clinical studies on adalimumab in the treatment of psoriasis and PsA. A systematic search was conducted using the Pubmed Medline database for primary articles. EXPERT OPINION: Treatment of psoriasis and PsA represents a therapeutic challenge for dermatologists and rheumatologists. The efficacy, tolerability, and safety profiles suggest adalimumab as a suitable anti psoriatic drug in the long-term treatment of psoriasis and PsA. Management of long-term treatment, loss of efficacy, and comorbidities has been described. PMID- 23930918 TI - Addressing moral distress: application of a framework to palliative care practice. AB - BACKGROUND: Moral distress is a pervasive reality of palliative care practice. An existing framework for understanding it has been proposed as a way to begin to address moral distress's detrimental effects on clinicians. OBJECTIVE: The objective was to illustrate the application of this adapted conceptual framework to a clinical case and to offer recommendations for enlarging the professional repertoire for responding to challenging cases involving moral distress. ANALYSIS: In the clinical case, clinicians are expected to respond to the patient's suffering based on four factors: empathy (emotional attunement), perspective taking (cognitive attunement), memory (personal experience), and moral sensitivity (ethical attunement). Each of these interrelated and iterative factors may become activated as clinicians care for patients with life-limiting conditions. This creates the foundations for clinicians' responses. When responses risk becoming aversive in the face of moral dilemmas, strategies are needed to foster principled compassion instead of unregulated moral outrage. A number of cognitive, attentional, affective, and somatic approaches derived from contemplative traditions are consistent with the framework. Combined with a systems-focused approach that incorporates organizational factors, they offer a means of improving professional repertoires for responding to difficult situations. CONCLUSION: Application of the proposed framework to a clinical case provides opportunities for understanding mechanisms of response that may be amenable to intervention and for suggesting appropriate alternative strategies and practices. A full understanding of the process can help to mitigate or to avoid the progression of distress and concurrently to appraise the situation that leads to moral distress or moral outrage. PMID- 23930919 TI - Evolution of end-of-life practices in a Spanish intensive care unit between 2002 and 2009. AB - BACKGROUND: Spanish cultural perception of end-of-life decision making has started to change within a new legal framework. OBJECTIVES: The objective of this study was to describe how life-sustaining treatments (LST) were withheld or withdrawn in an intensive care unit (ICU), to determine the degree of agreement between physicians and patients' families on end-of-life decisions, and to compare our results to those of studies undergone before these legal changes. DESIGN: This was an observational retrospective study. SETTING/SUBJECTS: The setting and subjects were patients admitted to a medical and surgical ICU in a metropolitan tertiary care center from January 2002 to December 2009 whose LST had been withheld or withdrawn. MEASUREMENTS: Study measurements included age and sex; comorbidities; functional status on admission; main diagnosis; SAPS II and APACHE II scores on admission; degree of agreement on end-of-life practices; and therapeutic interventions withheld or withdrawn and outcome. RESULTS: A total of 371 of 6526 patients (5.7%) had LST withheld or withdrawn; 339 of these patients died in the ICU. Patients whose LST was withheld or withdrawn were older, had a high number of comorbidities, and were admitted with higher SAPS II and APACHE II scores than the general ICU population. Active treatments and basic support were discontinued in 212 patients (57%) and 100 patients (26.9%), respectively. An agreement between the staff and the patient's family was reached in 318 cases (85.7%). Families were not involved in 30 cases (8.1%). CONCLUSIONS: Compared to prior studies, shared end-of-life decision making in the ICU has increased in recent years. Decisions to forgo treatments mainly involve advanced life support. PMID- 23930920 TI - Incidence of hydromorphone-induced neuroexcitation in hospice patients. AB - BACKGROUND AND OBJECTIVE: To date, there are no known published studies that prospectively followed hospice patients receiving hydromorphone to evaluate the development of hydromorphone-induced neuroexcitation (HINE). The first objective of this study was to determine the incidence of HINE. The second objective was to identify factors influencing the presence or absence of HINE symptoms in hospice patients. METHODS: This was a noninterventional, prospective study. This study population included hospice patients 18 years of age or older who were admitted to one of two Nathan Adelson Hospice inpatient units in Las Vegas, Nevada, and were initiated on a scheduled regimen of hydromorphone. A total of 156 patients were enrolled and analyzed in this study. Data collection was performed by the study investigators using a standard data tracking form, including hospice diagnosis, gender, renal function, hydromorphone regimen, and whether or not the patient experienced neuroexcitatory symptoms. Data collection occurred from November 2010 to March 2011. RESULTS AND CONCLUSIONS: Based on the data collected in this study, it appears that the likelihood of HINE does increase with larger doses, increasing age, increasing serum creatinine, and the presence of malignant neoplasm. However, after adjusting for the variables in the logistic regression model, diagnosis of malignant neoplasm was not a significant predictor of HINE. Future studies may focus on evaluating metabolite levels, such as hydromorphone-3 glucuronide (H3G), in patients developing HINE symptoms. This may help to determine if the metabolites of opioids, such as H3G, are involved in the development of the neurotoxic symptoms. PMID- 23930921 TI - [Can we refuse HPV vaccination for boys when French law allows same-sex marriage?]. PMID- 23930922 TI - Mining the characteristic interaction patterns on protein-protein binding interfaces. AB - Protein-protein interactions are observed in various biological processes. They are important for understanding the underlying molecular mechanisms and can be potential targets for developing small-molecule regulators of such processes. Previous studies suggest that certain residues on protein-protein binding interfaces are "hot spots". As an extension to this concept, we have developed a residue-based method to identify the characteristic interaction patterns (CIPs) on protein-protein binding interfaces, in which each pattern is a cluster of four contacting residues. Systematic analysis was conducted on a nonredundant set of 1,222 protein-protein binding interfaces selected out of the entire Protein Data Bank. Favored interaction patterns across different protein-protein binding interfaces were retrieved by considering both geometrical and chemical conservations. As demonstrated on two test tests, our method was able to predict hot spot residues on protein-protein binding interfaces with good recall scores and acceptable precision scores. By analyzing the function annotations and the evolutionary tree of the protein-protein complexes in our data set, we also observed that protein-protein interfaces sharing common characteristic interaction patterns are normally associated with identical or similar biological functions. PMID- 23930923 TI - Relationship between perceived burden of caring for a family member with Alzheimer's disease and decreased participation in meaningful activities. AB - ABSTRACT Objective: This study examines the relationship between caring for a family member with Alzheimer's disease (AD) and activity participation. METHOD: A 34-item caregiver questionnaire including items measuring the perceived caregiving burden and the level of participation in meaningful activities was completed by 54 caregivers. RESULTS: A significant negative correlation (r = .56, p <.0001) was demonstrated between the two variables: caregiving burden and participation in meaningful activities. DISCUSSION AND CONCLUSION: An increased perception of burden is related to a decrease of participation in desired occupations among family caregivers of people with AD. The findings can help occupational therapy practitioners develop interventions aiming at improving caregivers' quality of life through enhancing opportunities for meaningful occupations. PMID- 23930924 TI - Self-identity in an adolescent a decade after spinal cord injury. AB - ABSTRACT The purpose of this mixed methods case study was to describe the current self-identity of an adolescent a decade after spinal cord injury and how he recalls his rehabilitative journey through recovery. The instruments included three in-depth interviews, administration of the Lin Interest Check List, the Stress Profile, and the Tennessee Self Concept Scale: 2. An association between participation in meaningful occupations and regaining self-identity was articulated. Results revealed above average self-concept and adequate coping skills with high use of positive appraisal. Higher scores in family and social self-concept validate his strong reliance on spirituality and his local church as a support system. In contrast, this client also scored above average on negative appraisal and on self-criticism. Implications for improved practice for occupational therapists and other rehabilitation science professionals are discussed. PMID- 23930925 TI - Occupational justice as a quality indicator for occupational therapy services. AB - ABSTRACT Although a key concept in occupational therapy theoretical documents, the issue of occupational justice continues to be elusive to the everyday practitioner. The purpose of this article is to outline a quality improvement project focused on the incorporation of occupational justice concepts into daily treatment. For the purposes of this quality improvement project, occupational justice was explored through practitioners' perceptions of clients' preparation to face societal, physical, and political barriers based on the occupational therapy services they received. Project participants were able to identify current utilization of these concepts, barriers to utilizing concepts, and potential avenues for incorporation of occupational justice into daily practice. This project demonstrates that quality improvement activities, driven by practitioners providing direct care, can enrich occupational therapy programs and lead to the inclusion of social justice practices in occupational therapy services. PMID- 23930926 TI - Assessments used in occupational therapy practice: an exploratory study. AB - ABSTRACT The purpose of this study was to explore the assessments used in occupational therapy practice through identifying most commonly used assessments and the rationale for their use in different occupational therapy practice areas. The study utilized a nonprobability convenience sample of 260 occupational therapy practitioners attending the American Occupational Therapy Association's annual conference. A descriptive survey research design was used for conducting this study. The survey instrument addressed three major questions related to (a) the area of practice, (b) the specific assessments used, and (c) reasons for using the specific assessments. Descriptive statistics were utilized to analyze the results. Results indicated most of the assessments used in occupational therapy clinics target body structure and function. Assessments were used due to their convenient availability in clinics, clinical utility and standardization, client-centeredness, development by occupational therapists, being taught in school/fieldwork, and being satisfying to insurance companies. Implications for occupational therapy education, practice, and research are presented. PMID- 23930927 TI - The road to recovery: experiences and occupational lives of icelandic women with breast cancer. AB - ABSTRACT The purpose of this qualitative study was to explore the experiences and occupational lives of Icelandic women with breast cancer. In all 18 women were interviewed using the Occupational Performance History Interview as a guide. The women employed different modes of interpreting and responding to the cancer event with occupational participation being the central vehicle to resist the illness. Adjustment to breast cancer survivorship was characterized by permanent changes in the women's lives with both positive and negative consequences. When working with women with breast cancer, occupational therapists should focus on their needs as occupational beings. PMID- 23930928 TI - From the internet editor. PMID- 23930931 TI - One-pot colloidal chemistry route to homogeneous and doped colloidosomes. AB - Colloidosomes are usually produced from a series of building blocks with different sizes ranging from several nanometers to micrometers or various shapes, such as particles, microrods, and quantum dots. Colloidosomes can possess a variety of characteristics in terms of photics, electrology, mechanical strength, and selective permeability, derived from their building blocks. However, poor mechanical stability and complicated synthesis processes have limited the applications of colloidosomes. Here, we report a new one-pot colloidal chemistry route to synthesize phenol formaldehyde resin (PFR), Ag@PFR, and Au@PFR colloidosomes with high yields. The method can be modified to synthesize different kinds of doped colloidosomes with different components, which will provide a new approach to design colloidosomes with different functions. PMID- 23930929 TI - Effects of the brown rice diet on visceral obesity and endothelial function: the BRAVO study. AB - Brown rice (BR) and white rice (WR) produce different glycaemic responses and their consumption may affect the dietary management of obesity. In the present study, the effects of BR and WR on abdominal fat distribution, metabolic parameters and endothelial function were evaluated in subjects with the metabolic syndrome in a randomised cross-over fashion. In study 1, acute postprandial metabolic parameters and flow- and nitroglycerine-mediated dilation (FMD and NMD) of the brachial artery were determined in male volunteers with or without the metabolic syndrome after ingestion of either BR or WR. The increases in glucose and insulin AUC were lower after ingestion of BR than after ingestion of WR (P= 0.041 and P= 0.045, respectively). FMD values were decreased 60 min after ingestion of WR (P= 0.037 v. baseline), but the decrease was protected after ingestion of BR. In study 2, a separate cohort of male volunteers (n 27) with the metabolic syndrome was randomised into two groups with different BR and WR consumption patterns. The values of weight-based parameters were decreased after consumption of BR for 8 weeks, but returned to baseline values after a WR consumption period. Insulin resistance and total cholesterol and LDL-cholesterol levels were reduced after consumption of BR. In conclusion, consumption of BR may be beneficial, partly owing to the lowering of glycaemic response, and may protect postprandial endothelial function in subjects with the metabolic syndrome. Long-term beneficial effects of BR on metabolic parameters and endothelial function were also observed. PMID- 23930932 TI - Nanoemulsions for delivery of flavonoids: formulation and in vitro release of rutin as model drug. AB - The aim of the present study is to design and characterize a rutin-loaded nanoemulsion (RT-NE) and determine the release profile of the drug in vitro. RT NE was prepared by a high pressure homogenization technique. The obtained droplets were analyzed by optical microscopy and were shown to be of spherical shape. By dynamic light scattering, characterization of RT-NE showed an average diameter of 127 nm, polydispersity index of 0.168 and zeta potential values near neutrality (-3.49 mV). Encapsulation efficiency was of ~82% (82.3 +/- 1.62%). Drug release was characterized by an initial burst which decreased over the time, showing a sustained release profile. After 24 h, rutin released from NE reached nearly 65%. The developed system proved to be stable and suitable to encapsulating poorly water-soluble drugs. PMID- 23930933 TI - The context of learning anatomy: does it make a difference? AB - This study set out to ascertain whether the context in which anatomy is learnt made a difference to students' perceptions of learning. An Approach to Learning Inventory (ASSIST) and a 31-item Anatomy Learning Experience Questionnaire (ALE) were administered to 224 students (77 dental, 132 medical and 19 speech and language) as a multi-site study. Results revealed that 45% adopted a strategic, 39% a deep and 14% a surface approach. Trends between professions are similar for a deep or strategic approach (both ~ 40%). However, a surface approach differed between professions (7% dentistry, 16% medicine, 26% speech and language science). Dental students responded more to being able to use their knowledge than did other groups (P = 0.0001). Medical students found the dissecting environment an intimidating one and subsequently reported finding online resources helpful (P = 0.015 and P = 0.003, respectively). Speech and language science students reported that they experienced greater difficulties with learning anatomy; they reported finding the amount to learn daunting (P = 0.007), struggled to remember what they did last semester (P = 0.032) and were not confident in their knowledge base (P = 0.0001). All students responded strongly to the statement 'I feel that working with cadaveric material is an important part of becoming a doctor/dentist/health care professional'. A strong response to this statement was associated with students adopting a deep approach (P = 0.0001). This study has elucidated that local curriculum factors are important in creating an enabling learning environment. There are also a number of generic issues that can be identified as being inherent in the learning of anatomy as a discipline and are experienced across courses, different student groups and institutions. PMID- 23930934 TI - Deep brain stimulation of the subcallosal cingulate for medication-resistant type I bipolar depression: case report. PMID- 23930935 TI - T-2 toxin impairs antifungal activities of chicken macrophages against Aspergillus fumigatus conidia but promotes the pro-inflammatory responses. AB - Aspergillosis is the most common fungal disease of the avian respiratory tract and is caused primarily by Aspergillus fumigatus. The respiratory macrophages provide important defence against aspergillosis. T-2 toxin (T-2), a trichothecene mycotoxin produced by Fusarium spp. in improperly stored agricultural products, has immunomodulatory effects. We studied the impact of T-2 on the antifungal response of the chicken macrophage cell line HD-11 against A. fumigatus infection. The macrophages were first exposed to 0.5 to 10 ng/ml T-2 for 24 h, and then their viability, antifungal activity, and cytokine expression in response to A. fumigatus conidial infection were determined. The viability of macrophages decreased when exposed to T-2 at concentrations higher than 1 ng/ml. One hour after conidial infection, phagocytosed conidia were observed in 30% of the non-T-2-exposed macrophages, but in only 5% of the macrophages exposed to 5 ng/ml T-2. Seven hours after infection, 24% of the conidia associated with non-T 2-exposed macrophages germinated, in contrast to 75% of those with macrophages exposed to 5 ng/ml T-2. A. fumigatus infection induced upregulation of interleukin (IL)-1beta, CXCLi1, CXCLi2 and IL-12beta, and downregulation of transforming growth factor-beta4 in macrophages. Exposure of A. fumigatus infected macrophages to T-2 at 1 to 5 ng/ml further upregulated the expression of IL-1beta, IL-6, CCLi2, CXCLi1, CXCLi2, IL-18 (at 1 and 2 ng/ml) and IL-12beta, and further downregulated that of transforming growth factor-beta4 (at 5 ng/ml). In conclusion, T-2 impaired the antifungal activities of chicken macrophages against A. fumigatus conidia, but might stimulate immune response by upregulating the expression of pro-inflammatory cytokines, chemokines and T-helper 1 cytokines. PMID- 23930936 TI - Liquid mixtures involving hydrogenated and fluorinated chains: (p, rho, T, x) surface of (ethanol + 2,2,2-trifluoroethanol), experimental and simulation. AB - The effect of mixing hydrogenated and fluorinated molecules that simultaneously interact through strong hydrogen bonding was investigated: (ethanol + 2,2,2 trifluoroethanol) binary mixtures were studied both experimentally and by computer simulation. This mixture displays a very complex behavior when compared with mixtures of hydrogenated alcohols and mixtures of alkanes and perfluoroalkanes. The excess volumes are large and positive (unlike those of mixtures of hydrogenated alchools), while the excess enthalpies are large and negative (contrasting with those of mixtures of alkanes and perfluoroalkanes). In this work, the liquid density of the mixtures was measured as a function of composition, at several temperatures from 278.15 to 353.15 K and from atmospheric pressure up to 70 MPa. The corresponding excess molar volumes, compressibilities, and expansivities were calculated over the whole (p, rho, T, x) surface. In order to obtain molecular level insight, the behavior of the mixture was also studied by molecular dynamics simulation, using the OPLS-AA force field. The combined analysis of the experimental and simulation results indicates that the peculiar phase behavior of this system stems from a balance between the weak dispersion forces between the hydrogenated and fluorinated groups and a preferential hydrogen bond between ethanol and 2,2,2-trifluoroethanol. Additionally, it was observed that a 25% reduction of the F-H dispersive interaction in the simulations brings agreement between the experimental and simulated excess enthalpy but produces no effect in the excess volumes. This reveals that the main reason causing the volume increase in these systems is not entirely related to the weak dispersive interactions, as it is usually assumed, and should thus be connected to the repulsive part of the intermolecular potential. PMID- 23930937 TI - A research capacity strengthening project for infectious diseases in Honduras: experience and lessons learned. AB - BACKGROUND: In Honduras, research capacity strengthening (RCS) has not received sufficient attention, but an increase in research competencies would enable local scientists to advance knowledge and contribute to national priorities, including the Millennium Development Goals (MDGs). OBJECTIVE: This project aimed at strengthening research capacity in infectious diseases in Honduras, focusing on the School of Microbiology of the National Autonomous University of Honduras (UNAH). The primary objective was the creation of a research-based graduate program for the continued training of researchers. Parallel objectives included institutional strengthening and the facilitation of partnerships and networks. METHODS: Based on a multi-stakeholder consultation, an RCS workplan was designed and undertaken from 2007 to 2012. Due to unexpected adverse circumstances, the first 2 years were heavily dedicated to implementing the project's flagship, an MSc program in infectious and zoonotic diseases (MEIZ). In addition, infrastructure improvements and demand-driven continuing education opportunities were facilitated; biosafety and research ethics knowledge and practices were enhanced, and networks fostering collaborative work were created or expanded. RESULTS: The project coincided with the peak of UNAH's radical administrative reform and an unprecedented constitutional crisis. Challenges notwithstanding, in September 2009, MEIZ admitted the first cohort of students, all of whom undertook MDG-related projects graduating successfully by 2012. Importantly, MEIZ has been helpful in expanding the School of Microbiology's traditional etiology-based, disciplinary model to infectious disease teaching and research. By fulfilling its objectives, the project contributed to a stronger research culture upholding safety and ethical values at the university. CONCLUSIONS: The resources and strategic vision afforded by the project enhanced UNAH's overall research capacity and its potential contribution to the MDGs. Furthermore, increased research activity and the ensuing improvement in performance indicators at the prime Honduran research institution invoke the need for a national research system in Honduras. PMID- 23930938 TI - Assessment of transcriptional activity of Borrelia burgdorferi and host cytokine genes during early and late infection in a mouse model. AB - Differential gene expression by Borrelia burgdorferi spirochetes during mammalian infection facilitates their dissemination as well as immune evasion. Modulation of gene transcription in response to host immunity has been documented with the outer surface protein C, but the influence of transcription of other genes is largely unknown. A low-density array (LDA) was developed to study transcriptional activity of 43 B. burgdorferi genes and 19 host genes that may be involved in various host-agent interactions. Gene transcription in heart, joint, and muscle tissue was compared in immunocompetent C3H and immunodeficient C3H-scid mice during early (3 weeks) and late (2 months) B. burgdorferi infection. Among all tissue types, levels of relative transcription of over 80% of B. burgdorferi genes tested were one- to nine-fold less in C3H mice compared to C3H-scid mice. At the later time point, all genes were transcribed in C3H-scid mice, whereas transcription of 16 genes out of 43 tested was not detected in analyzed tissues of C3H mice. Our data suggest that during infection of immunocompetent mice, a majority of B. burgdorferi genes tested are downregulated in response to acquired host immunity. LDA revealed variable patterns of host gene expression in different tissues and at different intervals in infected mice. Higher levels of relative expression for IL-10 during both early and late infection were detected in heart base, and it was unchanged in the tibiotarsal joint. Comparative analysis of B. burgdorferi and host genes transcriptional activity revealed that increased flaB mRNA during early infection was followed by increases of CCL7, CCL8, interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha) in all assessed tissue types. LDA represents a valuable approach for sensitive and quantitative gene transcription profiling and for understanding Lyme borreliosis. PMID- 23930939 TI - Urbanicity, persecutory delusions, and clinical intervention: the development of a brief CBT module for helping patients with persecutory delusions enter social urban environments. AB - BACKGROUND: Substantial epidemiological research has shown that psychotic experiences are more common in densely populated areas. Many patients with persecutory delusions find it difficult to enter busy social urban settings. The stress and anxiety caused by being outside lead many patients to remain in-doors. We therefore developed a brief CBT intervention, based upon a formulation of the way urban environments cause stress and anxiety, to help patients with paranoid thoughts to feel less distressed when outside in busy streets. AIMS: The aim was to pilot the new intervention for feasibility and acceptability and gather preliminary outcome data. METHOD: Fifteen patients with persecutory delusions in the context of a schizophrenia diagnosis took part. All patients first went outside to test their reactions, received the intervention, and then went outside again. RESULTS: The intervention was considered useful by the patients. There was evidence that going outside after the intervention led to less paranoid responses than the initial exposure, but this was only statistically significant for levels of distress. CONCLUSIONS: Initial evidence was obtained that a brief CBT module specifically focused on helping patients with paranoia go outside is feasible, acceptable, and may have clinical benefits. However, it could not be determined from this small feasibility study that any observed improvements were due to the CBT intervention. Challenges in this area and future work required are outlined. PMID- 23930940 TI - Negatively charged metal oxide nanoparticles interact with the 20S proteasome and differentially modulate its biologic functional effects. AB - The multicatalytic ubiquitin-proteasome system (UPS) carries out proteolysis in a highly orchestrated way and regulates a large number of cellular processes. Deregulation of the UPS in many disorders has been documented. In some cases, such as carcinogenesis, elevated proteasome activity has been implicated in disease development, while the etiology of other diseases, such as neurodegeneration, includes decreased UPS activity. Therefore, agents that alter proteasome activity could suppress as well as enhance a multitude of diseases. Metal oxide nanoparticles, often developed as diagnostic tools, have not previously been tested as modulators of proteasome activity. Here, several types of metal oxide nanoparticles were found to adsorb to the proteasome and show variable preferential binding for particular proteasome subunits with several peptide binding "hotspots" possible. These interactions depend on the size, charge, and concentration of the nanoparticles and affect proteasome activity in a time-dependent manner. Should metal oxide nanoparticles increase proteasome activity in cells, as they do in vitro, unintended effects related to changes in proteasome function can be expected. PMID- 23930941 TI - Oral motor assessment in individuals with Moebius syndrome. AB - BACKGROUND: Moebius syndrome (MS) is a rare congenital condition that is characterised by facial hypomimia and congenital strabismus caused by complete or partial impairment of the 6th and 7th cranial nerves. MS may be further associated with other nerves or malformations, mainly involving the extremities. The objective of this study was to quantify the decrease in oral motor performance in people with MS compared with normoreactive individuals using the Oral Motor Assessment Scale (OMAS). METHODS: The study group comprised 33 subjects between the ages of 2 and 20 years (average age: 10 +/- 5 years) with MS along with 46 age- and gender-matched control subjects. RESULTS: The study group displayed a lower average functional score than the control group (P < 0.0001). A significant lack of lip closure (P = 0.03) and anterior lingual seal during swallowing (P = 0.03) occurred in the study group; in most cases, the individuals with MS were classified as 'subfunctional'. In addition, individuals with MS in the older age group displayed better functional scores than those in the younger group (P = 0.05). CONCLUSIONS: Functional damage to oral motor function in individuals with MS is evident, but differs among patients with respect to severity and the movements that are compromised. However, overall, improvements in the functional patterns of these individuals can be observed as they mature in age. PMID- 23930942 TI - Thermosensitive PHEMA microcarriers: ATRP synthesis, characterization, and usabilities in cell cultures. AB - In this study, we developed a novel microcarrier to enhance the production of anchorage-dependent mammalian cells in large scale by preserving them from the effects of shear forces and to enhance their removal from the surface without using proteolytic enzymes and chelating agents. This 'thermosensitive microcarrier' was synthesized by the grafting thermoresponsive molecule, N isopropylacrylamide (NIPAAm), to the crosslinked poly(2-hydroxyethyl methacrylate) (PHEMA) beads by surface-initiated atom transfer radical polymerization. NIPAAm was polymerized on bromine-activated beads' surfaces to prepare PHEMA-g-PNIPAAm microcarriers. Then, they were chemically characterized by attenuated total reflectance Fourier transform infrared and electron spectroscopy for chemical analysis. Surface morphologies were further investigated by scanning electron microscope and atomic force microscopy techniques. The results of characterization studies confirmed that PNIPAAm was successfully grafted onto PHEMA beads by the means of atom transfer radical polymerization reaction. The cellular activities of PHEMA-g-PNIPAAm microcarriers were evaluated at static and dynamic culture conditions by using two types of cell lines with different morphology, i.e. L929 mouse fibroblasts and HS2 epithelial human keratinocytes. The microcarriers exhibited better cell adhesion and proliferation characteristics for both cell lines. Although their thermally induced cell detachment efficiencies are lower than that of trypsinization, thermally harvested cells preserved their surface morphologies and proliferation characteristics. PMID- 23930943 TI - Electrochemical conversion of unreactive pyrene to highly redox-active 1,2 quinone derivatives on a carbon nanotube-modified gold electrode surface and its selective hydrogen peroxide sensing. AB - Pyrene (PYR) is a rigid, carcinogenic, unreactive, and nonelectrooxidizable compound. A multiwalled carbon nanotube (MWCNT)-modified gold electrode surface bound electrochemical oxidation of PYR to a highly redox-active surface-confined quinone derivative (PYRO) at an applied potential of 1 V versus Ag/AgCl in pH 7 phosphate buffer solution has been demonstrated in this work. Among various carbon nanomaterials examined, the pristine MWCNT-modified gold electrode showed effective electrochemical oxidation of the PYR. The MWCNT's graphite impurity promotes the electrochemical oxidation reaction. Physicochemical and electrochemical characterizations of MWCNT@PYRO by Raman spectroscopy, FT-IR, X ray photoelectron spectroscopy, and GC-MS reveal the presence of PYRO as pyrene tetrone within the modified electrode. The quinone position of PYRO was identified as ortho-directing by an elegantly designed ortho-isomer-selective complexation reaction with copper ion as an MWCNT@PYRO-Cu(2+/1+)-modified electrode. Finally, a cytochrome c enzyme-modified Au/MWCNT@PYRO (i.e., Au/MWCNT@PYRO-Cyt c) was also developed and further demonstrated for the selective biosensing of hydrogen peroxide. PMID- 23930944 TI - Stereoselective radical azidooxygenation of alkenes. AB - Radical azidooxygenation of various alkenes is described. A readily prepared N3 iodine(III) reagent acts as a clean N3-radical precursor. Radical generation is achieved with TEMPONa acting as a mild organic reducing reagent. The C-radical generated after N3-radical addition is efficiently trapped by in situ generated TEMPO. Yields are good to excellent, and for cyclic systems azidooxygenation occurs with excellent diastereoselectivity. PMID- 23930945 TI - Unique sail-like structure of cor triatriatum dexter in three-dimensional echocardiogram. AB - Cor triatriatum dexter (CTD) is an extremely rare congenital condition arising from the persistence of the right valve of the sinus venosus. It divides the right atrium (RA) into 2 separate chambers. We report a case of a 50-year-old man who had an incidental finding of CTD on transesophageal echocardiogram. An incomplete membrane of the RA was seen, and three-dimensional echocardiogram delineated the structure clearly as a triangular sail-like structure with multiple orifices and a fenestration. PMID- 23930946 TI - Quantifying area changes of internationally important wetlands due to water consumption in LCA. AB - Wetlands harbor diverse species assemblages but are among the world's most threatened ecosystems. Half of their global area was lost during the last century. No approach currently exists in life cycle impact assessment that acknowledges the vulnerability and importance of wetlands globally and provides fate factors for water consumption. We use data from 1184 inland wetlands, all designated as sites of international importance under the Ramsar Convention, to develop regionalized fate factors (FF) for consumptive water use. FFs quantify the change of wetland area caused per m(3)/yr water consumed. We distinguish between surface water-fed and groundwater-fed wetlands and develop FFs for surface water and groundwater consumption. FFs vary over 8 (surface water-fed) and 6 (groundwater-fed) orders of magnitude as a function of the site characteristics, showing the importance of local conditions. Largest FFs for surface water-fed wetlands generally occur in hyper-arid zones and smallest in humid zones, highlighting the dependency on available surface water flows. FFs for groundwater-fed wetlands depend on hydrogeological conditions and vary largely with the total amount of water consumed from the aquifer. Our FFs translate water consumption into wetland area loss and thus become compatible with life cycle assessment methodologies of land use. PMID- 23930947 TI - Counseling about medication-induced birth defects with clinical decision support in primary care. AB - BACKGROUND: We evaluated how computerized clinical decision support (CDS) affects the counseling women receive when primary care physicians (PCPs) prescribe potential teratogens and how this counseling affects women's behavior. METHODS: Between October 2008 and April 2010, all women aged 18-50 years visiting one of three community-based family practice clinics or an academic general internal medicine clinic were invited to complete a survey 5-30 days after their clinic visit. Women who received prescriptions were asked if they were counseled about teratogenic risks or contraception and if they used contraception at last intercourse. RESULTS: Eight hundred one women completed surveys; 27% received a prescription for a potential teratogen. With or without CDS, women prescribed potential teratogens were more likely than women prescribed safer medications to report counseling about teratogenic risks. However, even with CDS 43% of women prescribed potential teratogens reported no counseling. In multivariable models, women were more likely to report counseling if they saw a female PCP (odds ratio: 1.97; 95% confidence interval: 1.26-3.09). Women were least likely to report counseling if they received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Women who were pregnant or trying to conceive were not more likely to report counseling. Nonetheless, women who received counseling about contraception or teratogenic risks were more likely to use contraception after being prescribed potential teratogens than women who received no counseling. CONCLUSIONS: Physician counseling can reduce risk of medication induced birth defects. However, efforts are needed to ensure that PCPs consistently inform women of teratogenic risks and provide access to highly effective contraception. PMID- 23930948 TI - The association of migraine with menstrually related mood disorders and childhood sexual abuse. AB - BACKGROUND: Both female reproductive hormones and childhood sexual abuse (CSA) are implicated in migraine and in menstrually related mood disorders (MRMD). We examined the association of migraine, including migraine with aura (MA), and history of MRMD or CSA. METHODS: A total of 174 women (mean age 33.9 +/- 7.6 years) in this cross-sectional study were evaluated for (1) current MRMD using prospective daily ratings; (2) history of CSA using structured interview; and (3) MA and migraine without aura using the International Classification of Headaches Disorders II criteria. RESULTS: Ninety-six women met MRMD criteria (21 of whom had history of CSA) and 78 women were non-MRMD controls (16 with CSA histories). Migraine with aura was more prevalent in women with MRMD when compared to non MRMD controls (11/88 and 0/86, respectively, p=0.001). In MRMD women only, a CSA history was associated with higher MA rates (6/21 and 5/67, respectively, p=0.019). A combination of current MRMD diagnosis and a history CSA was associated with increased risk for MA, even after adjusting for potential confounders (odds ratio=12.08, 95% confidence interval 2.98-48.90, p<0.001). CONCLUSIONS: Women with MRMD may be vulnerable to the development of MA, and a history of CSA in women with a MRMD appears to increase that vulnerability. MRMDs and MA should be included among other poor mental and physical health outcomes of an abuse history. Routine screening for abuse histories would potentially improve identification of women with increased risk of experiencing abuse-related disorders. PMID- 23930951 TI - From the editor's desk. AB - No abstract available for this article. PMID- 23930950 TI - Lactobacillus acidophilus supplementation in human subjects and their resistance to enterotoxigenic Escherichia coli infection. AB - To assess the effect of Lactobacillus acidophilus (American Type Culture Collection (ATCC) 700396) on enterotoxigenic Escherichia coli (ETEC) infection, in the present study, a parallel, double-blind, placebo-controlled 4-week intervention was performed in healthy males. The subjects largely consumed their habitual diet, but had to abstain from consuming dairy foods generally high in Ca. The subjects were randomised into the L. acidophilus (dose 109 colony-forming units twice daily; n 20) or the placebo (n 19) group. After an adaptation period of 2 weeks, the subjects were orally infected with a live, but attenuated, ETEC vaccine, able to induce mild, short-lived symptoms. Before and after the challenge, the subjects recorded stool consistency, bowel habits, and frequency and severity of gastrointestinal complaints. The ETEC challenge led to a significant increase in faecal output on the 2nd day and a concomitant increase in Bristol stool scale scores. Likewise, abdominal pain, bloating, flatulence, fever, headache and nausea peaked 1 d after the oral challenge. The concentrations of faecal calprotectin and IgA peaked 2 d after and that of serum IgM peaked 9 and 15 d after the oral challenge. The concentrations of serum IgA and IgG were unaffected. The ETEC challenge led to a reduction in the number of Bacteroides-Prevotella, Bifidobacterium, Clostridium cluster XIVab and total faecal bacteria. Probiotic treatment was associated with a larger increase in Bristol stool scale scores and more fever, headache and nausea after the ETEC challenge compared with the placebo treatment. These differences were, however, small and with substantial variation within the groups. Oral application of an attenuated live ETEC vaccine provides a useful model for food-borne infections. Supplementation with L. acidophilus ATCC 700396, however, was ineffective in reducing ETEC infection symptoms in healthy men. PMID- 23930953 TI - Hand rehabilitation and occupational therapy. AB - Occupational therapy for hands has been recognized as a speciality within the profession since the 1940s. The growing numbers of patients with acquired or congenital problems affecting their hands as well as the newer surgical procedures now available to restore lost function has challenged therapists. To manage the highly specialized needs of the complicated hand problems seen in the clinical setting, there is emphasis on perfecting technical skill. Equally required is the ability to remediate not only the physical dysfunction but also the patient's response to this dysfunction. For it is in this holistic approach to patient care that occupational therapy has its true strength in helping to successfully remediate the difficulties of the patient with a hand problem. Practical application of this principle is shown in a case study. PMID- 23930949 TI - pH- and ion-sensitive polymers for drug delivery. AB - INTRODUCTION: Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body. AREAS COVERED: Having pH sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor targeted DDSs have been developed based on polymers with imidazole groups or poly(beta-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations. EXPERT OPINION: Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients. PMID- 23930954 TI - Wound management in hand therapy. AB - Competent wound management is critical to successful rehabilitation of the injured hand. The occupational therapist who treats patients with such injuries must know what is involved and how various treatment procedures and activities impact healing. This paper will review the physiology of wound healing, present a framework for evaluation of the wounded hand and provide practical suggestions for treatment. PMID- 23930955 TI - Clinical management of scar tissue. AB - This paper will review the physiology of scar formation including the properties of wound healing and scar remodeling. A clinical scar management program that includes evaluation of scar adhesions and use of a variety of therapy interventions to minimize the formation of scar will be described. Use of compression, massage, splints and functional activities is included in this program. The information is applicable for the general occupational therapist who sees patients with hand dysfunction as well as a therapist specializing in hand rehabilitation. Every therapist who treats hand trauma must be familiar with the sequence and the properties of scar formation in order to reestablish tendon gliding and facilitate early remodeling of scar tissue. Many treatment techniques can be directed toward scar adhesions and no one method is totally effective when used alone; used together, these techniques can positively influence scar formation and restore maximal hand function. PMID- 23930956 TI - Concepts and current trends in hand splinting. AB - The development of hand splinting within the practice of occupational therapy, rationale for appropriate splinting and recent trends in splint selection are reviewed. The therapist treating hand involved patients are employed in a variety of settings today: hospital base, freestanding clinics, physician offices, private practices or within the design of HMOs (Health Maintenance Organization). Having a sound background in kinesiology, upper extremity anatomy and bio mechanic principles of the hand to assess the patients' physical function enhances the therapist's ability to make prudent splinting choices. Utilizing her knowledge of splint design the therapist may select either a prefabricated splint or a custom-made one to meet individual patient needs. This article does not attempt to review the hand splinting products available today but rather cites examples which may prompt the reader to further explore the literature. PMID- 23930957 TI - Dexterity as a valid measure of hand function. AB - The evaluation of dexterity as a measure of hand function requires caution. The results of this pilot study demonstrate the importance of defining dexterity, of considering work strategies and of analyzing the work station before planning a hand rehabilitation program and a return to work. PMID- 23930958 TI - Proposal for splinting the adult hemiplegic hand to promote function. AB - Although there is no general consensus regarding splinting the hemiplegic hand, therapists continue to explore possibilities to facilitate functional use of the involved hand. A proposal for a dorsal splint adaptation, based on neurophysiological principles is described. Its use with two young hemiplegic patients, 10-11 months post onset, is presented. Following consistent use of the splint, both patients showed increased spontaneous use of the hemiplegic hand. PMID- 23930959 TI - EMG Biofeedback Training to Promote Hand Function in a Cerebral Palsied Child with Hemiplegia. AB - This paper will describe how EMG biofeedback can be used in training a hemiplegic cerebral palsied child. Specifically will be described how EMG biofeedback will promote relaxation of spastic upper-extremity muscles and active movements of antagonistic muscles, for potential improvement in hand function. To illustrate the biofeedback approach used, a case study will be presented. PMID- 23930960 TI - Occupational therapy and the treatment of the colles' fracture. AB - Colles' fracture is a frequently occurring injury, particularly in the older population, and well-known to most occupational therapists working in the area of physical dysfunction. The residual deficits associated with this fracture cause major functional problems for the patient and may be avoided by early referral to occupational therapy. Stages of fracture healing will be discussed with recommendations for timely therapeutic intervention. The importance of developing an automatic, early referral system between physicians and occupational therapy departments is stressed, in order to provide thoughtful, preventive, effective treatment to patients with this potentially disabling fracture. PMID- 23930961 TI - Pre and post operative occupational therapy for a toe to hand transplantation. AB - Thumb loss is a significant disability for the hand. This paper describes a traumatic thumb injury and amputation after which the occupational therapist placed an orthotic device to substitute for the thumb. When the patient was undecided about a proposed toe-to-hand transplant, the occupational therapist fabricated a mold of the toe, and attached it to the patient's hand. After training with the mold, the patient was ready to accept the toe-to-hand transplant. The post transplant occupational therapy program and patient's return to work was described. PMID- 23930962 TI - Pre- and postsurgical approaches to the treatment of the adult with hemiplegia having motor balancing surgery of the upper extremity. AB - This paper describes both the pre and post surgical treatment of the adult hemiplegic who has a disabling spasticity in the upper extremity. This includes discussion of general criteria for selection used y the therapist as well as guidelines for therapy after surgery. Emphasis is on close collaboration with the surgeon and in meeting the daily functional needs of the patient. PMID- 23930963 TI - Occupational therapy management of tendon transfers in persons with spinal cord injury quadriplegia. AB - Upper extremity surgical reconstruction can play an important role In helping the spinal cord injured quadriplegic patient achieve maximum independence in a variety of activities of daily living. The transfer of the brachioradialis to the extensor carpi radialis brevis, the brachioradialis to the flexor pollicis longus, and the posterior deltoid to the triceps each provide opportunities for functional improvement in this patient group. The occupational therapist's understanding of functional potentials and problems unique to spinal cord injury provides a realistic perspective to the team on potential benefits of each surgery. The occupational therapist also plays a critical role in identifying appropriate surgical candidates, in establishing treatment goals with the patient, and in administering a carefully planned post-operative treatment program. PMID- 23930964 TI - Choosing the components of an occupational therapy work assessment program for a psychiatric hospital. AB - Guiding adult psychiatric patients back to competitive employment is a challenge to any occupational therapist. This paper describes how a work assessment program was developed for an adult population in a long-term psychiatric care center despite the lack of applicable models for doing so. The resulting "common sense" approach, a "how to" for those searching for programming guidelines, is presented with recommendations for the development of similar programs in Occupational Therapy Departments. PMID- 23930967 TI - An investigation of cellular dynamics during the development of intramembranous bones: the scleral ossicles. AB - The development of intramembranous bone is a dynamic and complex process requiring highly coordinated cellular activities. Although the literature describes the detailed cellular dynamics of early mesoderm-derived endochondral bone, studies regarding neural crest-derived intramembranous bone have failed to keep pace. We analyzed the development of chick scleral ossicles from the onset of osteoid deposition to mineralization at morphological, histological, and ultrastructural levels. We find that the mesenchymal condensations from which ossicles develop change their shape from ellipsoidal to trapezoidal concurrent with an increase in size. Furthermore, the size of an ossicle is dependent upon its time of induction. Our histological analyses of condensation growth reveal cell migration and osteoid secretion as key cellular processes determining condensation size; these processes occur concomitantly to increase both the area and thickness of condensations. We also describe the formation of the zone of overlap between ossicles and conclude that the process is similar to that of cranial suture formation. Finally, transmission electron microscopy of early condensations demonstrates that early osteoblasts secrete collagen parallel to the long axis of the condensation. This study elucidates fundamental mechanisms of intramembranous bone development at the cellular level, furthering our knowledge of this important process among vertebrates. PMID- 23930966 TI - Repair of hydantoin lesions and their amine adducts in DNA by base and nucleotide excision repair. AB - An important feature of the common DNA oxidation product 8-oxo-7,8-dihydroguanine (OG) is its susceptibility to further oxidation that produces guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) lesions. In the presence of amines, G or OG oxidation produces hydantoin amine adducts. Such adducts may form in cells via interception of oxidized intermediates by protein-derived nucleophiles or naturally occurring amines that are tightly associated with DNA. Gh and Sp are known to be substrates for base excision repair (BER) glycosylases; however, large Sp-amine adducts would be expected to be more readily repaired by nucleotide excision repair (NER). A series of Sp adducts differing in the size of the attached amine were synthesized to evaluate the relative processing by NER and BER. The UvrABC complex excised Gh, Sp, and the Sp-amine adducts from duplex DNA, with the greatest efficiency for the largest Sp-amine adducts. The affinity of UvrA for all of the lesion duplexes was found to be similar, whereas the efficiency of UvrB loading tracked with the efficiency of UvrABC excision. In contrast, the human BER glycosylase NEIL1 exhibited robust activity for all Sp amine adducts irrespective of size. These studies suggest that both NER and BER pathways mediate repair of a diverse set of hydantoin lesions in cells. PMID- 23930968 TI - Epidemiological investigations on the possible risk of distribution of zoonotic bacteria through apparently healthy homing pigeons. AB - Clinically healthy homing pigeons may serve as an unnoticed reservoir for zoonotic bacteria. Hence, healthy pigeons from 172 different racing pigeon lofts were examined for Salmonella serovars, Campylobacter spp. and Chlamydophila (Chlamydia) psittaci. Two samplings were performed during the racing season in summer (1242 adult and 1164 juvenile pigeons) and two during winter (1074 adult pigeons). Each sampling was accompanied by a questionnaire to identify risk factors for positive lofts. Between 0.9 and 3.7%, 13.1 and 23.7%, and 12.8 and 42.6% of lofts were tested positive by cultural methods or polymerase chain reaction for Salmonella Typhimurium var. Copenhagen, Campylobacter jejuni and C. psittaci, respectively. The detection rate of C. psittaci was twice as high in samples from juvenile pigeons (29.1%) compared with samples from adult pigeons (15.0%, P <0.001). No other influence of age or season was detected. For the first time, pigeon-derived C. jejuni isolates (n=15) were characterized for their ability to invade human enterocytes in vitro. All isolates were invasive with an invasion index between 0.4 and 34.1 (human reference strain: average 11.3). Of 50 C. jejuni isolates tested for antimicrobial susceptibility, 46.0% were resistant to ciprofloxacin. All isolates were sensitive to erythromycin and tetracycline. The analysis of risk factors in association with the infection status of lofts for C. jejuni and C. psittaci suggested that biosecurity measures reduce the risk of infection. This study indicated a zoonotic potential of pigeon-derived C. jejuni. However, clinically healthy homing pigeons pose only a low risk for transmission of the investigated pathogens to humans. PMID- 23930969 TI - Thermodynamics-based mathematical model for solubility prediction of glibenclamide in ethanol-water mixtures. AB - Temperature-dependent solubility data of glibenclamide (GBN) in various ethanol water mixtures is not reported in literature so far. Therefore, the aim of this study was to determine the mole fraction solubility of GBN in various ethanol water mixtures at the temperature range of 293.15 to 318.15 K. The solubility of GBN was determined by reported shake flask method and the experimental data was fitted in thermodynamics-based modified Apelblat model. The solubility of GBN was found to be increased with increase in temperature and mass fraction of ethanol in ethanol-water mixtures. The experimental data of GBN was well correlated with the modified Apelblat model at each temperature range with correlation coefficient of 0.9940-1.0000. The relative absolute deviation (AD) was found to be less than 0.1% except in pure ethanol and water. The positive values of enthalpies and entropies for GBN dissolution indicated that its dissolution is endothermic and an entropy-driven process. PMID- 23930971 TI - Conceptualizing the clinical and professional development of child and adolescent mental health nurses. AB - Aspects of mental health nursing and its subspecialties are not easily defined. Child and adolescent mental health (CAMH) nursing is a subspecialty of mental health nursing, and some of its characteristics are tacit. This paper presents a deeper understanding of the meaning that CAMH nurses make of their role and work in the inpatient setting. The research was undertaken through a PhD candidature. The epistemological framework for the research was social constructionism. Interpretive enquiry was the methodology, as it allowed for the interpretation of multiple realities, which resulted in a rich description of the role and work of CAMH nurses. Methods of data collection were document analysis, focus group interviews, and individual interviews. Participants included nurses and multidisciplinary staff. Iterative and aggregative analyses were utilized for the documents. The focus group and individual interview data were analysed utilizing a thematic analysis process. This paper presents the findings of the combined analysis and the resultant holistic conceptual framework for the work of the CAMH nurse in the inpatient unit. The findings have contributed new knowledge to mental health nursing, specifically CAMH nursing, making the parameters of practice more explicit. Implications for practice, education, and research are identified. PMID- 23930970 TI - Association of -2518A>G promoter polymorphism in the monocyte chemoattractant protein-1 (MCP-1) gene with type 2 diabetes and coronary artery disease. AB - AIMS: Inflammatory markers play an important role in the development of diseases related to metabolic syndrome, such as type 2 diabetes (T2D) and coronary artery disease (CAD). The present study evaluates the association of -2518A>G polymorphism in the monocyte chemoattractant protein-1 (MCP-1) gene with T2D and CAD. RESULTS: The frequency of the G allele is greater in CAD cases (35%) as compared to T2D (24.6%) and controls (31%), while the frequency of the A allele is higher in T2D cases (75.4%) as compared to CAD cases (65%) and controls (69%). The analysis has revealed that in comparison to T2D cases, the G allele increases the risk of CAD by 1.9-fold (p=0.008; odds ratio [OR]=1.9, 1.18-3.06 at 95% confidence interval [CI]) but in comparison to controls the G-allele provided protection against T2D (p=0.011; OR=0.55, 0.35-0.87 at 95% CI), both under the dominant model (AG+GG vs. AA). CONCLUSION: Results of the present study suggests that G-allele of MCP-1 -2518A>G polymorphism is associated with reduced risk of T2D and increased risk of CAD in the population of Punjab. The results indicate that there is a difference in the association of risk alleles with phenotypes of metabolic syndrome. Body mass index and waist circumference are important risk factors for T2D in the population of Punjab. PMID- 23930972 TI - Role of traditional antimalarial plants in the battle against the global malaria burden. AB - Malaria continues to be a major global public health problem with 3.3 billion people at risk in 106 endemic countries. Globally, over 1000 plants have been used as potential antimalarials in resource-poor settings due to fragile health care systems and lack of accessibility and affordability of artemisinin-based combination therapies (ACTs). Although many believe that the use of medicinal plants that have folklore reputations for antimalarial properties is relatively safe, many herbs may be potentially toxic due to their intrinsic adverse side effects. Therefore, herbal-derived remedies require powerful and deep assessment of their pharmacological qualities to establish their mode of action, safety, quality, and efficacy. In addition, the evolution of drug resistance also demands new antimalarial agents. This can be achieved by forming a vibrant antimalarial discovery pipeline among all stakeholders, including traditional healers, ethnobotanists, scientists, entomologists, pharmacists, and research institutions, for the isolation and characterization of the bioactive compounds with the ultimate objective of finding novel modes of action antimalarial compounds that can be used to fight against drug-resistant malarial parasites. PMID- 23930973 TI - Serological evidence for exposure of dogs to Rickettsia conorii, Rickettsia typhi, and Orientia tsutsugamushi in Sri Lanka. AB - Vector-borne rickettsial infection is a major cause of febrile illnesses throughout the world. Although vertebrates hosting the vectors play a vital role in the natural cycle of rickettsiae, studies have not been conducted on them in Sri Lanka. Therefore, the present study was designed to determine the exposure of dog population in Rajawatta, Thambavita, and areas of the Western Slopes and Unawatuna of Sri Lanka to rickettsial pathogens. A total of 123 dog blood samples were collected from those areas. Samples were tested for antibodies against Rickettsia conorii (RC) of the spotted fever group (SFG), Rickettsia typhi (RT) of the typhus group (TG), and Orientia tsutsugamushi (OT) of the scrub typhus group (ST) of rickettsiae by indirect immunofluorescence antibody test (IFA). Samples with titers >= 1:64 were considered as positive in this study. Collectively, 49% dogs were found to have antibodies against the rickettsial agents. Of the dogs, 42%, 24%, and 2% had antibodies against RC, OT, and RT, respectively. The seropositive rate of 100% was observed in areas of the Western Slopes, whereas the lowest rate of 20% was in Unawatuna. Among the positive samples, antibody titers against RC and OT ranged from 1/64 to 1/8192. In contrast, the few dogs that tested positive for RT showed very low titers of 1/64 and 1/128. Results of this study show the extent of exposure to the pathogen and its dispersion in the natural ecology. We suggest that dogs could be acting as reservoirs in the rickettsial transmission cycle or could be effective tracer animals that can be used to detect areas with potential for future outbreaks. PMID- 23930974 TI - Co-infection with Arsenophonus nasoniae and Orientia tsutsugamushi in a traveler. AB - Here we report a case of co-infection with Orientia tsutsugamushi, the causative agent of scrub typhus, and Arsenophonus nasoniae in a woman with a rash and an eschar who returned from a trip to Southeast Asia. A. nasoniae was previously considered to be a secondary insect and tick endosymbiont of unknown pathogenicity in humans. We amplified both O. tsutsugamushi and A. nasoniae DNA from a skin eschar with qPCR, and a seroconversion for O. tsutsugamushi and A. nasoniae was observed with immunofluorescence assays and western blotting for this patient. And we used 2-D western blotting with an A. nasoniae antigen and polyclonal mouse anti-A. nasoniae antibodies produced in our laboratory to detect the specific antigenic A. nasoniae proteins. PMID- 23930975 TI - Trans-sialidase inhibition assay detects Trypanosoma cruzi infection in different wild mammal species. AB - The detection of Trypanosoma cruzi infection in mammals is crucial for understanding the eco-epidemiological role of the different species involved in parasite transmission cycles. Xenodiagnosis (XD) and hemoculture (HC) are routinely used to detect T. cruzi in wild mammals. Serological methods are much more limited because they require the use of specific antibodies to immunoglobulins of each mammalian species susceptible to T. cruzi. In this study we detected T. cruzi infection by trans-sialidase (TS) inhibition assay (TIA). TIA is based on the antibody neutralization of a recombinant TS that avoids the use of anti-immunoglobulins. TS activity is not detected in the co-endemic protozoan parasites Leishmania spp and T. rangeli. In the current study, serum samples from 158 individuals of nine wild mammalian species, previously tested by XD, were evaluated by TIA. They were collected from two endemic areas in northern Argentina. The overall TIA versus XD co-reactivity was 98.7% (156/158). All 18 samples from XD-positive mammals were TIA-positive (co-positivity, 100%) and co negativity was 98.5% (138/140). Two XD-negative samples from a marsupial (Didelphis albiventris) and an edentate (Dasypus novemcinctus) were detected by TIA. TIA could be used as a novel tool for serological detection of Trypanosoma cruzi in a wide variety of sylvatic reservoir hosts. PMID- 23930976 TI - Mosquito protein kinase G phosphorylates flavivirus NS5 and alters flight behavior in Aedes aegypti and Anopheles gambiae. AB - Many arboviral proteins are phosphorylated in infected mammalian cells, but it is unknown if the same phosphorylation events occur when insects are similarly infected. One of the mammalian kinases responsible for phosphorylation, protein kinase G (PKG), has been implicated in the behavior of multiple nonvector insects, but is unstudied in mosquitoes. PKG from Aedes aegypti was cloned, and phosphorylation of specific viral sites was monitored by mass spectrometry from biochemical and cell culture experiments. PKG from Aedes mosquitoes is able to phosphorylate dengue nonstructural protein 5 (NS5) at specific sites in cell culture and cell-free systems and autophosphorylates its own regulatory domain in a cell-free system. Injecting Aedes aegypti and Anopheles gambiae mosquitoes with a pharmacological PKG activator resulted in increased Aedes wing activity during periods of their natural diurnal/crepuscular activity and increased Anopheles nocturnal locomotor/flight activity. Thus, perturbation of the PKG signaling pathway in mosquitoes alters flight behavior. The demonstrated effect of PKG alterations is consistent with a viral PKG substrate triggering increased PKG activity. This increased PKG activity could be the mechanism by which dengue virus increases flight behavior and possibly facilitates transmission. Whether or not PKG is part of the mechanism by which dengue increases flight behavior, this report is the first to show PKG can modulate behavior in hematophagous disease vectors. PMID- 23930978 TI - Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer's disease. AB - Compelling evidence from basic molecular biology has demonstrated the dual roles of microglia in the pathogenesis of Alzheimer's disease (AD). On one hand, microglia are involved in AD pathogenesis by releasing inflammatory mediators such as inflammatory cytokines, complement components, chemokines, and free radicals that are all known to contribute to beta-amyloid (Abeta) production and accumulation. On the other hand, microglia are also known to play a beneficial role in generating anti-Abeta antibodies and stimulating clearance of amyloid plaques. Abeta itself, an inducer of microglia activation and neuroinflammation, has been considered as an underlying and unifying factor in the development of AD. A vicious cycle of inflammation has been formed between Abeta accumulation, activated microglia, and microglial inflammatory mediators, which enhance Abeta deposition and neuroinflammation. Thus, inhibiting the vicious cycle seems to be a promising treatment to restrain further development of AD. With increasing research efforts on microglia in AD, intervention of microglia activation and neuroinflammation in AD may provide a potential target for AD therapy in spite of the provisional failure of nonsteroidal antiinflammatory drugs in clinical trials. PMID- 23930977 TI - Recent circulation of West Nile virus and potentially other closely related flaviviruses in Southern France. AB - In recent years, the number of West Nile virus (WNV) cases reported in horses and humans has increased dramatically throughout the Mediterranean basin. Furthermore, the emergence of Usutu virus (USUV) in Austria in 2001, and its subsequent expansion to Hungary, Spain, Italy, Switzerland, the United Kingdom, and Germany, has given added cause for concern regarding the impact of the spread of flaviviruses on human and animal health in western Europe. Despite frequent detection of WNV and USUV cases in neighboring countries, no case of WNV has been detected in France since 2006 and USUV has never been reported. However, recent investigations focused on detecting the circulation of flaviviruses in France are lacking. We investigated the circulation of WNV and USUV viruses in wild birds in southern France on the basis of a serological survey conducted on a sentinel species, the magpie (Pica pica), in the Camargue area from November, 2009, to December, 2010. We detected WNV-neutralizing antibodies at a high titer (160) in a second-year bird showing recent exposure to WNV, although no WNV case has been detected in humans or in horses since 2004 in the Camargue. In addition, we observed low titers (10 or 20) of USUV-specific antibodies in six magpies, two of which were also seropositive for WNV. Such low titers do not give grounds for concluding that these birds had been exposed to USUV; cross-reactions at low titers may occur between antigenically closely related flaviviruses. But these results urge for further investigations into the circulation of flaviviruses in southern France. They also emphasize the necessity of undertaking epidemiological studies on a long-term basis, rather than over short periods following public health crises, to gain insight into viral dynamics within natural reservoirs. PMID- 23930979 TI - Visualization of phase evolution in model organic photovoltaic structures via energy-filtered transmission electron microscopy. AB - The morphology of the active layer in an organic photovoltaic bulk-heterojunction device is controlled by the extent and nature of phase separation during processing. We have studied the effects of fullerene crystallinity during heat treatment in model structures consisting of a layer of poly(3-hexylthiophene) (P3HT) sandwiched between two layers of [6,6]-phenyl-C61-butyric acid methyl ester (PCBM). Utilizing a combination of focused ion-beam milling and energy filtered transmission electron microscopy, we monitored the local changes in phase distribution as a function of annealing time at 140 degrees C. In both cases, dissolution of PCBM within the surrounding P3HT was directly visualized and quantitatively described. In the absence of crystalline PCBM, the overall phase distribution remained stable after intermediate annealing times up to 60 s, whereas microscale PCBM aggregates were observed after annealing for 300 s. Aggregate growth proceeded vertically from the substrate interface via uptake of PCBM from the surrounding region, resulting in a large PCBM-depleted region in their vicinity. When precrystallized PCBM was present, amorphous PCBM was observed to segregate from the intermediate P3HT layer and ripen the crystalline PCBM underneath, owing to the far lower solubility of crystalline PCBM within P3HT. This process occurred rapidly, with segregation already evident after annealing for 10 s and with uptake of nearly all of the amorphous PCBM by the crystalline layer after 60 s. No microscale aggregates were observed in the precrystallized system, even after annealing for 300 s. PMID- 23930980 TI - Two-dimensional heterospectral correlation analysis of the redox-induced conformational transition in cytochrome c using surface-enhanced Raman and infrared absorption spectroscopies on a two-layer gold surface. AB - The heme protein cytochrome c adsorbed to a two-layer gold surface modified with a self-assembled monolayer of 2-mercaptoethanol was analyzed using a two dimensional (2D) heterospectral correlation analysis that combined surface enhanced infrared absorption spectroscopy (SEIRAS) and surface-enhanced Raman spectroscopy (SERS). Stepwise increasing electric potentials were applied to alter the redox state of the protein and to induce conformational changes within the protein backbone. We demonstrate herein that 2D heterospectral correlation analysis is a particularly suitable and useful technique for the study of heme containing proteins as the two spectroscopies address different portions of the protein. Thus, by correlating SERS and SEIRAS data in a 2D plot, we can obtain a deeper understanding of the conformational changes occurring at the redox center and in the supporting protein backbone during the electron transfer process. The correlation analyses are complemented by molecular dynamics calculations to explore the intramolecular interactions. PMID- 23930981 TI - Pressure reentrant assembly: direct simulation of volumes of micellization. AB - Surfactants exhibit maxima in their critical micelle concentrations upon application of hydrostatic pressure, which is attributable to changes in their volumes of micellization from positive to negative values with increasing pressure. We present a direct molecular simulation analysis of the volumes of micellization of an anionic, cationic, and nonionic surfactant in aqueous solution at pressures up to 2500 bar. Excellent agreement with experiment is observed. A Kirkwood-Buff theory analysis based on proximal solvent distributions permits the breakdown of the volumes of micellization into constituent surfactant headgroup and tailgroup contributions. Although the micellization volume crossover is analogous to the transfer of an alkane from water to its pure liquid, significant differences are observed, including lower compressibilities of micelle volumes compared to that of the alkane liquid, negative partial compressibilites for anionic sulfated surfactant monomers, and large nonionic ethoxy headgroup contributions to the micellization volume. PMID- 23930982 TI - Ethnicity, socioeconomic characteristics and knowledge, beliefs and attitudes about HIV among Yunnanese Chinese, Hmong, Lahu and Northern Thai in a north western Thailand border district. AB - Data from ethnically diverse north-western Thailand with recent migrants from Myanmar (Burma) and China allow testing of hypotheses concerning between- and within-community differences in predominantly Yunnanese Chinese, Hmong and Lahu ethnic minority villages versus ethnic majority Thai villages. Topics include knowledge of HIV transmission, prevention and treatment, avoidance of people infected with HIV and constraints to use of health services. Respondents include women with one or more children under age five and their husbands/partners. Ethnicity is consistently associated with socioeconomic characteristics, knowledge of HIV transmission, prevention and treatment, avoidance of people living with HIV and AIDS, and constraints to use of services. Chinese community residents had the lowest levels of knowledge of HIV, especially with regard to mother-to-child transmission, the most intent to avoid contact with people living with HIV and AIDS, and the highest levels of constraints to using services, including ineligibility for government healthcare and limited Thai language ability. Associations of counselling with Thai language ability, and more knowledge and less avoidance of people living with HIV and AIDS, suggest that language-appropriate health education may help overcome disparities. PMID- 23930983 TI - AMIGAS: building a cervical cancer screening intervention for public health practice. AB - BACKGROUND: Many barriers to cervical cancer screening for Hispanic women have been documented, but few effective interventions exist. The Community Preventive Services Task Force recommends increasing cervical cancer screening through various methods. Building on this evidence, the Centers for Disease Control and Prevention funded the research and testing phases for an evidence-based and theoretically grounded intervention designed to increase cervical cancer screening among never and rarely screened Hispanic women of Mexican descent. In this article, we describe the development process of the AMIGAS (Ayudando a las Mujeres con Informacion, Guia, y Amor para su Salud) intervention, highlight the integration of scientific evidence and community-based participatory research principles, and identify opportunities for dissemination, adaptation, and implementation of this intervention. METHODS: The AMIGAS team was a collaboration among researchers, promotoras (community health workers), and program administrators. The multiyear, multiphase project was conducted in Houston, Texas; El Paso, Texas; and Yakima, Washington. The team completed several rounds of formative research, designed intervention materials and methodology, conducted a randomized controlled trial, created a guide for program administrators, and developed an intervention dissemination plan. RESULTS: Trial results demonstrated that AMIGAS was successful in increasing cervical cancer screening among Hispanic women. Adaptation of AMIGAS showed minimal reduction of outcomes. Dissemination efforts are underway to make AMIGAS available in a downloadable format via the Internet. CONCLUSIONS: Developing a community-based intervention that is evidence based and theoretically grounded is challenging, time-intensive, and requires collaboration among multiple disciplines. Inclusion of key stakeholders-in particular program deliverers and administrators-and planning for dissemination and translation to practice are integral components of successful intervention design. By providing explicit directions for adaptation for program deliverers, relevant information for program administrators, and access to the intervention via the Internet, AMIGAS is available to help increase cervical cancer screening among Hispanic women and other women disproportionately affected by cervical cancer. PMID- 23930984 TI - Cost of childhood diarrhoea in rural South Africa: exploring cost-effectiveness of universal zinc supplementation. AB - OBJECTIVE: To describe the cost of diarrhoeal illness in children aged 6-24 months in a rural South African community and to determine the threshold prevalence of stunting at which universal Zn plus vitamin A supplementation (VAZ) would be more cost-effective than vitamin A alone (VA) in preventing diarrhoea. DESIGN: We conducted a cost analysis using primary and secondary data sources. Using simulations we examined incremental costs of VAZ relative to VA while varying stunting prevalence. SETTING: Data on efficacy and societal costs were largely from a South African trial. Secondary data were from local and international published sources. SUBJECTS: The trial included children aged 6-24 months. The secondary data sources were a South African health economics survey and the WHO-CHOICE (CHOosing Interventions that are Cost Effective) database. RESULTS: In the trial, stunted children supplemented with VAZ had 2.04 episodes (95 % CI 1.37, 3.05) of diarrhoea per child-year compared with 3.92 episodes (95 % CI 3.02, 5.09) in the VA arm. Average cost of illness was $Int 7.80 per episode (10th, 90th centile: $Int 0.28, $Int 15.63), assuming a minimum standard of care (oral rehydration and 14 d of therapeutic Zn). In simulation scenarios universal VAZ had low incremental costs or became cost-saving relative to VA when the prevalence of stunting was close to 20 %. Incremental cost-effectiveness ratios were sensitive to the cost of intervention and coverage levels. CONCLUSIONS: This simulation suggests that universal VAZ would be cost-effective at current levels of stunting in parts of South Africa. This requires further validation under actual programmatic conditions. PMID- 23930985 TI - Nonuraemic nonfatal idiopathic calciphylaxis in a kitten. AB - BACKGROUND: Calciphylaxis is a rare cutaneous disorder, characterized by vascular calcification and progressive skin necrosis, not yet described in cats. It is scarcely reported in animals, mostly due to iatrogenic or uraemic disturbances of the calcium-phosphate balance. In human patients, it is most commonly seen with end-stage renal disease, but several nonuraemic disorders, including inherited dysfunctions of tissue calcification inhibitors, have also been described. HYPOTHESIS/OBJECTIVES: To describe a case of nonuraemic calciphylaxis in a cat. ANIMALS: A 10-week-old male domestic short hair kitten was presented with hyperacute skin lesions. Initial dermatological signs were characterized by sharp demarcated erosions and ulcerations on the face, including the nasal planum and lips. Cutaneous lesions rapidly progressed into thick crusts with ulcerations, involving parts of the face and pinna as well as abdominal skin. METHODS: Complete blood count, serum chemistry profile, urinalysis, parathyroid hormone measurement and histopathological examination of skin biopsies. RESULTS: Histopathology from newly developed abdominal skin lesions revealed severe epidermal necrosis and calcification, multifocal pannicular calcification and calcified subcutaneous vessels, supporting a diagnosis of calciphylaxis. Treatment consisted of systemic and topical antimicrobials, analgesics, pentoxifylline, Lantharenol((r)) , sodium thiosulfate and vitamin K. After initiation of therapy, no further progression was noticed; all medications could be discontinued eventually, and no relapse was seen in the following 2 years. CONCLUSIONS AND CLINICAL IMPORTANCE: Calciphylaxis should be considered as a differential diagnosis for ulcerative cutaneous disorders in young cats. More information on this disease is needed to elucidate the pathomechanism. PMID- 23930986 TI - How musical engagement promotes well-being in education contexts: the case of a young man with profound and multiple disabilities. AB - Students with profound intellectual disabilities disorders (IDDs) have the right to participate in educational opportunities that recognize their unique resources and needs, as do all children. Because of their specific communication challenges, positive relationships with attentive communication partners are critical for success. In fact, the power of positive relationships in schools is recognized to be connected to student well-being more broadly. This article examines the case of one young man with profound IDD and his relationship with his music therapist using a duo-ethnographic informed paradigmatic case study. Video analysis based on multi-voice perspectives is used to generate hermeneutic phenomenological findings to closely examine the relationship between a young man with profound IDD and a music therapist. The voices of four allied health researchers were also gathered to inform the authors' construction of an informed commentary on the phenomenon. The results suggest that the essence lay in a combination of attentive, responsive and creative being with the other person over time. Four principles of musical engagement were identified in the video footage as critical to the meaningful relationships through music: the music therapist listens; the music therapist takes responsibility for structure; spontaneous initiation is sought from the young person; and the relationship is built over time. These concepts are contextualized within a discussion of student well-being that is underpinned by positive relationships and leads to students achieving their full potential within diverse school contexts. PMID- 23930987 TI - Everyday music listening and affect regulation: the role of MP3 players. AB - The use of digital portable music devices such as MP3 players has rapidly increased during the last decade, and the sheer availability of music offered by such players raises questions about their impact on listeners' mental and physical health and well-being. This article explores MP3 player use as an everyday tactic for affect regulation, here understood as an individual's efforts to maintain or change the intensity or duration of a given affect. The ability to understand and regulate affects has significant health implications, and among the tactics relevant to such regulation, engagement with music has proven to be particularly successful. The material presented in this article is based on a qualitative interview study focused on MP3 player use as a medium for musical self-care. Because MP3 users can listen to whatever they want, whenever they want, and target their music in the interests of managing and regulating moods and emotions, the MP3 player represents a valuable and convenient technology of affect regulation. PMID- 23930988 TI - Can music serve as a "cultural immunogen"? An explorative study. AB - The aim of this study is to explore how people in contemporary society may apply music in their everyday life to improve their health and well-being. Through a series of qualitative interviews, informants gave their narratives about how music had become a part of their health practice. Six narratives concerning this type of everyday musical self-care are presented, and the following questions are sought to be answered: What kinds of musical practices do people apply in order to regulate their health and promote their sense of well-being? What kind of generative health mechanism can we observe or theorize when people use music to enhance their well-being? What kinds of rituals, contextual circumstances and personal health beliefs are operating in these situations? The findings suggests that some people may sing, participate in a choir, dance to music, compose songs, play precomposed music, or play in a band as part of a reflexive strategy to improve their health and well-being. Further analysis also identified six generative factors that may contribute to the immunogen functions of music: A pragmatic concept of music, music as a social and emotional resource, music as a supportive self object, musical competency, rituals, and locus of control. These findings may have implication for the field of music therapy as it will fill the gap between the clinical use of music done by professional music therapists and the everyday "musicking" performed by people outside the institutional practice. PMID- 23930989 TI - Improvisation and meaning. AB - This article presents and discusses a long-term repeated-immersion research process that explores meaning allocated to an episode of 50 seconds of music improvisation in early neurosurgical rehabilitation by a teenage boy with severe traumatic brain injury and his music therapist. The process began with the original therapy session in August 1994 and extends to the current time of writing in 2013. A diverse selection of qualitative research methods were used during a repeated immersion and engagement with the selected episodes. The multiple methods used in this enquiry include therapeutic narrative analysis and musicological and video analysis during my doctoral research between 2002 and 2004, arts-based research in 2008 using expressive writing, and arts-based research in 2012 based on the creation of a body cast of my right hand as I used it to play the first note of my music improvising in the original therapy episode, which is accompanied by reflective journaling. The casting of my hand was done to explore and reconsider the role of my own body as an embodied and integral, but originally hidden, part of the therapy process. Put together, these investigations explore the potential meanings of the episode of music improvisation in therapy in an innovative and imaginative way. However, this article does not aim at this stage to present a model or theory for neurorehabilitation but offers an example of how a combination of diverse qualitative methods over an extended period of time can be instrumental in gaining innovative and rich insights into initially hidden perspectives on health, well-being, and human relating. PMID- 23930990 TI - "Time after time": a Quali-T method for assessing music's impact on well-being. AB - This article considers the question of how to produce ecologically valid assessments of music's role as a health technology. To address this question, I consider critically some of the standard quantitative instruments used to assess well-being and quality of life. I suggest that these instruments do not lend themselves well to the production of ecologically valid assessments and understandings for two reasons: (1) the process of data elicitation is removed from everyday meanings and practices and therefore risks producing data that is an artifact of the situation in which it is elicited (2) standard, quantitative instruments are not neutral but are rather discursive texts that are inevitably imbued with a politics of expertise and an image of the health care client. For these reasons, I suggest that we consider the question of how to develop ecologically valid, client-centered assessment measures. To that end, I introduce a third critique of the standard quantitative instruments, namely that they are associated with, and promote, an ontology of wellness/illness that downplays the temporally variable and situationally emergent nature of both wellness/illness and musical interventions themselves. As an alternative mode of assessment, I suggest that we reconsider the value of singular case studies and I describe a set of principles that can assist researchers to produce ecologically valid assessments. To this end I introduce the concept of the musical event as a more ecologically valid means for illuminating the specific mechanisms by which music aids well-being. I suggest that the case study approach is temporally sensitive, that it lends itself to an emergent ontology of wellness/illness, and that it is client-centered (and can also be user-led). PMID- 23930992 TI - "Musical co-creation"? Exploring health-promoting potentials on the use of musical and interactive tangibles for families with children with disabilities. AB - The point of departure in this text is the ongoing qualitative interdisciplinary research project RHYME (www.RHYME.no), which addresses the lack of health promoting interactive and musical Information and Communications Technology (ICT) for families with children with severe disabilities. The project explores a new treatment paradigm based on collaborative, tangible, interactive net-based musical "smart things" with multimedia capabilities. The goal in RHYME is twofold: (1) to reduce isolation and passivity, and (2) to promote health and well-being. Co-creation is suggested as a possible path to achieving these goals, by evoking feelings, for example, or accommodating the needs to act and to create social relations; co-creation also motivates users to communicate and collaborate within (new) social relations. This article engages co-creation by incorporating aspects connected to interaction design and the field of music and health. Empirical observations will be referred to. The research question is as follows: What might co-creation imply for families of children with disabilities when musical and interactive tangibles are used as health-promoting implements? PMID- 23930991 TI - Music, health, and well-being: a review. AB - The relationship between arts participation and health is currently very topical. Motivated by a desire to investigate innovative, non-invasive, and economically viable interventions that embrace contemporary definitions of health, practitioners and researchers across the world have been developing and researching arts inventions. One of the key drivers in this vigorous research milieu is the growth of qualitative research within health care contexts and researchers interested in exploring the potential benefits of musical participation have fully embraced the advances that have taken place in health related qualitative research. The following article presents a number of different types of qualitative research projects focused on exploring the process and outcomes of music interventions. It also presents a new conceptual model for music, health and well-being. This new model develops on a previous version of MacDonald, Kreutz, and Mitchell (2012b) by incorporating new elements and contextualization and providing detailed experimental examples to support the various components. PMID- 23930993 TI - Music, health, and well-being. PMID- 23930994 TI - Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR). AB - A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design. PMID- 23930996 TI - Real time three-dimensional transthoracic echocardiography of ruptured left sinus of Valsalva aneurysm to left ventricle. AB - Aneurysms arising from the sinus of Valsalva are a rare cardiac defect that can present with various signs and symptoms, and if not diagnosed and treated rapidly can lead to fatal outcomes. Unruptured aneurysms are usually asymptomatic and found incidentally during diagnostic studies. More commonly, aneurysm of sinus of Valsalva is detected after the occurrence of rupture. Echocardiography has become the investigative tool of choice for this condition, not only for diagnosis but also for quantification of severity. We hereby report a rare case of a 15-year old patient presenting with complaints of effort dyspnea and palpitations. Two dimensional transthoracic echocardiography (TTE) showed aneurysmal dilatation of left sinus of Valsalva which had ruptured into the left ventricle. Also, there was an intimal flap within the sinus of Valsalva aneurysm. The anatomical relationship between the aorta, aneurysm, and the left ventricle as well as the intimal flap within the aneurysm was clearly delineated with the help of three dimensional TTE. After confirmation of the diagnosis with multidetector computed tomography, patient underwent successful surgical repair of the defect. PMID- 23930995 TI - Diagnosing heart failure with preserved ejection fraction. AB - INTRODUCTION: Heart failure with preserved ejection fraction (HFPEF) is a common syndrome, accounting for about 50% of all patients with heart failure (HF). Morbidity and mortality are similar to patients with HF with reduced ejection fraction (HFREF), yet no effective treatment has been identified in randomized clinical trials. AREAS COVERED: This article provides an overview of the available literature regarding diagnosing established HFPEF and potential new therapeutic targets for the early diagnosis of HFPEF. Vascular dysfunction, ventricular-arterial coupling, oxidative stress, extracellular matrix regulation, chronotropic incompetence, pulmonary hypertension, exercise testing and biomarkers were taken into consideration next to conventional measurements of diastolic dysfunction. EXPERT OPINION: Measuring diastolic dysfunction in HFPEF is considered important in many patients. Nevertheless, today we know that other causes besides diastolic dysfunction are also involved in the pathophysiology of many HFPEF patients and need to be investigated in order to make a correct diagnosis. Therefore, further research is required to allow better and more specific diagnostic and treatment options to reduce the morbidity and mortality for this ever-expanding HF population. PMID- 23930997 TI - Skull base osteomyelitis following a mastoidectomy. AB - Skull base osteomyelitis is a rare but life-threatening condition that is characterized by osteitis of the temporal bone and skull base. Although skull base osteomyelitis is recognized as a rare complication of malignant external otitis or middle ear infection, it may also occur following a mastoidectomy. We present a case of an 81-year-old woman who suffered severe otalgia with normal looking EAC and tympanic membrane that developed six weeks following a canal wall up mastoidectomy. Otalgia was the only abnormal feature to suspect occurrence of skull base osteomyelitis. PMID- 23930998 TI - High efficiency synthesis of F-18 fluoromethyl ethers: an attractive alternative for C-11 methyl groups in positron emission tomography radiopharmaceuticals. AB - A rapid and efficient method for the synthesis of O-fluoromethyl aliphatic and aromatic ethers is presented. This method is so mild that it can be used for the preparation of positron emission tomography (PET) radiopharmaceuticals bearing O [(18)F]fluoromethyl groups. PMID- 23931000 TI - From the editor's desk. AB - No abstract available for this article. PMID- 23931001 TI - Medical consumer education. AB - The need for health promotion programs in the workplace is more important today than ever before in these times of increased costs of health care. It is essential for corporations to develop efficient and effective health programs which will reduce the costs of employee health services while providing quality care. Occupational therapists can make significant contributions to the development and implementation of health promotion and health education programs in the corporate world. The Medical Marketplace project described was a federally funded research project designed to assess the effectiveness of a health consumer education and training program on the reduction of health care costs. The training was intended to increase the knowledge and skills of employees, making them wise and informed consumers of health services; to improve the quality of health care by helping consumers find appropriate care more quickly and directly; and to reduce employee health costs by eliminating the use of unnecessary or inappropriate services. The occupational therapist was the principal investigator of this project. PMID- 23930999 TI - Gamma camera imaging for studying intestinal absorption and whole-body distribution of selenomethionine. AB - Se metabolism in humans is not well characterised. Currently, the estimates of Se absorption, whole-body retention and excretion are being obtained from balance and tracer studies. In the present study, we used gamma camera imaging to evaluate the whole-body retention and distribution of radiolabelled selenomethionine (SeMet), the predominant form of Se present in foods. A total of eight healthy young men participated in the study. After consumption of a meal containing 4 MBq [75Se]L-SeMet ([75Se]SeMet), whole-body gamma camera scanning was performed for 45 min every hour over a 6 h period, every second hour for the next 18 h and once on each of the subsequent 6 d. Blood, urine and faecal samples were collected to determine the plasma content of [75Se]SeMet as well as its excretion in urine and faeces. Imaging showed that 87.9 (sd 3.3)% of the administered activity of [75Se]SeMet was retained within the body after 7 d. In contrast, the measured excretion in urine and faeces for the 7 d period was 8.2 (sd 1.1)% of the activity. Time-activity curves were generated for the whole body, stomach, liver, abdomen (other than the stomach and the liver), brain and femoral muscles. Gamma camera imaging allows for the assessment of the postprandial absorption of SeMet. This technique may also permit concurrent studies of organ turnover of SeMet. PMID- 23931002 TI - Health care systems models and occupational therapy. AB - Health care system models featuring four alternative future scenarios are discussed relative to occupational therapy. Five prevailing theoretical models of occupational therapy practice and three practice systems are described as they interact for service provision. Occupational therapy as an open system is presented as possessing the potential to successfully embrace and negotiate changes a in the health care system as projected for the future. PMID- 23931003 TI - Target marketing strategies for occupational therapy entrepreneurs. AB - Understanding marketing techniques is one of the skills needed by successful entre renews. Target marketing is an effective method for occupational therapy entrepreneurs to use in determining when and where to enter the marketplace. The two components of target marketing, market segmentation and the development of marketing mix strategies for each identified market segment, are described. The Profife of Attitudes Toward Health Care (PATH) method of psychographic market segmentation of health care consumers is presented. Occupational therapy marketing mix strategies for each PATH consumer group are delineated and compatible groupings of market segments are suggested. PMID- 23931004 TI - Barriers to occupational therapy practice in wellness. AB - Wellness programs are intended to increase the wellbeing of society and as a consequence reduce health care costs. Occupational therapy writers have urged therapists for the past two decades to move into wellness-related programming, yet current practice trends reflect only minimal involvement in wellness. The purpose of this study was to identify barriers to wellness practice, components of occupational therapy philosophy and practice that can promote wellness, and wellness concepts which can be incorporated into patient therapy sessions. Semi structured interviews were conducted with three occupational therapists, two related health professionals and two former patients, all of whom have made contributions in wellness programming. A summary of the barriers to occupational therapists, entry into wellness is presented. Also, recommendations are provided on how occupational therapists can expand their holistic approach to include wellness concepts in all areas of practice. PMID- 23931005 TI - Exercise and activity in the promotion of health. AB - Current trends indicate increases in the numbers of Americans participating in exercise and conditioning programs. These numbers are coupled with simultaneous interest by practitioners and researchers in the potential benefits associated with exercise as well as with activity participation to restore or promote general health. This annotated bibliography includes a number of revlews as well as efficacy studies exploring the potential benefits of exercise, particularly aerobic exercise, on physical and mental health. These references are provided as a resource for therapists to become aware of the present status of exercise related research as well as the nature of exercise and activity programs being developed and explored in practice today. PMID- 23931006 TI - Toward a balance of work and play. AB - When the occupational therapist meets the patient or client consumer of rehabilitation services, a therapeutic relationship is begun between persons who may have varying developmental backgrounds, value perspectives, social and physical environmental experiences, cultural ties, and lifestyle patterns. In order to develop significant evaluation and treatment strategies appropriate to the personal context of the consumer's life experience, it is the responslbility of the therapist to develop an understanding of the consumer's perspective. The following discussion describes a qualitative research project designed to explore the relationships of work, play, balance, and health in the life continuum of a 38-year-old woman who'suffered severe trauma at the age of 17 and regained control of her life through the development of a pattern of personal responsibility for her health. The study is discussed with regard to project procedures using tape-recorded interviews, outcomes, and applications to academic and clinical education. PMID- 23931007 TI - Issues and concerns of a health promotion consultant. AB - Burgeoning health care costs and the current organizational practices of leaner staffing patterns demand innovative approaches to the development of life skills. These approaches create requests for consulting and training programs in the area of personal and professional growth. This paper focuses on personal, professional/programmatic and business development issues and concerns of a consultant with a health promotion practice. PMID- 23931008 TI - From Hospital to Community - The Health Care Challenge of the 1980's. AB - This article describes one hospital's attempt to provide occupational therapy services to the community, an effort suggested some eighteen years ago by occupational therapy writers. The vehicle selected for the accomplishment of such a move is health promotion. The viability of using health promotion to expand occupational therapy services is examined in both an inpatient and outpatient setting. PMID- 23931009 TI - Coincidence to significance. AB - This article will describe the author's entrepreneurial experiences related to challenges of initiating, negotiating and completing a health promotion project for a Fortune 500 company. The events described begin with her casual meeting of a director of the health promotion section of an international food company and wncludes with the author's final development of a significant employee injury prevention program. The purpose of this paper is to demonstrate professional challenges an occupational therapist may encounter to successfully complete a corporate project. PMID- 23931010 TI - CeO2-TiO2 sorbents for the removal of elemental mercury from syngas. AB - A series of CeO2-TiO2 (CeTi) sorbents with different CeO2/TiO2 mass ratios were prepared by an impregnation method and employed to remove elemental mercury (Hg(0)) in simulated syngas. The CeTi sorbents with a CeO2/TiO2 mass ratio of 0.2 exhibited superior Hg(0) removal efficiency from 80 to 150 degrees C, which could be ascribed to the greater amount of surface chemisorbed oxygen resulted from Ce(3+) on the sample surface. H2S was the most effective syngas component responsible for Hg(0) removal. The use of 400 ppm H2S resulted in 98% Hg(0) removal efficiency under the experimental conditions. H2 and CO had a negligible effect on the efficiency of Hg removal. In the presence of H2S, a prohibitive effect of HCl and NH3 on Hg(0) removal was observed because of the consumption of the surface oxygen. Water vapor also inhibited Hg(0) removal due to competitive adsorption with H2S. Hg(0) removal over CeTi sorbents was proposed to follow the Eley-Rideal mechanism, in which active surface sulfur reacts with gas-phase Hg(0). This large oxygen storage capacity of CeTi sorbents is quite favorable to H2S catalytic oxidation and Hg(0) emission control in an extremely reducing environment, such as when there is a deficiency of O2. PMID- 23931011 TI - Multiplexed imaging of nanoparticles in tissues using laser desorption/ionization mass spectrometry. AB - Imaging of nanomaterials in biological tissues provides vital information for the development of nanotherapeutics and diagnostics. Multiplexed imaging of different nanoparticles (NPs) greatly reduces costs, the need to use multiple animals, and increases the biodistribution information that can enhance diagnostic applications and accelerate the screening of potential therapeutics. Various approaches have been developed for imaging NPs; however, the readout of existing imaging techniques relies on specific properties of the core material or surface ligands, and these techniques are limited because of the relatively small number of NPs that can be simultaneously measured in a single experiment. Here, we demonstrate the use of laser desorption/ionization mass spectrometry (LDI-MS) in an imaging format to investigate surface chemistry dictated intraorgan distribution of NPs. This new LDI-MS imaging method enables multiplexed imaging of NPs with potentially unlimited readouts and without additional labeling of the NPs. It provides the capability to detect and image attomole levels of NPs with almost no interferences from biomolecules. Using this new imaging approach, we find that the intraorgan distributions of same-sized NPs are directly linked to their surface chemistry. PMID- 23931012 TI - Role of induction therapy: surgical resection of non-small cell lung cancer after induction therapy. AB - Patients with Stage III non-small cell lung cancer are best managed by multimodality therapy. Patients with N2 disease can be treated with induction therapy (usually chemotherapy) followed by surgical resection. Patients whose medical comorbidities preclude surgery should be treated with definitive chemoradiotherapy. T3 or T4 tumors involving the superior sulcus or spine are best managed with induction chemoradiotherapy and surgical resection. PMID- 23931013 TI - Can we predict morbidity and mortality before an operation? AB - Estimation of perioperative morbidity and mortality has been the subject of numerous studies in patients undergoing major lung resection. Multivariate models have been developed with the goal of improving patient selection for surgery, especially with recent impetus for systems-based quality improvement and a need to provide high-quality data for evidence-based decision making for high-risk patients. This article explores relationships between the variables studied and predictors of outcome, and discusses if it is ever possible to accurately predict risk of morbidity and mortality after major lung resection. PMID- 23931014 TI - Radical sublobar resection for small-diameter lung cancers. AB - Sublobar resection is a compromise for patients with insufficient lung function. Recently small lung cancers are usually detected at the early stage, but sublobar resection in patients who can tolerate lobectomy is not yet standard treatment. Although a few old studies showed higher rates of local recurrence and a poorer prognosis after sublobar resection compared with lobectomy, most have indicated promising outcomes after sublobar resection. Large-scale, randomized, controlled multicenter trials are ongoing in the United States and Japan, the results of which could create revolutionary changes in general thoracic surgery. This article reviews the literature on surgical outcomes of radical sublobar resection. PMID- 23931015 TI - Management of tumors involving the chest wall including pancoast tumors and tumors invading the spine. AB - Bronchogenic carcinomas involving the chest wall include tumors invading the ribs and spine, as well as Pancoast tumors. In the past, such neoplasms were considered to be incurable, but with new multimodality regimens, including induction chemoradiation followed by surgery, they can now be completely resected and patients can benefit from prolonged survival. The most important prognostic factors are the completeness of resection and the pathologic nodal status. PMID- 23931016 TI - The role of surgery in patients with clinical n2 disease. AB - Patients with N2 non-small cell lung carcinoma have ipsilateral mediastinal adenopathy with stage IIIA disease. Most of these patients are still staged solely using imaging techniques, which causes a significant error in staging if not combined with some form of surgical staging of the mediastinum. N2 disease forms a spectrum of disease ranging from occult microscopic disease to bulky multistation adenopathy. Proper understanding of the prognosis and treatment implications for each form of mediastinal lymph node metastases has led to the selective use of surgery to treat these patients. This article reviews the role of surgery in the management of patients with N2 mediastinal involvement. PMID- 23931017 TI - Reconstruction of the bronchus and pulmonary artery. AB - Sleeve lobectomy (SL) (lobectomy associated with resection and reconstruction of the bronchus, the pulmonary artery, or both) has proved to be a suitable choice for the treatment of centrally sited non-small cell lung cancer. SL for lung cancer is indicated when a tumor or an N1 lymph node infiltrates the origin of a lobar bronchus, the origin of the lobar branches of the pulmonary artery, or both but not to the extent that a pneumonectomy is required. SL can be performed safely and effectively, even after induction therapy, without an increased complication rate. PMID- 23931018 TI - Current status of mediastinal lymph node dissection versus sampling in non-small cell lung cancer. AB - This article addresses the appropriate use of lymph node sampling versus dissection, recommendations for minimum sampling for staging, and the role of lymph node dissection in improving survival. PMID- 23931019 TI - Intraoperative nodal staging: role of sentinel node technology. AB - In cases of superficial malignancies such as melanoma or breast cancer, intraoperative lymph node mapping with a sentinel lymph node (SLN) biopsy is an effective and minimally invasive alternative to inguinal or axillary lymph node dissection for early-stage tumors. For primary lung cancer, although much effort has been made to investigate a variety of tracers, such as dyes, radioisotopes, magnetite, and iopamidol, for discerning SLNs, an appropriate agent that produces high identification and accuracy rates has yet to be developed. Further studies are needed to find an ideal tracer for practical use in patients with non-small cell lung cancer. PMID- 23931020 TI - Can stereotactic ablative radiotherapy in early stage lung cancers produce comparable success as surgery? AB - Early stage non-small cell lung cancer is a potentially curable manifestation of a disease that is typically associated with a grim prognosis. Therapies directed at early stage disease can be challenging to deliver because patients tend to be elderly with multiple comorbidities. Surgery, the standard of care, has been validated with long-term follow-up. However, the risk of perioperative mortality and morbidity can limit the feasibility of an operation for many high-risk patients. Stereotactic ablative radiotherapy uses highly focused, ablative doses of radiation to treat tumors and has emerged as an alternative to surgery. PMID- 23931021 TI - Surgeon's view: is palliative resection of lung cancer ever justified? AB - Thoracic surgeons are often asked to see patients with locally advanced primary lung cancer in whom the goal of treatment is palliation for relief of disabling symptoms. The last four decades have brought great changes in the care of patients with primary lung cancer. The goals of the treatment must be well defined by the interdisciplinary team. The thoracic surgeon has to make the final decision on whether to consider an operation for palliation and what is the expectation of the recommended treatment. PMID- 23931022 TI - Adjuvant chemotherapy after pulmonary resection for lung cancer. AB - Adjuvant chemotherapy using a cisplatin-based regimen is currently recommended for patients with stage II and III non-small cell lung cancer (NSCLC) after complete tumor resection and may be considered for patients with stage IB NSCLC. Although adjuvant chemotherapy after complete resection of localized NSCLC is associated with an absolute survival advantage of approximately 5% at 5 years, there is still a relatively high risk of relapse even for early-stage NSCLC. Efforts are ongoing to identify new treatments in the adjuvant setting and to select patients for individualized treatment based on biomarkers. PMID- 23931023 TI - Targeted therapy and new anticancer drugs in advanced disease. AB - The development of targeted therapies in lung cancer (mainly non-small cell lung cancer) has led to improvement in clinical outcomes and a more personalized approach to the management of these patients. This article discusses the main categories of novel targeted agents and the evidence behind their use. PMID- 23931024 TI - Biologic approaches to drug selection and targeted therapy: hype or clinical reality? AB - Oncology remains at the forefront of the application of individualized or genomics-driven approaches to cancer care. This approach acknowledges cancer as a genetic disease, driven by alterations in oncogenes and tumor suppressors, with the strategy of using this information to guide therapy based on therapeutics capable of targeting specific alterations. Recent advances suggest a changing landscape in how management decisions are approached for the patient with non small cell lung cancer. An expanding and functionally useful toolbox of novel targeted agents and biomarkers to drive therapeutic choices is beginning to impact patient care. This article reviews key advances, with commentary and perspective for the practicing thoracic surgical oncologist. PMID- 23931025 TI - What is the most practical, optimal, and cost effective method for performing follow-up after lung cancer surgery, and by whom should it be done? AB - Surgery is the treatment of choice for early stage non-small cell lung cancer. In this context, postoperative follow-up is important to diagnose late postoperative complications, as well as to detect recurring cancer or new primaries as early as possible. There is, however, no high-quality evidence regarding the benefits of monitoring programs on survival and quality of life. Most studies recommend clinical and radiological follow-up (radiograph or chest computed tomography) performed more intensively during the first two years and annually thereafter. The physician doing the follow-up can be the thoracic surgeon, the diagnosing physician, or the family physician. PMID- 23931026 TI - Quality of life after pulmonary resections. AB - Quality of life (QOL) is an important component of the conversation between any physician and patient. It is especially important between a surgeon and an operative candidate when considering treatment of lung cancer. Patients want reassurance that after removal of part of their lung that not only will they be cancer-free but also that they will be able to breathe well even when active. They do not want to be left physically or mentally handicapped. Recent studies have also shown the correlation between QOL and survival after resection. In this article the literature concerning QOL after pulmonary resection is reviewed. PMID- 23931027 TI - Palliative care principles for thoracic surgery. AB - Palliative care medicine is embedded within thoracic surgery due to its heavy oncological bias. Many thoracic procedures are entirely palliative in nature, designed to alleviate symptoms and to relieve suffering. At a global level, access to palliative care services is dismal, necessitating awareness and advocacy. Early identification of palliative needs improves patient quality and reduces cost. PMID- 23931028 TI - Recent advances in the surgery and adjuvant treatment of lung cancer: tribute to Robert J. Ginsberg. Preface. PMID- 23931029 TI - Tribute to Robert Jason Ginsberg (1940-2003). PMID- 23931031 TI - Study the effect of formulation variables on drug release from hydrophilic matrix tablets of milnacipran and prediction of in-vivo plasma profile. AB - The objective of this study was to design oral controlled release (CR) matrix tablets of Milnacipran using hydroxypropyl methylcellulose (HPMC) as the retardant polymer and to study the effect of various formulation factors such as polymer proportion, polymer viscosity, compression force and also the pH of dissolution medium on the in-vitro release of drug. Two viscosity grade of HPMC (15 K and 100 K) were used in the proportion of 50, 100, 150 and 200 mg per CR tablet. In-vitro release rate was characterized using various model dependent approaches and model independent dissolution parameters [T50% and T80% dissolution time, mean dissolution time (MDT), mean residence time (MRT), dissolution efficiency (DE)]. The statistical analysis was performed on all the model independent approaches using student t test and ANOVA. Results were found that as polymer concentration (50 mg to 200 mg) and viscosity (15 K to 100 K) increases, the MDT, MRT, T50% and T80% extended significantly. Drug release rate was found to be significantly different at different hardness. In-vivo human plasma concentration--time profile was predicted from in-vitro release data using convolution method. Predicted human pharmacokinetic parameters shows that the design CR formulation has capability to sustained the plasma drug level of milnacipran. PMID- 23931030 TI - Toward a new concept of "natural balance" in oral estroprogestin contraception. AB - The Pill has undergone many changes since its first appearance some 50 years ago. Key developments included the reduction of ethinylestradiol doses and the synthesis of new progestins in order to increase safety, compliance and efficiency. Low-dose combined oral contraceptives (COCs) are currently the preferred option for millions of women. Due to this widespread use, it has been argued that the safety of COCs should be even better, raising the threshold for excellence. Yet in spite of major improvements, there is still an associated risk of venous thromboembolism (VTE). The next step in COCs' evolution should take total estrogenicity and hepatic estro-androgenic balance into account. The focus on the estrogen component--which has not changed in 50 years--has yielded a new class of natural estrogen pills. Following the introduction of a first quadriphasic pill, a monophasic estradiol pill based on the concept of "natural balance" was subsequently made available. These recent achievements could represent a step forward in the evolution of COCs and pave the way for better safety. PMID- 23931032 TI - Chronobiology of the renin-angiotensin-aldosterone system in dogs: relation to blood pressure and renal physiology. AB - The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and volume homeostasis. Its contribution to the development of cardiovascular diseases has long been recognized. Extensive literature has shown that peptides of the RAAS oscillate with a circadian periodicity in humans, under strong influence of posture, sleep, and age. Although observations of time-variant changes in the renin cascade are available in dogs, no detailed chronobiological investigation has been conducted so far. The present studies were designed to explore the circadian variations of plasma renin activity (RA) and urinary aldosterone-to-creatinine ratio (UA:C) in relation to blood pressure (BP), sodium (UNa, UNa,fe), and potassium (UK, UK,fe) renal handling. Data derived from intensive blood and urine sampling, as well as continuous BP monitoring, were collected throughout a 24-h time period, and analyzed by means of nonlinear mixed-effects models. Differences between the geometric means of day and night observations were compared by parametric statistics. Our results show that variables of the renin cascade, BP, and urinary electrolytes oscillate with significant day-night differences in dogs. An approximately 2-fold (1.6-3.2-fold) change between the average day and night measurements was found for RA (p < 0.001), UA:C (p = 0.01), UK,fe (p = 0.01), and UNa (p = 0.007). Circadian variations in BP, albeit small (less than 10 mm Hg), were statistically significant (p < 0.01) and supported by the model-based analysis. For all variables but UNa and UNa,fe, the levels were higher at night than during the day. The data also indicate that blood pressure oscillates in parallel to the RAAS, such that, as opposed to healthy humans, BP does not drop at night in dogs. The postprandial decrease in RA is assumed to be related to body fluid volume expansion secondary to water and sodium intake, whereas the reduction of UA:C reflects aldosterone-stimulated secretion by the renin angiotensin II pathway. UNa and UNa,fe peaked in the afternoon, about 7-8 h after food intake, which is consistent with the "impulse-response pattern" of sodium excretion described in previous publications. Finally, UK and UK,fe mirrored aldosterone-mediated potassium secretion in the kidney tubules. To describe the circadian variations of the various variables, two different mathematical representations were applied. A cosine model with a fixed 24-h period was found to fit the periodic variations of RA, UA:C, UK, UK,fe, and BP well, whereas changes in UNa and UNa,fe were best characterized by a surge model. The use of nonlinear mixed effects allowed estimation of population characteristics that can influence the periodicity of the RAAS. Specifically, sodium intake was found to interact with the tonic and the phasic secretion of renin, suggesting that varying feeding time could also impact the chronobiology of the renin cascade. PMID- 23931033 TI - Bipolar disorder with seasonal pattern: clinical characteristics and gender influences. AB - Bipolar disorder (BD) has a multifactorial etiology with heterogeneous clinical presentations. Around 25% of BD patients may present with a depressive seasonal pattern (SP). However, there are limited scientific data on the prevalence of SP, its clinical manifestations, and any gender influence. Four hundred and fifty-two BD I and II cases (62% female), recruited from three French university-affiliated psychiatric departments, were assessed for SP. Clinical, treatment, and sociodemographic variables were obtained from structured interviews. One hundred and two (23%) cases met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for SP, with similar frequency according to gender. Multivariate analysis showed a significant association between SP and BD II (odds ratio [OR] = 1.99, p = 0.01), lifetime history of rapid cycling (OR = 2.05, p = 0.02), eating disorders (OR = 2.94, p = 0.003), and total number of depressive episodes (OR = 1.13, p = 0.002). Seventy-one percent of cases were correctly classified by this analysis. However, when stratifying the analyses by gender, SP was associated with BD II subtype (OR = 2.89, p = 0.017) and total number of depressive episodes (OR = 1.21, p = 0.0018) in males but with rapid cycling (OR = 3.02, p = 0.0027) and eating disorders (OR = 2.60, p = 0.016) in females. This is the first study to identify different associations between SP and clinical characteristics of BD according to gender. The authors suggest that SP represents a potentially important specifier of BD. These findings indicate that seasonality may reflect increased severity or complexity of disorder. PMID- 23931034 TI - Increasing density leads to generalization in both coarse-grained habitat selection and fine-grained resource selection in a large mammal. AB - Density is a fundamental driver of many ecological processes including habitat selection. Theory on density-dependent habitat selection predicts that animals should be distributed relative to profitability of habitat, resulting in reduced specialization in selection (i.e. generalization) as density increases and competition intensifies. Despite mounting empirical support for density-dependent habitat selection using isodars to describe coarse-grained (interhabitat) animal movements, we know little of how density affects fine-grained resource selection of animals within habitats [e.g. using resource selection functions (RSFs)]. Using isodars and RSFs, we tested whether density simultaneously modified habitat selection and within-habitat resource selection in a rapidly growing population of feral horses (Equus ferus caballus Linnaeus; Sable Island, Nova Scotia, Canada; 42% increase in population size from 2008 to 2012). Among three heterogeneous habitat zones on Sable Island describing population clusters distributed along a west-east resource gradient (west-central-east), isodars revealed that horses used available habitat in a density-dependent manner. Intercepts and slopes of isodars demonstrated a pattern of habitat selection that first favoured the west, which generalized to include central and east habitats with increasing population size consistent with our understanding of habitat quality on Sable Island. Resource selection functions revealed that horses selected for vegetation associations similarly at two scales of extent (total island and within-habitat zone). When densities were locally low, horses were able to select for sites of the most productive forage (grasslands) relative to those of poorer quality. However, as local carrying capacity was approached, selection for the best of available forage types weakened while selection for lower-quality vegetation increased (and eventually exceeded that of grasslands). Isodars can effectively describe coarse-grained habitat selection in large mammals. Our study also shows that the main predictions of density-dependent habitat selection are highly relevant to our interpretation of RSFs in space and time. At low but not necessarily high population size, density will be a leading indicator of habitat quality. Fitness maximization from specialist vs. generalist strategies of habitat and resource selection may well be apparent at multiple spatial extents and grains of resolution. PMID- 23931036 TI - Should sodium be the real target of fluid restriction? PMID- 23931035 TI - Using landscape history to predict biodiversity patterns in fragmented landscapes. AB - Landscape ecology plays a vital role in understanding the impacts of land-use change on biodiversity, but it is not a predictive discipline, lacking theoretical models that quantitatively predict biodiversity patterns from first principles. Here, we draw heavily on ideas from phylogenetics to fill this gap, basing our approach on the insight that habitat fragments have a shared history. We develop a landscape 'terrageny', which represents the historical spatial separation of habitat fragments in the same way that a phylogeny represents evolutionary divergence among species. Combining a random sampling model with a terrageny generates numerical predictions about the expected proportion of species shared between any two fragments, the locations of locally endemic species, and the number of species that have been driven locally extinct. The model predicts that community similarity declines with terragenetic distance, and that local endemics are more likely to be found in terragenetically distinctive fragments than in large fragments. We derive equations to quantify the variance around predictions, and show that ignoring the spatial structure of fragmented landscapes leads to over-estimates of local extinction rates at the landscape scale. We argue that ignoring the shared history of habitat fragments limits our ability to understand biodiversity changes in human-modified landscapes. PMID- 23931037 TI - Normothermic extracorporeal human liver perfusion following donation after cardiac death. AB - Liver transplantation is a major life-saving procedure and donation after cardiac death (DCD) has increased the pool of potential liver donors. However, livers procured after DCD are at increased risk of primary graft dysfunction and biliary tract ischaemia. Normothermic extracorporeal liver perfusion (NELP) may increase the ability to protect, evaluate and, in future, transplant DCD livers. We conducted a proof-of-concept experiment using a human liver procured by DCD (deemed not suitable for liver donation) to assess the short-term (3 hours) feasibility, histological effects and functional efficacy of NELP. We used an extracorporeal membrane oxygenation circuit with separate hepatic artery and portal vein perfusion to achieve physiological perfusion pressures, and coupled this with parenteral nutrition and an insulin infusion. We achieved NELP with evidence of liver function (bile production, paracetamol removal and control of ammonia, bilirubin and lactate levels) for 3 hours. There was essentially normal liver and biliary tract histology after 8 hours of perfusion. Our experiment justifies further investigation of the feasibility and efficacy of human DCD liver preservation by NELP. PMID- 23931038 TI - The ADRENAL study protocol: adjunctive corticosteroid treatment in critically ill patients with septic shock. AB - BACKGROUND: There is considerable global uncertainty on the role of low-dose corticosteroids in septic shock, which translates into variations in prescribing practices. OBJECTIVE: To describe the protocol for a large-scale multicentre randomised controlled trial in critically ill patients with septic shock, comparing the effects of hydrocortisone and placebo (in addition to standard treatment) on 90-day mortality and other outcomes such as shock reversal, duration of mechanical ventilation and quality of life. METHODS: We will recruit 3800 critically ill patients with septic shock treated in an intensive care unit, to concealed, randomised, parallel assignment of hydrocortisone or placebo. The primary outcome will be all-cause mortality at 90 days postrandomisation. Secondary outcomes will include ICU and hospital mortality, length of ICU stay and quality of life at 6 months. Subgroup analyses will be conducted in two predefined subgroups. All analyses will be conducted on an intention-to-treat basis. RESULTS AND CONCLUSIONS: The run-in phase has been completed and the main trial commenced in February 2013. The trial should generate results that will inform and influence prescribing of corticosteroids in septic shock. PMID- 23931039 TI - Fluid balance does not predict estimated sodium balance in critically ill mechanically ventilated patients. AB - BACKGROUND: Distribution of total body water (TBW) depends on local and systemic factors including osmolality, relative sodium content and permeability. Although positive fluid balance has been associated with increased morbidity and mortality in critically ill patients, the mechanisms and relative roles of sodium balance and water distribution are uncertain. OBJECTIVE: To track changes in sodium and fluid balance, respiratory function and body composition in patients who required mechanical ventilation for >=48 hours. DESIGN, SETTING AND PARTICIPANTS: Prospective observational study, set in a tertiary intensive care unit, of 10 patients (seven men) with a mean age of 60 years (standard deviation [SD],12 years) and mean admission Acute Physiology and Chronic Health Evaluation (APACHE) III score of 71 (SD, 26). METHODS: Sodium and fluid balances were estimated daily for up to 5 days, following institution of mechanical ventilation on Day 0. Serum sodium level, oxygenation (PaO(2)/FIO(2)), body weight, intracellular and extracellular fluid (ECF) distribution (bioelectrical impedance spectroscopy), and blinded chest x-ray oedema scores were performed daily. RESULTS: After 5 days of mechanical ventilation, the cumulative fluid balance was - 954 mL (SD, 3181 mL) and estimated cumulative sodium balance was 253 mmol (SD, 346 mmol). Serum sodium had increased from 140 mmol/L (SD, 4 mmol/L) to 147 mmol/L (SD, 5 mmol/L). Cumulative sodium balance was weakly correlated with worsening chest x-ray score (r = 0.35, P = 0.004), a reduction in PaO(2)/ FIO(2) ratio (r = - 0.52, P = 0.001) and 24-hour urinary sodium (r = - 0.24, P = 0.02). Between Days 1 and 5, body weight decreased (- 2.7 kg; SD, 1.4 kg) and TBW decreased (- 3.4 L; SD, 1.3 L), despite a rise in ECF distribution (1.4% of TBW; SD, 1.9% of TBW). CONCLUSIONS: Fluid balance may not reflect sodium balance in critically ill patients. As sodium balance correlates with respiratory dysfunction and increased extracellular volume, further studies examining sodium balance and morbidity seem warranted. PMID- 23931040 TI - Improving communication of the daily care plan in a teaching hospital intensive care unit. AB - BACKGROUND: Patients admitted to intensive care units have complex care needs. Accordingly, communication and handover of the medical care plan is very important. OBJECTIVE: To assess changes in ICU nurses' understanding of the medical daily care plan after development and implementation of a pro forma to improve documentation and communication of the plan. DESIGN, SETTING AND PARTICIPANTS: The study was conducted between February and November 2012 in a mixed medical-surgical, 18-bed, closed ICU in a teaching hospital. Baseline and post-intervention surveys assessed ICU bedside nurses' self-reported understanding of elements of the daily care plan. INTERVENTION: After receiving input from bedside nurses and medical staff, we developed the daily care plan as a single-page pro forma for handwritten documentation of a clinical problems list, plan and interventions list, daily chest x-ray results, a modified FAST-HUG checklist, and discharge planning during the evening consultant ward round. The finalised pro forma was introduced on 25 July 2012. RESULTS: Introduction of the pro forma daily care plan was associated with marked and statistically significant improvements in nurses' self-reported understanding of a list of the patient's clinical problems, the management plan after the ward round, issues for discharge for the following day (all P < 0.001) and, to a lesser extent, the physiological targets and aims (P = 0.003) and interpretation of the daily chest x-ray (P < 0.001). In the post-intervention survey, only 4/118 free-text comments (3.4%) suggested that documentation of the plan was doctor-dependent, compared with 28/198 (14.1%) at baseline (P = 0.002). CONCLUSIONS: Introduction of a single-page, handwritten, structured daily care plan produced marked improvements in ICU nurses' self-reported understanding of elements of the medical plan, and may have reduced practice variation in medical plan documentation. The effects of this intervention on patient outcomes remain untested. PMID- 23931041 TI - Severe sepsis and septic shock in patients with pre-existing non-cardiac pulmonary hypertension: contemporary management and outcomes. AB - OBJECTIVE: To review treatment and outcomes of septic shock in patients with pulmonary hypertension (PH) managed at a tertiary care institution. DESIGN, SETTING AND PATIENTS: We identified consecutive patients with non-cardiac PH (non Group 2 in the World Health Organization classification) who were treated for septic shock in four intensive care units at a tertiary care institution between July 2004 and July 2007. Patients with a left ventricular ejection fraction < 50%, diastolic dysfunction, pericardial effusion or significant valve disease were excluded. Descriptive statistics were used to analyse the data. MAIN OUTCOME MEASURES: Hospital mortality, duration of vasopressor and ventilatory support, length of hospital and ICU stay. RESULTS: The final group for analysis comprised 82 patients. The major causes of PH were chronic obstructive pulmonary disease, interstitial lung disease and portopulmonary hypertension. PH was mild in 46 patients (56%), moderate in 21 (26%) and severe in 15 (18%). Vasopressor treatment was initiated in 69 patients (84%) within the first 48 hours: noradrenaline was most commonly used (53 patients, 65%), and 51 patients (62%) were treated with more than one agent. Sixty-seven patients (82%) were mechanically ventilated, and 33 (40%) required renal replacement therapy. Fortythree patients (52%) survived to hospital discharge; 23 (28%) remained alive at 1 year. Hospital mortality increased with severity of PH: 28% in mild, 67% in moderate and 80% in severe PH. Nonsurvivors were more likely to have plateau pressures beyond 30 cm H(2)O while mechanically ventilated within the first 48 hours in the ICU (56% v 29%, P = 0.03), to develop atrial fibrillation (AF) (46% v 12%, P < 0.001), and to require longer vasopressor support (mean, 5.3 v 2.6 days, P = 0.003). In a multivariate logistic regression analysis, severity of PH (odds ratio [OR], 1.55; 95% CI, 1.04-2.46; P = 0.04), new-onset AF (OR, 6.51; 95% CI, 2.24-22.07; P < 0.001) and longer duration of vasopressor support (OR, 1.15; 95% CI, 1.03-1.34; P = 0.04) were associated with increased hospital mortality. CONCLUSIONS: The severity of PH, new-onset AF, and longer vasopressor support were associated with poor outcomes in patients with PH who developed severe sepsis and septic shock. PMID- 23931042 TI - Temperature management in patients with acute neurological lesions: an Australian and New Zealand point prevalence study. AB - BACKGROUND: Given the scientific uncertainty of the efficacy and safety of normothermia (36.0 degrees C to 37.5 degrees C) on disability and death after acute neurological lesions, we sought to understand how temperature is managed in usual clinical care for this patient population in Australia and New Zealand. OBJECTIVE: To describe temperature management in patients with acute neurological lesions. DESIGN: Prospective, observational, multicentre, single-day point prevalence study. PARTICIPANTS, SETTING AND METHODS: Observational data of usual practice were recorded for all patients with an intensive care admission diagnosis of acute neurological lesions and who were present in 33 intensive care units at 10:00 on the study day. Data were collected prospectively for the ensuing 24-hour period. MAIN OUTCOME MEASURES: Achieved temperature, interventions used to modify temperature and target temperature. RESULTS: There were 106 patients with acute neurological lesions (61% with either stroke or traumatic brain injury) with a mean APACHE (Acute Physiology and Chronic Health Evaluation) II score of 19.3 +/- 7.4, age of 53.5 +/- 19.0 years and median time from intensive care admission to data capture of 3 days (interquartile range, 1 9). A target temperature was specified in 24% of patients. Although paracetamol was commonly used (56%), it was infrequently used at the maximum licensed dose and there was no use recorded of non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors. Physical cooling was used in 25% of patients and core temperature was measured in 32%. Measured temperature often exceeded 37.0 degrees C (62% of readings), 37.5 degrees C (43%) and 38.0 degrees C (22%). CONCLUSIONS: Temperature readings above 37.5 degrees C are common. Further cohort studies are required to validate these preliminary, exploratory findings. PMID- 23931043 TI - A randomised controlled trial of induced hypermagnesaemia following aneurysmal subarachnoid haemorrhage. AB - BACKGROUND: The effect of serum magnesium concentration on the incidence of cerebral arterial vasospasm following aneurysmal subarachnoid haemorrhage (SAH) is unclear. OBJECTIVE: To test whether induced hypermagnesaemia reduces the incidence of cerebral arterial vasospasm following aneurysmal SAH. METHODS: The study was conducted at two tertiary hospitals in Australia and patients were recruited between 1 April 2005 and 31 December 2009. Within 72 hours of aneurysmal SAH, patients were randomly assigned to a high or normal target for serum magnesium concentration (1.60-2.50 mmol/L or 0.65-1.05 mmol/L, respectively). The primary end point was cerebral arterial vasospasm diagnosed by blinded assessment of digital subtraction angiography. Secondary outcomes included severity of vasospasm and functional recovery at 90 days. Analysis was by intention to treat. RESULTS: Of 162 patients, 81 were assigned to the normal range group and 81 were assigned to the high-range group; the primary outcome was available for 78 and 79 patients, respectively. The groups had similar baseline characteristics. Vasospasm occurred in 40 patients (50.6%) and 50 patients (64.1%) assigned to high-range and normal-range groups, respectively (adjusted OR, 0.51; 95% CI, 0.26-1.02; P = 0.06). At 90 days, neurological recovery between the groups was not significantly different (adjusted OR for worse outcome, 0.71; 95% CI, 0.39-1.32; P = 0.28). Patients in the high-range group were treated with more noradrenaline to support arterial blood pressure (79 [16- 218] mg) v 59 [14 129] mg; P = 0.03) and had lower mean (SD) serum calcium concentration (1.9 [0.2] mmol/L v 2.1 [0.2] mmol/L, P < 0.001). CONCLUSION: Patients assigned a higher serum magnesium concentration had a reduced incidence of vasospasm as seen by angiography, but the difference was not statistically significant. Clinically significant outcomes were not different between groups. A firm recommendation for induced hypermagnesaemia cannot be made from this study. TRIAL REGISTRATION NUMBER: ACTRN12605000058673. PMID- 23931044 TI - Safety evaluation of a trial of lipocalin-directed sodium bicarbonate infusion for renal protection in at-risk critically ill patients. AB - BACKGROUND: Urine alkalinisation with sodium bicarbonate decreases renal oxidative stress and might attenuate sepsisassociated acute kidney injury (s AKI). The safety and feasibility of urine alkalinisation in patients at risk of s AKI has never been tested. METHODS: We randomly assigned patients at risk of s AKI (those with systemic inflammatory response syndrome [SIRS], oliguria and elevated [>=150 ug/L] serum neutrophil gelatinase-associated lipocalin [sNGAL] concentration) to receive sodium bicarbonate (treatment group) or sodium chloride (placebo group) in a 0.5 mmol/kg bolus followed by an infusion of 0.2 mmol/kg/hour. RESULTS: Among 50 patients with SIRS and oliguria, 25 (50%) had an elevated sNGAL concentration. Of these, 13 were randomised to receive sodium bicarbonate and 12 to receive sodium chloride infusion. Study drugs were infused for a mean period of 25.9 hours (SD, 10 hours). Severe electrolyte abnormalities occurred in seven patients (28%) (four [30.8%] in the treatment group and three [25%] in the placebo group). These abnormalities resulted in early protocol cessation in six patients (24%) and study drug suspension in one patient (4%). This adverse event rate was judged to be unacceptable and the study was terminated early. There was no difference between the two groups in sNGAL or urinary NGAL concentrations over time, occurrence of acute kidney injury, requirement for renal replacement therapy, hospital length-of-stay or mortality. CONCLUSION: Administration of sodium bicarbonate and sodium chloride solutions to patients at risk of s-AKI was associated with frequent major electrolyte abnormalities and early protocol cessation. The tested protocol does not appear safe or feasible. PMID- 23931045 TI - Characteristics and outcomes of patients subject to intensive care nurse consultant review in a teaching hospital. AB - OBJECTIVE: To describe the evolution of our Intensive Care Nurse Consultant (ICNC) service, the characteristics and outcomes of the patients reviewed, and interventions performed. DESIGN, SETTING AND PARTICIPANTS: Retrospective observational study in a tertiary referral university-affiliated teaching hospital among all patients reviewed by the ICNC service between September 2007 and December 2009. MAIN OUTCOME MEASURES: Number and characteristics of patients reviewed, source of referral, interventions performed, inhospital mortality and hospital length of stay. RESULTS: Since August 2006, operating hours have increased and provision has been made for senior ICU nurses to undertake 6-month developmental allocations to the role. The name of the service was changed and a weekly report was commenced to capture patient referral source, and subsequent ICU medical referral. Additional changes included provision of an administration day, and use of an ICU discharge scoring tool. A total of 3118 (2278 post-ICU and 840 non-ICU) care episodes were provided by the ICNC service between September 2007 and December 2009. Median patient age was 64 years, inhospital mortality was about 9% and most reviews occurred in surgical patients and after ICU discharge. Most new ward referrals came from an ICU doctor or ward nurse, with few referrals from ward doctors. Communication with ward nurses was more common than with ward doctors. A common recommendation involved fluid and electrolyte management. In hospital mortality was higher among patients entering the service after review by a medical emergency team or de-novo referral than in patients after ICU discharge. CONCLUSIONS: Most interventions are relatively simple, and the ICNC role may be augmented by limited rights to prescribe electrolyte replacement. The effect of the intervention on patient outcomes and the reproducibility of our findings in other hospitals remain to be determined. PMID- 23931046 TI - Left ventricular puncture after intercostal catheter insertion. PMID- 23931047 TI - Treatment goals: health care improvement through setting and measuring patient centred outcomes. AB - OBJECTIVE: To determine how frequently stress ulcer prophylaxis (SUP) medications prescribed in the intensive care unit are inappropriately continued on the ward and on hospital discharge. DESIGN: Retrospective cohort study; chart review. SETTING: Two Australian ICUs: one tertiary centre and one metropolitan centre. PARTICIPANTS: We included 387 adult, non-pregnant patients who were admitted to the ICU between 1 February 2011 and 31 March 2011 and who survived to hospital discharge. MAIN OUTCOME MEASURES: Rate of unnecessary continuation of ICU prescribed SUP medications on the ward and on discharge from hospital. RESULTS: While in the ICU, 329 of the 387 patients (85%) were prescribed SUP medications. Of the 233 patients who had not been taking acid-suppressive medications before admission to the ICU, 190 were prescribed SUP medications in the ICU. Of these 190 patients, most (63%) had their SUP continued in the ward without any obvious indication, and many (39%) had their SUP medications inappropriately continued on discharge from hospital. CONCLUSIONS: SUP medications commenced in ICU are frequently continued unnecessarily, both in the wards and on hospital discharge. PMID- 23931048 TI - FT-IR and two-dimensional correlation analysis of the liquid crystalline phase transitions in the 4-Bromobenzylidene-4'-alkyloxyanilines. AB - The FT-IR spectra of the 4-bromobenzylidene-4'-alkyloxyanilines (nBBAA, for n = 4 12) were studied as a function of temperature. The molten state of the alkyloxy chain in smectic B (SmB), smectic A (SmA), and isotropic phases was analyzed. Generalized two-dimensional (2D) correlation spectroscopy has been applied to study changes in the conformational structure and specific interactions of molecules at phase transition in homologous series of nBBAA. A windowed autocorrelation analysis enabled us to locate transition points basing on the spectroscopic data. PMID- 23931049 TI - Postoperative cognitive dysfunction, Alzheimer's disease, and anesthesia. AB - Although aging itself is not a disease, there are many comorbidities that become more common with aging. Heart disease, cancer, and other chronic illnesses are either more common or more severe in aging patients. Approximately 5.5 million people in the United States have Alzheimer's disease (AD), with the principal risk factor being age. It is estimated that the incidence of AD diagnosis doubles every 5 years after the age of 65. Therefore, as the population ages, the impact of AD on the healthcare landscape will increase. Understanding how to manage patients with AD is critical as we begin to care for more elderly patients in the perioperative period. In addition to their other health considerations, aging surgical patients are increasingly more likely to have pre-existing AD or be at risk for developing AD. There is growing interest to determine how anesthesia affects the development or progression of AD. Similarly, a best practice for the anesthetic management of patients with AD is not yet defined. Finally, the relationship between AD and susceptibility to or exacerbation of postoperative cognitive dysfunction (POCD) is not well understood. In this review, we will discuss both the clinical and the preclinical data related to anesthesia and AD, describe the overlapping pathophysiology of neurodegeneration and provide some insight into the anesthetic care of patients with AD. PMID- 23931050 TI - Information generation and processing systems that regulate periodontal structure and function. AB - The periodontium is a very dynamic organ that responds rapidly to mechanical and chemical stimuli. It is very complex in that it is composed of two hard tissues (cementum and bone) and two soft connective tissues (periodontal ligament and gingiva). Together these tissues are defined by the molecules expressed by the resident periodontal cells in each compartment and this determines not only the structure and function of the periodontium but also how it responds to infection and inflammation. The biological activity of these molecules is tightly regulated in time and space to preserve tissue homeostasis, influence inflammatory responses and participate in tissue regeneration. In this issue of Periodontology 2000 we explore new experimental approaches and data sets which help to understand the molecules and cells that regulate tissue form and structure in health, disease and regeneration. PMID- 23931051 TI - Matrix mechanics and regulation of the fibroblast phenotype. AB - The oral cavity hosts a variety of different fibroblast populations that are generally responsible for maintaining homeostasis of the soft connective tissue. In addition to regulating the turnover and structural arrangement of collagen and other proteins of the extracellular matrix, fibroblasts perform a number of specialized functions. Certain fibroblast subpopulations in the gingiva, oral mucosa and periodontal ligament serve as progenitor cells with multilineage differentiation and self-renewal characteristics. In the periodontal ligament, fibroblasts further appear to function as mechanosensing entities that regulate collagen-secretory and collagen-remodeling activities according to the level of strain in the ligament. Mechanical challenge also plays an important role during the activation of periodontal fibroblasts in response to injury. Dysregulation of this activation process can lead either to poor healing and chronic wounds or to overly healed wounds with fibrosis. This review will elaborate on the roles of mechanical factors and mechanoperception in fibroblast activation, the molecular features of activated fibroblasts and the regulation mechanisms of fibroblast contraction. Pharmacological interference at each level is currently being pursued to improve the outcome of healing of injured periodontal tissue. PMID- 23931053 TI - Cell adhesion proteins: roles in periodontal physiology and discovery by proteomics. AB - Adhesion molecules expressed by periodontal connective tissue cells are involved in cell migration, matrix remodeling and inflammatory responses to infection. Currently, the processes by which the biologic activity of these molecules are appropriately regulated in time and space to preserve tissue homeostasis, and to control inflammatory responses and tissue regeneration, are not defined. As cell adhesions are heterogeneous, dynamic, contain a complex group of interacting molecules and are strongly influenced by the type of substrate to which they adhere, we focus on how cell adhesions in periodontal connective tissues contribute to information generation and processing that regulate periodontal structure and function. We also consider how proteomic methods can be applied to discover novel cell-adhesion proteins that could potentially contribute to the form and function of periodontal tissues. PMID- 23931054 TI - Expression of odontogenic ameloblast-associated and amelotin proteins in the junctional epithelium. AB - Two novel proteins - odontogenic ameloblast-associated protein and amelotin - have recently been identified in maturation-stage ameloblasts and in the junctional epithelium. This article reviews the structure and function of the junctional epithelium, the pattern of expression of odontogenic ameloblast associated and amelotin proteins and the potential involvement of these proteins in the formation and regeneration of the junctional epithelium. PMID- 23931052 TI - Role of integrins in the periodontal ligament: organizers and facilitators. AB - The periodontal ligament is the tissue that connects teeth to bone. The periodontal ligament is a fascinating tissue from a cell biologist's point of view, and because of its special properties and stem-cell content it has also come into the limelight in emerging fields of regenerative medicine. An increased range of genetically modified mouse models offer new tools for studying molecular mechanisms of tooth development. However, owing to species-specific organization of the tooth apparatus, the use of genetic animal models to study the role of the periodontal ligament in normal human tooth physiology and tooth pathology is challenging. PMID- 23931055 TI - Defensins and LL-37: a review of function in the gingival epithelium. AB - Antimicrobial peptides represent an important aspect of the innate defense system that contributes to the control of bacterial colonization and infection. As studies have progressed it has become clear that antimicrobial peptides manifest other functions in addition to their antimicrobial effects. These functions include chemotaxis of numerous types of host cells involved in both the innate and adaptive immune responses. In this review, the antimicrobial activity, the regulation and the contribution to host homeostasis of alpha-defensins and LL-37, as well as of beta-defensins, are discussed in the context of their specific tissue locations in the junctional epithelium and oral epithelium, respectively. PMID- 23931056 TI - Macrophage subsets and osteoimmunology: tuning of the immunological recognition and effector systems that maintain alveolar bone. AB - Chronic and aggressive periodontal diseases are characterized by the failure to resolve local inflammation against periodontopathogenic bacteria in the subgingival biofilm. Alveolar bone resorption is associated with altered innate and adaptive immune responses to periodontal pathogens. Macrophage-derived cytokines, chemokines and growth factors, present in both destructive and reparative phases of periodontitis, are elevated in numerous animal and human studies. Macrophage polarization to either a predominantly pro-inflammatory or anti-inflammatory phenotype may be a critical target for monitoring disease activity, modulating immune responses to subgingival biofilms in patients at risk and reducing alveolar bone loss. PMID- 23931058 TI - Matrix metalloproteinase processing of signaling molecules to regulate inflammation. AB - Inflammation is a complex and highly regulated process that facilitates the clearance of pathogens and mediates tissue repair. Failure to resolve inflammation can lead to chronic inflammatory diseases such as periodontitis. Matrix metalloproteinases are generally thought to be detrimental in disease because degradation of extracellular matrix contributes to pathology. However, proteomic techniques (degradomics) are revealing that matrix metalloproteinases process a diverse array of substrates and therefore have a broad range of functions. Many matrix metalloproteinase substrates modulate inflammation and hence, by processing these proteins, matrix metalloproteinases can orchestrate the inflammatory response. PMID- 23931057 TI - Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia. AB - As broadly demonstrated for the formation of a functional skeleton, proper mineralization of periodontal alveolar bone and teeth - where calcium phosphate crystals are deposited and grow within an extracellular matrix - is essential for dental function. Mineralization defects in tooth dentin and cementum of the periodontium invariably lead to a weak (soft or brittle) dentition in which teeth become loose and prone to infection and are lost prematurely. Mineralization of the extremities of periodontal ligament fibers (Sharpey's fibers) where they insert into tooth cementum and alveolar bone is also essential for the function of the tooth-suspensory apparatus in occlusion and mastication. Molecular determinants of mineralization in these tissues include mineral ion concentrations (phosphate and calcium), pyrophosphate, small integrin-binding ligand N-linked glycoproteins and matrix vesicles. Amongst the enzymes important in regulating these mineralization determinants, two are discussed at length here, with clinical examples given, namely tissue-nonspecific alkaline phosphatase and phosphate-regulating gene with homologies to endopeptidases on the X chromosome. Inactivating mutations in these enzymes in humans and in mouse models lead to the soft bones and teeth characteristic of hypophosphatasia and X linked hypophosphatemia, respectively, where the levels of local and systemic circulating mineralization determinants are perturbed. In X-linked hypophosphatemia, in addition to renal phosphate wasting causing low circulating phosphate levels, phosphorylated mineralization-regulating small integrin-binding ligand N-linked glycoproteins, such as matrix extracellular phosphoglycoprotein and osteopontin, and the phosphorylated peptides proteolytically released from them, such as the acidic serine- and aspartate-rich-motif peptide, may accumulate locally to impair mineralization in this disease. PMID- 23931060 TI - Neutrophil extracellular traps as a new paradigm in innate immunity: friend or foe? AB - The discovery of neutrophil extracellular traps in 2004 opened a fascinating new chapter in immune-mediated microbial killing. Brinkman et al. demonstrated that neutrophils, when catastrophically stimulated, undergo a novel form of programmed cell death (neutrophil extracellular trap formation) whereby they decondense their entire nuclear chromatin/DNA and release the resulting structure into the cytoplasm to mix with granule-derived antimicrobial peptides before extruding these web-like structures into the extracellular environment. The process requires the activation of the granule enzyme peptidyl arginine deiminase-4, the formation of reactive oxygen species (in particular hypochlorous acid), the neutrophil microtubular system and the actin cytoskeleton. Recent work by Yousefi et al. demonstrated that exposure to different agents for shorter stimulation periods resulted in neutrophil extracellular trap release from viable granulocytes, and that such neutrophil extracellular traps comprised mitochondrial DNA rather than nuclear DNA and were also capable of microbial entrapment and destruction. Deficiency in NADPH-oxidase production (as found in patients with chronic granulomatous disease) results in an inability to produce neutrophil extracellular traps and, along with their failure to produce antimicrobial reactive oxygen species, these patients suffer from severe, and sometimes life-threatening, infections. However, conversely the release of nuclear chromatin into tissues is also potentially autoimmunogenic and is now associated with the generation of anti-citrullinated protein antibodies in seropositive rheumatoid arthritis. Other neutrophil-derived nuclear and cytoplasmic contents are also pathogenic, either through direct effects on tissues or via autoimmune processes (e.g. autoimmune vasculitis). In this review, we discuss the plant origins of a highly conserved innate immune method of microbial killing, the history and biology of neutrophil extracellular traps and their role in defence and in human diseases. We attempt to resolve areas of controversy and propose roles for excess neutrophil extracellular trap release from hyperactive/reactive neutrophils and for the unique peptidyl arginine deiminase enzyme of Porphyromonas gingivalis in the pathogenesis of periodontitis, and subsequently a role for periodontitis/the peptidyl arginine deiminase enzyme of P. gingivalis in the causal pathway of autoimmune diseases such as rheumatoid arthritis. We propose that neutrophil extracellular trap and peptidyl arginine deiminase release may propagate tissue-destructive mechanisms rather than provide protection in susceptible individuals and that release of host-derived DNase may play an important role in the digestion and removal of neutrophil extracellular traps within tissues. PMID- 23931059 TI - Natural resolution of inflammation. AB - Inflammation is a protective response essential for maintaining human health and for fighting disease. As an active innate immune reaction to challenge, inflammation gives rise to clinical cardinal signs: rubor, calor, dolor, tumor and functio laesa. Termination of acute inflammation was previously recognized as a passive process; a natural decay of pro-inflammatory signals. We now understand that the natural resolution of inflammation involves well-integrated, active, biochemical programs that return tissues to homeostasis. This review focuses on recent advances in the understanding of the role of endogenous lipid mediators that modulate cellular fate and inflammation. Biosynthesis of eicosanoids and other lipids in exudates coincides with changes in the types of inflammatory cells. Resolution of inflammation is initiated by an active class switch in lipid mediators, such as classic prostaglandins and leukotrienes, to the production of proresolution mediators. Endogenous pro-resolving lipid mediators, including arachidonic acid-derived lipoxins, aspirin-triggered lipoxins, omega3 eicosapentaenoic acid-derived resolvins of the E-series, docosahexaenoic acid derived resolvins of the D-series, protectins and maresins, are biosynthesized during the resolution phase of acute inflammation. Depending on the type of injury and the type of tissue, the initial cells that respond are polymorphonuclear leukocytes, monocytes/macrophages, epithelial cells or endothelial cells. The selective interaction of specific lipid mediators with G protein-coupled receptors expressed on innate immune cells (e.g. G protein coupled receptor 32, lipoxin A4 receptor/formyl peptide receptor2, chemokine-like receptor 1, leukotriene B4 receptor type 1 and cabannoid receptor 2) induces cessation of leukocyte infiltration; vascular permeability/edema returns to normal with polymorphonuclear neutrophil death (mostly via apoptosis), the nonphlogistic infiltration of monocyte/macrophages and the removal (by macrophages) of apoptotic polymorphonuclear neutrophils, foreign agents (bacteria) and necrotic debris from the site. While an acute inflammatory response that is resolved in a timely manner prevents tissue injury, inadequate resolution and failure to return tissue to homeostasis results in neutrophil mediated destruction and chronic inflammation. A better understanding of the complex mechanisms of lipid agonist mediators, cell targets and actions allows us to exploit and develop novel therapeutic strategies to treat human inflammatory diseases, including periodontal diseases. PMID- 23931061 TI - Immunomodulatory effects of stem cells. AB - Adult-derived mesenchymal stem cells have received considerable attention over the past two decades for their potential use in tissue engineering, principally because of their potential to differentiate into multiple stromal-cell lineages. Recently, the immunomodulatory properties of mesenchymal stem cells have attracted interest as a unique property of these cells that may be harnessed for novel therapeutic approaches in immune-mediated diseases. Mesenchymal stem cells have been shown to inhibit the proliferation of activated T-cells both in vitro and in vivo but to stimulate T-regulatory cell proliferation. Mesenchymal stem cells are also known to be weakly immunogenic and to exert immunosuppressive effects on B-cells, natural killer cells, dendritic cells and neutrophils through various mechanisms. Furthermore, intravenous administration of allogeneic mesenchymal stem cells has shown a marked suppression of host immune reactions in preclinical animal models of large-organ transplant rejection and in various autoimmune- and inflammatory-based diseases. Some clinical trials utilizing human mesenchymal stem cells have also produced promising outcomes in patients with graft-vs.-host disease and autoimmune diseases. Mesenchymal stem cells identified from various dental tissues, including periodontal ligament stem cells, also possess multipotent and immunomodulatory properties. Hence, dental mesenchymal stem cells may represent an alternate cell source, not only for tissue regeneration but also as therapies for autoimmune- and inflammatory-mediated diseases. These findings have elicited interest in dental tissue mesenchymal stem cells as alternative cell sources for modulating alloreactivity during tissue regeneration following transplantation into human leukocyte antigen-mismatched donors. To examine this potential in periodontal regeneration, future work will need to assess the capacity of allogeneic periodontal ligament stem cells to regenerate periodontal ligament in animal models of periodontal disease. The present review describes the immunosuppressive effects of mesenchymal stem cells on various types of immune cells, the potential mechanisms through which they exert their mode of action and the preclinical animal studies and human clinical trials that have utilized mesenchymal stem cells, including those populations originating from dental structures. PMID- 23931062 TI - Role of the epithelial cell rests of Malassez in the development, maintenance and regeneration of periodontal ligament tissues. AB - Periodontitis is a highly prevalent inflammatory disease that results in damage to the tooth-supporting tissues, potentially leading to tooth loss. Periodontal tissue regeneration is a complex process that involves the collaboration of two hard tissues (cementum and alveolar bone) and two soft tissues (gingiva and periodontal ligament). To date, no periodontal-regenerative procedures provide predictable clinical outcomes. To understand the rational basis of regenerative procedures, a better understanding of the events associated with the formation of periodontal components will help to establish reliable strategies for clinical practice. An important aspect of this is the role of the Hertwig's epithelial root sheath in periodontal development and that of its descendants, the epithelial cell rests of Malassez, in the maintenance of the periodontium. An important structure during tooth root development, the Hertwig's epithelial root sheath is not only a barrier between the dental follicle and dental papilla cells but is also involved in determining the shape, size and number of roots and in the development of dentin and cementum, and may act as a source of mesenchymal progenitor cells for cementoblasts. In adulthood, the epithelial cell rests of Malassez are the only odontogenic epithelial population in the periodontal ligament. Although there is no general agreement on the functions of the epithelial cell rests of Malassez, accumulating evidence suggests that the putative roles of the epithelial cell rests of Malassez in adult periodontal ligament include maintaining periodontal ligament homeostasis to prevent ankylosis and maintain periodontal ligament space, to prevent root resorption, to serve as a target during periodontal ligament innervation and to contribute to cementum repair. Recently, ovine epithelial cell rests of Malassez cells have been shown to harbor clonogenic epithelial stem-cell populations that demonstrate similar properties to mesenchymal stromal/stem cells, both functionally and phenotypically. Therefore, the epithelial cell rests of Malassez, rather than being 'cell rests', as indicated by their name, are an important source of stem cells that might play a pivotal role in periodontal regeneration. PMID- 23931063 TI - Nanosized aspirin-Arg-Gly-Asp-Val: delivery of aspirin to thrombus by the target carrier Arg-Gly-Asp-Val tetrapeptide. AB - Resistance and nonresponse to aspirin dramatically decreases its therapeutic efficacy. To overcome this issue, a small-molecule thrombus-targeting drug delivery system, aspirin-Arg-Gly-Asp-Val (A-RGDV), is developed by covalently linking Arg-Gly-Asp-Val tetrapeptide with aspirin. The 2D ROESY NMR and ESI-MS spectra support a molecular model of an A-RGDV tetramer. Transmission electron microscopy images suggest that the tetramer spontaneously assembles to nanoparticles (ranging from 5 to 50 nm in diameter) in water. Scanning electron microscopy images and atomic force microscopy images indicate that the smaller nanoparticles of A-RGDV further assemble to bigger particles that are stable in rat blood. The delivery investigation implies that in rat blood A-RGDV is able to keep its molecular integrity, while in a thrombus it releases aspirin. The in vitro antiplatelet aggregation assay suggests that A-RGDV selectively inhibits arachidonic acid induced platelet aggregation. The mechanisms of action probably include releasing aspirin, modifying cyclic oxidase, and decreasing the expression of GPIIb/IIIa. The in vivo assay demonstrates that the effective antithrombotic dose of A-RGDV is 16700-fold lower than the nonresponsive dose of aspirin. PMID- 23931064 TI - MoS2 nanocrystals confined in a DNA matrix exhibiting energy transfer. AB - We report the wet chemical synthesis of MoS2 nanocrystals (NCs), a transition metal dichalcogenide, using DNA as a host matrix. As evidenced from transmission electron microscopy (TEM), the NCs are highly crystalline, with an average diameter of ~5 nm. Ultraviolet-visible (UV-vis) absorption studies along with band gap calculations confirm that NCs are in quantum confinement. A prominent red shift of the optical absorption bands has been observed upon formation of the thin film using hexadecyltrimethylammonium chloride (CTAC), i.e., in the case of MoS2@DNA-CTAC. In the thin film, strong electron-phonon coupling arises because of the resonance effect, which is reflected from the emergence of intense first-, second-, and third-order Raman peaks, whenever excited with the 488 nm line. We have established that our as-synthesized MoS2 NCs quench the fluorescence of a well-known DNA minor groove binding probe, Hoechst 33258. Unprecedented fluorescence quenching (94%) of donor (Hoechst 33258) emission and efficient energy transfer (89%) between Hoechst 33258 and MoS2 NCs (acceptor) are obtained. The donor-acceptor distance of these conjugates has been described by a Forster resonance energy transfer (FRET)-based model. Furthermore, employing a statistical method, we have estimated the probability of the distance distribution between the donor and acceptor. We believe that the study described herein may enable substantial advances in fields of optoelectronics, photovoltaics, catalysis, and many others. PMID- 23931065 TI - Greetings! here's my vision. PMID- 23931067 TI - Everything in moderation: what the female athlete triad teaches us about energy balance. PMID- 23931066 TI - Circulating level of TRAIL concentration is positively associated with endothelial function and increased by diabetic therapy in the newly diagnosed type 2 diabetic patients. AB - OBJECTIVE: Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is associated with atherosclerosis. This study was to investigate the changes of circulating TRAIL and its association with flow-mediated endothelium-dependent arterial dilation (FMD) before and after diabetic treatment in newly diagnosed type 2 diabetes. MATERIALS AND METHODS: The study subjects included 55 newly diagnosed type 2 diabetes and 52 healthy subjects. Circulating TRAIL concentration was measured by an ELISA, and high-resolution ultrasound was used to measure FMD of brachial artery. RESULTS: The circulating TRAIL in patients before treatment was 64.46 pg/ml, which was significantly lower than that in control (80.70 pg/ml, P < 0.001). After 6 months of diabetic treatment, TRAIL level increased markedly (75.11 pg/ml), which was still lower than that in control (P < 0.001). FMD was reduced compared with controls at baseline and increased after diabetic therapy (P < 0.001). In multivariate analysis, circulating TRAIL was significantly associated with FMD, fasting blood glucose (FBG), 2-h blood glucose (2-h BG), haemoglobinA1c (HbA1c) and C-reactive protein (CRP) at baseline (P < 0.01). The absolute change in TRAIL was correlated with the changes in FMD, FBG, 2-h BG, HbA1c and CRP (P < 0.01) before and after diabetic treatment. CONCLUSION: Circulating TRAIL level decreased in newly diagnosed type 2 diabetes and increased after 6 months of diabetic treatment significantly. The circulating TRAIL level is positively associated with endothelial function. Our data showed that circulating TRAIL level may be a protective maker of endothelial function in type 2 diabetes. PMID- 23931068 TI - Ultrastructure of lymphatic stomata in the tunica vaginalis of humans. AB - Lymphatic stomata are small openings of lymphatic capillaries on the surface of the mesothelium that lines the serous cavity and have the function of active absorption. They play an important role in physiological and pathological conditions. The cavity of the tunica vaginalis is a typical serous cavity of the testis, but the lymphatic stomata of the tunica vaginalis of humans have never been reported. Here, we studied their ultrastructure by scanning and transmission electron microscopy. The submesothelial connective tissue with foramina was investigated after the mesothelial cells were digested using NaOH solution. We found the lymphatic stomata in cuboidal mesothelial cell regions of the parietal layer of the tunica vaginalis of humans with a diameter of about 1-2 MUm. Sometimes, closed lymphatic stomata could be observed. Our study is the first to report the existence of lymphatic stomata of the tunica vaginalis of humans. We found that the tunica vaginalis cavity is connected with the lymphatic system through the stomata, which might provide a morphological basis for the drainage of hydrocele and tumor metastasis of the tunica vaginalis of humans. PMID- 23931069 TI - Intestinal microbiota, diet and health. AB - The human intestine is colonised by 1013 to 1014 micro-organisms, the vast majority of which belong to the phyla Firmicutes and Bacteroidetes. Although highly stable over time, the composition and activities of the microbiota may be influenced by a number of factors including age, diet and antibiotic treatment. Although perturbations in the composition or functions of the microbiota are linked to inflammatory and metabolic disorders (e.g. inflammatory bowel diseases, irritable bowel syndrome and obesity), it is unclear at this point whether these changes are a symptom of the disease or a contributing factor. A better knowledge of the mechanisms through which changes in microbiota composition (dysbiosis) promote disease states is needed to improve our understanding of the causal relationship between the gut microbiota and disease. While evidence of the preventive and therapeutic effects of probiotic strains on diarrhoeal illness and other intestinal conditions is promising, the exact mechanisms of the beneficial effects are not fully understood. Recent studies have raised the question of whether non-viable probiotic strains can confer health benefits on the host by influencing the immune system. As the potential health effect of these non-viable bacteria depends on whether the mechanism of this effect is dependent on viability, future research needs to consider each probiotic strain on a case-by case basis. The present review provides a comprehensive, updated overview of the human gut microbiota, the factors influencing its composition and the role of probiotics as a therapeutic modality in the treatment and prevention of diseases and/or restoration of human health. PMID- 23931070 TI - Direct olefination at the C-4 position of tryptophan via C-H activation: application to biomimetic synthesis of clavicipitic acid. AB - The first Pd-catalyzed method for direct olefination at the C4 position of tryptophan derivatives has been developed via C-H activation to prepare 4 substituted tryptophans, which could be used for the synthesis of many hemiterpenoid indole alkaloids. This reaction proceeds under mild reaction conditions and with exceptional tolerance to a variety of functional groups. Furthermore, the efficiency of this method is demonstrated by the rapid and biomimetic synthesis of clavicipitic acid. PMID- 23931071 TI - Canine pyoderma gangrenosum: a case series of two dogs. AB - BACKGROUND: Pyoderma gangrenosum (PG) is a rare disease, which, to the best of the authors' knowledge, has been the subject of only one case report in the peer reviewed veterinary literature. HYPOTHESIS/OBJECTIVES: To describe the history, clinical signs, diagnostic findings and treatment outcome in two cases of canine PG. ANIMALS: Two client-owned dogs presented to a private veterinary referral practice between 2008 and 2010 who received a diagnosis of PG by specialist veterinary dermatologists. METHODS: Medical records were analysed to retrieve relevant information. RESULTS: Both dogs were treated with prednisolone; this was combined with ciclosporin in case 1 and azathioprine in case 2. Case 2 had a more complete response of lesions to treatment and a longer survival time after diagnosis (763 days) than case 1 (81 days). CONCLUSIONS AND CLINICAL IMPORTANCE: Pyoderma gangrenosum is a rare disease distinguished by rapid progression of painful, necrolytic, cutaneous ulcers with irregular, violaceous undermined borders. Azathioprine with glucocorticoids may lead to a better outcome than ciclosporin and glucocorticoids (currently the first-line treatment in humans and the only reported treatment in dogs). PMID- 23931072 TI - Three-dimensional echocardiographic delineation of an acquired aorto-left atrial fistula complicating native aortic valve endocarditis - "advantage of three dimensions". AB - Aorto-atrial fistulas are rare, but important complications resulting from aortic valve infective endocarditis, aortic valve surgery, or aortic dissection. We hereby report a case of a 20-year male, referred to us with infective endocarditis of the native aortic valve with severe aortic regurgitation and symptoms of heart failure. Detailed evaluation with two-dimensional and three dimensional transthoracic echocardiography revealed aorto-left atrial fistula secondary to the involvement of the mitral-aortic intervalvular fibrosa (MAIVF) region. The patient underwent successful removal of the vegetations, closure of the defect along with aortic valve replacement, and mitral valve repair. PMID- 23931073 TI - A targeted, self-delivered, and photocontrolled molecular beacon for mRNA detection in living cells. AB - The spatiotemporal dynamics of specific mRNA molecules are difficult to image and detect inside living cells, and this has been a significant challenge for the chemical and biomedical communities. To solve this problem, we have developed a targeted, self-delivered, and photocontrolled aptamer-based molecular beacon (MB) for intracellular mRNA analysis. An internalizing aptamer connected via a double stranded DNA structure was used as a carrier probe (CP) for cell-specific delivery of the MB designed to signal target mRNA. A light activation strategy was employed by inserting two photolabile groups in the CP sequence, enabling control over the MB's intracellular function. After the probe was guided to the target cell via specific binding of aptamer AS1411 to nucleolin on the cell membrane, light illumination released the MB for mRNA monitoring. Consequently, the MB is able to perform live-cell mRNA imaging with precise spatiotemporal control, while the CP acts as both a tracer for intracellular distribution of the MB before photoinitiation and an internal reference for mRNA ratiometric detection. PMID- 23931075 TI - From the editors. AB - No abstract available for this article. PMID- 23931074 TI - Hydration of cations: a key to understanding of specific cation effects on aggregation behaviors of PEO-PPO-PEO triblock copolymers. AB - This work reports results from the interactions of a series of monovalent and divalent cations with a triblock copolymer, poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-PPO-PEO). Phase transition temperatures of the polymer in the presence of chloride salts with six monovalent and eight divalent cations were measured using an automated melting point apparatus. The polymer undergoes a two-step phase transition, consisting of micellization of the polymer followed by aggregation of the micelles, in the presence of all the salts studied herein. The results suggest that hydration of cations plays a key role in determining the interactions between the cations and the polymer. The modulation of the phase transition temperature of the polymer by cations can be explained as a balance between three interactions: direct binding of cations to the oxygen in the polymer chains, cations sharing one water molecule with the polymer in their hydration layer, and cations interacting with the polymer via two water molecules. Monovalent cations Na(+), K(+), Rb(+), and Cs(+) do not bind to the polymer, while Li(+) and NH4(+) and all the divalent cations investigated including Mg(2+), Ca(2+), Sr(2+), Ba(2+), Co(2+), Ni(2+), Cu(2+), and Cd(2+) bind to the polymer. The effects of the cations correlate well with their hydration thermodynamic properties. Mechanisms for cation-polymer interactions are discussed. PMID- 23931076 TI - Thoughts on leadership. AB - No abstract available for this article. PMID- 23931077 TI - Health promotion for babies and their parents. AB - Providing individualized developmental assessment and consultation to parents of well children fosters healthy parenting behavior and provides useful information about enrichment techniques. This article describes the Develo mental Enrichment Clinic which was implemented in 1983 at McLaren General Hospital in Flint, Michigan. Information about the program's philosophy, frame of reference and services is provided. Occupational therapists with expertise and interest in pediatrics can broaden their skills to benefit the well population, thus creating a niche for themselves in the wellness movement. PMID- 23931078 TI - Parent-child activity group treatment in preventive psychiatry. AB - This article describes the role that occupational therapy played in a community outreach program instituted collabora- tively by a major teaching hospital and a local day care center. The program focused on preschool children at risk for developing psychiatric disorders. A parent-child activity group was introduced and developed by an occupational therapist who was a member of the hospital staff. The frame of reference, the parent-child intervention including the use of play and group process, and the method of monitoring change in families are explained. A case study is also provided. PMID- 23931079 TI - Occupational Therapists's Involvement in Safe Transportation for the Handicapped. AB - The rapidly expanding demand for occupational therapy services encompasses the area of safe transportation for children with physical handicaps. Federal and state legislation, as well as societal trends, mandate changes in the quality of vehicular restraints for those who cannot be safely transported using conventional car seats because of conditions such as cerebral palsy, orthopedic surgery and casting, ventilator dependency, or low birth weight. Potential for and barriers to occupational therapy involvement will be discussed in this paper as well as the potenhl impacts that involvement in safe transportation will have on the traditional role and education of occupational therapists. Occupational therapist involvement in the growing area of safe transportation will be analyzed using the system approach. The Automotive Safety for Children Program at James Whitcomb Riley Hospital for Children will be described. PMID- 23931080 TI - A community mental health group designed by clients. AB - "Support," a group learning project, was conceived and designed by patients who completed a twenty-four hour occupational therapy stress management program offered by an occupational therapy assistant at a community mental health day treatment center in Upstate New York. The patients had become a very "close knit" group because of the nature and intensity of the therapeutic activities. As they moved to ex-patient status and to a self-directed group they identified familial and community stressors they expected would arise and wanted to strengthen their network. They sought resources to provide knowledge and practice for themselves and their families in the management of those stressors. This paper describes the rationale and the process of the "Support" group and the ways in which patients contributed to its formation, ongoing activities and closure. PMID- 23931081 TI - Cognition and learning in industrial accident injury prevention. AB - An industrial accident/injury primary prevention program similar to traditional "back school" training, but based upon educational psychology principles such as "transfer appropriate processing" and the use of "critical tasks," was conducted for a group of 110 workcrs at a major grocery distribution center. Occupational therapy prevention principles of environmental modification, work simplification, and proper body mechanics were emphasized. Workers and supervisors were trained in very small groups (4-6 persons) at their actual work stations. Results of the program were positive, and the program has continued to expand into a comprchensive accidentlinjury prevention project within the company. PMID- 23931082 TI - Health promotion. AB - This article will describe a marketing model for the development of a role for occupational therapy in the industrial market. Health promotion activities are used as a means to diversify existing revenue bases by establishing new referral sources in industry. The technique of need satisfaction -selling or marketing one's services to a customer based on needs expressed by the customer - is reviewed, and implementation of this approach is described from two settings, one in psychiatry and the other in rehabilitation. PMID- 23931083 TI - Education with activity. AB - In a nursing home it is traditional to encourage patients to assist themselves in their daily needs as a measure to prevent deterioration and to promote recovery. In this model, the concept of self-help was expanded into a formal program of patient education in health-enhancing strategies. The methods used by an occupational therapist to provide the program and to identify its outcomes are presented in detail. PMID- 23931084 TI - Home safety program for older adults. AB - A disproportionately high number of older adults are involved in home accidents at considerable cost to both the individual and the nation. Preventive measures are cost-effective and easy to accomplish, and occupational therapists are uniquely qualified to educate older adults about ways to modify their environment or activities of daily living to lessen the risk of accidental injury. This article describes the developmcnt and operation of a Home Safety Program for Older. Adults in an agency on aging in Charlottesville, VA. The program has two components: safety improvements for individual homes, and community education. Funding, services and staff are discussed and recommendations are made for replication. PMID- 23931085 TI - Education for and being educated by the well elderly. AB - This article describes the experiences of an occupational therapist as a wellness representative at an older adult retirement community. The position was a new challenge to the author, and skills such as responsiveness, listening, resourcefulness and flexibility were required for the author to achieve the goals of a new program in the well older adult community. The purpose of this paper is to stimulate the readers to consider developing such programs. PMID- 23931086 TI - (129)I dispersion in Argentina: concentrations in fresh and marine water and deposition fluences in Patagonia. AB - Measurements of total iodine (I) and iodine-129 ((129)I) concentrations in rivers and lakes of Argentina are presented. Their latitudinal distribution can be explained by taking into account their main sources (oceanic emissions and biomass burning for I, and atmospheric nuclear tests for (129)I), transport mechanisms, and fallout patterns. From the measured (129)I concentrations in the studied lakes, deposition fluences for their catchment areas were estimated. These results agree with a model of the global deposition pattern due to the (129)I released by atmospheric nuclear weapon tests and with other fluences reported for the southern hemisphere. In addition, the first measurements of (129)I in shallow seawater from the South Atlantic Ocean are presented and discussed. PMID- 23931087 TI - Kinetics of inhibitory effect of isoferulic acid on mushroom tyrosinase. AB - A study on the kinetics of inhibitory effect of isoferulic acid on the monophenolase and diphenolase activity of mushroom tyrosinase was carried out using enzymological kinetic analysis method in a Na2HPO4-NaH2PO4 buffer solution (pH = 6.8) at 30 degrees C. It was found that isoferulic acid efficiently inhibits both monophenolase and diphenolase activities of mushroom tyrosinase under experimental conditions. Concentrations of isoferulic acid leading to 50% rate inhibition (IC50) on monophenolase and diphenolase activity were calculated to be 0.13 mmol/L and 0.39 mmol/L, respectively, which are much lower than that of arbutin (IC50 = 5.3 mmol/L for diphenolase activity). The presence of isoferulic acid also prolongs the lag period in the oxidation process of l tyrosine via tyrosinase-a 4.3-min lagging was observed with the presence of 0.20 mmol/L isoferulic acid-compared to a 1.1-min lagging in the absence of isoferulic acid. The Lineweaver-Burk plot demonstrates a competitive behavior of isoferulic acid in the tyrosinase oxidation of l-3,4-dihydroxyphenylalanine, with maximum reaction rate (vm) and inhibition constant (KI) at 64.5 uM/min and 0.11 mmol/L, respectively. PMID- 23931088 TI - Influence of various environmental parameters on sweat gland activity. AB - The choice of environmental conditions when conducting antiperspirant studies greatly affects the quantity of sweat output. Our initial goal in this work was to develop an in-house procedure to test the efficacy of antiperspirant products using replica techniques in combination with image analysis. To ameliorate the skin replica method, we conducted rheological studies using dynamic mechanical analysis of the replica formulation. In terms of sweat output quantification, our preliminary results revealed a considerable amount of variation using the replica technique, leading us to conduct more fundamental studies of the factors that influence sweating behavior and how to best design the experimental strategy. In accordance with the FDA's protocol for antiperspirant testing, we carried out gravimetric analyses of axillae sweating under a variety of environmental conditions including temperature and humidity control. Subjects were first acclimatized in an environmentally controlled room for 30 min, and then placed in a sauna for an additional 30 or 45 min, depending on which test we administered. In Test 1 (30 min total in the sauna), the first 10 min in the sauna was another equilibration period, followed by a 20 min sweat production stage. We monitored axillae sweating during the last 20 min in the sauna by gravimetric analysis. At time (t) = 30 min in the sauna, skin replicas were taken and later analyzed using imaging and image analysis techniques. Test 1 was carried out on over 25 subjects, both male and female, from various racial backgrounds. In Test 2, subjects spent 45 min in the sauna after the initial 30-min period in the environmental room. During the 45 min, we obtained gravimetric readings of absorbent pads placed in the axillae. We conducted studies at various temperature and relative humidity settings. We also studied the influence of several external parameters on sudoriferous activity. Test 2 was a range-finding experiment on two subjects to determine the optimized environmental conditions for the hot room procedure. In addition to the replica and gravimetric techniques, we also measured flux density to determine the onset of firing of sweat glands to ensure that our environmental preconditioning step (30 min in the environmental room) brought subjects to the point that their sweat glands were activated. Although flux density measurements are usually carried out to determine transepidermal water loss (TEWL), we found that they can be equally useful for monitoring the onset of sweat production. Thermal infrared imaging experiments were also carried out allowing us to generate full-body images of subjects containing anatomical thermal distribution data with high accuracy. Overall, we conclude that our in house hot room procedure offers much potential as an effective and cost-efficient screening tool for narrowing copious antiperspirant formulations to a select few for expensive clinical evaluation. PMID- 23931089 TI - Alkaline peroxide treatment induces acquired unruly hair by apparently affecting distinct macrofibrils. AB - Individual hairs can be inherently curly; however, bleach treatment can cause damaged hairs to acquire a curl, a phenomenon we term acquired unintentional unruly hair. Because there have been no reports concerning acquired unintentional unruly hair, the influence of bleach treatment with alkaline peroxide that produce this phenomenon was investigated. First, it was validated that the radius of curvature in many curly hairs is reduced upon bleach treatment. Next, the influence of bleach treatment on the mechanical properties of inner components was studied by the force curve method using atomic force microscopy. This measurement revealed four types of macrofibrils-on the orthocortex- or the paracortex-like structure, and on the concave or the convex side-have different mechanical properties. Macrofibrils on the orthocortex-like structure on the convex side were especially influenced by alkaline peroxide treatment, and may be particularly important to acquired unintentional unruly hair. PMID- 23931090 TI - Lauroyl/palmitoyl glycol chitosan gels enhance skin delivery of magnesium ascorbyl phosphate. AB - Palmitoyl glycol chitosan (GCP) hydrogel has been reported as erodible controlled release systems for the delivery of both hydrophilic and hydrophobic molecules. In this study we prepared lauroyl/palmitoyl glycol chitosan (GCL/GCP) in gel form and evaluated their application for skin delivery of the hydrophilic compound, magnesium ascorbyl phosphate (MAP), which is widely used in cosmetic formulations. Release of MAP from the polymer gels was significantly decreased with increasing concentration of GCL/GCP in the formulations in comparison with glycol chitosan (GC). In both aqueous and 10% ethanol vehicles, MAP flux was increased 1.58- to 3.96-fold of 1% GC from 1% GCL/GCP. Increase in MAP flux was correlated to the increase in GCL/GCP concentration prepared in 10% ethanol vehicle. GCL/GCP, in either water or 10% ethanol vehicles, increased the skin penetration and skin deposition of MAP in comparison with GC, hydroxypropylmethylcellulose, and carbopol, while sustaining its release from the polymer gels. Both the enhancement in skin penetration/deposition and sustained release of MAP were depended on polymer concentration. Also, with increase in polymer concentration, epidermal to dermal drug deposition ratio tended to increase, which will be beneficial to its activity in the epidermis, such as inhibition of tyrosinase and protection from UV damage. These data suggested both GCL and GCP can be applied as delivery vehicles to improve percutaneous absorption of MAP. PMID- 23931091 TI - Cosmetic and amino acid analysis of the effects of lye and no-lye relaxer treatment on adult black female South African hair. AB - Surveys indicate that many South African women use relaxers to straighten their hair for cosmetic reasons, which can damage the hair and scalp. The objective of this study was to assess the effects of treating hair with two types of relaxers: Product A (a lye relaxer, sodium hydroxide base) and Product B (a no-lye relaxer, guanidine hydroxide base). Five adult black female South African subjects were used for the study that was divided into two parts. The first part used a half head study design in a clinical study in which the researcher and the subjects visually assessed various hair quality parameters before and after relaxer treatment. Product B was assessed to perform better (p = 0.032) than Product A in terms of hair straightening. The second part of the study involved hair amino acid analysis by reversed-phase high performance liquid chromatography. There was a decrease in the amount of cystine [Median (range) g/100 g hair] after treatment with both Product A [7.8 (2.5-9.9), p = 0.086] and Product B [4.0 (2.9-4.8), p = 0.005] compared to before treatment [9.1 (6.4-11.9)]; this decrease was greater (p = 0.085) for Product B. Reduction in cystine content was consistent with increased straightness. Product B (the no-lye relaxer) was found to be more effective and safer to use. PMID- 23931092 TI - Disparate SPF testing methodologies generate similar SPFs. AB - Regulatory agencies throughout the world have developed exclusive methodologies for assessing and classifying sunscreen product efficacy in their respective markets. Three prevalent methods, the Food and Drug Administration-Final Monograph (FDA-FM) method, the Australia/New Zealand (Aus/NZ) method, and the COLIPA International (International) method, contain procedural and statistical dissimilarities with undefined significance. The objective of our clinical trials was to evaluate the influence of these disparities on sun protection factor (SPF) values. Our clinical trials evaluated the SPF of 59 test materials, using two or all three of the aforementioned methods in simultaneous trials, providing two or three SPF values for each formulation. A total of 135 trials were conducted. The consequent mean SPF values generated per trial were used to compare methods in a correlation and variance analysis. The correlation coefficients for each method pair, International vs. FDA-FM, Aus/NZ vs. FDA-FM, and International vs. Aus/NZ, were each >=0.94. The difference in least square mean SPF for each method pair was 0.12, 0.62, and 0.81, respectively. Our juxtaposition of the mean SPFs produced by these methods clearly illustrate that any disparities between average SPF values produced by these methods are not clinically or statistically significant and that using one method should be sufficient for SPF labeling in all three respective markets. PMID- 23931094 TI - Advances in personalized therapy for lung cancer. AB - INTRODUCTION: Personalized medicine based on tumor characteristics is transforming the management of lung cancer. This review provides an overview of clinically approved strategies to personalize treatment for lung cancer as well as evolving strategies in various stages of clinical development. AREAS COVERED: Selecting therapy based on various tumor characteristics such as histology and presence of specific molecular alterations will be covered. This review will not only discuss the role of targeted agents in personalizing care for lung cancer but also the strategies to personalize traditional chemotherapeutic agents. EXPERT OPINION: Advances in genomic medicine to identify key genetic alterations with subsequent development of matching targeted agents are rapidly changing the management of lung cancer. Being able to target key driver molecular aberrations is certainly exciting and clinically meaningful, but only for a limited period of time. Intra- and intertumoral heterogeneity is a major contributor to therapy resistance, a substantial roadblock to durable response. Better understanding of resistance mechanism is at least as important as identifying new targetable genetic changes to effectively advance personalized therapy for lung cancer. Finally, optimization of biopsy specimens and rigorous validation steps to ensure reliability of diagnostic methods would be critical in moving forward. PMID- 23931093 TI - A randomized effectiveness study comparing trauma-focused cognitive behavioral therapy with therapy as usual for youth. AB - The efficacy of trauma-focused cognitive behavioral therapy (TF-CBT) has been shown in several randomized controlled trials. However, few trials have been conducted in community clinics, few have used therapy as usual (TAU) as a comparison group, and none have been conducted outside of the United States. The objective of this study was to evaluate the effectiveness of TF-CBT in regular community settings compared with TAU. One hundred fifty-six traumatized youth (M age = 15.1 years, range = 10-18; 79.5% girls) were randomly assigned to TF-CBT or TAU. Intent-to-treat analysis using mixed effects models showed that youth receiving TF-CBT reported significantly lower levels of posttraumatic stress symptoms (est. = 5.78, d = 0.51), 95% CI [2.32, 9.23]; depression (est. = 7.00, d = 0.54), 95% CI [2.04, 11.96]; and general mental health symptoms (est. = 2.54, d = 0.45), 95% CI [0.50, 4.58], compared with youth in the TAU group. Youth assigned to TF-CBT showed significantly greater improvements in functional impairment (est. = -1.05, d = -0.55), 95% CI [-1.67, -0.42]. Although the same trend was found for anxiety reduction, this difference was not statistically significant (est. = 4.34, d = 0.30), 95% CI [-1.50, 10.19]. Significantly fewer youths in the TF-CBT condition were diagnosed with posttraumatic stress disorder compared to youths in the TAU condition, chi(2)(1, N = 116) = 4.61, p = .031, Phi = .20). Findings indicate that TF-CBT is effective in treating traumatized youth in community mental health clinics and that the program may also be successfully implemented in countries outside the United States. PMID- 23931095 TI - From physiology to space use: energy reserves and androgenization explain home range size variation in a woodland rodent. AB - This study tested the relationships between both individual-level and predation risk factors and the size of two home-range regions (HRR), defined as areas of different intensities of use. We have expanded on previous home-range studies by testing the effects of two previously ignored individual-level factors: androgenization and energy reserves (body fat). Location data were collected for wild individuals of Apodemus sylvaticus using the novel method of implanted PIT tags and mobile recording stations. A total of 68 home ranges were estimated using kernel density estimation. Home ranges were split into two regions (HRR): the 'core', representing the most intensively used areas, and 'periphery' regions. Body mass, body fat, sex, anogenital distance (AGD) (a proxy for androgenization) and the proportion of HRR, covered by antipredatory features (shrubs and fallen trees), were tested for their relationship with the size of core and periphery HRRs. Models were constructed for each HRR for three seasons: nonbreeding season (NBS), early and late breeding seasons (LBSs), to account for seasonal variation in behaviour associated with changes in food abundance and reproductive cycles. Body fat had a negative relationship with periphery size and an interaction with sex on core size in the early breeding season (EBS). Body mass also had a significant interaction with sex on core size in the EBS. Androgenization has a strong effect on home range size in both sexes: AGD had a positive relationship with both HRRs for males in the LBS and females in the NBS. Males had larger peripheries than females in both early and LBSs. Habitat features that reduce predation risk explain HRR size throughout the breeding period. This study emphasizes the importance of embracing natural complexity to gain insight into the drivers of space use behaviour; the consideration of individual and ecological factors, the recognition of the species-specific selective pressures that seasonal change presents for each sex and the identification of biologically meaningful home range areas will help advance the field. PMID- 23931096 TI - Influence of body mass index on oncological outcomes in patients with upper urinary tract urothelial carcinoma treated with radical nephroureterectomy. AB - OBJECTIVE: To investigate the association between body mass index and oncological outcomes in Chinese patients who had undergone radical nephroureterectomy for upper urinary tract urothelial carcinoma. METHODS: Between August 1998 and October 2009, 236 consecutive Chinese patients underwent radical nephroureterectomy for upper urinary tract urothelial carcinoma at Sun Yat-sen University Cancer Center (Guangzhou, China). Body mass index data were available for 230 (97.5%) of these patients. All 230 patients were classified into three groups according to the body mass index criteria for Asians, issued by the Asia Cohort Consortium: underweight, body mass index <18.5 kg/m(2) (n = 21, 9.1%); normal weight, body mass index >=18.5 and <25 kg/m(2) (n = 151, 65.7%); and obesity, body mass index >=25 kg/m(2), (n = 58, 25.2%). Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. RESULTS: Being underweight was significantly associated with lymph node metastasis (P = 0.017) and Eastern Cooperative Oncology Group performance status (P = 0.003). Univariate analysis showed recurrence-free survival and cancer-specific survival were significantly worse in underweight patients than in patients with normal weight or obese patients. After adjustments for other clinicopathological variables, multivariate analysis confirmed that recurrence-free survival and cancer-specific survival were significantly worse in underweight patients than in patients with normal weight or obese patients (recurrence-free survival P = 0.014, cancer-specific survival P = 0.015). CONCLUSIONS: Preoperative underweight is an independent predictor of unfavorable recurrence-free survival and cancer-specific survival in Chinese patients with upper urinary tract urothelial carcinoma treated by radical nephroureterectomy, whereas obesity is associated with superior recurrence-free survival and cancer-specific survival. Further studies, including a multi institutional, prospective, Asian cohort study, are required to confirm these findings. PMID- 23931097 TI - Aortic stenosis: role of balloon aortic valvuloplasty. AB - Calcific aortic stenosis (AS) is the most frequent expression of aortic valve disease in the Western world, with an increasing prevalence as the population ages. Almost 4% of all adults 75 years of age or older have moderate or severe AS. Many patients do not undergo surgery because of prohibitive comorbidities or other high-risk features. Balloon aortic valvuloplasty (BAV) remains an option for temporary palliation and symptomatic relief in such patients. In addition, BAV continues to serve an important role as a bridge to either surgical or transcatheter aortic valve replacement in certain patients with AS requiring temporary hemodynamic stabilization. PMID- 23931098 TI - Transcatheter aortic valve replacement using the Edwards SAPIEN transcatheter heart valves. AB - Transcatheter aortic valve replacement has a place in the therapy for valvular aortic stenosis in a selected population of patients with increased risk for standard aortic valve replacement. The SAPIEN family of balloon-expandable transcatheter heart valves is the prototype that initiated this therapy and has undergone rapid development and evolution. The SAPIEN system has taught cardiologists and cardiac surgeons much about the nature of aortic stenosis and the potential for less invasive therapy. This article will review the SAPIEN transcatheter heart valves and the clinical experience. PMID- 23931099 TI - Transcatheter aortic valve replacement with CoreValve. AB - The treatment of aortic stenosis in high-risk surgical patients is now possible by transcatheter aortic valve replacement. The CoreValve is a new transcatheter valve with a unique design expanding its application in patients with aortic stenosis. The CoreValve is just completing clinical trial in the United States and not yet available for commercial use in the United States but is widely used in Europe. PMID- 23931100 TI - Transcatheter left atrial appendage occlusion. AB - Occlusion of the left atrial appendage (LAA) may reduce the risk of stroke in patients with atrial fibrillation (AF). Trials comparing LAA occlusion to warfarin anticoagulation in patients with nonvalvular AF showed a reduction in hemorrhagic stroke, although an increase in safety events due to procedural complications. Long-term follow-up suggests possible superiority of LAA occlusion due to fewer strokes and bleeding events. The superior dosing and safety profiles of the novel oral anticoagulants raise the accepted threshold for safety and efficacy of LAA occlusion procedures, and underscore the need for randomized studies comparing LAA occlusion with these newer anticoagulants. PMID- 23931101 TI - Atrial septal defect closure. AB - Congenital heart disease accounted for 0.3% of US hospital admissions in 2007, with 48% related to atrial septal defects (ASDs). More than one-fourth of adult congenital heart defects are ASDs, 75% of which are ostium secundum ASDs. The progressive impact of volume overload of the right cardiac chambers can be halted by ASD closure. This review focuses on percutaneous ASD closure. PMID- 23931102 TI - Patent foramen ovale. AB - Patent foramen ovale (PFO) is a common developmental anomaly that allows for the passage of blood and other substances from the venous to the arterial circulation. The study of PFO closure has been challenging due to widely available off-label closures performed outside the clinical trial setting. To date, no study has demonstrated benefit of closure using intention-to-treat analyses. Secondary and subpopulation analyses suggest that there is benefit to closure in patients with atrial septal aneurysms and/or substantial degrees of right-to-left shunting. This article reviews the history, associated technologies, and current data regarding PFO closure. PMID- 23931103 TI - Patent ductus arteriosus. AB - Patent ductus arteriosus in adults is usually an isolated lesion with a small to moderate degree of shunt, as a larger shunt becomes symptomatic earlier in childhood. The classic murmur of patent ductus arteriosus may be the first clue to its presence, or it may be detected accidently by transthoracic echocardiography, computed tomography, or magnetic resonance angiography for an unrelated condition. The percutaneous approach is safe and effective in more than 98% of patients. Subacute bacterial endocarditis prophylaxis is not indicated routinely except for 6 months following the closure percutaneously or surgically. PMID- 23931104 TI - Percutaneous paravalvular leak closure. AB - Percutaneous paravalvular leak closure is increasingly being performed as an alternative to reoperation in patients with symptomatic prosthetic paravalvular regurgitation. This article reviews the pathogenesis of paravalvular leaks and percutaneous techniques for closure. Newer multimodality imaging techniques, including 3-dimensional (3D) transesophageal echocardiography and 3D/4D computed tomographic angiography, allow improved preprocedural planning and intraprocedural guidance. Specific techniques can be used for challenging patient anatomy and larger paravalvular leaks. Outcomes from experienced centers show acceptable rates of technical and clinical success, with lower procedural morbidity than reoperation. PMID- 23931105 TI - A practical guide to the use of echocardiography in assisting structural heart disease interventions. AB - Echocardiography plays an integral role in the evaluation and treatment of patients undergoing percutaneous interventions for structural heart disease. Preprocedure, accurate echocardiographic assessment of cardiac anatomy is crucial in determining patient eligibility. During catheterization, echocardiography is used for procedural guidance. Postprocedure, echocardiography is used for patient follow-up and determining the effect of device placement on cardiac remodeling. This article provides a practical guide for using echocardiography in common interventional procedures, including percutaneous atrial septal defect closure, transcatheter aortic valve replacement, percutaneous repair of prosthetic valve paravalvular leaks, percutaneous mitral valve edge-to-edge repair, and percutaneous placement of appendage occlusion devices. PMID- 23931106 TI - Anesthesia for structural heart interventions. AB - Surgeries in general and cardiac procedures in particular are increasingly performed using catheter-based or minimally invasive techniques, often with sedation or general anesthesia. These new approaches require close cooperation and communication between the cardiologist and anesthesiologist to ensure patient safety. Anesthesia-related respiratory complications arising in the catheterization laboratory are more frequent and more severe than are seen in the operating room. The principals of safe anesthetic practice as they apply to procedures performed outside the operating room and suggestions to improve safety and outcome are reviewed in this article. PMID- 23931107 TI - Role of cross-sectional imaging for structural heart disease interventions. AB - With the aging population, significant valvular heart disease is increasingly identified in patients too frail to undergo surgery. Transcatheter therapies for structural heart disease represent an alternative therapeutic approach for these patients. During these procedures, direct visualization of the surgical field is replaced by image guidance for intraprocedural decision making. Advances in percutaneous devices and delivery systems, coupled with enhancements in 3 dimensional imaging with multiplanar reformatting, have allowed these procedures to be performed safely and with excellent results. This article describes the role of cross-sectional imaging for detailed assessment and preprocedural planning of aortic, mitral, and pulmonic valve interventions. PMID- 23931108 TI - Catheter intervention in structural heart disease. Preface. PMID- 23931109 TI - Aminoferrocene-based prodrugs and their effects on human normal and cancer cells as well as bacterial cells. AB - Aminoferrocene-based prodrugs are activated under cancer-specific conditions (high concentration of reactive oxygen species, ROS) with the formation of glutathione scavengers (p-quinone methide) and ROS-generating iron complexes. Herein, we explored three structural modifications of these prodrugs in an attempt to improve their properties: (a) the attachment of a -COOH function to the ferrocene fragment leads to the improvement of water solubility and reactivity in vitro but also decreases cell-membrane permeability and biological activity, (b) the alkylation of the N-benzyl residue does not show any significant affect, and (c) the attachment of the second arylboronic acid fragment improves the toxicity (IC50) of the prodrugs toward human promyelocytic leukemia cells (HL-60) from 52 to 12 MUM. Finally, we demonstrated that the prodrugs are active against primary chronic lymphocytic leukemia (CLL) cells, with the best compounds exhibiting an IC50 value of 1.5 MUM. The most active compounds were found to not affect mononuclear cells and representative bacterial cells. PMID- 23931110 TI - Parkinson's disease: in vivo metabolic changes in the frontal and parietal cortices in 6-OHDA treated rats during different periods. AB - This study aims to investigate metabolic changes in frontal and parietal cortices in the 6-OHDA induced Parkinson's rats. Ratios of N-acetyl-aspartic acid/creatine (NAA/Cr), choline/creatine (Cho/Cr), and glumatic acid and glutamine glutaminic acid/creatine (Glx/Cr) of regions of interests (ROIs) in the frontal and parietal cortices, and the substantia nigra were analyzed. NAA/Cr, Cho/Cr and Glx/Cr in the frontal and parietal cortices in the lesion side did not show any significant differences two weeks after operation compared with the contralateral side (p > 0.05). NAA/Cr in the frontal cortex in the lesion side was significantly lower in the five weeks after operation; Cho/Cr remained normal; Glx/Cr increased (p < 0.05), and all ratios of parietal cortex were normal. In the eight weeks after operation, NAA/Cr in the frontal cortex in the lesion side was lower than that of the five weeks (p < 0.01), Cho/Cr still remained normal while Glx/Cr was higher than before (p < 0.01). Regarding the parietal cortex, NAA/Cr increased significantly, while Cho/Cr and Glx/Cr remained normal. In the 12 weeks after operation, NAA/Cr, Cho/Cr and Glx/Cr in frontal cortex were consistent with that of the eight weeks, while they remained at the normal level in parietal cortex. The NAA/Cr in the substantia nigra decreased and Cho/Cr increased significantly during 2-8 weeks, and remained at the same level during 8-12 weeks. There are metabolic disturbances in PD rats. The transient hyperfunction in the parietal cortex can be considered as a compensation for the dysfunction of the frontal cortex and substantia nigra. PMID- 23931111 TI - Radiolabeling, stability studies, and pharmacokinetic evaluation of thulium-170 labeled acyclic and cyclic polyaminopolyphosphonic acids. AB - OBJECTIVE: Thulium-170 [T1/2=128.4 days, Ebeta(max)=968 keV, and Egamma=84 keV (3.26%)] could be considered an easily producible and cost-effective alternative to (89)Sr for the preparation of radiopharmaceuticals for palliation of bone pain arising due to skeletal metastases. Multidentate aminomethylene polyphosphonic acids have already been proven to be effective as carrier moieties for developing radiolabeled bone pain palliation agents using lanthanide radionuclides. Therefore, an attempt was made to evaluate the potential of a series of (170)Tm labeled acyclic (diethylenetriaminepentamethylene phosphonic acid and triethylenetetraminehexamethylene phosphonic acid) and cyclic polyaminopolyphosphonic acids (1,4,7,10-tetraazacyclododecane-1,4,7,10 tetramethylene phosphonic acid [DOTMP] and 1,4,8,11-tetraazacyclotetradecane 1,4,8,11-tetramethylene phosphonic acid [CTMP]) toward their use as alternative bone pain palliation agents. EXPERIMENTAL: Thulium-170 was produced by irradiating the natural Tm2O3 target at a thermal neutron flux of 7*10(13) n.cm( 2).s(-1) for a period of 60 days. All the phosphonic acid ligands were synthesized and characterized in-house. The protocols for radiolabeling the phosphonic acids with (170)Tm were standardized. Biological evaluation of the (170)Tm-labeled phosphonic acids were carried out in normal Wistar rats by biodistribution as well as by scintigraphic studies. RESULTS: Thulium-170 was produced with adequate specific activity (173 Ci/g, 6.41 TBq/g) and high radionuclidic purity (99.62%). All the (170)Tm-labeled phosphonic acids, except (170)Tm-CTMP, were prepared with very high radiochemical purity (>98%) under optimized reaction conditions and exhibited high stability. All the agents showed selective skeletal accumulation with insignificant uptake in other vital organs/tissues and major clearance through renal pathway. These findings were also substantiated by scintigraphic studies. CONCLUSIONS: Although all the (170)Tm-labeled phosphonic acids showed significant and selective skeletal accumulation, radiochemical studies indicate that (170)Tm-DOTMP is the best choice for carrying out further evaluation toward its use for clinical applications. PMID- 23931112 TI - Novel diagnosis for citrus stubborn disease by detection of a spiroplasma citri secreted protein. AB - Citrus stubborn disease (CSD), first identified in California, is a widespread bacterial disease found in most arid citrus-producing regions in the United States and the Mediterranean Region. The disease is caused by Spiroplasma citri, an insect-transmitted and phloem-colonizing bacterium. CSD causes significant tree damage resulting in loss of fruit production and quality. Detection of CSD is challenging due to low and fluctuating titer and sporadic distribution of the pathogen in infected trees. In this study, we report the development of a novel diagnostic method for CSD using an S. citri-secreted protein as the detection marker. Microbial pathogens secrete a variety of proteins during infection that can potentially disperse systemically in infected plants with the vascular flow. Therefore, their distribution may not be restricted to the pathogen infection sites and could be used as a biological marker for infection. Using mass spectrometry analysis, we identified a unique secreted protein from S. citri that is highly expressed in the presence of citrus phloem extract. ScCCPP1, an antibody generated against this protein, was able to distinguish S. citri infected citrus and periwinkle from healthy plants. In addition, the antiserum could be used to detect CSD using a simple direct tissue print assay without the need for sample processing or specialized lab equipment and may be suitable for field surveys. This study provides proof of a novel concept of using pathogen secreted protein as a marker for diagnosis of a citrus bacterial disease and can probably be applied to other plant diseases. PMID- 23931113 TI - Against the naming of fungi. AB - The use of molecular bar-coding and consensus on nomenclatural practices has encouraged optimism about the future of fungal taxonomy and systematics. There are, however, profound deficiencies in our understanding of fungal diversity and broader problems with the taxonomic enterprise that deserve greater attention. For 250 years mycologists have tried to reconcile fungal diversity with the Linnean fantasy of a divine order throughout nature that included unambiguous species. This effort has failed and today's taxonomy rests on an unstable philosophical foundation. Rather than persisting with the present endeavour, it may be more fruitful to abandon the notion of fungal species pending further basic research. In the meantime, mycologists should consider tagging collections with digital codes and assigning these operational taxonomic units to higher taxonomic ranks whose objective reality is corroborated by strong phylogenetic evidence. PMID- 23931114 TI - Morphological responses to high sugar concentrations differ from adaptation to high salt concentrations in the xerophilic fungi Wallemia spp. AB - Fungi from the food-borne basidiomycetous genus Wallemia, which comprises Wallemia ichthyophaga, Wallemia muriae and Wallemia sebi, are among the most xerophilic organisms described. Their morphological adaptations to life at high NaCl concentrations are reflected in increased cell-wall thickness and size of cellular aggregates. The objectives of this study were to examine their growth and to define cell morphology and any ultrastructural cell-wall changes when these fungi are grown in low and high glucose and honey concentrations, as environmental osmolytes. We analysed their growth parameters and morphological characteristics by light microscopy and transmission and scanning electron microscopy. Wallemia ichthyophaga grew slowly in all of the sugar-based media, while W. muriae and W. sebi demonstrated better growth. Wallemia ichthyophaga adapted to the high glucose and honey concentrations with formation of larger cellular aggregates, while cell-wall thickness was increased only at the high glucose concentration. Wallemia muriae and W. sebi demonstrated particularly smaller sizes of hyphal aggregates at the high glucose concentration, and different and less explicit changes in cell-wall thickness. Adaptive responses show that the phylogenetically more distant W. ichthyophaga is better adapted to high salt conditions, whereas W. muriae and W. sebi cope better with a high sugar environment. PMID- 23931115 TI - Phylogenetic overview of the Boletineae. AB - The generic and sub-generic relationships in the Boletineae (Boletales) were studied using nuclear large subunit (nuc-lsu), translation elongation factor 1 alpha (tef1), and DNA directed RNA polymerase largest subunit (RPB1). The Boletineae, with the exclusion of Hydnomerulius pinastri, was strongly supported and the status of the families Boletaceae and Paxillaceae is discussed. Members of the genus Boletus are found throughout the phylogeny, with the majority not closely related to the type species, Boletus edulis. Many of the traditional, morphologically defined genera are not supported as monophyletic and additional sampling and taxonomic revisions are needed. The majority of the Boletineae are confirmed or putatively ectomycorrhizal (ECM), but two putatively mycoparasitic lineages (one lineage of Buchwaldoboletus lignicola and Chalciporus piperatus and the second Pseudoboletus parasiticus) are strongly supported. PMID- 23931116 TI - Bacterial epibionts and endolichenic actinobacteria and fungi in the Lower Devonian lichen Chlorolichenomycites salopensis. AB - The charcoalified fragment of the dorsiventrally organized, internally stratified presumed green algal lichen Chlorolichenomycites salopensis from the Lower Devonian Lochkovian strata in the Welsh Borderland carries bacterial colonies on the upper surface, i.e. the cortex, and actinobacterial filaments in the medulla underneath the photobiont layer. Moreover relatively thin hyphae of presumed endolichenic fungi were found. As in extant lichens, which are best regarded as consortia with an unknown number of participants, this internally stratified, fossil thallus fragment of a presumed green algal lichen harbours a diverse microbial community. PMID- 23931117 TI - Lethal effects of high-intensity violet 405-nm light on Saccharomyces cerevisiae, Candida albicans, and on dormant and germinating spores of Aspergillus niger. AB - This study assessed the effects of high-intensity violet light on selected yeast and mould fungi. Cell suspensions of Saccharomyces cerevisiae, Candida albicans, and dormant and germinating spores (conidia) of the mould Aspergillus niger were exposed to high-intensity narrow band violet light with peak output at 405 nm generated from a light-emitting diode (LED) array. All three fungal species were inactivated by the 405-nm light without a requirement for addition of exogenous photosensitiser chemicals. Of the fungal species tested, S. cerevisiae was most sensitive and dormant conidia of A. niger were most resistant to 405-nm light exposure. Five-log10 colony forming units per millilitre (CFU ml(-1)) reductions of the tested species required exposure doses of 288 J cm(-2) for S. cerevisiae, 576 J cm(-2) for C. albicans, and a much higher value of 2.3 kJ cm(-2) for dormant conidia of A. niger. During germination, A. niger conidia became more sensitive to 405-nm light exposure and sensitivity increased as germination progressed over an 8 h test period. Light exposure under aerobic and anaerobic conditions, together with results obtained using ascorbic acid as a scavenger of reactive oxygen species, revealed that 405-nm light inactivation in fungi involved an oxygen-dependent mechanism, as previously described in bacteria. The inactivation results achieved with yeast cells and fungal spores together with operational advantages associated with the use of a visible (nonultraviolet (UV)) light source highlight the potential of 405-nm light for fungal decontamination applications. PMID- 23931118 TI - Laccase is upregulated via stress pathways in the phytopathogenic fungus Sclerotinia sclerotiorum. AB - We report on the factors affecting the production of the newly characterized laccase from the phytopathogenic fungus Sclerotinia sclerotiorum (Lib.) de Bary. The carbon/nitrogen ratio appears to be of great importance. Rather than a simple nutrient-rich nitrogen source, yeast extract (YE) behaves as a true laccase upregulator, apparently acting via a stress pathway. Chelidonium majus extract, a known antifungal agent, acts in a similar manner. The compound(s) in the YE responsible for enhancing laccase synthesis are suggested to be hydrolysable choline derivatives. Both extracts reduce biomass and sclerotia development and enhance laccase production, leading to an increase in laccase activity by one order of magnitude compared to controls. The pH of the medium, a well-known virulence regulator for this fungus, also acts as a true laccase regulator, though via a different mechanism. The effect of pH appeared to be linked to the acidification kinetics of the extracellular medium during fungal development. A number of other known laccase inducers were found to enhance laccase production at most twofold. PMID- 23931119 TI - Trematodes enhance the development of the nematode-trapping fungus Arthrobotrys (Duddingtonia) flagrans. AB - The capability of helminth (nematode and trematode) parasites in stimulating nematode trap and chlamydospore development of the nematophagous fungus Arthrobotrys (formerly Duddingtonia) flagrans was explored. Dead adult specimens of trematodes (the liver fluke Fasciola hepatica and the rumen fluke Calicophoron daubneyi) and nematodes (the ascarid Parascaris equorum and the strongylid Oesophagostomum spp.), as well as their secretory products, were placed onto corn meal agar plates concurrently inoculated with A. flagrans. Trapping organs were observed after 5 d and chlamydospores after 16 d, including in the control plates in the absence of parasitic stimulus. However, our data shows that both nematodes and trematodes increase trap and chlamydospore production compared with controls. We show for the first time that significantly higher numbers of traps and chlamydospores were observed in the cultures coinoculated with adult trematodes. We conclude that both the traps and chlamydospores formation are not only related to nematode-specific stimuli. The addition of secretory products of the trematode C. daubneyi to culture medium has potential for use in the large scale production of chlamydospores. PMID- 23931120 TI - Analysis of microsatellite markers in the genome of the plant pathogen Ceratocystis fimbriata. AB - Ceratocystis fimbriata sensu lato represents a complex of cryptic and commonly plant pathogenic species that are morphologically similar. Species in this complex have been described using morphological characteristics, intersterility tests and phylogenetics. Microsatellite markers have been useful to study the population structure and origin of some species in the complex. In this study we sequenced the genome of C. fimbriata. This provided an opportunity to mine the genome for microsatellites, to develop new microsatellite markers, and map previously developed markers onto the genome. Over 6000 microsatellites were identified in the genome and their abundance and distribution was determined. Ceratocystis fimbriata has a medium level of microsatellite density and slightly smaller genome when compared with other fungi for which similar microsatellite analyses have been performed. This is the first report of a microsatellite analysis conducted on a genome sequence of a fungal species in the order Microascales. Forty-seven microsatellite markers have been published for population genetic studies, of which 35 could be mapped onto the C. fimbriata genome sequence. We developed an additional ten microsatellite markers within putative genes to differentiate between species in the C. fimbriata s.l. complex. These markers were used to distinguish between 12 species in the complex. PMID- 23931121 TI - Agrobacterium-mediated transformation of Guignardia citricarpa: an efficient tool to gene transfer and random mutagenesis. AB - Guignardia citricarpa is the causal agent of Citrus Black Spot (CBS), an important disease in Citriculture. Due to the expressive value of this activity worldwide, especially in Brazil, understanding more about the functioning of this fungus is of utmost relevance, making possible the elucidation of its infection mechanisms, and providing tools to control CBS. This work describes for the first time an efficient and successful methodology for genetic transformation of G. citricarpa mycelia, which generated transformants expressing the gene encoding for the gfp (green fluorescent protein) and also their interaction with citrus plant. Mycelia of G. citricarpa were transformed via Agrobacterium tumefaciens, which carried the plasmid pFAT-gfp, contains the genes for hygromycin resistance (hph) as well as gfp. The optimization of the agrotransformation protocol was performed testing different conditions (type of membrane; inductor agent concentration [acetosyringone - AS] and cocultivation time). Results demonstrated that the best condition occurred with the utilization of cellulose's ester membrane; 200 MUM of AS and 96 h as cocultivation time. High mitotic stability (82 %) was displayed by transformants using Polymerase Chain Reaction (PCR) technique to confirm the hph gene insertion. In addition, the presence of gfp was observed inside mycelia by epifluorescence optical microscopy. This technique easy visualization of the behaviour of the pathogen interacting with the plant for the first time, allowing future studies on the pathogenesis of this fungus. The establishment of a transformation method for G. citricarpa opens a range of possibilities and facilitates the study of insertional mutagenesis and genetic knockouts, in order to identify the most important genes involved in the pathogenesis mechanisms and plant-pathogen interaction. PMID- 23931122 TI - Physiologic response of Agaricus subrufescens using different casing materials and practices applied in the cultivation of Agaricus bisporus. AB - Casing materials and practices used in the cultivation of Agaricus bisporus were evaluated in the cultivation of Agaricus subrufescens, using the best techniques for optimization of production, including the possibility of re-casing of the compost for the production of a second crop of mushroom. Casing based on peat moss, loam soil or coir was compared to casing material mixed with or without spawn-run compost. Based on the results, we conclude that the casing layer used in the cultivation of A. subrufescens should not necessarily be the same as that used in the cultivation of A. bisporus. For the tested strain cultivated with loam soil as casing layer, the ruffling technique is highly superior to CACing and should be pursued in further research. The re-casing of compost in new cycles showed good results suggesting that the currently used compost could be improved. PMID- 23931123 TI - Smooth perfluorinated surfaces with different chemical and physical natures: their unusual dynamic dewetting behavior toward polar and nonpolar liquids. AB - The effects of surface chemistry and the mobility of surface-tethered functional groups of various perfluorinated surfaces on their dewetting behavior toward polar (water) and nonpolar (n-hexadecane, n-dodecane, and n-decane) liquids were investigated. In this study, three types of common smooth perfluorinated surfaces, that is, a perfluoroalkylsilane (heptadecafluoro-1,1,2,2 tetrahydrooctyl-dimethylchlorosilane, FAS17) monomeric layer, an amorphous fluoropolymer film (Teflon AF 1600), and a perfluorinated polyether (PFPE) terminated polymer brush film (Optool DSX), were prepared and their static/dynamic dewetting characteristics were compared. Although the apparent static contact angles (CAs) of these surfaces with all probe liquids were almost identical to each other, the ease of movement of liquid drops critically depended on the physical (solidlike or liquidlike) natures of the substrate surface. CA hysteresis and substrate tilt angles (TAs) of all probe liquids on the Optool DSX surface were found to be much lower than those of Teflon AF1600 and FAS17 surfaces due to its physical polymer chain mobility at room temperature and the resulting liquidlike nature. Only 6.0 degrees of substrate incline was required to initiate movement for a small drop (5 MUL) of n-decane, which was comparable to the reported substrate TA value (5.3 degrees ) for a superoleophobic surface (theta(S) > 160 degrees , textured perfluorinated surface). Such unusual dynamic dewetting behavior of the Optool DSX surface was also markedly enhanced due to the significant increase in the chain mobility of PFPE by moderate heating (70 degrees C) of the surface, with substrate TA reducing to 3.0 degrees . CA hysteresis and substrate TAs rather than static CAs were therefore determined to be of greater consequence for the estimation of the actual dynamic dewetting behavior of alkane probe liquids on these smooth perfluorinated surfaces. Their dynamic dewettability toward alkane liquids is in the order of Optool DSX >> Teflon AF1600 ~ FAS17. PMID- 23931124 TI - Lectin interactions on surface-grafted glycostructures: influence of the spatial distribution of carbohydrates on the binding kinetics and rupture forces. AB - We performed quantitative analysis of the binding kinetics and affinity of carbohydrate-lectin binding and correlated them directly with the molecular and structural features of ligands presented at the nanoscale within the glycocalyx mimicking layers on surfaces. The surface plasmon resonance analysis identified that the mode of binding changed from multivalent to monovalent, which resulted in a near 1000-fold change in the equilibrium association constant, by varying the spatial distribution of carbohydrate ligands within the surface-grafted polymer layer. We identified, for the first time, that the manner in which the ligands presented on the surface has great influence on the binding at the first stage of bivalent chelating, not on the binding at the second stage. The rupture forces measured by atomic force microscope force spectroscopy also indicated that the mode of binding between lectin and ligands changed from multiple to single with variation in the ligand presentation. The dependence of lectin binding on the glycopolymer composition and grafting density is directly correlated with the nanoscale presentation of ligands on a surface, which is a determining factor in controlling the clustering and statistical effects contributing to the enhanced binding. PMID- 23931125 TI - Comparison of three algorithms for initiation and titration of insulin glargine in insulin-naive patients with type 2 diabetes mellitus. AB - BACKGROUND: Several titration algorithms can be used to adjust insulin dose and attain blood glucose targets. We compared clinical outcomes using three initiation and titration algorithms for insulin glargine in insulin-naive patients with type 2 diabetes mellitus (T2DM); focusing on those receiving both metformin and sulfonylurea (SU) at baseline. METHODS: This was a pooled analysis of patient-level data from prospective, randomized, controlled 24-week trials. Patients received algorithm 1 (1 IU increase once daily, if fasting plasma glucose [FPG] > target), algorithm 2 (2 IU increase every 3 days, if FPG > target), or algorithm 3 (treat-to-target, generally 2-8 IU increase weekly based on 2-day mean FPG levels). Glycemic control, insulin dose, and hypoglycemic events were compared between algorithms. RESULTS: Overall, 1380 patients were included. In patients receiving metformin and SU at baseline, there were no significant differences in glycemic control between algorithms. Weight-adjusted dose was higher for algorithm 2 vs algorithms 1 and 3 (P = 0.0037 and P < 0.0001, respectively), though results were not significantly different when adjusted for reductions in HbA1c (0.36 IU/kg, 0.43 IU/kg, and 0.31 IU/kg for algorithms 1, 2, and 3, respectively). Yearly hypoglycemic event rates (confirmed blood glucose <56 mg/dL) were higher for algorithm 3 than algorithms 1 (P = 0.0003) and 2 (P < 0.0001). CONCLUSIONS: Three algorithms for initiation and titration of insulin glargine in patients with T2DM resulted in similar levels of glycemic control, with lower rates of hypoglycemia for patients treated using simpler algorithms 1 and 2. PMID- 23931127 TI - Regular dental checkup and snack-soda drink consumption of preschool children are associated with early childhood caries in Korean caregiver/preschool children dyads. AB - OBJECTIVES: Early childhood caries (ECC) is a common oral disease among young Korean children. The purpose of this study was to examine the relationship of ECC with preschool children's oral health behavior and caregivers' oral health in Ulsan, Korea. METHODS: In 2006, cross-sectional survey of 1214 children under 6 years old and their care givers were surveyed. Two dentists examined according to the WHO criteria. Outcome variable was ECC, and explanatory variables were preschool children's oral health behavior and caregivers' oral health. The chi square test and multiple log-binomial regression models were performed. RESULTS: The prevalence of simple ECC was 47.5% and that of severe ECC was 34.8%. In bivariate analysis, ECC prevalence was increased according to children's age, caregiver's age, and type of housing. In multiple log-binomial regression models, preschool children's irregular oral checkup [prevalence ratio (PR): 1.7 for simple ECC and 1.8 for severe ECC] and frequent snack and soda drinking (PR: 1.2 for simple ECC, and 1.6 for severe ECC) were significant factors. CONCLUSIONS: This study demonstrates that the prevalence of ECC was high among Korean children. Early intervention programs for preschool children's oral health behavior should be developed based on the risk factors identified in this study. PMID- 23931126 TI - High HIV prevalence among low-income, Black women in New York City with self reported HIV negative and unknown status. AB - BACKGROUND: Black women are disproportionally affected by human immunodeficiency virus (HIV). This study investigates factors associated with newly identified HIV infection among previously self-reported HIV negative or unknown status black women living in high risk areas (HRAs) of New York City (NYC). METHODS: Heterosexuals residing in or socially connected to NYC HRAs were recruited using respondent driven sampling for participation in the United States Centers for Disease Control-sponsored National HIV Behavioral Surveillance System in 2010. Eligible individuals were interviewed and offered an HIV test. The analysis reported here focused on black women with valid HIV results who did not report being HIV positive, and examined factors related to HIV infection in this group. RESULTS: Of 153 black women who did not report being HIV positive at enrollment, 15 (9.8%) tested HIV positive. Age >=40 years, ever injected drugs, and in the last 12 months had unprotected vaginal sex, exchange sex, last sex partner used crack, non-injection crack use, and non-injection heroin use were significantly associated with HIV infection (p<0.05). Only ever injected drugs (prevalence ratio: 5.1; 95% confidence interval: 2.0, 12.9) was retained in the final model. CONCLUSIONS: Black women who had reported being either HIV negative or unaware of their serostatus had high HIV prevalence. Efforts to identify and treat HIV positive black women in HRAs should target those with a history of injection drug use. Frequent testing for HIV should be promoted in HRAs. PMID- 23931128 TI - A comparative scanning electron microscopy evaluation of smear layer removal from teeth with different irrigation solutions and lasers. AB - The aim of this study was to evaluate the efficacy of smear layer removal from teeth following root canals using lasers (Er:YAG and Nd:YAG), NaOCl, 17% EDTA, and MTAD by scanning electron microscopy (SEM). Root canals were irrigated with 3 mL of 5.25% NaOCl after each file. Teeth were randomly divided into five groups. In the final irrigation, canals were irrigated with 5.25% NaOCl (Group 1, control), 17% EDTA (Group 2), or BioPure MTAD (Group 3). Laser groups were irradiated with Er:YAG laser (1.8 W, 120 mJ, 15 Hz) (Group 4) or Nd:YAG laser (1 W, 100 mJ, 15 Hz) (Group 5). The smear layer at the apical, middle, and coronal thirds of each root canal was imaged using SEM. Smear layer removal by EDTA was the most effective in all regions. The difference between EDTA and MTAD was statistically significant in the coronal and middle (p < 0.05), but not the apical (p > 0.05), regions. The difference between the control and laser groups was not statistically significant (p > 0.05). In all regions, the difference between 17% EDTA-MTAD and the control-laser groups was statistically significant (p < 0.05). Although improvement was observed in removal of the smear layer using alternative materials and techniques, application of a combination of EDTA and NaOCl remains an effective technique. PMID- 23931129 TI - Pinhole mitral stenosis. PMID- 23931132 TI - M(12)L(24) spheres with endo and exo coordination sites: scaffolds for non covalent functionalization. AB - M12L24 spherical complexes incorporating 24 free pyridine rings on their interior or exterior surfaces were synthesized via the self-assembly of tridentate tris(pyridine) ligands with Pd(2+) ions. Coordination of secondary metal ions in the interior of the spherical framework was achieved through interactions of 24 Ag(+) ions with the free endo pyridine rings. PMID- 23931133 TI - An introduction to occupational science, a foundation for occupational therapy in the 21st century. AB - Occupational science is an emerging basic science which supports the practice of occupational therapy. Its roots in the rich traditions of occupational therapy are explored and its current configuration is introduced. Specifications which the science needs to meet as it is further developed and refined are presented. Compatible disciplines and research approaches are identified. example's of basic science research questions and their potential contributions to occupational therapy practice are suggested. PMID- 23931131 TI - Carotenoids are more bioavailable from papaya than from tomato and carrot in humans: a randomised cross-over study. AB - Carrot, tomato and papaya represent important dietary sources of beta-carotene and lycopene. The main objective of the present study was to compare the bioavailability of carotenoids from these food sources in healthy human subjects. A total of sixteen participants were recruited for a randomised cross-over study. Test meals containing raw carrots, tomatoes and papayas were adjusted to deliver an equal amount of beta-carotene and lycopene. For the evaluation of bioavailability, TAG-rich lipoprotein (TRL) fractions containing newly absorbed carotenoids were analysed over 9.5 h after test meal consumption. The bioavailability of beta-carotene from papayas was approximately three times higher than that from carrots and tomatoes, whereas differences in the bioavailability of beta-carotene from carrots and tomatoes were insignificant. Retinyl esters appeared in the TRL fractions at a significantly higher concentration after the consumption of the papaya test meal. Similarly, lycopene was approximately 2.6 times more bioavailable from papayas than from tomatoes. Furthermore, the bioavailability of beta-cryptoxanthin from papayas was shown to be 2.9 and 2.3 times higher than that of the other papaya carotenoids beta carotene and lycopene, respectively. The morphology of chromoplasts and the physical deposition form of carotenoids were hypothesised to play a major role in the differences observed in the bioavailability of carotenoids from the foods investigated. Particularly, the liquid-crystalline deposition of beta-carotene and the storage of lycopene in very small crystalloids in papayas were found to be associated with their high bioavailability. In conclusion, papaya was shown to provide highly bioavailable beta-carotene, beta-cryptoxanthin and lycopene and may represent a readily available dietary source of provitamin A for reducing the incidence of vitamin A deficiencies in many subtropical and tropical developing countries. PMID- 23931134 TI - From the editor. AB - No abstract available for this article. PMID- 23931135 TI - From the guest editor. AB - No abstract available for this article. PMID- 23931136 TI - Foward. AB - No abstract available for this article. PMID- 23931137 TI - Protein complexes: breaking up is hard to do well. AB - Mass spectrometry of protein assemblies reveals size and stoichiometry. In this issue of Structure, Hall and colleagues demonstrate that gas-phase dissociations can recapitulate solution structure for complexes with few intersubunit salt bridges, high charge density, inflexible subunits, or small intersubunit interfaces. PMID- 23931138 TI - Cystovirus maturation at atomic resolution. AB - Cystoviruses are dsRNA viruses that infect bacteria and include bacteriophages Phi8 and Phi6. In this issue of Structure, El Omari and colleagues and Nemecek and colleagues report crystal structures of capsid protein P1 pentamers found in procapsid cores of Phi8 and Phi6. The two structures show a striking resemblance in the absence of sequence similarity and offer new mechanistic and evolutionary insights. PMID- 23931139 TI - TGF-beta antagonists: same knot, but different hold. AB - In this issue of Structure, Nolan and colleagues present the structure of BMP antagonist, PRDC, which adopts a head-to-tail dimer with distinct structure and inhibitory mechanism compared to other dimeric antagonists of the TGF-beta superfamily, such as noggin. PMID- 23931140 TI - Gating of pentameric ligand-gated ion channels: structural insights and ambiguities. AB - Pentameric ligand-gated ion channels (pLGICs) mediate fast synaptic communication by converting chemical signals into an electrical response. Recently solved agonist-bound and agonist-free structures greatly extend our understanding of these complex molecular machines. A key challenge to a full description of function, however, is the ability to unequivocally relate determined structures to the canonical resting, open, and desensitized states. Here, we review current understanding of pLGIC structure, with a focus on the conformational changes underlying channel gating. We compare available structural information and review the evidence supporting the assignment of each structure to a particular conformational state. We discuss multiple factors that may complicate the interpretation of crystal structures, highlighting the potential influence of lipids and detergents. We contend that further advances in the structural biology of pLGICs will require deeper insight into the nature of pLGIC-lipid interactions. PMID- 23931141 TI - Structural biology of Arf and Rab GTPases' effector recruitment and specificity. AB - Arf and Rab proteins, members of small GTPases superfamily, localize to specific subcellular compartments and regulate intracellular trafficking. To carry out their cellular functions, Arfs/Rabs interact with numerous and structurally diverse effector proteins. Over the years, a number of Arf/Rab:effector complexes have been crystallized and their structures reveal shared binding modes including alpha-helical packing, beta-beta complementation, and heterotetrameric assemblies. We review available structural information and provide a framework for in-depth analysis of complexes. The unifying features that we identify are organized into a classification scheme for different modes of Arf/Rab:effector interactions, which includes "all-alpha-helical," "mixed alpha-helical," "beta beta zipping," and "bivalent" modes of binding. Additionally, we highlight structural determinants that are the basis of effector specificity. We conclude by expanding on functional implications that are emerging from available structural information under our proposed classification scheme. PMID- 23931142 TI - PRIME: probabilistic initial 3D model generation for single-particle cryo electron microscopy. AB - Low-dose electron microscopy of cryo-preserved individual biomolecules (single particle cryo-EM) is a powerful tool for obtaining information about the structure and dynamics of large macromolecular assemblies. Acquiring images with low dose reduces radiation damage, preserves atomic structural details, but results in low signal-to-noise ratio of the individual images. The projection directions of the two-dimensional images are random and unknown. The grand challenge is to achieve the precise three-dimensional (3D) alignment of many (tens of thousands to millions) noisy projection images, which may then be combined to obtain a faithful 3D map. An accurate initial 3D model is critical for obtaining the precise 3D alignment required for high-resolution (<10 A) map reconstruction. We report a method (PRIME) that, in a single step and without prior structural knowledge, can generate an accurate initial 3D map directly from the noisy images. PMID- 23931143 TI - A record number of fatalities in many categories of patients treated with deferasirox: loopholes in regulatory and marketing procedures undermine patient safety and misguide public funds? PMID- 23931144 TI - Model-based integration and analysis of biogeochemical and isotopic dynamics in a nitrate-polluted pyritic aquifer. AB - Leaching of nitrate from agricultural land to groundwater and the resulting nitrate pollution are a major environmental problem worldwide. Its impact is often mitigated in aquifers hosting sufficiently reactive reductants that can promote autotrophic denitrification. In the case of pyrite acting as reductant, however, denitrification is associated with the release of sulfate and often also with the mobilization of trace metals (e.g., arsenic). In this study, reactive transport modeling was used to reconstruct, quantify and analyze the dynamics of the dominant biogeochemical processes in a nitrate-polluted pyrite-containing aquifer and its evolution over the last 50 years in response to changing agricultural practices. Model simulations were constrained by measured concentration depth profiles. Measured (3)H/(3)He profiles were used to support the calibration of flow and conservative transport processes, while the comparison of simulated and measured sulfur isotope signatures acted as additional calibration constraint for the reactive processes affecting sulfur cycling. The model illustrates that denitrification largely prevented an elevated discharge of nitrate to surface waters, while sulfate discharges were significantly increased, peaking around 15 years after the maximum nitrogen inputs. PMID- 23931145 TI - Neighbor effect in complexation of a conjugated polymer. AB - Charge-transfer complex (CTC) formation between a conjugated polymer and low molecular-weight organic acceptor is proposed to be driven by the neighbor effect. Formation of a CTC on the polymer chain results in an increased probability of new CTC formation near the existing one. We present an analytical model for CTC distribution considering the neighbor effect, based on the principles of statistical mechanics. This model explains the experimentally observed threshold-like dependence of the CTC concentration on the acceptor content in a polymer:acceptor blend. It also allows us to evaluate binding energies of the complexes. PMID- 23931146 TI - Reduction of hepatitis A virus on FRhK-4 cells treated with Korean red ginseng extract and ginsenosides. AB - Red ginseng has a variety of bioactive functions and is widely used as an oriental medicinal herb and food ingredient. The aim of this study was to investigate the antiviral effect of red ginseng extract and ginsenosides against hepatitis A virus (HAV). To examine the antiviral effect against HAV, 0 to 10 MUg/mL of red ginseng and purified ginsenoside Rb1 and Rg1 were pre-treated or co treated on FRhK-4 cells. The HAV titer decreased significantly in all groups pretreated with red ginseng or purified ginsenosides. The reduction of HAV was significant in FRhK-4 cells pre-treated only with red ginseng. Our results showed that red ginseng and ginsenoside Rg1 and Rb1 could decrease HAV titers. PMID- 23931147 TI - A "turn-on" fluorescent sensor for methylglyoxal. AB - Methylglyoxal (MGO), a dicarbonyl metabolite produced by all living cells, has been associated with a number of human diseases. However, studies of the role(s) MGO plays biologically have been handicapped by a lack of direct methods for its monitoring and detection. To address this limitation, we have developed a fluorescent sensor (methyl diaminobenzene-BODIPY, or "MBo") that can detect MGO under physiological conditions. We show that MBo is selective for MGO over other biologically relevant dicarbonyls and is suitable for detecting MGO in complex environments, including that of living cells. In addition, we demonstrate MBo's utility in estimating plasma concentrations of MGO. The results reported herein have the potential to advance both clinical and basic science research and practice. PMID- 23931149 TI - The evolution of contralateral control of the body by the brain: is it a protective mechanism? AB - Contralateral control, the arrangement whereby most of the human motor and sensory fibres cross the midline in order to provide control for contralateral portions of the body, presents a puzzle from an evolutionary perspective. What caused such a counterintuitive and complex arrangement to become dominant? In this paper we offer a new perspective on this question by showing that in a complex interactive control system there could be a significant net survival advantage with contralateral control, associated with the effect of injuries of intermediate severity. In such cases an advantage could arise from a combination of non-linear system response combined with correlations between injuries on the same side of the head and body. We show that a simple mathematical model of these ideas emulates such an advantage. Based on this model, we conclude that effects of this kind are a plausible driving force for the evolution of contralateral control. PMID- 23931150 TI - Dorsal onlay (Barbagli technique) versus dorsal inlay (Asopa technique) buccal mucosal graft urethroplasty for anterior urethral stricture: a prospective randomized study. AB - OBJECTIVE: To compare both the dorsal onlay technique of Barbagli and the dorsal inlay technique of Asopa for the management of long anterior urethral stricture. METHODS: From January 2010 to May 2012, a total of 47 patients with long anterior urethral strictures were randomized into two groups. The first group included 25 patients who were managed by dorsal onlay buccal mucosal graft urethroplasty. The second group included 22 patients who were managed by dorsal inlay buccal mucosal graft urethroplasty. Different clinical parameters, postoperative complications and success rates were compared between both groups. RESULTS: The overall success rate in the dorsal onlay group was 88%, whereas in the dorsal inlay group the success rate was 86.4% during the follow-up period. The mean operative time was significantly longer in the dorsal onlay urethroplasty group (205 +/- 19.63 min) than in the dorsal inlay urethroplasty group (128 +/- 4.9 min, P-value <0.0001). The average blood loss was significantly higher in the dorsal onlay urethroplasty group (228 +/- 5.32 mL) than in the dorsal inlay urethroplasty group (105 +/- 12.05 mL, P-value <0.0001). CONCLUSIONS: The dorsal onlay technique of Barbagli and the dorsal inlay technique of Asopa buccal mucosal graft urethroplasty provide similar success rates. The Asopa technique is easy to carry out, provides shorter operative time and less blood loss, and it is associated with fewer complications for anterior urethral stricture repair. PMID- 23931151 TI - Preparation of polymer/poly(ionic liquid) composite particles by seeded dispersion polymerization. AB - Seeded dispersion polymerization of the ionic-liquid monomer ([2 (methacryloyloxy)ethyl]trimethylammonium bis(trifluoromethanesulfonyl)amide) ([MTMA][TFSA]) was performed in ethanol by using either polystyrene (PS) or poly(methyl methacrylate) (PMMA) particles as seeds. In the presence of PS seed particles, secondary nucleated poly(ionic liquid) (PIL) particles were formed, and no PS/PIL composite particles were observed. In the case of PMMA seeds particles, the diameters of the obtained particles increased compared to those of PMMA seed particles (without formation of particles that were formed as byproducts), which indicates that the PMMA/PIL composite particles were successfully prepared. Transmission electron microscopy studies of ultrathin cross sections of the PMMA/PIL particles revealed that the obtained particles had a sea-island structure consisting of PIL domains. These results are consistent with the theoretical considerations based on the spreading coefficients calculated from the interfacial tensions. PMID- 23931152 TI - The Annexin A2/p11 complex is required for efficient invasion of Salmonella Typhimurium in epithelial cells. AB - The facultative intracellular pathogen, Salmonella enterica, triggers its own uptake into non-phagocytic epithelial cells. Invasion is dependent on a type 3 secretion system (T3SS), which delivers a cohort of effector proteins across the plasma membrane where they induce dynamic actin-driven ruffling of the membrane and ultimately, internalization of the bacteria into a modified phagosome. In eukaryotic cells, the calcium- and phospholipid-binding protein Annexin A2 (AnxA2) functions as a platform for actin remodelling in the vicinity of dynamic cellular membranes. AnxA2 is mostly found in a stable heterotetramer, with p11, which can interact with other proteins such as the giant phosphoprotein AHNAK. We show here that AnxA2, p11 and AHNAK are required for T3SS-mediated Salmonella invasion of cultured epithelial cells and that the T3SS effector SopB is required for recruitment of AnxA2 and AHNAK to Salmonella invasion sites. Altogether this work shows that, in addition to targeting Rho-family GTPases, Salmonella can intersect the host cell actin pathway via AnxA2. PMID- 23931154 TI - Gene silencing of chordin improves BMP-2 effects on osteogenic differentiation of human adipose tissue-derived stromal cells. AB - Although bone morphogenic protein (BMP)-2 is known to potently induce osteogenic differentiation of human mesenchymal stem cells, strong individual differences have been reported. In part, this is due to internal antagonists of BMP-2 for example, noggin and chordin, secreted by differentiating cells. This enabling study was performed to prove the hypothesis that osteogenic effects of BMP-2 can be improved by transient nonviral gene silencing of chordin. We investigated the effect of siRNA against chordin on osteogenic differentiation in human adipose tissue-derived stromal cells (hASC). Cells of two different donors were isolated after liposuction and proliferated for passage 4 or 5. On seeding, hASCs were transfected with siRNA using a commercial liposomal transfection reagent. Subsequently, cells were differentiated in the presence or absence of BMP-2 (100 ng/mL). Noncoding siRNA as well as siRNA against noggin served as a control. Osteogenic differentiation of hASC was determined by alkaline phosphase (ALP) activity and matrix mineralization. ALP activity of hASC treated with siRNA against chordin was increased for cells of both donors. In contrast, silencing of noggin had no effect in any of the donors. In combination with BMP-2, silencing of either chordin or noggin showed strongly improved ALP activity compared with the control group that was also supplemented with BMP-2. Mineralization was observed to start earlier in groups that received siRNA against chordin or noggin and showed increased amounts of incorporated calcium on day 15 compared with the control groups. Silencing chordin in hASCs was successful to increase BMP-2 effects on osteogenic differentiation in both donors, while effects of noggin silencing were reliably observed only in one of the two investigated donors. In contrast to noggin silencing, chordin silencing also increased osteogenic differentiation without supplemented BMP-2. PMID- 23931155 TI - Biomimetic synthesis of ent-(-)-azonazine and stereochemical reassignment of natural product. AB - The first total synthesis of ent-(-)-azonazine has been accomplished using a hypervalent iodine-mediated biomimetic oxidative cyclization to construct the highly strained core. Based on the results from the completed synthesis, both the relative and absolute configurations of natural (+)-azonazine were revised. PMID- 23931156 TI - Liver alterations in two freshwater fish species (Carassius auratus and Danio rerio) following exposure to different TiO2 nanoparticle concentrations. AB - The toxicity of titanium dioxide nanoparticles (TIO2 NPs) and oxidative stress effects were studied in two freshwater fish species (Carassius auratus and Danio rerio) exposed for 21 days to different concentrations (0.01, 0.1, 1, 10, 100/mgL) of TiO2 NPs and to a control (tap water). Additional fish were transferred to clean water for 14 days to assess the ability to recover from exposure to TiO2 NPs. Activities of the enzyme glutathione-S-transferase (GST) and lipid peroxidation (LPO) (malondialdheyde) were measured as indicators of oxidative stress. Histological and ultra-structural changes in livers from both species of fish were evaluated by light and electron microscopy. Results show a general GST activity increase according to TiO2 NPs concentrations, which is in agreement with data from LPO. After 21 days, GST activities decreased possibly caused by suppression of GST synthesis as a result of severe stress. Histological and ultra-structural analysis of livers from exposed fish show degeneration of the hepatic tissue and alterations in hepatocytes such as glycogen depletion and an increase in lipofucsin lysosome-like granules. After a depuration period a partial recovery for biochemical markers and cells was observed. The results suggest that TiO2 promotes alterations in hepatic tissues compatible with oxidative stress. PMID- 23931153 TI - Is screening for depression in the perinatal period enough? The co-occurrence of depression, substance abuse, and intimate partner violence in culturally diverse pregnant women. AB - BACKGROUND: The perinatal period provides unique opportunities to identify and intervene with the co-occurrence of perinatal depression, intimate partner violence (IPV), and substance use problems. Psychosocial screening recommended for women seen in maternal child health settings tends to target single rather than multiple risk factors; there is limited research examining the co-occurrence of these issues especially in racially and ethnically diverse women across the perinatal period. These analyses explore the relationships of sociodemographic, psychosocial, and behavioral characteristics in a large, diverse sample of women. METHOD: Women receiving perinatal services at routinely scheduled visits, including the 6-week postpartum visit, were recruited from 10 community obstetric/gynecologic clinics. Data were collected on perinatal depression, IPV, maternal substance use, and sociodemographic characteristics by bilingual, bicultural research assistants. RESULTS: A total of 1868 women were screened, 1526 (82%) Latina, 1099 (58.8%) interviewed in Spanish; 20.4% (n=382) screened positive for depressive symptoms based on an Edinburgh Postnatal Depression Scale score of 10 or above, 20.9% reported harmful drinking, 4.3% reported drug use, 23% reported substance use problems, and 3.5% reported current or recent IPV. Women who were Black, Asian, Pacific Islander, or other race/ethnicity had greater odds for depressive symptoms relative to women who were Hispanic or Latino (odds ratio [OR]=1.81, p=0.005). Women reporting substance use problems (OR=2.37, p<0.0001) and IPV (OR=3.98, p<0.0001) had higher odds for depressive symptoms. CONCLUSION: In a predominately Latina sample, 1 in 5 mothers (20.4%) screened positive for depressive symptoms and over one third (36.7%) reported one or more psychosocial issues during the perinatal period. Screening for multiple risk factors rather than just one can help clinicians tailor interventions for the successful management of psychosocial issues. PMID- 23931157 TI - Indicaxanthin inhibits NADPH oxidase (NOX)-1 activation and NF-kappaB-dependent release of inflammatory mediators and prevents the increase of epithelial permeability in IL-1beta-exposed Caco-2 cells. AB - Dietary redox-active/antioxidant phytochemicals may help control or mitigate the inflammatory response in chronic inflammatory bowel disease (IBD). In the present study, the anti-inflammatory activity of indicaxanthin (Ind), a pigment from the edible fruit of cactus pear (Opuntia ficus-indica, L.), was shown in an IBD model consisting of a human intestinal epithelial cell line (Caco-2 cells) stimulated by IL-1beta, a cytokine known to play a major role in the initiation and amplification of inflammatory activity in IBD. The exposure of Caco-2 cells to IL 1beta brought about the activation of NADPH oxidase (NOX-1) and the generation of reactive oxygen species (ROS) to activate intracellular signalling leading to the activation of NF-kappaB, with the over-expression of inflammatory enzymes and release of pro-inflammatory mediators. The co-incubation of the cells with Ind, at a nutritionally relevant concentration (5-25 MUM), and IL-1beta prevented the release of the pro-inflammatory cytokines IL-6 and IL-8, PGE2 and NO, the formation of ROS and the loss of thiols in a dose-dependent manner. The co incubation of the cells with Ind and IL-1beta also prevented the IL-1beta-induced increase of epithelial permeability. It was also shown that the activation of NOX 1 and NF-kappaB was prevented by Ind and the expression of COX-2 and inducible NO synthase was reduced. The uptake of Ind in Caco-2 cell monolayers appeared to be unaffected by the inflamed state of the cells. In conclusion, our findings suggest that the dietary pigment Ind may have the potential to modulate inflammatory processes at the intestinal level. PMID- 23931158 TI - Robust, efficient, and practical electrogene transfer method for human mesenchymal stem cells using square electric pulses. AB - Mesenchymal stem cells (MSCs) are multipotent nonhematopoietic cells with the ability to differentiate into various specific cell types, thus holding great promise for regenerative medicine. Early clinical trials have proven that MSC based therapy is safe, with possible efficacy in various diseased states. Moreover, genetic modification of MSCs to improve their function can be safely achieved using electrogene transfer. We previously achieved transfection efficiencies of up to 32% with preserved viability in rat MSCs. In this study, we further improved the transfection efficiency and transgene expression in human MSCs (hMSCs), while preserving the cells viability and ability to differentiate into osteoblasts and adipocytes by increasing the plasmid concentration and altering the osmotic pressure of the electrotransfer buffer. Using a square-wave electric pulse generator, we achieved a transfection efficiency of more than 80%, with around 70% viability and a detectable transgene expression of up to 30 days. Moreover, we demonstrated that this transfection efficiency can be reproduced reliably on two different sources of hMSCs: the bone marrow and adipose tissue. We also showed that there was no significant donor variability in terms of their transfection efficiency and viability. The cell confluency before electrotransfer had no significant effect on the transfection efficiency and viability. Cryopreservation of transfected cells maintained their transgene expression and viability upon thawing. In summary, we are reporting a robust, safe, and efficient protocol of electrotransfer for hMSCs with several practical suggestions for an optimal use of genetically engineered hMSCs for clinical application. PMID- 23931159 TI - Toxic shock syndrome and persistent immune activation in an HIV-positive patient. AB - The case of an HIV-positive treatment-naive male with toxic shock syndrome (TSS) is presented herein. The course of TSS was favorable; however, the patient had extremely high plasma levels of MCP-1 and CD38 and HLA-DR expression on CD8+ T cells during the acute illness. Furthermore, the numbers of CD8+ T cells were reduced and CD4+ T cells remained stable during acute illness in comparison to baseline values. MCP-1 and HLA-DR gradually decreased, but they were still elevated after a month, whereas the number of circulating CD8+ T cells increased more than fivefold. CD38 expression remained stable during this period. A further decrease in CD38, HLA-DR and MCP-1 was noted five months after the initiation of antiretroviral therapy. PMID- 23931160 TI - A digital signal processing-based bioinformatics approach to identifying the origins of HIV-1 non B subtypes infecting US Army personnel serving abroad. AB - Two HIV-1 non B isolates, 98US_MSC5007 and 98US_MSC5016, which have been identified amongst the US Army personnel serving abroad, are known to have originated from other nations. Notwithstanding, they are categorized as American strains. This is because their countries of origin are unknown. American isolates are basically B subtype. 98US_MSC5007 belongs to Circulating Recombinant Form (CRF02_AG) while 98US_MSC5016 is of the C clade. Both sub-groups are recognized to have originated from African and Asian continents. It has become necessary to properly determine the countries of origin of microbes and viruses. This is because diversity and cross-subtyping have been found to mitigate the designing and development of vaccine and therapeutic interventions. The aim of this study therefore is to identify the countries of origin of the two American isolates found amongst US Army personnel serving abroad. A Digital Signal Processing-based Bioinformatics technique called Informational Spectrum Method (ISM) has been engaged. ISM entails translating the amino acids sequences of the protein into numerical sequences (signals) by means of one biological parameter (Amino Acids Scale). The signals are then processed using Discrete Fourier Transform (DFT) in order to uncover and present the embedded biological information as Informational Spectra (IS). Spectral Position of Maximum Binding Interaction (SPMBI) is used. Several approaches including Phylogeny have preliminarily been employed in the determination of evolutionary trends of organisms and viruses. SPMBI has preliminarily been used to re-establish the semblance and common originality that exist between human and Chimpanzee, evolutionary roadmaps in the Influenza and HIV viruses. The results disclosed that 98US_MSC5007 shared same semblance and originality with a Nigeria isolate (92NG083) while 98US_MSC5016 with the Zairian isolates (ELI, MAL, and Z2/CDC-34). These results appear to demonstrate that the American soldiers harboring these strains may have been infected by isolates from Nigeria and Zaire, respectively. This is because 98US_MSC5007 and the Nigerian isolate share SPMBI at position 44. Additionally, 98US_MSC5016, which has SPMBI at position 148, may have come from Zaire as it has similar SPMBI with the Zairian isolates at 150. SPMBI is a demonstration of Bio-functionality arising from maximum affinity by the proteins from different sources to a common protein. To help validate the findings, the experiment was further repeated using ISM based Phylogenetic technique. The outcome appears not to be in complete accord with the results obtained in this study. It is therefore recommended that the countries in which these US Army personnel are deployed be identified and where the findings made and the locations of the Army personnel appropriately correlate, this novel procedure be engaged in the identification of the nations of origins of all other such HIV isolates across all clades and nations. PMID- 23931162 TI - Vascular endothelial growth factor inhibitors and cognitive impairment: evidence and controversies. AB - INTRODUCTION: Chemotherapy-induced cognitive impairment, or 'chemobrain,' has been well established in the literature. However, neurocognitive toxic effect induced by targeted therapies such as anti-angiogenic agents is poorly investigated. Recently, emerging evidence suggests vascular endothelial growth factor (VEGF) to have a possible role in brain cognition giving rise to concerns whether VEGF inhibitors (VEGFIs) may induce neurotoxic effect on cancer patients' cognitive function. AREAS COVERED: The aim of this review was to evaluate the plausible mechanisms underlying VEGF and cognition, and to highlight the evidence and controversies surrounding the cognitive issues associated with the use of VEGFIs. EXPERT OPINION: This review paper has brought attention to the potential cognitive issues associated with the use of VEGFIs and has added a new, unexplored dimension to the problem of cancer treatment-related cognitive changes. However, the lack of evidence warrants the need for more well-designed studies to quantify the prevalence and severity of VEGFI-induced cognitive impairment in the cancer population, and to establish the role of VEGF in human cognitive function. PMID- 23931163 TI - Editorial. AB - No abstract available for this article. PMID- 23931161 TI - Cell-wall remodeling by the zinc-protease AmpDh3 from Pseudomonas aeruginosa. AB - Bacterial cell wall is a polymer of considerable complexity that is in constant equilibrium between synthesis and recycling. AmpDh3 is a periplasmic zinc protease of Pseudomonas aeruginosa , which is intimately involved in cell-wall remodeling. We document the hydrolytic reactions that this enzyme performs on the cell wall. The process removes the peptide stems from the peptidoglycan, the major constituent of the cell wall. We document that the majority of the reactions of this enzyme takes place on the polymeric insoluble portion of the cell wall, as opposed to the fraction that is released from it. We show that AmpDh3 is tetrameric both in crystals and in solution. Based on the X-ray structures of the enzyme in complex with two synthetic cell-wall-based ligands, we present for the first time a model for a multivalent anchoring of AmpDh3 onto the cell wall, which lends itself to its processive remodeling. PMID- 23931165 TI - Foward. AB - No abstract available for this article. PMID- 23931164 TI - Preface. AB - No abstract available for this article. PMID- 23931166 TI - Personal perspectives. AB - This article focuses on the personal stories, in their own words, of those affected by the human immunodeficiency virus (HIV). HIV does not discriminate, as is noted by the diversity of these personal perspectives. The authors hope that the reader will understand the many complex and varied issues that need to be addressed on an individual basis in assessment and treatment of people with HIV. There are no stereotypes of people with HIV. There are only human beings requiring dignified and respectful care and support. PMID- 23931167 TI - AIDS. AB - This chapter gives a concise overview of the Acquired Immunodeficiency Syndrome (AIDS), with special emphasis on clinical aspects relevant to rehabilitation professionals. AIDS is a novel form of an acquired immune deficit now known to be caused by the recently recognized Human Immunodeficiency Virus (HIV). Symptoms result from the direct effects of the virus on the immune system and the nervous system, which appear to be the primary targets. Much of the morbidity and mortality, however, is caused by opportunistic infections which occur in patients unable to mobilize the appropriate immune defenses against them. Characteristic, but previously rare, neoplasms also occur due to a failure of immune regulation. Improved medical care, however, has changed AIDS from a rapidly fatal disease to one where survival may be prolonged. The rehabilitation setting, the physical disability caused by AIDS, along with the psychosocial and economic impact of the disease on the patient have become increasingly important. Fatigue, decreased endurance, weight loss, edema, blindness and swallowing difficulties may all contribute to functional impairment. Neurological involvement is frequent and may cause dementia, hemiplegia, spastic paraparesis, painful neuropathies and proximal or distal muscle weakness. The clinical features and functional impact of these symptoms on the patient with AIDS is discussed, and the appropriate rehabilitation interventions outlined. Psychosocial and vocational issues are addressed as they pertain to the different clinical presentations. PMID- 23931168 TI - Transformed of HIV Infection and AIDS in Occupational Therapy. AB - HIV infection and AIDS can be transformed through an attitude change and a change in thinking about levels of productivity and function of people diagnosed with HIV. This change in thinking demands that people with HIV/AIDS are viewed as vital, functional, productive and contributing members of society and the world. This article focuses on transforming HIV/AIDS through an examination of personal and professional transformation. It is through personal and professional transformation that the transformation of HIV/AIDS will occur. New ways of thinking about HIV/ AIDS are explored. Present and future possibilities for therapeutic interventions are discussed. Transformation of HIV/AIDS will occur through empowerment of each other as human beings. PMID- 23931169 TI - Value and life goals. AB - This article will address the development of strategies and therapeutic interventions which may be used to help PWAs (people with AIDS) cope with the illness and assist them in the reevaluation of life goals and changes in values from those of the living to those of the dying. Clinical interventions designed to empower PWAs to take control of their lives and to play an active part In their medical care are outlined. PMID- 23931170 TI - Cultural considerations in the treatment of persons with AIDS. AB - The impact of AIDS has been most notable in three subpopulations in the United States: the gay community, intravenous drug abusers and minority groups, particularly Blacks and Hispanics. Little information is available on the cultural considerations which are relevant in the treatment of these individuals. This article describes basic principles of cross-cultural analysis, explores individual aspects of AIDS in these populations and discusses the implications for health care providers. PMID- 23931171 TI - AIDS. AB - Three primary spiritual aspects of HIV and AIDS are guilt, perceived experiential losses, and the search for meaning. The founding theoretical principles of occupational therapy, including moral treatment, are combined with spiritual components in this a per. The meaning of occupation and activities are discussed. emphasis is placed on hope and its effect on restoration of health in relation to the maximum functioning of the immune system. Occupational therapy combined with reaching spiritual well-being, which contributes to the quality of life, are seen as methods by which optimum health is achieved. PMID- 23931172 TI - Infants and Children with HIV Infection. AB - Infants and children with human immunodeficiency virus (HIV) infection are a rapidly growing population that can be viewed in the categoy of at risk. These children and their families require rehabilitation services to facilitate adaptive responses to HIV injection. This article addresses the clinical manifestations of HIV infection and normal growth and development. The impact of HIV on growth and development is presented through a description of clinical interventions that highlight basic clinical need areas of children with HIV and their families. A rehabilitation classification system is introduced as a means to identify rehabilitation needs of children with HIV. PMID- 23931173 TI - Occupational therapy. AB - Occupational therapists prevent dysfunction and maintain and restore function for people with HIV/AIDS in the areas of work, selfcare and play/leisure. These occupational areas are assessed and treated from psychosocial, physical and environmental perspectives. This article examines occupational therapy assessment and treatment for people with HIV/AIDS with the primary focus on adaptive equipment, energy conservation, habits and time management, and work. PMID- 23931174 TI - Psychosocial Issues of Children and Families with HIV/AIDS. AB - The complex psychosocial issues for families who have a child diagnosed with HIV infection present a series of unique challenges for all health care providers. All members of the interdiciplinary team must be knowledgeable about these factors in providing all aspects of care to the child within the context of the family unit. Fear and secrecy are at the core of all persons living with HIV and AIDS, and health care providers must respond with compassion, empathy and sensitivity. The issues that will be discussed address the multiple factors that most frequently impact on a family's ability to function following their child's diagnosis of HIV infection or clinical AlDS and through the bereavement process. Concerns related to school attendance and the use of community services will be highlighted. PMID- 23931175 TI - Women and AIDS. AB - This article examines the special issues which confront women with AIDS. The population of women with AIDS is described and differences in the course of the disease between women and men are briefly explored. The pyschosocial responses of women with AlDS are reviewed with respect to considerations of stigma, informational needs, economic impact, psychological responses and social supports. Lastly, the role of occupationa therapy is described as it relates to enablin and empowering women with AIDS to perform daily activities an role obligations and to achieve terminal occupational goals. PMID- 23931176 TI - Pain Management and Neuromuscular Reeducation for the HIV Patient. AB - As a multisystem chronic illness, two areas come to the forefront for management by the rehabilitation specialist. Pain and neuromuscular deficits may be a result of direct insult by the human immunodeficiency virus (HIV) or opportunistic infections affecting functional abilities. A brief overview of pathologic findings reveals that the types of pain experiences is based upon the disease processes that are occurring secondary to HIV. The management of pain and resultant functional changes depends on the source, symptoms and signs of pain. Physical and Occupational therapists are key health care professionals to conduct pain assessments and evaluate functional impairment to better employ non-invasive techniques for management of HIV complications. This article presents various modalities and modes of therapeutic intervention to enhance full participation of the person with HIV in activities of daily living. PMID- 23931177 TI - AIDS in a correctional setting. AB - This article will provide current, relevant information on human immuno deficiency virus (HIV) and Acquired Immune Deficiency Syndrome (AIDS) in the correctional setting. Issues pertinent to the correctional setting, as HIV testing and confidentiality, transmission of the HIV virus tn the correctional setting, and HIV related education will be explored. An occupational therapy program, outlining two separate programs for (1) those who are HIV positive and those who are diagnosed with AIDS and (2) those at risk for contracting the virus, will be described. PMID- 23931178 TI - St. Francis center. AB - The St. Francis Center in Washington, DC was founded in 1975 to provide support and guidance for individuals and organizations facing life-threatening illness and bereavement. The Center began seeing clients who were living with AIDS since 1983, and has expanded all of its services to include components specifically designed for people living with AIDS and organizations serving people with AIDS. This article describes the orgins of the Center and reveals how the organization grew to meet the challenges of AIDS. The Center can be seen as an organizational model for other pre-existing institutions. Brief case studies demonstrate the activities and techniques of the Center's counseling, training and volunteer support programs as they help people with AIDS, their families and service organizations. PMID- 23931180 TI - Gay grief. AB - This article is intended to provide an overview of the special needs for individuals who are gay and bereaved. Also included is a personal account from a lover whose partner died of AIDS. The intent of this article is to increase the level of understanding and sensitivity of practitioners who will be assisting persons affected by Human Immunodeficiency Virus (HIV). PMID- 23931179 TI - Adult day care for people with human immunodeficiency virus. AB - The human immunodeficiency virus (HIV) adult day care ADC) center is an important component in the continuum of care for the HIV ill client, providing therapeutic advantages to the client and administrative advantages to the community as it copes with the growing HIV epidemic. The HIV ADC center was designed using several models of adult day programs for developmental, psychosocial, geriatric and neuropsychiatric treatment. The HIV ADC client is typically in a non-acute phase of a chronic disability resulting from some combination of primary HIV pathology and secondary illnesses associated with the Acquired Immune Deficiency Syndrome (AIDS) and is in need of some level of rehabilitation. The HIV ADC client is. typicall a gay or bisexual male, a man or woman who is or has been adbicted to intravenously injected drugs, or the sexual partner of someone in these groups. Programming addresses the psychosocial needs and daily reallties of these populations. This article describes occupational therapy intervention focused on maintaining, restoring, or adapting functional skills, with special attention to the daily activities most affected by cognitive/ perceptual dysfunction. PMID- 23931181 TI - Resources. AB - No abstract available for this article. PMID- 23931182 TI - Volumetric study of the mixtures n-hexane + isomeric chlorobutane: experimental characterization and volume translated Peng-Robinson predictions. AB - The prhoTx behavior of the binary mixtures n-hexane + isomeric chlorobutane has been studied over the whole composition range at temperatures between 283.15 and 323.15 K and pressures from 0.1 to 65.0 MPa. Experimental densities have been used to obtain different excess properties: excess molar volume, excess isobaric expansibility, excess isothermal compressibility, and excess internal pressure. These excess properties have been analyzed in terms of molecular interactions and structural effects. Finally, experimental densities of the binary mixtures have been compared with the predictions of the volume translated Peng-Robinson (VTPR) model. The overall average deviation between experimental and calculated densities is 0.00427 g.cm(-3), which can be considered reasonably good predictions. PMID- 23931183 TI - Multiredox active [3 * 3] copper grids. AB - A nonanuclear copper grid complex, [Cu(II)9(L)6](BF4)6.1-PrOH.5H2O (1.1 PrOH.5H2O; L = 2,6-bis[5-(2-pyridinyl)-1H-pyrazol-3-yl]pyridine), was synthesized with a [3 * 3] grid structure consisting of nine Cu(II) ions and six deprotonated ligands and displayed four-step quasi-reversible redox behavior from [Cu(II)9] to [Cu(I)4Cu(II)5]. The corresponding heterovalent complex [Cu(I)2Cu(II)7(L)6](PF6)4.3H2O (2.3H2O) was successfully isolated and had a distorted core structure that radically changed the intramolecular magnetic coupling pathways. PMID- 23931184 TI - Use of fluoroform as a source of difluorocarbene in the synthesis of difluoromethoxy- and difluorothiomethoxyarenes. AB - Fluoroform, CHF3, a non-ozone-depleting, nontoxic, and inexpensive gas can be used as a difluorocarbene source in a process for the conversion of phenols and thiophenols to their difluoromethoxy and difluorothiomethoxy derivatives. The reactions are carried out at moderate temperatures and atmospheric pressure, using potassium hydroxide as base in a two-phase (water/dioxane or water/acetonitrile) process to provide moderate to good yields of the respective products. PMID- 23931185 TI - Photochemical Behavior and Photolysis of Protonated Forms of Levofloxacin. AB - The effect of intermolecular proton transfer on the spectral properties of levofloxacin in the ground and excited electronic states was studied. The preferred direction of possible protolytic reactions induced by UV irradiation in this compound was studied. It was found that the proton transfer processes have a considerable effect on the capability of the compound to emit light and occur on the nanosecond timescale. The photochemical reactions of the tree forms of levofloxacin (pH: 4.0, 7.0, 10.0) were studied by laser flash photolysis and product studies. Irradiation at pH 4 yielded a pulse and transient (lambdamax = 395, 515, 575 nm) assigned to the protonated triplet. Irradiation at pH 7 yielded a transient species (lambdamax = 525, 610 nm) assigned to the neutral form. Protonation of the anionic singlet excited state was also observed (lambdamax = 440, 570, 680 nm). PMID- 23931186 TI - Re: Prediagnostic circulating adipokine concentrations and risk of renal cell carcinoma in male smokers. PMID- 23931187 TI - Re: Practice-setting and surgeon characteristics heavily influence the decision to perform partial nephrectomy among American Urologic Association surgeons. PMID- 23931188 TI - Re: Evaluation of acute toxicity and symptoms palliation in a hypofractionated weekly schedule of external radiotherapy for elderly patients with muscular invasive bladder cancer. PMID- 23931190 TI - Re: Androgen-deprivation therapy and diabetes control among diabetic men with prostate cancer. PMID- 23931191 TI - Re: Retrospective evaluation reveals that long-term androgen deprivation therapy improves cause-specific and overall survival in the setting of dose-escalated radiation for high-risk prostate cancer. PMID- 23931192 TI - Re: Intermittent androgen suppression for rising PSA level after radiotherapy. PMID- 23931193 TI - Re: Abiraterone in metastatic prostate cancer without previous chemotherapy. PMID- 23931194 TI - Re: Long-term follow-up of a phase II trial of chemotherapy plus hormone therapy for biochemical relapse after definitive local therapy for prostate cancer. PMID- 23931195 TI - Re: Transition zone prostate cancer: detection and localization with 3-T multiparametric MR imaging. PMID- 23931198 TI - Re: The surgical management of upper tract stone disease among spinal cord injured patients. PMID- 23931200 TI - Re: Primary prevention of nephrolithiasis is cost-effective for a national healthcare system. PMID- 23931201 TI - Re: Randomized clinical trial comparing effectiveness of intracorpus spongiosum block versus topical anesthesia for performing visual internal urethrotomy for urethral stricture disease. PMID- 23931202 TI - Re: Outcome of penile revascularization for arteriogenic erectile dysfunction after pelvic fracture urethral injuries. PMID- 23931203 TI - Re: The effect of the WHO surgical safety checklist on complication rate and communication. PMID- 23931204 TI - Re: Preputial/penile skin flap, as a dorsal onlay or tubularized flap: a versatile substitute for complex anterior urethral stricture. PMID- 23931205 TI - Re: A contemporary assessment of nocturia: definition, epidemiology, pathophysiology, and management--a systematic review and meta-analysis. PMID- 23931206 TI - Re: Incontinence-associated dermatitis: consensus statements, evidence-based guidelines for prevention and treatment, and current challenges. PMID- 23931207 TI - Re: Two-year follow-up of an open-label multicenter study of polyacrylamide hydrogel (Bulkamid(r)) for female stress and stress-predominant mixed incontinence. PMID- 23931208 TI - Re: Transvaginal mesh kits--how "serious" are the complications and are they reversible? PMID- 23931209 TI - Re: The severity of urinary incontinence decreases health-related quality of life among community-dwelling elderly. PMID- 23931210 TI - Re: Antihypertensive drug class use and differential risk of urinary incontinence in community-dwelling older women. PMID- 23931211 TI - Re: Severity, not type, is the main predictor of decreased quality of life in elderly women with urinary incontinence: a population-based study as part of a randomized controlled trial in primary care. PMID- 23931212 TI - Re: Nurse-led flexible cystoscopy in Australia: initial experience and early results. PMID- 23931213 TI - Re: Characteristics of persons with overactive bladder of presumed neurologic origin: results from the Boston Area Community Health (BACH) survey. PMID- 23931214 TI - Re: Efficacy of alfuzosin and sildenafil combination in male patients with lower urinary tract symptoms. PMID- 23931215 TI - Re: Inhaled anticholinergic agents and acute urinary retention in men with lower urinary tract symptoms or benign prostatic hyperplasia. PMID- 23931216 TI - Re: Tadalafil enhances the inhibitory effects of tamsulosin on neurogenic contractions of human prostate and bladder neck. PMID- 23931217 TI - Re: Relationship between sexual function and quality of life in obese persons seeking weight reduction. PMID- 23931220 TI - Re: Dropout in the treatment of erectile dysfunction with PDE5: a study on predictors and a qualitative analysis of reasons for discontinuation. PMID- 23931222 TI - Re: Overweight men with nonobstructive azoospermia have worse pregnancy outcomes after microdissection testicular sperm extraction. PMID- 23931223 TI - Re: Successful delivery derived from vitrified-warmed spermatozoa from a patient with nonobstructive azoospermia. PMID- 23931224 TI - Re: The impact of surgical sperm retrieval on the in vitro fertilization outcomes of infertile patients with temporary ejaculation failure on their oocyte retrieval day. PMID- 23931225 TI - Re: Semen quality in ejaculates produced by masturbation in men with spinal cord injury. PMID- 23931227 TI - Re: National health spending in 2011: overall growth remains low, but some payers and services show signs of acceleration. PMID- 23931228 TI - Re: A survey analysis suggests that electronic health records will yield revenue gains for some practices and losses for many. PMID- 23931229 TI - Re: On average, physicians spend nearly 11 percent of their 40-year careers with an open, unresolved malpractice claim. PMID- 23931230 TI - Re: Symptomatic bilateral delayed partial ureteral obstruction after bilateral endoscopic correction of vesicoureteral reflux with dextranomer/hyaluronic acid polymer. PMID- 23931231 TI - Re: Is VCUG still indicated following the first episode of urinary tract infection in boys? PMID- 23931232 TI - Re: Is parental anxiety and coping associated with girls' distress during a VCUG? Preliminary findings. PMID- 23931233 TI - Re: Psychosocial difficulties in children referred to pediatric urology: a closer look. PMID- 23931234 TI - Re: A meta-analysis of the risk of boys with isolated cryptorchidism developing testicular cancer in later life. PMID- 23931235 TI - Re: PIK3CA mutation spectrum in urothelial carcinoma reflects cell context dependent signaling and phenotypic outputs. PMID- 23931236 TI - Re: p21-activated kinase 6 (PAK6) inhibits prostate cancer growth via phosphorylation of androgen receptor and tumorigenic E3 ligase murine double minute-2 (Mdm2). PMID- 23931237 TI - Re: Cox-2 inhibition enhances the activity of sunitinib in human renal cell carcinoma xenografts. PMID- 23931238 TI - Re: The role of prostanoids in urinary bladder physiology. PMID- 23931239 TI - Re: Robotic real-time near infrared targeted fluorescence imaging in a murine model of prostate cancer: a feasibility study. PMID- 23931240 TI - Whole air canister sampling coupled with preconcentration GC/MS analysis of part per-trillion levels of trimethylsilanol in semiconductor cleanroom air. AB - The costly damage airborne trimethylsilanol (TMS) exacts on optics in the semiconductor industry has resulted in the demand for accurate and reliable methods for measuring TMS at trace levels (i.e., parts per trillion, volume per volume of air [ppt(v)] [~ng/m(3)]). In this study I developed a whole air canister-based approach for field sampling trimethylsilanol in air, as well as a preconcentration gas chromatography/mass spectrometry laboratory method for analysis. The results demonstrate clean canister blanks (0.06 ppt(v) [0.24 ng/m(3)], which is below the detection limit), excellent linearity (a calibration relative response factor relative standard deviation [RSD] of 9.8%) over a wide dynamic mass range (1-100 ppt(v)), recovery/accuracy of 93%, a low selected ion monitoring method detection limit of 0.12 ppt(v) (0.48 ng/m(3)), replicate precision of 6.8% RSD, and stability (84% recovery) out to four days of storage at room temperature. Samples collected at two silicon wafer fabrication facilities ranged from 10.0 to 9120 ppt(v) TMS and appear to be associated with the use of hexamethyldisilazane priming agent. This method will enable semiconductor cleanroom managers to monitor and control for trace levels of trimethylsilanol. PMID- 23931241 TI - The validity and reliability of the Arabic Infant/Toddler Sensory Profile. AB - In this study, we report the translation process, validity, and reliability of the Arabic Infant/Toddler Sensory Profile (IT_SP). A multistep approach was implemented to ensure the accuracy and equivalency of the Arabic and original English IT_SP. Factor analysis indicated that item loadings for over 50% of the items on the Arabic version were identical to the English version; all but three items had logical loadings. Intraclass correlation coefficients (ICC) between scores on the Arabic and English versions reported by parents who were bilingual were >.90 supporting bilingual validity. Alpha coefficients for each section varied from .40 to .74, which was within the range of the English version (.17 to .86), and were thus similar. ICCs between scores for repeated assessments varied from .81 to .99 supporting test-retest reliability. The results support the validity and reliability of the Arabic IT_SP. PMID- 23931242 TI - Non cell autonomous upregulation of CDKN2 transcription linked to progression of chronic hepatitis C disease. AB - Chronic hepatitis C virus infection (C-HC) is associated with higher mortality arising from hepatic and extrahepatic disease. This may be due to accelerated biological aging; however, studies in C-HC have thus far been based solely on telomere length as a biomarker of aging (BoA). In this study, we have evaluated CDKN2 locus transcripts as alternative BoAs in C-HC. Our results suggest that C HC induces non-cell-autonomous senescence and accelerates biological aging. The CDKN2 locus may provide a link between C-HC and increased susceptibility to age associated diseases and provides novel biomarkers for assessing its impact on aging processes in man. PMID- 23931243 TI - Comparison of lornoxicam and fentanyl when added to lidocaine in intravenous regional anesthesia. AB - BACKGROUND AND OBJECTIVES: In this study, our goal was to compare intraoperative and postoperative analgesic effects of lornoxicam and fentanyl when added to lidocaine Intravenous Regional Anesthesia (IVRA) in a group of outpatients who underwent hand surgery. METHODS: This is a double blind randomized study. A total of 45 patients were included, randomized into three groups. Patients in Group I (L) received 3 mg.kg-1 of 2% lidocaine 40 mL; patients in Group II (LL) received 3 mg.kg-1 lidocaine 38 mL + 2 mL lornoxicam; patients in Group III (LF) received 3 mg.kg-1 lidocaine 38 mL + 2 mL fentanyl. Our primary outcome was fi rst analgesic requirement time at postoperative period. RESULTS: Lornoxicam added to lidocaine IVRA increased the sensory block recovery time without increasing side effects and increased fi rst analgesic requirement time at the postoperative period when compared to lidocaine IVRA (p < 0.001, p < 0.001 respectively) and fentanyl added to lidocaine IVRA (p < 0.001, p < 0.001 respectively). In addition, we also found that fentanyl decreased tourniquet pain (p < 0.01) when compared to lidocaine but showed similar analgesic effect with lornoxicam (p > 0.05) although VAS scores related to tourniquet pain were lower in fentanyl group. Lornoxicam added to lidocaine IVRA was not superior to lidocaine IVRA in decreasing tourniquet pain. CONCLUSIONS: Addition of fentanyl to lidocaine IVRA seems to be superior to lidocaine IVRA and lornoxicam added to lidocaine IVRA groups in decreasing tourniquet pain at the expense of increasing side effects. However, lornoxicam did not increase side effects while providing intraoperative and postoperative analgesia. Therefore, lornoxicam could be more appropriate for clinical use. PMID- 23931244 TI - Association of pain catastrophizing with the incidence and severity of acute and persistent perineal pain after natural childbirth: longitudinal cohort study. AB - BACKGROUND AND OBJECTIVES: Vaginal birth delivery may result in acute and persistent perineal pain postpartum. This study evaluated the association between catastrophizing, a phenomenon of poor psychological adjustment to pain leading the individual to magnify the painful experience making it more intense, and the incidence and severity of perineal pain and its relationship to perineal trauma. METHOD: Cohort study conducted with pregnant women in labor. We used the pain catastrophizing scale during hospitalization and assessed the degree of perineal lesion and pain severity in the fi rst 24 hours and after 8 weeks of delivery using a numerical pain scale. RESULTS: We evaluated 55 women, with acute pain reported by 69.1%, moderate/severe pain by 36.3%, and persistent pain by 14.5%. Catastrophizing mean score was 2.15 } 1.24. Catastrophizing patients showed a 2.90 relative risk (RR) for perineal pain (95% CI: 1.08-7.75) and RR: 1.31 for developing persistent perineal pain (95% CI: 1.05-1.64). They also showed a RR: 2.2 for developing acute and severe perineal pain (95% CI: 1.11-4.33). CONCLUSIONS: The incidence of acute and persistent perineal pain after vaginal delivery is high. Catastrophizing pregnant women are at increased risk for developing acute and persistent perineal pain, as well as severe pain. Perineal trauma increased the risk of persistent perineal pain. PMID- 23931245 TI - Comparative study related to cardiovascular safety between bupivacaine (S75-R25) and ropivacaine in brachial plexus block. AB - BACKGROUND AND OBJECTIVES: Bupivacaine is a fi rst choice for regional anesthesia considering its effectiveness, long duration and less motor blockade. Bupivacaine (S75-R25) is a mixture of optical isomers containing 75% levobupivacaine (S-) and 25% dextrobupivacaine (R+) created by a Brazilian pharmaceutical company. This investigation compared cardiac safety and efficacy of bupivacaine S75-R25 with vasoconstrictor and ropivacaine for brachial plexus blockade. METHODS: Patients were randomized to receive brachial plexus anesthesia with either bupivacaine S75 R25 with epinephrine 1:200,000 (bupi) or ropivacaine (ropi), both at 0.50%, in 30 mL solution.We registered a continuous Holter ECG throughout the procedure, as well as the Lovett scale of force in addition to monitoring (heart rate, pulse oximetry and non-invasive blood pressure). The incidence of adverse events was compared with the chi-square or Fisher test. RESULTS: We allocated forty-four patients into two groups. They did not show any difference related to age, weight or height, gender, as well as for surgical duration. Supraventricular arrhythmias were not different before or after the plexus blockade, independent of the local anestheticchosen. Loss of sensitivity was faster for the bupivacaine group (23.1 +/- 11.7 min) compared to the ropivacaine one (26.8 +/- 11.5 min), though not significant (p = 0.205, Student t). There was a reduction in the cardiac rate, observed during the twenty-four-hour Holter monitoring. CONCLUSIONS: This study showed similar efficacy between bupivacaine S75-R25 for brachial plexus blockade and ropivacaine, with similar incidences of supraventricular arrhythmias. PMID- 23931246 TI - Risk factors for perioperative complications in endoscopic surgery with irrigation. AB - BACKGROUND AND OBJECTIVES: Currently, endoscopic medicine is being increasingly used, albeit not without risks. Therefore, this study evaluated the factors associated with perioperative complications in endoscopic surgery with intraoperative irrigation. METHOD: A cohort study of six months duration. Patients aged >= 18 years undergoing endoscopic surgery with the use of irrigation fluids during the intraoperative period were included. Exclusion criteria were: use of diuretics, kidney failure, cognitive impairment, hyponatremia prior to surgery, pregnancy, and critically ill. The patients who presented with or without complications during the perioperative period were allocated into two groups. Complications evaluated were related to neurological, cardiovascular and renal changes, and perioperative bleeding. RESULTS: In total, 181 patients were enrolled and 39 excluded; therefore, 142 patients met the study criteria. Patients with complications amounted to 21.8%, with higher prevalence in endoscopic prostate surgery, followed by hysteroscopy, bladder, knee, and shoulder arthroscopy (58.1%, 36.9%, 19.4%, 3.8%, 3.2% respectively). When comparing both groups, we found association with complications in univariate analysis: age, sex, smoking, heart disease, ASA, serum sodium at the end of surgery, total irrigation fluid administered, TURP, and hysteroscopy. However, in multiple regression analysis for complications, only age (OR = 1.048), serum sodium (OR = 0.962), and volume of irrigation fluid administered during surgery (OR = 1.001) were independent variables. PMID- 23931247 TI - Ilioinguinal-iliohypogastric nerve block within travenous dexketoprofen improves postoperative analgesia in abdominal hysterectomies. AB - BACKGROUND AND OBJECTIVE: In this study, our aim was to evaluate the effects of intravenous dexketoprofen trometamol with ilioinguinal and iliohypogastric nerve block on analgesic quality and morphine consumption after total abdominal hysterectomy operations. METHODS: We conducted this randomized controlled clinical study on 61 patients. The study was conducted in the operation room, post-anesthesia care unit, and inpatient clinic. We randomly grouped the 61 patients into control group (group C), block group (group B) and dexketoprofen block group (group DB). Before the skin incision performed after anesthesia induction, we performed ilioinguinal iliohypogastric block (group C given saline and group P and DB given levobupivacaine). In contrast to group C and B, group DB was given dexketoprofen. We administered morphine analgesia to all patients by patient-controlled analgesia (PCA) during the postoperative 24 hours. We recorded Visual Analogue Scale (VAS), satisfaction scores, morphine consumption and side effects during postoperative 24 hours. RESULTS: We found the DB group's VAS scores to be lower than the control group and block group's (p < 0.05) values at postoperative 1st, 2nd, 6th and 12th hours. VAS scores of group C were higher than of group B at postoperative fi rst 2 hours. Time to fi rst PCA demand was longer, morphine consumption values were lower and satisfaction scores were higher in group DB than in the other two groups (p < 0.05). CONCLUSIONS: Ilioinguinal-iliohypogastric nerve block with IV dexketoprofen increases patient satisfaction by decreasing opioid consumption, increasing patient satisfaction, which suggests that dexketoprofen trometamol is an effective non-steroidal anti inflammatory analgesic in postoperative analgesia. PMID- 23931248 TI - Postoperative nausea and vomiting: validation of the portuguese version of the postoperative nausea and vomiting intensity score. AB - BACKGROUND AND OBJECTIVES: The Postoperative Nausea and Vomiting (PONV) Intensity Scale was developed to define clinically important PONV. The aim of this study was to translate, retranslate and validate the PONV Intensity Scale for use in Portuguese Post Anesthetic Care Unit (PACU) settings. METHODS: The PONV Intensity Scale was translated and back-translated in accordance with available guidelines. The research team conducted an observational and cohort prospective study in a PACU. One-hundred fifty-seven adult patients admiited after surgery over three weeks were evaluated for PONV. Measurements included nausea visual analogic scale (VAS) at 6 and 24 hours, postoperatively. We assessed reliability and observer disagreement using interclass correlation (ICC) and Information-Based Measure of Disagreement (IBMD). We compared VAS scores between patients with clinically significant (>= 50) and not significant (<50) PONV. RESULTS: Thirty-nine patients (25%) had PONV at 6 hours and 54 (34%) had PONV at 24 hours. Thirty-six and 54 patients experienced nausea at 6 and 24 hours, respectively. Among patients with PONV, 6 patients (15%) and 9 patients (27%) had a clinically signifi cant PONV intensity scale score at 6 and at 24 hours, respectively. The reliability was good both for PONV intensity scale score and for VAS and observer disagreement was slightly higher for VAS. The median nausea VAS scores were higher in patients with clinically significant PONV Intensity score. CONCLUSIONS: The PONV Intensity Scale appears to be an accurate and reliable assessment and monitoring instrument for PONV in the PACU settings. PMID- 23931249 TI - Preoperative evaluation: screening using a questionnaire. AB - BACKGROUND AND OBJECTIVE: Prior to elective surgery it is essential to know in advance the patient's clinical condition. The aim of this study was to compare the preoperative evaluation (POE) through questionnaire responses with preanesthetic evaluation by the anesthesiologist. METHOD: Prior to their preoperative evaluation, patients answered a questionnaire with information regarding age, weight, height, scheduled surgery, past medical and surgical history, allergies, medications and doses used, social history (illicit drugs, alcohol, smoking), functional capacity and exercise tolerance. Preoperative evaluation was performed by an anesthesiologist who had no access to the questionnaire data or knowledge about the research. The questionnaire data were compared with the preoperative evaluation by two independent investigators, in order to answer the questions: 1) Was the questionnaire evaluation effective - could the patient undergo surgery without the need for face-to-face consultation? 2) Has been there any relevant information - ability to change the anesthetic approach - not assessed by the questionnaire, but assessed by the face-to-face consultation? 3) Has been there any information added by the health questionnaire that was missed by face-to-face consultation? For statistical analysis, the paired Student's t-test was used for parametric data and chi-square test for categorical data, with p < 0.05 considered significant. RESULTS: Of the 269 eligible patients there was one refusal, and four agreed to participate but did not complete the questionnaire, in addition to 52 losses, totaling 212 participants. Questionnaire data added to the consultation in 109 cases (51.4%). The screening questionnaire alone was effective for 144 patients (67.93%), with no need for consultation. The anesthesiologist evaluation referred patients for surgery on their fi rst visit in 178 opportunities (84%). In the identification of cases of non-referral to surgery, the questionnaire showed a negative predictive value of 94.4%, positive predictive value of 38.2%, sensitivity of 76.5%, and specificity of 76.4%. Statistically significant (P < 0.05) clinical factors associated with non-referral to surgery were: age over 65 years, BMI > 30, low functional capacity, hypertension, diabetes mellitus, asthma, renal failure, hepatitis, and ischemic heart disease. CONCLUSION: The questionnaire was effective for screening patients who needed further evaluation and/or changes in treatment regimen prior to elective surgery. Moreover, the questionnaire added data not covered by clinical evaluation. PMID- 23931250 TI - Sedation-analgesia in elective colonoscopy: propofol-fentanyl versus propofol alfentanil. AB - BACKGROUND AND OBJECTIVES: Sedation-analgesia is recommended for comfortable colonoscopy procedures, which are invasive and can be painful. This study aimed to compare the combinations of propofol-alfentanil and propofol-fentanyl for sedation-analgesia in elective colonoscopy patients. METHODS: This prospective and randomized study was planned in ASA I-II groups and included 80 patients between the ages of 18 and 65 years. Sedation-analgesia induction was performed as 1 MUg.kg-1 fentanyl, 1 mg.kg-1 propofol in the propofol-fentanyl group (Group PF) and 10 MUg.kg-1 alfentanil, 1 mg.kg-1 propofol in the propofol-alfentanil group (Group PA). Patients' scores were limited to 3-4 values on the Ramsey Sedation Scale (RSS) by 0.5 mg.kg-1 bolus additional doses of propofol in sedation-analgesia maintenance. We recorded demographical data, heart rate, mean arterial pressure (MAP), oxygen saturation of hemoglobin (SpO2), RSS value, colonoscopy time, total dose of propofol, complications, recovery time, and discharge time, as well as colonoscopist and patient satisfaction scores. RESULTS: MAP at the 15th minute in Group PA was signifi cantly higher than in Group PF (p = 0.037). Group PA's beginning mean heart rate was higher than the mean heart rate at subsequent readings (p = 0.012, p = 0.002). The mean total propofol dose of Group PA was signifi cantly higher than the total dose of Group PF (p = 0.028). The mean recovery time of Group PA was signifi cantly longer than that of Group PF (p = 0.032). CONCLUSION: Fentanyl provides better operative conditions and reduces the need for additional propofol doses. These advantages cause a shorter recovery time. Therefore, propofol-fentanyl is superior to the propofol-alfentanil for sedation-analgesia in colonoscopy. PMID- 23931251 TI - Difficult airway intubation with flexible bronchoscope. AB - BACKGROUND AND OBJECTIVE: To describe the efficacy and safety of a flexible bronchoscopy intubation (FBI) protocol in patients with difficult airway. METHOD: We reviewed the medical records of patients diagnosed with difficult airway who underwent flexible bronchoscopy intubation under spontaneous ventilation and sedation with midazolam and fentanyl from March 2009 to December 2010. RESULTS: The study enrolled 102 patients, 69 (67.7%) men and 33 (32.3%) women, with a mean age of 44 years. FBI was performed in 59 patients (57.8%) with expected difficult airway in the operating room, in 39 patients (38.2%) in the Intensive Care Unit (ICU), and in 4 patients (3.9%) in the emergency room. Cough, decrease in transient oxygen saturation, and difficult progression of the cannula through the larynx were the main complications, but these factors did not prevent intubation. CONCLUSION: FBI according to the conscious sedation protocol with midazolam and fentanyl is effective and safe in the management of patients with difficult airway. PMID- 23931252 TI - Inadvertent venous air embolism during cesarean section: collapsible intravenous fluid bags without self-sealing outlet have risks. Case report. AB - The anesthesiologist must be aware of the causes, diagnosis and treatment of venous air embolism and adopt the practice patterns to prevent its occurrence. Although venous air embolism is a known complication of cesarean section, we describe an unusual inattention that causes iatrogenic near fatal venous air embolism during a cesarean section under spinal anesthesia. One of the reasons for using self-collapsible intravenous (IV) infusion bags instead of conventional glass or plastic bottles is to take precaution against air embolism. We also demonstrated the risk of air embolism for two kinds of plastic collapsible intravenous fluid bags: polyvinyl chloride (PVC) and polypropylene-based. Fluid bags without self-sealing outlets pose a risk for air embolism if the closed system is broken down, while the flexibility of the bag limits the amount of air entry. PVC-based bags, which have more flexibility, have significantly less risk of air entry when IV administration set is disconnected from the outlet. Using a pressure bag for rapid infusion can be dangerous without checking and emptying all air from the IV bag. PMID- 23931253 TI - Anesthesia management in a child with osteogenesis imperfecta and epidural hemorrhage. AB - Osteogenesis Imperfecta (OI) results from gene mutation that causes defective or insufficient collagen formation. It may cause various anesthetic complications due to the difficulty in airway management, existence of spinal deformity, respiratory disorders, cardiac anomalies, thrombocyte function disorder, risk of hyperthermia, bacillary invagination, bone deformities and metabolic disorders. The anesthesia management of OI patients should be exercised with caution given certain risks of respiratory disorders. These risks are due to thorax deformity, bone fractures during moving or changing position, mandibular and cervical fractures related with intubation, difficult intubation and malignant hyperthermia. The anesthetic technique using Total Intravenous Anesthesia (TIVA) and laryngeal mask airway is suitable for pediatric patient care with OI. However, these techniques have not yet been reported as useful in neurosurgery case reports. In this study, we present the use of TIVA and ProSeal Laringeal Mask in a child with OI and epidural hemorrhage. We came to the conclusion that LMA and TIVA can safely be used in the anesthetic management of OI patients with severe anesthetic problems. PMID- 23931254 TI - Anesthesia for cesarean section in a patient with Guillain-Barre syndrome: case report. AB - BACKGROUND AND OBJECTIVES: Guillain-Barre syndrome during pregnancy is considered a rare neurological complication, and there is no consensus in literature for anesthetic management for cesarean section in such patients. The objective of this paper is to report the case of a pregnant woman with Guillain-Barre syndrome undergoing cesarean section. CASE REPORT: Female patient, 22-year old, 35 weeks and 5 days of gestation, undergoing cesarean section, hospitalized, reporting decreased strength and lower limb paresthesias. Cerebrospinal fluid (CSF) analysis showed increased protein (304 mg.dL-1) without increased cellularity. The anesthetic technique used was general anesthesia induced with propofol (1.5 mg.kg-1) and maintained with 2% sevoflurane in oxygen and fentanyl (3 MUg.kg-1). The procedure was uneventful for both mother and neonate. The patient was discharged 10 days after admission, after progressive improvement of neurological symptoms. CONCLUSION: The anesthetic technique for pregnant women with Guillain Barre syndrome requiring cesarean section remains at the discretion of the anesthesiologist, who should be guided by the clinical conditions and comorbidities of each patient. PMID- 23931255 TI - The dissection of reinforced endotracheal tube internal wall causing intraoperative airway obstruction under general anesthesia: case report. AB - Endotracheal intubation is performed to establish a secure airway. However, this carries its risks and obstruction of an endotracheal tube (ETT) is a potentially life-threatening event. We report two cases with an obstruction of the resterilized, single use, spiral, reinforced endotracheal tubes by dissection of the internal wall. As a conclusion, we suggest not reusing and resterilizing single tubes in these cases to avoid a complication like dissection of the internal wall of the tube, as this has been the main cause. PMID- 23931256 TI - Cephalic angulation of epidural needle insertion may be an important factor to safely approach the epidural space: a mathematical model. PMID- 23931257 TI - "Double crap!" abuse and harmed identity in Fifty Shades of Grey. AB - BACKGROUND: While intimate partner violence (IPV) affects 25% of women and impairs health, current societal conditions-including the normalization of abuse in popular culture such as novels, film, and music-create the context to support such violence. Fifty Shades of Grey, a best-selling novel, depicts a "romantic" and "erotic" relationship involving 28-year-old megamillionaire, Christian Grey, and a 22-year-old college student, Anastasia Steele. We argue that the relationship is characterized by IPV, which is harmful to Anastasia. METHODS: All authors engaged in iterative readings of the text, and wrote narrative summaries to elucidate themes. Validity checks included double review of the first eight chapters of the novel to establish consistency in our analysis approach, iterative discussions in-person and electronically to arbitrate discrepancies, and review of our analysis with other abuse and sexual practice experts. To characterize IPV, we used the U.S. Centers for Disease Control and Prevention's definitions of emotional abuse (intimidation/threats; isolation; stalking; and humiliation) and sexual violence (forced sex acts/contact against a person's will, including using alcohol/drugs or intimidation/pressure). To characterize harm, we used Smith's conceptualizations of perceived threat, managing, altered identity, yearning, entrapment, and disempowerment experienced by abused women. RESULTS: Emotional abuse is present in nearly every interaction, including: stalking (Christian deliberately follows Anastasia and appears in unusual places, uses a phone and computer to track Anastasia's whereabouts, and delivers expensive gifts); intimidation (Christian uses intimidating verbal and nonverbal behaviors, such as routinely commanding Anastasia to eat and threatening to punish her); and isolation (Christian limits Anastasia's social contact). Sexual violence is pervasive-including using alcohol to compromise Anastasia's consent, as well as intimidation (Christian initiates sexual encounters when genuinely angry, dismisses Anastasia's requests for boundaries, and threatens her). Anastasia experiences reactions typical of abused women, including: constant perceived threat ("my stomach churns from his threats"); altered identity (describes herself as a "pale, haunted ghost"); and stressful managing (engages in behaviors to "keep the peace," such as withholding information about her social whereabouts to avoid Christian's anger). Anastasia becomes disempowered and entrapped in the relationship as her behaviors become mechanized in response to Christian's abuse. CONCLUSIONS: Our analysis identified patterns in Fifty Shades that reflect pervasive intimate partner violence-one of the biggest problems of our time. Further, our analysis adds to a growing body of literature noting dangerous violence standards being perpetuated in popular culture. PMID- 23931258 TI - Building an anisotropic meniscus with zonal variations. AB - Toward addressing the difficult problems of knee meniscus regeneration, a self assembling process has been used to re-create the native morphology and matrix properties. A significant problem in such attempts is the recapitulation of the distinct zones of the meniscus, the inner, more cartilaginous and the outer, more fibrocartilaginous zones. In this study, an anisotropic and zonally variant meniscus was produced by self-assembly of the inner meniscus (100% chondrocytes) followed by cell seeding the outer meniscus (coculture of chondrocytes and meniscus cells). After 4 weeks in culture, the engineered, inner meniscus exhibited a 42% increase in both instantaneous and relaxation moduli and a 62% increase in GAG/DW, as compared to the outer meniscus. In contrast, the circumferential tensile modulus and collagen/DW of the outer zone was 101% and 129% higher, respectively, than the values measured for the inner zone. Furthermore, there was no difference in the radial tensile modulus between the control and zonal engineered menisci, suggesting that the inner and outer zones of the engineered zonal menisci successfully integrated. These data demonstrate that not only can biomechanical and biochemical properties be engineered to differ by the zone, but they can also recapitulate the anisotropic behavior of the knee meniscus. PMID- 23931259 TI - Four-year follow-up of combined surgical therapy of advanced peri-implantitis evaluating two methods of surface decontamination. AB - OBJECTIVES: To investigate the impact of two surface decontamination methods on the long-term outcomes following combined surgical resective/regenerative therapy of advanced peri-implantitis lesions. MATERIAL AND METHODS: Seventeen patients (n = 17 combined supra- and intrabony-defects) completed the 48 months follow-up observation following access flap surgery, granulation tissue removal and implantoplasty at bucally and supracrestally exposed implant parts. The remaining unmodified implant surface areas were randomly treated using either (i) an Er:YAG laser (ERL), or (ii) plastic curets + cotton pellets + sterile saline (CPS), and augmented with a natural bone mineral + collagen membrane. RESULTS: At 48 months, CPS-treated sites tended to reveal higher reductions in mean BOP (CPS: 85.2 +/- 16.4% versus ERL: 71.6 +/- 24.9%) and CAL values (CPS: 1.5 +/- 2.0 mm versus ERL: 1.2 +/- 2.0 mm) when compared with the ERL group. In both groups, clinical outcomes were not directly influenced by the initial defect configuration. CONCLUSION: The 4-year clinical outcomes obtained following combined surgical resective/regenerative therapy of advanced peri-implantitis were not influenced by the method of surface decontamination. PMID- 23931260 TI - Consanguinity on Robinson Crusoe Island, an isolated Chilean population. AB - The population of Robinson Crusoe Island is estimated at 633 inhabitants. The current population has a common origin from the first eight families who colonized the island at the end of the 19th century. The objective of this study was to determine the rates of consanguinity, the average coefficients of inbreeding, the types of consanguineous marriages and the inbreeding evolution between 1900 and 2000 on the island. All marriages registered on the island, from the last colonization until 2000 (417 in total), were included in the analysis. In addition, extended genealogies were obtained. The consanguinity rate was 14.9% and the average coefficient of inbreeding (alpha) 54.05 * 10(-4). The most frequent type of consanguineous marriages was between second cousins, followed by first cousins. The average value of the first/second cousin ratio was 1.11. The population of Robinson Crusoe Island has a high rate of inbreeding. The unique characteristic of the island - its small current population, originating from just a few families, with small rate of gene flow - could explain the observed high and increasing consanguinity. PMID- 23931261 TI - Reconsidering remineralization strategies to include nanoparticle hydroxyapatite. AB - Dental caries is a transmissible biofilm-mediated disease of the teeth that is defined by prolonged periods of low pH resulting in net mineral loss from the teeth. Hydroxyapatite, fluorapatite, and the carbonated forms of calcium phosphate form the main mineral content of dental hard tissues: enamel, dentin, and cementum. Active dental caries results when the biofilm pH on the tooth surface drops below the dissolution threshold for hydroxyapatite and fluorapatite. The clinical evidence of this net mineral loss is porosity, whitespot lesions, caries lesions, and/or cavitation. The potential to reverse this mineral loss through remineralization has been well documented, although previous remineralization strategies for dental hard tissues have focused on the use of fluorides and forms of calcium phosphate. This in-vitro study documented the deposition of nanoparticle hydroxyapatite on demineralized enamel surfaces after treatment with an experimental remineralization gel. This finding supports consideration of an additional approach to remineralization that includes pH neutralization strategies and nanoparticle hydroxyapatite crystals. PMID- 23931262 TI - Alveolar ridge augmentation: combining bioresorbable scaffolds with osteoinductive bone grafts in atrophic sites. A follow-up to an evolving technique. AB - When a tooth or teeth are lost, the 3-dimensional (3-D) atrophy of alveolar ridges predictably ensues. This commonly precludes placement of dental implants, or at least complicates their insertion into favorable positions. Numerous methods of alveolar ridge augmentation have evolved, including blocks of autogenous bone-harvested from intra- and extraoral sources- being fixed to the resorbed ridge, and particulate grafts of autogenous, allogeneic, xenograft, or alloplasts, which are often combined with barrier membranes (guided bone regeneration GBR). Ridge-splitting techniques, where the narrow bone is fractured in a green-stick manner--often combined with exogenous grafts and GBR--is also commonly performed. This article will demonstrate a technique where a resorbable mesh (PLGA) is combined with an osteoinductive protein (rhBMP-2) and a readily acquired bone allograft (FDBA) to reconstruct severely resorbed alveolar ridges to facilitate prosthetically guided implant placement. PMID- 23931263 TI - The digitalizing of implant dentistry: a clinical evaluation of 15 patients. AB - This article introduces intraoral scanning technology as it applies to custom fabricated implant abutments. The author discusses its use and clinical applications, and provides an overview of the benefits of such a system in the clinical setting. In this clinical evaluation of 15 patients, the BellaTek Encode Impression System was combined with iTero intraoral scanning technology to demonstrate the technical feasibility of combining these two CAD/CAM technologies. The BellaTek Encode impression system protocol was established to allow the clinician to digitally impress special codes embedded on the occlusal surface of the BellaTek Encode healing abutment. Once a digital file was prepared for CAD/CAM processing, a duplicate STL file could be sent to iTero for fabrication of a polyurethane model of the definitive BellaTek abutment, from which an implant restoration could be created. This definitive prosthesis was able to be fabricated simultaneously while the definitive BellaTek abutment was being milled. PMID- 23931264 TI - Head and neck skin cancer: dentists' responsibility in early detection. AB - While there are 35,000 diagnosed oral cancers per year and 7,500 deaths, there are 30 times this amount when it comes to cases of skin cancer, the majority of which are found on the head and neck. Because many patients see their dentist more frequently than their medical doctor, dentistry is in an advantageous position to reduce the mortality/morbidity of this most common malignancy. This article discusses various types of head and neck skin cancer and how dental practitioners can perform clinical examinations to provide early detection for patients. PMID- 23931265 TI - High-risk esthetically driven restoration: begin with the end in mind. AB - A high-risk esthetically driven restorative case requires the dental team, along with the patient, to have a clear vision of the final outcome. In this case of a 33-year-old woman who wanted to improve her smile, esthetic problems stemmed from a retained deciduous maxillary left canine along with an impacted tooth No. 11. Among a number of concerns was the shape and color of the deciduous canine and the uneven length of the maxillary central incisors. A treatment plan that included orthodontics with removable aligners, occlusal adjustment, composite restorations, extraction and implant placement, indirect porcelain veneers, and a custom abutment and PFM crown was successfully executed in four phases over the course of more than 4 years. PMID- 23931266 TI - Combining monolithic zirconia crowns, digital impressioning, and regenerative cement for a predictable restorative alternative to PFM. AB - Advances in indirect esthetic materials in recent years have provided the dental profession higher levels of strength and esthetics than ever before with products like lithium disilicate and zirconium oxide. Providing excellent fit and versatile performance, and because there is no porcelain to delaminate, chip, or fracture, monolithic zirconia crowns have the potential to outperform other layered restorations such as porcelain-fused-to-metal (PFM). This review of monolithic zirconia highlights a clinical case in which all-zirconia restorations were combined with CAD/CAM technology for a successful esthetic restorative outcome. PMID- 23931267 TI - With abundance of whitening products, patients look to dentists for direction. PMID- 23931268 TI - Screw-access marking: a technique to simplify retrieval of cement-retained implant prostheses. AB - One of the commonly cited disadvantages of cement-retained implant prostheses is their inability to be retrievable. The screw-access marking technique discussed in this article allows for any clinician, at any time, to simply and predictably retrieve the cemented implant prosthesis. By applying a discrete, but easily recognizable, marking on the occlusal surface of the restoration, the entry point into the screw-access chamber can be precisely and safely created. The screw access marking technique is efficient, effective, and widely applicable. PMID- 23931269 TI - Human P-glycoprotein differentially affects antidepressant drug transport: relevance to blood-brain barrier permeability. AB - The pharmacological concept that inhibition of the drug efflux pump P glycoprotein (P-gp) enhances brain distribution of the antidepressant imipramine in the rat has recently been demonstrated. To determine if these findings are relevant to humans, the present study investigated if imipramine is a transported substrate of human P-gp. Furthermore, additional experiments were carried out to determine if findings in relation to imipramine and human P-gp would apply to other antidepressants from a range of different classes. To this end, bidirectional transport experiments were carried out in the ABCB1-transfected MDCKII-MDR1 cell line. Transported substrates of human P-gp are subjected to net efflux in this system, exhibiting a transport ratio (TR) >= 1.5, and directional efflux is attenuated by co-incubation of a P-gp inhibitor. Imipramine was identified as a transported substrate of human P-gp (TR = 1.68, attenuated by P gp inhibition). However, the antidepressants amitriptyline, duloxetine, fluoxetine and mirtazapine were not transported substrates of human P-gp (TR <= 1.16 in all cases). These results offer insight into the role of P-gp in the distribution of antidepressants, revealing that rodent findings pertaining to imipramine may translate to humans. Moreover, the present results highlight that other antidepressants may not be transported substrates of human P-gp. PMID- 23931271 TI - Development and in vitro proof-of-concept of interstitially targeted zinc- phthalocyanine liposomes for photodynamic therapy. AB - BACKGROUND: Photodynamic therapy (PDT) has been successfully used to treat various solid tumors. However, some cancer types respond poorly to PDT, including urothelial carcinomas, nasopharyngeal carcinomas, and extrahepatic cholangiocarcinomas. The therapeutic recalcitrance is in part due to the use of photosensitizers with suboptimal optical/ photochemical properties and unfavorable pharmacokinetics. OBJECTIVE: To circumvent these drawbacks, a second generation photosensitizer with improved optical/photochemical properties, zinc phthalocyanine (ZnPC), was encapsulated in interstitially targeted, polyethylene glycol-coated liposomes (ITLs) intended for systemic administration. The ZnPC ITLs were examined for reactive oxygen species (ROS) generation and oxidation capacity and validated for tumoricidal efficacy in human extrahepatic cholangiocarcinoma (Sk-Cha1) cells. ZnPC-ITL uptake and the mechanism and mode of PDT-induced cell death were studied. METHODS: The ITL formulation was optimized on the basis of fluorescence spectroscopy and photon correlation spectroscopy. The extent of ROS generation, protein oxidation, and membrane oxidation were determined by the 2',7'-dichlorodihydrofluorescein, tryptophan oxidation, and calcein leakage assays, respectively. PDT efficacy was evaluated by measuring mitochondrial activity and apoptosis-/necrosis-specific staining in combination with flow cytometry. The uptake of fluorescently labeled ITLs was assayed by confocal microscopy, flow cytometry, and fluorescence spectroscopy. RESULTS: ZnPC ITLs exhibited maximum ROS-generating and oxidation potential at a ZnPC:lipid molar ratio of 0.003. PDT of Sk-Cha1 cells incubated with ZnPC-ITLs induced cell death in a lipid concentration- dependent manner. The mode of PDT-induced cell death comprised both apoptosis and necrosis, with necrotic cell death predominating. Post-PDT cell death was attributable to pre-PDT ZnPC-ITL uptake by cancer cells, which was more efficient at smaller ITL diameters and a more positive surface charge. CONCLUSIONS: ZnPC-ITLs constitute a nanoparticulate photosensitizer delivery system capable of inducing apoptosis and necrosis in cultured extrahepatic cholangiocarcinoma cells by PDT-mediated oxidative processes. PDT-induced cell death is dependent on the extent of ITL uptake, which in turn relies on ITL size and zeta potential. PMID- 23931270 TI - Potential limitations of the NSG humanized mouse as a model system to optimize engineered human T cell therapy for cancer. AB - The genetic modification of peripheral blood lymphocytes using retroviral vectors to redirect T cells against tumor cells has been recently used as a means to generate large numbers of antigen-specific T cells for adoptive cell therapy protocols. However, commonly used retroviral vector-based genetic modification requires T cells to be driven into cell division; this potent mitogenic stimulus is associated with the development of an effector phenotype that may adversely impact upon the long-term engraftment potential and subsequent antitumor effects of T cells. To investigate whether the cytokines used during culture impact upon the engraftment potential of gene-modified T cells, a humanized model employing T cells engrafted with a MART-1-specific T cell receptor adoptively transferred into NOD/Shi-scid IL-2rgamma(-/-) (NSG) immune-deficient mice bearing established melanoma tumors was used to compare the effects of the common gamma chain cytokines IL-2, IL-7, and IL-15 upon gene-modified T cell activity. MART-1 specific T cells cultured in IL-7 and IL-15 demonstrated greater relative in vitro proliferation and viability of T cells compared with the extensively used IL-2. Moreover, the IL-15 culture prolonged the survival of animals bearing melanoma tumors after adoptive transfer. However, the combination of IL-7 and IL 15 produced T cells with improved engraftment potential compared with IL-15 alone; however, a high rate of xenogeneic graft-versus-host disease prevented the identification of a clear improvement in antitumor effect of these T cells. These results clearly demonstrate modulation of gene-modified T cell engraftment in the NSG mouse, which supports the future testing of the combination of IL-7 and IL-15 in adoptive cell therapy protocols; however, this improved engraftment is also associated with the long-term maintenance of xenoreactive T cells, which limits the ultimate usefulness of the NSG mouse model in this situation. PMID- 23931272 TI - Neuroprotective properties of curcumin in Alzheimer's disease--merits and limitations. AB - As demographics in developed nations shift towards an aging population, neurodegenerative pathologies, especially dementias such as Alzheimer's disease, pose one of the largest challenges to the modern health care system. Since there is yet no cure for dementia, there is great pressure to discover potential therapeutics for these diseases. One popular candidate is curcumin or diferuloylmethane, a polyphenolic compound that is the main curcuminoid found in Curcuma longa (family Zingiberaceae). In recent years, curcumin has been reported to possess anti-amyloidogenic, antiinflammatory, anti-oxidative, and metal chelating properties that may result in potential neuroprotective effects. Particularly, the hydrophobicity of the curcumin molecule hints at the possibility of blood-brain barrier penetration and accumulation in the brain. However, curcumin exhibits extremely low bioavailability, mainly due to its poor aqueous solubility, poor stability in solution, and rapid intestinal first-pass and hepatic metabolism. Despite the many efforts that are currently being made to improve the bioavailability of curcumin, brain concentration of curcumin remains low. Furthermore, although many have reported that curcumin possesses a relatively low toxicity profile, curcumin applied at high doses, which is not uncommon practice in many in vivo and clinical studies, may present certain dangers that in our opinion have not been addressed sufficiently. Herein, the neuroprotective potential of curcumin, with emphasis on Alzheimer's disease, as well as its limitations will be discussed in detail. PMID- 23931273 TI - Recent developments on synthetic tools towards structural and functional glycodiversity. AB - Despite being the most abundant type of biopolymers in Nature, the biological relevance of carbohydrates has systematically been underrated for decades, associating them far less sophisticated functions (structural or energy sourcing) than those unraveled for polynucleotides and proteins. The inherently large and complex diversity of carbohydrates and glycoconjugates, together with the lack of efficient technologies to either isolate them from natural sources or produce them synthetically in useful amounts, have burdened the appreciation of their utmost importance in the most fundamental biological processes. For these reasons, carbohydrate-mediated transmission of biological information was largely unexplored. However, over the decades, it became clear that the expression of complex carbohydrates is critical in the development of living systems. Nature uses this diverse repertoire of structures as codes in fundamental biological processes such as cellular differentiation, cellular signaling, fertilization or immune response, among many others. The urgency to elucidate the glycan code in terms of structure-function relationships has fuelled chemical biology approaches uncovering new frontiers in molecular biology, for which the term glycobiology had to be coined in the early 1980s'. Novel strategies for assembling oligosaccharides, glycoproteins, glycolipids and a range of glycoconjugates have flourished ever since providing access to glycomaterials for interrogating and interfering glycan function. This account focuses on the major breakthroughs made on the strategies during the last decades to synthetically reproduce the overwhelming glycodiversity, emphasizing on the dazzling array of concepts and techniques which development was required to cope with the task. In the first place, a succinct overview of the structural and functional diversity of biologically relevant saccharides and glycoconjugates will be given. Then, a selection of the most relevant strategies that composes the complex and diversity oriented toolbox that modern carbohydrate synthesis consists on will be dissected. Finally, a selection of the most recent applications of this synthetic toolbox to chemical biology will be captured. PMID- 23931274 TI - Viral RNA polymerase: a promising antiviral target for influenza A virus. AB - Influenza A virus, which has a high rate of morbidity and mortality, has become a serious threat to human health and society. Because of antigenic variation, the application of influenza vaccination is limited. Till now, the current antivirals are mainly against the M2 protein (such as adamantanes) and the neuraminidase (such as zanamivir and oseltamivir). However, many viral strains have developed resistance to these marketed antiviral drugs, and it is urgent to find new antivirals for the prevention and treatment of influenza. RNA polymerase that is crucial for the replication and transcription in the virus life cycle has been proved to be an effective target for design of new antivirals. In this review, we describe the recent progress of the structure, function, and inhibitors of the novel target. PMID- 23931275 TI - Usefulness of molecular modeling in characterizing the ligand-binding sites of proteins: experience with human PDI, PDIp and COX. AB - In this paper, we discussed our recent experience with the use of computational modeling tools in studying the binding interaction of small molecular weight ligands with their protein targets. Specific examples discussed here include the interaction of estrogens with human protein disulfide isomerase (PDI) and its pancreas-specific homolog (PDIp), and the interaction of dietary flavonoids with human cyclooxygenase (COX) I and II. Using human PDIp as an example, biochemical analysis revealed that the estrogen-binding activity is only associated with PDIp's b-b' domain combination but not associated with the single b or b' domain or any other domains. Homology modeling was then used to build a threedimensional structure of the human PDIp's b-b' fragment. Docking analyses predicted that a hydrogen bond, formed between the 3-hydroxyl group of estradiol and His278 of PDIp's E2-binding site, is critical for the binding interaction. This binding model was then experimentally confirmed by a series of experiments, such as selective mutations of the predicted binding site amino acid residues and the selective modifications of the functional groups of the ligands. Similar combinatorial approaches were used successfully to identify the binding site structure of human PDI for estradiol and the binding site structures of human COX I and II for their phenolic co-substrates. The success with these combinatorial approaches provides the basis for using computational modeling-guided approaches in characterizing the ligand binding site structures of complex proteins whose structures are difficult to decipher with crystallographic studies. PMID- 23931276 TI - Circulating aminopeptidase activities in men and women with essential hypertension. AB - Essential hypertension is one of the major contributors to premature morbidity and mortality due to the incresased risk for coronary heart disease, stroke, renal disease, peripheral vascular disease and vascular dementia for both men and women. However, its basic causes remain unknown. In the present work we studied the activity of several proteolytic regulatory enzymes related to renin angiotensin-system (RAS) (aminopeptidase A, APA; aminopeptidase N, APN; aminopeptidase B, APB; and insulin-regulated aminopeptidase, IRAP); with oxytocin regulation (oxytocinase); with the metabolism of GnRH and TRH (pyrrolidone carboxypeptidase, Pcp); and with enkephalins metabolism (enkephalindegrading activity, EDA), to elucidate their role in the mechanisms responsible of essential hypertension and to discuss the possible gender differences. Serum samples of 53 individuals with essential hypertension and 60 healthy volunteers were collected and used to assay enzyme activities, gonad hormones testosterone and estradiol, TSH and free thyroxin (fT4). Differences were observed in APA, APN, Pcp and EDA specific activities, and in serum gonad hormone levels between hypertensive and control groups. Only Pcp activity showed gender differences. Regarding the RAS, APA is reduced while APN is increased, suggesting increased levels of angiotensin II and a facilitation of the conversion of angiotensin III in angiotensin IV. Thus, the changes in several RAS-regulating specific activities and other enzyme activities involved in the neuroendocrine modulation of gonad and stress-related functions are related to essential hypertension with minor gender differences. Therefore, aminopeptidases constitute new elements for the knowledge of the causes of essential hypertension and an alternative as therapeutic targets against the illness. PMID- 23931277 TI - Updating the use of synthetic peptides as inhibitors of HIV-1 entry. AB - The use of synthetic peptides as HIV-1 inhibitors has been the object of research over recent years. A large number of peptides that affect different stages of the HIV-1 life cycle have been and continue to be studied due to their possible clinical application in the fight against HIV-1 infection. The main advantages of synthetic peptides as therapeutic agents are their low systemic toxicity, the fact that structural modifications can be made to them and their resulting capacity to mimic certain substrates or epitopes. HIV-1-inhibiting peptides have been identified and/or developed using different methods. Some therapeutic peptides such as enfuvirtide-already approved for clinical use-are derived from HIV-1 itself. Others are natural peptides such as chemokines, defensins or the "virus inhibitory peptide"; while still others have been designed and synthesized based on crystallographic data on HIV-1 proteins or from peptide libraries. Initial attempts at therapeutic applications focused on HIV-coded enzymes (reverse transcriptase, protease and, more recently, integrase). However, structural HIV proteins and, more specifically, the mechanisms that involve the virus in cell infection and replication are now also considered therapeutic targets. Several chemical strategies to improve both the stability of peptides and their pharmacokinetics, including prolonging their half-life, have recently been described in the literature. There is growing an interest in inhibitors that prevent HIV entry into the host cell (fusion inhibitors) which could lead to the development of new antiviral agents. Knowledge of the mechanism of action of fusion inhibitors is essential not only for the development of future generations of entry inhibitors, but also to gain an understanding of the form and kinetics of membrane fusion induced by the virus. The physico-chemical processes involved at the interface between the lipid surface of cells and enveloped viruses (such as HIV-1) are essential to the action of peptides that prevent HIV-1 entry into the host cell. The interaction of these peptides with biological membranes may be related to their inhibition efficiency and to their mechanism of action, as the HIV-1 gp41 glycoprotein is bound and confined between the cellular membrane and the viral envelope. PMID- 23931278 TI - Isoniazid: an update on the multiple mechanisms for a singular action. AB - Isoniazid (INH) is one of the most commonly used drugs in treatment of human tuberculosis and the most efficient. Although it has been 60 years since isoniazid was introduced in anti-tubercular therapy and despite the simplicity of its chemical structure (C6H7N3O) with few functional groups, its exact mechanism of action, which could account for its specificity and exceptional potency against Mycobacterium tuberculosis and justify all profiles of INH-resistance, remains elusive and debatable. This complexity can find an explanation in the high reactivity of INH and also in the possibility that multiple targets and pathways could co-exist for this medicinal agent. Indeed, since the discovery of isoniazid's anti-tubercular potency, several propositions for its mode of action have been reported, including its conversion, by a catalase peroxidase within M. tuberculosis, into an active metabolite able, after reaction with NAD, to inhibit an enzyme (InhA) crucial to M. tuberculosis survival. This represents the most consensual mechanism described to date. Nevertheless, none of the proposed mechanisms considered independently can explain the singular and privileged action of the isoniazid structure on the tubercle bacillus, or all the profiles of resistance. The aim of this paper is to reconsider the literature reporting the different modes of action described for isoniazid in the light of the present and most relevant knowledge, with special attention to understanding the molecular mechanistic aspects of the drug's action. PMID- 23931279 TI - Co-drug strategy for promoting skin targeting and minimizing the transdermal diffusion of hydroquinone and tranexamic acid. AB - Hydroquinone and tranexamic acids (TXA) are skin-lightening agents with a hydrophilic nature and low skin absorption. A high dose is needed for clinical use, resulting in a high incidence of skin irritation. Co-drugs formed by conjugating hydroquinone and TXA were synthesized and their in vitro and in vivo skin absorption characteristics were evaluated. The two synthesized co-drugs were 4-hydroxyphenyl 4-(aminomethyl)cyclohexanecarboxylate (HAC) and 1,4- phenylene bis(aminomethyl)cyclohexanecarboxylate (BAC). The co-drugs were chemically stable in aqueous solution, but rapidly degraded to the respective parent drug in esterases and skin homogenates. Compared to hydroquinone application, 7.2- and 2.4-fold increments in the hydroquinone skin deposition were obtained with the in vitro application of HAC and BAC. HAC and BAC led to 3- and 2-fold enhancements of equivalent TXA deposition compared to TXA administration. The in vivo experiment showed a further enhancement of co-drugs compared to the in vitro setup. The transdermal penetration of co-drugs, especially BAC, was much lower than that of hydroquinone and TXA. This indicated high-level skin targeting by the co-drugs. HAC and BAC revealed strong affinities for the viable epidermis/dermis. Hair follicles are important reservoirs for co-drug delivery. Daily administration of co-drugs to the skin did not generate irritation for up to 7 days. Both co-drugs are superior candidates for treating skin hyperpigmentation. PMID- 23931280 TI - Molecular basis of bicarbonate membrane transport in the male reproductive tract. AB - Bicarbonate (HCO3-) membrane transport systems are crucial players in the physiology of several tissues. The molecular basis of HCO3- membrane transport is of major physiological relevance since this ion is involved in the establishment of intracellular and extracellular ionic composition, osmolariy and pH. The membrane HCO3- transporters are divided in two main families: solute carrier 4 (SLC4) and solute carrier 26 (SLC26), although HCO3- concentration can also be regulated by the cystic fibrosis transmembrane regulator (CFTR). In most tissues the SLC4 family represents the majority of HCO3- transporters members, which can be divided in two subgroups: the Na+-dependent and the Na+-independent transporters. The SLC26 family consists of ten members that can transport diverse ions besides HCO3-. In the male reproductive tract, HCO3- transport occurs in several processes in order to assure a correct pursuance of the spermatogenetic event and spermatozoa capacitation, being also necessary for egg fertilization. Indeed, the formation of competent spermatozoa, the maintenance of an adequate ductal luminal milieu and spermatozoa capacitation are highly dependent of ionic balance and pH. Perturbations in these processes result in reduced male reproductive health and consequently male subfertility and/or infertility. Thus, it is imperative to understand HCO3- transport dynamics in order to identify and counteract possible alterations related with reduced male fertility caused by pathological conditions. Herein, we will review the major families and subfamilies of HCO3- membrane transport, discussing the molecular basis of HCO3- transport in the male reproductive tract and its role in male-associated subfertility and/or infertility. PMID- 23931283 TI - Intermolecular vibrations in hydrophobic amino acid crystals: experiments and calculations. AB - Intermolecular vibrations of amino acid crystals occur in the THz, or far infrared, region of the electromagnetic spectrum. We have measured the THz and Raman spectra of DL-leucine as well as two polymorphs of DL-valine, the spectroscopic properties of which have not previously been compared. Theoretical modeling of intermolecular vibrations in hydrophobic amino acids is challenging because the van der Waals interactions between molecules are not accounted for in standard density functional theory. Therefore, to calculate the vibrational modes, we used a recently developed approach that includes these nonlocal electron correlation forces. We discuss methods for comparing results from different theoretical models using metrics other than calculated vibrational frequency and intensity, and we also report a new approach enabling concise comparison of vibrational modes that involve complicated mixtures of inter- and intramolecular displacements. PMID- 23931281 TI - Salinomycin: a novel anti-cancer agent with known anti-coccidial activities. AB - Salinomycin, traditionally used as an anti-coccidial drug, has recently been shown to possess anti-cancer and anti-cancer stem cell (CSC) effects, as well as activities to overcome multi-drug resistance based on studies using human cancer cell lines, xenograft mice, and in case reports involving cancer patients in pilot clinical trials. Therefore, salinomycin may be considered as a promising novel anti-cancer agent despite its largely unknown mechanism of action. This review summarizes the pharmacologic effects of salinomycin and presents possible mechanisms by which salinomycin exerts its anti-tumorigenic activities. Recent advances and potential complications that might limit the utilization of salinomycin as an anti-cancer and anti-CSC agent are also presented and discussed. PMID- 23931284 TI - Protection from UVB Toxicity in Human Keratinocytes by Thailand Native Herbs Extracts. AB - Thai traditional medicine employs a wide range of indigenous herbs in the forms of tincture or tea for the cure of skin and systemic inflammatory diseases. The protection by Thai plants extracts against UVB DNA damage and cytotoxicity was investigated in human keratinocytes. Petroleum ether, dichloromethane and ethanol extracts were prepared from 15 Thai herb species, and the total phenolic and flavonoid contents, the antioxidant and UV-absorbing properties were assessed by standard procedures. Cytoprotective effects were evaluated on the basis of cell survival, caspase-3 activity and pyrimidine dimers determination. High total phenolic and flavonoid contents were found in the ethanol and dichloromethane fractions. Dichloromethane extract of turmeric was shown to possess the highest antioxidant activity. The maximum UV absorptions were found in the ethanol extract of turmeric and in the dichloromethane extract of ginger. These extracts stimulated the synthesis of Thioredoxin 1, an antioxidant protein, and could protect human HaCaT keratinocytes from UV-induced DNA damage and cytotoxicity. The present data support the utilization of turmeric and ginger extracts in anti UV cosmetic pharmaceuticals. PMID- 23931282 TI - Thalidomide-a notorious sedative to a wonder anticancer drug. AB - In the past 50 years, thalidomide has undergone a remarkable metamorphosis from a notorious drug inducing birth defects into a highly effective therapy for treating leprosy and multiple myeloma. Today, most notably, thalidomide and its analogs have shown efficacy against a wide variety of diseases, including inflammation and cancer. The mechanism underlying its teratogenicity as well as its anticancer activities has been intensively studied. This review summarizes the biological effects and therapeutic uses of thalidomide and its analogs, and the underlying mechanisms of thalidomide's action with a focus on its suppression of tumor growth. PMID- 23931285 TI - Enhanced thermoelectric figure of merit in stannite-kuramite solid solutions Cu(2+x)Fe(1-x)SnS(4-y) (x = 0-1) with anisotropy lowering. AB - In this Article, we elucidate the structural and thermoelectric properties of stannite-kuramite solid solutions, Cu(2+x)Fe(1-x)SnS(4-y) (x = 0-1), with sulfur defects (y) <= 0.4. Structural analysis revealed that anisotropy decreases and Cu/Sn disorder increases with an increase in x. The samples with x = 0.8-1 exhibit degenerate conduction, whereas the Seebeck coefficient (S) remains relatively high, S ~ 100 MUV K(-1) for x = 0.8 at 300 K. Thermal conductivities (kappa) of the solid solutions are in the range 10(-3)-10(-2) W cm(-1) K(-1), which is close to the kappa value of silicon dioxide. The dimensionless figure of merit (ZT) reaches 0.044 for x = 0.8 at 300 K. The ZT is enhanced significantly by an increase in temperature and is doubly larger than that of x = 0 at 300 K. These findings allow us to attain higher ZT values through optimization of chemical composition. PMID- 23931286 TI - Occupational therapy interventions with survivors of sexual abuse. AB - Many clients treated by occupational therapists in psychiatric settings are survivors of sexual abuse. The diagnosis of post-traumatic stress disorder (PTSD) and multiple personality disorder (MPD) most accurately reflect the experience of these clients, yet misdiagnosis is common. An overview of these diagnoses is presented. Psychotherapeutic principles are reviewed and a dual approach to occupational therapy is suggested. Within this dual approach, the model of human occupation (Kielhofner & Burke, 1980) is useful in addressing a client's present daily living concerns. Object relations theory guides an occupational therapy focus on recall and emotional recovery from past abuse experiences. A case study illustrating a dual approach to occupational therapy is presented. PMID- 23931287 TI - Activities for the treatment of combat-related post-traumatic stress disorder. AB - The purposes of this article are to review some of the common causes and symptoms of Post-Traumatic Stress Disorder (PTSD), particularly as it applies to combat related trauma experienced by the Vietnam veteran, and to offer a variety of treatment activities. These activities may be graded for use with other types of combat-related trauma or other forms of PTSD. The activities are listed so that they may be used cumulatively. to result in a final ceremony that becomes a ritual for the resolution of ambivalent emotions and/or the expression and release of powerful negative feelings of guilt, rage, or hurt. The objective is for these activities to be included with other treatment approaches aimed at enabling the client to let go of past trauma and make a positive transition to healthful and productive living. PMID- 23931288 TI - Occupational therapy and the treatment of eating disorders. AB - The occupational therapist is vital to providing a complete assessment and thorough treatment of the population with eating disorders. Symptoms and etiology that effect the occupational therapist's reasoning are explored followed by the theoretical frameworks used and specific group intervention at the Sheppard and Enoch Pratt Hospital. Two case studies conclude the article. PMID- 23931289 TI - Self-esteem and leisure patterns of persons in a residential chemical dependency treatment program. AB - Occupational therapists who work with persons who are alcohol and drug dependent often provide services to enhance self-esteem and to promote healthy leisure activities. This article describes a study conducted in a residential chemical dependency program with 101 subjects. Each subject was assessed for selfesteem and leisure interest patterns. Although for the entire group self-esteem was not found to be strongly correlated with a variety of and involvement in leisure activities, decreased past involvement in activities was found to be prevalent in those subjects with a low self-esteem. Treatment and evaluation implications for the occupational therapist in a chemical dependency setting are discussed. PMID- 23931290 TI - Neurocognition and alcoholism:. AB - Various neurocognitive deficits related to alcoholism interfere with participation in intensive treatment programs which often have strong learning components. Some of these learning impairments resolve with abstinence (timedependent recovery). Others, which normally do not recover with abstinence, may be remediated with selected neurocognitive stimulation (experiencedependent recovery). An overview of research findings examining experiencedependent recovery is provided, along with a neurocognitive model for occupational therapy intervention during detoxification of the person with alcohol dependence. Emphasis is given to occupational therapy evaluation and assessment of neurocognitive recovery and the corresponding treatment strategies designed to facilitate experience-dependent recovery in alcoholism. PMID- 23931291 TI - Neuropathology in schizophrenia:. AB - Though our understanding of brain functioning as it relates to schizophrenia is still in a stage of infancy, knowledge of available research can provide insight into the illness and influence treatment decisions. The literature on brain abnormalities and schizophrenia provides a foundation for understanding the functional deficits that ensue. Occupational therapists who work with individuals with schizophrenia must now incorporate biological models into existing theories and possibly alter treatment approaches. A neurorehabilitation approach used by occupational therapists may allow the treatment of patients labeled "chronic" or "treatment resistive." By initially addressing deficits at a cognitive level, patients may improve and take advantage of treatment groups at more complex levels. This paper supports a neurophysiological model for the etiology of schizophrenia and the need to re-adjust mental health treatment strategies with specific implications for occupational therapy. Issues discussed include assessment, types of treatment, and other treatment considerations and strategies for patients with schizophrenia. A case example is presented. PMID- 23931292 TI - Neutralizing the narcissistic style:. AB - The diagnosis of narcissistic personality disorder has become more prevalent in psychiatric settings over the last decade. Contemporary psychological literature has addressed this disorder, yet the occupational therapy literature has not. The author contends that occupational therapy provides relevant treatment for those with this syndrome. The article describes: (1) clinical features of the disorder, (2) current psychological theory and approach useful for treatment, (3) why and how occupational therapy is a unique, natural medium for treatment, and (4) an occupational therapy program tailored to the needs of those with narcissistic character disorder. PMID- 23931293 TI - The role of occupational therapy in a health maintenance program for pulmonary transplant candidates. AB - This article describes an intervention model for occupational therapists who treat individuals awaiting pulmonary transplantation. Supportive occupational therapy interventions aimed at helping patients cope with the physical and psychosocial stresses that impede functional performance are described. Psychosocial and physical indicators of the functional status of pulmonary transplant candidates that may be amenable to occupational therapy intervention are identified. Treatment issues related to occupational therapy are presented and implications for occupational therapy research are suggested. The model may also be applied to patient populations having chronic, debilitating illnesses. PMID- 23931294 TI - School-based occupational therapy for students with behavioral disorders. AB - Although occupational therapists are employed in large numbers by public schools, their services are limited to students whose handicapping conditions are primarily physiological. Students with behavioral disorders are rarely referred to occupational therapy. This article synthesizes education, psychology and occupational therapy literature to identify the essential constructs of a holistic intervention for the student with a behavioral disorder. A model program based on the concept of occupational activity illustrates implementation. PMID- 23931295 TI - Supervision processes for students and staff who treat persons with AIDS. AB - Supervision of students and staff working with persons who have AIDS is a challenging process under constant revision as new public policy and research about AIDS unfolds. A systematic process with a structured schema for supervision is proposed in this article to facilitate the application of well known supervisory processes to an area of treatment which is still developing. PMID- 23931296 TI - Level I fieldwork in a daycare for homeless children. AB - The author was part of a task force that developed a mental health cuniculum for a daycare for homeless children. An outgrowth of this involvement was the opportunity to use the facility as a Level I Fieldwork site. This article describes the cumculum and the student program. PMID- 23931297 TI - A model for selecting leadership styles. AB - Occupational therapists lead a variety of groups during their professional activities. Such groups include therapy groups, treatment teams and management meetings. Therefore it is important for each therapist to understand theories of leadership and be able to select the most effective style for him or herself in specific situations. This paper presents a review of leadership theory and research as well as therapeutic groups. It then integrates these areas to assist students and new therapists in identifying a style that is effective for a particular group. PMID- 23931298 TI - From the editor. AB - No abstract available for this article. PMID- 23931299 TI - Synthesis of 2-nitroglycals from glycals using the tetrabutylammonium nitrate trifluoroacetic anhydride-triethylamine reagent system and base-catalyzed Ferrier rearrangement of acetylated 2-nitroglycals. AB - A reagent system comprising tetrabutylammonium nitrate-trifluoroacetic anhydride triethylamine has been developed for the synthesis of 2-nitroglycals from various protected glycals. The base-catalyzed Ferrier rearrangement on tri-O-acetylated 2 nitroglycals has been reported for the first time. Reactivity of these nitroacetates and associated selectivity has been examined, and some of the products have been converted into 2,3-diamino-2,3-dideoxyglycosides and methyl N acetyl-D-lividosaminide. PMID- 23931300 TI - DNA capture and translocation through nanoscale pores-a fine balance of electrophoresis and electroosmosis. PMID- 23931301 TI - Efficiently refining a transition path using clustering. PMID- 23931302 TI - Force to divide: structural and mechanical requirements for actomyosin ring contraction. AB - One of the unresolved questions in the field of cell division is how the actomyosin cytoskeleton remains structurally organized while generating the contractile force to divide one cell into two. In analogy to the actomyosin-based force production mechanism in striated muscle, it was originally proposed that contractile stress in the actomyosin ring is generated via a sliding filament mechanism within an organized sarcomere-like array. However, over the last 30 years, ultrastructural and functional studies have noted important distinctions between cytokinetic structures in dividing cells and muscle sarcomeres. Myosin-II motor activity is not always required, and there is evidence that actin depolymerization contributes to contraction. In this Review, the architecture and contractile dynamics of the actomyosin ring at the cell division plane will be discussed. We will report the interdisciplinary advances in the field as well as their integration into a mechanistic understanding of contraction in cell division and in other biological processes that rely on an actomyosin-based force generating system. PMID- 23931304 TI - A simple kinetic model with explicit predictions for nuclear transport. AB - Molecular exchange between the cell nucleus and cytoplasm is one of the most fundamental features of eukaryotic cell biology. The nuclear pores act as a conduit of this transport, both for cargo that crosses the pore autonomously as well as that whose translocation requires an intermediary receptor. The major class of such receptors is regulated by the small GTPase Ran, via whose interaction the nucleo-cytoplasmic transport system functions as a selective molecular pump. We propose a simple analytical model for transport that includes both translocation and receptor binding kinetics. The model is suitable for steady-state kinetics such as fluorescence recovery after photobleaching. Time constants appear as a combination of parameters whose effects on measured kinetics are not separable. Competitive cargo binding to receptors and large cytoplasmic volume buffer the transport properties of any particular cargo. Specific limits to the solutions provide a qualitative insight and interpretation of nuclear transport in the cellular context. Most significantly, we find that under realistic conditions receptor binding, rather than permeability of the nuclear pores, may be rate-limiting for nucleo-cytoplasmic exchange. PMID- 23931303 TI - Four-dimensional spatial nanometry of single particles in living cells using polarized quantum rods. AB - Single particle tracking is widely used to study protein movement with high spatiotemporal resolution both in vitro and in cells. Quantum dots, which are semiconductor nanoparticles, have recently been employed in single particle tracking because of their intense and stable fluorescence. Although single particles inside cells have been tracked in three spatial dimensions (X, Y, Z), measurement of the angular orientation of a molecule being tracked would significantly enhance our understanding of the molecule's function. In this study, we synthesized highly polarized, rod-shaped quantum dots (Qrods) and developed a coating method that optimizes the Qrods for biological imaging. We describe a Qrod-based single particle tracking technique that blends optical nanometry with nanomaterial science to simultaneously measure the three dimensional and angular movements of molecules. Using Qrods, we spatially tracked a membrane receptor in living cells in four dimensions with precision close to the single-digit range in nanometers and degrees. PMID- 23931305 TI - Monitoring actin cortex thickness in live cells. AB - Animal cell shape is controlled primarily by the actomyosin cortex, a thin cytoskeletal network that lies directly beneath the plasma membrane. The cortex regulates cell morphology by controlling cellular mechanical properties, which are determined by network structure and geometry. In particular, cortex thickness is expected to influence cell mechanics. However, cortex thickness is near the resolution limit of the light microscope, making studies relating cortex thickness and cell shape challenging. To overcome this, we developed an assay to measure cortex thickness in live cells, combining confocal imaging and subresolution image analysis. We labeled the actin cortex and plasma membrane with chromatically different fluorophores and measured the distance between the resulting intensity peaks. Using a theoretical description of cortex geometry and microscopic imaging, we extracted an average cortex thickness of ~190 nm in mitotic HeLa cells and tested the validity of our assay using cell images generated in silico. We found that thickness increased after experimental treatments preventing F-actin disassembly. Finally, we monitored physiological changes in cortex thickness in real-time during actin cortex regrowth in cellular blebs. Our investigation paves the way to understanding how molecular processes modulate cortex structure, which in turn drives cell morphogenesis. PMID- 23931306 TI - Determinants of maximal force transmission in a motor-clutch model of cell traction in a compliant microenvironment. AB - The mechanical stiffness of a cell's environment exerts a strong, but variable, influence on cell behavior and fate. For example, different cell types cultured on compliant substrates have opposite trends of cell migration and traction as a function of substrate stiffness. Here, we describe how a motor-clutch model of cell traction, which exhibits a maximum in traction force with respect to substrate stiffness, may provide a mechanistic basis for understanding how cells are tuned to sense the stiffness of specific microenvironments. We find that the optimal stiffness is generally more sensitive to clutch parameters than to motor parameters, but that single parameter changes are generally only effective over a small range of values. By contrast, dual parameter changes, such as coordinately increasing the numbers of both motors and clutches offer a larger dynamic range for tuning the optimum. The model exhibits distinct regimes: at high substrate stiffness, clutches quickly build force and fail (so-called frictional slippage), whereas at low substrate stiffness, clutches fail spontaneously before the motors can load the substrate appreciably (a second regime of frictional slippage). Between the two extremes, we find the maximum traction force, which occurs when the substrate load-and-fail cycle time equals the expected time for all clutches to bind. At this stiffness, clutches are used to their fullest extent, and motors are therefore resisted to their fullest extent. The analysis suggests that coordinate parameter shifts, such as increasing the numbers of motors and clutches, could underlie tumor progression and collective cell migration. PMID- 23931307 TI - Quantification of biomass and cell motion in human pluripotent stem cell colonies. AB - Somatic cell reprogramming to pluripotency requires an immediate increase in cell proliferation and reduction in cell size. It is unknown whether proliferation and biomass controls are similarly coordinated with early events during the differentiation of pluripotent stem cells (PSCs). This impasse exists because PSCs grow in tight clusters or colonies, precluding most quantifying approaches. Here, we investigate live cell interferometry as an approach to quantify the biomass and growth of HSF1 human PSC colonies before and during retinoic acid induced differentiation. We also provide an approach for measuring the rate and coordination of intracolony mass redistribution in HSF1 clusters using live cell interferometry images. We show that HSF1 cells grow at a consistent, exponential rate regardless of colony size and display coordinated intracolony movement that ceases with the onset of differentiation. By contrast, growth and proliferation rates show a decrease of only ~15% decrease during early differentiation despite global changes in gene expression and previously reported changes in energy metabolism. Overall, these results suggest that cell biomass and proliferation are regulated independent of pluripotency during early differentiation, which is distinct from what occurs with successful reprogramming. PMID- 23931308 TI - Quantitative imaging of protein secretions from single cells in real time. AB - Protein secretions from individual cells create spatially and temporally varying concentration profiles in the extracellular environment, which guide a wide range of biological processes such as wound healing and angiogenesis. Fluorescent and colorimetric probes for the detection of single cell secretions have time resolutions that range from hours to days, and as a result, little is known about how individual cells may alter their protein secretion rates on the timescale of minutes or seconds. Here, we present a label-free technique based upon nanoplasmonic imaging, which enabled the measurement of individual cell secretions in real time. When applied to the detection of antibody secretions from single hybridoma cells, the enhanced time resolution revealed two modes of secretion: one in which the cell secreted continuously and another in which antibodies were released in concentrated bursts that coincided with minute-long morphological contractions of the cell. From the continuous secretion measurements we determined the local concentration of antibodies at the sensing array closest to the cell and from the bursts we estimated the diffusion constant of the secreted antibodies through the extracellular media. The design also incorporates transmitted light and fluorescence microscopy capabilities for monitoring cellular morphological changes and intracellular fluorescent labels. We anticipate that this technique can be adapted as a general tool for the quantitative study of paracrine signaling in both adherent and nonadherent cell lines. PMID- 23931309 TI - Cellular pressure and volume regulation and implications for cell mechanics. AB - In eukaryotic cells, small changes in cell volume can serve as important signals for cell proliferation, death, and migration. Volume and shape regulation also directly impacts the mechanics of cells and tissues. Here, we develop a mathematical model of cellular volume and pressure regulation, incorporating essential elements such as water permeation, mechanosensitive channels, active ion pumps, and active stresses in the cortex. The model can fully explain recent experimental data, and it predicts cellular volume and pressure for several models of cell cortical mechanics. Moreover, we show that when cells are subjected to an externally applied load, such as in an atomic force microscopy indentation experiment, active regulation of volume and pressure leads to a complex cellular response. Instead of the passive mechanics of the cortex, the observed cell stiffness depends on several factors working together. This provides a mathematical explanation of rate-dependent response of cells under force. PMID- 23931310 TI - Binding mechanism of the peptidoglycan hydrolase Acm2: low affinity, broad specificity. AB - Peptidoglycan hydrolases are bacterial secreted enzymes that cleave covalent bonds in the cell-wall peptidoglycan, thereby fulfilling major physiological functions during cell growth and division. Although the molecular structure and functional roles of these enzymes have been widely studied, the molecular details underlying their interaction with peptidoglycans remain largely unknown, mainly owing to the paucity of appropriate probing techniques. Here, we use atomic force microscopy to explore the binding mechanism of the major autolysin Acm2 from the probiotic bacterium Lactobacillus plantarum. Atomic force microscopy imaging shows that incubation of bacterial cells with Acm2 leads to major alterations of the cell-surface nanostructure, leading eventually to cell lysis. Single-molecule force spectroscopy demonstrates that the enzyme binds with low affinity to structurally different peptidoglycans and to chitin, and that glucosamine in the glycan chains is the minimal binding motif. We also find that Acm2 recognizes mucin, the main extracellular component of the intestinal mucosal layer, thereby suggesting that this enzyme may also function as a cell adhesion molecule. The binding mechanism (low affinity and broad specificity) of Acm2 may represent a generic mechanism among cell-wall hydrolases for guiding cell division and cell adhesion. PMID- 23931311 TI - Coupled global and local changes direct substrate translocation by neurotransmitter-sodium symporter ortholog LeuT. AB - Significant advances have been made in recent years in characterizing neurotransmitter:sodium symporter (NSS) family structure and function. Yet, many time-resolved events and intermediates that control the various stages of transport cycle remain to be elucidated. Whether NSSs harbor one or two sites for binding their substrates (neurotransmitters or amino acids), and what the role of the secondary site S2 is, if any, are still unresolved. Using molecular modeling and simulations for LeuT, a bacterial NSS, we present a comprehensive account of substrate-binding and -stabilization events, and subsequently triggered interactions leading to substrate (alanine) release. LeuT instantaneous conformation as it reconfigures from substrate-receiving (outward-facing) to releasing (inward-facing) state appears to be a determinant of its affinity to bind substrate at site S2. In the outward-facing state, S1 robustly binds alanine and regulates subsequent redistribution of interactions to trigger extracellular gate closure; whereas S2 is only a transient binding site. The substrate-binding affinity at S2 increases in an intermediate close to inward-facing state. LeuT harbors the two substrate-binding sites, and small displacements of second substrate near S2 are observed to induce concerted small translocations in the substrate bound to primary site S1, although complete release requires collective structural rearrangements that fully expose the intracellular vestibule to the cytoplasm. PMID- 23931312 TI - Stabilization of the GluCl ligand-gated ion channel in the presence and absence of ivermectin. AB - Improving our understanding of the mechanisms and effects of anesthetics is a critically important part of neuroscience. The currently dominant theory is that anesthetics and similar molecules act by binding to Cys-loop receptors in the postsynaptic terminal of nerve cells and potentiate or inhibit their function. Although structures for some of the most important mammalian channels have still not been determined, a number of important results have been derived from work on homologous cationic channels in bacteria. However, partly due to the lack of a nervous system in bacteria, there are a number of questions about how these results relate to higher organisms. The recent determination of a structure of the eukaryotic chloride channel, GluCl, is an important step toward accurate modeling of mammalian channels, because it is more similar in function to human Cys-loop receptors such as GABAAR or GlyR. One potential issue with using GluCl to model other receptors is the presence of the large ligand ivermectin (IVM) positioned between all five subunits. Here, we have performed a series of microsecond molecular simulations to study how the dynamics and structure of GluCl change in the presence versus absence of IVM. When the ligand is removed, subunits move at least 2 A closer to each other compared to simulations with IVM bound. In addition, the pore radius shrinks to 1.2 A, all of which appears to support a model where IVM binding between subunits stabilizes an open state, and that the relaxed nonIVM conformations might be suitable for modeling other channels. Interestingly, the presence of IVM also has an effect on the structure of the important loop C located at the neurotransmitter-binding pocket, which might help shed light on its partial agonist behavior. PMID- 23931313 TI - Dodecyl maltoside protects membrane proteins in vacuo. AB - Molecular dynamics simulations have been used to characterize the effects of transfer from aqueous solution to a vacuum to inform our understanding of mass spectrometry of membrane-protein-detergent complexes. We compared two membrane protein architectures (an alpha-helical bundle versus a beta-barrel) and two different detergent types (phosphocholines versus an alkyl sugar) with respect to protein stability and detergent packing. The beta-barrel membrane protein remained stable as a protein-detergent complex in vacuum. Zwitterionic detergents formed conformationally destabilizing interactions with an alpha-helical membrane protein after detergent micelle inversion driven by dehydration in vacuum. In contrast, a nonionic alkyl sugar detergent resisted micelle inversion, maintaining the solution-phase conformation of the protein. This helps to explain the relative stability of membrane proteins in the presence of alkyl sugar detergents such as dodecyl maltoside. PMID- 23931314 TI - Membrane structure correlates to function of LLP2 on the cytoplasmic tail of HIV 1 gp41 protein. AB - Mutation studies previously showed that the lentivirus lytic peptide (LLP2) sequence of the cytoplasmic C-terminal tail of the HIV-1 gp41 envelope protein inhibited viral-initiated T-cell death and T-cell syncytium formation, at which time in the HIV life cycle the gp41 protein is embedded in the T-cell membrane. In striking contrast, the mutants did not affect virion infectivity, during which time the gp41 protein is embedded in the HIV envelope membrane. To examine the role of LLP2/membrane interactions, we applied synchrotron x-radiation to determine structure of hydrated membranes. We focused on WT LLP2 peptide (+3 charge) and MX2 mutant (-1 charge) with membrane mimics for the T-cell and the HIV-1 membranes. To investigate the influence of electrostatics, cholesterol content, and peptide palmitoylation, we also studied three other LLP2 variants and HIV-1 mimics without negatively charged lipids or cholesterol as well as extracted HIV-1 lipids. All LLP2 peptides bound strongly to T-cell membrane mimics, as indicated by changes in membrane structure and bending. In contrast, none of the weakly bound LLP2 variants changed the HIV-1 membrane mimic structure or properties. This correlates well with, and provides a biophysical basis for, previously published results that reported lack of a mutant effect in HIV virion infectivity in contrast to an inhibitory effect in T-cell syncytium formation. It shows that interaction of LLP2 with the T-cell membrane modulates biological function. PMID- 23931315 TI - Investigation of homeodomain membrane translocation properties: insights from the structure determination of engrailed-2 homeodomain in aqueous and membrane mimetic environments. AB - In addition to their well-known DNA-binding properties, homeodomains have the ability to efficiently translocate across biological membranes through still poorly-characterized mechanisms. To date, most biophysical studies addressing the mechanisms of internalization have focused on small synthetic peptides rather than full-length globular homeodomains. In this work, we characterized the conformational properties of chicken Engrailed 2 homeodomain (En2HD) in aqueous solution and in membrane mimetic environments using circular dichroism, Trp fluorescence, and NMR spectroscopy. En2HD adopts a well-defined three-helical bundle fold in aqueous solution. The Trp-48 residue, which is critical for internalization, is fully buried in the hydrophobic core. Circular dichroism and fluorescence reveal that a conformational transition occurs in anionic lipid vesicles and in micelles. En2HD loses its native three-dimensional structure in micellar environments but, remarkably, near-native helical secondary structures are maintained. Long-range interactions could be detected using site-directed spin labels, indicating that the three helices do not adopt extended orientations. Noncovalent paramagnetic probes yielded information about helix positioning and unveiled the burial of critical aromatic and basic residues within the micelles. Our results suggest that electrostatic interactions with membranes may be determinant in inducing a conformational change enabling Trp-48 to insert into membranes. PMID- 23931316 TI - Interaction of the complexin accessory helix with the C-terminus of the SNARE complex: molecular-dynamics model of the fusion clamp. AB - SNARE complexes form between the synaptic vesicle protein synaptobrevin and the plasma membrane proteins syntaxin and SNAP25 to drive membrane fusion. A cytosolic protein, complexin (Cpx), binds to the SNARE bundle, and its accessory helix (AH) functions to clamp synaptic vesicle fusion. We performed molecular dynamics simulations of the SNARE/Cpx complex and discovered that at equilibrium the Cpx AH forms tight links with both synaptobrevin and SNAP25. To simulate the effect of electrostatic repulsion between vesicle and membrane on the SNARE complex, we calculated the electrostatic force and performed simulations with an external force applied to synaptobrevin. We found that the partially unzipped state of the SNARE bundle can be stabilized by interactions with the Cpx AH, suggesting a simple mechanistic explanation for the role of Cpx in fusion clamping. To test this model, we performed experimental and computational characterizations of the syx(3-69)Drosophila mutant, which has a point mutation in syntaxin that causes increased spontaneous fusion. We found that this mutation disrupts the interaction of the Cpx AH with synaptobrevin, partially imitating the cpx null phenotype. Our results support a model in which the Cpx AH clamps fusion by binding to the synaptobrevin C-terminus, thus preventing full SNARE zippering. PMID- 23931317 TI - NMR-based simulation studies of Pf1 coat protein in explicit membranes. AB - As time- and ensemble-averaged measures, NMR observables contain information about both protein structure and dynamics. This work represents a computational study to extract such information for membrane proteins from orientation dependent NMR observables: solid-state NMR chemical shift anisotropy and dipolar coupling, and solution NMR residual dipolar coupling. We have performed NMR restrained molecular dynamics simulations to refine the structure of the membrane bound form of Pf1 coat protein in explicit lipid bilayers using the recently measured chemical shift anisotropy, dipolar coupling, and residual dipolar coupling data. From the simulations, we have characterized detailed protein-lipid interactions and explored the dynamics. All simulations are stable and the NMR restraints are well satisfied. The C-terminal transmembrane (TM) domain of Pf1 finds its optimal position in the membrane quickly (within 6 ns), illustrating efficient solvation of TM domains in explicit bilayer environments. Such rapid convergence also leads to well-converged interaction patterns between the TM helix and the membrane, which clearly show the interactions of interfacial membrane-anchoring residues with the lipids. For the N-terminal periplasmic helix of Pf1, we identify a stable, albeit dynamic, helix orientation parallel to the membrane surface that satisfies the amphiphatic nature of the helix in an explicit lipid bilayer. Such detailed information cannot be obtained solely from NMR observables. Therefore, the present simulations illustrate the usefulness of NMR-restrained MD refinement of membrane protein structure in explicit membranes. PMID- 23931318 TI - Structure and topology of the huntingtin 1-17 membrane anchor by a combined solution and solid-state NMR approach. AB - The very amino-terminal domain of the huntingtin protein is directly located upstream of the protein's polyglutamine tract, plays a decisive role in several important properties of this large protein and in the development of Huntington's disease. This huntingtin 1-17 domain is on the one hand known to markedly increase polyglutamine aggregation rates and on the other hand has been shown to be involved in cellular membrane interactions. Here, we determined the high resolution structure of huntingtin 1-17 in dodecyl phosphocholine micelles and the topology of its helical domain in oriented phosphatidylcholine bilayers. Using two-dimensional solution NMR spectroscopy the low-energy conformations of the polypeptide were identified in the presence of dodecyl phosphocholine detergent micelles. In a next step a set of four solid-state NMR angular restraints was obtained from huntingtin 1-17 labeled with (15)N and (2)H at selected sites. Of the micellar ensemble of helical conformations only a limited set agrees in quantitative detail with the solid-state angular restraints of huntingtin 1-17 obtained in supported planar lipid bilayers. Thereby, the solid state NMR data were used to further refine the domain structure in phospholipid bilayers. At the same time its membrane topology was determined and different motional regimes of this membrane-associated domain were explored. The pronounced structural transitions of huntingtin 1-17 upon membrane-association result in a alpha-helical conformation from K6 to F17, i.e., up to the very start of the polyglutamine tract. This amphipathic helix is aligned nearly parallel to the membrane surface (tilt angle ~77 degrees ) and is characterized by a hydrophobic ridge on one side and an alternation of cationic and anionic residues that run along the hydrophilic face of the helix. This arrangement facilitates electrostatic interactions between huntingtin 1-17 domains and possibly with the proximal polyglutamine tract. PMID- 23931319 TI - Protein-mediated transformation of lipid vesicles into tubular networks. AB - Key cellular processes are frequently accompanied by protein-facilitated shape changes in the plasma membrane. N-BAR-domain protein modules generate curvature by means of complex interactions with the membrane surface. The way they assemble and the mechanism by which they operate are largely dependent on their binding density. Although the mechanism at lower densities has recently begun to emerge, how membrane scaffolds form at high densities remains unclear. By combining electron microscopy and multiscale simulations, we show that N-BAR proteins at high densities can transform a lipid vesicle into a 3D tubular network. We show that this process is a consequence of excess adhesive energy combined with the local stiffening of the membrane, which occurs in a narrow range of mechanical properties of both the membrane and the protein. We show that lipid diffusion is significantly reduced by protein binding at this density regime and even more in areas of high Gaussian curvature, indicating a potential effect on molecular transport in cells. Finally, we reveal that the breaking of the bilayer topology is accompanied by the nematic arrangement of the protein on the surface, a structural motif that likely drives the formation of reticular structures in living cells. PMID- 23931320 TI - Small-angle neutron scattering characterization of monoclonal antibody conformations and interactions at high concentrations. AB - Small-angle neutron scattering (SANS) is used to probe the solution structure of two protein therapeutics (monoclonal antibodies 1 and 2 (MAb1 and MAb2)) and their protein-protein interaction (PPI) at high concentrations. These MAbs differ by small sequence alterations in the complementarity-determining region but show very large differences in solution viscosity. The analyses of SANS patterns as a function of different solution conditions suggest that the average intramolecular structure of both MAbs in solution is not significantly altered over the studied protein concentrations and experimental conditions. Even though a strong repulsive interaction is expected for both MAbs due to their net charges and low solvent ionic strength, analysis of the SANS data shows that the effective PPI for MAb1 is dominated by a very strong attraction at small volume fraction that becomes negligible at large concentrations. The MAb1 PPI cannot be modeled simply by a spherically symmetric central forces model. It is proposed that an anisotropic attraction strongly affects the local interprotein structure and leads to an anomalously large viscosity of concentrated MAb1 solutions. Conversely, MAb2 displays a repulsive interaction potential throughout the concentration series probed and a comparatively small solution viscosity. PMID- 23931321 TI - Flexibility of the bacterial chaperone trigger factor in microsecond-timescale molecular dynamics simulations. AB - The bacterial chaperone trigger factor (TF) is the first chaperone to be encountered by a nascent protein chain as it emerges from the ribosome exit tunnel. Experimental results suggest that TF possesses considerable conformational flexibility, and in an attempt to provide an atomic-level view of this flexibility, we have performed independent 1.5-MUs molecular dynamics simulations of TF in explicit solvent using two different simulation force fields (OPLS-AA/L and AMBER ff99SB-ILDN). Both simulations indicate that TF possesses tremendous flexibility, with huge excursions from the crystallographic conformation caused by reorientations of the protein's constituent domains; both simulations also predict the formation of extensive contacts between TF's PPIase domain and the Arm 1 domain that is involved in nascent-chain binding. In the OPLS simulation, however, TF rapidly settles into a very compact conformation that persists for at least 1 MUs, whereas in the AMBER simulation, it remains highly dynamic; additional simulations in which the two force fields were swapped suggest that these differences are at least partly attributable to sampling issues. The simulation results provide potential rationalizations of a number of experimental observations regarding TF's conformational behavior and have implications for using simulations to model TF's function on translating ribosomes. PMID- 23931322 TI - Aggregation modulators interfere with membrane interactions of beta2 microglobulin fibrils. AB - Amyloid fibril accumulation is a pathological hallmark of several devastating disorders, including Alzheimer's disease, prion diseases, type II diabetes, and others. Although the molecular factors responsible for amyloid pathologies have not been deciphered, interactions of misfolded proteins with cell membranes appear to play important roles in these disorders. Despite increasing evidence for the involvement of membranes in amyloid-mediated cytotoxicity, the pursuit for therapeutic strategies has focused on preventing self-assembly of the proteins comprising the amyloid plaques. Here we present an investigation of the impact of fibrillation modulators upon membrane interactions of beta2 microglobulin (beta2m) fibrils. The experiments reveal that polyphenols (epigallocatechin gallate, bromophenol blue, and resveratrol) and glycosaminoglycans (heparin and heparin disaccharide) differentially affect membrane interactions of beta2m fibrils measured by dye-release experiments, fluorescence anisotropy of labeled lipid, and confocal and cryo-electron microscopies. Interestingly, whereas epigallocatechin gallate and heparin prevent membrane damage as judged by these assays, the other compounds tested had little, or no, effect. The results suggest a new dimension to the biological impact of fibrillation modulators that involves interference with membrane interactions of amyloid species, adding to contemporary strategies for combating amyloid diseases that focus on disruption or remodeling of amyloid aggregates. PMID- 23931323 TI - Single-molecule kinetics reveal cation-promoted DNA duplex formation through ordering of single-stranded helices. AB - In this work, the kinetics of short, fully complementary oligonucleotides are investigated at the single-molecule level. Constructs 6-9 bp in length exhibit single exponential kinetics over 2 orders of magnitude time for both forward (kon, association) and reverse (koff, dissociation) processes. Bimolecular rate constants for association are weakly sensitive to the number of basepairs in the duplex, with a 2.5-fold increase between 9 bp (k'on = 2.1(1) * 10(6) M(-1) s(-1)) and 6 bp (k'on = 5.0(1) * 10(6) M(-1) s(-1)) sequences. In sharp contrast, however, dissociation rate constants prove to be exponentially sensitive to sequence length, varying by nearly 600-fold over the same 9 bp (koff = 0.024 s( 1)) to 6 bp (koff = 14 s(-1)) range. The 8 bp sequence is explored in more detail, and the NaCl dependence of kon and koff is measured. Interestingly, kon increases by >40-fold (kon = 0.10(1) s(-1) to 4.0(4) s(-1) between [NaCl] = 25 mM and 1 M), whereas in contrast, koff decreases by fourfold (0.72(3) s(-1) to 0.17(7) s(-1)) over the same range of conditions. Thus, the equilibrium constant (Keq) increases by ~160, largely due to changes in the association rate, kon. Finally, temperature-dependent measurements reveal that increased [NaCl] reduces the overall exothermicity (DeltaDeltaH degrees > 0) of duplex formation, albeit by an amount smaller than the reduction in entropic penalty (-TDeltaDeltaS degrees < 0). This reduced entropic cost is attributed to a cation-facilitated preordering of the two single-stranded species, which lowers the association free energy barrier and in turn accelerates the rate of duplex formation. PMID- 23931325 TI - Mechanism of how salt-gradient-induced charges affect the translocation of DNA molecules through a nanopore. AB - Experiments using nanopores demonstrated that a salt gradient enhances the capture rate of DNA and reduces its translocation speed. These two effects can help to enable electrical DNA sequencing with nanopores. Here, we provide a quantitative theoretical evaluation that shows the positive net charges, which accumulate around the pore entrance due to the salt gradient, are responsible for the two observed effects: they reinforce the electric capture field, resulting in promoted molecule capture rate; and they induce cationic electroosmotic flow through the nanopore, thus significantly retarding the motion of the anionic DNA through the nanopore. Our multiphysical simulation results show that, during the polymer trapping stage, the former effect plays the major role, thus resulting in promoted DNA capture rate, while during the nanopore-penetrating stage the latter effect dominates and consequently reduces the DNA translocation speed significantly. Quantitative agreement with experimental results has been reached by further taking nanopore wall surface charges into account. PMID- 23931324 TI - Energetic and structural details of the trigger-loop closing transition in RNA polymerase II. AB - An evolutionarily conserved element in RNA polymerase II, the trigger loop (TL), has been suggested to play an important role in the elongation rate, fidelity of selection of the matched nucleoside triphosphate (NTP), catalysis of transcription elongation, and translocation in both eukaryotes and prokaryotes. In response to NTP binding, the TL undergoes large conformational changes to switch between distinct open and closed states to tighten the active site and avail catalysis. A computational strategy for characterizing the conformational transition pathway is presented to bridge the open and closed states of the TL. Information from a large number of independent all-atom molecular dynamics trajectories from Hamiltonian replica exchange and targeted molecular dynamics simulations is gathered together to assemble a connectivity map of the conformational transition. The results show that with a cognate NTP, TL closing should be a spontaneous process. One major intermediate state is identified along the conformational transition pathway, and the key structural features are characterized. The complete pathway from the open TL to the closed TL provides a clear picture of the TL closing. PMID- 23931326 TI - Pressure and temperature dependence of growth and morphology of Escherichia coli: experiments and stochastic model. AB - We have investigated the growth of Escherichia coli, a mesophilic bacterium, as a function of pressure (P) and temperature (T). Escherichia coli can grow and divide in a wide range of pressure (1-400 atm) and temperature (23-40 degrees C). For T > 30 degrees C, the doubling time of E. coli increases exponentially with pressure and exhibits a departure from exponential behavior at pressures between 250 and 400 atm for all the temperatures studied in our experiments. The sharp change in doubling time is followed by a sharp change in phenotypic transition of E. coli at high pressures where bacterial cells switch to an elongating cell type. We propose a model that this phenotypic change in bacteria at high pressures is an irreversible stochastic process, whereas the switching probability to elongating cell type increases with increasing pressure. The model fits well the experimental data. We discuss our experimental results in the light of structural and thus functional changes in proteins and membranes. PMID- 23931327 TI - The delicate bistability of CaMKII. AB - Calcium/calmodulin-dependent protein kinase II (CaMKII) is a synaptic, autophosphorylating kinase that is essential for learning and memory. Previous models have suggested that CaMKII functions as a bistable switch that could be the molecular correlate of long-term memory, but experiments have failed to validate these predictions. These models involved significant approximations to overcome the combinatorial complexity inherent in a multisubunit, multistate system. Here, we develop a stochastic particle-based model of CaMKII activation and dynamics that overcomes combinatorial complexity without significant approximations. We report four major findings. First, the CaMKII model system is never bistable at resting calcium concentrations, which suggests that CaMKII activity does not function as the biochemical switch underlying long-term memory. Second, the steady-state activation curves are either laserlike or steplike. Both are characterized by a well-defined threshold for activation, which suggests that thresholding is a robust feature of this system. Third, transiently activated CaMKII can maintain its activity over the time course of many experiments, and such slow deactivation may account for the few reports of bistability in the literature. And fourth, under in vivo conditions, increases in phosphatase activity can increase CaMKII activity. This is a surprising and counterintuitive effect, as dephosphorylation is generally associated with CaMKII deactivation. PMID- 23931328 TI - Macro- to microscale strain transfer in fibrous tissues is heterogeneous and tissue-specific. AB - Mechanical deformation applied at the joint or tissue level is transmitted through the macroscale extracellular matrix to the microscale local matrix, where it is transduced to cells within these tissues and modulates tissue growth, maintenance, and repair. The objective of this study was to investigate how applied tissue strain is transferred through the local matrix to the cell and nucleus in meniscus, tendon, and the annulus fibrosus, as well as in stem cell seeded scaffolds engineered to reproduce the organized microstructure of these native tissues. To carry out this study, we developed a custom confocal microscope-mounted tensile testing device and simultaneously monitored strain across multiple length scales. Results showed that mean strain was heterogeneous and significantly attenuated, but coordinated, at the local matrix level in native tissues (35-70% strain attenuation). Conversely, freshly seeded scaffolds exhibited very direct and uniform strain transfer from the tissue to the local matrix level (15-25% strain attenuation). In addition, strain transfer from local matrix to cells and nuclei was dependent on fiber orientation and tissue type. Histological analysis suggested that different domains exist within these fibrous tissues, with most of the tissue being fibrous, characterized by an aligned collagen structure and elongated cells, and other regions being proteoglycan (PG) rich, characterized by a dense accumulation of PGs and rounder cells. In meniscus, the observed heterogeneity in strain transfer correlated strongly with cellular morphology, where rounder cells located in PG-rich microdomains were shielded from deformation, while elongated cells in fibrous microdomains deformed readily. Collectively, these findings suggest that different tissues utilize distinct strain-attenuating mechanisms according to their unique structure and cellular phenotype, and these differences likely alter the local biologic response of such tissues and constructs in response to mechanical perturbation. PMID- 23931331 TI - Exploring the programmable assembly of a polyoxometalate-organic hybrid via metal ion coordination. AB - The conformational flexibility and programmed assembly of a dumbbell-shaped polyoxometalate-organic hybrid molecule comprising two Dawson-type polyoxometalates linked by a 2,2'-bipyridine unit, which can be coordinate to metal ions, in this case of Zn(2+), are described. SAXS, UV/vis, and NMR spectroscopic techniques confirm that the hybrid molecules exist as the trans dumbbell in metal-ion-free solutions and can be reversibly transformed into the cis dumbbell through coordination upon the addition of ZnCl2 into a DMSO solution containing the hybrid. Subsequent addition of EDTA reverses the switching process by extracting the Zn(2+) cations from the hybrid. During the interchange process between trans and cis dumbbells, a further reorganization of the hybrid molecules occurs through bond rotation to minimize steric clashes between the polyoxometalate subunits, in order to stabilize the corresponding dumbbell conformation. The Zn(2+)-controlled conformational transformation of the hybrid can be further utilized to manipulate the hybrid's solvophobic interaction-driven self-assembly behavior in the metal-ion driven reversible formation of 140 nm sized vesicles, studied by laser light scattering techniques. PMID- 23931329 TI - Oscillatory flow accelerates autocrine signaling due to nonlinear effect of convection on receptor-related actions. AB - We study effects of oscillatory convective flow in extracellular space on the velocity of chemical signal propagation having a form of a front wave above a cellular layer. We found that the time-averaged propagation velocity under oscillatory flow for a particular Peclet number amplitude is slower than the velocity under steady laminar flow regime for the same value of the Peclet number, but significantly faster than under no-flow conditions. We derive asymptotic values of the propagation velocity and asymptotic characteristics of the corresponding concentration fronts in high- and low-frequency regimes and show that the reason for the observed velocity increase under the oscillatory flow stems from a nonlinear dependence of the propagation velocity on the Peclet number, particularly from the convex character of the dependence. Our findings suggest that the specific responses of cellular cultures to different flow conditions in the extracellular space (for example, expression of atherosclerosis protective genes under steady laminar flow but not under oscillatory flow) is a consequence of a nonlinear coupling between the extracellular transport and complex intracellular reaction cascades forming a positive feedback loop of the autocrine signaling. This mechanism can operate independently of, or in conjunction with, a direct stress-sensing due to mechanotransduction. PMID- 23931330 TI - Ratiometric imaging of the T-cell actin cytoskeleton reveals the nature of receptor-induced cytoskeletal enrichment. AB - The T-cell actin cytoskeleton mediates adaptive immune system responses to peptide antigens by physically directing the motion and clustering of T-cell receptors (TCRs) on the cell surface. When TCR movement is impeded by externally applied physical barriers, the actin network exhibits transient enrichment near the trapped receptors. The coordinated nature of the actin density fluctuations suggests that they are composed of filamentous actin, but it has not been possible to eliminate de novo polymerization at TCR-associated actin polymerizing factors as an alternative cause. Here, we use a dual-probe cytoskeleton labeling strategy to distinguish between stable and polymerizing pools of actin. Our results suggest that TCR-associated actin consists of a relatively high proportion of the stable cytoskeletal fraction and extends away from the cell membrane into the cell. This implies that actin enrichment at mechanically trapped TCRs results from three-dimensional bunching of the existing filamentous actin network. PMID- 23931332 TI - High-alert medications for pediatric patients: an international modified Delphi study. AB - BACKGROUND: The available knowledge about high-alert medications for children is limited. Because children are particularly vulnerable to medication errors, a list of high-alert medication specifically for children would help to develop effective strategies to prevent patient harm. Therefore, we conducted an international modified Delphi study and validated the results with reports on medication incidents in children based on national data. OBJECTIVE: The objective of this study was to generate an internationally accepted list of high-alert medications for a pediatric inpatient population from birth to 18-years old. RESULTS: The rating panel consisted of 34 experts from 13 countries. In total, 14 medications and 4 medication classes were included with the predefined level of consensus of 75%. The high-alert medications were: amiodarone, digoxin, dopamine, epinephrine, fentanyl, gentamycin, heparine, insulin, morphine, norepinephrine, phenytoin, potassium, propofol and tacrolimus. The high-alert medication classes included in the final list were: chemotherapeutic drugs, immunosuppressive medications, lipid/total parenteral nutrition and opioids. CONCLUSION: An international group of experts defined 14 medications and 4 medication classes as high-alert for children. This list might be helpful as a starting point for individual hospitals to develop their own high-alert list tailored to their unique situation. PMID- 23931333 TI - A probabilistic model of neutral and selective dynamics of protein network evolution. AB - Comparative approaches in genomics have long relied on rigorous mathematical models of sequence evolution. Such models provide the basis for formulating and solving well-defined computational problems, in turn yielding key insights into the evolutionary processes acting on the genome. Analogous model-based approaches for analyzing biological networks are still under development. Here we describe a model-based approach for estimating the probability of network rewiring events during evolution. Our method builds on the standard duplication-and-divergence model and incorporates phylogenetic analysis to guide the comparison of protein networks across species. We apply our algorithm to study the evolution of functional modules and unconstrained network regions in seven available eukaryotic interactomes. Based on this analysis we identify a map of co functioning protein families whose members participate in strongly conserved interactions and form major complexes and pathways in the eukaryotic cell. The proposed approach provides principled means for inferring the probability of network rewiring events, enabling insights into the conservation and divergence of protein interactions and the formation of functional modules in protein networks. PMID- 23931334 TI - Stability of parent report on Mobility and Self-Care item scores of the Pediatric Evaluation of Disability Inventory. AB - Secondary analysis using data from a clinical trial was performed to evaluate the stability of individual items of the Mobility and Self-Care functional skills scales of the Pediatric Evaluation of Disability Inventory (PEDI). Parents of 113 children aged 1-6 years old with cerebral palsy completed the PEDI twice by questionnaire 6 months apart. An item was classified "unstable" if the score changed from capable to unable. The number of children with more than five unstable items and the number of items with more than five children having unstable scoring patterns were calculated. Nineteen children (17%) and 13 items had unstable scoring patterns. The majority of PEDI items demonstrated stability of parent scoring. Examination of unstable items suggests that parents may need assistance in understanding the difference between "usual" and "best" performance, interpreting descriptors such as "thoroughly," and maintaining the same context reference for outdoor mobility items. PMID- 23931335 TI - Positive margins in excised dermatofibrosarcoma protuberans: a study of 58 cases treated with slow-Mohs surgery. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is characterized by unpredictable subclinical extension, meaning that positive margins are frequently detected following conventional surgical excision. OBJECTIVE: To study the presence or absence of residual tumour in DFSP with positive margins after conventional surgery and identify possible predictors of residual tumour or clear margins following a single Mohs micrographic surgery (MMS) stage. METHODS: A retrospective study of patients with DFSP and positive margins following conventional excision referred for MMS was performed. We studied gender, age, tumour site, time from presentation to diagnosis, and affected margins. RESULTS: We studied 58 cases, 35 (60.3%) of which had histological evidence of residual tumour. Tumours of the head and neck were significantly associated with the persistence of tumour. A single MMS stage was sufficient to achieve clearance in the majority of cases (n = 46). All tumours with lateral involvement only were resolved with a single Mohs stage. CONCLUSIONS: DFSPs with positive margins after conventional surgical excision should undergo re-excision because the majority have histologic evidence of residual tumour. Re-excision with 1-cm margins beyond the scar could be an option in certain tumour sites, particularly when it is known which margins are involved. PMID- 23931336 TI - + 252A/G polymorphism in lymphotoxin-alpha gene influences long-term survival in patients with myelodysplastic syndrome with excess blasts. PMID- 23931337 TI - Serum C terminal telopeptide maintains its correlation with bone disease in patients with myeloma even under treatment with bisphosphonates. PMID- 23931338 TI - Do self-reported health indicators predict mortality? Evidence from Matlab, Bangladesh. AB - In order to understand current and changing patterns of population health, there is a clear need for high-quality health indicators. The World Health Organization Study on Global AGEing and Adult Health (SAGE) survey platform and the International Network for the Demographic Evaluation of Populations and Their Health in developing countries (INDEPTH) generated data for this study. A total of 4300 people aged 50 years or older were selected randomly from the Matlab Health and Demographic Surveillance System of the International Centre for Diarrhoeal Disease Research, Bangladesh. The health indicators derived from these survey data are self-rated general health, overall health state, quality of life and disability levels. The outcome of the study is mortality over a 2-year follow up since the survey. Among the four health indicators, only self-rated health was significantly associated with subsequent mortality irrespective of sex: those who reported bad health had higher mortality than those who reported good health, even after controlling for socio-demographic factors. For all other three health indicators, such associations exist but are significant only for males, while for females it is significant only for 'quality of life'. PMID- 23931339 TI - Effect of mood stabilizers on DNA methylation in human neuroblastoma cells. AB - Unraveling the epigenetic status of neuronal cells in the brain is critical to our understanding of the pathophysiology of psychiatric disorders, which may reflect a complex interaction between genetic and environmental factors. Several epigenetic studies of mood disorders have been conducted with postmortem brains. However, proper interpretation of the results is hampered by our scant understanding of the effects of mood stabilizers on the epigenetic status of neuronal cells. We performed both comprehensive and gene-specific analyses to examine DNA methylation in human neuroblastoma SK-N-SH cells treated with three mood stabilizers: lithium, valproate and carbamazepine. Measurement of the level of DNA methylation of about 27 000 CpG sites revealed a profound epigenetic effect of lithium, compared with the two other mood stabilizers. In addition, we found that the mood stabilizers have common epigenetic targets and a propensity to increase DNA methylation. Gene-specific analysis involved detailed analysis of the methylation of promoter regions of SLC6A4 and BDNF, both of which have been reported to show altered DNA methylation in bipolar disorder patients or suicide victims, by extensive bisulfite sequencing. We did not observe significant changes in DNA methylation at BDNF promoter IV. However, we found that CpG sites of SLC6A4, which were hypermethylated in patients with bipolar disorder, were hypomethylated in the neuroblastoma cells treated with mood stabilizers. Our results will contribute to a better understanding of the epigenetic changes associated with mood disorders, and they also provide new insight into the mechanisms of action of mood stabilizers. PMID- 23931340 TI - T-type calcium channel blockers inhibit autophagy and promote apoptosis of malignant melanoma cells. AB - We have recently reported that human melanoma cells express a variety of voltage gated calcium (Ca(2+) ) channel types, including low-voltage-activated T-type channels that play a significant role in melanoma cell cycle progression. Here, we challenged melanoma metastatic cells with T-type channel blockers of clinical use and found a dual effect on cell viability: (i) a reduction in the proliferation rate, through a halt in the progression to the G1 -S phase; and (ii) a promotion of cell death that was partially dependent on the activation of caspases. An in-depth analysis of the death process showed that the apoptotic pathway is preceded by endoplasmic reticulum stress and the subsequent inhibition of the basal macroautophagy which is active in these cells. The effects of pharmacological blockers on Ca(2+) homeostasis, autophagy, and cell death were mimicked by T-type channel gene silencing. These results provide the basis for a new pharmacological and/or gene silencing approach toward tackling melanoma metastasis. PMID- 23931342 TI - Quantum discord cannot be shared. AB - Bohr proposed that the outcome of a measurement becomes objective and real, and, hence, classical, when its results can be communicated by classical means. In this work we revisit Bohr's postulate using modern tools from quantum information theory. We find a full confirmation of Bohr's idea: if a measurement device is in a nonclassical state, the measurement results cannot be communicated perfectly by classical means. In this case some part of the information in the measurement apparatus is lost in the process of communication: the amount of this lost information turns out to be the quantum discord. The information loss occurs even when the apparatus is not entangled with the system of interest. The tools presented in this work allow us to generalize Bohr's postulate: we show that for pure system-apparatus states quantum communication does not provide any advantage when measurement results are communicated to more than one recipient. We further demonstrate the superiority of quantum communication to two recipients on a mixed system-apparatus state and show that this effect is fundamentally different from quantum state cloning. PMID- 23931343 TI - Quantum loop expansion to high orders, extended Borel summation, and comparison with exact results. AB - We compare predictions of the quantum loop expansion to (essentially) infinite orders with (essentially) exact results in a simple quantum mechanical model. We find that there are exponentially small corrections to the loop expansion, which cannot be explained by any obvious "instanton"-type corrections. It is not the mathematical occurrence of exponential corrections but their seeming lack of any physical origin which we find surprising and puzzling. PMID- 23931341 TI - Intravenous adeno-associated virus serotype 8 encoding urocortin-2 provides sustained augmentation of left ventricular function in mice. AB - Urocortin-2 (UCn2) peptide infusion increases cardiac function in patients with heart failure, but chronic peptide infusion is cumbersome, costly, and provides only short-term benefits. Gene transfer would circumvent these shortcomings. Here we ask whether a single intravenous injection of adeno-associated virus type 8 encoding murine urocortin-2 (AAV8.UCn2) could provide long-term elevation in plasma UCn2 levels and increased left ventricular (LV) function. Normal mice received AAV8.UCn2 (5*1011 genome copies, intravenous). Plasma UCn2 increased 15 fold 6 weeks and >11-fold 7 months after delivery. AAV8 DNA and UCn2 mRNA expression was persistent in LV and liver up to 7 months after a single intravenous injection of AAV8.UCn2. Physiological studies conducted both in situ and ex vivo showed increases in LV +dP/dt and in LV -dP/dt, findings that endured unchanged for 7 months. SERCA2a mRNA and protein expression was increased in LV samples and Ca2+ transient studies showed an increased rate of Ca2+ decline in cardiac myocytes from mice that had received UCn2 gene transfer. We conclude that a single intravenous injection of AAV8.UCn2 increases plasma UCn2 and increases LV systolic and diastolic function for at least 7 months. The simplicity of intravenous injection of a long-term expression vector encoding a gene with paracrine activity to increase cardiac function is a potentially attractive strategy in clinical settings. Future studies will determine the usefulness of this approach in the treatment of heart failure. PMID- 23931344 TI - Controlling and measuring quantum transport of heat in trapped-ion crystals. AB - Measuring heat flow through nanoscale devices poses formidable practical difficulties as there is no "ampere meter" for heat. We propose to overcome this problem in a chain of trapped ions, where laser cooling the chain edges to different temperatures induces a heat current of local vibrations (vibrons). We show how to efficiently control and measure this current, including fluctuations, by coupling vibrons to internal ion states. This demonstrates that ion crystals provide an ideal platform for studying quantum transport, e.g., through thermal analogues of quantum wires and quantum dots. Notably, ion crystals may give access to measurements of the elusive bosonic fluctuations in heat currents and the onset of Fourier's law. Our results are strongly supported by numerical simulations for a realistic implementation with specific ions and system parameters. PMID- 23931345 TI - Macroscopic diffusive transport in a microscopically integrable Hamiltonian system. AB - We demonstrate that a completely integrable classical mechanical model, namely the lattice Landau-Lifshitz classical spin chain, supports diffusive spin transport with a finite diffusion constant in the easy-axis regime, while in the easy-plane regime, it displays ballistic transport in the absence of any known relevant local or quasilocal constant of motion in the symmetry sector of the spin current. This surprising finding should open the way towards analytical computation of diffusion constants for integrable interacting systems and hints on the existence of new quasilocal classical conservation laws beyond the standard soliton theory. PMID- 23931346 TI - Universality, maximum radiation, and absorption in high-energy collisions of black holes with spin. AB - We explore the impact of black hole spins on the dynamics of high-energy black hole collisions. We report results from numerical simulations with gamma factors up to 2.49 and dimensionless spin parameter chi=+0.85, +0.6, 0, -0.6, -0.85. We find that the scattering threshold becomes independent of spin at large center-of mass energies, confirming previous conjectures that structure does not matter in ultrarelativistic collisions. It has further been argued that in this limit all of the kinetic energy of the system may be radiated by fine tuning the impact parameter to threshold. On the contrary, we find that only about 60% of the kinetic energy is radiated for gamma=2.49. By monitoring apparent horizons before and after scattering events we show that the "missing energy" is absorbed by the individual black holes in the encounter, and moreover the individual black-hole spins change significantly. We support this conclusion with perturbative calculations. An extrapolation of our results to the limit gamma->infinity suggests that about half of the center-of-mass energy of the system can be emitted in gravitational radiation, while the rest must be converted into rest mass and spin energy. PMID- 23931347 TI - Globally regular instability of 3-dimensional anti-de Sitter spacetime. AB - We consider three-dimensional anti-de Sitter (AdS) gravity minimally coupled to a massless scalar field and study numerically the evolution of small smooth circularly symmetric perturbations of the AdS3 spacetime. As in higher dimensions, for a large class of perturbations, we observe a turbulent cascade of energy to high frequencies which entails instability of AdS3. However, in contrast to higher dimensions, the cascade cannot be terminated by black hole formation because small perturbations have energy below the black hole threshold. This situation appears to be challenging for the cosmic censor. Analyzing the energy spectrum of the cascade we determine the width rho(t) of the analyticity strip of solutions in the complex spatial plane and argue by extrapolation that rho(t) does not vanish in finite time. This provides evidence that the turbulence is too weak to produce a naked singularity and the solutions remain globally regular in time, in accordance with the cosmic censorship hypothesis. PMID- 23931348 TI - PeV neutrinos from intergalactic interactions of cosmic rays emitted by active galactic nuclei. AB - The observed very high energy spectra of distant blazars are well described by secondary gamma rays produced in line-of-sight interactions of cosmic rays with background photons. In the absence of the cosmic-ray contribution, one would not expect to observe very hard spectra from distant sources, but the cosmic ray interactions generate very high energy gamma rays relatively close to the observer, and they are not attenuated significantly. The same interactions of cosmic rays are expected to produce a flux of neutrinos with energies peaked around 1 PeV. We show that the diffuse isotropic neutrino background from many distant sources can be consistent with the neutrino events recently detected by the IceCube experiment. We also find that the flux from any individual nearby source is insufficient to account for these events. The narrow spectrum around 1 PeV implies that some active galactic nuclei can accelerate protons to EeV energies. PMID- 23931349 TI - Nonsingular promises from Born-Infeld gravity. AB - Born-Infeld determinantal gravity formulated in Weitzenbock spacetime is discussed in the context of Friedmann-Robertson-Walker (FRW) cosmologies. It is shown how the standard model big bang singularity is absent in certain spatially flat FRW spacetimes, where the high energy regime is characterized by a de Sitter inflationary stage of geometrical character, i.e., without the presence of the inflaton field. This taming of the initial singularity is also achieved for some spatially curved FRW manifolds where the singularity is replaced by a de Sitter stage or a big bounce of the scale factor depending on certain combinations of free parameters appearing in the action. Unlike other Born-Infeld-like theories in vogue, the one here presented is also capable of deforming vacuum general relativistic solutions. PMID- 23931350 TI - Testing the MOND paradigm of modified dynamics with galaxy-galaxy gravitational lensing. AB - The MOND paradigm of modified dynamics predicts that the asymptotic gravitational potential of an isolated, bounded (baryonic) mass, M, is phi(r)=(MGa0)1/2ln(r). Relativistic MOND theories predict that the lensing effects of M are dictated by phi(r) as general-relativity lensing is dictated by the Newtonian potential. Thus MOND predicts that the asymptotic Newtonian potential deduced from galaxy-galaxy gravitational lensing will have (1) a logarithmic r dependence, and (2) a normalization (parametrized standardly as 2sigma2) that depends only on M: sigma=(MGa0/4)1/4. I compare these predictions with recent results of galaxy galaxy lensing, and find agreement on all counts. For the "blue"-lenses subsample ("spiral" galaxies) MOND reproduces the observations well with an r'-band M/Lr'~(1-3)(M/L)?, and for "red" lenses ("elliptical" galaxies) with M/Lr'~(3 6)(M/L)?, both consistent with baryons only. In contradistinction, Newtonian analysis requires, typically, M/Lr'~130(M/L)?, bespeaking a mass discrepancy of a factor ~40. Compared with the staple, rotation-curve tests, MOND is here tested in a wider population of galaxies, through a different phenomenon, using relativistic test objects, and is probed to several-times-lower accelerations-as low as a few percent of a0. PMID- 23931351 TI - Using the dipolar and quadrupolar moments to improve solar-cycle predictions based on the polar magnetic fields. AB - The solar cycle and its associated magnetic activity are the main drivers behind changes in the interplanetary environment and Earth's upper atmosphere (commonly referred to as space weather and climate). In recent years there has been an effort to develop accurate solar cycle predictions, leading to nearly a hundred widely spread predictions for the amplitude of solar cycle 24. Here we show that cycle predictions can be made more accurate if performed separately for each hemisphere, taking advantage of information about both the dipolar and quadrupolar moments of the solar magnetic field during minimum. PMID- 23931352 TI - New constraints on the early expansion history of the universe. AB - Cosmic microwave background measurements have pushed to higher resolution, lower noise, and more sky coverage. These data enable a unique test of the early Universe's expansion rate and constituents such as effective number of relativistic degrees of freedom and dark energy. Using the most recent data from Planck and WMAP9, we constrain the expansion history in a model-independent manner from today back to redshift z=10(5). The Hubble parameter is mapped to a few percent precision, limiting early dark energy and extra relativistic degrees of freedom within a model-independent approach to 2%-16% and 0.71 equivalent neutrino species, respectively (95% C.L.). Within dark radiation, barotropic ether, and Doran-Robbers models, the early dark energy constraints are 3.3%, 1.9%, and 1.2%, respectively. PMID- 23931353 TI - Dark matter detectors as dark photon helioscopes. AB - Light new particles with masses below 10 keV, often considered as a plausible extension of the standard model, will be emitted from the solar interior and can be detected on Earth with a variety of experimental tools. Here, we analyze the new "dark" vector state V, a massive vector boson mixed with the photon via an angle kappa, that in the limit of the small mass mV has its emission spectrum strongly peaked at low energies. Thus, we utilize the constraints on the atomic ionization rate imposed by the results of the XENON10 experiment to set the limit on the parameters of this model: kappa*mV<3*10(-12) eV. This makes low-threshold dark matter experiments the most sensitive dark vector helioscopes, as our result not only improves current experimental bounds from other searches by several orders of magnitude but also surpasses even the most stringent astrophysical and cosmological limits in a seven-decade-wide interval of mV. We generalize this approach to other light exotic particles and set the most stringent direct constraints on "minicharged" particles. PMID- 23931354 TI - Duality and decay of macroscopic F strings. AB - We study the decay of fundamental string loops of arbitrary size L/min(n,m)?sqrt[alpha'], labeled by (n, m; lambdan, lambda[over -]m), where n, m correspond to left- and right-mover harmonics and lambdan, lambda[over -]m to polarization tensors, and find that a description in terms of the recent coherent vertex operator construction of Hindmarsh and Skliros is computationally very efficient. We primarily show that the decay rates and mass shifts of vertex operators (n, m; lambdan, lambda[over -]m) and their "duals" (n, m; lambdan, lambda[over -]m*) are equal to leading order in the string coupling, implying, for instance, that decay rates of epicycloids equal those of hypocycloids. We then compute the power and decay rates associated with massless IR radiation for the trajectory (1, 1; lambda1, lambda[over -]1), and find that it is precisely reproduced by the low energy effective theory of Dabholkar and Harvey. Guided by this correspondence, we conjecture the result for arbitrary trajectories (n, m; lambdan, lambda[over -]m) and discover a curious relation between gravitational and axion plus dilaton radiation. It is now possible to start exploring string evolution in regimes where a low energy effective description is less useful, such as in the vicinity of cusps. PMID- 23931355 TI - Spherical parametrization of the Higgs boson candidate. AB - The latest results from the ATLAS and CMS experiments at the CERN Large Hadron Collider unequivocally confirm the existence of a resonance X with mass near 125 GeV which could be the Higgs boson of the standard model. Measuring the properties (quantum numbers and couplings) of this resonance is of paramount importance. Initial analyses by the LHC Collaborations disfavor specific alternative benchmark hypotheses, e.g., pure pseudoscalars or gravitons. However, this is just the first step in a long-term program of detailed measurements. We consider the most general set of operators in the decay channels X->ZZ, WW, Zgamma, gammagamma, and derive the constraint implied by the measured rate. This allows us to provide a useful parametrization of the orthogonal independent Higgs coupling degrees of freedom as coordinates on a suitably defined sphere. PMID- 23931356 TI - Color reconnection and flowlike patterns in pp collisions. AB - Increasingly, with the data collected at the LHC we are confronted with the possible existence of flow in pp collisions. In this work, we show that PYTHIA 8 produces flowlike effects in events with multiple hard subcollisions due to color string formations between final partons from independent hard scatterings, the so called color reconnection. We present studies of different identified hadron observables in pp collisions at 7 TeV. Studies have been done both for minimum bias and multiplicity intervals in events with and without color reconnection to isolate the flowlike effect. PMID- 23931357 TI - Study of X(3872) from effective field theory with pion-exchange interaction. AB - We study DD[over -]* (D*D[over -]) scattering in the framework of unitarized heavy meson chiral perturbation theory with pion exchange and a contact interaction. 3S1-3D1 mixing effects are taken into account. A loosely bound state X(3872), with the pole position being Mpole}=(3871.70-i0.39) MeV, is found. The result is not sensitive to the strength of the contact interaction. Our calculation provides a theoretical confirmation of the existence of the 1++ state X(3872). The light quark mass dependence of the pole position indicates it has a predominately DD[over -]* (D*D[over -]) molecular nature. When the pi mass is larger than 142 MeV, the pole disappears, which makes impossible the lattice simulation of this state at large quark mass. PMID- 23931359 TI - Lifetime and fragment correlations for the two-neutron decay of 26O ground state. AB - The structure and decay of 26O are investigated in a three-body 24O+n+n model suitable for studies of the long-lived (including radioactivity time scale) states. We have found extremely strong effects of the subbarrier configuration mixing on the decay width of true 2n emitters due to core recoil and neutron neutron final state interaction. This effect far exceeds the analogous effect in the true 2p emitters. Our calculations provide reasonably narrow boundaries for the lifetime vs decay energy dependence for the true 2n emission. An upper limit of ~1 keV for the decay energy of the unbound 26O is inferred based on the recent experimental lifetime value. PMID- 23931360 TI - Quenching of cross sections in nucleon transfer reactions. AB - Cross sections for proton knockout observed in (e,e'p) reactions are apparently quenched by a factor of ~0.5, an effect attributed to short-range correlations between nucleons. Here we demonstrate that such quenching is not restricted to proton knockout, but a more general phenomenon associated with any nucleon transfer. Measurements of absolute cross sections on a number of targets between 16O and 208Pb were analyzed in a consistent way, with the cross sections reduced to spectroscopic factors through the distorted-wave Born approximation with global optical potentials. Across the 124 cases analyzed here, induced by various proton- and neutron-transfer reactions and with angular momentum transfer l=0-7, the results are consistent with a quenching factor of 0.55. This is an apparently uniform quenching of single-particle motion in the nuclear medium. The effect is seen not only in (d,p) reactions but also in reactions with A=3 and 4 projectiles, when realistic wave functions are used for the projectiles. PMID- 23931361 TI - Double core-hole creation by sequential attosecond photoionization. AB - X-ray fluorescence spectroscopy demonstrates that a single core-hole krypton with a 170-as lifetime can be photoionized again to a double core-hole state by an intense x-ray pulse. The observation indicates that unconventional interaction between intense x rays and atoms is no more negligible in applications with x-ray free-electron lasers. Quantitative analysis of the double core-hole creation including effects of a pulsed and spiky temporal structure enables estimation of the x-ray pulse duration in the sub-10-fs range. PMID- 23931362 TI - Suppression of spin-exchange relaxation using pulsed parametric resonance. AB - We demonstrate that spin-exchange dephasing of Larmor precession at near-Earth scale fields is effectively eliminated by dressing the alkali-metal atom spins in a sequence of ac-coupled 2pi pulses, repeated at the Larmor precession frequency. The contribution of spin-exchange collisions to the spectroscopic linewidth is reduced by a factor of the duty cycle of the pulses. We experimentally demonstrate resonant transverse pumping in magnetic fields as high as 0.1 G, present experimental measurements of the suppressed spin-exchange relaxation, and show enhanced magnetometer response relative to a light-narrowed scalar magnetometer. PMID- 23931363 TI - Single-photon multiple detachment in fullerene negative ions: absolute ionization cross sections and the role of the extra electron. AB - We have obtained experimental photo-double- and photo-triple-detachment cross sections for the fullerene negative ion using Advanced Light Source photons of 17 90 eV. The cross sections are 2 and 2.5 times larger than those for C60 and appear to be compressed and shifted in photon energy as compared to C60. Our analysis reveals that the additional electron in C60- primarily produces screening which is responsible for the modification of the spectrum. Both screening effects, the shift and the compression, can be quantitatively accounted for by a linear transformation of the energy axis. Applying the transformation allows us to map the neutral and negative ion cross sections onto each other, pointing out the close relationship of correlated few-electron dynamics in neutral and negatively charged extended systems. In contrast, dynamics of neutral and negatively charged atoms or small molecules are typically not closely related. PMID- 23931364 TI - Transfer ionization in collisions with a fast highly charged ion. AB - Transfer ionization in fast collisions between a bare ion and an atom, in which one of the atomic electrons is captured by the ion whereas another one is emitted, crucially depends on dynamic electron-electron correlations. We show that in collisions with a highly charged ion a strong field of the ion has a very profound effect on the correlated channels of transfer ionization. In particular, this field weakens (strongly suppresses) electron emission into the direction opposite (perpendicular) to the motion of the ion. Instead, electron emission is redirected into those parts of the momentum space which are very weakly populated in fast collisions with low charged ions. PMID- 23931365 TI - Quantum-coherence-enhanced surface plasmon amplification by stimulated emission of radiation. AB - We investigate surface plasmon amplification in a silver nanoparticle coupled to an externally driven three-level gain medium and show that quantum coherence significantly enhances the generation of surface plasmons. Surface plasmon amplification by stimulated emission of radiation is achieved in the absence of population inversion on the spasing transition, which reduces the pump requirements. The coherent drive allows us to control the dynamics and holds promise for quantum control of nanoplasmonic devices. PMID- 23931366 TI - Dependence of the radiation pressure on the background refractive index. AB - The 1978 experiments by Jones and Leslie showing that the radiation pressure on a mirror depends on the background medium refractive index have yet to be adequately explained using a force model and have provided a leading challenge to the Abraham form of the electromagnetic momentum. Those experimental results are predicted for the first time using a force representation that incorporates the Abraham momentum by utilizing the power calibration method employed in the Jones and Leslie experiments. With an extension of the same procedure, the polarization and angle independence of the experimental data are also explained by this model. Prospects are good for this general form of the electromagnetic force density to be effective in predicting other experiments with macroscopic materials. Furthermore, the rigorous representation of material dispersion makes the representation important for metamaterials that operate in the vicinity of homogenized material resonances. PMID- 23931367 TI - Cavity optomechanics with synthetic Landau levels of ultracold fermi gas. AB - Ultracold fermionic atoms placed in a synthetic magnetic field arrange themselves in Landau levels. We theoretically study the optomechanical interaction between the light field and collective excitations of such fermionic atoms in synthetic magnetic field by placing them inside a Fabry-Perot cavity. We derive the effective Hamiltonian for particle hole excitations from a filled Landau level using a bosonization technique and obtain an expression for the cavity transmission spectrum. Using this we show that the cavity transmission spectrum demonstrates cold atom analog of Shubnikov-de Haas oscillation in electronic condensed matter systems. We discuss the experimental consequences for this oscillation for such a system and the related optical bistability. PMID- 23931368 TI - Determination of ionization and tunneling times in high-order harmonic generation. AB - From the numerical solution of the time-dependent Schrodinger equation, we obtain the times of ionization and return of the laser-driven electron in high-order harmonic generation by probing the dynamics with a second harmonic field polarized orthogonal to the fundamental field and observing the harmonic emission in dependence on the two-color delay. Our retrieval method using complex-time evolution gives ionization and return times in excellent agreement with the quantum-orbit model, while a retrieval based on real-time classical dynamics can introduce substantial errors. Because of the imaginary parts, the harmonic signal polarized along the probe field is nonzero for any two-color delay. The tunneling time can be retrieved under an assumption for the return time. PMID- 23931369 TI - Blackbody emission from light interacting with an effective moving dispersive medium. AB - Intense laser pulses excite a nonlinear polarization response that may create an effective flowing medium and, under appropriate conditions, a blocking horizon for light. Here, we analyze in detail the interaction of light with such laser induced flowing media, fully accounting for the medium dispersion properties. An analytical model based on a first Born approximation is found to be in excellent agreement with numerical simulations based on Maxwell's equations and shows that when a blocking horizon is formed, the stimulated medium scatters light with a blackbody emission spectrum. Based on these results, diamond is proposed as a promising candidate medium for future studies of Hawking emission from artificial, dispersive horizons. PMID- 23931370 TI - Internal composite bound states in deterministic reaction diffusion models. AB - By identifying potential composite states that occur in the Sel'kov-Gray-Scott (GS) model, we show that it can be considered as an effective theory at large spatiotemporal scales, arising from a more fundamental theory (which treats these composite states as fundamental chemical species obeying the diffusion equation) relevant at shorter spatiotemporal scales. When simulations in the latter model are performed as a function of a parameter M=lambda-1, the generated spatial patterns evolve at late times into those of the GS model at large M, implying that the composites follow their own unique dynamics at short scales. This separation of scales is an example of dynamical decoupling in reaction diffusion systems. PMID- 23931358 TI - Measurement of the cross section for direct-photon production in association with a heavy quark in pp[over -] collisions at sqrt[s]=1.96 TeV. AB - We report on a measurement of the cross section for direct-photon production in association with a heavy quark using the full data set of sqrt[s]=1.96 TeV proton-antiproton collisions corresponding to 9.1 fb-1 of integrated luminosity collected by the CDF II detector at the Fermilab Tevatron. The measurements are performed as a function of the photon transverse momentum, covering a photon transverse momentum between 30 and 300 GeV, photon rapidities |ygamma|<1.0, a heavy-quark-jet transverse momentum pTjet>20 GeV, and jet rapidities |yjet|<1.5. The results are compared with several theoretical predictions. PMID- 23931371 TI - Fast physical random-number generation based on room-temperature chaotic oscillations in weakly coupled superlattices. AB - An all-electronic physical random number generator at rates up to 80 Gbit/s is presented, based on weakly coupled GaAs/Ga0.55Al0.45As superlattices operated at room temperature. It is based on large-amplitude, chaotic current oscillations characterized by a bandwidth of several hundred MHz and do not require external feedback or conversion to an electronic signal prior to digitization. The method is robust and insensitive to external perturbations and its fully electronic implementation suggests scalability and minimal postprocessing in comparison to existing optical implementations. PMID- 23931372 TI - Multiscale geometry and scaling of the turbulent-nonturbulent interface in high Reynolds number boundary layers. AB - The scaling and surface area properties of the wrinkled surface separating turbulent from nonturbulent regions in open shear flows are important to our understanding of entrainment mechanisms at the boundaries of turbulent flows. Particle image velocimetry data from high Reynolds number turbulent boundary layers covering three decades in scale are used to resolve the turbulent nonturbulent interface experimentally and, for the first time, determine unambiguously whether such surfaces exhibit fractal scaling. Box counting of the interface intersection with the measurement plane exhibits power-law scaling, with an exponent between -1.3 and -1.4. A complementary analysis based on spatial filtering of the velocity fields also shows power-law behavior of the coarse grained interface length as a function of filter width, with an exponent between 0.3 and -0.4. These results establish that the interface is fractal-like with a multiscale geometry and fractal dimension of Df~2.3-2.4. PMID- 23931373 TI - Excitation of fountain and entrainment instabilities at the interface between two viscous fluids using a beam of laser light. AB - We report on two instabilities, called viscous fountain and viscous entrainment, triggered at the interface between two liquids by the action of bulk flows driven by a laser beam. These streaming flows are due to light scattering losses in turbid liquids, and can be directed either toward or forward the interface. We experimentally and numerically investigate these interface instabilities and show that the height and curvature of the interface deformation at the threshold and the jet radius after interface destabilization mainly depend on the waist of the laser beam. Analogies and differences between these two instabilities are characterized. PMID- 23931374 TI - Nonlinear brightness optimization in compton scattering. AB - In Compton scattering light sources, a laser pulse is scattered by a relativistic electron beam to generate tunable x and gamma rays. Because of the inhomogeneous nature of the incident radiation, the relativistic Lorentz boost of the electrons is modulated by the ponderomotive force during the interaction, leading to intrinsic spectral broadening and brightness limitations. These effects are discussed, along with an optimization strategy to properly balance the laser bandwidth, diffraction, and nonlinear ponderomotive force. PMID- 23931375 TI - Hot-spot mix in ignition-scale inertial confinement fusion targets. AB - Mixing of plastic ablator material, doped with Cu and Ge dopants, deep into the hot spot of ignition-scale inertial confinement fusion implosions by hydrodynamic instabilities is diagnosed with x-ray spectroscopy on the National Ignition Facility. The amount of hot-spot mix mass is determined from the absolute brightness of the emergent Cu and Ge K-shell emission. The Cu and Ge dopants placed at different radial locations in the plastic ablator show the ablation front hydrodynamic instability is primarily responsible for hot-spot mix. Low neutron yields and hot-spot mix mass between 34(-13,+50) ng and 4000(-2970,+17 160) ng are observed. PMID- 23931376 TI - Energetics of kinetic reconnection in a three-dimensional null-point cluster. AB - We perform three-dimensional particle-in-cell simulations of magnetic reconnection with multiple magnetic null points. Magnetic field energy conversion into kinetic energy is about five times higher than in traditional Harris sheet configuration. More than 85% of initial magnetic field energy is transferred to particle energy during 25 reversed ion cyclofrequencies. Magnetic reconnection in the cluster of null points evolves in three phases. During the first phase, ion beams are excited, then give part of their energy back to the magnetic field in the second phase. In the third phase, magnetic reconnection occurs in many small patches around the current channels formed along the stripes of a low magnetic field. Magnetic reconnection in null points essentially presents three dimensional features, with no two-dimensional symmetries or current sheets. PMID- 23931377 TI - Lightning-induced extensive charge sheets provide long range electrostatic thunderstorm detection. AB - By combining electrostatic measurements of lightning-induced electrostatic field changes with radio frequency lightning location, some field changes from exceptionally distant lightning events are apparent which are inconsistent with the usual inverse cube of distance. Furthermore, by using two measurement sites, a transition zone can be identified beyond which the electric field response reverses polarity. For these severe lightning events, we infer a horizontally extensive charge sheet above a thunderstorm, consistent with a mesospheric halo of several hundred kilometers' extent. PMID- 23931378 TI - Inhomogeneous state of few-fermion superfluids. AB - The few-fermion atomic gas is an ideal setting to explore inhomogeneous superfluid pairing analogous to the Larkin-Ovchinnikov state. Two up and one down spin atom is the minimal configuration that displays an inhomogeneous pairing density, whereas imbalanced systems containing more fermions present a more complex pairing topology. With more than eight atoms trapped the system approaches the macroscopic superfluid limit. An oblate trap with a central barrier offers a direct experimental probe of pairing inhomogeneity. PMID- 23931379 TI - Correlations of the upper branch of 1D harmonically trapped two-component fermi gases. AB - We present highly accurate energy spectra and eigenfunctions of small 1D harmonically trapped two-component Fermi gases with interspecies delta-function interactions, and analyze the correlations of the so-called upper branch (i.e., the branch that describes a repulsive Fermi gas consisting of atoms but no molecules) for positive and negative coupling constants. Changes of the two-body correlations as a function of the interspecies coupling strength reflect the competition of the interspecies interaction and the effective repulsion due to the Pauli exclusion principle, and are interpreted as a few-body analog of a transition from a nonmagnetic to a magnetic phase. Moreover, we show that the eigenstate psiadia of the infinitely strongly interacting system with |n1+n2|>2 and |n1-n2|theta' phase transformation. PMID- 23931386 TI - Dynamics of Majorana states in a topological Josephson junction. AB - Topological Josephson junctions carry 4pi-periodic bound states. A finite bias applied to the junction limits the lifetime of the bound state by dynamically coupling it to the continuum. Another characteristic time scale, the phase adjustment time, is determined by the resistance of the circuit "seen" by the junction. We show that the 4pi periodicity manifests itself by an even-odd effect in Shapiro steps only if the phase adjustment time is shorter than the lifetime of the bound state. The presence of a peak in the current noise spectrum at half the Josephson frequency is a more robust manifestation of the 4pi periodicity, as it persists for an arbitrarily long phase adjustment time. We specify, in terms of the circuit parameters, the conditions necessary for observing the manifestations of 4pi periodicity in the noise spectrum and Shapiro step measurements. PMID- 23931387 TI - Loschmidt echo and the many-body orthogonality catastrophe in a qubit-coupled Luttinger liquid. AB - We investigate the many-body generalization of the orthogonality catastrophe by studying the generalized Loschmidt echo of Luttinger liquids (LLs) after a global change of interaction. It decays exponentially with system size and exhibits universal behavior: the steady state exponent after quenching back and forth n times between 2 LLs (bang-bang protocol) is 2n times bigger than that of the adiabatic overlap and depends only on the initial and final LL parameters. These are corroborated numerically by matrix-product state based methods of the XXZ Heisenberg model. An experimental setup consisting of a hybrid system containing cold atoms and a flux qubit coupled to a Feshbach resonance is proposed to measure the Loschmidt echo using rf spectroscopy or Ramsey interferometry. PMID- 23931388 TI - Strong magnetophotoelectric effect in folded graphene. AB - We study electronic transport in graphene under the influence of a transversal magnetic field B(r)=B(x)ez with the asymptotics B(x->+/-infinity)=+/-B0, which could be realized via a folded graphene sheet in a constant magnetic field, for example. By solving the effective Dirac equation, we find robust modes with a finite energy gap which propagate along the fold-where particles and holes move in opposite directions. Exciting these particle-hole pairs with incident (optical or infrared) photons would then generate a nearly perfect charge separation and thus a strong magnetophotoelectric or magnetothermoelectric effect-even at room temperature. PMID- 23931389 TI - Spin-controlled superconductivity and tunable triplet correlations in graphene nanostructures. AB - We study graphene ferromagnet/superconductor/ferromagnet (F/S/F) nanostructures via a microscopic self-consistent Dirac Bogoliubov-de Gennes formalism. We show that as a result of proximity effects, experimentally accessible spin switching phenomena can occur as one tunes the Fermi level MUF of the F regions or varies the angle theta between exchange field orientations. Superconductivity can then be switched on and off by varying either theta or MUF (a spin-controlled superconducting graphene switch). The induced equal-spin triplet correlations in S can be controlled by tuning MUF, effectively making a graphene based two dimensional spin-triplet valve. PMID- 23931390 TI - Effects of transverse magnetic anisotropy on current-induced spin switching. AB - Spin-polarized transport through bistable magnetic adatoms or single-molecule magnets (SMMs), which exhibit both uniaxial and transverse magnetic anisotropy, is considered theoretically. The main focus is on the impact of transverse anisotropy on transport characteristics and the adatom's or SMM's spin. In particular, we analyze the role of quantum tunneling of magnetization (QTM) in the mechanism of the current-induced spin switching, and show that the QTM phenomenon becomes revealed as resonant peaks in the average values of the molecule's spin and in the charge current. These features appear at some resonant fields and are observable when at least one of the electrodes is ferromagnetic. PMID- 23931391 TI - Superconducting states in pseudo-Landau-levels of strained graphene. AB - We describe the formation of superconducting states in graphene in the presence of pseudo-Landau-levels induced by strain, when time reversal symmetry is preserved. We show that superconductivity in strained graphene is quantum critical when the pseudo-Landau-levels are completely filled, whereas at partial fillings superconductivity survives at weak coupling. In the weak coupling limit, the critical temperature scales linearly with the coupling strength and shows a sequence of quantum critical points as a function of the filling factor that can be accessed experimentally. We argue that superconductivity can be induced by electron-phonon coupling and that the transition temperature can be controlled with the amount of strain and with the filling fraction of the Landau levels. PMID- 23931392 TI - Charge relaxation in a single-electron Si/SiGe double quantum dot. AB - We measure the interdot charge relaxation time T1 of a single electron trapped in an accumulation mode Si/SiGe double quantum dot. The energy level structure of the charge qubit is determined using photon assisted tunneling, which reveals the presence of a low-lying excited state. We systematically measure T1 as a function of detuning and interdot tunnel coupling and show that it is tunable over four orders of magnitude, with a maximum of 45 MUs for our device configuration. PMID- 23931393 TI - Morphological tuning of the plasmon dispersion relation in dielectric-loaded nanofiber waveguides. AB - Understanding the impact of lateral mode confinement in plasmonic waveguides is of fundamental interest regarding potential applications in plasmonic devices. The knowledge of the frequency-wave vector dispersion relation provides the full information on electromagnetic field propagation in a waveguide. This Letter reports on the measurement of the real part of the surface plasmon polariton dispersion relation in the near infrared spectral regime for individual nanoscale plasmonic waveguides, which were formed by deposition of para-hexaphenylene (p 6P) based nanofibers on top of a gold film. A detailed structural characterization of the nanofibers provides accurate information on the dimensions of the investigated waveguides and enables us to quantify the effect of mode confinement by comparison with experimental results from continuous p-6P films and calculations based on the effective index method. PMID- 23931394 TI - Tuning the temperature domain of phonon drag in thin films by the choice of substrate. AB - At low temperatures, in reasonably pure conductors subjected to a thermal gradient, charge carriers (electrons and holes) are swept (dragged) by out of equilibrium phonons, giving rise to a large contribution to the Seebeck coefficient called phonon drag. We demonstrate a spectacular influence of substrate phonons on charge carriers in thin films of Bi2Te3. We show that one can control and tune the position and magnitude of the phonon-drag peak over a wide range of temperatures by depositing thin films on substrates with vastly different Debye temperatures. Our experiments also provide a way to study the nature of the phonon spectrum in thin films, which is rarely probed but clearly important for a complete understanding of thin film properties and the interplay of the substrate and films. PMID- 23931395 TI - Coexistence of half-metallic itinerant ferromagnetism with local-moment antiferromagnetism in Ba0.60K0.40Mn2As2. AB - Magnetization, nuclear magnetic resonance, high-resolution x-ray diffraction, and magnetic field-dependent neutron diffraction measurements reveal a novel magnetic ground state of Ba0.60K0.40Mn2As2 in which itinerant ferromagnetism (FM) below a Curie temperature TC~100 K arising from the doped conduction holes coexists with collinear antiferromagnetism (AFM) of the Mn local moments that order below a Neel temperature TN=480 K. The FM ordered moments are aligned in the tetragonal ab plane and are orthogonal to the AFM ordered Mn moments that are aligned along the c axis. The magnitude and nature of the low-T FM ordered moment correspond to complete polarization of the doped-hole spins (half-metallic itinerant FM) as deduced from magnetization and ab-plane electrical resistivity measurements. PMID- 23931396 TI - Floquet Majorana fermions for topological qubits in superconducting devices and cold-atom systems. AB - We develop an approach to realizing a topological phase transition and non Abelian braiding statistics with dynamically induced Floquet Majorana fermions (FMFs). When the periodic driving potential does not break fermion parity conservation, FMFs can encode quantum information. Quasienergy analysis shows that a stable FMF zero mode and two other satellite modes exist in a wide parameter space with large quasienergy gaps, which prevents transitions to other Floquet states under adiabatic driving. We also show that in the asymptotic limit FMFs preserve non-Abelian braiding statistics and, thus, behave like their equilibrium counterparts. PMID- 23931397 TI - Fractional quantization of the magnetic flux in cylindrical unconventional superconductors. AB - The magnetic flux threading a conventional superconducting ring is typically quantized in units of Phi0=hc/2e. The factor of 2 in the denominator of Phi0 originates from the existence of two different types of pairing states with minima of the free energy at even and odd multiples of Phi0. Here we show that spatially modulated pairing states exist with energy minima at fractional flux values, in particular, at multiples of Phi0/2. In such states, condensates with different center-of-mass momenta of the Cooper pairs coexist. The proposed mechanism for fractional flux quantization is discussed in the context of cuprate superconductors, where hc/4e flux periodicities were observed. PMID- 23931398 TI - Nematic state of pnictides stabilized by interplay between spin, orbital, and lattice degrees of freedom. AB - The nematic state of the iron-based superconductors is studied in the undoped limit of the three-orbital (xz, yz, xy) spin-fermion model via the introduction of lattice degrees of freedom. Monte Carlo simulations show that in order to stabilize the experimentally observed lattice distortion and nematic order, and to reproduce photoemission experiments, both the spin-lattice and orbital-lattice couplings are needed. The interplay between their respective coupling strengths regulates the separation between the structural and Neel transition temperatures. Experimental results for the temperature dependence of the resistivity anisotropy and the angle-resolved photoemission orbital spectral weight are reproduced by the present numerical simulations. PMID- 23931399 TI - Proposed chiral texture of the magnetic moments of unit-cell loop currents in the pseudogap phase of cuprate superconductors. AB - We propose a novel chiral order parameter to explain the unusual polar Kerr effect in underdoped cuprates. It is based on the loop-current model by Varma, which is characterized by the in-plane anapole moment N and exhibits the magnetoelectric effect. We propose a helical structure where the vector N(n) in the layer n is twisted by the angle pi/2 relative to N(n-1), thus breaking inversion symmetry. We show that coupling between magnetoelectric terms in the neighboring layers for this structure produces optical gyrotropy, which results in circular dichroism and the polar Kerr effect. PMID- 23931400 TI - Existence of Majorana-fermion bound states on disclinations and the classification of topological crystalline superconductors in two dimensions. AB - We prove a topological criterion for the existence of a zero-energy Majorana bound state on a disclination, a rotation symmetry breaking point defect, in fourfold symmetric topological crystalline superconductors (TCS) in two dimensions. We first establish a complete topological classification of TCS using the Chern invariant and three integral rotation invariants. By analytically and numerically studying disclinations, we algebraically deduce a Z2 index that identifies the parity of the number of Majorana zero modes at a disclination. Surprisingly, we also find weakly protected Majorana fermions bound at the corners of superconductors with trivial Chern and weak invariants. PMID- 23931401 TI - Ferromagnetic Kondo effect in a triple quantum dot system. AB - A simple device of three laterally coupled quantum dots, the central one contacted by metal leads, provides a realization of the ferromagnetic Kondo model, which is characterized by interesting properties like a nonanalytic inverted zero-bias anomaly and an extreme sensitivity to a magnetic field. Tuning the gate voltages of the lateral dots allows us to study the transition from a ferromagnetic to antiferromagnetic Kondo effect, a simple case of a Berezinskii Kosterlitz-Thouless transition. We model the device by three coupled Anderson impurities that we study by numerical renormalization group. We calculate the single-particle spectral function of the central dot, which at zero frequency is proportional to the zero-bias conductance, across the transition, both in the absence and in the presence of a magnetic field. PMID- 23931403 TI - Nonreciprocal rotating power flow within plasmonic nanostructures. AB - We theoretically explore the notion of nonreciprocal near-zone manipulation of electromagnetic fields within subwavelength plasmonic nanostructures embedded in magneto-optical materials. We derive an analytical model predicting a strong, magneto-optically induced time-reversal symmetry breaking of localized plasmonic resonances in topologically symmetric structures. Our numerical simulations of plasmon excitations reveal a considerable near-zone power flow rotation within such hybrid nanostructures, demonstrating nanoscale nonreciprocity. This can be considered as another mechanism for tuning plasmonic phenomena at the nanoscale. PMID- 23931402 TI - Electron-phonon and magnetoelastic interactions in ferromagnetic Co[N(CN)2]2. AB - We combined Raman and infrared vibrational spectroscopies with complementary lattice dynamics calculations and magnetization measurements to reveal the dynamic aspects of charge-lattice-spin coupling in Co[N(CN)2]2. Our work uncovers electron-phonon coupling as a magnetic field-driven avoided crossing of the low lying Co2+ electronic excitation with two ligand phonons and a magnetoelastic effect that signals a flexible local CoN6 environment. Their simultaneous presence indicates the ease with which energy is transferred over multiple length and time scales in this system. PMID- 23931404 TI - Resonant soft-X-ray emission as a bulk probe of correlated electron behavior in metallic SrxCa1-xVO3. AB - The evolution of electron correlation in SrxCa1-xVO3 has been studied using a combination of bulk-sensitive resonant soft x-ray emission spectroscopy, surface sensitive photoemission spectroscopy, and ab initio band structure calculations. We show that the effect of electron correlation is enhanced at the surface. Strong incoherent Hubbard subbands are found to lie ~20% closer in energy to the coherent quasiparticle features in surface-sensitive photoemission spectroscopy measurements compared with those from bulk-sensitive resonant soft x-ray emission spectroscopy, and a ~10% narrowing of the overall bandwidth at the surface is also observed. PMID- 23931405 TI - Measurement of the femtosecond optical absorption of LaAlO3/SrTiO3 heterostructures: evidence for an extremely slow electron relaxation at the interface. AB - The photocarrier relaxation dynamics of an n-type LaAlO3/SrTiO3 heterointerface is investigated using femtosecond transient absorption (TA) spectroscopy at low temperatures. In both LaAlO3/SrTiO3 heterostructures and electron-doped SrTiO3 bulk crystals, the TA spectrum shows a Drude-like free carrier absorption immediately after excitation. In addition, a broad absorption band gradually appears within 40 ps, which corresponds to the energy relaxation of photoexcited free electrons into self-trapped polaron states. We reveal that the polaron formation time is enhanced considerably at the LaAlO3/SrTiO3 heterointerface as compared to bulk crystals. Further, we discuss the interface effects on the electron relaxation dynamics in conjunction with the splitting of the t2g subbands due to the interface potential. PMID- 23931406 TI - Bulk elastic fingering instability in Hele-Shaw cells. AB - We demonstrate experimentally the existence of a purely elastic, nonviscous fingering instability which arises when air penetrates into an elastomer confined in a Hele-Shaw cell. Fingers appear sequentially and propagate within the bulk of the material as soon as a critical strain, independent of the elastic modulus, is exceeded. Key elements in the driving force of the instability are the confinement of the gel and its adhesion to the plates of the cell, which result in a considerable expense of elastic energy during the growth of the air bubble. PMID- 23931407 TI - Capillary fluctuations and film-height-dependent surface tension of an adsorbed liquid film. AB - Our understanding of both structure and dynamics of adsorbed liquids heavily relies on the capillary wave Hamiltonian, but a thorough test of this model is still lacking. Here we study the capillary wave fluctuations of a liquid film with short-range forces adsorbed on a solid exhibiting van der Waals interactions. We show for the first time that the measured capillary wave spectrum right above the first order wetting transition provides an interface potential consistent with independent calculations from thermodynamic integration. However, the surface tension exhibits an oscillatory film thick dependence which reveals a hitherto unnoticed capillary wave broadening mechanism beyond mere interfacial displacements. PMID- 23931408 TI - Transmission and reflection of strongly nonlinear solitary waves at granular interfaces. AB - The interaction of a solitary wave with an interface formed by two strongly nonlinear noncohesive granular lattices displays rich behavior, characterized by the breakdown of continuum equations of motion in the vicinity of the interface. By treating the solitary wave as a quasiparticle with an effective mass, we construct an intuitive (energy- and linear-momentum-conserving) discrete model to predict the amplitudes of the transmitted solitary waves generated when an incident solitary-wave front, parallel to the interface, moves from a denser to a lighter granular hexagonal lattice. Our findings are corroborated with simulations. We then successfully extend this model to oblique interfaces, where we find that the angle of refraction and reflection of a solitary wave follows, below a critical value, an analogue of Snell's law in which the solitary-wave speed replaces the speed of sound, which is zero in the sonic vacuum. PMID- 23931409 TI - Ghost particle velocimetry: accurate 3D flow visualization using standard lab equipment. AB - We describe and test a new approach to particle velocimetry, based on imaging and cross correlating the scattering speckle pattern generated on a near-field plane by flowing tracers with a size far below the diffraction limit, which allows reconstructing the velocity pattern in microfluidic channels without perturbing the flow. As a matter of fact, adding tracers is not even strictly required, provided that the sample displays sufficiently refractive-index fluctuations. For instance, phase separation in liquid mixtures in the presence of shear is suitable to be directly investigated by this "ghost particle velocimetry" technique, which just requires a microscope with standard lamp illumination equipped with a low-cost digital camera. As a further bonus, the peculiar spatial coherence properties of the illuminating source, which displays a finite longitudinal coherence length, allows for a 3D reconstruction of the profile with a resolution of few tenths of microns and makes the technique suitable to investigate turbid samples with negligible multiple scattering effects. PMID- 23931410 TI - Core hole-electron correlation in coherently coupled molecules. AB - We study the core hole-electron correlation in coherently coupled molecules by energy dispersive near edge x-ray absorption fine-structure spectroscopy. In a transient phase, which exists during the transition between two bulk arrangements, 1,4,5,8-naphthalene-tetracarboxylicacid-dianhydride multilayer films exhibit peculiar changes of the line shape and energy position of the x-ray absorption signal at the C K-edge with respect to the bulk and gas phase spectra. By a comparison to a theoretical model based on a coupling of transition dipoles, which is established for optical absorption, we demonstrate that the observed spectroscopic differences can be explained by an intermolecular delocalized core hole-electron pair. By applying this model we can furthermore quantify the coherence length of the delocalized core exciton. PMID- 23931411 TI - Cooperative force generation of KIF1A Brownian motors. AB - KIF1A is a kinesin motor protein that can work processively in a monomeric (single-headed) form by using a noise-driven ratchet mechanism. Here, we show that the combination of a passive diffusive state and finite-time kinetics of adenosine triphosphate hydrolysis provides a powerful mechanism of cooperative force generation, implying for instance that ~10 monomeric KIF1As can team up to become ~100 times stronger than a single one. Consequently, we propose that KIF1A could outperform conventional (double-headed) kinesin collectively and thus explain its specificity in axonal trafficking. We elucidate the cooperativity mechanism with a lattice model that includes multiparticle transitions. PMID- 23931412 TI - Electrostatically driven interactions between hybrid DNA-carbon nanotubes. AB - Single-stranded DNA is able to wrap around single-wall carbon nanotubes (CNT) and form stable DNA-CNT hybrids that are highly soluble in solution. Here we report quantitative measurements and analysis of the interactions between DNA-CNT hybrids at low salts. Condensation of DNA-CNT hybrids by neutral osmolytes leads to liquid crystalline phases, and varying the osmotic pressure modulates the interhybrid distance that is determined by x-ray diffraction. Thus obtained force distance dependencies of DNA-CNT hybrids show a remarkable resemblance to that of double-stranded DNA with differences that can be largely accounted for by their different diameters. This establishes their common physical nature of electrostatically driven interactions. Quantitative modeling further reveals the roles of hydration in mediating the interhybrid forces within the last nanometer of surface separation. This study also suggests the utility of osmotic pressure to control DNA-CNT assemblies at subnanometer precision. PMID- 23931413 TI - Five-stage near-infrared electrochromism in electropolymerized films composed of alternating cyclometalated bisruthenium and bis-triarylamine segments. AB - Oxidative electropolymerization of cyclometalated bisruthenium complexes [(Nptpy)2Ru2(tppyr)](PF6)2 and [(Nptpy)2Ru2(tpb)](PF6)2 produced adherent metallopolymeric films on electrode surfaces, where Nptpy is 4'-(p-N,N diphenylamino)phenyl-2,2':6',2"-terpyridine, tppyr is the 2,7-bisdeprotonated form of 1,3,6,8-tetra(pyrid-2-yl)pyrene, and tpb is the 3,6-bisdeprotonated form of 1,2,4,5-tetra(pyrid-2-yl)benzene. The resulting polymers are composed of two types of alternating constituent units: tppyr- or tpb-bridged cyclometalated bisruthenium units and biphenyl-bridged bis-triarylamine segments. These films exhibited four well-defined anodic redox couples as a result of the stepwise oxidations of these two units. By manipulating the intervalence charge-transfer transitions of mixed-valent bisruthenium and bis-triarylamine units, five-stage near-infrared electrochromism with stepwise color changes accompanied by good contrast ratio and coloration efficiency has been realized in these films. The film characterization by scanning electronic microscopy and X-ray photoelectron spectroscopy techniques are presented as well. PMID- 23931414 TI - Investigation on Photophysical Properties of D-pi-A-pi-D-Type Fluorenone-Based Linear Conjugated Oligomers by Using Femtosecond Transient Absorption Spectroscopy. AB - The effects of pi-spacer and electron donor groups on the photophysical behaviors of fluorenone-based linear conjugated oligomers have been systemically investigated. Solvent-dependent steady-state measurements exhibit that the fluorene vinylene (FV) spacer and the electron-donating ability of donor group are able to modulate the spectral features of oligomers and the fluorescence quantum yield could decrease with the increasing of the solvent polarity. Meanwhile, quantum chemical calculation simulates their absorption spectra, and analyzes their electron transition components simultaneously. The transient absorption measurements focus on the photoexcitation dynamics of these oligomers in the toluene solution, which show that an intramolecular charge transfer state exists in the relaxation process of excited states, and its generation process could accelerate with the introduction of FV spacer and the enhancement of donor strength. PMID- 23931415 TI - DNA adsorption to and elution from silica surfaces: influence of amino acid buffers. AB - Solid phase extraction and purification of DNA from complex samples typically requires chaotropic salts that can inhibit downstream polymerase amplification if carried into the elution buffer. Amino acid buffers may serve as a more compatible alternative for modulating the interaction between DNA and silica surfaces. We characterized DNA binding to silica surfaces, facilitated by representative amino acid buffers, and the subsequent elution of DNA from the silica surfaces. Through bulk depletion experiments, we found that more DNA adsorbs to silica particles out of positively compared to negatively charged amino acid buffers. Additionally, the type of the silica surface greatly influences the amount of DNA adsorbed and the final elution yield. Quartz crystal microbalance experiments with dissipation monitoring (QCM-D) revealed multiphasic DNA adsorption out of stronger adsorbing conditions such as arginine, glycine, and glutamine, with DNA more rigidly bound during the early stages of the adsorption process. The DNA film adsorbed out of glutamate was more flexible and uniform throughout the adsorption process. QCM-D characterization of DNA elution from the silica surface indicates an uptake in water mass during the initial stage of DNA elution for the stronger adsorbing conditions, which suggests that for these conditions the DNA film is partly dehydrated during the prior adsorption process. Overall, several positively charged and polar neutral amino acid buffers show promise as an alternative to methods based on chaotropic salts for solid phase DNA extraction. PMID- 23931416 TI - Health services research in radiology: meeting the needs of the professions and the patients. PMID- 23931417 TI - Major regulatory changes and the impact on diagnostic imaging in the United States 2005 to 2012*: *effective May 15, 2013. AB - Federal regulation of diagnostic imaging in the United States has increased dramatically in recent years. The primary statutes aimed at curbing escalating costs and reorienting the national priorities of health care have a direct effect on the specialty of diagnostic imaging. This paper surveys the major regulations and current issues that pose challenges to the practice of diagnostic imaging in the United States, from the Deficit Reduction Act of 2005 through the American Taxpayer Relief Act of 2012. PMID- 23931418 TI - The disruptive physician: a legal perspective. AB - RATIONALE AND OBJECTIVES: This article addresses the medical and legal implications of disruptive physician behavior. In addition, this article will address the appropriate use of due process in peer review of disruptive physician behavior. CONCLUSIONS: While most hospitals and even national organizations, like the American Medical Association, have definitions for what constitutes disruptive physician behavior, these definitions have been further examined and clarified in court rulings. These court rulings not only further clarify what constitutes disruptive behavior but also establish a threshold for revocation/nonrenewal of a physician's hospital privileges. PMID- 23931419 TI - The cost of disruptive and unprofessional behaviors in health care. AB - RATIONALE AND OBJECTIVES: In an era of decreased reimbursements and rising expenses, academic health care systems are seeking alternative sources of funding. We hypothesized that the costs associated with disruptive physician behavior represented a source of potential savings and hence a possible financial stream which could be redirected to support other academic activities. MATERIALS AND METHODS: To test this hypothesis, we reviewed costs associated with disruptive behavior in clinical and education settings and estimated their savings in academic health care systems. RESULTS: In a 400 bed hospital, the combined costs for disruptive physician behaviors (due to staff turnover, medication errors and procedural errors) exceed $1 million. CONCLUSIONS: Reducing disruptive physician behavior in academic health care systems is a potential funding stream with the added benefits of improved patient safety, reduced medical errors and improved medical student/resident education. PMID- 23931420 TI - Using health services research to meet ACGME resident research requirements. AB - Health services research is a field of research that crosses many disciplines. It represents a novel way to address the Accreditation Council for Graduate Medical Education requirements for scholarly activity of residents and faculty in academic radiology departments. In addition to meeting training requirements, it offers future radiologists the opportunity to develop skills that will be essential as we transition from a volume based health care delivery system to an outcome based delivery system. This report introduces examples of health services research projects and the types of data resources that are available to facilitate such projects. PMID- 23931421 TI - Impact of coronary CT angiography on surgical decision-making for coronary artery bypass graft surgery. AB - RATIONALE AND OBJECTIVES: To determine the impact of coronary computed tomography angiography (CCTA) on treatment decisions made by cardiac surgeons and to explore barriers to implementation of CCTA as first-line imaging workup before coronary artery bypass. MATERIALS AND METHODS: Tertiary academic medical center retrospective cohort study. Questionnaires administered to three cardiac surgeons regarding diagnosis and treatment decisions with level of confidence in decision making for 30 chest pain patients, after reviewing deidentified catheter coronary angiogram (CCA) and CCTA images on the same patients, several weeks apart. RESULTS: All surgeons tended to report more severe disease with CCTA than CCA (P < .05). Treatment decisions differed in 12 (40%), 14 (47%), and 18 (60%) patients within each individual surgeon based on CCTA images compared to CCA images (P = .11, .01, and .02, respectively). Confidence levels were significantly higher with CCA for the diagnosis and treatment of coronary artery disease for all three surgeons (P < .05). There was a tendency toward more invasive treatment choices (angioplasty, stent insertion, or coronary artery bypass graft) when making treatment decisions based upon CCTA images. CONCLUSIONS: Severity of disease may be overestimated by cardiac surgeons when using CCTA as a decision-making test, tending toward more invasive treatment choices compared to CCA. Additionally, cardiac surgeons may be more confident with their diagnosis and treatment based on CCA. These may be important limitations in the application of CCTA in clinical practice and may reflect the maturation of CCTA use in practice, diffusion of the technology and/or a reflection of the technology itself. PMID- 23931422 TI - Patient preferences for coronary computed tomography angiography versus conventional catheter angiography for the diagnosis of coronary artery disease. AB - RATIONALE AND OBJECTIVES: The aims of the study were: 1) to assess the baseline health-related quality of life (HRQOL) of patients with coronary artery disease (CAD) using the standard gamble; 2) to evaluate and compare patients' preference for catheter versus computed tomography (CT) coronary angiography using the wait tradeoff (WTO) and rating scales; and 3) to calculate test disutility for catheter and CT coronary angiography. MATERIALS AND METHODS: Thirty patients with CAD who underwent both CT and catheter angiography were interviewed by telephone within 6 months of testing. Patients were asked about their baseline symptoms and quality of life, their experience preparing for both CT and catheter angiography, their desire to undergo CT or catheter angiography, and immediate treatment versus having a waiting period between test results and treatment for a hypothetical "ideal test" with no side effects. Test disutility for CT and catheter angiography were calculated and compared. RESULTS: The mean and median baseline HRQOL utility values were 0.72 and 0.91. The patients were willing to wait a mean (median) time of 12 (3) days after the ideal test for the test results to avoid undergoing CT angiography. They were willing to wait a mean (median) of 7 (3) days after the ideal test for test results, to avoid undergoing catheter angiography. There was no significant difference between waiting times or between patients' rating for their experience preparing for the two tests. Test disutility for CT angiography was 1.30 quality-adjusted life days (QALD) versus 2.16 QALD for catheter angiography (P > .05). CONCLUSION: There was no significant difference in patient preference and test disutility between CT and catheter angiography in our small series. Future rigorously planned and adequately powered studies are required to confirm these findings in larger patient populations. PMID- 23931424 TI - The influence of education on appropriateness rates for CT pulmonary angiography in emergency department patients. AB - RATIONALE AND OBJECTIVES: To evaluate appropriate utilization rates for computed tomography (CT) pulmonary angiography (CTPA) in a tertiary center emergency department (ED), before and after a health care provider educational intervention. MATERIALS AND METHODS: Institutional Review Board-approved retrospective study. Records for 100 consecutive CTPA studies ordered by the ED were retrieved from a radiology database. Appropriateness rates for the studies were determined using information from existing literature (clinical decision rules and society guidelines). Where pretest probability was not performed, it was calculated by the authors. After ED health care provider education regarding appropriateness guidelines through a dedicated lecture and question-and-answer session, appropriateness rates for another 100 consecutive CTPA ordered by the ED were calculated. RESULTS: In the preeducational intervention, 1% of patients had Wells scores performed, 65% were women, and 29% were age <40 years. Before CTPA, 40% patients had d-dimer testing, 15% of patients had a "negative" d-dimer, 17% had alternative explanations for chest pain, and 76% had low or intermediate pretest probability. Appropriateness rates for CTPA was 7%, and 8% of studies were positive. Postintervention, no Wells scores were performed, 59% were women, and 34% <40 years. Before CTPA, 32% of patients had d-dimer, 16% had a "negative" d-dimer, 22% had alternative explanations for chest pain, and 84% had low or intermediate pretest probability. The appropriateness rate for CTPA was 6% and 10% of studies were positive. CONCLUSION: A single educational intervention had no effect on appropriate utilization rates for CTPA. Repeated and sustained educational interventions may help improve imaging ordering pathways through the ED and other departments. PMID- 23931423 TI - Diagnostic accuracy of diffusion tensor imaging in amyotrophic lateral sclerosis: a systematic review and individual patient data meta-analysis. AB - RATIONALE AND OBJECTIVES: There have been a large number of case-control studies using diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS). The objective of this study was to perform an individual patient data (IPD) meta analysis for the estimation of the diagnostic accuracy measures of DTI in the diagnosis of ALS using corticospinal tract data. MATERIALS AND METHODS: MEDLINE, EMBASE, CINAHL, and Cochrane databases (1966-April 2011) were searched. Studies were included if they used DTI region of interest or tractography techniques to compare mean cerebral corticospinal tract fractional anisotropy values between ALS subjects and healthy controls. Corresponding authors from the identified articles were contacted to collect individual patient data. IPD meta-analysis and meta-regression were performed using Stata. Meta-regression covariate analysis included age, gender, disease duration, and Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores. RESULTS: Of 30 identified studies, 11 corresponding authors provided IPD and 221 ALS patients and 187 healthy control subjects were available for study. Pooled area under the receiver operating characteristic curve (AUC) was 0.75 (95% CI: 0.66-0.83), pooled sensitivity was 0.68 (95% CI: 0.62-0.75), and pooled specificity was 0.73 (95% CI: 0.66-0.80). Meta-regression showed no significant differences in pooled AUC for each of the covariates. There was moderate to high heterogeneity of pooled AUC estimates. Study quality was generally high. Data from 19 of the 30 eligible studies were not ascertained, raising possibility of selection bias. CONCLUSION: Using corticospinal tract individual patient data, the diagnostic accuracy of DTI appears to lack sufficient discrimination in isolation. Additional research efforts and a multimodal approach that also includes ALS mimics will be required to make neuroimaging a critical component in the workup of ALS. PMID- 23931425 TI - Associations between presence of relevant information in referrals to radiology and prevalence rates in patients with suspected pulmonary embolism. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to assess if the presence of information including the pretest probability (Wells score), other known risk factors, and symptoms given on referrals for computed tomography (CT) pulmonary angiography correlated with prevalence rates for pulmonary embolism (PE). Also, to evaluate for differences between a university and a regional hospital setting regarding patient characteristics, amount of relevant information provided on referrals, and prevalence rates for pulmonary embolism. MATERIALS AND METHODS: Retrospective review of all consecutive referrals (emergency room, inpatient, and outpatient) for CT performed on children and adults for suspected PE from two sites: a tertiary (university) hospital (site 1) and a secondary (regional) hospital (site 2) over a 5-year period. RESULTS: The overall prevalence rate was 510/3641 or 14% of all referrals. Significantly higher number of males had a positive CT compared to women (18% versus 12%, P < .001). Although no statistically significant relationship between a greater amount of relevant information on the referral and the probability for positive finding existed, a slight trend was noted (P = .09). In two categories, "hypoxia" and "signs of deep vein thrombosis," the presence of this information conferred a higher probability for pulmonary embolism, P < .001. In the categories, "chest pain," "malaise," and "smoker/chronic obstructive pulmonary disease", the absence of information conferred a higher probability for pulmonary embolism. CONCLUSIONS: The amount of relevant clinical information on the request did not correlate with prevalence rates, which may reflect a lack of documentation on the part of emergency physicians who may use a "gestalt" approach. Request forms likely did not capture all relevant patient risks and many factors may interact with each other, both positively and negatively. Pretest probability estimations were rarely performed, despite their inclusion in major society guidelines. PMID- 23931426 TI - Noninvasive phosphorus magnetic resonance spectroscopic imaging predicts outcome to first-line chemotherapy in newly diagnosed patients with diffuse large B-cell lymphoma. AB - RATIONALE AND OBJECTIVES: Based on their association with malignant proliferation, using noninvasive phosphorus MR spectroscopic imaging ((31)P MRSI), we measured the tumor content of the phospholipid-related phosphomonoesters (PME), phosphoethanolamine and phospholcholine, and its correlation with treatment outcome in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) receiving standard first-line chemotherapy. EXPERIMENTAL DESIGN: The PME value normalized to nucleoside triphosphates (PME/NTP) was measured using (31)P MRSI in tumor masses of 20 patients with DLBCL before receiving standard first-line chemotherapy. Response at 6 months was complete in 13 patients and partial in seven. Time to treatment failure (TTF) was <=11 months in eight patients, from 18 to 30 months in three, and >=60 months in nine. RESULTS: On a t test, the pretreatment tumor PME/NTP mean value (SD, n) of patients with a complete response at 6 months was 1.42 (0.41, 13), which was significantly different from the value of 2.46 (0.40, 7) in patients with partial response (P < .00001). A Fisher test significantly correlated the PME/NTP values with response at 6 months (sensitivity and specificity at 0.85, P < .004) while a Cox proportional hazards regression significantly correlated the PME/NTP values with TTF (hazard ratio = 5.21, P < .02). A Kaplan-Meier test set apart a group entirely composed of patients with TTF <= 11 months (hazard ratio = 8.66, P < .00001). CONCLUSIONS: The pretreatment tumor PME/NTP values correlated with response to treatment at 6 months and time to treatment failure in newly diagnosed patients with DLBCL treated with first-line chemotherapy, and therefore they could be used to predict treatment outcome in these patients. PMID- 23931428 TI - Comparison of Fenestra LC, ExiTron nano 6000, and ExiTron nano 12000 for micro-CT imaging of liver and spleen in mice. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to compare different contrast agents for longitudinal liver and spleen imaging in a mouse model of liver metastasis. MATERIALS AND METHODS: Mice developing liver metastases underwent longitudinal micro-computed tomography imaging after injection of Fenestra LC, ExiTron nano 6000, or ExiTron nano 12000. Elimination times and contrast enhancement of liver and spleen were compared. RESULTS: For all contrast agents, liver contrast peaked at approximately 4 hours and spleen contrast at 48 hours postinjection. A single dose of 100 MUL of ExiTron nano 6000 or 12000 resulted in longstanding enhancement of liver and spleen tissue for longer than 3 weeks, whereas repeated injections of 400 MUL of Fenestra LC were required to retain contrast at acceptable levels and allowed imaging of the liver/spleen for up to 2 and 9 days, respectively. CONCLUSION: Both ExiTron nano agents provide longer and stronger contrast enhancement of liver and spleen compared to Fenestra LC, and they do so at a 75% lower injection volume in mice. PMID- 23931427 TI - Recommended iodine dose for multiphasic contrast-enhanced mutidetector-row computed tomography imaging of liver for assessing hypervascular hepatocellular carcinoma: multicenter prospective study in 77 general hospitals in Japan. AB - RATIONALE AND OBJECTIVES: To determine the recommended iodine dose of contrast material (CM) for hepatic arterial-dominant phase (HAP) and hepatic parenchymal phase (HPP) imaging to assess hypervascular hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This was a prospective study including 348 patients with hypervascular HCC in 77 hospitals as a postmarketing surveillance to investigate the effects of body weight-tailored dose of CM (300 mgI/mL of iohexol) for hepatic multiphasic contrast-enhanced multidetector-row computed tomography imaging. Informed consent was obtained from all patients who were enrolled. The tumor-to-liver contrast (TLC) of HAP images was assessed qualitatively (QL-TLC) and quantitatively (QT-TLC [HU]; computed tomography [CT] value of tumor-CT value of hepatic parenchyma). Minimal and sufficient QT-TLC were defined as CT values corresponding to the median and 75% of QL-TLC assigned with "good," respectively. The recommended iodine dose was estimated by the relationship between iodine dose (mgI/kg) and QT-TLC. RESULTS: There was a good correlation between QL-TLC and QT TLC. The recommended iodine dose of CM for HAP imaging was considered to be in the range of 567-647 mgI/kg based on minimal (33.7 HU) and sufficient QT-TLC (40.9 HU). Meanwhile, the recommended dose of CM for HPP imaging was 572 mgI/kg as a dose that gives hepatic enhancement more than 50 HU during HPP imaging. CONCLUSIONS: The recommended iodine dose of CM for HAP and HPP imaging may be different, being 567-647 mgI/kg and 572 mgI/kg, respectively, in assessing hypervascular HCC. PMID- 23931429 TI - Dual-energy CT spectral and energy weighted data sets: carotid stenosis and plaque detection. AB - RATIONALE AND OBJECTIVES: To evaluate dual-energy computed tomography spectral and energy weighted (W) image data sets concerning carotid stenosis and calcified plaque detection. MATERIALS AND METHODS: Ninety patients were evaluated using contrast media injection. Energy used for dual-energy computed tomography was tin filter with 140/80 kiloVoltage and effective milli Ampere second was 147.4/270.6. Image reconstruction was performed using D30f kernel and 0.0, 0.3, 0.6, 0.8, 1.0 weightings. Data sets were analyzed using both qualitative and quantitative methods. RESULTS: The signal-to-noise ratio, contrast-to-noise ratio, and figure of-merit were significantly higher in 0.6-W compared to 140-kV or 80-kV data (all P < .05). Plaque thickness, span, and longitudinal diameters were different for 140-kV, 0.6-W, and 80-kV data (all P < .05). Stenotic intra-luminal diameter was significantly different among 140 kV, 0.6 W, and 80 kV data (all P < .05). A comparison between 0.6 W and digital subtraction angiography was nonsignificant (P > .05) in normal lumen measurement. CONCLUSIONS: The dimension of calcified plaque and carotid artery with contrast media decreased with increased energy. The percentage of carotid artery stenosis does not vary with different energy. Care must be taken for procedural planning like sizing of stents. Measured diameters of the 0.6 W were close to digital subtraction angiography; we suggest that planning should be based on the images acquired using 0.6 weighting. PMID- 23931430 TI - Comparison of radiation dose estimates and scan performance in pediatric high resolution thoracic CT for volumetric 320-detector row, helical 64-detector row, and noncontiguous axial scan acquisitions. AB - RATIONALE AND OBJECTIVES: Efforts to decrease radiation exposure during pediatric high-resolution thoracic computed tomography (HRCT), while maintaining diagnostic image quality, are imperative. The objective of this investigation was to compare organ doses and scan performance for pediatric HRCT using volume, helical, and noncontiguous axial acquisitions. MATERIALS AND METHODS: Thoracic organ doses were measured using 20 metal oxide semiconductor field-effect transistor dosimeters. Mean and median organ doses and scan durations were determined and compared for three acquisition modes in a 5-year-old anthropomorphic phantom using similar clinical pediatric scan parameters. Image noise was measured and compared in identical regions within the thorax. RESULTS: There was a significantly lower dose in lung (1.8 vs 2.7 mGy, P < .02) and thymus (2.3 vs 2.7 mGy, P < .02) between volume and noncontiguous axial modes and in lung (1.8 vs 2.3 mGy, P < .02), breast (1.8 vs 2.6 mGy, P < .02), and thymus (2.3 vs 2.4 mGy, P < .02) between volume and helical modes. There was a significantly lower median image noise for volume compared to helical and axial modes in lung (55.6 vs 79.3 and 70.7) and soft tissue (76.0 vs 111.3 and 89.9). Scan times for volume, helical, and noncontiguous axial acquisitions were 0.35, 3.9, and 24.5 seconds, respectively. CONCLUSION: Volumetric HRCT provides an opportunity for thoracic organ dose and image noise reduction, at significantly faster scanning speeds, which may benefit pediatric patients undergoing surveillance studies for diffuse lung disease. PMID- 23931432 TI - Emergency radiology elective improves second-year medical students' perceived confidence and knowledge of appropriate imaging utilization. AB - RATIONALE AND OBJECTIVES: Given recent advances in and wider availability of complex imaging, physicians are expected to understand imaging appropriateness. We introduced second-year medical students to the American College of Radiology Appropriateness Criteria (ACR-AC) in an interactive case-based elective to demonstrate their use in imaging for common emergency department clinical complaints. MATERIALS AND METHODS: Prospective pre- and post-test design assessed second-year medical students' performance on case-based knowledge applications and self-assessed confidence related to ACR-AC guidelines compared to second-year students participating in a different concurrent radiology elective. Students participated in a 3-day elective covering the ACR-AC, comparative effective imaging, and risks associated with imaging radiation exposure, with outcomes of perceived confidence using a 5-point Likert scale and knowledge of ACR-AC using case-based multiple choice questions. Analysis included computing mean scores and assessing effect sizes for changes in knowledge. RESULTS: Before the elective, 24 students scored an average of 3.45 questions correct of 8 (43.1%). On course completion, students scored an average of 5.3 questions correct of the same questions (66.3%) (P < .001; effect size [Cohen's d] = 1.3940. In the comparison group, 12 students scored an average of 3.08 questions (38.5%) correctly pretest and 3.09 questions (38.6%) correctly post-test (P > .85; effect size = 0.008). Students' confidence in ordering appropriate imaging improved nearly 2-fold from a range of 1.9 to 3.2 (on a scale of 1.0 to 5.0) to a range of 3.7 to 4.5. CONCLUSIONS: Following a short radiology elective, second-year medical students improved their knowledge of appropriate image utilization and perceived awareness of the indications, contraindications, and effects of radiation exposure related to medical imaging. PMID- 23931431 TI - CT of urolithiasis: comparison of image quality and diagnostic confidence using filtered back projection and iterative reconstruction techniques. AB - RATIONALE AND OBJECTIVES: To compare the image quality and diagnostic confidence of low-dose computed tomography (CT) of urololithiasis using filtered back projection (FBP) and iterative reconstruction techniques (IRT). MATERIALS AND METHODS: A 4.8 * 4.3 * 5.2 mm(3) uric acid ureteral stone was placed inside an anthropomorphic Alderson phantom at the pelvic level. Fifteen scans were performed on a 64-row dual-source CT system using different tube voltages (80, 100, and 120 kV) and current-time products (8, 15, 30, 70, and 100 mAs). Image reconstruction using FBP and IRT (iterative reconstruction in image space) resulted in 30 data sets. Objective image quality was evaluated by noise measurements. Effective doses were estimated for each data set with use of an established dosimetry program. Subjective image quality and confidence level were rated by two radiologists. RESULTS: Noise was systematically lower for images reconstructed with IRT compared to FBP (55 +/- 30 vs 65 +/- 26 Hounsfield units; P = .004) for volume CT dose index values above about 0.6 mGy (or an effective dose of about 0.4 mSv for both sexes). For the 14 scans rated to have diagnostic image quality, the estimated effective doses ranged from 0.3 to 2.5 mSv for males and from 0.4 to 3.1 mSv for females. Subjective image quality and diagnostic confidence for IRT was not significantly better than those for FBP. CONCLUSIONS: In a phantom study for CT of urolithiasis, IRT improves objective image quality compared to FBP above a certain dose threshold. However, this does not translate into improved subjective image quality or a higher degree of confidence for the diagnosis of high-contrast urinary stones. PMID- 23931433 TI - Teaching professionalism through case studies. PMID- 23931434 TI - More radiology history. PMID- 23931435 TI - The multifactorial nature of Alzheimer's disease for developing potential therapeutics. AB - Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with several target proteins contributing to its aetiology. Pathological, genetic, biochemical, and modeling studies all point to a critical role of Abeta aggregation in AD. Though there are still many enigmatic aspects of the Abeta cascade, none of the gaps invalidate the hypothesis. The amyloid hypothesis determines that the production, aggregation and accumulation of Abeta in the brain gives rise to a cascade of neurotoxic events that proceed to neuronal degeneration. Different targets of the disease include APP pathogenic cleavage, cytoskeletal destabilization, neurotransmitter and ion dyshomeostasis, metal ion accumulation, protein misfolding, oxidative stress, neuronal death and gene mutations. Thus, disease-modifying treatments for AD must interfere with the pathogenic steps responsible for the clinical symptoms: the deposition of extracellular Abeta plaques, the intracellular neurofibrillary tangles, inflammation, oxidative stress, iron deregulation, among others. The observations supporting the development of multifunctional compounds in association with the perception that several dual binding site AChEIs were able to reach different targets guided the development of a new drug design strategy, the multi-target directed-ligand (MTDL) approach. This may be regarded as the buildup of hybrid molecules composed of distinct pharmacophores of different drugs. Thus, each pharmacophore of the new hybrid drug would preserve the capacity of interacting with their specific sites on the targets and, therefore, generate multiple specific pharmacological responses which would enable the treatment of multi factorial diseases. This review summarizes a few current therapeutic trends on MTDL strategy intended to halt or revert the progression of the disease. PMID- 23931436 TI - Emerging targets in neurodegeneration: new opportunities for Alzheimer's disease treatment? AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain associated with memory impairment, progressive cognitive decline and changes in personality and behavior, with rising incidence among elderly people. Reflecting the world population ageing, the scenario is expected to worsen in the next decades if novel drugs or mechanisms that help to counteract neurodegeneration will not be identified. The complex neuropathology of AD is characterized by cholinergic loss, extracellular deposition of amyloid-beta plaques, formation of intracellular neurofibrillary tangles, chronic brain inflammation and oxidative damage. To date, there are no effective treatments that can slow or halt the disease, and currently approved drugs only seem to act as palliative by temporary ameliorating cognitive impairment. On the other hand, the role played by other biological systems in the pathogenetic process is now clearly growing and, as knowledge on how AD develops and triggers brain damage proceeds, drug discovery attempts to identify new potential therapeutic targets. This review will focus on these emerging strategies, some of which could open new therapeutic perspectives in Alzheimer's disease, adding new elements for the medicinal chemist to handle and combine for the design of novel multi-target-directed ligands able to simultaneously modulate 'old classic' and newly identified targets. PMID- 23931437 TI - Natural products as sources of new lead compounds for the treatment of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most prevalent form of dementia and affects approximately 24 million people worldwide. One possible approach for the treatment of this disease is the restoration of the level of acetylcholine (ACh) through the inhibition of acetylcholinesterase (AChE) with reversible inhibitors. Naturally occurring alkaloids are an important source of AChE inhibitors. Galantamine and huperzine A have been used for the clinical treatment of AD patients. In this review, we summarise the natural products and their derivatives that were reported to act as AChE inhibitors for the treatment of AD in 2010 2013. Several characteristics were summarised from the literature results: 1) Amongst all of the natural products with AChE inhibitory activity, alkaloids appear to be the most promising compound class. 2) Coumarins, flavonoids, stilbenes, and other natural products are also important AChE inhibitors from natural products. Among these inhibitors, 146 (IC50 = 0.573 uM) was identified as the most potent AChE inhibitor. 3) A coumarin derivative (117, IC50 = 0.11 nM) exhibited more than 100-fold superior activity compared with the reference drug donepezil hydrochloride (IC50 = 14 nM). In conclusion, natural products and their derivatives are promising leads for the development of new drugs for the future treatment of AD. PMID- 23931438 TI - Clinical pharmacology of novel anti-Alzheimer disease modifying medications. AB - In recent years, efforts have been directed to develop "disease-modifying" medications to treat Alzheimer's disease (AD), able to halt or slow the pathological process. Because the earlier the treatment starts, the greater is the possibility of efficacy, it is important to set up biomarkers for early diagnosis of functional brain abnormalities, before the clinical manifestation of the overt disease. Up to now, strategies to develop disease-modifying drugs have mainly targeted beta amyloid (Abeta, accumulation, aggregation, clearance) and/or tau protein (phosphorylation and aggregation). Active and passive immunotherapy is the main strategy aimed at increasing Abeta clearance. Unfortunately several candidate diseasemodifying drugs have failed in phase III clinical trials conducted in mild to moderate AD. More recently, in phase III studies, bapineuzumab has been discontinued because it did not prove clinically effective (despite its significant effect on biomarkers), while solaneuzumab has been found effective in slowing AD progression. Several methological problems have been recently pointed out to explain the lack of clinical efficacy of novel disease modifying drug-treatments; moreover, new insights in pathophysiology of AD give the premise to develop novel drug targeting. Clinical trials recently completed and/or still ongoing are discussed in the present review. PMID- 23931439 TI - From the multifactorial nature of Alzheimer's disease to multitarget therapy: the contribution of the translational approach. AB - The drug discovery for disease-modifying agents in Alzheimer disease (AD) is facing a failure of clinical trials with drugs based on two driving hypotheses, i.e. the cholinergic and amyloidogenic hypotheses. In this article we recapitulate the main aspects of AD pathology, focusing on possible mechanisms for synaptic dysfunction, neurodegeneration and inflammation. We then present the pharmacological and neurobiological profile of a novel compound (CHF5074) showing both anti-inflammatory and gamma-secretase modulatory activities, discussing the possible time-window for effective treatment in an AD transgenic mouse model. Finally, the concept of cognitive reserve is introduced as possible target for preventive therapies. PMID- 23931440 TI - Dual inhibitors of beta-amyloid aggregation and acetylcholinesterase as multi target anti-Alzheimer drug candidates. AB - Notwithstanding the functional role that the aggregates of some amyloidogenic proteins can play in different organisms, protein aggregation plays a pivotal role in the pathogenesis of a large number of human diseases. One of such diseases is Alzheimer's disease (AD), where the overproduction and aggregation of the beta-amyloid peptide (Abeta) are regarded as early critical factors. Another protein that seems to occupy a prominent position within the complex pathological network of AD is the enzyme acetylcholinesterase (AChE), with classical and non classical activities involved at the late (cholinergic deficit) and early (Abeta aggregation) phases of the disease. Dual inhibitors of Abeta aggregation and AChE are thus emerging as promising multi-target agents with potential to efficiently modify the natural course of AD. In the initial phases of the drug discovery process of such compounds, in vitro evaluation of the inhibition of Abeta aggregation is rather troublesome, as it is very sensitive to experimental assay conditions, and requires expensive synthetic Abeta peptides, which makes cost prohibitive the screening of large compound libraries. Herein, we review recently developed multitarget anti-Alzheimer compounds that exhibit both Abeta aggregation and AChE inhibitory activities, and, in some cases also additional valuable activities such as BACE-1 inhibition or antioxidant properties. We also discuss the development of simplified in vivo methods for the rapid, simple, reliable, unexpensive, and high-throughput amenable screening of Abeta aggregation inhibitors that rely on the overexpression of Abeta42 alone or fused with reporter proteins in Escherichia coli. PMID- 23931441 TI - Lessons learnt from glycogen synthase kinase 3 inhibitors development for Alzheimer's disease. AB - Glycogen synthase kinase 3 (GSK-3) inhibitors have aroused a great interest for medicinal chemists and pharmaceutical companies in the last years. In fact, some candidates have reached to clinical trials as disease modifying drugs for Alzheimer's disease. This review will cover the great improvements recently done in the field of GSK-3 inhibitors switching from random discovery to rational drug design, from full GSK-3 inhibition to mild and controlled activity of enzyme reduction, from unknown therapeutic potential to validated efficacy in different animal models of diseases. Moreover some lessons learnt from clinical trials will be described with the aim to improve future designs. Collective results highlight the importance of mild GSK-3 inhibitors as innovative drugs for severe human unmet diseases. PMID- 23931444 TI - New approaches to the treatment of Alzheimer's disease. PMID- 23931443 TI - Multifunctional tacrine derivatives in Alzheimer's disease. AB - Tacrine (1) was the first acetylcholinesterase inhibitor (AChEI) introduced in therapy for the treatment of Alzheimer's disease (AD), but similarly to the most recent approved AChEIs and memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, it does not represent an effective drug in halting the progression of AD. The continuous research in this field has contributed to delineate AD as a multifactorial syndrome with several biological targets involved in its etiology. On these bases, the development of new effective therapeutics becomes crucial and the design of molecules that address more than one specific AD target should represent thus a succeeded strategy for AD treatment. This review will focus on and summarize multifunctional 1 derivatives starting from our last paper published on the same topic in 2010. In the last three years, the design and synthesis of 1 homo- and heterodimers, as well as of 1-hybrid structures for AD therapy, was aimed mainly to discover safer drugs, with decreased hepatotoxicity in comparison to 1, taking also into account the multifactorial pathogenesis of the disease. Most of these new hetero/homo-dimers and/or hybrids of 1, although addressed mainly to acetylcholinesterase (AChE) and Abeta aggregation inhibition, are able to hit additional targets relevant to AD, among which, beta-secretase (BACE1), reactive oxygen species (ROS), calcium channels, NMDAR and M1- muscarinic receptors. PMID- 23931442 TI - The structural evolution of beta-secretase inhibitors: a focus on the development of small-molecule inhibitors. AB - Effective treatment of Alzheimer's disease (AD) remains a critical unmet need in medicine. The lack of useful treatment for AD led to an intense search for novel therapies based on the amyloid hypothesis, which states that amyloid beta-42 (Abeta42) plays an early and crucial role in all cases of AD. beta-Secretase (also known as BACE-1 beta-site APP-cleaving enzyme, Asp-2 or memapsin-2) is an aspartyl protease representing the rate limiting step in the generation of Abeta peptide fragments, therefore it could represent an important target in the steady hunt for a disease-modifying treatment. Generally, beta-secretase inhibitors are grouped into two families: peptidomimetic and nonpeptidomimetic inhibitors. However, irrespective of the class, serious challenges with respect to blood brain barrier (BBB) penetration and selectivity still remain. Discovering a small molecule inhibitor of beta-secretase represents an unnerving challenge but, due to its significant potential as a therapeutic target, growing efforts in this task are evident from both academic and industrial laboratories. In this frame, the rising availability of crystal structures of beta-secretase-inhibitor complexes represents an invaluable opportunity for optimization. Nevertheless, beyond the inhibitory activity, the major issue of the current research approaches is about problems associated with BBB penetration and pharmacokinetic properties. This review follows the structural evolution of the early beta secretase inhibitors and gives a snap-shot of the hottest chemical templates in the literature of the last five years, showing research progress in this field. PMID- 23931446 TI - From the editor. AB - No abstract available for this article. PMID- 23931447 TI - Adaptive equipment:. AB - This article describes a quality assurance study of patient utilization of adaptive equipment. A major component of occupational therapy practice has been the prescription of equipment to increase independent living. However, little information exists in the literature regarding patients use of equipment. The researchers found an unexpected high rate (85%) of utilization. Reasons for non utilization are described. Caution is needed in interpreting the results as non responders (22%) may have been primarily non-users. Based on the findings, the authors suggest establishing a system to retrieve items needed for a short time and individualizing the process of issuing equipment based on environmental and personal needs as opposed to the standard protocol based on a diagnosis. PMID- 23931445 TI - Palladium-catalyzed alpha-arylation of zinc enolates of esters: reaction conditions and substrate scope. AB - The intermolecular alpha-arylation of esters by palladium-catalyzed coupling of aryl bromides with zinc enolates of esters is reported. Reactions of three different types of zinc enolates have been developed. alpha-Arylation of esters occurs in high yields with isolated Reformatsky reagents, with Reformatsky reagents generated from alpha-bromo esters and activated zinc, and with zinc enolates generated by quenching alkali metal enolates of esters with zinc chloride. The use of zinc enolates, instead of alkali metal enolates, greatly expands the scope of the arylation of esters. The reactions occur at room temperature or at 70 degrees C with bromoarenes containing cyano, nitro, ester, keto, fluoro, enolizable hydrogen, hydroxyl, or amino functionality and with bromopyridines. The scope of esters encompasses acyclic acetates, propionates, and isobutyrates, alpha-alkoxyesters, and lactones. The arylation of zinc enolates of esters was conducted with catalysts bearing the hindered pentaphenylferrocenyl di-tert-butylphosphine (Q-phos) or the highly reactive dimeric Pd(I) complex {[P(t-Bu)3]PdBr}2. PMID- 23931448 TI - A critical review of cognitive and memory assessment tools:. AB - A small percentage of cardiac clients experience cognitive and memory disorders after surgery. Since these disorders could limit a client's ability to function independently in daily activities, it would seem imperative that occupational therapists be able to examine the cognitive and memory dysfunctions of their cardiac clients. This paper presented information on the reliability and validity of a number of tools that have been administered by researchers and rehabilitation professionals to assess cognition. A critique of the information on assessment instruments and screening tools suggested that several tools could provide therapists with valuable diagnostic material on cognition. Promising screening tools and assessments appeared to require further research with a cardiac population. PMID- 23931450 TI - Personal selling:. AB - No abstract available for this article. PMID- 23931449 TI - Attrition, burnout, job dissatisfaction and occupational therapy managers. AB - At a time when there is growing concern about the person-power shortages in occupational therapy, there is a need to address reasons why therapists leave the job market. Two job-related reasons for attrition are burnout and job dissatisfaction. The burnout phenomenon occurs as a result of personnel shortages, high-stress demands on therapists, the severity and complexity of client's problems, and the therapist's own ''worker personality.'' Bureaucratic constraints, limited advancement, issues related to a profession which is made up predominantly of women, lack of autonomy, and type of management and supervision are factors that contribute to job dissatisfaction. Occupational therapy managers can consider the causes of burnout and job dissatisfaction and initiate resources to retain therapists. Managers can increase the job benefits, such as flexible working hours, take steps to reduce stress in the workplace, offer career laddering opportunities, and promote staff development. By identifying the causes for attrition and by addressing those causes, the threat of losing therapists from the work force may be averted. Respondents (n = 106) to a survey of occupational therapy managers indicated that job dissatisfaction, burnout, and attrition of registered occupational therapists were not major problems in their settings. They reported a variety of strategies to reduce job dissatisfaction, burnout, and attrition. When these problems were present, managers cited bureaucratic red tape, lack of opportunity for advancement, and increasing role demands as contributing factors. PMID- 23931451 TI - Sensorimotor half-day cAMP. AB - This paper describes a half-day sensorimotor camp program for young children. The camp program initially was offered to 4 pre-kindergarten children and supervised by one registered occupational therapist and one technician. The therapeutic format of the camp was multimodal. Principles of sensory integration, neurodevelopmental treatment, and education were incorporated in a structured, but varied sensorimotor environment. The goals of the camp were to provide (1) successful group play experiences, and opportunities to participate in (2) developmental/age appropriate sensorimotor activities, (3) recreational activities and (4) activities of daily living. The half-day sensorimotor camp offered a positive and successful experience to developmentally delayed children, which is usually not possible in many community based summer programs. PMID- 23931452 TI - Optometric and sensory motor changes in an adult. AB - This case study was designed to determine whether an adult with definable visual problems and sensory motor dysfunction would respond to a prescribed, periodically monitored home program of sensory motor activities. The subject was a 27-year-old college student who reported lifelong difficulties in visual postural mechanisms which were documented through an Occupational Therapy initial evaluation, administered by Occupational Therapists, and the Functional Visual Evaluation, administered by a Vision Therapist. An individualized home program, which included predominantly vestibular and proprioceptive activities, was followed by the subject for six months. Retesting showed positive increases in both postural mechanisms and the visual system. A need for collaboration between Occupational Therapists, Developmental Optometrists and Vision Therapists for the purpose of specifically recording hard data to document visual deficits and the effects of occupational therapy programs to remediate problem areas is discussed. PMID- 23931453 TI - A leisure-time frame of reference based on a literature analysis. AB - The aims of this study were, through literature analyses, to identify the concept 'leisure time,' to design a model of leisure time and to study the empirical methods used in research literature on leisure time. The data for this article consisted of occupational therapy literature including 48 articles found through a search of the MEDLINE and PsychLIT databases for the period 1975-1989. The methods used for identifying and coding these data based on a set of questions presented by Guba and Lincoln (1985). For discovering the empirical methods used in the material, the work of Ostrow and Caplan (1985) was followed. The data analysis led to the development of a frame of reference of leisure time as used in occupational therapy literature. This model consists of the following dimensions: time, intrinsic motivation, free choice of activity, capability, structure of social and culture environment, leisure-time activity engaged in, goals, pleasure for pleasure's sake, diversion, recreation, relaxation, self fulfillment, influence on individual, leisure role, leisure behavior, and satisfied harmonious person. PMID- 23931455 TI - Toxicokinetic and mechanistic basis for the safety and tolerability of liposomal amphotericin B. AB - INTRODUCTION: Amphotericin B (AmB) was first approved by the US Food and Drug Administration in 1959 with sodium deoxycholate (DAmB, Fungizone(r)). Extensive toxicities associated with the drug led to the development of lipid formulations of AmB, including liposomal amphotericin B (L-AmB, AmBisome(r)). Phase I studies as well as comparative Phase III clinical trials indicate that L-AmB is associated with less nephrotoxicity and reduced infusion-related toxicity. There is, however, no recent comprehensive review of the safety and tolerability of L AmB. AREAS COVERED: This article reviews the safety, tolerability and the mechanisms of the major toxicities associated with L-AmB, including nephrotoxicity, infusion-related reactions (IRRs), anemia and thrombocytopenia, and hepatic abnormalities. The article further discusses the mechanism of action and pharmacokinetics of L-AmB. EXPERT OPINION: L-AmB is a broad-spectrum antifungal agent that has significantly reduced toxicities compared to its predecessor, DAmB. PMID- 23931454 TI - Photoinduced electron transfer from PbS quantum dots to cobalt(III) Schiff base complexes: light activation of a protein inhibitor. AB - This paper describes the activation of a biologically inert Co(III) Schiff base [Co(III)-SB] complex to its protein inhibitor form by photoinduced electron transfer (PET) from a colloidal PbS quantum dot (QD, radii of 1.5-1.7 nm) to the cobalt center, with a charge separation time constant of 125 ns. Reduction of the Co(III)-SB complex initiates release of the native axial ligands, promoting replacement with the histidine mimic 4-methylimidazole. The rate of ligand displacement increases by a factor of approximately 8 upon exposure of the PbS QD/Co(III)-SB mixture to light with an energy greater than the energy of the first excitonic state of the QDs, from which PET occurs. These results suggest an approach for the preparation of inorganic therapeutic agents that can be specifically coupled to a biologically active site by cooperative redox binding ligation. PMID- 23931456 TI - Hollow-channel paper analytical devices. AB - We present a microfluidic paper analytical device (MUPAD) that relies on flow in hollow channels, rather than through a cellulose network, to transport fluids. The flow rate in hollow channels is 7 times higher than in regular paper channels and can be conveniently controlled from 0 to several mm/s by balancing capillary and pressure forces. More importantly, the pressure of a single drop of liquid (~0.2 mbar) is sufficient to induce fast pressure-driven flow, making hollow channels suitable for point of care diagnostics. We demonstrate their utility for simple colorimetric glucose and BSA assays in which the time for liquid transport is reduced by a factor of 4 compared to normal cellulose channels. PMID- 23931457 TI - Image diagnostic agreement in uveitis: a picture is worth a thousand words but is it sufficient to diagnose? PMID- 23931458 TI - Fundus image diagnostic agreement in uveitis utilizing free and open source software. AB - OBJECTIVE: To assess the adequacy of image agreement regarding uveitis based on color fundus and fluorescein angiography images alone, and to use free and open source applications to conduct an image agreement study. DESIGN: Cross-sectional agreement study. PARTICIPANTS: Baseline fundus and fluorescein images of patients with panuveitis, posterior, or intermediate uveitis enrolled in the Multi-center Uveitis Steroid Treatment (MUST) trial. METHODS: Three fellowship-trained specialists in uveitis independently reviewed patient images using ClearCanvasTM and responded using Epi InfoTM. The diagnoses of the 3 reviewers were compared with the MUST clinician as a gold standard. A rank transformation adjusted for the possible variation in number of responses per patient. Chance-corrected interobserver agreement among the 3 reviewers was estimated with the iota coefficient. Confidence interval (CI) and SE were bootstrapped. RESULTS: Agreement between the diagnoses of the respondents and the baseline MUST clinician's diagnosis was poor across all diagnostic categories, iota = 0.09 (95% CI, 0.07-0.11). The agreement among respondents alone also was poor, iota = 0.11 +/- 0.02 (95% CI, 0.08-0.13). The specialists requested more patient historical and clinical information to make a diagnosis on all patients. CONCLUSIONS: The role in distinguishing the multiple conditions in uveitis appears to be limited when based on fundus imaging alone. Future studies should investigate different categories of clinical data to supplement image data. Freely available applications have excellent utility in ophthalmic imaging agreement studies. PMID- 23931459 TI - Investigation of tear osmolarity in early rheumatoid arthritis: relation to disease activity. AB - OBJECTIVE: To investigate the frequency of dry eye (DE) by measuring tear osmolarity (TO) with the recently introduced TearLab system (TearLab Corp, San Diego, Calif.) in patients with early rheumatoid arthritis (ERA) and the relationship between the severity of DE and ERA disease activity. DESIGN: Prospective study PARTICIPANTS: Sixty-four eyes of 64 newly diagnosed and untreated patients with ERA were enrolled in this study. METHODS: TO measurements, tear break-up time (TBUT), and Schirmer tests were performed. ERA disease activity was evaluated according to the disease activity score 28 (DAS28). The patients were divided into 3 groups according to DAS28 scores as follows: mild (DAS28 <= 3.2), moderate (3.2 < DAS28 <= 5.1), and severe (DAS28 > 5.1). RESULTS: DE was identified in 46 (71.8%) patients with ERA according to the TO values. There were significant differences among these groups concerning TO (p = 0.001) and TBUT (p = 0.005) scores, whereas there was no significant difference between these groups regarding Schirmer scores (p = 0.200). In addition, DAS28 values were positively correlated with TO values (r = 0.710, p < 0.001), negatively correlated with Schirmer scores, (r = -0.251, p = 0.045), and negatively correlated with TBUT scores (r = -0.335, p = 0.007) among all patients. CONCLUSIONS: Our study demonstrated a relationship between the ERA disease activity and severity of DE by using TO measurements with the TearLab system. Therefore, TO measurement could be added to other classical DE tests for diagnosing DE and for assessing the degree of disease activity of ERA. PMID- 23931460 TI - Role of patient choice in influencing wait time for cataract surgery. AB - OBJECTIVE: To assess the role of patient choice in influencing wait time for cataract surgery. DESIGN: Cross-sectional study. PARTICIPANTS: 496 patients aged >=40 years presenting to Kensington Eye Institute in Toronto for cataract surgery in 2010-2011. METHODS: Patients were invited to complete a self-administered questionnaire about their experience with wait time management, sociodemographics, and satisfaction with wait time. Differences in median wait time were statistically tested with the Wilcoxon test. Factors associated with declining the first available surgery date were analyzed with prevalence ratios (PR) and 95% confidence intervals (CIs). RESULTS: Overall, 90% of patients had surgery within 21 weeks; 16% experienced a wait longer than the pan-Canadian benchmark (16 weeks). The median wait time was 8 weeks. Altogether, 21% declined the first available surgery date. Major reasons included planned travel/holidays (35%), family responsibilities (14%), and earlier date became available (13%). Excluding those with "earlier date became available" and "cancellation by surgeon," the proportion declining the first available date decreased to 18%. In multivariate analysis, individuals with a college/university education were 60% more likely to decline (PR 1.6, 95% CI 1.0-2.5). Conversely, individuals living alone were 50% less likely to decline (PR 0.5, 95% CI 0.3-0.9). The median wait time was 2.5 weeks longer for those who declined than for those who accepted (8.5 vs 6 weeks; p = 0.02). CONCLUSIONS: One in 5 patients declined the first available date for cataract surgery in 2010-2011 in Toronto. As wait time for cataract surgery improves, patient choice seems to play a greater role in influencing the wait. PMID- 23931461 TI - Cataract surgery with toric intraocular lens for correction of high corneal astigmatism. AB - OBJECTIVE: To analyze the outcomes of cataract surgery with high-power toric intraocular lens (IOL) implantation in patients with high corneal astigmatism. DESIGN: Retrospective case series. PARTICIPANTS: Twelve eyes of 9 patients. METHODS: Patients with idiopathic, pathologic, or postsurgical corneal astigmatism and a visually significant cataract were included in the study. Cataract extraction with implantation of a custom-made high-power toric IOL was performed on all patients. Outcomes included uncorrected and best corrected distance visual acuity (UDVA and BCDVA), manifest refraction, and mean and steepest keratometry. Analysis of astigmatic vectors was also performed. RESULTS: The mean follow-up time was 3.75 months. At the last follow-up visit, there was a significant improvement of UDVA (1 +/- 0.64 vs 0.39 +/- 0.21 logMAR; p < 0.05), cylindrical refraction (-4.72 +/- 1.13 vs -1.81 +/- 1.10 D; p < 0.01), and refractive spherical equivalent (-4.56 +/- 5.58 vs -0.36 +/- 1.19 D; p < 0.05). The BCDVA improvement did not reach statistical significance. Astigmatism on the target axis was reduced by an average of 5 D (p < 0.01). CONCLUSIONS: Cataract surgery with implantation of a high-power toric IOL was safe and effective in correcting high values of corneal astigmatism. PMID- 23931462 TI - Controversies in traumatic cataract classification and management: a review. AB - Traumatic cataract is one of the important causes of blindness after ocular trauma, either open or close globe. Visual outcome is unpredictable because it is not only lens that decides visual outcome. There is no standard classification, investigation, or treatment guidelines for the same. There are controversies regarding predictive models. We would like to highlight these controversies and try to reach certain guidelines that may help clinicians to manage traumatic cataracts. PMID- 23931463 TI - Effect of intraoperative manipulation during iris-claw phakic IOL implantation on endothelium. AB - OBJECTIVE: To evaluate the effect of intraoperative complications during iris claw phakic intraocular lens (pIOL) implantation on endothelial cell survival. DESIGN: Retrospective cohort study. PARTICIPANTS: Fifty-two eyes of 26 patients with high myopia treated with the iris-claw pIOL. METHODS: The patients were divided as group 1 (no intraoperative events) and 2 (intraoperative events) according to the intraoperative events such as intraoperative bleeding, postoperative intraocular pressure (IOP) rise, and late resolution of the chamber inflammation. Endothelial cell density was compared at 1, 2, 6, 12, and 24 months after the operation prospectively. RESULTS: Group 1 showed mean percentage of individual change of -0.04%+/-7.90% at 1 month, -0.01%+/-8.67% at 2 months, 0.02%+/-10.33% at 6 months, 0.05%+/-9.81% at 12 months, and 0.05%+/-5.33% at 24 months postoperatively. In group 2, mean percentage individual cell change was 0.17%+/-8.57% at 1 month, -0.13%+/-12.14% at 2 months, -0.13%+/-15.07% at 6 months, -0.17%+/-11.94% at 12 months, and -0.28%+/-13.54% at 24 months postoperatively. Two groups showed a significant differences in every visit. CONCLUSIONS: Even transient events, such as intraoperative bleeding, postoperative IOP rise, and late resolution of the chamber inflammation, would affect the survival of endothelial cells. PMID- 23931465 TI - Prevalence and impact of depressive symptoms in patients with age-related macular degeneration. AB - OBJECTIVE: This study sought to identify the point prevalence of depressive symptoms, quality-of-life (QOL) impairment, and demographic parameters associated with depression in patients with age-related macular degeneration (AMD) attending a retina clinic in Edmonton, Alberta. DESIGN: A cross-sectional design was used. METHODS: Consecutive patients with AMD were invited to participate in the study. Demographic data, as well as ophthalmic, medical, and psychiatric histories, were collected. Participants completed the Center for Epidemiological Studies Depression Scale (CES-D) and the Visual Function Questionnaire (VFQ-25) scales to quantify the burden of depressive symptoms and vision-related QOL impairment. RESULTS: The study enrolled 101 patients, of whom 7 (6.9%) had a previous history of depression. Twenty (21.3%) of the remaining patients endorsed severe symptoms of depression that had not yet been diagnosed. Significant differences in vision related QOL between depressed and not depressed patients were identified. Depressed patients were also found to have worse visual acuity (p = 0.047) and were less likely to live with others (p = 0.020) than those who were not depressed. CONCLUSIONS: After excluding patients with a history of diagnosed depression, 20 (21.3%) patients demonstrated severe symptoms of depression. Development of depression screening protocols for patients with AMD would improve identification and referral of patients at risk. The finding that patients who lived with others had a lower prevalence of depressive symptoms suggests that further research into the relationship between mood symptoms and environmental supports is merited. PMID- 23931464 TI - Primary care physicians' knowledge of the ophthalmic effects of diabetes. AB - OBJECTIVE: Previous studies suggest that many patients with diabetes do not receive an annual dilated eye examination because of a lack of referrals from primary care physicians (PCPs). This study aims to determine the depth of knowledge of PCPs regarding diabetic eye disease. DESIGN: Cross-sectional assessment. PARTICIPANTS: Ninety-seven PCPs. METHODS: An 8-question, multiple choice assessment was administered over a 3-month period to 208 PCPs in attendance at continuing medical education conferences. RESULTS: Ninety-seven PCPs completed the assessment. Participants had a mean total score of 5.9 of 8 possible (73.8%). Questions regarding screening, clinical findings, and prevention were answered correctly by >=81% of the respondents. However, questions regarding risk factors and complications were answered correctly by less than 35% of the respondents. No difference in scores was found based on the type of residency training received or the number of years in practice. CONCLUSIONS: Although PCPs may require greater education in the complications and risk factors of diabetic eye disease, study participants demonstrated a good overall depth of knowledge regarding diabetic eye disease. Thus, previous reports of only 35% to 55% of patients with diabetes receiving an annual dilated fundus examination are likely not due to a lack of physician education. PMID- 23931466 TI - Residual colour detection abilities in age-related macular degeneration. AB - OBJECTIVE: To quantify residual abilities to identify a target's colour in cases with age-related macular degeneration (AMD). METHODS: Subjects with AMD with best corrected visual acuity (BCVA) of 20/50 to 20/400 in the better eye (test eye) and age older than 55 years were recruited. A separate matching control group was recruited with subjects with BCVA of 20/40 or better. Each subject was presented sequentially with square-shaped colour targets corresponding in size to optotype sizes used in standard Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocols, all against a white background. Four major colour hues were selected for testing: blue, yellow, green, and red. The same subjects were tested with standard ETDRS targets (black on white), and results served as control group references. The primary outcome measure selected for analysis was the minimum angle of resolution (MAR) required to correctly identify the hue presented. RESULTS: Forty study subjects (14 males and 26 females) aged 55 to 95 years (mean 79.45 years, SD 8.82) were recruited. Thirty similar subjects were recruited for a control group. Red on white estimates were better than for other colours and related best to standard black on white ETDRS estimates (20/121 vs 20/132, respectively). Also, red on white estimates seem not to be affected by age. Estimates for colour detection for the control group were not different among colours tested and were not affected by age. CONCLUSIONS: Ranking abilities according to the MAR required to identify a hue can serve as a quantifying measure for residual colour vision. Our findings reflect functional abilities rather than psychophysical measurements. PMID- 23931467 TI - Screening for glaucoma using GDx-VCC in a population with >=1 risk factors. AB - OBJECTIVE: To estimate the diagnostic accuracy of the GDx-VCC for glaucoma screening in a population with >=1 risk factors for glaucoma. DESIGN: Cross sectional evaluation of a diagnostic test for screening. PARTICIPANTS: Two hundred forty-seven community-based volunteer participants with risk factors for glaucoma. METHODS: The peripapillary retinal nerve fibre layers (RNFL) of participants' eyes were scanned using the GDx-VCC. Based on an ophthalmologic examination and frequency doubling perimetry, eyes were classified into 4 categories: normal, possible glaucoma, probable glaucoma, and definitive glaucoma. The sensitivities, specificities, positive and negative predictive values, and positive and negative likelihood ratios of the RNFL parameters were calculated. RESULTS: The right eyes were retained for analyses. After excluding 5 eyes because of missing data and 23 eyes because of poor scan quality, the data of 219 right eyes were analyzed. Four eyes had definitive glaucoma. The best performing parameter was the nerve fibre indicator using a cutoff of 35 with a sensitivity of 75% (95% CI 19.4-99.4) at a specificity of 95% (95% CI 91.3-97.3), a positive predictive value of 25 (95% CI 4.3-48.1), a negative predictive value of 99 (95% CI 97.5-100.0), a positive likelihood ratio of 16 (95% CI 6.69-32.5), and a negative likelihood ratio of 0.20 (95% CI 0.05-1.44). CONCLUSIONS: The GDx VCC has inadequate sensitivity for screening of definitive glaucoma. PMID- 23931469 TI - Visuomotor control following surgical correction of strabismus in adults. AB - OBJECTIVE: To determine whether surgery to correct decompensated exotropia in adulthood had an impact on common visually guided manual tasks in the postoperative period. DESIGN: Case report. PARTICIPANTS: Three adult patients with long-standing strabismus. METHODS: Three adult patients took part in a series of preoperative and postoperative binocular and monocular reaching and grasping tasks before and after undergoing strabismus surgery. Tasks were designed to examine normal goal-directed actions (reaching to visual targets, grasping blocks) and to highlight differences between binocular and monocular control of action (grasping visible object in dark environment). RESULTS: A consistent pattern of change was not found in the 6- to 12-month postoperative period with the tasks provided. CONCLUSIONS: Surgery in adulthood to correct strabismus may not have a significant impact on the control of visually guided actions, at least in the first 6 to 12 months after surgery. Possibly, compensatory strategies used throughout their development (e.g., monocular cues) may continue to be used in the initial period postoperative period. More subjects and longer study period are recommended to make a definitive conclusion. PMID- 23931468 TI - Eye examinations improve visual acuity across ages. AB - OBJECTIVE: To investigate changes in distance best corrected visual acuity (BCVA) relative to presenting visual acuity (PVA) as a function of age and the number of years between eye examinations. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: 6397 patient files at a large Canadian Optometric Clinic. METHODS: A retrospective file review of patients aged 4 to 93 years from the University of Waterloo, Optometry Clinic was conducted. Mean decimal PVA values were calculated for all patients grouped by year of age, and a function was fit to these data using nonlinear regression. The same was done for BCVA and the functions were compared. In addition, the mean logMAR difference between PVA and BCVA was determined for patients grouped by the length of time between the study visual assessment and their previous visual assessment independent of patient age. RESULTS: Right and left eye functions were not significantly different from each other for either PVA or BCVA. BCVA functions were significantly greater than PVA functions for both right (F[3174] = 194.7, p < 0.0001) and left (F[3174] = 206.0, p < 0.0001) eyes. PVA differed (>=1 line) from BCVA in at least 1 eye in 70% (n = 4054) of patients. The difference between BCVA and PVA increased as the length of time between assessments increased from 0.075 logMAR for <1 year to 0.107 logMAR for >=5 years. CONCLUSIONS: Refractive testing resulted in an improvement in BCVA over PVA in the majority of patients, over a wide range of ages. PMID- 23931470 TI - The advancement of the medial rectus muscle for consecutive exotropia. AB - OBJECTIVE: To characterize the dose effect of the advancement of the medial rectus muscle (MR) for consecutive exotropia (XT) after corrective surgery for infantile esotropia (ET) and provide a guide for achieving orthotropia. DESIGN: Retrospective cohort study. PARTICIPANTS: Seventy-seven patients with consecutive XT that developed after surgery for infantile ET. METHODS: All patients underwent advancement of the unilateral or bilateral MR and were followed up for at least 1 year. The angle of deviation and stereopsis were retrospectively reviewed from patient records. RESULTS: At the time of surgery for infantile ET, the mean eso angle was 52.2 +/- 13.10 prism diopters (PD; mean age, 28.5 +/- 16.97 months). The exo-angle of consecutive XT was 25.6 +/- 8.47 PD (mean age at surgery, 132.7 +/- 82.32 months). The mean deviation was 1.8 +/- 10.40 PD XT at the final follow up (47.0 +/- 43.57 months). The corrective effect of the exo-angle for a 1-mm advancement of the MR was 3.1 PD at 1 year after surgery and 2.9 PD at the last follow-up. There was a significant positive relationship between the preoperative exo-angle and the corrective effect of the 1-mm advancement of the MR at the last follow-up (r = 0.367, p < 0.05). Postoperatively, orthotropia was present in 79.2% of patients, re-exodrift in 16.9%, and ET in 3.9%. Favourable stereopsis was achieved in 73.2%. CONCLUSIONS: MR advancement was effective for treating consecutive XT, followed by recession of the MR for infantile ET, achieving favourable stereopsis. The corrective value was 3 PD per 1-mm advancement of the MR. PMID- 23931471 TI - Treatment for suprachoroidal silicone oil migration following surgeries for open globe injuries. AB - OBJECTIVE: To evaluate the effect of scleral buckling surgery on the treatment of hypotony caused by choroidal holes and suprachoroidal silicone oil (SO) migration following surgical procedures for open globe injuries. DESIGN: Retrospective, consecutive, interventional case series. PARTICIPANTS: Ten eyes of 10 patients with hypotony caused by choroidal holes with suprachoroidal SO migration and choroidal detachment after vitrectomy for open globe injuries between October 2009 and December 2010. METHODS: All cases clinically diagnosed as hypotony caused by choroidal holes with suprachoroidal SO migration and choroidal detachment were identified. Those eyes with retinal detachment, ciliary body damage, ciliary body fibrosis, or cyclodialysis cleft were excluded. Scleral buckling with or without suprachoroidal SO drainage was performed. RESULTS: The mean preoperative intraocular pressure (IOP) was 6.7 +/- 1.4 mm Hg (5.3-9.0 mm Hg). The mean final follow-up IOP was 12.2 +/- 4.7 mm Hg (7.0-21.0 mm Hg; p = 0.005). In 7 eyes, the IOP increased to >=10 mm Hg, whereas 3 eyes showed no significant IOP elevations. The choroidal hole was closed, and the range of choroidal detachment was significantly reduced in those 7 eyes. Although the choroidal hole was not fully closed in 3 eyes, the choroidal detachment area was less extensive, and the IOP was stable at approximately 7 mm Hg. CONCLUSION: Scleral buckling surgery combined with suprachoroidal SO drainage is an effective way to manage hypotony caused by choroidal holes and suprachoroidal SO migration in a SO-filled eye after vitrectomy for open globe injuries. PMID- 23931472 TI - Impact of thiazolidinediones on macular thickness and volume in diabetic eyes. AB - OBJECTIVE: To assess the impact of thiazolidinedione (TZDs) use on macular thickness and volume in patients with diabetes with no macular edema and no diabetic retinopathy (DR) or mild nonproliferative diabetic retinopathy (NPDR). DESIGN: Cross-sectional prospective pilot study. PARTICIPANTS: One hundred twenty patients (60 in each group) were enrolled, but 108 completed the study (59 in the TZD group and 49 in the non-TZD group). METHODS: Patients with type II diabetes mellitus were categorized into 2 groups depending on TZD intake. Those with no prior history of treatment for DR were considered for the study. Patients in both groups had assessment of visual acuity and dilated fundus examination. Only patients with no evidence of macular edema and no DR or mild-NPDR were included. Spectral-domain ocular coherence tomography (SD-OCT) was used for measurement of central retinal thickness (CRT) and macular volume. Main outcome measure was difference in mean macular volume and central thickness between the TZD and the non-TZD groups. RESULTS: Baseline demographics and characteristics were well matched between both groups. There was no significant difference in mean CRT of both groups (p = 0.13), but macular volume was significantly lower in the TZD group (p = 0.038). CONCLUSIONS: Patients with no macular edema and no DR or mild NPDR on TZDs did not show evidence of fluid retention in the macula on SD-OCT. Larger studies are needed to confirm these results. PMID- 23931473 TI - Ranibizumab injection for diabetic macular edema: meta-analysis of systemic safety and systematic review. AB - OBJECTIVE: To conduct a systematic review on the safety of ranibizumab injections for diabetic macular edema by meta-analysis of recently conducted level 1 randomized clinical trials. DESIGN: A meta-analysis and systematic review. METHODS: Main outcome measures of permissible studies were extracted and reported. The relative risk (RR) for thromboembolic events (TEEs) was calculated for those studies that met this study's inclusion criteria. The fixed-effects model (Mantel-Haenszel method) was appropriately used to calculate the pooled RR. The quality of trials was assessed using the Jadad score. RESULTS: Of the 2072 patients who were included from 5 [corrected] eligible randomized clinical trials, 1295 patients received intravitreal ranibizumab injections. The pooled RR for TEEs after ranibizumab intravitreal injection was 0.74 (95% CI 0.52-1.06). CONCLUSIONS: Intravitreal ranibizumab for the treatment of diabetic macular edema did not increase the risk for TEEs as shown by this meta-analysis of 4 randomized, controlled clinical trials. PMID- 23931474 TI - 11 Years of experience in vitreoretinal surgery training in Nairobi, Kenya, from 2000 to 2010. AB - OBJECTIVE: We aim to demonstrate that vitreoretinal surgery can be established in Nairobi, Kenya, by intermittent short visits of experienced surgeons combined with clinical/surgical observerships over a longer period of cooperation. This strategy might be a model for other developing countries. DESIGN: Time series over 11 years. PARTICIPANTS: 685 operations were performed over 11 years. METHODS: After the 1998 al-Qaeda bomb assault on the U.S. embassy in Nairobi, Kenya, the Ludwig-Maximilians-University Munchen (Germany) provided materials for surgery of 42 victims with eye injuries. From the year 2000 onward, this equipment has been used to establish a training unit at the Kenyatta Hospital in Nairobi. In 1 annual "project week," 1 author (C-L.S.) performed vitreoretinal surgery at the University of Nairobi in cooperation with the Kenyatta National Hospital and supervised resident eye surgeons. After 7 years of training in Nairobi, clinical/surgical observerships of vitreoretinal surgeons and operating theatre staff were commenced in Munich by 4- to 12-week visits. The project week in Nairobi was carried on. Number, indications, operating surgeons, kind, difficulty, duration of operations, and preparation were recorded and evaluated. RESULTS: The percentage of operations by resident surgeons increased from 29% (in 2000) via 80% (in 2009) to 73% (in 2010) with a partial failure of the laser device. The learning curve of local surgeons is also reflected by an increase of the operations' difficulty with only a moderate increase in operation time and marked decrease of preparation time. CONCLUSIONS: A vitreoretinal unit has been established in Nairobi using our training model. This unit has the potential to train colleagues from other sub-Saharan countries. This strategy has advantages over long-term aid deployment of foreign physicians such as avoiding financial burden for the surgeons to be trained and improving the home facility, but it requires commitment for long-term cooperation. PMID- 23931475 TI - Correlation between spectral-domain optical coherence tomography and autofluorescence findings in sclerochoroidal calcification. AB - OBJECTIVE: The purpose of this article is to report the correlation between spectral domain-optical coherence tomography and autofluorescence findings in 3 consecutive cases with sclerochoroidal calcification. DESIGN: Observational case series. PARTICIPANTS: The study involved 3 patients with bilateral sclerochoroidal calcification. METHODS: B-scan ultrasonography, spectral domain optical coherence tomography, and autofluorescence were performed in each eye. The choroidal vascular thickness and autofluorescence patterns of the calcified plaques were evaluated with spectral domain-optical coherence tomography and autofluorescence, respectively. RESULTS: An important variation of choroidal vascular thickness overlying sclerochoroidal calcification was observed in spectral domain-optical coherence tomography. Autofluorescence showed 2 patterns of autofluorescence closely correlated with changes in choroidal vascular thickness. In those zones where the thicknesses of choriocapillaris complex were reduced, a hyperautofluorescence pattern was observed in autofluorescence. The hypoautofluorescence pattern was observed in outpouching zone of retinal pigment epithelium-choriocapillaris complex seen in spectral domain-optical coherence tomography. The hypoautofluorescence pattern was closely correlated with remarkable reduction of the choriocapillaris complex. There were no significant differences between the patterns of autofluorescence except the extension. CONCLUSIONS: Spectral domain-optical coherence tomography and autofluorescence are noninvasive complementary imaging studies that may help to improve our knowledge about sclerochoroidal calcification. Characteristic patterns of autofluorescence were closely correlated with spectral domain-optical coherence tomography findings. More patients need to be evaluated with both complementary studies to establish conclusions related with these findings. PMID- 23931476 TI - Endoscopic dacryocystorhinostomy with canalicular marsupialization in common canalicular obstruction. AB - OBJECTIVE: To evaluate the surgical outcomes of endoscopic dacryocystorhinostomy with canalicular marsupialization (EDCR CM) in common canalicular obstruction. DESIGN: Retrospective review of medical records. PARTICIPANTS: Thirty-six patients (38 eyes) who had undergone EDCR CM for chronic epiphora caused by common canalicular obstruction. METHODS: Surgical outcomes were evaluated postoperatively by improvement of subjective symptoms and patency of the neo ostium of DCR on nasal endoscopy. RESULTS: Subjective symptoms improved in 81.6% (31/38) after primary EDCR CM and 94.7% (36/38) after revision surgery. In cases of silicone stent intubation, the surgical results were relatively superior compared with patients without silicon stent insertion (83.3% and 75.0%, respectively; p = 0.624). On postoperative nasal examination after primary surgery, the patency of dacryocystorhinostomy site was lower in patients with silicone stent insertion than those without (86.70% and 100%, respectively; p = 0.560), and the patency rate of the canalicular neo-ostium was higher in patients with silicone stent insertion than those without (90.0% and 75.0%, respectively; p = 0.279). There were no serious intraoperative complications except mild punctual erosion (4 patients, 10.5%). CONCLUSION: EDCR CM showed favourable surgical outcomes and few surgical complications. This surgical treatment could be the first-line treatment for patients with distal common canalicular obstruction. PMID- 23931477 TI - Three cases with unusual ophthalmic phenotypes of congenital aniridia. AB - OBJECTIVE: To report 3 cases with unusual ophthalmic phenotypes of congenital aniridia. DESIGN: Interventional case series. PARTICIPANTS: A 10-day-old infant with cloudy and large cornea in both eyes, 1 month-old male with bilateral corneal opacity, and 27-year-old male with low vision. METHODS: Complete ophthalmic examination and genetic evaluation. RESULTS: Case 1 was a neonate with concurrent presentation of congenital aniridia and glaucoma. Case 2 was diagnosed as congenital aniridia combined with Peters anomaly in both eyes. Case 3 had 2 unusual features of aniridia, which were asymmetric iris involvement and absence of limbal deficiency. CONCLUSIONS: It is important to perform thorough ophthalmologic evaluations in patients with congenital aniridia because of the possibilities of coexistence of other ocular abnormalities. PMID- 23931478 TI - Re: intravitreal dexamethasone implant fragmentation. PMID- 23931479 TI - Re: monitoring patients on antimalarials: where are we now? Author reply. PMID- 23931480 TI - Author reply: To PMID 23419308. PMID- 23931481 TI - Dacryostenosis due to Paracoccidioides brasiliensis in a patient with an unnoted HIV-1 infection. PMID- 23931482 TI - [Dislocation in anterior chamber of dexamethasone intravitreal device]. PMID- 23931483 TI - Giant chondroid syringoma of the eyelid. PMID- 23931484 TI - Adjuvant pulse dose rate brachytherapy in a secondary leiomyosarcoma of the orbit. PMID- 23931485 TI - Scleral penetration of an unusually aggressive case of a retinal hemangioblastoma. PMID- 23931486 TI - Vitrectomy for X-linked retinoschisis: a case report and literature review. PMID- 23931487 TI - Bilateral extraocular muscles metastases from a choroidal melanoma. PMID- 23931488 TI - An illustrative case that demonstrates the importance of neuroimaging in midbrain corectopia. PMID- 23931489 TI - Dexamethasone implant for the treatment of edema related to idiopathic macular telangiectasia. PMID- 23931490 TI - Regression of choroidal neovascularization in response to systemic chemotherapy for cancer. PMID- 23931491 TI - Rapid growth of an epibulbar complex choristoma in organoid nevus syndrome. PMID- 23931492 TI - Visante OCT in the diagnosis of caterpillar-induced iritis. PMID- 23931493 TI - Amelanotic choroidal melanoma in 16-month-old child. PMID- 23931494 TI - Esotropia and Chiari 1 malformation: report of a case and review of outcomes of posterior fossa decompression and strabismus surgery. PMID- 23931495 TI - Role of adjunctive laser photocoagulation in a clinical setting of invisible subretinal worm. PMID- 23931496 TI - Intravitreal triamcinolone acetonide in management of ocular toxoplasmosis in an HIV patient: a case report. PMID- 23931497 TI - Intraocular (vitreoretinal) lymphoma following primary testicular lymphoma. PMID- 23931498 TI - Impact of adding prophylactic probiotics to a bundle of standard preventative measures for Clostridium difficile infections: enhanced and sustained decrease in the incidence and severity of infection at a community hospital. AB - BACKGROUND: In 2003, hospitals in Quebec, Canada experienced an increase of NAP1/027 Clostridium difficile infections following antibiotic administration (CDIAA). At Pierre-Le Gardeur Hospital (PLGH), the incidence increased from 10 to over 25 cases per 1000 patient admissions. METHODS: We report a quasi experimental, prospective cohort study evaluating the effect on CDIAA of a probiotic added to existing C. difficile infection (CDI) standard preventative measures (SPM) in 31,832 hospitalized patients receiving antibiotics. Phase I (1580) measured the impact of SPM alone. In Phase II, 50 to 60 * 10(9) cfu daily dose of oral Lactobacillus acidophilus CL1285 and L. casei LBC80R probiotic formula (Bio-K+) was administered to all patients receiving antibiotics. Phase III included the same intervention after a move to a new hospital facility. Phases II and III included 4968 patients. During Phase IV, 25,284 patients were submitted to the same regimen but outcome data were compared to those of similar hospitals in Quebec. RESULTS: At the end of Phase III, CDIAA had decreased from more than 18 cases per 1000 patient admissions in Phase I to less than 5 cases. Reductions of CDI cases (73%) (p < 0.001) and severe CDI cases (76.4%) (p < 0.001) were observed. CDI recurrence rate was reduced by 39% (p < 0.001). During the following 6 years, the CDI rate averaged 2.71 cases per 10,000 patient-days at PLGH compared to 8.50 cases per 10,000 patient-days in equivalent hospitals located in Quebec. STUDY LIMITATION: This study is not a randomized clinical trial; it is an open prospective study and should be treated as such. Also, following Phase II, PLGH moved into a new facility and this could have contributed to lower CDI. CONCLUSIONS: Specific probiotic product added to SPM and antibiotic stewardship activities resulted in a further reduction in CDI rates and was shown to be safe. PMID- 23931499 TI - Evidence and its interpretation and presentation. PMID- 23931500 TI - Microscope basics. AB - This chapter provides information on how microscopes work and discusses some of the microscope issues to be considered in using a video camera on the microscope. There are two types of microscopes in use today for research in cell biology-the older finite tube-length (typically 160mm mechanical tube length) microscopes and the infinity optics microscopes that are now produced. The objective lens forms a magnified, real image of the specimen at a specific distance from the objective known as the intermediate image plane. All objectives are designed to be used with the specimen at a defined distance from the front lens element of the objective (the working distance) so that the image formed is located at a specific location in the microscope. Infinity optics microscopes differ from the finite tube-length microscopes in that the objectives are designed to project the image of the specimen to infinity and do not, on their own, form a real image of the specimen. Three types of objectives are in common use today-plan achromats, plan apochromats, and plan fluorite lenses. The concept of mounting video cameras on the microscope is also presented in the chapter. PMID- 23931501 TI - The optics of microscope image formation. AB - Although geometric optics gives a good understanding of how the microscope works, it fails in one critical area, which is explaining the origin of microscope resolution. To accomplish this, one must consider the microscope from the viewpoint of physical optics. This chapter describes the theory of the microscope relating resolution to the highest spatial frequency that a microscope can collect. The chapter illustrates how Huygens' principle or construction can be used to explain the propagation of a plane wave. It is shown that this limit increases with increasing numerical aperture (NA). As a corollary to this, resolution increases with decreasing wavelength because of how NA depends on wavelength. The resolution is higher for blue light than red light. Resolution is dependent on contrast, and the higher the contrast, the higher the resolution. This last point relates to issues of signal-to-noise and dynamic range. The use of video and new digital cameras has necessitated redefining classical limits such as those of Rayleigh's criterion. PMID- 23931502 TI - Proper alignment of the microscope. AB - The light microscope is merely the first element of an imaging system in a research facility. Such a system may include high-speed and/or high-resolution image acquisition capabilities, confocal technologies, and super-resolution methods of various types. Yet more than ever, the proverb "garbage in-garbage out" remains a fact. Image manipulations may be used to conceal a suboptimal microscope setup, but an artifact-free image can only be obtained when the microscope is optimally aligned, both mechanically and optically. Something else is often overlooked in the quest to get the best image out of the microscope: Proper sample preparation! The microscope optics can only do its job when its design criteria are matched to the specimen or vice versa. The specimen itself, the mounting medium, the cover slip, and the type of immersion medium (if applicable) are all part of the total optical makeup. To get the best results out of a microscope, understanding the functions of all of its variable components is important. Only then one knows how to optimize these components for the intended application. Different approaches might be chosen to discuss all of the microscope's components. We decided to follow the light path which starts with the light source and ends at the camera or the eyepieces. To add more transparency to this sequence, the section up to the microscope stage was called the "Illuminating Section", to be followed by the "Imaging Section" which starts with the microscope objective. After understanding the various components, we can start "working with the microscope." To get the best resolution and contrast from the microscope, the practice of "Koehler Illumination" should be understood and followed by every serious microscopist. Step-by-step instructions as well as illustrations of the beam path in an upright and inverted microscope are included in this chapter. A few practical considerations are listed in Section 3. PMID- 23931503 TI - Fundamentals of fluorescence and fluorescence microscopy. AB - This chapter discusses the fundamental physics of fluorescence. The application of fluorescence to microscopy represents an important transition in the development of microscopy, particularly as it applies to biology. It enables quantitating the amounts of specific molecules within a cell, determining whether molecules are complexing on a molecular level, measuring changes in ionic concentrations within cells and organelles, and measuring molecular dynamics. This chapter also discusses the issues important to quantitative measurement of fluorescence and focuses on four of quantitative measurements of fluorescence- boxcar-gated detection, streak cameras, photon correlation, and phase modulation. Although quantitative measurement presents many pitfalls to the beginner, it also presents significant opportunities to one skilled in the art. This chapter also examines how fluorescence is measured in the steady state and time domain and how fluorescence is applied in the modern epifluorescence microscope. PMID- 23931505 TI - Live-cell fluorescence imaging. AB - This chapter examines the ways to optimize the signal-to-noise ratio while keeping the specimen healthy. Live cells expressing fluorescent protein fusions are usually dim compared to fixed specimens, both because the fluorescent proteins are not very bright and because there is, in most cases, only one fluorophores per protein. It is also favorable to choose cells that are expressing low levels of fluorescent protein fusions to minimize the difference from the levels of the endogenous protein in vivo. Long camera exposure times, which allow accumulation of weak signals, must be often avoided to reduce photobleaching and phototoxicity and to acquire images quickly enough to capture cell dynamics. Choices, such as objective lens and camera, determine the signal to-noise ratio of an imaging system. Optimizing the imaging system to maximize signal and minimize noise is critical for live-cell fluorescence imaging. Imaging with high signal-to-noise ratio will allow detection of low concentrations of fluorescent fusion proteins with illumination conditions that are less likely to damage cells. Automation of an imaging system allows collection of multidimensional data while helping to maintain focus and minimize specimen exposure to light. Under all imaging conditions, maintaining and verifying cell health is essential to the validity of the experimental results. PMID- 23931504 TI - Fluorescent protein applications in microscopy. AB - The use of fluorescent proteins (FPs) in modern cell biology and microscopy has had an extraordinary impact on our ability to investigate dynamic processes in living cells. FPs are unique in that fluorescence is encoded solely by the primary amino acid sequence of the FP and does not require enzymatic modification or cofactors. This genetically encoded fluorescence enables the expression of FPs in diverse cells and organisms and the detection of that fluorescence in living systems. This chapter focuses on microscopy-based applications of FP detection to monitor protein localization, dynamics, interaction, and the cellular environment. PMID- 23931506 TI - Practical aspects of adjusting digital cameras. AB - This chapter introduces the adjustment of digital camera settings using the tools found within image acquisition software and discusses measuring gray-level information such as (1) the histogram, (2) line scan, and (3) other strategies. The pixel values in an image can be measured within many image capture software programs in two ways. The first is a histogram of pixel gray values and the second is a line-scan plot across a selectable axis of the image. Understanding how to evaluate the information presented by these tools is critical to properly adjusting the camera to maximize the image contrast without losing grayscale information. This chapter discusses the 0-255 grayscale resolution of an 8-bit camera; however, the concepts are the same for cameras of any bit depth. This chapter also describes camera settings, such as exposure time, offset, and gain, and the steps for contrast stretching such as setting the exposure time, adjusting offset and gain, and camera versus image display controls. PMID- 23931507 TI - Cameras for digital microscopy. AB - This chapter reviews the fundamental characteristics of charge-coupled devices (CCDs) and related detectors, outlines the relevant parameters for their use in microscopy, and considers promising recent developments in the technology of detectors. Electronic imaging with a CCD involves three stages--interaction of a photon with the photosensitive surface, storage of the liberated charge, and readout or measurement of the stored charge. The most demanding applications in fluorescence microscopy may require as much as four orders of greater magnitude sensitivity. The image in the present-day light microscope is usually acquired with a CCD camera. The CCD is composed of a large matrix of photosensitive elements (often referred to as "pixels" shorthand for picture elements, which simultaneously capture an image over the entire detector surface. The light intensity information for each pixel is stored as electronic charge and is converted to an analog voltage by a readout amplifier. This analog voltage is subsequently converted to a numerical value by a digitizer situated on the CCD chip, or very close to it. Several (three to six) amplifiers are required for each pixel, and to date, uniform images with a homogeneous background have been a problem because of the inherent difficulties of balancing the gain in all of the amplifiers. Complementary metal oxide semiconductor sensors also exhibit relatively high noise associated with the requisite high-speed switching. Both of these deficiencies are being addressed, and sensor performance is nearing that required for scientific imaging. PMID- 23931508 TI - A high-resolution multimode digital microscope system. AB - This chapter describes the development of a high-resolution, multimode digital imaging system based on a wide-field epifluorescent and transmitted light microscope, and a cooled charge-coupled device (CCD) camera. The three main parts of this imaging system are Nikon FXA microscope, Hamamatsu C4880 cooled CCD camera, and MetaMorph digital imaging system. This chapter presents various design criteria for the instrument and describes the major features of the microscope components-the cooled CCD camera and the MetaMorph digital imaging system. The Nikon FXA upright microscope can produce high resolution images for both epifluorescent and transmitted light illumination without switching the objective or moving the specimen. The functional aspects of the microscope set-up can be considered in terms of the imaging optics, the epi-illumination optics, the transillumination optics, the focus control, and the vibration isolation table. This instrument is somewhat specialized for microtubule and mitosis studies, and it is also applicable to a variety of problems in cellular imaging, including tracking proteins fused to the green fluorescent protein in live cells. The instrument is also valuable for correlating the assembly dynamics of individual cytoplasmic microtubules (labeled by conjugating X-rhodamine to tubulin) with the dynamics of membranes of the endoplasmic reticulum (labeled with DiOC6) and the dynamics of the cell cortex (by differential interference contrast) in migrating vertebrate epithelial cells. This imaging system also plays an important role in the analysis of mitotic mutants in the powerful yeast genetic system Saccharomyces cerevisiae. PMID- 23931509 TI - Electronic cameras for low-light microscopy. AB - This chapter introduces to electronic cameras, discusses the various parameters considered for evaluating their performance, and describes some of the key features of different camera formats. The chapter also presents the basic understanding of functioning of the electronic cameras and how these properties can be exploited to optimize image quality under low-light conditions. Although there are many types of cameras available for microscopy, the most reliable type is the charge-coupled device (CCD) camera, which remains preferred for high performance systems. If time resolution and frame rate are of no concern, slow scan CCDs certainly offer the best available performance, both in terms of the signal-to-noise ratio and their spatial resolution. Slow-scan cameras are thus the first choice for experiments using fixed specimens such as measurements using immune fluorescence and fluorescence in situ hybridization. However, if video rate imaging is required, one need not evaluate slow-scan CCD cameras. A very basic video CCD may suffice if samples are heavily labeled or are not perturbed by high intensity illumination. When video rate imaging is required for very dim specimens, the electron multiplying CCD camera is probably the most appropriate at this technological stage. Intensified CCDs provide a unique tool for applications in which high-speed gating is required. The variable integration time video cameras are very attractive options if one needs to acquire images at video rate acquisition, as well as with longer integration times for less bright samples. This flexibility can facilitate many diverse applications with highly varied light levels. PMID- 23931510 TI - Camera technologies for low light imaging: overview and relative advantages. AB - "Camera Technologies for Low Light Imaging" is designed to offer the reader a summary of the current camera choices for low light imaging with special emphasis on the practical aspects related to each. Four major camera technologies, cooled charge-coupled device, cooled sCMOS, intensified cameras, and electron multiplier cameras, are discussed and compared. Supporting information about noise characteristics of photoelectrons and camera noise are provided and used for illuminating the practical aspects of using these cameras. PMID- 23931511 TI - Post-processing for statistical image analysis in light microscopy. AB - Image processing of images serves a number of important functions including noise reduction, contrast enhancement, and feature extraction. Whatever the final goal, an understanding of the nature of image acquisition and digitization and subsequent mathematical manipulations of that digitized image is essential. Here we discuss the basic mathematical and statistical processes that are routinely used by microscopists to routinely produce high quality digital images and to extract key features of interest using a variety of extraction and thresholding tools. PMID- 23931512 TI - 65,000 shades of grey: use of digital image files in light microscopy. AB - Computers dominate image capture and analysis in modern light microscopy. The output of an imaging experiment is a binary coded file, called an image file, which contains the spatial, temporal and intensity information present in the sample. Understanding what comprises an image file, and how these files are generated is necessary in order to optimize the use of the digital light microscope. In this chapter, we discuss image file formats, and the various components of these files, such as bit-depth, sampling rate, color theory, and compression, from the perspective of the non-computer scientist. We also discuss the problem of proprietary file formats, and how these often are incompatible with certain types of imaging software. We present several solutions to this issue. Finally, we present the use of digital movie formats, compression routines, and provide some real world examples for optimizing the generation of digital movies. PMID- 23931513 TI - Quantitative analysis of digital microscope images. AB - This chapter discusses quantitative analysis of digital microscope images and presents several exercises to provide examples to explain the concept. This chapter also presents the basic concepts in quantitative analysis for imaging, but these concepts rest on a well-established foundation of signal theory and quantitative data analysis. This chapter presents several examples for understanding the imaging process as a transformation from sample to image and the limits and considerations of quantitative analysis. This chapter introduces to the concept of digitally correcting the images and also focuses on some of the more critical types of data transformation and some of the frequently encountered issues in quantization. Image processing represents a form of data processing. There are many examples of data processing such as fitting the data to a theoretical curve. In all these cases, it is critical that care is taken during all steps of transformation, processing, and quantization. PMID- 23931514 TI - Evaluating optical aberrations using fluorescent microspheres: methods, analysis, and corrective actions. AB - Obtaining optimal performance from a microscopy system requires careful evaluation of the entire optics train of the imaging system. This evaluation starts with a fundamental evaluation of the optical components in the microscope. Concise and visual methods are provided for understanding the optical performance of the microscope as a system using subdiffraction fluorescent microspheres to evaluate both monochromatic and polychromatic aberrations. Further practical guides are given to troubleshooting optical problems and final comments are made on optimizing sample preparation. PMID- 23931515 TI - Ratio imaging: practical considerations for measuring intracellular Ca2+ and pH in living cells. AB - This chapter discusses the use of ratiometric fluorescent probes for measuring intracellular pH (pHi) and Cai(2+) concentration at the single cell level. The development of sensitive and stable probes for monitoring pHi and Cai(2+) in living cells has provided the scientists with invaluable tools for studying a multitude of cellular processes. These probes afford a noninvasive and semiquantitative assessment of pHi and Cai(2+), eliminating the need to impale cells with microelectrodes. The development and availability of membrane permeant Cai(2+)- and pH-specific fluorescent probes coupled to major advances in the technology and design of low-light-level charge-coupled devices geared toward biological applications, and improved microscope optics, have made it possible to visualize a two-dimensional fluorescence signal that is related to Cai(2+) and pHi. The chapter describes the basis for using dual excitation ratio imaging and tries to provide a framework for understanding and developing the technique for investigating the roles of Cai(2+) and pHi in cellular processes. The technique of quantitative ratio imaging for the measurement of pHi and Cai(2+) has revolutionized the field of cell physiology. Using the proper equipment and choosing the right dyes for the experimental needs should provide reliable and reproducible results. More importantly, the amount of data produced from each experiment, when analyzing pHi and Cai(2+) on an individual cell basis, yields valuable information on the heterogeneity of cellular responses. PMID- 23931516 TI - Quantitative fluorescence microscopy and image deconvolution. AB - Quantitative imaging and image deconvolution have become standard techniques for the modern cell biologist because they can form the basis of an increasing number of assays for molecular function in a cellular context. There are two major types of deconvolution approaches--deblurring and restoration algorithms. Deblurring algorithms remove blur but treat a series of optical sections as individual two dimensional entities and therefore sometimes mishandle blurred light. Restoration algorithms determine an object that, when convolved with the point-spread function of the microscope, could produce the image data. The advantages and disadvantages of these methods are discussed in this chapter. Image deconvolution in fluorescence microscopy has usually been applied to high-resolution imaging to improve contrast and thus detect small, dim objects that might otherwise be obscured. Their proper use demands some consideration of the imaging hardware, the acquisition process, fundamental aspects of photon detection, and image processing. This can prove daunting for some cell biologists, but the power of these techniques has been proven many times in the works cited in the chapter and elsewhere. Their usage is now well defined, so they can be incorporated into the capabilities of most laboratories. A major application of fluorescence microscopy is the quantitative measurement of the localization, dynamics, and interactions of cellular factors. The introduction of green fluorescent protein and its spectral variants has led to a significant increase in the use of fluorescence microscopy as a quantitative assay system. For quantitative imaging assays, it is critical to consider the nature of the image-acquisition system and to validate its response to known standards. Any image-processing algorithms used before quantitative analysis should preserve the relative signal levels in different parts of the image. A very common image-processing algorithm, image deconvolution, is used to remove blurred signal from an image. There are two major types of deconvolution approaches, deblurring and restoration algorithms. Deblurring algorithms remove blur, but treat a series of optical sections as individual two-dimensional entities, and therefore sometimes mishandle blurred light. Restoration algorithms determine an object that, when convolved with the point-spread function of the microscope, could produce the image data. The advantages and disadvantages of these methods are discussed. PMID- 23931517 TI - Practical aspects of quantitative confocal microscopy. AB - Confocal microscopes are in principle well suited for quantitative imaging. The 3D fluorophore distribution in a specimen is transformed by the microscope optics and detector into the 2D intensity distribution of a digital image by a linear operation, a convolution. If multiple 2D images of the specimen at different focal planes are obtained, then the original 3D distribution in the specimen can be reconstructed. This reconstruction is a low-pass spatially filtered representation of the original, but quantitatively preserves relative fluorophore concentrations, with of course some limitations on accuracy and precision due to aberrations and noise. Given appropriate calibration, absolute fluorophore concentrations are accessible. A few simple guidelines are given for setting up confocal microscopes and checking their performance. With a little care, the images collected should be suitable for most types of quantitative analysis. PMID- 23931518 TI - Theoretical principles and practical considerations for fluorescence resonance energy transfer microscopy. AB - Typically, light microscopic methodologies using conventional optics are limited by the diffraction limit yielding resolutions that cannot be reached lower than approximately 200nm. However, using appropriate donor-acceptor pairs, nonradiative fluorescence resonance energy transfer (FRET) allows the microscopist to detect, and in some cases quantify, molecular interactions on the order of Angstroms. In this chapter, the basic principles of FRET are introduced using both steady state and lifetime modes to detect the close association of fluorescent donor and acceptor molecules. The basic design of experiments and optical and imaging components is discussed to create a microscope that is capable of monitoring dynamic molecular associations in living cells. PMID- 23931519 TI - Fluorescence lifetime imaging microscopy for quantitative biological imaging. AB - Fluorescence lifetime imaging microscopy (FLIM) is a method for measuring fluorophore lifetimes with microscopic spatial resolution, providing a useful tool for cell biologists to detect, visualize, and investigate structure and function of biological systems. In this chapter, we begin by introducing the basic theory of fluorescence lifetime, including the characteristics of fluorophore decay, followed by a discussion of factors affecting fluorescence lifetimes and the potential advantages of fluorescence lifetime as a source of image contrast. Experimental methods for creating lifetime maps, including both time- and frequency-domain experimental approaches, are then introduced. Then, FLIM data analysis methods are discussed, including rapid lifetime determination, multiexponential fitting, Laguerre polynomial fitting, and phasor plot analysis. After, data analysis methods are introduced that improve lifetime precision of FLIM maps based upon optimal virtual gating and total variation denoising. The chapter concludes by highlighting several recent FLIM applications for quantitative biological imaging, including Forster resonance energy transfer FLIM, fluorescence correlation spectroscopy-FLIM, multispectral-FLIM, and multiphoton-FLIM. PMID- 23931520 TI - Fluorescence correlation spectroscopy: molecular complexing in solution and in living cells. AB - This chapter describes how the microscope can be used to measure a fluorescence signal from a small, confined volume of the sample-the confocal volume-and how these measurements are used to quantitate the dynamics and complexing of molecules, the technique of fluorescence correlation spectroscopy (FCS). FCS represents a significant example of how the microscope can be used to extract information beyond the resolution limit of classical optics. FCS enables studying events at the level of single molecules. With FCS, one can measure the diffusion times and the interaction of macromolecules, the absolute concentration of fluorescently labeled particles, and the kinetics of chemical reactions. Practical applications of FCS include studies on ligand-receptor binding, protein protein and protein-DNA interactions, and the aggregation of fluorescently labeled particles. The chapter focuses on the principles of FCS, demonstrates how FCS is used to study macromolecular interactions in solution and in living cells, and examines critical experimental parameters that must be considered. The chapter also discusses the minimum requirements for building a microscope-based FCS instrument and illustrates the key criteria for both instrument sensitivity and analysis of FCS data. It can be used to study single molecules both in solution and in living cells and can be used to monitor a variety of macromolecular interactions. When used as an in vitro technique, FCS measurements are easy to conduct and can be made on simplified instrumentation. When used in vivo on living cells, many additional factors must be considered when evaluating experimental data. Despite these concerns, FCS represents a new approach that has broad applicability for the determination of molecular stoichiometry both in vivo and in vitro for a variety of membrane and soluble receptor systems. PMID- 23931521 TI - Breaking the resolution limit in light microscopy. AB - The advancement in fluorescence microscopy has dramatically enhanced the obtainable optical resolution enabling the users to inspect the structures of interest at finer and finer level of detail. This chapter describes some of these methods and how they break the classical resolution limit. The labeling of targets, such as individual genetic loci, specific proteins, or organelles, is possible inside living cells, which led to the extensive use of fluorescence microscopy in life sciences. Other microscopic modes usually lack this high specificity but sometimes provide other useful information such as the orientation of molecular species in polarization microscopy. Modes, such as differential interference contrast, phase contrast, or dark field, are useful to discriminate and follow cells or structures within them without the need for specific labeling. However, classically the resolution of all of these light microscopic modes was far below that of the electron microscope, and only some recent approaches have made significant progress in resolution increase. Recently, many microscopy methods have dramatically enhanced the resolution. Gradually, these methods are now applied to solve biological problems. The most promising approaches are all based on fluorescence and use either nonlinear interaction of light with the sample (STED, nonlinear structured illumination, dynamic saturation optical microscopy, or saturation in the time domain) or precise localization of individual particles or molecules with subsequent image generation. PMID- 23931522 TI - Circumventing photodamage in live-cell microscopy. AB - Fluorescence microscopy has become an essential tool in cell biology. This technique allows researchers to visualize the dynamics of tissue, cells, individual organelles, and macromolecular assemblies inside the cell. Unfortunately, fluorescence microscopy is not completely "noninvasive" as the high-intensity excitation light required for excitation of fluorophores is inherently toxic for live cells. Physiological changes induced by excessive illumination can lead to artifacts and abnormal responses. In this chapter, we review major factors that contribute to phototoxicity and discuss practical solutions for circumventing photodamage. These solutions include the proper choice of image acquisition parameters, optimization of filter sets, hardware synchronization, and the use of intelligent illumination to avoid unnecessary light exposure. PMID- 23931523 TI - A user's guide to localization-based super-resolution fluorescence imaging. AB - Advances in far-field fluorescence microscopy over the past decade have led to the development of super-resolution imaging techniques that provide more than an order of magnitude improvement in spatial resolution compared to conventional light microscopy. One such approach, called Stochastic Optical Reconstruction Microscopy (STORM) uses the sequential, nanometer-scale localization of individual fluorophores to reconstruct a high-resolution image of a structure of interest. This is an attractive method for biological investigation at the nanoscale due to its relative simplicity, both conceptually and practically in the laboratory. Like most research tools, however, the devil is in the details. The aim of this chapter is to serve as a guide for applying STORM to the study of biological samples. This chapter will discuss considerations for choosing a photoswitchable fluorescent probe, preparing a sample, selecting hardware for data acquisition, and collecting and analyzing data for image reconstruction. PMID- 23931524 TI - Quantitative ratiometric imaging of FRET-biosensors in living cells. AB - Biosensors based on FRET have been useful in deciphering the dynamics of protein activation events in living cells at subcellular resolutions and in time scales of seconds. These new systems allow observations of dynamic processes which were not possible previously using more traditional biochemical and cell biological approaches. The image data sets obtained from these sensors require careful processing in order to represent the actual protein activation events. Here, we will cover the basic approaches useful for processing the raw image data sets into relativistic ratiometric measurements, capable of depicting relative differences in the protein activation states within a single cell. We will discuss in detail the approaches for genetically encoded, single-chain biosensor systems based on FRET, as well as those that are based on intermolecular, dual chain design. Additionally, the same analysis can be utilized for biosensor systems using solvatochromic dyes (Nalbant, Hodgson, Kraynov, Toutchkine, & Hahn, 2004), useful for detection of endogenous protein activation states. PMID- 23931525 TI - Tip-enhanced Raman spectroscopy for the base interrogation of DNA. AB - A combination of scanning probe and Raman microscopies allows for the label-free chemical mapping of surfaces with spatial resolutions one to two orders of magnitude below the diffraction limit. Because Raman spectroscopy provides a highly specific molecular "fingerprint," the resulting spectra allow speciation of even highly similar chemical compounds. The surface enhancement phenomenon allows Raman signals from a species to be enhanced by many orders of magnitude within the vicinity (~10nm) of a source of free electrons such as a noble metal. Presenting the metal surface as a single highly localized point, and moving this point with angstrom accuracy across a distributed, heterogenous surface while collecting Raman spectra, is what is known as tip-enhanced Raman spectroscopy, or TERS. PMID- 23931526 TI - Preface. Digital microscopy. PMID- 23931527 TI - Sport and exercise psychology research and Olympic success: an analytical and correlational investigation. AB - The aim of the current inquiry was to identify the national origin of scholars who lead the work in the area of Sport and Exercise Psychology, and to examine whether their research output is connected to the Olympic success of their national athletes. Consequently, the two specialised journals with the highest impact factors in this field were examined for the origin of publications throughout 11 years for authors' national affiliations. Subsequently, the link between national research output and Olympic medals was examined. The results revealed that over 50% of the publications originate from Canada, the U.K. and the U.S.A. National research output in Sport and Exercise Psychology was correlated with the number of Olympic medals; the proportion of shared variance was 42% and 57%, respectively, in the two journals. Nevertheless, it is posited that the observed link is primarily due to other factors that ought to be examined in future research. PMID- 23931528 TI - Valency-dependent affinity of bioactive hydroxyapatite-binding dendrons. AB - Hydroxyapatite (HA)-coated surfaces are used widely as stationary phase for protein and enzyme purification, coatings for dental and orthopedic implants, and composite materials for tissue engineering substrates. More advanced applications are envisioned, but progress has been slowed by the limited ability to controllably functionalize the surface of HA with biomolecules in a translationally relevant manner. Herein we report the synthesis and characterization of a series of multivalent, HA-binding peptide bioconjugates with variable valency and tether length which afford the ability to precisely tune the desired binding behavior. The respective binding affinities of the multivalent constructs to HA surface were characterized by quartz crystal microbalance with dissipation monitoring (QCM-D) techniques, and the relationship between dendron structure and binding affinity was revealed. Tetravalent constructs of HA-binding peptides show a 100-fold enhancement in binding affinity compared to HA-binding peptide sequences reported previously. Both biotin and bone morphogenic protein-2 (BMP-2) derivative peptide were successfully linked to the focal point as initial demonstrations. PMID- 23931529 TI - Formulation, characterization and permeability study of nano particles of lipo endomorphin-1 for oral delivery. AB - Three different formulations of a lipid-modified endomorphin-1 peptide (C10LAA Endo-1) were prepared, characterized, and evaluated for their permeability through Caco-2 cell membranes. Solid lipid nanoparticles (SLN), enteric coated (EC), and the EC-SLN of C10LAA-Endo-1 is a modified structure of endomorphin-1 for oral delivery. Physico-chemical characterization of the formulations showed that among all formulations, EC-[C10LAA-Endo-1] had the lowest particle size and the highest EE% and absolute zeta potential. Release of drug from SLN, EC-SLN and EC-[C10LAA-Endo-1] in acid media was 14.30 (+/-2.7)%, 3.0 (+/-1.0)% and 10.2 (+/ 3.0)%, respectively. Release data in buffer media (pH = 7.4) showed that enteric coated formulations released C10LAA-Endo-1 more slowly than uncoated formulations. It was also demonstrated that direct coating of C10LAA-Endo-1 with Eudragit(r) S100 significantly enhanced the permeability of the compound through Caco-2 cell membranes with a 39-fold higher P(app) compared to C10LAA-Endo-1. These findings indicated that EC-C10LAA-Endo-1 is a promising candidate to promote the oral delivery of the previously modified endomorphin-1 peptide analogue and is worthy of future animal investigations. PMID- 23931531 TI - 'When I use a word, it means just what I choose it to mean - neither more nor less'. PMID- 23931532 TI - The importance of non-verbal behaviour: issues for selection, training and assessment. PMID- 23931533 TI - Doctor-patient relationships in a post-racial era. PMID- 23931534 TI - Good research requires productive theories and guidelines. PMID- 23931535 TI - When I say ... triangulation. PMID- 23931536 TI - The role of non-verbal behaviour in racial disparities in health care: implications and solutions. AB - CONTEXT: People from racial minority backgrounds report less trust in their doctors and have poorer health outcomes. Although these deficiencies have multiple roots, one important set of explanations involves racial bias, which may be non-conscious, on the part of providers, and minority patients' fears that they will be treated in a biased way. Here, we focus on one mechanism by which this bias may be communicated and reinforced: namely, non-verbal behaviour in the doctor-patient interaction. METHODS: We review 2 lines of research on race and non-verbal behaviour: (i) the ways in which a patient's race can influence a doctor's non-verbal behaviour toward the patient, and (ii) the relative difficulty that doctors can have in accurately understanding the nonverbal communication of non-White patients. Further, we review research on the implications that both lines of work can have for the doctor-patient relationship and the patient's health. RESULTS: The research we review suggests that White doctors interacting with minority group patients are likely to behave and respond in ways that are associated with worse health outcomes. DISCUSSION: As doctors' disengaged non-verbal behaviour towards minority group patients and lower ability to read minority group patients' non-verbal behaviours may contribute to racial disparities in patients' satisfaction and health outcomes, solutions that target non-verbal behaviour may be effective. A number of strategies for such targeting are discussed. PMID- 23931537 TI - A hinting strategy for online learning of radiograph interpretation by medical students. AB - CONTEXT: We examined whether a 'hint' manoeuvre increases the time novice medical learners spend on reviewing a radiograph, thereby potentially increasing their interpretation accuracy. METHODS: Senior year medical students were recruited into a randomised control, three-arm, multicentre trial. Students reviewed an online 50-case learning set that varied in degree of 'hint' intervention. The 'hint' was a dialogue box that appeared after a student submitted an answer, encouraging the student to re-evaluate their interpretation. The students in the control group received no hints. In the weak intervention group, students received 'hints' with 66% of their incorrect interpretations and 33% of those that were correct. In the strong intervention group, the incorrect interpretation hint frequency was 80%, whereas for correct responses it was 20%. All students completed a 20-case post-test immediately and 2 weeks after the 50 cases. The primary outcome was student performance on the immediate post-test, measured as the ability to discriminate between normal and abnormal films (dPrime). Secondary outcomes included the probability of considering the hint, time spent on learning cases and knowledge retention at 2 weeks. RESULTS: We enrolled 117 medical students from three sites into the three study groups: control (36), weak intervention (40) and strong intervention (41) groups. The mean (standard deviation) dPrime in the control, weak and strong groups were 0.4 (1.1), 0.7 (1.1) and 0.4 (0.9), respectively (P = 0.4). In the weak and strong groups, participants reconsidered answers in 556 of 1944 (28.6%) hinting opportunities, and those who reconsidered their answers spent a mean (95% confidence interval) of 13.9 (11.9, 16.0) seconds longer on each case. There were no significant differences in knowledge retention at 2 weeks between the groups (P = 0.2). CONCLUSIONS: Although the implemented hinting strategy did result in students spending more time considering a proportion of the cases, overall it was not effective in improving student performance. PMID- 23931538 TI - Effects of modelling examples in complex procedural skills training: a randomised study. AB - CONTEXT: Learning complex procedural skills, such as bronchoscopy, through simulation training, imposes a high cognitive load on novices. Example-based learning has been shown to be an effective way to reduce cognitive load and enhance learning outcomes. Prior research has shown that modelling examples, in which a human model demonstrates the skill to a learner, were effective for learning basic surgical skills. However, principles derived from simple skills training do not necessarily generalise to more complex skills. Therefore, the present study examined the effectiveness of integrating modelling examples into simulation training for a more complex procedural skill - bronchoscopy. Moreover, this study extended previous simulation studies by using a physical demonstration rather than video-based modelling examples. METHODS: Forty-eight medical students were randomised into a modelling group and a control group. They all practised on eight bronchoscopy simulation cases individually, followed by standardised feedback from an instructor. Additionally, the modelling group watched three modelling examples of the simulated bronchoscopy, performed by the instructor. These modelling examples were interspersed between cases. Assessments were carried out at pre-, post- and 3-week retention tests with simulator-measured performance metrics. The primary outcome measure was the percentage of segments entered/minute. Other measures were wall collisions, red-out, the percentage of segments entered and the time to completion. Group differences were examined using repeated measures analysis of variance (anova). RESULTS: A clear learning curve was observed for both groups, but as hypothesised, the modelling group outperformed the control group on all parameters except the percentage of segments entered on the post-test and retained this superiority at the retention test. For the primary outcome measure, the percentage of segments entered/minute, the modelling group achieved a 46% higher score at the post-test and a 43% higher score at the retention test. CONCLUSIONS: The present study shows, that integrating modelling examples into the curriculum of bronchoscopy simulation training optimises the role of the instructor and enhances novices' learning outcomes, presumably by optimising cognitive load during training. PMID- 23931539 TI - The view from over there: reframing the OSCE through the experience of standardised patient raters. AB - CONTEXT: Ratings awarded by standardised patients (SPs) in UK objective structured clinical examinations (OSCEs) are typically based on humanistic (non technical) skills and are complementary to clinician-examiner ratings. In psychometric terms, SP ratings appear to differ from examiner ratings and improve reliability. For the first time, we used qualitative methods from a constructivist perspective to explore SP experiences of rating, and consider how these impact our understanding of assessment. METHODS: We used constructivist grounded theory to analyse data from focus groups and individual semi-structured interviews with 38 SPs and four examiners. Inductive coding, theoretical sampling and constant comparison continued until theoretical saturation was achieved. RESULTS: Standardised patients assessed students on the core process of relationship building. Three theoretical categories informed this process. The SP identity was strongly vocational and was both enacted and reinforced through rating as SPs exerted their agency to protect future patients by promoting student learning. Expectations of performance drew on individual life experiences in formulating expectations of doctors against which students were measured, and the patient experience was a lens through which all interactions were refracted. Standardised patients experienced the examination as real rather than simulated. They rated holistically, prioritised individuality and person-centredness, and included technical skill because the perception of clinical competence was an inextricable part of the patient experience. CONCLUSIONS: The results can be used to reframe understanding of the SP role and of the psychometric discourse of assessment. Ratings awarded by SPs are socially constructed and reveal the complexity of the OSCE process and the unfeasibility of absolute objectivity or standardisation. Standardised patients valued individuality, subjective experience and assessment for learning. The potential of SPs is under-used their greater involvement should be used to promote real partnership as educators move into a post-psychometric era. New-generation assessments should strive to value subjective experience as well as psychometric data in order to utilise the significant potential for learning within assessment. PMID- 23931540 TI - 'You're certainly relatively competent': assessor bias due to recent experiences. AB - CONTEXT: A recent study has suggested that assessors judge performance comparatively rather than against fixed standards. Ratings assigned to borderline trainees were found to be biased by previously seen candidates' performances. We extended that programme of investigation by examining these effects across a range of performance levels. Furthermore, we investigated whether confidence in the rating assigned predicts susceptibility to manipulation and whether prompting consideration of typical performance lessens the influence of recent experience. METHODS: Consultant doctors were randomised to groups within an internet experiment. The descending performance group judged videos of Foundation Year 1 (F1; postgraduate Year 1) doctors in descending order of proficiency; the ascending performance group judged the same videos in ascending order. For all videos, participants rated: (i) trainee competence; (ii) rater confidence and (iii) percentage better (the percentage of other F1 doctors who would perform better on the same task). RESULTS: Overall, the descending performance group assigned lower scores than the ascending performance group (2.97 [95% confidence interval 2.73-3.20] versus 3.50 [95% confidence interval 3.25-3.74]; F(1,47) = 9.80, p = 0.003, d = 0.52). Pairwise comparisons showed differences were significant for good and borderline performances. The percentage better ratings showed a similar pattern (descending performance mean = 57.4 [95% confidence interval 52.5-62.3], ascending performance mean = 43.4 [95% confidence interval 38.4-48.5]; F(1, 46) = 16.0, p < 0.001, d = 0.67). Confidence ratings did not vary by level of performance and showed no relationship with the effect of group. DISCUSSION: Assessors' judgements showed contrast effects at both good and borderline performance levels. Findings suggest that assessors use normative rather than criterion-referenced decision making while judging, and that the norms referenced are weakly represented in memory and easily influenced. Confidence ratings suggested a lack of insight into this phenomenon. Raters' judgements could be importantly influenced in ways that are unfair to candidates. PMID- 23931541 TI - When physician-expressed uncertainty leads to patient dissatisfaction: a gender study. AB - CONTEXT: Communication guidelines often advise physicians to disclose to their patients medical uncertainty regarding the diagnosis, origin of the problem, and treatment. However, the effect of the expression of such uncertainty on patient outcomes (e.g. satisfaction) has produced conflicting results in the literature that indicate either no effect or a negative effect. The differences in the results of past studies may be explained by the fact that potential gender effects on the link between physician-expressed uncertainty and patient outcomes have not been investigated systematically. OBJECTIVES: On the basis of previous research documenting indications that patients may judge female physicians by more severe criteria than they do male physicians, and that men are more prejudiced than women towards women, we predicted that physician-expressed uncertainty would have more of a negative impact on patient satisfaction when the physician in question was female rather than male, and especially when the patient was a man. METHODS: We conducted two studies with complementary designs. Study 1 was a randomised controlled trial conducted in a simulated setting (120 analogue patients Analogue patients are healthy participants asked to put themselves in the shoes of real medical patients by imagining being the patients of physicians shown on videos); Study 2 was a field study conducted in real medical interviews (36 physicians, 69 patients). In Study 1, participants were presented with vignettes that varied in terms of the physician's gender and physician-expressed uncertainty (high versus low). In Study 2, physicians were filmed during real medical consultations and the level of uncertainty they expressed was coded by an independent rater according to the videos. In both studies, patient satisfaction was assessed using a questionnaire. RESULTS: The results confirmed that expressed uncertainty was negatively related to patient satisfaction only when the physician was a woman (Studies 1 and 2) and when the patient was a man (Study 2). CONCLUSIONS: We believe that patients have the right to be fully informed of any medical uncertainties. If our results are confirmed in further research, the question of import will refer not to whether female physicians should communicate uncertainty, but to how they should communicate it. For instance, if it proves true that uncertainty negatively impacts on (male) patients' satisfaction, female physicians might want to counterbalance this impact by emphasizing other communication skills. PMID- 23931542 TI - Gender differences in worry during medical school. AB - OBJECTIVES: This research examined worry in medical students at various stages of training with reference to worries related to academic and clinical training, finances and relationships with peers. The study focused on gender differences in worries, testing the notion that being married or being in a long-term or cohabitating relationship with a partner would be linked to increased worry among women, but decreased worry among men. Additional goals included examining the relationship between worry and the seeking of counselling, and investigating the disadvantage for medical students associated with living with parents. METHODS: Data collected serially on class cohorts at one western US medical school yielded 868 responses from medical students, which were analysed using general linear models, generalised linear models and generalised estimation equations. RESULTS: Among four types of worry, academic and financial worries were similarly dominant (p < 0.001); financial worries were found to increase over the course of medical training (p < 0.001). Men reported more worry than women (p < 0.001). Gender differences were qualified by marital status (p = 0.007). Being married was linked to higher levels of academic and financial worry among women, whereas for men marriage was linked to lower academic, but higher financial worry (p < 0.001). Living with parents was always associated with a higher level of worry (p < 0.0001). Married male students were more likely to seek counselling than unmarried male students, whereas this pattern was reversed for female students (p = 0.002). CONCLUSIONS: This study confirms that both academic and financial stress represent the greatest sources of worry in medical students. It also represents the first research to demonstrate higher levels of worry in male than female medical students, which may be evidence of women's increased representation in the medical school population. These data also support the persistence of traditional gender roles in the marriages of medical students; marriage is related to an increased psychological burden in women in comparison with men. PMID- 23931543 TI - Better learning, better doctors, better community: how transforming clinical education can help repair society. PMID- 23931544 TI - The influence of cognitive biases on feedback seeking. PMID- 23931545 TI - Clinicians who can support remediation are not always approachable. PMID- 23931546 TI - Polypharmacy: the good, the bad and the ugly. PMID- 23931547 TI - Determinants of unprotected casual heterosexual sex in Ghana. AB - Casual heterosexual sex remains a significant contributor to HIV transmissions in Ghana. The study used data from the 2008 Ghana Demographic and Health Survey (GDHS) to assess the socio-demographic, economic and spatial factors influencing unprotected casual heterosexual sex among men and women. The results of the binary logistic regression models revealed that women aged 35-44 had significantly higher odds of engaging in unprotected casual heterosexual sex than those aged 15-24, unlike the men. There were significantly lower odds of unprotected casual heterosexual sex for women and men with exposure to print media compared with those without exposure. Compared with men residing in the Western Region, unprotected casual heterosexual sex was significantly less likely among those in the Upper East Region. There is the need for behavioural change campaigns in Ghana that take into consideration the multiplicity of factors that determine unprotected casual heterosexual sex. PMID- 23931548 TI - Rapid Detection of Bovine Respiratory Syncytial Virus in Poland Using a Human Patient-Side Diagnostic Assay. AB - Bovine respiratory syncytial virus (BRSV) plays a significant role in the etiopathogenesis of the respiratory syndrome in young cattle during their first year of life. Development of rapid and accurate BRSV diagnostic tools would aid in the appropriate control of this important pathogen. The objective of this study was to characterize infections induced by BRSV by means of rapid patient side immunomigration assays used for diagnosis of human respiratory syncytial virus (hRSV) in humans. Nasal and tracheal swabs were obtained from healthy calves of various beef and dairy breeds - Holstein-Friesian, Simmental, Charolais, Belgian Blue and Limousin, between the ages of 5 and 12 months, from 26 farms. BRSV was identified using two rapid immunomigration assays, TruRSV(r) and Clearview(r) RSV, and compared with RT-PCR as a reference technique. BRSV was found in 73.1% of all the herds tested. High agreement with RT-PCR was obtained for TruRSV(r) (kappa = 0.824), while in the case of the Clearview(r) RSV test, agreement with PCR was moderate (kappa = 0.420). The results demonstrate that rapid patient-side immunomigration assays designed to detect hRSV can be used to accurately detect BRSV in field samples collected from cattle. PMID- 23931549 TI - Introduction to special section: state of the science on wheeled mobility and seating. PMID- 23931550 TI - On the tip of the tongue: learning typing and pointing with an intra-oral computer interface. AB - PURPOSE: To evaluate typing and pointing performance and improvement over time of four able-bodied participants using an intra-oral tongue-computer interface for computer control. BACKGROUND: A physically disabled individual may lack the ability to efficiently control standard computer input devices. There have been several efforts to produce and evaluate interfaces that provide individuals with physical disabilities the possibility to control personal computers. METHOD: Training with the intra-oral tongue-computer interface was performed by playing games over 18 sessions. Skill improvement was measured through typing and pointing exercises at the end of each training session. RESULTS: Typing throughput improved from averages of 2.36 to 5.43 correct words per minute. Pointing throughput improved from averages of 0.47 to 0.85 bits/s. Target tracking performance, measured as relative time on target, improved from averages of 36% to 47%. Path following throughput improved from averages of 0.31 to 0.83 bits/s and decreased to 0.53 bits/s with more difficult tasks. CONCLUSIONS: Learning curves support the notion that the tongue can rapidly learn novel motor tasks. Typing and pointing performance of the tongue-computer interface is comparable to performances of other proficient assistive devices, which makes the tongue a feasible input organ for computer control. IMPLICATIONS FOR REHABILITATION: Intra-oral computer interfaces could provide individuals with severe upper-limb mobility impairments the opportunity to control computers and automatic equipment. Typing and pointing performance of the tongue-computer interface is comparable to performances of other proficient assistive devices, but does not cause fatigue easily and might be invisible to other people, which is highly prioritized by assistive device users. Combination of visual and auditory feedback is vital for a good performance of an intra-oral computer interface and helps to reduce involuntary or erroneous activations. PMID- 23931551 TI - Quaternary aluminum silicides grown in Al flux: RE5Mn4Al(23-x)Si(x) (RE = Ho, Er, Yb) and Er44Mn55(AlSi)237. AB - Four novel intermetallic silicides, RE5Mn4Al(23-x)Si(x) (x = 7.9(9), RE = Ho, Er, Yb) and Er44Mn55(AlSi)237, have been prepared by reaction in aluminum flux. Three RE5Mn4Al(23-x)Si(x) compounds crystallize in the tetragonal space group P4/mmm with the relatively rare Gd5Mg5Fe4Al(18-x)Si(x) structure type. Refinement of single-crystal X-ray diffraction data yielded unit cell parameters of a = 11.3834(9)-11.4171(10) A and c = 4.0297(2)-4.0575(4) A with volumes ranging from 522.41(5) to 528.90(8) A(3). Structure refinements on single-crystal diffraction data show that Er44Mn55(AlSi)237 adopts a new cubic structure type in the space group Pm3n with a very large unit cell edge of a = 21.815(3) A. This new structure is best understood when viewed as two sets of nested polyhedra centered on a main group atom and a manganese atom. These polyhedral clusters describe the majority of the atomic positions in the structure and form a perovskite-type network. We also report the electrical and magnetic properties of the title compounds. All compounds except the Ho analogue behave as normal paramagnetic metals without any observed magnetic transitions above 5 K and exhibit antiferromagnetic correlations deduced from the value of their Curie constants. Ho5Mn4Al(23-x)Si(x) exhibits a ferromagnetic transition at 20 K and an additional metamagnetic transition at 10 K, suggesting independent ordering temperatures for two distinct magnetic sublattices. PMID- 23931552 TI - A dominant repressor version of the tomato Sl-ERF.B3 gene confers ethylene hypersensitivity via feedback regulation of ethylene signaling and response components. AB - Ethylene Response Factors (ERFs) are downstream components of the ethylene signal transduction pathway, although their role in ethylene-dependent developmental processes remains poorly understood. As the ethylene-inducible tomato Sl-ERF.B3 has been shown previously to display a strong binding affinity to GCC-box containing promoters, its physiological significance was addressed here by a reverse genetics approach. However, classical up- and down-regulation strategies failed to give clear clues to its roles in planta, probably due to functional redundancy among ERF family members. Expression of a dominant repressor ERF.B3 SRDX version of Sl-ERF.B3 in the tomato resulted in pleiotropic ethylene responses and vegetative and reproductive growth phenotypes. The dominant repressor etiolated seedlings displayed partial constitutive ethylene response in the absence of ethylene and adult plants exhibited typical ethylene-related alterations such as leaf epinasty, premature flower senescence and accelerated fruit abscission. The multiple symptoms related to enhanced ethylene sensitivity correlated with the altered expression of ethylene biosynthesis and signaling genes and suggested the involvement of Sl-ERF.B3 in a feedback mechanism that regulates components of ethylene production and response. Moreover, Sl-ERF.B3 was shown to modulate the transcription of a set of ERFs and revealed the existence of a complex network interconnecting different ERF genes. Overall, the study indicated that Sl-ERF.B3 had a critical role in the regulation of multiple genes and identified a number of ERFs among its primary targets, consistent with the pleiotropic phenotypes displayed by the dominant repression lines. PMID- 23931553 TI - Effects of Laser Irradiation on Pulp Cells Exposed to Bleaching Agents. AB - The aim of this study was to evaluate the effect of low-level laser therapy (LLLT) on odontoblast-like cells exposed to a bleaching agent. Mouse dental papilla cell-23 cells were seeded in wells of 24-well plates. Eight groups were established according to the exposure to the bleaching agent and LLLT (0, 4, 10 and 15 J cm(-2) ). Enamel-dentin disks were adapted to artificial pulp chambers, which were individually placed in wells containing Dulbecco's modified Eagle's medium (DMEM). A bleaching agent (35% hydrogen peroxide [BA35%HP]) was applied on enamel (15 min) to obtain the extracts (DMEM + BA35%HP components diffused through enamel/dentin disks). The extracts were applied (1 h) to the cells, and then subjected to LLLT. Cell viability (Methyl tetrazolium assay), alkaline phosphatase (ALP) activity, as well as gene expression of ALP, fibronectin (FN) and type I collagen, were evaluated. The bleaching procedures reduced the cell viability, ALP activity and gene expression of dentin proteins. Laser irradiation did not modulate the cell response; except for FN, as LLLT decreased the gene expression of this protein by the cells exposed to the BA35%HP. It can be concluded that BA35%HP decreased the activities of odontoblasts that were not recovered by the irradiation of the damaged cells with low-level laser parameters tested. PMID- 23931554 TI - The role of membrane rafts in Lck transport, regulation and signalling in T cells. AB - Tyrosine phosphorylation is one of the key covalent modifications that occur in multicellular organisms. Since its discovery more than 30 years ago, tyrosine phosphorylation has come to be understood as a fundamentally important mechanism of signal transduction and regulation in all eukaryotic cells. The tyrosine kinase Lck (lymphocyte-specific protein tyrosine kinase) plays a crucial role in the T-cell response by transducing early activation signals triggered by TCR (T cell receptor) engagement. These signals result in the phosphorylation of immunoreceptor tyrosine-based activation motifs present within the cytosolic tails of the TCR-associated CD3 subunits that, once phosphorylated, serve as scaffolds for the assembly of a large supramolecular signalling complex responsible for T-cell activation. The existence of membrane nano- or micro domains or rafts as specialized platforms for protein transport and cell signalling has been proposed. The present review discusses the signals that target Lck to membrane rafts and the importance of these specialized membranes in the transport of Lck to the plasma membrane, the regulation of Lck activity and the phosphorylation of the TCR. PMID- 23931556 TI - Site-specific measurements of lipid membrane interfacial water dynamics with multidimensional infrared spectroscopy. AB - One route to accessing site-specific dynamical information available with ultrafast multidimensional infrared spectroscopy is the development of robust and versatile vibrational probes. Here we synthesize and characterize a vibrationally labeled cholesterol derivative, (cholesteryl benzoate) chromium tricarbonyl, to probe model lipid membranes, focusing specifically on the membrane-water interface. Utilizing FTIR and polarized-ATR spectroscopies, we determine the location of the chromium tricarbonyl motif to be situated at the water-membrane interface with an orientation of 46 +/- 2 degrees relative to the vector normal to the membrane surface. We test the dynamical sensitivity of the (cholesteryl benzoate) chromium tricarbonyl label with two different nonlinear infrared spectroscopy methods, both of which show that the probe is well-suited to the study of membrane dynamics as well as the dynamics of water at the membrane interface. The metal carbonyl vibrational probe located at the surface of a bicelle exhibits spectral diffusion dynamics induced by membrane hydration water that is roughly three times slower than observed using a nearly identical vibrational probe in bulk water. PMID- 23931557 TI - Growth-related disappearance of the childhood relationship between height and blood pressure levels. AB - CONTEXT: Although there is a positive relationship between height and blood pressure (BP) levels in children, there are no reports regarding the association between height and BP levels in adolescents and adults. OBJECTIVE: This study examined whether there is an association between height and BP levels in Japanese adolescents. METHODS: The source population was all fifth (10 and 11-year-olds) and ninth graders (14 and 15-year-olds) who attended 11 elementary schools and five junior high schools in the Iwata area from 2002-2008. School-based screenings were conducted annually by the local government from April to June. Data obtained from health examinations were analysed, including anthropometric measurements and BP levels, for 11 780 children (98.7% of the source population). RESULTS: Height showed significant positive relationships with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in childhood and in adolescent males. In contrast, the relationship between height and SBP was significantly weaker in adolescent females than in childhood and there was no significant relationship between height and DBP in adolescent females. CONCLUSION: The relationship between height and SBP was attenuated by development in females and the relationship between height and DBP disappeared. PMID- 23931558 TI - Editorial. AB - No abstract available for this article. PMID- 23931559 TI - Assessing learning capabilities during cognitive and perceptual evaluations for adults with traumatic brain injury. AB - Occupational therapists (OTs) typically identify cognitive and perceptual deficits in adults with Traumatic Brain Injury (TBI) through a combination of Activity of Daily Living (ADL) evaluations and cognitive/perceptual skill evaluations which provide information about clients' occupational performance and cognitive/ perceptual skill levels, respectively. These evaluations do not provide information about clients' abilities to learn new approaches to tasks or to transfer learning from one task to another. Since learning ability is an important determinant of clients' response to treatment, OTs need to evaluate that ability as part of their routine ADL and cognitive/perceptual evaluations. This paper presents a learning process approach to cognitive/perceptual evaluation that identifies ways OTs can evaluate clients' learning abilities with only slight modification of current evaluation practices. PMID- 23931560 TI - The Occupational Therapist's Role in a Transitional Living Program for Head Injured Clients. AB - The head injured patient typically undergoes a long period of transition, beginning with acute care, moving to a rehabilitation facility, and ending with community re-entry. A key point in the total rehabilitation process is the smooth transition from a hospital- like environment to a home environment. This paper describes the role of the occupational therapist in a transitional living program at a private facility. In this program, various health professionals work with clients in a home-like environment to facilitate community reintegration. The program uses a ''real world laboratory'' to re-train clients in functional daily tasks. The overall structure of the program, types of activities used, and goals of the program are discussed. PMID- 23931561 TI - Work simulation as a diagnostic tool in the rehabilitation setting. AB - Standardized tests are often used to assess the cognitive status of individuals who have sustained traumatic brain injuries. However, recent research indicates that these evaluation tools are not always reliable measures of cognitive function. This is particularly evident when assessing executive functions. This article illustrates the use of a work simulation model within a therapeutic setting. Described are two individuals with traumatic brain injury, both physicians, who exhibited high level cognitive deficits during formal testing and little insight into their problem areas. Specific components of the work simulations are explained as well as outcomes and applications of this diagnostic technique. PMID- 23931562 TI - Employment intervention strategies for individuals with brain injury. AB - A supported employment, case management and independent living program for survivors of brain injuries is described. The relationship between this program and the university occupational therapy academic department in which it is housed is discussed. Recent work reentry and supported employment project descriptions and outcome studies in the literature are reviewed to show types of services provided, as well as the results of such programs nationwide. A thorough definition of the supported employment model for brain injury survivors is provided. Seven unique support and intervention strategies: defining goals; providing reality checks; building a team; approaching intervention holistically; educating support systems; discussing social behavior; and assuring long-term follow-along support are described. Early program evaluation results are discussed, along with current research activities. The article concludes with a discussion of the need for longer-term, cost-efficient community-based therapies and supports for brain injury survivors. PMID- 23931563 TI - Providing instruction in independent living and vocational rehabilitation for individuals with head injuries within an entry-level occupational therapy curriculum. AB - With the goal of occupational therapy being to assist persons in living independently, few occupational therapists (OTs) work in independent living and vocational settings or are heavily engaged in independent living and vocational interventions. Ultimately, clients suffer when attempting to reintegrate into the community without adequate resources, especially persons with head injuries who present with numerous disabilities. Perhaps OTs are not well-trained to provide these services. This paper describes the incorporation of information about service provision within the independent living and vocational rehabilitation models, especially related to individuals with head injuries, into the University of Kansas' occupational therapy curriculum. Evaluations indicated success in increasing knowledge about and improving attitudes regarding service provision within these models and the community integration of individuals with head injuries. PMID- 23931564 TI - A NARIC Resource Guide for People with Head Injuries and Their Families. AB - No abstract available for this article. PMID- 23931565 TI - Software and products. AB - No abstract available for this article. PMID- 23931567 TI - Enigmas regarding the true extent and impact of tyrosine kinase inhibitor-related cardiotoxicity. AB - Cardiac sequelae of anticancer treatment remains a major concern among both oncologists and cardiologists caring for patients treated with potentially cardiotoxic regimens. While the toxicity of anthracyclines is well understood to destroy myocytes, the scenario with regard to newer agents, both monoclonal antibodies and small-molecule tyrosine kinase inhibitors, is substantially different. This article differentiates the toxicity of agents that directly destroy myocytes (type I agents) from those that are associated with cardiac damage more indirectly (type II agents). Some mechanistic considerations regarding type II toxicity, albeit not categorically proven, are presented. PMID- 23931568 TI - Effect of the interaction between periodontitis and type 1 diabetes mellitus on alveolar bone, mandibular condyle and tibia. AB - OBJECTIVE: This study examined the effect of the interaction between periodontitis and type 1 diabetes mellitus on alveolar bone, mandibular condyle and tibia in animal models. MATERIALS AND METHODS: Rats were divided into normal, periodontitis, diabetic and diabetic with periodontitis groups. After injection of streptozotocin to induce diabetes, periodontitis was induced by ligation of both lower-side first molars for 30 days. Alveolar bone loss and trabecular bone volume fraction (BVF) of the mandibular condyle and tibia were estimated via hematoxylin and eosin staining and micro-computed tomography, respectively. Osteoclastogenesis of bone marrow cells isolated from tibia and femur was assayed using tartrate-resistant acid phosphatase staining. RESULTS: The cemento-enamel junction to the alveolar bone crest distance and ratio of periodontal ligament area in the diabetic with periodontitis group were significantly increased compared to those of the periodontitis group. Mandibular condyle BVF did not differ among groups. The BVF of tibia in the diabetic and diabetic with periodontitis groups was lower than that of the normal and periodontitis groups. Osteoclastogenesis of bone marrow cells in the diabetic groups was higher than that in the non-diabetic groups. However, the BVF of tibia and osteoclastogenesis in the diabetic with periodontitis group were not significantly different than those in the diabetic group. CONCLUSIONS: Type 1 diabetes mellitus aggravates alveolar bone loss induced by periodontitis, but periodontitis does not alter the mandibular condyle and tibia bone loss induced by diabetes. Alveolar bone, mandibular condyle and tibia may have different responses to bone loss stimuli in the diabetic environment. PMID- 23931569 TI - Stepwise chemical reaction strategy for highly sensitive electrochemiluminescent detection of dopamine. AB - A stepwise chemical reaction strategy based on the specific recognition of boronic acid to diol, and N-hydroxysuccinimide (NHS) ester to amine group, was designed to construct a "signal on" electrochemiluminescence (ECL) platform for highly sensitive detection of dopamine. A boronic acid-functionalized pyrene probe was synthesized and was self-assembled on the sidewalls of carbon nanotubes via pi-pi stacking interactions as capture probes on a glassy carbon electrode. Meanwhile, 3,3'-dithiodipropionic acid di(N-hydroxysuccinimide ester) (DSP) functionalized CdTe quantum dots (QDs) were designed as signal probes and characterized with transmission electron microscopy and spectroscopic techniques. Upon stepwise chemical reaction of dopamine with boronic acid and then DSP-QDs, the QDs were captured on the electrode as ECL emitters for signal readout, leading to an ultralow background signal. By using O2 as an endogenous coreactant, the "signal on" ECL method was employed to quantify the concentration of dopamine from 50 pM to 10 nM with a detection limit of 26 pM. Moreover, the stepwise chemical reaction-based biosensor showed high specificity against cerebral interference and was successfully applied in the detection of dopamine in cerebrospinal fluid samples. The stepwise chemical reaction strategy should be a new concept for the design of highly selective analytical methods for the detection of small biomolecules. PMID- 23931570 TI - Defect-dominated shape recovery of nanocrystals: a new strategy for trimetallic catalysts. AB - Here we present a shape recovery phenomenon of Pt-Ni bimetallic nanocrystals that is unequivocally attributed to the defect effects. High-resolution electron microscopy revealed the overall process of conversion from concave octahedral Pt3Ni to regular octahedral Pt3Ni@Ni upon Ni deposition. Further experiments and theoretical investigations indicated that the intrinsic defect-dominated growth mechanism allows the site-selective nucleation of a third metal around the defects to achieve the sophisticated design of trimetallic Pt3Ni@M core-shell structures (M = Au, Ag, Cu, Rh). Consideration of geometrical and electronic effects indicated that trimetallic atomic steps in Pt3Ni@M could serve as reactive sites to significantly improve the catalytic performance, and this was corroborated by several model reactions. The synthesis strategy based on our work paves the way for the atomic-level design of trimetallic catalysts. PMID- 23931571 TI - Oncology in midlife and beyond. AB - The onset of the menopause is often a time when women's concerns can act as a powerful trigger to encourage healthy modifications in lifestyle which will maintain, or improve, their general health. This document aims to help women to understand their potential risks, to encourage them to find proactive preventive strategies by modifying some of their attitudes, and to use health resources (when available) to be screened. Cancer is an important cause of death but not the primary cause of mortality. Cardio/circulatory diseases represent 35-40% of causes of death in most developed countries and 20-25% of women will die from cancers in Western Europe, Australasia, high-income North America, high-income Asia Pacific, East Asia and Southern Latin America. Breast cancer, lung cancer and colorectal cancer are prevalent in most regions of the world. Cervical cancer remains a hallmark of low access to health care. Preventive strategies (decreasing smoking and alcohol consumption, losing weight, eating a healthy diet and undertaking physical activity) and implementation of screening could help to significantly decrease the incidence of and mortality from cancer. The mortality/incidence ratio is higher in developing countries compared to high income regions as well as in subgroups of populations in developed countries with lower socioeconomic levels. Implementation of better diagnostic methods and management of cancer according to the local resources will help to decrease the mortality rate in developing countries, and effort has to be made to decrease social inequities and improve access to health care for low-income groups. In conclusion, cancer incidence is increasing as a consequence of longer life expectancy all over the world. National health programs are mandatory to implement screening and to improve individual management. Finally, educating women so that they are aware of ways to improve their general health, to minimize their own risk factors and to identify signs of change in their own health which may be markers of impending cancer will help to reduce the burden of disease and improve the prognosis for tumors detected at an earlier stage. PMID- 23931572 TI - High-performance asymmetric supercapacitor based on nanoarchitectured polyaniline/graphene/carbon nanotube and activated graphene electrodes. AB - Hierarchical sulfonated graphene nanosheet/carboxylated multiwalled carbon nanotube/polyaniline (sGNS/cMWCNT/PANI) nanocomposites were synthesized through an interfacial polymerization method. Activated porous graphene (aGNS) was prepared by combining chemical foaming, thermal reduction, and KOH activation. Furthermore, we have successfully fabricated an asymmetric supercapacitor (ASC) using sGNS/cMWCNT/PANI and aGNS as the positive and negative electrodes, respectively. Because of its unique structure, high capacitive performance, and complementary potential window, the ASC device can be cycled reversibly at a cell voltage of 1.6 V in a 1 M H2SO4 aqueous electrolyte, delivering a high energy density of 20.5 Wh kg(-1) at a power density of 25 kW kg(-1). Moreover, the ASC device also exhibits a superior long cycle life with 91% retention of the initial specific capacitance after 5000 cycles. PMID- 23931573 TI - Picture-word interference reveals inhibitory effects of syllable frequency on lexical selection. AB - While previous research has shown that high syllable frequency can facilitate speech production at the level of phonological/phonetic encoding, little is known about its influence on prephonological processes, specifically lexical selection. The current study used a picture-word interference (PWI) task to (a) shed light on the stages of lexical access where syllable frequency is relevant, and (b) inform as to whether lexical selection is accomplished via competition among activated word options. Participants named pictures whose names had high frequency (HF) and low-frequency (LF) first syllables while ignoring phonologically related (same first syllable) or unrelated distractor words that were presented simultaneously. Word frequency was also manipulated, as half of the targets were HF words, and half were LF words. Results revealed inhibitory syllable frequency effects in all conditions, such that targets with HF first syllables were named more slowly than targets with LF first syllables. However, inhibitory syllable frequency effects were exacerbated in conditions thought to reflect heightened lexical competition, specifically in the presence of phonologically related distractors and for targets with low word frequency. These findings reveal novel evidence for first-syllable frequency effects on lexical selection and offer further support for models proposing delays at lexical selection due to activation of nontarget competitors. PMID- 23931574 TI - Growth and physiological responses of growing pigs to wheat-corn distillers dried grains with solubles. AB - Gaining a detailed knowledge on the impact of a feedstuff on pig growth and physiological responses is critical for its effective utilization. Thus, the purpose of this study was to investigate the effect of distillers dried grains with solubles derived from co-fermentation of wheat and corn (wcDDGS) on performance, carcass and visceral organ weights, whole-body O2 consumption and heat production (HP) in growing barrows. The experimental diets were as follows: corn-soybean meal diet (Control), Control + 15% wcDDGS and Control + 30% wcDDGS. In Exp. 1, 48 pair-housed pigs of average BW 18.6 +/- 1.5 kg (mean +/- SD) were allotted to the 3 diets (n = 8). Pigs had free access to water and feed for a 28 day period during which ADG and ADFI were calculated weekly. Thereafter, 1 pig/pen was killed to measure carcass and visceral organ weights. Overall, wcDDGS linearly decreased (p < 0.05) ADFI and ADG but had no effect on G:F (p > 0.10). The ADFI was 1.55, 1.45 and 1.36 kg/day for diets containing 0, 15 and 30% wcDDGS respectively; corresponding values for ADG were 0.79, 0.75 and 0.67 kg/day respectively. A linear decline (p = 0.01) in eviscerated hot carcass weight was observed as dietary wcDDGS increased. In Exp. 2, 18 pigs of average BW 20.4 +/- 2.4 kg (mean +/- SD) were individually housed in metabolism crates and fed the 3 diets (n = 6) at 550 kcal ME kg BW(-0.60) day for a 16-day period followed by measurement of O2 consumption using an indirect calorimeter. Diet had no effect (p > 0.10) on whole-body O2 consumption and HP. In conclusion, increasing wcDDGS content in growing pig diets linearly reduced ADFI, ADG and eviscerated hot carcass weight but had no effect on G:F, visceral organ weights or HP. PMID- 23931576 TI - Mammary analogue secretory carcinoma of salivary glands is a lipid-rich tumour, and adipophilin can be valuable in its identification. AB - AIMS: Mammary analogue secretory carcinoma (MASC) of salivary glands shows morphological similarities to milk-secreting mammary epithelial cells. The aim of this study was to analyse the immunohistochemical expression of adipophilin (a component of milk lipid globule membranes) and of proteins related to secretory mechanisms (STAT5a and mammaglobin) in MASC and other salivary tumours. METHODS AND RESULTS: Ten cases of MASC (all with ETV6 translocation) and 83 other salivary carcinomas were studied. In all MASC cases, adipophilin stained numerous large lipid droplets. These droplets were minute in other salivary carcinomas, except for sebaceous carcinoma. Overexpression of STAT5a was detected in all MASC cases, but only occasionally in other carcinomas. Mammaglobin expression occurred frequently in MASC (70% of cases), whereas, in other carcinomas, it was uncommon and limited. Only MASC showed cytoplasmic reactivity for p63, particularly in papillary-cystic areas. Positivity for S100, vimentin and high molecular weight keratin was observed in 100% of MASC cases. CONCLUSIONS: MASC is a lipid-rich tumour containing large lipid droplets covered by adipophilin. This finding can be included among its defining immunohistochemical features, and possibly represents lactation-like secretory differentiation. Strong expression of STAT5a and cytoplasmic p63 in MASC reinforces this hypothesis. PMID- 23931577 TI - In vitro and in vivo investigation of a novel two-phase delivery system of 2 methoxyestradiol liposomes hydrogel. AB - For improving effectiveness of conventional chemotherapy of subcutaneous tumor, we selected 2-methoxyestradiol (2-ME) as a model drug, local injectable PLGA-PEG PLGA copolymer thermosensitive hydrogel loading 2-ME liposomes instead of free 2 ME as a novel two-phase drug delivery system was developed, which avoid rapid clearance of liposomes following systemic administration. This new transport system was characterized in vitro and in vivo including rheological behavior, thermo-sensitiveness, stability, released character and intratumoral delivery. The PLGA-PEG-PLGA copolymer solution exhibited still reversible thermosensitive property and better syringeability after incorporated 2-ME liposomes. The 2-ME liposomes were demonstrated stable in the hydrogel by five methods such as scanning electron microscopy (SEM), fluorescent labeling, opalescence, particle size and ultrafiltration methods. Results showed that intact liposomes could be released from the hydrogel and following zero-order model, and sustained release one-two months in vitro and in vivo. In vivo release data demonstrating that 2-ME liposomes could be transported to tumor site, improved therapeutic efficacy and bioavailability of 2-ME liposomes in subcutaneous tumor chemotherapy. PMID- 23931578 TI - The effect of immunization against GnRF on nutrient requirements of male pigs: a review. AB - In most countries, male pigs are physically castrated soon after birth to reduce the risk of boar taint and to avoid behaviours such as fighting and mounting. However, entire male pigs are more feed efficient and deposit less fat than barrows. In addition, many animal welfare organizations are lobbying for a cessation of castration, with a likelihood that this could lead to inferior pork unless an alternative method is used to control boar taint. An alternative to physical castration is immunization against gonadotrophin releasing factor (GnRF) which allows producers to capitalize on the superior feed efficiency and carcass characteristics of boars without the risk of boar taint. From a physiological perspective, immunized pigs are entire males until shortly after the second dose, typically given 4 to 6 weeks before slaughter. Following full immunization, there is a temporary suppression of testicular function and a hormonal status that resembles that of a barrow. Nutrient requirements will be different in these two phases, before and after full immunization. Given that there have been few published studies comparing the lysine requirements of entire males and barrows in contemporary genotypes, it is useful to use gilt requirements as a benchmark. A series of meta-analyses comparing anti-GnRF immunized boars and physical castrates and use of nutritional models suggest that the lysine requirement of entire males before the second immunization is 5% higher than for gilts, from 25 to 50 kg BW, and by 8% from 50 to 95 kg. Given that the penalty in growth performance for having inadequate dietary lysine is greater in males than in gilts or barrows, it is important to ensure that lysine requirements are met to obtain the maximum benefits of entire male production during this phase. After the second immunization, the lysine requirement of immunized males decreases and may become more like that of barrows. In addition, a consistent effect of full immunization is a marked increase in voluntary feed intake from about 10 days after the second dose. Putting these together, the estimated lysine requirement, expressed in terms of diet composition, falls to 94% of the gilt level. Although general principles can be described now, further research is needed to fully define the lysine requirements of immunized boars. It is important that the temporal pattern of tissue deposition rates and feed intake be explored to be incorporated into models to predict nutrient requirements over the period of rapidly changing metabolism. PMID- 23931581 TI - Genetic and genomic approaches for the discovery of parasite genes involved in antimalarial drug resistance. AB - The biggest threat to the war on malaria is the continued evolution of drug resistance by the parasite. Resistance to almost all currently available antimalarials now exists in Plasmodium falciparum which causes the most suffering among all human malaria parasites. Monitoring of antimalarial efficacy and the development and subsequent spread of resistance has become an important part in the treatment and control of malaria. With recent reports of reduced efficacy of artemisinin, the current recommended treatment for uncomplicated malaria, there is urgent need for better methods to recognize and monitor drug resistance for effective treatment. Molecular markers have become a welcome addition to complement the more laborious and costly in vitro and in vivo methods that have traditionally been used to monitor drug resistance. However, there are currently no molecular markers for resistance to some antimalarials. This review highlights the role of the various genetic and genomic approaches that have been used in identifying the molecular markers that underlie drug resistance in P. falciparum. These approaches include; candidate genes, genetic linkage and genome-wide association studies. We discuss the requirements and limitations of each approach and use various examples to illustrate their contributions in identifying genomic regions of the parasite associated with antimalarial drug responses. PMID- 23931579 TI - Executive functioning in individuals with intellectual disabilities and autism spectrum disorders. AB - BACKGROUND: Executive functioning (EF) is important for adequate behavioural functioning and crucial for explaining symptoms of autism spectrum disorders (ASD) in individuals with normal intelligence, but is scarcely studied in individuals with ASD and intellectual disabilities (ID). We therefore study EF in an ID population by comparing performances on three frequently studied executive functions (shifting, inhibition and updating) between individuals with ASD and individuals without ASD. When studying ID populations, one should be aware of Spearman's Law of Diminishing Returns (SLODR), as it questions the possibility of measuring separate cognitive functions in ID populations. METHODS: Six EF tasks were administered to 50 individuals with mild to borderline ID, of which half was diagnosed with ASD. In order to investigate the distinctness of the three executive functions in this ID sample, the results on the six EF tasks were subjected to principal components analysis (PCA). Subsequently, a multivariate analysis of variance (MANOVA) was performed to assess differences between the ASD and non-ASD group on shifting, inhibition and updating. RESULTS: The PCA revealed the hypothesised EF trichotomy. MANOVA analysis showed no significant group differences on EF-performance. CONCLUSIONS: Three separate executive functions were measured in this ID population, but despite much evidence that individuals with ASD display more behavioural problems and the proven relevance of EF in behavioural functioning, no significant group difference was found on shifting, inhibition or updating. After this first effort to achieve more insight into EF of individuals with ASD and ID the relation between behavioural problems and EF will require further study. PMID- 23931582 TI - Synthesis and characterization of a novel sodium transition metal oxyfluoride: NaMnMoO3F3.H2O. AB - NaMnMoO3F3.H2O was precipitated at low temperature from aqueous dissolutions of Na2MoO4.2H2O in aqueous HF (or NaHF2) using either Mn(CH3COO)2.4H2O or MnF2 as manganese precursors. Chemical analysis, IR spectra, and effective paramagnetic moment are in agreement with the proposed formula. Electron microscopy studies indicate that the sample is constituted of very thin plate-like microcrystals. The average crystal structure (a = 3.5947(1), b = 21.246(1), and c = 7.3893(2) A and Cmcm (No. 63) SG) has been elucidated through powder diffraction methods (synchrotron and neutron). Tiny superstructure peaks are observed that can be indexed with the space group Pbca and cell parameters a = 7.1894(2), b = 21.246(1), and c = 7.3893(2) A. Electron diffraction confirms the doubling of a parameter. Ordering of O and F is proposed in agreement with Pauling's second crystal rule and bond strength sums for each anionic position. The structure that is formed has a layered stacking arrangement along the b-axis of the MnO4F2 octahedra layers that share corners along a- and c-directions. The large interlayer space contains MoO4F2 octahedra (connected to the layer) together with sodium ions and water molecules, tentatively forming hydrogen bonding with fluorine anions. The origin of the superstructure could not be fully elucidated, but it is presumably related to slight distortions within the MnO4F2 octahedra. PMID- 23931583 TI - Analysis of Recent Serotype O Foot-and-Mouth Disease Viruses from Livestock in Kenya: Evidence of Four Independently Evolving Lineages. AB - Foot-and-mouth disease (FMD) is endemic in Kenya where four serotypes (O, A, SAT 1 and SAT 2) of the virus are currently in circulation. Within 2010 and 2011, the National Laboratory recorded an increase in the number of FMD outbreaks caused by serotype O virus. The characteristics of these viruses were determined to ascertain whether these were independent outbreaks or one single strain spreading throughout the country. The sequences of the complete VP1-coding region were analysed from viruses sampled within different areas of Kenya during 2010 and 2011. The results indicated that the 2010 to 2011 outbreaks in Kenya were caused by four independent strains. By comparison with earlier type O isolates from Eastern Africa, it was apparent that the outbreaks were caused by viruses from three different lineages of topotype EA-2 and a fourth virus strain belonging to topotype EA-4. The topotypes EA-1 and EA-3 were not detected from these outbreaks. Implications of these results for FMD control in Eastern Africa are discussed. PMID- 23931584 TI - Dynamics of the amino-terminal and carboxyl-terminal helices of Arabidopsis phototropin 1 LOV2 studied by the transient grating. AB - Recently, conformational changes of the amino-terminal helix (A'alpha helix), in addition to the reported conformational changes of the carboxyl-terminal helix (Jalpha helix), have been proposed to be important for the regulatory function of the light-oxygen-voltage 2 domain (LOV2) of phototropin 1 from Arabidopsis. However, the reaction dynamics of the A'alpha helix have not been examined. Here, the unfolding reactions of the A'alpha and Jalpha helices of the LOV2 domain of phototropin 1 from Arabidopsis thaliana were investigated by the time-resolved transient grating (TG) method. A mutant (T469I mutant) that renders the A'alpha helix unfolded in the dark state showed unfolding of the Jalpha helix with a time constant of 1 ms, which is very similar to the time constant reported for the wild-type LOV2-linker sample. Furthermore, a mutant (I608E mutant) that renders the Jalpha helix unfolded in the dark state exhibited an unfolding process of the A'alpha helix with a time constant of 12 ms. On the basis of these experimental results, it is suggested that the unfolding reactions of these helices occurs independently. PMID- 23931585 TI - Occult hepatitis B infections among blood donors in Lao PDR. AB - BACKGROUND AND OBJECTIVES: In Lao People's Democratic Republic, hepatitis B virus is highly endemic. However, blood donations are only screened for HBsAg, leaving a risk of transmission by HBsAg-negative occult infected donors. Here, we characterized first-time blood donors to assess prevalence of hepatitis B virus infections and occult infected donors. MATERIALS AND METHODS: Sera were screened for HBsAg, HBeAg and anti-HBs, anti-HBc and anti-HBe antibodies. Occult HBV infections (OBIs) were assessed in HBsAg-negative sera by PCR, and sera of HBsAg positive and occult infected donors were phylogenetically characterized. RESULTS: 9.6% of the donors were HBsAg positive, and 45.5% were positive for at least one of the hepatitis B virus serum markers. More than 40% HBsAg carriers were HBeAg positive, with HBeAg seroconversion occurring around 30 years of age. Furthermore, 10.9% of HBsAg-negative, anti-HBc and/or anti-HBs-positive donors were occult infected with hepatitis B virus. Thus, at least 3.9% of blood donations would potentially be unsafe, but hepatitis B virus DNA copy numbers greatly varied between donors. CONCLUSION: In Lao People's Democratic Republic, a sizable proportion of HBsAg-negative and anti-HBc antibody-positive blood donations are potentially DNA positive and infective for hepatitis B. PMID- 23931586 TI - NS5A inhibitor, daclatasvir, for the treatment of chronic hepatitis C virus infection. AB - INTRODUCTION: Chronic Hepatitis C virus (HCV) infection is a major pandemic. The current standard of care includes peginterferon and ribavirin plus one of two protease inhibitors, boceprevir and telaprevir, for Genotype 1 patients and peginterferon and ribavirin for all other genotypes. The treatment landscape is rapidly evolving as a number of direct-acting antivirals (DAA) are being developed in clinical trials. AREAS COVERED: Daclatasvir, formerly labeled BMS 790052, is a first-in-class HCV NS5A inhibitor that has been demonstrated in Phase I and II trials to have a very potent antiviral effect across all genotypes and to have a potent clinical efficacy in both treatment naive and experienced cohorts. This review covers the whole spectrum of development of daclatasvir from Phase I to III programs. EXPERT OPINION: While daclatasvir has pangenotypic activity, it has a lower barrier to resistance in Genotype 1a but has been found to be very effective in Genotype 1b patients. However, Genotype 1a patients can be successfully treated with the addition of one or more DAAs alone or in combination with peginterferon and ribavirin. The future for daclatasvir and other DAAs is very encouraging in that all-oral therapies are likely to be effective and well-tolerated. PMID- 23931587 TI - Ethical dilemmas in health care reform. AB - This investigation examines the field of ethics as it relates to new trends in health care service delivery in the United States. Such new trends include managed care and managed competition. The ethical dilemmas which have been posed by these health care reform trends are problematic. PMID- 23931588 TI - Health care reform, managed care, and clinical reasoning: implications for ethical occupational therapy practice. PMID- 23931589 TI - Stroke caregivers: do they feel prepared? AB - A pilot study was administered to determine if stroke caregivers felt they were adequately educated, trained, and prepared to care for their stroke survivor upon discharge. The convenience sample consisted of 26 stroke caregivers from four Indiana facilities with established therapy/rehabilitation units and two Indiana stroke clubs. Subjects were divided into groups according to the amount of time after discharge in the caregiver role (1-3 days, 10-14 days, greater than 3 months). Survey results were obtained by phone interviews and by self administration. Compilation of data occurred over 5 months, and interpretation involved visual inspection and frequency distributions. Overall preparedness for the newer caregivers was a 4 (prepared); whereas, the more experienced caregivers' average score was a 3 (somewhat prepared). This study can help rehabilitation staff in their efforts to prepare caregivers for assisting stroke survivors at home. PMID- 23931590 TI - Comparison of service delivery models influencing teachers' use of assistive technology for students with severe disabilities. AB - Since the 70s and 80s the use of assistive technology in the classroom setting for individuals with severe disabilities has emerged. Assistive technology has provided a new set of tools which allow students to achieve a greater level of independence. Literature review has indicated the need for additional training of related service and classroom personnel in the use of this technology. Training would promote confidence levels in assistive technology application, which may result in increased daily use within the educational domains. The purpose of this research study was to investigate the perceived effectiveness of consultation versus direct service delivery models that influence special educators' and paraprofessionals' use Of assistive technology with students who have severe disabilities. Thirty special educators and sixteen paraprofessionals completed a questionnaire regarding their use of assistive technology with their students and the service delivery model they perceived to be most effective. The results indicated no significant difference between teachers' and paraprofessionals' perceived effectiveness of service delivery models. However, descriptive data did suggest that teachers were utilizing and benefiting from collaborative consultation services when training students with severe disabilities. Limitations to the study and recommendation for further research are also discussed. PMID- 23931591 TI - The use of voice recognition as a control interface for word processing. AB - The purpose of this case study was to compare the speed and accuracy of the subject's word processing skills using the Dragon Systems, Incorporated Dragon Dictate voice recognition system, to the speed and accuracy of the subject's current method of accessing a computer by mouthstick. The subject received fifteen hours of training and practice on the voice recognition technology. Following training the subject was asked to type a 216-word document using his mouthstick skills and again using voice recognition. The subject was able to type 13 words per minute using his current method of mouthstick access, resulting in 10 errors or 95.4% accuracy. Using voice recognition technology, the subject dictated 20 words per minute with 3 errors, resulting in 98.6% accuracy. The results of this objective clinical measurement indicate that voice recognition technology may be a viable means of word processing for individuals with severe upper extremity restrictions. PMID- 23931592 TI - Assume nothing: the tale of circular RNA. PMID- 23931593 TI - Simultaneous digital quantification and fluorescence-based size characterization of massively parallel sequencing libraries. AB - Due to the high cost of failed runs and suboptimal data yields, quantification and determination of fragment size range are crucial steps in the library preparation process for massively parallel sequencing (or next-generation sequencing). Current library quality control methods commonly involve quantification using real-time quantitative PCR and size determination using gel or capillary electrophoresis. These methods are laborious and subject to a number of significant limitations that can make library calibration unreliable. Herein, we propose and test an alternative method for quality control of sequencing libraries using droplet digital PCR (ddPCR). By exploiting a correlation we have discovered between droplet fluorescence and amplicon size, we achieve the joint quantification and size determination of target DNA with a single ddPCR assay. We demonstrate the accuracy and precision of applying this method to the preparation of sequencing libraries. PMID- 23931594 TI - A high-plex PCR approach for massively parallel sequencing. AB - Current methods for targeted massively parallel sequencing (MPS) have several drawbacks, including limited design flexibility, expense, and protocol complexity, which restrict their application to settings involving modest target size and requiring low cost and high throughput. To address this, we have developed Hi-Plex, a PCR-MPS strategy intended for high-throughput screening of multiple genomic target regions that integrates simple, automated primer design software to control product size. Featuring permissive thermocycling conditions and clamp bias reduction, our protocol is simple, cost- and time-effective, uses readily available reagents, does not require expensive instrumentation, and requires minimal optimization. In a 60-plex assay targeting the breast cancer predisposition genes PALB2 and XRCC2, we applied Hi-Plex to 100 ng LCL-derived DNA, and 100 ng and 25 ng FFPE tumor-derived DNA. Altogether, at least 86.94% of the human genome-mapped reads were on target, and 100% of targeted amplicons were represented within 25-fold of the mean. Using 25 ng FFPE-derived DNA, 95.14% of mapped reads were on-target and relative representation ranged from 10.1-fold lower to 5.8-fold higher than the mean. These results were obtained using only the initial automatically-designed primers present in equal concentration. Hi Plex represents a powerful new approach for screening panels of genomic target regions. PMID- 23931595 TI - Replacement of osmotic minipumps to extend the intracerebral infusion time of compounds into the mouse brain. AB - Osmotic minipumps represent a convenient and established method for targeted delivery of agents into the brain of small rodents. Agents unable to cross the blood brain barrier can be directly infused into the brain parenchyma or lateral ventricle through implanted cannulas. The small volume of the minipump reservoir typically limits the infusion time to 4-6 weeks. Pump changes with reattachment of a new pump reservoir to the cannula might lead to brain tissue irritation or increased intracranial pressure associated with hydrocephalus. Here, we describe a pump reservoir exchange technique using a Y-shaped connection piece (Y-con) between the infusion cannula and the pump reservoir. This allows repeated replacement of a subcutaneously installed pump reservoir for brain delivery of agents in mice. Experimental evaluation of Y-con pump replacement revealed no signs of tissue irritation or hydrocephalus and allowed extended controlled delivery of infusion agents in the brain. PMID- 23931596 TI - Mild hypothermia inhibits differentiation of human embryonic and induced pluripotent stem cells. AB - Culture of pluripotent stem cells at 35 degrees C strikingly reduces unwanted spontaneous differentiation during hESC and iPSC maintenance compared with 37 degrees C. Growth at 35 degrees C did not affect expression of pluripotency mRNAs nor induce expression of cold-inducible genes. Colony size was somewhat reduced at 35 degrees C. Thus, growth at 35 degrees C is a convenient, simple method to reduce the labor of removing spontaneously differentiated colonies when maintaining pluripotent cells. PMID- 23931597 TI - Low-cost media formulation for culture of brain tumor spheroids (neurospheres). AB - Recent studies have found that the biological features of primary tumors are faithfully recapitulated when a patient's tumor is processed and then maintained as a 3-D spheroid in specialized cell culture media. However, a major drawback for maintenance and routine passage of primary tumors as spheroids has been the high cost of custom-formulated media compared to regular serum-supplemented media. Here we report the formulation of a cost-effective, serum-free medium in which high-grade primary brain tumor (glioblastoma) explants can be established and maintained as spheroids. Based on DMEM, this formulation requires only supplementation with several amino acids, vitamins, synthetic EGF, and bFGF, with most of the cost being associated with the growth factors. A simple addition of BSA (fraction V) obviated the need for numerous other components (or human serum) commonly used in the specialized commercial media formulations. PMID- 23931598 TI - Relationship between different protein intake recommendations with muscle mass and muscle strength. AB - OBJECTIVE: The purpose of the present study was to examine the relationship between two different levels of protein intake (0.8 vs.1.2 g/kg body weight/day) with muscle mass and muscle strength. METHOD: Seventy-two postmenopausal women were recruited. Body composition (bioelectrical impedance analysis), muscle strength (dynamometer), energy metabolism (indirect calorimetry) and dietary intake (dietary journal) were measured. We divided the women into two groups. Women with a protein intake of >= 1.2 g/kg body weight/day were placed in the Protein >= 1.2 group (n = 35), whereas women with a protein intake of 0.8-1.19 g/kg body weight/day were categorized in the Protein 0.8-1.19 group (n = 32). RESULTS: No significant difference was observed between groups for age, height, skeletal muscle mass, resting energy expenditure, total energy expenditure, carbohydrate and lipid intake. Significant differences between groups were observed for body mass index (p < 0.001), fat mass (p < 0.001) and muscle strength (hand grip and knee extensors) (p < 0.001). More specifically, the Protein >= 1.2 group presented a higher muscle strength as well as a lower body mass index and fat mass compared to the Protein 0.8-1.19 group. In addition, the group with a protein intake of >= 1.2 g/kg body weight/day presented significantly higher energy intake (p = 0.002), and essential (p < 0.001) and non essential (p < 0.001) amino acid intake. Interestingly, when muscle strength was adjusted for essential or non-essential amino acids, differences in muscle strength persisted. CONCLUSION: The present study indicates higher levels of muscle strength in postmenopausal women with a protein intake of >= 1.2 g/kg body weight/day compared to 0.8-1.19 g/kg body weight/day despite no differences in muscle mass. PMID- 23931599 TI - Performance breakdown effects dissociate from error detection effects in typing. AB - Mistakes in skilled performance are often observed to be slower than correct actions. This error slowing has been associated with cognitive control processes involved in performance monitoring and error detection. A limited literature on skilled actions, however, suggests that preerror actions may also be slower than accurate actions. This contrasts with findings from unskilled, discrete trial tasks, where preerror performance is usually faster than accurate performance. We tested 3 predictions about error-related behavioural changes in continuous typing performance. We asked participants to type 100 sentences without visual feedback. We found that (a) performance before errors was no different in speed than that before correct key-presses, (b) error and posterror key-presses were slower than matched correct key-presses, and (c) errors were preceded by greater variability in speed than were matched correct key-presses. Our results suggest that errors are preceded by a behavioural signature, which may indicate breakdown of fluid cognition, and that the effects of error detection on performance (error and posterror slowing) can be dissociated from breakdown effects (preerror increase in variability). PMID- 23931601 TI - From the editor. AB - No abstract available for this article. PMID- 23931600 TI - Patterning and impregnation of superhydrophobic surfaces using aqueous solutions. AB - We report a solvent-assisted approach to the patterning and impregnation of porous superhydrophobic coatings that permits the use of entirely aqueous solutions. This approach permits immobilization of proteins and enzymes, creating opportunities to decorate superhydrophobic surfaces with hydrophilic domains and channels that can capture aliquots of aqueous media, guide and mix aqueous solutions, and chemically process streams of organic molecules. Because this approach does not require destruction of non-wetting features, it can also be used to transfer highly water-soluble polymers and small molecules without compromising superhydrophobicity, providing methods for post-fabrication loading of water-soluble agents into protective non-wetting coatings that are difficult to achieve using other approaches. PMID- 23931602 TI - Ethical perspectives on school-based practice: care, rights, justice, and compromise. AB - As the need for school-based therapy increases, so too do costs, and a growing public reluctance to pay for these services. This article examines the ethical complexities facing school-based therapists who must make hard choices about how best to allocate their time and skills to meet the needs of children living with disabilities. An actual case about the decision to reduce occupational therapy direct interventions provides the vehicle for articulating four different ethical perspectives. Hypothetical therapists respond to the case using the concepts and theoretical constructs from an Ethic of Care, Rights-Based Ethics, Justice, and Integrity-Preserving Compromise. PMID- 23931603 TI - NICU Treatment Team Function and Its Effect on Parental Stress. AB - Through a literature review this paper explores the operation of the NICU treatment team. It examines how the team's smooth functioning and family focus can effectively help the family cope with the stresses encountered in the birth of an infant with a critical medical condition. The paper progresses through a discussion of the following areas: (a) parental reactions to the birth of an infant with a chronic condition, and the causes of stress on the family unit, (b) the NICU environment and its part in parental stress, (c) stress factors for NICU treatment team members, (d) hospital culture and reducing stress through teamwork, (e) the role of the occupational therapist as a collaborator in the neonatal intensive care unit, and (f) reducing parental stress through the teamwork of family-centered care. The author concludes that a smoothly functioning treatment team, incorporating the principles of family-centered care, is essential to reducing parental stress and empowering the parent to take an active part in their infant's care. Involving the parent as an active member in a treatment team where interdependence and cooperation are fostered enables the parent to become confident in their own skills. It enables the parents to feel that they have some control over the situation and have an important role to play in the NICU process. PMID- 23931604 TI - A collaborative approach to meeting the need for quality personnel training in early intervention. AB - No abstract available for this article. PMID- 23931605 TI - The nature and diversity of problems leading to failure to thrive. AB - Failure to thrive increases a child's risk for developmental problems and warrants intensive intervention. At the same time, infants with failure to thrive and their families can present a complex number of issues that need to be addressed for successful outcome. The traditional approach which draws a distinction between organic and nonorganic failure to thrive does not reflect current work in the area and can be too simplistic to help the therapist develop an effective assessment and intervention strategy. This article examines the literature and presents a multi-systems model to organize the factors that can contribute to failure to thrive. By emphasizing the interactive nature of systems the occupational therapist will be able to identify the range of issues for assessment with multiple opportunities for intervention. PMID- 23931606 TI - Infants and children who fail to thrive: implications for occupational therapy practice. AB - Failure to thrive is a complex medical disorder characterized by impaired growth and often accompanied by developmental delay. The etiology of failure to thrive may be an organic problem, psychosocial factors within the environment, or a combination of both. The etiology of organic failure to thrive is a medical or constitutional problem. Nonorganic failure to thrive has been associated with various psychosocial factors, including disturbances in parent-child interaction and difficult infant temperament. As a member of the interdisciplinary medical team, the occupational therapist contributes to both the diagnosis and treatment of organic and nonorganic failure to thrive. PMID- 23931607 TI - The occupation of play: parent-child interaction in the service of social competence. AB - The occupation of play, as mutually engaged in by parents and young children, is theorized to be central to the development of social competence. Two conceptual heuristics, Vygotsky's zone of proximal development, and Gibson's affordances, frame this examination of play's role in the child's ability to generate adaptive responses and capitalize on environmental opportunities fostering social competence. Research describing mother-child interaction during play is used to illustrate the mother's orchestration and grading of social interactions to stretch the child's emerging abilities and optimize the child's performance. Finally, the practical application of these concepts and specific strategies which occupational therapists can use to "tune" their assistance to the needs of young children and to foster their development are described. PMID- 23931608 TI - Business planning: the key to success. AB - Entrepreneurial planning is the key to success in any business venture. For therapists, understanding and applying of business skills is a key component in the development of a successful idea. Critically analyzing, evaluating, and selecting opportunities are crucial for determining the potential success of a marketable concept. This article uses a case study to provide an overview of the steps involved for developing a school-based private practice. PMID- 23931609 TI - Comparison of parental attitudes towards their children as measured by the parent as a teacher inventory. AB - Occupational therapists work with children and their families to help children achieve their maximum potential. Therapists believe that parents' attitudes and beliefs have a significant impact upon a child's ability to succeed and that negative attitudes and beliefs can disrupt the success of treatment. This study examines the attitudes and beliefs of 30 parents whose children have cerebral palsy and compares them with 30 parents of children with no deficits. Parents completed the Parent as a Teacher Inventory which measures attitudes and beliefs of parents toward their children. The results of this study assist occupational therapists in more effectively designing and directing treatment for parents and children. PMID- 23931610 TI - A literature review of constructional performance in adults and children. AB - Occupational therapists often treat children with constructional difficulties. Constructional deficits have been extensively researched in the rehabilitation and neuropsychological literature on adults with brain damage. Little research has been conducted, however, on children's constructional disabilities. This paper provides a literature review on (1) how constructional functions are assessed in adults with brain damage and in typical and atypical children; (2) the development of constructional abilities in typical children; and (3) the similarities and differences in performance "errors" made by adults with brain damage and by typical and atypical children. It is hoped that the knowledge gained from these areas can help occupational therapists to better assess and treat children with constructional difficulties. Clinical implications and principles for intervention are suggested. PMID- 23931611 TI - Volatile heterometallic precursors for the low-temperature synthesis of prospective sodium ion battery cathode materials. AB - Heterometallic single-source precursors with a proper sodium:transition-metal ratio for nonoxide sodium ion battery cathode materials are reported. Heterometallic fluorinated beta-diketonates NaM(hfac)3 (M = Mn (1), Fe (2), Co (3), and Ni (4); hfac = hexafluoroacetylacetonate) have been obtained on a large scale, in high yield using a one-step reaction that employs commercially available reagents. The complexes are stable in open air and highly volatile. The mass spectrometric investigation indicates the existence of heterometallic molecules in the gas phase. The presence of heterometallic species in solutions of several solvents has been unambiguously confirmed. Heterometallic precursors were shown to exhibit clean, low-temperature decomposition in argon atmosphere that results in phase-pure perovskite fluorides NaMF3, the prospective cathode materials for sodium ion batteries. PMID- 23931612 TI - Diabetes voice. PMID- 23931613 TI - Faecal nitrogen excretion as an approach to estimate forage intake of wethers. AB - Data from twenty-two digestibility trials were compiled to examine the relationship between faecal N concentration and organic matter (OM) digestibility (OMD), and between faecal N excretion and OM intake (OMI) by wethers fed tropical or temperate forages alone or with supplements. Data set was grouped by diet type as follows: only tropical grass (n = 204), only temperate grass (n = 160), tropical grass plus supplement (n = 216), temperate grass plus supplement (n = 48), tropical grass plus tropical legume (n = 60) and temperate grass with ruminal infusion of tannins (n = 16). Positive correlation between OMD and either total faecal N concentration (Nfc, % of OM) or metabolic faecal N concentration (Nmetfc, % of OM) was significant for most diet types. Exceptions were the diet that included a tropical legume, where both relationships were negative, and the diet that included tannin extract, where the correlation between OMD and Nfc was not significant. Pearson correlation and linear regressions between OM intake (OMI, g/day) and faecal N excretion (Nf, g/day) were significant for all diet types. When OMI was estimated from the OM faecal excretion and Nfc-based OMD values, the linear comparison between observed and estimated OMI values showed intercept different from 0 and slope different from 1. When OMI was estimated using the Nf-based linear regressions, the linear comparison between observed and estimated OMI values showed neither intercept different from 0 nor slope different from 1. Both linear comparisons showed similar R(2) values (i.e. 0.78 vs. 0.79). In conclusion, linear equations are suitable for directly estimating OM intake by wethers, fed only forage or forage plus supplements, from the amount of N excreted in faeces. The use of this approach in experiments with grazing wethers has the advantage of accounting for individual variations in diet selection and digestion processes and precludes the use of techniques to estimate forage digestibility. PMID- 23931614 TI - Perifosine--a new option in treatment of acute myeloid leukemia? AB - INTRODUCTION: Perifosine is a novel targeted oral Akt inhibitor. In preclinical leukemia models, perifosine has an independent cytotoxic potential but also synergizes well with other rationally selected targeted agents. The evidence from clinical trials supporting the use of perifosine in the therapy of leukemias is limited. The optimal dose and schedule have yet to be defined. However, given its favorable toxicity profile and mechanism of action, the therapeutic potential of perifosine should be evaluated in well-designed clinical trials. AREAS COVERED: The role of the phosphatidylinositol-3 kinase (PI3K)/Akt zpathway in normal cells, cancer and leukemias is discussed. The mechanism of action of perifosine and the basic information on the development and chemical properties are summarized. The evidence from in vivo and in vitro studies is presented. The efficacy and side effect profile are summarized. EXPERT OPINION: The safety and tolerability profile of perifosine are satisfactory. The evidence from clinical trials in patients with leukemias is very limited. The preclinical data are encouraging. Perifosine has the potential to play a role in the treatment of leukemias in the future. Its role needs to be confirmed in clinical trials. PMID- 23931615 TI - Isolated congenital hereditary cataract in a dizygotic twin: prenatal ultrasonographic diagnosis. AB - Cataract, defined as opacity of the lens in one or both eyes, is a major cause of blindness throughout the world, and not uncommon, particularly in the elderly population. However, congenital cataracts are rare and occur with a frequency of 30 cases in 100,000 births. About one-third of the cases fall into the group inherited without systemic abnormality. Importantly, congenital cataracts produce deprivation amblyopia, refractive amblyopia, and retinal detachment, leading to lifelong visual impairment. Successful management is dependent on early diagnosis and referral for surgery when indicated. Here we present a case of hereditary bilateral cataracts in a dizygotic twin detected on prenatal ultrasound examinations and postnatally confirmed as congenital cataracts associated with posterior lenticonus. PMID- 23931616 TI - Incidence and clinicopathological characteristics of intraductal carcinoma detected in prostate biopsies: a prospective cohort study. AB - AIMS: Intraductal carcinoma of the prostate (IDC-P) is a distinct clinicopathological entity and is associated with aggressive, high-grade and high volume prostate carcinoma (PCa). The incidence, clinicopathological characteristics and prognostic significance of IDC-P have not been reported in prostate biopsies (PBx) that surgical pathologists encounter in their daily practice. METHODS AND RESULTS: In 1176 prospectively collected PBx, 33 IDC-P cases were identified (2.8%). The mean age of patients with IDC-P was 65 (range 46-79) years and mean serum prostate-specific antigen was 16.2 (range 0.4-105.6) ng/ml. Three (0.26%) IDC-P cases did not have a concomitant invasive PCa. Of 30 cases with concomitant invasive PCa, Gleason score was 7 in 16 (53.3%), 8 in four (13.3%) and 9 in 10 (33.3%) cases. The mean number of biopsy cores involved by PCa was 7.2 (range 1-14). Nine patients were treated with radical prostatectomy. Seminal vesicle invasion was found in four of nine (44%) cases, significantly higher than the risk of 12% predicted by Partin Tables (P = 0.016). CONCLUSIONS: This is the first prospective study that has investigated the incidence and prognostic significance of IDC-P diagnosed in PBx encountered in daily practice. It is critical for surgical pathologists to diagnose and report IDC-P in PBx. PMID- 23931617 TI - The status of occupational therapy education in the 90s'. AB - This review of the literature examines the status of occupational therapy education in the 90s'. As the millennium approaches, the American Occupational Therapy Association (AOTA) continues to play a pivotal role in supporting and monitoring occupational therapy (O.T.) training. There continues to be strong growth in the movement toward graduate occupational therapy education. The discipline of occupational science has been established, and serves as an academic basis for the profession of occupational therapy. Research efforts over the last decade have looked at a number of other areas of O.T. education. These include admissions, prerequisites, core requirements, instructional strategies, and clinical fieldwork training. There is evidence of a continued need for more research and monitoring in the area of occupational therapy education. This will assure the continued survival of the profession into the next century. PMID- 23931618 TI - A study of successful educational strategies in three entry-level graduate programs. AB - A naturalistic investigation in the area of Occupational Therapy (O.T.) graduate education was conducted. It examined the instructional strategies being employed at three existing graduate entry-level occupational therapy educational programs. The purpose of this study was to determine the educational strategies and approaches deemed most effective by the students and teachers at these institutions. On-site interviews were the key means of data collection. The results of the study show that students and faculty members value a number of facets and approaches to O.T. education. These include: (a) communication among students and faculty, (b) faculty clinical practice, (c) student participation and group experiences, (d) hands-on learning, (e) guest speakers, (f) fieldwork, (g) visual learning experiences, (h) theory, (i) purposeful activity, (j) research, and (k) medical/scientific knowledge. PMID- 23931619 TI - Successful educational strategies and the pyramid of occupational therapy learning. AB - This article provides further examination of research results described in the article called: "A Study of Successful Educational Strategies in Three Entry Level Graduate Programs." It aims to relate these study results to the literature. This report will also present an educational model, called the Pyramid of Occupational Therapy Learning, which was developed by the investigator. This pyramid is intended to be a guiding frame for graduate entry level instruction in occupational therapy. It illustrates the importance of four areas in the education of occupational therapists. These areas are: (a) student teacher commitment, trust, and communication, (b) medical/scientific knowledge, (c) holistic O.T. theories of human performance, and (d) application of O.T. theory to patient cases. Educators are encouraged to consider these factors when designing or refining their O.T. curricula. PMID- 23931620 TI - Determining the effectiveness of pencil grips: an electromyographical analysis. AB - Objective data regarding the effectiveness of various shaped pencil grips is not available to support the recommendations of such tools by occupational therapy practitioners. Eighteen right-hand dominant participants, ages 18 to 35 years, completed a writing sample using the three writing tools being tested: a standard #2 pencil with no grip, a standard #2 pencil with a triangular grip, and a standard #2 pencil with a pear-shaped grip. Surface electromyography was used to record the muscle activity in the four primary muscles used during handwriting to determine which writing tool elicited the least amount of motor unit recruitment. Although no significant difference was found, trends were noted that warrant further investigation to ensure practitioners recommend the appropriate pencil grip. PMID- 23931621 TI - A Clinician's Guide to Research Article Titles. PMID- 23931622 TI - Parasympathetic and sympathetic influences in neuro-occupation pertaining to play. AB - The occupation of play is a vital and necessary component of the developing child. Many factors underlie the overall ability of the child to engage in play, such as the physical and social environment and the child's desire for exploration. Using neuro-occupation as a foundational framework, the current paper addresses the relationship of play and the autonomic nervous system. The components of the autonomic nervous system are presented and basic neuronal pathways of the sympathetic and parasympathetic nervous systems are reviewed. The supportive role of the autonomic nervous system and specifically the sympathetic nervous system's response to stress is explained as it applies to the occupation of play. A case example is used to further illustrate the relationship of the autonomic nervous system and play as neuro-occupation. PMID- 23931623 TI - Synthesis of transition-metal steroid derivatives. PMID- 23931624 TI - Ultrasonographic examination in non-human primates with acute abdomen signs. AB - BACKGROUND: The acute abdomen is any abdominal disorder resulting in pain, shock, or sepsis. Although it has a multifactorial etiology, the primary cause is gastrointestinal tract pathology. The aim of this study was to assess the contribution of abdominal ultrasound as a complementary diagnostic tool in non human primates with an acute abdomen. METHODS: Three different non-human primates with clinical signs of acute abdomen were evaluated as follows: a chimpanzee (Pan troglodytes), a tufted capuchin (Cebus apella), and a black-tufted marmoset (Callithrix penicillata). RESULTS: Ultrasonographic examination assisted in the identification of a variety of differential diagnoses and was used in decision making for exploratory laparotomy, which was performed in two animals. Ultrasound examination confirmed the source of the acute abdomen as the gastrointestinal tract in the three animals studied. CONCLUSIONS: Abdominal ultrasound is a useful technique for the investigation of signs of acute abdomen in non-human primates. PMID- 23931625 TI - Effects of different doses of soy isoflavones on bone tissue of ovariectomized rats. AB - AIM: Studies report that hormone replacement prevents osteoporosis, but there are doubts whether isoflavones are really efficient in this process. The aim of this study was to evaluate the effects of different doses of soy isoflavones on bone tissue of ovariectomized rats. METHODS: Forty female rats at the age of 6 months were ovariectomized and, after 3 months, the animals were divided into four groups: GI - Control (treated with drug vehicle); GII - treated with isoflavones (80 mg/kg per day); GIII - treated with isoflavones (200 mg/kg per day) and GIV - treated with isoflavones (350 mg/kg per day). Soy isoflavones were administered by gavage for 90 consecutive days. After treatment, the rats were euthanized and their distal femurs were removed for histological routine, histochemistry and biochemical study. Histological sections were stained with hematoxylin-eosin or subjected to picrosirius red and alcian blue methods. Shafts of femurs were submitted to biochemical assay and tibias were subjected to biophysical and biomechanical tests. RESULTS: In distal femurs, the trabecular bone volume was higher in the groups treated with isoflavones, being higher in GIV, while the cortical bone width and the presence of mature type I collagen fibers were higher in GII. At the trabecular bone region, the percentage of total glycosaminoglycans (GAGs) was higher in GII and the percentage of only sulfated GAGs was higher in GIII, while the higher content of chondroitin sulfate in shafts of femurs was seen in GIV. Biophysical and biomechanical tests in tibias did not differ among the groups. CONCLUSION: Our data indicate that soy isoflavones improve bone quality in femurs of rats by increasing histomorphometric parameters, the content of GAGs and mature type I collagen fibers. These positive effects are dose dependent and it was different in cortical and trabecular bone. PMID- 23931626 TI - A pulmonary rehabilitation program reduces levels of anxiety and depression in COPD patients. AB - BACKGROUND: The presence of anxiety and depressive symptoms in COPD patients has been acknowledged for many years. The preponderance of recent studies supports the utility of pulmonary rehabilitation programs to reduce the levels of depression and anxiety in these patients. The aim of this study is to investigate possible changes in levels of anxiety and depression among patients enrolled in a pulmonary rehabilitation program, along with the role of disease severity in these changes. METHODS: In 101 COPD patients, who attended a pulmonary rehabilitation program, levels of trait anxiety (STAI) and depressive symptoms (BDI) were assessed at the beginning and at the end of the program. Age, sex, level of education in years and stage of disease severity were recorded. RESULTS: Our study included 80 male and 21 female patients. Mean age and mean education level were 64.1 +/- 8.1 and 11.3 +/- 4.1 years, respectively. Regarding COPD staging, 11 patients suffered from mild, 16 from moderate, 47 from severe and 27 from very severe COPD. Significant decreases in anxiety (from 39.7 to 34.0, p < 0.001) and depression rates (from 10.7 to 6.3, p < 0.001) were observed. A statistically significant reduction in anxiety and depression was revealed (p < 0.05)at all stages of COPD. CONCLUSION: Pulmonary rehabilitation programs should be offered to all COPD patients irrespective of disease severity, since they all lead to improvement in anxiety and depressive symptoms. PMID- 23931627 TI - Novel vaginal drug delivery system: deformable propylene glycol liposomes-in hydrogel. AB - Deformable propylene glycol-containing liposomes (DPGLs) incorporating metronidazole or clotrimazole were prepared and evaluated as an efficient drug delivery system to improve the treatment of vaginal microbial infections. The liposome formulations were optimized based on sufficient trapping efficiencies for both drugs and membrane elasticity as a prerequisite for successful permeability and therapy. An appropriate viscosity for vaginal administration was achieved by incorporating the liposomes into Carbopol hydrogel. DPGLs were able to penetrate through the hydrogel network more rapidly than conventional liposomes. In vitro studies of drug release from the liposomal hydrogel under conditions simulating human treatment confirmed sustained and diffusion-based drug release. Characterization of the rheological and textural properties of the DPGL-containing liposomal hydrogels demonstrated that the incorporation of DPGLs alone had no significant influence on mechanical properties of hydrogels compared to controls. These results support the great potential of DPGL-in-hydrogel as an efficient delivery system for the controlled and sustained release of antimicrobial drugs in the vagina. PMID- 23931628 TI - Comparison of transcriptional profiles between CD4+ and CD8+ T cells in HIV type 1-infected patients. AB - The CD4+/CD8+ T cell ratio is altered when HIV-1 infects the human immune system. However, the exact mechanisms of how CD4+ and CD8+T cells participate in HIV infection are still unknown. This study used bioinformatics methods to compare the transcriptional profiles between CD4+ and CD8+ T cells in HIV-1-infected patients in order to explore the potential molecular mechanisms of CD4+ and CD8+ T cells in HIV-1 infection. We found that expression patterns of differentially expressed genes (DEG) in CD4+T cells were dramatically different from those in CD8+ T cells. We also constructed protein-protein interaction (PPI) networks to extract functional modules at each stage, and found that some of the important genes such as BRCA1 were central hubs of the modules. Finally, we applied functional annotation to the modules and found that CD4+/CD8+ T cells played critical roles in regulating the cell cycle and other cellular pathways. Thus, this study would greatly further our understanding of the roles of T cells in HIV infection, and provide potential clues for developing AIDS vaccines in the future. PMID- 23931629 TI - The potential impact of new diagnostic criteria on the frequency of gestational diabetes mellitus in Sweden. AB - The International Association of Diabetes and Pregnancy Study Groups (IADPSG) has suggested new diagnostic criteria for gestational diabetes mellitus. Many centers in Europe still use the World Health Organization (WHO) criteria. In southern Sweden we use the 2-h threshold of the European Association for the Study of Diabetes criteria based on universal screening with a 75-g oral glucose tolerance test. We have retrospectively scrutinized oral glucose tolerance tests in a subset of 174 women included in a previous study, diagnosed with gestational diabetes mellitus 1996-1999. A complete repeat oral glucose tolerance test was performed directly after diagnosis in 120 women. When applying the current Swedish criteria, and the IADPSG and the WHO criteria to the material, gestational diabetes mellitus was confirmed in 67% (80/120), 84% (101/120), and 80% (96/120), respectively. Hence, 26% (101/80) more women were identified by the IADPSG criteria and 20% (96/80) more women by the WHO criteria, compared with the criteria presently in use. PMID- 23931630 TI - Development of an offline bidimensional high-performance liquid chromatography method for analysis of stereospecific triacylglycerols in cocoa butter equivalents. AB - Acyl migration is a serious problem in enzymatic modification of fats and oils, particularly in production of cocoa butter equivalent (CBE) through enzymatic acidolysis reaction, which leads to the formation of non-symmetrical triacylglycerols (TAGs) from symmetrical TAGs. Non-symmetrical TAGs may affect the physical properties of final products and are therefore often undesired. Consequently, an accurate method is needed to determine positional isomer TAGs during the production of CBE. A bidimentional high-performance liquid chromatography (HPLC) method with combination of non-aqueous reversed-phase HPLC and silver ion HPLC joining with an evaporative light scattering detector was successfully developed for the analysis of stereospecific TAGs. The best separation of positional isomer standards was obtained with a heptane/acetone mobile-phase gradient at 25 degrees C and 1 mL/min. The developed method was then used in multidimensional determination of the TAG positional isomers in fat and oil blends and successfully identified the TAGs and possible isomers in enzymatically acidolyzed CBE. PMID- 23931631 TI - Structural characterization of pyridylaminated oligosaccharides derived from neutral glycosphingolipids by high-sensitivity capillary electrophoresis-mass spectrometry. AB - High-sensitivity capillary electrophoresis-electrospray ionization quadrupole ion trap time-of-flight mass spectrometry (CE-ESI-QIT-TOF MS) was developed to structurally characterize four kinds of pyridylaminated (PA) oligosaccharides, i.e., lactose (Lac)-PA, globotriose (Gb3)-PA, globotetraose (Gb4)-PA, and IV(3) alphaGalNAc-Gb4 (Forssman antigen)-PA, derived from neutral glycosphingolipids. The CE-MS system included the head-column field-amplified sample stacking (HC FASS) method for effective sample injection into a capillary column in CE, a sheathless interface between CE and a mass spectrometer, and MS and tandem MS (MS(2)) measurements with narrow mass range repeated high-speed switching. The total sensitivity of the developed CE-MS system was about 20,000 times higher than that of the conventional CE-MS system consisting of pressure injection, a sheath-flow interface, and a wide mass range measurement. The MS and MS(2) spectra of the four PA-oligosaccharides at a concentration of 25 amol/MUL in mixtures (each 250 amol/10 MUL in a tube) clearly showed protonated molecular ions ([M + H](+)) and the fragment ions responsible for the sequential elimination of saccharides. The developed CE-MS system is a powerful method for the structural characterization of glycosphingolipids extracted from very small amounts of biological materials and could be extended to the structural characterization of oligosaccharides derived from glycoproteins. PMID- 23931632 TI - Unusual presentation of ocular tuberculosis: multiple chorioretinitis, retinal vasculitis and ischaemic central retinal vein occlusion. AB - A 54-year-old male patient presented with a sudden painless visual loss in his left eye. Ophthalmic examinations revealed panuveitis, ischaemic central retinal vein occlusion, multiple chorioretinitis and retinal vasculitis. The diagnosis of tuberculosis was confirmed with anterior tap analysis and QuantiFERON-TB test. Anti-tuberculosis treatment and intravitreal anti-vasculature endothelial growth factor therapy were performed. PMID- 23931633 TI - When does information about causal structure improve statistical reasoning? AB - Base rate neglect on the mammography problem can be overcome by explicitly presenting a causal basis for the typically vague false-positive statistic. One account of this causal facilitation effect is that people make probabilistic judgements over intuitive causal models parameterized with the evidence in the problem. Poorly defined or difficult-to-map evidence interferes with this process, leading to errors in statistical reasoning. To assess whether the construction of parameterized causal representations is an intuitive or deliberative process, in Experiment 1 we combined a secondary load paradigm with manipulations of the presence or absence of an alternative cause in typical statistical reasoning problems. We found limited effects of a secondary load, no evidence that information about an alternative cause improves statistical reasoning, but some evidence that it reduces base rate neglect errors. In Experiments 2 and 3 where we did not impose a load, we observed causal facilitation effects. The amount of Bayesian responding in the causal conditions was impervious to the presence of a load (Experiment 1) and to the precise statistical information that was presented (Experiment 3). However, we found less Bayesian responding in the causal condition than previously reported. We conclude with a discussion of the implications of our findings and the suggestion that there may be population effects in the accuracy of statistical reasoning. PMID- 23931635 TI - 2,2'-Bipyridine compounds of group 14 elements: a density functional theory study. AB - The molecular and electronic structures of the 2,2'-bipyridine containing series of group 14 compounds (a) [MF4(bpy)](0); (b) [MCl2(bpy)2](2+/0) (c) [MCl2(bpy)](0); (d) [M(bpy)2](2+/0); (e) [Si(bpy)3](1+,0,1-,2-); and (f) [M(bpy)3](0) (M = C, Si, Ge, Sn, Pb) have been calculated using density functional theory (DFT). Where possible, geometry optimized structures are compared with their experimentally determined structures. In general, good to excellent agreement is observed. It is shown that the three successive one electron reductions within the experimentally known series [Si(bpy)3](1+,0,1-,2-) are ligand-based and the Si center has a +IV oxidation state throughout. Hence, these species have the electronic structures [Si(IV)(bpy(*))3](+) (S = 1/2), [Si(IV)(bpy(*))2(bpy(2-))](0) (S = 0), [Si(IV)(bpy(*))(bpy(2-))2](-) (S = 1/2), and [Si(IV)(bpy(2-))3](2-) (S = 0). Similarly, it is shown that the crystallographically characterized compound [Si(bpy)2](0) (S = 0) possesses the electronic structure [Si(IV)(bpy(2-))2](0), which contains a tetravalent Si ion and two (bpy(2-))(2-) dianions. It should not be described as [Si(0)(bpy(0))2](0). For the heavier Ge, Sn, and Pb congeners the divalent state, characterized by a stereochemically active electron pair, becomes increasingly significant and dominates in 4-coordinate Sn and Pb species. PMID- 23931634 TI - Target-based drug discovery for human African trypanosomiasis: selection of molecular target and chemical matter. AB - Target-based approaches for human African trypanosomiasis (HAT) and related parasites can be a valuable route for drug discovery for these diseases. However, care needs to be taken in selection of both the actual drug target and the chemical matter that is developed. In this article, potential criteria to aid target selection are described. Then the physiochemical properties of typical oral drugs are discussed and compared to those of known anti-parasitics. PMID- 23931636 TI - Reduction in viscosity of quasi-2D-confined nanoimprint resin through the addition of fluorine-containing monomers: shear resonance study. AB - The fluidity of the resin for the nanoimprint lithography was investigated in a quasi-2D space by the shear resonance measurement, which enables us to measure the viscous property of the resin confined in a nanometer gap between mica surfaces. With this technique, we could observe that the resin fluidity was enhanced by the addition of the fluorine-containing monomer. The fluidity of the resin with the fluorine-containing monomer was maintained until the distance between mica surfaces became smaller than 15 nm, wheras the resin without the fluorine-containing monomer started losing its fluidity when the distance became 30 nm. Two reasons possibly explain the result; (i) the interaction between the resin and mica was reduced by the existence of the fluorine-containing segregated layer at the interface, and (ii) the reduction in viscosity took place by the addition of the fluorine-containing monomer that reduced the degree of chain entanglement in the resin because of its small intermolecular interaction force. The effect of the length of the perfluoroalkyl chain in the fluorine-containing monomer is also discussed. PMID- 23931637 TI - The role of mTOR inhibitors in the treatment of hepatocellular carcinoma. PMID- 23931638 TI - Abstracts of the 47th Annual Meeting of the German-Speaking Mycological Society (DMykG). September 5-7, 2013. Tubingen, Germany. PMID- 23931639 TI - Overdiagnosis of thyroid cancer and graves' disease. PMID- 23931640 TI - Endoparasites of the spiny mouse (Acomys spinosissimus) from South Africa. AB - The endoparasite fauna of the spiny mouse (Acomys spinosissimus) was studied for the first time from April 2007 until April 2009 in a population from the Limpopo Province of South Africa. In a total of 129 mice examined, only 6 endoparasite taxa were found, 2 nematode species (Syphacia minuta, Monanema joopi), 1 genus of cestodes ( Rodentolepis spp.), and unidentified hymenolepidid fragments. In addition, 1 pentastomid species (Armillifer grandis) as well as unidentified porocephalid specimens were recovered. The overall prevalence was low, at 15.5%, and only 1 individual harbored more than 1 parasite species. With 12.4% prevalence, S. minuta was the most prevalent parasite. Its prevalence and abundance were significantly higher during the dry and cooler season than during the wet and warm season, while a female-biased burden was observed during the wet season only. For the remaining parasite species, low prevalence prevented meaningful statistical analyses. The observed parasite species richness, prevalence, and abundance for A. spinosissimus were low compared to values reported for other Acomys spp. This may be linked to the lack of anthropogenic influences in the study population as well as the small size of A. spinosissimus . PMID- 23931641 TI - Heritability of resting state EEG functional connectivity patterns. AB - We examined the genetic architecture of functional brain connectivity measures in resting state electroencephalographic (EEG) recordings. Previous studies in Dutch twins have suggested that genetic factors are a main source of variance in functional brain connectivity derived from EEG recordings. In addition, qualitative descriptors of the brain network derived from graph analysis - network clustering and average path length - are also heritable traits. Here we replicated previous findings for connectivity, quantified by the synchronization likelihood, and the graph theoretical parameters cluster coefficient and path length in an Australian sample of 16-year-old twins (879) and their siblings (93). Modeling of monozygotic and dizygotic twins and sibling resemblance indicated heritability estimates of the synchronization likelihood (27-74%) and cluster coefficient and path length in the alpha and theta band (40-44% and 23 40% respectively) and path length in the beta band frequency (41%). This corroborates synchronization likelihood and its graph theoretical derivatives cluster coefficient and path length as potential endophenotypes for behavioral traits and neurological disorders. PMID- 23931642 TI - New insights into the role of aminopeptidases in the treatment for both preeclampsia and preterm labor. AB - INTRODUCTION: Evidence elucidating the pathophysiology and pharmacology of conventional drugs, beta-2 stimulants and magnesium sulfate, on safety and effectiveness for preeclampsia and preterm labor are rarely found. Both compounds pass through the placental barrier and could exert their adverse effects on the fetus. Exposure to these agents could be problematic long after the birth, and possibly result in diseases such as autism and cardiomyopathy. Since 1970 the possible roles of placental aminopeptidases, which degrade peptide hormones, in preeclampsia and preterm labor have been studied. AREAS COVERED: Many studies reveal that the fetus secretes peptide hormones, such as angiotensin II, vasopressin, and oxytocin, under hypoxia (stress) during the course of its growth, suggesting the critical effects these hormones have during pregnancy. The roles of placental aminopeptidases, the enzymes which degrade fetal hormones without passing through the placental barrier, were clarified. A first-step production system for recombinant aminopeptidases was established, by which engineered recombinant aminopeptidases were used for further experiments testing expected efficacy on controlling the level of hormones. EXPERT OPINION: The authors conclude that both aminopeptidase A and placental leucine aminopeptidase could be potentially safe and effective drugs for patients and their babies in the treatment of preeclampsia and preterm labor. PMID- 23931644 TI - Continuing Education: A Clinician's Guide to Monitoring and Promoting Competence. AB - The pressures of practice in a rapidly changing healthcare environment require therapists to maintain refined practice skills. Although continuing education is a commonly cited term, how it contributes to monitoring and promoting competence is often not discussed in detail. The purpose of this article is to describe three themes related to continuing education and competence that emerged in a review of the professional literature. These three themes are elements of competence, monitoring competence and methods to promote competence to assist clinicians in their own professional development. PMID- 23931643 TI - Eosinophil peroxidase in sputum represents a unique biomarker of airway eosinophilia. AB - BACKGROUND: Sputum eosinophilia has been shown to be a predictor of response to anti-eosinophil therapies in patients with airway diseases. However, quantitative cell counts and differentials of sputum are labor intensive. The objective of this study was to validate a novel ELISA-based assay of eosinophil peroxidase (EPX) in sputum as a rapid and reliable marker of airway eosinophils. METHODS: The utility of EPX-based ELISA as an eosinophil-specific assay was achieved through comparisons with sputum eosinophil differential counts in freshly prepared and archived patient samples from a variety of clinical settings. RESULTS: EPX levels in sputum correlated with eosinophil percentage (r(s) = 0.84) in asthma patients with varying degrees of airway eosinophilia. Significantly, unlike assays of other eosinophil granule proteins (e.g., ECP and EDN), which often detect the presence of these proteins even in asthma patients with neutrophilic bronchitis, EPX-based ELISA levels are not increased in this subset of asthma patients or in COPD patients lacking evidence of an airway eosinophilia. Moreover, sputum EPX was a surrogate marker of airway eosinophilia in other patient studies (e.g., allergen inhalation and treatment trials the anti (IL-5) therapeutic MepolizumabTM). Finally, EPX levels in cytocentrifuged prepared sputum supernatants correlated with those from rapidly prepared noncentrifuged filtrates of sputum (r(s) = 0.94). CONCLUSION AND CLINICAL IMPLICATION: EPX-based ELISA is a valid, reliable, repeatable, and specific surrogate marker of eosinophils and/or eosinophil degranulation in the sputum of respiratory patients. The novel EPX assay is a valid and reproducible eosinophil specific assay that can potentially be developed into a point-of-care assessment of eosinophil activity in airway secretions. PMID- 23931645 TI - Clinical Reasoning of a Novice versus an Experienced Occupational Therapist: A Qualitative Study. AB - The clinical reasoning process is an important aspect of occupational therapy practice. The purpose of this critical, focused ethnography was to compare the clinical reasoning process of an experienced and novice therapist. Individual semi-structured interviews were conducted with an experienced and a novice therapist after each had reviewed a sample case study to help elicit the clinical reasoning process. Observations in the clinical setting were conducted. Themes which emerged include definitions of clinical reasoning, sources used when reasoning, factors influencing clinical reasoning, ability to prioritize, patient viewed as an individual, patients' role in treatment, and clinical reasoning as an evolving process. Similarities and differences between the therapists are noted and discussed. Implications for practice, education, and future research are identified. PMID- 23931646 TI - A pilot study: attitudes toward leisure and leisure motivation in adults with spinal cord injury. AB - This pilot study explored the effect that an introduction to wheelchair sports would exert on attitudes and motivation toward leisure in a sample of adults with spinal cord injury. Individuals were tested using the Leisure Attitude Measurement (LAM) and the Leisure Motivation Scale (LMS) both before and after participating in a wheelchair sports program. Camp participants were demographically matched with a control group of persons who did not participate in a sports camp during the testing sessions. No significance was detected in within-group comparisons but high effect size and power on subscales of the LMS suggest a need for further studies. The experimental group, however, had significantly lower scores in stimulus avoidance as a leisure motivator which emphasizes the importance of social interaction in sports participation. PMID- 23931647 TI - The relationship between participation in a sports cAMP and students' attitudes towards persons with disabilities. AB - This study measured the attitudes of students before and after volunteering in a two-day camp for persons with disabilities. The Attitudes Toward Disabled Persons scale (ATDP) Form A was used to measure the attitudes of 54 university students in various health care majors. Twenty-five experimental group participants were volunteers at the camp. The students completed the scale three times: before, immediately following, and six weeks after the camp. The control group consisted of twenty-nine students and were administered the ATDP scale initially, then at one week and six weeks later during a scheduled health professions class. Results showed no significant difference in ATDP scores between groups and suggest that the camp alone was not a strong enough factor to produce a difference in attitudes. Further analysis did suggest that the camp may promote positive attitude changes for students with less positive attitudes initially, while not further changing the attitudes of students which were already positive. This study adds to the body of knowledge exploring different methods to change attitudes towards persons with disabilities and suggests that a camp could serve as a observation experience for students in occupational therapy curricula as a way to provide contact with persons with disabilities. PMID- 23931648 TI - Way station: a model of excellence in community mental health programs. AB - This article describes the services and programs of a community mental health center in Frederick, Maryland. Way Station was founded in 1978 by a small group of individuals who were committed to helping individuals with mental illness. Way Station follows the Club House philosophy which is based on treating the clients with mutual respect, understanding and accountability. Both the staff and clients work together in pursuit of rehabilitation goals in a very warm and accepting environment. In order to learn more about this exceptional mental health community, fifty staff members and clients were interviewed. Their thoughts and feelings are discussed in this article. PMID- 23931649 TI - A comparison study of the volar wrist cock-up splint and ulnar gutter splint in carpal tunnel syndrome. AB - The objective of the study was to compare the effects of the volar wrist cock-up splint and the ulnar gutter splint on three dependent measures: level of comfort, pain relief and hand function, in clients with early symptoms of carpal tunnel syndrome. Four clients with initial onset of carpal tunnel syndrome symptoms participated in a study with alternating treatment design that compared the effects of the two splints. Comfort and pain were measured with perceived analogue scales and hand function was assessed using six sub-tests of the Jebsen Hand Function test. Evaluations were done every 2 weeks concurrent with the alternation of the splints for a period of 8 weeks. Descriptive analysis was used to identify differences in the dependent measures. Three participants showed improved performance in hand function tests with reduced time taken in tests following use of splints. Three participants showed reduced pain after splint use. One participant did not show changes with time taken in hand function tests or with level of pain. The study showed clinical evidence that both the splints contributed to alleviation of carpal tunnel syndrome symptoms. It is imperative that more efficacy studies be done to gain more confidence with the results of this study. PMID- 23931650 TI - Morphology of non-sensory epithelium during post-natal development of the rabbit vomeronasal organ. AB - The vomeronasal organ (VNO), because of its ability to detect pheromones, has an important role in many social and sexual behaviours in mammals. It also mediates defensive behaviours through detection of protein pheromone homologues. A detailed morphological description of the post-natal development of the 'non sensory' epithelium (NSE) of the female rabbit is recorded. Histological techniques were used to study the NSE of the VNO in post-natal development of female rabbits. The study focused on the following post-natal ages: newborn, 1 week, 2 weeks and 1 month (five animals each) beside to two adult animals. The rabbit VNO was surrounded externally by bony capsule and internally by cartilaginous capsule. NSE was pseudostratified columnar partially ciliated epithelium without goblet cells. In addition to basal cells, NSE contained ciliated and three types of non-ciliated columnar cells (dark, pale and light). At birth, dark cells may have primary cilia. By 1 month, the cytoplasm became lighter with less free ribosomes. The pale cells had electron-lucent cytoplasm, which contained a few organelles. Mitotic figures were observed in basal and columnar cells, particularly during the first 2 weeks of post-natal development. Light columnar cells were common during the first week. Numerous leucocytes and a few nerve endings were detected intra-epithelial. Scanning electron microscope revealed a gradual increase in height of microvilli of non-ciliated cells. Ciliated cells had cilia and microvilli. Cells were arranged singly, in clumps or in a dense population of cells. The rabbit VNO-NSE had a unique morphological structure. PMID- 23931651 TI - Asthma and rhinitis in cleaning workers: a systematic review of epidemiological studies. AB - OBJECTIVE: This article presents a systematic review of epidemiological studies linking cleaning work and risk of asthma and rhinitis. METHODS: Published reports were identified from PubMed covering the years from 1976 through June 30, 2012. In total, we identified 24 papers for inclusion in the review. The quality of studies was evaluated using the Strengthening of the Reporting of Observational Studies in Epidemiology (STROBE) statement checklist of 22 items for cross sectional, cohort and case-control studies. RESULTS: Increased risk of asthma or rhinitis has been shown in 79% of included epidemiological studies. In four studies the increased risk of asthma in cleaning workers was confirmed by objective tests, such as bronchial hyper-reactivity or airflow obstruction. Level of exposure to cleaning products, cleaning sprays, bleach, ammonia, mixing products and specific job tasks has been identified as specific causes of asthma and rhinitis. CONCLUSIONS: Possible preventive measures encompass the substitution of cleaning sprays, bleach and ammonia, avoidance of mixing products, the use of respiratory protective devices, worker education and medical surveillance. PMID- 23931652 TI - East is east and West is west: perspectives on the menopause in Asia and The West. AB - There is a school of thought that believes that menopausal symptoms are a peculiarly 'Western' phenomenon, not experienced by women from other regions and particularly not from Asia where, it has been claimed, dietary, social and cultural factors afforded protection for women living in that region. More recently, studies conducted in multi-ethnic communities living in Western countries as well as in Asian communities have found that the menopause and its consequences are similar world-wide. Ethnic differences within Asia account for small differences in endogenous hormone levels and age at menopause between Asian and Western women, and the type of menopause symptoms and their prevalence also differ between those two communities. However, like in the West and perhaps because of a Western influence, the long-term health problems of postmenopausal women including cardiovascular disease, osteoporosis and breast cancer are of major importance to Asian women and health services in the 21st century. PMID- 23931653 TI - Forward light scatter and visual acuity through scratched protective eyewear. AB - BACKGROUND: Scratches and other surface abrasions on protective eyewear can shorten their life cycle by scattering light from the image, which will compromise visual performance. Although scratch and abrasion resistance testing is well developed, there is little information available regarding visual acuity through lenses scratched in an actual work environment. METHODS: We collected protective eyewear from mine and smelting operations that had been returned because vision through the lenses was unacceptable due to scratches and abrasions. Forward scattered light was measured on both cleaned and partially cleaned lenses using both haze and light diffusion measurements. Visual acuity through a selection of lenses was determined for both high and low contrast letters under photopic light levels. RESULTS: Lenses with scratches in the central region had haze values ranging from one to 30 per cent. The highest haze values were measured on lenses that were both scratched and covered with dirt, whereas haze values less than 10 per cent were measured on lenses that had the dirt removed and just had scratches in the central region. Light diffusion values were highly correlated with haze. Visual acuity for high and low contrast letters became worse as the percentage haze increased but the linear correlation was only moderate. CONCLUSION: The appearance of the scratches on the lens surfaces strongly suggests that they were a result of improper lens cleaning. The findings also suggest that haze values less than two per cent or a luminance reduction factor less than 3.0 cd/(m(2) lx) are unlikely to affect high and low contrast acuity. PMID- 23931654 TI - Acceptance of male circumcision among male rural-to-urban migrants in western China. AB - To describe the acceptability of male circumcision (MC) and explore potential factors associated with MC acceptability among male rural-to-urban migrants in western China, a cross-sectional survey of MC acceptability was conducted with 1,904 subjects in three western provinces with high HIV prevalence (Guangxi, Chongqing, and Xinjiang) in China between June 2009 and November 2009. Through face-to-face interviews, the participants completed a self-administered questionnaire about demographics, MC knowledge, willingness and reasons to accept or refuse MC, sexual behaviors, and other psychosocial variables. Factors associated with acceptability of MC were identified by multiple logistic regression analysis. Of the participants (n=1,904), 710 men were willing to accept MC (37.3%); the reasons included promotion of the partners' genital hygiene (54.9%), redundant prepuce or phimosis (43.1%), enhancement of sexual pleasure (40.6%), prevention of penile inflammation or cancer (35.5%), and protection against HIV and sexual transmitted diseases (STDs)(31.1%). A multivariable logistic regression showed that four factors were associated with acceptability of MC, including education level (OR=1.286, 95% CI=1.025~1.614), redundant prepuce or phimosis (OR=13.751, 95% CI=10.087~18.745), having one or more circumcised friends (OR=2.468, 95% CI=1.953~3.119), and having sexual intercourse with a temporary partner in the past year (OR=1.543, 95% CI=1.101~2.162). Compared with previously published data among the general population in China or worldwide, the acceptability of MC (37.3%) was low among the male rural-to-urban migrants in western China. Nevertheless, appropriate education could greatly improve the acceptability of MC. More public campaigns and health education on MC are needed to increase the rate of MC in China. PMID- 23931655 TI - Working memory supports inference learning just like classification learning. AB - Recent research has found a positive relationship between people's working memory capacity (WMC) and their speed of category learning. To date, only classification learning tasks have been considered, in which people learn to assign category labels to objects. It is unknown whether learning to make inferences about category features might also be related to WMC. We report data from a study in which 119 participants undertook classification learning and inference learning, and completed a series of WMC tasks. Working memory capacity was positively related to people's classification and inference learning performance. PMID- 23931658 TI - Asymmetric reduction of gold nanoparticles into thermoplasmonic polydimethylsiloxane thin films. AB - Polymer thin films containing gold nanoparticles (AuNPs) are of growing interest in photovoltaics, biomedicine, optics, and nanoelectromechanical systems (NEMs). This work has identified conditions to rapidly reduce aqueous hydrogen tetrachloroaurate (TCA) that is diffusing into one exposed interface of a partially cured polydimethylsiloxane (PDMS) thin film into AuNPs. Nanospheroids, irregular gold (Au) networks, and micrometer-sized Au conglomerates were formed in a ~5 MUm layer at dissolved TCA contents of 0.005, 0.05, and 0.5 mass percent, respectively. Multiscale morphological, optical, and thermal properties of the resulting asymmetric AuNP-PDMS thin films were characterized. Reduction of TCA diffusing into the interface of partially cured PDMS film increased AuNP content, robustness, and scalability relative to laminar preparation of asymmetric AuNP PDMS thin films. Optical attenuation and thermoplasmonic film temperature due to incident resonant irradiation increased in linear proportion to the order of magnitude increases in TCA content, from 0.005 to 0.05 to 0.5 mass percent. At the highest TCA content (0.05 mass percent), an asymmetric PDMS film 52-MUm-thick with a 7 MUm AuNP-containing layer was produced. It attenuated 85% of 18 mW of incident radiation and raised the local temperature to 54.5 degrees C above ambient. This represented an increase of 3 to 230-fold in photon-to-heat efficiency over previous thermoplasmonic AuNP-containing systems. PMID- 23931656 TI - Barriers to mental health treatment: results from the WHO World Mental Health surveys. AB - BACKGROUND: To examine barriers to initiation and continuation of mental health treatment among individuals with common mental disorders. METHOD: Data were from the World Health Organization (WHO) World Mental Health (WMH) surveys. Representative household samples were interviewed face to face in 24 countries. Reasons to initiate and continue treatment were examined in a subsample (n = 63,678) and analyzed at different levels of clinical severity. RESULTS: Among those with a DSM-IV disorder in the past 12 months, low perceived need was the most common reason for not initiating treatment and more common among moderate and mild than severe cases. Women and younger people with disorders were more likely to recognize a need for treatment. A desire to handle the problem on one's own was the most common barrier among respondents with a disorder who perceived a need for treatment (63.8%). Attitudinal barriers were much more important than structural barriers to both initiating and continuing treatment. However, attitudinal barriers dominated for mild-moderate cases and structural barriers for severe cases. Perceived ineffectiveness of treatment was the most commonly reported reason for treatment drop-out (39.3%), followed by negative experiences with treatment providers (26.9% of respondents with severe disorders). CONCLUSIONS: Low perceived need and attitudinal barriers are the major barriers to seeking and staying in treatment among individuals with common mental disorders worldwide. Apart from targeting structural barriers, mainly in countries with poor resources, increasing population mental health literacy is an important endeavor worldwide. PMID- 23931657 TI - Genetically encoded light-activated transcription for spatiotemporal control of gene expression and gene silencing in mammalian cells. AB - Photocaging provides a method to spatially and temporally control biological function and gene expression with high resolution. Proteins can be photochemically controlled through the site-specific installation of caging groups on amino acid side chains that are essential for protein function. The photocaging of a synthetic gene network using unnatural amino acid mutagenesis in mammalian cells was demonstrated with an engineered bacteriophage RNA polymerase. A caged T7 RNA polymerase was expressed in cells with an expanded genetic code and used in the photochemical activation of genes under control of an orthogonal T7 promoter, demonstrating tight spatial and temporal control. The synthetic gene expression system was validated with two reporter genes (luciferase and EGFP) and applied to the light-triggered transcription of short hairpin RNA constructs for the induction of RNA interference. PMID- 23931659 TI - The difficulty in defining extended donor criteria for liver grafts: the Eurotransplant experience. AB - Donor criteria for liver grafts have been expanded because of organ shortage. Currently, no exact definitions for extended donor grafts have been established. The aim of this study was to analyze the impact of donor-specific risk factors, independent of recipient characteristics. In collaboration with Eurotransplant and European Liver Transplant Register, solely donor-specific parameters were correlated with 1-year survival following liver transplantation. Analyses of 4701 donors between 2000 and 2005 resulted in the development of a nomogram to estimate graft survival for available grafts. Predictions by nomogram were compared to those by Donor Risk Index (DRI). In the multivariate analysis, cold ischemic time (CIT), highest sodium, cause of donor death, gamma-glutamyl transferase (gamma-GT), and donor sex (female) were statistically significant factors for 3 months; CIT, gamma-GT, and cause of donor death for 12-month survival. The median DRI of this study population was 1.45 (Q1: 1.17; Q3: 1.67). The agreement between the nomogram and DRI was weak (kappa = 0.23). Several donor specific risk factors were identified for early survival after liver transplantation. The provided nomogram will support quick organ quality assessment. Nevertheless, this study showed the difficulties of determining an exact definition of extended criteria donors. PMID- 23931660 TI - Breastfeeding rates and the relationship between breastfeeding and neonatal abstinence syndrome in women maintained on buprenorphine during pregnancy. AB - INTRODUCTION: Although a growing body of evidence suggests that buprenorphine is a safe alternative to methadone in the treatment of opioid-dependent pregnant women, little is known about breastfeeding in this population. The first objective of this study was to describe breastfeeding rates among opioid dependent pregnant women maintained on buprenorphine in an integrated medical and behavioral health program. The second objective was to determine whether breastfeeding is related to the duration, severity, and frequency of pharmacologic treatment for neonatal abstinence syndrome (NAS). METHODS: A retrospective chart review was conducted for all infants born to opioid-dependent pregnant women treated in the integrated buprenorphine program between December 2007 and August 2012. RESULTS: Eighty-five maternal-infant pairs were identified. Sixty-five women (76%) chose to breastfeed their infants after birth; of the women who initiated breastfeeding in the hospital, 66% were still breastfeeding 6 to 8 weeks postpartum. Although the data suggest that infants who were breastfed had less severe NAS (mean peak NAS, 8.83 vs 9.65 on a modified Finnegan Scoring System) and were less likely to require pharmacologic treatment (23.1% vs 30.0%) than infants who were not breastfed, these results were not statistically significant. DISCUSSION: More than three-quarters of the opioid-dependent pregnant women in this case series chose to breastfeed after birth. Although a direct comparison of care models is not possible, the integrated model of care potentially reduced some of the barriers to breastfeeding as the women accessed all their care in a single, infant-friendly setting. Further work is needed to definitively determine whether breastfeeding mitigates NAS. PMID- 23931662 TI - Increasing certified nurse-midwives' confidence in managing the obstetric care of women with female genital mutilation/cutting. AB - INTRODUCTION: In response to an increase in the number of women who immigrate to the United States from countries that practice female genital mutilation/cutting (FGM/C; infibulation), US clinicians can expand their knowledge and increase confidence in caring for women who have experienced infibulation. This article describes a comprehensive education program on FGM/C and the results of a pilot study that examined its effect on midwives' confidence in caring for women with infibulation. METHODS: An education program was developed that included didactic information, case studies, a cultural roundtable, and a hands-on skills laboratory of deinfibulation and repair. Eleven certified nurse-midwives (CNMs) participated in this pilot study. Participants completed a measure-of-confidence survey tool before and after the education intervention. RESULTS: Participants reported increased confidence in their ability to provide culturally competent care to immigrant women with infibulation when comparisons of preeducation and posteducation survey confidence logs were completed. DISCUSSION: Following the education program and the knowledge gained from it, these midwives were more confident about their ability to perform anterior episiotomy and to deliver necessary care to women with FGM/C in a culturally competent context. This education program should be expanded as more women who have experienced infibulation immigrate to the United States. PMID- 23931661 TI - Racial/ethnic differences in midlife women's attitudes toward physical activity. AB - INTRODUCTION: Women's racial/ethnic-specific attitudes toward physical activity have been pointed out as a plausible reason for their low participation rates in physical activity. However, very little is actually known about racial/ethnic commonalities and differences in midlife women's attitudes toward physical activity. The purpose of this study was to explore commonalities and differences in midlife women's attitudes toward physical activity among 4 major racial/ethnic groups in the United States (whites, Hispanics, African Americans, and Asians). METHODS: This was a secondary analysis of the qualitative data from a larger study that explored midlife women's attitudes toward physical activity. Qualitative data from 4 racial/ethnic-specific online forums among 90 midlife women were used for this study. The data were analyzed using thematic analysis, and themes reflecting commonalties and differences in the women's attitudes toward physical activity across the racial/ethnic groups were extracted. RESULTS: The themes reflecting the commonalities were: 1) physical activity is good for health, 2) not as active as I could be, 3) physical activity was not encouraged, 4) inherited diseases motivated participation in physical activity, and 5) lack of accessibility to physical activity. The themes reflecting the differences were: 1) physical activity as necessity or luxury, 2) organized versus natural physical activity, 3) individual versus family-oriented physical activity, and 4) beauty ideal or culturally accepted physical appearance. DISCUSSION: Developing an intervention that could change the social influences and environmental factors and address the women's racial/ethnic-specific attitudes would be a priority in increasing physical activity of racial/ethnic minority midlife women. PMID- 23931663 TI - Share with women. Miscarriage. PMID- 23931664 TI - Assessing the risk of alternative management strategies in a Mediterranean fishery: protecting the younger vs reducing fishing effort. AB - A stochastic age-structured population model was developed to explore biologically favourable levels of effort and closing periods within the sardine pelagic fishery in the eastern Mediterranean Sea. Results suggested that the developed age-structured model captured the observed biomass fluctuations and catches reasonably well and represents the first comprehensive investigation of alternative management strategies for eastern Mediterranean sardine fishery that include stochasticity. The present study provided direct evidence for the importance of the correct timing of the temporal fishing ban. Significant benefits were found both in terms of biomass and catch from a corrective shift in the fishing closed period. The current findings suggested that protecting the younger age groups from fishing in the period October-December, by shifting the ban period earlier than December may profit, biologically, the stock and economically the fishing sector. Progressive reductions in fishing mortality/effort also yield significant positive biological and fishery benefits in the short term. PMID- 23931665 TI - Water quality remediation faces unprecedented challenges from "legacy phosphorus". PMID- 23931667 TI - Authors' response to Canes. PMID- 23931668 TI - Mandatory continuing education: the future of occupational therapy professional development? AB - This literature review and analysis investigates continuing education in a variety of professions. It then examines the need for such legislative requirements in occupational therapy. Although there are some arguments which oppose the existence of mandatory continuing education requirements, they may be overshadowed by the many benefits which can be achieved by this type of decree. Currently, the state licensure board is the only mechanism that mandates continuing education requirements for occupational therapists. However, the National Board for Certification in Occupational Therapy (NBCOT) recently established the National Commission on Continuing Competency in Occupational Therapy. This body is currently developing national standards for continuing competency in occupational therapy. Nonetheless, occupational therapists in states where there are no mandatory continuing education requirements are encouraged to explore the potential benefits of such state regulations, and to work toward their implementation. PMID- 23931669 TI - Patterns of referral and intervention for persons with AIDS. AB - OBJECTIVE: This study identified reasons practitioners receive occupational therapy (OT) referrals for persons with AIDS (PWAs). Frequency of OT interventions and perceived priorities of PWAs at each Centers for Disease Control and Prevention (CDC) stage of the disease's progression were examined. METHOD: Surveys were sent to practitioners (N = 47) listed with AOTA having current or past work experience with PWAs. Twenty of the returned questionnaires were usable for analysis. Frequencies, ANOVAs, and weighted rank order statistics were used to bring meaning to the data. RESULTS: Significantly more referrals for OT services were received for PWAs in Stages 3 and 4 of the disease than Stages 1 and 2 (F = 43.99, df = 3, p <.001). Referrals for early stages of the disease focused on role status, and play/leisure activities. In the latter stages, referrals for cognitive/perceptual skills, adaptive equipment, and caregiver training were more frequent. Frequency of interventions used by practitioners tended to mirror referral patterns, as did the perceived priorities of the PWA. CONCLUSION: Reasons for referral and the interventions used with PWAs throughout the stages of the AIDS/HIV disease were similar to the perceived priorities of PWAs receiving services from OT practitioners, and reflected the typical symptoms experienced by PWAs at each CDC stage. PMID- 23931670 TI - Service dogs: a compensatory resource to improve function. AB - Objective. This study examined the physical, emotional, social, and economic functions of service dogs, the training methods for service dog/owner teams, and problems encountered with service dogs in relationship to occupational therapy literature and domain of concern. Method. A 31-question survey was developed based on the literature and Uniform Terminology (AOTA, 1994) and was completed by 202 service dog owners from 40 states and Canada. Results. Owners reported that service dogs assisted them in 28 functional tasks, helped them to feel safe, increased their social interaction, and reduced physical assistance by others. Problems with service dogs included difficulty with dog maintenance and public awareness of their role as a worker or assistant to the owner. Over 80% of respondents desired additional training in alternative ways to perform daily living tasks. Conclusion. The use of service dogs is consistent with the occupational therapy domain of concern and practice. Occupational therapists might collaborate with service dog trainers and potential owners in referral, assessment, training, and follow-up services. PMID- 23931671 TI - Nurse practitioners' knowledge of occupational therapy. AB - Objective. The purpose of this study was to determine what nurse practitioners (NPs) in western New York know about occupational therapy's (OT) roles and functions. Method. A self-designed survey of 27 questions was mailed to 150 randomly selected NPs in western New York who are members of New York State Coalition of Nurse Practitioners. A modified Dillman procedure was used for mailing the materials to the NPs. One hundred of the NPs responded. Results. The NPs have a broad general knowledge about OT although there are areas of uncertainty about the profession. Uncertainties about who formulates the patients' goals, who pays for OT, and aspects of OT, such as working with prosthetic devices, working with cardiovascular patients, working with young adults in prevocational and vocational skills, and making appropriate goals for elderly patients were identified. They also had limited awareness regarding the importance of OTs' contributions to patient care in certain work environments and regarding certain specialty areas. The results also suggested direct OT contact was their primary source of acquiring information about OT and also was the most beneficial method for their learning. Conclusion. This study may help to shape OTs' efforts in educating NPs since it identifies the areas of uncertain knowledge and the ways in which their information is best obtained. Some strategies for increasing NPs' understanding of OT include presenting information about OT at an NP conference, role playing or lecturing during the NPs' final clinical course, and direct discussions about cases regarding patient progress. PMID- 23931672 TI - 1H NMR derived metabolomic profile of neonatal asphyxia in umbilical cord serum: implications for hypoxic ischemic encephalopathy. AB - Neonatal hypoxic ischemic encephalopathy (HIE) is a severe consequence of perinatal asphyxia (PA) that can result in life-long neurological disability. Disease mechanisms, including the role and interaction of individual metabolic pathways, remain unclear. As hypoxia is an acute condition, aerobic energy metabolism is central to global metabolic pathways, and these metabolites are detectable using 1H NMR spectroscopy, we hypothesized that characterizing the NMR derived umbilical cord serum metabolome would offer insight into the consequences of PA that lead to HIE. Fifty-nine at-risk infants were enrolled, together with 1:1 matched healthy controls, and stratified by disease severity (n=25, HIE; n=34, non-HIE PA). Eighteen of 37 reproducibly detectable metabolites were significantly altered between study groups. Acetone, 3-hydroxybutyrate, succinate, and glycerol were significantly differentially altered in severe HIE. Multivariate data analysis revealed a metabolite profile associated with both asphyxia and HIE. Multiple-linear regression modeling using 4 metabolites (3 hydroxybutyrate, glycerol, O-phosphocholine, and succinate) predicted HIE severity with an adjusted R2 of 0.4. Altered ketones suggest that systemic metabolism may play a critical role in preventing neurological injury, while altered succinate provides a possible explanation for hypoxia-inducible factor 1 alpha (HIF-1alpha) stabilization in HI injury. PMID- 23931673 TI - Prevalence and predictors of maternal postpartum depressed mood and anhedonia by race and ethnicity. AB - Aims. Depression requires the presence of either depressed mood or anhedonia, yet little research attention has been focused on distinguishing these two symptoms. This study aimed to obtain the prevalence rates of these two core depression symptoms and to explore the risk factors for each symptom by race/ethnicity. Methods. 2423 White, African American, Hispanic and Asian/Pacific Islander (API) women from the Massachusetts area completed the Pregnancy Risk Assessment Monitoring System (PRAMS) from 2007 to 2008. Results. Socioeconomic variables (SES) accounted for increased rates in depressed mood and anhedonia among African Americans and Hispanics compared with Whites. API women were still 2.1 times more likely to report anhedonia after controlling for SES. Stressors were associated with depressed mood across groups and associated with anhedonia for Whites and Hispanics. Having a female infant was associated with depressed mood for APIs. Being non-US born was associated with anhedonia for Whites, APIs and African Americans, but not Hispanics. Conclusions. Prevalence rates for depressed mood and anhedonia differ across race/ethnic groups and risks associated with depressed mood and anhedonia depend on the race/ethnic group, suggesting the importance of distinguishing depressed mood from anhedonia in depression assessment and careful inquiry regarding symptom experiences with a diverse patient population. PMID- 23931674 TI - Association of hospitalizations for asthma with seasonal and pandemic influenza. AB - BACKGROUND AND OBJECTIVE: Although influenza has been associated with asthma exacerbations, it is not clear the extent to which this association affects health care use in the United States. The first goal of this project was to determine whether, and to what extent, the incidence of asthma hospitalizations is associated with seasonal variation in influenza. Second, we used influenza trends (2000-2008) to help predict asthma admissions during the 2009 H1N1 influenza pandemic. METHODS: We identified all hospitalizations between 1998 and 2008 in the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project during which a primary diagnosis of asthma was recorded. Separately, we identified all hospitalizations during which a diagnosis of influenza was recorded. We performed time series regression analyses to investigate the association of monthly asthma admissions with influenza incidence. Finally, we applied these time series regression models using 1998-2008 data, to forecast monthly asthma admissions during the 2009 influenza pandemic. RESULTS: Based on time series regression models, a strong, significant association exists between concurrent influenza activity and incidence of asthma hospitalizations (P-value < 0.0001). Use of influenza data to predict asthma admissions during the 2009 H1N1 pandemic improved the mean squared prediction error by 60.2%. CONCLUSIONS: Influenza activity in the population is significantly associated with asthma hospitalizations in the United States, and this association can be exploited to more accurately forecast asthma admissions. Our results suggest that improvements in influenza surveillance, prevention and treatment may decrease hospitalizations of asthma patients. PMID- 23931675 TI - Liver function test changes in centrally obese youth with metabolic syndrome in a Serbian population. AB - OBJECTIVE: The aim of this study was to investigate the association between metabolic syndrome and liver enzymes in overweight and obese adolescents and young adults. METHODS: A total of 126 overweight and obese adolescents and young adults (age, 15-26 years), 55 (43.6%) with metabolic syndrome and 71 (56.4%) without metabolic syndrome, were studied. RESULTS: Patients with metabolic syndrome had significantly higher alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP) levels compared to patients without metabolic syndrome [36.5+/-22.2 vs. 29.4+/-17.8 IU/L (P=0.043), 33.8+/ 17.8 vs. 26.9+/-18.4 IU/L (P=0.002), and 84.3+/-32.2 vs. 75.7+/-29.5 IU/L (P=0.063)]. Aspartate aminotransferase (AST) levels were similar in both groups (24.1+/-9.8 vs. 23.3+/-9.0 IU/L, P=0.674). Elevated AST, ALT, GGT, and ALP levels were observed in 6, 15, 18, and 5 patients (11%, 27%, 14%, and 9%) with metabolic syndrome compared to 6, 17, 6, and 4 (8%, 24%, 8% and 5%) patients without metabolic syndrome (P=0.872, P=0.826, P<0.001, and P=0.035). In multivariate regression models adjusted for age and gender, metabolic syndrome was not a significant predictor of ALT (P=0.967), GGT (P=0.526), and ALP levels (P=0.221), but insulin resistance was a significant predictor for ALT and GGT levels (P=0.001, P=0.028). CONCLUSION: Changes in liver function tests were observed in obese patients with metabolic syndrome, compared to patients without metabolic syndrome, especially in ALT and GGT levels. Insulin resistance is an independent pathogenic mechanism in liver function test changes regardless of metabolic syndrome in nondiabetic centrally obese youth. PMID- 23931676 TI - Pharmacokinetics and effect of intravenous nalbuphine in weaned Holstein calves after surgical castration. AB - The objective of this study was to investigate the pharmacokinetics and effect of nalbuphine administered intravenously to calves immediately prior to surgical castration. Ten healthy calves were randomly assigned to two treatments (n = 5): (i) 0.9% sodium chloride (CONT) placebo, (ii) nalbuphine hydrochloride (NAL) (0.4 mg/kg). Blood samples collected over 10 h postcastration were analyzed for nalbuphine and cortisol concentrations. Additionally, heart rate, respiratory rate, rectal temperature, and step count was compared between groups using a random-effects mixed model. Changes in behavior and attitude were assessed using a six-point ordinal scoring system and compared using chi-square analysis. Plasma NAL concentrations were only detectable for 3 h postadministration (T1/2 = 0.68 h; Range: 0.53-0.79 h). There was no effect of NAL treatment prior to castration on cortisol concentrations (P = 0.99), heart rate (P = 0.73), respiratory rate (P = 0.59), rectal temperature (P = 0.22), and step count (P = 0.08) but fewer calves showed signs of head shaking, kicking, and tail flicking in the NAL group compared with the CONT group (P = 0.036). Therefore, we conclude that a single intravenous injection of nalbuphine at 0.4 mg/kg reduced some pain-related behaviors but did not significantly eliminate the physiological signs of distress in calves after surgical castration. PMID- 23931677 TI - Regional specialisation of the ganglion cell density in the retina of the native duck (Anas platyrhynchos) of Bangladesh. AB - In this study, retinal whole-mount specimens were prepared and stained with 0.1% cresyl violet for the ganglion cell study in the native duck (Anas platyrhynchos). The total number, distribution and size of these cells were determined in different retinal regions. The mean total number of ganglion cells was 1 598 501. The retinal area centralis had the highest ganglion cell density with 11 200 cells/mm(2) . Number of ganglion cell bodies was the highest in temporal area, followed by dorsal, nasal and ventral areas. Ganglion cell size ranged from 5.25 to 80 MUm(2) . In the temporal and nasal region, most of the cells were ranged from 15 to 25 MUm(2) , and in the dorsal and ventral region, most of the cells were ranged from 12 to 25 MUm(2) . There was a marked trend for the retinal ganglion cell size to increase as the population density decrease towards the periphery. A population of small ganglion cells persisted into the central area just above the optic disc and the largest soma area was in the ventral zone of the retina. Thus, the specialisation of ganglion cell densities and their sizes support the notion that the conduction of visual information towards the brain from all regions of the retina is not uniform, and the central area is the fine quality area for vision in native duck. PMID- 23931678 TI - Bovine milk fat globule membrane proteins are affected by centrifugal washing processes. AB - The impact of washing on the release of proteins from the milk fat globule membrane (MFGM) was examined by applying washing procedures with different degrees of stringency to milk fat globule (MFG) surfaces in simulated milk ultrafiltrate buffer solution. Three washing methods, M1 (3000g, 5 min, three washes), M2 (3750g, 15 min, one wash), and M3 (15000g, 20 min, three washes) were chosen. MFG zeta-potential increased after M3 washing (P < 0.05), suggesting surface damage. For M1, in which the native MFG surface was least damaged, cluster of differentiation 36 (CD 36) and periodic acid schiff 6/7 proteins were more strongly bound to the MFGM compared with other major membrane proteins. For M3, CD 36 together with fatty acid-binding protein was more strongly bound to the MFGM. Washing by centrifugation and redispersal of the fat globules damaged the MFGM, with release into the aqueous phase of some membrane-associated proteins. The current results show the impact of washing processes on retention of functional MFGM proteins. PMID- 23931680 TI - Multiple recurrent sinus of valsalva aneurysms. AB - We report a case of multiple unruptured sinus of Valsalva aneurysms in an adult patient over nine years. PMID- 23931679 TI - Chronic traffic pollution exposure is associated with eosinophilic, but not neutrophilic inflammation in older adult asthmatics. AB - OBJECTIVE: Airway inflammatory patterns in older asthmatics are poorly understood despite high asthma-related morbidity and mortality. In this study, we sought to define the relationship between exposure to traffic pollutants, biomarkers in induced sputum, and asthma control in older adults. METHODS: Induced sputum was collected from 35 non-smoking adults >=65 years with a physician's diagnosis of asthma and reversibility with a bronchodilator or a positive methacholine challenge. Patients completed the Asthma Control Questionnaire (ACQ), and Elemental Carbon Attributable to Traffic (ECAT), a surrogate for chronic diesel particulate exposure, was determined. Equal numbers of subjects with high (>=0.39 ug/m(3)) versus low (<0.39 ug/m(3)) ECAT were included. Differential cell counts were performed on induced sputum, and myeloperoxidase (MPO) and eosinophil peroxidase (EPO) were measured in supernatants. Regression analyses were used to evaluate the relationship between sputum findings, ACQ scores, and ECAT. RESULTS: After adjustment for potential confounders, subjects with poorly controlled asthma based on ACQ >= 1.5 (n = 7) had significantly higher sputum eosinophils (median = 4.4%) than those with ACQ < 1.5 (n = 28; eosinophils = 2.6%; beta = 10.1 [95% CI = 0.1-21.0]; p = 0.05). Subjects with ACQ >= 1.5 also had significantly higher sputum neutrophils (84.2% versus 65.2%; beta = 7.1 [0.2 14.6]; p = 0.05). Poorly controlled asthma was associated with higher sputum EPO (beta = 2.4 [0.2-4.5], p = 0.04), but not MPO (p = 0.9). High ECAT was associated with higher eosinophils (beta = 10.1 [1.8-18.4], p = 0.02) but not higher neutrophils (p = 0.6). CONCLUSIONS: Poorly controlled asthma in older adults is associated with eosinophilic and neutrophilic inflammation. Chronic residential traffic pollution exposure may be associated with eosinophilic, but not neutrophilic inflammation in older asthmatics. PMID- 23931681 TI - A graphene oxide-based fluorescent biosensor for the analysis of peptide-receptor interactions and imaging in somatostatin receptor subtype 2 overexpressed tumor cells. AB - Analysis of peptide-receptor interactions provides insights for understanding functions of proteins in cells. In this work, we report the development of a fluorescent biosensor for the analysis of peptide-receptor interactions using graphene oxide (GO) and fluorescein isothiocyanate (FITC)-labeled octreotide (FOC). Octreotide is a synthesized cyclic peptide with somatostatin-like bioactivity that has been clinically employed. FOC exhibits high adsorption affinity for GO, and its binding results in efficient fluorescence quenching of FITC. Interestingly, the specific binding of the antibody anti-octreotide (AOC) with FOC competitively releases FOC from the GO surface, leading to the recovery of fluorescence. By using this GO-based fluorescent platform, we can detect AOC with a low detection limit of 2 ng/mL. As a step further, we employ this GO-FOC biosensor to image somatostatin receptor subtype 2 overexpressed AR42J tumor cells, which demonstrates high promise for molecular imaging in cancer diagnosis. PMID- 23931682 TI - Improving outcomes after coronary artery bypass surgery: lessons from indigenous Australians. PMID- 23931683 TI - Sex with women among men who have sex with men in China: prevalence and sexual practices. AB - Men who have sex with men and women (MSMW) are a potential bridge population for transmitting HIV to heterosexual women. This study assessed key characteristics of this subgroup of men who have sex with men (MSM) in China. Of 1141 eligible MSM, 45.6% reported bisexual behaviors. Besides marriage as a strong predictor (odds ratio: 23.90, 95% confidence interval: 14.29-39.98), older age (1.12, 1.10 1.15) and lower education (or no college education) (1.98, 1.52-2.59) were also independently associated with having ever had sex with women. MSMW reported higher proportions of alcohol drinking, heterosexual/bisexual orientation, and preference for an insertive role in anal sex than men who had sex with men only; but there was no statistically significant difference between two groups in prevalence of HIV and syphilis infections and in history of sexually transmitted infections. HIV prevention intervention programs should break the bridging role of HIV transmission in MSMW population. PMID- 23931684 TI - Comparative cost analysis of generalized anxiety disorder and major depressive disorder patients in secondary care from a national hospital registry in Finland. AB - BACKGROUND: Major depressive disorder (MDD) has shown to cause high costs to society. Earlier research indicates that generalized anxiety disorder (GAD) also causes high costs, but only limited data is available in varying settings. AIMS: To analyse the secondary care costs of GAD compared with those of MDD. METHODS: Retrospective database analysis from Finnish Hospital Discharge Registers (FHDR). All GAD and MDD patients diagnosed between 1 January 2007 and 31 December 2007 in FHDR were recorded and individual-level secondary care costs during a 48-month follow-up period were measured. RESULTS: The total mean cost of GAD with history of MDD or some other anxiety disorder was significantly higher than that of MDD with history of GAD or some other anxiety disorder during the 48-month follow-up period. The costs of pure GAD were comparable with those of pure MDD, but after adjusting for age and sex, the costs of pure MDD were higher than those of pure GAD. CONCLUSIONS: The economic burden of individual GAD patients is comparable with that of MDD patients in secondary care. PMID- 23931685 TI - Computational de novo design and characterization of a protein that selectively binds a highly hyperpolarizable abiological chromophore. AB - This work reports the first example of a single-chain protein computationally designed to contain four alpha-helical segments and fold to form a four-helix bundle encapsulating a supramolecular abiological chromophore that possesses exceptional nonlinear optical properties. The 109-residue protein, designated SCRPZ-1, binds and disperses an insoluble hyperpolarizable chromophore, ruthenium(II) [5-(4'-ethynyl-(2,2';6',2"-terpyridinyl))-10,20 bis(phenyl)porphinato]zinc(II)-(2,2';6',2"-terpyridine)(2+) (RuPZn) in aqueous buffer solution at a 1:1 stoichiometry. A 1:1 binding stoichiometry of the holoprotein is supported by electronic absorption and circular dichroism spectra, as well as equilibrium analytical ultracentrifugation and size exclusion chromatography. SCRPZ-1 readily dimerizes at micromolar concentrations, and an empirical redesign of the protein exterior produced a stable monomeric protein, SCRPZ-2, that also displayed a 1:1 protein:cofactor stoichiometry. For both proteins in aqueous buffer, the encapsulated cofactor displays photophysical properties resembling those exhibited by the dilute RuPZn cofactor in organic solvent: femtosecond, nanosecond, and microsecond time scale pump-probe transient absorption spectroscopic data evince intensely absorbing holoprotein excited states having large spectral bandwidth that penetrate deep in the near-infrared energy regime; the holoprotein electronically excited triplet state exhibits a microsecond time scale lifetime characteristic of the RuPZn chromophore. Hyper Rayleigh light scattering measurements carried out at an incident irradiation wavelength of 1340 nm for these holoproteins demonstrate an exceptional dynamic hyperpolarizabilty (beta1340 = 3100 * 10(-30) esu). X-ray reflectivity measurements establish that this de novo-designed hyperpolarizable protein can be covalently attached with high surface density to a silicon surface without loss of the cofactor, indicating that these assemblies provide a new approach to bioinspired materials that have unique electro-optic functionality. PMID- 23931686 TI - Specific detection of inflamed cells using TLR1 antibody and its secondary antibody-conjugated nano-beads. AB - Chronic inflammation can lead to several diseases, thus analysis of the inflammation state of live cells may have important clinical applications. However, there is not currently well-established method for specific detection of inflamed cells via live cell imaging. In this study, we developed an effective antibody (Ab)-based cell imaging method for the detection of inflamed cells using Ab-conjugated nano-beads. Several receptors were tested as potential biomarkers for cell inflammation, and corresponding fluorescence-labeled Abs and/or Ab conjugated nano-beads were used to detect inflamed cells via fluorescence imaging. Interestingly, when we employed sequential use of TLR1 primary Ab and size-optimized nano-beads conjugated with secondary Ab, we were able to clearly discriminate inflamed cells from normal ones. The Ab-based cell-imaging method described herein provides an important basis for the development of high throughput analysis of cell inflammation, potentially leading to the identification of factors involved in inflammation and anti-inflammatory drug candidates. PMID- 23931687 TI - Growth and metabolic activity of conventional and non-conventional yeasts immobilized in foamed alginate. AB - The aim of this research was to study how the cell immobilization technique of forming foamed alginate gels influences the growth, vitality and metabolic activity of different yeasts. Two distinct strains were used, namely conventional yeast (exemplified by Saccharomyces cerevisiae) and a non-conventional strain (exemplified by Debaryomyces occidentalis). The encapsulation of the yeast cells was performed by the traditional process of droplet formation, but from a foamed alginate solution. The activities of two key enzymes, succinate dehydrogenase and pyruvate decarboxylase, together with the ATP content were measured in both the free and immobilized cells. This novel method of yeast cell entrapment had some notable effects. The number of living immobilized cells reached the level of 10(6)-10(7) per single bead, and was stable during the fermentation process. Reductions in both enzyme activity and ATP content were observed in all immobilized yeasts. However, S. cerevisiae showed higher levels of ATP and enzymatic activity than D. occidentalis. Fermentation trials with immobilized repitching cells showed that the tested yeasts adapted to the specific conditions. Nevertheless, the mechanical endurance of the carriers and the internal structure of the gel need to be improved to enable broad applications of alginate gels in industrial fermentation processes, especially with conventional yeasts. This is one of the few papers and patents that describe the technique of cell immobilization in foamed alginate and shows the fermentative capacities and activities of key enzymes in immobilized yeast cells. PMID- 23931688 TI - Coenzyme A-acylating propionaldehyde dehydrogenase (PduP) from Lactobacillus reuteri: kinetic characterization and molecular modeling. AB - 3-Hydroxypropionic acid (3-HP), an important C3 chemical for a bio-based industry, is natively produced by Lactobacillus reuteri from glycerol. Conversion of glycerol occurs via the intermediate 3-hydroxypropionaldehyde (3-HPA), followed by an ATP-producing pathway initiated by the CoA-acylating propionaldehyde dehydrogenase (PduP). The pduP gene of L. reuteri was cloned and expressed in Escherichia coli and the recombinant enzyme was purified to homogeneity for characterization of its activity and properties. Kinetic studies with propionaldehyde as substrate showed a maximum specific activity of 28.9 U/mg, which is 80-fold higher than that reported previously. Maximum activity of 18 U/mg was obtained at 3-HPA concentration of 7 mM, above which substrate inhibition was observed. Substrate inhibition was also seen with coenzyme A at a concentration above 0.5mM and with NADP(+) above 9 mM. A structure of PduP is proposed based on homology modeling. In silico docking of the co-factors coenzyme A and NAD(+), respectively, showed a common binding site consisting of amino acids Thr145, Ile275, Cys277 and Ser417, which through site-directed mutagenesis to alanine and kinetic studies, were confirmed as essential for the catalytic activity of PduP. PMID- 23931689 TI - Role of a highly conserved proline-126 in ThDP binding of Mycobacterium tuberculosis acetohydroxyacid synthase. AB - Acetohydroxyacid synthase (AHAS) of Mycobacterium tuberculosis is a promising target for the development of anti-tuberculosis agents. With the absence of an available bacterial AHAS crystal structure, that of M. tuberculosis, site directed mutagenesis has been a useful tool for determining its structural and functional features. In this study, a highly conserved proline residue (P126 of M. tuberculosis AHAS) was selected, and the possible role was evaluated by site directed mutagenesis. P126 was replaced by valine, threonine, alanine, and glutamate to yield P126V, P126T, P126A, and P126E, respectively. All variants were expressed in their soluble forms in Escherichia coli and purified to near homogeneity. The molecular mass (SDS-PAGE) of the purified variants was ~68 kDa, which is similar to that of wild-type AHAS. The P126V, P126T, and P126A variants exhibited significantly lower activity than wild-type AHAS, whereas P126E was inactive under the tested assay conditions. Furthermore, the P126V and P126T variants showed a significantly decreased preference toward pyruvate and ThDP as substrate and cofactor respectively, whereas the P126A showed similar kinetics to that of wild-type AHAS. Like in AHAS from yeast Saccharomyces cerevisiae (PDB ID: 1N0H), residue P126 is located in the ThDP binding pocket of M. tuberculosis AHAS homology model. Collectively, these results suggest that the conserved P126 plays a significant role in the ThDP binding of M. tuberculosis AHAS. PMID- 23931690 TI - Simultaneous production of cellulase and reducing sugar through modification of compositional and structural characteristic of sugarcane bagasse. AB - This study examined the potential of untreated and alkali-pretreated sugarcane bagasse (SCB) in cellulase, reducing sugar (RS) and fungal biomass production via solid state fermentation (SSF) using Pycnoporus sanguineus. The impact of the composition, structure and cellulase adsorption ability of SCB on the production of cellulase, RS and fungal biomass was investigated. From the morphological and compositional analyses, untreated SCB has relatively more structural changes with a higher percentage of depolymerisation on the cellulose, hemicellulose and lignin content compared to alkali-pretreated SCB. Thus, untreated SCB favoured the production of cellulase and fungal biomass whereas alkali-pretreated SCB yielded a higher amount of RS. The composition and morphology of untreated SCB did not encourage RS production and this suggested that RS produced during SSF might be consumed in a faster rate by the more abundantly grown fungus. Besides that, alkali-pretreated SCB with higher cellulase adsorption ability could have adsorbed the cellulase produced and resulted in a lower cellulase titre. In short, the production of specific bioproducts via SSF is dependent on the structure and composition of the substrate applied. PMID- 23931691 TI - BOD biosensor based on the yeast Debaryomyces hansenii immobilized in poly(vinyl alcohol) modified by N-vinylpyrrolidone. AB - An amperometric biosensor for assessing the biochemical oxygen demand (BOD) was formed by immobilizing Debaryomyces hansenii VKM Y-2482 yeast cells in poly(vinyl alcohol) modified by N-vinylpyrrolidone. Modification provided for a high sensitivity and stability of the bioreceptor. A high oxidative activity of the receptor element and the absence of any toxic effect of assayed compounds were shown for 34 substrates (alcohols, carbohydrates, carboxylic acids, amino acids, nitrophenols and surfactants) that may occur in wastewaters. Estimates of the measurement range and region of the linear dependence of signals on the BOD level, pH and temperature sensitivities, dependences of signals on concentrations of salts, stability, Michaelis kinetic constants and assay rates were obtained. The BOD values determined by the biosensor in assayed wastewater samples were shown to have a high correlation with those obtained by the standard dilution method. PMID- 23931692 TI - Alkaline lipase from Pseudomonas fluorescens non-covalently immobilised on pristine versus oxidised multi-wall carbon nanotubes as efficient and recyclable catalytic systems in the synthesis of Solketal esters. AB - In order to produce effective and recyclable catalysts for enantioselective transesterification in the industrial applications, alkaline lipase from Pseudomonas fluorescens was non-covalently immobilised (ca. 6 wt%) on pristine multi-wall carbon nanotubes (MWCNTs) and oxidised MWCNTs (O-MWCNTs) using an adsorption technique. Mesoporous silica modified with n-octyl groups was used as a reference support. Irreversible transesterifications of three vinyl esters (acyl donors) by racemic Solketal with a chromatographically (GC) traced kinetics were selected as model reactions. The undertaken comparative studies revealed that different morphology and chemical functionalisation of the supports led to various enzyme loadings, catalytic activities and enantioselectivities. MWCNT lipase emerged as the exceptionally active (yield up to 98%, t=1h, 1320 Ug(-1), i.e. 9 times more active than native enzyme) whereas lipase immobilised on O MWCNTs as the most enantioselective system, particularly for longer acyl chain esters (e.e. up to 72% after 30 min at yield of 20%, 340 Ug(-1)). Moreover, the activity of all nanotube-based catalysts after 10 cycles of transesterification remained practically unchanged. The differences in performance of MWCNTs and O MWCNTs as solid supports were found to be based on geometry of pores, dominating hydrophobic interactions and absence/presence of the surface polar groups. Due to an excellent activity and reusability of the nanotube-lipase catalysts one can propose (O-)MWCNT as supports of a prospective industrial relevance. PMID- 23931693 TI - Kinetic study of a novel thermo-stable alpha-carbonic anhydrase for biomimetic CO2 capture. AB - Biomimetic CO2 capture includes environmentally friendly solutions based on carbonic anhydrase (CA), an enzyme that increases CO2 absorption rate in conventional acid-gas scrubbing processes. The present contribution reports the characterization of a new recombinant carbonic anhydrase, SspCA, isolated from the thermophile bacterium Sulphurhydrogenibium yellowstonense sp. YO3AOP1. The kinetics of SspCA was characterized in terms of first order CO2 hydration rate according to a procedure based on CO2 absorption tests in a stirred cell apparatus. The first order kinetic constant at 25 degrees C was 9.16 * 10(6) L/(mols). An appropriate investigation on SspCA stability was carried out to assess its long-term resistance to high temperatures as in all capture processes based on absorption/vacuum-desorption cycles. Its half-life was 53 and 8 days at 40 degrees C and 70 degrees C, respectively. PMID- 23931694 TI - Modulation of enzyme catalytic properties and biosensor calibration parameters with chlorides: studies with glucose oxidase. AB - We studied the modulation of calibration parameters of biosensors, in which glucose oxidase was used for bio-recognition, in the presence of different chlorides by following the transient phase dynamics of oxygen concentration with an oxygen optrode. The mechanism of modulation was characterized with the changes of the glucose oxidase catalytic constant and oxygen diffusion constant. The modulation of two biosensor calibration parameters were studied: the maximum calculated signal change was amplified for about 20% in the presence of sodium and magnesium chlorides; the value of the kinetic parameter decreased along with the addition of salts and increased only at sodium chloride concentrations over 0.5 mM. Besides glucose bioassay, the amplification of calibration parameters was also studied in cascaded two-enzyme lactose biosensor, where the initial step of lactose bio-recognition, the beta-galactosidase - catalyzed lactose hydrolysis, was additionally accelerated by magnesium ions. PMID- 23931695 TI - A self-sufficient Baeyer-Villiger biocatalysis system for the synthesis of E caprolactone from cyclohexanol. AB - In order to establish a new route for E-caprolactone production from the corresponding cyclohexanol with an internal cofactor recycling for NADPH, a recently redesigned thermostable polyol dehydrogenase (PDH) and the cyclohexanone monooxygenase (CHMO) from Acinetobacter calcoaceticus were combined. First, the expression of PDH could be improved 4.9-fold using E. coli C41 with co-expression of chaperones. Both enzymes were also successfully co-immobilized on glutaraldehyde-activated support (RelizymeTM HA403). Cyclohexanol could be converted to E-caprolactone (E-CL) with 83% conversion using the free enzymes and with 34% conversion using the co-immobilized catalysts. Additionally, a preparative scale biotransformation of E-caprolactone starting from cyclohexanol was performed using the soluble enzymes. The E-CL could be isolated by simple extraction and evaporation with a yield of 55% and a purity of >99%. PMID- 23931696 TI - Direct biocatalytic one-pot-transformation of cyclohexanol with molecular oxygen into E-caprolactone. AB - The development of a biocatalytic process concept for E-caprolactone, which directly converts cyclohexanol as an easily available industrial raw material into the desired E-caprolactone in a one-pot fashion while only requiring air as sole reagent, is reported. The desired product E-caprolactone was obtained with 94-97% conversion when operating at a substrate concentration in the range of 20 60 mM. At higher substrate concentrations, however, a significant drop of conversion was found. Subsequent detailed studies on the impact of the starting material, intermediate and product components revealed a significant inhibition and partial deactivation of the BVMO by the product E-caprolactone (in particular at higher concentrations) as well as an inhibition of the BVMO by cyclohexanol and cyclohexanone. PMID- 23931697 TI - Phase transitions and phase miscibility of mixed particles of ammonium sulfate, toluene-derived secondary organic material, and water. AB - The phase states of atmospheric particles influence their roles in physicochemical processes related to air quality and climate. The phases of particles containing secondary organic materials (SOMs) are still uncertain, especially for SOMs produced from aromatic precursor gases. In this work, efflorescence and deliquescence phase transitions, as well as phase separation, in particles composed of toluene-derived SOM, ammonium sulfate, and water were studied by hygroscopic tandem differential mobility analysis (HTDMA) and optical microscopy. The SOM was produced in the Harvard Environmental Chamber by photo oxidation of toluene at chamber relative humidities of <5 and 40%. The efflorescence and deliquescence relative humidities (ERH and DRH, respectively, studied by HTDMA) of ammonium sulfate decreased as the SOM organic fraction epsilon in the particle increased, dropping from DRH = 80% and ERH = 31% for epsilon = 0.0 to DRH = 58% and ERH = 0% for epsilon = 0.8. For epsilon < 0.2, the DRH and ERH to first approximation did not change with the organic volume fraction. This observation is consistent with independent behaviors for epsilon < 0.2 of water-infused toluene-derived SOM and aqueous ammonium sulfate, suggesting phase immiscibility between the two. Optical microscopy of particles prepared for epsilon = 0.12 confirmed phase separation for RH < 85%. For epsilon from 0.2 to 0.8, the DRH and ERH values steadily decreased, as studied by HTDMA. This result is consistent with one-phase mixing of ammonium sulfate, SOM, and water. Optical microscopy for particles of epsilon = 0.8 confirmed this result. Within error, increased exposure times of the aerosol in the HTDMA from 0.5 to 30 s affected neither the ERH(epsilon) nor DRH(epsilon) curves, implying an absence of kinetic effects on the observations over the studied time scales. For epsilon > 0.5, the DRH values of ammonium sulfate in mixtures with SOM produced at <5% RH were offset by -3 to -5% RH compared to the results for SOM produced at 40% RH, suggesting differences in SOM chemistry. The observed miscibility gap (i.e., phase separation) between toluene-derived SOM and aqueous ammonium sulfate across a limited range of organic volume fractions differentiates this SOM from previous reports for isoprene-derived SOM of full miscibility and for alpha-pinene-derived SOM of nearly full immiscibility with aqueous ammonium sulfate. PMID- 23931698 TI - Adsorption and desorption of methylene blue on porous carbon monoliths and nanocrystalline cellulose. AB - The dynamic batch adsorption of methylene blue (MB), a widely used and toxic dye, onto nanocrystalline cellulose (NCC) and crushed powder of carbon monolith (CM) was investigated using the pseudo-first- and -second-order kinetics. CM outperformed NCC with a maximum capacity of 127 mg/g compared to 101 mg/g for NCC. The Langmuir isotherm model was applicable for describing the binding data for MB on CM and NCC, indicating the homogeneous surface of these two materials. The Gibbs free energy of -15.22 kJ/mol estimated for CM unravelled the spontaneous nature of this adsorbent for MB, appreciably faster than the use of NCC (-4.47 kJ/mol). Both pH and temperature exhibited only a modest effect on the adsorption of MB onto CM. The desorption of MB from CM using acetonitrile was very effective with more than 94 % of MB desorbed from CM within 10 min to allow the reusability of this porous carbon material. In contrast, acetonitrile was less effective than ethanol in desorbing MB from NCC. The two solvents were incapable of completely desorbing MB on commercial granular coal-derived activated carbon. PMID- 23931699 TI - Comparative risk of venous thromboembolism between total knee and hip replacement: a 10-year nationwide population-based study in Taiwan. PMID- 23931702 TI - Older adults' perceptions of home telehealth services. AB - The success of home telemedicine depends on end-user adoption, which has been slow despite rapid advances in technological development. This study focuses on an examination of significant factors that may predict the successful adoption of home telemedicine services (HTS) among older adults. Based on previous studies in the fields of remote patient monitoring, assisted living technologies, and consumer health information technology acceptance, eight factors were identified as a framework for qualitative testing. Twelve focus groups were conducted with an older population living in both urban and rural environments. The results reveal seven predictors that play an important role in perceptions of HTS: perceived usefulness, effort expectancy, social influence, perceived security, computer anxiety, facilitating conditions, and physicians' opinion. The results provide important insights in the field of older adults' acceptance of HTS, with guidelines for the strategic planning, developing, and marketing of HTS for the graying market. PMID- 23931701 TI - Valorization of cereal based biorefinery byproducts: reality and expectations. AB - The growth of the biobased economy will lead to an increase in new biorefinery activities. All biorefineries face the regular challenges of efficiently and economically treating their effluent to be compatible with local discharge requirements and to minimize net water consumption. The amount of wastes resulting from biorefineries industry is exponentially growing. The valorization of such wastes has drawn considerable attention with respect to resources with an observable economic and environmental concern. This has been a promising field which shows great prospective toward byproduct usage and increasing value obtained from the biorefinery. However, full-scale realization of biorefinery wastes valorization is not straightforward because several microbiological, technological and economic challenges need to be resolved. In this review we considered valorization options for cereals based biorefineries wastes while identifying their challenges and exploring the opportunities for future process. PMID- 23931703 TI - Correlations between milk and plasma levels of amino and carboxylic acids in dairy cows. AB - The objective of this study was to investigate the relationship between the concentrations of 19 amino acids, glucose, and seven carboxylic acids in the blood and milk of dairy cows and their correlations with established markers of ketosis. To that end, blood plasma and milk specimens were collected throughout lactation in two breeds of dairy cows of different milk yield. Plasma concentrations of glucose, pyruvate, lactate, alpha-aminobutyrate, beta hydroxybutyrate (BHBA), and most amino acids, except for glutamate and aspartate, were on average 9.9-fold higher than their respective milk levels. In contrast, glutamate, aspartate, and the Krebs cycle intermediates succinate, fumarate, malate, and citrate were on average 9.1-fold higher in milk than in plasma. For most metabolites, with the exception of BHBA and threonine, no significant correlations were observed between their levels in plasma and milk. Additionally, milk levels of acetone showed significant direct relationships with the glycine to-alanine ratio and the BHBA concentration in plasma. The marked decline in plasma concentrations of glucose, pyruvate, lactate, and alanine in cows with plasma BHBA levels above the diagnostic cutoff point for subclinical ketosis suggests that these animals fail to meet their glucose demand and, as a consequence, rely increasingly on ketone bodies as a source of energy. The concomitant increase in plasma glycine may reflect not only the excessive depletion of protein reserves but also a potential deficiency of vitamin B6. PMID- 23931704 TI - A systematic review of studies performing the hypo-osmotic swelling test to evaluate the quality of canine spermatozoa. AB - The hypo-osmotic swelling test (HOS test) is a simple and inexpensive test to evaluate the functional integrity of sperm cell membranes. According to the existing literature, its simple applicability has turned it into a valuable additional parameter to standard canine semen analysis. In the recent years, much research has been conducted in this field. The aim of this systematic review was to evaluate the quality of published literature in canine reproduction concerning the HOS test. Using two distinguished databases, 38 articles were detected and analysed subsequently according to various aspects, for example study design, population, semen sampling and implementation concerning the HOS test. Although there are numerous articles available, the diagnostic value of the HOS test remains ambiguous. Until now, neither a recognized test protocol nor reliable reference values have been defined. Most of the trials evaluated show serious methodological flaws and therefore do not permit drawing reliable conclusions. According to our results, approximately half of the studies (n = 20) included a sample size of five or less animals. None of the studies examined the inter- or intraobserver agreement for the HOS test. Further research is warranted including appropriate statistical methods and a sufficient number of animals to establish a standardized test protocol as well as reliable reference values. Most importantly, it is required to clarify a correlation between the HOS test and the fertilizing capacity to determine the diagnostic value of the HOS test. PMID- 23931706 TI - The effects of therapeutic riding on sitting posture in individuals with disabilities. AB - This study describes the effects of therapeutic horseback riding on the sitting posture of individuals with disabilities. Three participants (ages 10-40) with various disabilities were recruited from a therapeutic riding center in the Midwest. The researchers took measures of the sitting posture of these participants before and after an eight week therapeutic riding program. Posture measures were taken using a super VHS video-camera and motion analysis equipment. The video data was analyzed using Peak Motus 32 motion analysis software. Angles were calculated from the sitting posture of participants, and analyzed for any change from pre-test to post-test periods. Findings showed significant changes in four of the eight measures of sitting posture, which suggests a positive effect of therapeutic riding on sitting posture in people with physical disabilities. Future research is recommended with a larger subject pool and inclusion of a control group to validate the effects of therapeutic riding. Research is also suggested to further establish the validity of motion analysis equipment as a quantitative measure of posture. PMID- 23931705 TI - Neural substrates of behavioral variability in attention deficit hyperactivity disorder: based on ex-Gaussian reaction time distribution and diffusion spectrum imaging tractography. AB - BACKGROUND: Increased intra-individual variability (IIV) in reaction time (RT) across various tasks is one ubiquitous neuropsychological finding in attention deficit hyperactivity disorder (ADHD). However, neurobiological underpinnings of IIV in individuals with ADHD have not yet been fully delineated. The ex-Gaussian distribution has been proved to capture IIV in RT. The authors explored the three parameters [MU (mu), sigma (sigma), tau (tau)] of an ex-Gaussian RT distribution derived from the Conners' continuous performance test (CCPT) and their correlations with the microstructural integrity of the frontostriatal-caudate tracts and the cingulum bundles. METHOD: We assessed 28 youths with ADHD (8-17 years; 25 males) and 28 age-, sex-, IQ- and handedness-matched typically developing (TD) youths using the CCPT, Wechsler Intelligence Scale for Children, 3rd edition and magnetic resonance imaging (MRI). Microstructural integrity, indexed by generalized fractional anisotropy (GFA), was measured by diffusion spectrum imaging tractrography on a 3-T MRI system. RESULTS: Youths with ADHD had larger sigma (s.d. of Gaussian distribution) and tau (mean of exponential distribution) and reduced GFA in four bilateral frontostriatal tracts. With increased inter-stimulus intervals of CCPT, the magnitude of greater tau in ADHD than TD increased. In ADHD youths, the cingulum bundles and frontostriatal integrity were associated with three ex-Gaussian parameters and with MU (mean of Gaussian distribution) and tau, respectively; while only frontostriatal GFA was associated with MU and tau in TD youths. CONCLUSIONS: Our findings suggest the crucial role of the integrity of the cingulum bundles in accounting for IIV in ADHD. Involvement of different brain systems in mediating IIV may relate to a distinctive pathophysiological processing and/or adaptive compensatory mechanism. PMID- 23931707 TI - Understanding occupational therapy: nursing and physician assistant students' knowledge about occupational therapy. AB - The purpose of this study was to discover whether nursing and physician's assistant students at a large Midwestern university get a sufficient overview in their professional curriculums about the role of occupational therapy and its implications in healthcare services. These professionals play an important role in the prescription of occupational therapy (OT). Attempts at targeting these populations for marketing the OT profession and increasing the awareness of its various roles is of critical value to the OT profession. This study involved a two part survey consisted of scaled and open-ended questions asking what the students know about OT, how they learned about the profession, and a checklist testing their actual knowledge level about occupational therapy's role in the healthcare system. Correlation between section one and section two of the survey was done to understand whether students who believe they are educated about the role of OT are in fact knowledgeable about the profession. Even though a low positive correlation was found between the physician assistant students' perceived knowledge of OT and their actual knowledge, the results were not statistically significant. It was also found that most students in both the nursing and physician's assistant curriculums responded to occupational therapy's role within a very narrow scope, consisting of mainly activities of daily living (ADLs). The authors emphasize the need for targeting other health professions for marketing OT. PMID- 23931708 TI - Understanding the issue of home adaptation: searching for a conceptual framework. AB - It is by now standard practice for occupational therapists to be involved in the elimination of architectural barriers, particularly in the home setting, for a person using a wheelchair. In order to expand understanding of the issues related to home adaptation, the occupational therapist would be well served by having reference to a conceptual framework and to an assessment tool. Various studies of the person-environment model have been reviewed, and those, whose orientation can be related to the home adaptation situation, have been analyzed. The present discussion points to the need for a new theoretical model which would better serve occupational therapists toward a broader understanding of the varied home adaptation issues. PMID- 23931709 TI - Validation of the fieldwork evaluation for the occupational therapist. AB - The psychometric properties of the Fieldwork Evaluation for the Occupational Therapist were examined, in particular the evidence supporting the independent use of the performance, attitude, and judgment scales to determine suitability for entry-level work. High levels of internal consistency were found on all of the scales and on the Evaluation as a whole, a reflection of the high correlations among items. A factor analysis was performed that suggested that the Evaluation primarily measures a single factor. PMID- 23931710 TI - The effects of chronic illness on roles and emotions of caregivers. AB - Approximately one fourth of the population is affected by chrome illness or disability (Schuster and Ashburn, 1992). It has been reported that caregivers of individuals with chronic illness or disability have feelings that were associated with their caregiving role. Olshansky (1962) described and termed these feelings "chronic sorrow." This study looked at the intensity of chronic sorrow in caregivers of adults with mental illness, geriatric and pediatric individuals with chronic illnesses. We also examined the possible relationship between the caregiver's roles and the intensity of chronic sorrow they experienced. The feelings of caregivers were analyzed at different stages during the caretaking period. Using quantitative measures this study determined that chronic sorrow can linger well past diagnosis and that there are trigger events that can increase chronic sorrow. Armed with this knowledge occupational therapists can make interventions that will more fully address the client and caregivers needs. PMID- 23931712 TI - Xanthomonas filamentous hemagglutinin-like protein Fha1 interacts with pepper hypersensitive-induced reaction protein CaHIR1 and functions as a virulence factor in host plants. AB - Pathogens have evolved a variety of virulence factors to infect host plants successfully. We previously identified the pepper plasma-membrane-resident hypersensitive-induced reaction protein (CaHIR1) as a regulator of plant disease- and immunity-associated cell death. Here, we identified the small filamentous hemagglutinin-like protein (Fha1) of Xanthomonas campestris pv. vesicatoria as an interacting partner of CaHIR1 using yeast two-hybrid screening. Coimmunoprecipitation and bimolecular fluorescence complementation experiments revealed that Fha1 specifically interacts with CaHIR1 in planta. The endocytic tracker FM4-64 staining showed that the CaHIR1-Fha1 complex localizes in the endocytic vesicle-like structure. The X. campestris pv. vesicatoria Deltafha1 mutant strain exhibited significantly increased surface adherence but reduced swarming motility. Mutation of fha1 inhibited the growth of X. campestris pv. vesicatoria and X. campestris pv. vesicatoria DeltaavrBsT in tomato and pepper leaves, respectively, suggesting that Fha1 acts as a virulence factor in host plants. Transient expression of fha1 and also infiltration with purified Fha1 proteins induced disease-associated cell death response through the interaction with CaHIR1 and suppressed the expression of pathogenesis-related (PR) genes. Silencing of CaHIR1 in pepper significantly reduced DeltaavrBsT growth and Fha1 triggered susceptibility cell death. Overexpression of fha1 in Arabidopsis retarded plant growth and triggered disease-associated cell death, resulting in altered disease susceptibility. Taken together, these results suggest that the X. campestris pv. vesicatoria virulence factor Fha1 interacts with CaHIR1, induces susceptibility cell death, and suppresses PR gene expression in host plants. PMID- 23931713 TI - Birth of an abstraction: a dynamical systems account of the discovery of an elsewhere principle in a category learning task. AB - Human participants and recurrent ("connectionist") neural networks were both trained on a categorization system abstractly similar to natural language systems involving irregular ("strong") classes and a default class. Both the humans and the networks exhibited staged learning and a generalization pattern reminiscent of the Elsewhere Condition (Kiparsky, 1973). Previous connectionist accounts of related phenomena have often been vague about the nature of the networks' encoding systems. We analyzed our network using dynamical systems theory, revealing topological and geometric properties that can be directly compared with the mechanisms of non-connectionist, rule-based accounts. The results reveal that the networks "contain" structures related to mechanisms posited by rule-based models, partly vindicating the insights of these models. On the other hand, they support the one mechanism (OM), as opposed to the more than one mechanism (MOM), view of symbolic abstraction by showing how the appearance of MOM behavior can arise emergently from one underlying set of principles. The key new contribution of this study is to show that dynamical systems theory can allow us to explicitly characterize the relationship between the two perspectives in implemented models. PMID- 23931714 TI - Point-of-care glucose analysis in neonates using modified quinoprotein glucose dehydrogenase. AB - BACKGROUND: Asymptomatic hypoglycemia in neonates may contribute to neurologic deficits during development. Whole-blood glucose sensors are often imprecise and inaccurate at the low glucose concentrations found in neonates. SUBJECTS AND METHODS: In this study, a glucose sensor using a mutated glucose dehydrogenase that does not cross-react significantly with maltose was evaluated at three pediatric centers. Blood samples (n=575) from infants less than 30 days of age (hematocrit 23-70%) were analyzed using six reagent lots on three ACCU-CHEK((r)) meters (Roche Diagnostics, Indianapolis, IN): the Inform II, Performa, and Aviva. Reference glucose level was determined in duplicate in perchloric acid extracts using a coupled hexokinase procedure. RESULTS: Imprecision of glucose measurement using stable control materials ranged from 2.0% to 3.1% (coefficient of variation) using the glucose meters and from 0.8% to 5.3% (coefficient of variation) in perchloric acid-treated controls. The difference between meter glucose values and reference values showed a slight dependence on hematocrit from 23% to 70% (r=-0.391, P<0.001) but not in the typical range of neonatal hematocrit from 45% to 70% (r=-0.036, P=0.239). Linear regression of the aggregated results yielded the following relationship: Meter glucose=0.99*Reference Glucose+0.04; r(2)=0.976; Syx=0.249. Receiver-operator characteristic analysis of the data using 2.2 mmol/L as the reference threshold for hypoglycemia yielded an area under the curve value of 0.993. All infants with a glucose level of <2.2 mmol/L were detected (100% sensitivity) when the meter glucose value was below 2.8 mmol/L. CONCLUSIONS: These data indicate that the modified ACCU-CHEK chemistry may be used effectively in neonatal settings to detect clinically significant hypoglycemia. PMID- 23931715 TI - Effects of low-carbohydrate/high-monounsaturated fatty acid liquid diets on diurnal glucose variability and insulin dose in type 2 diabetes patients on tube feeding who require insulin therapy. AB - OBJECTIVE: A low-carbohydrate/high-monounsaturated fatty acid liquid diet (LC/HMD) was investigated for its role in long-term glycemic control in tube-fed type 2 diabetes patients who require insulin therapy. PATIENTS AND METHODS: The study included 10 type 2 diabetes patients requiring insulin therapy who were being tube-fed with a high-carbohydrate liquid diet (HCD). With stable glucose control maintained, these patients were monitored for glucose levels for 4 consecutive days by using continuous glucose monitoring (CGM). The patients were continued on HCD during the first 2 days and were switched to an LC/HMD during the final 2 days. The patients were then continued on the LC/HMD, and seven of the 10 patients were monitored for glucose levels for 2 consecutive days by using CGM after 3 months of feeding with the LC/HMD. Insulin regimens used included basal-bolus insulin in five of these seven patients and intermediate-acting insulin in two patients. RESULTS: Based on CGM data, the indices for glucose variability, such as SDs of 288 glucose levels for 24 h, total area for the range of glucose variability, mean amplitude of glycemic excursions, and 24-h mean glucose levels were significantly decreased 3 months after switching from the HCD to the LC/HMD. Additionally, despite the significant decrease in required insulin dose, the hemoglobin A1c (HbA1c) values were significantly decreased 3 months after switching. CONCLUSIONS: Study results demonstrated that the LC/HMD not only narrowed the range of glucose variability, but also decreased the required insulin dose and HbA1c values in diabetes patients on tube feeding who required insulin therapy, suggesting the LC/HMD may be useful in long-term glycemic control in these patients. PMID- 23931716 TI - Adsorption of triazine derivatives with humic fraction-immobilized silica gel in hexane: a mechanistic consideration. AB - A fraction of humic acid is collected under acidic conditions, then immobilized on silica gel and used as the adsorbent for various symmetrical triazine (s triazine) derivatives in hexane. The enhanced hydrogen bonding between the analyte and humic fraction molecules, not the complexation interaction, is responsible for the adsorption observed in hexane, based on Fourier transform infrared (FTIR) spectroscopy results. The percentage of adsorption in hexane for all s-triazine derivatives reaches nearly 100% in 1 h, independent of the type, position, and size of the substituent on the aromatic nitrogen heterocyclic ring. Other factors leading to the variation of the percentage of adsorption include the type of liquid phase and the additive of acidic or basic origin present in the matrix. PMID- 23931717 TI - Satisfaction with medical treatment in patients with hand dermatitis - a cross sectional study. AB - BACKGROUND: Despite the significant clinical and economic burden of hand dermatitis, data on patients' satisfaction with treatment and related determining factors are lacking. PATIENTS AND METHODS: We performed a cross-sectional study using a standardized survey, including all patients with hand dermatitis treated between 12/2001 and 11/2008 at the Department of Dermatology, TU Dresden. Patients were asked about socio-demographic data, disease characteristics, occupational data, quality of life, treatment satisfaction and their treatment goals. Based on an a priori model, possible impact factors on treatment satisfaction were analyzed using regression modeling. RESULTS: Of 382 contacted patients, 215 agreed to participate in the study (133 [61.3%] female). The mean age was 42 years. 155 patients (72.1%) had had severe or very severe hand dermatitis in the past. The majority of the patients were satisfied with the medical treatment. Treatment satisfaction was determined by the impression of professional competence (p < 0.001), physicians' empathy (p < 0.001), sufficient information on course, prognosis, and treatment options (p < 0.001), the patients' self-treatment competency (p < 0.001), quality of life (p = 0.007), as well as on the severity of hand dermatitis (p < 0.001). CONCLUSIONS: The data point out that in the therapy of chronic hand dermatitis, along with professional competence, the physicians' empathy, provision of sufficient information about the disease, and teaching self-treatment competency play a prominent role in improving the treatment satisfaction of the patients. PMID- 23931718 TI - New concepts in clinical research - an expansion of the possibilities. PMID- 23931719 TI - Diffusion capacity in children: what happens with exercise? AB - There is comparatively little data on diffusion capacity in children during exercise. With the advent of improved technology, there is an increasing interest in exercise testing of children in order to predict the evolution of lung disease. In addition to the standard measure of exercise capacity, the VO(2max), interest is evolving in the consequences of alterations in diffusion capacity which may be unmasked with exercise. This review will consider what is known about diffusion capacity with exercise in children with well documented lung disease in the form of cystic fibrosis, healthy controls and swimmers as elite athletes with the largest lung volumes. PMID- 23931720 TI - Newer treatment modalities for pediatric obstructive sleep apnea. AB - The obstructive sleep apnea syndrome is common and its prevalence is expected to increase with the current obesity epidemic. If left untreated, it is associated with important morbidity such as growth failure, neurocognitive impairment, systemic and pulmonary hypertension, and endothelial dysfunction. Recent research has shown that many children, especially the obese or those with other underlying medical conditions, have residual obstructive sleep apnea after adenotonsillectomy (the primary treatment for childhood obstructive sleep apnea). These children could be effectively treated with continuous positive airway pressure but poor adherence is a significant limitation of this therapy. Therefore, new treatment modalities for the pediatric obstructive sleep apnea syndrome are needed. Current research has focused on newer therapies for pediatric obstructive sleep apnea, such as anti-inflammatories, dental treatments, high-flow nasal cannula, and weight loss. However, there are few randomized controlled trials assessing the effectiveness of these therapies. Further research is warranted. PMID- 23931721 TI - Protein-mimetic, molecularly imprinted nanoparticles for selective binding of bile salt derivatives in water. AB - A tripropargylammonium surfactant with a methacrylate-terminated hydrophobic tail was combined with a bile salt derivative, divinyl benzene (DVB), and a photo cross-linker above its critical micelle concentration (CMC). Surface-cross linking with a diazide, surface-functionalization with an azido sugar derivative, and free-radical-core-cross-linking under UV irradiation yielded molecularly imprinted nanoparticles (MINPs) with template-specific binding pockets. The MINPs resemble protein receptors in size, complete water-solubility, and tailored binding sites in their hydrophobic cores. Strong and selective binding of bile salt derivatives was obtained, depending on the cross-linking density of the system. PMID- 23931722 TI - Estimating the lowest detectable dose of ionizing radiation by the cytokinesis block micronucleus assay. AB - The frequency of binucleated cells containing one or more micronuclei (MNBN cells) in cytokinesis-blocked peripheral blood lymphocytes can be used to determine whether a person has received an overexposure to ionizing radiation. However, the absence of a pre-exposure sample can preclude precise dosimetry. Here we use a database of MNBN cell frequencies in peripheral blood lymphocytes from 3,104 apparently healthy, unexposed, control subjects aged birth to 88 years, contributed by laboratories participating in the HUMN project. To determine whether a putatively exposed person has actually received a measurable dose, that person's peripheral blood lymphocyte MNBN frequency is compared to values from age and gender-matched controls in the database. If the subject's frequency is significantly higher than the controls, then a cobalt-60 dose response curve obtained with the cytokinesis-block micronucleus (CBMN) assay in human peripheral blood lymphocytes is used to estimate the minimum dose of low LET radiation that could have caused the increase. The response curve was generated with 11 acutely administered doses ranging from 0-4 Gy; the majority of doses were in the low end of this range to provide an accurate estimate of the linear portion of the response. The minimum detectable acute whole-body dose at the 95% prediction level and their corresponding 95% confidence intervals are 0.18 Gy (0.15-0.22) and 0.20 (0.17-0.24) Gy for 20-year-old males and females, respectively. Corresponding values for 50 year olds are 0.23 Gy (0.19-0.26) and 0.25 (0.21-0.29) Gy, and for 70 year olds are 0.24 (0.21-0.28) Gy and 0.26 (0.22 0.31) Gy. The minimum detectable chronic doses are approximately fivefold higher for both genders. These types of analyses, including knowledge of assay variability, will improve our understanding of the requirements and limitations for biodosimetry when a pre-exposure micronucleus value is unavailable and reliance on historical baseline micronucleus values is required. PMID- 23931723 TI - Radiation-induced bystander signaling from somatic cells to germ cells in Caenorhabditis elegans. AB - Recently, radiation-induced bystander effects (RIBE) have been studied in mouse models in vivo, which clearly demonstrated bystander effects among somatic cells. However, there is currently no evidence for RIBE between somatic cells and germ cells in animal models in vivo. In the current study, the model animal Caenorhabditis elegans was used to investigate the bystander signaling from somatic cells to germ cells, as well as underlying mechanisms. C. elegans body size allows for precise microbeam irradiation and the abundant mutant strains for genetic dissection relative to currently adopted mouse models make it ideal for such analysis. Our results showed that irradiation of posterior pharynx bulbs and tails of C. elegans enhanced the level of germ cell apoptosis in bystander gonads. The irradiation of posterior pharynx bulbs also increased the level of DNA damage in bystander germ cells and genomic instability in the F1 progeny of irradiated worms, suggesting a potential carcinogenic risk in progeny even only somatic cells of parents are exposed to ionizing radiation (IR). It was also shown that DNA damage-induced germ cell death machinery and MAPK signaling pathways were both involved in the induction of germ cell apoptosis by microbeam induced bystander signaling, indicating a complex cooperation among multiple signaling pathways for bystander effects from somatic cells to germ cells. PMID- 23931724 TI - Direct innominate artery cannulation in surgery for annuloaortic ectasia. AB - INTRODUCTION: The selection of the ideal cannulation site is still one of the major concerns in ascending aortic surgery. In the last decade, many surgeons have chosen to utilize antegrade cerebral perfusion in hypothermic circulatory arrest. In this study, we aimed to evaluate arterial cannulation techniques in patients who underwent root replacement for annuloaortic ectasia. MATERIALS AND METHODS: Between 2005 and 2012, a total of 69 patients with a diagnosis of annuloaortic ectasia underwent aortic root replacement with femoral artery, axillary artery, and direct innominate artery cannulation (IAC). Patients demographic, operative, and postoperative data were collected prospectively and analyzed. RESULTS: A total of 69 patients were investigated. Their ages varied from 13 to 78 (mean age was 54.25 +/- 15.69) and 48 patients were male (69.5%). Mean aortic diameter was 5.65 +/- 1.58 cm (min: 4.5 cm to max: 7.8 cm) by computerized tomography. The procedures included modified Bentall operation in 61 patients, and Cabrol operation in eight patients. In hospital, the mortality rate was 1.85%, and a 30-day mortality rate was 3.7% in the IAC group and 6.6% in patients who underwent femoral and axillary artery cannulation. Temporary cognitive dysfunction and stroke rate were similar between groups. CONCLUSION: Innominate cannulation is associated with low morbidity and mortality in patients who underwent ascending aorta surgery. PMID- 23931726 TI - Perovskite chromates cathode with exsolved iron nanoparticles for direct high temperature steam electrolysis. AB - Recently, composite cathodes based on doped lanthanum chromates have been widely employed for direct steam electrolysis. However, this approach limits the electrode performances and Faraday efficiency due to insufficient electrocatalytic activity. This study addresses the drawbacks and reports an improved electrocatalytic activity and Faraday efficiency of composite cathode with a reversibly exsolved iron nanoparticles anchored on the surface of doped lanthanum chromates. A-site deficient and B-site excess (La0.75Sr0.25)0.85(Cr0.5Fe0.5)0.85Fe0.15O3-delta (LSCrFF) was designed as the parent material to anchor the exsolved iron nanoparticles on the surface of perovskite chromate (La0.75Sr0.25)(Cr0.5Fe0.5)O3-delta (LSCrF) via high temperature reduction. The electrical properties of LSCrF and Fe/LSCrF were systematically investigated and correlated with electrochemical performance of the composite electrodes in symmetrical cells and electrolysis cells. The iron nanoparticles significantly improve the electrical conductivity of LSCrF from 1.80 to 6.35 S cm(-1) for Fe/LSCrF at 800 degrees C and Po2 of 10(-15) atm. The polarization resistance, Rp, of the symmetrical cells was accordingly enhanced from 4.26 Omega cm2 with LSCrF to 2.58 Omega cm2 with Fe/LSCrF in hydrogen atmosphere at 800 degrees C. The Faraday efficiency for the direct steam electrolysis showed a marked increase of 89.3% with LSCrFF cathode at 800 degrees C and 1.8 V as opposed to 76.7% with the cathodes based on LSCrF. The synergetic effect of catalytic-active iron nanoparticles and redox-stable LSCrF substrate produced improved performances and excellent stability for the direct steam electrolysis without a flow of reducing gas over the composite cathodes. PMID- 23931725 TI - Novel drug delivery system of plant extract for the management of diabetes: an antidiabetic study. AB - CONTEXT: Moringa oleifera leaves have been reported to have antidiabetic, antitumor, hypotensive, anti-inflammatory, and diuretic properties as well as antibiotic, antitryponosomal, hypotensive, and anti-inflammatory activities. They are outstanding source of vitamins A, B, C, and also rich in calcium and protein. OBJECTIVES: The aim of the study was to formulate Moringa oleifera powdered leaf tablets and to study the in vitro and in vivo properties of the herbal drug from the tablets. MATERIAL AND METHODS: The Moringa oleifera powdered leaf was formulated into tablets by direct compression. The in vitro properties of the tablets were evaluated in terms of uniformity of weight, hardness, disintegration time, friability and dissolution rate. Also, the in vivo antidiabetic properties of Moringa oleifera tablets were studied using Wistar rats. RESULTS AND DISCUSSION: The results of the tablets' weight uniformity gave percentage deviation that was below 5%. Tablet disintegration time ranged from 11.50 +/- 0.11 to 14.90 +/- 0.27 min. The tablets exhibited friability results lower than 2% and exhibited about 82% to 83% release of the extract at 15 min. In vivo antidiabetic studies showed that at 8 hr, about 54.4% and 40% of glucose reduction occurred in groups that received Moringa oleifera tablets and glibenclamide (Daonil(r)) respectively, while the negative control groups showed increased blood glucose level with time. CONCLUSIONS: This study has shown that Moringa oleifera leaves formulated into tablets possess good physicochemical and antidiabetic properties in addition to being a supplement. PMID- 23931727 TI - Controlled drug loading and release of a stimuli-responsive lipogel consisting of poly(N-isopropylacrylamide) particles and lipids. AB - Environmentally responsive materials are attractive for advance biomedicine applications such as controlled drug delivery and gene therapies. Recently, we have introduced the fabrication of a novel type of stimuli-sensitive lipogel composite consisting of poly(N-isopropylacrylamide) (pNIPAM) microgel particles and lipids. In this study, we demonstrated the temperature-triggered drug release behavior and the tunable drug loading and release capacities of the lipogel. At room temperature (22 degrees C), no calcein was released from the lipogel over time. At body temperature (37 degrees C), the release process was significantly promoted; lipids in the lipogel acted as drug holders on the pNIPAM scaffold carrier and prolonged the calcein release process from 10 min to 2 h. Furthermore, the loading and release of calcein could be effectively controlled by modulating the relative amount of lipids incorporated in the lipogel, which can be realized by the salt-induced lipid release of the lipogel. PMID- 23931728 TI - Are you sure? Delusion conviction moderates the behavioural and emotional consequences of paranoid ideas. AB - INTRODUCTION: Paranoid beliefs strongly impact behaviour and emotion: most people with paranoid delusions engage in safety behaviours and a relevant minority even commits violent acts under the influence of delusional thoughts. The present study examined whether different levels of belief conviction modulate subsequent behaviour and emotion. To be able to control for important confounds, we set up an analogue study using nonclinical participants. METHODS: Participants were recruited from the general population (N=1935) and asked to fill out the Paranoia Checklist. Individuals had to imagine being persecuted by a secret service, whereby the level of subjective conviction was set at 20%, 40%, 60%, 80%, 90%, or 100%. Subsequently, participants had to estimate for 37 behavioural and emotional items how they might respond to this threat. RESULTS: Three quarters of the sample affirmed the presence of at least one paranoid idea from the Paranoia Checklist over the duration of a month. The level of belief conviction and paranoia was positively associated with behavioural and emotional consequences. CONCLUSIONS: Our investigation suggests that a higher degree of belief conviction aggravates the behavioural consequences of persecutory beliefs in a linear fashion. The study is limited by its "what if" character and should be replicated with clinical participants. The study suggests that treatment approaches that aim to reduce overconviction may positively impact behaviour in psychosis. PMID- 23931729 TI - Telemedicine: a cost-reducing means of delivering psychotherapy to rural combat veterans with PTSD. AB - BACKGROUND: Although effective psychotherapies for posttraumatic stress disorder (PTSD) exist, high percentages of Veterans in need of services are unable to access them. One particular challenge to providing cost-effective psychological treatments to Veterans with PTSD involves the difficulty and high cost of delivering in-person, specialized psychotherapy to Veterans residing in geographically remote locations. The delivery of these services via clinical videoteleconferencing (CVT) has been presented as a potential solution to this access to care problem. MATERIALS AND METHODS: This study is a retrospective cost analysis of a randomized controlled trial investigating telemedicine service delivery of an anger management therapy for Veterans with PTSD. The parent trial found that the CVT condition provided clinical results that were comparable to the in-person condition. Several cost outcomes were calculated in order to investigate the clinical and cost outcomes associated with the CVT delivery modality relative to in-person delivery. RESULTS: The CVT condition was significantly associated with lower total costs compared with the in-person delivery condition. The delivery of mental health services via CVT enables Veterans who would not normally receive these services access to empirically based treatments. Additional studies addressing long-term healthcare system costs, indirect cost factors at the patient and societal levels, and the use of CVT in other geographic regions of the United States are needed. CONCLUSIONS: The results of this study provide evidence that CVT is a cost-reducing mode of service delivery to Veterans with PTSD relative to in-person delivery. PMID- 23931731 TI - Testing a top-down strategy for establishing a sustainable telemedicine program in a developing country: the Arizona telemedicine program-US Army-Republic of Panama Initiative. AB - OBJECTIVE: Many developing countries have shown interest in embracing telemedicine and incorporating it into their healthcare systems. In 2000, the U.S. Army Yuma Proving Ground (YPG) initiated a program to assist the Republic of Panama in establishing a demonstration Panamanian rural telemedicine program. YPG engaged the Arizona Telemedicine Program (ATP) to participate in the development and implementation of the program. MATERIALS AND METHODS: The ATP recommended adoption of a "top-down" strategy for creating the program. Early buy-in of the Panamanian Ministry of Health and academic leaders was regarded as critical to the achievement of long-term success. RESULTS: High-level meetings with the Minister of Health and the Rectors (i.e., Presidents) of the national universities gained early program support. A telemedicine demonstration project was established on a mountainous Indian reservation 230 miles west of Panama City. Today, three rural telemedicine clinics are linked to a regional Ministry of Health hospital for teleconsultations. Real-time bidirectional videoconferencing utilizes videophones connected over Internet protocol networks at a data rate of 768 kilobits per second to the San Felix Hospital. Telepediatrics, tele-obstetrics, telepulmonology, teledermatology, and tele emergency medicine services became available. Telemedicine services were provided to the three sites for a total of 1,013 cases, with numbers of cases increasing each year. These three demonstration sites remained in operation after discontinuation of the U.S. involvement in September 2009 and serve as a model program for other telemedicine initiatives in Panama. CONCLUSIONS: Access to the assets of a partner-nation was invaluable in the establishment of the first model telemedicine demonstration program in Panama. After 3 years, the Panamanian Telemedicine and Telehealth Program (PTTP) became self-sufficient. The successful achievement of sustainability of the PTTP after disengagement by the United States fits the Latifi-Weinstein model for establishing telemedicine programs in developing countries. PMID- 23931730 TI - Using mobile phone technology to provide recovery support for women offenders. AB - BACKGROUND: Mobile technology holds promise as a recovery tool for people with substance use disorders. However, some populations who may benefit the most may not have access to or experience with mobile phones. Incarcerated women represent a group at high risk for recidivism and relapse to substance abuse. Cost effective mechanisms must be in place to support their recovery upon release. This study explores using mobile technology as a recovery management tool for women offenders residing in the community following release from jail. SUBJECTS AND METHODS: This study surveyed 325 minority women offenders with substance use disorders to determine whether or not they use cell phones, their comfort with texting and search features, and the social networks that they access from mobile phones. RESULTS: We found that 83% of survey subjects had cell phones; 30% of those were smartphones. Seventy-seven percent of the women reported access to supportive friends, and 88% had close family members they contacted regularly using mobile technology. Results indicated that most of the women were comfortable using a mobile phone, although the majority of them had prepaid minutes rather than plans, and most did currently use smartphones or have the capability to download applications or access social networks via their phones. Most women reported that they would be comfortable using a mobile phone to text, e-mail, and answer surveys. CONCLUSIONS: The high rate of adoption of mobile technology by women offenders makes them a promising target for recovery support delivered via mobile phone. PMID- 23931733 TI - Effect of different levels of glycerol and cholesterol-loaded cyclodextrin on cryosurvival of ram spermatozoa. AB - This study was conducted to determine the optimum level of glycerol and cholesterol-loaded cyclodextrin (CLC) in a Tris-based diluent for cryopreservation of ram spermatozoa. Ram semen was treated with 0, 1.5, 3 or 4.5 mg CLC/120 * 10(6) cells in Tris-based diluents containing 3, 5 or 7% glycerol in a factorial arrangement 3 * 4 and frozen in liquid nitrogen vapour. Sperm motility, viability (eosin-nigrosin staining) and functional membrane integrity (hypo-osmotic swelling test) were assessed immediately after thawing (0 h) and subsequently after 3 and 6 h at 37 degrees C. There was an interaction between CLC and glycerol on the functional membrane integrity (p < 0.05). In the presence of 3% glycerol, the highest functional membrane integrity (32.2%) was found in the spermatozoa treated with 1.5 mg CLC/120 * 10(6) sperm. Post-thaw sperm motility was highest in 1.5 mg CLC immediately after thawing (40.5%) and after 3 h (30.6%) incubation at 37 degrees C (p < 0.05). Viability of spermatozoa was higher in all CLC treatments than in the untreated samples, and it was highest (33.9%) in the spermatozoa treated with 1.5 mg CLC (p < 0.05). These data indicate that the addition of cholesterol to sperm membranes by 1.5 mg CLC/120 * 10(6) cells may allow the use of a lower concentration of glycerol (3%), which is sufficient to mitigate the detrimental effects of freezing and thawing. PMID- 23931732 TI - Vesicular trafficking and stress response coupled to PI3K inhibition by LY294002 as revealed by proteomic and cell biological analysis. AB - LY294002 is a synthetic quercetin-like compound, which, unlike wortmannin, is more specific inhibitor of phosphatidylinositol 3-kinase (PI3K). It inhibits endocytosis and vacuolar transport. We report here on the proteome-wide effects of LY294002 on Arabidopsis roots focusing on proteins involved in vesicular trafficking and stress response. At the subcellular level, LY294002 caused swelling and clustering of late endosomes leading to inhibition of vacuolar transport. At the proteome level, this compound caused changes in abundances of proteins categorized to 10 functional classes. Among proteins involved in vesicular trafficking, a small GTPase ARFA1f was more abundant, indicating its possible contribution to the aggregation and fusion of late endosomes triggered by LY294002. Our study provides new information on storage proteins and vacuolar hydrolases in vegetative tissues treated by LY294002. Vacuolar hydrolases were downregulated, while storage proteins were more abundant, suggesting that storage proteins were protected from degradation in swollen multivesicular bodies upon LY294002 treatment. Upregulation of 2S albumin was validated by immunoblotting and immunolabeling analyses. Our study also pointed to the control of antioxidant enzyme machinery by PI3K because LY294002 downregulated two isozymes of superoxide dismutase. This most likely occurred via PI3K-mediated downregulation of protein AtDJ1A. Finally, we discuss specificity differences of LY294002 and wortmannin against PI3K, which are reflected at the proteome level. Compared with wortmannin, LY294002 showed more narrow and perhaps also more specific effects on proteins, as suggested by gene ontology functional annotation. PMID- 23931735 TI - Parity of esteem begins at home: translating empirical psychiatric research into effective public mental health. AB - There is increasing recognition that parity of esteem between mental and physical health disorders is essential to improve the course, outcome and quality of life of individuals within different populations. Achieving this parity now underpins the objectives of several nations. Here, we argue that parity of esteem between mental and physical health can only be realized when parity of esteem also exists across mental health disorders, particularly in terms of service commissioning and planning. Using first-episode psychosis and early intervention in psychosis services as a motivating example, we demonstrate how carefully conducted psychiatric epidemiology can be translated to develop precise forecasts of the anticipated incidence of first-episode psychosis in different populations, based on an understanding of underlying local needs and inequalities. Open-access prediction tools such as PsyMaptic will allow commissioners of mental health services to more effectively allocate resources across services, based on empirical evidence and local need, thus reducing inequalities in access to mental health care. PMID- 23931734 TI - Chemical library screening using a SPR-based inhibition in solution assay: simulations and experimental validation. AB - We have developed a surface plasmon resonance (SPR)-based inhibition in solution assay (ISA) to search for inhibitors of the medium affinity (KD = 0.8 MUM) interaction between an E6-derived peptide (E6peptide) immobilized on the sensor and a PDZ domain (MAGI-1 PDZ1) in the mobile phase. DZ domains are widespread protein-protein interaction modules that recognize the C-terminus of various partners. Simulations indicated that relatively low compound concentrations (10 MUM) and limited peptide densities (Rmax < 200 resonance units) should allow the detection of inhibitors with a target affinity close to 100 MUM, which was then demonstrated experimentally. ISA screening, carried out on the Prestwick Chemical Library(r) (1120 compounds), identified 36 compounds that inhibited the interaction by more than 5%. Concentration-dependent ISA, carried out on a subset of 19 potential inhibitors, indicated that 13 of these indeed affected the interaction between MAGI-1 PDZ1 and the E6peptide. No effect was observed for 84 compounds randomly chosen among noninhibitors. One of the four best inhibitors was a peptide binder, and three were PDZ binders with KD in the 10-50 MUM range. We propose that a medium (MUM) affinity between the target and surface-bound partner is optimal for SPR-based ISA screening. PMID- 23931736 TI - Making the professionalism curriculum for undergraduate medical education more relevant. AB - BACKGROUND: This study was an assessment of the professionalism curriculum at a community-based medical school from the perspective of undergraduate medical students. AIMS: The goal of this study was to ascertain the perspectives of faculty and students on their interpretations of professionalism and its role in medical education to improve and expand existing professionalism curricula. METHOD: An online survey was created and sent to all students (n = 245) and selected faculty (n = 41). The survey utilized multiple choice and open-ended questions to allow responders to provide their insights on the definition of professionalism and detail how professionalism is taught and evaluated at their institution. A content analysis was conducted to categorize open-ended responses and the resulting themes were further examined using SPSS 20.0 for Windows (IBM Corp., Armonk, NY) frequency analyses. RESULTS: Students and faculty respondents were similar in their definitions of medical professionalism and their perceptions of teaching methods. Role modeling was the most common and preferred method of professionalism education. Responses to whether evaluations of professional behavior were effective suggested both students and faculty are unclear about current professionalism assessments. CONCLUSION: This study showed that a cohesive standardized definition of professionalism is needed, as well as clearer guidelines on how professionalism is assessed. PMID- 23931737 TI - Racial differences in type of alcoholic beverage consumed during adolescence in the Pittsburgh Girls Study. AB - BACKGROUND: White, compared with Black, adolescents have higher rates of alcohol use and show more rapid increases in alcohol use. Racial differences in type of alcohol beverage (i.e., beer, wine, and liquor) consumed by youth have received scant attention, and little is known regarding changes in type of alcohol beverage consumed during adolescence, when experimentation may transition to more regular use. METHODS: This study used repeated measures latent class analysis to identify distinct profiles that represent change in type of alcohol beverage consumed across ages 11 to 18 and to examine predictors (e.g., caretaker alcohol use, perceived peer alcohol use, ease in accessing alcohol, perceived neighborhood risk indicated by witnessing drug dealing), most of which were measured at ages 11 to 12, of alcohol use profiles in the Pittsburgh Girls Study (n = 2,171; 57% Black, 43% White), a community sample with annual follow-ups. RESULTS: Among Black girls, 2 profiles were identified: Low Use (76%), and Alcohol Use involving primarily liquor starting around age 15 (24%). Among White girls, 4 profiles were identified: Wine sippers (11%); a Low Use profile with low probability of drinking until age 18, when use of beer and liquor increased (52%); an Increasing Use profile with increased probability of drinking beer and liquor starting at age 15 (23%); and a High Alcohol Use profile, starting with use of wine, then shifting to use primarily of beer and liquor after age 13 (14%). Separate risk factor analyses conducted by race indicated similar predictors for Black and White girls: perceived ease in accessing alcohol, witnessing neighborhood drug dealing, and perceived peer alcohol use were each associated with heavier drinking profiles. CONCLUSIONS: Longitudinal profiles of type of alcoholic beverages, within and across racial groups, can guide the tailoring of interventions to address developmentally salient turning points in alcohol use for specific subgroups of girls. PMID- 23931739 TI - ProAct study: new features of insulin pumps improve diabetes management and glycemic control in patients after transition of continuous subcutaneous insulin infusion systems. AB - BACKGROUND: Continuous subcutaneous insulin infusion (CSII) patients experience switches of pump systems on a regular basis. We investigated the impact of transition from older pumps to the Accu-Chek((r)) Combo system (Roche Diagnostics Deutschland GmbH, Mannheim, Germany) on a patient's glycemic control and diabetes management. PATIENTS AND METHODS: In total, 299 patients (172 female, 127 male; mean+/-SD age, 39.4+/-15.2 years; CSII duration, 7.0+/-5.2 years) were enrolled by 61 European sites into this uncontrolled prospective trial. Glycemic control, safety, and diabetes management parameters were measured at baseline and after 3 and 6 months. Changes from baseline were analyzed. RESULTS: After transition to the new insulin pump, mean+/-SD hemoglobin A1c (HbA1c) values decreased from 7.8+/-1.1% (baseline) to 7.7+/-1.1% (end point). The proportion of patients with HbA1c <7.0% was slightly higher at the end of the study (29.6%) than at baseline (25.2%), whereas the proportion of patients with HbA1c >8.0% decreased (baseline, 36.2%; end point, 32.7%; P<0.05). The number of hypoglycemic episodes (blood glucose<70 mg/dL) improved slightly during the study (baseline, 40.4+/-34.0 events/quarter; end point, 39.2+/-33.9 events/quarter). Glycemic control improved significantly in the group with an initial HbA1c >8.0% (-0.46%; P<0.001) and remained solidly stable in the group with an initial HbA1c <7% (+0.04%; not significant). Short-term (<3 years) pump users (n=48) had a larger HbA1c decrease (-0.40%) than long-term (>=3 years) users (n=251) (-0.07%; P<0.05). The number of blood glucose measurements increased (3.7+/-1.9/day vs. 4.4+/-1.8/day; P<0.05), whereas the number of insulin boluses decreased (5.1+/-1.9/day vs. 4.6+/-1.5/day; P<0.05) during the study. CONCLUSIONS: Transition from older pump systems to the Accu-Chek Combo system in a large patient population resulted in stable glycemic control with significant improvements in HbA1c in patients with unsatisfactory baseline HbA1c and shorter pump use. Increased frequency of self-monitoring of blood glucose and decrease of bolus frequency could suggest a more confident diabetes management and a reduced need for correction boluses. PMID- 23931740 TI - Possibility to reduce mortality in diabetic ketoacidosis. PMID- 23931741 TI - Possibility to reduce diabetic ketoacidosis-related mortality in type 1 diabetes: prevention versus treatment. PMID- 23931742 TI - Postharvest accumulation of resveratrol and piceatannol in sugarcane with enhanced antioxidant activity. AB - A new plant source, sugarcane, was used to produce the stilbenes piceatannol and resveratrol. Both stilbenes were identified in sugarcane billet stalks (12 mm) after incubation at room temperature for 3 days. Low concentrations of piceatannol (30.6 MUg/g) and resveratrol (12.3 MUg/g) were detected at day 3. At day 7 of incubation higher concentrations of piceatannol (1659 MUg/g) and resveratrol (73 MUg/g) were produced. Sugarcane juice obtained from billets that were incubated for 7 days contained high levels of piceatannol (8.5 mg/L) and resveratrol (1.2 mg/L). Although high stilbene concentrations were determined in the sugarcane variety L 97-128, two other varieties (Ho 95-988 and LCP 85-384) displayed lower stilbene concentrations after incubation for 7 days. The total phenolic content (TPC) and antioxidant activities of incubated sugarcane extracts were determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and ferric reducing antioxidant power (FRAP). The TPC and antioxidant activities were highest in sugarcane extracts that were incubated for 7 days. This study details a postharvest method to produce stilbene-enriched sugarcane with increased levels of piceatannol and resveratrol. PMID- 23931744 TI - Phosphatidylserine synthase 1 is required for inflorescence meristem and organ development in Arabidopsis. AB - Phosphatidylserine (PS), a quantitatively minor membrane phospholipid, is involved in many biological processes besides its role in membrane structure. One PS synthesis gene, PHOSPHATIDYLSERINE SYNTHASE1 (PSS1), has been discovered to be required for microspore development in Arabidopsis thaliana L. but how PSS1 affects postembryonic development is still largely unknown. Here, we show that PSS1 is also required for inflorescence meristem and organ development in Arabidopsis. Disruption of PSS1 causes severe dwarfism, smaller lateral organs and reduced size of inflorescence meristem. Morphological and molecular studies suggest that both cell division and cell elongation are affected in the pss1-1 mutant. RNA in situ hybridization and promoter GUS analysis show that expression of both WUSCHEL (WUS) and CLAVATA3 (CLV3) depend on PSS1. Moreover, the defect in meristem maintenance is recovered and the expression of WUS and CLV3 are restored in the pss1-1 clv1-1 double mutant. Both SHOOTSTEMLESS (STM) and BREVIPEDICELLUS (BP) are upregulated, and auxin distribution is disrupted in rosette leaves of pss1-1. However, expression of BP, which is also a regulator of internode development, is lost in the pss1-1 inflorescence stem. Our data suggest that PSS1 plays essential roles in inflorescence meristem maintenance through the WUS-CLV pathway, and in leaf and internode development by differentially regulating the class I KNOX genes. PMID- 23931745 TI - Disseminated tuberculosis in an immunocompetent patient. AB - Miliary tuberculosis refers to the clinical disease resulting from the hematogenous dissemination of Mycobacterium tuberculosis. A tuberculous aneurysm of the aorta is exceedingly rare. Contiguous tuberculosis in the form of lymphadenitis is generally responsible for the aortic involvement. We report a case of tuberculous mycotic aneurysm in patient with miliary disease, not affected by a cellular immunodeficiency and with no other common risk factor for infection. He received anti-tubercular therapy and endovascular stenting before the identification of Mycobacterium tuberculosis in lung, lymph nodes, and gastric lavage. The clinician should be aware that a mycotic abdominal aortic aneurysm could be caused by M. tuberculosis, even if microbiological confirmation is lacking or is negative, especially if a contiguous focus of tubercular infection is detected. PMID- 23931746 TI - Effects of oil from the 2010 Macondo well blowout on marsh foraminifera of Mississippi and Louisiana, USA. AB - Foraminifera responded to both heavy and light oiling of marshes relative to unoiled control sites by changes to both standing stock and depth of habitation (DOH) in sediment following the 2010 Macondo well blowout. Push cores were taken from the middle marsh at sites classified as unoiled, lightly oiled, and heavily oiled based on concentrations of total polycyclic aromatic hydrocarbons ([TPAH]). Cores were sliced and stained with rose Bengal to detect live specimens of foraminifera. Short-term, sediment-mixing depths were determined using the penetration depths of excess (234)Th, and sedimentary organic carbon and carbonate were measured to distinguish depositional environments. Marsh foraminifera reacted to the highest oil concentration (5,000-18,000 ng/g of TPAH) by reducing standing stock and shortening the DOH compared with the control sites. At a second, less heavily oiled site, foraminifera responded with a shallower DOH, but with a boom in standing stock. Deformed, dead foraminifera occurred in all heavily oiled cores-but not elsewhere. Live foraminifera responded with a population boom at lightly oiled sites with [TPAH] near 1,100 ng/g. Changes in standing stock and DOH with [TPAH] suggest disturbance to the marsh food web, apparently due to oil pollution, and support the use of foraminifera as sentinel species. PMID- 23931747 TI - A CO-derived iron dicarbyne that releases olefin upon hydrogenation. AB - An iron diphosphineborane platform that was previously reported to facilitate a high degree of N2 functionalization is herein shown to effect reductive CO coupling. Disilylation of an iron dicarbonyl precursor furnishes a structurally unprecedented iron dicarbyne complex. Several complexes related to this process are also characterized which allows for a comparative analysis of their respective Fe-B and Fe-C bonding. Facile hydrogenation of the iron dicarbyne at ambient temperature and 1 atm H2 results in release of a CO-derived olefin. PMID- 23931748 TI - Mitochondrial dysfunction indirectly elevates ROS production by the endoplasmic reticulum. AB - Mitochondrial dysfunction is often associated with increased reactive oxygen species (ROS) production by the organelle itself. Leadsham et al. (2013) now show that the link between mitochondrial damage and ROS is more complicated, at least in yeast, where signals from damaged mitochondria increase ROS production from the endoplasmic reticulum surface. PMID- 23931749 TI - I function, therefore I am: overcoming skepticism about mitochondrial supercomplexes. AB - The mitochondrial respiratory chain is believed to dynamically arrange in suprastructures known as supercomplexes or respirasomes, though their function remains elusive. A recent study in Science (Lapuente-Brun et al., 2013) now reports that dynamic supercomplex assembly determines electron flux from different substrates through the respiratory chain. PMID- 23931750 TI - Macrofinancing efficient remodeling of damaged muscle tissue. AB - In this issue of Cell Metabolism, Mounier et al. (2013) show that AMPKalpha1 is a crucial contributor to the regeneration of damaged muscle tissues, acting in macrophages at the nexus between proinflammatory debris removal and resolution of muscle tissue inflammation. PMID- 23931751 TI - Bile acid look-alike controls life span in C. elegans. AB - Extensive transcriptional networks maintain sterol homeostasis across species, underscoring the importance of sterol balance for healthy life. Magner et al. (2013) now show that, in C. elegans, the nuclear receptor NHR-8 is key in regulation of cholesterol balance and production of dafachronic acid, a bile acid like steroid that controls longevity. PMID- 23931752 TI - Chronic sympathoexcitation through loss of Vav3, a Rac1 activator, results in divergent effects on metabolic syndrome and obesity depending on diet. AB - The role of the sympathetic nervous system, stress, and hypertension in metabolic syndrome and obesity remains unclear. To clarify this issue, we utilized genetically engineered mice showing chronic sympathoexcitation and hypertension due to lack of Vav3, a Rac1 activator. Here, we report that these animals develop metabolic syndrome under chow diet. However, they show protection from metabolic syndrome and obesity under fatty diets. These effects are elicited by alpha1 adrenergic- and diet-dependent metabolic changes in liver and the alpha1/beta3 adrenergic-mediated stimulation of brown adipocyte thermogenesis. These responses seem to be engaged by the local action of noradrenaline in target tissues rather than by long-range effects of adrenaline. By contrast, they are not triggered by low parasympathetic drive or the hypertensive state present in Vav3-deficient mice. These results indicate that the sympathetic system plays divergent roles in the etiology of metabolic diseases depending on food regimen, sympathoexcitation source, and disease stage. PMID- 23931753 TI - The NHR-8 nuclear receptor regulates cholesterol and bile acid homeostasis in C. elegans. AB - Hormone-gated nuclear receptors (NRs) are conserved transcriptional regulators of metabolism, reproduction, and homeostasis. Here we show that C. elegans NHR-8 NR, a homolog of vertebrate liver X and vitamin D receptors, regulates nematode cholesterol balance, fatty acid desaturation, apolipoprotein production, and bile acid metabolism. Loss of nhr-8 results in a deficiency in bile acid-like steroids, called the dafachronic acids, which regulate the related DAF-12/NR, thus controlling entry into the long-lived dauer stage through cholesterol availability. Cholesterol supplementation rescues various nhr-8 phenotypes, including developmental arrest, unsaturated fatty acid deficiency, reduced fertility, and shortened life span. Notably, nhr-8 also interacts with daf 16/FOXO to regulate steady-state cholesterol levels and is synthetically lethal in combination with insulin signaling mutants that promote unregulated growth. Our studies provide important insights into nuclear receptor control of cholesterol balance and metabolism and their impact on development, reproduction, and aging in the context of larger endocrine networks. PMID- 23931754 TI - ABCA12 regulates ABCA1-dependent cholesterol efflux from macrophages and the development of atherosclerosis. AB - ABCA12 is involved in the transport of ceramides in skin, but it may play a wider role in lipid metabolism. We show that, in Abca12-deficient macrophages, cholesterol efflux failed to respond to activation with LXR agonists. Abca12 deficiency caused a reduction in the abundance of Abca1, Abcg1, and Lxrbeta. Overexpression of Lxrbeta reversed the effects. Mechanistically, Abca12 deficiency did not affect expression of genes involved in cholesterol metabolism. Instead, a physical association between Abca1, Abca12, and Lxrbeta proteins was established. Abca12 deficiency enhanced interaction between Abca1 and Lxrbeta and the degradation of Abca1. Overexpression of ABCA12 in HeLa-ABCA1 cells increased the abundance and stability of ABCA1. Abca12 deficiency caused an accumulation of cholesterol in macrophages and the formation of foam cells, impaired reverse cholesterol transport in vivo, and increased the development of atherosclerosis in irradiated Apoe(-/-) mice reconstituted with Apoe(-/-)Abca12(-/-) bone marrow. Thus, ABCA12 regulates the cellular cholesterol metabolism via an LXRbeta dependent posttranscriptional mechanism. PMID- 23931756 TI - AMPKalpha1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. AB - Macrophages control the resolution of inflammation through the transition from a proinflammatory (M1) to an anti-inflammatory (M2) phenotype. Here, we present evidence for a role of AMPKalpha1, a master regulator of energy homeostasis, in macrophage skewing that occurs during skeletal muscle regeneration. Muscle regeneration was impaired in AMPKalpha1(-/-) mice. In vivo loss-of-function (LysM Cre;AMPKalpha1(fl/fl) mouse) and rescue (bone marrow transplantation) experiments showed that macrophagic AMPKalpha1 was required for muscle regeneration. Cell based experiments revealed that AMPKalpha1(-/-) macrophages did not fully acquire the phenotype or the functions of M2 cells. In vivo, AMPKalpha1(-/-) leukocytes did not acquire the expression of M2 markers during muscle regeneration. Skewing from M1 toward M2 phenotype upon phagocytosis of necrotic and apoptotic cells was impaired in AMPKalpha1(-/-) macrophages and when AMPK activation was prevented by the inhibition of its upstream activator, CaMKKbeta. In conclusion, AMPKalpha1 is crucial for phagocytosis-induced macrophage skewing from a pro- to anti inflammatory phenotype at the time of resolution of inflammation. PMID- 23931757 TI - Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating beta-oxidation-dependent mitochondrial ROS production. AB - Evidence suggests the bactericidal activity of mitochondria-derived reactive oxygen species (mROS) directly contributes to killing phagocytozed bacteria. Infection-responsive components that regulate this process remain incompletely understood. We describe a role for the mitochondria-localizing enzyme encoded by Immunoresponsive gene 1 (IRG1) during the utilization of fatty acids as a fuel for oxidative phosphorylation (OXPHOS) and associated mROS production. In a zebrafish infection model, infection-responsive expression of zebrafish irg1 is specific to macrophage-lineage cells and is regulated cooperatively by glucocorticoid and JAK/STAT signaling pathways. Irg1-depleted macrophage-lineage cells are impaired in their ability to utilize fatty acids as an energy substrate for OXPHOS-derived mROS production resulting in defective bactericidal activity. Additionally, the requirement for fatty acid beta-oxidation during infection responsive mROS production and bactericidal activity toward intracellular bacteria is conserved in murine macrophages. These results reveal IRG1 as a key component of the immunometabolism axis, connecting infection, cellular metabolism, and macrophage effector function. PMID- 23931755 TI - Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. AB - Mitochondrial respiratory dysfunction is linked to the pathogenesis of multiple diseases, including heart failure, but the specific mechanisms for this link remain largely elusive. We modeled the impairment of mitochondrial respiration by the inactivation of the Ndufs4 gene, a protein critical for complex I assembly, in the mouse heart (cKO). Although complex I-supported respiration decreased by >40%, the cKO mice maintained normal cardiac function in vivo and high-energy phosphate content in isolated perfused hearts. However, the cKO mice developed accelerated heart failure after pressure overload or repeated pregnancy. Decreased NAD(+)/NADH ratio by complex I deficiency inhibited Sirt3 activity, leading to an increase in protein acetylation and sensitization of the permeability transition in mitochondria (mPTP). NAD(+) precursor supplementation to cKO mice partially normalized the NAD(+)/NADH ratio, protein acetylation, and mPTP sensitivity. These findings describe a mechanism connecting mitochondrial dysfunction to the susceptibility to diseases and propose a potential therapeutic target. PMID- 23931758 TI - Loss of cytochrome c oxidase promotes RAS-dependent ROS production from the ER resident NADPH oxidase, Yno1p, in yeast. AB - Many disease states, including the aging process, are associated with the accumulation of mitochondria harboring respiratory dysfunction. Mitochondrial dysfunction is often accompanied by increased ROS levels that can contribute to cellular dysfunction and disease etiology. Here we use the model eukaryote S. cerevisiae to investigate whether reduced cytochrome c oxidase (COX) activity, commonly reported in aging organisms and associated with neurodegenerative disorders, leads to ROS production from mitochondria. We provide evidence that although reduced COX complex activity correlates with ROS accumulation, mitochondria are not the major production center. Instead we show that COX deficient mitochondria activate Ras upon their outer membrane that establishes a pro-ROS accumulation environment by suppressing antioxidant defenses and the ERAD mediated turnover of the ER-localized NADPH oxidase Yno1p. Our data suggest that dysfunctional mitochondria can serve as a signaling platform to promote the loss of redox homeostasis, ROS accumulation, and accelerate aging in yeast. PMID- 23931759 TI - TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid. AB - Cardiolipin (CL), a mitochondria-specific glycerophospholipid, is required for diverse mitochondrial processes and orchestrates the function of various death inducing proteins during apoptosis. Here, we identify a complex of the p53 regulated protein TRIAP1 (p53CSV) and PRELI in the mitochondrial intermembrane space (IMS), which ensures the accumulation of CL in mitochondria. TRIAP1/PRELI complexes exert lipid transfer activity in vitro and supply phosphatidic acid (PA) for CL synthesis in the inner membrane. Loss of TRIAP1 or PRELI impairs the accumulation of CL, facilitates the release of cytochrome c, and renders cells vulnerable to apoptosis upon intrinsic and extrinsic stimulation. Survival of TRIAP1- and PRELI-deficient cells is conferred by an excess of exogenously provided phosphatidylglycerol. Our results reveal a p53-dependent cell-survival pathway and highlight the importance of the CL content of mitochondrial membranes in apoptosis. PMID- 23931761 TI - What reassurances do the community need regarding life extension? Evidence from studies of community attitudes and an analysis of film portrayals. AB - It is increasingly recognized that community attitudes impact on the research trajectory, entry, and reception of new biotechnologies. Yet biogerontologists have generally been dismissive of public concerns about life extension. There is some evidence that biogerontological research agendas have not been communicated effectively, with studies finding that most community members have little or no knowledge of life extension research. In the absence of knowledge, community members' attitudes may well be shaped by issues raised in popular portrayals of life extension (e.g., in movies). To investigate how popular portrayals of life extension may influence community attitudes, I conducted an analysis of 19 films depicting human life extension across different genres. I focussed on how the pursuit of life extension was depicted, how life extension was achieved, the levels of interest in life extension shown by characters in the films, and the experiences of extended life depicted both at an individual and societal level. This paper compares the results of this analysis with the literature on community attitudes to life extension and makes recommendations about the issues in which the public may require reassurance if they are to support and accept life extension technologies. PMID- 23931760 TI - DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries. Liver samples from morbidly obese patients (n = 45) with all stages of NAFLD and controls (n = 18) were analyzed by array based DNA methylation and mRNA expression profiling. NAFLD-specific expression and methylation differences were seen for nine genes coding for key enzymes in intermediate metabolism (including PC, ACLY, and PLCG1) and insulin/insulin-like signaling (including IGF1, IGFBP2, and PRKCE) and replicated by bisulfite pyrosequening (independent n = 39). Transcription factor binding sites at NAFLD specific CpG sites were >1,000-fold enriched for ZNF274, PGC1A, and SREBP2. Intraindividual comparison of liver biopsies before and after bariatric surgery showed NAFLD-associated methylation changes to be partially reversible. Postbariatric and NAFLD-specific methylation signatures were clearly distinct both in gene ontology and transcription factor binding site analyses, with >400 fold enrichment of NRF1, HSF1, and ESRRA sites. Our findings provide an example of treatment-induced epigenetic organ remodeling in humans. PMID- 23931762 TI - An evidence-based systematic review of active hexose correlated compound (AHCC) by the Natural Standard Research Collaboration. AB - An evidence-based systematic review of active hexose correlated compound (AHCC) by the Natural Standard Research Collaboration consolidates the safety and efficacy data available in the scientific literature using a validated, reproducible grading rationale. This article includes written and statistical analysis of clinical trials, plus a compilation of expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 23931763 TI - Infected cardiac myxoma. AB - A 66-year-old male presenting with low-grade fever and general fatigue was diagnosed as having infected myxoma of the left atrium. Blood cultures grew Streptococcus mitis. He underwent urgent resection and histological examination revealed tumor cells in a mucopolysaccharide matrix and bacterial colonies along with active inflammation. Infected cardiac myxoma is extremely rare; however, it contains a potential risk of arterial embolization and so early diagnosis and urgent surgery should be considered. PMID- 23931764 TI - A novel avenue to gold nanostructured microtubes using functionalized fiber as the ligand, the reductant, and the template. AB - Gold nanostructured microtubes (AuNMTs) are prepared using a tertiary amine group functionalized polyethylene (PE)-coated polypropylene (PP) nonwoven fabric as a ligand, a reductant, and a template, which takes advantage of the different radiation effects of PE and PP. The Au(III) ions are absorbed and reduced only in the PE layer to form the aggregation of gold nanoparticles; thus, AuNMTs are obtained after the calcination. PMID- 23931765 TI - Letter to the editor: Simulator for spine pathologies. PMID- 23931766 TI - A systematic review of evaluation methods for neonatal brachial plexus palsy. AB - Object Neonatal brachial plexus palsy (NBPP) affects 0.4-2.6 newborns per 1000 live births in the US. Many infants recover spontaneously, but for those without spontaneous recovery, nerve and/or secondary musculoskeletal reconstruction can restore function to the affected arm. This condition not only manifests in a paretic/paralyzed arm, but also affects the overall health and psychosocial condition of the children and their parents. Currently, measurement instruments for NBPP focus primarily on physical ability, with limited information regarding the effect of the disablement on activities of daily living and the child's psychosocial well-being. It is also difficult to assess and compare overall treatment efficacy among medical (conservative) or surgical management strategies without consistent use of evaluation instruments. The purpose of this study is to review the reported measurement evaluation methods for NBPP in an attempt to provide recommendations for future measurement usage and development. Methods The authors systematically reviewed the literature published between January 1980 and February 2012 using multiple databases to search the keywords "brachial plexus" and "obstetric" or "pediatrics" or "neonatal" or "congenital." Original articles with primary patient outcomes were included in the data summary. Four types of evaluation methods (classification, diagnostics, physical assessment, and functional outcome) were distinguished among treatment management groups. Descriptive statistics and 1-way ANOVA were applied to compare the data summaries among specific groups. Results Of 2836 articles initially identified, 307 were included in the analysis, with 198 articles (9646 patients) reporting results after surgical treatment, 70 articles (4434 patients) reporting results after medical treatment, and 39 articles (4247 patients) reporting results after combined surgical and medical treatment. Among medical practitioners who treat NBPP, there was equivalence in usage of classification, diagnostic, and physical assessment tools (that focused on the Body Function and Structures measure of the International Classification of Functioning, Disability, and Health [ICF]). However, there was discordance in the functional outcome measures that focus on ICF levels of Activity and Participation. Of the 126 reported evaluation methods, only a few (the Active Movement Scale, Toronto Scale Score, Mallet Scale, Assisting Hand Assessment, and Pediatric Outcomes Data Collection Instrument) are specifically validated for evaluating the NBPP population. Conclusions In this review, the authors demonstrate disparities in the use of NBPP evaluation instruments in the current literature. Additionally, valid and reliable evaluation instruments specifically for the NBPP population are significantly lacking, manifesting in difficulties with evaluating the overall impact and effectiveness of clinical treatments in a consistent and comparative manner, extending across the various subspecialties that are involved in the treatment of patients with NBPP. The authors suggest that all ICF domains should be considered, and future efforts should include consideration of spontaneous (not practitioner-elicited) use of the affected arm in activities of daily living with attention to the psychosocial impact of the disablement. PMID- 23931767 TI - Worsening or development of syringomyelia following Chiari I decompression: case report. AB - OBJECT: The effects of posterior fossa decompression on Chiari malformation Type I-induced syringomyelia have been well described. However, treatment of worsening syringomyelia after Chiari decompression remains enigmatic. This paper defines patient and clinical characteristics as well as treatment and postoperative radiological and clinical outcomes in patients experiencing this complication. METHODS: The authors performed a retrospective review of patients at the Children's Hospital of Pittsburgh and Children's of Alabama who developed worsening syringomyelia after Chiari decompression was performed. RESULTS: Fourteen children (age range 8 months to 15 years), 7 of whom had preoperative syringomyelia, underwent posterior fossa decompression. Aseptic meningitis (n = 3) and bacterial meningitis (n = 2) complicated 5 cases (4 of these patients were originally treated at outside hospitals). Worsening syringomyelia presented a median of 1.4 years (range 0.2-10.3 years) after the primary decompression. Ten children presented with new, recurrent, or persistent symptoms, and 4 were asymptomatic. Secondary Chiari decompression was performed in 11 of the 14 children. The other 3 children were advised to undergo secondary decompression. A structural cause for each failed primary Chiari decompression (for example, extensive scarring, suture in the obex, arachnoid web, residual posterior arch of C-1, and no duraplasty) was identified at the secondary operation. After secondary decompression, 8 patients' symptoms completely resolved, 1 patient's condition stabilized, and 2 patients remained asymptomatic. Radiologically, 10 of the 11 children had a decrease in the size of their syringes, and 1 child experienced no change (but improved clinically). The median follow-up from initial Chiari decompression was 3.1 years (range 0.8-14.1 years) and from secondary decompression, 1.3 years (range 0.3-4.5 years). No patient underwent syringopleural shunting or other nonposterior fossa treatment for syringomyelia. CONCLUSIONS: Based on the authors' experience, children with worsening syringomyelia after decompression for Chiari malformation Type I generally have a surgically remediable structural etiology, and secondary exploration and decompression should be considered. PMID- 23931768 TI - Reduction in neural injury with earlier delivery in a mouse model of congenital myelomeningocele: laboratory investigation. AB - OBJECT: The authors undertook this study to assess the effect of preterm delivery with respect to neural protection in a congenital myelomeningocele (MMC) mouse model. METHODS: After confirmation of pregnancy in 15 female mice, a congenital MMC model was produced by administration of retinoic acid on the 7th day of gestation. The pregnant mice underwent cesarean sections on Days 15 (n = 5, Group E15), 17 (n = 5, Group E17), and 19 (n = 5, Group E19). Histological analyses were conducted on the lumbar defect and on the craniocervical junction in all fetuses with MMC. RESULTS: Fetuses in Group E19 showed the most significant injury to neural tissue of the spinal cord at the MMC area followed by those in Group E17, with Group E15 being the least affected. All groups exhibited a degree of Chiari malformation; Group E19 was the most affected, followed by Group E17, and Group E15 was the least affected. CONCLUSIONS: Development of both Chiari malformation and exposed spinal cord injury are progressive during gestation. Preterm delivery in this mouse model of congenital MMC may minimize the degree of injury to the spinal cord neural tissue and the degree of Chiari malformation. PMID- 23931769 TI - Clinical utility of immunohistochemistry for the detection of the BRAF v600e mutation in papillary thyroid carcinoma. AB - BACKGROUND: BRAF V600E mutation is the most common genetic alteration in papillary thyroid cancer (PTC). We used a mutation-specific antibody for immunohistochemical (IHC) detection of the BRAF V600E mutation and correlated expression with clinicopathologic features. The study was designed to validate the accuracy and determine the clinical importance of IHC detection of the BRAF V600E mutation in PTC. METHODS: Direct sequencing and IHC for BRAF V600E mutation was performed in 37 consecutive patients with PTCs. IHC was scored on an intensity proportion scale. IHC positive tumors were stratified into intensity categories. The categories were assessed for clinicopathologic variables, including age, extrathyroidal extension, lymphovascular invasion, and lymph node metastases. RESULTS: A total of 25 PTCs were BRAF V600E-positive and 12 were BRAF mutation-negative on IHC. The BRAF V600E mutation-specific antibody had a sensitivity of 89% and specificity of 100% for detecting the mutation. Tumors with high-intensity staining were more likely to have extrathyroidal extension. CONCLUSION: IHC is an accurate method for the detection of the BRAF V600E mutation in PTC, and its ability to quantify the mutation expression may serve as a better predictor of tumor behavior than molecular sequencing. It provides a potentially rapid, easily applicable, and economic alternative to current techniques. PMID- 23931771 TI - Prelude to the peripheral neuropathies. PMID- 23931770 TI - Hypoxia-induced miR-210 modulates tissue response to acute peripheral ischemia. AB - AIMS: Peripheral artery disease is caused by the restriction or occlusion of arteries supplying the leg. Better understanding of the molecular mechanisms underpinning tissue response to ischemia is urgently needed to improve therapeutic options. The aim of this study is to investigate hypoxia-induced miR 210 regulation and its role in a mouse model of hindlimb ischemia. RESULTS: miR 210 expression was induced by femoral artery dissection. To study the role of miR 210, its function was inhibited by the systemic administration of a miR-210 complementary locked nucleic acid (LNA)-oligonucleotide (anti-miR-210). In the ischemic skeletal muscle, anti-miR-210 caused a marked decrease of miR-210 compared with LNA-scramble control, while miR-210 target expression increased accordingly. Histological evaluation of acute tissue damage showed that miR-210 inhibition increased both apoptosis at 1 day and necrosis at 3 days. Capillary density decrease caused by ischemia was significantly more pronounced in anti-miR 210-treated mice; residual limb perfusion decreased accordingly. To investigate the molecular mechanisms underpinning the increased damage triggered by miR-210 blockade, we tested the impact of anti-miR-210 treatment on the transcriptome. Gene expression analysis highlighted the deregulation of mitochondrial function and redox balance. Accordingly, oxidative damage was more severe in the ischemic limb of anti-miR-210-treated mice and miR-210 inhibition increased oxidative metabolism. Further, oxidative-stress resistant p66(Shc)-null mice displayed decreased tissue damage following ischemia. INNOVATION: This study identifies miR 210 as a crucial element in the adaptive mechanisms to acute peripheral ischemia. CONCLUSIONS: The physiopathological significance of miR-210 is context dependent. In the ischemic skeletal muscle it seems to be cytoprotective, regulating oxidative metabolism and oxidative stress. PMID- 23931773 TI - Gross anatomy and development of the peripheral nervous system. AB - The nervous system is divided into the central nervous system (CNS) composed of the brain, the brainstem, the cerebellum, and the spinal cord and the peripheral nervous system (PNS) made up of the different nerves arising from the CNS. The PNS is divided into the cranial nerves III to XII supplying the head and the spinal nerves that supply the upper and lower limbs. The general anatomy of the PNS is organized according to the arrangement of the fibers along the rostro caudal axis. The control of the development of the PNS has been unravelled during the last 30 years. Motor nerves arise from the ventral neural tube. This ventralization is induced by morphogenetic molecules such as sonic hedgehog. In contrast, the sensory elements of the PNS arise from a specific population of cells originating from the roof of the neural tube, namely the neural crest. These cells give rise to the neurons of the dorsal root ganglia, the autonomic ganglia and the paraganglia including the adrenergic neurons of the adrenals. Furthermore, the supportive glial Schwann cells of the PNS originate from the neural crest cells. Growth factors as well as myelinating proteins are involved in the development of the PNS. PMID- 23931772 TI - Microscopic anatomy: normal structure. AB - A peripheral nerve trunk is composed of nerve fascicles supported in a fibrous collagenous sheath and defined by concentric layers of cells (the perineurium) that separate the contents (the endoneurium) from its fibrous collagen support (the epineurium). In the endoneurium are myelinated and unmyelinated fibers that are axons combined with their supporting Schwann cells to provide physical and electrical connections with end-organs such as muscle fibers and sensory endings. Axons are tubular neuronal extensions with a cytoskeleton of neurotubules and tubulin along which organelles and proteins can travel between the neuronal cell body and the axon terminal. During development some axons enlarge and are covered by a chain of Schwann cells each associated with just one axon. As the axons grow in diameter, the Schwann cells wrap round them to produce a myelin sheath. This consists of many layers of compacted Schwann cell membrane plus some additional proteins. Adjacent myelin segments connect at highly specialized structures, the nodes of Ranvier. Myelin insulates the axon so that the nerve impulse can jump from one node to the next. The region adjacent to the node, the paranodal segment, is the site of myelin terminations on the axolemma. There are connections here between the Schwann cell and the axon via a complex chain of proteins. The Schwann cell cytoplasm in the adjacent segment, the juxtaparanode, contains most of the Schwann cell mitochondria. In addition to the node, continuity of myelin lamellae is broken at intervals along the internode by helical regions of decompaction known as Schmidt-Lanterman incisures; these are seen as paler conical segments in suitably stained microscopical preparations and provide a pathway between the adaxonal and abaxonal cytoplasm. Smaller axons without a myelin sheath conduct very much more slowly and have a more complex relationship with their supporting Schwann cells that has important implications for repair. PMID- 23931774 TI - Physiology and pathophysiology of myelinated nerve fibers. AB - The chief role of the axon is that of impulse conduction, which depends on the electrical cable structure and voltage-dependent ion channels of the axonal membrane. Over recent decades, the development of specialized techniques such as patch clamping and site-directed mutagenesis have established the contribution of neuronal ion channel function to the processes of impulse conduction in myelinated nerves. Recently, these insights from in vitro studies have been translated into the clinical realm. In keeping with this progress, clinical axonal excitability techniques have been developed to provide information related to the activity of a variety of ion channels, energy-dependent pumps, and ion exchange processes activated during impulse conduction in peripheral axons. These noninvasive techniques have been extensively applied to the study of the biophysical properties of human peripheral nerves in vivo and have provided important insights into axonal ion channel function in health and neurological disease, particularly in relation to the pathophysiological mechanisms that underlie neuropathy. PMID- 23931775 TI - Biology of Schwann cells. AB - The fundamental roles of Schwann cells during peripheral nerve formation and regeneration have been recognized for more than 100 years, but the cellular and molecular mechanisms that integrate Schwann cell and axonal functions continue to be elucidated. Derived from the embryonic neural crest, Schwann cells differentiate into myelinating cells or bundle multiple unmyelinated axons into Remak fibers. Axons dictate which differentiation path Schwann cells follow, and recent studies have established that axonal neuregulin1 signaling via ErbB2/B3 receptors on Schwann cells is essential for Schwann cell myelination. Extracellular matrix production and interactions mediated by specific integrin and dystroglycan complexes are also critical requisites for Schwann cell-axon interactions. Myelination entails expansion and specialization of the Schwann cell plasma membrane over millimeter distances. Many of the myelin-specific proteins have been identified, and transgenic manipulation of myelin genes have provided novel insights into myelin protein function, including maintenance of axonal integrity and survival. Cellular events that facilitate myelination, including microtubule-based protein and mRNA targeting, and actin based locomotion, have also begun to be understood. Arguably, the most remarkable facet of Schwann cell biology, however, is their vigorous response to axonal damage. Degradation of myelin, dedifferentiation, division, production of axonotrophic factors, and remyelination all underpin the substantial regenerative capacity of the Schwann cells and peripheral nerves. Many of these properties are not shared by CNS fibers, which are myelinated by oligodendrocytes. Dissecting the molecular mechanisms responsible for the complex biology of Schwann cells continues to have practical benefits in identifying novel therapeutic targets not only for Schwann cell-specific diseases but other disorders in which axons degenerate. PMID- 23931776 TI - Neurophysiological approach to disorders of peripheral nerve. AB - Disorders of the peripheral nerve system (PNS) are heterogeneous and may involve motor fibers, sensory fibers, small myelinated and unmyelinated fibers and autonomic nerve fibers, with variable anatomical distribution (single nerves, several different nerves, symmetrical affection of all nerves, plexus, or root lesions). Furthermore pathological processes may result in either demyelination, axonal degeneration or both. In order to reach an exact diagnosis of any neuropathy electrophysiological studies are crucial to obtain information about these variables. Conventional electrophysiological methods including nerve conduction studies and electromyography used in the study of patients suspected of having a neuropathy and the significance of the findings are discussed in detail and more novel and experimental methods are mentioned. Diagnostic considerations are based on a flow chart classifying neuropathies into eight categories based on mode of onset, distribution, and electrophysiological findings, and the electrophysiological characteristics in each type of neuropathy are discussed. PMID- 23931777 TI - Testing the autonomic nervous system. AB - Autonomic testing is used to define the role of the autonomic nervous system in diverse clinical and research settings. Because most of the autonomic nervous system is inaccessible to direct physiological testing, in the clinical setting the most widely used techniques entail the assessment of an end-organ response to a physiological provocation. The noninvasive measures of cardiovascular parasympathetic function involve the assessment of heart rate variability while the measures of cardiovascular sympathetic function assess the blood pressure response to physiological stimuli. Tilt-table testing, with or without pharmacological provocation, has become an important tool in the assessment of a predisposition to neurally mediated (vasovagal) syncope, the postural tachycardia syndrome, and orthostatic hypotension. Distal, postganglionic, sympathetic cholinergic (sudomotor) function may be evaluated by provoking axon reflex mediated sweating, e.g., the quantitative sudomotor axon reflex (QSART) or the quantitative direct and indirect axon reflex (QDIRT). The thermoregulatory sweat test provides a nonlocalizing measure of global pre- and postganglionic sudomotor function. Frequency domain analyses of heart rate and blood pressure variability, microneurography, and baroreflex assessment are currently research tools but may find a place in the clinical assessment of autonomic function in the future. PMID- 23931778 TI - Imaging of the peripheral nervous system. AB - This chapter summarizes progress in the evaluation of peripheral nerve (PN) lesions and disorders by imaging techniques encompassing magnetic resonance imaging (MRI) and nerve ultrasound (US). Due to the radiation exposure and limited sensitivity in soft tissue contrast, computed-tomography (CT) plays no significant role in the diagnostic work-up of PN disorders. MRI and US are complementary techniques for the evaluation of peripheral nerves, each having particular advantages and disadvantages. Nerve injury induces intrinsic MRI signal alterations on T2-weighted sequences in degenerating or demyelinating nerve segments as well as in corresponding muscle groups exhibiting denervation which can be exploited diagnostically. Nerve US is based on changes in the nerve echotexture due to tumor formation or focal enlargement caused by entrapment or inflammation. Both MRI and US provide morphological information on the precise site and extent of nerve injury. While US has the advantage of easy accessibility, providing images with superior spatial resolution at low cost, MRI shows better soft tissue contrast and better image quality for deep-lying nerve structures since imaging is not hindered by bone. Recent advances have remarkably increased spatial resolution of both MRI and US making imaging indispensible for the elucidation of causes of nerve compression, peripheral nerve tumors, and focal inflammatory conditions. Both MRI and US further guide neurosurgical exploration and can simplify treatment. Importantly, imaging can reveal treatable conditions even in the absence of gross electrophysiological alterations, illustrating its increasing role in clinical practice. In experimental settings, novel molecular and cellular MRI contrast agents allow in-vivo assessment of nerve regeneration as well as monitoring of neuroinflammation. Depending on further clinical development, contrast-enhanced MRI has the potential to follow cellular responses over time in vivo and to overcome the current limitations of histological assessment of nerve afflictions. Further advances in contrast enhanced US has the potential for developing into a tool for the assessment of nerve blood perfusion, paving the way for better assessments of ischemic neuropathies. PMID- 23931779 TI - The nerve biopsy: indications, technical aspects, and contribution. AB - This chapter discusses the indications for biopsying a peripheral nerve and the factors involved in justifying this decision and then deciding which nerve to take. There is a table summarizing some of the causes of neuropathy and attempting to relate these to the probability that nerve biopsy would be helpful in diagnosis. The surgical procedure for the nerve biopsy is described including aftercare and possible complications. The techniques involved in processing and staining the nerve are discussed. This section includes the possibilities of creating artefactual damage by mishandling or poor technique, and how to avoid these. Modification to the standard resin processing schedule to allow the teasing out of individual nerve fibers is briefly described, as are methods for measuring fiber density, fiber size and myelin thickness. There is also a brief discussion of the applications of immunohistochemistry. This is followed by a section on interpretation by light and electron microscopy in which some of the more important diagnostic features are described and illustrated, as are nonspecific morphological findings. Interpretation of teased fiber preparations is discussed. Finally, some common causes of incorrect interpretation are mentioned. PMID- 23931780 TI - The cutaneous nerve biopsy: technical aspects, indications, and contribution. AB - Skin biopsy with a 3mm disposable circular punch is easy to perform and allows, after proper processing, the visualization of epidermal, dermal, and sweat gland nerve fibers. A technique of sampling the epidermis alone by applying a suction capsule, the "blister" technique, has also been developed. It is most common to stain immunohistochemically for the pan-axonal marker protein gene product 9.5 (PGP 9.5), an ubiquitin C-terminal hydroxylase. The sections are then observed and analyzed with bright-field microscopy or with indirect immunofluorescence with or without confocal microscopy. Most studies report quantification of intraepidermal nerve fiber density displayed in bright-field microscopy. Normative values have been established, particularly from the distal part of the leg, 10cm above the external malleolus. In diabetes mellitus early degeneration of intraepidermal nerve fibers is induced and there is slower regeneration even when there is no evidence of neuropathy. Skin biopsy is of particular value in the diagnosis of small fiber neuropathy when nerve conduction studies are normal. It may also be repeated in order to study the progressive nature of the disease and also has the potential of studying regeneration of nerve fibers and thus the effects of treatment. Inflammatory demyelinating neuropathies may also involve loss of small-diameter nerve fibers and IgM deposits in dermal myelinated nerve fibers in anti-MAG neuropathy. In some cases the presence of vasculitis in skin may indicate a nonsystemic vasculitic neuropathy and in HIV neuropathy intraepidermal nerve fiber density is reduced in a length-dependent manner. In several hereditary neuropathies intraepidermal nerve fiber density may be reduced but other abnormalities can also be demonstrated in dermal myelinated fibers. Some small swellings and varicosities may be present in the distal leg skin biopsy of healthy individuals but large axonal swellings are considered as evidence of a pathological process affecting the normal structure of nerves. The indirect immunofluorescence technique with confocal microscopy provides the opportunity to study the complex structure of sensory receptors and cutaneous myelinated fibers and the innervation of sweat glands, arrector pilorum muscles, and vessels. PMID- 23931781 TI - Antibody testing in peripheral nerve disorders. AB - The identification of autoantibodies associated with dysimmune neuropathies was a major contribution to the characterization of peripheral nerve disorders, the understanding of their pathophysiology, and the clinical diagnosis of neuropathies. Antibodies directed to GM1, GQ1b, and disyalilated gangliosides, and anti-MAG antibodies are very useful in the diagnosis of acute or chronic motor or sensory-motor neuropathies with or without monoclonal IgM. Anti onconeural anti-Hu and anti-CV2/CRMP antibodies allow when they are detected the diagnosis of paraneoplastic neuropathies. This chapter focuses on the description of these antibodies as diagnostic markers and on their immunopathogenesis. We give a background overview on the origin of these antibodies, their detection, and review those studies, which clearly show that these antibodies are capable of binding to the target tissues in peripheral nerve and thereby can exert a variety of pathophysiological effects. The corresponding electrophysiological and histological changes observed both in human and animal models are exemplified in order to get a better understanding of the immune mechanisms of these antibody mediated neuropathies. PMID- 23931782 TI - DNA testing in hereditary neuropathies. AB - The inherited neuropathies are a clinically and genetically heterogeneous group of disorders in which there have been rapid advances in the last two decades. Molecular genetic testing is now an integral part of the evaluation of patients with inherited neuropathies. In this chapter we describe the genes responsible for the primary inherited neuropathies. We briefly discuss the clinical phenotype of each of the known inherited neuropathy subgroups, describe algorithms for molecular genetic testing of affected patients and discuss genetic counseling. The basic principles of careful phenotyping, documenting an accurate family history, and testing the available genes in an appropriate manner should identify the vast majority of individuals with CMT1 and many of those with CMT2. In this chapter we also describe the current methods of genetic testing. As advances are made in molecular genetic technologies and improvements are made in bioinformatics, it is likely that the current time-consuming methods of DNA sequencing will give way to quicker and more efficient high-throughput methods, which are briefly discussed here. PMID- 23931783 TI - Examination and clinical care of the patient with neuropathy. AB - Examination of a patient with peripheral neuropathy starts with careful questioning of the patient about the history of symptoms and signs and of a possible familial disorder. Several steps are required during examination of the patient with peripheral neuropathy: first the pattern of neuropathy and site of lesions should be determined: roots, nerve trunks, focal, multifocal, length dependent generalized polyneuropathy, the type of nerve fibers predominantly affected, the association with trophic changes and autonomic dysfunction, the course of the disease ranging from acute inflammatory polyneuritis or fulminant multifocal neuropathy to an extremely slow progression as in Charcot-Marie-Tooth syndromes. At the end of this first contact with the patient, the neurologist must decide which investigations seem necessary and their timing including electrophysiological tests, imaging, CSF examination, blood tests, nerve and muscle biopsy, DNA testing, etc. In some cases, life-threatening manifestations, including weakness of respiratory muscles or swallowing difficulty, or autonomic dysfunction, require urgent therapeutic decisions. PMID- 23931784 TI - How to explore a patient with a chronic axonal polyneuropathy. AB - Chronic axonal polyneuropathies are very frequently encountered by physicians. It is important to take a systematic approach when evaluating these patients. In this chapter we present such an approach. We present the diagnostic recommendations based on previously published evidence-based reviews and guidelines. PMID- 23931785 TI - Evaluation of a patient with suspected chronic demyelinating polyneuropathy. AB - Demyelinating neuropathies are typically characterized by physiological slowing of conduction velocity and pathologically by segmental loss of myelin and in some instances, evidence of remyelination. Clinically, patients with demyelinating neuropathy can be seen with inherited disorders (Charcot-Marie-Tooth disease) or acquired disorders, typically immune-mediated or inflammatory. The acquired disorders can be either acute or subacute as seen in the acute inflammatory demyelinating polyneuropathy (AIDP) form of Guillain-Barre syndrome or chronic progressive or relapsing disorders such as chronic inflammatory demyelinating polyneuropathy. It is important to develop a logical approach to diagnosing these disorders. This requires an understanding of the clinical, genetic, physiological, and pathological features of these neuropathies. Clinically, important features to consider are the temporal progression, degree of symmetry, and involvement of proximal as well as distal muscles. Genetically, recognizing the different inheritance patterns and age of onset allow for a coordinated approach to determining a specific genotype. Physiologically, besides nerve conduction slowing, other physiological hallmarks of demyelination include temporal dispersion of compound motor action potentials (CMAP) on proximal stimulation, conduction block, and distal CMAP duration prolongation with certain patterns of involvement pointing to specific disorders. This chapter focuses on these various aspects of the evaluation of patients with chronic acquired demyelinating neuropathies to develop a comprehensive and thoughtful diagnostic concept. PMID- 23931786 TI - Sensory-motor assessment in clinical research trials. AB - The assessment of changes in sensory-motor function in clinical research presents a unique set of difficulties. Clinimetrics is the science of measurement as related to the identification of a clinical disorder, the tracing of the progression of the condition under study, and calculation of its impact. The selection of appropriate measures for clinical studies of sensory-motor function must consider validity, sensitivity, specificity, responsiveness, reliability, and feasibility. Reasonable measures of motor function in clinical research include manual examination of muscle strength, electrophysiology, functional scales, patient-reported outcomes (e.g., quality of life), and for severe conditions such as ALS, survival. The assessment of sensory function includes targeted electrophysiology and QOL, as well as more focused measures such as quantitative sensory testing and the scoring of positive symptoms. Each individual measure and each combination of endpoints has its strengths and limitations. PMID- 23931787 TI - Management of painful neuropathies. AB - Neuropathic pain is the most common type of pain in neuropathy. In painful polyneuropathies the pain usually has a "glove and stocking" distribution. The pain may be predominantly spontaneous, e.g., with a burning, pricking, or shooting character or characterized by evoked pain such as mechanical or cold allodynia. In the clinical setting, the prevention of painful neuropathies and treatment of underlying neuropathy remains inadequate and thus symptomatic treatment of the pain and related disability needs to be offered. Most randomized, double-blind, placebo-controlled trials (RCTs) published in painful neuropathy have been conducted in patients with diabetes and to what extent a treatment which is found effective in painful diabetic polyneuropathy can be expected to relieve other conditions like chemotherapy- or HIV-induced neuropathy is unknown. Tricyclic antidepressants (TCAs), gabapentin, pregabalin, and serotonin noradrenaline reuptake inhibitors (SNRIs) are first drug choices. In patients with localized neuropathic pain, a topical lidocaine patch may also be considered. Second-line treatments are tramadol and other opioids. New types of treatment include botulinum toxin type A (BTX-A), high-dose capsaicin patches, and cannabinoids. Other types of anticonvulsant drugs such as lamotrigine, oxcarbazepine, and lacosamide have a more questionable efficacy in painful polyneuropathy but may have an effect in a subgroup of patients. Combination therapy may be considered in patients with insufficient effect from one drug. Treatment is usually a trial-and-error process and has to be individualized to the single patient, taking into account all comorbidities such as possible concomitant depression, anxiety, diseases, and drug interactions. Side-effects to antidepressants include dry mouth, nausea, constipation, orthostatic hypotension, and sedation. ECG should always be obtained prior to treatment with TCAs, which also should not be used in patients with cardiac incompensation and epilepsy. The most common side-effects of gabapentin and pregabalin are CNS-related side effects with dizziness and somnolence. Peripheral edema, weight gain, nausea, vertigo, asthenia, dry mouth, and ataxia may also occur. Topical treatments are better tolerated due to lack of systemic side-effects but there is still limited evidence for the long-term efficacy of these drugs. With available drugs, the average pain reduction is about 20-30%, and only 20-35% of the patients will achieve at least 50% pain reduction, which stresses the need of a multidisciplinary approach to pain treatment. PMID- 23931788 TI - Diagnosis of brachial and lumbosacral plexus lesions. AB - To most doctors, brachial and lumbosacral plexopathies are known as difficult disorders, because of their complicated anatomy and relatively rare occurrence. Both the brachial, lumbar, and sacral plexuses are extensive PNS structures stretching from the neck to axillary region and running in the paraspinal lumbar and pelvic region, containing 100000-200000 axons with 12-15 major terminal branches supplying almost 50 muscles in each limb. The most difficult part in diagnosing a plexopathy is probably that it requires an adequate amount of clinical suspicion combined with a thorough anatomical knowledge of the PNS and a meticulous clinical examination. Once a set of symptoms is recognized as a plexopathy the patients' history and course of the disorder will often greatly limit the differential diagnosis. The most common cause of brachial plexopathy is probably neuralgic amyotrophy and the most common cause of lumbosacral plexopathy is diabetic amyotrophy. Traumatic and malignant lesions are fortunately rarer but just as devastating. This chapter provides an overview of both common and rarer brachial and lumbosacral plexus disorders, focusing on clinical examination, the use of additional investigative techniques, prognosis, and treatment. PMID- 23931789 TI - Compression and entrapment neuropathies. AB - Peripheral nerve entrapments are frequent. They usually appear in anatomical tunnels such as the carpal tunnel. Nerve compressions may be due to external pressure such as the fibular nerve at the fibular head. Malignant or benign tumors may also damage the nerve. For each nerve from the upper and lower limbs, detailed clinical, electrophysiological, imaging, and therapeutic aspects are described. In the upper limbs, carpal tunnel syndrome and ulnar neuropathy at the elbow are the most frequent manifestations; the radial nerve is less frequently involved. Other nerves may occasionally be damaged and these are described also. In the lower limbs, the fibular nerve is most frequently involved, usually at the fibular head by external compression. Other nerves may also be involved and are therefore described. The clinical and electrophysiological examination are very important for the diagnosis, but imaging is also of great use. Treatments available for each nerve disease are discussed. PMID- 23931790 TI - Facial nerve palsy and hemifacial spasm. AB - Facial nerve lesions are usually benign conditions even though patients may present with emotional distress. Facial palsy usually resolves in 3-6 weeks, but if axonal degeneration takes place, it is likely that the patient will end up with a postparalytic facial syndrome featuring synkinesis, myokymic discharges, and hemifacial mass contractions after abnormal reinnervation. Essential hemifacial spasm is one form of facial hyperactivity that must be distinguished from synkinesis after facial palsy and also from other forms of facial dyskinesias. In this condition, there can be ectopic discharges, ephaptic transmission, and lateral spread of excitation among nerve fibers, giving rise to involuntary muscle twitching and spasms. Electrodiagnostic assessment is of relevance for the diagnosis and prognosis of peripheral facial palsy and hemifacial spasm. In this chapter the most relevant clinical and electrodiagnostic aspects of the two disorders are reviewed, with emphasis on the various stages of facial palsy after axonal degeneration, the pathophysiological mechanisms underlying the various features of hemifacial spasm, and the cues for differential diagnosis between the two entities. PMID- 23931791 TI - The Guillain-Barre syndrome. AB - The latest estimation for the frequency of Guillain-Barre syndrome (GBS) is 1.1 to 1.8 per 100000 persons per year. Guillain-Barre syndrome is today divided into two major subtypes: acute inflammatory demyelinating polyneuropathy (AIDP) and the axonal subtypes, acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN). The axonal forms of GBS are caused by certain autoimmune mechanisms, due to a molecular mimicry between antecedent bacterial infection (particularly Campylobacter jejuni) and human peripheral nerve gangliosides. Improvements in patient management in intensive care units has permitted a dramatic drop in mortality rates. Immunotherapy, including plasma exchange (PE) or intravenous immunoglobulin (IVIg), seems to shorten the time to recovery, but their effect remains limited. Further clinical investigations are needed to assess the effect of PE or IVIg on the GBS patients with mild affection, no response, or relapse. PMID- 23931792 TI - Chronic inflammatory demyelinative polyneuropathy. AB - Chronic inflammatory demyelinative polyneuropathy (CIDP) is an acquired polyneuropathy presumably of immunological origin. It is characterized by a progressive or a relapsing course with predominant motor deficit. The diagnosis rests on the association of non-length-dependent predominantly motor deficit following a progressive or a relapsing course associated with increased CSF protein content. The demonstration of asymmetrical demyelinating features on nerve conduction studies is needed for diagnosis. The outcome depends on the amplitude of axon loss associated with demyelination. CIDP must be differentiated from acquired demyelinative neuropathies associated with monoclonal gammopathies. CIDP responds well to treatment with corticosteroids, intravenous immunoglobulins, and plasma exchanges, at least initially. PMID- 23931793 TI - Treatment of chronic inflammatory demyelinating polyradiculoneuropathy. AB - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a sporadically occurring, acquired neuropathic condition of autoimmune origin with chronic progressive or relapsing-remitting disease course. CIDP is a treatable disorder; a variety of immunosuppressive and immunomodulatory agents are available to modify, impede, and even reverse the neurological deficits and sequelae that manifest in the course of the disease. However, in many cases CIDP is not curable. Challenges that remain in the treatment of CIDP patients are well recognized and include a remarkably individual heterogeneity in terms of disease course and treatment response as well as a lack of objective and feasible measures to predict and monitor the responsiveness to the available therapies. In this chapter an overview of the currently used drugs in the treatment of CIDP patients is given and some important and controversial issues that arise in the context of care for CIDP patients are discussed. PMID- 23931794 TI - Multifocal motor neuropathy. AB - Multifocal motor neuropathy (MMN) is a rare disorder in which the symptoms are caused by persistent conduction block lesions. The mononeuropathy multiplex progresses over time with increasing axonal loss. The cause of the conduction blocks and axonal loss are not completely understood but immune mechanisms are involved and response to intravenous immunoglobulin has been established. The importance of MMN goes beyond its clinical incidence as the increasing understanding of the pathogenesis of this disorder has implications for other peripheral nerve diseases and for our knowledge of peripheral nerve biology. PMID- 23931795 TI - Neuropathy and monoclonal gammopathy. AB - The association of neuropathy with monoclonal gammopathy has been known for several years, even if the clinical and pathogenetic relevance of this association is not completely defined. This is not a marginal problem since monoclonal gammopathy is present in 1-3% of the population above 50 years in whom it is often asymptomatic, and in at least 8% of patients is associated with a symptomatic neuropathy, representing one of the leading causes of neuropathy in aged people. Monoclonal gammopathy may result from malignant lymphoproliferative diseases including multiple myeloma or solitary plasmocytoma, Waldenstrom's macroglobulinemia (WM), other IgM-secreting lymphoma or chronic lymphocytic leukemia, and primary systemic amyloidosis (AL). In most instances it is not associated with any of these disorders and is defined monoclonal gammopathy of undetermined significance (MGUS) for its possible, though infrequent, evolution into malignant forms. Several data support the pathogenetic role of the monoclonal gammopathy in the neuropathy particularly when of IgM isotype where IgM reactivity to several neural antigens has been reported. Increased levels of VEGF have been implicated in POEMS syndrome. However, there are as yet no defined therapies for these neuropathies, as their efficacy has not been confirmed in randomized trials. PMID- 23931796 TI - Vasculitic neuropathy. AB - Vasculitis is a primary phenomenon in autoimmune diseases such as polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, and essential mixed cryoglobulinemia. As a secondary feature vasculitis may complicate, for example, connective tissue diseases, infections, malignancies, and diabetes. Vasculitic neuropathy is a consequence of destruction of the vessel wall and occlusion of the vessel lumen of small epineurial arteries. Sometimes patients present with nonsystemic vasculitic neuropathy, i.e., vasculitis limited to peripheral nerves and muscles with no evidence of further systemic involvement. Treatment with corticosteroids, sometimes in combination with other immunosuppressants, is required to control the inflammatory process and prevent further ischemic nerve damage. PMID- 23931797 TI - Sarcoidosis of the peripheral nervous system. AB - Neurological manifestations of sarcoidosis are relatively rare but constitute a treatable cause of central and peripheral neurological manifestations. Regarding the peripheral nervous system, cranial nerves are predominantly affected, and peripheral facial nerve palsy, often bilateral, is the most common neurological manifestation of sarcoidosis. Multifocal peripheral neuropathy is a rare event in sarcoidosis. In some cases, however, peripheral neuropathy is the presenting manifestation and seemingly the only organ affected. Definite diagnosis of sarcoidosis rests ideally on histological demonstration of sarcoid granulomas in tissue biopsy specimens. PMID- 23931798 TI - Leprous neuropathy. AB - Leprous neuropathy, which is due to infection of nerve cells by Mycobacterium leprae, still affects millions of people in many developing countries. The clinical and pathological manifestations are determined by the natural resistance of the host to invasion of M. Leprae. Failure of early detection of leprosy often leads to severe disability in spite of eradication of mycobacterium at a later date. In the lepromatous type, bacilli are easily found in the skin and in nerve cells including Schwann cells, endothelial cells, and macrophages. In the tuberculoid type, a strong cell-mediated immune reaction leads to formation of granulomas and destruction of cells harboring bacilli and neighboring nerve fibers. In many cases, treatment of patients with the multibacillary leprosy is complicated by reversal reaction and further nerve damage. Nerve lesions lead to a symmetrical, pseudo-polyneuritic pattern in most cases of lepromatous leprosy, which is usually associated with typical skin lesions, but pure neuritic forms occur in up to 10% of patients with lepromatous leprosy. In the pure neuropathic cases, only nerve biopsy permits diagnosis. The multifocal pattern is more common in tuberculoid leprosy. Treatment is currently based on multidrug therapy with dapsone, rifampicin, and clofazimine. The use of corticosteroids can reduce or prevent nerve damage in reversal reactions. It is important to remember that sequelae, especially sensory loss, are extremely common, which can lead to secondary trophic changes due to repeated trauma in painless areas. PMID- 23931799 TI - HIV peripheral neuropathy. AB - Peripheral neuropathies are the most common neurological manifestations occurring in HIV-infected individuals. Distal symmetrical sensory neuropathy is the most common form encountered today and is one of the few that are specific to HIV infection or its treatment. The wide variety of other neuropathies is akin to the neuropathies seen in the general population and should be managed accordingly. In the pre-ART era, neuropathies were categorized according to the CD4 count and HIV viral load. In the early stages of HIV infection when CD4 count is high, the inflammatory demyelinating neuropathies predominate and in the late stages with the decline of CD4 count opportunistic infection-related neuropathies prevail. That scenario has changed with the present almost universal use of ART (antiretroviral therapy). Hence, HIV-associated peripheral neuropathies are better classified according to their clinical presentations: distal symmetrical polyneuropathy, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), mononeuropathies, mononeuropathies multiplex and cranial neuropathies, autonomic neuropathy, lumbosacral polyradiculomyelopathy, and amyotrophic lateral sclerosis (ALS)-like motor neuropathy. Treated with ART, HIV-infected individuals are living longer and are at a higher risk of metabolic and age-related complications; moreover they are also prone to the potentially neurotoxic effects of ART. There are no epidemiological data regarding the incidence and prevalence of the peripheral neuropathies. In the pre-ART era, most data were from case reports, series of patients, and pooled autopsy data. At that time the histopathological evidence of neuropathies in autopsy series was almost 100%. In large prospective cohorts presently being evaluated, it has been found that 57% of HIV-infected individuals have distal symmetrical sensory neuropathy and 38% have neuropathic pain. It is now clear that distal symmetrical sensory neuropathy is caused predominantly by the ART's neurotoxic effect but may also be caused by the HIV itself. With a sizeable morbidity, the neuropathic pain caused by distal symmetrical sensory neuropathy is very difficult to manage; it is often necessary to change the ART regimen before deciding upon the putative role of HIV infection itself. If the change does not improve the pain, there are few options available; the most common drugs used for neuropathic pain are usually not effective. One is left with cannabis, which cannot be recommended as routine therapy, recombinant human nerve growth factor, which is unavailable, and topical capsaicin with its side-effects. Much has been done to and learned from HIV infection in humans; HIV infected individuals, treated with ART, are now dying mostly from cardiovascular disease and non-AIDS-related cancers. It hence behooves us to find new approaches to mitigate the residual neurological morbidity that still impacts the quality of life of that population. PMID- 23931800 TI - Human T-cell leukemia virus (HTLV)-associated neuropathy. AB - Symptomatic peripheral neuropathy occurs in a small proportion of HTLV-1 infected patients. Peripheral manifestations are often masked by symptoms and signs of the tropical spastic myelopathy characteristic of the disease. Peripheral neuropathy is often characterized by alteration of small-fiber functions, with inflammatory lesions of peripheral nerves, sometimes associated with symptomatic polymyositis, which may occur in isolation in this setting. PMID- 23931801 TI - Herpes virus infection of the peripheral nervous system. AB - Among the human herpes viruses, three are neurotropic and capable of producing severe neurological abnormalities: herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV). Both the acute, primary infection and the reactivation from the site of latent infection, the dorsal sensory ganglia, are associated with severe human morbidity and mortality. The peripheral nervous system is one of the major loci affected by these viruses. The present review details the virology and molecular biology underlying the human infection. This is followed by detailed description of the symtomatology, clinical presentation, diagnosis, course, therapy, and prognosis of disorders of the peripheral nervous system caused by these viruses. PMID- 23931802 TI - Lyme neuroborreliosis. AB - Lyme neuroborreliosis (LNB) designates the nervous system disorders caused by the tick-borne spirochete Borrelia burgdorferi (Bb). The clinical syndromes are usually distinct and are classified as early and the rare late or chronic LNB. Early LNB occurs 3-6 weeks after infection most frequently as a lymphocytic meningoradiculoneuritis (LMR). Symptoms are mainly due to a painful sensory radiculitis and a multifocal motor radiculo-neuritis. Fifty percent have cranial nerve involvement predominantly uni- or bilateral facial nerve palsies. Meningitic symptoms occur primarily in children. Nerve biopsies, autopsies, animal models, and nerve conduction studies showed that the pathology is a lymphocytic perineuritis leading to multisegmental axonal injury of nerve roots, spinal ganglia, and distal nerve segments. Due to meningeal and root inflammation cerebrospinal fluid (CSF) shows lymphocytic inflammation. The only evidence that Bb causes peripheral neuropathy without CSF inflammation is seen in patients with acrodermatitis chronica atrophicans (ACA), a chronic dermatoborreliosis. In the rare chronic or late LNB the pathology and thus the clinical presentation is primarily due to chronic meningitis and meningovascular CNS involvement, whereas the peripheral nervous system is not primarily affected. In early and late LNB the diagnosis is based on a characteristic clinical appearance and CSF inflammation with Bb-specific intrathecal antibody production. Both conditions, but not the ACA-associated neuropathy, respond to antibiotic therapy. PMID- 23931803 TI - Diabetic neuropathy. AB - Diabetes is the most common cause of peripheral neuropathy in the world. Both type 1 (insulin-dependent) and type 2 diabetes are commonly complicated by peripheral nerve disorders. Two main types of neuropathy are observed: the most common is a nerve fiber length-dependent, distal symmetrical sensory polyneuropathy with little motor involvement but frequent, and potentially life threatening, autonomic dysfunction. Alteration of temperature and pain sensations in the feet is an early manifestation of diabetic polyneuropathy. The second pattern is a focal neuropathy, which more commonly complicates or reveals type 2 diabetes. Poor diabetic control increases the risk of neuropathy with subsequent neuropathic pains and trophic changes in the feet, which can be prevented by education of patients. PMID- 23931804 TI - Biology of diabetic neuropathy. AB - More than half of all patients with diabetes develop neuropathic disorders affecting the distal sensory and/or motor nerves, or autonomic or cranial nerve functions. Glycemic control can decrease the incidence of neuropathy but is not adequate alone to prevent or treat the disease. This chapter introduces diabetic neuropathy with a morphological description of the disease then describes our current understanding of metabolic and molecular mechanisms that contribute to neurovascular dysfunctions. Key mechanisms include glucose and lipid imbalances and insulin resistance that are interconnected via oxidative stress, inflammation, and altered gene expression. These complex interactions should be considered for the development of new treatment strategies against the onset or progression of neuropathy. Advances in understanding the combined metabolic stressors and the novel study of epigenetics suggest new therapeutic targets to combat this morbid and intractable disease affecting millions of patients with type 1 or type 2 diabetes. PMID- 23931805 TI - Uremic neuropathy. AB - Polyneuropathy is a common complication of end-stage renal failure especially when treatment with periodic hemodialysis is started too late. Large myelinated fibers bear the brunt of the many biological changes associated with renal failure. Nerve conduction slowing is common in this setting. Compression of the median nerve in the carpal tunnel commonly occurs in these patients, as a result of amyloid deposits at this site. End-stage renal failure in diabetic patients is often associated with severe distal motor and sensory deficits. Improved quality of periodic hemodialysis and renal transplantation have dramatically reduced the prevalence and severity of peripheral neuropathy in these patients. PMID- 23931806 TI - Porphyric neuropathy. AB - Porphyric neuropathy often poses a diagnostic dilemma; it is typically associated with the hepatic porphyrias, characterized by acute life-threatening attacks of neurovisceral symptoms that mimic a range of acute medical and psychiatric conditions. The development of acute neurovisceral attacks is responsive to environmental factors, including drugs, hormones, and diet. This chapter reviews the clinical manifestations, genetics, pathophysiology, and mechanisms of neurotoxicity of the acute hepatic porphyrias. While the etiology of the neurological manifestations in the acute porphyrias remains undefined, the main hypotheses include toxicity of porphyrin precursors and deficiency of heme synthesis. These hypotheses will be discussed with reference to novel experimental models of porphyric neuropathy. PMID- 23931807 TI - Fabry disease. AB - Fabry disease results from deficient activity of the enzyme alpha-galactosidase A and progressive lysosomal deposition of globotriaosylceramide (GL-3) in cells throughout the body. The main neurological presentations of Fabry disease patients are painful neuropathy, hypohidrosis, and stroke. Fabry neuropathy is characterized as a length-dependent peripheral neuropathy affecting mainly the small myelinated (Adelta) fibers and unmyelinated (C) fibers. Enzyme replacement therapy (ERT) has been shown to have some positive effects on the reduction of neuropathic pain, the improvement of detection threshold for thermal sensation, and sweat function. On the contrary, the effect of ERT on the central nervous system has not been established. Early initiation of ERT before irreversible organ failure is extremely important, and alternative therapeutic approaches are currently being explored. Heterozygotes suffer from peripheral neuropathy at a higher rate than previously shown, significant multisystemic disease, and severely decreased quality of life. As well as being carriers, heterozygotes also display symptoms of Fabry disease, and should be carefully monitored and given adequate therapy. PMID- 23931808 TI - Transthyretin familial amyloid polyneuropathy. AB - TTR FAP is characterized by phenotypic and genotypic heterogeneity. The severity of polyneuropathy along with autonomic dysfunction and heart involvement makes it a life-threatening disease. This protein is mainly produced by the liver. Molecular genetic testing is essential in the diagnostic strategy. TTR-Val30Met is the most frequent substitution, resulting in a guanine to cytosine mutation in exon 2 of the gene. It is virtually the only variant detected in Portugal, Brazil, and Sweden. By contrast, as many as 30 different TTR variants are reported in Japan and in other European countries. A less severe phenotype with late onset has been reported. Diagnosis should be performed as early as possible since upcoming pharmacological therapeutic approaches are now available, in addition to liver transplantation. PMID- 23931809 TI - Hereditary gelsolin amyloidosis. AB - Hereditary gelsolin amyloidosis (HGA) is an autosomally dominantly inherited form of systemic amyloidosis, characterized mainly by cranial and sensory peripheral neuropathy, corneal lattice dystrophy, and cutis laxa. HGA, originally reported from Finland and now increasingly from other countries in Europe, North and South America, and Asia, may still be underdiagnosed worldwide. It is the first and so far only known disorder caused by a gelsolin gene defect, namely a G654A or G654T mutation. Gelsolin is a principal actin-modulating protein, implicated in multiple biological processes, also in the nervous system, e.g. axonal transport, myelination, neurite outgrowth, and neuroprotection. The gelsolin gene defect causes expression of variant gelsolin, followed by systemic deposition of gelsolin amyloid (AGel) in HGA patients and even other consequences on the metabolism and function of gelsolin. In HGA, specific therapy is not yet available but correct diagnosis enables adequate symptomatic treatment which decisively improves the quality of life in these patients. A transgenic murine model of HGA expressing AGel is available, in anticipation of new treatment options targeted toward this slowly progressive but devastating amyloidosis. Present and future lessons learned from HGA may be applicable even in diagnosis and treatment of other hereditary and sporadic amyloidoses. PMID- 23931810 TI - Malignant cell infiltration in the peripheral nervous system. AB - The peripheral nervous system can be affected by malignancies involving different mechanisms. Neoplastic nerve lesion by compression, invasion, and infiltration is rare and occurs in particular in leukemia (neuroleukemiosis) and lymphoma (neurolymphomatosis). Its occurrence is much rarer in cancer, and even less so in sarcoma. The neoplastic infiltration of peripheral nerves by solid tumors is characterized by specific topographical sites such as the base of the skull, the ear, nose and throat region, and the cervico-brachial plexus as well as the lumbar and sacral plexus. Rarely malignant invasion affects the cranial nerves of the face where it can spread centripetally. Autonomic nerves and ganglia can also be affected. The retrograde spread of cancer in nerves is a bad prognostic sign. The clinical diagnosis is determined by tumor type, the pattern of involvement, and often pain. PMID- 23931811 TI - Paraneoplastic neuropathy. AB - Recent progress in serological screening of paraneoplastic antibodies and in diagnostic imaging techniques to detect malignancies has enabled a broadening of the concept of paraneoplastic neurological syndromes by integrating nonclassic clinical features. The peripheral nervous system is frequently involved in patients with paraneoplastic syndrome and may be seen alone or in combination with involvement of other areas of the nervous system. Destruction of dorsal root ganglion cells due to lymphocytic infiltration, especially with CD8-positive cytotoxic T cells, has been postulated to mediate the classic syndrome of subacute sensory neuronopathy. However, the motor and autonomic nervous systems are frequently affected. Indeed, patients can develop clinical features compatible with Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, or brachial plexopathy. Other forms of paraneoplastic neuropathy are vasculitic neuropathy, autoimmune autonomic ganglionopathy, and chronic intestinal pseudo-obstruction. Various onconeural antibodies, including anti-Hu, anti-CV2/CRMP-5, and anti-ganglionic acetylcholine receptor antibodies, are associated with neuropathy. Somatic neuropathy is the most common manifestation in patients with anti-Hu and anti-CV2/CRMP-5 antibodies, while anti-ganglionic acetylcholine receptor antibody is associated with autonomic neuropathies. A whole-body fluorodeoxyglucose positron emission tomography scan may be useful to detect malignancy in patients with unremarkable conventional radiological findings. Recognition and diagnosis of paraneoplastic neuropathy is important, as neuropathic symptoms usually precede the identification of the primary tumor, and treatment at an earlier stage provides better chances of good outcomes. PMID- 23931812 TI - Drug-induced neuropathies. AB - Although drug-induced neuropathies account for only 2-4% of referrals, their identification is important. Numerically, chemotherapy and antiretroviral drugs are the most important worldwide. Research is currently focused on elucidating pathogenic mechanisms and the earliest presymptomatic changes using neurophysiological and pharmacogenetic techniques in order to avoid the drug or make dosage changes before irreversible damage occurs. Chemoprotectants against chemotherapy-induced neuropathy are also an active area of research. This chapter focuses on the pathophysiology of drug-induced neuropathies in general, followed by detailed reviews of neuropathy due to; newer compounds such as TNF (tumor necrosis factor) alpha antagonists and antibiotics such as linezolid; chemotherapeutic agents, old and new, where significant progress has been made; antiretroviral drugs; and amiodarone, which is unusual in that it causes a demyelinating neuropathy. The controversial issue of statin-induced neuropathy is also reviewed. PMID- 23931813 TI - Late radiation injury to peripheral nerves. AB - Although the peripheral nerve has often been considered as radioresistant, clinical practice demonstrates the occurrence of radiation-induced peripheral neuropathies. Because these complications appear late, usually several years after the course of radiotherapy, their occurrence is explained by improvement in the prognosis of several cancers. Their physiopathology is not fully understood. Compression by radio-induced fibrosis probably plays a central role but direct injury to nerves and blood vessels is probably also involved. The most frequent and best known form of postradiation neuropathy is brachial plexopathy, which may follow irradiation for breast cancer. Recent reports demonstrate that postradiation neuropathies show a great heterogeneity, particularly in the anatomical sites, but also in the clinical, electrophysiological, and neuroimaging features. The link with radiotherapy may be difficult for the clinician to establish. Patients with radiation-induced lumbosacral radiculoplexopathy may be misdiagnosed with amyotrophic lateral sclerosis as they often present with pure lower motor neuron syndrome, or with leptomeningeal metastases since nodular MRI enhancement of the nerve roots of the cauda equina and increased CSF protein content can be observed. From a pathophysiological perspective, radiation-induced neuropathy offers an interesting model for deciphering the mechanisms of peripheral neuropathies due to environmental factors. Recent developments show promising strategies for the prevention and treatment of these complications, which have a considerable impact on a patient's quality of life. PMID- 23931814 TI - Neuromuscular complications of critical illness. AB - Patients admitted to intensive care units (ICUs) suffer from a wide range of neurological disorders. Some develop within the ICU rendering weakness and difficulty in weaning patients from ventilator support. ICUAW, or ICU acquired weakness, is a broad term that includes several more specific neuromuscular problems. After exclusion of other causes of weakness, ICUAW includes critical illness polyneuropathy (CIP), first described by Charles Bolton, critical illness myopathy (CIM), and disorders of neuromuscular junction transmission. This chapter reviews the clinical, electrophysiological, and pathological features of these conditions and provides clinicians with approaches toward diagnosing and investigating ICUAW. PMID- 23931815 TI - The surgery of peripheral nerves (including tumors). AB - Surgical pathology of the peripheral nervous system includes traumatic injury, entrapment syndromes, and tumors. The recent significant advances in the understanding of the pathophysiology and cellular biology of peripheral nerve degeneration and regeneration has yet to be translated into improved surgical techniques and better outcome after peripheral nerve injury. Decision making in peripheral nerve surgery continues to be a complex challenge, where the mechanism of injury, repeated clinical evaluation, neuroradiological and neurophysiological examination, and detailed knowledge of the peripheral nervous system response to injury are prerequisite to obtain the best possible outcome. Surgery continues to be the primary treatment modality for peripheral nerve tumors and advances in adjuvant oncological treatment has improved outcome after malignant peripheral nerve tumors. The present chapter provides background knowledge of surgical peripheral nerve disease and some general and practical guidance toward its clinical management. PMID- 23931816 TI - Peripheral neuropathy in the elderly. AB - Peripheral neuropathy is an important factor of disability in the elderly, which is significant now that up to 20% of the population is older than 60 years in industrialized countries. Potentially treatable neuropathies including primary inflammatory polyneuropathies and systemic disorders, especially vasculitic neuropathies, are as common in this age group as in younger patients. Neuropathies associated with diabetes, malignancy, and monoclonal gammopathies are even more common in these patients. It is thus essential to identify the causes of these neuropathies in this group of patients and treat them whenever feasible. PMID- 23931817 TI - Dominant Charcot-Marie-Tooth syndrome and cognate disorders. AB - Charcot-Marie-Tooth neuropathy (CMT) is a group of genetically heterogeneous disorders sharing a similar phenotype, characterized by wasting and weakness mainly involving the distal muscles of lower and upper limbs, variably associated with distal sensory loss and skeletal deformities. This chapter deals with dominantly transmitted CMT and related disorders, namely hereditary neuropathy with liability to pressure palsies (HNPP) and hereditary neuralgic amyotrophy (HNA). During the last 20 years, several genes have been uncovered associated with CMT and our understanding of the underlying molecular mechanisms has greatly improved. Consequently, a precise genetic diagnosis is now possible in the majority of cases, thus allowing proper genetic counseling. Although, unfortunately, treatment is still unavailable for all types of CMT, several cellular and animal models have been developed and some compounds have proved effective in these models. The first trials with ascorbic acid in CMT type 1A have been completed and, although negative, are providing relevant information on disease course and on how to prepare for future trials. PMID- 23931818 TI - Recessively transmitted predominantly motor neuropathies. AB - Recessively transmitted predominantly motor neuropathies are rare and show a severe phenotype. They are frequently observed in populations with a high rate of consanguineous marriages. At least 15 genes and six loci have been found to be associated with autosomal recessive CMT (AR-CMT) and X-linked CMT (AR-CMTX) and also distal hereditary motor neuronopathy (AR-dHMN). These disorders are genetically heterogeneous but the clinical phenotype is relatively homogeneous. Distal muscle weakness and atrophy predominating in the lower extremities, diminished or absent deep tendon reflexes, distal sensory loss, and pes cavus are the main clinical features of this disorder with occasional cranial nerve involvement. Although genetic diagnosis of some of subtypes of AR-CMT are now available, rapid advances in the molecular genetics and cell biology show a great complexity. Animal models for the most common subtypes of human AR-CMT disease provide clues for understanding the pathogenesis of CMT and also help to reveal possible treatment strategies of inherited neuropathies. This chapter highlights the clinical features and the recent genetic and biological findings in these disorders based on the current classification. PMID- 23931819 TI - Early onset (childhood) monogenic neuropathies. AB - Hereditary neuropathies (HN) with onset in childhood are categorized according to clinical presentation, pathogenic mechanism based on electrophysiology, genetic transmission and, in selected cases, pathological findings. Especially relevant to pediatrics are the items "secondary" versus "primary" neuropathy, "syndromic versus nonsyndromic," and "period of life." Different combinations of these parameters frequently point toward specific monogenic disorders. Ruling out a neuropathy secondary to a generalized metabolic disorder remains the first concern in pediatrics. As a rule, metabolic diseases include additional, orienting symptoms or signs, and their biochemical diagnosis is based on logical algorithms. Primary, motor sensory are the most frequent HN and are dominated by demyelinating autosomal dominant (AD) forms (CMT1). Other forms include demyelinating autosomal recessive (AR) forms, axonal AD/AR forms, and forms with "intermediate" electrophysiological phenotype. Peripheral motor neuron disorders are dominated by AR SMN-linked spinal muscular atrophies. (Distal) hereditary motor neuropathies represent <10% of HN but exhibit large clinical and genetic heterogeneity. Sensory/dysautonomic HN involves five classic subtypes, each one related to specific genes. However, genetic heterogeneity is larger than initially suspected. Syndromic HN distinguish "purely neurological syndromes", which are multisystemic, such as spinocerebellar atrophies +, spastic paraplegias +, etc. Peripheral neuropathy is possibly the presenting feature, including in childhood. Autosomal recessive forms, on average, start more frequently in childhood. "Multiorgan syndromes", on the other hand, are more specific to Pediatrics. AR forms, which are clearly degenerative, prompt the investigation of a large set of pleiotropic genes. Other syndromes expressed in the perinatal period are mainly developmental disorders, and can sometimes be related to specific transcription factors. Systematic malformative workup and ethical considerations are necessary. Altogether, >40 genes with various biological functions have been found to be responsible for primary HN. Many are responsible for various phenotypes, including some without the polyneuropathic trait, and some for various types of transmission. PMID- 23931820 TI - Hereditary sensory and autonomic neuropathies. AB - Hereditary sensory and autonomic neuropathies (HSN/HSAN) are clinically and genetically heterogeneous disorders of the peripheral nervous system that predominantly affect the sensory and autonomic neurons. Hallmark features comprise not only prominent sensory signs and symptoms and ulcerative mutilations but also variable autonomic and motor disturbances. Autosomal dominant and autosomal recessive inheritance has been reported. Molecular genetics studies have identified disease-causing mutations in 11 genes. Some of the affected proteins have nerve-specific roles but underlying mechanisms have also been shown to involve sphingolipid metabolism, vesicular transport, structural integrity, and transcription regulation. Genetic and functional studies have substantially improved the understanding of the pathogenesis of the HSN/HSAN and will help to find preventive and causative therapies in the future. PMID- 23931821 TI - Peripheral nerve involvement in hereditary cerebellar and multisystem degenerative disorders. AB - Hereditary ataxias (HA) encompass an increasing number of degenerative disorders characterized by progressive cerebellar ataxia usually accompanied by extracerebellar semeiology including peripheral nerve involvement. Classically, HA were classified according to their pathological hallmark comprising three main forms: (1) spinal form predominantly with degeneration of spinocerebellar tracts, posterior columns, and pyramidal tracts (Friedreich's ataxia, FA); (2) olivopontocerebellar atrophy (OPCA); and (3) cortical cerebellar atrophy (CCA). In the 1980s Harding proposed a clinico-genetic classification based upon age of onset, modality of transmission, and clinical semeiology. The main categories in this classification were as follows: (1) early onset cerebellar ataxia (EOCA) with age of onset below 25 years and usually with autosomal recessive (AR) transmission (this group encompasses FA and syndromes different from FA); (2) autosomal dominant cerebellar ataxia (ADCA) with adult onset and with either cerebellar-plus syndrome or pure cerebellar semeiology; and (3) idiopathic late onset onset cerebellar ataxia (ILOCA). With the advent of molecular genetics, the nosology of HA has been in a state of constant flux. At present EOCA comprises at least 17 genotypes (designated with the acronym of ARCA derived from AR cerebellar ataxia), whereas under the umbrella of ADCA 30 genotypes have been reported. In this chapter we will review peripheral nerve involvement in classical pathological entities (OPCA and CCA), ARCA, ADCA, and ILOCA paying special attention to the most prevalent syndromes in each category. As a general rule, nerve involvement is relatively common in any form of ataxia except ILOCA, the most common pattern being either sensory or sensorimotor neuronopathy with a dying-back process. An exception to this rule is AR spastic ataxia of Charlevoix Saguenay where nerve conduction studies show the characteristic pattern of intermediate neuropathy implying that sacsin mutation causes both axonal and Schwann cell dysfunction. PMID- 23931822 TI - Giant axonal neuropathy. AB - Giant axonal neuropathy (GAN) is a rare hereditary autosomal recessive neurodegenerative disease affecting both the peripheral and the central nervous system. Clinically it is characterized by an age of onset during the first decade, progressive and severe motor sensory neuropathy followed, in some patients, by the occurrence of various central nervous system signs such as cerebellar syndrome, upper motor neuron signs, or epilepsy. Although kinky hairs are reported in the majority of patients, it is not a constant finding. The prognosis is usually severe with death occurring during the second or third decade; nevertheless a less severe course is reported in some patients. The presence of a variable number of giant axons filled with neurofilaments in the nerve biopsy represents the pathological feature of the disease and it is usually associated to a variable degree with axonal loss and demyelization. Giant axons are also found in the central nervous system associated with Rosenthal fibers and a variable degree of involvement of white matter and neuronal loss. The disease is caused by mutation in the GAN gene encoding for gigaxonin, a member of BTB Kelch. Up to now 37 mutations in the GAN gene have been reported. These mutations are scattered over the 11 exons of the gene without a clear genotype-phenotype correlation. These mutations resulting in gigaxonin deficiency lead to a slow down in ubiquitin-mediated protein degradation and possibly of other unidentified proteins. GAN represents a good model of a neurodegenerative disorder in which there is a primary defect of the ubiquitin proteasome system and its network with neurofilaments. The clarification of molecular mechanisms involved in GAN can help in understanding other frequent neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson disease. PMID- 23931823 TI - Neurofibromatosis type 1 (NF1): diagnosis and management. AB - Neurofibromatosis 1 (NF1) is an inherited neurocutaneous disease that has a major impact on the nervous system, eye, skin, and bone. Individuals with NF1 have a predisposition to benign and malignant tumor formation and the hallmark lesion is the neurofibroma, a benign peripheral nerve sheath tumor. The gene for NF1 was cloned on chromosome 17q11.2 and neurofibromin, the NF1 protein, controls cell growth and proliferation by regulating the proto-oncogene Ras and cyclic adenosine monophosphate (AMP). Advances in molecular biology and mouse models of disease have enhanced our understanding of the pathogenesis of NF1 complications and facilitated targeted therapy. Progress has been made in developing robust clinical and radiological outcome measures and clinical trials are underway for children with learning difficulties and for individuals with symptomatic plexiform neurofibromas. PMID- 23931824 TI - Neurofibromatosis type 2 (NF2): diagnosis and management. AB - Neurofibromatosis type 2 (NF2) is an autosomal dominant inherited tumor predisposition syndrome caused by mutations in the NF2 gene on chromosome 22. Affected individuals develop schwannomas typically involving both vestibular nerves leading to hearing loss and eventual deafness. Rehabilitation with brainstem implants and in some cases cochlear implants is improving this outcome. Schwannomas also occur on other cranial nerves, on spinal nerve roots and peripheral nerves, and intracutaneously as plaques. Cranial and spinal meningiomas and spinal ependymomas are other common tumors. Fifty to sixty percent of patients represent de novo mutations and as many as 33% of these are mosaic for the underlying disease causing mutation. Truncating mutations (nonsense, frameshift insertions/deletions) are the most frequent germline events and cause the most severe disease, whilst single and multiple exon deletions are common and are usually associated with milder NF2. Neurological deficits are a major feature of the condition and neurologists have a pivotal role in assigning symptoms to lesions and in managing neuropathies. NF2 represents a difficult management problem with most patients facing substantial morbidity and reduced life expectancy. Surgery remains the focus of current management although watchful waiting and occasionally radiation treatment have a role. We are seeing the advent of tailored drug therapies aimed at the genetic level and these are likely to provide huge improvements for this devastating, life-limiting condition. PMID- 23931827 TI - Massive haemolysis and methaemalbuminaemia in a patient with decompensated haemoglobin H disease. PMID- 23931828 TI - The long-term outcomes of heroin dependent-treatment-resistant patients with bipolar 1 comorbidity after admission to enhanced methadone maintenance. AB - OBJECTIVE: The aim of this study was to compare the long-term outcomes of treatment-resistant bipolar 1 heroin addicts with peers who were without DSM-IV axis I psychiatric comorbidity (dual diagnosis). METHOD: 104 Heroin-dependent patients (TRHD), who also met criteria for treatment resistance - 41 of them with DSM-IV-R criteria for Bipolar 1 Disorder (BIP1-TRHD) and 63 without DSM-IV-R axis I psychiatric comorbidity (NDD-TRHD) - were monitored prospectively (3 years on average, min. 0.5, max. 8) along a Methadone Maintenance Treatment Programme (MMTP). RESULTS: The rates for survival-in-treatment were 44% for NDD-TRHD patients and 58% for BIP1-TRHD patients (p=0.062). After 3 years of treatment such rates tended to become progressively more stable. BIP1-TRHD patients showed better outcome results than NDD-TRHD patients regarding CGI severity (p<0.001) and DSM-IV GAF (p<0.001). No differences were found regarding urinalyses for morphine between groups during the observational period. Bipolar 1 patients needed a higher methadone dosage in the stabilization phase, but this difference was not statistically significant. LIMITATIONS: The observational nature of the protocol, the impossibility of evaluating a follow-up in the case of the patients who dropped out, and the multiple interference caused by interindividual variability, the clinical setting and the temporary use of adjunctive medications. CONCLUSIONS: Contrary to expectations, treatment-resistant patients with bipolar 1 disorder psychiatric comorbidity showed a better long-term outcome than treatment-resistant patients without psychiatric comorbidity. PMID- 23931829 TI - Symptoms, comorbidity, and clinical course of depression in immigrants: putting psychopathology in context. AB - BACKGROUND: Migration is considered a depression risk factor when associated with psychosocial adversity, but its impact on depression's clinical characteristics has not been specifically studied. We compared 85 migrants to 34 controls, examining depression's severity, symptomatology, comorbidity profile and clinical course. METHOD: A MINI interview modified to assess course characteristics was used to assign DSM-IV axis I diagnoses; medical files were used for Somatoform Disorders. Severity was assessed with the Montgomery-Asberg scale. Wherever possible, we adjusted comparisons for age and gender using logistic and linear regressions. RESULTS: Depression in migrants was characterized by higher comorbidity (mostly somatoform and anxiety disorders), higher severity, and a non recurrent, chronic course. LIMITATIONS: Our sample comes from a single center, and should be replicated in other health care facilities and other countries. Somatoform disorder diagnoses were solely based on file-content. CONCLUSION: Depression in migrants presented as a complex, chronic clinical picture. Most of our migrant patients experienced significant psychosocial adversity before and after migration: beyond cultural issues, our results suggest that psychosocial adversity impacts on the clinical expression of depression. Our study also suggests that migration associated with psychosocial adversity might play a specific etiological role, resulting in a distinct clinical picture, questioning the DSM-IV unitarian model of depression. The chronic course might indicate a resistance to standard therapeutic regimen and hints at the necessity of developing specific treatment strategies, adapted to the individual patients and their specific context. PMID- 23931830 TI - Serum methylarginines and incident depression in a cohort of older adults. AB - BACKGROUND: Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in depression. This study measured serum concentrations of l arginine, asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in a representative sample of older community-dwelling adults and determined their association with incident depression over 6-years of follow-up. METHODS: Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and l arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults (Median age=64 years; IQR=60-70) from the Hunter Community Study. Clinical depression was defined as a Centre for Epidemiological Studies Depression Scale (CES-D) score >=16 or use of antidepressant medications. RESULTS: In adjusted analyses ADMA (Q3), SDMA (Q2), l-arginine (Q2), gender, and asthma remained statistically significant predictors of incident depression at follow-up. Quartile 3 of ADMA concentration was associated with 3.5 times the odds of developing depression compared with Q1 (OR=3.54; 95% CI: 1.25-9.99). LIMITATIONS: Limitations of our study include the use of a subjective self reported questionnaire tool using a dichotomous cut-off, together with use of antidepressant medications, as proxies for clinical depression. Moreover, similarly to most population studies on methylated arginines, the measurement of ADMA and SDMA from blood does not necessarily reflect intracellular concentrations of these compounds. Finally, there were no measures of nitric oxide metabolites to determine if these levels were altered in the presence of elevated methylarginines and depression. CONCLUSIONS: After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum ADMA was independently associated with incident depression at 6-years follow-up. PMID- 23931831 TI - Mechanisms of change underlying the efficacy of cognitive behaviour therapy for chronic fatigue syndrome in a specialist clinic: a mediation analysis. AB - BACKGROUND: Several randomized controlled trials (RCTs) have shown that cognitive behavioural psychotherapy (CBT) is an efficacious treatment for chronic fatigue syndrome (CFS). However, little is known about the mechanisms by which the treatment has its effect. The aim of this study was to investigate potential mechanisms of change underlying the efficacy of CBT for CFS. We applied path analysis and introduce novel model comparison approaches to assess a theoretical CBT model that suggests that fearful cognitions will mediate the relationship between avoidance behaviour and illness outcomes (fatigue and social adjustment). METHOD: Data from 389 patients with CFS who received CBT in a specialist service in the UK were collected at baseline, at discharge from treatment, and at 3-, 6- and 12-month follow-ups. Path analyses were used to assess possible mediating effects. Model selection using information criteria was used to compare support for competing mediational models. RESULTS: Path analyses were consistent with the hypothesized model in which fear avoidance beliefs at the 3-month follow-up partially mediate the relationship between avoidance behaviour at discharge and fatigue and social adjustment respectively at 6 months. CONCLUSIONS: The results strengthen the validity of a theoretical model of CBT by confirming the role of cognitive and behavioural factors in CFS. PMID- 23931832 TI - Executive summary of the consensus statement on assistance to women with HIV infection in the health care sector. National AIDS Plan (PNS) and AIDS Study Group (GeSIDA). AB - The aim of this paper was to develop a consensus on clinical recommendations for health care assistance for women with HIV infection. To this end, a panel of experts, appointed by the Secretariat of the National AIDS Plan and GeSIDA was assembled, that included internal medicine physicians with expertise in the field of HIV infection, gynecologists, pediatricians and psychologists, with two members of the panel acting as coordinators. Scientific information was reviewed in publications and conference reports up to October 2012. In keeping with the criteria of the Infectious Disease Society of America, two levels of evidence were applied to support the proposed recommendations: the strength of the recommendation according to expert opinion (A, B, C) and the level of empirical evidence (I, II, III), already used in previous documents from SPNS/GESIDA. Multiple recommendations are provided for the clinical management of women with HIV infection, considering both the diagnostic and possible therapeutic strategies. This document presents recommendations for the treatment of women with HIV infection. This must be multidisciplinary, taking into account the differences that can be found in the diagnosis, development of disease and treatment between men and women. PMID- 23931834 TI - Molecular detection of respiratory viruses. AB - Over the past several years a wide variety of molecular assays for the detection of respiratory viruses has reached the market. The tests described herein range from kits containing primers and probes detecting specific groups of viruses, to self-contained systems requiring specialized instruments that extract nucleic acids and perform the polymerase chain reaction with little operator input. Some of the tests target just the viruses involved in large yearly epidemics such as influenza, or specific groups of viruses such as the adenoviruses or parainfluenza viruses; others can detect most of the known respiratory viruses and some bacterial agents. PMID- 23931833 TI - Laboratory detection of sepsis: biomarkers and molecular approaches. AB - Sepsis, severe sepsis, and septic shock cause significant morbidity and mortality worldwide. Rapid diagnosis and therapeutic interventions are desirable to improve the overall mortality in patients with sepsis. However, gold standard laboratory diagnostic methods for sepsis, pose a significant challenge to rapid diagnosis of sepsis by physicians and laboratories. This article discusses the usefulness and potential of biomarkers and molecular test methods for a more rapid clinical and laboratory diagnosis of sepsis. Because new technologies are quickly emerging, physicians and laboratories must appreciate the key factors and characteristics that affect the clinical usefulness and diagnostic accuracy of these test methodologies. PMID- 23931835 TI - Molecular diagnostics and parasitic disease. AB - Molecular parasitology represents an emerging field in microbiology diagnostics. Although most assays use nonstandardized, laboratory-developed methods, a few commercial systems have recently become available and are slowly being introduced into larger laboratories. In addition, a few methodologies show promise for use in field settings in which parasitic infections are endemic. This article reviews the available techniques and their applications to major parasitic diseases such as malaria, leishmaniasis, and trichomoniasis. PMID- 23931836 TI - Invasive fungal infections: biomarkers and molecular approaches to diagnosis. AB - The biomarkers galactomannan and 1,3-beta-d-glucan have been well studied over the past years and are gaining a role in the diagnosis of invasive fungal infections. Although not as well studied until recently, molecular methods for the diagnosis of invasive fungal infection are also being evaluated. Outcomes data for molecular testing are expanding, but have not yet provided enough evidence for inclusion of molecular diagnostics in formal clinical guidelines. Lack of standardization and validation of the various molecular assays and platforms has hindered their widespread acceptance in the evaluation of invasive fungal infections, although the future is promising. PMID- 23931837 TI - Advanced techniques for detection and identification of microbial agents of gastroenteritis. AB - Gastroenteritis persists as a worldwide problem, responsible for approximately 2 million deaths annually. Traditional diagnostic methods used in the clinical microbiology laboratory include a myriad of tests, such as culture, microscopy, and immunodiagnostics, which can be labor intensive and suffer from long turnaround times and, in some cases, poor sensitivity. [corrected]. This article reviews recent advances in genomic and proteomic technologies that have been applied to the detection and identification of gastrointestinal pathogens. These methods simplify and speed up the detection of pathogenic microorganisms, and their implementation in the clinical microbiology laboratory has potential to revolutionize the diagnosis of gastroenteritis. PMID- 23931838 TI - Molecular approaches and biomarkers for detection of Mycobacterium tuberculosis. AB - Tuberculosis (TB) continues to be a public health emergency, compounded by the lack of adequate diagnostic testing in many regions of the world. New advances in the molecular detection of Mycobacterium tuberculosis, including faster and simpler nucleic acid amplification tests, have resulted in rapid and cost effective methods to diagnose TB and test for drug resistance. Ongoing research on biomarkers for TB infection may lead to new tests for blood, urine, breath, and sputum. Sustained investment in the development and dissemination of diagnostic tests for TB is critical for increasing TB case finding, placing patients on appropriate treatment, and reducing transmission. PMID- 23931839 TI - Automation in the clinical microbiology laboratory. AB - Imagine a clinical microbiology laboratory where a patient's specimens are placed on a conveyor belt and sent on an automation line for processing and plating. Technologists need only log onto a computer to visualize the images of a culture and send to a mass spectrometer for identification. Once a pathogen is identified, the system knows to send the colony for susceptibility testing. This is the future of the clinical microbiology laboratory. This article outlines the operational and staffing challenges facing clinical microbiology laboratories and the evolution of automation that is shaping the way laboratory medicine will be practiced in the future. PMID- 23931840 TI - Maldi-tof mass spectrometry for microorganism identification. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a rapid, reliable, and high-throughput diagnostic tool for the identification of microorganisms. The technology is unique in clinical microbiology, allowing laboratories to definitively identify bacterial and fungal isolates within minutes. The rapid turnaround time and minimal cost for consumables per specimen compared with conventional identification methods have resulted in MALDI-TOF MS being increasingly used in clinical laboratories worldwide. This article summarizes the current literature on MALDI-TOF MS for microbial identification and provides a preview of the method's potential future applications in clinical microbiology. PMID- 23931841 TI - Beyond identification: emerging and future uses for MALDI-TOF mass spectrometry in the clinical microbiology laboratory. AB - The routine use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has revolutionized microorganism identification in the clinical microbiology laboratory. Building from these now common microorganism identification strategies, this review explores future clinical applications of MALDI-TOF MS. This includes practical approaches for laboratorians interested in implementing direct identification processing methods for MALDI-TOF detection of microbes in bloodstream infection (BSI) and urinary tract infection (UTI), as well as, post-analytical approaches for classifying MALDI-TOF spectral data to detect characteristics other and species-level identification (e.g. strain-level classification, typing, and resistance mechanisms). PMID- 23931842 TI - Bacterial strain typing. AB - Over the course of the past several decades, rapid advancements in molecular technologies have revolutionized the practice of public health microbiology, and have fundamentally changed the nature, accuracy, and timeliness of laboratory data for outbreak investigation and response. Whole-genome sequencing, in particular, is becoming an increasingly feasible and cost-effective approach for near real-time high-resolution strain typing, genomic characterization, and comparative analyses. This review discusses the current state of the art in bacterial strain typing for outbreak investigation and infectious disease surveillance, and the impact of emerging genomic technologies on the field of public health microbiology. PMID- 23931843 TI - Diagnostic assays for identification of microorganisms and antimicrobial resistance determinants directly from positive blood culture broth. AB - The detection of blood stream infections is one of the most important functions of the clinical microbiology laboratory. Sepsis is a clinical emergency, and mortality increases if commencement of appropriate antimicrobial therapy is delayed. Automated blood culture systems are the most sensitive approach for detection of the causative agent of sepsis. Several laboratory methods have been developed to expedite identification of organisms directly from positive blood culture broth. The principle and analytical performance characteristics of these methods are described in this review. PMID- 23931844 TI - Future-generation sequencing and clinical microbiology. AB - Sequencing technologies are changing the way both laboratory medicine and clinical practice impact patient care. This article focuses on the clinical microbiology laboratory and the potential benefits and limitations of coming generations of sequencing technology. Nucleic acid sequencing technology is rapidly outpacing the infrastructure needed to accurately educate, analyze, and interpret complex massive data sets that are rapidly becoming integrated into clinical practice. PMID- 23931845 TI - Integration of technology into clinical practice. AB - It is an exciting time in clinical microbiology. New advances in technology are revolutionizing every aspect of the microbiology laboratory, from processing of specimens to bacterial identification; as a result, the microbiology laboratory is rapidly changing. With this change comes the challenge of selecting and implementing the technology that is most appropriate for each laboratory and clinical setting. This review focuses on issues surrounding implementation of new technology such that the improvements to clinical care are maximized. PMID- 23931846 TI - Automation and emerging technology in clinical microbiology. PMID- 23931847 TI - Effects of visual search vs. auditory tasks on postural control in children with autism spectrum disorder. AB - Recent research in motor control shows the interactive role of cognitive factors in postural control. However, there is little understanding in how children with autism spectrum disorder (ASD) develop their postural behaviors. This study compares the interference of visual or auditory tasks on postural control in children with ASD. We examined 19 children with ASD (10-15 years old) and also 28 age-matched typically developing (TD) children. They were asked to perform two tasks during postural control: (1) a visual searching task (2) an auditory digit span task. Postural performances were measured with a force platform. Results showed that children with ASD indicated higher postural sway scores in visual task vs. auditory task; as root mean square (p=0.04), mean velocity (p=0.01) and sway area (p=0.02) but TD children scores remained unchanged. Children with ASD also showed significantly higher sway scores than TD children in all parameters. We conclude that in addition to primary differences in patterns of postural control of children with ASD compared to TD children, visual and auditory tasks may differently influence the postural control in this population. PMID- 23931848 TI - 3D motion capture using the HUX model for monitoring functional changes with arthroplasty in patients with degenerative osteoarthritis. AB - BACKGROUND: Although shoulder hemiarthroplasty (SHA) can improve function in osteoarthritic shoulders, the ability to perform activities of daily living (ADL) may remain impaired. Shoulder surgeons routinely measure parameters such as range of motion, pain, satisfaction and strength. A common subjective assessment of ADL is part of the Constant Score (CS). However, there is limited objective evidence on whether or not shoulder hemiarthroplasty can restore normal range of motion (ROM) in ADL. METHODS: The study included eight consecutive patients (n=8; seven women, one man), who underwent SHA for glenohumeral osteoarthritis. The patients were examined the day before, as well as 6 months and 3 years after shoulder replacement. They were compared with a control group with no shoulder pathology, and shoulder movement was measured with 3D motion analysis using the "Heidelberg Upper Extremity" (HUX) model. Measurements included static maximum values and four ADL. RESULTS: Comparing the preoperative to the 3-year postoperative static maximum values, there were significant improvements for abduction from 50.5 degrees (SD +/- 3 2.4 degrees ) to 72.4 degrees (SD +/- 38.2 degrees ; p=0.031), for adduction from 6.2 degrees (SD +/- 7.7 degrees ) to 66.7 degrees (SD +/- 18.0 degrees ; p=0.008), for external rotation from 15.1 degrees (SD +/- 27.9 degrees ) to 50.9 degrees (SD +/- 27.3 degrees ; p=0.031), and for internal rotation from -0.6 degrees (SD +/- 3.9 degrees ) to 35.8 degrees (SD +/- 28.2 degrees ; p=0.031). There was a trend of improvement for flexion from 105.8 degrees (SD +/- 45.7 degrees ) to 161.9 degrees (SD +/- 78.2 degrees ; p=0.094) and for extension from 20.6 degrees (SD +/- 17.0 degrees ) to 28.0 degrees (SD +/- 12.5 degrees ; p=0.313). The comparison of the 3-year postoperative ROM between the SHA group and controls showed significant differences in abduction; 3 year postoperative SHA ROM 72.4 degrees (SD +/- 38.2 degrees ) vs. 113.5 degrees (SD +/- 29.7 degrees ) among controls (p=0.029). There were no significant differences compared to the control group in adduction, flexion/extension and rotation 3 years after SHA surgery. In performing the ADL, the pre- to the 6 month and 3-year postoperative status of the SHA group resulted in a significant increase in ROM in all planes (p<0.05). Comparing the preoperative to the 3-year postoperative ROM used in ADL, there was an improvement in the flexion/extension plane, showing an improvement trend from preoperative 85 degrees -0 degrees -25 degrees to postoperative 127 degrees -0 degrees -38 degrees (p=0.063). In comparison, controls used a significantly greater ROM during ADL with mean flexion/extension of 139 degrees -0 degrees -63 degrees (p=0.028). For the abduction/adduction plane, ROM improved significantly from preoperative 25 degrees -0 degrees -19 degrees to postoperative 78 degrees -0 degrees -60 degrees (p=0.031). In comparison to controls with abduction/adduction of 118 degrees -0 degrees -37 degrees 3 years postoperative, the SHA group also used significantly less ROM in the abduction/adduction plane (p=0.028). CONCLUSION: While SHA improves ROM in ADL in patients with degenerative glenohumeral osteoarthritis, it does not restore the full ROM available for performing ADL compared to controls. 3D motion analysis with the HUX model is an appropriate measurement system to detect surgery-related changes in shoulder arthroplasty. PMID- 23931849 TI - Detection of novel paraja ring finger 2-fer tyrosine kinase mRNA chimeras is associated with poor postoperative prognosis in non-small cell lung cancer. AB - Previously, we reported that the overexpression of fer tyrosine kinase (FER), a non-receptor tyrosine kinase, is correlated with poor postoperative prognosis and cancer-cell survival in non-small cell lung cancer (NSCLC). In the present study, we further analyzed FER-overexpressed NSCLC cases and identified various patterns of chimeric mRNAs, composed of paraja ring finger 2 (PJA2) and FER. We detected no genomic rearrangements between PJA2 and FER and attributed these chimeric mRNAs to alterations at the transcriptome level: i.e., trans-splicing. Several chimeric patterns were detected concurrently in each patient, and the pattern sets varied among patients, although the pattern in which PJA2 exon 1 was fused to FER exon 3 (designated as Pe1-Fe3 mRNA) was detected constantly. Therefore, in a wide screening for PJA2-FER mRNAs in NSCLC, we focused on this chimeric pattern as a representative chimera. In analyses of 167 NSCLC samples, Pe1-Fe3 mRNA was identified in about 10% of the patients, and the presence of chimeric mRNA was significantly correlated with a high expression level of parental FER mRNA. Furthermore, we found that the detection of Pe1-Fe3 mRNA was correlated with poor postoperative survival periods in NSCLC, consistent with a previous finding in which FER overexpression was correlated with poor postoperative prognosis in NSCLC. This report is the first to suggest a correlation between chimeric mRNA and the expression level of parental mRNA. Furthermore, our findings may be clinically beneficial, suggesting that PJA2-FER mRNAs might serve as a novel prognostic biomarker in NSCLC. PMID- 23931850 TI - Axial involvement with facet joint arthropathy and bony ankylosis in a case of camptodactyly, arthropathy, coxa vara, pericarditis (CACP) syndrome. AB - Familial arthropathy associated with congenital camptodactyly has been previously recognized as a definite clinical entity in the literature. The clinical spectrum of this disease seems to be variable. The typical features of congenital camptodactyly, arthropathy, coxa vara and pericarditis (CACP syndrome) appear to be a more frequent presentation in children from the Middle East and North Africa. Musculoskeletal presentation of this rare familial form of arthropathy is unique and heterogeneous. In all previous reports, non-inflammatory pattern of arthropathy involving the peripheral joints with typical coxa vara deformity were described, and in a few cases spine abnormalities, including kyphosis, lordosis, or scoliosis. We describe the first case of axial involvement in a typical case of CACP syndrome with facet joint arthropathy and ankylosis at L5/S1 levels. PMID- 23931851 TI - Widespread psoriasis induced by rituximab in a patient with rheumatoid arthritis: an unexpected adverse reaction. PMID- 23931852 TI - Optimal withdrawal and examination in colonoscopy. AB - The primary goal of most colonoscopies, whether performed for screening, surveillance, or diagnostic examinations (those performed for symptoms or positive screening tests other than colonoscopy) is the detection of neoplasia and its subsequent removal by either endoscopic polypectomy or referral for surgical resection. Unfortunately, colonoscopy has proved to be a highly operator dependent procedure with regard to detection. Variable detection results in some of the cancers that occur in the interval before the next colonoscopy. PMID- 23931853 TI - Colonoscopic polypectomy: current techniques and controversies. AB - Colonoscopic polypectomy is fundamental to effective colonoscopy. Through its impact on the polyp-cancer sequence, colonoscopic polypectomy reduces colorectal cancer incidence and mortality. Because it eliminates electrosurgical risk, cold snaring has emerged as the preferred technique for most small and all diminutive polyps. Few clinical trial data are available on the effectiveness and safety of specific techniques. Polypectomy technique seems highly variable between endoscopists, with some techniques more effective than others are. Further research is needed to investigate operator variation in polypectomy outcomes and establish an evidence base for best practice. PMID- 23931854 TI - Advanced endoscopic resection of colorectal lesions. AB - Advanced endoscopic resection techniques allow curative treatment of difficult colonic lesions and avoid the need for surgery in certain cases. If endoscopic resection is indicated, the choice of the most appropriate resection technique depends on lesion characteristics and endoscopist expertise. PMID- 23931855 TI - Cap-assisted colonoscopy. AB - Cap-assisted colonoscopy is a simple, practical, and inexpensive technique that serves several useful purposes in enhancing the performance of colonoscopy. It helps improve polyp detection by its ability to visualize otherwise blind mucosal areas on the proximal aspects of folds and flexures, although its effect on adenoma detection is inconsistent. By helping navigate the colon more efficiently, it facilitates intubation of the cecum faster, with lesser patient discomfort. Cap-assisted colonoscopy can be tried as a salvage procedure in cases of failed cecal intubation with regular colonoscopy and can be of assistance during polypectomy, especially for polyps located on the proximal aspects of folds. PMID- 23931856 TI - Retroview colonoscopy. AB - A retroview in the colon permits an 11-25% increase in the adenoma detection rate when compared with a standard straight forward view during colonoscopy. This can often be accomplished in the rectum or the proximal colon by using dial controls and shaft manipulation to turn the tip of a standard colonoscope 180 degrees . A special slim caliber instrument, the "Third Eye Retroscope" (a backward viewing device) has been developed which is inserted through the working channel of a colonoscope. New colonoscopes are being developed that have the capability of side vision with accompanying light illumination which, with wide angle lenses, provide an almost complete retroview of the colon. PMID- 23931857 TI - Water-aided colonoscopy. AB - Water-aided methods for colonoscopy include the established water immersion and the recent novel modification of water exchange. Water immersion entails the use of water as an adjunct to air insufflations to facilitate insertion. Water exchange evolved from water immersion to facilitate completion of colonoscopy without discomfort in unsedated patients. Infused water is removed predominantly during insertion rather than withdrawal. A higher adenoma detection rate has been reported with water exchange. Aggregate data of randomized controlled trials suggest that water exchange may be superior to water immersion in attenuating colonoscopy discomfort and optimizing adenoma detection, particularly in the proximal colon. PMID- 23931858 TI - Chromocolonoscopy. AB - Chromocolonoscopy is the process of endoscopically examining the colon mucosa after it has been stained with dye. The goal is to allow the endoscopist to identify subtle features in the mucosa, such as morphologically flat polyps or crypt patterns. Studies examining the efficacy of chromocolonoscopy to identify adenomas missed by conventional colonoscopy have shown that although chromocolonoscopy increases polyp yield, most additional lesions are small in size. Staining can also help in differentiating neoplastic from non-neoplastic polyps. Perhaps the most useful aspect of chromocolonoscopy is increasing the yield for dysplasia in patients undergoing colonoscopy for inflammatory bowel disease surveillance. PMID- 23931859 TI - Ancillary imaging techniques and adenoma detection. AB - Advancements in image technology have allowed recognition of mucosal architecture in more detail and may improve adenoma detection. This review provides a technical overview on individual imaging technologies and their effect on detection of adenomas. Only high-definition endoscopy has been shown to improve detection of small adenomas. None of the digital chromoendoscopy technologies improves adenoma detection. Limited studies on autoimmunfluorescence imaging in conjunction with high-definition endoscopy may improve detection of small adenomas. PMID- 23931860 TI - Real-time histology in colonoscopy. AB - Gastrointestinal endoscopy had major technological improvements and novel technologies in recent years. High-definition endoscopy has permitted an increasingly detailed view of the mucosa during colonoscopy. Filter techniques that enhance analysis of vessel and surface structures. Autofluorescence imaging relies on functional imaging of tissue alterations. Endocytoscopy is an ultrahigh contact microscopy procedure for cellular analysis of the epithelium. Endomicroscopy is an adaption of laser scanning microscopy for real-time intravital surface and subsurface microscopy during endoscopy. With these technologies, endoscopy has moved from prediction of histology based on morphologic patterns toward visualization of cellular and subcellular details, providing real-time histology. PMID- 23931861 TI - The modern bowel preparation in colonoscopy. AB - Adequate bowel preparation is essential for optimal colonoscopy. Suboptimal bowel preparation occurs in 25% to 40% of cases and is associated with canceled procedures, prolonged procedure time, incomplete examination, increased cost, and missed pathology. There are several effective formulations for colon cleansing with a good safety profile. Split dosing should be implemented whenever possible in an effort to enhance tolerance and adherence, and improve mucosal visibility and overall quality of the examination. In this review, modern bowel preparations are discussed including their mechanism of action, mode of use, safety, and how to optimize outcomes. PMID- 23931863 TI - Colonoscopy and colorectal cancer incidence and mortality. AB - There is substantial indirect evidence for the effectiveness of colonoscopy in reducing colorectal cancer incidence and mortality. However, several recent studies have raised questions on the magnitude of effect for right-sided colorectal cancers. Well-documented variation in outcomes when colonoscopy is performed by different groups of endoscopists suggests that the recent emphasis on the quality of the procedures should lead to improved outcomes after colonoscopy including reduction in incidence and mortality due to right-sided colorectal cancers. PMID- 23931862 TI - Colonoscopy quality: metrics and implementation. AB - Colonoscopy is an excellent area for quality improvement because it is high volume, has significant associated risk and expense, and there is evidence that variability in its performance affects outcomes. The best end point for validation of quality metrics in colonoscopy is colorectal cancer incidence and mortality, but a more readily accessible metric is the adenoma detection rate. Fourteen quality metrics were proposed in 2006, and these are described in this article. Implementation of quality improvement initiatives involves rapid assessments and changes on an iterative basis, and can be done at the individual, group, or facility level. PMID- 23931864 TI - Complications of colonoscopy. AB - Colonoscopy is a relatively invasive modality for the diagnosis and treatment of colorectal disease and for the prevention or early detection of colorectal neoplasia. Millions of colonoscopies are performed each year in the United States by endoscopists with varying levels of skill in colons that present varying levels of challenge. Although better scope technology has made colonoscopy gentler and more accurate, the sheer number of examinations performed means that complications inevitably occur. This article considers the most common complications of colonoscopy, and advises how to minimize their incidence and how to treat them if they do occur. PMID- 23931865 TI - Training and teaching innovations in colonoscopy. AB - Optimization of training and teaching methods in colonoscopy at all levels of experience is critical to ensure consistent high-quality procedures in practice. Competency in colonoscopy may not be achieved until more than 250 colonoscopies are performed by trainees. Such tools as computer-based endoscopic simulators can aid in accelerating the early phases of training in colonoscopy, and magnetic endoscopic imaging technology can guide the position of the colonoscope and aid with loop reduction. Periodic feedback and retraining experienced endoscopists can improve the detection of colonic lesions. PMID- 23931867 TI - Colonoscopy and polypectomy: moving forward in the battle against colorectal cancer. PMID- 23931866 TI - New platforms and devices in colonoscopy. AB - Gastrointestinal endoscopy is a rapidly evolving field. Techniques in endoscopy continue to become more sophisticated, as do the devices and platforms, particularly in colonoscopy and endoscopic resection. This article reviews new platforms for endoscopic imaging of the colon, and discusses new endoscopic accessories and developments in endoscopic resection. PMID- 23931870 TI - Report on the 5th Slovenian Congress of Nephrology. PMID- 23931869 TI - [Practical aspects for minimizing errors in the cross-cultural adaptation and validation of quality of life questionnaires]. AB - BACKGROUND: The development and validation of questionnaires for evaluating quality of life (QoL) has become an important area of research. However, there is a proliferation of non-validated measuring instruments in the health setting that do not contribute to advances in scientific knowledge. AIMS: To present, through the analysis of available validated questionnaires, a checklist of the practical aspects of how to carry out the cross-cultural adaptation of QoL questionnaires (generic, or disease-specific) so that no step is overlooked in the evaluation process, and thus help prevent the elaboration of insufficient or incomplete validations. METHODS: We have consulted basic textbooks and Pubmed databases using the following keywords quality of life, questionnaires, and gastroenterology, confined to "validation studies" in English, Spanish, and Portuguese, and with no time limit, for the purpose of analyzing the translation and validation of the questionnaires available through the Mapi Institute and PROQOLID websites. RESULTS: A checklist is presented to aid in the planning and carrying out of the cross-cultural adaptation of QoL questionnaires, in conjunction with a glossary of key terms in the area of knowledge. The acronym DSTAC was used, which refers to each of the 5 stages involved in the recommended procedure. In addition, we provide a table of the QoL instruments that have been validated into Spanish. CONCLUSIONS: This article provides information on how to adapt QoL questionnaires from a cross-cultural perspective, as well as to minimize common errors. PMID- 23931871 TI - Renal replacement therapy in Slovenia: excerpts from 2011 data. AB - This report provides a summary of the 2011 Slovenian renal replacement therapy (RRT) data. Data were obtained from 24 renal centers: 23 dialysis and one transplant center, referred as of 31 December 2011, with 100% response rate to individual patient questionnaires. Slovenia has a population of approximately 2 million (2 052 496 in 2011). The total number of patients treated by RRT was 2011,that is, 980 per million of population (pmp); 0.4% decrease compared to 2010. 1347 (67.0%) were treated by hemodialysis, 60 (3.0%) by peritoneal dialysis, and 604 (30.0%) had a functioning kidney graft. A total of 236 incident patients, 115 pmp (at day one), started RRT, their median age was 68 years, 64.8% were men, 36.4% were diabetics. Regarding hemodialysis patients, 59.3% were treated with on-line hemodiafiltration, 86% with ultrapure dialysis fluid. Median weekly duration of hemodialysis was 12.5 h, median dry body weight 70 kg, mean blood flow 275 +/- 46 mL/min, 7.1% were dialyzed in a single-needle mode. Vascular accesses were native arteriovenous fistula in 79%, polytetrafluoroethylene graft in 6%, and catheter in 15%. The crude death rate was 15.9% in dialysis patients, 1.9% in transplant recipients, and 12.0% in all RRT patients (both dialysis and transplant, incident patients at day 1 included). Slovenia has been a member of Eurotransplant since 2000. Forty-six kidney transplantations were performed in 2011, all from deceased donors. A slight decrease in prevalent number of RRT patients was observed in 2011, for the first time in 40 years. The number and proportion of patients with functioning kidney grafts is increasing, reaching 30% in 2011. PMID- 23931872 TI - Chronic kidney disease progression to end stage renal disease: a single center experience of the role of the underlying kidney disease. AB - Chronic kidney disease (CKD) is common and several factors affect its progression to end-stage renal disease (ESRD). The main goal of our study was to assess the influence of underlying kidney disease and some other important factors during the time of CKD progression to ESRD. A retrospective study of 91 patients (57 men, 34 women; average age 57.7 +/- 13.2 years) was carried out. Patients were monitored at least one month before the first renal replacement treatment (RRT). Estimated glomerular filtration rate (eGFR) at first referral to nephrologist was determined by Modification of Diet in Renal Disease equation. Proteinuria was assessed semiquantitatively with dipsticks. Thirty-five patients (38.5%) had diabetic nephropathy (DN), 21 (23.1%) hypertensive nephrosclerosis (HN), 21 (23.1%) adult polycystic kidney disease (APKD) and 14 (15.4%) immunoglobulin A nephropathy (IgAN). Average eGFR at first referral for DN patients was 20.1, and then 23.4 for HN, 35.5 for APKD, and 36.4 mL/min per 1,73 m(2) for IgAN patients. Average time between first nephrological visit and first RRT was 28.4 months for DN patients, 41 for HN, 80.8 for APKD, and 70.1 for IgAN patients. Comparison of all four groups of CKD patients showed that in patients with APKD and IgAN impairment of kidney function to ESRD had progressed statistically significantly slower (P < 0.001). When eGFR at referral, proteinuria, smoking, and renin angiontensin-aldosterone blockade treatment had been added into the model, patients with APKD and IgAN had a statistically significant longer period between first nephrological visit and first RRT (P < 0.026). In comparison with patients with other underlying causes of CKD, patients with APKD and IgAN had a statistically significant slower progression rate of CKD to ESRD. PMID- 23931873 TI - Paricalcitol reduces proteinuria in non-dialysis chronic kidney disease patients. AB - Existing treatment of proteinuria is not sufficient to halt the chronic kidney disease (CKD) epidemic. Therefore the aim of our study was to evaluate the effect of paricalcitol on proteinuria in non-dialysis CKD patients with secondary hyperparathyroidism treated according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Forty-one non-dialysis CKD patients with secondary hyperparathyroidism (iPTH >65 pg/mL), serum calcium <2.6 mmol/L, serum phosphate <1.8 mmol/L and proteinuria (>150 mg/day) were treated with paricalcitol 1 MUg/day. Most were treated for 6 months, with the exception of three patients having iPTH <30 pg/mL after 3 months, in whom therapy was stopped. All patients were followed for 6 months. 24-h ambulatory blood pressure (24hABP) monitoring was performed at 0 and 6 months. Fixed doses of ACE inhibitors and/or ARBs and/or statins were kept for 3 months before and during the study. Forty-one patients (30 men, 11 women; age 62.44 +/- 11.93 years) with different primary causes of CKD were enrolled in the study. Urinary albumin/creatinine ratio (UACR), 24-h urinary albuminuria (24hUA) and 24-h urinary quantitative proteinuria (24hUQP) were measured. Values at 0 and 6 months of these parameters were log-transformed for statistical analysis. After treatment with paricalcitol, statistically significant reduction (paired t-test) in 24hUA (P < 0.011) and 24hUQP (P < 0.0001) were found. The reduction of UACR was not significant (P = 0.074). In the observational period no statistically significant reduction in 24hABP was found. Treatment with 1 MUg paricalcitol daily according to clinical practice in non dialysis CKD patients with secondary hyperparathyroidism and proteinuria significantly reduces 24hUA and 24hUQP without significant change in 24hABP. PMID- 23931874 TI - Ankle-brachial index and cardiovascular mortality in nondiabetic hemodialysis patients. AB - Atherosclerosis is a leading cause of morbidity and mortality in hemodialysis (HD) patients. Low (<0.90) and high (>1.40) ankle-brachial index (ABI) is known as a non-invasive diagnostic marker for generalized atherosclerosis associated with higher cardiovascular (CV) mortality in the general population. Less is known about associations between ABI and CV mortality in HD patients. The aim of our study was to determine the impact of the ABI on CV mortality in nondiabetic HD patients. Fifty-two nondiabetic HD patients (mean age 59 years, range 22 - 76 years) were enrolled in our study. Twenty-three (44%) were women and 29 (56%) men. The ABI was determined using an automated, non-invasive, waveform analysis device. All patients were divided according to the ABI into three groups: low ABI (<0.9), normal ABI (0.9-1.4) and high ABI (>1.4). The presence of arterial hypertension and smoking was established. Serum cholesterol (HDL and LDL) and triglycerides were measured by routine laboratory methods. Survival rates were analyzed using Kaplan-Meier survival curves. The Cox regression model was used to assess the influence of the ABI on CV outcomes. The model was adjusted for age, arterial hypertension, smoking, cholesterol and triglycerides. Mean ABI value was 1.2 +/- 0.3 (range 0.2-2.2). Patients were observed from the date of the ABI measurement until their death or maximally up to 1620 days. Kaplan-Meier survival analysis showed that the risk for CV death was higher for HD patients with low and high ABI compared to normal ABI (log rank test: P < 0.006; P < 0.0001). In the adjusted Cox multivariable regression model low and high ABI (P < 0.011; P < 0.003) remained predictors of mortality in our patients. The results indicate a U shaped association between the ABI and CV mortality in nondiabetic HD patients and showed that low and high ABI were directly associated with higher mortality of our patients. PMID- 23931875 TI - Radiographic assessment of vascular calcification, aortic pulse wave velocity, ankle-brachial index and fibroblast growth factor-23 in chronic hemodialysis patients. AB - Vascular calcification is a frequent complication of chronic kidney disease and end stage renal disease. In both the general population and patients with end stage renal disease, vascular calcification is related to arterial stiffness and is a predictor of cardiovascular morbidity and mortality. Various diagnostic methods are currently used to assess vascular calcification. There is a preference for simple, reliable methods that can be used in daily practice. Therefore, several imaging and laboratory methods are investigated. Twenty-eight patients with mean age of 62 years on chronic hemodialysis were enrolled in the study. The mean duration of hemodialysis treatment was 70 months (range 3 to 350 months). Vascular calcification was assessed with coronary computed tomography and lateral lumbar, pelvic and hand radiographs. Vascular stiffness was evaluated using aortic pulse wave velocity and ankle-brachial index measurements, and finally serum levels of fibroblast growth factor-23 were followed. A statistically significant correlation was demonstrated between all the following parameters: coronary artery calcification score, aortic pulse wave velocity, abdominal aortic calcification score, simple vascular calcification scores in pelvis and hand. A statistically significant correlation of ankle-brachial index >1.3 to coronary artery calcification score was found. There was no correlation between the previous parameters and fibroblast growth factor-23. The results of our study indicate that simple imaging methods could provide confident vascular damage assessment and therefore potentially guide therapy adjustments. An association between fibroblast growth factor-23 and the other diagnostic modalities in our study was not found. PMID- 23931876 TI - Ascorbic Acid for the prevention of contrast-induced nephropathy after coronary angiography in patients with chronic renal impairment: a randomized controlled trial. AB - To determine the incidence of contrast-induced nephropathy (CIN) and to assess the effectiveness of ascorbic acid in the prevention of CIN after coronary angiography in patients with chronic renal impairment. CIN is the third most common cause of hospital-acquired renal failure. It is well documented that periprocedural hydration is effective in the prevention of CIN. Little data exist on the effectiveness of ascorbic acid, a vitamin with antioxidative action. Patients with stable serum creatinine level >107 MUmol/L (n = 81) undergoing coronary angiography were randomized to receive either ascorbic acid (N = 40) or placebo (N = 41) before the procedure. All patients received intravenous volume expansion with normal saline before the procedure. CIN was defined as an increase of serum creatinine level >25% from baseline measured 3 to 4 days after the procedure. CIN occurred totally in 5/81 patients (6.2%); in two patients (3%) in the ascorbic acid group and in three patients (7.3%) in the placebo group (P = 0.512). Postprocedural worsening of renal function (postprocedural increase of serum creatinine level) was present in 10/81 patients (12.3%) in the ascorbic acid group and in 19/81 patients (23.4%) in the placebo group (P = 0.038). No patient required dialysis treatment. We found no statistically significant impact of ascorbic acid on the incidence of CIN in patients with chronic renal impairment undergoing coronary arteriography or angioplasty. Ascorbic acid may still have some protective role in CIN reflected in lower incidence of worsening of renal function in the treated group. PMID- 23931877 TI - Use of myoglobin as a marker and predictor in myoglobinuric acute kidney injury. AB - Serum creatine kinase (CK) is routinely used as a marker in the assessment of rhabdomyolysis and acute myoglobinuric kidney injury (Mb-AKI), while the use of myoglobin is much less explored in this respect. We retrospectively analyzed the incidence of Mb-AKI (creatinine [Cr] > 200 MUmol/L) and the need for hemodialysis (HD) in 484 patients (70.5% males) with suspected rhabdomyolysis, grouped according to peak serum myoglobin (A: 1-5 mg/L, B: 5-15 mg/L, C: >15 mg/L). The median peak myoglobin was 7163 MUg/L. Both peak Cr and peak CK were significantly higher in group C. The incidence of Mb-AKI was 24.6% in group A, 38.6% in group B (P < 0.01 vs. group A), and significantly higher (64.9%) in group C (P < 0.001 vs. groups A and B). Fifty-one patients (10.5%) needed HD, the proportion increasing from 6.7% in group A, and 12.3% in group B (NS), to 28.1% in group C (P < 0.001 vs. group A, P 0.01 vs. group B), and reaching 36.8% with myoglobin >20 mg/L. Creatine kinase correlated with the severity of rhabdomyolysis, but less so with Mb-AKI. The peak Cr levels were not significantly different between patients divided by CK 60 MUkat/L, or grouped into CK tertiles or quartiles. A significant proportion of patients with rhabdomyolysis experienced Mb-AKI, whose frequency increased in parallel with myoglobin levels. Myoglobin levels above 15 mg/L were most significantly related to the development of AKI and the need for HD. Blood myoglobin could serve as a valuable early predictor and marker of rhabdomyolysis and Mb-AKI. PMID- 23931878 TI - Some kinetic considerations in high cut-off hemodiafiltration for acute myoglobinuric renal failure. AB - The kinetics of myoglobin in severe rhabdomyolysis and dialysis-dependent myoglobinuric acute kidney injury (Mb-AKI) is still not well elucidated, and more detailed knowledge could improve the now empiric use of rapid extracorporeal myoglobin removal by high cut-off (HCO) hemodialysis treatments. Eighteen adult patients with severe dialysis-dependent Mb-AKI (median serum concentration of myoglobin 57.4 mg/L) participated in the prospective clinical study, assessing myoglobin kinetics during HCO hemodiafiltration (HCO HDF). High initial serum concentrations of myoglobin (median 57.4 mg/L), together with protracted myoglobin appearance in the blood, indicated a large accumulation of myoglobin in body fluids. Extra-renal endogenous metabolic myoglobin clearance was delayed, with a slow exponential fall in serum myoglobin (t1/2 35 h). A mean myoglobin clearance of 90-94 mL/min, a reduction ratio of 80%, and a rapid exponential fall (t1/2 1 h) in serum and dialysate myoglobin were achieved by HCO HDF. Half of the cumulative myoglobin removal was accomplished in 3-5 h, with an additional removal of 7% each hour thereafter. A 2.4-fold rebound in serum myoglobin followed the HCO procedures. Large amounts of myoglobin are released into the circulation, and its endogenous metabolic clearance in dialysis-dependent Mb-AKI is slow. Owing to its rapid and highly efficient myoglobin elimination, HCO HDF may represent a valuable tool in the initial management of severe Mb-AKI, with a potential for earlier application in the future. PMID- 23931879 TI - Successful treatment of severe hantavirus nephritis with corticosteroids: a case report and literature review. AB - Hantaviruses can be associated with severe form of hemorrhagic fever with renal syndrome although there are only a few cases reporting chronic kidney disease after hantavirus infection. We report a severe nonresolving chronic renal failure after protracted Dobrava hantavirus infection successfully treated with corticosteroids. Ten days after working in a basement a 33-year-old man fell seriously ill, with high fever, chills, diffuse myalgia, headache and abdominal pain. After hospital admission a diagnosis of hemorrhagic fever with renal syndrome caused by Dobrava hantavirus was made. Acute oliguric kidney injury developed in the first 3 days after admission, in a few days diuresis restored and he became polyuric. Nevertheless renal failure persisted and he needed hemodialysis. Because of nonresolving kidney failure, nephrogenic diabetes insipidus and renoparenchymal arterial hypertension persisting 2 months after onset of symptoms, a kidney biopsy was performed, showing severe necrotizing tubulointerstitial nephritis. High dose methylprednisolone therapy was started and his renal function significantly improved. Two months later a second renal biopsy showed persisting elements of active necrotizing tubulointerstitial nephritis. We decided to stop corticosteroid treatment and introduced aldosterone antagonist eplerenon as anti-fibrotic agent, and his renal function further improved and remained stable. Nine months later his serum creatinine concentration was 227 MUmol/L, proteinuria 0.156 g/day and well controlled nephrogenic diabetes insipidus. PMID- 23931880 TI - Fibroblast growth factor 23 and left ventricular mass index in maintenance hemodialysis patients: standard versus long nocturnal hemodialysis. AB - Elevated levels of fibroblast growth factor 23 (FGF23) and phosphorus (P) have been linked to greater risks of left ventricular hypertrophy (LVH) in patients with end stage renal disease (ESRD). The aim of this study was to test if differences exist in a long nocturnal HD group in comparison with a group treated with standard daily thrice weekly dialysis. The attempt was to evaluate if elevated FGF-23 levels, intact parathyroid hormone and P might be associated with left ventricular mass index (LVMI). Quantitative echocardiographic analyses were performed at baseline in 50 maintenance HD patients (17 women and 33 men, mean age: 56.4 +/- 15.35 years, mean HD vintage: 9.06 +/- 8.86 years, all patients are on HD thrice a week-median duration 15 h/week, 10 of them on long nocturnal HD, median duration 24 h/week). LVMIs were calculated. FGF23 was measured in duplicate using a second generation C-terminal enzyme-linked immunosorbent assay and log of FGF-23 values were computed. Mean LVMI was 136.44 +/- 44.44 g/m(2) . Serum FGF-23 levels were elevated when compared to population data with preserved kidney function (median 1388.5 RU/mL, range 252 to 24 336 RU/mL). There were no correlations recorded between log FGF-23 levels and LVMI (r = 0.2, P = 0.66). LVMI was significantly lower in HD patients on long nocturnal dialysis procedure (r = -0.31, P = 0.05). Patients treated with long nocturnal HD showed lower LV mass, lower P-values and higher 25-OH-D3 supply. Plasma FGF-23 concentration was comparable between the groups and was not associated with LVMI in our maintenance HD patients. PMID- 23931881 TI - Effect of switching to nocturnal thrice-weekly hemodialysis on clinical and laboratory parameters: our experience. AB - Long or frequent hemodialysis schedules are reported to improve clinical outcomes. We report here our experience with an in-center, nocturnal, thrice weekly hemodialysis program. We retrospectively analyzed the effect of switching 10 patients (8 male, age 45 +/- 11 years, renal replacement therapy vintage 12 +/ 8 years) from regular, 4-5 h, thrice-weekly hemodialysis to 8 h nocturnal, in center hemodialysis as regards dialysis efficiency, chronic kidney disease metabolic and bone disease (CKD-MBD) parameters, blood pressure, and anemia. With more intense dialysis, the mean predialysis creatinine and urea decreased significantly (1092 +/- 195 vs. 961 +/- 154 MUmol/L, P < 0.01 and 30.8 +/- 4.6 vs. 25.5 +/- 2.9 mmol/L, P < 0.01), while the decrease in potassium was insignificant (5.9 +/- 0.7 vs. 5.6 +/- 0.5 mmol/L), but in 3/10 patients, dialysate potassium was increased. Three months after starting nocturnal hemodialysis, no significant influence on pre-dialysis blood pressure was observed (143/80 vs. 140/80 mmHg), but antihypertensive medications were reduced in two patients. The mean dry weight reduced (74 +/- 12 to 72 +/- 12 kg) and the mean ultrafiltration increased insignificantly (3123 +/- 1174 to 3434 +/- 1341 mL). Serum calcium was stable, while phosphate reduced insignificantly (1.5 +/- 0.5 to 1.2 +/- 0.2 mmol/L), but 6/10 patients were able to discontinue phosphate binders, the dose was reduced in one, and phosphate was added to dialysate in 3/10 patients. Intact parathyroid hormone values were within the target range, except in patients post-parathyroidectomy. There were no differences in hemoglobin (121 +/- 6 vs. 122 +/- 8 g/L), and the mean epoetin dose decreased insignificantly (5950 +/- 3947 vs. 5250 +/- 4238 IU/week). To conclude, improved phosphate and potassium control and reduction in phosphate binders were observed after switching to nocturnal hemodialysis. There was an insignificant reduction of epoetin dose and antihypertensive medications. PMID- 23931882 TI - Arteriovenous grafts in the thigh: an excellent hemodialysis vascular access when arm vasculature is exhausted. AB - The aim of our retrospective analysis with prospective collected data was to evaluate the patency of thigh expanded polytetrafluoroethylene (ePTFE) arteriovenous (AV) grafts, which were placed in chronic hemodialysis patients by the same interventional nephrologist skilled in hemodialysis access vascular surgery. From February 1991 until March 2013, 35 thigh ePTFE grafts were placed in 31 chronic hemodialysis patients. Twenty (57%) were women, mean age 58.7 +/- 14.5, dialysis vintage 11.9 +/- 7.3 years, mean number of previous vascular accesses 4.4 +/- 1.9. Two of the 35 (5.7%) grafts were lost to follow-up, immediate failure occurred in 1/35 (2.8%) grafts, and thrombosis appeared within 30 days in 2/35 (5.7%) grafts. Four of the 31 patients died with functioning grafts, while in 9/31 patients the grafts are still patent. In the remaining 17 AV grafts that thrombosed, no surgical intervention was performed in 8/17, while 18 thrombectomies (two per graft) were performed in 9/17 to maintain graft patency. The immediate success rate was 97.1%. Primary patency was from 0-3251 days, on average 906 +/- 898, median 472, cumulative patency (N = 33) was from 0 3251 days, on average 1174 +/- 954, median 966. Cumulative patency of the grafts that were patent for more than 30 days (N = 30) was from 153-3251 days, on average 1298 +/- 921, median 1207. The ePTFE graft survival after the 1st year was 78%, after the 2nd year 74%, after the 3rd year 66%, after the 4th year 56%, after the 5th year 52%, and after the 9th year 13 %. The longest patency was 3251 days without any intervention. Steal syndrome occurred in two patients after 2522 and 275 days after fistula placement. PMID- 23931883 TI - Reasons for refusing kidney transplantation among chronic dialysis patients. AB - The aim of the prospective clinical study was to evaluate the reasons for refusing kidney transplantation among chronic dialysis patients. A total of 164 adult chronic dialysis patients participated in the study. They were asked to complete a detailed questionnaire on specific issues regarding transplantation. The mean age was 60.9 +/- 16.0 (20-89) years, 61.6% were male, 11.6% had had a previous transplant. The majority, that is, 72.0%, of the patients believed that transplantation improved the quality of life, and 55.5% believed that transplantation prolonged life. Nevertheless, 45.0% of the patients wanted to be transplanted, 35.0% refused transplantation, and 20.0% were undecided. Patients refusing transplantation were significantly older compared to the patients wanting to be transplanted (67 +/- 16 vs. 57 +/- 16 years; P < 0.001). The main reasons for refusing transplantation (57 patients) were the side-effects of immunosuppressive therapy (31.6%), unpredictability of transplant outcome (29.8%), and unfavorable outcomes in fellow patients (28.1%). The side-effects of immunosuppressive therapy that patients were most concerned about included mobility problems (29.8%), new-onset diabetes (26.3%), increased risk of severe infections (26.3%), problems with vision (22.8%), and increased risk of cancer (21.1%). Many patients did not want to accept organs from expanded criteria donors (ECD) (44.6% of the patients wanting and 64.9% of those refusing transplantation). The majority believed that patients should be informed if an organ from an ECD donor is being offered (64.9% of patients wanting and 63.2% of those refusing transplantation). The main reasons for refusing kidney transplantation were the side-effects of immunosuppressive therapy, unpredictability of transplant outcome, and unfavorable outcomes in fellow patients. PMID- 23931884 TI - Influence of renin-angiotensin-aldosterone system-blocking drugs on peritoneal membrane in peritoneal dialysis patients. AB - Therapy with renin-angiotensin-aldosterone system (RAAS)-blocking drugs prevents the development of fibrosis and angiogenesis in animal models and humans. In our study we have evaluated the systemic effect of RAAS blockade and the effect on peritoneal growth factors, cytokine production and membrane transport characteristics in patients on peritoneal dialysis. Thirty-seven peritoneal dialysis (PD) patients were enrolled in our cross-sectional study. Aldosterone and angiotensin II concentrations were measured in serum to determine the RAAS activity. The inflammatory and profibrotic activity was evaluated by measuring the concentration of C-reactive protein (CRP), serum albumin, and peritoneal concentration of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), plasminogen activator inhibitor-1 (PAI-1), transforming growth factor-beta (TGF beta) and cancer antigen-125 (CA-125). The transport characteristics of the peritoneal membrane were analyzed with a peritoneal equilibration test (PET). Results were compared between the group with RAAS-blocking drugs (RAAS group) and the group without them (non-RAAS group). Mean serum aldosterone concentration was significantly lower in patients treated with ARB-blocking drugs (P = 0.001) and serum angiotensin II concentration was lower in patients treated with ACE inhibitors (P = 0.009). RAAS blockade resulted in lower peritoneal PAI-1 levels (748.1 to 1222.7 ng/L; P = 0.07) without any influence on CRP, peritoneal concentrations of IL-6, VEGF, TGF-beta and CA-125, or alteration in peritoneal membrane characteristics tested by PET. RAAS-blocking drugs could be effective in preventing peritoneal fibrosis due to possible reduction of peritoneal PAI-1 concentrations that have already been etiologically linked with fibrin deposition in the pathogenesis of encapsulating peritoneal sclerosis. PMID- 23931885 TI - Fulminant peritonitis presumably caused by Panton-Valentine leukocidin-positive Staphylococcus aureus in a girl on peritoneal dialysis. AB - Peritonitis is a significant complication of peritoneal dialysis (PD) and the most common cause of technique failure. Panton-Valentine leukocidin (PVL), a cytotoxin produced by certain strains of Staphylococcus aureus (SA), causes destruction of neutrophils, and is associated with severe invasive infections. We present a 2.5-year-old girl on PD, who presented suddenly with an unusually fulminant and protracted course of peritonitis. Only a few hours after the onset of clinical signs, septic shock developed. PVL-positive methicillin-sensitive SA (MSSA) was grown and initial empiric antibiotic treatment changed to flucloxacillin and rifampicin in order to minimize toxin production. In spite of adequate antibiotic treatment and PD-catheter removal, recovery was slow. No PD related peritonitis in children associated with PVL-producing strains have been reported so far and no specific recommendation exists for treatment. We speculate that PVL contributed to the severity and outcome of peritonitis in our patient. PMID- 23931886 TI - Plasmapheresis and immunoadsorption for treatment and prophylaxis of recurrent focal segmental glomerulosclerosis in adult recipients of deceased donor renal grafts. AB - Recurrent focal segmental glomerulosclerosis has a great impact on kidney graft survival. This retrospective study presents immunoadsorption-plasmapheresis treatment and outcome in our renal graft recipients with significant post transplant proteinuria (>1 g/day) and focal segmental glomerulosclerosis in native kidneys. Recurrence was defined as occurrence of nephrotic range proteinuria or biopsy-confirmed diagnosis. Successful treatment was defined as sustained reduction of proteinuria to <1 g/day. From 2000 through 2011, 548 adult patients received kidney grafts from deceased donors. In 20 of these patients (3.6%) end-stage renal disease was a consequence of focal segmental glomerulosclerosis. Recurrence was confirmed in five of seven treated patients. Immunoadsorption-plasmapheresis treatment was successful in five patients (70%). Their age at disease diagnosis in native kidneys was 12 to 44 years. Time to end stage renal disease was 3 to 14 years. Recipient age at transplantation was 21 to 61 years. Onset of significant proteinuria was 2 to 87 days after transplantation. Immunoadsorption or plasmapheresis started 1 to 7 days after recurrence of significant proteinuria. Treatment period was 1 to 103 months and 12 to 206 procedures were performed per patient. Follow-up period after cessation of plasmapheresis was 11 to 58 months. Final urine protein/creatinine ratio was 8.8 to 98.0 mg/mmol and final serum creatinine was 63 to 148 MUmol/L. Follow-up after transplantation was 18 to 135 months. One patient was still on treatment. One graft was lost to recurrence. No serious adverse effects occurred during immunoadsorption and plasmapheresis. Immunoadsorption and plasmapheresis appears to be successful in the majority of patients, probably due to their early start. PMID- 23931887 TI - Hemodialysis arteriovenous fistula-related complications and surgery in kidney graft recipients. AB - Arteriovenous fistula (AVF) remains functional after kidney transplantation in many patients. The aim of this historical cohort study was to evaluate the data on AVF-related complications and surgery performed after kidney transplantation in our patients. The study cohort included the recipients of a kidney transplant with AVF complications between January 2006 and April 2012. 74 renal transplant recipients (47% male, mean age 51 +/- 10, range 14 to 73 years) with complications related to AVF were analyzed. Among all AVFs, 51 (72%) were located in the forearm, nine (13%) in the upper arm, and 14 (15%) in the elbow. Complications occurred in 12.5% (74/592) of kidney graft recipients who were treated at our Outpatient Transplant Unit during the study period. The most common complication was painful thrombosis with or without thrombophlebitis, which occurred in 32 patients (43.2%). Other complications included growing aneurysms (27%, 20/74), venous hypertension with arm edema (8.1%, 6/74), distal hypoperfusion (8.1%, 6/74), high flow AVF with cardiac failure (8.1%, 6/74), trauma (1.3%, 1/74), and cosmetic appearance (4%, 3/74). Fifty-one surgical interventions were performed in 49 patients (mean age 52 +/- 12, range 28 to 73 years). AVF closure was performed in 29/51 (56%) patients. Furthermore, an extirpation of aneurysm was performed in 12/51 (23%) and an extirpation of thrombosed AVF was performed in 1/51 (2%) patients, simple trombectomies were performed in 5/51 (10%) and a thrombectomy with reanastomosis was performed in 4/51 (8%) patients. One patient underwent percutaneous transluminal angioplasty for underlying stenosis after surgery. The most common AVF-related complications in kidney graft recipients are painful thrombosis (often accompanied with thrombophlebitis) and growing aneurysms. Surgical intervention is performed in a significant proportion of patients, mainly AVF closure, aneurysm extirpation, and thrombectomy. PMID- 23931888 TI - Abdominal aortic calcification is an independent predictor of cardiovascular events in peritoneal dialysis patients. AB - Abdominal aortic calcification (AAC) is reported as a predictor for cardiovascular events in general population and in hemodialysis patients. At present, there are no AAC data in peritoneal dialysis. The purpose of this study was to evaluate the prognostic role of AAC score on cardiovascular events in peritoneal dialysis patients. Seventy-four peritoneal dialysis patients were enrolled. AAC was measured on baseline lateral abdomen radiographs by the semi quantitative method as described by Kauppila. The other cardiovascular risk factors were obtained from patient history and blood examination. The Kaplan Meier method was used to evaluate freedom from cardiovascular events, and differences were assessed with the log-rank statistic. Multivariate Cox regression models addressed time to cardiovascular events. The median period of follow-up was 30.5months (IQR 19.4-32.7). During follow-up, there were 29 cardiovascular events (39.2%). In univariable analysis, patient's age (HR=1.050; P=0.001), urine output (HR=0.999; P=0.02), and AAC stratified by tertiles (overall P-value<0.001) were significantly associated with cardiovascular events. In multivariable regression analysis, AAC score stratified by tertiles was the only independent predictor for cardiovascular events (overall P-value<0.001). To our knowledge, we have shown for the first time that AAC score is an independent predictor of cardiovascular events in peritoneal dialysis patients. Risk stratification by assessment of AAC score may provide important information for the management of cardiovascular disease in peritoneal dialysis patients without any additional expense, because these patients have several abdominal X-ray scans to evaluate the catheter position. PMID- 23931889 TI - Effect on extrapulmonary sepsis-induced acute lung injury by hemoperfusion with neutral microporous resin column. AB - The aim of this study was to investigate the effect of neutral microporous resin hemoperfusion on oxygenation improvement, removal of inflammatory cytokines in plasma and bronchoalveolar lavage, and mortality in acute lung injury induced by extrapulmonary sepsis. Forty-six patients with acute lung injury induced by extrapulmonary sepsis were randomized to HA type hemoperfusion treatment (N=25) or standard therapy (N=21). Those undergoing hemoperfusion treatment received HA330 hemoperfusion. We measured the plasma and bronchoalveolar lavage concentrations of TNF-alpha and IL-1, and the following parameters were compared between the control group and the hemoperfusion group on days 0, 3 and 7: lung injury measurements (arterial oxygen tension/fractional inspired oxygen ratio, lung injury score, chest X-ray score); interstitial edema of lung (extravascular lung water). Duration of mechanical ventilation, hospital, 28-day, and intensive care unit mortality were also observed. Patients treated with HA hemoperfusion showed a significant removal of plasma and bronchoalveolar lavage TNF-alpha and IL-1 over time while in the study. Patients in the HA group also demonstrated not only significant improvement of PaO2 /FiO2 , but also decreased Lung Injury Score and chest X-ray score at days 3 and 7. Furthermore, the measurements of the arterial oxygen tension/fractional inspired oxygen ratio, lung injury score and extravascular lung water (EVLWI) significantly correlated with and the concentration of cytokines in the plasma (all P<0.05). The HA hemoperfusion treatment group had a significant reduction in duration of mechanical ventilation, length of intensive care unit stay, and intensive care unit mortality. Significant removal of inflammatory cytokines from circulation and lung by hemoperfusion treatment using the HA type cartridge may contribute to the improvement of lung injury and intensive care unit outcome in extrapulmonary septic patients. PMID- 23931890 TI - Plasmapheresis-refractory transplantation-associated thrombotic microangiopathy successfully treated with pravastatin and limaprost alfadex. PMID- 23931891 TI - Severe hypertriglyceridemia-related acute pancreatitis. PMID- 23931892 TI - Severe hypertriglyceridemia-related acute pancreatitis: myth or reality? PMID- 23931895 TI - Intrasternal anastomotic pseudoaneurysm following ascending aortic graft replacement. PMID- 23931896 TI - Redox-responsive mesoporous silica nanoparticles: a physiologically sensitive codelivery vehicle for siRNA and doxorubicin. AB - AIMS: Efficient siRNA/drug codelivery carriers can offer great promises to cancer treatment on account of synergistic effect provided from cancer-associated gene and anticancer drugs. In this work, a redox-responsive drug/siRNA codelivery vehicle based on mesoporous silica nanoparticles was fabricated to simultaneously deliver siRNA and doxorubicin (Dox) in vitro and in vivo. RESULTS: The nanoparticle surface was functionalized with the adamantane (AD) units. Formation of stable host-guest complex between disulfide bond linked-AD and ethylenediamine modified beta-cyclodextrin is capable of fully blocking drugs inside the nanopores, while amino groups can complex with siRNA via electrostatic interaction. Relatively high concentration of glutathione in biophysical environment provides natural reducing agent to trigger drug/siRNA release by cleaving pre-introduced disulfide bonds. B-cell lymphoma 2 (Bcl-2) siRNA was codelivered to silence Bcl-2 protein expression in HeLa cells, resulting in enhanced chemotherapy efficacy in vitro. In vivo delivery experiment carried out in transgenic zebrafish larvae indicates that the delivery of Dox inhibits the development of choroid plexus in a dose-dependent manner, leading to successful decrease of green fluorescence protein transcription in choroid plexus. Reduction of liver tumor was also demonstrated after injection of Dox-loaded nanoparticles. INNOVATION: We successfully demonstrated that functional nanoparticles could serve as an efficient carrier for the delivery of Bcl-2 siRNA and Dox in HeLa cells and in transgenic zebrafish larvae, leading to enhanced therapeutic efficacy. CONCLUSION: Enhanced cytotoxicity caused by simultaneous delivery of Bcl-2 siRNA and Dox was observed in HeLa cells. Drug-loaded nanoparticles were internalized in vivo, inhibiting the development of choroid plexus and the progression of liver tumor. PMID- 23931897 TI - Diagnostic testing for Helicobacter Pylori in patients with atrophic gastritis. PMID- 23931898 TI - Viral hepatitis and the kidney. PMID- 23931900 TI - Structural basis for hyperpermeability of tumor vessels in advanced lung adenocarcinoma complicated by pleural effusion. AB - BACKGROUND: Malignant pleural effusion (MPE) has a profound impact on quality of life and survival in patients with lung cancer. Identification of the factors within the tumor and its environment that mediate MPE is still lacking. PATIENTS AND METHODS: Intratumoral microvessel density (MVD), endothelial cell and pericyte (PC) capillary coverage, endothelial cell (EC)-PC relationship, lymphatic endothelium integrity, and the expression of receptor tyrosine kinases were all assessed immunohistochemically in pleural tumor biopsy specimens from 24 patients with lung adenocarcinoma (ADC) with and without pleural disease, with the aim to evaluate the involvement with MPE. RESULTS: In the effusion-positive+ specimens, MVD values were found to be significantly higher, and a number of vessels were noted to lack immunoreactivity for ECs (CD31). Likewise, PC alpha smooth muscle actin (alphaSMA) expression was also less extensive in the MPE+ cases. The observation of only sporadic staining of PCs can also explain the findings regarding platelet-derived growth factor receptors (PDGFRs), the expression of which, although more prominent in MPE+ samples, were almost exclusively detected on tumor stromal cells and not on vascular PCs. Conversely, vascular endothelial growth factor receptors (VEGFRs) appeared on both kinds of cells. With respect to lymphatic vessels, lymphatic intraluminal tumor cells were occasionally found in MPE+ specimens. CONCLUSION: Our study suggests that disturbed vessel wall integrity, as well as abnormalities of fluid clearance by the lymphatic system, together with overexpression of growth factors, may take part in the pleural fluid accumulation in lung ADCs. Results of the decreased PC capillary coverage and PDGFR expression in MPE are discussed. PMID- 23931899 TI - Clinical benefit from pemetrexed before and after crizotinib exposure and from crizotinib before and after pemetrexed exposure in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer. AB - BACKGROUND: Crizotinib produces high response rates and prolonged PFS in ALK+ NSCLC. Retrospective analyses suggest enhanced sensitivity to pemetrexed in crizotinib naive ALK+ NSCLC. Cross-resistance between crizotinib and pemetrexed has not been previously investigated. PATIENTS AND METHODS: Patients with stage IV ALK+ NSCLC treated with PEM-CRIZ, or CRIZ-PEM were identified. Overall PFS and PFS excluding central nervous system events (eCNS) were compared. RESULTS: Objective response rates in evaluable patients were 66% (PEM-CRIZ) and 75% (CRIZ PEM) for pemetrexed and 84% (CRIZ-PEM) and 66% (PEM-CRIZ) for crizotinib. For PEM CRIZ (n = 29), median PFS and eCNS PFS were both 6 months with pemetrexed, and 10 and 14.5 months, respectively, with crizotinib. For CRIZ-PEM (n = 9), median PFS and eCNS PFS were 4.5 and 3 months, respectively, with pemetrexed, and 8.5 and 7.5 months, respectively, with crizotinib. There was a statistically significant increase in the risk of an overall PFS event with pemetrexed when administered after crizotinib (P = .0277; hazard ratio [HR], 2.5898; 95% confidence interval [CI], 1.1100-6.0424), but differences in the risk of an eCNS PFS event were not significant (P = 0.4913; HR, 1.3521; 95% CI, 0.5727-3.1920). Neither overall nor eCNS PFS for patients while taking crizotinib was associated with a sequence effect relative to pemetrexed. CONCLUSION: Crizotinib and pemetrexed are active drugs in ALK+ NSCLC. PFS benefit appeared higher with crizotinib than with pemetrexed. PFS benefit from pemetrexed was less after crizotinib compared with before crizotinib, however, this difference was only statistically significant for overall and not eCNS PFS. Pemetrexed exposure did not seem to affect crizotinib outcomes. PMID- 23931901 TI - Endoscopic ophthalmic surgery of the anterior segment. AB - We summarize the uses of anterior segment endoscopic techniques and the basic science and technology of endoscopic cyclophotocoagulation (ECP) as compared with transscleral cyclophotocoagulation. This is followed by an analysis of patient selection for ECP, a description of surgical techniques, and clinical results. In addition, the ophthalmic endoscope has other uses in anterior segment surgeries. We discuss the techniques for these endoscope-assisted surgeries. PMID- 23931902 TI - Response to the Letter to the Editor regarding "Investigating the burden of hyperbilirubinemia in resource-constrained settings". PMID- 23931903 TI - HEAR MAPS a classification for congenital microtia/atresia based on the evaluation of 742 patients. AB - OBJECTIVE: Describe anatomical and radiological findings in 742 patients evaluated for congenital aural atresia and microtia by a multidisciplinary team. Develop a new classification method to enhance multidisciplinary communication regarding patients with congenital aural atresia and microtia. METHODS: Retrospective chart review with descriptive analysis of findings arising from the evaluation of patients with congenital atresia and microtia between January 2008 and January 2012 at a multidisciplinary tertiary referral center. RESULTS: We developed a classification method based on the acronym HEAR MAPS (Hearing, Ear [microtia], Atresia grade, Remnant earlobe, Mandible development, Asymmetry of soft tissue, Paralysis of the facial nerve and Syndromes). We used this method to evaluate 742 consecutive congenital atresia and microtia patients between 2008 and January of 2012. Grade 3 microtia was the most common external ear malformation (76%). Pre-operative Jahrsdoerfer scale was 9 (19%), 8 (39%), 7 (19%), and 6 or less (22%). Twenty three percent of patients had varying degrees of hypoplasia of the mandible. Less than 10% of patients had an identified associated syndrome. CONCLUSION: Patients with congenital aural atresia and microtia often require the intervention of audiology, otology, plastic surgery, craniofacial surgery and speech and language professionals to achieve optimal functional and esthetic reconstruction. Good communication between these disciplines is essential for coordination of care. We describe our use of a new classification method that efficiently describes the physical and radiologic findings in microtia/atresia patients to improve communication amongst care providers. PMID- 23931904 TI - The effects of alkalinity and acidity of process water and hydrochar washing on the adsorption of atrazine on hydrothermally produced hydrochar. AB - Hydrothermal carbonization of simulated food waste was performed at 250 degrees C for 20 h using deionized water (DI) and 0.01 N solutions of HCl, NaCl, and NaOH. The hydrochars produced were washed with acetone and the adsorptive capacity of the washed and unwashed hydrochars for atrazine were characterized. Using a generalized linear model, it was shown that the adsorptive capacity of the washed hydrochar was significantly higher than that of the unwashed hydrochars. The HCl processed unwashed hydrochar has a slightly higher adsorptive capacity compared to the DI processed hydrochar while both the NaOH processed washed and unwashed hydrochars were slightly lower than the corresponding DI processed hydrochars. (13)C solid-state NMR results showed no discernible differences in surface functional groups among the washed hydrochars and among the unwashed hydrochars. A clear decrease in alkyl groups and an increase in aromatic/olefinic-C groups were observed after acetone washing. (1)H liquid-phase NMR showed carbon alkyl chains were present in the acetone wash. Interaction energies calculated using dispersion corrected density functional theory show that atrazine is more strongly adsorbed to surfaces without weakly associated alkyl groups. PMID- 23931905 TI - Trace elements biomonitoring in a historical mining district (les Malines, France). AB - The aim of this study is to investigate the trace elements (TE) contents of potential biomonitors in a historical Zn-Pb mining district: apiary products (honey, royal-jelly and beeswax) lichen and moss were sampled and analysed. In spite of high TE concentrations in mining waste and soil, apiary products are free of TE contamination originating from historical mining. Lichen/moss show high TE levels, which suggest atmospheric input of local dust. Pb isotopes analysis proved the origin of TE found in lichen/moss to be mainly mining waste. These results help discuss the choice of relevant organisms for monitoring TE in the environment and bring additional data on the potential impacts of brownfields left after mining, especially on food products from apiaries. PMID- 23931906 TI - Migration and leaching risk of extraneous antimony in three representative soils of China: lysimeter and batch experiments. AB - Antimony (Sb) distribution, solubility and mobility onto natural soils of China were studied in lysimeter and batch experiments as a function of physicochemical properties of the soil. An outdoor lysimeter experiment investigated the leaching and migration of Sb in the soils with Sb-polluted topsoil and unpolluted subsoil over a 5month period. Soil solutions were collected by suction cups installed at different depth of lysimeters, and leachates were regularly collected and analyzed for Sb concentrations. The majority of the added Sb was retained in the topsoil layers, but small portions were moved to the sub-layers. Sb concentrations in the soil solutions and leachates ranged from 0-755.5 (6.38+/-54 on average) MUg l(-1) and 0-0.45 (smaller than the detection limit) MUg l(-1) respectively, indicating the low solubility of Sb in the soils. Batch experiments were performed in order to determine the sorption capacity and the partition coefficient (Kd). Freundlich isotherm described properly the equilibrium experimental data and results show that the Kd values for Primosol, Isohumosol, Ferrosol equal to 22.5, 87.8, 704 L kg(-1), respectively. These results showed the strong capacity of the soils to retain Sb, and prevent it being leached down the profile. The mobilizable Sb was in the order: Primosol>Isohumosol>Ferrosol. Sb migration in the soils was mainly associated with the exchangeable, carbonate bound, and metal-organic complex-bound fractions. Health risk assessment indicates that Sb leaching from Ferrosol will not harm to human health through groundwater under the test conditions, while it has certain health risks from the Isohumosol and Primosol. PMID- 23931907 TI - Poly(ethylene oxide)-co-poly(propylene oxide)-based gel electrolyte with high ionic conductivity and mechanical integrity for lithium-ion batteries. AB - Using gel polymer electrolytes (GPEs) for lithium-ion batteries usually encounters the drawback of poor mechanical integrity of the GPEs. This study demonstrates the outstanding performance of a GPE consisting of a commercial membrane (Celgard) incorporated with a poly(ethylene oxide)-co-poly(propylene oxide) copolymer (P(EO-co-PO)) swelled by a liquid electrolyte (LE) of 1 M LiPF6 in carbonate solvents. The proposed GPE stably holds LE with an amount that is three times that of the Celgard-P(EO-co-PO) composite. This GPE has a higher ionic conductivity (2.8*10(-3) and 5.1*10(-4) S cm(-1) at 30 and -20 degrees C, respectively) and a wider electrochemical voltage range (5.1 V) than the LE swelled Celgard because of the strong ion-solvation power of P(EO-co-PO). The active ion-solvation role of P(EO-co-PO) also suppresses the formation of the solid-electrolyte interphase layer. When assembling the GPE in a Li/LiFePO4 battery, the P(EO-co-PO) network hinders anionic transport, producing a high Li+ transference number of 0.5 and decreased the polarization overpotential. The Li/GPE/LiFePO4 battery delivers a discharge capacity of 156-135 mAh g(-1) between 0.1 and 1 C-rates, which is approximately 5% higher than that of the Li/LE/LiFePO4 battery. The IR drop of the Li/GPE/LiFePO4 battery was 44% smaller than that of the Li/LE/LiFePO4. The Li/GPE/LiFePO4 battery is more stable, with only a 1.2% capacity decay for 150 galvanostatic charge-discharge cycles. The advantages of the proposed GPE are its high stability, conductivity, Li+ transference number, and mechanical integrity, which allow for the assembly of GPE-based batteries readily scalable to industrial levels. PMID- 23931908 TI - Leadership change and health at UN Women. PMID- 23931909 TI - Facing up to restraint in mental health units. PMID- 23931910 TI - Afghan civilian casualties: a grim reality. PMID- 23931911 TI - A milestone in the response to non-communicable diseases. PMID- 23931912 TI - GBD 2013: open call for collaborators. PMID- 23931913 TI - Highlights 2013: health through the lens. PMID- 23931914 TI - Community treatment orders for patients with psychosis. PMID- 23931915 TI - Community treatment orders for patients with psychosis. PMID- 23931916 TI - Community treatment orders for patients with psychosis. PMID- 23931917 TI - Community treatment orders for patients with psychosis. PMID- 23931918 TI - Community treatment orders for patients with psychosis - Authors' reply. PMID- 23931919 TI - Transmission of M abscessus in patients with cystic fibrosis. PMID- 23931920 TI - Practical criteria for maternal near miss needed for low-income settings. PMID- 23931921 TI - Transmission of M abscessus in patients with cystic fibrosis - Authors' reply. PMID- 23931922 TI - Practical criteria for maternal near miss needed for low-income settings - Authors' reply. PMID- 23931923 TI - Somatic treatments for severe bipolar disorder. PMID- 23931924 TI - Moving beyond gender stereotypes. PMID- 23931925 TI - Pleural effusions in a patient with tuberculosis on dialysis. PMID- 23931926 TI - Adherence to imatinib therapy in patients with gastrointestinal stromal tumors. AB - Imatinib mesylate, an oral tyrosine kinase inhibitor, is indicated for first-line treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumors (GIST). Imatinib also is approved as adjuvant therapy for patients following resection of primary GIST. Despite the efficacy of imatinib for the treatment of patients with GIST, adherence to treatment can prove difficult. Clinical studies have identified a number of factors that have a significant association with non-adherence to therapy, including age >51years, female sex, a high number of concomitant medications, and complications with patients' therapy or the disease itself. Moreover, treatment-related adverse events and increased healthcare costs have been shown to have an impact on patients' adherence to therapy. A study of perceptions of adherence to therapy found discrepancies between actual and perceived adherence rates; both patients and physicians overestimate adherence to treatment. Non-adherence to treatment is not exclusive to oncology, and occurs in other disease areas, particularly with chronic conditions. Evidence from other disease areas suggests that routine assessment of adherence and the implementation of adherence programs can lead to improvements in health status and reduced healthcare costs. Improving patient adherence to imatinib treatment for patients with unresectable/metastatic GIST is particularly important, because non-adherence has a significant impact on clinical outcomes and healthcare costs. Therefore, the effective management of treatment-related adverse events along with patient education may be important in keeping patients compliant with continuous therapy. PMID- 23931927 TI - ALK inhibitors in the treatment of advanced NSCLC. AB - Pharmacologic agents that target protein products of oncogenes in tumors are playing an increasing clinical role in the treatment of cancer. Currently, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. Subsequently other genetic abnormalities with "driver" characteristics - implying transforming and tumor maintenance capabilities have been extensively reported in several small distinct subsets of NSCLC. Among these rare genetic changes, anaplastic lymphoma kinase (ALK) gene rearrangements, most often consisting in a chromosome 2 inversion leading to a fusion with the echinoderm microtubule associated protein like 4 (EML4) gene, results in the abnormal expression and activation of this tyrosine kinase in the cytoplasm of cancer cells. This rearrangement occurs in 2-5% of NSCLC, predominantly in young (50 years or younger), never- or former-smokers with adenocarcinoma. This aberration most commonly occurs a independently of EGFR and KRAS gene mutations. A fluorescent in situ hybridization assay was approved by the US Food and Drug Administration (FDA) as the standard method for the detection of ALK gene rearrangement in clinical practice and is considered the gold standard. Crizotinib, a first-in class dual ALK and c-MET inhibitor, has been shown to be particularly effective against ALK positive NSCLC, showing dramatic and prolonged responses with low toxicity, predominantly restricted to the gastro-intestinal and visual systems, and generally self-limiting or easily managed. However, resistance to crizotinib inevitably emerges. The molecular mechanisms of resistance are currently under investigation, as are therapeutic approaches including crizotinib-based combination therapy and novel agents such as Hsp90 inhibitors. This review aims to present the current knowledge on this fusion gene, the clinic-pathological profile of ALK rearranged NSCLC, and to review the existing literature on ALK inhibitors, focusing on their role in the treatment of NSCLC. PMID- 23931928 TI - Students' and teachers' views of written feedback at undergraduate level: a literature review. AB - OBJECTIVES: To explore undergraduate students' expectations and teachers' views of written feedback. DESIGN: Narrative literature review. DATA SOURCES: Seven electronic databases were searched for primary research published in English with additional manual searches and reference tracking. REVIEW METHODS: Systematic approach to search strategy, selection and appraisal of papers, data extraction and synthesis following Hawker et al.'s (2002) guidelines. RESULTS: 21 studies met the inclusion criteria. Four student themes were identified concerning written feedback: quality, quantity and location of feedback, feed-forward and timeliness. Teachers reported that time pressures, institutional policies, and administrative issues affect feedback provision. CONCLUSIONS: Rigorous research is needed to gain a better understanding of students' expectations of written feedback. Strategies need to be adopted to meet students' expectations and educate students to take an active role and reflect on the feedback received. PMID- 23931929 TI - Continuing education among Chinese nurses: a general hospital-based study. AB - BACKGROUND: Continuing education (CE) is increasingly critical for nurses to keep abreast of rapid changes in patient care due to advancements in knowledge and technology. OBJECTIVE: The objective of this study was to explore Chinese nurses' perceptions on continuing education, how best CE practices meet their learning needs, and the motivation and barriers nurses face in completing CE. METHODS: A cross-sectional study of 2727 hospital-employed Chinese nurses from ten general hospitals was conducted from September to October 2010. Nurses' perceptions on CE, as well as motivational and preventive factors in CE were assessed. RESULTS: The majority of nurses (97.3%) attended CE activities in the last twelve months. More than 92.2% of the nurses were familiar with the value of CE. Nurses expected CE activities to take place within a five-day period and to consist of 2h per activity. The major factors that motivate nurses to participate in CE are the desire to gain and update their knowledge of the newest nursing development and procedures, to improve their practical skills and comprehensive qualities, to maintain professional status and to receive an academic degree. Factors that hindered nurses' participation in CE included time constraints, work commitments, a lack of opportunity, cost of the courses and previous negative experiences with CE programs. CONCLUSION: Chinese nurses considered CE an extremely important measure to further develop their professional competency. Nurses' actual expectations for CE and the motivation and barriers for participation in CE from nurses' individual, family and hospital perspective must be taken into the account in order to make CE programs more effective. PMID- 23931930 TI - Circulating cell-free DNA, SLC5A8 and SLC26A4 hypermethylation, BRAF(V600E): A non-invasive tool panel for early detection of thyroid cancer. AB - PURPOSE: In the latest years, high levels of circulating cell-free DNA (cf-DNA) have been found to be associated with cancer diagnosis and progression, and cf DNA has become a potential candidate as biomarker for tumor detection. cf-DNA has been investigated in plasma or serum of many tumor patients affected by different malignancies, but not yet in thyroid cancer (TC). Furthermore, in TC cells the capability to metabolize iodine is frequently lost. SLC5A8 and SLC26A4 genes are both involved in the iodine metabolism, and SLC5A8 hypermethylation status is associated with the BRAF(V600E) mutation, which is the most frequent genetic event underlying the development of papillary TC. The aim of our study is the development of a new non-invasive tool for the diagnosis and prognosis of TC based on cf-DNA, SLC5A8 and SLC26A4 hypermethylation, and BRAF(V600E) analysis. METHODS: cf-DNA was measured by quantitative real-time PCR in nine cases of anaplastic thyroid cancer (ATC), 58 medullary thyroid cancers (MTC), five of synchronous medullary and follicular thyroid cancers (SMFC), 23 follicular adenomas (FA), 86 papillary thyroid cancers (PTC). A control group of 19 healthy subjects was taken. Moreover, in the PTC group we analyze the state of hypermethylation of SLC5A8 and SLC26A4, BRAF(V600E) mutation, and their involvement in the loss of function of the thyroid. RESULTS: cf-DNA showed a high ability to discriminate healthy individuals from cancer patients. cf-DNAALU83 and cf-DNAALU244 values were significantly correlated with the histological type of TC (P-value < 0.0001). A significant increase in the amount of cf-DNAALU83 and cf DNAALU244 when methylation occurs was observed (P-value = 0.02). A correlation between BRAF(V600E) and cf-DNAALU244/ALU83 was also found (P-value = 0.02). CONCLUSIONS: According to our experimental results, the panel including cf-DNA, SLC5A8 and SLC26A4 hypermethylation, and BRAF(V600E) analysis appears easy, reproducible, and non-invasive for the diagnosis on TC. Its possible implication in clinical setting remains to be elucidated. PMID- 23931931 TI - Lack of association of SLC1A1 variants with schizophrenia in Chinese Han population. AB - In this study, we analyzed four single nucleotide polymorphisms (SNPs) (rs10491734, rs2228622, rs301430 and rs301443) of the solute carrier family 1 gene (SLC1A1) in a set of 616 schizophrenia patients and 638 matched healthy controls of Han Chinese descent. No significant differences of genotype or allele distribution were identified between the patients and controls. Our data suggest that SLC1A1 is unlikely to be a major susceptibility gene for schizophrenia in Han Chinese. PMID- 23931932 TI - Can lipid analysis help identify repeatedly violent patients after discharge from acute psychiatry? AB - In this study of 196 patients discharged from an acute psychiatric ward, 11 patients (6%) were identified as exhibiting repeated violence and having frequent readmissions. Compared with non-violent patients and those with only one violent post-discharge episode, repeatedly violent patients were significantly characterised by male gender, higher rates of previous threats of violence, lack of empathy, more severe violence during follow-up, and lower high-density lipoprotein levels. PMID- 23931933 TI - Reproductive factors and clinical features of Parkinson's disease. AB - BACKGROUND: Literature suggests that sex steroid hormones may modify the risk for Parkinson's disease (PD). We investigated the potential effect of reproductive factors on the clinical features of idiopathic PD (IPD) patients. METHODS: All IPD female patients admitted to and evaluated at our Institute over a 12-month period were included in the present cross-sectional study. We investigated the effect of the following parameters by multivariate linear regression analysis: age at menarche, age at menopause, length of fertile life, duration of exposure to endogenous estrogens and cumulative length of pregnancies, use of contraceptives and hormonal replacement therapy. RESULTS: In total, 579 patients were evaluated and 497 reported menopause before PD onset. In this population, age at PD onset was positively associated with age at menarche and at menopause, length of fertile life and duration of estrogen exposure. Moreover, UPDRS motor score was inversely associated with age at menopause, length of fertile life and duration of estrogen exposure. Increasing age at menarche was also associated with predominant resting tremor at PD onset. In models refitted on patients with early PD (disease duration <5 years; N = 226) all the associations found were confirmed. The relationship between surrogates of estrogen exposure and UPDRS motor score actually became more significant. CONCLUSIONS: Our observations support the concept that hormonal exposure of the nigro-striatal network during life may influence its susceptibility to degenerative stimuli in later life, but the association does not seem to be unique? unidirectional. In particular, increased severity of PD signs correlates with shorter duration of estrogen exposure. The underlying mechanisms need to be clarified. PMID- 23931935 TI - Safety and efficacy of botulinum toxin in primary orthostatic tremor. AB - Primary orthostatic tremor (POT) is a rapid 13-18 Hertz tremor that produces a subjective feeling of unsteadiness when standing, and is absent when seated or supine. It predominantly affects the legs during isometric contraction though a similar tremor can be seen in the arms and jaw. When present in the jaw this rapid tremor has been successfully treated with botulinum toxin. We sought to test whether symptoms of POT improved following injection of abobotulinumtoxinA to muscles in the legs. This randomised, double blind, placebo controlled cross over design study enrolled eight patients with electrophysiologically confirmed POT. Each patient received injections of either 200 mU abobotulinumtoxinA or 0.9% saline in the tibialis anterior bilaterally, with cross-over after 20 weeks. Electrophysiological and clinical assessments were performed before and 6 weeks after each injection. Seven patients completed the study. No significant differences were seen in the primary outcome measures of time from standing to unsteadiness or symptom diary scores. Electrophysiological characteristics of POT remained remarkably constant throughout the study in all patients with variability of less than 1 Hertz in the frequency recorded. Falls were common, with one patient experiencing a fall with upper limb fracture whilst on the placebo. The frequency of falls correlated with both the severity of the self rated symptoms and a shorter time to feeling unsteady with eyes closed. In conclusion, treatment with 200 mU of abobotulinumtoxinA in the tibialis anterior does not alter subjective experience of unsteadiness in POT. Postural instability and falls are common. PMID- 23931937 TI - A novel APP mutation (D678H) in a Taiwanese patient exhibiting dementia and cerebral microvasculopathy. AB - We report a novel missense mutation, D678H, in the APP gene in a Taiwanese patient who had progressive cognitive decline beginning in middle age. Brain MRI showed leukoencephalopathy, cortical microhemorrhages and focal superficial cortical hemosiderosis, which are consistent with cerebral amyloid angiopathy. A phenotype of combined dementia and cerebral microvasculopathy suggested concurrent increases in brain parenchymal and cerebrovascular beta-amyloid peptide (Abeta) deposition in this patient. The promotion of Abeta aggregation has been postulated to underlie the pathogenic mechanism of the mutation. PMID- 23931938 TI - CT navigated lateral interbody fusion. AB - Lateral interbody fusion techniques are heavily reliant on fluoroscopy for retractor docking and graft placement, which expose both the patient and surgeon to high doses of radiation. Use of image-guided technologies with CT-based images, however, can eliminate this radiation exposure for the surgeon. We describe the surgical technique of performing lateral lumbar interbody fusion using CT navigation. PMID- 23931936 TI - Surgical treatment options and management strategies of metastatic renal cell carcinoma to the lumbar spinal nerve roots. AB - Spinal nerve root metastasis of renal cell carcinoma is a rare occurrence. In addition to treatment of the primary lesion, surgical resection of the nerve root metastasis, occasionally with sacrifice of the involved nerve, is the accepted standard of treatment. Resection often resolves presenting motor and pain symptoms due to relief of neural compression. We describe two patients with nerve root metastasis of renal cell carcinoma and their management. While locally advanced and metastatic renal cell carcinoma has been shown to be chemo- and radio-resistant, immunotherapy is a promising treatment. Given the high prevalence of systemic disease in patients with intradural metastases, systemic (and possibly intracranial) imaging can be used to identify other potential areas of disease. PMID- 23931939 TI - Educational differences in disability-free life expectancy: a comparative study of long-standing activity limitation in eight European countries. AB - Healthy life expectancy is a composite measure of length and quality of life and an important indicator of health in aging populations. There are few cross country comparisons of socioeconomic differences in healthy life expectancy. Most of the existing comparisons focus on Western Europe and the United States, often relying on older data. To address these deficiencies, we estimated educational differences in disability-free life expectancy for eight countries from all parts of Europe in the early 2000s. Long-standing severe disability was measured as a Global Activity Limitation Indicator (GALI) derived from the European Union Statistics on Income and Living Conditions (EU-SILC) survey. Census-linked mortality data were collected by a recent project comparing health inequalities between European countries (the EURO-GBD-SE project). We calculated sex-specific educational differences in disability-free life expectancy between the ages of 30 and 79 years using the Sullivan method. The lowest disability-free life expectancy was found among Lithuanian men and women (33.1 and 39.1 years, respectively) and the highest among Italian men and women (42.8 and 44.4 years, respectively). Life expectancy and disability-free life expectancy were directly related to the level of education, but the educational differences were much greater in the latter in all countries. The difference in the disability-free life expectancy between those with a primary or lower secondary education and those with a tertiary education was over 10 years for males in Lithuania and approximately 7 years for males in Austria, Finland and France, as well as for females in Lithuania. The difference was smallest in Italy (4 and 2 years among men and women, respectively). Highly educated Europeans can expect to live longer and spend more years in better health than those with lower education. The size of the educational difference in disability-free life expectancy varies significantly between countries. The smallest and largest differences appear to be in Southern Europe and in Eastern and Northern Europe, respectively. PMID- 23931940 TI - Social exclusion, deprivation and child health: a spatial analysis of ambulatory care sensitive conditions in children aged 0-4 years in Victoria, Australia. AB - Recent Australian policy initiatives regarding primary health care focus on planning services around community needs and delivering these at the local area. As in many other countries, there has also been a growing concern over social inequities in health outcomes. The aims of the analysis presented here were firstly to describe small area variations in hospital admissions for ambulatory care sensitive conditions (ACSC) among children aged 0-4 years between 2003 and 2009 in the state of Victoria, Australia, and secondly to explore the relationship of ACSC hospitalisations with socio-economic disadvantage using a comparative analysis of the Child Social Exclusion (CSE) index and the Composite Score of Deprivation (CSD). This is a cross sectional secondary data analysis, with data sourced from 2003 to 2009 ACSC data from the Victorian State Government Department of Health; the Australian Standard Geographical Classification of remoteness; the Australian 2006 Census of Population and Housing; and AMPCo General Practitioner data from 2010. The relationship between the indexes and child health outcomes was examined through bivariate analysis and visually through a series of maps. The results show there is significant variation in the geographical distribution of the relationship between ACSCs and socio-economic disadvantage, with both indexes capturing important social gradients in child health conditions. However, measures of access, such as geographical accessibility and workforce supply, detect additional small area variation in child health outcomes. This research has important implications for future primary health care policy and planning of services, as these findings confirm that not all areas are the same in terms of health outcomes, and there may be benefit in tailoring mechanisms for identifying areas of need depending on the outcome intended to be affected. PMID- 23931941 TI - Gender, family status and physician labour supply. AB - With the increasing participation of women in the physician workforce, it is important to understand the sources of differences between male and female physicians' market labour supply for developing effective human resource policies in the health care sector. Gendered associations between family status and physician labour supply are explored in the Canadian labour market, where physicians are paid according to a common fee schedule and have substantial discretion in setting their hours of work. Canadian 1991, 1996, 2001 and 2006 twenty percent census files with 22,407 physician observations are used for the analysis. Although both male and female physicians have statistically indistinguishable hours of market work when never married and without children, married male physicians have higher market hours, and their hours are unchanged or increased with parenthood. In contrast, female physicians have lower market hours when married, and much lower hours when a parent. Little change over time in these patterns is observed for males, but for females two offsetting trends are observed: the magnitude of the marriage-hours effect declined, whereas that for motherhood increased. Preferences and/or social norms induce substantially different labour market outcomes. In terms of work at home, the presence of children is associated with higher hours for male physicians, but for females the hours increase is at least twice as large. A male physician's spouse is much less likely to be employed, and if employed, has lower market hours in the presence of children. In contrast, a female physician's spouse is more likely to be employed if there are three or more children. Both male and female physicians have lower hours of work when married to another physician. Overall, there is no gender difference in physician market labour supply after controlling for family status and demographics. PMID- 23931942 TI - Streetscape greenery and health: stress, social cohesion and physical activity as mediators. AB - Several studies have shown a positive relationship between local greenspace availability and residents' health, which may offer opportunities for health improvement. This study focuses on three mechanisms through which greenery might exert its positive effect on health: stress reduction, stimulating physical activity and facilitating social cohesion. Knowledge on mechanisms helps to identify which type of greenspace is most effective in generating health benefits. In eighty neighbourhoods in four Dutch cities data on quantity and quality of streetscape greenery were collected by observations. Data on self reported health and proposed mediators were obtained for adults by mail questionnaires (N = 1641). Multilevel regression analyses, controlling for socio demographic characteristics, revealed that both quantity and quality of streetscape greenery were related to perceived general health, acute health related complaints, and mental health. Relationships were generally stronger for quality than for quantity. Stress and social cohesion were the strongest mediators. Total physical activity was not a mediator. Physical activity that could be undertaken in the public space (green activity) was, but less so than stress and social cohesion. With all three mediators included in the analysis, complete mediation could statistically be proven in five out of six cases. In these analyses the contribution of green activity was often not significant. The possibility that the effect of green activity is mediated by stress and social cohesion, rather than that it has a direct health effect, is discussed. PMID- 23931943 TI - From altruism to monetisation: Australian women's ideas about money, ethics and research eggs. AB - We report the results of a qualitative study carried out in metropolitan Australia between 2009 and 2011 that canvassed the issue of payment for research oocyte donation with participants drawn from three potential donor groups; fertility patients, reproductive donors and young, non-patient women. Research oocytes are controversial tissues because women around the world have proved largely unwilling to donate them altruistically. In the ensuing international debate about procurement, the issue of money and its appropriate and inappropriate uses in tissue donation has taken centre stage. While there is now an abundance of expert commentary on this matter, there are almost no studies that probe this issue with potential donor populations. Our study asked the three groups of women about their understandings of altruistic, reimbursed, subsidised, compensated and paid donation for both reproductive and research eggs. We identify a resistance to the introduction of money into the sphere of reproductive donation, which the majority of respondents felt should remain an area of personalised gift relations. In the area of research donation we find a strong relationship between degrees of liquidity (the extent to which money is constrained or unconstrained) and a sense of ethical appropriateness. We also describe a culturally specific sense of fairness and equity among participants, associated with the relatively high public subsidisation of fertility treatment in Australia, which they used to benchmark their sense of appropriate and inappropriate uses of money. While the participant responses reflect the regulatory environment in Australia, particularly the absence of a US style market in reproductive oocytes, they also make an important contribution to the global debate. PMID- 23931944 TI - Do slums matter? Location and early childhood preventive care choices among urban residents of Bangladesh. AB - Upward trends in the relative proportions of slum residents in developing countries have led to widespread concern regarding the impact of slum residency on health behaviors. Measurement of these impacts requires recognizing that unobservable household characteristics that affect the location decision may also affect health care choices and outcomes. To address the potential for bias, this paper models the location decision and the household's demand for maternal and child health services simultaneously using a flexible, semi-parametric approach. It uses a unique urban data set from Bangladesh that incorporates sophisticated geographical mapping techniques to carefully delineate between slum and non-slum areas at a particular point in time. The results suggest that accounting for the endogenous location decision of a family substantially reduces bias in estimated marginal effects of slum residence on preventive care demand. While community infrastructure variables appear correlated with preventive care demand, the causal effect of the availability of primary health care facilities is indistinguishable from zero when unobserved heterogeneity is taken into account. The findings suggest that improvements in community infrastructure in urban areas of developing countries are a more favorable health policy solution at the margin than the construction of additional health care facilities. PMID- 23931945 TI - Prioritizing treatment of rare diseases: a survey of preferences of Norwegian doctors. AB - Understanding doctors' preferences for prioritizing treatment of rare diseases can provide an important context for policy makers who must decide whether to exempt rare disease treatments, which are often quite expensive, from standard cost-effectiveness criteria. We surveyed a random sample of 551 Norwegian doctors in November 2011 and compared results to a similar survey of the Norwegian population. Respondents chose whether to prioritize treatment of patients with rare versus common diseases and then decided how to allocate funds between the two groups for each of two scenarios: (1) equal costs per person and (2) higher costs for the rare disease. Respondents were randomized to treatment costs for the rare disease in the second scenario that were either 8 or 25 times higher than treating the common disease. Except for different prevalence, the diseases were described identically. Doctors displayed no general preference for prioritizing treatment of rare diseases, but a large number favored the principle of reserving a small share of funds for rare disease patients. Doctors' responses differed significantly from those of the general population when the rare disease was more costly to treat. A larger share of doctors prioritized the common disease group for treatment while a smaller share expressed indifference. When dividing funds between the two patient groups, doctors allocated a smaller share of funds to the rare disease. Doctors were much less likely than the general population to divide funds equally between the groups. This study indicates that there is little support among Norwegian doctors for prioritizing the treatment of rare diseases. PMID- 23931946 TI - Interacting institutional logics in general dental practice. AB - We investigate the organisational field of general dental practice and how agents change or maintain the institution of values associated with the everyday work of health care provision. Our dataset comprise archival literature and policy documents, interview data from field level actors, as well as service delivery level interview data and secondary data gathered (2011-12) from 16 English dental practices. Our analysis provides a typology of institutional logics (prevailing systems of value) experienced in the field of dental practice. Confirming current literature, we find two logics dominate how care is assessed: business-like health care and medical professionalism. We advance the literature by finding the business-like health care logic further distinguished by values of commercialism on the one hand and those of accountability and procedural diligence on the other. The logic of professionalism we also find is further distinguished into a commitment to clinical expertise and independence in delivering patient care on the one hand, and concerns for the autonomy and sustainability of a business enterprise on the other. PMID- 23931947 TI - Divorce and changes in the prevalence of psychotropic medication use: a register based longitudinal study among middle-aged Finns. AB - The annual prevalence of psychotropic medication use exceeds 10 percent in Europe and the United States, the prevalence being higher among the divorced than the married. We analysed changes in the three-month prevalence of psychotropic medication use (psycholeptics and psychoanaleptics excluding medication for dementia) by proximity to divorce, sex, medication type and socio-demographic characteristics, using register-data on 304,111 Finns between 25 and 64 years of age, of whom 23,956 divorced between 1995 and 2003 and 142,093 were continuously married from 1995 to 2004. Five years before divorce, men and women already displayed about one percentage point higher prevalence of psychotropic medication use than those who continued their marriage. The excess prevalence increased with approaching divorce and peaked six to nine months before divorce, reaching 7.3 percent (95% CI 6.8-8.0) among divorcing men and 8.1 percent (95% CI 7.5-8.8) among divorcing women. The peak was followed by an 18-month decline, after which the excess compared to the continuously married settled at nearly three percentage points. The excess was not due to being socio-economically disadvantaged, and socio-demographic factors also seemed to have few modifying effects. The changes in prevalence were largest for antidepressants and almost non-existent for antipsychotics. Our results suggest that the high prevalence of psychotropic medication use among the divorced results both from selective factors already present five years before divorce and the acute and long-term causal effects of becoming and being divorced. Counselling is needed for individuals in the process of divorce, rather than economic support for divorced individuals. PMID- 23931948 TI - Methods don't make assumptions, researchers do: a response to Marchal et al. PMID- 23931949 TI - Does social participation improve self-rated health in the older population? A quasi-experimental intervention study. AB - Social participation has been linked to healthy aging and the maintenance of functional independence in older individuals. However, causality remains tenuous because of the strong possibility of reverse causation (healthy individuals selectively participate in social activities). We describe a quasi-experimental intervention in one municipality of Japan designed to boost social participation as a way of preventing long-term disability in senior citizens through the creation of 'salons' (or community centers). In this quasi-experimental intervention study, we compared 158 participants with 1391 non-participants in salon programs, and examined the effect of participation in the salon programs on self-rated health. We conducted surveys of community residents both before (in 2006) and after (in 2008) the opening of the salons. Even with a pre/post survey design, our study could be subject to reverse causation and confounding bias. We therefore utilized an instrumental variable estimation strategy, using the inverse of the distance between each resident's dwelling and the nearest salon as the instrument. After controlling for self-rated health, age, sex, equivalized income in 2006, and reverse causation, we observed significant correlations between participation in the salon programs and self-rated health in 2008. Our analyses suggest that participation in the newly-opened community salon was associated with a significant improvement in self-rated health over time. The odds ratio of participation in the salon programs for reporting excellent or good self-rated health in 2008 was 2.52 (95% CI 2.27-2.79). Our study provides novel empirical support for the notion that investing in community infrastructure to boost the social participation of communities may help promote healthy aging. PMID- 23931950 TI - Housing affordability and mental health: does the relationship differ for renters and home purchasers? AB - There is increasing evidence of a direct association between unaffordable housing and poor mental health, over and above the effects of general financial hardship. Type of housing tenure may be an important factor in determining how individuals experience and respond to housing affordability problems. This study investigated whether a relationship exists between unaffordable housing and mental health that differs for home purchasers and private renters among low-income households. Data from 2001 to 2010 of the longitudinal Household, Income and Labour Dynamics in Australia (HILDA) survey were analysed using fixed-effects linear regression to examine change in the SF-36 Mental Component Summary (MCS) score of individuals aged 25-64 years, associated with changes in housing affordability, testing for an interaction with housing tenure type. After adjusting for age, survey year and household income, among individuals living in households in the lower 40% of the national income distribution, private renters in unaffordable housing experienced somewhat poorer in mental health than when their housing was affordable (difference in MCS = -1.18 or about 20% of one S.D. of the MCS score; 95% CI: 1.95,-0.41; p = 0.003) while home purchasers experienced no difference on average. The statistical evidence for housing tenure modifying the association between unaffordable housing and mental health was moderate (p = 0.058). When alternatives to 40% were considered as income cut-offs for inclusion in the sample, evidence of a difference between renters and home purchasers was stronger amongst households in the lowest 50% of the income distribution (p = 0.020), and between the 30th and 50th percentile (p = 0.045), with renters consistently experiencing a decline in mental health while mean MCS scores of home purchasers did not change. In this study, private renters appeared to be more vulnerable than home purchasers to mental health effects of unaffordable housing. Such a modified effect suggests that tenure-differentiated policy responses to poor housing affordability may be appropriate. PMID- 23931951 TI - Nonmotor symptoms in Parkinson's disease: expanding the view of Parkinson's disease beyond a pure motor, pure dopaminergic problem. AB - Nonmotor symptoms (NMS) of Parkinson's disease (PD) are critical to identify and treat because of their impact on quality of life. Despite growing evidence of the importance of NMS on patients' quality of life, gaps remain in their recognition and treatment. The result is a need for increased information and understanding of specific NMS and the clinical approaches for their assessment and management in the context of PD as a whole. This article discusses the NMS of PD, their relationship to the pathologic basis of PD, and how NMS can be best managed. PMID- 23931952 TI - Wearing off, dyskinesia, and the use of continuous drug delivery in Parkinson's disease. AB - Motor fluctuations (wearing off) and motor complications (dyskinesia) are common features of the long-term treatment of Parkinson's disease (PD). The basis of both is considered to be a reflection of the progression of neuronal degeneration, coupled with the nature of drug treatment used to control motor symptoms. The concept of continuous dopaminergic stimulation has been used to explain both the onset of wearing off and dyskinesia and their avoidance through pharmacologic manipulation. This review focuses on using with the transdermal dopamine agonist, rotigotine, for continuous dopaminergic drug delivery in the treatment of PD. PMID- 23931953 TI - The development of the rotigotine transdermal patch: a historical perspective. AB - The rotigotine transdermal system is a dopamine receptor agonist delivered over a 24-hour period. It is approved for the treatment of idiopathic Parkinson's disease (PD). This article reviews the development of the rotigotine transdermal system, including rotigotine's receptor profile, steady-state pharmacokinetics, and metabolism. Preclinical studies of rotigotine in animal models of PD and proof-of-concept studies in patients with PD are reviewed. These preclinical and clinical studies established this system as an effective method for providing continuous rotigotine delivery across the skin providing the basis for continued clinical development of rotigotine for the treatment of early and advanced PD. PMID- 23931954 TI - Outcomes of rotigotine clinical trials: effects on motor and nonmotor symptoms of Parkinson's disease. AB - Rotigotine transdermal system is a nonergot, 24-hour dopamine agonist approved for the treatment of early and advanced Parkinson's disease (PD). Recent studies have demonstrated significant improvements with rotigotine in motor function in early PD and significant improvements in daily off-time and motor function in advanced PD. In addition to motor improvements, nonmotor symptoms have been shown to be improved with rotigotine in both early and advanced PD. Rotigotine has been shown in large, controlled studies to be safe and efficacious for the treatment of motor and some nonmotor symptoms of early and advanced PD. PMID- 23931955 TI - Treatment of motor and NMS of Parkinson's disease with the rotigotine transdermal system. PMID- 23931956 TI - Response to Chandler et al., Substance, structure and stigma: parents in the UK accounting for opioid substitution therapy during the antenatal and postnatal periods. PMID- 23931957 TI - Examining the construction and representation of drugs as a policy problem in Australia's National Drug Strategy documents 1985-2010. AB - BACKGROUND: National drug policies are often regarded as inconsequential, rhetorical documents, however this belies the subtlety with which such documents generate discourse and produce (and re-produce) policy issues over time. Critically analysing the ways in which policy language constructs and represents policy problems is important as these discursive constructions have implications for how we are invoked to think about (and justify) possible policy responses. METHODS: Taking the case of Australia's National Drug Strategies, this paper used an approach informed by critical discourse analysis theory and aspects of Bacchi's (2009) 'What's the Problem Represented to be' framework to critically explore how drug policy problems are constructed and represented through the language of drug policy documents over time. RESULTS: Our analysis demonstrated shifts in the ways that drugs have been 'problematised' in Australia's National Drug Strategies. Central to these evolving constructions was the increasing reliance on evidence as a way of 'knowing the problem'. Furthermore, by analysing the stated aims of the policies, this case demonstrates how constructing drug problems in terms of 'drug-related harms' or alternately 'drug use' can affect what is perceived to be an appropriate set of policy responses. The gradual shift to constructing drug use as the policy problem altered the concept of harm minimisation and influenced the development of the concepts of demand- and harm reduction over time. CONCLUSIONS: These findings have implications for how we understand policy development, and challenge us to critically consider how the construction and representation of drug problems serve to justify what are perceived to be acceptable responses to policy problems. These constructions are produced subtly, and become embedded slowly over decades of policy development. National drug policies should not merely be taken at face value; appreciation of the construction and representation of drug problems, and of how these 'problematisations' are produced, is essential. PMID- 23931958 TI - Organisational identity and alcohol use among young employees: a case study of a professional services firm. AB - BACKGROUND: Cultural influences on young people's drinking have been the focus of much research and policy practice. Young people's drinking is influenced by a range of institutions, including the workplace, yet this has received comparatively little attention by researchers and policymakers. This study examines the workplace influences on young people's drinking through the conceptual lens of organisational identification. METHODS: Data was collected through 16 semi-structured interviews with mainly young employees of a professional services firm in New Zealand. The interviews were coded and analysed thematically, generating five themes of alcohol use at work. RESULTS: Alcohol was used in a number of ways by the respondents in relation to their work, from acting as a means of relieving stress or anxiety induced by work, to providing a means for bonding with work colleagues. Their work also impacted on their alcohol use in more 'positive' ways (e.g. respondents limiting their intake to prevent damage to their career prospects). CONCLUSION: The study highlights how processes of organisational identification both encourage and inhibit alcohol use. The consumption of alcohol at work provides young professionals with a medium to engage in a variety of organisational identification processes. An understanding of these processes can assist policymakers in focusing on the workplace, an area largely ignored to date, as a target for their campaigns aimed at reducing the harmful effects of young people's heavy alcohol use. PMID- 23931959 TI - Novel insights into autoimmune liver diseases provided by genome-wide association studies. AB - Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are complex disorders, resulting from the interaction of genetic and environmental factors. For many years, investigators have attempted to delineate the genetic architecture of these conditions, aiming to elucidate disease pathogenesis and identify molecular targets for pharmacotherapy. Early genetic studies consisted of HLA association studies and non-HLA candidate gene association studies, designed to identify association with selected HLA or non-HLA loci. HLA association studies identified HLA risk loci that are now well-established. Non-HLA candidate gene studies were less fruitful because they were mostly underpowered to detect modest effects and were frequently designed to investigate one or two functional polymorphisms, meaning that gene coverage was poor. Furthermore, weak associations detected in one small cohort were often never validated. If replication studies were undertaken, the results were often conflicting. More recently, a series of genome-wide association studies (GWAS) and related study designs have evaluated the impact of common genetic variants (frequency >5% in the general population) across the entire genome. These studies have identified several non-HLA risk loci for autoimmune liver disease. The majority of risk loci detected are similar to those of non-hepatic immune-mediated diseases, suggesting that outcomes from GWAS and related genetic studies reflect broad phenotypic themes rather than traditional clinical conditions. The specific genetic basis of these PBC and PSC associated inflammatory themes as determined by GWAS is described and discussed in the context of interacting genetic and non-genetic (including environmental) factors. PMID- 23931960 TI - 3D-MSCT imaging of bullet trajectory in 3D crime scene reconstruction: two case reports. AB - Postmortem investigations are increasingly assisted by three-dimensional multi slice computed tomography (3D-MSCT) and have become more available to forensic pathologists over the past 20years. In cases of ballistic wounds, 3D-MSCT can provide an accurate description of the bullet location, bone fractures and, more interestingly, a clear visual of the intracorporeal trajectory (bullet track). These forensic medical examinations can be combined with tridimensional bullet trajectory reconstructions created by forensic ballistic experts. These case reports present the implementation of tridimensional methods and the results of 3D crime scene reconstruction in two cases. The authors highlight the value of collaborations between police forensic experts and forensic medicine institutes through the incorporation of 3D-MSCT data in a crime scene reconstruction, which is of great interest in forensic science as a clear visual communication tool between experts and the court. PMID- 23931961 TI - Effect of alignment changes on socket reaction moments during gait in transfemoral and knee-disarticulation prostheses: case series. AB - The alignment of a lower-limb prosthesis is critical to the successful prosthetic fitting and utilization by the wearer. Loads generated by the socket applied to the residual limb while walking are thought to be different in transfemoral and knee-disarticulation prostheses. The aim of this case series was to compare the socket reaction moments between transfemoral and knee-disarticulation prostheses and to investigate the effect of alignment changes on them. Two amputees, one with a transfemoral prosthesis and another with a knee-disarticulation prosthesis, participated in this study. A Smart PyramidTM was used to measure socket reaction moments while walking under 9 selected alignment conditions; including nominally aligned, angle malalignments of 6 degrees (flexion, extension, abduction and adduction) and translation malalignments of 15 mm (anterior, posterior, medial and lateral) of the socket relative to the foot. This study found that the pattern of the socket reaction moments was similar between transfemoral and knee-disarticulation prostheses. An extension moment in the sagittal plane and a varus moment in the coronal plane were dominant during stance under the nominally aligned condition. This study also demonstrated that alignment changes might have consistent effects on the socket reaction moments in transfemoral and knee-disarticulation prostheses. Extension and posterior translation of the socket resulted in increases in an extension moment, while abduction and lateral translation of the socket resulted in increases in a varus moment. The socket reaction moments may potentially serve as useful biomechanical parameters to evaluate alignment in transfemoral and knee-disarticulation prostheses. PMID- 23931962 TI - Alcohol misuse and psychosocial outcomes in young adulthood: results from a longitudinal birth cohort studied to age 30. AB - PURPOSE: This study examined the associations between measures of alcohol abuse/dependence symptoms and a range of psychosocial outcomes from ages 21 to 30 in a New Zealand birth cohort. METHODS: Outcome measures included measures of: criminal offending, family violence and relationship instability, sexual risk taking and consequences, mental health, and other adverse health and adjustment outcomes. Bivariate associations between a three-level classification of alcohol misuse (no symptoms, subclinical level of symptoms, met criteria for alcohol dependence) and each outcome during the period 21-30 years were computed using Generalised Estimating Equation models. These associations were then adjusted for non-observed sources of confounding using conditional fixed effects regression modelling, augmented by time-dynamic covariate factors. For both sets of models estimates of the attributable risk (AR) were computed. RESULTS: There were statistically significant (p<.05) bivariate associations between alcohol misuse and each of the fifteen outcome measures, with estimates of the AR ranging from 7.4% to 46.5%. Adjustment for non-observed fixed effects generally reduced the magnitude of these associations; however, after adjustment, 12 of the 15 associations remained statistically significant (p<.05). Estimates of the AR after adjustment for fixed effects ranged from 3.6% to 44.3%. CONCLUSIONS: The results suggest that there are pervasive and persistent linkages between alcohol misuse and a range of adverse psychosocial outcomes. A reduction in levels of alcohol misuse amongst individuals of this age group could reduce substantially the overall level of personal and societal cost of hazardous levels of alcohol consumption. PMID- 23931963 TI - [Primary prevention and chronic disease strategies: overcoming our own reluctance and ignoring what others say]. PMID- 23931964 TI - Using the ovarian sensitivity index to define poor, normal, and high response after controlled ovarian hyperstimulation in the long gonadotropin-releasing hormone-agonist protocol: suggestions for a new principle to solve an old problem. AB - OBJECTIVE: To explore the utility of using the ratio between oocyte yield and total dose of FSH, i.e., the ovarian sensitivity index (OSI), to define ovarian response patterns. DESIGN: Retrospective cross-sectional study. SETTING: University-affiliated private center. PATIENT(S): The entire unselected cohort of 7,520 IVF/intracytoplasmic sperm injection treatments (oocyte pick-ups [OPUs]) during an 8-year period (long GnRH agonist-recombinant FSH protocol). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The distribution of the OSI (oocytes recovered * 1,000/total dose of FSH), the cutoff levels for poor and high response, set at +/-1 SD, and the relationship between OSI and treatment outcome. RESULT(S): OSI showed a log-normal distribution with cutoff levels for poor and high response at 1.697/IU and 10.07/IU, respectively. A nomogram is presented. Live-birth rates per OPU were 10.5 +/- 0.1%, 26.9 +/- 0.6%, and 36.0 +/- 1.4% for poor, normal, and high response treatments, respectively. The predictive power (C-statistic) for OSI to predict live birth was superior to that of oocyte yield. CONCLUSION(S): The OSI improves the definition of ovarian response patterns because it takes into account the degree of stimulation. The nomogram presents evidence-based cutoff levels for poor, normal, and high response and could be used for unifying study designs involving ovarian response patterns. PMID- 23931965 TI - Cellular immune environment in endometrial polyps. AB - STUDY OBJECTIVE: To investigate the immune environment of endometrial polyps (EPs). DESIGN: Prospective case-control study. SETTING: Teaching hospital and university research laboratory. PATIENT(S): Reproductive-age women undergoing hysteroscopy dilation and curettage for benign indications. Samples were collected from women with (n = 23) and without (n = 40) EPs. INTERVENTION(S): Endometrial samples were immunohistochemically stained with antibodies against mast cells (MCs) and regulatory T cells (Tregs). MAIN OUTCOME MEASURE(S): Tryptase+, chymase+, and c-Kit+ MCs and Foxp3+ Tregs were quantified in EPs and polyp-adjacent, polyp-distant, and control endometrium. RESULT(S): Densities of all MC types were highly significantly increased in EPs compared with adjacent, distant, and control endometrium. Chymase+ and c-Kit+ MCs were increased in density in adjacent compared with control endometrium. c-Kit+ MCs were also increased in distant compared with control endometrium. Foxp3+ Treg density was increased in EPs compared with distant and control endometrium and decreased in distant compared with control endometrium. CONCLUSION(S): This study provides novel insights into localized disturbances in the cellular immune environment within EPs consistent with EPs being inflammatory lesions associated with MC overactivity. Tregs are likely to be recruited to EPs in an attempt to suppress the inflammatory process due to the greatly increased presence of MCs. These immunologic disturbances are likely to be involved in the causation of abnormal bleeding and infertility in premenopausal women with EPs, and their role in the pathophysiology requires further research. PMID- 23931966 TI - Hyperprolactinemia changes the sulfated glycosaminoglycan amount on the murine uterus during the estrous cycle. AB - OBJECTIVE: To evaluate the effects of hyperprolactinemia on the sulfated glycosaminoglycans (GAGs) of the murine uterus. DESIGN: Experimental research. SETTING: University biochemistry laboratory. ANIMAL(S): Eighty female mice were divided into two groups of 40 animals each and treated with 0.2 mL of saline solution (controls, Ctr) and 200 MUg of metoclopramide (experimental, HPrl). Treatments lasted for 50 consecutive days. The animals were divided into four subgroups of 10 animals each per treatment (Ctr and HPrl) and sacrificed according to the phase of the estrous cycle. The uterine horns were removed for biochemical analyses, and blood samples were collected for hormone measurements. INTERVENTION(S): Induced hyperprolactinemia. MAIN OUTCOME MEASURE(S): To quantify the sulfated GAGs, and PRL and sex steroid levels. RESULT(S): The endometrium during the estrus phase was significantly thicker in the HPrl animals than in the Ctr mice. The levels of chondroitin and dermatan sulfate were significantly increased in the HPrl group than in the Ctr group during all phases except metestrus. The amounts of heparan sulfate were lower during estrus and diestrus and higher in the metestrus phase in HPrl than in Ctr animals. Serum PRL levels were increased whereas the levels of E2 and P were decreased in all phases in the HPrl group than in the Ctr group. CONCLUSION(S): The hyperprolactinemia changed the amounts of uterine sulfated GAGs. Our data suggest that these changes may not be correlated with ovarian steroid levels. PMID- 23931967 TI - Impact of prosthesis-patient mismatch on tricuspid valve regurgitation and pulmonary hypertension following mitral valve replacement. AB - BACKGROUND: Mitral PPM can be equated to residual mitral stenosis, which may halt the expected postoperative improvement of PH and concomitant functional tricuspid regurgitation (fTR). Aim of the present study is to evaluate the impact of mitral prosthesis-patient mismatch (PPM) on late tricuspid valve regurgitation and pulmonary hypertension (PH). METHODS: A total of 210 patients undergoing isolated mitral valve replacement (MVR) were investigated. Mitral valve effective orifice area was determined by the continuity equation and indexed for body surface area (EOAi) and PPM was defined as EOAi <= 1.2 cm(2)/m(2). Pulmonary hypertension (PH) was defined as systolic pulmonary artery pressure (sPAP) > 40 mmHg. Clinical and echocardiographic follow-up (median 27 months) was 100% completed. A total of 88/210 (42%) patients developed mitral PPM. RESULTS: There were no significative differences in baseline and operative characteristics between patients with and without PPM. At follow-up, the prevalence of fTR >= 2+ (57%vs.22%; p = 0.0001), and PH (62%vs.24%;p < 0.0001) were significantly higher in patients with PPM. On multivariable regression analysis, EOAi (p < 0.0001) and preoperative left ventricular (LV) end-diastolic diameter (p < 0.0001) were found to be independently associated with fTR decrease after MVR. In addition, EOAi (p < 0.0001) and LV ejection fraction (p < 0.0001) were independently associated with PH decrease after MVR. No significant differences in mortality rates were found between patients having or not PPM. CONCLUSIONS: This study shows that mitral PPM is associated with the persistence of fTR and PH following MVR. These findings support the realization of tricuspid valve annuloplasty when PPM is anticipated at the time of operation. PMID- 23931968 TI - Regional differences in the utilisation of coronary angiography as initial investigation for the evaluation of patients with suspected coronary artery disease. PMID- 23931969 TI - Psoriasis and risk of cardiovascular disease: a meta-analysis of cohort studies. PMID- 23931970 TI - Cardiac fibrosis, arrhythmia and sudden death in myotonic dystrophy type 1: could TGF-beta1 improve the predictive accuracy of patients at risk, opening new therapeutic challenges? PMID- 23931971 TI - Transcatheter aortic valve implantation and bleeding: focus on Valve Academic Research Consortium-2 classification. PMID- 23931972 TI - Histone deacetylase inhibition improved cardiac functions with direct antifibrotic activity in heart failure. AB - BACKGROUND: Histone deacetylases (HDACs), important epigenetic regulatory enzymes, can reduce cardiac hypertrophy and cardiac fibrosis. However, the mechanisms underlying the antifibrotic activity of HDAC inhibitors remain unclear. The purposes of this study were to evaluate the effects of an HDAC inhibitor on systolic heart failure (HF) and investigate the potential mechanisms. METHODS: Echocardiographic, histologic, atrial natriuretic peptide (ANP), and Western blot measurements were performed in HF rats (isoproterenol 100 mg/kg, subcutaneous injection) with and without orally administered (100 mg/kg for 7 consecutive days) MPT0E014 (a novel HDAC inhibitor). Western blot, migration and proliferation assays were carried out on primary isolated cardiac fibroblasts with and without MPT0E014 (0.1 and 1 MUM) for 24 h. RESULTS: MPT0E014 treated HF rats (n = 6) had better fraction shortening (48 +/- 2 vs. 33 +/- 4%, p = 0.006) and smaller left ventricular end diastolic diameter (4.6 +/- 0.2 vs. 5.6 +/- 0.3 mm, p = 0.031) and systolic diameter (2.4 +/- 0.2 vs. 3.9 +/- 0.3 mm, p = 0.006) than HF (n = 7) rats. MPT0E014-treated HF rats had lower ANP, cardiac fibrosis, and angiotensin II type I receptor (AT1R), transforming growth factor (TGF)-beta, and CaMKIIdelta protein levels compared to HF rats. MPT0E014 (at 1 MUM, but not 0.1 MUM) decreased the migration and proliferation of cardiac fibroblasts. MPT0E014 (0.1 and 1 MUM) decreased expression of the AT1R and TGF beta. CONCLUSIONS: MPT0E014 improved cardiac contractility and attenuated structural remodeling in isoproterenol-induced dilated cardiomyopathy. The direct antifibrotic activity may have contributed to these beneficial effects. PMID- 23931973 TI - Gentamicin once-daily in enterococcal endocarditis. PMID- 23931974 TI - Iron therapy in patients with heart failure. A straight shot. PMID- 23931975 TI - Combined effects of fibrinogen genetic variability on atherosclerosis in patients with or without stable angina pectoris: focus on the coagulation cascade and endothelial function. AB - BACKGROUND: Fibrinogen is a coagulation/inflammatory biomarker strongly associated with atherogenesis. Data have reported that the genetic variability on fibrinogen chains may affect the atherosclerotic process and the risk of coronary artery disease (CAD). We examined the combined effects of the G455A and the G58A fibrinogen genetic polymorphisms on prothrombotic profile, endothelial function and the risk of CAD in a Caucasian population. METHODS: We recruited 422 patients with angiographically documented CAD and 277 controls matched for age and gender. The two polymorphisms were genotyped by polymerase chain reaction and restriction endonuclease digestion. Fibrinogen and D-Dimers levels, as well as factors' (f) V, X activity were measured by standard coagulometry techniques. Endothelial function was assessed by the flow mediated dilatation (FMD) of the brachial artery. RESULTS: The two polymorphisms had no significant effect on the risk for CAD. Although the 58AA subjects had not significantly different levels of fibrinogen compared with the 58GG+GA in both groups (p=NS), we importantly found that the 455AA homozygosity was associated with increased fibrinogen levels not only in the control group (p=0.035), but also in the CAD group (p<0.001) compared to the G allele carriers. Moreover, both the 58AA (p=0.016) and 455AA homozygotes (p=0.022) presented with higher levels of D-Dimers in the CAD group. Interestingly, the 455AA homozygotes had increased fV activity in the CAD group (p=0.048). However, no significant effects were observed on fX activity and FMD. CONCLUSIONS: Both fibrinogen polymorphisms are capable to modify the atherosclerotic process via their effects on the coagulation cascade. PMID- 23931976 TI - Frailty and heart disease. AB - Frailty is emerging as a syndrome of pre-disability that can identify persons at risk for negative outcomes. Its presence places the individual at risk for rapid deterioration when a major event such as myocardial infarction or hospitalization occurs. In patients with cardiovascular disease, frailty is about three times more prevalent than among elderly persons without. Screening for frailty in heart disease is important not only because of its prognostic value, but also because a variety of therapeutic interventions are available. PMID- 23931977 TI - Paravalvular leak after CoreValve implantation in the Italian Registry: predictors and impact on clinical outcome. PMID- 23931978 TI - Incremental value of color coding in 3D volume rendered CT images for interpretation of complex cardiothoracic vascular malformations. AB - OBJECTIVES: To evaluate the benefit of color coding of CT angiography images for the assessment of complex cardiovascular malformations by comparing the quality of 3D (dimensional) volume rendered (VR) images before and after vessel color coding. METHODS: Cardiothoracic CT images of 34 patients with complex vascular malformations were retrospectively selected for post processing. 3D VR images were created without and after color coding of the target vessels. Source images as well as selected 3D VR images without and with color coding were reviewed independently by 4 observers and scores were recorded on a 4-point scale for overall image quality, visualization conspicuity of target vessels, and final interpretation of target structures. RESULTS: Overall diagnostic advantages of color coded VR images compared with non-color coded VR images included; improved visualization of the anatomical course of vessels, improved visualization of the extent of abnormality, better understanding of the spatial relationship of structures (i.e. to right ventricle outflow tract), and improved overall quality of the images. For all comparisons the color coded score was statistically significantly better than the non-color coded score (p<0.0001). A trend showed that review speed was faster for color coded images (p=0.06). Good inter-observer agreement was achieved for the target conspicuity and final interpretation scores with weighted Kappa score of 0.66 (95% CI: 0.54, 0.79) and 0.71 (95% CI: 0.60, 0.81) respectively. CONCLUSION: Color coded 3D VR images can optimize visualization of vascular structures and improve interpretation of complex vascular malformation in cardiothoracic CT studies. PMID- 23931979 TI - Predictors of the incidence of all-cause mortality and deaths due to diabetes and renal diseases among patients newly prescribed antihypertensive agents: a cohort study. AB - BACKGROUND: Randomized trials have shown that the major antihypertensive drug classes are similarly effective to reduce mortality, but whether these drug class difference exists in clinical practice has been scarcely explored. This study evaluated the association between antihypertensive drug class, all-cause mortality and deaths due to diabetes or renal disease in real-life clinical settings. METHODS: A clinical database in Hong Kong included all patients who were prescribed their first-ever antihypertensive agents between 2001 and 2005 from the public healthcare sector. All patients were followed up for five years, and grouped according to the initial antihypertensive prescription. The associations between antihypertensive drug class, all-cause mortality or combined diabetes and renal mortality, respectively, were evaluated by Cox proportional hazard models. RESULTS: From 218,047 eligible patients, 33,288 (15.3%) died within five years after their first-ever antihypertensive prescription and among which 1055 patients (0.48%) died of diabetes or renal disease. After adjusted for age, gender, socioeconomic status, service settings, district of residence, medication adherence, and the number of comorbidities, each drug class was similarly likely to be associated with mortality due to diabetes or renal disease [Adjusted Hazard Ratios (AHR) ranged from 0.92 to 1.73, p=0.287-0.939] and all cause mortality (AHR ranged from 0.83 to 1.02) except for beta-blockers (AHR=0.815, 95% C.I. 0.68-0.87, p=0.024) when ACEI was used as a reference group in propensity score-adjusted analysis. CONCLUSIONS: These findings provide real life evidence reinforcing that any major antihypertensive drug class is suitable as a first-line agent for management of hypertension as recommended by international guidelines. PMID- 23931980 TI - Renal function measurements and mortality in patients with acute heart failure. PMID- 23931981 TI - Efficacy of second intra-tendinous platelet-rich-plasma injection in case of incomplete response of the first injection: three-year follow up experience. AB - PURPOSE: Tendinopathy is a frequent and ubiquitous disease developing early disorganized collagen fibers with neo-angiogenesis on histology. Peritendinous injection of corticosteroid is the commonly accepted strategy despite the absence of inflammation in tendinopathy. Platelet-rich plasma (PRP) might be a useful strategy to rapidly accelerate healing of the tendinopathy but there is a lack ok knowledge about the amount of PRP to be injected and the opportunity of a second injection in case of partial pain relief. The aim of our study was to assess the potential therapeutic effect of early second PRP intra-tendinous to treat persistent painful tendon tear and tendinosis in a long-term follow-up by ultrasonography (US) and clinical data in case of incomplete efficiency of first PRP treatment injection. MATERIALS AND METHODS: Twenty-four consecutive patients referred for US treatment of tendon tear or tendinosis (T+) were included retrospectively. All had previously received a single intra-tendinous injection of PRP under US guidance (PRPT+) and benefited of a second PRP injection (PRPT2+) under US guidance in order to treat persistent painful. US and clinical data were collected for each anatomic compartment for upper and lower limbs before treatment (D0), 6 weeks (W6) after first treatment, 6 weeks (W12) after second treatment and until 32-month follow-up. We used Mac Nemar test and regression model to compare US and clinical data. RESULTS: The residual US size of lesions was not significantly lower at W12 after PRPT2+ as compared to W6 (P=0.86 in upper and P=NS in lower member) independently of age (P=0.22), gender (P=0.97) and kind of tendinopathy (P=NS). Quick dash test values and WOMAC values were not significantly lower in PRPT+ at W12 (average: 21.5 months) as compared to W6 (P>0.66) and long-term follow-up (P>0.75) independently of age (P=0.39), gender (P=0.63) and kind of tendinopathy (P=NS). Nevertheless, comparison between D0 and long-term follow-up (LTF) functionnal score was statistically significant (p<0.001 in upper and lower member). CONCLUSION: Our study suggests that second early intra-tendinous PRP injection under US guidance does not permit rapid decrease of tendinopathy area in US, nor does it quickly improve clinical pain and functional data in case of incomplete efficiency of first PRP injection. However, in long-term follow-up, patients improved their ability to mobilize pathologic tendons. PMID- 23931982 TI - Association between nutrition and the evolution of multimorbidity: the importance of fruits and vegetables and whole grain products. AB - BACKGROUND & AIMS: Multimorbidity is a common health status. The impact of nutrition on the development of multimorbidity remains to be determined. The aim of this study is to determine the association between foods, macronutrients and micronutrients and the evolution of multimorbidity. METHODS: Data from 1020 Chinese who participated in the Jiangsu longitudinal Nutrition Study (JIN) were collected in 2002 (baseline) and 2007 (follow-up). Three-day weighted food records and status for 11 chronic diseases was determined using biomedical measures (hypertension, diabetes, hypercholesterolemia and anemia) or self reports (coronary heart disease, asthma, stroke, cancer, fracture, arthritis and hepatitis). Participants were divided in six categories of stage of evolution of multimorbidity. Association of foods, macronutrients and micronutrients at baseline with stages in the evolution of multimorbidity were determined. Data were adjusted for age, sex, BMI, marital status, sedentary lifestyle, smoking status, annual income, education and energy intake. RESULTS: The prevalence of multimorbidity increased from 14% to 34%. A high consumption of fruit and vegetables (p < 0.05) and grain products other than rice and wheat (p < 0.001) were associated with healthier stages in the evolution of multimorbidity. The consumption of grain products other than rice and wheat was highly correlated with dietary fibers (r = 0.77, p < 0.0001), iron (r = 0.46, p < 0.0001), magnesium (r = 0.49, p < 0.0001) and phosphorus (r = 0.57, p < 0.0001) intake which were also associated with healthier stages. CONCLUSION: This study provides the first evidence of an association between nutrition and evolution towards multimorbidity. More precisely, greater consumption of fruits and vegetable and whole grain products consumption appear to lower the risk of multimorbidity. PMID- 23931983 TI - Evidence for a normal HPA axis response to psychosocial stress in patients remitted from depression. AB - The purpose of this study was to investigate subjective mood and the effect of a psychosocial stress challenge on cortisol response in patients remitted from depression in comparison to healthy controls. Only few studies on small samples have been conducted on the influence of psychosocial stress on HPA system responsivity in this group. Results regarding patients who have achieved clinical remission from depression remain inconclusive so far. In comparison to healthy controls, some studies found blunted cortisol responses to a psychological stressor in patients with remitted depression. However, others found no differences. This discrepancy may be due to use of heterogeneous stress measures or dissimilar sample sizes and characteristics, e.g. including patients with comorbid generalized anxiety or patients with an unknown duration of remission. The present study included 77 healthy controls and 70 unipolar depressed patients who had achieved stable, full remission for at least 6 months (average 31 months) with no further Axis I disorder. Participants underwent the Trier Social Stress Test and salivary cortisol levels and mood were assessed repeatedly during the experimental procedure. For both groups, we observed a marked cortisol response and worsening of mood after the stress challenge. However, no differences between formerly depressed patients and healthy participants were observed. Assuming a disturbed HPA system regulation in acute depression, we interpret these findings as evidence for a restored HPA axis function in fully remitted patients. PMID- 23931984 TI - External laryngeal injuries in children--comparison of diagnostic methods. AB - OBJECTIVES: The injuries of the larynx constitute around 1% of all injuries. The great majority of the injuries of the larynx happens during playing. The effects of these injuries may appear insignificant however, not always the direct clinical symptoms correlate with the degree of respiratory tract failure. The symptoms of laryngeal injuries depend on the extension and strength of the trauma and always relate to impair patency of respiratory tract. The aim of the study is to compare two diagnostic methods: laryngoscopy and ultrasonography in evaluation of laryngeal injuries in children. METHODS: In the Department of Pediatric Otolaryngology, Medical University of Warsaw, in the period between 2004 and 2010 there were hospitalised 15 children with external injury of the larynx. RESULTS: From among 15 hospitalized children, 7 were qualified as not serious trauma and were treated preservatively and the other 8 as sever trauma. The mechanism of traumas was diverse. Dyspnea was a predominating symptom, the others included hoarsness, change in voice quality, even aphonia, pain while speaking and swallowing, cough and hemoptysis. CONCLUSIONS: Direct laryngoscopy is a standard in diagnostics of the injuries of the larynx. Ultrasonography of the larynx is recommended in every case of laryngeal injury as an additional non-invasive complementary diagnostic examination. PMID- 23931985 TI - Sympathetic neuropathy and dysphagia following doxycycline sclerotherapy. AB - This case report demonstrates neurologic sequela following treatment with doxycycline sclerotherapy. A six-week-old child presented with respiratory distress from a macrocystic lymphatic malformation, extending from the skull base to the anterior mediastinum. Following doxycycline sclerotherapy, the airway symptoms resolved; however, the child developed silent aspiration and Horner's syndrome. Two months following treatment the patient resumed oral diet and at one year post-intervention there has been no recurrence of symptoms, with only mild ptosis remaining. While neuropathies following doxycycline sclerotherapy have been described, aspiration has never been documented. This case demonstrates a single patient's clinical course and resolution of their neuropathies. PMID- 23931986 TI - Otitis media with effusion in children with cleft lip and palate: a narrative review. AB - OBJECTIVE: Repair surgery of cleft lip and palate (CLP) can produce satisfactory cosmetic results but the problem of recurrent otitis media with effusion (OME) secondary to CLP may persist. This can cause long-term hearing loss and affect linguistic, academic, and personal development. The aim of this review is to provide the most recent information regarding OME in children with CLP. METHODS: All papers referring to children with CLP and OME were identified from searches in Medline, PubMed, Cochrane Library, and Web of Science. Abstracts were read and relevant papers were obtained. Additional studies were obtained from the references of the selected articles. RESULTS: Both current and previous research on OME in children with CLP focused on the controversy over treatment strategies. Evidence on the optimal treatment for OME in CLP children was lacking. Ventilation tube surgery using the same anesthetic as lip or palate procedures was not well-supported. After summarizing the literature review, a flowchart of management guidance for such patients is also recommended. Updated reviews such as this will provide clinicians and patients/parents with a valuable reference. CONCLUSIONS: The lack of evidence on the optimal treatment for OME in children with CLP should prompt a relatively conservative approach. However, only a consensus between patients/parents and surgeons regarding the most suitable treatment strategy for OME can ensure the greatest benefit to individual patients. PMID- 23931987 TI - Letter to the Editor regarding 'Investigating the burden of hyperbilirubinemia in resource-constrained settings'. PMID- 23931988 TI - A novel approach toward noninvasive monitoring of transcutaneous CO(2). AB - The continuous monitoring of transcutaneous gases is an integral part of neonatal intensive care. Present monitors measure the equilibrating values of these gases by raising the skin temperature to 42 degrees C or above. Because neonatal skin is very sensitive and delicate, this often leads to serious skin injuries. In this work, we present a new approach to the noninvasive measurement of transcutaneous partial pressure of carbon dioxide (tcpCO2) based on the initial pseudo steady state diffusion rates instead of the mass-transfer equilibrium. Because we are following initial diffusion rates, each measurement takes no more than a few minutes. Additionally, raising the surface temperature is not required, thus, skin irritation and burns are highly unlikely. A dual-chamber diffusion vessel with either porcine skin or dialysis membrane placed between the two chambers was used to mimic neonatal skin. LI-820 CO2 Analyzer was used to measure the CO2 diffusing through the membrane or skin. Initial experiments on adult human skin under varying physical activities, food intake and breathing patterns showed a strong influence of the various conditions on the amount of CO2 diffusing through skin. These initial findings suggest that this method can be used not only on neonates but to a wider population of patients. PMID- 23931989 TI - K+ channel regulation of multicompartmental signal integration. AB - Determining how neurons integrate different streams of information is critical to understanding circuit computational functions. In this issue of Neuron, Harnett et al. (2013) show that voltage-gated K+ channels control multiple layers of dendritic integration in layer 5 pyramidal neurons. PMID- 23931990 TI - Alcohol and tobacco: how smoking may promote excessive drinking. AB - Cigarette smokers tend to drink more alcohol than their nonsmoking peers. In this issue of Neuron, Doyon et al. (2013) found that nicotine-induced increases in stress hormones can augment ethanol self-administration in rats, suggesting that a drug interaction may contribute to this phenomenon. PMID- 23931991 TI - Top-down control of cortical state. AB - Sensory cortices receive inputs not only from thalamus but also from higher-order cortical regions. Here, Zagha et al. (2013) show that motor cortical inputs can switch barrel cortex into a desynchronized state that enables more faithful representation of subtle sensory stimuli. PMID- 23931992 TI - The need for research maps to navigate published work and inform experiment planning. AB - The increasing volume, complexity, and interconnectedness of published studies in neuroscience make it difficult to determine what is known, what is uncertain, and how to contribute effectively to one's field. There is a pressing need to develop automated strategies to help researchers navigate the vastness of the published record. Simplified, interactive, and unbiased representations of previous findings (i.e., research maps) would be invaluable in preparing research surveys, in guiding experiment planning, and in evaluating research plans and contributions. Principles normally used in weighing research findings, including reproducibility and convergence, could be automated and incorporated into research maps. Here, we discuss a series of recent advances that are bringing us closer than ever to being able to derive systematic, comprehensive, but also interactive and user-friendly research maps. These maps could revolutionize the way we review the literature, plan experiments, and fund and publish science. PMID- 23931994 TI - Leucine-rich repeat transmembrane proteins are essential for maintenance of long term potentiation. AB - Leucine-rich repeat transmembrane proteins (LRRTMs) are synaptic cell adhesion molecules that trigger excitatory synapse assembly in cultured neurons and influence synaptic function in vivo, but their role in synaptic plasticity is unknown. shRNA-mediated knockdown (KD) of LRRTM1 and LRRTM2 in vivo in CA1 pyramidal neurons of newborn mice blocked long-term potentiation (LTP) in acute hippocampal slices. Molecular replacement experiments revealed that the LRRTM2 extracellular domain is sufficient for LTP, probably because it mediates binding to neurexins (Nrxs). Examination of surface expression of endogenous AMPA receptors (AMPARs) in cultured neurons suggests that LRRTMs maintain newly delivered AMPARs at synapses after LTP induction. LRRTMs are also required for LTP of mature synapses on adult CA1 pyramidal neurons, indicating that the block of LTP in neonatal synapses by LRRTM1 and LRRTM2 KD is not due to impairment of synapse maturation. PMID- 23931995 TI - Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway. AB - The convergence of APP (substrate) and BACE-1 (enzyme) is a rate-limiting, obligatory event triggering the amyloidogenic pathway-a key step in Alzheimer's disease (AD) pathology. However, as both APP/BACE-1 are highly expressed in brain, mechanisms precluding their unabated convergence are unclear. Exploring dynamic localization of APP/BACE-1 in cultured hippocampal neurons, we found that after synthesis via the secretory pathway, dendritic APP/BACE-1-containing vesicles are largely segregated in physiologic states. While BACE-1 is sorted into acidic recycling endosomes, APP is conveyed in Golgi-derived vesicles. However, upon activity induction-a known trigger of the amyloidogenic pathway-APP is routed into BACE-1-positive recycling endosomes via a clathrin-dependent mechanism. A partitioning/convergence of APP/BACE-1 vesicles is also apparent in control/AD brains, respectively. Considering BACE-1 is optimally active in an acidic environment, our experiments suggest that neurons have evolved trafficking strategies that normally limit APP/BACE-1 proximity and also uncover a pathway routing APP into BACE-1-containing organelles, triggering amyloidogenesis. PMID- 23931993 TI - Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. AB - Breakthrough discoveries identifying common genetic causes for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have transformed our view of these disorders. They share unexpectedly similar signatures, including dysregulation in common molecular players including TDP-43, FUS/TLS, ubiquilin-2, VCP, and expanded hexanucleotide repeats within the C9ORF72 gene. Dysfunction in RNA processing and protein homeostasis is an emerging theme. We present the case here that these two processes are intimately linked, with disease-initiated perturbation of either leading to further deviation of both protein and RNA homeostasis through a feedforward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression. PMID- 23931996 TI - Cajal-Retzius cells instruct neuronal migration by coincidence signaling between secreted and contact-dependent guidance cues. AB - Cajal-Retzius (CR) cells are a transient cell population of the CNS that is critical for brain development. In the neocortex, CR cells secrete reelin to instruct the radial migration of projection neurons. It has remained unexplored, however, whether CR cells provide additional molecular cues important for brain development. Here, we show that CR cells express the immunoglobulin-like adhesion molecule nectin1, whereas neocortical projection neurons express its preferred binding partner, nectin3. We demonstrate that nectin1- and nectin3-mediated interactions between CR cells and migrating neurons are critical for radial migration. Furthermore, reelin signaling to Rap1 promotes neuronal Cdh2 function via nectin3 and afadin, thus directing the broadly expressed homophilic cell adhesion molecule Cdh2 toward mediating heterotypic cell-cell interactions between neurons and CR cells. Our findings identify nectins and afadin as components of the reelin signaling pathway and demonstrate that coincidence signaling between CR cell-derived secreted and short-range guidance cues direct neuronal migration. PMID- 23931997 TI - Sonic hedgehog regulates its own receptor on postcrossing commissural axons in a glypican1-dependent manner. AB - Upon reaching their intermediate target, the floorplate, commissural axons acquire responsiveness to repulsive guidance cues, allowing the axons to exit the midline and adopt a contralateral, longitudinal trajectory. The molecular mechanisms that regulate this switch from attraction to repulsion remain poorly defined. Here, we show that the heparan sulfate proteoglycan Glypican1 (GPC1) is required as a coreceptor for the Shh-dependent induction of Hedgehog-interacting protein (Hhip) in commissural neurons. In turn, Hhip is required for postcrossing axons to respond to a repulsive anteroposterior Shh gradient. Thus, Shh is a cue with dual function. In precrossing axons it acts as an attractive guidance molecule in a transcription-independent manner. At the same time, Shh binds to GPC1 to induce the expression of its own receptor, Hhip, which mediates the repulsive response of postcrossing axons to Shh. Our study characterizes a molecular mechanism by which navigating axons switch their responsiveness at intermediate targets. PMID- 23931998 TI - A conformational intermediate in glutamate receptor activation. AB - Ionotropic glutamate receptors (iGluRs) transduce the chemical signal of neurotransmitter release into membrane depolarization at excitatory synapses in the brain. The opening of the transmembrane ion channel of these ligand-gated receptors is driven by conformational transitions that are induced by the association of glutamate molecules to the ligand-binding domains (LBDs). Here, we describe the crystal structure of a GluA2 LBD tetramer in a configuration that involves an ~30 degrees rotation of the LBD dimers relative to the crystal structure of the full-length receptor. The configuration is stabilized by an engineered disulfide crosslink. Biochemical and electrophysiological studies on full-length receptors incorporating either this crosslink or an engineered metal bridge show that this LBD configuration corresponds to an intermediate state of receptor activation. GluA2 activation therefore involves a combination of both intra-LBD (cleft closure) and inter-LBD dimer conformational transitions. Overall, these results provide a comprehensive structural characterization of an iGluR intermediate state. PMID- 23931999 TI - Potassium channels control the interaction between active dendritic integration compartments in layer 5 cortical pyramidal neurons. AB - Active dendritic synaptic integration enhances the computational power of neurons. Such nonlinear processing generates an object-localization signal in the apical dendritic tuft of layer 5B cortical pyramidal neurons during sensory-motor behavior. Here, we employ electrophysiological and optical approaches in brain slices and behaving animals to investigate how excitatory synaptic input to this distal dendritic compartment influences neuronal output. We find that active dendritic integration throughout the apical dendritic tuft is highly compartmentalized by voltage-gated potassium (KV) channels. A high density of both transient and sustained KV channels was observed in all apical dendritic compartments. These channels potently regulated the interaction between apical dendritic tuft, trunk, and axosomatic integration zones to control neuronal output in vitro as well as the engagement of dendritic nonlinear processing in vivo during sensory-motor behavior. Thus, KV channels dynamically tune the interaction between active dendritic integration compartments in layer 5B pyramidal neurons to shape behaviorally relevant neuronal computations. PMID- 23932001 TI - Formation and reverberation of sequential neural activity patterns evoked by sensory stimulation are enhanced during cortical desynchronization. AB - Memory formation is hypothesized to involve the generation of event-specific neural activity patterns during learning and the subsequent spontaneous reactivation of these patterns. Here, we present evidence that these processes can also be observed in urethane-anesthetized rats and are enhanced by desynchronized brain state evoked by tail pinch, subcortical carbachol infusion, or systemic amphetamine administration. During desynchronization, we found that repeated tactile or auditory stimulation evoked unique sequential patterns of neural firing in somatosensory and auditory cortex and that these patterns then reoccurred during subsequent spontaneous activity, similar to what we have observed in awake animals. Furthermore, the formation of these patterns was blocked by an NMDA receptor antagonist, suggesting that the phenomenon depends on synaptic plasticity. These results suggest that anesthetized animals with a desynchronized brain state could serve as a convenient model for studying stimulus-induced plasticity to improve our understanding of memory formation and replay in the brain. PMID- 23932000 TI - Spatial segregation of adaptation and predictive sensitization in retinal ganglion cells. AB - Sensory systems change their sensitivity based on recent stimuli to adjust their response range to the range of inputs and to predict future sensory input. Here, we report the presence of retinal ganglion cells that have antagonistic plasticity, showing central adaptation and peripheral sensitization. Ganglion cell responses were captured by a spatiotemporal model with independently adapting excitatory and inhibitory subunits, and sensitization requires GABAergic inhibition. Using a simple theory of signal detection, we show that the sensitizing surround conforms to an optimal inference model that continually updates the prior signal probability. This indicates that small receptive field regions have dual functionality--to adapt to the local range of signals but sensitize based upon the probability of the presence of that signal. Within this framework, we show that sensitization predicts the location of a nearby object, revealing prediction as a functional role for adapting inhibition in the nervous system. PMID- 23932002 TI - Coding of information in the phase of local field potentials within human medial temporal lobe. AB - There is increasing evidence that the phase of ongoing oscillations plays a role in neural coding, but its relative importance throughout the brain has yet to be understood. We assessed single-trial phase coding in four temporal lobe and four frontal lobe regions of the human brain using local field potentials (LFPs) recorded during a card-matching task. In the temporal lobe, classification of correct/incorrect matches based on LFP phase was significantly better than classification based on amplitude and comparable to the full LFP signal. Surprisingly, in these regions, the correct/incorrect mean phases became aligned to one another before they diverged and coded for trial outcome. Neural responses in the amygdala were consistent with a mechanism of phase resetting, while parahippocampal gyrus activity was indicative of evoked potentials. These findings highlight the importance of phase coding in human medial temporal lobe and suggest that different brain regions may represent information in diverse ways. PMID- 23932003 TI - [Resurfacing of an ischial and trochanteric recurrent pressure sore by a pedicled fasciocutaneous anterolateral thigh flap]. AB - Ischial pressure sores, common in paraplegic patient, are the most difficult to treat, and poor prognosis associated with a high rate of postoperative recurrence. Many surgical techniques by muscular or myocutaneous flap coverage have been described. We report an original use of a fasciocutaneous pedicled anterolateral thigh (ALTp) flap for coverage of an ischial pressure sore combined with a trochanteric pressure sore, exceeded beyond any conventional therapeutic solution. A 45-year-old paraplegic patient suffered from a trochanteric and ischial pressure sore, which had already received coverage by a muscular flap of biceps femoris and gluteus maximus. At 1 year, the result is satisfactory, with good coverage without recurrence. The fasciocutaneous ALTp flap can be a solution to cover recurrent ischial pressure sores beyond conventional methods. PMID- 23932004 TI - A rare complication of small bowel perforation caused by gastric stent migration: a case report. PMID- 23932005 TI - Comparison of cholecystectomy cases after Roux-en-Y gastric bypass, sleeve gastrectomy, and gastric banding. AB - BACKGROUND: Rapid weight loss after bariatric surgery has been a factor of inducing gallstones postoperatively. Many studies have reported increased gallstone formation after laparoscopic Roux-en-Y gastric bypass (LRYGB). However, not many studies have compared symptomatic gallstone frequencies between LRYGB, laparoscopic sleeve gastrectomy (LSG), and laparoscopic adjustable gastric banding (LAGB). The aim of our study is to evaluate symptomatic cholelithiasis cases requiring cholecystectomy after each bariatric procedure. METHODS: Between January 2009 and August 2011, a total of 937 patients underwent bariatric surgery at our institution. Of these patients, 598 had primary LRYGB, 197 had LSG, and 142 had LAGB. We excluded patients with previous cholecystectomy or concomitant cholecystectomy at the time of bariatric procedure. A retrospective review of a prospectively collected database was performed for all patients. RESULTS: Of 367 LRYGB patients, 5.7% (n = 21) had symptomatic gallstones. Of 115 LSG patients, 6.1% (n = 7) required cholecystectomy, and of 104 LAGB patients, .0% (n = 0) developed symptomatic gallstones. The differences in the occurrences of symptomatic gallstones between LRYGB and LSG were not statistically significant (P>.88). However, statistical significance was present between LRYGB and LAGB (P<.02), as well as between LSG and LAGB (P<.02). Mean percentage of excess weight loss (%EWL) at 24 months was 85.7%, 58.8%, and 38.3% in LRYGB, LSG, and LAGB patients, respectively. There was no complication related to the cholecystectomy procedure. CONCLUSIONS: Frequency of symptomatic gallstones after LRYGB and LSG was not significantly different and after LAGB was significantly lower. Slow and less amount of weight loss would have contributed to the low rate of symptomatic gallstone formation in the LAGB patients. PMID- 23932006 TI - Systematic review of laparoscopic adjustable gastric banding in patients with body mass index <=35 kg/m2. AB - BACKGROUND: Recently, the Food and Drug Administration (FDA) panel approved laparoscopic adjustable gastric banding (LAGB) in patients with a body mass index (BMI) >=30 kg/m(2) and related co-morbidities. To our knowledge there is no systematic review assessing LAGB in this group. The objective of this study was to analyze the use of LAGB in patients with BMI <=35 kg/m(2). METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to systematically search MEDLINE and Embase using the medical subject headings (MeSH) terms "bariatric surgery" and "obese" with equivalent free text searches and cross-references. Studies that described LAGB in patients with BMI <=35 kg/m(2) were reviewed with particular focus on weight loss after LAGB as well as morbidity/mortality, co-morbidity resolution. RESULTS: Six studies evaluating 515 patients were included. Mean percentage excess weight loss (%EWL) ranged from 52.5 (+/-13.2) to 78.6 (+/-9.4) at 1 year and 57.6 (+/ 29.3) to 87.2 (+/-9.5) at 2 years postoperatively. Two studies reported weight loss at 3 years with mean %EWL of 53.8 (+/-32.8) to 64.7 (+/-12.2). The only study with follow-up data after 3 years reported a mean %EWL of 68.8 (+/-15.3) and 71.9 (+/-10.7) at 4 and 5 years, respectively. Thirty-four patients (6.6%) developed complications. There was 1 reported mortality (.19%), which occurred at 20 months postoperatively. CONCLUSION: This systematic review shows that LAGB is well tolerated and effective in patients with a BMI <=35 kg/m(2). There are encouraging suggestions that co-morbidities show partial or total resolution; however, a paucity of data remains in this BMI group, particularly with regard to long-term outcomes. PMID- 23932007 TI - Wernicke encephalopathy after Roux-en-Y gastric bypass and hyperemesis gravidarum. PMID- 23932009 TI - Endoscopic treatment of malignant gastric and duodenal strictures: a prospective, multicenter study. AB - BACKGROUND: Malignant gastric outlet obstruction is often treated by stent placement. OBJECTIVE: To investigate the outcomes of stent placement in the palliative treatment of malignant neoplasms. DESIGN: Prospective, observational, multicenter registry. SETTING: Six tertiary care centers in 5 countries. PATIENTS: A total of 108 adult patients with malignant gastric outlet obstruction. INTERVENTIONS: Placement of an uncovered, self-expandable, metal duodenal stent. MAIN OUTCOME MEASUREMENTS: The primary endpoint was stent patency at 14 days after stent implantation. Secondary endpoints included stent patency at 1, 2, 3, and 6 months, gastric outlet obstruction scoring system (GOOSS) scores at 14 days and 1, 2, 3, and 6 months after stent deployment, technical success, adverse events, and patient survival (ie, confirmed duration of the implant). RESULTS: Technical success was achieved in 99.1% of stent placements. Stent patency at 14 days was 94.6%. Kaplan-Meier estimates of stent patency were 92.9% at 1 month, 86.2% at 2 months, 81.9% at 3 months, and 63.4% at 6 months. At 14 days, GOOSS scores increased by a median of 1 point. The overall GI adverse event rate was 32.4%; however, the stent-related adverse event rate was 19.4%. The median implant duration was 47 days (range 0-195 days). LIMITATIONS: Observational study, no control group. CONCLUSIONS: Duodenal stent placement resulted in prompt relief of malignant gastric outlet obstruction and improved GOOSS scores. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00991614.). PMID- 23932008 TI - The influence of sexual partner on condom use among urban adolescents. AB - PURPOSE: The influence of partner context (e.g., drinking alcohol in the 2 hours prior to sex, >=3 years age discordant, met in public) on adolescent boys' and girls' condom use is unclear. Among an urban cohort of primarily (86%) minority 17-18-year-olds who reported having sex (n = 1,469), we assessed the association between condom use and partner characteristics for the most recent sexual experience. METHODS: We used logistic regression to examine the odds of condom use by measured partner familiarity (casual or unexpected) and context characteristics. Analyses were stratified by gender. RESULTS: Adolescent boys and girls were twice as likely to use condoms with partners they considered casual or unexpected. Adjusting for partner familiarity risk, adolescent boys' tended to decrease condom use with risky context partners. Adjusting for partner familiarity risk, adolescent girls were half as likely to use condoms with partners drinking alcohol 2 hours prior to sex [Odds Ratio (OR) = .6, 95% Confidence Interval (CI) = .4-.9]; >=3 years age discordant (OR = .5, 95% CI = .3 .8); or met in public places (OR = .6, 95% CI = .4-.8). CONCLUSIONS: Regardless of partner familiarity risk, adolescent boys and girls faced barriers to condom use with risky context partners. Increased understanding of adolescents' perceptions of and control over partner risk and condom use with risky context partners is needed. Interventions aimed at decreasing adolescent sexually transmitted infections should include strategies for adolescents to choose less risky context partners and negotiate condoms with risky context partners. PMID- 23932010 TI - Large-cell neuroendocrine lung tumor presenting as acute pancreatitis. PMID- 23932011 TI - The evolving role of stroke prediction schemes for patients with atrial fibrillation. AB - Our approach to managing patients with atrial fibrillation has changed substantially over the past 10 years, as a result of numerous high-quality observation studies and randomized trials. In this article, we will provide practical guidance for the use of oral anticoagulation therapy in patients with atrial fibrillation. We will review the evolution of stroke and bleeding risk prediction schemes and discuss their role in patient care. Initially, stroke prediction schemes were used to identify patients with atrial fibrillation at the highest risk of stroke, in whom the use of oral anticoagulant therapy was believed to be the most important. However; with the advent of new, safer, and more convenient oral anticoagulant drugs, the role of these schemes has shifted to the identification of the lowest risk patients, representing the minority of patients with atrial fibrillation, in whom oral anticoagulant therapy is not recommended. At the same time, schemes were developed to predict bleeding, the major risk of oral anticoagulant therapy. However; use of these schemes has been limited by their complexity and significant correlation with stroke schemes. In general, it is advisable to base the decision to use oral anticoagulation on the patient's stroke risk and use bleeding schemes to identify absolute contraindications or modifiable risk factors for bleeding. Prediction schemes have been useful clinical tools, invaluable in the design of clinical trials, and have assisted greatly in economic analyses. However, the nature and role of such schemes is now adapting to the current era of novel oral anticoagulant agents. PMID- 23932012 TI - Which oral anticoagulant for which atrial fibrillation patient: recent clinical trials and evidence-based choices. AB - Current practice guidelines recommend oral anticoagulant therapy for most patients with nonvalvular atrial fibrillation with more than a low risk of stroke. Although warfarin is very effective and the risk of major bleeding is acceptable, the use of the drug is challenging for patients and physicians. The 3 novel oral anticoagulants (NOACs), dabigatran, rivaroxaban, and apixaban, have been shown to be either noninferior or superior to warfarin for the prevention of stroke and/or systemic embolism and their rates of major bleeding are no greater than warfarin. They are much easier for patients to use and for physicians to manage. Except for certain situations in which the NOACs have not been evaluated or some feature of warfarin is preferable, clinical guidelines generally recommend a preference for a NOAC over warfarin when oral anticoagulation is indicated. Although the NOACs have many similarities in their advantageous pharmacokinetic and pharmacodynamic characteristics, there are a number of difference between them with regard to particular patient characteristics (eg, age >= 75 years, renal dysfunction, coronary artery disease, venous thromboembolism, risk of bleeding, prior stroke and/or transient ischemic attack, side effects, dose regimens, and cost-effectiveness). These differences are outlined and discussed in terms of their potential relevance in deciding among the 3 available NOACs for stroke prevention in atrial fibrillation. PMID- 23932013 TI - Molecular basis and thrombotic manifestations of antithrombin deficiency in 15 unrelated Chinese patients. AB - INTRODUCTION: Antithrombin (AT) deficiency is associated with an increasing risk of thrombosis. MATERIALS AND METHODS: 15 unrelated patients with AT deficiency defined by thrombophilic assays were recruited and detailed clinical information about patients, focusing on the personal and family history of thromboembolism (TE), were recorded. Mutation analysis was performed by direct sequencing of an AT gene (SERPINC1) in the patients and their family members. RESULTS: A total of 15 heterozygous causative mutations, each being identified in one family, were identified. Five mutations (33.3%) were reported here for the first time, including three null mutations (Ser36X, Lys70X and Try307X) and two missense mutations (Phe123Cys and Leu340Phe) probably impairing the structural integrity and stability of protein based on the AT structural analysis. Of the 15 patients, 33.3% (5/15) had additional risk factors and only one patient presented with additional genetic alteration causing an early onset of thrombosis. Fourteen patients (93.9%) suffered from multisite recurrent thrombotic episodes after a first episode of thrombosis. 93.3% of the patients experienced deep vein thrombosis (DVT) and 40.0% presented with mesenteric venous thrombosis (MVT). In addition, both venous and arterial thrombosis was present in two unrelated patients. 51.0% subjects with AT deficiency in the 15 unrelated pedigrees experienced TE events. CONCLUSIONS: Prophylactic anticoagulation may be suggested in AT-deficient patients to avoid the recurrent and multisite thrombosis. The association of primary MVT and AT deficiency is highlighted. PMID- 23932014 TI - Do women bleed more than men when prescribed novel oral anticoagulants for venous thromboembolism? A sex-based meta-analysis. AB - INTRODUCTION: Bleeding complications occur more frequently in women than men in clinical trials of warfarin and thrombolytics. It is unknown whether these sex related differences exist for new oral anticoagulants, including dabigatran, rivaroxaban, and apixaban. To determine whether women suffer more bleeding complications with these agents, we conducted a systematic review and meta analysis of randomized controlled trials on new oral anticoagulants for venous thromboembolism (VTE). MATERIALS AND METHODS: Medline, Embase, and the Cochrane controlled trial register on the Cochrane library were searched to identify studies that evaluated novel oral anticoagulants versus any comparator, and reported outcomes, including major bleeding and recurrent VTE, stratified by sex. No language restrictions were applied. Studies were evaluated according to a priori inclusion criteria and critically appraised using established internal validity criteria. Pooled relative risk was estimated using a random effects model. RESULTS: Eight studies were eligible, comprising 9417 patients. There was no difference in the primary efficacy outcome of recurrent VTE between men and women [Relative Risk (RR) 1.02, 95% confidence interval (CI) 0.74-1.39]. However, men had less major bleeding with novel oral anticoagulants compared to women [RR 0.79, 95% CI 0.66-0.97, p=0.03]. All-cause mortality was not reported by sex in any of the studies. CONCLUSION: Women suffer more bleeding complications than men when receiving novel oral anticoagulants for VTE. Future clinical trials should report outcomes stratified by sex, and further studies are needed to investigate the clinical impact of this sex-related safety difference. PMID- 23932015 TI - Dispersion analysis of leaky guided waves in fluid-loaded waveguides of generic shape. AB - A fully coupled 2.5D formulation is proposed to compute the dispersive parameters of waveguides with arbitrary cross-section immersed in infinite inviscid fluids. The discretization of the waveguide is performed by means of a Semi-Analytical Finite Element (SAFE) approach, whereas a 2.5D BEM formulation is used to model the impedance of the surrounding infinite fluid. The kernels of the boundary integrals contain the fundamental solutions of the space Fourier-transformed Helmholtz equation, which governs the wave propagation process in the fluid domain. Numerical difficulties related to the evaluation of singular integrals are avoided by using a regularization procedure. To improve the numerical stability of the discretized boundary integral equations for the external Helmholtz problem, the so called CHIEF method is used. The discrete wave equation results in a nonlinear eigenvalue problem in the complex axial wavenumbers that is solved at the frequencies of interest by means of a contour integral algorithm. In order to separate physical from non-physical solutions and to fulfill the requirement of holomorphicity of the dynamic stiffness matrix inside the complex wavenumber contour, the phase of the radial bulk wavenumber is uniquely defined by enforcing the Snell-Descartes law at the fluid-waveguide interface. Three numerical applications are presented. The computed dispersion curves for a circular bar immersed in oil are in agreement with those extracted using the Global Matrix Method. Novel results are presented for viscoelastic steel bars of square and L-shaped cross-section immersed in water. PMID- 23932016 TI - [A rare cause of nasal obstruction]. PMID- 23932017 TI - Synergistic physical properties of cocured networks formed from di- and tricyanate esters. AB - The co-cyclotrimerization of two tricyanate ester monomers, Primaset PT-30 and 1,2,3-tris(4-cyanato)propane (FlexCy) in equal parts by weight with Primaset LECy, a liquid dicyanate ester, was investigated for the purpose of exploring synergistic performance benefits. The monomer mixtures formed stable, homogeneous blends that remained in the supercooled liquid state for long periods at room temperature, thereby providing many of the processing advantages of LECy in combination with significantly higher glass transition temperatures (315-360 degrees C at full cure) due to the presence of the tricyanate-derived segments in the conetwork. Interestingly, the glass transition temperatures of the conetworks after cure at 210 degrees C, at full cure, and after immersion in 85 degrees C water for 96 h were all higher than predicted by the Flory-Fox equation, most significantly for the samples immersed in hot water. Conetworks comprising equal parts by weight of PT-30 and LECy retained a "wet" glass transition temperature near 270 degrees C. The onset of thermochemical degradation for conetworks was dominated by that of the thermally less stable component, while char yields after the initial degradation step were close to values predicted by a linear rule of mixtures. Values for moisture uptake and density in the conetworks also showed behavior that was not clearly different from a linear rule of mixtures. An analysis of the flexural properties of catalyzed versions of these conetworks revealed that, when cured under the same conditions, conetworks containing 50 wt % PT-30 and 50 wt % LECy exhibited higher modulus than networks containing only LECy while conetworks containing 50 wt % FlexCy and 50 wt % LECy exhibited a lower modulus but significantly higher flexural strength and strain to failure. Thus, in the case of "FlexCy", LECy was copolymerized with a tricyanate that provided both improved toughness and a higher glass transition temperature. PMID- 23932018 TI - Review of combination therapy with mTOR inhibitors and tacrolimus minimization after transplantation. AB - We evaluated the efficacy and safety of immunosuppressive regimens containing a mammalian target of rapamycin (mTOR) inhibitor with tacrolimus (TAC) minimization therapy in solid organ transplant recipients. A PubMed search was conducted using the terms (mTOR OR sirolimus OR everolimus) AND tacrolimus AND renal AND (low OR reduced OR reduction OR minimization) AND transplant*; limited to title/abstract and English-language articles published from January 1, 2003, through January 28, 2013. Twenty-one relevant studies of TAC minimization therapy were identified and evaluated in the context of known concerns associated with immunosuppressive therapy. Review of these studies suggests that immunosuppressive regimens including an mTOR inhibitor and TAC minimization therapy better preserve renal function versus standard-dose TAC, without significant changes in patient survival or graft rejection rates. Among patients treated with an mTOR inhibitor plus TAC minimization therapy in 12 randomized controlled trials (n=856 kidney, n=190 heart, n=108 lung, n=719 liver patients), reported rates of infection (BK, cytomegalovirus, or Epstein-Barr virus) and malignancy were low (0% to 7%). Other adverse events were more commonly reported including dyslipidemia/hyperlipidemia in up to two thirds of patients, new-onset diabetes mellitus in up to 38%, wound complications in up to 22%, and hypertension in up to 17%. PMID- 23932019 TI - Telomerase: central regulator of all of the hallmarks of cancer. AB - The hallmarks of cancer described by Hanahan and Weinberg are properties that cancer cells must possess for successful transformation. It is believed that each of these hallmarks is independently driven. Although elongation of telomeres is thought to be the prime function of reactivated telomerase reverse transcriptase, this activity does not account for all its effects, such as increasing cell proliferation, resistance to apoptosis, and invasion. Recent studies suggest that the telomerase subunit telomerase reverse transcriptase (TERT) has novel molecular functions including transcriptional regulation and metabolic reprogramming. We summarize these functions and discuss how they could directly regulate the various hallmarks of cancer. Finally, we suggest that therapeutics targeting noncanonical telomerase functions may work better than those that target its role in telomere extension. PMID- 23932020 TI - Bacterial promotion of bisphosphonate-induced osteonecrosis in Wistar rats. AB - Clinically, bisphosphonate-related osteonecrosis (BRON) only occurs in the jaw (BRONJ). We aimed to determine differences between the jaw and other bones, as well as the relationship between periodontal pathogens and BRON. Twelve male Wistar rats were divided into two groups: group Z (n=6) were subcutaneously injected with zoledronic acid weekly for 4 weeks; group C (n=6) were injected with saline. One week after the final injection, rats in both groups were divided into three subgroups: Aa subgroup was injected with freeze-dried Aggregatibacter actinomycetemcomitans into bone marrow of the mandibles and femurs, while CFA and saline subgroups were injected with complete Freund's adjuvant (CFA) or saline using the same protocol. Four weeks after those injections, the rats were euthanized. Areas of osteonecrosis were measured histologically. Statistically, rats in group Z showed significantly wider osteonecrosis areas in both mandibles and femurs with each type of local injection than rats in group C. In group Z, mandibles and femurs stimulated with A. actinomycetemcomitans or CFA had significantly wider osteonecrosis areas than those stimulated with saline. We have developed a rat model with BRONJ-like lesions. Our results showed BRON to develop not only in the jaw but also in other types of bone following an inflammatory stimulus. PMID- 23932021 TI - Effect of hyperbaric oxygen treatment on oxygen tension and vascular capacity in irradiated skin and mucosa. AB - The aim of this study was to evaluate the effect of hyperbaric oxygen therapy (HBOT) on vascular function and tissue oxygenation in irradiated facial skin and gingival mucosa. Twenty-two patients, aged 51-90 years, were randomly allocated to a treatment or control group. All had a history of radiotherapy (50-70 Gy) to the orofacial region 2-20 years previously. Skin and mucosal perfusion were recorded with laser Doppler flowmetry (LDF). Tissue oxygenation was recorded by transcutaneous oximetry (TcPO(2)). Measurements were taken before HBOT and 3 and 6 months after a mean of 28 HBOT sessions (partial pressure of oxygen of 240 kPa for 90 min). For control subjects, measurements were taken on two occasions 6 months apart. After HBOT, blood flow in mucosa and skin after heat provocation increased significantly (P < 0.05). TcPO(2) increased significantly in the irradiated cheek (P < 0.05), but not at reference points outside the field of radiation. There were no differences between the 3- and 6-month follow-ups. In the control group, no significant changes in LDF or TcPO(2) were observed. It is concluded that oxygenation and vascular capacity in irradiated facial skin and gingival mucosa are increased by HBOT. The effects persist for at least 6 months. PMID- 23932022 TI - The development of rapid online control in children aged 6-12 years: reaching performance. AB - Rapid online control during reaching has an important bearing on movement accuracy and flexibility. It is surprising then that few studies have investigated the development of rapid online control in children. In this study, we were particularly interested in age-related changes in the nature of motor control in response to visual perturbation. We compared the performance of younger (6-7 years of age), mid-aged (8-9), and older (10-12) children, as well as healthy young adults using a double-step reaching task. Participants were required to make target-directed reaching movements in near space, while also responding to visual perturbations that occurred at movement onset for a small percentage of trials. Results showed that both the older and mid-aged children corrected their reaching in response to the unexpected shifts in target location significantly faster than younger children, manifest by reduced time to correction. In turn, the responses of adults were faster than older children in terms of movement time and on kinematic measures such as time to correction and time to peak velocity. These results indicate that the capacity to utilize forward estimates of limb position in the service of online control of early perturbations to ballistic (or rapid) reaching develops in a non-linear fashion, progressing rapidly between early and middle childhood, showing a degree of stability over mid and later childhood, but then evidence for continued refinement between childhood and young adulthood. The pattern of change after childhood and into early adolescence requires further investigation, particularly during the rapid phase of physical growth that accompanies puberty. PMID- 23932023 TI - Forage selection by Royle's pika (Ochotona roylei) in the western Himalaya, India. AB - Forage selection decisions of herbivores are often complex and dynamic; they are modulated by multiple cues, such as quality, accessibility and abundance of forage plants. To advance the understanding of plant-herbivore interactions, we explored foraging behavior of the alpine lagomorph Royle's pika (Ochotona roylei) in Kedarnath Wildlife Sanctuary, India. Pika bite counts on food plants were recorded through focal sampling in three permanently marked plots. Food plant abundance was recorded by traditional quadrat procedures; forage selection was estimated with Jacob's selection index. Multiple food-choice experiments were conducted to determine whether forage selection criteria would change with variation in food plant composition. We also analyzed leaf morphology and nutrient content in both major food plants and abundantly available non-food plants. Linear regression models were used to test competing hypotheses in order to identify factors governing forage selection. Royle's pika fed primarily on 17 plant species and each forage selection decision was positively modulated by leaf area and negatively modulated by contents of avoided substances (neutral detergent fiber, acid detergent fiber, acid detergent lignin and tannin) in food plants. Furthermore, significance of the interaction term "leaf size * avoided substance" indicates that plants with large leaves were selected only when they had low avoided substance content. The forage selection criteria did not differ between field and laboratory experiments. The parameter estimates of best fit models indicate that the influence of leaf size or amount of avoided substance on pika forage selection was modulated by the magnitude of predation risk. PMID- 23932024 TI - Rectal shaving using PlasmaJet in deep endometriosis of the rectum. AB - OBJECTIVE: To report an original technique of rectal shaving using the PlasmaJet system (Plasma Surgical, Inc.) for the management of deep endometriosis of the rectum. DESIGN: Video demonstration of a new surgical technique. SETTING: Hospital. PATIENT(S): A 34 year-old primipara with a deep endometriosis involving the vagina and the mid-rectum over 30 mm. INTERVENTION(S): An original technique of rectal shaving. MAIN OUTCOME MEASURE(S): The procedure is based on the specific properties of PlasmaJet: the lack of lateral thermal spread around the jet of plasma making the dissection on contact of rectal wall safe, the precise ablative property allowing for in situ ablation of rectal endometriosis implants, and the kinetic energy enhancing the dissection of subperitoneal spaces. The steps of the technique and the role of PlasmaJet are emphasized. The surgical technique report using anonymous patients is exempt from ethical approval by the IRB. RESULT(S): The patient's outcome was uneventful, and colorectal complaints were completely relieved one week after surgery. Since November 2012, we have employed this technique in 18 patients, with only favorable outcomes. CONCLUSION(S): The technique described in this video article may represent a step toward a more complete removal of endometriotic implants and better colorectal outcomes. PMID- 23932025 TI - Extraction of tetracyclinic antibiotic residues from fish filet: comparison and optimization of different procedures using liquid chromatography with fluorescence detection. AB - Anti-microbials have been used to control the quality of the aquatic environment for both prophylactic and therapeutic purposes. Tetracyclines are among the main antimicrobials used in aquaculture, and present a particular difficulty for extraction, due to a complex structure and high interaction with components of the biological matrix. In this study, different techniques of extraction and clean-up of antimicrobials of the tetracycline class in tilapia filets have been optimized and compared, followed by validation of the methodology using the best procedure. Oxytetracycline, doxycycline, tetracycline and chlortetracycline were analyzed by HPLC-fluorescence under the following conditions: organic mobile phase composed of methanol:acetonitrile (1:1, v/v) and aqueous mobile phase containing sodium acetate (0.0375molL(-1)), calcium chloride (0.0175molL(-1)) and EDTA (0.0125molL(-1)) at pH 7.00. The chromatographic analysis was performed using a mobile phase gradient with a flow rate of 1mLmin(-1) and detection wavelength of 385/528nm (lambdaexc/lambdaem). Four extraction methods have been evaluated, namely: liquid-liquid partition; solid phase extraction (SPE) using phenyl, C18 and polymeric Oasis-HLB stationary phases; dispersive SPE (dSPE) using polymeric adsorbent XAD 16 resin; and QuEChERS. The methods have been optimized with fractional factorial experimental design and compared by the extraction efficiency. The liquid-liquid extraction and the QuEChERS methods showed low extraction efficiencies (14-30%) for the analytes. The use of dSPE showed good efficiency (40-60%), but with low precision and high consumption of time. Among the evaluated extraction techniques the use of SPE showed the best results, with emphasis on the phenyl phase (58-76%), and has been validated for analysis of residues of tetracyclines in tilapia muscle regarding selectivity, linearity, precision and limits of detection and quantification. The validated method was adequate for the investigation of the analytes at residue levels. PMID- 23932026 TI - A dual-channel gas chromatography method for the quantitation of low and high concentrations of NF3 and CF4 to study membrane separation of the two compounds. AB - A dual-channel gas chromatographic method is described in this paper that can be conveniently used for quantitation of NF3/CF4 mixtures with a thermal conductivity detector (TCD) on one channel for the quantitation of high concentrations, and a pulsed discharge helium ionization detector (PDHID) on a second channel for the quantitation of low concentrations. It is shown that adequate separation is achieved on both channels with this dual single-column setup in which column switching as used for NF3/CF4 analysis in industrial chromatographic methods are not required, thus yielding an effective analysis method for laboratory-scale investigations. In addition, the use of packed columns with purified divinylbenzene-styrene co-polymers as the sole stationary phase yields satisfactory resolution between NF3 and CF4 at isothermal conditions of 30 degrees C, with elution times of less than 8min on the TCD channel and less than 4min on the PDHID channel. Consequently, this method allows for reliable, straight-forward quantitation of NF3/CF4 mixtures, which is necessary when studying the commercially important problem of NF3 and CF4 separation by different methods. Therefore, the applicability of the method to studying membrane separation of NF3 and CF4 is briefly discussed and illustrated, for which the dual-channel setup is especially beneficial. PMID- 23932027 TI - Dispersive micro solid-phase extraction for the rapid analysis of synthetic polycyclic musks using thermal desorption gas chromatography-mass spectrometry. AB - A simple and solvent-free method for the rapid analysis of five synthetic polycyclic musks in water samples is described. The method involves the use of dispersive micro solid-phase extraction (D-MU-SPE) coupled with direct thermal desorption (TD) gas chromatography-mass spectrometry (GC-MS) operating in the selected-ion-storage (SIS) mode. The parameters affecting the extraction efficiency of the target analytes from water sample and the thermal desorption conditions in the GC injection-port were optimized using a central composite design method. The optimal extraction conditions involved immersing 3.2mg of a typical octadecyl (C18) bonded silica adsorbent (i.e., ENVI-18) in a 10mL water sample. After extraction by vigorously shaking for 1.0min, the adsorbents were collected and dried on a filter. The adsorbents were transferred to a micro-vial, which was directly inserted into GC temperature-programmed injector, and the extracted target analytes were then thermally desorbed in the GC injection-port at 337 degrees C for 3.8min. The limits of quantitation (LOQs) were determined to be 1.2-3.0ng/L. Precision, as indicated by relative standard deviations (RSDs), was less than 9% for both intra- and inter-day analysis. Accuracy, expressed as the mean extraction recovery, was between 74 and 90%. A preliminary analysis of the river water samples revealed that galaxolide (HHCB) and tonalide (AHTN) were the two most common synthetic polycyclic musks present. Using a standard addition method, their concentrations were determined to in the range from 11 to 140ng/L. PMID- 23932028 TI - Analysis of lignocellulose derived phenolic monomers by headspace solid-phase microextraction and gas chromatography. AB - A headspace solid-phase microextraction method with subsequent GC-MS (HS-SPME/GC MS) was established for the quantitative analysis of volatile lignin derived phenolic monomers in complex aqueous solutions. Extraction was done using a polyacrylate fiber. The optimization of HS-SPME - parameters was performed using a multi component model solution of six representative phenolic monomers identified in liquid hot water (LHW) supernatants of hydrothermally treated lignocellulosic biomass: p-coumaric acid, guaiacol, vanillin, acetosyringone, 4 hydroxy-3-methoxyphenylacetone, and acetophenone. Plackett-Burman design was applied for pre-evaluation and 2(3) central composite designs with star points for parameter optimization. LOQ (S/N>10) and LOD (S/N>3) were determined for 12 phenols yielding LOQ of <0.005-618nM and LOD of <0.005-412nM. Within-day and between-day tests (n=6) showed different results for the tested phenols. RSD ranged from 2% to 30% and recovery rates from 99% to 160% in LHW matrix. Tests on storage of LHW supernatants for several weeks indicated a considerable influence of temperature on the stability of the solutions which may even have to be taken into account for auto sampler handling. All in all the method allows a fast and solvent free analysis requiring low sample volumes making it a powerful tool for screening or high-throughput analysis of aqueous solutions of lignin derived aromatics. PMID- 23932029 TI - A cost-effective plate-based sample preparation for antibody N-glycan analysis. AB - During early cell line and process development of therapeutic antibodies, a cost effective high-throughput approach to characterize the N-linked glycans is highly desired given that a large number of samples need to be analyzed. Using commercially available, low cost 96-well plates, we developed a practical procedure to prepare fluorescently labeled N-linked glycans for both qualitative and quantitative analysis by mass spectrometry (MS) and ultrahigh performance liquid chromatography (UPLC). Antibody samples were continuously denatured, reduced, and deglycosylated in a single 96-well hydrophobic membrane filter plate. Subsequently, released glycans were fluorescently labeled in a collection plate, and cleaned-up using a hydrophilic membrane filter plate. Carried out entirely in ready-to-use 96-well plates with simple buffer systems, this procedure requires less than 90min to finish. We applied the optimized procedure to examine the N-linked glycosylation of trastuzumab and were able to quantify ten major N-linked glycans. The results from different amounts of starting materials (10-200MUg) were highly similar and showed the robustness of this procedure. Compared to other methods, this new procedure is simple to implement, economically more affordable, and could be very valuable for early screenings of antibody development. PMID- 23932030 TI - Preparation and retention mechanism study of graphene and graphene oxide bonded silica microspheres as stationary phases for high performance liquid chromatography. AB - Graphene oxide (GO) bonded stationary phase for high performance liquid chromatography (HPLC) was fabricated by coating GO sheets onto aminosilica microspheres via covalent coupling. Graphene (G) functionalized HPLC stationary phase was then prepared through hydrazine reduction of GO bonded silica (GO@SiO2) composite, which was the first example of using graphene as stationary-phase component for HPLC. Effective separations of the tested neutral and polar compounds on both GO@SiO2 and graphene bonded silica (G@SiO2) columns were achieved under the optimal experimental conditions. Compared with commercial C18 column, the different chromatographic performances of GO and graphene bonded columns were ascribed to their unique retention mechanisms. The polyaromatic scaffold of GO and graphene gives pi-pi stacking property and hydrophobic effect, and other retention mechanisms, such as pi-pi electron-donor-acceptor (EDA) interaction for the separation of nitroaromatic compounds and hydrogen bonding for hydroxyl and amino compounds, may also be taken into consideration. Experimental results indicated that the mixed-mode retention mechanism can facilitate the separation of analytes with similar hydrophobicity, which is a unique property compared with C18 column. Additionally, G@SiO2 showed higher affinity to aromatic analytes in contrast with GO@SiO2 and its retention mechanism was not consistent with the typical reversed phase behavior. The separation of aromatic compounds on G@SiO2 column relies primarily on the pi-pi stacking interaction and then the hydrophobicity, while the two interactions have equal shares on GO@SiO2 column. PMID- 23932031 TI - Quantification of complex polycyclic aromatic hydrocarbon mixtures in standard reference materials using comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry. AB - This research is the first to quantify complex PAH mixtures in NIST SRMs using comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC*GC/ToF-MS), with and without extract cleanup, and reports previously unidentified PAH congeners in the NIST SRMs. We tested a novel, high orthogonality GC column combination (LC-50*NSP-35), as well as with a commonly used column combination (Rtx-5ms*Rxi-17) for the quantification of a complex mixture of 85 different PAHs, including parent (PAHs), alkyl- (MPAHs), nitro- (NPAHs), oxy- (OPAHs), thio- (SPAHs), bromo- (BrPAHs), and chloro-PAHs (ClPAHs) in extracts from two standard reference materials: NIST SRM1650b (diesel particulate matter), with cleanup and NIST SRM1975 (diesel particulate extract), with and without extract cleanup. The LC-50*NSP-35 column combination resulted in an average absolute percent difference of 33.8%, 62.2% and 30.8% compared to the NIST certified PAH concentrations for NIST SRM1650b, NIST SRM1975 with cleanup and NIST SRM1975 without cleanup, while the Rtx-5ms*Rxi-17 resulted in an absolute percent difference of 38.6%, 67.2% and 79.6% for NIST SRM1650b, NIST SRM1975 with cleanup and NIST SRM1975 without cleanup, respectively. This GC*GC/ToF-MS method increases the number of PAHs detected and quantified in complex environmental extracts using a single chromatographic run. Without clean up, 7 additional compounds were detected and quantified in NIST SRM1975 using the LC-50*NSP-35 column combination. These results suggest that the use of the LC 50*NSP-35 column combination in GC*GC/ToF-MS not only results in better chromatographic resolution and greater orthogonality for the separation of complex PAH mixtures, but can also be used for the accurate quantification of complex PAH mixtures in environmental extracts, such as diesel particulate matter, without silica gel cleanup. PMID- 23932032 TI - Mixed-mode chromatography with zwitterionic phosphopeptidomimetic selectors from Ugi multicomponent reaction. AB - In the present contribution a novel Ugi multicomponent reaction (MCR) was used to generate zwitterionic chromatographic selectors with capability for application in mixed-mode chromatography featuring complementary selectivities in reversed phase (RP) and hydrophilic interaction liquid chromatography (HILIC). Aminophosphonate zwitterionic chromatographic ligands were synthesized adopting a one pot microwave assisted three-component UGI-MCR synthesis and, after purification, were immobilized by thiol-ene click chemistry on silica beads. Chromatographic characteristics of these stationary phases were evaluated by variation of experimental conditions for a set of diverse analytes with neutral, acidic, basic and zwitterionic character revealing the presence of multimodal retention capabilities (i.e. tunable retention increments from ion exchange, hydrophobic and hydrophilic interaction were observed). To further investigate and classify the retention properties of the novel stationary phases we performed a comparative chromatographic study with commercially available mixed mode, HILIC and RP columns. The resultant chromatographic data were analyzed by principal component analysis (PCA). PCA revealed that the new reversed-phase/zwitterionic ion-exchangers (RP/ZWIX) are complementary to common RP, HILIC and mixed-mode phases on the market and could be a promising alternative in impurity profiling and 2D-HPLC concepts. Moreover, the adopted synthetic approach offers the capability to generate chemical diversity simply by the variation of the starting aldehyde, aminophosphonic acid and/or isonitrile components. This unique characteristics offer great possibility for the design of novel selectors for mixed mode chromatography like RP/ZWIX, HILIC, affinity and chiral chromatography. PMID- 23932034 TI - [Accuracy of morphological simulation for orthognatic surgery. Assessment of a 3D image fusion software.] AB - INTRODUCTION: The CT/CBCT data allows for 3D reconstruction of skeletal and untextured soft tissue volume. 3D stereophotogrammetry technology has strongly improved the quality of facial soft tissue surface texture. The combination of these two technologies allows for an accurate and complete reconstruction. The 3D virtual head may be used for orthognatic surgical planning, virtual surgery, and morphological simulation obtained with a software dedicated to the fusion of 3D photogrammetric and radiological images. TECHNICAL NOTE: The imaging material include: a multi-slice CT scan or broad field CBCT scan, a 3D photogrammetric camera. The operative image processing protocol includes the following steps: 1) pre- and postoperative CT/CBCT scan and 3D photogrammetric image acquisition; 2) 3D image segmentation and fusion of untextured CT/CBCT skin with the preoperative textured facial soft tissue surface of the 3D photogrammetric scan; 3) image fusion of the pre- and postoperative CT/CBCT data set virtual osteotomies, and 3D photogrammetric soft tissue virtual simulation; 4) fusion of virtual simulated 3D photogrammetric and real postoperative images, and assessment of accuracy using a color-coded scale to measure the differences between the two surfaces. PMID- 23932033 TI - [Radio-opaque masses detected on orthopantomograph]. PMID- 23932035 TI - Assessment of the implementation of the model of integrated and humanised midwifery health services in Santiago, Chile. AB - OBJECTIVES: during 2007 the Chilean Ministry of Public Health introduced the Model of Integrated and Humanized Health Services, in addition to the Clinical Guide for Humanized Care during Delivery. Three years after its implementation, a study was conducted (i) to describe selected clinical outcomes of women who received care within this model, (ii) to identify the degree of maternal-newborn well-being and (iii) to explore the perception of this humanised attention during labour and delivery by both the professional staff (obstetricians and midwives) and consumers. DESIGN AND METHOD: a cross-sectional, descriptive study using both quantitative and qualitative methods was conducted with 508 women who delivered in two major hospitals within the National Health System in the metropolitan area of Santiago, Chile, from September 2010 until June 2011. The quantitative methods included a validated survey of maternal well-being and an adapted version of the American College of Nurse-Midwives (ACNM) standardised antepartum and intrapartum data set. The qualitative methods included six focus groups discussions (FGDs), with midwives, obstetricians and consumers. Additionally, two in depth interviews were carried out with the directors of the maternity units. FINDINGS: the quantitative findings showed poor implementation of the guidelines: 92.7% of the women had medically induced labours (artificial rupture of the membranes and received oxytocin and epidural anaesthesia), and almost one-third of the women reported discontent with the care they received. The qualitative findings showed that the main complaint perceived by the midwives was that the health system was highly hierarchical and medicalised and that the obstetricians were not engaged in this modality of assistance. The women (consumers) highlighted that professionals (midwives and obstetricians) were highly technically skilled, and they felt confident in their assistance. However, women complained about receiving inadequate personal treatment from these professionals. The obstetricians showed no self-critique, stating that they always expressed concern for their patients and that they provided humanised professional assistance. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: by illuminating the main strengths and weakness with regard to the application of the model, these findings can help to inform strategies and actions to improve its implementation. PMID- 23932036 TI - The role of psychosocial factors in exclusive breastfeeding to six months postpartum. AB - OBJECTIVE: to investigate the psychosocial variables associated with the ability to exclusively breastfeed to six months postpartum. Additionally, to evaluate a conceptual model of psychosocial correlates of exclusive breastfeeding duration. DESIGN: online, retrospective questionnaire. SETTING: the questionnaire was placed online and participants accessed it through social networking sites including groups relating to breastfeeding, motherhood and parenting. Participants were also able to share the link with their own networks. This online setting facilitated recruitment of a wide range of Australian and international participants. PARTICIPANTS: 174 women aged 18 years and older who had given birth between six months to two years prior. Participants completed an online questionnaire, which asked them to report on three time points: pre pregnancy, during pregnancy and during the first six months postpartum. Data were collected from June to December 2011. MEASUREMENTS: psychometrically validated tools such as the breastfeeding Self-Efficacy Scale, Body Attitude Questionnaire, Depression Anxiety and Stress Scale, Fetal Health Locus of Control Scale, and the brief COPE scale were used to measure psychosocial variables. Additional scales were developed by the researchers and met scale reliability criteria. FINDINGS: correlation analyses, t-tests and path analysis were used to statistically analyse the data. Results showed that women who exclusively breast fed to six months postpartum exhibited higher intention to exclusively breastfeed, breastfeeding self-efficacy, comfort breastfeeding in public, perceived physical strength and reported less perceived breastfeeding difficulties. Path analyses indicated that breastfeeding self-efficacy was a strong significant predictor of both exclusive breastfeeding intention and duration. Maternal attitude towards pregnancy (both during pregnancy and postpartum), psychological adjustment and early breastfeeding difficulties were also found to be significant predictors of exclusive breastfeeding intention and duration. KEY CONCLUSIONS: psychosocial factors are likely to play a significant role in the maintenance of exclusive breastfeeding for six months post-birth. Future research should adopt a prospective study design to examine the influence of psychosocial factors systematically and rigorously. IMPLICATIONS FOR PRACTICE: longitudinal, prospective studies are needed to further examine the role of psychosocial factors on exclusive breastfeeding outcomes. Interventions, which involve improving psychosocial factors such as breastfeeding self-efficacy, may improve exclusive breastfeeding outcomes. PMID- 23932037 TI - Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. AB - BACKGROUND: The main challenge for warfarin anticoagulation is the risk for hemorrhagic complications. Although certain pharmacogenetic factors may explain the individual variabilities about the therapeutic warfarin dose requirement, the genetic factors to warfarin hemorrhagic complications due to over-anticoagulation are largely unknown. To interpret the potential role of warfarin-related genotypes on over-anticoagulation and hemorrhagic complications, we conducted a meta-analysis based on 22 published studies. METHODS: A comprehensive search was applied to the reports on over-anticoagulation and hemorrhagic complications published prior to December 31, 2012 in PubMed and EMBASE. References were identified by strict inclusion and exclusion criteria, with additional information obtained by consulting with the authors of primary studies. The roles of genotypes in CYP2C9 and VKORC1 on over-anticoagulation (INR > 4) and hemorrhagic complications were analyzed by Revman 5.0.2 software. RESULTS: A total of 6272 patients in 22 reports were included in the meta-analysis, including studies of 18 from Caucasians (3 from both Caucasian and African American), 3 from Asians, and 1 from Brazilians. Compared to CYP2C9 wild genotype (CYP2C9*1), both CYP2C9*2 (rs 1799853, c. 430 C > T, p. Arg144Cys) and *3 (rs 1057910, c. 1075 A >C, p. Ile359Leu) confer significantly higher risk for warfarin over-anticoagulation and hemorrhagic complications. After stratification by CYP2C9 allele status, significantly higher risk for hemorrhagic complications was found only in carriers of at least 1 copy of CYP2C9*3 [For total hemorrhages: *1/*3 HR: 2.05 (1.36-3.10), p < 0.001; *3/*3 HR: 4.87 (1.38-17.14), p = 0.01; For major hemorrhages: *1/*3 HR: 2.43 (1.17-5.06), p = 0.02; *3/*3 HR: 4.81 (0.95 24.22), p = 0.06]. Furthermore, similar susceptibility of total hemorrhage by CYP2C9 genotypes was observed in Caucasians and Asians. After stratification by the occurrence time, both CYP2C9*2 and *3 are risk factors for over anticoagulation within 30 days of warfarin treatment [*2 HR: 1.64 (1.11-2.43), p = 0.01; *3 HR: 2.48 (1.56-3.96), p < 0.001], and only CYP2C9*3 showed higher risk for over-anticoagulation after 30 days [HR: 1.86 (1.08-3.20), P = 0.03]. For VKORC1 c. -1639G > A (rs 9923231) genotypes, GA and AA contributed significantly higher risk for over-anticoagulation within 30 days [HR: 2.14 (1.75-2.62), p < 0.001], but not for over-anticoagulation after 30 days [HR:0.78 (0.46-1.33), p = 0.36]. No significant association was found between VKORC1 genotypes and hemorrhagic complications. CONCLUSIONS: Both CYP2C9 and VKORC1 genotypes are associated with an increased risk for warfarin over-anticoagulation, with VKORC1 c. -1639G > A more sensitive early in the course of anticoagulation. CYP2C9*3 is the main genetic risk factor for warfarin hemorrhagic complications. PMID- 23932038 TI - 'Stoned' people can get stunned myocardium: a case of heroin withdrawal precipitating Tako-Tsubo cardiomyopathy. PMID- 23932039 TI - Impact of baseline prehypertension on cardiovascular events and all-cause mortality in the general population: a meta-analysis of prospective cohort studies. PMID- 23932040 TI - Various morphological types of fragmented ventricular premature beats on 12 lead Holter ECG had positive relationship with LV fibrotic volume on CMR in HCM subjects. PMID- 23932041 TI - Pressure reflection in the pulmonary circulation by echocardiography in patients with left heart disease indicates reactive pulmonary hypertension. AB - OBJECTIVES: The two hemodynamic profiles in left heart disease (LHD) with pulmonary hypertension (PH), passive PH with increased pulmonary venous pressure and reactive PH with increased pulmonary vascular resistance (PVR > 3 Wood units, WU), are difficult to distinguish non-invasively. We hypothesized that echocardiographic signs of pressure reflection (PR) in the pulmonary circulation can be used to diagnose reactive PH. MATERIAL AND METHODS: The study comprised 122 patients divided into three groups: patients without PH (No PH, n = 61), patients with LHD, PH and normal PVR (passive PH, n = 29) and patients with LHD, PH and increased PVR (reactive PH, n = 32). Echocardiography and right heart catheterization were performed within 24 h. Three parameters were selected related to PR [the acceleration of flow in the right ventricular outflow tract (RVOT), the interval and the augmentation of pressure between peak RVOT flow and peak RV pressure]. Cutoff values aiming at ruling in (high positive likelihood ratio, PLR) and ruling out (low negative likelihood ratio, NLR) increased PVR were determined using receiver operator characteristic (ROC) curves. RESULTS: The proportions of the patients with PH and PVR > 3 WU were 50% and 29%. Twenty-one percent had both increased pulmonary capillary wedge pressure and PVR. The area under the ROC curve for the PR parameters was 0.82-0.89. The PLR with ruling in cutoff values ranged from 4.7 to 9.4. The NLR with ruling out cutoff values ranged from 0.20 to 0.12. CONCLUSIONS: Echocardiographic assessment of PR in patients with LHD can be used to identify or exclude reactive PH. PMID- 23932042 TI - Clinical variants in Ebstein's anomaly. PMID- 23932043 TI - The fate of large-diameter Dacron(r) vascular grafts in surgical practice: are we really satisfied? PMID- 23932044 TI - Prevalence of undiagnosed asymptomatic aortic valve stenosis in the general population older than 65 years. A screening strategy using cardiac auscultation followed by Doppler-echocardiography. PMID- 23932045 TI - Detection and quantification of acute reperfused myocardial infarction in rabbits using DISA-SPECT/CT and 3.0T cardiac MRI. AB - BACKGROUND: Necrosis avid tracer (123)I-hypericin ((123)I-HYP) enables hot-spot imaging on acute myocardial infarction (MI). We explored dual-isotope simultaneous acquisition single photon emission computed tomography/computed tomography (DISA-SPECT/CT) by using (123)I-HYP and standard (99m)Tc-sestamibi ((99m)Tc-MIBI), in comparison with cardiac magnetic resonance imaging (cMRI), autoradiography (AutoRx) and histomorphometry. METHODS: Acute MI was induced by 90-min coronary artery occlusion and 24-h reperfusion in 9 rabbits. They were scanned with cMRI at 3.0T, followed by intravenous injections of (123)I-HYP, and 8h later, of (99m)Tc-MIBI. Then, they were imaged with DISA-SPECT/CT for detection and localization of MI. The excised heart was sectioned for AutoRx, triphenyltetrazolium chloride (TTC) histochemistry, and haematoxylin-eosin (HE) staining. DISA-SPECT/CT and cMRI were co-registered, and MI was compared between different modalities and techniques for correlation with ex vivo findings. Tracer/contrast uptakes were quantified on polar maps. One way-ANOVA and Bonferroni's tests were used for comparison of multiple techniques. Linear regression and Bland-Altman analysis were used to compare measurements of MI. RESULTS: MI volumes were not significantly different as by (99m)Tc-MIBI-SPECT, (123)I-HYP-SPECT, cMRI and TTC (38.94 +/- 13.97%, 37.76 +/- 13.16%, 35.19 +/- 12.53% and 33.26 +/- 10.65%; p > 0.05). The MI areas were 41.13 +/- 18.70%, 40.19 +/- 18.45%, 38.23 +/- 16.86%, 36.83 +/- 16.70%, 36.16 +/- 16.15% and 35.03 +/- 14.75% on (99m)Tc-MIBI-SPECT, (123)I-HYP-SPECT, cMRI, AutoRx, TTC and HE. There was no significant differences between each of two techniques (p = 0.9). Tracer/contrast uptakes were well correlated ((123)I-HYP vs (99m)Tc-MIBI r(2) = 0.66; (123)I-HYP vs cMRI r(2) = 0.63; (99m)Tc-MIBI vs cMRI r(2) = 0.64). Infarct/normal myocardium activity ratio was 40/1 and 23/1 by AutoRx and gamma counting. CONCLUSION: (123)I-HYP has shown pronounced necrosis-avidity, which proves complementary for imaging MI with potential clinical applicability for myocardial viability determination. PMID- 23932046 TI - An overview of the crosstalk between inflammatory processes and metabolic dysregulation during diabetic cardiomyopathy. AB - Metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus are all linked to cardiovascular diseases such as cardiac hypertrophy and heart failure. Diabetic cardiomyopathy in particular, is characterized by structural and functional alterations in the heart muscle of people with diabetes that finally lead to heart failure, and which is not directly attributable to coronary artery disease or hypertension. Several mechanisms have been involved in the pathogenesis of diabetic cardiomyopathy, such as alterations in myocardial energy metabolism and calcium signaling. Metabolic disturbances during diabetic cardiomyopathy are characterized by increased lipid oxidation, intramyocardial triglyceride accumulation, and reduced glucose utilization. Overall changes result in enhanced oxidative stress, mitochondrial dysfunction and apoptosis of the cardiomyocytes. On the other hand, the progression of heart failure and cardiac hypertrophy usually entails a local rise in cytokines in cardiac cells and the activation of the proinflammatory transcription factor nuclear factor (NF)-kappaB. Interestingly, increasing evidences are arising in the recent years that point to a potential link between chronic low-grade inflammation in the heart and metabolic dysregulation. Therefore, in this review we summarize recent new insights into the crosstalk between inflammatory processes and metabolic dysregulation in the failing heart during diabetes, paying special attention to the role of NF-kappaB and peroxisome proliferator activated receptors (PPARs). In addition, we briefly describe the role of the AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1) and other pathways regulating cardiac energy metabolism, as well as their relationship with diabetic cardiomyopathy. PMID- 23932047 TI - In-hospital results of transcatheter aortic valve implantation (TAVI) in a district hospital--an approach to treat TAVI patients in rural areas. PMID- 23932048 TI - Circulating concentrations of fibroblast activation protein alpha in apparently healthy individuals and patients with acute coronary syndrome as assessed by sandwich ELISA. AB - BACKGROUND: Fibroblast activation protein alpha (FAP) is a membrane glycoprotein with dipeptidyl-peptidase and collagenase activity and is expressed in cancer, arthritis, and atherosclerotic plaques. We hypothesized that FAP can be measured quantitatively in the circulation and provide prognostic information in acute coronary syndrome (ACS). METHODS: We assessed the performance of a commercially available FAP ELISA and the pre-analytic characteristics of the marker. We determined FAP concentrations in EDTA plasma samples from 101 apparently healthy blood donors and 407 patients with ACS. Patients were followed for 12 months regarding all-cause mortality and non-fatal myocardial infarction (MI). RESULTS: FAP was stable at room temperature (for 1 day) and 4 degrees C (3 days) and resistant to 3 freeze/thaw cycles. Recovery of recombinant human FAP ranged from 78 to 103% and serial dilutions of spiked samples resulted in measurements within 91 to 120% of expected values. Patients with ACS had lower plasma FAP concentrations compared with blood donors [median (25th-75th percentiles): 84 (69 101) ng/mL vs. 108 (87-124) ng/mL, P < 0.001]. Patients presenting with FAP concentrations in the first quartile had a 3.0-fold higher risk of death (95% confidence interval 1.4-6.2) compared with patients in the second to fourth quartiles (P = 0.004). FAP concentration was not related to the risk of MI. CONCLUSIONS: Our study is the first to associate FAP with prognosis in ACS. The favorable pre-analytic characteristics of FAP will facilitate future studies of the marker in other disease settings associated with altered FAP expression. PMID- 23932049 TI - Semaphoring 3A: an association between traumatic brain injury and enhanced osteogenesis. AB - An accelerated speed of fracture-healing in patients with traumatic brain injury (TBI) is often encountered in clinical practice. However the mechanisms responsible for this phenomenon are remain unclear. After TBI, many cytokines have been reported change their expressions, suggest that the phenomenon of accelerated speed of fracture-healing may be associated with these cytokines. Semaphorin 3A is a secreted cytokine regulated by neural injury, and it is known to guide axon/dendrite growth and neuronal migration. Recent studies suggest that Semaphorin 3A is so far the only molecule that can regulate bone resorption and formation synchronously. However, a Semaphoring 3A which could perhaps induce enhanced osteogenesis under TBI condition has not yet been identified. Therefore, we presume that Semaphoring 3A may play a key role in accelerated fracture healing under TBI condition, and these will make Sema3A as a promising potential therapeutic target for facilitating fracture healing. PMID- 23932050 TI - Embryogenesis, morphogens and cancer stem cells: putting the puzzle together. AB - This paper describes a model which puts together three key elements of cancer theory: the analogies between embryogenesis and carcinogenesis, the role played in both processes by morphogens and related pathways, and the recently emerged paradigm of cancer stem cells. The model is called Epigenetic Tracking. Originally conceived as a model of embryonic development, it was later extended to interpret other aspects of biology, such as the presence of junk DNA, the phenomenon of ageing and the process of cancer formation. In this work we deepen our vision of carcinogenesis, and propose a novel hypothesis on the role of morphogen-processing pathways. According to the hypothesis, the interplay of these pathways leads in stem cells to the production of new transcription factors, which act as drivers of cellular differentiation. The disruption of these pathways, caused by mutations in specific genes, would represent the first and most distinctive event in the carcinogenic process. Our hypothesis allows us to make testable predictions on patterns of gene mutations involved in carcinogenesis. Our hypothesis also suggests that cancer stem cells can stay dormant until they are activated in a process that resembles activation of stem cells during tissue repair or at a specific time during development. PMID- 23932051 TI - Glycyrrhizic acid confers neuroprotection after subarachnoid hemorrhage via inhibition of high mobility group box-1 protein: a hypothesis for novel therapy of subarachnoid hemorrhage. AB - Subarachnoid hemorrhage usually results in poor clinical outcome and devastating neurological deficits. The early brain injury and delayed vasospasm after subarachnoid hemorrhage (SAH) are involved in the poor prognosis to the patients, while the mechanisms have not been well elucidated. Previous studies found an up regulation of Toll-like receptor 4 (TLR4), inflammatory factors and high-mobility group box 1 (HMGB1) in the cortex after SAH. Increased inflammatory response contributes to the early brain injury and delayed vasospasm after SAH. Moreover, we found that the inflammatory response could be induced and amplified following recombinant HMGB1 (rHMGB1) addition in cultured neurons. Based on the latest researches in this field, we raised a hypothesis that HMGB1, a prototypical member of damage-associated molecular pattern (DAMP) family, could be passively released from the damaged neuroglia cells and hemotocyte lysis after SAH. Extracellular HMGB1 initiated the inflammation through its receptors. The inflammatory mediators then acted on the neurocytes to make them actively release HMGB1 continuously, manifesting an double phases. HMGB1 might be the key factor to induce sterile inflammation, and thus be one of the origin of early brain injury and delayed vasospasm after SAH. Inhibition of extracellular HMGB1 activities might be a novel therapeutic target for SAH to reduce the damaging inflammatory response. Glycyrrhizic acid (GA) which was extracted from liquorice and confirmed as a nature inhibitor of HMGB1 with little side-effects could inhibit extracellular HMGB1 cytokine activities and reduce the level of inflammatory response, thus alleviating early brain injury and cerebrovasospasm. GA might be a new novel therapy of SAH for better outcomes. PMID- 23932052 TI - Compliance and efficacy of saline irrigation in pediatric chronic rhinosinusitis. AB - OBJECTIVE: The objective of this study was to evaluate compliance with and effectiveness of nasal irrigation in children with chronic rhinosinusitis (CRS) and to assess its clinical course. METHODS: Seventy-seven children with refractory CRS resistant to medical treatment including antibiotics and nasal corticosteroids were included. We evaluated patients' nasal symptom and Lund Mackay CT scores at baseline. All patients were educated about nasal irrigation and encouraged to perform nasal irrigation 1-3 times a day. After 1 month, patients were reevaluated regarding compliance with the protocol and improvement of CRS by assessing symptom score and endoscopic evaluation. The patients were followed up for at least two months to assess need for further treatment including surgery. RESULTS: Mean age of patients was 8.3 years ranging from 4 to 13 years. Mean follow-up duration with nasal saline irrigation was 6.2 months (2 32 months). Forty nine patients (63.6%) successfully carried out nasal irrigation during follow-up (good compliance [GC] group) and 28 patients (36.4%) did not successfully carry out nasal irrigation (poor compliance [PC] group). There were no significant differences between GC and PC groups regarding clinical characteristics and baseline Lund-MacKay CT scores. Subjective and objective improvements were observed in 36 patients (73.5%) in the GC group and 14 patients (50.0%) in the PC group. Surgery including endoscopic sinus surgery and/or adenoidectomy was performed in 8 patients (16.3%) in the GC group and 12 patients (42.9%) in the PC group. The rate of surgical treatment was significantly different between the groups (p=0.019). CONCLUSION: Nasal irrigation in children with long standing CRS is relatively well tolerated (63.6%) and effective. Nasal saline irrigation should be considered as a primary treatment tool in CRS even in pediatric age group. PMID- 23932053 TI - Tuberculosis diagnostics: why we need more qualitative research. PMID- 23932054 TI - Risk analysis of needle stick and sharp object injuries among health care workers in a tertiary care hospital (Saudi Arabia). AB - OBJECTIVE: To study different risk factors associated with needle stick injury among health care workers of a tertiary care hospital in Saudi Arabia. SUBJECTS AND METHODOLOGY: Retrospective study involving all reported cases of needle stick and sharp object injury among health care workers through using EpinetTM access U.K. version 1.3 program in King Saud Medical City (KSMC) during the period (January 2007-December 2011). RESULTS: During the study period, 477 needle stick and sharp object injuries were reported with peak incidence (13.84%) during 2009. Distribution of needle stick and sharp object injuries according to the location of their occurrence clarified that patient room/ward was the most common place of occurrence of NSSIs 150/477, followed by emergency department 82/477, then the intensive and critical care units 70/477. The study presented that nurses were encountered as the most affected job category and use of items is the most common activity associated with the incidents. Most of the incidents were caused by needles with disposable needle and hands were the most affected body parts. CONCLUSION: Needle stick and sharp object injuries represent a major occupational challenge to health care workers. Prevention should be based on different working lines including immunization, education of health care workers and proper engineering control measures. PMID- 23932055 TI - Skin diseases in patients with primary psychiatric conditions: a hospital based study. AB - BACKGROUND: Although the relationship between skin diseases in patients with primary psychiatric conditions is important for patient management, studies on this issue are limited. OBJECTIVE: To detect the frequency and type of cutaneous disorders among patients with primary psychiatric conditions. SUBJECTS AND METHODS: This analytic cross-sectional study was conducted on a total of 400 subjects - 200 patients with primary psychiatric disorders and 200 age and sex matched individuals free from primary psychiatric disorders. Patients included in the study were diagnosed according to The Diagnostic and Statistical Manual of Mental Disorders (DMS IV) Criteria. A specially designed questionnaire including socio-demographic data, medical history, family history and dermatological examination was applied. The data were statistically analyzed. RESULTS: There was a significant statistical increase in the prevalence of skin diseases in general and infectious skin diseases in particular in psychiatric patients compared with non-psychiatric patients (71.5% versus 22%, P<0.001) and (48% versus 11%, P<0.001), respectively. Parasitic infestations (42.7%) were the most common infectious skin diseases in psychiatric patients (P<0.001). Infectious skin diseases in psychiatric patients were seen most in patients diagnosed with schizophrenia (83.6%) and least in obsessive compulsive disorders (30%)(P<0.001). Psychogenic skin disorders were found in 8.4% of psychiatric patients with skin diseases; delusional parasitosis was the most common (50%). CONCLUSION: Health education of psychiatric patients and/or of their caregiver and periodic monthly inspection of psychiatric patients are highly indicated for the prevention and control of infectious skin diseases in primary psychiatric patients. PMID- 23932056 TI - Socioeconomic inequity in health care utilization, Iran. AB - Reducing poor-rich inequities in health is one of the priorities of both national and international organizations and is also one of the main challenges of health sectors in Iran. Since, in the view of policy making, quantifying the size of inequity in health care utilization (HCU) is a prerequisite for achieving this goal, the current study aimed to determine and compare the socioeconomic inequity in HCU by concentration (C) index and odds ratio (OR). METHODS: A total of 758 households, consisting of 2,131 subjects who were aged 15 or older, were involved in this cross-sectional study, and their data were gathered through interviews. Household economic index (HEI) was created by the factor analysis from the asset data. The C index and OR were used as measures to determine the overall inequity in HCU according to sex (male/female), living area (urban/rural), insurance, and types of HCU (general physician [GP], specialist, and Health Workers [HWs]). RESULTS: The overall rate of HCU was 66.4%. The rates of using GP, specialist care, and HW care were 21.4%, 21.6% and 21.8%, respectively. The overall inequity in HCU was equal to 0.05 (95% confidence interval; -0.069 to 0.165). The C indexes in HCU, according to the subgroups of HCU, were measured as 0.11 (0.09 0.12) for GP, 0.115 (0.01-0.13) for specialist and -0.065 (-0.08 to -0.05) for HWs. Although the rate of utilization increased from poor to rich quintiles, the inequity regarding sex and living area was also low and non-significant. CONCLUSION: People with higher HEI used more specialist and GP care, while people with lower HEI used more HW care. The inequity in HCU was low and non-significant in different quintiles of males, females, urban and rural, as well as those who were insured. PMID- 23932058 TI - Bayesian lead time estimation for the Johns Hopkins Lung Project data. AB - PROBLEM STATEMENT: Lung cancer screening using X-rays has been controversial for many years. A major concern is whether lung cancer screening really brings any survival benefits, which depends on effective treatment after early detection. The problem was analyzed from a different point of view and estimates were presented of the projected lead time for participants in a lung cancer screening program using the Johns Hopkins Lung Project (JHLP) data. METHOD: The newly developed method of lead time estimation was applied where the lifetime T was treated as a random variable rather than a fixed value, resulting in the number of future screenings for a given individual is a random variable. Using the actuarial life table available from the United States Social Security Administration, the lifetime distribution was first obtained, then the lead time distribution was projected using the JHLP data. RESULTS: The data analysis with the JHLP data shows that, for a male heavy smoker with initial screening ages at 50, 60, and 70, the probability of no-early-detection with semiannual screens will be 32.16%, 32.45%, and 33.17%, respectively; while the mean lead time is 1.36, 1.33 and 1.23 years. The probability of no-early-detection increases monotonically when the screening interval increases, and it increases slightly as the initial age increases for the same screening interval. The mean lead time and its standard error decrease when the screening interval increases for all age groups, and both decrease when initial age increases with the same screening interval. CONCLUSION: The overall mean lead time estimated with a random lifetime T is slightly less than that with a fixed value of T. This result is hoped to be of benefit to improve current screening programs. PMID- 23932057 TI - Prevalence of modifiable cardiovascular risk factors among tea garden and general population in Dibrugarh, Assam, India. AB - INTRODUCTION: Risk factors for cardiovascular disease (CVD) are multifactorial. Previous research has reported a high prevalence of CVD risk factors in tea garden workers. This study was conducted to assess prevalence and level of modifiable cardiovascular risk factors among tea-garden and general population in Dibrugarh, Assam. METHODS: A community-based cross-sectional study using the World Health Organization's (WHO) Stepwise methodology was conducted in Dibrugarh District of Assam. A multistep random sampling was done to include adults aged 35 years and above, with an intended equal sampling from tea-garden and general population. INTERHEART modifiable non-laboratory based risk score was estimated. Salt consumption was estimated using questionnaire-based methods in both subgroups. RESULTS: A total of 2826 individuals participated in the study (1231 [43.6%] tea-garden workers; 1595 [56.4%] general population). Tobacco consumption was higher in tea-garden workers as compared with general population (85.2% vs. 41.7% (p < 0.0001). Mean daily per-capita salt consumption was also significantly higher among tea-garden workers (29.60 vs. 22.89 g, p = 0.0001). Overall prevalence of hypertension was similar (44.4% vs. 45.2%), but among those who had hypertension, prevalence of undiagnosed hypertension was higher in tea-garden workers (82.8% vs. 74.4%, p < 0.0001). Tea-garden workers had lower BMI, were more physically active, and had a lower prevalence of diabetes mellitus and metabolic syndrome. Their INTERHEART modifiable risk score was also lower (1.44 [2.5] vs. 1.79 [2.8], p = 0.001). CONCLUSION: High prevalence of modifiable risk factors like tobacco consumption, high salt intake and high prevalence of hypertension indicates the need for early implementation of preventive actions in this population. PMID- 23932059 TI - Prevalence and characteristics of community carriage of methicillin-resistant Staphylococcus aureus in Malta. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen worldwide. Malta is one of the countries with the highest MRSA prevalence in Europe, as identified from hospital blood cultures [1]. However, community prevalence of MRSA has never previously been investigated. This study aimed at establishing the prevalence of community MRSA nasal colonization in Maltese individuals and identifying the clonal characteristics of the detected isolates. Nasal swabs were collected from 329 healthy individuals who were also asked to complete a brief questionnaire about risk factors commonly associated with MRSA carriage and infection. The swabs were transported and enriched in a nutrient broth supplemented with NaCl. The presence of MRSA was then determined by culturing on MRSA Select chromogenic agar and then confirming by several assays, including catalase, coagulase and PBP2a agglutination tests. The isolates were assayed for antibiotic susceptibilities and typed by microarray analysis to determine the clonal characteristics of each strain. The prevalence of MRSA nasal colonization in the healthy Maltese population was found to be 8.81% (95% confidence interval [CI], 5.75-11.87%), much higher than that found in other studies carried out in several countries. No statistical association was found between MRSA carriage and demographics or risk factors; however, this was hindered by the small sample size. Almost all the isolates were fusidic-acid resistant. The majority were found to belong to a local endemic clone (CC5) which seems to be replacing the previously prevalent European clone UK-EMRSA-15 in the country. A new clone (CC50-MRSA-V) was also characterized. The presence of such a significant community reservoir of MRSA increases the burdens already faced by the local healthcare system to control the MRSA epidemic. Colonization of MRSA in otherwise healthy individuals may represent a risk for endogenous infection and transmission to hospitalized patients after admission to a healthcare facility, leading to longer hospital stays and, consequently, increased healthcare costs. PMID- 23932060 TI - Impact of the Family Health Program on gastroenteritis in children in Bahia, Northeast Brazil: an analysis of primary care-sensitive conditions. AB - In seeking to provide universal health care through its primary care-oriented Family Health Program, Brazil has attempted to reduce hospitalization rates for preventable illnesses such as childhood gastroenteritis. We measured rates of Primary Care-sensitive Hospitalizations and evaluated the impact of the Family Health Program on pediatric gastroenteritis trends in high-poverty Northeast Brazil. We analyzed aggregated municipal-level data in time-series between years 1999-2007 from the Brazilian health system payer database and performed qualitative, in-depth key informant interviews with public health experts in municipalities in Bahia. Data were sampled for Bahia's Salvador microregion, a population of approximately 14 million. Gastroenteritis hospitalization rates among children aged less than 5 years were evaluated. Declining hospitalization rates were associated with increasing coverage by the PSF (P = 0.02). After multivariate adjustment for garbage collection, sanitation, and water supply, evidence of this association was no longer significant (P = 0.28). Qualitative analysis confirmed these findings with a framework of health determinants, proximal causes, and health system effects. The PSF, with other public health efforts, was associated with decreasing gastroenteritis hospitalizations in children. Incentives for providers and more patient-centered health delivery may contribute to strengthening the PSF's role in improving primary health care outcomes in Brazil. PMID- 23932061 TI - Predicting date of birth and examining the best time to date a pregnancy. AB - OBJECTIVE: To compare the estimated date of birth (eDOB) from the last menstrual period (LMP) and ultrasound scans at varying gestations (<7(0), 7(0)-10(6), 11(0) 14(0), 14(1)-19(6), and 20(0)-27(6)weeks) with the actual date of birth (aDOB). METHODS: In a retrospective study, data were analyzed from 18 708 women with spontaneous labor who delivered a single neonate without major anomalies in a local health district in Australia between 2007 and 2011. Data were sourced from a computerized population birth database. The study outcomes were duration of pregnancy expressed as total days, and the difference between aDOB and eDOB by dating method. RESULTS: Only 5% of births occurred on the eDOB, regardless of the dating method or timing of the dating. Approximately 66% of births occurred within 7days of the eDOB, and there was little difference among the ultrasound examinations performed at varying gestational weeks. The ultrasound scans at 11(0)-14(0)weeks of gestation performed as well as ultrasound scans conducted at other gestational ages. CONCLUSION: On a population basis, there were no meaningful differences in the prediction of date of birth by ultrasound scan date. An early dating scan (<=10weeks) is unnecessary if LMP is reliable. PMID- 23932062 TI - Human rights to in vitro fertilization. AB - The Inter-American Court of Human Rights (the Court) has ruled that the Supreme Court of Costa Rica's judgment in 2000 prohibiting in vitro fertilization (IVF) violated the human right to private and family life, the human right to found and raise a family, and the human right to non-discrimination on grounds of disability, financial means, or gender. The Court's conclusions of violations contrary to the American Convention on Human Rights followed from its ruling that, under the Convention, in vitro embryos are not "persons" and do not possess a right to life. Accordingly, the prohibition of IVF to protect embryos constituted a disproportionate and unjustifiable denial of infertile individuals' human rights. The Court distinguished fertilization from conception, since conception-unlike fertilization-depends on an embryo's implantation in a woman's body. Under human rights law, legal protection of an embryo "from conception" is inapplicable between its creation by fertilization and completion of its implantation in utero. PMID- 23932063 TI - The LRRK2 G2019S mutation status does not affect the outcome of subthalamic stimulation in patients with Parkinson's disease. AB - BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapy for advanced Parkinson's disease (PD). The most common genetic mutation associated with PD identified to date is the G2019S mutation of the LRRK2 gene, which is highly prevalent in the Ashkenazi Jewish population. The effect of STN-DBS surgery in patients carrying this mutation has not been systematically studied. We therefore performed a case-control study to evaluate the impact of the G2019S mutation status on the outcomes of bilateral STN-DBS. METHODS: The study sample included 39 Jewish PD patients with bilateral STN-DBS. Thirteen patients (5 females) were G2019S mutation heterozygous. The control group consisted of 26 PD patients with bilateral STN-DBS, negative for the mutation, matched (2:1) for gender, age at PD onset, and disease duration at surgery. Clinical data including the Unified PD Rating Scale scores (UPDRS), levodopa equivalent daily dose (LEDD), and clinical global impression of change (CGIC) concerning both motor and neuropsychiatric outcome- were available at 3 time points (preoperative baseline, 6-12 months and 3 years postoperatively). RESULTS: Implementing a linear mixed model, a significant improvement (p < 0.05) was found for the whole group concerning reduction in motor UPRDS (off state) and LEDD pre- vs. postoperatively, as expected. No difference in clinical outcome was found between carriers and matched non-carriers at baseline or at postoperative follow-up (up to 3 years). CONCLUSIONS: In our study, STN-DBS outcomes were not influenced by the LRRK2 G2019S mutation, and thus knowledge of carrier status may not be relevant to the considerations of patient selection for surgery. PMID- 23932064 TI - Early cortical gray matter loss and cognitive correlates in non-demented Parkinson's patients. AB - BACKGROUND: Whereas the motor dysfunction in Parkinson's disease (PD) has been related to deficits in basal ganglia (BG) structures, neural correlates of cognitive changes remain to be fully defined. This study tested the hypothesis that cognitive changes in non-demented PD may be related to cortical gray matter (GM) loss. METHODS: High-resolution T1-weighted magnetic resonance images of the brain and comprehensive cognitive function tests were acquired in 40 right handed, non-demented PD subjects and 40 matched controls. GM changes were assessed using voxel-based morphometry (VBM) in FSL. VBM and cognitive results were compared between PD and controls, and correlation analyses were performed between those brain areas and cognitive domains that showed significant group differences. RESULTS: PD patients demonstrated significant GM reduction localized predominantly in frontal and parieto-occipital regions. Patients also showed reduced performance in fine motor speed and set-shifting compared to controls. Fine motor speed and set-shifting were associated with GM volume in the frontal cortex in controls, whereas these domains were associated primarily with occipital GM regions in PD patients. CONCLUSIONS: Non-demented PD subjects demonstrate cortical structural changes in frontal and parieto-occipital regions compared to controls. The association between typically recognized "frontal lobe" function and occipital lobe volume suggested a compensatory role of occipital lobe to primary fronto-striatal pathology in PD. Further longitudinal study of these changing structure-function relationships is needed to understand the neural bases of symptom progression in PD. PMID- 23932065 TI - Cerebrospinal fluid and plasma clusterin levels in Parkinson's disease. AB - Clusterin is a multifunctional chaperone protein that has repeatedly been linked to Alzheimer's disease (AD) pathogenesis and, more recently, also to Parkinson's disease (PD) by both genetic and proteomic analyses. Although clusterin is detectable in cerebrospinal fluid (CSF) and plasma, studies comparing clusterin levels in PD patients and controls have been scarce and yielded conflicting data. The aim of the present study was to determine whether CSF and/or plasma clusterin levels differ between PD patients and controls and are related to disease severity. We measured CSF and plasma clusterin levels in a group of 52 PD patients and in 50 age-matched neurologically healthy controls and found that clusterin levels in CSF and plasma were not different between the two groups. Furthermore, clusterin levels in CSF and plasma were not associated with disease duration, stage or severity. CSF clusterin levels did, however, correlate with CSF levels of total tau, phospho-tau and amyloid-beta-42. We elaborate on the identified correlations between levels of clusterin and AD related proteins and on possible explanations for the discrepant findings in clusterin studies in PD so far. PMID- 23932066 TI - The efficacy and safety of ropinirole prolonged release tablets as adjunctive therapy in Chinese subjects with advanced Parkinson's disease: a multicenter, double-blind, randomized, placebo-controlled study. AB - AIM: The first evaluation of the efficacy and safety of ropinirole prolonged release (PR) as an adjunct to L-dopa in Chinese patients with advanced Parkinson's disease (PD) not optimally controlled with L-dopa. METHODS: In a 24 week, double-blind, placebo-controlled, parallel-group study, subjects with advanced PD were randomized 1:1 to ropinirole PR (N = 175) or placebo (N = 170) as add-on therapy to L-dopa. Primary outcome measure was change from baseline in awake time spent "off". Starting dose of ropinirole PR was 2 mg/day, titrated based on clinical response (maximum 24 mg/day). RESULTS: At week 24, the mean dose of ropinirole PR was 11.4 mg/day with a mean reduction of L-dopa from 506.6 to 411.6 mg/day. Subjects receiving ropinirole PR experienced a significant reduction of "off" time (2.1 h) compared with placebo (0.4 h). Secondary outcome measures including hours of "on" time without troublesome dyskinesis were significantly increased in the ropinirole PR group (1.7 h) compared with placebo (0.3 h). Subjects classified as responders were significantly more frequent in the ropinirole PR (22.8%) than placebo group (2.5%). Efficacy outcomes including Unified Parkinson's disease Rating Scale and PDQ-39 subscales of mobility were significantly improved in the ropinirole PR versus placebo group. The most frequent adverse event experienced in the ropinirole PR group was dyskinesia. CONCLUSIONS: This study demonstrated for the first time in Chinese subjects that ropinirole PR improved Parkinson's disease symptoms, permitting a reduction in L dopa dose. The adverse events observed were consistent with the established safety profile of ropinirole, with no new safety signal identified. PMID- 23932067 TI - Longitudinal study to evaluate the association between thermal environment and Salmonella shedding in a midwestern US swine farm. AB - The objective of this study was to document the association between the thermal environment in the barn and Salmonella shedding in finishing pigs. For this purpose, individual fecal samples from 900 finishing pigs (8 collections per pig) were repeatedly collected from 18 cohorts (50 pigs per cohort) on 3 sites of a multi-site farrow-to-finish production system in a longitudinal study. Pen temperature and humidity were measured every 2 min during the study period. The thermal parameters of interest were: hourly average temperature, minimum and maximum temperature, hourly temperature variation, temperature humidity index (THI) and cumulative number of hours/degree above and below the thermal neutral zone at the pen level prior to fecal sampling for 6 time periods (12h, 24h, 48 h, 72 h, 1 week and 1 month). Additional potential risk factors at the individual (e.g., sex, health events), cohort (e.g., mortality, morbidity, Salmonella status of the nursery) and pen level (e.g., type of pen) were also evaluated. Multilevel logistic models using generalized linear models, with random intercepts at pig, pen and cohort levels to account for clustering (individual samples nested within pigs, pigs nested within pens, pens within cohorts) were constructed. Site (A, B, C) was considered as a fixed effect in order to control for clustering within site. The outcome variable was Salmonella fecal status of the individual sample. Cold exposure (temperatures below the thermal neutral zone) and exposure to a THI>72 were both positively associated with risk Salmonella shedding. Nursery Salmonella status was positively associated with Salmonella shedding and pig age was negatively associated with Salmonella shedding. In the multilevel intercept only model the largest proportion of model variance was associated with the individual fecal sample (44.8%) followed by cohort (24.5%), pen (20.5%) and pig (10.2%). The present study allowed the investigation of the association of time variant thermal factors and Salmonella shedding. Interventions that target the thermal environment may have an effect on reducing Salmonella shedding in swine and also improve pig well-being and production efficiency. Alternatively, thermal parameters may be used to identify groups of pigs at high risk for Salmonella shedding. Future studies should be performed to investigate the cost-efficacy of interventions to improve the thermal environment of swine. PMID- 23932068 TI - Sexual health and socioeconomic-related factors in Spain. AB - PURPOSE: The aim of the present study was to describe sexual health in Spain according to three important indicators of the World Health Organization definition and explore the influence of socioeconomic factors. METHODS: We performed a population-based cross-sectional study of sexually active people aged 16-44 years residing in Spain in 2009 (2365 women and 2532 men). Three main aspects of sexual health were explored: sexual satisfaction, safe sex, and sexual abuse. The independent variables explored were age, age at first intercourse, reason for first intercourse, type of partner, level of education, country of origin, religiousness, parity, and social class. Bivariate and multivariate logistic regression models were fitted. RESULTS: Both men and women were quite satisfied with their sexual life, their first sexual intercourse, and their sexual relationships during the previous year. Most participants had practiced safe sex both at first intercourse and during the previous year. Levels of sexual abuse were similar to those in other developed countries. People of disadvantaged socioeconomic position have less satisfying, more unsafe, and more abusive sexual relationships. Women experienced more sexual abuse and had less satisfaction at their first intercourse. CONCLUSIONS: The state of sexual health in Spain is relatively good. However, we observed inequalities according to gender and socioeconomic position. PMID- 23932069 TI - How neurons make meaning: brain mechanisms for embodied and abstract-symbolic semantics. AB - How brain structures and neuronal circuits mechanistically underpin symbolic meaning has recently been elucidated by neuroimaging, neuropsychological, and neurocomputational research. Modality-specific 'embodied' mechanisms anchored in sensorimotor systems appear to be relevant, as are 'disembodied' mechanisms in multimodal areas. In this paper, four semantic mechanisms are proposed and spelt out at the level of neuronal circuits: referential semantics, which establishes links between symbols and the objects and actions they are used to speak about; combinatorial semantics, which enables the learning of symbolic meaning from context; emotional-affective semantics, which establishes links between signs and internal states of the body; and abstraction mechanisms for generalizing over a range of instances of semantic meaning. Referential, combinatorial, emotional affective, and abstract semantics are complementary mechanisms, each necessary for processing meaning in mind and brain. PMID- 23932070 TI - Medicinal attributes of pyrazolo[3,4-d]pyrimidines: a review. AB - Pyrazolopyrimidines are the fused heterocyclic ring systems which structurally resemble purines which prompted biological investigations to assess their potential therapeutic significance. They are known to play a crucial role in numerous disease conditions. The advent of their first bioactivity as adenosine antagonistic property divulged their medicinal potential. Radioactivity test on mice cells, morphometric and serological tests on rat hepatocytes, antitumor testing against L1210 and P388 leukemias in mice threw light on their biophysical aspects of significance. Biochemical properties were explored via xanthine oxidase assay, antioxidant enzyme assays, Western blot analysis, mRNA expression of apoptopic genes, receptor binding assays, and tryptan blue exclusion cytotoxicity evaluation. The collective results of biochemical and biophysical properties foregrounded their medicinal significance in central nervous system, cardiovascular system, cancer, inflammation etc. The present manuscript to the best of our knowledge is the first compilation on synthesis and medicinal aspects including structure-activity relationships of pyrazolo[3,4-d]pyrimidines reported to date. PMID- 23932071 TI - Exploration of N-(2-aminoethyl)piperidine-4-carboxamide as a potential scaffold for development of VEGFR-2, ERK-2 and Abl-1 multikinase inhibitor. AB - VEGFR, ERK and Abl had been respectively identified as good drug targets, and their crosstalk also had been well elaborated. Multitarget drugs were more advantageous for cancer treatment, however, no inhibitors simultaneously acting on the three proteins were developed due to their structural diversities. Herein, N-(4-((2-(2-(naphthaen-1-yl)acetamido)ethyl)carbamoyl)piperidin-4-yl)-6 (trifluoromethyl)nicotinamide (NEPT, 6a) was discovered as an active scaffold against VEGFR-2, ERK-2 and Abl-1 kinases through the combination of support vector machine, similarity searching and molecular docking. NEPT and its derivatives were synthesized by convenient routine, their in vitro anti proliferative abilities against human liver cancer cell line HepG2 were preliminarily evaluated. A representative compound 6b showed an IC50 value of 11.3 MUM and induced significant HepG2 cells apoptosis. Besides, these compounds displayed better anti-proliferative abilities against K562 cells (a cell line with typical hyperactivity of the above multikinases), for example compound 6b exhibited an IC50 value of 4.5 MUM. Based on hepatotoxicity case reports of Abl inhibitors, cytotoxicity of synthetic compounds against normal liver cell lines (QSG7701 and HL7702) was studied, 6b had a similar toxic effect with positive control imatinib, and most compounds showed less than 35% inhibition activities at 100 MUM. Molecular docking study disclosed interactions of 6b with VEGFR-2, ERK-2 and Abl-1 kinases, respectively. Our data suggested the biological activities of 6b may derived from collaborative effects of VEGFR-2, ERK-2 and Abl 1 inhibition. PMID- 23932073 TI - Simultaneous vs staged bilateral total knee arthroplasty among Medicare beneficiaries, 2000-2009. AB - Simultaneous bilateral total knee arthroplasty (TKA) reportedly has higher postoperative complication rates than staged procedures, but little is known about recent trends and outcomes among Medicare patients. In a 5% national sample of Medicare beneficiaries older than 65 years, we identified 83,441 patients who underwent elective TKA between 2000 and 2009 and compared patients undergoing simultaneous bilateral TKA (n=4519) to staged TKA (n=3788). Use of simultaneous TKA did not change over time (3 in 10,000), but use of staged TKA increased three fold from 1.4 to 4.4 in 10,000 person-years. We assessed length of stay; 5-year risk of revision; periprocedural (i.e., 90-day) risk of infection; hospitalization for venous thromboembolism (VTE) and myocardial infarction (MI); and death using Kaplan-Meier methods. Simultaneous TKA had higher 90-day risk of death (0.7% vs. 0.3%, P=0.02), VTE (0.9% vs. 0.5%, P=0.07), and MI (0.5% vs. 0.2%, P=0.02). Infection and revision rates were similar between the two groups. PMID- 23932074 TI - High-yield production of highly fluorinated graphene by direct heating fluorination of graphene-oxide. AB - By employing honeycomb GO with large surface area as the starting materials and using elemental fluorine, we developed a novel, straightforward topotactic route toward highly fluorinated graphene in really large quantities at low temperature. The value of F/C molar ratio approaches to 1.02. Few-layer fluorinated graphene sheets are obtained, among which the yield of monolayered FG sheet is about 10% and the number of layers is mainly in the range of 2-5. Variations in morphology and chemical structure of fluorinated graphene were explored, and some physical properties were reported. PMID- 23932072 TI - Histamine induces proliferation in keratinocytes from patients with atopic dermatitis through the histamine 4 receptor. AB - BACKGROUND: Epidermal hyperproliferation resulting in acanthosis is an important clinical observation in patients with atopic dermatitis, and its underlying mechanisms are not completely understood. OBJECTIVE: Because increased levels of histamine are present in lesional skin, we investigated the effect of histamine, especially with regard to histamine 4 receptor (H4R) activation, on the proliferation of human and murine keratinocytes. METHODS: The expression of H4R on human and murine keratinocytes was detected by using real-time PCR. Keratinocyte proliferation was evaluated by using different in vitro cell proliferation assays, scratch assays, and measurement of the epidermal thickness of murine skin. RESULTS: We detected H4R mRNA on foreskin keratinocytes and on outer root sheath keratinocytes; H4R mRNA was more abundant in keratinocytes from patients with atopic dermatitis compared with those from nonatopic donors. Stimulation of foreskin keratinocytes, atopic dermatitis outer root sheath keratinocytes, and H4R-transfected HaCaT cells with histamine and H4R agonist resulted in an increase in proliferation, which was blocked with the H4R-specific antagonist JNJ7777120. Abdominal epidermis of H4R-deficient mice was significantly thinner, and the in vitro proliferation of keratinocytes derived from H4R-deficient mice was lower compared with that seen in control mice. Interestingly, we only detected H4R expression on murine keratinocytes after stimulation with LPS and peptidoglycan. CONCLUSION: H4R is highly expressed on keratinocytes from patients with atopic dermatitis, and its stimulation induces keratinocyte proliferation. This might represent a mechanism that contributes to the epidermal hyperplasia observed in patients with atopic dermatitis. PMID- 23932075 TI - Fatal atypical O:3 Yersinia pseudotuberculosis infection in cynomolgus macaques. AB - Fatal Yersinia pseudotuberculosis infection in cynomolgus macaques was diagnosed based upon pathology, microbiology and PCR for this study. Pathological findings included acute, erosive to ulcerative, necrohemorrhagic enterocolitis. Genotyping by PCR showed an O:3 pattern (gmd-fcl(+), ddhC-prt(+), manB(+), ddhA-B(+)), but an additional gene, wbyK, was detected. This is the second report to identify wbyK+ O:3 genotype as the cause of fatal yersiniosis. The first case was reported in 2008, and involved farm deer in the U.S. As the frequency of wbyK+ O:3 genotype is found more often in different carriers, O:3 genotype is proposed to be divided into two subtypes: O:3a without wbyK and O:3b with wbyK. Virulence gene analysis showed the presence of inv, ypmC, irp1, ybtP-ybtQ, yadA, yopB, yopH, lcrF, and suggested that this O:3b isolate could be a highly pathogenic strain to cynomolgus macaques. PMID- 23932076 TI - Equine rotaviruses--current understanding and continuing challenges. AB - Equine rotaviruses were first detected in foals over 30 years ago and remain a major cause of infectious diarrhoea in foals. During this time, there has been substantial progress in the development of sensitive methods to detect rotaviruses in foals, enabling surveillance of the genotypes present in various horse populations. However, there has been limited epidemiological investigation into the significance of these circulating genotypes, their correlation with disease and the use of vaccination in these animal populations. Our knowledge of the pathogenesis of rotavirus infection in foals is based on a limited number of studies on a small number of foals and, therefore, most of our understanding in this area has been extrapolated from studies in other species. Questions such as the concentrations of rotavirus particles shed in the faeces of infected foals, both with and without diarrhoea, and factors determining the presence or absence of clinical disease remain to be investigated, as does the relative and absolute efficacy of currently available vaccines. The answer to these questions may help direct research into the development of more effective control measures. PMID- 23932077 TI - Animal and human Staphylococcus aureus associated clonal lineages and high rate of Staphylococcus pseudintermedius novel lineages in Spanish kennel dogs: predominance of S. aureus ST398. AB - Methicillin-susceptible Staphylococcus aureus (MSSA) and Staphylococcus pseudintermedius (MSSP) are gaining interest to track the evolution of emerging methicillin-resistant strains in animals and humans. We focused on the characterization of the methicillin-susceptible coagulase-positive staphylococci (MSCoPS) recovered from nasal samples of 98 healthy kennel-dogs. Isolates were typed by spa, agr, MLST and SmaI/ApaI-PFGE. Antimicrobial resistance and virulence profiles were investigated. Presence of the human-associated Immune Evasion-Cluster (IEC) genes was analyzed in MSSA. Twenty-four MSSA, 16 MSSP and one MS Staphylococcus schleiferi subspecies coagulans were obtained. Thirteen spa types and 12 sequence-types (STs) were detected among MSSA, with ST398 predominance (7/24, 29.2%). MSSA isolates were enclosed within 6 clonal complexes (no. of isolates): CC5 (8), CC398 (7), CC88 (4), CC45 (2), CC133 (1), and CC22 (1), and one singleton. High clonal diversity was observed among MSSP, and 14 STs (10 of them new) were detected. Twelve (50%) MSSA and 12 (75%) MSSP isolates showed resistance to at least one of the tested antimicrobials, with low MSSA penicillin resistance (5 isolates) and high MSSP tetracycline resistance (9 isolates). MSSA isolates ST398, ST133, ST1 and ST2329[new] were susceptible to all antimicrobials and were the only ones lacking the scn, chp and/or sak IEC genes. High diversity of enterotoxin genes was detected among non-ST398/ST133 MSSA isolates. MSSP showed a more homogeneous virulence genes profile. Our results give evidence that dogs can be S. aureus carriers of not only typical human associated lineages but also lineages commonly detected among other animal species. Continue surveillance on CoPS in dogs is required to unveil their role in the dissemination of clones adapted to other animal species. PMID- 23932078 TI - The effects of MucR on expression of type IV secretion system, quorum sensing system and stress responses in Brucella melitensis. AB - MucR is a transcriptional regulator in many bacterial pathogens and is required for virulence in mice and macrophages, resistance to stress responses, and modification of the cell envelope in Brucella spp. To determine why the mucR deleted mutant is attenuated in vivo and in vitro, we performed RNA-seq analysis using Brucella melitensis RNA obtained from B. melitensis 16M and 16MDeltamucR grown under the same conditions. We found 442 differentially expressed genes; 310 were over expressed, and 132 were less expressed in 16MDeltamucR. Many genes identified are involved in metabolism, cell wall/envelope biogenesis, replication, and translation. Notably, genes involved in type IV secretion system and quorum sensing system were down-regulated in 16MDeltamucR. In addition, genes involved in tolerance to acid and iron-limitation were also affected and experimentally verified in this study. The effects of MucR on Brucella survival and persistence in mice and macrophages were related to type IV secretion system, quorum sensing system, and stress tolerance, which also provide added insight to the MucR regulon. PMID- 23932080 TI - Effect of water washing on the thermal behavior of rice straw. AB - Rice straw can be used as a renewable fuel for heat and power generation. It is a viable mean of replacing fossil fuels and preventing pollution caused by open burning, especially in the areas where this residual biomass is generated. Nevertheless, the thermal conversion of rice straw can cause some operating problems such as slag formation, which negatively affects thermal conversion systems. So, the main objective of this research is studying the combustion behavior of rice straw samples collected from various regions by applying thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). In addition, the thermal behavior of ashes from rice straw was also analyzed in order to detect their melting points, and ash sintering was detected at different temperatures within the range between 550 and 1000 degrees C. Since washing rice straw with water could reduce the content of undesirable inorganic compounds related to the ash fusibility, samples of washed rice straw were analyzed under combustion conditions to investigate its differences regarding the thermal behavior of rice straw. The results showed that rice straw washing led to a significant improvement in its thermal behavior, since it reduced the ash contents and sintering formation. PMID- 23932079 TI - Occurrence of scalp-fast oscillations among patients with different spiking rate and their role as epileptogenicity marker. AB - INTRODUCTION: We aim to analyze the fast oscillations in the scalp EEG of focal epilepsy patients with low-to-high rates of interictal epileptiform discharges (IEDs), in order to determine how this neurophysiological feature influences fast oscillation occurrence and their significance as markers of the seizure onset zone (SOZ). METHODS: Thirty-two patients were studied, subdivided in four categories based on IED frequency: groups A, B and C respectively with high, intermediate and low IED rate, and group D with no IED. Thirty minutes of slow wave sleep EEG, low-pass filtered at 300Hz and sampled at 1000Hz, were reviewed. IEDs and fast oscillations (gamma activity, 40-80Hz; and ripples, >80Hz) were marked. Each channel was classified as inside or outside the irritative zone and the SOZ. We calculated the number and rates of IEDs and fast oscillation, their co-occurrence, their frequency in the irritative zone and SOZ, and the specificity, sensitivity and accuracy to determine the SOZ in the overall population and separately for each group. RESULTS: We analyzed 984 channels. Group A (high IED rate) showed the highest fast oscillation rate (gamma: 0.37+/ 0.73; ripples: 0.17+/-0.26), followed by group B (gamma: 0.08+/-0.06; ripples: 0.07+/-0.05), group C (gamma: 0.06+/-0.06; ripples: 0.04+/-0.01), and finally group D, with very low values (gamma: 0.03+/-0; ripples: 0.03+/-0). IEDs co occurred with gamma in 9.5% and with ripples in 3.2%; and gamma and ripples co occurred with IEDs in 46.2% and 44.4%, respectively. The fast oscillations were more frequent inside than outside the irritative zone and the SOZ (p<0.001). Compared to the IEDs, the fast oscillations were less sensitive (sensitivity: IEDs 78%, gamma 66% and ripples 48%) but more specific (specificity: IEDs 50%, gamma 76% and ripples 83%) and accurate (accuracy: IEDs 54%, gamma 74% and ripples 77%) in identifying the SOZ; the same results were reproduced for the different groups separately. CONCLUSIONS: This study confirms that fast oscillations can be recorded from the scalp EEG. Gamma activity and ripples are more frequent in patients with frequent IEDs and, in general, inside the irritative zone. However, compared to IEDs, gamma and ripples are less sensitive but more specific and accurate in identifying the SOZ, and this remains in patients with low fast oscillation rates. These findings suggest that IEDs and fast oscillations could share some common neuronal network, but gamma activity and ripples are a better biomarker of epileptogenicity. PMID- 23932081 TI - A dielectric study on colloidal silica nanoparticle Layer-by-Layer assemblies on polycarbonate. AB - This study focuses on the dielectrical characterization of polycarbonate films coated with silica nanoparticle bilayers assembled through the Layer-by-Layer (LbL) technique. This is the first attempt of dielectric characterization performed on LbL-treated plastic substrates. To this aim, LbL coatings consisting of oppositely charged colloidal silica have been built on a polymeric substrate (polycarbonate). Then, dielectric features such as space charge accumulation, electrical voltage breakdown, and resistance to corona discharge (through laser ablation) have demonstrated that the colloidal silica nanoparticle assemblies can influence the nature of the trapped space charges and affect the resistance of polycarbonate to corona discharge, changing the distribution of the laser energy on impact. PMID- 23932082 TI - XRD, TEM, and thermal analysis of Arizona Ca-montmorillonites modified with didodecyldimethylammonium bromide. AB - An Arizona SAz-2 calcium montmorillonite was modified by a typical dialkyl cationic surfactant (didodecyldimethylammonium bromide, abbreviated to DDDMA) through direct ion exchange. The obtained organoclays were characterized by X-ray diffraction (XRD), high-resolution transmission electron microscopy (HR-TEM), high-resolution thermogravimetric analysis (HR-TG), and infrared emission spectroscopy (IES). The intercalation of surfactants greatly increased the basal spacing of the interlayers and the conformation arrangement of the loaded surfactant were assessed based on the XRD and TEM measurements. This work shows that the dialkyl surfactant can be directly intercalated into the montmorillonite without first undergoing Na(+) exchange. Moreover, the thermal stability of organoclays and the different arrangements of the surfactant molecules intercalated in the SAz-2 Ca-montmorillonite were determined by a combination of TG and IES techniques. The detailed conformational ordering of different intercalated surfactants under different conditions was also studied. The surfactant molecule DDDMA has proved to be thermally stable even at 400 degrees C which indicates that the prepared organoclay is stable to significantly high temperatures. This study offers new insights into the structure and thermal stabilities of SAz-2 Ca-montmorillonite modified with DDDMA. The experimental results also confirm the potential applications of organic SAz-2 Ca montmorillonites as adsorbents and polymer-clay nanocomposites. PMID- 23932083 TI - Preparation of disk-like particles with micro/nano hierarchical structures. AB - A facile, reproductive method has been successfully developed to produce disk like microparticles self-assembled from monodispersed hybrid silica nanoparticles under certain circumstance. The disk-like microparticles with micro/nano hierarchical structures could be obtained in large amount under a mild condition and further used to biomimetic design of the superhydrophobic surface of lotus leaf. After traditional surface modification with dodecyltrichlorosiliane, the static contact angle of water on the surface with micro/nano hierarchical structure could reach 168.8 degrees . The method of surface modification could be further simplified by click reaction with the introduction of thiol groups under mild condition. The present strategy for constructing the surface with micro/nano hierarchical structures offers the advantage of simple and large area fabrication, which enables a variety of superhydrophobic applications. PMID- 23932084 TI - Quartz Crystal Microbalance with Dissipation (QCM-D) studies of the viscoelastic response from a continuously growing grafted polyelectrolyte layer. AB - Poly(acrylic acid) was grown from substrates by photopolymerization, and the grafting process was monitored in situ by Quartz Crystal Microbalance with Dissipation (QCM-D) measurements in a 1:1 v/v mixture of water/ethanol. The polymerization process was monitored into the thick film region, where the change in frequency and dissipation with increasing film mass changes sign as predicted by the Voigt viscoelastic model. Our experimental data are compared with predictions of this model, and satisfactory agreement is found for low overtone numbers. The Voigt model was applied to analyze the measured changes in frequency, Deltaf, and dissipation, DeltaD, in order to extract information on layer thickness, shear elasticity, MU, and shear viscosity, eta, of the growing film. The increasing rate of changes in Deltaf and DeltaD observed after about 150s of polymerization was found to correlate with an increasing growth rate of the film thickness. For longer polymerization times a close to linear increase in thickness with time was observed. The sensitivity, defined as the derivatives of Deltaf and DeltaD with respect to thickness, depends on overtone number and is different for the frequency and dissipation signals - facts that should be considered when investigating small changes in thick films used in e.g. sensor applications. PMID- 23932085 TI - Gold nanoparticles deposited on linker-free silicon substrate and embedded in aluminum Schottky contact. AB - Given the enormous importance of Au nanoparticles (NPs) deposition on Si substrates as the precursor for various applications, we present an alternative approach to deposit Au NPs on linker-free n- and p-type Si substrates. It is demonstrated that, all conditions being similar, there is a significant difference between densities of the deposited NPs on both substrates. The Zeta potential and polarity of charges surrounding the hydroxylamine reduced seeded growth Au NPs, are determined by a Zetasizer. To investigate the surface properties of Si substrates, contact angle measurement is performed. Field emission scanning electron microscope is then utilized to distinguish the NPs density on the substrates. Finally, Al/Si Schottky barrier diodes with embedded Au NPs are fabricated, and their structural and electrical characteristics are further evaluated using an energy-filtered transmission electron microscope and current-voltage measurements, respectively. The results reveal that the density of NPs is significantly higher on n-type Si substrate and consequently has more pronounced effects on the electrical characteristics of the diode. It is concluded that protonation of Si-OH group on Si surface in low pH is responsible for the immobilization of Au NPs, which eventually contributes to the lowering of barrier height and enhances the electrical characteristics. PMID- 23932086 TI - Superoleophobic polymers with metal ion affinity toward materials with both oleophobic and hydrophilic properties. AB - Bis(trifluoromethane)sulfonimide salts are used as electrolyte for the elaboration of superoleophobic properties by electrodeposition using a monomer containing a short perfluorobutyl (C4F9), separated from the polymer backbone by a long alkyl spacer, to reduce the mobility of these chains, and an amido connector to form complexes with ions. The electrodeposition in some of these electrolytes induces the formation of microstructures composed of nanosheets able to reach superoleophobic properties. When complexant ions (Na(+), Mg(2+), Ca(2+), Ba(2+)) are used as cation of the electrolyte, these ions are incorporated in the polymer leading to a material with higher oleophobicity than hydrophobicity. Indeed, when a water droplet is deposited on the surface, the migration of the ions induces a decrease in the surface hydrophobicity, while the deposition of an oil droplet (diiodomethane or hexadecane) does not induce this migration. If the incorporation of these ions is not sufficiently stable for applications in oil/water separation, this work opens new strategies in the elaboration of both superoleophobic/oleophobic and superhydrophilic/hydrophilic materials. Such materials can also be used for the ion capture and release. PMID- 23932087 TI - Investigation of structure-surface properties relationship of semi-fluorinated polymerizable cationic surfactants. AB - Novel hybrid hydrocarbon/fluorocarbon ammonium type surfactant monomers (surfmers) of the general formula RF (CH2)l N(CH3)2(CH2)mOCOCH=CH2 with (RF=C4F9, C6F13, C8F17, l=4, 6, 11, and m=2-11) were synthesized and characterized. They exhibit very low surface tension as well as low critical micellar concentrations down to 1.39*10(-5)mol/L. Special attention was focused on theeffect of the polymerizable moiety, the length of the hydrocarbon spacers, and the fluorinated chains on surface activities of the reactive surfactants as compared to hydrocarbon surfmer analogs. Results indicate that the acrylic function has a pronounced effect on increasing the hydrophobic micelle character. This was confirmed by surface tensions and average surfaces occupied by these molecules at the water-gas interface. The micellar sizes were investigated by dynamic light scattering. PMID- 23932088 TI - Association of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality. AB - BACKGROUND: Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality. STUDY DESIGN: Observational. SETTING & POPULATION: 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies. PREDICTORS: We estimated the association of rs13038305 with eGFRcys and serum creatinine-based eGFR (eGFRcr) and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305. OUTCOMES: We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45-59, 60-89, and >= 90 mL/min/1.73 m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis. RESULTS: In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%) was associated with a 6.4% lower cystatin C concentration, 5.5-mL/min/1.73 m(2) higher eGFRcys, and 36% [95% CI, 29%-41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14-1.20) and mortality (HR, 1.22; 95% CI, 1.19-1.24) per 10-mL/min/1.73 m(2) lower eGFRcys were similar with or without rs13038305 adjustment. 1,134 (7.7%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, -0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD. LIMITATIONS: rs13038305 explains only a small proportion of cystatin C variation. CONCLUSIONS: Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest. PMID- 23932089 TI - Treatment of metabolic acidosis in patients with CKD. AB - Metabolic acidosis is a common complication of chronic kidney disease and is believed to contribute to a number of sequelae, including bone disease, altered protein metabolism, skeletal muscle wasting, and progressive glomerular filtration rate loss. Small trials in animal models and humans suggest a role for alkali therapy to lessen these complications. Recent studies support this notion, although more definitive evidence is needed on the long-term benefits of alkali therapy and the optimal serum bicarbonate level. The role of dietary modification also should be given greater consideration. In addition, potential adverse effects of alkali treatment must be taken into consideration, including sodium retention and the theoretical concern of promoting vascular calcification. This teaching case summarizes the rationale for and benefits and complications of base therapy in patients with chronic kidney disease. PMID- 23932091 TI - Analysis of factors influencing safety management for metro construction in China. AB - With the rapid development of urbanization in China, the number and size of metro construction projects are increasing quickly. At the same time, and increasing number of accidents in metro construction make it a disturbing focus of social attention. In order to improve safety management in metro construction, an investigation of the participants' perspectives on safety factors in China metro construction has been conducted to identify the key safety factors, and their ranking consistency among the main participants, including clients, consultants, designers, contractors and supervisors. The result of factor analysis indicates that there are five key factors which influence the safety of metro construction including safety attitude, construction site safety, government supervision, market restrictions and task unpredictability. In addition, ANOVA and Spearman rank correlation coefficients were performed to test the consistency of the means rating and the ranking of safety factors. The results indicated that the main participants have significant disagreement about the importance of safety factors on more than half of the items. Suggestions and recommendations on practical countermeasures to improve metro construction safety management in China are proposed. PMID- 23932090 TI - Association of income level with kidney disease severity and progression among children and adolescents with CKD: a report from the Chronic Kidney Disease in Children (CKiD) Study. AB - BACKGROUND: Among adults, lower socioeconomic status (SES) is a risk factor for chronic kidney disease (CKD), progression to end-stage renal disease, and poor health outcomes; but its impact on young people with CKD is not established. STUDY DESIGN: Prospective cohort study. SETTINGS & PARTICIPANTS: 572 children and adolescents aged 1-16 years with mild to moderate CKD residing in the United States and Canada who were enrolled in the Chronic Kidney Disease in Children (CKiD) Study. PREDICTOR: Self-reported annual household income category as a proxy measure for SES: >=$75,000 (high income), $30,000 to <$75,000 (middle income) and <$30,000 (low income). OUTCOMES & MEASUREMENTS: Clinical characteristics and CKD severity at baseline (glomerular filtration rate [GFR] and comorbid conditions related to disease severity and management) and longitudinally (GFR decline and changes in blood pressure z scores and height z scores per year). RESULTS: At baseline, low and middle household incomes, compared to high income, were associated with minority race (39% and 20% vs. 7%), lower maternal education (28% and 5% vs. 1%), abnormal birth history (34% and 32% vs. 21%), and having at least one clinical comorbid condition (66% and 64% vs. 55%). Baseline median GFRs were similar across income categories (43-45 mL/min/1.73 m2). After adjusting for baseline differences, average GFR declines per year for the low-, middle-, and high-income categories were -2.3%, -2.7%, and -1.9%, respectively, and were not statistically significantly different among groups. Blood pressure control tended to improve in all groups (z score, -0.10 to -0.04) but higher income was associated with a faster improvement. Each group showed similar deficits in height at baseline. Height deficits diminished over time for participants from high-income families, but not among those from low income families (z scores for height per year, 0.05 and -0.004, respectively; P = 0.03 for comparison of high and low income). LIMITATIONS: Income is an imperfect measure for SES; CKiD participants are not representative of children and adolescents with CKD who are uninsured or not receiving care; statistical power to detect associations by income level is limited. CONCLUSIONS: GFR decline was similar across income groups but better improvement in BP was observed among those with high income. Children and adolescents with CKD from lower income households are at higher risk of impaired growth. PMID- 23932092 TI - An efficient diagnostic strategy for small, depressed early gastric cancer with magnifying narrow-band imaging: a post-hoc analysis of a prospective randomized controlled trial. AB - BACKGROUND: We previously reported that magnifying narrow-band imaging (M-NBI) is a high-performance diagnostic tool for small, depressed gastric cancer. However, an efficient diagnostic strategy using endoscopic findings has not been fully elucidated. OBJECTIVE: To identify the endoscopic findings that contribute to accurate diagnosis of small, depressed gastric cancer and to propose the ideal diagnostic approach to such lesions. DESIGN: Post-hoc analysis of a prospective, randomized, controlled trial. SETTING: Nine hospitals. PATIENTS: Three hundred fifty-three patients with small, depressed gastric lesions. INTERVENTIONS: In the M-NBI group (n = 177), cancer diagnosis was made with diagnostic criteria including a demarcation line (DL) and an irregular microvascular pattern (IMVP). In the conventional white-light imaging (C-WLI) group (n = 176), diagnostic criteria were both an irregular margin and a spiny depressed area. In the C-WLI group, M-NBI was performed after C-WLI diagnosis. MAIN OUTCOME MEASUREMENTS: The diagnostic performance of each criterion in M-NBI alone, C-WLI, and M-NBI after C WLI was investigated. RESULTS: M-NBI after C-WLI ultimately showed the best diagnostic performance in each diagnostic criterion. In M-NBI after C-WLI, evaluation of DL is technically easier than that of IMVP, and DL alone had a high sensitivity (95%) and negative predictive value (99%). The IMVP in M-NBI after C WLI had a high sensitivity and specificity (95% and 96%, respectively) for diagnosis of cancer. LIMITATIONS: Lesions were limited to the small, depressed type. CONCLUSIONS: For a diagnosis using M-NBI after C-WLI, identification of DL is the first step, and subsequent inspection of IMVP diagnosed by DL is an efficient strategy. PMID- 23932094 TI - The role of nurses in tackling female genital mutilation. PMID- 23932093 TI - Transcolonic peritoneoscopy by using submucosal endoscopy with mucosal flap for the detection of peritoneal bead targeting in the porcine survival model: a feasibility and effectiveness study. AB - BACKGROUND: Staging peritoneoscopy is typically done by laparoscopy in the operating room. Natural orifice transluminal endoscopic surgery peritoneoscopy is an appealing alternative to the current approach. Transcolonic submucosal endoscopy with mucosal flap (SEMF) may provide natural orifice transluminal endoscopic surgery peritoneoscopy. OBJECTIVE: The aim was to verify the feasibility and safety of transcolonic peritoneoscopy with SEMF (TCPS) in a porcine survival model. DESIGN: Survival study. SETTING: Animal research unit. INTERVENTION: Seven target beads were placed in the peritoneal cavity by laparoscopy in each of 6 animals, and TCPS was performed to identify and touch beads to simulate biopsy. Animals were euthanized after 1 week, at which time, laparotomy was performed and the SEMF site was resected for histological analysis. MAIN OUTCOME MEASUREMENTS: The number of beads identified and touched during peritoneoscopy, rate of successful completion of TCPS, procedure time, mortality equivalent 1 week after TCPS, adverse event rate, histological assessment of SEMF site. RESULTS: All 7 beads in all 6 pigs were identified and touched during TCPS. The success rate of TCP was 100%. No major adverse events occurred during the procedure. The median procedure times for the creation of a submucosal tunnel, peritoneoscopy, closure of mucosal incision, and entire procedure were 19.5, 17, 9.5, and 45 minutes, respectively. All pigs survived until euthanasia, and there was no evidence of peritonitis or severe infection. LIMITATIONS: Animal study, single endoscopist, small sample size. CONCLUSION: Results of this study indicate that TCPS is feasible and safe in a porcine survival model. PMID- 23932095 TI - TGFbeta-pathway is down-regulated in a uterine carcinosarcoma: a case study. AB - Data assessing the role of various genetic alterations in uterine carcinosarcoma (CS), particularly the transforming growth factors-beta (TGFbeta) that play a crucial role in many cellular processes, including proliferation, differentiation, adhesion and migration, are scarce. TGFbeta exert their effects through specific receptors and associated auxiliary receptors. In the current study, we investigated the expression of TGFbeta isoforms and their receptors, as well as selected genes in a case of CS. We applied the real-time fluorescence detection PCR method with FAM dye-labeled TaqMan specific probes. In a comparison to the normal counterpart, TGFB1, TGFB2, TGFBRII, TGFBR3, ENG and CD109 were all down-regulated in uterine CS samples at different extents. BIRC5 and hTERT, markers of tumor survival, were up-regulated in CS as compared with normal counterparts. A concomitant increase of the hypoxia marker HIF1A expression pattern was noted, whereas the expression of GPR120, responsible for free fatty acids sensing, was not different in both counterparts evaluated. In conclusion, deregulation of various cellular mechanisms in uterine CS is associated with alterations at many levels - cell growth and proliferation, apoptosis, and impaired response to stimuli from extracellular environment. PMID- 23932096 TI - Comparison of PET-CT and magnetic resonance diffusion weighted imaging with body suppression (DWIBS) for initial staging of malignant lymphomas. AB - OBJECTIVE: To evaluate the clinical impact of diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) in staging of malignant lymphoma. METHODS: Twenty-three patients with proven malignant lymphomas were prospectively enrolled. DWIBS (b=0, 1000 s/mm(2)) examinations and PET-CT were performed respectively on an Intera 1.5 T unit and a Gyroscan PET-CT scan (Philips Medical system, Best, the Netherland). The criteria for positive node involvement were a size over 10 mm or an apparent diffusion coefficient (ADC) value under 0.7510(-3) mm(2)/s for nodes under 10mm. For extranodal analysis, a high or heterogeneous signal on DWIBS was considered as positive. In cases of discordance, the reference standard for each region or organ was established at 6 months after the diagnosis according to all available clinical, biological information, as well as histological evidence or follow-up to prove or disprove the presence of disease. RESULTS: DWIBS and PET-CT results were congruent in 333 node regions on the 345 areas analyzed, with excellent agreement (kappa=0.97, P<0.0001). From 433 organs analyzed (one patient had splenectomy) extranodal disease was detected in 22 organs on DWIBS. The two imaging techniques agreed on 430 organs (kappa=0.99, P<0.0001). Finally, Ann Arbor stages based on DWIBS and those of PET/CT were in agreement for 23 patients. CONCLUSIONS: For malignant lymphoma in a pre-therapeutic context, agreement between diffusion-weighted whole body imaging and PET/CT is high for Ann Arbor staging. PMID- 23932097 TI - Correlation study of 3T-MR-DTI measurements and clinical symptoms of cervical spondylotic myelopathy. AB - OBJECTIVE: To discuss the correlation between diffusion tensor imaging (DTI) measurements, diffusion tensor tractography and the clinical symptoms of cervical spondylotic myelopathy. METHODS: Based on the Japanese Orthopedics Association (JOA) score, 104 cervical spondylotic myelopathy cases were first divided into four groups: mild, moderate, severe and serious groups. According to lesion signal characteristics, all cases were again divided into three groups: A(N/N): normal signal in both T1WI and T2WI; B (N/H): normal signal in T1WI but high signal in T2WI; and C (L/H): low signal in T1WI and high signal in T2WI. The apparent diffusion coefficient (ADC), fractional anisotropy (FA), lambda1, lambda2, and lambda3 were measured and diffusion tensor tractography was performed in the seriously compressed section of the spinal cord. RESULTS: The FA values were positively correlated with JOA scores (r=0.883, P<0.05), and significantly different among four JOA groups (P<0.05). The ADC, lambda2, and lambda3 were significantly different among the moderate, severe and serious groups as well as among the A, B, and C groups (P<0.05). Declining FA values were found associated with increasing fiber bundle damage. CONCLUSIONS: The FA values and the change patterns of fiber bundle were more sensitive than T2WI for spinal cord lesion, and were positively correlated with clinical symptoms. PMID- 23932098 TI - Herd-level factors associated with the presence of bovine viral diarrhoea virus in herds participating in the voluntary phase of the Irish national eradication programme. AB - A risk factor study was conducted to identify variables associated with initial positive or inconclusive results for bovine viral diarrhoea virus (BVDV) in ear punch samples collected from calves between 1st January and 15th July 2012 (the study period) as part of the voluntary phase of the Irish national BVD eradication programme based on testing of ear tag tissue samples from calves born in participating herds. Univariable analysis indicated significant associations with the following factors: herd type; the number of cows in the herd; the number of calves born in the study period; the number of calves tested in the study period; the number of cattle purchased in 2011, between 2009 and 2011 and between 2007 and 2011; the number of tested calves whose dams had been purchased within 9 months of their calving date; and the percentage of calf mortality within 28 days of birth. The percentage of the cows in each herd that was homebred, location (province) the number of separate land parcels used by each herd, the presence of an associated sheep enterprise and the purchase of cattle through marts were not found to be significant. An initial logistic regression model was developed to model the probability of a herd having one or more BVD virus-positive or inconclusive calves. When vaccination status was initially excluded, province, log of the numbers of cows in the herd, the number of cows purchased between 2009 and 2011, the number of tested calves whose dams had been purchased within 9 months of their calving date and calf mortality were significant. When vaccination status was included, using a subset of the data based on farmers responding to a survey on vaccination status, it was retained as a significant variable along with the same variables already listed, showing a significant 2 way interaction with the log of the number of cows. There was not a significant association between an initial positive or inconclusive result and the length of time for which herds had been vaccinating. The study provides a series of key communication messages relating to both the delivery of, and benefits from, the national eradication programme. PMID- 23932099 TI - Patient characteristics in low back pain subgroups based on an existing classification system. A descriptive cohort study in chiropractic practice. AB - Sub-grouping of low back pain (LBP) is believed to improve prediction of prognosis and treatment effects. The objectives of this study were: (1) to examine whether chiropractic patients could be sub-grouped according to an existing pathoanatomically-based classification system, (2) to describe patient characteristics within each subgroup, and (3) to determine the proportion of patients in whom clinicians considered the classification to be unchanged after approximately 10 days. A cohort of 923 LBP patients was included during their first consultation. Patients completed an extensive questionnaire and were examined according to a standardised protocol. Based on the clinical examination, patients were classified into diagnostic subgroups. After approximately 10 days, chiropractors reported whether they considered the subgroup had changed. The most frequent subgroups were reducible and partly reducible disc syndromes followed by facet joint pain, dysfunction and sacroiliac (SI)-joint pain. Classification was inconclusive in 5% of the patients. Differences in pain, activity limitation, and psychological factors were small across subgroups. Within 10 days, 82% were reported to belong to the same subgroup as at the first visit. In conclusion, LBP patients could be classified according to a standardised protocol, and chiropractors considered most patient classifications to be unchanged within 10 days. Differences in patient characteristics between subgroups were very small, and the clinical relevance of the classification system should be investigated by testing its value as a prognostic factor or a treatment effect modifier. It is recommended that this classification system be combined with psychological and social factors if it is to be useful. PMID- 23932100 TI - The central nervous system--an additional consideration in 'rotator cuff tendinopathy' and a potential basis for understanding response to loaded therapeutic exercise. AB - Tendinopathy is a term used to describe a painful tendon disorder but despite being a well-recognised clinical presentation, a definitive understanding of the pathoaetiology of rotator cuff tendinopathy remains elusive. Current explanatory models, which relate to peripherally driven nocioceptive mechanisms secondary to structural abnormality, or failed healing, appear inadequate on their own in the context of current literature. In light of these limitations this paper presents an extension to current models that incorporates the integral role of the central nervous system in the pain experience. The role of the central nervous system (CNS) is described and justified along with a potential rationale to explain the favourable response to loaded therapeutic exercises demonstrated by previous studies. This additional consideration has the potential to offer a useful way to explain pain to patients, for clinicians to prescribe appropriate therapeutic management strategies and for researchers to advance knowledge in relation to this clinically challenging problem. PMID- 23932101 TI - Clinical decision-making and therapeutic approaches in osteopathy - a qualitative grounded theory study. AB - There is limited understanding of how osteopaths make decisions in relation to clinical practice. The aim of this research was to construct an explanatory theory of the clinical decision-making and therapeutic approaches of experienced osteopaths in the UK. Twelve UK registered osteopaths participated in this constructivist grounded theory qualitative study. Purposive and theoretical sampling was used to select participants. Data was collected using semi structured interviews which were audio-recorded and transcribed. As the study approached theoretical sufficiency, participants were observed and video-recorded during a patient appointment, which was followed by a video-prompted interview. Constant comparative analysis was used to analyse and code data. Data analysis resulted in the construction of three qualitatively different therapeutic approaches which characterised participants and their clinical practice, termed; Treater, Communicator and Educator. Participants' therapeutic approach influenced their approach to clinical decision-making, the level of patient involvement, their interaction with patients, and therapeutic goals. Participants' overall conception of practice lay on a continuum ranging from technical rationality to professional artistry, and contributed to their therapeutic approach. A range of factors were identified which influenced participants' conception of practice. The findings indicate that there is variation in osteopaths' therapeutic approaches to practice and clinical decision-making, which are influenced by their overall conception of practice. This study provides the first explanatory theory of the clinical decision-making and therapeutic approaches of osteopaths. PMID- 23932102 TI - Toward aggregation-resistant antibodies by design. AB - Monoclonal antibodies are attractive therapeutics for treating a wide range of human disorders due to their exquisite binding specificity and high binding affinity. However, a limitation of antibodies is their highly variable and difficult-to-predict propensities to aggregate when concentrated during purification and delivery. Despite the large size and complex structure of antibodies, recent findings suggest that antibody solubility can be dramatically improved using rational design methods in addition to conventional selection methods. Here, we review key advances and unmet challenges in engineering the variable and constant regions of antibody fragments and full-length antibodies to resist aggregation without reducing their binding affinity. These experimental and computational discoveries should accelerate the development of robust algorithms for designing aggregation-resistant antibodies. PMID- 23932103 TI - Preface. PMID- 23932104 TI - Multi-objective evolutionary optimization for greywater reuse in municipal sewer systems. AB - Sustainable design and implementation of greywater reuse (GWR) has to achieve an optimum compromise between costs and potable water demand reduction. Studies show that GWR is an efficient tool for reducing potable water demand. This study presents a multi-objective optimization model for estimating the optimal distribution of different types of GWR homes in an existing municipal sewer system. Six types of GWR homes were examined. The model constrains the momentary wastewater (WW) velocity in the sewer pipes (which is responsible for solids movement). The objective functions in the optimization model are the total WW flow at the outlet of the neighborhoods sewer system and the cost of the on-site GWR treatment system. The optimization routing was achieved by an evolutionary multi-objective optimization coupled with hydrodynamic simulations of a representative sewer system of a neighborhood located at the coast of Israel. The two non-dominated best solutions selected were the ones having either the smallest WW flow discharged at the outlet of the neighborhood sewer system or the lowest daily cost. In both solutions most of the GWR types chosen were the types resulting with the smallest water usage. This lead to only a small difference between the two best solutions, regarding the diurnal patterns of the WW flows at the outlet of the neighborhood sewer system. However, in the upstream link a substantial difference was depicted between the diurnal patterns. This difference occurred since to the upstream links only few homes, implementing the same type of GWR, discharge their WW, and in each solution a different type of GWR was implemented in these upstream homes. To the best of our knowledge this is the first multi-objective optimization model aimed at quantitatively trading off the cost of local/onsite GW spatially distributed reuse treatments, and the total amount of WW flow discharged into the municipal sewer system under unsteady flow conditions. PMID- 23932105 TI - Piggyback multifocal IOLs for a hyperopic-presbyopic surprise after cataract surgery in high myopic patients. AB - PURPOSE: To demonstrate the utility of piggyback multifocal intraocular lenses (IOLs) for a hyperopic-presbyopic surprise after cataract surgery in highly myopic patients. METHODS: Case report. RESULTS: A 43-year-old woman with high myopia presented with dense subcapsular cataracts. The IOL power calculated with the Haigis formula gave a lens of -7D for emmetropia in the right eye. The refractive result was a spherical equivalent refractive error of +2.25. To overcome refractive surprise, a refractive multifocal +3D Sulcoflex 653F with an additional 3.5D for near vision was implanted, achieving a best-corrected visual acuity of 20/40. The lens offered her good intermediate vision for computer work. CONCLUSIONS: With a Sulcoflex IOL, it is possible to achieve good near intermediate visual acuity and spectacle independence, especially in highly myopic eyes with good near visual acuity. In addition, the implantation of these IOLs might correct residual refractive errors following previous implantation of a monofocal IOL. PMID- 23932106 TI - Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. AB - Epileptic encephalopathies are genetically heterogeneous severe disorders in which epileptic activity contributes to neurological deterioration. We studied two unrelated children presenting with a distinctive early-onset epileptic encephalopathy characterized by refractory epilepsy and absent developmental milestones, as well as thick and short corpus callosum and persistent cavum septum pellucidum on brain MRI. Using whole-exome sequencing, we identified biallelic mutations in seizure threshold 2 (SZT2) in both affected children. The causative mutations include a homozygous nonsense mutation and a nonsense mutation together with an exonic splice-site mutation in a compound-heterozygous state. The latter mutation leads to exon skipping and premature termination of translation, as shown by RT-PCR in blood RNA of the affected boy. Thus, all three mutations are predicted to result in nonsense-mediated mRNA decay and/or premature protein truncation and thereby loss of SZT2 function. Although the molecular role of the peroxisomal protein SZT2 in neuronal excitability and brain development remains to be defined, Szt2 has been shown to influence seizure threshold and epileptogenesis in mice, consistent with our findings in humans. We conclude that mutations in SZT2 cause a severe type of autosomal-recessive infantile encephalopathy with intractable seizures and distinct neuroradiological anomalies. PMID- 23932107 TI - Genetic evidence for recent population mixture in India. AB - Most Indian groups descend from a mixture of two genetically divergent populations: Ancestral North Indians (ANI) related to Central Asians, Middle Easterners, Caucasians, and Europeans; and Ancestral South Indians (ASI) not closely related to groups outside the subcontinent. The date of mixture is unknown but has implications for understanding Indian history. We report genome wide data from 73 groups from the Indian subcontinent and analyze linkage disequilibrium to estimate ANI-ASI mixture dates ranging from about 1,900 to 4,200 years ago. In a subset of groups, 100% of the mixture is consistent with having occurred during this period. These results show that India experienced a demographic transformation several thousand years ago, from a region in which major population mixture was common to one in which mixture even between closely related groups became rare because of a shift to endogamy. PMID- 23932108 TI - Mapping the human reference genome's missing sequence by three-way admixture in Latino genomes. AB - A principal obstacle to completing maps and analyses of the human genome involves the genome's "inaccessible" regions: sequences (often euchromatic and containing genes) that are isolated from the rest of the euchromatic genome by heterochromatin and other repeat-rich sequence. We describe a way to localize these sequences by using ancestry linkage disequilibrium in populations that derive ancestry from at least three continents, as is the case for Latinos. We used this approach to map the genomic locations of almost 20 megabases of sequence unlocalized or missing from the current human genome reference (NCBI Genome GRCh37)-a substantial fraction of the human genome's remaining unmapped sequence. We show that the genomic locations of most sequences that originated from fosmids and larger clones can be admixture mapped in this way, by using publicly available whole-genome sequence data. Genome assembly efforts and future builds of the human genome reference will be strongly informed by this localization of genes and other euchromatic sequences that are embedded within highly repetitive pericentromeric regions. PMID- 23932109 TI - Investigating the role of matrix components in protection of Burkholderia cepacia complex biofilms against tobramycin. AB - BACKGROUND: Burkholderia cepacia complex (Bcc) organisms produce a wide variety of potential virulence factors, including exopolysaccharides (EPS), and exhibit intrinsic resistance towards many antibiotics. In the present study we investigated the contribution of Bcc biofilm matrix components, including extracellular DNA, cepacian and poly-beta-1,6-N-acetylglucosamine, to tobramycin susceptibility. METHODS: The in vitro bactericidal activity of tobramycin in combination with recombinant human DNase (rhDNase), NaClO and dispersin B was tested against Bcc biofilms. RESULTS: EPS degradation by NaClO pretreatment and specific PNAG degradation by dispersin B significantly increased the bactericidal effect of tobramycin towards some of the Bcc biofilms tested, including the strains of Burkholderia cenocepacia, B. cepacia and Burkholderia metallica. The presence of rhDNase during biofilm treatment and/or development had no influence on tobramycin activity. CONCLUSION: These results suggest that EPS play a role in tobramycin susceptibility of Bcc biofilms and that matrix degrading combination therapy could improve treatment of Bcc biofilm infections. PMID- 23932110 TI - Benefits of donor milk in the feeding of preterm infants. AB - Mother's own milk is widely recognized as the optimal feeding for term infants, but also provides health benefits that are of vital importance for sick and preterm infants in neonatal intensive care units (NICUs), even though the growth and neurodevelopmental needs of very premature infants are best met by appropriate fortification of human milk (HM). When mother's milk is unavailable or in short supply, donor milk (DM) represents the second best alternative and, although some nutritional elements are inactivated by the pasteurization process, it still has documented advantages compared to formula. Occasionally, the concern that the use of DM might decrease breastfeeding is being raised, but reports exist in literature showing that the use of donor HM in the NICU increases breastfeeding rates at discharge for VLBW infants. The demonstrated benefits of HM highlight the importance of educating health care professionals in breastfeeding support. PMID- 23932111 TI - The total value equation: a suggested framework for understanding value creation in diagnostic radiology. AB - As a result of macroeconomic forces necessitating fundamental changes in health care delivery systems, value has become a popular term in the medical industry. Much has been written recently about the idea of value as it relates to health care services in general and the practice of radiology in particular. Of course, cost, value, and cost-effectiveness are not new topics of conversation in radiology. Not only is value one of the most frequently used and complex words in management, entire classes in business school are taught around the concept of understanding and maximizing value. But what is value, and when speaking of value creation strategies, what is it exactly that is meant? For the leader of a radiology department, either private or academic, value creation is a core function. This article provides a deeper examination of what value is, what drives value creation, and how practices and departments can evaluate their own value creation efficiencies. An equation, referred to as the Total Value Equation, is presented as a framework to assess value creation activities and strategies. PMID- 23932112 TI - Alteration of cartilage degeneration and inflammation markers in temporomandibular joint osteoarthritis occurs proportionally. AB - PURPOSE: There is a growing interest in markers for cartilage degradation in synovial joints because of their potential diagnostic and prognostic value. Therefore, the aim of this study was to identify valuable degradation markers for temporomandibular joint (TMJ) osteoarthritis (OA) by comparing the relative concentrations of carboxyterminal telopeptides type I and II (CTX-I and II), cartilage oligomeric matrix protein (COMP), and prostaglandin E2 (PGE2) in the synovial fluid (SF) of TMJs with OA with those of healthy symptom-free TMJs. MATERIALS AND METHODS: In this cross-sectional case-control study, participants were recruited from the University Medical Center Groningen (Groningen, the Netherlands). Cases were defined as patients with TMJ OA, and control patients had symptom-free TMJs. The outcome variables were the relative concentrations of CTX-I, CTX-II, COMP, and PGE2 in osteoarthritic TMJ SF compared with symptom-free joints. An independent-samples Mann-Whitney U test was used to compare the relative concentrations. RESULTS: Thirty cases (9 male, 21 female; mean age, 40.1 yr; standard deviation, 15.3 yr) and 10 controls (5 male, 5 female; mean age, 30.3 yr; standard deviation, 10.8 yr) were studied. No significant differences in relative concentrations of CTX-I (P = .548), CTX-II (P = .842), COMP (P = .140), and PGE2 (P = .450) were found between the groups. Unexpected low relative concentrations of CTX-I and high relative concentrations of CTX-II were observed. CONCLUSIONS: Assumed changes in the SF concentration of CTX-I, CTX-II, COMP, and PGE2 in TMJ OA seem to occur proportionally. Furthermore, the unexpected large contribution of CTX-II suggests that this marker may be useful to quantify cartilage degradation in TMJ OA. PMID- 23932113 TI - Physical findings associated with active temporomandibular joint inflammation in children with juvenile idiopathic arthritis. AB - PURPOSE: To identify the physical findings associated with active temporomandibular joint (TMJ) inflammation (ie, synovitis) in children with juvenile idiopathic arthritis (JIA). PATIENTS AND METHODS: This was a retrospective study of children with JIA evaluated at Boston Children's Hospital. The patients were included if they had a confirmed diagnosis of JIA and had undergone a TMJ magnetic resonance imaging (MRI) study with contrast. Medical records and imaging studies were reviewed to document the demographic, physical (ie, facial asymmetry, joint noises, maximal incisal opening, deviation on opening, occlusal cant), and MRI findings. The outcome variable was TMJ synovitis on the MRI study. Descriptive and bivariate statistics were computed. Multiple regression models were used to identify associations (P <= .05, significance). RESULTS: A total of 51 patients with JIA were evaluated during the study period. Of these, 43 patients (33 girls) with a mean age of 11.4 years met the inclusion criteria. MRI demonstrated TMJ synovitis in 27 patients. The age-adjusted limited maximal incisal opening (MIO) and deviation on opening were the only physical findings significantly associated with synovitis on MRI (P = .003 and P = .043, respectively). Using these parameters as predictors of synovitis, a limited MIO and deviation on opening had a high specificity (86% and 94%, respectively). Patients with a limited MIO were 6.7 times more likely to have synovitis than those with a normal MIO. All patients with a limited MIO and deviation on opening had TMJ synovitis on the MRI scan. CONCLUSIONS: The results of this study indicate that, in children with JIA, limited MIO and deviation on opening can be used to predict the presence of TMJ synovitis. Documentation of these parameters should be an essential part of the clinical examination and longitudinal follow up of children with JIA. PMID- 23932114 TI - Evaluation of minimal versus conventional presurgical orthodontics in skeletal class III patients treated with two-jaw surgery. AB - PURPOSE: The purpose of this study was to compare changes in hard and soft tissues and the treatment efficacy of 2-jaw surgery combined with nonextraction treatment for skeletal Class III malocclusion in patients who received minimal presurgical orthodontics (MPO) versus those who received conventional presurgical orthodontics (CPO). MATERIALS AND METHODS: Thirty-two patients (16 in each group) with skeletal Class III malocclusion who underwent 2-jaw surgery were included in the study. Serial lateral cephalometric films were traced at 4 stages: before treatment (T0), before surgery (T1), 1 month after surgery (T2), and at debonding (T3). Cephalometric measurements and treatment duration were compared using independent t test and Mann-Whitney U test. RESULTS: After the presurgical treatment phase, the angle between the lower incisor axis and mandibular plane, overjet, and soft tissue pogonion to the vertical reference line showed larger changes (P < 0.01) in the CPO group, whereas the pogonion to the horizontal reference line showed larger changes (P < .05) in the MPO group. In the postsurgical phase (T2 to T3), there were no significant differences between the 2 groups. Total treatment duration was significantly shorter in the MPO group. CONCLUSIONS: There were no significant differences between the MPO and CPO groups in the hard and soft tissue cephalometric variables. The MPO group had a shorter total treatment time. It is therefore recommended that clinicians consider these results when selecting MPO as a treatment option for accurate diagnosis and treatment planning of Class III surgical patients. PMID- 23932115 TI - Combined elliptical window genioglossus advancement, hyoid bone suspension, and uvulopalatopharyngoplasty decrease apnea hypopnea index and subjective daytime sleepiness in obstructive sleep apnea. AB - PURPOSE: The objective and subjective outcomes of combined mandibular elliptical window genioglossus advancement, hyoid bone suspension, and uvulopalatopharyngoplasty procedures have not been evaluated. This study was conducted to evaluate postoperative changes in the apnea hypopnea index (AHI) and subjective daytime sleepiness with this combination of procedures in the surgical management of obstructive sleep apnea (OSA). PATIENTS AND METHODS: This was a retrospective cohort analysis of patients who had undergone combined elliptical window genioglossus advancement, hyoid bone suspension, and uvulopalatopharyngoplasty performed at Allegheny General Hospital (Pittsburgh, PA) from July 1, 2006 through December 31, 2008 for polysomnogram-confirmed OSA. Inclusion criteria included patients who had undergone the combined elliptical window genioglossus advancement, hyoid bone suspension, and uvulopalatopharyngoplasty procedures with preoperative and minimum 6-month postoperative AHI and Epworth Sleepiness Scale (ESS). Statistical significance between mean differences of pre- and postoperative AHI and ESS was determined with the 2-tailed paired t test and 95% confidence intervals. RESULTS: Thirteen male patients (average age, 43.0 +/- 2.4 yr; average follow-up, 18.0 +/- 3.6 months) were included in this study. There were statistically significant differences between mean pre- and postoperative AHI (28.3 vs 12.1; P < .05; mean change, -16.2; 57.2% decrease) and ESS (15.2 vs 6.3; P < .05; mean change, -8.9; 58.6% decrease). CONCLUSION: The combined mandibular elliptical window genioglossus advancement, hyoid bone suspension, and uvulopalatopharyngoplasty procedures for the treatment of OSA decrease AHI and subjective daytime sleepiness. PMID- 23932116 TI - Dental extraction in the thrombocytopenic patient is safe and complications are easily managed. AB - PURPOSE: To characterize bleeding risk and management of bleeding in thrombocytopenic patients undergoing dental extraction. MATERIALS AND METHODS: This retrospective cohort study included 68 patients with hematologic disease and concomitant thrombocytopenia undergoing dental extractions. The inclusion criterion was a platelet count of 100,000/MUL or less at the time of consultation or extraction. Patients using anticoagulation therapy were excluded from the study. Predictors measured were age, gender, platelet count, platelet transfusion before or during surgery, local hemostatic measurements at the time of surgery (absorbable hemostat or antifibrinolytic rinse), number of teeth extracted, diagnosis, and extraction type. The primary outcome was postoperative bleeding requiring intervention. A secondary outcome was surgical site infection. Descriptive and bivariate statistics were computed and the P value was set at .05. No logistic regression was used based on the distribution of outcomes. RESULTS: Sixty-eight patients underwent extraction of 200 teeth. Five (7.4%) had postoperative bleeding that was always controlled with routine intervention. Mean platelet count was 44,647/MUL. Bleeding was more frequent with lower platelet levels (P = .048). Thirty-two patients received platelet transfusion and 26 received local measures. Platelet transfusion and local hemostatic measures had no effect on bleeding outcomes. CONCLUSION: Surgical and routine extractions are safe procedures in patients with thrombocytopenia, and postoperative bleeding is typically well handled with simple local measures. The benefits of pre- or intraoperative platelet transfusion are unclear in this population. Likewise, the benefit of prophylactic local hemostatic measures is unclear and should be based on the surgeon's discretion and experience. PMID- 23932117 TI - Upper extremity injuries in Homer's Iliad. AB - Homer's Iliad remains a fascinating source of medical history. This epic poem, compiled around 800 BCE, describes several weeks of the last year of the 10-year siege of Troy (Ilion) by the Achaeans. Homer composed the epic by combining and formalizing oral poems, legends, customs, and experiences that originated in the later Mycenaean age (1600-1100 bce). The story centers on the rage of the great warrior Achilles. The Iliad remains the oldest record of Greek medicine and a unique source of surgical history. This study examines the upper extremity injuries described in the Iliad and compares them to those other sites of injury. PMID- 23932118 TI - Vena cava filters for management of venous thromboembolism: a clinical review. AB - Venous thromboembolism (VTE) is the common cause of morbidity and mortality. Vena cava filters (VCF) represent an important alternative to anticoagulation for management of VTE. VCF use has increased dramatically with the availability of retrievable filters. Since indiscriminate use of VCF can be associated with net patient harm, knowledge of the risks and benefits of these devices is essential to optimal evidence-based practice. In this review, we will examine the characteristics of available permanent and optional VCF, their efficacy and safety in management of VTE and discuss appropriate, extended and unsubstantiated indications for VCF use. We will also review the clinical outcomes of VCF in alternative placement sites (supra-renal inferior vena cava and superior vena cava) and in specialized patient populations (bariatric surgery, cancer, etc.), recommendations regarding anticoagulation for prevention of thrombosis as well as recommended follow up for patients with VCF. PMID- 23932119 TI - Schwannomas of the foot and ankle: a technical report. AB - The present technical report provides a detailed description of open surgical resection of peripheral nerve sheath tumors in the foot and ankle. We present 3 cases to illustrate important differences in the technique based on the presentation, anatomic location, and intraoperative neurophysiologic monitoring findings. It is important for surgeons to understand that surgical excision of many peripheral nerve sheath tumors can be undertaken without en bloc resection of the entire nerve trunk. PMID- 23932122 TI - Pulmonary embolism as a cause of seizure. PMID- 23932121 TI - Genetically targeted optical electrophysiology in intact neural circuits. AB - Nervous systems process information by integrating the electrical activity of neurons in complex networks. This motivates the long-standing interest in using optical methods to simultaneously monitor the membrane potential of multiple genetically targeted neurons via expression of genetically encoded fluorescent voltage indicators (GEVIs) in intact neural circuits. No currently available GEVIs have demonstrated robust signals in intact brain tissue that enable reliable recording of individual electrical events simultaneously in multiple neurons. Here, we show that the recently developed "ArcLight" GEVI robustly reports both subthreshold events and action potentials in genetically targeted neurons in the intact Drosophila fruit fly brain and reveals electrical signals in neurite branches. In the same way that genetically encoded fluorescent sensors have revolutionized the study of intracellular Ca(2+) signals, ArcLight now enables optical measurement in intact neural circuits of membrane potential, the key cellular parameter that underlies neuronal information processing. PMID- 23932120 TI - From structure to systems: high-resolution, quantitative genetic analysis of RNA polymerase II. AB - RNA polymerase II (RNAPII) lies at the core of dynamic control of gene expression. Using 53 RNAPII point mutants, we generated a point mutant epistatic miniarray profile (pE-MAP) comprising ~60,000 quantitative genetic interactions in Saccharomyces cerevisiae. This analysis enabled functional assignment of RNAPII subdomains and uncovered connections between individual regions and other protein complexes. Using splicing microarrays and mutants that alter elongation rates in vitro, we found an inverse relationship between RNAPII speed and in vivo splicing efficiency. Furthermore, the pE-MAP classified fast and slow mutants that favor upstream and downstream start site selection, respectively. The striking coordination of polymerization rate with transcription initiation and splicing suggests that transcription rate is tuned to regulate multiple gene expression steps. The pE-MAP approach provides a powerful strategy to understand other multifunctional machines at amino acid resolution. PMID- 23932123 TI - Caution with interpreting laboratory results after lipid rescue therapy. AB - Intravenous lipid rescue therapy (LRT) may be implemented to attenuate drug toxicity. Little is known about LRT interference with laboratory tests in overdose settings. A 54-year-old man with a history of depression consumed unknown amounts of diphenhydramine, amitriptyline, and acetaminophen (APAP). Initial workup showed aspartate aminotransferase (AST) of 138 U/L, APAP of 177 MUg/mL, and a QRS interval of 136 milliseconds. N-acetylcysteine, sodium bicarbonate, and 20% intravenous LRT were initiated. Laboratory test results drawn less than 6 hours later showed an APAP level of 44 MUg/mL and an undetectable AST (Siemens Vista 1500 analyzer, lower limit of detection: alanine aminotransferase, 6 U/L; AST, 3 U/L). N-acetylcysteine and LRT infusions were stopped. Eight hours later, serum AST was measured at 488 U/L and increased over the next 2 days to a peak of 1600 U/L before recovery. Given a gradually rising course of AST following APAP ingestion, a single undetectable measurement is highly unlikely and probably erroneous. For this Siemens analyzer, serum lipid concentrations greater than 400 mg/dL cause interference with the AST measurement. Because lipid levels greater than 400 mg/dL with other similar analyzers are known to falsely decrease the AST, it is possible that extreme lipemia caused this laboratory result; a triglyceride level of 3648 mg/dL has been reported after LRT infusion. This conclusion is limited by the lack of repeat measurement of liver enzymes or measurement of serum lipid levels. Lipid rescue therapy may cause lipemia that interferes with the assay for liver enzymes. Suspected abnormal laboratory values should be repeated, or other techniques can be used to remove lipemic interference. PMID- 23932124 TI - Longus colli tendonitis, clinical consequences of a misdiagnosis. AB - Numerous pathologies diagnosed in the emergency department (ED) are treated with invasive procedures involving anesthetic and surgical risks. Retropharyngeal abscess is a serious condition requiring emergent treatment, often in need of trans-oral incision and drainage under general anesthesia. A misdiagnosis, especially after surgical treatment, might generate undesirable consequences, more so if the final diagnosis is a non-surgical pathology such as longus colli (LC) tendonitis. To discuss the etiology, differential diagnosis and treatment of LC tendonitis, a clinical condition still misdiagnosed despite advanced imaging techniques. A middle-aged man presented to a satellite ED with sore throat, neck pain and stiffness. A computed tomography (CT) scan of the neck with intravenous contrast was read as retropharyngeal abscess. He was transferred to our ED after acceptance by ear-nose-throat (ENT) surgery. He was scheduled for open incision and drainage under general anesthesia. A detailed evaluation by our ED staff revealed a nontoxic patient with no compromise of the airway. His physical exam was unrevealing and a second review of the CT demonstrated typical radiological signs for LC tendonitis. After a discussion with ENT the patient was discharged home on anti-inflammatory medications and oral steroids. He recovered well and no further intervention was needed. Longus colli tendonitis is a rare condition that mimics emergent surgical conditions. Emergency physicians are qualified to make a clinical and radiological diagnosis. While CT scan can provide a diagnosis, the primary evaluation tool is an adequate medical interview and physical exam. PMID- 23932125 TI - The role of pluripotency gene regulatory network components in mediating transitions between pluripotent cell states. AB - Pluripotency is a property that early embryonic cells possess over a considerable developmental time span. Accordingly, pluripotent cell lines can be established from the pre-implantation or post-implantation mouse embryo as embryonic stem (ES) or epiblast stem (EpiSC) cell lines, respectively. Maintenance of the pluripotent phenotype depends on the function of specific transcription factors (TFs) operating within a pluripotency gene regulatory network (PGRN). As cells move from an ES cell to an EpiSC state, the PGRN changes with expression of some TFs reduced (e.g. Nanog) or eliminated (e.g. Esrrb). Re-expressing such TFs can move cells back to an earlier developmental identity and is being applied to attempt establishment of human cell lines with the properties of mouse ES cells. PMID- 23932126 TI - Ways, means and consequences of shaping morphogen gradients. PMID- 23932127 TI - Toward directed reprogramming through exogenous factors. AB - Direct reprogramming of one cell type into another provides unprecedented opportunities to study fundamental biology, model disease, and develop regenerative medicine. Different paradigms of reprogramming strategies with different sets of factors have been developed to generate various cell types, including induced pluripotent stem cells, neuronal or neural precursor cells, cardiomyocyte-like cells, endothelial cells, and hepatocyte-like cells. Various exogenous factors, especially small molecules modulating signaling, cellular state, and transcription, have been identified to enhance and enable reprogramming. With an increased understanding of reprogramming mechanisms and discovery of new molecules, it is conceivable that reprogramming can be achieved in a more directed and deterministic manner under entirely chemically defined conditions. PMID- 23932128 TI - Factors affecting economics of using sexed semen in dairy cattle. AB - The use of sexed semen in the dairy industry has grown rapidly. However, high costs and low fertility have limited the use of this potentially valuable tool. This study used simulation to evaluate 160,000 combinations of key variables in 3 spheres of influence related to profit feasibility: (1) market (e.g., milk and calf prices), (2) dairy farm management (e.g., conception rates), and (3) technology (e.g., accuracy of sexing). These influential variables were used to determine the most favorable circumstances in which managers or technicians can effect change. Three distinct scenarios were created to model 3 initiatives that a producer might take with sexed semen: (1) using sexed semen on heifers, (2) using sexed semen on heifers and a fraction of the genetically superior cows, and (3) using sexed semen on heifers and a fraction of the genetically superior cows, and breeding all other cows with beef semen. Due to the large number of management, market, and technology combinations, a response surface and interpretive graphs were created to map the scope of influence for the key variables. Technology variables such as the added cost of sexed semen had relatively little effect on profitability, defined as net present value gain per cow, whereas management variables such as conception rate had a significant effect. Milk price had relatively little effect within each scenario, but was important across scenarios. Profitability was very sensitive to the price of dairy heifer calves, relative to beef and dairy bull calves. Scenarios 1 and 2 added about $50 to $75 per cow in net present value, which ranged from $0 to $200 and from $100 to $300, respectively. Scenario 3 usually was not profitable, primarily because fewer excess dairy replacement heifers were available for sale. Dairy heifer price proved to be the most influential variable, regardless of scenario. PMID- 23932129 TI - Random Forests approach for identifying additive and epistatic single nucleotide polymorphisms associated with residual feed intake in dairy cattle. AB - Feed efficiency is an economically important trait in the beef and dairy cattle industries. Residual feed intake (RFI) is a measure of partial efficiency that is independent of production level per unit of body weight. The objective of this study was to identify significant associations between single nucleotide polymorphism (SNP) markers and RFI in dairy cattle using the Random Forests (RF) algorithm. Genomic data included 42,275 SNP genotypes for 395 Holstein cows, whereas phenotypic measurements were daily RFI from 50 to 150 d postpartum. Residual feed intake was defined as the difference between an animal's feed intake and the average intake of its cohort, after adjustment for year and season of calving, year and season of measurement, age at calving nested within parity, days in milk, milk yield, body weight, and body weight change. Random Forests is a widely used machine-learning algorithm that has been applied to classification and regression problems. By analyzing the tree structures produced within RF, the 25 most frequent pairwise SNP interactions were reported as possible epistatic interactions. The importance scores that are generated by RF take into account both main effects of variables and interactions between variables, and the most negative value of all importance scores can be used as the cutoff level for declaring SNP effects as significant. Ranking by importance scores, 188 SNP surpassed the threshold, among which 38 SNP were mapped to RFI quantitative trait loci (QTL) regions reported in a previous study in beef cattle, and 2 SNP were also detected by a genome-wide association study in beef cattle. The ratio of number of SNP located in RFI QTL to the total number of SNP in the top 188 SNP chosen by RF was significantly higher than in all 42,275 whole-genome markers. Pathway analysis indicated that many of the top 188 SNP are in genomic regions that contain annotated genes with biological functions that may influence RFI. Frequently occurring ancestor-descendant SNP pairs can be explored as possible epistatic effects for further study. The importance scores generated by RF can be used effectively to identify large additive or epistatic SNP and informative QTL. The consistency in results of our study and previous studies in beef cattle indicates that the genetic architecture of RFI in dairy cattle might be similar to that of beef cattle. PMID- 23932130 TI - Subacute ruminal acidosis and total mixed ration preference in lactating dairy cows. AB - Subacute ruminal acidosis (SARA) is a condition where the pH of the rumen becomes abnormally acidic because of increased and altered production of volatile fatty acids. The objective of this experiment was to determine how a SARA challenge affects total mixed ration selection in dairy cows. In this study, 8 multiparous, lactating, ruminally cannulated Holstein cows were given a choice between a long forage-particle-size diet with slow-fermenting starch (LC) and a short-forage particle-size diet with fast-fermenting starch in a crossover design. Cows were allowed to adapt to this feeding scheme and were then subjected to a rumen challenge to induce a bout of SARA. The rumen challenge successfully decreased rumen pH and altered rumen volatile fatty acid profiles. Daily average rumen pH decreased from 6.02 to 5.77, and average minimum rumen pH decreased from 5.59 to 5.28. In addition, following the rumen challenge, concentrations of acetate, butyrate, and valerate, and acetate-to-propionate ratio increased. In response to the rumen challenge, intake of LC increased from the baseline level of 18.1% of total daily dry matter intake to 38.3% for that day. During the first recovery day after the rumen challenge, LC intake moderated to 28.0% of total daily dry matter intake. On the second recovery day, LC intake returned to baseline levels at 18.6%. These results indicate that cows are able to alter their diet preference for higher physically effective fiber and slower starch fermentability during a bout of SARA and that they can effectively fully recover from this type of SARA within 72 h when appropriate diets are available. PMID- 23932131 TI - Effects of feeding wheat or corn-wheat dried distillers grains with solubles in low- or high-crude protein diets on ruminal function, omasal nutrient flows, urea N recycling, and performance in cows. AB - A study was conducted to determine the effects of including either wheat-based (W DDGS) or corn-wheat blend (B-DDGS) dried distillers grains with solubles as the major protein source in low- or high-crude protein (CP) diets fed to dairy cows on ruminal function, microbial protein synthesis, omasal nutrient flows, urea-N recycling, and milk production. Eight lactating Holstein cows (768.5 +/- 57.7 kg of body weight; 109.5 +/- 40.0 d in milk) were used in a replicated 4 * 4 Latin square design with 28-d periods (18d of dietary adaptation and 10d of measurements) and a 2 * 2 factorial arrangement of dietary treatments. Four cows in one Latin square were ruminally cannulated for the measurement of ruminal fermentation characteristics, microbial protein synthesis, urea-N recycling kinetics, and omasal nutrient flow. The treatment factors were type of distillers co-product (W-DDGS vs. B-DDGS) and dietary CP content [15.2 vs. 17.3%; dry matter (DM) basis]. The B-DDGS was produced from a mixture of 15% wheat and 85% corn grain. All diets were formulated to contain 10% W-DDGS or B-DDGS on a DM basis. No diet effect was observed on DM intake. Yields of milk, fat, protein, and lactose, and plasma urea-N and milk urea-N concentrations were lower in cows fed the low-CP compared with those fed the high-CP diet. Although feeding B-DDGS tended to reduce ruminal ammonia-N (NH3-N) concentration compared with feeding W DDGS (9.3 vs. 10.5mg/dL), no differences were observed in plasma urea-N and milk urea-N concentrations. Additionally, dietary inclusion of B-DDGS compared with W DDGS did not affect rumen-degradable protein supply, omasal flows of total N, microbial nonammonia N (NAN), rumen-undegradable protein, and total NAN, or urea N recycling kinetics and milk production. However, cows fed the low-CP diet had lower N intake, rumen-degradable protein supply, ruminal NH3-N concentration, and omasal flows of N, microbial NAN, and total NAN compared with those fed the high CP diet. Feeding the low-CP compared with the high-CP diet also resulted in lower endogenous urea-N production, urea-N recycled to the gastrointestinal tract, and urea-N excretion in urine. In summary, our results indicate that both W-DDGS and B-DDGS can be included as the major protein sources in dairy cow diets without compromising nutrient supply and production performance. However, feeding the low CP diet lowered omasal flows of microbial protein and metabolizable protein, which, in turn, resulted in lower milk production compared with feeding the high CP diet. PMID- 23932132 TI - Investigation of the migration of triclabendazole residues to milk products manufactured from bovine milk, and stability therein, following lactating cow treatment. AB - Triclabendazole (TCB) is a flukicide used in the treatment of liver fluke in cattle; however, its use is currently prohibited in lactating dairy cows. In this study, following administration of 10% Fasinex (triclabendazole, Novartis Animal Health UK Ltd., Camberley, UK) the milk of 6 animals was used to manufacture dairy products, to ascertain if TCB residues in milk migrate into dairy products. The detection limit of the ultra-high-performance liquid chromatography-tandem mass spectrometry method used was 0.67 MUg/kg. The highest concentrations of TCB residue measured, within the individual cow milk yield, was 1,529 +/- 244 ug/kg (n=6), on d 2 posttreatment. Days 2 and 23 posttreatment represented high and low residue concentrations, respectively. At each of these 2 time points, the milk was pooled into 2 independent aliquots and refrigerated. Milk products, including cheese, butter, and skim milk powder were manufactured using pasteurized and unpasteurized milk from each aliquot. The results for high residue milks demonstrated that TCB residues concentrated in the cheese by a factor of 5 (5,372 vs. 918 ug/kg for cheese vs. milk) compared with the starting milk. Residue concentrations are the sum of TCB and its metabolites, expressed as keto-TCB. Residues were concentrated in the butter by a factor of 9 (9,177 vs. 1,082 MUg/kg for butter vs. milk) compared with the starting milk. For milk, which was separated to skim milk and cream fractions, the residues were concentrated in the cream. Once skim milk powder was manufactured from the skim milk fraction, the residue in powder was concentrated 15-fold compared with the starting skim milk (7,252 vs. 423 ug/kg for powder vs. skim milk), despite the high temperature (185 degrees C) required during powder manufacture. For products manufactured from milk with low residue concentrations at d 23 posttreatment, TCB residues were detected in butter, cheese, and skim milk powder, even though there was no detectable residue in the milk used to manufacture these products. Triclabendazole residues were concentrated in some milk products (despite manufacturing treatments), exceeding residue levels in the starting milk and, depending on the storage conditions, may be relatively stable over time. PMID- 23932133 TI - Early mammary gland metabolic and immune responses during natural-like and forceful drying-off in high-yielding dairy cows. AB - The present work compared metabolic and immune responses in genetically high producing cows that produced a low amount of milk before expected involution and in cows with the same genetic potential that produced copious amounts of milk before their scheduled drying-off. Ten multiparous lactating Israeli Holstein cows producing approximately 10,500 L in the current lactation, without bacterial infection and scheduled for drying-off approximately 60 d before their expected parturition, were studied. Five of the cows that exhibited a sharp, spontaneous reduction in milk yield at the end of their lactation and produced less than ~14L/d were defined as cows approaching natural involution (ANI), and 5 cows that produced between 25 and 35 L/d were defined as cows approaching forced involution (AFI). Three days before scheduled drying-off, milking was stopped and milk samples were collected from each quarter. After milking cessation, only modest swelling was observed in the udders of the ANI cows. In the ANI cows, lactose and fat concentrations decreased and the fat:lactose concentration ratio indicated that on d 1 and 2 fat concentrations decreased faster than lactose concentration, whereas on d 3, the rate of reduction was about the same for lactose and fat. In contrast, in AFI cows, fat concentrations increased on d 1 and the fat:lactose ratio indicated that changes in fat secretion were minor compared with those of lactose secretion. Rennet clotting time of milk after drying-off in the ANI cows increased, whereas curd firmness decreased rapidly, such that mammary secretions did not coagulate on d 3. In the AFI cows, such significant changes were observed only on d 3. The inflammatory response increased in both groups, but at each stage the increase was greater in ANI cows than in AFI cows. On d 1, the increase in leukocyte numbers in the ANI cows was made up of mononuclear cells (i.e., T lymphocytes and macrophages). In contrast, in the AFI cows, we observed a marked increase in leukocyte numbers, mainly in the form of polymorphonuclear cells. Our data indicate that the abrupt mammary involution induced in AFI cows provoked signs of distress, which were associated with neutrophilia in milk. In contrast, in the ANI cows, cessation of milking occurred without evidence of engorgement of the udder. Physiological differences in ANI and AFI cows are distinct and are reflected in the differences in the leukocyte populations in milk. PMID- 23932134 TI - Comparisons of milk quality on North Carolina organic and conventional dairies. AB - The organic dairy industry is growing rapidly across the United States and has recently expanded into the southeastern states. To date, no published comparisons of milk quality exist between organic and conventional dairies in the Southeastern United States. Maintaining high milk quality is challenging in this region due to the longer periods of high heat and humidity. The objective of this observational study was to compare milk quality on organic and conventional dairies in North Carolina during the warm summer months of the year. Data were compared from 7 organically and 7 conventionally managed herds in North Carolina. To assess milk quality, milk samples were aseptically collected from each functional quarter of each cow in the milking herds at the time of sampling and linear somatic cell scores (SCS) were obtained for individual cows. A total of 4,793 quarter milk samples (2,526 conventional and 2,267 organic) were collected from 1,247 cows (652 conventional and 595 organic). Milk samples were cultured and bacterial growth was identified using protocols consistent with those of the National Mastitis Council (Verona, WI). Subclinical mastitis was defined as the presence of SCS >= 4 and also a microbiological infection in at least 1 quarter. The proportion of cows with subclinical mastitis did not differ between conventional (20.8%) and organic (23.3%) herds. No significant difference was observed between herd management types in the proportion of cows without microbiological growth in milk samples. Also, no significant differences were observed between organic and conventional herds for cow-level prevalence of Staphylococcus aureus, coagulase-negative Staphylococcus spp., Streptococcus spp., or Corynebacterium spp. Two of the organic herds had a notably higher prevalence of Corynebacterium spp. and higher SCS. Coliforms were found in 5 of 7 conventional herds and in only 1 of 7 organic herds. Mean SCS did not differ between conventional (3.3+/-0.2) and organic (3.5+/-0.2) herds. Despite differences in herd management, milk quality was remarkably similar between the organic and conventional dairies compared for this study. PMID- 23932135 TI - Physiological and behavioral stress parameters in calves in response to partial scrotal resection, orchidectomy, and Burdizzo castration. AB - Establishing artificial cryptorchids by partial scrotal resection without removing the testicles is a technique for castration of bull calves that recently has gained new interest. In contrast to orchidectomy and Burdizzo castration, the stress response of calves to shortening of the scrotum is unknown. In this study, partial scrotal resection in bull calves was compared with orchidectomy, Burdizzo castration, and controls without intervention (n=10 per group, ages 56 +/- 3 d). Procedures were performed under xylazine sedation and local anesthesia. We hypothesized that partial scrotal resection is least stressful. Salivary cortisol, heart rate, heart rate variability, behavior, and locomotion were analyzed. Cortisol concentration peaked 60 min after start of the procedures. Cortisol release was at least in part xylazine induced and none of the experimental procedures released additional cortisol. Heart rate increased in calves of all groups with initial handling, but immediately after xylazine sedation decreased to 30% below initial values and was not modified by surgical procedures. The heart rate variability variables standard deviation of beat-to beat interval and root mean square of successive beat-to-beat differences increased when calves were placed on the surgery table but effects were similar in calves submitted to surgeries and control calves. Locomotion increased, whereas lying time decreased in response to all surgeries. Locomotion increase was most pronounced after orchidectomy. Plasma fibrinogen concentrations increased after orchidectomy only. With adequate pain medication, orchidectomy, Burdizzo castration, and partial scrotal resection do not differ with regard to acute stress and, by inference, pain. Partial scrotal resection when carried out under xylazine sedation and local anesthesia thus is an acceptable castration technique in bull calves. PMID- 23932136 TI - Evaluating results of the Welfare Quality multi-criteria evaluation model for classification of dairy cattle welfare at the herd level. AB - The Welfare Quality multi-criteria evaluation (WQ-ME) model aggregates scores of single welfare measures into an overall assessment for the level of animal welfare in dairy herds. It assigns herds to 4 welfare classes: unacceptable, acceptable, enhanced, or excellent. The aim of this study was to demonstrate the relative importance of single welfare measures for WQ-ME classification of a selected sample of Dutch dairy herds. Seven trained observers quantified 63 welfare measures of the Welfare Quality protocol in 183 loose housed- and 13 tethered Dutch dairy herds (herd size: 10 to 211 cows). First, values of welfare measures were compared among the 4 welfare classes, using Kruskal-Wallis and Chi squared tests. Second, observed values of single welfare measures were replaced with a fictitious value, which was the median value of herds classified in the next highest class, to see if improvement of a single measure would enable a herd to reach a higher class. Sixteen herds were classified as unacceptable, 85 as acceptable, 78 as enhanced, and none as excellent. Classification could not be calculated for 17 herds because data were missing (15 herds) or data were deemed invalid because the stockperson disturbed behavioral observations (2 herds). Herds classified as unacceptable showed significantly more very lean cows, more severely lame cows, and more often an insufficient number of drinkers than herds classified as acceptable. Herds classified as acceptable showed significantly more cows with high somatic cell count, with lesions, that could not be approached closer than 1m, colliding with components of the stall while lying down, and lying outside the lying area, and showed fewer cows with diarrhea, more often had an insufficient number of drinkers, and scored lower for the descriptors "relaxed" and "happy" than herds classified as enhanced. Increasing the number of drinkers and reducing the percentage of cows colliding with components of the stall while lying down were the changes most effective in allowing herds classified as unacceptable and acceptable, respectively, to reach a higher class. The WQ-ME model was not very sensitive to improving single measures of good health. We concluded that a limited number of welfare measures had a strong influence on classification of dairy herds. Classification of herds based on the WQ-ME model in its current form might lead to a focus on improving these specific measures and divert attention from improving other welfare measures. The role of expert opinion and the type of algorithmic operator used in this model should be reconsidered. PMID- 23932137 TI - Short communication: a note on the correction for the effect of freezing on the outcome of pregnancy-associated glycoprotein measurement in blood and serum of cows. AB - Early pregnancy detection is a measure of considerable economic relevance for dairy cattle breeders, and analysis of pregnancy-associated glycoprotein (PAG) values in blood is one of the methods implemented in practice. Starting from d 30 postconception, cows are considered to be pregnant at PAG levels of 2.0 ng of PAG/mL of blood and higher. However, little is known about preanalytic sources of errors that might affect PAG values. Based on blood samples from 65 dairy cows, the present study showed that freezing of samples, such as may be the case during shipping in wintertime, will lower PAG values considerably. Therefore, a Bland Altman analysis was used to derive a correction factor. Overall, the mean differences (+/- standard deviation) between frozen and respective fresh samples was -5.5 +/- 7.4 ng of PAG/mL of blood and 0.9 +/- 6.1 ng of PAG/mL of serum. However, the Bland-Altman plot revealed a concentration-dependent effect of freezing on PAG values with higher variability and larger declines at higher PAG levels. Therefore, to minimize chances of false-negative results, different correction factors are suggested for different levels of PAG (e.g., based on the upper bound of the 95% confidence interval 0.67 for PAG levels between 2.0 and 3.9 ng of PAG/mL and 0.25 for PAG levels between 4.0 and 7.9 ng of PAG/mL). With these concentration-dependent correction factors, implementation into practice will be possible. The accuracy is adequate because no quantitative information but qualitative results (pregnant vs. nonpregnant) are required. However, due to larger chances of false-negative results, the application of the correction factor should only be a last resort if temperature exposure of a sample is unknown. PMID- 23932138 TI - Systemic prepartum treatment of end-term dairy heifers with penethamate hydriodide: effect on udder health, milk yield, and culling until 120 days in milk. AB - Prepartum intramammary treatment with antimicrobials of end-term dairy heifers has frequently been proposed as a practice to reduce the prevalence of intramammary infections (IMI) at calving. From a safety standpoint for both animal and administrator, systemic treatment is preferred. A clinical trial was conducted on heifers from 10 well-managed, commercial dairy farms with a low prevalence of heifer mastitis. The aim was to assess both the short- and long term effects of a systemic prepartum therapy with penethamate hydriodide on udder health and milk production. Because it was hypothesized that some herds would benefit more from this treatment than others, specific herd-level information was collected before the start of the actual trial to screen for and explain potential herd-specific treatment effects. Further, the effect of treatment on antimicrobial susceptibility of staphylococcal isolates was monitored. End-term heifers were either treated systemically (over 3 consecutive days) 2 wk before expected calving date with penethamate hydriodide (n=76) or remained untreated (n=73). Systemic prepartum treatment of end-term heifers with penethamate hydriodide resulted in fewer IMI in early lactation. However, all 6 cases of clinical mastitis in early lactation occurred in the treatment group [Streptococcus uberis (n=1), Corynebacterium bovis (n=1), Staphylococcus aureus (n=1); 1 sample was contaminated; 2 samples remained culture negative]. No long term treatment effects (from 4 to 120 d in milk) on milk production, udder health, or culling hazard during later lactation were detected, although treated heifers belonging to herds classified as having low-yielding heifers out-produced the control heifers. Moreover, penicillin susceptibility of staphylococci isolated from milk samples of treated or control heifers did not differ. Herds with a low prevalence of heifer mastitis are not likely to benefit from prepartum systemic antimicrobial treatment of the end-term heifers. PMID- 23932139 TI - Short communication: Influence of long-chain inulin and Lactobacillus paracasei subspecies paracasei on the sensory profile and acceptance of a traditional yogurt. AB - The objectives of this study were to evaluate the influence of the addition of long-chain inulin as a fat replacer and prebiotic agent (20g/L) and (or) probiotic Lactobacillus paracasei ssp. paracasei on the sensory profile and acceptance of yogurts, and to assess the influence of descriptive attributes on the sensory acceptance of the products. The addition of inulin to low-fat yogurt improved its brightness and firmness, which was similar to the full-fat yogurt. However, the use of long-chain inulin increased the separation of serum and no influence on creaminess was observed. Regarding the product's acceptability, the low-fat yogurt with added inulin presented similar acceptance compared with the full-fat yogurt. The addition of Lb. paracasei ssp. paracasei did not affect the sensory profile and acceptance of the low-fat yogurt. Using external preference mapping, it was possible to verify that the sensory acceptance was driven positively by the sweetness and creaminess and negatively driven by firmness (appearance and texture) and homogeneity (appearance). It was possible to formulate low-fat yogurts with added probiotics that presented similar sensory characteristics to those of full-fat yogurts, and this was due to the addition of the long-chain inulin as a fat replacer. PMID- 23932140 TI - Heparin/N-acetylcysteine: an adjuvant in the management of burn inhalation injury: a study of different doses. AB - PURPOSE: Nebulized heparin may reduce fibrin cast formation and reduce the degree of airway obstruction in burn inhalation injury. METHODS: Twenty-nine patients admitted to burn intensive care unit (ICU) within 24 hours of burn inhalation injury were included in this prospective double-blinded randomized study. Group H5 received nebulized heparin sulfate 5,000 IU, and group H10 received nebulized heparin sulfate 10,000 IU. Heparin was given in alternation with N-acetylcysteine every 2 hours. Lung injury score assessed daily for 7 days was the primary outcome. Duration of mechanical ventilation, coagulation profile, length of ICU stay, and mortality were the secondary outcomes. RESULTS: Median lung injury scores were significantly lower in group H10 on days 5 (1.9 vs 1), 6 (1.4 vs 0.5), and 7 (1.3 vs 0.5). Group H10 had also a lower duration of mechanical ventilation than did group H5 (P = .037). The groups had no significant difference in coagulation parameters, length of ICU stay (P = .17), and mortality (P = .6). CONCLUSIONS: Nebulized heparin 10,000 IU decreased lung injury scores and duration of mechanical ventilation but had no effect on length of ICU stay and mortality. Moreover, nebulized heparin 10,000 IU was safe and had no effect on coagulation parameters. PMID- 23932142 TI - Engineered ion channels as emerging tools for chemical biology. AB - Over the last 25 years, researchers have developed exogenously expressed, genetically engineered, semi-synthetic, and entirely synthetic ion channels. These structures have sufficient fidelity to serve as unique tools that can reveal information about living organisms. One of the most exciting success stories is optogenetics: the use of light-gated channels to trigger action potentials in specific neurons combined with studies of the response from networks of cells or entire live animals. Despite this breakthrough, the use of molecularly engineered ion channels for studies of biological systems is still in its infancy. Historically, researchers studied ion channels in the context of their own function in single cells or in multicellular signaling and regulation. Only recently have researchers considered ion channels and pore-forming peptides as responsive tools to report on the chemical and physical changes produced by other biochemical processes and reactions. This emerging class of molecular probes has a number of useful characteristics. For instance, these structures can greatly amplify the signal of chemical changes: the binding of one molecule to a ligand-gated ion channel can result in flux of millions of ions across a cell membrane. In addition, gating occurs on sub-microsecond time scales, resulting in fast response times. Moreover, the signal is complementary to existing techniques because the output is ionic current rather than fluorescence or radioactivity. And finally, ion channels are also localized at the membrane of cells where essential processes such as signaling and regulation take place. This Account highlights examples, mostly from our own work, of uses of ion channels and pore forming peptides such as gramicidin in chemical biology. We discuss various strategies for preparing synthetically tailored ion channels that range from de novo designed synthetic molecules to genetically engineered or simply exogenously expressed or reconstituted wild-type channels. Next we consider aspects of experimental design by comparing various membrane environments or systems that make it possible to quantify the response of ion channels to biochemical processes of interest. We present applications of ion channels to answer questions in chemical biology, and propose potential future developments and applications of these single molecule probes. Finally we discuss the hurdles that impede the routine use of ion channel probes in biochemistry and cell biology laboratories and developments and strategies that could overcome these problems. Optogenetics has facilitated breakthroughs in neuroscience, and these results give a dramatic idea of what may lie ahead for designed ion channels as a functional class of molecular probes. If researchers can improve molecular engineering to increase ion channel versatility and can overcome the barriers to collaborating across disciplines, we conclude that these structures could have tremendous potential as novel tools for chemical biology studies. PMID- 23932141 TI - Associations between poor sleep quality and psychosocial stress with obesity in reproductive-age women of lower socioeconomic status. AB - BACKGROUND: Prior studies have not examined the role of psychosocial stress in the relationship between poor sleep quality and obesity among women of lower socioeconomic status (SES). We tested the following hypotheses in a sample of reproductive-age women of lower SES: 1) Poor sleep quality is related to increased risk of obesity, and 2) psychosocial stress confounds this association between poor sleep quality and obesity. METHODS: A total of 927 women age 16 to 40 years attending public health clinics in Southeastern Texas provided information on the Pittsburgh Sleep Quality Index and sociodemographic and health characteristics, including the Perceived Stress Scale. Height, weight, and waist circumference (WC) were measured in clinic. A series of models examined the associations between sleep disturbance, perceived stress, and weight outcomes, accounting for potential confounding factors. RESULTS: Nearly 30% of women were overweight, and 35% were obese. Half of women had a WC of greater than 35 inches. Most women had poor sleep quality and high levels of stress. Sleep quality and perceived stress were not related to body mass index category or WC in models that adjusted for age and race/ethnicity. Adjusting for potential confounding factors did not alter results. Perceived stress did not modify the association between sleep quality and weight outcomes. CONCLUSIONS: Poor sleep quality and psychosocial stress were not related to weight in reproductive-aged women of lower SES. However, poor sleep quality, high stress, overweight, and obesity were common in this group. PMID- 23932143 TI - Potency evaluation of tissue engineered and regenerative medicine products. AB - Methodologies for the rigorous and quantitative evaluation of biological activity or potency are an essential aspect of the developmental pathway for all biologic product candidates. Such assays typically leverage key mechanistic pathways demonstrated to mediate observed therapeutic outcomes. Tissue engineered/regenerative medicine (TE/RM) therapeutics include cell based therapies as well as engineered tissues and neo-organs for which clarity regarding the mechanism or mechanisms of action may not be forthcoming. Here, we discuss how strategies for the development of potency assays for TE/RM product candidates may harness potential mechanisms of action or other therapeutically relevant bioactivity along with cell number and viability. As the pipeline for TE/RM product candidates expands through 2014 and beyond, the establishment of a defined framework for potency assays will facilitate successful translational outcomes. PMID- 23932144 TI - Brachytherapy or stereotactic body radiotherapy boost for early-stage oropharyngeal cancer: comparable outcomes of two different approaches. AB - OBJECTIVES: To compare outcome, toxicity and QoL of two boost modalities for T1-2 oropharyngeal carcinoma (OPC). MATERIALS AND METHODS: Between 2000 and 2012, 250 consecutive patients with T1-2N0-3 were treated with 46-Gy of IMRT followed by boost using brachytherapy (BTB) or stereotactic body radiotherapy (CKB). Endpoints were local control (LC), disease-free survival (DFS), overall survival (OS), toxicity and prospective QoL-assessment. RESULTS: The 3-year actuarial incidence of LC were 97% and 94% for the CKB and BTB, respectively (p=0.33). The figures for DFS were 92% and 86% (p=0.15) and for OS were 81% and 83% (p=0.82), respectively. The incidence of tube feeding were 17% and 20%, respectively (p=0.47). The figures for grade ?2 late dysphagia were 11% and 8% (p=0.34) and for xerostomia were 16% and 12% (p=0.28), respectively. For both modalities, clinically relevant deteriorations were seen on all scales at end of treatment but the scores returned to almost baseline levels within 6-12months, with exception of QLQ-H&N35-xerostomia. The difference on that scale was neither statistically significant nor clinically relevant between both modalities. CONCLUSION: Comparable outcome, toxicity and QoL-scores were achieved with both modalities. In the light of the logistical hassle around the implantation, the need of dexterity, and the risk of anaesthesia and peri-operative complications associated with BTB, CKB might be regarded as the optimal option to boost early stage OPC. However, in radiotherapy departments where no facilities are available for stereotactic radiotherapy, BTB is an elegant option to achieve excellent outcome with low toxicity profile and good QoL. PMID- 23932145 TI - Kinetics of the biodegradation pathway of endosulfan in the aerobic and anaerobic environments. AB - The enriched mixed culture aerobic and anaerobic bacteria from agricultural soils were used to study the degradation of endosulfan (ES) in aqueous and soil slurry environments. The extent of biodegradation was ~95% in aqueous and ~65% in soil slurry during 15 d in aerobic studies and, ~80% in aqueous and ~60% in soil slurry during 60 d in anaerobic studies. The pathways of aerobic and anaerobic degradation of ES were modeled using combination of Monod no growth model and first order kinetics. The rate of biodegradation of beta-isomer was faster compared to alpha-isomer. Conversion of ES to endosulfan sulfate (ESS) and endosulfan diol (ESD) were the rate limiting steps in aerobic medium and, the hydrolysis of ES to ESD was the rate limiting step in anaerobic medium. The mass balance indicated further degradation of endosulfan ether (ESE) and endosulfan lactone (ESL), but no end-products were identified. In the soil slurries, the rates of degradation of sorbed contaminants were slower. As a result, net rate of degradation reduced, increasing the persistence of the compounds. The soil phase degradation rate of beta-isomer was slowed down more compared with alpha-isomer, which was attributed to its higher partition coefficient on the soil. PMID- 23932146 TI - The sea-air exchange of mercury (Hg) in the marine boundary layer of the Augusta basin (southern Italy): concentrations and evasion flux. AB - The first attempt to systematically investigate the atmospheric mercury (Hg) in the MBL of the Augusta basin (SE Sicily, Italy) has been undertaken. In the past the basin was the receptor for Hg from an intense industrial activity which contaminated the bottom sediments of the Bay, making this area a potential source of pollution for the surrounding Mediterranean. Three oceanographic cruises have been thus performed in the basin during the winter and summer 2011/2012, where we estimated averaged Hgatm concentrations of about 1.5+/-0.4 (range 0.9-3.1) and 2.1+/-0.98 (range 1.1-3.1) ng m(-3) for the two seasons, respectively. These data are somewhat higher than the background Hg atm value measured over the land (range 1.1+/-0.3 ng m(-3)) at downtown Augusta, while are similar to those detected in other polluted regions elsewhere. Hg evasion fluxes estimated at the sea/air interface over the Bay range from 3.6+/-0.3 (unpolluted site) to 72+/-0.1 (polluted site of the basin) ng m(-2) h(-1). By extending these measurements to the entire area of the Augusta basin (~23.5 km(2)), we calculated a total sea-air Hg evasion flux of about 9.7+/-0.1 g d(-1) (~0.004 tyr(-1)), accounting for ~0.0002% of the global Hg oceanic evasion (2000 tyr(-1)). The new proposed data set offers a unique and original study on the potential outflow of Hg from the sea-air interface at the basin, and it represents an important step for a better comprehension of the processes occurring in the marine biogeochemical cycle of this element. PMID- 23932147 TI - Occurrence of perfluorinated carboxylic acids (PFCAs) in personal care products and compounding agents. AB - Perfluorinated carboxylic acids (PFCAs), including perfluorooctanoic acid (PFOA), are persistent organic pollutants that pose human health risks. However, sources of contamination and exposure pathways of PFCAs have not been explored. In this study, PFCA concentrations were quantified in personal care products. Among 24 samples that listed fluorinated compounds, such as polyfluoroalkyl phosphate esters (PAPs), in their international nomenclature of cosmetic ingredients (INCI) labels, 21contained PFCAs (13 of 15 cosmetic samples, and 8 of 9 sunscreen samples). The concentrations of total PFCAs ranged from not detected to 5.9 MUg g(-1) for cosmetics and from not detected to 19 MUg g(-1) for sunscreens. We also investigated components of PFCAs in cosmetics and sunscreens. Commercially available compounding agents, mica and talc, which were treated with PAPs were analyzed and high concentrations of PFCAs were detected (total PFCAs 2.5 MUg g( 1) for talc treated with PAPs, 35.0 MUg g(-1) for mica treated with PAPs). To the best of our knowledge, this is the first report on contamination of end consumer products containing PAPs with high concentrations of PFCAs. PMID- 23932149 TI - Competence of consent and associated factors among inpatients of schizophrenia in Changsha, China. PMID- 23932151 TI - Predictive factors for oropharyngeal mycosis during radiochemotherapy for head and neck carcinoma and consequences on treatment duration. Results of mycosis in radiotherapy (MIR): a prospective longitudinal study. AB - BACKGROUND AND PURPOSE: Oropharyngeal mycosis (OPM) is a complication of radiotherapy (RT) treatments for head and neck (H&N) cancer, worsening mucositis and dysphagia, causing treatment interruptions and increasing overall treatment time. Prophylaxis with antifungals is expensive. Better patient selection through the analysis of prognostic factors should improve treatment efficacy and reduce costs. MATERIALS AND METHODS: A multicentre, prospective, controlled longitudinal study, with ethics committee approval, examined H&N cancer patients who were candidates for curative treatments with radio-chemotherapy. Patients were divided in groups according to OPM appearance: before the starting of RT (cases), during RT (new cases) and never (no cases). RESULTS: Of 410 evaluable patients, 20 were existing cases, 201 new cases and 189 did not report OPM. In our study OPM appears in 42.4% of people >70years and in 58.2% of younger individuals (p=0.0042), and in 68.6% of women versus 50.8% of men (p=0.0069). Mucositis and dysphagia were higher and salivation reduced among people with OPM (p<0.0000). Patients with OPM had longer hospitalization (p=0.0002) and longer (>12days) treatment interruptions (p=0.0288). CONCLUSIONS: Patients with OPM had higher toxicity and a greater number of long treatment interruptions. Analyses of prognostic factors can help clinicians understand OPM distribution and select patients with the highest probability of OPM for antifungal prophylaxis. PMID- 23932150 TI - Involvement of anthocyanins in the resistance to chilling-induced oxidative stress in Saccharum officinarum L. leaves. AB - Whether anthocyanins elevate resistance to chilling-induced oxidative stress in Saccharum officinarum L. cv Badila seedlings is investigated. Plants with four fully expanded leaves were exposed to chilling stress (8 degrees C/4 degrees C, 11 h photoperiod) for 3 days and then transferred to rewarming condition (25 degrees C/20 degrees C, 11 h photoperiod) for another 2 days. At the end of the chilling period, H2O2 and superoxide radical (O2-) levels increased sharply and were near the same in the central (CL) and the final fully expanded leaves (FL). Moreover, the degree of chilling injury indicated by malonaldehyde concentration and percent of ion leakage also was near the same. Most of the tested parameters returned near to the control level after 2 days of rewarming. With further analyzing, we found that superoxide dismutase (EC 1.15.1.1), ascorbate peroxidase (EC 1.11.1.11), glutathione reductase (EC 1.6.4.2) activities increased much higher and catalase (EC 1.11.1.6) activity and ascorbate/dehydroascorbate ratio decreased much more in FL than CL in response to chilling. However, anthocyanins concentration coupling with glutathione/oxidized glutathione increased much higher in CL than FL under chilling stress. These finds suggest that anthocyanins at least partially compensate the relative deficiency of antioxidants in CL compared with FL. alpha,alpha-Diphenyl-beta-picrylhydrazyl assays further confirmed this idea. The relationships between anthocyanins and antioxidants were analyzed and the possible mechanisms of the affection of anthocyanins on antioxidant metabolism were discussed. PMID- 23932148 TI - Self-disturbances as a possible premorbid indicator of schizophrenia risk: a neurodevelopmental perspective. AB - Self-disturbances (SDs) are increasingly identified in schizophrenia and are theorized to confer vulnerability to psychosis. Neuroimaging research has shed some light on the neural correlates of SDs in schizophrenia. But, the onset and trajectory of the neural alterations underlying SDs in schizophrenia remain incompletely understood. We hypothesize that the aberrant structure and function of brain areas (e.g., prefrontal, lateral temporal, and parietal cortical structures) comprising the "neural circuitry of self" may represent an early, premorbid (i.e., pre-prodromal) indicator of schizophrenia risk. Consistent with neurodevelopmental models, we argue that "early" (i.e., perinatal) dysmaturational processes (e.g., abnormal cortical neural cell migration and mini columnar formation) affecting key prefrontal (e.g., medial prefrontal cortex), lateral temporal cortical (e.g., superior temporal sulcus), and parietal (e.g., inferior parietal lobule) structures involved in self-processing may lead to subtle disruptions of "self" during childhood in persons at risk for schizophrenia. During adolescence, progressive neurodevelopmental alterations (e.g., aberrant synaptic pruning) affecting the neural circuitry of self may contribute to worsening of SDs. This could result in the emergence of prodromal symptoms and, eventually, full-blown psychosis. To highlight why adolescence may be a period of heightened risk for SDs, we first summarize the literature regarding the neural correlates of self in typically developing children. Next, we present evidence from neuroimaging studies in genetic high-risk youth suggesting that fronto-temporal-parietal structures mediating self-reflection may be abnormal in the premorbid period. Our goal is that the ideas presented here might provide future directions for research into the neurobiology of SDs during the pre-psychosis development of youth at risk for schizophrenia. PMID- 23932152 TI - Long-term risk of secondary skin cancers after radiation therapy for Hodgkin's lymphoma. AB - PURPOSE: Survivors of Hodgkin's lymphoma (HL) are at risk of secondary tumors. We investigated the risk of secondary skin cancers after radiotherapy compared to treatment without radiation and to an age-matched population. MATERIAL AND METHODS: We conducted a retrospective cohort study of 889 HL patients treated between 1965 and 2005. Data on secondary skin cancers and treatment fields were retrieved. Incidence rates were compared to observed rates in the Dutch population. RESULTS: 318 skin cancers were diagnosed in 86 patients, showing significantly higher risks of skin cancers, the majority being BCC. The standardized incidence ratio (SIR) of BCC in HL survivors was significantly increased (SIR 5.2, 95% CI 4.0-6.6), especially in those aged <35 years at diagnosis (SIR 8.0, 95% CI 5.8-10.7). SIR increased with longer follow-up to 15.9 (95% CI 9.1-25.9) after 35 years, with 626 excess cases per 10,000 patients per year. Most (57%) skin cancers developed within the radiation fields, with significantly increased risk in patients treated with radiotherapy compared to chemotherapy alone (p=0.047, HR 2.75, 95% CI 1.01-7.45). CONCLUSION: Radiotherapy for HL is associated with a strongly increased long-term risk of secondary skin cancers, both compared to the general population and to treatment with chemotherapy alone. PMID- 23932153 TI - Neorectal hyposensitivity after neoadjuvant therapy for rectal cancer. AB - BACKGROUND AND PURPOSE: Preoperative radiotherapy for rectal cancer has a detrimental effect on long-term anorectal function and quality of life, additional to that observed after rectal resection. The exact physiological mechanisms for the excess impairment remain unknown. We aimed to investigate neorectal and anal sphincter properties in patients treated with neoadjuvant therapy (NT) prior to total mesorectal excision (TME). MATERIAL AND METHODS: Sixteen patients (NT+ patients) were examined by multimodal neorectal stimulation and standard anorectal physiological testing. Data were compared to the results of 23 patients, who underwent TME without NT (NT- patients). RESULTS: NT+ patients had elevated sensory thresholds to heat (median temperature, 60 vs. 55 degrees C; p<0.01) and mechanical distension (median tension, 2513 vs. 1521 mmHg mm; p=0.05) in the fasting state, and altered perception of the sensory response to heat (p=0.01) and cold (p=0.01) compared to NT- patients. No differences in the biomechanical properties of the neorectal wall were detected. Anal resting pressure was lower in NT+ patients compared to NT- patients (median pressure, 31 vs. 45 cm H2O; p=0.05). CONCLUSIONS: Pelvic radiotherapy causes neorectal hyposensitivity to mechanical and thermal stimuli in patients receiving NT prior to TME surgery for rectal cancer, possibly due to impaired afferent nerve function. PMID- 23932154 TI - Identification of a microRNA expression signature for chemoradiosensitivity of colorectal cancer cells, involving miRNAs-320a, -224, -132 and let7g. AB - BACKGROUND AND PURPOSE: Preoperative chemoradiotherapy (CRT) represents the standard treatment for locally advanced rectal cancer. Tumor response and progression vary considerably. MicroRNAs represent master regulators of gene expression, and may therefore contribute to this diversity. MATERIAL AND METHODS: Genome-wide microRNA (miRNA) profiling was performed for 12 colorectal cancer (CRC) cell lines and an individual in vitro signature of chemoradiosensitivity was established. Functional relevance of selected miRNAs was established by transfecting miRNA-mimics into SW480 and SW837 cells. The prognostic value of selected miRNAs was assessed in 128 pretherapeutic patient biopsies. RESULTS: Thirty-six miRNAs were identified to significantly correlate with sensitivity to CRT (Q < 0.05) including miR-320a and other miRNAs involved in the MAPK-, TGF- and Wnt-pathway. Transfection of selected miRNAs (let-7g, miR-132, miR-224, miR 320a) each induced a shift of sensitivity. High expression of let-7 g was associated with a good prognosis in rectal cancer patients (P = 0.03). CONCLUSIONS: This is the first report of a miRNA expression signature for in vitro chemoradiosensitivity of CRC cell lines. Many of the identified miRNAs have not been linked to the response to CRT and may represent potential molecular targets to sensitize resistant cancers. If further validated, let7g expression may serve as predictive biomarker. PMID- 23932155 TI - HPV-positive HNSCC cell lines but not primary human fibroblasts are radiosensitized by the inhibition of Chk1. AB - PURPOSE: Despite the comparably high cure rates observed for HPV-positive HNSCC, there is still a great need for specific tumor radiosensitization due to the often severe side effects resulting from intense radiochemotherapy. We recently demonstrated that HPV-positive HNSCC cell lines are characterized by a defect in DNA double-strand break repair associated with a pronounced G2-arrest. Here we tested whether abrogation of this radiation-induced G2-arrest by the inhibition of Chk1 results in specific radiosensitization of HPV-positive HNSCC cells. MATERIALS AND METHODS: Experiments were performed with five HPV and p16-positive (93-VU-147T, UM-SCC-47, UT-SCC-45, UD-SCC-2, UPCI-SCC-154) and two HPV and p16 negative HNSCC cell lines, as well as two normal human fibroblast strains. Chk1 was inhibited by the selective inhibitor PF-00477736. Cell cycle distribution was determined by flow cytometry, Chk1-activity via Western blot and cell survival by colony formation assay. RESULTS: With the exception of UPCI-SCC-154, the inhibition of Chk1 was found to abolish the pronounced radiation-induced G2 arrest in all HPV-positive cells utilized. All tumor cell lines that demonstrated the abrogation of G2-arrest also demonstrated radiosensitization. Notably, in G1 arrest-proficient normal human fibroblasts no radiosensitization was induced. CONCLUSION: Abrogation of the G2 checkpoint through the inhibition of Chk1 may be used to selectively increase the cellular radiosensitivity of HPV-positive HNSCC without affecting the surrounding normal tissue. PMID- 23932156 TI - 111In-cetuximab-F(ab')2 SPECT imaging for quantification of accessible epidermal growth factor receptors (EGFR) in HNSCC xenografts. AB - BACKGROUND AND PURPOSE: Immunohistochemical epidermal growth factor receptor (EGFR) expression does not correlate with treatment response in head and neck squamous cell carcinomas (HNSCC). Aim was to apply the tracer (111)In-cetuximab F(ab')2 for EGFR microSPECT imaging and to investigate if tracer uptake correlated with response to EGFR-inhibition by cetuximab in HNSCC xenografts. Usage of F(ab)2 fragments allows for shorter interval between tracer injection and imaging. MATERIALS AND METHODS: Mice with HNSCC xenografts, SCCNij202, 153, 185 and 167 were imaged with microSPECT using (111)In-cetuximab-F(ab')2. Subsequently, tumors were analyzed by autoradiography and immunohistochemistry and tracer concentration was determined. Tumor uptake was correlated with previously assessed response to cetuximab treatment. RESULTS: MicroSPECT imaging showed preferential uptake in HNSCC xenografts. Tumor-to-liver ratios were 3.1 +/ 0.2 (SCCNij202), 2.8 +/- 0.4 (SCCNij153), 2.0 +/- 0.8 (SCCNij185), 2.0 +/- 0.4 (SCCNij167). Immunohistochemical EGFR fractions (fEGFR) differed significantly between xenografts; 0.77 +/- 0.07 (SCCNij202), 0.66 +/- 0.11 (SCCNij153), 0.57 +/ 0.19 (SCCNij185), 0.16 +/- 0.10 (SCCNij167) (p < 0.001). Tumor fEGFR correlated with (111)In-cetuximab-F(ab')2 tumor uptake (r = 0.6, p < 0.01) and tracer autoradiography (r = 0.7, p < 0.0001). Tumor uptake of (111)In-cetuximab-F(ab')2 was proportionally associated with cetuximab treatment response in three out of four xenograft models. CONCLUSION: (111)In-cetuximab-F(ab')2 showed good tumor-to background contrast on microSPECT imaging, allowing noninvasive assessment of EGFR expression in vivo, and possibly evaluation of treatment response to EGFR inhibition. PMID- 23932157 TI - Quality of life among prostate cancer patients: a prospective longitudinal population-based study. AB - PURPOSE: To investigate the course of quality of life (QoL) among prostate cancer patients treated with external beam radiotherapy and to compare the results with QoL of a normal age-matched reference population. PATIENTS AND METHODS: The study population was composed of 227 prostate cancer patients, treated with radiotherapy. The EORTC QLQ-C30 was used to assess QoL before radiotherapy and six months, one year, two years and three years after completion of radiotherapy. Mixed model analyses were used to investigate longitudinal changes in QoL. QoL of prostate cancer patients was compared to that of a normative cohort using a multivariate analysis of covariance. RESULTS: A significant decline in QoL was observed after radiotherapy (p<0.001). The addition of hormonal therapy to radiotherapy was associated with a lower level of role functioning. Patients with coronary heart disease and or chronic obstructive pulmonary disease or asthma had a significantly worse course in QoL. Although statistically significant, all differences were classified as small or trivial. CONCLUSION: Prostate cancer patients experience a small worsening of QoL as compared with baseline and as compared with a normal reference population. As co-morbidity modulates patients' post-treatment QoL, a proper assessment of co-morbidity should be included in future longitudinal analyses on QoL. PMID- 23932158 TI - A phase I/II study piloting accelerated partial breast irradiation using CT guided intensity modulated radiation therapy in the prone position. AB - BACKGROUND AND PURPOSE: External beam accelerated partial breast irradiation (EB aPBI) is noninvasive with broader potential applicability than aPBI using brachytherapy. However, it has inherent challenges in daily reproducibility. Image-guide radiotherapy (IGRT) can improve daily reproducibility, allowing smaller treatment margins. Our institution proposed IG-IMRT in the prone position to evaluate dose homogeneity, conformality, normal tissue avoidance, and reliable targeting for EB-aPBI. We report preliminary results and toxicity from a phase I/II study evaluating the feasibility of EB-aPBI in the prone position using IG IMRT. MATERIALS AND METHODS: Twenty post-menopausal women with node-negative breast cancer, excised tumors <3.0 cm, negative sentinel lymph node biopsy, and surgical clips demarcating the lumpectomy cavity underwent prone EB-aPBI using IG IMRT on an IRB-approved phase I/II study. All patients underwent CT planning in the prone position. The lumpectomy cavity PTV represented a 2.0 cm expansion. 38.5 Gy was delivered in 10 fractions over 5 days, such that 95% of the prescribed dose covered >99% of the PTV. Dose constraints for the whole breast, lungs and heart were met. RESULTS: The median patient age was 61.5. Mean tumor size was 1.0 cm. 35% of patients had DCIS. Median PTV was 243 cc (108-530) and median breast reference volume was 1698 cc (647-3627). Average daily shifts for IGRT were (0.6, -4.6, 1.7 mm) with standard deviations of (6.3, 6.5, 6.4mm). Acute toxicity was G1 erythema in 80%, and G2 erythema, G2 fatigue, and G2 breast pain each occurred in 1 patient. With a median follow-up of 18.9 months (12-35), 40% of patients have G1 fibrosis and 30% have G1 hyperpigmentation. 95% of patients have good to excellent cosmesis. There have been no recurrences. CONCLUSIONS: These data demonstrate that EB-aPBI in the prone position using IG IMRT is well tolerated, yields good dosimetric conformality, and results in promising early toxicity profiles. PMID- 23932159 TI - A middle school intervention to improve health behaviors and reduce cardiac risk factors. AB - OBJECTIVE: This study aimed to measure the impact of a school-based multidisciplinary intervention program on risk factors for atherosclerosis in sixth-grade middle school students. We also measured health behaviors before and after the intervention using a validated questionnaire. METHODS: A prospective study was performed in which students served as historical controls. Sixth-grade students from 23 middle schools in 12 cities with varying populations were exposed to a program promoting healthful activity and nutrition habits through educational and environmental change. Along with a modified School-Based Nutrition Monitoring behavioral questionnaire, physiologic risk factors were studied, including body mass index, systolic and diastolic blood pressures, cholesterol panel, and random blood glucose, which were measured before the 10 week program and again 1 to 3 months after program completion. RESULTS: Of 4021 sixth graders (male, 49%) at 23 middle schools completing a before and after behavioral survey, 2118 students, aged 11.56 +/- 0.47 years, consented to participate in the screening. The mean total cholesterol value decreased from 161.64 +/- 28.99 mg/dL to 154.77 +/- 27.26 mg/dL (P < .001). The low-density lipoprotein value decreased from 89.37 +/- 25.08 mg/dL to 87.14 +/- 24.25 mg/dL (P < .001). The high-density lipoprotein value decreased from 52.15 +/- 13.35 md/dL to 49.95 +/- 13.28 mg/dL (P < .001). The measure of triglycerides decreased from 113.34 +/- 73.19 mg/dL to 101.22 +/- 63.93 mg/dL (P < .001). The random glucose value decreased from 97.51 +/- 16.00 to 94.94 +/- 16.62 (P < .001). The mean systolic blood pressure decreased from 109.47 +/- 15.26 mm Hg to 107.76 +/- 10.87 mm Hg (P < .001), and the mean diastolic blood pressure decreased from 64.78 +/- 8.57 mm Hg to 63.35 +/- 7.81 mm Hg (P < .001). These changes in physiologic measures seemed to correlate with self-reported increases in vegetable and fruit consumption, increases in physical activity, and less screen time. CONCLUSIONS: Project Healthy Schools, a middle school intervention to improve childhood cardiovascular risk factors, is feasible and seems to be effective. The results showed significant improvements in risk factors associated with early atherosclerosis among sixth-grade students, including total cholesterol, low-density lipoprotein cholesterol, triglycerides, and systolic and diastolic blood pressures. Further study with a larger group of students and a longer follow-up period would be valuable. PMID- 23932160 TI - Psycho-emotional manifestations of valvular heart diseases: prospective assessment in mitral regurgitation. AB - OBJECTIVE: To define the prevalence and consequences of post-traumatic stress disorder (PTSD) as an emotional response to cardiac diseases in patients with mitral regurgitation. METHODS: We prospectively enrolled 186 patients with moderate or severe organic mitral regurgitation, presenting class I (absent) or II (minimal) dyspnea, who were compared with 80 controls of similar age (38 with completely normal cardiac function; 42 with mild mitral-valve prolapse; all with no, or at most mild, mitral regurgitation). Mitral-regurgitation severity and consequences were comprehensively measured, simultaneously with PTSD, anxiety, and depression. RESULTS: PTSD prevalence was higher in mitral-regurgitation patients vs controls (23% vs 9%, P <.01). Although mitral-regurgitation objective severity (regurgitant volume 77.8 +/- 28.9 vs 79.0 +/- 27.5 mL, P = .8) and objective consequences (left-atrial volume 59.1 +/- 20.9 vs 54.02 +/- 15.6 mL, P = .1; right-ventricular systolic pressure 34.1 +/- 11.4 vs 32.9 +/- 7.2 mm Hg, P = .6) were similar with and without PTSD (all P >=.1), patients with PTSD were more symptomatic (class II 74 vs 38%; fatigue 71% vs 38%, both P <.0001) and had higher anxiety and depressions scores (P <.0001). CONCLUSIONS: PTSD is prevalent in organic moderate or severe mitral-regurgitation patients but is not determined by objective mitral-regurgitation severity or consequences. PTSD is linked to anxiety and depression and to symptoms usually considered cardiac, such as dyspnea. Thus, PTSD and psycho-emotional manifestations, linked to symptoms, represent important responses to chronic-valve disease that may affect clinical outcomes. PMID- 23932161 TI - Bilateral proptosis as initial manifestation of mantle cell lymphoma. PMID- 23932162 TI - Reversal of fortunes: recognizing misplacement of ECG electrodes. PMID- 23932163 TI - Genomic regions associated with fertility traits in male and female cattle: advances from microsatellites to high-density chips and beyond. AB - A current challenge in genetic improvement of cattle is to identify genomic selection strategies that could work across breeds. Breed differences, scarcity of data, and lack of quantitative trait loci (QTL) validation contribute to this challenge. We conducted a review of the literature to identify QTL, markers, and candidate genes that are associated with fertility across breeds to arrive at an integrated view of bovine fertility genomics and to guide the direction of future studies. This review considers both male and female fertility traits as these are economically relevant for all breeds and production systems. Regions associated with fertility traits were found in each of the 30 bovine chromosomes, confirming the complexity of these polygenic traits. Across breeds, regions on chromosomes 1, 5, 14, and 16 were associated with female reproductive traits. The X chromosome was associated with male reproductive traits in both dairy and beef bulls. It has recently been proposed that a Y chromosome anomaly may be involved in infertility in cows. Knowledge of these QTL may assist discovery of causative mutations and has the potential to improve the accuracy of genomic selection, especially across breeds of cattle. PMID- 23932164 TI - Egg laying pattern, egg weight, body weight at hatch, and sex ratio bias relative to oviposition time of young-and mid-age broiler breeders. AB - Two experiments were conducted to determine oviposition pattern and the effect of oviposition time on egg weight, body weight at hatch, and sex ratio of hatched chickens. In Experiment 1, eggs were collected from young and mid-age broiler flocks for 6 consecutive days at hourly intervals between 0400 and 2000h. In Experiment 2, eggs were categorized to represent eggs where oviposition occurred early, middle and late in the clutch (later in the day). These eggs were incubated to determine body weight at hatch and sex ratio of hatched chickens relative to oviposition time. Time of oviposition was affected by age. For the young flock, the percentage of ovipositions occurring before the 1100h was 79%. In contrast to the young flock, the percentage of ovipositions occurring before the 1100h in the mid-age flock was less (68%; P<0.01). Furthermore, for the mid age flock, the percentage of ovipositions occurring from 1200 to 1700h was greater (P<0.01) at 32% in comparison to that of the younger flock at 21%. Egg weights when oviposition occurred earlier in the day were greater (P<0.01) than when oviposition occurred in the middle and later in the clutch (later in the day). Similarly, body weight at hatch of chicks from eggs where oviposition occurred earlier in the day was heavier than when oviposition occurred in the middle and later in the clutch (later in the day).With hatching of the eggs from hens when ovipositions occurred earlier in the day, there was a female sex bias. Differences in egg weights, body weight at hatch, and sex ratio due to time of oviposition suggest that oviposition time together with incubation conditions should be considered for obtaining greater uniformity and growth of chickens. PMID- 23932165 TI - The social determinants of child health. PMID- 23932167 TI - Semantic embodiment, disembodiment or misembodiment? In search of meaning in modules and neuron circuits. AB - "Embodied" proposals claim that the meaning of at least some words, concepts and constructions is grounded in knowledge about actions and objects. An alternative "disembodied" position locates semantics in a symbolic system functionally detached from sensorimotor modules. This latter view is not tenable theoretically and has been empirically falsified by neuroscience research. A minimally-embodied approach now claims that action-perception systems may "color", but not represent, meaning; however, such minimal embodiment (misembodiment?) still fails to explain why action and perception systems exert causal effects on the processing of symbols from specific semantic classes. Action perception theory (APT) offers neurobiological mechanisms for "embodied" referential, affective and action semantics along with "disembodied" mechanisms of semantic abstraction, generalization and symbol combination, which draw upon multimodal brain systems. In this sense, APT suggests integrative-neuromechanistic explanations of why both sensorimotor and multimodal areas of the human brain differentially contribute to specific facets of meaning and concepts. PMID- 23932166 TI - "I felt like a superhero": the experience of responding to drug overdose among individuals trained in overdose prevention. AB - BACKGROUND: Overdose prevention programs (OPPs) train people who inject drugs and other community members to prevent, recognise and respond to opioid overdose. However, little is known about the experience of taking up the role of an "overdose responder" for the participants. METHODS: We present findings from qualitative interviews with 30 participants from two OPPs in Los Angeles, CA, USA from 2010 to 2011 who had responded to at least one overdose since being trained in overdose prevention and response. RESULTS: Being trained by an OPP and responding to overdoses had both positive and negative effects for trained "responders". Positive effects include an increased sense of control and confidence, feelings of heroism and pride, and a recognition and appreciation of one's expertise. Negative effects include a sense of burden, regret, fear, and anger, which sometimes led to cutting social ties, but might also be mitigated by the increased empowerment associated with the positive effects. CONCLUSION: Findings suggest that becoming an overdose responder can involve taking up a new social role that has positive effects, but also confers some stress that may require additional support. OPPs should provide flexible opportunities for social support to individuals making the transition to this new and critical social role. Equipping individuals with the skills, technology, and support they need to respond to drug overdose has the potential to confer both individual and community-wide benefits. PMID- 23932168 TI - Different computer-assisted sperm analysis (CASA) systems highly influence sperm motility parameters. AB - In this study, we examined different computer-assisted sperm analysis (CASA) systems (CRISMAS, Hobson Sperm Tracker, and Image J CASA) on the exact same video recordings to evaluate the differences in sperm motility parameters related to the specific CASA used. To cover a wide range of sperm motility parameters, we chose 12-second video recordings at 25 and 50 Hz frame rates after sperm motility activation using three taxonomically distinct fish species (sterlet: Acipenser ruthenus L.; common carp: Cyprinus carpio L.; and rainbow trout: Oncorhynchus mykiss Walbaum) that are characterized by essential differences in sperm behavior during motility. Systematically higher values of velocity and beat cross frequency (BCF) were observed in video recordings obtained at 50 Hz frame frequency compared with 25 Hz for all three systems. Motility parameters were affected by the CASA and species used for analyses. Image J and CRISMAS calculated higher curvilinear velocity (VCL) values for rainbow trout and common carp at 25 Hz frequency compared with the Hobson Sperm Tracker, whereas at 50 Hz, a significant difference was observed only for rainbow trout sperm recordings. No significant difference was observed between the CASA systems for sterlet sperm motility at 25 and 50 Hz. Additional analysis of 1-second segments taken at three time points (1, 6, and 12 seconds of the recording) revealed a dramatic decrease in common carp and rainbow trout sperm speed. The motility parameters of sterlet spermatozoa did not change significantly during the 12-second motility period and should be considered as a suitable model for longer motility analyses. Our results indicated that the CASA used can affect motility results even when the same motility recordings are used. These results could be critically altered by the recording quality, time of analysis, and frame rate of camera, and could result in erroneous conclusions. PMID- 23932169 TI - Hormone concentrations temporally associated with contralateral and ipsilateral relationships between the CL and preovulatory follicle during the third follicular wave in heifers. AB - Concentrations of circulating hormones after Day 14 (Day 0 = ovulation) were determined daily in 87 interovulatory intervals (IOIs) in heifers. The IOIs were grouped into four permutations according to an ipsilateral (Ipsi) or contralateral (Contra) relationship between the CL and the preovulatory follicle and two (2W) or three (3W) follicular waves per IOI. The number of IOIs per group differed (P < 0.005) from equality among the Ipsi-2W (n = 27), Contra-2W (n = 31), Ipsi-3W (n = 9), and Contra-3W (n = 20) groups. A continuous decrease in progesterone (luteolysis) began later (P < 0.05) in the Contra-3W group (Day 18.0 +/- 0.4) than in each of the Ipsi-2W (15.4 +/- 0.2), Contra-2W (15.6 +/- 0.2), and Ipsi-3W (16.2 +/- 0.5) groups. Concentrations of LH and estradiol began to increase near the beginning of luteolysis in each group. A minor FSH surge that did not stimulate a major follicular wave developed in about 50% of the IOIs in each group, except that none were detected in the Ipsi-3W group. The minor FSH surge reached a peak about 4 days before ovulation and several days after wave 3 had emerged. The hypothesis that luteolysis begins earliest in two-wave IOIs, intermediate in three-wave IOIs with an ipsilateral CL/follicle relationship, and latest in three-wave IOIs with a contralateral relationship was supported. The hypothesis that a minor FSH surge occurs most frequently in association with three follicular waves was not supported. PMID- 23932170 TI - Apgar score after induction of anesthesia for canine cesarean section with alfaxalone versus propofol. AB - The effects of alfaxalone and propofol on neonatal vitality were studied in 22 bitches and 81 puppies after their use as anesthetic induction agents for emergency cesarean section. After assessment that surgery was indicated, bitches were randomly allocated to receive alfaxalone 1 to 2 mg/kg body weight or propofol 2 to 6 mg/kg body weight for anesthetic induction. Both drugs were administered intravenously to effect to allow endotracheal intubation, and anesthesia was maintained with isoflurane in oxygen. Neonatal vitality was assessed using a modified Apgar score that took into account heart rate, respiratory effort, reflex irritability, motility, and mucous membrane color (maximum score = 10); scores were assigned at 5, 15, and 60 minutes after delivery. Neither the number of puppies delivered nor the proportion of surviving puppies up to 3 months after delivery differed between groups. Anesthetic induction drug and time of scoring were associated with the Apgar score, but delivery time was not. Apgar scores in the alfaxalone group were greater than those in the propofol group at 5, 15, and 60 minutes after delivery; the overall estimated score difference between the groups was 3.3 (confidence interval 95%: 1.6-4.9; P < 0.001). In conclusion, both alfaxalone and propofol can be safely used for induction of anesthesia in bitches undergoing emergency cesarean section. Although puppy survival was similar after the use of these drugs, alfaxalone was associated with better neonatal vitality during the first 60 minutes after delivery. PMID- 23932171 TI - Efficacy of four synchronization protocols on the estrus behavior and conception in native Korean cattle (Hanwoo). AB - Ineffective estrus detection is the foremost limiting factor in the fertility of farmed cattle worldwide. Failure to detect estrus or erroneous diagnosis of estrus results in great economic losses in Korea each year. This study was carried out in order to comprehensively describe the estrus behaviors and conception rates of different estrus synchronization protocols applied to 40 cycling native Korean cattle (Hanwoo). The cows were grouped into four (n = 10) and treated with the following protocols: (1) Day -15: controlled intravaginal drug-releasing device (CIDR) for 12 days; Day -5: prostaglandin F2alpha (PGF2alpha), (2) ovulation synchronization (OVS): Day -15: GnRH; Day -6: PGF2alpha; Day -4: GnRH, (3) Day -15: progesterone-releasing intravaginal device for 12 days; Day -5: PGF2alpha; and (4) Day -15: PGF2alpha; Day -4: PGF2alpha. Artificial insemination was performed 12 hours after the detection of estrus using frozen-thawed semen. Estrus signs were compared using a charge-coupled device camera (CCDC) and a control method (direct visual observation). The pregnancy of the cows was determined by transrectal ultrasonography at Days 25 to 30 postinsemination. The results indicated that the day of estrus return was significantly earlier using the CCDC method compared with direct visualization (P < 0.05). Mounting of other cows was the most predominant sign of estrus among the flock (P < 0.05), as analyzed using the CCDC. In the OVS group, a lower rate of mounting was observed than in the other three groups. Moreover, significantly fewer estrus behaviors were noticed in the OVS protocol group (P < 0.05). Both first service conception and overall conception rates were significantly higher (P < 0.05) in the CIDR and OVS treatment groups. In conclusion, the CIDR and OVS protocols appear to be the best practice for the synchronization of estrus for reproductive competence through the CCDC in Hanwoo cows. However, CIDR has a practical advantage over OVS with respect to estrus detection. PMID- 23932172 TI - Secretion of prostaglandins and leukotrienes by endometrial cells in cows with subclinical and clinical endometritis. AB - The aims of this study were (1) to measure the secretion of prostaglandin F2alpha (PGF2alpha), prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and leukotriene C4 (LTC4) by endometrial cells collected by a cytobrush from healthy cows and cows with subclinical and clinical endometritis in the fourth week postpartum, and (2) to evaluate the relationship between the mediators' levels of secretion and the number of polymorphonuclear neutrophils (PMNs) in the uterine smears of cows with subclinical endometritis. The study included cows without any signs of clinical endometritis (n = 63) and cows with clinical endometritis as a positive control (ENDOM, n = 12). Two different threshold ratios (>5% and >18% of PMNs) were used to categorize the cows without clinical signs as with or without cytologic endometritis (CE). Considering the first or second threshold, the animals with CE were included in group CE POS I or CE POS II, whereas the healthy cows were assigned to group CE NEG I or CE NEG II, respectively. The prevalence of CE was 68.25% (42/63) and 57.14% (36/63) according to the first and second thresholds, respectively. The highest level of secretion of all of the measured mediators occurred in the ENDOM group and differed significantly (P < 0.05) from the CE POS and CE NEG groups, regardless of the threshold. PGF2alpha secretion in the CE POS II group (1629 pg/mL) was significantly lower (P < 0.05) when compared with the CE NEG II group (2797 pg/mL), whereas there was no significant difference between the CE POS I and CE NEG I groups. PGE2 secretion differed between both groups with CE; higher concentrations were measured in the CE POS II group (6.68 ng/mL) when compared with the CE POS I (2.4 ng/mL) and CE NEG II (2.37 ng/mL) groups (P < 0.05). No significant differences were observed in the LTB4 and LTC4 secretion between the CE POS and CE NEG groups, considering both thresholds. It seems that CE does not fully mimic the inflammatory cascade associated with clinical signs. The response in the subclinical cases was limited to enhanced production of PGE2, which was particularly well-pronounced in cows with high numbers of PMNs (>18%) in the endometrial scrapings. PMID- 23932173 TI - Cryoprotective effect of different glycerol concentrations on domestic cat spermatozoa. AB - Cryopreservation of spermatozoa is a pivotal tool in assisted reproduction, and studies aiming to establish optimal freezing/thawing protocols are essential to enhance sperm survival. The objectives of the present study were to (1) compare the cryoprotective efficiency of three different glycerol concentrations (3%, 5%, and 7%) on the basis of post-thaw sperm quality and (2) investigate whether the incidence of morphologically abnormal sperm in fresh samples is related to cryodamage sensitivity. Semen was collected from six tomcats using an artificial vagina (total 18 ejaculates). Each ejaculate was diluted using Tris-egg yolk based extender (TEY), evaluated, equally divided into three aliquots, and rediluted using TEY with and without glycerol to achieve final concentrations of 3%, 5%, and 7%. Samples were loaded into 0.25 mL straws, equilibrated for 60 minutes at 5 degrees C, frozen, and then thawed at 46 degrees C for 12 seconds. Fresh and frozen-thawed samples were evaluated for sperm motion parameters (computer-assisted sperm analysis), plasma membrane integrity (PMI; propidium iodide and carboxyfluorescein diacetate), and DNA integrity (acridine orange). Plasma and acrosomal membrane integrity were assessed by flow cytometry (propidium iodide and fluorescein isothiocyanate-conjugated pea (Pisum sativum) agglutinin) immediately after thawing. Sperm motion parameters were also evaluated at 30 and 60 minutes of postincubation. For all treatment groups, cryopreservation significantly impaired the PMI and sperm motion parameters, except for straightness and amplitude of lateral head displacement. DNA integrity showed a slight reduction (P < 0.05) when 3% glycerol was used. The percentage of total motility, progressive motility, and rapid spermatozoa were significantly lower immediately after thawing and up to 60 minutes of incubation for the 3% glycerol group when compared with 5% and 7%. No difference (P > 0.05) was found for PMI, acrosome integrity, and DNA integrity among post-thaw groups. However, higher (P < 0.05) incidence of viable cells with reacted acrosome and dead cells with intact acrosome were observed with 7% and 3% glycerol, respectively. Percentage of morphologically abnormal spermatozoa in fresh sample was positively correlated with PMI only in the 3% glycerol group and negatively correlated with sperm motility in the 5% and 7% groups. In conclusion, the final concentration of 5% glycerol offered better cryoprotective effect for ejaculated cat sperm, and the relationship found between prefreezing sperm morphology and post-thaw sperm quality showed to be dependent on final glycerol concentration. PMID- 23932174 TI - Effect of increasing GnRH and PGF2alpha dose during Double-Ovsynch on ovulatory response, luteal regression, and fertility of lactating dairy cows. AB - Ovsynch-type synchronization of ovulation protocols have suboptimal synchronization rates due to reduced ovulation to the first GnRH treatment and inadequate luteolysis to the prostaglandin F2alpha (PGF2alpha) treatment before timed artificial insemination (TAI). Our objective was to determine whether increasing the dose of the first GnRH or the PGF2alpha treatment during the Breeding-Ovsynch portion of Double-Ovsynch could improve the rates of ovulation and luteolysis and therefore increase pregnancies per artificial insemination (P/AI). In experiment 1, cows were randomly assigned to a two-by-two factorial design to receive either a low (L) or high (H) doses of GnRH (Gonadorelin; 100 vs. 200 MUg) and a PGF2alpha analogue (cloprostenol; 500 vs. 750 MUg) resulting in the following treatments: LL (n = 263), HL (n = 277), LH (n = 270), and HH (n = 274). Transrectal ultrasonography and serum progesterone (P4) were used to assess ovulation to GnRH1, GnRH2, and luteal regression after PGF2alpha during Breeding-Ovsynch in a subgroup of cows (n = 651 at each evaluation). Pregnancy status was assessed 29, 39, and 74 days after TAI. In experiment 2, cows were randomly assigned to LL (n = 220) or HH (n = 226) treatment as described for experiment 1. For experiment 1, ovulation to GnRH1 was greater (P = 0.01) for cows receiving H versus L GnRH (66.6% [217/326] vs. 57.5% [187/325]) treatment, but only for cows with elevated P4 at GnRH1. Cows that ovulated to GnRH1 had increased (P < 0.001) fertility compared with cows that did not ovulate (52.2% vs. 38.5%); however, no effect of higher dose of GnRH on fertility was detected. The greater PGF2alpha dose increased luteal regression primarily in multiparous cows (P = 0.03) and tended to increase fertility (P = 0.05) only at the pregnancy diagnosis 39 days after TAI. Overall, P/AI was 47.0% at 29 days and 39.7% at 74 days after TAI; P/AI did not differ (P = 0.10) among treatments at 74 days (LL, 34.6%; HL, 40.8%; LH, 42.2%; HH, 40.9%) and was greater (P < 0.001) for primiparous cows than for multiparous cows (46.1% vs. 33.8%). For experiment 2, P/AI did not differ (P = 0.21) between H versus L treatments (44.2% [100/226] vs. 40.5% [89/220]). Thus, despite an increase in ovulatory response to GnRH1 and luteal regression to PGF2alpha, there were only marginal effects of increasing dose of GnRH or PGF2alpha on fertility to TAI after Double-Ovsynch. PMID- 23932175 TI - A comparison of a subjective body assessment of men and women of the Polish social elite. AB - The objective of the study was to compare the level of dissatisfaction with body image of men and women of the social elite in the Wielkopolska region, Poland, in the light of anthropometric indicators. All studied individuals have had university education, performed public functions and their age ranged from 40 to 60 years. In total, information about 167 individuals, 70 women and 97 men, was collected. In the analysis the body mass index (BMI) and the waist to height ratio (WHtR) were taken into consideration. To study body image the Colour-A Person Body Dissatisfaction Test (CAPT) and weight self-assessment were used. In the group of women there was a significant relationship between a subjective assessment of weight as well as body mass index (BMI) and a degree of dissatisfaction with their body. Women who classified themselves in the category of overweight (self-assessment) had the highest BMI values and were the most dissatisfied with their body image (CAPT=3.61). Individuals who believed that their body weight corresponded to the standard limits had a mean score of CAPT=2.28, and women with normal BMI values were the most satisfied with their body. For men, there were no significant relationships. Sex and size of anthropometric indicators were significantly related to the understanding of one's own body among the studied individuals. This is in line with reports of other authors who explain their results by different social expectations, according to which a woman's self-esteem is linked to her physical attractiveness. On the other hand, the studied women have been characterised by a significant body awareness which may be related to their education and professional status. PMID- 23932176 TI - End-of-life communication: a retrospective survey of representative general practitioner networks in four countries. AB - CONTEXT: Effective communication is central to high-quality end-of-life care. OBJECTIVES: This study examined the prevalence of general practitioner (GP) patient discussion of end-of-life topics (according to the GP) in Italy, Spain, Belgium, and The Netherlands and associated patient and care characteristics. METHODS: This cross-sectional, retrospective survey was conducted with representative GP networks. Using a standardized form, GPs recorded the health and care characteristics in the last three months of life, and the discussion of 10 end-of-life topics, of all patients who died under their care. The mean number of topics discussed, the prevalence of discussion of each topic, and patient and care characteristics associated with discussions were estimated per country. RESULTS: In total, 4396 nonsudden deaths were included. On average, more topics were discussed in The Netherlands (mean=6.37), followed by Belgium (4.45), Spain (3.32), and Italy (3.19). The topics most frequently discussed in all countries were "physical complaints" and the "primary diagnosis," whereas "spiritual and existential issues" were the least frequently discussed. Discussions were most prevalent in The Netherlands, followed by Belgium. The GPs from all countries tended to discuss fewer topics with older patients, noncancer patients, patients with dementia, patients for whom palliative care was not an important treatment aim, and patients for whom their GP had not provided palliative care. CONCLUSION: The prevalence of end-of-life discussions varied across the four countries. In all countries, training priorities should include the identification and discussion of spiritual and social problems and early end-of-life discussions with older patients, those with cognitive decline if possible, and those with non malignant diseases. PMID- 23932177 TI - Long-term analgesic effects of transcranial direct current stimulation of the motor cortex on phantom limb and stump pain: a case report. PMID- 23932178 TI - Loading conditions influence reliability of the echocardiographic ramp test in continuous-flow left ventricular assist devices. PMID- 23932179 TI - Extempore interventional closure of a broken CircuLite Synergy micropump inflow graft defect. PMID- 23932180 TI - Solid-state NMR studies of biomineralization peptides and proteins. AB - Nature has evolved sophisticated strategies for engineering hard tissues through the interaction of proteins, and ultimately cells, with inorganic mineral phases. This process, called biomineralization, is how living organisms transform inorganic materials such as hydroxyapatite, calcite, and silica into highly intricate and organized structures. The remarkable material properties of shell, bone, and teeth come from the activities of proteins that function at the organic inorganic interface. A better understanding of the biomolecular mechanisms used to promote or retard the formation of mineral-based structures could provide important design principles for the development of calcification inhibitors and promoters in orthopedics, cardiology, urology, and dentistry. With the knowledge of the structural basis for control of hard tissue growth by proteins, scientists could potentially develop materials using biomimetic principles with applications in catalysis, biosensors, electronic devices, and chromatographic separations, to name a few. Additionally, biomineralization also has potential applications in electronics, catalysis, magnetism, sensory devices, and mechanical design. Where man-made hard materials require the use of extreme temperatures, high pressure, and pH, biological organisms can accomplish these feats at ambient temperature and at physiological pH. Despite the fact that many researchers want to identify and control the structure of proteins at material and biomineral interfaces, there is a decided lack of molecular-level structure information available for proteins at biomaterial interfaces in general. In particular, this holds for mammalian proteins that directly control calcification processes in hard tissue. The most fundamental questions regarding the secondary and tertiary structures of proteins adsorbed to material surfaces, how proteins catalyze the formation of biomineral composites, or how proteins interact at biomaterial interfaces remain unanswered. This is largely due to a lack of methods capable of providing high resolution structural information for proteins adsorbed to material surfaces under physiologically relevant conditions. In this Account, we highlight recent work that is providing insight into the structure and crystal recognition mechanisms of a salivary protein model system, as well as the structure and interactions of a peptide that catalyzes the formation of biosilica composites. To develop a better understanding of the structure and interactions of proteins in biomaterials, we have used solid-state NMR techniques to determine the molecular structure and dynamics of proteins and peptides adsorbed onto inorganic crystal surfaces and embedded within biomineral composites. This work adds to the understanding of the structure and crystal recognition mechanisms of an acidic human salivary phosphoprotein, statherin. PMID- 23932181 TI - Prevention of ovarian hyperstimulation syndrome in GnRH agonist IVF cycles in moderate risk patients: randomized study comparing hydroxyethyl starch versus cabergoline and hydroxyethyl starch. AB - OBJECTIVE: To assess whether, in GnRH agonist IVF cycles where there is a risk of ovarian hyperstimulation syndrome (OHSS), the addition of cabergoline to the hydroxyethyl starch (HES) infusion could decrease OHSS incidence and severity. MATERIALS AND METHODS: Prospective randomized study. The population under study consisted of women undergoing IVF cycles with GnRH agonist protocols, at risk of OHSS (more than 20 follicles observed larger than 12 mm in diameter and/or estradiol levels of 3000-5000 pg/mL). Women received a slow infusion of 500 mL of 6% HES during follicular aspiration alone or combined with 0.5mg cabergoline administration for 8 days, starting on the day of hCG administration. RESULTS: The rates of OHSS (both early and late) were very similar in the HES alone group (3.19% (3/94)) and in the HES plus cabergoline group (5.68% (5/88)), as were the rates of severe cases of OHSS (1.06% and 2.27%). Pregnancy rates (PR) were also similar in the two groups (ongoing PR per transfer, 47.56% and 47.50%). COMMENTS: The co-administration of cabergoline in patients receiving HES due to OHSS risk did not reduce the rate or severity of OHSS in GnRH agonist IVF cycles. PMID- 23932182 TI - Maternal and neonatal outcomes following additional doses of vaginal prostaglandin E2 for induction of labour: a retrospective cohort study. AB - OBJECTIVE: To assess maternal and neonatal outcomes following the use of additional doses of vaginal prostaglandins (PGE2) above the recommended dose for induction of labour in post-dates pregnancies. STUDY DESIGN: Retrospective cohort study set in Aberdeen Maternity Hospital, Aberdeen, UK. A total of 3514 nulliparous women with labour induced with vaginal PGE2 (3mg tablet or 2mg gel) for a post-dates singleton pregnancy from January 1994 to December 2009 were included. Women receiving<=2 doses of PGE2 were compared with those receiving>2 doses (maximum 5 doses). Binary logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). Primary outcomes included mode of delivery, terbutaline use, indication for CS, postpartum haemorrhage, neonatal unit admission, and Apgar score<7. A further analysis was conducted which stratified for number of doses of PGE2 given. RESULTS: Of the 3514 women who met inclusion criteria, 605 (17%) received PGE2 that exceeded the licensed dose. They were more likely to deliver by caesarean section (53.4% vs. 31.8%, OR 2.2, 95% CI 1.8-2.6), have a caesarean section for 'failed' induction of labour (11.4% vs. 1.9%, OR 4.1, 95% CI 1.3-13.2) or lack of progress in labour (37% vs. 17%, OR 2.8, 95% CI 2.3-3.4), but not for fetal concerns (8.2% vs. 8.8% OR 0.9, 95% CI 0.7-1.3). Terbutaline use and postpartum haemorrhage was no more likely (0.7% vs. 0.9% OR 0.6 95% CI 0.3-1.5 and 19.8% vs. 18.9% OR1.01, 95% CI 0.97-1.06 respectively). Apgar score<7 (1.1% vs. 1.3% OR 0.9 95% CI 0.8-1.1) and neonatal unit admission (13.7% vs. 10.7% OR 1.2 95% CI 0.8-1.6) were similar in both groups. CONCLUSION: The use of additional doses of vaginal PGE2 above the recommended dose for induction of labour was not associated with increased maternal or neonatal morbidity and almost half of these women achieved a vaginal delivery. PMID- 23932183 TI - Implementation of laparoscopic virtual-reality simulation training in gynaecology: a mixed-methods design. AB - OBJECTIVES: Virtual-reality (VR) training has been demonstrated to improve laparoscopic surgical skills in the operating theatre. The incorporation of laparoscopic VR simulation into surgical training in gynaecology remains a significant educational challenge. We undertook a pilot study to assess the feasibility of the implementation of a laparoscopic VR simulation programme into a single unit. STUDY DESIGN: An observational study with qualitative analysis of semi-structured group interviews. Trainees in gynaecology (n=9) were scheduled to undertake a pre-validated structured training programme on a laparoscopic VR simulator (LapSim((r))) over six months. The main outcome measure was the trainees' progress through the training modules in six months. Trainees' perceptions of the feasibility and barriers to the implementation of laparoscopic VR training were assessed in focus groups after training. RESULTS: Sixty-six percent of participants completed six of ten modules. Overall, feedback from the focus groups was positive; trainees felt training improved their dexterity, hand eye co-ordination and confidence in theatre. Negative aspects included lack of haptic feedback, and facility for laparoscopic port placement training. Time restriction emerged as the main barrier to training. CONCLUSIONS: Despite positive perceptions of training, no trainee completed more than two-thirds of the modules of a self-directed laparoscopic VR training programme. Suggested improvements to the integration of future laparoscopic VR training include an additional theoretical component with a fuller understanding of benefits of VR training, and scheduled supervision. Ultimately, the success of a laparoscopic VR simulation training programme might only be improved if it is a mandatory component of the curriculum, together with dedicated time for training. Future multi-centred implementation studies of validated laparoscopic VR curricula are required. PMID- 23932185 TI - Determining the contribution of glycosaminoglycans to tendon mechanical properties with a modified shear-lag model. AB - Tendon has a complex hierarchical structure composed of both a collagenous and a non-collagenous matrix. Despite several studies that have aimed to elucidate the mechanism of load transfer between matrix components, the roles of glycosaminoglycans (GAGs) remain controversial. Thus, this study investigated the elastic properties of tendon using a modified shear-lag model that accounts for the structure and non-linear mechanical response of the GAGs. Unlike prior shear lag models that are solved either in two dimensions or in axially symmetric geometries, we present a closed-form analytical model for three-dimensional periodic lattices of fibrils linked by GAGs. Using this approach, we show that the non-linear mechanical response of the GAGs leads to a distinct toe region in the stress-strain response of the tendon. The critical strain of the toe region is shown to decrease inversely with fibril length. Furthermore, we identify a characteristic length scale, related to microstructural parameters (e.g. GAG spacing, stiffness, and geometry) over which load is transferred from the GAGs to the fibrils. We show that when the fibril lengths are significantly larger than this length scale, the mechanical properties of the tendon are relatively insensitive to deletion of GAGs. Our results provide a physical explanation for the insensitivity for the mechanical response of tendon to the deletion of GAGs in mature tendons, underscore the importance of fibril length in determining the elastic properties of the tendon, and are in excellent agreement with computationally intensive simulations. PMID- 23932186 TI - [Clinical image in gastroenterology. Choledochocele diagnosed by endoscopic ultrasound]. PMID- 23932187 TI - Predictors of recanalization in patients with life-threatening hemoptysis requiring artery embolization. AB - INTRODUCTION: Artery embolization (AE) is a safe and useful procedure in the management of massive hemoptysis. The objective of our study was to describe the experience of AE in a tertiary referral center, to characterize angiographic findings at the time of recurrence, and to analyze factors associated with these findings. MATERIAL AND METHODS: Observational retrospective study of patients presenting with life-threatening hemoptysis. All consecutive patients with at least one episode of hemoptysis that required AE during a 13-year period were included. The effects of i)time to recurrence; ii)use of coils, and iii)number of arteries embolized on the likelihood that the recurrence was secondary to recanalization were assessed. RESULTS: One hundred seventy-six patients were included in the study. Twenty-two patients (12.5%) died due to hemoptysis. Probability of recurrence-free survival at one month was 0.91 (95%CI: 0.87 to 0.95), at 12months was 0.85 (95%CI: 0.79 to 0.91), and after 3 years was 0.75 (95%CI: 0.66 to 0.83). A longer time to recurrence was associated with a higher probability that the hemorrhage affected the same artery (estimate=0.0157, z value=2.41, p-value=0.016). CONCLUSION: AE is a safe and useful technique in the management of massive and recurrent hemoptysis. Nevertheless, recurrence after embolization is not uncommon. Recurring hemoptysis due to recanalization is related to time to recurrence, but not to the use of coils or number of arteries embolized. PMID- 23932189 TI - Effect of head-up tilt-table testing on left ventricular longitudinal strain in patients with neurocardiogenic syncope. AB - Recent studies have shown conflicting data regarding left ventricular (LV) function in patients with neurocardiogenic syncope, with some investigators reporting a marked decrease in LV end-systolic wall stress and stress-corrected fractional shortening. We sought to determine the characteristics of resting LV deformation in patients with neurocardiogenic syncope by selective motion tracking of subendocardial and subepicardial regions using speckle tracking echocardiography. We assessed resting LV function in 82 patients undergoing head up tilt-table (HUTT) testing. Patients were divided into 3 groups based on a positive HUTT test with associated co-morbid conditions (n = 30), no associated co-morbid conditions (n = 30), or negative HUTT results (n = 22). LV longitudinal, circumferential, and radial strains were obtained by speckle tracking echocardiography of subendocardial and subepicardial regions in each group and compared with resting LV deformation in 20 healthy control subjects. Compared with endocardial longitudinal strain in control subjects, that in patients with positive HUTT results was attenuated, irrespective of co-morbid conditions (p <0.05). Circumferential and radial strains did not differ among groups. On multivariate logistic regression analysis, endocardial longitudinal strain was an independent predictor (odds ratio, 1.16; p = 0.01) of positive HUTT test results. In conclusion, resting LV longitudinal strain is attenuated in patients with positive HUTT test results. Overall, these results may suggest that an increase in resting LV contractility is not a prerequisite for development of neurocardiogenic syncope. PMID- 23932188 TI - Systematic review of effectiveness of oral sirolimus after bare-metal stenting of coronary arteries for prevention of in-stent restenosis. AB - Neointimal hyperplasia after percutaneous coronary intervention is a major determinant of in-stent restenosis (ISR). Drug-eluting stents (DES) mitigate neointimal hyperplasia and thereby lead to a lower rate of ISR compared with bare metal stents (BMS). Recent studies have demonstrated that short-term use of oral sirolimus after BMS leads to a significant reduction in ISR. We therefore sought to do a systematic review of studies to determine the angiographic and clinical benefits of early short-term use of oral sirolimus after BMS of native coronary arteries. We conducted PubMed, Embase, Cochrane database review, and Web of Science search of studies comparing oral sirolimus after BMS to BMS alone or DES. Outcomes analyzed were ISR and target lesion revascularization (TLR) as well as major adverse cardiovascular events. A total of 488 patients from 4 studies were included in the review (2006 to 2010). Three studies, comparing BMS alone versus BMS plus oral sirolimus, demonstrated significant reduction in ISR in the oral sirolimus group. Two of these studies also demonstrated significant reduction in TLR at 6-12 month follow-up. The fourth study comparing BMS plus oral sirolimus versus DES showed a lower but nonsignificant reduction in TLR in addition to significant cost saving in the group treated with oral sirolimus. In conclusion, our systematic review demonstrates that early short-term systemic use of sirolimus after BMS resulted in a significant reduction in ISR and TLR. In addition, ISR rates were comparable to DES with the added benefit of cost saving. PMID- 23932184 TI - The Alzheimer's Disease Neuroimaging Initiative: a review of papers published since its inception. AB - The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by beta-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151-3) and tau mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [(18)F] fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, beta-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants. PMID- 23932190 TI - Characterization of electrically evoked field potentials in the medial prefrontal cortex and orbitofrontal cortex of the rat: modulation by monoamines. AB - Medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) play critical roles in cognition and behavioural control. Glutamatergic, GABAergic, and monoaminergic dysfunction in the prefrontal cortex has been hypothesised to underlie symptoms in neuropsychiatric disorders. Here we characterised electrically-evoked field potentials in the mPFC and OFC. Electrical stimulation evoked field potentials in layer V/VI of the mPFC and layer V of the OFC. The earliest component (approximately 2 ms latency) was insensitive to glutamate receptor blockade and was presumed to be presynaptic. Later components were blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX (20 uM)) and were assumed to reflect monosynaptic (latency 4-6 ms) and polysynaptic activity (latency 6-40 ms) mediated by glutamate via AMPA/kainate receptor. In the mPFC, but not the OFC, the monosynaptic component was also partly blocked by 2-amino-5 phosphonopentanoic acid (AP-5 (50-100uM)) indicating the involvement of NMDA receptors. Bicuculline (3-10 uM) enhanced the monosynaptic component suggesting electrically-evoked and/or glutamate induced GABA release inhibits the monosynaptic component via GABAA receptor activation. There were complex effects of bicuculline on polysynaptic components. In the mPFC both the mono- and polysynaptic components were attenuated by 5-HT (10-100 uM) and NA (30 and 60 uM) and the monosynaptic component was attenuated by DA (100 uM). In the OFC the mono and polysynaptic components were also attenuated by 5-HT (100 uM), NA (10-100 uM) but DA (10-100 uM) had no effect. We propose that these pharmacologically characterised electrically-evoked field potentials in the mPFC and OFC are useful models for the study of prefrontal cortical physiology and pathophysiology. PMID- 23932191 TI - Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expression. AB - BACKGROUND AND PURPOSE: In muscle-invasive bladder cancer there is an urgent need to identify relatively non-toxic radiosensitising agents for use in elderly patients. Histone deacetylase inhibitors radiosensitise tumour cells but not normal cells in vitro and variously downregulate DNA damage signalling, homologous recombination (HR) and non-homologous end-joining (NHEJ) repair proteins. We investigated panobinostat (PAN) as a potential radiosensitiser in bladder cancer cells. MATERIALS AND METHODS: Clonogenic assays were performed in RT112 bladder cancer cells, and RT112 cells stably knocked down for RAD51 or Ku80 by shRNAi. Resolution of gammaH2AX foci was determined by immunofluorescence confocal microscopy, cell cycle progression by FACS analysis and protein expression by western blotting. RESULTS: PAN had a greater radiosensitising effect in Ku80KD than RT112 or RAD51KD cells; enhancement ratios 1.35 for Ku80KD at 10nM (IC(20) for Ku80KD) and 1.31 for RT112 and RAD51KD at 25 nM (IC(40) for both). PAN downregulated MRE11, NBS1 and RAD51, but not Ku70 and Ku80, increased gammaH2AX foci formation in a dose-dependent manner and delayed gammaH2AX foci repair after ionising radiation. CONCLUSIONS: PAN acts as a radiosensitiser in bladder cancer cell lines, and appears to target HR rather than NHEJ. As muscle invasive bladder tumours have reduced Ku-DNA binding, PAN could be particularly useful as a radiosensitiser in bladder cancer. PMID- 23932192 TI - Progressive resistance training rebuilds lean body mass in head and neck cancer patients after radiotherapy--results from the randomized DAHANCA 25B trial. AB - PURPOSE: The critical weight loss observed in head and neck squamous cell carcinoma (HNSCC) patients following radiotherapy is mainly due to loss of lean body mass. This is associated with decreases in muscle strength, functional performance and Quality of Life (QoL). The present study investigated the effect of progressive resistance training (PRT) on lean body mass, muscle strength and functional performance in HNSCC patients following radiotherapy. PATIENTS AND METHODS: Following radiotherapy HNSCC patients were randomized into two groups: Early Exercise (EE, n=20) initiated 12 weeks of PRT followed by 12 weeks of self chosen physical activity. Delayed Exercise (DE, n=21) initiated 12 weeks of self chosen physical activity followed by 12 weeks of PRT. Lean body mass, muscle strength, functional performance and QoL were evaluated at baseline and after week 12 and 24. RESULTS: In the first 12 weeks lean body mass increased by 4.3% in EE after PRT and in the last 12 weeks by 4.2% in DE after PRT. These increases were significantly larger than the changes after self-chosen physical activity (p <= 0.005). Regardless of PRT start-up time, the odds ratio of increasing lean body mass by more than 4% after PRT was 6.26 (p<0.05). PRT significantly increased muscle strength, whereas functional performance increased significantly more than after self-chosen physical activity only after delayed onset of PRT. Overall QoL improved significantly more in EE than DE from baseline to week 12. CONCLUSION: PRT effectively increased lean body mass and muscle strength in HNSCC patients following radiotherapy, irrespectively of early or delayed start-up. PMID- 23932193 TI - Comparison of carbon ion radiotherapy to photon radiation alone or in combination with temozolomide in patients with high-grade gliomas: explorative hypothesis generating retrospective analysis. AB - PURPOSE: To compare retrospectively outcome after photon radiotherapy alone, radiochemotherapy with temozolomide (TMZ), and carbon ion radiotherapy in patients with high-grade gliomas and to generate a hypothetical outcome curve for C12 and TMZ. PATIENTS AND METHODS: Patients treated within a Phase I/II Trial with a carbon ion boost were compared retrospectively with randomly chosen patients treated with photons or photons in combination with TMZ in a retrospective analysis. Per treatment group, 16 patients with anaplastic astocytoma (AA), and 32 patients with glioblastoma (GBM) were included. Treatment outcome with focus on progression-free survival (PFS) and overall survival (OS) was analyzed. RESULTS: Median OS for patients with GBM was 9 months with RT, 14 months with RCHT group, and 18 months in the C12 group. There was no significant difference between the C12 and the RCHT group. For patients with AA, median OS was 13 months for RT, 39 months for RCHT, and 35 months after C12. The difference from RCHT to C12 was not significant. Median PFS for patients with GBM was 5 months in the RT group, 6 months in the RCHT group, and 8 months in the C12 group. There was a significant difference between the RCHT group and the C12 group. For AA, median PFS was 15 months with RT, 6 months with RCHT, and 34 with C12. Comparing subgroups, C12 was significantly different from RCHT. Based on the significant OS increase from RT to RCHT, and from RT to C12, we projected the potential increase in outcome when combined C12 and TMZ would have been applied. A generated hypothetical curve based on the abovementioned outcome as well as preclinical examinations suggests there might be a benefit from the addition of C12 in patients with high-grade gliomas. CONCLUSIONS: This exploratory retrospective study suggests a potential benefit of carbon ions in patients with high-grade gliomas. This hypothesis is now being evaluated prospectively in GBM within the randomized CLEOPATRA clinical trial. PMID- 23932194 TI - New dental remains of Anoiapithecus and the first appearance datum of hominoids in the Iberian Peninsula. AB - New dental remains of the fossil great ape Anoiapithecus brevirostris are described from the Middle Miocene local stratigraphic series of Abocador de Can Mata (ACM) in els Hostalets de Pierola (Valles-Penedes Basin, NE Iberian Peninsula). These specimens correspond to maxillary fragments with upper teeth from two female individuals from two different localities: left P(3)-M(1) (IPS41712) from ACM/C3-Aj (type locality; 11.9 Ma [millions of years ago]); and right M(1)-M(2) and left P(4)-M(2) (IPS35027) from ACM/C1-E* (12.3-12.2 Ma). Relative enamel thickness is also computed in the latter individual and re evaluated in other Middle Miocene hominoids from ACM, in order to better assess their taxonomic affinities. With regard to maxillary sinus development, occlusal morphology, molar proportions and enamel thickness, the new specimens show greater resemblances with the (male) holotype specimen of A. brevirostris. They differ from Pierolapithecus catalaunicus in displaying less inflated crests, a more lingually-located hypocone, and relatively lower-crowned molars; from Dryopithecus fontani, in the relatively thicker enamel and lower-crowned molars; from Hispanopithecus spp., in the more inflated crown bases, less peripheral cusps and more restricted maxillary sinus; and from Hispanopithecus laietanus also in the thicker crests, more restricted occlusal foveae, and relatively lower crowned molars. The new specimens of A. brevirostris show some slight differences compared with the holotype of this species: smaller size (presumably due to sexual size dimorphism), and less distally-tapering M(2) occlusal contour (which is highly variable in both extant and extinct hominoids). The reported remains provide valuable new evidence on dental intraspecific variation and sexual dimorphism in Anoiapithecus. From a taxonomic viewpoint, they support the distinction of this taxon from both Dryopithecus and Pierolapithecus. From a chronostratigraphic perspective, IPS35027 from ACM/C1-E* enlarges the known temporal distribution of Anoiapithecus, further representing the oldest record (first appearance datum) of hominoids in the Iberian Peninsula. PMID- 23932195 TI - Re-establishing the merits of electrical brain stimulation. AB - During the past decades, direct electrical stimulation (DES) has been a key method not only in determining the organization of brain networks mediating movement, language, and cognition but also in establishing many central concepts of modern neuroscience, such as the electrical nature of neural transmission, the localization of brain functions, and the homuncular arrangement of sensorimotor areas. However, recent criticisms have questioned the utility of DES and argued that data collected with this technique may be flawed and unreliable. As with every other neuroscientific method, DES does have limitations. However, existing evidence argues strongly for its validity and usefulness by demonstrating that DES produces highly specific outcomes at well-defined anatomical sites and significantly minimizes postoperative deficits in brain-damaged patients. PMID- 23932196 TI - Future waste treatment and energy systems--examples of joint scenarios. AB - Development and use of scenarios for large interdisciplinary projects is a complicated task. This article provides practical examples of how it has been carried out in two projects addressing waste management and energy issues respectively. Based on experiences from the two projects, recommendations are made for an approach concerning development of scenarios in projects dealing with both waste management and energy issues. Recommendations are given to develop and use overall scenarios for the project and leave room for sub-scenarios in parts of the project. Combining different types of scenarios is recommended, too, in order to adapt to the methods and tools of different disciplines, such as developing predictive scenarios with general equilibrium tools and analysing explorative scenarios with energy system analysis tools. Furthermore, as marginals identified in differing future background systems determine the outcomes of consequential life cycle assessments (LCAs), it is considered advisable to develop and use explorative external scenarios based on possible marginals as a framework for consequential LCAs. This approach is illustrated using an on-going Danish research project. PMID- 23932197 TI - The role of the titanium functionally dynamic bridging plate for the treatment of the atrophic mandible fractures. AB - The role of the titanium functionally dynamic bridging plate (TFDBP) in the fracture treatment of the severely atrophic mandible was assessed retrospectively. In 28 consecutive patients with fractures of a severely atrophic mandible fixation was carried out with TFDBPs. Twenty-one patients with 27 fractures were included in the study and then followed up for complications and the progress of fracture healing for 17 months postoperatively on average. There was only one case that required plate removal. All patients showed bone healing 3 months after surgery. The mental nerve sensation improved in 12 out of 23 fractures that had presented with nerve function disturbance. Every patient who had dentures prior to sustaining the fracture was able to return to denture wearing 3 weeks after surgery. No major complications occurred. A high proportion of bone healing with a low complication rate was observed with the use of TFDBPs in the treatment of severely atrophic mandible fractures. The TFDBP is an excellent alternative to conventional plating of the severely atrophic mandible. PMID- 23932199 TI - The molecular switches controlling the interaction between complement proteases of the classical and lectin pathways and their substrates. AB - Complement represents a major bridge between the innate and adaptive immune systems of the body. It plays a vital role in host defences against pathogens, but has also been implicated in numerous inflammatory diseases. The system has been the subject of intensive research in recent times with a number of key structural insights into the functioning of the system. Here, we will give an overview of the activation of each pathway, following which recent developments in our understanding of the mechanisms governing the interaction between enzymes and substrates in the classical and lectin pathways in particular will be discussed. PMID- 23932198 TI - The next step in the treatment of persistent temporomandibular joint pain following arthrocentesis: a retrospective study of 18 cases. AB - Temporomandibular joint disorders affect a big portion of the population. There are a variety of treatment methods currently in use. Conservative treatment modalities are followed by more invasive approaches like arthrocentesis or arthroscopy. The aim of the study is to compare the effects of intra-articular tenoxicam injection and arthrocentesis plus viscosupplementation on patients in which a previous arthrocentesis plus viscosupplementation has failed to relieve pain and restore function. The study group consists of 18 TMJs in 16 patients (15 female and 1 male) and the patients were randomly divided into two groups as the arthrocentesis plus viscosupplementation group (n: 8) and tenoxicam injection (n: 10). 20 mg of tenoxicam was injected to the upper compartments of 10 joints without arthrocentesis. The other 8 joints were treated with a second arthrocentesis and sodium hyaluronate injection. VAS scores and maximum mouth opening with and without assistance were recorded in the post operative first week, first month and third month. The results show that there is little benefit in using relatively conservative methods once an arthrocentesis together with viscosupplementation has failed to relieve the patients pain. It is concluded that more invasive procedures should be considered for the patients who do not benefit from arthrocentesis. PMID- 23932200 TI - Formation of transient protein complexes. AB - The encounter complex of two proteins is a dynamic intermediate state that guides proteins to their binding site, thus enhancing the rate of complex formation. It is particularly useful for complexes that must balance a biological requirement for high turnover with the need for specific binding, such as electron transfer complexes. Here, we describe the current methods for studying and visualizing encounter complexes. We discuss recent developments in mapping the energy landscapes, the role of hydrophobic interactions during encounter complex formation and the discovery of futile encounter complexes. These studies have not only provided insight into encounter complexes of electron transfer proteins, but also opened up new questions and approaches for studying encounter complexes in other weakly associated proteins. PMID- 23932201 TI - Fluorine-19 NMR of integral membrane proteins illustrated with studies of GPCRs. AB - Fluorine-19 is a spin-1/2 NMR isotope with high sensitivity and large chemical shift dispersion, which makes it attractive for high resolution NMR spectroscopy in solution. For studies of membrane proteins it is further of interest that (19)F is rarely found in biological materials, which enables observation of extrinsic (19)F labels with minimal interference from background signals. Today, after a period with rather limited use of (19)F NMR in structural biology, we witness renewed interest in this technology for studies of complex supramolecular systems. Here we report on recent (19)F NMR studies with the G protein-coupled receptor family of membrane proteins. PMID- 23932202 TI - Cryptic organelle homology in apicomplexan parasites: insights from evolutionary cell biology. AB - The economic and clinical significance of apicomplexan parasites drives interest in their many evolutionary novelties. Distinctive intracellular organelles play key roles in parasite motility, invasion, metabolism, and replication, and understanding their relationship with the organelles of better-studied eukaryotic systems suggests potential targets for therapeutic intervention. Recent work has demonstrated divergent aspects of canonical eukaryotic components in the Apicomplexa, including Golgi bodies and mitochondria. The apicoplast is a relict plastid of secondary endosymbiotic origin, harboring metabolic pathways distinct from those of host species. The inner membrane complex (IMC) is derived from the cortical alveoli defining the superphylum Alveolata, but in apicomplexans functions in parasite motility and replication. Micronemes and rhoptries are associated with establishment of the intracellular niche, and define the apical complex for which the phylum is named. Morphological, cell biological and molecular evidence strongly suggest that these organelles are derived from the endocytic pathway. PMID- 23932203 TI - Iron and heme metabolism in Plasmodium falciparum and the mechanism of action of artemisinins. AB - During the asexual blood stage of its lifecycle, the malaria parasite Plasmodium falciparum grows and multiplies in the hemoglobin-rich environment of the human erythrocyte. Although the parasite has evolved unique strategies to survive in this environment, its interaction with iron represents an Achilles' heel that is exploited by many antimalarial drugs. Recent work has shed new light on how the parasite deals with hemoglobin breakdown products and on the role of iron as a mediator of the action of the antimalarial drug, artemisinin. PMID- 23932204 TI - Organelle transcriptomes: products of a deconstructed genome. AB - Genetic drift and mutational pressure have shaped the evolution of mitochondrial and chloroplast genomes, giving rise to mechanisms that regulate their gene expression, which often differ from those in their prokaryotic ancestors. Advances in next generation sequencing technologies have enabled highly detailed characterization of organelle transcriptomes and the discovery of new transcripts and mechanisms for controlling gene expression. Here we discuss the common features of organelle transcriptomes that stem from their prokaryotic origin and some of the new innovations that are unique to organelles of multicellular organisms. PMID- 23932205 TI - Experimental foundation for in vivo measurement of the elasticity of the aorta in computed tomography angiography. AB - OBJECTIVE: This study was performed to determine the feasibility of measuring the elastic properties of the arterial wall in vivo. To prove this concept, elastic parameters were calculated from an aortic model of elastic behavior similar to a human aorta using computed tomography angiography (CTA) images. METHODS: We first constructed an aortic model from polydimethylsiloxane (PDMS). This model was inserted into a pulsatile flow loop. The model was then placed inside a computed tomography scanner. To estimate the elasticity values, we measured the cross sectional area and the pressure changes in the model during each phase of the simulated cardiac cycle. A discrete wavelet transform (DWT) algorithm was applied to the CTA data to calculate the geometric changes in the pulsatile model over a simulated cardiac cycle for various pulsatile rates and elasticity values of the PDMS material. The elastic modulus of the aortic model wall was derived from these geometric changes. The elastic moduli derived from the CTA data were compared with those obtained by testing strips of the same PDMS material in a tensile testing machine. Our two aortic models had elastic values at both extremes of those found in normal human aortas. RESULTS: The results show a good comparison between the elastic values derived from the CTA data and those obtained in a tensile testing machine. In addition, the elasticity values were found to be independent of the pulsatile rate for mixing ratios of 6:1 and 9:1 (p = .12 and p = .22, respectively). CONCLUSIONS: The elastic modulus of a pulsatile aortic model may be measured by electrocardiographically-gated multi-detector CTA protocol. This preliminary study suggests the possibility of determining non invasively the elastic properties of a living, functioning aorta using CTA data. PMID- 23932207 TI - Anticancer drug delivery system based on calcium carbonate particles loaded with a photosensitizer. AB - In photodynamic therapy (PDT), photosensitizers are required to arrive in high concentrations at selective targets like cancer cells avoiding toxicity in healthy tissue. In this work, we propose the application of porous calcium carbonate carriers in the form of polycrystalline vaterite for this task. We investigated the loading efficiency for the photosensitizer Photosens in vaterite micro- and nanocarriers. A possible release mechanism depending on the surrounding pH was studied, showing a fast degradation of the carriers in buffers below pH7. These results hold out the prospect of a novel PDT drug delivery system. Variation of particle size or additional coatings allow custom-design of workload release curves. An intrinsic cancer-sensitivity can be expected from the pH-dependent release in the acidic microenvironment of cancer tissue. PMID- 23932206 TI - Impact of low-density lipoprotein cholesterol on cardiovascular outcomes in people with type 2 diabetes: a meta-analysis of prospective cohort studies. AB - AIMS: To estimate the prospective association of low-density lipoprotein (LDL) cholesterol on cardiovascular disease (CVD) risk among people with type 2 diabetes. METHODS: We used extensive literature searching strategies to locate prospective cohort studies that reported LDL cholesterol levels as a risk factor for cardiovascular events. We conducted meta-analytic procedures for two outcomes: incident CVD and CVD mortality. RESULTS: A total of 16 studies were included in this analysis with a mean follow-up range of 4.8-11 years. The pooled relative risk associated with a 1mmol/L increase in LDL cholesterol in people with type 2 diabetes was 1.30 (95% confidence interval [CI], 1.19-1.43) for incident CVD, and 1.50 (95% CI, 1.25-1.80) for CVD mortality, respectively. Subgroup analyses showed that for incident CVD, the pooled relative risk was 1.28 (95% CI, 1.17-1.41) for 7 studies adjusted for blood pressure and/or glucose concentration (or insulin concentration, glycated hemoglobin) and 1.40 (95% CI, 1.05-1.86) for 3 studies that did not adjust for these variables. CONCLUSIONS: Our study demonstrates that LDL cholesterol was associated with an increased risk for cardiovascular outcomes in people with type 2 diabetes, independent of other conventional risk factor. PMID- 23932208 TI - Spontaneous neck hematoma due to rupture of parathyroid adenoma: report of 3 cases and literature review. PMID- 23932209 TI - EMAS position statement: Late parenthood. AB - INTRODUCTION: During the last decades, couples in Europe have been delaying parenthood, mainly due to socio-demographic factors that include increased rates of university education and employment in women and poorer financial status. AIMS: The aim of this position statement is to provide and critically appraise evidence on the impact of late parenthood, focusing on the pathophysiology and management of male and female infertility, pregnancy complications and long-term offspring health. MATERIALS AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS: Advanced parental age is associated with infertility and pregnancy complications and may have an impact on long-term offspring health. All adults of reproductive age should receive counseling on the risks of advanced parental age, so they can make informed decisions about the timing of childbearing. All parents-to-be of advanced age should receive advice on the potential pregnancy, neonatal and long-term offspring health-related issues. These tasks require an interdisciplinary approach that could lead to patient-centered, informed decision-making strategies. PMID- 23932210 TI - Influence of specimen dimensions and their derivatives (C-factor and volume) on polymerization stress determined in a high compliance testing system. AB - OBJECTIVE: To verify the null hypothesis that in a high compliance testing system stress magnitude was not influenced by specimen dimensions and, therefore, by its cavity configuration factor (C-factor) and volume. METHODS: Twelve experimental groups were defined according to the specimen height (0.5, 1, 2 or 4mm) and diameter (4, 6 or 8mm). A selfcure composite (Bisfil 2B, Bisco) was inserted between the flat surfaces of two acrylic rods attached to the opposite ends of a universal testing machine. An extensometer with a gauge length of 10mm was attached to both rods to monitor specimen height. Force development was monitored for 30min and nominal stress was calculated dividing the maximum force value by the crossection of the rod. A second set of data was obtained dividing nominal stress by the corresponding longitudinal compliance (LC) of the system for that particular specimen size. Data was analyzed using two-way ANOVA/Tukey test (nominal stress), Kruskal/Wallis (normalized stress), both at alpha=5%, and regression analysis having either C-factor or volume as independent variable. RESULTS: Regression analysis involving nominal stress did not reveal strong relationships with the independent variables (C-factor: 0.437, volume: 0.662). A strong relationship was found between normalized stress and specimen volume (Radj(2)=0.886). Normalized stress showed no relationship with specimens' C factor. Pairwise comparisons between groups with similar volumes revealed that normalized stress increased at higher C-factors. SIGNIFICANCE: By eliminating the influence of longitudinal compliance, a strong relationship between polymerization stress and specimen volume was revealed in a high compliance testing system. PMID- 23932211 TI - Latent iron deficiency in utero is associated with abnormal auditory neural myelination in >= 35 weeks gestational age infants. AB - OBJECTIVE: To determine whether cord serum ferritin level is associated with auditory brainstem evoked response interpeak latencies, an index of auditory neural myelination, in infants at >= 35 weeks gestational age (GA). STUDY DESIGN: This prospective study compared auditory neural myelination in infants with latent iron deficiency (cord serum ferritin, 11-75 ng/mL) and infants with normal iron status (cord serum ferritin, >75 ng/mL) at birth. Our inclusion criteria were infants born at >= 35 weeks GA who had cord blood collected soon after birth and had 1 or more of the following risk factors for poor in utero iron status: maternal diabetes mellitus, pregnancy-induced hypertension, and intrauterine growth restriction. Cord serum ferritin level was measured using the chemiluminescence immunoassay method. Auditory brainstem evoked response was measured using 80-dB normal hearing level click stimuli at a rate of 69.9/second within 48 hours after birth to evaluate interpeak latencies, a measure of nerve conduction velocity or myelination. RESULTS: Of the 45 infants studied, 12 had latent iron deficiency. On repeated-measures ANCOVA using interpeak latencies I III, III-V, and I-V as multiple outcomes, infants with latent iron deficiency had significantly prolonged interpeak latencies (P = .01) compared with infants with normal iron status after controlling for confounders. CONCLUSION: In utero latent iron deficiency is associated with abnormal auditory neural myelination at birth in infants born at >= 35 weeks GA. PMID- 23932212 TI - Breakthrough varicella in a cancer patient with persistent varicella antibody after one varicella vaccination. AB - A boy with Hodgkin disease contracted breakthrough varicella from his father, who had chickenpox. The boy had received a single varicella vaccination and was seropositive by enzyme-linked immunosorbent assay before being diagnosed with breakthrough varicella. Seropositivity after a single varicella vaccination does not guarantee complete protection in an immunocompromised child. PMID- 23932213 TI - Focal fibrocartilaginous dysplasia and spontaneously resolving bowing of the leg. PMID- 23932214 TI - Budesonide for juvenile autoimmune hepatitis? Not yet. PMID- 23932216 TI - Lifetime risk of blindness in open-angle glaucoma. AB - PURPOSE: To determine the lifetime risk and duration of blindness in patients with manifest open-angle glaucoma (OAG). DESIGN: Retrospective chart review. METHODS: We studied glaucoma patients who died between January 2006 and June 2010. Most glaucoma patients living in the catchment area (city of Malmo; n = 305 000) are managed at the Department of Ophthalmology at Skane University Hospital in Malmo. From the patient records we extracted visual field status, visual acuity, and low vision or blindness as defined by the World Health Organization (WHO) criteria and caused by glaucoma at the time of diagnosis and during follow up. We also noted age at diagnosis and death and when low vision or blindness occurred. RESULTS: Five hundred and ninety-two patients were included. At the time of the last visit 250 patients (42.2%) had at least 1 blind eye because of glaucoma, while 97 patients (16.4%) were bilaterally blind, and 12 patients (0.5%) had low vision. Median time with a glaucoma diagnosis was 12 years (<1 29), median age when developing bilateral blindness was 86 years, and median duration of bilateral blindness was 2 years (<1-13). The cumulative incidences of blindness in at least 1 eye and bilateral blindness from glaucoma were 26.5% and 5.5%, respectively, after 10 years, and 38.1% and 13.5% at 20 years. CONCLUSIONS: Approximately 1 out of 6 glaucoma patients was bilaterally blind from glaucoma at the last visit. Median duration of bilateral blindness was 2 years. PMID- 23932215 TI - Candidate gene analysis of the surfactant protein D gene in pediatric diffuse lung disease. AB - Mutations in surfactant-associated genes cause childhood diffuse lung disease. Mice lacking surfactant protein D develop lung disease with age. However, we identified no novel surfactant protein D gene (SFTPD) coding or splice region variants in 73 unrelated children with diffuse lung disease from a cohort enriched for genetic surfactant dysfunction. PMID- 23932217 TI - Selective laser trabeculoplasty following failed combined phacoemulsification cataract extraction and ab interno trabeculectomy. AB - PURPOSE: To assess the effect of selective laser trabeculoplasty (SLT) following failed phacoemulsification cataract extraction combined with ab interno trabeculectomy (AIT) using the Trabectome (phaco-trabectome). DESIGN: Randomized, interventional case series. METHODS: Retrospectively, the medical records of patients who underwent SLT between March 2010 and July 2012 by 1 surgeon at a single center after a failed phaco-AIT were evaluated. Inclusion criteria were age >=18 years with no upper limit and prior failed phaco-AIT attributable to glaucoma progression. Exclusion criterion was performance of any additional glaucoma procedure with influence on intraocular pressure (IOP) during follow-up and a follow-up after surgery of <3 months. Success was defined by reduction of IOP of >3 mm Hg and 20% and number of antiglaucoma medications equal to or less than baseline. Main outcome measures were IOP, antiglaucoma medications, time to failure, and Kaplan-Meier survival curve. RESULTS: Fourteen eyes of 13 subjects were included. Mean follow-up after SLT was 12.9 +/- 8.7 months. Total laser energy was 59.5 +/- 8.7 mJ. Baseline IOP was 17.9 +/- 3.3 mm Hg and number of antiglaucoma medications at baseline was 2.0 +/- 1.0. All SLT procedures failed. Median time to failure after SLT was 3.6 +/- 0.8 (range 2.1-5.1) months. Number of antiglaucoma medications did not change. CONCLUSIONS: In eyes in which the IOP was no longer controlled following phaco-trabectome, SLT had a limited duration of significant IOP-lowering effect. Other alternatives, such as incisional filtration surgery, should be considered following failed phaco-trabectome. PMID- 23932218 TI - A probiotic trial: tipping the balance of evidence? PMID- 23932219 TI - Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. AB - BACKGROUND: Antibiotic-associated diarrhoea (AAD) occurs most frequently in older (>=65 years) inpatients exposed to broad-spectrum antibiotics. When caused by Clostridium difficile, AAD can result in life-threatening illness. Although underlying disease mechanisms are not well understood, microbial preparations have been assessed in the prevention of AAD. However, studies have been mostly small single-centre trials with varying quality, providing insufficient data to reliably assess effectiveness. We aimed to do a pragmatic efficacy trial in older inpatients who would be representative of those admitted to National Health Service (NHS) and similar secondary care institutions and to recruit a sufficient number of patients to generate a definitive result. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, pragmatic, efficacy trial of inpatients aged 65 years and older and exposed to one or more oral or parenteral antibiotics. A computer-generated randomisation scheme was used to allocate participants (in a 1:1 ratio) to receive either a multistrain preparation of lactobacilli and bifidobacteria, with a total of 6 * 10(10) organisms, one per day for 21 days, or an identical placebo. Patients, study staff, and specimen and data analysts were masked to assignment. The primary outcomes were occurrence of AAD within 8 weeks and C difficile diarrhoea (CDD) within 12 weeks of recruitment. Analysis was by modified intention-to-treat. This trial is registered, number ISRCTN70017204. FINDINGS: Of 17,420 patients screened, 1493 were randomly assigned to the microbial preparation group and 1488 to the placebo group. 1470 and 1471, respectively, were included in the analyses of the primary endpoints. AAD (including CDD) occurred in 159 (10.8%) participants in the microbial preparation group and 153 (10.4%) participants in the placebo group (relative risk [RR] 1.04; 95% CI 0.84-1.28; p=0.71). CDD was an uncommon cause of AAD and occurred in 12 (0.8%) participants in the microbial preparation group and 17 (1.2%) participants in the placebo group (RR 0.71; 95% CI 0.34-1.47; p=0.35). 578 (19.7%) participants had one or more serious adverse event; the frequency of serious adverse events was much the same in the two study groups and none was attributed to participation in the trial. INTERPRETATION: We identified no evidence that a multistrain preparation of lactobacilli and bifidobacteria was effective in prevention of AAD or CDD. An improved understanding of the pathophysiology of AAD is needed to guide future studies. FUNDING: Health Technology Assessment programme; National Institute for Health Research, UK. PMID- 23932220 TI - Barriers to and consequences of mandated reporting of child abuse by nurse practitioners. AB - INTRODUCTION: The objective of this study was to examine the experiences of pediatric nurse practitioners (PNPs) in the identification and management of child abuse, determine the frequency of their reporting, and describe the effects, attitudes, and confidence in reporting child abuse. METHODS: A survey based on the 2006 CARES survey was disseminated via e-mail through use of Survey Monkey to 5,764 PNP members of the National Association of Pediatric Nurse Practitioners. The data from this survey were then subjected to statistical analysis, and the resultant findings were compared and contrasted with other similar studies. RESULTS: Data analysis revealed that smaller numbers of PNPs in the sample group failed to report suspected child abuse than did their physician colleagues. PNPs and physicians encountered similar perceived barriers to reporting and used similar processes in dealing with them. Both physicians and PNPs with recent child abuse continuing education hours expressed greater confidence in child abuse management skills and were more likely to report suspected cases of abuse. DISCUSSION: Much information was learned about PNP reporting practices regarding child abuse. The most significant facts that emerged from this study were that all health care providers require further child abuse education, both in their curriculum preparation and continuing education, to effectively diagnose and manage child abuse. PMID- 23932222 TI - A paradigm shift in the surgical reconstruction of extra-articular distal humeral fractures: single-column plating. AB - OBJECTIVES: The study aimed (1) to examine if there are equivalent results in terms of union, alignment and elbow functionally comparing single- to dual-column plating of AO/OTA 13A2 and A3 distal humeral fractures and (2) if there are more implant-related complications in patients managed with bicolumnar plating compared to single-column plate fixation. DESIGN: This was a multi-centred retrospective comparative study. SETTING: The study was conducted at two academic level 1 trauma centres. PATIENTS/PARTICIPANTS: A total of 105 patients were identified to have surgical management of extra-articular distal humeral fractures Arbeitsgemeinschaft fur Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) 13A2 and AO/OTA 13A3). INTERVENTION: Patients were treated with traditional dual-column plating or a single-column posterolateral small fragment pre-contoured locking plate used as a neutralisation device with at least five screws in the short distal segment. MAIN OUTCOME MEASUREMENTS: The patients' elbow functionality was assessed in terms of range of motion, union and alignment. In addition, the rate of complications between the groups including radial nerve palsy, implant-related complications (painful prominence and/or ulnar nerve neuritis) and elbow stiffness were compared. RESULTS: Patients treated with single-column plating had similar union rates and alignment. However, single-column plating resulted in a significantly better range of motion with less complications. CONCLUSIONS: The current study suggests that exposure/instrumentation of only the lateral column is a reliable and preferred technique. This technique allows for comparable union rates and alignment with increased elbow functionality and decreased number of complications. PMID- 23932223 TI - Rapid and simple neurotoxin-based distinction of Chinese and Japanese star anise by direct plant spray mass spectrometry. AB - Ingestion of products containing Chinese star anise (Illicium verum) fruits contaminated or adulterated with Japanese star anise (Illicium anisatum) fruits can cause poisoning due to the neurotoxin anisatin that is present in Japanese star anise. Thus a rapid, simple and unambiguous distinction between the morphologically similar Chinese star anise and toxic Japanese star anise fruits is important for guaranteeing food safety. After adding ~200 MUL of methanol to one star anise carpel placed at 7-10mm from the inlet of a mass spectrometer and applying a potential of ~5 kV to the carpel, an electrospray is created. The formation of the electrospray is immediate, robust and stable and lasts for at least a minute. The presence or absence of anisatin could be monitored by orbitrap high resolution mass spectrometry (HRMS) in negative mode by observing the [M-H](-) ion at m/z 327.1074 (C15H19O8) or in positive mode the [M+K](+) ion at m/z 367.079 (C15H20KO8). Several parameters like wetting solvent, voltage, distance and set-up were optimised. The anisatin signal was ~250 times higher in Japanese than in Chinese star anise. An existing Direct Analysis in Real Time (DART) HRMS for anisatin was used for benchmarking. Alternatively a linear ion trap mass spectrometer could be used in negative selective reaction monitoring (SRM) mode albeit with lower selectivity than the HRMS method. The transition of the [M-H](-) ion at m/z 327 to the fragment at m/z 265 was monitored. Direct plant spray and DART ionisation are both robust and provided the same yes/no answer in seconds without any prior sample preparation. Compared with the DART HRMS procedure, the direct plant spray method is simpler in terms of equipment, yields a more stable signal, does not require heating of the sample but is slightly less selective and requires working with high voltages. PMID- 23932224 TI - Ionic liquid-mediated molecularly imprinted solid-phase extraction coupled with gas chromatography-electron capture detector for rapid screening of dicofol in vegetables. AB - New ionic liquid-mediated molecularly imprinted polymers (IL-MIPs) were prepared by precipitation polymerization using 1-butyl-3-methylimidazolium hexafluorophosphate (BMIM(+)PF6(-)) as the auxiliary solvent, alpha-chloro-DDT as the dummy template, and they were successfully applied as the sorbents of solid phase extraction (SPE) for rapid screening of dicofol from cabbage, tomato, and carrot samples. The IL-MIPs were characterized by FTIR, FE-SEM, static adsorption and chromatographic evaluation, and the results revealed that the IL-MIPs had higher adsorption capacity and selectivity to dicofol in aqueous solution than that of ionic liquid-mediated non-imprinted polymers (IL-NIPs) and non-imprinted polymers (NIPs). Under the optimized conditions, the IL-MIPs-SPE-GC method offered good linearity (0.4-40.0ngg(-1), r(2)=0.9995) and the average recoveries of dicofol at three spiked levels were in a range of 84.6-104.1% (n=3) with RSD<=7.6%. The proposed method obviously improved the selectivity and purification effect, and eliminated the effect of template leakage on dicofol quantitative analysis. PMID- 23932226 TI - Relationship between prefrontal function during a cognitive task and social functioning in male Japanese workers: a multi-channel near-infrared spectroscopy study. AB - To investigate whether prefrontal function during a cognitive task reflects the social functioning of male Japanese workers, prefrontal function during a working memory task in 181 male workers was measured by multi-channel near-infrared spectroscopy (NIRS). Social functioning was assessed using the Social Adaptation Self-Evaluation Scale (SASS). The results indicated that cortical oxygenation level increases in dorsolateral prefrontal region showed significant positive correlations with the interest and motivation factor scores on the SASS. These results suggest that dorsolateral prefrontal function is associated with the interest and motivation factor in social functioning in male workers and that NIRS could be an addition to the medical tools for monitoring these characteristics on mental health examination. PMID- 23932225 TI - Interoceptive-reflective regions differentiate alexithymia traits in depersonalization disorder. AB - It is unclear to what degree depersonalization disorder (DPD) and alexithymia share abnormal brain mechanisms of emotional dysregulation. We compared cerebral processing of facial expressions of emotion in individuals with DPD to normal controls (NC). We presented happy and sad emotion expressions in increasing intensities from neutral (0%) through mild (50%) to intense (100%) to DPD and non referred NC subjects in an implicit event-related fMRI design, and correlated respective brain activations with responses on the 20-item Toronto Alexithymia Scale (TAS-20) and its three subscales F1-F3. The TAS-20 predicts clinical diagnosis of DPD with a unique variance proportion of 38%. Differential regression analysis was utilized to ascertain brain regions for each alexithymia subscale. Differential regions of total alexithymia severity for happy emotion were the globus pallidus externus; for identifying feelings (TAS-20 F1 subscale), the right anterior insula; for description of feelings (F2), the right dorsal mid anterior cingulate gyrus (BA 24); and for externally oriented cognitive style (F3), the left paracingulate gyrus (BA 32). For sad emotion, the differential region for the total TAS-20 score was the dorsal anterior cingulate gyrus (BA 24); for TAS-20 F1, the left inferior anterior insula; for TAS-20 F2, the right PCC (BA 31); and for TAS-20 F3, the right orbital gyrus (BA 10). Supporting our hypotheses, the ascertained brain regions for TAS-20 subscales subserve interoception, monitoring and reflection of internal states and emotion. The presented analyses provide evidence that alexithymia plays a substantial role in emotional dysregulation in DPD, presumably based on restrictions in interoception. PMID- 23932227 TI - Group management of pharmacotherapy for alcohol dependence: feasibility and impact on adoption. AB - One of the barriers to initiating patients on medications for alcohol dependence is concern about the work involved in providing ongoing medication management. In this brief report, we describe our initial experiences with a medication management group, initially implemented to provide continued access during a staffing shortage. We describe the group structure and functioning, and provide initial analysis of the groups' impact on access and adoption of pharmacotherapy for alcohol dependence. Results of an interrupted time series analysis in one Veterans Health Administration (VHA) facility provide support for the notion that the group format is not only feasible but can actually increase access to these under-utilized medications (e.g., naltrexone and acamprosate). The number of patients receiving these medications was already increasing in this facility before the switch to group appointments, but this rate of initiation increased almost 3-fold after the onset of the groups. PMID- 23932228 TI - New cardiac models of care reduce patient access to specialist nurses: a Victorian cross-sectional pilot study. AB - BACKGROUND: Several studies have shown that the acuity and complexity of patients admitted to coronary care units is rising. Advances in medical technology and management of these patients have resulted in shorter lengths of hospital stay. Together, these changing care patterns have led to an emergence of new models of care delivery that differ from traditional coronary care units (CCU). The effect of these new models on workforce and resources in this area is unknown. AIM: To describe the workforce and workplace resources of adult CCUs in Victoria, Australia. METHOD: This pilot study used an investigator-developed survey to audit all adult CCUs operating in Victoria in 2010. RESULTS: A total of 24 CCUs participated in the audit of which the majority were located in metropolitan public hospitals. In terms of model of care of CCUs: 25% (6) of CCUs were a combination of a CCU/cardiology ward, 17% (4) a combined CCU/ICU or combined CCU/ICU/HDU and 12.5% (3) of CCUs were a dedicated unit. Only 15% (4) of all units met the international standards for a nursing workforce with critical care qualifications. The CCU/day procedure/HDU models had 24% of critical care qualified staff followed by CCU/cardiology ward model with 35% compared to an average of 54-80% of qualified staff in the other models of care of CCU. CONCLUSIONS: This pilot study has highlighted the heterogeneity in models of CCU and a shortage of qualified critical care nurses, particularly in the CCU/cardiology ward model. This may have implications for the quality of care delivered in CCUs. PMID- 23932229 TI - Massive lipid keratopathy after Elizabethkingia meningosepticum keratitis. AB - PURPOSE: To report the occurrence of massive lipid deposition in the cornea after Elizabethkingia meningoseptica keratitis. METHODS: A 52-year-old female presented to the ophthalmology outpatient department of the Hong Kong Eye Hospital in January 2012 with complaints of pain, redness, watering and blurred vision in her left eye for 6 days. Past records showed that the patient underwent radiotherapy for mucoepidermoid carcinoma of the maxillary antrum which was later complicated by radiotherpay associated dry eye syndrome in her left eye. At the time of presentation, her best-corrected visual acuity was 0.7 OD and hand motions close to face OS. Slit lamp examination of the left eye showed a small infiltrate 1.4mm*1.2mm in size with an overlying epithelial defect. Elizabethkingia meningosepticum was isolated on broth. Good clinical response was observed with hourly 5% vancomycin eye drops. RESULTS: At the end of 8 weeks, slit lamp examination of the left eye revealed a corneal scar with mild lipid deposition at the site of previous corneal infiltrate. The lipid deposits increased tremendously over the next 4 weeks. The final visual acuity in the right eye dropped down to perception of light. The patient refused any further surgical intervention and is on regular follow-up in our clinic. CONCLUSIONS: Our case report highlights the occurrence of post-keratitis lipid keratopathy with E. meningosepticum. PMID- 23932231 TI - The epigenetic landscape in the course of time: Conrad Hal Waddington's methodological impact on the life sciences. AB - It seems that the reception of Conrad Hal Waddington's work never really gathered speed in mainstream biology. This paper, offering a transdisciplinary survey of approaches using his epigenetic landscape images, argues that (i) Waddington's legacy is much broader than is usually recognized--it is widespread across the life sciences (e.g. stem cell biology, developmental psychology and cultural anthropology). In addition, I will show that (ii) there exist as yet unrecognized heuristic roles, especially in model building and theory formation, which Waddington's images play within his work. These different methodological facets envisioned by Waddington are used as a natural framework to analyze and classify the manners of usage of epigenetic landscape images in post-Waddingtonian 'landscape approaches'. This evaluation of Waddington's pictorial legacy reveals that there are highly diverse lines of traditions in the life sciences, which are deeply rooted in Waddington's methodological work. PMID- 23932230 TI - Inhibition of the tumour necrosis factor-alpha autocrine loop enhances the sensitivity of multiple myeloma cells to anticancer drugs. AB - Several autocrine soluble factors, including macrophage inflammatory protein 1alpha and tumour necrosis factor-alpha (TNF-alpha), promote the survival and growth of multiple myeloma (MM) cells. We hypothesised that inhibition of the TNF alpha autocrine loop may enhance the cytotoxic effect of anticancer drugs in MM cell lines. In the present study, a TNF-alpha-neutralizing antibody suppressed cell proliferation and enhanced the cytotoxic effect of anticancer drugs on MM cells. In addition, combination treatment with the TNF-alpha-neutralizing antibody and the chemotherapy agent melphalan inhibited nuclear factor kappaB (NF kappaB) p65 nuclear translocation and mammalian target of rapamycin (mTOR) activation and upregulated the expression of Bax and Bim. Treatment of ARH-77 cells with the NF-kappaB inhibitor dimethyl fumarate or the mTOR inhibitor rapamycin suppressed NF-kappaB p65 nuclear translocation and enhanced the cytotoxic effect of melphalan. Furthermore, infliximab, a monoclonal antibody against TNF-alpha, also enhanced the cytotoxic effect of anticancer drugs in ARH 77 cells. These results indicated that TNF-alpha-neutralizing antibodies or infliximab enhanced the cytotoxic effect of anticancer drugs by suppressing the TNF receptor/mTOR/NF-kappaB pathways. The inhibition of TNF-alpha may thus provide a new therapeutic approach to control tumour progression and bone destruction in MM patients. PMID- 23932232 TI - The Wolffian roots of Kant's teleology. AB - Kant's teleology as presented in the Critique of Judgment is commonly interpreted in relation to the late eighteenth-century biological research of Johann Friedrich Blumenbach. In the present paper, I show that this interpretative perspective is incomplete. Understanding Kant's views on teleology and biology requires a consideration of the teleological and biological views of Christian Wolff and his rationalist successors. By reconstructing the Wolffian roots of Kant's teleology, I identify several little known sources of Kant's views on biology. I argue that one of Kant's main contributions to eighteenth-century debates on biology consisted in demarcating biology from metaphysics. Kant rejected Wolffian views on the hierarchy of sciences, according to which propositions specifying the functions of organisms are derived from theological truths. In addition, Kant argued that organic self-organization necessitates a teleological description in order to show that self-organization does not support materialism. By demarcating biology and metaphysics, Kant made a small yet important contribution to establishing biology as a science. PMID- 23932233 TI - Outcomes of prospectively-collected consecutive cases of antenatal-suspected placenta accreta. AB - BACKGROUND: Accurate diagnosis of placenta accreta is tentative before surgery. This study developed a predictive score for antenatal diagnosis of placenta accreta through mathematical modeling using clinical signs. METHODS: Antenatal cases of suspected placenta accreta were collected prospectively in a single-site tertiary delivery center. Women with clinical signs of placenta accreta (placenta previa, number of previous cesarean deliveries and/or ultrasound suspicion of placenta accreta) were included. The diagnosis of accreta was confirmed surgically. The primary endpoint was the proportion of surgically-diagnosed placenta accreta among all suspected cases. Logistic regression modeling was performed to assess preoperative risk factors for placenta accreta. The risk score was tested on a receiver operator characteristic curve to identify subjects with placenta accreta and the optimum cut-point was chosen. RESULTS: Over nine years, 92 suspected accreta cases were identified from 46623 deliveries (0.2%). The diagnosis was confirmed at surgery in 52/92 cases (56%) and there were no maternal deaths. Blood transfusion requirements were greater in patients with placenta accreta versus patients without placenta accreta (median 7 [range 0-25, interquartile range 3-10] versus 0 [0-6, 0-2] units of blood, P <0.0001). Area under the curve of the receiver operator characteristic curve was 0.846, with contribution from three variables (placenta previa, number of previous cesarean deliveries and ultrasound suspicion), each with a P value <0.05. From the ROC curve a cut-point with 100% sensitivity and specificity 25% (95% CI 12.69% 41.20%) was achieved, compared with 86.6% sensitivity (95% CI 74.21%-94.41%) and 60.0% specificity (95% CI 43.33%-75.14%) using ultrasound alone. CONCLUSIONS: Combining diagnostic features associated with placenta accreta through mathematical modeling has better positive predictive value than ultrasound alone. PMID- 23932235 TI - Dorso-ventral contributions in the formation of the embryonic aorta and the control of aortic hematopoiesis. AB - The embryonic dorsal aorta plays a pivotal role in the production of the first hematopoietic stem cells (HSCs), the founders of the adult hematopoietic system. HSC production is polarized by being restricted to the aortic floor where a specialized subset of endothelial cells (ECs) endowed with hemogenic properties undergo an endothelial-to-hematopoietic production resulting in the formation of the intra-aortic hematopoietic clusters. This production is tightly time- and space-controlled with the transcription factor Runx1 playing a key role in this process and the surrounding tissues controlling the aortic shape and fate. In this paper, we shall review (a) how hemogenic ECs differentiate from the mesoderm, (b) how the different aortic components assemble coordinately to establish the dorso-ventral polarity, and (c) how this results in the initiation of Runx1 expression in hemogenic ECs and the initiation of the hematopoietic program. These observations should elucidate the first steps in HSC commitment and help in developing techniques to manipulate adult HSCs. PMID- 23932234 TI - Erythroid development in the mammalian embryo. AB - Erythropoiesis is the process by which progenitors for red blood cells are produced and terminally differentiate. In all vertebrates, two morphologically distinct erythroid lineages (primitive, embryonic, and definitive, fetal/adult) form successively within the yolk sac, fetal liver, and marrow and are essential for normal development. Red blood cells have evolved highly specialized functions in oxygen transport, defense against oxidation, and vascular remodeling. Here we review key features of the ontogeny of red blood cell development in mammals, highlight similarities and differences revealed by genetic and gene expression profiling studies, and discuss methods for identifying erythroid cells at different stages of development and differentiation. PMID- 23932236 TI - The impact of trisomy 21 on foetal haematopoiesis. AB - The high frequency of a unique neonatal preleukaemic syndrome, transient abnormal myelopoiesis (TAM), and subsequent acute myeloid leukaemia in early childhood in patients with trisomy 21 (Down syndrome) points to a specific role for trisomy 21 in transforming foetal haematopoietic cells. N-terminal truncating mutations in the key haematopoietic transcription factor GATA1 are acquired during foetal life in virtually every case. These mutations are not leukaemogenic in the absence of trisomy 21. In mouse models, deregulated expression of chromosome 21-encoded genes is implicated in leukaemic transformation, but does not recapitulate the effects of trisomy 21 in a human context. Recent work using primary human foetal liver and bone marrow cells, human embryonic stem cells and iPS cells shows that prior to acquisition of GATA1 mutations, trisomy 21 itself alters human foetal haematopoietic stem cell and progenitor cell biology causing multiple abnormalities in myelopoiesis and B-lymphopoiesis. The molecular basis by which trisomy 21 exerts these effects is likely to be extremely complex, to be tissue specific and lineage-specific and to be dependent on ontogeny-related characteristics of the foetal microenvironment. PMID- 23932237 TI - Brain activity for visual judgment of lifted weight. AB - It is well established that humans can recognize high-level aspects from point light biological motion, such as gender and mood. If the task is to judge the manipulated weight we expected that sensorimotor regions should be recruited in the brain. Moreover, we have recently shown that chronic pain in a limb that is involved in the presented movement disturbs the weight judgment. We therefore hypothesized that some cortical regions usually activated during the processing of pain will also be activated while viewing point-light biological motion with the instruction to judge the manipulated weights. We investigated point-light biological motion of two types of movements performed with different weights in a blocked fMRI experiment in healthy subjects. In line with our a priori hypothesis, we found strong activity in the regions known as the neuromatrix of pain, such as the anterior cingulate (ACC), insula, as well as primary and secondary somatosensory regions. We also found activation in the occipital and temporal regions that are typical for biological motion, as well as regions in the cerebellum and prefrontal cortex. The activation of the somatosensory regions probably serves the judgment of the biological motion stimuli. Activation of the anterior cingulate and the insula might be explained by their role in the integration of behaviorally relevant information. Alternatively, these structures are known to be involved in the processing of nociceptive information and pain. So it seems possible that the interference between judgment of weights and perception of pain in chronic pain patients occurs in the somatosensory areas, anterior cingulate and/or insula. This finding provides important information as to the underlying mechanisms used for the weight judgment task, but also why chronic pain interferes with this task. PMID- 23932241 TI - Iran and science publishing: an open letter - Editors' reply. PMID- 23932242 TI - Iran and science publishing: an open letter. PMID- 23932243 TI - Transcranial sonography in obsessive-compulsive disorder. AB - There is convergent evidence that basal ganglia structures are involved in the pathogenesis of obsessive-compulsive disorder (OCD). It has been also assumed that OCD is caused by a central serotonergic dysfunction. Transcranial sonography (TCS) has become a reliable, sensitive and non-invasive diagnostic tool concerning the evaluation of extrapyramidal movement disorders. This study used TCS to examine the alterations in different parenchymal regions, especially concerning serotonergic brainstem raphe nuclei as well as basal ganglia in OCD. Thirty-one OCD patients were compared with 31 matched healthy controls. Echogenecities were investigated according to the examination protocol for extrapyramidal disorders using a Siemens Sonoline((r)) Elegra system. Obsessive compulsive disorder patients showed reduced echogenity of the serotonergic brainstem raphe nuclei (32.3%) compared with healthy controls (16.1%). In nine OCD-patients (31%), but only in 2 control subjects (6.2%), a hyperechogenicity of the caudate nucleus was found. Patients with OCD significantly more often reveal a hypoechogenic brainstem raphe possibly reflecting altered serotonergic neurons there and a hyperechogenicity of caudate nucleus indicating structural or molecular cell changes. Further research is warranted to examine, whether TCS is useful in order to classify OCD and its subtypes. PMID- 23932244 TI - Effects of yoga therapy on postural stability in patients with schizophrenia spectrum disorders: a single-blind randomized controlled trial. AB - INTRODUCTION: Postural instability is a serious concern in patients with schizophrenia-spectrum disorders since it is expected to increase the risk of falls that may lead to fractures. The impact of yoga therapy on postural stability has not been investigated. METHODS: In this eight-week single-blind randomized controlled study with an eight-week follow-up, outpatients with schizophrenia or related psychotic disorder (ICD-10) were randomly assigned to either yoga therapy or a control group. In the yoga therapy group, the subjects received weekly sessions of 60-min yoga therapy for eight weeks in addition to their ongoing treatment. In the control group, the subjects received a weekly regular day-care program. The assessments that were performed at the baseline and endpoint included the Clinical Stabilometric Platform (CSP), anteflexion in standing. RESULTS: Forty-nine patients participated in this study (32 men; mean +/- SD age, 53.1 +/- 12.3 years): yoga therapy group (n = 25) and control group (n = 24). In the yoga group, significant improvements were observed in a total length of trunk motion, the Romberg ratio, and anteflexion in standing at week 8 (mean +/- SD: 63.9 +/- 40.7-53.4 +/- 26.2 cm, 1.6 +/- 0.9-1.1 +/- 0.6, and -8.7 +/- 9.5 to -3.8 +/- 12.4 cm, respectively) while there were no significant changes in the control group. However, those clinical gains returned to the baseline level at week 16. CONCLUSIONS: The results confirmed the beneficial effects of the yoga therapy on postural stability in patients with schizophrenia. However, the therapeutic effects seemed transient, which warrants further investigations on strategies to sustain the improvements. PMID- 23932245 TI - Directing stem cell fate on hydrogel substrates by controlling cell geometry, matrix mechanics and adhesion ligand composition. AB - There is a dynamic relationship between physical and biochemical signals presented in the stem cell microenvironment to guide cell fate determination. Model systems that modulate cell geometry, substrate stiffness or matrix composition have proved useful in exploring how these signals influence stem cell fate. However, the interplay between these physical and biochemical cues during differentiation remains unclear. Here, we demonstrate a microengineering strategy to vary single cell geometry and the composition of adhesion ligands - on substrates that approximate the mechanical properties of soft tissues - to study adipogenesis and neurogenesis in adherent mesenchymal stem cells. Cells cultured in small circular islands show elevated expression of adipogenesis markers while cells that spread in anisotropic geometries tend to express elevated neurogenic markers. Arraying different combinations of matrix protein in a myriad of 2D and pseudo-3D geometries reveals optimal microenvironments for controlling the differentiation of stem cells to these "soft" lineages without the use of media supplements. PMID- 23932246 TI - The effect of ligand composition on the in vivo fate of multidentate poly(ethylene glycol) modified gold nanoparticles. AB - Multidentate ligands are expected to improve the performance of inorganic nanoparticles (NPs) in biological application. Designing robust multidentate ligands by a facile way and understanding the impact of ligand composition on NP's property are greatly important. We report the effective synthesis of hydrophilic copolymers containing pendent thiol groups along a polyethylene glycol (PEG) methacrylate backbone by classical free radical copolymerization. Gold nanoparticles (AuNPs) coated by these multidentate ligands with two different ratios of thiols to PEG segment (~ 1:1 and 1:2) showed much higher colloidal stability in the presence of dithiothreitol (DTT) than AuNPs coated by monothiol-anchored PEG, and AuNPs coated by ligands with higher fraction of thiol groups showed slightly better resistance to DTT competition than did AuNPs coated by ligands with lower thiol fraction, but both of them exhibited excellent stabilities in biological media without obvious difference. In vitro study of uptake by macrophages did not showed significant difference between the two AuNPs with very low endocytosis. However, AuNPs coated by ligands with higher PEG content were found to accumulate in liver with a significantly lower level but a higher level in spleen than AuNPs coated by ligands with lower PEG contents. Moreover, the AuNPs coated with by ligands with higher PEG content showed higher tumor uptake. Additionally, AuNPs coated with both ligands demonstrated good biocompatibility as evaluated by cytotoxicity assays and histological analysis. Together, the composition of multidentate ligands will not only affect the stability of NPs under extreme conditions but also result in quite different fate of NPs in vivo, which can be tailored case by case. PMID- 23932247 TI - SPECT/CT imaging of radiolabeled cubosomes and hexosomes for potential theranostic applications. AB - We have developed a highly efficient method for the radiolabeling of phytantriol (PHYT)/oleic acid (OA)-based hexosomes based on the surface chelation of technetium-99m ((99m)Tc) to preformed hexosomes using the polyamine 1, 12-diamino 3, 6, 9-triazododecane (SpmTrien) as chelating agent. We also report on the unsuccessful labeling of cubosomes using the well-known chelating agent hexamethylpropyleneamine oxime (HMPAO). The (99m)Tc-labeled SpmTrien-hexosomes ((99m)Tc-SpmTrien-hexosomes) were synthesized with good radiolabeling (84%) and high radiochemical purity (>90%). The effect of radiolabeling on the internal nanostructure and the overall size of these aqueous dispersions was investigated by using synchrotron small angle X-ray scattering (SAXS), dynamic light scattering (DLS), and transmission electron cryo microscopy (cryo-TEM). Further, we show the utility of (99m)Tc-SpmTrien-hexosomes for the in vivo imaging of healthy mice using single photon emission computed tomography (SPECT) in combination with computed tomography (CT), i.e. SPECT/CT. SPECT/CT experiments of subcutaneously administered (99m)Tc-SpmTrien-hexosomes to the flank of mice showed a high stability in vivo allowing imaging of the distribution of the radiolabeled hexosomes for up to 24 h. These injected (99m)Tc-SpmTrien-hexosomes formed a deposit within the subcutaneous adipose tissue, displaying a high biodistribution of ~ 343% injected dose/g tissue (%ID/g), with negligible uptake in other organs and tissues. The developed (99m)Tc labeling method for PHYT/OA based hexosomes could further serve as a useful tool for investigating and imaging the in vivo performance of cubosomal and hexosomal drug nanocarriers. PMID- 23932248 TI - Click conjugated polymeric immuno-nanoparticles for targeted siRNA and antisense oligonucleotide delivery. AB - Efficient and targeted cellular delivery of small interfering RNAs (siRNAs) and antisense oligonucleotides (AONs) is a major challenge facing oligonucleotide based therapeutics. The majority of current delivery strategies employ either conjugated ligands or oligonucleotide encapsulation within delivery vehicles to facilitate cellular uptake. Chemical modification of the oligonucleotides (ONs) can improve potency and duration of activity, usually as a result of improved nuclease resistance. Here we take advantage of innovations in both polymeric delivery vehicles and ON stabilization to achieve receptor-mediated targeted delivery of siRNAs or AONs for gene silencing. Polymeric nanoparticles comprised of poly(lactide-co-2-methyl, 2-carboxytrimethylene carbonate)-g-polyethylene glycol-furan/azide are click-modified with both anti-HER2 antibodies and nucleic acids on the exterior PEG corona. Phosphorothioate (PS), 2'F-ANA, and 2'F-RNA backbone chemical modifications improve siRNA and AON potency and duration of activity. Importantly, delivery of these nucleic acids on the exterior of the polymeric immuno-nanoparticles are as efficient in gene silencing as lipofectamine transfection without the associated potential toxicity of the latter. PMID- 23932249 TI - Boronate-dextran: an acid-responsive biodegradable polymer for drug delivery. AB - Stimuli-responsive drug carriers have great potential to deliver bioactive materials on demand and to a specific location within the human body. Acid responsive drug carriers can specifically release their payload in the acidic microenvironments of tumors or in the endosomal or lysosomal compartments within a cell. Here we describe an approach to functionalize vicinal diols of dextran with hydrophobic boronate esters in order to produce a water insoluble boronate dextran polymer (B-Dex), which spontaneously forms acid-responsive nanoparticles in water. We show the encapsulation of a hydrophobic anticancer drug doxorubicin into the particles. Hydrolysis of the boronate esters under mild acidic conditions recovers the hydrophilic hydroxyl groups of the dextran and disrupts the particles into water soluble fragments thereby leading to a pH-responsive release of the drug. According to dynamic light scattering (DLS) and UV/Vis spectroscopy, mild acidic conditions (pH 5.0) lead to a three-fold increase in the degradation of the particles and a four-fold increase in the release of the drug compared to the behavior of particles at pH 7.4. In vitro tests in Hela cells show no toxicity of the empty B-Dex nanoparticles, while the toxicity of doxorubicin-loaded B-Dex nanoparticles is comparable to that of the doxorubicin . HCl drug. Confocal fluorescence microscopy reveals that 100% of the Hela cells uptake doxorubicin-loaded B-Dex nanoparticles with a preferential accumulation of the nanoparticles in the cytoplasm. PMID- 23932250 TI - Polyethyleneimine-mediated synthesis of folic acid-targeted iron oxide nanoparticles for in vivo tumor MR imaging. AB - We report a facile polyethyleneimine (PEI)-mediated approach to synthesizing folic acid (FA)-targeted magnetic iron oxide nanoparticles (Fe3O4 NPs) for in vivo magnetic resonance (MR) imaging of tumors. In this study, stable PEI-coated Fe3O4 NPs were prepared by a one-pot hydrothermal route. The aminated Fe3O4 NPs with PEI coating enabled covalent conjugation of fluorescein isothiocyanate (FI) and folate-conjugated polyethylene glycol (PEG) with one end of carboxyl groups (FA-PEG-COOH). Followed by final acetylation, FA-targeted PEGylated Fe3O4 NPs (Fe3O4-PEI-Ac-FI-PEG-FA NPs) were formed. The formed multifunctional Fe3O4 NPs were characterized via different techniques. We show that the PEI-mediated approach along with the PEGylation conjugation enables the generation of water dispersible and stable multifunctional Fe3O4 NPs, and the particles are quite cytocompatible and hemocompatible in the given concentration range as confirmed by in vitro cytotoxicity assay, cell morphology observation, and hemolysis assay. In addition, flow cytometry and confocal microscopy data show that the multifunctional Fe3O4 NPs are able to target a model cancer cell line (KB cells) overexpressing FA receptors in vitro. Importantly, the FA-targeted Fe3O4 NPs are able to be used as an efficient nanoprobe for MR imaging of cancer cells in vitro and a xenografted tumor model in vivo via an active FA targeting pathway. With the facile PEI-mediated formation strategy and PEGylation conjugation chemistry, the Fe3O4 NPs may be multifunctionalized with other biological ligands for MR imaging of different biological systems. PMID- 23932251 TI - Cardiac resynchronization therapy allows the optimization of medical treatment in heart failure patients. AB - AIM: Cardiac resynchronization therapy (CRT) is recommended for selected patients with advanced heart failure (HF) despite optimal medical treatment. However, the doses of pharmaceuticals in this population are often limited by adverse effects. We compared the drug regimens of 21 patients before and 6 months after they underwent the implantation CRT systems. METHODS: We studied 17 men and four women (mean age=63.4 +/- 11 years) presenting in New York Heart Association HF classes III-IV, and with a left ventricular ejection fraction (LVEF) <= 35% and cardiac dyssynchrony, who underwent implantation of CRT systems. RESULTS: At baseline, 52% of patients were treated with beta-adrenergic blockers (beta-B), though in optimal doses in only 19%. The introduction of (beta-B) was complicated by cardiogenic shock in three patients. At baseline, all patients were treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), of whom 76% received optimal doses. After 6 months of CRT, beta-B were administered to 76% of patients, in optimaklon ACE or ARB but 75% of them were receiving maximal doses. After 6 months of CRT, beta blockers have been introduced in 72% of patients and maximal doses have been achieved in 60% of them. Maximal doses of ACE or ARB were reached in 95% of the study population. We noticed that systolic blood pressure was higher after implantation. There was also a significant improvement in functional status and left ventricular ejection fraction compared to baseline. CONCLUSION: CRT is an efficacious adjunctive device therapy to standard medical therapy for patients with heart failure and cardiac dyssynchrony. Its benefits are in addition to those afforded by standard pharmacological therapy. Achieving maximal doses of medical treatment and the possibility of introducing beta blockers after CRT prove that CRT and pharmacological treatment are complementary strategies and should not be considered as competitive. PMID- 23932252 TI - Early intrauterine embryonic development of the bothriocephalidean cestode Clestobothrium crassiceps (Rudolphi, 1819), a parasite of the teleost Merluccius merluccius (L., 1758) (Gadiformes: Merlucciidae). AB - The early intrauterine embryonic development of the bothriocephalidean cestode Clestobothrium crassiceps (Rudolphi, 1819), a parasite of the teleost Merluccius merluccius (L., 1758), was studied by means of light (LM) and transmission electron microscopy (TEM). Contrary to the generic diagnosis given in the CABI Keys to the cestode parasites of vertebrates, the eggs of C. crassiceps, the type of species of Clestobothrium Luhe, 1899, are operculate and embryonated. Our LM and TEM results provide direct evidence that an operculum is present and that the eggs exhibit various stages of intrauterine embryonic development, and in fact represent a good example of early ovoviviparity. The intrauterine eggs of this species are polylecithal and contain numerous vitellocytes, generally ~30, which are pushed to the periphery and remain close to the eggshell, whereas the dividing zygote and later the early embryo remain in the egg centre. During early intrauterine embryonic development, several cleavage divisions take place, which result in the formation of three types of blastomeres, i.e. macro-, meso- and micromeres. These can be readily differentiated at the TEM level, not only by their size, but also by the ultrastructural characteristics of their nuclei and cytoplasmic organelles. The total number of blastomeres in these early embryos, enclosed within the electron-dense eggshells, can be up to ~20 cells of various sizes and characteristics. Mitotic divisions of early blastomeres were frequently observed at both LM and TEM levels. Simultaneously with the mitotic cleavage divisions leading to blastomere multiplication and their rapid differentiation, there is also a deterioration of some blastomeres, mainly micromeres. A similar degeneration of vitellocytes begins even earlier. Both processes show a progressive degeneration of both vitellocytes and micromeres, and are good examples of apoptosis, a process that provides nutritive substances, including lipids, for the developing embryo. PMID- 23932253 TI - Thermal threshold and sensitivity of the only symbiotic Mediterranean gorgonian Eunicella singularis by morphometric and genotypic analyses. AB - The only symbiotic Mediterranean gorgonian, Eunicella singularis, has faced several mortality events connected to abnormal high temperatures. Since thermotolerance data remain scarce, heat-induced necrosis was monitored in aquarium by morphometric analysis. Gorgonian tips were sampled at two sites: Medes (Spain) and Riou (France) Islands, and at two depths: -15 m and-35 m. Although coming from contrasting thermal regimes, seawater above 28 degrees C led to rapid and complete tissue necrosis for all four populations. However, at 27 degrees C, the time length leading to 50% tissue necrosis allowed us to classify samples within three classes of thermal sensitivity. Irrespectively of the depth, Medes specimens were either very sensitive or resistant, while Riou fragments presented a medium sensitivity. Microsatellite analysis revealed that host and symbiont were genetically differentiated between sites, but not between depths. Finally, these genetic differentiations were not directly correlated to a specific thermal sensitivity whose molecular bases remain to be discovered. PMID- 23932254 TI - The impact of environmental degradation on reproduction of the black-chinned tilapia Sarotherodon melanotheron from various coastal marine, estuarine and freshwater habitats. AB - There is growing evidence that climate change has greatly altered environmental conditions in many aquatic ecosystems over the last decades, leading to changes in fish distribution and life history traits. Recent works conducted in Senegalese and Gambian coastal marine, estuarine and freshwater ecosystems have shown important changes in the intensity, frequency and breeding timing of wild population of Sarotherodon melanotheron in response to changes in salinity regimes. In addition to salinity, this study investigates the potential influences of other environmental factors that have received less attention on the reproduction of S. melanotheron from three different aquatic ecosystems in Senegal. The results demonstrate that day-length and temperature affect sexual maturity in both males and females from Guiers Lake and Hann Bay, but no such effects were found in upstream of the Saloum Estuary, where the spawning activity seems to be under the synergetic control of rainfall and salinity that apparently predominate over all the other ambient factors. This study demonstrated for the first time that aside from photoperiod and temperature, rainfall also influences fish reproduction in Hann Bay probably through its effects on water quality. Furthermore, our results confirm previous findings that changes in salinity regimes resulting from seasonal variations in precipitation and evaporation are the ultimate causes of temporal changes in the reproductive activity of the species in this estuary. PMID- 23932255 TI - Evidence of sibling species between two host-associated populations of brown planthopper, N. lugens (stal) (Homoptera: Delphacidea) complex based on morphology and host-plant relationship studies. AB - Morphological and host-plant relationship studies were conducted to differentiate two sympatric populations of brown planthopper (BPH), Nilaparvata lugens, one from rice (Oryza sativa) and the other from Leersia hexandra, a weed grass. In morphometric studies based on esterase activities, an UPGMA dendrogram using 17 quantitative morphological characters, including stridulatory organs (courtship signal-producing organs) between two sympatric populations of N. lugens, one from rice and the other from L. hexandra, a weed grass revealed that both populations were separated from each other. An out-group, N. bakeri, was found to be completely different from the two sympatric populations of N. lugens. Rice plants were best suited for the establishment of the rice-infesting population, and L. hexandra was a favourable host for the Leersia-infesting population. The individuals derived from one host did not thrive on the other host, as shown by a significant reduction in survival and nymphal development, ovipositional preferences, ovipositional response, and egg hatchability. Therefore, morphological and host-plant relationship studies indicate that rice-associated population with high esterase activities and L. heaxandra-associated population with low esterase activities are two closely related sibling species. PMID- 23932256 TI - The impact of Acacia saligna invasion on Italian coastal dune EC habitats. AB - Alien species can represent a threat to several ecosystems because they can alter species relationships and ecosystem function. In Italy, Acacia saligna is a major invader and it forms dense stands in coastal environments. We analyze the impact of A. saligna in Italian Mediterranean dune systems. We randomly sampled coastal dune vegetation and investigated its floristic composition with ordination techniques. We compared species richness in invaded and non-invaded plots with rarefaction curves and analyzed the frequency of focal and ruderal species. A. saligna invaded Mediterranean scrub (habitats 2250* and 2260) and coastal Pinus dune wood (habitat 2270*) and it is particularly prevalent in sunny areas of habitat 2270*. We observed an increase in ruderal species and a decrease in focal species in the invaded plots of habitat 2270*. We suggest that more open and disturbed areas are more prone to A. saligna invasion. PMID- 23932257 TI - First record of a cave species of Euscorpiops Vachon from Viet Nam (Scorpiones, Euscorpiidae, Scorpiopinae). AB - Euscorpiops cavernicola sp. n., belonging to the family Euscorpiidae Laurie, is described on the basis of two male and two female specimens collected in the Hua Ma cave located in the Quang Khe commune, Ba Be district of Bac Kan province in Viet Nam. The new species presents most features exhibited by scorpions within the genus Euscorpiops, however it may represent the first discovered Scorpiopinae species exhibiting certain adaptations to cave life. PMID- 23932258 TI - Association between obesity and postoperative atrial fibrillation in patients undergoing cardiac operations: a systematic review and meta-analysis. AB - In a systematic review and random-effects meta-analysis, we evaluated whether obesity is associated with postoperative atrial fibrillation (POAF) in patients undergoing cardiac operations. We selected 18 observational studies until December 2011 that excluded patients with preoperative AF (n=36,147). Obese patients had a modest higher risk of POAF compared with nonobese (odds ratio, 1.12; 95% confidence interval, 1.04 to 1.21; p=0.002). The association between obesity and POAF did not vary substantially by type of cardiac operation, study design, or year of publication. POAF was significantly associated with a higher risk of stroke, respiratory failure, and operative death. PMID- 23932259 TI - Broad counseling for adolescents about combined hormonal contraceptive methods: the choice study. AB - PURPOSE: The Contraceptive Health Research of Informed Choice Experience study involved 11 European countries with the goal of evaluating the influence of counseling on the user's choice among three different types of combined hormonal contraceptive (CHC) administration: pill, transdermal patch, and vaginal ring. Here, we report the results of the youngest age group (age 15-20 years) for Switzerland. METHODS: A total of 1,032 adolescent women who contemplated a CHC form of contraception were counseled about the three CHCs. Questionnaires were filled out to determine the women's preferred choice before and after counseling, and the reason for their final decision. RESULTS: After counseling, more than one third of the women decided to use a different contraceptive method than initially intended. The fraction of vaginal ring users increased from 7.5% to 21.8%, and that of patch users from 3.3% to 5.8%. At pre-counseling, 225 women had no preconceived idea about which method to choose. Only 29 women were still undecided post-counseling. The main reasons adolescent women chose the vaginal ring or the patch were the monthly or weekly use and the ease of use. CONCLUSIONS: Adolescent women's decision about which CHC to use is greatly influenced by counseling that provides balanced information on all CHCs. PMID- 23932260 TI - Instrumental and bioanalytical measures of dioxin-like compounds and activities in sediments of the Pohang Area, Korea. AB - Pohang is a mid-sized city in which Korea's largest manufacturer of steel is located. The Hyeongsan River, which runs through Pohang and empties into Yeongil Bay, is therefore expected to be affected by various municipal and industrial inputs. In order to characterize aryl hydrocarbon receptor (AhR)-mediated activities in sediments from the Pohang area, a total of eight locations along the Hyeongsan River were chosen and 16 sediment samples were collected during two sampling campaigns in 2010. Organic extracts of sediments were characterized by both quantitative chemical analyses of dioxin-like chemicals and the in vitro H4IIE-luc bioassay. Significant dioxin-like activities were observed in sediments from industrial and municipal areas, which indicates that most of the dioxin-like chemicals were associated with surrounding anthropogenic sources. In general, responses of the H4IIE-luc assay were significantly correlated with concentrations of target compounds including dioxins, furans, co-planar PCBs, and dioxin-like PAHs. A potency balance analysis indicated that instrumentally derived TCDD equivalents (TEQs) explained about 77% of the bioassay-derived TCDD equivalents (TCDD-EQs). Among the target chemicals measured, certain penta chlorinated dioxin and furan compounds accounted for the majority of dioxin-like activities associated with sediments. Compositional analysis of target chemicals the sources of such dioxin-like activities were mainly derived from the local activities such as the iron and steel industries. Concentrations and activities of AhR agonists were similar to what was measured approximately 10 years ago. Thus, while AhR agonists seem to be persistent in sediments there seem to have been no large increases in these chemicals in the Pohang area. PMID- 23932261 TI - Spontaneous vitreous hemorrhage in children. AB - PURPOSE: To determine the clinical profile, causes, and outcomes of "spontaneous" vitreous hemorrhage in children (<18 years). DESIGN: Retrospective computer assisted chart review. METHODS: Charts of 124 eyes of 76 children who presented with nontraumatic, nonsurgical vitreous hemorrhage between 2002 and 2012 were reviewed. All children underwent an appropriate ocular and systemic examination. Data collected included demographics, visual acuity, cause of "spontaneous" vitreous hemorrhage, ocular and systemic findings at presentation and at last follow-up, investigations, management details, and visual outcomes. RESULTS: The median age was 153.45 +/- 56.19 months. There were 39 female and 37 male patients. Forty-eight patients had bilateral vitreous hemorrhage. The most common presenting complaints were diminished vision (96.45%) and behavioral changes (87.24%). The mean baseline BCVA in logMAR was 2.25 +/- 1.11. The most common causes included vasculitis (34.6%) and hematologic disorders (27.4%). Patients were given medical therapy (topical and/or systemic) or underwent laser photocoagulation (29%) and/or surgery (55.6%). Twenty-nine eyes (23.3%) did not require any intervention. The mean number of surgeries was 1.89 +/- 1.45 (range 1 4 surgeries). The mean final visual acuity was 0.76 +/- 0.58 logMAR and was significantly better than the baseline (P < .001). The best anatomic and visual outcomes were seen in vasculitis, whereas congenital disorders such as retinoschisis had the worst. CONCLUSIONS: Spontaneous pediatric vitreous hemorrhage has a diverse etiology, vasculitis being the most common cause in our series. A comprehensive evaluation (systemic and ocular) is required to ensure that vision- and life-threatening conditions are not missed. PMID- 23932262 TI - Evaluation of corneal microstructure in keratoconus: a confocal microscopy study. AB - PURPOSE: To compare the corneal microstructure in patients with manifest keratoconus (KCN), subclinical KCN, and topographically normal relatives of patients with KCN and in healthy controls. DESIGN: Prospective and cross sectional study. METHODS: We enrolled 145 subjects in the study. The participants were divided into 4 groups, based on clinical and topographical evaluation: the manifest KCN group (n = 30), the subclinical KCN group (n = 32), the KCN relatives group (n = 53), and the control group (n = 30). Corneal microstructure was assessed by corneal in vivo confocal microscopy in all of the individuals. Mean outcome measures were basal epithelial cell density, endothelial cell density, anterior keratocyte density, posterior keratocyte density, sub-basal nerve density, sub-basal nerve diameter, and stromal nerve diameter. RESULTS: The mean basal epithelial cell density, endothelial cell density, and sub-basal nerve diameter were not significantly different among the 4 groups (P = 0.057, P = 0.592, and P = 0.393, respectively). The mean anterior and posterior stromal keratocyte densities were significantly lower in the manifest group, in the subclinical group, and in the relatives group when compared with the control group (for both parameters; P < 0.001, P < 0.001, and P< 0.001, respectively). The mean stromal nerve diameter in the manifest group, subclinical group, and relatives group was significantly higher than in the control group (P = 0.001, P = 0.049, and P = 0.004, respectively). CONCLUSION: The anterior and posterior stromal keratocyte densities were statistically lower and stromal nerve diameter was statistically higher in patients with manifest KCN, subclinical KCN, and topographically normal KCN relatives compared with controls. Confocal microscopy may be useful for the determination of early corneal microstructural changes before manifestation of typical or subtle topographic signs. PMID- 23932263 TI - Novel technique for the preparation of corneal grafts for descemet membrane endothelial keratoplasty. AB - PURPOSE: To report a simple novel technique to facilitate preparation of Descemet membrane grafts for Descemet membrane endothelial keratoplasty (DMEK). DESIGN: Laboratory investigation and retrospective, single-center, consecutive case series. METHODS: Preparation of the endothelial graft is performed on an artificial anterior chamber, endothelial side up. After an incomplete circular superficial trephination, we describe a simple technique using a 27 gauge cannula to detach the Descemet membrane (DM). Endothelial cell density (ECD) was measured before dissection on 12 human corneas for research and 3 days after storage in organ culture. Histologic and electron microscopy analysis were performed. A DMEK was performed in 50 patients with Fuchs dystrophy. Visual acuity and ECD were evaluated 2 and 6 months after surgery. RESULTS: ECD was 2765 +/- 256 cells/mm(2) on corneas for research before dissection and 2651 +/- 305 cells/mm(2) after 3 days in organ culture (P < .01). Histologic and electronic sections confirm that the cleavage was between DM and posterior stroma. Clinically, preparation of 2 corneas from a single donor was unsuccessful; 48 corneas were clear at 2 months and 47 at 6 months. At 2 months 77% of the patients had recovered a visual acuity of at least 20/30. At 6 months, 91.5% of the patients had a visual acuity of at least 20/30. ECD was 2656 +/- 28 cells/mm(2) (range: 2450-3100 cells/mm(2)) preoperatively, 1797 +/- 41 cells/mm(2) (range: 1100-2700 cells/mm(2)) at 2 months, and 1658 +/- 43 cells/mm(2) (range: 900-2600 cells/mm(2)) at 6 months. CONCLUSION: We report here a reliable and efficient technique for the preparation of pure Descemet membrane grafts. PMID- 23932264 TI - A comparison of ambulance responses to incidents of Medical Emergency Teams led by nurses and paramedics--A retrospective single-center study. AB - BACKGROUND: In Poland there are currently two main types of Medical Emergency Team: basic, run by nurses or paramedics, and specialist, led by physicians. They differ not only in professional qualifications but also in their terms of reference. OBJECTIVES: We compared the responses to incidents of Medical Emergency Teams led by nurses and paramedics, in terms of the frequency of pharmacotherapy use and medical rescue activities. STUDY DESIGN: Ambulance call reports. SETTINGS: Medical Emergency Teams in Eastern Poland. PARTICIPANTS: Medical Emergency Teams led by nurses or paramedics. Exclusion criteria were cancelation of calls by the dispatcher, calls with no patient on the scene, and neonatal and interhospital transportation. METHODS: A retrospective analysis of ambulance call reports. A comparison of actions of nurses and paramedics taken in the field, and decisions concerning transportation of the patient to a hospital or leaving the home were collected. RESULTS: Of 1115 Medical Emergency Teams calls, those led by paramedics (60.5%) were more common. Paramedics, more often than nurses, provided aid solely in the field-27.5% and 16.0%, respectively-and less frequently transported patients to the hospital-38.5% and 50.7%, respectively. Significant differences in administration of oxygen therapy and analgesics were identified; paramedics used them more often than nurses. Paramedics used cervical collars, 3.6% and 1.1% (p=0.01), respectively, and performed 12-lead electrocardiograms, 4.7% and 1.4% (p=0.002), respectively, significantly more frequently than did nurses. CONCLUSIONS: Despite the comparable competency of paramedics and emergency nurses in Poland, Medical Emergency Teams' activities varied depending on whether a nurse or a paramedic was the team leader. It is recommended that further in-depth research is conducted in this area. PMID- 23932265 TI - Introduction of the editor to a dispute on quercetin conformers. PMID- 23932266 TI - Comment on the paper: "Spectroscopic and computational study of the major oxidation products formed during the reaction of two quercetin conformers with a free radical". AB - The title paper reports a study on the structural elucidation by spectroscopic and computational methods of the products obtained from the reaction of two conformers of quercetin with the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH(*)). Many points of criticism, concerning both theoretical principles and experimental data, are highlighted in the present communication. PMID- 23932267 TI - Comments on the "Clinical practice guidelines for assessment and treatment of transsexuality" issued by the Sexual Identity and Differentiation Group of the SEEN (GIDSEEN). PMID- 23932268 TI - [Improving vital organs perfusion by the respiratory pump: physiology and clinical use]. AB - OBJECTIVE: In this article, we review the effects of the respiratory pump to improve vital organ perfusion by the use of an inspiratory threshold device. DATA SOURCES: Medline and MeSH database. STUDY SELECTION: All papers with a level of proof of I to III have been used. DATA EXTRACTION: The analysis of the papers has focused on the physiological modifications induced by intrathoracic pressure regulation. DATA SYNTHESIS: Primary function of breathing is to provide gas exchange. Studies of the mechanisms involved in animals and humans provide the physiological underpinnings for "the other side of breathing": to increase circulation to the heart and brain. We describe studies that focus on the fundamental relationship between the generation of negative intrathoracic pressure during inspiration through a low-level of resistance created by an impedance threshold device and the physiologic effects of a respiratory pump. A decrease in intrathoracic pressure during inspiration through a fixed resistance resulting in an intrathoracic pressure of -7 cmH2O has multiple physiological benefits including: enhanced venous return, cardiac stroke volume and aortic blood pressure; lower intracranial pressure; resetting of the cardiac baroreflex; elevated cerebral blood flow oscillations and increased tissue blood flow/pressure gradient. CONCLUSION: The clinical and animal studies support the use of the intrathoracic pump to treat different clinical conditions: hemorrhagic shock, orthostatic hypotension, septic shock, and cardiac arrest. PMID- 23932269 TI - Sono-myography and sono-myoelastography of the tender points of women with fibromyalgia. AB - Sono-myography and sono-myoelastography have been found useful in the investigation of myofascial trigger points. The objective of this study was to use the same techniques to investigate the morphology, stiffness and blood flow of tender points in women with fibromyalgia and to compare the results with those for samples from healthy patients. Algometry tests indicated significant differences between groups (p < 0.001). Elliptical and hypoechoic areas were observed in the ultrasound images of the upper trapezius in both groups. No differences between groups were found in the number of hypoechoic areas (p = 0.167, t = 1.008); blood flow also did not differ between the groups. Larger hypoechoic areas were found in the fibromyalgia group (p = 0.139, t = 1.317). Sono-myoelastography did not reveal greater stiffness in these areas compared with the rest of the muscle. These results lead us to believe that sono myoelastography and sono-myography, used in the diagnosis of myofascial trigger points, may not be able to discriminate tender points. PMID- 23932270 TI - Statistics of acoustically induced bubble-nucleation events in in vitro blood: a feasibility study. AB - Bubbles can form in biological tissues through ultrasonic activation of natural gas nuclei. The damaging aftereffects raise safety concerns. However, the population of nuclei is currently unknown, and bubble nucleation is stochastic and thus unpredictable. This study investigates the statistical behavior of bubble nucleation experimentally and introduces a model-based analysis to determine the distribution of nuclei in biological samples-two pig blood samples in vitro. Combined ultra-fast passive and active cavitation detection with a linear array was used to detect nucleation from pulsed ultrasound excitations at 660 kHz. Single nucleation events were detected at peak rarefaction pressures from -3.6 to -24 MPa, and the nucleation probability over the range 0 to 1 was estimated from more than 330 independent acquisitions per sample. Model fitting of the experimental probability revealed that the distribution of nuclei is most likely continuous, and nuclei are rare in comparison to blood cells. PMID- 23932271 TI - Temperature-dependent thermal properties of ex vivo liver undergoing thermal ablation. AB - Thermotherapy uses a heat source that raises temperatures in the target tissue, and the temperature rise depends on the thermal properties of the tissue. Little is known about the temperature-dependent thermal properties of tissue, which prevents us from accurately predicting the temperature distribution of the target tissue undergoing thermotherapy. The present study reports the key thermal parameters (specific heat capacity, thermal conductivity and heat diffusivity) measured in ex vivo porcine liver while being heated from 20 degrees C to 90 degrees C and then naturally cooled down to 20 degrees C. The study indicates that as the tissue was heated, all the thermal parameters resulted in plots with asymmetric quasi-parabolic curves with temperature, being convex downward with their minima at the turning temperature of 35-40 degrees C. The largest change was observed for thermal conductivity, which decreased by 9.6% from its initial value (at 20 degrees C) at the turning temperature (35 degrees C) and rose by 45% at 90 degrees C from its minimum (at 35 degrees C). The minima were 3.567 mJ/(m(3) ? K) for specific heat capacity, 0.520 W/(m.K) for thermal conductivity and 0.141 mm(2)/s for thermal diffusivity. The minimum at the turning temperature was unique, and it is suggested that it be taken as a characteristic value of the thermal parameter of the tissue. On the other hand, the thermal parameters were insensitive to temperature and remained almost unchanged when the tissue cooled down, indicating that their variations with temperature were irreversible. The rate of the irreversible rise at 35 degrees C was 18% in specific heat capacity, 40% in thermal conductivity and 38.3% in thermal diffusivity. The study indicates that the key thermal parameters of ex vivo porcine liver vary largely with temperature when heated, as described by asymmetric quasi-parabolic curves of the thermal parameters with temperature, and therefore, substantial influence on the temperature distribution of the tissue undergoing thermotherapy is expected. PMID- 23932273 TI - Attenuation and de-focusing during high-intensity focused ultrasound therapy through peri-nephric fat. AB - High-intensity focused ultrasound (HIFU) is an attractive therapy for kidney cancer, but its efficacy can be limited by heat deposition in the pre-focal tissues, notably in fat around the kidney (peri-nephric fat), the acoustic properties of which have not been well characterized. Measurements of attenuation were made using a modified insertion-loss technique on fresh, unfixed peri nephric fat obtained from patients undergoing kidney surgery for cancer. The de focusing effect of changing the position of the fat layers was also investigated using fresh subcutaneous fat from euthanized pigs. The mean attenuation of human peri-nephric fat was found to be 11.9 +/- 0.9 Np/m (n = 10) at 0.8 MHz, the frequency typically used for HIFU ablation of kidney tumors, with a frequency dependence of f(1.2). A typical 2- to 4-cm thickness of peri-nephric fat would result in a de-rated intensity of 3% - 62% at 0.8 MHz compared with a hypothetical patient with no peri-nephric fat. Through the use of freshly excised porcine subcutaneous fat, the presence of fat 100 mm in front of the focus was found to have a de-focusing effect of approximately 1 mm in both transverse directions, which corresponds to a full HIFU beam width off-target. Peri-nephric fat may significantly affect both the intensity and accuracy of HIFU fields used for the ablation of kidney cancer. PMID- 23932274 TI - Feasibility of bone assessment with ultrasonic backscatter signals in neonates. AB - The objective of this study was to assess the value of ultrasonic backscatter signals and the backscatter coefficient (BSC) in the analysis of bone status in neonates and to analyze the relationships between the BSC and gestational age, birth weight, length, head circumference and gender. A total of 122 neonates participated in the study, including 83 premature infants and 39 full-term infants. Their BSCs were measured by ultrasound after birth. The results revealed a significant correlation between the BSC and gestational age (R = 0.47, p < 0.001), birth weight (R = 0.47, p < 0.0001) and length at birth (R = 0.43, p < 0.001) at a frequency of 5.0 MHz. This study suggests that the use of ultrasonic backscattering and the BSC is feasible for assessment of the bone status of neonates. PMID- 23932272 TI - Acoustic characterization and pharmacokinetic analyses of new nanobubble ultrasound contrast agents. AB - In contrast to the clinically used microbubble ultrasound contrast agents, nanoscale bubbles (or nanobubbles) may potentially extravasate into tumors that exhibit more permeable vasculature, facilitating targeted molecular imaging and drug delivery. Our group recently presented a simple strategy using the non-ionic surfactant Pluronic as a size control excipient to produce nanobubbles with a mean diameter of 200 nm that exhibited stability and echogenicity on par with microbubbles. The objective of this study was to carry out an in-depth characterization of nanobubble properties as compared with Definity microbubbles, both in vitro and in vivo. Through use of a tissue-mimicking phantom, in vitro experiments measured the echogenicity of the contrast agent solutions and the contrast agent dissolution rate over time. Nanobubbles were found to be more echogenic than Definity microbubbles at three different harmonic frequencies (8, 6.2 and 3.5 MHz). Definity microbubbles also dissolved 1.67 times faster than nanobubbles. Pharmacokinetic studies were then performed in vivo in a subcutaneous human colorectal adenocarcinoma (LS174T) in mice. The peak enhancement and decay rates of contrast agents after bolus injection in the liver, kidney and tumor were analyzed. No significant differences were observed in peak enhancement between the nanobubble and Definity groups in the three tested regions (tumor, liver and kidney). However, the decay rates of nanobubbles in tumor and kidney were significantly slower than those of Definity in the first 200-s fast initial phase. There were no significant differences in the decay rates in the liver in the initial phase or in three regions of interest in the terminal phase. Our results suggest that the stability and acoustic properties of the new nanobubble contrast agents are superior to those of the clinically used Definity microbubbles. The slower washout of nanobubbles in tumors suggests potential entrapment of the bubbles within the tumor parenchyma. PMID- 23932275 TI - Heterogeneous delayed enhancement of the liver after administration of ultrasound contrast agents: are we sure that it is a harmless phenomenon? PMID- 23932277 TI - Value of acoustic radiation force impulse imaging elastography for non-invasive evaluation of patients with nonalcoholic fatty liver disease. AB - The goals of the work described here were to evaluate the clinical utility of acoustic radiation force impulse (ARFI) elastography in differentiating non alcoholic fatty liver disease (NAFLD) histologic subtypes and to determine if ARFI elastography measurements correlate with the severity of liver fibrosis. We compared ARFI elastography measurements with clinical, biologic and histologic features (simple steatosis or steatohepatitis) in 64 patients with histologically proven NAFLD. ARFI elastography is suitable for distinguishing patients with non alcoholic steatohepatitis from those with simple steatosis, with an area under the receiver operating characteristic curve (AUROC) of 0.867 (95% confidence interval = 0.782-0.953). There was a highly significant correlation (r = 0.843) between ARFI elastography measurements and fibrosis (p < 0.001). In patients with non-alcoholic steatohepatitis, the diagnostic performance of ARFI elastography in predicting significant fibrosis (F >= 2) had an AUROC of 0.944. ARFI elastography better predicted F = 4 fibrosis (AUROC = 0.984). In conclusion, ARFI elastography is a promising method for differentiating patients with non-alcoholic steatohepatitis from patients with simple steatosis and can also predict significant fibrosis in these patients. PMID- 23932276 TI - Short-lag spatial coherence imaging of cardiac ultrasound data: initial clinical results. AB - Short-lag spatial coherence (SLSC) imaging is a novel beamforming technique that reduces acoustic clutter in ultrasound images. A clinical study was conducted to investigate clutter reduction and endocardial border detection in cardiac SLSC images. Individual channel echo data were acquired from the left ventricle of 14 volunteers, after informed consent and institutional review board approval. Paired B-mode and SLSC images were created from these data. Contrast, contrast-to noise, and signal-to-noise ratios were measured in paired images, and these metrics were improved with SLSC imaging in most cases. Three cardiology fellows rated the visibility of endocardial segments in randomly ordered B-mode and SLSC cine loops. SLSC imaging offered 22%-33% improvement (p < 0.05) in endocardial border visibility when B-mode image quality was poor (i.e., 80% or more of the endocardial segments could not be visualized by the three reviewers). The percentage of volunteers with poor-quality images was decreased from 21% to 7% with the SLSC beamformer. Results suggest that SLSC imaging has the potential to improve clinical cardiac assessments that are challenged by clutter. PMID- 23932278 TI - Preparation of protamine cationic nanobubbles and experimental study of their physical properties and in vivo contrast enhancement. AB - In this study, we aimed to prepare a novel type of microbubble (MB), protamine cationic nanobubble (NB), to provide a new vector for tumor gene therapy. We prepared cationic NBs with protamine and other lipid components using mechanical oscillation. The protamine cationic NBs had a mean diameter of 521.2 +/- 37.57 nm, a zeta potential of +18.5 mV, and a gene-carrying capacity of 15.69 MUg androgen receptor (AR) siRNA per 10(8) NBs. The cationic NBs exhibited superior contrast enhancement for in vivo imaging compared with SonoVue (Bracco, Geneva, Switzerland), and their physical properties did not change significantly after 1 wk; meanwhile, the transfection efficiency of the cationic NBs in androgen independent prostate cancer cells mediated by ultrasound irradiation was better than that of liposomes (82.17 +/- 7.4% vs. 55.04 +/- 5.4%, p < 0.01). Therefore, the protamine cationic NB can be considered for use as a novel type of gene loading MB for ultrasound imaging and MB-mediated gene therapy of tumors. PMID- 23932279 TI - Evaluation of bi-ventricular coronary flow patterns using high-frequency ultrasound in mice with transverse aortic constriction. AB - Using high-frequency color and pulsed Doppler ultrasound, we evaluated the flow patterns of the left (LCA), septal (SCA) and right (RCA) coronary arteries in mice with and without transverse aortic constriction (TAC). Fifty-two male C57BL/6J mice were subjected to TAC or a corresponding sham operation. At 2 and 8 wk post-surgery, Doppler flow spectra from the three coronary arteries, together with morphologic and functional parameters of the left and right ventricles, were measured. Histology was performed to evaluate myocyte size and neo-angiogenesis in both ventricles. In sham-operated mice, the LCA and SCA both exhibited low flow waveforms during systole and dominantly higher-flow waveforms during diastole. The RCA exhibited generally lower flow velocity, with similar systolic and diastolic waveforms. TAC significantly increased the systolic flow velocities of all coronary arteries, but enhanced the flow mainly in the LCA and SCA. In the left ventricle, coronary flow reserve was partially preserved 2 wk post-TAC, but decreased at 8 wk, consistent with changes in neo-angiogenesis and systolic function. In contrast, no significant change was found in the coronary flow reserve, structure or function of the right ventricle. This study has established a protocol for evaluating the flow pattern in three principal coronary arteries in mice using Doppler ultrasound and illustrated the difference among three vessels at baseline. In mice with TAC, the difference in the associating pattern of coronary flow dynamics with the myocardial structure and function between the left and right ventricles provides further insights into ventricular remodeling under pressure overload. PMID- 23932280 TI - Echocardiographic integrated backscatter for assessing reduction of aortic valve calcifications by R-568 in a rat model of chronic kidney disease. AB - Chronic kidney disease (CKD) and secondary hyper-parathyroidism are associated with calcific aortic valve disease (CAVD). Innovative modalities for imaging CAVD are warranted. Our aim was to use echocardiographic calibrated integrated backscatter (cIB) to quantitatively determine the preventive effect of the calcimimetic R-568 on CAVD in a CKD rat model, and to compare the results with those of micro-computed tomography and histology. Thirty-six male Wistar rats were followed for 7 wk. Rats were divided into four groups with respect to treatment: (1) adenine 0.5% to induce CKD + vehicle; (2) adenine + R-568 (30 mg/kg/d); (3) control, normal diet + vehicle; (4) controls, normal diet + R-568. At week 7, cIB values of the aortic valve were significantly lower in R-568 treated group 2 than in vehicle-treated group 1. This was confirmed by the significantly lower calcified volume observed on micro-computed tomography and the calcified area observed on histology. There were no significant differences in fractional area change and aortic valve area between groups. In conclusion, echocardiographic cIB was able to quantitatively assess a reduction in CAVD by R 568 in a rat model of CKD. PMID- 23932281 TI - Acoustic radiation force impulse and supersonic shear imaging versus transient elastography for liver fibrosis assessment. AB - Our study compared three elastographic methods--transient elastography (TE), acoustic radiation force impulse (ARFI) imaging and supersonic shear imaging (SSI)--with respect to the feasibility of their use in liver fibrosis evaluation. We also compared the performance of ARFI imaging and SSI, with TE as the reference method. The study included 332 patients, with or without hepatopathies, in which liver stiffness was evaluated using TE, ARFI and SSI. Reliable measurements were defined as a median value of 10 (TE, ARFI imaging) or 5 (SSI) liver stiffness measurements with a success rate >=60% and an interquartile range interval <30%. A significantly higher percentage of reliable measurements were obtained using ARFI than by using TE and SSI: 92.1% versus 72.2% (p < 0.0001) and 92.1% versus 71.3% (p < 0.0001). Higher body mass index and older age were significantly associated with inability to obtain reliable measurements of liver stiffness using TE and SSI. In 55.4% of patients, reliable liver stiffness measurements were obtained using all three elastographic methods, and ARFI imaging and TE were similarly accurate in diagnosing significant fibrosis and cirrhosis, with TE as the reference method. PMID- 23932283 TI - Effect of fuel type on carbon monoxide accumulation in tents of varied design. AB - OBJECTIVE: The use of backpacking stoves in tents has been recognized to result in elevated carboxyhemoglobin levels and even death among tent inhabitants. A study was performed to evaluate carbon monoxide production occurring in varying tents with variable fuel types. METHODS: Using a popular backpacking stove, both white gas and regular unleaded gasoline were used to heat a pot of water inside 2 tents of differing levels of weather resistance ("3-season tent" and "4-season tent") under controlled settings. A remote carbon monoxide sensor measured levels over a 20-minute period. Multiple 20-minute runs were performed with varying fuel and tent combinations to assess peak levels and rates of carbon monoxide production. RESULTS: Mean peak carbon monoxide levels were obtained in the 3 season tent and 4-season tent when white gas was burned measuring 60.5 ppm (95% CI: 31.2 to 89.8) and 154.5 ppm (95% CI: 112.8 to 195.7; P = .002), respectively. The use of regular unleaded gasoline in the 3-season and 4-season tents resulted in mean peak carbon monoxide levels of 102.9 ppm (95% CI: 77.8 to 128.0) and 210.6 ppm (95% CI: 37.4 to 383.1; P = .06), respectively. Using regular unleaded gasoline resulted in significantly increased mean peak carbon monoxide levels compared with white gas in the 3-season tent (P = .006); however, the difference was not significant in the 4-season tent (P = .23). CONCLUSIONS: The use of backpacking stoves in tents produces varying levels of carbon monoxide related to fuel type and tent styles. Efforts should continue to educate persons of the risk of carbon monoxide poisoning with the use of any stove while inside tents. PMID- 23932282 TI - Non-invasive assessment of elastic modulus of arterial constructs during cell culture using ultrasound elasticity imaging. AB - Mechanical strength is a key design factor in tissue engineering of arteries. Most existing techniques assess the mechanical property of arterial constructs destructively, leading to sacrifice of a large number of animals. We propose an ultrasound-based non-invasive technique for the assessment of the mechanical strength of engineered arterial constructs. Tubular scaffolds made from a biodegradable elastomer and seeded with vascular fibroblasts and smooth muscle cells were cultured in a pulsatile-flow bioreactor. Scaffold distension was computed from ultrasound radiofrequency signals of the pulsating scaffold via 2-D phase-sensitive speckle tracking. Young's modulus was then calculated by solving the inverse problem from the distension and the recorded pulse pressure. The stiffness thus computed from ultrasound correlated well with direct mechanical testing results. As the scaffolds matured in culture, ultrasound measurements indicated an increase in Young's modulus, and histology confirmed the growth of cells and collagen fibrils in the constructs. The results indicate that ultrasound elastography can be used to assess and monitor non-invasively the mechanical properties of arterial constructs. PMID- 23932285 TI - "Whose data is it anyway?" The implications of putting small area-level health and social data online. AB - Data from electronic patient management systems, routine national health databases, and social administrative systems have increased significantly over the past decade. These data are increasingly used to create maps and analyses communicating the geography of health and illness. The results of these analyses can be easily disseminated on the web often without due consideration for the identification, access, ethics, or governance, of these potentially sensitive data. Lack of consideration is currently proving a deterrent to many organisations that might otherwise provide data to central repositories for invaluable social science and medical research. We believe that exploitation of such data is needed to further our understanding of the determinants of health and inequalities. Therefore, we propose a geographical privacy-access continuum framework, which could guide data custodians in the efficient dissemination of data while retaining the confidentiality of the patients/individuals concerned. We conclude that a balance of restriction and access is needed allowing linkage of multiple datasets without disclosure, enabling researchers to gather the necessary evidence supporting policy changes or complex environmental and behavioural health interventions. PMID- 23932284 TI - Super-resolution fluorescence imaging with single molecules. AB - The ability to detect, image and localize single molecules optically with high spatial precision by their fluorescence enables an emergent class of super resolution microscopy methods which have overcome the longstanding diffraction barrier for far-field light-focusing optics. Achieving spatial resolutions of 20 40nm or better in both fixed and living cells, these methods are currently being established as powerful tools for minimally-invasive spatiotemporal analysis of structural details in cellular processes which benefit from enhanced resolution. Briefly covering the basic principles, this short review then summarizes key recent developments and application examples of two-dimensional and three dimensional (3D) multi-color techniques and faster time-lapse schemes. The prospects for quantitative imaging - in terms of improved ability to correct for dipole-emission-induced systematic localization errors and to provide accurate counts of molecular copy numbers within nanoscale cellular domains - are discussed. PMID- 23932286 TI - Green microalga Scenedesmus acutus grown on municipal wastewater to couple nutrient removal with lipid accumulation for biodiesel production. AB - The green microalga Scenedesmus acutus was cultivated in two different municipal wastewater discharges (pre- and post-treated), and was compared to a culture medium with basic nutrients (20% of N, P, K), in order to study the simultaneous potential of nutrient removal and lipid accumulation ability. The highest level of nutrient removal was found in the pretreated wastewater discharge (achieving a high removal of phosphorus [66%] and organic nitrogen [94%]). Likewise, better results on biomass productivity and lipid accumulation were found in cultures using pretreated wastewater compared to enriched medium, obtaining 79.9 mg/L, and 280 mg/L, respectively. Since the best results were found in pretreated wastewater, the biodiesel preparation was performed using said medium at small scale. After cultivation, 249.4 mg/L of biodiesel were obtained. According to this analysis, S. acutus could be used for wastewater treatment producing biomass with a suitable content of lipids, convenient for biodiesel production. PMID- 23932287 TI - Development of a UBFC biocatalyst fuel cell to generate power and treat industrial wastewaters. AB - Agro-industry wastewaters normally contain high levels of organic matter and require suitable treatment before discharge. The use of Microbial fuel cells, a novel wastewater treatment, can provide advantages over existing treatment methods. In this study, an up-flow bio-filter circuit (UBFC) for treating wastewaters without chemical treatment or nutrient supplement, was developed to solve a clogging problem. The optimal conditions included an organic loading rate of 30.0 g COD/L-d, hydraulic retention time of 1.04 day, pH level of 5.6-6.5 and aeration at 2.0 L/min. External resistance of the circuit was tested. COD removal levels of 8.08, 20.1 and 26.67 g COD/L-d were obtained, while fed with sea food, biodiesel and palm oil mill wastewater, respectively. These rates are higher than for conventional technologies. The carbon fiber brush immobilized base increased the performance of the new UBFC by 17.54% over that obtained in a previous study, while the cost was slightly decreased about 4.48%. PMID- 23932288 TI - Image-guided and tumor-targeted drug delivery with radiolabeled unimolecular micelles. AB - Unimolecular micelles formed by dendritic amphiphilic block copolymers poly(amidoamine)-poly(L-lactide)-b-poly(ethylene glycol) conjugated with anti CD105 monoclonal antibody (TRC105) and 1,4,7-triazacyclononane-N, N', N-triacetic acid (NOTA, a macrocyclic chelator for (64)Cu) (abbreviated as PAMAM-PLA-b-PEG TRC105) were synthesized and characterized. Doxorubicin (DOX), a model anti cancer drug, was loaded into the hydrophobic core of the unimolecular micelles formed by PAMAM and PLA via physical encapsulation. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. TRC105-conjugated unimolecular micelles showed a CD105-associated cellular uptake in human umbilical vein endothelial cells (HUVEC) compared with non-targeted unimolecular micelles, which was further validated by cellular uptake in CD105 negative MCF-7 cells. In 4T1 murine breast tumor-bearing mice, (64)Cu-labeled targeted micelles exhibited a much higher level of tumor accumulation than (64)Cu labeled non-targeted micelles, measured by serial non-invasive positron emission tomography (PET) imaging and confirmed by biodistribution studies. These unimolecular micelles formed by dendritic amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics. PMID- 23932289 TI - Therapeutic nanomedicine based on dual-intelligent functionalized gold nanoparticles for cancer imaging and therapy in vivo. AB - A novel strategy to construct a therapeutic system based on functionalized AuNPs which can specifically respond to tumor microenvironment was reported. In the therapeutic system, doxorubicin was conjugated to AuNPs via thiol-Au bond by using a peptide substrate, CPLGLAGG, which can be specifically cleaved by the protease. In vivo study shows that after injection of the functionalized AuNPs to the tumor-bearing mice, the over-expressed protease of MMP-2 in tumor tissue and intracellular GSH can lead to the rapid release of the anti-tumor drug (doxorubicin) from the functionalized AuNPs to inhibit tumor growth and realize fluorescently imaging simultaneously. The functionalized AuNPs with tumor triggered drug release property can further improve the efficacy and reduce side effects significantly. PMID- 23932291 TI - Quantum dots-based in situ molecular imaging of dynamic changes of collagen IV during cancer invasion. AB - Cancer invasion and metastasis remains the root cause of mortality. This process involves alterations of tumor microenvironment, particularly the remodeling of extracellular matrix, characterized by collagen IV uncoiling, degradation, fragments deposition and cross-linking. Quantum dots-labeled molecular probes are promising platforms to simultaneously study several subtle changes of key biomolecules, because of their unique optical and chemical properties. Here we report on a quantum dots-based imaging technology to study key components in tumor microenvironment during cancer progression, so as to gain new insights into the role of collagen IV plays, to define the cancer "invasion unit" and to develop the "pulse-mode" of cancer invasion. PMID- 23932290 TI - Non-invasive monitoring of cell metabolism and lipid production in 3D engineered human adipose tissues using label-free multiphoton microscopy. AB - Non-linear optical microscopy methods can characterize over time multiple functional properties of engineered tissues during development. Here, we demonstrate how the combined use of third-harmonic generation (THG) and two photon excited fluorescence (2PEF) imaging can provide direct quantitative biomarkers of adipogenic stem cell differentiation and metabolic state, respectively. Specifically, we imaged over nine weeks silk scaffolds embedded with human mesenchymal stem cells and exposed to either propagation (PM) or adipogenic differentiation media (AM). THG was employed to visualize the formation of lipid droplets. 2PEF was used to assess the metabolic state of the cells through the redox ratio defined based on the endogenous FAD and NADH fluorescence. The redox ratio of cells in the AM scaffold was significantly lower than that in the PM scaffold during week 5 and 9, and correlated with significant increases in lipid-to-cell volume ratio, and number and size of lipid droplets in the AM scaffold. These findings indicate that the decrease in redox ratio during adipogenic differentiation is associated with fatty acid synthesis and lipid accumulation. Our methods therefore enabled us to identify and measure dynamic correlations between lipid droplet formation and cell metabolic state, while providing insight on the spatial heterogeneity of the observed signals. PMID- 23932292 TI - A review of the clinical implications of anti-infective biomaterials and infection-resistant surfaces. AB - Infection is currently regarded as the most severe and devastating complication associated to the use of biomaterials. The important social, clinical and economic impacts of implant-related infections are promoting the efforts to obviate these severe diseases. In this context, the development of anti-infective biomaterials and of infection-resistant surfaces is being regarded as the main strategy to prevent the establishment of implant colonisation and biofilm formation by bacteria. In this review, the attention is focused on the biomaterial-associated infections, from which the need for anti-infective biomaterials originates. Biomaterial-associated infections differ markedly for epidemiology, aetiology and severity, depending mainly on the anatomic site, on the time of biomaterial application, and on the depth of the tissues harbouring the prosthesis. Here, the diversity and complexity of the different scenarios where medical devices are currently utilised are explored, providing an overview of the emblematic applicative fields and of the requirements for anti-infective biomaterials. PMID- 23932293 TI - Hybrid PET/MR imaging of tumors using an oleanolic acid-conjugated nanoparticle. AB - Research into multifunctional nanoparticles is focused on creating an agent for use in an all-in-one multimodal imaging system that includes diagnostic imaging, drug delivery, and therapeutic monitoring. We designed a new dual-modality tumor targeting agent with a new tumor-targeting molecule, oleanolic acid (OA), which is derived from a natural compound and coupled with a macrocyclic chelating agent such as 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), iron oxide nanoparticles (IONP), and radiolabeling components such as (68)Ga for dual modality positron emission tomography (PET)/magnetic resonance imaging (MRI). We attempted to obtain fusion PET/MR images with the (68)Ga-NOTA-OA-IONP hybrid tumor-targeting imaging agent using colon cancer (HT-29) xenograft mice models. The HT-29 cancer cells showed high uptake of (68)Ga-NOTA-OA-IONP, which also had an inhibitory effect on the cells. Moreover, we obtained PET and MRI tumor images as well as fusion PET/MRI images of the tumors using (68)Ga-NOTA-OA-IONP. Therefore, the dual-modality cancer-targeting radiolabeled nanoparticle reported here is a potent imaging agent that is suitable for PET, MRI, and PET/MRI-based diagnosis of tumors; it also has the advantage of not only detecting tumor functionality, but also simultaneously aiding in tumor resolution. PMID- 23932294 TI - The role of surface chemistry in determining in vivo biodistribution and toxicity of CdSe/ZnS core-shell quantum dots. AB - To examine the effect of surface chemistry and surface charge on in vivo biodistribution and toxicity of CdSe/ZnS core-shell quantum dots (QDs), QDs with positive, negative, or PEG coating are used in this study for in vivo evaluation in a mouse model. The results suggest that QDs coated with cationic polydiallyldimethylammonium chloride (PDDA) preferentially deposit in the lung other than in the liver, while the negative and PEGylated QDs render abundant accumulation in the liver. At higher doses positive QDs with PDDA coating show severe acute toxicity due to pulmonary embolism. Independent of their surface coatings, all QDs cause injuries in specific tissues like liver, spleen, lung, and kidney, after acute and long-term exposure, and the degree of injuries is dominated by their surface properties. For the positively charged QDs, the acute phase toxicity is primarily contributed by the coating material PDDA, while coating on QDs may amplify both in vitro and in vivo toxicity of PDDA. PEGylated QDs display the slightest chronic injuries in the long-term toxicity examination in comparison to positive or negative ones. PMID- 23932295 TI - Consequences of exposure to peri-articular injections of micro- and nano particulate cobalt-chromium alloy. AB - Metal hip replacements generate both metal particles and ions. The biological effects of peri-articular exposure to nanometre and micron sized cobalt chrome (CoCr) wear particles were investigated in a mouse model. Mice received injections of two clinically relevant doses of nanoparticles (32 nm), one of micron sized (2.9 MUm) CoCr particles or vehicle alone into the right knee joint at 0, 6, 12 and 18 weeks. Mice were analysed for genotoxic and immunological effects 1, 4 and 40 weeks post exposure. Nanoparticles but not micron particles progressively corroded at the injection site. Micron sized particles were physically removed. No increase of Co or Cr was seen in peripheral blood between 1 and 40 weeks post exposure to particles. No significant inflammatory changes were observed in the knee tissues including ALVAL or necrosis. DNA damage was increased in bone marrow at one and forty weeks and in cells isolated from frontal cortex at 40 weeks after injection with nanoparticles. Mice exposed to the micron sized, but not nanoparticles became immunologically sensitized to Cr(III), Cr (VI) and Ni(II) over the 40 week period as determined by lymphocyte transformation and ELISpot (IFN-gamma and IL-2) assays. The data indicated that the response to the micron sized particles was Th1 driven, indicative of type IV hypersensitivity. This study adds to understanding of the potential adverse biological reactions to metal wear products. PMID- 23932296 TI - Combinational delivery of c-myc siRNA and nucleoside analogs in a single, synthetic nanocarrier for targeted cancer therapy. AB - The treatment of aggressive non-small-cell lung cancer (NSCLC) depends on the creation of new therapeutic regimens in clinical settings. In this study, we developed a Lipid/Calcium/Phosphate (LCP) nanoparticle that combines chemotherapy with gene therapy. By encapsulating a chemodrug, gemcitabine monophosphate (GMP), and siRNA specific to the undruggable cMyc oncogene (cMyc siRNA) into a single nano-sized vesicle and systemically administering them to nude mice, we achieved potent anti-tumor activity in both subcutaneous and orthotopic models of NSCLC. The improvements in therapeutic response over either cMyc siRNA or GMP therapy alone, were demonstrated by the ability to effectively induce the apoptosis of tumor cells and the significant reduction of proliferation of tumor cells. The combination therapy led to dramatic inhibition of tumor growth, with little in vivo toxicity. Additionally, the current studies demonstrated the possibility of incorporating both nucleic acid molecules and phosphorylated small molecule drugs into the inner core of a single nanoparticle formulation. Co-encapsulation of an oncogene-modulating siRNA and a chemotherapeutic agent will allow simultaneous interruption of diverse anti-cancer pathways, leading to increased therapeutic efficacy and reduced toxicities. PMID- 23932297 TI - The effect of urine-derived stem cells expressing VEGF loaded in collagen hydrogels on myogenesis and innervation following after subcutaneous implantation in nude mice. AB - Impairment of sphincter muscles or their neural and vascular support leads to stress urinary incontinence. The aim of this study was to determine the role of urine-derived stem cells (USCs) over-expressing vascular endothelial growth factor (VEGF) in collagen-I gel on angiogenesis, cell survival, cell growth, myogenic phenotype differentiation of the implanted cells and innervations following implantation in vivo. USCs were infected with adenovirus containing the human VEGF165 and green fluorescent protein genes. A total of 5 * 10(6) cells, USCs alone, or plus endothelial cells or human skeletal myoblasts (as control) suspended in collagen-I gel were subcutaneously implanted into nude mice. Extensive vascularization and more implanted cells was noted in VEGF-expressing USCs groups compared to the non-VEGF groups in vivo. Numbers of the cells displaying endothelial markers (CD 31 and von Willebrand's factor) and myogenic markers (myf-5, MyoD and desmin), and regenerated nerve fibers displaying neural markers (S-100, GFAP and neurofilament) significantly increased in the grafts of VEGF-expressing USCs. Improved angiogenesis by VEGF-expressing USCs enhanced grafted cell survival, recruited the resident cells and promoted myogenic phenotype differentiation of USCs and innervation. This approach has important clinical implications for the development of cell therapies for the correction of stress urinary incontinence. PMID- 23932298 TI - The glutathione S-transferase T1 deletion is associated with susceptibility to multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) occurs as a result of interaction between genetic and environmental factors. Recent data support the view that oxidative damage is one of an early event in MS tissue injury. The safe elimination of reactive oxygen species and toxins via glutathione S-transferase (GST) pathways is required in order to protect cells against reactive oxygen-induced damage. The aim of our study was to analyze the possible association of GSTM1 and GSTT1 gene polymorphisms with the susceptibility and clinical parameters of MS, in 455 consecutive patients and 366 controls. METHODS: A multiplex polymerase chain reaction (PCR) was used to detect the deletions in GSTM1 and GSTT1 genes. RESULTS: Patients with MS had significantly higher frequency of GSTT1 null genotype compared to controls (37.36% vs. 21.86%, respectively, p<0.0001, adjusted OR 2.13 (1.56-2.90)), as well as double deletions (15.38% vs. 10.38%, respectively, p<0.05). The carriers of GSTM1 deletion had significantly earlier onset of MS compared to the wild-type carriers (28.31 +/- 8.45 vs. 30.64 +/- 9.30 years, respectively, p = 0.03). CONCLUSION: This study suggests the potential pathogenic role of GSTT1 deletion on MS susceptibility. There are no similar data published so far, yet this study should be replicated in other populations. PMID- 23932299 TI - Leptin promotes human endometrial carcinoma cell proliferation by enhancing aromatase (P450arom) expression and estradiol formation. AB - OBJECTIVE: Leptin, a multifunctional peptide hormone encoded by the obese (ob) gene, plays an important role in modulating lipid metabolism and energy equilibrium. Leptin reportedly acts as a cell growth factor and enhances the proliferation of various tumors. We investigated the effect of leptin on aromatase (P450arom) expression and estradiol (E2) formation in a model of endometrial carcinoma. STUDY DESIGN: We established a co-culture model of endometrial fibroblasts and the Ishikawa endometrial carcinoma cell line. P450arom mRNA and protein expression were measured with RT-PCR and immunoblotting, respectively, before and after leptin treatment. The effect of leptin on estradiol formation in endometrial carcinoma cells was also detected with a radioimmunological method. RESULTS: P450arom mRNA expression was increased in co-cultures treated with 100 ng/ml leptin (P<0.01). Estradiol synthesis was induced when androstenedione was added to the culture medium, and significantly higher estradiol concentration was observed in co-cultures treated with 100 ng/ml leptin, CONCLUSIONS: Leptin is an important component of the microenvironment and stimulates endometrial carcinoma cell proliferation via enhancing P450arom expression and estradiol synthesis. PMID- 23932300 TI - Cervical cancer screening: which HPV test should be used--L1 or E6/E7? AB - Cervical cancer can and should be a historical disease. The reality, however, is that every year more than half a million women are diagnosed with cervical cancer and a quarter of a million die of this disease. The causal factor for cervical cancer is a persistent HPV infection and therefore a vaccine was developed: prophylactic HPV vaccination will reduce cervical cancer by 70%. Screening based on cytology will miss more than 40% of the abnormalities. The introduction of vaccination should lead to the reintroduction of cervical cancer screening based on HPV detection. Primary HPV screening followed by cytology will detect almost all abnormalities. Not all HPV tests, however, are the same! Clinicians are generally not aware that there is a huge difference among HPV tests. If a low grade lesion progresses to a high grade or invasive cancer, their HPV is likely to integrate. During integration L1 expression can be lost, but E6/E7 expression will always remain present. If the viral HPV is completely integrated then a L1 test looking for only L1 expression will miss this (pre)cancer, while the E6/E7 test will not miss it. HPV tests used in cervical cancer screening should be based on the early (E) and the late (L) genes in order not to miss the abnormality. PMID- 23932301 TI - Gynaecologists and the treatment of Garibaldi's ankle wound. AB - The hero of Italian Unification, Guiseppe Garibaldi, sustained a bullet wound to the ankle that caused an international sensation at the time as various surgeons from Italy, France, Russia and Great Britain vied to manage the injury. In particular the question was whether the bullet was still present. Eventually Nelaton from France won the race by the use of a porcelain-tipped probe which stained with the presence of lead. The actual extraction of the bullet was with the use of an expandable tent. It seems probable that Dr. James Marion Sims, the well-known American gynaecologist, supplied tents of the seaweed Laminaria digitata through Nelaton, to open up the wound and allow easy extraction of the bullet. Thus an unknown gynaecological connection seems to be part of an historical cause celebre. PMID- 23932302 TI - Morphometry of paravaginal ganglia from the pelvic plexus: impact of multiparity, primiparity, and pregnancy. AB - OBJECTIVES: (1) To describe the morphology of paravaginal ganglia and the neurochemical pattern of their neurons in virgin rabbits. (2) To analyze the effects of multiparity, primiparity and late pregnancy on morphometry of ganglia and their neurons. STUDY DESIGN: The morphology and neurochemical pattern of paravaginal ganglia were described in virgin nulliparous Chinchilla breed rabbits. Acetylcholinesterase histochemistry, Masson's trichrome, and immunohistochemistry for cholinergic and adrenergic neurons, and estrogen receptors (ERs) were undertaken. The area covered by ganglia (ganglionic area), the number of neurons, and the neuron soma area were measured in multiparas (4 consecutive and successive deliveries) and age-matched nulliparas. The same variables were measured in primiparous, late-pregnant, and age-matched nulliparous rabbits. RESULTS: Paravaginal ganglia were adjoined to the dorsolateral walls of the pelvic vagina. Their neurons were mostly cholinergic and expressed ERalpha and ERbeta. Multiparity increased the ganglionic area and reduced the number of ganglionic neurons. Late pregnancy transiently reduced the neuron soma area, which was coincident with a low expression of ERs. CONCLUSION: Multiparity but not primiparity affected the morphometry of ganglia. The hormonal state present in late pregnancy alters the neuron soma area and ER expression. Our findings support the notion that reproduction influences the morphometry of the pelvic plexus. PMID- 23932303 TI - The effectiveness of antepartum surveillance in reducing the risk of stillbirth in patients with advanced maternal age. AB - OBJECTIVE: To estimate the effectiveness of antepartum surveillance and delivery at 41 weeks in reducing the risk of stillbirth in advanced maternal age (AMA) patients. STUDY DESIGN: Retrospective cohort study of all patients managed in one maternal-fetal medicine practice from June 2005 to May 2012. We included all singleton pregnancies delivered at >= 20 weeks of gestation. All AMA patients (age >= 35 years at their estimated delivery date) underwent weekly biophysical profile testing beginning at 36 weeks, as well as planned delivery at 41 weeks, or sooner if indicated. We compared the rate of fetal death at >= 20 weeks and fetal death at >= 36 weeks in AMA vs. non-AMA patients. Fetal deaths due to lethal and chromosomal abnormalities were excluded. RESULTS: 4469 patients met the inclusion criteria: 1541 (34.5%) were AMA and 2928 (65.5%) were non-AMA. Using our AMA protocol for surveillance and timing of delivery, the incidence of stillbirth was similar to the non-AMA population (stillbirth >= 20 weeks: 3.9 per 1000 vs. 3.4 per 1000, p=0.799; stillbirth >= 36 weeks: 1.4 per 1000 vs. 1.1 per 1000, p=0.773). When looking at women age <35, age 35-39, and age >= 40, the incidence of stillbirth >= 20 weeks and >= 36 weeks did not increase across the three groups. Our findings were similar when we excluded all patients with other indications for antepartum surveillance. CONCLUSIONS: In AMA patients, antepartum surveillance and delivery at 41 weeks appears to reduce the risk of stillbirth to that of the non-AMA population. Routine antepartum surveillance should be considered in all AMA patients. PMID- 23932304 TI - Uterine necrosis following pelvic arterial embolization for post-partum hemorrhage: review of the literature. AB - Uterine necrosis is one of the rarest complications following pelvic arterial embolization for postpartum hemorrhage (PPH). With the increasing incidence of cesarean section and abnormal placental localization (placenta previa) or placental invasion (placenta accreta/increta/percreta), more and more cases of uterine necrosis after embolization are being diagnosed and reported. Pelvic computed tomography or magnetic resonance imaging provides high diagnostic accuracy, and surgical management includes hysterectomy. We performed a Medline database query following the first description of uterine necrosis after pelvic embolization (between January 1985 and January 2013). Medical subheading search words were the following: "uterine necrosis"; "embolization"; "postpartum hemorrhage". Seventeen citations reporting at least one case of uterine necrosis after pelvic embolization for PPH were included, with a total of 19 cases. This literature review discusses the etiopathogenesis, clinical and therapeutic aspects of uterine necrosis following pelvic arterial embolization, and guidelines are detailed. The mean time interval between pelvic embolization and diagnosis of uterine necrosis was 21 days (range 9-730). The main symptoms of uterine necrosis were fever, abdominal pain, menorrhagia and leukorrhea. Surgical management included total hysterectomy (n=15, 78%) or subtotal hysterectomy (n=2, 10%) and partial cystectomy with excision of the necrotic portion in three cases of associated bladder necrosis (15%). Uterine necrosis was partial in four cases (21%). Regarding the pathophysiology, four factors may be involved in uterine necrosis: the size and nature of the embolizing agent, the presence of the anastomotic vascular system and the embolization technique itself with the use of free flow embolization. PMID- 23932305 TI - The role of autophagy in reproduction from gametogenesis to parturition. AB - Autophagy is an intracellular process responsible for maintaining cellular homeostasis by the removal of cytoplasmic organelles, intracellular bacteria and viruses, and is a critical component of both the innate and acquired immune systems. A failure in physiological activation, assembly and function of the autophagic pathway has been implicated in a broad range of diseases including neurogenerative diseases, cardiopathy, infectious diseases, autoimmunity and cancer. Its involvement in reproduction, however, has not been extensively studied. Its activity is fundamental to many processes across the reproduction spectrum from development of the primordial follicle and spermatozoa to embryogenesis, placental development and maintaining uterine quiescence during pregnancy. Malfunctions in autophagy are associated with deleterious repercussions throughout reproduction. In this review we examine what is known about the involvement of autophagy in gamete formation, early post-fertilization embryogenesis, placental development and parturition, and propose promising areas for future research. PMID- 23932307 TI - A randomized study of simultaneous hCG administration with intrauterine insemination in stimulated cycles. AB - OBJECTIVE(S): To compare the clinical pregnancy rates between intrauterine insemination (IUI) simultaneously or 34-36 h following hCG injection in gonadotropin-stimulated IUI cycles. STUDY DESIGN: Randomized, prospective, controlled, study conducted in a university infertility clinic. Of 923 infertile couples, 220 couples with unexplained infertility or mild male factor infertility were included to the study. Before ovarian stimulation patients were randomized into two groups: IUI at 34-36 h after hCG injection (group I) (n=106) and IUI simultaneously with hCG administration (group II) (n=98). The primary outcome was clinical pregnancy rates. RESULTS: There was no significant difference between the groups according to baseline patient and cycle characteristics. Clinical pregnancy rates were 9.4% and 12.2% in group I and group II, respectively (p=0.523). Although group II had better outcomes there was no statistically significant difference in clinical pregnancy rates between the different timing methods: IUI simultaneously with hCG versus IUI at 34-36 h after hCG (odds ratio (OR)=1.35, 95% CI 0.53-3.42). CONCLUSION(S): There is no difference in simultaneous use of hCG injection compared to cycles in which IUI is performed after 34-36 h following hCG injection. Prospective randomized trials with larger sample sizes or meta-analyses are required. PMID- 23932306 TI - Gene expression of stem cells at different stages of ontological human development. AB - OBJECTIVES: To compare multipotent mesenchymal stem cells (MSCs) obtained from chorionic villi (CV), amniotic fluid (AF) and placenta, with regard to their phenotype and gene expression, in order to understand if MSCs derived from different extra-embryonic tissues, at different stages of human ontological development, present distinct stemness characteristics. STUDY DESIGN: MSCs obtained from 30 samples of CV, 30 of AF and 10 placentas (obtained from elective caesarean sections) were compared. MSCs at second confluence cultures were characterized by immunophenotypic analysis with flow cytometry using FACS CANTO II. The expression of the genes Oct-4 (Octamer-binding transcription factor 4, also known as POU5F1), Sox-2 (SRY box-containing factor 2), Nanog, Rex-1 (Zfp-42) and Pax-6 (Paired Box Protein-6), was analyzed. Real-time quantitative PCR was performed by ABI Prism 7700, after RNA isolation and retro-transcription in cDNA. Statistical analysis was performed using non-parametric test Kruskal-Wallis (XLSTAT 2011) and confirmed by REST software, to estimate fold changes between samples. Each gene was defined differentially expressed if p-value was <0.05. RESULTS: Cells from all samples were negative for haematopoietic antigens CD45, CD34, CD117 and CD33 and positive for the typical MSCs antigens CD13, CD73 and CD90. Nevertheless, MSCs from AF and placentas showed different fluorescence intensity, reflecting the heterogeneity of these tissues. The gene expression of OCT-4, SOX-2, NANOG was not significantly different among the three groups. In AF, REX-1 and PAX-6 showed a higher expression in comparison to CV. CONCLUSIONS: MSCs of different extra-embryonic tissues showed no differences in immunophenotype when collected from second confluence cultures. The expression of OCT-4, NANOG and SOX-2 was not significantly different, demonstrating that all fetal sources are suitable for obtaining MSCs. These results open new possibilities for the clinical use of MSCs derived from easily accessible sources, in order to develop new protocols for clinical and experimental research. PMID- 23932308 TI - The interaction of Urocortin II and Urocortin III with amygdalar and hypothalamic cotricotropin-releasing factor (CRF)--reflections on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. AB - Urocortin II (Ucn II) and Urocortin III (Ucn III) are selective agonists of the CRF receptor type 2 (CRFR2). The aim of the present experiments was to investigate the effects of Ucn II and Ucn III on the central CRF and peripheral glucocorticoids in rats. Increasing doses (0.5-1-2-5 MUg/2 MUl) of Ucn II or Ucn III were administered intracerebroventricularly, then CRF concentration was determined by immunoassays in two different brain regions, the amygdala and the hypothalamus, and in two different time paradigms, 5 and 30 min after the administration of peptides. In parallel with the second determination, plasma corticosterone concentration was measured by chemofluorescent assay. The amygdalar CRF amount was increased significantly by 0.5 and 5 MUg of UCN II and 2 and 5 MUg of UCN III in the 5 min experiments and by 5 MUg of UCN II and 0.5 and 5 MUg of UCN III in the 30 min experiments. The hypothalamic CRF content was not affected considerably in the 5 min paradigm, but it was influenced significantly in the 30 min paradigm, with 0.5 and 1 MUg of UCN II and 0.5-2 MUg of UCN III decreasing, and 2 and 5 MUg of UCN II and 5 MUg of UCN III increasing the hormone concentration, respectively. The plasma corticosterone concentration was decreased by 1 and 2 MUg of UCN II and UCN III and increased by 0.5 and 5 MUg of UCN III. The present results demonstrate that central administration of Ucn II and Ucn III modulate time-dependently and dose-dependently the amygdalar and the hypothalamic CRF concentration, and, directly or indirectly, the plasma corticosterone concentration. The present experiments suggest that the role of CRFR2 in the regulation of the HPA axis can be inhibitory or stimulatory, depending on the actual concentration of their agonists. PMID- 23932309 TI - Vocal economy in vocally trained actresses and untrained female subjects. AB - OBJECTIVES: Vocally trained actresses are expected to have more vocal economy than nonactresses. Therefore, we hypothesize that there will be differences in the electroglottogram-based voice economy parameter quasi-output cost ratio (QOCR) between actresses and nonactresses. This difference should remain across different levels of intensity. METHODS: A total of 30 actresses and 30 nonactresses were recruited for this study. Participants from both groups were required to sustain the vowels /a/, /i/, and /u/, in habitual, moderate, and high intensity levels. Acoustic variables such as sound pressure level (SPL), fundamental frequency (F0), and glottal contact quotient (CQ) were obtained. The QOCR was then calculated. RESULTS: There were no significant differences among the groups for QOCR. Positive correlations were observed for QOCR versus SPL and QOCR versus F0 in all intensity levels. Negative correlation was found between QOCR and CQ in all intensity levels. Considering the differences among intensity levels, from habitual to moderate and from moderate to loud, only the CQ did not differ significantly. The QOCR, SPL, and F0 presented significant differences throughout the different intensity levels. CONCLUSION: The QOCR did not reflect the level of vocal training when comparing trained and nontrained female subjects in the present study. Both groups demonstrated more vocal economy in moderate and high intensity levels owing to more voice output without an increase in glottal adduction. PMID- 23932310 TI - In vitro evaluation of DispersinB on methicillin-resistant Staphylococcus pseudintermedius biofilm. AB - Methicillin resistant Staphylococcus pseudintermedius (MRSP) is an important canine pathogen that has been shown to produce biofilm in vitro. Biofilm production may be an important virulence factor and methods to eliminate biofilm associated infections are required. An enzyme of Aggregatibacter actinomycetemcomitans, DispersinB, has been shown to degrade the extracellular matrix in the biofilm of a variety of bacteria including Staphylococcus aureus and Staphylococcus epidermidis. The objective of this study was to determine the effect of DispersinB on MRSP biofilm production and eradication in vitro. A quantitative microtitre plate assay was used to assess the impact of DispersinB on 30 MRSP isolates from dogs. While DispersinB did not have any effect on MRSP growth (P=0.98), it reduced biofilm formation (P=0.0002) and degraded established biofilm (P=0.0001). These data indicate that in vivo study of the effect of this enzyme in indicated to determine if it may be a useful treatment option for MRSP biofilm-associated infections. PMID- 23932311 TI - Detection of diarrheagenic Escherichia coli strains isolated from dogs and cats in Brazil. AB - Escherichia coli are gut microbiota bacteria that can cause disease in some humans and other animals, including dogs and cats that humans often keep as pets. Diarrheagenic E. coli (DEC) strains are classified into six categories: enteropathogenic (EPEC), enterotoxigenic (ETEC), Shiga toxin-producing (STEC), enteroinvasive (EIEC), enteroaggregative (EAEC), and diffuse-adhering E. coli (DAEC). In this study 144 and 163 E. coli colonies were isolated from the fecal samples of 50 dogs and 50 cats, respectively, with and without diarrhea from a Veterinary Hospital (clinical isolates). The virulence factors were determined using multiplex Polymerase Chain Reaction. Adherence assays, antibacterial susceptibility and serotyping (somatic or flagellar antigens) were performed on DEC isolates. We found 25 (17.4%) and 4 (2.5%) DEC strains isolated from dogs and cats, respectively. Only the EPEC and EAEC pathotypes were found in both animals. Meanwhile, genes from other pathotypes (STEC, EIEC, and ETEC) were not found in these clinical isolates. All of the DEC strains showed mannose-resistant adherence to HEp-2 and HeLa cells, and aggregative adherence was predominant in these isolates. Multiresistant strains to antimicrobials were found in most DEC strains including usual and unusual antimicrobials in veterinary practices. The serotypes of these DEC isolates were variable. The ONT serotype was predominant in these isolates. Some serotypes found in our study were described to human DEC. Here, we demonstrate that pets carry virulent DEC genes, which are mainly strains of EPECs and EAECs. The presence of these virulence factors in isolates from animals without diarrhea suggests that pets can act as a reservoir for human infection. PMID- 23932312 TI - Effect of tocilizumab combined with methotrexate on circulating biomarkers of synovium, cartilage, and bone in the LITHE study. AB - OBJECTIVE: We investigated the effects of tocilizumab (TCZ) on joint tissue remodeling in patients with moderate to severely active RA by measuring tissue specific biomarker. METHODS: The LITHE biomarker study (n = 740) was a phase III study of 4- and 8-mg/kg TCZ in combination with MTX. Early response was evaluated at week 16 as +/-20% improvement in swollen/tender joint counts; and ACR50 was evaluated at week 52. Biomarkers (tissue inflammation: C3M, CRPM, and VICM; cartilage degradation: C2M; and bone turnover: CTx and osteocalcin) were tested in serum from baseline, week 4, 16, 24, and 52, and dose-dependent effect was investigated. Patients were divided into the following three groups: early non responders (ENR), ACR50 responders, and non-responders; their biomarker profiles were compared. RESULTS: At week 52, CRP was inhibited to 4% and 40% of baseline by TCZ8 and TCZ4, respectively. CRPM (63%), C2M (84%), C3M (69%), and VICM (42%) were significantly (p < 0.05) reduced by TCZ8, but not by TCZ4. MMP3 and osteocalcin changed to <58% and >111%, respectively, in response to TCZ. CTx was not changed significantly. ENRs had significantly less inhibition of CRPM (p < 0.05), C2M (p < 0.01), and C3M (p < 0.01) compared to early responders. There was a significant difference in the C2M, C3M, and CRPM profiles of the ENRs, non responders, and responders. ACR50 responders had significantly inhibited levels (p < 0.001), irrespective of dose. CONCLUSIONS: TCZ8 strongly inhibited the biomarkers of joint tissue remodeling suggesting that TCZ actively suppresses key pathobiological processes at the site of inflammation in RA patients. The differences in biomarkers' profiles of responders and non-responders indicate that specific responder profiles exist. PMID- 23932313 TI - Recognizing and treating myocarditis in recent-onset systemic sclerosis heart disease: potential utility of immunosuppressive therapy in cardiac damage progression. AB - OBJECTIVES: Scleroderma heart disease is a major risk of death in systemic sclerosis (SSc). Mechanisms underlying myocardial damage are still unclear. We performed an extensive study of SSc patients with recent-onset symptoms for heart disease and examined the efficacy of immunosuppressive therapy. METHODS: A cohort of 181 SSc patients was enrolled. Of these, 7 patients newly developed clinical symptoms of heart disease (heart failure, chest pain, and palpitation); all of them showed mild but persistent increase in cardiac enzymes. These patients underwent Holter ECG, 2D-echocardiography, perfusional scintigraphy, delayed enhancement-cardiac magnetic resonance (DE-CMR), coronary angiography, and endomyocardial biopsy. Patients were treated for at least 12 months and followed up for 5 years. RESULTS: Ventricular ectopic beats (VEBs) were found in 4 patients, wall motion abnormalities in 3, pericardial effusion in 6, and DE in CMR in 6 with T2-hyperintensity in 2. In all patients, histology showed upregulation of endothelium adhesion molecules and infiltration of activated T lymphocytes, with (acute/active myocarditis in 6) or without (chronic/borderline myocarditis in 1) myocyte necrosis. Parvovirus B19 genome was detected in 3. None showed occlusion of coronary arteries or microvessels. Compared with SSc controls, these patients more often had early disease, skeletal myositis, c ANCA/anti-PR3 positivity, VEBs, pericardial effusion, and systolic and/or diastolic dysfunction. Immunosuppressive therapy improved symptoms and led to cardiac enzyme negativization; however, 2 patients died of sudden death during follow-up. CONCLUSIONS: Myocarditis is a common finding in SSc patients with recent-onset cardiac involvement. Its early detection allowed to timely start an immunosuppressive treatment, preventing cardiac damage progression in most cases. PMID- 23932314 TI - Polyacrylamide phantom for self-actuating needle-tissue interaction studies. AB - This study presents a polyacrylamide gel as a phantom material for needle insertion studies specifically developed for self-actuating needles to enhance the precise placement of needles in prostate. Bending of these self-actuating needles within tissue is achieved by Nitinol actuators attached to the needle body; however these actuators usually involve heating that can thermally damage the tissue surrounding the needles. Therefore, to develop and access feasibility of these needles, a polyacrylamide gel has been developed that mimics the thermal damage and mechanical properties of prostate tissue. Mechanical properties of the polyacrylamide gel was controlled by varying the concentrations of acrylamide monomer and N,N-methylene-bisacrylamide (BIS) cross-linker, and thermal sensitivity was achieved by adding bovine serum albumin (BSA) protein. Two polyacrylamide gels with different concentrations were developed to mimic the elastic modulus of the tissue. The two phantoms showed different rupture toughness and different deflection of bevel-tip needle. To study the thermal damage, a Nitinol wire was embedded in the phantom and resistively heated. The measured opaque zone (0.40mm) formed around the wire was close to the estimated damage zone (0.43mm) determined using the cumulative equivalent minutes at 43 degrees C. PMID- 23932315 TI - Maternal race/ethnicity and survival experience of children with congenital heart disease. AB - OBJECTIVE: To investigate the existence of racial/ethnic disparity in mortality risk among children with individual congenital heart defects and identify any other risk factors. STUDY DESIGN: The study cohort, comprising children born between 1983 and 2006 with a selected congenital heart defect, was matched to death records to ascertain vital status. The birth and maternal risk factors were obtained from birth certificates. RESULTS: After adjusting for covariates using a multivariate regression model, the risk of mortality was significantly higher in children of non-Hispanic black mothers with transposition of the great arteries (hazard ratio (HR), 1.31; 95% CI, 1.07-1.60), tetralogy of Fallot (HR, 1.34; 95% CI, 1.06-1.69), and coarctation of the aorta (HR, 1.40; 95% CI, 1.10-1.79), compared with children of non-Hispanic white mothers. Time trends analysis examining the mortality risk by survival age and birth period found a significant decrease in 5-year mortality risk from 1983 to 2003 births, with a nearly 50% reduction for hypoplastic left heart syndrome and coarctation of the aorta across 3 maternal racial/ethnic groups examined. CONCLUSION: Our findings may help identify at-risk populations and mortality risk factors and thereby contribute to improved survival and quality of life for these children across the lifespan. PMID- 23932316 TI - Maternal diagnosis of obesity and risk of cerebral palsy in the child. AB - OBJECTIVE: To examine the association between maternal hospital diagnoses of obesity and risk of cerebral palsy (CP) in the child. STUDY DESIGN: For all California hospital births from 1991-2001, we linked infant and maternal hospitalization discharge abstracts to California Department of Developmental Services records of children receiving services for CP. We identified maternal hospital discharge diagnoses of obesity (International Classification of Diseases, 9th edition 646.1, 278.00, or 278.01) and morbid obesity (International Classification of Diseases, 9th edition 278.01), and performed logistic regression to explore the relationship between maternal obesity diagnoses and CP. RESULTS: Among 6.2 million births, 67 200 (1.1%) mothers were diagnosed with obesity, and 7878 (0.1%) with morbid obesity; 8798 (0.14%) children had CP. A maternal diagnosis of obesity (relative risk [RR] 1.30, 95% CI 1.09-1.55) or morbid obesity (RR 2.70, 95% CI 1.89-3.86) was associated with increased risk of CP. In multivariable analysis adjusting for maternal race, age, education, prenatal care, insurance status, and infant sex, both obesity (OR 1.27, 95% CI 1.06-1.52) and morbid obesity (OR 2.56, 95% CI 1.79-3.66) remained independently associated with CP. On stratified analyses, the association of obesity (RR 1.72, 95% CI 1.25-2.35) or morbid obesity (RR 3.79, 95% CI 2.35-6.10) with CP was only significant among women who were hospitalized prior to the birth admission. Adjusting for potential comorbidities and complications of obesity did not eliminate this association. CONCLUSIONS: Maternal obesity may confer an increased risk of CP in some cases. Further studies are needed to confirm this finding. PMID- 23932317 TI - Antithrombin concentrate use in children: a multicenter cohort study. AB - OBJECTIVE: To describe the off-label use of antithrombin concentrate in tertiary care pediatric hospitals across the US. STUDY DESIGN: This is a retrospective, multicenter, cohort study of 4210 admissions of children younger than 18 years of age who received antithrombin concentrate between 2002 and 2011 within the Pediatric Health Information System administrative database. An on-label admission was defined as an admission with an International Classification of Diseases diagnostic code for a primary hypercoagulable state; admissions without this code were classified as off-label. RESULTS: During the 10-year study period, off-label use of antithrombin concentrate increased 5-fold. Overall, 97% of study subjects received antithrombin off-label. Neonates younger than 30 days of age comprised the largest age group (45.7%) of use; 87% of patients had at least one complex chronic condition, with congenital heart/lung defects being the most prevalent primary diagnosis (36.3%). Extracorporeal membrane oxygenation was the most common procedure associated with antithrombin use (43.7%). CONCLUSIONS: The off-label use of antithrombin concentrate is increasing rapidly, particularly in critically ill children receiving extracorporeal membrane oxygenation, with few parallel studies to substantiate its safety or efficacy. Further preclinical and controlled clinical studies are critical to expanding our knowledge of this drug. In the meantime, antithrombin concentrate should be used judiciously by clinicians and following guidelines instated by hospitals. PMID- 23932318 TI - Nonresectional single-suture leaflet remodeling for degenerative mitral regurgitation facilitates minimally invasive mitral valve repair. AB - BACKGROUND: Both leaflet resection and neochordal construction are effective mitral repair techniques, but they may become incrementally time-consuming when using minimally invasive approaches. We have used a single-suture leaflet remodeling technique of inverting the prolapsed or flail segment tissue into the left ventricle. This repair is straightforward, expeditious, and facilitates a minimally invasive approach. METHODS: Ninety-nine patients with degenerative mitral regurgitation (MR) underwent a minimally invasive single-suture repair of the mitral valve from May 2007 through December 2012. Preoperative and perioperative echocardiograms as well as patient outcomes were analyzed and compared with those obtained from patients undergoing minimally invasive mitral valve repair using quadrangular resection at the same institution during the same period. RESULTS: All 99 patients had a successful mitral repair through a sternal sparing minimally invasive approach. Ninety-one of the 99 patients had zero MR on postoperative echocardiogram, and 8 of 99 had trace to mild MR. Patients in the nonresectional group had significantly shorter cardiopulmonary bypass and cross clamp times compared with the quadrangular resection group (115.8 +/- 41.7 minutes versus 144.9 +/- 38.2 minutes; p < 0.001; 76.2 +/- 28.1 minutes versus 112.6 +/- 33.5 minutes; p < 0.001, respectively). The mean length of stay was 7.5 +/- 3 days. All patients were discharged alive and free from clinical symptoms of MR. There have been no reoperations for recurrent MR on subsequent average follow up of 1 year. CONCLUSIONS: An effective, highly efficient, and thus far durable single-suture mitral leaflet-remodeling technique facilitates minimally invasive repair of degenerative MR. PMID- 23932319 TI - The impact of EGFR mutation status on outcomes in patients with resected stage I non-small cell lung cancers. AB - BACKGROUND: Mutations of the epidermal growth factor hormone receptor (EGFR) gene have been associated with improved treatment response and prognosis in advanced non-small lung cancer (NSCLC). However, their prognostic role in early-stage NSCLC is not well defined. In this study we sought to identify the pure prognostic role of EGFR mutation in patients with completely resected stage I NSCLC who received no adjuvant therapy. METHODS: Mutation status was tested in treatment-naive patients who had complete resection of stage I (T1-2aN0) NSCLC (from 2004 to 2011) using direct sequencing or multiplex polymerase chain reaction-based assay. Recurrence rates, disease-free survival, and overall survival were compared between EGFR-mutant and wild-type patients using Kaplan Meier methods and Cox regression models. RESULTS: Three hundred seven patients were included in this study; 62 harbored tumors with EGFR mutations and 245 had wild-type EGFR. Tumors in patients with EGFR mutations were associated with a significantly lower recurrence rate (9.7% versus 21.6%; p=0.03), greater median disease-free survival (8.8 versus 7.0 years; p=0.0085), and improved overall 5 year survival (98% versus 73%; p=0.003) compared with wild-type tumors. Lobectomy was the most frequently performed procedure, accounting for 209 of 307 operations. Among these patients, EGFR mutation was associated with superior overall survival (hazard ratio, 0.45; 95% confidence interval, 0.13 to 0.83; p=0.017), with an estimated 5-year survival of 98% versus 70%. The presence of EGFR mutation (p=0.026) and tumor size less than 2 cm (p=0.04) were identified as independent prognostic markers for disease-free survival, whereas age, sex, and smoking status were not. CONCLUSIONS: Completely resected stage I EGFR mutation positive NSCLC patients have a significant survival advantage compared with EGFR wild-type patients. Mutation of the EGFR gene is a positive prognostic marker in completely resected stage I NSCLC. PMID- 23932320 TI - The role of cardiac resynchronization therapy for arterial switch operations complicated by complete heart block. AB - BACKGROUND: As mortality in patients with D-loop transposition of the great arteries (D-TGA) has decreased after the arterial switch operation (ASO), the focus has shifted to higher risk groups and outcomes that impact long-term morbidity and mortality, such as left ventricular (LV) dysfunction. We sought to examine the perioperative factors associated with LV dysfunction in patients with D-TGA and ventricular septal defects (VSD) after ASO. METHODS: A retrospective study was made of all patients with D-TGA/VSD who underwent ASO/VSD closure from 2001 to 2011. Patients with prematurity, L-looped ventricles, and straddling atrioventricular valves were excluded. The primary endpoint was moderate or severe LV dysfunction measured by echocardiogram 2 months or more after surgery. RESULTS: A total of 112 patients underwent ASO/VSD closure at a median age of 5 days. Median time of follow-up was 6.5 months, with no mortality noted. Six patients (8%) were noted to have at least moderate LV dysfunction. Risk factors were heart block requiring pacemaker placement (p<0.001) and length of intensive care unit admission (p=0.04). All 6 patients with heart block had an epicardial lead on the right ventricular free wall; 4 had moderate or severe LV dysfunction and underwent upgrade to cardiac resynchronization therapy (CRT); median time from initial pacemaker to CRT was 5 months. With a median follow-up of 5 months after CRT, LV function improved to normal (2 patients) or mild dysfunction (2 patients). CONCLUSIONS: Left ventricular dysfunction after surgical repair for D TGA/VSD is low, with heart block and pacemaker insertion playing a significant role. The LV function improved after patients were upgraded to a CRT device. PMID- 23932321 TI - Course, predictors of diaphragm recovery after phrenic nerve injury during pediatric cardiac surgery. AB - BACKGROUND: Hemidiaphragm paralysis from phrenic nerve injury is a known complication of congenital cardiac surgery. Return of diaphragm function has been reported; however, prior studies on this subject have been limited by small numbers, static assessment methods, or observation of plicated or non-plicated patients alone. To describe return of function, we reviewed fluoroscopy and ultrasonography in all diagnosed cases of diaphragmatic paralysis. METHODS: Surgical cases at our institution between 1991 and 2010 were identified for patients with postoperative hemidiaphragm paralysis diagnosed by chest X-ray, ultrasound, or fluoroscopy. Follow-up ultrasound and fluoroscopic studies were reviewed for return of diaphragm function. RESULTS: Seventy-two cases of postoperative hemidiaphragm paralysis were identified. Forty cases were plicated prior to discharge. Plicated patients were younger at time of diagnosis (median 46 days average 3.6 months; p=0.025) and had a larger proportion of single ventricle diagnoses (48% vs 16%) compared with non-plicated patients. Twenty-six patients with paralysis were excluded in follow-up due to lack of studies documenting diaphragm function after the diagnostic study. Of the remaining 46 cases, median follow-up was 353 days (range: 6 days to 17 years). Plicated and non-plicated patients regained function at similar frequency (60% and 54.8%, respectively). Plication status, Risk Adjustment for Congenital Heart Surgery (RACHS) 1 score, age at diagnosis, and side of paralysis did not predict failure of recovery. CONCLUSIONS: In the current era, return of diaphragm function after phrenic nerve injury sustained during congenital cardiac surgery is a known occurrence; however, predicting recovery continues to be difficult. PMID- 23932322 TI - A protocol-driven approach to cardiac reoperation reduces mortality and cardiac injury at the time of resternotomy. AB - BACKGROUND: The purpose of this study was to determine whether an established protocol-driven approach to cardiac reoperations would improve patient outcomes and reduce resternotomy injuries. METHODS: From 1995 to 2010, 946 patients undergoing cardiac reoperations were stratified into reoperative protocol (n=344, age=61+/-17 years) vs no-protocol (n=602, age=64+/-14 years) comparison groups. RESULTS: Protocol patients underwent more complex reoperations (procedure type "other": 24% vs 15%, p<0.001). Initiation of CPB before sternotomy was similar between study groups (5% vs 3%, p=0.07). Resternotomy ventricular injuries were most common. Mortality was lower for protocol patients (6% vs 10%, p=0.04), and the use of a reoperative protocol was associated with a significantly reduced incidence of resternotomy injury (3% vs. 10%, p<0.001). On multivariate analysis, reoperative protocol was associated with a nearly 70% reduction in risk-adjusted odds of resternotomy injury (p=0.001). CONCLUSIONS: A protocol-driven approach to cardiac reoperations is associated with reduced cardiac injury upon resternotomy and decreased mortality. The protocol-driven use of routine preoperative computed tomography angiography, alternative cannulation planning, avoidance of prior internal mammary artery grafts, and the early initiation of cardiopulmonary bypass before sternotomy for selected cases should be considered to improve operative results and efficiency. PMID- 23932323 TI - Clustering of HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and infective dermatitis associated with HTLV-1 (IDH) in Salvador, Bahia, Brazil. AB - Fifteen families with clustering of infective dermatitis associated with HTLV-1 (IDH) and/or HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) were observed among 28 families of IDH index cases, 93% of them occurring in two generations. With the exception of two mothers of children with IDH, all the mothers with HAM/TSP had at least one child with HAM/TSP. This is the first report of such clustering involving many families. PMID- 23932324 TI - High-phosphorus/zinc-free diet aggravates hypertension and cardiac dysfunction in a rat model of the metabolic syndrome. AB - BACKGROUND: Cardiac dysfunction is reported in patients with the metabolic syndrome. We assessed the effects of high-phosphorus and zinc-free diet on cardiovascular system in spontaneously hypertensive rats (SHR)/NDmcr-cp (SHR/cp), a rat model of the metabolic syndrome. We also investigated the effects of N acetyl-L-cysteine (NAC), an antioxidant, on the development of cardiac dysfunction under such conditions. METHODS: Male SHR/cp and control [Wistar Kyoto (WKY)] rats were divided into three groups and fed control diet (P 0.3% w/w, Zn 0.2% w/w) or high-phosphorus and zinc-free (P 1.2% w/w, Zn 0.0% w/w) diet. The latter group was treated with either NAC (1.5 mg/g per day) or vehicle from 6 to 18 weeks of age (n=6 or 8 for each group). RESULTS: High-phosphate and zinc-free diet increased systolic blood pressure in both WKY and SHR/cp. Echocardiography showed that high-phosphate and zinc-free diet markedly reduced left ventricular systolic and diastolic function in SHR/cp. Histopathologically, the same diet induced severe myocardial fibrosis in SHR/cp, and this effect was prevented by NAC. Whereas treatment with NAC prevented diastolic dysfunction induced by the same diet in WKY, it only improved systolic function but not diastolic function in SHR/cp. CONCLUSIONS: High-phosphate and zinc-free diet induced hypertension and cardiac dysfunction. These changes hamper the protective effects of NAC in the metabolic syndrome. SUMMARY: The present study showed that consumption of high-phosphorus and zinc-free diet increased the myocardial expression of connective tissue growth factor and reduced the expression of metallothionein, which enhanced the development of severe cardiac dysfunction in rats with the metabolic syndrome. The results suggest that the metabolic syndrome seems to aggravate cardiac dysfunction and hamper the protective effects of antioxidant, NAC. PMID- 23932325 TI - Evidence for an exposure-response relationship between trunk flexion and impairments in trunk postural control. AB - Prolonged trunk flexion alters passive and active trunk tissue behaviors, and exposure-response relationships between the magnitude of trunk flexion exposure and changes in these behaviors have been reported. This study assessed whether similar exposure-response relationships exist between such exposures and impairments in trunk postural control. Twelve participants (6 M, 6 F) were exposed to three distinct trunk flexion conditions (and a no-flexion control condition), involving different flexion durations with/without an external load, and which induced differing levels of passive tissue creep. Trunk postural control was assessed prior to and immediately following trunk flexion exposures, and during 10 min of standing recovery, by tracking center of pressure (COP) movements during a seated balance task. All COP-based sway measures increased following each flexion exposure. In the anteroposterior direction, these increases were larger with increasing exposure magnitude, whereas such a relationship was not evident for mediolateral sway measures. All measures were fully recovered following 10 min of standing. The present results provide evidence for an exposure-response relationship between trunk flexion exposures and impairments in trunk postural control; specifically, larger impairments following increased exposures (i.e., longer flexion duration and presence of external load). Such impairments in trunk postural control may result from some combination of reduced passive trunk stiffness and altered/delayed trunk reflex responses, and are generally consistent with prior evidence of exposure-dependent alterations in trunk mechanical and neuromuscular behaviors assessed using positional trunk perturbations. Such evidence suggests potential mechanistic pathways through which trunk flexion exposures may contribute to low-back injury risk. PMID- 23932326 TI - Inertial sensor based method for identifying spherical joint center of rotation. AB - The miniaturized wireless inertial measurement unit (IMU) technology and algorithms presented herein promote rapid and accurate predictions of the center of-rotation (CoR) for ball/spherical joints. The algorithm improves upon existing IMU-based methods by directly utilizing the measured acceleration and angular velocity provided by the IMU to deduce the CoR in lieu of relying on error-prone velocity and position estimates. Results demonstrate that this new method resolves the position of the CoR to within a 3mm sphere of the true CoR determined by a precision coordinate measuring machine. Such accuracy may render this method attractive for broad use in field, laboratory and clinical settings requiring non-invasive and rapid estimates of joint CoR. PMID- 23932327 TI - Stress-strain analysis of jejunal contractility in response to flow and ramp distension in type 2 diabetic GK rats: effect of carbachol stimulation. AB - Investigation of intestinal motility in a genetic model of GK rats abandons the possible neurotoxic effect of streptozotocin in streptozotocin-induced diabetic model. Seven GK male rats (GK group) and nine normal Wistar rats (Normal group) were used in the study. The motility experiments were carried out in an organ bath containing physiological Krebs solution. Before and after 10(-5)M carbachol application, the pressure and diameter changes of jejunum were obtained in relation to (1) basic contraction, (2) flow-induced contraction with different outlet resistance pressures and (3) contractions induced by ramp distension. The frequency and amplitude of contractions were analyzed from pressure-diameter curves. Distension-induced contraction thresholds and maximum contraction amplitude of basic and flow-induced contractions were calculated in terms of stress and strain. (1) The contraction amplitude increased to the peak value in less than 10s after adding carbachol. More than two peaks were observed in the GK group. (2) Carbachol decreased the pressure and stress threshold and Young's modulus in the GK group (P<0.01). (3) Carbachol increased the maximum pressure and stress of flow-induced contractions at most outlet pressure levels in both two groups (P<0.001). Furthermore, the flow-induced contractions were significantly bigger at low outlet pressure levels in GK group (P<0.05 and P<0.01). (4) The contraction frequency, the strain threshold and the maximum contraction strain did not differ between the two groups (P>0.05) and between before and after carbachol application (P>0.05). In GK diabetic rats, the jejunal contractility was hypersensitive to flow and distension stimulation after carbachol application. PMID- 23932328 TI - Coronary air embolism associated with atrioesophageal fistula after ablation of atrial fibrillation. AB - A 68-year-old man presented with multiple embolic strokes and sepsis 50 days after catheter ablation of atrial fibrillation. Cardiac computed tomography scan demonstrated an atrioesophageal fistula at the left atrial posterior wall and hypermobile materials with hypoattenuating lesions in the left atrium. On the 12th hospital day, he presented with acute ST-elevation in the inferior leads. A bedside echocardiogram revealed unusually high myocardial echogenecity and akinesia on the right coronary artery territory. These findings disappeared within a few minutes. This case shows characteristic images of coronary air embolism in gas-containing endocarditis caused by atrioesophageal fistula after catheter ablation of atrial fibrillation. PMID- 23932329 TI - Autologous pericardial reinforcement after detachment of the coronary buttons of the proximal anastomosis in the Bentall procedure. AB - The present report describes a simple modification to the reinforcement technique by Copeland et al. using autologous pericardium for the Bentall procedure. Our modified technique may decrease the probability of leaks at the aortic root. Further, this technique preserves the advantages of the Valsalva graft, including tension-free coronary anastomosis and anatomical adaptability. PMID- 23932330 TI - Maize rhizosphere in Sichuan, China, hosts plant growth promoting Burkholderia cepacia with phosphate solubilizing and antifungal abilities. AB - Plant growth-promoting rhizobacteria promote plant growth by direct and indirect mechanisms. We isolated twelve bacterial strains showing different degrees of phosphate solubilizing activity from maize rhizosphere. Four isolates solubilized over 300 MUg mL-1 phosphate from insoluble Ca3(PO4)2, with isolate SCAUK0330 solubilizing over 450 MUg mL-1. Based on the 16S rRNA gene sequence analysis SCAUK0330 was identified as Burkholderia cepacia. SCAUK0330 grew at 10-40 degrees C and pH 4.0-10.0, tolerated up to 5% NaCl, and showed antagonism against nine pathogenic fungi. SCAUK0330 promoted the growth of both healthy and Helminthosporium maydis infected maize plants, indicating that the isolate was a good candidate to be applied as a biofertilizer and a biocontrol agent under a wide range of environmental conditions.The expression of a single SCAUK0330 gene gave E. coli a pH decrease linked ability to solubilize phosphate. The nucleotide and the deduced amino acid sequences of this phosphate solubilization linked gene showed high degree of sequence identity with B. cepacia E37gabY. The production of gluconic acid is considered as the principle mechanism for phosphate solubilization. In agreement with the proposed periplasmic location of the gluconic acid production, the predicted signal peptide and transmembrane regions implied that GabY is membrane bound. PMID- 23932331 TI - Definition and evaluation of mucosal healing in clinical practice. AB - Since the introduction of biological therapy, endoscopic and histological remission, i.e. mucosal healing, has become an important therapeutic goal in Crohn's Disease and Ulcerative Colitis. Mucosal healing is associated with lower rates of hospitalization and surgery, although its role in preventing progression and changing the natural history of the disease has not been clearly demonstrated. A precise definition of mucosal healing has not yet been established, although the concept used in clinical trials is the "complete absence of all inflammatory and ulcerative lesions in all segments of gut" at endoscopy. This definition does not include mucosal improvement and does not distinguish among grades of mucosal healing. In both Crohn's Disease and Ulcerative Colitis trials, several qualitative and quantitative numeric endoscopic indices have been proposed to measure and distinguish endoscopic changes. In addition, the microscopic features associated with inflammatory bowel diseases are considerably modified by the course of the disease and the treatments adopted. However, it is not yet clear whether microscopic healing should be a primary endpoint in clinical trials. In this paper we discuss endoscopic and histological findings and the limitations of the endoscopic and histological indices as a basis for a standardised diagnosis of mucosal healing. PMID- 23932332 TI - The genetics of insomnia--evidence for epigenetic mechanisms? AB - Sleep is a complex physiological process and still remains one of the great mysteries of science. Over the past 10 y, genetic research has provided a new avenue to address the regulation and function of sleep. Gene loci that contribute quantitatively to sleep characteristics and variability have already been identified. However, up to now, a genetic basis has been established only for a few sleep disorders. Little is yet known about the genetic background of insomnia, one of the most common sleep disorders. According to the conceptualisation of the 3P model of insomnia, predisposing, precipitating and perpetuating factors contribute to the development and maintenance of insomnia. Growing evidence from studies of predisposing factors suggests a certain degree of heritability for insomnia and for a reactivity of sleep patterns to stressful events, explaining the emergence of insomnia in response to stressful life events. While a genetic susceptibility may modulate the impact of stress on the brain, this finding does not provide us with a complete understanding of the capacity of stress to produce long-lasting perturbations of brain and behaviour. Epigenetic gene-environment interactions have been identified just recently and may provide a more complex understanding of the genetic control of sleep and its disorders. It was recently hypothesised that stress-response-related brain plasticity might be epigenetically controlled and, moreover, several epigenetic mechanisms have been assumed to be involved in the regulation of sleep. Hence, it might be postulated that insomnia may be influenced by an epigenetic control process of both sleep mechanisms and stress-response-related gene-environment interactions having an impact on brain plasticity. This paper reviews the evidence for the genetic basis of insomnia and recent theories about epigenetic mechanisms involved in both sleep regulation and brain-stress response, leading to the hypothesis of an involvement of epigenetic mechanisms in the development and maintenance of insomnia. PMID- 23932333 TI - Biodiversity and clinico-demographic characteristics of human rhinoviruses from hospitalized children with acute lower respiratory tract infections in Malaysia. AB - BACKGROUND: There is accumulating evidence that human rhinovirus (HRV) causes acute lower respiratory tract infections (ALRTI). Recently, HRV-C was identified as a new species of HRV, but its spectrum of clinical disease is not well understood. OBJECTIVES: We investigated the molecular epidemiology, demographic and clinical characteristics of HRVs among hospitalized children with ALRIs. STUDY DESIGN: One hundred and sixty-five nasopharangeal aspirates taken from children <5 years hospitalized with ALRTIs in Serdang Hospital, Malaysia, were subject to reverse transcriptase-PCR for HRV. Phylogenetic analysis on VP4/VP2 and 5'-NCR regions was used to further characterize HRV. Other respiratory viruses were also investigated using semi-nested multiplex RT-PCR assay. Clinical parameters were analyzed between HRV, RSV and IFV-A mono-infections and between HRV species. RESULTS: HRV was detected in 54 (33%) patients for both single (36 samples) and multiple (18 samples) infections, 61.1% (22/36) represents HRV-A strains while the remaining 14 HRV-C. Strain P51 was the first reported representative of HRV98. The majority of the single HRV cases were in the second half of infancy; HRV-C occurred among older children compared with HRV-A. HRV children were admitted significantly earlier and less febrile than RSV and IFV-A infection. HRV-C infected children were more likely to have rhonchi and vomiting as compared to HRV-A. Pneumonia was the most common discharge diagnosis followed by bronchiolitis and post-viral wheeze in HRV patients. CONCLUSION: Our study showed high prevalence of HRVs and detection of HRV-C among hospitalized children with ALRTIs in Malaysia. Analysis of clinical parameters suggested specific features associated with HRVs infections and specific HRV groups. PMID- 23932334 TI - Molecular epidemiology of norovirus strains in Paraguayan children during 2004 2005: description of a possible new GII.4 cluster. AB - BACKGROUND: Noroviruses (NoV) have been shown to be an important cause of morbidity and mortality in children worldwide, only second after Group A rotaviruses (RVA). In Paraguay, acute gastroenteritis (AGE) is the third cause of mortality in children <=5 years old. OBJECTIVES: To analyze the presence and diversity of NoV in Paraguayan children <=5 years old presenting AGE. STUDY DESIGN: Three hundred seventy eight fecal samples, negative for pathogenic bacteria and RVA, were collected from children admitted as ambulatory and hospitalized patients in a large private hospital from Asuncion, Paraguay from 2004 to 2005. The presence and diversity of NoV was determined by two different RT-PCR strategies and nucleotide sequencing. RESULTS: One hundred and sixty one samples were positive for NoV by partial amplification of the viral polymerase gene (RdRp). No seasonality or differences in the viral prevalence for the different age-groups were detected. GII and GI NoVs were associated to 58% and 42% of the infections, respectively. The genotype was determined in 18% (29/161) NoV-positive samples. The genotypes detected were: GII.4 (18%), GII.17 (18%), GII.6 (14%), GII.7 (14%), GII.3 (10%), GII.5 (3%), GII.8 (3%), GII.16 (3%), GI.3 (14%) and GI.8 (3%). Amplification of the ORF2 from the GII.4 strains showed the presence of a new GII.4 variant. CONCLUSIONS: The results showed a continuous circulation of NoV in children throughout the two years of study and an extensive diversity of genotypes co-circulating, highlighting the need for better surveillance of NoV in Paraguayan children. PMID- 23932335 TI - Hormone receptor loss in endometrial carcinoma curettage predicts lymph node metastasis and poor outcome in prospective multicentre trial. AB - BACKGROUND: Preoperative histologic examination of tumour tissue is essential when deciding if endometrial cancer surgery should include lymph node sampling. We wanted to investigate if biomarkers could improve prediction of lymph node metastasis and outcome. PATIENTS AND METHODS: Curettage specimens from 832 endometrial carcinoma patients prospectively recruited from 10 centres in the MoMaTEC trial (Molecular Markers in Treatment of Endometrial Cancer) were investigated for hormone receptor and p53 status. RESULTS: Eighteen per cent of tumours were double negative for oestrogen- and progesterone receptors (ER/PR loss), 24% overexpressed p53. Pathologic expression of all markers correlated with nodal metastases, high FIGO (Federation International of Gynecology and Obstetrics) stage, non-endometrioid histology, high grade and poor prognosis (all P<0.001). ER/PR loss independently predicted lymph node metastasis (odds ratios (OR) 2.0, 95% confidence interval (CI) 1.1-3.7) adjusted for preoperative curettage histology and predicted poor disease-specific survival adjusted for age, FIGO stage, histologic type, grade and myometrial infiltration (hazard ratio (HR) 2.3, 95% CI 1.4-3.9). For lymph node negative endometrioid tumours, ER/PR loss influenced survival independent of grade. CONCLUSION: Double negative hormone receptor status in endometrial cancer curettage independently predicts lymph node metastasis and poor prognosis in a prospective multicentre setting. Implementing hormone receptor status to improve risk-stratification for selecting patients unlikely to benefit from lymphadenectomy seems justified. PMID- 23932336 TI - The exponentiated exponential mixture and non-mixture cure rate model in the presence of covariates. AB - This paper presents estimates for the parameters included in long-term mixture and non-mixture lifetime models, applied to analyze survival data when some individuals may never experience the event of interest. We consider the case where the lifetime data have a two-parameters exponentiated exponential distribution. The two-parameter exponentiated exponential or the generalized exponential distribution is a particular member of the exponentiated Weibull distribution introduced by [31]. Classical and Bayesian procedures are used to get point and confidence intervals of the unknown parameters. We consider a general survival model where the scale, shape and cured fraction parameters of the exponentiated exponential distribution depends on covariates. PMID- 23932337 TI - Complex congenital abdominal wall hypoplasia repaired with PTFE mesh using an abdominoplasty approach. PMID- 23932338 TI - Differences in time to disease progression do not predict for cancer-specific survival in patients receiving immediate or deferred androgen-deprivation therapy for prostate cancer: final results of EORTC randomized trial 30891 with 12 years of follow-up. AB - BACKGROUND: Trials assessing the benefit of immediate androgen-deprivation therapy (ADT) for treating prostate cancer (PCa) have often done so based on differences in detectable prostate-specific antigen (PSA) relapse or metastatic disease rates at a specific time after randomization. OBJECTIVE: Based on the long-term results of European Organization for Research and Treatment of Cancer (EORTC) trial 30891, we questioned if differences in time to progression predict for survival differences. DESIGN, SETTING, AND PARTICIPANTS: EORTC trial 30891 compared immediate ADT (n=492) with orchiectomy or luteinizing hormone-releasing hormone analog with deferred ADT (n=493) initiated upon symptomatic disease progression or life-threatening complications in randomly assigned T0-4 N0-2 M0 PCa patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to first objective progression (documented metastases, ureteric obstruction, not PSA rise) and time to objective castration-resistant progressive disease were compared as well as PCa mortality and overall survival. RESULTS AND LIMITATIONS: After a median of 12.8 yr, 769 of the 985 patients had died (78%), 269 of PCa (27%). For patients receiving deferred ADT, the overall treatment time was 31% of that for patients on immediate ADT. Deferred ADT was significantly worse than immediate ADT for time to first objective disease progression (p<0.0001; 10-yr progression rates 42% vs 30%). However, time to objective castration-resistant disease after deferred ADT did not differ significantly (p=0.42) from that after immediate ADT. In addition, PCa mortality did not differ significantly, except in patients with aggressive PCa resulting in death within 3-5 yr after diagnosis. Deferred ADT was inferior to immediate ADT in terms of overall survival (hazard ratio: 1.21; 95% confidence interval, 1.05-1.39; p [noninferiority]=0.72, p [difference] = 0.0085). CONCLUSIONS: This study shows that if hormonal manipulation is used at different times during the disease course, differences in time to first disease progression cannot predict differences in disease-specific survival. A deferred ADT policy may substantially reduce the time on treatment, but it is not suitable for patients with rapidly progressing disease. PMID- 23932339 TI - New phenstatin-fatty acid conjugates: synthesis and evaluation. AB - New phenstatin-fatty acid conjugates have been synthesized and tested against the KB-3-1, H460, MCF-7 and HEK293 cell lines, with an increase in anti-proliferative activity being observed at the micro-molar level paralleling an increase in un saturation in the fatty acid component. PMID- 23932340 TI - A new strategy for the synthesis of crucigasterin A, and cytotoxic activity of this compound and its related analogues. AB - Stereoselective total synthesis of bioactive marine natural product crucigasterin A has been accomplished from commercially available and inexpensive L-(-)-malic acid as a starting material. Julia olefination and chelation controlled Grignard additions are the key steps involved in the present synthesis. Cytotoxic properties of crucigasterin A and its related analogues crucigasterins B and D have been evaluated. Crucigasterin A showed promising activities against both the human cervical cancer cell line and human breast adenocarcinoma cell line. PMID- 23932341 TI - It may take more than a shot: alternatives to immunotherapy for Alzheimer's disease. PMID- 23932343 TI - Refining the clinical presentation of the C9ORF72 hexanucleotide repeat expansion. PMID- 23932342 TI - Functional connectivity in Alzheimer's disease: measurement and meaning. PMID- 23932344 TI - Giant aneurysm of saphenous vein graft to right coronary artery. PMID- 23932345 TI - Recurrent sustained ventricular tachycardia, hypertrophic cardiomyopathy, and apical aneurysm: electroanatomic map-guided surgical ablation and left ventricular restoration. PMID- 23932346 TI - Geoepidemiology of primary sclerosing cholangitis: a critical review. AB - Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin, characterized by progressive destruction of bile ducts caused by diffuse inflammation and fibrosis. Previous epidemiological studies in Northern Europe and North America demonstrated that incidence and prevalence rates are ranging from 0.5 to 1.3 and from 3.85 to 16.2 per 100,000 inhabitants per year, respectively. It is of note that the incidence of PSC appears to be gradually increasing. We have extensively reviewed the geoepidemiology of PSC and attempted to place it in context with the incidence in Japan. In 2012, the clinical diagnostic criteria of IgG4-SC were established and published by the Japan Biliary Association, rendering it possible for physicians to clinically differentiate PSC from IgG4-SC. We conducted a new nationwide survey for PSC as well as IgG4-SC, and have identified 197 patients with PSC and 43 patients with IgG4-SC without pancreatic involvement. In this survey we estimated prevalence rate of PSC in Japan as 0.95, lower than those in North America and European countries. Also we identified other unique features of Japanese PSC patients, including 2 peaks in age distribution at diagnosis and fewer presences of comorbid inflammatory bowel diseases, occurring in only 34% of PSC. This data is placed in the perspective of the international experience on PSC. PMID- 23932348 TI - Antiangiogenic behaviours of heparin derivatives may effect survival in lung cancer. PMID- 23932349 TI - Comparison of the effect of edoxaban, a direct factor Xa inhibitor, with a direct thrombin inhibitor, melagatran, and heparin on intracerebral hemorrhage induced by collagenase in rats. AB - INTRODUCTION: Intracerebral hemorrhage (ICH) is a major clinical concern with anticoagulation therapy. The effect of a new oral direct FXa inhibitor, edoxaban, was determined in a rat model of ICH and compared with a direct thrombin inhibitor, melagatran, and heparin. METHODS: To induce ICH, 0.1 U collagenase type VII was injected into the striatum of male Wistar rats under anesthesia with thiopental or halothane. Immediately after ICH induction, edoxaban, melagatran, or heparin were infused intravenously. Five hours after ICH induction, the brain was removed and ICH size was measured. To estimate the margin of safety, antithrombotic effects were evaluated in a rat venous thrombosis model. RESULTS: Edoxaban at 6mg/kg/h significantly increased ICH volume (1.8-fold) and prolonged prothrombin time (PT) 2.8-fold compared to the vehicle group. No deaths were observed with edoxaban. Melagatran at 1mg/kg/h increased ICH volume at 1mg/kg/h (2.8-fold) with 6.1-fold PT prolongation. At 3mg/kg/h, all rats died due to severe ICH (3.9-fold). Heparin at both 100 and 500U/kg/h significantly increased ICH. At 500U/kg/h, 5 out of 8 rats died. The doses required for 50% inhibition of thrombosis of edoxaban, melagatran, and heparin were 0.045mg/kg/h, 0.14mg/kg/h, and 55U/kg/h, respectively. The safety margins between antithrombotic and ICH exacerbation effects of these anticoagulants were 133, 7.1, and 1.8, respectively. CONCLUSION: The safety margin of edoxaban was wider than that of melagatran or heparin. These results suggest that edoxaban may be preferable from the perspective of ICH exacerbation risk. PMID- 23932347 TI - A multicenter observational study on the role of comorbidities in the recurrent episodes of benign paroxysmal positional vertigo. AB - OBJECTIVE: Primary objective of this study was to find a statistical link between the most worldwide comorbidities affecting the elderly population (hypertension, diabetes, osteoarthrosis, osteoporosis and depression) and recurrent episodes of BPPV. Secondary objective was defining possible "groups of risk" for people suffering recurrent positional vertigo related to the presence of a well documented comorbidity. METHODS: This was an observational, cross-sectional, multicenter, spontaneous, non-pharmacological study. The data of 1092 patients suffering BPPV evaluated in 11 different Departments of Otolaryngology, Otoneurology and Neurology, referring Centers for positional vertigo evaluation, were retrospectively collected. RESULTS: Regarding evaluated comorbidities (hypertension, diabetes, osteoarthrosis, osteoporosis and depression), data analysis showed the presence of at least one comorbid disorder in 216 subjects (19.8%) and 2 or more in 408 subjects (37.4%). Moreover there was a statistical significant difference between the number of comorbidities and the number of recurrences, otherwise said as comorbidity disorders increased the number of relapses increased too. CONCLUSION: The presence of a systemic disease may worsen the status of the posterior labyrinth causing a more frequent otolith detachment. This condition increases the risk for patients suffering BPPV to have recurrent episodes, even if correctly managed by repositioning maneuvers. The combination of two or more of aforementioned comorbidities further increases the risk of relapsing BPPV, worsened by the presence of osteoporosis. On the basis of this results it was possible to define "groups of risk" useful for predicting BPPV recurrence in patients with one or more comorbidity. PMID- 23932350 TI - Bronchopulmonary dysplasia: the earliest and perhaps the longest lasting obstructive lung disease in humans. AB - Bronchopulmonary dysplasia (BPD) is one of the most important sequelae of premature birth and the most common form of chronic lung disease of infancy. From a clinical standpoint BPD subjects are characterized by recurrent respiratory symptoms, which are very frequent during the first years of life and, although becoming less severe as children grow up, they remain more common than in term born controls throughout childhood, adolescence and into adulthood. From a functional point of view BPD subjects show a significant airflow limitation that persists during adolescence and adulthood and they may experience an earlier and steeper decline in lung function during adulthood. Interestingly, patients born prematurely but not developing BPD usually fare better, but they too have airflow limitations during childhood and later on, suggesting that also prematurity per se has life-long detrimental effects on pulmonary function. For the time being, little is known about the presence and nature of pathological mechanisms underlying the clinical and functional picture presented by BPD survivors. Nonetheless, recent data suggest the presence of persistent neutrophilic airway inflammation and oxidative stress and it has been suggested that BPD may be sustained in the long term by inflammatory pathogenic mechanisms similar to those underlying COPD. This hypothesis is intriguing but more pathological data are needed. A better understanding of these pathogenetic mechanisms, in fact, may be able to orient the development of novel targeted therapies or prevention strategies to improve the overall respiratory health of BPD patients. PMID- 23932351 TI - Culture as a predictor of resistance to change: a study of competing values in a psychiatric nursing context. AB - It is well known that a conservative organizational culture can hinder the implementation of new organizational models. Prior to introducing something new it is important to identify the culture within the organization. This paper sets out to detect the feasibility of reform in a psychiatric clinic in a Swedish hospital prior to implementation of a new working method - a structured tool based on the International Classification of Functioning Disability and Health. A survey consisting of two instruments - an organizational values questionnaire (OVQ) and a resistance to change scale (RTC) - was distributed to registered and assistant nurses at the clinic. The association between the organizational subcultures and resistance to change was investigated with regression analysis. The results revealed that the dominating cultures in the outpatient centers and hospital wards were characterized by human relation properties such as flexibility, cohesion, belongingness, and trust. The mean resistance to change was low, but the subscale of cognitive rigidity was dominant, reflecting a tendency to avoid alternative ideas and perspectives. An instrument like the one employed in the study could be a useful tool for diagnosing the likelihood of extensive and costly interventions. PMID- 23932352 TI - Thigh compartment syndrome in urban trauma: bullets to blame, not collisions. AB - BACKGROUND: Compartment syndrome of the thigh is a surgical emergency rarely reported in the literature. The most common etiologies include blunt trauma, vascular injuries from penetrating trauma, and hematoma formation. Thigh compartment syndrome (TCS) is important as it is often associated with concomitant severe injury with mortality rates as high as 47%. This study aims to identify mechanisms of injury, clinical presentation, and outcomes associated with TCS in the urban trauma patient population. METHODS: Demographic and clinical information for all patients with a diagnosis of TCS at a level 1 urban trauma center over a 10.5-y period were reviewed. Collected data included age, sex, mechanism of injury, method of diagnosis, time taken for diagnosis and management, methods of decompression, wound management, lengths of stay in the intensive care unit and hospital, amputation rate, and hospital disposition. RESULTS: Ten patients were identified with diagnosis of TCS. The mechanism of injury was penetrating in six patients and blunt in four. The mean time from injury to diagnosis was 23.4 h. Intensive care unit and hospital lengths of stay were significantly increased among patients sustaining penetrating injuries compared with blunt injuries. Two of the six penetrating injury patients underwent an amputation. Eight of 10 patients were ambulatory on discharge. There were no mortalities. CONCLUSIONS: Among urban trauma patients, penetrating injuries of the thigh and adjacent vascular structures and the need for decompressive fasciotomy of the lower leg are the major risk factors for TCS. Clinical diagnosis and early intervention with fasciotomy remain the mainstay of treatment. PMID- 23932353 TI - The manner of the inflammation-boosting effect caused by acute hyperglycemia secondary to overfeeding and the effects of insulin therapy in a rat model of sepsis. AB - BACKGROUND: The aim of the study was to investigate both the inflammation boosting effect and the metabolic stress induced by acute hyperglycemia secondary to overfeeding with excessive glucose infusion and the effects of insulin therapy on those events in a rat model of sepsis. MATERIALS AND METHODS: Sprague-Dawley rats underwent cecal ligation and puncture (CLP) or sham operation. Preestablished continuous intravenous glucose infusion was initiated immediately after surgery. First, rats with CLP-inducing sepsis were divided into three groups on the basis of the target blood glucose (BG) levels: high glucose (HG) group (overfed, >300 mg/dL), moderate glucose group (moderate hyperglycemia, 200 300 mg/dL), and no glucose group (100-150 mg/dL). The sham group received the same glucose infusion as that of the HG group. BG and plasma interleukin (IL) 6 levels were monitored over time. All rats were sacrificed 9 h after surgery to evaluate lung histology and measure hepatic total glutathione and malondialdehyde contents. Based on the results, the high glucose and insulin (HI) group was added to septic groups as a model of insulin therapy, in which insulin with the same HG dose as that in the HG group was administered to maintain moderate hyperglycemia. RESULTS: BG level in all groups remained in the preestablished target range throughout the experiment. Plasma IL-6 level in all septic groups increased in a time-dependent manner, whereas that in the sham group with moderate hyperglycemia hardly increased. Nine hours after CLP, plasma IL-6 level in the HG group rose to 7407.5 +/- 1987.3 pg/mL, which was three times higher than that in the other septic groups. There was no significant difference among moderate glucose, no glucose, and HI groups, in which BG level remained constant at <300 mg/dL. The HG group showed the worst consequences of lung injury and oxidative stress in the liver, which were completely stable in HI group. CONCLUSIONS: Acute severe hyperglycemia in critical illness might excessively boost the existing systemic inflammatory response in a threshold-based manner. Insulin therapy under overfeeding could strongly inhibit such a boosting effect and oxidative stress in the liver. PMID- 23932354 TI - Focal task-specific lower extremity dystonia associated with intense repetitive exercise: a case series. AB - BACKGROUND: Focal task-specific dystonia of the lower extremity associated with intense repetitive exercise has recently been recognized. The clinical course, treatment response and prognosis remain poorly understood. METHODS: Individuals with lower extremity task-specific dystonia evaluated at UCSF's Movement Disorders Center (2004-2012) were eligible for this descriptive case study series if he/she had a history of strenuous and prolonged exercise involving the lower extremity and had no abnormal neurological or medical conditions to explain the involuntary movements. Data was gathered from the medical history and a self report questionnaire. The findings were compared to 14 cases previously reported in the literature. RESULTS: Seven cases (4M/3F) were identified with a diverse set of exercise triggers (cycling, hiking, long-distance running, drumming). The mean age of symptom onset was 53.7 +/- 6.1 years. The median symptom duration prior to diagnosis was 4 (9.5) years. Several patients underwent unnecessary procedures prior to being appropriately diagnosed. Over a median of 2 (3.5) years, signs and symptoms progressed to impair walking. Seven patients had improvement in gait with treatment (e.g. botulinum toxin injections, benzodiazepines, physical therapy, bracing, body weight supported gait training and/or functional electrical stimulation of the peroneal nerve) and six returned to a reduced intensity exercise routine. CONCLUSIONS: Isolated lower extremity dystonia associated with strenuous, repetitive exercise is relatively uncommon, but disabling and challenging to treat. The pathophysiology may be similar to task-specific focal dystonias of the upper limb. Prompt recognition of leg dystonia associated with extreme exercise could minimize unnecessary testing and procedures, and facilitate earlier treatment. PMID- 23932355 TI - Biophysical science in Italy: SIBPA turns 40. AB - This Special Issue of Biophysical Chemistry includes a selection of the papers presented at the XXI Congress of the Italian Society of Pure and Applied Biophysics (i.e., SIBPA, Societa Italiana di Biofisica Pura ed Applicata) held on September 2012 at the University of Ferrara, Ferrara, Italy. Topics cover all biophysical disciplines, from molecular to cellular, to integrative biophysics giving an almost comprehensive view of the interdisciplinary and multidisciplinary approaches, proper of the modern biophysics. SIBPA, which celebrates its 40th anniversary in 2013, has steadily grown and appeals to both specialists and a wider general audience. PMID- 23932356 TI - Hematogones: an overview. AB - Hematogones were initially described as mysterious cells in bone marrow smears more than 70 years ago. These cells are normal bone marrow B-lymphocyte precursors with properties that overlap those of lymphoblasts. Their morphological and immunological features are described here with an update on the knowledge of hematogones in hematological and non-hematological disorders. PMID- 23932357 TI - Increase in stearidonic acid by increasing the supply of histidine to oleaginous Saccharomyces cerevisiae. AB - Increasing concentration of histidine significantly increased stearidonic acid production and cell growth in oleaginous Saccharomyces cerevisiae that has been genetically modified by Deltasnf2 disruption, DGA1 and Delta6 desaturase gene overexpression, and LEU2 expression. High concentration of histidine in wild-type transformant and HIS3 expression in Deltasnf2 transformant also increased stearidonic acid. PMID- 23932358 TI - Evaluation of internally illuminated photobioreactor for improving energy ratio. AB - The internally illuminated photobioreactor (IIPBR) design has been shown to be more efficient in utilizing the incident light energy than the externally illuminated designs. This study evaluated (i) optimal sparging of the IIPBR with CO2-enriched air (CEA) to enhance biomass productivity; and, (ii) single-stage and two-stage operation of the IIPBR to enhance lipid productivity. Growth data from two algal cultures-Scenedesmus sp. and Nannochloropsis salina, cultivated in an 18-L prototype version of the IIPBR were used to establish the optimal conditions for the two goals in terms of the energy ratio. Based on the optimized results under sparging with CEA, the energy ratio in the IIPBR in the first stage with Nannochloropsis salina was at least 6 times higher due to optimal performance of the IIPBR at lower energy input than typical literature results for other PBR designs, whereas the energy ratios in the second stage were comparable to literature results. PMID- 23932359 TI - Chemical variation from the neoantimycin depsipeptide assembly line. AB - Here we report the biosynthetic pathway for the neoantimycin and present three novel neoantimycin analogues, neoantimycin D (1), E (2) and F (3), from this assembly system from Streptoverticillium orinoci. Identification of these novel neoantimycin variants was achieved by selective MS/MS interrogation of natural product extracts using diagnostic fragments of the known neoantimycins. Their structures, including the absolute configurations, were elucidated using a combination of NMR experiments, detailed MS/MS experiments and the advanced Marfey's method. The biosynthetic pathway of neoantimycin was dissected by genome sequencing data analysis for the first time, which includes a hybrid nonribosomal peptide synthetase (NRPS) and polyketide synthetase (PKS) assembly lines. PMID- 23932360 TI - Identification of fragments targeting an alternative pocket on HIV-1 gp41 by NMR screening and similarity searching. AB - The HIV-1 envelope glycoprotein gp41 fusion intermediate is a promising drug target for inhibiting viral entry. However, drug development has been impeded by challenges inherent in mediating the underlying protein-protein interaction. Here we report on the identification of fragments that bind to a C-terminal sub-pocket adjacent to the well-known hydrophobic pocket on the NHR coiled coil. Using a specifically designed assay and ligand-based NMR screening of a fragment library, we identified a thioenylaminopyrazole compound with a dissociation constant of ~500 MUM. Interaction with the C-terminal sub-pocket was confirmed by paramagnetic relaxation enhancement NMR experiments, which also yielded the binding mode. Shape-based similarity searching detected additional phenylpyrazole and phenyltriazole fragments within the library, enriching the hit rate over random screening, and revealing molecular features required for activity. Discovery of the novel scaffolds and binding mechanism suggests avenues for extending the interaction surface and improving the potency of a hydrophobic pocket binding inhibitor. PMID- 23932361 TI - One-pot synthesis and cytotoxicity studies of new Mannich base derivatives of polyether antibiotic--lasalocid acid. AB - Seven Mannich base derivatives of polyether antibiotic Lasalocid acid (2a-2g) were synthesized and screened for their antiproliferative activity against various human cancer cell lines. A novel chemoselective one-pot synthesis of these Mannich bases was developed. Compounds 2a-2c and 2g with sterically smaller dialkylamine substituent, displayed potent antiproliferative activity (IC50: 3.2 7.3 MUM), and demonstrated higher than twofold selectivity for specific type of cancer. The nature of Mannich base substituent on C-2 atom at the aromatic ring may be critical in the search for selectivity towards a particular cancer cell. PMID- 23932362 TI - Response to dasatinib in a patient with SQCC of the lung harboring a discoid receptor-2 and synchronous chronic myelogenous leukemia. AB - We report a patient with squamous cell carcinoma (SQCC) of the lung and a discoid receptor-2 (DDR2) kinase domain mutation that responded to dasatinib treatment. Our case report is consistent with previous publications suggesting that DDR2 mutation may confer sensitivity to dasatinib. PMID- 23932363 TI - Diagnostic method for the detection of KIF5B-RET transformation in lung adenocarcinoma. AB - KIF5B-RET fusions have recently been reported to occur in pulmonary adenocarcinomas, thereby being proposed as a novel genetic alteration in adenocarcinoma of the lung. However, clinically useful methods to detect RET rearrangement in pulmonary adenocarcinoma have not been well established. 53 cases of lung adenocarcinomas harbored "triple (EGFR, KRAS and ALK)-negative" were tested for KIF5B-RET fusions using whole-transcriptome sequencing, fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and long range PCR. Dual color break-apart probes and KIF5B-RET fusion probes were used for FISH. Three different commercial antibodies against C-terminal RET protein were tested for IHC. Primers designed for 3 different variants of KIF5B-RET fusions were used for long-range PCR. Three patients (5.6%) showed RET rearrangement in whole-transcriptome sequencing, which were used as a gold standard. All those three patients were also positive in FISH for both KIF5B-RET fusion and RET break-apart probes. None of remaining patients showed positive result, resulting in 100% concordance rate of FISH and transcriptome sequencing methods. However, fused RET proteins were not detected by IHC in none of true positive patients. Moreover, 6 patients without RET fusions showed gain of gene copy number of both KIF5B and RET. All those three true positive cases were detected by long-range PCR methods and none with true negative cases were positive. Both FISH and PCR may be useful methods to detect novel KIF5B-RET rearrangements in pulmonary adenocarcinomas rather than IHC. However, as there may be additional variant of fusion mutation, FISH may be better than PCR method in terms of sensitivity. PMID- 23932364 TI - High expression of SNIP1 correlates with poor prognosis in non-small cell lung cancer and SNIP1 interferes with the recruitment of HDAC1 to RB in vitro. AB - The Rb tumor suppressor gene performs a critical role in controlling cell proliferation and tumorigenesis; it recruits HDAC1 protein into the E2F complexes to repress transcription. In this study, we demonstrate that SNIP1, RB and HDAC1 were significantly expressed in same lung cancer tissues in a tissue microarray (TMA) containing 300 non-small cell lung cancers (NSCLC). High expression level of SNIP1 in tumor patients was significantly correlated with poor prognosis in NSCLC (log-rank P for OS = 0.01, log-rank P for DFS = 0.001). Functionally, SNIP1 competes with HDAC1 for binding to RB and reduces HDAC activity in vitro. Knockdown of SNIP1 reduced colony formation ability of lung cancer cells. These findings may indicate the involvement of SNIP1 in progression of lung cancer by regulating the RB/HDAC1 interaction. PMID- 23932365 TI - Reproducibility of the effects of theta burst stimulation on motor cortical plasticity in healthy participants. AB - OBJECTIVE: Theta-burst stimulation (TBS) is a repetitive transcranial magnetic stimulation (TMS) protocol, capable of enhancing or suppressing the amplitude of contralateral motor-evoked potentials (MEP) for several minutes after stimulation over the primary motor cortex. Continuous TBS (cTBS) produces a long-term depression (LTD)-like reduction of cortical excitability. The purpose of this study was to assess the test-retest reproducibility of the effects of cTBS and to investigate which neurophysiologic markers of cTBS-induced plasticity are most reproducible. METHODS: In ten healthy participants we evaluated in two different sessions the effects of cTBS (using AP-PA current direction, opposite to most commercial rTMS stimulators) on MEPs induced by single-pulse suprathreshold TMS (using AP-PA or PA current direction) over left motor cortex in the first dorsal interosseus (FDI) muscle. RESULTS: Results demonstrate that the marker of cTBS induced-plasticity with highest within-subject reproducibility is the modulation of corticospinal excitability measured 5min after cTBS. CONCLUSION: Overall the effects of cTBS modulation show limited test-retest reproducibility and some measures of the cTBS effects are more reproducible than others. SIGNIFICANCE: Studies comparing cTBS effects in healthy subjects and patients need to proceed with care. Further characterization of the effects of TBS and identification of the best metrics warrant future studies. PMID- 23932366 TI - Clinical characteristics of children and adults hospitalized for influenza virus infection. AB - BACKGROUND/PURPOSE: Influenza infection has different clinical presentations and outcomes in children and adults, and bacterial coinfection is associated with significantly higher morbidity and mortality. This study compared the clinical features in children and adults hospitalized for influenza virus infection and the role of concomitant bacteremia. METHODS: A retrospective observational cohort study was conducted by a review of medical records of all consecutive patients admitted for influenza infection between April 1, 2009 and February 28, 2011. RESULTS: Of the 1203 patients, 76.2% were children, and ranged in age from 1 month to 99 years, with a mortality of 3.1% for adults; no children died. Pneumonia, acute respiratory distress syndrome, acute respiratory failure, septic shock, and cardiovascular complications were more common in adults. Bacteremia was more common in adults than in children (3.5% vs. 0.4%). C-reactive protein (CRP) > 4 mg/dL and a longer hospital stay occurred more often in children with bacteremia than in the group without bacteremia. In adults with bacteremia, acute respiratory failure, septic shock, and cardiovascular complications were more common, with a mortality of 50% versus 1.4% compared with those without bacteremia, and thrombocytopenia and increased CRP were independent risk factors. Using receiver operating characteristic analysis, CRP >= 14 mg/dL had a sensitivity of 90.0% and a specificity of 80.0%. CONCLUSION: Influenza infection in adults is associated with increased risk of complications, bacteremia, and mortality compared with that in children. Bacteremia in adults with influenza is associated with increased complications and mortality; thrombocytopenia and elevated CRP levels could identify those at risk. PMID- 23932367 TI - Elevated serum ApoE levels are associated with bacterial infections in pediatric patients. AB - BACKGROUND/PURPOSE(S): We aimed to determine the variations in serum apolipoprotein E (ApoE) levels in pediatric patients with a variety of infectious diseases, and to investigate the potential mechanism of elevated ApoE serum levels during infection. METHODS: A total of 279 pediatric patients with a variety of infections and 58 normal controls were enrolled in this study. Serum ApoE levels were detected using an immunoturbidimetric assay. A mouse sepsis model was established to evaluate the expression of ApoE and its receptors by real-time polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: Serum ApoE was markedly increased in cases with bacterial infections including sepsis, bacterial meningitis, and bacterial pneumonia, compared to healthy controls. No significantly elevated serum ApoE levels were observed in aseptic meningitis patients or mycoplasma pneumonia patients. The mice sepsis models showed a similar pattern of increased serum ApoE levels in the early stage of infections. We found reduced expression of ApoE and its receptors in the liver tissues in these mice models. CONCLUSION: Serum ApoE may represent a novel indicator for diagnosis of bacterial infections, especially sepsis, in pediatric patients. The decreased expression of low-density lipoprotein receptor (LDLR), LDL receptor related protein (LRP), and heparin sulfate proteoglycan (HSPG) syndecan-1 (SDC1) may contribute to reduced ApoE clearance and accumulation in the blood. PMID- 23932368 TI - Identification of cytochrome P450s involved in the metabolism of arachidonic acid in human platelets. AB - Although cytochrome P450s (CYPs) have been identified in most human cells, identification of CYPs in human platelets remains poorly explored. CYP expressions in human platelets were screened by using reverse transcriptase polymerase chain reaction and western blot analysis followed by functional assays using arachidonic acid (ARA). CYP1A1, 2U1, 2J2, 4A11, 4F2, and 5A1 were expressed as both proteins and mRNAs in platelets. Ethoxyresorufin-O-deethylase activity was observed in platelets and this activity was significantly decreased after treatment with the general P450 inhibitor SKF-525A and the CYP1A inhibitor, alpha naphthoflavone (40-45%, P<0.001). Seventeen ARA metabolites were detected in ARA treated platelets. Among these, the levels of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids were significantly decreased with the treatment of the P450 omega-hydroxylase inhibitor 17-octadecynoic acid (P<0.05-0.001). In summary, multiple ARA-metabolizing P450s were identified in human platelets. These findings may provide an important resource for understanding physiological function of platelet. PMID- 23932369 TI - Sample loading influences studies comparing isoelectric focusing vs. strong cation exchange peptide fractionation. PMID- 23932370 TI - Different headspace solid phase microextraction--gas chromatography/mass spectrometry approaches to haloanisoles analysis in wine. AB - Three approaches in determination of six haloanisoles (2,4,6-trichloroanisole, 2,3,4-trichloroanisole, 2,3,6-trichloroanisole, tetrachloroanisole, pentachloroanisole and 2,4,6-tribromoanisole) in wine were compared. Comprehensive gas chromatography - time of flight mass spectrometry (GC*GC-ToF MS) was described for the first time for this application and compared to gas chromatography-tandem mass spectrometry (GC-MS/MS) using triple quadrupole instrument. These techniques were compared with "standard" analytical approach using GC-MS(SIM). SPME method was developed and used for all separation methods (DVB/PDMS fiber, 70 degrees C, 30%NaCl, 20 min extraction). Extraction dependence on matrix was discussed using model wines with different ethanol contents (8%, 12%, and 18%) as well as water and different wines (dry white, dry red and sweet liqueur), with the lowest sensitivities obtained for highest ethanol contents in model wine and for liqueur wine. Limits of detection for GC*GC-ToF-MS method were 0.09-2.92 ng/L depending on the examined compound and matrix (compared to 0.1-13.3 ng/L obtained using GC/MS(SIM)). For GC-MS/MS method lower detection limits were achieved than for the GC*GC method (0.01-0.1 ng/L), however comprehensive gas chromatography-mass spectrometry provides full spectral information on analyzed compounds. Both methods had limits of detection far below odor thresholds of haloanisoles in wine, good linearity up to 2000 ng/L tested and good precision, what makes them suitable for analysis of these compounds in low ppt levels. PMID- 23932371 TI - Continuous purification of influenza virus using simulated moving bed chromatography. AB - Continuous size exclusion chromatography for the separation of cell culture derived influenza virus from contaminating proteins was established successfully. Therefore, an open loop simulated moving bed (SMB) setup with one column per zone was applied. Several operating conditions were tested and overall trends were found to be in agreement with expectations derived from theory. Furthermore, the separation performance was compared to an optimized conventional batch chromatography. The yield of influenza virus in the product fraction, based on a hemagglutination assay, was 70% (SMB) and 80% (batch), respectively. The amount of contaminating protein per product was 0.61MUgkHAU(-1) (SMB) compared to 0.29MUgkHAU(-1) (batch). This corresponds to a reduction of the respective amount in the feed solution by 60% and 80%, respectively. For both processes, the estimated amount of total protein per vaccine dose would meet the level required for manufacturing of human influenza vaccines prepared in cell cultures. Depending on the strategy chosen for sanitization and equilibration of columns the calculated overall productivity for the SMB process was up to 3.8 times higher compared to the batch mode. SMB, therefore, has the potential to replace single column discontinuous chromatography in order to design more efficient purification trains for production of cell culture-derived influenza vaccines. PMID- 23932372 TI - Selective liquid chromatographic separation of yttrium from heavier rare earth elements using acetic acid as a novel eluent. AB - One of the major difficulties in the rare earth elements separation is purification of yttrium from heavy rare earth elements. Thus, an HPLC method using acetic acid as novel eluent was explored for selective separation of yttrium form the heavy rare earth elements. When acetic acid is used as a mobile phase yttrium eluted with the lighter lanthanides. This is contrary to its relative position amongst heavier lanthanides when eluents commonly used for separation of rare earth elements were employed. The shift in elution position of yttrium with acetic acid as eluent may reflect a relatively lower stability constant of the yttrium-AcOH complex (in the same order as for the lighter lanthanides) compared to the corresponding AcOH complexes with heavy lanthanides, enabling selective separation of yttrium from the latter. The method was successfully used for selective separation of yttrium in mixed rare earth sample containing about 80% of yttrium and about 20% of heavy rare earth oxides. Thus, the use of AcOH as eluent is an effective approach for separating and determining the trace amounts of heavy rare earth elements in large amounts of yttrium matrix. Separation was performed on C18 column by running appropriate elution programs. The effluent from the column was monitored with diode array detector at absorbance wavelength of 658nm after post column derivatization with Arsenazo III. PMID- 23932373 TI - Analysis of the unsaponifiable fraction of lipids belonging to various milk-types by using comprehensive two-dimensional gas chromatography with dual mass spectrometry/flame ionization detection and with the support of high resolution time-of-flight mass spectrometry for structural elucidation. AB - The present investigation is focused on the use of a comprehensive two dimensional GC (GC*GC) method, with dual mass spectrometry/flame ionization detection (MS/FID), for the qualitative and quantitative analysis of the unsaponifiable fraction of milk lipids (cow butter, buffalo, ewe, and goat milks). The structure of many constituents (particularly sterols) was confirmed by using GC-high resolution time-of-flight MS. The GC*GC column set used consisted of a low-polarity first dimension, and a medium-polarity secondary one, both characterized by a high thermal stability. The use of dual detection enabled the attainment of both mass spectral information and relative % FID data. The complexity of the fingerprint, generated by the unsaponifiable fraction, justified the employment of the two-dimensional GC technology. However, it was two other GC*GC characteristics that contributed most to the attainment of promising results, namely sensitivity enhancement and the formation of group-type patterns. Because many milk lipid constituents were not contained in the MS databases employed, exact mass information proved to be valuable for identification purposes. PMID- 23932374 TI - Green chromatography. AB - Analysis of organic compounds in samples characterized by different composition of the matrix is very important in many areas. A vast majority of organic compound determinations are performed using gas or liquid chromatographic methods. It is thus very important that these methods have negligible environmental impact. Chromatographic techniques have the potential to be greener at all steps of the analysis, from sample collection and preparation to separation and final determination. The paper summarizes the approaches used to accomplish the goals of green chromatography. While complete elimination of sample preparation would be an ideal approach, it is not always practical. Solventless extraction techniques offer a very good alternative. Where solvents must be used, the focus should be on the minimization of their consumption. The approaches used to make chromatographic separations greener differ depending on the type of chromatography. In gas chromatography it is advisable to move away from using helium as the carrier gas because it is a non-renewable resource. GC separations using low thermal mass technology can be greener because of energy savings offered by this technology. In liquid chromatography the focus should be on the reduction of solvent consumption and replacement of toxic and environmentally hazardous solvents with more benign alternatives. Multidimensional separation techniques have the potential to make the analysis greener in both GC and LC. The environmental impact of the method is often determined by the location of the instrument with respect to the sample collection point. PMID- 23932375 TI - The value of the progesterone-to-estradiol ratio on the day of hCG administration in predicting ongoing pregnancy and live birth rates in normoresponders undergoing GnRH antagonist cycles. AB - OBJECTIVE: To investigate the relationship of the progesterone-to-estradiol (P/E2) ratio on the day of hCG administration with ongoing pregnancy rates in patients with normal ovarian reserve undergoing GnRH antagonist cycles. STUDY DESIGN: Observational cohort study including 129 women with normal ovarian reserve undergoing the GnRH antagonist protocol at the IVF unit of Ankara University School of Medicine. Receiver operating characteristics (ROC) analysis was performed to determine cut-off values for the P/E2 ratio detrimental to IVF/ICSI-ET outcomes. The ongoing pregnancy rate was the primary outcome measure. Groups were compared using the independent-samples Student's t-test, Mann Whitney and Chi-Square tests. Multivariate logistic regression analysis was used to study the association between the variables and the P/E2 ratio. RESULTS: The optimal cut-off value for P/E2 ratio in GnRH antagonist cycles was 0.48; ongoing pregnancy rates and live birth rates were found to be significantly higher in patients with P/E2 ratios<=0.48 than those with>0.48 (50% vs 22.4%, p=0.001 and 38.5% vs 19.7%, p=0.02, respectively). In logistic regression analysis, the P/E2 ratio was found to be an independent predictor for pregnancy, but the sensitivity (69%), specificity (61%) and overall accuracy (67%) were low as a predictor test for cycle outcome. CONCLUSION: Although a P/E2 ratio<=0.48 on the day of hCG administration was associated with significantly higher ongoing pregnancy and live birth rates, it has poor predictive value for cycle outcome in patients with normal ovarian reserve undergoing GnRH antagonist cycles. PMID- 23932376 TI - Quality of life in patients with endometrial cancer treated with or without systematic lymphadenectomy. AB - OBJECTIVE: To compare the quality of life (QoL) of women affected by endometrial cancer treated with surgery with or without systematic lymphadenectomy. STUDY DESIGN: Consecutive patients affected by stages I and II endometrial cancer and treated with surgery between 2008 and 2011 were selected. Eligible subjects were divided into two groups: Group A consisted of 36 patients who had hysterectomy plus bilateral salpingo-oophorectomy without lymphadenectomy; Group B consisted of 40 patients who had hysterectomy plus salpingo-oophorectomy plus pelvic and aortic lymphadenectomy. The EORTC Quality of Life Questionnaire-Cancer Module (QLQ-C30) and Quality of Life Questionnaire-Endometrial Cancer Module (QLQ-EN24) were administered to selected patients. All data were recorded and then analyzed using the scoring manual of the EORTC Quality of Life Group. RESULTS: Among symptom scales, only lymphedema gave a statistically significant difference among two groups, with a score of 10.64 +/- 17.43 in Group A and 21.66 +/- 24.51 in Group B (p=0.0285). The p value obtained comparing the "Global Health Status" (items 29 and 30) in Group A and in Group B was not statistically significant. CONCLUSION: Lymphadenectomy did not influence negatively global health status, but lymphadenectomy maintained its importance in determining a patient's prognosis and in tailoring adjuvant therapies. We therefore support its practice as part of the surgical procedure in patients affected by high risk endometrial cancer. PMID- 23932377 TI - A comparison of intrauterine balloon, intrauterine contraceptive device and hyaluronic acid gel in the prevention of adhesion reformation following hysteroscopic surgery for Asherman syndrome: a cohort study. AB - OBJECTIVE: To compare the efficacy of intrauterine balloon, intrauterine contraceptive device and hyaluronic acid gel in the prevention of the adhesion reformation after hysteroscopic adhesiolysis for Asherman's syndrome. STUDY DESIGN: Retrospective cohort study of 107 women with Asherman's syndrome who were treated with hysteroscopic division of intrauterine adhesions. After hysteroscopic adhesiolysis, 20 patients had intrauterine balloon inserted, 28 patients had intrauterine contraceptive device (IUD) fitted, 18 patients had hyaluronic acid gel instilled into the uterine cavity, and 41 control subjects did not have any of the three additional treatment measures. A second-look hysteroscopy was performed in all cases, and the effect of hysteroscopic adhesiolysis was scored by the American Fertility Society classification system. RESULTS: Both the intrauterine balloon group and the IUD group achieved significantly (P<0.001) greater reduction in the adhesion score than that of the hyaluronic acid gel group and control group. The efficacy of the balloon was greater than that of the IUD (P<0.001). There was no significant difference in results between the hyaluronic acid gel group and the control groups. CONCLUSION: The insertion of an intrauterine balloon or intrauterine device is more effective than the use of hyaluronic acid gel in the prevention of intra-uterine adhesion reformation. PMID- 23932378 TI - Microclimate in ski boots--temperature, relative humidity, and water absorption. AB - Ski boot quality is determined by mechanical properties and comfort. Comfort is strongly affected by cold feet. The purpose of this study was to determine the microclimate in ski boots. Climate chamber tests with five male subjects and field tests with two male subjects were conducted. Temperature and relative humidity were measured using four sensors placed on the foot and one on the liner. Absorbed water in liners and socks was measured with a precision balance. The subjects gave subjective ratings for comfort. The toe sensor temperature dropped below 20 degrees C at an ambient temperature of 0 degrees C, -10 degrees C, and -20 degrees C. Relative humidity values at the foot were as high as 78% in the climate chamber and 93% in the field. Water absorption in socks and liners ranged from 4 to 10 g in the climate chamber and 19 to 45.5 g in the field. The results reveal the importance of keeping the feet and in particular the toes warm during skiing. One possible improvement may be to construct the liner so that sweat and melted snow are kept as far away as possible from the foot. Liner material with high water absorption capacity and hydrophobic socks were suggested to prevent wet feet. PMID- 23932379 TI - Interpretation of way-finding healthcare symbols by a multicultural population: navigation signage design for global health. AB - The interpretation of way-finding symbols for healthcare facilities in a multicultural community was assessed in a cross-sectional study. One hundred participants recruited from Al Ain city in the United Arab Emirates were asked to interpret 28 healthcare symbols developed at Hablamos Juntos (such as vaccinations and laboratory) as well as 18 general-purpose symbols (such as elevators and restrooms). The mean age was 27.6 years (16-55 years) of whom 84 (84%) were females. Healthcare symbols were more difficult to comprehend than general-purpose signs. Symbols referring to abstract concepts were the most misinterpreted including oncology, diabetes education, outpatient clinic, interpretive services, pharmacy, internal medicine, registration, social services, obstetrics and gynecology, pediatrics and infectious diseases. Interpretation rates varied across cultural backgrounds and increased with higher education and younger age. Signage within healthcare facilities should be tested among older persons, those with limited literacy and across a wide range of cultures. PMID- 23932380 TI - Acute cerebellitis following hemolytic streptococcal infection. AB - BACKGROUND: Acute cerebellitis is a rare inflammatory syndrome in children, with either infectious or autoimmune etiologies. PATIENT: We describe a 7-year-old girl with a presentation of cerebellitis following group A streptococcal infection. RESULTS: Magnetic resonance imaging showed diffuse symmetrical swelling and edema of the cerebellum resulting in compression of the fourth ventricle and hydrocephalus. Autoantibodies against glutamate receptor delta2 were detected in the cerebrospinal fluid, suggesting that the cerebellum might be injured by postinfectious immunologic reaction. The most common causes of cerebellitis are acute viral infection, postinfection, and following vaccination. No examples of acute cerebellitis following group A streptococcal infection have been documented. CONCLUSION: Our report demonstrates that group A streptococcal can lead to acute cerebellitis. PMID- 23932381 TI - Evaluation of the "Take Five School": an education programme for people with Type 2 Diabetes in the Western Cape, South Africa. AB - AIM: To evaluate the Take Five School (TFS) group education programme for patients with Type 2 Diabetes in South Africa. METHODS: Questionnaires, administered before and after 4 sessions of an hour each of group education, measured the effect on self-care activities in 84 patients from 6 different clinics. Individual interviews with health care workers (HCWs) and focus group interviews (FGI's) with patients explored attitudes. RESULTS: A significant improvement in adherence to a diabetic diet, physical activity, foot care and the perceived ability to teach others was seen. There was no significant change in smoking or adherence to medication. Qualitative data revealed that comprehensive education was appreciated, that the group process was deemed supportive, that HCWs doubt the effect of education in general and that a combination of group and individual sessions was seen as an option worth exploring. Strengths, weaknesses, opportunities and threats to the TFS are identified. Recommendations are made to improve the programme and its environment. CONCLUSION: Significant self-reported improvements in self-care activities after a group-education programme support the view that introducing structured group education for Type 2 Diabetics in a South African public sector primary care context holds promise. Group education for diabetics, especially in resource limited settings, should be sustained and further research should focus on clinical outcomes. PMID- 23932382 TI - 184th ENMC International Workshop: pain and fatigue in neuromuscular disorders: 20-22 May 2011, Naarden, The Netherlands. PMID- 23932383 TI - Therapeutic and prognostic implications of subarachnoid hemorrhage in patients who suffered cardiopulmonary arrest and underwent cardiopulmonary resuscitation during an emergency room stay. AB - OBJECTIVE: Aneurysmal subarachnoid hemorrhage (SAH) is a well-known cause of sudden cardio-pulmonary arrest (CPA). Even after successful cardio-pulmonary resuscitation (CPR), the prognosis of patients following an aneurysmal SAH presenting with CPA remains dismal. However, there have been anecdotal reports of good outcomes with appropriate interventions. Pseudo-SAH resulting from marked elevation of intracranial pressure (ICP) after CPR, can mimic SAH in head computed tomographic (CT) scan. Such manifestations hamper resuscitation or delay appropriate neurosurgical management. This study assessed incidence and clinical characteristics of SAH-CPR or pseudo-SAH-CPR patients among non-traumatic CPA-CPR patients, and investigated their therapeutic and prognostic implication. METHODS: During the 5-year observation period, 63 non-traumatic coma patients with CT evidence of high attenuation areas in the basal cistern who suffered arrest and underwent CPR during initial resuscitation in the emergency room, were reviewed retrospectively. They were divided into two groups according to the imaging pattern: true-SAH vs. pseudo-SAH, and then true-SAH group were further divided into two groups according to the CT acquisition time: brain CT before arrest vs. brain CT after arrest. Demographic, clinical, and CT data were assessed, and the primary outcome was measured using the 30-day Glasgow Outcome Scale (GOS) score, and the final outcome was evaluated at the end of 3 months post-ictus. RESULTS: When compared with pseudo-SAH (n=28) patients, true-SAH (n=35) patients showed a higher Hounsfield unit values in the affected area, earlier CT acquisition time before CPR, more survivors beyond 3 months (all p<0.05); however, the 30-day survival rate was not significantly different. Of the true-SAH patients, ruptured intracranial aneurysms were found in eight patients, and definite intervention was administered in four patients. When SAH patients were categorized according to the temporal relationship with CPR, the group of 24 patients undergoing CT scan before CPR showed a lower frequency of intraventricular hemorrhage, but showed a higher chance of surgical treatment and survival at 30 days and 3 months compared to the group undergoing CT scan after CPR. CONCLUSION: The overall survival between true-SAH and pseudo-SAH group was different significantly. Administering definite treatment for a ruptured aneurysm in instances of true SAH could save patients, albeit infrequently. A Prompt CT scan could guarantee recognition of high-density area, blood in the ventricle, and subsequent identification of the ruptured aneurysm, altogether preventing re-bleeding and warranting further systemic resuscitation. PMID- 23932384 TI - Computer-aided diagnosis system: a Bayesian hybrid classification method. AB - A novel method to classify multi-class biomedical objects is presented. The method is based on a hybrid approach which combines pairwise comparison, Bayesian regression and the k-nearest neighbor technique. It can be applied in a fully automatic way or in a relevance feedback framework. In the latter case, the information obtained from both an expert and the automatic classification is iteratively used to improve the results until a certain accuracy level is achieved, then, the learning process is finished and new classifications can be automatically performed. The method has been applied in two biomedical contexts by following the same cross-validation schemes as in the original studies. The first one refers to cancer diagnosis, leading to an accuracy of 77.35% versus 66.37%, originally obtained. The second one considers the diagnosis of pathologies of the vertebral column. The original method achieves accuracies ranging from 76.5% to 96.7%, and from 82.3% to 97.1% in two different cross validation schemes. Even with no supervision, the proposed method reaches 96.71% and 97.32% in these two cases. By using a supervised framework the achieved accuracy is 97.74%. Furthermore, all abnormal cases were correctly classified. PMID- 23932385 TI - Design of fuzzy classifier for diabetes disease using Modified Artificial Bee Colony algorithm. AB - In this study, diagnosis of diabetes disease, which is one of the most important diseases, is conducted with artificial intelligence techniques. We have proposed a novel Artificial Bee Colony (ABC) algorithm in which a mutation operator is added to an Artificial Bee Colony for improving its performance. When the current best solution cannot be updated, a blended crossover operator (BLX-alpha) of genetic algorithm is applied, in order to enhance the diversity of ABC, without compromising with the solution quality. This modified version of ABC is used as a new tool to create and optimize automatically the membership functions and rules base directly from data. We take the diabetes dataset used in our work from the UCI machine learning repository. The performances of the proposed method are evaluated through classification rate, sensitivity and specificity values using 10-fold cross-validation method. The obtained classification rate of our method is 84.21% and it is very promising when compared with the previous research in the literature for the same problem. PMID- 23932386 TI - The role of epidermal growth factor in prevention of oxidative injury and apoptosis induced by intestinal ischemia/reperfusion in rats. AB - Intestinal ischemia/reperfusion is a major problem which may lead to multiorgan failure and death. The aim of the study was to evaluate the effects of epidermal growth factor (EGF) on apoptosis, cell proliferation, oxidative stress and the antioxidant system in intestinal injury induced by ischemia/reperfusion in rats and to determine if EGF can ameliorate these toxic effects. Intestinal ischemia/reperfusion injury was produced by causing complete occlusion of the superior mesenteric artery for 60 min followed by a 60-min reperfusion period. Animals received intraperitoneal injections of 150 MUg/kg human recombinant EGF 30 min prior to the mesenteric ischemia/reperfusion. Mesenteric ischemia/reperfusion caused degeneration of the intestinal mucosa, inhibition of cell proliferation, stimulation of apoptosis and oxidative stress in the small intestine of rats. In the ischemia/reperfusion group, lipid peroxidation was stimulated accompanied by increased intestinal catalase and glutathione peroxidase activities, however, glutathione levels and superoxide dismutase activities were markedly decreased. EGF treatment to rats with ischemia/reperfusion prevented the ischemia/reperfusion-induced oxidative injury by reducing apoptosis and lipid peroxidation, and by increasing antioxidant enzyme activities. These results demonstrate that EGF has beneficial antiapoptotic and antioxidant effects on intestinal injury induced by ischemia/reperfusion in rats. PMID- 23932387 TI - Radiology-pathology case report: isolated extranodal Rosai-Dorfman disease of the skull base. AB - Rosai-Dorfman disease is a rare pathologic entity characterized by massively enlarged painless cervical lymph nodes. Exclusive extranodal disease is much less common than the characteristic presentation with exclusive central nervous system and skull base involvement being quite rare. We present a case of exclusive extranodal Rosai-Dorfman disease of the skull base and briefly discuss the entity. PMID- 23932388 TI - Omental infarction preceded by anatomically upturned omentum. AB - We report the case of a 49-year-old man who presented with acute abdominal pain. Contrast-enhanced computed tomography of the abdomen revealed spontaneous omental torsion with no other noticeable findings. Notably, a computed tomography exam 6 months prior demonstrated the omentum located within the anterior hepatic space, suggesting that the patient had a hypermobile, upturned omentum. To our knowledge, this is the first case report illustrating an anatomically upturned omentum as precursor to omental infarction. PMID- 23932389 TI - 18F-FDG PET/CT in suspected recurrences of epithelial malignant pleural mesothelioma in asbestos-fibers-exposed patients (comparison to standard diagnostic follow-up). AB - This retrospective study evaluated the role of 18-fluorine-labeled 2-deoxy-2 fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with previous occupational or environmental exposure to asbestos, with histopathological diagnosis of epithelial malignant pleural mesothelioma and suspected recurrences, comparing the data from 18F-FDG PET/CT and computed tomography with contrast enhancement (CECT). 18F-FDG PET/CT has greater sensitivity than CECT in identifying local extent, lymph nodes, and metastasis. 18F-FDG PET/CT whole-body explorations are useful to monitor the follow-up and evaluate the metabolic response to chemo- and radiotherapy, modifying the scheduled treatment plan. PMID- 23932390 TI - Aggressive angiomyxoma of the scrotum. AB - INTRODUCTION: Aggressive angiomyxoma (AAM) is a rare, benign mass with propensity for local invasion and recurrence after resection. Infrequently, this tumor can be found arising from the scrotum or cord structures in males. AIM/METHODS: A case report is presented followed by a review of relevant literature addressing the diagnosis, imaging, management and follow-up for aggressive angiomyxoma of the scrotum. RESULTS: Imaging can assist in further characterization of masses noted on physical exam. Scrotal sonography is typically the primary imaging modality utilized and magnetic resonance imaging is able to provide further anatomic detail. Treatment mainstay is surgical resection with necessary long term surveillance. PMID- 23932391 TI - Effects of fish oil on ovarian development in spotted scat (Scatophagus argus). AB - The effects of different concentrations of dietary fish oil (0, 2%, or 6%) on ovarian development in 2-year-old female Scatophagus argus were investigated. The levels of serum sex steroid hormones (estradiol-17beta, E2; testosterone, T), protein phosphorus (SPP), and protein calcium (SPC), as well as vitellogenin (vtg) mRNA expression in livers and ovaries were measured. Over the eight week experimental period, oocytes did not develop further and remained at phase III in fish fed with the control diet with no supplement of fish oil. Fish fed with 2% fish oil supplement had oocytes at transition phase from III to IV. Fish fed with 6% fish oil supplement had oocytes at late phase IV. Higher gonadosmatic index, serum E2, SPP, SPC, and liver vtg expression were found in 6% fish oil group compared to that in the 2% fish oil group (except E2) and the control group (P<0.05). In addition, vtg expression in livers was 600-1000 times higher than that in the ovaries. Gonadosmatic index, E2, and SPP, as well as liver vtg expression increased during the experiment and peaked at the end of experiment. However, hepatosomatic index, serum T, and ovarian vtg expression peaked at 4 weeks, and then decreased at 8 weeks, with no significant difference among the 3 groups. In summary, we showed that 6% fish oil supplementation in S. argus could effectively promote ovarian development, with associated increases in E2 secretion and increased liver vtg mRNA expression. PMID- 23932392 TI - Severe punishment of children by staff in Romanian placement centers for school aged children: effects of child and institutional characteristics. AB - The objective of this study was to determine whether children's characteristics and/or institutional characteristics were predictors of severe punishments (including beatings) and/or frequency of punishments that children received from staff in Romanian institutions. The data was hierarchical with institutionalized children (N=1391) nested within 44 institutions, and the measurement of punishments by the staff and frequency of punishments had a binary distribution. Thus, multilevel logistic regression models were used to examine the effects of individual and institutional level variables on reported punishments and to account for the clustering of the children within institutions. Two general patterns of results emerged. First, regarding individual level variables, it was found that: (1) amount of time spent by children in their current institutions had a significant effect on the probability of being punished by staff and the frequency of this punishment; (2) the probability of being punished was higher for boys than for girls; and (3) having no siblings in the institution increased the odds of being punished several times. Second, regarding institutional level variables: (4) being in placement centers for school-aged children with a traditional type of institutional organization increased the odds of severe punishment compared to a familial/mixed type. The results of the present study highlight the importance of understanding the consequences of institutionalization in a broader way, where children not only experienced early severe psychosocial deprivation as documented in other studies, but also high levels of severe punishments administered by institutional staff. PMID- 23932393 TI - Multilevel correlates of behavioral resilience among children in child welfare. AB - Resilience, defined as positive adaptation and functioning following exposure to significant adversity, is an important topic of investigation in child welfare. The current study used data from the Ontario Looking After Children (OnLAC) project to estimate the prevalence of behavioral resilience (i.e., lower frequency of conduct and emotional problems, higher frequency of prosocial behavior) in 531 5-9 year olds living in out-of-home care, and to determine how behaviorally-resilient children are functioning in other domains (i.e., peer relationships and academic performance). Furthermore, hierarchical linear modeling was used to examine the contribution of four levels of analysis (i.e., child, family, child welfare worker, and child welfare agency) on behaviors and to identify the contribution of predictor variables within each of these levels. Findings indicated that 50-70% of children exhibited resilience on one behavioral outcome while approximately 30% showed resilience on at least two of the outcomes. Also, 8.4-9.6% exhibited resilience on one of the behavioral outcomes in addition to peer relationships and academic performance. The child level accounted for the highest proportion of total explained variance in behavioral outcomes, followed by the family-, child welfare worker-, and child welfare agency-levels. A number of child and foster family variables predicted behavioral functioning. Findings indicate that it is important to inquire about children's functioning across multiple domains to obtain a comprehensive developmental assessment. Also, child and foster family characteristics appear to play considerable roles in the promotion of behavioral resilience. PMID- 23932394 TI - A role of NF-E2 in chronic inflammation and clonal evolution in essential thrombocythemia, polycythemia vera and myelofibrosis? AB - A novel murine model for myeloproliferative neoplasms (MPNs) generated by overexpression of the transcription factor NF-E2 has recently been described. Sustained overexpression of NF-E2 in this model induced myeloid expansion with anemia, leukocytosis and thrombocytosis. Herein, it is debated if NF-E2 overexpression also might have induced a sustained state of in vivo leukocyte and platelet activation with chronic and self-perpetuating production of inflammatory products from activated leukocytes and platelets. If so, this novel murine model also may excellently describe the deleterious impact of sustained chronic NF-E2 overexpression during uncontrolled chronic inflammation upon the hematopoietic system--the development of clonal myeloproliferation. Accordingly, this novel murine model may also have delivered the proof of concept of chronic inflammation as a trigger and driver of clonal evolution in MPNs. PMID- 23932395 TI - Impact of multidetector CT-angiography on the emergency management of severe hemoptysis. AB - BACKGROUND: Multidetector CT-angiography (MDCTA) is commonly used in patients with severe haemoptysis requiring admission to intensive care unit. However, the impact of MDCTA on the management of severe haemoptysis in emergency setting is poorly evaluated. METHODS: We prospectively compared data provided by clinical bedside evaluation (clinical examination, chest-X-ray and fiberoptic bronchoscopy) to MDCTA data in terms of lateralization, location of the bleeding site, etiology as well as impact on the treatment choice. RESULTS: Over a 13 month period, 87 patients (men n=58, median age=61 years, median haemoptysis expectorated volume=180 mL) were included. Etiology was mainly (67%) bronchiectasis, tuberculosis sequelae and tumor. MDCTA and clinical bedside evaluation were equally effective in determining lateralization (87.4% and 93.1%, respectively, p=0.23) and location (85% and 82.7%, respectively, p=0.82) of the bleeding site. MDCTA was significantly more accurate than the clinical bedside strategy in determining the haemoptysis cause (86% and 70%, respectively, p=0.007). Moreover, MDCTA suggested the involvement of systemic arteries as bleeding mechanism in 92% of cases, leading to the modification of the treatment initially considered after bedside evaluation in 21.8% of patients. CONCLUSION: MDCTA provides useful information for the management of patients with severe haemoptysis, especially in the treatment choice. Thus, in the absence of emergency fiberoptic bronchoscopy (FOB) requirement for airways management, MDCTA should be the first-line procedure performed in emergency clinical setting. PMID- 23932396 TI - Pseudotumours in chronic kidney disease: can diffusion-weighted MRI rule out malignancy. AB - OBJECTIVES: To evaluate whether diffusion-weighted MRI (DW-MRI) can distinguish pseudotumours in chronic kidney disease (CKD pseudotumours) from renal-cell carcinomas (RCCs) (with or without CKD) and whether it offers additional benefit over conventional MRI. METHODS: One-hundred patients underwent MDCT, MRI and DW MRI (at b-values of 0 and 500s/mm(2)) for evaluation of focal renal lesions. Of these, 20 patients with 40 CKD pseudotumours and 36 patients with 40 RCCs were retrospectively analyzed. T1-weighted, T2-weighted, diffusion-weighted images were evaluated, apparent-diffusion-coefficient (ADC) values were compared and receiver-operating-characteristic (ROC) curves were drawn to establish cut-off ADC-values. RESULTS: 92.5% of CKD pseudotumours remained indeterminate after conventional MRI. On DW-MRI, none of them showed restricted diffusion and thus malignancy could be ruled out in 100% of the lesions. In contrast, all the solid RCCs showed diffusion restriction. Mean ADC-value for CKD pseudotumours was significantly higher than RCCs and surrounding diseased parenchyma [2.50 vs 1.56 (*10(-3)mm(2)/s) (P<0.0001) and 2.05 (*10(-3)mm(2)/s) (P=0.0001) respectively]. ROC analysis for differentiating CKD pseudotumours and RCC yielded high sensitivity (91.7%) and specificity (100%) for cut-off ADC-value of 2.04 (*10( 3)mm(2)/s). CONCLUSIONS: CKD pseudotumors usually remain indeterminate on conventional non-contrast MRI. DW-MRI can distinguish CKD pseudotumors from RCCs and offers a non-contrast non-invasive alternative for ruling out malignancy. PMID- 23932397 TI - Directed evolution of thermotolerant malic enzyme for improved malate production. AB - The directed evolution of the thermotolerant NADP(H)-dependent malic enzyme from Thermococcus kodakarensis was conducted to alter the cofactor preference of the enzyme from NADP(H) to NAD(H). The construction and screening of two generations of mutant libraries led to the isolation of a triple mutant that exhibited 6-fold higher kcat/Km with NAD(+) than the wild type. We serendipitously found that, in addition to the change in the cofactor preference, the reaction specificity of the mutant enzyme was altered. The reductive carboxylation of pyruvate to malate catalyzed by the wild type enzyme is accompanied by HCO(3)(-)-independent reduction of pyruvate and gives lactate as a byproduct. The reaction specificity of the triple mutant was significantly shifted to malate production and the mutant gave a less amount of the byproduct than the wild type. When the triple mutant enzyme was used as a catalyst for pyruvate carboxylation with NADH, the enzyme gave 1.2 times higher concentration of malate than the wild type with NADPH. Single-point mutation analysis revealed that the substitution of Arg221 with Gly is responsible for the shift in reaction specificity. This finding may shed light on the catalytic mechanisms of malic enzymes and other related CO2- and/or HCO(3)(-)-fixing enzymes. PMID- 23932398 TI - Objectification of psychogenic postural instability by trunk sway analysis. AB - INTRODUCTION: The attribution of balance or gait disorders to psychogenic origin can be exceedingly challenging, as clinical tests involving distraction maneuvers are prone to subjective bias. We tested the value of biomechanical balance analysis to identify psychogenic balance and gait (PBG) disorders. METHODS: We quantified and compared the effects of distraction maneuvers on balance based on four stance conditions (eyes open, EO; eyes closed, EC; EO on foam, EOF; and EC on foam; ECF) in subjects with suspected PBG (n = 12), subjects with balance and gait disorder due to multiple sclerosis (MS; n = 12) and healthy controls (n = 12). We measured trunk inclination in transverse plane ( degrees )(2) and the corresponding body angular velocity ( degrees /s). Distractibility of postural stability was analysed using ANOVA with repeated measures. RESULTS: In evident contrast to the MS group and healthy controls, the PBG group showed increased values of ( degrees )(2) and ( degrees /s) and significant distractibility in all four stance conditions. CONCLUSIONS: Biomechanical balance analysis can help clinicians to get objective, quantified results of distraction maneuvers and confirm a positive diagnosis of PBG disorders. Large prospective studies are needed to confirm these results. PMID- 23932399 TI - Para-hydrogen perspectives in hyperpolarized NMR. AB - The first instance of para-hydrogen induced polarization (PHIP) in an NMR experiment was serendipitously observed in the 1980s while investigating a hydrogenation reaction (Seldler et al., 1983; Bowers and Weitekamp, 1986, 1987; Eisenschmid et al., 1987) [1-4]. Remarkably a theoretical investigation of the applicability of para-hydrogen as a hyperpolarization agent was being performed in the 1980's thereby quickly providing a theoretical basis for the PHIP-effect (Bowers and Weitekamp, 1986) [2]. The discovery of signal amplification by a non hydrogenating interaction with para-hydrogen has recently extended the interest to exploit the PHIP effect, as it enables investigation of compounds without structural alteration while retaining the advantages of spectroscopy with hyperpolarized compounds [5]. In this article we will place more emphasis of the future applications of the method while only briefly discussing the efforts that have been made in the understanding of the phenomenon and the development of the method so far. PMID- 23932400 TI - A comparative review of aging and B cell function in mice and humans. AB - Immune system function declines with age. Here we review and compare age associated changes in murine and human B cell pools and humoral immune responses. We summarize changes in B cell generation and homeostasis, as well as notable changes at the subcellular level; then discuss how these changes help to explain alterations in immune responses across the adult lifespan of the animal. In each section we compare and contrast findings in the mouse, arguably the best animal model of the aging immune system, with current understanding of B cell immunity in humans. PMID- 23932401 TI - Reduction of influence of task difficulty on perceptual decision making by STN deep brain stimulation. AB - Neurocomputational models of optimal decision making ascribe a crucial role-the computation of conflict between choice alternatives-to the subthalamic nucleus (STN). Specifically, these models predict that deep brain stimulation (DBS) of the STN will diminish the influence of decision conflict on decision making. In this work, patients with Parkinson's disease judged the direction of motion in random dot stimuli while ON and OFF DBS. To induce decision conflict, we varied the task difficulty (motion coherence), leading to increased reaction time (RT) in trials with greater task difficulty in healthy subjects. Results indicate that DBS significantly influences performance for perceptual decisions under high decision conflict. RT increased substantially OFF DBS as the task became more difficult, and a diffusion model best accounted for behavioral data. In contrast, ON DBS, the influence of task difficulty on RT was significantly reduced and a race model best accounted for the observed data. Individual data fits of evidence accumulation models demonstrate different information processing under distinct DBS states. Furthermore, ON DBS, speed-accuracy tradeoffs affected the magnitude of decision criterion adjustment significantly less compared to OFF DBS. Together, these findings suggest a crucial role for the STN in adjusting decision making during high-conflict trials in perceptual decision making. PMID- 23932402 TI - Dauer-specific dendrite arborization in C. elegans is regulated by KPC-1/Furin. AB - BACKGROUND: Dendrites often display remarkably complex and diverse morphologies that are influenced by developmental and environmental cues. Neuroplasticity in response to adverse environmental conditions entails both hypertrophy and resorption of dendrites. How dendrites rapidly alter morphology in response to unfavorable environmental conditions is unclear. The nematode Caenorhabditis elegans enters into a stress-resistant dauer larval stage in response to an adverse environment. RESULTS: Here we show that the IL2 bipolar sensory neurons undergo dendrite arborization and axon remodeling during dauer development. When dauer larvae are returned to favorable environmental conditions, animals resume reproductive development and IL2 dendritic branches retract, leaving behind remnant branches in postdauer L4 and adult animals. The C. elegans furin homolog KPC-1 is required for dauer IL2 dendritic arborization and dauer-specific nictation behavior. KPC-1 is also necessary for dendritic arborization of PVD and FLP sensory neurons. In mammals, furin is essential, ubiquitously expressed, and associated with numerous pathologies, including neurodegenerative diseases. While broadly expressed in C. elegans neurons and epithelia, KPC-1 acts cell autonomously in IL2 neurons to regulate dauer-specific dendritic arborization and nictation. CONCLUSIONS: Neuroplasticity of the C. elegans IL2 sensory neurons provides a paradigm to study stress-induced and reversible dendritic branching, and the role of environmental and developmental cues in this process. The newly discovered role of KPC-1 in dendrite morphogenesis provides insight into the function of proprotein convertases in nervous system development. PMID- 23932403 TI - Native architecture of the centriole proximal region reveals features underlying its 9-fold radial symmetry. AB - BACKGROUND: Centrioles are cylindrical microtubule-based structures whose assembly is critical for the formation of cilia, flagella, and centrosomes. The centriole proximal region harbors a cartwheel that dictates the 9-fold symmetry of centrioles. Although the cartwheel architecture has been recently analyzed, how it connects to the peripheral microtubules is not understood. More generally, a high-resolution view of the proximal region of the centriole is lacking, thus limiting understanding of the underlying assembly mechanisms. RESULTS: We report the complete architecture of the Trichonympha centriole proximal region using cryotomography. The resulting 3D map reveals several features, including additional densities in the cartwheel that exhibit a 9-fold symmetrical arrangement, as well as the structure of the Pinhead and the A-C linker that connect to microtubules. Moreover, we uncover striking chiral features that might impart directionality to the entire centriole. Furthermore, we identify Trichonympha SAS-6 and demonstrate that it localizes to the cartwheel in vivo. CONCLUSIONS: Our work provides unprecedented insight into the architecture of the centriole proximal region, which is key for a thorough understanding of the mechanisms governing centriole assembly. PMID- 23932404 TI - Shared signatures of parasitism and phylogenomics unite Cryptomycota and microsporidia. AB - Fungi grow within their food, externally digesting it and absorbing nutrients across a semirigid chitinous cell wall. Members of the new phylum Cryptomycota were proposed to represent intermediate fungal forms, lacking a chitinous cell wall during feeding and known almost exclusively from ubiquitous environmental ribosomal RNA sequences that cluster at the base of the fungal tree [1, 2]. Here, we sequence the first Cryptomycotan genome (the water mold endoparasite Rozella allomycis) and unite the Cryptomycota with another group of endoparasites, the microsporidia, based on phylogenomics and shared genomic traits. We propose that Cryptomycota and microsporidia share a common endoparasitic ancestor, with the clade unified by a chitinous cell wall used to develop turgor pressure in the infection process [3, 4]. Shared genomic elements include a nucleotide transporter that is used by microsporidia for stealing energy in the form of ATP from their hosts [5]. Rozella harbors a mitochondrion that contains a very rapidly evolving genome and lacks complex I of the respiratory chain. These degenerate features are offset by the presence of nuclear genes for alternative respiratory pathways. The Rozella proteome has not undergone major contraction like microsporidia; instead, several classes have undergone expansion, such as host-effector, signal-transduction, and folding proteins. PMID- 23932406 TI - Giant optical activity of sugar in thin soap films. AB - We report on enhanced experimental optical activity measurements of thin soap films in the presence of sugar. This unusual optical activity is linked to the intramolecular chiral conformation of the glucose molecules at the air/liquid interface. Choosing sodium dodecylsulfate (SDS) as a model surfactant and glucose as model sugar, favorable interactions between the anionic group -OSO3(-)- and the glucose molecules are highlighted. This induces an interfacial anchoring of glucose molecules leading to a perturbing influence of the asymmetric chiral environment. PMID- 23932405 TI - Matrix microarchitecture and myosin II determine adhesion in 3D matrices. AB - BACKGROUND: Reports of adhesions in cells growing in 3D vary widely-from nonexistent to very large and elongated-and are often in apparent conflict, due largely to our minimal understanding of the underlying mechanisms that determine 3D cell phenotype. We address this problem directly by systematically identifying mechanisms that determine adhesion in 3D matrices and, from our observations, develop principles widely applicable across 2D and 3D substrates. RESULTS: We demonstrate that nonmuscle myosin II activity guides adhesion phenotype in 3D as it does in 2D; however, in contrast to 2D, decreasing bulk matrix stiffness does not necessarily inhibit the formation of elongated adhesions. Even in soft 3D matrices, cells can form large adhesions in areas with appropriate local matrix fiber alignment. We further show that fiber orientation, apart from influencing local stiffness, modulates the available adhesive area and thereby determines adhesion size. CONCLUSIONS: Thus adhesion in 3D is determined by both myosin activity and the immediate microenvironment of each adhesion, as defined by the local matrix architecture. Important parameters include not only the resistance of the fiber to pulling (i.e., stiffness) but also the orientation and diameter of the fiber itself. These principles not only clarify conflicts in the literature and point to adhesion modulating factors other than stiffness, but also have important implications for tissue engineering and studies of tumor cell invasion. PMID- 23932407 TI - Salt- and pH-induced desorption: Comparison between non-aggregated and aggregated mussel adhesive protein, Mefp-1, and a synthetic cationic polyelectrolyte. AB - Mussel adhesive proteins are of great interest in many applications due to their ability to bind strongly to many types of surfaces under water. Effective use such proteins, for instance the Mytilus edulis foot protein - Mefp-1, for surface modification requires achievement of a large adsorbed amount and formation of a layer that is resistant towards desorption under changing conditions. In this work we compare the adsorbed amount and layer properties obtained by using a sample containing small Mefp-1 aggregates with that obtained by using a non aggregated sample. We find that the use of the sample containing small aggregates leads to higher adsorbed amount, larger layer thickness and similar water content compared to what can be achieved with a non-aggregated sample. The layer formed by the aggregated Mefp-1 was, after removal of the protein from bulk solution, exposed to aqueous solutions with high ionic strength (up to 1M NaCl) and to solutions with low pH in order to reduce the electrostatic surface affinity. It was found that the preadsorbed Mefp-1 layer under all conditions explored was significantly more resistant towards desorption than a layer built by a synthetic cationic polyelectrolyte with similar charge density. These results suggest that the non-electrostatic surface affinity for Mefp-1 is larger than for the cationic polyelectrolyte. PMID- 23932408 TI - To let hair be, or to not let hair be? Gender and body hair removal practices in Aotearoa/New Zealand. AB - Research and anecdotal evidence suggest women continue to remove body hair, and there is some evidence for cultural changes in men's hair removal practices. This paper reports on data collected using an online mix-methods survey from 584 New Zealanders between the ages of 18-35 (mean age 26, 48.9% male, 50.6% female). The data demonstrated that substantial proportions of both women and men in Aotearoa/New Zealand remove body hair from many sites. However, gendered differences remain, and a key dimension of gendered difference appears in the concept of flexible choice around body hair removal or retention. This was seen in the difference between perceived acceptability of having body hair (81% for men, 11% for women). These findings suggest that although men, like women, are now coming under some pressure to remove body hair, there is still a great difference in men and women's capacity to choose whether to bow to it. PMID- 23932409 TI - The academic welfare state: making peer-review count. AB - The peer-review process is a central pillar of academic publishing. However, the work that goes into ensuring the quality of published content is rarely recognised. Here we present a correction factor for the h-index, one of the most popular metrics for quantifying academic output, that will allow for the inclusion of peer-review effort in the evaluation of the outputs produced by an academic. PMID- 23932410 TI - Increased orosomucoid in urine is an independent predictor of cardiovascular and all-cause mortality in patients with type 2 diabetes at 10 years of follow-up. AB - AIMS: To evaluate whether increased urinary orosomucoid excretion rate (UOER) is an independent predictor of cardiovascular and all-cause mortality in type 2 diabetes (T2DM) and type 1 diabetes (T1DM) at 10years of follow-up. METHOD: We followed 430 patients with T2DM and 148 patients with T1DM until emigration, death or November 2011. We measured UOER levels in overnight urine samples. RESULTS: Descriptive data are given in the article. In patients with T2DM and T1DM, all-cause mortality (log-rank test, p<0.01 for both types) and cardiovascular mortality (log-rank test, p<0.01 for T2DM and p=0.04 for T1DM) were significantly higher in patients with increased UOER. Normoalbuminuric patients with T2DM and increased UOER levels had higher all-cause and cardiovascular mortality (log-rank test, p<0.01 for both types). UOER was independently predictive of all-cause (HR 1.52; 95% CI 1.10-2.09; p=0.01) and cardiovascular (HR 2.31; 95% CI 1.46-3.66; p<0.01) mortality in patients with T2DM, but not in patients with T1DM. CONCLUSION: UOER is an independent predictor of all-cause and cardiovascular mortality even in normoalbuminuric patients with T2DM at 10years of follow-up. Further studies are needed in order to evaluate the prognostic and clinical relevance. PMID- 23932411 TI - Sensitivity of free-living amoeba trophozoites and cysts to water disinfectants. AB - Free-living amoebae are naturally present in water. These protozoa could be pathogenic and could also shelter pathogenic bacteria. Thus, they are described as a potential hazard for health. Also, free-living amoebae have been described to be resistant to biocides, especially under their cyst resistant form. There are several studies on amoeba treatments but none of them compare sensitivity of trophozoites and cysts from different genus to various water disinfectants. In our study, we tested chlorine, monochloramine and chlorine dioxide on both cysts and trophozoites from three strains, belonging to the three main genera of free living amoebae. The results show that, comparing cysts to trophozoites inactivation, only the Acanthamoeba cysts were highly more resistant to treatment than trophozoites. Comparison of the disinfectant efficiency led to conclude that chlorine dioxide was the most efficient treatment in our conditions and was particularly efficient against cysts. In conclusion, our results would help to adapt water treatments in order to target free-living amoebae in water networks. PMID- 23932412 TI - A micro-environmental study of the Zn(+2)-Abeta1-16 structural properties. AB - Relying on a combination of classical molecular dynamics and hybrid QM/MM computational methods, we study the influence of the nature of the local physico chemical environment on the structural features of beta-amyloid peptides complexed with Zn(+2) ions. The analysis is carried out by comparing among themselves different Zn(+2)-ligand force fields and studying their influence on metal coordination and long-range peptide folding. The system in the non physiological so-called "gas phase" (no solvent) was also simulated with the purpose of identifying to what extent, if at all, the solvent can affect the Zn coordination mode, besides its long-range structural properties. There are two main results of this investigation. The first is that the Zn(+2) coordination mode in classical molecular dynamics simulations markedly depends on the partial charge attributed to the ion and the atoms surrounding it. Comparing with experiments, it is possible to identify the most appropriate Zn(+2) force field for the Zn(+2)-Abeta1-16 complex in study. Secondly, although the presence of water naturally influences the peptide folding propensity, it does not affect the structure of the Zn(+2) inner coordination shell. A useful way to validate classical results and in particular those referring to the structural differences visible when different force fields are employed, was to use a hybrid QM/MM optimization step. When the classical system configurations are submitted to such a quantum minimization step, the geometries of the resulting Zn(+2) site turn out to be all very similar and structurally in good agreement with what is experimentally known. PMID- 23932413 TI - Policy analysis: palliative care in Ireland. AB - Palliative care for patients with advanced illness is a subject of growing importance in health services, policy and research. In 2001 Ireland became one of the first nations to publish a dedicated national palliative care policy. This paper uses the 'policy analysis triangle' as a framework to examine what the policy entailed, where the key ideas originated, why the policy process was activated, who were the key actors, and what were the main consequences. Although palliative care provision expanded following publication, priorities that were unaddressed or not fully embraced on the national policy agenda are identified. The factors underlying areas of non-fulfilment of policy are then discussed. In particular, the analysis highlights that policy initiatives in a relatively new field of healthcare face a trade-off between ambition and feasibility. Key policy goals could not be realised given the large resource commitments required; the competition for resources from other, better-established healthcare sectors; and challenges in expanding workforce and capacity. Additionally, the inherently cross-sectoral nature of palliative care complicated the co-ordination of support for the policy. Policy initiatives in emerging fields such as palliative care should address carefully feasibility and support in their conception and implementation. PMID- 23932414 TI - Developing a universal tool for the prioritization of patients waiting for elective surgery. AB - The objective was to elaborate a priority scoring system for patients on waiting lists for elective surgery to be implemented in the Catalan public health system. This tool should ideally be universal (for all patients and across the entire region) with common criteria and weights (for all surgical procedures), simple and user-friendly. A tool based on a point-count linear scale ranging from 0 (lowest priority) to 100 (highest priority) was developed. Patients are scored in three major dimensions: clinical and functional impairment, expected benefit, and social role, which include 8 criteria (with their weights): disease severity (23%), pain (or other main symptoms) (14%), rate of disease progression (15%), difficulty in doing activities of daily life (14%), probability and degree of improvement (12%), being dependent with no caregiver (5%), limitation to care for one's dependents (if that be the case) (8%), and limitations in the ability to work, study or seek for employment (9%). As in previous studies developed in Canada, New Zealand and Catalonia, the tool obtained is mainly based on severity and need. The success of this tool depends very much on implementation mechanisms. Furthermore, prior to implementation, a definition of specificities in the selected criteria for the most frequent surgical procedures is advised. PMID- 23932415 TI - Recommendations for the organization of mental health services for children and adolescents in Belgium: use of the soft systems methodology. AB - The prevalence of mental health problems among children and adolescents in Western countries is high. Belgium, like many other Western countries, struggles with the set-up of a coherent and effective strategy for dealing with this complex societal problem. This paper describes the development of a policy scenario for the organization of child and adolescent mental health care services (CAMHS) in Belgium. The development process relied on Soft Systems Methodology including a participatory process with 66 stakeholders and a review of the existing (inter-)national evidence. A diagnostic analysis illustrated that the Belgian CAMHS is a system in serious trouble characterized by fragmentation and compartmentalization. A set of 10 strategic recommendations was formulated to lay down the contours of a future, more effective CAMHS system. They focus on mastering the demands made on scarce and expensive specialized mental health services; strengthening the range of services - in particular for those with serious, complex and multiple mental health problems - and strengthening the adaptive capacity of and the ethical guidance within the future CAMHS system. PMID- 23932416 TI - Outcomes of endovascular management for complicated chronic type B aortic dissection: effect of the extent of stent graft coverage and anatomic properties of aortic dissection. AB - PURPOSE: To assess the effect of the extent of stent graft coverage and anatomic properties of aortic dissection on the outcomes of thoracic endovascular aortic repair (TEVAR) for complicated chronic type B aortic dissection (CCBAD) in terms of survival, reintervention, and false lumen thrombosis. MATERIALS AND METHODS: A retrospective analysis was performed of 71 patients who underwent TEVAR for CCBAD. Mean patient age was 54.7 years. Distal extent of stent graft coverage was categorized as short (<= T7) or long (>= T8) coverage. Indications of reintervention were categorized into three groups: proximal, alongside, and distal according to the anatomic relationship of the culprit lesion and the stent graft. Overall survival, reintervention-free survival, and extent of false lumen thrombosis were compared. RESULTS: The technical success rate was 97.2%. The 1 year, 3-year, and 5-year overall survival rates were 97.1%, 88.9%, and 88.9%, and 1-year, 3-year, and 5-year reintervention-free survival rates were 80.7%, 73.8%, and 60.6%. There were no differences in overall survival, reintervention-free survival rates, and extent of false lumen thrombosis between the groups. In the short coverage group, distal reintervention was more frequent in patients with an abdominal aortic diameter >= 37 mm compared with patients with an abdominal aortic diameter < 37 mm (P = .005). CONCLUSIONS: TEVAR was effective for CCBAD with a high technical success rate and low mortality. The extent of stent graft coverage did not make a difference in terms of survival and false lumen thrombosis. Reinterventions were more frequently performed in patients with a large baseline abdominal aortic diameter who were treated with short stent graft coverage, and so longer coverage is recommended in such patients. PMID- 23932417 TI - Surgical or endovascular therapy of abdominal penetrating aortic ulcers and their natural history: a systematic review. AB - Little is known regarding the outcomes of endovascular and surgical treatment of penetrating ulcers in the abdominal aorta. The potential benefit of conservative management of asymptomatic disease is also debatable. A systematic review of the literature was undertaken to investigate these issues. PMID- 23932418 TI - Seemingly unrelated intervention time series models for effectiveness evaluation of large scale environmental remediation. AB - Large scale environmental remediation projects applied to sea water always involve large amount of capital investments. Rigorous effectiveness evaluations of such projects are, therefore, necessary and essential for policy review and future planning. This study aims at investigating effectiveness of environmental remediation using three different Seemingly Unrelated Regression (SUR) time series models with intervention effects, including Model (1) assuming no correlation within and across variables, Model (2) assuming no correlation across variable but allowing correlations within variable across different sites, and Model (3) allowing all possible correlations among variables (i.e., an unrestricted model). The results suggested that the unrestricted SUR model is the most reliable one, consistently having smallest variations of the estimated model parameters. We discussed our results with reference to marine water quality management in Hong Kong while bringing managerial issues into consideration. PMID- 23932419 TI - Eco-hydro-acoustic modeling and its use as an EIA tool. AB - The effects of anthropogenic underwater noise on marine life is of growing concern and assessment of impacts on marine life is often carried out using predictive underwater noise models to map zones of influence for marine species. However, these models do not predict how a species may react to that noise. In this paper, the results from a modified predictive underwater noise model and a hydrodynamic model are used in an individual based model (IBM) to predict the impacts on cod (Gadhus moruha) from noise generated during a pile driving event at an offshore wind farm in Liverpool Bay, UK. The model included cod which were sensitive to noise and those which were insensitive ('deaf'). Fish movement was from the outer bay into the Dee Estuary, a known feeding ground. The IBM indicated that the cod which could hear took up to 7 days longer to reach their destination than the cod which were deaf. This technique could be used during the consenting process for offshore projects to better understand the potential impact on marine species. PMID- 23932420 TI - Interspecific introgression and changes in population structure in a flatfish species complex after the Prestige accident. AB - Oil spills cause aggressive impacts on marine ecosystems affecting immense areas and the species inhabiting them. If wastes are not cleaned up properly, the remnants may affect local populations for a long time. This work focuses on the long-term impacts of the Prestige spillage that occurred off Galician coast (Spain) in November 2002. Model species were two sympatric flatfish, the megrims Lepidorhombus whiffiagonis and Lepidorhombus boscii. Samples obtained before and nine years after the Prestige accident from affected and unaffected areas were genotyped for six hypervariable nuclear markers and for the mitochondrial D-loop sequence. The results revealed a high proportion of post-F1 interspecific hybrids in the area affected, and also increased intraspecific population differentiation likely due to such localized introgression of foreign genes. These changes suggest the appearance of a hybrid zone following the accident and emphasize the need of paying special attention to potential evolutionary impacts of oil spills. PMID- 23932421 TI - Isolated primary malignant lymphoma arising from the optic chiasm. AB - Isolated primary malignant lymphoma rarely arises from the anterior visual pathway. A 59-year-old previously healthy man presented with progressive, painless, bilateral visual disturbance. Neurological imaging revealed an enhancing mass arising from the optic chiasm. Open biopsy was carried out under monitoring of visual evoked potentials and a histopathological diagnosis of diffuse large B-cell lymphoma was made. As systemic examination did not show any evidence of systemic lymphoma, we concluded that this patient had an isolated primary malignant lymphoma at the anterior visual pathway. PMID- 23932422 TI - Trends in surgical treatment for trigeminal neuralgia in the United States of America from 1988 to 2008. AB - Current surgical treatments for refractory trigeminal neuralgia (TN) include microvascular decompression (MVD), percutaneous rhizotomy, and stereotactic radiosurgery (SRS). We aimed to map the trends of utilization of these procedures in the USA and examine factors associated with morbidities and discharge outcome. We performed a retrospective cohort study with time trends of patients admitted to US hospitals for TN between 1988 and 2008 who received MVD, percutaneous rhizotomy, or SRS as reported in the Nationwide Inpatient Sample. Univariate and multivariate analyses were conducted to examine patient demographics, hospital characteristics, and other hospitalization factors affecting complications and discharges. The use of MVD increased significantly by 194% from 1988 to 2008 while rhizotomy decreased by 92%. The use of radiosurgery, introduced in the early 1990s, peaked in 2004 and has declined since. Univariate analysis revealed patient age, length of hospitalization, hospital teaching status, and hospital patient volume to be associated with discharge and complications. Multivariate analysis showed that for MVD, younger age and high hospital volume were predictive of a good discharge outcome. For rhizotomy, age, median income, urban location, and hospital volumes were associated with discharge outcome, but only teaching status, urban location, and hospital volume were associated with complications. For SRS, patient age and length of stay were found to be important by multivariate analysis on discharge. Mortality rates for MVD (0.22%), rhizotomy (0.42%), and SRS (0.12%) were low. The clinical practices for surgical treatment of TN have evolved over time with the rise of MVD and dwindling of rhizotomy procedures. PMID- 23932423 TI - Central nervous system and head and neck imaging findings of MYC/BCL2 "double hit" B cell lymphoma. AB - MYC/BCL2 double hit lymphoma (DHL) is a rare, recently recognised and highly aggressive subtype of non-Hodgkin lymphoma, with an affinity to involve the central nervous system and the head and neck either at initial presentation or during relapse. We present a case of 43-year-old woman with MYC/BCL2 DHL relapse in the nasopharynx with extensive spread to the neck, skull base, and the central nervous system. To our knowledge, this is the first reported case in the literature describing the MRI and CT scan findings and the profound pattern of disease involvement of this rare neoplasm. PMID- 23932424 TI - L-PRP diminishes bone matrix formation around autogenous bone grafts associated with changes in osteocalcin and PPAR-gamma immunoexpression. AB - Leucocyte- and platelet-rich plasma (L-PRP) is an autogenous platelet concentrate enriched with leukocytes that releases various growth factors responsible for the proliferation, regulation, and differentiation of mesenchymal cells during wound healing. Since the bone and medullary tissue are contiguous and share the same origin, this study evaluated the effect of L-PRP on the repair of calvaria bone using histomorphometric analysis of the newly formed bone, and compared the results in the presence of osteocalcin (OC) and peroxisome proliferator-activated receptor gamma (PPAR-gamma) detected by immunohistochemistry. Artificial circular bone defects (5mm diameter) were produced in the calvaria of 42 rats. The defects were treated with autograft, autograft combined with L-PRP, or without grafting material (sham). The animals were euthanized at 15 or 40 days postsurgery (n=7 in each group). Data obtained were analyzed by Student-Newman-Keuls test for histomorphometric and immunohistochemical interpretation. The development of bone matrix was significantly less in the defects treated with L-PRP, while the medullary area composed of fatty cells was larger. This coincided with the minor expression of OC and expressive presence of PPAR-gamma. These results suggest that L-PRP may impair osteoneogenesis and alter the ratio of differentiation between bone matrix and fatty cells, increasing the medullary tissue. PMID- 23932425 TI - Palliative balloon angioplasty in a cat with right pulmonary arterial branch stenoses and concurrent absence of the left pulmonary artery. AB - Unilateral absence of the left or right pulmonary artery with concurrent contralateral pulmonary arterial branch stenoses is an exceptionally rare disorder. We describe this anomaly in a cat with severe exercise intolerance and respiratory distress. Transthoracic echocardiography and angiography demonstrated the absence of the left pulmonary artery with concurrent right pulmonary branch stenosis. Palliative balloon angioplasty of the right pulmonary artery substantially reduced right ventricular systolic pressure load and alleviated the patient's clinical signs. PMID- 23932426 TI - Towards measurement of the Healthy Ageing Phenotype in lifestyle-based intervention studies. AB - INTRODUCTION: Given the biological complexity of the ageing process, there is no single, simple and reliable measure of how healthily someone is ageing. Intervention studies need a panel of measures which capture key features of healthy ageing. To help guide our research in this area, we have adopted the concept of the "Healthy Ageing Phenotype" (HAP) and this study aimed to (i) identify the most important features of the HAP and (ii) identify/develop tools for measurement of those features. METHODS: After a comprehensive assessment of the literature we selected the following domains: physiological and metabolic health, physical capability, cognitive function, social wellbeing, and psychological wellbeing which we hoped would provide a reasonably holistic characterisation of the HAP. We reviewed the literature and identified systematic reviews and/or meta-analysis of cohort studies, and clinical guidelines on outcome measures of these domains relevant to the HAP. Selection criteria for these measures included: frequent use in longitudinal studies of ageing; expected to change with age; evidence for strong association with/prediction of ageing related phenotypes such as morbidity, mortality and lifespan; whenever possible, focus on studies measuring these outcomes in populations rather than on individuals selected on the basis of a particular disease; (bio)markers that respond to (lifestyle-based) intervention. Proposed markers were exposed to critique in a Workshop held in Newcastle, UK in October 2012. RESULTS: We have selected a tentative panel of (bio)markers of physiological and metabolic health, physical capability, cognitive function, social wellbeing, and psychological wellbeing which we propose may be useful in characterising the HAP and which may have utility as outcome measures in intervention studies. In addition, we have identified a number of tools which could be applied in community-based intervention studies designed to enhance healthy ageing. CONCLUSIONS: We have proposed, tentatively, a panel of outcome measures which could be deployed in community-based, lifestyle intervention studies. The evidence base for selection of measurement domains is less well developed in some areas e.g. social wellbeing (where the definition of the concept itself remains elusive) and this has implications for the identification of appropriate tools. Although we have developed this panel as potential outcomes for intervention studies, we recognise that broader agreement on the concept of the HAP and on tools for its measurement could have wider utility and e.g. could facilitate comparisons of healthy ageing across diverse study designs and populations. PMID- 23932427 TI - Contraception during the perimenopause. AB - Although the absolute risk of pregnancy is lower during the perimenopause due to decreased fertility and decreased coital frequency, unintended pregnancy occurs at ratios similar to those observed in young women, and pregnancies that do occur are at high risk for maternal complications and poor outcomes such as miscarriage or chromosomal abnormalities. Therefore all premenopausal women should receive counselling that includes discussion of sexual habits and contraception during routine health care encounters. The majority of US women in this age group use permanent contraception, but other methods can be safe and effective and can have non-contraceptive benefits. No contraceptive method is contraindicated based on age alone. However, estrogen-containing methods should be reserved for women without cardiovascular or thrombotic risk factors. The levonorgestrel intrauterine system (LNG-IUS, Mirena((r))) has particular benefits during perimenopause and is safe for use in nearly all women. The LNG-IUS is approved for treatment of heavy menstrual bleeding, a common concern during the perimenopause. A substantial literature supports the use of the LNG-IUS for endometrial protection during transition from contraception to hormone therapy, although this is off-label in the United States. Reliable contraception should be used until menopause is confirmed either by cessation of menses for 2 years prior to age 50, for 1 year after age 50, or by two elevated follicle-stimulating hormone (FSH) values >=20-30IU/l while off hormonal methods for at least 2 weeks. Sterility cannot be assumed until at least age 60 because spontaneous pregnancies have been reported in women up to age 59. PMID- 23932428 TI - Inter-limb coordination and energy cost in swimming. AB - OBJECTIVES: This study investigated the relationship between inter-arm coordination and the energy cost of locomotion in front crawl and breaststroke and explored swimmers' flexibility in adapting their motor organization away from their preferred movement pattern. DESIGN: Nine front-crawlers performed three 300 m in front crawl and 8 breaststrokers performed three 200-m in breaststroke at constant submaximal intensity and with 5-min rests. Each trial was performed randomly in a different coordination pattern: freely chosen, 'maximal glide' and 'minimal glide'. Two underwater cameras videotaped frontal and side views to analyze speed, stroke rate, stroke length and inter-limb coordination. METHODS: In front crawl, inter-arm coordination was quantified by the index of coordination (IdC) and the leg beat kicks were counted. In breaststroke, four time gaps quantified the arm to leg coordination (i.e., time between leg and arm propulsions; time between beginning, 90 degrees flexion and end of arm and leg recoveries). The energy cost of locomotion was calculated from gas exchanges and blood lactate concentration. RESULTS: In both front crawl and breaststroke, the freely chosen coordination corresponded to glide pattern and showed the lowest energy cost (12.8 and 17.1Jkg(-1)m(-1), respectively). Both front-crawlers and breaststrokers were able to reach 'maximal glide' condition (respectively, +35% and +28%) but not 'minimal glide' condition for front crawl. CONCLUSIONS: The freely chosen pattern appeared more economic because more trained. When coordination was constrained, the swimmers had higher coordination flexibility in breaststroke than in front crawl, suggesting that breaststroke coordination was easier to regulate by changing glide time. PMID- 23932429 TI - Comparative study on trace metal accumulation in the liver of two fish species (Torpedinidae): concentration-size relationship. AB - Metal concentrations (Hg, Cd, Pb, As, Cr, Cu, Zn and Ni) were measured in the liver of two fish, Torpedo nobiliana (electric ray) and Torpedo marmorata (marbled electric ray), from the Mediterranean Sea in order to comparatively investigate their current pollution status. Maximum mean levels of Hg were detected in electric ray (mean: 2.16MUgg(-1) ww), while marbled electric ray accumulated especially Cd (mean: 0.06MUgg(-1) ww), Cu (mean: 3.83MUgg(-1) ww) and As (mean: 32.64MUgg(-1) ww). The metal concentrations are similar to those reported in literature, except for Cd, As and Ni. Hg concentrations increased with increasing fish body length in both species, whilst no significant concentration-size relationship was found for other metals. To the best of our knowledge this is the first report providing information on trace metal levels and relationship between concentration and size of these cartilaginous fishes. Future studies on the concentrations and effects of environmental contaminants in various torpedinid species are surely needed. PMID- 23932430 TI - Temporal patterns of digestive enzyme activities and feeding rate in gammarids (Gammarus fossarum) exposed to inland polluted waters. AB - The aim of this study was to use digestive enzyme activities in Gammarus fossarum as biomarkers during active biomonitoring. Standardised gammarids were transplanted for 7 days to five sites in the Riou Mort watershed contaminated by polymetallic pollution. This experiment was conducted on seven different dates from February 2009 to June 2010. Feeding rates were tracked, along with amylase, cellulase and trypsin activities. We found that feeding rate and digestive capacity were reduced in the most polluted site, "Joany," in comparison with the reference site "Up.Lot". The results suggested that trypsin was more sensitive than the other two carbohydrases. In the four other sites, seasonal differences were observed during the 2yr but no clear pattern can be established. This study highlights the ability of G. fossarum to demonstrate environmental disturbances and suggests the use of a caging process in certain seasons. Caging organisms and feeding ad libitum is advantageous, as it reduces inter-individual variability and removes dependence on the native food fluctuations. However, confounding factors other than temperature were present, and the interpretation of digestive enzyme activities is complex. PMID- 23932431 TI - When love hurts: assessing the intersectionality of ethnicity, socio-economic status, parental connectedness, child abuse, and gender attitudes in juvenile violent delinquency. AB - Researchers have not yet reached agreement about the validity of several competing explanations that seek to explain ethnic differences in juvenile violent offending. Ethnicity cannot solely explain why boys with an ethnic minority background commit more (violent) crimes. By assessing the intersectionality of structural, cultural and individual considerations, both the independent effects as well as the interplay between different factors can be examined. This study shows that aforementioned factors cumulatively play a role in severe violent offending, with parental connectedness and child abuse having the strongest associations. However, since most variables interact and ethnicity is associated with those specific factors, a conclusion to be drawn is that ethnicity may be relevant as an additional variable predicting severe violent offending although indirectly. PMID- 23932432 TI - Effects of active vs. passive recovery during Wingate-based training on the acute hormonal, metabolic and psychological response. AB - OBJECTIVE: The exercise-induced metabolic stress can be influenced by the mode of recovery and is associated with acute hormonal responses. Therefore, it is hypothesized that active recovery between high intensity intervals reduces the metabolic stimulus and therefore the hormonal response compared to passive recovery. DESIGN: 12 male cyclist/triathletes performed four 30s all-out intervals, either with active (A) or passive (P) recovery between each bout. Human growth hormone (hGH), testosterone and cortisol, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and macrophage migration inhibitory factor (MIF) were determined pre, 0', 30', 60' and 180' after both interventions. Metabolic stimuli and perturbations were characterized by lactate, blood gas (pH, BE, HCO3(-), PO2, PCO2), and spirometric analysis. RESULTS: Both interventions caused a transient increase in circulating levels of cortisol, testosterone, testosterone/cortisol-ratio, hGH, VEGF and HGF. Transient differences between A- and P-recovery were found only for testosterone and HGF directly after exercise, despite significant differences in metabolic disturbances (lactate, acid base status). CONCLUSION: Based on the data of testosterone, hGH and the testosterone/cortisol-ratio, as well as on the data of VEGF and HGF it appears that this kind of exercise protocol may promote anabolic processes and may lead to pro-angiogenic conditions independent of the mode of recovery. However transient differences between A- and P-recovery were shown for testosterone and HGF. In contrast, cortisol and hGH, which are known to be sensitive for metabolic perturbations (e.g. pH) showed no differences. Therefore, it is proposed that if a certain threshold for metabolic perturbations is exceeded, a hormonal response is induced, which does not differ between A- and P recovery. PMID- 23932433 TI - Insights into ancient leprosy and tuberculosis using metagenomics. AB - Leprosy and tuberculosis were widespread in the past and remain significant diseases today. Comparison of ancient and modern genomes of Mycobacterium leprae and Mycobacterium tuberculosis gives insight into their evolution and a calibration of the timescale for observed changes. Recently, whole genome sequencing has revealed genotypes and mixed-strain infections. PMID- 23932434 TI - A preliminary investigation into the application of processing instruction as therapy for aphasia in Spanish speakers. AB - PURPOSE: This study was a preliminary investigation into the use of processing instruction (PI) to improve the use of the personal 'a' to assign thematic roles in Spanish sentences for second language (L2) learners and persons with aphasia (PWA). Evidence suggests that PI is an effective teaching method for L2 learners with errant processing strategies. However its use with PWA with an acquired inability to process syntactic cues is unknown. METHODS: Thirty non-impaired Spanish as a second language learners and two Spanish-speaking PWA participated in this study. PI involved the use of explicit instruction and structured input activities with nouns and pronouns. Each participant's performance was assessed pre and post treatment. Two experimental and one control groups of L2 learners completed the PI activities over two days. PWA completed PI in individual sessions over four day and received additional cues. CONCLUSIONS: L2 learners who received PI demonstrated significant improvement in the comprehension and production of 'a'. However, the Spanish-speaking PWA demonstrated mixed results. Both of the PWA exhibited gains in the comprehension of 'a' on referential tasks. One participant with aphasia demonstrated improved comprehension post-testing, and neither participant demonstrated gains on production post-testing. Results suggest that PI may be useful for increasing syntactic comprehension in people with aphasia. Findings from the current study are used to guide suggestions for further modification and use of PI as a treatment strategy for PWA. LEARNING OUTCOMES: Readers will be able to: (a) define processing instruction, (b) discuss the role of specific syntactic cues in Spanish comprehension, and (c) explain how PI might be modified for use with Spanish speakers with aphasia. PMID- 23932435 TI - Corticospinal excitability in juvenile myoclonic epilepsy: The story so far. PMID- 23932436 TI - Modulation of CD8(+) T-cell activation events by monocytic and granulocytic myeloid-derived suppressor cells. AB - Myeloid-derived suppressor cells are immature myeloid cells, consisting of a monocytic and a granulocytic fraction, that are known to suppress anti-tumor immune responses. Important targets of the immunosuppressive capacity of MDSC are CD8(+) T cells, which are crucial cytotoxic effector cells in immunotherapeutic settings. CD8(+) T-cell activation and differentiation comprises a well orchestrated series of events, starting from early TCR-mediated signaling and leading to cytokine secretion, the expression of activation markers, proliferation and the differentiation into several subsets of effector and memory cells. In this review, we summarize the available data on how the production of reactive oxygen species, nitric oxide, the arginase-mediated depletion of l arginine and Cystine depletion by MDSCs interfere with the signaling molecules necessary for normal CTL differentiation and activation. PMID- 23932437 TI - The role of immune-related myeloid cells in angiogenesis. AB - Macrophage function is not restricted to the innate and adaptive immune responses, but also includes host defence, wound healing, angiogenesis and homeostatic processes. Within the spectrum of macrophage activation there are two extremes: M1 classically activated macrophages which have a pro-inflammatory phenotype, and M2 alternatively activated macrophages which are pro-angiogenic and anti-inflammatory. An important property of macrophages is their plasticity to switch from one phenotype to the other and they can be defined in their polarisation state at any point between the two extremes. In order to determine what stage of activation macrophages are in, it is essential to profile various phenotypic markers for their identification. This review describes the angiogenic role for myeloid cells: circulating monocytes, Tie-2 expressing monocytes (TEMs), myeloid-derived suppressor cells (MDSCs), tumour associated macrophages (TAMs), and neutrophils. Each cell type is discussed by phenotype, roles within angiogenesis and possible targets as a cell therapy. In addition, we also refer to our own research on myeloid angiogenic cells (MACs), outlining their ability to induce angiogenesis and their similarities to alternatively activated M2 macrophages. MACs significantly contribute to vascular repair through paracrine mechanisms as they lack the capacity to differentiate into endothelial cells. Since MACs also retain plasticity, phenotypic changes can occur according to disease states and the surrounding microenvironment. This pro-angiogenic potential of MACs could be harnessed as a novel cellular therapy for the treatment of ischaemic diseases, such as diabetic retinopathy, hind limb ischaemia and myocardial infarction; however, caution needs to be taken when MACs are delivered into an inflammatory milieu. PMID- 23932439 TI - Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. AB - CONTEXT: The clinical significance of positive surgical margins (PSMs) in radical prostatectomy (RP) specimens and the management of affected patients remain unclear. OBJECTIVE: To address pitfalls in the pathologic interpretation of margin status; provide an update on the incidence, predictors, and long-term oncologic implications of PSMs in the era of robot-assisted laparoscopic RP (RALRP); and suggest a practical evidence-based approach to patient management. EVIDENCE ACQUISITION: A systematic review of the literature was performed in April 2013 using Medline/PubMed, Web of Science, and Scopus databases and the Cochrane Database of Systematic Reviews. Studies focusing on PSMs in RP pertinent to the objectives of this review were included. Particular attention was paid to publications within the last 5 yr and those concerning RALRP. EVIDENCE SYNTHESIS: A total of 74 publications were retrieved. Standardized measures to overcome variability in the pathologic interpretation of surgical margins have recently been established by the International Society of Urological Pathology. The average rate of PSMs in contemporary RALRP series is 15% (range: 6.5-32%), which is higher in men with a more advanced pathologic stage and equivalent to the rate reported in prior open and laparoscopic prostatectomy series. The likelihood of PSMs is strongly influenced by the surgeon's experience irrespective of the surgical approach. Technical modifications using the robotic platform and the role of frozen-section analysis to reduce the margin positivity rate continue to evolve. Positive margins are associated with a twofold increased hazard of biochemical relapse, but their association with more robust clinical end points is controversial. Level 1 evidence suggests that adjuvant radiation therapy (RT) may favorably affect prostate-specific antigen recurrence rates, but whether the therapy also affects systemic progression, prostate cancer-specific mortality, and overall survival remains debatable. CONCLUSIONS: Although positive margins in prostate cancer are considered an adverse oncologic outcome, their long-term impact on survival is highly variable and largely influenced by other risk modifiers. Adjuvant RT appears to be effective, but further study is required to determine whether early salvage RT is an equivalent alternative. PMID- 23932440 TI - Population estimates of Australian children's exposure to food and beverage sponsorship of sports clubs. AB - OBJECTIVES: Sponsorship by manufacturers of unhealthy food can undermine the health promoting goals of sport. This study aimed to describe Australian children's exposure to organised sport, and compare time spent in specific sports with patterns of sponsorship of children's sport identified in previous studies. DESIGN: Cross-sectional survey on children's sport participation collected by proxy report using a random-digit-dialling survey of 3416 parents. METHODS: Data from the 2009/10 Australian Sports Commission's Exercise, Recreation and Sport Survey were used to calculate weekly total person-time exposure to sports for Australian children, as a product of median weekly exposure (minutes) and the number of children participating. Exposures for children in NSW were calculated based on population distribution. Based on a previous survey of sport clubs in NSW, cumulative weekly exposure to food/beverage sponsorship at sports clubs was estimated for children living in NSW. RESULTS: 77.3% of Australian children aged 5-14 participated in organised sport. In NSW, weekly total person-time exposure for children was highest for outdoor soccer (91,200 children*median frequency of 2 sessions per week of 1h duration=182,400h/week). Considering rates of sponsorship at different sports, children would be exposed to food/beverage sponsorship to the greatest extent for rugby league and outdoor cricket. CONCLUSIONS: Children's high frequency of participation in organised sport and time spent engaging in these activities highlights the potentially huge reach of food/beverage sponsorship promotions. Policy interventions to limit children's exposure to this sponsorship should target those sports that have both the highest levels of children's participation and food/beverage sponsorship arrangements. PMID- 23932438 TI - Combination therapy with solifenacin and tamsulosin oral controlled absorption system in a single tablet for lower urinary tract symptoms in men: efficacy and safety results from the randomised controlled NEPTUNE trial. AB - BACKGROUND: Storage symptoms are particularly bothersome in men with lower urinary tract symptoms (LUTS) but may not be adequately treated by alpha-blocker monotherapy. OBJECTIVE: To assess the efficacy and safety of a fixed-dose combination (FDC) of solifenacin and an oral controlled absorption system (OCAS) formulation of tamsulosin compared with placebo and compared with tamsulosin OCAS (TOCAS) monotherapy in men with moderate to severe storage symptoms and voiding symptoms. DESIGN, SETTING, AND PARTICIPANTS: A double-blind 12-wk phase 3 study in 1334 men with storage and voiding LUTS: total International Prostate Symptom Score (IPSS) >= 13, maximum urinary flow rate (Qmax) 4.0-12.0 ml/s, two or more urgency episodes per 24 h of Patient Perception of Intensity of Urgency Scale grade 3 or 4, and eight or more micturitions per 24h. INTERVENTION: Patients were randomised to placebo, TOCAS 0.4 mg, FDC solifenacin 6 mg plus TOCAS 0.4 mg, or FDC solifenacin 9 mg plus TOCAS 0.4 mg. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary efficacy end points were (1) total IPSS and (2) Total Urgency and Frequency Score (TUFS). An FDC met the success criteria if it demonstrated superiority compared with placebo and noninferiority compared with TOCAS for total IPSS, as well as superiority compared with TOCAS for TUFS. RESULTS AND LIMITATIONS: Reductions in total IPSS and TUFS were observed with both solifenacin 6 mg plus TOCAS (-7.0 and -8.1, respectively) and solifenacin 9 mg plus TOCAS (-6.5 and -7.6, respectively) compared with TOCAS (-6.2 and -6.7, respectively) and placebo (-5.4 and -4.4, respectively). Solifenacin 6 mg plus TOCAS met all prespecified success criteria for both primary end points, while solifenacin 9 mg plus TOCAS met success criteria compared with placebo but not compared with TOCAS. Both FDCs improved quality of life (QoL) measures and were well tolerated, with low incidences of acute urinary retention. CONCLUSIONS: The FDC of solifenacin 6 mg plus TOCAS significantly improved storage and voiding symptoms, as well as QoL parameters, compared with placebo. This FDC also improved storage symptoms and QoL compared with TOCAS alone in men with moderate to severe storage symptoms and voiding symptoms, and it was well tolerated. PMID- 23932441 TI - Factors influencing serum caffeine concentrations following caffeine ingestion. AB - OBJECTIVES: To determine whether differences in training status, body composition and/or habitual caffeine intake influenced serum caffeine concentrations following caffeine ingestion. DESIGN: Single-blind. METHODS: Trained cyclists/triathletes (n=14) and active (n=14) males consumed 6 mg kg(-1) anhydrous caffeine. Peak, total and time to peak serum caffeine concentrations were determined from venous blood samples at baseline and 6 time-points over 4h following intake. Body composition was assessed by dual energy X-ray absorptiometry and habitual caffeine intake by a questionnaire. RESULTS: Trained cyclists/triathletes had 16% lower peak caffeine concentrations following caffeine ingestion compared to active individuals, although this was not statistically significant (p=0.066). There was no significant difference between trained cyclists/triathletes and active males in total (p=0.131) or time to peak (p=0.249) serum caffeine concentrations. Fat mass was significantly associated with total (r=0.427, p=0.038) but not peak (r=0.343, p=0.101) or time to peak serum caffeine concentration (beta=0.00008, p=0.961). There were no associations between habitual caffeine intake and peak, total or time to peak serum caffeine concentrations. CONCLUSIONS: Following caffeine ingestion three findings from the study were evident: (1) endurance-trained athletes trended towards lower peak caffeine concentrations compared to active males; (2) higher fat mass was associated with higher concentrations of caffeine in the blood over 4h, and (3) habitual caffeine intake does not appear to influence serum caffeine concentrations. Identification of the optimal conditions to ensure peak availability of caffeine within the blood and/or overcoming some of the variation in how individuals respond to caffeine requires consideration of the training status and body composition of the athlete. PMID- 23932442 TI - Outcome of unplanned right ventricular assist device support for severe right heart failure after implantable left ventricular assist device insertion. AB - BACKGROUND: The use of a right ventricular assist device (RVAD) becomes necessary for severe right ventricular (RV) failure after left ventricular assist device (LVAD) insertion. Although temporary support could lead to successful RVAD weaning in certain patients, the data remain scarce. METHODS: We retrospectively reviewed 398 patients who underwent implantable LVAD insertion between January 2000 and December 2012. Of these patients, 44 (11%) required unplanned RVAD support due to severe RV failure after LVAD insertion. For comparison, 37 patients who underwent planned biventricular assist device (BiVAD) insertion were identified during the same study period. We analyzed the early and late outcomes in these patients. RESULTS: The mean duration of RVAD support was 21 +/- 23 days. Of the 44 patients, 21 (49%) were weaned from the RVAD (weaning group), whereas 23 (51%) required continued biventricular support (failure group). The failure group had ongoing end-organ dysfunction after RVAD insertion. Hospital mortality was significantly lower in the weaning group (24%) and in the planned BiVAD group (30%) as compared to the failure group (74%, p = 0.0009). The 6-month actuarial survival rate was 75% in the weaning group, 62% in the planned BiVAD group and 13% in the failure group (p < 0.0001). Successful bridge to transplant was achieved in 14 patients (67%) in the weaning group as compared with 8 patients (35%) in the failure group (p = 0.03). On multivariate logistic regression analyses, pre-operative white blood cell (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.04 to 1.50, p = 0.016) and creatinine (OR 0.26, 95% CI 0.079 to 0.88, p = 0.03) levels were significant predictors for RVAD removal. CONCLUSIONS: Among patients who developed acute RV failure after LVAD insertion, only half could be weaned from the temporary RVAD support. An alternative strategy is necessary in patients who require continuous RVAD support. PMID- 23932443 TI - QRS prolongation is strongly associated with life-threatening ventricular arrhythmias in children with dilated cardiomyopathy. AB - BACKGROUND: The incidence of sudden death in children with dilated cardiomyopathy has been estimated at < 1% annually. This number, however, may underestimate the incidence of life-threatening arrhythmias. The objective of this study was to assess the incidence of and identify risk factors for life-threatening arrhythmias in children with dilated cardiomyopathy. METHODS: We conducted a retrospective record review of 183 children with dilated cardiomyopathy treated at a single center between 2000 and 2011. Life-threatening arrhythmia was defined as any ventricular arrhythmia that resulted in syncope or hypotension and required medical intervention. Risk factors for life-threatening arrhythmias were identified with univariate analyses. A prediction model was constructed with multivariate logistic regression and receiver operating characteristic curves. RESULTS: Nineteen patients experienced life-threatening arrhythmias, representing an annualized rate of 4.9%. Outpatient life-threatening arrhythmias occurred at a rate of 2.2% per year. Predictors of outpatient life-threatening arrhythmias were longer QRS duration (p = 0.003) and increased left ventricular posterior wall (LVPWd) thickness (p = 0.03). Only QRS duration remained significant in multivariate logistic regression (odds ratio, 1.8 for every unit increase in z score; 95% CI, 1.01-1.9; p = 0.04). For all life-threatening arrhythmias, prolonged QRS duration was the only significant risk factor in multivariate logistic regression (odds ratio, 1.5; 95% CI, 1.1-2.2; p = 0.02). CONCLUSION: In children with dilated cardiomyopathy, as QRS duration increases, so too does the risk of life-threatening arrhythmias. Life-threatening arrhythmias occurred at an annual rate of 5%, which was much higher than the previously reported rate of sudden cardiac death in this population. PMID- 23932444 TI - Early identification of tethered cord syndrome: a clinical challenge. AB - Tethered cord syndrome (TCS) is a progressive clinical condition that arises from excessive spinal cord tension. The clinical signs and symptoms of TCS may be cutaneous, neurologic, musculoskeletal, genitourinary, and/or gastrointestinal. Patients also may be asymptomatic, which does not exclude the diagnosis of TCS. Although the exact etiology is unknown, early identification and lifelong surveillance or surgical treatment is an essential component of patient management. In this article we review the pathophysiology, various etiologies, clinical presentation, and long-term sequelae of TCS. This information will help pediatric nurse practitioners identify TCS early and anticipate the patient's needs and management requirements. PMID- 23932445 TI - [Corkscrew-like hair and perifollicular purpura as a vitamin C deficiency sign]. PMID- 23932447 TI - Field visual perspective during autobiographical memory recall is less frequent among patients with schizophrenia. AB - There is growing interest in clinical research regarding the visual perspective adopted during memory retrieval, because it reflects individuals' self-attitude towards their memories of past personal events. Several autobiographical memory deficits, including low specificity of personal memories, have been identified in schizophrenia, but visual perspective during autobiographical memory retrieval has not yet been investigated in patients. The aim of this study was therefore to investigate the visual perspective with which patients visualize themselves when recalling autobiographical memories and to assess the specificity of their memories which is a major determinant of visual perspective. Thirty patients with schizophrenia and 30 matched controls recalled personal events from 4 life periods. After each recall, they were asked to report their visual perspective (Field or Observer) associated with the event. The specificity of their memories was assessed by independent raters. Our results showed that patients reported significantly fewer Field perspectives than comparison participants. Patients' memories, whether recalled with Field or Observer perspectives, were less specific and less detailed. Our results indicate that patients with schizophrenia adopt Field perspectives less frequently than comparison participants, and that this may contribute to a weakened sense of the individual of being an actor of his past events, and hence to a reduced sense of self. They suggest that this may be related to low specificity of memories and that all the important aspects involved in re-experiencing autobiographical events are impaired in patients with schizophrenia. PMID- 23932446 TI - Acculturative stress and psychotic-like experiences among Asian and Latino immigrants to the United States. AB - Previous studies have shown variation in the prevalence and incidence of psychosis across immigrant groups, but the underlying mechanisms are not fully understood. Stress related to acculturation may increase risk for psychosis among immigrant groups. In this study we examine the association between acculturative stress and psychotic-like experiences in a sample of Latino- and Asian-American immigrants to the United States in the National Latino and Asian American Study (n=2434). Acculturative stress was associated with visual and auditory hallucinations among Asians, but only with hearing voices among Latinos. Increased risk for psychotic-like experiences among Latinos was primarily associated with younger age of immigration. Acculturative stress appears to be a promising candidate mechanism explaining the relationship between immigration and psychosis, particularly among Asian Americans. Ethnic differences may reflect variability between groups that integrate more readily into the host culture and those that are subject to greater discrimination and environmental adversity. PMID- 23932448 TI - Chrysophaentins are competitive inhibitors of FtsZ and inhibit Z-ring formation in live bacteria. AB - The bacterial cell division protein FtsZ polymerizes in a GTP-dependent manner to form a Z-ring that marks the plane of division. As a validated antimicrobial target, considerable efforts have been devoted to identify small molecule FtsZ inhibitors. We recently discovered the chrysophaentins, a novel suite of marine natural products that inhibit FtsZ activity in vitro. These natural products along with a synthetic hemi-chrysophaentin exhibit strong antimicrobial activity toward a broad spectrum of Gram-positive pathogens. To define their mechanisms of FtsZ inhibition and determine their in vivo effects in live bacteria, we used GTPase assays and fluorescence anisotropy to show that hemi-chrysophaentin competitively inhibits FtsZ activity. Furthermore, we developed a model system using a permeable Escherichia coli strain, envA1, together with an inducible FtsZ yellow fluorescent protein construct to show by fluorescence microscopy that both chrysophaentin A and hemi-chrysophaentin disrupt Z-rings in live bacteria. We tested the E. coli system further by reproducing phenotypes observed for zantrins Z1 and Z3, and demonstrate that the alkaloid berberine, a reported FtsZ inhibitor, exhibits auto-fluorescence, making it incompatible with systems that employ GFP or YFP tagged FtsZ. These studies describe unique examples of nonnucleotide, competitive FtsZ inhibitors that disrupt FtsZ in vivo, together with a model system that should be useful for in vivo testing of FtsZ inhibitor leads that have been identified through in vitro screens but are unable to penetrate the Gram-negative outer membrane. PMID- 23932449 TI - Synthesis and biological evaluation of furopyrimidine N,O-nucleosides. AB - A series of modified N,O-nucleosides, characterized by the presence of a furopyrimidine moiety, has been synthesized by exploiting a Sonogashira cross coupling reaction of 1-isoxazolidinyl-5-iodouracil with alkynes, followed by treatment with CuI in refluxing TEA/MeOH mixture. The obtained compounds were screened against both RNA and DNA viruses. None of the compounds were endowed with antiviral activity at subtoxic concentrations. However, some of them were able to inhibit proliferation of MRC-5, Vero, BS-C-1 cells by 50% (CC50) at concentrations ranging from 0.7 to 62.5 mM. PMID- 23932450 TI - Structural studies of beta-hairpin peptidomimetic antibiotics that target LptD in Pseudomonas sp. AB - We report structural studies in aqueous solution on backbone cyclic peptides that possess potent antimicrobial activity specifically against Pseudomonas sp. The peptides target the beta-barrel outer membrane protein LptD, which plays an essential role in lipopolysaccharide transport to the outer membrane. The peptide L27-11 contains a 12-residue loop (T(1)W(2)L(3)K(4)K(5)R(6)R(7)W(8)K(9)K(10)A(11)K(12)) linked to a DPro-LPro template. Two related peptides were also studied, one with various Lys to ornithine or diaminobutyric acid substitutions as well as a DLys(6) (called LB 01), and another containing the same loop sequence, but linked to an LPro-DPro template (called LB-02). NMR studies and MD simulations show that L27-11 and LB 01 adopt beta-hairpin structures in solution. In contrast, LB-02 is more flexible and importantly, adopts a wide variety of different backbone conformations, but not beta-hairpin conformations. L27-11 and LB-01 show antimicrobial activity in the nanomolar range against Pseudomonas aeruginosa, whereas LB-02 is essentially inactive. Thus the beta-hairpin structure of the peptide is important for antimicrobial activity. An alanine scan of L27-11 revealed that tryptophan side chains (W(2)/W(8)) displayed on opposite faces of the beta-hairpin represent key groups contributing to antimicrobial activity. PMID- 23932451 TI - Synthesis and biological evaluation of berberine-thiophenyl hybrids as multi functional agents: Inhibition of acetylcholinesterase, butyrylcholinesterase, and Abeta aggregation and antioxidant activity. AB - A series of berberine-thiophenyl hybrids were designed, synthesised, and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and beta-amyloid (Abeta) aggregation and as antioxidants. Among these hybrids, compounds 4f and 4i, berberine linked with o-methylthiophenyl and o chlorothiophenyl by a 2-carbon spacer, were observed to be potent inhibitors of AChE, with IC50 values of 0.077 and 0.042 MUM, respectively. Of the tested compounds, 4i was also the most potent inhibitor of BuChE, with an IC50 value of 0.662 MUM. Kinetic studies and molecular modelling simulations of the AChE inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives. The biological studies also demonstrated that these hybrids displayed interesting activities, including Abeta aggregation inhibition and antioxidant properties. PMID- 23932453 TI - Cloning, expression and molecular characterization of a 14-3-3 gene from a parasitic ciliate, Cryptocaryon irritans. AB - Cryptocaryon irritans is a parasitic ciliate and responsible for cryptocaryosis of ocean teleostean. In this paper, one gene homologous to 14-3-3 was isolated from cDNA library of C. irritans trophont/protomont stage and designated as Ci14 3-3. The full-length cDNA of the gene was 892bp with an open reading frame of 744bp, which encoded a polypeptide of 247 amino acids with a predicted molecular weight of 28.4kDa. After modification of the non-universal genetic codes, the open reading frame of Ci14-3-3 was inserted into plasmid pGEX-4T-1, transformed into Escherichia coli DH5alpha strain and then expressed as a glutathione S transferase fusion protein (rCi14-3-3). The result of western blot analysis showed that the rCi14-3-3 had antigenicity and the Ci14-3-3 gene in C. irritans was expressed at all stages of life cycle. The endogenous Ci14-3-3 not only distributed in cytoplasm, but also presented on the plasma membrane and the front end of cytostome in newly hatched theronts. However, when theronts were dying the protein appeared as dot-like aggregates around the nucleuses. The murine anti rCi14-3-3 sera were capable of causing agglutination/immobilization of theronts, suggesting its potential for vaccine development. PMID- 23932454 TI - Presence of zoonotic Enterocytozoon bieneusi in cats in a temple in central Thailand. AB - Enterocytozoon bieneusi is a common opportunistic intestinal pathogen in humans and animals. To investigate the prevalence, genotype and host specificity of E. bieneusi, 111 dog faecal samples were collected from dairy cattle farms, and 95 and 80 faecal samples were collected from dogs and cats, respectively, in a temple in central Thailand. E. bieneusi was found in 25 (31.3%) cats by nested PCR, but not in dogs. Genotyping analysis targeting the internal transcribed spacer of the rRNA gene identified genotype D - and other novel genotypes very similar to genotype D - which is a zoonotic genotype reported in both HIV patients and villagers in rural communities in Thailand. This is the first study to find E. bieneusi genotype D in cats, and it may be that cats are found to play an important role in E. bieneusi zoonotic transmission to humans. The present study indicates that further molecular epidemiological investigations of E. bieneusi among cats are necessary to evaluate their possible role as reservoir hosts and the potential risk they represent to humans. PMID- 23932455 TI - Immune response and protection provided by live tachyzoites and native antigens from the NC-6 Argentina strain of Neospora caninum in pregnant heifers. AB - The aim of the present study was to compare the immunogenicity and protective efficacy of live tachyzoites and native antigen extract obtained from the NC-6 Argentina strain against vertical transmission of Neospora caninum, following experimental challenge in pregnant heifers with the NC-1 strain. Sixteen pregnant heifers were divided in 4 groups of 4 animals, each receiving different inoculation before mating: group A animals were intravenously (iv) inoculated with 6.25*10(7) live tachyzoites of the NC-6 strain, group B heifers were inoculated twice subcutaneously (sc) with N. caninum native antigen extract formulated with ISCOMs, group C heifers were sc injected with sterile phosphate buffered saline (PBS) and group D heifers received sc ISCOM-matrix (ISCOMs without antigen). All groups were iv challenged with the NC-1 strain at 70 days of gestation. Serum and heparinized blood samples were collected eight times on weeks 0, 2, 3, 5, 9, 13, 16 and 17 post-inoculation. Dams were slaughtered at the 17th week of experiment (104 days of pregnancy) and placental and fetal tissue samples were collected. Specific antibody responses in heifers were tested by indirect enzyme linked immunosorbent assay (iELISA). The cellular immune response in dams was assessed by quantifying IFN-gamma production and the percentages of T cells (CD4(+), CD8(+) and gammadelta(+)) and monocytes in peripheral blood mononuclear cells (PBMC). Fetal fluids and tissue samples were tested using the indirect fluorescence antibody test, western blot, histopathology, immunohistochemistry and nested-PCR. A significant increase in N. caninum antibody response was detected in heifers of groups A and B from week 3 after inoculation (P<0.001). IFN-gamma production was similar in groups A and B at week 13 (P>0.05). All fetuses were viable at necropsy. Specific IgG against N. caninum was detected in 1/4 fetal fluids recovered from groups A, C and D heifers and 3/4 fetal fluids from group B. Transplacental transmission could be determined in one fetus from group A and three fetuses from group B by nPCR. All fetuses from groups C and D were positive by nPCR. It is noteworthy that dams with higher CD4(+)/CD8(+) ratios in PBMC, regardless of the experimental group, had lower pathology scores. The results of this study confirm that inoculation with live parasites pre-mating may provide at least partial protection against vertical transmission of N. caninum following challenge in heifers at early gestation. PMID- 23932456 TI - Assessment of palliative care for advanced non-small-cell lung cancer in France: a prospective observational multicenter study (GFPC 0804 study). AB - INTRODUCTION: Few studies assessed, in real life, symptoms, specific interventions and factors influencing palliative care (PC) initiation for patients with advanced non-small-cell lung cancer (NSCLC). The objective of this study was to examine, in a prospective cohort of advanced NSCLC patients, PC use and factors associated with early (<=3 months after diagnosis) PC initiation. METHODS: It was an observational multicenter study. Each center included 10 consecutive patients with PC initiation. RESULTS: 514 patients were enrolled by 39 centers (age: 62.3 +/- 10.7 years, performance status: 0/1; 68.6% cases). At baseline, the most frequent symptoms concerned pain (43.6%), malnutrition (37%) and psychological disorders (25.3%). Specific interventions were infrequent for pain control and malnutrition, but were more numerous for psychological and social problems and terminal care. Median time between diagnosis and PC initiation was 35 [13-84] days, median PC duration was 4.2 [0.6-9.3] months. Median overall survival was 8.6 [6.6-10.7] months; median survival after PC initiation was 3.6 [3.2-4.5] months. In multivariate analysis, only PS >=2 was linked to early PC. CONCLUSION: This study showed that early PC initiation is not a standard for patients with advanced NSCLC. PMID- 23932457 TI - Support service use and interest in support services among lung cancer patients. AB - OBJECTIVES: This study examined support service use and interest in support services among lung cancer patients (N = 165) at two comprehensive medical centers in the midwestern United States. MATERIALS AND METHODS: Patients completed an assessment of support service use (i.e., receipt of mental health services, complementary and alternative medicine [CAM], and help from a spiritual leader), interest in support services, and physical and psychological symptoms. RESULTS: Only 40% of patients with significant anxiety and depressive symptoms and 28% of the entire sample reported current mental health service use. However, nearly half (47%) of all patients were receiving support from a spiritual leader. Having late-stage lung cancer and a religious affiliation predicted receipt of spiritual support. Few patients who were not receiving mental health services or spiritual support were interested in these services (range = 4-18%). Conversely, although interest in CAM was expressed by a substantial minority of patients (27%) who were not using these services, rates of CAM use were relatively low (22%). CONCLUSIONS: Findings suggest that distressed lung cancer patients underuse mental health services, but many patients receive help from spiritual leaders. Given the lack of interest in mental health services among patients who are not receiving them, efforts are needed to enhance palatability of services and identify and reduce barriers to evidence-based service use. PMID- 23932458 TI - Validation and psychometric properties of the Asthma Control Questionnaire among children. AB - BACKGROUND: The Asthma Control Questionnaire (ACQ) is a patient-centered tool for evaluating asthma control. It has been validated in adults, but not well validated among children. OBJECTIVE: We evaluated the reliability, validity, and responsiveness to change of the ACQ for assessing asthma control in children ages 6 to 17 years. A threshold value for poor disease control and a minimally important difference were also determined. METHODS: Data from 305 asthmatic children enrolled in a clinical trial were examined. The ACQ was administered at 8 visits. We analyzed results for the combined age group and for the 6- to 11 year-old and 12- to 17-year-old age groups separately. RESULTS: Overall, the Cronbach alpha value (internal consistency) for the ACQ was 0.74 at baseline, and the intraclass correlation coefficient (test-retest reliability) for repeated questionnaires among stable patients was 0.53. The Pearson correlations between the ACQ and other asthma questionnaires were moderate to strong (-0.64 to -0.73). Mean ACQ scores were higher (worse) in patients whose peak flow decreased, who used more rescue medications, or who sought medical care for asthma than in patients who were stable (P < .0001 for all measures). Changes in ACQ scores were significantly different among patients with deteriorating, improving, or stable asthma symptoms (P <= .01). The optimal threshold indicating poor asthma control was 1.25 or greater. The minimally important difference was established to be 0.40. Results for the separate age groups were similar. CONCLUSION: The ACQ is a moderately reliable, valid, and responsive tool with adequate psychometric properties for assessing recent asthma control among children. PMID- 23932460 TI - Age-stratified comparison of large and peripheral airway/alveolar nitric oxide levels in children and young adults. PMID- 23932461 TI - Neuronal chemorepellent Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration. AB - BACKGROUND: Chronic airway diseases, including asthma, are characterized by increased airway smooth muscle (ASM) mass that is due in part to growth factor mediated ASM cell proliferation and migration. However, the molecular mechanisms underlying these effects are not completely understood. Semaphorin 3E (Sema3E) has emerged as an essential mediator involved in cell migration, proliferation, and angiogenesis, although its role in ASM cell function is not investigated. OBJECTIVES: We sought to determine the expression of Sema3E receptor, plexinD1, in human ASM cells (HASMCs); effect of Sema3E on basal and platelet-derived growth factor (PDGF)-induced proliferation and migration; and underlying signaling pathways. METHODS: Expression of plexinD1 in HASMCs was studied with RT PCR, immunostaining, and flow cytometry. The effect of Sema3E on HASMC proliferation and migration was evaluated by 5-ethynyl-2'-deoxyuridine (EdU) incorporation, cell count, and Boyden chamber assay. Sema3E-mediated intracellular signaling was investigated with fluorescent microscopy, flow cytometry, Rac1 activation, and Western blot analysis. RESULTS: HASMCs from healthy persons expressed plexinD1 more than HASMCs from asthmatic patients. Sema3E increased plexinD1 expression in HASMCs from asthmatic patients. Recombinant Sema3E inhibited PDGF-mediated HASMC proliferation and migration, which was associated with F-actin depolymerization, suppression of PDGF-induced Rac1 guanosine triphosphatase activity, and Akt and extracellular signal regulated kinase 1 and 2 phosphorylation. Bronchial biopsies from patients with mild asthma displayed immunoreactivity of plexinD1, suggesting the potential in vivo role of Sema3E-PlexinD1 axis in HASMC function. CONCLUSION: This study provides the first evidence that Sema3E receptor is expressed and plays functional roles in HASMCs. Our data suggest a regulatory role of Sema3E in PDGF mediated proliferation and migration, leading to downregulation of ASM remodeling. PMID- 23932459 TI - Genome-wide association study of lung function phenotypes in a founder population. AB - BACKGROUND: Lung function is a long-term predictor of mortality and morbidity. OBJECTIVE: We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. METHODS: We performed a genome-wide association study (GWAS) of FEV1, forced vital capacity (FVC), and FEV1/FVC in 1144 Hutterites aged 6 to 89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. RESULTS: Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7 * 10(-8) to 3.4 * 10( 9)). Nine SNPs at or near 4 additional loci had P < 10(-5) with FEV1/FVC. Only 2 SNPs were found with P < 10(-5) for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, 6 loci were identified that had a significant degree of functional connectivity (GRAIL P < .05), including 3 clusters of beta-defensin genes, 2 chemokine genes (CCL18 and CXCL12), and TNFRSF13B. CONCLUSION: This study identifies genome-wide significant associations and replicates results of previous GWASs. Multimarker modeling implicated for the first time common variation in genes involved in antimicrobial immunity in airway mucosa that influences lung function. PMID- 23932462 TI - Effects of aggressive statin therapy on patients with coronary saphenous vein bypass grafts: a systematic review and meta-analysis of randomized, controlled trials. AB - OBJECTIVES: The aim of this study was to investigate the effectiveness and safety of aggressive statin versus moderate statin therapy on patients with saphenous vein grafts (SVGs) in randomized, controlled trials (RCTs). METHODS: We searched MEDLINE (1980-June 2012), the Cochrane Controlled Trials Register, EMBASE, Science Citation Index, and PubMed (to June 2012), and found 10 relevant RCTs, including 7 substudy analyses from a Post-CABG trial, and 1 pooled analysis of the PROVE-IT TIMI 22 trial (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators) and A to Z trial. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes; phase Z of the A to Z trial. RESULTS: A total of 6645 of participants, ages ranging from 21 to 75 years old, were treated with coronary artery bypass graft (CABG) and were followed for 2 to 5 years. Eight studies showed that aggressive statin therapy had lower LDL-C levels and a decrease of 39% in graft atherosclerotic progression, 12% in new occlusions, and 19% in new lesions more than moderate statin therapy. Three reports indicated that aggressive statin therapy lowered the risk of repeated myocardial infarction more than moderate statin therapy for coronary revascularization (95% CI, 0.66-0.95; risk ratio [RR] = 0.80; and 95% CI, 0.66-0.85; RR = 0.75) and lowered the risk of cardiac death as well (95% CI, 0.64-1.08; RR = 0.83). Aggressive statin therapy had safety similar to that of moderate statin therapy except for a slight increase in myopathic events and aminotransferase levels. Seventy percent to 90% of patients took statin treatment as prescribed in long-term. CONCLUSIONS: Compared with moderate statin therapy, long-term aggressive statin lowered the LDL-C level significantly, further decreased the atherosclerotic progression of SVG, reduced the risks of repeated myocardial infarction and coronary revascularization after CABG, and revealed similar patient compliance and statin related adverse effects but slightly increased myopathy events and aminotransferase levels. PMID- 23932463 TI - Ambulatory blood pressure response to once-daily fimasartan: an 8-week, multicenter, randomized, double-blind, active-comparator, parallel-group study in Korean patients with mild to moderate essential hypertension. AB - BACKGROUND: Fimasartan, a selective angiotensin II type 1 receptor blocker, was approved in Korea for the treatment of patients with mild to moderate hypertension. OBJECTIVE: The aim of this study was to evaluate the 24-hour blood pressure (BP) profiles before and after 8-week treatment with fimasartan and to compare them with those of valsartan. METHODS: A multicenter, randomized, double blind, active-controlled, parallel-group study was conducted using ambulatory BP monitoring (ABPM). Korean patients with mild to moderate essential hypertension were enrolled and randomly received once-daily oral fimasartan 60 or 120 mg or valsartan 80 mg for 8 weeks. ABPM was performed before and after 8-week treatment, and clinic BP was also measured. Based on ABPM data, trough-to-peak ratio and smoothness index were derived. Tolerability was monitored throughout the study. RESULTS: Ninety-two patients were enrolled (mean [SD] age, 54.1 [8.2] years; weight, 67.9 [10.2] kg). After 8 weeks, 24-hour, daytime, and nighttime mean ambulatory systolic and diastolic BPs (SBP and DBP, respectively) were significantly decreased in all 3 treatment groups (range: SBP, -9.2 to -15.6 mm Hg; DBP, -5.0 to -10.7 mm Hg; P <0.0001-<0.05). The global trough-to-peak ratios of ambulatory DBP in the fimasartan groups were 0.74 (60 mg/d) and 0.81 (120 mg/d)--45.1% and 58.8% higher, respectively, than the ratio of 0.51 in the valsartan group. Fimasartan 60 mg/d was associated with 53.5% (SBP) and 68.3% (DBP) greater smoothness index scores compared with those with valsartan 80 mg/d (SBP, 1.52 vs. 0.99; DBP, 1.38 vs. 0.82). The decrease in clinic-measured DBP was significantly greater in the fimasartan 60-mg/d group compared with that in the valsartan 80-mg/d group (-14.0 vs -8.7 mm Hg; P = 0.0380). Fimasartan was well tolerated; headache was the most common adverse event. CONCLUSION: Once-daily fimasartan effectively maintained a BP-reduction profile over the full 24-hour dosing interval; this profile was comparable to or slightly better than that of once-daily valsartan. Fimasartan was well tolerated; headache was the most common adverse event. PMID- 23932464 TI - Assessing attitudes toward spinal immobilization. AB - BACKGROUND: Prospective studies have improved knowledge of prehospital spinal immobilization. The opinion of Emergency Medical Services (EMS) providers regarding spinal immobilization is unknown, as is their knowledge of recent research advances. STUDY OBJECTIVES: To examine the attitudes, knowledge, and comfort of prehospital and Emergency Department (ED) EMS providers regarding spinal immobilization performed under a non-selective protocol. METHODS: An online survey was conducted from May to July of 2011. Participants were drawn from the Howard County Department of Fire and Rescue Services and the Howard County General Hospital ED. The survey included multiple choice questions and responses on a modified Likert scale. Correlation analysis and descriptive data were used to analyze results. RESULTS: Comfort using the Kendrick Extrication Device was low among ED providers. Experienced providers were more likely to indicate comfort using this device. Respondents often believed that spinal immobilization is appropriate in the management of penetrating trauma to the chest and abdomen. Reported use of padding decreased along with the frequency with which providers practice and encounter immobilized patients. Respondents often indicated that they perform spinal immobilization due solely to mechanism of injury. Providers who feel as if spinal immobilization is often performed unnecessarily were more likely to agree that immobilization causes an unnecessary delay in patient care. CONCLUSIONS: The results demonstrate the need for improved EMS education in the use of the Kendrick Extrication Device, backboard padding, and spinal immobilization in the management of penetrating trauma. The attitudes highlighted in this study are relevant to the implementation of a selective spinal immobilization protocol. PMID- 23932465 TI - Emergency bedside ultrasound diagnosis of superior mesenteric artery dissection complicating acute aortic dissection. AB - BACKGROUND: A timely diagnosis of aortic dissection is associated with lower mortality. The use of emergent bedside ultrasound has been described to diagnose aortic dissection. However, there is limited literature regarding the use of bedside ultrasound to identify superior mesenteric artery dissection, a known high-risk feature of aortic dissection. OBJECTIVE: Our aim was to present a case of superior mesenteric artery dissection identified by bedside ultrasound and review the utility of bedside ultrasound in the diagnosis of aortic emergencies. CASE REPORT: We report a case of superior mesenteric artery dissection found on emergent bedside ultrasound in a 46-year-old male complaining of abdominal pain with a history of cocaine abuse and prior aortic dissection. Bedside ultrasound in the emergency department revealed an intimal flap in the descending aorta with extension into the superior mesenteric artery prompting early surgical consultation before computed tomography because of concern for acute mesenteric ischemia. CONCLUSION: Superior mesenteric artery dissection is a high-risk feature of aortic dissection and can be identified with emergent bedside ultrasound. PMID- 23932466 TI - Hygienic quality of faeces treated in urine diverting vermicomposting toilets. AB - On-site sanitation solutions have gained much interest in recent years. One such solution is the urine diverting vermicomposting toilet (UDVT). This study evaluated the hygienic quality of the composted material in six UDVTs in operation in France. Samples were taken from three sampling positions in each toilet, with increasing distance from the fresh material. The concentration of Salmonella spp., Enterococcus spp., thermotolarent coliforms and coliphages were analysed and plotted against a number of variables. The variables found to have the greatest impact was the pH (for Enterococcus spp. and thermotolarent coliforms (TTC)) and time since last maintenance (coliphages). The pH was found to correlate with the material maturity. The current practise of maintenance can cause recontamination of the stabilised material and increase the risk of regrowth of pathogenic microorganisms. A modification in the maintenance procedure, in which a fourth maturation point is introduced, would eliminate this risk. UDVTs were found to be a good on-site sanitation option as the maintenance requirement is small and the system effectively reduced odour and concentration of pathogen and indicator organisms in human waste while keeping the accumulation of material down to a minimum. If the vermicompost is to be used for crops consumed raw, an additional sanitisation step is recommended. PMID- 23932467 TI - Intractable hiccups resolved after resection of a cavernous malformation of the medulla oblongata. PMID- 23932468 TI - Non-traumatic superior hypophyseal aneurysm with associated pseudoaneurysm presenting with massive epistaxis. PMID- 23932469 TI - Lateral convexial tributary sinus of superior sagittal sinus. A rare anatomic variation and the importance of its recognition. PMID- 23932470 TI - Spinal granulomas associated with intradural morphine delivery systems: early diagnosis and surgical treatment. PMID- 23932471 TI - Microsurgical treatment of a ruptured dissecting labyrinthine artery aneurysm. PMID- 23932472 TI - Seasonal variations of biomarker responses in the marine blue mussel (Mytilus spp.). AB - Biomarkers, which can detect changes at the biochemical level, have been used for many years as early warning tools in environmental monitoring. In order to distinguish between natural variability and the potential effects of anthropogenic pollution, it is essential to identify background levels and establish the potential influence of abiotic (season, temperature and salinity) and biotic (gametogenesis) factors. In this study, we examined various biomarkers of stress (glutathione S-transferase (GST)), reproduction (vitellin-like proteins) and damage (lipid peroxidation (LPO) and DNA damage (DNA)) in marine mussels (Mytilus spp.) from a known pristine hybrid zone. Levels of all biomarker expression varied between seasons and appeared to be linked to the reproductive cycle. Oxidative stress in winter, with low GST expression and a higher expression of LPO and DNA damage displayed could be explained by low food availability. These data provide vital baseline information for future ecotoxicological and environmental monitoring studies. PMID- 23932473 TI - Climate change and the oceans--what does the future hold? AB - The ocean has been shielding the earth from the worst effects of rapid climate change by absorbing excess carbon dioxide from the atmosphere. This absorption of CO2 is driving the ocean along the pH gradient towards more acidic conditions. At the same time ocean warming is having pronounced impacts on the composition, structure and functions of marine ecosystems. Warming, freshening (in some areas) and associated stratification are driving a trend in ocean deoxygenation, which is being enhanced in parts of the coastal zone by upwelling of hypoxic deep water. The combined impact of warming, acidification and deoxygenation are already having a dramatic effect on the flora and fauna of the oceans with significant changes in distribution of populations, and decline of sensitive species. In many cases, the impacts of warming, acidification and deoxygenation are increased by the effects of other human impacts, such as pollution, eutrophication and overfishing. The interactive effects of this deadly trio mirrors similar events in the Earth's past, which were often coupled with extinctions of major species' groups. Here we review the observed impacts and, using past episodes in the Earth's history, set out what the future may hold if carbon emissions and climate change are not significantly reduced with more or less immediate effect. PMID- 23932474 TI - Incidence of entanglements with marine debris by northern gannets (Morus bassanus) in the non-breeding grounds. AB - The quantification of entanglements of megafauna with plastic debris at sea is difficult to assess for several reasons, such as detection and reporting biases. We used standardized vessel based counts to describe and quantify the occurrence of marine debris entanglements in northern gannets Morus bassanus at five of its main wintering areas. We observed 34 entangled birds in total, representing 0.93% of all gannets counted (n=3672 individuals). The incidence of entanglements largely varied geographically, being exceptionally high off Mauritania (20.2% of the birds in late spring). Most birds affected were immature (1.88% compared to 0.06% in adults), which in turn represented 52.4% of all the birds. Entanglements in the lower bill mandible were the most frequent, mainly with red-colored plastic objects. Further research is urgently needed to evaluate the impact of entanglements at the population level and its occurrence in other marine species, and to seek potential solutions. PMID- 23932475 TI - Hg bioaccumulation in marine copepods around hydrothermal vents and the adjacent marine environment in northeastern Taiwan. AB - The Hg concentration in seawater and copepod samples collected from the area around hydrothermal vents at Kueishan Island and the adjacent marine environment in northeastern Taiwan were analyzed to study Hg bioaccumulation in copepods living in polluted and clean marine environments. The seawater collected from the hydrothermal vent area had an extremely high concentration of dissolved Hg, 50.6 256 ng l(-1). There was slightly higher Hg content in the copepods, 0.08-0.88 MUg g(-1). The dissolved Hg concentration in the hydrothermal vent seawater was two to three orders of magnitude higher than that in the adjacent environment. The bioconcentration factor of the studied copepods ranged within 10(3)-10(6), and showed higher dissolved concentration as the bioconcentration factor was lower. A substantial abundance, but with less copepod diversity was recorded in the seawater around the hydrothermal vent area. Temora turbinata was the species of opportunity under the hydrothermal vent influence. PMID- 23932476 TI - Trace and major elements distribution and transfer within a benthic system: polychaete Chaetopterus variopedatus, commensal crab Polyonyx gibbesi, worm tube, and sediments. AB - Samples of the polychaete Chaetopterus variopedatus, worm tubes, commensal crab Polyonyx gibbesi and sediments were collected in eight sites in Todos os Santos Bay, Brazil, in order to evaluate the potential use of the polychaetes and crabs as biomonitors and to assess the relationships and accumulation of trace and major elements in different benthic compartments. Trace and major elements were determined by ICP OES. Organic carbon, total nitrogen and sulfur were determined by CNS elemental analyser. Tubes, crabs and polychaetes were important in the retention of trace and major elements. Metals that presented the highest accumulation in polychaetes (i.e. Mg>Al>Fe>Zn>Mn>Co>Cu>Ba>Cr) where the same for crabs (i.e. Mg>Al>Fe>Mn>Co>Zn>Cu>Ba>Cr). High concentrations of Al, Ba, Cr, Mn and Fe, from terrigenous sources, were observed in tubes, which presented accumulation factors up to 81.5 for Mn. Sedentary polychaetes are seen as good biomonitor alternatives for metal contamination studies, because they are one of the most abundant taxon in the benthic system, live in direct contact with sediments, are present in broad distributions and can also handle relatively high concentrations of metals ensuring chronic exposition. The possibility to work with not only the polychaete but also its tube offers advantages compared to bivalves that generally do not accumulate certain metals in very high levels. PMID- 23932477 TI - Guiding principles for the improved governance of port and shipping impacts in the Great Barrier Reef. AB - The Great Barrier Reef (GBR) region of Queensland, Australia, encompasses a complex and diverse array of tropical marine ecosystems of global significance. The region is also a World Heritage Area and largely within one of the world's best managed marine protected areas. However, a recent World Heritage Committee report drew attention to serious governance problems associated with the management of ports and shipping. We review the impacts of ports and shipping on biodiversity in the GBR, and propose a series of guiding principles to improve the current governance arrangements. Implementing these principles will increase the capacity of decision makers to minimize the impacts of ports and shipping on biodiversity, and will provide certainty and clarity to port operators and developers. A 'business as usual' approach could lead to the GBR's inclusion on the List of World Heritage in Danger in 2014. PMID- 23932478 TI - Formation of iron plaque on mangrove Kandalar. Obovata (S.L.) root surfaces and its role in cadmium uptake and translocation. AB - In this study, a pot experiment was conducted to investigate the formation of iron plaque under Cd stress and its role in Cd uptake and translocation by mangrove Kandalar. Obovata (S.L.). Results showed: 1. the Fe in dithionite citrate-bicarbonate (DCB) extracts increased with an increasing rate of Cd treatments. 2. the Cd in DCB extracts and in roots and above-ground tissues significantly increased with an increasing Cd application; 3. significant positive correlation between concentration of Cd and Fe in DCB extracts existed (p < 0.05); and that 4. the proportion of Cd in DCB extracts was significantly lower than that in roots or above-ground tissues (p < 0.001). In conclusion, formation of Fe plaque can precipitate Cd on root surfaces and impede its uptake and translocation in Kandalar. Obovata (S.L.). However, in comparison with root tissues, Fe plaque is of little significance. It is the mangrove root tissue that acts as the main buffer to Cd uptake and translocation. PMID- 23932480 TI - [Bilateral orbital involvement as the presenting sign of chronic lymphocytic leukemia]. PMID- 23932479 TI - Potential functional roles of DNA demethylation intermediates. AB - DNA methylation in the form of 5-methylcytosine (5mC) is a key epigenetic regulator in mammals, and the dynamic balance between methylation and demethylation impacts various processes from development to disease. The recent discovery of the enzymatic generation and removal of the oxidized derivatives of 5mC, namely 5-hydroxymethylcysotine (5hmC), 5-formylcytosine (5fC), and 5 carboxylcytosine (5caC) in mammalian cells has led to a paradigm shift in our understanding of the demethylation process. Interestingly, emerging evidence indicates that these DNA demethylation intermediates are dynamic and could themselves carry regulatory functions. Here, we discuss 5hmC, 5fC, and 5caC as new epigenetic DNA modifications that could have distinct regulatory functions in conjunction with potential protein partners. PMID- 23932481 TI - [Bilateral retinal folds and familial high hyperopia: a case report]. PMID- 23932482 TI - [Rapidly worsening bilateral papilledema secondary to carcinomatous meningitis. Case report and review of the literature]. PMID- 23932483 TI - [Spontaneous rupture of a drusenoid pigment epithelium detachment]. PMID- 23932484 TI - [Structural imaging of keratoconus after corneal cross-linking]. PMID- 23932485 TI - [Epidemiology of uveitis in the Tunis area]. AB - PURPOSE: To identify the epidemiological characteristics and the most common etiologies of uveitis in the Tunis area. METHODS: Medical records for all uveitis patients seen from September 2003 through October 2009 were included. RESULTS: A total of 424 patients (596 eyes) were included. The mean age at onset of uveitis was 36 years, and the male-to-female ratio was 0.66. Uveitis was unilateral in 56.4%. Anterior uveitis was most common (48%), followed by panuveitis (33.6%), posterior uveitis (13.3%), and intermediate uveitis (5%). The most common causes were Behcet disease (14.7%), toxoplasmosis (10.2%), Vogt-Koyanagi-Harada (VKH) syndrome (3.7%) and sarcoidosis (3.3%). Retinal vasculitis was found in 20%. Behcet disease was the most common cause of chronic uveitis. The most common complications were cataract (21.6%), ocular hypertension (12%) and macular edema (5.6%). CONCLUSION: In our study, the most common causes of uveitis were Behcet disease, toxoplasmosis, VKH syndrome and sarcoidosis. PMID- 23932487 TI - Inter-observer reproducibility of semi-automatic tumor diameter measurement and volumetric analysis in patients with lung cancer. AB - OBJECTIVES: Therapy monitoring in oncologic patient requires precise measurement methods. In order to improve the precision of measurements, we used a semi automated generic segmentation algorithm to measure the size of large lung cancer tumors. The reproducibility of computer-assisted measurements were assessed and compared with manual measurements. METHODS: CT scans of 24 consecutive lung cancer patients who were referred to our hospital over a period of 6 months were analyzed. The tumor sizes were measured manually by 3 independent radiologists, according to World Health Organization (WHO) and the Revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. At least 10 months later, measurements were repeated semi-automatically on the same scans by the same radiologists. The inter-observer reproducibility of all measurements was assessed and compared between manual and semi-automated measurements. RESULTS: Manual measurements of the tumor longest diameter were significantly (p < 0.05) smaller compared with the semi-automated measurements. The intra-rater correlations coefficients were significantly higher for measurements of longest diameter (intra-class correlation coefficients: 0.998 vs. 0.986; p < 0.001) and area (0.995 vs. 0.988; p = 0.032) using semi-automated compared with manual method. The variation coefficient for manual measurement of the tumor area (WHO guideline, 15.7% vs. 7.3%) and the longest diameter (RECIST guideline, 7.7% vs. 2.7%) was 2-3 times that of semi-automated measurement. CONCLUSIONS: By using computer-assisted size assessment in primary lung tumor, interobserver variability can be reduced to about half to one-third compared to standard manual measurements. This indicates a high potential value for therapy monitoring in lung cancer patients. PMID- 23932488 TI - Transgenes and protein localization: myths and legends. AB - Fluorescent protein (FP) fusions are frequently used to localize and follow the movement of proteins in living cells. However, a consensus is missing about the experimental design and controls that guarantee the reliability of the results. Here, we discuss possible artifacts and try to navigate through the many methods, preferences, and assumptions that surround protein localization in plants that make it difficult to design a universal approach to achieve reliable results. PMID- 23932486 TI - Smoking status and self-reported race affect the frequency of clinically relevant oncogenic alterations in non-small-cell lung cancers at a United States-based academic medical practice. AB - INTRODUCTION: The identification of somatic genomic aberrations in non-small-cell lung cancer (NSCLC) is part of evidence-based practice guidelines for care of patients with NSCLC. We sought to establish the frequency and correlates with these changes in routine patient-tumor sample pairs. METHODS: Clinicopathologic data and tumor genotype were retrospectively compiled and analyzed from an overall cohort of 381 patient-tumor samples. RESULTS: Of these patients, 75.9% self-reported White race, 13.1% Asian, 6.5% Black, 27.8% were never-smokers, 54.9% former-smokers and 17.3% current-smokers. The frequency of EGFR mutations was 23.9% (86/359), KRAS mutations 34.2% (71/207) and ALK FISH positivity 9.1% (23/252) in tumor samples, and almost all had mutually exclusive results for these oncogenes. In tumors from White, Black and Asian patients, the frequencies of EGFR mutations were 18.4%, 18.2% and 62%, respectively; of ALK FISH positivity 7.81%, 0% and 14.8%, respectively; and of KRAS mutations 41.6%, 20% and 0%. These patterns changed significant with increasing pack-year history of smoking. In White patients, the frequencies of EGFR mutations and ALK FISH positivity decreased with increasing pack-year cohorts; while the frequencies of KRAS mutations increased. Interestingly, in Asian patients the frequencies of EGFR mutations were similar in never smokers and in the cohorts with less than 45pack year histories of smoking and only decreased in the 45pack-year plus cohort. CONCLUSIONS: The frequencies of somatic EGFR, KRAS, and ALK gene abnormalities using routine lung cancer tissue samples from our United States-based academic medical practice reflect the diverse ethnicity (with a higher frequency of EGFR mutations in Asian patients) and smoking patterns (with an inverse correlation between EGFR mutation and ALK rearrangement) of our tested population. These results may help other medical practices appreciate the expected results from introduction of routine tumor genotyping techniques into their day-to-day care of NSCLC. PMID- 23932489 TI - Use of Onyx for endovascular embolization of pediatric spinal perimedullary (Type IV) fistula: case report. PMID- 23932490 TI - Distinct representations of cognitive and motivational signals in midbrain dopamine neurons. AB - Dopamine is essential to cognitive functions. However, despite abundant studies demonstrating that dopamine neuron activity is related to reinforcement and motivation, little is known about what signals dopamine neurons convey to promote cognitive processing. We therefore examined dopamine neuron activity in monkeys performing a delayed matching-to-sample task that required working memory and visual search. We found that dopamine neurons responded to task events associated with cognitive operations. A subset of dopamine neurons were activated by visual stimuli if the monkey had to store the stimuli in working memory. These neurons were located dorsolaterally in the substantia nigra pars compacta, whereas ventromedial dopamine neurons, some in the ventral tegmental area, represented reward prediction signals. Furthermore, dopamine neurons monitored visual search performance, becoming active when the monkey made an internal judgment that the search was successfully completed. Our findings suggest an anatomical gradient of dopamine signals along the dorsolateral-ventromedial axis of the ventral midbrain. PMID- 23932492 TI - Seasonal variations of date of diagnosis and birth for neuroblastoma patients in Italy. AB - BACKGROUND: Analysis of seasonal variation of diagnosis or birth of childhood cancers may provide useful insight about possible aetiological risk factors, such as infectious agents and environmental exposures, but studies on neuroblastoma are lacking. PROCEDURE: Two thousand seven hundred fifty-six cases of neuroblastoma, diagnosed between 1980 and 2010, registered in the Italian Neuroblastoma Registry, were included in the study. Subgroup analyses were carried out by age, gender and stage at diagnosis. Seasonal trend was assessed by a harmonic function in a Poisson regression model, adjusted for the number of live births. RESULTS: No trend in the date of diagnosis was found either in the entire cohort or in the various sub-groups. Similarly, a seasonal trend of birth was not observed in the whole cohort. Conversely, in the subgroup of infants with stage 4S, a significant peak of July births was found (23.6% increment from the average, p=0.042). The summer peak was confirmed after stratifying 4S patients by gender and period of diagnosis. CONCLUSIONS: A major effect of risk factors related to seasonality does not appear to affect the risk of developing neuroblastoma. However, the time pattern of birth observed by stage at diagnosis is consistent with the hypothesis that Stage 4S is a distinct disease with probably a different aetiology, as indicated by investigations on its metastatic pattern and its peculiar gene expression. An aetiological role of seasonally related factors, e.g., favouring the survival of defective neural crest stem cells, remains speculative and need confirmation by independent studies. PMID- 23932493 TI - Realization of radioactive equilibrium in the KRISS radon chamber. AB - The maintenance of radioactive equilibrium between radon and its decay products in a radon chamber is necessary to calibrate radon decay product monitors. In this study, the activity concentrations of radon decay products have been measured, and mosquito-repellent incense has been used to produce aerosol particles in the chamber. Filter papers with 8 MUm pore size were used to collect aerosol in the chamber. The activity concentrations of radon decay products have been evaluated by the Modified Tsivoglou Method. The correction factors due to the differences in counting time requirements of the Modified Tsivoglou Method and the time delay between consecutive measurements have been determined. Finally, the radioactive equilibrium has been confirmed by applying the Bateman equation. PMID- 23932491 TI - Natural scene statistics account for the representation of scene categories in human visual cortex. AB - During natural vision, humans categorize the scenes they encounter: an office, the beach, and so on. These categories are informed by knowledge of the way that objects co-occur in natural scenes. How does the human brain aggregate information about objects to represent scene categories? To explore this issue, we used statistical learning methods to learn categories that objectively capture the co-occurrence statistics of objects in a large collection of natural scenes. Using the learned categories, we modeled fMRI brain signals evoked in human subjects when viewing images of scenes. We find that evoked activity across much of anterior visual cortex is explained by the learned categories. Furthermore, a decoder based on these scene categories accurately predicts the categories and objects comprising novel scenes from brain activity evoked by those scenes. These results suggest that the human brain represents scene categories that capture the co-occurrence statistics of objects in the world. PMID- 23932494 TI - Prospective analysis of the association between estrogen receptor gene variants and the risk of cognitive decline in elderly women. AB - A plethora of data suggests a role for estrogen in cognitive function and genetic variants in the estrogen receptors ESR1 and ESR2 have been implicated in a range of hormone-sensitive diseases. It remains unknown however, whether ESR polymorphisms are associated with the risk of decline in specific domains of cognitive function. Data came from 3799 non-demented, community-dwelling elderly women recruited in France to the 3C Study. A short cognitive test battery was administered at baseline and 2, 4 and 7 years follow-up to assess global function, verbal fluency, visual memory, psychomotor speed and executive function. Detailed socio-demographic, behavioral, physical and mental health information was also gathered and genotyping of five common ESR1 and ESR2 polymorphisms was also performed. In multivariable-adjusted Cox analysis, ESR1 rs2234693 and rs9340799 were not significantly associated with the risk of decline on any of the cognitive tasks. However, significant associations with ESR2 polymorphisms were identified. The A allele of rs1256049 was associated with an increased risk of substantial decline in visual memory (HR:1.64, 95% CI: 1.23 2.18, p=0.0007), psychomotor speed (HR:1.43, 95% CI: 1.12-1.83, p=0.004), and on the incidence of Mild Cognitive Impairment (HR:1.31, 95% CI: 1.05-1.64, p=0.02). There was also a weaker association between the A allele of rs4986938 and a decreased risk of decline in psychomotor speed. Our large multicentre prospective study provides preliminary evidence that ESR2 genetic variants may be associated with specific cognitive domains and suggests that further examination of the role of this gene in cognitive function is warranted. PMID- 23932495 TI - Prenatal MAM administration affects histone H3 methylation in postnatal life in the rat medial prefrontal cortex. AB - Several findings have indicated that schizophrenia may be connected with the impaired epigenetic regulation of gene transcription. The present study investigated the epigenetic modifications connected with histone H3 methylation at lysine (K)4 and K9 in the medial prefrontal cortex (mPFC) in a neurodevelopmental model of schizophrenia based on prenatal administration of methylazoxymethanol (MAM) at embryonic day 17, which impairs the sensorimotor gating process in adult but not adolescent animals. The effect of MAM was determined at different postnatal ages, pre-puberty (P15, P30 and P45) and post puberty (P60 and P70), using western blot analyses. MAM treatment altered the levels of H3K9me2 before puberty. H3K9me2 was decreased at P15 and P45 but was increased at P30. In contrast, H3K4me3 was noticeably decreased in adult rats. Immunofluorescence experiments revealed that H3K9me2 protein levels were increased in neuronal cells at P30 and that H3K4me3 levels were decreased in astrocytes at P60 after MAM administration. Decreases in the methyltransferase ASH2L protein levels at P45, P60 and P70 were also observed, while the protein levels of the methyltransferase G9a did not change. In addition, levels of the demethylases LSD1 and JARID1c were analysed after MAM administration. LSD1 protein levels were increased at P15 but decreased at P30. JARID1c protein levels were increased in the MAM-treated animals at P60. Decreased Gad1 mRNA levels were found in adult MAM-treated animals, similar to alternation observed in schizophrenia. The present study indicates that prenatal MAM administration evokes changes in the methylation patterns of histone H3 during postnatal life. PMID- 23932496 TI - Macrophages engulfing apoptotic thymocytes produce retinoids to promote selection, differentiation, removal and replacement of double positive thymocytes. AB - The thymus provides the microenvironment in which thymocytes develop into mature T-cells, and interactions with thymic stromal cells are thought to provide the necessary signals for thymocyte maturation. Recognition of self-MHC by T-cells is a basic requirement for mature T-cell functions, and those thymocytes that do not recognize or respond too strongly to the peptide-loaded self-MHC molecules found in the thymus undergo apoptosis. As a result, 95% of the thymocytes produced will die and be subsequently cleared by macrophages. This review describes a complex crosstalk between developing thymocytes and engulfing macrophages which is mediated by retinoids produced by engulfing macrophages. The interaction results in the harmonization of the rate of cell death of dying double positive cells with their clearance and replacement, and in promotion of the differentiation of the selected cells in the thymus. PMID- 23932497 TI - Diaphragmatic muscle reconstruction with an aligned electrospun poly(epsilon caprolactone)/collagen hybrid scaffold. AB - Large diaphragmatic muscle defects in congenital diaphragmatic hernia (CDH) are reconstructed by prosthetic materials or autologous grafts, which are associated with high complications and reherniation. In this study we examined the feasibility of using aligned electrospun poly(epsilon-caprolactone) (PCL)/collagen hybrid scaffolds for diaphragmatic muscle reconstruction. The hybrid scaffolds were implanted into a central left hemi-diaphragmatic defect (approximately 70% of the diaphragmatic tissue on the left side) in rats. Radiographic and magnetic resonance imaging (MRI) analyses showed no evidence of herniation or retraction up to 6 months after implantation. Histological and immunohistochemical evaluations revealed ingrowth of muscle tissue into the scaffolds. The mechanical properties of the retrieved diaphragmatic scaffolds were similar to those of normal diaphragm at the designated time points. Our results show that the aligned electrospun hybrid scaffolds allowed muscle cell migration and tissue formation. The aligned scaffolds may provide implantable functional muscle tissues for patients with diaphragmatic muscle defects. PMID- 23932498 TI - Transferrin-conjugated magnetic silica PLGA nanoparticles loaded with doxorubicin and paclitaxel for brain glioma treatment. AB - The effective treatment of malignant brain glioma is hindered by the poor transport across the blood-brain barrier (BBB) and the low penetration across the blood-tumor barrier (BTB). In this study, transferrin-conjugated magnetic silica PLGA nanoparticles (MNP-MSN-PLGA-Tf NPs) were formulated to overcome these barriers. These NPs were loaded with doxorubicin (DOX) and paclitaxel (PTX), and their anti-proliferative effect was evaluated in vitro and in vivo. The in vitro cytotoxicity of drug-loaded NPs was evaluated in U-87 cells. The delivery and the subsequent cellular uptake of drug-loaded NPs could be enhanced by the presence of magnetic field and the usage of Tf as targeting ligand, respectively. In particular, cells treated with DOX-PTX-NPs-Tf with magnetic field showed the highest cytotoxicity as compared to those treated with DOX-PTX-NPs-Tf, DOX-PTX NPs, DOX-PTX-NPs-Tf with free Tf. The in vivo therapeutic efficacy of drug-loaded NPs was evaluated in intracranial U-87 MG-luc2 xenograft of BALB/c nude mice. In particular, the DOX-PTX-NPs-Tf treatment exhibited the strongest anti-glioma activity as compared to the PTX-NPs-Tf, DOX-NPs-Tf or DOX-PTX-NPs treatment. Mice did not show acute toxicity after administrating with blank MNP-MSN-PLGA-Tf NPs. Overall, MNP-MSN-PLGA-Tf NPs are promising carriers for the delivery of dual drugs for effective treatment of brain glioma. PMID- 23932499 TI - Nitric oxide integrated polyethylenimine-based tri-block copolymer for efficient antibacterial activity. AB - The work demonstrated a successful synthesis of nitric oxide (NO)-releasing material and its antibacterial effect on Gram-negative Escherichia coli (E. coli), Gram-positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA). The polymeric support composed of thermosensitive Pluronic F68 having good biocompatibility and branched polyethylenimine (BPEI) housed N diazeniumdiolates (NONOates) which could store and release NO under appropriate physiological condition. The developed F68-BPEI-NONOates releases a sufficient amount of NO under physiological condition to elicit effective killing of E. coli, S. aureus and MRSA. The antibacterial ability of the released NO was compared to untreated control or unmodified F68 polymer by using confocal microscopy; F68-BPEI-NONOates demonstrated excellent antibacterial activity with in vitro low cytotoxicity. TEM investigation also revealed the destruction of bacteria membrane caused by NO. The effectiveness of F68-BPEI-NONOates against resistant strains such as MRSA provides a very simple but highly efficient strategy to combat drug-resistant bacterial infections. PMID- 23932500 TI - Preformed albumin corona, a protective coating for nanoparticles based drug delivery system. AB - The non-specific interaction between nanoparticles (NPs) and plasma proteins occurs immediately after NPs enter the blood, resulting in the formation of the protein corona that thereafter replaces the original NPs and becomes what the organs and cells really see. Consequently, the in vivo fate of NPs and the biological responses to the NPs are changed. This is one substantial reason for the two main problems of the NPs based drug delivery system, i.e. nanotoxicity and rapid clearance of NPs from the blood after intravenous injection. Here, we demonstrate the successful application of the preformed albumin corona in inhibiting the plasma proteins adsorption and decreasing the complement activation, and ultimately in prolonging the blood circulation time and reducing the toxicity of the polymeric PHBHHx NPs. Since the interaction of proteins with various nano-materials and/or -particles is ubiquitous, pre-forming albumin corona has a great potential to be a versatile strategy for optimizing the NPs based drug delivery system. PMID- 23932501 TI - An annulus fibrosus closure device based on a biodegradable shape-memory polymer network. AB - Injuries to the intervertebral disc caused by degeneration or trauma often lead to tearing of the annulus fibrosus (AF) and extrusion of the nucleus pulposus (NP). This can compress nerves and cause lower back pain. In this study, the characteristics of poly(D,L-lactide-co-trimethylene carbonate) networks with shape-memory properties have been evaluated in order to prepare biodegradable AF closure devices that can be implanted minimally invasively. Four different macromers with (D,L-lactide) to trimethylene carbonate (DLLA:TMC) molar ratios of 80:20, 70:30, 60:40 and 40:60 with terminal methacrylate groups and molecular weights of approximately 30 kg mol(-1) were used to prepare the networks by photo crosslinking. The mechanical properties of the samples and their shape-memory properties were determined at temperatures of 0 degrees C and 40 degrees C by tensile tests- and cyclic, thermo-mechanical measurements. At 40 degrees C all networks showed rubber-like behavior and were flexible with elastic modulus values of 1.7-2.5 MPa, which is in the range of the modulus values of human annulus fibrosus tissue. The shape-memory characteristics of the networks were excellent with values of the shape-fixity and the shape-recovery ratio higher than 98 and 95%, respectively. The switching temperatures were between 10 and 39 degrees C. In vitro culture and qualitative immunocytochemistry of human annulus fibrosus cells on shape-memory films with DLLA:TMC molar ratios of 60:40 showed very good ability of the networks to support the adhesion and growth of human AF cells. When the polymer network films were coated by adsorption of fibronectin, cell attachment, cell spreading, and extracellular matrix production was further improved. Annulus fibrosus closure devices were prepared from these AF cell compatible materials by photo-polymerizing the reactive precursors in a mold. Insertion of the multifunctional implant in the disc of a cadaveric canine spine showed that these shape-memory devices could be implanted through a small slit and to some extent deploy self-sufficiently within the disc cavity. PMID- 23932502 TI - Bioimaging and pulmonary applications of self-assembled Flt1 peptide-hyaluronic acid conjugate nanoparticles. AB - Despite wide exploitation of corticosteroid drugs for the treatment of asthma, the poor therapeutic effect on a neutrophilic subtype of asthma prohibits the full recovery of asthma patients. In this work, dexamethasone (Dexa) was loaded in Flt1 peptide-hyaluronic acid (HA) conjugate nanoparticles to overcome the limitation of corticosteroid resistance for the treatment of neutrophilic pulmonary inflammation. Flt1 peptide-HA conjugates are self-assembled to nanoparticles because of hydrophobic Flt1 peptide conjugated to HA by benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) chemistry. In vitro bioimaging showed efficient internalization of Flt1 peptide HA conjugate nanoparticles into lung epithelial cells by HA-receptor mediated endocytosis. Also, ex vivo imaging for the biodistribution in ICR mice revealed long-term retention of Flt1 peptide-HA conjugate nanoparticles in deep lung tissues possibly due to mucoadhesive property of HA. On the basis of bioimaging results for pulmonary drug delivery applications, we prepared Dexa-loaded Flt1 peptide-HA conjugate nanoparticles. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) confirmed the formation of nanoparticles, which reduced cytokine levels of lipopolysaccharide (LPS)-stimulated cells more efficiently than free Dexa. Furthermore, according to the bronchoalveolar lavage (BAL) cellularity and histological analysis, Dexa loaded Flt1 peptide-HA conjugate nanoparticles showed remarkable therapeutic effects in both eosinophilic and neutrophilic asthma model mice. PMID- 23932503 TI - Therapeutic angiogenesis by a myoblast layer harvested by tissue transfer printing from cell-adhesive, thermosensitive hydrogels. AB - Peripheral arterial disease (PAD) is characterized by the altered structure and function of arteries caused by accumulated plaque. There have been many studies on treating this disease by the direct injection of various types of therapeutic cells, however, the low cell engraftment efficiency and diffusion of the transplanted cells have been major problems. In this study, we developed an approach (transfer printing) to deliver monolayer of cells to the hindlimb ischemic tissue using thermosensitive hydrogels, and investigated its efficacy in long term retention upon transplantation and therapeutic angiogenesis. We first investigated the in vitro maintenance of robust cell-cell contacts and stable expression of the ECM proteins in myoblast layer following transfer printing process. In order to confirm the therapeutic effect of the myoblasts in vivo, we cultured a monolayer of C2C12 myoblasts on thermosensitive hydrogels, which was then transferred to the hindlimb ischemia tissue of athymic mice directly from the hydrogel by conformal contact. The transferred myoblast layer was retained for a longer period of time than an intramuscularly injected cell suspension. In addition, the morphology of the mice and laser Doppler perfusion (28 days after treatment) supported that the myoblast layer enhanced the therapeutic effects on the ischemic tissue. In summary, the transplantation of the C2C12 myoblast layer using a tissue transfer printing method could represent a new approach for the treatment of PAD by therapeutic angiogenesis. PMID- 23932505 TI - Multi-detector computed tomography (MDCT) in persistent fifth aortic arch (PFAA). PMID- 23932504 TI - Tuning mechanical performance of poly(ethylene glycol) and agarose interpenetrating network hydrogels for cartilage tissue engineering. AB - Hydrogels are attractive for tissue engineering applications due to their incredible versatility, but they can be limited in cartilage tissue engineering applications due to inadequate mechanical performance. In an effort to address this limitation, our team previously reported the drastic improvement in the mechanical performance of interpenetrating networks (IPNs) of poly(ethylene glycol) diacrylate (PEG-DA) and agarose relative to pure PEG-DA and agarose networks. The goal of the current study was specifically to determine the relative importance of PEG-DA concentration, agarose concentration, and PEG-DA molecular weight in controlling mechanical performance, swelling characteristics, and network parameters. IPNs consistently had compressive and shear moduli greater than the additive sum of either single network when compared to pure PEG DA gels with a similar PEG-DA content. IPNs withstood a maximum stress of up to 4.0 MPa in unconfined compression, with increased PEG-DA molecular weight being the greatest contributing factor to improved failure properties. However, aside from failure properties, PEG-DA concentration was the most influential factor for the large majority of properties. Increasing the agarose and PEG-DA concentrations as well as the PEG-DA molecular weight of agarose/PEG-DA IPNs and pure PEG-DA gels improved moduli and maximum stresses by as much as an order of magnitude or greater compared to pure PEG-DA gels in our previous studies. Although the viability of encapsulated chondrocytes was not significantly affected by IPN formulation, glycosaminoglycan (GAG) content was significantly influenced, with a 12-fold increase over a three-week period in gels with a lower PEG-DA concentration. These results suggest that mechanical performance of IPNs may be tuned with partial but not complete independence from biological performance of encapsulated cells. PMID- 23932506 TI - Wild daffodils of the section Ganymedes from the Iberian Peninsula as a source of mesembrane alkaloids. AB - The aim of this work was to perform a detailed study of the alkaloid content of Narcissus triandrus, as well as a complete analysis of the alkaloid profile of 18 wild populations, comprising all the taxa of the section Ganymedes. Through the application of a combination of spectroscopic and chromatographic methods, the isolation and structural elucidation of 3 compounds are reported for the first time from a natural source (2-oxomesembrenone, 7,7a-dehydromesembrenone and 2 oxoepimesembranol), together with the identification of 5 major common mesembrane alkaloids. Additionally, the GC-MS analysis of the alkaloid profile demonstrated the regular presence of mesembranes in all the studied plants, showing mesembrenone as the predominant compound without any typical Amaryllidaceae alkaloid being detected. PMID- 23932507 TI - [Diffuse gastric polyposis]. PMID- 23932508 TI - Sensitivity of species to chemicals: dose-response characteristics for various test types (LC(50), LR(50) and LD(50)) and modes of action. AB - While variable sensitivity of model species to common toxicants has been addressed in previous studies, a systematic analysis of inter-species variability for different test types, modes of action and species is as of yet lacking. Hence, the aim of the present study was to identify similarities and differences in contaminant levels affecting cold-blooded and warm-blooded species administered via different routes. To that end, data on lethal water concentrations LC50, tissue residues LR50 and oral doses LD50 were collected from databases, each representing the largest of its kind. LC50 data were multiplied by a bioconcentration factor (BCF) to convert them to internal concentrations that allow for comparison among species. For each endpoint data set, we calculated the mean and standard deviation of species' lethal level per compound. Next, the means and standard deviations were averaged by mode of action. Both the means and standard deviations calculated depended on the number of species tested, which is at odds with quality standard setting procedures. Means calculated from (BCF) LC50, LR50 and LD50 were largely similar, suggesting that different administration routes roughly yield similar internal levels. Levels for compounds interfering biochemically with elementary life processes were about one order of magnitude below that of narcotics disturbing membranes, and neurotoxic pesticides and dioxins induced death in even lower amounts. Standard deviations for LD50 data were similar across modes of action, while variability of LC50 values was lower for narcotics than for substances with a specific mode of action. The study indicates several directions to go for efficient use of available data in risk assessment and reduction of species testing. PMID- 23932509 TI - Toxic effects of malathion in carp, Cyprinus carpio carpio: protective role of lycopene. AB - The present study was carried out in order to investigate the potential protective effects of lycopene against malathion-induced toxicity in carp. The fish were exposed to sublethal concentrations of malathion (0.5 and 1mgL(-1)) for 14 days, and lycopene (10mgkg(-1) of fish weight) was simultaneously administered. Samples of the blood and tissue (liver, kidneys, and gills) were collected at the end of the experimental period and their haematological profiles [red blood cell (RBC) counts, haemoglobin (Hb) concentrations, haematocrit (Ht) levels, and erythrocyte indices, including the mean corpuscular volume (MCV), the mean corpuscular haemoglobin (MCH) and the mean corpuscular haemoglobin concentration (MCHC)], immune responses [white blood cell (WBC) counts, oxidative radical production (nitroblue tetrazolium (NBT) activity), total plasma protein (TP) and total immunoglobulin (TI) levels and phagocytic activities (PA)] and oxidant/antioxidant statuses [malondialdehyde (MDA) levels, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities, and reduced glutathione (GSH) concentrations] were analysed. The findings of the present study demonstrated that the exposure of carp to malathion resulted in alterations in the haematological profiles and immune responses, and lead to increased reactive oxygen species formation, resulting in oxidative damage and inhibition of the antioxidant capacities. However, the administration of lycopene prevented malathion-induced toxic effects. PMID- 23932510 TI - Acute toxicity testing with the tropical marine copepod Acartia sinjiensis: optimisation and application. AB - Globally there is limited toxicity data for tropical marine species, and there has been a call for further research and development in the area of tropical marine ecotoxicology. An increase in developmental pressures in northern tropical Australia is causing a higher demand for toxicity test protocols with ecologically relevant species. Copepods are a diverse group of zooplankton that are major components of marine food webs. The calanoid copepod Acartia sinjiensis is widely distributed across tropical and sub-tropical brackish to marine waters of Australia and was identified in a recent comprehensive review of marine tropical toxicity testing in Australia as a suitable test organism. Through a number of optimisation steps including feeding trials, changes to culture and test conditions; a 48-h acute toxicity test with A. sinjiensis was modified to become a highly reliable and reproducible standard test protocol. Control mobility was improved significantly, and the sensitivity of A. sinjiensis to copper (EC50 of 33ug/L), ammonia (EC50 of 10mg/L) and phenol (EC50 of 13mg/L) fell within the ranges of those reported previously, indicating that the modifications did not alter its sensitivity. In a comprehensive literature search we found that this species was the most sensitive to copper out of a range of marine copepods. The test was also successfully applied in toxicity assessments of four environmental samples: two produced formations waters (PFWs) and two mine tailing liquors (MTLs). The toxicity assessments utilised toxicity data from a suite of marine organisms (bacteria, microalgae, copepods, sea urchins, oysters, prawns, and fish). For the PFWs, which were predominantly contaminated with organic chemicals, A. sinjiensis was the most sensitive species (EC50 value 2-17 times lower than for any other test species). For the predominantly metal contaminated mine tailing liquors, its sensitivity was similar to that of other test species used. The modified 48-h acute toxicity test with A. sinjiensis proved to be a valuable tool in these toxicity assessments, and is recommended for use in tropical marine toxicity assessments for northern Australia. PMID- 23932511 TI - Comparative toxicity of CuO nanoparticles and CuSO4 in rainbow trout. AB - This study compared the toxicity and accumulation of two different Cu compounds, CuO nanoparticles (NPs) and soluble CuSO4, in erythrocytes and different tissues in rainbow trout (Oncorhynchus mykiss). The crystal structure of CuO NP analysed by XRD indicates that the NP are Tenorite, a monoclinic CuO. The in vitro toxicity results indicate that both Cu compounds increase the haemolysis rate in a dose-dependent way, but the effect was reduced treating cells with CuO NP. Moreover, both Cu compounds induce DNA damage and the entity of the damage, similarly to haemolysis, was more marked in cells treated with CuSO4. In vivo results, obtained after intraperitoneal injection, showed that Cu concentrations were significantly higher in gills (p<0.0001), kidney (p=0.007) and liver (p<0.05) of exposed fish with a significant increase in plasma Cu concentration 15h after CuSO4 treatment. Cu concentrations were significantly higher in fish exposed to CuSO4 than CuO in kidney (p<0.05) and gills (p<0.0001). Significant DNA damage with respect to controls was detected only when Cu was injected as CuSO4. The present data could serve to evaluate environmental Cu toxicity in fish depending on Cu speciation. PMID- 23932512 TI - Rituximab maintenance versus radio-immunotherapy consolidation in first remission follicular non-Hodgkin lymphoma. PMID- 23932513 TI - Bioengineering heart tissue for in vitro testing. AB - A classical paradigm of tissue engineering is to grow tissues for implantation by using human stem cells in conjunction with biomaterial scaffolds (templates for tissue formation) and bioreactors (culture systems providing environmental control). A reverse paradigm is now emerging through microphysiological platforms for preclinical testing of drugs and modeling of disease that contain large numbers of very small human tissues. We discuss the biomimetic approach as a common underlying principle and some of the specifics related to the design and utilization of platforms with heart micro-tissues for high-throughput screening in vitro. PMID- 23932514 TI - Changing incidence of lens extraction over 20 years: the Beaver Dam eye study. AB - OBJECTIVE: To investigate trends in the incidence of lens extraction over the past 20 years. DESIGN: Longitudinal population-based cohort study. PARTICIPANTS: Persons who participated in the Beaver Dam Eye Study. METHODS: Eligible persons 43 to 84 years of age living in the city or township of Beaver Dam, Wisconsin, were recruited from 1987 through 1988. Participants were followed up every 5 years from 1993 through 1995, from 1998 through 2000, from 2003 through 2005, and from 2008 through 2010 after the baseline examination from 1988 through 1990. Examinations consisted of ocular examination with lens photography and grading; medical history; and measurements of blood pressure, height, and weight. Adjustments were made for age and gender. Values of risk variables were updated, and the incidence of lens extraction surgery was calculated in each 5-year interval. MAIN OUTCOME MEASURES: Incidence of lens extraction with regard to presence of clinically significant lens opacity and visual function. RESULTS: Age and gender-adjusted incidence of lens extraction increased over the 4 intervals from 1.8% (95% confidence interval [CI], 1.3%-2.5%) in the interval between the first and second study examinations to 11.7% (95% CI, 9.9%-13.8%) in the most recent study interval. The increase in incidence of surgery was significantly higher at successive intervals in persons without clinically significant lens opacity at each preceding examination (interval 1, 0.8% [95% CI, 0.6%-1.1%]; interval 4, 9.4% [95% CI, 7.8%-11.2%]) compared with persons with at least 1 detectable type of opacity (interval 1, 9.2% [95% CI, 6.4%-13.2%]; interval 4, 16.5% [95% CI, 13.4%-20.0%]). Recency of examination was not attenuated by adjusting for additional risk factors. There was no evidence that the increased incidence in surgery was preceded by poorer visual acuity, near vision, or contrast sensitivity at the beginning of each interval. CONCLUSIONS: The incidence of lens extraction has increased over the past 20 years in persons older than 65 years. The relative increase of surgery is higher in those without any clinically significant lens opacity and in persons with visual acuity better than 20/40 at an examination as measured 5 years before observed incidence of lens extraction. PMID- 23932515 TI - The association between health literacy and indicators of cognitive impairment in a diverse sample of primary care patients. AB - OBJECTIVES: To confirm the association of health literacy scores as measured by Health Literacy Assessment Using Talking Touchscreen Technology (Health LiTT) with cognitive ability and education. To determine whether this association differs by cognitive task. METHODS: Cognitive impairment was measured using the Mini-Cog, which combines a delayed word recall task (WRT) and a clock drawing task (CDT) to yield an overall classification of normal versus cognitively impaired. Participants were recruited from primary care clinics that provide care to underserved patients. RESULTS: Participants (n=574) were predominantly non Hispanic black (67%) with a mean age of 46 years, 50% did not have health insurance, 56% had a high school education or less and 21% screened positive for cognitive impairment. Overall cognitive ability and education were significantly associated with health literacy after adjusting for other variables, including race/ethnicity and physical health. We observed a stronger association between the CDT and health literacy than between the WRT and health literacy. CONCLUSION: By confirming hypothesized associations, this study provides additional support of the validity of Health LiTT. PRACTICE IMPLICATIONS: Health LiTT is a reliable and valid tool that researchers and clinicians can use to identify individuals who might have difficulty understanding health information. PMID- 23932517 TI - The asexual cycle of apicomplexan parasites: new findings that raise new questions. PMID- 23932516 TI - Bacterial cell division as a target for new antibiotics. AB - Bacterial resistance to currently applied antibiotics complicates the treatment of infections and demands the evaluation of new strategies to counteract multidrug-resistant bacteria. In recent years, the inhibition of the bacterial divisome, mainly by targeting the central cell division mediator FtsZ, has been recognized as a promising strategy for antibiotic attack. New antibiotics were shown to either interfere with the natural dynamics and functions of FtsZ during the cell cycle or to activate a bacterial protease to degrade FtsZ and thus bring about bacterial death in a suicidal manner. Their efficacy in animal models of infection together with resistance-breaking properties prove the potential of such drugs and validate the inhibition of bacterial cell division as an attractive approach for antibiotic intervention. PMID- 23932518 TI - [XXXIX National Congress of the Spanish Society of Intensive Nursing and Coronary Units, Tenerife 2013]. PMID- 23932519 TI - [Work setting, satisfaction and burnout of the nurses in critical care units and hospitalization units. RN4CAST-Spain project]. AB - OBJECTIVE: To know if there are differences between the critical care units and the medical-surgical care units regarding the perception of the nurses working in National Health System hospitals about their work environment, burnout level and job satisfaction. METHOD: A cross-sectional study was conducted with 6,417 nurses from the medical-surgical care units and with 1,122 nurses from critical care units of 59 Spanish hospitals with more than 150 beds. Socio-demographic, job satisfaction, perception of work environment (Practice Environment Scale of the Nursing Work Index [PES-NWI questionnaire]) and burnout measured with the Maslach Burnout Inventory (MBI) data were collected. RESULTS: The PES-NWI showed differences in 4 out of its 5 factors. It showed better values in medical surgical units in all the factors, except for Staffing and resource adequacy (P<.001), where critical care units showed a mean level of agreement of 2.41 versus 2.19 for the medical-surgical units. Regarding burnout, this was higher in the medical-surgical care units (P=.039) where 23% (952) of the nurses had high levels. Job satisfaction was lower in the critical care units (P=.044) with 70% (578) of nurses being very or strongly satisfied. CONCLUSIONS: The opinion of the nurses, working in critical care units about their hospital is unfavorable. They showed lower levels of burnout than those working in medical-surgical units. PMID- 23932520 TI - Questions remain about Vitamin D. PMID- 23932521 TI - Research safeguards protected areas: the important role of governments. PMID- 23932522 TI - Pearls and pitfalls of laparoscopic harvest of omental flap for sternal wound reconstruction in patients with significant cardiac dysfunction. PMID- 23932523 TI - PIP silicone breast implants. PMID- 23932524 TI - One-step breast reconstruction with polyurethane-covered implants after skin sparing mastectomy. AB - BACKGROUND AND AIM: Skin-sparing mastectomy (SSM) and immediate one-step breast reconstruction with implants has become an increasingly popular, effective treatment for selected patients with breast carcinoma. However, it is associated with high complication rates. Breast augmentation with polyurethane-covered implants (PCIs) has consistently had optimal short-term and long-term results with low rates of capsular contracture. The aim of this study was to evaluate the clinical and aesthetic outcomes of immediate one-step breast reconstruction with PCI after SSM in early breast cancer patients at a single institution. METHODS: We reviewed the records of 221 consecutive breast cancer patients who underwent one-stage immediate reconstruction with PCI after SSM from 1995 through 2005. Patient and tumour characteristics, type of reconstruction, postoperative complications, aesthetic results and recurrence rate were analysed. RESULTS: The mean age of the patients was 52+/-11 years (range, 30-76; standard deviation (SD), 11). The American Joint Committee on Cancer (AJCC) pathologic stages were 0 (10%), I (63.3%) and II (26.7%). Thirty-nine (17.65%; confidence interval (CI)=13.04-23.1) of the 221 patients had complications; seven had prosthesis extrusion requiring an implant (five due to skin necrosis, one due to infection and one due to late haematoma). In six of these seven cases, the procedure was indicated for local recurrence after conservative breast surgery with adjunctive radiation therapy (rescue procedure). Thirty-two (14.4%) patients had minor complications: 12 had cutaneous rash, four had malpositioned implants and 16 had inadequate implant projection. At long-term follow-up, four (1.8%) patients had developed grade IV capsular contracture associated with postoperative radiation therapy. At a median follow-up of 98 months (range, 36-156), 14 (6.3%) patients had tumour recurrence and 12.2% had distant metastasis. Nineteen patients had died of cancer, and 192 (86.8%) remained disease free. CONCLUSION: One-stage immediate breast reconstruction with PCI after SSM appears to be oncologically safe and provides a high level of patient satisfaction. PMID- 23932525 TI - Genetic manipulation of the Fusarium fujikuroi fusarin gene cluster yields insight into the complex regulation and fusarin biosynthetic pathway. AB - In this work, the biosynthesis and regulation of the polyketide synthase/nonribosomal peptide synthetase (PKS/NRPS)-derived mutagenic mycotoxin fusarin C was studied in the fungus Fusarium fujikuroi. The fusarin gene cluster consists of nine genes (fus1-fus9) that are coexpressed under high-nitrogen and acidic pH conditions. Chromatin immunoprecipitation revealed a correlation between high expression and enrichment of activating H3K9-acetylation marks under inducing conditions. We provide evidence that only four genes are sufficient for the biosynthesis. The combination of genetic engineering with nuclear magnetic resonance and mass-spectrometry-based structure elucidation allowed the discovery of the putative fusarin biosynthetic pathway. Surprisingly, we indicate that PKS/NRPS releases its product with an open ring structure, probably as an alcohol. Our data indicate that 2-pyrrolidone ring closure, oxidation at C-20, and, finally, methylation at C-20 are catalyzed by Fus2, Fus8, and Fus9, respectively. PMID- 23932526 TI - Capturing linear intermediates and C-terminal variants during maturation of the thiopeptide GE2270. AB - Thiopeptides are ribosomally synthesized, posttranslationally modified peptides with potent activity against Gram-positives. However, only GE2270 has yielded semisynthetic derivatives under clinical investigations. The pbt gene cluster from the GE2270 producer Planobispora rosea was successfully expressed in the genetically tractable Nonomuraea ATCC39727. Gene deletions established that PbtO, PbtM1, PbtM2, PbtM3, and PbtM4 are involved in regiospecific hydroxylation and methylations of GE2270, leading to the generation of various derivatives with altered decorations. Further deletions established that PbtH and PbtG1 are involved in C-terminal amide and oxazoline formation, respectively. Surprisingly, preventing either step resulted in the accumulation of linear precursors in which the pyridine-generated macrocycle failed to form, and only one of the pyridine forming serine residues had been dehydrated. Often, these linear precursors present a shortened C terminus but retain the full set of methylation and hydroxylation decorations. PMID- 23932527 TI - The early-career consultation psychiatrist: the give and take of mentorship. PMID- 23932528 TI - The prevalence of bipolar disorder in primary care patients with depression or other psychiatric complaints: a systematic review. AB - BACKGROUND: Bipolar disorder prevalence in primary care patients with depression or other psychiatric complaints has been measured in several studies but has not been systematically reviewed. OBJECTIVE: To systematically review studies measuring bipolar disorder prevalence in primary care patients with depression or other psychiatric complaints. METHODS: We conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method in January 2013. We searched 7 databases using a comprehensive list of search terms. Included articles had a sample size of 200 patients or more and assessed bipolar disorder using a structured clinical interview or bipolar screening questionnaire in adult primary care patients with a prior diagnosis of depression or had an alternate psychiatric complaint. RESULTS: Our search yielded 5595 unique records. Seven cross-sectional studies met our inclusion criteria. The percentage of primary care patients with bipolar disorder was measured in 4 studies of patients with depression, 1 study of patients with trauma exposure, 1 study of patients with any psychiatric complaint, and 1 study of patients with medically unexplained symptoms. The percentage of patients with bipolar disorder ranged from 3.4%-9% in studies using structured clinical interviews and from 20.9%-30.8% in studies using screening measures. CONCLUSIONS: Bipolar disorder likely occurs in 3%-9% of primary care patients with depression, a trauma exposure, medically unexplained symptoms, or a psychiatric complaint. Screening measures used for bipolar disorder detection overestimate the occurrence of bipolar disorder in primary care owing to false positives. PMID- 23932529 TI - Increased risk of chronic liver disease in patients with schizophrenia: a population-based cohort study. AB - OBJECTIVE: To investigate the prevalence and incidence of chronic liver disease in patients with schizophrenia in Taiwan. METHODS: We used a random sample of 661,266 subjects aged >= 18 from the National Health Research Institute database in the year 2000. Subjects with at least one primary diagnosis of schizophrenia (The International Classification of Diseases, Ninth Revision, Clinical Modification: 295) in 2000 were selected. Patients with a primary or secondary diagnosis of chronic liver disease (The International Classification of Diseases, Ninth Revision, Clinical Modification: 571) were also defined. We compared the prevalence and associated factors of chronic liver disease between patients with schizophrenia and the general population in 2000. We also compared the incidence of chronic liver disease in patients with schizophrenia and the general population from 2001 through 2010. RESULTS: The prevalence of chronic liver disease in patients with schizophrenia (7.0%) was 1.27 times as high as that of the general population (6.1%) in 2000. The average annual incidence of chronic liver disease in patients with schizophrenia from 2001-2010 was also higher than that of the general population (2.9% vs 2.5%, risk ratio, 1.15; 95% confidence interval, 1.07-1.24). Younger patients with schizophrenia were found to have a much higher prevalence and incidence than those in the general population, and diabetes was a risk factor for patients with schizophrenia in developing chronic liver disease. CONCLUSIONS: Patients with schizophrenia exhibited a significantly higher prevalence and incidence of chronic liver disease than those in the general population, and younger patients with schizophrenia have a much higher prevalence and incidence than those in the general population. Co-morbidity with diabetes was the primary risk factor for patients with schizophrenia to develop chronic liver disease. PMID- 23932531 TI - Psychiatric manifestations of anti-NMDA receptor encephalitis: neurobiological underpinnings and differential diagnostic implications. AB - OBJECTIVE: Anti-N-methyl-d-aspartate receptor (NMDA-R) encephalitis is a recently discovered disorder with prominent psychiatric manifestations that is often misdiagnosed. The objective of this review is to raise awareness of the disorder among psychiatrists and to expand upon the diagnostic considerations that arise in the context of the neurobiology and symptomatology of this disorder. We also aim to examine the similarities in terms of symptoms and underlying neurobiology between anti-NMDA-R encephalitis and schizophrenia-spectrum illnesses. METHODS: The information presented will reflect a review of the literature of the symptomatology and pathophysiology of anti-NMDA-R encephalitis and the role of the NMDA-R in both anti-NMDA-R encephalitis and schizophrenia-spectrum illnesses. RESULTS: The studies reviewed highlight the role of the NMDA-R in both anti-NMDA R encephalitis and schizophrenia in terms of symptom presentation and neurobiology. Studies have also begun to identify involvement of NMDA-R antibodies in patients diagnosed with schizophrenia. CONCLUSIONS: There is an increasing need for psychiatrists to become aware of the disorder and consider it in their differential diagnosis, as they are often the first to be consulted on patients with anti-NMDA-R encephalitis. The similarities identified between anti NMDA-R encephalitis and schizophrenia-spectrum illnesses also raise questions about a common underlying pathophysiology particularly in regard to the NMDA-R. PMID- 23932530 TI - Specialty behavioral health service use among chronically ill medicare advantage patients with substance use problems. AB - OBJECTIVE: This study examines the use of substance abuse and mental health services among older adults with substance use disorders. METHODS: Participants were members of Humana Cares, a subsidiary of Humana, Inc., a care management program for chronically ill Medicare Advantage members, between 2008 and 2010. All adults aged 65 and older with a substance use disorder identified with International Classification of Diseases-9 codes were included. We compared utilization of substance abuse and mental health services among participants with no psychiatric comorbidity (n = 585), with comorbid depression (n = 605), and with comorbid severe and persistent mental illness (severe and persistent mental illness, n = 95). RESULTS: Twenty-eight percent utilized substance abuse services and 36% utilized mental health services. After adjusting for covariates, comorbid depression (odds ratio = 4.27, 95% confidence interval: 3.22-5.65) and severe and persistent mental illness (odds ratio = 10.75, 95% confidence interval: 5.22 20.13) were independently associated with specialty service use (either substance abuse or mental health services). CONCLUSION: Although few chronically ill older adults with substance use disorders in this Medicare Advantage program received any specialty substance abuse or mental health services, utilization was higher among those who had concurrent psychiatric disorders. PMID- 23932532 TI - Catatonia and glucose-6-phosphate dehydrogenase deficiency: a report of two cases and a review. PMID- 23932533 TI - Telephone effect in akinetic mutism from traumatic brain injury. PMID- 23932534 TI - Safety of electroconvulsive therapy in patients receiving dabigatran therapy. PMID- 23932535 TI - Popular dietary supplement causes false-positive drug screen for amphetamines. PMID- 23932536 TI - Response-suicide screening in general hospitals. PMID- 23932537 TI - Leuprolide-induced extrapyramidal symptoms successfully treated with propranolol. PMID- 23932538 TI - Acute mania associated with levetiracetam treatment. PMID- 23932539 TI - A novel substance with allelopathic activity in Ginkgo biloba. AB - Ginkgo (Ginkgo biloba) is one of the oldest living tree species and has been widely used in traditional medicine. Leaf extracts of ginkgo, such as the standardized extract EGb761, have become one of the best-selling herbal products. However, no bioactive compound directed at plants has been reported in this species. Therefore, we investigated possible allelopathic activity and searched for allelopathically active substances in ginkgo leaves. An aqueous methanol leaf extract inhibited the growth of roots and shoots of garden cress (Lepidium sativum), lettuce (Lactuca sativa), timothy (Phleum pratense) and ryegrass (Lolium multiflorum) seedlings. The extract was purified by several chromatographic runs and an allelopathically active substance was isolated and identified by spectral analysis to be the novel compound 2-hydroxy-6-(10 hydroxypentadec-11-enyl)benzoic acid. The compound inhibited root and shoot growth of garden cress and timothy at concentrations greater than 3 MUM. The activity of the compound was 10- to 52-fold that of nonanoic acid. These results suggest that 2-hydroxy-6-(10-hydroxypentadec-11-enyl)benzoic acid may contribute to the allelopathic effect caused by ginkgo leaf extract. The compound may also have potential as a template for the development of new plant control substances. PMID- 23932540 TI - Ketoprofen combined with artery graft entubulization improves functional recovery of transected peripheral nerves. AB - The objective was to assess the local effect of ketoprofen on sciatic nerve regeneration and functional recovery. Eighty healthy male white Wistar rats were randomized into four experimental groups of 20 animals each: In the transected group (TC), the left sciatic nerve was transected and nerve cut ends were fixed in the adjacent muscle. In the treatment group the defect was bridged using an artery graft (AG/Keto) filled with 10 microliter ketoprofen (0.1 mg/kg). In the artery graft group (AG), the graft was filled with phosphated-buffer saline alone. In the sham-operated group (SHAM), the sciatic nerve was exposed and manipulated. Each group was subdivided into four subgroups of five animals each and regenerated nerve fibres were studied at 4, 8, 12 and 16 weeks post operation. Behavioural testing, sciatic nerve functional study, gastrocnemius muscle mass and morphometric indices showed earlier regeneration of axons in AG/Keto than in AG group (p < 0.05). Immunohistochemical study clearly showed more positive location of reactions to S-100 in AG/Keto than in AG group. When loaded in an artery graft, ketoprofen improved functional recovery and morphometric indices of the sciatic nerve. Local usage of this easily accessible therapeutic medicine is cost saving and avoids the problems associated with systemic administration. PMID- 23932541 TI - Randomized clinical study comparing piezosurgery and conventional rotatory surgery in mandibular cyst enucleation. AB - PURPOSE: The aim of the present study is to compare piezoelectric surgery to the conventional rotatory surgery in mandibular cyst enucleation, and to determine the 2 method's suitability and the postoperative outcomes. MATERIAL AND METHODS: Eighty patients were included in the study. 35 male and 45 female, which showed cystic mandibular lesions, compared with the inferior alveolar nerve or the mental nerve. The patients were randomly divided into two groups. In the test group, cystectomy was performed using conventional rotatory instrumentation (rotatory-group), and in the other one piezoelectric surgery (piezo-group). The swelling was documented 24/48/72 h and 1 week post-surgery and the patients recorded their subjective postoperative pain daily for 7 days using a Visual Analog Scale (VAS). RESULTS: Patients treated with piezoelectric technique have presented a lower VAS, minor swelling and less recovery time compared to the rotatory-group. No lesions of the mandible nerve were detected with piezosurgery whereas surgery with rotary instruments resulted in 8% hypesthesia at least up to one week. CONCLUSION: The results of this study suggest that piezosurgery may be considered effective in cyst enucleation compared to traditional procedures with burs, since it grants the patients significantly less post-surgical pain and swelling. PMID- 23932542 TI - Maxillary-fronto-temporal approach for removal of recurrent malignant infratemporal fossa tumors: Anatomical and clinical study. AB - PURPOSE: For recurrent malignant tumors occurring in the infratemporal fossa, it is difficult to select a proper surgical approach. We explore the efficiency of a new approach for removal of recurrent malignant tumors involving the infratemporal fossa based on the measurement on three-dimension CT, observation of six cadaveric specimens, and our surgical experience. MATERIALS AND METHODS: The distances between the surgical landmarks in the infratemporal fossa were measured using CT data to determine the safe distance. And anatomy observation was examined on 6 formalin-fixed cadaveric specimens. Data from seven patients with recurrent malignant infratemporal fossa tumors were retrospectively analyzed. RESULTS: The mean distance of the medial pterygoid plate from the zygoma was 52.12 mm. The maxillary artery can be found between the deep surface of the condyle and the sphenomandibular ligament, with mean distance of 8.25 +/- 3.22 mm to the inferior border of the capsule of the temporomandibular joint. All tumors got gross resection using the maxillary-fronto-temporal approach with minor complication. CONCLUSIONS: The advantages of the new approach include adequate protection of facial nerve with extended operation field; the exposed temporal muscle could be used to fill the dead space. This technique is especially useful to remove recurrent malignant infratemporal tumors safely. PMID- 23932543 TI - The clinical and radiographical characteristics of zygomatic complex fractures: a comparison between the surgically and non-surgically treated patients. AB - BACKGROUND: In this retrospective study we evaluated the epidemiological data and the clinical and radiographical differences between surgically and non-surgically treated patients with zygomatic complex fractures at their initial assessment in our clinic over a period of 5 years. More knowledge of the clinical similarities and/or differences between the non-surgical and the surgical group will provide us a more complete view and may help physicians to develop any future methods in clinical decision making or even methods in distinguishing patients benefiting from a surgical treatment. METHODS: Surgically and non-surgically treated patients were included in the study, if clinical and radiographical confirmation of zygomatic complex fractures were present at initial assessment. The patient groups were divided into surgically treated zygomatic complex fractures, and non surgically treated fractures, with and without displacement. The groups were compared according to age, gender, degree of fracture displacement and clinical signs. RESULTS: In total 283 patients were diagnosed with zygomatic complex fractures, with a mean age of 43 years (+/-20 years) and a domination of male patients. The mean age was higher in the non-surgically treated group and contained more female patients. Overall type C fractures and the majority of the type B fractures were treated surgically. Only 2.1% of the type A fractures were treated surgically. Overall facial swelling and paraesthesia of the infraorbital nerve were found as most common clinical findings. Additionally, malar depression and extraoral steps were frequently found in the surgically treated group, as in the non-surgically treated group only facial swelling was found frequently, whether there was fracture displacement or not. The clinical characteristics 'extraoral steps', 'intraoral steps', and 'malar depression' were found to be significantly related to surgical treatment. CONCLUSION: Extraoral steps, intraoral steps, and malar depression were significantly related to surgical treatment. The group of non-surgically treated zygomatic complex fractures is a valuable group to investigate as this group also consists of patients with displaced fractures (i.e. surgical indication) and thus, could provide us more insight in future clinical decision methods. Therefore, we highly recommend more research of the non-surgically treated group. PMID- 23932544 TI - Platelet rich plasma enhances osteoconductive properties of a hydroxyapatite-beta tricalcium phosphate scaffold (Skelite) for late healing of critical size rabbit calvarial defects. AB - The use of platelet rich plasma (PRP) in bone repair remains highly controversial. In this work, we evaluated the effect of lyophilized PRP on bone regeneration when associated with a silicon stabilized hydroxyapatite tricalcium phosphate scaffold in a rabbit calvarial defect (Skelite). Critical defects were created in the calvaria of twenty-four rabbits. The periosteum was removed and the defects were either left empty or filled with allogeneic PRP gel; Skelite particles; Skelite and PRP gel. Four animals were killed after 4 weeks, 10 animals after 8 and 10 after 16 weeks. Specimens were processed for X-ray microtomography (MUCT) and for resin embedded histology. MUCT analysis revealed significant osteoid-like matrix and new bone deposition in PRP + Skelite group at both 8 and 16 weeks in respect to Skelite alone. Histologically, PRP + Skelite defects were highly cellular with more abundant osteoid deposition and more regular collagen fibres. Moreover, in vitro migration assays confirmed the chemotactic effect of PRP to endothelial and osteoprogenitor cells. We conclude that the addition of PRP influenced the local tissue microenvironment by providing key cryptic factors for regeneration, thereby enhancing progenitor cell recruitment, collagen and bone matrix deposition, and by creating a bridging interface between the scaffold and bone. PMID- 23932545 TI - Evaluation of the presence of VEGF, BMP2 and CBFA1 proteins in autogenous bone graft: histometric and immunohistochemical analysis. AB - AIMS: The purpose of this study was to evaluate the expression of proteins that participate in the osteoinduction stage (VEGF, BMP2 and CBFA1) of the process of bone regeneration of defects created in rat calvariae and filled with autogenous bone block grafts. MATERIALS AND METHODS: 10 adult male rats (Rattus norvegicus albinus, Wistar) were used, who received two bone defects measuring 5 mm each in the calvariae. The bone defects constituted two experimental groups (n = 10): Control Group (CONT) (defects filled with a coagulum); Graft Group (GR) (defects filled with autogenous bone removed from the contralateral defect). The animals were submitted to euthanasia at 7 and 30 days post-operatively. RESULTS: Quantitative analysis demonstrated significantly greater bone formation in Group GR, but the presence of the studied proteins was significantly greater in the CONT Group in both time intervals of observation. CONCLUSION: It was not possible in this study in cortical bone block groups to detect the osteoinductive proteins in a significant amount during the repair process. PMID- 23932546 TI - Evaluating the additional effects of arthrocentesis on the condylar pathways of temporomandibular joint in patients with internal derangement treated with stabilizing splint. AB - OBJECTIVES: The purpose of this investigation is to find out the differences in the condylar pathways of the temporomandibular joint (TMJ) in patients treated with stabilizing splint and arthrocentesis accompanied by stabilizing splint in 6 months period. STUDY DESIGN: Forty patients who were assigned a clinical diagnosis of internal derangement of the TMJ were included in this study. Full arch stabilizing splints were made for all patients. Patients were divided into two groups; group A (patients who underwent arthrocentesis), group B (patients who did not underwent arthrocentesis). Computerized axiography was performed for each group before therapy (T0), on the 3(rd) month (T1), after arthrocentesis (TA) (for group A) and on 6th month (T2). Curve parameters were recorded in three dimension; X axis (posteroanterior), Y axis (mediolateral), Z axis (superoinferior). Also the distance from the starting point of the movement on sagittal plane (S) was calculated. RESULTS: There was a significant increase in the value of Z (p = 0.014) and S (p = 0.038) in mediotrusion movement in group A. Also, there was a significant increase in the value of Z (p = 0.007) in protrusion/retrusion movement, value of Z (p = 0.019) and S value (p = 0.002) in mediotrusion movement and value of Y in open/close movement in group B. CONCLUSIONS: No positive effects on condylar pathways of an additional arthrocentesis to splint therapy alone in patients with internal derangement were found in this study. PMID- 23932547 TI - Adjuvant bevacizumab: positive data from a negative trial. PMID- 23932549 TI - Multiple myeloma-induced hyperammonemic encephalopathy: an entity associated with high in-patient mortality. AB - Hyperammonemia attributed to multiple myeloma (MM) has been rarely reported. We present 6 patients from our institution and 34 from the literature with MM induced hyperammonemic encephalopathy. The median age was 67 years with male:female ratio of 1.8:1. The median ammonia level was 114 umol/L. IgG and IgA MM was seen in 40% and 35% of cases, respectively. The in-patient mortality was 48%. The in-patient mortality was 31% in patients who received MM-directed therapy and 100% in those who did not received MM-directed therapy. Hyperammonemic encephalopathy is a rare complication in MM and is associated with high in-patient mortality. PMID- 23932548 TI - Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. AB - BACKGROUND: The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. METHODS: For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. FINDINGS: Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31.5 months (IQR 25.6-36.8) in the chemotherapy-alone group and 32.0 months (27.5-36.9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0.87, 95% CI 0.72-1.07; p=0.18). 3-year IDFS was 82.7% (95% CI 80.5-85.0) with chemotherapy alone and 83.7% (81.4-86.0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0.84, 95% CI 0.64-1.12; p=0.23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR 2 might benefit from the addition of bevacizumab (Cox interaction test p=0.029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [<0.5%]), and treatment discontinuation (bevacizumab, chemotherapy, or both; 256 [20%] vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [<0.5%] vs three [<0.5%]). INTERPRETATION: Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival. PMID- 23932550 TI - New LDL-cholesterol lowering therapies: pharmacology, clinical trials, and relevance to acute coronary syndromes. AB - BACKGROUND: Reduction in plasma low-density lipoprotein cholesterol (LDL-C) is a fundamental treatment for the prevention of acute coronary syndromes (ACS). Although statin therapy confers significant protection against ACS in both primary and secondary prevention, a considerable residual risk remains after intensive therapy. In addition, a significant proportion of high-risk patients do not achieve the optimal LDL-C goal recommended in the current guidelines (<1.8 mmol/L). Hence, novel LDL-C-lowering agents that act via mechanisms distinct from HMG-CoA reductase inhibition are under investigation. OBJECTIVE: We reviewed the recent literature on the development of novel LDL-C-lowering agents that could potentially be used as an alternative or adjunct to statin therapy in high-risk coronary patients. METHODS: PubMed and Scopus databases were searched to retrieve studies on the efficacy and/or tolerability of novel LDL-C-lowering agents in animals and humans. RESULTS: Agents that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein (apo) B, and microsomal triglyceride transfer protein (MTTP) are the most promising therapies. Inhibition of PCSK9, apoB, and MTTP has been achieved mostly via fully humanized monoclonal antibodies (mAbs), antisense oligonucleotides, and synthetic compounds, respectively. PCSK9 inhibitors increase the hepatic uptake of LDL-C, while apoB and MTTP inhibitors decrease the synthesis and secretion of apoB-containing lipoproteins. These 3 mechanisms lead to marked reductions in plasma LDL-C in patients with hypercholesterolemia at risk for ACS, particularly those with familial hypercholesterolemia. Moreover, these agents can exert additional benefits by decreasing plasma levels of apoB, triglycerides, and lipoprotein(a). Mipomersen and lomitapide have been approved by the United States Food and Drug Administration (US FDA) for use in patients with homozygous familial hypercholesterolemia. PCSK9 inhibitors are currently under final evaluation in clinical outcomes studies and are anticipated to find wide application either as monotherapy or as an adjunct to statins. A main safety concern is the risk for hepatic steatosis with apoB and MTTP inhibitors, which needs to be explored in prospective, long-term trials. CONCLUSIONS: PCSK9, apoB, and MTTP inhibitors can exert potent reductions in plasma LDL-C and apoB concentrations, either as monotherapy or in combination with statins. These effects are particularly relevant to high-risk individuals with marked hypercholesterolemia, such as those with familial hypercholesterolemia. Although the use of mipomersen and lomitapide is limited to severe familial hypercholesterolemia as a replacement for LDL apheresis, PCSK9 inhibitors are likely to be more widely prescribed in patients at high risk for CVD, especially those who are resistant to or intolerant of high intensity statin therapy. PCSK9 mAbs are efficacious and have an excellent safety profile, but their long-term impact on cardiovascular events is currently under investigation. Whether PCSK9 mAbs decrease the rates of recurrent cardiovascular events within 3 months following ACS is questionable; however, these agents, unlike statins, may not have pleiotropic benefits on the unstable plaque. PMID- 23932551 TI - Epidural failure rate using a standardised definition. AB - INTRODUCTION: There is no globally-accepted definition of epidural failure; this leads to wide differences in reported failure rates. A definition of epidural failure was standardised using a modified Delphi approach involving senior obstetric anaesthetists in the UK. Using this definition, epidural failures were calculated in our institution. METHODS: Following clinical governance approval, anonymised data from 1521 epidurals inserted between September 2010 and December 2011 were collected from our database. Details included pain relief 45 min from the start of the procedure, accidental dural puncture, epidural re-siting, maternal satisfaction, time of insertion and positioning for insertion. RESULTS: The overall failure rate was 23%. Individual failure rates for trainees were: Year 2, 26.8%; Year 3, 26.3%; Year 4, 21.4%; Year 5, 25%; Year 6, 18.5%; and Year 7, 13.5%. Epidural re-site rates for trainees were: Year 2, 6.5%; Year 3, 3.5%; Year 4, 4%; Year 5 and above, 1.5%. Cervical dilatation, time of day and position for insertion did not have a statistically significant association with the failure rate. However, the failure rate of the Year 2, Year 3, and Year 4 trainees was significantly higher when compared to that of Year 5 and above. The re-site rate was statistically higher for Year 2 and Year 4 trainees when compared to those of Year 5 and above. The accidental dural puncture rate was statistically higher among Year 3 trainees when compared to Year 5 and above. CONCLUSION: The study identified epidural failure rates using a standardised definition. This information could be used to guide training decisions and to support doctors during their training period. PMID- 23932552 TI - Iron(III) and aluminium(III) complexes with substituted salicyl-aldehydes and salicylic acids. AB - The chelating properties toward iron(III) and aluminium(III) of variously substituted salicyl-aldehydes and salicylic acids have been evaluated, together with the effect of methoxy and nitro substituents in ortho and para position with respect to the phenolic group. The protonation and iron and aluminium complex formation equilibria have been studied by potentiometry, UV-visible spectrophotometry and (1)H NMR spectroscopy. The overall results highlight that salicyl-aldehydes present good chelating properties toward iron(III), with pFe ranging from 14.2 with nitro to 15.7 with methoxy substituent, being ineffective toward aluminium; the pFe values for salicylic acids are generally lower than those for salicyl-aldehydes, and about 4 units higher than the corresponding pAl values. The effect of the two substituents on the chelating properties of the ligands can be rationalized in terms of the Swain-Lupton treatment which accounts for the field and resonance effects. The structural characterization of the 1:2 iron complex with p-nitro salicylic acid shows that iron(III) ion exhibits an octahedral surrounding where two salicylate chelating ligands supply two O phenolate and two O-carboxylate donor atoms in a roughly equatorial plane. The trans-apical sites are occupied by two aqua ligands. PMID- 23932553 TI - Development of upper tract stones in patients with congenital neurogenic bladder. AB - OBJECTIVE: Patients with neurogenic bladder are at increased risk of developing upper tract stones. We hypothesized that patients with lower urinary tract stone disease are at greater risk of developing upper tract stones. METHODS: We performed a 10-year retrospective case-control study of patients with neurogenic bladder to determine the association between bladder and upper tract stones. Independent risk factors for upper tract stones were assessed. Cases and controls were matched 1:1. Univariable analysis was performed by Fisher's exact test and the Mann-Whitney U test. Multivariable logistic regression was performed. RESULTS: 52 cases and controls were identified. Cases were significantly more likely to be non-ambulatory, have bowel-urinary tract interposition, thoracic level dysraphism, and history of bladder stones. On multivariable analysis, independent predictors of stone formation were male sex (OR 2.82; p = 0.02), dysraphism involving the thoracic spine (OR 3.37; p = 0.014) bowel-urinary tract interposition (OR 2.611; p = 0.038), and a history of bladder stones (OR 3.57; p = 0.015). CONCLUSION: Patients with neurogenic bladder are at increased risk for upper tract stones. The presence of bladder stones may herald the development of upper tract stones. The predictors of stone disease identified should guide prospective studies to better understand the natural history of upper tract stone development in this population. PMID- 23932554 TI - [The iceberg of caesarean deliveries without indication]. PMID- 23932555 TI - Interest in both acute thromboembolism and chronic venous disease has greatly increased among vascular surgeons in recent years. Introduction. PMID- 23932556 TI - Genomics of varicose veins and chronic venous insufficiency. AB - Recent sequencing of the human genome has opened up new areas of investigation for genetic aberrations responsible for the pathogenesis of many human diseases. To date, there have been no studies that have investigated the entire human genome for the genetic underpinnings of chronic venous insufficiency (CVI). Utilizing Gene Chip Arrays we analyzed the relative expression levels of more than 47,000 transcripts and variants and approximately 38,500 well-characterized genes from each of 20 patients (N (CVI)=10; N (Control Group)=10). Relative gene expression profiles significantly differed between patients with CVI and patients unaffected by CVI. Regulatory genes of mediators of the inflammatory reaction and collagen production were up-regulated and down-regulated, respectively in CVI patients. DNA microarray analysis also showed that relative gene expression of multiple genes which function remains to be elucidated was significantly different in CVI patients. Fundamental advancements in our knowledge of the human genome and understanding of the genetic basis of CVI represents an opportunity to develop new diagnostic, prognostic, preventive and therapeutic modalities in the management of CVI. PMID- 23932557 TI - Pulmonary embolism after endovenous thermal ablation of the saphenous vein. AB - Pulmonary embolism (PE) after venous procedures is fortunately rare. Our goal was to analyze the data of patients who developed PE after endovenous thermal ablation and phlebectomy for varicose veins and to review the literature on this subject. We report on three patients who developed PE after radiofrequency ablation of the great saphenous vein and mini phlebectomy for symptomatic primary lower-extremity varicose veins. Early postoperative duplex scans confirmed successful closure of the great saphenous vein in all. One patient presented with chest pain and dyspnea, one with blood-tinged sputum, and the third with symptoms of saphenous thrombophlebitis. Two patients had PE from the saphenous vein thrombus and the third had gastrocnemius vein thrombosis extending into the popliteal vein. One had previous deep vein thrombosis. Computed tomography of the chest confirmed PE in all. Two patients were treated with anticoagulation, but the third patient with small PE declined such treatment. One patient underwent temporary inferior vena cava filter placement because of recurrent PE. In conclusion, PE is very rare but it can occur after endovenous thermal ablation of lower-extremity varicose veins. Selective thrombosis prophylaxis and preoperative counseling of the patients about signs and symptoms of deep vein thrombosis and PE are warranted for early recognition and rapid treatment. PMID- 23932558 TI - Complications of inferior vena cava filters. AB - With the introduction of retrievable inferior vena cava filters, the number being placed for protection from pulmonary embolism is steadily increasing. Despite this increased usage, the true incidence of complications associated with inferior vena cava filters is unknown. This article reviews the known complications associated with these filters and suggests recommendations and techniques for inferior vena cava filter removal. PMID- 23932559 TI - Tips and tricks for stenting the inferior vena cava. AB - Chronic occlusion of the Inferior Vena Cava (IVC) can go unnoticed because of the remarkable compensatory mechanism of the human body. On the other hand, IVC occlusion can have a significant and debilitating effect on an individual's ability to live a normal lifestyle and be an active and productive member of society. With the introduction of endovascular technology, new treatment options have opened for patients with this condition. This article describes the technical aspects of IVC recanalization and briefly discusses follow-up care and limited reports on outcomes from the procedure. PMID- 23932560 TI - Renal nutcracker syndrome: surgical options. AB - Nutcracker syndrome is one of the abdominal venous entrapments, caused by compression of the left renal vein between the superior mesenteric artery and the abdominal aorta. Occasionally a retro-aortic left renal vein is compressed between the aorta and the vertebral body (posterior nutcracker syndrome). The renal vein distal to the compression is dilated and renal venous flow can be diverted toward the pelvis through an incompetent, refluxing, left ovarian or spermatic vein, in addition to drainage through retroperitoneal venous collaterals. In this article, we describe the different surgical and endovascular techniques that are used to treat this syndrome. PMID- 23932561 TI - Endovenous removal of dislodged left renal vein stent in a patient with nutcracker syndrome. AB - Stent migration and dislodgment is a potential complication after endovenous stenting of the left renal vein (LRV) for nutcracker syndrome. Our purpose is to describe the technique for endovenous removal of such a dislodged stent that was used in a 36-year-old woman with nutcracker syndrome initially treated with renal vein transposition. Recurrent renal vein compression and symptoms developed and a 14 * 20-mm self-expanding stent was placed in the LRV and was noted to be dislodged into the inferior vena cava on the first post-procedure day. Through right internal jugular access, the stent was stabilized by cannulating a cell of the stent using a guide wire and an angled angiographic catheter. A 20Fr sheath was then placed via right femoral vein access into the inferior vena cava. The stent lumen was cannulated from femoral approach and the stent straightened with a stiff wire. An 18-mm angioplasty balloon was then used to capture the stent. The stent was then compressed with two 25-mm loop snares while simultaneously deflating the balloon as it was pulled into the 20Fr sheath and removed. The LRV was restented with an 18 * 40-mm self-expanding stent. Stenting of LRV for nutcracker syndrome can result in stent migration. Endovenous removal of such a dislodged self-expanding stent is feasible. Our technique emphasizes stent stabilization with cell cannulation and capture over a larger diameter balloon. PMID- 23932562 TI - Outcomes of sclerotherapy and embolization for arteriovenous and venous malformations. AB - Vascular malformations result from an arrest of development of a normal vascular structure or from abnormal growth of a vascular structure. Treatment continues to be a challenge. We sought to study the outcomes of sclerotherapy and embolization for vascular malformations. We reviewed clinical data of all patients treated with sclerotherapy or embolization for arteriovenous or venous malformations between 2006 and 2010 at Mayo Clinic. Follow-up information was obtained from clinical charts and a questionnaire sent to all patients. Overall, 60 patients (24 male and 36 female; mean age 31.7 years; range, 5.6 to 72.4 years) had 163 unique sclerotherapy or embolization procedures for lesions involving the lower extremity (55%), upper extremity (18.3%), pelvis (11.7%), abdomen (5%), chest (5%), back (3.3%), and multiple locations (1.7%). Thirty-one patients had low flow venous malformations and 29 patients had high-flow arteriovenous malformations. Twenty-four patients required more than three sessions. The most common indication for intervention was pain (57 of 60 [95%]). Sixteen patients (27%) had documented or patient-reported complications. There was no significant difference in complication rates or lesion size between patients with low-flow or high-flow lesions. There were no procedural deaths. Mean available follow-up was 2.0 +/- 1.3 years (range, 0.5 to 5.0 years). Median pain scores at most recent follow-up decreased significantly (P<.001). Eighty-three percent of the responders (24 of 29) would recommend treatment to others. With appropriate patient selection, sclerotherapy and embolization can decrease the pain of patients with arteriovenous and venous malformations. Multiple interventions might be necessary. Practitioners should be aware of the potential complications and counsel their patients about these risks. PMID- 23932563 TI - Coupling simulation and experiment: The bimodal strategy in integrative systems biology. AB - The importation of computational methods into biology is generating novel methodological strategies for managing complexity which philosophers are only just starting to explore and elaborate. This paper aims to enrich our understanding of methodology in integrative systems biology, which is developing novel epistemic and cognitive strategies for managing complex problem-solving tasks. We illustrate this through developing a case study of a bimodal researcher from our ethnographic investigation of two systems biology research labs. The researcher constructed models of metabolic and cell-signaling pathways by conducting her own wet-lab experimentation while building simulation models. We show how this coupling of experiment and simulation enabled her to build and validate her models and also triangulate and localize errors and uncertainties in them. This method can be contrasted with the unimodal modeling strategy in systems biology which relies more on mathematical or algorithmic methods to reduce complexity. We discuss the relative affordances and limitations of these strategies, which represent distinct opinions in the field about how to handle the investigation of complex biological systems. PMID- 23932564 TI - [Reply]. PMID- 23932565 TI - [Gene therapy for the treatment of inborn errors of metabolism]. AB - Due to the enzymatic defect in inborn errors of metabolism, there is a blockage in the metabolic pathways and an accumulation of toxic metabolites. Currently available therapies include dietary restriction, empowering of alternative metabolic pathways, and the replacement of the deficient enzyme by cell transplantation, liver transplantation or administration of the purified enzyme. Gene therapy, using the transfer in the body of the correct copy of the altered gene by a vector, is emerging as a promising treatment. However, the difficulty of vectors currently used to cross the blood brain barrier, the immune response, the cellular toxicity and potential oncogenesis are some limitations that could greatly limit its potential clinical application in human beings. PMID- 23932566 TI - Two short interventions to reduce health care requirements in asthma patients. A multicentre controlled study (ASTHMACAP II). AB - BACKGROUND AND OBJECTIVE: Asthma control is suboptimal. The objective of this study was to reduce health care requirements and work absenteeism. MATERIAL AND METHODS: Multicenter randomized controlled study investigating asthma control, educational parameters, health service use, and absenteeism. After adjusting treatment according to GINA recommendations, control group patients (CG) followed their physician's recommendations, while intervention group (IG) patients additionally underwent a 5-minute educational intervention. This protocol was repeated at 3 months, and a final assessment was carried out at 6 months. RESULTS: 479 patients (mean age 40 (SD 17) years) were recruited from primary care, and 334 completed the study. Comparatively, IG patients showed an improvement at the 3- and 6-month evaluations in the six educational parameters (P<0.001) and required fewer urgent visits to the GP for exacerbations [RR=0.49 (95% CI 0.26-0.90); P<0.04], and before the third evaluation, also in urgent GP visits [RR=0.25 (95% CI 0.12-0.52); P<0.001]. Before this third evaluation, IG had fewer scheduled visits to the GP [RR=0.48 (95% CI 0.28-0.82); P<0.003], and fewer visits to the primary care [RR=0.40 (95% CI 0.18-0.87); P<0.05], and to hospital emergency rooms [RR=0.13 (95% CI 0.04-0.42); P<0.001]. In addition, before the third evaluation, IG patients were less often absent from work [RR=0.22 (95% CI 0.05-0.98); P<0.03] or unable to work at home [RR=0.31 (95% CI 0.12-0.82); P<0.02]. CONCLUSIONS: Two short educational interventions improved asthma education and decreased the use of health resources and work absenteeism. PMID- 23932567 TI - [Disability attributable to excess weight in Spain]. AB - BACKGROUND AND OBJECTIVE: To estimate the disability attributable to higher than optimal body mass index in the Spanish population in 2006. POPULATION AND METHOD: Excess body weight prevalence data were obtained from the 2006 National Health Survey (NHS), while the prevalence of associated morbidities was extracted from the 2006 NHS and from a national hospital data base. Population attributable fractions were applied and disability attributable was expressed as years life with disability (YLD). RESULTS: In 2006, in the Spanish population aged 35-79 years, 791.650 YLD were lost due to higher than optimal body mass index (46.7% in males and 53.3% in females). Overweight (body mass index 25-29.9) accounted for 45.7% of total YLD. Males YLD were higher than females under 60. The 35-39 quinquennial group showed a difference for males of 16.6% while in the 74-79 group the difference was 23.8% for women. Osteoarthritis and chronic back pain accounted for 60% of YLD while hypertensive disease and type 2 diabetes mellitus were responsible of 37%. CONCLUSIONS: Excess body weight is a health risk related to the development of various diseases with an important associated disability burden and social and economical cost. YLD analysis is a useful monitor tool for disease control interventions. PMID- 23932568 TI - Systems biology of host-mycobiota interactions: dissecting Dectin-1 and Dectin-2 signalling in immune cells with DC-ATLAS. AB - Modelling the networks sustaining the fruitful coexistence between fungi and their mammalian hosts is becoming increasingly important to control emerging fungal pathogens. The C-type lectins Dectin-1 and Dectin-2 are involved in host defense mechanisms against fungal infection driving inflammatory and adaptive immune responses and complement in containing fungal burdens. Recognizing carbohydrate structures in pathogens, their engagement induces maturation of dendritic cells (DCs) into potent immuno-stimulatory cells endowed with the capacity to efficiently prime T cells. Owing to these properties, Dectin-1 and Dectin-2 agonists are currently under investigation as promising adjuvants in vaccination procedures for the treatment of fungal infection. Thus, a detailed understanding of events' cascade specifically triggered in DCs upon engagement is of great interest in translational research. Here, we summarize the current knowledge on Dectin-1 and Dectin-2 signalling in DCs highlighting similarities and differences. Detailed maps are annotated, using the Biological Connection Markup Language (BCML) data model, and stored in DC-ATLAS, a versatile resource for the interpretation of high-throughput data generated perturbing the signalling network of DCs. PMID- 23932569 TI - Leukoreduction system chambers are an efficient, valid, and economic source of functional monocyte-derived dendritic cells and lymphocytes. AB - The demand for human monocyte-derived dendritic cells (moDCs), as well as for primary human B and T lymphocytes for immunological research purposes has been increased in recent years. Classically, these monocytes are isolated from blood, leukapheresis products or buffy coats of healthy donors by plastic adherence of peripheral blood mononuclear cells (PBMCs), followed by stimulation with granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, while lymphocytes are usually isolated from the non-adherent fraction (NAF) by magnetic cell sorting. However, donor-blood is a limited resource and not every blood bank offers leukapheresis products or buffy coats for laboratory use. Additionally, a leukapheresis is very expensive and also the generation/isolation of cells is time- and cost-intensive. To overcome some of these obstacles, we evaluated if low-cost leukoreduction system chambers (LRSCs), which arise after routine donor plateletpheresis procedures, and are usually discarded, would be an alternative and appropriate source of PBMCs to generate moDCs and to isolate lymphocytes. By analyzing the number and phenotype of immature and mature dendritic cells (DCs), as well as of B and T lymphocytes derived from LRSCs, we found all cells to be of high quantity and quality. Further investigations on DCs comprising transwell migration assays, allogeneic mixed lymphocyte reactions (MLR), cytokine secretion assays, and cytotoxic T cell induction assays revealed high migratory, as well as stimulatory capacity of these cells. In addition, DCs and T cells were efficiently electroporated with mRNA and showed characteristic cytokine production after co-culture, demonstrating LRSCs as an efficient, valid, and economic source for generation of moDCs and lymphocytes for research purposes. PMID- 23932570 TI - The transcription factor Foxo1 controls central-memory CD8+ T cell responses to infection. AB - Memory T cells protect hosts from pathogen reinfection, but how these cells emerge from a pool of antigen-experienced T cells is unclear. Here, we show that mice lacking the transcription factor Foxo1 in activated CD8+ T cells have defective secondary, but not primary, responses to Listeria monocytogenes infection. Compared to short-lived effector T cells, memory-precursor T cells expressed higher amounts of Foxo1, which promoted their generation and maintenance. Chromatin immunoprecipitation sequencing revealed the transcription factor Tcf7 and the chemokine receptor Ccr7 as Foxo1-bound target genes, which have critical functions in central-memory T cell differentiation and trafficking. These findings demonstrate that Foxo1 is selectively incorporated into the genetic program that regulates memory CD8+ T cell responses to infection. PMID- 23932571 TI - Environmental cues dictate the fate of individual CD8+ T cells responding to infection. AB - Many studies have examined pathways controlling effector T cell differentiation, but less is known about the fate of individual CD8+ T cells during infection. Here, we examine the antiviral and antibacterial responses of single CD8+ T cells from the polyclonal repertoire. The progeny of naive clonal CD8+ T cells displayed unique profiles of differentiation based on extrinsic pathogen-induced environmental cues, with some clones demonstrating extreme bias toward a single developmental pathway. Moreover, even within the same animal, a single naive CD8+ T cell exhibited distinct fates that were controlled by tissue-specific events. However, memory CD8+ T cells relied on intrinsic factors to control differentiation upon challenge. Our results demonstrate that stochastic and instructive events differentially contribute to shaping the primary and secondary CD8+ T cell response and provide insight into the underlying forces that drive effector differentiation and protective memory formation. PMID- 23932572 TI - TGF-beta cytokine signaling promotes CD8+ T cell development and low-affinity CD4+ T cell homeostasis by regulation of interleukin-7 receptor alpha expression. AB - Interleukin-7 receptor alpha chain (IL-7Ralpha) is induced upon T cell positive selection and controls thymic CD8-lineage specification and peripheral naive T cell homeostasis. How IL-7Ralpha expression is regulated in developing thymocytes is unclear. Here, we show that transforming growth factor beta (TGF-beta) signaling promoted IL-7Ralpha expression and CD8+ T cell differentiation. In addition, TGF-beta signaling was required for high IL-7Ralpha expression in CD4+ T cells bearing low-affinity T cell receptors, and the abrogation of TGF-beta receptor expression led to failed maintenance of peripheral CD4+ T cells. Compromised IL-7Ralpha expression in TGF-beta-receptor-deficient T cells was associated with increased expression of the Il7ra transcriptional repressor, Gfi 1. IL-7Ralpha transgenesis or T-cell-specific ablation of Gfi-1 restored IL 7Ralpha expression and largely ameliorated the development and homeostasis defects of TGF-beta-receptor-deficient T cells. These findings reveal functions for TGF-beta signaling in controlling IL-7Ralpha expression and in promoting T cell repertoire diversification. PMID- 23932574 TI - Evidence for impaired sound intensity processing during prepulse inhibition of the startle response in a rodent developmental disruption model of schizophrenia. AB - A number of studies have implicated disruptions in prepulse inhibition (PPI) of the startle response in both schizophrenia patients and animal models of this disorder. These disruptions are believed to reflect deficits in sensorimotor gating and are ascribed to aberrant filtering of sensory inputs leading to sensory overload and enhanced "noise" in neural structures. Here we examined auditory evoked potentials in a rodent model of schizophrenia (MAM-GD17) during an auditory PPI paradigm to better understand this phenomenon. MAM rats exhibited reductions in specific components of auditory evoked potentials in the orbitofrontal cortex and an abolition of the graded response to stimuli of differing intensities indicating deficient intensity processing in the orbitofrontal cortex. These data indicate that aberrant sensory information processing, rather than being attributable to enhanced noise in neural structures, may be better attributed to diminished evoked amplitudes resulting in a reduction in the "signal-to-noise" ratio. Therefore, the ability for sensory input to modulate the ongoing background activity may be severely disrupted in schizophrenia yielding an internal state which is insufficiently responsive to external input. PMID- 23932573 TI - Dopaminergic gene polymorphisms and cognitive function in a north Indian schizophrenia cohort. AB - BACKGROUND: Associations of polymorphisms from dopaminergic neurotransmitter pathway genes have mostly been reported in Caucasian ancestry schizophrenia (SZ) samples. As studies investigating single SNPs with SZ have been inconsistent, more detailed analyses utilizing multiple SNPs with the diagnostic phenotype as well as cognitive function may be more informative. Therefore, these analyses were conducted in a north Indian sample. METHODS: Indian SZ case-parent trios (n = 601 families); unscreened controls (n = 468) and an independent set of 118 trio families were analyzed. Representative SNPs in the Dopamine D3 receptor (DRD3), dopamine transporter (SLC6A3), vesicular monoamine transporter 2 (SLC18A2), catechol-o-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) were genotyped using SNaPshot/SNPlex assays (n = 59 SNPs). The Trail Making Test (TMT) was administered to a subset of the sample (n = 260 cases and n = 302 parents). RESULTS: Eight SNPs were nominally associated with SZ in either case-control or family based analyses (p < 0.05, rs7631540 and rs2046496 in DRD3; rs363399 and rs10082463 in SLC18A2; rs4680, rs4646315 and rs9332377 in COMT). rs6271 at DBH was associated in both analyses. Haplotypes of DRD3 SNPs incorporating rs7631540 rs2134655-rs3773678-rs324030-rs6280-rs905568 showed suggestive associations in both case-parent and trio samples. At SLC18A2, rs10082463 was nominally associated with psychomotor performance and rs363285 with executive functions using the TMT but did not withstand multiple corrections. CONCLUSIONS: Suggestive associations with dopaminergic genes were detected in this study, but convincing links between dopaminergic polymorphisms and SZ or cognitive function were not observed. PMID- 23932576 TI - Plasma B-type natriuretic peptide study in children with severe enterovirus 71 infection: a pilot study. AB - OBJECTIVES: Severe enterovirus 71 (EV71) infections in children can result in acute heart failure. B-type natriuretic peptide (BNP) is a good biomarker of myocardial stress. The purpose of this study was to use plasma BNP for the detection of EV71 infection with cardiac involvement. METHODS: Patients with severe EV71 infections and healthy control subjects were studied: group 1 (n=30), normal controls; group 2 (n=20), EV71 infection with central nervous system involvement; and group 3 (n=3), EV71 infection with cardiopulmonary failure. The demographic and laboratory data including plasma BNP levels were analyzed statistically. RESULTS: All group 2 patients recovered completely without neurological sequelae, and all group 3 patients survived without cardiac complications. Group 3 patients had higher troponin I, MB fraction of creatine kinase, and BNP levels than patients of the other groups. The median BNP values were <5 pg/ml in group 1, 9.5 pg/ml in group 2, and 238 pg/ml in group 3. Using a BNP cut-off value of 100 pg/ml to identify cases with severe EV71 infection and acute heart failure, the sensitivity and specificity were both 100%. CONCLUSIONS: Children with severe EV71 infections have varying degrees of myocardial stress. Plasma BNP would be a sensitive and reliable biomarker for the detection of cardiac involvement in children with severe EV71 infections. PMID- 23932575 TI - DSM-IV personality disorders and associations with externalizing and internalizing disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - BACKGROUND: Although associations between personality disorders and psychiatric disorders are well established in general population studies, their association with liability dimensions for externalizing and internalizing disorders has not been fully assessed. The purpose of this study is to examine associations between personality disorders (PDs) and lifetime externalizing and internalizing Axis I disorders. METHODS: Data were obtained from the total sample of 34,653 respondents from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drawing on the literature, a 3-factor exploratory structural equation model was selected to simultaneously assess the measurement relations among DSM-IV Axis I substance use and mood and anxiety disorders and the structural relations between the latent internalizing-externalizing dimensions and DSM-IV PDs, adjusting for gender, age, race/ethnicity, and marital status. RESULTS: Antisocial, histrionic, and borderline PDs were strong predictors for the externalizing factor, while schizotypal, borderline, avoidant, and obsessive-compulsive PDs had significantly larger effects on the internalizing fear factor when compared to the internalizing misery factor. Paranoid, schizoid, narcissistic, and dependent PDs provided limited discrimination between and among the three factors. An overarching latent factor representing general personality dysfunction was significantly greater on the internalizing fear factor followed by the externalizing factor, and weakest for the internalizing misery factor. CONCLUSION: Personality disorders offer important opportunities for studies on the externalizing-internalizing spectrum of common psychiatric disorders. Future studies based on panic, anxiety, and depressive symptoms may elucidate PD associations with the internalizing spectrum of disorders. PMID- 23932577 TI - The role of preoperative oxidative stress and mandibular third molar postoperative outcome. PMID- 23932578 TI - A new role for stereolithic models in the management of complex mandibular fractures. AB - The author discusses a new role for stereolithic models in the management of complex mandibular fractures with reference to two case studies. PMID- 23932579 TI - Use of a titanium cutting guide to assist raising the composite radial forearm free flap. AB - The use of composite radial free tissue transfer has been overtaken by other composite flaps. This is due to donor site morbidity and the poor volume of bone yielded. The advantages and potential complications of composite radial flaps are well described. Use of the composite radial forearm free flap has been largely superseded in mandible reconstruction, but applications such as a salvage option still exist. Additionally it may be used in the reconstruction of midface defects. The use of a cutting guide to reduce the donor site complications and yet produce a maximal yield of bone is described herein. With the use of a skilled maxillofacial laboratory, the planning allows precise cuts and placement of the free flap and allows accurate prophylactic plating of the radius. A precise titanium cutting guide and custom distal radius plate are used. Details of three cases where these techniques have been implemented are described. The paper demonstrates the significant advantages of using laboratory-based technology to assist in performing composite radial free flaps. This paper reveals that composite radial free tissue transfer still has a place in the reconstruction of very selective defects of the head and neck. In particular, its use in reconstruction of Class 5 and 6 maxillary defects (Brown classification) is illustrated. Correct case selection and planning results in increased confidence to use this flap. PMID- 23932580 TI - Differential miRNA expression between equine ovulatory and anovulatory follicles. AB - Relatively little is known about the physiological roles of microRNAs (miRNAs) during follicular development. Previous evidence from in vitro studies suggests specific roles for a subset of miRNAs, including miR-21, miR-23a, miR-145, miR 503, miR-224, miR-383, miR-378, miR-132, and miR-212, in regulating ovarian follicle development. The objective of this study was to gain insight on the involvement of these miRNAs during follicle maturation. Follicular fluid was aspirated from dominant follicles (>32 mm) during the ovulatory season (July to October) and the anovulatory season (January to March) in each of 5 mares, and the levels of steroids, IGF1, and miRNAs were analyzed by immunoassays and quantitative PCR. Levels of progesterone, testosterone, and IGF1 were lower (P <= 0.05) in anovulatory than in ovulatory follicles. Relative to ovulatory follicles, anovulatory follicles had higher (P < 0.05) mean levels of miR-21, miR 23b, miR-378, and miR-202 and tended to have higher (P = 0.06) levels of miR-145. Levels of miR-224 and miR-383 could not be detected in follicular fluid. These novel results indicate a physiological association between increases in follicular miRNA levels and seasonal anovulation in mares; further studies should elucidate the precise involvement of miR-21, miR-23b, miR-145, miR-378, and miR 202 in follicle maturation in the mare. PMID- 23932581 TI - IGF-I retards proper development of acinar structures formed by bovine mammary epithelial cells via sustained activation of Akt kinase. AB - Insulin-like growth factor-I is involved in mammary gland development, promoting proliferation and inhibiting apoptosis of mammary epithelial cells (MECs). Mitogenic actions of IGF-I are mainly mediated by the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway. We have found that in the presence of IGF-I bovine BME-UV1 MECs cultured on reconstituted basement membrane form large spheroids with disrupted polarity and no cavity in the center. These cells showed enhanced phosphorylation of Akt, decreased level of cleaved caspase-3, and sustained proliferative activity throughout the 16-d period of 3-dimensional culture. Inhibition of the PI3K/Akt pathway by a specific inhibitor of PI3K, LY294002, resulted in the restoration of the normal acinar phenotype. However, this effect was noted only when LY294002 was added in the second week of 3 dimensional culture, which corresponded with the time of cell cycle arrest and polarity formation under control conditions. Normal development of acini was also obtained when BME-UV1 cells were treated simultaneously with IGF-I and 17beta estradiol. The addition of 17beta-estradiol regulated Akt activation, enabling the subsequent initiation of polarization processes. 17beta-Estradiol also increased the level of IGFBP-3 protein in MECs cultured on Matrigel in the presence of IGF-I. The presented results indicate important interactions between signaling pathways activated by estrogen and IGF-I, which regulate alveologenesis in bovine mammary gland. PMID- 23932582 TI - Surgical strategies and modern therapeutic options in the treatment of craniopharyngiomas. AB - The optimal treatment of patients with craniopharyngioma remains controversial. In particular, the role of aggressive treatment compared to less aggressive therapeutic options is poorly understood. Radical resection is the therapy of choice at any age, because it is associated with the best outcome in terms of survival. Nevertheless, aggressive behaviour, location, involvement of critical structures, tumour size, calcifications, and patient age may limit the extent of resection. Surgery can also carry significant morbidity in terms of visual, hypothalamic, and endocrinological disturbances. Long term sequelae reduce the quality of life in 50% of long-term survivors, notably obesity and neurobehavioral impairment due to hypthalamic involvement and iatrogenic induced lesions. The quality of life should be considered as a clinically important endpoint in patients, who currently experience good overall survival rates, regardless of the degree of surgical resection. Tendency to recur despite negative postoperative imaging led many authors to advocate a less aggressive surgical treatment followed by radiation therapy. We review the data reported in the literature, especially early outcome after surgical treatment and factors affecting the risk of tumour recurrence, to elucidate the role of attempted radical resection in the treatment of craniopharyngioma and to identify the clinical and morphological characteristics predictive for the best surgical prognosis. PMID- 23932584 TI - [Ptosis secondary to cavernous sinus meningioma]. AB - INTRODUCTION: Meningiomas of the cavernous sinus are often the cause of neuro ophthalmologic manifestations. Fifty percent of affected patients present with ptosis. We report a case of ptosis acquired during the first year of life due to oculomotor nerve palsy secondary to a cavernous sinus meningioma. We then discuss the causes of third cranial nerve palsy and treatment options for ptosis associated with CN III palsy. OBSERVATION: A fifteen-year-old female patient presented with ptosis due to a third cranial nerve palsy appearing within the first year of life. Magnetic resonance imaging (MRI) revealed a cavernous sinus meningioma. The ptosis was treated by frontalis suspension using autologous temporalis fascia. The meningioma required regular follow-up. DISCUSSION: Ptosis due to third cranial nerve palsy is rare in children. The most common etiologies are congenital and represent 33 to 40% of cases in various studies. Other etiologies are traumatic, tumoral, vascular and infectious. The cause needs to be found by imaging over the entire course of the nerve. Cavernous sinus meningioma is one cause of third cranial nerve palsy. The surgical treatment of ptosis due to third cranial nerve palsy is levator resection or frontalis suspension with a strip of fascia lata or temporalis fascia. PMID- 23932585 TI - [Optic nerve head drusen complicated by serous retinal detachment overlying choroidal neovasculation]. PMID- 23932586 TI - [Oncocytoma of the lacrimal sac: case report]. PMID- 23932583 TI - Calcium and vitamin D supplementation and loss of bone mineral density in women undergoing breast cancer therapy. AB - An unintended consequence of breast cancer therapies is an increased risk of osteoporosis due to accelerated bone loss. We conducted a systematic review of calcium and/or vitamin D (Ca+/-D) supplementation trials for maintaining bone mineral density (BMD) in women with breast cancer using the "before-after" data from the Ca+/-D supplemented comparison group of trials evaluating the effect of drugs such as bisphosphonates on BMD. Whether Ca+/-D supplements increase BMD in women undergoing breast cancer therapy has never been tested against an unsupplemented control group. However, results from 16 trials indicate that the Ca+/-D doses tested (500-1500mg calcium; 200-1000IU vitamin D) were inadequate to prevent BMD loss in these women. Cardiovascular disease is the main cause of mortality in women with breast cancer. Because calcium supplements may increase cardiovascular disease risk, future trials should evaluate the safety and efficacy of Ca+/-D supplementation in women undergoing breast cancer therapy. PMID- 23932587 TI - [Refractive errors among schoolchildren in the central region of Togo]. AB - Untreated refractive errors represent the main visual impairment in the world but also the easiest to avoid. The goal of this survey is to use clinical and epidemiological data to efficiently plan distribution of corrective glasses in a project supported by the Swiss Red Cross in the central region of Togo. To achieve this goal, 66 primary schools were identified randomly in the catchment area of the project. The teachers at these schools were previously trained to test visual acuity (VA). The schoolchildren referred by these teachers were examined by eye care professionals. The schoolchildren with ametropia (VA<=7/10 in at least one eye) underwent cycloplegic autorefraction. Of a total of 19,252 registered schoolchildren, 13,039 underwent VA testing by the teachers (participation rate=68%). Among them, 366 cases of ametropia were identified (prevalence about 3%). The average age of the schoolchildren examined was 10.7+/ 2.3years, with a sex ratio of 1.06. Autorefraction, which was performed for 37% of the schoolchildren with ametropia allowed them to be classified into three groups: hyperopia (4%), myopia (5%) and astigmatism of all types (91%). Regardless of the type of ametropia, the degree of severity was mild in 88%. The results of this survey have highlighted the importance of the teachers' contribution to eye care education in the struggle against refractive errors within the school environment, as well as helping to efficiently plan actions against ametropia. PMID- 23932588 TI - The differential regulation of p38alpha by the neuronal kinase interaction motif protein tyrosine phosphatases, a detailed molecular study. AB - The MAP kinase p38alpha is essential for neuronal signaling. To better understand the molecular regulation of p38alpha we used atomistic and molecular techniques to determine the structural basis of p38alpha regulation by the two neuronal tyrosine phosphatases, PTPSL/PTPBR7 (PTPRR) and STEP (PTPN5). We show that, despite the fact that PTPSL and STEP belong to the same family of regulatory proteins, they interact with p38alpha differently and their distinct molecular interactions explain their different catalytic activities. Although the interaction of PTPSL with p38alpha is similar to that of the previously described p38alpha:HePTP (PTPN7) complex, STEP binds and regulates p38alpha in an unexpected manner. Using NMR and small-angle X-ray scattering data, we generated a model of the p38alpha:STEP complex and define molecular differences between its resting and active states. Together, these results provide insights into molecular regulation of p38alpha by key regulatory proteins. PMID- 23932589 TI - Conservation of protein structure over four billion years. AB - Little is known about the evolution of protein structures and the degree of protein structure conservation over planetary time scales. Here, we report the X ray crystal structures of seven laboratory resurrections of Precambrian thioredoxins dating up to approximately four billion years ago. Despite considerable sequence differences compared with extant enzymes, the ancestral proteins display the canonical thioredoxin fold, whereas only small structural changes have occurred over four billion years. This remarkable degree of structure conservation since a time near the last common ancestor of life supports a punctuated-equilibrium model of structure evolution in which the generation of new folds occurs over comparatively short periods and is followed by long periods of structural stasis. PMID- 23932590 TI - Architecture and DNA recognition elements of the Fanconi anemia FANCM-FAAP24 complex. AB - Fanconi anemia (FA) is a disorder associated with a failure in DNA repair. FANCM (defective in FA complementation group M) and its partner FAAP24 target other FA proteins to sites of DNA damage. FANCM-FAAP24 is related to XPF/MUS81 endonucleases but lacks endonucleolytic activity. We report a structure of an FANCM C-terminal fragment (FANCMCTD) bound to FAAP24 and DNA. This S-shaped structure reveals the FANCM (HhH)2 domain is buried, whereas the FAAP24 (HhH)2 domain engages DNA. We identify a second DNA contact and a metal center within the FANCM pseudo-nuclease domain and demonstrate that mutations in either region impair double-stranded DNA binding in vitro and FANCM-FAAP24 function in vivo. We show the FANCM translocase domain lies in proximity to FANCMCTD by electron microscopy and that binding fork DNA structures stimulate its ATPase activity. This suggests a tracking model for FANCM-FAAP24 until an encounter with a stalled replication fork triggers ATPase-mediated fork remodeling. PMID- 23932591 TI - Crystal structures of botulinum neurotoxin DC in complex with its protein receptors synaptotagmin I and II. AB - Botulinum neurotoxins (BoNTs) can cause paralysis at exceptionally low concentrations and include seven serotypes (BoNT/A-G). The chimeric BoNT/DC toxin has a receptor binding domain similar to the same region in BoNT/C. However, BoNT/DC does not share protein receptor with BoNT/C. Instead, it shares synaptotagmin (Syt) I and II as receptors with BoNT/B, despite their low sequence similarity. Here, we present the crystal structures of the binding domain of BoNT/DC in complex with the recognition domains of its protein receptors, Syt-I and Syt-II. The structures reveal that BoNT/DC possesses a Syt binding site, distinct from the established Syt-II binding site in BoNT/B. Structure-based mutagenesis further shows that hydrophobic interactions play a key role in Syt binding. The structures suggest that the BoNT/DC ganglioside binding sites are independent of the protein receptor binding site. Our results reveal the remarkable versatility in the receptor recognition of the BoNTs. PMID- 23932592 TI - Structural basis for the interaction of the Golgi-Associated Retrograde Protein Complex with the t-SNARE Syntaxin 6. AB - The Golgi-Associated Retrograde Protein (GARP) complex is a tethering factor involved in the fusion of endosome-derived transport vesicles to the trans-Golgi network through interaction with components of the Syntaxin 6/Syntaxin 16/Vti1a/VAMP4 SNARE complex. The mechanisms by which GARP and other tethering factors engage the SNARE fusion machinery are poorly understood. Herein, we report the structural basis for the interaction of the human Ang2 subunit of GARP with the Syntaxin 6 and the closely related Syntaxin 10. The crystal structure of the Syntaxin 6 Habc domain in complex with a peptide from the N terminus of Ang2 shows a binding mode in which a dityrosine motif of Ang2 interacts with a highly conserved groove in Syntaxin 6. Structure-based mutational analyses validate the crystal structure and support the phylogenetic conservation of this interaction. PMID- 23932594 TI - Mitochondrial respiratory complex I defects in Fanconi anemia. AB - Fanconi anemia (FA) is a rare, complex disorder that manifests in childhood. Children with FA suffer bone marrow failure, leukemias, or solid tumors. FA associated mutations are found in 15 proteins that are involved in DNA repair. Some of these proteins have extranuclear activities involving redox balance, apoptosis, and energy metabolism; and recent data demonstrate respiratory impairment in FA cells, suggesting that altered mitochondrial function is a factor in this disease. PMID- 23932593 TI - Branched signal wiring of an essential bacterial cell-cycle phosphotransfer protein. AB - Vital to bacterial survival is the faithful propagation of cellular signals, and in Caulobacter crescentus, ChpT is an essential mediator within the cell-cycle circuit. ChpT functions as a histidine-containing phosphotransfer protein (HPt) that shuttles a phosphoryl group from the receiver domain of CckA, the upstream hybrid histidine kinase (HK), to one of two downstream response regulators (CtrA or CpdR) that controls cell-cycle progression. To understand how ChpT interacts with multiple signaling partners, we solved the crystal structure of ChpT at 2.3 A resolution. ChpT adopts a pseudo-HK architecture but does not bind ATP. We identified two point mutation classes affecting phosphotransfer and cell morphology: one that globally impairs ChpT phosphotransfer, and a second that mediates partner selection. Importantly, a small set of conserved ChpT residues promotes signaling crosstalk and contributes to the branched signaling that activates the master regulator CtrA while inactivating the CtrA degradation signal, CpdR. PMID- 23932595 TI - Comparative performance of trace element bioaccumulation and biomonitoring in the plant species Typha domingensis, Phragmites australis and Arundo donax. AB - Toxic levels of trace elements in the environment have been reported worldwide over the last few decades, and their increasing concentrations are of the utmost concern because of the adverse effects on human life and ecosystems. Several plant species are able to accumulate trace elements, and may be used for monitoring and remediation of polluted sites. This study compared the capacity of trace element bioaccumulation in three wetland plants distributed worldwide: Typha domingensis, Phragmites australis and Arundo donax. The aims were to identify which species show better potential for removal and monitoring of these elements: Al, As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, Zn. Results showed that all species may be used as biomonitors of trace element contamination in sediment, but only P. australis and A. donax showed also a correlation with water. Overall, T. domingensis and P. australis showed a greater capacity of bioaccumulation as well as a greater efficiency of element removal than A. donax. In particular, T. domingensis and P. australis may be used for Hg phytostabilization, the former acted also as a hyperaccumulator for Hg phytoextraction and as a promising species for As phytostabilization. In contaminated wetlands, the presence of T. domingensis and P. australis may increase the general retention of trace elements, thus, their introduction is recommended for possible actions of phytoremediation and biomonitoring. PMID- 23932596 TI - Extent of thyroidectomy affects vocal and throat functions: a prospective observational study of lobectomy versus total thyroidectomy. AB - BACKGROUND: Voice and throat dysfunction may occur in patients after thyroidectomy, even in the absence of apparent laryngeal nerve injury. We evaluated the impact of thyroid surgery on voice and throat function using perceptive, objective, and subjective measurements in a prospectively enrolled and serially followed cohort of thyroid cancer patients. We assessed the impact of surgical extent and intensity of postoperative treatment, including addition radioactive iodine treatment (RIT), on these functions. METHODS: Consenting patients undergoing thyroid lobectomy (TL; n = 33), total thyroidectomy (TT; n = 41), or TT plus RIT (n = 81), none of whom had laryngeal nerve dysfunction perioperatively, were enrolled prospectively. All underwent comprehensive functional evaluations, including perceptive voice quality using the grade, roughness, breathiness, asthenia, strain (GRBAS) scale and acoustic voice analysis with multiple parameters, and filled out subjective questionnaires, including the Voice Handicap Index (VHI) and the Glasgow Edinburgh Throat Scale, before thyroidectomy and at 1, 6, and 12 months postoperatively. RESULTS: In this study, 14-83% of the patients developed some element of voice and throat dysfunction, shown consistently in different evaluations. Typical patterns were alterations of perceptive voice, deranged acoustic parameters, and subjective worsening on the VHI and GETS. Moreover, these changes were correlated with the extent of treatment, especially within 3 months after operation, and often persisted 12 months postoperatively. RIT had no effects on voice outcomes throughout the follow-up. CONCLUSION: Voice and throat dysfunction are evident after thyroidectomy, more severely after TT than TL. These potential disabilities should be considered carefully to further enhance patients' quality of life. PMID- 23932597 TI - Research in global surgery: what is true science? PMID- 23932598 TI - The cell biology of synaptic specificity during development. AB - Proper circuit connectivity is critical for nervous system function. Connectivity derives from the interaction of two interdependent modules: synaptic specificity and synaptic assembly. Specificity involves both targeting of neurons to specific laminar regions and the formation of synapses onto defined subcellular areas. In this review, we focus discussion on recently elucidated molecular mechanisms that control synaptic specificity and link them to synapse assembly. We use these molecular pathways to underscore fundamental cell biological concepts that underpin, and help explain, the rules governing synaptic specificity. PMID- 23932600 TI - Tuberculin skin test conversion rate among short-term health care workers returning from Gaborone, Botswana. AB - Our objective was to determine tuberculin skin test conversion rate of health care workers traveling to Botswana. The rate of tuberculin skin test conversion was 4.2% for the entire group studied or 6.87 per 1000 person weeks (95% CI, 1.87 17.60). BACKGROUND: International travel by health care workers traveling from low incidence countries to areas of the world where tuberculosis is highly endemic places the health care worker at an increased risk of acquiring tuberculosis. OBJECTIVES: To determine the tuberculin skin test conversion rate of health care workers living in the United States with previously negative tuberculin skin test results working for less than 1 year in a hospital in Botswana where tuberculosis is highly endemic. METHODS: We performed a cross sectional survey among health care workers affiliated with the University of Pennsylvania School of Medicine who participated in patient care in Botswana between July 1st 2004 and June 30th 2009. We recruited health care workers after returning from Botswana who had a documented negative tuberculin skin test in the year prior to travel, who spent at least 2 weeks but not more than 1 year and who had a documented tuberculin skin test 2-3 months post travel. The main study outcome was a positive tuberculin skin test 6-12 weeks after returning from Botswana, defined by an area of at least 10mm induration 48-72h after placement of the tuberculin skin test. RESULTS: 95 Subjects participated in the study and there were 4 tuberculin skin test conversions. The rate of tuberculin skin test conversion in our study population was 4.2% for the entire group studied or 6.87 per 1000 person weeks (95% CI, 1.87-17.60). CONCLUSIONS: The tuberculin skin test conversion rate was higher than the reported conversion rates for those not working in a health care setting. PMID- 23932599 TI - Fourier-domain optical coherence tomography imaging in keratoconus: a corneal structural classification. AB - OBJECTIVE: To study corneal morphologic changes in a large keratoconic population and to establish a structural optical coherence tomography (OCT) classification. DESIGN: Cross-sectional, observational study. PARTICIPANTS: A total of 218 keratoconic eyes from 218 patients and 34 eyes from 34 normal subjects. METHODS: A Fourier-domain OCT system with 5-MUm axial resolution was used. For each patient, 3 high-resolution scans were made across the keratoconus cone. All scans were analyzed by keratoconus specialists who were not given access to patients' clinical and topographic data, and who established an OCT classification. The reproducibility of the classification and its correlation with clinical and paraclinical characteristics of patients with keratoconus were evaluated. The OCT examinations were performed every 4 months to follow up structural corneal changes. MAIN OUTCOME MEASURES: Evaluation of the structural corneal changes occurring in keratoconus cases with various stages of severity based on OCT findings. RESULTS: Fourier-domain OCT classification containing 5 distinct keratoconus stages is proposed. Stage 1 demonstrates thinning of apparently normal epithelial and stromal layers at the conus. Stage 2 demonstrates hyperreflective anomalies occurring at the Bowman's layer level with epithelial thickening at the conus. Stage 3 demonstrates posterior displacement of the hyperreflective structures occurring at the Bowman's layer level with increased epithelial thickening and stromal thinning. Stage 4 demonstrates pan-stromal scar. Stage 5 demonstrates hydrops; 5a, acute onset: Descemet's membrane rupture and dilaceration of collagen lamellae with large fluid-filled intrastromal cysts; 5b, healing stage: pan-stromal scarring with a remaining aspect of Descemet's membrane rupture. The reproducibility of the classification was very high between the corneal specialist observers. Clinical and paraclinical characteristics of keratoconus, including visual acuity, corneal epithelium and stromal thickness changes, corneal topography, biomechanical corneal characteristics, and microstructural changes observed on confocal microscopy, were concordant with our OCT grading. CONCLUSIONS: Optical coherence tomography provides an accurate assessment of structural changes occurring in keratoconus eyes. These changes were correlated with clinical and paraclinical characteristics of patients. The established classification not only allows structural follow-up of patients with keratoconus but also provides insight into the pathogenesis of keratoconus and treatment strategies for future research. PMID- 23932601 TI - The ACGME case log: general surgery resident experience in pediatric surgery. AB - BACKGROUND: General surgery (GS) residents in ACGME programs log cases performed during their residency. We reviewed designated pediatric surgery (PS) cases to assess for changes in performed cases over time. METHODS: The ACGME case logs for graduating GS residents were reviewed from academic year (AY) 1989-1990 to 2010 2011 for designated pediatric cases. Overall and designated PS cases were analyzed. Data were combined into five blocks: Period I (AY1989-90 to AY1993-94), Period II (AY1994-95 to AY1998-99), Period III (AY1999-00 to AY2002-03), Period IV (AY2003-04 to AY2006-07), and Period V (AY2007-08 to AY2010-11). Periods IV and V were delineated by implementation of duty hour restrictions. Student t tests compared averages among the time periods with significance at P < .05. RESULTS: Overall GS case load remained relatively stable. Of total cases, PS cases accounted for 5.4% in Period I and 3.7% in Period V. Designated pediatric cases declined for each period from an average of 47.7 in Period I to 33.8 in Period V. These changes are due to a decline in hernia repairs, which account for half of cases. All other cases contributed only minimally to the pediatric cases. The only laparoscopic cases in the database were anti-reflux procedures, which increased over time. CONCLUSIONS: GS residents perform a diminishing number of designated PS cases. This decline occurred before the onset of work-hour restrictions. These changes have implications on the capabilities of the current graduating workforce. However, the case log does not reflect all cases trainees may be exposed to, so revision of this list is recommended. PMID- 23932602 TI - The effect of race and gender on pediatric surgical outcomes within the United States. AB - PURPOSE: The purpose of this study was to examine risk-adjusted associations between race and gender on postoperative morbidity, mortality, and resource utilization in pediatric surgical patients within the United States. METHODS: 101,083 pediatric surgical patients were evaluated using the U.S. national KID Inpatient Database (2003 and 2006): appendectomy (81.2%), pyloromyotomy (9.8%), intussusception (6.2%), decortication (1.9%), congenital diaphragmatic hernia repair (0.7%), and colonic resection for Hirschsprung's disease (0.2%). Patients were stratified according to gender (male: 63.1%, n=63,783) and race: white (n=58,711), Hispanic (n=26,118), black (n=9,103), Asian (n=1,582), Native American (n=474), and other (n=5,096). Multivariable logistic regression modeling was utilized to evaluate risk-adjusted associations between race, gender, and outcomes. RESULTS: After risk adjustment, race was independently associated with in-hospital death (p=0.02), with an increased risk for black children. Gender was not associated with mortality (p=0.77). Postoperative morbidity was significantly associated with gender (p<0.001) and race (p=0.01). Gender (p=0.003) and race (p<0.001) were further associated with increased hospital length of stay. Importantly, these results were dependent on operation type. CONCLUSION: Race and gender significantly affect postoperative outcomes following pediatric surgery. Black patients are at disproportionate risk for postoperative mortality, while black and Hispanic patients have increased morbidity and hospital resource utilization. While gender does not affect mortality, gender is a determinant of both postoperative morbidity and increased resource utilization. PMID- 23932603 TI - Comparison of pediatric surgical outcomes by the surgeon's degree of specialization in children. AB - INTRODUCTION: Improved surgical outcomes in children have been associated with pediatric surgical specialization, previously defined by surgeon operative volume or fellowship training. The present study evaluates pediatric surgical outcomes through classifying surgeons by degrees of pediatric versus adult operative experience. METHODS: A cross-sectional study was performed using nationally representative hospital discharge data from 1998 to 2007. Patients under 18 years of age undergoing inpatient operations in neurosurgery, otolaryngology, cardiothoracic, general surgery, orthopedic surgery, and urology were included. An index was created, calculating the proportion of children treated by each surgeon. In-hospital mortality and length of stay were compared by index quartiles. Multivariate analysis was adjusted for patient and hospital characteristics. RESULTS: A total of 119,164 patients were operated on by 13,141 surgeons. Within cardiothoracic surgery, there were 1.78 (p=0.02) and 2.61 (p<0.01) increased odds of mortality comparing surgeons in the lowest two quartiles for pediatric specialization respectively with the highest quartile. For general surgery, a 2.15 (p=0.04) increase in odds for mortality was found when comparing surgeons between the lowest and the highest quartiles. Comparing the least to the most specialized surgeons, length of stay increased 1.14 days (p=0.02) for cardiothoracic surgery, 0.58 days (p=0.04) for neurosurgery, 0.23 days (p=0.02) for otolaryngology, and decreased by 1.06 days (p<0.01) for orthopedic surgery. CONCLUSION: The present study demonstrates that surgeons caring preferentially for children-as a proportion of their overall practice generally have improved mortality outcomes in general and cardiothoracic surgery. These data suggest a benefit associated with increased referral of children to pediatric practitioners, but further study is required. PMID- 23932604 TI - Esophageal atresia: data from a national cohort. AB - PURPOSE: A prospective national register was established in 2008 to record all new cases of live-birth newborns with esophageal atresia (EA). This epidemiological survey was recommended as part of a national rare diseases plan. METHODS: All 38 national centers treating EA participated by completing for each patient at first discharge a questionnaire validated by a national committee of experts. Data were centralized by the national reference center for esophageal anomalies. Quantitative and qualitative analyses were performed, with P-values of less than 0.05 considered statistically significant. Results of the 2008-2009 data collection are presented in this report. RESULTS: Three hundred seven new living cases of EA were recorded between January 1, 2008, and December 31, 2009. The male/female sex ratio was 1.3, and the live-birth prevalence of EA was 1.8 per 10,000 births. Major characteristics were comparable to those reported in the literature. Survival was 95%, and no correlation with caseload was noted. CONCLUSIONS: Epidemiologic surveys of congenital anomalies such as EA, which is a rare disease, provide valuable data for public health authorities and fulfill one important mission of reference centers. When compared with previous epidemiological data, this national population-based registry suggests that the incidence of EA remains stable. PMID- 23932605 TI - Esophageal transplantation in the rat. AB - PURPOSE: Esophageal replacement surgery has been used to treat long-gap esophageal atresia, caustic esophageal stricture, and esophageal avulsion. Here, we report total esophageal transplantation in rats without vascular anastomosis as an option for esophageal replacement surgery. METHODS: Fourteen total segments of esophageal transplants were harvested from 24-week-old male Sprague-Dawley rats using a harvesting procedure. The segments were transplanted through the mediastinum in the esophageal bed of 15-week-old male Sprague-Dawley rats without adjacent vascular anastomosis using the transhiatal pull-up technique. The ends of the transplanted esophagus were ostomized using cervical and abdominal esophagostomies. An immunosuppressive-treated (IT) group (n = 7) received cyclosporine and cotrimoxazole for 10 days, while an untreated (UT) group (n = 7) received only cotrimoxazole for 10 days. On post-operative day 10, the rats were sacrificed, and the transplant and recipient esophagi were evaluated macroscopically and histopathologically. RESULTS: All transplantations were successful and all transplanted rats survived. Upon macroscopic evaluation, no evidence of complications was observed and all transplanted esophagi in the two groups appeared to exhibit excellent firm tissue; however, mild necrosis was observed in the cervical end of the transplant in one rat in the IT group. Histopathologic examination showed a viable esophageal structure in all rats. Inflammation and muscular atrophy were lower in the IT group than in the UT group, whereas vascularity was higher in the IT group than in the UT group. CONCLUSION: Total esophageal transplantation was performed directly without vascular anastomosis into recipients in a rat model. This procedure should be done in larger animal models before being attempted in humans. PMID- 23932606 TI - Balloon dilation in the management of severe airway stenosis in children and adolescents. AB - BACKGROUND/PURPOSE: Children and adolescents with airway stenosis pose a clinical challenge. Recently, balloon dilation has been described, primarily for the treatment of early, immature, less severe airway stenosis. We describe our experience with 8 children and adolescents managed with balloon dilation, including severe, mature subglottic and tracheal stenosis. METHODS: This is a case series of 8 children and adolescents with acquired subglottic and tracheal stenosis treated by the primary author with balloon dilation between August 2006 and April 2010 at an academic tertiary care center. In the four patients who were tracheotomy-dependent at the time of presentation, suprastomal stents or Montgomery T-tubes were used. In 1 patient with 99% subglottic stenosis (SGS), balloon dilation and stenting were used to create a lumen prior to laryngotracheal reconstruction (LTR). RESULTS: All 4 patients with tracheotomy were decannulated. The remaining 4 patients were successfully managed without tracheotomy. CONCLUSIONS: Mature, severe laryngeal and tracheal stenosis in pediatric patients can be successfully managed with balloon dilation. In the most severe cases with prior tracheotomy, stenting is necessary. Balloon dilation with stenting can also facilitate LTR. In patients without prior tracheotomy, tracheotomy and stenting can often be safely avoided with appropriate postoperative management. PMID- 23932607 TI - Early childhood outcomes of infants born with gastroschisis. AB - PURPOSE: To describe neonatal and childhood outcomes of a contemporary cohort of infants with gastroschisis. METHODS: Observational, single center, inception cohort of children born with gastroschisis from January 2005 to December 2008. RESULTS: Of 63 infants, 61 survived to hospital discharge and 39 were seen for follow-up. Complications included sepsis (37%), necrotizing enterocolitis (10%), parenteral nutrition related cholestasis (25%), and short bowel syndrome (13%). Of survivors, 5% had visual impairment and 10% had hearing loss. No child tested had mental delay or cerebral palsy. Early gestational age predicted death or disability (OR 0.60, 95% CI 0.38, 0.96; p=0.033). There was a high incidence of prescription medications for presumed gastroesophageal reflux (90%). Some infants continued to require tube feeds (15%). There were improvements in longitudinal growth reflected in increasing z-scores. CONCLUSIONS: Although children with gastroschisis are at risk for disability, childhood outcomes are encouraging. PMID- 23932608 TI - Growth and developmental outcomes of infants with gastroschisis at one year of age: a retrospective study. AB - BACKGROUND: The aim of the study was to describe the physical growth and developmental outcomes of babies born with gastroschisis. METHODS: We retrospectively reviewed all cases of gastroschisis in Western Australia born between 1997 and 2010. RESULTS: In the 128 pregnancies with fetal gastroschisis, 117 babies were live born. 112 (95.7%) survived to one year. 19% had z scores of< 1.28 for weight at birth (<10th centiles) compared with 30% at one year. Neurodevelopmental data were available in 88/112 (79%) of survivors (Griffiths scores in 67; reports of ages and stages questionnaire (ASQ) in 21). The mean GQ at 12 months was 99 (SD 9.8). Suboptimal neurodevelopmental outcomes were noted in eight. Complex gastroschisis (present at birth) and acquired gut related complications were associated with adverse long term outcomes. The incidence of acquired gut complications was least (5%) in those who underwent silo reduction as the primary management. However, on univariate and multivariate analysis, the type of primary reduction did not significantly influence the outcome. CONCLUSIONS: A large proportion of infants with gastroschisis exhibit suboptimal weight gain during the first year. The incidence of adverse developmental outcomes appears to be low. PMID- 23932609 TI - Protective effects of hydrogen-rich saline on necrotizing enterocolitis in neonatal rats. AB - PURPOSE: The aim of this study was to test the hypothesis that hydrogen-rich saline (HRS) might have protective effects on the development of necrotizing enterocolitis (NEC) in a neonatal rat model. METHODS: NEC was induced in male newborn Sprague-Dawley rats by formula feeding, exposure to asphyxia and cold stress. Sixty-four rat pups were divided randomly into four groups: C+NS (n=11), C+H2 (n=11), NEC+NS (n=20), and NEC+H2 (n=22). Rats in the former two groups were mother-fed. Pups received intra-peritoneal injection of HRS (10 ml/kg, 10 min before asphyxia stress twice a day) or the same dose of normal saline. Rats were monitored until 96 h after birth. Body weight, histological NEC score, survival time, malondialdehyde, antioxidant capacity, inflammatory mediators, and mucosal integrity were assessed. RESULTS: HRS treatment maintained the body weight, reduced the incidence of NEC from 85% (17/20) to 54.5% (12/22), increased the survival rate from 25% (5/20) to 68.2% (15/22), and attenuated the severity of NEC. In addition, HRS inhibited the mRNA expression of pro-inflammatory mediators (inducible nitric oxide synthase, tumor necrosis factor-alpha, and interleukin 6), down-regulated lipid peroxidation, enhanced total antioxidant capacity, and prevented the increase of diamine oxidase in serum. However, no significant influence of HRS on the interleukin-10 mRNA expression was observed. CONCLUSIONS: HRS showed beneficial effects on neonatal rats with NEC via decreasing oxidative stress, increasing antioxidant capacity, suppressing inflammation, and preserving mucosal integrity. PMID- 23932610 TI - Protective effect of sildenafil on liver injury induced by intestinal ischemia/reperfusion. AB - BACKGROUND: This study evaluated the protective effect of sildenafil on liver injury induced by intestinal ischemia-reperfusion. METHODS: Forty female Sprague Dawley rats were divided into 4 groups: sham-control (SC), ischemia (I), ischemia reperfusion (IR), and ischemia-reperfusion+sildenafil (SIL; sildenafil gavaged at 50mg/kg before operating). A 2-h ischemia-reperfusion was performed by clamping the superior mesenteric artery. Liver function, plasma alanine (ALT) and aspartate (AST) aminotransferase, and intestinal and liver malondialdehyde (MDA) were measured at the end of the experiment. Intestinal and liver tissue damage was examined by histology. Liver samples were immunologically stained for endothelial nitric oxide synthase (eNOS) and proliferating cell nuclear antigen (PCNA). RESULTS: The ALT and AST levels were highest in the IR group and were lower in the SIL group (p<0.05). Intestinal MDA levels were statistically higher in the IR group than in the SC, I and SIL groups. Liver MDA levels were significantly higher in the IR group than in the I and SC groups (p<0.05) and higher than in the SIL group (p>0.05). Intestinal damage based on Chiu scoring was more severe in the IR than in the SIL group (p<0.05). Sildenafil reduced damage and also increased eNOS and PCNA immunoreactivity in liver tissue. CONCLUSIONS: Sildenafil shows a protective effect on intestinal ischemia reperfusion-induced liver injury, possibly by decreasing vascular resistance through increased nitric oxide levels. PMID- 23932611 TI - Laparoscopic cholecystectomy for biliary dyskinesia in children: frequency increasing. AB - PURPOSE: The treatment of children with biliary dyskinesia (BD) is controversial. As we recently observed an increasing frequency of referrals for BD in our institution the aim of the study was to re-evaluate the long-term outcome in children with BD. METHODS: Children with laparoscopic cholecystectomy (LC) for suspected BD between 8/2006 and 5/2011 were included. A pathologic ejection fraction (EF) was defined as <35%. The long-term effect of cholecystectomy was assessed via a Likert scale symptom questionnaire. RESULTS: 82 children (median age 13.5 years, mean BMI 25.8) were included. CCK-HIDA scan was pathologic in 74 children (90.2%). Mean EF was 16.4%. Histology revealed chronic cholecystitis in 48 (58.5%) children and was normal in 30 children (36.5%). The frequency of LC for suspected BD increased by a factor of 4.3 in the last 10 years. Long term follow-up showed that only 23/52 children (44.2%) were symptom-free after LC. Patients with chronic inflammation were more likely to have persistent symptoms (p=0.017). An EF<15% was associated with a resolution of symptoms (p=0.031). CONCLUSION: The frequency of LC for suspected BD in our institution has increased significantly during recent years. The long-term efficacy in our cohort was only 44.2%. We believe that laparoscopic cholecystectomy is likely helpful in patients with an EF<15%. However, in children with an EF of 15%-35%, based upon our data, we would highly recommend an appropriately thorough pre-op testing to exclude other gastrointestinal disorders prior to consideration of operative management. PMID- 23932612 TI - Central venous cutdown in neonates: feasibility as a bedside procedure without general anesthesia. AB - BACKGROUND/PURPOSE: A silicone central venous catheter (CVC) is usually inserted using a percutaneous technique under general anesthesia. However, there are numerous reports on the postoperative adverse effects of general anesthesia in neonates. The aim of this study is to investigate the feasibility of open surgical cutdown (OSC) for central venous access without general anesthesia. METHODS: The medical records of patients who underwent OSC at bedside under sedation and local anesthesia were reviewed. Chloral hydrate (100mg/kg) was given orally for the induction of moderate to deep sedation 15 minutes before OSC; then the operative field was infiltrated with 1% lidocaine. When adequate sedation was not achieved, a bolus of phenobarbital (20mg/kg) was given intravenously. RESULTS: Thirteen Broviac lines were inserted into 12 patients. At insertion, the median gestational age was 29 weeks, birth weight was 1,140 g and age was 33 days. No patients required invasive ventilator care; 7 patients received nasal non-invasive ventilator care. Neither intubation nor inotropics were required during the intra- or postoperative period and no perioperative surgical complications occurred. The median catheter duration was 19.5 days. CONCLUSION: OSC at bedside for CVC insertion, using adequate sedation and local anesthesia, is a feasible procedure in neonates. PMID- 23932613 TI - Clinical outcomes in children with adrenal neuroblastoma undergoing open versus laparoscopic adrenalectomy. AB - BACKGROUND: Laparoscopic resection of adrenal neuroblastoma has become a common alternative to open surgery. Prior reports have largely focused on short-term operative complications. This study compares long-term oncologic outcomes in children undergoing laparoscopic or open adrenalectomy for neuroblastoma. METHODS: Seventy-nine patients at a single center met inclusion criteria for having adrenal neuroblastoma and undergoing operative resection. Patients were assigned to high or low/intermediate (L/I) risk groups based upon Children's Oncology Group (COG) trial enrollment. Criteria for laparoscopic resection were absence of vascular encasement and size <= 5 cm in greatest dimension. Comparison between open versus laparoscopic groups was performed by Wilcoxon ranked-sum and Fisher's exact test. Multivariate Cox proportional hazard models analyzed the primary outcomes of mortality and recurrence. RESULTS: In the L/I risk category (N=30) there was one non-neuroblastoma related death in the open cohort. Six of 7 patients in the High risk Group who underwent laparoscopic resection had favorable outcomes. Only higher tumor stage (Hazard Ratio 8.455, P=0.01) and earlier tumor recurrence were associated with increased mortality (Hazards Ratio 0.932, P=0.0002). Among patients who met selection criteria for laparoscopic surgery there was no difference in mortality or recurrence rates between High risk and L/I risk. CONCLUSIONS: Laparoscopic resection of adrenal neuroblastoma is feasible and can be performed with equivalent recurrence and mortality rates in L/I risk patients and selected High risk patients. These data suggest that laparoscopic resection of adrenal neuroblastoma should be considered in patients who meet selection criteria, irrespective of risk group categorization. PMID- 23932614 TI - Quality of life in pediatric patients with unremitting constipation pre and post Malone Antegrade Continence Enema (MACE) procedure. AB - OBJECTIVE: The primary aim of this study was to determine if there is a change in the quality of life in pediatric patients with unremitting functional constipation and/or encopresis after undergoing a MACE procedure. METHODS: Patients, ages 5 to 18 years with unremitting constipation and a normal evaluation, including anorectal manometry and colonic manometry, who opted to undergo a MACE procedure were contacted to participate in the study. Patients with congenital anorectal malformations as well as spinal cord disorders were excluded from the study. The patient's parent/guardian completed the PedsQL(TM) Generic Core Scales QOL survey prior to the operation, 6 months, and 12 months after the procedure. RESULTS: A total of 15 consecutive patients meeting protocol criteria were recruited within a period of 20 months. The mean age at the MACE procedure was 9.8 years (range 7.0-11.1). 5 patients were female. The mean QOL score pre-MACE was 64.1. At 6 months post-MACE the mean overall QOL score was 90.2, and it was 92.0 at 12 months. All 15 patients at the 6 month follow up had significant improvement in their QOL (p=1.9 * 10(-7)) and all subcategories of QOL were significantly improved as well. CONCLUSIONS: A MACE procedure is of benefit to otherwise normal pediatric patients who have unremitting functional constipation with failure of medical treatment. Our patients had a significant improvement in all QOL categories and overall QOL. PMID- 23932615 TI - Comparative effects of different sclerosing agents used to treat rectal prolapse: an experimental study in rats. AB - BACKGROUND/PURPOSE: Sclerosing agents injected into the rectal submucosal area produce an inflammatory response and scar that prevent rectal prolapse. This study aimed to investigate the histopathological changes following submucosal injection of different sclerosing agents in rats. METHODS: Rats (n=35) were divided into control, sham, and five experimental groups, each treated with a different sclerosing agent: cow's milk, 30% saline solution, 30% dextrose solution, 70% ethyl alcohol, and 5% phenol in almond oil (PAO). All agents were injected into the submucosal area. After 4 weeks, all animals were sacrificed. Histopathological evaluation was performed according to a semi-quantitative fibrosis scoring system (grades 0 to 3), by using Masson trichrome and hematoxylin and eosin staining. RESULTS: Histopathological changes in the 5% phenol in almond oil group were significantly different from other groups (p=0.0001). Prominent submucosal fibrosis (grade 3), lymphatic vascular dilation, foreign body reaction, and lipogranuloma were observed in the 5% PAO group (p=0.007). No significant histopathological differences were seen between the 30% saline, 30% dextrose, and 70% ethyl alcohol groups. Significantly increased mucosal fibroblast proliferation (grade 2) was seen in 60% rats of the 30% dextrose group (p=0.026). The cow's milk and ethyl alcohol groups had mucosal erosions and congestion (grade 1) which were significantly different from the control group (p=0.024). No statically significant difference was observed between the 30% saline group and the control group. CONCLUSIONS: In this study we showed that 5% PAO can induce some histopathological changes in the submucosal area that increase the mucosal tightness of the mucosa, which are necessary for the treatment of rectal prolapse. PMID- 23932616 TI - Treatment of adolescent pilonidal disease with a new modification to the Limberg flap: symmetrically rotated rhomboid excision and lateralization of the Limberg flap technique. AB - BACKGROUND/PURPOSE: Pilonidal disease is a common and frustrating problem among adolescents due to its high recurrence rate. The rhomboid excision and Limberg flap techniques promise successful results, but the lower part of the incision left on the intergluteal sulcus is prone to recurrences. Consequently, we have developed a new modification to this technique and have designed a descriptive prospective study to evaluate its efficiency. METHODS: We conducted this prospective study between March 2011 and March 2012. All of the patients who were operated on for sacrococcygeal pilonidal disease were included in this study. The surgical procedure primarily consisted of symmetrically rotated (clockwise) rhomboid excision and lateralization of the Limberg flap in order to keep the inferior corner of the suture line apart from the intergluteal sulcus. RESULTS: A total of 15 adolescents (8 boys and 7 girls) were included in the study group. Of the patients, 47% were normal, 13% were overweight, and 40% were obese. Five patients were operated on under general anesthesia, and 10 were operated on under spinal anesthesia. The length of the flap margins ranged from 2.5 to 7 cm (median=4 cm). The median duration of hospitalization was 5 days, and the median duration of suction drainage was 4 days. The median postoperative follow-up period was 4 months (ranging from 1 to 12 months), and we did not encounter any wound infection or recurrent disease during this period. Only one patient had wound hematoma as a result of drain breakdown and was treated with wound care without any additional complications. CONCLUSION: Although the number of patients in this study was small and the follow-up period was short, we obtained satisfactory results without any recurrence by performing a symmetrically rotated rhomboid excision and lateralized Limberg flap procedure. PMID- 23932617 TI - Work-related upper limb musculoskeletal disorders in paediatric laparoscopic surgery. A multicenter survey. AB - BACKGROUND: Surgeons are at risk for developing work-related musculoskeletal symptoms (WMS). The present study aims to examine the physical factors and their association with WMS among pediatric laparoscopic surgeons. METHODS: A questionnaire consisting of 21 questions was created and mailed to 25 pediatric laparoscopic surgeons (LG). 23/25 surgeons (92%) completed the survey. The questionnaire was analyzed and then split into 2 groups. Group 1 (LG1) included surgeons with greater laparoscopic experience, and group 2 (LG2) included surgeons with less important laparoscopic experience. In addition, we constructed and sent to the same surgeons a similar questionnaire focused on WMS after an open procedure (OG) with the aim to compare results of LG with OG. RESULTS: The prevalence rate of WMS with shoulder symptoms was 78.2% in surgeons that performed laparoscopy for more than 10 years, with 60.8% also reporting other pain. In 66.6% this pain is evident only after a long-lasting procedure. Forty four percent of these surgeons require painkillers at least twice a week. Fifty percent of these surgeons also suffer at home. Fifty-five and one half percent of surgeons indicate that this pain is related to their laparoscopic activity. Forty three and a half percent think that laparoscopy is beneficial only for the patient but has a bad ergonomic effect for surgeons. Sixty-five and two-tenths percent think that robotic surgery can be helpful to improve ergonomics. Comparing the groups, WMS occur more frequently in LG (78.2%) than in OG (56.5%), but this difference was not statistically significant (chi(2)=0.05). In addition, WMS occur more frequently in LG1 (84.6%) than in LG2 (70%), but this difference was not statistically significant (chi(2)=0.05). CONCLUSIONS: These results confirmed a strong association between WMS and the number of laparoscopic procedures performed. Skilled laparoscopic surgeons have more pain than less skilled laparoscopic surgeons. WMS in the same group of surgeons are more frequent after laparoscopy than after open procedures. The majority of surgeons refer to shoulder symptoms. PMID- 23932618 TI - Watercraft and watersport injuries in children: trauma mechanisms and proposed prevention strategies. AB - PURPOSE: Watercraft-associated trauma (WAT) in children has received little attention so far, despite the potentially severe and debilitating resulting injuries. The aim of this study was to evaluate all cases of major watercraft associated trauma admitted to the Children's of Alabama during the past 10 years, identify patterns in mechanism and injury, and propose future prevention strategies. METHODS: We reviewed our (prospective) database for children admitted through our trauma center after major WAT. Charts were abstracted for mechanism, epidemiologic data, injury type and injury severity scale (ISS), as well as outcome. RESULTS: We identified 15 children (6 males, 9 females, age range 7 to 15, mean 12 +/- 2 years), involved in 14 accidents. Sharp trauma was inflicted by a propeller (n=4) or a rope (n=1). Towed tubing (riding an inflatable tube while being pulled by a boat) was the most prevalent mechanism (n=6). There was a trend towards higher ISS after towed tubing (24.8 +/- 12.4) compared to all other mechanisms (15.1+/-7.7). Mean length of stay was longer after towed tubing accidents (14.2 +/- 7.2 versus 4.9 +/- 3.4 days). All patients survived and eventually were discharged home. In one of the incidences, involving 2 victims of this series, the driver of the boat was intoxicated with alcohol. CONCLUSIONS: Pediatric watercraft-related accidents are infrequent, but often result in major injuries. More awareness for safety measures to prevent these injuries is warranted. Alcohol is not a major factor in pediatric watercraft-associated trauma. Tubes towed by a boat seem to be particularly dangerous, perhaps because of the rider's limited maneuverability and the fact that centrifugal force lets the tube travel well outside the wake in curves. Limiting boat speed and the use of protective gear on towed tubes when children are involved may decrease the incidence and severity of pediatric WAT. PMID- 23932619 TI - Mathematical modelling of gubernaculum during inguino-scrotal migration shows limb bud characteristics. AB - PURPOSE: The gubernaculum is postulated to grow like an embryonic limb bud during inguinoscrotal descent in rodents. Recently, modelling of limb bud growth suggests the undifferentiated, distal "progress zone" provides molecular morphogenic signals, rather than cell division, as previously thought. We aimed to develop a mathematical gubernacular growth model, hypothesising that it would mimic limb buds through evolutionary conservation. METHODS: Histology was done on Sprague-Dawley rats (day 2, 8; n=7/group) to determine gubernacular length, width, cell density in distal growth centre, middle and proximal cremaster muscle. Analysis of measurements enabled gubernacular growth modelling under variable growth centre sizes/densities, assuming no apoptosis. RESULTS: Modelling found that gubernacular growth occurred mostly within cremaster muscle, rather than primarily in the undifferentiated mesenchymal tip, despite its higher mitotic rate. The growth centre accounted for <= 10% of total gubernacular enlargement/elongation. CONCLUSIONS: These results suggest the gubernaculum elongates by proliferation throughout cremaster muscle like a limb bud. The distal undifferentiated tip may provide signalling molecules for growth, which could be a fruitful source for causes of failed migration/elongation in cryptorchidism. PMID- 23932620 TI - Analysis of 3,776 pediatric inguinal hernia and hydrocele cases in a tertiary center. AB - BACKGROUND/PURPOSE: This study describes the pediatric inguinal hernia and hydrocele experience of a tertiary care training hospital. METHODS: A total of 3776 patients who had been operated between January 2005 and June 2009 for inguinal hernia, cord hydrocele, and hydrocele were included. The surgeries and patient follow-up were performed by 6 pediatric surgery specialists and 8 pediatric surgery residents. RESULTS: The patient age varied from 6 days to 17 years. There were 2959 (78.4%) males and 817 (21.6%) females (ratio: 3.6:1). The hernia was on the right in 2306 (61.1%) patients, on the left in 1111 (29.4%) patients, and bilateral in 359 (9.5%) patients. Age at presentation was younger in males (p<.001). Contralateral hernia repair was required later on during follow-up in 2% of the patients. Postoperative complications developed in 1.2% of the patients. Reoperation was needed because of wound infection in 0.6%, recurrence in 0.4%, hematoma in 0.1%, testicular atrophy in 1 patient, and acquired undescended testis in 1 patient. CONCLUSIONS: The age of first hernia symptoms was younger in males compared to females and in premature babies compared to term babies (p<.05). The recurrent hernia rate was higher in infancy. The complication rate was higher in hernia surgery in the newborn period and in cases of incarcerated hernia compared to the overall rate (p<.05). There was no indication for contralateral routine exploration. PMID- 23932621 TI - Cystic intratesticular lesions in pediatric patients. AB - BACKGROUND/PURPOSE: Intratesticular cysts are a rare clinical entity in the pediatric population. Recently, testes sparing surgery has been recommended. We share our experience with the management of pediatric testicular cysts. METHODS: A retrospective review of all pediatric patients referred for intratesticular cysts was conducted at a single pediatric institution from 2002 to 2010. Charts were evaluated for patient demographics, diagnosis, and management. RESULTS: Seven patients were identified and included in this series. After partial orchiectomy, the final diagnosis in three patients was epidermoid cyst. Three further patients were diagnosed as mature cystic teratoma, with two of these demonstrating adjacent intra-tubular germ cell neoplasia (ITGCN). One cyst in the series underwent spontaneous resolution after eight months. CONCLUSION: All of the cystic lesions in our case series were benign with one undergoing complete resolution. The remainder became smaller and developed a solid component prompting surgery. The pre-pubertal findings of ITGCN in two patients raise a dilemma regarding the optimal long-term management for these patients. Initial conservative observation is an option for the majority of pre-pubertal cystic testicular lesions until such time that testis sparing surgery is deemed technically feasible. Testes sparing surgery should be advocated in those patients undergoing surgical management. PMID- 23932622 TI - Functional urethral obstruction following tubularised incised plate repair of hypospadias. AB - PURPOSE: To report functional urethral obstruction (FUO) following the tubularised incised plate (TIP) procedure for hypospadias repair and its management. MATERIALS AND METHODS: Between January 2003 and December 2010, 263 patients were referred with complications following TIP repair and who were reviewed on regular follow up after further correction. One hundred and twenty nine of these patients presented with persistent obstructive voiding signs and symptoms in spite of apparently successful calibration or dilatation, 32 presented with persistent stenosis, and 97 with recurrent fistula. The mean age at surgery was 2.9 years (range 1-4). The complications were corrected using 1 of 2 techniques: modified Mathieu (112) and lateral onlay flap (17). The mean follow up was 4 years (range 1-9). RESULTS: The obstructive symptoms were corrected with a single procedure in 120 (93%). Nine patients (7%) developed complications in the form of fistula (7 patients) and glanular dehiscence (2 patients) that were corrected successfully in a second operation. CONCLUSIONS: The incised urethral plate may heal forming a deep narrow groove resulting in FUO. Patients with FUO present with obstructive voiding symptoms in spite of successful calibration or dilatation. These symptoms disappear after reconstruction of a wide fully epithelised neo-urethra. PMID- 23932623 TI - 3D virtual rendering before laparoscopic partial splenectomy in children. AB - INTRODUCTION: Partial splenectomy in children is a good surgical option for hematological diseases and focal splenic tumors because it allows the preservation of the spleen's immunological function. Furthermore, it can be performed by laparoscopy in children as it is a safe procedure, offering the benefits of a minimally invasive approach. MATERIALS AND METHODS: The software VR render LE version 0.81 is a system that enables the visualization of bidimentional 3D images with magnification of anatomical details. We have applied this system to five cases of non-parasitic splenic cysts before laparoscopic partial splenectomy. RESULTS: The images obtained with VR rendering software permitted the preoperative reconstruction of the vascularization of the splenic hilum, allowing the surgeon safe vessel control during laparoscopic procedures. All five partial splenectomies were carried out with no complications or major blood loss. CONCLUSIONS: Laparoscopic partial splenectomy should be a first choice procedure because it is feasible, reproducible, and safe for children; furthermore, it preserves enough splenic tissue thereby preventing post splenectomy infections. Volume rendering provides high anatomical resolution and can be useful in guiding the surgical procedure. PMID- 23932624 TI - Laparoscopic treatment of intussusception in children: a systematic review. AB - BACKGROUND: Idiopathic intussusception is one of the most common causes of small bowel obstruction in children. In the event of failed radiological reduction, laparotomy remains the treatment of choice. There is still no agreement in pediatric surgery about safety and effectiveness of the use of minimally invasive surgery in this common pediatric condition. By reviewing available data we aimed to establish whether laparoscopy should be the primary technique in the surgical reduction of intussusception. METHODS: A systematic review of all publications on the laparoscopic treatment of pediatric intussusception from January 1990 to April 2012 was performed. The following variables were analyzed: age, laparoscopic success rate, reason for conversion, enterotomy rate, operative time, complications, and length of stay (LOS). RESULTS: Ten retrospective studies treating 276 cases of laparoscopically reduced intussusception were identified. A total of 80 conversions corresponded to a 71.0% laparoscopic success rate. Only one case of intraoperative iatrogenic intestinal perforation was reported (0.4%). Postoperative complications occurred in 8 patients (2.9%), and adhesive small bowel obstruction was reported in 1 case (0.4%). Recurrence rate after laparoscopy was 3.6%. Three of 10 papers compared results between laparoscopic and open reduction of intussusception showing a shorter mean LOS in the former group (4.0 vs. 7.1 days, p<0.01). CONCLUSION: Laparoscopy is safe and effective in the treatment of pediatric intussusception. Tertiary centers with adequate minimally invasive skills should establish laparoscopy as the primary surgical technique in the treatment of this condition. PMID- 23932625 TI - Comparison of LILT and STEP procedures in children with short bowel syndrome -- a systematic review of the literature. AB - PURPOSE: To compare LILT and STEP, the two principal procedures to lengthen the native bowel in children with a short bowel syndrome (SBS), by discussing the indications and presenting the outcome from published data. METHODS: A review of literature was performed. N=39 publications were reviewed. RESULTS: For LILT and STEP, failure to achieve intestinal autonomy by conservative therapy represents the main indication, and end-stage liver disease the main contraindication. A sufficiently dilated intestinal segment is a common anatomical precondition for both procedures. STEP can be performed on shorter intestinal segments and on intricate segments such as the duodenum, which is technically not feasible for LILT. Both procedures have a similar extent of intestinal lengthening (approximately 70%) and result in improvement of enteral nutrition and reversal of complications of parenteral nutrition. STEP seems to have a lower mortality and overall progression to transplantation. CONCLUSIONS: STEP and LILT are both accepted procedures for non-transplant surgical management of SBS in children. The outcome after STEP seems to be more favourable, but larger series are needed to further assess accurate selection of eligible patients and to estimate effectiveness of procedures. A considerably higher number of cases for evaluation might be accomplished through the widespread use of a centralised registry. PMID- 23932626 TI - The diagnostic value of MRI fistulogram and MRI distal colostogram in patients with anorectal malformations. AB - Contrast fistulogram (FG) and distal pressure colostogram (DPCG) are standard diagnostic methods for the assessment of anorectal malformations. Pelvic magnetic resonance imaging (MRI) earned a place among essential diagnostic methods in preoperative investigations after the Currarino syndrome and a high incidence of associated spinal dysraphism were described. The aim of our study was to evaluate the possibility of substituting FG and DPCG by a modified pelvic MRI, e.g. MRI fistulogram (MRI-FG) and MRI colostogram (MRI-DPCG). The prospective study involved 29 patients with anorectal malformations who underwent a modified pelvic MRI. The length and course of fistulas and rectum, and the presence of sacral anomalies were studied on MRI images and compared with images obtained by radiologic examinations. Modified MRI brought identical results as contrast studies in 25 patients when related to the fistula and rectum length and course. MRI was more accurate for the detection of sacral anomalies. MRI-FG was the only imaging method used in the four most recent patients. The results support the assumption that conventional contrast examinations for the assessment of anorectal malformations can be replaced by MRI, thus reducing the radiation dose. PMID- 23932627 TI - A simple method for percutaneous endoscopic gastrostomy tube removal: "tie and retrograde pull". AB - BACKGROUND/PURPOSE: Various techniques have been presented to remove the percutaneous endoscopically placed gastrostomy tube in children, but tubes with semi-rigid internal retaining discs are difficult or impossible to remove by external traction. We describe a simple and effective endoscopic removal technique that should be applicable to any type of percutaneous endoscopic gastrostomy tube. METHODS: Percutaneous endoscopic gastrostomy tube removal was performed with the "tie and retrograde pull" technique. After a polypropylene suture was placed and tied 1cm over the skin level, the percutaneous endoscopic gastrostomy tube was cut 0.5 cm over the knot. The suture was cut from the connection point between the needle and the suture. The distal end of the suture was pushed through the stoma into the stomach. Then a forceps was inserted through the gastroscope. The suture was caught, and the residual percutaneous endoscopic gastrostomy portion was retrieved via retrograde traction on the suture. RESULTS: The causes of exchange were determined to be planned tube replacement in 9, buried bumper syndrome in 1, and tube occlusion in 3 patients. The mean tube dwell time was 10.8 +/- 3.9 months. Esophageal mucosal tear developed in 1 patient with epidermolysis bullosa during removal. No other complications occurred during PEG tube exchanges. CONCLUSION: This is a rapid and useful technique that does not require any complex endoscopic devices. PMID- 23932628 TI - A modified technique for ureteral reimplantation: intravesical detrusorrhaphy. AB - PURPOSE: To describe the surgical procedure of intravesical detrusorrhaphy, a modified technique of ureteral reimplantation, and report our initial experience. METHODS: From October 2007 to March 2012, 55 children with vesicoureteral reflux (VUR) and 13 children with obstructive megaureter (OM) underwent intravesical detrusorrhaphy. All surgical procedures were performed via an open intravesical approach. The ureter was mobilized, and the bladder mucosa was separated from the detrusor in a cephalad direction. The separated detrusor was incised vertically and repaired underneath the mobilized ureter to create the submucosal tunnel. The ureteral orifice was anastomosed to its orthotopic position. RESULTS: Of 31 patients treated with bilateral intravesical detrusorrhaphy, no patient had postoperative urinary retention. Follow-up voiding cystourethrography was performed in 45 patients with 72 reimplanted ureters. VUR was resolved in 41 patients (91.1%) with 68 ureters (94.4%). Among 13 patients with 14 ureters treated for OM, hydroureteronephorosis improved in 11 patients (84.6%) with 12 ureters (85.7%). CONCLUSIONS: Intravesical detrusorrhaphy is modified technique of ureteral reimplantation, which recreates the neo-ureteric orifice in the orthotopic position and does not produce postoperative urinary retention in bilateral cases. Intravesical detrusorrhaphy is safe and effective in treating patients with VUR or OM. PMID- 23932629 TI - A safer way of suturing in Foker's technique. AB - BACKGROUND/PURPOSE: Foker's technique allows esophageal lengthening facilitating end to end anastomosis in long gap esophageal atresia. The problem faced with this technique is that the traction sutures cut through the tissues leading to re operations. Our aim was to find a technique of suturing that will prevent the sutures from cutting through the esophagus. METHODS: After dissection of the upper and lower esophageal pouches, purse string sutures were placed, two each on both pouches. Clips were applied at the ends of both the pouches. Sutures were brought out on the posterior chest wall and traction applied. This was tried in a total of three cases. Case 1 was a newborn with pure esophageal atresia, Case 2 was an eighteen month old child with cervical esophagostomy and gastrostomy, and Case 3 had esophageal atresia with distal fistula. Two cases were done thoracoscopically and the third one by thoracotomy. RESULTS: In all three cases sutures held and lengthening could be obtained. In the first case it took twelve days, in the second case six days, and in third case eight days for the ends to come together. CONCLUSION: This modification of traction sutures is simple and reduces the risk of suture disruption. PMID- 23932630 TI - "A thrill of extreme magnety": Robert E. Gross and the beginnings of cardiac surgery. AB - Seventy-five years ago, a 7-year-old girl underwent the first successful ligation of a patent ductus arteriosus. This procedure transformed her health and was a milestone in the development of cardiac surgery. The operation was performed by Dr. Robert E. Gross, then the surgical chief resident at Boston Children's Hospital, who went on to have a distinguished career in pediatric surgery. The patient is now a great-grandmother and the oldest known survivor of cardiac surgery. PMID- 23932631 TI - Laparoscopic-assisted removal of gastric trichobezoar: a novel technique to reduce operative complications and time. PMID- 23932632 TI - Reply to letter to the editor. PMID- 23932633 TI - Extrahepatic vitelline vein aneurysm: prenatal diagnosis and follow up. AB - Umbilical vein varix is a well-described prenatal anomaly in which the prognosis remains unclear. We describe a very rare venous malformation that mimicked an umbilical vein varix consisting of a persistent vitelline vein. From 2003 to 2010, three patients were referred starting at 20 weeks gestation to our prenatal centers for an umbilical vein varix diagnosis. Fetal follow up was unremarkable, with the exception of the dilated vein size (mean: 35 mm at 33 weeks gestation). After birth, the three children presented with thrombosis from the aneurysmal sac to the portal trunk. All the children underwent surgical thrombectomy and resection of the aneurysmal sac after birth. Operative findings showed no umbilical vein but an abnormal dilated and thrombosed vein coming from the umbilicus to the portal vein following the right vitelline vein trajectory. One child was treated with systemic heparin. Median follow up is 5.6 years. Currently, one patient has a normal portal flow. The other two have persistent portal vein thrombosis with portal cavernoma and portal hypertension. This malformation is rare and should be considered in cases of early diagnosed umbilical vein varix whose diameter is greater than 20mm. We advocate an early surgical thrombectomy with heparinization to prevent portal vein thrombosis. PMID- 23932634 TI - Cloacogenic polyps in an adolescent: a rare cause of rectal bleeding. AB - Cloacogenic polyps are rare inflammatory lesions occurring around the anal transitional zone and in the lower rectum which can mimic neoplasia. They should be given diagnostic consideration in patients presenting with symptoms of rectal bleeding, tenesmus, and altered bowel habits. PMID- 23932635 TI - Peliosis hepatis in a child with myotubular myopathy: successful treatment using hepatic artery embolization. AB - Peliosis hepatis (PH) is a rare condition characterized by multiple blood-filled spaces within the hepatic parenchyma that can lead to fatal hemorrhage. There is no consensus on the best treatment algorithm for PH, and therapy is directed at removing the potential causative agent with operative intervention when necessary. Here we present the first known case of PH in a child with myotubular myopathy who was successfully treated with angiography and hepatic artery embolization as a first line therapy, without the need for operative intervention. Awareness of this condition and the available treatment modalities may lead to favorable outcomes in future cases. PMID- 23932636 TI - Detection and classification of different liver lesions: comparison of Gd-EOB DTPA-enhanced MRI versus multiphasic spiral CT in a clinical single centre investigation. AB - OBJECTIVE: To compare the diagnostic efficacy of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) vs. multidetector computed tomography (MDCT) for the detection and classification of focal liver lesions, differentiated also for lesion entity and size; a separate analysis of pre- and postcontrast images as well as T2-weighted MRI sequences of focal and exclusively solid lesions was integrated. METHODS: Twenty-nine patients with 130 focal liver lesions underwent MDCT (64-detector-row; contrast medium iopromide; native, arterial, portalvenous, venous phase) and MRI (1.5-T; dynamic and tissue-specific phase 20 min after application of Gd-EOB-DTPA). Hepatic lesions were verified against a standard of reference (SOR). CT and MR images were independently analysed by four blinded radiologists on an ordinal 6-point-scale, determining lesion classification and diagnostic confidence. RESULTS: Among 130 lesions, 68 were classified as malignant and 62 as benign by SOR. The detection of malignant and benign lesions differed significantly between combined and postcontrast MRI vs. MDCT; overall detection rate was 91.5% for combined MRI and 80.4% for combined MDCT (p<0.05). Considering all four readers together, combined MDCT achieved sensitivity of 66.2%, specificity of 79.0%, and diagnostic accuracy of 72.3%; combined MRI reached superior diagnostic efficacy: sensitivity 86.8%, specificity 94.4%, accuracy 90.4% (p<0.05). Differentiated for lesion size, in particular lesions <20mm revealed diagnostic benefit by MRI. Postcontrast MRI also achieved higher overall sensitivity, specificity, and accuracy compared to postcontrast MDCT for focal and exclusively solid liver lesions (p<0.05). CONCLUSION: Combined and postcontrast Gd-EOB-DTPA-enhanced MRI provided significantly higher overall detection rate and diagnostic accuracy, including low inter-observer variability, compared to MDCT in a single centre study. PMID- 23932637 TI - Normal breast tissue stiffness measured by a new ultrasound technique: virtual touch tissue imaging quantification (VTIQ). AB - OBJECTIVE: To evaluate normal breast tissue stiffness with virtual touch tissue imaging quantification (VTIQ) using prospectively collected data. MATERIALS AND METHODS: B-mode ultrasound and VTIQ were performed in 132 breasts in 97 women. Mean values of VTIQ for parenchyma and fatty tissue were compared between those measured in healthy breasts and in the surrounding of histologically proven benign and malignant breast lesions. Moreover we reviewed VTIQ values according to breast density measured by the American College of Radiology (ACR) categories. In addition we analyzed re-test reliability of VTIQ. RESULTS: In 132 breasts the mean VTIQ values in parenchyma were significantly higher than in fatty tissue (3.23 m/s +/- 0.74 versus 2.5 m/s +/- 0.61; p<0.0001). In healthy breasts as well as in the surrounding of a benign or malignant lesions the VTIQ values of parenchyma were similar (p=0.12). In fatty tissue, small differences between mean VTIQ values of 2.25 m/s +/- 0.51, 2.52 m/s +/- 0.48 and 2.65 m/s +/- 0.71 (p=0.01) in the respective groups were observed. The comparison of mean VTIQ values of parenchyma and fatty tissue in more and less dense breasts (ACR 1+2 versus ACR 3+4 breasts) also yielded no statistically significant difference. The re-test reliability of VTIQ assessed with three independent measurements was moderate (interclass-correlation of 0.52 (p<0.0001)). CONCLUSION: VTIQ is a reliable method for measuring the stiffness of breast tissue. We propose standard values for healthy parenchyma and fatty tissues independent of the surrounding tissue or the ACR category. PMID- 23932638 TI - A novel distinguishing system for the diagnosis of malignant pancreatic cystic neoplasm. AB - PURPOSE: To explore a simple and reliable non-invasive distinguishing system for the pre-operative evaluation of malignancy in pancreatic cystic neoplasm (PCN). METHODS: This study first enrolled an observation cohort of 102 consecutive PCN patients. Demographic information, results of laboratory examinations, and computed tomography (CT) presentations were recorded and analyzed to achieve a distinguishing model/system for malignancy. A group of 21 patients was then included to validate the model/system prospectively. RESULTS: Based on the 11 malignancy-related features identified by univariate analysis, a distinguishing model for malignancy in PCN was established by multivariate analysis: PCN malignant score=2.967 * elevated fasting blood glucose (FBG) (>=6.16 mmol/L) +/- 4.496 * asymmetrically thickened wall (or mural nodules >= 4 mm) +/- 1.679 * septum thickening (>=2 mm)-5.134. With the optimal cut-off value selected as -2.8 in reference to the Youden index, the proposed system for malignant PCN was established: septum thickening (>2 mm), asymmetrically thickened wall (or mural nodules>4 mm), or elevated FBG (>6.16 mmol/L, accompanying commonly known malignant signs), the presence of at least one of these 3 features indicated malignancy in PCN. The accuracy, sensitivity and specificity of this system were 81.4%, 95.8% and 76.9%, respectively. MRI was performed on 32 patients, making correct prediction of malignancy explicitly in only 68.8% (22/32). The subsequent prospective validation study showed that the proposed distinguishing system had a predictive accuracy of 85.7% (18/21). Moreover, a higher model score, or aggregation of the features in the proposed system, indicated a higher grade of malignancy (carcinoma) in PCN. CONCLUSION: Elevated FBG (>6.16 mmol/L), asymmetrically thickened wall (or mural nodules>4 mm) and septum thickening (>2 mm) are of great value in differentiating the malignancy in PCN. The developed distinguishing system is reliable in the diagnosis of malignant PCN. PMID- 23932639 TI - Transfer of Cystoisospora suis-specific colostral antibodies and their correlation with the course of neonatal porcine cystoisosporosis. AB - Cystoisospora suis is the most pathogenic species of coccidia in suckling piglets, affecting them predominantly within their first three weeks of life. The clinical signs of neonatal cystoisosporosis include watery diarrhea and wasting, leading to significant economic losses for the farmer. Since neonatal piglets have an immature immune system, colostral transfer of maternal factors such as immune cells or antibodies is essential for controlling infections at that age. However, the role of C. suis-specific antibodies transferred from the sow to the piglets and possible correlations between antibody levels in the piglets acquired from colostrum with the clinical outcome of disease are currently not understood. To address this issue, 12 non-infected piglets and 14 piglets experimentally infected with C. suis on the third day of life were examined during their first four weeks of life. IgG, IgA, and IgM titers in the blood serum specific for sporozoites and merozoites of C. suis were evaluated, along with oocyst excretion and fecal consistency. Additionally, the antibody content in the colostrum and milk of three mother sows was determined. A transfer of naturally acquired C. suis-specific antibodies from sows to piglets with the colostrum could be demonstrated. Maternal antibodies in piglets' blood sera did not persist for longer than 14-21 days except for IgG which was present in high titers until the end of the study. Within 2-3 weeks after birth the onset of endogenous antibody production was noticed. Titers in blood serum showed a correlation with the severity of diarrhea which was positive for IgG and IgM (possibly due to increased consumption or loss of these antibodies) and negative for IgA. C. suis specific mucus antibodies isolated from infected and non-infected piglets (n=6/group) on the 28th day of life were present in both groups, showing significantly higher titers of IgA and IgM in infected piglets. Maternally transferred antibodies acquired by natural infections of sows as observed in this study did not provide protection against the clinical manifestation of disease. The level and effect of transferrable maternal factors necessary for protection still need to be elucidated. However, correlations between antibody titers and fecal consistency in the piglets indicate that C. suis-specific antibodies might be useful markers for the expectable clinical severity of cystoisosporosis. PMID- 23932640 TI - Prevalence of Toxoplasma gondii and Leishmania spp. infection in cats from Brazil. AB - A total of 386 feline blood samples from Brazil were collected and analyzed by the indirect immunofluorescence antibody test (IFAT) for the presence of Toxoplasma gondii and Leishmania spp. antibodies. Specific antitoxoplasma IgG were found in 63 of 386 (16.3%) cats and immunoglobulin G against Leishmania spp. was detected in two serum samples. The overall prevalence was significantly higher in adult cats than in juvenile cats for T. gondii infection. There were no significant differences between positivity and gender or breed. The frequency of T. gondii antibodies found in domestic cats of Brazil suggests active transmission within an urban environment. This study proved the occurrence of two important protozoan zoonosis in felines from Brazilian endemic area for visceral leishmaniasis. PMID- 23932641 TI - Predictors of inaccurate coronary arterial stenosis assessment by CT angiography. AB - OBJECTIVES: This study sought to investigate the clinical and imaging characteristics associated with diagnostic inaccuracy of computed tomography angiography (CTA) for detecting obstructive coronary artery disease (CAD) defined by quantitative coronary angiography (QCA). BACKGROUND: Although diagnostic performance metrics of CTA have been reported, there are sparse data on predictors of diagnostic inaccuracy by CTA. METHODS: The clinical characteristics of 291 patients (mean age: 59 +/- 10 years; female: 25.8%) enrolled in the multicenter CorE-64 (Coronary Artery Evaluation Using 64-Row Multi-detector Computed Tomography Angiography) study were examined. Pre-defined CTA segment level characteristics of all true-positive (N = 237), false-positive (N = 115), false-negative (FN) (N = 159), and a random subset of true-negative segments (N = 511) for >=50% stenosis with QCA as the reference standard were blindly abstracted in a central core laboratory. Factors independently associated with corresponding levels of CTA diagnostic inaccuracies on a patient level and coronary artery segment level were determined using multivariable logistic regression models and generalized estimating equations, respectively. RESULTS: An Agatston calcium score of >=1 per patient (odds ratio [OR]: 5.2; 95% confidence interval [CI]: 1.1 to 24.6) and the presence of within-segment calcification (OR: 10.2; 95% CI: 5.2 to 19.8) predicted false-positive diagnoses. Conversely, absence of within-segment calcification was an independent predictor of an FN diagnosis (OR: 2.0; 95% CI: 1.2 to 3.5). Prior percutaneous revascularization was independently associated with patient-level misdiagnosis of obstructive CAD (OR: 4.2; 95% CI: 1.6 to 11.2). Specific segment characteristics on CTA, notably segment tortuosity (OR: 3.5; 95% CI: 2.4 to 5.1), smaller luminal caliber (OR: 0.48; 95% CI: 0.36 to 0.63 per 1-mm increment), and juxta-arterial vein conspicuity (OR: 2.1; 95% CI: 1.4 to 3.2), were independently associated with segment-level misdiagnoses. Attaining greater intraluminal contrast enhancement independently lowered the risk of an FN diagnosis (OR: 0.96; 95% CI: 0.94 to 0.99 per 10-Hounsfield unit increment). CONCLUSIONS: We identified clinical and readily discernible imaging characteristics on CTA predicting inaccurate CTA diagnosis of obstructive CAD defined by QCA. Knowledge and appropriate considerations of these features may improve the diagnostic accuracy in clinical CTA interpretation. (Diagnostic Accuracy of Multi-Detector Spiral Computed Tomography Angiography Using 64 Detectors [CORE-64]; NCT00738218). PMID- 23932642 TI - CMR quantification of myocardial scar provides additive prognostic information in nonischemic cardiomyopathy. AB - OBJECTIVES: This study sought to determine whether the extent of late gadolinium enhancement (LGE) can provide additive prognostic information in patients with a nonischemic dilated cardiomyopathy (NIDC) with an indication for implantable cardioverter-defibrillator (ICD) therapy for the primary prevention of sudden cardiac death (SCD). BACKGROUND: Data suggest that the presence of LGE is a strong discriminator of events in patients with NIDC. Limited data exist on the role of LGE quantification. METHODS: The extent of LGE and clinical follow-up were assessed in 162 patients with NIDC prior to ICD insertion for primary prevention of SCD. LGE extent was quantified using both the standard deviation based (2-SD) method and the full-width half-maximum (FWHM) method. RESULTS: We studied 162 patients with NIDC (65% male; mean age: 55 years; left ventricular ejection fraction [LVEF]: 26 +/- 8%) and followed up for major adverse cardiac events (MACE), including cardiovascular death and appropriate ICD therapy, for a mean of 29 +/- 18 months. Annual MACE rates were substantially higher in patients with LGE (24%) than in those without LGE (2%). By univariate association, the presence and the extent of LGE demonstrated the strongest associations with MACE (LGE presence, hazard ratio [HR]: 14.5 [95% confidence interval (CI): 6.1 to 32.6; p < 0.001]; LGE extent, HR: 1.15 per 1% increase in volume of LGE [95% CI: 1.12 to 1.18; p < 0.0001]). Multivariate analyses showed that LGE extent was the strongest predictor in the best overall model for MACE, and a 7-fold hazard was observed per 10% LGE extent after adjustments for patient age, sex, and LVEF (adjusted HR: 7.61; p < 0.0001). LGE quantitation by 2-SD and FWHM both demonstrated robust prognostic association, with the highest MACE rate observed in patients with LGE involving >6.1% of LV myocardium. CONCLUSIONS: LGE extent may provide further risk stratification in patients with NIDC with a current indication for ICD implantation for the primary prevention of SCD. Strategic guidance on ICD therapy by cardiac magnetic resonance in patients with NIDC warrants further study. PMID- 23932643 TI - Graft union formation in artichoke grafting onto wild and cultivated cardoon: an anatomical study. AB - In order to develop a non-chemical method such as grafting effective against well known artichoke soil borne diseases, an anatomical study of union formation in artichoke grafted onto selected wild and cultivated cardoon rootstocks, both resistant to Verticillium wilt, was performed. The cardoon accessions Belgio (cultivated cardoon) and Sardo (wild cardoon) were selected as rootstocks for grafting combinations with the artichoke cv. Romolo. Grafting experiments were carried out in the autumn and spring. The anatomical investigation of grafting union formation was conducted by scanning electron microscopy (SEM) on the grafting portions at the 3rd, 6th, 10th, 12th day after grafting. For the autumn experiment only, SEM analysis was also performed at 30 d after grafting. A high affinity between artichoke scion and cardoon rootstocks was observed, with some genotype differences in healing time between the two bionts. SEM images of scion/rootstock longitudinal sections revealed the appearance of many interconnecting structures between the two grafting components just 3d after grafting, followed by a vascular rearrangement and a callus development during graft union formation. De novo formation of many plasmodesmata between scion and rootstock confirmed their high compatibility, particularly in the globe artichoke/wild cardoon combination. Moreover, the duration of the early-stage grafting process could be influenced not only by the scion/rootstock compatibility, but also by the seasonal conditions, being favored by lower temperatures and a reduced light/dark photoperiod. PMID- 23932645 TI - [Difficult situations in radiotherapy: agitated adult patients]. AB - The causes of agitation in adult patients are numerous. Agitation may cause difficulty or impossibility to initiate the radiotherapy technique but also can lead to accidents harmful to patients. However, the decision to not irradiate agitated patients may lead to a loss of curability chance or chance to palliate symptoms. Before taking such a decision, thinking about the possibilities available to calm the patient should be undertaken with the patient and the referring practitioners to attempt to make this therapy if it is considered major in the management of cancer. In all cases, current adaptations of radiotherapy should be used to deliver an effective radiation of a suitable time and safely. It is notable that the medical literature is extremely rare on this subject. PMID- 23932644 TI - Novel effects of the cannabinoid inverse agonist AM 251 on parameters related to metabolic syndrome in obese Zucker rats. AB - BACKGROUND AND OBJECTIVE: Recent research suggests that cannabinoid receptor CB1 antagonists can affect appetite and body weight gain, although their influence on other parameters related to metabolic syndrome is not well documented. The present study was designed to assess the effects of chronic treatment with the CB1 receptor inverse agonist AM 251 (3 mg/kg for 3 weeks) in obese and lean Zucker rats on parameters related to metabolic syndrome. MATERIALS AND METHODS: Four groups of rats were used: lean Zucker rats, untreated obese Zucker rats, AM 251-treated obese Zucker rats and a pair-fed obese Zucker rat experimental group which received the same amount of food as that consumed by the animals treated with AM251. Food intake, body weight gain, energy expenditure, plasma biochemical parameters, leptin, insulin and hepatic status markers were analysed. RESULTS: Daily injection of AM 251 in obese Zucker rats produced a marked and sustained decrease in daily food intake and body weight and a considerable increase in energy expenditure in comparison with untreated obese Zucker rats. AM 251 administration to obese rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol whereas HDL cholesterol plasma levels increased. The results also showed a decrease in liver/weight body ratio and total fat content in the liver. The main effects of AM251 (3 mg/kg) found in this study were not observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with AM 251. The results obtained in obese rats can be interpreted as a decrease in leptin and insulin resistance, thereby improving glucose and lipid metabolism, alleviating the steatosis present in the metabolic syndrome and thus favourably modifying plasma levels of hepatic biomarkers. CONCLUSION: Our results indicate that the cannabinoid CB1 inverse agonist AM 251 represents a promising therapeutic strategy for the treatment of obesity and metabolic syndrome. PMID- 23932646 TI - Synthesis and preclinical characterization of [64Cu]NODAGA-MAL-exendin-4 with a Nepsilon-maleoyl-L-lysyl-glycine linkage. AB - INTRODUCTION: Renal localization of high radioactivity levels during targeted imaging compromises tissue visualization in the kidney region and limits diagnostic accuracy. Radioiodinated antibody fragments with a renal enzyme cleavable N(epsilon)-maleoyl-L-lysyl-glycine (MAL) linkage demonstrated low renal radioactivity levels in mice, from early postinjection times. This study tested the hypothesis whether a (64)Cu-labeled NODAGA-exendin-4 peptide with a MAL linkage ([(64)Cu]NODAGA-MAL-exendin-4) could decrease kidney radioactivity levels in rats, compared to a [(64)Cu]NODAGA-exendin-4 reference, without impairing the radioactivity levels in the target tissue. METHODS: NODAGA-MAL-exendin-4 was synthesized in a two-phase approach using solid support to prepare maleoyl derivatized NODAGA followed by Michael addition to cysteine-derivatized exendin-4 in solution. Radiolabeling was performed in buffered aqua with [(64)Cu]CuCl2, which was produced via the (64)Ni(p,n)(64)Cu nuclear reaction. The in vitro and in vivo stability, lipophilicity, and distribution kinetics in major rat organs for [(64)Cu]NODAGA-MAL-exendin-4 were studied and compared to [(64)Cu]NODAGA exendin-4. Labeling of pancreatic islets was assessed using autoradiography. RESULTS: NODAGA-MAL-exendin-4 was synthesized, with an overall yield of 9%, and radiolabeled with (64)Cu with high specific radioactivity. Serum incubation studies showed high stability for [(64)Cu]NODAGA-MAL-exendin-4. Similar tissue distribution kinetics was observed for [(64)Cu]NODAGA-MAL-exendin-4 and [(64)Cu]NODAGA-exendin-4, with high kidney radioactivity levels. CONCLUSIONS: The incorporated MAL linkage in [(64)Cu]NODAGA-MAL-exendin-4 was unable to reduce kidney radioactivity levels, compared to [(64)Cu]NODAGA-exendin-4. The applicability of metabolizable linkages in the design of kidney-saving exendin-4 analogs requires further investigation. PMID- 23932647 TI - Clinical significance of serum high-mobility group box 1 level in alopecia areata. AB - BACKGROUND: Alopecia areata (AA), a chronic, relapsing hair-loss disorder, is considered to be a T-cell-mediated autoimmune disease. High-mobility group box 1 (HMGB1), released by necrotic cells and in response to various inflammatory stimuli, is currently considered to be a significant target antigen in diverse autoimmune diseases. OBJECTIVE: We sought to investigate the clinical significance of serum HMGB1 levels in AA. METHODS: We compared levels of HMGB1 in scalp specimens from 7 patients with AA and 8 healthy control subjects and in blood samples from 45 patients with AA and 10 healthy control subjects. Moreover, we evaluated the correlation between HMGB1 level and clinical severity. RESULTS: Immunohistochemical staining of scalp tissues from patients with AA revealed higher HMGB1 levels than in healthy control subjects. In addition, serum HMGB1 levels in the AA group were generally higher, and showed concordance with the patients' clinical characteristics, including onset, hair-pull test results, and treatment response. LIMITATIONS: The number of patients and healthy control subjects evaluated was small. CONCLUSION: These results suggest that HMGB1 plays a significant role in the pathogenesis of AA, and that it is a promising predictor of prognosis and treatment response. Moreover, this study identifies a new potential therapeutic target for the treatment of AA. PMID- 23932648 TI - Margin comments in dermatopathology reports on dysplastic nevi influence re excision rates. AB - BACKGROUND: Dermatopathology reports influence clinical management, but it is not clear to what extent comments on margin involvement of histopathologically dysplastic nevi (HDN) influence decisions about re-excision or complete excision. OBJECTIVE: We sought to determine if standardized margin comments (MCs) on HDN influence re-excision rates. METHODS: By reviewing medical records, we compared re-excision rates of HDN reported with (May 2011 to December 2012) and without (January 2007 to December 2010) standardized MCs, and surveyed clinicians to assess perceptions of the impact of MCs on their management of HDN. RESULTS: Of 584 HDN, 302 had MCs and 282 did not. Re-excision was recommended or performed at a significantly higher rate for patients in the group without MCs (51.8%, 146 of 282) than in the MC group (39.4%, 119 of 302); P = .003 regardless of margin status. This difference was observed among HDN diagnosed as mildly and moderately dysplastic but not for severely dysplastic nevi. In all, 40% (16 of 40) of clinicians responded that they are more likely to biopsy pigmented lesions with a clinical margin of normal-appearing skin than they were before MCs were routinely included in dermatopathology reports. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Re-excision rates were significantly lower in patients who had HDN reported with standardized MCs. MCs may help reduce re-excision rates, with associated reduction in health care use, cost, and morbidity. PMID- 23932649 TI - Drug-induced exanthems: correlation of allergy testing with histologic diagnosis. AB - BACKGROUND: Skin biopsies are commonly performed to confirm drug-induced exanthem (DIE). However, the relevance of histologic examination in discriminating between DIE and non-DIE (NDIE) is controversial. OBJECTIVE: A retrospective analysis was performed to evaluate the reliability of histologic diagnosis of DIE. METHODS: In all, 91 patients with a skin biopsy specimen of an acute exanthem temporally related to a single identifiable drug underwent complete allergy testing. Their biopsy specimens were retrospectively re-evaluated by 2 dermatopathologists blinded to the original reports to test for discrimination between DIE versus NDIE. RESULTS: In 35 patients, non-IgE-mediated drug allergy was confirmed by allergy testing, whereas in 56 patients drug hypersensitivity could be excluded. Sensitivity of pathology reports for diagnosis of DIE reached 62.9% with a positive predictive value of 40.7%. Specificity was 41.1% with a negative predictive value of 69.7%. No significant difference in tissue eosinophilia was detected between DIE and NDIE. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Dermatopathologic evaluation of skin biopsy specimens is of limited use in differentiating between DIE and NDIE. All efforts should be made to subject these patients to thorough allergy testing for definitely confirming or ruling out drug hypersensitivity. PMID- 23932650 TI - The 53rd International Field Emission Symposium (IFES). Preface. PMID- 23932651 TI - Opportunities for international collaboration in dog breeding from the sharing of pedigree and health data. AB - Pooling of pedigree and phenotype data from different countries may improve the accuracy of derived indicators of both genetic diversity and genetic merit of traits of interest. This study demonstrates significant migration of individuals of four pedigree dog breeds between Sweden and the United Kingdom. Correlations of estimates of genetic merit (estimated breeding values, EBVs) for the Federation Cynologique Internationale and the British Veterinary Association and Kennel Club evaluations of hip dysplasia (HD) were strong and favourable, indicating that both scoring schemes capture substantially the same genetic trait. Therefore pooled use of phenotypic data on hip dysplasia would be expected to improve the accuracy of EBV for HD in both countries due to increased sample data. PMID- 23932652 TI - Newborn calf vitality: risk factors, characteristics, assessment, resulting outcomes and strategies for improvement. AB - Dystocia is a stressful and traumatic event for both the cow and calf. As the prevalence of dystocia has increased over time, attention has been focused on maintaining the health and longevity of the cow. Lack of vitality in the newborn calf may go unnoticed and result in short or long-term implications for calf health and performance. A prolonged or assisted delivery may increase birth stress in calves causing a variety of effects including injury, inflammation, hypoxia, acidosis, pain and an inability to maintain homeostasis. Each of these effects can further contribute to a reduced state of vitality in the newborn calf. Newborn vitality is essential to the health, survival and welfare of the calf. If the calf is not vital at birth, it may be unwilling or unable to get up and suckle colostrum in a timely manner. Early colostrum intake improves passive transfer of immunoglobulins, energy uptake and thermoregulation. Intervention may be required to assist these calves such as respiratory and thermal support, manual feeding of colostrum or the administration of non-steroidal anti inflammatory drugs to aid health and long-term survival. However, more research is needed to determine ways in which newborn calf vitality can be assessed and improved in order to reduce the increased risk of morbidity and mortality and long-term effects on performance. PMID- 23932653 TI - Canine leishmaniasis: bridging science, public health and politics. PMID- 23932654 TI - Evaluation of CHD7 as a candidate gene for choanal atresia in alpacas (Vicugna pacos). AB - Choanal atresia (CA) is a craniofacial malformation characterized by obstruction of the posterior nasal aperture, resulting in laborious respiratory inspiration and exhalation. Alpaca crias with CA typically develop fatal pneumonia, frequently as the result of milk aspiration during nursing, and euthanasia is usually inevitable. Nonsense or missense mutations in the CHD7 gene cause a comparable condition (CHARGE syndrome) in humans. In this study, the coding region of CHD7 was sequenced in six CA-affected alpacas. Forty-nine sequence variants were identified, of which 10 would result in amino acid changes (non synonymous), some with potentially deleterious effects. However, none of the observed variants would result in the obvious deleterious effects caused by nonsense or missense mutations. Although a role for CHD7 mutations in CA cannot be definitively dismissed, these do not appear to be the primary cause of CA in alpacas. PMID- 23932655 TI - Variations in procedure time based on surgery resident postgraduate year level. AB - BACKGROUND: With increasing scrutiny being placed on the allocation of health care dollars, data supporting the increased resources used to teach residents in the operating room (OR) are lacking. METHODS: All cases of patients undergoing laparoscopic cholecystectomies (LCs) and pancreaticoduodenectomies (PDs) from July 1, 2006 to July 1, 2011 were analyzed. Procedures were excluded based on the following: more than one resident listed in the operative report, with the exception of interns; LC requiring cholangiogram or conversion to an open procedure; or if a PD required additional procedures. Multiple linear regression was used to evaluate the association between procedure time and postgraduate year (PGY), adjusting for patient age and estimated blood loss. RESULTS: A total of 236 PDs and 357 LCs were included in the study. For LCs, after multiple linear regression, the association between procedure time and resident PGY was marginally significant (P = 0.0519) and suggested an inverse relationship; for every increase in resident PGY, there was a 2.66-min decrease in OR time. Based on our institution's figure of $18.13/min of OR time, the cost difference between PGYs 1 and 5 performing a LC would be $192.90 per case. For PDs, however, the association between procedure time and resident PGY was not significant. CONCLUSIONS: Junior residents likely prolong procedure times for more basic procedures such as LC but not for more complex procedures such as PD. PMID- 23932656 TI - Activation of protein kinase C delta reduces hepatocellular damage in ischemic preconditioned rat liver. AB - BACKGROUND: Liver ischemic preconditioning (IPC), pre-exposure of the liver to transient ischemia, has been applied as a useful surgical method to prevent liver ischemia and reperfusion (I/R) injury. Although activation of protein kinase C (PKC), especially novel PKCs, has been known as central signaling responsible for the liver protection of IPC, determination of the involved isozyme in strong protection afforded by IPC has not been elucidated. MATERIALS AND METHODS: Rats were subjected to 90 min of partial liver ischemia followed by 3, 6, and 24 h of reperfusion. IPC was induced by 10 min of ischemia after 10 min of reperfusion before sustained ischemia. Rottlerin, a PKC-delta selective inhibitor; PKC epsilonV1-2 peptide, a selective PKC-epsilon inhibitor; and 3,7-dimethyl-1-[2 propargyl] xanthine, an adenosine A2 receptor antagonist, were intravenously injected before IPC. N-acetyl-L-cysteine, a strong antioxidant, and Nomega-nitro L-arginine methyl ester, a nonselective nitric oxide synthase inhibitor, were injected intraperitoneally before IPC. RESULTS: IPC resulted in strong protection against liver I/R injury as evidenced by biochemical and histologic analyses. Inhibition of PKC-delta strongly attenuated the IPC-induced liver protection, whereas PKC-epsilon inhibition did not exert any effect on IPC-induced protection. Although inhibition of reactive oxygen species, adenosine, and nitric oxide attenuated the beneficial effects of IPC, inhibition of adenosine only attenuated PKC-delta and -epsilon translocation. CONCLUSIONS: Our findings suggest that IPC protects against I/R-induced hepatic injury through activation of PKC-delta. PMID- 23932658 TI - Calibration of high-frequency hydrophone up to 40 MHz by heterodyne interferometer. AB - A calibration technique for high-frequency hydrophone utilizing a heterodyne interferometer is presented in this article. The calibration system is mainly composed of optical and signal processing modules. In the displacement measurement, a pellicle is mounted at the surface of water to avoid acousto optical interaction. The phase modulated carrier signal is digitized and transferred to the computer, then processed by digital phase demodulation. A phase unwrapping algorithm is employed to remove ambiguity of the arctangent function and has proven effective in large displacement measurements. Pellicle displacement and voltage output of the hydrophone in focused ultrasonic field are processed by DFT to determine the amplitudes of the fundamental and harmonic components. Experiments show that the heterodyne technique can provide hydrophone calibration up to 40 MHz, with a slightly smaller sensitivity compared with the National Physical Laboratory (NPL) calibration results for most frequency ranges. Since the heterodyne technique is independent on assumptions about the geometry of the ultrasonic field and the performance of the transducer, it can be easily extended to high frequency and high power ultrasound measurement applications. PMID- 23932657 TI - Prediction of postoperative complications in elderly patients with hepatocellular carcinoma. AB - BACKGROUND: The aim of the present study was to investigate whether advanced age was associated with a higher rate of postoperative complications and identify the predictive factors for postoperative complications in elderly patients with hepatocellular carcinoma (HCC). METHODS: Between January 2000 and December 2010, 256 patients who underwent hepatectomy for HCC were investigated. Elderly patients were defined as those aged >=75 y. The clinicopathologic data and outcomes after hepatectomy for 64 elderly and 192 younger patients were retrospectively collected and compared. RESULTS: There were no significant differences in the incidence of postoperative complications (P = 0.936) or the long-term survival after hepatectomy (P = 0.641) between the elderly and younger patients. In multivariate analysis, the estimation of physiological ability and surgical stress-preoperative risk score (PRS) was an independent risk factor for postoperative morbidity in the elderly patients (P < 0.01). Moreover, the patients were analyzed according to the PRS for the assessment of their general preoperative condition and liver damage grade based on the hepatic reserve. The rate of postoperative complications in the patients with a PRS >=0.5 and liver damage B was significantly higher in the elderly patients (P < 0.01), whereas a PRS and liver damage grade did not affect the incidence of postoperative morbidity in the younger patients (P = 0.516). CONCLUSIONS: Hepatectomy for elderly patients with HCC is feasible as well as safe, and the preoperative assessment using the estimation of physiological ability and surgical stress scoring system, combined with the liver damage grade, can help to improve the safety of this procedure for elderly HCC patients. PMID- 23932659 TI - [Medium-term outcome, follow-up, and quality of life in children treated for type III esophageal atresia]. AB - The aim of this study was to evaluate the medium-term outcome (health status, medical and surgical French National Health Authority-recommended follow-up, and quality of life) of children born with type III esophageal atresia (EA). Previous events (during the perinatal period, associated abnormalities, respiratory and digestive complications) of children treated for type III EA at the Marseille university hospitals between 1999 and 2009 were noted. Parents completed a standardized questionnaire concerning the health of their children during the previous year, and a quality-of-life questionnaire (PedsQL 4.0) was also completed by children aged more than 8 years. Among the 68 children treated, 44 responded to our solicitation (mean age, 7.6 years; range, 3-12.8 years). Previous important events were : pneumonia(s) (65%), asthma before the age of 3 years (66%), hospitalization for a respiratory event (45%), fundoplication (20%), and esophageal dilatation (45%). We noted current chronic cough (16%), asthma (30%), dysphagia (39%), and symptomatic gastroesophageal reflux (9%). National guidelines were not respected, except for the surgical indications in children aged less than 6 years. The quality-of-life scores (n=43 children) were similar to healthy controls but were negatively influenced by a gastrostomy procedure (P=0.020), pneumonia (P=0.013), and hospitalization due to a respiratory event (P=0.006) or a digestive event (P=0.010), and also by current asthma (P=0.004). In conclusion, despite recurrent respiratory or digestive symptoms and inadequate recommended follow-up, the quality of life of children treated for type III of EA is good. PMID- 23932660 TI - [Anthropological approach to current parental perceptions of children's seizures]. AB - Pediatric seizures are a common symptom, especially when associated with fever. This phenomenon is still shocking and traumatic for parents. The study analyzed current parental perceptions of seizures in order to improve the quality of management, care, and explanations provided to families at our emergency unit. METHODS: Using an anthropological approach, we analyzed 28 interviews of 37 parents whose child was admitted to our pediatric emergency unit between November 2007 and August 2008 due to a first seizure. RESULTS: The parental experience of the crisis was marked by upsetting memories of a "scary"-looking body and the perception of imminent death. Parental interpretations of the pathophysiology of the event were often wrong; very few mentioned the possibility of its cerebral origin, leading to inappropriate rescue attempts (e.g., giving CPR). The meaning attributed by parents to the word "seizure" and "epilepsy" usually referred to an exact clinical description of the phenomenon, but many admitted being unfamiliar with the term or at least its origin. Many studies have found the expectation of imminent death as well as inappropriate behaviors. This is the first study to consider interpretations expressed by parents around the convulsive phenomenon and to confirm a low level of knowledge of the symptom. Some historical interpretations persisted (e.g., the influence of excessive mood, anger, menstruation, demonic possession). CONCLUSION: Understanding and integrating these parental interpretations seems essential to improving care for families who first experience this symptom. This study motivated the implementation of a special educational workshop on seizures in 2010. PMID- 23932661 TI - [Pulmonary necrotizing cavity caused by Mycoplasma pneumoniae infection]. PMID- 23932662 TI - [Six-month training in Aweil (South-Sudan)]. PMID- 23932663 TI - Deconstructing sub-clinical psychosis into latent-state and trait variables over a 30-year time span. AB - BACKGROUND: Our aim was to deconstruct the variance underlying the expression of sub-clinical psychosis symptoms into portions associated with latent time dependent states and time-invariant traits. METHODS: We analyzed data of 335 subjects from the general population of Zurich, Switzerland, who had been repeatedly measured between 1979 (age 20/21) and 2008 (age 49/50). We applied two measures of sub-clinical psychosis derived from the SCL-90-R, namely schizotypal signs (STS) and schizophrenia nuclear symptoms (SNS). Variance was decomposed with latent state-trait analysis and associations with covariates were examined with generalized linear models. RESULTS: At ages 19/20 and 49/50, the latent states underlying STS accounted for 48% and 51% of variance, whereas for SNS those estimates were 62% and 50%. Between those age classes, however, expression of sub-clinical psychosis was strongly associated with stable traits (75% and 89% of total variance in STS and SNS, respectively, at age 27/28). Latent states underlying variance in STS and SNS were particularly related to partnership problems over almost the entire observation period. STS was additionally related to employment problems, whereas drug-use was a strong predictor of states underlying both syndromes at age 19/20. The latent trait underlying expression of STS and SNS was particularly related to low sense of mastery and self-esteem and to high depressiveness. CONCLUSIONS: Although most psychosis symptoms are transient and episodic in nature, the variability in their expression is predominantly caused by stable traits. Those time-invariant and rather consistent effects are particularly influential around age 30, whereas the occasion-specific states appear to be particularly influential at ages 20 and 50. PMID- 23932664 TI - Predictors of recovery in first episode psychosis: the OPUS cohort at 10 year follow-up. AB - BACKGROUND: Recovery, the optimal goal in treatment, is the attainment of both symptomatic and functional remission over a sustained period of time. Identification of factors that promote recovery can help develop interventions that facilitate good outcomes for people with first episode psychosis. AIM: To examine long-term outcomes within a cohort of people with first episode psychosis in relation to symptom remission, functioning and recovery, 10 years after diagnosis. METHOD: The study had a prospective design. Participants from the OPUS trial (1998-2000) (n=496) completed a series of interviews and questionnaires to measure current levels of psychopathology and social/vocational functioning, ten years after diagnosis. Predictors of recovery were identified using socio demographic and clinical characteristics collected at baseline. RESULTS: A total of 304 participants were interviewed, giving a follow-up rate of 61%. A total of 42 people (14%) met the criteria for symptomatic and psychosocial recovery at 10 years. A multivariable binary logistic regression analysis indicated that baseline predictors accounted for 22% of the variance of full recovery. Lower severity of negative symptoms at baseline (Odds Ratio (OR) 0.53, 95% confidence interval CI 0.36-0.78, p<0.001) and earlier age of diagnosis (OR 0.92, 95% CI 0.86-0.99, p<0.05) predicted better rates of recovery at 10 years. CONCLUSION: Results of this study indicated that negative symptoms could play a central role in the process of recovery from schizophrenia. A challenge for clinicians and researchers is to understand the mechanisms behind negative symptoms and develop interventions that can prevent or ameliorate these symptoms in order to promote recovery. PMID- 23932665 TI - Secondary mania in a patient with delayed anoxic encephalopathy after carbon monoxide intoxication caused by a suicide attempt. AB - We report herein a female patient presenting with delayed anoxic encephalopathy after carbon monoxide (CO) intoxication. Five months after she attempted suicide in her car using burning charcoal, she showed manic symptoms including aggressive behaviors, irritability, decreased total sleep time, increased energy and sexual interest, and hyperactivity, as well as illusions and visual hallucinations related to bugs, certain animals, monsters and her ex-husband. Fluid-attenuated inversion recovery and T2-weighted images in brain magnetic resonance imaging showed white-matter hyperintensity in the frontal lobe and periventricular area. Her manic symptoms and psychotic features improved following daily administration of valproate (600 mg) and olanzapine (10 mg). These observations indicate that clinicians should monitor for delayed neuropsychiatric symptoms in patients with CO intoxication. PMID- 23932666 TI - Aripiprazole associated urine retention in a male schizophrenia patient. AB - Urine retention and voiding dysfunction are infrequent adverse effects in second generation antipsychotics. We present a male patient who developed voiding difficulties after aripiprazole treatment. Close follow-up of a patient after initiating aripiprazole treatment is critical. Lowering the dosage of aripiprazole or changing the antipsychotic medication might be helpful in this situation. PMID- 23932667 TI - A secondary data analysis examining the needs of graduate nurses in their transition to a new role. AB - This paper describes the views of new graduate nurses on what factors they believe are important contributors for successful transition to registered nurse practice. Transition from student to new graduate nurse is challenging and stressful, with health care providers expecting graduates to "hit the ground running". The reality is that most graduates experience role adjustment difficulties and require support from senior colleagues within health care organisations. Drawing on a larger Australian study that examined pre registration paid employment and its impact on graduate nurse transition, findings in this paper suggest that successful transition is linked to post registration or employer factors and less so to pre-registration paid employment factors. Utilising interpretive description of two qualitative data sets; three organising themes were identified: a matching skill set, the beginning foundation and a job well done. The global theme, valuing beginning practice describes newly qualified nurse's views on being valued by the nursing profession and how they were accepted into the work environment. Despite the stressors faced by the majority of new graduate nurses adjusting to the rigours of practice, graduate transition can be improved by supportive institutional practices and fostering collegial respect. Successful graduate nurse transition improves job satisfaction and is an effective strategy to address the ongoing pressures of recruitment and retention of new graduates. PMID- 23932668 TI - Radionuclide-guided biopsy of bone lesions in cancer patients; a reliable, well tolerated technique. AB - OBJECTIVES: In follow up or primary analysis of malignant disease, use of nuclear medicine imaging techniques is increasing. The lesions, detected by these modalities, do not always present with a matching radiological abnormality suitable for radiological biopsy. A method to confirm, or rule out, metastatic disease in these cases is radionuclide-guided surgical biopsy. PATIENTS AND METHODS: The technique consists of injecting a Technetium-99m labelled diphosphonate, performing a bone scan and marking the lesion; under general anaesthetic a surgical biopsy is taken through a small incision guided by a gamma probe. We evaluated the combined experience of two teaching hospitals, by conducting retrospective chart review, over a period of 5.5 years. Sixty-nine procedures with 79 biopsies were performed. The patients previously had breast cancer in 42%, lung cancer in 32%, both gastrointestinal and urological malignancies in 13%, miscellaneous or unknown origin were reported in 9%. In 68% a rib biopsy was taken, in 15% a pelvis biopsy and in 11% a sternum or clavicle biopsy. RESULTS: In 46.8% metastatic disease was confirmed and in 2.6% a new malignancy (M Kahler) was identified. During a median clinical follow up period of 31 months (1-70), 1 initially negative biopsy site was found to contain a metastasis. Apart from local pain in 3% of cases, no complications were mentioned. CONCLUSION: In conclusion we can state that, in this retrospective series, radionuclide-guided bone biopsy is a reliable, well-tolerated technique to determine the diagnosis of these lesions with a sensitivity of 97% and specificity of 100%. PMID- 23932669 TI - Pelvic fractures presenting with haemodynamic instability: treatment options and outcomes. AB - The management of trauma patients with haemodynamic instability and an unstable pelvic fracture is an issue of vivid debate in "trauma community". A multidisciplinary approach needs to be instituted regarding the required diagnostic and therapeutic measures. Control of haemorrhage is the first priority. Arterial embolization and/or preperitoneal pelvic packing follow the provisional skeletal pelvic stabilization. The sequence of these interventions still remains an issue of controversy. It needs to be determined on an institutional basis based on the available local resources such as angiography suite and whole-body CT scan and the expertise of the treating surgical team. Despite the fact that recent advances in diagnostic modalities and trauma care systems have improved the overall outcome of patients with pelvic fractures, the early mortality associated with high-energy pelvic injuries presenting with haemodynamic instability remains high. Any suspected injured person with pelvic ring injury should automatically be taken to a level one-trauma centre where all the facilities required are in place for these patients to survive. PMID- 23932670 TI - Attitudes of the medical profession to whole body and organ donation. AB - Cadaveric dissection remains an important part of undergraduate medical education in anatomy. In a concerted effort to rise the number of doctors in practice in Ireland the amount of medical school placements has been increased steadily since 1995. This poses a problem as the number of cadavers has remained unchanged despite an overall increase in the population Ireland over the last twenty years. The medical profession plays a central part in raising public awareness of living and post-mortem organ donation. Previous studies have examined the attitudes of medical students to whole body donation, however to our knowledge this is the first study that evaluates the attitudes of medical professionals. We assess the opinions of junior and senior doctors at the time of their dissection experience and in their current practice. We show that their attitudes have changed as their clinical experience grows. PMID- 23932671 TI - Who decides the position for birth? A follow-up study of a randomised controlled trial. AB - BACKGROUND: Physical benefits are suggested for women and their babies when women adopt an upright position of their choice at birth. Available care options during labour influence women's impressions of what intrapartum care is. This indicates that choice of birth positions may be determined more by midwives than by women's preferences. QUESTION: The aims of this study were to investigate factors associated with adherence to allocated birth position and also to investigate factors associated with decision-making for birth position. METHOD: An invitation to answer an on-line questionnaire was mailed. FINDINGS: Despite being randomised, women who gave birth on the seat were statistically significantly more likely to report that they participated in decision-making and that they took the opportunity to choose their preferred birth position. They also reported statistically significantly more often than non-adherers that they felt powerful, protected and self-confident. CONCLUSIONS: Midwives should be conscious of the potential impact that birth positions have on women's birth experiences and on maternal outcomes. Midwives should encourage women's autonomy by giving unbiased information about the birth seat. An upright birth position may lead to greater childbirth satisfaction. Women's experience of and preferences for birth positions are consistent with current evidence for best practice. PMID- 23932672 TI - Gadoxetate uptake as a possible marker of hepatocyte damage after liver resection preliminary data. AB - AIM: To determine the feasibility of evaluating surgically induced hepatocyte damage using gadoxetate disodium (Gd-EOB-DTPA) as a marker for viable hepatocytes at magnetic resonance imaging (MRI) after liver resection. MATERIAL AND METHODS: Fifteen patients were prospectively enrolled in this institutional review board approved study prior to elective liver resection after informed consent. Three Tesla MRI was performed 3-7 days after surgery. Three-dimensional (3D) T1 weighted (W) volumetric interpolated breath-hold gradient echo (VIBE) sequences covering the liver were acquired before and 20 min after Gd-EOB-DTPA administration. The signal-to-noise ratio (SNR) was used to compare the uptake of Gd-EOB-DTPA in healthy liver tissue and in liver tissue adjacent to the resection border applying paired Student's t-test. Correlations with potential influencing factors (blood loss, duration of intervention, age, pre-existing liver diseases, postoperative change of resection surface) were calculated using Pearson's correlation coefficient. RESULTS: Before Gd-EOB-DTPA administration the SNR did not differ significantly (p = 0.052) between healthy liver tissue adjacent to untouched liver borders [59.55 +/- 25.46 (SD)] and the liver tissue compartment close to the resection surface (63.31 +/- 27.24). During the hepatocyte-specific phase, the surgical site showed a significantly (p = 0.04) lower SNR (69.44 +/- 24.23) compared to the healthy site (78.45 +/- 27.71). Dynamic analyses revealed a significantly lower increase (p = 0.008) in signal intensity in the healthy tissue compared to the resection border compartment. CONCLUSION: EOB-DTPA enhanced MRI may have the potential to be an effective non-invasive tool for detecting hepatocyte damage after liver resection. PMID- 23932673 TI - Re: Acute aortic syndrome: CT findings. PMID- 23932674 TI - MRI of optic tract lesions: review and correlation with visual field defects. AB - Visual field defects are a conglomerate of patterns of visual impairment derived from diseases affecting the optic nerve as it extends from the globe to the visual cortex. They are complex signs requiring perimetry or visual confrontation for delineation and are associated with diverse aetiologies. This review considers the chiasmatic and post-chiasmatic causes of visual disturbances, with an emphasis on magnetic resonance imaging (MRI) techniques. Newer MRI sequences are considered, such as diffusion-tensor imaging. MRI images are correlated with perimetric findings in order to demonstrate localization of lesions in the visual pathway. This may serve as a valuable reference tool to clinicians and radiologists in the early diagnostic process of differentiating causes of various visual field defects in daily practice. PMID- 23932675 TI - Current literature and imaging techniques of aseptic lymphocyte-dominated vasculitis-associated lesions (ALVAL). AB - Aseptic lymphocyte-dominated vasculitis-associated lesions (ALVAL) are a recognized complication of metal-on-metal bearing hip prostheses. There is an impending concern regarding the future investigation and management of patients who have received such implants. The current literature is discussed, and the current guidelines for management of these patients in the UK are reviewed. The various imaging techniques available, such as computed tomography, metal artefact reduction magnetic resonance imaging, and ultrasound are discussed and evaluated with respect to the assessment of patients with suspected ALVAL. The histopathological findings are discussed with images of the tissue changes provided. Images of the radiological findings are also provided for all general radiological methods. ALVAL and its radiological presentation is an important issue that unfortunately may become a significant clinical problem. PMID- 23932676 TI - Re: Imaging and management of complications of central venous catheters. A reply. PMID- 23932677 TI - Re: Imaging and management of complications of central venous catheters. PMID- 23932678 TI - Comparing T1-weighted and T2-weighted three-point Dixon technique with conventional T1-weighted fat-saturation and short-tau inversion recovery (STIR) techniques for the study of the lumbar spine in a short-bore MRI machine. AB - AIM: To compare T1-weighted (W) fat-water separation (Dixon's technique) with T1W fat-saturation (FS) and T2W Dixon with short-tau inversion recovery (STIR) images for fat suppression in a short-bore MRI machine. MATERIALS AND METHODS: Thirteen patients with lumbar disease were studied on using 1.5 T MRI machine. The protocol included T1 FS (with contrast medium administration) and/or STIR and T1W and/or T2W Dixon, for comparison. Three neuroradiologists scored the images from the two-pairs of techniques for fat suppression uniformity and lesion conspicuity. Clinical usefulness of fat-only images was also evaluated. RESULTS: Regarding uniformity of fat suppression, mean scores were 2.28 (+/-0.49), 3.06 (+/-0.49), 2.39 (+/-0.49), and 3.15 (+/-0.35) for T1W FS, T1W Dixon, STIR, and T2W Dixon sequences, respectively. For the same pulse sequences, lesion conspicuity scores were 2.78 (+/-0.50), 2.78 (+/-0.27), 2.76 (+/-0.47), and 2.91 (+/-0.4), respectively. Both T1W and T2W Dixon sequences showed more homogeneous fat-suppression when compared to T1W FS (p = 0.026) and STIR (p = 0.008) techniques, but no significant difference was found for lesion conspicuity. Mean scores for the diagnostic utility of fat-only maps were, respectively, 1.72 (+/ 0.39) and 2.48 (+/-0.50) for T1W and T2W Dixon. CONCLUSION: Fat suppression quality was superior with Dixon when compared to the conventional sequences, but not lesion conspicuity, suggesting that both techniques are reliable for diagnosis. Dixon may be advantageous in cases where inhomogeneity artefacts are an issue. Water-only maps appear to be useful in the clinical setting. PMID- 23932679 TI - Anatomy of our journal. PMID- 23932680 TI - Investigating the self-reported behavior of drivers and their attitudes to traffic violations. AB - INTRODUCTION: Driving behavior theoretical models consider attitudes as an important determinant of driver behavior. Moreover, the association between the self-reported tendency to commit violations and accident involvement is widely recognized. This research investigates drivers' self-reported behavior and attitudes to risky behaviors related to the traffic violations of speeding, drink driving, and cell phone use using cluster analysis. METHOD: A sample of 601 Greek drivers participating at the SARTRE 4 pan-European survey is utilized. The analysis identified three clusters of drivers. Drivers in Cluster 1 commit traffic violations more often; drivers in Cluster 2 favor traffic violation countermeasures while having moderate views toward compliance with traffic rules; and drivers in Cluster 3 strongly support traffic violation countermeasures and also have strong views toward compliance with traffic rules. Risky behaviors and related attitudes that differentiate the three distinct groups of drivers (clusters) were determined. RESULTS: The findings indicate that differences in attitudes and behaviors may be attributed to factors such as age, gender, and area of residence. The research findings also provided some insight about the current level of drivers' attitudes to traffic violations, especially those that negatively affect traffic safety. The pattern of their views on violations may form the basis of risk behavior-related interventions tailored to the identified groups, aiming at informing, educating, and raising the awareness of the public. IMPACT ON INDUSTRY: Agencies focused on safety interventions could exploit this information in designing and implementing education campaigns, enforcement programs and in defining relevant priorities. PMID- 23932681 TI - The comparison of road safety survey answers between web-panel and face-to-face; Dutch results of SARTRE-4 survey. AB - INTRODUCTION: In the Netherlands, a comparison of an online and a face-to-face sample of car drivers was made to study differences on a number of selected questions from the SARTRE-4 road safety survey. RESULTS: Contrary to expectations, there was no indication that online respondents were more likely to come from higher educated or more privileged social groups. Confirming earlier research, the results indicated that online respondents were less inclined to give socially desirable answers and were less inclined to use more extreme ratings in their opinions about measures. Contrary to expectations, face-to-face respondents did not tend to give more positive answers in judgment of road safety measures. Weighting to make samples comparable on gender, age, and education had almost no effect on outcomes. CONCLUSIONS: The implications for a transition from face-to-face survey to online panel method are discussed. PMID- 23932682 TI - Validation of the group nuclear safety climate questionnaire. AB - INTRODUCTION: Group safety climate is a leading indicator of safety performance in high reliability organizations. Zohar and Luria (2005) developed a Group Safety Climate scale (ZGSC) and found it to have a single factor. METHOD: The ZGSC scale was used as a basis in this study with the researchers rewording almost half of the items on this scale, changing the referents from the leader to the group, and trying to validate a two-factor scale. The sample was composed of 566 employees in 50 groups from a Spanish nuclear power plant. Item analysis, reliability, correlations, aggregation indexes and CFA were performed. RESULTS: Results revealed that the construct was shared by each unit, and our reworded Group Safety Climate (GSC) scale showed a one-factor structure and correlated to organizational safety climate, formalized procedures, safety behavior, and time pressure. IMPACT ON INDUSTRY: This validation of the one-factor structure of the Zohar and Luria (2005) scale could strengthen and spread this scale and measure group safety climate more effectively. PMID- 23932683 TI - Bayesian road safety analysis: incorporation of past evidence and effect of hyper prior choice. AB - PROBLEM: This paper aims to address two related issues when applying hierarchical Bayesian models for road safety analysis, namely: (a) how to incorporate available information from previous studies or past experiences in the (hyper) prior distributions for model parameters and (b) what are the potential benefits of incorporating past evidence on the results of a road safety analysis when working with scarce accident data (i.e., when calibrating models with crash datasets characterized by a very low average number of accidents and a small number of sites). METHOD: A simulation framework was developed to evaluate the performance of alternative hyper-priors including informative and non-informative Gamma, Pareto, as well as Uniform distributions. Based on this simulation framework, different data scenarios (i.e., number of observations and years of data) were defined and tested using crash data collected at 3-legged rural intersections in California and crash data collected for rural 4-lane highway segments in Texas. RESULTS: This study shows how the accuracy of model parameter estimates (inverse dispersion parameter) is considerably improved when incorporating past evidence, in particular when working with the small number of observations and crash data with low mean. The results also illustrates that when the sample size (more than 100 sites) and the number of years of crash data is relatively large, neither the incorporation of past experience nor the choice of the hyper-prior distribution may affect the final results of a traffic safety analysis. CONCLUSIONS: As a potential solution to the problem of low sample mean and small sample size, this paper suggests some practical guidance on how to incorporate past evidence into informative hyper-priors. By combining evidence from past studies and data available, the model parameter estimates can significantly be improved. The effect of prior choice seems to be less important on the hotspot identification. IMPACT ON INDUSTRY: The results show the benefits of incorporating prior information when working with limited crash data in road safety studies. PMID- 23932684 TI - Learner driver experiences and crash risk as an unsupervised driver. AB - OBJECTIVE: The purpose of this study was to describe the driving experiences of learner licensed drivers and examine the association between these driving experiences, associated factors, and on-road car crash involvement during the unsupervised restricted license stage. METHODS: Data were drawn from a cohort investigation of newly licensed drivers. Information on demographic characteristics, personality, and risk behaviors was collected at the baseline interview. At the first follow-up interview (restricted license stage) study members were asked details about their experiences as a learner licensed driver: professional driving lessons, supervised driving, unsupervised driving, and driving courses in which they participated. During the second follow-up interview (full license stage), data were collected on crash involvement and driving exposure during the restricted license stage. Regression analysis was used to determine independent relationships between learner license driving experience variables and crash involvement. RESULTS: After adjusting for demographic, personality factors, and driving exposure at the restricted license stage, increased time spent on the learner license was associated with a reduced risk of crash involvement during the unsupervised restricted license stage. CONCLUSION: Results presented in this paper suggest that learner drivers in New Zealand should be encouraged to spend more time on their learner license to enable them to gain skills and experience to help reduce their crash risk when they are allowed to drive unsupervised. IMPACT ON INDUSTRY: Compared with novice drivers who are on their learner license for the least amount of time, those who spend the most amount of time on their learner license have reduced risk of on-road crash involvement as an unsupervised driver. Learner drivers and their supervisors need to be aware of the length of time required for practice in order to reduce the risks of crash involvement when they are able to drive unsupervised (O'Brien et al., 2012). The recently introduced increase in the minimum driver licensing age in NZ, tougher restricted license stage driving test (aimed at encouraging 120 hours of supervised driving), and the Safe Teen driver campaign (NZ Transport Agency, 2012) are all strategies targeted at improving the safety of learner drivers. These strategies need to be evaluated to ensure they are achieving their goals. PMID- 23932685 TI - Risky riding behavior on two wheels: the role of cognitive, social, and personality variables among young adolescents. AB - OBJECTIVE: The main objective of this study was to analyze and estimate the relations between risky riding behaviors and some personality and sociocognitive variables through structural equation modeling. We focused on two-wheel riding behavior among a sample of 1,028 Italian adolescents at their first driving experience. CONCLUSIONS: The main findings confirmed the role of personality in influencing riding behavior directly as well as indirectly through risk perception. In particular, risk perception was a significant mediator between personality, social norm, and riding behavior. The significant relations that emerged in the general sample were further confirmed in the two specific sub samples of males and females. In terms of social marketing and educational communication, it may consequently be advisable to proceed in an integrated and coordinated manner at both the cognitive and social level, taking into account some "dispositions to risk" related to personality. IMPACT ON INDUSTRY: The integrated and coordinated action on different levels--cognitive, social, and personality--may therefore allow more effective and significant results in reducing those risky riding behaviors that often underlie young two-wheel riders' higher involvement in traffic accidents. PMID- 23932686 TI - Fatal connections--socioeconomic determinants of road accident risk and drunk driving in Sweden. AB - PROBLEM: In recent years a considerable number of papers have examined socioeconomic factors influencing the number and the outcome of traffic accidents. There is however more research needed to confirm the previous results in order to generalize them and a need to examine additional factors that might have an impact. METHOD: This paper uses both regional panel data and national time series data combined with filtering techniques to determine what factors influence the number of accidents, the accident outcome and detected drunk driving. RESULTS: Using time series data, it is found that the number of traffic fatalities increases for both per capita and per person kilometer travelled during economic booms. This indicates that the death risk rises not only because of increased mileage or motorization during booms. Using panel data, it is found that traffic fatalities decrease with unemployment, whereas personal injuries increase on a per capita basis with youth and the number of cars. In contrast to property crimes and other types of crime, drunk driving in Sweden decreases during economic contractions. DISCUSSION: The main policy conclusion from our results is that resources for safety measures should not be spend uniformly across time and space. Instead, safety measures should be concentrated to areas with a high share of young people and to periods with low unemployment. The results of the time series analysis suggest that factors other than increased mileage during booms contribute to the higher rate of fatalities during good times. Increased risk taking, such as drunk driving, might be an explanatory factor. IMPACT ON INDUSTRY: The results might be interesting for safety-oriented car and truck producers as well for developers of traffic safety products, since the results indicate in what regional markets and under what market conditions their products are most needed. PMID- 23932687 TI - Effect of driver's age and side of impact on crash severity along urban freeways: a mixed logit approach. AB - INTRODUCTION: This study identifies geometric, traffic, environmental, vehicle related, and driver-related predictors of crash injury severity on urban freeways. METHOD: The study takes advantage of the mixed logit model's ability to account for unobserved effects that are difficult to quantify and may affect the model estimation, such as the driver's reaction at the time of crash. Crashes of 5 years occurring on 89 urban freeway segments throughout the state of Florida in the United States were used. Examples of severity predictors explored include traffic volume, distance of the crash to the nearest ramp, and detailed driver's age, vehicle types, and sides of impact. To show how the parameter estimates could vary, a binary logit model was compared with the mixed logit model. RESULTS: It was found that the at-fault driver's age, traffic volume, distance of the crash to the nearest ramp, vehicle type, side of impact, and percentage of trucks significantly influence severity on urban freeways. Additionally, young at fault drivers were associated with a significant severity risk increase relative to other age groups. It was also observed that some variables in the binary logit model yielded illogic estimates due to ignoring the random variation of the estimation. Since the at-fault driver's age and side of impact were significant random parameters in the mixed logit model, an in-depth investigation was performed. It was noticed that back, left, and right impacts had the highest risk among middle-aged drivers, followed by young drivers, very young drivers, and finally, old and very old drivers. IMPACT ON INDUSTRY: To reduce side impacts due to lane changing, two primary strategies can be recommended. The first strategy is to conduct campaigns to convey the hazardous effect of changing lanes at higher speeds. The second is to devise in-vehicle side crash avoidance systems to alert drivers of a potential crash risk. CONCLUSIONS: The study provided a promising approach to screening the predictors before fitting the mixed logit model using the random forest technique. Furthermore, potential countermeasures were proposed to reduce the severity of impacts. PMID- 23932688 TI - Tweens at risk: examining car safety practices in four economically disadvantaged urban elementary schools in Virginia. AB - INTRODUCTION: Children aged 8- to 12-years-old ("tweens") are at high risk for crash injury, and motor vehicle crashes are their leading cause of death. METHOD: Data are presented from behavioral observations (N=243), surveys (N=677), and focus groups (N=26) conducted with tweens attending four urban elementary schools in Virginia. The populations assessed were predominantly black (77.9%) and economically disadvantaged (61.9%). RESULTS: Focus groups revealed a number of inconsistencies in and misconceptions about safety practices. Among the 677 tweens who completed anonymous surveys, the majority (58.1%) reported wearing their seat belts "not very much at all" or "never." Many students (47.8%) reported usually sitting in the front seat or sitting in the front and back seats equally. This is despite the fact that most (92.0%) knew that the back seat was the safest place to sit. Of the 243 tweens observed in vehicles, 65.0% were unrestrained and 60.1% were seated in the front passenger seat. IMPACT ON INDUSTRY: Findings of this study shed light on the great disparity between the national rates for child safety practices and those of children living in an economically disadvantaged urban school district. Additional intervention programs that are culturally appropriate and specifically target this age group are needed. PMID- 23932689 TI - Transferability and robustness of real-time freeway crash risk assessment. AB - INTRODUCTION: This study examines the data from single loop detectors on northbound (NB) US-101 in San Jose, California to estimate real-time crash risk assessment models. METHOD: The classification tree and neural network based crash risk assessment models developed with data from NB US-101 are applied to data from the same freeway, as well as to the data from nearby segments of the SB US 101, NB I-880, and SB I-880 corridors. The performance of crash risk assessment models on these nearby segments is the focus of this research. RESULTS: The model applications show that it is in fact possible to use the same model for multiple freeways, as the underlying relationships between traffic data and crash risk remain similar. IMPACT ON INDUSTRY: The framework provided here may be helpful to authorities for freeway segments with newly installed traffic surveillance apparatuses, since the real-time crash risk assessment models from nearby freeways with existing infrastructure would be able to provide a reasonable estimate of crash risk. The robustness of the model output is also assessed by location, time of day, and day of week. The analysis shows that on some locations the models may require further learning due to higher than expected false positive (e.g., the I-680/I-280 interchange on US-101 NB) or false negative rates. The approach for post-processing the results from the model provides ideas to refine the model prior to or during the implementation. PMID- 23932690 TI - Investigating the different characteristics of weekday and weekend crashes. AB - INTRODUCTION: This study provides a systematic approach to investigate the different characteristics of weekday and weekend crashes. METHOD: Weekend crashes were defined as crashes occurring between Friday 9 p.m. and Sunday 9 p.m., while the other crashes were labeled as weekday crashes. In order to reveal the various features for weekday and weekend crashes, multi-level traffic safety analyses have been conducted. For the aggregate analysis, crash frequency models have been developed through Bayesian inference technique; correlation effects of weekday and weekend crash frequencies have been accounted. A multivariate Poisson model and correlated random effects Poisson model were estimated; model goodness-of fits have been compared through DIC values. In addition to the safety performance functions, a disaggregate crash time propensity model was calibrated with Bayesian logistic regression model. Moreover, in order to account for the cross section unobserved heterogeneity, random effects Bayesian logistic regression model was employed. RESULTS: It was concluded that weekday crashes are more probable to happen during congested sections, while the weekend crashes mostly occur under free flow conditions. Finally, for the purpose of confirming the aforementioned conclusions, real-time crash prediction models have been developed. Random effects Bayesian logistic regression models incorporating the microscopic traffic data were developed. Results of the real-time crash prediction models are consistent with the crash time propensity analysis. Furthermore, results from these models would shed some lights on future geometric improvements and traffic management strategies to improve traffic safety. IMPACT ON INDUSTRY: Utilizing safety performance to identify potential geometric improvements to reduce crash occurrence and monitoring real-time crash risks to pro-actively improve traffic safety. PMID- 23932691 TI - Safety risk assessment using analytic hierarchy process (AHP) during planning and budgeting of construction projects. AB - INTRODUCTION: The inherent and unique risks on construction projects quite often present key challenges to contractors. Health and safety risks are among the most significant risks in construction projects since the construction industry is characterized by a relatively high injury and death rate compared to other industries. In construction project management, safety risk assessment is an important step toward identifying potential hazards and evaluating the risks associated with the hazards. Adequate prioritization of safety risks during risk assessment is crucial for planning, budgeting, and management of safety related risks. METHOD: In this paper, a safety risk assessment framework is presented based on the theory of cost of safety (COS) model and the analytic hierarchy process (AHP). The main contribution of the proposed framework is that it presents a robust method for prioritization of safety risks in construction projects to create a rational budget and to set realistic goals without compromising safety. THE IMPACT TO THE INDUSTRY: The framework provides a decision tool for the decision makers to determine the adequate accident/injury prevention investments while considering the funding limits. The proposed safety risk framework is illustrated using a real-life construction project and the advantages and limitations of the framework are discussed. PMID- 23932692 TI - Tactical, strategic, and life-goal self-regulation of driving by older adults: development and testing of a questionnaire. AB - INTRODUCTION: Appropriate self-regulation of driving - that is, adjusting one's driving patterns by driving less or avoiding specific situations considered challenging - shows promise as a strategy for extending safe driving. However, results on the extent of self-regulatory practices among older drivers vary considerably across studies. METHOD: The purpose of this study was to develop and test a questionnaire to measure self-regulation at multiple levels of driver performance and decision making, using a sample of older drivers comprised of individuals with clinically-determined functional impairments, as well as older adults recruited from the general population. RESULTS: Results suggest that the questionnaire is a user-friendly instrument for gathering information from older adults about their self-regulatory practices which has good construct validity. Feedback on the questionnaire was positive. Construct validity of the questionnaire was assessed by comparing the recruitment populations along various dimensions on which they might be expected to differ (e.g., self-rated health and functioning, abilities for safe driving, and feelings of driving comfort/safety) and looking for correlations between variables that one would reasonably expect to be correlated. CONCLUSIONS: Overall, participants rated their general health and functioning, and abilities for safe driving quite highly. However, participants from the clinic population rated themselves lower than participants from the general population on several abilities including seeing clearly during the day and night, remembering things, and processing information. While participants reported high levels of driving comfort and safety for most driving situations, the clinic population reported lower levels of comfort and safety for every driving circumstance except driving alone. High correlations were found between comfort and safety and the absolute mean scores were nearly identical for each driving circumstance. Finally, the clinic population was more likely to report trying to avoid driving at night, in unfamiliar areas, and on the expressway, as well as chatting with passengers. IMPACT ON THE INDUSTRY: Results of this pilot work provide insights into the self-regulatory driving process that could eventually inform efforts to extend safe mobility among older adults. PMID- 23932693 TI - A comparison of fatal occupational injury event characteristics from the Census of Fatal Occupational Injuries and the Vital Statistics Mortality System. AB - OBJECTIVES: The aim of this study was to examine utility of appending International Classification of Diseases (ICD) codes from Vital Statistics Mortality (VSM) data to Bureau of Labor Statistics (BLS) Census of Fatal Occupational Injuries (CFOI), and compare occupational event characteristics based on ICD external cause and BLS Occupational Injury and Illness Classification System (OIICS) event codes. METHODS: We linked VSM records with CFOI records for 2003 and 2004. RESULTS: Ninety-five percent of approximately 11,000 CFOI cases were linked to VSM cases. Linked data suggest that CFOI OIICS event and VSM ICD codes identified similar leading events. However, VSM data were generally less specific. CONCLUSION: Lack of detail inherent in ICD codes and death narratives limits specificity of injury characteristics in VSM data. Appending ICD codes to CFOI appears to offer little value. Research comparing work- and non-work-related events may be better served by having a defined framework to crosswalk both coding schemes to facilitate comparisons. IMPACT ON INDUSTRY: Over the last two decades, both ICD and OIICS have been used to characterize occupational injury circumstances; however, this is the first study to use linked case comparisons of the OIICS and ICD codes at a detailed level. This study confirmed that multiple source data systems provide more detail surrounding an incident than a single source data system does. Our results suggest that OIICS-coded CFOI data are a better source for occupational injury research and prevention purposes. For future comparison studies requiring ICD, it would be advantageous to have a defined framework that could easily be used to map both coding schemes (OIICS and ICD). PMID- 23932694 TI - Discounting the value of safety: effects of perceived risk and effort. AB - INTRODUCTION: Although falls from heights remain the most prevalent cause of fatalities in the construction industry, factors impacting safety-related choices associated with work at heights are not completely understood. Better tools are needed to identify and study the factors influencing safety-related choices and decision making. METHOD: Using a computer-based task within a behavioral economics paradigm, college students were presented a choice between two hypothetical scenarios that differed in working height and effort associated with retrieving and donning a safety harness. Participants were instructed to choose the scenario in which they were more likely to wear the safety harness. Based on choice patterns, switch points were identified, indicating when the perceived risk in both scenarios was equivalent. RESULTS: Switch points were a systematic function of working height and effort, and the quantified relation between perceived risk and effort was described well by a hyperbolic equation. CONCLUSION: Choice patterns revealed that the perceived risk of working at heights decreased as the effort to retrieve and don a safety harness increased. IMPACT ON INDUSTRY: Results contribute to the development of computer-based procedure for assessing risk discounting within a behavioral economics framework. Such a procedure can be used as a research tool to study factors that influence safety-related decision making with a goal of informing more effective prevention and intervention strategies. PMID- 23932695 TI - Identifying crash-prone traffic conditions under different weather on freeways. AB - INTRODUCTION: Understanding the relationships between traffic flow characteristics and crash risk under adverse weather conditions will help highway agencies develop proactive safety management strategies to improve traffic safety in adverse weather conditions. METHOD: The primary objective is to develop separate crash risk prediction models for different weather conditions. The crash data, weather data, and traffic data used in this study were collected on the I 880N freeway in California in 2008 and 2010. This study considered three different weather conditions: clear weather, rainy weather, and reduced visibility weather. The preliminary analysis showed that there was some heterogeneity in the risk estimates for traffic flow characteristics by weather conditions, and that the crash risk prediction model for all weather conditions cannot capture the impacts of the traffic flow variables on crash risk under adverse weather conditions. The Bayesian random intercept logistic regression models were applied to link the likelihood of crash occurrence with various traffic flow characteristics under different weather conditions. The crash risk prediction models were compared to their corresponding logistic regression model. RESULTS: It was found that the random intercept model improved the goodness-of fit of the crash risk prediction models. The model estimation results showed that the traffic flow characteristics contributing to crash risk were different across different weather conditions. The speed difference between upstream and downstream stations was found to be significant in each crash risk prediction model. Speed difference between upstream and downstream stations had the largest impact on crash risk in reduced visibility weather, followed by that in rainy weather. The ROC curves were further developed to evaluate the predictive performance of the crash risk prediction models under different weather conditions. The predictive performance of the crash risk model for clear weather was better than those of the crash risk models for adverse weather conditions. IMPACT ON INDUSTRY: The research results could promote a better understanding of the impacts of traffic flow characteristics on crash risk under adverse weather conditions, which will help transportation professionals to develop better crash prevention strategies in adverse weather. PMID- 23932696 TI - Comprehension of hazard communication: effects of pictograms on safety data sheets and labels. AB - INTRODUCTION: The United Nations has proposed the Globally Harmonized System (GHS) of Classification and Labelling of Chemicals to make hazard communication more uniform and to improve comprehension. METHOD: Two experiments were conducted to test whether the addition of hazard and precautionary pictograms to safety data sheets and product labels would improve the transfer of information to users compared to safety data sheets and product labels containing text only. Additionally, naive users, workers, and experts were tested to determine any potential differences among users. RESULTS: The effect of adding pictograms to safety data sheets and labels was statistically significant for some conditions, but was not significant across all conditions. One benefit of the addition of pictograms was that the time to respond to the survey questions decreased when the pictograms were present for both the SDS and the labels. GHS format SDS and labels do provide benefits to users, but the system will need further enhancements and modifications to continue to improve the effectiveness of hazard communication. IMPACT ON INDUSTRY: The final rule to modify the HCS to include the Globally Harmonized System (GHS) for the Classification and Labelling of Chemicals announced by OSHA (2012b) will change the information content of every chemical SDS and label used in commerce. This study suggests that the inclusion of GHS hazard pictograms and precautionary pictograms to SDS and labels may benefit the user. PMID- 23932697 TI - Passenger behavior in trains during emergency situations. AB - INTRODUCTION: This research presents a methodology for analyzing the behavior of people (passengers and crew) involved in emergency situations on passenger trains. METHODS: This methodological tool centers around a qualitative character study coming from Focus Groups (FG) and in-depth interviews to extract the determinant variables on passenger and crew behavior when faced with certain emergency situations on trains. RESULTS: This research has led to the creation of a classification of possible behaviors associated to each type of incident and dependent on certain variables. The qualitative study was used as the basis for modeling stated preference data using logit type discrete choice models to characterize and quantify the behavior. The most important results show that the determinant variables on passenger behavior correspond to the type of emergency suffered (its degree of seriousness), the type of passenger, the reasons for the journey (demands of time), the information received during the incident, the relationship between crew and passengers, the duration of the incident and the conditions (temperature control, availability of water, occupancy of the train), the distance to the destination station, and finally, the outside weather conditions. This research was carried out using the Spanish railway network as its reference, although it is applicable to any geographical area. IMPACT ON INDUSTRY: The results show that the information variable should be considered in the development of future research and that the evidences of this research can be used to develop behavioral models for modeling railway passenger evacuations. PMID- 23932698 TI - Trends in driver licensing status and driving among high school seniors in the United States, 1996-2010. AB - INTRODUCTION: Understanding the reasons for fluctuations in teenage driver crashes over time in the United States is clouded by the lack of information on licensure rates and driving exposure. METHODS: We examined results from the Monitoring the Future survey to estimate the proportion of high school seniors who possessed a driver's license and the proportion of seniors who did not drive "during an average week" during the 15-year period of 1996-2010. RESULTS: During 1996-2010, the proportion of high school seniors in United States who reported having a driver's license declined by 12 percentage points (14%) from 85% to 73%. Two-thirds of the decline (8 percentage points) occurred during 2006-2010. During the same 15-year period, the proportion of high school seniors who did not drive during an average week increased by 7 percentage points (47%) from 15% in 1996 to 22% in 2010, with essentially all of the increase occurring during 2006-2009. DISCUSSION: Findings in this report suggest that the economic recession in recent years has reduced rates of licensure and driving among high school seniors. PMID- 23932699 TI - Recent childbirth is an adverse prognostic factor in breast cancer and melanoma, but not in Hodgkin lymphoma. AB - BACKGROUND: The relationship between gestation, childbirth and cancer prognosis is unknown for most cancers (e.g. Hodgkin lymphoma), whereas a body of evidence exists for melanoma and breast cancer. METHODS: The national cancer registration and hospital discharge data for women in England (1998-2007) were linked, and the records for Hodgkin lymphoma, melanoma and breast cancer were indexed as to whether women had delivered a child in separate time periods prior to their cancer diagnosis. Survival analyses were conducted in order to characterise prognosis in relation to childbirth, with statistical adjustment for age and (where possible) stage. FINDINGS: For melanoma and breast cancer, survival was strongly reduced in women who gave birth in the year prior to cancer diagnosis. The age-adjusted hazard ratios (HR) with 95% confidence intervals (CI) were 2.06 (1.42-3.01) for melanoma and 1.84 (1.64-2.06) for breast cancer. The associations were only slightly attenuated by further adjustment for tumour stage. For breast cancer, the excess death rate in women with a recent childbirth peaked at 2 years and remained elevated for 6 to 8 years. Previous childbirth had no overall effect on the outcome of Hodgkin lymphoma. INTERPRETATION: Melanoma and breast cancer prognosis are adversely affected by recent gestation and childbirth in a way that is not due to stage of the cancer, but rather to inherent biological properties of the tumours. Possible biological mechanisms include immunosuppression (melanoma), the hormonal milieu in gestation and a tumour promoting microenvironment post-partum (breast cancer). PMID- 23932700 TI - Colloid solutions for fluid resuscitation in patients with sepsis: systematic review of randomized controlled trials. AB - BACKGROUND: Colloids are widely used for fluid resuscitation in patients with sepsis. But the optimal type of fluid remains unclear. OBJECTIVE: Our aim was to assess the effects on mortality and safety of different colloid solutions in patients with sepsis requiring volume replacement by examining direct comparisons of colloid solutions. METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, China Biological Medicine Database, VIP Chinese Journals Database, and CNKI China National Knowledge Infrastructure Whole Article Database. Randomized clinical trials comparing different colloids in septic patients needing fluid resuscitation were selected. RESULTS: Seventeen randomized clinical trials with a total 1281 participants met the inclusion criteria. Mortality was obtained in all trials. For intervention of albumin vs. hydroxyethyl starch solution (HES), the relative risk (RR) of death was 0.98 (95% confidence interval [CI] 0.74-1.30). For intervention of albumin vs. gelatin, the RR of death was 2.4 (95% CI 0.31-18.35). For intervention of gelatin vs. HES, the RR of death was 1.02 (95% CI 0.79-1.32). For the intervention of HES vs. dextran, the RR of death was 1.38 (95% CI 0.28-6.78). For the intervention of gelatin vs. dextran, RR of death was not estimable. For albumin vs. dextran, no trial was included. Four trials of intervention of albumin vs. HES recorded the change of severity score. CONCLUSIONS: There is no evidence that one colloid solution is more effective and safer than another for fluid resuscitation in sepsis. The severity score is improved in HES, but the confidence intervals are wide. PMID- 23932701 TI - A fish tale: flushing and pruritis after tuna ingestion. PMID- 23932703 TI - Can zinc(II) ions be doped into the crystal structure of L-proline cadmium chloride monohydrate? AB - The bivalent metals Cd(II) and Zn(II) exhibit different stereochemical requirements for the set of chloride and L-proline ligands, which precludes the doping of Zn(II) ions into the crystal structure of dichloro(l proline)cadmium(II) hydrate also referred to as L-proline cadmium chloride monohydrate (L-PCCM). Hence, the reported claim of growth of zinc doped L-PCCM crystals namely Zn(0.4 mol):LPCCM and Zn(0.2 mol):LPCCM by Vetrivel et al. (S. Vetrivel, P. Anandan, K. Kanagasabapathy, S. Bhattacharya, S. Gopinath, R. Rajasekaran, Effect of zinc chloride on the growth and characterization of l proline cadmium chloride monohydrate semiorganic NLO single crystals, Spectrochim. Acta 110A (2013) 317-323), is untenable. PMID- 23932702 TI - Patient factors associated with failure to diagnose tuberculosis in the emergency department. AB - BACKGROUND: Emergency department (ED) presentation of pulmonary tuberculosis (TB) can be highly atypical and an ED visit might be the only health care interaction for high-risk patients. OBJECTIVE: Our objective was to identify patient factors associated with discharge without a diagnosis of TB during an infectious ED visit. METHODS: The study population consisted of 150 patients from 2000 to 2009 with 190 infectious ED visits. Patients were initially identified from the state registry of confirmed TB cases and epidemiological characteristics were identified prospectively during case investigation. A retrospective review was performed for clinical characteristics of visits dichotomized according to whether the diagnosis of TB was made during the ED visit. RESULTS: Analysis revealed that 77% of all infectious-patient visits ended with a diagnosis of TB. A TB diagnosis was more likely when patients presented with pulmonary or infectious chief complaints, endorsed cough, subjective fever, chills, dyspnea, previous TB infection, or had an abnormal lung examination or chest x-ray study. Patients were significantly less likely to be diagnosed with TB when they were unresponsive during clinical evaluation or when they reported a history of both homelessness and any substance abuse during the last year. In addition, these characteristics were independent predictors of nondiagnosis when traditional TB risk factors or abnormal vital signs were considered. CONCLUSIONS: Patients with atypical presentations, as well as those who were unresponsive or reported a history of homelessness and substance abuse, were at greater risk for nondiagnosis of TB during an infectious ED visit. PMID- 23932704 TI - Immunity and squamous cell carcinoma of the anus: epidemiological, clinical and therapeutic aspects. AB - Squamous cell carcinoma of the anus (SCCA) is a rare disease, but its incidence has been increasing dramatically since the 1970s. Men who have sex with men (MSM) and infection with human immunodeficiency virus (HIV) are the two main risk factors. Risk of developing SCCA is increased more than 100-fold in HIV seropositive MSM. We review here how immunodeficiency could promote SCCA and how restoration of immunity since the advent of combined antiretroviral therapy can influence the natural history and incidence of SCCA. We also review the prognostic and therapeutic implications of immunosuppression in these patients. Finally, we show how, with anti-HPV vaccines, immunity is a target in the prevention of SCCA and could in the future be used in its treatment. PMID- 23932705 TI - Is HBsAg quantification ready, for prime time? AB - Despite the availability of an efficient hepatitis B vaccine, approximately 240 million individuals are chronically infected with hepatitis B virus worldwide. One-fourth of hepatitis B surface antigen (HBsAg)-positive patients will develop complications, such as cirrhosis or hepatocellular carcinoma, both major causes of liver-related deaths. Antiviral therapies, such as pegylated interferon alpha or nucleoside/nucleotide analogues, are effective in suppressing HBV DNA and reducing the subsequent risk of fibrosis progression, cirrhosis and hepatocellular carcinoma. HBsAg has proven to be a steady, reliable marker of chronic HBV carriage that can also be used to predict clinical outcomes. Three commercial enzyme immunoassays are now available for HBsAg quantification. A number of recent studies have shown clinical utility of HBsAg quantification in combination with HBV DNA levels to identify inactive carriers who need antiviral therapy and in interferon treated-patients in order to predict the virological response to pegylated interferon alpha. PMID- 23932707 TI - Treatment of chronic lymphocytic leukemia. PMID- 23932706 TI - AST/ALT ratio is not an index of liver fibrosis in chronic hepatitis C when aminotransferase activities are determinate according to the international recommendations. AB - OBJECTIVE: The aspartate aminotransferase activity (AST)/alanine aminotransferase activity (ALT) ratio is used as liver fibrosis index whereas the reported data are conflicting. In chronic hepatitis C (CHC), reported diagnostic accuracies range from none to good for significant fibrosis and to excellent for cirrhosis. Assuming that AST/ALT increases are mainly due to vitamin B6 defects since pyridoxal phosphate (PLP), active form of B6, acts as coenzyme in transamination reactions, we evaluated the diagnostic accuracy of the AST/ALT ratio using standardized methods for AST and ALT activities, with PLP addition as recommended, in a prospective multicenter cohort of CHC patients. METHODS: ALT and AST activities were measured using the recommended IFCC methods with addition of pyridoxal 5'-phosphate. We evaluated the AST/ALT ratio for the diagnosis of liver fibrosis or cirrhosis in a cohort of CHC patients included in a multicenter prospective study. A liver biopsy was performed in each patient and reviewed by two independent pathologists in order to determine the fibrosis stage according to Metavir classification which was the reference standard. RESULTS: AST/ALT ratio significantly increased with histological stage of liver fibrosis and there was a significant correlation between Metavir fibrosis stage and AST/ALT ratio (r=0.129, P<0.0035). The ROC curve analyses showed that the AST/ALT ratio does not discriminate significant fibrosis (F>=2) (AUROC=0.531) and had only very poor diagnostic accuracies for severe fibrosis (F>=3) (AUROC=0.584) or cirrhosis (F4) (AUROC=0.626). CONCLUSION: AST/ALT ratio is not a good and discriminative index of liver fibrosis in CHC when aminotransferase activities are determinate according to the international recommendations. PMID- 23932708 TI - Substance use over the military-veteran life course: an analysis of a sample of OEF/OIF veterans returning to low-income predominately minority communities. AB - This paper presents an overview of substance use patterns of recent veterans returning to low-income predominately minority communities over four periods of the military-veteran career. Respondent driven sampling (RDS) was used so that unbiased estimates could be obtained for the characteristics of the target population. The majority of participants had used marijuana but no other illegal drugs. In the military, marijuana use was substantially lower and alcohol was the drug of choice; the majority were binge drinkers and nearly half were heavy drinkers. While deployed, alcohol and marijuana use were both lower, though some participants (6%) initiated the misuse of prescription painkillers. After separating from the military and returning to civilian life, heavy drinking was much lower, marijuana use increased, and some veterans misused prescription painkillers (7%). Further research based on these data will examine these distinct periods of substance use, contexts of use, related substance and mental health problems, treatment use and avoidance, and civilian reintegration. PMID- 23932709 TI - The origin of B cell recurrent chromosomal translocations: proximity versus DNA damage. PMID- 23932710 TI - Response to Casellas et al. PMID- 23932711 TI - Competition by the masses. AB - Is the activity of the complex molecular machineries in charge of gene expression saturated in the cell? In this issue, Munding et al. (2013) report that titration of spliceosomal components by abundant ribosomal protein transcripts controls splicing of other genes and contributes to meiosis-specific splicing in budding yeast. PMID- 23932712 TI - Now at the Met: fine art of reversible sulfoxidation. AB - In this issue, Lee et al. (2013) exhibit methionine sulfoxidation in a new light. By bringing together two antagonistic enzymes affecting methionine redox state, the authors demonstrate that methionine oxidation constitutes a reversible, posttranslational regulatory mechanism, akin to protein phosphorylation. PMID- 23932713 TI - Quality control of integral membrane proteins by assembly-dependent membrane integration. AB - Cell-surface multiprotein complexes are synthesized in the endoplasmic reticulum (ER), where they undergo cotranslational membrane integration and assembly. The quality control mechanisms that oversee these processes remain poorly understood. We show that less hydrophobic transmembrane (TM) regions derived from several single-pass TM proteins can enter the ER lumen completely. Once mislocalized, they are recognized by the Hsp70 chaperone BiP. In a detailed analysis for one of these proteins, the alphabetaT cell receptor (alphabetaTCR), we show that unassembled ER-lumenal subunits are rapidly degraded, whereas specific subunit interactions en route to the native receptor promote membrane integration of the less hydrophobic TM segments, thereby stabilizing the protein. For the TCR alpha chain, both complete ER import and subunit assembly depend on the same pivotal residue in its TM region. Thus, membrane integration linked to protein assembly allows cellular quality control of membrane proteins and connects the lumenal ER chaperone machinery to membrane protein biogenesis. PMID- 23932714 TI - Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. AB - Recent studies suggest a hierarchical model in which lineage-determining factors act in a collaborative manner to select and prime cell-specific enhancers, thereby enabling signal-dependent transcription factors to bind and function in a cell-type-specific manner. Consistent with this model, TLR4 signaling primarily regulates macrophage gene expression through a pre-existing enhancer landscape. However, TLR4 signaling also induces priming of ~3,000 enhancer-like regions de novo, enabling visualization of intermediates in enhancer selection and activation. Unexpectedly, we find that enhancer transcription precedes local mono and dimethylation of histone H3 lysine 4 (H3K4me1/2). H3K4 methylation at de novo enhancers is primarily dependent on the histone methyltransferases Mll1, Mll2/4, and Mll3 and is significantly reduced by inhibition of RNA polymerase II elongation. Collectively, these findings suggest an essential role of enhancer transcription in H3K4me1/2 deposition at de novo enhancers that is independent of potential functions of the resulting eRNA transcripts. PMID- 23932716 TI - The long noncoding RNA RMST interacts with SOX2 to regulate neurogenesis. AB - Long noncoding RNAs (lncRNAs) are abundant in the mammalian transcriptome, and many are specifically expressed in the brain. We have identified a group of lncRNAs, including rhabdomyosarcoma 2-associated transcript (RMST), which are indispensable for neurogenesis. Here, we provide mechanistic insight into the role of human RMST in modulating neurogenesis. RMST expression is specific to the brain, regulated by the transcriptional repressor REST, and increases during neuronal differentiation, indicating a role in neurogenesis. RMST physically interacts with SOX2, a transcription factor known to regulate neural fate. RMST and SOX2 coregulate a large pool of downstream genes implicated in neurogenesis. Through RNA interference and genome-wide SOX2 binding studies, we found that RMST is required for the binding of SOX2 to promoter regions of neurogenic transcription factors. These results establish the role of RMST as a transcriptional coregulator of SOX2 and a key player in the regulation of neural stem cell fate. PMID- 23932717 TI - Structure of the PAN3 pseudokinase reveals the basis for interactions with the PAN2 deadenylase and the GW182 proteins. AB - The PAN2-PAN3 deadenylase complex functions in general and miRNA-mediated mRNA degradation and is specifically recruited to miRNA targets by GW182/TNRC6 proteins. We describe the PAN3 adaptor protein crystal structure that, unexpectedly, forms intertwined and asymmetric homodimers. Dimerization is mediated by a coiled coil that links an N-terminal pseudokinase to a C-terminal knob domain. The PAN3 pseudokinase binds ATP, and this function is required for mRNA degradation in vivo. We further identified conserved surfaces required for mRNA degradation, including the binding surface for the PAN2 deadenylase on the knob domain. The most remarkable structural feature is the presence of a tryptophan-binding pocket at the dimer interface, which mediates binding to TNRC6C in human cells. Together, our data reveal the structural basis for the interaction of PAN3 with PAN2 and the recruitment of the PAN2-PAN3 complex to miRNA targets by TNRC6 proteins. PMID- 23932715 TI - Mismatch repair inhibits homeologous recombination via coordinated directional unwinding of trapped DNA structures. AB - Homeologous recombination between divergent DNA sequences is inhibited by DNA mismatch repair. In Escherichia coli, MutS and MutL respond to DNA mismatches within recombination intermediates and prevent strand exchange via an unknown mechanism. Here, using purified proteins and DNA substrates, we find that in addition to mismatches within the heteroduplex region, secondary structures within the displaced single-stranded DNA formed during branch migration within the recombination intermediate are involved in the inhibition. We present a model that explains how higher-order complex formation of MutS, MutL, and DNA blocks branch migration by preventing rotation of the DNA strands within the recombination intermediate. Furthermore, we find that the helicase UvrD is recruited to directionally resolve these trapped intermediates toward DNA substrates. Thus, our results explain on a mechanistic level how the coordinated action between MutS, MutL, and UvrD prevents homeologous recombination and maintains genome stability. PMID- 23932718 TI - Calnexin controls the STAT3-mediated transcriptional response to EGF. AB - Calnexin is a well-characterized transmembrane chaperone involved in the folding of newly synthesized glycoproteins in the lumen of the endoplasmic reticulum (ER). Here, we reveal a previously unrecognized function of calnexin in regulating the transcriptional response downstream of epidermal growth factor receptor (EGF), the product of a well-known human oncogene. We find that cell stimulation with EGF leads to the caspase-8-dependent cleavage of the calnexin cytoplasmic domain, preferentially at ER-mitochondria interaction sites. The released fragment translocates into the nucleus, binds to PIAS3--a natural inhibitor of activated STAT3--and, thus, acts as an enhancer of the STAT3 mediated transcriptional response to EGF. Also, we reveal the unsuspected capacity of calnexin to sense ER stress and, in response, prevent the EGF-induced processing of its cytosolic domain. Thus, cells integrate the health status of the ER to determine the amplitude of their response to EGF. PMID- 23932719 TI - Valsalva maneuver for termination of supraventricular tachycardia. PMID- 23932720 TI - Should neuraminidase inhibitors be prescribed for patients with influenza? PMID- 23932721 TI - Indenoisoquinoline derivatives as topoisomerase I inhibitors that suppress angiogenesis by affecting the HIF signaling pathway. AB - Both Topoisomerase I and angiogenesis factors have caught pharmaceutical chemists' attention in antitumor chemotherapy field. A series of indenoisoquinoline derivatives with high Top I inhibitory from our previous work were evaluated for their anti-angiogenesis property using classic in vitro and vivo models. The results demonstrated that all the compounds could significantly decrease the proliferation of endothelial cells in a concentration-dependent manner. Besides, compound 1 exerted marked inhibition of angiogenesis in vivo and in vitro models. The HIF signaling pathway in HUVECs was affected by compound 1 in a time-dependent manner. These data suggest that the tested compound 1 could serve as promising lead compound for further development and optimization. PMID- 23932722 TI - Risk of herpes/herpes zoster during anti-tumor necrosis factor therapy in patients with rheumatoid arthritis. Systematic review and meta-analysis. AB - BACKGROUND: TNF blockers have demonstrated efficacy in inflammatory rheumatic diseases (IRDs). The drugs are associated with a moderate but definite risk of bacterial infection, but risk of viral infection is not clearly known. OBJECTIVE: To assess the risk of herpes zoster (HZ) reactivation in patients with rheumatoid arthritis (RA) receiving TNF blockers as compared with DMARDs. METHODS: A systematic search of literature up to March 2013 was performed, in MEDLINE, EMBASE, the Cochrane library and abstracts from the ACR and EULAR congresses from 2008 to 2011. Studies were included if they reported the incidence of HZ, respectively, in patients receiving anti-TNF and conventional DMARDs. RESULTS: The literature search identified 3446 articles and 88 congress abstracts; a manual search retrieved seven articles. Finally, 26 articles and nine abstracts were included; six articles and one abstract were of meta-analyses estimating the relative risk of HZ in patients with RA with a total follow-up of 163,077 patient years. From the meta-analyses of data for seven registries, the pooled risk ratio for HZ with TNF blockers was 1.61 [95% CI 1.16-2.23] (P = 0.004). Proportions of severe HZ ranged from 4.9% to 20.9% with TNF-blockers and from 2.0% to 5.5% with conventional DMARDs, in the different registries. CONCLUSIONS: This meta-analysis revealed a significantly increased risk of HZ, up to 61%, in patients with IRD receiving TNF blockers. These data raise the issue of systematic prophylactic treatment with known history of HZ or vaccination without this history. PMID- 23932723 TI - Plasma chemerin levels in rheumatoid arthritis are correlated with disease activity rather than obesity. PMID- 23932724 TI - The lumbar intervertebral disc: from embryonic development to degeneration. AB - Lumbar intervertebral discs (IVDs) are prone to degeneration upon skeletal maturity. In fact, this process could explain approximately 40% of the cases of low back pain in humans. Despite the efficiency of pain-relieving treatments, the scientific community seeks to develop innovative therapeutic approaches that might limit the use of invasive surgical procedures (e.g., spine fusion and arthroplasty). As a prerequisite to the development of these strategies, we must improve our fundamental knowledge regarding IVD pathophysiology. Recently, several studies have demonstrated that there is a singular phenotype associated with Nucleus pulposus (NP) cells, which is distinct from that of articular chondrocytes. In parallel, recent studies concerning the origin and development of NP cells, as well as their role in intervertebral tissue homeostasis, have yielded new insights into the complex mechanisms involved in disc degeneration. This review summarizes our current understanding of IVD physiology and the complex cell-mediated processes that contribute to IVD degeneration. Collectively, these recent advances could inspire the scientific community to explore new biotherapeutic strategies. PMID- 23932725 TI - Axial calcium pyrophosphate dihydrate deposition disease revealed by recurrent sterile spondylodiscitis and epidural abscess. AB - Spondylodiscitis are frequent and clinical challenge for practionners. Axial calcium pyrophosphate dihydrate deposition disease (CPDD) is well known for cervical spine involvement with the crowned dens syndrome but other localisations are probably underdiagnosed in sterile spondylodiscitis. We report a case of recurrent sterile spondylodiscitis with epidural abscess related to CPDD proved by vertebral percutaneous needle biopsy with rapid favourable course under colchicine therapy. Axial CPDD could mimic septic spondylodiscitis with epidural abscess on MRI. Sterile spondylodiscitis are probably underdiagnosed forms of microcrystalline disease. Investigations of the presence of microcrystals should be systematically undertaken with tamponed formalin fixed biopsies. If axial CPDD is suspected, colchicine therapy could be a good therapeutic test and would avoid unnecessary antibiotic treatment. PMID- 23932726 TI - Frequency of CYP2C9 polymorphisms in Polynesian people and potential relevance to management of gout with benzbromarone. AB - OBJECTIVES: Gout is a major health problem in Polynesians and allopurinol, the drug of choice for the management gout, appears to be less effective in Polynesian patients. The uricosuric drug benzbromarone is an alternative treatment but CYP2C9 poor metabolisers (PMs) may be at a heightened risk of benzbromarone-induced hepatotoxicity. The objectives of this study were to determine the frequency of the PM alleles CYP2C9*2 and CYP2C9*3 in New Zealand (NZ) Caucasian and Polynesian gout cohorts; and then to test for novel CYP2C9 polymorphisms in Polynesians. METHODS: Eight hundred and fifty-two Caucasians (537 controls, 315 gout patients) and 1072 Maori and Pacific Island (Polynesian) people (620 controls, 452 gout patients) were genotyped for CYP2C9*2 and CYP2C9*3. Forty Polynesians were screened for novel CYP2C9 polymorphisms using whole genome sequencing. RESULTS: Frequency of CYP2C9 PM alleles was significantly higher in Caucasians compared to Polynesians (CYP2C9*2: 13.5% versus 3.1%; CYP2C9*3: 5.5% versus 1.6%, P<1.2E-11). Within Polynesians, CYP2C9 PM alleles were rarer in Western Polynesians (Samoa, Tonga) than Eastern Polynesians (NZ and Cook Island Maori; CYP2C9*2: 0.6% versus 2.5%; CYP2C9*3: 0.4% versus 2.0%; P<0.03). A total of 152 SNPs were found by sequencing. None of these variants were predicted by in silico analysis to significantly impact on CYP2C9 expression or activity. CONCLUSION: Prospective CYP2C9 genotyping of Caucasian gout patients may be warranted for benzbromarone, whereas the low frequencies of CYP2C9 PM alleles in Polynesians suggests that the CYP2C9 polymorphism may be of little or no relevance to benzbromarone prescribing in this population. PMID- 23932727 TI - Validity and role of vertebral fracture assessment in detecting prevalent vertebral fracture in patients with rheumatoid arthritis. AB - OBJECTIVES: We aimed to identify the validity and the role of vertebral fracture assessment (VFA) for the diagnosis of prevalent vertebral fracture (VF) in rheumatoid arthritis (RA) patients. METHODS: Total of 100 women with RA who were 50 years or older were enrolled. All participants underwent lateral imaging of the thoraco-lumbar spine by radiography and VFA. All radiographs were analyzed by two radiologists. Discrepancies between radiologists for spine radiography were resolved by consensus and these results were defined as the reference standard. VFA interpretation was done independently by two nuclear medicine physicians. Fracture defined by VFA measure was done only when two physicians both independently reported fracture. The inter-rater agreement for the detection of VF on VFA was evaluated by kappa statistics. We calculated percent values for the diagnostic validity of VFA in detecting VF in the 100 women as a whole and according to the presence of previous fracture or back pain. RESULTS: The prevalence of VF identified by spine radiography was 47%. Inter-rater agreement of VFA per vertebra by two VFA readers showed moderate agreement (kappa=0.60). The sensitivity, PPV, specificity and NPV of VFA compared to spine radiography were 57.3%, 30.9%, 89.1% and 96.1% for total vertebrae. All patients with history of previous VF (n=13) were visualized with VFA with 100% sensitivity but it has 64.7% sensitivity and 79.3% specificity in patients without previous VF (n=87). CONCLUSION: VFA is most useful to identify patients without VF because of its high specificity and NPV in all spine level. PMID- 23932728 TI - Ivory vertebra and systemic mastocytosis. Comments on the article by Frenzel et al. PMID- 23932729 TI - Clinical and molecular mechanisms favoring cancer initiation and progression in diabetic patients. AB - Cancer incidence and mortality are higher among diabetic patients. This review examines the mechanisms, both general and site-specific, for this increase. Hyperglycemia and hyperinsulinemia, which are the major abnormalities that characterize diabetes, can promote cancer via both independent and synergic mechanisms. Insulin is both a metabolic hormone and a growth factor that promotes cell proliferation. When insulin levels are increased due to either insulin resistance or insulin treatment, their mitogenic effect is more marked in malignant cells that frequently overexpress the insulin receptor and, more specifically, its A isoform that has predominant mitogenic activity. Hyperglycemia provides energy for malignant cell proliferation and, via the peculiar energy utilization of cancer cells, favors cancer growth and neoangiogenesis. Additionally, diabetes-associated obesity has cancer-promoting effects due to mechanisms that are specific to excess fat cells (such as increased peripheral estrogens, increased pro-mitogen cytokines and growth factors). Also fat-associated chronic inflammation can favor cancer via the cell damage caused by reactive oxygen species (ROS) and via the production of inflammatory cytokines and transcription factors that stimulate cancer growth and invasiveness. Finally, the multiple drugs involved in the treatment of diabetes can also play a role. Diabetes-associated comorbidities, tissue-specific inflammation, and organ-specific dysfunctions can explain why the risk of cancer can differ by tissue type among diabetic patients. The increased risk of cancer related mortality is moderate among individual patients with diabetes (RR = 1.25), but the pandemic nature of the disease means that a considerable number of lives could be spared through a better understanding of the factors associating diabetes and cancer. PMID- 23932730 TI - Toxoplasma gondii in free-ranging wild small felids from Brazil: molecular detection and genotypic characterization. AB - Brazil harbors the largest number of wild Neotropical felid species, with ten of the twelve species recorded in the American continent. Although these animals are considered to be definitive hosts for Toxoplasma gondii, there are few descriptions of the parasite in these species. Here, we performed a molecular detection of T. gondii by amplification of the marker ITS-1 from tissue samples obtained from 90 free-ranging wild small Neotropical felids from Rio Grande do Sul - Brazil. Of the sampled animals, 34.4% (n=31) were positive including the species Puma yagouaroundi - jaguarondi (9/22), Leopardus geoffroyi - Geoffroy's cat (6/22), Leopardus tigrinus - oncilla (8/28), Leopardus wiedii - margay (6/10), Leopardus pardalis - ocelot (1/1) and Leopardus colocolo - Pampas cat (1/7). Toxoplasma DNA was detected with a frequency of 14.6% (63/433) in primary samples of tongue (16/56), brain (8/43), skeletal muscle (15/83), heart (7/63), diaphragm (3/56), vitreous humor (2/44), eye muscle (6/44) and eyeball (6/44). Multilocus PCR-RFLP genotyping of eleven small Neotropical felids using the molecular markers SAG1, 5'3'SAG2, alt. SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, Apico and CS3 allowed the partial characterization of eight genotypes. We fully characterized two new genotypes that have not been described previously in Brazil (Lw#31Tn from L. wiedii and Py#21Sm from P. yagouaroundi) and one genotype Py#56Br from P. yagouaroundi that has been described previously in isolates from cats, dogs and capybaras from Sao Paulo state. This study constitutes the first detection and genotypic characterization of T. gondii in free-ranging felids in Brazil, demonstrating the occurrence of the parasite in wild populations and suggesting its potential transmissibility to humans and other domestic and wild animals. PMID- 23932731 TI - Diseases associated with human papillomavirus infection. AB - Human papillomaviruses (HPVs) are ubiquitous, well adapted to their host and cleverly sequestered away from immune responses. HPV infections can be productive, subclinical or latent in both skin and mucosa. The causal association of HPV with cervical cancer, and increasingly with rising numbers of squamous cell carcinomas at other sites in both men and women, is increasingly recognised, while the morbidity of cutaneous HPV lesions, particularly in the immunosuppressed population is also significant. This chapter sets out the range of infections and clinical manifestations of the consequences of infection and its persistence and describes why HPVs are both highly effective pathogens and carcinogens, challenging to eliminate. PMID- 23932732 TI - Introduction to the special issue: The global state of the ocean; interactions between stresses, impacts and some potential solutions. Synthesis papers from the International Programme on the State of the Ocean 2011 and 2012 workshops. PMID- 23932733 TI - Mannitol in Amanita muscaria--an osmotic blood-brain barrier disruptor enhancing its hallucinogenic action? AB - Hypothesis have been made that relatively high level of mannitol present in the tissues of fly agaric (Amanita muscaria) enables more efficient transportation of these active substances into the brain and thus enhance their total activity. It may have been supported by the fact that hallucinogenic effect after A. muscaria consumption is greater than after ingestion of an active substance quantity which the eaten fungi dose contain. PMID- 23932734 TI - Gradual and stepwise increase of blood pressure in hemorrhagic shock: Mimicking ischemic post-conditioning. AB - Hemorrhagic shock, and subsequent resuscitation leads to global ischemia/reperfusion injury. It may result in multiple organ injury and death. Ischemic post-conditioning has been suggested to reduce organ injury. It may lead to gradual increase in tissue oxygen delivery and tissue acidosis may be reduced gradually. Gradual increase of blood pressure or blood flow in ischemic organs has been reported to decrease tissue injury. We propose that gradual and stepwise increase of blood pressure may decrease tissue injury and mortality in hemorrhagic shock by mimicking ischemic post-conditioning. PMID- 23932735 TI - Administration of aluminium to neonatal mice in vaccine-relevant amounts is associated with adverse long term neurological outcomes. AB - Our previous ecological studies of autism spectrum disorder (ASD) has demonstrated a correlation between increasing ASD rates and aluminium (Al) adjuvants in common use in paediatric vaccines in several Western countries. The correlation between ASD rate and Al adjuvant amounts appears to be dose-dependent and satisfies 8 of 9 Hill criteria for causality. We have now sought to provide an animal model to explore potential behavioural phenotypes and central nervous system (CNS) alterations using s.c. injections of Al hydroxide in early postnatal CD-1 mice of both sexes. Injections of a "high" and "low" Al adjuvant levels were designed to correlate to either the U.S. or Scandinavian paediatric vaccine schedules vs. control saline-injected mice. Both male and female mice in the "high Al" group showed significant weight gains following treatment up to sacrifice at 6 months of age. Male mice in the "high Al" group showed significant changes in light-dark box tests and in various measures of behaviour in an open field. Female mice showed significant changes in the light-dark box at both doses, but no significant changes in open field behaviours. These current data implicate Al injected in early postnatal life in some CNS alterations that may be relevant for a better understanding of the aetiology of ASD. PMID- 23932737 TI - Development and assessment of national performance indicators for infection prevention and control and antimicrobial stewardship in European long-term care facilities. AB - BACKGROUND: Healthcare-associated infections in long-term care facilities (LTCFs) are of increasing importance. AIM: To develop consensus national performance indicators (NPIs) for infection control (ICPI) and antimicrobial stewardship (ASPI) in LTCFs, and assess the performance of 32 European countries against these NPIs. METHODS: Previously established European standards were the basis for consensus and the same iterative approach with national representatives from the 32 countries. A World Health Organization scoring system recorded how close each country was to implementing each standard. FINDINGS: The 42 agreed component indicators were grouped into six NPI categories: 'national programme', 'guidelines', 'expert advice', 'IC structure' (not present in the ASPI), 'surveillance' and 'composite'. 'Guidelines' scored the highest mean total possible score (60%, range 20-100%), followed by 'composite' (53%, range 30 100%), 'expert advice' (48%, range 20-100%), 'surveillance' (47%, range 20-83%), 'national programme' (42%, range 20-100%) and 'IC structure' (39%, range 20 100%). Although several scores were low, some countries were able to implement all NPIs, indicating that this was feasible. Most NPIs were very significantly related, indicating that they were considered to be important by the countries. 'Guidelines' and 'IC structure' were significantly related to European region (P <= 0.05). Accreditation/inspection was not evident in seven (22%) countries, nine (28%) countries had accreditation/inspection that included IC assessments, and seven (22%) countries had accreditation/inspection that included IC and antimicrobial stewardship assessments. Multi-variable analysis found that only the NPI and the ICPI 'expert advice' were associated with accreditation/inspection which included IC and antimicrobial stewardship. CONCLUSION: The identified gaps represent significant potential patient safety issues. The NPIs should serve as a basis for monitoring improvements over the coming years. PMID- 23932736 TI - The bipolar disorder prodrome revisited: Is there a symptomatic pattern? AB - OBJECTIVES: To assess the phenomenology and course of pre-(hypo)manic and pre depressed prodromal symptoms, including mood swings, as precursors of bipolar disorder (BD) in a German multi-center study. METHODS: Semi-structured interviews [Bipolar Prodrome Symptom Scale-Retrospective (BPSS-R); Semi-structured Interview for Mood Swings] were administered to patients within 8 years of BD (BD I, BD II) onset. RESULTS: Forty two outpatients were included (40.5% male, mean age 35.1+/ 10.0 years, illness onset at 30.5+/-9.5 years). Feeling extremely energetic (85.7%), racing thoughts (78.6%), physical agitation (76.2%), overtalkativeness (71.4%), and low sleep requirement (71.4%) occurred most frequently prior to the first (hypo)manic episode, whereas depressed mood (83.0%), reduced vitality (81.0%), physical exhaustion (78.6%), tiredness (76.2%), and insomnia (66.7%) preceded pre-depressively. Mood lability (p=.006), odd ideas (p=.003) and the psychosis index score (p=.003) differed significantly in prevalence depending on the episodes' mood. Extremely energetic (p=.046), overtalkativeness (p<.001), and racing thoughts (p=.013) lasted significantly longer prior to depression. Neither severity nor frequency of prodromal symptoms differed significantly. Most of the symptoms emerged during the proximal prodromal phase. Links between mood swings and subsequent BD were found. LIMITATIONS: Symptoms were evaluated retrospectively with self-reporting tools in bipolar patients from academic treatment settings without comparison to clinical controls. CONCLUSIONS: Not only specific depressive or manic but also general symptoms occurred prior to both affective episodes. The pre-depressive prodrome lasted longer than the pre-manic one, but severity and frequency did not differ significantly. Mood swings and disturbed diurnal rhythm occurred prior to both episodes as early signs of BD. PMID- 23932738 TI - 'Twin2twin' an innovative method of empowering midwives to strengthen their professional midwifery organisations. AB - BACKGROUND: midwives need professional support from a national midwifery organisation to be able to provide the services that are by regulatory mechanisms and accreditation expected of them. Not all midwives in the world are united in a professional organisation. The aim of this project was to strengthen the midwifery organisations of Sierra Leone and the Netherlands. During the process of the project it was realised that the development of a platform of exchange at organisational level would be enhanced by introducing personal exchange between individual midwives. In response to this new insight the original project plan was adjusted by incorporating the twin2twin method. METHOD: twin2twin is a feminist methodology of mutual exchange between twenty pairs of midwives from different organisations (in this case Sierra Leone and the Netherlands). The method can be distinguished by 10 specific steps. It was developed, used and (re)evaluated through focus group discussions, storytelling and written evaluations. FINDINGS: twinning of organisations was strengthened by adding a human component to the process. With the use of the 'twin2twin' method, midwives were encouraged to invested in a professional and personal bond with their 'twin sister'. This bond was independent and went beyond the relatively short four year project period. Through personal engagement and mutual exchange of knowledge and skills, midwives empowered each other to build and strengthen their midwifery organisations both in Sierra Leone and the Netherlands. (Empowerment refers to the expansion in people's ability to make strategic life choices in a context where this ability was previously denied to them (Narayan, 2005); organisational empowerment includes processes and structures that enhance members' skills and provides them with the mutual support necessary to effect community level change (Zimmerman, 1995).). CONCLUSION AND IMPLICATIONS FOR PRACTICE: despite challenges we are convinced that twin2twin can be of additional benefit for the success of other projects involved in strengthening midwifery organisations in the long term. It can be used independently or alongside other forms of (co)development not only in midwifery but also in other professions. PMID- 23932739 TI - The hardware and software implications of hospital birth room design: a midwifery perspective. AB - OBJECTIVE: to explore the impacts of physical and aesthetic design of hospital birth rooms on midwives. BACKGROUND: the design of a workplace, including architecture, equipment, furnishings and aesthetics, can influence the experience and performance of staff. Some research has explored the effects of workplace design in health care environments but very little research has examined the impact of design on midwives working in hospital birth rooms. METHODS: a video ethnographic study was undertaken and the labours of six women cared for by midwives were filmed. Filming took place in one birth centre and two labour wards within two Australian hospitals. Subsequently, eight midwives participated in video-reflexive interviews whilst viewing the filmed labour of the woman for whom they provided care. Thematic analysis of the midwife interviews was undertaken. FINDINGS: midwives were strongly affected by the design of the birth room. Four major themes were identified: finding a space amongst congestion and clutter; trying to work underwater; creating ambience in a clinical space and being equipped for flexible practice. Aesthetic features, room layout and the design of equipment and fixtures all impacted on the midwives and their practice in both birth centre and labour ward settings. CONCLUSION AND IMPLICATIONS FOR PRACTICE: the current design of many hospital birth rooms challenges the provision of effective midwifery practice. Changes to the design and aesthetics of the hospital birth room may engender safer, more comfortable and more effective midwifery practice. PMID- 23932741 TI - Detection of extended-spectrum beta-lactamases and AmpC beta-lactamases in Salmonella enterica isolates from patients in Denmark during 2008-2010. PMID- 23932740 TI - Epidemiology, demographics, and outcomes of craniomaxillofacial gunshot wounds in a level I trauma center. AB - BACKGROUND: Gunshot injuries to the craniomaxillofacial region are a challenge to the trauma and reconstructive surgeon. Although management of these injuries has been standardized and early rather than late intervention is advocated, the patient characteristics before, during, and after have been poorly elucidated. METHODS: A prospectively maintained Level I trauma center database was queried as to gunshot wounds of the craniomaxillofacial skeleton. Over a five-year period (2007-2011), 168 patients were identified with these injuries. Charts were reviewed as to demographics, presentations, and outcomes and these were tested for significant relationships with hospital length of stay, numbers and types of procedures, morbidity, and mortality. RESULTS: Gunshot wounds to the craniofacial skeleton resulted in 71 deaths in this patient population. Those that died were significantly older, presented with a lower GCS, had a shorter LOS, and a higher INR than those that lived. Subgroup analysis of mechanism demonstrated mortality was more likely to occur as a result of self-inflicted injury in whites and due to assault in the African-American population. CONCLUSIONS: Data gathered from this study disputes some commonly held beliefs regarding the epidemiology of gunshot injuries and should allow for better characterization of which outcomes are consistent with which presentations. PMID- 23932742 TI - Conceptual and perceptuo-motor action control and action recognition. PMID- 23932743 TI - A randomized controlled trial of the effectiveness of educating parents about distraction to decrease postoperative pain in children at home after tonsillectomy. AB - Today, parents are more involved with postoperative pain management, because children are discharged as early as possible after surgery. The purpose of this randomized controlled trial was to determine the effectiveness of educating parents to provide distraction in addition to pharmacologic pain management in decreasing postoperative pain at home for children ages 3 to 7 years. Ninety three children aged 3-7 years having tonsillectomy at Landspitali, The National University Hospital of Iceland, and their parents were randomized to one of two intervention groups. The interventions were pharmacologic pain management education (control group) and pharmacologic pain management education with distraction (experimental group). Pain was measured by parent's report of pain behavior during the evening on postoperative days 1 and 2 and child's report of pain intensity on eight time points on postoperative days 1 and 2. Sixty-nine children had complete data. The results from RM-ANCOVA showed that when adjusting for pain intensity in the morning on postoperative day 1 that educating parents about distraction in addition to educating them about pain medication management decreases mean pain behavior scores (p < .001). There was no difference in pain intensity between the groups using RM-ANCOVA. However, there was association between pain intensity in the morning on postoperative day 1 and follow-up pain intensity (p < .001). The results from this study support the importance of educating parents of children having tonsillectomy about distraction in addition to educating them about pain medication management. PMID- 23932744 TI - Supplementation of medium with diammonium hydrogen phosphate enhanced the D lactate dehydrogenase levels leading to increased D-lactic acid productivity. AB - The production of D-lactic acid by Lactobacillus lactis RM2-24 was investigated using modified media to increase the efficiency of the fermentation process. The results indicated that the addition of 5 g/l peptone and 1 g/l (NH4)2HPO4 enhanced D-lactic acid production by 32%, as compared to that obtained from non supplemented media, with a productivity of 3.0 g/l/h. Lactate dehydrogenase (LDH) expression profile in these different media was studied which resulted in appearance of additional LDH isoform produced by cells when they were grown in HSYE supplemented with (NH4)2HPO4. The additional LDH appears to be L-LDH contributing to production of L-lactic acid in the fermented broth. This is totally new information in the lactic acid fermentation and could be very useful to industries engaged in D-lactic acid production. PMID- 23932745 TI - A clinician's guide to factors affecting withdrawal times for equine therapeutic medications. AB - Equine forensic science can now detect concentrations down to 25 femtograms/mL (parts per quadrillion, ppq) or less in blood and urine. As such, horsemen are increasingly at risk of inadvertent 'positives' due to therapeutic medication 'overages' or trace identifications of dietary or environmental substances. Reviewed here are the factors which determine detection times and 'withdrawal times' for substances administered to horses. Withdrawal times are affected by many factors, including dose, formulation, route and frequency of administration, bioavailability, plasma half-life, sensitivity of the analytical process, the testing matrix (plasma, urine, or other), and the environmental presence and/or persistence of administered substances. Of these factors only dose is known precisely. For any given administration, horse-to-horse differences in the volumes of distribution, systemic clearance, and terminal plasma elimination half life of substances are major and totally uncontrollable factors driving horse-to horse variability in withdrawal times. A further complication is that chemically stable medications administered to horses and eliminated in the urine inevitably become part of the environment of the horse. The presence of these substances in the equine environment is increasingly giving rise to trace identifications long after nominal administration of these substances has ceased. Because of the unknown and uncontrollable horse-to-horse variability in medication pharmacokinetics, any therapeutic medication administration to a horse by definition includes the possibility of an inadvertent medication overage. As such, the caveat that there are no guarantees in life most assuredly applies to advisories concerning equine therapeutic medication withdrawal times. PMID- 23932746 TI - Small intestinal cancers among adults in an Egyptian district: a clinicopathological study using a population-based cancer registry. AB - BACKGROUND: Small intestinal cancers (SICs) are very rare all over the world and little is known about them in Egypt. METHODS: This a retrospective study. Between 2000 and 2002, 30 cases with SICs were identified in the Gharbiah population based cancer registry (GPBCR); 17 cases of whom were treated at Tanta Cancer Center (TCC). RESULTS: The median age was 51 years with female predominance. The duodenum was the commonest site (43%) followed by the ileum then the jejunum. Adenocarcinoma (AC), carcinoids, gastrointestinal stromal tumors (GISTs), lymphoma and sarcoma represented 50%, 10%, 17%, 13% and 10% respectively. Abdominal pain was the commonest symptom and localized disease was the commonest presentation. Surgery, chemotherapy and radiotherapy were employed in 65%, 35% and 0% of patients, respectively. The median overall survival and progression free survival (OS, PFS) were 18 and 15 months (95% CI: 10.4-25.6 and 3.6-26.4), respectively. AC had inferior OS and PFS to other histologies (p = 0.08 and 0.12, respectively). Also, duodenum subsite was inferior in OS and PFS to other sites (p = 0.25 and 0.35, respectively). CONCLUSIONS: SICs in Gharbiah, Egypt are characterized by predominance of female gender and adenocarcinoma histology. One year survival is 64% with a poor outcome for adenocarcinoma and duodenal subsite. PMID- 23932747 TI - CCAAT/enhancer binding protein alpha gene expression in Egyptian patients with acute myeloid leukemia. AB - BACKGROUND: Transcription factors play a crucial role in myeloid differentiation and lineage determination. Tumor suppressor protein C/EBPa is a key regulator of granulocytic differentiation whose functional inactivation has become a pathophysiological signature of myeloid leukemia. Given the role that CCAAT/enhancer binding protein alpha (C/EBP alpha) plays in myelopoiesis, we anticipated that their expression might be disrupted in myeloid neoplasms. PURPOSE: To estimate the expression of C/EBPalpha mRNA in patients with acute myeloid leukemia and correlate its expression with the pathogenesis of the disease. PATIENTS AND METHODS: Forty AML patients and 20 age and sex matched healthy controls were included in the study. Blood samples of patients and controls were analyzed for CEBPalpha mRNA expression by quantitative RT-real time PCR using TaqMan technology & DeltaDeltaCt method for calculation of gene expression. RESULTS: Twenty-nine (72.5%) patients out of the 40 showed low expression levels of CEBPalpha mRNA below the cutoff value with median of 0.19 (range:0-0.87). While eleven (27.5%) patients out of the 40 showed higher expression levels of CEBPalpha above the cutoff value with median of 1.52 (range:1.07-2). Seven patients out of the 11 showed higher expression levels of CEBPalpha mRNA belong to the M3 subtype of AML harboring the t(15;17) PML-RARa translocation. CONCLUSION: We conclude that the majority of the AML patients analyzed, express low levels of C/EBPa mRNA. However, a subset of patients represented by the M3 subtype, express higher levels of C/EBPa. PMID- 23932748 TI - Groin recurrence in patients with early vulvar cancer following superficial inguinal node dissection. AB - OBJECTIVE: To investigate the causes of groin recurrence in patients with vulval cancer who previously had negative nodes following superficial inguinal node dissection (SIND). MATERIAL AND METHODS: Forty-one patients with squamous cell carcinoma of the vulva (stage I or II) were operated upon. The primary treatment was wide local excision with 2 cm safety margin and superficial inguinal lymphadenectomy. Six patients had ipsilateral and one patient had bilateral groin recurrence. Those patients were subjected to deep inguinal node dissection (one patient required bilateral node dissection). RESULTS: The mean age at time of diagnosis was 59 years (range 51-68). The median follow-up period for all patients was 63 months (range 24-71) and that of the recurrent cases was 20 months (range 12-38). The mean depth of invasion of the recurrent cases was 5.5mm (range 5-5.9 mm) and the mean diameter of the primary tumor in recurrent cases was 3.8 cm (range 3-4.5 cm). All recurrent cases had a high grade of the primary tumor. The median interval to recurrence was 21 months (range 12-57). The groin recurrence rate after negative SIND was 17% (7/41 patients).The mean number of nodes resected per groin was eight (range 1-17). The nodes ranged in size from 0.2 to 4.0 cm. CONCLUSION: Carcinoma of the vulva with the following criteria (size of tumor is greater than 3 cm, depth of invasion greater than 5mm, and high grade tumors) is at high risk of recurrence. PMID- 23932749 TI - Angiomyolipoma of the kidney: clinicopathological and immunohistochemical study. AB - OVERVIEW: Although angiomyolipoma (AML) is a relatively rare entity, it is the most common benign mesenchymal neoplasm of the kidney. THE AIM OF THIS STUDY: To highlight the clinicopathological characteristics of AML and to assess the role of Human Melanoma Black-45 (HMB-45), Melan-A, smooth muscle actin (SMA), S-100 and cytokeratin in its diagnosis. MATERIALS AND METHODS: The study included 15 cases of AML. Clinical and radiological data were retrieved from the archival files and all cases were subjected to a histopathological evaluation as well as immunohistochemical staining for HMB-45, Melan-A, SMA, S-100, and cytokeratin. RESULTS: AML was more common in females (female:male = 4:1), the mean age was 53.9 +/- 6.45 years. 60% of patients were symptomatic while the remaining 40% were asymptomatic. A statistically significant relationship was found between size of the tumor and the presence of the symptoms (P = 0.02). Patients with tumor size less than 4 cm were asymptomatic, while those with tumor size larger than 4 cm had different symptoms. Thirteen cases were classic AML, while 2 cases were epithelioid AML. Classic AML demonstrated admixture of fatty tissue, thick walled blood vessels, and smooth muscle, while epithelioid AML was composed mainly of epithelioid cells and contained no fat. HMB-45 was positive in all cases of AML (100%), Melan-A was positive in 13/15 (87%) while SMA was positive in 11/15 (73%) of AML with variable staining intensity. All cases of AML were negative for S-100 and cytokeratin. CONCLUSION: AMLs have characteristic clinicopathological and immunohistochemical features and their recognition is crucial for proper diagnosis and treatment. PMID- 23932750 TI - The prognostic significance of minimal residual disease in adult Egyptian patients with precursor acute lymphoblastic leukemia. AB - BACKGROUND: Minimal residual disease (MRD) studies in adult acute lymphoblastic leukemia (ALL) give highly significant prognostic information superior to other standard criteria as age, gender and total leucocytic count (TLC) in distinguishing patients at high and low risk of relapse. OBJECTIVES: We aimed to determine the value of MRD monitoring by flowcytometry (FCM) in predicting outcome in adult Precursor ALL patients. PATIENTS AND METHODS: Bone marrow (BM) samples were analyzed by 4-color FCM collected at diagnosis and after induction therapy (MRD1) to correlate MRD positivity with disease free survival (DFS) and overall survival (OS). RESULTS: Study included 57 adult ALL patients (44 males and 13 females) with a median age of 22 years (18-49). DFS showed no significant difference with age, gender and initial TLC (p=0.838, 0.888 and 0.743, respectively). Cumulative DFS at 2 years was 34% for B-lineage ALL (n: 35) and 57% for T-lineage ALL (n: 18) (p = 0.057). Cumulative DFS at 2 years was 7% for MRD1 positive (high risk, HR) versus 57% for MRD1 negative patients (Low risk, LR) (p < 0.001). Cumulative DFS at 2 years was 29% for HR patients (n: 26) versus 55% for LR (n: 27) according to GMALL classification (p = 0.064). Cumulative OS did not differ according to age, gender and TLC (p = 0.526, 0.594 and 0.513, respectively). Cumulative OS at 2 years was 36% for B ALL (n: 39) versus 77% for TALL (n: 18) (p = 0.016) and was 49% for Philadelphia chromosome (Ph) negative patients versus 0% for Ph-positive patients (p < 0.001). Regarding MRD1, OS at 2 years was 18% for MRD1 HR (n: 17) versus 65% for MRD1 LR (n: 38) (p < 0.001). OS was 35% for high-risk patients (n: 30) and 62% for low-risk patients (n: 27) classified according to GMALL risk stratification (p = 0.017). CONCLUSION: MRD by FCM is a strong independent predictor of outcome in terms of DFS and OS and is a powerful informative parameter in guiding individual treatment in ALL patients. PMID- 23932751 TI - Transarterial chemoembolization for the treatment of hepatocellular carcinoma: a single center experience including 221 patients. AB - BACKGROUND: Hepatocelluar carcinoma (HCC) is a major health problem in Egypt as well as in many countries. Transarterial chemoemoblization (TACE) is a treatment modality applicable to locally advanced HCC beyond surgery or ablative therapies and is associated with survival improvements. The aim of this study was to assess the outcomes of TACE in our center over the past four years. METHODS: This is a retrospective cohort study that included 221 patients with locally advanced HCC treated with TACE in a single center between the years 2007 and 2010. The median age was 57 years with male predominance. Liver cirrhosis, viral hepatitis and Bilharziasis were encountered in 64%, 31% and 8% of patients, respectively. Abdominal pain was the most common presenting symptom (67%). Most cases were diagnosed based on radiology (57%) with a TNM stage I or II (73%) and a median AFP value of 150 ng/mL. RESULTS: 221 patients received 440 cycles of TACE with a median of 2 cycles per patient. Cisplatin and doxorubicin (50mg per cycle, each) were the most commonly used drugs. Impaired liver function was the most common toxicity. Liver cell failure occurred in 17% of patients. An objective tumor response was achieved in 44% of cases. The median overall survival (OS) was 16 months (95% CI, 13-19 months) and the median progression free survival (PFS) was 6 months (95% CI, 4.3-7.8 months). Responding patients, Child-Pugh class A and patients receiving standard doses of chemotherapy had a significantly better OS than their counterparts. Only Child-Pugh class A was associated with significantly longer PFS (p < 0.001). CONCLUSION: TACE produces reasonable responses and fair survival rates in locally advanced HCC but with noticeable toxicities. Proper patients' selection and prompt liver support are mandates for improving TACE outcomes. PMID- 23932752 TI - Comparison of abdominoperineal resection and low anterior resection in lower and middle rectal cancer. AB - INTRODUCTION: This study aimed to investigate local control and survival rates following abdominoperineal resection (APR) compared with low anterior resection (LAR) in lower and middle rectal cancer. METHODS: In this retrospective study, 153 patients with newly histologically proven rectal adenocarcinoma located at low and middle third that were treated between 2004 and 2010 at a tertiary hospital. The tumors were pathologically staged according to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system. Surgery was applied for 138 (90%) of the patients, of which 96 (70%) underwent LAR and 42 were (30%) treated with APR. Total mesorectal excision was performed for all patients. In addition, 125 patients (82%) received concurrent (neoadjuvant, adjuvant or palliative) pelvic chemoradiation, and 134 patients (88%) received neoadjuvant, adjuvant or concurrent chemotherapy. Patients' follow-up ranged from 4 to 156 (median 37) months. RESULTS: Of 153 patients, 89 were men and 64 were women with a median age of 57 years. One patient (0.7%) was stage 0, 15 (9.8%) stage I, 63 (41.2%) stage II, 51 (33.3%) stage III and 23 (15%) stage IV. There was a significant difference between LAR and APR in terms of tumor distance from anal verge, disease stage and combined modality therapy used. However, there was no significant difference regarding 5-year local control, disease free and overall survival rates between LAR and APR. CONCLUSION: LAR can provide comparable local control, disease free and overall survival rates compared with APR in eligible patients with lower and middle rectal cancer. PMID- 23932753 TI - Primary nodular lymphocyte predominant Hodgkin lymphoma of the palate: a rare incidence which was also associated with progressive transformation of germinal centres of cervical lymph node. AB - Primary manifestation of nodular lymphocyte predominant Hodgkin lymphoma in oral cavity is very rare. We are describing such a case which was associated with progressive transformation of germinal centres in a cervical lymph node. PMID- 23932754 TI - A trial of indication based prescribing of antihypertensive medications during computerized order entry to improve problem list documentation. AB - BACKGROUND: Maintenance of problem lists in electronic medical records is required for the meaningful use incentive and by the Joint Commission. Linking indication with prescribed medications using computerized physician order entry (CPOE) can improve problem list documentation. Prescribing of antihypertensive medications is an excellent target for interventions to improve indication-based prescribing because antihypertensive medications often have multiple indications and are frequently prescribed. OBJECTIVE: To measure the accuracy and completeness of electronic problem list additions using indication-based prescribing of antihypertensives. DESIGN: Clinical decision support (CDS) was implemented so that orders of antihypertensives prompted ordering physicians to select from problem list additions indicated by that medication. An observational analysis of 1000 alerts was performed to determine the accuracy of physicians' selections. RESULTS: At least one accurate problem was placed 57.5% of the time. Inaccurate problems were placed 4.8% of the time. Accuracy was lower in medications with multiple indications and the likelihood of omitted problems was higher compared to medications whose only indication was hypertension. Attending physicians outperformed other clinicians. There was somewhat lower accuracy for inpatients compared to outpatients. CONCLUSION: CDS using indication-based prescribing of antihypertensives produced accurate problem placement roughly two thirds of time with fewer than 5% inaccurate problems placed. Performance of alerts was sensitive to the number of potential indications of the medication and attendings vs. other clinicians prescribing. Indication-based prescribing during CPOE can be used for problem list maintenance, but requires optimization. PMID- 23932755 TI - The trends in EMR and CPOE adoption in Japan under the national strategy. AB - PURPOSE: We evaluate the status of health information system (HIS) adoption (In this paper, "HIS" means electronic medical record system (EMR) and computerized provider order entry system (CPOE)). We also evaluate the affect of the policies of Japanese government. METHODS: The status of HIS adoption in Japan from 2002 to 2011 was investigated using reports from complete surveys of all medical institutions conducted by the Ministry of Health, Labour and Welfare (MHLW). HIS related budgets invested by the Japanese government from 2000 to 2008 were surveyed mainly using literatures and administrative documents of the Japanese government (MHLW and Ministry of Economy, Trade and Industry). RESULTS: The rates of HIS adoption in Japan in 2011 were: 20.9% for the rate of EMR adoption in clinics, 20.1% for the rate of EMR adoption and 36.6% for the rate of CPOE adoption in hospitals. In hospitals, the rate of EMR and CPOE adoption were 51.5% and 78.6% in 822 large hospitals (400 or more beds), 27.3% and 52.1% in 1832 medium hospitals (200-399 beds), and 13.5% and 26.0% in 5951 small hospitals (less than 200 beds), respectively. Japan has a large number of medical institutions (99,547 clinics and 8605 hospitals) with a low rate of EMR adoption in clinics and a high rate of HIS adoption in hospitals. The national budget to expand HIS use was implemented for medium and large hospitals mainly. The policy target of New IT Reform Strategy was not achieved. CONCLUSION: The rate of HIS adoption in Japanese medium and large hospitals is high compared to small hospitals and clinics, and this is attributable to the fact that the Japanese government placed the target for HIS adoption on key hospitals with a large number of beds and concentrated budget investment in those hospitals. Besides, legal approval of EMR and the introduction of Diagnostic Procedure Combination system facilitated EMR adoption. There is less financial support for small hospitals than medium and large hospitals. The low rate of EMR adoption in clinics stems from the facts that there was little subsidies or incentives in the national remuneration for medical services, lack of cooperation from medical associations, and a failed attempt to mandate computerization of medical accounting (medical billing). Giving financial incentives is an effective means of raising EMR adoption rate. For wide usage of HIS, more financial support and incentive may be necessary for small hospitals and clinics. PMID- 23932756 TI - Physical activity counseling intervention at a federally qualified health center: improves autonomy-supportiveness, but not patients' perceived competence. AB - OBJECTIVE: To assess the effect of a pilot intervention to promote clinician patient communication about physical activity on patient ratings of their perceived competence for physical activity and their clinicians' autonomy supportiveness. METHODS: Family medicine clinicians (n=13) at two urban community health centers were randomized to early or delayed (8 months later) communication training groups. The goal of the training was to teach the 5As (Ask, Advise, Agree, Assist, Arrange) for physical activity counseling. Outcome measures were changes in patient perceptions of autonomy support (modified Health Care Climate Questionnaire, mHCCQ) and perceived competence (Perceived Competence Scale for physical activity, PCS) completed via surveys at baseline, post-intervention and six-month follow-up. RESULTS: Patients (n=326) were mostly female (70%) and low income. Using a generalized estimating equations model (GEE) with patients nested within clinician, patient perceived autonomy support increased at post intervention compared to baseline (mean HCCQ scores 3.68-4.06, p=0.03). There was no significant change in patient perceived competence for physical activity. CONCLUSIONS: A clinician-directed intervention increased patient perceptions of clinician autonomy support but not patient perceived competence for physical activity. PRACTICE IMPLICATIONS: Clinicians working with underserved populations can be taught to improve their autonomy supportiveness, according to patient assessments of their clinicians. PMID- 23932757 TI - Transfer of hip arthroplasty patients leads to increased cost and resource utilization in the receiving hospital. AB - Factors other than complexity of care often drive the transfer of orthopedic patients to tertiary centers. We sought to compare the demographics, diagnoses, insurance data, peri-operative outcomes and institutional costs of total hip arthroplasty patients transferred from outside facilities with those of patients derived from our clinics. We analyzed 419 consecutive patients as part of a prospective risk study. Transferred patients were older (P=0.01), less likely to have private insurance (P<0.0001), and more likely to be admitted on weekends (P=0.04). Both dislocation and fracture were more prevalent in transferred patients (P=0.04; P=0.003). Across all key metrics - including length of stay, mortality scoring, peri-operative complications, and direct and total costs - transferred patients more significantly strained the resources of our arthroplasty center. PMID- 23932758 TI - The fate of unplanned retention of prosthetic articulating spacers for infected total hip and total knee arthroplasty. AB - Eighteen patients with periprosthetic joint infection (11 hips and 7 knees) treated by prosthetic articulating spacers retained their spacers and were followed up at an average of 43.8 months(range, 13-78 months). Fifteen patients maintained well-functioning spacers for an average of 42.7 months, of which 4 patients died with the spacers in situ at an average of 48.7 months. The mean Harris Hip Score and Knee Society knee and function scores of survivors were 92, 92, 88, respectively. Spacers were revised in 3 patients because of recurrent infection (n = 1) at 24 months and mechanical loosening (n = 2) at 74 and 50 months. Findings of this study suggest that a proportion of patients with unplanned retention of prosthetic spacers appear to function well up to 6 years without necessarily requiring further surgical intervention. PMID- 23932759 TI - Factors affecting the use of anti-malaria preventive measures among Taiwan immigrants returning to malaria-endemic regions. AB - The aim of this study was to investigate the predictors of anti-malaria preventive measures (AMPMs) among Taiwan immigrants returning to their country of origin using the Health Belief Model (HBM). Between March and May 2011, all permanent immigrants originating from malaria-endemic countries, attended by either the Taipei or Tainan Immigrant Service Center, Taiwan, and who reported a history of returning to their country of origin within the preceding year during the malarious season in their country of origin were enrolled in the study. Complete information was collected from 316 immigrants, with a response rate of 87% (316/364). The mean age of the subjects was 38.1 years (SD = 9.9). The majority (70%) of participants did not receive travel information through a pre travel consultation; more than 40% reported that they did not use measures to prevent insect bites. Multiple regression analyses revealed that Chinese proficiency, travel consultation before travel, lower perceived susceptibility to malaria, higher perceived severity of malaria infection, higher perceived benefit for taking measures, and higher self-efficacy for taking measures significantly predicted the use of AMPMs during the return to their country of origin (R(2) = 0.20; F = 50.42; P < 0.001). A high proportion of immigrants were not using appropriate AMPMs when they returned to their country. Educational approaches should be targeted toward immigrants who return to visit their country of origin. PMID- 23932760 TI - Dental stem cells as an alternative source for cardiac regeneration. AB - Dental tissues contains stem cells or progenitors that have high proliferative capacity, are clonogenic in vitro and demonstrate the ability to differentiate to multiple type cells involving neurons, bone, cartilage, fat and smooth muscle. Numerous experiments have demonstrated that the multipotent stem cells are not rejected by immune system and therefore it may be possible to use these cells in allogeneic settings. In addition, these remarkable cells are easily abundantly available couple with less invasive procedure in isolating comparing to bone marrow aspiration. Here we proposed dental stem cells as candidate for cardiac regeneration based on its immature characteristic and propensity towards cardiac lineage via PI3-Kinase/Aktsignalling pathway. PMID- 23932761 TI - Serum bilirubin may serve as a marker for increased heme oxygenase activity and inducibility in tissues--a rationale for the versatile health protection associated with elevated plasma bilirubin. AB - Unconjugated bilirubin functions intracellularly as a potent inhibitor of NADPH oxidase complexes, and albumin-bound bilirubin contributes significantly to the oxidant scavenging activity of plasma. So it is not surprising that serum levels of bilirubin have been found to correlate inversely with risk for vascular diseases and a host of other disorders. Nonetheless, recent Mendelian randomization analyses reveal that individuals who carry low expression alleles of the hepatic bilirubin conjugating enzyme UGT1A1, and hence have somewhat elevated levels of plasma bilirubin throughout life, are not at decreased risk for vascular disorders. This likely reflects the fact that, in most people, plasma levels of unconjugated, unbound bilirubin--the fraction of bilirubin capable of fluxing back into cells--are so low (near 1 nM) that they can exert only a trivial antioxidant influence on cells. In light of these findings, it is reasonable to propose that the inverse correlation of plasma bilirubin and disease risks noted in many studies often reflect the fact that elevated plasma bilirubin can serve as a marker for an increased propensity to generate bilirubin within cells. Consistent with this view, high expression alleles of the major enzymatic source of bilirubin, heme oxygenase-1 (HO-1), do associate with decreased vascular risk in the majority of studies that have addressed this issue, and increased plasma bilirubin has been reported in carriers of these alleles. Hence, the consistent reduction in vascular risk noted in people with Gilbert syndrome (traditionally defined as having serum bilirubin in excess of 20 MUM) is likely attributable to an increased rate of bilirubin generation within tissues, rather than to the decreased hepatic UGT1A1 activity that characterizes this syndrome. However, there is good reason to suspect that, at some sufficiently high plasma bilirubin level--as in individuals with very intense Gilbert syndrome or in Gunn rats lacking UGT1A1 activity--the plasma bilirubin pool does indeed provide some antioxidant protection to cells. Strategies for boosting bilirubin production within cells via HO-1 induction, or for mimicking bilirubin's antioxidant activity with cyanobacterial phycobilins, may have important potential for health promotion. PMID- 23932762 TI - Blaschko line analogies in the central nervous system: a hypothesis. AB - In X-chromosome-linked skin disorders the pattern of involvement follows Blaschko lines. Patterns of changes analogous to cutaneous Blaschko lines in different X linked diseases existed in other organs. There is no commonly accepted analogy to Blaschko lines in the central nervous system (CNS). The objective of this study was to consider a hypothesis of the existence of Blaschko lines in the CNS in the example of incontinentia pigmenti (IP). Articles were analyzed in which brain imaging methods were used in IP patients with CNS anomalies. In IP patients with neurological signs brain lesions usually were localized and extended radially. Affected areas did not correspond to territories vascularized by any determined artery. Radially distributed brain lesions morphologically match the radial unit model of cortical development. It can be proposed that in IP in CNS Blaschko line analogies, similar to those in the skin, represent the trace of development of the clone of neurons arising from the cell marked with IKBKG mutation. The hypothesis of the existence of Blaschko line analogies in CNS is supported by radially distributed CNS image findings in IP, the radial unit model of CNS development, and the common embryonic origin of skin, CNS, and eyes. PMID- 23932763 TI - The olfactory system. AB - Any dysfunction in olfaction requires a radiological exploration comprising the nasal cavity, the anterior base of the skull, in particular the frontal and temporal lobes. MRI is the reference examination, due to the frontal plane and the T1, T2 volume maps. In the child, aplasia of the olfactory bulbs falls within a polymalformation (CHARGE) or endocrine (Kallman) context. In the adult, rhino sinus disease and meningiomas are the most common etiologies. Frontal or temporal impairment: tumoral or vascular and neurodegenerative disorders (Parkinson's disease) may accompany a loss of olfaction. PMID- 23932764 TI - Breast cancers with round lumps: correlations between imaging and anatomopathology. AB - A round lump with a well-defined outline is, in most cases, benign. However, in 10 to 20% of all cases, a round and well-defined lump may correspond to a cancer. Most often, it consists of grade III infiltrating ductal carcinoma (IDC). Other histological sub-types may provide round masses with smooth contours: colloid carcinoma (still called mucinous carcinoma), medullary carcinoma, intramammary metastases, intra-cystic papillary carcinoma, lymphoma and high-grade phyllode tumours. PMID- 23932765 TI - Urinary C reactive protein levels in dogs with leishmaniasis at different stages of renal damage. AB - The objectives of the study were to validate a time-resolved immunofluorometric assay for C reactive protein (CRP) quantification in urine of dogs and to investigate the influence that the presence of proteinuria and azotemia could have on serum and urinary CRP (uCRP) values in dogs with leishmaniasis. Samples obtained from dogs naturally infected with Leishmania infantum were classified into four groups on the basis of the results of urinary protein/creatinine ratio and serum creatinine (sCr). In addition, 7 dogs were monitored at initial diagnosis and after a follow up visit. The assay showed good analytical performance based on precision, accuracy and limit of detection results. Results of the study suggested that CRP is present in urine of dogs with leishmaniasis and renal damage since uCRP/creatinine ratio was significantly increased in dogs with proteinuria, being the highest values observed in dogs with proteinuria and elevated sCr, and that the measurement of uCRP could be a tool to detect and evaluate the possible kidney damage associated with this disease. PMID- 23932766 TI - Characterization of the dynamics of fat cell turnover in different bovine adipose tissue depots. AB - In many but not all high producing cows, the energy requirements for milk yield and maintenance exceed energy intake by voluntary feed intake during early lactation. Prioritizing milk secretion, body reserves mainly from adipose tissue are mobilized and imply an increased risk for metabolic diseases. Reducing the energy output via milk by decreasing the milk fat content through feed supplements containing conjugated linoleic acids (CLAs) may attenuate the negative energy balance during this period. In two separate trials, variables characterizing fat cell turnover were investigated in different subcutaneous and visceral fat depots from primiparous heifers (n = 25) during early lactation, and subcutaneous fat from non-lactating, over-conditioned heifers (n = 12) by immunohistochemistry. The portion of apoptotic adipocytes was consistently greater than that of proliferating cells and preadipocytes; the sporadically observed effects of CLA were limited to visceral fat. Lactating heifers had more apoptosis and less preadipocytes than non-lactating heifers. PMID- 23932768 TI - [Major upper limb trauma: patients' outcomes in 22 cases]. AB - In front of a major upper limb trauma, do we need to make everything possible to keep the limb with the risk of facing poor functional outcomes? This study was performed to evaluate and compare long-term functional, psychological and social outcomes following major upper extremity trauma between patients treated with amputation and those who underwent limb salvage. This was a retrospective monocenter cohort study of 22 patients who sustained an upper limb injury requiring either amputation or limb salvage. The characteristics of the patient, trauma and initial take-care were studied. The outcomes of amputation and upper limb salvage were compared by using functional scores (DASH, Chen), autonomy (activities of the everyday life, work, driving, leisure activities), psychological and quality of life evaluation (NHP, EVA, Russel's score). Twenty two patients were supported. Eleven limb salvages were performed with six secondary amputations. Sixteen patients were reviewed: five with limb salvage and 11 amputees with a mean follow-up of 12 years and 5 months. All patients were autonomous. There were no significant differences between both groups regarding DASH and NHP scores or to work status and driving ability. Russel's score showed that patients with salvaged upper limb were pleased to have kept it and would recommend this treatment. Although the results of upper limb macro-replantation are sometimes disappointing, the satisfaction for these patients to keep their upper limb and their body integrity seems to justify such upper limb salvage when it is technically possible. PMID- 23932767 TI - c-kit positive cells and networks in tooth germs of human midterm fetuses. AB - Numerous studies have attempted to characterize the dental pulp stem cells. However, studies performed on prenatal human tissues have not been performed to evaluate the in situ characterization and topography of progenitor cells. We aimed to perform such a study using of antibodies for CD117/c-kit and multiplex antibody for Ki67+ caspase 3. Antibodies were applied on samples dissected from five human midterm fetuses. Positive CD117/c-kit labeling was found in mesenchymal derived tissues, such as the dental follicle and the dental papilla. The epithelial tissues, that is, dental lamina, enamel organ and oral epithelia, also displayed isolated progenitor cells which were CD117/c-kit positive. Interestingly, CD117/c-kit positive cells of mesenchymal derived tissues extended multiple prolongations building networks; the most consistent of such networks were those of the dental follicle and the perivascular networks of the dental papilla. However, the mantle of the dental papilla was also positive for CD117/c kit positive stromal networks. The CD117/c-kit cell populations building networks appeared mostly with a Ki67 negative phenotype. The results suggest that CD117/c kit progenitor cells of the prenatal tooth germ tissues might be involved in intercellular signaling. PMID- 23932769 TI - The use of extemporaneously compounded 1% tetracaine to improve adherence with clotrimazole 1% topical solution in the treatment of ear infection: a case report. AB - For most medically amenable conditions, adherence to drug therapy is a necessary condition for a successful outcome. Drug side effects, especially pain, can interfere with the desired outcome. We report a case of non-adherence due to severe pain associated with the topical use of clotrimazole 1% solution in the ear. Instillation of tetracaine 1% solution prior to the administration of the clotrimazole blocked the pain sensation allowing the patient to successfully complete the antifungal therapy. PMID- 23932770 TI - [Helicobacter pylori infection and its association with alcohol consumption: a case-control study]. AB - INTRODUCTION: There is a high prevalence worldwide of Helicobacter pylori (Hp) infection associated with gastritis and extending to gastric cancer. Reports have suggested that alcohol has antibacterial action and that its concentration and the amount consumed reduce the risk for Hp infection. In contrast, different studies suggest that tobacco and coffee consumption are risk factors for Hp infection, but their results are controversial. AIMS: To compare the frequency of alcohol consumption in patients infected by Hp with that of non-infected subjects and, as a secondary aim, to compare the association of smoking and coffee consumption with Hp infection. MATERIAL AND METHODS: A case-control study was conducted on Sinaloa State workers that underwent endoscopy and the Hp serology test. Cases were defined as patients with a positive Hp serology test or a positive biopsy with the rapid urease test. Alcohol consumption was categorized as: no consumption, low-risk, and at-risk. The sample included 269 subjects per group. Odds ratio (OR) and 95% confidence interval (CI) were calculated. RESULTS: In both groups, the mean age of the subjects was 45.7 (SD: 9) years (P=.99), 139 of the subjects were women (51.7%) and 130 were men (48.3%); alcohol consumption was present in 108 (40.1%) and 85 (31.6%) of the cases and controls, respectively (P=.039), OR 1.45 (95%CI 1.019-2.069). The quantity of grams of alcohol in subjects with at-risk consumption was significant; However, there were no significant differences in relation to smoking and coffee consumption between the groups. CONCLUSIONS: An association between alcohol consumption and HP infection was observed and no relation with HP infection was found with respect to smoking and coffee consumption. PMID- 23932771 TI - A modeling approach to describe ZVI-based anaerobic system. AB - Zero-valent iron (ZVI) is increasingly being added into anaerobic reactors to enhance the biological conversion of various less biodegradable pollutants (LBPs). Our study aimed to establish a new structure model based on the Anaerobic Digestion Model No. 1 (ADM1) to simulate such a ZVI-based anaerobic reactor. Three new processes, i.e., electron release from ZVI corrosion, H2 formation from ZVI corrosion, and transformation of LBPs, were integrated into ADM1. The established model was calibrated and tested using the experimental data from one published study, and validated using the data from another work. A good relationship between the predicted and measured results indicates that the proposed model was appropriate to describe the performance of the ZVI-based anaerobic system. Our model could provide more precise strategies for the design, development, and application of anaerobic systems especially for treating various LBPs-containing wastewaters. PMID- 23932772 TI - Cardiovascular disorders in pregnancy: diagnosis and management. AB - Cardiovascular diseases (CVDs) are a major cause of complications in pregnancy worldwide and the number of patients who develop cardiac problems during pregnancy is increasing. This review summarises recent literature on the aetiology and the underlying pathophysiology, diagnostic tools, risk stratification and prognosis in women who develop heart failure during pregnancy and in the peri-partum phase as well as in patients with pre-existing cardiomyopathies undergoing pregnancy. We specifically highlight peri-partum cardiomyopathy, valvular disease and Marfan's syndrome. Furthermore, we provide overviews on established treatment concepts and novel therapeutic strategies for these different disease types, stressing the point that pregnancy-associated cardiac disease requires interdisciplinary concepts for diagnosis, management and treatment. PMID- 23932773 TI - Three-dimensional reconstruction of the pharyngeal tonsil innervation pattern in sheep. AB - The pharyngeal tonsil has recently been identified as a new participant in airborne contamination by the ovine scrapie agent. In the context of scrapie pathogenesis, we conducted a three-dimensional reconstruction of the innervation pattern in the lymphoid compartments of this tonsil. This model confirmed that very few nerve fibres penetrated the lymphoid follicles and suggested that the nerve fibre distribution in the interfollicular and subepithelial areas is more suitable with neuro-invasion through direct contact between these nerve fibres and prion-transporting cells prior to or after prion amplification in the germinal centre of the pharyngeal tonsil lymphoid follicles. PMID- 23932774 TI - Effects of fatiguing treadmill running on sensorimotor control in athletes with and without functional ankle instability. AB - BACKGROUND: Sensorimotor control is permanently impaired following functional ankle instability and temporarily decreased following fatigue. Little is known on potential interactions between both conditions. The purpose was to investigate the effect of fatiguing exercise on sensorimotor control in athletes with and without (coper, controls) functional ankle instability. METHODS: 19 individuals with functional ankle instability, 19 ankle sprain copers, and 19 non-injured controls participated in this cohort study. Maximum reach distance in the star excursion balance test, unilateral jump landing stabilization time, center of pressure sway velocity in single-leg-stance, and passive ankle joint position sense were assessed before and immediately after fatiguing treadmill running. A three factorial linear mixed model was specified for each outcome to evaluate the effects of group, exhausting exercise (fatigue) and their interactions (group by fatigue). Effect sizes were calculated as Cohen's d. FINDINGS: Maximum reach distance in the star excursion balance test, jump stabilization time and sway velocity, but not joint position sense, were negatively affected by fatigue in all groups. Effect sizes were moderate, ranging from 0.27 to 0.68. No significant group by fatigue interactions were found except for one measure. Copers showed significantly larger prefatigue to postfatigue reductions in anterior reach direction (P<=0.001; d=-0.55) compared to the ankle instability (P=0.007) and control group (P=0.052). INTERPRETATION: Fatiguing exercise negatively affected postural control but not proprioception. Ankle status did not appear to have an effect on fatigue-induced sensorimotor control impairments. PMID- 23932775 TI - Postoperative spinal cord herniation with pseudomeningocele in the cervical spine: a case report. AB - BACKGROUND CONTEXT: Postoperative spinal cord herniation with pseudomeningocele is a rare disease, with only five cases reported before the present study. PURPOSE: To describe the clinical features and radiologic findings of postoperative spinal cord herniation with pseudomeningocele. STUDY DESIGN: Case report. METHODS: A case of a 51-year-old man who suffered from postoperative spinal cord herniation with pseudomeningocele was reported, and previous reports on this subject are reviewed. RESULTS: He had undergone excision of a spinal cord tumor in the cervical spine 10 years previously. He had progressive paraparesis and urinary disturbance 10 years later. The Computed Tomography Multi Planner Reconstruction myelogram showed dilation of the ventral subarachnoid space with left deviation of the spinal cord into the pseudomeningocele at C7. On observation at surgery, the spinal cord appeared displaced dorsally and herniated through the defect of the dorsal dura mater. The spinal cord was tightly adhesive around the dural defect. We released the adhesion of the spinal cord and the dural defect under the spinal cord, and the dural defect was repaired using an artificial dura mater. CONCLUSIONS: The release of adhesion around dural defect and repair of dural defect under spinal cord monitoring resulted in a satisfactory neurologic recovery. Surgical repair of the dural defect with a dural substitute was necessary. PMID- 23932776 TI - A pure fluid-filled intradural cyst associated with intradural disc herniation and possible pathogenesis: a case report. AB - BACKGROUND CONTEXT: Lumbar intradural disc herniation (IDH) is rare, and intradural cyst associated with IDH is quite rare. Only seven cases of an intradural cyst associated with lumbar disc herniation have been reported, and all were gas-filled cysts. We report the first case, to our knowledge, of a fluid filled intradural cyst associated with IDH. PURPOSE: To report an extremely rare case of a fluid-filled intradural cyst associated with lumbar IDH and suggests the possible pathogenesis. STUDY DESIGN: Case report. METHODS: An 82-year-old woman presented with right leg pain and motor weakness. Computed tomography and magnetic resonance imaging (MRI) scans showed calcified lumbar disc herniation and an intradural cystic mass at the L1-L2 level. An MRI, which was performed 2 years before admission, showed an IDH without a cyst at the same level. RESULTS: Surgical resection of the intradural cyst was performed. Intraoperative finding showed a fluid-filled intradural cyst with 1-cm diameter of displacing nerve rootlets. The cyst was connected with extradural cystic components through a ventral dural hole, but the tract was blocked by fibrous septum. Histopathologic examination showed a pseudocyst that consisted of degenerative cartilaginous and fibrous tissues, including degenerative disc materials. We concluded that the cyst was an intradural cyst transformed from the intradural disc fragment. CONCLUSIONS: The current case is the first report to our knowlege of a fluid filled intradural cyst associated with IDH. The possible mechanism may be focal degeneration and spontaneous absorption of the intradural disc with fluid production. Unlike the gas-filled intradural cysts, the cause of the pure fluid filled cyst may be disconnection from the intervertebral vacuum because of a calcified disc and septation of the cyst. PMID- 23932777 TI - An unexpected complication of occipitocervical stabilization surgery: retropharyngeal hematoma. AB - BACKGROUND CONTEXT: To report a unique case of an unexpected complication of occipitocervical stabilization surgery that is retropharyngeal hematoma (RH). PURPOSE: Postoperative RH is a very rare complication and has never been reported after posterior occipitocervical surgery. STUDY DESIGN: Case report. METHODS: A 44-year-old woman being treated for rheumatoid arthritis for 20 years was admitted to our hospital in a wheelchair with the complaints of neck pain and weakness in both upper and lower extremities. She was diagnosed with basilar invagination, and occipitocervical (C0-C5) transpedicular fixation with osteosynthesis using iliac autograft was performed. The airway was seen as obstructed after extubation. The airway was maintained with laryngeal mask, and computed tomography revealed an RH. Emergent tracheotomy was performed. The patient was decannulated because of the resorption of RH after 10 days and was discharged. CONCLUSION: This patient is the first patient, to our knowledge, to be reported for unexplained RH after cervical posterior spinal surgery. PMID- 23932778 TI - Surgical treatment of cervical vertebral hemangioma associated with adjacent cervical spondylotic myelopathy. AB - BACKGROUND CONTEXT: Symptoms may vary from simple vertebral pain to progressive neurologic deficit because of cervical vertebral hemangioma associated with adjacent cervical spondylotic myelopathy (CVHAWACSM). Often resistant to conservative medical treatment, surgery has been the treatment of choice for these patients, but the optimal surgical strategy for CVHAWACSM has not been defined. PURPOSE: This study aimed to investigate the methods and efficacy in the treatment of CVHAWACSM. STUDY DESIGN: Retrospective review of patients enrolled in prospective randomized trial. PATIENT SAMPLE: Procedure was performed in 18 patients (11 men and 7 women) with CVHAWACSM, who were enrolled between January 2006 and September 2011. OUTCOME MEASURES: Radiographic examinations were carried out to assess total filling of polymethylmethacrylate in the vertebral body, fusion rates, implant failure, and general complications. The recovery of neurologic function and neck and shoulder pain relief were measured based on the Japanese Orthopedic Association (JOA) and the visual analog scale (VAS) scores. METHODS: Eighteen patients had single vertebral hemangioma, including one case at C3, three at C4, six at C5, five at C6, and three at C7. The X-ray films showed a typical "palisade" change. According to the clinical and imaging features, there were 12 cases of Type II and 6 of Type IV cervical hemangioma. Standard anterior cervical decompression and fusion with a stand-alone polyetheretherketone cage (filled with autologous cancellous iliac bone) was performed, followed by vertebroplasty. Clinical and radiologic follow-ups were performed. RESULTS: The mean follow-up was 24.1 months, with a range of 18 to 36 months. The symptoms of all 18 patients were improved, by varying degrees, and the lesion vertebra did not show anterior bone cement leakage or injuries in the spinal cord and nerves. The forming vertebra did not show fracture or collapse, and there was no recurrence of the hemangioma. During the follow-up, there was no implant loosening, displacement, or breakage. The JOA and the VAS scores were significantly recovered at 3 months after the operation and in the last follow up, compared with the preoperative level (p<.05). The JOA scores in the last follow-up showed 13 excellent, 4 good, 1 fair, and 0 poor cases. CONCLUSIONS: This procedure seems to be a safe efficient method to treat symptomatic CVHAWACSM. It seems to serve the purpose of providing vertebral augmentation, cord decompression, and rigid fusion at the same sitting. Although the present outcomes are promising, long-term follow-up studies with larger patient numbers are required to confirm this effect. PMID- 23932779 TI - Fibular flap reconstruction of the cervical spine for repair of osteoradionecrosis. AB - BACKGROUND CONTEXT: Although cervical spine reconstruction with osteocutaneous fibular flap microvascular grafting has been described, simultaneous reconstruction of the cervical vertebral column and laryngectomy have not been described. PURPOSE: To present a unique case of combined cervical spine and laryngectomy reconstruction. STUDY DESIGN: Case report. METHODS: We modified a previously reported procedure reconstituting the cervical spine and pharynx with a single fibular flap in a case of posterior pharyngeal ulceration and osteomyelitis/osteoradionecrosis without spinal deformity. RESULTS: We present a case of simultaneous cervical stabilization and pharynx reconstruction with a fibular graft in a life-saving treatment of osteoradionecrosis complicated by acute cervical kyphosis and spinal cord compression in a 55-year-old patient with extensive head and neck cancer history and recent recurrence of hypopharyngeal cancer. CONCLUSIONS: Rigid anterior plate fixation and subsequent posterior fixation were required after corpectomy and total laryngectomy in our patient with extensive surgical scarring and radiation history because of severe spinal deformity secondary to osteoradionecrosis. We achieved successful preservation of neurologic function and resolution of pain. PMID- 23932780 TI - The little elongation complex functions at initiation and elongation phases of snRNA gene transcription. AB - The small nuclear RNA (snRNA) genes have been widely used as a model system for understanding transcriptional regulation due to the unique aspects of their promoter structure, selectivity for either RNA polymerase (Pol) II or III, and because of their unique mechanism of termination that is tightly linked with the promoter. Recently, we identified the little elongation complex (LEC) in Drosophila that is required for the expression of Pol II-transcribed snRNA genes. Here, using Drosophila and mammalian systems, we provide genetic and molecular evidence that LEC functions in at least two phases of snRNA transcription: an initiation step requiring the ICE1 subunit, and an elongation step requiring ELL. PMID- 23932781 TI - Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. AB - Increased fatty acid synthesis is required to meet the demand for membrane expansion of rapidly growing cells. ATP-citrate lyase (ACLY) is upregulated or activated in several types of cancer, and inhibition of ACLY arrests proliferation of cancer cells. Here we show that ACLY is acetylated at lysine residues 540, 546, and 554 (3K). Acetylation at these three lysine residues is stimulated by P300/calcium-binding protein (CBP)-associated factor (PCAF) acetyltransferase under high glucose and increases ACLY stability by blocking its ubiquitylation and degradation. Conversely, the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY. Substitution of 3K abolishes ACLY ubiquitylation and promotes de novo lipid synthesis, cell proliferation, and tumor growth. Importantly, 3K acetylation of ACLY is increased in human lung cancers. Our study reveals a crosstalk between acetylation and ubiquitylation by competing for the same lysine residues in the regulation of fatty acid synthesis and cell growth in response to glucose. PMID- 23932782 TI - Risk factors for depression in the elderly inflammatory bowel disease population. AB - BACKGROUND AND AIMS: Little is known about depression in elderly individuals with inflammatory bowel diseases (IBD). We assessed the point prevalence of depression and determined associations with disease activity, quality of life, and medication adherence in elderly patients with IBD. METHODS: We identified elderly (>= 65 years) individuals within Crohn's and Colitis Foundation of America Partners, an online IBD cohort. Individuals completed the short geriatric depression scale (GDS). We used bivariate statistics to determine whether demographic or disease-related factors, disease activity, quality of life or medication adherence was associated with depression. We used logistic regression to estimate independent effects of depression on medication adherence. RESULTS: A total of 359 elderly individuals with IBD completed the GDS. The mean age was 70.2 years (SD 4.7); mean disease duration was 25.6 years (SD 17.6), and 62.6% had Crohn's disease (CD). The point prevalence of depression was 22.6%. Lower education levels (p=0.001), higher corticosteroid use (<0.01) and lower exercise levels (<0.001) were associated with depression. For both CD and ulcerative colitis (UC), those with depression had increased disease activity (short Crohn's disease activity index 52.5 versus 29, p=0.005, and simple clinical colitis activity index 5 versus 2, p=0.003). Depressed patients had lower quality of life (short IBD questionnaire 4.6 versus 5.7, p<0.001). Depressed individuals had reduced medication adherence (adjusted OR 2.18; 95% CI 1.04-4.57). CONCLUSIONS: Depression is common in this geriatric IBD cohort. Depression is independently associated with reduced medication adherence. Recognition and treatment of depression in elderly patients with IBD could improve outcomes. PMID- 23932784 TI - Reply to Drs. Walmsley and Casey letter. PMID- 23932783 TI - The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients. AB - BACKGROUND AND AIMS: A drug interaction between infliximab and azathioprine has previously been reported in Crohn's disease patients: the concentration of the main active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), increased 1-3 weeks after the first infliximab infusion by 50% compared to baseline. The aim of this prospective study was to determine the effect of adalimumab on thiopurine metabolism in Crohn's disease patients, evaluated by 6 TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement. METHODS: Crohn's disease patients on azathioprine or mercaptopurine maintenance therapy starting with concomitant adalimumab treatment were included. 6-TGN and 6-MMPR concentrations were determined before initiation of adalimumab and after 2, 4, 6 and 12 weeks of combination therapy. The activity of three essential enzymes involving thiopurine metabolism, thiopurine S-methyltransferase (TPMT), hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inosine triphosphate pyrophosphatase (ITPase), was evaluated at baseline and week 4. Clinical outcome was evaluated by the Crohn's disease activity index and C reactive protein concentrations at baseline, week 4 and week 12. RESULTS: Twelve Crohn's disease patients were analyzed. During the follow-up period of 12 weeks the median 6-TGN and 6-MMPR concentrations did not significantly change compared to baseline. TPMT, ITPase and HGPRT enzyme activity did not change either after 4 weeks. In two patients (17%) myelotoxicity was observed within 2-4 weeks, in whom both low therapeutic 6-TGN and 6-MMPR concentrations were found. CONCLUSIONS: In this study in Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine. PMID- 23932785 TI - Infliximab versus azathioprine to prevent postoperative recurrence in Crohn's disease: are all controversial issues defined? PMID- 23932786 TI - High C-reactive protein in Crohn's disease patients predicts nonresponse to infliximab treatment. AB - BACKGROUND: Infliximab (IFX) is effective in treating Crohn's disease (CD) and C reactive protein (CRP) is a useful biomarker in assessing inflammatory activity. AIM: Correlate CRP levels before beginning of IFX, at week 14 and CRP delta within the first year of IFX treatment. METHODS: Retrospective study of CD patients undergoing treatment with IFX. Primary nonresponse (PNR) was defined as no symptomatic improvement and CRP persistently elevated; sustained response (SR) as symptomatic improvement for at least 1 year without therapeutic adjustment; response after therapeutic adjustment (RTA) as analytic and clinical response but requiring IFX dose/frequency adjustment or association with another drug. RESULTS: Baseline CRP levels were higher in PNR compared with SR (26.2mg/L vs 9.6 mg/L, p=0.015) and RTA (26.2mg/L vs 7.6 mg/L, p=0.007). CRP levels greater than 15 mg/L at baseline predict PNR with 67% sensitivity and 65% specificity. Lower CRP levels at week 14 were more likely to predict SR relative to RTA (3.1mg/L vs 7.6 mg/L p=0.019) and PNR (3.1mg/L vs 9.1mg/L; p=0.013). CRP levels greater than 4.6 mg/L at week 14 predict PNR with 67% sensitivity and 62% specificity. A higher CRP delta between beginning of treatment and week 14 is more likely to predict SR relative to RTA (5.2mg/L vs 0.6 mg/L p=0.027). CONCLUSION: CRP levels at week 14 were associated with SR in patients treated with IFX, independently of baseline CRP serum levels. High inflammatory burden at beginning of IFX treatment was correlated with a worse response. PMID- 23932787 TI - Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene. AB - Mitochondrial DNA (mtDNA) depletion syndromes (MDSs) are a clinically and molecularly heterogeneous group of mitochondrial cytopathies characterized by severe mtDNA copy number reduction in affected tissues. Clinically, MDSs are mainly categorized as myopathic, encephalomyopathic, hepatocerebral, or multi systemic forms. To date, the myopathic form of MDS is mainly caused by mutations in the TK2 gene, which encodes thymidine kinase 2, the first and rate limiting step enzyme in the phosphorylation of pyrimidine nucleosides. We analyzed 9 unrelated families with 11 affected subjects exhibiting the myopathic form of MDS, by sequencing the TK2 gene. Twelve mutations including 4 novel mutations were detected in 9 families. Skeletal muscle specimens were available from 7 out of 11 subjects. Respiratory chain enzymatic activities in skeletal muscle were measured in 6 subjects, and enzymatic activities were reduced in 3 subjects. Quantitative analysis of mtDNA content in skeletal muscle was performed in 5 subjects, and marked mtDNA content reduction was observed in each. In addition, we outline the molecular and clinical characteristics of this syndrome in a total of 52 patients including those previously reported, and a total of 36 TK2 mutations are summarized. Clinically, hypotonia and proximal muscle weakness are the major phenotypes present in all subjects. In summary, our study expands the molecular and clinical spectrum associated with TK2 deficiency. PMID- 23932789 TI - A novel protocol to accelerate dynamic combinatorial chemistry via isolation of ligand-target adducts from dynamic combinatorial libraries: a case study identifying competitive inhibitors of lysozyme. AB - A novel protocol based on size-exclusion chromatography (SEC) and MS was established to accelerate dynamic combinatorial chemistry (DCC) in this study. By isolating ligand-target adducts from the dynamic combinatorial library (DCL), ligands could be identified directly by MS after denaturation. Three new inhibitors for lysozyme were discovered by this SEC-MS protocol in a case study. Km Data for these new inhibitors was also determined. PMID- 23932788 TI - N-terminal guanidinylation of TIPP (Tyr-Tic-Phe-Phe) peptides results in major changes of the opioid activity profile. AB - Derivatives of peptides of the TIPP (Tyr-Tic-Phe-Phe; Tic=1,2,3,4 tetrahydroisoquinoline-3-carboxylic acid) family containing a guanidino (Guan) function in place of the N-terminal amino group were synthesized in an effort to improve their blood-brain barrier permeability. Unexpectedly, N-terminal amidination significantly altered the in vitro opioid activity profiles. Guan analogues of TIPP-related delta opioid antagonists showed delta partial agonist or mixed delta partial agonist/MU partial agonist activity. Guanidinylation of the mixed MU agonist/delta antagonists H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) and H-Dmt TicPsi[CH2NH]Phe-Phe-NH2 (DIPP-NH2[Psi]) converted them to mixed MU agonist/delta agonists. A docking study revealed distinct positioning of DIPP-NH2 and Guan-DIPP NH2 in the delta receptor binding site. Lys(3)-analogues of DIPP-NH2 and DIPP NH2[Psi] (guanidinylated or non-guanidinylated) turned out to be mixed MU/kappa agonists with delta antagonist-, delta partial agonist- or delta full agonist activity. Compounds with some of the observed mixed opioid activity profiles have therapeutic potential as analgesics with reduced side effects or for treatment of cocaine addiction. PMID- 23932790 TI - A hit to lead discovery of novel N-methylated imidazolo-, pyrrolo-, and pyrazolo pyrimidines as potent and selective mTOR inhibitors. AB - A series of N-7-methyl-imidazolopyrimidine inhibitors of the mTOR kinase have been designed and prepared, based on the hypothesis that the N-7-methyl substituent on imidazolopyrimidine would impart selectivity for mTOR over the related PI3Kalpha and delta kinases. The corresponding N-Me substituted pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines also show potent mTOR inhibition with selectivity toward both PI3alpha and delta kinases. The most potent compound synthesized is pyrazolo[4,3-d]pyrimidine 21c. Compound 21c shows a Ki of 2 nM against mTOR inhibition, remarkable selectivity (>2900*) over PI3 kinases, and excellent potency in cell-based assays. PMID- 23932791 TI - Synthesis, DNA binding and anti-leukemic activity of an aminoacyl nucleolipid. AB - The synthesis and characterization of a new class of DNA binding molecule exhibiting potent and selective anti-leukemic activity is described. The synthesis of an aminoacyl nucleolipid was developed from an efficient EEDQ coupling strategy, in which a series of seven bioconjugates were synthesized in yields of 53-78%. Guanosine bioconjugate 7, was used as building block for the synthesis of a target aminoacyl nucleolipid 14. Its GRP78 DNA binding affinity was confirmed by gel shift assay, CD spectroscopy, Tm measurements and dynamic light scattering experiments. Moreover, in a single dose (10 MUM) screen against a panel of 60 cancer cell lines, aminoacyl nucleolipid 14 was found to selectively trigger greater than 90% cell death in a SR human leukemia cancer cell line. The reported aminoacyl nucleolipid represents a useful model for a new class of DNA binding molecules for the development of potent and selective anti cancer agents. PMID- 23932793 TI - Interpersonal problems as predictors of alliance, symptomatic improvement and premature termination in treatment of depression. AB - BACKGROUND: Previous studies reported inconsistent findings regarding the association of interpersonal problems with therapy outcome. The current study investigates if interpersonal problems predict process and outcome of three different treatments for depression. METHODS: The data originate from a randomized clinical trial comparing supportive-expressive psychotherapy, antidepressant medication and pill-placebo for treatment of depression. Interpersonal problems were used as predictors of alliance, symptomatic improvement and premature termination of treatment. RESULTS: Interpersonal problems related to communion predicted better alliances, but slower symptomatic improvement. Low agency predicted slower symptomatic improvement in supportive expressive psychotherapy, but not in the medication or placebo condition. Lower interpersonal distress was associated with an increased likelihood to terminate treatment prematurely. LIMITATIONS: The sample size did not allow the detection of small effects within the treatment groups. CONCLUSIONS: Interpersonal problems are influential for the treatment of depression, but parts of their effects depend on the type of treatment. PMID- 23932792 TI - Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu1. AB - Development of SAR in an octahydropyrrolo[3,4-c]pyrrole series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. The octahydropyrrolo[3,4-c]pyrrole scaffold was chosen as an isosteric replacement for the piperazine ring found in the initial hit compound. Characterization of selected compounds in protein binding assays was used to identify the most promising analogs, which were then profiled in P450 inhibition assays in order to further assess the potential for drug-likeness within this series of compounds. PMID- 23932794 TI - [Changing c.106delG (p.Ala36fs*6) loss syndrome associated with congenital Finnish type: first case diagnosed in Togo]. AB - OBJECTIVE: To report the first case of congenital nephrotic syndrome of the Finnish type (SNCF) in Togo associated with a new mutation of NPHS1. OBSERVATION: Our study focused on a female infant of 10months, born premature at 34weeks 6days, followed from birth to pure SNC discovered the 10th day of life. Monitoring and pregnancy outcome unremarkable. It is the third in a family of three children, the first two are killed in a similar table but not explored before 1year of age. The diagnosis is confirmed by the SNCF genetic study NPHS1 gene encoding nephrin performed in our patient and her parents showed a double mutation of which c.[106delG]+[2728T>C] and p. at the nucleotide level. [Ala36fs*6]+[Ser91OPro] at the protein level inherited from each parent. The change was made to the 10th month of death in life after sepsis in a third of cortico-resistance. CONCLUSION: The SNCF, autosomal recessive disease early, which remains a serious diagnosis, is genetic. This new mutation could she explained the severity of the SNCF in this family? PMID- 23932795 TI - The effects of post-stroke upper-limb training with an electromyography (EMG) driven hand robot. AB - Loss of hand function and finger dexterity are main disabilities in the upper limb after stroke. An electromyography (EMG)-driven hand robot had been developed for post-stroke rehabilitation training. The effectiveness of the hand robot assisted whole upper limb training was investigated on persons with chronic stroke (n=10) in this work. All subjects attended a 20-session training (3 5times/week) by using the hand robot to practice object grasp/release and arm transportation tasks. Significant motor improvements were observed in the Fugl Meyer hand/wrist and shoulder/elbow scores (p<0.05), and also in the Action Research Arm Test and Wolf Motor Function Test (p<0.05). Significant reduction in spasticity of the fingers as was measured by the Modified Ashworth Score (p<0.05). The training improved the muscle co-ordination between the antagonist muscle pair (flexor digitorum (FD) and extensor digitorum (ED)), associated with a significant reduction in the ED EMG level (p<0.05) and a significant decrease of ED and FD co-contraction during the training (p<0.05); the excessive muscle activities in the biceps brachii were also reduced significantly after the training (p<0.05). PMID- 23932796 TI - Influence of muscle activity on musculotendinous stiffness quantification in stunted, prepubertal children. AB - The quick-release technique to estimate musculotendinous (MT) stiffness has been extensively used over the last years, in both animals and humans, to gain insights in the adaptive process of the series elastic component (SEC). Recently, MT stiffness quantification, i.e., SEC behavior, has been revisited for subjects not able to fully activate their muscles (effects of long-term spaceflight or non mature muscles). Such a phenomenon can also be encountered in stunted children. So, the aim of the present study was to analyze the effect of stunting on MT stiffness taking into account possible defect in muscle activation. For this study, 20 eutrophic children (EU) with an average age of 9years+/-4months were compared to 11age matched stunted children (S) evaluated by the height-to-age index. The MT stiffness index was obtained with regard to stiffness-torque and stiffness-soleus EMG relationships. The children of the S group presented a significantly lower Maximal Voluntary Contraction (MVC) in plantar flexion in comparison with children of the EU group (-37.8%). The significantly lower MT stiffness index for S children (-42.6%) was evidenced only when quantified with regard to the stiffness-soleus EMG relationship (66.5+/-42.8 vs. 38.2+/-19.9 Nmrad(-1)%(-1)). Possible delay in fiber type differentiation or tendinous structure maturation can account for the lower MT stiffness index in S children. In conclusion, stunting during early childhood delays the differentiation and maturation processes of musculotendinous structures as shown by the lower MT stiffness quantified with regards to muscle activity, also altered for stunted prepubertal children. PMID- 23932797 TI - Influence of joint angle on EMG-torque model during constant-posture, quasi constant-torque contractions. AB - Electromyogram (EMG)-torque modeling is of value to many different application areas, including ergonomics, clinical biomechanics and prosthesis control. One important aspect of EMG-torque modeling is the ability to account for the joint angle influence. This manuscript describes an experimental study which relates the biceps/triceps surface EMG of 12 subjects to elbow torque at seven joint angles (spanning 45-135 degrees ) during constant-posture, quasi-constant-torque contractions. Advanced EMG amplitude (EMGsigma) estimation processors (i.e., whitened, multiple-channel) were investigated and three non-linear EMGsigma torque models were evaluated. When EMG-torque models were formed separately for each of the seven distinct joint angles, a minimum "gold standard" error of 4.23+/-2.2% MVCF90 resulted (i.e., error relative to maximum voluntary contraction at 90 degrees flexion). This model structure, however, did not directly facilitate interpolation across angles. The best model which did so (i.e., parameterized the angle dependence), achieved an error of 4.17+/-1.7% MVCF90. Results demonstrated that advanced EMGsigma processors lead to improved joint torque estimation. We also contrasted models that did vs. did not account for antagonist muscle co-contraction. Models that accounted for co-contraction estimated individual flexion muscle torques that were ~29% higher and individual extension muscle torques that were ~68% higher. PMID- 23932798 TI - The importance of the orthopaedic doctors' appearance: a cross-regional questionnaire based study. AB - OBJECTIVES: Critics of the Department of Health 'bare below the elbow' guidelines have raised concerns over the impact of these dress regulations on the portrayed image and professionalism of doctors. However, the importance of the doctor's appearance in relation to other professional attributes is largely unknown. The purpose of this study was to determine the opinion of patients on the importance of appearance and the style of clothing worn by doctors. DESIGN: Patient questionnaire survey, administered across four Scottish regions. SETTING: Orthopaedic outpatient departments. PARTICIPANTS: 427 patients and accompanying relatives. MAIN OUTCOME MEASURES: The absolute and relative importance of the doctors' appearance, as reported using a 5-point Likert scale. The absolute and relative importance of the style of clothing worn by doctors, as reported using a 5-point Likert scale. The rank preferences for four different styles of doctors' attire as illustrated by standardised clinical photographs. RESULTS: The study was appropriately powered to identify a 0.5 difference in mean rank values with 0.90 power at a = 0.05. The majority of participants felt the doctors' appearance was important but not as important as compassion, politeness and knowledge. Only 50% felt that the style of doctors clothing mattered; what proved more important was an impression of cleanliness and good personal hygiene. In terms of how patients would prefer doctors to dress in clinic, the most popular choice proved to be the smart casual style of dress, which conforms with the 'bare below the elbows' dress code policy. The smart casual clothing style was the highest ranked choice irrespective of patient age, gender, regional or socioeconomic background. CONCLUSIONS: The doctors' appearance is of importance to patients and their relatives, but they view many other attributes as more important than how we choose to dress. While not specifically addressing the role of doctors clothing in the transmission of infection, our results do support the preference of patients for 'bare below the elbows' workplace attire. PMID- 23932799 TI - Current and future practices in surgical retraction. AB - Retraction of tissues and anatomical structures is an essential component of all forms of surgery. The means by which operative access is gained through retraction are many and diverse. In this article, the various forms of retraction methods currently available are reviewed, with special reference to hand held, self-retaining and compliant techniques. The special challenges posed by laparoscopic surgery are considered and future developments in new retraction techniques are anticipated. PMID- 23932801 TI - Discussion. PMID- 23932800 TI - Re: The article "Dinopoulos H, Dimitriou R, Giannoudis PV. Bone graft substitutes: what are the options? Surgeon. 2012 Aug;10(4):230-9. PMID- 23932802 TI - Endovascular treatment of a giant hepatic artery aneurysm with Amplatzer vascular plug. AB - Hepatic artery aneurysms are uncommon and account for 20% of visceral aneurysms. Some authors consider endovascular procedures as the first line treatment for most hepatic artery aneurysms, being the conventional surgery reserved for unstable ruptured aneurysms or if the anatomy is unsuitable for endovascular repair. In this report, we describe the endovascular treatment of a giant common hepatic artery aneurysm with an Amplatzer vascular plug. PMID- 23932804 TI - Effect of physical exercise on muscle mass and strength in cancer patients during treatment--a systematic review. AB - Cancer treatment and its side effects may cause muscle wasting. Physical exercise has the potential to increase muscle mass and strength and to improve physical function in cancer patients undergoing treatment. A systematic review was conducted to study the effect of physical exercise (aerobic, resistance or a combination of both) on muscle mass and strength in cancer patients with different type and stage of cancer disease. Electronic searches were performed up to January 11th 2012, identifying 16 randomised controlled trials for final data synthesis. The studies demonstrated that aerobic and resistance exercise improves upper and lower body muscle strength more than usual care. Few studies have assessed the effect of exercise on muscle mass. Most studies were performed in patients with early stage breast or prostate cancer. Evidence on the effect of physical exercise on muscle strength and mass in cancer patients with advanced disease is lacking. More exercise studies in patients with advanced cancer and at risk of cancer cachexia are warranted. PMID- 23932803 TI - Statin use and lower extremity amputation risk in nonelderly diabetic patients. AB - OBJECTIVE: To examine the association between use of statin and nonstatin cholesterol-lowering medications and risk of nontraumatic major lower extremity amputations (LEAs) and treatment failure (LEA or death). METHODS: A retrospective cohort of patients with Type I and Type 2 diabetes mellitus (diabetes) was followed for 5 years between 2004 and 2008. The follow-up exposure duration was divided into 90-day periods. Use of cholesterol-lowering agents, diabetic medications, hemoglobin A1c, body mass index, and systolic and diastolic blood pressures were observed in each period. Demographic factors were observed at baseline. Major risk factors of LEA including peripheral neuropathy, peripheral artery disease, and foot ulcers were observed at baseline and were updated for each period. LEA and deaths were assessed in each period and their hazard ratios (HRs) were estimated. The study took place in the U.S. Department of Veterans Affairs Healthcare system, and the subjects consisted of cholesterol drug-naive patients with Type I or II diabetes who were treated in the U.S. Department of Veterans Affairs Healthcare system in 2003 and were <65 years old at the end of follow-up. RESULTS: Of 83,953 patients in the study cohort, 217 (0.3%) patients experienced a major LEA and 11,716 (14.0%) patients experienced an LEA or death (treatment failure) after a mean follow-up of 4.6 years. Compared with patients who did not use cholesterol-lowering agents, statin users were 35% to 43% less likely to experience an LEA (HR, 0.65; 95% confidence interval [CI], 0.42-0.99) and a treatment failure (HR, 0.57; 95% CI, 0.54-0.60). Users of other cholesterol lowering medications were not significantly different in LEA risk (HR, 0.95; 95% CI, 0.35-2.60) but had a 41% lower risk of treatment failure (HR, 0.59; 95% CI, 0.51-0.68). CONCLUSIONS: This is the first study to report a significant association between statin use and diminished amputation risk among patients with diabetes. In this nonrandomized cohort, beneficial effects of statin therapy were similar to that seen in large-scale clinical trial experience. For LEA risk, those given nonstatins did not have a statistically significant benefit and its effect on LEA risk was much smaller compared with statins. Unanswered questions to be explored in future studies include a comparison of statins of moderate vs high potency in those with high risk of coronary heart disease and an exploration of whether the effects seen in this study are simply effects of cholesterol lowering or possibly pleiotropic effects. PMID- 23932805 TI - Toward better recognition of early predictors for autism spectrum disorders. AB - BACKGROUND: Identification and diagnosis of autism spectrum disorders is essentially based on behavioral presentation and developmental history. The current average age at diagnosis is older than 3 years. METHODS: Over the past 15 years, there has been increasing documentation of the early signs of autism spectrum disorders through both individual retrospective parental reports and screening studies. Recent longitudinal studies have focused on early medical and behavioral features of children regarded at risk, namely younger siblings of children with autism spectrum disorders or children who required neonatal intensive care, with a later diagnosis of autism spectrum disorders. RESULTS: Potentially useful early neurological signs and developmental predictors for autism spectrum disorders could be identified, with a typical profile that evolved with age. CONCLUSIONS: Assessment of early social attention and communication skills with adapted scales in children before the age of 18 months in very large community-based settings may lead to high positive predictive values. PMID- 23932806 TI - Neuropathic cachexia associated with type 1 diabetes in an adolescent girl. AB - BACKGROUND: Diabetic neuropathic cachexia is a rare and little understood variant of diabetic neuropathy. It predominantly affects men with type 2 diabetes mellitus in their sixth to seventh decades of life and is characterized by the subacute onset of a painful sensory neuropathy, rapid weight loss, and psychiatric comorbidity. METHODS: We present the only female pediatric case described to date, and one of only a handful of cases reported to affect type 1 diabetics. RESULTS: In this patient a diagnosis of diabetic neuropathic cachexia was based on the rapid onset of severe allodynic pain, polyneuropathy, and marked weight loss in the setting of poorly controlled diabetes, without evidence of end organ disease and exclusion of other known causes of neuropathy. CONCLUSIONS: Diabetic neuropathic cachexia is a complex neuroendocrinologic disorder characterized by profound weight loss, neuropathic pain, and mood disturbance. Electrodiagnostic abnormalities were pronounced showing a moderately severe generalized sensorimotor polyneuropathy. PMID- 23932807 TI - Seizures from valproate-carbapenem interaction. AB - BACKGROUND: Antiepileptic medication interactions can complicate the management of epilepsy, by either increasing or reducing the effective serum concentrations thereby causing adverse effects or loss of seizure control. RESULTS: A 14-year old girl with well-controlled juvenile absence epilepsy lost control of her seizures acutely following the administration of carbapenem for pneumonia. Serum valproate concentrations fell by 90% within 48 hours following carbapenem and returned to baseline following its discontinuation. CONCLUSIONS: Awareness of this clinically significant interaction alters clinical practice by avoiding carbapenem or temporary use of adjunctive medication to prevent the clinical consequences of this significant drug interaction. PMID- 23932808 TI - What causes sleep-disordered breathing in Chiari I malformation? Comment on: "MRI findings and sleep apnea in children with Chiari I malformation". PMID- 23932809 TI - Next generation sequencing for human papillomavirus genotyping. AB - BACKGROUND: Human papillomavirus (HPV) genotyping using next generation sequencing (NGS) could be useful to study the HPV variant-specific epidemiology, including monitoring for possible emergence of new HPV variants after introduction of HPV vaccination programs. OBJECTIVES: We wished to design and validate a method for rapid HPV detection, typing and sequencing in clinical samples. STUDY DESIGN: Plasmids of 15 different HPV types were mixed and serially diluted in human DNA in concentrations ranging from 1 to 100 copies per sample, amplified using the HPV general PCR primer pair PGMY and sequenced using 454 technology. Sixty cervical samples were tested both with the NGS-based method and with a comparison method based on genotyping using type-specific probes bound to fluorescent beads (Luminex). Thirty-three clinical samples were repeat tested using NGS to evaluate reproducibility. RESULTS: The NGS-based method correctly identified all 15 mixed HPV types when present in 100 copies/sample and 13/15 types when present in 10 copies/sample. For 36/60 cervical samples genotyping results using NGS and Luminex were identical. For 12/60 samples the NGS method was more sensitive than the Luminex test and most of the remaining discrepancies could be explained by the different type coverage of the assays. Reproducibility testing found complete or partial concordance in 30/33 samples. CONCLUSIONS: NGS provides a sensitive and accurate method for genotyping of HPV. The fact that also the amplimer sequence is obtained could be important for studying the epidemiology of viral variants and monitoring of HPV vaccination. PMID- 23932810 TI - Mechanistic investigations in sono-hybrid techniques for rice straw pretreatment. AB - This paper reports comparative study of two chemical techniques (viz. dilute acid/alkali treatment) and two physical techniques (viz. hot water bath and autoclaving) coupled with sonication, termed as sono-hybrid techniques, for hydrolysis of rice straw. The efficacy of each sono-hybrid technique was assessed on the basis of total sugar and reducing sugar release. The system of biomass pretreatment is revealed to be mass transfer controlled. Higher sugar release is obtained during dilute acid treatment than dilute alkali treatment. Autoclaving alone was found to increase sugar release marginally as compared to hot water bath. Sonication of the biomass solution after autoclaving and stirring resulted in significant rise of sugar release, which is attributed to strong convection generated during sonication that assists effective transport of sugar molecules. Discrimination between individual contributions of ultrasound and cavitation to mass transfer enhancement reveals that contribution of ultrasound (through micro streaming) is higher. Micro-turbulence as well as acoustic waves generated by cavitation did not contribute much to enhancing of mass transfer in the system. PMID- 23932811 TI - Effects of ultrasonic vibration on the micro-molding processing of polylactide. AB - A new ultrasonic micro-molding system was used to process polylactide (PLA) and fabricate reduced dimension specimens. Plasticization and molding of PLA were achieved by applying ultrasonic waves after feeding the polymer into a plasticizing chamber. Chemical and physical characteristics of processed PLA varied depending on the processing window (i.e. changes in ultrasonic wave amplitude between 14.2 and 48.1 MUm and molding pressure between 0.5 in 6 bars). In terms of chemical effects, the application of ultrasound can lead to lower molecular weights (e.g. decreases of more than 45% in the weight average molecular weight), revealing partial degradation of the material. Also, the processed materials exhibited slightly higher thermal degradability than pure PLA because ultrasonic vibrations break molecular linkages and worsen the polymer structure. Finally, the processing conditions for the preparation of PLA specimens could be optimized without causing degradation and preserving structural characteristics and mechanical properties. Specifically, the use of an amplitude of 48.1 MUm and a pressure of 3 bars gave samples with the same molecular weight as the raw material (i.e. 117,500 g/mol as opposed to 117,300 g/mol for Mw). PMID- 23932812 TI - Bilateral scaphotrapezium-trapezoid coalition with bipartite scaphoid: case report. AB - We report on a 15-year-old girl with bilateral scaphotrapezium-trapezoid coalitions and bipartite scaphoids. There was no history of trauma or any other associated pathology. Wrist pain was alleviated by arthrodesis of the pseudarthrosis of the scaphoid component of the coalitions. Coalition of the distal portions of the scaphoids may have interfered with union of 2 ossification centers of the scaphoid. It is also possible that the carpal coalitions predisposed the scaphoid to fracture and that this represents bilateral nonunion. PMID- 23932813 TI - Median to radial nerve transfers for restoration of wrist, finger, and thumb extension. AB - Radial nerve injury results in loss of wrist, finger, and thumb extension. Traditionally, radial nerve palsies that fail to recover spontaneously have been reconstructed with tendon transfers or nerve grafts. Nerve transfers are a novel approach to the surgical management of Sunderland grade IV and V radial nerve injuries. We describe our technique for median to radial nerve transfers. In this procedure, the flexor digitorum superficialis nerve is transferred to the extensor carpi radialis brevis nerve for wrist extension, and the flexor carpi radialis nerve is transferred to the posterior interosseous nerve for finger and thumb extension. Our experience with these nerve transfers has demonstrated excellent outcomes up to 10 months after injury. Indeed, unlike tendon transfers, median to radial nerve transfers have the potential to restore normal radial nerve function, including independent finger motion. Tension-free nerve coaptation and postoperative motor re-education are critical factors to achieving these successful outcomes. PMID- 23932814 TI - Inflammatory mediators in posttraumatic radiocarpal osteoarthritis. AB - PURPOSE: To identify the mediator profile in healthy, pre-osteoarthritis (OA) and end-stage OA radiocarpal joints. We hypothesized that there would be an increase in soluble mediators in posttraumatic wrist OA. METHODS: We obtained radiocarpal synovial fluid samples from 3 groups of patients: healthy control (n = 12) samples were collected during wrist ganglion resection; pre-osteoarthritic (n = 16) samples, during a 3-ligament tenodesis procedure for complete scapholunate dissociation; and end-stage OA (n = 20) samples in patients with proven radiological OA changes. Using a multiplex enzyme-linked immunosorbent assay, we measured 12 mediators: interleukin (IL)-1beta, tumor necrosis factor-alpha, oncostatin-M, interferon-gamma, IL-4, IL-6, IL-7, IL-8, IL-10, IL-13, IL-1RA, and osteoprotegerin. Statistical analysis was performed using analysis of variance and Bonferroni-corrected post hoc tests. RESULTS: Mediators IL-6, IL-10, and interferon-gamma were increased in OA wrists compared to healthy and pre-OA samples. Tumor necrosis factor-alpha, oncostatin-M, osteoprotegerin, IL-8, and IL 1RA were detected but not at increased levels in OA wrists. We found no differences between healthy and pre-OA joints in all 12 mediators. Mediators IL 4, IL-7, IL-13, and IL-1beta were not detected in either healthy, pre-OA or end stage OA samples. CONCLUSIONS: We identified no differences between healthy and pre-OA samples, suggesting no alteration in inflammatory status at the time of the 3-ligament tenodesis procedure. Consequently, mechanical disturbance seems to be the driving force toward OA and OA-associated inflammation in this stage of scapholunate dissociation. Increased levels of interferon-gamma, IL-6, and IL-10 confirm inflammatory changes in the mechanically disturbed posttraumatic radiocarpal joint. PMID- 23932815 TI - Symptomatic swelling on the lingual surface of the mandible. PMID- 23932816 TI - Chronic intracerebroventricular infusion of nerve growth factor improves recognition memory in the rat. AB - Nerve Growth Factor (NGF) plays pivotal roles in neuronal survival in the adult mammalian brain and may modulate forms of structural and functional plasticity, including neurogenesis. We have shown previously that six weeks of housing in an enriched environment (EE) that did not include access to running wheels resulted in improved recognition memory concomitant with increased NGF expression and neurogenesis in the hippocampus. Here we have attempted to probe a causal link between NGF and the observed enrichment-induced changes in hippocampal function by assessing the effects of six weeks continuous intracerebroventricular (i.c.v.) infusion of NGF on recognition memory and cell proliferation. We report that NGF infused rats show enhanced recognition memory when compared with vehicle-treated controls. Expression of NGF and its receptor, TrkA, was increased in treated rats, as was expression of the synaptic vesicle protein, synapsin. Finally, we observed an increase in cell proliferation in the dentate gyrus of NGF-treated rats. These data indicate that chronic infusion of NGF can stimulate an improvement in learning and memory that is associated with specific cellular changes in the hippocampus, including synaptogenesis and cell proliferation. PMID- 23932817 TI - Reply of the authors. PMID- 23932818 TI - Acupuncture - placebo? PMID- 23932819 TI - Seasonal and spatial variations of 210Po and 210Pb activity concentrations in Mytilus galloprovincialis from Croatian coast of the Adriatic Sea. AB - Results of 2 years monitoring of (210)Po and (210)Pb activity concentrations in soft tissue of the species Mytilus galloprovincialis from Croatian part of the Adriatic coast are presented. The samples were collected at thirteen coastal stations (some of which are also a part of the Mediterranean Mussel Watch Project) in spring and autumn of 2010 and 2011. The collected mussels were ranging between 4 cm and 6 cm in shell length. After sample pre-treatment lead and polonium were radiochemically separated on Sr resin. (210)Po was determined by alpha-particle spectrometry and (210)Pb was determined, via (210)Bi, by a low level gas proportional counter. The results of (210)Po activity concentrations were found to vary between (104+/-11) and (1421+/-81) Bq kg(-1) dry weight while (210)Pb activity concentrations were much lower and in range (8.2+/-5.3)-(94.1+/ 29.8) Bq kg(-1) dry weight. Higher (210)Po and (210)Pb activity concentrations were determined in spring period. The inter-site differences seen in their activity concentrations can be due to natural background levels of sites. The (210)Po/(210)Pb activity concentration ratios in all cases exceeded unity for all mussel samples and ranged between 4.0 and 47.9. PMID- 23932820 TI - Low dose effects and non-monotonic dose responses for endocrine active chemicals: science to practice workshop: workshop summary. AB - A workshop was held in Berlin September 12-14th 2012 to assess the state of the science of the data supporting low dose effects and non-monotonic dose responses ("low dose hypothesis") for chemicals with endocrine activity (endocrine disrupting chemicals or EDCs). This workshop consisted of lectures to present the current state of the science of EDC action and also the risk assessment process. These lectures were followed by breakout sessions to integrate scientists from various backgrounds to discuss in an open and unbiased manner the data supporting the "low dose hypothesis". While no consensus was reached the robust discussions were helpful to inform both basic scientists and risk assessors on all the issues. There were a number of important ideas developed to help continue the discussion and improve communication over the next few years. PMID- 23932821 TI - Earlier-start versus usual-start dialysis in patients with community-acquired acute kidney injury: a randomized controlled trial. AB - BACKGROUND: Optimum timing of the initiation of dialysis therapy in acute kidney injury is not clear. STUDY DESIGN: Prospective, open label, 2-arm, randomized, controlled trial. SETTING & PARTICIPANTS: 208 adults with acute kidney injury with progressively worsening azotemia at the artificial kidney dialysis unit of a tertiary-care referral center in western India. INTERVENTION: Earlier-start dialysis was initiated when serum urea nitrogen and/or creatinine levels increased to 70 and 7 mg/dL, respectively, whereas the usual-start dialysis patients (control group) received dialysis when clinically indicated as judged by treating nephrologists. OUTCOMES: Primary outcome was in-hospital mortality and dialysis dependence at 3 months. Secondary outcome in patients receiving dialysis was time to recovery of kidney function, computed from time of enrollment to the last dialysis session. RESULTS: Of 585 screened patients, 102 were assigned to earlier-start dialysis, and 106 to usual-start dialysis. Baseline characteristics were similar between randomized groups. 93 (91.1%) and 88 (83.1%) participants received dialysis in the intervention and control groups, respectively. Mean serum urea nitrogen and serum creatinine levels at dialysis therapy initiation were 71.7 +/- 21.7 (SD) and 7.4 +/- 5.3 mg/dL, respectively, in the intervention group versus 100.9 +/- 32.6 and 10.41 +/- 3.3 mg/dL in the control group. Data on primary outcome were available for all patients. In-hospital mortality was 20.5% and 12.2% in the intervention and control groups, respectively (relative risk, 1.67; 95% CI, 0.88-3.17; P = 0.2). 4.9% and 4.7% of patients in the intervention and control groups, respectively, were dialysis dependent at 3 months (relative risk, 1.04; 95% CI, 0.29-3.7; P = 0.9). LIMITATIONS: Study was not double blind, event rate (ie, mortality) was less than predicted, wide CIs preclude definitive findings. CONCLUSIONS: Our data do not support the earlier initiation of dialysis therapy in community-acquired acute kidney injury. PMID- 23932822 TI - Percutaneous anterior occiput-to-axis screw fixation: technique aspects and case series. AB - BACKGROUND CONTEXT: Posterior occipitocervical fusion techniques have been previously described; however, traditional open anterior approaches are plagued by exposure difficulty. A minimally invasive percutaneous anterior occipitocervical fixation approach avoids this difficult exposure procedure. PURPOSE: This article describes a novel technique of percutaneous anterior occiput-to-axis screw fixation and its clinical outcomes. STUDY DESIGN: Technique report. METHODS: Anteroposterior, lateral and open-mouth views, and computed tomography scans are preoperatively obtained to appraise the feasibility of surgery. We extend our experience of using percutaneous anterior transarticular screw fixation to occiput-to-axis screw fixation. This procedure was performed on six patients. RESULTS: The operation was successfully performed on all patients without technical difficulties, and no vertebral artery, nerve injury or soft tissue (such as esophageal) complications occurred. All six patients followed up 10 to 39 months (averaged 20.5 months). Bone union was achieved in five patients, and the one patient lacking bone union was stable at final follow-up. The syringomyelia of four patients is almost complete reduction. No screw loosening or breakage has occurred. CONCLUSIONS: With the correct puncture point, angle of insertion, and use of the appropriate tools, we suggest that percutaneous anterior occiput-to-axis fixation technique is a feasible, safe, and minimally invasive procedure. PMID- 23932823 TI - Intramedullary arachnoid cyst in association with cervical spondylosis: case report. AB - BACKGROUND CONTEXT: Intramedullary spinal arachnoid cysts are considered to be very rare, and only 11 cases have been reported previously. Development of such a cyst in association with marked cervical spondylosis has not been reported until recently. PURPOSE: Brief review of reported cases and debate on likely treatment strategy when such a cyst is associated with symptomatic spondylosis. STUDY DESIGN: To report the first example of a cervicothoracic intramedullary arachnoid cyst along with a symptomatic cervical spondylosis. METHODS: Evaluation of quadriparesis in a 58-year-old female resulted in detection of a cervical spondylotic stenosis that was accompanied with an intramedullary cystic lesion. Parallel management of both pathologies was through a wide laminectomy extending from the lower edge of C3 to T2 with subsequent fenestration and partial resection of the cyst wall via an appropriate dorsal entry root zone myelotomy. Cervicothoracic instrumentation from C3 down to T2 was done to prevent postlaminectomy deformity. RESULT: Histopathological findings were consistent with the diagnosis of arachnoid cyst. Postoperatively, the patient exhibited marked improvement in neurologic status. CONCLUSION: Through the review of the current case, first example from the literature, we concluded that surgery should target toward the proper management of both pathologies in a single-stage operation. PMID- 23932824 TI - Anti-proliferative effects of a new docosapentaenoic acid monoacylglyceride in colorectal carcinoma cells. AB - N-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to inhibit the induction and progression of many tumor types. However, the anticancer effect of n-3 PUFA monoglyceride on colorectal cancer has yet to be assessed. The aim of the present study was to determine the anti-tumorigenic effects of docosahexaenoic acid monoglyceride (MAG-DHA), eicosapentaenoic acid monoglyceride (MAG-EPA) and docosapentaenoic acid (22:5n-3) monoglyceride (MAG-DPA) in colorectal carcinoma cells. Our results demonstrate that MAG-DHA, MAG-EPA and MAG DPA all decreased cell proliferation and induced apoptosis in HCT116 cells, with MAG-DPA having the higher anti-proliferative and pro-apoptotic effects in vitro. In a HCT116 xenograft mouse model, oral administration of MAG-DPA significantly inhibited tumor growth. Furthermore, MAG-DPA treatments decreased NFkappaB activation leading to a reduction in Bcl-2, CyclinD1, c-myc, COX-2, MMP9 and VEGF expression levels in tumor tissue sections. Altogether, these data provide new evidence regarding the mode of action of MAG-DPA in colorectal cancer cells. PMID- 23932825 TI - Evaluation of respiratory protection programs and practices in California hospitals during the 2009-2010 H1N1 influenza pandemic. AB - BACKGROUND: Emergence of the novel 2009 influenza A H1N1 virus in California led to an evaluation of hospital respiratory protection programs (RPPs) and practices by the California Department of Public Health during the 2009-2010 influenza season. METHODS: Onsite evaluation of 16 hospitals consisted of interviews with managers and health care workers about RPPs and practices, review of written RPPs, and limited observations of personnel using respirators. Data were analyzed using descriptive statistics. RESULTS: All hospitals had implemented policies requiring the minimum use of N95 filtering facepiece respirators when working with patients with H1N1 virus infection; 95.5% of health care workers (n = 199) reported they would wear at least this level of protection when in close contact with a patient with confirmed or suspected H1N1 virus infection. However, evaluation of written RPPs indicated deficiencies in required areas, most commonly in recordkeeping, designation of a program administrator, program evaluation, employee training, and fit testing procedures. CONCLUSIONS: Health care workers were aware of respiratory protection required when providing care for patients with confirmed or suspected H1N1 virus infection. Hospitals should improve written RPPs, fully implement written procedures, and conduct periodic program evaluation to ensure effectiveness of respirator use for health care worker protection. Increased accessibility of resources tailored for hospital respirator program administrators may be helpful. PMID- 23932826 TI - Comprehensive survey of hand hygiene measurement and improvement practices in the Veterans Health Administration. AB - BACKGROUND: Veterans Health Administration (VHA) is a national health care system with variation in hand hygiene (HH) measurement and improvement practices across its facilities. The objective of this national survey was to characterize this variability and identify opportunities for standardization. METHODS: Survey covered 3 major areas of HH: (1) methods of measuring HH compliance, (2) interventions to improve HH compliance, and (3) site-specific targets for HH compliance. RESULTS: One hundred forty-one (100%) VHA medical centers returned the survey. A majority (98.6%) of the medical centers conduct direct observations to measure HH compliance rates. Fewer than half (45.3%) validate the observer process at the onset, and fewer still (39.6%) continue to validate observers. Main behaviors that are considered HH opportunities are room entry (69.1%) and exit (71.9%). Improvement interventions include posters (97.2%), feedback (eg, 98.6% to leadership), and improved access to HH products (eg, 90.6% provide individual hand sanitizers to staff). Mandatory education programs for clinical staff are conducted in 88.5% of the medical centers. The majority of the medical centers (77.3%) set their HH compliance target over 90%. CONCLUSION: Although HH improvement interventions are relatively similar across VHA medical centers, variation exists in compliance monitoring. Findings will assist in standardizing surveillance and next steps in hand hygiene policy in VHA. PMID- 23932827 TI - Compliance of Jordanian registered nurses with infection control guidelines: a national population-based study. AB - BACKGROUND: This national study aims to evaluate compliance of Jordanian staff nurses with infection control guidelines. METHODS: Cross-sectional, descriptive design was used. Proportional-multistage, probability sampling was used to obtain a sample of 10% of all staff nurses working in Jordanian hospitals. Standardized self-reported instruments were used to evaluate the compliance. RESULTS: The total sample consisted of 22 hospitals, of which 8 were governmental, 7 military, 5 private, and 2 university-affiliated hospitals. Of the total 889 participating nurses, 52.6% were females, 81.9% holding a bachelor degree. The mean age was 29.0 years (standard deviation [SD] = 5.9) with a mean of experience of 6.9 years (SD = 5.8). According to the scale categories, 65.0% of participants demonstrated "high compliance," 32.3% "weak compliance," and 2.7% "unsafe compliance." Nurses who received infection control training in the hospital demonstrated higher compliance (mean = 120.2, SD = 13.6); than those who never received such training (mean = 115.8, SD = 15.2), P < .001. Nurses who work in university affiliated hospitals demonstrated higher compliance than other types of hospital (P < .001). CONCLUSION: This study provides information about infection control practices in various health care sectors in Jordan. Results from this study expected to guide efforts to develop educational tools, programs, and curricula to improve infection control practices in Jordan. PMID- 23932828 TI - Inappropriate use of antibiotics and Clostridium difficile infection. AB - We assessed appropriateness of preceding and concurrent antibiotics in 126 consecutive patients with hospital-associated Clostridium difficile infection. In 93 (73.8%) episodes, at least 1 preceding course of antibiotics was inappropriate. We provided feedback on concurrent antibiotics on the day of diagnosis during the final 8 months: 17 of 74 (23.0%) patients were on inappropriate antibiotics. Our recommendations were well received. Reviewing C difficile-infected patients allowed for identification of opportunities to improve antibiotic utilization and potentially improved patient outcomes. PMID- 23932830 TI - [Breast cancer in males. Presentation of a case]. PMID- 23932829 TI - First step to reducing infection risk as a system: evaluation of infection prevention processes for 71 hospitals. AB - BACKGROUND: Hospitals can better focus their efforts to prevent health care associated infections (HAIs) if they identify specific areas for improvement. METHODS: We administered a 96-question survey to infection preventionists at 71 Ascension Health hospitals to evaluate opportunities for the prevention of catheter-associated urinary tract infection, central line-associated bloodstream infection, ventilator-associated pneumonia, and surgical site infection. RESULTS: Seventy-one (100%) infection preventionists completed the survey. The majority of hospitals had established policies for urinary catheter placement and maintenance (55/70, 78.6%), central venous catheter maintenance (68/71, 95.8%), and care for the mechanically ventilated patient (62/66, 93.9%). However, there was variation in health care worker practice and evaluation of competencies and outcomes. When addressing device need, 55 of 71 (77.5%) hospitals used a nurse-driven evaluation of urinary catheter need, 26 of 71 (36.6%) had a team evaluation for central venous catheters on transfer out of intensive care, and 53 of 57 (93%) assessed daily ventilator support for continued need. Only 19 of 71 (26.8%) hospitals had annual nursing competencies for urinary catheter placement and maintenance, 29 of 71 (40.8%) for nursing venous catheter maintenance, and 38 of 66 (57.6%) for appropriate health care worker surgical scrubbing. CONCLUSION: We suggest evaluating infection prevention policies and practices as a first step to improvement efforts. The next steps include implementing spread of evidence-based practices, with focus on competencies and feedback on performance. PMID- 23932831 TI - [Low back pain: atypical presentation of multiple sclerosis]. PMID- 23932832 TI - [The next society]. PMID- 23932833 TI - Sedation-related outcomes in postoperative management of pediatric laryngotracheal reconstruction. AB - OBJECTIVE: Examine outcomes of varied postoperative sedation management in pediatric patients recovering from single stage laryngotracheal reconstruction. DESIGN: Retrospective review of 34 patients treated with single stage laryngotracheal reconstruction from 2001 through 2011. SETTING: Tertiary children's hospital. METHODS: Patients were divided into 2 groups: those managed postoperatively with sedation, with or without paralysis (group 1), and those managed awake with narcotic pain medication as needed for primary management (group 2). Outcomes were measured as a function of sedation management. Outcomes investigated focused on those related to the success of the airway reconstruction, and those related to sedation management. RESULTS: Out of 68 cases of laryngotracheal reconstruction reviewed from 2001 to 2011, 34 were single stage reconstructions. Nineteen patients were sedated postoperatively (group 1) and fifteen patients were left awake (group 2). There were no significant differences between groups in airway-related outcomes, including risk of accidental decannulation, revision rates, and need for secondary airway procedures such as balloon dilation. Sedation-related outcomes, specifically focusing on differences in medical management, showed significant increases in rates of withdrawal (p<0.0001), nursing concerns of withdrawal (p<0.0001) and sedation level (p<0.0001), pulmonary complications (OR 7.7, p=0.008), and prolonged hospital stay due to withdrawal (p=0.0005) in patients managed with sedation with or without paralysis. Multivariable regression analysis revealed that duration of sedation was the primary risk factor for increased postoperative morbidity, while younger age, lower weight, and use of a posterior graft were also significant variables assessed. CONCLUSION: Avoiding sedation as the standard for postoperative management of single stage laryngotracheal reconstruction airway patients leads to an overall decreased risk of morbidity without increasing risk of airway-specific morbidity. This is specifically as related to withdrawal, pulmonary complications, concerns about sedation level and prolonged hospital course, all of which increase significantly with increased level and duration of sedation. PMID- 23932834 TI - Evaluation of the effect of aromatherapy with lavender essential oil on post tonsillectomy pain in pediatric patients: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of aromatherapy with Lavandula angustifolia essential oil on post-tonsillectomy pain in pediatric patients. METHODS: This was a randomized controlled prospective clinical trial. In this study, 48 post tonsillectomy patients aged 6-12 years were randomly assigned to two groups (24 patients in each group). After tonsillectomy surgery, all patients received acetaminophen (10-15 mg/kg/dose, PO) every 6h as necessary to relieve pain. The patients of the case group also inhaled lavender essential oil. The frequencies of daily use of acetaminophen and nocturnal awakening due to pain, and pain intensity (evaluated using visual analog scale [VAS]) were recorded for each patient for 3 days after surgery. Finally, the mean values of variables were compared between two groups separately for each post-operative day. RESULTS: The use of lavender essential oil caused statistically significant reduction in daily use of acetaminophen in all three post-operative days but had not significant effects on pain intensity and frequency of nocturnal awakening. CONCLUSION: Aromatherapy with lavender essential oil decreases the number of required analgesics following tonsillectomy in pediatric patients. PMID- 23932835 TI - Praseodymium-142 microspheres for brachytherapy of nonresectable hepatic tumors. AB - PURPOSE: To perform dosimetric study of (142)Pr microspheres for the use as a possible choice of radionuclide in microsphere brachytherapy of nonresectable hepatic tumor for faster dose delivery and facilitated dosimetry for quality assurance. METHODS AND MATERIALS: Dose distributions of (142)Pr and (90)Y microspheres within hepatic tumors and blood vessels were calculated using MCNPX2.6 Monte Carlo code. The biological effective doses (BEDs) for (142)Pr and (90)Y microspheres were calculated and compared using the linear-quadratic model. RESULTS: Dose distributions due to beta particles were similar for both (142)Pr and (90)Y. Total initial activity required to achieve the same total dose of 150 Gy at 2 cm from the center of the tumor was 0.662 GBq and 0.191 GBq for (142)Pr and (90)Y, respectively. For alpha/beta ratio equal to 10 Gy, calculated BED values were 301.0 and 194.7 for (142)Pr and (90)Y, respectively, considering a total physical dose of 150 Gy. CONCLUSIONS: Total dose delivery and dose distributions for both (142)Pr and (90)Y within tumors and blood vessels were obtained and compared. Shorter half-life of (142)Pr is an advantage, enabling a faster dose delivery. The higher BED found for (142)Pr implies potential improvement in the treatment effectiveness. (142)Pr showed to be an attractive option for applications in microsphere brachytherapy. PMID- 23932836 TI - Emphysematous prostatic abscess: rare case and systematic review. PMID- 23932837 TI - Cost-effectiveness analysis of carrier and prenatal genetic testing for X-linked hemophilia. AB - BACKGROUND/PURPOSE: Hemophilia involves a lifelong burden from the perspective of the patient and the entire healthcare system. Advances in genetic testing provide valuable information to hemophilia-affected families for family planning. The aim of this study was to analyze the cost-effectiveness of carrier and prenatal genetic testing in the health-economic framework in Taiwan. METHODS: A questionnaire was developed to assess the attitudes towards genetic testing for hemophilia. We modeled clinical outcomes of the proposed testing scheme by using the decision tree method. Incremental cost-effectiveness analysis was conducted, based on data from the National Health Insurance (NHI) database and a questionnaire survey. RESULTS: From the NHI database, 1111 hemophilic patients were identified and required an average medical expenditure of approximately New Taiwan (NT) $2.1 million per patient-year in 2009. By using the decision tree model, we estimated that 26 potential carriers need to be tested to prevent one case of hemophilia. At a screening rate of 79%, carrier and prenatal genetic testing would cost NT $85.9 million, which would be offset by an incremental saving of NT $203 million per year by preventing 96 cases of hemophilia. Assuming that the life expectancy for hemophilic patients is 70 years, genetic testing could further save NT $14.2 billion. Higher screening rates would increase the savings for healthcare resources. CONCLUSION: Carrier and prenatal genetic testing for hemophilia is a cost-effective investment in healthcare allocation. A case management system should be integrated in the current practice to facilitate patient care (e.g., collecting family pedigrees and providing genetic counseling). PMID- 23932838 TI - Anxiety comorbidity in schizophrenia. AB - Diagnostic and treatment hierarchical reductionisms have led to an oversight of anxiety syndromes in schizophrenia. Nevertheless, recent data have indicated that anxiety can be a significant source of morbidity in this patient group. This paper reviews current knowledge concerning anxiety comorbidity in schizophrenia, its epidemiology, course, and treatment. A computerized search of the literature published from 1966 to July 2012 was conducted on Medline. Comorbid anxiety disorders are present in 38.3% of subjects with schizophrenia spectrum disorders. The most common anxiety disorder is social phobia followed by post-traumatic stress disorder and obsessive compulsive disorder. The presence and severity of symptoms of anxiety are associated with more severe clinical features and poorer outcomes. Available literature on the treatment consists primarily of case reports and open trials. Fragments of data support the notion of treating these anxiety states and syndromes as co-occurring clinical conditions with adjunctive medications and psychosocial interventions. However, additional work remains to be done on this issue before firm conclusions can be drawn. PMID- 23932839 TI - The taxonicity of schizotypy: does the same taxonic class structure emerge from analyses of different attributes of schizotypy and from fundamentally different statistical methods? AB - Findings on the population distribution of schizotypy consistently point toward an underlying class structure. However, past research is methodologically homogeneous, chiefly involving analysis of attribute-specific indicators and coherent cut kinetic methods such as maximum covariance (MAXCOV) analysis. Two questions are examined. Are different or overlapping classes identified from different attributes of the schizophrenia phenotype? Do fundamentally different approaches to analysis yield consistent results? Participants (n=1074) completed the Schizotypal Personality Questionnaire (SPQ). Following item screening, MAXCOV analyses were conducted iteratively on attribute-specific item sets (cognitive perceptual, interpersonal, and disorganized) and a general item set. Latent variable modeling (factor analysis, latent class analysis, and factor-mixture modeling) was used to examine the consistency of the MAXCOV results using items retained in the general set following MAXCOV analysis. Attribute-specific and general item sets gave taxonic MAXCOV curves and base rates of 8.4-10.4% and 3.6%, respectively. Classes were not independent. No latent variable model emerged as uniquely superior but five models distinguished a small high-scoring class populated by members of the MAXCOV general class. Different attributes distinguished overlapping yet nonredundant taxa, and a general schizotypy taxon identified with MAXCOV was also identified in latent variable modeling. PMID- 23932840 TI - Vocational functioning in schizotypal and paranoid personality disorders. AB - Impaired vocational functioning is a hallmark of schizophrenia, but limited research has evaluated the relationships between work and schizophrenia-spectrum personality disorders, including schizotypal (SPD) and paranoid personality disorder (PPD). This study compared employment history and job characteristics of 174 individuals drawn from the community or clinic, based on four personality disorder groups: SPD Only, PPD Only, SPD+PPD, and No SPD or PPD. Symptoms and cognitive functioning were also assessed. Both PPD and/or SPD were associated with lower rates of current employment, and a history of having worked at less cognitively complex jobs than people without these disorders. Participants with PPD were less likely to have a history of competitive work for one year, whereas those with SPD tended to have worked at jobs involving lower levels of social contact, compared with those without these disorders. When the effects of symptoms and cognitive functioning were statistically controlled, PPD remained a significant predictor of work history, and SPD remained a significant predictor of social contact on the job. The findings suggest that impaired vocational functioning is an important characteristic of SPD and PPD. PMID- 23932841 TI - Maternal alcohol consumption producing fetal alcohol spectrum disorders (FASD): quantity, frequency, and timing of drinking. AB - BACKGROUND: Concise, accurate measures of maternal prenatal alcohol use are needed to better understand fetal alcohol spectrum disorders (FASD). METHODS: Measures of drinking by mothers of children with specific FASD diagnoses and mothers of randomly-selected controls are compared and also correlated with physical and cognitive/behavioral outcomes. RESULTS: Measures of maternal alcohol use can differentiate maternal drinking associated with FASD from that of controls and some from mothers of alcohol-exposed normals. Six variables that combine quantity and frequency concepts distinguish mothers of FASD children from normal controls. Alcohol use variables, when applied to each trimester and three months prior to pregnancy, provide insight on critical timing of exposure as well. Measures of drinking, especially bingeing, correlate significantly with increased child dysmorphology and negative cognitive/behavioral outcomes in children, especially low non-verbal IQ, poor attention, and behavioral problems. Logistic regression links (p<.001) first trimester drinking (vs. no drinking) with FASD, elevating FASD likelihood 12 times; first and second trimester drinking increases FASD outcomes 61 times; and drinking in all trimesters 65 times. Conversely, a similar regression (p=.008) indicates that drinking only in the first trimester makes the birth of a child with an FASD 5 times less likely than drinking in all trimesters. CONCLUSIONS: There is significant variation in alcohol consumption both within and between diagnostic groupings of mothers bearing children diagnosed within the FASD continuum. Drinking measures are empirically identified and correlated with specific child outcomes. Alcohol use, especially heavy use, should be avoided throughout pregnancy. PMID- 23932842 TI - Differential effects of methadone and buprenorphine on the response of D2/D3 dopamine receptors in adolescent mice. AB - BACKGROUND: There is a lack of studies that examine the effects of opioid maintenance drugs on the developing adolescent brain, limiting the ability of physicians to conduct a science-based risk assessment on the appropriateness of these treatments for that age group. Our recent observations indicate higher potential risks in repeated exposure to morphine during adolescence, specifically to the D2/D3 dopamine receptors' signaling. Disturbances in dopaminergic signaling could have broader implications for long-term mental health. Thus, this study examined whether buprenorphine and methadone differentially alter the responses of the D2/D3 dopamine receptors in adolescents. METHODS: Adolescent mice were orally administered buprenorphine (0.1-0.4 mg/kg), methadone (25-100 mg/kg), or saline once daily for 6 days. Two hours or three days later, the mice were tested for their locomotor response to 10 mg/kg quinpirole, a D2/D3 dopamine receptor agonist. RESULTS: Buprenorphine-treated adolescent mice did not significantly differ from control drug-naive animals in their response to quinpirole. However, an enhanced response was observed in methadone-treated adolescent animals. This enhanced locomotion was significantly higher two hours following the final dose of methadone, as compared to three days afterwards. CONCLUSIONS: This study suggests that exposure to various opioids carries differential probabilities of altering the highly sensitive neurochemistry of adolescent brains. Methadone exposure disturbs the D2-like receptor's response, indicating a potential risk in administering methadone to adolescents (either for the treatment of opioid dependency/abuse or for pain management). In contrast, buprenorphine appears to have a significantly lower effect on the behavioral sensitivity of D2/D3 dopamine receptors in adolescents. PMID- 23932843 TI - Client and staff experiences of a co-located service for hepatitis C care in opioid substitution treatment settings in New South Wales, Australia. AB - BACKGROUND: Internationally, there are ongoing efforts to increase access to hepatitis C (HCV) assessment and treatment to counter a generally low uptake of treatment among people with a history of injecting drug use. The aim of this qualitative study was to examine client and staff attitudes towards and experience of co-location of HCV and opioid substitution treatment (OST) services. METHODS: In-depth interviews were conducted with 57 clients and 19 staff from four NSW clinics participating in the Australian ETHOS study. RESULTS: Client and staff participants typically welcomed integrated treatment, citing issues of convenience, reduced travel time and costs, persistent cues to engagement and immediacy of access to care. Positive attitudes towards the initiative were expressed even by clients who had not engaged with HCV care. Providing co-located care largely avoided the negative, stigmatising or discriminatory experiences that participants reported encountering in settings less familiar with people who use drugs. A minority of client participants expressed concerns about the lack of privacy and/or confidentiality available in the co-located model, preferring to seek HCV care elsewhere. CONCLUSIONS: The co location of HCV care in OST clinics was welcomed by the large majority of participants in this study. Besides issues of convenience, the appeal of the co located service centred on the familiarity of existing relationships between clients and staff in the OST setting. While some clients remained distrustful of OST and chose not to take up HCV care in this setting, the co-located treatment model was overwhelmingly successful amongst both client and staff participants. PMID- 23932844 TI - A review of medical and substance use co-morbidities in Central Asian prisons: implications for HIV prevention and treatment. AB - BACKGROUND: HIV incidence in Central Asia is rising rapidly. People who inject drugs (PWIDs) contribute greatest to the epidemic, with more than a quarter of all HIV cases being in the criminal justice system (CJS). This review assembled and aggregated recent data on drug-related health problems and respective healthcare services in the CJS of Central Asia and the Republic of Azerbaijan. METHODS: Online databases and published literature (peer-reviewed and gray) were reviewed. Additionally, prison officials in the 6 countries were invited to participate in a survey and prison administrators from Kazakhstan, Kyrgyzstan and Tajikistan completed it. RESULTS: The data on conditions and healthcare in Central Asian prisons are inconsistent and lack unbiased details. Reporting is primarily based on "official" disease registries, which markedly underestimate prevalence. Even these limited data, however, indicate that HIV prevalence and drug-related health problems are high, concentrated and, in some countries, rising rapidly in CJS. Only some of the range of HIV prevention interventions recommended by international organizations have been implemented in the region with two of the crucial interventions, needle and syringe exchange programs (NSP) and opioid substitution therapy (OST), only available in prisons in Kyrgyzstan, with Tajikistan implementing a pilot NSP and contemplating introduction of prison based OST. CONCLUSIONS: Despite deficiencies in routine health reporting and insufficient HIV sentinel surveillance undertaken in prisons, the data available on the concentration of HIV within at-risk populations in prisons indicate a necessity to broaden the range and increase the scale the scale of HIV prevention and treatment services. PMID- 23932845 TI - Use of IAEA's phase-space files for the implementation of a clinical accelerator virtual source model. AB - In the present work, phase-space data files (phsp) provided by the International Atomic Energy Agency (IAEA) for different accelerators were used in order to develop a Virtual Source Model (VSM) for clinical photon beams. Spectral energy distributions extracted from supplied phsp files were used to define the radiation pattern of a virtual extended source in a hybrid model which is completed with a virtual diaphragm used to simulate both electron contamination and the shape of the penumbra region. This simple virtual model was used as the radiation source for dosimetry calculations in a water phantom. The proposed model proved easy to build and test, and good agreement with clinical accelerators dosimetry measurements were obtained for different field sizes. Our results suggest this simple method could be useful for treatment planning systems (TPS) verification purposes. PMID- 23932847 TI - Population data of the 46 insertion-deletion (INDEL) loci in population in Piaui State, Northeastern Brazil. PMID- 23932846 TI - Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance. AB - Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40 50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance is associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contributes to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin-angiotensin-aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance. PMID- 23932849 TI - Temporal variability in urinary excretion of bisphenol A and seven other phenols in spot, morning, and 24-h urine samples. AB - Human exposure to modern non-persistent chemicals is difficult to ascertain in epidemiological studies as exposure patterns and excretion rates may show temporal and diurnal variations. The aim of this study was to assess the temporal variability in repeated measurements of urinary excretion of bisphenol A (BPA) and seven other phenols. All analytes were determined using TurboFlow-LC-MS/MS. Two spot, three first morning and three 24-h urine samples were collected from 33 young Danish men over a three months period. Temporal variability was estimated by means of intraclass correlation coefficients (ICCs). More than 70% of the urine samples had detectable levels of BPA, triclosan (TCS), benzophenone-3 (BP 3) and sum of 2,4-dichlorophenol and 2,5-dichlorophenol (SigmaDCP). We found low to moderate ICCs for BPA (0.10-0.42) and SigmaDCP (0.39-0.72), whereas the ICCs for BP-3 (0.69-0.80) and TCS (0.55-0.90) were higher. The ICCs were highest for the two spot urine samples, which were collected approximately 4 days apart, compared with the 24-h urine samples and the first morning urine samples, which were collected approximately 40 days apart. A consequence of the considerable variability in urinary excretion of BPA may be misclassification of individual BPA exposure level in epidemiological studies, which may lead to attenuation of the association between BPA and outcomes. Our data do not support that collection of 24-h samples will improve individual exposure assessment for any of the analysed phenols. PMID- 23932850 TI - Trauma and reconstruction: it is in our DNA. PMID- 23932848 TI - Inheritance of the fittest mitochondria in yeast. AB - Eukaryotic cells compartmentalize their biochemical processes within organelles, which have specific functions that must be maintained for overall cellular health. As the site of aerobic energy mobilization and essential biosynthetic activities, mitochondria are critical for cell survival and proliferation. Here, we describe mechanisms to control the quality and quantity of mitochondria within cells with an emphasis on findings from the budding yeast Saccharomyces cerevisiae. We also describe how mitochondrial quality and quantity control systems that operate during cell division affect lifespan and cell cycle progression. PMID- 23932851 TI - Reply to: EVOCAPE 2 study: lack of prognostic significance of conventional peritoneal cytology in colorectal and gastric cancer? PMID- 23932852 TI - EVOCAPE 2 study: lack of prognostic significance of conventional peritoneal cytology in colorectal and gastric cancer? PMID- 23932853 TI - Sustained function of genetically modified porcine lungs in an ex vivo model of pulmonary xenotransplantation. AB - BACKGROUND: Xenotransplantation could provide a solution to the donor shortage that is currently the major barrier to solid-organ transplantation. The ability to breed pigs with multiple genetic modifications provides a unique opportunity to explore the immunologic challenges of pulmonary xenotransplantation. METHODS: Explanted lungs from wild-type and 3 groups of genetically modified pigs were studied: (i) alpha1,3-galactosyltransferase gene knockout (GTKO); (ii) GTKO pigs expressing the human complementary regulatory proteins CD55 and CD59 (GTKO/CD55 59); and (iii) GTKO pigs expressing both CD55-59 and CD39 (GTKO/CD55-59/CD39). The physiologic, immunologic and histologic properties of porcine lungs were evaluated on an ex vivo rig after perfusion with human blood. RESULTS: Lungs from genetically modified pigs demonstrated stable pulmonary vascular resistance and better oxygenation of the perfusate, and survived longer than wild-type lungs. Physiologic function was inversely correlated with the degree of platelet sequestration into the xenograft. Despite superior physiologic profiles, lungs from genetically modified pigs still showed evidence of intravascular thrombosis and coagulopathy after perfusion with human blood. CONCLUSIONS: The ability to breed pigs with multiple genetic modifications, and to evaluate lung physiology and histology in real-time on an ex vivo rig, represent significant advances toward better understanding the challenges inherent to pulmonary xenotransplantation. PMID- 23932854 TI - Weighing the evidence: risks and benefits of participatory documentary in corporatized clinics. AB - This paper describes the effects of one U.S.-based public psychiatry clinic's shift to a centralized, corporate style of management, in response to pressures to cut expenditures by focusing on "evidence based" treatments. Participant observation research conducted between 2008 and 2012 for a larger study involving 127 interviews with policy makers, clinic managers, clinical practitioners and patients revealed that the shift heralded the decline of arts based therapies in the clinic, and of the social networks that had developed around them. It also inspired a participatory video self-documentary project among art group members, to portray the importance of arts-based therapies and garner public support for such therapies. Group members found a way to take action in the face of unilateral decision making, but experienced subsequent restrictions on clinic activities and discharge of core members from the clinic. The paper ends with a discussion of biopolitics, central legibility through corporate standardization, and the potential and risks of participatory documentaries to resist these trends. PMID- 23932855 TI - Special issue on health system reform in Asia. PMID- 23932856 TI - Scaling-up the medical workforce in Timor-Leste: challenges of a great leap forward. AB - The health services system of Timor-Leste (T-L) will, by 2015, add 800 physicians, most of them trained in Cuba, to the 233 employed by the national health system in 2010-2011. The need for more physicians is not in discussion: poor health indicators, low coverage and utilization of services, and poor quality of services are well documented in T-L. However, the choice of this scaling-up, with a relatively narrow focus on the medical workforce, needs to be assessed for its relevance to the health profile of the country, for its comprehensiveness in terms of other complementary measures needed to make it effective. This article discusses the potential effects of the rapid scaling-up of the medical workforce, and the organizational capacity needed to monitor the process and eventually mitigate any deleterious consequences. The analysis is based on a review of documentation collected on site (T-L) and on interviews with key-informants conducted in 2011. We stress that any workforce scaling-up is not simply a matter of increasing numbers of professionals, but should combine improved training, distribution, working conditions, management and motivation, as a means towards better performing health services' systems. This is a major challenge in a context of limited organizational and managerial capacity, underdeveloped information systems, limited training and research capacity, and dependency on foreign aid and technical assistance. Potential risks are associated with funding the additional costs of recruiting more personnel, associated expenditures on infrastructure, equipment and consumables, the impact on current staff mix, and the expected increased demand for services. We conclude that failing to manage effectively the forthcoming "great leap forward" will have long term effects: formal policies and plans for the balanced development of the health workforce, as well as strengthened institutions are urgently needed. PMID- 23932857 TI - Integral backstepping sliding mode control for underactuated systems: swing-up and stabilization of the Cart-Pendulum System. AB - In this paper an integral backstepping sliding mode controller is proposed for controlling underactuated systems. A feedback control law is designed based on backstepping algorithm and a sliding surface is introduced in the final stage of the algorithm. The backstepping algorithm makes the controller immune to matched and mismatched uncertainties and the sliding mode control provides robustness. The proposed controller ensures asymptotic stability. The effectiveness of the proposed controller is compared against a coupled sliding mode controller for swing-up and stabilization of the Cart-Pendulum System. Simulation results show that the proposed integral backstepping sliding mode controller is able to reject both matched and mismatched uncertainties with a chattering free control law, while utilizing less control effort than the sliding mode controller. PMID- 23932858 TI - A fractional-order controller for vibration suppression of uncertain structures. AB - The problem of active control of vibration structures has attracted much attention over the past decades. A general description of the control problem of vibration systems is to design an active controller to suppress the vibrations of the system induced by external disturbances such as an earthquake. In this paper, a novel fractional-order sliding mode control is introduced to attenuate the vibrations of structures with uncertainties and disturbances. After establishing a stable fractional sliding surface, a sliding mode control law is proposed. Then, the global asymptotic stability of the closed-loop system is analytically proved using fractional Lyapunov stability theorem. Finally, the robustness and applicability of the technique are verified using two examples, including a three degree of freedom structure and a two-story shear building. PMID- 23932859 TI - Intrapulmonary shear stress enhancement: a new therapeutic approach in acute myocardial ischemia. AB - OBJECTIVE: Ischemic heart disease (IHD) is a leading cause of mortality with insufficient results of current therapies, most probably due to maintained endothelial dysfunction conditions. Alternatively, we propose a new treatment that promotes endothelial shear stress (ESS) enhancement using an intrapulmonary pulsatile catheter. METHODS: Twelve piglets, divided in equal groups of 6: pulsatile (P) and non-pulsatile (NP), underwent permanent left anterior descending coronary artery ligation through sternotomy. After 1 h of ischemia and heparin injection (150 IU/kg): in P group, a pulsatile catheter was introduced into the pulmonary trunk and pulsated intermittently over 1 h, and irrespective of heart rate (110 bpm). In NP group, nitrates were given (7 +/- 2 mg/kg/min) for 1 h. RESULTS: In P group all 6 animals survived ischemia for 120 min, but in NP group only 2 animals survived. The 4 animals that died during the experiment in NP group survived for 93 +/- 14 min. Hemodynamics and cardiac output (CO) were significantly improved in P group compared with NP group: CO was 0.92 +/- 0.15 vs. 0.52 +/- 0.08 in NP group (L/min; p < 0.05), respectively. Vascular resistances (dynes.s.cm(-5)/kg) were significantly (p < 0.05) lower in P group versus NP group: pulmonary resistance was 119 +/- 13 vs. 400 +/- 42 and systemic resistance was 319 +/- 43 vs. 1857 +/- 326, respectively. Myocardial apoptosis was significantly (p < 0.01) lower in P group (0.66 +/- 0.07) vs. (4.18 +/- 0.27) in NP group. Myocardial endothelial NO synthase mRNA expression was significantly (p < 0.01) greater in P group (0.90 +/- 0.09) vs. (0.25 +/- 0.04) in NP group. CONCLUSIONS: Intrapulmonary pulsatile catheter could improve hemodynamics and myocardial contractility in acute myocardial ischemia. This represents a cost effective method, suitable for emergency setting as a first priority, regardless of classical coronary reperfusion. PMID- 23932861 TI - Magnetocardiographic demonstration of complex ventricular preexcitation resulting in ablation failure. PMID- 23932860 TI - Relationship of CRP, IL-6, and fibrinogen with right ventricular structure and function: the MESA-Right Ventricle Study. AB - BACKGROUND/OBJECTIVES: Inflammation contributes to the pathogenesis of disease associated with the left ventricle (LV); yet, our understanding of the effect of inflammation on the right ventricle (RV) is quite limited. METHODS AND RESULTS: The relationships of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with RV morphology and function (from cardiac MRI) were examined in participants free of clinical cardiovascular disease (n=4009) from the Multi Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of CRP, IL-6 and fibrinogen with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF). Unadjusted and adjusted analyses revealed strong inverse associations between both CRP and IL-6 with RV mass, RVEDV, RVESV and RVSV (all p<0.01); there were no associations with RVEF. These relationships remained significant after adjustment for the respective LV parameters and lung function. However, GAM models suggested that extreme values of CRP and IL-6 might have positive associations with RV parameters. Fibrinogen showed significant associations in unadjusted models, but no associations after adjustment or in sensitivity analyses. CONCLUSION: Levels of CRP and IL-6 are independently associated with RV morphology even after adjustment for the respective LV measure in this multi-ethnic population free of clinical cardiovascular disease. Systemic inflammation may contribute to RV structural changes independent of effects on the LV. PMID- 23932862 TI - Optical coherence tomography analysis of strut coverage in biolimus- and sirolimus-eluting stents: 3-month and 12-month serial follow-up. AB - BACKGROUND: No randomized studies have been conducted to investigate serial changes in optical coherence tomography (OCT) analyses following implantation of biolimus-A9-eluting stents (BES) and sirolimus-eluting stents (SES). METHODS: A total of 60 patients fulfilling the study criteria were randomly assigned into BES (n=30) and SES (n=30) implantation groups. Serial OCT evaluation at post procedure, 3- and 12-month follow-up was performed in 46 patients [BES (n=22) and SES (n=24)]. OCT analyses were compared according to the type of stents and the follow-up time intervals. The percentage of uncovered struts was defined as the ratio of uncovered struts to total struts in all cross-sections. The primary endpoint was the percentage change (Delta) of uncovered struts in the 3- and 12 month follow-up samples. RESULTS: The percentage of uncovered struts at the 3 month time period was not significantly different in the BES and SES groups; the median value (interquartile range) was 14.7% (0.0-23.4) versus 8.6% (0.7-21.5) (p=0.98), respectively. However, OCT at the 12-month follow-up showed a significantly lower percentage of uncovered struts [2.6% (0.8-5.6) versus 6.2% (1.7-14.7), (p=0.028), respectively] without significant difference of neointimal thickness. BES showed a greater reduction of percentage Delta of uncovered struts from 3-12 months than that of SES [-17.2+/-14.5% versus -7.7+/-16.3%, respectively (p=0.043)]. CONCLUSIONS: Both drug-eluting stents showed a high percentage of incomplete strut coverage at 3 months. However, BES showed a significantly lower percentage of uncovered struts at 12 months compared to that of SES. This was achieved by superior strut coverage from 3 to 12 months. PMID- 23932863 TI - Are the guidelines universal and time-independent? PMID- 23932864 TI - Safety and efficacy of saline infusion for optical coherence tomography evaluation of vascular lesion induced by renal nerve ablation. PMID- 23932865 TI - Homocysteine-lowering interventions are ineffective in preventing myocardial infarction. PMID- 23932866 TI - Anemic comorbidity reduces capacity of endogenous thrombin generation and is associated with consumptive coagulopathy in patients with heart failure. PMID- 23932867 TI - Treatment of acute left internal mammary artery graft failure using a bio absorbable scaffold, guided by 3-dimensional optical coherence tomography. PMID- 23932868 TI - Dynamic left ventricular outflow tract obstruction as a complication of severe kyphosis: jeopardy of the excessive thoracic kyphosis. PMID- 23932869 TI - Cardioprotective SUR2A promotes stem cell properties of cardiomyocytes. PMID- 23932870 TI - Evaluation of diagnostic accuracy of 75th percentile threshold for a contemporary sensitive and a high-sensitivity cardiac troponin I immunoassays. PMID- 23932871 TI - What was new about vascular risk in the year 2012? PMID- 23932872 TI - Reduction and surveillance of device-associated infections in adult intensive care units at a Saudi Arabian hospital, 2004-2011. AB - BACKGROUND: Device-associated infections (DAI) are recognized as a marker of patient safety. Data regarding DAI rates in Saudi Arabia are sparse. METHODS: This was a prospective surveillance study of DAI rates conducted in the adult intensive care units of the Saudi Aramco Medical Services Organization, carried out using the DAI definition provided by the Centers for Disease Control and Prevention's National Healthcare Safety Network. DAI prevention bundles were introduced in 2006 for ventilator-associated pneumonia (VAP), in mid-2010 for catheter-associated urinary tract infections (CAUTI), and in 2008 for central line-associated blood stream infections (CLABSI). RESULTS: DAI rates for VAP, CLABSI, and CAUTI are reported for the study period from 2004 to 2011. CAUTI was the most common DAI (42.2%), followed by CLABSI (38.5%) and VAP (19.3%). The overall rate of each infection type per 1000 device-days was 8.18 for CAUTI, 10 for CLABSI, and 4.52 for VAP. Annual DAI rates showed a significant reduction over time from the beginning of the study to the end of the study for CLABSI (16.3 vs. 6.06), CAUTI (6.75 vs. 3.41), and VAP (9.8 vs. 1.3) (p<0.05). CONCLUSIONS: CAUTI was the most common infection, and the use of DAI prevention bundles was associated with a significant decrease in DAI rates over time. PMID- 23932873 TI - [Reasons for low usage of strep A rapid antigen detection tests for pharyngitis in private medical practice]. AB - Rapid group A Streptococcus (GAS) antigen detection tests (RDT) have high diagnostic performance for the management of acute pharyngitis and are recommended before any antibiotic (ATB) prescription in France to reduce ATB use. The rate of general practitioners (GPs) using GAS RDT is low and decreasing. Our aims were to describe the reasons for pediatricians and GPs not using RDT or for prescribing ATB despite of a negative RDT. METHODS: In 2011, a survey was conducted in a random sample of 368 GPs plus all ambulatory pediatricians (n=82) in the Nord-Pas-de-Calais region of France. RESULTS: Response rates were 74% (n=61) for pediatricians and 18% (n=68) for GPs. RDTs for pharyngitis were used by 75% [95% CI: 63-85] of pediatricians and 53% [95% CI: 41-64] of GPs (P<0.001). RDTs were systematically used in children 3years of age and older by only 59% of all physicians using RDTs. An ATB was systematically prescribed in case of positive RDT by 96% of physicians and eventually prescribed in case of negative RDT by 74%. The main reasons for ATB prescription in case of negative RDT were association with otitis media (51%), second visit for the same pharyngitis (45%), and high clinical suspicion of GAS pharyngitis (36%). Forty percent of non-RDT users had used them in the past. The 3 main reasons for not using RDT were the lack of time (57%), high confidence in clinical data to discriminate GAS pharyngitis (48%), and low confidence in RDT (27%). DISCUSSION: This survey highlights the lack of knowledge about low and high discriminant values of clinical data and RDT, respectively, especially the excellent negative predictive value of RDTs, and an erroneous assessment of the low risk of missing GAS pharyngitis compared to the consequences of inappropriate ATB use. PMID- 23932874 TI - [Giant hydronephrosis in a child: case report]. AB - Giant hydronephrosis in children is uncommon. Congenital ureteropelvic junction obstruction is the most frequent cause. The CT scan is very important for the diagnosis. We report on a case of hydronephrosis in a 12-year-old child who presented with enormous abdominal distension. The treatment included nephrectomy after waiting nephrostomy. The current literature is also reviewed. PMID- 23932875 TI - [Chronic cough upon return from Morocco]. PMID- 23932876 TI - [Methemoglobinemia: a rare but important condition to recognize]. PMID- 23932877 TI - [Validity of a French screening questionnaire for binge eating disorders in adolescents]. AB - Binge eating disorder is often associated with obesity. It has many psychosocial and somatic consequences and affects obesity treatment outcome. Binge eating has been observed in very young populations. Studies have shown that complications associated with binge eating disorder can appear in children, even when all the criteria included in the definition of the disorder for adults are not met. Therefore, provisional criteria have been proposed to investigate binge eating disorder among children and adolescents. There is an urgent need to enhance the screening of binge eating disorder in the young population, first in order to document the disorder and second to allow for tailored treatment of these populations. Currently, there is no scale in French to detect this type of disorder among children or adolescents. The aim of this study was to develop a self-administered questionnaire in French, which could be used as a screening tool for binge eating disorder among adolescents. We have developed a self administered questionnaire, based on a previous questionnaire and provisional criteria proposed in the English-speaking world. In the present study, we assessed how the target population understood the expressions used in the questionnaire and refined terminology according to the results. Nineteen adolescents aged 11-18 years (normal weight or with obesity) were interviewed about their understanding of the questionnaire, using a structured individual interview. After completing the questions on their own, because the goal was to end up with a self-administered tool, they were asked to explain their own understanding of each question and to reformulate the terms used. The results highlighted that some words or sentences were misunderstood by adolescents, and we developed more adequate formulations as a consequence. Some terms used in their figurative sense had to be modified. Respondents found it difficult to assess duration and frequency of their behavior and suggested changing the open ended answers to categories. Over the course of answering the questionnaire, they tended to forget the context and related their answers to their general eating behavior. Therefore, the context (binging) was repeated in each question of the modified version. A self-administered questionnaire can be effective in detecting problematic eating behaviors among adolescents and is a good first step before a diagnosis clarification by a professional. Our results show the importance of development and evaluation with the target population. The discriminant validity of the questionnaire will be evaluated by comparison with an assessment by a professional in a further study. PMID- 23932878 TI - [Lennox-Gastaut syndrome: Experience of Marrakech University Hospital]. PMID- 23932879 TI - Effect of mild cognitive impairment on the patterns of neural activity in early Parkinson's disease. AB - We have previously observed decreased activation of corticostriatal loops involved in planning (cognitive loop) and execution (motor loop) of a set shift in patients with early Parkinson's disease (PD) compared with control subjects. Here, we aimed to assess whether cognitive impairment in PD could drive these differences. Nondemented patients underwent a comprehensive neuropsychological evaluation and participated in our Wisconsin Card Sorting task functional magnetic resonance imaging protocol. Patients were separated into 2 groups according to the presence of mild cognitive impairment (MCI). Patients with MCI displayed reduced activity in the cognitive corticostriatal loop, which includes the caudate nucleus and prefrontal cortex while planning a set shift, whereas non MCI patients exhibited activation patterns similar to those of healthy participants from our previous studies. Furthermore, reduced activation was observed in the premotor cortex of the MCI patients. Finally, hippocampal activity, correlated with individual memory scores, suggesting a compensatory mechanism in patients with preserved memory. These results suggest that the presence of MCI in PD affects activity in the prefrontal cortex and caudate nucleus as well as motor-related regions. PMID- 23932880 TI - L-type Ca2+ currents at CA1 synapses, but not CA3 or dentate granule neuron synapses, are increased in 3xTgAD mice in an age-dependent manner. AB - Abnormal neuronal excitability and impaired synaptic plasticity might occur before the degeneration and death of neurons in Alzheimer's disease (AD). To elucidate potential biophysical alterations underlying aberrant neuronal network activity in AD, we performed whole-cell patch clamp analyses of L-type (nifedipine-sensitive) Ca(2+) currents (L-VGCC), 4-aminopyridine-sensitive K(+) currents, and AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid) and NMDA (N-methyl-D-aspartate) currents in CA1, CA3, and dentate granule neurons in hippocampal slices from young, middle-age, and old 3xTgAD mice and age-matched wild type mice. 3xTgAD mice develop progressive widespread accumulation of amyloid beta-peptide, and selective hyperphosphorylated tau pathology in hippocampal CA1 neurons, which are associated with cognitive deficits, but independent of overt neuronal degeneration. An age-related elevation of L-type Ca(2+) channel current density occurred in CA1 neurons in 3xTgAD mice, but not in wild type mice, with the magnitude being significantly greater in older 3xTgAD mice. The NMDA current was also significantly elevated in CA1 neurons of old 3xTgAD mice compared with in old wild type mice. There were no differences in the amplitude of K(+) or AMPA currents in CA1 neurons of 3xTgAD mice compared with wild type mice at any age. There were no significant differences in Ca(2+), K(+), AMPA, or NMDA currents in CA3 and dentate neurons from 3xTgAD mice compared with wild type mice at any age. Our results reveal an age-related increase of L-VGCC density in CA1 neurons, but not in CA3 or dentate granule neurons, of 3xTgAD mice. These findings suggest a potential contribution of altered L-VGCC to the selective vulnerability of CA1 neurons to tau pathology in the 3xTgAD mice and to their degeneration in AD patients. PMID- 23932881 TI - Effects of cerebrovascular disease and amyloid beta burden on cognition in subjects with subcortical vascular cognitive impairment. AB - Cerebrovascular disease (CVD) and amyloid burden are the most frequent pathologies in subjects with cognitive impairment. However, the relationship between CVD, amyloid burden, and cognition are largely unknown. We aimed to evaluate whether CVD (lacunes, white matter hyperintensities, and microbleeds) and amyloid burden (Pittsburgh compound B [PiB] retention ratio) contribute to cognitive impairment independently or interactively. We recruited 136 patients with subcortical vascular cognitive impairment who underwent magnetic resonance imaging, PiB-positron emission tomography, and neuropsychological testing. The number of lacunes was associated with memory, frontal dysfunctions, and disease severity. The volume of white matter hyperintensities and the PiB retention ratio were associated only with memory dysfunction. There was no direct correlation between CVD markers and PiB retention ratio except that the number of lacunes was negatively correlated with the PiB retention ratio. In addition, there were no interactive effects of CVD and PiB retention ratio on cognition. Our findings suggest that CVD and amyloid burden contribute independently and not interactively to specific patterns of cognitive dysfunction in patients with subcortical vascular cognitive impairment. PMID- 23932882 TI - Vascular brain lesions, brain atrophy, and cognitive decline. The Second Manifestations of ARTerial disease--Magnetic Resonance (SMART-MR) study. AB - We examined the association between brain atrophy and vascular brain lesions (i.e., white matter lesions [WMLs] or brain infarcts), alone or in combination, with decline in memory and executive functioning over 4 years of follow-up in 448 patients (57 +/- 9.5 years) with symptomatic atherosclerotic disease from the Second Manifestations of ARTerial disease--Magnetic Resonance SMART-MR study. Automated brain segmentation was used to quantify volumes of total brain, ventricles, cortical gray matter, and WMLs on 1.5-T magnetic resonance imaging (MRI). Brain infarcts were rated visually. WML volume was associated with significant decline in z score of executive functioning. No independent associations between MRI measures and memory decline were found. Significant declines in z scores of memory performance and of executive functioning were observed in patients with a combination of severe atrophy (upper quartile) and most vascular brain lesions (upper quartile) compared with those with minimal atrophy (lowest quartile) and fewest vascular brain lesions (lowest quartile). Our findings suggest that in patients with symptomatic atherosclerotic disease, the combination of brain atrophy and WMLs or brain infarcts accelerates cognitive decline over 4 years. PMID- 23932883 TI - Bacterial flagellin and diphtheria toxin co-stimulate IL-17-producing thymocytes. AB - IL-17-producing thymocytes have been recently described and are believed to play a role as an immune cell population which is able to react against microbial components rapidly. For this reason, we here investigated the ability of two microbial stimulants, bacterial flagellin (a ligand for TLR5) and diphtheria toxin from Corynebacterium diphtheriae, to activate or co-activate (together with alpha-CD3 stimulation) thymocyte cytokine production. We find that both bacterial molecules do not induce cytokine-production by themselves, but co-activate IL-17 producing thymocytes together with alpha-CD3. Since diphtheria toxin is unlikely to affect mouse cells through the same mechanism as the lethal effect on human cells, our results point to an additional mechanism of diphtheria toxin to act on immune cells. However, there is no additive or super-additive effect after stimulation with diphtheria toxin combined with flagellin and alpha-CD3 co activation, which suggests that microbial stimuli used in this study can only activate a limited number of IL-17 producing thymocytes. PMID- 23932884 TI - Painful fingers. PMID- 23932885 TI - Transcatheter aortic valve implantation in nonagenarians: effective and safe. AB - BACKGROUND: The number of nonagenarians is rising dramatically. These patients often develop severe aortic stenosis for which transcatheter aortic valve implantation (TAVI) is an attractive option. The aim of this study was to analyze the outcome of TAVI performed in a cohort of nonagenarian patients. METHODS: Between August 2008 and November 2012, 23 consecutive patients in their 90th year of age or older underwent TAVI in our institution after having been assessed by the local heart team. Data concerning baseline characteristics, procedural details and outcome were prospectively entered into a dedicated database. Transthoracic echocardiography and clinical follow-up were performed pre procedure, at discharge, at 6 and 12 months and then annually post TAVI. RESULTS: Patients were male in 52% with a mean age of 90.3 +/- 2.3 years. Mean logistic EuroSCORE and STS score were 26.6 +/- 14.5% and 8.7 +/- 2.9%, respectively. Transcatheter heart valve (THV) could be implanted in all but one patient. Mortality at 30 days was 8.7% overall and 4.8% for transfemoral approach. At 30 days the rate of stroke was 4.3%, paravalvular leak grade >= 2 was 8.7%, life threatening bleeding was 13.0% and pacemaker implantation was 13%. Device success was 73.9%. The rate of all-cause mortality increased to 27.3% at one-year follow up and 42.8% at a median follow-up of 417 days. CONCLUSIONS: TAVI is safe and effective even in a selected population of nonagenarians. Consequently, these patients should not be refused such a procedure based only on their age. Multi disciplinary assessment is essential in order to properly select candidates. PMID- 23932886 TI - [Aortic coarctation surgery in children]. PMID- 23932887 TI - [Joint evolution of cardiovascular imaging techniques and their publications]. PMID- 23932888 TI - Fitness benefits in patients with ischemic heart disease. PMID- 23932889 TI - Amphetamine dephosphorylates ERM proteins in the nucleus accumbens core and lithium attenuates its effects. AB - The ezrin-radixin-moesin (ERM) proteins have been implicated not only in cell shape determination but also in cellular signaling pathway. We have previously shown that cocaine decreases phosphorylation levels of these proteins in the nucleus accumbens (NAcc), an important brain area mediating addictive behaviors. Here we further revealed that the phosphorylation levels of ERM were decreased in the NAcc core, but not in the shell, by a single injection of amphetamine (AMPH) (2 mg/kg, i.p.). When lithium (100 mg/kg, i.p.) was co-administered with AMPH, the decreases of phosphorylation levels for ERM by AMPH were recovered back to basal levels in the NAcc core. Together, these results suggest that psychomotor stimulants like AMPH regulate phosphorylation levels of ERM in the NAcc core and lithium-involved signaling pathway has a regulatory role in the opposite direction in this site. PMID- 23932890 TI - Proteomic analysis of time-dependent changes in proteins expressed in mouse hippocampus during synaptic plasticity induced by GABAA receptor blockade. AB - Protein synthesis is required for long-lasting synaptic plasticity. We examined the time-dependent changes in protein expression that occurred in the hippocampus during synaptic plasticity using two-dimensional gel electrophoresis followed by mass spectrometry. The levels of 15 proteins were significantly changed in mouse hippocampus 8h after bicuculline application (1.0mg/kg, i.p.). Expression of 14 proteins (i.e., dihydropyrimidinase-related protein 2, alpha-tubulin isotype M alpha-2, tubulin beta-1 chain, tubulin beta-2A chain, protein disulfide-isomerase ERp61 precursor, chaperonin-containing T complex polypeptide 1 beta subunit, T complex polypeptide 1 [partial], creatine kinase B-type, cytosolic malate dehydrogenase [partial], vacuolar adenosine triphosphatase subunit A, and uncharacterized protein LOC433182) was increased and expression of one protein (i.e., actin gamma, cytoplasmic 1) was decreased. Western blotting also validated the changes in dihydropyrimidinase-related protein 2, creatine kinase B-type, and vacuolar adenosine triphosphatase subunit A levels in mouse hippocampus 8h after bicuculline application. The identified proteins were effectors of cellular functions including neuronal differentiation, cytoskeletal dynamics, folding of proteins, stress response, energy metabolism, synapse formation, and unknown function. Taken together, these findings indicate that the identified proteins play an important role in synaptic plasticity in the hippocampus. PMID- 23932891 TI - NKCC1 and KCC2 protein expression is sexually dimorphic in the hippocampus and entorhinal cortex of neonatal rats. AB - Seizure susceptibility appears to be greater in males than females during the early developmental stages of the brain when the gamma-aminobutyric acid (GABA), acting through its GABA-A receptor, predominantly produces neuronal depolarization. GABA-mediated excitation has been observed when the NKCC1 (chloride importer) expression level is higher than KCC2 (chloride exporter). In this study, the relative protein expression of NKCC1 and KCC2 over beta-actin was evaluated in the hippocampus and entorhinal cortex of male and female rats during postnatal days (PND) 1, 3, 5, 7, 9, 11, 13 and 15 using Western blotting assays. For both cerebral regions in the females, the NKCC1/beta-actin expression ratio was constant during all evaluated ages, whereas the KCC2/beta-actin expression ratio increased gradually until reaching a maximal level at PND9 that was nearly three- and ten-fold higher in the hippocampus and entorhinal cortex, respectively, compared with the initial level. In males, the NKCC1/beta-actin expression ratio was constant during the first week, peaking almost three-fold higher than the initial level at PND9 in the hippocampus and at PND11 in the entorhinal cortex and then returning to the initial values at PND13, whereas the KCC2/beta-actin expression ratio increased gradually to reach a maximal and steady level at PND5, which were nearly two- and four-fold higher in the hippocampus and entorhinal cortex, respectively, compared with the intial level. In conclusion, the NKCC1/beta-actin and KCC2/beta-actin expression ratios displayed a specific expression profile for each gender and cerebral region, which could be related with the differences in seizure susceptibility observed between genders. PMID- 23932892 TI - Differentiation state affects morphine induced cell regulation in neuroblastoma cultured cells. AB - Neuroblastoma (NB) is the most common extracranial solid cancer in childhood and the most common cancer in infancy. Our purpose was to investigate in vitro how cancer cell survival occurs in presence of morphine in undifferentiated and differentiated SHSY-5Y human neuroblastoma cultured cell line. Exposure of differentiated cells to morphine dose-dependently induced apoptosis in these cells through c-Jun N-terminal kinase (JNK)/caspase pathway. Otherwise, morphine induced activation for mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, caused positive regulation of cell survival in undifferentiated cells. Therefore, cell differentiation state bimodally affects the cellular regulation activity triggered by morphine in isolated cultured neuroblastoma cells raising concerns about the application of morphine to this type of cancer patients. PMID- 23932893 TI - The role of preoperative ultrasound evaluation of inguinal lymph nodes in patients with vulvar malignancy. AB - OBJECTIVES: Inguinal lymphadenectomy in vulvar malignancies is associated with significant morbidity, especially in patients over 70 years old. Under certain conditions, surgical guidelines recommend biopsy and evaluation of the sentinel node in early vulvar cancer. The purpose of our study is to evaluate ultrasonography as a predictor of inguinal lymph node involvement. METHODS: A retrospective study was performed with 60 patients who had vulvar malignancies (92% of which were squamous cell carcinomas) and who were treated at our hospital between 2002 and 2012. The patients ranged in age from 35 to 89 years, with a median age of 76 years. In total, 118 groin scans were retrospectively evaluated for sonographic evidence of lymph node involvement (i.e., absence of fatty hilum, irregular shape, cortical region diameter and vascularization pattern). The results were then compared with histopathologically confirmed lymph node status. RESULTS: Histopathologically confirmed lymph node status was available for 107 of the inguinal nodes examined by ultrasound, and lymph node metastases were found in 38 (35.5%) cases. The presence or absence of inguinal lymph node metastases was correctly identified by sonography in 92 (86.0%) of the scanned areas. Sensitivity was 76.3%, specificity was 91.3%, and positive and negative predictive values were 82.9% and 87.5%, respectively. CONCLUSIONS: Ultrasonography of the inguinal lymph nodes showed a relatively high sensitivity and specificity for predicting inguinal tumor metastases. However, our results indicate that surgical lymph node staging is still needed to precisely determine inguinal lymph node status in vulvar cancer, especially because a missed lymph node-metastasis is often fatal. PMID- 23932894 TI - Contribution of Leptospira, Neospora caninum and bovine viral diarrhea virus to fetal loss of beef cattle in New Zealand. AB - The profitability of beef breeding farms in New Zealand depends principally on optimal reproductive performance. The aim of this study was to estimate the impact of four major pathogens, bovine viral diarrhea virus (BVDV), Neospora caninum (N. caninum), Leptospira borgpetersenii serovar Hardjo (Hardjo), and Leptospira interrogans serovar Pomona (Pomona), on rates of fetal loss in commercial beef breeding herds. Farms reporting fetal loss were recruited, and a blood sample from aborting cows (cases) was collected. Controls were normally calving cows from the same farm. At least four controls were selected from each farm contributing cases. Samples were tested using ELISA for detection of antibodies against BVDV and N. caninum, and microscopic agglutination test (MAT) for detection of antibody against Hardjo and Pomona. A selection of titer cut offs was conducted to evaluate the relationship between fetal loss and seropositivity to each pathogen using conditional logistic regression. The cut off titer with the strongest association with fetal loss was included in the multivariate model. A significant increased risk of fetal loss was found for animals seropositive to N. caninum (odds ratio (OR)=3.36; 95% confidence interval (95% CI)=1.27-8.89), Hardjo (OR=1.84; 95% CI=1.01-3.33), and Pomona in non vaccinated cows (OR=14.91, 95% CI=1.73-128.84) at the ELISA titer >= 30, and MAT titers of >= 1:384 and >= 1:768 for a positive sample, respectively. A marginally non-significant increased risk of fetal loss was found for animals exposed to BVDV (OR=2.01; 95% CI=0.99-4.11) at the ELISA titer of <= 1. Vaccination did not affect ORs for Hardjo or BVDV and no herd vaccinated against N. caninum. Approximately 14.0% of all fetal loss in the beef breeding cattle population in New Zealand may be attributable to BVDV (3.5%), N. caninum (3.0%), Hardjo (4.7%), and Pomona (3.6%). PMID- 23932895 TI - Ectoparasites and anti-Leishmania antibodies: association in an observational case-control study of dogs from a Brazilian endemic area. AB - It has been proposed that the transmission of canine visceral leishmaniasis might involve the participation of mechanical vectors, including ticks of the family Ixodidae, in particular the brown dog tick Rhipicephalus sanguineus, and the cat flea Ctenocephalides felis felis. Here, the association between the infestation by R. sanguineus and C. felis felis and the occurrence of anti-Leishmania antibodies was evaluated in an observational case-control study of dogs living in a Brazilian endemic area for canine visceral leishmaniasis. Blood samples were taken once every three months for one year from 96 initially seronegative domestic dogs, and submitted to indirect immunofluorescence antibody assay. All dogs were evaluated for the presence of ticks and fleas, and the results were expressed qualitatively as infested or non-infested, irrespective of the intensity of infestation. At the end of follow-up, twenty dogs had turned seropositive, while 68 remained seronegative and 8 were excluded because of incomplete data. All the dogs were asymptomatic. The odds of infection was significantly greater (OR=3.54, CI95%=1.10-12.53) for dogs infested by C. felis felis compared to their non-infested counterparts. In contrast, the odds of infection showed no significance difference between non-infested and R. sanguineus-infested groups of dogs (OR=0.31, CI95%=0.03-1.52). This study provides further evidence for the potential role of C. felis felis in mechanically transmitting Leishmania among the canine population. PMID- 23932896 TI - Circulating levels of soluble apoptosis-related molecules in patients with multiple sclerosis. AB - Evidence exists that apoptotic elimination of autoreactive T lymphocytes is defective in multiple sclerosis (MS). Here, we measured serum levels of soluble forms of Fas (sFas), Fas ligand (sFasL) and TNF-related apoptosis-inducing ligand (sTRAIL) in 38 healthy controls (HC) and 92 untreated MS patients with different clinical forms and activity phases of the disease by immunoassay. Serum levels of sFas, sFasL and sTRAIL did not differ between MS patients and HC. sTRAIL levels were significantly decreased in RRMS during relapses. These findings support a role of TRAIL in the pathogenesis of MS, especially during the acute phases of the disease. PMID- 23932897 TI - Airway drug pharmacokinetics via analysis of exhaled breath condensate. AB - Although the airway surface is the anatomic target for many lung disease therapies, measuring drug concentrations and activities on these surfaces poses considerable challenges. We tested whether mass spectrometric analysis of exhaled breath condensate (EBC) could be utilized to non-invasively measure airway drug pharmacokinetics and predicted pharmacological activities. Mass spectrometric methods were developed to detect a novel epithelial sodium channel blocker (GS 9411/P-680), two metabolites, a chemically related internal standard, plus naturally occurring solutes including urea as a dilution marker. These methods were then applied to EBC and serum collected from four (Floridian) sheep before, during and after inhalation of nebulized GS-9411/P-680. Electrolyte content of EBC and serum was also assessed as a potential pharmacodynamic marker of drug activity. Airway surface concentrations of drug, metabolites, and electrolytes were calculated from EBC measures using EBC:serum urea based dilution factors. GS 9411/P-680 and its metabolites were quantifiable in the sheep EBC, with peak airway concentrations between 1.9 and 3.4 MUM measured 1 h after inhalation. In serum, only Metabolite #1 was quantifiable, with peak concentrations ~60-fold lower than those in the airway (45 nM at 1 h). EBC electrolyte concentrations suggested a pharmacological effect; but this effect was not statistical significant. Analysis of EBC collected during an inhalation drug study provided a method for quantification of airway drug and metabolites via mass spectrometry. Application of this methodology could provide an important tool in development and testing of drugs for airways diseases. PMID- 23932898 TI - Evaluation of viral peptide targeting to porcine sialoadhesin using a porcine reproductive and respiratory syndrome virus vaccination-challenge model. AB - Targeting antigens to professional antigen presenting cells resident at the sites where effective immune responses are generated is a promising vaccination strategy. As such, targeting sialoadhesin (Sn)-expressing macrophages, abundantly present in spleen and lymph nodes where they appear to be strategically placed for antigen capture and processing, is recently gaining increased attention. Previously, we have shown that humoral immune responses to the model antigen human serum albumin can be enhanced by using a porcine Sn-specific monoclonal antibody to target the model antigen to Sn-expressing macrophages. To date however, no studies have been performed to evaluate whether targeted delivery of a pathogen-derived antigen can enhance the pathogen-specific immune response. Therefore, we selected a linear epitope on glycoprotein 4 of porcine reproductive and respiratory syndrome virus (PRRSV), which is known to be a target of virus neutralizing antibodies. This paper reports on the targeted delivery of this viral peptide to porcine Sn-expressing macrophages and the evaluation of the subsequent immune response in a vaccination-challenge set-up. Four copies of the selected PRRSV epitope were genetically fused to a previously developed porcine Sn-targeting recombinant antibody or an irrelevant isotype control. Fusion proteins were shown to be efficiently purified from HEK293T cell supernatants and subsequently, only Sn-specific fusion proteins were shown to bind to and to be internalized into Sn-expressing cells. Subsequent immunizations with a single dose of the fusion proteins showed that peptide-specific immune responses and neutralizing antibody responses after PRRSV challenge were enhanced in animals receiving a single 500 MUg intramuscular dose of the Sn-targeting fusion protein, although correlations between the two read-outs were hard to effectuate. Furthermore, a minor beneficial effect on viral clearance was observed. Together, these data show that viral peptide targeting to porcine Sn-expressing macrophages can improve the anti-viral immune response, although more research will be needed to further explore vaccination potential. PMID- 23932899 TI - Molecular diagnostics for the detection of Bokeloh bat lyssavirus in a bat from Bavaria, Germany. AB - A brain sample of a Natterer's bat tested positive for rabies with classical virological techniques. Molecular techniques confirmed the presence of Bokeloh bat lyssavirus (BBLV) in Germany for the second time. Sequence analysis revealed a close genetic relationship to the initial German BBLV case. Using a TaqMan RT PCR specific for BBLV viral RNA was detected in various other organs albeit with differences in the relative viral load. PMID- 23932900 TI - Early Trichinella spiralis and Trichinella nativa infections induce similar gene expression profiles in rat jejunal mucosa. AB - Trichinella spiralis causes a significantly higher parasite burden in rat muscle than Trichinella nativa. To assess whether the difference in infectivity is due to the early intestinal response, we analyzed gene expression changes in the rat jejunum during Trichinella infection with a whole-genome microarray. The rats were euthanized on day five of infection, and their jejunal mucosa was sampled for microarray analysis. In addition, intestinal histology and hematology were examined. Against our expectations, the gene expression changes were similar in both T.nativa- and T. spiralis-infected groups. The two groups were hence pooled, and in the combined Trichinella-infected group, 551 genes were overexpressed and 427 underexpressed when compared to controls (false discovery rate <= 0.001 and fold change at least 2 in either direction). Pathway analysis identified seven pathways significantly associated with Trichinella infection (p < 0.05). The microarray data suggested nonspecific damage and an inflammatory response in the jejunal mucosa. Histological findings, including hyperemia, hemorrhage and a marked infiltration of inflammatory cells, supported the microarray data. Trichinella infection caused complex gene expression changes that indicate a host response to tissue damage in the mucosa of the jejunum, but the changes were not notably dependent on the studied species of Trichinella. PMID- 23932901 TI - Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: a clinical update. AB - Cardiovascular disease (CVD) is a significant cause of death in Europe. In addition to patients with proven CVD, those with type 2 diabetes (T2D) are at a particularly high-risk of CVD and associated mortality. Treatment for dyslipidaemia, a principal risk factor for CVD, remains a healthcare priority; evidence supports the reduction of low-density lipoprotein cholesterol (LDL-C) as the primary objective of dyslipidaemia management. While statins are the treatment of choice for lowering LDL-C in the majority of patients, including those with T2D, many patients retain a high CVD risk despite achieving the recommended LDL-C targets with statins. This 'residual risk' is mainly due to elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. Following statin therapy optimisation additional pharmacotherapy should be considered as part of a multifaceted approach to risk reduction. Fibrates (especially fenofibrate) are the principal agents recommended for add-on therapy to treat elevated TG or low HDL-C levels. Currently, the strongest evidence of benefit is for the addition of fenofibrate to statin treatment in high-risk patients with T2D and dyslipidaemia. An alternative approach is the addition of agents to reduce LDL-C beyond the levels attainable with statin monotherapy. Here, addition of fibrates and niacin to statin therapy is discussed, and novel approaches being developed for HDL-C and TG management, including cholesteryl ester transfer protein inhibitors, Apo A-1 analogues, mipomersen, lomitapide and monoclonal antibodies against PCSK9, are reviewed. PMID- 23932902 TI - PHD1 links cell-cycle progression to oxygen sensing through hydroxylation of the centrosomal protein Cep192. AB - PHD1 belongs to the family of prolyl-4-hydroxylases (PHDs) that is responsible for posttranslational modification of prolines on specific target proteins. Because PHD activity is sensitive to oxygen levels and certain byproducts of the tricarboxylic acid cycle, PHDs act as sensors of the cell's metabolic state. Here, we identify PHD1 as a critical molecular link between oxygen sensing and cell-cycle control. We show that PHD1 function is required for centrosome duplication and maturation through modification of the critical centrosome component Cep192. Importantly, PHD1 is also required for primary cilia formation. Cep192 is hydroxylated by PHD1 on proline residue 1717. This hydroxylation is required for binding of the E3 ubiquitin ligase SCF(Skp2), which ubiquitinates Cep192, targeting it for proteasomal degradation. By modulating Cep192 levels, PHD1 thereby affects the processes of centriole duplication and centrosome maturation and contributes to the regulation of cell-cycle progression. PMID- 23932903 TI - PRC2 controls Drosophila oocyte cell fate by repressing cell cycle genes. AB - The oocyte is a unique cell type that undergoes extensive chromosome changes on its way to fertilization, but the chromatin determinants of its fate are unknown. Here, we show that Polycomb group (PcG) proteins of the Polycomb repressive complex 2 (PRC2) determine the fate of the oocyte in Drosophila. Mutation of the enzymatic PRC2 subunit Enhancer of zeste (E(z)) in the germline abolishes spatial and temporal control of the cell cycle and induces sterility via transdetermination of the oocyte into a nurse-like cell. This fate switch depends on loss of silencing of two PRC2 target genes, Cyclin E and the cyclin-dependent kinase inhibitor dacapo. By contrast, the PRC1 component Polycomb (Pc) plays no role in this process. Our results demonstrate that PRC2 plays an exquisite role in the determination of the oocyte fate by preventing its switching into an endoreplicative program. PMID- 23932904 TI - Impact of birth weight and gender on early postnatal hypothalamic energy balance regulatory gene expression in the young lamb. AB - Intra-uterine growth restriction (IUGR) is involved in developmental metabolic programming and here we test the hypothesis that IUGR affects the developing hypothalamic energy balance regulatory pathways in a sex-specific manner. This experiment investigated early postnatal hypothalamic gene expression for six primary leptin- and insulin-sensitive neuropeptides and receptors in male and female IUGR (n = 8 and 9, respectively) and normal (N) birth weight lambs (n = 8 per gender) gestated and suckled by overnourished mothers. IUGR lambs were smaller at birth, had increased fractional growth rates (FGR), lower final body weight (11 weeks) and similar body fat content compared with N lambs, while males had higher final body weight and insulinemia but lower body fat and leptinemia than females. In situ hybridization revealed greater gene expression in the hypothalamic arcuate nucleus at 11 weeks for anorexigenic genes in females and orexigenic genes in males, with no effect of IUGR. Leptinemia correlated with gene expression for neuropeptide Y (NPY, negatively) in both sexes and pro opiomelanocortin (POMC, positively) in females but with leptin receptor (negatively) only in males. Current FGR for girth correlated negatively with gene expression for NPY in males and POMC in females. Neither IUGR nor gender affected suckling activity (proxy for appetite) assessed at 3 weeks, but final NPY gene expression correlated with suckling weight gain in males. This study has revealed no effect of IUGR on early postnatal hypothalamic energy balance gene expression but a major effect of gender associated with major sex differences in adiposity and leptinemia. PMID- 23932906 TI - The impact of network medicine in gastroenterology and hepatology. AB - In the footsteps of groundbreaking achievements made by biomedical research, another scientific revolution is unfolding. Systems biology draws from the chaos and complexity theory and applies computational models to predict emerging behavior of the interactions between genes, gene products, and environmental factors. Adaptation of systems biology to translational and clinical sciences has been termed network medicine, and is likely to change the way we think about preventing, predicting, diagnosing, and treating complex human diseases. Network medicine finds gene-disease associations by analyzing the unparalleled digital information discovered and created by high-throughput technologies (dubbed as "omics" science) and links genetic variance to clinical disease phenotypes through intermediate organizational levels of life such as the epigenome, transcriptome, proteome, and metabolome. Supported by large reference databases, unprecedented data storage capacity, and innovative computational analysis, network medicine is poised to find links between conditions that were thought to be distinct, uncover shared disease mechanisms and key drivers of the pathogenesis, predict individual disease outcomes and trajectories, identify novel therapeutic applications, and help avoid off-target and undesirable drug effects. Recent advances indicate that these perspectives are increasingly within our reach for understanding and managing complex diseases of the digestive system. PMID- 23932905 TI - Prevalence of iron overload vs iron deficiency in multiple myeloma: resembling or different from MDS--and stem cell transplant (SCT)--patients? AB - BACKGROUND: Most MM patients develop anemia with progression to symptomatic disease. Usually, this is normocytic/normochromic, with normal or low iron and elevated ferritin levels. Because ferritin levels alone do not correctly reflect iron stores, we performed a comprehensive analysis of iron parameters (iron, ferritin, transferrin, transferrin saturation [TRFS]) to more precisely assess patients' iron metabolism. PATIENTS AND METHODS: We analyzed: (1) the frequency of IO vs. ID in 136 consecutive MM patients; (2) the prognostic effect on progression-free (PFS) and overall survival (OS); and (3) specific risk groups according to patients' iron metabolism. RESULTS: Most patients had normal iron metabolism or ID: median iron, ferritin, transferrin, and TRFS values were 75 MUg/dL, 446 MUg/L, 195 mg/dL, and 26%, respectively. Ferritin levels of < 400 MUg/L, 400 to 1000 MUg/L, and > 1000 MUg/L were observed in 46%, 30%, and 24%, and TRFS levels < 20%, 20% to 45%, and > 45% in 32%, 46%, and 22% of patients, respectively. When patients with modified (ID or IO) vs. normal iron metabolism were compared, laboratory parameters (prohormone of brain natriuretic peptide, estimated glomerular filtration rate, c-reactive protein, reflecting cardiac, renal, or infectious impairment), and PFS and OS appeared impaired with modified metabolism, albeit age- and disease-specific differences were insignificant. CONCLUSION: Normal iron metabolism and ID is more frequent in MM patients than IO. ID and IO correlate with organ impairment and impaired survival in MM. This knowledge should be incorporated into the design of future studies that will determine the benefit of iron supplementation with ID, and iron chelators with IO in MM. PMID- 23932907 TI - Identification, characterization, and expression profiles of two subtypes of kisspeptin receptors in a scombroid fish (chub mackerel). AB - The kisspeptin receptor (Kiss1R) is a cognate receptor for kisspeptin (Kiss), and this Kiss-Kiss1R system has been shown to regulate seasonal reproduction in vertebrates. Our previous study found the chub mackerel (Scomber japonicus) brain expresses both kiss1 and kiss2 and exhibits sexually dimorphic changes during the seasonal reproductive cycle. The present study cloned two subtypes of kissr from the chub mackerel brain, and their signal transduction pathways to Kiss1 and Kiss2 were characterized in a mammalian cell line. Results of identification showed that kissr1 and kissr2 mRNAs encode 369 and 378 deduced amino acids, respectively, and share 52% similarity in amino acid sequences. In vitro functional analysis revealed that chub mackerel Kiss receptor signals are also preferentially transduced via the protein kinase C (PKC) rather than protein kinase A (PKA) pathway. Synthetic chub mackerel Kiss1-15 and Kiss2-12 peptides showed the highest potency for the activation of KissR1 and KissR2, respectively, stronger than their corresponding Kiss-10 peptides. Tissue distribution analyses indicated that both genes are highly expressed in the brain and that only kissr2 mRNA is expressed in the pituitary of both sexes. Unexpectedly, both kissr1 and kissr2 mRNAs were detected only in the testes. Seasonal expression changes showed higher expression levels of both kissr1 and kissr2 mRNAs in the brain of females during the early vitellogenic period; however, no significant differences were found in the brain of males. Pituitary kissr2 mRNA levels showed no significant variations. In the testes, the kissr1 mRNA expression level increased dramatically at spermiation compared with the immature and post-spawning periods. However, kissr2 mRNA levels in the testes did not vary significantly at different testicular stages. These results suggest that both kissr1 and kissr2 likely participate in the seasonal ovarian development of females, and thus in males, we propose a paracrine or autocrine role for kissr1 in testicular development. PMID- 23932908 TI - Temporal associations between spouse criticism/hostility and pain among patients with chronic pain: a within-couple daily diary study. AB - Chronic musculoskeletal pain can strain marriages, perhaps even to the point of engendering spouse criticism and hostility directed toward patients. Such negative spouse responses may have detrimental effects on patient well-being. While results of cross-sectional studies support this notion, we extended these efforts by introducing expressed emotion (EE) and interpersonal theoretical perspectives, and by using electronic diary methods to capture both patient and spouse reports in a prospective design. Patients with chronic low back pain (CLBP) and their spouses (N = 105 couples) reported on perceived spouse behavior and patient pain 5 times/day for 14 days using Personal Data Assistants (PDAs). Concurrent and lagged within-couple associations between patient's perceptions of spouse criticism/hostility and patient self-reported pain and spouses' observations of patient pain behaviors revealed that (1) patient perceived spouse criticism and hostility were correlated significantly with pain intensity, and spouse observed patient pain behavior was related significantly with patient perceived hostility at the same time point; (2) patient perceived spouse hostility significantly predicted patient pain intensity 3 hours later, and spouse observed pain behaviors significantly predicted patient perceived spouse hostility 3 hours later. Results support both EE and interpersonal models, and imply that a comprehensive model would combine these conceptualizations to fully illustrate how spouse criticism/hostility and patient pain interact to produce a negative spiral. Given that marital interactions are amenable to clinical intervention, improved insight into how spouse behavior and patient pain are tightly linked will encourage productive translational efforts to target this neglected area. PMID- 23932910 TI - Implicit associations between pain and self-schema in patients with chronic pain. AB - Chronic pain often interferes with daily functioning, and may become a threat to an individual's sense of self. Despite the development of a recent theoretical account focussing upon the relationship between the presence of chronic pain and a person's self, research investigating this idea is limited. In the present study we aimed to (1) compare the strength of association between self- and pain schema in patients with chronic pain and healthy control subjects and (2) research whether the strength of association between self- and pain-schema is related to particular pain-related outcomes and individual differences of patients with chronic pain. Seventy-three patients with chronic pain (M(age) = 49.95; SD = 9.76) and 53 healthy volunteers (M(age) = 48.53; SD = 10.37) performed an Implicit Association Test (IAT) to assess the strength of association between pain- and self-schema. Patients with chronic pain also filled out self-report measures of pain severity, pain suffering, disability, depression, anxiety, acceptance, and helplessness. Results indicated that the pain- and self-schema were more strongly associated in patients with chronic pain than in healthy control subjects. Second, results indicated that, in patients with chronic pain, a stronger association between self- and pain-schema, as measured with the IAT, is related to a heightened level of pain severity, pain suffering, anxiety, and helplessness. Current findings give first support for the use of an IAT to investigate the strength of association between self- and pain schema in patients with chronic pain and suggest that pain therapies may incorporate techniques that intervene on the level of self-pain enmeshment. PMID- 23932911 TI - Legionella oakridgensis ATCC 33761 genome sequence and phenotypic characterization reveals its replication capacity in amoebae. AB - Legionella oakridgensis is able to cause Legionnaires' disease, but is less virulent compared to L. pneumophila strains and very rarely associated with human disease. L. oakridgensis is the only species of the family legionellae which is able to grow on media without additional cysteine. In contrast to earlier publications, we found that L. oakridgensis is able to multiply in amoebae. We sequenced the genome of L. oakridgensis type strain OR-10 (ATCC 33761). The genome is smaller than the other yet sequenced Legionella genomes and has a higher G+C-content of 40.9%. L. oakridgensis lacks a flagellum and it also lacks all genes of the flagellar regulon except of the alternative sigma-28 factor FliA and the anti-sigma-28 factor FlgM. Genes encoding structural components of type I, type II, type IV Lvh and type IV Dot/Icm, Sec- and Tat-secretion systems could be identified. Only a limited set of Dot/Icm effector proteins have been recognized within the genome sequence of L. oakridgensis. Like in L. pneumophila strains, various proteins with eukaryotic motifs and eukaryote-like proteins were detected. We could demonstrate that the Dot/Icm system is essential for intracellular replication of L. oakridgensis. Furthermore, we identified new putative virulence factors of Legionella. PMID- 23932913 TI - Anterior knee laxity measurement using stress radiographs and the GNRB((r)) system versus intraoperative navigation. AB - BACKGROUND: Anterior knee laxity measurement serves both to diagnose and to evaluate the severity of anterior cruciate ligament (ACL) damage. HYPOTHESIS: We tested the hypothesis that anterior laxity measurements of ACL-deficient knees obtained using the GNRB((r)) system and stress radiographs differed from each other and from intraoperative navigation measurement taken as the reference standard. MATERIAL AND METHODS: Twenty-one patients with chronic ACL deficiency underwent arthroscopic ACL reconstruction. Anterior knee laxity was measured preoperatively using the GNRB((r)) system without anaesthesia and anterior-drawer stress radiographs under anaesthesia then intraoperatively using a non-image based navigation system. RESULTS: The three measurements differed significantly (P=0.05). A systematic measurement error of -3.7 mm occurred for both preoperative measurements versus the reference standard. No significant difference was found between the two preoperative measurements. DISCUSSION: The GNRB((r)) system should be preferred over stress radiographs, as reliability is similar but no radiation exposure is required. Both preoperative measurement methods underestimate anterior laxity as measured intraoperatively using the navigation system. This systematic bias may be relevant to treatment decision making. LEVEL OF EVIDENCE: II, development of a diagnostic criterion in consecutive patients versus a validated reference standard. PMID- 23932909 TI - Exercise-mediated improvements in painful neuropathy associated with prediabetes in mice. AB - Recent research suggests that exercise can be effective in reducing pain in animals and humans with neuropathic pain. To investigate mechanisms in which exercise may improve hyperalgesia associated with prediabetes, C57Bl/6 mice were fed either standard chow or a high-fat diet for 12 weeks and were provided access to running wheels (exercised) or without access (sedentary). The high-fat diet induced a number of prediabetic symptoms, including increased weight, blood glucose, and insulin levels. Exercise reduced but did not restore these metabolic abnormalities to normal levels. In addition, mice fed a high-fat diet developed significant cutaneous and visceral hyperalgesia, similar to mice that develop neuropathy associated with diabetes. Finally, a high-fat diet significantly modulated neurotrophin protein expression in peripheral tissues and altered the composition of epidermal innervation. Over time, mice that exercised normalized with regards to their behavioral hypersensitivity, neurotrophin levels, and epidermal innervation. These results confirm that elevated hypersensitivity and associated neuropathic changes can be induced by a high-fat diet and exercise may alleviate these neuropathic symptoms. These findings suggest that exercise intervention could significantly improve aspects of neuropathy and pain associated with obesity and diabetes. Additionally, this work could potentially help clinicians determine those patients who will develop painful versus insensate neuropathy using intraepidermal nerve fiber quantification. PMID- 23932914 TI - Results with a minimum of 10 years follow-up of the Coonrad/Morrey total elbow arthroplasty. AB - INTRODUCTION: Few series have evaluated the long-term results of total elbow arthroplasty (TEA). MATERIALS AND METHODS: Fifteen patients with a Coonrad/Morrey total elbow implant were reviewed with a minimum follow-up of 10 years. There were nine women and six men with a mean age of 55 years at surgery. The aetiology was rheumatoid arthritis in eight cases, post-traumatic arthritis in five, psoriatic arthritis in one, and sequelae of neonatal septic arthritis in one. The TEA was performed as primary surgery in ten cases and during a revision surgery in four. RESULTS: At 136 months average follow-up (120-160), MEPS was 82 +/- 14 points (range 60-100) with a Quick DASH score of 41 points (range 13-83). Fourteen patients had no or slight pain and six had a functional range of motion. Elbow function was normal in eight of 15 patients. Radiolucent lines were found around the humerus in six cases (all of them incomplete) and around the ulnar component in eight (five of them complete) with loosening and migration of the ulnar stem occurring in two cases. Wear of the bushings was moderate in five cases and severe in two. There were ten complications with a revision needed in three cases. Revision-free survival rate for the implant was 100% at 5 years and 90% at 10 and 13 years. DISCUSSION: The Coonrad/Morrey total elbow gives long term satisfactory results. Increased incidence of radiolucent lines around the ulnar stem and bushing wear with longer follow-up is of concern and represents the failure mode for this total elbow arthroplasty implant. LEVEL OF EVIDENCE: IV. PMID- 23932912 TI - Changes in Streptococcus pyogenes causing invasive disease in Portugal: evidence for superantigen gene loss and acquisition. AB - The emergence of highly virulent and successful Streptococcus pyogenes (group A streptococci - GAS) clones has been attributed to the exchange of virulence factors by lateral gene transfer mechanisms, which strongly contribute to genomic diversity. We characterized a collection of 191 GAS isolates recovered from normally sterile sites in Portugal during 2006-2009 and compared them to invasive isolates obtained during 2000-2005. Antimicrobial resistance rates did not change significantly between the two periods and were generally low. In 2006-2009, emm1, emm89, emm3, and emm6 represented 60% of the isolates. The chromosomally encoded superantigen (SAg) genes speG and smeZ were present in the majority (>90%) of the isolates, while speJ was found in only 45%. The phage encoded SAgs varied greatly in prevalence (2-53%). The distribution of emm types, pulsed-field gel electrophoresis profiling (PFGE) clusters, and SAg profiles changed significantly between the periods, although there were no statistically supported changes in the prevalence of individual types. While the macrolide susceptible clone emm1-T1 ST28 remained dominant (28%), there was a significant decrease in clonal diversity as indicated by both PFGE profiling and emm typing. This was accompanied by intra-clonal divergence of SAg profiles, which was statistically confirmed for isolates representing emm1, emm28, and emm44. This diversification was associated with the loss and acquisition of SAg genes, carried by phages and of chromosomal origin. These data suggest an ongoing genomic diversification of GAS invasive isolates in Portugal that may contribute to the persistence of clones with improved fitness or virulence. PMID- 23932915 TI - Neuroimaging of gastric distension and gastric bypass surgery. AB - Several neuroimaging studies are presented, which derive from prior work on gastric distension. Using a nonsurgical approach, we inserted gastric balloons into rats, which led to a marked decrease in food intake that normalized at 8 weeks. Body weight, however, remained below controls, which encouraged pursuit of studies in humans. A gastric balloon was inserted in obese and lean subjects, and filled through a tube that led behind the subject with water to 0, 200, 400, 600, 800 mL, on different days prior to ingestion of a liquid meal. As gastric volume increased, intake decreased by about 40%. Stomach capacity was then investigated using a gastric balloon, by assessing subjective (maximal tolerance) and objective measures (gastric compliance). Obese individuals had a much larger stomach capacity than lean by both measures. Next, in a 2-month study, an indwelling gastric balloon was inflated to 400 mL for 1 month and deflated for 1 month in counterbalanced order. Body weight was reduced during the month when the balloon was inflated within the 2nd and 3rd week. The subsequent study involved fMRI in response to gastric distension of 0, 250, and 500 mL while the subject was in a scanner. Ratings of fullness, but not discomfort, increased at 500 mL. Amygdala and insula activation were associated with gastric distension. The amygdala, as part of the limbic system, is involved in emotion and reward, and the insula in interoception. The right amygdala activation was inversely related to BMI, consistent with greater gastric capacity at a higher BMI. The next fMRI study in obese and lean subjects used visual and auditory stimuli of high energy dense (ED) and low ED foods. Increased activation was observed in the midbrain, putamen, posterior cingulate gyrus, hippocampus, and superior temporal gyrus in the obese vs. lean group in response to high vs. low ED food cues. Several of these areas lie within the mesolimbic reward pathway, and greater activation to high ED foods in the obese, suggests they have increased reward-driven eating behavior. Lastly, an fMRI study using the same stimuli was conducted pre and post gastric bypass surgery. There were postsurgical reductions in neural activity in mesolimbic areas including the prefrontal cortex, and to a greater degree for high ED than low ED cues, reflecting more normalized responses. Through the use of various methodologies, the stomach's influence on food intake, sensations of fullness, and brain activation is presented with suggestions for future research. PMID- 23932916 TI - Plasma levels of neuron specific enolase quantify the extent of neuronal injury in murine models of ischemic stroke and multiple sclerosis. AB - OBJECTIVE: We aimed at validating a plasma biomarker for neuronal damage that can be used in acute and chronic models of neurological diseases. METHODS: We investigated two different models, middle cerebral artery occlusion followed by reperfusion and MOG35-55-induced experimental autoimmune encephalomyelitis (EAE). In stroke experiments we measured infarct sizes by magnetic resonance imaging and vital stainings and correlated them with plasma levels of neuron specific enolase (NSE) at different time points after reperfusion. Equally, in EAE experiments, we correlated NSE levels with neurological scores and histopathological damage of axons at different time points. We detected plasma NSE levels by ELISA. RESULTS: Plasma NSE levels correlated significantly with stroke size, EAE score and histopathological damage in EAE. Investigations into the dynamics of neuronal loss over time correlated well with the dynamics of NSE levels. NSE even predicted the onset of EAE, before clinical signs were recordable. CONCLUSIONS: Plasma NSE is a valid and simple experimental biomarker that allows quantifying the degree of neuronal injury in a non-invasive approach. PMID- 23932917 TI - NMDA-receptor inhibition increases spine stability of denervated mouse dentate granule cells and accelerates spine density recovery following entorhinal denervation in vitro. AB - Neuronal networks are reorganized following brain injury. At the structural level this is in part reflected by changes in the spine turnover of the denervated neurons. Using the entorhinal cortex lesion in vitro model, we recently showed that mouse dentate granule cells respond to entorhinal denervation with coordinated functional and structural changes: During the early phase after denervation spine density decreases, while excitatory synaptic strength increases in a homeostatic manner. At later stages spine density increases again, and synaptic strength decreases back to baseline. In the present study, we have addressed the question of whether the denervation-induced homeostatic strengthening of excitatory synapses could not only be a result of the deafferentation, but could, in turn, affect the dynamics of the spine reorganization process following entorhinal denervation in vitro. Using a computational approach, time-lapse imaging of neurons in organotypic slice cultures prepared from Thy1-GFP mice, and patch-clamp recordings we provide experimental evidence which suggests that the strengthening of surviving synapses can lead to the destabilization of spines formed after denervation. This activity dependent pruning of newly formed spines requires the activation of N-methyl-d aspartate receptors (NMDA-Rs), since pharmacological inhibition of NMDA-Rs resulted in a stabilization of spines and in an accelerated spine density recovery after denervation. Thus, NMDA-R inhibitors may restore the ability of neurons to form new stable synaptic contacts under conditions of denervation induced homeostatic synaptic up-scaling, which may contribute to their beneficial effect seen in the context of some neurological diseases. PMID- 23932918 TI - Ursolic acid from Agastache mexicana aerial parts produces antinociceptive activity involving TRPV1 receptors, cGMP and a serotonergic synergism. AB - Agastache mexicana is a plant that has long been used in large demands in Mexican folk medicine to treat anxiety, insomnia and pain, among others affections. Chromatographic technique was used to identify ursolic acid (UA), 130.7 mg/g and 20.3 mg/g, as an antinociceptive active compound identified in ethyl acetate and methanol extracts of A. mexicana aerial parts, respectively. Temporal course curves of the antinociceptive response demonstrated a dose-dependent and significant activity of UA (1 to 100 mg/kg, i.p.) with an ED50=2 mg/kg in comparison to the efficacy of diclofenac (1 or 30 to 100 mg/kg, i.p.), a non steroidal anti-inflammatory drug, with an ED50=11.56 mg/kg. The antinociceptive response consisted in the reduction of abdominal constrictions induced with 1% acetic acid in mice. Similarly, UA at 2 mg/kg produced significant antinociception in the intracolonic administration of 0.3% capsaicin (a TRPV1 agonist) in mice. It has been reported the inhibition produced by UA on the calcium-flux induced by capsaicin on TRPV1 receptor suggesting the antagonistic activity of this receptor. Finally, an ED50=44 mg/kg was calculated in the neurogenic and inflammatory nociception induced in the formalin test in rats. The antinociceptive response of UA in the formalin test was not modified in presence of naloxone, flumazenil or L-arginine. Nevertheless, it was reverted in presence of 1-H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, an inhibitor of soluble guanylyl cyclase) and increased in presence of N(G)-L-nitro-arginine methyl ester (L-NAME, inhibitor of nitric oxide synthase), theophylline (inhibitor of phosphodiesterase) and WAY100635 (an antagonist of 5-HT1A receptors). Current results provide evidence that the antinociceptive response of A. mexicana depends in part on the presence of UA. Moreover, this triterpene may exerts its antinociceptive effect mediated by the presence of cGMP and an additive synergism with 5HT1A receptors, but also an antagonistic activity towards TRPV1 receptors may be involved. PMID- 23932919 TI - Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat. AB - Tesofensine is a triple monoamine reuptake inhibitor which inhibits noradrenaline, 5-HT and dopamine reuptake. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong and sustained effects in obesity management is not clarified. Tesofensine effectively induces appetite suppression in the diet-induced obese (DIO) rat partially being ascribed to an indirect stimulation of central dopamine receptor function subsequent to blocked dopamine transporter activity. This is interesting, as obese patients have reduced central dopaminergic activity thought to provide a drive for compensatory overeating, but whether treatment with an uptake inhibitor counteracts these changes or not has not been investigated. Tesofensine treatment (2.0 mg/kg/day for 14 days) caused a pronounced anorexigenic and weight-reducing response in DIO rats as compared to age-matched chow-fed rats. DIO rats also exhibited a marked reduction in baseline extracellular dopamine levels in the nucleus accumbens (NAcc) and prefrontal cortex (PFC), as compared to chow-fed rats using microdialysis. While acute administration of tesofensine (2.0 mg/kg) normalized accumbal dopamine levels in DIO rats, the drug had no effect on dopamine levels in chow-fed rats. Tesofensine evoked a stronger stimulatory response on NAcc and PFC dopamine levels in DIO rats, and also induced discrete changes in striatal dopamine D2 receptor expression and transporter binding. In conclusion, tesofensine produces weight loss together with reversal of lowered forebrain dopamine levels in DIO rats, suggesting that tesofensine's anti-obesity effects, at least in part, are associated with positive modulation of central dopaminergic activity. PMID- 23932920 TI - Curcumin pretreatment attenuates brain lesion size and improves neurological function following traumatic brain injury in the rat. AB - Turmeric has been in use since ancient times as a condiment and due to its medicinal properties. Curcumin, the yellow coloring principle in turmeric, is a polyphenolic and a major active constituent. Besides anti-inflammatory, thrombolytic and anti-carcinogenic activities, curcumin also possesses strong antioxidant property. The neuroprotective effects of curcumin were evaluated in a weight drop model of cortical contusion trauma in rat. Male Wistar rats (350-400 g, n=9) were anesthetized with sodium pentobarbital (60 mg/kg i.p.) and subjected to head injury. Five days before injury, animals randomly received an i.p. bolus of either curcumin (50 and 100 mg/kg/day, n=9) or vehicle (n=9). Two weeks after the injury and drug treatment, animals were sacrificed and a series of brain sections, stained with hematoxylin and eosin (H&E) were evaluated for quantitative brain lesion volume. Two weeks after the injury, oxidative stress parameter (malondialdehyde) was also measured in the brain. Curcumin (100 mg/kg) significantly reduced the size of brain injury-induced lesions (P<0.05). Neurological examinations (rotarod and inclined-plane tests) were performed on days 1, 3, 7 and 14 post-brain injury. Control injured rats had a significant neurological deficit during 2 weeks (P<0.001). The injury increased brain levels of the malondialdehyde by 35.6% and these increases were attenuated by curcumin (100 mg/kg). Curcumin treatment significantly improved the neurological status evaluated during 2 weeks after brain injury. The study demonstrates the protective efficacy of curcumin in rat traumatic brain injury model. PMID- 23932922 TI - Muscle atrophy: from molecular pathways to clinical therapy. PMID- 23932921 TI - DDX6 post-transcriptionally down-regulates miR-143/145 expression through host gene NCR143/145 in cancer cells. AB - In various human malignancies, widespread dysregulation of microRNA (miRNA) expression is reported to occur and affects various cell growth programs. Recent studies suggest that the expression levels of miRNAs that act as tumor suppressors are frequently reduced in cancers because of chromosome deletions, epigenetical changes, aberrant transcription, and disturbances in miRNA processing. MiR-143 and -145 are well-recognized miRNAs that are highly expressed in several tissues, but down-regulated in most types of cancers. However, the mechanism of this down-regulation has not been investigated in detail. Here, we show that DEAD-box RNA helicase 6, DDX6 (p54/RCK), post-transcriptionally down regulated miR-143/145 expression by prompting the degradation of its host gene product, NCR143/145 RNA. In human gastric cancer cell line MKN45, DDX6 protein was abundantly expressed and accumulated in processing bodies (P-bodies). DDX6 preferentially increased the instability of non-coding RNA, NCR143/145, which encompasses the miR-143/145 cluster, and down-regulated the expression of mature miR-143/145. In human monocytic cell line THP-1, lipopolysaccharide treatment promoted the assembly of P-bodies and down-regulated the expression of NCR143/145 and its miR-143/145 rapidly. In these cells, cycloheximide treatment led to a loss of P-bodies and to an increase in NCR143/145 RNA stability, thus resulting in up-regulation of miR-143/145 expression. These data demonstrate that DDX6 contributed to the control of NCR143/145 RNA stability in P-bodies and post transcriptionally regulated miR-143/145 expression in cancer cells. PMID- 23932923 TI - Nanotechnology and pulmonary delivery to overcome resistance in infectious diseases. AB - Used since ancient times especially for the local treatment of pulmonary diseases, lungs and airways are a versatile target route for the administration of both local and systemic drugs. Despite the existence of different platforms and devices for the pulmonary administration of drugs, only a few formulations are marketed, partly due to physiological and technological limitations. Respiratory infections represent a significant burden to health systems worldwide mainly due to intrahospital infections that more easily affect immune-compromised patients. Moreover, tuberculosis (TB) is an endemic infectious disease in many developing nations and it has resurged in the developed world associated with the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic. Currently, medicine faces the specter of antibiotic resistance. Besides the development of new anti-infectious drugs, the development of innovative and more efficient delivery systems for drugs that went off patent appears as a promising strategy pursued by the pharmaceutical industry to improve the therapeutic outcomes and to prolong the utilities of their intellectual property portfolio. In this context, nanotechnology-based drug delivery systems (nano-DDS) emerged as a promising approach to circumvent the limitations of conventional formulations and to treat drug resistance, opening the hypothesis for new developments in this area. PMID- 23932924 TI - MicroRNA-106a induces multidrug resistance in gastric cancer by targeting RUNX3. AB - Multidrug resistance (MDR) is the main barrier to the success of chemotherapy for gastric cancer (GC). miR-106a, which is highly expressed in GC, influences a variety of aspects of GC. However, the function of miR-106a in MDR of GC still remains unclear. In the present study, we found that miR-106a is elevated in MDR cell lines. miR-106a promotes chemo-resistance of GC cells, accelerates ADR efflux, and suppresses drug-induced apoptosis. Finally, we show that runt-related trans factor 3 (RUNX3) is the functional target of miR-106a. Collectively, these findings demonstrate that miR-106a may promote MDR in GC cells by targeting RUNX3. PMID- 23932925 TI - New steroidal 7-azaindole platinum(II) antitumor complexes. AB - Two new steroidal 7-azaindole-based N-donor ligands 17-alpha-[7-azaindole-5 ethynyl]-17-beta-testosterone (ET-Haza) (1) and 17-alpha-[7-azaindole-5-ethynyl] 19-nortestosterone (LEV-Haza) (2), and two new DNA damaging warheads with an enhanced lipophilicity [Pt(dmba)Cl(L)] (dmba=N,N-dimethylbenzylamine kappaN,kappaC; L=ET-Haza (3) and LEV-Haza (4)) have been prepared and characterized. Values of IC50 were calculated for complexes 3 and 4 against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cis) and breast cancers (T47D). At 48 h of incubation time 3 and 4 showed very low resistance factors (RF of 1) against an A2780 cell line which has acquired resistance to cisplatin, IC50 values of the new complexes towards normal human LLC-PK1 renal cells at 48 h being about double than that of cisplatin. 3 and 4 are able to react with 9-ethylguanine (9-EtG) yielding the corresponding monoadduct [Pt(dmba)(L)(9-EtG)](+) derivatives as followed by ESI-MS. Compound 3 interacts mainly with double-stranded (DS) oligonucleotides as shown by analysis with ESI-TOF-MS, being also able to displace ethidium bromide (EB) from DNA, as observed by an electrophoretic mobility study. 3 and 4 are good cathepsin B inhibitors. Theoretical calculations at the COSMO(CHCl3)/B3LYP-D/def2 TZVPPecp//B3LYP-D/def2-TZVPecp level and energy evaluations at the COSMO(CHCl3)/PWPB95-D3/def2-TZVPPecp level of theory on compound 4 and model systems have been done. PMID- 23932927 TI - Cardiovascular risk assessment according to a national calibrated score risk index in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. AB - OBJECTIVE: To assess cardiovascular (CV) risk in psoriatic arthritis (PsA) patients without clinically evident CV disease or classic atherosclerosis risk factors according to the SCORE chart following the EULAR recommendations. METHODS: Eighty PsA patients without previous CV events or atherosclerosis risk factors and eighty matched controls were included. Information on demographic, anthropometric and clinical-serological data of disease was assessed. The national calibrated Systematic Coronary Risk Evaluation (SCORE) index was calculated and the association between this SCORE and clinical-serological data of these patients was analyzed. RESULTS: PsA patients had higher acute phase reactants as well as higher SCORE mean values than healthy controls (1.99+/-3.52 vs. 1.0+/-1.74; P=0.028). According to SCORE definitions, 71 (89%) patients had low-intermediate CV risk and 9 (11%) were above the threshold of high risk. In the control group, 76 (95%) had low-intermediate risk and four (5%) had high CV risk. However, there were no differences in CV risk stratification between both groups (P=0.148). PsA patients with high-very high CV risk had longer disease duration (P=0.001) and higher levels of triglycerides (P=0.009). PsA patients showed a significant correlation between SCORE values and disease duration (beta=0.185; P=0.0001) and the average annual levels of C reactive protein (CRPa), beta=2.38; P=0.014. CONCLUSION: CV risk assessment in PsA patients without clinically evident CV disease or classic atherosclerosis risk factors may be underestimated by using only the SCORE chart. In these patients, disease duration and the CRPa may help to establish a better stratification of the actual CV risk. PMID- 23932926 TI - Successful use of rituximab in a young patient with immunoglobulin G4-related disease and refractory scleritis. PMID- 23932928 TI - A novel mutation in the COL2A1 gene in a Chinese family with Spondyloepiphyseal dysplasia congenita. AB - Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant skeletal dysplasia characterized by short stature, diminished joint mobility, dislocation of hip, absent femoral head ossification, scoliosis and flattened vertebral bodies. SEDC is caused by mutations in the gene encoding the type II procollagen alpha-1 chain (COL2A1). We screened COL2A1 gene mutations in four affected individuals from a Chinese family with SEDC. A novel missense mutation c.3257G>T (p.G1086V), which located in the triple-helical domain, was identified in the SEDC patients. Our study extends the mutation spectrum of SEDC and confirms genotype-phenotype relationship between mutations in the COL2A1 gene and clinical findings of SEDC. PMID- 23932929 TI - Two rare cases of adult-onset phalangeal microgeodic syndrome with magnetic resonance imaging-proven bone edema transiently occurring in winter. AB - We report two rare cases of adult-onset phalangeal microgeodic syndrome (PMS), which commonly develops in children. Both cases were Japanese women, with case 1: 60 years old and case 2: 58 years old. They developed swelling and stiffness in their fingers in winter, and their symptoms disappeared without any treatment in summer. Magnetic resonance imaging (MRI) of bilateral hands showed diffuse bone edema of the middle and proximal phalanges in winter, but the abnormal findings also disappeared in summer. The specific abnormalities observed on MRI were very useful for the diagnosis of PMS. Interestingly, they appeared in winter and disappeared in summer in parallel with the symptoms. PMID- 23932930 TI - Rapid differentiation of citrus Hop stunt viroid variants by real-time RT-PCR and high resolution melting analysis. AB - The RNA genome of pathogenic and non-pathogenic variants of citrus Hop stunt viroid (HSVd) differ by five to six nucleotides located within the variable (V) domain referred to as the "cachexia expression motif". Sensitive hosts such as mandarin and its hybrids are seriously affected by cachexia disease. Current methods to differentiate HSVd variants rely on lengthy greenhouse biological indexing on Parson's Special mandarin and/or direct nucleotide sequence analysis of amplicons from RT-PCR of HSVd-infected plants. Two independent high throughput assays to segregate HSVd variants by real-time RT-PCR and High-Resolution Melting Temperature (HRM) analysis were developed: one based on EVAGreen dye; the other based on TaqMan probes. Primers for both assays targeted three differentiating nucleotides in the V domain which separated HSVd variants into three clusters by distinct melting temperatures with a confidence level higher than 98%. The accuracy of the HRM assays were validated by nucleotide sequencing of representative samples within each HRM cluster and by testing 45 HSVd-infected field trees from California, Italy, Spain, Syria and Turkey. To our knowledge, this is the first report of a rapid and sensitive approach to detect and differentiate HSVd variants associated with different biological behaviors. Although, HSVd is found in several crops including citrus, cachexia variants are restricted to some citrus-growing areas, particularly the Mediterranean Region. Rapid diagnosis for cachexia and non-cachexia variants is, thus, important for the management of HSVd in citrus and reduces the need for bioindexing and sequencing analysis. PMID- 23932932 TI - Phospholipase D-mediated hypersensitivity at central synapses is associated with abnormal behaviours and pain sensitivity in rats exposed to prenatal stress. AB - Adverse events at critical stages of development can lead to lasting dysfunction in the central nervous system (CNS). To seek potential underlying changes in synaptic function, we used a newly developed protocol to measure alterations in receptor-mediated Ca(2+) fluorescence responses of synaptoneurosomes, freshly isolated from selected regions of the CNS concerned with emotionality and pain processing. We compared adult male controls and offspring of rats exposed to social stress in late pregnancy (prenatal stress, PS), which showed programmed behavioural changes indicating anxiety, anhedonia and pain hypersensitivity. We found corresponding increases, in PS rats compared with normal controls, in responsiveness of synaptoneurosomes from frontal cortex to a glutamate receptor (GluR) agonist, and from spinal cord to activators of nociceptive afferents. Through a combined pharmacological and biochemical strategy, we found evidence for a role of phospholipase D1 (PLD1)-mediated signalling, that may involve 5 HT2A receptor (5-HT2AR) activation, at both levels of the nervous system. These changes might participate in underpinning the enduring alterations in behaviour induced by PS. PMID- 23932931 TI - The expression analysis of Sfrs10 and Celf4 during mouse retinal development. AB - Processing of mRNAs including, alternative splicing (AS), mRNA transport and translation regulation are crucial to eukaryotic gene expression. For example, >90% of the genes in the human genome are known to undergo alternative splicing thereby expanding the proteome production capacity of a limited number of genes. Similarly, mRNA export and translation regulation plays a vital role in regulating protein production. Thus, it is important to understand how these RNA binding proteins including alternative splicing factors (ASFs) and mRNA transport and translation factors regulate these processes. Here we report the expression of an ASF, serine-arginine rich splicing factor 10 (Sfrs10) and a mRNA translation regulation factor, CUGBP, elav like family member 4 (Celf4) in the developing mouse retina. Sfrs10 was expressed throughout postnatal (P) retinal development and was observed progressively in newly differentiating neurons. Immunofluorescence (IF) showed Sfrs10 in retinal ganglion cells (RGCs) at P0, followed by amacrine and bipolar cells, and at P8 it was enriched in red/green cone photoreceptor cells. By P22, Sfrs10 was observed in rod photoreceptors in a peri-nuclear pattern. Like Sfrs10, Celf4 expression was also observed in the developing retina, but with two distinct retinal isoforms. In situ hybridization (ISH) showed progressive expression of Celf4 in differentiating neurons, which was confirmed by IF that showed a dynamic shift in Celf4 localization. Early in development Celf4 expression was restricted to the nuclei of newly differentiating RGCs and later (E16 onwards) it was observed in the initial segments of RGC axons. Later, during postnatal development, Celf4 was observed in amacrine and bipolar cells, but here it was predominantly cytoplasmic and enriched in the two synaptic layers. Specifically, at P14, Celf4 was observed in the synaptic boutons of rod bipolar cells marked by Pkc-alpha. Thus, Celf4 might be regulating AS early in development besides its known role of regulating mRNA localization/translation. In all, our data suggests an important role for AS and mRNA localization/translation in retinal neuron differentiation. PMID- 23932933 TI - Effect of caffeine on cycling time-trial performance in the heat. AB - OBJECTIVES: The purpose of this investigation was to determine whether a moderate dose of caffeine would improve a laboratory simulated cycling time-trial in the heat. METHODS: Nine well-trained male subjects (VO2max 64.4+/-6.8mLmin(-1)kg(-1), peak power output 378+/-40W) completed one familiarisation and two experimental laboratory simulated cycling time-trials in environmental conditions of 35 degrees C and 25% RH 90min after consuming either caffeine (3mgkg(-1) BW) or placebo, in a double blind, cross-over study. RESULTS: Time-trial performance was faster in the caffeine trial compared with the placebo trial (mean+/-SD, 3806+/ 359s versus 4079+/-333s, p=0.06, 90%CI 42-500s, 86% likelihood of benefit, d= 0.79). Caffeine ingestion was associated with small to moderate increases in average heart rate (p=0.178, d=0.39), VO2 (p=0.154, d=0.45), respiratory exchange ratio (p=0.292, d=0.35) and core temperature (p=0.616, d=0.22) when compared to placebo, however, these were not statistically significant. Average RPE during the caffeine supplemented time-trial was not significantly different from placebo (p=0.41, d=-0.13). CONCLUSION: Caffeine supplementation at 3mgkg(-1) BW resulted in a worthwhile improvement in cycling time-trial performance in the heat. DESIGN: Double-blind cross-over study. PMID- 23932934 TI - ActiGraph GT3X+ cut-points for identifying sedentary behaviour in older adults in free-living environments. AB - OBJECTIVES: To determine the ActiGraph GT3X+ cut-points with the highest accuracy for estimating time spent in sedentary behaviour in older adults in free-living environments. ActivPAL(3)TM was used as the reference standard. DESIGN: Cross sectional study. METHODS: 37 participants (13 males and 24 females, 73.5 +/- 7.3 years old) wore an ActiGraph GT3X+ and an ActivPAL(3)TM for 7 consecutive days. For ActivPAL(3)TM, variables were created based on posture. For ActiGraph GT3X+, sedentary behaviour was defined as (1) vector magnitude and (2) vertical axis counts for 1-s, 15-s and 1-min epochs, with cut-points for 1-s epochs of <1 to <10 counts, for 15-s epochs of <1 to <100 counts and for 1-min epochs of <1 to <400 counts. For each of the ActiGraph GT3X+ cut-points, area under the receiver operating characteristic curve (area under the curve), sensitivity, specificity, and percentage correctly classified were calculated. Bias and 95% limits of agreement were calculated using the Bland-Altman method. RESULTS: The highest areas under the curve were obtained for the vector magnitude cut-points: <1 count/s, <70 counts/15-s, and <200 counts/min; and for the vertical axis cut points: <1 count/s, <10 counts/15-s and <25 counts/min. Mean biases ranged from 4.29 to 124.28 min/day. The 95% limits of agreement for these cut-points were +/- 2 h suggesting great inter-individual variation. CONCLUSIONS: The results suggest that cut-points are dependent on unit of analyses (i.e. epoch length and axes); cut-points for a given epoch length and axis cannot simply be extrapolated to other epoch lengths. Limitations regarding inter-individual variability and misclassification of standing activity as sitting/lying must be considered. PMID- 23932935 TI - The Bonar score revisited: region of evaluation significantly influences the standardized assessment of tendon degeneration. AB - OBJECTIVES: Tendinopathy is a common, costly condition affecting both sporting and sedentary populations. Research into tendinopathy frequently involves the evaluation of tendinosis, a pathology characterized by a lack of inflammatory cells, collagen disruption, neovascularisation, altered cell numbers and morphology and increased glycosaminoglycans. Evaluation of these characteristics can be undertaken using the Bonar histopathology score, but the characteristics are heterogeneous throughout tendon specimens with no standardized method of determining the area to be evaluated. The objective of this study was to assess whether the Bonar score varies depending on the criteria used to define the area of evaluation. DESIGN: Case series. METHODS: Two independent assessors, with a third to resolve disputes, evaluated 103 areas from 35 tendon specimens using the Bonar score. Specimens were scored once each in the area of worst collagen disruption, degree of vascularization, and cell morphological changes. The inter tester reliability of the updated Bonar scale was good (r(2)=0.71) RESULTS: The Bonar score was highest in the areas of worst cell morphological (CM) changes, followed by collagen disruption (CD) and lowest for the area of most extensive vascular proliferation (VS) (regression: CD vs. CM, p=0.008, CM vs. VS, p<0.001, CD vs. VS, p=0.013). Suggested modifications to the Bonar score include the addition of a cellularity domain, specific definitions of hypo- and hypercellularity, and changes to the vascularity score to include pathological avascularity. CONCLUSIONS: The updated Bonar score includes a standardized method of selecting the area of evaluation, which should provide increased reliability when assessing the extent of tendon degeneration. PMID- 23932938 TI - Transcriptome analysis of neuropeptides and G-protein coupled receptors (GPCRs) for neuropeptides in the brown planthopper Nilaparvata lugens. AB - The genes encoding neuropeptides, neurohormones and their putative G-protein coupled receptors were identified in the brown planthopper (BPH), Nilaparvata lugens (Stal) by transcriptome analysis (RNA-seq). Forty-eight candidate genes were found to encode neuropeptides or peptide hormones. These include all known insect neuropeptides and neurohormones, with the exception of neuropeptide-like precursor 2 (NPLP2) and trissin. The gene coding for prothoracicotropic hormone (PTTH) was first identified from hemimetabolous insect. A total of 57 putative neuropeptide GPCR genes were identified and phylogenetic analysis showed most of them to be closely related to insect GPCRs. A notable finding was the occurrence of vertebrate hormone receptors, thyrotropin-releasing hormone receptor (TRHR) like GPCR and parathyroid hormone receptor (PTHR)-like GPCRs. These results suggest that N. lugens possesses the most comprehensive neuropeptide system yet found in insects. Moreover, our findings demonstrate the power of RNA-seq as a tool for analyzing the neuropeptide-related genes in the absence of whole genome sequence information. PMID- 23932937 TI - Neuropeptide Y Y5-receptor activation on breast cancer cells acts as a paracrine system that stimulates VEGF expression and secretion to promote angiogenesis. AB - Accumulating data implicate a pathological role for sympathetic neurotransmitters like neuropeptide Y (NPY) in breast cancer progression. Our group and others reported that NPY promotes proliferation and migration in breast cancer cells, however the angiogenic potential of NPY in breast cancer is unknown. Herein we sought to determine if NPY promotes angiogenesis in vitro by increasing vascular endothelial growth factor (VEGF) expression and release from 4T1 breast cancer cells. Western blot analysis revealed that NPY treatment caused a 52 +/- 14% increase in VEGF expression in the 4T1 cells compared to non-treated controls. Using selective NPY Y-receptor agonists (Y1R, Y2R and Y5R) we observed an increase in VEGF expression only when cells were treated with Y5R agonist. Congruently, using selective Y1R, Y2R, or Y5R antagonists, NPY-induced increases in VEGF expression in 4T1 cells were attenuated only under Y5R antagonism. Endothelial tube formation assays were conducted using conditioned media (CM) from NPY treated 4T1 cells. Concentration-dependent increases in number of branch points and complete endothelial networks were observed in HUVEC exposed to NPY CM. CM from Y5R agonist treated 4T1 cells caused similar increases in number of branch points and complete endothelial networks. VEGF concentration was quantified in CM (ELISA) from agonist experiments; we observed a 2-fold and 2.5 fold increase in VEGF release from NPY and Y5R agonist treated 4T1 cells respectively. Overall these data highlight a novel mechanism by which NPY may promote breast cancer progression, and further implicate a pathological role of the NPY Y5R. PMID- 23932939 TI - Differential mode of antimicrobial actions of arginine-rich and lysine-rich histones against Gram-positive Staphylococcus aureus. AB - We previously reported the activities and modes of action of arginine (Arg)-rich histones H3 and H4 against Gram-negative bacteria. In the present study, we investigated the properties of the Arg-rich histones against Gram-positive bacteria in comparison with those of lysine (Lys)-rich histone H2B. In a standard microdilution assay, calf thymus histones H2B, H3, and H4 showed growth inhibitory activity against Staphylococcus aureus with minimum effective concentration values of 4.0, 4.0, and 5.6 MUM, respectively. Laser confocal microscopic analyses revealed that both the Arg-rich and Lys-rich histones associated with the surface of S. aureus. However, while the morphology of S. aureus treated with histone H2B appeared intact, those treated with the histones H3 and H4 closely resembled each other, and the cells were blurred. Electrophoretic mobility shift assay results revealed these histones have binding affinity to lipoteichoic acid (LTA), one of major cell surface components of Gram positive bacteria. Scanning electron microscopic analyses demonstrated that while histone H2B elicited no obvious changes in cell morphology, histones H3 and H4 disrupted the cell membrane structure with bleb formation in a manner similar to general antimicrobial peptides. Consequently, our results suggest that bacterial cell surface LTA initially attracts both the Arg- and Lys-rich histones, but the modes of antimicrobial action of these histones are different; the former involves cell membrane disruption and the latter involves the cell integrity disruption. PMID- 23932940 TI - Plasmodium falciparum rhoptry neck protein 5 peptides bind to human red blood cells and inhibit parasite invasion. AB - Plasmodium falciparum malaria parasite invasion of erythrocytes is an essential step in host infection and the proteins involved in such invasion are the main target in developing an antimalarial vaccine. Secretory organelle-derived proteins (micronemal AMA1 protein and the RON2, 4, and 5 rhoptry neck proteins) have been recently described as components of moving junction complex formation allowing merozoites to move into a newly created parasitophorous vacuole. This study led to identifying RON5 regions involved in binding to human erythrocytes by using a highly robust, sensitive and specific receptor-ligand interaction assay; it is further shown that the RON5 protein remains highly conserved throughout different parasite strains. It is shown that the binding peptide erythrocyte interaction is saturable and sensitive to chymotrypsin and trypsin. Invasion inhibition assays using erythrocyte binding peptides showed that the RON5-erythrocyte interaction could be critical for merozoite invasion of erythrocytes. This work provides evidence (for the first time) suggesting a fundamental role for RON5 in erythrocyte invasion. PMID- 23932941 TI - Effects of recombinant trout leptin in superoxide production and NF-kappaB/MAPK phosphorylation in blood leukocytes. AB - Studies in mammals indicate that leptin is a multifunctional cytokine involved in regulation of energy metabolism and the modulation of the immune function. However, evidence for an immunomodulatory effect of leptin in fish is still missing. At least in part, this lack of knowledge is due to the absence of materials and models. In this study, we produced trout recombinant leptin (rt lep) and tested its capacity to trigger cellular pathways, usually active in mammal immune system cells. STAT3, NF-kappaB, and the three major MAPK cascades (JNK, p38 and ERK), were activated by rt-lep in in vitro incubations with blood leucocytes of the rainbow trout Oncorhynchus mykiss. We also showed that rt-lep causes a decrease in superoxide anion production in trout blood leucocytes. Thus our data indicate that as in mammals also in teleosts leptin plays pleiotropic activities. Importantly, its actions in fishes do not always conform to the picture emerging for mammals. PMID- 23932942 TI - Antigen selection in B-cell lymphomas--tracing the evidence. AB - While signaling through the B cell receptor (BcR) facilitates B cell development and maintenance, it also carries intertwined risks for the development of lymphomas since malignant B cells can exploit these pathways in order to trigger and fuel clonal expansion. This corruption of the normal B cell response to antigens, leading to sustained BcR signaling, has given great impulse to investigate in detail the role of antigen in lymphomas. Suffice it to conclude from such studies, largely immunogenetics based, that the evidence implicating antigens (exogenous or self) in lymphoma development is substantial and that lymphomagenesis is functionally driven and dynamic, rather than a simple stochastic process. As the paradigm of antigen-driven lymphoma evolves, further investigation will be paramount to the identification of the inciting agent(s) that may be responsible for immunoproliferative neoplasms and also for the development of therapeutic agents targeting effectors of the BcR signaling pathway. PMID- 23932943 TI - Cuticular hydrocarbons as a tool for the identification of insect species: puparial cases from Sarcophagidae. AB - The external surface of all insects is covered by a species-specific complex mixture of highly stable, very long chain cuticular hydrocarbons (CHCs). Gas chromatography coupled to mass spectrometry was used to identify CHCs from four species of Sarcophagidae, Peckia (Peckia) chrysostoma, Peckia (Pattonella) intermutans, Sarcophaga (Liopygia) ruficornis and Sarcodexia lambens. The identified CHCs were mostly a mixture of n-alkanes, monomethylalkanes and dimethylalkanes with linear chain lengths varying from 23 to 33 carbons. Only two alkenes were found in all four species. S. lambens had a composition of CHCs with linear chain lengths varying from C23 to C33, while the other three species linear chain lengths from 24 to 31 carbons. n-Heptacosane, n-nonacosane and 3 methylnonacosane, n-triacontane and n-hentriacontane occurred in all four species. The results show that these hydrocarbon profiles may be used for the taxonomic differentiation of insect species and are a useful additional tool for taxonomic classification, especially when only parts of the insect specimen are available. PMID- 23932945 TI - Analysis of the genitalia rotation in the male Anopheles funestus (Diptera: Culicidae). AB - Anopheles funestus is a major malaria vector in Africa. Insecticide resistance has developed in populations of this species in several African countries, prompting the need to develop additional vector control methods such as the sterile insect technique (SIT). This technique requires an understanding of those underlying physiological events that lead to sexual maturity of An. funestus males, the rotation of their genitalia in particular. The aim of this study was to qualitatively and quantitatively describe genital rotation in An. funestus males as it is an essential function of sexual maturation. Genital rotation of all the males reached its final rotation stage (135-180 degrees rotation) 36 h post emergence at 23 +/- 1 degrees C in laboratory colonised An. funestus males. These males had a comparable rotation rate to wild caught An. funestus at the same temperature setting. A temperature change (either 18 +/- 1 degrees C or 29 +/- 1 degrees C versus 23 +/- 1 degrees C) significantly influenced the genital rotation rate such that this rate increased with increasing temperature. This information enhances our knowledge of the An. funestus male biology. This is important in terms of applying the sterile insect technique as the understanding and manipulation of the rate of sexual maturation in males has implications for the timing of sterile male release. PMID- 23932944 TI - Schistosoma mansoni infection: is it a risk factor for development of hepatocellular carcinoma? AB - The burden of hepatocellular carcinoma (HCC) in Egypt has been increasing with a doubling in the incidence rate in the past 10 years, which necessitates the investigation of the possible risk factors to its development. The present study aimed at investigating the role of Schistosoma mansoni infection as a risk factor for development of HCC. Five hundred parasite free mice were categorized into four groups: Group I (induction of carcinoma by diethylnitrosamine (DEN)), Group II (DEN+Infection), Group III (Infection) and Group IV (Control). Groups I and II were further subdivided into 4 subgroups according to the dose of DEN given. Serum samples from each group were examined for levels of tumor markers alpha fetoprotein (AFP) and ferritin by ELISA, then mice were sacrificed and subjected to histopathological examination of their livers. These were repeated every week till the end of the experiment. The results of the histopathological examination clarified the role of S. mansoni in enhancing and aggravating the carcinogenic effect of DEN; dysplastic changes appeared earlier, with a higher grade and with a smaller dose of DEN in Group II compared to Group I. Serum levels of tumor markers showed earlier statistically significant differences in Group II than in Group I when compared to Group IV. We conclude that S. mansoni accelerates hepatic dysplastic changes in the presence of other risk factors making cancer appear early and with a more aggressive nature, compared to the same risk in absence of schistosomiasis. PMID- 23932946 TI - Determination of triglycerides with special emphasis on biosensors: a review. AB - Triglycerides (TG) are transesterification product of fatty acids and glycerol and engaged in the transportation of fats. Elevated triglyceride level is associated with coronary heart disease (CAD), atherosclerosis and hypolipoprotenemia. Convenient and reproducible assay systems based on enzymes are an attractive alternative to conventional analytical methods. Triglyceride biosensors (TGBs) are based on either measurement of oxygen consumed or electron generated from splitting of H2O2, an ultimate product, of immobilized enzymes. TGBs work optimally within 2-900 s, between pH 6.4-8.5 and the potential 0.5-4V. TGBs measure TG level in serum directly and can be used over a period of 14 to 168 days. This review describes the analytic characteristics of various methods available for determination of TGs with special emphasis on TGBs. PMID- 23932947 TI - Great expectations. Eating expectancies as mediators of reinforcement sensitivity and eating. AB - Eating expectancies are proposed as cognitive pathways linking reinforcement (reward and punishment) sensitivities and the tendency to over-eat in response to appetitive and emotional cues. In Study One (N=243 university women) explicit eating expectancies were tested as potential mediators of reinforcement sensitivities and eating styles. Broadly, expectancies that eating alleviates negative affect/boredom mediated both reward and punishment sensitivity and emotional eating. The expectancy that eating is pleasurable and rewarding mediated reward sensitivity and external eating. In Study Two (N=109), using an implicit eating expectancy task, reward sensitivity and external eating was mediated via positive expectancy statements, notably, that eating is pleasurable and rewarding. Reward sensitivity and emotional eating was mediated specifically by expectancies that eating manages boredom. Punishment sensitivity was not associated with any implicit expectancies. Findings support the role of expectancies as cognitive mediators in the relationship between reinforcement sensitivities and emotionally-driven versus externally-driven eating styles. However, the largely appetitive implicit expectancies task only supported an association with reward sensitivity. PMID- 23932948 TI - Estimating food portions. Influence of unit number, meal type and energy density. AB - Estimating how much is appropriate to consume can be difficult, especially for foods presented in multiple units, those with ambiguous energy content and for snacks. This study tested the hypothesis that the number of units (single vs. multi-unit), meal type and food energy density disrupts accurate estimates of portion size. Thirty-two healthy weight men and women attended the laboratory on 3 separate occasions to assess the number of portions contained in 33 foods or beverages of varying energy density (1.7-26.8 kJ/g). Items included 12 multi-unit and 21 single unit foods; 13 were labelled "meal", 4 "drink" and 16 "snack". Departures in portion estimates from reference amounts were analysed with negative binomial regression. Overall participants tended to underestimate the number of portions displayed. Males showed greater errors in estimation than females (p=0.01). Single unit foods and those labelled as 'meal' or 'beverage' were estimated with greater error than multi-unit and 'snack' foods (p=0.02 and p<0.001 respectively). The number of portions of high energy density foods was overestimated while the number of portions of beverages and medium energy density foods were underestimated by 30-46%. In conclusion, participants tended to underestimate the reference portion size for a range of food and beverages, especially single unit foods and foods of low energy density and, unexpectedly, overestimated the reference portion of high energy density items. There is a need for better consumer education of appropriate portion sizes to aid adherence to a healthy diet. PMID- 23932949 TI - It takes some effort. How minimal physical effort reduces consumption volume. AB - Plenty of studies have demonstrated that effort influences food choice. However, few have been conducted to analyze the effect of effort on consumption volume. Moreover, the few studies that have measured consumption volume all have strong limitations. The goal of the present paper is to disentangle confounding variables in earlier research and to rule out various alternative explanations. In a tasting setting focusing on snacking behavior, either unwrapping a food product or grabbing it with sugar tongs was enough to significantly reduce consumption, regardless of whether an unhealthy or healthy food item was used. Hardly any cognitive resources seem to be necessary for the effect to occur, as cognitive load did not affect the findings. In light of obesity being a pressing concern, these findings might be valuable for individuals as well as for the food industry. PMID- 23932950 TI - Imaging the upper gastrointestinal tract in unsedated patients using tethered capsule endomicroscopy. PMID- 23932951 TI - Current strategies for inhibiting FGFR activities in clinical applications: opportunities, challenges and toxicological considerations. AB - Aberrations in fibroblast growth factor receptor (FGFR) signaling are instrumental to the pathophysiology of several malignancies and disorders. Hence, FGFR inhibitors are explored in therapeutics with early candidates developed as competitors for the ATP-binding pocket in the kinase domain. More recent programs yielded compounds of diverse scaffolds with alternative binding modes. Concurrently, monoclonal antibodies and peptide-based agents provide independent options for clinical development. Notwithstanding this rapid progress, we contemplate the toxicological impact of FGFR inhibition based on the defined role of FGFR family members in physiology and homeostasis. The high homology among FGFR1-4 and also with other kinase subfamilies creates an additional challenge in developing selective inhibitors. It orchestrates an ongoing conundrum of moderating a balance between synergism through multitargeting kinase inhibition and minimizing off-target toxicities. PMID- 23932952 TI - Treating osteoporosis by targeting parathyroid hormone to bone. AB - Osteoporosis is a major public health problem despite widespread use of bisphosphonate therapy. PTH(1-34) is a more effective treatment; but its use has been limited by side effects (hypercalcemia, tumor risk) and inconvenient dosing (daily injection). Long-acting forms of PTH are also effective but cause severe hypercalcemia, presumably from effects in kidney. We hypothesized that targeted delivery of PTH to bone using a collagen binding domain (PTH-CBD) could reduce hypercalcemia. PTH-CBD is cleared from serum within 12hours after subcutaneous administration. In ovariectomized rats, monthly administration of PTH-CBD increased spinal BMD by 14.2% with no associated hypercalcemia. Such bone targeted anabolic agents may ultimately allow the superior efficacy of anabolic therapy to be obtained with the dosing convenience of bisphosphonates. PMID- 23932953 TI - Traditional use of medicinal agents: a valid source of evidence. AB - Traditional knowledge uncovered by serious historical research may help to identify new therapeutic agents. It also plays a part in safety evaluation and drug regulation. So far, however, this way of gaining knowledge is very much neglected in the concept of evidence based medicine, which is in no way contradictory to traditional use. Thus, the true meaning of the word 'tradition' is described, while reliable historical sources are quoted. It is then shown how research into the traditional use of medicinal plants is able to reveal knowledge about efficacy and safety of natural products. Several examples successfully leading to new therapeutic options are given. It is then referred to the concept of 'social validation' developed by the Canadian medical historian John Crellin, who also established guidelines for respective research. Eventually, it is proposed to modify the list of evidence levels by inserting an evidence level 4b 'Traditional use in more than one regional cluster'. PMID- 23932954 TI - Neurostimulation with ultrasound guidance for intercostal nerve block. PMID- 23932955 TI - Loss of motoneurons in the ventral compartment of the rat hypoglossal nucleus following early postnatal exposure to alcohol. AB - Perinatal alcohol exposure (AE) has multiple detrimental effects on cognitive and various behavioral outcomes, but little is known about its impact on the autonomic functions. In a rat model of fetal alcohol spectrum disorders (FASD), we investigated neurochemical and neuroanatomical alterations in two brainstem nuclei, the hypoglossal nucleus (XIIn) and the dorsal nucleus of the vagus nerve (Xdn). One group of male Sprague-Dawley rats (n=6) received 2.625 g/kg ethanol intragastrically twice daily on postnatal days (PD) 4-9, a period equivalent to the third trimester of human pregnancy, and another group (n=6) was sham intubated. On PD 18-19, the rats were perfused and medullary sections were immunohistochemically processed for choline acetyltransferase (ChAT) or two aminergic receptors that mediate excitatory drive to motoneurons, alpha1 adrenergic (alpha1-R) and serotonin 2A (5-HT(2A)-R), and c-Fos. Based on ChAT labeling, AE rats had reduced numbers of motoneurons in the ventral XIIn (XIIn-v; 35.4+/-1.3 motoneurons per side and section vs. 40.0+/-1.2, p=0.022), but not in the dorsal XIIn or Xdn. Consistent with ChAT data, both the numbers of alpha1-R labeled motoneurons in the XIIn-v and the area of the XIIn-v measured using 5 HT(2A)-R staining were significantly smaller in AE rats (19.7+/-1.5 vs. 25.0+/ 1.4, p=0.031 and 0.063 mm2 +/-0.002 vs. 0.074+/-0.002, p=0.002, respectively). Concurrently, both 5-HT(2A)-R and c-Fos staining tended to be higher in AE rats, suggesting an increased activation. Thus, postnatal AE causes motoneuronal loss in the XIIn-v. This may compromise upper airway control and contribute to increased risk of upper airway obstructions and sudden infant death in FASD victims. PMID- 23932956 TI - The efficacy of massage on short and long term outcomes in preterm infants. AB - PURPOSE: Premature infants lack the tactile stimulation they would have otherwise experienced in the womb. Infant massage is a developmentally supportive intervention that has been documented for several decades to have a positive effect on both full term and preterm infants. The purpose of this study was to assess the short and long term benefits of massage on stable preterm infants. METHODS: A quasi experimental design was used, 66 infants were recruited from two university hospitals with tertiary level NICUs; 32 infants received the massage therapy by their mothers. Data collection by a researcher blind to the infants' group assignments included weight at discharge, pain responses on the PIPP scale at discharge, length of stay in hospital, neuro-developmental outcome (Bayley scores) and breastfeeding duration at 12 months corrected age. RESULTS: Infants who were massaged had significantly lower scores on the PIPP after a heel-stick compared to before the massage and had lower PIPP scores at discharge compared to the control group. Massaged infants had higher cognitive scores at 12 months corrected age. Weight gain, length of stay, breastfeeding duration and motor scores did not differ between groups. CONCLUSION: Stable preterm infants benefit from massage therapy given by their mothers and may be a culturally acceptable form of intervention to improve the outcomes of preterm infants. PMID- 23932957 TI - Trajectories and predictors of developmental skills in healthy twins up to 24 months of age. AB - BACKGROUND: Low birth weight and low 5-min Apgar scores have been associated with developmental delay, while older maternal age is a protective factor. Little is known about trajectories and predictors of developmental skills in infant twins, who are generally born with lower birth weights, lower Apgar scores and to older mothers. METHODS: Developmental skills were assessed at 3, 6, 9, 12, 18 and 24 months using the Ages and Stages Questionnaires in 152 twins from the Birmingham Registry for Twin and Heritability Studies. Multilevel spline and linear regression models (adjusted for gestational age, gender, maternal age) were used to estimate developmental trajectories and the associations between birth weight, maternal age and Apgar scores on developmental skills. RESULTS: Twins performed worse than singletons on communication, gross motor, fine motor, problem solving and personal-social skills (p < 0.001). Twins caught up around 6 months (score within -1 standard deviation of norm), except on gross motor skills, which did not catch up until after the age of 12 months. A one-year increase in maternal age was significantly associated with decreases in gross motor and personal social z-scores of up to -0.09, whereas one unit increases in Apgar score increased z-scores up to 0.90 (p < 0.01). CONCLUSIONS: Healthy twins should be considered at a higher risk for developmental delay. Whether these results are comparable to preterm singletons, or whether there are twin-specific issues involved, should be further investigated in a study that uses a matched singleton control group. PMID- 23932958 TI - Revealing the complexity of chronic obstructive pulmonary disease. PMID- 23932959 TI - Genetic characterization of Plasmodium falciparum allelic variants infecting mothers at delivery and their children during their first plasmodial infections. AB - INTRODUCTION: Infants born to mothers with placental malaria at delivery develop Plasmodium falciparum parasitemia earlier than those born to mothers without placental infection. This phenomenon may be explained by the development of immune tolerance due to exposure to P. falciparum antigens in utero. The hypothesis of this study is that this increased susceptibility might be related to infections by parasites expressing the same blood stage allele's antigens as those to which the infants were exposed in utero. METHODS: The comparison of P.falciparum msp2 (3D7 and FC27) and glurp gene polymorphisms of infected mothers at delivery to those of their offspring's infections during infancy was realized and the possible associations of the different polymorphisms with clinical outcomes were assessed. A second approach consisted in the use of a Geographic Information System to determine whether the antigen alleles were homogeneously distributed in the area of study. This was necessary to analyze whether the biological observations were due to high exposure to a particular antigen allelic form in the environment or to high infant permissiveness to the same allelic antigen polymorphism as the placental one. RESULTS: Infants born to mothers with placental malaria at delivery were more susceptible to infections by parasites carrying the same glurp allele as encountered in utero compared to distinct alleles, independently of their geographic distribution. CONCLUSION: The increased permissiveness of infants to plasmodial infections with shared placental-infant glurp alleles sheds light on the role that P. falciparum blood stage antigen polymorphisms may play in the first plasmodial infections in infancy. PMID- 23932960 TI - Reassessment of MLST schemes for Leptospira spp. typing worldwide. AB - Leptospirosis is a neglected zoonosis of global importance. Several multilocus sequence typing (MLST) methods have been developed for Leptospira spp., the causative agent of leptospirosis. In this study we reassessed the most commonly used MLST schemes in a set of worldwide isolates, in order to select the loci that achieve the maximum power of discrimination for typing Leptospira spp. Global eBURST algorithm was used to detect clonal complexes among STs and phylogenetic relationships among concatenated and individual sequences were inferred through maximum likelihood (ML) analysis. The evaluation of 12 loci combined to type a subset of strains rendered 57 different STs. Seven of these loci were selected into a final scheme upon studying the number of alleles and polymorphisms, the typing efficiency, the discriminatory power and the ratio dN/dS per nucleotide site for each locus. This new 7-locus scheme was applied to a wider collection of worldwide strains. The ML tree constructed from concatenated sequences of the 7 loci identified 6 major clusters corresponding to 6 Leptospira species. Global eBURST established 8 CCs, which showed that genotypes were clearly related by geographic origin and host. ST52 and ST47, represented mostly by Argentinian isolates, grouped the higher number of isolates. These isolates were serotyped as serogroups Pomona and Icterohaemorrhagiae, showing a unidirectional correlation in which the isolates with the same ST belong to the same serogroup. In summary, this scheme combines the best loci from the most widely used MLST schemes for Leptospira spp. and supports worldwide strains classification. The Argentinian isolates exhibited congruence between allelic profile and serogroup, providing an alternative to serological methods. PMID- 23932961 TI - Determination of paclitaxel in hyaluronic acid polymeric micelles in rat blood by protein precipitation-micelle breaking method: application to a pharmacokinetic study. AB - An efficient dissociation of paclitaxel (PTX) from the home-made hyaluronic acid octadecyl (HA-C18) polymeric micelles formulation in rat blood could not be achieved using previously published PTX analytical methods. So, we intended to develop the micelle-breaking method to determine paclitaxel encapsulated in the HA-C18 polymeric micelles in blood. The pretreatment method of blood samples adopted a simple one-step protein precipitation-micelle breaking process with methanol as micelle-breaking and protein precipitant solvents for complete extraction of PTX from HA-C18 micelles in blood. The micelle breaking efficiency of methanol was as high as 97.7%. Separation was carried out by gradient elution on an Acquity UPLC BEH C18 column with a mobile phase consisting of water (containing 0.1% formic acid) and acetonitrile. A total single run time was as short as 3.0min. Detection was performed by triple-quadrupole mass spectrometry with positive electrospray ionization as source ionization in multiple-reaction monitoring mode at m/z 854.3->286.2 for PTX and m/z 808.5->527.3 for the internal standard, docetaxel. The method demonstrated good linearity at the concentrations ranging from 20 to 10,000ng/mL. The intra- and inter-day relative standard deviations were less than 9.9%. The mean extraction recoveries of PTX and IS were 94.7% and 87.5%, respectively. In summary, the methanol protein precipitation micelle breaking method could extract PTX completely from the polymeric micelles. Finally, the method was successfully applied to a pharmacokinetic study of the home-made PTX-loaded HA-C18 polymeric micelles and Taxol solution after intravenous administration in rats. PMID- 23932962 TI - Activation of extracellular signal-regulated kinase (ERK) and DeltaFosB in emotion-associated neural circuitry after asymptotic levels of active avoidance behavior are attained. AB - Avoidance susceptibility may constitute a vulnerability to develop anxiety disorders, and Wistar-Kyoto (WKY) rats exhibit unique features in their acquisition of avoidance behavior that appear to promote susceptibility to this form of learning, namely the absence of the commonly observed "warm-up" effect. The present study sought to determine if strain differences in acquired avoidance behavior, between WKY and Sprague Dawley rats, could be attributed to differences in dopamine-related plasticity, represented by extracellular signal-regulated kinase (ERK) activity, and prolonged neuronal activation, represented by DeltaFosB accumulation, in three key areas of the brain: the medial prefrontal cortex (mPFC), dorsal striatum (DS), and basolateral amygdala (BLA). Consistent with earlier work, WKY rats exhibited a higher level of asymptotic performance of avoidance behavior, which included an absence of warm-up in the first few trials of later training sessions, and they exhibited more non-reinforced anticipatory responses in the single minute prior to the initiation of the first warning signal presentation of each training session. In the brain, phosyphorylated ERK2 (pERK2) activation was higher in avoidance trained rats in both the mPFC and DS, although the difference in DS was mostly observed in WKY rats. Avoidance-training was associated with higher levels of DeltaFosB expression in the mPFC of SD rats, but not WKY rats. The strain differences in pERK2 activation in the DS and DeltaFosB levels in the mPFC may underlie the strain-specific differences observed in warm-up, the emission of non-reinforced anticipatory responses, and general differences in asymptotic performance of active avoidance behavior. The mPFC and DS require further study as potential neural targets for understanding avoidance susceptibility and, as a result, anxiety vulnerability. PMID- 23932963 TI - Feeding impairs chill coma recovery in the migratory locust (Locusta migratoria). AB - Low temperature causes loss of neuromuscular function in a wide range of insects, such that the animals enter a state known as chill coma. The ability to recover from chill coma (chill coma recovery time) is often a popular phenotype to characterise chill tolerance in insects. Chill coma in insects has been shown to be associated with a decrease in haemolymph volume and a marked increase in [K(+)], causing dissipation of K(+) equilibrium potential and resting membrane potential. High potassium diet (wheat) has also previously been shown to increase haemolymph [K(+)] in Locusta migratoria leading to sluggish behaviour. The present study combined these two independent stressors of ion and water homeostasis, in order to investigate the role of K(+)- and water-balance during recovery from chill coma, in the chill sensitive insect L. migratoria. We confirmed that cold shock elicits a fast increase in haemolymph [K(+)] which is likely caused by a water shift from the haemolymph to the muscles and other tissues. Recovery of haemolymph [K(+)] is however not only reliant on recovery of haemolymph volume, as the recovery of water and K(+) is decoupled. Chill coma recovery time, after 2h at -4 degrees C, differed significantly between fasted animals and those fed on high K(+) diet. This difference was not associated with an increased disturbance of haemolymph [K(+)] in the fed animals, instead it was associated with a slowed recovery of muscle [K(+)], muslce water, haemolymph [Na(+)] and K(+)equilibrium potential in the fed animals. PMID- 23932964 TI - Male Drosophila melanogaster show adaptive mating bias in response to female infection status. AB - Given the non-trivial cost of reproduction for males and substantial variation in female quality, males have been predicted to show mating bias as an evolved strategy. Using a large outbred population of Drosophila melanogaster, we test this prediction and show that males may adaptively bias their mating effort in response to the infection status of females. Given a simultaneous choice between females infected with pathogenic bacteria and sham infected females, males preferentially mated with the latter, who had a higher reproductive output compared to infected females. This may provide evidence for pre-copulatory male mate choice. Assessment of the reproductive behaviour ensured that the observed pattern of mating bias was not due to differences in receptivity between females infected with pathogenic bacteria and sham infected females. Further, there was no evidence for post-copulatory male mate choice measured in terms of copulation duration. PMID- 23932965 TI - Thermal acclimation in a complex life cycle: the effects of larval and adult thermal conditions on metabolic rate and heat resistance in Culex pipiens (Diptera: Culicidae). AB - It has now been well established that insects can respond to variation in their environment via acclimation, yet the extent of the response varies among populations and environmental characteristics. One under-investigated theme which may contribute to this variation concerns acclimation effects across the life cycle. The present study explores how acclimation in the larval stage of Culex pipiens affects thermal relations in the adult stage. Mosquitoes were reared in a full factorial design at 18 or 26 degrees C as larvae and adults, then critical thermal maxima (CTmax) and metabolic rate-temperature relationships (MR-T) were determined for all 4 treatments. CTmax was positively affected by both larval and adult acclimation treatments. MR-T slope was significantly affected only by adult treatment: warm acclimated adults had on average shallower slopes and higher y intercepts than cool acclimated ones. These results demonstrate that larval acclimation effects can alter adult phenotypes in a species whose life cycle includes two drastically different environments, an aquatic and a terrestrial stage. Studying insects with complex life cycles, especially those with aquatic or subterranean larval stages, can provide valuable information on the effects of thermal variability and predictability on phenotypic plasticity. PMID- 23932967 TI - Serum level of prostate-specific antigen (PSA) in women with breast cancer. AB - OBJECTIVE: To identify the diagnostic role of total and free prostate-specific antigen (TPSA and FPSA) in breast cancer in women. METHODS: Blood samples of 55 women with breast cancer were prospectively analyzed for PSA before and after breast surgery, with a control group of 82 healthy women. RESULTS: Total and free PSA levels were significantly higher in women with breast cancer (preoperatively) than in healthy women (P<0.001). Both serum TPSA and FPSA showed a significant decline in their pre-surgical values after surgical removal of the tumor (P<0.001). A significant proportion of breast cancer patients (83.6%) had free PSA as the predominant molecular form in serum as compared to 0% of controls and 1.8% of postoperative groups (P<0.001). TPSA and FPSA levels were significantly associated with younger age and earlier cancer stage, whereas no significant association was found between these two variables and FPSA as a predominant molecular form. CONCLUSIONS: This study indicated a clinical significance of preoperative measurement of serum TPSA and FPSA in the diagnosis of women with breast cancer, and may be a useful marker for monitoring the response to treatment. PMID- 23932968 TI - Education attenuates the negative impact of traumatic brain injury on cognitive status. AB - OBJECTIVE: To investigate whether the cognitive reserve hypothesis helps to explain differential cognitive impairment among survivors of traumatic brain injury (TBI), whereby survivors with greater intellectual enrichment (estimated with education) are less vulnerable to cognitive impairment. DESIGN: Cross sectional study. SETTING: Medical rehabilitation research center. PARTICIPANTS: Survivors of moderate or severe TBI (n=44) and healthy controls (n=36). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Intellectual enrichment was estimated with educational attainment. Group was defined as TBI or healthy control. Current cognitive status (processing speed, working memory, episodic memory) was evaluated with neuropsychological tasks. RESULTS: TBI survivors exhibited worse cognitive status than healthy persons (P<.001), and education was positively correlated with cognitive status in TBI survivors (r=.54, P<.001). Most importantly, regression analysis revealed an interaction between group and education (R(2) change=.036, P=.004), whereas higher education attenuated the negative impact of TBI on cognitive status. TBI survivors with lower education performed much worse than matched healthy persons, but this TBI-related performance discrepancy was attenuated at higher levels of education. CONCLUSIONS: Higher intellectual enrichment (estimated with education) reduces the negative effect of TBI on cognitive outcomes, thereby supporting the cognitive reserve hypothesis in persons with TBI. Future work is necessary to investigate whether intellectual enrichment can build cognitive reserve as a rehabilitative intervention in survivors of TBI. PMID- 23932970 TI - Inhibition of brain ST8SiaIII sialyltransferase leads to impairment of procedural memory in mice. AB - Several glycoproteins in mammalian brains contain alpha2,8-linked disialic acid residues. We previously showed a constant expression of disialic acid (DiSia) in the hippocampus, olfactory bulb and cortex, and a gradual decrease of expression in the cerebellum from neonatal to senile mice. Previous publications indicate that neurite extension of neuroblastoma-derived Neuro2A cells is inhibited in the presence of DiSia antibody. Based on this, we treated Neuro2A cell cultures with RNA interference for ST8SiaIII mRNA, the enzyme responsible for DiSia formation. We observed that neurite extension was inhibited by this treatment. Taking this evidence into consideration and the relationship of the cerebellum with learning and memory, we studied the role of DiSia expression in a learning task. Through delivery of pST8SiaIII into the brains of C57BL/6 neonatal mice, we inhibited the expression of ST8SiaIII. ST8SiaIII mRNA and protein expressions were analyzed by real-time PCR and western blot, respectively. In this work, we showed that pST8SiaIII-treated mice presented a significantly reduced level of ST8SiaIII mRNA in the cerebellum (p<0.01) in comparison to control mice at 8 days after treatment. It is also noted that these levels returned to baseline values in the adulthood. Then, we evaluated behavioural performance in the T-Maze, a learning task that estimates procedural memory. At all ages, pST8SiaIII-treated mice showed a lower performance in the test session, being most evident at older ages (p<0.001). Taken all together, we conclude that gene expression of ST8SiaIII is necessary for some cognitive tasks at early postnatal ages, since reduced levels impaired procedural memory in adult mice. PMID- 23932969 TI - Patient-reported upper extremity outcome measures used in breast cancer survivors: a systematic review. AB - OBJECTIVES: (1) To identify English-language published patient-reported upper extremity outcome measures used in breast cancer research and (2) to examine construct validity and responsiveness in patient-reported upper extremity outcome measures used in breast cancer research. DATA SOURCES: PubMed, Cumulative Index to Nursing and Allied Health Literature, and ProQuest MEDLINE databases were searched up to February 5, 2013. STUDY SELECTION: Studies were included if a patient-reported upper extremity outcome measure was administered, the participants were diagnosed with breast cancer, and the study was published in English. DATA EXTRACTION: A total of 865 articles were screened. Fifty-nine full text articles were assessed for eligibility. A total of 46 articles met the initial eligibility criteria for aim 1. Eleven of these articles reported means and SDs for the outcome scores and included a comparison group analysis for aim 2. DATA SYNTHESIS: Construct validity was evaluated by calculating effect sizes for known-group differences in 6 studies using the Disabilities of Arm, Shoulder and Hand (DASH), University of Pennsylvania Shoulder Score, Shoulder Disability Questionnaire-Dutch, and 10 Questions by Wingate. Responsiveness was analyzed comparing a treatment and control group by calculating the coefficient of responsiveness in 5 studies for the DASH and 10 Questions by Wingate. CONCLUSIONS: Eight different patient-reported upper extremity outcome measures have been reported in the peer-review literature for women with breast cancer; some that were specifically developed for breast cancer survivors (n=3) and others that were not (n=5). Based on the current evidence, we recommend administering the DASH to assess patient-reported upper extremity function in breast cancer survivors because the DASH has the most consistently large effects sizes for construct validity and responsiveness. Future large studies are needed for more definitive recommendations. PMID- 23932971 TI - Ezh1 and Ezh2 differentially regulate PSD-95 gene transcription in developing hippocampal neurons. AB - Polycomb Repressive Complex 2 (PRC2) mediates transcriptional silencing by catalyzing histone H3 lysine 27 trimethylation (H3K27me3), but its role in the maturation of postmitotic mammalian neurons remains largely unknown. We report that the PRC2 paralogs Ezh1 and Ezh2 are differentially expressed during hippocampal development. We show that depletion of Ezh2 leads to increased expression of PSD-95, a critical plasticity gene, and that reduced PSD-95 gene transcription is correlated with enrichment of Ezh2 at the PSD-95 gene promoter; however, the H3K27me3 epigenetic mark is not present at the PSD-95 gene promoter, likely due to the antagonizing effects of the H3S28P and H3K27Ac marks and the activity of the H3K27 demethylases JMJD3 and UTX. In contrast, increased PSD-95 gene transcription is accompanied by the presence of Ezh1 and elongation-engaged RNA Polymerase II complexes at the PSD-95 gene promoter, while knock-down of Ezh1 reduces PSD-95 transcription. These results indicate that Ezh1 and Ezh2 have antagonistic roles in regulating PSD-95 transcription. PMID- 23932972 TI - Spatial distribution of the trace elements zinc, strontium and lead in human bone tissue. AB - Trace elements are chemical elements in minute quantities, which are known to accumulate in the bone. Cortical and trabecular bones consist of bone structural units (BSUs) such as osteons and bone packets of different mineral content and are separated by cement lines. Previous studies investigating trace elements in bone lacked resolution and therefore very little is known about the local concentration of zinc (Zn), strontium (Sr) and lead (Pb) in BSUs of human bone. We used synchrotron radiation induced micro X-ray fluorescence analysis (SR MU XRF) in combination with quantitative backscattered electron imaging (qBEI) to determine the distribution and accumulation of Zn, Sr, and Pb in human bone tissue. Fourteen human bone samples (10 femoral necks and 4 femoral heads) from individuals with osteoporotic femoral neck fractures as well as from healthy individuals were analyzed. Fluorescence intensity maps were matched with BE images and correlated with calcium (Ca) content. We found that Zn and Pb had significantly increased levels in the cement lines of all samples compared to the surrounding mineralized bone matrix. Pb and Sr levels were found to be correlated with the degree of mineralization. Interestingly, Zn intensities had no correlation with Ca levels. We have shown for the first time that there is a differential accumulation of the trace elements Zn, Pb and Sr in BSUs of human bone indicating different mechanisms of accumulation. PMID- 23932973 TI - Surgical outcome and cost comparison between total vaginal hysterectomy and laparoscopic hysterectomy for uteri weighing >500 g. AB - STUDY OBJECTIVE: To compare surgical outcomes and overall costs of less invasive methods of hysterectomy to treat benign disease including total vaginal hysterectomy (TVH) and total laparoscopic hysterectomy (TLH) in women with a uterus weighing >500 g. DESIGN: Retrospective review of medical records (Canadian Task Force classification III). SETTING: University-associated hospital. PATIENTS: One hundred three women with a uterus weighing >500 g who had undergone either total vaginal hysterectomy (TVH) (n = 52) or total laparoscopic hysterectomy (TLH) (n = 51). MEASUREMENTS AND MAIN RESULTS: Cost data were extracted from the hospital billing system. Patient characteristics, surgical outcomes, and hospital costs were compared between the 2 groups. Patient characteristics were similar in both groups except for a history of surgery (TVH 11.5%, and TLH 37.3%; p = .01). Insofar as surgical outcomes, mean (SD) operative time was shorter in the TVH group compared with the TLH group (110.00 [28.68] minutes vs 180.47 [51.32] minutes; p < .001), and hospital stay was longer (8.08 [0.68] days vs 7.45 [1.03] days; p < .001). Other surgical outcomes including estimated blood loss (p = .20) and decrease in hemoglobin (p = .12) did not differ between the 2 groups. Total hospital costs (converted from Korean won to US dollars) were significantly lower in the TVH group than in the TLH group ($2076.59 [$666.58] vs $2744.03 [$715.76]; p < .001). CONCLUSION: Our data suggest that TVH is a safe and economic procedure even in women with a uterus weighing >500 g. Skilled surgeons should preferentially consider TVH for treatment of benign uterine disease, regardless of uterine size. PMID- 23932974 TI - Developmental role of nuclear factor E2-related factor 2 in mitigating methamphetamine fetal toxicity and postnatal neurodevelopmental deficits. AB - Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that mediates protective responses to oxidative stress, but its developmental role is unknown. Herein, we treated pregnant Nrf2-deficient knockout mice with methamphetamine (METH) (5-40 mg/kg ip), which increases fetal reactive oxygen species (ROS) and oxidatively damaged DNA in fetal brain tissue. METH-exposed Nrf2(-/-) fetuses were unable to increase mRNA levels of ROS-protective heme oxygenase-1, NAD(P)H:quinone oxidoreductase, or oxoguanine glycosylase 1, unlike wild-type controls, and exhibited enhanced DNA oxidation, fetal resorption, edema, and reduced fetal weight, with greater toxicity in female Nrf2(-/-) fetuses. Postnatal neurodevelopmental deficits in activity and olfactory function were exacerbated, with gender-dependent differences, and the olfactory bulb GABAergic marker GAD-65 was decreased in Nrf2(-/-) offspring exposed in utero to METH. In utero METH-initiated olfactory deficits may be a sensitive postnatal functional test for long-term neurotoxicity, and indicated a broad fetal role for Nrf2. The results show that fetal Nrf2 deficiency enhances METH-initiated oxidative DNA damage and toxicity, suggesting that Nrf2 activation of cytoprotective proteins mitigates the effects of ROS and their oxidative damage to cellular macromolecules, thereby protecting the developing fetus from adverse structural and postnatal neurodevelopmental consequences. PMID- 23932975 TI - Morphological and molecular characterization of a microsporidian parasite, Takaokaspora nipponicus n. gen., n. sp. from the invasive rock pool mosquito, Ochlerotatus japonicus japonicus. AB - A new genus and species of Microsporidia, Takaokaspora nipponicus n. gen., n. sp. is described from Ochlerotatus japonicus japonicus (Theobald) and Ochlerotatus hatorii (Yamada) based on light microscope and ultrastructural morphology, developmental features, transmission cycles and comparative sequence analyses of the small subunit ribosomal DNA (SSU rDNA). The microsporidium is both vertically and horizontally transmitted, exhibits dimorphic development alternating between diplokaryotic and monokaryotic stages and produces two morphologically distinct spores, one in larvae and another in adult females. Horizontal transmission of infection to larval mosquitoes occurs via direct oral ingestion of uninucleate spores that are produced in vertically-infected larval hosts. Development in horizontally-infected hosts is diplokaryotic following karyokinesis of uninucleate schizonts and binary fission to produce small (4.3MUm * 2.0MUm) membrane free, ovoid, binucleate spores that are confined to adult female reproductive tissues (ovariole sheath and oviducts). Vertical transmission of the microsporidium from adult females to larval progeny takes place via surface contamination of the egg (transovum). Microsporidian development in vertically infected larvae is haplophasic with unpaired nuclei throughout, producing rosette shaped sporogonial plasmodia contained within a thin non-persistent sporophorous vesicle and culminating in the formation of membrane free, uninucleate, conical spores (7.0MUm*2.8MUm). Development is confined to host fat body tissue which appears as swollen white masses in the thorax and selected segments of the abdomen causing larvae to appear abnormally distorted and results in death during the third and fourth instar stages. The SSU rDNA sequences obtained from the two morphologically identical microsporidia isolated from Oc. j. japonicus and Oc. hatorii were nearly identical and unique when compared with GenBank entries of all other mosquito-parasitic species. Phylogenetic trees constructed by Maximum Parsimony, Maximum Likelihood and bootstrap analyses using the Neighbor Joining search parameter yielded similar typologies. In each case, the novel microsporidium was the sister group to the clade containing Parathelohania species from Anopheles mosquitoes and the monotypic Novothelohania ovalae from Ochlerotatus caspius showing approximately 10-13% sequence divergence to those two genera providing strong support for establishment as a separate genus. PMID- 23932976 TI - Arthropod viruses and small RNAs. AB - The recently characterized small RNAs provide a new paradigm for physiological studies. These molecules have been shown to be integral players in processes as diverse as development and innate immunity against bacteria and viruses in eukaryotes. Several of the well-characterized small RNAs including small interfering RNAs, microRNAs and PIWI-interacting RNAs are emerging as important players in mediating arthropod host-virus interactions. Understanding the role of small RNAs in arthropod host-virus molecular interactions will facilitate manipulation of these pathways for both management of arthropod pests of agricultural and medical importance, and for protection of beneficial arthropods such as honey bees and shrimp. This review highlights recent research on the role of small RNAs in arthropod host-virus interactions with reference to other host pathogen systems. PMID- 23932978 TI - A novel core-satellite CdTe/Silica/Au NCs hybrid sphere as dual-emission ratiometric fluorescent probe for Cu2+. AB - Herein, we synthesized a novel core-satellite CdTe/Silica/Au NCs hybrid sphere by covalently linking the separately synthesized highly fluorescent bovine serum albumin (BSA) stabilized gold nanoclusters (Au@BSA NCs) to the surface of the amino functionalized CdTe@SiO2 spheres by using the EDC chemistry. Numerous "satellites" of Au NCs were linked on the surface of the CdTe@SiO2 by the way of amide bonding. The synthesized dual-emission hybrid spheres were further characterized by the transmission electron microscopy (TEM), energy dispersive X ray spectroscopy (EDS), UV-vis absorption spectroscopy, Fourier transform infrared (FTIR) spectroscopy, photoluminescence (PL), etc. Finally, the CdTe/Silica/Au NCs hybrid spheres were developed as ratiometric fluorescence probe for the determination of Cu(2+) with high sensitivity and selectivity. The fluorescence intensity ratio (F545 nm/F655 nm) of the probe against the concentration of Cu(2+) showed a good linear relationship from 6.0*10(-7) mol L( 1) to 100.0*10(-7) mol L(-1). It showed an excellent reproducibility (0.67% relative standard deviation for 10 replicate measurements of Cu(2+) at 40.0*10( 7) mol L(-1)) and low detection limit (4.1*10(-7) mol L(-1)). Furthermore, the ratiometric fluorescent probe was successfully applied in the determination of Cu(2+) in vegetable samples with satisfactory results. PMID- 23932977 TI - Hairpin DNA probe with 5'-TCC/CCC-3' overhangs for the creation of silver nanoclusters and miRNA assay. AB - A facile strategy for the assay of target miRNA using fluorescent silver nanoclusters (AgNCs) has been described. Due to the preferable interaction between cytosine residues and Ag(+), a short cytosine-rich oligonucleotide (ODN) with only six bases 5'-TCCCCC-3' served as an efficient scaffold for the creation of the AgNCs. The AgNCs displayed a bright red emission when excited at 545nm. Such ODN base-stabilized AgNCs have been exploited for miRNA sensing. Overhangs of TCC at the 5' end (5'-TCC) and CCC at the 3' end (CCC-3') (denoted as 5' TCC/CCC-3') appended to the hairpin ODN probe which also contains recognition sequences for target miRNA were included. Interestingly, the AgNCs/hairpin ODN probe showed similar spectral properties as that templated by 5'-TCCCCC-3'. The formation of the hairpin ODN probe/miRNA duplex separated the 5'-TCC/CCC-3' overhangs, thus disturbing the optical property or structure of the AgNCs. As a result, fluorescence quenching of the AgNCs/hairpin ODN probe was obtained, which allows for facile determination of target miRNA. The proposed method is simple and cost-effective, holding great promise for clinical applications. PMID- 23932979 TI - Development of antibiotic selection kit towards veterinary applications using glycine passivated magnetic particles. AB - Glycine functionalized (Gly/Fe3O4) and non-functionalized (Fe3O4) magnetic particles were synthesized in an autoclave and characterized by transmission electron microscopy (TEM), Fourier transformed infrared spectroscopy (FTIR), vibrating sample magnetometer (VSM), energy-dispersive X-ray spectroscopy (EDX), differential scanning calorimetry (DSC), X-ray diffraction patterns (XRD) and zeta potential. The size of the both these particles were in the range of 220-230 nm but the shape of the Gly/Fe3O4 particles was hexagonal in contrast to the spherical shape of Fe3O4 particles. The particle characterization tests confirmed that glycine was functionalized on the Gly/Fe3O4 particles, they were positively charged and possessed strong magnetic property. These particles possessed the ability to bind to bacteria such as Escherichia coli, Streptococcus and Staphylococcus in the range of 72-90%. They were used to entrap bacteria from clinical mastitic milk samples from cows. The entrapped bacteria of the above species from these samples were isolated and used individually in the conventional disc-diffusion method of antibiotic susceptibility determination. The results were compared with that of the bacterial species isolated directly from the mastitic milk samples and were found to be 100% concordant (n=25). The developed portable antibiotic selection kit was tested with twenty five samples of mastitic milk. The results indicated that, antibiotic resistant bacteria turned the methylene blue in to white color while the bacteria that were killed (sensitive) retained the blue color of the dye. Thus the right choice of the antibiotic to treat cows with mastitis could be determined based on the naked eye. In conclusion, the kit gave quicker results, was easy to assay and read and can be 'farm-gate' applicable than the presently available conventional method. PMID- 23932980 TI - Flow-through sensor array applied to cytotoxicity assessment in cell cultures for drug-testing purposes. AB - The viability of cells cultured in microsystems for drug screening purposes is usually tested with a variety of colorimetric/fluorescent methods. In this work we propose an alternative way of assessing cell viability-flow-through sensor array that can be connected in series with cell microbioreactors as compatible detection system. It is shown, that the presented device is capable of cytotoxic effect detection and estimation of cell viability after treatment with 1,4 dioxane and 5-fluorouracil, which proves that it can be used for truly non invasive, fast, reliable, continuous cell culture monitoring in microscale. PMID- 23932981 TI - Anti-viral immune responses in a primitive lung: characterization and expression analysis of interferon-inducible immunoproteasome subunits LMP2, LMP7 and MECL-1 in a sarcopterygian fish, the Nigerian spotted lungfish (Protopterus dolloi). AB - Lungfishes (Dipnoi) represent the closest ancestor of tetrapods. Dipnoi have dual breathing modes extracting oxygen from water and air. The primitive lungs of lungfishes are exposed to external antigens including viruses. To date, the immune response of lungfishes against viruses has not been investigated. During viral immune responses, cell exposure to type I interferon induces the replacement of the constitutive proteasome with LMP2, LMP7 and MECL-1 beta subunits forming the immunoproteasome and enhancing antigen presentation to MHC class I molecules. In order to study the immune defense system of the lungfish lung, we have characterized for the first time the three immunoproteasome subunits in the sarcopterygian fish, the Nigerian spotted lungfish (Protopterus dolloi). LMP2, LMP7 and MECL-1 were identified in P. dolloi and their sequences encoded predicted proteins of 216, 275 and 278 amino acids, respectively. The mRNA of these three genes was expressed in multiple tissues, including the lung, with the highest abundance observed in kidney and post-pyloric spleen. In vitro stimulation of lungfish lung and kidney primary cell cultures with PolyI:C for 4 and 12 h resulted in increased LMP2, LMP7 and MECL-1 expression in both tissues. These results suggest a central role of these genes in the activation of an antiviral immune response in lungfish. Importantly, they indicate that the primitive lung of the common ancestor of all tetrapods is capable of inducing the expression of these genes in response to viral stimulation. PMID- 23932982 TI - First characterization of a teleost Epstein-Barr virus-induced gene 3 (EBI3) reveals a regulatory effect of EBI3 on the innate immune response of peripheral blood leukocytes. AB - Epstein-Barr virus-induced gene 3 (EBI3) encodes a protein that in mammals is known to be a subunit of interleukin (IL)-27 and IL-35, both which regulate cytokine production and inflammatory response. To date, no studies on fish EBI3 have been documented. In this work, we report the identification of an EBI3 homologue, CsEBI3, from tongue sole (Cynoglossus semilaevis) and analysis of its expression and biological effect. CsEBI3 is composed of 245 amino acid residues and possesses a Fibronectin type 3 (FN3) domain that is preserved in lower and higher vertebrates. Expression of CsEBI3 was detected in a wide range of tissues, in particular those of immune relevant organs, and upregulated in a time dependent manner by experimental challenge with bacterial and viral pathogens. Bacterial infection of peripheral blood leukocytes (PBL) enhanced CsEBI3 expression and caused extracellular secretion of CsEBI3. Purified recombinant CsEBI3 (rCsEBI3) stimulated the respiratory burst activity of PBL and upregulated the expression of IL-1beta, IL-8, Myd88, interferon-induced gene 15, CD28, and chemokines. In contrast, rCsEBI3M, a mutant CsEBI3 that lacks the FN3 domain failed to activate PBL and induced much weaker expression of the immune genes. Treatment of PBL with rCsEBI3, but not with the mutant rCsEBI3M, enhanced cellular resistance against bacterial invasion, whereas antibody blocking of CsEBI3 on PBL significantly reduced cellular resistance against bacterial infection. Taken together, these results indicate for the first time that a teleost EBI3 possesses immunoregulatory property in a manner that is dependent on the conserved FN3 domain, and that CsEBI3 is involved in the innate immune defense of PBL against microbial pathogens. PMID- 23932983 TI - Neuroprotective effects of edaravone on cognitive deficit, oxidative stress and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats. AB - Oxidative stress is implicated as an important factor in the development of Alzheimer's disease (AD). In the present study, we have investigated the effects of edaravone (9mg/kg, 3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, in a streptozotocin (STZ-3mg/kg) induced rat model of sporadic AD (sAD). Treatment with edaravone significantly improved STZ-induced cognitive damage as evaluated in Morris water maze and step-down tests and markedly restored changes in malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE) adducts, hydroxyl radical (OH), hydrogen peroxide (H2O2), total superoxide dismutase (T SOD), reduced glutathione (GSH), glutathione peroxidase (GPx) and protein carbonyl (PC) levels. In addition, histomorphological observations confirmed the protective effect of edaravone on neuronal degeneration. Moreover, hyperphosphorylation of tau resulting from intracerebroventricular streptozotocin (ICV-STZ) injection was decreased by the administration of edaravone. These results provide experimental evidence demonstrating preventive effects of edaravone on cognitive dysfunction, oxidative stress and hyperphosphorylation of tau in ICV-STZ rats. Since edaravone has been used for treatment of patients with stroke, it represents a safe and established therapeutic intervention that has the potential for a novel application in the treatment of age-related neurodegenerative disorders associated with cognitive decline, such as AD. PMID- 23932984 TI - Two novel Toll genes (EsToll1 and EsToll2) from Eriocheir sinensis are differentially induced by lipopolysaccharide, peptidoglycan and zymosan. AB - Tolls/Toll-like receptors (TLRs) play an essential role in initiating innate immune responses against pathogens and are found throughout the insect kingdom but have not yet been reported in the crustacean, Eriocheir sinensis. For this purpose, we cloned two novel Toll genes from E. sinensis, EsToll1 and EsToll2. The full-length cDNA of EsToll1 was 3963 bp with a 3042-bp open reading frame (ORF) encoding a 1013-amino acid protein. The extracellular domain of this protein contains 17 leucine-rich repeats (LRRs) and a 139-residue cytoplasmic Toll/interleukin-1 receptor (TIR) domain. The cDNA full-length of EsToll2 was 4419 bp with a 2667-bp ORF encoding an 888-amino acid protein with an extracellular domain containing 10 LRRs and a 139-residue cytoplasmic TIR domain. By phylogenetic analysis, EsToll1 and EsToll2 clustered into one group together with Tolls from other crustaceans. Quantitative RT-PCR analysis demonstrated that a) both EsToll1 and EsToll2 were constitutively expressed in all tested crab tissues; b) EsToll1 and EsToll2 were differentially induced after injection of lipopolysaccharides (LPS), peptidoglycan (PG) or zymosan (GLU). Importantly, EsToll2 expression was significantly upregulated at almost all time intervals post-challenge with LPS, PG and GLU. Our study indicated that EsToll1 and EsToll2 are differentially inducibility in response to various PAMPs, suggesting their involvement in a specific innate immune recognition mechanism in E. sinensis. PMID- 23932985 TI - Recombinant TNFalpha as oral vaccine adjuvant protects European sea bass against vibriosis: insights into the role of the CCL25/CCR9 axis. AB - Vibrio anguillarum is the main causative agent of vibriosis in cultured sea bass. Unfortunately, available vaccines against this disease do not achieve the desired protection. In this study, to accomplish uptake, processing, and presentation of luminal antigens, a commercial sea bass oral vaccine against V. anguillarum was improved with the addition of recombinant fish-self tumor necrosis factor alpha (rTNFalpha), as adjuvant. To explore mechanisms, systemic and local responses were analyzed through serum specific IgM titers, gene expression, lymphocytes spatial distribution in the gut, and in vitro functional assays. We found along the trial, over expressed transcripts of genes encoding cytokines and antimicrobial molecules at the gut of rTNFalpha supplied group. Orally immunized fish with vaccine alone confer protection against V. anguillarum challenge throughout a short time period. In contrast, adjuvant-treated group significantly extended the response. In both cases, achieved protection was independent of serum IgM. Yet, IgT transcripts were found to increase in the gut of rTNFalpha treated fish. More importantly, fish treated with rTNFalpha showed a dramatic change of their T lymphocytes distribution and localization in gut mucosal tissue, suggesting specific antigen recognition and further intraepithelial T lymphocytes (IEL) activation. To determine the mechanism behind IEL infiltration, we characterized the constitutive and activated pattern of chemokines in sea bass hematopoietic tissues, identifying for the first time in fish gut, an intimate relation between the chemokine ligand/receptor CCL25/CCR9. Ex-vivo, chemotaxis analyses confirmed these findings. Together, our results demonstrate that improved oral vaccines targeting key cytokines may provide a means to selectively modulate fish immune defence. PMID- 23932986 TI - Properties of Litopenaeus vannamei Dscam (LvDscam) isoforms related to specific pathogen recognition. AB - Arthropod Down syndrome cell adhesion molecules (Dscam) may sometimes function as hypervariable pathogen recognition receptors. They consist of an extracellular region and a cytoplasmic tail, both of which are highly variable. In shrimp, tail less Dscam proteins (Dscams) have recently been identified, and these appear to be unlike other arthropod extracellular Dscams that are released from the cell membrane by proteolytic cleavage. Here we investigate the properties of these unique shrimp proteins and show that they can be directly secreted from transfected cells. We also investigate the diverse cytoplasmic tail variants of membrane-bound shrimp Dscams, and show that elements E1A and E3 seem to be related to Dscam immune function. Challenge with Vibrio harveyi not only enhanced total Dscam and the immune-related cytoplasmic tail variants, but also induced expression of certain Ig2 + Ig3 combinations. A pathogen binding assay with these Ig2 + Ig3 extracellular variants showed that both the V. harveyi-induced Dscams and Dscams induced by buffer injection could be either pathogen-specific or specific only for Gram-negative pathogens, while other "general" Dscam variants were sensitive to a wide range of pathogens. The same assay also suggested that shrimp Dscam isoforms show a stronger response to the host's natural pathogens. PMID- 23932987 TI - Immunological study of the outer membrane proteins of Vibrio harveyi: insights that link immunoprotectivity to interference with bacterial infection. AB - Vibrio harveyi is a bacterial pathogen that affects marine vertebrates and invertebrates. In this study, we identified 13 outer membrane proteins (OMPs) from a pathogenic V. harveyi strain and analyzed their immunological properties. In vivo immunogenicity analysis showed that antibodies specific to recombinant proteins of the 13 OMPs were detected in the antiserum of V. harveyi-infected rat. When used as subunit vaccines to immunize Japanese flounder (Paralichthys olivaceus), all OMPs were able to elicit specific serum antibody production in the vaccinated fish; however, only two OMPs (OMP173 and OMP214) induced high levels (>70%) of relative percent survival. Pre-incubation of V. harveyi with the antisera of protective OMPs significantly impaired bacterial infectivity against peripheral blood leukocytes (PBL), whereas the antisera of non-protective OMPs had no apparent effect on infection. OMP173 antibodies could bind whole V. harveyi cells and exhibit bactericidal effect in a complement-dependent manner. Passive immunization showed that fish received OMP173 antiserum before being infected with V. harveyi exhibited significantly reduced mortality rate and lower bacterial loads in liver, spleen, and kidney. Finally, treatment of FG cells with OMP173 prior to V. harveyi infection protected the cells from bacterial invasion to a significant extent. Take together, these results indicate that two of the examined OMPs induce protective immunity through production of specific antibodies that block bacterial invasion, and that one OMP is likely to be involved in host cell interaction during the infection process. Thus, the immunoprotectivity of the OMPs is probably associated with functional participations of the OMPs in bacterial infection. PMID- 23932988 TI - Combined effects of dietary fructooligosaccharide and Bacillus licheniformis on innate immunity, antioxidant capability and disease resistance of triangular bream (Megalobrama terminalis). AB - This study was conducted to investigate the effects of fructooligosaccharide (FOS) and Bacillus licheniformis (B. licheniformis) and their interaction on innate immunity, antioxidant capability and disease resistance of triangular bream Megalobrama terminalis (average initial weight 30.5 +/- 0.5 g). Nine experimental diets were formulated to contain three FOS levels (0, 0.3% and 0.6%) and three B. licheniformis levels (0, 1 * 10(7), 5 * 10(7) CFU g(-1)) according to a 3 * 3 factorial design. At the end of the 8-week feeding trial, fish were challenged by Aeromonas hydrophila (A. hydrophila) and survival rate was recorded for the next 7 days. The results showed that leucocyte counts, alternative complement activity as well as total serum protein and globulin contents all increased significantly (P < 0.05) as dietary B. licheniformis levels increased from 0 to 1 * 10(7) CFU g(-1), while little difference (P > 0.05) was observed in these parameters in terms of dietary FOS levels. Both plasma alkaline phosphatase and phenoloxidase activities were significantly (P < 0.05) affected only by dietary FOS levels with the highest values observed in fish fed 0.6 and 0.3% FOS, respectively. Both immunoglobulin M content and liver superoxide dismutase (SOD) activity were significantly affected (P > 0.05) by both FOS and B. licheniformis. Liver catalase, glutathione peroxidase as well as plasma SOD activities of fish fed 1 * 10(7) CFU g(-1)B. licheniformis were all significantly (P < 0.05) higher than that of the other groups, whereas the opposite was true for malondialdehyde content. After A. hydrophila challenge, survival rate was not affected (P > 0.05) by either FOS levels or B. licheniformis contents, whereas a significant (P < 0.05) interaction between these two substances was observed with the highest value observed in fish fed 0.3% FOS and 1 * 10(7) CFU g(-1)B. licheniformis. The results of this study indicated that dietary FOS and B. licheniformis could significantly enhance the innate immunity and antioxidant capability of triangular bream, as well as improve its disease resistance. The best combination of these two prebiotics and/or probiotics was 0.3% FOS and 1 * 10(7) CFU g(-1)B. licheniformis. PMID- 23932990 TI - Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population. AB - BACKGROUND: The value of genotyping to predict variant phenotypes in patients with phenylalanine hydroxylase (Pah) deficiency is a matter of debate. However, there exists no comprehensive population relationship study focused on the Han Chinese. METHODS: We analyzed genotype-phenotype correlation for 186 different genotypes in 338 unrelated Chinese patients harboring 109 different Pah mutations. Two systems were used in this process. The first was a phenotype prediction system based on arbitrary values (AV) attributed to each mutation. The second was a pair-wise correlation analysis. The observed phenotype for AV analysis was the corresponding metabolic phenotype stratified according to the pretreatment phenylalanine (Phe) value. RESULTS: We found that the observed phenotype matched the predicted phenotype in 54.41% of 272 patients for whom AV information was available; the highest degree of concordance (61.83%) was found in patients with null/null genotypes, whereas the lowest "concordance rate" (32.69%) was observed for patients with expected mild-PKU phenotype. There are repeated inconsistencies for such mutations as R241C, R243Q, R261Q, V388M, V399V, R408Q, A434D and EX6-96A>G which are associated with variable phenotypes in patients with identical genotype. Significant correlations were disclosed between pretreatment Phe values and predicted residual activity (r=-0.45643, P<0.0001) or AV sum (r=-0.59523, P<0.0001). CONCLUSION: Our study supports the notion that the Pah mutation genotype is the main determinant of metabolic phenotype in most patients in a particular population, and provided novel insights into the values that underpin the subsequent treatment and the prognosis of PKU in Chinese. PMID- 23932989 TI - Identification and characterization of starvation induced msdgc-1 promoter involved in the c-di-GMP turnover. AB - C-di-GMP [Bis-(3'-5')-cyclic-dimeric-guanosine monophosphate], a second messenger is involved in intracellular communication in the bacterial species. As a result several multi-cellular behaviors in both Gram-positive and Gram-negative bacteria are directly linked to the intracellular level of c-di-GMP. The cellular concentration of c-di-GMP is maintained by two opposing activities, diguanylate cyclase (DGC) and phosphodiesterase (PDE-A). In Mycobacterium smegmatis, a single bifunctional protein MSDGC-1 is responsible for the cellular concentration of c di-GMP. A better understanding of the regulation of c-di-GMP at the genetic level is necessary to control the function of above two activities. In this work, we have characterized the promoter element present in msdgc-1 along with the +1 transcription start site and identified the sigma factors that regulate the transcription of msdgc-1. Interestingly, msdgc-1 utilizes SigA during the initial phase of growth, whereas near the stationary phase SigB containing RNA polymerase takes over the expression of msdgc-1. We report here that the promoter activity of msdgc-1 increases during starvation or depletion of carbon source like glucose or glycerol. When msdgc-1 is deleted, the numbers of viable cells are ~10 times higher in the stationary phase in comparison to that of the wild type. We propose here that msdgc-1 is involved in the regulation of cell population density. PMID- 23932991 TI - Identification, genotyping, and molecular evolution analysis of duck circovirus. AB - Duck circovirus (DuCV) is a contagious immunosuppressive virus affecting many duck species, which is responsible for multiple outbreaks in poultry industries worldwide. In this study, the first DuCV isolate GH01 was identified in Sichuan by PCR, which shared a high level of nucleotide identity (81.8-99.4%) with sequences of other DuCV isolates available in GenBank. Comparative phylogenetic and pairwise sequence comparison analyses indicated that DuCV could be divided into two genotypes (DuCV-1 and DuCV-2) and six subtypes (1a, 1b, 1c, 2a, 2b and 2c) based on the complete genome sequence. The results revealed that both DuCV-1 and DuCV-2 had evolved from the same ancestor but undergone divergent evolution. Interestingly, phylogenetic analyses indicated that three isolates were classified into a cluster DuCV-2a using complete DuCV genome sequence and cap gene, except rep gene. Recombination analyses revealed that DuCV-2a arose from recombination between DuCV-1a and DuCV-2b isolates within the rep genes, and the recombination events mainly occur both in non-structural protein coding region and structural protein coding region. In addition, the mechanisms of recombination supporting the genetic variability in DuCV isolates were investigated. Likewise, selective pressure indicated that purifying selection had been a major driving force in maintaining diversity among the DuCV isolates. Because eradicating the virus from commercial ducks is impossible, it is necessary to take effective control measures and implement them throughout the world. PMID- 23932992 TI - Association of myasthenia gravis with polymorphisms in the gene of histamine N methyltransferase. AB - INTRODUCTION: Histamine N-methyltransferase (HNMT) is the main metabolizing enzyme of histamine. Histamine modulates immune responses and plays a role in the pathogenesis of autoimmune disorders. METHODS: The non-synonymous HNMT C314T polymorphism and the A939G single-nucleotide polymorphism (SNP) influencing HNMT mRNA stability were genotyped in 213 patients with myasthenia gravis (MG) and 342 healthy controls. RESULTS: The carrier frequency of the A allele of the A939G SNP was over-represented among patients with anti-AchR and anti-Titin antibodies (P = 0.05 and P = 0.004, respectively); the presence of the minor G allele was protective against anti-AchR and anti-Titin positive MG (OR = 0.67 and OR = 0.54, respectively). The combination of the G allele carrier status with wild-type C314C homozygosity was also protective against MG (OR = 0.55, P = 0.008) and against the development of anti-AchR antibodies (OR = 0.37, P = 0.01). DISCUSSION: The A939G HNMT polymorphism is associated with autoimmune MG, while no association with C314T SNP was found. PMID- 23932994 TI - Polymorphic mutations in mouse mitochondrial DNA regulate a tumor phenotype. AB - To examine whether polymorphic mtDNA mutations that do not induce significant respiration defects regulate phenotypes of tumor cells, we used mouse transmitochondrial tumor cells (cybrids) with nuclear DNA from C57BL/6 (B6) strain and mtDNA from allogenic C3H strain. The results showed that polymorphic mutations of C3H mtDNA in the cybrids induced hypoxia sensitivity, resulting in a delay of tumor formation on their subcutaneous inoculation into B6 mice. Therefore, the effects of polymorphic mutations in normal mtDNA have to be carefully considered, particularly when we apply the gene therapy to the embryos to replace their pathogenic mtDNA by normal mtDNA. PMID- 23932993 TI - School and cognitive functioning problems in adolescent bariatric surgery candidates. AB - BACKGROUND: Prior studies have reported that students with overweight and obesity have impairments in performance IQ and executive function and worse school functioning in comparison with peers of normal weight. The present study assessed school and cognitive functioning in a sample of adolescents with severe obesity being evaluated for laparoscopic adjustable gastric banding. METHODS: Eligible candidates for bariatric surgery were referred for psychiatric evaluation, which included a semistructured clinical interview measuring school functioning and the vocabulary and matrix reasoning subtests of the Wechsler Abbreviated Scale of Intelligence (WASI). RESULTS: Self-reported school problems were common, with 55.5% of adolescents failing a grade or subject, 38.7% attending summer school, and 17.8% failing a citywide examination. A significant relationship was observed between body mass index, estimated WASI IQ (r = -.250; P = .005), and the vocabulary subtest (r = -.241; P = .006), but not matrix reasoning (r = -.126; P = NS). CONCLUSION: Even among a sample of adolescents with severe obesity, increased body mass index was associated with lower WASI IQ and vocabulary subtest scores. Increasing awareness of potential cognitive and school problems in bariatric candidates among teachers, school counselors, and other mental health providers is an important first step to improving academic support and educational systems deficiencies for students with overweight and obesity. PMID- 23932996 TI - Induced forgetting and reduced confidence in our personal past? The consequences of selectively retrieving emotional autobiographical memories. AB - People build their sense of self, in part, through their memories of their personal past. What is striking about these personal memories is that, in many instances, they are inaccurate, yet confidently held. Most researchers assume that confidence ratings are based, in large part, on the memory's mnemonic features. That is, the more vivid or detailed the memory, the higher the confidence people have in its accuracy. However, we explore a heretofore underappreciated source on which confidence ratings may be based: the accessibility of memories as a result of selective retrieval. To explore this possibility, we use Anderson, Bjork, and Bjork's retrieval-induced forgetting (RIF) paradigm with emotional (positive and negative) autobiographical memories. We found the standard RIF effect for memory recall across emotional valence. That is, selective retrieval of emotional autobiographical memories induced forgetting of related, but not retrieved emotional autobiographical memories compared to the baseline. More interestingly, we found that the confidence ratings for positive memories mirrored the RIF pattern: decreased confidence for related, unpracticed autobiographical memories relative to the baseline. For negative memories, we found the opposite pattern: increased confidence for both practiced autobiographical memories and related, unpracticed autobiographical memories. We discuss these results in terms of accessibility, the diverging mnemonic consequences of selectively retrieving positive and negative autobiographical memories and personal identity. PMID- 23932995 TI - Gastric cancer: adding glycosylation to the equation. AB - Gastric cancer has a high incidence and mortality, so there is a pressing need to understand the underlying molecular mechanisms in order to discover novel biomarkers. Glycosylation alterations are frequent during gastric carcinogenesis and cancer progression. This review describes the role of glycans from the initial steps of the carcinogenesis process, in which Helicobacter pylori adheres to host mucosa glycans and modulates the glycophenotype, as well as how glycans interfere with epithelial cell adhesion by modulating epithelial cadherin functionality in gastric cancer progression. Other mechanisms regulating gastric cancer malignant behavior are discussed, such as increased sialylation interfering with key signaling pathways and integrin glycosylation leading to an invasive phenotype. Applications of these glycosylation alterations in the clinical management of gastric cancer patients are discussed. PMID- 23932997 TI - Simultaneous attentional guidance by working-memory and selection history reveals two distinct sources of attention. AB - Recent theories of attention have proposed that selection history is a separate, dissociable source of information that influences attention. The current study sought to investigate the simultaneous involvement of selection history and working-memory on attention during visual search. Experiments 1 and 2 used target feature probability to manipulate selection history and found significant effects of both working-memory and selection history, although working-memory dominated selection history when they cued different locations. Experiment 3 eliminated the contribution of voluntary refreshing of working-memory and replicated the main effects, although selection history became dominant. Using the same methodology, but with reduced probability cue validity, both effects were present in Experiment 4 and did not significantly differ in their contribution to attention. Effects of selection history and working-memory never interacted. These results suggest that selection history and working-memory are separate influences on attention and have little impact on each other. Theoretical implications for models of attention are discussed. PMID- 23932998 TI - Enhancing inhibition: how impulsivity and emotional activation interact with different implementation intentions. AB - Implementation intentions, a strategy in which a strong link is created between a cue and a to-be-performed action, have been shown to be efficacious in improving self-regulation. The relative efficacy of verbal and visual implementation intentions, however, has yet to be determined. Implementation intentions have also been shown to be inefficacious in participants with high impulsivity, specifically in individuals who reported having a high tendency to commit rash or regrettable actions as a result of intense affect (high urgency). Nevertheless, previous studies did not assess whether the individuals were in an emotional context at the time of the experiment. In the current study, we compared different forms of implementation intentions (verbal/visual/combined verbal visual) on a computerized inhibition task while assessing impulsivity and emotional activation. The results showed that all types of implementation intentions improved inhibition performances significantly in participants with high urgency, but only when their emotional activation was low. There was no difference between the three types of implementation intentions. PMID- 23932999 TI - Whole-body posture planning in anticipation of a manual prehension task: prospective and retrospective effects. AB - This study examined the extent to which the anticipation of a manual action task influences whole-body postural planning and orientation. Our participants walked up to a drawer, opened the drawer, then grasped and moved an object in the drawer to another location in the same drawer. The starting placement of the object within the drawer and the final placement of the object in the drawer were varied across trials in either a blocked design (i.e., in trials where the same start and end location were repeated consecutively) or in a mixed fashion. Of primary interest was the posture adopted at the moment of grasping the drawer handle before pulling it out prior to the object manipulation task. Of secondary interest was whether there were sequential effects such that postures adopted in preceding trials influenced postures in subsequent trials. The results indicated that the spatial properties of the forthcoming object manipulation influenced both the postures adopted by the participants and the degree to which the drawer was opened, suggesting a prospective effect. In addition, the adopted postures were more consistent in blocked trials than in mixed trials, suggesting an additional retrospective effect. Overall, our findings suggest that motor planning occurs at the level of the whole body, and reflects both prospective and retrospective influences. PMID- 23933000 TI - Comparative judgments of symbolic and non-symbolic stimuli yield different patterns of reaction times. AB - Are different magnitudes, such as Arabic numerals, length and area, processed by the same system? Answering this question can shed light on the building blocks of our mathematical abilities. A shared representation theory suggested that discriminability of all magnitudes complies with Weber's law. The current work examined this suggestion. We employed comparative judgment tasks to investigate different types of comparisons - conceptual comparison of numbers, physical comparison of numbers and physical comparison of different shapes. We used 8 different size ratios and plotted reaction time as a function of these ratios. Our findings suggest that the relationship between discriminability and size ratio is not always linear, as previously suggested; rather, it is modulated by the type of comparison and the type of stimuli. Hence, we suggest that the representation of magnitude is not as rigid as previously suggested; it changes as a function of task demands and familiarity with the compared stimuli. PMID- 23933001 TI - Spatial integration of boundaries in a 3D virtual environment. AB - Prior research, using two- and three-dimensional environments, has found that when both human and nonhuman animals independently acquire two associations between landmarks with a common landmark (e.g., LM1-LM2 and LM2-LM3), each with its own spatial relationship, they behave as if the two unique LMs have a known spatial relationship despite their never having been paired. Seemingly, they have integrated the two associations to create a third association with its own spatial relationship (LM1-LM3). Using sensory preconditioning (Experiment 1) and second-order conditioning (Experiment 2) procedures, we found that human participants integrated information about the boundaries of pathways to locate a goal within a three-dimensional virtual environment in the absence of any relevant landmarks. Spatial integration depended on the participant experiencing a common boundary feature with which to link the pathways. These results suggest that the principles of associative learning also apply to the boundaries of an environment. PMID- 23933002 TI - The link between mental rotation ability and basic numerical representations. AB - Mental rotation and number representation have both been studied widely, but although mental rotation has been linked to higher-level mathematical skills, to date it has not been shown whether mental rotation ability is linked to the most basic mental representation and processing of numbers. To investigate the possible connection between mental rotation abilities and numerical representation, 43 participants completed four tasks: 1) a standard pen-and-paper mental rotation task; 2) a multi-digit number magnitude comparison task assessing the compatibility effect, which indicates separate processing of decade and unit digits; 3) a number-line mapping task, which measures precision of number magnitude representation; and 4) a random number generation task, which yields measures both of executive control and of spatial number representations. Results show that mental rotation ability correlated significantly with both size of the compatibility effect and with number mapping accuracy, but not with any measures from the random number generation task. Together, these results suggest that higher mental rotation abilities are linked to more developed number representation, and also provide further evidence for the connection between spatial and numerical abilities. PMID- 23933003 TI - Event-method directed forgetting: forgetting a video segment is more effortful than remembering it. AB - Videos were presented depicting events such as baking cookies or cleaning a fish tank. Periodically, the video paused and an instruction to Remember (R) or Forget (F) the preceding video segment was presented; the video then resumed. Participants later responded more accurately to cued-recall questions (E1) and to true/false statements (E2-5) regarding R segments than F segments. This difference was larger for specific information (the woman added 3 cups of flour) than for general information (the woman added flour). Participants were also slower to detect visual probes presented following F instructions compared to those presented following R instructions. These findings suggest that intentional forgetting is an effortful process that can be performed even on segments of otherwise continuous events and that the result is a relatively impoverished representation of the unwanted information in memory. PMID- 23933005 TI - A dynamic population model for estimating all-cause mortality due to lifetime exposure history. AB - We developed a comprehensive, flexible dynamic model that estimates all-cause mortality for a hypothetical cohort. All model input is user-specified. In the base case, members of the cohort may be exposed to a high risk product as they age. The counterfactual scenario includes exposure to both a high risk and a lower risk product. The model sorts the population into age and exposure categories, and applies the appropriate mortality rates to each category. The model tracks individual exposure histories, and estimates, at the end of each modeled age category, the number of survivors in the two exposure scenarios (base case and counterfactual), and the difference between them. Markov Chain Monte Carlo techniques are used to estimate the variability of the results. Model output was compared against US and Swedish life tables using population-specific tobacco exposure transition probabilities derived from the literature, and it produced similar survival estimates. PMID- 23933004 TI - Host genetic determinants of influenza pathogenicity. AB - Despite effective vaccines, influenza remains a major global health threat due to the morbidity and mortality caused by seasonal epidemics, as well as the 2009 pandemic. Also of profound concern are the rare but potentially catastrophic transmissions of avian influenza to humans, highlighted by a recent H7N9 influenza outbreak. Murine and human studies reveal that the clinical course of influenza is the result of a combination of both host and viral genetic determinants. While viral pathogenicity has long been the subject of intensive efforts, research to elucidate host genetic determinants, particularly human, is now in the ascendant, and the goal of this review is to highlight these recent insights. PMID- 23933006 TI - Good relationship between saliva cotinine kinetics and plasma cotinine kinetics after smoking one cigarette. AB - This study investigated the relationship between plasma and saliva cotinine kinetics after smoking one cigarette and the relationship between cotinine kinetics and estimated nicotine intake, which was calculated as mouth level exposure (MLE) of nicotine, from smoking two test cigarettes with different nicotine yields. This study was conducted in 16 healthy adult Japanese smokers, who did not have null nor reduced-activity alleles of CYP2A6, with a quasi randomized crossover design of smoking a low-tar cigarette or a high-tar cigarette. Saliva cotinine showed similar concentration profiles to plasma cotinine, and all of the calculated pharmacokinetic parameters of cotinine showed the same values in plasma and saliva. The Cmax and AUC of cotinine showed almost the same dose-responsiveness to the estimated MLE of nicotine between plasma and saliva, but the tmax and t1/2 of cotinine were not affected by the estimated MLE of nicotine in either plasma or saliva. The results show that saliva cotinine kinetics reflects plasma cotinine kinetics, and measurement of saliva cotinine concentration gives the same information as plasma cotinine on the nicotine intake. Thus, saliva cotinine would be a good and less-invasive exposure marker of cigarette smoke, reflecting the plasma cotinine concentration and kinetics. PMID- 23933007 TI - Comparative assessment of multiple criteria for the in silico prediction of cross reactivity of proteins to known allergens. AB - Genetically modified crops are becoming important components of a sustainable food supply and must be brought to market efficiently while also safeguarding the public from cross-reactivity of novel proteins to known allergens. Bioinformatic assessments can help to identify proteins warranting further experimental checks for cross-reactivity. This study is a large-scale in silico evaluation of assessment criteria, including searches for: alignments between a query and an allergen having >= 35% identity over a length >= 80; any sequence (of some minimum length) found in both a query and an allergen; any alignment between a query and an allergen with an E-value below some threshold. The criteria and an allergen database (AllergenOnline) are used to assess 27,243 Viridiplantae proteins for potential allergenicity. (A protein is classed as a "real allergen" if it exceeds a test-specific level of identity to an AllergenOnline entry; assessment of real allergens in the query set is against a reduced database from which the identifying allergen has been removed.) Each criterion's ability to minimize false positives without increasing false negative levels of current methods is determined. At best, the data show a reduction in false positives to ~6% (from ~10% under current methods) without any increase in false negatives. PMID- 23933008 TI - Physical activity and arterial stiffness in chronic obstructive pulmonary disease. AB - Arterial stiffness is predictive of cardiovascular events and is elevated in chronic obstructive pulmonary disease (COPD). As physical inactivity and exercise intolerance are associated with elevated arterial stiffness in health, we hypothesized that lower physical activity would be related to increased arterial stiffness in COPD; and that active COPD patients would have reduced arterial stiffness compared to sedentary counterparts. Arterial stiffness was evaluated using pulse wave velocity (PWV) in 33 COPD patients (FEV1=65% predicted) and 10 controls. FEV(1%pred), peak oxygen consumption (VO(2peak)), and physical activity data were obtained. The inactive COPD group had higher PWV than controls (9.6 vs. 8.3 ms(-1), p<0.05); while there was no difference in PWV between the active COPD group and controls. Within the COPD patients, VO(2peak) (r=-0.44, p=0.01) and physical activity (r=-0.38, p=0.03) were the best predictors of PWV. Physical inactivity and exercise intolerance appear to be related to arterial stiffness in COPD, and may contribute to increased cardiovascular disease risk in COPD. PMID- 23933009 TI - Central respiratory failure during acute organophosphate poisoning. AB - Organophosphate (OP) pesticide poisoning is a global health problem with over 250,000 deaths per year. OPs affect neuronal signaling through acetylcholine (Ach) neurotransmission via inhibition of acetylcholinesterase (AChE), leading to accumulation of Ach at the synaptic cleft and excessive stimulation at post synaptic receptors. Mortality due to OP agents is attributed to respiratory dysfunction, including central apnea. Cholinergic circuits are integral to many aspects of the central control of respiration, however it is unclear which mechanisms predominate during acute OP intoxication. A more complete understanding of the cholinergic aspects of both respiratory control as well as neural modification of pulmonary function is needed to better understand OP induced respiratory dysfunction. In this article, we review the physiologic mechanisms of acute OP exposure in the context of the known cholinergic contributions to the central control of respiration. We also discuss the potential central cholinergic contributions to the known peripheral physiologic effects of OP intoxication. PMID- 23933011 TI - Crystal structures of the free and ligand-bound FK1-FK2 domain segment of FKBP52 reveal a flexible inter-domain hinge. AB - The human Hsp90 co-chaperone FKBP52 belongs to the family of FK506-binding proteins, which act as peptidyl-prolyl isomerases. FKBP52 specifically enhances the signaling of steroid hormone receptors, modulates ion channels and regulates neuronal outgrowth dynamics. In turn, small-molecule ligands of FKBP52 have been suggested as potential neurotrophic or anti-prostate cancer agents. The usefulness of available ligands is however limited by a lack of selectivity. The immunophilin FKBP52 is composed of three domains, an FK506-binding domain with peptidyl-prolyl isomerase activity, an FKBP-like domain of unknown function and a TPR-clamp domain, which recognizes the C-terminal peptide of Hsp90 with high affinity. The herein reported crystal structures of FKBP52 reveal that the short linker connecting the FK506-binding domain and the FKBP-like domain acts as a flexible hinge. This enhanced flexibility and its modulation by phosphorylation might explain some of the functional antagonism between the closely related homologs FKBP51 and FKBP52. We further present two co-crystal structures of FKBP52 in complex with the prototypic ligand FK506 and a synthetic analog thereof. These structures revealed the molecular interactions in great detail, which enabled in-depth comparison with the corresponding complexes of the other cytosolic FKBPs, FKBP51 and FKBP12. The observed subtle differences provide crucial insights for the rational design of ligands with improved selectivity for FKBP52. PMID- 23933010 TI - Elucidating the native architecture of the YidC: ribosome complex. AB - Membrane protein biogenesis in bacteria occurs via dedicated molecular systems SecYEG and YidC that function independently and in cooperation. YidC belongs to the universally conserved Oxa1/Alb3/YidC family of membrane insertases and is believed to associate with translating ribosomes at the membrane surface. Here, we have examined the architecture of the YidC:ribosome complex formed upon YidC mediated membrane protein insertion. Fluorescence correlation spectroscopy was employed to investigate the complex assembly under physiological conditions. A slightly acidic environment stimulates binding of detergent-solubilized YidC to ribosomes due to electrostatic interactions, while YidC acquires specificity for translating ribosomes at pH-neutral conditions. The nanodisc reconstitution of the YidC to embed it into a native phospholipid membrane environment strongly enhances the YidC:ribosome complex formation. A single copy of YidC suffices for the binding of translating ribosome both in detergent and at the lipid membrane interface, thus being the minimal functional unit. Data reveal molecular details on the insertase functioning and interactions and suggest a new structural model for the YidC:ribosome complex. PMID- 23933012 TI - Interactions between an injected polydnavirus and per os baculovirus in gypsy moth larvae. AB - Larval gypsy moths, Lymantria dispar (Lepidoptera:Lymantriidae) were co-infected with the L. dispar nucleopolyhedrovirus (LdMNPV) and the Cotesia melanoscela (Hymenoptera:Braconidae) polydnavirus (CmeBV). CmeBV was given along with a parasitoid egg and calyx products in a stinging event, or in the form of an injection of calyx-derived extract. LdMNPV was delivered per os, integrated into artificial diet. Mortality from all sources was recorded over the subsequent three-week period. Neither parasitism nor injections of purified CmeBV with toxin had any effect on the amount of mortality caused by concurrent challenges with LdMNPV. PMID- 23933013 TI - Reduced competitiveness of Wolbachia infected Aedes aegypti larvae in intra- and inter-specific immature interactions. AB - Wolbachia are maternally inherited intracellular bacteria that frequently infect a diverse range of arthropod species. Empirical and theoretical studies examining Wolbachia invasiveness have emphasized Wolbachia effects on adult hosts, but recent studies show that Wolbachia impacts on immature hosts can be important also. Here, we have examined for effects of Wolbachia infection in Aedes aegypti. Specifically, differential survivorship is observed when young larvae (1st instar) are exposed to older Aedes albopictus larvae (4th instar) or con-specific larvae. In an additional experiment, we have examined for differential behavior and observed that Wolbachia-infected larvae differ from uninfected larvae in their reaction to light stimulation. Our results support a hypothesized effect of Wolbachia on A. aegypti larval behavior. The results are discussed in relation to the ability of Wolbachia to invade natural populations and recently applied public health strategies that target the replacement or suppression of this important disease vector. PMID- 23933014 TI - Exposure to toluene and stress during pregnancy impairs pups' growth and dams' lactation. AB - Inhalant misuse starts at an early age, and a large number of users are women in reproductive age. This study investigates whether exposure to toluene, a commonly misused solvent, alone or combined with restraint stress during pregnancy, produces adverse effects in pregnant mice and their offspring during lactation and adulthood. Pregnant animals were exposed to either 8000ppm toluene (30min/twice daily from gestational days 7-19), restraint stress (three times/day during the same gestation period) or both; control mice were only exposed to air. Our results show that toluene, stress and their combination reduced body weight gain in pregnant females without changing food consumption. In the offspring, all treatments resulted in low body weight at weaning, but with the toluene and stress combination this effect was seen from birth. Weight deficiency could not be attributed to poor maternal behavior during the first 3weeks of age, but to a reduction in pro-TRH mRNA expression in the hypothalamic paraventricular nucleus and serum prolactin levels in dams. After weaning, pups that were subjected to toluene and stress during gestation had lower body weight and ate less than control animals. In conclusion, the combined exposure to toluene and stress during pregnancy lead to more pronounced effects in dams and longer-lasting actions in pups than exposure to either toluene or stress. PMID- 23933015 TI - Infected hip hemiarthroplasties and total hip arthroplasties: Differential findings and prognosis. AB - OBJECTIVES: Infected hip hemiarthroplasties (HHA) are classically analyzed along with infected total hip arthroplasties (THA), but patients with either one or other device are different. We describe the clinical presentation, etiology and prognosis of infected HHA compared with infected THA. METHODS: Comparative study of patients with infected HHA and THA from a prospective database of prosthetic joint infection (PJI) cases in our hospital (2003-2011), focusing on patients managed with debridement, antibiotics and implant retention (DAIR). RESULTS: 210 episodes of hip-PJI (age 74 years, 63% women): 62 (39%) HHA and 148 (61%) THA. HHA-patients were older and had more comorbidities. Late-chronic and hematogenous infections were more frequent in THA. 123 (59%) patients were managed with DAIR: 72 THA and 51 HHA. Staphylococcus aureus was more frequent in THA (44% vs 26%, p = 0.032), while Gram-negative bacilli were more prevalent in HHA (73% vs 51%, p = 0.018), with a higher prevalence of fluoroquinolone-resistance in cemented-HHA. Overall failure was 37%, with no significant differences among groups. A higher mortality was observed in HHA cases (21% vs 4%, p = 0.005), particularly in cemented-HHA. CONCLUSION: Infected THA and HHA have different characteristics, etiology and prognosis. Overall failure was similar, probably balanced by different predictors among groups, but mortality was higher among cemented-HHA. PMID- 23933016 TI - Expression of the glucocorticoid receptor is decreased in experimental Staphylococcus aureus sepsis. AB - INTRODUCTION: Glucocorticoid treatment in septic shock remains controversial after recent trials. We hypothesized that failure to respond to steroid therapy may be caused by decreased expression and/or function of glucocorticoid receptors (GR) and studied this in a mouse model of Staphylococcus aureus sepsis. The impact of timing of dexamethasone treatment was also investigated. METHODS: Male C57BL/6J mice were intravenously inoculated with S. aureus and GR expression and binding ability in blood, spleen and lymph nodes were analysed by means of flow cytometry. GR translocation was analysed using Image Stream. Septic mice were administered dexamethasone at 22, 26, 48, 72 and 96 h after inoculation and body weight, as a sign of dehydration, was observed. RESULTS: GR expression was decreased in septic animals, but not the ligand binding capacity. GR translocation was decreased in septic mice compared to control animals. Early dexamethasone treatment (22 and 26 h) improved clinical outcome as studied by weight gain compared to when treatment was started at later time points (48, 72 and 96 h). CONCLUSION: Our data provide evidence that GR expression is progressively decreased in experimental sepsis and that dexamethasone has a decreased ability to translocate into the cell nucleus. This may explain why steroid treatment is only beneficial when administered early in sepsis and septic shock. PMID- 23933017 TI - Light-harvesting complex II (LHCII) and its supramolecular organization in Chlamydomonas reinhardtii. AB - LHCII is the most abundant membrane protein on earth. It participates in the first steps of photosynthesis by harvesting sunlight and transferring excitation energy to the core complex. Here we have analyzed the LHCII complex of the green alga Chlamydomonas reinhardtii and its association with the core of Photosystem II (PSII) to form multiprotein complexes. Several PSII supercomplexes with different antenna sizes have been purified, the largest of which contains three LHCII trimers (named S, M and N) per monomeric core. A projection map at a 13A resolution was obtained allowing the reconstruction of the 3D structure of the supercomplex. The position and orientation of the S trimer are the same as in plants; trimer M is rotated by 45 degrees and the additional trimer (named here as LHCII-N), which is taking the position occupied in plants by CP24, is directly associated with the core. The analysis of supercomplexes with different antenna sizes suggests that LhcbM1, LhcbM2/7 and LhcbM3 are the major components of the trimers in the PSII supercomplex, while LhcbM5 is part of the "extra" LHCII pool not directly associated with the supercomplex. It is also shown that Chlamydomonas LHCII has a slightly lower Chlorophyll a/b ratio than the complex from plants and a blue shifted absorption spectrum. Finally the data indicate that there are at least six LHCII trimers per dimeric core in the thylakoid membranes, meaning that the antenna size of PSII of C. reinhardtii is larger than that of plants. PMID- 23933018 TI - The branched mitochondrial respiratory chain from Debaryomyces hansenii: components and supramolecular organization. AB - The branched respiratory chain in mitochondria from the halotolerant yeast Debaryomyces hansenii contains the classical complexes I, II, III and IV plus a cyanide-insensitive, AMP-activated, alternative-oxidase (AOX). Two additional alternative oxidoreductases were found in this organism: an alternative NADH dehydrogenase (NDH2e) and a mitochondrial isoform of glycerol-phosphate dehydrogenase (MitGPDH). These monomeric enzymes lack proton pump activity. They are located on the outer face of the inner mitochondrial membrane. NDH2e oxidizes exogenous NADH in a rotenone-insensitive, flavone-sensitive, process. AOX seems to be constitutive; nonetheless, most electrons are transferred to the cytochromic pathway. Respiratory supercomplexes containing complexes I, III and IV in different stoichiometries were detected. Dimeric complex V was also detected. In-gel activity of NADH dehydrogenase, mass spectrometry, and cytochrome c oxidase and ATPase activities led to determine the composition of the putative supercomplexes. Molecular weights were estimated by comparison with those from the yeast Y. lipolytica and they were IV2, I-IV, III2-IV4, V2, I-III2, I-III2-IV, I-III2-IV2, I-III2-IV3 and I-III2-IV4. Binding of the alternative enzymes to supercomplexes was not detected. This is the first report on the structure and organization of the mitochondrial respiratory chain from D. hansenii. PMID- 23933019 TI - Brucine, an alkaloid from seeds of Strychnos nux-vomica Linn., represses hepatocellular carcinoma cell migration and metastasis: the role of hypoxia inducible factor 1 pathway. AB - Brucine is an alkaloid derived from the seeds of Strychnos nux-vomica Linn. which have long been used as a traditional medicine for the treatment of hepatocellular carcinoma (HCC) in China. HCC prognosis can be greatly influenced by metastasis. There has thus far been little research into brucine as a source of anti metastasis activity against HCC. In this study, we revealed that brucine dramatically repressed HepG2 and SMMC-7721 HCC cell migration with few cytotoxic effects. Hypoxia inducible factor 1 (HIF-1) is a key transcription factor mediating cell migration and invasion. Brucine suppressed HIF-1-dependent luciferase activity in HepG2 cells. The transcriptions of four known HIF-1 target genes involved in HCC metastasis, i.e., fibronectin, matrix metallopeptidase 2, lysyl oxidase, and cathepsin D, were also attenuated after brucine treatment. Experiments in vivo showed that an intraperitoneal injection of 5 and 15 mg/kg of brucine resulted in dose-dependent decreases in the lung metastasis of H22 ascitic hepatoma cells. Moreover, a dosage of brucine at 15 mg/kg exhibited very low toxic effects to tumor-bearing mice. Consistently, brucine downregulated expression levels of HIF-1 responsive genes in vivo. Our current study demonstrated the capacity of brucine in suppressing HCC cell migration in vitro and lung metastasis in vivo. The inhibition of the HIF-1 pathway is implicated in the anti-metastasis activity of brucine. PMID- 23933020 TI - Treatment of azo dye-containing synthetic textile dye effluent using sulfidogenic anaerobic baffled reactor. AB - This study aims at investigating azo dye reduction performance of a sulfidogenic anaerobic baffled reactor (ABR) for around 400 days. ABR was operated at 30 degrees C in a temperature-controlled room and hydraulic retention time (HRT) was kept constant at 2 days. The robustness of ABR was assessed under varying azo dye loadings and COD/sulfate ratios. Additionally, oxygen was supplied (1-2 L air/m(3)reactor min) to the last compartment to investigate the removal of azo dye breakdown products. ABR performed well in terms of COD, sulfate and azo dye removals throughout the reactor operation. Maximum azo dye, COD and sulfate removals were 98%, 98% and 93%, respectively, at COD/sulfate ratio of 0.8. Aeration created different redox conditions in last compartment, which enhanced the removal of COD and breakdown products. The adverse effects of aeration on azo dye reduction were eliminated thanks to the compartmentalized structure of the ABR. PMID- 23933021 TI - An efficient process for the saccharification of wood chips by combined ionic liquid pretreatment and enzymatic hydrolysis. AB - A process concept combining pretreatment of wood in ionic liquids and subsequent enzymatic hydrolysis to sugars is herein investigated to identify operating conditions which allow for (i) the processing of larger wood chips of 10 mm length, (ii) low temperature, (iii) high sugar yield, and (iv) short processing time. A careful quantitative study of the interaction of pretreatment and hydrolysis reveals that hydrolysis is most effective if beech chips are first disintegrated in [EMIM][Ac] at 115 degrees C for 1.5 h. The cellulose conversion varies between 70.5 wt% and 90.2wt% for hydrolysis times between 5 h and 72 h. A complete recovery of cellulose and xylan resulting in a total saccharification of 65 wt% of the wood chips could be demonstrated. It is shown that short pretreatment times are required to enable high sugar yield as well as to limit product degradation. PMID- 23933022 TI - Biomass torrefaction characteristics in inert and oxidative atmospheres at various superficial velocities. AB - The reaction characteristics of four biomass materials (i.e. oil palm fiber, coconut fiber, eucalyptus, and Cryptomeria japonica) with non-oxidative and oxidative torrefaction at various superficial velocities are investigated where nitrogen and air are used as carrier gases. Three torrefaction temperatures of 250, 300, and 350 degrees C are considered. At a given temperature, the solid yield of biomass is not affected by N2 superficial velocity, revealing that the thermal degradation is controlled by heat and mass transfer in biomass. Increasing air superficial velocity decreases the solid yield, especially in oil palm fiber and coconut fiber, implying that the torrefaction reaction of biomass is dominated by surface oxidation. There exists an upper limit of air superficial velocity in the decrement of solid yield, suggesting that beyond this limit the thermal degradation of biomass is no longer governed by surface oxidation, but rather is controlled by internal mass transport. PMID- 23933023 TI - Removal of ammonia nitrogen from wastewater using an aerobic cathode microbial fuel cell. AB - A new system for removing ammonia nitrogen was developed, which integrated a microbial fuel cell (MFC) with an aerobic bioreactor. A three-chamber reactor consisted of an anode chamber, a middle chamber and a cathode chamber. The chambers were separated by an anion exchange membrane and a cation exchange membrane (CEM), respectively. Driven by the power generated by the MFC, NH4(+) in the middle chamber could migrate through CEM into the cathode chamber. The migrated NH4(+) further removed via biological denitrification in the cathode chamber. Up to 90.2% of total NH4(+)-N could be removed with an initial concentration of 100 mg/L in 98 h. Affecting factors were investigated on the removal efficiency including cathode surface area, electrode spacing, chemical oxygen demand concentration, dissolved oxygen concentration, and NH4(+)-N concentration. The system was characterized by simple configuration and high efficiency, and was successfully applied to the treatment of brewery wastewater. PMID- 23933024 TI - Influence of pH and natural organic matter on zinc biosorption in a model lignocellulosic biofuel biorefinery effluent. AB - The effect of dissolved natural organic matter (NOM) and pH on microbial biosorption of Zn was evaluated in a model lignocellulosic biofuel refinery effluent rich in NOM. Batch culture experiments conducted with two model microorganisms (yeast, Candida tropicalis; bacteria Novosphingobium nitrogenifigens Y88(T)), showed an inhibitory effect of NOM, and an optimum pH for Zn removal at 7.5-8.0. Membrane bioreactors with mixed autochthonous organisms were operated at pH 6.5 and pH 8.0 to better simulate real-world remediation scenarios. More Zn was removed at the high (91%) than at the low (26%) pH, presumably because the higher pH freed negatively-charged functional groups on the cellular biomass for passive Zn binding. Manipulating the pH of bioreactors can significantly improve metal removal in NOM rich wastewater. Such reactors could maintain water quality for closed-cycle biorefineries, leading to reduced water consumption, and a more sustainable biofuel. PMID- 23933025 TI - Fractionation and delignification of empty fruit bunches with low reaction severity for high sugar recovery. AB - Fractionation and delignification of empty fruit bunches (EFB) was conducted in a series of two steps under low reaction severity with the aim of minimizing the neutralization of hydrolyzates. In EFB underwent acid fractionation, the glucan content was increased to 62.4%, at which point 86.9% of the hemicellulosic sugar and 20.5% of the lignin were extracted from the raw EFB. Xylose-rich hydrolyzate, indicating a high selectivity of 17.7 could be separated. Through the consecutive delignification of acid-fractionated EFB using sodium hydroxide, solid residue with a high glucan content (70.4%) and low hemicellulosic sugar content (3.7%) could be obtained, which indicated that 95.9% of the hemicellulosic sugar and 67.5% of the lignin were extracted based on raw EFB. The final pretreated solid residue was converted to glucose through enzyme hydrolysis, which resulted in an enzymatic digestibility of 76.9% was achieved. PMID- 23933026 TI - Rapid analysis of purified cellulose extracted from perennial ryegrass (Lolium perenne) by instrumental analysis. AB - Dried, milled perennial ryegrass samples were processed using chemical and physical treatments and the extracted cellulose products were analysed for yield, crystallinity by X-ray Diffraction (XRD) and for purity using Thermogravimetric Analysis (TGA), Pyrolysis-Gas Chromatography/Mass Spectrometry (Py-GC/MS) and Fourier Transform Infrared (FTIR) spectroscopy. Extraction protocols examined the use of chemical chelation, acid and alkaline hydrolysis, along with physical degradation methods. Highest product yields were obtained using single step chemical protocols followed by physical processing, however, these products had low crystallinity and higher amorphous fraction content. Multistep chemical processing to completely remove hemicellulose and lignin with an alkali refluxing step, delivered lower yielding cellulose products of greater crystallinity and purity. In combination, the four instrumental techniques highlighted removal of amorphous fractions, providing rapid, accurate compositional data on the extracted cellulose products. PMID- 23933027 TI - Induction of lipids and resultant FAME profiles of microalgae from coastal waters of Pearl River Delta. AB - This article presents a study on identification, cultivation and characterisation of microalgal strains from the coastal waters of the Pearl River Delta in Guangdong, China. Thirty-seven identified strains belong to the families: Chlorellaceae, Scotiellocystoidaceae, Scenedesmaceae,Selenastraceae,Micractiniaceae, Coccomyxaceae, Trebouxiaceae and Chlorococcaceae. Of isolated strains, Hindakia PKUAC 169 was selected for lipid induction using two methods: nitrogen starvation and salt stress. After derivatisation of algal lipids through in situ transesterification, lipid profiles of the alga under the two methods were analysed. The results have shown that both lipid yield and fatty acid profiles vary with the methods. Of the two tested methods of inducing lipid production, salt stress yielded three-fold higher lipid productivity than nitrogen starvation. The lipids are predominantly composed of C14-C18 fatty acids, which are favourable for biodiesel production. Moreover, the content of polyunsaturated fatty acids was below the limit of 12% set by EN14214 biodiesel standard. PMID- 23933028 TI - Felled oil palm trunk as a renewable source for biobutanol production by Clostridium spp. AB - This study aimed to convert felled oil palm trunk to biobutanol by Clostridium spp. For efficient utilization of oil palm trunk, it was separated into sap and trunk fiber. The sap was used directly while the trunk fiber was hydrolyzed to fermentable sugars before use. Among five clostridia strains screened, Clostridium acetobutylicum DSM 1731 was the most suitable strain for butanol production from the sap without any supplementation of nutrients. It produced the highest amount of butanol (14.4 g/L) from the sap (sugar concentration of 50 g/L) with butanol yield of 0.35 g/g. When hydrolysate from the trunk fiber was used as an alternative carbon source (sugar concentration of 30 g/L), of the strains tested Clostridium beijerinckii TISTR 1461 produced the highest amount of butanol (10.0 g/L) with butanol yield of 0.41 g/g. The results presented herein suggest that oil palm trunk is a promising renewable substrate for biobutanol production. PMID- 23933029 TI - Transcranial direct-current stimulation reduced the excitability of diaphragmatic corticospinal pathways whatever the polarity used. AB - We investigated effects of transcranial direct-current stimulation (tDCS) on the diaphragmatic corticospinal pathways in healthy human. Anodal, cathodal, and sham tDCS were randomly applied upon the left diaphragmatic motor cortex in twelve healthy right-handed men. Corticospinal pathways excitability was assessed by means of transcranial magnetic stimulation (TMS) elicited motor-evoked-potential (MEP). For each tDCS condition, MEPs were recorded before (Pre) tDCS then after 10 min (Post1, at tDCS discontinuation in the anodal and cathodal sessions) and 20 min (Post2). As result, both anodal and cathodal tDCS significantly decreased MEP amplitude of the right hemidiaphragm at both Post1 and Post2, versus Pre. MEP amplitude was unchanged versus Pre during the sham condition. The effects of cathodal and anodal tDCS applied to the diaphragm motor cortex differ from those observed during tDCS of the limb motor cortex. These differences may be related to specific characteristics of the diaphragmatic corticospinal pathways as well as to the diaphragm's functional peculiarities compared with the limb muscles. PMID- 23933030 TI - Interaction of tobacco smoke exposure and ovalbumin-sensitization promotes goblet cell and submucosal gland metaplasia in guinea pigs. AB - Exposure to irritants such as tobacco smoke (TS) causes acute airway inflammation. Chronic exposure may cause airway remodeling contributing to enhanced airway resistance. We hypothesize that combining airway sensitization and inhalation of irritants enhances the number of mucous producing cells beyond either agent alone. Guinea pigs were antigen sensitized or treated with its vehicle. These two groups were further divided into daily exposure to TS or air. After 3 months airway reactivity to ovalbumin (OA) was determined, airway and blood samples were examined and lung substance P quantified. Combining sensitization and TS exposure increased airway reactivity to OA, goblet cell and submucosal gland populations. Airway eosinophilia was greatest in the OA sensitized group exposed to air rather than with its combination with TS exposure. Lung substance P levels were similarly elevated in both OA-sensitized groups. Airway irritant exposure in which airway sensitization exists enhances the potential of mucus production, airway resistance and mucus plugging of the airways through increasing the number of goblet cells and submucosal glands. PMID- 23933031 TI - The risk-based approach to ATMP development - generally accepted by regulators but infrequently used by companies. AB - Advanced therapy medicinal products (ATMPs) are the cutting edge of drug innovation. ATMPs have different challenges than other drug classes. To accommodate these challenges and facilitate science-driven development, flexibility in the requirements to demonstrate the safety and efficacy of this rapidly evolving drug class is necessary. To create flexibility, the European Union introduced the risk-based approach. This approach provides the possibility of omitting guideline-based studies based on risk analyses. To gain insight into the effect of the risk-based approach on the non-clinical development of ATMPs, two questions are addressed in this paper. Firstly, "Do companies use a risk based approach for the non-clinical development of ATMPs?" and, secondly, "Does the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) accept non-clinical development programs based on the risk based approach?" Scientific advice letters formulated by the CHMP were analyzed. The risk-based approach was used to justify deviations from the guidelines in the majority (75%) of the cases. The CHMP accepted 40% of the proposals to omit studies and stated that additional data was necessary to make an informed decision for 35% of the proposals. This indicates that the risk-based approach facilitates the science-driven development of ATMPs. PMID- 23933032 TI - Combining benefits of an adrenergic and a muscarinic blocker in a single formulation - a pharmacokinetic evaluation. AB - A pharmacokinetic bioequivalence study was conducted in Asian subjects, to compare a fixed dose combination capsule single oral dose of alpha adrenoceptor blocker-Alfuzosin hydrochloride 10mg extended release and muscarinic antagonists Solifenacin succinate 5mg against individually administered Xatral XL 10mg tablets (Alfuzosin) of Sanofi Synthelabo Limited, United Kingdom (UK) and Vesicare 5mg tablets (Solifenacin) of Astellas Pharma Limited, UK under fed conditions. Blood samples were collected pre-dose up to 72 h post dose for determination of plasma Alfuzosin and Solifenacin concentrations and calculation of the pharmacokinetic parameters. ANOVA was performed on the log (natural) transformed pharmacokinetic parameters. A 90% confidence interval for the ratios of the test and reference product averages (least square means) were calculated for alfuzosin and solifenacin. The 90% confidence intervals obtained for alfuzosin for Cmax, AUC0-t and AUC0-infinity were 102.74-122.75%, 95.84-116.96% and 95.82-116.76%, respectively. The 90% confidence intervals obtained for Solifenacin for Cmax, and AUC0-72 were 89.55-97.91% and 90.47-99.38%, respectively. Based on the results, the fixed dose combination was concluded to be bioequivalent to individually administered products. PMID- 23933033 TI - Assessing receptivity in the endometrium: the need for a rapid, non-invasive test. AB - Successful implantation of an embryo into the uterus requires synchrony between the blastocyst and the endometrium. Endometrial preparedness, or receptivity, occurs only for a very short time during the mid-secretory phase of the menstrual cycle in fertile women. Failure to achieve receptivity results in infertility and is a rate-limiting step for IVF success. Frozen embryo transfer in non stimulation cycles is already improving live birth rates. However, an important tool that is missing in the armoury of reproductive specialists is a means to rapidly assess endometrial receptivity, either during initial assessment or immediately prior to embryo transfer. The development of a wealth of omics technologies now opens the way for identifying potential receptivity markers, although validation of these is still a major issue. This review assesses the current state of the field and the requirements to proceed to a valid clinical test. PMID- 23933034 TI - Epigenetic effects on the embryo as a result of periconceptional environment and assisted reproduction technology. AB - The early embryonic environment has been shown to be remarkably influential on the developing organism, despite the relative brevity of this developmental stage. The cells of the zygote and cleavage-stage embryo hold the potential to form all cell lineages of the embryonic and extra-embryonic tissues, with gradual fate restriction occurring from the time of compaction and blastocyst formation. As such, these cells carry with them the potential to influence the phenotype of all successive cell types as the organism grows, differentiates and ages. The implication is, therefore, that sublethal adverse conditions which alter the developmental trajectory of these cells may have long-term implications for the health and development of the resulting offspring. One confirmed mechanism for the translation of environmental cues to phenotypic outcome is epigenetic modification of the genome to modulate chromatin packaging and gene expression in a cell- and lineage-specific manner. The influence of the periconceptional milieu on the epigenetic profile of the developing embryo has become a popular research focus in the quest to understand the effects of environment, nutrition and assisted reproduction technology on human development and health. PMID- 23933035 TI - Implantation in assisted reproduction: a look at endometrial receptivity. AB - Implantation failure in assisted reproduction is thought to be mainly due to impaired uterine receptivity. With normal uterine anatomy, changes in endocrine profile during ovarian stimulation and medical conditions of the mother (i.e. thrombophilia and abnormal immunological response) could result in a non receptive endometrium. High oestradiol concentrations during ovarian stimulation lead to premature progesterone elevation, causing endometrial advancement and hampering implantation, which can be overcome by a freeze-all approach and embryo transfer in natural cycles or by milder stimulation protocols. Patients with recurrent implantation failure (RIF) should be tested for inherited and acquired thrombophilias. Each patient should be individually assessed and counselled regarding therapy with low-molecular-weight heparin (LMWH). Empirical treatment with LMWH, aspirin or corticosteroids is not effective for women with RIF who have negative thrombophilic tests. If thrombophilic tests are normal, patients should be tested for immunological causes. If human leukocyte antigen dissimilarity is proven, treatment with intravenous immunoglobulin might be beneficial. Preliminary observational studies using intralipid infusion in the presence of increased natural killer cytotoxic activity are interesting but the proposed rationale is controversial and randomized controlled trials are needed. Hysteroscopy and/or endometrial scratching in the cycle preceding ovarian stimulation should become standard for patients with RIF. PMID- 23933036 TI - New approaches to embryo selection. AB - Embryo selection has been an important topic since the introduction of assisted reproduction, with embryo morphology being the most obvious criterion. Although morphology serves as indicator for overall IVF laboratory quality, its statistical assessment limits the possibility to identify the most implantation competent embryos. In order to reach a direct picture of the developing embryo, invasive procedures such as preimplantation genetic screening or transcriptome and proteome analysis of biopsied embryonic tissue were initially prioritized and are still under investigation. More recently, focus has shifted towards noninvasive techniques that maintain the integrity of the embryo. Metabolomic profiling of culture medium from growing embryos attracted much research. Although successful in a pilot study, that approach failed in a randomized controlled trial. Other metabolomics studies are on their way but not yet available for routine clinical use. The most promising strategy at present is the combined evaluation of morphology and developmental kinetics using time-lapse imaging. This has brought new insights into certain characteristics that enable deselection of embryos at an early stage of development and to identify others with high potential for successful implantation. However, there is still considerable room for improvement. Further strategies will most likely involve the combination of several different approaches. PMID- 23933038 TI - Advances in functional magnetic resonance imaging of the human brainstem. AB - The brainstem is of tremendous importance for our daily survival, and yet the functional relationships between various nuclei, their projection targets, and afferent regulatory areas remain poorly characterized. The main reason for this lies in the sub-optimal performance of standard neuroimaging methods in this area. In particular, fMRI signals are much harder to detect in the brainstem region compared to cortical areas. Here we describe and validate a new approach to measure activation of brainstem nuclei in humans using standard fMRI sequences and widely available tools for statistical image processing. By spatially restricting an independent component analysis to an anatomically defined brainstem mask, we excluded those areas from the analysis that were strongly affected by physiological noise. This allowed us to identify for the first time intrinsic connectivity networks in the human brainstem and to map brainstem cortical connectivity purely based on functionally defined regions of interest. PMID- 23933037 TI - Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity. AB - Embryo attachment and implantation is critical to successful reproduction of all eutherian mammals, including humans; a better understanding of these processes could lead to improved infertility treatments and novel contraceptive methods. Experience with assisted reproduction, especially oocyte donation cycles, has established that despite the diverse set of hormones produced by the ovary in a cycle-dependent fashion, the sequential actions of only two of them, oestrogen and progesterone, are sufficient to prepare a highly receptive endometrium in humans. Further investigation on the endometrial actions of these two hormones is currently providing significant insight into the implantation process in women, strongly suggesting that an abnormal response to progesterone underlies infertility in some patients. PMID- 23933039 TI - Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD. AB - BACKGROUND: Atomoxetine (ATX), a drug for treatment of depression and ADHD, has a high affinity for the norepinephrine transporter (NET); however, our previous study showed it had a blocking effect similar to fluoxetine on binding of [(11)C]DASB, a selective serotonin transporter (SERT) ligand. Whether the therapeutic effects of ATX are due to inhibition of either or both transporters is not known. Here we report our comparative PET imaging studies with [(11)C]MRB (a NET ligand) and [(11)C]AFM (a SERT ligand) to evaluate in vivo IC50 values of ATX in monkeys. METHODS: Rhesus monkeys were scanned up to four times with each tracer with up to four doses of ATX. ATX or saline (placebo) infusion began 2h before each PET scan, lasting until the end of the 2-h scan. The final infusion rates were 0.01-0.12mg/kg/h and 0.045-1.054mg/kg/h for the NET and SERT studies, respectively. ATX plasma levels and metabolite-corrected arterial input functions were measured. Distribution volumes (VT) and IC50 values were estimated. RESULTS: ATX displayed dose-dependent occupancy on both NET and SERT, with a higher occupancy on NET: IC50 of 31+/-10 and 99+/-21ng/mL plasma for NET and SERT, respectively. At a clinically relevant dose (1.0-1.8mg/kg, approx. 300-600ng/mL plasma), ATX would occupy >90% of NET and >85% of SERT. This extrapolation assumes comparable free fraction of ATX in humans and non-human primates. CONCLUSION: Our data suggests that ATX at clinically relevant doses greatly occupies both NET and SERT. Thus, therapeutic modes of ATX action for treatment of depression and ADHD may be more complex than selective blockade of NET. PMID- 23933040 TI - Battery powered thought: enhancement of attention, learning, and memory in healthy adults using transcranial direct current stimulation. AB - This article reviews studies demonstrating enhancement with transcranial direct current stimulation (tDCS) of attention, learning, and memory processes in healthy adults. Given that these are fundamental cognitive functions, they may also mediate stimulation effects on other higher-order processes such as decision making and problem solving. Although tDCS research is still young, there have been a variety of methods used and cognitive processes tested. While these different methods have resulted in seemingly contradictory results among studies, many consistent and noteworthy effects of tDCS on attention, learning, and memory have been reported. The literature suggests that although tDCS as typically applied may not be as useful for localization of function in the brain as some other methods of brain stimulation, tDCS may be particularly well-suited for practical applications involving the enhancement of attention, learning, and memory, in both healthy subjects and in clinical populations. PMID- 23933042 TI - Validity of modulation and optimal settings for advanced voxel-based morphometry. AB - Voxel-based morphometry (VBM) is a widely-used structural neuroimaging technique for comparing meso- and macroscopic regional brain volumes between patients and controls in vivo, but some of its steps, particularly the modulation, lack an experimental validation. The aims of this study were two-fold: a) to assess the effects of modulation to detect mesoscopic (i.e. between microscopic and macroscopic) abnormalities on published, classic VBM; and b) to suggest a set of potentially optimal settings for detecting mesoscopic abnormalities with new, advanced, high-resolution diffeomorphic VBM normalization algorithms. Sensitivity and false positive rate after modulating or not in classic VBM using different software packages and spatial statistics, and after setting a range of different parameters in advanced VBM (ANTS-SyN), were calculated in 10 VBM comparisons of 32 altered vs. 32 unaltered gray matter images from different healthy controls. Simulated brain abnormalities comprised mesoscopic volume differences mainly due to cortical thinning. In classic VBM, modulation was associated with a substantial decrease of the sensitivity to detect mesoscopic abnormalities (p<0.001). Optimal settings for advanced VBM included the omission of modulation, the use of large smoothing kernels, and the application of voxel-based or threshold-free cluster enhancement (TFCE) spatial statistics. The modulation related decrease in sensitivity was due to an increase in variance, and it was more severe in higher-resolution normalization algorithms. Findings from this study suggest the use of unmodulated VBM to detect mesoscopic abnormalities such as cortical thinning. PMID- 23933043 TI - On the use of Cramer-Rao minimum variance bounds for the design of magnetic resonance spectroscopy experiments. AB - Localized Magnetic Resonance Spectroscopy (MRS) is in widespread use for clinical brain research. Standard acquisition sequences to obtain one-dimensional spectra suffer from substantial overlap of spectral contributions from many metabolites. Therefore, specially tuned editing sequences or two-dimensional acquisition schemes are applied to extend the information content. Tuning specific acquisition parameters allows to make the sequences more efficient or more specific for certain target metabolites. Cramer-Rao bounds have been used in other fields for optimization of experiments and are now shown to be very useful as design criteria for localized MRS sequence optimization. The principle is illustrated for one- and two-dimensional MRS, in particular the 2D separation experiment, where the usual restriction to equidistant echo time spacings and equal acquisition times per echo time can be abolished. Particular emphasis is placed on optimizing experiments for quantification of GABA and glutamate. The basic principles are verified by Monte Carlo simulations and in vivo for repeated acquisitions of generalized two-dimensional separation brain spectra obtained from healthy subjects and expanded by bootstrapping for better definition of the quantification uncertainties. PMID- 23933044 TI - Change-related auditory P50: a MEG study. AB - Changes in continuous sounds elicit a preattentive component that peaks at around 100ms (Change-N1m) on electroencephalograms or magnetoencephalograms (MEG). Change-N1m is thought to reflect brain activity relating to the automatic detection of changes, which facilitate processes for the execution of appropriate behavior in response to new environmental events. The aim of the present MEG study was to elucidate whether a component relating to auditory changes existed earlier than N1m. Change-related cortical responses were evoked by abrupt sound movement in a train of clicks at 100Hz. Sound movement was created by inserting an interaural time delay (ITD) of 0.15, 0.25, 0.35, and 0.45ms into the right ear. Ten out of 12 participants exhibited clear change-related cortical responses earlier than Change-N1m at around 60ms (Change-P50m). The results of source analysis showed that Change-P50m originated from the superior temporal gyrus of both hemispheres and that its location did not differ significantly from dipoles for the response to the sound onset. The magnitude of Change-P50m increased and the peak latency shortened with an increase in the ITD, similar to those of Change-N1m. These results suggest that change-related cortical activity is present as early as its onset latency at around 50ms. PMID- 23933041 TI - Frontal midline theta oscillations during working memory maintenance and episodic encoding and retrieval. AB - Neural oscillations in the theta band (4-8 Hz) are prominent in the human electroencephalogram (EEG), and many recent electrophysiological studies in animals and humans have implicated scalp-recorded frontal midline theta (FMT) in working memory and episodic memory encoding and retrieval processes. However, the functional significance of theta oscillations in human memory processes remains largely unknown. Here, we review studies in human and animals examining how scalp recorded FMT relates to memory behaviors and also their possible neural generators. We also discuss models of the functional relevance of theta oscillations to memory processes and suggest promising directions for future research. PMID- 23933045 TI - Synthesis, biological evaluation and molecular docking studies of pyrazole derivatives coupling with a thiourea moiety as novel CDKs inhibitors. AB - It was discovered that a number of cyclin dependent kinase inhibitors containing the pyrazole core structure exhibited high inhibitory potency against broad-range CDKs and corresponding anti-proliferative activities. This information guided us to design and synthesize a series of 1,3-diphenyl-N-(phenylcarbamothioyl)-1H pyrazole-4-carboxamide derivatives (5a-10d), and evaluate their biological activities as CDKs inhibitors. Among all the synthesized compounds, compound 10b inhibited CDK2 with an IC50 value of 25 nM, counteracting tumor cell proliferation of three cancer cell lines (H460, MCF-7, A549) in the micromolar range (from 0.75 MUM to 4.21 MUM), In addition, flow cytometry indicated that compound 10b could induce cycle G0/G1 phase arrest in A549 cells with a dose dependent. Taken together, compound 10b could be selected for further preclinical evaluation. PMID- 23933046 TI - Discovery of novel histidine-derived lipo-amino acids: applied in the synthesis of ultra-short antimicrobial peptidomimetics having potent antimicrobial activity, salt resistance and protease stability. AB - Here we report for the first time the synthesis of Histidine (His) derived lipo amino acids having pendant lipid tails at N(tau)- and N(pi)-positions on imidazole group of His and applied it into synthesis of lipo-peptides. The attachment of His-derived lipo-amino acid into the very short inactive cationic peptides endows potent antimicrobial activity against Gram-positive and Gram negative bacteria without hemolytic activity. Furthermore, our designed His derived lipo-peptidomimetics (HDLPs) consisting of two or three residues displayed strong anti-MRSA activity and protease stability as well as retained potent antimicrobial activity under high salt concentration. Our results demonstrate that the novel lipo-amino acid is highly flexible to synthesize and carry out the extensive structure-activity relationship (SAR) on lipo antimicrobial peptidomimetics and represents a unique amenable platform for modifying parameters important for antimicrobial activity. Through this study, we proved that the discovery of His-derived lipo-amino acid and the corresponding HDLPs are an excellent candidate as a lead compound for the development of novel antimicrobial agents. PMID- 23933047 TI - Molecular design and synthesis of HCV inhibitors based on thiazolone scaffold. AB - A series of thiazolone derivatives was designed and synthesized as potential HCV NS5B allosteric polymerase inhibitors at the allosteric site thumb II. Their antiviral activity was evaluated and molecular modeling was utilized to give further envision on their probable binding modes in the allosteric binding site. Among the tested molecules, compound 9b displayed sub-micromolar inhibitory activity with an EC50 of 0.79 MUM indicating excellent potency profile. It also showed good safety profile (CC50>=75 MUM and SI>=94.3). PMID- 23933048 TI - Strong and tough mineralized PLGA nanofibers for tendon-to-bone scaffolds. AB - Engineering complex tissues such as the tendon-to-bone insertion sites require a strong and tough biomimetic material system that incorporates both mineralized and unmineralized tissues with different strengths and stiffnesses. However, increasing strength without degrading toughness is a fundamental challenge in materials science. Here, we demonstrate a promising nanofibrous polymer hydroxyapatite system, in which, a continuous fibrous network must function as a scaffold for both mineralized and unmineralized tissues. It is shown that the high toughness of this material system could be maintained without compromising on the strength with the addition of hydroxyapatite mineral. Individual electrospun poly (lactide-co-glycolide) (PLGA) nanofibers demonstrated outstanding strain-hardening behavior and ductility when stretched uniaxially, even in the presence of surface mineralization. This highly desirable hardening behavior which results in simultaneous nanofiber strengthening and toughening was shown to depend on the initial cross-sectional morphology of the PLGA nanofibers. For pristine PLGA nanofibers, it was shown that ellipsoidal cross-sections provide the largest increase in fiber strength by almost 200% compared to bulk PLGA. This exceptional strength accompanied by 100% elongation was shown to be retained for thin and strongly bonded conformal mineral coatings, which were preserved on the nanofiber surface even for such very large extensions. PMID- 23933049 TI - Protein biomarker validation via proximity ligation assays. AB - The ability to detect minute amounts of specific proteins or protein modifications in blood as biomarkers for a plethora of human pathological conditions holds great promise for future medicine. Despite a large number of plausible candidate protein biomarkers published annually, the translation to clinical use is impeded by factors such as the required size of the initial studies, and limitations of the technologies used. The proximity ligation assay (PLA) is a versatile molecular tool that has the potential to address some obstacles, both in validation of biomarkers previously discovered using other techniques, and for future routine clinical diagnostic needs. The enhanced specificity of PLA extends the opportunities for large-scale, high-performance analyses of proteins. Besides advantages in the form of minimal sample consumption and an extended dynamic range, the PLA technique allows flexible assay reconfiguration. The technology can be adapted for detecting protein complexes, proximity between proteins in extracellular vesicles or in circulating tumor cells, and to address multiple post-translational modifications in the same protein molecule. We discuss herein requirements for biomarker validation, and how PLA may play an increasing role in this regard. We describe some recent developments of the technology, including proximity extension assays, the use of recombinant affinity reagents suitable for use in proximity assays, and the potential for single cell proteomics. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. PMID- 23933050 TI - In vitro and in vivo correlation of disintegration and bitter taste masking using orally disintegrating tablet containing ion exchange resin-drug complex. AB - Although the taste-masking of bitter drug using ion exchange resin has been recognized, in vitro testing using an electronic tongue (e-Tongue) and in vivo bitterness test by human panel test was not fully understood. In case of orally disintegrating tablet (ODT) containing bitter medicine, in vitro and in vivo disintegration is also importance for dosage performance. Donepezil hydrochloride was chosen as a model drug due to its bitterness and requires rapid disintegration for the preparation of ODT. In this study, ion exchange resin drug complex (IRDC) at three different ratios (1:2, 1:1, 2:1) was prepared using a spray-drying method and then IRDC-loaded ODT containing superdisintegrants (crospovidone, croscarmellose sodium, and sodium starch glycolate) were prepared by the direct compression method. The physical properties and morphologies were then characterized by scanning electron microscopy (SEM), X-ray powder diffraction (PXRD) and electrophoretic laser scattering (ELS), respectively. The in vitro taste-masking efficiency was measured with an electronic tongue (e Tongue). In vivo bitterness scale was also evaluated by human volunteers and then we defined new term, "bitterness index (BI)" to link in vitro e-Tongue. There was a good correlation of IRDC between in vitro e-Tongue values and in vivo BI. Furthermore, IRDC-loaded ODT showed good in vitro/in vivo correlation in the disintegration time. The optimal IRDC-loaded ODTs displayed similar drug release profiles to the reference tablet (Aricept((r)) ODT) in release media of pH 1.2, pH 4.0, pH 6.8 and distilled water but had significantly better palatability in vivo taste-masking evaluation. The current IRDC-loaded ODT according to the in vitro and in vivo correlation of disintegration and bitter taste masking could provide platforms in ODT dosage formulations of donepezil hydrochloride for improved patient compliances. PMID- 23933051 TI - Biopharmaceutical profiling of a pyrido[4,3-d] pyrimidine compound library. AB - The pyrido-pyrimidine structure is associated with different biological activities, including kinase inhibition and antibacterial activity. However, drug like properties of this scaffold have not been explored thoroughly. Therefore, the biopharmaceutical profile of ten pyrido[4,3-d]pyrimidines with different substitution pattern was determined at the intestinal and hepatic level. The compounds' biopharmaceutical properties were significantly affected by the substitution pattern, resulting in a broad range in fasted state simulated intestinal fluid solubility values (1.9 MUM-4.2 mM) and Caco-2 permeability coefficients (0.17*10(-6) cm/s to 52*10(-6) cm/s). A phenylhydrazido group was responsible for the low FaSSIF solubility. Caco-2 permeability was impaired by a dimethoxyphenyl substituent. All analogs were metabolically stable in human intestinal microsomes. The hepatic metabolism, reflected by the extraction ratio, was intermediate to high (ER>0.3). Aliphatic chains, methoxy groups on a phenyl substituent, ketone and amine substituents were predicted as most susceptible sites for hepatic metabolism. Correlations were found between polar surface area of the compound and Caco-2 permeability (R=0.86) and metabolic stability (R=0.76). No toxicity was seen for the pyrido[4,3-d]pyrimidines with Caco-2 cells and sandwich-cultured rat hepatocytes. In conclusion, the large diversity of substituents on the pyrido[4,3-d]pyrimidine core highly influenced the compounds' drug-like properties. PMID- 23933052 TI - Yield strength of microcrystalline cellulose: experimental evidence by dielectric spectroscopy. AB - The water-induced ionic charge transport in compacted microcrystalline cellulose (MCC) has been reported to be governed by the densification behaviour. Hence, mechanical properties were expected to correlate with conductivity behaviour of MCC compacts. Both in-die and out-of-die compaction behaviour of MCC powder was investigated using a fully instrumented rotary tablet press. The dielectric measurements were carried out using a Novocontrol Concept 40 broadband dielectric spectrometer and dc conductivity (sigmadc) was extracted from the low frequency conductivity data at room temperature. As postulated, compaction pressure corresponding to maximum conductivity (sigmadc max) was observed to correlate with yield strength of MCC, determined using in-die and out-of-die Heckel analysis. Although Heckel transformation is most commonly used in pharmaceutical technology, its general use to characterise the mechanical properties of organic pharmaceutical materials has been criticized. The present study has provided experimental evidence that Heckel equation is practically useful to describe plastic deformation of organic pharmaceutical powders. PMID- 23933053 TI - Emergency department visits in the United States for upper urinary tract stones: trends in hospitalization and charges. AB - PURPOSE: Using the Nationwide Emergency Department Sample (NEDS) we examined trends in visits, hospitalization and charges for patients with upper urinary tract stones who presented to the emergency department in the United States. MATERIALS AND METHODS: All visits with a primary diagnosis of kidney calculus (ICD-9-CM code 592.0), ureter calculus (592.1) or urinary calculus unspecified (592.9) were extracted from NEDS between 2006 and 2009. A weighted sample was used to calculate incidence rates. Temporal trends were quantified by the estimated annual percent change. Patient and hospital characteristics associated with hospitalization were evaluated using logistic regression models adjusted for clustering. RESULTS: Between 2006 and 2009 there were 3,635,054 emergency department visits for upper urinary tract stones. The incidence increased from 289 to 306/100,000 individuals. More men visited than women but women showed significant increases in visits (estimated annual percent change 2.85%, p = 0.018). Total monthly emergency department visits ranged from 5.8% in February to 8.4% in August. Overall 12.0% of patients were hospitalized and the hospitalization rate remained stable (estimated annual percent change -1.02%, p = 0.634). Patients were more likely to be hospitalized if they were female, more ill, seen at an urban teaching or low volume hospital, or had Medicaid or Medicare (each p <0.001). Sepsis was associated with the highest likelihood of hospital admission (OR 69.64, p <0.001). In 2009 charges for emergency department visits increased to $5 billion (estimated annual percent change 10.06%, p = 0.003). CONCLUSIONS: Women showed significant annual increases in emergency department visits for upper urinary tract stones. While emergency department charges increased substantially, hospitalization rates remained stable. Greater use of computerized tomography and medical expulsive therapy could be the reasons for this observation, which warrants further study. PMID- 23933054 TI - Changes in plasma Brain-derived neurotrophic factor (BDNF) levels induced by methylphenidate in children with Attention deficit-hyperactivity disorder (ADHD). AB - OBJECTIVES: It has been suggested that BDNF may play a role in the pathogenesis of ADHD. Our aim is to determine whether methylphenidate can induce changes in plasma BDNF levels of children with ADHD. METHODS: We assessed levels of plasma BDNF in 28 ADHD patients (age range = 3.5-10 years) before and after 6 weeks treatment with effective dosages of methylphenidate. Then we evaluated the correlation of levels of plasma BDNF with clinical variables, especially ADHD Conner's parents rating scale. RESULTS: According to the paired sample T-test, the mean plasma BDNF level in the baseline was 193.06 pg/ml, whereas 271.06 pg/ml in the end point, thus showing significantly higher mean plasma BDNF levels in the post-treatment situation than in the pretreatment (t = -3.393, df = 27, p = 0.002). Pearson's correlation test revealed that there was also significant negative correlation between levels of BDNF in the plasma of ADHD patients before treatment and improvement in hyperactivity symptoms with treatment (Pearson's correlation = -0.395, p = 0.037). CONCLUSION: The mean plasma BDNF levels increased after 6 weeks of treatment with methylphenidate. Also, we found an improvement in hyperactivity symptoms with decreasing baseline plasma BDNF levels. We recommend that more studies should be conducted in order to assess the possible roles of plasma BDNF levels in treatment response prediction and prognosis. PMID- 23933055 TI - Reproducible paired sources from concurrent EEG-fMRI data using BICAR. AB - We introduce BICAR, an algorithm for obtaining robust, reproducible pairs of temporal and spatial components at the individual subject level from concurrent electroencephalographic and functional magnetic resonance imaging data. BICAR assigns a task-independent measure of component quality, reproducibility, to each paired source. Under BICAR a reproducibility cutoff is derived that can be used to objectively discard spuriously paired EEG-fMRI components. BICAR is run on minimally processed data: fMRI images undergo the standard preprocessing steps (alignment, motion correction, etc.) and EEG data, after scanner artifact removal, are simply bandpass filtered. This minimal processing allows the secondary scoring of the same set of BICAR components for a variety of different endpoint analyses; in this manuscript we propose a general method for scoring components for task event synchronization (evoked response analysis), but scoring using many other criteria, for example frequency content, are possible. BICAR is applied to five subjects performing a visual search task, and among the most reproducible components we find biologically relevant paired sources involved in visual processing, motor planning, execution, and attention. PMID- 23933056 TI - The bacterial membrane insertase YidC is a functional monomer and binds ribosomes in a nascent chain-dependent manner. PMID- 23933057 TI - A shifty chaperone for phage tail assembly. PMID- 23933058 TI - Factor analysis of the "Questionnaire for the evaluation of occupational burnout syndrome" in peruvian medical students. PMID- 23933059 TI - Structural determination of importin alpha in complex with beak and feather disease virus capsid nuclear localization signal. AB - Circoviruses represent a rapidly increasing genus of viruses that infect a variety of vertebrates. Replication requires shuttling viral molecules into the host cell nucleus, a process facilitated by capsid-associated protein (Cap). Whilst a nuclear localization signal (NLS) has been shown to mediate nuclear translocation, the mode of nuclear transport remains to be elucidated. To better understand this process, beak and feather disease virus (BFDV) Cap NLS was crystallized with nuclear import receptor importin-alpha (Impalpha). Diffraction yielded structural data to 2.9A resolution, and the binding site on both Impalpha and BFDV Cap NLS were well resolved. The binding mechanism for the major site is likely conserved across circoviruses as supported by the similarity of NLSs in circovirus Caps. This finding illuminates a crucial step for infection of host cells by this viral family, and provides a platform for rational drug design against the binding interface. PMID- 23933060 TI - Distortion of the CoreValve during transcatheter aortic valve-in-valve implantation due to valve dislocation. AB - Nowadays transcatheter aortic valve implantation (TAVI) is an accepted alternative to surgical aortic valve replacement for high-risk patients (pts). Successful TAVI procedures for failed aortic surgical bioprosthesis (TAV-in-SAV) have already been reported. In the presented two cases of TAV-in-SAV implantation a strut distortion of the stent was revealed on angiographic imaging and confirmed on control CT scan. In both procedures, a dislocation of the medtronic core valve (MCV) prosthesis during implantation led to valve retrieval, with a necessity of reloading it in the 18F introducer before subsequent implantation of the same valve in correct position. PMID- 23933061 TI - Imidacloprid does not induce Cyp genes involved in insecticide resistance of a mutant Drosophila melanogaster line. AB - Certain xenobiotics have the capacity to induce the expression of genes involved in various biological phenomena, including insecticide resistance. The induction potential of different chemicals, among them different insecticides, has been documented for a number of insect species. In this study, we have analyzed the induction potential of Imidacloprid, a widely used member of the neonicotinoid insecticide family. Genes Cyp6g1 and Cyp6a2, known to be involved in the resistance of mutant Drosophila melanogaster line MiT[W-]3R2 to Imidacloprid and DDT were included in the analyzed sample. We find that Imidacloprid does not induce expression of the analyzed genes. PMID- 23933062 TI - Arecoline inhibits and destabilizes agrin-induced acetylcholine receptor cluster formation in C2C12 myotubes. AB - Areca nut (Areca catechu) is chewed as a medical and psychoactive food by roughly 10% of the world population. Areca nut chewing may lead to low birth weight, premature delivery and impaired muscle development. Our previous study showed that arecoline, a major alkaloid in the areca nut, inhibited the myogenic differentiation of C2C12 myoblastic cells. The clustering of acetylcholine receptors (AChRs) in the postsynaptic membrane at the neuromuscular junction (NMJ) by agrin, a signaling protein released by motor neurons, is critical for the development of functional muscles. Here, we further investigate whether arecoline affects the AChR clustering using cultured C2C12 myotubes. Rhodamine conjugated alpha-bungarotoxin was used to detect the presence of AChR clusters. Our results showed that arecoline inhibited the formation of agrin-induced AChR clusters and destabilized agrin-induced or spontaneous AChR cluster formation. In addition, arecoline inhibited the expression of myogenin in C2C12 myotubes. These results shed light on the important role of arecoline on the detrimental effect of areca nut to muscle development. PMID- 23933063 TI - Differential expression of Oct4 variants and pseudogenes in normal urothelium and urothelial cancer. AB - The transcription factor octamer-binding protein 4 (Oct4; encoded by POU5F1) has a key role in maintaining embryonic stem cell pluripotency during early embryonic development and it is required for generation of induced pluripotent stem cells. Controversy exists concerning Oct4 expression in somatic tissues, with reports that Oct4 is expressed in normal and in neoplastic urothelium carrying implications for a bladder cancer stem cell phenotype. Here, we show that the pluripotency-associated Oct4A transcript was absent from cultures of highly regenerative normal human urothelial cells and from low-grade to high-grade urothelial carcinoma cell lines, whereas alternatively spliced variants and transcribed pseudogenes were expressed in abundance. Immunolabeling and immunoblotting studies confirmed the absence of Oct4A in normal and neoplastic urothelial cells and tissues, but indicated the presence of alternative isoforms or potentially translated pseudogenes. The stable forced expression of Oct4A in normal human urothelial cells in vitro profoundly inhibited growth and affected morphology, but protein expression was rapidly down-regulated. Our findings demonstrate that pluripotency-associated isoform Oct4A is not expressed by normal or malignant human urothelium and therefore is unlikely to play a role in a cancer stem cell phenotype. However, our findings also indicate that urothelium expresses a variety of other Oct4 splice-variant isoforms and transcribed pseudogenes that warrant further study. PMID- 23933064 TI - Sphingosine kinase 1 deficiency confers protection against hyperoxia-induced bronchopulmonary dysplasia in a murine model: role of S1P signaling and Nox proteins. AB - Bronchopulmonary dysplasia of the premature newborn is characterized by lung injury, resulting in alveolar simplification and reduced pulmonary function. Exposure of neonatal mice to hyperoxia enhanced sphingosine-1-phosphate (S1P) levels in lung tissues; however, the role of increased S1P in the pathobiological characteristics of bronchopulmonary dysplasia has not been investigated. We hypothesized that an altered S1P signaling axis, in part, is responsible for neonatal lung injury leading to bronchopulmonary dysplasia. To validate this hypothesis, newborn wild-type, sphingosine kinase1(-/-) (Sphk1(-/-)), sphingosine kinase 2(-/-) (Sphk2(-/-)), and S1P lyase(+/-) (Sgpl1(+/-)) mice were exposed to hyperoxia (75%) from postnatal day 1 to 7. Sphk1(-/-), but not Sphk2(-/-) or Sgpl1(+/-), mice offered protection against hyperoxia-induced lung injury, with improved alveolarization and alveolar integrity compared with wild type. Furthermore, SphK1 deficiency attenuated hyperoxia-induced accumulation of IL-6 in bronchoalveolar lavage fluids and NADPH oxidase (NOX) 2 and NOX4 protein expression in lung tissue. In vitro experiments using human lung microvascular endothelial cells showed that exogenous S1P stimulated intracellular reactive oxygen species (ROS) generation, whereas SphK1 siRNA, or inhibitor against SphK1, attenuated hyperoxia-induced S1P generation. Knockdown of NOX2 and NOX4, using specific siRNA, reduced both basal and S1P-induced ROS formation. These results suggest an important role for SphK1-mediated S1P signaling-regulated ROS in the development of hyperoxia-induced lung injury in a murine neonatal model of bronchopulmonary dysplasia. PMID- 23933065 TI - Generation of a dual-functioning antitumor immune response in the peritoneal cavity. AB - Tumor cell metastasis to the peritoneal cavity is observed in patients with tumors of peritoneal organs, particularly colon and ovarian tumors. Following release into the peritoneal cavity, tumor cells rapidly attach to the omentum, a tissue consisting of immune aggregates embedded in adipose tissue. Despite their proximity to potential immune effector cells, tumor cells grow aggressively on these immune aggregates. We hypothesized that activation of the immune aggregates would generate a productive antitumor immune response in the peritoneal cavity. We immunized mice i.p. with lethally irradiated cells of the colon adenocarcinoma line Colon38. Immunization resulted in temporary enlargement of immune aggregates, and after challenge with viable Colon38 cells, we did not detect tumor growth on the omentum. When Colon38-immunized mice were challenged with cells from the unrelated breast adenocarcinoma line E0771 or the melanoma line B16, these tumors also did not grow. The nonspecific response was long-lived and not present systemically, highlighting the uniqueness of the peritoneal cavity. Cellular depletions of immune subsets revealed that NK1.1(+) cells were essential in preventing growth of unrelated tumors, whereas NK1.1(+) cells and T cells were essential in preventing Colon38 tumor growth. Collectively, these data demonstrate that the peritoneal cavity has a unique environment capable of eliciting potent specific and nonspecific antitumor immune responses. PMID- 23933066 TI - Efficiency of twice weekly concurrent training in trained elderly men. AB - This study compared the effects of different weekly training frequencies on the cardiovascular and neuromuscular adaptations induced by concurrent training in previously trained elderly. After 20weeks of combined strength and endurance training, twenty-four healthy elderly men (65+/-4 years) were randomly placed into two frequency training groups: strength and endurance training performed twice a week (SE2, n=12); or, strength and endurance training performed three times per week (SE3, n=12). The interventions lasted 10 weeks and each group performed identical exercise intensity and volume per session. Before and after the exercise training, one maximum repetition test (1RM), isometric peak torque (PT), maximal surface electromyographic activity (EMG), as well as muscle thickness (MT) were examined. Additionally, peak oxygen uptake (VO(2peak)), maximum aerobic workload (W(max)), first and second ventilatory thresholds (VT1 and VT2) were evaluated. There were significant increases in upper and lower-body 1RM, MT, VO(2peak), VT1 and VT2, with no differences between groups. There were no changes after training in maximal EMG and isometric peak torque. W(max) was improved only in SE3. After 10 weeks of training, twice weekly combined strength and endurance training leads to similar neuromuscular and cardiovascular adaptations as three times per week, demonstrating the efficiency of lower frequency of concurrent training in previously trained elderly men. PMID- 23933068 TI - MERS-CoV: the intermediate host identified? PMID- 23933067 TI - Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. AB - BACKGROUND: A new betacoronavirus-Middle East respiratory syndrome coronavirus (MERS-CoV)-has been identified in patients with severe acute respiratory infection. Although related viruses infect bats, molecular clock analyses have been unable to identify direct ancestors of MERS-CoV. Anecdotal exposure histories suggest that patients had been in contact with dromedary camels or goats. We investigated possible animal reservoirs of MERS-CoV by assessing specific serum antibodies in livestock. METHODS: We took sera from animals in the Middle East (Oman) and from elsewhere (Spain, Netherlands, Chile). Cattle (n=80), sheep (n=40), goats (n=40), dromedary camels (n=155), and various other camelid species (n=34) were tested for specific serum IgG by protein microarray using the receptor-binding S1 subunits of spike proteins of MERS-CoV, severe acute respiratory syndrome coronavirus, and human coronavirus OC43. Results were confirmed by virus neutralisation tests for MERS-CoV and bovine coronavirus. FINDINGS: 50 of 50 (100%) sera from Omani camels and 15 of 105 (14%) from Spanish camels had protein-specific antibodies against MERS-CoV spike. Sera from European sheep, goats, cattle, and other camelids had no such antibodies. MERS-CoV neutralising antibody titres varied between 1/320 and 1/2560 for the Omani camel sera and between 1/20 and 1/320 for the Spanish camel sera. There was no evidence for cross-neutralisation by bovine coronavirus antibodies. INTERPRETATION: MERS CoV or a related virus has infected camel populations. Both titres and seroprevalences in sera from different locations in Oman suggest widespread infection. FUNDING: European Union, European Centre For Disease Prevention and Control, Deutsche Forschungsgemeinschaft. PMID- 23933069 TI - Gbx2 functions as a transcriptional repressor to regulate the specification and morphogenesis of the mid-hindbrain junction in a dosage- and stage-dependent manner. AB - The Gbx subfamily of homeodomain transcription factors is involved in the positioning of the isthmus, which patterns the midbrain and cerebellum in vertebrates. To uncover the details of Gbx functions, we first examined the dose dependency of its effects on brain formation in zebrafish and found that high dose gbx2 mRNA injection affected the entire forebrain and midbrain, whereas low dose mRNA specifically disrupted the isthmic folding at the midbrain-hindbrain boundary (MHB) but only weakly affected the expression of genes involved in MHB specification. Thus, isthmus morphogenesis, and not its early specification, is highly sensitive to gbx2. Transient induction of heat-inducible gbx2 using transgenic fish showed that MHB specification is most sensitive to gbx2 at the end of epiboly and further suggested that otx2 is the direct target gene. These together demonstrate that gbx2 regulates both specification and morphogenesis of the MHB/isthmus region. Deletion analyses showed that both the N- and C-terminal regions contribute to the suppressive activity of Gbx2 against the anterior brain and that the N-terminal core region, including the Eh1 and proline-rich sequences, is required for this Gbx2 activity. Comparison of the effects of activated and repressive forms with wild-type Gbx2 suggested that Gbx2 functions as a transcriptional repressor, which was further evidenced by a luciferase assay in which gbx2 repressed the MHB enhancer of fgf8a in mouse P19 cells. PMID- 23933070 TI - A species-to-be? The genetic status and colonization history of the critically endangered Killarney shad. AB - Typically anadromous, the twaite shad (Alosa fallax) can become landlocked and adapt to a fully freshwater life. The only landlocked shad population in Northwestern Europe is found in a lake in Ireland, Lough Leane. The Killarney shad, Alosa killarnensis (or Alosa fallax killarnensis, as it is mostly referred to) displays a level of morphological divergence that indicates a long-term isolation in the lake. Microsatellites and mtDNA control region sequences were used within a coalescent framework (BEAST and Approximate Bayesian Computation (ABC)) to investigate its colonization history and to clarify its taxonomic status. Results indicate that the lake was likely colonized in two independent events, the first coinciding with the retreat of the ice sheet from the area after the Last Glacial Maximum and the second after the Younger Dryas. Microsatellite data has shown that these two landlocked lineages have completely admixed within the lake, and have started diverging significantly from their closest ancestor, the twaite shad. We argue that our molecular results (together with the life-history and physiological divergence between Killarney and twaite shad) are conspicuous enough to view the landlocked population as a new species, and one whose future existence would certainly not be insured by its sister taxon. PMID- 23933071 TI - Phylogeography of Beck's Desert Scorpion, Paruroctonus becki, reveals Pliocene diversification in the Eastern California Shear Zone and postglacial expansion in the Great Basin Desert. AB - The distribution of Beck's Desert Scorpion, Paruroctonus becki (Gertsch and Allred, 1965), spans the 'warm' Mojave Desert and the western portion of the 'cold' Great Basin Desert. We used genetic analyses and species distribution modeling to test whether P. becki persisted in the Great Basin Desert during the Last Glacial Maximum (LGM), or colonized the area as glacial conditions retreated and the climate warmed. Phylogenetic and network analyses of mitochondrial cytochrome c oxidase 1 (cox1), 16S rDNA, and nuclear internal transcribed spacer (ITS-2) DNA sequences uncovered five geographically-structured groups in P. becki with varying degrees of statistical support. Molecular clock estimates and the geographical arrangement of three of the groups suggested that Pliocene geological events in the tectonically dynamic Eastern California Shear Zone may have driven diversification by vicariance. Diversification was estimated to have continued through the Pleistocene, during which a group endemic to the western Great Basin diverged from a related group in the eastern Mojave Desert and western Colorado Plateau. Demographic and network analyses suggested that P. becki underwent a recent expansion in the Great Basin. According to a landscape interpolation of genetic distances, this expansion appears to have occurred from the northwest, implying that P. becki may have persisted in part of the Great Basin during the LGM. This prediction is supported by species distribution models which suggest that climate was unsuitable throughout most of the Great Basin during the LGM, but that small patches of suitable climate may have remained in areas of the Lahontan Trough. PMID- 23933072 TI - Evaluation of a reverse line blot assay for genotyping common human rotaviruses. AB - To allow high-throughput genotyping of group A rotaviruses (RVA) in a routine surveillance setting, we developed a reverse line blotting method for the determination of the most common human RVA G- and P-genotypes: G1-G4, G9, G12, P[4], P[6] and P[8]. Using the reverse line blotting method on 951 clinical RVA positive feces samples, in 905 (95%) of the samples the G-genotyping yielded a result while in 945 (99%) of the samples the P-genotyping was successful. Comparison of the reverse line blotting-method as it is used currently to a sequence based method for genotyping RVAs showed an agreement of 96% for single strain infections (75 out of 78) but only 48% for mixed infections (10 out of 21). The reverse line blotting method is successful in genotyping common RVA strains in surveillance settings. For genotyping of rare strains, the number of probes on the blot can be expanded or a sequence-based method can be performed as a complementary approach on the samples that are positive in the detection PCR but negative in the reverse line blotting genotyping assay. The complete reverse line blotting protocol takes 8h to complete for 36 samples, with 3h hands-on time. In conclusion, a RVA genotyping method that is accurate, cheap and fast is presented. PMID- 23933073 TI - Human defined antigenic region on the nucleoprotein of Crimean-Congo hemorrhagic fever virus identified using truncated proteins and a bioinformatics approach. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne viral zoonosis widely distributed in Africa, Asia and eastern Europe. In this study, amino acid sequence data for the CCHFV nucleoprotein (NP) was used to identify potential linear epitopic regions which were subsequently included in the design of large and small truncated recombinant NP antigens and peptide libraries. Two truncated recombinant CCHFV NP antigens were prepared based on results of prediction studies to include epitopic regions and exclude hydrophobic regions that could influence protein expression and solubility. Serum samples were collected from acute and convalescent patients. An IgG antibody response was detected in 16/16 samples tested using the large recombinant NP-based ELISA and in 2/16 using the small recombinant NP-based ELISA. A total of 60 peptides covering predicted epitopic regions of the NP were synthesized and peptide NRGGDENPRGPVSR at amino acid position 182-195, reacted with 13/16 human serum samples. In summary, functional assays are required to determine the biological activity of predicted epitopes for development of peptide based assays for antibody detection. Bacterially expressed complete NP antigens have previously been shown to be useful tools for antibody detection. Truncation of the antigen to remove the hydrophobic C terminus had no impact on the ability of the antigen to detect IgG antibody in human sera. The results indicate that the region from amino acids 123 to 396 includes a highly antigenic region of the NP with application in development of antibody detection assays. PMID- 23933074 TI - Patterns of polymorphism and divergence in the VP1 gene of enterovirus 71 circulating in the Asia-Pacific region between 1994 and 2013. AB - Enterovirus 71 has been implicated in several outbreaks of hand, foot and mouth disease in the Asia-Pacific region. The present study aimed to achieve comprehensive evolutionary dynamic aspects of EV71 during 1994-2013, based on phylogenetic analyses of the VP1 sequences. The results indicated that 4 genotypes, namely C4, C1, C2 and B4 are the predominant strains, especially in Southeast Asian countries. No common ancestor was shared in different countries. Fourteen sites of substitutions were detected in the VP1 gene sequences; including the most common sites related to neutralization at position V249I [47.1% (189/401)] and A289T [42.6% (171/401)]. However, the sites Q22H and Q22R associated with increased virulence were recognized only in 13.7% (55/401) and 18% (72/401), respectively. None of the above mutations seemed to become fixed because the ratio of Ka/Ks was greater than 1.0. Mutations K43E, A58T, S184T, and T240S could possibly change the spatial structure. Two mutations, G145E and T240S, could obviously affect the hydrophobicity of VP1 and thus alter the EV71 immunoreactivity. In conclusion, the VP1 gene of EV71 strains circulating in the Asia-Pacific region during 1994-2013, showed polymorphisms and divergence with very slow evolution rate, which may be one of the reasons for periodic outbreaks in this area. PMID- 23933075 TI - Display of the VP1 epitope of foot-and-mouth disease virus on bacteriophage T7 and its application in diagnosis. AB - Foot-and-mouth disease (FMD) is a highly contagious epidemic disease threatening the cattle industry since the sixteenth century. In recent years, the development of diagnostic assays for FMD has benefited considerably from the advances of recombinant DNA technology. In this study, the immunodominant region of the capsid protein VP1 of the foot-and-mouth disease virus (FMDV) was fused to the T7 bacteriophage and expressed on the surface of the bacteriophage capsid protein. The recombinant protein of about 42 kDa was detected by the anti-T7 tag monoclonal antibody in Western blot analysis. Phage ELISA showed that both the vaccinated and positive infected bovine sera reacted significantly with the recombinant T7 particle. This study demonstrated the potential of the T7 phage displaying the VP1 epitope as a diagnostic reagent. PMID- 23933076 TI - One-step reverse transcription loop-mediated isothermal amplification for the rapid detection of cucumber green mottle mosaic virus. AB - Cucumber green mottle mosaic virus (CGMMV) has caused serious damage to Cucurbitaceae crops worldwide. The virus is considered one of the most serious Cucurbitaceae quarantine causes in many countries. In this study, a highly efficient and practical one-step reverse transcription loop-mediated isothermal amplification (RT-LAMP) was developed for the detection of CGMMV. The total RNA or crude RNA extracted from watermelon plants or seeds could be detected easily by this RT-LAMP assay. The RT-LAMP assay was conducted in isothermal (63 degrees C) conditions within 1h. The amplified products of CGMMV could be detected as ladder-like bands using agarose gel electrophoresis or visualized in-tube under UV light with the addition of a fluorescent dye. The RT-LAMP amplification was specific to CGMMV, as no cross-reaction was observed with other viruses. The RT LAMP assay was 100-fold more sensitive than that of reverse-transcription polymerase chain reaction (RT-PCR). This is the first report of the application of the RT-LAMP assay to detect CGMMV. The sensitive, specific and rapid RT-LAMP assay developed in this study can be applied widely in laboratories, the field and quarantine surveillance of CGMMV. PMID- 23933077 TI - Improved silencing suppression and enhanced heterologous protein expression are achieved using an engineered viral helper component proteinase. AB - RNA silencing limits transient expression of heterologous proteins in plants. Co expression of viral silencing suppressor proteins can increase and prolong protein expression, but highly efficient silencing suppressors may stress plant tissue and be detrimental to protein yields. Little is known whether silencing suppression could be improved without harm to plant tissues. This study reports development of enhanced silencing suppressors by engineering the helper component proteinase (HCpro) of Potato virus A (PVA). Mutations were introduced to a short region of HCpro (positions 330-335 in PVA HCpro), which is hypervariable among potyviruses. Three out of the four HCpro mutants suppressed RNA silencing more efficiently and sustained expression of co-expressed jellyfish green fluorescent protein for a longer time than wild-type HCpro in agroinfiltrated leaves of Nicotiana benthamiana. Leaf tissues remained healthy-looking without any visible signs of stress. PMID- 23933078 TI - Chimeric adenoviral vector Ad5F35L containing the Ad5 natural long-shaft exhibits efficient gene transfer into human T lymphocytes. AB - Adoptive therapy using T cells modified with tumour antigen-specific T cell receptor (TCR) genes has become a popular area of research in tumour biotherapy research. However, the efficiency of this treatment is low. To increase the efficiency of this therapy, the antigen specific TCR expression in the T cells needs to be improved. Adenoviral vector-mediated gene expression is an attractive approach to bypass the issue of TCR gene modification. The efficiency of adenovirus vector serotype 5 (Ad5) infection is low due to the absence of coxsackievirus B-adenovirus receptor (CAR) expression in T cells. In the present study, a chimeric adenoviral vector (Ad5F35L) was generated; this construct contained both the natural long-shaft of Ad5 and the Ad35 knob. A transduction study showed that the Ad5F35L vector exhibited a higher transduction efficiency in human primary T lymphocytes than the Ad5 vector and the Ad5F35S vector, which contained the Ad35 natural short-shaft and the Ad35 knob. Similar transduction efficiencies were observed for both CD4(+) T lymphocytes and CD8(+) T lymphocytes and the transfection was independent of the expression of cell surface receptors. The activation of T lymphocytes resulted in an improvement of the Ad5F35L transduction efficiency in CD4(+) T cells and a decrease in Ad5F35L transduction efficiency in CD8(+) T cells. The results demonstrate that Ad5F35L is a promising viral vector and will facilitate the clinical application of tumour antigen specific TCR gene therapy. PMID- 23933079 TI - Application of quality control planning methods for the improvement of a quantitative molecular assay. AB - Hepatitis B virus (HBV) DNA measurement has an important role in the diagnosis and management of patients with chronic HBV infection. In cases of chronic hepatitis B, clinical decision is based on either the absolute amount of HBV DNA level, or else the relative change in HBV DNA level. To produce high quality and comparable results, assay performance characteristics must be verified and statistical quality control methods must be planned. In this study, systematic and random error values in an assay of plasma HBV DNA were determined. Performance of the method was examined by employing a normalized operational process specifications (OPSpecs) chart. The systematic error at low and high control levels were 0.33 and 0.22 log(IU/mL) respectively. At both levels, the standard deviations (SD) of the assay were 0.17 log(IU/mL). In addition, a single rule of 12.5SD with 2 control measurements was selected as a candidate quality control method. The assay performed well and was acceptable for clinical use. Further improvement may be attained by switching to automated purification methods. In this study, the well-established discipline of statistical quality control was applied to a real-time quantitative PCR. It was concluded that by employing statistical quality control (QC) methods, which utilize long-term controls, critical changes in the measurement system could be detected. PMID- 23933080 TI - Quantitative RT-PCR for titration of replication-defective recombinant Semliki Forest virus. AB - Virus titration may constitute a drawback in the development and use of replication-defective viral vectors like Semliki Forest virus (SFV). The standardization and validation of a reverse transcription quantitative PCR (qRT PCR) method for SFV titration is presented here. The qRT-PCR target is located within the nsp1 gene of the non-structural polyprotein SFV region (SFV RNA), which allows the strategy to be used for several different recombinant SFV constructs. Titer determinations were carried out by performing virus titration and infection assays with SFVs containing an RNA coding region for the rabies virus glycoprotein (RVGP) or green fluorescent protein (GFP). Results showed that the standardized qRT-PCR is applicable for different SFV constructs, and showed good reproducibility. To evaluate the correlation between the amount of functional SFV RNA in a virus lot and its infectivity in BHK-21 cell cultures, a temperature mediated titer decrease was performed and successfully quantitated by qRT-PCR. When used for cell infection at the same multiplicity of infection (MOI), the temperature treated SFV-RVGP samples induced the same levels of RVGP expression. Similarly, when different SFV-GFP lots with different virus titers, as accessed by qRT-PCR, were used for cell infection at the same MOI, the cultures showed comparable amounts of fluorescent cells. The data demonstrate a good correlation between the amount of virus used for infection, as measured by its SFV RNA, and the protein synthesis in the cells. In conclusion, the qRT-PCR method developed here is accurate and enables the titration of replication defective SFV vectors, an essential aid for viral vector development as well as for establishment of production bioprocesses. PMID- 23933081 TI - Radiocesium concentrations in epigeic earthworms at various distances from the Fukushima Nuclear Power Plant 6 months after the 2011 accident. AB - We investigated the concentrations of radiocesium in epigeic earthworms, litter, and soil samples collected from forests in Fukushima Prefecture 6 months after the Fukushima Dai-ichi Nuclear Power Plant accident in 2011. Radiocesium concentrations in litter accumulated on the forest floor were higher than those in the soil (0-5 cm depth). The highest average (134+137)Cs concentrations in earthworms (approximately 19 Bq g(-1) of wet weight with gut contents and 108 Bq g(-1) of dry weight without gut contents) were recorded from a plot that experienced an air dose rate of 3.1 MUSv h(-1), and earthworm concentrations were found to increase with litter and/or soil concentrations. Average (134)Cs and (137)Cs concentrations (with or without gut contents) were intermediate between accumulated litter and soil. Different species in the same ecological groups on the same plots had similar concentrations because of their use of the same habitats or their similar physiological characteristics. The contribution of global fallout (137)Cs to earthworms with gut contents was calculated to be very low, and most (137)Cs in earthworms was derived from the Fukushima accident. Transfer factors from accumulated litter to earthworms, based on their dry weights, ranged from 0.21 to 0.35, in agreement with previous field studies. PMID- 23933082 TI - Inoculation with arbuscular mycorrhizae does not improve 137Cs uptake in crops grown in the Chernobyl region. AB - Methods for cleaning up radioactive contaminated soils are urgently needed. In this study we investigated whether the use of arbuscular mycorrhizal (AM) fungi can improve (137)Cs uptake by crops. Barley, cucumber, perennial ryegrass, and sunflower were inoculated with AM fungi and grown in low-level radionuclide contaminated soils in a field experiment 70 km southwest of Chernobyl, Ukraine, during two successive years (2009-2010). Roots of barley, cucumber and sunflower plants were slightly or moderately infected with AM fungus and root infection frequency was negatively or non-correlated with (137)Cs uptake by plants. Roots of ryegrass were moderately infected with AM fungus and infection frequency was moderately correlated with (137)Cs uptake by ryegrass. The application of AM fungi to soil in situ did not enhance radionuclide plant uptake or biomass. The responsiveness of host plants and AM fungus combination to (137)Cs uptake varied depending on the soil, although mycorrhization of soil in the field was conditional and did not facilitate the uptake of radiocesium. The total amount of (137)Cs uptake by plants growing on inoculated soil was equal to amounts in plant cultivated on non-inoculated soil. Thus, the use of AM fungi in situ for bioremediation of soil contaminated with a low concentration of (137)Cs could not be recommended. PMID- 23933083 TI - Dating of sediment record at two contrasting sites of the Seine River using radioactivity data and hydrological time series. AB - Sediment cores were collected at the outlet of the highly anthropogenized catchment of the Seine River at two contrasting sites: a flood plain of the lower Seine River and a quasi-permanently submerged harbour basin (or wet dock) in the upper tidal estuary. Analyses of artificial radionuclides ((137)Cs and plutonium isotopes), coupled with hydrological and bathymetric data, lead to a precise dating of the sediment cores collected at the two sites. (137)Cs signals originating from global fallout (early 1960s) and from the Chernobyl accident (1986) are identified, but at different levels due to the incomplete nature or variable continuity of the records. Anomalous (238)Pu concentrations found at both sites (1-2 Bq kg(-1)) are attributed to unknown industrial releases originating from upstream. Interpolating (137)Cs sediment activities under the assumption of a constant sediment rate, those releases were dated back to 1975 +/ 1, thus providing a local but reliable time-marker. Age models have highlighted a very contrasting sediment filling dynamics in these two sites. This study presents the first sediment record of alpha- and gamma-emitting artificial radionuclides obtained at the outlet of the huge catchment area of the River Seine, over a period covering the last 50 years. PMID- 23933084 TI - A high spatial resolution outdoor dose rate map of the Rio de Janeiro city, Brasil, risk assessment and urbanization effects. AB - Geophysical surveys have been widely used for geological mapping, and with appropriate ground calibration the database can be converted to radiometric surveys. Herein we present a case study of a high resolution map of the City of Rio de Janeiro, Brazil, constructed by integrating aerial and in situ (ground) measurements. This allowed assessing the influence of urbanization observed between 1978 and 2009 on radiation external exposure. Radiometric, geological and demographics databases were integrated in a Geographic Information System (GIS) facility. The average absorbed dose rate recorded for the city was 96 +/- 0.3 nGy h(-1) and ranged from 22 to 152 nGy h(-1) among districts. The corresponding annual effective dose was determined as 0.09 +/- 0.01 mSv. The number of people at risk per year according to the estimated natural radiation levels was 17 +/- 1.4, among the 28,000 new cases estimated by the INCA (Brazilian National Cancer Institute) within a population of approximately 6.3 million people. PMID- 23933085 TI - Detection of radioxenon in Darwin, Australia following the Fukushima Dai-ichi nuclear power plant accident. AB - A series of (133)Xe detections in April 2011 made at the Comprehensive Nuclear Test-Ban Treaty Organisation (CTBTO) International Monitoring System noble gas station in Darwin, Australia, were analysed to determine the most likely source location. Forward and backwards atmospheric transport modelling simulations using FLEXPART were conducted. It was shown that the most likely source location was the Fukushima Dai-ichi nuclear power plant accident. Other potential sources in the southern hemisphere were analysed, including the Australian Nuclear Science and Technology Organisation (ANSTO) radiopharmaceutical facility, but it was shown that sources originating from these locations were highly unlikely to be the source of the observed (133)Xe Darwin detections. PMID- 23933086 TI - Highlights in basic autonomic neurosciences: Is an increase in sympathetic nerve activity involved in the development and maintenance of hypertension? AB - The 21st century has brought renewed energy to the field of neural control of the cardiovascular system with interest in assessing directly the role of sympathetic nerve activity (SNA) in initiating and/or maintaining an elevated level of arterial pressure in animal models of cardiovascular disease and in human subjects. Below is a review of some recent studies that use continuous nerve recordings of SNA to look at the time course of changes in activity as hypertension develops. These studies have advanced our understanding of the role of SNA in hypertension, but they also leave us wanting to know more. PMID- 23933088 TI - Myf5-positive satellite cells contribute to Pax7-dependent long-term maintenance of adult muscle stem cells. AB - Skeletal muscle contains Pax7-expressing muscle stem or satellite cells, enabling muscle regeneration throughout most of adult life. Here, we demonstrate that induced inactivation of Pax7 in Pax7-expressing cells of adult mice leads to loss of muscle stem cells and reduced heterochromatin condensation in rare surviving satellite cells. Inactivation of Pax7 in Myf5-expressing cells revealed that the majority of adult muscle stem cells originate from myogenic lineages, which express the myogenic regulators Myf5 or MyoD. Likewise, the majority of muscle stem cells are replenished from Myf5-expressing myogenic cells during adult life, and inactivation of Pax7 in Myf5-expressing cells after muscle damage leads to a complete arrest of muscle regeneration. Finally, we demonstrate that a relatively small number of muscle stem cells are sufficient for efficient repair of skeletal muscles. We conclude that Pax7 acts at different levels in a nonhierarchical regulatory network controlling muscle-satellite-cell-mediated muscle regeneration. PMID- 23933087 TI - The BAF complex interacts with Pax6 in adult neural progenitors to establish a neurogenic cross-regulatory transcriptional network. AB - Numerous transcriptional regulators of neurogenesis have been identified in the developing and adult brain, but how neurogenic fate is programmed at the epigenetic level remains poorly defined. Here, we report that the transcription factor Pax6 directly interacts with the Brg1-containing BAF complex in adult neural progenitors. Deletion of either Brg1 or Pax6 in the subependymal zone (SEZ) causes the progeny of adult neural stem cells to convert to the ependymal lineage within the SEZ while migrating neuroblasts convert to different glial lineages en route to or in the olfactory bulb (OB). Genome-wide analyses reveal that the majority of genes downregulated in the Brg1 null SEZ and OB contain Pax6 binding sites and are also downregulated in Pax6 null SEZ and OB. Downstream of the Pax6-BAF complex, we find that Sox11, Nfib, and Pou3f4 form a transcriptional cross-regulatory network that drives neurogenesis and can convert postnatal glia into neurons. Taken together, elements of our work identify a tripartite effector network activated by Pax6-BAF that programs neuronal fate. PMID- 23933089 TI - Cognitive bias in action: evidence for a reciprocal relation between confirmation bias and fear in children. AB - BACKGROUND AND OBJECTIVES: Some cognitive models propose that information processing biases and fear are reciprocally related. This idea has never been formally tested. Therefore, this study investigated the existence of a vicious circle by which confirmation bias and fear exacerbate each other. METHODS: One hundred-and-seventy-one school children (8-13 years) were first provided with threatening, ambiguous, or positive information about an unknown animal. Then they completed a computerized information search task during which they could collect additional (negative, positive, or neutral) information about the novel animal. Because fear levels were repeatedly assessed during the task, it was possible to examine the reciprocal relationship between confirmation bias and fear. RESULTS: A reciprocal relation of mutual reinforcement was found between confirmation bias and fear over the course of the experiment: increases in fear predicted subsequent increases in the search for negative information, and increases in the search for negative information further enhanced fear on a later point-in-time. In addition, the initial information given about the animals successfully induced diverging fear levels in the children, and determined their first inclination to search for additional information. LIMITATIONS: As this study employed a community sample of primary school children, future research should test whether these results can be generalized to clinically anxious youth. CONCLUSIONS: These findings provide first support for the notion that fearful individuals may become trapped in a vicious circle in which fear and a fear related confirmation bias mutually strengthen each other, thereby maintaining the anxiety pathology. PMID- 23933090 TI - Finger creases lend a hand in Kabuki syndrome. AB - Kabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS. PMID- 23933091 TI - Physiological and pathological significance of human telomerase reverse transcriptase splice variants. AB - Human telomerase reverse transcriptase (hTERT) is tightly regulated at various transcriptional and post-transcriptional levels. Alternative splicing of hTERT has been shown in many human tissues and cell lines regardless of telomerase status and may play a role in regulation of telomerase activity and other cellular functions. Catalytically inactive splice variants make up a substantial proportion of total hTERT mRNA and are at least partly translated into protein. Shifts in splicing patterns occur in development, tumorigenesis and in response to exogenous stimuli in a tissue- and cell type-specific manner. This review focuses on prevalence, patterns and regulation of hTERT alternative splicing, describes associations with telomerase activity and telomere length, and discusses the potential significance of hTERT alternative splice variants in cancer as well as possible telomere-independent functions. PMID- 23933092 TI - Peroxisomal metabolism and oxidative stress. AB - Peroxisomes are ubiquitous and multifunctional organelles that are primarily known for their role in cellular lipid metabolism. As many peroxisomal enzymes catalyze redox reactions as part of their normal function, these organelles are also increasingly recognized as potential regulators of oxidative stress-related signaling pathways. This in turn suggests that peroxisome dysfunction is not only associated with rare inborn errors of peroxisomal metabolism, but also with more common age-related diseases such as neurodegeneration, type 2 diabetes, and cancer. This review intends to provide a comprehensive picture of the complex role of mammalian peroxisomes in cellular redox metabolism. We highlight how peroxisomal metabolism may contribute to the bioavailability of important mediators of oxidative stress, with particular emphasis on reactive oxygen species. In addition, we review the biological properties of peroxisome-derived signaling messengers and discuss how these molecules may mediate various biological responses. Furthermore, we explore the emerging concepts that peroxisomes and mitochondria share an intricate redox-sensitive relationship and cooperate in cell fate decisions. This is particularly relevant to the observed demise of peroxisome function which accompanies cellular senescence, organismal aging, and age-related diseases. PMID- 23933093 TI - Is the taste of fat regulated? AB - Over the last decade, converging data have been accumulated both in rodents and humans, supporting the existence of a sixth taste modality devoted to the perception of dietary lipids. It is well known that the sense of taste is determinant for the food choice and that the overconsumption of highly palatable energy-dense foods contributes to the current obesity epidemic. Thus, an important issue in terms of Public Health is to understand the mechanisms by which the oro-sensory perception of fat is regulated. An overview of our current knowledge in this field of investigations is proposed in this mini-review. PMID- 23933094 TI - New steroidal 17beta-carboxy derivatives present anti-5alpha-reductase activity and anti-proliferative effects in a human androgen-responsive prostate cancer cell line. AB - The androgens testosterone (T) and dihydrotestosterone (DHT), besides playing an important role in prostate development and growth, are also responsible for the development and progression of benign prostate hyperplasia (BPH) and prostate cancer. Therefore, the actions of these hormones can be antagonized by preventing the irreversible conversion of T into DHT by inhibiting 5alpha-reductase (5alpha R). This has been a useful therapeutic approach for the referred diseases and can be achieved by using 5alpha-reductase inhibitors (RIs). Steroidal RIs, finasteride and dutasteride, are used in clinic for BPH treatment and were also proposed for chemoprevention of prostate cancer. Nevertheless, due to the increase in bone and muscle loss, impotency and occurrence of high-grade prostate tumours, it is important to seek for other potent and specific molecules with lower side effects. In the present work, we designed and synthesized steroids with the 3-keto-Delta(4) moiety in the A-ring, as in the 5alpha-R substrate T, and with carboxamide, carboxyester or carboxylic acid functions at the C-17beta position. The inhibitory 5alpha-R activity, in human prostate microsomes, as well as the anti-proliferative effects of the most potent compounds, in a human androgen-responsive prostate cancer cell line (LNCaP cells), were investigated. Our results showed that steroids 3, 4 and 5 are good RIs, which suggest that C 17beta lipophylic amides favour 5alpha-R inhibition. Moreover, these steroids induce a decrease in cell viability of stimulated LNCaP cells, in a 5alpha-R dependent-manner, similarly to finasteride. PMID- 23933095 TI - Sesamol induces apoptosis in human platelets via reactive oxygen species-mediated mitochondrial damage. AB - Platelets play an indispensable role in human health and disease. Platelets are very sensitive to oxidative stress, as it leads to the damage of mitochondrial DNA, which is the initial step of a sequence of events culminating in the cell death through the intrinsic pathway of apoptosis. Owing to a lot of reports on secondary complications arising from oxidative stress caused by therapeutic drug overdose, the present study concentrated on the influence of sesamol on oxidative stress-induced platelet apoptosis. Sesamol, a phenolic derivative present in sesame seeds is an exceptionally promising drug with lots of reports on its protective functions, including its inhibitory effects on platelet aggregation at concentrations below 100 MUM, and its anti-cancer effect at 1 mM. However, the present study explored the toxic effects of sesamol on human platelets. Sesamol at the concentration of 0.25 mM and above induced platelet apoptosis through endogenous generation of ROS, depletion of thiol pool, and Ca(2+) mobilization. It also induced mitochondrial membrane potential depolarization, caspase activation, cytochrome c translocation and phosphatidylserine exposure, thus illustrating the pro-apoptotic effect of sesamol at higher concentration. However, even at high concentration of 2 mM sesamol effectively inhibited collagen/ADP/epinephrine-induced platelet aggregation. The study demonstrates that even though sesamol inhibits platelet aggregation, it has the tendency to elicit platelet apoptosis at higher concentrations. Sesamol has a potential as thrombolytic agent, nevertheless the current work highlights the significance of an appropriate dosage of sesamol when it is used as a therapeutic drug. PMID- 23933096 TI - Ceramide and the mitochondrial respiratory chain. AB - Ceramide is a group of sphingolipids found in cell membranes, composed of a sphingoid base linked to a fatty acid of varying chain length. Initially regarded as purely structural components, this group of molecules is now recognized as a key signaling and regulatory elements in cell biology. Ceramide species differing in acyl chain length, with distinct biophysical properties, execute distinct functions and effects. Some of these modulate mitochondrial function and oxidative phosphorylation (OXPHOS). Certain ceramides were associated with decreased mitochondrial respiratory chain (MRC) activity, increased reactive oxygen species (ROS) production and oxidative stress, mitochondrial outer membrane permeabilization (MOMP), reduced mitochondrial membrane potential, mitophagy and apoptosis. In this review we aim to summarize the most relevant findings linking ceramide to mitochondria. The physiological significance of synthetic short and naturally occurring long chain ceramides in modulating mitochondrial function with emphasis on the MRC will be discussed. PMID- 23933097 TI - Involvement of cocaine- and amphetamine-regulated transcript peptide in the hyperphagic and body weight promoting effects of allopregnanolone in rats. AB - Allopregnanolone (ALLO), a gamma-aminobutyric acid (GABA) type A receptor active neurosteroid, elicits hyperphagic response in rodents. Since GABA-A receptors are present on the peptidergic neurons in the hypothalamus, we were interested in finding out if ALLO and neuropeptide cocaine- and amphetamine-regulated transcript (CART) interact and influence feeding behavior. While subcutaneous ALLO treatment, for a period of 7 days, produced a significant increase in food intake and body weight, pretreatment with subthreshold dose of CART (intracerebroventricular) attenuated both the effects. On the other hand, subcutaneous administration of dehydroepiandrosterone sulfate (DHEAS; GABA-A inhibitor neurosteroid) for a period of 7 days resulted in a significant reduction in food intake and body weight. These effects of DHEAS were potentiated by intracerebroventricular pretreatment with subeffective dose of CART. The brains of ALLO-treated rats were processed for the immunohistochemical analysis of CART immunoreactive elements. ALLO treatment resulted in a significant reduction in CART immunoreactivity in the hypothalamic arcuate, paraventricular and lateral nuclei, and nucleus accumbens shell. The results of the present study suggest that ALLO and CART might interact in the brain, and influence food intake and body weight. However, further investigations are needed to clarify the precise mechanisms by which ALLO modulate feeding behavior. PMID- 23933098 TI - Representation of frequency-modulated sounds in the human brain. AB - Frequency-modulation is a ubiquitous sound feature present in communicative sounds of various animal species and humans. Functional imaging of the human auditory system has seen remarkable advances in the last two decades and studies pertaining to frequency-modulation have centered around two major questions: a) are there dedicated feature-detectors encoding frequency-modulation in the brain and b) is there concurrent representation with amplitude-modulation, another temporal sound feature? In this review, we first describe how these two questions are motivated by psychophysical studies and neurophysiology in animal models. We then review how human non-invasive neuroimaging studies have furthered our understanding of the representation of frequency-modulated sounds in the brain. Finally, we conclude with some suggestions on how human neuroimaging could be used in future studies to address currently still open questions on this fundamental sound feature. This article is part of a Special Issue entitled Human Auditory Neuroimaging. PMID- 23933099 TI - Simvastatin rises reactive oxygen species levels and induces senescence in human melanoma cells by activation of p53/p21 pathway. AB - Recent studies demonstrated that simvastatin has antitumor properties in several types of cancer cells, mainly by inducing apoptosis and inhibiting growth. The arrest of proliferation is a feature of cellular senescence; however, the occurrence of senescence in melanoma cells upon simvastatin treatment has not been investigated until now. Our results demonstrated that exposure of human metastatic melanoma cells (WM9) to simvastatin induces a senescent phenotype, characterized by G1 arrest, positive staining for senescence-associated beta galactosidase assay, and morphological changes. Also, the main pathways leading to cell senescence were examined in simvastatin-treated human melanoma cells, and the expression levels of phospho-p53 and p21 were upregulated by simvastatin, suggesting that cell cycle regulators and DNA damage pathways are involved in the onset of senescence. Since simvastatin can act as a pro-oxidant agent, and oxidative stress may be related to senescence, we measured the intracellular ROS levels in WM9 cells upon simvastatin treatment. Interestingly, we found an increased amount of intracellular ROS in these cells, which was accompanied by elevated expression of catalase and peroxiredoxin-1. Collectively, our results demonstrated that simvastatin can induce senescence in human melanoma cells by activation of p53/p21 pathway, and that oxidative stress may be related to this process. PMID- 23933100 TI - Characterization of polyethylene wear particle: The impact of methodology. AB - Due to the prevalence of problems caused by wear particles, the reduced durability of total joint replacements is well documented. The characterization of wear debris enables the size and morphology of these wear particles to be measured and provides an assessment of the biological response in vivo. However, the impact of different methodologies of particle analysis is not yet clear. Hence, the aim of this investigation was to analyze the influence of different particle characterization methods performed by three research centers within the scope of a "round robin test". To obtain knowledge about possible pitfalls, single steps of the particle characterization process (storage, pore size of the filter, coating durations by gold sputtering and scanning electron microscopy (SEM) magnification) were analyzed. The round robin test showed significant differences between the research groups, especially for the morphology of the particles. The SEM magnification was identified as having the greatest influence on the size and shape of the particles, followed by the storage conditions of the wear particle containing lubricant. Gold sputter coating and filter pore size also exhibit significant effects. However, even though they are statistically significant, it should be emphasized that the differences are small. In conclusion, particle characterization is a complex analytical method with a multiplicity of influencing factors. It becomes apparent that a comparison of wear particle results between different research groups is challenging. PMID- 23933101 TI - Combining self-assembling peptide gels with three-dimensional elastomer scaffolds. AB - Some of the problems raised by the combination of porous scaffolds and self assembling peptide (SAP) gels as constructs for tissue engineering applications are addressed for the first time. Scaffolds of poly(ethyl acrylate) and the SAP gel RAD16-I were employed. The in situ gelation of the SAP gel inside the pores of the scaffolds was studied. The scaffold-cum-gel constructs were characterized morphologically, physicochemically and mechanically. The possibility of incorporating an active molecule (bovine serum albumin, taken here as a model molecule for others) in the gel within the scaffold's pores was assessed, and the kinetics of its release in phosphate-buffered saline was followed. Cell seeding and colonization of these constructs were preliminarily studied with L929 fibroblasts and subsequently checked with sheep adipose-tissue-derived stem cells intended for further preclinical studies. Static (conventional) and dynamically assisted seedings were compared for bare scaffolds and the scaffold-cum-gel constructs. The SAP gel inside the pores of the scaffold significantly improved the uniformity and density of cell colonization of the three-dimensional (3-D) structure. These constructs could be of use in different advanced tissue engineering applications, where, apart from a cell-friendly extracellular matrix like aqueous environment, a larger-scale 3-D structure able to keep the cells in a specific place, give mechanical support and/or conduct spatially the tissue growth could be required. PMID- 23933103 TI - Diameter-selective dispersion of carbon nanotubes by beta-lactoglobulin whey protein. AB - The beta-lactoglobulin (beta-LG) protein was discovered to be an efficient and selective dispersant for carbon nanotubes (CTNs) with certain diameters. A dispersion process of CTNs by the beta-LG was studied, focusing on the relationships between the surface curvature of the CNT and the beta-LG's efficiency in dispersing them, using cryogenic-transmission electron microscopy (cryo-TEM) and optical spectroscopy. Plausible binding sites of the beta-LG, responsible for the interaction of the protein with CNTs of various diameters (surface curvatures) were also investigated and were found to be in good agreement with corresponding docking calculations. PMID- 23933104 TI - Analysis and classification of collective behavior using generative modeling and nonlinear manifold learning. AB - In this paper, we build a framework for the analysis and classification of collective behavior using methods from generative modeling and nonlinear manifold learning. We represent an animal group with a set of finite-sized particles and vary known features of the group structure and motion via a class of generative models to position each particle on a two-dimensional plane. Particle positions are then mapped onto training images that are processed to emphasize the features of interest and match attainable far-field videos of real animal groups. The training images serve as templates of recognizable patterns of collective behavior and are compactly represented in a low-dimensional space called embedding manifold. Two mappings from the manifold are derived: the manifold-to image mapping serves to reconstruct new and unseen images of the group and the manifold-to-feature mapping allows frame-by-frame classification of raw video. We validate the combined framework on datasets of growing level of complexity. Specifically, we classify artificial images from the generative model, interacting self-propelled particle model, and raw overhead videos of schooling fish obtained from the literature. PMID- 23933102 TI - Sculpting the blank slate: how fibrin's support of vascularization can inspire biomaterial design. AB - Fibrin is the primary extracellular constituent of blood clots, and plays an important role as a provisional matrix during wound healing and tissue remodeling. Fibrin-based biomaterials have proven their utility as hemostatic therapies, scaffolds for tissue engineering, vehicles for controlled release, and platforms for culturing and studying cells in three dimensions. Nevertheless, fibrin presents a complex milieu of signals to embedded cells, many of which are not well understood. Synthetic extracellular matrices (ECMs) provide a blank slate that can ostensibly be populated with specific bioactive cues, including growth factors, growth factor binding motifs, adhesive peptides and peptide crosslinks susceptible to proteases, thereby enabling a degree of customization for specific applications. However, the continued evolution and improvement of synthetic ECMs requires parallel efforts to deconstruct native ECMs and decipher the cues they provide to constituent cells. The objective of this review is to reintroduce fibrin, a protein with a well-characterized structure and biochemistry, and its ability to support angiogenesis specifically. Although fibrin's structure-function relationships have been studied for decades, opportunities to engineer new and improved synthetic hydrogels can be realized by further exploiting fibrin's inspiring design. PMID- 23933105 TI - Linear regression model of short k-word: a similarity distance suitable for biological sequences with various lengths. AB - Originating from sequences' length difference, both k-word based methods and graphical representation approaches have uncovered biological information in their distinct ways. However, it is less likely that the mechanisms of information storage vary with sequences' length. A similarity distance suitable for sequences with various lengths will be much near to the mechanisms of information storage. In this paper, new sub-sequences of k-word were extracted from biological sequences under a one-to-one mapping. The new sub-sequences were evaluated by a linear regression model. Moreover, a new distance was defined on the invariants from the linear regression model. With comparison to other alignment-free distances, the results of four experiments demonstrated that our similarity distance was more efficient. PMID- 23933106 TI - Uroflowmetry in the management of lower urinary tract symptoms of children and adolescents with cerebral palsy. AB - OBJECTIVE: To evaluate uroflow measurements in the initial management of lower urinary tract dysfunction in children and adolescents with cerebral palsy. MATERIALS AND METHODS: A total of 54 patients was enrolled in this study. All patients reported their urinary symptoms and underwent a physical examination, renal and urinary tract ultrasonography, and uroflow assessment. RESULTS: Twenty three patients were female. Mean age was 9 years and 6 months (SD: 2 years and 10 months), with a range of 5-18 years. Twenty-eight of the patients (51.8%) were symptomatic. Urgency (42.6%), urge incontinence (40.7%), and enuresis (16.7%) were the most frequently observed symptoms. No association was found between gender, ambulatory status, or distribution of the paralysis and uroflow parameters. Symptomatic patients presented a statistically lower maximum flow (Qmax) than asymptomatic patients (17.2 +/- 7.8 ml/s vs 22.6 +/- 7.5 ml/s, p = 0.013, respectively). Normal bell-shaped curves were observed more frequently in asymptomatic patients, while abnormal curves were observed more frequently in symptomatic patients (p = 0.022). CONCLUSIONS: Gender, ambulatory status, and the distribution of the paralysis do not affect Qmax rate or flow pattern. Symptomatic patients present lower Qmax and may also have an abnormal uroflow curve. Uroflowmetry may be useful in the initial urological evaluation. PMID- 23933107 TI - Attentional bias and emotional reactivity as predictors and moderators of behavioral treatment for social phobia. AB - Cognitive behavioral therapy (CBT) is a well-established treatment for anxiety disorders, and evidence is accruing for the effectiveness of acceptance and commitment therapy (ACT). Little is known about factors that relate to treatment outcome overall (predictors), or who will thrive in each treatment (moderators). The goal of the current project was to test attentional bias and negative emotional reactivity as moderators and predictors of treatment outcome in a randomized controlled trial comparing CBT and ACT for social phobia. Forty-six patients received 12 sessions of CBT or ACT and were assessed for self-reported and clinician-rated symptoms at baseline, post treatment, 6, and 12 months. Attentional bias significantly moderated the relationship between treatment group and outcome with patients slow to disengage from threatening stimuli showing greater clinician-rated symptom reduction in CBT than in ACT. Negative emotional reactivity, but not positive emotional reactivity, was a significant overall predictor with patients high in negative emotional reactivity showing the greatest self-reported symptom reduction. PMID- 23933108 TI - Integrated Behavior Therapy for Selective Mutism: a randomized controlled pilot study. AB - OBJECTIVE: To evaluate the feasibility, acceptability, and preliminary efficacy of a novel behavioral intervention for reducing symptoms of selective mutism and increasing functional speech. METHOD: A total of 21 children ages 4 to 8 with primary selective mutism were randomized to 24 weeks of Integrated Behavior Therapy for Selective Mutism (IBTSM) or a 12-week Waitlist control. Clinical outcomes were assessed using blind independent evaluators, parent-, and teacher report, and an objective behavioral measure. Treatment recipients completed a three-month follow-up to assess durability of treatment gains. RESULTS: Data indicated increased functional speaking behavior post-treatment as rated by parents and teachers, with a high rate of treatment responders as rated by blind independent evaluators (75%). Conversely, children in the Waitlist comparison group did not experience significant improvements in speaking behaviors. Children who received IBTSM also demonstrated significant improvements in number of words spoken at school compared to baseline, however, significant group differences did not emerge. Treatment recipients also experienced significant reductions in social anxiety per parent, but not teacher, report. Clinical gains were maintained over 3 month follow-up. CONCLUSION: IBTSM appears to be a promising new intervention that is efficacious in increasing functional speaking behaviors, feasible, and acceptable to parents and teachers. PMID- 23933109 TI - Tumor extracellular acidity-activated nanoparticles as drug delivery systems for enhanced cancer therapy. AB - pH-responsive nanoparticles (NPs) are currently under intense development as drug delivery systems for cancer therapy. Among various pH-responsiveness, NPs that are designed to target slightly acidic extracellular pH environment (pHe) of solid tumors provide a new paradigm of tumor targeted drug delivery. Compared to conventional specific surface targeting approaches, the pHe-targeting strategy is considered to be more general due to the common occurrence of acidic microenvironment in solid tumors. This review mainly focuses on the design and applications of pHe-activated NPs, with special emphasis on pHe-activated surface charge reversal NPs, for drug and siRNA delivery to tumors. The novel development of NPs described here offers great potential for achieving better therapeutic effects in cancer treatment. PMID- 23933110 TI - Luteolin 8-C-beta-fucopyranoside inhibits invasion and suppresses TPA-induced MMP 9 and IL-8 via ERK/AP-1 and ERK/NF-kappaB signaling in MCF-7 breast cancer cells. AB - Matrix metalloproteinase 9 (MMP-9) and interleukin-8 (IL-8) play major roles in tumor progression and invasion of breast cancer cells. The present study was undertaken to investigate the inhibitory mechanism of cell invasion by luteolin 8 C-beta-fucopyranoside (named as LU8C-FP), a C-glycosylflavone, in human breast cancer cells. We investigated whether LU8C-FP would inhibit MMP-9 activation and IL-8 expression in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated MCF-7 breast cancer cells. LU8C-FP suppressed TPA-induced MMP-9 and IL-8 secretion and mRNA expression via inhibition of the MAPK signaling pathway and down-regulation of nuclear AP-1 and NF-kappaB. TPA-induced phosphorylation of ERK 1/2 was suppressed by LU8C-FP, whereas JNK and p38 MAPK phosphorylation were unaffected. In addition, LU8C-FP blocked the ERK 1/2 pathways following expression of MMP-9 and IL-8. These results suggest LU8C-FP may function to suppress invasion of breast cancer cells through the ERK/AP-1 and ERK/NF-kappaB signaling cascades. PMID- 23933111 TI - Novel pyrrolopyridinone derivatives as anticancer inhibitors towards Cdc7: QSAR studies based on dockings by solvation score approach. AB - A series of pyrrolopyridinone derivatives as specific inhibitors towards the cell division cycle 7 (Cdc7) was taken into account, and the efficacy of these compounds was analyzed by QSAR and docking approaches to gain deeper insights into the interaction mechanism and ligands selectivity for Cdc7. By regression analysis the prediction models based on Grid score and Zou-GB/SA score were found, respectively with good quality of fits (r(2)=0.748, 0.951; r(cv)(2)=0.712, 0.839). The accuracy of the models was validated by test set and the deviation of the predicted values in validation set using Zou-GB/SA score was smaller than that using Grid score, suggesting that the model based on Zou-GB/SA score provides a more effective method for predicting potencies of Cdc7 inhibitors. PMID- 23933112 TI - Methods to evaluate and improve the injection site tolerability of intravenous formulations prior to first-in-human testing. AB - INTRODUCTION: Evaluation of infusion site tolerability is required for the development of intravenous formulations of New Molecular Entities and is of particular importance for investigational drugs that have the potential to precipitate on contact with the blood stream. Based on a comprehensive set of in vitro and in vivo studies conducted with JNJ-X, a development stage small molecule investigational drug, with a pH-dependent solubility that showed potential to cause infusion site irritation at high concentrations, we have developed a systematic approach for evaluating and selecting suitable intravenous formulations for compounds that show potential to precipitate at the infusion site. METHODS: Aqueous formulations containing a range of concentrations of JNJ-X with different excipients, and buffering agents at different pHs (3.9-7.4) were evaluated in an in vitro solubility assay, a modified hen's egg test chorioallantoic membrane assay (HET-CAM(VT)) and in vivo in rabbit, rat, and dog intravenous infusion toxicity studies. RESULTS: The data obtained with JNJ-X in the different in vitro and in vivo studies were compared and used to support the development of an in silico model and to create a systematic approach to screen and identify candidate intravenous formulations with improved tolerability. DISCUSSION/CONCLUSION: This approach provides a framework that can be used to assess the risk for infusion site irritation and identify better tolerated formulations with a reduced need for in vivo testing. PMID- 23933113 TI - A high content screening assay to predict human drug-induced liver injury during drug discovery. AB - INTRODUCTION: Adverse drug reactions are a major cause for failures of drug development programs, drug withdrawals and use restrictions. Early hazard identification and diligent risk avoidance strategies are therefore essential. For drug-induced liver injury (DILI), this is difficult using conventional safety testing. To reduce the risk for DILI, drug candidates with a high risk need to be identified and deselected. And, to produce drug candidates without that risk associated, risk factors need to be assessed early during drug discovery, such that lead series can be optimized on safety parameters. This requires methods that allow for medium-to-high throughput compound profiling and that generate quantitative results suitable to establish structure-activity-relationships during lead optimization programs. METHODS: We present the validation of such a method, a novel high content screening assay based on six parameters (nuclei counts, nuclear area, plasma membrane integrity, lysosomal activity, mitochondrial membrane potential (MMP), and mitochondrial area) using ~100 drugs of which the clinical hepatotoxicity profile is known. RESULTS DISCUSSION: We find that a 100-fold TI between the lowest toxic concentration and the therapeutic Cmax is optimal to classify compounds as hepatotoxic or non hepatotoxic, based on the individual parameters. Most parameters have ~50% sensitivity and ~90% specificity. Drugs hitting >=2 parameters at a concentration below 100-fold their Cmax are typically hepatotoxic, whereas non-hepatotoxic drugs typically hit <2 parameters within that 100-fold TI. In a zone classification model, based on nuclei count, MMP and human Cmax, we identified an area without a single false positive, while maintaining 45% sensitivity. Hierarchical clustering using the multi-parametric dataset roughly separates toxic from non-toxic compounds. We employ the assay in discovery projects to prioritize novel compound series during hit-to-lead, to steer away from a DILI risk during lead optimization, for risk assessment towards candidate selection and to provide guidance of safe human exposure levels. PMID- 23933114 TI - Label-free cell phenotypic assessment of the biased agonism and efficacy of agonists at the endogenous muscarinic M3 receptors. AB - INTRODUCTION: Efficacy describes the property of a ligand that enables the receptor to change its behavior towards the host cell, while biased agonism defines the ability of a ligand to differentially activate some of the vectorial pathways over others mediated through the receptor. However, little is known about the molecular basis defining the efficacy of ligands at G protein-coupled receptors. Here we characterize the biased agonism and cell phenotypic efficacy of seven agonists at the endogenous muscarinic M3 receptors in six different cell lines including HT-29, PC-3, HeLa, SF268, CCRF-CEM and HCT-15 cells. METHODS: Quantitative real-time PCR and multiple label-free whole cell dynamic mass redistribution (DMR) assays were used to determine the functional muscarinic receptors in each cell line. DMR pathway deconvolution assay was used to determine the pathway biased activity of the muscarinic agonists. Operational agonism model was used to quantify the pathway bias, while macro-kinetic data reported in literature was used to analyze the biochemical mechanism of action of these agonists. RESULTS: Quantitative real-time PCR and ligand pharmacology studies showed that all the native cell lines endogenously express functional M3 receptors. Furthermore, different agonists triggered distinct DMR signals in a specific cell line as well as in different cell lines. DMR pathway deconvolution using known G protein modulators revealed that the M3 receptor in all the six cell lines signals through multiple G protein-mediated pathways, and certain agonists display biased agonism in a cell line-dependent manner. The whole cell efficacy and potency of these agonists were found to be sensitive to the assay time as well as the cell background. Correlation analysis suggested that the whole cell efficacy of agonists is correlated well with their macro-dissociation rate constants. DISCUSSION: This study implicates that the endogenous M3 receptors are coupled to multiple pathways, and the muscarinic agonists can display distinct biased agonism and whole cell phenotypic efficacy. PMID- 23933116 TI - Ribonucleotide reductase inhibitors hydroxyurea, didox, and trimidox inhibit human cytomegalovirus replication in vitro and synergize with ganciclovir. AB - Ganciclovir (GCV) is a deoxyguanosine analog that is effective in inhibiting human cytomegalovirus (HCMV) replication. In infected cells GCV is converted to GCV-triphosphate which competes with dGTP for incorporation into the growing DNA strand by the viral DNA polymerase. Incorporated GCV promotes chain termination as it is an inefficient substrate for elongation. Because viral DNA synthesis also relies on cellular ribonucleotide reductase (RR) to synthesize deoxynucleotides, RR inhibitors are predicted to inhibit HCMV replication. Moreover, as dGTP competes with GCV-triphosphate for incorporation, RR inhibitors may also synergize with GCV by reducing intracellular dGTP levels and there by promoting increased GCV-triphosphate utilization by DNA polymerase. To investigate potential of RR inhibitors as anti-HCMV agents both alone and in combination with GCV, HCMV-inhibitory activities of three RR inhibitors, hydroxyurea, didox, and trimidox, were determined. In both spread inhibition and yield reduction assays RR inhibitors had modest anti-HCMV activity with 50% inhibitory concentrations ranging from 36+/-1.7 to 221+/-52MUM. However, all three showed significant synergy with GCV at concentrations below their 50% inhibitory and 50% toxic concentrations. These results suggest that combining GCV with relatively low doses of RR inhibitors could significantly potentiate the anti-HCMV activity of GCV in vivo and could improve clinical response to therapy. PMID- 23933115 TI - New-generation screening assays for the detection of anti-influenza compounds targeting viral and host functions. AB - Current options for influenza antiviral therapy are limited to the neuraminidase inhibitors, and knowledge that high levels of oseltamivir resistance have been seen among previously circulating H1N1 viruses increases the urgency to find new influenza therapeutics. To feed this pipeline, assays that are appropriate for use in high-throughput screens are being developed and are discussed in this review. Particular emphasis is placed on cell-based assays that capture both inhibitors of viral functions as well as the host functions that facilitate optimal influenza virus replication. Success in this area has been fueled by a greater understanding of the genome structure of influenza viruses and the ability to generate replication-competent recombinant viruses that carry a reporter gene, allowing for easy monitoring of viral infection in a high throughput setting. This article forms part of a symposium in Antiviral Research on "Treatment of influenza: targeting the virus or the host." PMID- 23933117 TI - Differential gene expression in HIV-infected individuals following ART. AB - Previous studies of the effect of ART on gene expression in HIV-infected individuals have identified small numbers of modulated genes. Since these studies were underpowered or cross-sectional in design, a paired analysis of peripheral blood mononuclear cells (PBMCs), isolated before and after ART, from a robust number of HIV-infected patients (N=32) was performed. Gene expression was assayed by microarray and 4157 differentially expressed genes (DEGs) were identified following ART using multivariate permutation tests. Pathways and gene ontology (GO) terms over-represented for DEGs reflected the transition from a period of active virus replication before ART to one of viral suppression (e.g., repression of JAK-STAT signaling) and possible prolonged drug exposure (e.g., oxidative phosphorylation pathway) following ART. CMYC was the DEG whose product made the greatest number of interactions at the protein level in protein interaction networks (PINs), which has implications for the increased incidence of Hodgkin's lymphoma (HL) in HIV-infected patients. The differential expression of multiple genes was confirmed by RT-qPCR including well-known drug metabolism genes (e.g., ALOX12 and CYP2S1). Targets not confirmed by RT-qPCR (i.e., GSTM2 and RPL5) were significantly confirmed by droplet digital (ddPCR), which may represent a superior method when confirming DEGs with low fold changes. In conclusion, a paired design revealed that the number of genes modulated following ART was an order of magnitude higher than previously recognized. PMID- 23933119 TI - Ecdysteroids from the flowers of Aerva javanica. AB - Four new ecdysteroids (1-4), along with three known steroids, beta-ecdysone (5), 5-beta-2-deoxyintegristerone A (6) and 24-epi-makisterone A (7) (Fig. 1), were isolated from the methanolic extract of the flowers of Aerva javanica by using normal and reverse phase chromatography. The structures of the new compounds (1 4) were determined due to 1D ((1)H and (13)C), 2D NMR (HSQC, HMBC, COSY, NOESY) techniques and high resolution mass spectrometry (HREIMS). The known compounds (5 7) were characterized based on the 1D NMR spectroscopy and mass spectrometry and by comparison with the literature values. All isolates were evaluated for their inhibitory activities against enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and lipoxygenase (LOX). PMID- 23933118 TI - Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). AB - Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. Four major forms of MEN, which are autosomal dominant disorders, are recognized and referred to as: MEN type 1 (MEN1), due to menin mutations; MEN2 (previously MEN2A) due to mutations of a tyrosine kinase receptor encoded by the rearranged during transfection (RET) protoncogene; MEN3 (previously MEN2B) due to RET mutations; and MEN4 due to cyclin-dependent kinase inhibitor (CDNK1B) mutations. Each MEN type is associated with the occurrence of specific tumors. Thus, MEN1 is characterized by the occurrence of parathyroid, pancreatic islet and anterior pituitary tumors; MEN2 is characterized by the occurrence of medullary thyroid carcinoma (MTC) in association with phaeochromocytoma and parathyroid tumors; MEN3 is characterized by the occurrence of MTC and phaeochromocytoma in association with a marfanoid habitus, mucosal neuromas, medullated corneal fibers and intestinal autonomic ganglion dysfunction, leading to megacolon; and MEN4, which is also referred to as MENX, is characterized by the occurrence of parathyroid and anterior pituitary tumors in possible association with tumors of the adrenals, kidneys, and reproductive organs. This review will focus on the clinical and molecular details of the MEN1 and MEN4 syndromes. The gene causing MEN1 is located on chromosome 11q13, and encodes a 610 amino-acid protein, menin, which has functions in cell division, genome stability, and transcription regulation. Menin, which acts as scaffold protein, may increase or decrease gene expression by epigenetic regulation of gene expression via histone methylation. Thus, menin by forming a subunit of the mixed lineage leukemia (MLL) complexes that trimethylate histone H3 at lysine 4 (H3K4), facilitates activation of transcriptional activity in target genes such as cyclin-dependent kinase (CDK) inhibitors; and by interacting with the suppressor of variegation 3-9 homolog family protein (SUV39H1) to mediate H3K methylation, thereby silencing transcriptional activity of target genes. MEN1-associated tumors harbor germline and somatic mutations, consistent with Knudson's two-hit hypothesis. Genetic diagnosis to identify individuals with germline MEN1 mutations has facilitated appropriate targeting of clinical, biochemical and radiological screening for this high risk group of patients for whom earlier implementation of treatments can then be considered. MEN4 is caused by heterozygous mutations of CDNK1B which encodes the 196 amino-acid CDK1 p27Kip1, which is activated by H3K4 methylation. PMID- 23933120 TI - Profiling of urinary formestane and confirmation by isotope ratio mass spectrometry. AB - Formestane (F, androst-4-en-4-ol-3,17-dione) is an irreversible aromatase inhibitor with the ability to suppress the estrogen production from anabolic steroids. Consequently, F is mentioned on the World Anti-Doping Agency (WADA) prohibited list and because studies have shown that F is produced endogenously in small amounts, a threshold for urinary excreted F of 150 ng/mL was introduced. Lower concentrations could be due to endogenous production and need further investigation to prove the exact origin through determination of the carbon isotope ratio. However, because the current screening methods are a lot more sensitive, F is detected in practically every urine sample. A strict implementation of this WADA rule would imply that almost every urine sample needs additional investigation to verify an exogenous or endogenous origin. The main aim of this study was to propose and introduce a lower concentration limit of 25 ng/mL beneath which the detected F is considered as being endogenous and no further investigation is needed. The data presented in this paper suggests that this threshold provides a good balance between a sufficiently large detection window and not having to perform isotope ratio mass spectrometry (IRMS) analyses on negative urine samples. PMID- 23933121 TI - Nanomolar ouabain elicits apoptosis through a direct action on HeLa cell mitochondria. AB - The steroid Na(+)/K(+) ATPase (NKA) blocker ouabain has been shown to exhibit pro apoptotic effects in various cell systems; however, the mechanism involved in those effects is unclear. Here, we have demonstrated that incubation of HeLa cells during 24h with nanomolar concentrations of ouabain or digoxin causes apoptotic death of 30-50% of the cells. Ouabain caused the activation of caspases 3/7 and -9; however, caspase-8 was unaffected. The fact that compound Z-LEHD-FMK reduced both apoptosis and caspase-9 activation elicited by ouabain, suggest a mitochondrially-mediated pathway. This was strengthened by the fact that ouabain caused ATP depletion and the release of mitochondrial cytochrome c into the cytosol. Furthermore, upon ouabain treatment mitochondrial disruption and redistribution into the cytosol were observed. A mitochondrial site of action for ouabain was further corroborated by tight co-localisation of fluorescent ouabain with mitochondria. Finally, in ouabain-treated cells the histamine-elicited elevation of cytosolic Ca(2+) concentration ([Ca(2+)]c) suggests an additional effect on the endoplasmic reticulum (ER) leading to Ca(2+) store depletion. We conclude that fluorescent ouabain is taken up and tightly co-localises with mitochondria of HeLa cells. This indicates that apoptosis may be triggered by a direct action of ouabain on mitochondria. PMID- 23933122 TI - Calculation of HbA1c and glycated albumin from serially measured self-monitored blood glucose in patients with type 1 diabetes mellitus. AB - BACKGROUND: Both HbA1c and glycated albumin (GA) values are influenced by weighted mean of preceding blood glucose levels depending on each half-life. Based on this principle, we developed formulas for calculation of HbA1c and GA using data from self-monitored blood glucose (SMBG). We also calculated HbA1c and GA in diabetic patients using the developed formulas. METHODS: This study included 9 patients with childhood-onset type 1 diabetes mellitus (6 males and 3 females; aged 11.4+/-4.2 y). From the weekly mean blood glucose (MBG) values obtained by the SMBG data during the previous 20 weeks, we calculated HbA1c and GA using the developed formulas and compared the calculated values with the measured values (n=42). RESULTS: The measured and the calculated values of HbA1c were 8.5+/-0.9% and 8.3+/-1.2%, respectively. The measured and the calculated values of GA were 24.9+/-3.7% and 26.4+/-4.0%, respectively. There were strong positive correlations between both values of HbA1c and GA (P<0.0001). CONCLUSIONS: The calculated HbA1c and GA values using the developed formulas from the SMBG data were generally in agreement with the measured values. Using the calculation formulas, the values of HbA1c and GA could be estimated from serially measured SMBG data. PMID- 23933123 TI - Electrochemical immunosensors in breast and ovarian cancer. AB - During the last decades the incidence of cancer increased dramatically especially in developed countries. In spite of the fact that the immunochemical methods allowed the diagnosis in early stages, the biopsies are generally invasive methods that create discomfort to patients. The need for fast, sensitive, easy to use and noninvasive diagnosis tools is actually of great interest for many research groups all over the world. Immunosensors (ISs) are miniaturized measuring devices, which selectively detect their targets by means of antibodies (Abs) and provide concentration-dependent signals. Ab binding leads to a variation in electric charge, mass, heat or optical properties, which can be detected directly or indirectly by a variety of transducers. A great number of proteins could be considered as recognition element. In this review the attention was focused on main cancer biomarkers, currently used by immunological methods (immunohistochemistry, ELISA, flow cytometry, Western blot, immunofluorescence etc) and in the development of electrochemical immunoassays that could be used in cancer diagnosis, prognosis and therapy monitoring. PMID- 23933124 TI - In situ application of activated carbon and biochar to PCB-contaminated soil and the effects of mixing regime. AB - The in situ use of carbon amendments such as activated carbon (AC) and biochar to minimize the bioavailability of organic contaminants is gaining in popularity. In the first in situ experiment conducted at a Canadian PCB-contaminated Brownfield site, GAC and two types of biochar were statistically equal at reducing PCB uptake into plants. PCB concentrations in Cucurbita pepo root tissue were reduced by 74%, 72% and 64%, with the addition of 2.8% GAC, Burt's biochar and BlueLeaf biochar, respectively. A complementary greenhouse study which included a bioaccumulation study of Eisenia fetida (earthworm), found mechanically mixing carbon amendments with PCB-contaminated soil (i.e. 24 h at 30 rpm) resulted in shoot, root and worm PCB concentrations 66%, 59% and 39% lower than in the manually mixed treatments (i.e. with a spade and bucket). Therefore, studies which mechanically mix carbon amendments with contaminated soil may over-estimate the short-term potential to reduce PCB bioavailability. PMID- 23933125 TI - Ultrastructural changes and Heat Shock Proteins 70 induced by atmospheric pollution are similar to the effects observed under in vitro heavy metals stress in Conocephalum conicum (Marchantiales--Bryophyta). AB - Changes in ultrastructure and induction of Heat Shock Proteins 70 have been studied in Conocephalum conicum (Marchantiales) collected in different urban and country sites in Italy. These results were compared to the effects in vitro of exposition to different heavy metals for several days. At urban sites, cellular ultrastructure was modified, and heavy metals could be observed accumulating in cell walls. Simultaneously, a strong increment in Hsp70 was detected, compared with results observed on control specimens. When C. conicum was exposed to heavy metals in vitro, comparable effects as in polluted sites were observed: Cd and Pb accumulated mostly within parenchyma and, within cells, were absorbed to cell walls or concentrated in vacuoles. Moreover, severe alterations were observed in organelles. Concomitantly, a progressive accumulation of Hsp70 was detected following heavy metals exposition. These effects are discussed in order to describe the dose and time-dependent response to heavy metal stress in C. conicum. PMID- 23933127 TI - Effects of local and spatial conditions on the quality of harvested rainwater in the Mekong Delta, Vietnam. AB - The objective of this study was to assess the quality of harvested rainwater in the Mekong Delta (MD), Vietnam for local (roof types, storage system and duration) and spatial (proximity of industry, main roads, coastline) conditions. 78 harvested rainwater samples were collected in the MD and analyzed for pH, turbidity, TDS, COD, nutrients (NH4, NO3, NO2, o-PO4), trace metals and coliforms. The results show that thatch roofs lead to an increase of pollutants like COD (max 23.2 mgl(-1)) and turbidity (max 10.1 mgl(-1)) whereas galvanized roofs lead to an increase of Zn (max 2.2 mgl(-1)). The other local and spatial parameters had no or only minor influence on the quality of household harvested rainwater. However, lead (Pb) (max. 16.9 MUgl(-1)) and total coliforms (max. 102 500 CFU100 ml(-1)) were recorded at high concentrations, probably due to a variety of household-specific conditions such as rainwater storage, collection and handling practices. PMID- 23933128 TI - The analog brain: how wave theory may explain complex physiological processes. PMID- 23933126 TI - Mineralogy affects geoavailability, bioaccessibility and bioavailability of zinc. AB - We correlated mineralogical and particle characteristics of Zn-containing particles with Zn geoavailability, bioaccessibility, and bioavailability following gavage and intranasal (IN) administration in rats. We compared samples of Zn/Pb mine waste and five pulverized pure-phase Zn minerals (<38 MUm). Particles were neutron-activated to produce radioactive (65)Zn. We assessed geoavailability using sequential extractions and bioaccessibility using in vitro extraction tests simulating various pH and biological conditions. Zn in vivo bioavailability and in vitro bioaccessibility decreased as follows: mine waste > hydrozincite > hemimorphite > zincite ~ smithsonite >> sphalerite. We found significant correlations among geoavailability, bioaccessibility and bioavailability. In particular, Zn bioavailability post-gavage and post-IN was significantly correlated with bioaccessibility in simulated phagolysosomal fluid and gastric fluid. These data indicate that solid phase speciation influences biological uptake of Zn and that in vitro tests can be used to predict Zn bioavailability in exposure assessment and effective remediation design. PMID- 23933129 TI - Is timing of cranioplasty following posttraumatic craniectomy related to neurological outcome? AB - BACKGROUND: With the use of decompressive craniectomy for traumatic brain injury (TBI) come a corresponding number of cranioplasties. TBI causes dynamic processes to commence or change during the period from injury to recovery; hence, the role of the timing of surgical intervention should be emphasized. AIMS: We attempt to identify the relationship between the timing of cranioplasty and neurological outcomes following posttraumatic craniectomy. METHODS: In this 3-year retrospective study, 105 patients undergoing decompressive craniectomies and subsequent cranioplasties for TBI were enrolled. We documented the patients' demographic information, including Glasgow Coma Scale (GCS) at admission for trauma. The follow-up period was terminated by death or a minimum of 6 months after TBI. Glasgow Outcome Scale (GOS) at the end of follow-up was used as an outcome measure. Unfavorable outcome was defined as a GOS score of 1-3. RESULTS: The 105 patients included 71 male and 34 female subjects. The mean age was 41.94 +/- 19.73 years. Neurological assessment showed that admission GCS was 8.50 +/- 3.15, on average. The mean time interval between cranioplasty and craniectomy was 78.84 +/- 49.04 days (range, 13-245 days). Univariate logistic regression analysis showed that the association between the timing of cranioplasty and unfavorable outcomes was not statistically significant (odds ratio = 1.005, confidence interval 0.997-1.013; p = 0.195). CONCLUSION: The timing of cranioplasty following posttraumatic craniectomy was not related to the neurological outcomes of TBI. Despite the limitations of the retrospective design, the analyses provide preliminary information to elucidate the question. PMID- 23933130 TI - Identification of SLC26A transporters involved in the Cl-/HCO3- exchange in proximal tubular cells from WKY and SHR. AB - AIMS: slc26a proteins are responsible for a large number of functions either in normal physiology or in human disease. We have previously reported that proximal tubular epithelial (PTE) cells immortalized from spontaneously hypertensive rats (SHRs) were endowed with increased Cl(-)/HCO3(-) exchanger activity and slc26a6 protein expression compared with PTE cells immortalized from normotensive Wistar Kyoto (WKY) rats. The aim of the present study was to identify slc26a members responsible for the Cl(-)/HCO3(-) exchange in WKY and SHR PTE cells. MAIN METHODS: Cl(-)/HCO3(-) exchanger activity was assessed as the initial rate of pHi recovery after removal of HCO3(-) or after removal of Cl(-). The presence of slc26a genes was evaluated by means of reverse transcriptase-PCR (RT-PCR) in WKY and SHR PTE cell lines and in the kidney of WKY and SHR. Transcript abundance was measured by quantitative real-time polymerase chain reaction (PCR). KEY FINDINGS: We detected slc26a4, slc26a6, slc26a7 and slc26a9 transcripts in the rat kidney of WKY and SHR. In WKY and SHR PTE cell lines we detected slc26a4, slc26a6 and slc26a9 transcripts, which were, respectively, 12-, 4- and 15-fold upregulated in SHR cells. Gene silencing with small interfering RNAs (siRNAs) targeting slc26a4, slc26a6 and slc26a9 reduced Cl(-)/HCO3(-) exchanger activity in both cell lines. SIGNIFICANCE: These results indicate that Cl(-)/HCO3(-) exchanger activity is mediated by, at least in part, slc26a4, slc26a6 and slc26a9 in cultured WKY and SHR cells. The overexpression of these slc26a members in SHR cells may correspond to an adaptive process to cope with the sustained increase in proximal tubular sodium reabsorption. PMID- 23933131 TI - The inhibitory effect of naringenin on atopic dermatitis induced by DNFB in NC/Nga mice. AB - AIMS: Atopic dermatitis (AD) is a chronic and relapsing inflammatory dermatitis characterized by pruritic and eczematous skin lesions. Here, we investigated the therapeutic effect of the fruit flavonoid naringenin on DNFB induced atopic dermatitis mice model. MAIN METHODS: AD-like skin lesion was induced by repetitive skin contact with DNFB in NC/Nga mice and the effects of the fruit flavonoid naringenin were evaluated on the basis of histopathological findings of skin, ear swelling and cytokine production of CD4(+)T cells. KEY FINDINGS: Intraperitoneal injection of naringenin for one week after DNFB challenge significantly lowered ear swelling and improved back skin lesions. In addition, naringenin significantly suppressed production of interferon-gamma (IFN-gamma) by activated CD4(+) T cells and serum IgE level. Furthermore, naringenin reduced DNFB-induced infiltration of eosinophils, mast cells, CD4(+) T cells, and CD8(+) T cells in skin lesions. SIGNIFICANCE: Naringenin may suppress the development of AD-like skin lesions in DNFB-treated NC/Nga mice by reducing IFN-gamma production of activated CD4(+) T cells, serum IgE levels and infiltration of immune cells to skin lesion. PMID- 23933132 TI - The BRCT domain and the specific loop 1 of human PolMU are targets of Cdk2/cyclin A phosphorylation. AB - Human family X polymerases contribute both to genomic stability and variability through their specialized functions in DNA repair. PolMU participates in the repair of spontaneous double strand breaks (DSB) by non homologous end-joining (NHEJ), and also in the V(D)J recombination process after programmed DSBs. PolMU plays this dual role due to its template-dependent and terminal transferase (template-independent) polymerization activities. In this study we evaluated if PolMU could be regulated by Cdk phosphorylation along the cell cycle. In vitro kinase assays showed that the S phase-associated Cdk2/cyclin A complex was able to phosphorylate PolMU. We identified Ser12, Thr21 (located in the BRCT domain) and Ser372 (located in loop1) as the target residues. Mutation of these residues to alanine indicated that Ser372 is the main phosphorylation site. Mobilization of loop1, which mediates DNA end micro-synapsis, is crucial both for terminal transferase and NHEJ. Interestingly, the phospho-mimicking S372E mutation specifically impaired these activities. Our evidences suggest that PolMU could be regulated in vivo by phosphorylation of the BRCT domain (Ser12/Thr21) and of Ser372, affecting the function of loop1. Consequently, PolMU's most distinctive activities would be turned off at specific cell-cycle phases (S and G2), when these promiscuous functions might be harmful to the cell. PMID- 23933133 TI - Proteomic analysis of grapevine (Vitis vinifera L.) leaf changes induced by transition to autotrophy and exposure to high light irradiance. AB - Using a proteomics approach, we evaluated the response of heterotrophic and autotrophic leaves of grapevine when exposed to high light irradiation. From a total of 572 protein spots detected on two-dimensional gels, 143 spots showed significant variation caused by changes in the trophic state. High light treatment caused variation in 90 spots, and 51 spots showed variation caused by the interaction between both factors. Regarding the trophic state of the leaf, most of the proteins detected in the heterotrophic stage decreased in abundance when the leaf reached the autotrophic stage. Major differences induced by high light were detected in autotrophic leaves. In the high-light-treated autotrophic leaves several proteins involved in the oxidative stress response were up regulated. This pattern was not observed in the high-light-treated heterotrophic leaves. This indicates that in these types of leaves other mechanisms different to the protein antioxidant system are acting to protect young leaves against the excess of light. This also suggests that these protective mechanisms rely on other sets of proteins or non-enzymatic molecules, or that differences in protein dynamics between the heterotrophic and autotrophic stages makes the autotrophic leaves more prone to the accumulation of oxidative stress response proteins. BIOLOGICAL SIGNIFICANCE: Transition from a heterotrophic to an autotrophic state is a key period during which the anatomical, physiological and molecular characteristics of a leaf are defined. In many aspects the right functioning of a leaf at its mature stage depends on the conditions under what this transition occurs. This because apart of the genetic control, environmental factors like mineral nutrition, temperature, water supply, light etc. are also important in its control. Many anatomical and physiological changes have been described in several plant species, however in grapevine molecular data regarding changes triggered by this transition or by light stress are still scarce. In this study, we identify that the transition from heterotrophic to autotrophic state in grapevine triggers major changes in the leaf proteome, which are mainly related to processes such as protein synthesis, protein folding and degradation, photosynthesis and chloroplast development. With the exception of proteins involved in carbon fixation, that increased in abundance, most of the proteins detected during the heterotrophic stage decreased in abundance when the leaf reached its autotrophic stage. This is most likely because leaves have reached their full size and from now they have to work as a carbon source for sink organs located in other parts of the plant. Despite the potential control of this transition by light, to date, no studies using a proteomics approach have been conducted to gain a broader view of the effects of short-term high light stress. Our results indicate that short-term high light exposure has a major impact on the proteome of the autotrophic leaves, and trigger a differential accumulation of several proteins involved in the oxidative stress response. Surprisingly, heterotrophic leaves do not display this pattern which can be attributed to a lower sensitivity of these leaves to high light stimulus. In fact we discovered that heterotrophic leaves are more tolerant to light stress than autotrophic leaves. This finding is of high biological significance because it helps to understand how young leaves are able to evolve to autotrophy in areas where high light intensities are predominant. This also reveals in this type of leaves the existence of alternative mechanisms to address this stressful condition. These observations provide new insights into the molecular changes occurring during transition of leaves to autotrophy particularly when this transition occurs under high light intensities. This for example occurs during the springtime when the grapevine buds burst and the young leaves are suddenly exposed to high light intensities. PMID- 23933134 TI - Quantitative profiling of tyrosine phosphorylation revealed changes in the activity of the T cell receptor signaling pathway upon cisplatin-induced apoptosis. AB - In order to better understand the cellular responses to the chemotherapeutic drug cisplatin and the mechanisms leading to apoptosis and potential side effects, we performed a SILAC-based quantitative phosphotyrosine analysis of Jurkat T cells exposed to cisplatin. Signaling molecules in the T cell receptor (TCR) pathway were enriched among proteins displaying reduced phosphorylation levels. The results were verified by immunoblotting and/or phospho-flow cytometry for a selected set of proteins, including the tyrosine kinases Lck and Zap70, and downstream targets Itk, Plcgamma1 and Erk. In contrast to the effects on the T cell signaling pathways, the dually phosphorylated form of p38alpha MAPK was increased in treated cells, and activation of this signaling pathway was verified by immunoblot analysis of phosphorylation levels of p38alpha MAPK and the downstream targets Atf2 and MAPKAPK2. Activation of the p38alpha MAPK signaling pathway has been suggested to be one of the main mechanisms by which cisplatin induces apoptosis. Our results indicate that cisplatin may reduce the activity of proteins involved in the TCR signaling pathway, which has an important role in regulating proliferation of T cells, and may contribute to explain previous observations where cisplatin has been reported to inhibit proliferation of T cells. BIOLOGICAL SIGNIFICANCE: In this study, a quantitative phosphotyrosine analysis was performed to identify changes of the phosphoproteome during exposure of Jurkat T cells by cisplatin. The results of the phosphoproteome analysis were complemented with immunoblotting and temporal phospho-flow analysis. An initial activation of the p38alpha MAPK signaling pathway was detected at early time points of cisplatin treatment, a response previously suggested to be part of the mechanism by which cisplatin induces apoptosis. Furthermore, reduced phosphorylation levels of proteins involved in signaling downstream of the TCR during apoptosis were found by the phosphotyrosine proteome analysis. Our study can support to elucidate the mechanism behind the previously observed immunosuppressive effect of cisplatin. PMID- 23933135 TI - Interactions of phenothiazine drugs with surfactants: a detailed physicochemical overview. AB - Phenothiazine drugs have been the subject of great interest due to their interesting aggregation properties and ability to interact with surfactants, model lipid bilayers, and biomembranes. Since these drugs show enormous pharmacological actions and deposits on the biomembranes, their pharmacological activities seem to be related to the drug-membrane interactions or to the absorbability on the membrane. Further, the mechanisms for the various biological activities of phenothiazines can be explained by exploring these drug-membrane interactions. Keeping these points in view, many researchers have investigated the interactions of these drugs with surfactants. This review describes the physicochemical aspects of the interactions between phenothiazine drugs and surfactants which have been discussed under three sections: (i) micellar and interfacial studies, (ii) spectroscopic studies, (iii) phase separation studies (CP) and (iv) miscellaneous. PMID- 23933136 TI - CD11b(+) cells in donor-specific transfusion prolonged allogenic skin graft survival through indoleamine 2,3-dioxygenase. AB - The aim of this study is to show the effect of donor-specific transfusion (DST) in inducing immunological tolerance mediated by regulatory T cells (Treg) and indoleamine 2,3-dioxygenase (IDO). Skin grafts from H2(d) Balb/c were transplanted into H2(k) C3H/He 7days after the infusion of donor splenocytes, isolated each immune cell populations. Graft survival prolonged in recipients who received splenocytes, MHC class II(+) CD90(-) cells and CD3(-)CD19(-) cells (p<0.001, p<0.05 and p<0.01, respectively). CD11b(+) cell infusion resulted in prolongation of graft survival when compared to CD11c(+) cell infusion (p<0.01). Foxp3(+)CD4(+)CD25(+) T cells were increased after the transplant in recipients infused with CD11b(+) cells (p<0.05). The mixed lymphocyte reaction showed donor specificity (p<0.001). High IDO expression was observed in CD11b(+) cell infusion group. Graft survival with DST using IDO antagonist (1MT) were not prolonged. In conclusion, DST allows induction of donor-specific tolerance which involves Foxp3(+)CD4(+)CD25(+) T cells and IDO expression. PMID- 23933138 TI - A differentiating empirical linguistic analysis of dreamer activity in reports of EEG-controlled REM-dreams and hypnagogic hallucinations. AB - We present Activity Analysis as a new method for the quantification of subjective reports of altered states of consciousness with regard to the indicated level of simulated motor activity. Empirical linguistic activity analysis was conducted with dream reports conceived immediately after EEG-controlled periods of hypnagogic hallucinations and REM-sleep in the sleep laboratory. Reports of REM dreams exhibited a significantly higher level of simulated physical dreamer activity, while hypnagogic hallucinations appear to be experienced mostly from the point of passive observer. This study lays the groundwork for clinical research on the level of simulated activity in pathologically altered states of subjective experience, for example in the REM-dreams of clinically depressed patients, or in intrusions and dreams of patients diagnosed with PTSD. PMID- 23933137 TI - Drosophila-Cdh1 (Rap/Fzr) a regulatory subunit of APC/C is required for synaptic morphology, synaptic transmission and locomotion. AB - The assembly of functional synapses requires the orchestration of the synthesis and degradation of a multitude of proteins. Protein degradation and modification by the conserved ubiquitination pathway has emerged as a key cellular regulatory mechanism during nervous system development and function (Kwabe and Brose, 2011). The anaphase promoting complex/cyclosome (APC/C) is a multi-subunit ubiquitin ligase complex primarily characterized for its role in the regulation of mitosis (Peters, 2002). In recent years, a role for APC/C in nervous system development and function has been rapidly emerging (Stegmuller and Bonni, 2005; Li et al., 2008). In the mammalian central nervous system the activator subunit, APC/C-Cdh1, has been shown to be a regulator of axon growth and dendrite morphogenesis (Konishi et al., 2004). In the Drosophila peripheral nervous system (PNS), APC2, a ligase subunit of the APC/C complex has been shown to regulate synaptic bouton size and activity (van Roessel et al., 2004). To investigate the role of APC/C Cdh1 at the synapse we examined loss-of-function mutants of Rap/Fzr (Retina aberrant in pattern/Fizzy related), a Drosophila homolog of the mammalian Cdh1 during the development of the larval neuromuscular junction in Drosophila. Our cell biological, ultrastructural, electrophysiological, and behavioral data showed that rap/fzr loss-of-function mutations lead to changes in synaptic structure and function as well as locomotion defects. Data presented here show changes in size and morphology of synaptic boutons, and, muscle tissue organization. Electrophysiological experiments show that loss-of-function mutants exhibit increased frequency of spontaneous miniature synaptic potentials, indicating a higher rate of spontaneous synaptic vesicle fusion events. In addition, larval locomotion and peristaltic movement were also impaired. These findings suggest a role for Drosophila APC/C-Cdh1 mediated ubiquitination in regulating synaptic morphology, function and integrity of muscle structure in the peripheral nervous system. PMID- 23933139 TI - Subliminal understanding of negation: unconscious control by subliminal processing of word pairs. AB - A series of five experiments investigated the extent of subliminal processing of negation. Participants were presented with a subliminal instruction to either pick or not pick an accompanying noun, followed by a choice of two nouns. By employing subjective measures to determine individual thresholds of subliminal priming, the results of these studies indicated that participants were able to identify the correct noun of the pair--even when the correct noun was specified by negation. Furthermore, using a grey-scale contrast method of masking, Experiment 5 confirmed that these priming effects were evidenced in the absence of partial awareness, and without the effect being attributed to the retrieval of stimulus-response links established during conscious rehearsal. PMID- 23933140 TI - Inhalable DNase I microparticles engineered with biologically active excipients. AB - Highly viscous mucus poses a big challenge for the delivery of particulates carrying therapeutics to patients with cystic fibrosis. In this study, surface modifying DNase I loaded particles using different excipients to achieve better lung deposition, higher enzyme stability or better biological activity had been exploited. For the purpose, controlled release microparticles (MP) were prepared by co-spray drying DNase I with the polymer poly-lactic-co-glycolic acid (PLGA) and the biocompatible lipid surfactant 1,2-dipalmitoyl-Sn-phosphatidyl choline (DPPC) using various hydrophilic excipients. The effect of the included modifiers on the particle morphology, size, zeta potential as well as enzyme encapsulation efficiency, biological activity and release had been evaluated. Powder aerosolisation performance and particle phagocytosis by murine macrophages were also investigated. The results showed that more than 80% of enzyme activity was recovered after MP preparation and that selected surface modifiers greatly increased the enzyme encapsulation efficiency. The particle morphology was greatly modified altering in turn the powders inhalation indices where dextran, ovalbumin and chitosan hydrochloride increased considerably the respirable fraction compared to the normal hydrophilic carriers lactose and PVP. Despite of the improved aerosolisation caused by chitosan hydrochloride, yet retardation of chitosan coated particles in artificial mucus samples discouraged its application. On the other hand, dextran and polyanions enhanced DNase I effect in reducing cystic fibrosis mucus viscosity. DPPC proved good ability to reduce particles phagocytic uptake even in the presence of the selected adjuvants. The prepared MP systems were biocompatible with lung epithelial cells. To conclude, controlled release DNase I loaded PLGA-MP with high inhalation indices and enhanced mucolytic activity on CF sputum could be obtained by surface modifying the particles with PGA or dextran. PMID- 23933141 TI - Effects of nucleus accumbens core and shell lesions on autoshaped lever-pressing. AB - Certain Pavlovian conditioned stimuli (CSs) paired with food unconditioned stimuli (USs) come to elicit approach and even consumption-like behaviors in rats (sign-tracking). We investigated the effects of lesions of the nucleus accumbens core (ACbC) or shell (ACbS) on the acquisition of sign-tracking in a discriminative autoshaping procedure in which presentation of one lever CS was followed by delivery of sucrose, and another was not. Although we previously found that bilateral lesions of the whole ACb disrupted the initial acquisition of sign-tracking, neither ACbC or ACbS lesions affected the rate or percentage of trials in which rats pressed the CS+. In addition, detailed video analysis showed no effect of either lesion on the topography of the sign-tracking conditioned response (CR). These and other results from lesion studies of autoshaping contrast with those from previous sign-tracking experiments that used purely visual cues (Parkinson et al., 2000a,b), suggesting that the neural circuitry involved in assigning incentive value depends upon the nature of the CS. PMID- 23933142 TI - Topography of the sleep/wake states related EEG microstructure and transitions structure differentiates the functionally distinct cholinergic innervation disorders in rat. AB - In order to identify the differences for the onset and progression of functionally distinct cholinergic innervation disorders, we investigated the effect of bilateral nucleus basalis (NB) and pedunculopontine tegmental nucleus (PPT) lesions on sleep/wake states and electroencephalographic (EEG) microstructure in rats, chronically implanted for sleep recording. Bilateral NB lesion transiently altered Wake/NREM duration within the sensorimotor cortex, and Wake/REM duration within the motor cortex, while there was no change in the sleep/wake states distributions following the bilateral PPT lesion. Bilateral PPT lesion sustainably increased the Wake/REM and REM/Wake transitions followed by inconsistent dysregulation of the NREM/REM and REM/NREM transitions in sensorimotor cortex, but oppositely by their increment throughout four weeks in motor cortex. Bilateral NB lesion sustainably decreased the NREM/REM and REM/NREM transitions during four weeks in the sensorimotor cortex, but oppositely increased them in the motor cortex. We have shown that the sustained beta and gamma augmentation within the sensorimotor and motor cortex, and across all sleep/wake states, simultaneously with Wake delta amplitude attenuation only within the sensorimotor cortex, were the underlying EEG microstructure for the sleep/wake states transitions structure disturbance following bilateral PPT lesion. In contrast, the bilateral NB lesion only augmented REM theta in sensorimotor cortex during three weeks. We have shown that the NB and PPT lesions induced differing, structure-related EEG microstructure and transition structure disturbances particularly expressed in motor cortex during NREM and REM sleep. We evidenced for the first time the different topographical expression of the functionally distinct cholinergic neuronal innervation impairment in rat. PMID- 23933143 TI - Serotonin2A/C receptors mediate the aggressive phenotype of TLX gene knockout mice. AB - Deleting the tailless (TLX) gene in mice produces a highly aggressive phenotype yet to be characterized in terms of heterozygous animals or neurotransmitter mechanisms. We sought to establish pharmacological control over aggression and study the role of serotonin (5-HT)(2A/C) receptors in mediating changes in aggression. We analyzed aggression in mice heterozygous (+/-) or homozygous (-/-) for the TLX gene and wild-types (+/+) using a resident-intruder paradigm. No +/+ mice were aggressive, 36% of +/- TLX and 100% of -/- TLX mice showed aggression. Dose-effect functions were established for clozapine (0.1-1.5mg/kg, ip), ketanserin (0.3-1.25 mg/kg, ip), and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane [(+/-)DOI] (0.5-2.0 mg/kg, ip). Injecting clozapine decreased the frequency and duration of attacks for +/- TLX and -/- TLX mice. Clozapine did not decrease grooming in either +/- TLX or -/- TLX mice but may have increased locomotion for -/- TLX mice. Injecting ketanserin, a 5-HT(2A/C) receptor antagonist, produced differential decreases in frequency and latency to aggression between genotypes and corresponding increases in locomotor behavior. Injecting (+/-)DOI, a 5-HT(2A/C) receptor agonist, increased the frequency and duration of attacks, decreased the latency to attacks, and decreased locomotion in +/- and -/- TLX mice. Results of the current study suggest aggression displayed by TLX null and heterozygous mice involves 5-HT(2A/C) receptors. PMID- 23933144 TI - Melatonin ameliorates cognitive impairment induced by sleep deprivation in rats: role of oxidative stress, BDNF and CaMKII. AB - Sleep deprivation (SD) has been shown to induce oxidative stress which causes cognitive impairment. Melatonin, an endogenous potent antioxidant, protects neurons from oxidative stress in many disease models. The present study investigated the effect of melatonin against SD-induced cognitive impairment and attempted to define the possible mechanisms involved. SD was induced in rats using modified multiple platform model. Melatonin (15 mg/kg) was administered to the rats via intraperitoneal injection. The open field test and Morris water maze were used to evaluate cognitive ability. The cerebral cortex (CC) and hippocampus were dissected and homogenized. Nitric oxide (NO) and malondialdehyde (MDA) levels and the superoxide dismutase (SOD) enzyme activity of hippocampal and cortical tissues (10% wet weight per volume) were performed to determine the level of oxidative stress. The expression of brain-derived neurotrophic factor (BDNF) and calcium-calmodulin dependent kinase II (CaMKII) proteins in CC and hippocampus was assayed by means of immunohistochemistry. The results revealed that SD impairs cognitive ability, while melatonin treatment prevented these changes. In addition, melatonin reversed SD-induced changes in NO, MDA and SOD in both of the CC and hippocampus. The results of immunoreactivity showed that SD decreased gray values of BDNF and CaMKII in CC and hippocamal CA1, CA3 and dentate gyrus regions, whereas melatonin improved the gray values. In conclusion, our results suggest that melatonin prevents cognitive impairment induced by SD. The possible mechanism may be attributed to its ability to reduce oxidative stress and increase the levels of CaMKII and BDNF in CC and hippocampus. PMID- 23933145 TI - Effects of acute nicotine on prepulse inhibition of auditory change-related cortical responses. AB - Prepulse inhibition (PPI) of startle is a measure of inhibitory function in which a weak leading stimulus suppresses the startle response to an intense stimulus. Usually, startle blink reflexes to an intense sound are used for measuring PPI. A recent magnetoencephalographic study showed that a similar phenomenon is observed for auditory change-related cortical response (Change-N1m) to an abrupt change in sound features. It has been well established that nicotine enhances PPI of startle. Therefore, in the present magnetoencephalographic study, the effects of acute nicotine on PPI of the Change-N1m were studied in 12 healthy subjects (two females and 10 males) under a repeated measures and placebo-controlled design. Nicotine (4 mg) was given as nicotine gum. The test Change-N1m response was elicited with an abrupt increase in sound pressure by 6 dB in a continuous background sound of 65 dB. PPI was produced by an insertion of a prepulse with a 3-dB-louder or 6-dB-weaker sound pressure than the background 75 ms before the test stimulus. Results show that nicotine tended to enhance the test Change-N1m response and significantly enhanced PPI for both prepulses. Therefore, nicotine's enhancing effect on PPI of the Change-N1m was similar to that on PPI of the startle. The present results suggest that the two measures share at least some mechanisms. PMID- 23933146 TI - The H/Rouen mouse model displays depression-like and anxiety-like behaviors. AB - Cardinal symptoms of depression include helplessness and anhedonia. In addition, depression and anxiety are often comorbid disorders. H/Rouen mice, a genetic mouse model of depression, display helpless behavior in the tail suspension test, whereas non-helpless NH/Rouen mice show the opposite behavior. It is unknown whether H/Rouen mice display an anxious behavior as compared to NH/Rouen mice, and is unclear whether they display anhedonia. Time spent in the periphery of an open-field, an index of anxiety, was found to be higher in male and female H/Rouen mice as compared to NH/Rouen mice. In the elevated plus-maze, a decrease in the number of entries and in the time spent in the open arms was observed in both male and female H/Rouen. In the light/dark box, the number of entries and the time spent in the anxiogenic bright compartment was significantly reduced in male and female H/Rouen mice. In addition, the preference of consumption of a 2% sucrose solution was significantly reduced in male and female H/Rouen mice as compared to NH/Rouen and I/Rouen mice in a two-bottle choice paradigm but was restored by a chronic (3 weeks) fluoxetine treatment. H/Rouen mice thus display both anxiety and anhedonia making them a potent animal model in the treatment of forms depression comorbidly expressed with anxiety. PMID- 23933147 TI - Physical and immunogenic stability of spray freeze-dried influenza vaccine powder for pulmonary delivery: comparison of inulin, dextran, or a mixture of dextran and trehalose as protectants. AB - One of the advantages of dry influenza vaccines over conventional liquid influenza vaccines is that they can be used for alternative routes of administration. Previous studies showed that spray freeze-drying is an excellent technique to prepare vaccine containing powders for pulmonary delivery (J.P. Amorij, V. Saluja, A.H. Petersen, W.L.J. Hinrichs, A. Huckriede, H.W. Frijlink, Pulmonary delivery of an inulin-stabilized influenza subunit vaccine prepared by spray-freeze drying induces systemic, mucosal humoral as well as cell-mediated immune responses in BALB/c mice, Vaccine 25 (2007) 8707-8717; S.A. Audouy, G. van der Schaaf, W.L.J. Hinrichs, H.W. Frijlink, J. Wilschut, A. Huckriede. Development of a dried influenza whole inactivated virus vaccine for pulmonary immunization, Vaccine (2011)). The aim of this study was to investigate the physical and immunogenic stability of spray freeze-dried whole inactivated virus influenza vaccine prepared by using inulin, dextran, and a mixture of dextran and trehalose as protectants. Physical and biochemical characteristics of the vaccine powder were maintained at temperatures up to 30 degrees C for 3 months. In addition, in vivo data indicate that also, the immunogenic properties of the vaccine were maintained under these storage conditions. On the other hand, in vivo results also revealed that subtle changes in powder characteristics were induced during storage at 30 degrees C. However, laser diffraction measurements showed that problems associated with these subtle changes can be overcome by using dry powder inhalers with an efficient powder dispersing capacity. PMID- 23933148 TI - Novel mutational mechanism in the thyroglobulin gene: imperfect DNA inversion as a cause for hereditary hypothyroidism. AB - The objective of this study was to perform genetic analysis in three brothers of Turkish origin born from consanguineus parents and affected by congenital hypothyroidism, goiter and low levels of serum TG. The combination of sequencing of DNA, PCR mapping, quantitative real-time PCR, inverse-PCR (I-PCR), multiplex PCR and bioinformatics analysis were used in order to detect TG mutations. We demonstrated that the three affected siblings are homozygous for a DNA inversion of 16,962bp in the TG gene associated with two deleted regions at both sides of the inversion limits. The inversion region includes the first 9bp of exon 48, 1015bp of intron 47, 191bp of exon 47, 1523bp of intron 46, 135bp of exon 46 and the last 14,089bp of intron 45. The proximal deletion corresponds to 27bp of TG intron 45, while the distal deletion spans the last 230bp of TG exon 48 and the first 588bp of intergenic region downstream TG end. The parents were heterozygous carriers of the complex rearrangement. In conclusion, a novel large imperfect DNA inversion within the TG gene was identified by the strategy of I-PCR. This aberration was not detectable by normal sequencing of the exons and exon/intron boundaries. Remarkably, the finding represents the first description of a TG deficiency disease caused by a DNA inversion. PMID- 23933149 TI - Breast cancer: current and future endocrine therapies. AB - Endocrine therapy forms a central modality in the treatment of estrogen receptor positive breast cancer. The routine use of 5 years of adjuvant tamoxifen has improved survival rates for early breast cancer, and more recently has evolved in the postmenopausal setting to include aromatase inhibitors. The optimal duration of adjuvant endocrine therapy remains an active area of clinical study with recent data supporting 10 years rather than 5 years of adjuvant tamoxifen. However, endocrine therapy is limited by the development of resistance, this can occur by a number of possible mechanisms and numerous studies have been performed which combine endocrine therapy with agents that modulate these mechanisms with the aim of preventing or delaying the emergence of resistance. Recent trial data regarding the combination of the mammalian target of rapamycin (mTOR) inhibitor, everolimus with endocrine therapy have resulted in a redefinition of the clinical treatment pathway in the metastatic setting. This review details the current endocrine therapy utilized in both early and advanced disease, as well as exploring potential new targets which modulate pathways of resistance, as well as agents which aim to modulate adrenal derived steroidogenic hormones. PMID- 23933150 TI - RAB7 and TSG101 are required for the constitutive recycling of unliganded EGFRs via distinct mechanisms. AB - Both constitutive and ligand-mediated membrane trafficking regulate Epidermal Growth Factor Receptor (EGFR) signaling. The constitutive endocytosis and recycling of the unliganded EGFR is a critical determinant of cell surface EGFR expression and the cell's sensitivity to ligands. We report that two proteins with established roles in trafficking the EGF:EGFR complex to the lysosome also regulate the recycling of the unliganded EGFR. Knock down of either Tumor suppressor gene 101 (TSG101) or RAB7 causes the endosomal accumulation of the inactive, unliganded receptor in morphologically and biochemically distinct organelles. Knock down of TSG101 causes the EGFR to accumulate in low density endosomes whereas RAB7 knock down results in EGFR accumulation in high density endosomes. Knock down of either protein caused the receptor to co-localize primarily with LAMP-1, but not EEA1. These two proteins regulate EGFR slow, perinuclear recycling, via distinct mechanism and are new molecular targets that regulate cell surface EGFR expression. PMID- 23933151 TI - PELP1: a review of PELP1 interactions, signaling, and biology. AB - Proline, glutamic acid, and leucine rich protein 1 (PELP1) is a large multi domain protein that has been shown to modulate an increasing number of pathways and biological processes. The first reports describing the cloning and characterization of PELP1 showed that it was an estrogen receptor coactivator. PELP1 has now been shown to be a coregulator for a growing number of transcription factors. Furthermore, recent reports have shown that PELP1 is a member of chromatin remodeling complexes. In addition to PELP1 nuclear functions, it has been shown to have cytoplasmic signaling functions as well. In the cytoplasm PELP1 acts as a scaffold molecule and mediates rapid signaling from growth factor and hormone receptors. PELP1 signaling ultimately plays a role in cancer biology by increasing proliferation and metastasis, among other cellular processes. Here we will review (1) the cloning and characterization of PELP1 expression, (2) interacting proteins, (3) PELP1 signaling, and (4) PELP1-mediated biology. PMID- 23933152 TI - Tianeptine interferes with microtubule organization and hormone secretion of pheochromocytoma cells. AB - Pheochromocytoma originates from chromaffin cells in the adrenal medulla and sympathetic paraganglia. 36-53% of pheochromocytoma becomes malignant and, thereafter, resistant to conventional treatments. Pheochromocytoma also causes hyper-secretion of catecholamines that cause severe hypertension. We found that an antidepressant, tianeptine, interfered with normal life cycle of pheochromocytoma cells at its clinical doses. Treatment with tianeptine caused microtubule bundling and specific degradation of cytoplasmic dynein, a retrograde microtubule motor that mediates various microtubule-dependent processes during interphase and mitosis, in the rat pheochromocytoma PC12 cells. Tianeptine also increased the levels of pro-apoptotic proteins, slowed cell cycle progression, and increased apoptosis in PC12 cells. Importantly, tianeptine treatment decreased high K(+)-stimulated secretion of norepinephrine and chromogranin A in PC12 cells and of epinephrine in the mouse pheochromocytoma MPC cells. Our study demonstrates, for the first time, that tianeptine interferes with normal life cycle of pheochromocytoma cells. PMID- 23933153 TI - Familial pheochromocytomas and paragangliomas. AB - Pheochromocytomas and paragangliomas are neural crest cell tumors of the adrenal medulla and parasympathetic/sympathetic ganglia, respectively, that are often associated with catecholamine production. Genetic research over the years has led to our current understanding of the association 13 susceptibility genes with the development of these tumors. Most of the susceptibility genes are now associated with specific clinical presentations, biochemical makeup, tumor location, and associated neoplasms. Recent scientific advances have highlighted the role of somatic mutations in the development of pheochromocytoma/paraganglioma as well as the usefulness of immunohistochemistry in triaging genetic testing. We can now approach genetic testing in pheochromocytoma/paraganglioma patients in a very organized scientific way allowing for the reduction of both the financial and emotional burden on the patient. The discovery of genetic predispositions to the development of pheochromocytoma/paraganglioma not only facilitates better understanding of these tumors but will also lead to improved diagnosis and treatment of this disease. PMID- 23933155 TI - Lack of association between MPC2 variants and schizophrenia in a replication study of Han Chinese. AB - Schizophrenia (SCZ) is a common, complex and severe psychiatric disorder associated with many different risk factors, both genetic and environmental. A recent genome-wide association study (GWAS) of Han Chinese identified a single nucleotide polymorphism (SNP, rs10489202) in the mitochondrial pyruvate carrier 2 gene (MPC2, also known as BRP44) as a possible susceptibility locus for schizophrenia. Hoping to validate this finding, we conducted a case-control study of Han Chinese with 1093 schizophrenia cases and 1022 healthy controls, using the LDR-PCR method to genotype polymorphisms (rs10489202 and a TagSNP rs203861) in the MPC2 gene. However, we found no significant difference (P>0.05) in either allele or genotype frequency in the SNPs between patients and controls. These results did not support the previous finding suggesting the further study by using a large-scale association analysis in the future should be warranted in Han Chinese populations. PMID- 23933156 TI - Independent of 5-HT1A receptors, neurons in the paraventricular hypothalamus mediate ACTH responses from MDMA. AB - Acute and chronic complications from the substituted amphetamine 3,4 methylenedioxymethamphetamine (MDMA) are linked to activation of the hypothalamic pituitary-adrenal (HPA) axis. How MDMA activates the HPA axis is not known. HPA responses to stress are known to be mediated through the paraventricular (PVH) hypothalamus and to involve serotonin-1a (5-HT1A) receptors. We sought to determine if the PVH and 5-HT1A receptors were also involved in mediating HPA responses to MDMA. Rats were pretreated with either saline or a 5-HT1A antagonist, WAY-100635 (WAY), followed by a systemic dose of MDMA (7.5mg/kg i.v.). Animals pretreated with WAY had significantly lower plasma ACTH concentrations after MDMA. To determine if neurons in the PVH were involved, and if their involvement was mediated by 5-HT1A receptors, rats implanted with guide cannulas targeting the PVH were microinjected with the GABAA receptor agonist muscimol, aCSF, or WAY followed by MDMA. Compared to aCSF, microinjections of muscimol significantly attenuated the MDMA-induced rise in plasma ACTH (126 vs. 588pg/ml, P=<0.01). WAY had no effect. Our data demonstrates that neurons in the PVH, independent of 5-HT1A receptors, mediate ACTH responses to MDMA. PMID- 23933157 TI - Lunasin-induced behavioural effects in mice: focus on the dopaminergic system. AB - The present study for the first time is devoted to identify central effects of synthetic lunasin, a 43 amino acid peptide. A markedly expressed neuroleptic/cataleptic effect was observed at low (0.1-10 nmol/mouse) centrally administered doses in male C57Bl/6 mice. Lunasin considerably reduced the amphetamine hyperlocomotion but weakly apomorphine climbing behaviour. No influence on ketamine and bicuculline effects was observed. Binding assay studies demonstrated modest affinity of lunasin for the dopamine D1 receptor (Ki=60 +/- 15 MUM). In a functional assay of cAMP accumulation on live cells lunasin antagonised apomorphine effect on D1 receptor activation (pEC50=6.1 +/- 0.3), but had no effect in cells expressing D2 receptors. The obtained data suggest that lunasin's action at least in part is provided via dopaminergic D1 receptor pathways. However, other non-identified mechanisms (probably intracellular) may play an important role in lunasin's central action. Nevertheless further studies of lunasin are promising, particularly taking into account a necessity for novel type of antipsychotic drugs. PMID- 23933158 TI - Effect of intercellular junction protein expression on water transport during freezing of MIN6 cells. AB - A mouse insulinoma (MIN6) strain in which connexin expression has been inhibited by antisense technology holds promise as an experimental model system for investigating the role of gap junctions in intercellular ice propagation. However, to properly interpret measurements of intracellular ice formation kinetics, the effects of cell dehydration on cytoplasmic supercooling must be determined. Thus, the cell membrane water permeability in monolayer cultures of the antisense-transfected MIN6 strain was measured using a fluorescence quenching method. By repeating the experiments at 4 degrees C, 12 degrees C, 21 degrees C, and 37 degrees C, the activation energy for water transport was determined to be E(a) = 51 +/- 3 k J/mol. Although differences between membrane permeability measurements in theantisense and wild-type strains were not statistically significant, simulation of water transport during rapid freezing (130 degrees C/min) predicted that intracellular supercooling in the genetically modified MIN6 strain may become significantly larger than the supercooling in wild-type cells at temperatures below -15 degrees C. PMID- 23933154 TI - Genetics and epigenetics of sporadic thyroid cancer. AB - Thyroid carcinoma is the most common endocrine malignancy, and although the disease generally has an excellent prognosis, therapeutic options are limited for patients not cured by surgery and radioiodine. Thyroid carcinomas commonly contain one of a small number of recurrent genetic mutations. The identification and study of these mutations has led to a deeper understanding of the pathophysiology of this disease and is providing new approaches to diagnosis and therapy. Papillary thyroid carcinomas usually contain an activating mutation in the RAS cascade, most commonly in BRAF and less commonly in RAS itself or through gene fusions that activate RET. A chromosomal translocation that results in production of a PAX8-PPARG fusion protein is found in follicular carcinomas. Anaplastic carcinomas may contain some of the above changes as well as additional mutations. Therapies that are targeted to these mutations are being used in patient care and clinical trials. PMID- 23933159 TI - Large precursor tolerance database search - a simple approach for estimation of the amount of spectra with precursor mass shifts in proteomic data. AB - Mass measurement and precursor mass assignment are independent processes in proteomic data acquisition. Due to misassignments to C-13 peak, or for other reasons, extensive precursor mass shifts (i.e., deviations of the measured from calculated precursor neutral masses) in LC-MS/MS data obtained with the high accuracy LTQ-Orbitrap mass spectrometers have been reported in previous studies. Although computational methods for post-acquisition reassignment to monoisotopic mass have been developed to curate the MS/MS spectra prior to database search, a simpler method for estimating the fraction of spectra with precursor mass shift so as to determine whether the data require curation remains desirable. Here, we provide the evidence that an easy approach, which applies a large precursor tolerance (2.1Da or higher) in SEQUEST search against a forward and decoy protein sequence database and then filters the data with PeptideProphet peptide identification probability (p>=0.9), could detect most of the MS/MS spectra containing inaccurate precursor masses. Furthermore, through the implementation of artificial mass shifts on 4000 randomly selected MS/MS spectra, which originally had accurate precursor mass assigned by the mass spectrometers, we demonstrated that the accuracy of the precursor mass has almost negligible influence on the efficacy and fidelity of peptide identification. BIOLOGICAL SIGNIFICANCE: Integral precursor mass shift is a known problem and thus proteomic data should be handled and analyzed properly to avoid losing important protein identification and/or quantification information. A quick and easy approach for estimating the number of MS/MS spectra with inaccurate precursor mass assignments would be helpful for evaluating the performance of the instrument, determining whether the data requires curation prior to database search or should be searched with specific search parameter(s). Here we demonstrated most of the MS/MS spectra with inaccurate mass assignments (integral or non-integral changes) that could be easily identified by database search with large precursor tolerance windows. PMID- 23933160 TI - Method and platform standardization in MRM-based quantitative plasma proteomics. AB - There exists a growing demand in the proteomics community to standardize experimental methods and liquid chromatography-mass spectrometry (LC/MS) platforms in order to enable the acquisition of more precise and accurate quantitative data. This necessity is heightened by the evolving trend of verifying and validating candidate disease biomarkers in complex biofluids, such as blood plasma, through targeted multiple reaction monitoring (MRM)-based approaches with stable isotope-labeled standards (SIS). Considering the lack of performance standards for quantitative plasma proteomics, we previously developed two reference kits to evaluate the MRM with SIS peptide approach using undepleted and non-enriched human plasma. The first kit tests the effectiveness of the LC/MRM-MS platform (kit #1), while the second evaluates the performance of an entire analytical workflow (kit #2). Here, these kits have been refined for practical use and then evaluated through intra- and inter-laboratory testing on 6 common LC/MS platforms. For an identical panel of 22 plasma proteins, similar concentrations were determined, regardless of the kit, instrument platform, and laboratory of analysis. These results demonstrate the value of the kit and reinforce the utility of standardized methods and protocols. BIOLOGICAL SIGNIFICANCE: The proteomics community needs standardized experimental protocols and quality control methods in order to improve the reproducibility of MS-based quantitative data. This need is heightened by the evolving trend for MRM-based validation of proposed disease biomarkers in complex biofluids such as blood plasma. We have developed two kits to assist in the inter- and intra-laboratory quality control of MRM experiments: the first kit tests the effectiveness of the LC/MRM-MS platform (kit #1), while the second evaluates the performance of an entire analytical workflow (kit #2). In this paper, we report the use of these kits in intra- and inter-laboratory testing on 6 common LC/MS platforms. This article is part of a Special Issue entitled: Standardization and Quality Control in Proteomics. PMID- 23933162 TI - Clinical presentation of mild cystic fibrosis in a Serbian patient homozygous for the CFTR mutation c.1393-1G>A. AB - We present a case of a 19-year old male with uncommon initial clinical cystic fibrosis (CF) presentation and a rare CFTR genotype, homozygote for c.1393-1G>A mutation (legacy name 1525-1G>A). PMID- 23933163 TI - Involvement of purinergic system in inflammation and toxicity induced by copper in zebrafish larvae. AB - The use of zebrafish (Danio rerio) is increasing as an intermediate preclinical model, to prioritize drug candidates for mammalian testing. As the immune system of the zebrafish is quite similar to that of mammals, models of inflammation are being developed for the screening of new drugs. The characterization of these models is crucial for studies that seek for mechanisms of action and specific pharmacological targets. It is well known that copper is a metal that induces damage and cell migration to hair cells of lateral line of zebrafish. Extracellular nucleotides/nucleosides, as ATP and adenosine (ADO), act as endogenous signaling molecules during tissue damage by exerting effects on inflammatory and immune responses. The present study aimed to characterize the inflammatory status, and to investigate the involvement of the purinergic system in copper-induced inflammation in zebrafish larvae. Fishes of 7 days post fertilization were exposed to 10 MUM of copper for a period of 24 h. The grade of oxidative stress, inflammatory status, copper uptake, the activity and the gene expression of the enzymes responsible for controlling the levels of nucleotides and adenosine were evaluated. Due to the copper accumulation in zebrafish larvae tissues, the damage and oxidative stress were exacerbated over time, resulting in an inflammatory process involving IL-1beta, TNF-alpha, COX-2 and PGE2. Within the purinergic system, the mechanisms that control the ADO levels were the most involved, mainly the reactions performed by the isoenzyme ADA 2. In conclusion, our data shed new lights on the mechanisms related to copper-induced inflammation in zebrafish larvae. PMID- 23933161 TI - The Human Proteome Organization Chromosome 6 Consortium: integrating chromosome centric and biology/disease driven strategies. AB - The Human Proteome Project (HPP) is designed to generate a comprehensive map of the protein-based molecular architecture of the human body, to provide a resource to help elucidate biological and molecular function, and to advance diagnosis and treatment of diseases. Within this framework, the chromosome-based HPP (C-HPP) has allocated responsibility for mapping individual chromosomes by country or region, while the biology/disease HPP (B/D-HPP) coordinates these teams in cross functional disease-based groups. Chromosome 6 (Ch6) provides an excellent model for integration of these two tasks. This metacentric chromosome has a complement of 1002-1034 genes that code for known, novel or putative proteins. Ch6 is functionally associated with more than 120 major human diseases, many with high population prevalence, devastating clinical impact and profound societal consequences. The unique combination of genomic, proteomic, metabolomic, phenomic and health services data being drawn together within the Ch6 program has enormous potential to advance personalized medicine by promoting robust biomarkers, subunit vaccines and new drug targets. The strong liaison between the clinical and laboratory teams, and the structured framework for technology transfer and health policy decisions within Canada will increase the speed and efficacy of this transition, and the value of this translational research. BIOLOGICAL SIGNIFICANCE: Canada has been selected to play a leading role in the international Human Proteome Project, the global counterpart of the Human Genome Project designed to understand the structure and function of the human proteome in health and disease. Canada will lead an international team focusing on chromosome 6, which is functionally associated with more than 120 major human diseases, including immune and inflammatory disorders affecting the brain, skeletal system, heart and blood vessels, lungs, kidney, liver, gastrointestinal tract and endocrine system. Many of these chronic and persistent diseases have a high population prevalence, devastating clinical impact and profound societal consequences. As a result, they impose a multi-billion dollar economic burden on Canada and on all advanced societies through direct costs of patient care, the loss of health and productivity, and extensive caregiver burden. There is no definitive treatment at the present time for any of these disorders. The manuscript outlines the research which will involve a systematic assessment of all chromosome 6 genes, development of a knowledge base, and development of assays and reagents for all chromosome 6 proteins. We feel that the informatic infrastructure and MRM assays developed will place the chromosome 6 consortium in an excellent position to be a leading player in this major international research initiative. This article is part of a Special Issue: Can Proteomics Fill the Gap Between Genomics and Phenotypes? PMID- 23933164 TI - Anticancer effect of genistein on BG-1 ovarian cancer growth induced by 17 beta estradiol or bisphenol A via the suppression of the crosstalk between estrogen receptor alpha and insulin-like growth factor-1 receptor signaling pathways. AB - The interaction between estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathway plays an important role in proliferation of and resistance to endocrine therapy to estrogen dependent cancers. Estrogen (E2) upregulates the expression of components of IGF-1 system and induces the downstream of mitogenic signaling cascades via phosphorylation of insulin receptor substrate-1 (IRS-1). In the present study, we evaluated the xenoestrogenic effect of bisphenol A (BPA) and antiproliferative activity of genistein (GEN) in accordance with the influence on this crosstalk. BPA was determined to affect this crosstalk by upregulating mRNA expressions of ERalpha and IGF-1R and inducing phosphorylation of IRS-1 and Akt in protein level in BG-1 ovarian cancer cells as E2 did. In the mouse model xenografted with BG-1 cells, BPA significantly increased a tumor burden of mice and expressions of ERalpha, pIRS-1, and cyclin D1 in tumor mass compared to vehicle, indicating that BPA induces ovarian cancer growth by promoting the crosstalk between ER and IGF-1R signals. On the other hand, GEN effectively reversed estrogenicity of BPA by reversing mRNA and protein expressions of ERalpha, IGF-1R, pIRS-1, and pAkt induced by BPA in cellular model and also significantly decreased tumor growth and in vivo expressions of ERalpha, pIRS-1, and pAkt in xenografted mouse model. Also, GEN was confirmed to have an antiproliferative effect by inducing apoptotic signaling cascades. Taken together, these results suggest that GEN effectively reversed the increased proliferation of BG-1 ovarian cancer by suppressing the crosstalk between ERalpha and IGF-1R signaling pathways upregulated by BPA or E2. PMID- 23933165 TI - Hydroxysafflor yellow A suppresses oleic acid-induced acute lung injury via protein kinase A. AB - Inflammation response and oxidative stress play important roles in acute lung injury (ALI). Activation of the cAMP/protein kinase A (PKA) signaling pathway may attenuate ALI by suppressing immune responses and inhibiting the generation of reactive oxygen species (ROS). Hydroxysafflor yellow A (HSYA) is a natural flavonoid compound that reduces oxidative stress and inflammatory cytokine mediated damage. In this study, we examined whether HSYA could protect the lungs from oleic acid (OA)-induced injury, which was used to mimic ALI, and determined the role of the cAMP/PKA signaling pathway in this process. Arterial oxygen tension (PaO2), carbon dioxide tension, pH, and the PaO2/fraction of inspired oxygen ratio in the blood were detected using a blood gas analyzer. We measured wet/dry lung weight ratio and evaluated tissue morphology. The protein and inflammatory cytokine levels in the bronchoalveolar lavage fluid and serum were determined using enzyme-linked immunoassay. The activities of superoxide dismutase, glutathione peroxidase, PKA, and nicotinamide adenine dinucleotide phosphate oxidase, and the concentrations of cAMP and malondialdehyde in the lung tissue were detected using assay kits. Bcl-2, Bax, caspase 3, and p22(phox) levels in the lung tissue were analyzed using Western blotting. OA increased the inflammatory cytokine and ROS levels and caused lung dysfunction by decreasing cAMP synthesis, inhibiting PKA activity, stimulating caspase 3, and reducing the Bcl-2/Bax ratio. H-89 increased these effects. HSYA significantly increased the activities of antioxidant enzymes, inhibited the inflammatory response via cAMP/PKA pathway activation, and attenuated OA-induced lung injury. Our results show that the cAMP/PKA signaling pathway is required for the protective effect of HSYA against ALI. PMID- 23933166 TI - Quantitative assessment of biological impact using transcriptomic data and mechanistic network models. AB - Exposure to biologically active substances such as therapeutic drugs or environmental toxicants can impact biological systems at various levels, affecting individual molecules, signaling pathways, and overall cellular processes. The ability to derive mechanistic insights from the resulting system responses requires the integration of experimental measures with a priori knowledge about the system and the interacting molecules therein. We developed a novel systems biology-based methodology that leverages mechanistic network models and transcriptomic data to quantitatively assess the biological impact of exposures to active substances. Hierarchically organized network models were first constructed to provide a coherent framework for investigating the impact of exposures at the molecular, pathway and process levels. We then validated our methodology using novel and previously published experiments. For both in vitro systems with simple exposure and in vivo systems with complex exposures, our methodology was able to recapitulate known biological responses matching expected or measured phenotypes. In addition, the quantitative results were in agreement with experimental endpoint data for many of the mechanistic effects that were assessed, providing further objective confirmation of the approach. We conclude that our methodology evaluates the biological impact of exposures in an objective, systematic, and quantifiable manner, enabling the computation of a systems-wide and pan-mechanistic biological impact measure for a given active substance or mixture. Our results suggest that various fields of human disease research, from drug development to consumer product testing and environmental impact analysis, could benefit from using this methodology. PMID- 23933167 TI - SEF14 fimbriae from Salmonella enteritidis play a role in pathogenitic to cell model in vitro and host in vivo. AB - The role of SEF14 fimbriae in virulence remains to be elucidated and in this study, we showed that sefA mutant constructed in the wild-type (WT) Salmonella enteritidis strain 50336 displayed increased invasion to IPEC-J2 cell lines and survival in mouse peritoneal macrophages, and the lethal dose 50% (LD50) in 6 week-old Balb/c mice intra-peritoneally injected with WT S. enteritidis strain decreased significantly upon deletion of sefA indicating their role in virulence. Overall, these results demonstrated that expression of sefA of SEF14 fimbriae enhances S. enteritidis adhesion to epithelial cells and survival in macrophages and contributes to S. enteritidis virulence in mice. PMID- 23933168 TI - Establishment of caudal fin cell lines from tropical ornamental fishes Puntius fasciatus and Pristolepis fasciata endemic to the Western Ghats of India. AB - Two new cell lines, PFF and CFF were established from the caudal fin of the Puntius fasciatus, and Pristolepis fasciata respectively. Since their initiation, these cell lines (PFF and CFF) have been subcultured in L-15 medium with 10% fetal bovine serum for more than 35 passages at 28 degrees C and both the cell lines were characterized. Karyotyping analysis of PFF and CFF cells at 25th passage indicated that the modal chromosome number was 2n=50 and 2n=48 respectively. The cell line was cryopreserved in liquid nitrogen at -196 degrees C and could be recovered from storage after six months with good cell viability. Polymerase chain reaction amplification of the fragments of two mitochondrial genes, 16S rRNA and COI confirmed that the cell lines originated from the respective species. The bacterial extracellular products from Vibrio cholerae MTCC3904 and Aeromonas hydrophila were found to be toxic to PFF and CFF. Both the cells were resistant to the marine viral nervous necrosis virus (VNNV). No CPE could be found in both cell lines inoculated with the fish samples and cell culture supernatants were demonstrated free of SVC, iridovirus and KHV by molecular methods. These results indicated the absence of SVC, iridovirus and KHV in the ornamental fishes collected from the Western Ghats of India. PMID- 23933170 TI - Can working memory predict target-to-target interval effects in the P300? AB - It has been suggested that the P300 component of the ERP is an electrophysiological index of memory-updating processes associated with task relevant stimuli. Component magnitude varies with the time separating target stimuli (target-to-target interval: TTI), with longer TTIs eliciting larger P300 amplitudes. According to the template-update perspective, TTI effects observable in the P300 reflect the updating of stimulus-templates in working memory (WM). The current study explored whether young adults' memory-task ability could predict TTI effects in P300. EEG activity was recorded from 50 university students (aged 18-25 years) while they completed an auditory equiprobable Go/NoGo task with manipulations of TTIs. Participants also completed a CogState(r) battery and were sorted according to their WM score. ERPs were analysed using a temporal PCA. Two P300 components, P3b and the Slow Wave, were found to linearly increase in amplitude to longer TTIs. This TTI effect differed between groups only for the P3b component: The high WM group showed a steeper increase in P3b amplitude with TTI than the low WM group. These results suggest that TTI effects in P300 are directly related to WM processes. PMID- 23933171 TI - Directional migration of leading-edge mesoderm generates physical forces: Implication in Xenopus notochord formation during gastrulation. AB - Gastrulation is a dynamic tissue-remodeling process occurring during early development and fundamental to the later organogenesis. It involves both chemical signals and physical factors. Although much is known about the molecular pathways involved, the roles of physical forces in regulating cellular behavior and tissue remodeling during gastrulation have just begun to be explored. Here, we characterized the force generated by the leading edge mesoderm (LEM) that migrates preceding axial mesoderm (AM), and investigated the contribution of LEM during Xenopus gastrulation. First, we constructed an assay system using micro needle which could measure physical forces generated by the anterior migration of LEM, and estimated the absolute magnitude of the force to be 20-80nN. Second, laser ablation experiments showed that LEM could affect the force distribution in the AM (i.e. LEM adds stretch force on axial mesoderm along anterior-posterior axis). Third, migrating LEM was found to be necessary for the proper gastrulation cell movements and the establishment of organized notochord structure; a reduction of LEM migratory activity resulted in the disruption of mediolateral cell orientation and convergence in AM. Finally, we found that LEM migration cooperates with Wnt/PCP to form proper notochord. These results suggest that the force generated by the directional migration of LEM is transmitted to AM and assists the tissue organization of notochord in vivo independently of the regulation by Wnt/PCP. We propose that the LEM may have a mechanical role in aiding the AM elongation through the rearrangement of force distribution in the dorsal marginal zone. PMID- 23933172 TI - New regulatory circuit controlling spatial and temporal gene expression in the sea urchin embryo oral ectoderm GRN. AB - The sea urchin oral ectoderm gene regulatory network (GRN) model has increased in complexity as additional genes are added to it, revealing its multiple spatial regulatory state domains. The formation of the oral ectoderm begins with an oral aboral redox gradient, which is interpreted by the cis-regulatory system of the nodal gene to cause its expression on the oral side of the embryo. Nodal signaling drives cohorts of regulatory genes within the oral ectoderm and its derived subdomains. Activation of these genes occurs sequentially, spanning the entire blastula stage. During this process the stomodeal subdomain emerges inside of the oral ectoderm, and bilateral subdomains defining the lateral portions of the future ciliary band emerge adjacent to the central oral ectoderm. Here we examine two regulatory genes encoding repressors, sip1 and ets4, which selectively prevent transcription of oral ectoderm genes until their expression is cleared from the oral ectoderm as an indirect consequence of Nodal signaling. We show that the timing of transcriptional de-repression of sip1 and ets4 targets which occurs upon their clearance explains the dynamics of oral ectoderm gene expression. In addition two other repressors, the direct Nodal target not, and the feed forward Nodal target goosecoid, repress expression of regulatory genes in the central animal oral ectoderm thereby confining their expression to the lateral domains of the animal ectoderm. These results have permitted construction of an enhanced animal ectoderm GRN model highlighting the repressive interactions providing precise temporal and spatial control of regulatory gene expression. PMID- 23933173 TI - mTOR activation in immature cells of primary nasopharyngeal carcinoma and anti tumor effect of rapamycin in vitro and in vivo. AB - The mammalian target of rapamycin (mTOR) signaling is a key pathway in the progression of different cancers and in the homeostasis of stem cells. Here, we investigated the link between mTOR signaling and cancer stem cells (CSCs) in nasopharyngeal carcinoma (NPC). We found that human primary NPC expressed embryonic stem cell (ESC) markers: CD133, SOX2 and OCT4 as well as pmTOR and pS6. Primary ESC-positive NPC cells could form secondary NPC in BALB/c nude mice. Rapamycin, an mTOR inhibitor, significantly suppressed ESC-positive NPC cell growth in vitro and tumor formation in vivo. Our findings suggest that mTOR signaling is activated in CSC-like cells and plays an important role in NPC growth. PMID- 23933169 TI - Aging is not a disease: distinguishing age-related macular degeneration from aging. AB - Age-related macular degeneration (AMD) is a disease of the outer retina, characterized most significantly by atrophy of photoreceptors and retinal pigment epithelium accompanied with or without choroidal neovascularization. Development of AMD has been recognized as contingent on environmental and genetic risk factors, the strongest being advanced age. In this review, we highlight pathogenic changes that destabilize ocular homeostasis and promote AMD development. With normal aging, photoreceptors are steadily lost, Bruch's membrane thickens, the choroid thins, and hard drusen may form in the periphery. In AMD, many of these changes are exacerbated in addition to the development of disease-specific factors such as soft macular drusen. Para-inflammation, which can be thought of as an intermediate between basal and robust levels of inflammation, develops within the retina in an attempt to maintain ocular homeostasis, reflected by increased expression of the anti-inflammatory cytokine IL-10 coupled with shifts in macrophage plasticity from the pro-inflammatory M1 to the anti-inflammatory M2 polarization. In AMD, imbalances in the M1 and M2 populations together with activation of retinal microglia are observed and potentially contribute to tissue degeneration. Nonetheless, the retina persists in a state of chronic inflammation and increased expression of certain cytokines and inflammasomes is observed. Since not everyone develops AMD, the vital question to ask is how the body establishes a balance between normal age-related changes and the pathological phenotypes in AMD. PMID- 23933174 TI - Technical considerations for analyzing EMT-MET data from surgical samples. AB - With an increase of neoadjuvant therapy, biopsy samples have become imperative for cancer research; however, what kind of difference between surgical and endoscopic biopsy samples in gene expression profiles was still unclear. Recently, we reported artificially induced epithelial-mesenchymal transition (aiEMT) in the surgical samples by comparison between gene expression profiles of both samples of the esophagus. This was also found in mouse epithelium under an ischemic condition for 4h. This study will evoke underestimation of the prognostic evaluation power of EMT related markers in past cancer research and prevalence of biopsy samples for in vivo expression profiling with low biases. PMID- 23933175 TI - E. coli and colon cancer: is mutY a culprit? AB - The recent demonstration of a role of Escherichia coli in the development of invasive carcinoma in mice ushers a new era of bacterial involvement in cancer etiology. It has been shown previously that the colonic mucosa of colorectal carcinoma (CRC) is exclusively colonized by intracellular E. coli instead of extracellular form found in normal colonic mucosa. Surprisingly, the DNA repair gene MUTYH, which is a homologue of the E. coli gene mutY, is responsible for CRC. The current paper discusses the potential role of mutY in CRC etiology and concludes that research in this area can bring together the diverse threads of the CRC etiology puzzle. PMID- 23933176 TI - Genomics and epigenomics of clear cell renal cell carcinoma: recent developments and potential applications. AB - Majority of clear cell renal cell carcinomas (ccRCCs) are diagnosed in the advanced metastatic stage resulting in dramatic decrease of patient survival. Thereby, early detection and monitoring of the disease may improve prognosis and treatment results. Recent technological advances enable the identification of genetic events associated with ccRCC and reveal significant molecular heterogeneity of ccRCC tumors. This review summarizes recent findings in ccRCC genomics and epigenomics derived from chromosomal aberrations, DNA sequencing and methylation, mRNA, miRNA expression profiling experiments. We provide a molecular insight into ccRCC pathology and recapitulate possible clinical applications of genomic alterations as predictive and prognostic biomarkers. PMID- 23933177 TI - Novel synthetic curcumin analogues EF31 and UBS109 are potent DNA hypomethylating agents in pancreatic cancer. AB - DNA methylation is a rational therapeutic target in pancreatic cancer. The activity of novel curcumin analogues EF31 and UBS109 as demethylating agents were investigated. MiaPaCa-2 and PANC-1 cells were treated with vehicle, curcumin, EF31 or UBS109. EF31 and UBS109 resulted in significantly higher inhibition of proliferation and cytosine methylation than curcumin. Demethylation was associated with re-expression of silenced p16, SPARC, and E-cadherin. EF31 and UBS109 inhibited HSP-90 and NF-kappaB leading to downregulation of DNA methyltransferase-1 (DNMT-1) expression. Transfection experiments confirmed this mechanism of action. Similar results were observed in vitro when subcutaneous tumors (MiaPaCa-2) were treated with EF31 and UBS109. PMID- 23933179 TI - Development of numerical estimation in Chinese preschool children. AB - Although much is known about the development of mental representations of numbers, it is not clear how early children begin to represent numbers on a linear scale. The current study aimed to examine the development of numerical estimation of Chinese preschoolers. In total, 160 children of three age groups (51 3- and 4-year-olds, 50 5-year-olds, and 59 6-year-olds) were administered the numerical estimation task on three types of number lines (Arabic numbers, dots, and objects). All three age groups took the test on the 0-10 number lines, and the oldest group also took it on the 0-100 and 0-1000 Arabic number lines. Results showed that (a) linear representation of numbers increased with age, (b) representation of numbers was consistent across the three types of tasks, (c) Chinese participants generally showed earlier onset of various landmarks of attaining linear representations (e.g., linearity of various number ranges, accuracy, intercepts) than did their Western counterparts, as reported in previous studies, and (d) the estimates of older Chinese preschoolers on the 0 100 and 0-1000 symbolic number lines fitted the two-linear and linear models better than alternative models such as the one-cycle, two-cycle, and logarithmic models. These results extend the small but accumulating literature on the earlier development of number cognition among Chinese preschoolers compared with their Western counterparts, suggesting the importance of cultural factors in the development of early number cognition. PMID- 23933178 TI - Review: molecular mechanism of microglia stimulated glioblastoma invasion. AB - Glioblastoma multiforme is one of the deadliest human cancers and is characterized by a high degree of microglia and macrophage infiltration. The role of these glioma infiltrating macrophages (GIMs) in disease progression has been the subject of recent investigation. While initially thought to reflect an immune response to the tumor, the balance of evidence clearly suggests GIMs can have potent tumor-tropic functions and assist in glioma cell growth and infiltration into normal brain. In this review, we focus on the evidence for GIMs aiding mediating glioblastoma motility and invasion. We survey the literature for molecular pathways that are involved in paracrine interaction between glioma cells and GIMs and assess which of these might serve as attractive targets for therapeutic intervention. PMID- 23933180 TI - Sex-related preferences for real and doll faces versus real and toy objects in young infants and adults. AB - Findings of previous studies demonstrate sex-related preferences for toys in 6 month-old infants; boys prefer nonsocial or mechanical toys such as cars, whereas girls prefer social toys such as dolls. Here, we explored the innate versus learned nature of this sex-related preferences using multiple pictures of doll and real faces (of men and women) as well as pictures of toy and real objects (cars and stoves). In total, 48 4- and 5-month-old infants (24 girls and 24 boys) and 48 young adults (24 women and 24 men) saw six trials of all relevant pairs of faces and objects, with each trial containing a different exemplar of a stimulus type. The infant results showed no sex-related preferences; infants preferred faces of men and women regardless of whether they were real or doll faces. Similarly, adults did not show sex-related preferences for social versus nonsocial stimuli, but unlike infants they preferred faces of the opposite sex over objects. These results challenge claims of an innate basis for sex-related preferences for toy real stimuli and suggest that sex-related preferences result from maturational and social development that continues into adulthood. PMID- 23933181 TI - Anti-nociceptive effect of a conjugate of substance P and light chain of botulinum neurotoxin type A. AB - Neuropathic pain is a debilitating condition resulting from damage to sensory transmission pathways in the peripheral and central nervous system. A potential new way of treating chronic neuropathic pain is to target specific pain processing neurons based on their expression of particular receptor molecules. We hypothesized that a toxin-neuropeptide conjugate would alter pain by first being taken up by specific receptors for the neuropeptide expressed on the neuronal cells. Then, once inside the cell the toxin would inhibit the neurons' activity without killing the neurons, thereby providing pain relief without lesioning the nervous system. In an effort to inactivate the nociceptive neurons in the trigeminal nucleus caudalis in mice, we targeted the NK1 receptor (NK1R) using substance P (SP). The catalytically active light chain of botulinum neurotoxin type A (LC/A) was conjugated with SP. Our results indicate that the conjugate BoNT/A-LC:SP is internalized in cultured NK1R-expressing neurons and also cleaves the target of botulinum toxin, a component-docking motif necessary for release of neurotransmitters called SNAP-25. The conjugate was next tested in a murine model of Taxol-induced neuropathic pain. An intracisternal injection of BoNT/A-LC:SP decreased thermal hyperalgesia as measured by the operant orofacial nociception assay. These findings indicate that conjugates of the light chain of botulinum toxin are extremely promising agents for use in suppressing neuronal activity for extended time periods, and that BoNT/A-LC:SP may be a useful agent for treating chronic pain. PMID- 23933182 TI - Does severe acute pain provoke lasting changes in attentional and emotional mechanisms of pain-related processing? A longitudinal study. AB - Pain experiences, learning, and genetic factors have been proposed to shape attentional and emotional processes related to pain. We aimed at investigating whether a singular major pain experience also changes cognitive-emotional processing. The influence of acute postoperative pain after cosmetic surgery of the thorax was tested in 80 preoperatively pain-free male individuals. Acute pain was measured as independent variable during the first week postsurgery by pain intensity ratings and the requested analgesic boluses (Patient-Controlled Epidural Analgesia (PCEA)). Pain catastrophizing (Pain Catastrophizing Scale (PCS)), pain anxiety (Pain Anxiety and Symptom Scale (PASS)), pain hypervigilance (Pain Vigilance and Awareness Questionnaire (PVAQ)), and attentional biases to emotionally loaded stimuli (including pain) in a dot-probe task were assessed 1 week, 3 months, and 6 months postsurgery as dependent variables. Hierarchical regression analyses were performed to test whether the 2 acute pain parameters can predict these cognitive-emotional variables. As a rigorous test, significant prediction was required in addition to the prediction of the dependent variables by themselves with lag-1. Acute pain (mainly the pain ratings) appeared to be a significant predictor for PCS, PASS, and PVAQ 1 week after surgery (deltaR(2) = [8.7% to 11.3%]). In contrast, the attentional biases in the dot-probe task could not be predicted by the pain ratings. The levels of pain catastrophizing and pain hypervigilance increased in the acute phase after surgery when influenced by acute pain and declined, along with pain anxiety, during the next 3 months. In conclusion, a one-time intense pain experience, such as acute postoperative pain, appeared to produce at least short-lived changes in the attentional and emotional processing of pain. PMID- 23933183 TI - The words patients use to describe chronic pain: implications for measuring pain quality. AB - Patients with low back pain (LBP; N = 102), fibromyalgia (FM; N = 100), and headache (HA; N = 100) were asked to describe their pain in their own words, and the words and phrases they used were then classified into 7 global domains (eg, Pain Quality, Pain Magnitude) and as many specific subdomains as needed to capture all of the ideas expressed (eg, under Pain Quality, subdomains such as sharp, achy, and throbbing). Fifteen pain quality subdomains were identified as most common. Nine of these demonstrated significant between-group differences in frequency. For example, patients with FM described their pain as achy more often than patients with LBP or HA; patients with HA described their pain as more throbbing than patients with LBP or FM; and patients with LBP described their pain as more shooting than patients with FM or HA. With the 15 pain quality subdomains representing the universe of most important pain qualities to assess, only 2 of 8 descriptive measures of pain quality were determined to have content validity. The findings are generally consistent with a study that used similar procedures in other patient samples to identify the most common words patients use to describe pain, supporting their generalizability. The findings also support the use of pain quality measures for discriminating between chronic pain conditions. Finally, the findings have important implications for evaluating and modifying pain quality measures as needed. PMID- 23933185 TI - Tridimensional ultrastructure and glycolipid pattern studies of Trypanosoma dionisii. AB - Trypanosoma (Schizotrypanum) dionisii is a non-pathogenic bat trypanosome closely related to Trypanosoma cruzi, the etiological agent of Chaga's disease. Both kinetoplastids present similar morphological stages and are able to infect mammalian cells in culture. In the present study we examined 3D ultrastructure aspects of the two species by serial sectioning epimastigote and trypomastigote forms, and identified common carbohydrate epitopes expressed in T. dionisii, T. cruzi and Leishmania major. A major difference in 3D morphology was that T. dionisii epimastigote forms present larger multivesicular structures, restricted to the parasite posterior region. These structures could be related to T. cruzi reservosomes and are also rich in cruzipain, the major cysteine-proteinase of T. cruzi. We analyzed the reactivity of two monoclonal antibodies: MEST-1 directed to galactofuranose residues of glycolipids purified from Paracoccidioides brasiliensis, and BST-1 directed to glycolipids purified from T. cruzi epimastigotes. Both antibodies were reactive with T. dionisii epimastigotes by indirect immunofluorescense, but we noted differences in the location and intensity of the epitopes, when compared to T. cruzi. In summary, despite similar features in cellular structure and life cycle of T. dionisii and T. cruzi, we observed a unique morphological characteristic in T. dionisii that deserves to be explored. PMID- 23933184 TI - Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting the TRPA1 channel. AB - Although feverfew has been used for centuries to treat pain and headaches and is recommended for migraine treatment, the mechanism for its protective action remains unknown. Migraine is triggered by calcitonin gene-related peptide (CGRP) release from trigeminal neurons. Peptidergic sensory neurons express a series of transient receptor potential (TRP) channels, including the ankyrin 1 (TRPA1) channel. Recent findings have identified agents either inhaled from the environment or produced endogenously that are known to trigger migraine or cluster headache attacks, such as TRPA1 simulants. A major constituent of feverfew, parthenolide, may interact with TRPA1 nucleophilic sites, suggesting that feverfew's antimigraine effect derives from its ability to target TRPA1. We found that parthenolide stimulates recombinant (transfected cells) or natively expressed (rat/mouse trigeminal neurons) TRPA1, where it, however, behaves as a partial agonist. Furthermore, in rodents, after initial stimulation, parthenolide desensitizes the TRPA1 channel and renders peptidergic TRPA1-expressing nerve terminals unresponsive to any stimulus. This effect of parthenolide abrogates nociceptive responses evoked by stimulation of peripheral trigeminal endings. TRPA1 targeting and neuronal desensitization by parthenolide inhibits CGRP release from trigeminal neurons and CGRP-mediated meningeal vasodilatation, evoked by either TRPA1 agonists or other unspecific stimuli. TRPA1 partial agonism, together with desensitization and nociceptor defunctionalization, ultimately resulting in inhibition of CGRP release within the trigeminovascular system, may contribute to the antimigraine effect of parthenolide. PMID- 23933186 TI - Seasonal and nonseasonal dynamics of Aedes aegypti in Rio de Janeiro, Brazil: fitting mathematical models to trap data. AB - Mathematical models suggest that seasonal transmission and temporary cross immunity between serotypes can determine the characteristic multi-year dynamics of dengue fever. Seasonal transmission is attributed to the effect of climate on mosquito abundance and within host virus dynamics. In this study, we validate a set of temperature and density dependent entomological models that are built-in components of most dengue models by fitting them to time series of ovitrap data from three distinct neighborhoods in Rio de Janeiro, Brazil. The results indicate that neighborhoods differ in the strength of the seasonal component and that commonly used models tend to assume more seasonal structure than found in data. Future dengue models should investigate the impact of heterogeneous levels of seasonality on dengue dynamics as it may affect virus maintenance from year to year, as well as the risk of disease outbreaks. PMID- 23933187 TI - The anti-chemoresistant effect and mechanism of MUC1 aptamer-miR-29b chimera in ovarian cancer. AB - OBJECTIVE: Currently, there are no effective therapies for advanced ovarian cancer. In this study, we aim to determine the anti-tumor effect of MUC1 aptamer miR-29b chimera in xenograft ovarian cancer models and chemo-resistance tumor model and to further explore the associated mechanism. METHODS: Xenograft ovarian cancer animal models were established using OVCAR-3, OVCA420, and OVCAR-3-Taxol cancer cells. The chimera (Chi-29b) was delivered through intraperitoneal injections. Tumor growth was evaluated. Gene expression and PTEN methylation were measured. RESULTS: We demonstrated that intratumoral injection of Chi-29b chimera significantly inhibited the growth of xenograft OVCAR-3 tumors through downregulating PTEN methylation, subsequent PTEN expression, as well as downregulating MAPK 4 and IGF1 expressions. In contrast, Chi-29b inhibited tumor growth in OVCA420 tumors by downregulating MAPK 4 & 10 and IGF1 expression without affecting PTEN expression. Intraperitoneal injection of Chi-29b significantly increased apoptosis in paclitaxel-resistant OVCAR-3 cells and inhibited the growth of xenograft OVCAR-3-Taxol tumors. The anti-chemoresistant role of Chi-29b in OVCAR-3-Taxol tumors was associated with the activation of PTEN signaling and downregulation of MAPK 4 and 10 and IGF1 expression. CONCLUSION: Our study indicated that Chi-29b chimera can effectively exert an anti-tumor effect in xenograft tumor models and an anti-chemoresistant role through inhibiting cancer stem cell activation. PMID- 23933188 TI - Helper T cells down-regulate CD4 expression upon chronic stimulation giving rise to double-negative T cells. AB - Double-negative T (DNT) cells are alphabetaTCR(+)CD3(+)CD4(-)CD8(-)NK1.1(-) cells that constitute a small but significant proportion of the alphabetaTCR(+) T cells. Their developmental pathway and pathological significance remain unclear. In the present study, we utilized chronic in vitro stimulation of CD4(+) T cells to mimic immune hyper-activation of autoimmune lymphoproliferative syndrome and systemic lupus erythematosus, conditions characterized by DNT cells accumulation. After approximately 4-5 rounds of stimulation, the CD3(+)CD4(-) population became apparent. These cells did not express CD8, NK1.1, gammadeltaTCR, or B220, exhibited a highly proliferative effector phenotype, and were dependent on T cell receptor (TCR) stimulation for survival. Moreover, CD3(+)CD4(-) cells expressed MHC class II-restricted alphabetaTCR, indicative of their origin from a CD4(+) T cell population. The results presented herein illustrate a novel method of DNT cell generation in vitro and suggest that immune hyper-activation could also be implicated in the genesis of the disease-associated DNT cells in vivo. PMID- 23933189 TI - Genetic boundaries to delineate the typhoid agent and other Salmonella serotypes into distinct natural lineages. AB - The deadly human typhoid agent was initially classified as a species called Salmonella typhi but later reclassified as a serovar of Salmonella enterica together with other pathogenically diverse serovars. The dynamic changes of Salmonella taxonomy reflect the need to clarify the phylogenetic status of the Salmonella serovars: are they discrete lineages or variants of a genetic lineage? To answer this question, we compared S. typhi and other Salmonella serotypes. We found that the S. typhi and Salmonella typhimurium strains had over 90% and ca. 80%, respectively, of their genes identical; however, between S. typhi and S. typhimurium, this percentage dropped to 6%, suggesting the existence of genetic boundaries between them. We conclude that S. typhi and the other compared Salmonella serovars have developed into distinct lineages circumscribed by the genetic boundary. This concept and methods may be used to delineate other Salmonella serotypes, many of which are polyphyletic, needing differentiation. PMID- 23933190 TI - External surface area determination of lipid vesicles using trinitrobenzene sulfonate and ultraviolet/visible spectrophotometry. AB - The lamellarity of liposomes is an important parameter to be controlled in liposomal delivery-release applications. A practical estimate of the degree of liposome lamellarity can be obtained by measuring the relative external surface area of the liposomes using a chemical assay. All such assays are based on a signal change caused by exposed marker lipids on reaction with a specific externally added reagent. However, a quantitative determination is often distorted by background reactions and contributions of internal lipid labeling. In the so-called TNBS assay, the marker lipid is phosphatidylethanolamine (PE) and the externally added reagent is TNBS (2,4,6-trinotrobenzene sulfonate). Mechanistic aspects of the TNBS assay were considered for improving the assay. Internal lipid labeling via PE flip-flop and/or TNBS permeation was minimal not only in cholesterol-containing liposomes but also in cholesterol-free liposomes if in the latter case membrane fluidity was decreased by slightly increasing the PE content. Compared with earlier versions of the TNBS assay, the amount of marker lipid and the time for analysis could be reduced considerably. The elaborated protocol was also applied to liposomes prepared from lipidic egg yolk isolates, offering a simple and inexpensive method for the development and in process control of new liposome formation technologies. PMID- 23933191 TI - Case study: the role of mechanistic network models in systems toxicology. AB - Twenty first century systems toxicology approaches enable the discovery of biological pathways affected in response to active substances. Here, we briefly summarize current network approaches that facilitate the detailed mechanistic understanding of the impact of a given stimulus on a biological system. We also introduce our network-based method with two use cases and show how causal biological network models combined with computational methods provide quantitative mechanistic insights. Our approach provides a robust comparison of the transcriptional responses in different experimental systems and enables the identification of network-based biomarkers modulated in response to exposure. These advances can also be applied to pharmacology, where the understanding of disease mechanisms and adverse drug effects is imperative for the development of efficient and safe treatment options. PMID- 23933192 TI - Primary biliary cirrhosis: is there still a place for histological evaluation? PMID- 23933193 TI - Hepatitis C virus infection in hemodialysis patients. AB - Hepatitis C virus (HCV) infection is observed in around 20% of dialysis patients and in allograft recipients and results in a significant morbidity and mortality, especially after transplantation. Its prevalence has markedly decreased in patients who are candidates for transplantation since the introduction of screening, hygiene and prevention measures, including systematic screening of blood and organ donations, use of erythropoietin, and compliance with universal hygiene rules. A liver biopsy is preferable to non-invasive biochemical and/or morphological tests of fibrosis to evaluate liver fibrosis before and even after transplantation. In HCV-infected dialyzed patients who are not candidates for renal transplantation, the indication for antiviral therapy is limited to significant fibrosis (fibrosis >= 2 on the METAVIR scale). Antiviral treatment should be proposed to any HCV-infected candidate for renal transplantation, whatever the baseline histopathology. The recommendation is to use standard interferon-alpha as monotherapy, but pegylated interferon can be used, resulting in sustained virological response, while low doses of combined ribavirin may enhance the antiviral efficacy. After transplantation, interferon-alpha is contra indicated but may be used in patients for whom the benefits of antiviral treatment clearly outweigh the risks, especially that of allograft rejection. All cirrhotic patients should be screened for hepatocellular carcinoma, whose risk is enhanced by immunosuppressive regimens. Sustained suppression of necro inflammation may result in the reversal of cirrhosis, which reduces liver-related morbidity and improves patient and allograft survival. Finally, due to the high mortality after renal transplantation, active cirrhosis must be considered to be a contraindication to kidney transplantation, but an indication to combined liver kidney transplantation; on the contrary, inactive compensated cirrhosis may permit renal transplantation alone. PMID- 23933194 TI - Putative prognostic epithelial-to-mesenchymal transition biomarkers for aggressive prostate cancer. AB - Prostate cancer is the second most frequently diagnosed cancer worldwide and is the sixth leading cause of cancer deaths in men, yet it varies greatly in its aggressiveness. Currently, it is not possible to adequately differentiate between patients whose tumors will remain indolent and those patients whose disease will progress, resulting in unnecessary aggressive treatment. Consequently, there is an urgent need to identify markers of prostate cancer progression, invasiveness and metastasis to more accurately predict prognosis. The aim of this study was to assess the ability of key epithelial-to-mesenchymal transition molecules in identifying prostate cancer patients who are likely to develop aggressive tumors. Using 215 archival patient tissue samples, immunohistochemistry was applied to examine the expression and sub-cellular localization of E-Cadherin, Snail, Slug, Twist, Vimentin, BMP-2 and BMP-7. Of the seven markers assessed, a significantly increased expression of Snail protein was observed within the nucleus of prostate cancer cells and was strongly associated with increasing Gleason score and clinical stage. In addition, loss of E-Cadherin expression at the cellular membrane of prostate cancer cells was also significantly associated with increasing Gleason score, clinical stage, and additionally, a reduction in survival. PMID- 23933195 TI - Cytotoxicity and phytotoxicity of trichothecene mycotoxins produced by Fusarium spp. AB - Trichothecenes, a major class of mycotoxins produced by Fusarium, Myrothecium, and Stachybotrys species, are toxic to both plants and mammals. Simple trichothecenes, including type A (e.g., T-2 toxin) and type B (e.g., deoxynivalenol), are generally less toxic than macrocyclic trichothecenes. We sought to determine if simple trichothecenes are a potential source of candidates for development as bioherbicides, which require high phytotoxicity and low mammalian toxicity. We examined 28 simple trichothecenes in vitro for phytotoxicity using a small aquatic plant, Lemna pausicostata, and for mammalian toxicity using four cultured mammalian cell lines. Several structure-activity relationships were identified, including the following two, which may be relevant to bioherbicide development: peracetylation of type B trichothecenes and de epoxidation of type A trichothecenes both substantially reduced mammalian toxicity with little effect on phytotoxicity. It was concluded that simple trichothecenes possessing strong phytotoxicity and minimal mammalian toxicity in vitro can be identified. PMID- 23933196 TI - Molecular and biochemical characterization of a cytolysin from the Scorpaena plumieri (scorpionfish) venom: evidence of pore formation on erythrocyte cell membrane. AB - Previously, a potent hemolytic toxin (Sp-CTx - 121 kDa) was isolated from Atlantic Scorpionfish Scorpaena plumieri venom. In the present work, we aimed to elucidate the action mechanisms involved in the hemolytic activity induced by this toxin, but to achieve our goal we faced the need to optimize its purification procedure in order to improve its activity and protein recovery. In this new method, Sp-CTx was purified to homogeneity through a combination of sequential ammonium sulfate precipitation and two chromatographic steps: hydrophobic interaction (Butyl HP) and anion exchange (Synchropak SAX 300). Orbitrap mass spectrometry analysis revealed that the amino acids sequences determined to Sp-CTx peptides are shared by other hemolytic toxins from fish venoms. The hemolytic activity of Sp-CTx upon rabbit erythrocytes was attenuated in the presence of osmotic protectants (polyethylene glycol polymers), and molecules larger than 6 nm in diameter inhibited cell lysis. This result strongly suggests that Sp-CTx may be a pore-forming protein, since it lacks phospholipase A2 activity. All these results contribute to the better understanding of Sp-CTx molecular/cellular actions in envenomation caused by S. plumieri. The results are also in agreement with previous reports of structural and functional similarities among piscine hemolytic toxins. PMID- 23933197 TI - Assessment of the mutagenic potential of cyanobacterial extracts and pure cyanotoxins. AB - The aim of the study was to assess the mutagenic potential of extracts obtained from the cyanobacterial bloom-forming cells harvested from the water body located in Lubelszczyzna region of southeastern Poland. Three cyanotoxins, microcystin LR, cylindrospermopsin and anatoxin-a were detected in some of the studied samples in different concentrations. All extracts were assessed for their potential mutagenic effects with the use of a short-term bacterial assay, the Ames test. Mutagenic activity was observed in four of all ten studied extracts, mainly toward the Salmonella typhimurium TA100 strain. On the contrary, the cyanotoxins in purified forms occurred not to be mutagenic or cytotoxic towards S. typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2 uvrA and WP2 [pKM101] up to a concentration of 10 MUg/ml. Similarly, there were no effects after bacteria exposure to the mixture of purified toxins. It has been also detected that after fractionation, genotoxic impact of previously mutagenic extracts was weaker and the highest potency in revertant induction possessed fractions containing very hydrophilic compounds. The results indicate, that while tested cyanotoxins were not directly responsible for the observed mutagenicity of the extracts analysed, some synergistic interactions with other unidentified cyanobacterial-derived factors involved in the process are possible. PMID- 23933199 TI - Thermal effects of transcranial near-infrared laser irradiation on rabbit cortex. AB - Transcranial near-infrared laser therapy (TLT) improves stroke outcome in animal models. Adequate laser doses are necessary to exert therapeutic effects. However, applying higher laser energy may cause cortical tissue heating and exacerbate stroke injury. The objective of this study is to examine the thermal effect and safety of transcranial near-infrared laser therapy. Diode laser with a wavelength of 808 nm was used to deliver different power densities to the brain cortex of rabbits. Cortical temperature was monitored and measured using a thermal probe during the 2 min transcranial laser irradiation. Neuro-pathological changes were examined with histological staining 24 h after laser treatment. Transcranial laser irradiation for 2 min at cortical power densities of 22.2 and 55.6 mW/cm(2) with continuous wave (CW) did not increase cortical temperature in rabbits. With the same treatment regime, cortical power density at 111.1 mW/cm(2) increased brain temperature gradually by 0.5 degrees C over the 2 min exposure and returned to baseline values within 1-2 min post-irradiation. Separately, histological staining was evaluated after triple laser exposure of 22.2 mW/cm(2) CW and 111.1 mW/cm(2) pulse wave (PW) and showed normal neural cell morphology. The present study demonstrated that the TLT powers currently utilized in animal stroke studies do not cause cortical tissue heating and histopathological damage. PMID- 23933198 TI - Amelioration of an undesired action of deguelin. AB - The pharmaceutical world has greatly benefited from the well-characterized structure-function relationships of toxins with endogenous biomolecules, such as ion-channels, receptors, and signaling molecules. Thus, therapeutics derived from toxins have been aggressively pursued. However, the multifunctional role of various toxins may lead to undesirable off-target effects, hindering their use as therapeutic agents. In this paper, we suggest that previously unsuccessful toxins (due to off-target effects) may be revisited with mixtures by utilizing the pharmacodynamic response to the potential primary therapeutic as a starting point for finding new targets to ameliorate the unintended responses. In this proof of principle study, the pharmacodynamic response of HepG2 cells to a potential primary therapeutic (deguelin, a plant-derived chemopreventive agent) was monitored, and a possible secondary target (p38MAPK) was identified. As a single agent, deguelin decreased cellular viability at higher doses (>10 MUM), but inhibited oxygen consumption over a wide dosing range (1.0-100 MUM). Our results demonstrate that inhibition of oxygen consumption is related to an increase in p38MAPK phosphorylation, and may only be an undesired side effect of deguelin (i.e., one that does not contribute to the decrease in HepG2 viability). We further show that deguelin's negative effect on oxygen consumption can be diminished while maintaining efficacy when used as a therapeutic mixture with the judiciously selected secondary inhibitor (SB202190, p38MAPK inhibitor). These preliminary findings suggest that an endogenous response-directed mixtures approach, which uses a pharmacodynamic response to a primary therapeutic to determine a secondary target, allows previously unsuccessful toxins to be revisited as therapeutic mixtures. PMID- 23933200 TI - Altered phospholipid molecular species and glycolipid composition in brain, liver and fibroblasts of Zellweger syndrome. AB - We studied the altered molecular species of lipids in brain and liver tissues, and fibroblasts from patients with Zellweger syndrome (ZS). ZS cerebellum samples contained a higher amount of sphingomyelin with shorter chain fatty acids compared to that in normal controls. The amount of phosphatidylethanolamine (PE) was less than half of that in controls, with the absence of the PE-type of plasmalogen. Gangliosides were accumulated in the brains and fibroblasts of ZS patients. To investigate whether or not impaired beta-oxidation of very long chain fatty acids and/or plasmalogen synthesis affects glycolipids metabolism, RNAi of peroxisomal acylCo-A oxidase (ACOX1) and glyceronephosphate O acyltransferase (GNPAT) was performed using cultured neural cells. In neuronal F3 Ngn1 cells, ACOX1 and GNPAT silencing up-regulated ceramide galactosyltransferase (UGT8) mRNA expression, and down-regulated UDP-glucose ceramide glucosyltransferase (UGCG). These results suggest that both impaired beta oxidation of very long chain fatty acids and plasmalogen synthesis affect glycolipid metabolism in neuronal cells. PMID- 23933201 TI - The role of the sonic hedgehog signaling pathway in early brain injury after experimental subarachnoid hemorrhage in rats. AB - Previous studies have demonstrated that the sonic hedgehog (Shh) pathway plays a neuro-protective role. However, whether the Shh pathway is induced by subarachnoid hemorrhage (SAH) has not been investigated. We sought to investigate Shh activation in the cortex in the early stage of SAH, and assessed the effect of cyclopamine (a specific inhibitor of the Shh pathway) on Shh pathway regulation and evaluated the impact of cyclopamine on SAH. We found that the Shh pathway was up-regulated in the cortex after SAH, and that blocking the Shh pathway increased cell apoptosis. Early brain damages, including brain edema, blood-brain barrier impairment, and cortical apoptosis were significantly aggravated following with cyclopamine treatment compared with vehicle treatment. Our results suggest that the Shh pathway should be activated in the brain after SAH, and plays a beneficial role in SAH development, possibly by inhibiting cerebral oxidative stress through induction of antioxidant and detoxifying enzymes. PMID- 23933202 TI - Visual scanning of emotional faces in schizophrenia. AB - This study investigated eye movement differences during facial emotion recognition between 101 patients with chronic schizophrenia and 101 controls. Independent of facial emotion, patients with schizophrenia processed facial information inefficiently; they showed significantly more direct fixations that lasted longer to interest areas (IAs), such as the eyes, nose, mouth, and nasion. The total fixation number, mean fixation duration, and total fixation duration were significantly increased in schizophrenia. Additionally, the number of fixations per second to IAs (IA fixation number/s) was significantly lower in schizophrenia. However, no differences were found between the two groups in the proportion of number of fixations to IAs or total fixation number (IA fixation number %). Interestingly, the negative symptoms of patients with schizophrenia negatively correlated with IA fixation number %. Both groups showed significantly greater attention to positive faces. Compared to controls, patients with schizophrenia exhibited significantly more fixations directed to IAs, a higher total fixation number, and lower IA fixation number/s for negative faces. These results indicate that facial processing efficiency is significantly decreased in schizophrenia, but no difference was observed in processing strategy. Patients with schizophrenia may have special deficits in processing negative faces, and negative symptoms may affect visual scanning parameters. PMID- 23933203 TI - ERP evidence for the time course of mental rotation in the mirror reading of Chinese words. AB - The present study investigated the neuro-mechanism of mirror reading using two character Chinese words and event related potentials (ERPs). Seventeen Chinese participants performed a lexico-semantic decision task on normal or reversed words (presented normally or in mirror images). Behavioral results showed a clear processing advantage for the normal words, compared with the reversed ones. ERP components including N200, N400, and LPC showed differences between the two word types, indicating the presence of mental rotation and its overlap in time with the two major stages of word recognition, namely word form identification and lexico-semantic processing. The results support parallel processing models proposing that mental rotation takes place parallelly with word recognition in mirror reading. PMID- 23933205 TI - Effect of transcranial direct current stimulation (tDCS) during complex whole body motor skill learning. AB - The aim of the study was to investigate tDCS effects on motor skill learning in a complex whole body dynamic balance task (DBT). We hypothesized that tDCS over the supplementary motor area (SMA), a region that is known to be involved in the control of multi-joint whole body movements, will result in polarity specific changes in DBT learning. In a randomized sham-controlled, double-blinded parallel design, we applied 20 min of tDCS over the supplementary motor area (SMA) and prefrontal cortex (PFC) while subjects performed a DBT. Anodal tDCS over SMA with the cathode placed over contralateral PFC impaired motor skill learning of the DBT compared to sham. This effect was still present on the second day of training. Reversing the polarity (cathode over SMA, anode over PFC) did not affect motor skill learning neither on the first nor on the second day of training. To better disentangle whether the impaired motor skill learning was due to a modulation of SMA or PFC, we performed an additional control experiment. Here, we applied anodal tDCS over SMA together with a larger and presumably more ineffective electrode (cathode) over PFC. Interestingly this alternative tDCS electrode setup did not affect the outcome of DBT learning. Our results provide novel evidence that a modulation of the (right) PFC seems to impair complex multi joint motor skill learning. Hence, future studies should take the positioning of both tDCS electrodes into account when investigating complex motor skill learning. PMID- 23933204 TI - Sex and estrogen receptor expression influence opioid peptide levels in the mouse hippocampal mossy fiber pathway. AB - The opioid peptides, dynorphin (DYN) and enkephalin (L-ENK) are contained in the hippocampal mossy fiber pathway where they modulate synaptic plasticity. In rats, the levels of DYN and L-ENK immunoreactivity (-ir) are increased when estrogen levels are elevated (Torres-Reveron et al., 2008, 2009). Here, we used quantitative immunocytochemistry to examine whether opioid levels are similarly regulated in wildtype (WT) mice over the estrous cycle, and how these compared to males. Moreover, using estrogen receptor (ER) alpha and beta knock-out mice (AERKO and BERKO, respectively), the present study examined the role of ERs in rapid, membrane-initiated (6 h), or slower, nucleus-initiated (48 h) estradiol effects on mossy fiber opioid levels. Unlike rats, the levels of DYN and L-ENK-ir did not change over the estrous cycle. However, compared to males, females had higher levels of DYN-ir in CA3a and L-ENK-ir in CA3b. In WT and BERKO ovariectomized (OVX) mice, neither DYN- nor L-ENK-ir changed following 6 or 48 h estradiol benzoate (EB) administration. However, DYN-ir significantly increased 48 h after EB in the dentate gyrus (DG) and CA3b of AERKO mice only. These findings suggest that cyclic hormone levels regulate neither DYN nor L-ENK levels in the mouse mossy fiber pathway as they do in the rat. This may be due to species-specific differences in the mossy fiber pathway. However, in the mouse, DYN levels are regulated by exogenous EB in the absence of ERalpha possibly via an ERbeta-mediated pathway requiring new gene transcription. PMID- 23933206 TI - Distinct patterns of expression of traumatic brain injury biomarkers after blast exposure: role of compromised cell membrane integrity. AB - Glial fibrillary acidic protein (GFAP), a protein enriched in astrocytes, and Tau, a protein abundant in neuronal microtubules, are being widely studied as biomarkers of brain injury, and persistent severity-dependent increases in brain and blood have been reported. Studies on the acute changes of these proteins after blast exposure are limited. Using a mouse model of closely-coupled repeated blast exposures, we have evaluated acute changes in the levels of GFAP and total Tau by Western blotting. Brain levels of GFAP and Tau proteins decreased significantly at 6 h and increased considerably at 24 h after repeated blast exposures. Plasma samples showed a similar initial decrease and later increase over this timeframe. This biphasic pattern points to possible absorption or sequestration of these proteins from plasma immediately after repeated blast exposures. Liver and spleen tissue showed significant increases in the levels of GFAP and Tau protein at 6 and 24 h post-blast exposures whereas semi-quantitative RT-PCR analysis of liver showed no significant changes in the levels of GFAP or Tau mRNAs. These results suggest that blast exposure causes transient changes in cell membrane integrity in multiple organs leading to abnormal migration of proteins from the tissues to the plasma and vice versa. This transient changes in cell membrane permeability and subsequent bidirectional movement of molecules may contribute to the pathophysiology of TBI and polytrauma after blast exposure. PMID- 23933207 TI - Migration of neural stem cells to ischemic brain regions in ischemic stroke in rats. AB - An established rat model of ischemic stroke, produced by temporary middle cerebral artery occlusion and reperfusion (MCAO/R), was used in the evaluation of organ migration of intra-arterial (IA) transplantation of neural stem cells (NSCs). Immediately after transplantation, ischemic rats (n=8) transplanted with either NSCs (MCAO/R+NSC group) or NSC growth medium (MCAO/R+medium group) exhibited neurological dysfunction but rats in a sham+NSCs group (n=5) did not. During the post-operative period, neurological function improved to a similar extent in both MCAO/R groups. At 10 and 14 days post-transplantation, neurological function in the MCAO/R+NSC group was superior to that in the MCAO/R+medium group (p<0.001). Hematoxylin-eosin staining showed neuronal degeneration and necrosis in ischemic rats. Immunofluorescence staining revealed that NSCs had migrated to the frontal and parietal lobes, caudate, and putamen. Some cells had begun differentiating into neurons and astrocytes. Rat NSCs can migrate into the ischemic region, survive, and differentiate into astrocytes and neurons, and thereby potentially improve neurologic function after cerebral ischemia. PMID- 23933208 TI - Increased aggregation of polyleucine compared with that of polyglutamine in dentatorubral-pallidoluysian atrophy protein. AB - Polyglutamine (polyQ) diseases result from expansion of CAG trinucleotide repeats in their responsible genes. Although gene products with polyQ expansions undergo conformational changes to aggregate in neurons, the relationship between inclusions and neurotoxicity remains unclear. Dentatorubral-pallidoluysian atrophy (DRPLA) is a polyQ disease, and DRPLA protein, also known as atrophin-1 (ATN1), carries an expanded polyQ tract. To investigate how an expanded polyQ tract influences ATN1 aggregation and localization, we compared the aggregation of ATN1 with a polyQ tract to that of ATN1 with a polyleucine (polyL) tract. In COS-7 cells, polyL-ATN1 triggered more aggregation than polyQ-ATN1 of similar repeat sizes. Immunocytochemical and biochemical studies revealed that replacement of the polyQ tract with polyL alters ATN1 localization, leading to retention of polyL-ATN1 in the cytoplasm. Despite this change in localization, polyL-ATN1 and polyQ-ATN1 demonstrate comparable repeat length dependent toxicity. These results suggest that expanded polyQ repeats in ATN1 may contribute to neurodegeneration via alterations in both protein aggregation and intracellular localization. PMID- 23933209 TI - Susceptibility to oxygen-glucose deprivation is reduced in acute hippocampal slices from euthermic Syrian golden hamsters relative to slices from Sprague Dawley rats. AB - Hibernation in mammals is characterised by a marked decrease in body temperature and a dramatic suppression of metabolism. In addition, despite experiencing a reduced cardiac output that would normally cause profound cerebral ischaemia, hibernating animals display robust neuroprotection. However, whether the reduced susceptibility to neural injury displayed by hibernators is attributable to an innate factor, or to the physiologic changes that accompany hibernation, remains uncertain. To help clarify the nature of the ischaemic tolerance displayed by hibernators, the current study examined hippocampal slices from rodents not capable of hibernation (rat) and rodents that could undergo hibernation (hamsters), but were active immediately prior to slice preparation. Slices from each species were subjected to oxygen-glucose deprivation (OGD; a commonly used in vitro model of ischaemia), and their viability examined after a recovery period. Although OGD reduced plasma membrane integrity in each species, rat derived slices displayed a nearly threefold greater degree of effect. In addition, only slices harvested from rats showed reductions in synaptic mitochondrial function. While the improved ischaemic tolerance displayed by euthermic hamster brain slices maintained at a physiological temperature suggests an intrinsic, protection-related variable, the synaptic level of the GluN1 subunit (which is required to form functional NMDA receptors) was not found to be different between the two species. Further work is needed to improve understanding of the molecular mechanisms underlying the intrinsic injury tolerance of hibernator brain, which should help provide inspiration for new approaches to neuroprotection. PMID- 23933210 TI - Pharmacokinetic evidence for the long-lasting effect of nor-binaltorphimine, a potent kappa opioid receptor antagonist, in mice. AB - Nor-binaltorphimine (nor-BNI) is kappa opioid receptor (KOR) antagonist with the extremely long duration in mice analgesic assay, in vivo. For the evaluation of long-lasting effect of nor-BNI, brain content and serum concentration of nor-BNI were quantified in comparison with those of naloxone (a short-acting non-specific opioid receptor antagonist) by high-performance liquid chromatography with electrochemical detector in mice. After concomitant administration (20 mg/kg, s.c.) of nor-BNI and naloxone, nor-BNI in brain and serum showed biphasic elimination, with a rapid phase for 0.75-4 h and a slow phase for 4-48 h. Elimination rate in brain was slower than that of serum. Naloxone in brain and serum was detected for 3 h and 4 h, respectively. The brain/serum ratio of nor BNI gradually increased over 0.75-48 h, while that of naloxone rapidly declined. After concomitant administration (30 mg/kg, s.c.) of nor-BNI and naloxone, brain nor-BNI was detected in all mice from day 1 to day 21 and in two of six mice at day 28, while serum nor-BNI was detected in all mice at day 1, three of seven at day 3 and one of six at day 7. After that, serum nor-BNI was not detected. Naloxone in brain and serum was not detected at day 1. These results provide pharmacokinetic support for the long-lasting antagonistic effects of nor-BNI. PMID- 23933211 TI - Muscle-specific regulation of the mTOR signaling pathway in MuSK antibody seropositive (MuSK+) experimental autoimmune Myasthenia gravis (EAMG). AB - Myasthenia gravis (MG) patients with antibodies against muscle specific tyrosine kinase (MuSK+) typically present focal fatigue and atrophy of the facial and bulbar muscles, including the masseter muscle, whereas leg muscles often are clinically spared. This study addresses the regulation of the mTOR signaling pathway in the masseter muscle versus the leg muscle tibialis anterior (TA). We analyzed muscle morphology, protein levels of mTOR components as well as atrogenes and mitochondrial markers in these muscles of healthy control mice and mice with different clinical severity grades of MuSK+ experimental autoimmune MG (EAMG). Protein levels of mTOR components were reduced in the atrophic masseter muscle of MuSK+ EAMG mice, whereas enhanced accumulation of mTOR components was observed in the TA muscles. Two other muscles: omohyoid and soleus showed intermediate spectra. In conclusion, the anabolic mTOR signaling pathway is differentially regulated even in muscles with the same activity pattern in the same neuromuscular disease. This could in part explain the clinical phenotype in MuSK+ EAMG as well as in muscular dystrophies. PMID- 23933212 TI - Transcriptional evidence for small RNA regulation of pupal diapause in the flesh fly, Sarcophaga bullata. AB - Understanding the molecular basis of diapause, a phenotypically plastic, alternative developmental pathway, is key to predicting the seasonal distribution of economically and medically important insect species. Small regulatory RNAs, including piwi-related RNAs, small-interfering RNAs, and miRNAs, represent one type of epigenetic process that can alter the phenotype of organisms independent of changes in genome sequence. We hypothesize that small RNAs regulate pupal diapause and a maternal block of diapause in the flesh fly Sarcophaga bullata. We assessed the relative abundance of eight genes related to small RNA biogenesis and function using qRT-PCR in pre-diapause and diapause stages compared to their non-diapause counterparts. Elevated mRNA expression of piwi and spindle-E, as well as argonaute2 and r2d2, in photosensitive 1st instar larvae reared in diapause-inducing conditions indicate involvement of the piwi-associated RNA and small-interfering RNA pathways, respectively, in programming the switch from direct development to a developmental pathway that includes diapause. Two genes, related to the microRNA pathway, argonaute1 and loquacious, are upregulated during pupal diapause, suggesting a role for this pathway in maintaining diapause. Substantial reduction in transcript abundance of small RNA-related genes in photosensitive 1st instar larvae from mothers with a diapause history compared to those from mothers with no diapause history also suggest a role for small RNA pathways in regulating a diapause maternal effect in S. bullata. Together, the results point to a role for small RNAs in regulating the developmental trajectory in this species. PMID- 23933213 TI - Inhibition of host cell encapsulation through inhibiting immune gene expression by the parasitic wasp venom calreticulin. AB - Parasitoid wasps inject venom into the host to protect their offspring against host immune responses. In our previous study, we identified a calreticulin (CRT) in Pteromalus puparum venom. In this study, we expressed the wild-type and the coiled-coil domain deletion mutant P. puparum calreticulins (PpCRTs) in Escherichia coli and prepared polyclonal antibody in rabbit against PpCRT. Western blot analysis showed that PpCRT protein was not only present in the venom but also in all the tissues tested. Real time PCR results indicated that PpCRT mRNA was highly expressed in the venom gland. The transcript level of PpCRT in the venom gland was peaked at 2 days post-eclosion, while the PpCRT protein in the venom was maintained at a constant level. Both recombinant wild-type and mutant PpCRT proteins could bind to the surface of P. puparum eggs. Recombinant PpCRT inhibited hemocyte spreading and cellular encapsulation of the host Pieris rapae in vitro, and the coiled-coil domain is important for the inhibitory function of PpCRT. Immunocytochemistry results showed that PpCRT entered P. rapae hemocytes, and the coiled-coil domain played a role in this process. After injection of recombinant PpCRT into P. rapae pupae, real time PCR results showed that PpCRT inhibited transcript levels of host encapsulation-related genes, including calreticulin and scavenger receptor genes. In conclusion, our results suggest that P. puparum venom protects its offspring against host cellular immune responses via its functional component PpCRT to inhibit the expression of host cellular response-related genes. PMID- 23933214 TI - Midgut aminopeptidase N isoforms from Ostrinia nubilalis: activity characterization and differential binding to Cry1Ab and Cry1Fa proteins from Bacillus thuringiensis. AB - Aminopeptidase N (APN) isoforms from Lepidoptera are known for their involvement in the mode of action of insecticidal Cry proteins from Bacillus thuringiensis. These enzymes belong to a protein family with at least eight different members that are expressed simultaneously in the midgut of lepidopteran larvae. Here, we focus on the characterization of the APNs from Ostrinia nubilalis (OnAPNs) to identify potential Cry receptors. We expressed OnAPNs in insect cells using a baculovirus system and analyzed their enzymatic activity by probing substrate specificity and inhibitor susceptibility. The interaction with Cry1Ab and Cry1Fa proteins (both found in transgenic insect-resistant maize) was evaluated by ligand blot assays and immunocytochemistry. Ligand blots of brush border membrane proteins showed that both Cry proteins bound mainly to a 150 kDa-band, in which OnAPNs were greatly represented. Binding analysis of Cry proteins to the cell expressed OnAPNs showed that OnAPN1 interacted with both Cry1Ab and Cry1Fa, whereas OnAPN3a and OnAPN8 only bound to Cry1Fa. Two isoforms, OnAPN2 and OnAPN3b, did not interact with any of these two proteins. This work provides the first evidence of a differential role of OnAPN isoforms in the mode of action of Cry proteins in O. nubilalis. PMID- 23933215 TI - Body mass index, but not FTO genotype or major depressive disorder, influences brain structure. AB - Obesity and major depressive disorder (MDD) are highly prevalent and often comorbid health conditions. Both are associated with differences in brain structure and are genetically influenced. Yet, little is known about how obesity, MDD, and known risk genotypes might interact in the brain. Subjects were 81 patients with MDD (mean age 48.6 years) and 69 matched healthy controls (mean age 51.2 years). Subjects underwent 1.5T magnetic resonance imaging, genotyping for the fat mass and obesity associated (FTO) gene rs3751812 polymorphism, and measurements for body mass index (BMI). We conducted a whole brain voxelwise analysis using tensor-based morphometry (TBM) to examine the main and interaction effects of diagnosis, BMI and FTO genotype. Significant effects of BMI were observed across widespread brain regions, indicating reductions in predominantly subcortical and white matter areas associated with increased BMI, but there was no influence of MDD or FTO rs3751812 genotype. There were no significant interaction effects. Within MDD patients, there was no effect of current depressive symptoms; however the use of antidepressant medication was associated with reductions in brain volume in the frontal lobe and cerebellum. Obesity affects brain structure in both healthy participants and MDD patients; this influence may account for some of the brain changes previously associated with MDD. BMI and the use of medication should ideally be measured and controlled for when conducting structural brain imaging research in MDD. PMID- 23933216 TI - Blockade of the dorsal hippocampal dopamine D1 receptors inhibits the scopolamine induced state-dependent learning in rats. AB - In the present study, we investigated the possible role of the dorsal hippocampal (CA1) dopamine D1 receptors on scopolamine-induced amnesia as well as scopolamine state-dependent memory in adult male Wistar rats. Animals were bilaterally implanted with chronic cannulae in the CA1 regions of the dorsal hippocampus, trained in a step-through type inhibitory avoidance task, and tested 24h after training for their step-through latency. Results indicated that pre-training or pre-test intra-CA1 administration of scopolamine (1.5 and 3 MUg/rat) dose dependently reduced the step-through latency, showing an amnestic response. The pre-training scopolamine-induced amnesia (3 MUg/rat) was reversed by the pre-test administration of scopolamine, indicating a state-dependent effect. Similarly, the pre-test administration of dopamine D1 receptor agonist, 1-phenyl-7,8 dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF38393; 1, 2 and 4 MUg/rat, intra-CA1), could significantly reverse the scopolamine-induced amnesia. Interestingly, administration of an ineffective dose of scopolamine (0.25 MUg/rat, intra-CA1) before different doses of SKF38393, blocked the reversal effect of SKF38393 on the pre-training scopolamine-induced amnesia. Moreover, while the pre-test intra-CA1 injection of the dopamine D1 receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0.1 and 0.5 MUg/rat, intra-CA1), resulted in apparent memory impairment, microinjection of the same doses of this agent inhibited the scopolamine-induced state-dependent memory. These results indicate that the CA1 dopamine D1 receptors may potentially play an important role in scopolamine induced amnesia as well as the scopolamine state-dependent memory. Furthermore, our results propose that dopamine D1 receptor agonist, SKF38393 reverses the scopolamine-induced amnesia via acetylcholine release and possibly through the activation of muscarinic receptors. PMID- 23933217 TI - Electrophysiological and amperometric evidence that modafinil blocks the dopamine uptake transporter to induce behavioral activation. AB - Although the wake-promoting drug modafinil has been shown to bind quite exclusively to the dopamine transporter (DAT), its action in the brain has been thought to be partially independent from the facilitation of the dopaminergic signals. Here we used electrophysiological and amperometric techniques to investigate the effects of modafinil on the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and on the synaptic overflow of dopamine in the dorsal striatum from the sliced tissue of wild-type and cocaine-insensitive genetically modified mice (DAT-CI). Moreover, we examined the consequences of modafinil administration on the locomotor behavior of wild-type and DAT-CI mice. In in vitro experiments, modafinil inhibited the spontaneous firing discharge of the dopaminergic neurons. More consistently, it potentiated firing inhibition and the membrane responses caused by exogenously applied dopamine on these cells. Furthermore, it augmented the stimulus-evoked outflow of DA in the striatum. Noteworthy, modafinil caused locomotor activation in wild-type mice. On the other hand, neither the electrophysiological nor the behavioral effects of modafinil were detected in DAT-CI animals. These results demonstrate that modafinil potentiates brain dopaminergic signals via DAT inhibition by acting at the same binding site of cocaine. Therefore, this mechanism of action explains most of the pharmacological properties of this compound in the clinical setting. PMID- 23933218 TI - Roadside ditches as conduits of fecal indicator organisms and sediment: implications for water quality management. AB - Roadside ditches are ubiquitous, yet their role in water pollution conveyance has largely been ignored, especially for bacteria and sediment. The goal of this study was to determine if roadside ditches are conduits for fecal indicator organisms and sediment, and if land use, specifically manure amendment, affects the concentrations and loadings. Seven roadside ditches in central New York, adjacent to either manure amended fields or predominately forested land, were monitored for one year for Escherichia coli (E. coli), total suspended solids (TSS) and flow. E. coli concentrations in water samples following storms averaged 4616 MPN of E. coli/100 mL. Concentrations reached as high as >241,960 MPN of E. coli/100 mL and frequently exceeded New York State and US EPA recommendations. Concentrations peaked in both summers following manure spreading, with declining levels thereafter. However, viable organisms were detected throughout the year. The concentrations were also high in the forested sites, with possible sources including wildlife, pets, septic wastes and livestock. E. coli concentrations and loadings were related to TSS concentrations and loadings, whether manure had been spread in the last 30 days and for concentrations only, antecedent rainfall. Viable E. coli were also present in ditch sediment between storm events and were available for resuspension and transport. Total suspended solids concentrations averaged 0.51 g/L and reached as high as 52.2 g/L. Loads were similarly high, at an average of 631.6 kg/day. Both concentrations and loads tended to be associated with discharge and rainfall parameters. The cumulative pollutant contribution from the ditch network was estimated to be large enough to produce detectable and sometimes high concentrations in a receiving stream in a small, rural watershed. Roadside drainage networks need to be actively managed for water quality improvements, because they capture and rapidly shunt stormwater and associated contaminants to streams. PMID- 23933219 TI - Inspecting environmental management from within: the role of street-level bureaucrats in environmental policy implementation. AB - In this paper, we assert that an important element is largely missing in much of the current environmental policy literature regarding different management ideals: street-level bureaucrats (i.e., the practicing and, typically, anonymous civil servants at the very end of the environmental policy chain). Thus, we aim to enhance a deeper understanding of the role that street-level bureaucrats play within different management ideals, and through this discussion, we indicate how they affect the functionality of governing structures and processes. We do so by interviewing street-level bureaucrats carrying out their role in different management settings, enabling evaluations of the degree to which their practices correspond with the ideals expressed in the literature and in official directives. We find a rather poor match between these ideals on one hand and the way street-level bureaucrats actually perceive that they are internally steered and how they carry out their commissions on the other hand. PMID- 23933220 TI - Cost effectiveness in site selection to protect native plant communities from the weed, bitou bush, in New South Wales, Australia. AB - Government funding to protect native plant communities is usually limited. For cost effectiveness, priority sites for conservation must therefore be identified and funds allocated to protect these sites according to the quantity of communities conserved per dollar of cost. In 1999, invasion of coastal vegetation in New South Wales (NSW) by bitou bush was listed as a key threatening process under the NSW Threatened Species Conservation Act 1995. In accordance with the Act, a Threat Abatement Plan (TAP) was prepared to reduce the impacts of the weed to threatened biodiversity at priority sites. In the present study, data collected for the TAP were analysed by linear programming to determine the feasibility of achieving cost effectiveness in identifying sites and allocating funds, and to explore the impact of associated economic issues on the quantity of native plant communities that are protected. In addition to the total funds and costs per site, the quantity was influenced by alternative funding policies and different site selection strategies. Allocations that recognise these issues can enhance protection outcomes, and promote the cost effectiveness of weed management. PMID- 23933221 TI - Failure to rescue after major gynecologic surgery. AB - OBJECTIVE: There is growing recognition that, in addition to occurrence of perioperative complications, the treatment of patients with complications influences outcome. We examined complications, failure to rescue (death in patients with a complication), and mortality rates for women who underwent abdominal hysterectomy. STUDY DESIGN: Women who underwent abdominal hysterectomy from 1998-2010 and whose data were recorded in the Nationwide Inpatient Sample were identified. Hospitals were stratified based on risk-adjusted mortality rates into 5 quintiles, and rates of complications and failure to rescue were examined. RESULTS: A total of 664,229 women who had been treated at 741 hospitals were identified. The overall mortality rate for the cohort was 0.17%. The risk adjusted, hospital-level mortality rate ranged from 0-1.12%. The complication rate was 6.5% at the hospitals with the lowest mortality rates, 9.9% at the second quintile hospitals, 9.5% at both the third and fourth quintile hospitals, and 7.9% at the hospitals with the highest mortality rates. In contrast to complications, the failure-to-rescue rate increased with each successive risk adjusted mortality quintile. The failure-to-rescue rate was 0% at the hospitals with the lowest mortality rates and increased with each successive quintile to 1.1%, 2.1%, 2.7%, and 4.4% in the hospitals with the highest mortality rates (P < .0001). CONCLUSION: For women who underwent abdominal hysterectomy, hospital complication rates correlated poorly with mortality rates; failure-to-rescue is strongly associated with in-hospital mortality rates. The treatment of complications, not the actual development of a complication, is the most important factor to use to predict death after major gynecologic surgery. PMID- 23933222 TI - Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study. AB - OBJECTIVE: Drugs of abuse affect pregnancy outcomes, however, the mechanisms in which cannabis exerts its effects are not well understood. The aim of this study was to examine the influence of short-term (1-2 hours) exposure to cannabidiol, a major phytocannabinoid, on human placental breast cancer resistance protein function. STUDY DESIGN: The in vitro effect of short-term exposure to cannabidoil on breast cancer resistance protein in BeWo and Jar cells (MCF7/P-gp cells were used for comparison) was tested with mitoxantrone uptake, and nicardipine was used as positive control. The ex vivo perfused cotyledon system was used for testing the effect of cannabidoil on glyburide transport across the placenta. Glyburide (200 ng/mL) was introduced to maternal and fetal compartments through a recirculating 2 hour perfusion, and its transplacental transport was tested with (n = 8) or without (n = 8) cannabidoil. RESULTS: (1) Cannabidoil inhibition of breast cancer resistance protein-dependent mitoxantrone efflux was concentration dependent and of a noncell type specific nature (P < .0001); (2) In the cotyledon perfusion assay, the administration of cannabidoil to the maternal perfusion media increased the female/male ratio of glyburide concentrations (1.3 +/- 0.1 vs 0.8 +/- 0.1 at 120 minutes of perfusion, P < .001). CONCLUSION: (1) Placental breast cancer resistance protein function is inhibited following even a short term exposure to cannabidoil; (2) the ex vivo perfusion assay emphasize this effect by increased placental penetration of glyburide to the fetal compartment; and (3) these findings suggest that marijuana consumption enhances placental barrier permeability to xenobiotics and could endanger the developing fetus. Thus, the safety of drugs that are breast cancer resistance protein substrates is questionable during cannabis consumption by pregnant women. PMID- 23933223 TI - Gene expression data reveal common pathways that characterize the unifocal nature of ovarian cancer. AB - OBJECTIVE: The objective of the study was to evaluate the biological validity of ovarian cancer (OVCA) screening and early detection efforts and to characterize signaling pathways associated with human cancer metastasis and patient survival. STUDY DESIGN: Using genome-wide expression profiling and deoxyribonucleic acid sequencing, we compared pelvic and matched extrapelvic implants from 30 patients with advanced-stage OVCA for expression of molecular signaling pathways and p53 gene mutations. Differentially expressed pathways were further evaluated in a series of primary or early-stage vs metastatic or recurrent cancer samples from 389 ovarian, prostate, and oral cancer patients. Metastasis pathways were also evaluated for associations with survival in 9 independent clinicogenomic datasets from 1691 ovarian, breast, colon, brain, and lung cancer and leukemia patients. The inhibitory effects of 1 pathway (transforming growth factor [TGF]-WNT) on in vitro OVCA cell migration were studied. RESULTS: Pelvic and extrapelvic OVCA implants demonstrated similar patterns of signaling pathway expression and identical p53 mutations. However, we identified 3 molecular pathways/cellular processes that were differentially expressed between pelvic and extrapelvic OVCA samples and between primary/early-stage and metastatic/advanced or recurrent ovarian, oral, and prostate cancers. Furthermore, their expression was associated with overall survival from ovarian cancer (P = .006), colon cancer (1 pathway at P = .005), and leukemia (P = .05). Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration. CONCLUSION: Advanced-stage OVCA has a unifocal origin in the pelvis. Molecular pathways associated with extrapelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease. PMID- 23933224 TI - Is park visitation associated with leisure-time and transportation physical activity? AB - OBJECTIVE: The aim of this study was to examine whether frequency of park visitation was associated with time spent in various domains of physical activity among adults living in a disadvantaged neighbourhood of Victoria, Australia. METHODS: In 2009, participants (n=319) self-reported park visitation and physical activity including: walking and cycling for transport, leisure-time walking, leisure-time moderate- to vigorous-intensity physical activity, and total physical activity. RESULTS: The mean number of park visits per week was 3.3 (SD=3.8). Park visitation was associated with greater odds of engaging in high (as compared to low) amounts of transportation physical activity, leisure-time walking, leisure-time moderate- to vigorous-intensity physical activity (MVPA) and total physical activity. Each additional park visit per week was associated with 23% greater odds of being in the high category for transportation physical activity, 26% greater odds of engaging in high amounts of leisure-time walking, 11% greater odds of engaging in MVPA, and 40% greater odds of high total physical activity. CONCLUSIONS: Acknowledging the cross-sectional study design, the findings suggest that park visitation may be an important predictor and/or destination for transportation and leisure-time walking and physical activity. Findings highlight the potentially important role of parks for physical activity. PMID- 23933225 TI - Smoking habits in relation to reproductive events among Japanese women: findings of the Japanese Nurses' Health Study. AB - OBJECTIVE: The purposes of this study were to examine smoking habits in relation to the reproductive events of pregnancy and menopause and clarify the reasons for smoking cessation among ex-smokers. METHOD: This is a cross-sectional study based on a baseline survey of a prospective cohort study. From 2001 to 2007, a self administered questionnaire survey was conducted on 49,927 female nurses from all 47 prefectures in Japan. Logistic regression models were used to estimate age adjusted odds ratios. RESULTS: Of the respondents, 17.2% were current smokers, 11.6% were ex-smokers and 69.8% had never smoked. The prevalence of smoking during pregnancy was 7.8%. Among ex-smokers, 30.3% gave "reproductive events" as their reason for smoking cessation. Current smoking and the number of cigarettes smoked per day before menopause were significantly related to onset of menopause. CONCLUSION: Women's smoking habits have mutual relationships with reproductive events such as pregnancy and menopause. Although "reproductive events" were an important reason for smoking cessation among women, 7.8% of women still smoked during pregnancy. Smoking was correlated with onset of menopause. Support for smoking cessation is an important healthcare issue throughout women's lifetimes. PMID- 23933226 TI - Wheat zinc finger protein TaLSD1, a negative regulator of programmed cell death, is involved in wheat resistance against stripe rust fungus. AB - Genetic characterization of the Arabidopsis lesion simulating disease 1 (lsd1) mutant, a lesion mimic mutant (LMM), has revealed the essential role of AtLSD1 in the negative regulation of cell death and disease resistance. The three zinc finger motifs found in AtLSD1 revealed a novel plant-specific gene family, whose members are significantly related to programmed cell death (PCD). In this study, we characterized a functional homologue to AtLSD1, TaLSD1, in the wheat-stripe rust fungus pathosystem. The expression of TaLSD1 was differentially induced during incompatible and compatible interactions between wheat and Puccinia striiformis f. sp. tritici (Pst) and was up-regulated by oxidative stress generated by methyl viologen (MV). TaLSD1 was found to be predominately localized in the nucleus of onion epidermal cell. Transient overexpression assays in Nicotiana benthamiana demonstrated that TaLSD1 partially inhibited programmed cell death triggered by a mouse Bax protein, whereas expression of TaLSD1 alone had no influence on the phenotype of tobacco. Knocking down the expression of TaLSD1 through virus-induced gene silencing (VIGS) increased wheat resistance against Pst accompanied by an enhanced hypersensitive response (HR), an increase in PR1 gene expression and a reduction in Pst hyphal growth. Our results suggest that TaLSD1 functions negatively in regulating the plant hypersensitive cell death and is involved in disease resistance of wheat against the stripe rust pathogen. PMID- 23933227 TI - Nicotine-encapsulated poly(lactic-co-glycolic) acid nanoparticles improve neuroprotective efficacy against MPTP-induced parkinsonism. AB - For some instances of Parkinson disease (PD), current evidence in the literature is consistent with reactive oxygen species being involved in the etiology of the disease. The management of PD is still challenging owing to its ambiguous etiology and lack of permanent cure. Because nicotine offers neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, the neuroprotective efficacy of nicotine-encapsulated poly(lactic-co-glycolic) acid (PLGA) nanoparticles and the underlying mechanism of improved efficacy, if any, over bulk nicotine were assessed in this study. The selected indicators of oxidative stress, dopaminergic neurodegeneration and apoptosis, were measured in both in vitro and rodent models of parkinsonism in the presence or absence of "nanotized" or bulk nicotine. The levels of dopamine and its metabolites were measured in the striatum, nicotine and its metabolite in the nigrostriatal tissues while the immunoreactivities of tyrosine hydroxylase (TH), metallothionein-III (MT-III), inducible nitric oxide synthase (iNOS) and microglial activation were checked in the substantia nigra of controls and treated mice. GSTA4-4, heme oxygenase (HO)-1, tumor suppressor protein 53 (p53), caspase-3, lipid peroxidation (LPO), and nitrite levels were measured in the nigrostriatal tissues. Nicotine-encapsulated PLGA nanoparticles improved the endurance of TH-immunoreactive neurons and the number of fiber outgrowths and increased the mRNA expression of TH, neuronal cell adhesion molecule, and growth associated protein-43 over bulk against 1-methyl-4-phenyl pyridinium ion-induced degeneration in the in vitro model. MPTP reduced TH immunoreactivity and levels of dopamine and its metabolites and increased microglial activation, expression of GSTA4-4, iNOS, MT-III, HO-1, p53, and caspase-3, and levels of nitrite and LPO. Whereas both bulk nicotine and nicotine-encapsulated PLGA nanoparticles modulated the changes toward controls, the modulation was more pronounced in nicotine-encapsulated PLGA nanoparticle-treated parkinsonian mice. The levels of nicotine and cotinine were elevated in nicotine-encapsulated PLGA nanoparticle treated PD mouse brain compared with bulk. The results obtained from this study demonstrate that nanotization of nicotine improves neuroprotective efficacy by enhancing its bioavailability and subsequent modulation in the indicators of oxidative stress and apoptosis. PMID- 23933228 TI - Genome as a stochastic evolutionary machine: comment on "How life changes itself: the Read-Write (RW) genome" by James Shapiro. PMID- 23933229 TI - Emerging computational approaches for the study of protein allostery. AB - Allosteric regulation of protein function is key in controlling cellular processes so its underlying mechanisms are of primary concern to research in areas spanning protein engineering and drug design. However, due to the complex nature of allosteric mechanisms, a clear and predictive understanding of the relationship between protein structure and allosteric function remains elusive. Well established experimental approaches are available to offer a limited degree of characterization of mechanical properties within proteins, but the analytical capabilities of computational methods are evolving rapidly in their ability to accurately define the subtle and concerted structural dynamics that comprise allostery. This review includes a brief overview of allostery in proteins and an exploration of relevant experimental methods. An explanation of the transition from experimental toward computational methods for allostery is discussed, followed by a review of existing and emerging methods. PMID- 23933230 TI - MicroRNAs as diagnostic markers for pancreatic ductal adenocarcinoma and its precursor, pancreatic intraepithelial neoplasm. AB - Since the discovery of small non-coding RNAs, the analysis of microRNA (miRNA) expression patterns in human cancer have provided new insights into cancer biology. Evidence suggests that deregulated miRNA expression is associated with pancreatic cancer development. In this study, we analyzed the expression of several miRNAs in different types of pancreatic disease to determine if miRNA expression could aid in the diagnosis of pancreatic ductal adenocarcinoma (PDAC) and its precursor, pancreatic intraepithelial neoplasm (PanIN). Pancreatic resection specimens were selected, which included PDAC (n = 16), benign pancreatic parenchyma from corresponding carcinoma cases (n = 16), chronic pancreatitis (n = 4), normal pancreatic parenchyma (n = 5), and PanIN (n = 5). The expression levels of five miRNA (miR-148a, miR-217, miR-21, miR-196a, and miR 10b) were assessed by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) assays. Our data demonstrate that compared to the normal pancreatic parenchyma, miR-148a and miR-217 expression levels were down-regulated in PanIN, particularly in PanIN II-III and PDAC, whereas the level of miR-196 was significantly up-regulated in PDAC and its precursor, PanIN II-III. In addition, we observed that miR-21 was significantly overexpressed in PDAC, and miR-10b was highly expressed in PanIN II-III. Our study demonstrates that certain miRNAs, especially miR-148a, miR-217, and miR-196a, are significantly deregulated in PDAC, including in the early stage of PDAC. These markers can potentially be used as diagnostic markers to distinguish PDAC and its precursor from benign lesions. PMID- 23933231 TI - Long-term exposure to depleted uranium in Gulf-War veterans does not induce chromosome aberrations in peripheral blood lymphocytes. AB - Depleted uranium (DU) is a high-density heavy metal that has been used in munitions since the 1991 Gulf War. DU is weakly radioactive and chemically toxic, and long-term exposure may cause adverse health effects. This study evaluates genotoxic effects of exposure to DU by measuring chromosome damage in peripheral blood lymphocytes with fluorescence in situ hybridization whole-chromosome painting. Study participants are Gulf War-I Veterans with embedded DU fragments and/or inhalation exposure due to involvement in friendly-fire incidents; they are enrolled in a long-term health surveillance program at the Baltimore Veterans Administration Medical Center. Blood was drawn from 35 exposed male veterans aged 39 to 62 years. Chromosomes 1, 2, and 4 were painted red and chromosomes 3, 5, and 6 were simultaneously labeled green. At least 1800 metaphase cells per subject were scored. Univariate regression analyses were performed to evaluate the effects of log(urine uranium), age at time of blood draw, log(lifetime X rays), pack-years smoked and alcohol use, against frequencies of cells with translocated chromosomes, dicentrics, acentric fragments, color junctions and abnormal cells. No significant relationships were observed between any cytogenetic endpoint and log(urine uranium) levels, smoking, or log(lifetime X rays). Age at the time of blood draw showed significant relationships with all endpoints except for cells with acentric fragments. Translocation frequencies in these Veterans were all well within the normal range of published values for healthy control subjects from around the world. These results indicate that chronic exposure to DU does not induce significant levels of chromosome damage in these Veterans. PMID- 23933232 TI - Comparison of cooling and EMLA to reduce the burning pain during capsaicin 8% patch application: a randomized, double-blind, placebo-controlled study. AB - Topical capsaicin 8% was developed for the treatment of peripheral neuropathic pain. The pain reduction is associated with a reversible reduction of epidermal nerve fiber density (ENFD). During its application, topical capsaicin 8% provokes distinct pain. In a randomized, double-blind study analyzed with a block factorial analysis of variance, we tested whether cooling the skin would result in reliable prevention of the application pain without inhibiting reduction of ENFD. A capsaicin 8% patch was cut into 4 quarters and 2 each were applied for 1 hour on the anterior thighs of 12 healthy volunteers. A randomization scheme provided for 1 of the application sites of each thigh to be pretreated with EMLA and the other with placebo, whereas both application sites of 1 thigh, also randomly selected, were cooled by cool packs, resulting in a site temperature of 20 degrees C during the entire treatment period. The maximum pain level given for the cooled sites (visual analogue scale [VAS] 1.3 +/- 1.4) proved to be significantly lower than for the non-cooled sites (VAS 7.5 +/- 1.9) (P < .0001). In contrast, there was no significant difference in application pain between the sites pretreated with EMLA or with placebo (VAS 4.1 +/- 3.6 vs 4.8 +/- 3.5, P = .1084). At all application sites, ENFD was significantly reduced by 8.0 +/- 2.8 (ENF/mm +/- SD, P < .0001), that is, 70%, with no significant differences between the sites with the different experimental conditions. In conclusion, cooling the skin to 20 degrees C reliably prevents the pain from capsaicin 8% patch application, whereas EMLA does not. ENFD reduction is not inhibited by cooling. PMID- 23933233 TI - Inflammation meets sensitization--an explanation for spontaneous nociceptor activity? AB - Anti-nerve growth factor (anti-NGF) treatment is analgesic in chronic inflammatory pain conditions without reducing inflammation. Hypothesizing that ongoing pain induced by inflammatory mediators is increased by long term sensitization of nociceptors, we combined the non-inflammatory NGF-sensitization model with an inflammatory ultraviolet-B (UV-B) model in human volunteers. UV-B irradiation of the skin presensitized with NGF 3 weeks before intensified the pre existing NGF hyperalgesia during the inflammatory phase of UV-B and caused spontaneous pain in about 70% of the subjects. Pain levels paralleled the intensity of UVB inflammation. Hyperalgesia recorded on a VAS (0-100) was additive after combined NGF/UV-B treatment versus single NGF or UV-B treatment for mechanical impact and tonic heat stimuli, again paralleling the intensity of the UV-B inflammation. In contrast, ratings to tonic mechanical pressure (100 kPa for 10 seconds, peak VAS 58 +/- 7 vs VAS 21 +/- 5 [NGF] and VAS 12 +/- 3 [UV-B]) and pinprick (150 mN for 5 seconds, peak VAS 33 +/- 7 vs VAS 10 +/- 2 [NGF] and VAS 8 +/- 3 [UV-B]) increased in a supra-additive manner. This supra-additive effect faded 24 hours after irradiation, although heat sensitization remained increased. Hyperalgesia and spontaneous pain coexisted in NGF/UV-B treated skin but did not significantly correlate (r < -0.1 at day 1 and r < 0.2 at day 3). We conclude that NGF can sensitize nociceptive endings such that inflammatory mediators may cause sufficient excitation to provoke spontaneous pain. Our results suggest that neuronal sensitization and level of inflammation represent independent therapeutic targets in chronic inflammatory pain conditions. PMID- 23933234 TI - Electrochemical techniques for characterization of stem-loop probe and linear probe-based DNA sensors. AB - Here we present a summary of the sensor performance of the stem-loop probe (SLP) and linear probe (LP) electrochemical DNA sensors when interrogated using alternating current voltammetry (ACV), cyclic voltammetry (CV), and differential pulse voltammetry (DPV). Specifically, we identified one critical parameter for each voltammetric technique that can be adjusted for optimal sensor performance. Overall, the SLP sensor displayed good sensor performance (i.e., 60+% signal attenuation in the presence of the target) over a wider range of experimental conditions when compared to the LP sensor. When used with ACV, the optimal frequency range was found to be between 5 and 5000 Hz, larger than the 5-100 Hz range observed with the LP sensor. A similar trend was observed for the two sensors in CV; the LP sensor was operational only at scan rates between 30 and 100 V/s, whereas the SLP sensor performed well at scan rates between 1 and 1000 V/s. Unlike ACV and CV, DPV has demonstrated to be a more versatile sensor interrogation technique for this class of sensors. Despite the minor differences in total signal attenuation upon hybridization to the target DNA, both SLP and LP sensors performed optimally under most pulse widths used in this study. More importantly, when used with longer pulse widths, both sensors showed "signal-on" behavior, which is generally more desirable for sensor applications. PMID- 23933236 TI - Elongate microparticles for enhanced drug delivery to ex vivo and in vivo pig skin. AB - The delivery of therapeutics and cosmaceuticals into and/or through the skin is hindered by epidermal barriers. To overcome the skin's barriers we have developed a novel cutaneous delivery method using high aspect ratio elongate microparticles (EMPs). Using ex vivo and in vivo pig skin we assess the penetration and delivery characteristics of the elongate microparticles. With reflectance confocal microscopy we observed that the elongate microparticles successfully penetrated the epidermis and upper dermis. Delivery was then assessed using two different length populations of EMPs, comparing their delivery profile to topical alone using sodium fluorescein and confocal microscopy. We observed a relatively uniform and continuous delivery profile in the EMP treated area within the upper layers of the skin--up to seven times greater than topical alone. Finally, we delivered two therapeutically relevant compounds (Vitamins A and B3), showing enhanced delivery using the EMPs. To our knowledge this is the first report using high aspect ratio elongate microparticles in this manner for enhanced topical delivery to the skin. PMID- 23933235 TI - The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage. AB - Despite the clinical introduction of an increasing number of polyethylene glycol (PEG)-conjugated substances, PEG has been named as the cause of an unexpected immunogenic response known as the "accelerated blood clearance (ABC) phenomenon." This phenomenon has been extensively observed during the repeated administration of PEG-conjugated substances and PEGylated nanocarriers including PEGylated liposomes, PEGylated nanoparticles, PEGylated micelles, etc., resulting in the increased clearance and reduced efficacy of PEG-conjugated substances/PEGylated nanocarriers. In this review, therefore, we focused on the possible mechanisms underlying the induction of such a phenomenon and emphasized the factors affecting its magnitude. In addition, the clinical implications of the ABC phenomenon on the therapeutic efficacy of PEG-conjugated substances/PEGylated nanocarriers, along with the new approaches that can be applied to manage and/or abrogate the induction of the ABC phenomenon, are also discussed. PMID- 23933237 TI - Chemical composition, antimicrobial and antioxidant activities of anethole-rich oil from leaves of selected varieties of fennel [Foeniculum vulgare Mill. ssp. vulgare var. azoricum (Mill.) Thell]. AB - The chemical composition and biological activity of the essential oils obtained from the leaves of two different cultivars of Florence fennel cropped under three different fertilization treatments (Control not fertilized; Mineral Fertilization; Compost from Municipal Solid Wastes) have been analyzed. All the oils were characterized by high anethole concentration and some showed also a good percentage of limonene. Thus, the leaves of Florence fennel, which are agricultural wastes, could be used for the recovery of anethole to be used for its flavoring and biomedical properties. The antimicrobial activity expressed by assays on the examined oils indicates an appreciable effect, generally higher on Gram-positive bacteria. The various samples of Florence fennel analyzed did not show any results with FRAP test. The DPPH test showed a weak capacity of the samples to catch the free radicals from the solution, attributable to their content in anethole. PMID- 23933238 TI - Chemical constituents from the rice fermented with the edible mushroom Pleurotus eryngii and their quinone oxidoreductase 1 inducing effect. AB - The fruiting bodies or mycelia of mushrooms have been used as food and food flavoring material for centuries due to their nutritional and medicinal values and the diversity of their bioactive components. The present research was the first to study the chemical components in rice fermented with the edible mushroom Pleurotus eryngii and the quinone oxidoreductase 1 inducing effect of these compounds. Through chemical investigation, one new compound, ((6S,7S)-6,7 dihydroxy-6-methyl-2-(3-methylbutanoyl)-4,5,6,7-tetrahydrobenzofuran-3-yl)methyl acetate (1) and eight known compounds (2-9) were isolated from the P. eryngii fermented rice. All of these compounds were isolated from rice fermented with the edible mushroom P. eryngii for the first time. Their structures were elucidated by MS and NMR data analyses. Alternariol-5-O-methyl ether (2) showed strong quinone oxidoreductase 1 inducing effect with an IR value of 2.58 at the concentration of 20 MUg/ml. The content of adenosine (8) in the fermented rice (175.64 MUg/g) is much higher than that of non-fermented rice (14.38 MUg/g). PMID- 23933239 TI - The mere exposure effect is modulated by selective attention but not visual awareness. AB - Repeated exposures to an object will lead to an enhancement of evaluation toward that object. Although this mere exposure effect may occur when the objects are presented subliminally, the role of conscious perception per se on evaluation has never been examined. Here we use a binocular rivalry paradigm to investigate whether a variance in conscious perceptual duration of faces has an effect on their subsequent evaluation, and how selective attention and memory interact with this effect. Our results show that face evaluation is positively biased by selective attention but not affected by visual awareness. Furthermore, this effect is not due to participants recalling which face had been attended to. PMID- 23933240 TI - A possible new mechanism for the control of miRNA expression in neurons. AB - The control of gene expression by miRNAs has been widely investigated in different species and cell types. Following a probabilistic rather than a deterministic regimen, the action of these short nucleotide sequences on specific genes depends on intracellular concentration, which in turn reflects the balance between biosynthesis and degradation. Recent studies have described the involvement of XRN2, an exoribonuclease, in miRNA degradation and PAPD4, an atypical poly(A) polymerase, in miRNA stability. Herein, we examined the expression of XRN2 and PAPD4 in developing and adult rat hippocampi. Combining bioinformatics and real-time PCR, we demonstrated that XRN2 and PAPD4 expression is regulated by the uncorrelated action of transcription factors, resulting in distinct gene expression profiles during development. Analyses of nuclei position and nestin labeling revealed that both proteins progressively accumulated during neuronal differentiation, and that they are weakly expressed in immature neurons and absent in glial and endothelial cells. Despite the differences in subcellular localization, both genes were concurrently identified within identical neuronal subpopulations, including specific inhibitory interneurons. Thus, we cope with a singular circumstance in biology: an almost complete intersected expression of functional-opposed genes, reinforcing that their antagonistically driven actions on miRNAs "make sense" if simultaneously present at the same cells. Considering that the transcriptome in the nervous system is finely tuned to physiological processes, it was remarkable that miRNA stability-related genes were concurrently identified in neurons that play essential roles in cognitive functions such as memory and learning. In summary, this study reveals a possible new mechanism for the control of miRNA expression. PMID- 23933241 TI - Synthesis and characterization of novel fluorogenic substrates of coagulation factor XIII-A. AB - Further development of our recently published Glu(pNA)-containing peptides (Anal. Biochem. 428 (2012) 73-80) provided new fluorogenic substrates for the activated blood coagulation factor XIII. A first series was designed by incorporation of Glu(AMC) at the penultimate position from the N terminus. For the best derivative H-Tyr-Glu(AMC)-Val-Lys-Val-Ile-NH2, a moderate kcat/Km value of 34s(-1)M(-1) was determined, which is more than 100-fold reduced compared with the previously reported Glu(pNA) substrates. Furthermore, two fluorescence resonance energy transfer (FRET) substrates were prepared by incorporation of an N-methyl anthraniloyl fluorophore and a 2,4-dinitrophenyl quencher. Both substrates were excellently cleaved by FXIII-A2(*), which is generated from its zymogen by activation of thrombin in the presence of calcium ions. In the absence and presence of H-Gly-ethyl ester, kcat/Km values of 8010 and 8660s(-)(1)M(-)(1), respectively, were found for the conversion of H-Lys(N(Me)Abz)-Glu(NH-(CH2)4-NH Dnp)-Val-Lys-Val-Ile-Gly-NH2 (substrate 8). These values are more than 200-fold improved compared with the Glu(AMC) substrates. Substrate 8 is suitable for the measurement of FXIII-A2(*) activities in plasma samples as well as for in vitro measurements. Furthermore, it was used for the determination of the inhibitory potency of a newly synthesized chloromethyl ketone derivative, Cbz-Phe-Glu(CMK) Val-Lys-Val-Ile-Gly-NH2, which was found to be a potent irreversible inhibitor of FXIII-A2(*). PMID- 23933242 TI - Cross-platform compatibility of Hi-Plex, a streamlined approach for targeted massively parallel sequencing. AB - Although per-base sequencing costs have decreased during recent years, library preparation for targeted massively parallel sequencing remains constrained by high reagent cost, limited design flexibility, and protocol complexity. To address these limitations, we previously developed Hi-Plex, a polymerase chain reaction (PCR) massively parallel sequencing strategy for screening panels of genomic target regions. Here, we demonstrate that Hi-Plex applied with hybrid adapters can generate a library suitable for sequencing with both the Ion Torrent and the TruSeq chemistries and that adjusting primer concentrations improves coverage uniformity. These results expand Hi-Plex capabilities as an accurate, affordable, flexible, and rapid approach for various genetic screening applications. PMID- 23933243 TI - Non-dioxin-like PCBs inhibit [(3)H]WIN-35,428 binding to the dopamine transporter: a structure-activity relationship study. AB - Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) are neurotoxic compounds with known effects at the dopaminergic system in the brain. In a previous study we demonstrated that NDL-PCBs inhibit uptake of dopamine into rat brain synaptosomes, an effect most likely mediated by inhibition of the dopamine transporter (DAT). Here, using the cocaine analogue [(3)H]WIN-35,428 binding assay and synaptosomes, we directly investigate whether NDL-PCBs act via DAT and explore the structure-activity relationship of this effect. In total, thirty PCBs were investigated, including a previously selected training set of twenty PCBs covering the structural variation within tri- to hepta-chlorinated NDL-PCBs, and an additional set of ten NDL-PCB congeners selected to validate the structure activity pattern of neurotoxic PCBs. Since previous work has demonstrated that NDL-PCBs can also inhibit the vesicular monoamine transporter 2 (VMAT2), we additionally examined whether some PCB congeners favour an effect on VMAT2 and others on DAT. Our results show that NDL-PCBs are potent inhibitors of [(3)H]WIN 35,428 binding to DAT. In fact, we identify a PCB congener (PCB 110) with similar potency for [(3)H]WIN-35,428 binding inhibition as cocaine. All active congeners were ortho-chlorinated PCBs, and in particular, tetra- and penta-chlorinated with 2-3 chlorine atoms in the ortho position were potent inhibitors of [(3)H]WIN 35,428 binding. Notably, the most active PCBs are highly prevalent in commercial mixtures of PCBs (Aroclor 1242, 1254 and 1260), which indicates that DAT inhibition could be one of the factors contributing to behavioural effects after Aroclor exposure. Derived data correlated well with the recently derived neurotoxic equivalency factors (NEQs), indicating the generality and applicability of the NEQ scheme in risk assessments of PCBs. PMID- 23933244 TI - Quercetin deformable liposome: preparation and efficacy against ultraviolet B induced skin damages in vitro and in vivo. AB - Ultraviolet (UV) radiation has deleterious effects on cells through direct damage to DNA or through increasing generation of reactive oxygen species (ROS). The flavonol quercetin (Qu) provides cellular protection against UV radiation and the current investigation was carried out to develop a deformable liposome formulation of Qu to enhance its delivery into human skin and to improve its anti UVB effect. The influence of surfactants (including Span 20, Tween 80 and sodium cholate) on the properties of Qu deformable liposomes was investigated. Liposomes composed of Qu, phosphatidylcholine (PC), cholesterol (Chol), and Tween 80 showed high entrapment efficiencies (80.41+/-4.22%), small particle sizes (132+/-14nm), high elasticity (10.48+/-0.71), and prolonged drug release. The cell viability in UVB-irradiated HaCaT cells increased to 89.89+/-4.5% at 24h and 78.8+/-3.19% at 48h following treatment with Qu defomable liposomes. The ROS and malondialdehyde (MDA) level were also reduced. The penetration rate was 3.8-fold greater than that of the Qu suspension. Moreover, the edema and inflammation was alleviated by Qu deformable liposomes. These results showed the potential of deformable liposomes to enhance the anti-UVB effects of Qu both in vitro and in vivo. PMID- 23933245 TI - Ultraviolet resources over Northern Eurasia. AB - We propose a new climatology of UV resources over Northern Eurasia, which includes the assessments of both detrimental (erythema) and positive (vitamin D synthesis) effects of ultraviolet radiation on human health. The UV resources are defined by using several classes and subclasses - UV deficiency, UV optimum, and UV excess - for 6 different skin types. To better quantifying the vitamin D irradiance threshold we accounted for an open body fraction S as a function of effective air temperature. The spatial and temporal distribution of UV resources was estimated by radiative transfer (RT) modeling (8 stream DISORT RT code) with 1*1 degrees grid and monthly resolution. For this purpose special datasets of main input geophysical parameters (total ozone content, aerosol characteristics, surface UV albedo, UV cloud modification factor) have been created over the territory of Northern Eurasia. The new approaches were used to retrieve aerosol parameters and cloud modification factor in the UV spectral region. As a result, the UV resources were obtained for clear-sky and mean cloudy conditions for different skin types. We show that the distribution of UV deficiency, UV optimum and UV excess is regulated by various geophysical parameters (mainly, total ozone, cloudiness and open body fraction) and can significantly deviate from latitudinal dependence. We also show that the UV optimum conditions can be simultaneously observed for people with different skin types (for example, for 4 5 skin types at the same time in spring over Western Europe). These UV optimum conditions for different skin types occupy a much larger territory over Europe than that over Asia. PMID- 23933246 TI - Binding of hen egg white lysozyme fibrils with nucleic acids. AB - Non proteinaceous substances are found to be associated with toxic protein aggregates commonly known as fibrils. Hen egg white lysozyme (HEWL) is able to form fibrillar species under various conditions. Here for the first time we report concentration dependent binding affinities of preformed HEWL fibrils towards DNA and RNA at physiological pH (pH 7.4). We have found that HEWL fibrils bind with DNA and RNA that is distinctly different when compared to native HEWL. The association constant (Ka) of native HEWL and ct-DNA at pH 7.4 is 6.8*10(5)M( 1). We have also investigated the conformational alterations of DNA that occur on binding with HEWL fibrils. Our study has demonstrated dominant electrostatic interactions between oppositely charged polyelectrolytes which accounts for the binding of nucleic acids with fibrils. The affinity between the moieties could lead to disruption in the functions of cellular components that might be attributed to the toxicity of the aggregates formed in vivo. PMID- 23933247 TI - Residence time modeling of hot melt extrusion processes. AB - The hot melt extrusion process is a widespread technique to mix viscous melts. The residence time of material in the process frequently determines the product properties. An experimental setup and a corresponding mathematical model were developed to evaluate residence time and residence time distribution in twin screw extrusion processes. The extrusion process was modeled as the convolution of a mass transport process described by a Gaussian probability function, and a mixing process represented by an exponential function. The residence time of the extrusion process was determined by introducing a tracer at the extruder inlet and measuring the tracer concentration at the die. These concentrations were fitted to the residence time model, and an adequate correlation was found. Different parameters were derived to characterize the extrusion process including the dead time, the apparent mixing volume, and a transport related axial mixing. A 2(3) design of experiments was performed to evaluate the effect of powder feed rate, screw speed, and melt viscosity of the material on the residence time. All three parameters affect the residence time of material in the extruder. In conclusion, a residence time model was developed to interpret experimental data and to get insights into the hot melt extrusion process. PMID- 23933248 TI - Capillary malformation-arteriovenous malformation syndrome: a report of 2 cases, diagnostic criteria, and management. AB - Capillary malformation-arteriovenous malformation syndrome is a rare type of vascular malformation first described in 2003. It is an autosomal dominant inherited disorder that has been reported in association with heterozygous mutations in the RASA1 gene, which encodes the protein RASp21. The clinical picture is characterized by multiple small capillary malformations which are associated with either arteriovenous malformations or arteriovenous fistulas in both the affected individual and other members of their family. We describe 2 new familial cases of this syndrome that were clinically and genetically diagnosed and studied in our hospital. PMID- 23933249 TI - Superficial granulomatous pyoderma. Report of 2 cases treated with topical tacrolimus. PMID- 23933250 TI - Fetuin-A (alpha2HS-glycoprotein) is a serum chemo-attractant that also promotes invasion of tumor cells through Matrigel. AB - The present study was conducted to determine whether fetuin-A, a dominant serum protein plays a role in chemo-attraction and chemo-invasion of carcinoma cells in vitro. Serum is normally used as positive chemotaxis control in Boyden chamber motility assays, prompting the need to identify the factor/s in serum that contributes the bulk of chemo-taxis and invasion. Serum has a plethora of chemotactic factors including stromal derived factor 1 also known as CXCL12. Using highly purified fetuin-A, we compared its chemo-attraction potential to culture medium containing 10% fetal bovine serum. We also investigated its ability to attract tumor cells through a bed of Matrigel (invasion assay). We demonstrated, using similar concentration range of fetuin-A found in blood, that it robustly supports both directed chemo-attraction and invasion of breast tumor cells. More importantly, we showed that at low concentrations (fetuin-A coated wells) itinteracts synergistically with CXCL12 to promote chemotaxis. The presence of plasminogen (PL) blunted the fetuin-A mediated chemotaxis. Taken together, the data suggest an in vivo chemotaxis/invasion role for fetuin-A. PMID- 23933251 TI - An in-cell NMR study of monitoring stress-induced increase of cytosolic Ca2+ concentration in HeLa cells. AB - Recent developments in in-cell NMR techniques have allowed us to study proteins in detail inside living eukaryotic cells. The lifetime of in-cell NMR samples is however much shorter than that in culture media, presumably because of various stresses as well as the nutrient depletion in the anaerobic environment within the NMR tube. It is well known that Ca(2+)-bursts occur in HeLa cells under various stresses, hence the cytosolic Ca(2+) concentration can be regarded as a good indicator of the healthiness of cells in NMR tubes. In this study, aiming at monitoring the states of proteins resulting from the change of cytosolic Ca(2+) concentration during experiments, human calbindin D9k (P47M+C80) was used as the model protein and cultured HeLa cells as host cells. Time-resolved measurements of 2D (1)H-(15)N SOFAST-HMQC experiments of calbindin D9k (P47M+C80) in HeLa cells showed time-dependent changes in the cross-peak patterns in the spectra. Comparison with in vitro assignments revealed that calbindin D9k (P47M+C80) is initially in the Mg(2+)-bound state, and then gradually converted to the Ca(2+) bound state. This conversion process initiates after NMR sample preparation. These results showed, for the first time, that cells inside the NMR tube were stressed, presumably because of cell precipitation, the lack of oxygen and nutrients, etc., thereby releasing Ca(2+) into cytosol during the measurements. The results demonstrated that in-cell NMR can monitor the state transitions of stimulated cells through the observation of proteins involved in the intracellular signalling systems. Our method provides a very useful tool for in situ monitoring of the "healthiness" of the cells in various in-cell NMR studies. PMID- 23933252 TI - Advanced glycation end products suppress osteoblastic differentiation of stromal cells by activating endoplasmic reticulum stress. AB - Advanced glycation end products (AGEs) are involved in bone quality deterioration in diabetes mellitus. We previously showed that AGE2 or AGE3 inhibited osteoblastic differentiation and mineralization of mouse stromal ST2 cells, and also induced apoptosis and decreased cell growth. Although quality management for synthesized proteins in endoplasmic reticulum (ER) is crucial for the maturation of osteoblasts, the effects of AGEs on ER stress in osteoblast lineage are unknown. We thus examined roles of ER stress in AGE2- or AGE3-induced suppression of osteoblastogenesis of ST2 cells. An ER stress inducer, thapsigargin (TG), induced osteoblastic differentiation of ST2 cells by increasing the levels of Osterix, type 1 collagen (Col1), alkaline phosphatase (ALP) and osteocalcin (OCN) mRNA. AGE2 or AGE3 suppressed the levels of ER stress sensors such as IRE1alpha, ATF6 and OASIS, while they increased the levels of PERK and its downstream molecules, ATF4. A reduction in PERK level by siRNA did not affect the AGEs induced suppression of the levels of Osterix, Col1 and OCN mRNA. In conclusion, AGEs inhibited the osteoblastic differentiation of stromal cells by suppressing ER stress sensors and accumulating abnormal proteins in the cells. This process might accelerate AGEs-induced suppression of bone formation found in diabetes mellitus. PMID- 23933253 TI - Plasma membrane characterization, by scanning electron microscopy, of multipotent myoblasts-derived populations sorted using dielectrophoresis. AB - Multipotent progenitor cells have shown promise for use in biomedical applications and regenerative medicine. The implementation of such cells for clinical application requires a synchronized, phenotypically and/or genotypically, homogenous cell population. Here we have demonstrated the implementation of a biological tag-free dielectrophoretic device used for discrimination of multipotent myoblastic C2C12 model. The multipotent capabilities in differentiation, for these cells, diminishes with higher passage number, so for cultures above 70 passages only a small percentage of cells is able to differentiate into terminal myotubes. In this work we demonstrated that we could recover, above 96% purity, specific cell types from a mixed population of cells at high passage number without any biological tag using dielectrophoresis. The purity of the samples was confirmed by cytometric analysis using the cell specific marker embryonic myosin. To further investigate the dielectric properties of the cell plasma membrane we co-culture C2C12 with similar size, when in suspension, GFP-positive fibroblast as feeder layer. The level of separation between the cell types was above 98% purity which was confirmed by flow cytometry. These levels of separation are assumed to account for cell size and for the plasma membrane morphological differences between C2C12 and fibroblast unrelated to the stages of the cell cycle which was assessed by immunofluorescence staining. Plasma membrane conformational differences were further confirmed by scanning electron microscopy. PMID- 23933254 TI - Visual sustained attention and numerosity sensitivity correlate with math achievement in children. AB - In this study, we investigated in school-age children the relationship among mathematical performance, the perception of numerosity (discrimination and mapping to number line), and sustained visual attention. The results (on 68 children between 8 and 11 years of age) show that attention and numerosity perception predict math scores but not reading performance. Even after controlling for several variables, including age, gender, nonverbal IQ, and reading accuracy, attention remained correlated with math skills and numerosity discrimination. These findings support previous reports showing the interrelationship between visual attention and both numerosity perception and math performance. It also suggests that attentional deficits may be implicated in disturbances such as developmental dyscalculia. PMID- 23933256 TI - A truncated form of dicer tilts the balance of RNA interference pathways. AB - The RNase III enzyme Dicer is responsible for key steps in the biogenesis of small RNA species in multiple RNA interference pathways. Here, we show that, in the adult C. elegans soma, half of the total DCR-1 protein is expressed as a truncated, stable C-terminal fragment named small DCR-1 (sDCR-1). sDCR-1 operates independently of full-length DCR-1 in two distinct RNAi pathways; it enhances exogenous RNAi (exoRNAi) and concurrently acts as a negative regulator of microRNA (miRNA) biogenesis. Enhancement of exoRNAi relies on sDCR-1 catalytic activity, whereas impinging on miRNA processing does not. Instead, sDCR-1 competes with pre-miRNA processing by interacting with the miRNA-dedicated Argonautes ALG-1 and ALG-2. Finally, triggering a strong exoRNAi response in the presence of elevated levels of sDCR-1 exacerbates the miRNA processing defect. Our results unveil a surprising role for a truncated form of DCR-1 in the modulation of multiple RNAi activities and in the regulation of mechanistic boundaries between pathways. PMID- 23933255 TI - CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. AB - The transcription factor STAT1 is important in natural killer (NK) cells, which provide immediate defense against tumor and virally infected cells. We show that mutation of a single phosphorylation site (Stat1-S727A) enhances NK cell cytotoxicity against a range of tumor cells, accompanied by increased expression of perforin and granzyme B. Stat1-S727A mice display significantly delayed disease onset in NK cell-surveilled tumor models including melanoma, leukemia, and metastasizing breast cancer. Constitutive phosphorylation of S727 depends on cyclin-dependent kinase 8 (CDK8). Inhibition of CDK8-mediated STAT1-S727 phosphorylation may thus represent a therapeutic strategy for stimulating NK cell mediated tumor surveillance. PMID- 23933257 TI - Integrating genomic, epigenomic, and transcriptomic features reveals modular signatures underlying poor prognosis in ovarian cancer. AB - Ovarian cancer has a poor prognosis, with different outcomes for different patients. The mechanism underlying this poor prognosis and heterogeneity is not well understood. We have developed an unbiased, adaptive clustering approach to integratively analyze ovarian cancer genome-wide gene expression, DNA methylation, microRNA expression, and copy number alteration profiles. We uncovered seven previously uncategorized subtypes of ovarian cancer that differ significantly in median survival time. We then developed an algorithm to uncover molecular signatures that distinguish cancer subtypes. Surprisingly, although the good-prognosis subtypes seem to have not been functionally selected, the poor prognosis ones clearly have been. One subtype has an epithelial-mesenchymal transition signature and a cancer hallmark network, whereas the other two subtypes are enriched for a network centered on SRC and KRAS. Our results suggest molecular signatures that are highly predictive of clinical outcomes and spotlight "driver" genes that could be targeted by subtype-specific treatments. PMID- 23933258 TI - Low-affinity T cells are programmed to maintain normal primary responses but are impaired in their recall to low-affinity ligands. AB - T cell responses to low-affinity T cell receptor (TCR) ligands occur in the context of infection, tumors, and autoimmunity despite diminished TCR signal strength. The processes that enable such responses remain unclear. We show that distinct mechanisms drive effector/memory development in high- and low-affinity T cells. Low-affinity cells preferentially differentiate into memory precursors of a central memory phenotype that are interleukin (IL)-12R(lo), IL-7R(hi), and Eomes(hi). Strikingly, in contrast to naive cells, low-affinity memory cells were impaired in the response to low- but not high-affinity ligands, indicating that low-affinity cells are programmed to generate diverse immune responses while avoiding autoreactivity. Affinity and antigen dose directly correlated with IL 12R signal input and T-bet but not with Eomes expression because low- affinity signals were more potent inducers of Eomes at a high antigen dose. Our studies explain how weak antigenic signals induce complete primary immune responses and provide a framework for therapeutic intervention. PMID- 23933259 TI - Chronic lymphocytic leukemia cells are activated and proliferate in response to specific T helper cells. AB - There is increasing interest in the chronic lymphocytic leukemia (CLL) microenvironment and the mechanisms that may promote CLL cell survival and proliferation. A role for T helper (Th) cells has been suggested, but current evidence is only circumstantial. Here we show that CLL patients had memory Th cells that were specific for endogenous CLL antigens. These Th cells activated autologous CLL cell proliferation in vitro and in human -> mouse xenograft experiments. Moreover, CLL cells were efficient antigen-presenting cells that could endocytose and process complex proteins through antigen uptake pathways, including the B cell receptor. Activation of CLL cells by Th cells was contact and CD40L dependent. The results suggest that CLL is driven by ongoing immune responses related to Th cell-CLL cell interaction. We propose that Th cells support malignant B cells and that they could be targeted in the treatment of CLL. PMID- 23933260 TI - Systematic identification of proteins binding to chromatin-embedded ubiquitylated H2B reveals recruitment of SWI/SNF to regulate transcription. AB - Chromatin posttranslational modifications (PTMs), including monoubiquitylation of histone H2B on lysine 120 (H2Bub1), play a major role in regulating genome functions. To elucidate the molecular mechanisms of H2Bub1 activity, a chromatin template uniformly containing H2Bub1 was used as an affinity matrix to identify preferentially interacting human proteins. Over 90 such factors were found, including proteins and protein complexes associated with transcription, RNA posttranscriptional modifications, and DNA replication and repair. Notably, we found that the SWI/SNF chromatin remodeling complex associates preferentially with H2Bub1-rich chromatin. Moreover, SWI/SNF is required for optimal transcription of a subset of genes that are selectively dependent on H2Bub1. Our findings substantially expand the known H2Bub1 interactome and provide insights into the functions of this PTM in mammalian gene regulation. PMID- 23933261 TI - Global proteome analysis of the NCI-60 cell line panel. AB - The NCI-60 cell line collection is a very widely used panel for the study of cellular mechanisms of cancer in general and in vitro drug action in particular. It is a model system for the tissue types and genetic diversity of human cancers and has been extensively molecularly characterized. Here, we present a quantitative proteome and kinome profile of the NCI-60 panel covering, in total, 10,350 proteins (including 375 protein kinases) and including a core cancer proteome of 5,578 proteins that were consistently quantified across all tissue types. Bioinformatic analysis revealed strong cell line clusters according to tissue type and disclosed hundreds of differentially regulated proteins representing potential biomarkers for numerous tumor properties. Integration with public transcriptome data showed considerable similarity between mRNA and protein expression. Modeling of proteome and drug-response profiles for 108 FDA-approved drugs identified known and potential protein markers for drug sensitivity and resistance. To enable community access to this unique resource, we incorporated it into a public database for comparative and integrative analysis (http://wzw.tum.de/proteomics/nci60). PMID- 23933262 TI - Supplementary studies and molecular data on Henneguya cerebralis Pronin, 1972 (Myxozoa: Myxosporea), a parasite from Kosogol grayling Thymallus arcticus nigrescens in Mongolia. AB - Henneguya cerebralis Pronin, 1972 (Myxozoa) was described from Kosogol graylings Thymallus arcticus nigrescens Dorogostaisky, 1923 in Lake Khovsgol (Mongolia) in 1972. H. cerebralis was redescribed using critical morphological features and 18S ribosomal DNA (rDNA) gene sequence. Parasite infects cranial cartilage of fish host. Plasmodia are white rounded or ovoid, by 0.1 to 2mm in size, containing large quantities of spores. Spore body is ovoid or rounded, 11.18 +/- 0.13 MUm (range 9,71-12,56) in length and 9.06 +/- 0.16 MUm (range 7.22-10,06) in width with equal polar capsules (4.7*2.6 MUm). The two caudal appendages have different lengths (one of them was shorter in 20%). Phylogenetic position inferred by 18S rDNA shows that H. cerebralis is closely related with H. zschokkei, H. nuesslini, H. salminicola and H. cartilaginis which are histozoic parasites of salmonid fish. PMID- 23933263 TI - Tumor cell-mediated neovascularization and lymphangiogenesis contrive tumor progression and cancer metastasis. AB - Robust neovascularization and lymphangiogenesis have been found in a variety of aggressive and metastatic tumors. Endothelial sprouting angiogenesis is generally considered to be the major mechanism by which new vasculature forms in tumors. However, increasing evidence shows that tumor vasculature is not solely composed of endothelial cells (ECs). Some tumor cells acquire processes similar to embryonic vasculogenesis and produce new vasculature through vasculogenic mimicry, trans-differentiation of tumor cells into tumor ECs, and tumor cell-EC vascular co-option. In addition, tumor cells secrete various vasculogenic factors that induce sprouting angiogenesis and lymphangiogenesis. Vasculogenic tumor cells actively participate in the formation of vascular cancer stem cell niche and a premetastatic niche. Therefore, tumor cell-mediated neovascularization and lymphangiogenesis are closely associated with tumor progression, cancer metastasis, and poor prognosis. Vasculogenic tumor cells have emerged as key players in tumor neovascularization and lymphangiogenesis and play pivotal roles in tumor progression and cancer metastasis. However, the mechanisms underlying tumor cell-mediated vascularity as they relate to tumor progression and cancer metastasis remain unclear. Increasing data have shown that various intrinsic and extrinsic factors activate oncogenes and vasculogenic genes, enhance vasculogenic signaling pathways, and trigger tumor neovascularization and lymphangiogenesis. Collectively, tumor cells are the instigators of neovascularization. Therefore, targeting vasculogenic tumor cells, genes, and signaling pathways will open new avenues for anti-tumor vasculogenic and metastatic drug discovery. Dual targeting of endothelial sprouting angiogenesis and tumor cell-mediated neovascularization and lymphangiogenesis may overcome current clinical problems with anti-angiogenic therapy, resulting in significantly improved anti-angiogenesis and anti-cancer therapies. PMID- 23933264 TI - The involvement of PDGF/VEGF related factor in regulation of immune and neuroendocrine in Chinese mitten crab Eriocheir sinensis. AB - Members of the platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF) family have been implicated in cell proliferation, cell differentiation, and cell migration, vascular development, angiogenesis and neural development. In the present study, a novel PDGF/VEGF related factor gene was cloned and identified in Chinese mitten crab Eriocheir sinensis (designated as EsPVF1). The full-length cDNA of EsPVF1 was of 1173 bp, consisting a 5' untranslated region (UTR) of 54 bp, a 3' UTR of 1131 bp with a poly (A) tail, and an open reading frame (ORF) of 588 bp encoding 196 amino acid residues. A signal peptide of 20 amino acid residues, a PDGF/VEGF homology growth factor domain of 81 amino acids, and a typical cysteine knot motif (CXCXC) were identified in the deduced amino acid sequence of EsPVF1. By fluorescent quantitative real-time PCR, the EsPVF1 mRNA was detected ubiquitously in the select tissues of hemocytes, gonad, heart, muscle, hepatopancreas and gill, with the high abundance in hemocytes and gonad. The mRNA expression level of EsPVF1 was up-regulated and reached the highest at 24 h after Vibrio anguillarum challenge, while it was induced at 3 h, 6 h, 12 h, 24 h and 48 h compared with the untreated group after Pichia pastoris GS115 challenge. Tissue injury also induced the mRNA expression of EsPVF1 in hemocytes of crabs, and the expression level increased obviously at 8 h. The cDNA fragment encoding mature peptide of EsPVF1 was recombined and expressed in Escherichia coli BL21 (DE3) pLysS. Biogenic amine in hemolymph pre incubated with recombinant protein of EsPVF1 (rEsPVF1) was detected by fluorimetric method. Norepinephrine and dopamine in hemolymph incubated with rEsPVF1 were higher than that in the blank group. Therefore, EsPVF1 could significantly provoke the release of norepinephrine and dopamine. The results collectively indicated that EsPVF1 was involved in regulation of the immune response and neuroendocrine system in crabs. PMID- 23933265 TI - Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients. AB - BACKGROUND & AIMS: Unhealthy food intake, specifically fructose, has been associated with metabolic alterations and with the severity of liver fibrosis in patients with non-alcoholic fatty liver disease. In a cohort of patients with genotype 1 chronic hepatitis C (G1 CHC), we tested the association of fructose intake with the severity of liver histology. METHODS: Anthropometric and metabolic factors, including waist circumference (WC), waist-to-hip ratio (WHR), dorso-cervical lipohypertrophy and HOMA were assessed in 147 consecutive biopsy proven G1 CHC patients. Food intake, namely industrial and fruit fructose, was investigated by a three-day structured interview and a computed database. All biopsies were scored by an experienced pathologist for staging and grading (Scheuer classification), and graded for steatosis, which was considered moderate severe if >= 20%. Features of non-alcoholic steatohepatitis (NASH) in CHC were also assessed (Bedossa classification). RESULTS: Mean daily intake of total, industrial and fruit fructose was 18.0+/-8.7g, 6.0+/-4.7g, and 11.9+/-7.2g, respectively. Intake of industrial, not fruit fructose, was independently associated with higher WHR (p=0.02) and hypercaloric diet (p<0.001). CHC patients with severe liver fibrosis (?F3) reported a significantly higher intake of total (20.8+/-10.2 vs. 17.2+/-8.1g/day; p=0.04) and industrial fructose (7.8+/-6.0 vs. 5.5+/-4.2; p=0.01), not fruit fructose (12.9+/-8.0 vs. 11.6+/-7.0; p=0.34). Multivariate logistic regression analysis showed that older age (OR 1.048, 95% CI 1.004-1.094, p=0.03), severe necroinflammatory activity (OR 3.325, 95% CI 1.347 8.209, p=0.009), moderate-severe steatosis (OR 2.421, 95% CI 1.017-6.415, p=0.04), and industrial fructose intake (OR 1.147, 95% CI 1.047-1.257, p=0.003) were independently linked to severe fibrosis. No association was found between fructose intake and liver necroinflammatory activity, steatosis, and the features of NASH. CONCLUSIONS: The daily intake of industrial, not fruit fructose is a risk factor for metabolic alterations and the severity of liver fibrosis in patients with G1 CHC. PMID- 23933266 TI - Assessment of chronic rejection in liver graft recipients receiving immunosuppression with low-dose calcineurin inhibitors. AB - BACKGROUND & AIMS: Calcineurin inhibitors represent the cornerstone immunosuppressants after liver transplantation despite their side effects. As liver graft is particularly well tolerated, low doses may be proposed. The aim of this study was to assess the prevalence of chronic rejection in patients with low calcineurin inhibitors regimen and to compare their characteristics with patients under standard doses. METHODS: All patients with liver transplantation between 1997 and 2004 were divided into two groups. Low-dose patients (n=57) had tacrolimus baseline levels <5ng/ml or cyclosporine levels <50ng/ml at t0 or <100ng/ml at t+2h and were prospectively proposed a liver biopsy, searching for chronic rejection according to Banff criteria. The remaining patients constituted the standard-doses group (n=40). RESULTS: Among the low-dose group, 36 patients in the low-dose group were assessed by biopsy. No chronic rejection was found. Fifty-six percent had only calcineurin inhibitors and 8% received other immunosuppressants only. The median time between liver transplantation and biopsy was 90 months (64-157) and between IS regimen decrease and biopsy was 41 months (11-115). Liver tests were normal in 72% of the patients. Low-dose patients had more often hepatitis B (p=0.045), less past acute rejection episodes (p=0.028), and better renal function (p=0.040). Decrease of calcineurin inhibitors failed in 15% of standard-dose patients without impacting the graft function. In the low dose group, co-prescription of other immunosuppressants facilitated the decrease (p=0.051). CONCLUSIONS: The minimization, or even cessation, of calcineurin inhibitors may be an achievable goal in the long term for most of the liver graft recipients. PMID- 23933267 TI - Effects of a playground marking intervention on school recess physical activity in French children. AB - OBJECTIVE: Playground interventions offer an opportunity to enhance school recess physical activity. We aimed to assess the effects of playground marking on objectively measured school recess physical activity in French children. METHODS: Participants were four hundred and twenty children (6-11years old) from 4 primary schools in Nord-Pas de Calais, France. Children's physical activity (PA) was measured with a uniaxial accelerometer twice a day (morning and afternoon recess) during a 4-day school week in April and May 2009. Two experimental schools (EG) received a recess-based intervention (playground markings) and two others served as controls (CG). Percentage of time spent on the following intensities of physical activity during school recess was measured before and after intervention: sedentary (SED), light physical activity (LPA), moderate physical activity (MPA), vigorous physical activity (VPA), very high physical activity (VHPA) and moderate-to-vigorous physical activity (MVPA). RESULTS: At baseline, school recess PA among children from CG was significantly (p<0.001) higher than that among EG children. No interaction was observed between the recess-based intervention and gender. After the intervention, the EG spent significantly (p<0.05) more time in MPA, VPA and MVPA with a concomitant significant decrease in SED (p<0.05) compared to baseline, while the PA in CG remained unchanged. CONCLUSION: Painted playground markings had a positive short-term effect on school recess physical activity levels. PMID- 23933268 TI - Impact of a multi-level intervention to prevent secondhand smoke exposure in schoolchildren: a randomized cluster community trial. AB - OBJECTIVE: To assess the effectiveness of a multi-level (individual, family, and school) school-based intervention to prevent the exposure to secondhand smoke (SHS) in a population of schoolchildren (12-14 years old). METHOD: This was a community trial with cluster randomization of schools to an intervention and comparison group (ClinicalTrials.Gov identifier NCT01881607). The intervention targeted schoolchildren in Terrassa (Catalonia, Spain). We assessed SHS exposure in different settings and tobacco consumption by means of a questionnaire before and one year after the intervention. RESULTS: We analyzed data from 1734 students with both baseline and follow-up data. The crude analysis showed that SHS exposure among students in the intervention group significantly decreased at school (-14.0%), at home (-19.9%), and on transportation (-21.8%). In the comparison group, SHS exposure significantly decreased only at home (-16.9%). After adjustment for potential confounders, the good accomplishment of the activities showed a possible trend towards a non-significant reduction in exposure at home, transportation, and leisure time. CONCLUSION: While this school based multi-level intervention had no overall effect in SHS exposure, the improvement of the activities focused on preventing SHS would be needed in order to achieve a significant decrease in the proportion of children exposed to SHS. PMID- 23933269 TI - cDNA cloning, genomic organization and expression analysis during somatic embryogenesis of the translationally controlled tumor protein (TCTP) gene from Japanese larch (Larix leptolepis). AB - A full-length cDNA and genomic sequences of a translationally controlled tumor protein (TCTP) gene were isolated from Japanese larch (Larix leptolepis) and designated LaTCTP. The length of the cDNA was 1, 043 bp and contained a 504 bp open reading frame that encodes a predicted protein of 167 amino acids, characterized by two signature sequences of the TCTP protein family. Analysis of the LaTCTP gene structure indicated four introns and five exons, and it is the largest of all currently known TCTP genes in plants. The 5'-flanking promoter region of LaTCTP was cloned using an improved TAIL-PCR technique. In this region we identified many important potential cis-acting elements, such as a Box-W1 (fungal elicitor responsive element), a CAT-box (cis-acting regulatory element related to meristem expression), a CGTCA-motif (cis-acting regulatory element involved in MeJA-responsiveness), a GT1-motif (light responsive element), a Skn-1 motif (cis-acting regulatory element required for endosperm expression) and a TGA element (auxin-responsive element), suggesting that expression of LaTCTP is highly regulated. Expression analysis demonstrated ubiquitous localization of LaTCTP mRNA in the roots, stems and needles, high mRNA levels in the embryonal suspensor mass (ESM), browning embryogenic cultures and mature somatic embryos, and low levels of mRNA at day five during somatic embryogenesis. We suggest that LaTCTP might participate in the regulation of somatic embryo development. These results provide a theoretical basis for understanding the molecular regulatory mechanism of LaTCTP and lay the foundation for artificial regulation of somatic embryogenesis. PMID- 23933270 TI - Screening of transcription factors with transcriptional initiation activity. AB - A majority of mammalian promoters are associated with CpG islands. CpG island promoters frequently lack common core promoter elements, such as the TATA box, and often have dispersed transcription start sites. The mechanism through which CpG island promoters are transcriptionally initiated remains unclear. We speculate that some transcription factors can direct transcription initiation by themselves. To test this hypothesis, we screened a variety of transcription factors to see whether they could initiate transcription. Most transcription factors, including specificity protein 1 (Sp1) and nuclear factor Y (NF-Y), showed little transcriptional initiation activity. However, nuclear respiratory factor 1 (NRF-1), the basic helix-loop-helix/leucine zipper (bHLH/ZIP) family of proteins and the E-twenty six (Ets) family of proteins had strong transcriptional activity. We further demonstrated that these transcription factors initiate dispersed transcription. Our studies provide perspectives to the mechanism of transcription initiation from CpG island promoters. PMID- 23933271 TI - The effects of age and gender on the relationship between HMGCR promoter-911 SNP (rs33761740) and serum lipids in patients with coronary heart disease. AB - BACKGROUND: Hydroxymethylglutaryl-Coenzyme A Reductase (HMGCR) catalyzes the rate limiting step of cholesterol biosynthesis. This enzyme is the target of the widely available cholesterol lowering statins. In this population-based case control study, the frequencies of -911 C>A polymorphism (rs3761740) of the HMGCR gene in patients with coronary heart disease (CHD) and healthy subjects were investigated and the correlations between the different genotypes and hypercholesterolemia with cardiovascular risk factors were analyzed. METHODS: The HMGCR genotypes were determined in 365 patients with CHD and 365 controls by PCR RFLP assay. Anthropometric measurements were measured in all participants. RESULTS: There was no significant difference in the genotype frequencies of the HMGCR polymorphism between the male subjects of both patient and control groups, however, the HMGCR-CC genotype was found to be more frequent in female patients with CHD than female controls (p=0.002). The HMGCR-CC genotype showed higher total-cholesterol (TC) and LDL-cholesterol (LDL-C) levels than the CA+AA genotypes in male CHD patients (p=0.018). Due to this significant sex interaction, a multivariate analysis was conducted on the patient group. In the multivariate logistic regression analysis, the HMGCR-CC genotype was significantly associated with age<55 (OR=2.837, p=0.001) and TC >= 5.18 mmol/L (OR=1.970, p=0.027) in male subjects. However, this association was not observed in female patients (p>0.05). This analysis confirmed that the HMGCR-CC genotype was associated with elevated TC levels in male CHD patients with age<55 years. CONCLUSION: These results suggest that age and sex modify the contribution of the HMGCR-911 polymorphism to fasting serum TC, LDL-C levels and risk of CHD. PMID- 23933272 TI - A novel t(4;16)(q25;q23.1) associated with EGF and ELOVL6 deregulation in acute myeloid leukemia. AB - About 50% of acute myeloid leukemia (AML) patients show the occurrence of non random chromosome rearrangements. Most of the recurrent karyotypic rearrangements in AML have been defined as distinct disease entities in the 2008 World Health Organization (WHO) classification. In this paper we report an AML case showing a novel t(4;16)(q25;q23.1) rearrangement causing the activation of epidermal growth factor (EGF) and elongation of long-chain fatty acids family member 6 (ELOVL6) genes, rather than the generation of a novel fusion gene. PMID- 23933273 TI - Antagonistic functional duality of cancer genes. AB - Cancer evolution is a stochastic process both at the genome and gene levels. Most of tumors contain multiple genetic subclones, evolving in either succession or in parallel, either in a linear or branching manner, with heterogeneous genome and gene alterations, extensively rewired signaling networks, and addicted to multiple oncogenes easily switching with each other during cancer progression and medical intervention. Hundreds of discovered cancer genes are classified according to whether they function in a dominant (oncogenes) or recessive (tumor suppressor genes) manner in a cancer cell. However, there are many cancer "gene chameleons", which behave distinctly in opposite way in the different experimental settings showing antagonistic duality. In contrast to the widely accepted view that mutant NADP(+)-dependent isocitrate dehydrogenases 1/2 (IDH1/2) and associated metabolite 2-hydroxyglutarate (R)-enantiomer are intrinsically "the drivers" of tumourigenesis, mutant IDH1/2 inhibited, promoted or had no effect on cell proliferation, growth and tumorigenicity in diverse experiments. Similar behavior was evidenced for dozens of cancer genes. Gene function is dependent on genetic network, which is defined by the genome context. The overall changes in karyotype can result in alterations of the role and function of the same genes and pathways. The diverse cell lines and tumor samples have been used in experiments for proving gene tumor promoting/suppressive activity. They all display heterogeneous individual karyotypes and disturbed signaling networks. Consequently, the effect and function of gene under investigation can be opposite and versatile in cells with different genomes that may explain antagonistic duality of cancer genes and the cell type- or the cellular genetic/context-dependent response to the same protein. Antagonistic duality of cancer genes might contribute to failure of chemotherapy. Instructive examples of unexpected activity of cancer genes and "paradoxical" effects of different anticancer drugs depending on the cellular genetic context/signaling network are discussed. PMID- 23933274 TI - Determination of the CCR5?32 frequency in Emiratis and Tunisians and the screening of the CCR5 gene for novel alleles in Emiratis. AB - BACKGROUND: The chemokine receptor components play crucial roles in the immune system and some of them serve as co-receptors for the HIV virus. Several studies have documented that variants in chemokine receptors are correlated with susceptibility and resistance to infection with HIV virus. For example, mutations in the chemokine receptor 5 gene (CCR5) resulting in loss-of-function (such as the homozygous CCR5?32) confer high degree of resistance to HIV infection. Heterozygotes for these variants exhibit slow progression to AIDS. The prevalence of CCR5 polymorphisms varies among ethnic and geographical groups. For example, the CCR5?32 variant is present in 10-15% of north Europeans but is rarely encountered among Africans. This study aims to identify the prevalence of some CCR5 variants in two geographically distant Arab populations (namely Emiratis and Tunisians). METHODOLOGY: The prevalence of CCR5 gene variants including CCR5?32, FS299, C101X, A29S and C178R has been determined using PCR and direct DNA sequencing. A total of 403 unrelated healthy individuals (253 Emiratis and 150 Tunisians) were genotyped for the CCR5?32 variant using PCR amplification and gel electrophoresis. In addition, 200 Emiratis have been screened for other SNPs using Sanger DNA sequencing. RESULTS: Among Emiratis, the allele frequency of the CCR5?32 variant has been found to be 0.002. In addition, two variants L55Q and A159 were found at a frequency of 0.002. Moreover, the prevalence of the CCR5?32 variant in Tunisians was estimated to be 0.013 which is relatively higher than its frequency in Emiratis but lower than Europeans. CONCLUSION: We conclude that the allele frequency of the most critical CCR5 polymorphism (?32) is extremely low among Emiratis compared to other Arabs and North Europeans. In addition, very low allele frequencies of other CCR5 polymorphisms have been detected among Emiratis. PMID- 23933275 TI - Identification of a PTC-containing DlRan transcript and its differential expression during somatic embryogenesis in Dimocarpus longan. AB - RAN (Ras-related nuclear protein) plays crucial roles in multiple cellular processes in yeast, animals and plants. Here we present a DlRan gene and its alternative splicing transcripts containing premature terminator codons (PTCs), identified from embryogenic cultures in longan. Multiple alignment and splicing pattern analyses indicated that DlRan-1 transcript harboring PTC was the consequence of alternative splicing. The accumulation of DlRan PTC-containing transcripts increased significantly when the embryogenic calli were treated with the translation inhibitor, cycloheximide, indicating that DlRan-1 may be targeted by NMD. The analysis of expression profiles of DlRan transcripts revealed that differential expression levels of the alternative spliced DlRan transcripts occurred during the development of embryogenic callus, globular-shaped embryos, and cotyledon-shaped embryos, respectively, in the longan somatic embryogenesis, and were in consistent with the embryo development in corresponding wild-type transcripts. The present work offers evidence to speculate that the alternatively spliced PTC-containing transcripts can be functional and may shed light on expression regulation of DlRan during development of the longan somatic embryos. PMID- 23933276 TI - Increased TERC gene copy number and cells in senescence in primary sclerosing cholangitis compared to colitis and control patients. AB - OBJECTIVE: Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder that involves inflammatory and fibrotic changes in the bile ducts. Up to 80% of patients have concomitant inflammatory bowel disease (IBD) with colitis. PSC patients are predisposed to develop hepatobiliary, colonic and other extrahepatic malignancies, probably related to inflammatory processes that might promote carcinogenesis. Telomerase is an enzyme complex that lengthens telomeres and has enhanced expression in numerous malignancies. In this study, we evaluated the TERC gene copy number, the proportion of cells in senescence and the amount of fragmentation in the senescent state. METHODS: Fluorescence in situ hybridization (FISH) for the TERC gene was applied to lymphocytes retrieved from PSC (N=19), colitis (N=20) and healthy control patients (N=20) to determine the TERC copy number. On the same FISH slides, cells stained with DAPI were also analyzed for senescence-associated heterochromatin foci (SAHF) status, including the number of cells with fragments and the number of SAHF fragments in each cell. RESULTS: A higher TERC gene copy number was observed in cells from PSC patients compared to colitis and control group patients. It was also higher in the colitis than in the control group. Significantly more cells in the senescent state and more fragmentation in each cell were observed in the PSC group compared to colitis and control groups. CONCLUSION: The TERC gene copy number and the number of cells in the senescent state were increased in PSC patients compared to the colitis and control groups. These findings are probably related to the genetic instability parameters that reflect the higher tendency of this patient group to develop malignancies. PMID- 23933277 TI - A fast SNP identification and analysis of intraspecific variation in the medicinal Panax species based on DNA barcoding. AB - Medicinal plants of the Panax genus belonging to Araliaceae family are well known, rare plants used as tonics in traditional Chinese medicine and have been described in the Chinese Pharmacopoeia. Because of the high price and the huge human demand, these commercial products often contain adulterants. In this study, 377 sequences from four species were analyzed. Single nucleotide polymorphisms (SNPs) were detected and patterns of intragenomic variation in internal transcribed spacer 2 (ITS2) from the four Panax species were studied. Intraspecific variations were analyzed based on three typical DNA barcodings (ITS2, matK and psbA-trnH). Results from this study revealed that intraspecific genetic distances in Panax ginseng and Panax quinquefolius were quite low (0 0.002) and the multi-copy ITS2 could be considered a single locus in the genomes of these two species. Five stable SNPs were detected in ITS2 region to identify the Panax medicinal species. Considering the mixed powder of P. ginseng and P. quinquefolius, double peaks could be clearly examined at SNP positions and the height of the peaks could indicate the mixed ratio roughly. Our findings indicate that SNP-based molecular barcodes could be developed as a routine method for the identification of the Panax genus with closely related species and the mixed powder P. ginseng and P. quinquefolius. PMID- 23933279 TI - A combined molecular docking-based and pharmacophore-based target prediction strategy with a probabilistic fusion method for target ranking. AB - Herein, a combined molecular docking-based and pharmacophore-based target prediction strategy is presented, in which a probabilistic fusion method is suggested for target ranking. Establishment and validation of the combined strategy are described. A target database, termed TargetDB, was firstly constructed, which contains 1105 drug targets. Based on TargetDB, the molecular docking-based target prediction and pharmacophore-based target prediction protocols were established. A probabilistic fusion method was then developed by constructing probability assignment curves (PACs) against a set of selected targets. Finally the workflow for the combined molecular docking-based and pharmacophore-based target prediction strategy was established. Evaluations of the performance of the combined strategy were carried out against a set of structurally different single-target compounds and a well-known multi-target drug, 4H-tamoxifen, which results showed that the combined strategy consistently outperformed the sole use of docking-based and pharmacophore-based methods. Overall, this investigation provides a possible way for improving the accuracy of in silico target prediction and a method for target ranking. PMID- 23933278 TI - Evaluation and selection of reliable reference genes for gene expression under abiotic stress in cotton (Gossypium hirsutum L.). AB - Reference genes are critical for normalization of the gene expression level of target genes. The widely used housekeeping genes may change their expression levels at different tissue under different treatment or stress conditions. Therefore, systematical evaluation on the housekeeping genes is required for gene expression analysis. Up to date, no work was performed to evaluate the housekeeping genes in cotton under stress treatment. In this study, we chose 10 housekeeping genes to systematically assess their expression levels at two different tissues (leaves and roots) under two different abiotic stresses (salt and drought) with three different concentrations. Our results show that there is no best reference gene for all tissues at all stress conditions. The reliable reference gene should be selected based on a specific condition. For example, under salt stress, UBQ7, GAPDH and EF1A8 are better reference genes in leaves; TUA10, UBQ7, CYP1, GAPDH and EF1A8 were better in roots. Under drought stress, UBQ7, EF1A8, TUA10, and GAPDH showed less variety of expression level in leaves and roots. Thus, it is better to identify reliable reference genes first before performing any gene expression analysis. However, using a combination of housekeeping genes as reference gene may provide a new strategy for normalization of gene expression. In this study, we found that combination of four housekeeping genes worked well as reference genes under all the stress conditions. PMID- 23933280 TI - Molecular detection of Leishmania infection in sand flies in border line of Iran Turkmenistan: restricted and permissive vectors. AB - A molecular study was carried out to incriminate sand fly vectors of cutaneous leishmaniasis (CL) in rural areas of Sarakhs district, Khorassane-Razavi Province, northeastern Iran, in 2011. Sand flies of Sergentomyia with three species and Phlebotomus with six species respectively comprised 73.3% and 26.7% of the specimens. Phlebotomus papatasi was the most common Phlebotomine species in outdoor and indoor resting places. Leishmania infection was found at least in 17 (22%) specimens including Ph. papatasi (n=9 pool samples), Phlebotomus caucasicus (n=6), Phlebotomus alexandri (n=1), and Sergentomyia sintoni (n=1). The parasites were found comprised Leishmania major (n=5), Leishmania turanica (n=10), and Leishmania gerbilli (n=4). Infection of Ph. papatasi with both L. major and L. turanica supporting the new suggestion indicating that it is not restricted only with L. major. Circulation of L. major by Ph. alexandri, and both L. gerbilli and L. turanica by Ph. caucasicus, in addition to previous data indicating the ability of Ph. alexandri to circulate Leishmania infantum and Leishmania donovani, and Ph. caucasicus to circulate L. major, suggests that these two species can be permissive vectors. The results suggest that Ph. papatasi and Ph. alexandri are the primary and secondary vectors of CL where circulating L. major between human and reservoirs, whereas Ph. caucasicus is circulating L. turanica and L. gerbilli between the rodents in the region. PMID- 23933281 TI - Liposomal-lupane system as alternative chemotherapy against cutaneous leishmaniasis: macrophage as target cell. AB - Leishmania amazonensis causes human diseases that range from self-healing to diffusion cutaneous lesions. The chemotherapy of leishmaniasis requires long-term treatment and has been based on the use of pentavalent antimonials. Liposomes have been used as antileishmanial drug carries and have adjuvant activity in vaccines against several microorganisms, representing an important option to the development of new therapeutics for the disease. In this study, we developed a liposomal formulation containing lupane [3beta,6beta,16beta-trihydroxylup-20(29) ene], isolated from fruits of Combretum leprosum with pharmacological properties as antinociceptive, anti-inflammatory, antiulcerogenic and antileishmanial activities. The aim of the present study was to evaluate the efficacy of liposomal-lupane in L. amazonensis-infection model. Liposomes were prepared by the extrusion method with DPPC, DPPS and cholesterol at 5:1:4 weight ratio. The lupane (2 mg/mL) was added to the lipid mixture, solubilized in chloroform and dried under nitrogen flow. The activity of liposomal-lupane was conducted in vitro with mouse peritoneal infected macrophages. Furthermore, mice were infected in the right hind footpad with 10(5) stationary growth phase of L. amazonensis promastigotes. After 6 weeks, animals were treated with liposomal-lupane for 15 days by intraperitoneal injection. The evolution of disease was monitored weekly by measuring footpad thickness with a caliper. Three days after the treatment, peritoneal macrophages were collected, plated and production of the cytokines IL 10 and IL-12 was evaluated in supernatants of the cultures after 24 h. The results indicate that the liposomal system containing lupane achieved here is a promising tool to confer antileishmanial activity to infected macrophages. PMID- 23933282 TI - Influence of treatment with 3'-deoxyadenosine associated deoxycoformycin on hematological parameters and activity of adenosine deaminase in infected mice with Trypanosoma evansi. AB - This study aimed to verify the effect of 3'-deoxyadenosine and deoxycoformycin on hematologic parameters and adenosine deaminase (ADA) activity in plasma and brain of mice infected with Trypanosoma evansi. Seventy animals were divided into seven groups, which were divided into two subgroups each for sampling on days 4 and 8 post-infection (PI). The groups were composed of three uninfected groups (A-C), namely, not-treated (A), treated with 3'-deoxyadenosine (B), and treated with deoxycoformycin (C) and four infected groups, mice with T. evansi (D-G), namely, not-treated (D), treated with 3'-deoxyadenosine (E), treated with deoxycoformycin (F), and treated with a combination 3'-deoxyadenosine and deoxycoformycin (G). Hematological parameters and ADA activity were evaluated in plasma and brain. Animals in groups B and C exhibited a reduction in the levels of plasma total protein compared group A. Animals in groups D and F showed changes in the hematological parameters. The ADA activity significantly reduced in the animals of groups C, D, F and G. Mice in the group E presented increased ADA activity in plasma. Therefore, we conclude that the treatment interferes significantly in the hematologic parameters in mice infected with T. evansi. On the other hand, when the ADA inhibitor was used we observed a significant decrease in the values of hematocrit, total erythrocytes, and hemoglobin concentration. The deoxycoformycin was able to inhibit the ADA activity of parasite thus it may be one of the mechanisms of efficacy of this treatment. PMID- 23933283 TI - Interactions of subunits Asa2, Asa4 and Asa7 in the peripheral stalk of the mitochondrial ATP synthase of the chlorophycean alga Polytomella sp. AB - Mitochondrial F1FO-ATP synthase of chlorophycean algae is a complex partially embedded in the inner mitochondrial membrane that is isolated as a highly stable dimer of 1600kDa. It comprises 17 polypeptides, nine of which (subunits Asa1 to 9) are not present in classical mitochondrial ATP synthases and appear to be exclusive of the chlorophycean lineage. In particular, subunits Asa2, Asa4 and Asa7 seem to constitute a section of the peripheral stalk of the enzyme. Here, we over-expressed and purified subunits Asa2, Asa4 and Asa7 and the corresponding amino-terminal and carboxy-terminal halves of Asa4 and Asa7 in order to explore their interactions in vitro, using immunochemical techniques, blue native electrophoresis and affinity chromatography. Asa4 and Asa7 interact strongly, mainly through their carboxy-terminal halves. Asa2 interacts with both Asa7 and Asa4, and also with subunit alpha in the F1 sector. The three Asa proteins form an Asa2/Asa4/Asa7 subcomplex. The entire Asa7 and the carboxy-terminal half of Asa4 seem to be instrumental in the interaction with Asa2. Based on these results and on computer-generated structural models of the three subunits, we propose a model for the Asa2/Asa4/Asa7 subcomplex and for its disposition in the peripheral stalk of the algal ATP synthase. PMID- 23933284 TI - Clinical significance of microRNA-148a in patients with early relapse of stage II stage and III colorectal cancer after curative resection. AB - Development of robust prognostic/predictive biomarkers in patients with colorectal cancer (CRC) is imperative for advancing treatment strategies for this disease. We aimed to determine whether expression status of microRNAs might be a simple and reliable biomarker to detect postoperative early relapse in patients with CRC after radical resection. We used microRNA arrays and identified that microRNA-148a (miRNA-148a) had substantially different expression levels in early and nonearly relapsed stage II and III CRC tissues. The validation study, which included 55 early relapsed patients and 55 nonearly relapsed patients, further confirmed overexpression of miRNA-148a in nonearly relapsed samples. Subsequently, we explored whether the serum level of miRNA-148a can be used to predict early CRC recurrence. The in vitro and in vivo effects of miRNA-148a were examined by cell proliferation, migration, and invasion, as well as cell cycles, and xenograft in null mice. Last, miRNA-148a was investigated as a potential biomarker for identifying early relapse. Cellular studies demonstrated that the overexpression of miRNA-148a inhibited colon cancer cell proliferation and migration but not invasion. The cell cycle studies also revealed that miRNA-148a caused an accumulation of the G2 population. Moreover, lower levels of miRNA-148a expression were associated with significantly shorter disease-free survival rates and poorer overall survival rates. This study showed that miRNA-148a can inhibit tumorigenesis and reduce the early recurrence of CRC. These findings suggest that miRNA-148a may have potential clinical applications for predicting the early relapse of patients with CRC after radical resection. PMID- 23933286 TI - Detection of (1,3)-beta-D-glucans in situ in a Candida albicans brain granuloma. PMID- 23933285 TI - Characterisation of the RNA interference response against the long-wavelength receptor of the honeybee. AB - Targeted knock-down is the method of choice to advance the study of sensory and brain functions in the honeybee by using molecular techniques. Here we report the results of a first attempt to interfere with the function of a visual receptor, the long-wavelength-sensitive (L-) photoreceptor. RNA interference to inhibit this receptor led to a reduction of the respective mRNA and protein. The interference effect was limited in time and space, and its induction depended on the time of the day most probably because of natural daily variations in opsin levels. The inhibition did not effectively change the physiological properties of the retina. Possible constraints and implications of this method for the study of the bee's visual system are discussed. Overall this study underpins the usefulness and feasibility of RNA interference as manipulation tool in insect brain research. PMID- 23933287 TI - PA-356R is a unique signature of the avian influenza A (H7N9) viruses with bird to-human transmissibility: potential implication for animal surveillances. PMID- 23933288 TI - Serological survey in close contacts with a confirmed case of H7N9 influenza in Taiwan. PMID- 23933289 TI - Novel regenerable sorbent based on Zr-Mn binary metal oxides for flue gas mercury retention and recovery. AB - To capture and recover mercury from coal-fired flue gas, a series of novel regenerable sorbents based on Zr-Mn binary metal oxides were prepared and employed at a relatively low temperature. PXRD, TEM, TPR, XPS, and N2-adsorption methods were employed to characterize the sorbents. The Hg(0) adsorption performance of the sorbents was tested, and the effects of the main operation parameters and the gas components on the adsorption were investigated. Zr significantly improved the sorbent's mercury capacity, which was nearly 5mg/g for Zr0.5Mn0.5Oy. Furthermore, the spent sorbent could be regenerated by heating to 350 degrees C, and the highly concentrated elemental mercury released could be facilely recycled. Therefore, a much greener process for mercury capture and recovery could be anticipated based on this regenerable sorbent. PMID- 23933290 TI - Behind adhesion of uranyl onto montmorillonite surface: a molecular dynamics study. AB - We have performed molecular dynamics simulations to investigate the adsorption of radionuclide elements species onto substituted Montmorillonite (001) surface in the presence of different counterions. The structure and the dynamics of uranyl ion as well as its aquo, chloride ion, and carbonate complexes are analyzed. In addition, we have studied the surface energy between layered Montmorillonite sheets and the work of adhesion between radionuclide and charged Montmorillonite. The clay model used here is a Wyoming-type Montmorillonite with 0.75e negative charge per unit cell resulting from substitutions in Octahedral and Tetrahedral sheets. The system model was constructed based on CLAYFF force field potential model. To evaluate the thermodynamic work of adhesion, each surface and clay layer regions are converted to a thin film model. One and two species of radionuclide elements (UO2(H2O)5,UO2CO3(H2O)5, and UO2Cl2(H2O)5) were deposited near the clay surface in a pseudo-two-dimensional periodic cell. Analysis shows that the uranyl ion structure is preserved with two axial oxygen atoms detected at 1.8A. Radial distribution functions results indicate that average UOw distances are 2.45-2.61A, and 2.29-2.40A for UOc distance. Average UCl distances are 2.78-3.08A, which is relatively larger than that of Uranium atom-Oxygen atom because of electrostatic factors. PMID- 23933291 TI - Preparation and enhanced visible-light photocatalytic activity of graphitic carbon nitride/bismuth niobate heterojunctions. AB - A series of graphitic carbon nitride/bismuth niobate (g-C3N4/Bi5Nb3O15) heterojunctions with g-C3N4 doping level of 10-90 wt% were prepared by a facile milling-heat treatment method. The phase and chemical structures, surface compositions, electronic and optical properties as well as morphologies of the prepared g-C3N4/Bi5Nb3O15 were well-characterized. Subsequently, the photocatalytic activity and stability of g-C3N4/Bi5Nb3O15 were evaluated by the degradation of aqueous methyl orange (MO) and 4-chlorophenol (4-CP) under the visible-light irradiation. At suitable g-C3N4 doping levels, g-C3N4/Bi5Nb3O15 exhibited enhanced visible-light photocatalytic activity compared with pure g C3N4 or Bi5Nb3O15. This excellent photocatalytic activity was revealed in terms of the extension of visible-light response and efficient separation and transportation of the photogenerated electrons and holes due to coupling of g C3N4 and Bi5Nb3O15. Additionally, the active species yielded in the pure g-C3N4- and g-C3N4/Bi5Nb3O15-catalyzed 4-CP photodegradation systems were investigated by the free radical and hole scavenging experiments. PMID- 23933292 TI - Why do children overimitate? Normativity is crucial. AB - Recent research has documented that children readily engage in overimitation, that is, the reproduction of causally irrelevant elements within a bigger action sequence. Different explanations have been put forward. Affiliation accounts claim that children overimitate to affiliate with the model. Causal confusion accounts claim that children mistakenly perceive causally irrelevant elements as causally relevant and, thus, imitate them. Normativity accounts claim that overimitation arises when children view causally irrelevant elements as an essential part of an overarching conventional activity. To test among these accounts, we had children watch a model produce some effect by performing a sequence of causally irrelevant and relevant acts, with the latter resulting in some effect. In two conditions, the model presented the action sequence as focused either more on the method or more on the goal, with the normativity account predicting that children should interpret the causally irrelevant element as essential more often in the method condition than in the goal condition. Three measures were used: (a) children's own overimitation, (b) their spontaneous responses to a puppet engaging in or refraining from overimitation, and (c) their explicit judgments about the puppet's behavior. Results revealed that overimitation was frequent in both conditions. In addition, however, children protested against the puppet only when she did not overimitate, they did so more in the method condition than in the goal condition, and they explicitly judged omission of the irrelevant actions to be a mistake in the method condition. These results are not readily compatible with affiliation and causal confusion accounts, and they speak in favor of normativity accounts. PMID- 23933293 TI - Microbiological and parasitological investigation among food handlers in hotels in the Dead Sea area, Jordan. AB - BACKGROUND/PURPOSE: Intestinal parasitic and bacterial infections constitute a major health issue in developing countries. The present study investigates and assesses infection rates among food handlers with intestinal parasites and microbial agents in luxurious hotels in the Dead Sea area of Jordan. METHODS: A total of 901 stool samples were collected from food handlers (35 females and 866 males) employed in four main hotels in the Dead Sea area. Fecal samples were examined microscopically for intestinal parasites. Standard culture and biochemical techniques were used for the isolation and identification of Salmonella and Shigella spp. in stool samples. RESULTS: Five species of protozoan (Blastocystis hominis, Giardia intestinalis, Entamoeba coli, Entamoeba histolytica, and Endolimax nana), one helminth (Hymenolepis nana), and one cylindrical worm (Enterobius vermicularis) were recovered with an overall infection rate of 3.7%. G. intestinalis was the most prevalent parasitic infection with infection rate of 2.44%. All samples were negative for both Salmonella and Shigella. CONCLUSION: Findings highlight the important role of food handlers in the transmission of intestinal parasites to high-class clients accommodated in luxury hotels, and stress the urgent need for regular health and parasitologic examination of food handlers. PMID- 23933294 TI - Cortical control of VTA function and influence on nicotine reward. AB - Tobacco use is a major public health problem. Nicotine acts on widely distributed nicotinic acetylcholine receptors (nAChRs) in the brain and excites dopamine (DA) neurons in the ventral tegmental area (VTA). The elicited increase of DA neuronal activity is thought to be an important mechanism for nicotine reward and subsequently the transition to addiction. However, the current understanding of nicotine reward is based predominantly on the data accumulated from in vitro studies, often from VTA slices. Isolated VTA slices artificially terminate communications between neurons in the VTA and other brain regions that may significantly alter nicotinic effects. Consequently, the mechanisms of nicotinic excitation of VTA DA neurons under in vivo conditions have received only limited attention. Building upon the existing knowledge acquired in vitro, it is now time to elucidate the integrated mechanisms of nicotinic reward on intact systems that are more relevant to understanding the action of nicotine or other addictive drugs. In this review, we summarize recent studies that demonstrate the impact of prefrontal cortex (PFC) on the modulation of VTA DA neuronal function and nicotine reward. Based on existing evidence, we propose a new hypothesis that PFC VTA functional coupling serves as an integration mechanism for nicotine reward. Moreover, addiction may develop due to nicotine perturbing the PFC-VTA coupling and thereby eliminating the PFC-dependent cognitive control over behavior. PMID- 23933295 TI - Low-amplitude, left vagus nerve stimulation significantly attenuates ventricular dysfunction and infarct size through prevention of mitochondrial dysfunction during acute ischemia-reperfusion injury. AB - BACKGROUND: Right cervical vagus nerve stimulation (VNS) provides cardioprotective effects against acute ischemia-reperfusion injury in small animals. However, inconsistent findings have been reported. OBJECTIVE: To determine whether low-amplitude, left cervical VNS applied either intermittently or continuously imparts cardioprotection against acute ischemia-reperfusion injury. METHODS: Thirty-two isoflurane-anesthetized swine (25-30 kg) were randomized into 4 groups: control (sham operated, no VNS), continuous-VNS (C-VNS; 3.5 mA, 20 Hz), intermittent-VNS (I-VNS; continuously recurring cycles of 21 second ON, 30-second OFF), and I-VNS + atropine (1 mg/kg). Left cervical VNS was applied immediately after left anterior descending artery occlusion (60 minutes) and continued until the end of reperfusion (120 minutes). The ischemic and nonischemic myocardium was harvested for cardiac mitochondrial function assessment. RESULTS: VNS significantly reduced infarct size, improved ventricular function, decreased ventricular fibrillation episodes, and attenuated cardiac mitochondrial reactive oxygen species production, depolarization, and swelling, compared with the control group. However, I-VNS produced the most profound cardioprotective effects, particularly infarct size reduction and decreased ventricular fibrillation episodes, compared to both I-VNS + atropine and C-VNS. These beneficial effects of VNS were abolished by atropine. CONCLUSIONS: During ischemia-reperfusion injury, both C-VNS and I-VNS provide significant cardioprotective effects compared with I-VNS + atropine. These beneficial effects were abolished by muscarinic blockade, suggesting the importance of muscarinic receptor modulation during VNS. The protective effects of VNS could be due to its protection of mitochondrial function during ischemia-reperfusion. PMID- 23933296 TI - Inhibition of I(f) in the atrioventricular node as a mechanism for dronedarone's reduction in ventricular rate during atrial fibrillation. AB - BACKGROUND: In clinical trials, dronedarone lowers ventricular rate during atrial fibrillation (AF). This agent was recently demonstrated to inhibit If in the sinoatrial node. OBJECTIVE: The purpose of this study was to examine whether dronedarone inhibits If at the atrioventricular (AV) node to reduce ventricular rate during AF by slowing conduction at the AV node. METHODS: We studied the effects of dronedarone (1.0 mg/kg IV bolus) before and after administration of the If inhibitor ivabradine (0.5 mg/kg IV). Ventricular rate, mean arterial pressure, dominant frequency of AF, PR and QT intervals, and atrial (AERP) and ventricular effective refractory periods (VERP) were measured during atrial pacing at 150 bpm in an anesthetized pig model of AF induced by intrapericardial acetylcholine and burst pacing. RESULTS: Dronedarone reduced ventricular rate during AF by 22.1% (from 213 +/- 11.1 bpm to 166 +/- 8.3 bpm, P = .01) and increased PR interval by 8.7% (from 173 +/- 5.6 ms to 188 +/- 5.2 ms, P = .001), QT interval by 3.3% (from 272 +/- 6.2 ms to 281 +/- 4.9 ms, P = .05), and AERP and VERP by 6.2% and 11.7%, respectively. All other parameters remained unchanged. Dronedarone plasma levels were low (29 +/- 4 nM), and concentration in tissue was 15- to 21-fold higher than in plasma. Ivabradine reduced ventricular rate during AF by 39.5% (from 200 +/- 14.6 bpm to 121 +/- 20.1 bpm, P = .005) and increased PR interval by 20.4% (from 157 +/- 9.5 ms to 189 +/- 7.4 ms, P <.05). Administration of dronedarone after ivabradine did not further alter these endpoints. CONCLUSION: Dronedarone, which is concentrated in myocardial tissue, reduces ventricular rate during AF by slowing AV conduction. Absence of this effect after ivabradine administration implicates If inhibition as a mechanism. PMID- 23933297 TI - From ion channel to organismic phenotype: an example of integrative translational research into cardiac electromechanics. PMID- 23933298 TI - Shock efficacy of the entirely subcutaneous defibrillator for termination of spontaneous ventricular fibrillation in Brugada syndrome. PMID- 23933299 TI - Intraoral herpes simplex virus infection in a patient with common variable immunodeficiency. AB - We report a challenging case of an atypical presentation of recrudescent herpes simplex virus infection in a patient with common variable immunodeficiency. Oral infections in immunosuppressed patients may present with unusual clinical features that can mimic non-infectious diseases. This report discusses the diagnostic steps necessary for definitive diagnosis and to guide appropriate and effective management. PMID- 23933300 TI - Proline rich-oligopeptides: diverse mechanisms for antihypertensive action. AB - Bradykinin-potentiating peptides from Bothrops jararaca (Bj) discovered in the early 1960s, were the first natural inhibitors of the angiotensin-converting enzyme (ACE). These peptides belong to a large family of snake venom proline-rich oligopeptides (PROs). One of these peptides, Bj-PRO-9a, was essential for defining ACE as effective drug target and development of captopril, an active site-directed inhibitor of ACE used worldwide for the treatment of human arterial hypertension. Recent experimental evidences demonstrated that cardiovascular effects exerted by different Bj-PROs are due to distinct mechanisms besides of ACE inhibition. In the present work, we have investigated the cardiovascular actions of four Bj-PROs, namely Bj-PRO-9a, -11e, -12b and -13a. Bj-PRO-9a acts upon ACE and BK activities to promote blood pressure reduction. Although the others Bj-PROs are also able to inhibit the ACE activity and to potentiate the BK effects, our results indicate that antihypertensive effect evoked by them involve new mechanisms. Bj-PRO-11e and Bj-PRO-12b involves induction of [Ca(2+)]i transients by so far unknown receptor proteins. Moreover, we have suggested argininosuccinate synthetase and M3 muscarinic receptor as targets for cardiovascular effects elicited by Bj-PRO-13a. In summary, the herein reported results provide evidence that Bj-PRO-mediated effects are not restricted to ACE inhibition or potentiation of BK-induced effects and suggest different actions for each peptide for promoting arterial pressure reduction. The present study reveals the complexity of the effects exerted by Bj-PROs for cardiovascular control, opening avenues for the better understanding of blood pressure regulation and for the development of novel therapeutic approaches. PMID- 23933301 TI - Involvement of substance P and the NK-1 receptor in cancer progression. AB - Many data suggest the deep involvement of the substance P (SP)/neurokinin (NK)-1 receptor system in cancer: (1) Tumor cells express SP, NK-1 receptors and mRNA for the tachykinin NK-1 receptor; (2) Several isoforms of the NK-1 receptor are expressed in tumor cells; (3) the NK-1 receptor is involved in the viability of tumor cells; (4) NK-1 receptors are overexpressed in tumor cells in comparison with normal ones and malignant tissues express more NK-1 receptors than benign tissues; (5) Tumor cells expressing the most malignant phenotypes show an increased percentage of NK-1 receptor expression; (6) The expression of preprotachykinin A is increased in tumor cells in comparison with the levels found in normal cells; (7) SP induces the proliferation and migration of tumor cells and stimulates angiogenesis by increasing the proliferation of endothelial cells; (8) NK-1 receptor antagonists elicit the inhibition of tumor cell growth; (9) The specific antitumor action of NK-1 receptor antagonists on tumor cells occurs through the NK-1 receptor; (10) Tumor cell death is due to apoptosis; (11) NK-1 receptor antagonists inhibit the migration of tumor cells and neoangiogenesis. The NK-1 receptor is a therapeutic target in cancer and NK-1 receptor antagonists could be considered as broad-spectrum antitumor drugs for the treatment of cancer. It seems that a common mechanism for cancer cell proliferation mediated by SP and the NK-1 receptor is triggered, as well as a common mechanism exerted by NK-1 receptor antagonists on tumor cells, i.e. apoptosis. PMID- 23933302 TI - Combining two technologies: multifunctional polymers and self-nanoemulsifying drug delivery system (SNEDDS) for oral insulin administration. AB - The aim of the study is to develop a self-nanoemulsifying drug delivery system (SNEDDS) based on thiolated chitosan for oral insulin administration. The preparations were characterized by particle size, entrapment efficiency, stability and drug release. Serum insulin concentrations were determined after oral administration of all formulations. Insulin SNEDDS formulation was served as control. The optimized SNEDDS consists of 65% (w/w) miglyol 840, 25% (w/w) cremophor EL, 10% (w/w) co-solvents (a mixture of DMSO and glycerol). The formulations in the presence or absence of insulin (5mg/mL) were spherical with the size range between 80 and 160 nm. Entrapment efficiency of insulin increased significantly when the thiolated chitosan was employed (95.14+/-2.96%), in comparison to the insulin SNEDDS (80.38+/-1.22%). After 30 min, the in vitro release profile of insulin from the nanoemulsions was markedly increased compared to the control. In vivo results showed that insulin/thiolated chitosan SNEDDS displayed a significant increase in serum insulin (p-value=0.02) compared to oral insulin solution. A new strategy to combine SNEDDS and thiolated chitosan described in the study would therefore be a promising and innovative approach to improve oral bioavailability of insulin. PMID- 23933303 TI - Studies on the molecular significance in the interaction of bilirubin with collagen. AB - The present investigation is aimed to understand the physiological significance of bilirubin interaction with collagen. In human skin, collagen absorbs both free bilirubin and serum bound bilirubin from the human system. Interaction between bilirubin and collagen depends on time, temperature and concentration of bilirubin. There is an increase in the aggregation rate of collagen in the presence of biliruibin. At physiological condition, 125 nM of bilirubin is the maximum concentration absorbed by per mg of collagen molecule. Bilirubin accelerates the lateral growth of collagen fibrils by shifting its rate of nucleation. Moreover, collagen-bilirubin complex exhibit a tendency to undergo adsorption onto the surface of the fibroblast cells, showing detrimental effects on fibroblasts proliferations. Based on the collagen binding assays, the binding of bilirubin to collagen is found to be electrostatic in nature, which confirms binding between the amino acid fragment of alpha1 (I) region of collagen and carboxyl group of bilirubin. The biotinylated bilirubin derivatives show better binding to alpha1 (I) chain rather than alpha2 (I) chains which clearly designates that bilirubin shows greater affinity to alpha1 chains of collagen. This novel approach directs to reduce the occurrence of bilirubin in hyperbilirubinemia patients. PMID- 23933304 TI - Separate parts of occipito-temporal white matter fibers are associated with recognition of faces and places. AB - A central finding of functional MRI studies is the highly selective response of distinct brain areas in the occipital temporal cortex to faces and places. However, little is known about the association of white matter fibers with the processing of these object categories. In the current study we used DTI-based tractography to reconstruct two main fibers that connect the occipital lobe with the anterior temporal lobe (inferior longitudinal fasciculus-ILF) and with the frontal lobe (inferior fronto-occipital fasciculus-IFOF) in normal individuals. In addition to MRI scans subjects performed face, scene and body recognition tasks outside the scanner. Results show that recognition of faces and scenes were selectively associated with separate parts of the ILF. In particular, face recognition was highly associated with the fractional anisotropy (FA) of the anterior part of the ILF in the right hemisphere. In contrast, scene recognition was strongly correlated with the FA of the posterior and middle but not the anterior part of the ILF bilaterally. Our findings provide the first demonstration that faces and places are not only associated with distinct brain areas but also with separate parts of white matter fibers. PMID- 23933305 TI - Multimodal imaging of subventricular zone neural stem/progenitor cells in the cuprizone mouse model reveals increased neurogenic potential for the olfactory bulb pathway, but no contribution to remyelination of the corpus callosum. AB - Multiple sclerosis is a devastating demyelinating disease of the central nervous system (CNS) in which endogenous remyelination, and thus recovery, often fails. Although the cuprizone mouse model allowed elucidation of many molecular factors governing remyelination, currently very little is known about the spatial origin of the oligodendrocyte progenitor cells that initiate remyelination in this model. Therefore, we here investigated in this model whether subventricular zone (SVZ) neural stem/progenitor cells (NSPCs) contribute to remyelination of the splenium following cuprizone-induced demyelination. Experimentally, from the day of in situ NSPC labeling, C57BL/6J mice were fed a 0.2% cuprizone diet during a 4 week period and then left to recover on a normal diet for 8weeks. Two in situ labeling strategies were employed: (i) NSPCs were labeled by intraventricular injection of micron-sized iron oxide particles and then followed up longitudinally by means of magnetic resonance imaging (MRI), and (ii) SVZ NSPCs were transduced with a lentiviral vector encoding the eGFP and Luciferase reporter proteins for longitudinal monitoring by means of in vivo bioluminescence imaging (BLI). In contrast to preceding suggestions, no migration of SVZ NSPC towards the demyelinated splenium was observed using both MRI and BLI, and further validated by histological analysis, thereby demonstrating that SVZ NSPCs are unable to contribute directly to remyelination of the splenium in the cuprizone model. Interestingly, using longitudinal BLI analysis and confirmed by histological analysis, an increased migration of SVZ NSPC-derived neuroblasts towards the olfactory bulb was observed following cuprizone treatment, indicative for a potential link between CNS inflammation and increased neurogenesis. PMID- 23933306 TI - Gustatory solitary tract development: a role for neuropilins. AB - The rostral nucleus of the solitary tract (rNST) receives orosensory information from taste bud cells in the tongue and palate via cranial nerves VII and IX. These nerves enter the brainstem, form the solitary tract (ST) and synapse with neurons in the rNST, which then relay incoming sensory information to other brain areas to process external gustatory stimuli. Factors that direct or regulate the trajectory of the developing ST are largely unknown. We used 1,1'-dioctadecyl 3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) to identify ST projections originating from cells in the geniculate ganglia of embryonic rats from embryonic day 14 through 18 (E14-E18). After identifying the ST fibers, immunolabeling for and protein expression analysis of the axon guidance molecules neuropilin-1 (Npn-1) and neuropilin-2 (Npn-2) and their binding partners, semaphorin-3A (Sema-3A) and semaphorin-3F (Sema-3F) were performed. The results detail the formation of ST projections into the gustatory brainstem and their relationship to developing rNST neurons. DiI-labeled ST fibers were present in the brainstem as early as E14. Npn-1 was expressed in the ST and in the trigeminal tract at E14, but levels of the protein declined through E18. The expression levels of the binding partner of Npn-1, Sema-3A, increased from E14 to E18. Npn-2 was expressed in the ST and, additionally, in radially oriented, tuft like structures within the brainstem at E14. Expression levels of Npn-2 also declined through E18, in contrast to the expression levels of its binding partner, Sema-3F, which increased during this time period. For the first time, the time course and particular molecular components involved in development of the ST have been identified. These results indicate that the neuropilin and semaphorin families of axon guidance molecules are potential molecular participants in ST formation. PMID- 23933307 TI - Electrophysiological identification of medial and lateral perforant path inputs to the dentate gyrus. AB - The medial perforant path (MPP) and lateral perforant path (LPP) inputs to the hippocampal dentate gyrus form two distinct laminar inputs onto the middle and distal aspects of granule cell dendrites. Previous evidence indicated that paired stimuli reliably produced paired-pulse depression (PPD) in the MPP and paired pulse facilitation (PPF) in the LPP. Despite this, several years of practical experience in our laboratory questioned the utility of using paired-pulse administration to reliably differentiate the MPP and LPP in vitro. Using visualized field and whole-cell recordings in male Sprague-Dawley rats, we demonstrate that both pathways show net PPF of the excitatory postsynaptic potential (fEPSP) at 50-ms interpulse intervals. LPP afferents did reliably exhibit greater PPF than MPP afferents. Thus, the LPP reliably exhibits a greater paired-pulse ratio than the MPP. The magnitude of the paired-pulse ratio was reduced in both afferents by raising calcium levels or lowering the temperature of the recording chamber. PPD of MPP-evoked fEPSPs was only reliably detected at moderate to high stimulus intensities when population spike activity was evident. PPD was more evident in whole cell voltage clamp recordings but nonetheless was not completely diagnostic as PPD was occasionally observed with LPP stimulation as well. We found the MPP and LPP could be reliably identified using conventional microscopy with hippocampal slices, and that they could be distinguished through the analysis of evoked waveform kinetics. This work refines our knowledge of electrophysiological differences between MPP and LPP projections and will help to facilitate the selective activation of these pathways. PMID- 23933309 TI - Developmental and hypoxia-induced cell death share common ultrastructural and biochemical apoptotic features in the central nervous system. AB - Hypoxic insults during the perinatal period lead to motor and cognitive impairments that later appear during childhood. In the adult brain, hypoxic events often lead to necrotic neuronal death, depending on the region and intensity of the event. During development an active apoptotic cell death occurs and could be an important variable affecting the hypoxic insult outcome. In the present work we performed a comparative study, in a chick embryo model, of the phenotypes and molecular markers exhibited during developmental and hypoxic cell death (HxCD). Ultrastructural analysis of optic tectum cells of embryos subjected to hypoxia (8% O2, 60 min) revealed a clear apoptotic morphology that did not differ from the one exhibited during developmental cell death. Integrity of plasma membrane, condensation of chromatin in round well-defined bodies, and gradual shrinkage of the cell are all hallmarks of the apoptotic process and were present in both control and hypoxic cells. To elucidate if hypoxic and developmental cell deaths share a common mechanism we evaluated the activation of both intrinsic and extrinsic apoptotic pathways. A basal cleavage of caspase-9 and cytochrome c release was observed by co-immunofluorescence in control embryos, but hypoxic insult significantly increased the incidence of this colocalization. Caspase-8 cleavage remained unchanged after the hypoxic insult, suggesting that the extrinsic pathway would not be involved in hypoxic death. We also observed a significant decrease of Akt activation immediately after hypoxia, possibly facilitating the later release of cytochrome c. In addition we analyzed the influence of retinal ganglion cells (RGC) in neuronal survival. Transection of RGC fibers at embryonic day (ED) 3 did not induce any change in developmental and HxCD at ED12. In conclusion, our findings demonstrate that a hypoxic insult in the developing brain triggers the same apoptotic pathway as the active developmental death. PMID- 23933310 TI - Regional distribution of putative rhythm-generating and pattern-forming components of the mammalian locomotor CPG. AB - The ventromedial spinal cord of mammals contains a neural network known as the locomotor central pattern generator (CPG) which underlies the basic generation and coordination of muscle activity during walking. To understand how this neural network operates, it is necessary to identify, characterize, and map connectivity among its constituent cells. Recently, a series of studies have analyzed the activity pattern of interneurons that are rhythmically active during locomotion and suggested that they belong to one of two functional levels; one responsible for rhythm generation and the other for pattern formation. Here we use electrophysiological techniques to identify locomotor-related interneurons in the lumbar spinal cord of the neonatal mouse. By analyzing their activity during spontaneous deletions that occur during fictive locomotion we are able to distinguish between those likely to belong to the rhythm-generating and pattern forming levels, and determine the regional distribution of each. Anatomical tracing techniques are also employed to investigate the morphological characteristics of cells belonging to each level. Results demonstrate that putative rhythm-generating cells are medially located and extend locally projecting axons, while those with activity consistent with pattern formation are located more laterally and send axonal projections to the lateral edge of the spinal cord, in the direction of the motoneuron pools. Results of this study provide insight into the detailed anatomical organization of the locomotor CPG. PMID- 23933308 TI - DNA methylation and childhood maltreatment: from animal models to human studies. AB - Childhood maltreatment (CM) has estimated prevalence among Western societies between 10% and 15%. As CM associates with increased risk of several psychiatric disorders, early age of illness onset, increased comorbidity and negative clinical outcome, it imposes a major public health, social and economic impact. Although the clinical consequences of CM are well characterized, a major challenge remains to understand how negative early-life events can affect brain function over extended periods of time. We review here both animal and human studies indicating that the epigenetic mechanism of DNA methylation is a crucial mediator of early-life experiences, thereby maintaining life-long neurobiological sequelae of CM, and strongly determining psychopathological risk. PMID- 23933311 TI - Transgenic overexpression of the cell adhesion molecule L1 in neurons facilitates recovery after mouse spinal cord injury. AB - It has been shown that the X-chromosome-linked neural cell adhesion molecule L1 plays a beneficial role in regeneration after spinal cord injury (SCI) in young adult rodents when applied in various molecular and cellular forms. In an attempt to further characterize the multiple functions of L1 after severe SCI we analyzed locomotor functions and measured axonal regrowth/sprouting and sparing, glial scarring, and synaptic remodeling at 6 weeks after severe spinal cord compression injury at the T7-9 levels of L1-deficient mice (L1-/y) and their wild-type (L1+/y) littermates, as well as mice that overexpress L1 under the control of the neuron-specific Thy-1 promoter (L1tg) and their wild-type littermates (L1+/+). No differences were found in the locomotor scale score and single frame motion analysis between L1-/y and L1+/y mice during 6 weeks after SCI, most likely due to the very low expression of L1 in the adult spinal cord of wild-type mice. L1tg mice, however, showed better locomotor recovery than their L1+/+ littermates, being associated with enhanced numbers of catecholaminergic axons in the lumbar spinal cord, but not of cholinergic, GABAergic or glutamatergic terminals around motoneuron cell bodies in the lumbar spinal cord. Additionally, no difference between L1tg and L1+/+ mice was detectable in dieback of corticospinal tract axons. Neuronal L1 overexpression did not influence the size of the glial fibrillary acidic protein-immunoreactive astrocytic scar 6 weeks after injury. We conclude that neuronal overexpression of L1 improves functional recovery from SCI by increasing catecholaminergic axonal regrowth/sprouting and/or sparing of severed axons without affecting the glial scar size. PMID- 23933312 TI - Accumbal core: essential link in feed-forward spiraling striato-nigro-striatal in series connected loop. AB - The goal of the present study was to establish the behavioral role of the nucleus accumbens (Nacc) core in the feed-forward spiraling striato-nigro-striatal circuitry that transmits information from the Nacc shell toward the dorsal subregion of the neostriatum (DS) in freely moving rats. Unilateral injection of MU-opioid receptor agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO; 1 and 2 MUg), but not the delta 1-opioid receptor agonist [D-Pen(2,5)]-enkephalin (4 MUg) or the delta2-opioid receptor agonist [D-Ala(2),Glu(4)]-deltorphin (2 MUg), into the ventral tegmental area (VTA) produced contraversive circling in a dose-dependent manner. The effect of DAMGO was MU-opioid receptor-specific, because the MU-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (0.1 and 1 MUg), which alone did not elicit any turning behavior, dose dependently inhibited the effect of DAMGO. Injection of the dopamine D1/D2 receptor antagonist cis-(Z)-flupentixol (1 and 10 MUg) into the Nacc shell ipsilaterally to the VTA significantly inhibited DAMGO (2 MUg)-induced circling. Similar injections of cis-(Z)-flupentixol into the Nacc core inhibited DAMGO induced circling, but, in addition, replaced circling by pivoting, namely turning behavior during which the rat rotates around its disfunctioning hindlimb. The present findings show that unilateral stimulation of MU-, but not delta-, opioid receptors in the VTA elicits contraversive circling that requires a relatively hyperdopaminergic activity in both the shell and the core of the Nacc at the opioid-stimulated side of the brain. The Nacc core plays an essential role in the transmission of information directing the display of pivoting that is elicited by an increased dopaminergic activity in the Nacc shell. It is concluded that the Nacc core is an essential link in the feed-forward spiraling striato-nigro striatal circuitry that transmits information from the Nacc shell toward the DS in freely moving rats. PMID- 23933313 TI - An ethnobotanical study of medicinal plants in Turgutlu (Manisa-Turkey). AB - ETHNOPHARMACOLOGICAL RELEVANCE: A comprehensive ethnobotanical study was made in Turgutlu. This paper contains folk medicinal plants and ethnopharmacological information of this ethnobotanical study. AIM OF STUDY: The aim of this study is to collect and identify the plants used in therapy by the local people and to reveal information on traditional herbal medicine. MATERIALS AND METHODS: This study was made between 2010 and 2011 and its materials were the plants collected during the field work. The information was obtained through open and semi structured interviews with the local people. In addition, informant consensus factor (FIC) and use value (UV) were calculated. RESULTS: 76 Folk medicinal plants belonging to 44 families were identified in this study. Among them, 68 species are wild and eight species are cultivated plants. The most common families are Asteraceae (11.8%), Rosaceae (9.2%), Lamiaceae (7.9%), Apiaceae (3.9%) and Malvaceae (3.9%); the most common preparations were infusion (37%) and decoction (18.5%). A total of 177 medicinal uses (remedies) was recorded. Digestive system disorders have the highest FIC (0.73). According to use value (UV) the most important plants were Rosa canina (0.75), Ficus carica subsp. carica (0.74), Tilia platyphyllos (0.71) and Vitex agnus-castus (0.70). CONCLUSION: In the research area the use of traditional folk medicine is still prevalent in the community especially in the villages. PMID- 23933314 TI - Use of herbal medicines during pregnancy in a group of Palestinian women. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The use of herbal medicines during pregnancy is common worldwide due to physiological changes that lead to pregnancy related problems. OBJECTIVES: The aims of this study were to measure the prevalence and predictors of herb use among a group of Palestinian pregnant women and the possible influence of herbal consumption on pregnancy outcomes. METHODS: This study was a questionnaire-based cross sectional descriptive study. It was conducted in the maternity ward of a governmental hospital between March and May 2012, a random sample of women who gave birth during the study period were met and asked to answer a face to face questionnaire. RESULTS: Out of 300 women, 120 women (40.0%) used herbs during pregnancy; most women preferred to use herbs because they thought herbs are safer than medications (82.5%), women based in their choices mainly on advice from family or doctors (36.7%, 33.0%, respectively), 65.8% of them told their doctors that they used herbs, 91.7% considered these therapies beneficial, and 99.2% reported no side effects. The most commonly used herbs were anise (Pimpinella anisum) (61.7%), chamomile (Matricaria recutita) (53.3%), sage (Salvia officinalis) (55%), mixture of herbs (33.3%), and thyme (Thymus vulgaris) (29.2%). Most women were using herbs on as needed bases. There were no statistically significant differences between users and non-users of herbs in all socio-demographic variables and pregnancy outcomes. CONCLUSIONS: This study found that the use of herbs during pregnancy is very common among Palestinian women. Infrequent use of herbs during pregnancy seems to be safe and beneficial. To provide the best care to pregnant women who use herbal products, clinicians and pharmacist are recommended to stay up to date with herb use and their safety in pregnancy. Not all women tell their doctors about herbal products use, so the physicians are recommended to ask pregnant women about this to avoid any possible negative outcomes on the mother or the fetus. PMID- 23933315 TI - Bitter plants used as substitute of Cinchona spp. (quina) in Brazilian traditional medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bitter tasting plant species are used as tonics and have been previously used to treat intermittent fevers in Brazil, the principal symptom of malaria. Many of these species were named quina and were used as substitutes of Cinchona spp., the source of quinine. AIM OF THE STUDY: To present data on these bitter species named quina and to discuss their potential as sources of bioactive substances. MATERIALS AND METHODS: Data about the plants were obtained from a survey of the literature and documents written by early naturalists and clinical doctors living in the 18th and 19th centuries in Brazil. Correlated pharmacological studies were obtained from different scientific databases. RESULTS: A total of 29 species were recorded. The largest number of species belonged to the Rubiaceae family (14), being Remijia ferruginea (A. St. Hil) DC. the most representative. Strychnos pseudoquina A. St.-Hil. (Loganiaceae), Hortia brasiliana Vand. ex DC. (Rutaceae) and Solanum pseudoquina A. St.-Hil. (Solanaceae) were also frequently mentioned in the historical bibliography. Pharmacological studies have shown the presence of bitter bioactive substances useful to treat digestive disorders and/or with antimalarial activities, in all of the recorded botanic families. CONCLUSION: This study shows that several bitter species named quina were used in the past as substitute of Cinchona spp. and studying these plants can lead to the development of new products. PMID- 23933316 TI - Studies on neuropharmacological profile of ethanol extract of Moringa oleifera leaves in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Moringa oleifera (family Moringaceae), commonly called Horseradish or tree of life, is traditionally used for the treatment of epilepsy and neurologic conditions. AIM OF THE STUDY: The objective of this study is to investigate the neurobehavioural and anticonvulsant properties of the ethanol extract from the leaves of Moringa oleifera. MATERIALS AND METHODS: Neurobehavioural properties were evaluated using the open field, hole board, Y maze, elevated plus maze (EPM) and pentobarbitone-induced hypnosis. Pentylenetetrazole (leptazol), picrotoxin and strychnine induced convulsion tests were used to investigate the anti-convulsive actions of Moringa oleifera. RESULTS: The result showed that the extract (250-2000mg/kg) caused a significant dose-dependent decrease in rearing, grooming, head dips and locomotion (P<0.001). It also enhanced learning and memory and increased anxiogenic effect. In addition, the extract (2000mg/kg) protected mice against pentylenetetrazol induced convulsion, but has no effect on picrotoxin and strychnine induced convulsion. The effects of the extract in the various models were comparable to those of the standard drugs used except in Y-maze, EPM and picrotoxin and strychnine induced convulsion. The LD50 obtained for the acute toxicity studied using oral route of administration was >6.4g/kg. CONCLUSION: The findings from this study suggest that the ethanol extract of Moringa oleifera leaves possesses CNS depressant and anticonvulsant activities possibly mediated through the enhancement of central inhibitory mechanism involving release gamma-amino butyric acid (GABA). The results partially justified the traditional use of the extract for the treatment of epilepsy. PMID- 23933317 TI - Sceptridium ternatum extract exerts antiasthmatic effects by regulating Th1/Th2 balance and the expression levels of leukotriene receptors in a mouse asthma model. AB - AIM OF THE STUDY: Sceptridium ternatum Lyon (ST), a common Chinese herb, has been used in treatment of allergic asthma and whooping cough. In the present study, we investigated the Th1/Th2 ratio of peripheral blood and mRNA levels of leukotriene receptors after the treatment of ST in allergic asthma mouse model. MATERIALS AND METHODS: Mouse asthma model was developed by ovalbumin (OVA) sensitization followed by the inhalation of aerosol allergen. Montelukast (10mg/kg), as a positive control drug, and ST were administrated six days before the OVA sensitization for ten days. Airway responsiveness was evaluated by the Medlab 12.0 biological signal processing system. The ratio of Th1/Th2 cells was determined by flow cytometry. The expression level of Cyslt1 was measured by PCR. Pathological changes of lung tissues were examined by H&E staining. RESULTS: ST significantly reduced the airway responsiveness, elevated the ratio of Th1/Th2, and decreased Cyslt1 mRNA level in a dose-dependent manner. High-dose ST distinctly prevented the pathological changes of lung tissues. CONCLUSION: High dose ST had the same efficacy as Montelukast in a mouse asthma model, and ST could be a potential anti-asthmatic agent. PMID- 23933318 TI - Activation of the canonical nuclear factor-kappaB pathway is involved in isoflurane-induced hippocampal interleukin-1beta elevation and the resultant cognitive deficits in aged rats. AB - Although much recent evidence has demonstrated that neuroinflammation contributes to volatile anesthetic-induced cognitive deficits, there are few existing mechanistic explanations for this inflammatory process. This study was conducted to investigate the effects of the volatile anesthetic isoflurane on canonical nuclear factor (NF)-kappaB signaling, and to explore its association with hippocampal interleukin (IL)-1beta levels and anesthetic-related cognitive changes in aged rats. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in IkappaB kinase and IkappaB phosphorylation, as well as a reduction in the NF-kappaB inhibitory protein (IkappaBalpha), were observed in the hippocampi of isoflurane-exposed rats compared with control rats. These events were accompanied by an increase in NF-kappaB p65 nuclear translocation at 6h after isoflurane exposure and hippocampal IL-1beta elevation from 1 to 6h after isoflurane exposure. Nevertheless, no significant neuroglia activation was observed. Pharmacological inhibition of NF-kappaB activation by pyrrolidine dithiocarbamate markedly suppressed the IL-1beta increase and NF-kappaB signaling, and also mitigated the severity of cognitive deficits in the Morris water maze task. Overall, our results demonstrate that isoflurane-induced cognitive deficits may stem from upregulation of hippocampal IL-1beta, partially via activation of the canonical NF-kappaB pathway, in aged rats. PMID- 23933319 TI - Runx2 induces bone osteolysis by transcriptional suppression of TSSC1. AB - Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, however, the underlying mechanisms are poorly understood. Runx2, a bone specific transcriptional factor, is abnormally expressed in highly metastatic breast cancer cells. Here, we found that TSSC1 inhibits breast cancer cell invasion. Subsequently, TSSC1 is confirmed as a target of Runx2 and is negatively regulated by Runx2. Furthermore, overexpression of Runx2 induces bone osteolysis in a TSSC1-dependent manner. Our results may provide a strategy for the treatment of breast cancer and the prevention of skeletal metastasis. PMID- 23933320 TI - Senescence marker protein 30 inhibits angiotensin II-induced cardiac hypertrophy and diastolic dysfunction. AB - BACKGROUND AND OBJECTIVE: Senescence marker protein 30 (SMP30) is assumed to behave as an anti-aging factor. Recently, we have demonstrated that deficiency of SMP30 exacerbates angiotensin II-induced cardiac hypertrophy, dysfunction and remodeling, suggesting that SMP30 may have a protective role in the heart. Thus, this study aimed to test the hypothesis that up-regulation of SMP30 inhibits cardiac adverse remodeling in response to angiotensin II. METHODS: We generated transgenic mice with cardiac-specific overexpression of SMP30 gene using alpha myosin heavy chain promoter. Transgenic mice and wild-type littermate mice were subjected to continuous angiotensin II infusion (800 ng/kg/min). RESULTS: After 14 days, heart weight and left ventricular weight were lower in transgenic mice than in wild-type mice, although blood pressure was similarly elevated during angiotensin II infusion. Cardiac hypertrophy and diastolic dysfunction in response to angiotensin II were prevented in transgenic mice compared with wild type mice. The degree of cardiac fibrosis by angiotensin II was lower in transgenic mice than in wild-type mice. Angiotensin II-induced generation of superoxide and subsequent cellular senescence were attenuated in transgenic mouse hearts compared with wild-type mice. CONCLUSIONS: Cardiac-specific overexpression of SMP30 inhibited angiotensin II-induced cardiac adverse remodeling. SMP30 has a cardio-protective role with anti-oxidative and anti-aging effects and could be a novel therapeutic target to prevent cardiac hypertrophy and remodeling due to hypertension. PMID- 23933321 TI - Crystal structure of the CueO mutants at Glu506, the key amino acid located in the proton transfer pathway for dioxygen reduction. AB - Glu506 involved in the hydrogen bond network leading from solvent waters to the trinuclear copper center in a multicopper oxidase, CueO plays a crucial role to transport protons in the four-electron reduction of dioxygen to water. We performed X-ray crystal structure analyses of the Glu506Ala and Glu506Ile mutants, showing the formation of a compensatory proton transport pathway with only water molecules and a disruption of the hydrogen bond network due to the bulky side chain, respectively. We discuss the efficiency of proton transport through the hydrogen bond network based on the present results and our previous modification of the proton transport pathway by the Glu506 to Gln mutation, which have allowed us to trap and characterize the reaction intermediates. PMID- 23933322 TI - DZNep, inhibitor of S-adenosylhomocysteine hydrolase, down-regulates expression of SETDB1 H3K9me3 HMTase in human lung cancer cells. AB - 3-Deazaneplanocin A (DZNep), an epigenetic anticancer drug, leads to the indirect suppression of S-adenosyl methionine-dependent cellular methylations by inhibiting S-adenosyl homocystein (AdoHcy) hydrolase. Although it is well known that DZNep targets the degradation of EZH2 protein, H3K27me3 HMTase, there are still uncertainties about the regulation of other types of HMTases during cell death. In this study, we describe that SETDB1 gene expression was regulated by DZNep treatment in human lung cancer cells. We confirm that DZNep induced growth inhibition and increased the dead cell population of lung cancer cells. DZNep treatment affected histone methylations, including H3K27me3 and H3K9me3, but not H3K4me3. Reduced levels of H3K27me3 and H3K9me3 were related with the decreased EZH2 and SETDB1 proteins. Real time PCR analysis showed that SETDB1 gene expression was decreased by DZNep treatment, but no effect was observed for EZH2 gene expression. We cloned the promoter region of SETDB1 and SUV39H1 genes, and performed luciferase assays. The promoter activity of SETDB1 gene was down regulated by DZNep treatment, whereas no effect on SUV39H1 promoter activity was observed. In conclusion, we suggest that DZNep regulates not only on H3K27me3 HMTase EZH2, but also H3K9 HMTase SETDB1 gene expression at the transcription level, implicating that the mechanism of action of DZNep targets multiple HMTases during the death of lung cancer cells. PMID- 23933323 TI - Comparison of bioanalytical methods for the quantitation of PEGylated human insulin. AB - PURPOSE: The quality of bioanalytical data is dependent upon selective, sensitive, and reproducible analytical methods. With evolving technologies available, bioanalytical scientists must assess which is most appropriate for their molecule through proper method validation. For an early stage PEGylated insulin program, the characteristics of four platforms, ELISA, ECL, Gyrolab, and LC-MS/MS, were evaluated using fit-for-purpose method development and validation, while also evaluating costs. METHOD: Methods selected for validation required acceptable performance based on satisfaction of a priori criteria prior to proceeding to subsequent stages of validation. LBA pre-validation included reagent selection, evaluation of matrix interference, and range determination. LC MS/MS pre-validation included selection of a signature peptide; optimization of sample preparation, HPLC, and LC-MS/MS conditions; and calibration range determination. Pre-study validation tested accuracy and precision (mean bias criteria+/-30%; precision<=30%). Pharmacokinetic (PK) parameters were estimated for an in vivo study with WinNonlin noncompartmental analysis. Statistics were performed with JMP using ANOVA and Tukey-Kramer post hoc analysis. A cost analysis was performed for a 200-sample PK study using the methods from this study. RESULTS: All platforms, except Gyrolab, were taken through validation. However, a typical Gyrolab method was included for the cost analysis. Ranges for the ELISA, ECLA, and LC-MS/MS were 8.52-75, 2.09-125, and 100-1000 ng/mL, respectively, and accuracy and precision fell within a priori criteria. PK samples were analyzed in the 3 validated methods. PK profiles and parameters are similar for all methods, except LC-MS/MS, which differed at t=24h and with AUC0 24. Further investigation into this difference is warranted. The cost analysis identified the Gyrolab platform as the most expensive and ELISA as the least expensive, with method specific consumables attributing significantly to costs. CONCLUSIONS: ECLA had a larger dynamic range and sensitivity, allowing accurate assessment of PK parameters. Although this method was more expensive than the ELISA, it was the most appropriate for the early stage PEGylated insulin program. While this case study is specific to PEGylated human insulin, it highlights the importance of evaluating and selecting the most appropriate platform for bioanalysis during drug development. PMID- 23933325 TI - Development of a biosensor-based immunogenicity assay capable of blocking soluble drug target interference. AB - As with other protein therapeutics, trebananib (AMG 386), an investigational peptide Fc-fusion protein ("peptibody") that inhibits angiogenesis by neutralizing the interaction of angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) with the Tie2 receptor, has the potential to trigger an immune response in cancer patients treated with the therapeutic. An electrochemiluminescence bridging anti drug antibody (ADA) assay that was utilized to support early-phase clinical trials in the development of trebananib was found to lack adequate sensitivity and drug tolerance in later-phase clinical studies when higher doses of trebananib were administered. Therefore, we developed a surface plasmon resonance (SPR) immunoassay method utilizing a secondary confirmatory detector antibody (goat anti-human IgG F[ab']2) known to cross-react with human IgG and IgM to better assess the potential impact of immunogenicity on the pharmacokinetics, pharmacodynamics, and toxicity of trebananib. The SPR method was more sensitive than the electrochemiluminescence bridging assay because of signal amplification from the confirmatory binding of the detector antibody; drug tolerance was improved since antibody binding avidity does not affect detection on this platform. Despite the inability of the confirmatory detector antibody to bind angiopoietins in protein-free buffer, false-positive ADA results were generated from patient serum samples containing Ang1 and Ang2 through an apparently specific binding between the angiopoietins and the confirmatory detector antibody, likely mediated by the interaction of the angiopoietins with serum immunoglobulins. Addition to the sample diluent of a human antibody that specifically binds to Ang1 and Ang2 with high affinity resulted in a complete block of angiopoietin interference without affecting ADA detection. This biosensor-based assay provides a reliable method for assessing immunogenicity in phase 3 clinical trials. PMID- 23933324 TI - The abrogation of TCR-independent interactions with human serum ensures a selective capture of therapeutic virus-specific CD8+ T-cells by multimer technology in Adoptive Immunotherapy. AB - Multimers are complexes of recombinant MHC-class I molecules conjugated with antigenic immunodominant peptides and labeled with fluorescent molecules or magnetic microbeads that allow the quantification and selection of virus-specific cytotoxic T-cell subpopulations. Specific T-cell receptors recognize the immunodominant peptides and bind to the multimers. Although these complexes are only recognized by CD8(+) T cells with specific T-cell receptors for the particular antigen, it has been observed that multimers can also bind non specifically to CD8- cells, such as B-cells and monocytes. Using PBMCs from CMV seropositive healthy donors, we analyze the tendency of Pentamer and Streptamer multimers towards non-specific interactions and describe a method to avoid this unwanted event. We find that a notable proportion of multimer-positive cells are likely to represent cross-contamination by cells lacking a TCR specific for pp65. In addition, we demonstrate that this unspecific interaction can be overcome by the pre-incubation of multimer-stained PBMCs with human AB serum, without altering their capacity to bind specifically to the CD8(+) T cell population of interest. In conclusion, in this study we characterize a novel method to abrogate TCR-independent interactions of multimers to ensure a pure and safe therapeutic product for Adoptive Immunotherapy. PMID- 23933326 TI - Dr. Jessie Wright: breaking new ground in pediatric physical medicine and rehabilitation. PMID- 23933327 TI - Refined methodology for implantation of a head fixation device and chronic recording chambers in non-human primates. AB - The present study was aimed at developing a new strategy to design and anchor custom-fitted implants, consisting of a head fixation device and a chronic recording chamber, on the skull of adult macaque monkeys. This was done without the use of dental resin or orthopedic cement, as these modes of fixation exert a detrimental effect on the bone. The implants were made of titanium or tekapeek and anchored to the skull with titanium screws. Two adult macaque monkeys were initially implanted with the head fixation device several months previous to electrophysiological investigation, to allow optimal osseous-integration, including growth of the bone above the implant's footplate. In a second step, the chronic recording chamber was implanted above the brain region of interest. The present study proposes two original approaches for both implants. First, based on a CT scan of the monkey, a plastic replicate of the skull was obtained in the form of a 3D print, used to accurately shape and position the two implants. This would ensure a perfect match with the skull surface. Second, the part of the implants in contact with the bone was coated with hydroxyapatite, presenting chemical similarity to natural bone, thus promoting excellent osseous integration. The longevity of the implants used here was 4 years for the head fixation device and 1.5 years for the chronic chamber. There were no adverse events and daily care was easy. This is clear evidence that the present implanting strategy was successful and provokes less discomfort to the animals. PMID- 23933329 TI - Block-bootstrapping for noisy data. AB - BACKGROUND: Statistical inference of signals is key to understand fundamental processes in the neurosciences. It is essential to distinguish true from random effects. To this end, statistical concepts of confidence intervals, significance levels and hypothesis tests are employed. Bootstrap-based approaches complement the analytical approaches, replacing the latter whenever these are not possible. NEW METHOD: Block-bootstrap was introduced as an adaption of the ordinary bootstrap for serially correlated data. For block-bootstrap, the signals are cut into independent blocks, yielding independent samples. The key parameter for block-bootstrapping is the block length. In the presence of noise, naive approaches to block-bootstrapping fail. Here, we present an approach based on block-bootstrapping which can cope even with high noise levels. This method naturally leads to an algorithm of block-bootstrapping that is immediately applicable to observed signals. RESULTS: While naive block-bootstrapping easily results in a misestimation of the block length, and therefore in an over estimation of the confidence bounds by 50%, our new approach provides an optimal determination of these, still keeping the coverage correct. COMPARISON WITH EXISTING METHODS: In several applications bootstrapping replaces analytical statistics. Block-bootstrapping is applied to serially correlated signals. Noise, ubiquitous in the neurosciences, is typically neglected. Our new approach not only explicitly includes the presence of (observational) noise in the statistics but also outperforms conventional methods and reduces the number of false positive conclusions. CONCLUSIONS: The presence of noise has impacts on statistical inference. Our ready-to-apply method enables a rigorous statistical assessment based on block-bootstrapping for noisy serially correlated data. PMID- 23933328 TI - A novel behavioral assay for the assessment of acute tinnitus in rats optimized for simultaneous recording of oscillatory neural activity. AB - BACKGROUND: Human magneto/electrophysiology studies suggest that the phantom sound of tinnitus arises from spontaneous oscillatory neural activity in auditory cortex; however, in animal models, behavioral techniques suitable for testing this hypothesis in combination with electrophysiology recordings have yet to be evaluated. While electrophysiological studies of tinnitus have been reported in passive, awake animals, these studies fail to control for attentional mechanisms likely to play a role in the perception of tinnitus. NEW METHOD: A novel appetitive operant conditioning, two-alternative identification task was developed for detecting acute tinnitus in rats. The procedure optimizes conditions for simultaneously recording oscillatory neural activity while controlling for the attentional state of the animal. RESULTS: Tinnitus was detected in six of seven rats following systemic injection with sodium salicylate (200mg/kg IP), a known inducer of tinnitus. Analysis of ongoing local field potentials recorded from chronically implanted electrodes in auditory cortex of a rat reporting tinnitus revealed changes in the spectrum of ongoing neural activity. Comparison with existing method(s): Existing tinnitus-detection methods were not explicitly designed for the simultaneous recording of neural activity. The behavioral method reported here is the first to provide the conditions necessary for obtaining these recordings in chronically implanted rats. CONCLUSIONS: The behavioral assay presented here will facilitate research into the neural mechanisms of tinnitus by allowing researchers to compare the electrophysiological data in animals with confirmed tinnitus. PMID- 23933330 TI - Determining thermodynamic properties of molecular interactions from single crystal studies. AB - The concept of single crystals of macromolecules as thermodynamic systems is not a common one. However, it should be possible to derive thermodynamic properties from single crystal structures, if the process of crystallization follows thermodynamic rules. We review here an example of how the stabilizing potentials of molecular interactions can be measured from studying the properties of DNA crystals. In this example, we describe an assay based on the four-stranded DNA junction to determine the stabilizing potentials of halogen bonds, a class of electrostatic interactions, analogous to hydrogen bonds, that are becoming increasing recognized as important for conferring specificity in protein-ligand complexes. The system demonstrates how crystallographic studies, when coupled with calorimetric methods, allow the geometries at the atomic level to be directly correlated with the stabilizing energies of molecular interactions. The approach can be generally applied to study the effects of DNA sequence and modifications of the thermodynamic stability of the Holliday junction and, by inference, on recombination and recombination dependent processes. PMID- 23933331 TI - Propensities for loop structures of RNA & DNA backbones. AB - RNA oligonucleotides exhibit a large tendency to bend and form a loop conformation which is a major motif contributing to their complex three dimensional structure. This is in contrast to DNA molecules that predominantly form the double-helix structure. In this paper we investigate by molecular dynamics simulation, as well as, by its combination with the replica-exchange method, the propensity of RNA chains containing the GCUAA pentaloop to form spontaneously a hairpin conformation. The results were then compared with those of analogous hybrid oligonucleotides in which the ribose groups in the loop region were substituted by deoxyriboses. We find that the RNA oligomers exhibit a marginal excess stability to form loop structures. The equilibrium constant for opening the loop to an extended conformation is twice as large in the hybrid than it is in the RNA chain. Analyses of the hydrogen bonds indicate that the excess stability for forming a hairpin is a result of hydrogen bonds the 2'-hydroxyls in the loop region form with other groups in the loop. Of these hydrogen bonds, the most important is the hydrogen bond donated from the 2'-OH at the first position of the loop to N7 of adenine at the forth position. RNA and DNA backbones are characterized by different backbone dihedral angles and sugar puckering that can potentially facilitate or hamper the hydrogen bonds involving the 2'-OH. Nevertheless, the sugar puckerings of all the pentaloop nucleotides were not significantly different between the two chains displaying the C3'-endo conformation characteristic to the A-form double helix. All of the other backbone dihedrals also did not show any considerable difference in the loop-region except of the delta-dihedral. In this case, the RNA loop exhibited bimodal distributions corresponding to, both, the RNA and DNA backbones, whereas the loop of the hybrid chain behaved mostly as that of a DNA backbone. Thus, it is possible that the behavior of the delta-dihedrals in the loop-region of the RNA adopts conformations that facilitate the intra-nucleotide hydrogen bondings of the 2' hydroxyls, and consequently renders loop structures in RNA more stable. PMID- 23933332 TI - Quantifying the impact of dissimilar HPV vaccination uptake among Manitoban school girls by ethnicity using a transmission dynamic model. AB - BACKGROUND: Gardasil, a human papillomavirus (HPV) vaccine, began among grade 6 girls in Manitoba, Canada in 2008. In Manitoba, there is evidence that First Nations, Metis, and Inuit women (FNMI) have higher HPV prevalence, lower invasive cervical cancer (ICC) screening, and higher ICC incidence than all other Manitoban (AOM) women. We developed a mathematical model to assess the plausible impact of unequal vaccination coverage among school girls on future cervical cancer incidence. METHODS: We fit model estimated HPV prevalence and ICC incidence to corresponding empirical estimates. We used the fitted model to evaluate the impact of varying levels of vaccination uptake by FNMI status on future ICC incidence, assuming cervical screening uptake among FNMI and AOM women remained unchanged. RESULTS: Depending on vaccination coverage, estimated ICC incidence by 2059 ranged from 15% to 68% lower than if there were no vaccination. The level of cross-ethnic sexual mixing influenced the impact that vaccination rates among FNMI has on ICC incidence among AOM, and vice versa. The same level of AOM vaccination could result in ICC incidence that differs by up to 10%, depending on the level of FNMI vaccination. Similarly, the same level of FNMI vaccination could result in ICC incidence that differs by almost 40%, depending on the level of AOM vaccination. CONCLUSIONS: If we are unable to equalize vaccination uptake among all school girls, policy makers should prepare for higher levels of cervical cancer than would occur under equal vaccination uptake. PMID- 23933333 TI - Peptide nanofiber hydrogel adjuvanted live virus vaccine enhances cross protective immunity to porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is prevalent in swine farms worldwide and is a major source of economic loss and animal suffering. Rapid genetic variation of PRRSV makes it difficult for current vaccines to confer protection against newly emerging strains. We recently demonstrated that a novel peptide nanofiber hydrogel (H9e) could act as a potent adjuvant for killed H1N1 vaccines. Therefore, the objective of this study was to evaluate H9e as an adjuvant for PRRSV modified live virus (MLV) vaccines. Pigs were vaccinated with Ingelvac PRRSV MLV with or without H9e adjuvant before being challenged with the VR-2332 (parental vaccine strain) or MN184A (genetically diverse strain) PRRSV. Pigs vaccinated with MLV+H9e had higher levels of circulating vaccine virus. More importantly, pigs vaccinated with MLV+H9e had improved protection against challenge by both PRRSV strains, as demonstrated by reduced challenge-induced viremia compared with pigs vaccinated with MLV alone. Pigs vaccinated with MLV+H9e had lower frequency of T-regulatory cells and IL-10 production but higher frequency of Th/memory cells and IFN-gamma secretion than that in pigs vaccinated with MLV alone. Taken together, our studies suggest that the peptide nanofiber hydrogel H9e, when combined with the PRRSV MLV vaccine, can enhance vaccine efficacy against two different PRRSV strains by modulating both host humoral and cellular immune responses. PMID- 23933334 TI - A model international partnership for community-based research on vaccine preventable diseases: the Kamphaeng Phet-AFRIMS Virology Research Unit (KAVRU). AB - This paper describes an international collaboration to carry out studies that contributed to the understanding of pathogenesis, diagnosis, treatment, and prevention of several diseases of public health importance for Thailand and the United States. In Kamphaeng Phet Province, Thailand, febrile syndromes, including encephalitis, hepatitis, hemorrhagic fever, and influenza-like illnesses, occurred commonly and were clinically diagnosed, but the etiology was rarely confirmed. Since 1982, the Kamphaeng Phet Provincial Hospital, the Thai Ministry of Public Health, and the US Army Component of the Armed Forces Research Institute of Medical Sciences, along with vaccine manufacturers and universities, have collaborated on studies that evaluated and capitalized on improved diagnostic capabilities for infections caused by Japanese encephalitis, hepatitis A, dengue, and influenza viruses. The collaboration clarified clinical and epidemiological features of these infections and, in large clinical trials, demonstrated that vaccines against Japanese encephalitis and hepatitis A viruses were over 90% efficacious, supporting licensure of both vaccines. With the introduction of Japanese encephalitis vaccines in Thailand's Expanded Program on Immunization, reported encephalitis rates dropped substantially. Similarly, in the US, particularly in the military populations, rates of hepatitis A disease have dropped with the use of hepatitis A vaccine. Studies of the pathogenesis of dengue infections have increased understanding of the role of cellular immunity in responding to these infections, and epidemiological studies have prepared the province for studies of dengue vaccines. Approximately 80 publications resulted from this collaboration. Studies conducted in Kamphaeng Phet provided experience that contributed to clinical trials of hepatitis E and HIV vaccines, conducted elsewhere. To provide a base for continuing studies, The Kamphaeng Phet-AFRIMS Virology Research Unit (KAVRU) was established. This paper reviews the origins of the collaboration and the scientific observations made between 1982 and 2012. PMID- 23933335 TI - An unbiased peptide-wide discovery approach to select Mycobacterium tuberculosis antigens that target CD8+ T cell response during infection. AB - Accruing data strongly support the possible role of CD8+ T cells in immunity against tuberculosis (TB). Multivalent vaccines against Mycobacterium tuberculosis (Mtb) that incorporate CD8+ T cell antigens with those that elicit CD4+ T cells are therefore highly desirable. To screen for potential CD8+ T cell antigens that are produced by Mtb during infection, we isolated pathogen-derived peptides that bound to MHC Class I molecules expressed in adherent splenocytes obtained from Mtb-infected mice. Mass spectroscopy analysis revealed the following four nonamer peptides that had 100% homology with Mtb proteins: DGYVGAPAH (MT_0401), TTMPLFAD (MT_1164), RSGAATPVR (MT_2160.1) and LAAVVGVVL (MT_0078). The gene MT_0401 codes the protein 5'-phosphoribosylglycinamide transformylase 2 and the other three genes code for hypothetical proteins with unknown function. The NCBI/Blast analysis showed that among the four peptides DGYVGAPAH had the highest maximum alignment score and lowest E value (number of alignments expected by chance). Therefore, we assessed whether MT_0401 expressed in two genetic vaccine formulations was capable of stimulating CD8+ T cell response that is specific to DGYVGAPAH peptide. When mice were immunized with a recombinant plasmid DNA and an E1/E3-deleted Adenovirus 5 expressing MT0401 protein, using both homologous and heterologous prime-boost protocols, they developed strong DGYVGAPAH-specific CD8+ T cell response as well as antibody and CD4+ specific T cell response to the full length MT0401 protein. Equally important was the observation that mice infected with Mtb developed DGYVGAPAH specific CD8+ T cell responses in both spleen and lungs. These results demonstrate that Mtb antigens that are processed and presented via MHC Class I machinery can be readily identified by the described approach and may be useful candidate antigens to stimulate specific CD8+ T cell responses in vaccine development programs. PMID- 23933336 TI - Effectiveness of meningococcal serogroup C vaccine programmes. AB - Since the introduction of monovalent meningococcal serogroup C (MenC) glycoconjugate (MCC) vaccines and the implementation of national vaccination programmes, the incidence of MenC disease has declined markedly as a result of effective short-term vaccination and reduction in acquisition of MenC carriage leading to herd protection. Monovalent and quadrivalent conjugate vaccines are commonly used vaccines to provide protection against MenC disease worldwide. Studies have demonstrated that MCC vaccination confers protection in infancy (0 12 months) from the first dose but this is only short-term. NeisVac-C((r)) has the greatest longevity of the currently licensed MCC vaccines in terms of antibody persistence, however antibody levels have been found to fall rapidly after early infant vaccination with two doses of all MCC vaccines - necessitating a booster at ~12 months. In toddlers, only one dose of the MCC vaccine is required for routine immunization. If herd protection wanes following catch-up campaigns, many children may become vulnerable to infection. This has led many to question whether an adolescent booster is also required. PMID- 23933337 TI - A universal virus-like particle-based vaccine for human papillomavirus: longevity of protection and role of endogenous and exogenous adjuvants. AB - Antibodies targeting epitopes within the amino terminus of the minor capsid protein L2 of human papillomavirus (HPV) are broadly neutralizing against diverse HPV isolates. We have constructed bacteriophage virus-like particle (VLP)-based vaccines that display short L2 peptides and elicit high-titer and broadly protective antibody responses. Here, we further characterize two additional features of these VLP-based vaccines; the longevity of protection and the role of endogenous and exogenous adjuvants on the magnitude and characteristics of the antibody response. We show that vaccinated mice have long-lived antibody responses against L2, persisting over 18 months after vaccination. Vaccinated mice were strongly protected against infection by diverse HPV pseudoviruses over a year after immunization. We also show that exogenous and endogenous adjuvants (LPS and encapsidated single-stranded RNA) have minor effects on antibody titers. Immunization with VLPs containing encapsidated ssRNA predominantly shifts the response to a Th1, rather than a Th2-like response. Importantly, immunization with L2-VLPs (without endogenous and exogenous adjuvants) in the presence of alum hydroxide elicited a robust antibody response. PMID- 23933338 TI - Epitope engineering and molecular metrics of immunogenicity: a computational approach to VLP-based vaccine design. AB - Developing antiviral vaccines is increasingly challenging due to associated time and cost of production as well as emerging drug-resistant strains. A computer aided vaccine design strategy is presented that could greatly accelerate the discovery process and yield vaccines with high immunogenicity and thermal stability. Our strategy is based on foreign viral epitopes engineered onto well established virus-like particles (VLPs) and demonstrates that such constructs present similar affinity for antibodies as does a native virus. This binding affinity serves as one molecular metric of immunogenicity. As a demonstration, we engineered a preS1 epitope of hepatitis B virus (HBV) onto the EF loop of human papillomavirus VLP (HPV-VLP). HBV-associated HzKR127 antibody displayed binding affinity for this structure at distances and strengths similar to those for the complex of the antibody with the full HBV (PDBID: 2EH8). This antibody binding affinity assessment, along with other molecular immunogenicity metrics, could be a key component of a computer-aided vaccine design strategy. PMID- 23933339 TI - In vivo evaluation of chitosan as an adjuvant in subcutaneous vaccine formulations. AB - Vaccines utilising pure antigens instead of whole pathogens and alternative administration routes require the use of potent adjuvants and effective antigen delivery systems. Chitosan has been reported to act as both an adjuvant as well as a matrix for delivery systems. Chitosan is a natural product produced predominantly from crab shell and commercially available preparations vary in molecular weight, degree of deacetylation and purity. In this study, the impact of chitosan characteristics (molecular weight, degree of deacetylation, particle size, viscosity and impurities) on adjuvant activity were examined. It could be shown that the degree of immune response differed if different chitosan qualities were used and this could be attributed to different characteristics of the chitosan qualities: the immunoadjuvant effect of chitosan probably is a result of an interplay between chemical properties such as molecular weight and degree of deacetylation and physical properties such as particle size and preparation technique, which impacts characteristics such as solubility and viscosity. Hence, the chitosan quality to be used as adjuvant in vaccine preparations needs to be selected carefully. PMID- 23933340 TI - Using solar-powered refrigeration for vaccine storage where other sources of reliable electricity are inadequate or costly. AB - Large areas of many developing countries have no grid electricity. This is a serious challenge that threatens the continuity of the vaccine cold chain. The main alternatives to electrically powered refrigerators available for many years- kerosene- and gas-driven refrigerators--are plagued by problems with gas supply interruptions, low efficiency, poor temperature control, and frequent maintenance needs. There are currently no kerosene- or gas-driven refrigerators that qualify under the minimum standards established by the World Health Organization (WHO) Performance, Quality, and Safety (PQS) system. Solar refrigeration was a promising development in the early 1980s, providing an alternative to absorption technology to meet cold chain needs in remote areas. Devices generally had strong laboratory performance data; however, experience in the field over the years has been mixed. Traditional solar refrigerators relied on relatively expensive battery systems, which have demonstrated short lives compared to the refrigerator. There are now alternatives to the battery-based systems and a clear understanding that solar refrigerator systems need to be designed, installed, and maintained by technicians with the necessary knowledge and training. Thus, the technology is now poised to be the refrigeration method of choice for the cold chain in areas with no electricity or extremely unreliable electricity (less than 4h per average day) and sufficient sunlight. This paper highlights some lessons learned with solar-powered refrigeration, and discusses some critical factors for successful introduction of solar units into immunization programs in the future including: *Sustainable financing mechanisms and incentives for health workers and technicians are in place to support long-term maintenance, repair, and replacement parts. *System design is carried out by qualified solar refrigerator professionals taking into account the conditions at installation sites. *Installation and repair are conducted by well-trained technicians. *Temperature performance is continuously monitored and protocols are in place to act on data that indicate problems. PMID- 23933341 TI - Differential adhesion-inhibitory patterns of antibodies raised against two major variants of the NTS-DBL2X region of VAR2CSA. AB - BACKGROUND: VAR2CSA is a large polymorphic Plasmodium falciparum protein expressed on infected erythrocytes (IE) that allows their binding in the placenta, thus precipitating placental malaria (PM). The N-terminal part of VAR2CSA that contains the binding site to placental chondroitin sulfate A (CSA) is currently recognized as the most attractive region for vaccine development. An ultimate challenge is to define epitopes in this region that induce a broad cross reactive adhesion inhibitory antibody response. METHODS: Based on phylogenetic data that identified a dimorphic sequence motif in the VAR2CSA DBL2X, we raised antibodies against the NTS-DBL2X constructs containing one sequence or the other (3D7 and FCR3) and tested their functional properties on P. falciparum isolates from pregnant women and on laboratory-adapted strains. RESULTS: The CSA binding inhibitory capacity of the antibodies induced varied from one parasite isolate to another (range, 10%-100%), but the combined analysis of individual activity highlighted a broader functionality that increased the total number of isolates inhibited. Interestingly, the differential inhibitory effect of the antibodies observed on field isolates resulted in significant inhibition of all field isolates tested, suggesting that optimal inhibitory spectrum on field isolates from pregnant women might be achieved with antibodies targeting limited variants of the N-terminal VAR2CSA. CONCLUSIONS: Our findings indicate that the NTS-DBL2X region of VAR2CSA can elicit strain-transcending anti-adhesion antibodies and suggest that the combination of the two major variants used here could represent the basis for an effective bivalent VAR2CSA-based vaccine. PMID- 23933342 TI - The role of hormones on semen parameters in patients with idiopathic or varicocele-related oligoasthenoteratozoospermia (OAT) syndrome. AB - BACKGROUND: Oligoasthenoteratozoospermia (OAT) syndrome is the most frequently seen phenotype in male infertility. Spermatogenesis relies closely on hormone regulation. The aim of this study was to assess the correlation between hormone profile and semen parameters in infertile men with idiopathic or varicocele related OAT syndrome. We tried to illustrate the correlative factors for better semen parameters in these patients. METHODS: A total of 96 patients with idiopathic or varicocele-related OAT were included for assessment. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2), prolactin (PRL), and the combinative ratios of these hormones, such as T/E2, T/FSH, T/LH, T/(FSH * LH), PRL * T/FSH, PRL * T/LH, PRL * T/(FSH * LH), were compared individually with sperm parameters. The parameters included sperm concentration, total sperm count (TC), percent motile sperm count, percent normal sperm count, total motile sperm count (TMC), total normal sperm count (TNC), and total motile normal sperm count (TMNC). RESULTS: T correlated well with percent normal sperm count (p = 0.031). PRL positively correlated with sperm concentration (p = 0.019), TMC (p < 0.001), TNC (p = 0.003), and TMNC (p < 0.001). In hormonal combinative ratios, T/FSH, T/LH, T/(FSH * LH), PRL * T/FSH, PRL * T/LH, and PRL * T/(FSH * LH) all showed significant correlations to concentration and count-related parameters including TC, TMC, TNC, and TMNC. CONCLUSION: For patients with OAT syndrome, T, PRL, T/FSH, T/LH, T/(FSH * LH), PRL * T/FSH, PRL * T/LH, and PRL * T/(FSH * LH) may be used as predictive markers for better semen quality. This investigation could be a catalyst for future studies on the extent to which manipulating the hormonal combinative ratios can affect the quality of spermatogenesis in infertile males with OAT syndrome. PMID- 23933343 TI - Taiwan consensus of pharmacological treatment for bipolar disorder. AB - Bipolar disorder is an important psychiatric disorder with different disease phases. The pharmacological treatment is complicated, and is updated frequently as new research evidence emerges. For the purpose of international collaboration, research, and education, the Taiwan consensus of pharmacological treatment for bipolar disorders was initiated by the Taiwanese Society of Biological Psychiatry and Neuropsychopharmacology (TSBPN) - the Bipolar Chapter, which was established in August 2010 and approved as a member of International Society of Bipolar Disorder. TSBPN is the country member of the World Federation of Societies of Biological Psychiatry (WFSBP). The development of the Taiwan consensus for bipolar disorder was mainly based on the template of WFSBP Guidelines, with references to other international guidelines including the Canadian Network for Mood and Anxiety Treatments, and British Association for Psychopharmacology. We have also added Taiwanese experts' experience, Taiwan national health insurance data, and the indications for the pharmacological treatment of bipolar disorder given by the Taiwan Department of Health, to emphasize the balance between efficacy and safety, and to make this consensus a concise, empirical, and important reference for clinical psychiatric practice. PMID- 23933344 TI - Amniotic fluid may act as a transporting pathway for signaling molecules and stem cells during the embryonic development of amniotes. AB - Amniotic fluid (AF) is formed at the very early stages of pregnancy, and is present throughout embryonic development of amniotes. It is well-known that AF provides a protective sac around the fetus that allows fetal movement and growth, and prevents mechanical and thermal shock. However, a growing body of evidence has shown that AF contains a number of proteins and peptides, including growth factors and cytokines, which potently affect cellular growth and proliferation. In addition, pluripotent stem cells have recently been identified in AF. Herein, this article reviews the biological properties of AF during embryonic development and speculates that AF may act as a transporting pathway for signaling molecules and stem cells during amniote embryonic development. Defining this novel function of AF is potentially significant for further understanding embryonic development and regenerative medicine, preventing genetic diseases, and developing therapeutic options for human malignancies. PMID- 23933345 TI - Induced pluripotent stem cells and hepatic differentiation. AB - Induced pluripotent stem cells (iPSCs) are generated by reprogramming somatic cells to a pluripotent state by the introduction of specific factors. They can be generated from cells of different origins, such as fibroblasts, keratinocytes, hepatocytes, and blood. iPSCs are similar to embryonic stem cells (ESCs) in several aspects, such as morphology, expression of pluripotency markers, and the ability to develop teratoma that contains tissue from three germ layers. In addition, iPSCs can undergo tridermal differentiation, including hepatic specific lineages. Considering that iPSCs could be a source of hepatocyte regeneration, iPSC-based therapy has been widely implicated in the treatment of liver disease and hepatic regeneration. In the present review, we discuss the therapeutic potential of iPSCs in hepatic repair and focus on the clinical applications of iPSCs. PMID- 23933346 TI - Plasma homocysteine levels in patients with multiple sclerosis in the Greek population. AB - BACKGROUND: In recent years, there has been increasing interest in the role of plasma homocysteine (Hcy) as a possible risk factor for several diseases of the central nervous system. The aim of this study was to determine the plasma levels of Hcy in a group of multiple sclerosis (MS) patients from a Greek population and the possible correlation with age, disability status, activity or duration of disease, sex, and treatment. METHODS: The MS group that was studied consisted of 46 patients and a total of 42 healthy individuals served as a control group. Plasma Hcy levels were determined by means of high-performance liquid chromatography coupled with fluorescence detection, after precolumn derivatization with 4-Fluoro-7-aminosulfonylbenzofurazan (ABD-F). RESULTS: Statistical analysis revealed that, in the MS patients, Hcy levels were not significantly different as compared to those in the controls. Men presented with higher Hcy levels than women in the MS group; however, age, disease subtype, disease duration, relapse rate, and Expanded Disability Status Scale score/Multiple Sclerosis Severity Score did not significantly affect Hcy levels in MS patients. CONCLUSION: The preliminary data suggest that Hcy levels were not elevated in our sample of Greek MS patients, which does not support previous findings of a significant correlation between elevated serum Hcy levels and MS. Further studies to establish a possible association between MS and Hcy levels in the context of different ethnic groups with different habits are needed. PMID- 23933347 TI - Novel avian-origin influenza A (H7N9) virus in the human. PMID- 23933348 TI - Reply to "novel avian-origin influenza A (H7N9) virus in the human". PMID- 23933349 TI - Natural image sequences constrain dynamic receptive fields and imply a sparse code. AB - In their natural environment, animals experience a complex and dynamic visual scenery. Under such natural stimulus conditions, neurons in the visual cortex employ a spatially and temporally sparse code. For the input scenario of natural still images, previous work demonstrated that unsupervised feature learning combined with the constraint of sparse coding can predict physiologically measured receptive fields of simple cells in the primary visual cortex. This convincingly indicated that the mammalian visual system is adapted to the natural spatial input statistics. Here, we extend this approach to the time domain in order to predict dynamic receptive fields that can account for both spatial and temporal sparse activation in biological neurons. We rely on temporal restricted Boltzmann machines and suggest a novel temporal autoencoding training procedure. When tested on a dynamic multi-variate benchmark dataset this method outperformed existing models of this class. Learning features on a large dataset of natural movies allowed us to model spatio-temporal receptive fields for single neurons. They resemble temporally smooth transformations of previously obtained static receptive fields and are thus consistent with existing theories. A neuronal spike response model demonstrates how the dynamic receptive field facilitates temporal and population sparseness. We discuss the potential mechanisms and benefits of a spatially and temporally sparse representation of natural visual input. PMID- 23933350 TI - Omental mucinous cystadenoma near the spleen. PMID- 23933352 TI - Gynecologic endoscopy skills training and assessment: review. AB - Training in and assessment of endoscopic skills is currently undergoing a period of evolution. Several recognized factors driving this evolution include working pattern, training opportunities, cost, and patient safety. In addition, the need to continuously monitor competence is punctuated by the rapid technologic changes and rising consumer expectation. These challenges present an opportunity to positively enhance the learning and performance of surgical practice. PMID- 23933351 TI - Efficacy of estrogen therapy in patients with intrauterine adhesions: systematic review. AB - Hysteroscopic adhesiolysis has become the preferred option for management of intrauterine adhesions (IUA). Use of estrogen as perioperative adjuvant therapy has been suggested for preventing recurrent adhesions. The primary objective of this article was to review the literature for evidence of the efficacy of estrogen therapy in the management of IUA. All eligible studies were identified using computerized databases (PubMed, Scopus. and Web of Science) from their earliest publication date to July 2013. Additional relevant articles were identified from citations in these publications. Twenty-six studies were identified that reported use of hormone therapy as ancillary treatment after adhesiolysis. Of these studies, 19 used at least one of the following methods: intrauterine device, Foley catheter, hyaluronic acid gel, or amnion graft, in addition to hormone therapy as ancillary treatment. In 7 studies, hormone therapy was used as a single ancillary treatment. In 2 studies, no adjunctive therapy was used after adhesiolysis. Meta-analysis could not be performed because of the differences in treatment methods in these articles. There was a wide range of reported menstrual and fertility outcomes. Better menstrual and fertility outcomes were associated with use of estrogen in combination with other methods of ancillary treatment. At present, hormone therapy, in particular estrogen therapy, is beneficial in patients with IUA, regardless of stage of adhesions. However, estrogen therapy needs to be combined with ancillary treatment to obtain maximal outcomes, in particular in patients with moderate to severe IUA. PMID- 23933353 TI - Effect of obesity on patients undergoing vaginal hysterectomy. PMID- 23933354 TI - Lignans of sesame: purification methods, biological activities and biosynthesis- a review. AB - Lignans are a group of compounds consisting of dimers of phenyl propane units. They are found in diverse forms distributed in a variety of plants. Sesame lignans in particular are obtained from Sesamum indicum, a highly prized oilseed crop cultivated widely in many countries in the east. The plant is the main source of clinically important antioxidant lignans such as sesamin, sesamolin, sesaminol and sesamol. These lignans exhibit antihypertensive, anticancerous and hypocholesterolemic activities as well especially in humans due to which they have become compounds of tremendous research interest in recent times. Sesamin is synthesized from shikimic acid through phenylpropanoid pathway and metabolised into enterolignans which play a pivotal role in protection against several hormone related diseases. In this paper we present an overview of current status of research on sesame lignans with respect to the analytical methods employed, the biological activities and biosynthesis of sesame lignans. PMID- 23933355 TI - Structural and diffusion properties of formamide/water mixture interacting with TiO2 surface. AB - The photoreaction and adsorption properties on surfaces, thermal decomposition, chemical transformation, and other properties of the formamide molecule are widely used to understand the origins of the formation of biological molecules (nucleosides, amino acids, DNA, monolayers, etc.) needed for life. The titanium oxide (TiO2) surface can act both as a template on which the accumulation of adsorbed molecules like formamide occurs through the concentration effect, and as a catalytic material that lowers the activation energy needed for the formation of intermediate products. In this paper, a formamide-water solution interacting with TiO2 (anatase) surface is simulated using the molecular dynamics method. The structural, diffusion and density properties of formamide-water mixture on TiO2 are established for a wide temperature range from T=250 K up to T=400 K. PMID- 23933356 TI - Entire sequence of the colonization factor coli surface antigen 6-encoding plasmid pCss165 from an enterotoxigenic Escherichia coli clinical isolate. AB - Coli surface antigen 6 (CS6) is one of the most prevalent colonization factors among enterotoxigenic Escherichia coli (ETEC) isolated in developing countries. Although it is known that CS6 is encoded by a plasmid, there are no reports on the sequence analysis of the CS6-encoding plasmid or genes exhibiting similar behavior to CS6. Here, we report the isolation of the CS6-encoding plasmid, pCss165Kan, from 4266 DeltacssB::kanamycin (Km) and its complete nucleotide sequence. This plasmid consisted of 165,311bp and 222 predicted coding sequences. Remarkably, there were many insertion sequence (IS) elements, which comprised 24.4% of the entire sequence. Virulence-associated genes such as heat-stable enterotoxin, homologues of ATP-binding cassette transporter in enteroaggregative E. coli (EAEC), and ETEC autotransporter A were also present, although the ETEC autotransporter A gene was disrupted by the integration of IS629. We found that 2 transcriptional regulators belonging to the AraC family were not involved in CS6 expression. Interestingly, pCss165 had conjugative transfer genes, as well as 3 toxin-antitoxin systems that potentially exclude other plasmid-free host bacteria. These genes might be involved in the prevalence of CS6 among ETEC isolates. PMID- 23933357 TI - Protective effect of polypeptides from larva of housefly (Musca domestica) on hydrogen peroxide-induced oxidative damage in HepG2 cells. AB - Housefly (Musca domestica) is an important medical insect and its larva is an ideal high protein food source. We isolated from housefly larvae the polypeptides hydrolyzed by neutral protease (PHNP), and investigated the protective effect of PHNP on hydrogen peroxide (H2O2)-induced oxidative damage in HepG2 cells. Cells exposed to H2O2 showed a marked decrease in proliferation and intracellular superoxide dismutase (SOD) activity, and a significant increase in reactive oxygen species (ROS) level and malondialdehyde (MDA) content. H2O2 also caused apoptosis and mitochondrial dysfunction including mitochondrial fragmentation and the loss of mitochondrial membrane potential. Pretreatment with PHNP at concentrations of 2.5, 5, 10 MUg/mL blocked these H2O2-induced cellular events in a dose-dependent manner. The effect of PHNP at 10 MUg/mL is equal to that of ascorbic acid at 10 MUM. In summary, PHNP has a protective effect against H2O2 induced oxidative injury in cells due to its ability to decrease intracellular ROS and elevate antioxidant enzyme activities. PMID- 23933358 TI - The E-screen test and the MELN gene-reporter assay used for determination of estrogenic activity in fruits and vegetables in relation to pesticide residues. AB - Endocrine-disrupting chemicals (EDCs) may lead to adverse systemic effects by interfering with normal hormone homeostasis, and diet is considered to be among the main routes of EDC exposure. The present study investigated the total estrogenic activity of fruits and vegetables by calculating the 17-beta-estradiol equivalent quantity (EEQ) using two in vitro tests: the human breast cancer cell line (MCF-7 BUS) proliferation assay (E-screen test) and the luciferase transfected human breast cancer cell line (MELN) gene-reporter assay. Of the 24 analyzed fruits and vegetables, 14 contained from 1 to 4 pesticide residues in concentrations ranging from 0.02 to 1.19 ppm, whereas the other 10 did not contain any pesticide residues. The EEQ values for all positive samples ranged from 0.010 to 0.616 MUg/100g for the above in vitro tests. Our study demonstrates that estrogenic activity was present in fruits and vegetables and that the concentration of allowable pesticide residues and EEQ values were positively correlated; however, no correlation was found by comparing the estrogenic activity and the intrinsic content of phytoestrogens obtained from the available literature. A theoretical adult dietary intake of 0.7-0.9 ng EEQ/L/day from fruits and vegetables was calculated. PMID- 23933359 TI - Rapeseed oil-rich diet alters in vitro menadione and nimesulide hepatic mitochondrial toxicity. AB - Diet-induced changes in the lipid composition of mitochondrial membranes have been shown to influence physiological processes. However, the modulation effect of diet on mitochondrially-active drugs has not yet received the deserved attention. Our hypothesis is that modulation of membrane dynamics by diet impacts drug-effects on liver mitochondrial functioning. In a previous work, we have shown that a diet rich in rapeseed oil altered mitochondrial membrane composition and bioenergetics in Wistar rats. In the present work, we investigated the influence of the modified diet on hepatic mitochondrial activity of two drugs, menadione and nimesulide, and FCCP, a classic protonophore, was used for comparison. The results showed that the effects of menadione and nimesulide were less severe on liver mitochondria for rats fed the modified diet than on rats fed the control diet. A specific effect on complex I seemed to be involved in drug induced mitochondria dysfunction. Liver mitochondria from the modified diet group were more susceptible to nimesulide effects on MPT induction. The present work demonstrates that diet manipulation aimed at modifying mitochondrial membrane properties alters the toxicity of mitochondria active agents. This work highlights that diet may potentiate mitochondrial pharmacologic effects or increase drug-induced liabilities. PMID- 23933360 TI - Zinc(II)-curcumin accelerates the healing of acetic acid-induced chronic gastric ulcers in rats by decreasing oxidative stress and downregulation of matrix metalloproteinase-9. AB - Gastric ulcers form as a result of a multifaceted process which includes acid secretion, reactive oxygen species generation and extracellular matrix (ECM) degradation. The aim of this study was to investigate the possible mechanisms underlying the anti-ulcerogenic effects of the Zn(II)-curcumin complex, a curcumin derivative, on the healing of acetic acid-induced gastric ulcers in rats. The severely ulcerated gastric mucosa of control animals had a lower glutathione level (GSH) and superoxide dismutase activity (SOD), and increased malondialdehyde (MDA) content compared to sham operated rats (P<0.001). Zn(II) curcumin solid dispersions (equivalent to 12, 24 and 48 mg/kg) dose-dependently reduced the gastric ulcer index, significantly increased SOD activity and GSH levels, and reduced the MDA content and matrix metalloproteinase-9 (MMP-9) mRNA expression in the gastric mucosa (P<0.05, compared to control animals). Zn(II) curcumin exerted a greater anti-ulcerogenic effect than curcumin at the same dose (24 mg/kg), leading to a reduced severity of gastric ulcers, lower MDA content, and increased SOD activity and GSH levels (P<0.05). In conclusion, these results confirm that the Zn(II)-curcumin complex possesses an enhanced mucosal barrier defense activity compared to curcumin alone, due to its synergistic ability to decrease oxidative stress and attenuate MMP-9-mediated inflammation. PMID- 23933361 TI - Dietary exposure to silver nanoparticles in Sprague-Dawley rats: effects on oxidative stress and inflammation. AB - Due to undesirable hazardous interactions with biological systems, we evaluated the effect of silver nanoparticles (AgNPs) intake on oxidative stress and inflammation. Rats received for 81 days a standard diet (Controls) or a standard diet plus 500 mg/d/kg BW AgNPs. We assayed plasma lipids, and oxidative stress was assessed by measuring liver and heart superoxide anion production (O2 degrees -) and liver malondialdehyde levels (MDA). Antioxidant status was appraised using plasma paraoxonase activity (PON), plasma antioxidant capacity (PAC) and liver superoxide dismutase activity (SOD). Liver inflammatory cytokines TNFalpha and IL 6 levels and plasma alanine aminotransferase (ALT) were assayed. Compared with Controls, AgNPs raised cholesterolemia (9.5%), LDL-cholesterol (30%), and lowered triglycerides (41%). They also increased liver (30%) and cardiac (41%) O2 degrees - production, reduced PON activity (15%) and raised liver TNFalpha (9%) and IL-6 (~12%). Plasma ALT activity rose (12%) after treatment with AgNPs. However, PAC and liver MDA and SOD activity were unchanged. These features indicate that exposure to 500 mg/d/kg BW of AgNPs results in liver damage by a dysregulation of lipid metabolism, highlighting liver and heart as the most sensitive organs to the deleterious effects. Our findings also demonstrate for the first time the oxidative and inflammatory effects of dietary AgNPs. PMID- 23933362 TI - Red ginseng protects against gentamicin-induced balance dysfunction and hearing loss in rats through antiapoptotic functions of ginsenoside Rb1. AB - The authors evaluated the protective effects of Korean red ginseng (KRG) against gentamicin (GM)-induced unilateral vestibular and hearing dysfunction and investigated its effective mechanism using in vitro cell cultures. Vestibular function was comprehensively evaluated by a scoring system that ranged from 0 (normal) to 3 (worst) points, using head tilt, tail hanging, and swimming tests. The GM group showed significantly more deteriorated vestibular function (0 point- 5 rats, 1 point--1 rat, 2 points--3 rats, and 3 points--3 rats) than the KRG+GM group (0 point--9 rats and 1 point--1 rat) (p<0.01). The hearing thresholds were better in the KRG+GM group than in the GM group (p<0.05). Quantitative analysis of hair cell damage in the scanning electron microscopy was closely related with vestibular and hearing functional results. In vitro study showed that ginsenoside Rb1 (gRb1) attenuated reactive oxygen species production, suppressed JNK activation, up-regulated Bcl-xL and down-regulated Bax, cytochrome c, caspase 3, and cleaved poly (ADP-ribose) polymerase in GM-treated VOT-E36 cells. These findings suggest that KRG including gRb1 component protects against vestibular/hearing dysfunction by inhibiting apoptotic pathways when ototoxicity is induced by unilateral intratympanic injection with GM in rats. PMID- 23933363 TI - Dealcoholated red wine induces autophagic and apoptotic cell death in an osteosarcoma cell line. AB - Until recently, the supposed preventive effects of red wine against cardiovascular diseases, the so-called "French Paradox", has been associated to its antioxidant properties. The interest in the anticancer capacity of polyphenols present in red wine strongly increased consequently to the enormous number of studies on resveratrol. In this study, using lyophilized red wine, we present evidence that its anticancer effect in a cellular model is mediated by apoptotic and autophagic cell death. Using a human osteosarcoma cell line, U2Os, we found that the lyophilized red wine was cytotoxic in a dose-dependent manner with a maximum effect in the range of 100-200 MUg/ml equivalents of gallic acid. A mixed phenotype of types I/II cell death was evidenced by means of specific assays following treatment of U2Os with lyophilized red wine, e.g., autophagy and apoptosis. We found that cell death induced by lyophilized red wine proceeded through a mechanism independent from its anti-oxidant activity and involving the inhibition of PI3K/Akt kinase signaling. Considering the relative low concentration of each single bioactive compound in lyophilized red wine, our study suggests the activation of synergistic mechanism able to inhibit growth in malignant cells. PMID- 23933364 TI - IL-4 and IL-13 mediated down-regulation of CD8 expression levels can dampen anti viral CD8+ T cell avidity following HIV-1 recombinant pox viral vaccination. AB - We have shown that mucosal HIV-1 recombinant pox viral vaccination can induce high, avidity HIV-specific CD8(+) T cells with reduced interleukin (IL)-4 and IL 13 expression compared to, systemic vaccine delivery. In the current study how these cytokines act to regulate anti-viral CD8(+) T, cell avidity following HIV-1 recombinant pox viral prime-boost vaccination was investigated. Out of a panel of T cell avidity markers tested, only CD8 expression levels were found to be enhanced on, KdGag197-205 (HIV)-specific CD8(+) T cells obtained from IL-13(-/-), IL-4(-/-) and signal transducer and, activator of transcription of 6 (STAT6)(-/-) mice compared to wild-type (WT) controls following, vaccination. Elevated CD8 expression levels in this instance also correlated with polyfunctionality, (interferon (IFN)-gamma, tumour necorsis factor (TNF)-alpha and IL-2 production) and the avidity of HIVspecific CD8(+) T cells. Furthermore, mucosal vaccination and vaccination with the novel adjuvanted IL-13 inhibitor (i.e. IL-13Ralpha2) vaccines significantly enhanced CD8 expression levels on HIV-specific CD8(+), T cells, which correlated with avidity. Using anti-CD8 antibodies that blocked CD8 availability on CD8(+), T cells, it was established that CD8 played an important role in increasing HIV-specific CD8(+) T cell avidity and polyfunctionality in IL 4(-/-), IL-13(-/-) and STAT6(-/-) mice compared to WT controls, following vaccination. Collectively, our data demonstrate that IL-4 and IL-13 dampen CD8 expression levels on anti-viral CD8(+) T cells, which can down-regulate anti viral CD8(+) T cell avidity and, polyfunctionality following HIV-1 recombinant pox viral vaccination. These findings can be exploited to, design more efficacious vaccines not only against HIV-1, but many chronic infections where high, avidity CD8(+) T cells help protection. PMID- 23933365 TI - Pertussis in the Netherlands, is the current vaccination strategy sufficient to reduce disease burden in young infants? AB - BACKGROUND: Pertussis has resurged in the Netherlands since 1996. Several measures, i.e. acceleration of the schedule, introduction of a preschool acellular pertussis booster and change from an infant whole cell to an acellular pertussis combination vaccine were implemented in the National Immunisation Programme to decrease disease burden, in particular among very young infants who have the highest morbidity and mortality of pertussis. Nevertheless, a large outbreak occurred in 2011-2012. METHODS: 1996-2010 was divided in 3-year-periods to assess the impact of the measures taken, using notifications and hospitalisations. These results were compared with 2011-2012. Mean Incidence rates (IRs) per 100,000 were calculated. RESULTS: Although the measures taken resulted in decreased IRs among the targeted age groups after implementation, overall mean IRs of notifications increased from 32 (1996-2004) to 37 (2005-2010) and 63 (2011-2012). Young infants, not yet vaccinated, did not benefit; during the 2011-2012 outbreak, IR in 0-2-month-olds amounted to 259.6. IR among persons over 9 years of age increased from 6.8 (1996-1999) to 59.1 (2011-2012) For hospitalisations overall mean IRs decreased from 1.95 per 100,000 (1997-2004) to 0.88 (2005-2010) and 0.76 (2011). CONCLUSION: The measures taken reduced IRs of notifications and hospitalisations among groups eligible for vaccination, but had no effect on the increasing IRs in adolescents and adults. This trend is also observed in other countries. The high IRs in 2012 in adolescents and adults probably resulted in increased transmission to infants, who are at risk for contracting severe pertussis. Therefore, additional measures to protect this group should be considered. PMID- 23933366 TI - Nasal vaccination with attenuated Salmonella expressing VapA: TLR2 activation is not essential for protection against R. equi infection. AB - Virulent strains of Rhodococcus equi have a large plasmid of 80-90kb, which encodes several virulence-associated proteins (Vap), including VapA, a lipoprotein highly associated with disease. We have previously demonstrated that oral immunisation with attenuated Salmonella enterica Typhimurium strain expressing the antigen VapA (STM VapA+) induces specific and long-term humoral and cellular immunity against R. equi. It was shown that VapA activates Toll-like receptor 2 (TLR2) on macrophages by establishing an interaction that ultimately favours immunity against R. equi infection. The purpose of this study was to evaluate the immune response triggered by nasal immunisation with STM VapA+ and to determine whether TLR2 supports the vaccine effect. We developed an optimised protocol for a single nasal immunisation that conferred protection against R. equi infection in mice, which was manifested by efficient R. equi clearance in challenged animals. Nasal vaccination with STM VapA+ has also induced protection in Tlr2(-/-) mice and mice with non-functional TLR4. Moreover, spleen cells of vaccinated mice augmented T-bet expression, as well as the production of IL-12, IFN-gamma, nitric oxide and hydrogen peroxide. Notably, the population of CD4(+) T cells with memory phenotype significantly increased in the spleens of vaccinated mice challenged 1 or 5 months after immunisation. In these animals, the spleen bacterial burden was also reduced. When similar experimental procedures were performed in TLR2 knockout mice, an increase in CD4(+) T cells with memory phenotype was not observed. Consequently, we conclude that nasal vaccination with attenuated Salmonella expressing the R. equi virulence factor VapA confers long-lasting protection against experimental rhodoccocosis and that TLR2 engagement was not crucial to induce this protection but may be required for a long-term immune response. PMID- 23933367 TI - Working Group on quality, safety and efficacy of typhoid Vi capsular polysaccharide conjugate, vaccines, Jeju, Republic of Korea, 5-7 September 2012. AB - Typhoid fever is a gastrointestinal disease transmitted through the ingestion of contaminated water or food. The bacterium, Salmonella enterica subspecies enterica serovar Typhi is an important cause of illness and death in many poor countries where access to safe water and basic sanitation is limited. Humans are the only natural host and reservoir of S. Typhi. Typhoid fever causes around 21 million cases and at least 200,000 deaths per year. Currently, several groups are developing typhoid conjugate vaccines that are expected to be safe and effective in infancy or early childhood. The World Health Organization convened a meeting, in collaboration with the Korea Food and Drug Administration, with experts group in September 2012 to develop guidelines for regulatory evaluation of the quality, safety and efficacy of typhoid conjugate vaccines. This report summarizes collective views on scientific and technical issues that need to be considered in the guidelines. PMID- 23933368 TI - The comparative effectiveness of adjuvanted and unadjuvanted trivalent inactivated influenza vaccine (TIV) in the elderly. AB - BACKGROUND: Influenza is associated with a high mortality and morbidity in older adults. Vaccination remains the most effective method of preventing influenza and its consequences, however, vaccine effectiveness decreases with increasing age and increasing immunosenescence. In older adults, immunogenicity studies suggest an MF59 adjuvanted influenza vaccine (ATIV, Fluad((r))) may help. METHODS: We evaluated the comparative effectiveness of ATIV, and unadjuvanted trivalent influenza vaccine (TIV) in reducing laboratory confirmed influenza in the elderly. Elderly in three health authorities during winter 2011-12 were included in a community based case control study design. Cases tested positive and controls tested negative for influenza. Subjects with known immunosuppression were excluded. Logistic regression was used to calculate the odds ratio of vaccination (vs. no vaccination) in cases and controls. ATIV and TIV effectiveness was described. RESULTS: A total of 282 eligible participants were enrolled (84 cases). Almost half (136) were in a long term care facility and were 85 years of age or older (132) vaccine effectiveness decreased with increasing age. In a variety of multivariate analyses, ATIV was significantly protective at around 60% (p=0.02), with only residence in long term care and health authority also significant. Vaccine effectiveness increased in non-long term care residents. In multivariate analyses TIV was ineffective. CONCLUSION: An MF59 adjuvanted vaccine provided significantly improved protection against influenza in the elderly. PMID- 23933370 TI - Reply to response to Limitations of the study "Cost-effectiveness of tick-borne encephalitis vaccination in Slovenian adults". PMID- 23933369 TI - Expression of human CEACAM1 in transgenic mice limits the Opa-specific immune response against meningococcal outer membrane vesicles. AB - Outer membrane vesicles (OMVs) have been extensively investigated as meningococcal vaccine candidates. Among their major components are the opacity (Opa) proteins, a family of surface-exposed outer membrane proteins important for bacterial adherence and entry into host cells. Many Opa-dependent interactions are mediated through the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family of receptors. Importantly, binding of Opa to CEACAM1 has been reported to suppress human CD4 T cell proliferation in vitro in response to OMV preparations. This raises the question whether OMV vaccines should contain Opa proteins at all. Until now it has been difficult to answer this question, as the proposed immunosuppressive effect was only demonstrated with human cells in vitro, while immunization experiments in mice are not informative because the Opa interaction is specific for human CEACAM1. In the present study we have used Opa+ and Opa- OMVs for immunization experiments in a human CEACAM1 transgenic mouse model. OMVs were prepared from a meningococcal strain H44/76 variant expressing the CEACAM1-binding OpaJ protein, and from an isogenic variant in which all opa genes have been inactivated. Both the CEACAM1 expressing transgenic mice and their congenic littermates lacking it were immunized twice with the OMV preparations, and the sera were analyzed for bactericidal activity and ELISA antibody titres. Total IgG antibodies against the OMVs were similar in both mouse strains. Yet the titres for IgG antibodies specific for purified OpaJ protein were significantly lower in the mice expressing human CEACAM1 than in the nontransgenic mice. No significant differences were found in bactericidal titres among the four groups. Overall, these data indicate that expression of human CEACAM1 confers a reduced Opa-specific antibody response in vivo without affecting the overall immune response against other OMV antigens. PMID- 23933371 TI - Estimates of influenza vaccine effectiveness in primary care in Scotland vary with clinical or laboratory endpoint and method--experience across the 2010/11 season. AB - AIM: This study examines estimation of seasonal influenza vaccine effectiveness (VE) for a cohort of patients attending general practice in Scotland in 2010/11. The study focuses on the variation in estimation of VE for both virological and clinical consultation outcomes and understanding the dependency on date of analysis during the season, methodological approach and the effect of use of a propensity score model. METHODS: For the clinical outcomes, three methodological approaches were considered; adjusted Poisson multi-level modelling splitting consultations in vaccinated individuals into those before and after vaccination, adjusted Cox proportional hazards modelling and finally the screening method. For the virological outcome, the test-negative case-control study design was employed. RESULTS: VE was highest for the most specific outcomes of ILI (Poisson end-of-season VE=47% (95% CI: -69%, 83%); Cox VE=34% (95% CI: -64%, 73.2%); Screening VE=52.8% (95% CI: 3.8%, 76.8%)) and a virological diagnosis (VE=54% (95% CI: -37%, 85%)). Using the Cox approach, adjusted for propensity score only gave VE=46.5% (95% CI: -30.4%, 78.0%). CONCLUSION: Our approach illustrated the ability to achieve relatively consistent estimates of seasonal influenza VE using both specific and less specific outcomes. Construction of a propensity score and use for bias adjustment increased the estimate of ILI VE estimated from the Cox model and made estimates more similar to the Poisson approach, which models differences in consultation behaviour of vaccinated individuals more inherently in its structure. VE estimation for the same data was found to vary by methodology which should be noted when comparing results from different studies and countries. PMID- 23933372 TI - Protection of red-legged partridges (Alectoris rufa) against West Nile virus (WNV) infection after immunization with WNV recombinant envelope protein E (rE). AB - West Nile virus (WNV) is maintained in nature in an enzootic transmission cycle between birds and mosquitoes, although it occasionally infects other vertebrates, including humans, in which it may result fatal. To date, no licensed vaccines against WNV infection are available for birds, but its availability would certainly benefit certain populations, as birds grown for restocking, hunting activities, or alimentary purposes, and those confined to wildlife reservations and recreation installations. We have tested the protective capability of WNV envelope recombinant (rE) protein in red-legged partridges (Alectoris rufa). Birds (n=28) were intramuscularly immunized three times at 2-weeks interval with rE and a control group (n=29) was sham-immunized. Except for 5 sham-immunized birds that were not infected and housed as contact controls, partridges were subcutaneously challenged with WNV. Oropharyngeal and cloacal swabs and feather pulps were collected at several days after infection and blood samples were taken during vaccination and after infection. All rE-vaccinated partridges elicited anti-WNV antibodies before challenge and survived to the infection, while 33.3% of the sham-immunized birds succumbed, as did 25% of the contact animals. Most (84%) unvaccinated birds showed viremia 3 d.p.i., but virus was only detected in 14% of the rE vaccinated birds. WNV-RNA was detected in feathers and swabs from sham-immunized partridges from 3 to 7 d.p.i., mainly in birds that succumbed to the infection, but not in rE vaccinated birds. Thus, rE vaccination fully protected partridges against WND and reduced the risk of virus spread. PMID- 23933374 TI - Using the impact of pneumococcal vaccines on nasopharyngeal carriage to aid licensing and vaccine implementation; a PneumoCarr meeting report March 27-28, 2012, Geneva. AB - An international consultation was convened in March 2012 to provide feedback on the Case for Carriage, a summary statement by the Pneumococcal Carriage Consortium (PneumoCarr) proposing nasopharyngeal (NP) colonization as a supplementary or alternative endpoint in vaccine licensure. PneumoCarr members provided information to vaccine manufacturers, regulators and the WHO on the evidence for NP carriage as a precursor to pneumococcal disease, standardization of laboratory methods for the detection of multiple serotype carriage, definition and estimation of pneumococcal vaccine efficacy against carriage (VE-col), and the direct and indirect impact of vaccination on carriage. Manufacturers and regulators had the opportunity to respond to the information compiled by PneumoCarr and share their perspectives. VE-col as a licensure endpoint may be more useful for the next generation pneumococcal vaccine products, particularly those for which the immunological correlate of protection is not established, whereas it may be less needed for pneumococcal conjugate vaccines which have an established licensure pathway. The consultation supported the importance of NP carriage data as a critical element linking vaccine impact on the individual direct risk of disease to the population-level impact: indirect effects such as herd protection and serotype replacement. The indirect effects of vaccination, however, are not currently established as part of the licensure process and to include them would be a paradigm shift for regulatory agencies who currently consider this information in the post-licensure setting. More discussion and consensus-building is needed around the rationale and optimal mechanism to include carriage data in the licensure pathway for new pneumococcal vaccines. The WHO and national advisory groups on immunization policy may have an important role in considering the evidence for the indirect benefit of vaccination as informed by its impact on NP carriage. PMID- 23933373 TI - DNA vaccine encoding the Toxoplasma gondii bradyzoite-specific surface antigens SAG2CDX protect BALB/c mice against type II parasite infection. AB - The surface antigens SAG2C, SAG2D, and SAG2X, which expressed specifically on bradyzoite stage of Toxoplasma gondii, have been demonstrated to be important for persistence of cyst in the brain. In this study, DNA vaccines expressing SAG2C, SAG2D, and SAG2X of T. gondii were constructed and their protective efficacy were evaluated in BALB/c mice. Mice vaccinated with pVAX1-SAG2C (pSAG2C), pVAX1-2D (pSAG2D) or pVAX1-2X (pSAG2C) showed higher levels of serum IgG antibodies and lymphocyte proliferation response compared to PBS and pVAX1 treated mice (p<0.05). The immune response was characterized by a strong Th1 response and increased cytokine production of IL-2 and IFN-gamma. Vaccinated mice displayed significant protection against the challenge with the cyst of T. gondii genotype II strain of PRU (cyst-forming in mouse). A significant reduction in the brain cyst burden was detected in the mice immunized with pSAG2C (72%), pSAG2D (23%), pSAG2X (69%) alone and even more reduction rate, 77%, was achieved in the combination group compared to PBS treated mice. The results implied that immunization with DNA vaccines expressing SAG2C, SAG2D, and SAG2X, and, in particular, a combination of all three DNA plasmids, could effectively protect the mice against T. gondii chronic infection. PMID- 23933375 TI - Genetic stability of Brucella abortus S19 and RB51 vaccine strains by multiple locus variable number tandem repeat analysis (MLVA16). AB - The aims of the present study were (i) to assess the in vitro genetic stability of S19 and RB51 Brucella abortus vaccines strains and (ii) to evaluate the ability of multiple-locus variable-number tandem repeat (VNTR) analysis (MLVA) as a tool to be used in the quality control of live vaccines against brucellosis. Sixty-three batches of commercial S19 (n=53) and RB51 (n=10) vaccines, produced between 2006 and 2009, were used in this study. S19 and RB51 vaccines were obtained from, respectively, seven and two different manufacturers. Ten in vitro serial passages were performed on reference strains and on selected batches of commercial vaccines. All batches, reference strains and strains of serial passages were typed by the MLVA16. The results demonstrated that B. abortus S19 and RB51 vaccine strains are genetically stable and very homogeneous in their respective groups. Anyway, batches of S19 from one manufacturer and batches of RB51 from another presented genotypes distincts from the reference vaccine strains. In both cases, differences were found on locus Bruce07, which had addition of one repeat unit in the case of S19 batches and the deletion of one repeat unit in the case of RB51 batches. In summary, MLVA16 proved to be a molecular tool capable of discriminating small genomic variations and should be included in in vitro official tests. PMID- 23933376 TI - Physical exercise improves learning in zebrafish, Danio rerio. AB - Zebrafish is an ideal vertebrate model for neuroscience studies focusing on learning and memory. Although genetic manipulation of zebrafish is available, behavioral protocols are often lacking. In this study we tested whether physical activity can facilitate zebrafish's learning process in an associative conditioning task. Learning was inferred by the approach of the feeding area just after the conditioned stimulus (light). Unexercised zebrafish showed conditioning response from the 5th testing day while fish previously submitted to swim against the water current showed learning by the 3rd day of testing. It seems that physical activity may accelerate associative learning response in zebrafish, indicating the benefits of exercise for cognitive processes. We suggest that this preliminary work could be useful for high throughput screening. PMID- 23933377 TI - The effect of preferential paw usage on dogs' (Canis familiaris) performance in a manipulative problem-solving task. AB - In a number of species, individuals showing lateralized hand/paw usage (i.e. the preferential use of either the right or left paw) compared to ambilateral individuals have been shown to be more proactive in novel situations. In the current study we used an established test to assess preferential paw usage in dogs (the Kong test) and then compared the performance of ambilateral and lateralized dogs as well as left- vs. right-pawed dogs in a novel manipulative problem solving task. Results showed an equal proportion of ambilateral and lateralized dogs but contrary to predictions non-lateralized dogs were faster at accessing the apparatus in test trials. No differences emerged between right- and left-pawed dogs. Results are discussed in relation to previous studies on lateralization. PMID- 23933378 TI - Associative learning in a harvestman (Arachnida, Opiliones). AB - Associative learning has been demonstrated in many species of invertebrates, but has not been studied in arachnids, except for some spiders and a whip-spider. Herein, we tested the ability of a Neotropical harvestman, Discocyrtus invalidus (Arachnida, Opiliones) to associate a shelter with a chemical stimulus. We used an arena with a white light at the top and two openings on the floor, one giving access to a dark shelter and the other one closed with a mesh. Filter paper with different chemicals (mate or green tea) surrounded both openings. A harvestman (n=37) was released in the arena and its behavior recorded. The procedure was repeated for 14 consecutive days with each individual. We found that harvestmen got faster at finding the refuge, became less exploratory and tended to move toward the open shelter as the days passed. We conclude that the animals learned to associate the chemical stimulus with the shelter. PMID- 23933379 TI - Basic science and clinical application of platelet-rich plasma for cartilage defects and osteoarthritis: a review. AB - Cartilage defects (CDs) and the most common joint disease, osteoarthritis (OA), are characterized by degeneration of the articular cartilage that ultimately leads to joint destruction. Current treatment strategies are inadequate: none results in restoration of fully functional hyaline cartilage, for uncertain long term prognosis. Tissue engineering of cartilage with auto-cartilage cells or appropriate mesenchymal stem cell (MSC)-derived cartilage cells is currently being investigated to search for new therapies. Platelet-rich plasma (PRP), an autologous source of factors obtained by centrifugation, possesses various functions. For culture of MSCs and cartilage cells, it might be substituted for fetal bovine serum (FBS) with high efficiency and safety. It enhances the regeneration of cartilage cells when added to cartilage tissue engineering constructs for repairing CDs and as regenerative injection therapy for OA. But challenges also remain. Some of the growth factors (GFs) present in PRP have negative effects on the OA joint. It is therefore unlikely that a mix of GFs some of which have negative effects in the OA joint, as present in PRP, will be of benefit in OA. Future directions of PRP application may concentrate on seeking an appropriate and innocuous agent like anti-VEGF antibody that can modulate and control the effect of PRP. PMID- 23933380 TI - Intradiploic epidermoid cyst mimicking skull metastasis in a patient with primitive neuroectodermal tumor: correct diagnosis with 99mTc-MDP hybrid SPECT CT. PMID- 23933381 TI - Molecular neuroimaging in degenerative dementias. AB - In the context of the limitations of structural imaging, brain perfusion and metabolism using SPECT and PET have provided relevant information for the study of cognitive decline. The introduction of the radiotracers for cerebral amyloid imaging has changed the diagnostic strategy regarding Alzheimer's disease, which is currently considered to be a "continuum." According to this new paradigm, the increasing amyloid load would be associated to the preclinical phase and mild cognitive impairment. It has been possible to observe "in vivo" images using 11C PIB and PET scans. The characteristics of the 11C-PIB image include specific high brain cortical area retention in the positive cases with typical distribution pattern and no retention in the negative cases. This, in combination with 18F-FDG PET, is the basis of molecular neuroimaging as a biomarker. At present, its prognostic value is being evaluated in longitudinal studies. 11C-PIB-PET has become the reference radiotracer to evaluate the presence of cerebral amyloid. However, its availability is limited due to the need for a nearby cyclotron. Therefore, 18F labeled radiotracers are being introduced. Our experience in the last two years with 11C-PIB, first in the research phase and then as being clinically applied, has shown the utility of the technique in the clinical field, either alone or in combination with FDG. Thus, amyloid image is a useful tool for the differential diagnosis of dementia and it is a potentially useful method for early diagnosis and evaluation of future treatments. PMID- 23933382 TI - [Training of nuclear medicine specialists: current status and perspectives]. PMID- 23933383 TI - Diagnostic imaging work-up for disease relapse after radical treatment for prostate cancer: how to differentiate local from systemic disease? The urologist point of view. AB - About 40% of all patients undergoing radical treatment for localized prostate cancer (PCa) develop biochemical relapse (BCR) during lifetime but only 10-20% of them will show clinically detectable recurrences. Prostatic bed, pelvic or retroperitoneal lymph nodes (LN) and bones (especially the spine) are the sites where we must focus our attention in the early phase of PSA relapse. Time to PSA relapse, PSA kinetics, pathological Gleason score and pathological stage are the main factors related to the likelihood of local vs. distant relapse. Before an extensive diagnostic work-up in patients with BCR, is mandatory to understand if there is a therapeutic consequence or not for the patient. Current imaging techniques have some potential but many limits are yet encountered in the diagnosis of disease relapse. Transrectal ultrasound (TRUS) and Multiparametric Magnetic Resonance Imaging (MRI) have low accuracy in the detection of the recurrence. Today, Choline PET/CT may visualize the site of recurrence earlier, with better accuracy than conventional imaging, in a single step and even in the presence of low PSA level. In recent years, the new radiotracer (18)F-FACBC has been proposed as a possible alternative radiopharmaceutical to detect PCa relapse. From a clinical point of view, first clinical studies showed very promising and reproducible results with an improvement in sensitivity is about 20 25% with respect to Choline PET/CT, rendering the FACBC the possible radiotracer of the future for PCa. In conclusion, many improvements have been recently achieved in imaging techniques for PCa restaging, essentially in Nuclear Medicine and MRI, but negative results remain in many cases. Low sensitivity, costs, availability of technologies and confirmation of the results remain the major limitations in most cases. PMID- 23933384 TI - alpha7 nicotinic receptor agonist reactivates neurogenesis in adult brain. AB - Reactivation of neurogenesis by endogenous Neural Stem/Progenitor Cells (NS/PC) in the adult brain or spinal cord holds the key for treatment of CNS injuries as well as neurodegenerative disorders, which are major healthcare issues for the world's aging population. Recent studies show that targeting the alpha7 nicotinic acetylcholine receptors (alpha7nAChR) with a specific TC-7020 agonist inhibits proliferation and stimulates neuronal differentiation of NS/PC in subventricular zone (SVZ) in the adult mouse brain. TC-7020-induced neuronogenesis is observed in different brain regions, including: (1) betaIII Tubulin-expressing cortical neurons, (2) calretinin expressing hippocampal neurons and (3) cells in substantia nigra (SN) expressing predopaminergic Nurr1+phenotype. Reactivation of developmental integrative nuclear FGFR1 signaling (INFS), via gene transfection reinstates neurogenesis in the adult brain by promoting neuronal differentiation of brain NS/PC. TC-7020 neuronogenic effect is associated with a robust accumulation of endogenous FGFR1 in the nuclei of differentiating cells. Furthermore, direct in vitro stimulation of neural stem/progenitor cells with alpha7nAChR agonist activates INFS and neuronal-like differentiation and activation of neuronal genes. The alpha7nAChR upregulation of early neuronal betaIII-Tubulin gene involves neurogenic FGFR1-Nur signaling and direct FGFR1 interaction with the gene promoter. The reactivation of developmental INFS and neurogenesis in adult brain by the alpha7nAChR agonist may offer new strategy to treat brain injuries, neurodegenerative and neurodevelopmental diseases. PMID- 23933386 TI - Gene expression profiling for analysis acquired oxaliplatin resistant factors in human gastric carcinoma TSGH-S3 cells: the role of IL-6 signaling and Nrf2/AKR1C axis identification. AB - Oxaliplatin treatment is a mainstay of treatment for advanced gastrointestinal tract cancer, but the underlying mechanisms of acquired oxaliplatin resistance remain largely obscured. We previously demonstrated that increased DNA repair capacity and copper-transporting ATPase 1 (ATP7A) level contributed to oxaliplatin resistance in the human gastric carcinoma cell line TSGH-S3 (S3). In the present study, we applied gene array technology to identify additional resistance factors in S3 cells. We found that interleukin-6 (IL-6), aldo-keto reductase 1C1 (AKR1C1), and AKR1C3 are the top 3 upregulated genes in S3 cells when compared with parent TSGH cells. Despite a higher level of endogenous IL-6 in S3, IL-6 receptor (IR-6R, gp-80, and gp-130) levels were similar between TSGH and S3 cells. The addition of exogenous IL-6, IL-6 targeted siRNA, or neutralizing antibodies neither affected Stat3 activation, a downstream target of IL-6, nor changed oxaliplatin sensitivity in S3 cells. However, manipulation of AKR1C activity with siRNA or AKR1C inhibitors significantly reversed oxaliplatin resistance. AKR1Cs are classical antioxidant response element (ARE) genes that can be transcriptionally upregulated by nuclear factor erythroid 2-related factor 2 (Nrf2). Knockdown of Nrf2 not only decreased the levels of AKR1C1, AKR1C2, and AKR1C3 mRNA and protein but also reversed oxaliplatin resistance in S3 cells. Taken together, these results suggest that activation of the Nrf2/AKR1C axis may contribute to oxaliplatin resistance in S3 cells but that the IL-6 signaling pathway did not contribute to resistance. Manipulation of Nrf2/AKR1Cs activity may be useful for management of oxaliplatin-refractory gastric cancers. PMID- 23933387 TI - The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo. AB - Aminopeptidase N (APN) has been reported to have a functional role in tumor angiogenesis and repeatedly reported to be over-expressed in human tumors. The melphalan-derived prodrug melphalan-flufenamide (melflufen, previously designated J1) can be activated by APN. This suggests that this alkylating prodrug may exert anti-angiogenic properties, which will possibly contribute to the anti-tumoral activity in vivo. This work presents a series of experiments designed to investigate this effect of melflufen. In a cytotoxicity assay we show that bovine endothelial cells were more than 200 times more sensitive to melflufen than to melphalan, in HUVEC cells the difference was more than 30-fold and accompanied by aminopetidase-mediated accumulation of intracellular melphalan. In the chicken embryo chorioallantoic membrane (CAM) assay it is indicated that both melflufen and melphalan inhibit vessel ingrowth. Two commercially available assays with human endothelial cells co-cultured with fibroblasts (TCS Cellworks AngioKit, and Essen GFP-AngioKit) also illustrate the superior anti-angiogenic effect of melflufen compared to melphalan. Finally, in a commercially available in vivo assay in mice (Cultrex DIVAA angio-reactor assay) melflufen displayed an anti angiogenic effect, comparable to bevacizumab. In conclusion, this study demonstrates through all methods used, that melphalan-flufenamide besides being an alkylating agent also reveals anti-angiogenic effects in different preclinical models in vitro and in vivo. PMID- 23933388 TI - Functional selectivity of G-protein-coupled receptors: from recombinant systems to native human cells. AB - In the mid 1990s, it was assumed that a two-state model, postulating an inactive (R) state and an active (R*) state provides the molecular basis for GPCR activation. However, it became clear that this model could not accommodate many experimental observations. Accordingly, the two-state model was superseded by a multi-state model according to which any given ligand stabilizes a unique receptor conformation with distinct capabilities of activating down-stream G proteins and beta-arrestin. Much of this research was conducted with the beta2 adrenoceptor in recombinant systems. At the molecular level, there is now no doubt anymore that ligand-specific receptor conformations, also referred to as functional selectivity, exist. This concept holds great potential for drug discovery in terms of developing drugs with higher selectivity for specific cells and/or cell functions and fewer side effects. A major challenge is the analysis for functional selectivity in native cells. Here, I discuss our current knowledge on functional selectivity of three representative GPCRs, the beta2-adrenoceptor and the histamine H2- and H4-receptors, in recombinant systems and native human cells. Studies with human neutrophils and eosinophils support the concept of functional selectivity. A major strategy for the analysis of functional selectivity in native cells is to generate complete concentration/response curves with a large set of structurally diverse ligands for multiple parameters. Next, correlations of potencies and efficacies are analyzed, and deviations of the correlations from linearity are indicative for functional selectivity. Additionally, pharmacological inhibitors are used to dissect cell functions from each other. PMID- 23933389 TI - Quantitative versus qualitative data: the numerical dimensions of drug action. AB - The application of detailed quantitative analyses of the concentration dependence of the biological responses mediated by endogenous hormones and other mediators, drugs, and related compounds has been the foundation of pharmacology for the past century or more. This approach has been remarkably successful in identifying the specific molecular targets for these mediators and drugs, in establishing the mechanisms for those effects at both the cellular and whole organismal levels, and in the development of new chemical entities (NCEs) with great selectivity for individual molecular targets. The availability of such compounds has unfortunately led to a mindset that detailed quantitative analyses are no longer necessary to use such compounds in understanding biological system function and to draw valid conclusions in regard to the utility of NCEs selective for putative drug targets in the potential treatment of human disease states. This lack of appreciation for quantitative approaches has contributed significantly to the all too-frequent failures of new drug candidates in early-stage clinical trials. The present article reviews basic drug/receptor concepts together with the mathematical relationships that underlie the quantitative analysis of dose response and concentration-effect relationships for individual compounds and for more complex systems, such as the comparative analysis of multiple compounds at a single receptor. A thorough understanding of these concepts and their associated analyses, along with their proper and rigorous application in all pre-clinical drug development studies, is an essential component of an integrated approach toward improving drug development. PMID- 23933391 TI - Crystallographic control on the substructure of nacre tablets. AB - Nacre tablets of mollusks develop two kinds of features when either the calcium carbonate or the organic portions are removed: (1) parallel lineations (vermiculations) formed by elongated carbonate rods, and (2) hourglass patterns, which appear in high relief when etched or in low relief if bleached. In untreated tablets, SEM and AFM data show that vermiculations correspond to aligned and fused aragonite nanogloblules, which are partly surrounded by thin organic pellicles. EBSD mapping of the surfaces of tablets indicates that the vermiculations are invariably parallel to the crystallographic a-axis of aragonite and that the triangles are aligned with the b-axis and correspond to the advance of the {010} faces during the growth of the tablet. According to our interpretation, the vermiculations appear because organic molecules during growth are expelled from the a-axis, where the Ca-CO3 bonds are the shortest. In this way, the subunits forming nacre merge uninterruptedly, forming chains parallel to the a-axis, whereas the organic molecules are expelled to the sides of these chains. Hourglass patterns would be produced by preferential adsorption of organic molecules along the {010}, as compared to the {100} faces. A model is presented for the nanostructure of nacre tablets. SEM and EBSD data also show the existence within the tablets of nanocrystalline units, which are twinned on {110} with the rest of the tablet. Our study shows that the growth dynamics of nacre tablets (and bioaragonite in general) results from the interaction at two different and mutually related levels: tablets and nanogranules. PMID- 23933390 TI - Anti-amnestic properties of Ginkgo biloba extract on impaired memory function induced by aluminum in rats. AB - Aluminum is the most widely used non-ferrous metal. However, recently it is reported to be a neurotoxic agent that could induce biochemical defects in brain by affecting levels of neurotransmitters and generating reactive oxygen species resulting in oxidative stress. This study aimed at evaluating neuroprotective effect of Ginkgo biloba extract(2) (GBE) (200 mg/kg for 28 days) in antagonizing aluminum-induced neurotoxicity through investigating certain parameters such as serum aluminum level, brain aluminum content, brain regional distribution of aluminum, brain oxidative stress biomarkers' content, and brain acetylcholinesterase(3) (AChE) activity. Passive avoidance paradigm was used to assess memory retrieval of rats. Rats' activities were studied using open field test. Results showed that administration of aluminum (10 mg/kg for 28 days) impaired rats' memory retrieval associated with marked elevation of aluminum brain content, serum aluminum level and AChE activity. In addition, aluminum treatment induced significant elevation in its brain content in all tested regions. GBE treatment attenuated neurotoxic effects of aluminum as evidenced by improving rats' performance in passive avoidance and lowering brain AChE activity. Moreover, marked elevation in brain content of oxidized glutathione(4) (GSSG) and malonedialdehyde(5) (MDA) as well as depletion of reduced glutathione(6) (GSH) demonstrated following aluminum administration were reversed reaching normal levels after GBE treatment. Open field test, demonstrated no changes in latency period, number of ambulation, rearing, and grooming following aluminum or other treatments. Therefore, GBE may be a promising therapy ameliorating neurotoxicity of aluminum as an environmental toxic agent. PMID- 23933385 TI - Cognition as a therapeutic target in late-life depression: potential for nicotinic therapeutics. AB - Depression is associated with impairments to cognition and brain function at any age, but such impairments in the elderly are particularly problematic because of the additional burden of normal cognitive aging and in some cases, structural brain pathology. Individuals with late-life depression exhibit impairments in cognition and brain structural integrity, alongside mood dysfunction. Antidepressant treatment improves symptoms in some but not all patients, and those who benefit may not return to the cognitive and functional level of nondepressed elderly. Thus, for comprehensive treatment of late-life depression, it may be necessary to address both the affective and cognitive deficits. In this review, we propose a model for the treatment of late-life depression in which nicotinic stimulation is used to improve cognitive performance and improve the efficacy of an antidepressant treatment of the syndrome of late-life depression. The cholinergic system is well-established as important to cognition. Although muscarinic stimulation may exacerbate depressive symptoms, nicotinic stimulation may improve cognition and neural functioning without a detriment to mood. While some studies of nicotinic subtype specific receptor agonists have shown promise in improving cognitive performance, less is known regarding how nicotinic receptor stimulation affects cognition in depressed elderly patients. Late-life depression thus represents a new therapeutic target for the development of nicotinic agonist drugs. Parallel treatment of cognitive dysfunction along with medical and psychological approaches to treating mood dysfunction may be necessary to ensure full resolution of depressive illness in aging. PMID- 23933392 TI - Particle quality assessment and sorting for automatic and semiautomatic particle picking techniques. AB - Three-dimensional reconstruction of biological specimens using electron microscopy by single particle methodologies requires the identification and extraction of the imaged particles from the acquired micrographs. Automatic and semiautomatic particle selection approaches can localize these particles, minimizing the user interaction, but at the cost of selecting a non-negligible number of incorrect particles, which can corrupt the final three-dimensional reconstruction. In this work, we present a novel particle quality assessment and sorting method that can separate most erroneously picked particles from correct ones. The proposed method is based on multivariate statistical analysis of a particle set that has been picked previously using any automatic or manual approach. The new method uses different sets of particle descriptors, which are morphology-based, histogram-based and signal to noise analysis based. We have tested our proposed algorithm with experimental data obtaining very satisfactory results. The algorithm is freely available as a part of the Xmipp 3.0 package [http://xmipp.cnb.csic.es]. PMID- 23933393 TI - A microstructural study of individual nacre tablet of Pinctada maxima. AB - Nacre tablets from the shell of Pinctada maxima were studied with SEM, TEM and STEM. The systematic nanolath morphology on the (001) surface of nacre tablets was observed after acidic etching and mechanical polishing. The nanolaths were along the [100] crystallographic orientation of aragonite crystal. The (010) and (100) cross section surfaces of the nacre tablets showed nanolath and nanograin morphologies, respectively, which was consistent with [100] crystallographic orientation of nanolath on the (001) surface. Sheet-like defects with low mass density were observed on the (001) plane inside nacre tablets and were considered to be the cause of nanolath morphology revealed on the surfaces by acidic etching and mechanical polishing. On the other hand, large block [110] twins that divide the nacre tablets into two sectors were identified. The implication of these twins on the understanding to the crystallization mechanism of nacre tablets was discussed. PMID- 23933394 TI - Analysis of Kaposi's sarcoma-associated herpesvirus latent replication using a real-time polymerase chain reaction technique. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) undergoes replication independently via latent and lytic pathways. Latent replication is mediated by latent-associated nuclear antigen (LANA), the sole viral trans element for genome maintenance and replication. According to previous studies, LANA tethers the KSHV genome to the host chromosome during latency and interacts with host factors to ensure proper latent replication. Studies using Southern blot experiments have revealed consistently that vector constructs containing the viral terminal repeat (TR) region as a cis element in latent replication are replicated in the presence of LANA. However, Southern blotting is a time-intensive, complicated technique that requires multiple reagents. In addition, it has a limited ability to detect slight changes in replication efficiency under different conditions owing to its relatively low sensitivity. In the current study, a real-time polymerase chain reaction method was developed for detecting transient KSHV replication and was found to be capable of further identifying several factors that affect latent replication. This technique should provide a useful tool for the detection of KSHV latent replication under various conditions, including overexpression of viral or cellular factors and chemical stimulation. PMID- 23933395 TI - Factors affecting relative fitness measurements in pairwise competition assays of human immunodeficiency viruses. AB - Cell culture growth competition assays of human immunodeficiency virus type 1 (HIV-1) are used to estimate viral fitness and quantify the impact of mutations conferring drug resistance and immunological escape. A comprehensive study of growth competition assays was conducted and identified experimental parameters that can impact measurements of relative fitness including multiplicity of infection, viral input ratio, number, timing and interval of time points used to evaluate selective outgrowth, and the algorithm for calculating fitness values. An optimized protocol is developed here that is a multi-point growth competition assay that resolves reproducibly small differences in viral fitness. The optimized protocol uses an MOI of 0.005, a consistent ratio of mutant: parental viruses (70:30), and a multipoint [1+s 4,7] algorithm that uses data points within the logarithmic phase of viral growth for assessing fitness differences. PMID- 23933396 TI - Recombinant glycoprotein G analog for determination of specific immunoglobulins to herpes simplex virus type 2 by ELISA. AB - In order to the detection of type-specific IgG to herpes simplex virus type 2 (HSV-2) in human serum or plasma the recombinant analog of HSV-2 glycoprotein G (gG2) was created. To construct an expression vector the DNA fragment with a sequence identical to immunodominant regions of HSV-2 gG2 was cloned into modified vector pET28a containing of the glutation-S-transferase sequence (pET28 GST). Escherichia coli BL21 (DE3) were transformed with the recombinant plasmid. The target protein was expressed mainly in soluble form. Chromatographic purification of soluble GST-gG2 protein was performed taking into account the features of its primary structure that are 6His-tag and GST-tag. To determine the affinity constant of the specific IgG to GST-gG2 we used the method proposed by Friguet et al. (1985). The affinity constants were within the range of 10(7) 10(8)M(-1) proving their high-affinity. The purified recombinant HSV-2 antigen was used to design a diagnostic ELISA kit, which was evaluated with referent controls and standard panels of sera containing and/or not containing anti-HSV-2 IgG. Comparative evaluation of this kit and the commercially available "HSV-Type 2 IgG-ELISA" (NovaTec, Dietzenbach, Germany) kit was performed. There was no significant difference (P>0.05). It allows to use developed ELISA kit for clinical diagnosis of HSV-2 infection. PMID- 23933397 TI - Sexual function in adult life following Passerini-Glazel feminizing genitoplasty in patients with congenital adrenal hyperplasia. AB - PURPOSE: We assessed external genitalia sensitivity and sexual function in adults with congenital adrenal hyperplasia who had undergone Passerini-Glazel feminizing genitoplasty as children, and compared them to a control group of healthy counterparts. MATERIALS AND METHODS: Inclusion criteria were congenital adrenal hyperplasia, Passerini-Glazel feminizing genitoplasty, adult age and penetrative vaginal intercourse. Thermal and vibratory sensitivity of the clitoris, vagina and labia minora were analyzed using the Genito Sensory Analyzer (Medoc Ltd., Minnetonka, Minnesota). Psychosexual outcome was assessed with the Beck Depression Inventory, Zung Self-Rating Anxiety Scale, Female Sexual Distress Scale and Female Sexual Function Index. Matched analyses were performed to compare outcomes in patients to controls (healthy medical students). All statistical tests were performed using SPSS(r), version 18.0 RESULTS: A total of 12 patients (10%) entered the study. Thermal and vibratory clitoral sensitivity was significantly decreased in all patients compared to healthy controls (p <0.01). There was no difference in thermal or vibratory vaginal sensitivity between patients and controls. On the Female Sexual Distress Scale 11 patients (91.6%) and 11 controls (91.6%) described a stable satisfactory relationship. All patients reported active sexual desire, good arousal, adequate lubrication and orgasm. No significant difference in Female Sexual Function Index global score or single domain scores was observed between patients and controls. CONCLUSIONS: Although clitoral sensitivity in sexually active patients with congenital adrenal hyperplasia treated with Passerini-Glazel feminizing genitoplasty is significantly reduced compared to controls, sexual function in those patients is not statistically or clinically significantly different from their healthy counterparts. Finally, 1-stage Passerini-Glazel feminizing genitoplasty seems to allow normal adult sexual function. PMID- 23933398 TI - The combination of glycosaminoglycans and fibrous proteins improves cell proliferation and early differentiation of bovine primary skeletal muscle cells. AB - Primary muscle cell model systems from farm animals are widely used to acquire knowledge about muscle development, muscle pathologies, overweight issues and tissue regeneration. The morphological properties of a bovine primary muscle cell model system, in addition to cell proliferation and differentiation features, were characterized using immunocytochemistry, western blotting and real-time PCR. We observed a reorganization of the Golgi complex in differentiated cells. The Golgi complex transformed to a highly fragmented network of small stacks of cisternae positioned throughout the myotubes as well as around the nucleus. Different extracellular matrix (ECM) components were used as surface coatings in order to improve cell culture conditions. Our experiments demonstrated improved proliferation and early differentiation for cells grown on surface coatings containing a mixture of both glycosaminoglycans (GAGs) and fibrous proteins. We suggest that GAGs and fibrous proteins mixed together into a composite biomaterial can mimic a natural ECM, and this could improve myogenesis for in vitro cell cultures. PMID- 23933399 TI - Angiotensin II promotes cardiac differentiation of embryonic stem cells via angiotensin type 1 receptor. AB - As embryonic stem cells (ESCs) represent an attractive candidate cell source for obtaining cardiomyocytes to be used in cell replacement therapy, it is thus of considerable importance to understand the mechanism by which cardiac differentiation is regulated. In previous studies, we have shown that angiotensin type 1 receptor (AT1R) expressed in cardiomyocytes derived from mouse embryonic stem cells. However, little is known about the role of AT1R in cardiac differentiation, which plays a key role in cardiac physiology and pharmacology. In the present study, we demonstrated that AT1R agonist significantly enhanced cardiac differentiation as determined by increased percentage of beating embryoid bodies and a higher expression level of cardiac markers. On the contrary, AT1R agonist stimulated differentiation was reversed in the presence of AT1R antagonist. In addition, by administering selective inhibitors we found that the effect of AT1R was driven via extracellular-signal regulated kinase, c-Jun NH2 terminal kinase and p38 mitogen-activated protein kinase pathways. These findings suggest that AT1R signaling plays a key role in cardiac differentiation of ESCs. PMID- 23933400 TI - Generation of induced pluripotent stem cells from human foetal fibroblasts using the Sleeping Beauty transposon gene delivery system. AB - Transposon gene delivery systems offer an alternative, non-viral-based approach to generate induced pluripotent stem cells (iPSCs). Here we used the Sleeping Beauty (SB) transposon to generate four human iPSC lines from foetal fibroblasts. In contrast to other gene delivery systems, the SB transposon does not exhibit an integration bias towards particular genetic elements, thereby reducing the risk of insertional mutagenesis. Furthermore, unlike the alternative transposon piggyBac, SB has no SB-like elements within the human genome, minimising the possibility of mobilising endogenous transposon elements. All iPSC lines exhibited the expected characteristics of pluripotent human cells, including the ability to differentiate to derivatives of all three germ layers in vitro. Re expression of the SB transposase in the iPSCs after reprogramming resulted in the mobilisation of some of the transposons. These results indicate that the SB transposon system is a useful addition to methods for generating human iPSCs, both for basic and applied biomedical research, and in the context of future therapeutic application. PMID- 23933401 TI - Prevalence of antibodies for the hepatitis C virus in the lowland (bajio) region of Mexico. AB - BACKGROUND AND AIMS: Infection with the hepatitis C virus (HVC) is one of the most common viral infections worldwide. Approximately 170 million individuals are infected worldwide. HCV is an important cause of morbidity and mortality. In Mexico, according to the National Health Survey 2000, it is estimated that 70,000 cases exist. We undertook this study to estimate the prevalence of anti-HCV antibodies in patients with association to the risk factors for HCV infection in the lowland (bajio) region. METHODS: There were 2803 individuals 15 years of age or older who were treated at the General Hospital Zone #4 who were included in this study. Following informed consent, the participants were given a questionnaire listing the major risk factors for hepatitis C. If they answered positive to any of these identified factors, a blood sample was taken to determine anti-HCV antibodies via ELISA analysis. RESULTS: Average age in this study was 38.4 +/- 13.5 years, and 75.5% were female (n = 2116). Anti-HCV antibodies were isolated in 1.3% of the patients (n = 36). The most commonly identified risk factor among all the participants was a history of previous transfusions (28.8 % of all patients, n = 813 and 41.7%, n = 15 of those with positive HCV antibodies). This was the only statistically significant risk factor identified in this study (p = 0.066). CONCLUSIONS: Mexico is currently considered to have a lower prevalence for HCV in relation to developed countries and other endemic areas. The figures reported are lower than those observed in this study, suggesting that the strategies for detecting HCV in Mexico may be inadequate. PMID- 23933402 TI - Synthesis, docking study and relaxant effect of 2-alkyl and 2-naphthylchromones on rat aorta and guinea-pig trachea through phosphodiesterase inhibition. AB - Chromone (4), which form the base structure of various flavonoids isolated as natural products, is capable of relaxing smooth muscle. This is relevant to the treatment of high blood pressure, asthma and chronic obstructive pulmonary disease. The former disorder involves the contraction of vascular smooth muscle (VSM), and the latter two bronchoconstriction of airway smooth muscle (ASM). One of the principal mechanisms by which flavonoids relax muscle tissue is the inhibition of phosphodiesterases (PDEs), present in both VSM and ASM. Therefore, a study was designed to analyze the structure-activity relationship of chromone derivatives in vaso- and bronchorelaxation through the inhibition of PDE. Docking studies showed that these chromones bind at the catalytic site of PDEs. Consequently, we synthesized analogs of chromones substituted at position C-2 with alkyl and naphthyl groups. These compounds were synthesized from 2 hydroxyacetophenone and acyl chlorides in the presence of DBU and pyridine, modifying the methodology reported for the synthesis of 3-acylchromones by changing the reaction temperature from 80 to 30 degrees C and using methylene chloride as solvent, yielding the corresponding phenolic esters 10a-10h. These compounds were cyclized with an equivalent of DBU, pyridine as solvent, and heated at reflux temperature, yielding the chromones 11a-11h. Evaluation of the vasorelaxant effect of 4, 11a-11h on rat aorta demonstrated that potency decreases with branched alkyl groups. Whereas the EC50 of compound 11d (substituted by an n-hexyl group) was 8.64+/-0.39 MUM, that of 11f (substituted by an isobutyl group) was 14.58+/-0.64 MUM. Contrarily, the effectiveness of the compound is directly proportional to the length of the alkyl chain, as evidenced by the increase in maximal effect of compound 11c versus 11d (66% versus 100%) and 11e versus 11f (60% versus 96%). With an aromatic group like naphthyl as the C-2 substituent, the effectiveness was only 43%. All compounds tested on guinea pig trachea showed less than 55% effectiveness. Compounds 4, 11a-11h were evaluated as PDE inhibitors in vitro, with 11d showing the greatest effect (73%), corroborating the importance of a long alkyl chain, which inhibits the decomposition of cGMP. Docking studies showed that the compound 11d was selective for the inhibition of PDE-5. PMID- 23933403 TI - Association of MCP-1 -2518A/G and -362G/C variants and tuberculosis susceptibility: a meta-analysis. AB - A number of studies have found that the -2518A/G and -362G/C polymorphisms in the monocyte chemoattractant protein-1 (MCP-1) gene are implicated in the susceptibility to tuberculosis. However, the results are inconsistent. To investigate the relationship between -2518A/G and -362G/C polymorphisms in MCP-1 gene and the susceptibility of tuberculosis, a systematic literature search for relevant articles published up to January, 2013 was conducted in the databases of PubMed, Elsevier, Web of Science, Wanfang and CNKI. A total number of twenty-two case-control studies that included 9365 cases and 10149 controls on two single nucleotide polymorphisms (SNPs): -2518A/G and -362G/C, were identified. The results indicated that the G allele of -2518A/G polymorphism was associated with increased risk of tuberculosis (GG vs. AA+AG: OR 1.455, 95% CI 1.092-1.937, P = 0.01). In the subgroup analysis by ethnicity, significant elevated risks were found in Asians and Americans, but not in Africans. The C allele of -362G/C polymorphism was associated with resistance to tuberculosis (CC vs. GG+GC: OR 0.837, 95% CI 0.772-0.987, P = 0.03). This meta-analysis suggests that the G allele of -2518A/G polymorphism is a risk factor for tuberculosis in Asians and Americans, while not in Africans. It further indicates that C allele of -362G/C polymorphism is a protective factor for tuberculosis. PMID- 23933404 TI - The phylogeny and population structure of Mycobacterium bovis in the British Isles. AB - To further understand the epidemic of bovine tuberculosis in Great Britain, Northern Ireland and the Republic of Ireland, we identified 16 mutations that are phylogenetically informative for Mycobacterium bovis strains from these regions. We determined the status of these mutations among a collection of 501 strains representing the molecular diversity found in these three regions of the British Isles. The resulting linear phylogenies from each region were concordant, showing that the same lineage of M. bovis was present. The dominance of this lineage is unique within Europe, and suggests that in the past the populations were homogenous. Comparison of approximately 500 strains isolated in 2005 from each region by spoligotype and 5 locus VNTR profiling, revealed distinct differences in the genotype frequencies and sub-lineage makeup between each region. We concluded that whilst each region shared the same major phylogenetic lineage of M. bovis, more recent evolution had resulted in the development of region specific populations. Regional differences in the M. bovis populations suggest that it may be possible to identify the movement of strains from one region to another. PMID- 23933405 TI - Distinct effects of methamphetamine on autophagy-lysosome and ubiquitin proteasome systems in HL-1 cultured mouse atrial cardiomyocytes. AB - The aim of this study is to investigate the molecular mechanism underling the cardiotoxicity of methamphetamine, a psychostimulant drug that is currently abused in the world. A mouse atrial cardiac cell line, HL-1, which retains phenotypes of cardiac cells and serves as a useful model for examining cardiac pathophysiology, was used for this purpose. During treatment with 1mM methamphetamine (MAP) for 3-48h, massive but transient cytoplasmic vacuolization (3-12h) followed by an intracellular accumulation of granules (24-48h) was observed under light microscopy. The vacuoles were surrounded by the lysosome membrane marker LAMP1, while the granules colocalized with the autophagy markers LC3 and p62 as well as ubiquitinated proteins. Western blot analysis showed that LC3 was activated during MAP administration, although p62 was not degraded but rather accumulated. Concordant with p62 accumulation, the nuclear translocation of an anti-oxidative transcription factor, Nrf2, and the subsequent induction of its target gene, HO-1, was observed, suggesting an impairment of autophagic protein degradation and the subsequent activation of the p62/Nrf2/HO-1 pathway. In addition, proteomic analysis revealed a reduction in myosin heavy chain (MHC) protein levels during MAP administration. The ubiquitination of MHC and the induction of the muscle sarcomere protein-specific E3 ubiquitin ligases MuRF1 and atrogin-1 were proved by immunoprecipitation and quantitative real-time PCR, respectively. Taken together, the vacuolization of lysosomes and the subsequent accumulation of autophagosomes indicate an impairment of autophagic protein degradation during MAP administration; on the other hand, the ubiquitination and subsequent degradation of MHC indicate the proper progression of proteasomal degradation. PMID- 23933406 TI - Related factors to atazanavir plasma levels in a cohort of HIV positive individuals with undetectable viral load. AB - OBJECTIVE: To evaluate the factors associated with plasma concentrations of atazanavir (ATV) in a cohort of well-controlled HIV infected subjects (undetectable viremia). DESIGN: Cross-sectional study where 69 subjects were consecutively enrolled between April and November, 2011. METHODS: Patients had to be on atazanavir for at least six months, undetectable viral load for a period equal to or longer than 12 months, T CD4+ lymphocyte count higher than 200 cells/mm(3), and aged between 18 years and 70 years old. Exclusion criteria were pregnancy, any neurologic disease, active opportunistic disease, hepatitis or cancer. Atazanavir plasma levels were measured by ultra-performance liquid chromatography. RESULTS AND DISCUSSION: Overall, 54 patients (mean age of 47 years and 50% women) were included in the analysis. Those without ritonavir (unboosted atazanavir) had statistically lower plasma concentrations than those with ritonavir boosted atazanavir (p=0.001) and total and indirect bilirubin were statistically associated with plasma concentration of atazanavir (r=0.32 and r=0.33 respectively; p<0.05 in both cases). No statistical association was found among gender, ethnicity, age, weight, body mass index (BMI), lipid profile, and the plasma concentration of atazanavir. CONCLUSION: In summary, as expected, concomitant ritonavir use was the only factor associated with atazanavir plasma levels. Prospective studies with a larger sample size might help to observe an association of atazanavir concentrations to other characteristics such as body weight, since the p-value showed to be close to significance (p=0.068). PMID- 23933407 TI - Sexually transmitted diseases among psychiatric patients in Brazil. AB - Sexually transmitted diseases are still highly prevalent worldwide and represent an important public health problem. Psychiatric patients are at increased risk of sexually transmitted diseases but there are scarce published studies with representative data of this population. We sought to estimate the prevalence and correlates of self-reported sexually transmitted diseases among patients with mental illnesses under care in a national representative sample in Brazil (n=2145). More than one quarter of the sample (25.8%) reported a lifetime history of sexually transmitted disease. Multivariate analyses showed that patients with a lifetime sexually transmitted disease history were older, had history of homelessness, used more alcohol and illicit drugs, suffered violence, perceived themselves to be at greater risk for HIV and had high risk sexual behavioral: practised unprotected sex, started sexual life earlier, had more than ten sexual partners, exchanged money and/or drugs for sex and had a partner that refused to use condom. Our findings indicate a high prevalence of self-reported sexually transmitted diseases among psychiatric patients in Brazil, and emphasize the need for implementing sexually transmitted diseases prevention programs in psychiatric settings, including screening, treatment, and behavioral modification interventions. PMID- 23933408 TI - Leprosy and hepatitis B coinfection in southern Brazil. AB - To investigate the association of leprosy with hepatitis B virus (HBV) infection, as yet unknown for South Brazil, we assessed hepatitis B virus coinfection in 199 South Brazilian leprosy patients (119 lepromatous, 15 tuberculoid, 30 borderline, 12 undetermined and 23 unspecified) and in 681 matched blood donors by screening for the hepatitis B virus markers HBSAg and anti-HBc, using ELISA. Positive samples were retested and anti-HBc+ only samples were tested for the hepatitis B surface antibody (anti-HBs). There was a strong association between leprosy and hepatitis B virus infection (OR=9.8, 95% CI=6.4-14.7; p=0.004 . E(-30)), as well as an association between HBV infection and lepromatous leprosy, compared to other forms (OR=2.4, 95% CI=1.2-4.8; p=0.017). We also found that confinement due to leprosy was associated with hepatitis B virus infection (OR=3.9, 95% CI=2.1 7.4; p=0.015 . E(-3)). Leprosy patients are susceptible to develop hepatitis B virus infection, especially lepromatous. Institutionalized patients, who probably present a stronger Th2 response, have higher risk of being exposed to hepatitis B virus. This clearly emphasizes the need for special care to leprosy patients in preventing hepatitis B virus coinfection in South Brazil. PMID- 23933409 TI - Modified immunoslotblot assay to detect hemi and sulfur mustard DNA adducts. AB - Sulfur mustard (SM) is an old chemical warfare agent causing blisters (vesicant). Skin toxicity is thought to be partly caused by SM induced DNA damage. SM and the hemi mustard 2-chloroethyl ethyl sulfide (CEES) are bi- and monofunctional DNA alkylating agents, respectively. Both chemicals react especially with N7 guanine. The most abundant adducts are 7-hydroxyethylthioethylguanine for SM (61%) and 7 ethyl thioethylguanine for CEES. Thus, DNA alkylation should serve as a biomarker of SM exposure. A specific monoclonal antibody (2F8) was previously developed to detect SM and CEES adducts at N7 position by means of immunoslotblot (ISB) technique (van der Schans et al. (2004) [16]). Nitrogen mustards (HN-1, HN-2, HN 3) are alkylating agents with structural similarities, which can form DNA adducts with N7 guanine. The aim of the presented work was to modify the van der Schans protocol for use in a field laboratory and to test the cross reactivity of the 2F8 antibody against nitrogen mustards. Briefly, human keratinocytes were exposed to SM and CEES (0-300MUM, 60min) or HN-1, HN-2, HN-3 (120min). After exposure, cells were scraped and DNA was isolated and normalized. 1MUg DNA was transferred to a nitrocellulose membrane using a slotblot technique. After incubation with 2F8 antibody, the DNA adducts were visualized with chromogen staining (3,3' diaminobenzidine (DAB), SeramunGrun). Blots were photographed and signal intensity was quantified. In general, DAB was superior to SeramunGrun stain. A staining was seen from 30nM to 300MUM of SM or CEES, respectively. However, statistically significant DNA adducts were detected after CEES and SM exposure above 30MUM which is below the vesicant threshold. No signal was observed after HN-1, HN-2, HN-3 exposure. The total hands-on time to complete the assay was about 36h. Further studies are necessary to validate SM or CEES exposure in blister roofs of exposed patients. PMID- 23933410 TI - In vitro glutathione peroxidase mimicry of ebselen is linked to its oxidation of critical thiols on key cerebral suphydryl proteins - A novel component of its GPx mimic antioxidant mechanism emerging from its thiol-modulated toxicology and pharmacology. AB - The antioxidant mechanism of ebselen in rats brain is largely linked with its glutathione peroxidase (GPx) rather than its peroxiredoxin mimicry ability. However, the precise molecular dynamics between the GPx-mimicry of ebselen and thiol utilization is yet to be fully clarified and thus still open. Herein, we investigated the influence of dithiothreitol (DTT) on the antioxidant action of ebselen against oxidant-induced cerebral lipid peroxidation and deoxyribose degradation. Furthermore, the critical inhibitory concentrations of ebselen on the activities of sulphydryl enzymes such as cerebral sodium pump, delta aminolevulinic acid dehydratase (delta-ALAD) and lactate dehydrogenase (LDH) were also investigated. We observe that ebselen (at >=42 MUM) markedly inhibited lipid peroxidation in the presence and absence of DTT, whereas it inhibited deoxyribose degradation only in the presence of DTT. Furthermore, under in vitro conditions, ebselen inhibited the thiol containing enzymes; cerebral sodium pump (at >=40 MUM), delta-ALAD (>=10 MUM) and LDH (>=1 MUM) which were either prevented or reversed by DTT. However, the inhibition of the activities of these sulphydryl proteins in diabetic animals was prevented by ebselen. Summarily, it is apparent that the effective in vitro inhibitory doses of ebselen on the activity of the sulphydryl proteins are far less than its antioxidant doses. In addition, the presence of DTT is evidently a critical requirement for ebselen to effect its antioxidant action against deoxyribose degeradation and not lipid peroxidation. Consequently, we conclude that ebselen possibly utilizes available thiols on sulphydryl proteins to effect its GPx mimicry antioxidant action against lipid peroxidation in rat brain homogenate. PMID- 23933411 TI - Mesenchymal stem cells are highly resistant to sulfur mustard. AB - The effect of sulfur mustard (SM) to the direct injured tissues of the skin, eyes and airways is well investigated. Little is known about the effect of SM to mesenchymal stem cells (MSC). However, this is an interesting aspect. Comparing the clinical picture of SM it is known today that MSC play an important role e.g. in chronic impaired wound healing. Therefore we wanted to get an understanding about how SM affects MSC and if these findings might become useful to get a better understanding of the effect of sulfur mustard gas with respect to skin wounds. We used mesenchymal stem cells, isolated from femoral heads from healthy donors and treated them with a wide range of SM to ascertain the dose-response curve. With the determined inhibitory concentrations IC1 (1MUM), IC5 (10MUM), IC10 (20MUM) and IC25 (40MUM) we did further investigations. We analyzed the migratory ability and the differentiation capacity under influence of SM. Already very low concentrations of SM demonstrated a strong effect to the migratory activity whereas the differentiation capacity seemed not to be affected. Putting these findings together it seems to be likely that a link between MSC and the impaired wound healing after SM exposure might exist. Same as in patients with chronic impaired wound healing MSC had shown a reduced migratory activity. The fact that MSC are able to tolerate very high concentrations of SM and still do not lose their differentiation capacity may reveal new ways of treating wounds caused by sulfur mustard. PMID- 23933412 TI - Mosaic small supernumerary marker chromosome 1 at amniocentesis: prenatal diagnosis, molecular genetic analysis and literature review. AB - We present prenatal diagnosis and molecular cytogenetic analysis of mosaic small supernumerary marker chromosome 1 [sSMC(1)]. We review the literature of sSMC(1) at amniocentesis and chromosome 1p21.1-p12 duplication syndrome. We discuss the genotype-phenotype correlation of the involved genes of ALX3, RBM15, NTNG1, SLC25A24, GPSM2, TBX15 and NOTCH2 in this case. PMID- 23933413 TI - Prediction value of intercellular adhesion molecule-1 gene polymorphisms for epithelial ovarian cancer risk, clinical features, and prognosis. AB - Intercellular adhesion molecule-1 (ICAM-1, encoded by ICAM-1) is implicated in tumorigenesis and tumor progression. ICAM-1 modulates the susceptibility to several types of cancer and the disease prognosis; however, its role in epithelial ovarian cancer (EOC) is unclear. Here, we evaluate single nucleotide polymorphisms (SNPs) in ICAM-1 as predictors of EOC risk and prognosis. Six ICAM 1 polymorphisms were genotyped in 408 patients with EOC and 520 controls using the MassARRAY system. The ICAM-1 mRNA levels in 89 EOC tissues and 35 normal ovarian tissues were examined using quantitative PCR. The ICAM-1 rs5498 G allele was associated with increased tumor grade (OR=2.650) and EOC risk (OR=1.405). This risk was more evident in females who had first-degree relatives (FDRs) with a tumor (OR=3.475) or who experienced early menarche (OR=2.774). The ICAM-1 expression in the cancerous tissue was elevated compared with that of normal ovarian tissues (p<0.0001), and it was associated with an rs5498 genotype (p=0.0002). ICAM-1 SNPs did not significantly predict the overall EOC survival (p>0.05). However, the rs5498 G allele correlated with EOC survival time in patients whose FDRs suffered from a tumor (p=0.001). ICAM-1 rs5498 likely confers a high risk for EOC in G allele carriers accompanied by up-regulation of ICAM-1 expression during carcinogenesis. The combination of ICAM-1 rs5498 and tumor history predicts the EOC prognosis. PMID- 23933414 TI - MTHFR C677T and A1298C gene polymorphisms and their relation to homocysteine level in Egyptian children with congenital heart diseases. AB - OBJECTIVE: To investigate the association of combined MTHFR C677T and A1298C gene polymorphisms with congenital heart diseases (CHD) in Egyptian children and their mothers and to determine their effect on homocysteine level in these children. MATERIAL AND METHODS: MTHFR C677T and A1298C polymorphisms were genotyped in 160 Egyptian children (80 patients with CHD and 80 healthy controls) and their mothers using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), while, homocysteine (Hcy) level was measured optically by enzymatic method. RESULTS: We found that MTHFR 677TT genotype, T allele, 1298CC genotype, and C allele were associated with 2.61, 2.0, 2.91 and 1.99 fold increased risk of CHD in Egyptian children respectively. Furthermore, the frequencies of MTHFR 1298AC and CC genotypes and C allele significantly increased in mothers with CHD affected children. The homocysteine levels were significantly increased in MTHFR 677TT and 1298CC genotypes in children with CHD. CONCLUSIONS: Our study demonstrated an association of MTHFR A1298C polymorphisms with CHD in Egyptian children and their mothers, while, MTHFR C677T polymorphisms were significantly associated with the risk of CHD in the children only. An association between combined MTHFR A1298C and C677T polymorphisms and CHD was recorded in the children and their mothers. Also, homocysteine levels were significantly increased with both MTHFR 677TT and 1298CC genotypes in Egyptian children with CHD. PMID- 23933415 TI - Identification of dysregulated microRNAs in lymphocytes from children with Down syndrome. AB - Given the important roles of miRNAs in post-transcriptional regulation and its implications for the development of immune tissues and cells, characterization of miRNAs promotes us to uncover the molecular mechanisms underlying the pathway of trisomic chromosome 21 that disrupts the disomic genes expression and immunological defects related to Down syndrome (DS). In the present study, we analyzed global changes and chromosome distribution characteristics of miRNAs expression in lymphocytes from children with trisomy 21 by means of the Illumina high-throughput sequencing technology. Two small libraries were constructed using pool RNA of normal and DS children. The results have been further validated by stem-loop quantitative RT-PCR. Comparison between DS and normal profiles revealed that most of identified miRNAs were expressed at similar levels. The chromosome 21 that contributes to the abundantly expressed miRNAs was small, and not all Hsa21-derived miRNAs were over-expressed with ratios significantly >= 1.5 in Down syndrome children lymphocytes. Based on the deep sequencing technology, 108 novel candidate miRNAs have been identified, and 2 of them were derived from human chromosome 21. For the 114 significantly differentially expressed miRNAs, function annotation of target genes indicated that a set of highly abundantly and significantly differentially expressed miRNAs were involved in hematopoietic or lymphoid organ development, thymus development, and T/B cell differentiation and activation. Our results indicated that these abnormally expressed miRNAs might be associated with the mechanisms that trisomy 21 results in dysregulation of disomic genes and involved in the immunological defects seen in DS. PMID- 23933416 TI - An interstitial deletion of 8q23.3-q24.22 associated with Langer-Giedion syndrome, Cornelia de Lange syndrome and epilepsy. AB - We present a 19-year-old male with laxity of skin and joints, sparse scalp hair, facial dysmorphism, epilepsy, multiple exostoses, scoliosis, gastroesophageal reflux, cardiovascular defects, and an 8q23.3-q24.22 deletion detected by array comparative genomic hybridization. The patient was previously misdiagnosed as having Ehlers-Danlos syndrome. However, his clinical findings are in fact correlated with trichorhinophalangeal syndrome type II/Langer-Giedion syndrome and Cornelia de Lange syndrome-4. We discuss the genotype-phenotype correlation and the consequence of haploinsufficiency of TRPS1, RAD21, EXT1 and KCNQ3 in this case. PMID- 23933417 TI - Prenatal diagnosis and molecular cytogenetic characterization of mosaic ring chromosome 13. AB - We present prenatal diagnosis and molecular cytogenetic characterization of de novo mosaic r(13). A 32-year-old woman underwent amniocentesis at 18 weeks of gestation because of maternal anxiety. Amniocentesis revealed a karyotype of 46,XY,r(13)[33]/45,XY,-13[19]. aCGH on uncultured amniocytes at repeated amniocentesis detected a 4.22-Mb deletion at 13q34. Interphase FISH on 100 uncultured amniocytes showed the ratio of r(13):-13:idic r(13) as 85%:13%:2%. The cord blood had a karyotype of 46,XY,r(13)[91]/46,XY,idic r(13)[6]/45,XY,-13[3]. The placenta had a karyotype of 46,XY,mar(13)[31]/45,XY,-13[3]. Metaphase FISH confirmed that the marker chromosomes in placenta were derived from chromosome 13. aCGH on cultured placental cells detected a 77.81-Mb deletion at 13q13.3-q34. The fetus postnatally manifested facial dysmorphism. Prenatal diagnosis of r(13) should alert mosaicism for deletion/duplication of r(13) and distal 13q deletion. Fetoplacental chromosomal discrepancy of r(13) may exist in case of mosaic r(13) detected by amniocentesis. PMID- 23933418 TI - Promoter polymorphisms in trefoil factor 2 and trefoil factor 3 genes and susceptibility to gastric cancer and atrophic gastritis among Chinese population. AB - The polymorphisms in trefoil factor (TFF) gene family that protect gastrointestinal epithelium might influence individual vulnerability to gastric cancer (GC) and atrophic gastritis. We used the Sequenom MassARRAY platform to identify the genotypes of TFF2 rs3814896 and TFF3 rs9981660 polymorphisms in 478 GC patients, 652 atrophic gastritis patients, and 724 controls. For the TFF2 rs3814896 polymorphism, in the subgroup aged <= 50 years, we found that AG+GG genotypes were associated with a 0.746-fold decreased risk of atrophic gastritis [p=0.023, 95% confidence interval (CI)=0.580-0.960], a 0.626-fold decreased risk of GC (p=0.005, 95% CI=0.451-0.868), and a 0.663-fold decreased risk of diffuse type GC (p=0.034, 95% CI=0.452-0.970) compared with the common AA genotype. For the TFF3 rs9981660 polymorphism, in the male subgroup, individuals with variant AG+AA genotype were associated with a 0.761-fold decreased risk of diffuse-type GC compared with the common GG genotype (p=0.043, 95% CI=0.584-0.992). Additionally, we found that in subjects aged <= 50 years compared with common AA genotype, TFF2 rs3814896 AG+GG genotypes were associated with increased TFF2 mRNA levels in the total gastric cancer specimens and in the diffuse-type gastric cancer specimens; and in males aged <= 50 years compared with common GG genotype, TFF3 rs9981660 AA+AG genotypes were associated with TFF3 mRNA levels in diffuse type gastric cancer tissues and their corresponding non-cancerous tissues. To our knowledge, this is the first report of an association between the TFF2 rs3814896 AG+GG genotypes and decreased risks of GC, diffuse-type GC, and atrophic gastritis in younger people aged <= 50 years, and an association between TFF3 rs9981660 AG+AA genotype and decreased risk of diffuse-type GC in men. Moreover, we found that TFF2 rs3814896 AG+GG genotypes in people aged <= 50 years and TFF3 rs9981660 AG+AA genotypes in younger males with diffuse-type GC were associated with higher levels of TFF2 and TFF3 mRNA respectively. PMID- 23933419 TI - Polymorphism of angiotensinogen gene M235T in myocardial infarction and brain infarction: a meta-analysis. AB - The angiotensinogen (AGT) gene M235T polymorphism has been reported to be associated with myocardial infarction (MI) and brain infarction (BI), but the results remain inconclusive. This meta-analysis was designed to clarify these controversies. Electronic databases were systematically searched before February 2013. A total of 38 studies with 17304 subjects met our inclusion criteria. In East Asian group, significant association was found between AGT M235T polymorphism and risk of MI (for dominant model: OR=1.79; 95% CI=1.04-3.06; for recessive model OR=2.01; 95% CI=1.21-3.36; for additive model OR=1.79; 95% CI=1.14-2.86) as well as BI (for dominant model: OR=1.66; 95% CI=1.22-2.27; for recessive model OR=1.78, 95% CI=1.29-2.46; for additive model: OR=1.64, 95% CI=1.34-2.00), while the M235T polymorphism did not impact the risk of MI in total population and other ethnicity. In the subgroup analyses by gender and age, there was lack of evidence for the association. This meta-analysis suggested an association between the M235T polymorphism and MI as well as BI in East Asian population. Further studies with larger numbers of worldwide participants are needed to understand the genetic basis of MI and BI. PMID- 23933420 TI - Chinese goose (Anser cygnoides) CD8a: cloning, tissue distribution and immunobiological in splenic mononuclear cells. AB - CD8 molecule is a cell membrane glycoprotein, which plays an important role in cell-mediated immunity. Here, we identified Chinese goose CD8alpha (goCD8alpha) gene for the first time. The full-length cDNA of goCD8alpha is 1459bp in length and contains a 711bp open reading frame. Phylogenetic analysis shows that the waterfowl CD8alpha formed a monophyletic group. Semi-quantitative RT-PCR analysis showed that transcripts of goCD8alpha mRNA were high in the immune-related organs and mucosal immune system in gosling, and high in thymus and spleen comparing to other immune-related tissues in goose. The obvious increase of CD8alpha expression was observed in spleen of acute new type gosling viral enteritis virus (NGVEV) infected bird, while the increase of CD8alpha were observed in the thymus, bursa of fabricius, and cecum of chronic infected bird. The CD8alpha mRNA transcription level in spleen mononuclear cells was significantly up-regulated when stimulated by phytohemagglutinin, but not by lipopolysaccharide in vitro. PMID- 23933421 TI - Culicoides biting midges, arboviruses and public health in Europe. AB - The emergence of multiple strains of bluetongue virus (BTV) and the recent discovery of Schmallenberg virus (SBV) in Europe have highlighted the fact that exotic Culicoides-borne arboviruses from remote geographic areas can enter and spread rapidly in this region. This review considers the potential for this phenomenon to impact on human health in Europe, by examining evidence of the role of Culicoides biting midges in the zoonotic transmission and person-to-person spread of arboviruses worldwide. To date, the only arbovirus identified as being primarily transmitted by Culicoides to and between humans is Oropouche virus (OROV). This member of the genus Orthobunyavirus causes major epidemics of febrile illness in human populations of South and Central America and the Caribbean. We examine factors promoting sustained outbreaks of OROV in Brazil from an entomological perspective and assess aspects of the epidemiology of this arbovirus that are currently poorly understood, but may influence the risk of incursion into Europe. We then review the secondary and rarely reported role of Culicoides in the transmission of high-profile zoonotic infections, while critically reviewing evidence of this phenomenon in endemic transmission and place this in context with the presence of other potential vector groups in Europe. Scenarios for the incursions of Culicoides-borne human-to-human transmitted and zoonotic arboviruses are then discussed, along with control measures that could be employed to reduce their impact. These measures are placed in the context of legislative measures used during current and ongoing outbreaks of Culicoides-borne arboviruses in Europe, involving both veterinary and public health sectors. PMID- 23933422 TI - A home-based training program improves caregivers' skills and dementia patients' aggressive behaviors: a randomized controlled trial. AB - OBJECTIVE: To investigate the effects of an individualized, home-based caregiver training program for caregivers of elderly patients with dementia and behavioral problems. METHODS: Using a randomized clinical trial in the neurologic clinics of two hospitals and a community care management center in northern Taiwan, we tested an individualized home-based caregiver-training program for managing behavioral problems, with referrals to community services and telephone consultation. Participants were patients with dementia and their caregivers (N = 129): 63 in the intervention group and 66 in the control group. The control group received only written instructions and social telephone follow-ups. Behavioral problems of elderly dementia patients were assessed by the Chinese version of the Cohen-Mansfield Agitation Inventory, community form. Family caregivers' outcomes were measured by the Agitation Management Self-efficacy Scale and the Preparedness and Competence Scales. These instruments were administered before the program and 2 weeks, 3 months, and 6 months afterward. RESULTS: Family caregivers who received the individualized home-based training program had better preparedness (t = 2.72, df = 127, p <0.01), competence (t = 4.77, df = 126, p <0.001), and overall self-efficacy (t = 3.81, df = 127, p <0.001) at 3 months than those in the control group. Moreover, the growth rate by treatment interaction effect was significant for caregiver competence (t = 2.25, df = 127, p <0.05) and overall self-efficacy for managing behavioral problems (t = 2.16, df = 127, p <0.05). The probability of physically aggressive behavior for patients in the intervention group decreased from 0.27 to 0.12. CONCLUSION: Our individualized home-based caregiver-training program improved caregivers' preparedness, competence, and self-efficacy for managing problematic behaviors and decreased physical aggressiveness of elderly patients with dementia. PMID- 23933423 TI - Health outcomes and cost of care among older adults with schizophrenia: a 10-year study using medical records across the continuum of care. AB - OBJECTIVES: The population of older patients with schizophrenia is increasing. This study describes health outcomes, utilization, and costs over 10 years in a sample of older patients with schizophrenia compared with older patients without schizophrenia. METHODS: An observational cohort study of 31,588 older adults (mean age: 70.44 years) receiving care from an urban public health system, including a community mental health center, during 1999-2008. Of these, 1,635 (5.2%) were diagnosed with schizophrenia and 757 (2.4%) had this diagnosis confirmed in the community mental health center. Patients' electronic medical records were merged with Medicare claims, Medicaid claims, the Minimum Dataset, and the Outcome and Assessment Information Set. Information on medication use was not available. MEASUREMENTS: Rates of comorbid conditions, healthcare utilization, costs, and mortality. RESULTS: Patients with schizophrenia had significantly higher rates of congestive heart failure (45.05% versus 38.84%), chronic obstructive pulmonary disease (52.71% versus 41.41%), and hypothyroidism (36.72% versus 26.73%) than the patients without schizophrenia (p <0.001). They had significantly lower rates of cancer (30.78% versus 43.18%) and significantly higher rates of dementia (64.46% versus 32.13%). The patients with schizophrenia had significantly higher mortality risk (hazard ratio: 1.25, 95% confidence interval: 1.07-1.47) than the patients without schizophrenia. They also had significantly higher rates of healthcare utilization. The mean costs for Medicare and Medicaid were significantly higher for the patients with schizophrenia than for the patients without schizophrenia. CONCLUSIONS: The management of older adult patients with schizophrenia is creating a serious burden for our healthcare system, requiring the development of integrated models of healthcare. PMID- 23933424 TI - Differences between suicide attempters and nonattempters in depressed older patients: depression severity, white-matter lesions, and cognitive functioning. AB - OBJECTIVES: The population of older adults with major depressive disorder (MDD) has the highest rate of suicide. White-matter brain lesions (WML) are a potential biologic marker for suicidality in young and middle-aged adults and are correlated with cognitive impairment in older adults. In this study of older patients with MDD, we examined 1) if a history of suicide attempts was associated with a more severe course of MDD; 2) if WML are a biologic marker for suicide; and 3) if suicide attempt history is associated with cognitive impairment mediated by WML. SETTING: Data from the Neurocognitive Outcomes of Depression in the Elderly study. PARTICIPANTS: Depressed patients (60+) who had ever attempted suicide (n = 23) were compared with depressed patients (60+) who had not attempted suicide (n = 223). MEASUREMENTS: Baseline and follow-up assessments were obtained for depressive symptoms (every 3 months) and cognitive functioning (every 6 months) over 2 years. Three magnetic resonance imaging scans were conducted. RESULTS: At baseline, suicide attempters reported more severe past and present symptoms (e.g., depressive symptoms, current suicidal thoughts, psychotic symptoms, earlier age of onset, and more lifetime episodes) than nonattempters. Suicide attempters had more left WML at baseline, and suicide attempt history predicted a greater growth in both left and right WML. WML predicted cognitive decline; nonetheless, a history of suicide attempt was unrelated to cognitive functioning. CONCLUSIONS: Severity of depressive symptoms and WML are associated with suicide attempts in geriatric depressed patients. Suicide attempts predicted neurologic changes, which may contribute to poorer long-term outcomes in elder attempters. PMID- 23933425 TI - Influence of social environment on loneliness in older adults: Moderation by polymorphism in the CRHR1. AB - OBJECTIVE: Both adverse social environments and genetic factors contribute to loneliness in old age. Mixed findings between older adults' social relations with their children and their levels of loneliness suggested that a gene * social environment interaction may be operating. We examine whether the effects of infrequent contact with children and low levels of perceived social support from children on loneliness in older adults are moderated by two candidate single nucleotide polymorphisms (i.e., rs1876831 and rs242938) in the corticotrophin releasing hormone receptor 1 (CRHR1) gene. DESIGN: This was a longitudinal observational study. SETTING: and PARTICIPANTS: A population-based sub-sample of 1,374 community-dwelling older adults aged 65 years and older was examined from both the 2003-2004 and 2006-2007 English Longitudinal Study of Aging assessments. MEASUREMENTS: Our main outcome measure is loneliness, which was assessed by four items extracted from the ULCA loneliness scale. RESULTS: Compared with older adults carrying the CT/TT genotypes, individuals homozygous for the C allele of rs1876831 reported higher levels of loneliness in the context of infrequent social contact with children and lower levels of perceived social support from children. No gene * social environment interactions were found for loneliness between rs242938 and an adverse social environment related to children. CONCLUSIONS: This study provides the first evidence in humans that the CRHR1 gene interacts with exposure to a negative social environment to predict loneliness in older adults. PMID- 23933426 TI - The anti-apoptotic and neuro-protective effects of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) on acute optic nerve injury is transient. AB - Progressive death of retinal ganglion cells (RGCs) is a major cause of irreversible visual impairment after optic nerve injury. Clinically, there are still no effective treatments for recovering the visual function at present. The probable approaches to maintain the vision and RGCs function involve in preventing RGCs from death and/or promoting the regeneration of damaged RGCs. Previous studies have shown that mesenchymal stem cells (MSCs) take neuroprotective effects on ischemia-induced cortical and spinal cord injury, however, whether MSCs have a beneficial effect on the optical nerve injury is not clearly determined. In present study, we transplanted MSCs derived from human umbilical cord blood (hUCB-MSCs) into the vitreous cavity of adult rats and investigated the probable capacity of anti-apoptosis and pro-neuroprotective effects on RGCs. RGCs were retrogradely traced by fluorescent gold particles (FG); cellular apoptosis was investigated by caspase-3 immunohistochemistry and terminal dUTP nick end labeling (TUNEL) staining. Hematoxylin-eosin (HE) staining was used to observe the morphological changes of the retina. Growth associated protein 43 (GAP-43), an established marker for axonal regeneration, was used to visualize the regenerative process over time. Expression of P2X7 receptors (P2X7R), which are responsible for inflammatory and immune responses, was also monitored in our experiments. We found that the hUCB-MSC transplantation significantly decreased cellular apoptosis and promoted the survival of RGCs in early phase. However, this protection was transient and the RGCs could not be protected from death in the end. Consistent with apoptosis detection, P2X7R was also significantly decreased in hUCB-MSC transplanted rats in the early time but without obvious difference to the rats from control group in the end. Thus, our results imply that hUCB-MSCs take anti-apoptotic, pro-neuroregenerative and anti inflammatory effects in the early time for acute optic nerve injury in adult rats but could not prevent RGCs from death eventually. PMID- 23933427 TI - Differential arsenic binding in the sediments of two sites in Chile's lower Loa River basin. AB - Fluvial sediments from two lower Loa River basin sites in northern Chile were compared in order to probe the effects of vegetation and organic matter (OM) on As accumulation in fluvial environments. The two sites were the Sloman dam, which lacks macrophytes and has a low OM content (2.4%) in sediments, and the Quillagua Oasis, which is 23 km downstream from the Sloman site and has a higher OM (6.2%) in sediments and abundant aquatic plant life. The Quillagua site had preferential As enrichment with a co-occurrence pattern that differed from that of the Sloman site, which had a lower As concentration (1528 vs. 262 mg/kg d.w., respectively). At the Quillagua site, As concentration was strongly correlated with Mn and OM (r = 0.91 and 0.85, respectively); while at the Sloman site, As concentration in sediments was significantly correlated with Ca and Sr (r = 0.63 and 0.54, respectively). Sequential extraction analyses showed that the Sloman site had higher percentage of easily exchangeable As within the surface sediment (12%, 45 mg/kg d.w.) compared with the Quillagua site (3%, 40 mg/kg d.w.). These contrasting results suggest that both vegetation and OM control the immobilization and accumulation of As in the arid Loa River basin. PMID- 23933428 TI - Detection of vancomycin-resistant enterococci (VRE) at four U.S. wastewater treatment plants that provide effluent for reuse. AB - Vancomycin-resistant enterococci (VRE), a leading cause of hospital-acquired infections, can occur in wastewater. However, to date, no previous studies have evaluated the occurrence of VRE at wastewater treatment plants (WWTPs) that send their treated effluent to reuse sites. We evaluated the occurrence, concentration, and antimicrobial resistance patterns of VRE at U.S. WWTPs associated with reuse sites. We collected 44 wastewater samples, representing treatment steps from influent to effluent, from two Mid-Atlantic and two Midwest WWTPs between October 2009 and October 2010. Samples were analyzed for total enterococci and VRE using membrane filtration. Isolates were confirmed using biochemical tests and PCR. Antimicrobial susceptibility testing was performed by Sensititre microbroth dilution. Data were analyzed by two-sample proportion tests and analysis of variance. We detected VRE in 27% (12/44) of all wastewater samples collected and VRE represented 3% of total enterococci detected at all WWTPs. More samples were VRE-positive from the Mid-Atlantic compared to the Midwest WWTPs (p=0.008). VRE concentrations decreased as treatment progressed at all WWTPs, except at Mid-Atlantic WWTP1 where there was an increase in VRE concentrations in activated sludge reactor samples. VRE were not detected in chlorinated effluent, but were detected in one un-chlorinated effluent sample. All unique VRE isolates were multidrug resistant. Fifty-five percent (12/22) of the isolates displayed high-level aminoglycoside resistance. Our findings show that chlorination reduces the occurrence of VRE in wastewater. However, WWTP workers could be exposed to VRE during wastewater treatment. Our data also raise potential concerns about VRE exposure among individuals who come into contact with un-chlorinated reclaimed water. PMID- 23933429 TI - Investigation of PPCPs in wastewater treatment plants in Greece: occurrence, removal and environmental risk assessment. AB - In the present work, an extensive study on the presence of eighteen pharmaceuticals and personal care products (PPCPs) in eight wastewater treatment plants (WWTPs) of Greece has been conducted. The study covered four sampling periods over 1-year, where samples (influents; effluents) from eight WWTPs of various cities in Greece were taken. All WWTPs investigated are equipped with conventional activated sludge treatment. A common pre-concentration step based on SPE was applied, followed by LC-UV/Vis-ESI-MS. Further confirmation of positive findings was accomplished by using LC coupled to a high resolution Orbitrap mass spectrometer. The results showed the occurrence of all target compounds in the wastewater samples with concentrations up to 96.65 MUg/L. Paracetamol, caffeine, trimethoprim, sulfamethoxazole, carbamazepine, diclofenac and salicylic acid were the dominant compounds, while tolfenamic acid, fenofibrate and simvastatin were the less frequently detected compounds with concentrations in effluents below the LOQ. The removal efficiencies showed that many WWTPs were unable to effectively remove most of the PPCPs investigated. Finally, the study provides an assessment of the environmental risk posed by their presence in wastewaters by means of the risk quotient (RQ). RQs were more than unity for various compounds in the effluents expressing possible threat for the aquatic environment. Triclosan was found to be the most critical compound in terms of contribution and environmental risk, concluding that it should be seriously considered as a candidate for regulatory monitoring and prioritization on a European scale on the basis of realistic PNECs. The results of the extensive monitoring study contributed to a better insight on PPCPs in Greece and their presence in influent and effluent wastewaters. Furthermore, the unequivocal identification of two transformation products of trimethoprim in real wastewaters by using the advantages of the LTQ Orbitrap capabilities provides information that should be taken into consideration in future PPCP monitoring studies in wastewaters. PMID- 23933430 TI - Improvement of the R-SWAT-FME framework to support multiple variables and multi objective functions. AB - Application of numerical models is a common practice in the environmental field for investigation and prediction of natural and anthropogenic processes. However, process knowledge, parameter identifiability, sensitivity, and uncertainty analyses are still a challenge for large and complex mathematical models such as the hydrological/water quality model, Soil and Water Assessment Tool (SWAT). In this study, the previously developed R program language-SWAT-Flexible Modeling Environment (R-SWAT-FME) was improved to support multiple model variables and objectives at multiple time steps (i.e., daily, monthly, and annually). This expansion is significant because there is usually more than one variable (e.g., water, nutrients, and pesticides) of interest for environmental models like SWAT. To further facilitate its easy use, we also simplified its application requirements without compromising its merits, such as the user-friendly interface. To evaluate the performance of the improved framework, we used a case study focusing on both streamflow and nitrate nitrogen in the Upper Iowa River Basin (above Marengo) in the United States. Results indicated that the R-SWAT-FME performs well and is comparable to the built-in auto-calibration tool in multi objective model calibration. Overall, the enhanced R-SWAT-FME can be useful for the SWAT community, and the methods we used can also be valuable for wrapping potential R packages with other environmental models. PMID- 23933431 TI - Spring geochemistry in an active volcanic environment (Sao Miguel, Azores): source and fluxes of inorganic solutes. AB - Mineral waters were monthly sampled in selected springs from Furnas and Fogo trachytic central volcanoes (Sao Miguel, Azores, Portugal). Water temperatures between 15.1 degrees C and 90.2 degrees C, characterize poorly mineralized waters of Na-HCO3 and Na-HCO3-Cl types. According to the spring location, two watersheds were selected in each volcano to evaluate solute fluxes and chemical weathering rates (Fogo volcano: Ribeira Grande river - RRG; Furnas volcano: Ribeira Quente river - RRQ). Na, Mg, K and Ca fluxes in groundwater represented 43%, 60%, 46% and 57% of the total (subsurface plus surface fluxes) in RRG, and respectively 43%, 53%, 46% and 49% in RRQ. Average HCO3 flux is ten times higher in RRQ (130.1 * 10(6) mol/yr) compared to RRG (13.8 * 10(6) mol/yr), reflecting the volcano degassing and the lower ratio between groundwater and river water fluxes. Based on these values, total CO2-consumption by weathering ranged from 1.5 * 10(6)mol/km(2)/yr (RRG) to 4 * 10(6)mol/km(2)/yr (RRQ). TDS load varied between 3772 t/yr (RRG) and 15388 t/yr (RRQ), and the ratio between values in groundwater and in surface water is respectively equal to 0.72 and 2.04. The associated chemical weathering rates in groundwater were 206 t/km(2)/yr (RRG) and 399 t/km(2)/yr (RRQ). Coupled to river water, these values indicate that total chemical weathering rates are respectively equal to 493 t/km(2)/yr and 594 t/km(2)/yr. A similar approach developed for the entire archipelago showed that the chemical weathering rates due to groundwater are in the range from 33 to 321 t/km(2)/yr, being partially controlled by the age of the islands. Results of the present study point out to the need to consider groundwater solute fluxes due to weathering when establishing geochemical budgets. PMID- 23933432 TI - Natural attenuation process via microbial oxidation of arsenic in a high Andean watershed. AB - Rivers in northern Chile have arsenic (As) concentrations at levels that are toxic for humans and other organisms. Microorganism-mediated redox reactions have a crucial role in the As cycle; the microbial oxidation of As (As(III) to As(V)) is a critical transformation because it favors the immobilization of As in the solid phase. We studied the role of microbial As oxidation for controlling the mobility of As in the extreme environment found in the Chilean Altiplano (i.e., > 4000 meters above sea level (masl) and < 310 mm annual rainfall), which are conditions that have rarely been studied. Our model system was the upper Azufre River sub-basin, where the natural attenuation of As from hydrothermal discharge (pH 4-6) was observed. As(III) was actively oxidized by a microbial consortium, leading to a significant decrease in the dissolved As concentrations and a corresponding increase in the sediment's As concentration downstream of the hydrothermal source. In-situ oxidation experiments demonstrated that the As oxidation required biological activity, and microbiological molecular analysis confirmed the presence of As(III)-oxidizing groups (aroA-like genes) in the system. In addition, the pH measurements and solid phase analysis strongly suggested that the As removal mechanism involved adsorption or coprecipitation with Fe-oxyhydroxides. Taken together, these results indicate that the microorganism-mediated As oxidation contributed to the attenuation of As concentrations and the stabilization of As in the solid phase, therefore controlling the amount of As transported downstream. This study is the first to demonstrate the microbial oxidation of As in Altiplano basins and its relevance in the immobilization of As. PMID- 23933433 TI - Molecular cloning, subcelluar location and expression profile of signal transducer and activator of transcription 2 (STAT2) from turbot, Scophthalmus maximus. AB - Signal transducer and activator of transcription 2 (STAT2) is an important molecule involved in the type I interferon signalling pathway. To date, little STAT2 homologue is available in fish except Atlantic salmon and goldfish. In this paper, STAT2 was firstly cloned and characterized from turbot, a marine flatfish with high economic value. Briefly, turbot STAT2 cDNA is 3206 bp in length encoding a predicted protein of 793 amino acids. The phylogenetic tree shows that turbot STAT2 protein shared the closest relationship with Atlantic salmon. Analysis of subcellular distribution indicates that STAT2 is mainly present in the cytoplasm of TK cells. Stat2 mRNA is constitutively expressed in widespread tissues and induced by several folds in turbot tissues and TK cells after stimulation with Vibrio anguillarum and lymphocystis disease virus (LCDV). Unlike the higher vertebrate STAT2, turbot STAT2 nuclear export signal (NES) exists not in the C-terminal 79 amino acids but in N-terminal 137-312 amino acids (STAT_alpha domain). The nuclear translocation of turbot STAT2 after Poly(I:C) treatment proved its transcription activity in TK cells. All these results suggested that STAT2 may be involved in the immune response in turbot as a transcription factor. PMID- 23933435 TI - Reversible posterior leukoencephalopathy after venomous bites and stings. PMID- 23933434 TI - Antibiotic resistance gene profiling of faecal and oral anaerobes collected during an antibiotic challenge trial. AB - Here we describe a study examining the antibiotic resistance gene carriage in anaerobes collected during a clinical study. The results demonstrated that genes normally associated with anaerobes were most prevalent such as tetQ, cepA and cblA although several genes associated with Enterobacteriaceae including sul2, blaSHV and strB were also detected. PMID- 23933436 TI - Quercetin inhibits depolarization-evoked glutamate release in nerve terminals from rat cerebral cortex. AB - Quercetin, a naturally occurring flavonoid, has been reported to have a neuroprotective profile. An excessive release of glutamate is widely considered to be one of the molecular mechanisms of neuronal damage in several neurological diseases. This study investigated whether quercetin affected glutamate release in rat cerebral cortex nerve terminals (synaptosomes) and explored the possible mechanism. Quercetin inhibited the release of glutamate evoked by the K(+) channel blocker 4-aminopyridine (4-AP), and this effect was prevented by the chelating extracellular Ca(2+) ions. Quercetin decreased the depolarization induced increase in the cytosolic free Ca(2+) concentration ([Ca(2+)]C), whereas it did not alter 4-AP-mediated depolarization and Na(+) influx. The quercetin mediated inhibition of glutamate release was prevented by blocking the Cav2.2 (N type) and Cav2.1 (P/Q-type) channels, but not by blocking intracellular Ca(2+) release. Combined inhibition of protein kinase C (PKC) and protein kinase A (PKA) also prevented the inhibitory effect of quercetin on evoked glutamate release. Furthermore, quercetin decreased the 4-AP-induced phosphorylation of PKC and PKA. These results suggest that quercetin inhibits glutamate release from rat cortical synaptosomes and this effect is linked to a decrease in presynaptic voltage dependent Ca(2+) entry and to the suppression of PKC and PKA activity. PMID- 23933437 TI - Novel o-naphthoquinones induce apoptosis of EL-4 T lymphoma cells through the increase of reactive oxygen species. AB - Novel beta-lapachone analogs 2-phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ1), 2-p-tolyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ3) and 2-methyl-2 phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ7), which have trypanocidal activity, were assayed for cytotoxic effects on murine EL-4 T lymphoma cells. The NQs inhibited the proliferation of EL-4 cells at concentrations above 1MUM. Nuclear staining of the EL-4 cells revealed chromatin condensation and a nuclear morphology compatible with the induction of apoptosis. Flow cytometry assays with annexin V-FITC and propidium iodide confirmed the cell death by apoptosis. Using electron paramagnetic resonance (EPR), a semiquinone radical was detected in EL-4 cells treated with NQs. In addition, a decrease in the GSH level in parallel with reactive oxygen species (ROS) production was observed. Preincubation with n acetyl-l-cysteine (NAC) was able to reverse the inhibitory effects of the NQs on cell proliferation, indicating that ROS generation is involved in NQ-induced apoptosis. In addition, the NQs induced a decrease in the mitochondrial membrane potential and increased the proteolytic activation of caspases 9 and 3 and the cleavage of Poly (ADP-Ribose) Polymerase (PARP). In conclusion, these results indicate that redox cycling is induced by the NQs in the EL-4 cell line, with the generation of ROS and other free radicals that could inhibit cellular proliferation as a result of the induction of the intrinsic apoptosis pathway. PMID- 23933438 TI - Modification of a cyclo-olefin surface by radio-sterilization: is there any effect on the interaction with drug solutions? AB - A cyclo-olefin copolymer was subjected to an e-beam ionizing treatment. Two doses were studied: one corresponding to the recommended dose for the sterilization of pharmaceutical packaging (25 kGy), and a greater one to enhance the modifications caused by the treatment (150 kGy). The surface modifications were studied by X ray photoelectron spectroscopy (XPS), contact angle measurements and atomic force microscopy (AFM). The roughness and the wettability of the surface were enhanced by the treatment. The consequences of the surface modifications on the drug interaction with the polymer were studied. PMID- 23933440 TI - A liposomal delivery system that targets liver endothelial cells based on a new peptide motif present in the ApoB-100 sequence. AB - Liver dysfunction is associated with a variety of liver diseases, including viral or alcoholic hepatitis, fibrosis, cirrhosis, and portal hypertension. A targeted drug delivery system would be very useful in the treatment of these diseases. We herein describe the development of a system comprised of a new peptide-lipid conjugate for the efficient delivery of molecules to LEC. The RLTRKRGLK sequence (3359-3367), which mediates the association of LDL with arterial CSPG and an LDL receptor, was utilized as a ligand for achieving this goal. The peptide modified PEG-LPs (RLTR-PEG-LPs) were efficiently taken up by primary liver endothelial cells (liver ECs) and other types of cells. In vivo biodistribution and confocal microscopy analysis showed that RLTR-PEG-LPs became widely accumulated in LECs within a short time. Distribution of RLTR-PEG-LPs was greatly reduced with a pretreatment of unlabeled RLTR-PEG-LPs, not cationic LPs, indicating that the sequence is important for LECs. The findings indicate that a reverse sequence of RLTR (KLGR) modified PEG-LPs (KLGR-PEG-LP) did the same pattern compared with RLTR-PEG-LPs, suggesting that the RKR or RXXR sequence might be essential for LECs targeting. Collectively RLTR-PEG-LPs and KLGR-PEG-LPs have the potential for delivering drugs to LECs. PMID- 23933439 TI - Poly(amido amine) dendrimers as absorption enhancers for oral delivery of camptothecin. AB - Oral delivery of camptothecin has a treatment advantage but is limited by low bioavailability and gastrointestinal toxicity. Poly(amido amine) or PAMAM dendrimers have shown promise as intestinal penetration enhancers, drug solubilizers and drug carriers for oral delivery in vitro and in situ. There have been very limited studies in vivo to evaluate PAMAM dendrimers for oral drug delivery. In this study, camptothecin (5 mg/kg) was formulated and co-delivered with cationic, amine-terminated PAMAM dendrimer generation 4.0 (G4.0) (100 and 300 mg/kg) and anionic, carboxylate-terminated PAMAM generation 3.5 (G3.5) (300 and 1000 mg/kg) in CD-1 mice. Camptothecin associated to a higher extent with G4.0 than G3.5 in the formulation, attributed to an electrostatic interaction on the surface of G4.0. Both PAMAM G4.0 and G3.5 increased camptothecin solubilization in simulated gastric fluid and caused a 2-3 fold increase in oral absorption of camptothecin when delivered at 2 h. PAMAM G4.0 and G3.5 did not increase mannitol transport suggesting that the oral absorption of camptothecin was not due to tight junction modulation. Histologic observations of the epithelial layer of small intestinal segments of the gastrointestinal tract (GIT) at 4 h post dosing supported no evidence of toxicity at the evaluated doses of PAMAM dendrimers. This study demonstrates that both cationic (G.4) and anionic (G3.5) PAMAM dendrimers were effective in enhancing the oral absorption of camptothecin. Results suggest that drug inclusion in PAMAM interior controlled solubilization in simulated gastric and intestinal fluids, and increased oral bioavailability. PMID- 23933441 TI - Overcoming the stromal barrier for targeted delivery of HPMA copolymers to pancreatic tumors. AB - Delivery of macromolecules to pancreatic cancer is inhibited by a dense extracellular matrix composed of hyaluronic acid, smooth muscle actin and collagen fibers. Hyaluronic acid causes a high intratumoral fluidic pressure which prevents diffusion and penetration into the pancreatic tumor. This study involves the breaking down of hyaluronic acid by treating CAPAN-1 xenograft tumors in athymic nu/nu mice with targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers radiolabeled with (111)In for single photon emission computerized tomography (SPECT) imaging. Two targeting strategies were investigated including alphavbeta3 integrin and HER2 receptors. HPMA copolymers were targeted to these receptors by conjugating short peptide ligands cRGDfK and KCCYSL to the side chains of the copolymer. Results demonstrate that tumor targeting can be achieved in vivo after treatment with hyaluronidase. This approach shows promise for enhanced delivery of polymer-peptide conjugates to solid tumors. PMID- 23933442 TI - Preparation and drug release mechanism of CTS-TAX-NP-MSCs drug delivery system. AB - Targeting delivery of anticancer agents is a promising field in anticancer therapy. Inherent tumor-tropic and migratory properties of mesenchymal stem cells (MSCs) make them potential vehicles for targeting drug delivery systems for tumors. Although, MSCs have been successfully studied and discussed as a vehicle for cancer gene therapy, they have not yet been studied adequately as a potential vehicle for traditional chemical anticancer drugs. In this study, we have engineered MSCs as a potential targeting delivery vehicle for paclitaxel (TAX) loaded nanoparticles (NPs). The size, surface charge, starving time of MSCs, incubating time and concentration of NPs could influence the efficiency of NPs uptake. In vitro release of TAX from CTS (chitosan)-TAX-NP-MSCs and the expression of P-glycoprotein demonstrated that release of TAX from MSCs might involve both passive diffusion and active transport. In vitro migration assays indicated that MSCs at passage number 3 have the highest migrating ability. Although, the migration ability of CTS-TAX-NP-MSCs could be inhibited by uptake of CTS-TAX-NPs, this ability could recover 6 days after the internalization. PMID- 23933443 TI - Compound retroauricular advancement flap. PMID- 23933444 TI - Surgical treatment of Papillon-Lefevre Syndrome with bovine collagen and skin graft. PMID- 23933446 TI - Characteristics of tobacco retailers in New Zealand. AB - Using data on known tobacco outlets throughout NZ, GIS was used to map outlets, deprivation and secondary schools. A total of 5008 tobacco outlets were identified, giving a density of one outlet per 617 people or one outlet per 129 smokers. One-half of secondary schools had an outlet within 500 m. Tobacco outlets were more densely located in areas of higher socioeconomic deprivation. One third of all tobacco outlets had a licence to sell alcohol. This study indicates the widespread retail availability of tobacco and the need for a mandatory system of registration for better enforcement of smokefree legislation. PMID- 23933445 TI - Spatial patterning of supermarkets and fast food outlets with respect to neighborhood characteristics. AB - A large body of literature has reported differences in exposure to environments supporting either healthy (e.g. supermarkets) or unhealthy (e.g. fast food outlets) dietary choices by neighborhood characteristics. We explored the associations of both supermarkets and fast food outlets availability with neighborhood characteristics, and clustering of these two outlet types in a largely rural state. Compared to block groups without a supermarket, those with a supermarket had a significantly higher income, higher housing value, larger population with high school education and above, lower minority population and lower population living below poverty even after controlling for urbanicity and population density of census block groups. Surprisingly, a similar relationship was found for block groups with and without fast food outlets. This was due to spatial co-occurrence and clustering of fast food outlets around supermarket locations. Hence, future studies exploring the associations of food environment with diet or diet-related health outcome should concurrently examine all aspects of food environment (healthy and unhealthy). PMID- 23933447 TI - What makes Internet addicts continue playing online even when faced by severe negative consequences? Possible explanations from an fMRI study. AB - In this study, we designed a continuous wins-and-losses task to monitor the mental activities during decision-making and their effects on subsequent decisions in Internet addiction disorder (IAD) subjects. In behavioral performance, IAD subjects show longer response time, lower repeat rate and greater Stroop effect than healthy controls. In neuroimaging results, IAD subjects show increased brain activities in the inferior frontal cortex, insula, anterior cingulate cortex and decreased activation in the caudate and posterior cingulate cortex after continuous wins than healthy controls. In addition, IAD subjects show increased brain activities in the inferior frontal gyrus and decreased brain activation in the posterior cingulate cortex after continuous losses. Thus, we concluded that IAD subjects engage more cognitive activities to finish the decision-making task. As a result, they cannot sufficiently focus on the executive function during this process. They also do not pay adequate attention to considering previous selections and relevant outcomes during decision-making. PMID- 23933448 TI - Effects of fungicides and biofungicides on population density and community structure of soil oribatid mites. AB - To compare the side-effects of chemical versus biofungicides on non-target organisms in agricultural soil, a study of population structure, spatial distribution and fecundity of oribatid mites, a diverse and species-rich group of microarthropods indicative of decomposer activity in soil was done. Plots laid out in agricultural fields of a research station in Egypt, were cultivated with cucumber and treated with two chemical fungicides: Ridomil Plus 50% wp (active ingredients=metalaxyl and copper oxychloride) and Dithane M-45 (active ingredient=mancozeb), and two biofungicides: Plant Guard (containing the antagonistic fungus Trichoderma harzianum) and Polyversum (containing the fungi parasitic oomycete Pythium oligandrum). All treatments were done using both low volume and high-volume spraying techniques to check whether any effects were dependent on the method of application. Oribatid mite communities were assessed from soil core samples collected during the growing season. Total abundance of oribatids was not different across the plots, but some species decreased in number, while one species increased. Species diversity and community equitability decreased with the application of chemical and biofungicides especially when using high-volume spraying. In control plots most oribatid species showed a significant degree of aggregation, which tended to decrease under fungicide treatment. Ridomil Plus, Plant Guard and Polyversum had a negative effect on the gravid/ungravid ratio of some species. Egg number averaged over the whole adult population was not directly related to the application of chemical and biofungicides but it showed a species-specific relationship with population density. In general biofungicides had a smaller effect on population size and community structure of oribatid mite species than chemical fungicides. The results indicate that biofungicides may be the preferred option when aiming to prevent side-effects on sensitive groups among the species-rich soil detritivore community. PMID- 23933449 TI - Impacts on particles and ozone by transport processes recorded at urban and high altitude monitoring stations. AB - In order to evaluate the influence of particle transport episodes on particle number concentration temporal trends at both urban and high-altitude (Aitana peak 1558 m a.s.l.) stations, a simultaneous sampling campaign from October 2011 to September 2012 was performed. The monitoring stations are located in southeastern Spain, close to the Mediterranean coast. The annual average value of particle concentration obtained in the larger accumulation mode (size range 0.25-1 MUm) at the mountain site, 55.0 +/- 3.0 cm(-3), was practically half that of the value obtained at the urban station (112.0 +/- 4.0 cm(-3)). The largest difference between both stations was recorded during December 2011 and January 2012, when particles at the mountain station registered the lowest values. It was observed that during urban stagnant episodes, particle transport from urban sites to the mountain station could take place under specific atmospheric conditions. During these transports, the major particle transfer is produced in the 0.5-2 MUm size range. The minimum difference between stations was recorded in summer, particularly in July 2012, which is most likely due to several particle transport events that affected only the mountain station. The particle concentration in the coarse mode was very similar at both monitoring sites, with the biggest difference being recorded during the summer months, 0.4 +/- 0.1cm(-3) at the urban site and 0.9 +/- 0.1cm(-3) at the Aitana peak in August 2012. Saharan dust outbreaks were the main factor responsible for these values during summer time. The regional station was affected more by these outbreaks, recording values of >4.0 cm(-3), than the urban site. This long-range particle transport from the Sahara desert also had an effect upon O3 levels measured at the mountain station. During periods affected by Saharan dust outbreaks, ozone levels underwent a significant decrease (3-17%) with respect to its mean value. PMID- 23933450 TI - Soil as a source of dioxin contamination in eggs from free-range hens on a Polish farm. AB - The transfer of dioxins from contaminated soil into the food chain has recently become an up-and-coming topic in the environmental policy and health-related consumer protection. Within the framework of the 2011 National Food Survey that monitored the levels of PCDD/Fs and PCBs in foods of animal origin, the sum of the WHO-PCDD/F/PCB-TEQ concentrations exceeding two-fold the European Union's maximum level was detected in eggs from a free-range farm (12.55 +/- 2.37 pg WHOPCDD/F/PCB-TEQ/g fat). Investigations have revealed that the source of egg contamination was the backyard soil on which the hens were foraging. A follow-up study of laying hens from this farm has demonstrated the transfer of dioxins into all tested tissues (breast and leg muscles, abdominal fat), liver and ovarian follicles. The bioaccumulation of dioxins was found to be congener and tissue dependent. The highest concentration was found in the liver, followed by the ovarian follicles, and the adipose tissue. The PCDD/F levels in the liver often were approximately two times higher from those in other materials from the same hen. The potential dioxin intakes with eggs were expressed as the percent of the Tolerable Weekly Intake (TWI), and the Provisional Tolerable Monthly Intake (PTMI). The weekly intake of dioxins would be 3.5 pg WHO-TEQ/kg b.w. (24.9% TWI) for an adult and 20.3 pg WHO-TEQ/kg b.w. (145.2% TWI) for a 3-year old child. Considering a monthly consumption of such contaminated eggs, intake of dioxins would be slightly lower, but still over 100% of the PTMI for a child. The obtained results complement the knowledge on possible dioxin sources in food and are important for risk management authorities. PMID- 23933451 TI - An exploratory study on the influence of socio-demographic characteristics on water end uses inside buildings. AB - Any strategy of water demand management needs the collaboration of the population involved and so it is important to know how characteristics as residence area, number of residents, presence/absence of children/elders, income level, and educational level, among others, may influence the use of water. Empirical studies that quantify relationship between socio-demographic factors and the water end use patterns inside buildings are still largely lacking. To help to fill this gap this paper gathers information about the characterization of water end use per domestic device in three regions of north of Portugal with different socio-demographic characteristics. The main research goal was to establish indoor water end use patterns per domestic device and to evaluate possible relations between these patterns with the socio-demographic characteristics of the area where the household is, namely the number of residents, the presence/absence of children/elders, the income level and educational level. The washbasin is in average the domestic device with more number of uses in a day (responsible for 34% of the total use), close followed by the kitchen sink (32%), the toilet flush (23%), the bathtub (6%) and finally the dishwasher (3%) and the washing machine (2%). The results found might reflect differences in rural and urban lifestyles once that, with the exception of the kitchen sink, Valpacos is the city that registers the lowest number of uses in the appliances monitored. Significant correlations were found in the following cases: between the residence area and the number of uses in washbasin and in the toilet flush; between the presence of children in the household and the use in the dishwasher; between the income level and the number of uses in the washbasin, in the bathtub, in the washing machine and in the dishwasher. PMID- 23933452 TI - Effects of nano-TiO2 on the agronomically-relevant Rhizobium-legume symbiosis. AB - The impact of nano-TiO2 on Rhizobium-legume symbiosis was studied using garden peas and the compatible bacterial partner Rhizobium leguminosarum bv. viciae 3841. Exposure to nano-TiO2 did not affect the germination of peas grown aseptically, nor did it impact the gross root structure. However, nano-TiO2 exposure did impact plant development by decreasing the number of secondary lateral roots. Cultured R. leguminosarum bv. viciae 3841 was also impacted by exposure to nano-TiO2, resulting in morphological changes to the bacterial cells. Moreover, the interaction between these two organisms was disrupted by nano-TiO2 exposure, such that root nodule development and the subsequent onset of nitrogen fixation were delayed. Further, the polysaccharide composition of the walls of infected cells of nodules was altered, suggesting that the exposure induced a systemic response in host plants. Therefore, nano-TiO2 contamination in the environment is potentially hazardous to the Rhizobium-legume symbiosis system. PMID- 23933453 TI - Sediments in urban river basins: identification of sediment sources within the Lago Paranoa catchment, Brasilia DF, Brazil - using the fingerprint approach. AB - The development of effective sediment management strategies is a key requirement in tropical areas with fast urban development, like Brasilia DF, Brazil, because of the limited resources available. Accurate identification and management of sediment sources areas, however, is hampered by the dearth of reliable information on the primary sources of sediment. Few studies have attempted to quantify the source of sediment within fast urbanizing, mixed used, tropical catchments. In this study, statistically verified composite fingerprints and a multivariate mixing model have been used to identify the main land use specific sources of sediment deposited in the artificial Lago Paranoa, Central Brazil. Because of the variability of urban land use types within the Lago Paranoa sub catchments, the fingerprinting approach was additionally undertaking for the Riacho Fundo sub-catchment. The main contributions from individual source types (i.e. surface materials from residential areas, constructions sites, road deposited sediment, cultivated areas, pasture, farm tracks, woodland and natural gullies) varied between the whole catchment and the Riacho Fundo sub-catchment, reflecting the different proportions of land uses. The sediments deposited in the silting zones of the Lago Paranoa originate largely from urban sources (85 +/- 4%). Areas with (semi-) natural vegetation and natural gullies contribute 10 +/- 2% of the sediment yield. Agricultural sites have only a minor sediment contribution of about 5 +/- 4% within the whole catchment. Within the Riacho Fundo sub-catchment there is a significant contribution from urban (53 +/- 4%) source, such as residential areas with semi-detached housings (42 +/- 3%) with unpaved roads (12 +/- 3%) and construction sites (20 +/- 3%) and agricultural areas (31 +/- 2%). The relative contribution from land use specific sources to the sediment deposition in the silting zone of the Lago Paranoa demonstrated that most of the sediment is derived from sites with high anthropogenic impact. PMID- 23933454 TI - Polybrominated diphenyl ethers in farmland soils: source characterization, deposition contribution and apportionment. AB - Polybrominated diphenyl ethers (PBDEs), a group of persistent organic pollutants (POPs), are caused for concern recently due to their adverse health effects and environmental ubiquity. In this study, atmospheric and soil PBDE levels in Taizhou, one of the largest WEEE dismantling areas in the world, were measured, ranging from 884 to 2791 pg m(-3) with an average of 1968 pg m(-3) for atmosphere and 2.96 to 200 ng g(-1)dry weight (dw) with the mean of 65.2 ng g(-1)dw for farmland soils, respectively. The close connection between soil PBDE accumulation and atmospheric deposition was also revealed by the estimation of the annual PBDE deposition flux (3.1 +/- 0.9 mg m(-2)a(-1)) and the similarity between deposited congener pattern and soil congener profile. Positive matrix factorization (PMF) was conducted to extract possible sources of farmland soil PBDEs and to calculate their contributions. Based on the measured source profiles of PBDE-related activities, five sources were identified representing WEEE dumping, WEEE dismantling, WEEE open burning, residential waste dismantling, and residential waste open burning. WEEE-related recycling activities contributed primary percentage (52%) to farmland soil PBDE concentration, and open burning was an important pathway for PBDEs entering the environment. PMID- 23933455 TI - Single-walled carbon nanotubes alter soil microbial community composition. AB - Recent developments in nanotechnology may lead to the release of nanomaterials into the natural environment, such as soils, with largely unknown consequences. We investigated the effects of single-walled carbon nanotubes (SWCNTs), one of the most widely used nanomaterials, on soil microbial communities by incubation of soils to which powder or suspended forms of SWCNTs were added (0.03 to 1 mg g( 1) soil). To determine changes in soil microbial community composition, phospholipid fatty acid (PLFA) profiles were analyzed at 25th day of the incubation experiment. The biomass of major microbial groups including Gram positive and Gram-negative bacteria, and fungi showed a significant negative relationship with SWCNT concentration, while the relative abundance of bacteria showed a positive relationship with SWCNT concentration. Furthermore, soils under distinct concentrations of SWCNT treatments had PLFA profiles that were significantly different from one another. Our results indicate that the biomass of a broad range of soil microbial groups is negatively related with SWCNT concentration and upon entry into soils, SWCNTs may alter microbial community composition. Our results may serve as foundation for scientific guideline on regulating the discharge of nanomaterials such as SWCNTs to the soil ecosystem. PMID- 23933456 TI - CloudNMF: a MapReduce implementation of nonnegative matrix factorization for large-scale biological datasets. AB - In the past decades, advances in high-throughput technologies have led to the generation of huge amounts of biological data that require analysis and interpretation. Recently, nonnegative matrix factorization (NMF) has been introduced as an efficient way to reduce the complexity of data as well as to interpret them, and has been applied to various fields of biological research. In this paper, we present CloudNMF, a distributed open-source implementation of NMF on a MapReduce framework. Experimental evaluation demonstrated that CloudNMF is scalable and can be used to deal with huge amounts of data, which may enable various kinds of a high-throughput biological data analysis in the cloud. CloudNMF is freely accessible at http://admis.fudan.edu.cn/projects/CloudNMF.html. PMID- 23933457 TI - Reply by authors. PMID- 23933458 TI - Re: Inhibition of mTORC2 but not mTORC1 up-regulates E-cadherin expression and inhibits cell motility by blocking HIF-2alpha expression in human renal cell carcinoma: S. Maru, Y. Ishigaki, N. Shinohara, T. Takata, N. Tomosugi and K. Nonomura J Urol 2013; 189: 1921-1929. PMID- 23933459 TI - Is sperm DNA integrity assessment useful? PMID- 23933460 TI - The electronic medical record: how not to communicate. PMID- 23933461 TI - Editorial comment. PMID- 23933463 TI - Paraperitoneal ureteroinguinal hernia. PMID- 23933464 TI - Room temperature ordering of dipalmitoyl phosphatidylserine bilayers induced by short chain alcohols. AB - Using differential scanning calorimetry and small and wide angle X-ray diffraction, we show that, following extended incubation at room temperature, methanol, propanol, and three of the isomers of butanol can induce ordering in dipalmitoyl phosphatidylserine (DPPS) gel phase bilayers. The organization of the bilayers in the presence of ethanol, described previously, is now observed to be a general effect of short chain alcohols. Evidence is presented for tilting of the acyl chains with respect to the bilayer normal in the presence of ethanol or propanol. However, the different chain lengths of the alcohols, and isomeric form, influence the thermal stability of the ordered gel to different extents. This behavior is unlike that of the gel state phosphatidylcholine analog which, in the presence of short chain alcohols, undergoes hydrocarbon chain interdigitation. Dipalmitoyl phosphatidylcholine added to DPPS in the presence of 20 vol% ethanol, acts to suppress the ordered gel phase. PMID- 23933465 TI - Geraniol hydroxylase and hydroxygeraniol oxidase activities of the CYP76 family of cytochrome P450 enzymes and potential for engineering the early steps of the (seco)iridoid pathway. AB - The geraniol-derived (seco)iridoid skeleton is a precursor for a large group of bioactive compounds with diverse therapeutic applications, including the widely used anticancer molecule vinblastine. Despite of this economic prospect, the pathway leading to iridoid biosynthesis from geraniol is still unclear. The first geraniol hydroxylation step has been reported to be catalyzed by cytochrome P450 enzymes such as CYP76B6 from Catharanthus roseus and CYP76C1 from Arabidopsis thaliana. In the present study, an extended functional analysis of CYP76 family members was carried-out to identify the most effective enzyme to be used for pathway reconstruction. This disproved CYP76C1 activity and led to the characterization of CYP76C4 from A. thaliana as a geraniol 9- or 8-hydroxylase. CYP76B6 emerged as a highly specialized multifunctional enzyme catalyzing two sequential oxidation steps leading to the formation of 8-oxogeraniol from geraniol. This dual function was confirmed in planta using a leaf-disc assay. The first step, geraniol hydroxylation, was very efficient and fast enough to outcompete geraniol conjugation in plant tissues. When the enzyme was expressed in leaf tissues, 8-oxogeraniol was converted into further oxidized and/or reduced compounds in the absence of the next enzyme of the iridoid pathway. PMID- 23933467 TI - GABAB receptor ligands do not modify conditioned fear responses in BALB/c mice. AB - The GABA(B) receptor has been well characterised as a substrate of unconditioned anxiety behaviour. Indeed, the anxiolytic effects of positive modulators of the GABA(B) receptor have been demonstrated across a range of behavioural tests of innate anxiety, whereas GABA(B) receptor deficient mice have an elevated anxiety phenotype. However, the role of the GABA(B) receptor in regulating conditioned anxiety behaviour; an important facet of the preclinical study of anxiety disorders such as post-traumatic stress disorder is less well understood. In vitro data suggests that the GABA(B) receptor plays an important role in regulating the neural circuitry that underpins conditioned fear learning and extinction, but whether these effects translate into alterations in conditioned anxiety behaviour has not been widely investigated. This represents a crucial deficit in the preclinical characterisation of these drugs as putative anxiolytic agents. Using the highly anxious mouse strain, BALB/c, and an auditory fear conditioning protocol, we sought to characterise the GABA(B) receptor positive modulator GS39783 and GABA(B) receptor antagonist CGP52432, two compounds not previously evaluated for their effects on conditioned fear. Neither GS39783 nor CGP52432 altered freezing behaviour irrespective of whether drugs were administered before the acquisition, recall or extinction training sessions. These findings suggest limitations to the potential role of GABA(B) receptor active drugs as clinical agents in the treatment of anxiety. PMID- 23933466 TI - Determinants of novel object and location recognition during development. AB - In the novel object recognition (OR) paradigm, rats are placed in an arena where they encounter two sample objects during a familiarization phase. A few minutes later, they are returned to the same arena and are presented with a familiar object and a novel object. The object location recognition (OL) variant involves the same familiarization procedure but during testing one of the familiar objects is placed in a novel location. Normal adult rats are able to perform both the OR and OL tasks, as indicated by enhanced exploration of the novel vs. the familiar test item. Rats with hippocampal lesions perform the OR but not OL task indicating a role of spatial memory in OL. Recently, these tasks have been used to study the ontogeny of spatial memory but the literature has yielded conflicting results. The current experiments add to this literature by: (1) behaviorally characterizing these paradigms in postnatal day (PD) 21, 26 and 31 day-old rats; (2) examining the role of NMDA systems in OR vs. OL; and (3) investigating the effects of neonatal alcohol exposure on both tasks. Results indicate that normal-developing rats are able to perform OR and OL by PD21, with greater novelty exploration in the OR task at each age. Second, memory acquisition in the OL but not OR task requires NMDA receptor function in juvenile rats [corrected]. Lastly, neonatal alcohol exposure does not disrupt performance in either task. Implications for the ontogeny of incidental spatial learning and its disruption by developmental alcohol exposure are discussed. PMID- 23933468 TI - The mesolimbic system participates in the naltrexone-induced reversal of sexual exhaustion: opposite effects of intra-VTA naltrexone administration on copulation of sexually experienced and sexually exhausted male rats. AB - Male rats allowed to copulate until reaching sexual exhaustion exhibit a long lasting sexual behavior inhibition (around 72 h) that can be reversed by systemic opioid receptor antagonist administration. Copulation activates the mesolimbic dopaminergic system (MLS) and promotes endogenous opioid release. In addition, endogenous opioids, acting at the ventral tegmental area (VTA), modulate the activity of the MLS. We hypothesized that endogenous opioids participate in the sexual exhaustion phenomenon by interacting with VTA opioid receptors and consequently, its reversal by opioid antagonists could be exerted at those receptors. In this study we determined the effects of intra-VTA infusion of different doses of the non-specific opioid receptor antagonist naltrexone (0.1 1.0 MUg/rat) on the already established sexual behavior inhibition of sexually exhausted male rats. To elucidate the possible involvement of VTA delta-opioid receptors in the naltrexone-mediated reversal of sexual exhaustion, the effects of different doses of the selective delta-opioid receptor antagonist, naltrindole (0.03-1.0 MUg/rat) were also tested. Results showed that intra-VTA injection of 0.3 MUg naltrexone reversed the sexual inhibition of sexually exhausted rats, evidenced by an increased percentage of animals capable of showing two successive ejaculations. Intra-VTA infused naltrindole did not reverse sexual exhaustion at any dose. It is concluded that the MLS is involved in the reversal of sexual exhaustion induced by systemic naltrexone, and that MU-, but not delta-opioid receptors participate in this effect. Intra-VTA naltrexone infusion to sexually experienced male rats had an inhibitory effect on sexual activity. The opposite effects of intra-VTA naltrexone on male rat sexual behavior expression of sexually experienced and sexually exhausted rats is discussed. PMID- 23933469 TI - Language comprehension interrupted: both language errors and word degradation activate Broca's area. AB - The proposal of a general conflict resolution mechanism in lIFG was investigated further in relation to language errors. In an fMRI study participants read sentences containing syntactic and plausibility violations. Furthermore, they were presented with sentences that were difficult to comprehend, due to degradation of the bottom-up signal (i.e., the visual form) of the language. We were interested whether comprehension difficulties caused by degradation would activate cognitive control mechanisms in the same manner as other language violations. To localize cognitive control processes participants performed a Stroop task. Both the violations and the visual degradation condition elicited co localized lIFG activation with the Stroop conflict. These results indicate that lIFG implements control adjustments to resolve situations in which extra attention is needed more generally. Next to biasing attention to resolve representational conflicts arising from different types of errors, lIFG may also adjust control to compensate for a temporary lack of bottom-up information. PMID- 23933470 TI - Distinguishable neurofunctional effects of task practice and item practice in picture naming: a BOLD fMRI study in healthy subjects. AB - Practice of language tasks results in improved performance and BOLD signal changes. We distinguish changes correlated with repeated exposure to a picture naming task, from changes associated with naming specific items trained during practice. Task practice affected trained and untrained items, yielding left-sided BOLD deactivations in extrastriate, prefrontal and superior temporal areas (consistent with their putative role in perceptual priming, articulatory planning and phonological lexical retrieval, respectively). Item practice effects were restricted to trained words. There was deactivation in left posterior fusiform (supporting its role in accessing structural object representations), anterior cingulate and left insular/inferior frontal cortices (consistent with their role in processing low-frequency words). Central precuneus and posterior cingulate were hyperactivated (consistent with their putative role in episodic memory for trained items, probably due to functional connections with language areas). In healthy subjects, naming practice modifies stored linguistic representations, but mostly affects ease of access to trained words. PMID- 23933471 TI - Neural basis of semantic and syntactic interference in sentence comprehension. AB - According to the cue-based parsing approach (Lewis, Vasishth, & Van Dyke, 2006), sentence comprehension difficulty derives from interference from material that partially matches syntactic and semantic retrieval cues. In a 2 (low vs. high semantic interference)*2 (low vs. high syntactic interference) fMRI study, greater activation was observed in left BA44/45 for high versus low syntactic interference conditions following sentences and in left BA45/47 for high versus low semantic interference conditions following comprehension questions. A conjunction analysis showed BA45 associated with both types of interference, while BA47 was associated with only semantic interference. Greater activation was also observed in the left STG in the high interference conditions. Importantly, the results for the LIFG could not be attributed to greater working memory capacity demands for high interference conditions. The results favor a fractionation of the LIFG wherein BA45 is associated with post-retrieval selection and BA47 with controlled retrieval of semantic information. PMID- 23933472 TI - How damaged brains repeat words: a computational approach. AB - Two routes have been proposed for auditory repetition: a lexical route which activates a lexical item and retrieves its phonology, and a nonlexical route which maps input phonology directly onto output phonology. But when is the nonlexical route recruited? In a sample of 103 aphasic patients, we use computational models to select patients who do and do not recruit the nonlexical route, and compare them in light of three hypotheses: 1 - Lexical-phonological hypothesis: when the lexical route is weak, the nonlexical route is recruited. 2 Nonlexical hypothesis: when the nonlexical route is weak, it is abandoned. 3 - Semantic-access hypothesis: when access to meaning fails, the nonlexical route is recruited. In neurocognitive terms, hypotheses 1 and 2 identify different aspects of the intactness of the dorsal stream, while the third hypothesis focuses on the ventral stream. Our findings (and a subsequent meta-analysis of four studies) support hypotheses 2 and 3. Ultimately, we claim that the choice about whether to recruit the nonlexical route is guided, not by assessment of production abilities that support repetition, but instead by relying on accessible cues, namely whether the speaker understands the word, or can remember its sequence of phonemes. PMID- 23933473 TI - The activation of modality-specific representations during discourse processing. AB - Previous research has shown that readers generate mental images of events. Most studies have investigated imagery during the reading of short texts, which also included explicit judgment tasks. In two fMRI studies, we assessed whether modality-specific imagery occurs during naturalistic, discourse comprehension. We identified clauses in the texts that elicited auditory, motor, or visual imagery. In both studies, reading motor imagery clauses was associated with increases in activity in left postcentral and precentral sulci, and reading auditory imagery clauses was associated with increases in left superior temporal gyrus and perisylvian language-related regions. Study 2 compared presentation of connected discourse to a condition in which unconnected sentences were presented, preventing the establishment of global coherence. Sensorimotor imagery was strongest when readers were able to generate a globally coherent discourse representation. Overall, these results suggest that modality-specific imagery occurs during discourse comprehension and it is dependent on the development of discourse-level representations. PMID- 23933474 TI - Neurocognitive enhancement in older adults: comparison of three cognitive training tasks to test a hypothesis of training transfer in brain connectivity. AB - The ultimate goal of cognitive enhancement as an intervention for age-related cognitive decline is transfer to everyday cognitive functioning. Development of training methods that transfer broadly to untrained cognitive tasks (far transfer) requires understanding of the neural bases of training and far transfer effects. We used cognitive training to test the hypothesis that far transfer is associated with altered attentional control demands mediated by the dorsal attention network and trained sensory cortex. In an exploratory study, we randomly assigned 42 healthy older adults to six weeks of training on Brain Fitness (BF-auditory perception), Space Fortress (SF-visuomotor/working memory), or Rise of Nations (RON-strategic reasoning). Before and after training, cognitive performance, diffusion-derived white matter integrity, and functional connectivity of the superior parietal cortex (SPC) were assessed. We found the strongest effects from BF training, which transferred to everyday problem solving and reasoning and selectively changed integrity of occipito-temporal white matter associated with improvement on untrained everyday problem solving. These results show that cognitive gain from auditory perception training depends on heightened white matter integrity in the ventral attention network. In BF and SF (which also transferred positively), a decrease in functional connectivity between SPC and inferior temporal lobe (ITL) was observed compared to RON-which did not transfer to untrained cognitive function. These findings highlight the importance for cognitive training of top-down control of sensory processing by the dorsal attention network. Altered brain connectivity - observed in the two training tasks that showed far transfer effects - may be a marker for training success. PMID- 23933475 TI - Dynamic changes in positive interferon-gamma release assay in a dialysis population: An observational cohort study. AB - BACKGROUND: Interferon-gamma release assay (IGRA) is popular for detecting latent tuberculosis infection (LTBI), but its dynamic change is uncertain in high-risk groups such as dialysis patients. METHODS: Patients undergoing dialysis were prospectively enrolled. The QuantiFERON-TB Gold In-Tube (QFT-GIT) was used to detect LTBI. After 6 and 12 months, QFT-GIT was repeated to monitor dynamic changes. RESULTS: Only 204 of 391 enrolled patients completed the study. The initial QFT-GIT positive rate of 22.1% decreased to 19.6% after 6 months and to 14.2% after 12 months. The 6-month reversion rate was 45.9% while the conversion rate was 7.7%. Sub-population with new QFT-GIT positivity had 87.5% reversion rate, higher than the 20.8% of patients with persistent QFT-GIT positivity. The QFT-GIT response was independently associated with persistent QFT-GIT positivity. Using 0.93 IU/ml of the initial QFT-GIT response as the threshold can detect 79% persistent positivity in 6-month follow-up. Prior TB had a borderline significance for predicting conversion. CONCLUSIONS: In the dialysis population, reversion and conversion occur frequently within six months. The QFT-GIT positive population is heterogeneous and sub-populations have different reversion rates. Higher QFT-GIT positivity threshold can identify patients with persistent QFT-GIT positivity to prioritize follow-up and LTBI therapy. PMID- 23933476 TI - Reliable noninvasive prenatal testing by massively parallel sequencing of circulating cell-free DNA from maternal plasma processed up to 24h after venipuncture. AB - OBJECTIVES: Circulating cell-free fetal DNA (ccffDNA) in maternal plasma is an attractive source for noninvasive prenatal testing (NIPT). The amount of total cell-free DNA significantly increases 24h after venipuncture, leading to a relative decrease of the ccffDNA fraction in the blood sample. In this study, we evaluated the downstream effects of extended processing times on the reliability of aneuploidy detection by massively parallel sequencing (MPS). DESIGN AND METHODS: Whole blood from pregnant women carrying normal and trisomy 21 (T21) fetuses was collected in regular EDTA anti-coagulated tubes and processed within 6h, 24 and 48h after venipuncture. Samples of all three different time points were further analyzed by MPS using Z-score calculation and the percentage of ccffDNA based on X-chromosome reads. RESULTS: Both T21 samples were correctly identified as such at all time-points. However, after 48h, a higher deviation in Z-scores was noticed. Even though the percentage of ccffDNA in a plasma sample has been shown previously to significantly decrease 24h after venipuncture, the percentages based on MPS results did not show a significant decrease after 6, 24 or 48h. CONCLUSIONS: The quality and quantity of ccffDNA extracted from plasma samples processed up to 24h after venipuncture are sufficiently high for reliable downstream NIPT analysis by MPS. Furthermore, we show that it is important to determine the percentage of ccffDNA in the fraction of the sample that is actually used for NIPT, as downstream procedures might influence the fetal or maternal fraction. PMID- 23933477 TI - Measurement of pulmonary transit time in healthy cats by use of ultrasound contrast media "Sonovue(r)": feasibility, reproducibility, and values in 42 cats. AB - OBJECTIVE: To evaluate the feasibility of measuring pulmonary transit time (PTT) in healthy cats by transthoracic echocardiography using the ultrasound contrast agent Sonovue((r)). To determine normalized PTT (nPTT) values in 42 healthy cats and to estimate the interobserver variability and the within-day repeatability of nPTT measurements. ANIMALS: Forty-two privately owned healthy cats of different breeds, gender and age presented for cardiac examination. METHODS: A bolus injection of contrast agent (Sonovue((r))) was administered intravenously. The right parasternal short axis echocardiographic view was used to record the contrast agent's transit time from the pulmonary artery to the left atrium. Pulmonary transit time and nPTT were determined independently by three examiners with different levels of experience. RESULTS: Normalized PTT was 4.12 +/- 1.0 (mean +/- SD) in our population. The median interobserver variability across our population was 6.8%, the median within-day variability for the three observers were 13.1%, 12.7% and 13%. No effect of the observer's experience on nPTT measurement was identified. Age, sex and body weight did not significantly influence nPTT. CONCLUSIONS: This study demonstrates that nPTT measurement is feasible in cats using ultrasound and the blood pool contrast media Sonovue((r)). Measurements of nPTT can be performed in a clinical setting. Normalized PTT values in healthy cats are comparable with those reported in healthy dogs. PMID- 23933478 TI - Utility of N-terminal pro-brain natriuretic peptide for assessing hemodynamic significance of patent ductus arteriosus in dogs undergoing ductal repair. AB - OBJECTIVE: Determine if plasma N-terminal pro-brain natriuretic peptide (NT proBNP) correlates with markers of hemodynamically significant patent ductus arteriosus (PDA) in dogs. ANIMALS: Ten dogs with PDA and 30 healthy dogs of similar ages. METHODS: Prospective case series with control population. Dogs with PDA were initially evaluated with thoracic radiographs, transthoracic echocardiography, pulmonary capillary wedge pressure (PCWP) and NT-proBNP. Following ductal occlusion, NT-proBNP and echocardiography were repeated within 24 h and at day 90. PCWP was repeated at day 90. Correlation between NT-proBNP and hemodynamic measurements was assessed, and accuracy of NT-proBNP for identifying PDA severity was estimated. RESULTS: NT-proBNP was significantly higher (median; absolute range) in dogs with PDA (895; 490-7118 pmol/L) than controls (663; 50-1318 pmol/L) (p = 0.025). NT-proBNP decreased significantly 90 days post-ductal closure (597; 154-1858 pmol/L) (p = 0.013). Left atrial and ventricular size decreased significantly within 24 h and at day 90 as did PCWP (day 90 only). NT-proBNP correlated with vertebral heart size (VHS) and indexed left ventricular systolic diameter (iLVIDs); concentrations >= 1224 pmol/L distinguished dogs with elevated VHS and iLVIDs. CONCLUSIONS: NT-proBNP is elevated in dogs with PDA, decreases following PDA closure and correlates with select radiographic and echocardiographic markers of cardiac remodeling. PMID- 23933479 TI - Cross-correlations between three units in cat primary auditory cortex. AB - Here we use a modification of the Joint-Peri-Stimulus-Time histogram (JPSTH) to investigate triple correlations between cat auditory cortex neurons. The modified procedure allowed the decomposition of the xy-pair correlation into a part that is due to the correlation of the x and y units with the trigger unit, and a remaining 'pair correlation'. We analyzed 16 sets of 15-minute duration stationary spontaneous recordings in primary auditory cortex (AI) with between 11 and 14 electrodes from 2 arrays of 8 electrodes each that provided spontaneous firing rates above 0.22 sp/s and for which reliable frequency-tuning curves could be obtained and the characteristic frequency (CF) was estimated. Thus we evaluated 11,282 conditional cross-correlation functions. The predictor for the conditional cross-correlation, calculated on the assumption that the trigger unit had no effect on the xy-pair correlation but using the same fraction of xy spikes, was equal to the conventional pair-wise correlation function between units xy. The conditional correlation of the xy-pair due to correlation of the x and/or y unit with the trigger unit decreased with the geometric mean distance of the xy pair to the trigger unit, but was independent of the pair cross correlation coefficient. The conditional pair correlation coefficient was estimated at 78% of the measured pair correlation coefficient. Assuming a geometric decreasing effect of activities of units on other electrodes on the conditional correlation, we estimated the potential contribution of a large number of contributing units on the measured pair correlation at 35-50 of that correlation. This suggests that conventionally measured pair correlations in auditory cortex under ketamine anesthesia overestimate the 'true pair correlation', likely resulting from massive common input, by potentially up to a factor 2. PMID- 23933480 TI - DNA-methylation dependent regulation of embryo-specific 5S ribosomal DNA cluster transcription in adult tissues of sea urchin Paracentrotus lividus. AB - We have previously reported a molecular and cytogenetic characterization of three different 5S rDNA clusters in the sea urchin Paracentrotus lividus and recently, demonstrated the presence of high heterogeneity in functional 5S rRNA. In this paper, we show some important distinctive data on 5S rRNA transcription for this organism. Using single strand conformation polymorphism (SSCP) analysis, we demonstrate the existence of two classes of 5S rRNA, one which is embryo-specific and encoded by the smallest (700 bp) cluster and the other which is expressed at every stage and encoded by longer clusters (900 and 950 bp). We also demonstrate that the embryo-specific class of 5S rRNA is expressed in oocytes and embryonic stages and is silenced in adult tissue and that this phenomenon appears to be due exclusively to DNA methylation, as indicated by sensitivity to 5-azacytidine, unlike Xenopus where this mechanism is necessary but not sufficient to maintain the silenced status. PMID- 23933481 TI - Evaluation of potential ionizing irradiation protectors and mitigators using clonogenic survival of human umbilical cord blood hematopoietic progenitor cells. AB - We evaluated the use of colony formation (colony-forming unit-granulocyte macrophage [CFU-GM], burst-forming unit erythroid [BFU-E], and colony-forming unit-granulocyte-erythroid-megakaryocyte-monocytes [CFU-GEMM]) by human umbilical cord blood (CB) hematopoietic progenitor cells for testing novel small molecule ionizing irradiation protectors and mitigators. The following compounds were added before (protection) or after (mitigation) ionizing irradiation: GS nitroxides (JP4-039 and XJB-5-131), the bifunctional sulfoxide MMS-350, the phosphoinositol-3-kinase inhibitor LY29400, triphenylphosphonium-imidazole fatty acid, the nitric oxide synthase inhibitor (MCF-201-89), the p53/mdm2/mdm4 inhibitor (BEB55), methoxamine, isoproterenol, propranolol, and the adenosine triphosphate-sensitive potassium channel blocker (glyburide). The drugs XJB-5 131, JP4-039, and MMS-350 were radiation protectors for CFU-GM. JP4-039 was also a radiation protector for CFU-GEMM. The drugs XJB-5-131, JP4-039, and MMS-350 were radiation mitigators for BFU-E, MMS-350 and JP4-039 were mitigators for CFU GM, and MMS350 was a mitigator for CFU-GEMM. In contrast, other drugs were effective in murine assays; TTP-IOA, LY294002, MCF201-89, BEB55, propranolol, isoproterenol, methoxamine, and glyburide but showed no significant protection or mitigation in human CB assays. These data support the testing of new candidate clinical radiation protectors and mitigators using human CB clonogenic assays early in the drug discovery process, thus reducing the need for animal experiments. PMID- 23933482 TI - Lateral temporal hyper-activation as a novel biomarker of mild cognitive impairment. AB - Memory dysfunction in mild cognitive impairment (MCI) due to Alzheimer's pathology is primarily associated with episodic memory deficits linked to deterioration of the medial temporal lobes (MTLs). Currently, there is a call to discover novel biomarkers of MCI in order to improve research criteria. Functional activation differences in MCI during episodic memory-task performance are often evidenced in the MTLs, and frontal and parietal lobes, but it has been suggested that examination of working memory (WM) differences may be more useful in detecting MCI. In the current study, MCI and control participants performed a complex WM span (CWMS) task while functional magnetic resonance imaging (fMRI) data were acquired. Results indicated hyper-activation of the lateral temporal lobes, MTLs, and frontal and parietal regions during encoding and maintenance, and hyper-activation of the lateral temporal, frontal, and parietal lobes during CWMS recall for the MCI participants. Medial and lateral temporal differences during encoding and maintenance are consistent with previous findings, but lateral temporal differences are often not elaborated upon. Hyper-activation of the lateral temporal lobes during WM encoding and maintenance, and also during recall, suggests that this region may provide valuable information regarding WM impairment in MCI and Alzheimer's. Given that whole-brain functional imaging of the MTLs is often limited due to artifact and partial voluming of sub-fields, examination of lateral temporal differences may provide a novel biomarker related to WM impairment in MCI. PMID- 23933483 TI - Neural basis of auditory expectation within temporal cortex. AB - Predictive coding frameworks of perception propose that neural networks form predictions of expected input and generate prediction errors when the external input does not match expectation. We therefore investigated the processing of unexpected sounds and silence in the auditory cortex using fMRI. Unexpected sounds, when compared to expected sounds, evoked greater activation in large areas of the left temporal and insular cortices. Additionally the left middle temporal gyrus exhibited greater activation to unexpected events in general, whether sounds or silence, when compared to the corresponding expected events. These findings support predictive coding models of perception, which suggest that regions of the temporal cortex function to integrate sensory information with predictive signals during auditory perception. PMID- 23933484 TI - Characterization of controlled low-strength material obtained from dewatered sludge and refuse incineration bottom ash: mechanical and microstructural perspectives. AB - Potential reuse of dewatered sludge (DS) and municipal solid waste incineration (MSWI) bottom ash as components to develop controlled low-strength material (CLSM) was explored. The effects of DS:MSWI bottom ash:calcium sulfoaluminate (CS A) cement ratio and thermal treatment of MSWI bottom ash at 900 degrees C on the mechanical and microstructural properties of CLSM were intensively studied to optimize the process. Results showed DS and MSWI bottom ash could be utilized for making CLSM. The CLSM prepared with milled MSWI bottom ash gave higher unconfined compressive strength (UCS) of 2.0-6.2 MPa following 1 year of curing at 1.0:0.1:0.9 <= DS:MSWI bottom ash:CS-A <= 1.0:0.8:0.2. However, the corresponding strengths for CLSM containing thermally treated MSWI bottom ash ranged from 0.7 to 4.6 MPa, decreasing 26-65%. The microstructural analysis by X-ray powder diffraction (XRD), Fourier transforms infrared spectroscopy (FT-IR), as well as scanning electron microscopy (SEM) combined with an energy dispersive X-ray spectroscopy (EDS) revealed that ettringite (C3A.3CS-.H32, or AFt) crystals were the most important strength-producing constituents which grew into and filled the CLSM matrix pores. Milled MSWI bottom ash addition favored the formation of highly crystalline AFt phases and accordingly enhanced compressive strengths of CLSM specimens. In contrast, thermal treatment at 900 degrees C produced new phases such as gehlenite (Ca2Al2SiO7) and hydroxylapatite (Ca5(PO4)3(OH)), which deteriorated the pozzolanic activity of bottom ash and caused the strengths to decrease. Leaching tests evidenced that leachable substances from CLSM samples exhibited negligible health and environmental risks. The results of this study suggested that MSWI bottom ash can be effectively recycled together with DS in developing CLSM mixtures with restricted use of CS-A cement. PMID- 23933485 TI - Multiaxial mechanical response and constitutive modeling of esophageal tissues: Impact on esophageal tissue engineering. AB - Congenital defects of the esophagus are relatively frequent, with 1 out of 2500 babies suffering from such a defect. A new method of treatment by implanting tissue engineered esophagi into newborns is currently being developed and tested using ovine esophagi. For the reconstruction of the biological function of native tissues with engineered esophagi, their cellular structure as well as their mechanical properties must be considered. Since very limited mechanical and structural data for the esophagus are available, the aim of this study was to investigate the multiaxial mechanical behavior of the ovine esophagus and the underlying microstructure. Therefore, uniaxial tensile, biaxial tensile and extension-inflation tests on esophagi were performed. The underlying microstructure was examined in stained histological sections through standard optical microscopy techniques. Moreover, the uniaxial ultimate tensile strength and residual deformations of the tissue were determined. Both the mucosa submucosa and the muscle layers showed nonlinear and anisotropic mechanical behavior during uniaxial, biaxial and inflation testing. Cyclical inflation of the intact esophageal tube caused marked softening of the passive esophagi in the circumferential direction. The rupture strength of the mucosa-submucosa layer was much higher than that of the muscle layer. Overall, the ovine esophagus showed a heterogeneous and anisotropic behavior with different mechanical properties for the individual layers. The intact and layer-specific multiaxial properties were characterized using a well-known three-dimensional microstructurally based strain energy function. This novel and complete set of data serves the basis for a better understanding of tissue remodeling in diseased esophagi and can be used to perform computer simulations of surgical interventions or medical-device applications. PMID- 23933486 TI - Functionalization of biomaterials with small osteoinductive moieties. AB - Human mesenchymal stem cells (MSCs) are currently recognized as a powerful cell source for regenerative medicine, notably for their capacity to differentiate into multiple cell types. The combination of MSCs with biomaterials functionalized with instructive cues can be used as a strategy to direct specific lineage commitment, and can thus improve the therapeutic efficacy of these cells. In terms of biomaterial design, one common approach is the functionalization of materials with ligands capable of directly binding to cell receptors and trigger specific differentiation signaling pathways. Other strategies focus on the use of moieties that have an indirect effect, acting, for example, as sequesters of bioactive ligands present in the extracellular milieu that, in turn, will interact with cells. Compared with complex biomolecules, the use of simple compounds, such as chemical moieties and peptides, and other small molecules can be advantageous by leading to less expensive and easily tunable biomaterial formulations. This review describes different strategies that have been used to promote substrate-mediated guidance of osteogenic differentiation of immature osteoblasts, osteoprogenitors and MSCs, through chemically conjugated small moieties, both in two- and three-dimensional set-ups. In each case, the selected moiety, the coupling strategy and the main findings of the study were highlighted. The latest advances and future perspectives in the field are also discussed. PMID- 23933487 TI - Tumor necrosis factor inhibition modulates thrombospondin-1 expression in human inflammatory joint disease through altered NR4A2 activity. AB - We examined thrombospondin-1 (THBS1, alias TSP-1) expression in human synovial tissue (ST) during the resolution phase of chronic inflammation and elucidated its transcriptional regulation by the orphan receptor 4A2 (NR4A2). In vivo, rheumatoid arthritis (RA) serum and ST revealed altered expression levels and tissue distribution of TSP-1. After anti-tumor necrosis factor therapy, a reciprocal relationship between TSP-1 and NR4A2 expression levels was measured in patients with clinical and ST responses to biological treatment. In vitro, primary RA fibroblast-like synoviocytes (FLSs) expressed minimal TSP-1 mRNA levels with high transcript levels of NR4A2, vascular endothelial growth factor (VEGF), and IL-8 measured. Hypoxic modulation of RA FLSs resulted in inverse expression levels of TSP-1 compared with NR4A2, IL-8, and VEGF. Ectopic NR4A2 expression led to reduced TSP-1 mRNA and protein levels with concomitant increases in proangiogenic mediators. NR4A2 transcriptional activity, independent of DNA binding, repressed the hTSP-1 promoter leading to reduced mRNA and protein release in immortalized K4IM FLSs. Bioinformatic and deletion studies identified a 5' region of the TSP-1 promoter repressed by NR4A2 and proangiogenic transcription factors, including NF-kappaB and Ets1/2. Stable depletion of NR4A2 levels resulted in a shift in the TSP-1/VEGF expression ratio. Thus, modulation of TSP-1 expression is achieved through anti-tumor necrosis factor therapy effects on specific transcriptional networks, suggesting that enhanced TSP-1 expression may help restore tissue homeostasis during resolution of inflammation. PMID- 23933488 TI - 15-Lipoxygenases in cancer: a double-edged sword? AB - Among the lipoxygenases, a diverse family of fatty acid dioxygenases with varying tissue-specific expression, 15-lipoxygenase (15-LOX) was found to be involved in many aspects of human cancer, such as angiogenesis, chronic inflammation, metastasis formation, and direct and indirect tumor suppression. Herein, evidence for the expression and action of 15-LOX and its orthologs in various neoplasms, including solid tumors and hematologic malignancies, is reviewed. The debate surrounding the impact of 15-LOX as either a tumor-promoting or a tumor suppressing enzyme is highlighted and discussed in the context of its role in other biological systems. PMID- 23933489 TI - Genome duplication and multiple evolutionary origins of complex migratory behavior in Salmonidae. AB - Multiple rounds of whole genome duplication have repeatedly marked the evolution of vertebrates, and correlate strongly with morphological innovation. However, less is known about the behavioral, physiological and ecological consequences of genome duplication, and whether these events coincide with major transitions in vertebrate complexity. The complex behavior of anadromy - where adult fishes migrate up rivers from the sea to their natal site to spawn - is well known in salmonid fishes. Some hypotheses suggest that migratory behavior evolved as a consequence of an ancestral genome duplication event, which permitted salinity tolerance and osmoregulatory plasticity. Here we test whether anadromy evolved multiple times within salmonids, and whether genome duplication coincided with the evolution of anadromy. We present a method that uses ancestral character simulation data to plot the frequency of character transitions over a time calibrated phylogenetic tree to provide estimates of the absolute timing of character state transitions. Furthermore, we incorporate extinct and extant taxa to improve on previous estimates of divergence times. We present the first phylogenetic evidence indicating that anadromy evolved at least twice from freshwater salmonid ancestors. Results suggest that genome duplication did not coincide in time with changes in migratory behavior, but preceded a transition to anadromy by 55-50 million years. Our study represents the first attempt to estimate the absolute timing of a complex behavioral trait in relation to a genome duplication event. PMID- 23933491 TI - Essential role of Bmp signaling and its positive feedback loop in the early cell fate evolution of chordates. AB - In chordates, early separation of cell fate domains occurs prior to the final specification of ectoderm to neural and non-neural as well as mesoderm to dorsal and ventral during development. Maintaining such division with the establishment of an exact border between the domains is required for the formation of highly differentiated structures such as neural tube and notochord. We hypothesized that the key condition for efficient cell fate separation in a chordate embryo is the presence of a positive feedback loop for Bmp signaling within the gene regulatory network (GRN), underlying early axial patterning. Here, we therefore investigated the role of Bmp signaling in axial cell fate determination in amphioxus, the basal chordate possessing a centralized nervous system. Pharmacological inhibition of Bmp signaling induces dorsalization of amphioxus embryos and expansion of neural plate markers, which is consistent with an ancestral role of Bmp signaling in chordate axial patterning and neural plate formation. Furthermore, we provided evidence for the presence of the positive feedback loop within the Bmp signaling network of amphioxus. Using mRNA microinjections we found that, in contrast to vertebrate Vent genes, which promote the expression of Bmp4, amphioxus Vent1 is likely not responsible for activation of cephalochordate ortholog Bmp2/4. Cis-regulatory analysis of amphioxus Bmp2/4, Admp and Chordin promoters in medaka embryos revealed remarkable conservation of the gene regulatory information between vertebrates and basal chordates. Our data suggest that emergence of a positive feedback loop within the Bmp signaling network may represent a key molecular event in the evolutionary history of the chordate cell fate determination. PMID- 23933490 TI - Inactivation of Tgfbr2 in Osterix-Cre expressing dental mesenchyme disrupts molar root formation. AB - It has been difficult to examine the role of TGF-beta in post-natal tooth development due to perinatal lethality in many of the signaling deficient mouse models. To address the role of Tgfbr2 in postnatal tooth development, we generated a mouse in which Tgfbr2 was deleted in odontoblast- and bone-producing mesenchyme. Osx-Cre;Tgfbr2(fl/fl) mice were generated (Tgfbr2(cko)) and post natal tooth development was compared in Tgfbr2(cko) and control littermates. X ray and MUCT analysis showed that in Tgfbr2(cko) mice radicular dentin matrix density was reduced in the molars. Molar shape was abnormal and molar eruption was delayed in the mutant mice. Most significantly, defects in root formation, including failure of the root to elongate, were observed by postnatal day 10. Immunostaining for Keratin-14 (K14) was used to delineate Hertwig's epithelial root sheath (HERS). The results showed a delay in elongation and disorganization of the HERS in Tgfbr2(cko) mice. In addition, the HERS was maintained and the break up into epithelial rests was attenuated suggesting that Tgfbr2 acts on dental mesenchyme to indirectly regulate the formation and maintenance of the HERS. Altered odontoblast organization and reduced Dspp expression indicated that odontoblast differentiation was disrupted in the mutant mice likely contributing to the defect in root formation. Nevertheless, expression of Nfic, a key mesenchymal regulator of root development, was similar in Tgfbr2(cko) mice and controls. The number of osteoclasts in the bone surrounding the tooth was reduced and osteoblast differentiation was disrupted likely contributing to both root and eruption defects. We conclude that Tgfbr2 in dental mesenchyme and bone is required for tooth development particularly root formation. PMID- 23933492 TI - The NF-Y complex negatively regulates Caenorhabditis elegans tbx-2 expression. AB - T-box genes are frequently expressed in dynamic patterns during animal development, but the mechanisms controlling expression of these genes are not well understood. The Caenorhabditis elegans T-box gene tbx-2 is essential for development of the ABa-derived pharyngeal muscles, specification of neural cell fate in the HSN/PHB lineage, and adaptation in olfactory neurons. The tbx-2 expression pattern is complex, and expression has been described in pharyngeal precursors and body wall muscles during embryogenesis, and amphid sensory neurons and pharyngeal neurons in adults. To examine mechanisms regulating tbx-2 gene expression, we performed an RNAi screen of transcription factor genes in strains containing a Ptbx-2::gfp reporter and identified the Nuclear Factor Y (NF-Y) complex as a negative regulator of tbx-2 expression. NF-Y is a heterotrimeric CCAAT-binding complex consisting of A-C subunits, and reduction of the NF-Y subunits nfya-1, nfyb-1, or nfyc-1 by RNAi or using mutants results in ectopic Ptbx-2::gfp expression in hypodermal seam cells and gut. Mutation of two CCAAT boxes in the tbx-2 promoter results in a similar pattern of ectopic Ptbx-2::gfp expression, suggesting NF-Y directly represses the tbx-2 promoter. tbx-2 mRNA is moderately increased in nfya-1 null mutants, indicating NF-Y represses expression of endogenous tbx-2. Finally we identify and characterize a second-site mutation that enhances lethality of a temperature sensitive tbx-2 mutant and show that this mutation is a deletion in the nfyb-1 gene. Together, these results identify NF-Y as an important regulator of tbx-2 function in vivo. PMID- 23933493 TI - A comparison of lipid storage in Phaeodactylum tricornutum and Tetraselmis suecica using laser scanning confocal microscopy. AB - Microalgae contain lipid bodies (LBs) composed of triacylglycerols, which can be converted to biodiesel. Here we demonstrate a method to study the accumulation patterns of LBs in different microalgae strains and culture conditions utilizing laser scanning confocal microscopy (LSCM) with BODIPY 505/515 (4,4-difluoro 1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene) staining, in parallel with Nile Red (9-diethylamino-5H-benzo-a-phenoxazine-5-one) fluorescence analysis of intracellular lipids in microplates. Phaeodactylum tricornutum and Tetraselmis suecica were selected as model organisms and monitored throughout the growth phases in standard and nitrogen-deficient growth conditions. Utilizing image quantification techniques, the number and morphology of LBs suggest that P. tricornutum accumulates lipids by merging with existing LBs, while T. suecica synthesizes new LBs. We observed that T. suecica accumulates a higher number of LBs and total volume of lipids per cell, while P. tricornutum accumulates only 1 2 LBs with a larger volume per LB. LSCM analysis complements Nile Red (NR) methods because LSCM provides three-dimensional images of lipid accumulation at a cellular level, while NR analysis can quickly monitor the total levels of intracellular lipids for phenotypic screening. Using NR analysis, we have observed that the optimal harvest date for P. tricornutum and T. suecica in standard cultivation conditions is 24 and 42 days, respectively. Comparison with nitrogen-deficient growth conditions is utilized as a model to confirm that LSCM and NR analysis can be used to study lipid storage and productivity for diverse growth conditions and various strains of microalgae. PMID- 23933494 TI - An improved protocol for electroporation in members of the genus Gordonia. AB - Gordonia are high GC gram-positive bacteria that have not yet been exploited well for biotechnological purposes because of the limited genetic tools. Described here is an improved protocol for electroporation, which is useful for several Gordonia species. The maximum transformation efficiency obtained was 2.8 * 10(4)/MUg (Gordonia rubropertinctus, Gordonia sp), and 1.7 * 10(3)/MUg (Gordonia amarae). PMID- 23933495 TI - Association of ITPA polymorphisms rs6051702/rs1127354 instead of rs7270101/rs1127354 as predictor of ribavirin-associated anemia in chronic hepatitis C treated patients. AB - Functional variants rs7270101 and rs1127354 of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of no functional rs6051702 polymorphism. Since a simultaneous evaluation of the three ITPA SNPs for hemolytic anemia has not yet been investigated, we aimed to understand the contribution of each SNPs and its potential clinical use to predict anemia in HCV treated patients. A retrospective analysis included 379 HCV treated patients. The ITPA variants rs6051702, rs7270101 and rs1127354 were genotyped and tested for association with achieving anemia at week 4. We also investigated, using multivariate logistic regression, the impact of each single and paired associated polymorphism on anemia onset. All SNPs were associated with Hb decrease. The carrier of at least one variant allele in the functional ITPA SNPs was associated with a lower decrement of Hb, as compared to patients without a variant allele. In multivariate logistic regression analyses the carrier of a variant allele in the rs6051702/rs1127354 association (OR=0.11, p=1.75*10(-5)) and Hb at baseline (OR=1.51, p=1.21*10(-4)) were independently associated with protection against clinically significant anemia at week 4. All ITPA polymorphisms considered were shown to be significantly associated with anemia onset. A multivariate regression model based on ITPA genetic polymorphisms was developed for predicting the risk of anemia. Considering the characterization of pre-therapy anemia predictors, rs6051702 SNP in association to rs1127354 is more informative in order to avoid this relevant adverse event. PMID- 23933496 TI - Comparative proteome approach demonstrates that platelet-derived growth factor C and D efficiently induce proliferation while maintaining multipotency of hMSCs. AB - This is the first study that comprehensively describes the effects of the platelet-derived growth factor (PDGF) isoforms C and D during in vitro expansion of human mesenchymal stem cells (hMSCs). Our results show that PDGFs can enhance proliferation of hMSCs without affecting their multipotency. It is of great value to culture and expand hMSCs in a safe and effective manner without losing their multipotency for manipulation and further development of cell-based therapies. Moreover, differential effects of PDGF isoforms have been observed on lineage specific differentiation induced by BMP2 and Vitamin D3. Based on label-free LC based quantitative proteomics approach we have furthermore identified specific pathways induced by PDGFs during the proliferation process, showing the importance of bioinformatics tools to study cell function. PMID- 23933497 TI - Hepatoprotective action of Orthosiphon diffusus (Benth.) methanol active fraction through antioxidant mechanisms: an in vivo and in vitro evaluation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Preparations of Orthosiphon diffusus (Benth.) have been used by folk medicinal practitioners in the Western Ghats of India for treating inflammation, hepatitis and jaundice for many years and their effectiveness is widely acclaimed among the tribal communities. AIM OF THE STUDY: To evaluate the mechanisms behind the antioxidant and hepatoprotective potential of Orthosiphon diffusus methanol active fraction (MAF) using in vivo (rat) and in vitro (cell culture) models. MATERIALS AND METHODS: Neutralization of CCl4 induced hepatotoxicity by MAF was evaluated in rats. Towards this, serum levels of hepatic injury markers (lactate dehydrogenase and alkaline phosphatase), antioxidant enzymes in the liver homogenates, and histological examination were performed. In in vitro studies, mechanisms of neutralization of H2O2-induced toxicity by MAF using MTT, Comet assay and up-regulation of antioxidant enzymes at genetic level (RT-PCR) was performed in HepG2 cells. RESULTS: Rats pre-treated with Orthosiphon diffusus MAF demonstrated significantly reduced levels of serum LDH (1.3-fold, p<0.05) and ALP (1.6-fold, p<0.05). Similarly, multiple dose MAF administration demonstrated significantly enhanced levels (p<0.05) of antioxidant enzymes in the liver homogenates. Histological analysis revealed complete neutralization of CCl4-induced liver injury by the extract. The in vitro studies demonstrated that, pre-treatment of MAF effectively prevented H2O2-induced oxidative stress, genotoxicity and significantly enhanced (~6-fold, p<0.01) expression of genes for antioxidant enzymes. CONCLUSIONS: Orthosiphon diffusus MAF demonstrated significant hepatoprotection against CCl4-induced hepatotoxicity by antioxidant mechanisms comparable to silymarin. H2O2-induced oxidative stress was completely neutralized by MAF through enhanced expression of genes for antioxidant enzymes. Therefore, this study validates the use of Orthosiphon diffusus by folk medicinal practitioners in India. Further, MAF of Orthosiphon diffusus can serve as a strong candidate for the development of herbal hepatoprotective agents. PMID- 23933498 TI - Evidence does not support the suggestion that gustatory exposure to bitter tastants reduces cardiac activity. PMID- 23933500 TI - Heterogeneity of calretinin expression in the avian cerebellar cortex of pigeons and relationship with zebrin II. AB - The cerebellar cortex has a fundamental parasagittal organization that is reflected in the physiological responses of Purkinje cells, projections of Purkinje cells, afferent inputs from climbing and mossy fibres and the expression of several molecular markers. The most thoroughly studied of these molecular markers is zebrin II (ZII; a.k.a. aldolase C). ZII is differentially expressed in Purkinje cells, resulting in a pattern of sagittal stripes of high expression (ZII+ve) interdigitated with stripes of little or no expression (ZII-ve). The calcium binding protein calretinin (CR) is expressed heavily in mossy fibres terminating throughout the cerebellar cortex, but whether CR is heterogeneously expressed in parasagittal stripes, like ZII, is unknown. In this study, we examined CR expression in the cerebellum of pigeons and compared it to that of ZII. CR was expressed heavily in the granule layer in mossy fibres and their terminal rosettes. Moreover, CR is expressed heterogeneously in the granule layer such that there are sagittal stripes of heavy CR labelling (CR+ve) alternating with stripes of weaker labelling (CR-ve). The CR heterogeneity is most notable in folium IXcd and folia II-IV in the anterior lobe. In the anterior lobe, the central CR+ve stripe spanning the midline is aligned with the central ZII+ve stripe, whereas the other CR+ve stripes are aligned with the ZII-ve stripes. In IXcd, the CR+ve stripes are aligned with the ZII+ve stripes. This combination of aligned and unaligned CR+ve stripes, relative to ZII+ve stripes, differs from that of parvalbumin and other neurochemical markers, but the functional consequences of this is unclear. With respect to the posterior lobe, we suggest that the CR+ve mossy fibres to IXcd originate in two retinal recipient nuclei that are involved in the processing of optic flow. PMID- 23933499 TI - Antidiabetic effect of total flavonoids from Sanguis draxonis in type 2 diabetic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sanguis draxonis (SD) is a kind of red resin obtained from the wood of Dracaena cochinchinensis (Lour.) S. C. Chen (Dracaena cochinchinensis). It is a Chinese traditional herb that is prescribed for the handling of diabetic disorders, which is also supported by an array of scientific studies published in recent years. Although chemical constituents of this plant material have also been previously evaluated (Tang et al., 1995; Wei et al., 1998), it still remains poorly understood which constituent is the major contributor to its antidiabetic activities. Moreover, very little is known about the molecular mechanisms underlying antidiabetic activities of SD. Flavonoids exist at a high level in SD. The aim of this study is to evaluate the antidiabetic effects of total flavonoids from SD (SDF) in type 2 Diabetes mellitus (T2DM) rats. MATERIALS AND METHODS: T2DM rats were induced by 4 weeks high-fat diet and a singular injection of streptozotocin (STZ) (35mg/kg). Then T2DM rats were treated with SDF for 21 days, using normal saline as the negative control. For comparison, a standard antidiabetic drug, metformin (200mg/kg), was used as a positive control. Three weeks later, relative biochemical indexes were determined and histopathological examinations were performed to assess the antidiabetic activities of SDF. RESULTS: SDF not only exhibited a significant hypoglycemic activity, but also alleviated dyslipidemia, tissue steatosis, and oxidative stress associated with T2DM. Moreover, considerable pancreatic islet protecting effects could be observed after SDF treatment. Further investigations revealed a potential anti-inflammation activity of SDF by determining serum levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and C reactive protein (CRP). CONCLUSIONS: This study demonstrates both hypoglycemic and hypolipidemic effects of SDF in T2DM rats, suggesting that flavonoids are the major active ingredients accounting for the antidiabetic activity of SD. Alleviating chronic inflammation responses and protecting pancreatic islets are possible mechanisms involved in the antidiabetic activity of SDF. PMID- 23933501 TI - Urotensin II exerts antiapoptotic effect on NRK-52E cells through prostacyclin mediated peroxisome proliferator-activated receptor alpha and Akt activation. AB - Urotensin II (UII) is a cyclic vasoactive peptide which is mainly expressed in kidneys. Although elevated plasma UII levels are associated with renal impairment, the influence of UII on renal injury is unclear. In this study, we monitored the influence of UII on gentamicin-induced apoptosis in rat tubular cells (NRK-52E). We found that UII significantly reduced gentamicin-induced apoptosis and apoptotic signals. Blocking endogenous UII secretion caused cells to be more susceptible to gentamicin. In gentamicin-treated mice, UII also expressed protective effect on renal tubular cells. UII was also found to induce prostacyclin (PGI2) production, which caused peroxisomal proliferator-activated receptor alpha (PPARalpha) activation as revealed by both PGI2 synthase siRNA transfection and piroxicam treatment. Blockage of PPARalpha by siRNA transfection inhibited UII-induced Akt phosphorylation and the antiapoptotic effect of UII. Our results suggest that UII can protect renal tubular cells from gentamicin induced apoptosis through PGI2-mediated PPARalpha and Akt activation. PMID- 23933502 TI - Adaptive evolution of attack ability promotes the evolutionary branching of predator species. AB - In this paper, with the methods of adaptive dynamics and critical function analysis, we investigate the evolutionary branching phenomenon of predator species. We assume that both the prey and predators are density-dependent and the predator's attack ability can adaptively evolve, but this has a cost in terms of its death rate. First, we identify the general properties of trade-off relationships that allow for a continuously stable strategy and evolutionary branching in the predator strategy. It is found that if the trade-off curve is weakly concave near the singular strategy, then the singular strategy may be an evolutionary branching point. Second, we find that after the branching has occurred in the predator strategy, if the trade-off curve is convex-concave convex, the predator species will eventually evolve into two different types, which can stably coexist on the much longer evolutionary timescale and no further branching is possible. PMID- 23933503 TI - The radium legacy: Contaminated land and the committed effective dose from the ingestion of radium contaminated materials. AB - The manufacture and use of radium in the early to mid-20th century within industrial, medicinal and recreational products have resulted in a large number of contaminated sites across a number of countries with notable examples in the USA and Europe. These sites, represent a significant number of unregulated sources of potential radiological exposure that have collectively and hitherto not been well characterised. In 2007, the Radioactive Contaminated Land (RCL) Regulations came into force in the UK, providing the statutory guidance for regulators to classify and deal with RCL. Here we report on results derived from digestion experiments to estimate committed effective dose, a key aspect of the RCL Regulations, from the ingestion of radium contaminated sources that can be found in the environment. This case study includes particles, clinker and artefacts that arise from past military activities on a site that was once an airfield at Dalgety Bay on the Firth of Forth, UK. Since 2011 the number of radium contaminated finds has increased by one order of magnitude on the foreshore areas of Dalgety Bay. The increase in finds may in large part be attributed to a change in monitoring practice. A subsample of sixty sources was selected, on the basis of their activity and dimensions, and subjected to digestion in simulated stomach and lower intestine solutions. The study demonstrated that more radium-226 ((226)Ra) and lead-210 ((210)Pb; driven by Polonium solubility) are dissolved from sources in artificial 'stomach' solutions compared with 'lower intestine' solutions. The combined 'gut' solubility for (226)Ra and apparent (210)Pb varied from less than 1% to up to 35% ICRP 72 conversion factors were used to convert the activities measured in solution to committed effective dose. A little over 10% of the sources tested dissolved sufficient radioactivity to result in 100mSv committed effective dose to an infant. Using the solubility of 35% as a worst case, minimum source activities necessary to deliver 100mSv to the full age range of users of the foreshore were estimated. All the estimated activities have been detected and recovered through routine monitoring. PMID- 23933504 TI - Global DNA hypermethylation is associated with high serum levels of persistent organic pollutants in an elderly population. AB - Dioxin exposure has experimentally been associated with changes in DNA methylation, an epigenetic change that is associated with disease. The present study aims to investigate if serum levels of dioxin and other persistent environmental pollutants are related to global DNA methylation in a human sample. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (all aged 70), global DNA methylation was measured by the Luminometric Methylation Assay in 524 subjects. Twenty-three different POPs, including 16 PCBs, five pesticides, one dioxin (OCDD) and one brominated flame retardant (BDE47) were analysed by HRGC/HRMS. Ten single nucleotide polymorphisms (SNPs) in the Aryl hydrocarbon (Ah)-receptor were analysed by mini-sequencing. High levels of toxic equivalency (TEQ) for PCBs and dioxin were associated with DNA hypermethylation (p=0.030). This was mainly attributed to coplanar non-ortho PCBs. While no significant associations were found between DNA methylation and SNPs in the Ah-receptor, an interaction was found between the SNP rs2237297 and TEQ so that TEQ was associated with hypermethylation (p=0.009) only in subjects with one G-allele (n=103). Also high levels of the PCB126 congener, the OCDD, and the pesticide metabolite p,p'-DDE were related to DNA hypermethylation (p=0.01, 0.03 and 0.003, respectively). In conclusion, in a sample of elderly subjects, high TEQ including PCBs and the dioxin OCDD and high serum levels of PCB126, OCDD, and p,p'-DDE were related to global DNA hypermethylation in a cross sectional analysis. PMID- 23933505 TI - Paranormal believers are more prone to illusory agency detection than skeptics. AB - It has been hypothesized that illusory agency detection is at the basis of belief in supernatural agents and paranormal beliefs. In the present study a biological motion perception task was used to study illusory agency detection in a group of skeptics and a group of paranormal believers. Participants were required to detect the presence or absence of a human agent in a point-light display. It was found that paranormal believers had a lower perceptual sensitivity than skeptics, which was due to a response bias to 'yes' for stimuli in which no agent was present. The relation between paranormal beliefs and illusory agency detection held only for stimuli with low to intermediate ambiguity, but for stimuli with a high number of visual distractors responses of believers and skeptics were at the same level. Furthermore, it was found that illusory agency detection was unrelated to traditional religious belief and belief in witchcraft, whereas paranormal beliefs (i.e. Psi, spiritualism, precognition, superstition) were strongly related to illusory agency detection. These findings qualify the relation between illusory pattern perception and supernatural and paranormal beliefs and suggest that paranormal beliefs are strongly related to agency detection biases. PMID- 23933506 TI - Enhanced phytoremediation of mixed heavy metal (mercury)-organic pollutants (trichloroethylene) with transgenic alfalfa co-expressing glutathione S transferase and human P450 2E1. AB - Soil contamination is a global environmental problem and many efforts have been made to find efficient remediation methods over the last decade. Moreover, remediation of mixed contaminated soils are more difficult. In the present study, transgenic alfalfa plants pKHCG co-expressing glutathione S-transferase (GST) and human P450 2E1 (CYP2E1) genes were used for phytoremediation of mixed mercury (Hg)-trichloroethylene (TCE) contaminants. Simultaneous expression of GST and CYP2E1 may produce a significant synergistic effect, and leads to improved resistance and accumulation to heavy metal-organic complex contaminants. Based on the tolerance and accumulation assays, pKHCG transgenic plants were more resistant to Hg/TCE complex pollutants and many folds higher in Hg/TCE accumulation than the non-transgenic control plants in mixed contaminated soil. It is confirmed that GST and CYP2E1 co-expression may be a useful strategy to help achieve mixed heavy metal-organic pollutants phytoremediation. PMID- 23933507 TI - Buccal cell FISH and blood PCR-Y detect high rates of X chromosomal mosaicism and Y chromosomal derivatives in patients with Turner syndrome. AB - Turner syndrome (TS) is the result of (partial) X chromosome monosomy. In general, the diagnosis is based on karyotyping of 30 blood lymphocytes. This technique, however, does not rule out tissue mosaicism or low grade mosaicism in the blood. Because of the associated risk of gonadoblastoma, mosaicism is especially important in case this involves a Y chromosome. We investigated different approaches to improve the detection of mosaicisms in 162 adult women with TS (mean age 29.9 +/- 10.3). Standard karyotyping identified 75 patients (46.3%) with a non-mosaic monosomy 45,X. Of these 75 patients, 63 underwent additional investigations including FISH on buccal cells with X- and Y-specific probes and PCR-Y on blood. FISH analysis of buccal cells revealed a mosaicism in 19 of the 63 patients (30.2%). In five patients the additional cell lines contained a (derivative) Y chromosome. With sensitive real-time PCR we confirmed the presence of this Y chromosome in blood in three of the five cases. Although Y chromosome material was established in ovarian tissue in two patients, no gonadoblastoma was found. Our results confirm the notion that TS patients with 45,X on conventional karyotyping often have tissue specific mosaicisms, some of which include a Y chromosome. Although further investigations are needed to estimate the risk of gonadoblastoma in patients with Y chromosome material in buccal cells, we conclude that FISH or real-time PCR on buccal cells should be considered in TS patients with 45,X on standard karyotyping. PMID- 23933508 TI - GM-CSF as a therapeutic target in inflammatory diseases. AB - GM-CSF is a well-known haemopoietic growth factor that is used in the clinic to correct neutropaenia, usually as a result of chemotherapy. GM-CSF also has many pro-inflammatory functions and recent data implicates GM-CSF as a key factor in Th17 driven autoimmune inflammatory conditions. In this review we summarize the findings that have led to the development of GM-CSF antagonists for the treatment of autoimmune diseases like rheumatoid arthritis (RA) and discuss some results of recent clinical trials of these agents. PMID- 23933509 TI - Conformational plasticity at the IgE-binding site of the B-cell receptor CD23. AB - IgE antibodies play a central role in allergic disease. They recognize allergens via their Fab regions, whilst their effector functions are controlled through interactions of the Fc region with two principal cell surface receptors, FcERI and CD23. Crosslinking of FcERI-bound IgE on mast cells and basophils by allergen initiates an immediate inflammatory response, while the interaction of IgE with CD23 on B-cells regulates IgE production. We have determined the structures of the C-type lectin "head" domain of CD23 from seven crystal forms. The thirty-five independent structures reveal extensive conformational plasticity in two loops that are critical for IgE binding. PMID- 23933511 TI - The antigenic architecture of the hemagglutinin of influenza H5N1 viruses. AB - Human infection with the highly pathogenic avian influenza A virus H5N1 is associated with a high mortality and morbidity. H5N1 continues to transmit from poultry to the human population, raising serious concerns about its pandemic potential. Current influenza H5N1 vaccines are based upon the elicitation of a neutralizing antibody (Ab) response against the major epitope regions of the viral surface glycoprotein, hemagglutinin (HA). However, antigenic drift mutations in immune-dominant regions on the HA structure allow the virus to escape Ab neutralization. Epitope mapping using neutralizing monoclonal antibodies (mAb) helps define mechanisms of antigenic drift, neutralizing escape and can facilitate pre-pandemic vaccine design. This review explores the current knowledge base of the antigenic sites of the H5N1 HA molecule. The relationship between the epitope architecture of the H5N1 HA, antigenic evolution of the different H5N1 lineages and the antigenic complexity of the H5N1 virus lineages that constitute potential pandemic strains are discussed in detail. PMID- 23933510 TI - CD8low T-cell subpopulation is increased in patients with chronic hepatitis B virus infection. AB - Recent studies suggest that CD8(+) T cells with down-regulated CD8 expression (CD3(+)CD8(low) T cells) represented as a distinct phenotype of CD8(+) T cells are increased and linked to disease severity in some chronically persistent infection, such as chronic HIV and parasite infection. However, the role of CD3(+)CD8(low) T cells in the context of chronic HBV infection is poorly understood. In this study, peripheral blood samples of 47 chronic hepatitis B patients and 19 healthy controls were collected and tested for the frequency and phenotype of CD8(low) T cells. The circulating CD8(low) T cells were significantly more frequent in the patients compared to those in healthy controls, and the CD8(low) T cells in the patients expressed less IFN-gamma and more mTGF-beta1 than those in the controls, suggesting their type-2 polarized and suppressive properties. Meanwhile, the concentrations of plasma soluble HLA class I molecules were found elevated in the patients, and positively associated with the frequencies of CD8(low) T cells. Furthermore, the CD8(low) T-cell frequency in the HLA-A2-positive patients (n=21) was found negatively correlated with the T cell responsiveness against the HBc18-27 peptide, the latter was impaired as revealed by IFN-gamma Elispot assay. Our findings suggested that a better understanding of the involvement of CD8(low) T cells in chronically persistent HBV infection would add to our knowledge of the impaired T-cell response in the patients. PMID- 23933512 TI - Lipoteichoic acid from Staphylococcus aureus directly affects cardiomyocyte contractility and calcium transients. AB - Lipoteichoic acid (LTA) is the key pathogenic factor of gram-positive bacteria and contributes significantly to organ dysfunction in sepsis, a frequent complication in critical care patients. We hypothesized that LTA directly affects cardiomyocyte function, thus contributing to cardiac failure in sepsis. This study was designed to evaluate the effects of LTA on contractile properties and calcium-transients of isolated adult rat cardiomyocytes. When myocytes were exposed to LTA for 1h prior to analysis, the amplitudes of calcium-transients as well as sarcomere shortening increased to 130% and 142% at 1 Hz stimulation frequency. Relengthening of sarcomeres as well as decay of calcium-transients was accelerated after LTA incubation. Exposure to LTA for 24 h resulted in significant depression of calcium-transients as well as of sarcomere shortening compared to controls. One of the major findings of our experiments is that LTA most likely affects calcium-handling of the cardiomyocytes. The effect is exacerbated by reduced extracellular calcium, which resembles the clinical situation in septic patients. Functionally, an early stimulating effect of LTA with increased contractility of the cardiomyocytes may be an in vitro reflection of early hyperdynamic phases in clinical sepsis. Septic disorders have been shown to induce late hypodynamic states of the contractile myocardium, which is also supported at the single-cell level in vitro by results of our 24h-exposure to LTA. PMID- 23933513 TI - Molecular cloning and functional characterization of a short peptidoglycan recognition protein (HcPGRPS1) from the freshwater mussel, Hyriopsis cumingi. AB - Peptidoglycan recognition proteins (PGRPs), which are evolutionarily conserved from invertebrates to vertebrates, function as pattern-recognition and effector molecules in innate immunity. In the present study, a short-form PGRP, designated as HcPGRPS1 was identified from freshwater mussel Hyriopsis cumingi. The deduced amino acid sequence of HcPGRPS1 is composed of 235 residues which contains a conserved PGRP domain at the C-terminus. Sequence analysis showed that HcPGRPS1 shared high identities with other known PGRPs. The mRNA of HcPGRPS1 is constitutively expressed in a wide range of all tested tissues, with highest expression level in hepatopancreas, and its expression in tissues (gonad, nephridium, gill and foot) was up-regulated significantly after LPS or PGN stimulation (P<0.05). The recombinant protein of HcPGRPS1 exhibited binding activity and peptidoglycan-lytic amidase activity toward Lys-PGN from Staphylococcus aureus and DAP-PGN from Bacillus subtilis. Furthermore, recombinant HcPGRPS1 displayed strong antibacterial activity to both Gram negative bacteria Escherichia coli, Aeromonas hydrophila, Aeromonas sobria and Gram-positive bacteria S. aureus in the presence of Zn(2+). These results suggested that HcPGRPS1 plays a multifunctional role in the defense and protection mechanisms of mussel innate immunity against infections. PMID- 23933514 TI - Head anatomy of adult Sisyra terminalis (Insecta: Neuroptera: Sisyridae)- functional adaptations and phylogenetic implications. AB - The external and internal head anatomy of Sisyra terminalis is described in detail and compared with data from literature. A salivary pump consisting of a peculiar reservoir and a hitherto unknown muscle, M. ductus salivarii, is newly described for Neuroptera. The upward folded paraglossae form a secondary prolongation of the salivary system. These structures are discussed as functional adaptations for feeding on aphids and desiccated honeydew. In a phylogenetic analysis the basal position of the Sisyridae within Neuroptera is retrieved. The following new synapomorphies are postulated: (1) for Neuropterida, the presence of a M. submentomentalis and prepharyngeal ventral transverse muscles, and the absence of a M. submentopraementalis; (2) for Neuroptera and Sialidae, the presence of a mandibular gland; (3) for Neuroptera, the presence of four scapopedicellar muscles; (4) for Neuroptera exclusive Nevrorthidae and Sisyridae, the weakening of dorsal tentorial arms, the presence of a M. tentoriomandibularis medialis superior and the shifted origin of M. tentoriocardinalis. PMID- 23933515 TI - Comparison of the Norway lobster (Nephrops norvegicus) gut bacterial communities using 16S rDNA clone libraries and pyrosequencing. AB - By comparing 16S rDNA cloning and 454 pyrosequencing in the Nephrops norvegicus midgut, several common bacterial OTUs were detected. However, when only one method is to be selected, it needs to be considered whether the revealing of rare OTUs or their accurate phylogenetic relationships is mostly preferred. PMID- 23933516 TI - Wakefulness-promoting role of the inferior colliculus. AB - The inferior colliculus (IC) is a mesencephalic auditory nucleus involved in several functions including the analysis of the frequency and intensity of sounds as well as sound localization. In addition to auditory processes, the IC controls the expression of defensive responses. The objective of the present study was to test the hypothesis that the IC contributes to the maintenance of wakefulness. For this purpose, several experimental approaches were performed in urethane anesthetized guinea pigs. Electrical or chemical stimulation of the IC resulted in electroencephalographic (EEG) desynchronization, theta rhythm in the hippocampus and an increase in heart rate; all of these effects suggest an arousal reaction. Furthermore, by means of extracellular unit recordings, we determined that most IC neurons increased their spontaneous and tone-evoked responses in association with EEG desynchronization. We also studied the effect on sleep and wakefulness of bilateral acute inhibition of the IC by microinjections of muscimol (a GABAA agonist), as well as the effect of bilateral IC lesions in chronically-instrumented (drug-free) guinea pigs. Acute (via muscimol microinjections), but not chronic (via electrolytic lesions) inhibition of the IC decreased wakefulness., We conclude that the IC plays an active role in the maintenance of wakefulness. Further, we propose that this nucleus may mediate arousal responses induced by biologically significant sounds. PMID- 23933518 TI - Cell-matrix interactions: new tools and fresh perspectives. PMID- 23933517 TI - RAF and antioxidants prevent cell death induction after growth factor abrogation through regulation of Bcl-2 proteins. AB - We have shown previously that mitochondrial ROS production is essential to turn growth factor (GF) removal into cell death. Activated RAF, AKT, Bcl-2 and antioxidants protected equally well against ROS accumulation and subsequent death. Here we investigated whether protection by survival signaling and antioxidants utilizes shared or distinct targets. Using serum deprivation from NIH 3T3 fibroblasts and IL-3 withdrawal from promyeloid 32D cells, we showed that pro-survival signaling by activated RAF but not AKT prevented the decline in Mcl 1 following GF abrogation. GF starvation increased levels of Bim in both model systems, which was prevented by RAF in 32D cells but not in NIH 3T3 fibroblasts. RAF and AKT suppressed activation and mitochondrial translocation of BAX. Also, antioxidant treatment efficiently prevented BAX activation and death of 32D cells but showed little effect on its mitochondrial translocation. No significant impact of antioxidant treatment on Bim or Mcl-1 expression was observed. ROS produced during GF abrogation also did not alter the activity of intracellular signaling pathways, which have been implicated previously in cell killing by pro oxidants. Together these data suggest Bcl-2 family proteins as convergence point for RAF and ROS in life and death decisions. PMID- 23933519 TI - Cardiac regeneration in non-mammalian vertebrates. AB - The heart is a robust organ, capable of pumping nutrients and transferring oxygen throughout the body via a network of capillaries, veins and arteries, for the entirety of a human's life. However, the fragility of mammalian hearts is also evident when it becomes damaged and parts of the organ fail to function. This is due to the fact that rather than replenishing the damaged areas with functional cellular mass, fibrotic scar tissue is the preferred replacement, resulting in an organ with functional deficiencies. Due to the mammalian hearts incapability to regenerate following damage and the ever-increasing number of people worldwide suffering from heart disease, tireless efforts are being made to discover ways of inducing a regenerative response in this most important organ. One such avenue of investigation involves studying our distantly related non-mammalian vertebrate cousins, which over the last decade has proved to us that cardiac regeneration is possible. This review will highlight these organisms and provide insights into some of the seminal discoveries made in the heart regeneration field using these amazing chordates. PMID- 23933520 TI - Surfactant-dependence of nanoparticle treatment in murine experimental colitis. AB - Inflammatory bowel disease is a chronic relapsing inflammation of the gut with the two main forms being ulcerative colitis and Crohn's disease. Nanoparticulate drug carrier systems have been proven to enhance the therapeutic efficiency and to diminish adverse effects of the anti-inflammatory treatment due to their size dependent accumulation in the inflamed regions of the gut. The influence of surface properties on the accumulation selectivity and intensity of such nanoparticles is mainly unclear. Accordingly sized particles (~200 nm) were prepared by the emulsification solvent evaporation technique using different surfactants (polysorbate 20, sodium dodecyl sulphate, sodium cholate, cetyltrimethylammonium bromide, polyvinyl alcohol). In a murine colitis model the particles prepared with polysorbate 20 as surfactant led to a 34.8-fold higher particle content in the inflamed areas of the colon compared to the healthy gut and to a 4.5-fold increase of the particle content in the inflamed segments compared to particles prepared with sodium dodecyl sulphate. This effect translates also into a significantly higher mitigating effect when entrapping betamethasone into such nanoparticles. This study shows the importance of surface properties for the passive targeting approach in experimental colitis. The influence seems to be as important as the influence of the particle size. PMID- 23933521 TI - The 16th International Symposium on Recent Advances in Drug Delivery, February 3 6, 2013, Salt Lake City, UT, USA. PMID- 23933522 TI - SPIO nanoparticle-stabilized PAA-F127 thermosensitive nanobubbles with MR/US dual modality imaging and HIFU-triggered drug release for magnetically guided in vivo tumor therapy. AB - Nanobubbles can serve as promising, next-generation theranostic platforms for ultrasound (US) and magnetic resonance (MR) imaging, and combined magnetic targeting (MT) and high-intensity focused ultrasound (HIFU)-triggered drug release for tumor therapy. Nanobubble-based dual contrast enhancement agents encapsulated with perfluoropentane and stabilized with superparamagnetic iron oxide (SPIO) nanoparticles have been synthesized through a single-step emulsion process from thermosensitive F127 and polyacrylic acid (PAA). Both US and MR imaging contrast can be optimized by varying the shell thickness and SPIO embedded concentration. The US contrast can be enhanced from a mean gray value of 62 to 115, and the MR r2 value can be enhanced from 164 to 208 (s(-1)mM (-1)Fe) by increasing the SPIO concentration from 14.1 to 28.2mg/mL, respectively. In vivo investigations of SPIO-embedded nanobubbles in excised tumors under external MT revealed that the US and MR signals change quantitatively compared to the same site without MT. This combined strategy enables the nanobubbles to enhance both passive targeting (increasing the permeability by HIFU) and physical MT of chemotherapeutic drugs to tumors. The integration of functionalities makes this nanobubble system a powerful and viable new tool to achieve simultaneous in vivo tumor imaging and efficacious cancer therapy. PMID- 23933523 TI - Bioengineered sequential growth factor delivery stimulates brain tissue regeneration after stroke. AB - Stroke is a leading cause of disability with no effective regenerative treatment. One promising strategy for achieving tissue repair involves the stimulation of endogenous neural stem/progenitor cells through sequential delivery of epidermal growth factor (EGF) followed by erythropoietin (EPO). Yet currently available delivery strategies such as intracerebroventricular (ICV) infusion cause significant tissue damage. We designed a novel delivery system that circumvents the blood brain barrier and directly releases growth factors to the brain. Sequential release of the two growth factors is a key in eliciting tissue repair. To control release, we encapsulate pegylated EGF (EGF-PEG) in poly(lactic-co glycolic acid) (PLGA) nanoparticles and EPO in biphasic microparticles comprised of a PLGA core and a poly(sebacic acid) coating. EGF-PEG and EPO polymeric particles are dispersed in a hyaluronan methylcellulose (HAMC) hydrogel which spatially confines the particles and attenuates the inflammatory response of brain tissue. Our composite-mediated, sequential delivery of EGF-PEG and EPO leads to tissue repair in a mouse stroke model and minimizes damage compared to ICV infusion. PMID- 23933524 TI - Microfluidics: a focus on improved cancer targeted drug delivery systems. AB - Pharmaceutical science aims to localize the pharmacological activity of the drug at the site of action. Targeted drug delivery systems can directly deliver the payload to the desired site of action without undesired interaction with normal cells. This is especially important for anticancer drugs to avoid side effects and improve therapeutic response and patient compliance. Number of targeted drug delivery systems for anticancer drugs are in market and many more are in research phase. Most of the methods so far used suffer from poor drug loading, variation in composition, attachment of targeting ligands to carriers, and in vivo and in vitro cellular uptake in cancer cell. Recently microfluidic techniques are gaining attention from researchers and formulation scientists due to the ability of having a better control over the above said parameters not to mention saving cost, material, time and the possibility offered to synthesize different system morphologies from nano to microscale. This article reviews the recent advances in the design of various targeted systems obtained through microfluidics and to some extent addresses challenges and hurdles faced during cancer cell treatment. PMID- 23933526 TI - Evaluating nanoparticle breakthrough during drinking water treatment. AB - BACKGROUND: Use of engineered nanoparticles (NPs) in consumer products is resulting in NPs in drinking water sources. Subsequent NP breakthrough into treated drinking water is a potential exposure route and human health threat. OBJECTIVES: In this study we investigated the breakthrough of common NPs--silver (Ag), titanium dioxide (TiO2), and zinc oxide (ZnO)--into finished drinking water following conventional and advanced treatment. METHODS: NPs were spiked into five experimental waters: groundwater, surface water, synthetic freshwater, synthetic freshwater containing natural organic matter, and tertiary wastewater effluent. Bench-scale coagulation/flocculation/sedimentation simulated conventional treatment, and microfiltration (MF) and ultrafiltration (UF) simulated advanced treatment. We monitored breakthrough of NPs into treated water by turbidity removal and inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: Conventional treatment resulted in 2-20%, 3-8%, and 48-99% of Ag, TiO2, and ZnO NPs, respectively, or their dissolved ions remaining in finished water. Breakthrough following MF was 1-45% for Ag, 0-44% for TiO2, and 36-83% for ZnO. With UF, NP breakthrough was 0-2%, 0-4%, and 2-96% for Ag, TiO2, and ZnO, respectively. Variability was dependent on NP stability, with less breakthrough of aggregated NPs compared with stable NPs and dissolved NP ions. CONCLUSIONS: Although a majority of aggregated or stable NPs were removed by simulated conventional and advanced treatment, NP metals were detectable in finished water. As environmental NP concentrations increase, we need to consider NPs as emerging drinking water contaminants and determine appropriate drinking water treatment processes to fully remove NPs in order to reduce their potential harmful health outcomes. PMID- 23933525 TI - Adjuvant formulation structure and composition are critical for the development of an effective vaccine against tuberculosis. AB - One third of the world is infected with Mycobacterium tuberculosis (Mtb) with eight million new cases of active tuberculosis (TB) each year. Development of a new vaccine to augment or replace the only approved TB vaccine, BCG, is needed to control this disease. Mtb infection is primarily controlled by TH1 cells through the production of IFN-gamma and TNF which activate infected macrophages to kill the bacterium. Here we examine an array of adjuvant formulations containing the TLR4 agonist GLA to identify candidate adjuvants to pair with ID93, a lead TB vaccine antigen, to elicit protective TH1 responses. We evaluate a variety of adjuvant formulations including alum, liposomes, and oil-in-water emulsions to determine how changes in formulation composition alter adjuvant activity. We find that alum and an aqueous nanosuspension of GLA synergize to enhance generation of ID93-specific TH1 responses, whereas neither on their own are effective adjuvants for generation of ID93-specific TH1 responses. For GLA containing oil-in-water emulsions, the selection of the oil component is critical for adjuvant activity, whereas a variety of lipid components may be used in liposomal formulations of GLA. The composition of the liposome formulation of ID93/GLA does alter the magnitude of the TH1 response. These results demonstrate that there are multiple solutions for an effective formulation of a novel TB vaccine candidate that enhances both TH1 generation and protective efficacy. PMID- 23933527 TI - Anterior and posterior corneal stroma elasticity after corneal collagen crosslinking treatment. AB - The purpose of this project was to assess anterior and posterior corneal stromal elasticity after corneal collagen cross linking (CXL) treatment in human cadaver eyes using Atomic Force Microscopy (AFM) through indentation. Twenty four human cadaver eyes (12 pairs) were included in this study and divided into 2 groups (6 pairs per group). In both groups, the left eye (OS) served as a control (no riboflavin or CXL treatment was performed) and the right eye (OD) underwent CXL treatment (30 min of riboflavin pretreatment followed by 30 min of exposure to 3 mW/cm(2) of ultraviolet light). In group 1, the anterior stroma was exposed by manual delamination of approximately 50 MUm of the corneal stroma including Bowman's membrane. In group 2, the posterior stroma was exposed by delamination of the anterior 50% of the corneal stroma including Bowman's membrane. Delamination was performed after crosslinking treatment in the case of the treated eyes. In all eyes, the stromal elasticity was quantified using AFM through indentation. Young's modulus of elasticity for the anterior cornea (group 1) was 245.9 +/- 209.1 kPa (range: 82.3-530.8 kPa) for the untreated control eyes, and 467.8 +/- 373.2 kPa (range: 157.4-1126 kPa) for the CXL treated eyes. Young's modulus for the posterior cornea (group 2) was 100.2 +/- 61.9 kPa (range: 28.1-162.6 kPa) for the untreated control eyes and 66.0 +/- 31.8 kPa (range: 31.3 101.7 kPa) for the CXL treated eyes. Young's modulus of the anterior stroma significantly increased after CXL treatment (p = 0.024), whereas the posterior stroma did not demonstrate a significant difference in Young's modulus after CXL treatment (p = 0.170). The anterior stroma was stiffer than the posterior stroma for both the control and CXL treatment groups (p = 0.077 and p = 0.023, respectively). Our findings demonstrate that stiffness of the anterior corneal stroma after CXL treatment seems to increase significantly, while the posterior stroma does not seem to be affected by CXL. PMID- 23933529 TI - Proximal renal tubular injury in rats sub-chronically exposed to low fluoride concentrations. AB - Fluoride is usually found in groundwater at a very wide range of concentration between 0.5 and 25 ppm. At present, few studies have assessed the renal effects of fluoride at environmentally relevant concentrations. Furthermore, most of these studies have used insensitive and nonspecific biomarkers of kidney injury. The aim of this study was to use early and sensitive biomarkers to evaluate kidney injury after fluoride exposure to environmentally relevant concentrations. Recently weaned male Wistar rats were exposed to low (15 ppm) and high (50 ppm) fluoride concentrations in drinking water for a period of 40 days. At the end of the exposure period, kidney injury biomarkers were measured in urine and renal mRNA expression levels were assessed by real time RT-PCR. Our results showed that the urinary kidney injury molecule (Kim-1), clusterin (Clu), osteopontin (OPN) and heat shock protein 72 excretion rate significantly increased in the group exposed to the high fluoride concentration. Accordingly, fluoride exposure increased renal Kim-1, Clu and OPN mRNA expression levels. Moreover, there was a significant dose-dependent increase in urinary beta-2-microglobulin and cystatin C excretion rate. Additionally, a tendency towards a dose dependent increase of tubular damage in the histopathological light microscopy findings confirmed the preferential impact of fluoride on the tubular structure. All of these changes occurred at early stages in which, the renal function was not altered. In conclusion using early and sensitive biomarkers of kidney injury, we were able to found proximal tubular alterations in rats sub-chronically exposed to fluoride. PMID- 23933528 TI - Lymphocyte mitochondria: toward identification of peripheral biomarkers in the progression of Alzheimer disease. AB - Alzheimer disease (AD) is an age-related neurodegenerative condition. AD is histopathologically characterized by the presence of three main hallmarks: senile plaques (rich in amyloid-beta peptide), neuronal fibrillary tangles (rich in phosphorylated tau protein), and synapse loss. However, definitive biomarkers for this devastating disease in living people are still lacking. In this study, we show that levels of oxidative stress markers are significantly increased in the mitochondria isolated from lymphocytes of subjects with mild cognitive impairment (MCI) compared to cognitively normal individuals. Further, an increase in mitochondrial oxidative stress in MCI is associated with MMSE score, vitamin E components, and beta-carotene. Further, a proteomics approach showed that alterations in the levels of thioredoxin-dependent peroxide reductase, myosin light polypeptide 6, and ATP synthase subunit beta might be important in the progression and pathogenesis of AD. Increased understanding of oxidative stress and protein alterations in easily obtainable peripheral tissues will be helpful in developing biomarkers to combat this devastating disorder. PMID- 23933530 TI - Hemocompatibility and biocompatibility of antibacterial biomimetic hybrid films. AB - In previous work, we developed novel antibacterial hybrid coatings based on dextran containing dispersed Ag NPs (~5 nm, DEX-Ag) aimed to offer dual protection against two of the most common complications associated with implant surgery, infections and rejection of the implant. However, their blood-material interactions are unknown. In this study, we assess the hemocompatibility and biocompatibility of DEX-Ag using fresh blood and two cell lines of the immune system, monocytes (THP-1 cells) and macrophages (PMA-stimulated THP-1 cells). Glass, polyurethane (PU) and bare dextran (DEX) were used as reference surfaces. PU, DEX and DEX-Ag exhibited non-hemolytic properties. Relative to glass (100%), platelet attachment on PU, DEX and DEX-Ag was 15%, 10% and 34%, respectively. Further, we assessed cell morphology and viability, pro-inflammatory cytokines expression (TNF-alpha and IL-1beta), pro-inflammatory eicosanoid expression (Prostaglandin E2, PGE2) and release of reactive oxygen species (ROS, superoxide and H2O2) following incubation of the cells with the surfaces. The morphology and cell viability of THP-1 cells were not affected by DEX-Ag whereas DEX-Ag minimized spreading of PMA-stimulated THP-1 cells and caused a reduction in cell viability (16% relative to other surfaces). Although DEX-Ag slightly enhanced release of ROS, the expression of pro-inflammatory cytokines remained minimal with similar levels of PGE2, as compared to the other surfaces studied. These results highlight low toxicity of DEX-Ag and hold promise for future applications in vivo. PMID- 23933532 TI - The cathepsin B inhibitor, z-FA-CMK is toxic and readily induced cell death in human T lymphocytes. AB - The cathepsin B inhibitor, benzyloxycarbonyl-phenylalanine-alanine chloromethylketone (z-FA-CMK) was found to be toxic and readily induced cell death in the human T cell line, Jurkat, whereas two other analogs benzyloxycarbonyl-phenylalanine-alanine-fluoromethylketone (z-FA-FMK) and benzyloxycarbonyl-phenylalanine-alanine-diazomethylketone (z-FA-DMK) were not toxic. The toxicity of z-FA-CMK requires not only the CMK group, but also the presence of alanine in the P1 position and the benzyloxycarbonyl group at the N terminal. Dose-response studies showed that lower concentrations of z-FA-CMK induced apoptosis in Jurkat T cells whereas higher concentrations induced necrosis. In z-FA-CMK-induced apoptosis, both initiator caspases (-8 and -9) and effector caspases (-3, -6 and -7) were processed to their respective subunits in Jurkat T cells. However, only the pro-form of the initiator caspases were reduced in z-FA-CMK-induced necrosis and no respective subunits were apparent. The caspase inihibitor benzyloxycarbonyl-valine-alanine-aspartic acid-(O-methyl) fluoromehylketone (z-VAD-FMK) inhibits apoptosis and caspase processing in Jurkat T cells treated with low concentration of z-FA-CMK but has no effect on z-FA-CMK induced necrosis and the loss of initiator caspases. This suggests that the loss of initiator caspases in Jurkat T cells during z-FA-CMK-induced necrosis is not a caspase-dependent process. Taken together, we have demonstrated that z-FA-CMK is toxic to Jurkat T cells and induces apoptosis at low concentrations, while at higher concentrations the cells die of necrosis. PMID- 23933531 TI - Comparative effects of parathion and chlorpyrifos on extracellular endocannabinoid levels in rat hippocampus: influence on cholinergic toxicity. AB - Parathion (PS) and chlorpyrifos (CPF) are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). Endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) can modulate neurotransmission by inhibiting neurotransmitter release. We proposed that differential inhibition of eCB-degrading enzymes (fatty acid amide hydrolase, FAAH, and monoacylglycerol lipase, MAGL) by PS and CPF leads to differences in extracellular eCB levels and toxicity. Microdialysis cannulae were implanted into hippocampus of adult male rats followed by treatment with vehicle (peanut oil, 2 ml/kg, sc), PS (27 mg/kg) or CPF (280 mg/kg) 6-7 days later. Signs of toxicity, AChE, FAAH and MAGL inhibition, and extracellular levels of AEA and 2AG were measured 2 and 4 days later. Signs were noted in PS-treated rats but not in controls or CPF-treated rats. Cholinesterase inhibition was extensive in hippocampus with PS (89-90%) and CPF (78-83%) exposure. FAAH activity was also markedly reduced (88-91%) by both OPs at both time-points. MAGL was inhibited by both OPs but to a lesser degree (35-50%). Increases in extracellular AEA levels were noted after either PS (about 2-fold) or CPF (about 3-fold) while lesser treatment-related 2-AG changes were noted. The cannabinoid CB1 receptor antagonist/inverse agonist AM251 (3mg/kg, ip) had no influence on functional signs after CPF but markedly decreased toxicity in PS-treated rats. The results suggest that extracellular eCBs levels can be markedly elevated by both PS and CPF. CB1-mediated signaling appears to play a role in the acute toxicity of PS but the role of eCBs in CPF toxicity remains unclear. PMID- 23933533 TI - Regioselective synthesis of phenanthrenes and evaluation of their anti-oxidant based anti-inflammatory potential. AB - Regioselective synthesis of 9,10-dihydro-2,5-dimethoxyphenanthrene-1,7-diol (1) and 9,10-dihydro-2,7-dimethoxyphenanthrene-1,5-diol (2) was achieved using regioselective methylation, Wittig reaction, intramolecular cyclization and hydrogenation as key steps. The synthesis was successfully completed in total of 15 steps with 3.3% overall yield in case of 1 and in total of 13 steps with 9.0% overall yield in case of 2. All compounds (1-4) showed good antioxidant and anti inflammatory activity in in vitro assays and these activities were found to be due the presence of phenolic hydroxyl groups. PMID- 23933534 TI - Synthesis and study of 1-ethyl-3-carbohydrazide and 3-[1-oxo-2-hydrazino-3-{p toluenesulfon}]quinolone derivatives against bacterial infections. AB - We have synthesized newer series of quinolone derivatives substituted with hydrazine group (6a-e) and sulfonamide group (7a-e). These compounds were screened for antibacterial activity. All these compounds were fully characterized by spectroscopic means and elemental analysis. From minimum inhibitory concentration (MIC) data, it has been observed that all the synthesized compounds exhibited good antibacterial activity in vitro. PMID- 23933535 TI - Prediction of coronary risk by SYNTAX and derived scores: synergy between percutaneous coronary intervention with taxus and cardiac surgery. AB - The introduction of the SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score has prompted a renewed interest for angiographic risk stratification in patients undergoing percutaneous coronary intervention. Syntax score is based on qualitative and quantitative characterization of coronary artery disease by including 11 angiographic variables that take into consideration lesion location and characteristics. Thus far, this score has been shown to be an effective tool to risk-stratify patients with complex coronary artery disease undergoing percutaneous coronary intervention in the landmark SYNTAX trial, as well as in other clinical settings. This review provides an overview of its current applications, including its integration with other nonangiographic clinical scores, and explores future applications of the SYNTAX and derived scores. PMID- 23933537 TI - Heart rate reduction: it is not just for ventricles anymore. PMID- 23933536 TI - Multislice computed tomography angiography for noninvasive assessment of the 18 month performance of a novel radiolucent bioresorbable vascular scaffolding device: the ABSORB trial (a clinical evaluation of the bioabsorbable everolimus eluting coronary stent system in the treatment of patients with de novo native coronary artery lesions). PMID- 23933538 TI - The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. PMID- 23933539 TI - Cardiac arrest at exercise facilities: implications for placement of automated external defibrillators. AB - OBJECTIVES: This study sought to characterize the relative frequency, care, and survival of sudden cardiac arrest in traditional indoor exercise facilities, alternative indoor exercise sites, and other indoor sites. BACKGROUND: Little is known about the relative frequency of sudden cardiac arrest at traditional indoor exercise facilities versus other indoor locations where people engage in exercise or about the survival at these sites in comparison with other indoor locations. METHODS: We examined every public indoor sudden cardiac arrest in Seattle and King County from 1996 to 2008 and categorized each event as occurring at a traditional exercise center, an alternative exercise site, or a public indoor location not used for exercise. Arrests were further defined by the classification of the site, activity performed, demographics, characteristics of treatment, and survival. For some location types, annualized site incident rates of cardiac arrests were calculated. RESULTS: We analyzed 849 arrests, with 52 at traditional centers, 84 at alternative exercise sites, and 713 at sites not associated with exercise. The site incident rates of arrests at indoor tennis facilities, indoor ice arenas, and bowling alleys were higher than at traditional fitness centers. Survival to hospital discharge was greater at exercise sites (56% at traditional and 45% at alternative) than at other public indoor locations (34%; p = 0.001). CONCLUSIONS: We observed a higher rate of cardiac arrests at some alternative exercise facilities than at traditional exercise sites. Survival was higher at exercise sites than at nonexercise indoor sites. These data have important implications for automated external defibrillator placement. PMID- 23933540 TI - Chromosome 9p21.3 locus for coronary artery disease: how little we know. PMID- 23933541 TI - Small changes in troponin T levels are common in patients with non-ST-segment elevation myocardial infarction and are linked to higher mortality. AB - OBJECTIVES: The purpose of this study was to examine the extent of change in troponin T levels in patients with non-ST-segment elevation myocardial infarction (NSTEMI). BACKGROUND: Changes in cardiac troponin T (cTnT) levels are required for the diagnosis of NSTEMI, according to the new universal definition of acute myocardial infarction. A relative change of 20% to 230% and an absolute change of 7 to 9 ng/l have been suggested as cutoff points. METHODS: In a clinical setting, where a change in cTnT was not mandatory for the diagnosis of NSTEMI, serial samples of cTnT were measured with a high-sensitivity cTnT (hs-cTnT) assay, and 37 clinical parameters were evaluated in 1,178 patients with a final diagnosis of NSTEMI presenting <24 h after symptom onset. RESULTS: After 6 h of observation, the relative change in the hs-cTnT level remained <20% in 26% and the absolute change <9 ng/l in 12% of the NSTEMI patients. A relative hs-cTnT change <20% was linked to higher long-term mortality across quartiles (p = 0.002) and in multivariate analyses (hazard ratio: 1.61 [95% confidence interval: 1.17 to 2.21], p = 0.004), whereas 30-day mortality was similar across quartiles of relative hs-cTnT change. CONCLUSIONS: Because stable hs-TnT levels are common in patients with a clinical diagnosis of NSTEMI in our hospital, a small hs-cTnT change may not be useful to exclude NSTEMI, particularly as these patients show both short-term and long-term mortality at least as high as patients with large changes in hs-cTnT. PMID- 23933542 TI - The 9p21 locus does not affect risk of coronary artery disease through induction of type 1 interferons. AB - OBJECTIVES: The study objective was to determine whether the coronary artery disease (CAD)-associated genotype at chromosome 9p21 modulates basal or induced expression of type I interferons (IFN-I). BACKGROUND: The mechanism responsible for the association between common variants in chromosome 9p21.3 and CAD remains unclear. It has been reported that the CAD risk locus is rich in enhancer-like elements and that chromosome looping can lead to its physical proximity with the IFN-I gene cluster, raising the possibility that the locus influences CAD risk by modulating expression of IFN-Is. METHODS: We examined whether genotype at the lead CAD-associated single nucleotide polymorphism (rs1333049) in 9p21 was associated with: 1) basal levels of IFN-I in plasma from 148 healthy male subjects; 2) induction of IFN-I by Toll-like receptor stimulants in peripheral blood mononuclear cells of 60 healthy volunteers assessed by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, Western blot, and IFN-I bioassay; and 3) enhancer activity of predicted IFN regulatory factor 3/7 binding sites within the 9p21 CAD risk region in reporter assays. RESULTS: No significant effects of 9p21 genotype were observed for plasma levels of IFN alpha, IFN-alpha21, or CXCL10, or leukocyte induction of IFN-alpha, IFN-alpha21, IFN-beta, CXCL10, or total IFN-I measured at the mRNA, protein, and biological activity levels. There was also no enhancement of reporter activity by predicted IFN regulatory factor 3/7 binding sites in the CAD risk locus of either genotype. CONCLUSIONS: The mechanism underlying the association between common 9p21 variants and CAD does not involve differential regulation of IFN-I responses. PMID- 23933544 TI - Real-world application of "delta" troponin: diagnostic and prognostic implications. PMID- 23933543 TI - A case of inferior vena cava obstruction: restenosis with pseudoaneurysm. PMID- 23933545 TI - Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients. AB - OBJECTIVES: The study aimed to determine whether isolated heart rate (HR) reduction with ivabradine reduces afterload of patients with systolic heart failure. BACKGROUND: The effective arterial elastance (Ea) represents resistive and pulsatile afterload of the heart derived from the pressure volume relation. HR modulates Ea, and, therefore, afterload burden. METHODS: Among the patients with systolic heart failure (ejection fraction <=35%) randomized to either placebo or ivabradine in the SHIFT (Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial), 275 patients (n = 132, placebo; n = 143, ivabradine 7.5 mg twice a day) were included in the echocardiographic substudy. Ea, total arterial compliance (TAC), and end-systolic elastance (Ees) were calculated at baseline and after 8 months of treatment. Blood pressure was measured by arm cuff; stroke volume (SV), ejection fraction, and end-diastolic volume were assessed by echocardiography. RESULTS: At baseline Ea, TAC, HR, and Ees did not differ significantly between ivabradine- and placebo-treated patients. After 8 months of treatment, HR was significantly reduced in the ivabradine group (p < 0.0001) and was accompanied by marked reduction in Ea (p < 0.0001) and improved TAC (p = 0.004) compared with placebo. Although contractility remained unchanged, ventricular-arterial coupling was markedly improved (p = 0.002), resulting in a higher SV (p < 0.0001) in the ivabradine-treated patients. CONCLUSIONS: Isolated HR reduction by ivabradine improves TAC, thus reducing Ea. Because Ees is unaltered, improved ventricular-arterial coupling is responsible for increased SV. Therefore, unloading of the heart may contribute to the beneficial effect of isolated HR reduction in patients with systolic heart failure. PMID- 23933546 TI - Cardiac Imaging in FIP1L1-PDGFRA. PMID- 23933547 TI - Two centuries of resuscitation. PMID- 23933548 TI - Gold nanoflowers based colorimetric detection of Hg2+ and Pb2+ ions. AB - An optical detection method based on the interaction of gold nanoflowers with Hg(2+) and Pb(2+) has been described. After interaction, gold nanoflowers change the color from violet to wine red. The nanoflowers are capable of determining Hg(2+) and Pb(2+) over a dynamic range of 1.0 * 10(-6) and 1.0 * 10(-5)M, respectively. The response time of nanoflowers depends on the concentration of ions. The presence of both Hg(2+) and Pb(2+) ions in the mixture having Au nanoflowers induced color changes of the solution within several seconds even at 1.0 * 10(-6)M. Common metal ions were chosen to investigate their interference in Hg(2+) and Pb(2+) detection, and the concentration of each metal ion studied was 1.0 * 10(-5)M. Other metallic ions could not induce color change even at 1.0 * 10(-5)M. The feasibility of our method to detect Hg(2+) and Pb(2+) ions at high concentration in real water samples was verified. Water samples were from our own laboratory and no pretreatment was made. As the particles are stable they can be used for more than 3 months without observing any major deviation. PMID- 23933549 TI - QTAIM charge-charge flux-dipole flux models for the fundamental infrared intensities of BF3 and BCl3. AB - Quantum Theory of Atoms in Molecules Charge-Charge Flux-Dipole Flux (QTAIM/CCFDF) models have been determined for the BF3 and BCl3 molecules. Model parameters were obtained from MP2/6-31G(2d,2p) wave functions owing to their accurate estimations of the BF3 intensities and were found to be insensitive to changes in basis sets with polarization functions and to the level of electron correlation treatment, MP2, QCISD and DFT. The BF3 stretching intensity has a very dominant equilibrium charge contribution with small charge and dipole fluxes occurring in the opposite direction to the charge movement. Large equilibrium charge and small dynamic contributions are also characteristic of stretching vibrations in the ionic diatomic molecules, NaF, NaCl, LiF and LiCl. Furthermore the Laplacians of the electron density at the bond critical points of BF3 and these diatomics are all positive indicating electron depletion in their bonding regions relative to large electronic densities concentrated around their nuclei that is characteristic of ionic bonds. The MP2/6-31G(2d,2p) BCl3 stretching intensity can be accurately estimated by equilibrium charge movement since the charge and dipole fluxes almost exactly cancel one another. Both in-plane and out-of-plane BF3 and BCl3 bending deformations are described by equilibrium charge movements that are partially canceled by opposing dipole fluxes that measure the effect on the dipole moment change from electron densities polarized in the opposite direction. Charge fluxes are calculated to be small for the in-plane deformations and are zero by symmetry for the out-of-plane ones. PMID- 23933550 TI - Synthesis, crystal growth and spectroscopic investigation of second order organic nonlinear optical single crystal: 2-chloro-N-[4 (dimethylamino)benzylidene]aniline. AB - Organic nonlinear optical (NLO) crystal 2-chloro-N-[4 (dimethylamino)benzylidene]aniline (2Cl4DBA) was synthesized and grown by restricted slow evaporation technique at room temperature using acetone as solvent with good degree of transparency. The lattice parameters were determined and found to be noncentrosymmetric orthorhombic system by single crystal X-ray diffraction. The crystalline nature of the synthesized material was recorded by the powder X-ray diffraction pattern. Molecular structure of the grown crystal was investigated by (1)H and (13)C NMR and functional groups were identified by FTIR spectrum analysis. The optical absorbance of the grown crystal was ascertained by recording UV-Visible spectrum. Thermal and physiochemical stability of the grown material was investigated by TG/DTA analysis. SHG efficiency was determined by Kurtz-Perry Powder SHG technique and found to be 4.2 and 1.54 times greater that of standard KDP and urea crystals respectively. PMID- 23933551 TI - Control of H-dimer formation of acridine orange using nano clay platelets. AB - Acridine orange (AO) forms dimer even in aqueous solution. In layer-by-layer (LbL) film of AO dimeric sites predominate over monomeric sites. This communication reports the control of H-dimer of AO in LbL film by incorporating nano clay platelets. This was studied by using UV-Vis absorption spectroscopy. Atomic force microscopic (AFM) image of the LbL film was taken to confirm the presence of nano clay platelets in the LbL film. PMID- 23933552 TI - Confirmation of the assignment of vibrations of goethite: an ATR and IES study of goethite structure. AB - Transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM/EDS) and X-ray diffraction (XRD) were used to characterize the morphology of synthetic goethite. The behavior of the hydroxyl/water molecular units of goethite and its thermally treated products were characterized using Fourier transform-infrared emission spectroscopy (FT-IES) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The results showed that all the expected vibrational bands between 4000 and 650 cm(-1) including the resolved bands (3800-2200 cm(-1)) were confirmed. A band attributed to a new type of hydroxyl unit was found at 3708 cm(-1) and assigned to the FeO-H stretching vibration without hydrogen bonding. This hydroxyl unit was retained up to the thermal treatment temperature of 500 degrees C. On the whole, seven kinds of hydroxyl units, involving three surface hydroxyls, a bulk hydroxyl, a FeO-H without hydrogen bonding, a nonstoichiometric hydroxyl and a reversed hydroxyl were observed, and three kinds of adsorbed water were found in/on goethite. PMID- 23933553 TI - The molecular structure of the borate mineral inderite Mg(H4B3O7)(OH) . 5H2O--a vibrational spectroscopic study. AB - We have undertaken a study of the mineral inderite Mg(H4B3O7)(OH) . 5H2O a hydrated hydroxy borate mineral of magnesium using scanning electron microscopy, thermogravimetry and vibrational spectroscopic techniques. The structure consists of [Formula: see text] soroborate groups and Mg(OH)2(H2O)4 octahedra interconnected into discrete molecules by the sharing of two OH groups. Thermogravimetry shows a mass loss of 47.2% at 137.5 degrees C, proving the mineral is thermally unstable. Raman bands at 954, 1047 and 1116 cm(-1) are assigned to the trigonal symmetric stretching mode. The two bands at 880 and 916 cm(-1) are attributed to the symmetric stretching mode of the tetrahedral boron. Both the Raman and infrared spectra of inderite show complexity. Raman bands are observed at 3052, 3233, 3330, 3392 attributed to water stretching vibrations and 3459 cm(-1) with sharper bands at 3459, 3530 and 3562 cm(-1) assigned to OH stretching vibrations. Vibrational spectroscopy is used to assess the molecular structure of inderite. PMID- 23933554 TI - Vibrational spectroscopic characterization of the sulphate mineral khademite Al(SO4)F.5(H2O). AB - Vibrational spectroscopy has been used to characterize the sulphate mineral khademite Al(SO4)F.5(H2O). Raman band at 991 cm-1 with a shoulder at 975 cm-1 is assigned to the nu1 (SO4)2- symmetric stretching mode. The observation of two symmetric stretching modes suggests that the sulphate units are not equivalent. Two low intensity Raman bands at 1104 and 1132 cm-1 are assigned to the nu3 (SO4)2- antisymmetric stretching mode. The broad Raman band at 618 cm-1 is assigned to the nu4 (SO4)2- bending modes. Raman bands at 455, 505 and 534 cm-1 are attributable to the doubly degenerate nu2 (SO4)2- bending modes. Raman bands at 2991, 3146 and 3380 cm-1 are assigned to the OH stretching bands of water. Five infrared bands are noted at 2458, 2896, 3203, 3348 and 3489 cm-1 are also due to water stretching bands. The observation of multiple water stretching vibrations gives credence to the non-equivalence of water units in the khademite structure. Vibrational spectroscopy enables an assessment of the structure of khademite. PMID- 23933555 TI - NBO, NMR, UV, FT-IR, FT-Raman spectra and molecular structure (monomeric and dimeric structures) investigation of 4-Chloro-3,5-Xylenol: a combined experimental and theoretical study. AB - In this work, a joint experimental (FTIR and FT-Raman) and theoretical (DFT and ab initio) study on the structure and the vibrations of 4-Chloro-3,5-Xylenol (CXL) are compared and analyzed. CXL is a chlorinated phenolic antiseptic which is a bactericide against most gram-positive bacteria. The first hyperpolarizability (beta0) of this novel molecular system and related non-linear properties of CXL are calculated using HF/6-311++G(d,p) method on the finite field approach. The energy and oscillator strength calculated using absorption spectra (UV-Vis spectrum), this spectral analysis confirms the charge transfer of the molecule. The theoretical (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by Gauge Including Atomic Orbital (GIAO) method, to analyze the molecular environment as well as the delocalization activities of electron clouds. The directly calculated ionization potential (IP), electron affinity (EA), electronegativity (chi), chemical hardness (eta), first electron excitation energy (tau) and electrophilicity index (omega) as well as local reactivity (S) analyzed using HOMO and LUMO energies; the energy band gap are also determined. NBO analysis shows that charge in electron density(ED) in the sigma(*) and pi(*) antibonding orbitals and E((2)) energies confirms the occurrence of ICT (Intramolecular Charge Transfer) within the molecule. Inter molecular hydrogen bonds exist between -OH group, give the evidence for the formation of dimer entities in the title molecule. The influences of chlorine atom, hydroxyl group and methyl group on the geometry of benzene and its normal modes of vibrations (monomer and dimer of CXL) have also been discussed. Finally the calculated results were applied to simulate Infrared and Raman spectra of the title molecule which show good agreement with observed spectra. PMID- 23933556 TI - A critical evaluation of the s-cis-trans isomerism of 2-acetylpyrrole and its N methyl derivative through infrared and NMR spectroscopies and theoretical calculations. AB - Literature data are controversial regarding the conformational equilibria of 2 acetylpyrrole (AP) and its N-methyl derivative (AMP). Now, a detailed study through infrared spectroscopy and theoretical calculations has shown that previous data were erroneously interpreted, since only a N,O-cis conformer is present in solution and that it is the stable conformer in the isolated state (DeltaE(trans-cis) = 5.05 kcal mol(-1), for AP; DeltaE(trans-cis) = 7.14 kcal mol(-1), for AMP). Carbonyl and NH absorption data in different solvents, supported by theoretical results taking into account the solvent effects [at IEFPCM-B3LYP/6-311++G(3df,3p) level of theory] clearly demonstrated that only the N,O-cis conformer is present in solution. However, a doublet was observed for AP, in CCl4, which can be attributed to this conformer and the lowest wavenumber component to the cis dimer form, stabilized through intermolecular hydrogen bonds (NH . . . OC). The overall preference for the N,O-cis conformer, in AP and AMP, as interpreted by the NBO analysis, indicated that the hyperconjugative effect is the main contribution to stabilize this rotamer, overcoming the possible steric repulsion. (13)C NMR experiments at low temperature in two different solvents (CS2/CDCl2 and acetone-d6) confirmed the occurrence of a single conformer since no separated signals were observed. PMID- 23933557 TI - Raman and infrared spectroscopic study of the mineral goyazite SrAl3(PO4)2(OH)5.H2O. AB - We have studied the mineral goyazite using Raman and infrared spectroscopy. Goyazite is a member of the crandallite subgroup of the alunite supergroup. The crystal structure is of the alunite-type and consists of sheets of corner-sharing AlO6 octahedra parallel to (0001). The octahedrally coordinated Sr(2+) cations occupy cavities between pairs of octahedral sheets and are surrounded by six oxygen atoms from the Al(3+)O6 octahedra. The very intense sharp band at 983 cm( 1) is assigned to the nu1PO4(3-) symmetric stretching mode. The observation of a single band supports the concept that all the phosphate units are equivalent in the structure of goyazite. Raman bands observed at 1029 cm(-1) and 1037 cm(-1) are assigned to the nu3PO4(3-) antisymmetric stretching vibrations. Two Raman bands at 895 and 927 cm(-1) are attributed to the stretching vibrations of H2PO4; thus indicating some hydrogen phosphate units in the structure of goyazite. Raman bands at 556, 581, 596 and 612 cm(-1) are assigned to the nu4PO4(3-) bending modes, suggesting a reduction of symmetry of phosphate units. Two sharp Raman bands at 3609 and 3631 cm(-1) are attributed to OH stretching vibrations from the goyazite hydroxyl units. Broad Raman bands at 2924, 3043, 3210, 3429 and 3511 cm( 1) are assigned to water stretching vibrations. This research shows that from a vibrational spectroscopic point of view, the formula SrAl3(H PO4,PO4)2(OH)6 . H2O is a better formulation for the mineral goyazite. Vibrational spectroscopy enables subtle details of the molecular structure of goyazite to be determined. PMID- 23933558 TI - Diverging role for coronin 1 in antiviral CD4+ and CD8+ T cell responses. AB - Coronin 1 is a member of the evolutionary conserved WD repeat protein family and is highly expressed in hematopoietic cells. Coronin 1 is essential for Ca(2+) mobilization upon T cell receptor (TCR) stimulation providing a pro-survival signal for naive peripheral T cells. Both in mouse and in human, coronin 1 deficiency is associated with severe T cell lymphopenia. In this work, we have analyzed antiviral T cell-mediated immunity in the presence and absence of coronin 1 in vivo after infection with lymphocytic choriomenigitis virus (LCMV) and vesicular stomatitis virus (VSV) in mice. Despite low peripheral T cell numbers we found that LCMV-specific CD8(+) T cell responses were normal in the absence of coronin 1 and kinetics of LCMV-clearance were similar compared to wild type mice. In contrast, CD4(+) T cell responses were profoundly decreased after LCMV- and VSV-infection. We propose that coronin 1 plays a differential role in CD8(+) versus CD4(+) T cell responses and activation. PMID- 23933559 TI - Expression and mutational status of treatment-relevant targets and key oncogenes in 123 malignant salivary gland tumours. AB - BACKGROUND: Malignant tumours of the salivary glands (MSGT) are rare and pleomorphic entities. Patients with advanced disease may benefit from targeted therapy; however, specific targets for optimising and personalising treatments are yet to be identified. DESIGN: Immunohistochemistry for C-KIT, EGFR, HER2, MUC1, phospho-mTOR, androgen/estrogens/progesterone receptors and Ki67 was carried out and evaluated in terms of progression-free and overall survival. High throughput molecular screening of key oncogenes was done in 107 patients using routine diagnostic methods and Sequenom technology. RESULTS: Several therapy leads were identified, including high levels of HER2 and androgen receptors in salivary duct carcinomas, C-KIT in myoepithelial carcinomas and EGFR in mucoepidermoid carcinomas. Recurrent mutations involving downstream elements of the EGFR pathway were found in HRAS, notably in tumours with a myoepithelial component, and in other key oncogenes (KRAS/NRAS/PI3KCA/BRAF/MAP2K). On the other hand, <1% of samples had EGFR or HER2 mutations. CONCLUSION: Several tumour subtypes overexpressed targets of directed therapies suggesting potential therapy leads. Genotyping results suggest activation downstream of EGFR in 18 of the 107 samples that could be associated with low efficacy of EGFR inhibitors. Other molecules, such as PI3K/MEK or mTOR inhibitors, may have anti-tumour activity in this subgroup. The high mutation rate in HRAS highlights a novel key oncogenic event in MSGT. PMID- 23933560 TI - Reduced risk of distant recurrence after adjuvant chemotherapy in patients with stage III colon cancer aged 75 years or older. AB - BACKGROUND: Little is known about the effects of adjuvant chemotherapy on the risk of distant recurrence in elderly with stage III colon cancer, treated in daily practice. PATIENTS AND METHODS: One thousand two hundred and ninety-one stage III colon cancer patients diagnosed in the southern Netherlands between 2003 and 2008 were included. Propensity score matching was applied to create a subsample to reduce bias caused by differences between patients receiving adjuvant chemotherapy and patients not receiving adjuvant chemotherapy. For both the total study population and the propensity score matched sample, Cox regression analysis was used to discriminate independent risk factors for distant recurrence. RESULTS: Adjuvant chemotherapy (CT) was correlated with a reduced risk of distant recurrence in both the total study population [hazard ratio (HR) CT versus nCT 0.55, 95% confidence interval (CI) 0.42-0.70] and in the propensity score matched sample (HR CT versus nCT 0.46, 95% CI 0.33-0.63). In separate analyses for patients aged <75 and >=75 years, the effect of adjuvant chemotherapy on the risk of distant recurrence remained comparable for both age groups (HR CT versus nCT 0.50, 95% CI 0.37-0.68 and 0.57, 95% CI 0.36-0.90, respectively). CONCLUSION: Distant recurrence risks at higher age definitely warrant consideration of adjuvant chemotherapy for elderly stage III colon cancer patients. This decision should be based on a multidisciplinary and functional assessment of the patient, not on age. PMID- 23933561 TI - Dynamic metabolic modelling of volatile fatty acids conversion to polyhydroxyalkanoates by a mixed microbial culture. AB - In this work, we present a dynamic metabolic model that describes the uptake of complex mixtures of volatile fatty acids (VFA) and respective conversion into PHA by mixed microbial cultures (MMC). This model builds upon a previously published flux balance analysis model [1] that identified the minimization of TCA cycle activity as the key metabolic objective to predict PHA storage fluxes and respective composition. The model was calibrated either with experimental data of PHA production from fermented sugar cane molasses or from synthetic mixtures of VFA. All PHA production experiments were performed using a MMC selected with fermented sugar cane molasses under feast and famine regimen. The model was able to capture the process dynamics denoted by an excellent fit between experimental and computed time profiles of concentrations with the regression coefficients always above 0.92. The introduced VFA uptake regulatory factor reflects the decrease of acetyl-CoA and propionyl-CoA available to TCA cycle in conformity with the hypothesis that the minimization of TCA cycle is a key metabolic objective for MMC subjected to feast and famine regimen for the maximization of PHA production. PMID- 23933562 TI - Highly efficient synthetic iron-dependent nucleases activate both intrinsic and extrinsic apoptotic death pathways in leukemia cancer cells. AB - The nuclease activity and the cytotoxicity toward human leukemia cancer cells of iron complexes, [Fe(HPClNOL)Cl2]NO3 (1), [Cl(HPClNOL)Fe(MU O)Fe(HPClNOL)Cl]Cl2.2H2O (2), and [(SO4)(HPClNOL)Fe(MU-O)Fe(HPClNOL)(SO4)].6H2O (3) (HPClNOL=1-(bis-pyridin-2-ylmethyl-amino)-3-chloropropan-2-ol), were investigated. Each complex was able to promote plasmid DNA cleavage and change the supercoiled form of the plasmid to circular and linear ones. Kinetic data revealed that (1), (2) and (3) increase the rate of DNA hydrolysis about 278, 192 and 339 million-fold, respectively. The activity of the complexes was inhibited by distamycin, indicating that they interact with the minor groove of the DNA. The cytotoxic activity of the complexes toward U937, HL-60, Jukart and THP-1 leukemia cancer cells was studied employing 3-(4,5-dimethythiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT), fluorescence and electronic transmission microscopies, flow cytometry and a cytochrome C release assay. Compound (2) has the highest activity toward cancer cells and is the least toxic for normal ones (i.e. peripheral blood mononuclear cells (PBMCs)). In contrast, compound (1) is the least active toward cancer cells but displays the highest toxicity toward normal cells. Transmission electronic microscopy indicates that cell death shows features typical of apoptotic cells, which was confirmed using the annexin V FITC/PI (fluorescein isothiocyanate/propidium iodide) assay. Furthermore, our data demonstrate that at an early stage during the treatment with complex (2) mitochondria lose their transmembrane potential, resulting in cytochrome C release. A quantification of caspases 3, 9 (intrinsic apoptosis pathway) and caspase 8 (extrinsic apoptosis pathway) indicated that both the intrinsic (via mitochondria) and extrinsic (via death receptors) pathways are involved in the apoptotic stimuli. PMID- 23933563 TI - Application of multiple parallel perfused microbioreactors: Synthesis, characterization and cytotoxicity testing of the novel rare earth complexes with indole acid as a ligand. AB - Three novel complexes, [La(phen)2(IAA)2].NO3 (1), [Sm(phen)2(IAA)2].NO3 (2) and [Sm(IBA)3(phen)].phen.HNO3.H2O (3) (phen: 1,10-phenanthroline, IAA: indole-3 acetic acid, IBA: indole-3-butyric acid), were synthesized and characterized with spectroscopy (infrared and UV-visible), X-ray crystal diffraction and elemental analysis. Structural analysis revealed that each lanthanide atom in complexes 1-3 held a distorted tricapped trigonal prism geometry in a nine-coordinate mode. There were two types of coordination modes of the IAA ligand in complexes 1 and 2: a MU2-eta(1):eta(2) bridging mode linking two lanthanide atoms and a MU2 eta(1):eta(1) double monodentate bridging mode. There were three types of coordination modes of the IBA ligand: a MU2-eta(1):eta(1) double monodentate bridging mode, a MU1-eta(2) bridging mode and a MU2-eta(1):eta(2) bridging mode linking two lanthanide atoms. Adjacent Sm atoms were linked via the MU2-bridging carboxylate groups of the IBA ligands to generate a binuclear building unit. The biological activity of the complexes was evaluated in human adipose tissue derived stem cells (hADSCs) and Chang liver cells using a multiple parallel perfused microbioreactor. The results showed that cytotoxicity increased as the concentrations of complexes 1-3 increased. PMID- 23933564 TI - Rapid and sensitive liquid chromatography-tandem mass spectrometry method for determination of 1-beta-d-arabinofuranosyluracil in human plasma and application to therapeutic drug monitoring in patient with leukemia. AB - A specific and reliable HPLC-MS/MS method was developed and validated for the determination of ara-U in human plasma. The analyte was separated on a C18 column (50 mm * 2.1mm, 1.7 MUm) and a triple-quadrupole mass spectrometry equipped with an electrospray ionization (ESI) source was applied for detection. The plasma sample was prepared by a simple protein precipitation pretreatment and the recovery was about 80%. The calibration curves were linear over a concentration range of 1.0-7000.0 ng/mL for ara-U. The intra-day and inter-day precision was less than 15% and the relative error (RE) was all within +/- 15%. It was successfully applied to assess the disposition characteristics of ara-U and support the therapeutic drug monitoring after the patients with leukemia were infused with ara-C. PMID- 23933565 TI - Characterization of degradation products of idarubicin through LC-UV, MS(n) and LC-MS-TOF studies. AB - Idarubicin was subjected to forced degradation under the ICH recommended conditions of hydrolysis, oxidation, dry heat and photolysis to characterize its possible impurities and/or degradation products. The drug was found unstable to acid hydrolysis at 85 degrees C and to alkaline hydrolysis, and oxidation at room temperature. The hydrolytic and oxidative degradation products were resolved with gradient and isocratic elution, respectively on an Inertsil RP18 (250 mm * 4.6mm; 5 MU) column with HCOONH4 (20mM, pH 3.0) and acetonitrile. The drug degraded to two products (O-I and O-II) in oxidative condition, two products (K-I and K-II) in alkaline hydrolytic, and one product (A-I) in acidic hydrolytic conditions. The purity of each in the LC-UV chromatogram was ascertained through LC-PDA analysis. The products were characterized through +ESI-MS(n) studies on the drug and LC-MS-TOF studies on the degraded drug solutions. Based on the multistage mass fragmentation pattern of idarubicin and accurate mass analysis of the degradation products, the O-I, O-II and A-I were characterized as desacetylidarubicin hydroperoxide, desacetylidarubicin and deglucosaminylidarubicin, respectively. The products K-I and K-II were not characterized due to their low concentrations and/or extremely weak ionization. The mechanisms of degradation of idarubicin to these products were proposed and discussed. PMID- 23933566 TI - Reversed-phase thin-layer chromatography technique for the comparison of the lipophilicity of selected non-steroidal anti-inflammatory drugs. AB - The chromatographic behavior of a series of coxibs and oxicams, drugs from a group of non-steroidal anti-inflammatory drugs, was studied by reversed-phase thin-layer chromatography with binary mobile phases containing water and the organic modifiers: methanol, acetone, 1,4-dioxane, acetonitrile and 2-propanol. Linear relationships were obtained between the retention RM values of the compounds and the concentration of organic modifier in the mobile phase. Values of RM0, represent the theoretical RM values at 0% organic solvent in the mobile phase were calculated by extrapolation. These experimental lipophilicity values were correlated with lipophilicity (logP) from databases. The obtained results show that reversed-phase chromatography (experimental parameters) may be a good instrument for analytics in describing the lipophilic nature of investigated compounds as well as the activity. PMID- 23933567 TI - Experiments for a systematic comparison between stable-isotope-(deuterium) labeling and radio-((14)C) labeling for the elucidation of the in vitro metabolic pattern of pharmaceutical drugs. AB - A systematic comparison between two labeling approaches for the investigation of the in vitro metabolic pattern of pharmaceutical drugs was performed by examining the use of (i) radiolabeled drugs analyzed with LC-MS-offline radiodetection and (ii) stable-isotope labeled drugs, used in a defined mixture with the unlabeled drug and analyzed by LC-MS with recognition of the specific isotopic pattern. (14)C was used for the radioisotope-approach and deuterium for the stable-isotope approach. Olanzapine, diclofenac and ketoconazole were chosen as model drugs, as they are commercially available in their non-, radio- and stable-isotope labeled forms. For all three model drugs, liver microsome- and hepatocyte-incubations (both from rat) were performed with various concentrations and incubation times for both, the radio- and the stable-isotope approaches. The metabolic pattern, including structure elucidation of all detected metabolites, was performed independently for all individual compounds and incubations. Subsequently, the metabolic patterns of the radio-, and the stable-isotope approaches were compared. In conclusion, all metabolites found with the radioisotope approach could also be found with the stable-isotope approach. Although the stable-isotope approach does not provide a quantitative result, it can be considered to be a highly suited analytical alternative for early in vitro metabolism investigations, especially when radiolabeled drug analogues are not yet available and quantitative results are not yet necessary. PMID- 23933568 TI - Metastatic breast carcinoma induces vascular endothelial dysfunction in Balb-c mice: Role of the tumor necrosis factor-alpha and NADPH oxidase. AB - Although the oxidative stress and inflammation are closely related with breast cancer, there is no study directly examining the possible changes in vascular functions in the presence of breast carcinoma. The goal of the present study was to evaluate changes in vascular reactivity in tumor-bearing mice. In this study, highly metastatic breast carcinoma cells which were derived from liver or brain metastasis of 4T1 murine breast carcinoma (4TLM and 4TBM, respectively), and 67NR cells which were tumorigenic but non-metastatic cells were used. Female Balb-c mice 8-10weeks old were divided into following groups: (1) control, (2) injected with 67NR, (3) injected with 4TLM, and (4) injected with 4TBM orthotopically. Thoracic aorta was removed 23-25days after injection of tumor cells. Isometric tension studies were performed in response to potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh, an endothelium-dependent vasodilator), and sodium nitroprusside (SNP, an endothelium-independent vasodilator). Endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (Ser 1177) (p eNOS), gp91(phox), and tumor necrosis factor-alpha (TNF-alpha) expressions in aortic tissues were demonstrated by immunohistochemistry. The level of TNF-alpha in vascular tissue was measured by ELISA. The presence of tumor was resulted in significant inhibition of response to ACh in both 4TLM and 4TBM injected mice, but not 67NR injected mice. Furthermore, both KCl and Phe-induced contraction of thoracic aorta was not changed significantly in tumor-bearing animals. eNOS and p eNOS expressions decreased while gp91(phox) and TNF-alpha expressions increased in endothelium of 4TLM and 4TBM mice compared to 67NR injected and control mice. Moreover, TNF-alpha levels of thoracic aorta in mice with metastatic breast carcinoma were significantly higher than that of 67NR mice. Tumor-induced endothelial dysfunction determined by ACh-induced relaxation improved by superoxide dismutase (SOD), apocynin (a NADPH oxidase inhibitor), and infliximab (a TNF-alpha monoclonal antibody). The findings of this study suggest that the presence of metastatic breast carcinoma may cause a significant reduction in endothelium-dependent relaxation of thoracic aorta via NADPH oxidase-mediated oxidative stress and TNF-alpha production. PMID- 23933569 TI - Reconstruction of damaged corneal epithelium using Venus-labeled limbal epithelial stem cells and tracking of surviving donor cells. AB - Limbal epithelial stem cells are responsible for the self-renewal and replenishment of the corneal epithelium. Although it is possible to repair the ocular surface using limbal stem cell transplantation, the mechanisms behind this therapy are unclear. To investigate the distribution of surviving donor cells in a reconstructed corneal epithelium, we screened a Venus-labeled limbal stem cell strain in goats. Cells were cultivated on denuded human amniotic membrane for 21 days to produce Venus-labeled corneal epithelial sheets. The Venus-labeled corneal epithelial sheets were transplanted to goat models of limbal stem cell deficiency. At 3 months post-surgery, the damaged corneal epithelia were obviously improved in the transplanted group compared with the non-transplanted control, with the donor cells still residing in the reconstructed ocular surface epithelium. Using Venus as a marker, our results indicated that the location and survival of donor cells varied, depending on the corneal epithelial region. Additionally, immunofluorescent staining of the reconstructed corneal epithelium demonstrated that many P63(+) cells were unevenly distributed among basal and suprabasal epithelial layers. Our study provides a new model, and reveals some of the mechanisms involved in corneal epithelial cell regeneration research. PMID- 23933570 TI - Measurement of the anisotropic thermal conductivity of the porcine cornea. AB - Accurate thermal models for the cornea of the eye support the development of thermal techniques for reshaping the cornea and other scientific purposes. Heat transfer in the cornea must be quantified accurately so that a thermal treatment does not destroy the endothelial layer, which cannot regenerate, and yet is responsible for maintaining corneal transparency. We developed a custom apparatus to measure the thermal conductivity of ex vivo porcine corneas perpendicular to the surface and applied a commercial apparatus to measure thermal conductivity parallel to the surface. We found that corneal thermal conductivity is 14% anisotropic at the normal state of corneal hydration. Small numbers of ex vivo feline and human corneas had a thermal conductivity perpendicular to the surface that was indistinguishable from the porcine corneas. Aqueous humor from ex vivo porcine, feline, and human eyes had a thermal conductivity nearly equal to that of water. Including the anisotropy of corneal thermal conductivity will improve the predictive power of thermal models of the eye. PMID- 23933571 TI - Role of FDG-PET/CT in diagnosis of aortitis caused by Takayasu arteritis and IgG4 related systemic disease. PMID- 23933573 TI - Impaired oxidoreduction by 11beta-hydroxysteroid dehydrogenase 1 results in the accumulation of 7-oxolithocholic acid. AB - 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mediates glucocorticoid activation and is currently considered as therapeutic target to treat metabolic diseases; however, biomarkers to assess its activity in vivo are still lacking. Recent in vitro experiments suggested that human 11beta-HSD1 metabolizes the secondary bile acid 7-oxolithocholic acid (7-oxoLCA) to chenodeoxycholic acid (CDCA) and minor amounts of ursodeoxycholic acid (UDCA). Here, we provide evidence from in vitro and in vivo studies for a major role of 11beta-HSD1 in the oxidoreduction of 7-oxoLCA and compare its level and metabolism in several species. Hepatic microsomes from liver-specific 11beta-HSD1-deficient mice were devoid of 7-oxoLCA oxidoreductase activity. Importantly, circulating and intrahepatic levels of 7-oxoLCA and its taurine conjugate were significantly elevated in mouse models of 11beta-HSD1 deficiency. Moreover, comparative enzymology of 11beta-HSD1-dependent oxidoreduction of 7-oxoLCA revealed that the guinea-pig enzyme is devoid of 7-oxoLCA oxidoreductase activity. Unlike in other species, 7-oxoLCA and its glycine conjugate are major bile acids in guinea-pigs. In conclusion, the oxidoreduction of 7-oxoLCA and its conjugated metabolites are catalyzed by 11beta-HSD1, and the lack of this activity leads to the accumulation of these bile acids in guinea-pigs and 11beta-HSD1-deficient mice. Thus, 7-oxoLCA and its conjugates may serve as biomarkers of impaired 11beta-HSD1 activity. PMID- 23933572 TI - Research on the premotor symptoms of Parkinson's disease: clinical and etiological implications. AB - BACKGROUND: The etiology and natural history of Parkinson's disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years. OBJECTIVES: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications. METHODS: This review was based on a workshop, Parkinson's Disease Premotor Symptom Symposium, held 7-8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. DISCUSSION: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood. CONCLUSION: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis. PMID- 23933574 TI - Endogenous alpha-synuclein influences the number of dopaminergic neurons in mouse substantia nigra. AB - The presynaptic protein alpha-synuclein is central to the pathogenesis of alpha synucleinopathies. We show that the presence of endogenous mouse alpha-synuclein leads to higher number of dopaminergic neurons in the substantia nigra of wild type C57Bl/6J mice compared with C57Bl/6S mice with a spontaneous deletion of the alpha-synuclein gene or C57Bl/6J mice with a targeted deletion of the alpha synuclein gene. This effect of alpha-synuclein on dopaminergic neuron occurs during development between E10.5 and E13.5 and persists in adult life supporting the involvement of alpha-synuclein in the development of a subset of dopaminergic neurons. PMID- 23933575 TI - Chewing the fat: genetic approaches to model dyslipidemia-induced diabetic neuropathy in mice. AB - Emerging clinical evidence now suggests that dyslipidemia may be strongly linked with the development and progression of neuropathy in diabetic patients, and dyslipidemia is considered an important risk factor for the development of diabetic neuropathy. However, because of important species differences, current animal models fall short of accurately replicating human diabetic dyslipidemia. Rodents resist expansion in low-density lipoprotein cholesterol (LDL-C) and typically maintain or increase high-density lipoprotein cholesterol (HDL-C), despite prolonged high-fat feeding. Here, we discuss the findings of Hinder et al., in which they utilized novel genetic experimental approaches to develop a diabetic mouse model with human-like dyslipidemia. The authors created a mouse with an apolipoprotein E (ApoE) knockout in conjunction with a leptin receptor mutation. A triple mutant mouse with both ApoE and apolipoprotein B48 knockout and leptin deficiency was also created in an effort to generate a model of diabetic dyslipidemia that better mimics the human condition. The long-term goal of these studies is to develop more faithful models to address how hyperglycemia and hyperlipidemia may drive the development and progression of neuropathy. Hinder and colleagues were successful at creating a diabetic mouse model with severe hypertriglyceridemia, hypercholesterolemia, and a significant increase in the total cholesterol to HDL-C ratio. This work was successful in establishing a model of diabetic dyslipidemia that more closely emulates the poor lipid profile observed in human diabetic patients with neuropathy. This commentary will also review current models used to study the effects of dyslipidemia on diabetic neuropathy and highlight a proposed mechanism for the role of dyslipidemia in the pathogenesis of diabetic neuropathy. PMID- 23933576 TI - Functional characterization of ClC-1 mutations from patients affected by recessive myotonia congenita presenting with different clinical phenotypes. AB - Myotonia congenita (MC) is caused by loss-of-function mutations of the muscle ClC 1 chloride channel. Clinical manifestations include the variable association of myotonia and transitory weakness. We recently described a cohort of recessive MC patients showing, at a low rate repetitive nerves stimulation protocol, different values of compound muscle action potential (CMAP) transitory depression, which is considered the neurophysiologic counterpart of transitory weakness. From among this cohort, we studied the chloride currents generated by G190S (associated with pronounced transitory depression), F167L (little or no transitory depression), and A531V (variable transitory depression) hClC-1 mutants in transfected HEK293 cells using patch-clamp. While F167L had no effect on chloride currents, G190S dramatically shifts the voltage dependence of channel activation and A531V reduces channel expression. Such variability in molecular mechanisms observed in the hClC-1 mutants may help to explain the different clinical and neurophysiologic manifestations of each ClCN1 mutation. In addition we examined five different mutations found in compound heterozygosis with F167L, including the novel P558S, and we identified additional molecular defects. Finally, the G190S mutation appeared to impair acetazolamide effects on chloride currents in vitro. PMID- 23933577 TI - Adult motor axons preferentially reinnervate predegenerated muscle nerve. AB - Preferential motor reinnervation (PMR) is the tendency for motor axons regenerating after repair of mixed nerve to reinnervate muscle nerve and/or muscle rather than cutaneous nerve or skin. PMR may occur in response to the peripheral nerve pathway alone in juvenile rats (Brushart, 1993; Redett et al., 2005), yet the ability to identify and respond to specific pathway markers is reportedly lost in adults (Uschold et al., 2007). The experiments reported here evaluate the relative roles of pathway and end organ in the genesis of PMR in adult rats. Fresh and 2-week predegenerated femoral nerve grafts were transferred in correct or reversed alignment to replace the femoral nerves of previously unoperated Lewis rats. After 8 weeks of regeneration the motoneurons projecting through the grafts to recipient femoral cutaneous and muscle branches and their adjacent end organs were identified by retrograde labeling. Motoneuron counts were subjected to Poisson regression analysis to determine the relative roles of pathway and end organ identity in generating PMR. Transfer of fresh grafts did not result in PMR, whereas substantial PMR was observed when predegenerated grafts were used. Similarly, the pathway through which motoneurons reached the muscle had a significant impact on PMR when grafts were predegenerated, but not when they were fresh. Comparison of the relative roles of pathway and end organ in generating PMR revealed that neither could be shown to be more important than the other. These experiments demonstrate unequivocally that adult muscle nerve and cutaneous nerve differ in qualities that can be detected by regenerating adult motoneurons and that can modify their subsequent behavior. They also reveal that two weeks of Wallerian degeneration modify the environment in the graft from one that provides no modality-specific cues for motor neurons to one that actively promotes PMR. PMID- 23933578 TI - Burn injury-induced mechanical allodynia is maintained by Rac1-regulated dendritic spine dysgenesis. AB - Although nearly 11 million individuals yearly require medical treatment due to burn injuries and develop clinically intractable pain, burn injury-induced pain is poorly understood, with relatively few studies in preclinical models. To elucidate mechanisms of burn injury-induced chronic pain, we utilized a second degree burn model, which produces a persistent neuropathic pain phenotype. Rats with burn injury exhibited reduced mechanical pain thresholds ipsilateral to the burn injury. Ipsilateral WDR neurons in the spinal cord dorsal horn exhibited hyperexcitability in response to a range of stimuli applied to their hindpaw receptive fields. Because dendritic spine morphology is strongly associated with synaptic function and transmission, we profiled dendritic spine shape, density, and distribution of WDR neurons. Dendritic spine dysgenesis was observed on ipsilateral WDR neurons in burn-injured animals exhibiting behavioral and electrophysiological evidence of neuropathic pain. Heat hyperalgesia testing produced variable results, as expected from previous studies of this model of second-degree burn injury in rats. Administration of Rac1-inhibitor, NSC23766, attenuated dendritic spine dysgenesis, decreased mechanical allodynia and electrophysiological signs of burn-induced neuropathic pain. These results support two related implications: that the presence of abnormal dendritic spines contributes to the maintenance of neuropathic pain, and that therapeutic targeting of Rac1 signaling merits further investigation as a novel strategy for pain management after burn injury. PMID- 23933579 TI - Uric acid and risk of heart failure: a systematic review and meta-analysis. AB - AIMS: We aimed to perform a systematic review and meta-analysis to assess the association between serum uric acid and incident heart failure (HF)/prognosis of HF patients. METHODS AND RESULTS: A systematic electronic literature search was conducted in Embase (Ovid SP, from 1974 to May 2013), Medline (Ovid SP, from 1946 to May 2013), and the Chinese Biomedical Literature Database (CBM, from 1978 to May 2013) to identify studies reporting on the association between serum uric acid and HF. Either a random effects model or a fixed effects model was used for pooling data. Five studies reporting on incident HF and 28 studies reporting on the adverse outcomes of HF patients were included. The results showed that hyperuricaemia was associated with an increased risk of incident HF [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.41-1.94], and the risk of all-cause mortality (HR 2.15, 95% CI 1.64-2.83), cardiovascular mortality (HR 1.45, 95% CI 1.18-1.78), and the composite of death or cardiac events (HR 1.39, 95% CI 1.18 1.63) in HF patients. For every 1 mg/dL increase in serum uric acid, the odds of development of HF increased by 19% (HR 1.19, 95% CI 1.17-1.21), and the risk of all-cause mortality and the composite endpoint in HF patients increased by 4% (HR 1.04, 95% CI 1.02-1.06) and 28% (HR 1.28, 95% CI 0.97-1.70), respectively. Subgroup analyses supported the positive association between serum uric acid and HF. CONCLUSIONS: Elevated serum uric acid is associated with an increased risk of incident HF and adverse outcomes in HF patients. PMID- 23933580 TI - Slc26a6 functions as an electrogenic Cl-/HCO3- exchanger in cardiac myocytes. AB - AIMS: Alterations in cardiac acid-base balance can produce profound impact on excitation-contraction coupling and precipitate cardiac dysfunction and arrhythmias. A member of the solute carrier (SLC) family, Slc26a6, has been shown to be a chloride-hydroxyl exchanger and the predominant chloride-bicarbonate exchanger in the mouse heart. However, the exact isoforms and functional characteristics of cardiac Slc26a6 remain unknown. The objective of the present study is to determine the molecular identity of cardiac Slc26a6 isoforms, to examine their cellular expressions in the heart, and to test the function of Slc26a6 in cardiomyocytes. METHODS AND RESULTS: We examined the expression and function of slc26a6 in mouse cardiomyocytes using RT-PCR, immunofluorescence confocal microscopy, and patch-clamp technique coupled with the fast solution exchange system. We identified four cardiac Slc26a6 isoforms, denoted C-a, C-b, C c, and C-d, and detected significant expression of Slc26a6 in the plasma membrane of both atrial and ventricular myocytes. Isoforms C-a and C-b share the same sequence with the previously reported murine Slc26a6a and Slc26a6b, respectively. Isoform C-c lacks an alternate in-frame exon 12, whereas C-d is a C-terminal truncated form resulting from 102 bp exon insertion between exons 15 and 16 compared with C-b. Patch-clamp recordings demonstrated electrogenic Cl(-)/oxalate and electrogenic Cl(-)/HCO3(-) exchange activities in cardiomyocytes. CONCLUSION: We demonstrate that cardiac myocytes express different isoforms of Slc26a6, which encode electrogenic Cl(-)/HCO3(-) and Cl(-)/oxalate exchangers. The electrogenic nature of the Cl(-)/HCO3(-) exchange of cardiac Slc26a6 suggests important roles in regulating acid-base balance in the heart. PMID- 23933581 TI - Urotensin-II promotes vascular smooth muscle cell proliferation through store operated calcium entry and EGFR transactivation. AB - AIMS: Urotensin-II (UII) is a vasoactive peptide that promotes vascular smooth muscle cells (VSMCs) proliferation and is involved in the pathogenesis of atherosclerosis, restenosis, and vascular remodelling. This study aimed to determine the role of calcium (Ca(2+))-dependent signalling and alternative signalling pathways in UII-evoked VSMCs proliferation focusing on store-operated Ca(2+) entry (SOCE) and epithelium growth factor receptor (EGFR) transactivation. METHODS AND RESULTS: We used primary cultures of VSMCs isolated from Wistar rat aorta to investigate the effects of UII on intracellular Ca(2+) mobilization, and proliferation determined by the 5-bromo-2-deoxyuridine (BrdU) assay. We found that UII enhanced intracellular Ca(2+) concentration ([Ca(2+)]i) which was significantly reduced by classical SOCE inhibitors and by knockdown of essential components of the SOCE such as stromal interaction molecule 1 (STIM1), Orai1, or TRPC1. Moreover, UII activated a Gd(3+)-sensitive current with similar features of the Ca(2+) release-activated Ca(2+) current (ICRAC). Additionally, UII stimulated VSMCs proliferation and Ca(2+)/cAMP response element-binding protein (CREB) activation through the SOCE pathway that involved STIM1, Orai1, and TRPC1. Co-immunoprecipitation experiments showed that UII promoted the association between Orai1 and STIM1, and between Orai1 and TRPC1. Moreover, we determined that EGFR transactivation, extracellular signal-regulated kinase (ERK) and Ca(2+)/calmodulin-dependent kinase (CaMK) signalling pathways were involved in both UII-mediated Ca(2+) influx, CREB activation and VSMCs proliferation. CONCLUSION: Our data show for the first time that UII-induced VSMCs proliferation and CREB activation requires a complex signalling pathway that involves on the one hand SOCE mediated by STIM1, Orai1, and TRPC1, and on the other hand EGFR, ERK, and CaMK activation. PMID- 23933583 TI - Binding to G-quadruplex RNA activates the mitochondrial GTPase NOA1. AB - NOA1 is an evolutionary conserved, nuclear encoded GTPase essential for mitochondrial function and cellular survival. The function of NOA1 for assembly of mitochondrial ribosomes and regulation of OXPHOS activity depends on its GTPase activity, but so far no ligands have been identified that regulate the GTPase activity of NOA1. To identify nucleic acids that bind to the RNA-binding domain of NOA1 we employed SELEX (Systemic Evolution of Ligands by EXponential Enrichment) using recombinant mouse wildtype NOA1 and the GTPase mutant NOA1 K353R. We found that NOA1 binds specifically to oligonucleotides that fold into guanine tetrads (G-quadruplexes). Binding of G-quadruplex oligonucleotides stimulated the GTPase activity of NOA1 suggesting a regulatory link between G quadruplex containing RNAs, NOA1 function and assembly of mitochondrial ribosomes. PMID- 23933582 TI - Differential regulation of cardiac excitation-contraction coupling by cAMP phosphodiesterase subtypes. AB - AIMS: Multiple phosphodiesterases (PDEs) hydrolyze cAMP in cardiomyocytes, but the functional significance of this diversity is not well understood. Our goal here was to characterize the involvement of three different PDEs (PDE2-4) in cardiac excitation-contraction coupling (ECC). METHODS AND RESULTS: Sarcomere shortening and Ca(2+) transients were recorded simultaneously in adult rat ventricular myocytes and ECC protein phosphorylation by PKA was determined by western blot analysis. Under basal conditions, selective inhibition of PDE2 or PDE3 induced a small but significant increase in Ca(2+) transients, sarcomere shortening, and troponin I phosphorylation, whereas PDE4 inhibition had no effect. PDE3 inhibition, but not PDE2 or PDE4, increased phospholamban phosphorylation. Inhibition of either PDE2, 3, or 4 increased phosphorylation of the myosin-binding protein C, but neither had an effect on L-type Ca(2+) channel or ryanodine receptor phosphorylation. Dual inhibition of PDE2 and PDE3 or PDE2 and PDE4 further increased ECC compared with individual PDE inhibition, but the most potent combination was obtained when inhibiting simultaneously PDE3 and PDE4. This combination also induced a synergistic induction of ECC protein phosphorylation. Submaximal beta-adrenergic receptor stimulation increased ECC, and this effect was potentiated by individual PDE inhibition with the rank order of potency PDE4 = PDE3 > PDE2. Identical results were obtained on ECC protein phosphorylation. CONCLUSION: Our results demonstrate that PDE2, PDE3, and PDE4 differentially regulate ECC in adult cardiomyocytes. PDE2 and PDE3 play a more prominent role than PDE4 in regulating basal cardiac contraction and Ca(2+) transients. However, PDE4 becomes determinant when cAMP levels are elevated, for instance, upon beta-adrenergic stimulation or PDE3 inhibition. PMID- 23933584 TI - Hip2 ubiquitin-conjugating enzyme overcomes radiation-induced G2/M arrest. AB - Radiation induces cell cycle arrest and/or cell death in mammalian cells. In the present study, we show that Hip2, a ubiquitin-conjugating enzyme, can overcome radiation-induced G2/M cell cycle arrest and trigger the entry into mitosis. Ionizing radiation increased the levels of Hip2 by preventing its degradation but not its gene transcription. The stability of Hip2 in irradiated cells was further confirmed using live cell fluorescence imaging. Flow cytometric and molecular analyses revealed that Hip2 abrogated radiation-induced G2/M arrest, promoting entry into mitosis. Bimolecular fluorescence complementation assays and co immunoprecipitation experiments showed that Hip2 interacted with and targeted p53 for degradation via the ubiquitin proteasome system, resulting in the activation of cdc2-cyclin B1 kinase to promote mitotic entry. These results contribute to our understanding of the mechanisms that regulate cell cycle progression and DNA damage-induced G2/M checkpoint cellular responses. PMID- 23933585 TI - Interferon-stimulated genes and their role in controlling hepatitis C virus. AB - Infections with the hepatitis C virus (HCV) are a major cause of chronic liver disease. While the acute phase of infection is mostly asymptomatic, this virus has the high propensity to establish persistence and in the course of one to several decades liver disease can develop. HCV is a paradigm for the complex interplay between the interferon (IFN) system and viral countermeasures. The virus induces an IFN response within the infected cell and is rather sensitive against the antiviral state triggered by IFNs, yet in most cases HCV persists. Numerous IFN-stimulated genes (ISGs) have been reported to suppress HCV replication, but in only a few cases we begin to understand the molecular mechanisms underlying antiviral activity. It is becoming increasingly clear that blockage of viral replication is mediated by the concerted action of multiple ISGs that target different steps of the HCV replication cycle. This review briefly summarizes the activation of the IFN system by HCV and then focuses on ISGs targeting the HCV replication cycle and their possible mode of action. PMID- 23933586 TI - Inhibition of Src activation with cardiotoxin III blocks migration and invasion of MDA-MB-231 cells. AB - Cardiotoxin III (CTX III), a basic polypeptide isolated from Naja naja atra venom, has been demonstrated to display anticancer activity. Breast cancer is a highly malignant carcinoma and most deaths of breast cancer are caused by metastasis. In this study, we show that CTX III blocks migration and invasion of MDA-MB-231 breast cancer cells without affecting apoptosis or cell cycle arrest. CTX III caused significant block of Src kinase activity in MDA-MB-231 cells. Moreover, CTX III treatment was correlated with reduced phosphorylation of FAK at Tyr576, 861 and 925 sites, p130(Cas) at Tyr410, and paxillin at Tyr118. CTX III also suppressed the activation of extracellular signal-regulated kinase1/2 and phosphatidylinositol 3-kinase/Akt. Consistent with inhibition of these signaling pathways and invasion, CTX III inhibited the expression of matrix metalloproteinase-9. In addition, Src specific inhibitor PP2 caused a significant decrease in the phosphorylation of FAK, p130(Cas), paxillin, PI3K/Akt, and ERK1/2. Taken together, CTX III significantly inhibited phosphorylation of Src and downstream molecules as well as cell migration and invasion. Our findings provide evidences that CTX III inhibits Src-mediated signaling pathways involved in controlling MDA-MB-231 cell migration and invasion, suggesting that it has therapeutic potential in breast cancer treatment. PMID- 23933587 TI - Endothelin regulates neural crest deployment and fate to form great vessels through Dlx5/Dlx6-independent mechanisms. AB - Endothelin-1 (Edn1), originally identified as a vasoconstrictor peptide, is involved in the development of cranial/cardiac neural crest-derived tissues and organs. In craniofacial development, Edn1 binds to Endothelin type-A receptor (Ednra) to induce homeobox genes Dlx5/Dlx6 and determines the mandibular identity in the first pharyngeal arch. However, it remains unsolved whether this pathway is also critical for pharyngeal arch artery development to form thoracic arteries. Here, we show that the Edn1/Ednra signaling is involved in pharyngeal artery development by controlling the fate of neural crest cells through a Dlx5/Dlx6-independent mechanism. Edn1 and Ednra knock-out mice demonstrate abnormalities in pharyngeal arch artery patterning, which include persistent first and second pharyngeal arteries, resulting in additional branches from common carotid arteries. Neural crest cell labeling with Wnt1-Cre transgene and immunostaining for smooth muscle cell markers revealed that neural crest cells abnormally differentiate into smooth muscle cells at the first and second pharyngeal arteries of Ednra knock-out embryos. By contrast, Dlx5/Dlx6 knockout little affect the development of pharyngeal arch arteries and coronary arteries, the latter of which is also contributed by neural crest cells through an Edn dependent mechanism. These findings indicate that the Edn1/Ednra signaling regulates neural crest differentiation to ensure the proper patterning of pharyngeal arch arteries, which is independent of the regional identification of the pharyngeal arches along the dorsoventral axis mediated by Dlx5/Dlx6. PMID- 23933589 TI - Developmental dissociation of visual dorsal stream parvo and magnocellular representations and the functional impact of negative retinotopic BOLD responses. AB - Localized neurodevelopmental defects provide an opportunity to study structure function correlations in the human nervous system. This unique multimodal case report of epileptogenic dysplasia in the visual cortex allowed exploring visual function across distinct pathways in retinotopic regions and the dorsal stream, in relation to fMRI retinotopic mapping and spike triggered BOLD responses. Pre surgical EEG/video monitoring, MRI/DTI, EEG/fMRI, PET and SPECT were performed to characterize structure/function correlations in this patient with a very early lesion onset. In addition, we included psychophysical methods (assessing parvo/konio and magnocellular pathways) and retinotopic mapping. We could identify dorsal stream impairment (with extended contrast sensitivity deficits within the input magno system contrasting with more confined parvocellular deficits) with disrupted active visual field input representations in regions neighboring the lesion. Simultaneous EEG/fMRI identified perilesional and retinotopic bilaterally symmetric BOLD deactivation triggered by interictal spikes, which matched the contralateral spread of magnocellular dysfunction revealed in the psychophysical tests. Topographic changes in retinotopic organization further suggested long term functional effects of abnormal electrical discharges during brain development. We conclude that fMRI based visual field cortical mapping shows evidence for retinotopic dissociation between magno and parvocellular function well beyond striate cortex, identifiable in high level dorsal visual representations around visual area V3A which is consistent with the effects of epileptic spike triggered negative BOLD. PMID- 23933588 TI - Pkd1 is required for male reproductive tract development. AB - Reproductive tract abnormalities and male infertility have higher incidence in ADPKD patients than in general populations. In this work, we reveal that Pkd1, whose mutations account for 85% of ADPKD cases, is essential for male reproductive tract development. Disruption of Pkd1 caused multiple organ defects in the murine male reproductive tract. The earliest visible defect in the Pkd1(-/ ) reproductive tract was cystic dilation of the efferent ducts, which are derivatives of the mesonephric tubules. Epididymis development was delayed or arrested in the Pkd1(-/-) mice. No sign of epithelial coiling was seen in the null mutants. Disruption of Pkd1 in epithelium alone using the Pax2-cre mice was sufficient to cause efferent duct dilation and coiling defect in the epididymis, suggesting that Pkd1 is critical for epithelium development and maintenance in male reproductive tract. In-depth analysis showed that Pkd1 is required to maintain tubulin cytoskeleton and important for Tgf-beta/Bmp signal transduction in epithelium of male reproductive tract. Altogether, our results for the first time provide direct evidence for developmental roles of Pkd1 in the male reproductive tract and provide new insights in reproductive tract abnormalities and infertility in ADPKD patients. PMID- 23933590 TI - Visceral adiposity is associated with SIRT1 expression in peripheral blood mononuclear cells: a pilot study. AB - Sirtuin1 (SIRT1) is activated during calorie restriction and appears to be related to energy balance through glucose or lipid metabolism and insulin signaling. These findings suggest that SIRT1 may play a role in the pathophysiology of visceral obesity. Therefore, we investigated the relationship between SIRT1 gene expression in circulating peripheral blood mononuclear cells (PBMCs) and abdominal visceral adiposity as measured by computed tomography. We recruited 43 men and women without history of diabetes or cardiovascular disease Biomarkers of metabolic disease and body composition by computed tomography were assessed. SIRT1 gene expression was determined using isolated PBMCs. SIRT1 expression levels negatively correlated with body mass index, waist circumference, abdominal visceral fat area, and homeostasis model of assessment of insulin resistance (HOMA-IR) and positively correlated with adiponectin levels. Results of step-wise multiple regression analysis revealed that abdominal visceral fat area and HOMA-IR were independently associated with SIRT1 expression. The significant association between abdominal visceral fat accumulation and SIRT1 gene expression in PBMCs suggests that SIRT1 may be a new therapeutic target for the prevention of disease related to obesity, especially visceral obesity. PMID- 23933591 TI - Association analysis between genetic variants of MDM2 gene and osteosarcoma susceptibility in Chinese. AB - Osteosarcoma (OS) is the most common pediatric bone malignancy worldwide. The MDM2 gene is an important candidate gene for influencing the susceptibility to OS. The objective of this study aimed to detect the potential association between MDM2 genetic variants and OS susceptibility in Chinese Han population. We recruited 415 OS patients and 431 cancer-free controls in this case-control study. The c.44C>T and c.1002T>C genetic variants in MDM2 gene were investigated using created restriction site-polymerase chain reaction (CRS-PCR) and PCR restriction fragment length polymorphism (PCR-RFLP), respectively. We found that the genotypes/alleles of c.44C>T and c.1002T>C were statistically associated with the increased risk of OS (for c.44C>T, TT versus (vs.) CC: OR = 2.43, 95% CI 1.49 3.95, p < 0.001; T vs. C: OR = 1.36, 95% CI 1.11-1.67, p = 0.003; for c.1002T>C, CC vs. TT: OR = 2.38, 95% CI 1.37-4.13, p = 0.002; C vs. T: OR = 1.27, 95% CI 1.02-1.56, p = 0.030). The T allele and TT genotype of c.44C>T and C allele and CC genotype of c.1002T>C could be increased risk factors for the susceptibility to OS. Results from this study suggest that MDM2 genetic variants are potentially related to OS susceptibility in Chinese Han population, and might be used as molecular markers for assessing OS susceptibility. PMID- 23933592 TI - Multimodal function of the sweet taste receptor expressed in pancreatic beta cells: generation of diverse patterns of intracellular signals by sweet agonists. AB - The sweet taste receptor is expressed in the taste bud and is activated by numerous sweet molecules with diverse chemical structures. It is, however, not known whether these sweet agonists induce a similar cellular response in target cells. Using MIN6 cells, a pancreatic beta-cell line expressing endogenous sweet taste receptor, we addressed this question by monitoring changes in cytoplasmic Ca2+ ([Ca2+]i) and cAMP ([cAMP]i) induced by four sweet taste receptor agonists. Glycyrrhizin evoked sustained elevation of [Ca2+]i but [cAMP]i was not affected. Conversely, an artificial sweetener saccharin induced sustained elevation of [cAMP]i but did not increase [Ca2+]i. In contrast, sucralose and acesulfame K induced rapid and sustained increases in both [Ca2+]i and [cAMP]i. Although the latter two sweeteners increased [Ca2+]i and [cAMP]i, their actions were not identical: [Ca2+]i response to sucralose but not acesulfame K was inhibited by gurmarin, an antagonist of the sweet taste receptor which blocks the gustducin dependent pathway. In addition, [Ca2+]i response to acesulfame K but not to sucralose was resistant to a Gq inhibitor. These results indicate that four types of sweeteners activate the sweet taste receptor differently and generate distinct patterns of intracellular signals. The sweet taste receptor has amazing multimodal functions producing multiple patterns of intracellular signals. PMID- 23933593 TI - Agents and trends in health care workers' occupational asthma. AB - BACKGROUND: There is a disproportionately high number of cases of work-related asthma occurring in health care occupations due to agents such as glutaraldehyde, latex and cleaning products. AIMS: To understand the causes and measure trends over time of occupational asthma (OA) in health care workers (HCWs). METHODS: We reviewed OA notifications from the Midland Thoracic Society's Surveillance Scheme of Occupational Asthma (SHIELD) database in the West Midlands, UK, from 1991 to 2011 and gathered data on occupation, causative agent and annual number of notifications. RESULTS: There were 182 cases of OA in HCWs (median annual notifications = 7; interquartile range [IQR] = 5-11), representing 5-19% of annual SHIELD notifications. The modal annual notification was 20 (in 1996); notifications have declined since then, in line with total SHIELD notifications. The majority of cases (136; 75%) occurred in nursing, operating theatre, endoscopy and radiology staff. The most frequently implicated agents were glutaraldehyde (n = 69), latex (n = 47) and cleaning products (n = 27), accounting for 79% of the 182 cases. Cleaning product-related OA was an emerging cause with 22 cases after 2001 and only 5 cases between 1991 and 2000. CONCLUSIONS: Control measures within the UK National Health Service have seen a decline in OA in HCWs due to latex and glutaraldehyde, though OA remains a problem amongst HCWs exposed to cleaning products. Continuing efforts are required to limit the number of cases in this employment sector. PMID- 23933594 TI - A new clade, based on partial LSU rDNA sequences, of unarmoured dinoflagellates. AB - The order Gymnodiniales comprises unarmoured dinoflagellates. However, the lack of sequences hindered determining the phylogenetic positions and systematic relationships of several gymnodinioid taxa. In this study, a monophyletic clade was defined for the species Ceratoperidinium margalefii Loeblich III, Gyrodinium falcatum Kofoid & Swezy, three Cochlodinium species, and two Gymnodinium-like dinoflagellates. Despite their substantial morphotypic differentiation, Cochlodinium cf. helix, G. falcatum and 'Gymnodinium' sp. 1 share a common shape of the acrobase. The phylogenetic data led to the following conclusions: (1) C. margalefii is closely related to several unarmoured dinoflagellates. Its sulcus shape has been observed for the first time. (2) G. falcatum was erroneously assigned to the genus Gyrodinium and is transferred to Ceratoperidinium (C. falcatum (Kofoid & Swezy) Rene & de Salas comb. nov.). (3) The genus Cochlodinium is polyphyletic and thus artificial; our data support its separation into three different genera. (4) The two Gymnodinium-like species could not be morphologically or phylogenetically related to any other gymnodinioid species sequenced to date. While not all studied species have been definitively transferred to the correct genus, our study is a step forward in the classification of inconspicuous unarmoured dinoflagellates. The family Ceratoperidiniaeceae and the genus Ceratoperidinium are emended. PMID- 23933595 TI - Megalocytivirus-induced proteins of turbot (Scophthalmus maximus): identification and antiviral potential. AB - Megalocytivirus is an important fish pathogen with a broad host range that includes turbot. In this study, proteomic analysis was conducted to examine turbot proteins modulated in expression by megalocytivirus infection. Thirty five proteins from spleen were identified to be differentially expressed at 2days post viral infection (dpi) and 7dpi. Three upregulated proteins, i.e. heat shock protein 70 (Hsp70), Mx protein, and natural killer enhancing factor (NKEF), were further analyzed for potential antiviral effect. For this purpose, turbot were administered separately with the plasmids pHsp70, pMx, and pNKEF, which express Hsp70, Mx, and NKEF respectively, before megalocytivirus infection. Viral dissemination and propagation in spleen were subsequently determined. The results showed that the viral loads in fish administered with pNKEF were significantly reduced. To examine the potential of Hsp70, Mx, and NKEF as immunological adjuvant, turbot were immunized with a DNA vaccine in the presence of pHsp70, pMx, or pNKEF. Subsequent analysis showed that the presence of pNKEF and pHsp70, but not pMx, significantly reduced viral infection and enhanced fish survival. Taken together, these results indicate that NKEF exhibits antiviral property against megalocytivirus, and that both NKEF and Hsp70 may be used in DNA vaccine based control of megalocytivirus infection. BIOLOGICAL SIGNIFICANCE: This study provides the first proteomic picture of turbot in response to megalocytivirus infection. We demonstrated that megalocytivirus infection modulates the expression of turbot proteins associated with various cellular functions, and that one of the upregulated proteins, NKEF, exhibits antiviral effect when overexpressed in vivo, while another upregulated protein, Hsp70, exhibits adjuvant effect when co-immunized with a DNA vaccine. These results add molecular insights into turbot immune response induced by megalocytivirus and provide candidate proteins with application potentials in the control of megalocytivirus associated disease. PMID- 23933596 TI - Thermal mapping of a scanning thermal microscopy tip. AB - Scanning thermal microscopy (SThM) is a very promising technique for local investigation of temperature and thermal properties of nanostructures with great application potential in contemporary nanoelectronics and nanotechnology. In order to increase the localization of SThM measurements, the size of probes has recently substantially decreased, which results in novel types of SThM probes manufactured with the use of modern silicon microfabrication technology. Quantitative SThM measurements with these probes need methods, which enable to assess the quality of thermal contact between the probe and the investigated surface. In this paper we propose a tip thermal mapping (TThM) procedure, which is used to estimate experimentally the distribution of power dissipated by the tip of an SThM probe. We also show that the proposed power dissipation model explains the results of active-mode SThM measurements and that the TThM procedure is reversible for a given probe and sample. PMID- 23933597 TI - Development of nanomanipulator using a high-speed atomic force microscope coupled with a haptic device. AB - The atomic force microscope (AFM) has been widely used for surface fabrication and manipulation. However, nanomanipulation using a conventional AFM is inefficient because of the sequential nature of the scan-manipulation scan cycle, which makes it difficult for the operator to observe the region of interest and perform the manipulation simultaneously. In this paper, a nanomanipulation technique using a high-speed atomic force microscope (HS-AFM) is described. During manipulation using the AFM probe, the operation is periodically interrupted for a fraction of a second for high-speed imaging that allows the topographical image of the manipulated surface to be periodically updated. With the use of high-speed imaging, the interrupting time for imaging can be greatly reduced, and as a result, the operator almost does not notice the blink time of the interruption for imaging during the manipulation. This creates a more intuitive interface with greater feedback and finesse to the operator. Nanofabrication under real-time monitoring was performed to demonstrate the utility of this arrangement for real-time nanomanipulation of sample surfaces under ambient conditions. Furthermore, the HS-AFM is coupled with a haptic device for the human interface, enabling the operator to move the HS-AFM probe to any position on the surface while feeling the response from the surface during the manipulation. PMID- 23933598 TI - Quantifying nanoscale order in amorphous materials via scattering covariance in fluctuation electron microscopy. AB - Fluctuation Transmission Electron Microscopy (FTEM) has a unique ability to probe topological order on the 1-3 nm length scale in diffraction amorphous materials. However, extracting a quantitative description of the order has been challenging. We report that the FTEM covariance, computed at two non-degenerate Bragg reflections, is able to distinguish different regimes of size vs. volume fraction of order. The covariance analysis is general and does not require a material specific atomistic model. We use a Monte-Carlo approach to compute different regimes of covariance, based on the probability of exciting multiple Bragg reflections when a STEM nanobeam interacts with a volume containing ordered regions in an amorphous matrix. We perform experimental analysis on several sputtered amorphous thin films including a-Si, nitrogen-alloyed GeTe and Ge2Sb2Te5. The samples contain a wide variety of ordered states. Comparison of experimental data with the covariance simulation reveals different regimes of nanoscale topological order. PMID- 23933599 TI - Psychometric properties of the social phobia and anxiety inventory-child version in a Swedish clinical sample. AB - The social phobia and anxiety inventory for children (SPAI-C) is a 26 item, empirically derived self-report instrument developed for assessing social phobic fears in children. Evidence for satisfactory psychometric properties of the SPAI C has been found in multiple community studies. Since its development, however, no study has presented an extensive psychometric evaluation of SPAI-C in a sample of carefully diagnosed children with social phobia. The present study sought to replicate and expand previous studies by administrating the SPAI-C to a sample of 59 children that fulfilled DSM-IV criteria for social phobia, and 49 children with no social phobia diagnosis. An exploratory factor analysis resulted in a three factor solution reflecting: (1) fear of social interactions, (2) fear of public performance situations, and (3) physical and cognitive symptoms connected with social phobia. These factors appear to parallel domains of social phobia also evident in adults. The SPAI-C total scale and each factor was found to possess good internal consistency, good test-retest reliability and was generally strongly correlated with both self-report and clinician measures of anxiety and fears. The discriminative properties of the total scale were satisfactory. PMID- 23933600 TI - Effect of heat and cold on tendon flexibility and force to flex the human knee. AB - BACKGROUND: It is commonly believed in medicine that using heat will increase the distensability and flexibility of soft tissue. If true, increased flexibility would be a positive factor to reduce injuries in sports. However, cold should have the opposite effect and is often used to treat sports injuries. This study was accomplished to quantify the effect of heat and cold on the force needed to flex the knee and laxness of the anterior and posterior cruciate ligaments. MATERIAL AND METHODS: The present study examined 20 male and female subjects to determine if heat would increase extensibility of the anterior and posterior cruciate ligaments of the knee and reduce the force needed to flex the knee. Cold exposure was examined to see if it would have the opposite effect. There were 4 experiments in the series: The first was a room temperature series; the second was a series where cold was applied with an ice pack for 20 minutes; in the third, hydrocollator heat packs were applied for 20 minutes; and in the fourth, ThermaCare heat wraps were applied for 4 hours on the quadriceps and knee. Tendon extensibility was measured with a KT2000. The force for flexing the knee was measured by passive movement being applied (CPM) to the knee through 30 degrees and the force required to move the leg was measured. RESULTS: The results show that the anterior and posterior cruciate ligament flexibility increased and the force needed to move the knee decreased with heat by about 25% compared to cold application. CONCLUSIONS: Heat is beneficial in increasing muscle and ligament flexibility and may help reduce athletic injuries, but cold treatment may have the opposite effect. PMID- 23933601 TI - Improvement of thiolate/disulfide mediated dye-sensitized solar cells through supramolecular lithium cation assembling of crown ether. AB - A supramolecular lithium cation assemblies of crown ether, [Li 12-crown-4](+), has been used to replace conventional tetraalkylammonium counterion in thiolate/disulfide (ET(-)/BET) mediated dye-sensitized solar cells (DSCs), which exhibit high stability and efficiency of 6.61% under 100 mW.cm(-2) simulated sunlight illumination. PMID- 23933602 TI - Bile acids increase levels of microRNAs 221 and 222, leading to degradation of CDX2 during esophageal carcinogenesis. AB - BACKGROUND & AIMS: Bile reflux contributes to development of Barrett's esophagus (BE) and could be involved in its progression to esophageal adenocarcinoma (EAC). We investigated whether bile acids affect levels or functions of microRNAs (MIRs) 221 and 222, which bind to the 3'-UTR of p27Kip1 messenger RNA to inhibit its translation. Reduced p27Kip1 increases degradation of the transcription factor CDX2; levels of CDX2 have been reported to decrease during progression of BE to EAC. METHODS: We used quantitative reverse transcriptase polymerase chain reaction to compare levels of MIRs 221 and 222 and immunohistochemistry to compare levels of p27Kip1 and CDX2 proteins in areas of BE and EAC from each of 11 patients. We examined the effects of bile acid exposure on levels of MIRs 221 and 222 and CDX2 in EAC cells. We investigated the effects of inhibitors of MIRs 221 and 222 on growth of human EAC xenograft tumors in NOD/SCID/IL-2Rgamma(null) mice. RESULTS: Levels of MIRs 221 and 222 increased and levels of p27Kip1 and CDX2 decreased in areas of EAC vs BE. Levels of MIRs 221 and 222 increased, along with activity of nuclear bile acid receptor/farnesoid X receptor (FXR), when cultured cells were exposed to bile acids. Incubation of cells with bile acids increased degradation of CDX2; this process was reduced when cells were also incubated with proteasome inhibitors. Overexpression of MIRs 221 and 222 reduced levels of p27Kip1 and CDX2, and knockdown of these MIRs increased levels of these proteins in cultured cells. Inhibitors of MIRs 221 and 222 increased levels of p27Kip1 and CDX2 in EAC cells and reduced growth of xenograft tumors in NOD/SCID/IL-2Rgamma(null) mice. CONCLUSIONS: We observed increased levels of MIRs 221 and 222 in human EAC tissues, compared with areas of BE from the same patient. We found that exposure of esophageal cells to bile acids activates FXR and increases levels of MIRs 221 and 222, reducing levels of p27Kip1 and promoting degradation of CDX2 by the proteasome. Our work opened the perspective of therapeutically targeting this pathway either via FXR antagonists or inhibitors of MIRs as a treatment option for BE and EAC. PMID- 23933604 TI - Electronic and molecular behaviors of a novel ionic paramagnetic ruthenium(III) complex. AB - The geometric structures, electronic and molecular properties of the novel ionic paramagnetic ruthenium(III) complex-bis[1-butyl-2-(diphenylphosphanyl)-3 methylimidazolium]tetrachloridoruthenium(III) hexafluorophosphate, which was synthesized experimentally very recently, are investigated by means of first principles calculations. The molecular structures consistent with the experiment were obtained by optimized calculations. The detailed analysis of the chemical bonding in the ruthenium(III) complex indicates that the interactions of Ru-Cl and Ru-P are dominated by an ionic interaction, while the P-C bonding is of mainly covalent interaction. Our results also show that the ruthenium(III) complex is of magnetic character with a magnetic moment of 1 MUb contributed by the central metal atom-Ru. In addition, identifying the orbital compositions in the frontier electronic structures, we proposed that the high catalytic performance of the Ruthenium(III) complex mainly arises from the strong interaction of the frontier orbitals between the reactants and the catalyst. These findings can contribute to a comprehensive understanding about such types of transition metal complexes and shed insight into the synthesis and application of catalyst precursors for the transfer hydrogenation of ketones. PMID- 23933603 TI - MUC15 inhibits dimerization of EGFR and PI3K-AKT signaling and is associated with aggressive hepatocellular carcinomas in patients. AB - BACKGROUND & AIMS: Aberrant expression of MUC15 correlates with development of colorectal adenocarcinoma, and MUC15 has been reported to prevent trophoblast invasion of human placenta. However, little is known about the role of MUC15 in pathogenesis of hepatocellular carcinoma (HCC). METHODS: We analyzed HCC samples and matched nontumor liver tissues (controls) collected from 313 patients who underwent hepatectomy in Shanghai, China, from January 2006 through September 2009. Levels of messenger RNAs and proteins were determined by immunohistochemical, quantitative reverse transcription polymerase chain reaction, and immunoblot analyses. Statistical analyses were used to associate levels of MUC15 with tumor features and patient outcomes. RESULTS: Levels of MUC15 messenger RNA and protein were reduced in a greater percentage of HCC samples than control tissues. Tumors with reduced levels of MUC15 were more likely to have aggressive characteristics (eg, high levels of alpha-fetoprotein, vascular invasion, lack of encapsulation, and poor differentiation) than those with low levels. Patients whose tumors had reduced levels of MUC15 had shorter overall survival times (24 months vs 46 months for patients with tumors with high levels of MUC15) and time to disease recurrence. Stable expression of MUC15 in HCC cell lines (SMMC-7721 and HCC-LM3) reduced their proliferation and invasive features in vitro, and ability to form metastatic tumors in mice. MUC15 reduced transcription of the matrix metalloproteinases 2 and 7 increased expression of tissue inhibitor of metalloproteinase-2, which required phosphoinositide 3-kinase v-akt murine thymoma viral oncogene homolog signaling. Physical interaction between MUC15 and epidermal growth factor receptor led to its relocation and degradation within early endosomes and was required for inactivation of phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling. CONCLUSIONS: Reduced levels of MUC15 in HCCs are associated with shorter survival times of patients and reduced time to disease recurrence. Expression of MUC15 in HCC cells reduces their aggressive behavior in vitro and in mice by inducing dimerization of epidermal growth factor receptor and decreasing phosphoinositide 3-kinase signaling via v-akt murine thymoma viral oncogene homolog. PMID- 23933605 TI - An improved method for quantification of Vibrio vulnificus in oysters. AB - Chromogenic agar was compared with the FDA recommended cellobiose-colistin agar for assessment of Vibrio vulnificus in oysters. A two-step culture confirmation method was also evaluated. The inclusion of CA gave a 33% increase in the detection rate and the two-step culture confirmation eliminated 62.5% of false positives. PMID- 23933606 TI - [New methods for the ambulatory evaluation of female infertility]. AB - Incidence of infertility increased in the past years and it affects 15% of couples. Female and male factors are responsible in 40% and 40% of the cases, respectively, while factors present in both females and males can be found in 20% of cases. Female factors can be further divided into organic and functional ones. Function of the female organs can be evaluated in an outpatient setting by well developed laboratory techniques but evaluation of the uterine cavity and inspection of the tubal patency have been traditionally carried out in one-day surgery. However, the latter can be performed under ambulatory setting with the use of office hysteroscopy, so that the use of operating theatre and staff costs can be saved. Using selective pertubation for the evaluation of tubal patency via office hysteroscopy can reduce cost further. The new methods in infertility workup which can be performed in ambulatory setting have several advantages for the patients. PMID- 23933607 TI - [Intraoperative, postoperative and long-term oncosurgical safety of therapeutic mammaplasty]. AB - INTRODUCTION: (Pre)malignant lesion in the breast requiring mastectomy conventionally may be treated with breast conservation by using oncoplastic breast surgical techniques, which is called therapeutic mammaplasty. However, no reliable data has been published so far as regards the oncological safety of this method. AIM: The aim of the authors was to analyse the oncological safety of therapeutic mammaplasty in a series of patients. METHOD: 99 patients were treated with therapeutic mammaplasty and data were collected in a breast surgical database prospectively. Results were analysed with respect to intraoperative, postoperative and long-term oncological safety. RESULTS: Incomplete resection rate was 14.1%, which correlated with tumour size (p = 0.023), and multifocality (p = 0.012). Time between surgery (therapeutic mammaplasty) and chemotherapy was similar to time between conventional breast surgeries (wide excision, mastectomy, mastectomy with immediate reconstruction) and chemotherapy (mean 29-31 days; p<0.05). Overall recurrence rate was 6.1%, locoregional recurrence rate was 2% during 27 month (1-88) mean follow-up. CONCLUSIONS: Since literature data are based on relatively short follow-up and low patient number, it is highly important that all data on therapeutic mammaplasty is collected in a prospectively maintained breast surgical database in order to determine true recurrence after long-follow-up. PMID- 23933608 TI - [Short and long term prognosis of patients with myocardial infarction. Hungarian Myocardial Infarction Registry]. AB - INTRODUCTION: Mortality data of patients with acute myocardial infarction are incomplete in Hungary. AIM: The aim of the authors was to analyse the data of 8582 myocardial infarction patients (4981 with ST-elevation myocardial infarction) registered in the Hungarian Myocardial Infarction Register in order to define the hospital, 30-day, and 1-year mortality. To evaluate the prehospital mortality of myocardial infarction, all myocardial infarction and sudden death were registered in five districts of Budapest. METHOD: Multivariate logistic regression was performed to define risk factors of mortality and the model were assessed using c statistics. RESULTS: The hospital, 30-day and 1-year mortality of patients with ST elevation myocardial infarction were 3.7%, 9.5% and 16.5%, respectively. In patients without ST elevation myocardial infarction these figures were 4%, 9.8% and 21.7%, respectively. The 1-year mortality of patients without ST elevation was higher than those of with ST elevation and the difference was statistically significant. Age, Killip class, diabetes mellitus, history of stroke and myocardial infarction were independent predictors of death. Coronary intervention improved the prognosis of patients with myocardial infarction significantly. CONCLUSIONS: The rate of pre-hospital mortality was considerably high; 72.5% of 30 day mortality occurred before admission to hospital. PMID- 23933609 TI - [Cesarean delivery on maternal request: survey among obstetricians/gynecologists in south-east Hungary]. AB - INTRODUCTION: increased frequency of maternal request for cesarean delivery may be a contributing factor to the rising cesarean section rate in Hungary, although there is no formal indication that would allow Hungarian obstetricians to perform this procedure legally. Thus, it is difficult to estimate the role of maternal request in the rising cesarean rate. AIM: The aim of the authors was to assess the attitudes of obstetricians toward this procedure. METHOD: In early 2010 anonymous questionnaires were distributed to each of the 137 obstetricians working in the maternity wards of counties Bacs-Kiskun, Bekes and Csongrad, with a response rate of 74.5% (n = 102). RESULTS: More than half of the respondents refused the possibility of a legalized indication for this procedure in Hungary; however, in case it was legalized, 81 (79.4%) obstetricians would feel ready to perform it. CONCLUSIONS: The resistance of more than half of the obstetricians to an explicit indication for the procedure is in conflict with the theoretical willingness of the majority of them to perform it. PMID- 23933611 TI - [Recent investigations on the renoprotective effects of hypotensive agents]. PMID- 23933610 TI - [Hashimoto encephalopathy]. AB - The authors present a case report and review the literature on Hashimoto encephalopathy. The onset of the disease may be marked by focal and then progressively generalized seizures or other neurological symptoms, but a cognitive decline or various psychiatric symptoms may also emerge. High levels of anti-thyroid peroxidase antibodies and/or anti-thyroglobulin antibodies are present in the serum. Corticosteroid treatment usually results in an improvement of symptoms. The syndrome is frequently overlooked and, therefore, the authors strongly recommend testing serum thyroid autoantibodies in cases with encephalopathy of unknown origin independently on the presence of thyroid disease in the patient or family history. The importance of long-term immunosuppressive treatment should also be stressed. PMID- 23933613 TI - Identification of the absorbed constituents after oral administration of Yuanhu Zhitong prescription extract and its pharmacokinetic study by rapid resolution liquid chromatography/quadrupole time-of-flight. AB - Yuanhu Zhitong prescription (YZP) is well known for its analgesic effect. However, its multiple bioactive components in vivo remain unclear. In this paper, a rapid resolution liquid chromatography/quadrupole time-of-flight (RRLC-ESI Q/TOF) was employed to identify the bioactive components and partial metabolites after oral administration of YZP extracts. Meanwhile, a RRLC-ESI-Q/TOF method was established and validated for the simultaneous quantification of protopine, alpha allocryptopine, tetrahydropalmatine, corydaline, tetrahyberberine and byakangelicin in rat plasma and applied for their pharmacokinetic research. The results showed that twenty-one bioactive components of YZP were absorbed into the blood circulation and seventeen components were detected in cerebrospinal fluid (CSF). Moreover, the kinetic profiles of six analytes were obtained and the results suggested that the six analytes peaked between 3.5 and 5.0h and Cmax ranged from 214.6 to 858.3. The works could provide key information for identification of bioactive constituents and understanding the metabolism as well as pharmacological actions for YZP. PMID- 23933614 TI - Population structure determines functional differences among species and ecosystem processes. AB - Linking the structure of communities to ecosystem functioning has been a perennial challenge in ecology. Studies on ecosystem function are traditionally focused on changes in species composition. However, this species-centric approach neglects the often dramatic changes in the ecology of organisms during their development, thereby limiting our ability to link the structure of populations and communities to the functioning of natural ecosystems. Here we experimentally demonstrate that the impact of organisms on community structure and ecosystem processes often differ more among developmental stages within a species than between species, contrary to current assumptions. Importantly, we show that functional differences between species vary depending on the specific demographic structure of predators. One important implication is that changes in the demography of populations can strongly alter the functional composition of communities and change ecosystem processes long before any species are extirpated from communities. PMID- 23933615 TI - The protective effect of albumin on bevacizumab activity and stability in PLGA nanoparticles intended for retinal and choroidal neovascularization treatments. AB - The rapidly growing applications of antibody-based therapeutics requires novel approaches to develop efficient drug delivery systems in which biodegradable polymeric nanoparticles are amongst the best candidates. In the present study bevacizumab loaded PLGA nanoparticles were formulated by water-in-oil-in-water emulsion method. Protein inactivation and aggregation are the major drawbacks of this technique. Therefore protective ability of various stabilizers was studied during entrapment process. Probable changes in VEGF165 binding capability of bevacizumab was assayed by ELISA which portrays the antibody's bio-efficiency. Probable breakage of bevacizumab and its secondary and tertiary structural integrity upon entrapment were analyzed by SDS-PAGE and circular dichroism spectroscopy, respectively. In vitro and ex vivo released bevacizumab from the prepared nanoparticles was also investigated. Results revealed that the protein interfacial adsorption is the foremost destabilizing factor in the double emulsion method and incorporation of appropriate concentrations of albumin could protect bevacizumab against entrapment stress. Ex vivo release results, in rabbit vitreous, indicated the ability of prepared nanoparticles in prolonged release of the active antibody. Consequently this approach was an attempt to achieve sustained release PLGA nanoparticle formulation with the aim of protecting integrity and performance of entrapped bevacizumab. PMID- 23933616 TI - Microfluidic and lab-on-a-chip preparation routes for organic nanoparticles and vesicular systems for nanomedicine applications. AB - In recent years, advancements in the fields of microfluidic and lab-on-a-chip technologies have provided unique opportunities for the implementation of nanomaterial production processes owing to the miniaturisation of the fluidic environment. It has been demonstrated that microfluidic reactors offer a range of advantages compared to conventional batch reactors, including improved controllability and uniformity of nanomaterial characteristics. In addition, the fast mixing achieved within microchannels, and the predictability of the laminar flow conditions, can be leveraged to investigate the nanomaterial formation dynamics. In this article recent developments in the field of microfluidic production of nanomaterials for drug delivery applications are reviewed. The features that make microfluidic reactors a suitable technological platform are discussed in terms of controllability of nanomaterials production. An overview of the various strategies developed for the production of organic nanoparticles and colloidal assemblies is presented, focusing on those nanomaterials that could have an impact on nanomedicine field such as drug nanoparticles, polymeric micelles, liposomes, polymersomes, polyplexes and hybrid nanoparticles. The effect of microfluidic environment on nanomaterials formation dynamics, as well as the use of microdevices as tools for nanomaterial investigation is also discussed. PMID- 23933618 TI - Preparation of cell-encapsulation devices in confined microenvironment. AB - The entrapment of cells into hydrogel microdevice in form of microparticles or microfibers is one of the most appealing and useful tools for cell-based therapy and tissue engineering. Cell encapsulation procedures allow the immunoisolation of cells from the surrounding environment, after their transplantation and the maintenance of the normal cellular physiology. Factors affecting the efficacy of microdevices, which include size, size distribution, morphology, and porosity are all highly dependent on the method of preparation. In this respect, microfluidic based methods offer a promising strategy to fabricate highly uniform and morphologically controlled microdevices with tunable chemical and mechanical properties. In the current review, various cell microencapsulation procedures, based on a microfluidics, are critically analyzed with a special focus on the effect of the procedure on the morphology, viability and functions of the embedded cells. Moreover, a brief introduction about the optimal characteristics of microdevice intended for cell encapsulation, together with the currently used materials for the production is reported. A further challenging application of microfluidics for the development of "living microchip" is also presented. Finally, the limitations, challenging and future work on the microfluidic approach are also discussed. PMID- 23933619 TI - Association of television viewing time with overweight/obesity independent of meeting physical activity guidelines: do joint exposures yield independence? PMID- 23933620 TI - Television viewing time is associated with overweight/obesity among older adults, independent of meeting physical activity and health guidelines: reply to Stabler and colleagues. PMID- 23933617 TI - Carbon nanotubes in hyperthermia therapy. AB - Thermal tumor ablation therapies are being developed with a variety of nanomaterials, including single- and multiwalled carbon nanotubes. Carbon nanotubes (CNTs) have attracted interest due to their potential for simultaneous imaging and therapy. In this review, we highlight in vivo applications of carbon nanotube-mediated thermal therapy (CNMTT) and examine the rationale for use of this treatment in recurrent tumors or those resistant to conventional cancer therapies. Additionally, we discuss strategies to localize and enhance the cancer selectivity of this treatment and briefly examine issues relating the toxicity and long term fate of CNTs. PMID- 23933621 TI - Associations of prenatal mercury exposure from maternal fish consumption and polyunsaturated fatty acids with child neurodevelopment: a prospective cohort study in Italy. AB - BACKGROUND: Mercury is a neurotoxin, and limited prenatal exposure to it can affect long-term child neurodevelopment. However, results of epidemiologic studies of such exposure have been inconsistent. We examined the association of prenatal mercury exposure from maternal fish consumption with child neurodevelopment in northern Italy. METHODS: A population-based cohort of 606 children and their mothers was studied from pregnancy to age 18 months. Mercury levels were measured in maternal hair and blood during pregnancy and in umbilical cord blood and breast milk. Levels of polyunsaturated fatty acids (PUFAs) were measured in maternal serum. Maternal and child intakes of fish were assessed by using a food frequency questionnaire. The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) was used to evaluate child neurodevelopment. Multivariate linear regression was used to examine the association of mercury exposure with BSID-III scores, after controlling for maternal fish intake, PUFAs during pregnancy, and several other confounders. RESULTS: Mean weekly fish intake during pregnancy was less than 2 servings. Mercury concentrations in biological samples were low (mean, 1061 ng/g in hair) and moderately correlated with fish intake, particularly of carnivorous species. Maternal omega-3 PUFA concentrations were poorly correlated with fish intake. Maternal intelligence quotient (IQ) and child intake of fish were significantly associated with neurodevelopment scores. In multivariate models, the level of Hg exposure was not associated with neurodevelopmental performance at 18 months. CONCLUSIONS: In this Italian population, neurodevelopment at 18 months was associated with child intake of fresh fish and maternal IQ rather than with mercury exposure. The expected beneficial effect of maternal fish intake (from maternal omega-3 PUFAs) was not found. PMID- 23933622 TI - Relationship of living conditions with dietary patterns among survivors of the great East Japan earthquake. AB - BACKGROUND: During the year after the Great East Japan Earthquake on March 11, 2011, the health conditions and lifestyles of survivors were extensively surveyed. We examined the relationship between living conditions and dietary pattern among survivors. METHODS: A total of 10 466 survivors aged 18 years or older (25% of the population of that age in the area) participated in a survey of Iwate Prefecture. The average frequency of daily consumption of 8 food groups was determined by questionnaire. After excluding staple foods, which were consumed 3 times a day by 85% of participants, factor analysis was performed on 7 food groups among 9789 people (3795 men, 5994 women). RESULTS: Factor analysis identified 2 dietary patterns-prudent and meat. The prudent dietary pattern is characterized by high intakes of fish and shellfish, soybean products, vegetables, fruit, and dairy products and was more evident among older participants and women. The meat dietary pattern is characterized by high intakes of meat and eggs and was more evident among younger participants and men. Age adjusted multiple logistic regression analyses showed that male and female current smokers and men and women living in difficult conditions were likely to have a lower prudent dietary pattern score; male current smokers and male daily alcohol drinkers were likely to have a higher meat dietary pattern score. CONCLUSIONS: During the year after the earthquake, the prudent dietary pattern was associated with better living conditions among survivors, whereas the meat dietary pattern was not. PMID- 23933623 TI - Underlying cause and place of death among patients with amyotrophic lateral sclerosis in Taiwan: a population-based study, 2003-2008. AB - BACKGROUND: Few studies have assessed cause of death among patients with amyotrophic lateral sclerosis (ALS). We investigated underlying cause and place of death among patients with ALS in Taiwan during 2003-2008. METHODS: The data source was the Taiwan National Health Insurance database for the period 2003 2008. In total, 751 patients older than 15 years with a primary diagnosis of ALS were included and followed until 2008 in the national mortality database. Crude mortality rates (per 100 person-years) and standardized mortality ratios (SMRs) were calculated in relation to cause of death, sex, and age group (15-44, 45-64, 65+ years). RESULTS: In total, 297 (39.6%) patients died during the follow-up period, an age- and sex-standardized mortality rate 13 times (95% CI, 10.6-15.6) that of the Taiwanese general population. The leading cause of death among the patients was respiratory diseases, and the second most frequent cause was cardiovascular diseases. During the first year after an ALS diagnosis, suicide was much more frequent (SMR, 6.9; 95% CI, 1.9-17.6) than among the general population. CONCLUSIONS: During 2003-2008, respiratory diseases and cardiovascular diseases were the most frequent causes of death among Taiwanese patients with ALS. In addition, our findings indicate that suicide prevention is an urgent priority during the period soon after an ALS diagnosis. PMID- 23933624 TI - Amphiphilic oligomer-based micelles as cisplatin nanocarriers for cancer therapy. AB - Polymeric micelles (~10 nm) have been prepared from the amphiphilic oligomer comprising oligomeric polystyrene as the hydrophobic inner core and half of EDTA (-N(CH2COOH)2) as the hydrophilic outermost shell. After chelating cisplatin with -N(CH2COOH)2 in water, polymeric micelles containing Pt on the spherical surface have been easily obtained. Since the chelate group is introduced into the amphiphilic oligomer as the terminal group by a RAFT agent, the chelation of cisplatin with PS(COOH)2 is almost stoichiometric. The drug carrier based on PS(COOH)2 showed a high loading efficiency (>70%) towards cisplatin. The release of the therapeutic Pt from the cisplatin-loaded composites (PS(COOH)2-Pt) triggered under weak acidic conditions resulted in good Pt-release and accumulation in tumor cells. Both in vitro and in vivo, the chelated cisplatin inhibited Sk-Br3 cancer more effectively than the intact cisplatin does. Furthermore, neither PS(COOH)2 nor PS(COOH)2-Pt showed obvious systematic toxicity. PMID- 23933626 TI - Could cardiovascular disease risk stratification and management in rheumatoid arthritis be enhanced? PMID- 23933625 TI - A prospective open-label pilot study of fluvastatin on proinflammatory and prothrombotic biomarkers in antiphospholipid antibody positive patients. AB - OBJECTIVE: To determine if proinflammatory and prothrombotic biomarkers are differentially upregulated in persistently antiphospholipid antibody (aPL) positive patients, and to examine the effects of fluvastatin on these biomarkers. METHODS: Four groups of patients (age 18-65) were recruited: (a) primary antiphospholipid syndrome; (b) systemic lupus erythematosus (SLE) with antiphospholipid syndrome (APS) (SLE/APS); (c) persistent aPL positivity without SLE or APS (Primary aPL); and (d) persistent aPL positivity with SLE but no APS (SLE/aPL). The frequency-matched control group, used for baseline data comparison, was identified from a databank of healthy persons. Patients received fluvastatin 40 mg daily for 3 months. At 3 months, patients stopped the study medication and they were followed for another 3 months. Blood samples for 12 proinflammatory and prothrombotic biomarkers were collected monthly for 6 months. RESULTS: Based on the comparison of the baseline samples of 41 aPL-positive patients with 30 healthy controls, 9/12 (75%) biomarkers (interleukin (IL)-6, IL1beta, vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF) alpha, interferon (IFN)-alpha, inducible protein-10 (IP10), soluble CD40 ligand (sCD40L), soluble tissue factor (sTF) and intracellular cellular adhesion molecule (ICAM)-1) were significantly elevated. Twenty-four patients completed the study; fluvastatin significantly and reversibly reduced the levels of 6/12 (50%) biomarkers (IL1beta, VEGF, TNFalpha, IP10, sCD40L and sTF). CONCLUSIONS: Our prospective mechanistic study demonstrates that proinflammatory and prothrombotic biomarkers, which are differentially upregulated in persistently aPL-positive patients, can be reversibly reduced by fluvastatin. Thus, statin induced modulation of the aPL effects on target cells can be a valuable future approach in the management of aPL-positive patients. PMID- 23933627 TI - Long-term developmental outcome after early hemispherotomy for hemimegalencephaly in infants with epileptic encephalopathy. AB - This study aimed to identify the effect of early hemispherotomy on development in a consecutive series of 12 infants with hemimegalencephaly (HME) demonstrating epileptic encephalopathy. Mean age at onset was 20.4 days (range, 1-140), mean age at surgery was 4.3 months (range, 2-9), and mean follow-up time was 78.8 months (range, 36-121). Eleven patients had a history of early infantile epileptic encephalopathy. Vertical parasagittal hemispherotomy was performed without mortality or severe morbidities. At follow-up, seizure freedom was obtained in 8 patients (66.7%), who showed significantly higher postoperative developmental quotient (DQ) (mean, 31.3; range, 7-61) than those with seizures (mean, 5.5; range, 3-8) (p=0.02). Within the seizure-free group, postoperative DQ correlated with preoperative seizure duration (r=-0.811, p=0.01). Our results showed that shorter seizure duration during early infancy could provide better postoperative DQ in infants with HME and epileptic encephalopathy. PMID- 23933628 TI - New antiepileptic drug safety information is not transmitted systematically and accepted by U.S. neurologists. AB - We surveyed U.S. neurologists in order to evaluate their knowledge of, and sources for, recent FDA safety warnings regarding antiepileptic drugs (AEDs) and whether they incorporate this information into their practices. Survey respondents (N=505) were predominantly board-certified American Academy of Neurology members. Approximately 20% of respondent neurologists were not aware of warnings about four drug safety risks: suicidality with newer AEDs, increased birth defect risks from in utero divalproex exposure, impaired cognitive development from in utero divalproex exposure, and the requirement of haplotype screening in patients of Asian descent starting carbamazepine. Most respondents were aware of a recommendation for haplotype screening, yet did not routinely perform the safety screening, and 18 reported patients that had hypersensitivity reactions to carbamazepine. Respondents learned about drug safety risks from varied sources; only notifications from specialty organizations were associated with accurate knowledge of drug safety warnings. Most surveyed neurologists would prefer implementing "a formal warning process via specialty organizations" with e mails of updated product insert warnings. PMID- 23933629 TI - Pattern and predictors of complementary and alternative medicine (CAM) use among pediatric patients with epilepsy. AB - Parents of pediatric patients with chronic conditions such as epilepsy increasingly opt for complementary and alternative medicine (CAM). However, data on the pattern and reasons of CAM use in childhood epilepsy are scarce. The objectives of this study were as follows: first, to characterize CAM use among pediatric patients with epilepsy by assessing its spectrum, prevalence, costs, and frequency of use; second, to evaluate the influence of CAM use on compliance and satisfaction with conventional care as well as to explore parent-child neurologist communication concerning CAM; and third, to investigate predictors of CAM use. A postal survey was administered to all parents of pediatric outpatients with epilepsy aged 6 to 12, who have received treatment at the neuropediatric outpatient clinic of the University Children's Hospital Heidelberg between 2007 and 2009. One hundred thirty-two of the 297 distributed questionnaires were suitable for inclusion in statistical analysis (44.7%). Forty-nine participants indicated that their children used CAM during the previous year (37.1%). Thirty different types of CAM were used, with homeopathy (55.1%), osteopathy (24.5%), and kinesiology (16.3%) being the most commonly named. A mean of 86? (0?-500?) and 3h (1 h-30 h) per month was committed to CAM treatment. Only 53% of the users informed their child neurologist of the additional CAM treatment, while 85.6% of all parents wished to discuss CAM options with their child neurologist. Seventy five percent of users considered the CAM treatment effective. Among the participants most likely to seek CAM treatment are parents whose children show a long duration of epileptic symptoms, parents who make use of CAM treatment themselves, and parents who value a holistic and natural treatment approach. A substantial portion of pediatric patients with epilepsy receive CAM treatment. The high prevalence of use and significant level of financial and time resources spent on CAM indicate the high importance of these treatment options for parents. On the other hand, communication concerning CAM with the child neurologist is largely insufficient despite the wish to speak about CAM. Complementary and alternative medicine users' high compliance with conventional treatment and high perceived effectiveness of CAM support an integrative approach to CAM for pediatric patients with epilepsy. Our study implies that in addition to open parent-child neurologist communication, active inquiry on CAM treatments is necessary to enable informed decision making by parents and to establish the suitability of CAM treatment for the patient. Reliable predictors for CAM use, which allow for improved identification of patients with a high likelihood to receive CAM treatment, are the duration of the illness, use of CAM by the parents themselves, and the desire of the parents to receive a holistic and natural treatment for their child. PMID- 23933630 TI - Evaluation of anti-Listeria meat borne Lactobacillus for biofilm formation on selected abiotic surfaces. AB - The ability of meat borne anti-Listeria Lactobacillus to form biofilms under different in vitro conditions and on abiotic surfaces was investigated. Biofilm formation by the adhesion to polystyrene microtiter plates was determined, this being higher for Lactobacillus curvatus CRL1532 and CRL705 and Lactobacillus sakei CRL1862. The physicochemical properties of the cell surface were relatively hydrophilic and acidic in character; L. sakei CRL1862 exhibiting the strongest autoaggregation. The adhesion of lactobacilli to stainless steel (SS) and polytetrafluoroethylene (PTFE) supports at 10 degrees C was found to be maximal for L. sakei CRL1862 on SS after 6 days. When biofilm architecture was characterized by epifluorescence and SEM, L. sakei CRL1862 homogeneously covered the SS surface while cell clusters were observed on PTFE; the extracellular polymeric substance matrix adapted to the topography and hydrophilic/hydrophobic characteristics of each material. The feasibility of L. sakei CRL1862 to form biofilm on materials used in meat processing highlights its potential as a control strategy for Listeria monocytogenes biofilms. PMID- 23933631 TI - Effect of muscle and intensity of finishing diet on meat quality of foals slaughtered at 15 months. AB - The effect of muscle and intensity of finishing diet on meat quality of foals slaughtered at 15 months was study. For this work, a total of twenty one foals and six muscles: longissimus dorsi (LD), semimembranosus (SM), semitendinosus (ST), biceps femoris (BF), triceps brachii (TB) and Psoas major & minor (PM) from two different intensities of finishing diet (1.5 vs. 3 kg/day) were analysed. Meat quality (chemical composition, colour characteristics, and textural traits), fatty and amino acid profile and mineral composition were studied. In general the factor muscle had more effect on all traits measured in this study than finishing effect, especially in the fatty acids and mineral composition. SM muscle showed the highest percentage of protein in both finishing groups (22.34 and 21.74% for 3 and 1.5 kg of commercial feeding, respectively). The intramuscular fat content in the analysed muscles ranged between 0.15% (LD in 1.5 group) and 1.83% (PM in 3.0 group). The highest values of iron heme that were obtained in TB muscle (2.46 mg/100 g meat) are a considerable source of bioavailable iron content. The three most abundant fatty acids in both groups and for all muscles studied were oleic acid, palmitoleic acid and linoleic acid. From a healthy point of view, muscles from foals finishing with a minor amount of commercial fodder were the best. The best nutritional value was reached for PM and ST with 14.73% of total omega 3 and the highest polyunsaturated/saturated ratio (1.10), respectively. Concerning amino acid profile, values of essential/non-essential ratio were significantly higher (P<0.001) in muscles of 1.5 diet group foals (0.856) than the other group (0.833). Finally, potassium (243 mg/100 g) and phosphorous (202 mg/100 g) were the two main minerals, followed by sodium (54 mg/100 g) and magnesium (26 mg/100 g). PMID- 23933632 TI - Review: Automation and meat quality-global challenges. AB - The global meat industry has seen significant changes in the methods used to harvest and process fresh meat over the past century. Increased use of automation has led to significant increases in line speed for beef, pork, sheep, poultry and fish operations. For example, currently the fastest line observed has been broilers at 13,500/h. Such developments have required in-depth understanding of the pre and post rigor processes to prevent defects. Procedures such as maturation chilling and electrical stimulation are now common in red meat and poultry processing; allowing shorter time to deboning, while harvesting high quality meat. Robots designed to cut meat are also appearing on the market, and replacing traditional manual operations. This is a challenge, because high speed equipment is not necessarily sensitive to variations in size/quality issues, and requires development of unique sensors and control systems. Also, progress in breeding and genetics is contributing to greater product uniformity and quality; helping in operating automated equipment. PMID- 23933633 TI - Association of forkhead box J3 (FOXJ3) polymorphisms with rheumatoid arthritis. AB - The aim of this study was to investigate the correlation between single nucleotide polymorphisms (SNPs) of the forkhead box J3 (FOXJ3) gene and rheumatoid arthritis (RA). For the association studies, 307 patients with RA and 476 control patients without RA were recruited. Eleven SNPs (rs2282404, rs2455084, rs1393009, rs7539485, rs4660616, rs510157, rs343386, rs12732892, rs343389, rs343376 and rs585320) were genotyped using direct sequencing and the resulting data were analyzed using the SNPStats, Haploview and Helixtree programs. Seven SNPs (rs2455084, rs1393009, rs7539485, rs4660616, rs510157, rs343386 and rs343389) were associated with RA in three alternative models (log additive, dominant and recessive models; P<0.05). A strong linkage disequilibrium block, including all 11 SNPs, was constructed using the Gabriel method. Two haplotypes, TCCTTGTCTTT and TCTTCTGTCAC, were significantly associated with RA (P<0.05). In clinical characteristic analysis, the SNP rs585320 was also associated with the anti-cyclic citrullinated peptide. These results suggest that FOXJ3 may be associated with the development of RA. PMID- 23933634 TI - CTCF depletion alters chromatin structure and transcription of myeloid-specific factors. AB - Differentiation is a multistep process tightly regulated and controlled by complex transcription factor networks. Here, we show that the rate of differentiation of common myeloid precursor cells increases after depletion of CTCF, a protein emerging as a potential key factor regulating higher-order chromatin structure. We identified CTCF binding in the vicinity of important transcription factors regulating myeloid differentiation and showed that CTCF depletion impacts on the expression of these genes in concordance with the observed acceleration of the myeloid commitment. Furthermore, we observed a loss of the histone variant H2A.Z within the selected promoter regions and an increase in non-coding RNA transcription upstream of these genes. Both abnormalities suggest a global chromatin structure destabilization and an associated increase of non-productive transcription in response to CTCF depletion but do not drive the CTCF-mediated transcription alterations of the neighbouring genes. Finally, we detected a transient eviction of CTCF at the Egr1 locus in correlation with Egr1 peak of expression in response to lipopolysaccharide (LPS) treatment in macrophages. This eviction is also correlated with the expression of an antisense non-coding RNA transcribing through the CTCF-binding region indicating that non coding RNA transcription could be the cause and the consequence of CTCF eviction. PMID- 23933635 TI - ESCRT components regulate the expression of the ER/Golgi calcium pump gene PMR1 through the Rim101/Nrg1 pathway in budding yeast. AB - The endosomal sorting complex required for transport (ESCRT) complexes function to form multivesicular bodies for sorting of proteins destined for the yeast vacuole or the mammalian lysosome. ESCRT components are well conserved in eukaryotes, and their mutations cause neurodegenerative diseases and other cellular pathologies in humans. PMR1 is the orthologous gene of two human genes for calcium pumps secretory pathway Ca(2+)-ATPase (SPCA1, ATP2C1) and sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA, ATP2A2), which are mutated in Hailey-Hailey and Darier genetic diseases, respectively. Here we show that deletion mutation of ESCRT components Snf7, Snf8, Stp22, Vps20, Vps25, Vps28, or Vps36 activates the calcium/calcineurin signaling in yeast cells, but surprisingly leads to a nearly 50% reduction in expression of the ER/Golgi calcium pump gene PMR1 independent of calcium stress. These ESCRT mutants are known to have a defect in Rim101 activation. Ectopic expression of a constitutively active form of Rim101 or further deletion of NRG1 in these mutants partially suppresses their calcium hypersensitivity. Deletion of NRG1 also completely rescues the expression of PMR1 in these mutants to the level of the wild type. Promoter mutagenesis, gel electrophoretic mobility shift assay, and chromatin immunoprecipitation analysis demonstrate that Nrg1 binds to two motifs in the PMR1 promoter. In addition, expression of PMR1 under the control of its promoters with mutated Nrg1-binding motifs suppresses the calcium hypersensitivity of these ESCRT mutants. Collectively, these data have uncovered a function of ESCRT components in regulating PMR1 expression through the Nrg1/Rim101 pathway. Our findings provide important clues for understanding human diseases related to calcium homeostasis. PMID- 23933636 TI - [Screening for colorectal cancer: even with virtual colography?]. AB - Colorectal cancer (CRC) is responsible for 27,000 deaths and 65,000 new cancers in Germany each year, although this should be unnecessary as CRC is preventable because it is possible to remove the precursors, harmless polyps and adenomas. However, only 2.5 % of people in health insurance make use of screening colonoscopy annually so that it becomes necessary to check out other screening tests. The most commonly used test is the Guaiak-based test for fecal occult blood (gFOBT) which is highly specific but not very sensitive (only approximately 10 %). New immunological stool tests are more sensitive but the specificity is reduced from 90 % to approximately 80 %. Virtual colonoscopy based on computed tomography (CT) or magnetic resonance imaging (MRI) is comparable to endoscopy for diagnostics with overall accuracy rates of approximately 80-90 % for polyps larger than 5 mm but for radiation protection reasons CT is not usable in Germany and MRI is internationally not adequately established by large study trials. For the future there is much hope in molecular blood tests. It is of great importance that every physician is aware of the different tests, their strengths and weaknesses and advises all patients to use the different screening possibilities. PMID- 23933637 TI - [Turnaround time for reporting results of radiological examinations in intensive care unit patients: an internal quality control]. AB - AIMS: The radiological examinations performed in intensive care units (ICUs) were analyzed for the purpose of internal quality control. Data included the type of examination performed, the time of day the examination was performed and the differences in radiologist report turnaround times. MATERIAL AND METHODS: A retrospective analysis of the radiology information system (RIS) database of all radiological examinations performed in the ICU of a large German hospital from 2009 through 2011 was carried out. The search retrieved 75,169 examinations performed in ICU patients which were included in the analysis. The records were analyzed for type of radiological examination performed, i.e. conventional X-ray, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), angiography and nuclear medicine examinations, time of day the examination was performed and the interval between examination and time of reporting and release of the final report. RESULTS: Cross-modality it took on average 52 min until a report was written and approximately 7 h before the final report was released. Turnaround times were shortest for ultrasound, conventional X-ray and CT. Over the 3-year observation period there was an overall tendency toward shorter turnaround times whereby improvement in time until reporting was most marked for conventional X-ray, MRI and ultrasound (reduction of 24, 17, and 15 min, respectively). The time until release of the final report improved most markedly for CT, conventional X-ray and angiography (improvement of approximately 6.67, 5.08 and 0.78 h, respectively). CONCLUSIONS: During the 3-year observation period a reduction in turnaround times for reporting results and release of finalized reports could be observed, despite an increase in the total number of cases. PMID- 23933638 TI - Cardiovascular genomics: implications for acute and critical care nurses. AB - As genomic health care becomes commonplace, nurses will be asked to provide genomic care in all health care settings including acute care and critical care. Three common cardiac conditions are reviewed, Marfan syndrome, bicuspid aortic valve, and hypertrophic cardiomyopathy, to provide acute care and critical care nurses with an overview of these pathologies through the lens of genomics and relevant case studies. This information will help critical care nursing leaders become familiar with genetics related to common cardiac conditions and prepare acute care and critical care nurses for a new phase in patient diagnostics, with greater emphasis on early diagnosis and recognition of conditions before sudden cardiac death. PMID- 23933639 TI - Airway pressure release ventilation: improving oxygenation: indications, rationale, and adverse events associated with airway pressure release ventilation in patients with acute respiratory distress syndrome for advance practice nurses. AB - Airway pressure release ventilation (APRV) is a mode of ventilation that has been around since the 1980s and was originally viewed as a type of continuous positive pressure mode of ventilation. Conceptually, APRV can be thought of as a type of inverse-ratio, pressure-controlled, intermittent mandatory ventilation during which the maintenance of spontaneous breathing and prolonged application of high mean airway pressure contribute to the clinical benefits. The aim of this review article was to familiarize the bedside clinician working in the intensive care unit with the theory and rationale behind this mode of ventilation. The potential advantages and disadvantages of APRV will also be discussed to empower the advance practice clinician and bedside nurse to advocate for their patient diagnosed with the often-high mortality disease of acute respiratory distress syndrome. PMID- 23933641 TI - Inhaled epoprostenol to support the severely hypoxemic patient with acute respiratory distress syndrome. AB - This article presents a case study demonstrating various rescue therapies considered in the care of a patient with severe, refractory hypoxemia secondary to acute respiratory distress syndrome. In particular, inhaled epoprostenol (Flolan) is becoming an increasingly common alternative to nitric oxide in the treatment of severe, refractory hypoxemia. Research comparing the 2 inhaled vasodilators suggests that epoprostenol is equally efficacious, easier to administer, less costly, and has fewer adverse effects. This article, using a case study approach, discusses the practical implications of this emerging therapy. PMID- 23933642 TI - Nursing students identify fears regarding working with diverse critically ill patients: development of guidelines for caring for diverse critically ill older adults. AB - Undergraduate students need to gain more exposure to communicating, assessing, and planning appropriate care and evaluating outcomes of care with diverse critically ill geriatric patients. This project developed teaching strategies that facilitated additional opportunities for gaining these valuable learning experiences for students. Nurse educators can use the Guidelines for Caring for Diverse Critically Ill Older Adults, the case study and simulation examples, and topical outline to assist them in teaching critical care students and nurses about diverse critically ill older adults. PMID- 23933644 TI - Transfer out of intensive care: an evidence-based literature review. AB - Critical care beds are a finite resource. Transfer or discharge of patients from the intensive care unit affects the flow of patients in critical care. Effective whole hospital bed management is key to the successful management of the critical care service. However, admission to the critical care unit alone can be extremely frightening, distressing, and traumatic not only for the patients but their families as well. Although transfer to the medical floors is a positive step toward physical recovery, it can be equally traumatic, and many patients and their families exhibit stress, fear, and anxiety. The purpose of this article was to systematically review the effects of intensive care unit transfer or discharge to medical-surgical floors on adult critically ill patients, their family members and nurses. PMID- 23933646 TI - Differences in manual and automatic blood pressures in telemetry patients with atrial fibrillation. AB - The purpose of this study was to evaluate the differences between automated and manual blood pressure results in patients with atrial fibrillation. Data collection took place on 3 telemetry units at a 519-bed community hospital. Findings indicate that there are statistically significant differences between automated and manual blood pressures in this patient population; however, the results are not clinically significant. PMID- 23933647 TI - A pilot study on delirium in the intensive care unit: a creative inquiry project with undergraduate nursing students. AB - INTRODUCTION: Delirium continues to be a major issue in intensive care units (ICUs). Sedation and lack of rapid eye movement (REM) sleep could be important factors in the development of delirium. Improper sedation may interfere with a patient's sleep pattern, specifically time spent in REM sleep, and could be a contributor to the development of delirium. The research team has discovered through this pilot study that there is a possible correlation between sedation, disruptions, and sleep. The goal of our research was to determine the relationship between these variables using a sleep monitor to capture actual sleep activity compared with patient characteristics and real-time activity in the ICU environment. MATERIALS AND METHODS: This was a pilot study of 7 new patients, aged 65 years or older, who were intubated and sedated. Data on patient sleep cycles were collected using a wireless sleep monitor. A time sheet was placed outside each room to record time and type of interruption during nighttime hours (9 PM-6 AM). The patients were observed for 1 to 7 nights dependent on their length of stay in the ICU. RESULTS: Preliminary results demonstrated that, on average, between 9 PM and 6 AM, 48% remained awake (range, 8%-88%), 30% were in light sleep (range, 2%-50%), 18.5% were in REM (range, 2%-60%), and 3.4% were in a deep sleep (range, 0%-9%). Subject 1 remained awake 52% to 88% of the time during the entire admission of 7 days, had an Intensive Care Delirium Screening Checklist score of 5, and had a self-extubation; sedation ordered was Versed as needed. Subject 5 had no interventions done between 12 midnight and 4:50 AM, with the exception of turning once, and had an REM recorded of 60% on 1 night, which equals to 4 hours 49 minutes of rest. All patients with the exception of 1 were on fentanyl and Versed drips with varying dose adjustments throughout their admission. IMPLICATIONS: Preliminary results show that there is a relationship between lack of REM sleep and delirium. The pilot study was a useful model to demonstrate the need for further investigation in a larger population. PMID- 23933649 TI - Submitting a manuscript to DCCN. PMID- 23933650 TI - Determinants of participation in a web-based health risk assessment and consequences for health promotion programs. AB - BACKGROUND: The health risk assessment (HRA) is a type of health promotion program frequently offered at the workplace. Insight into the underlying determinants of participation is needed to evaluate and implement these interventions. OBJECTIVE: To analyze whether individual characteristics including demographics, health behavior, self-rated health, and work-related factors are associated with participation and nonparticipation in a Web-based HRA. METHODS: Determinants of participation and nonparticipation were investigated in a cross sectional study among individuals employed at five Dutch organizations. Multivariate logistic regression was performed to identify determinants of participation and nonparticipation in the HRA after controlling for organization and all other variables. RESULTS: Of the 8431 employees who were invited, 31.9% (2686/8431) enrolled in the HRA. The online questionnaire was completed by 27.2% (1564/5745) of the nonparticipants. Determinants of participation were some periods of stress at home or work in the preceding year (OR 1.62, 95% CI 1.08 2.42), a decreasing number of weekdays on which at least 30 minutes were spent on moderate to vigorous physical activity (OR(dayPA)0.84, 95% CI 0.79-0.90), and increasing alcohol consumption. Determinants of nonparticipation were less-than positive self-rated health (poor/very poor vs very good, OR 0.25, 95% CI 0.08 0.81) and tobacco use (at least weekly vs none, OR 0.65, 95% CI 0.46-0.90). CONCLUSIONS: This study showed that with regard to isolated health behaviors (insufficient physical activity, excess alcohol consumption, and stress), those who could benefit most from the HRA were more likely to participate. However, tobacco users and those who rated their overall health as less than positive were less likely to participate. A strong communication strategy, with recruitment messages that take reasons for nonparticipation into account, could prove to be an essential tool for organizations trying to reach employees who are less likely to participate. PMID- 23933651 TI - Modulation of A2a receptor antagonist on D2 receptor internalization and ERK phosphorylation. AB - AIM: To explore the effects of heterodimerization of D2 receptor/A2a receptor (D2R/A2aR) on D2R internalization and D2R downstream signaling in primary cultured striatal neurons and HEK293 cells co-expressing A2aR and D2R in vitro. METHODS: Primary cultured rat striatal neurons and HEK293 cells co-expressing A2aR and D2R were treated with A2aR- or D2R-specific agonists. D2R internalization was detected using a biotinylation assay and confocal microscopy. ERK, Src kinase and beta-arrestin were measured using Western blotting. The interaction between A2aR and D2R was detected using bioluminescence resonance energy transfer (BRET) and immunoprecipitation. RESULTS: D2R and A2aR were co localized and formed complexes in striatal neurons, while both the receptors formed heterodimers in the HEK293 cells. In striatal neurons and the HEK293 cells, the D2R agonist quinpirole (1 MUmol/L) marked increased Src phosphorylation and beta-arrestin recruitment, thereby D2R internalization. Co treatment with the A2aR antagonist ZM241385 (100 nmol/L) significantly attenuated these D2R-mediated changes. Furthermore, both ZM241385 (100 nmol/L) and the specific Src kinase inhibitor PP2 (5 MUmol/L) blocked D2R-mediated ERK phosphorylation. Moreover, expression of the mutant beta-arrestin (319-418) significantly attenuated D2R-mediated ERK phosphorylation in HEK293 cells expressing both D2R and A2aR, but not in those expressing D2R alone. CONCLUSION: A2aR antagonist ZM241385 significantly attenuates D2R internalization and D2R mediated ERK phosphorylation in striatal neurons, involving Src kinase and beta arrestin. Thus, A2aR/D2R heterodimerization plays important roles in D2R downstream signaling. PMID- 23933652 TI - Inhibitory effects of rosiglitazone on paraquat-induced acute lung injury in rats. AB - AIM: To investigate the effects of the PPAR-gamma agonist rosiglitazone on acute lung injury induced by the herbicide paraquat (PQ) and the underlying mechanisms of action. METHODS: Male Sprague-Dawley rats were injected with PQ (20 mg/kg, ip). Rosiglitazone (3 or 10 mg/kg, ip) was administered 1 h before PQ exposure. Peripheral blood was collected at 4, 8, 24 and 72 h after PQ exposure for measuring the levels of MDA, TNF-alpha and IL-1beta, and the SOD activity. Lung tissues were collected at 72 h after PQ exposure to determine the wet-to-dry (W/D) ratios and lung injury scores, as well as the protein levels of NF kappaBp65, PPAR-gamma, Nrf2, IkappaBalpha and pIkappaBalpha. RESULTS: At 72 h after PQ exposure, the untreated rats showed a 100% cumulative mortality, whereas no death was observed in rosiglitazone-pretreated rats. Moreover, rosiglitazone pretreatment dose-dependently attenuated PQ-induced lung edema and lung histopathological changes. The pretreatment significantly reduced the levels of TNF-alpha, IL-1beta and MDA, increased SOD activity in the peripheral blood of PQ treated rats. The pretreatment also efficiently activated PPAR-gamma, induced Nrf2 expression and inhibited NF-kappaB activation in the lung tissues of PQ treated rats. Furthermore, the pretreatment dose-dependently inhibited IkappaB alpha degradation and phosphorylation, thus inhibiting NF-kappaB activation. CONCLUSION: Pretreatment with rosiglitazone protects rats against PQ-induced acute lung injury by activating PPAR-gamma, inducing Nrf2 expression and inhibiting NF-kappaB activation. PMID- 23933653 TI - Discovery of a retigabine derivative that inhibits KCNQ2 potassium channels. AB - AIM: Retigabine, an activator of KCNQ2-5 channels, is currently used to treat partial-onset seizures. The aim of this study was to explore the possibility that structure modification of retigabine could lead to novel inhibitors of KCNQ2 channels, which were valuable tools for KCNQ channel studies. METHODS: A series of retigabine derivatives was designed and synthesized. KCNQ2 channels were expressed in CHO cells. KCNQ2 currents were recorded using whole-cell voltage clamp technique. Test compound in extracellular solution was delivered to the recorded cell using an ALA 8 Channel Solution Exchange System. RESULTS: A total of 23 retigabine derivatives (HN31-HN410) were synthesized and tested electrophysiologically. Among the compounds, HN38 was the most potent inhibitor of KCNQ2 channels (its IC50 value=0.10 +/- 0.05 MUmol/L), and was 7-fold more potent than the classical KCNQ inhibitor XE991. Further analysis revealed that HN38 (3 MUmol/L) had no detectable effect on channel activation, but accelerated deactivation at hyperpolarizing voltages. In contrast, XE991 (3 MUmol/L) did not affect the kinetics of channel activation and deactivation. CONCLUSION: The retigabine derivative HN38 is a potent KCNQ2 inhibitor, which differs from XE991 in its influence on the channel kinetics. Our study provides a new strategy for the design and development of potent KCNQ2 channel inhibitors. PMID- 23933654 TI - Exploring the intrinsic limits of nitrogenase transfer from bacteria to eukaryotes. AB - Biological nitrogen fixation is widespread among the Eubacteria and Archae domains but completely absent in eukaryotes. The lack of lateral transfer of nitrogen-fixation genes from prokaryotes to eukaryotes has been partially attributed to the physiological requirements necessary for the function of the nitrogenase complex. However, symbiotic bacterial nitrogenase activity is protected by the nodule, a plant structure whose organogenesis can be trigged in the absence of bacteria. To explore the intrinsic potentiality of this plant organ, we generated rhizobium-independent nodules in alfalfa by overexpressing the MsDMI3 kinase lacking the autoinhibitory domain. These transgenic nodules showed similar levels of leghemoglobin, free oxygen, ATP, and NADPH to those of efficient Sinorhizobium meliloti B399-infected nodules, suggesting that the rhizobium-independent nodules can provide an optimal microenvironment for nitrogenase activity. Finally, we discuss the intrinsic evolutionary constraints on transfer of nitrogen-fixation genes between bacteria and eukaryotes. PMID- 23933655 TI - Cardiovascular autonomic dysfunction in animal models of Parkinson's disease. AB - Cardiovascular autonomic dysfunction is a common non-motor symptom associated with synucleinopathies such as Parkinson's disease (PD). Several recent clinical studies indicate that cardiovascular autonomic impairments including orthostatic hypotension and sympathetic denervation may precede the development of the cardinal motor symptoms in PD, making cardiovascular dysfunction an attractive target for the development of biomarkers for early detection and potential neuroprotective strategies for PD. However, the pathologic mechanisms underlying cardiovascular dysfunction as well as many of the non-motor symptoms in PD remain unknown. This is likely due, in part, to an initial under-appreciation of PD as a systemic disorder as well as limited research in cardiovascular dysfunction in animal models of PD. Here, we highlight studies that have investigated cardiovascular dysfunction in rodent models of PD and the potential usefulness of genetic mouse models of PD for this endeavor. PMID- 23933656 TI - Putaminal upregulation of FosB/DeltaFosB-like immunoreactivity in Parkinson's disease patients with dyskinesia. AB - The transcription factor DeltaFosB is a mediator of maladaptive neuroplasticity in animal models of Parkinson's disease (PD) and L-DOPA-induced dyskinesia. Using an antibody that recognizes all known isoforms of FosB and DeltaFosB, we have examined the expression of these proteins in post-mortem basal ganglia sections from PD patients. The patient cases were classified as being dyskinetic or non dyskinetic based on their clinical records. Sections from neurologically healthy controls were also included in the study. Compared to both controls and non dyskinetic cases, the dyskinetic group showed a higher density of FosB/DeltaFosB immunopositive cells in the posterior putamen, which represents the motor region of the striatum in primates. In contrast, the number of FosB/DeltaFosB-positive cells did not differ significantly among the groups in the caudate, a region primarily involved with the processing of cognitive and limbic-related information. Only sparse FosB/DeltaFosB immunoreactivity was found in the in the pallidum externum and internum, and no significant group differences were detected in these nuclei. The putaminal elevation of FosB/DeltaFosB-like immunoreactivity in patients who had been affected by L-DOPA-induced dyskinesia is consistent with results from both rat and non-human primate models of this movement disorder. The present findings support the hypothesis of an involvement of DeltaFosB-related transcription factors in the molecular mechanisms of L-DOPA induced dyskinesia. PMID- 23933657 TI - Membrane interaction of alpha-synuclein in different aggregation states. AB - Aggregated alpha-synuclein in Lewy bodies is one of the hallmarks of Parkinson's disease (PD). Earlier observations of alpha-synuclein aggregates in neurons grafted into brains of PD patients suggested cell-to-cell transfer of alpha synuclein and a prion-like mechanism. This prompted the current investigation of whether alpha-synuclein passes over model phospholipid bilayers. We generated giant unilamellar vesicles (GUVs) containing a small amount of a lipid-conjugated red emitting dye (rhodamine B) and varied the membrane charge by using different molar ratios of DOPC and DOPS or cardiolipin. We then used confocal fluorescence microscopy to examine how monomer, fibril as well as on-pathway alpha-synuclein species labeled with a green emitting fluorophore (Alexa488) interacted with the phospholipid bilayers of the GUV. We defined conditions that yielded reproducible aggregation kinetics under basal conditions and with none or moderate shaking. We found that on-pathway alpha-synuclein species and equilibrium amyloid aggregates, but not alpha-synuclein monomers, bound to lipid membranes. alpha-Synuclein was particularly strongly associated with GUVs containing the anionic lipids cardiolipin or DOPS, whereas it did not associate with GUVs containing only zwitterionic DOPC. We found that alpha-synuclein progressively aggregated at the surface of the GUVs, typically in distinct domains rather than uniformly covering the membrane, and that both lipid and protein were incorporated in the aggregates. Importantly, we never observed transport of alpha-synuclein over the GUV bilayer. This suggests that alpha-synuclein transport over membranes requires additional molecular players and that it might rely on active transport. PMID- 23933658 TI - Survival of human induced pluripotent stem cell-derived midbrain dopaminergic neurons in the brain of a primate model of Parkinson's disease. AB - Before induced pluripotent stem cells (iPSCs) can be used to treat neurologic diseases, human iPSC-derived neural cells must be analyzed in the primate brain. In fact, although mouse and human iPSCs have been used to generate dopaminergic (DA) neurons that are beneficial in rat models of Parkinson's disease (PD), human iPSC-derived neural progenitor cells (NPCs) have not been examined in primate brains. Here, we generated NPCs at different stages of predifferentiation using a feeder-free culture method, and grafted them into the brains of a monkey PD model and NOD-SCID mice. Magnetic resonance imaging (MRI), positron emission tomography (PET), immunocytochemistry, and behavioral analyses revealed that NPCs pretreated with Sonic hedgehog and fibroblast growth factor-8 followed by glial cell-derived neurotrophic factor, brain-derived neurotrophic factor, ascorbic acid, and dibutyryl cyclic AMP resulted in smaller grafts than those without these treatments, and survived as DA neurons in a monkey brain as long as six months. Thus, for the first time, we describe a feeder-free neural differentiation method from human iPSCs and an evaluation system that can be used to assess monkey PD models. PMID- 23933660 TI - In vivo time-gated fluorescence imaging with biodegradable luminescent porous silicon nanoparticles. AB - Fluorescence imaging is one of the most versatile and widely used visualization methods in biomedical research. However, tissue autofluorescence is a major obstacle confounding interpretation of in vivo fluorescence images. The unusually long emission lifetime (5-13 MUs) of photoluminescent porous silicon nanoparticles can allow the time-gated imaging of tissues in vivo, completely eliminating shorter-lived (<10 ns) emission signals from organic chromophores or tissue autofluorescence. Here using a conventional animal imaging system not optimized for such long-lived excited states, we demonstrate improvement of signal to background contrast ratio by >50-fold in vitro and by >20-fold in vivo when imaging porous silicon nanoparticles. Time-gated imaging of porous silicon nanoparticles accumulated in a human ovarian cancer xenograft following intravenous injection is demonstrated in a live mouse. The potential for multiplexing of images in the time domain by using separate porous silicon nanoparticles engineered with different excited state lifetimes is discussed. PMID- 23933661 TI - Submerged liquid plasma for the synthesis of unconventional nitrogen polymers. AB - Glow discharge polymerization is not well understood due to the rapid/complex reaction at the plasma/gas precursor interface. Plasma reaction in a submerged condition allows post-plasma-polymerization, leading to further polymer growth and thus a stable structure. Electron collision with acetonitrile at the interface initiates the formation of radical monomers, which undergoes further rearrangement to form low-molecular (LM) nitrogen polymers (NPs). The radical rich LM NPs go through further polymerization, forming stable high-molecular (HM) NPs (as determined using liquid chromatography/mass spectrometry). LM NPs absorb light at a wavelength of 270 nm (lambda max) whereas HM NPs show absorption at 420 nm (lambda max), as determined from ultraviolet-visible absorption spectra. The fluorescence spectra of HM NPs show characteristic emission at 430 nm, which indicates the presence of nitrogen functional groups with external conjugation. The proposed structure of HM NPs is verified with different analytical instruments. PMID- 23933662 TI - Is Alzheimer's disease a homogeneous disease entity? AB - The epidemic proportions of dementia in old age are a cause of great concern for the medical profession and the society at large. It is customary to consider Alzheimer's disease (AD) as the most common cause of dementia, and vascular dementia (VaD) as being the second. This dichotomous view of a primary neurodegenerative disease as opposed to a disorder where extrinsic factors cause brain damage led to separate lines of research in these two entities. New biomarkers, particularly the introduction of modern neuroimaging and cerebrospinal fluid changes, have, in recent years, helped to identify anatomical and chemical changes of VaD and of AD. Nevertheless, there is a substantial difference between the two entities. While it is clear that VaD is a heterogeneous entity, AD is supposed to be a single disorder. Nobody attempts to use CADASIL as a template to develops treatment for sporadic VaD. On the other hand, early-onset AD is used to develop therapy for sporadic AD. This paper will discuss the problems relating to this false concept and its consequences. PMID- 23933663 TI - Protective effect of low-level laser therapy (LLLT) on acute zymosan-induced arthritis. AB - The aim of this study was to evaluate the effect of low-level laser therapy on acute zymosan-induced arthritis, with respect to the laser action on inflammatory cells influx, release of pro-inflammatory mediators, metalloproteinases activity into the joint cavity and the cartilage repair process. Arthritis was induced in male Wistar rats (250-280 g) by intra-articular injection of zymosan (1 mg dissolved in 50 MUl of a sterile saline solution) into one rear knee joint. Animals were irradiated immediately, 1 and 2 h after zymosan administration with a semiconductor laser InGaAIP (660 nm, 10 mW, 2.5 J/cm(2), 10 s). In the positive control group, animals were injected with the anti-inflammatory drug dexamethasone 1 h prior to the zymosan administration. Treatment with laser significantly inhibited leukocytes influx, the release of IL-1 and IL-6 and also the activity of metalloproteinase-2 and 9, into the joint cavity. In conclusion, laser therapy was effective in reducing inflammation to sites of injury and inhibit activation of proteases (gelatinase) suggesting less degradation of collagen tissue in experimental model of acute arthritis. PMID- 23933665 TI - Impaired dynamic balance is associated with falling in post-stroke patients. AB - Falling is one of the most common complications of stroke. The purpose of this study was to investigate the impact of falling on cognitive and physical function in post-stroke patients. Further, the predictive factors associated with independence of activity of daily living (ADL) in stroke patients with falls experience were investigated. Sixty-six participants were divided into 2 groups according to history of falling: faller (n = 34) and non-faller (n = 32). All participants were examined for cognitive and physical function. Static balance was measured by postural sway using a force platform. Dynamic balance was measured using the Berg Balance Scale (BBS) and the Modified Rivermead Mobility Index (MRMI), which shows the degree of performance for balance tasks. ADL was measured using the Modified Barthel Index (MBI), which shows the degree of independence. The fallers showed lower cognitive and physical function than the non-fallers (p < 0.05). This finding indicates that falling is associated with reduced physical function, as well as reduced cognitive function. In the fallers, the ADL (MBI) was moderately correlated with each of cognition [MMSE (r = 0.388, p = 0.023)], dynamic balance [MRMI (r = 0.514, p = 0.002) and BBS (r = 0.572, p < 0.000)]. In addition, regression analysis showed that BBS was a primary predictor for ADL performance (R(2) = 0.327, beta = 0.572, p < 0.000). Our findings indicate that enhancement of dynamic balance is needed to improve in activities necessary for normal self-care of stroke patients with falls experience. PMID- 23933664 TI - Metallic ureteral stents in malignant ureteral obstruction: short-term results and radiological features predicting stent failure in patients with non urological malignancies. AB - PURPOSE: To provide short-term result of the metallic ureteral stent in patients with malignant ureteral obstruction and identify radiological findings predicting stent failure. MATERIALS AND METHODS: The records of all patients with non urological malignant diseases who have received metallic ureteral stents from July 2009 to March 2012 for ureteral obstruction were reviewed. Stent failure was detected by clinical symptoms and imaging studies. Survival analysis was used to estimate patency rates and factors predicting stent failure. RESULTS: A total of 74 patients with 130 attempts of stent insertion were included. A total of 113 (86.9 %) stents were inserted successfully and 103 (91.2 %) achieved primary patency. After excluding cases without sufficient imaging data, 94 stents were included in the survival analysis. The median functional duration of the 94 stents was 6.2 months (range 3-476 days). Obstruction in abdominal ureter (p = 0.0279) and lymphatic metastasis around ureter (p = 0.0398) were risk factors for stent failure. The median functional durations of the stents for abdominal and pelvic obstructions were 4.5 months (range 3-263 days) and 6.5 months (range 4 476 days), respectively. The median durations of the stents with and without lymphatic metastasis were 5.3 months (range 4-398 days) and 7.8 months (range 31 476 days), respectively. CONCLUSION: Metallic ureteral stents are effective and safe in relieving ureteral obstructions resulting from non-urological malignancies, and abdominal ureteral obstruction and lymphatic metastasis around ureter were associated with shorter functional duration. PMID- 23933666 TI - Combination of Miller-Dieker syndrome and VACTERL association causes extremely severe clinical presentation. AB - We report a Japanese boy, who showed overlapping clinical features of Miller Dieker syndrome (lissencephaly and facial dysmorphism) and vertebral defect, anal atresia, cardiac malformation and limb anomalies (VACTERL) association. The overall clinical presentation was much more severe than that normally associated with each disorder, and the infant died on day 100 of life despite aggressive therapy. Fluorescence in situ hybridization using a commercially available LIS1 probe failed to detect a deletion, but chromosomal microarray analysis detected a 2.50-Mb microdeletion in 17p13.3 which involved partially the LIS1 gene, and thus was compatible with Miller-Dieker syndrome. It may represent an example of a combination of two congenital disorders with blended phenotypes explaining unexpectedly severe phenotypes occurring with known chromosomal rearrangements. CONCLUSION: We report the first case of a combination of Miller-Dieker syndrome and VACTERL association with an unusually severe phenotype. PMID- 23933667 TI - Propranolol therapy for cutaneous infantile haemangiomas initiated safely as a day-case procedure. AB - Propranolol is emerging as the treatment of choice for high-risk infantile haemangiomas. Current protocols recommend overnight admission for initiation of propranolol as well as baseline investigations including electrocardiography (ECG) and echocardiography (ECHO). Our study examined the safety profile of propranolol for the treatment of infantile haemangiomas using a simplified day case initiation protocol. We evaluated 20 consecutive patients commencing propranolol as a day case for the treatment of an infantile haemangioma over an 18-month period. Investigations were carried out according to our local protocol. Cardiac investigations were not routinely performed. Patients were observed for 2 h following administration of the first dose of propranolol (0.5 mg/kg orally). If no adverse effects were observed, patients were discharged on a daily dose of propranolol of 1 mg/kg, increased to 2 mg/kg on day 4. Patients were reviewed on the day ward on day 8. All haemangiomas requiring treatment were small to moderate in size (median maximum diameter 2.35 cm). Except for capillary blood glucose measurement, no patient required venepuncture for additional blood investigations. As all patients had a normal clinical examination, none required ECHO. An ECG was performed on just one patient. No adverse reactions were observed following administration of propranolol. All patients were discharged home on the same day. No serious adverse events were reported at follow-up. We demonstrate that with targeted cardiac screening, propranolol can be safely initiated on a day-case basis for the treatment of small- to moderate-sized infantile haemangiomas. PMID- 23933668 TI - Primary hypothyroidism: an unusual manifestation of Wolcott-Rallison syndrome. AB - Wolcott-Rallison syndrome has been reported to be associated with early-onset diabetes, epiphyseal dysplasia, hepatic and renal dysfunction, mental retardation, severe growth retardation, neutropenia, exocrine pancreatic dysfunction, and central hypothyroidism. We report on primary hypothyroidism, which has not been previously described, of a patient with Wolcott-Rallison syndrome due to novel mutation (W521X), who showed improved growth after thyroid hormone treatment. PMID- 23933669 TI - Delay and stability of central venous administration of norepinephrine in children: a bench study. AB - In children, because of the dead volume of the central venous catheter (CVC) and the low flow rate of norepinephrine (NE) infusion, the delay between start-up and effective administration can be adversely long. A theoretical calculation enables to estimate the delay and variations of effective administration. However, numerous factors can hinder this theoretical approach. Herein, we measured via bench testing the actual delay and stability of NE administration kinetics. Using an assembly reproducing our currently-implemented catecholamine administration protocol, diluted NE (200 MUg ml(-1)) was infused at an initial rate of 2 ml h( 1) (theoretically 6.67 MUg min(-1)) for a period of 24 h. An assay measuring the amount of NE (MUg) exiting the CVC was conducted by high-pressure liquid chromatography with colorimetric detection. The theoretical calculation of the delay in administered NE, taking into account a CVC dead volume of 0.3 ml, was 9 min. The measured percentage of the administered dose as a function of time in minutes (M) was M0-M3 (0 %), M3-M6 (0 %), M6-M9 (13 %), M9-M12 (28 %), M12-M15 (70 %), and M15-M18 (100 %) The amount of NE (MUg) at fixed rate (2 ml h(-1)) was established at 6.9 +/- 0.4 MUg min(-1) during the 24 h. CONCLUSION: Continuous NE infusion via a CVC at low rate is stable. In children, because of CVC dead volume and low flow rate infusion, the delay in achieving intended dose delivery is significantly longer than that estimated by theoretical calculation. New modalities of initiation of catecholamine infusion adapted to the child are warranted. PMID- 23933670 TI - Influence of mask type and mask position on the effectiveness of bag-mask ventilation in a neonatal manikin. AB - Anatomical face mask with an air cushion rim might be placed accidentally in a false orientation on the newborn's face or filled with various amounts of air during neonatal resuscitation. Both false orientation as well as variable filling may reduce a tight seal and therefore hamper effective positive pressure ventilation (PPV). We aimed to measure the influence of mask type and mask position on the effectiveness of PPV. Twenty neonatal staff members delivered PPV to a modified, leak-free manikin. Resuscitation parameters were recorded using a self-inflatable bag PPV with an Intersurgical anatomical air cushion rim face mask (IS) and a size 0/1 Laerdal round face mask. Three different positions of the IS were tested: correct position, 90 degrees and 180 degrees rotation in reference to the midline of the face. IS masks in each correct position on the face but with different inflation of the air cushion (empty, 10, 20 and 30 mL). Mask leak was similar with mask rotation to either 90 degrees or 180 degrees but significantly increased from 27 (13-73) % with an adequate filled IS mask compared to 52 (16-83) % with an emptied air cushion rim. CONCLUSION: Anatomical shaped face mask had similar mask leaks compared to round face mask. A wrongly positioned anatomical-shaped mask does not influence mask leak. Mask leak significantly increased once the air cushion rim was empty, which may cause failure in mask PPV. PMID- 23933671 TI - Hymenal anomalies in twins--review of the literature and case report. AB - Subocclusive hymenal variants, such as microperforate or septate hymen, impair somatic functions (e.g., vaginal intercourse or menstrual hygiene) and can negatively impact the quality of life of young women. We know little about the prevalence and inheritance of subocclusive hymenal variants. So far, eight cases of familial occurrence of occlusive hymenal anomalies (imperforate hymen) have been reported. In one of these cases, monozygotic twins were affected. We are reporting the first case of subocclusive hymenal variants (microperforate hymen and septate hymen) in 16-year-old white dizygotic twins. In addition, we review and discuss the current evidence. CONCLUSION: The mode of inheritance of hymenal variants has not been determined so far. Because surgical corrections of hymenal variants should be carried out in asymptomatic patients (before menarche), gynecologists and pediatricians should keep in mind that familial occurrences may occur. PMID- 23933672 TI - Clinical and genetic features of Prader-Willi syndrome in China. AB - We set out to delineate the phenotypic and genotypic characteristics of Prader Willi syndrome (PWS), a congenital neurodevelopmental disorder caused by the lack of expression of the paternally inherited imprinted genes on chromosome 15q11-13 in 31 Chinese patients. They were genotyped to identify deletions using methylation-specific polymerase chain reaction analysis and subsequent methylation-specific multiplex ligation-dependent probe amplification analysis. Microsatellite linkage analysis was performed to distinguish maternal uniparental disomy (UPD) from imprinting defect. Clinical manifestations were recorded and compared between patients with paternal 15q11-13 deletion and UPD. Deletions in the 15q11-13 region were present in 26 (83.9 %) patients, and UPD was observed in 5 (16.1 %) patients. The mean maternal age at the time of childbirth for mUPD children (32.8 +/- 5.1 years) was significantly higher than that of children with paternal 15q11-13 deletion (27.1+/-3.2 years, P < 0.05). All patients had neonatal hypotonia, feeding difficulties in infancy, and decreased fetal activity, but only 12.9 % of the patients showed short stature, 54.8 % presented typical facial features, and 35.5 % showed skin picking lesions. CONCLUSION: Significant heterogeneity in clinical phenotypes and genotypes in PWS were observed between Chinese and Western populations in this study. This suggests that ethnic differences may be relevant to the diagnostic criteria for PWS. PMID- 23933674 TI - Juvenile polyp. AB - The most frequent clinical presentation of intestinal polyps is painless rectal bleeding. Although colonoscopy is the modality of choice for the diagnosis of intestinal polyps, sonography may be the first diagnostic tool in the evaluation of children with bloody stools. Ultrasonography has the advantage of being safe and noninvasive. PMID- 23933673 TI - Initial anticonvulsant monotherapy in routine care of children and adolescents: levetiracetam fails more frequently than valproate and oxcarbazepine due to a lack of effectiveness. AB - Since anticonvulsants such as valproate or oxcarbazepine have quite a disadvantageous profile of possible adverse drug events (ADEs), safer alternatives are being sought. The newer anticonvulsant levetiracetam is often considered advantageous. We performed a chart review of children and adolescents aged from 0.5 to 16.9 years, who had been started on an initial monotherapy with levetiracetam, valproate, or oxcarbazepine between 2007 and 2011, in order to analyze the therapy's failure rate during the first year. We differentiated failure of monotherapy due to a lack of effectiveness and due to ADEs. No psychometric tests were performed. Lack of effectiveness and inacceptable ADEs were assumed according to the judgment of physicians and families. Anticonvulsive monotherapy failed in 29/61 (48 %) levetiracetam patients and in 18/49 (37 %) valproate patients (for focal and generalized epilepsies; n.s.). This was caused by a lack of effectiveness in 25/61 (41 %) levetiracetam patients and in 11/49 (22 %) valproate patients (p <= 0.05). A modification of therapy due to ADEs was performed in 4/61 (7 %) levetiracetam patients and in 7/49 (14 %) valproate patients (n.s.). An anticonvulsive monotherapy failed in 21/42 (50 %) patients treated with levetiracetam and in 10/34 (29 %) patients treated with oxcarbazepine (for focal epilepsies; n.s.). Changes of monotherapy were caused by a lack of effectiveness in 17/42 (40 %) of levetiracetam patients and in 6/34 (18 %) of oxcarbazepine patients (p <= 0.05). ADEs leading to changes in therapy were reported for 4/42 (10 %) of levetiracetam and 4/34 (12 %) of oxcarbazepine patients (n.s.). An initial monotherapy of levetiracetam failed more frequently due to a lack of effectiveness than a monotherapy with valproate or oxcarbazepine. We found no significant difference in therapy failure due to ADEs. PMID- 23933675 TI - Transition voltage spectroscopy reveals significant solvent effects on molecular transport and settles an important issue in bipyridine-based junctions. AB - Results of a seminal study (B. Xu and N. J. Tao, Science, 2003, 301, 1221) on the single-molecule junctions based on bipyridine placed in a solvent have been challenged recently (S. Y. Quek et al., Nat. Nano, 2009, 4, 230) by implicitly assuming a negligible solvent impact on the molecular transport and by merely considering low bias conductance data. In this paper we demonstrate that solvent effects on the molecular transport are important, and to show this we focus our attention on the energy offset epsilon(0) of the dominant molecular orbital (LUMO) relative to the electrode Fermi level. To estimate the energy offset epsilon(0)(sol) from the full I-V curves presented by Xu and Tao for wet junctions, we resort to the recently proposed transition voltage spectroscopy (TVS). TVS, which plays a key role in the present analysis, emphasizes that data beyond the ohmic conductance regime are needed to reveal the solvent impact. We show that epsilon(0)(sol) significantly differs from the energy offset epsilon(0)(0)deduced for dry junctions (J. R. Widawsky et al., Nano Lett., 2012, 12, 354). The present work demonstrates that solvent effects on molecular transport are important and can be understood quantitatively. Results of ab initio calculations with and without solvent are reported that excellently explain the difference deltaepsilon(0) = epsilon(0)(sol)-epsilon(0)(0). deltaepsilon(0) = DeltaDeltaG + deltaPhi + deltaW can be disentangled in contributions with a clear physical content: solvation energies (DeltaDeltaG), image charges (deltaPhi), and work functions (deltaW). Accurate analytical formulae for DeltaDeltaG and deltaPhi are reported, which provide experimentalists with a convenient framework to quantify solvent effects obviating demanding numerical efforts. PMID- 23933676 TI - Double helix dipole design applied to magnetic resonance: a novel NMR coil. AB - A new radio frequency coil design for NMR experiments is presented. The coil generates a magnetic field purely perpendicular to the longitudinal axis of the main magnet, and its sensitivity is higher than the traditional transversal resonators. This is achieved by adding the contribution of two tilted solenoid coils fed with opposite currents. The work presents the mathematical model for the new coil, numerical simulations performed to validate that model and a comparison with an equivalent saddle coil. The new design is tested experimentally in low- and high-field NMR experiments and compared with results obtained with equivalent saddle coils. The results lead to conclude that the new design provides better sensitivity than the transverse resonators commonly used in NMR. PMID- 23933677 TI - Functionalized magnetic nanoparticles for sample preparation in proteomics and peptidomics analysis. AB - Sample preparation is a fundamental step in the proteomics and peptidomics workflow. Due to their good biocompatibility, superparamagnetic property, and high binding capacity, magnetic nanoparticles (MNPs) functionalized with different active moieties have been widely applied in recent years in various sample preparation procedures in proteomics and peptidomics analysis. The magnetic cores of the MNPs facilitate elegant handling using only magnetic devices and their small diameters are advantageous for increasing the sensitivity when using subsequent mass spectrometry (MS) analysis or gel electrophoresis. This review mainly focuses on overviewing present advances in the preparation and application of functionalized magnetic nanoparticles for sample preparation in proteomics and peptidomics analysis, including protein digestion, enrichment of low-abundance peptides/proteins and specific enrichment of peptides/proteins with post-translational modifications, such as phosphorylation and glycosylation. PMID- 23933678 TI - Increase in tetrahydrobiopterin concentration with aging in the cerebral cortex of the senescence-accelerated mouse prone 10 strain caused by abnormal regulation of tetrahydrobiopterin biosynthesis. AB - 6R-L-Erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase (TH) activity and is a risk factor for cognitive decline and brain atrophy. Previous studies have shown that the decline in TH activity in the cerebral cortex of senescence-accelerated mouse prone 10 (SAMP10) mice is caused, at least in part, by a decrease in Fe, ferritin, and TH phosphorylation. We determined the concentrations of BH4 and the enzymes GTP cyclohydrolase-1,6 pyruvoyltetrahydropterin synthase and sepiapterin reductase (SPR) in the de novo pathway of BH4 biosynthesis. Dihydrofolate reductase (DHFR), which converts BH2 to BH4 in the salvage pathway of BH4 synthesis was also determined in the cerebral cortex of SAM mice at 3 and 12 months of age. The BH4 concentration was measured by HPLC, and the protein levels of enzymes involved in BH4 synthesis were measured by western blot analysis. At 12 months of age, BH4 concentration in the cerebral cortex of SAMP10 mice showed significantly higher values as compared to that of control mice. Further, the protein level of SPR in SAMP10 mice was significantly higher than that in SAMR1 mice at 3 and 12 months of age. In contrast to SPR, the protein level of DHFR in SAMP10 mice was significantly lower than that in SAMR1 mice. These results indicate that abnormal regulation of BH4 metabolism occurs in the cerebral cortex of SAMP10 where the dysfunction of the salvage pathway of BH4 synthesis may cause overproduction of BH4 through the de novo pathway, which is considered characteristic in the cerebral cortex of SAMP10 with aging. Therefore, there is a possibility that the excess amounts of BH4 lead to age-related brain dysfunction in the cerebral cortex of SAMP10. PMID- 23933679 TI - Genetic and genotoxic impacts in the oyster Crassostrea gigas exposed to the harmful alga Alexandrium minutum. AB - Genotoxic, genetic and behavioral impacts of the paralytic shellfish toxin (PST) producing alga Alexandrium minutum on the oyster Crassostrea gigas were assessed using RAPD-PCR, qPCR and valve activity recording. Oysters were exposed to a dose mimicking an algal bloom (~1600 cells ml(-1)) for 48 h. Results indicate a rapid and sustained behavioral disturbance. Animals remained open but exhibited reduced valve-opening amplitude, correlated to the amount of toxin accumulated in the digestive gland. They also exhibited increased micro-closures. In the gills, gene transcription levels were modified: a transcriptional repression of genes involved in oxidative and mitochondrial metabolism, endogenous clock, immunity and detoxification processes was observed. DNA impacts, both quantitative and qualitative, were observed as well. Indeed, both the PCR product profile and the number of hybridization sites for the RAPD probe OPB7 were modified. These results indicate genotoxic effects and gene repression in C. gigas following behavioral disturbance by A. minutum. PMID- 23933681 TI - Regioselective monochloro substitution in carbohydrates and non-sugar alcohols via Mitsunobu reaction: applications in the synthesis of reboxetine. AB - A regioselective high yielding monochloro substitution (chlorohydrin formation) via Mitsunobu reaction is reported. In carbohydrates and sterically hindered non sugars, only the primary hydroxyl group is chlorinated, whereas in the non-sugar 1,2- and 1,3-alcohols, predominantly the secondary chloride substitution occurs. The versatile methodology provides indirect access to epoxides with the retention of configuration, as against conventional Mitsunobu reaction which generates epoxides with inversion. The methodology was successfully used as a key step in the synthesis of optically active diastereoisomers of the antidepressant drug reboxetine from (R)-2,3-O-cyclohexylidene-d-glyceraldehyde in ~43% overall yields. PMID- 23933680 TI - Purification and partial characterization of vitellogenin from spotted wolffish (Anarhichas minor) and development of an enzyme-linked immunosorbent assay for the determination of gender and sexual maturity. AB - Vitellogenin (VTG) from spotted wolffish, Anarhichas minor, a candidate species for cold-water marine aquaculture, was purified by MgCl2/EDTA precipitation followed by a two-step chromatographic procedure. VTG had an apparent molecular mass of 470 kDa, as determined by gel filtration, and an amino acid composition similar to those of other teleosts. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of the purified VTG revealed a major band with a relative molecular weight of 166 kDa and some minor bands. Spotted wolffish VTG (sw-VTG) is relatively robust to in vitro degradation, as shown when samples of purified VTG and plasma from mature females subjected to various storage conditions or multiple freeze/thaw cycles were analyzed by Western blot. We developed an indirect competitive enzyme-linked immunosorbent assay (ELISA) using an antibody against Atlantic wolffish (Anarhichas lupus) VTG and purified sw-VTG. The ELISA had a detection limit of 6.7 ng/ml and a working range of 16.2-787.5 ng/ml, with intra- and inter-assay coefficients of variation ranging from 1.5 to 7.3 % and 7.1 to 14.3 %, respectively. The assay could distinguish males from immature females and discriminate maturing females at different stage of oocyte development. These results suggest that the sw-VTG ELISA would be useful in spotted wolffish aquaculture to determine sex and monitor female maturation. PMID- 23933682 TI - Dual-delivery of vancomycin and icariin from an injectable calcium phosphate cement-release system for controlling infection and improving bone healing. AB - Infectious bone diseases following severely contaminated open fractures are frequently encountered in clinical practice. It is difficult to successfully repair bone and control infection at the same time. To identify a better treatment method, we prepared a dual-drug release system that was comprised of icariin (IC, a natural osteoinductive molecule), vancomycin (VA) and injectable calcium phosphate cement (CPC). The ultrastructure of the dual-drug release system was evaluated by scanning electron microscopy and the biocompatibility was assessed by cell culture. In addition, the release kinetics of IC and VA were respectively investigated by using high-performance liquid chromatography. Finally, this system was used to repair Staphylococcus aureus-contaminated bone defects in a rabbit model. Twelve weeks after the implantation of IC-VA/CPC, the contaminated bone defects were completely repaired, with significantly improved formation of lamellar bone and recanalization of the marrow cavity compared with the controls (CPC without antibiotics or osteoinductive agent). These results demonstrate that this dual-drug release system, with its concomitant antibiotic and osteoinductive properties, has significant potential for the treatment of contaminated bone injury or infectious bone disease. PMID- 23933683 TI - Neither separate nor equivalent: relationships between feature representations within bound objects. AB - Evidence suggests that binding, or encoding a feature with respect to other features in time and space, can convey cognitive advantages. However, evidence across many kinds of stimuli and paradigms presents a mixed picture, alternatively showing cognitive costs or cognitive advantages associated with maintaining bound representations. We examined memory for colored letters drawn from similar and distinct color sets under circumstances that encouraged or discouraged the maintenance of color-letter binding. Our results confirmed previous change recognition research showing feature recognition improvement under explicit instructions to maintain binding. Color memory improved during binding, showing a reduced detrimental effect of feature similarity on retrieval, particularly when the letter served as the retrieval cue for a letter-color object. We found that feature recognition improved when two conditions were met: 1) relationships between features were to-be-remembered, and 2) the feature conjunction was relevant at test. Our results further suggest that this feature advantage arises because the encoded relationship between the features facilitates retrieval, not because features and objects are represented simultaneously in separate buffers. PMID- 23933684 TI - Body image distortions in healthy adults. AB - Distortions of body image have often been investigated in clinical disorders. Much of this literature implicitly assumes healthy adults maintain an accurate body image. We recently developed a novel, implicit, and quantitative measure of body image - the Body Image Task (BIT). Here, we report a large-scale analysis of performance on this task by healthy adults. In both an in-person and an online version of the BIT, participants were presented with an image of a head as an anchoring stimulus on a computer screen, and told to imagine that the head was part of a mirror image of themselves in a standing position. They were then instructed to judge where, relative to the head, each of several parts of their body would be located. The relative positions of each landmark can be used to construct an implicit perceptual map of bodily structure. We could thus measure the internally-stored body image, although we cannot exclude contributions from other representations. Our results show several distortions of body image. First, we found a large and systematic over-estimation of width relative to height. These distortions were similar for both males and females, and did not closely track the idiosyncrasies of individual participant's own bodies. Comparisons of individual body parts showed that participants overestimated the width of their shoulders and the length of their upper arms, relative to their height, while underestimating the lengths of their lower arms and legs. Principal components analysis showed a clear spatial structure to the distortions, suggesting spatial organisation and segmentation of the body image into upper and lower limb components that are bilaterally integrated. These results provide new insight into the body image of healthy adults, and have implications for the study and rehabilitation of clinical populations. PMID- 23933685 TI - Observation of higher stiffness in nanopolycrystal diamond than monocrystal diamond. AB - Diamond is the stiffest known material. Here we report that nanopolycrystal diamond synthesized by direct-conversion method from graphite is stiffer than natural and synthesized monocrystal diamonds. This observation departs from the usual thinking that nanocrystalline materials are softer than their monocrystals because of a large volume fraction of soft grain-boundary region. The direct conversion causes the nondiffusional phase transformation to cubic diamond, producing many twins inside diamond grains. We give an ab initio-calculation twinned model that confirms the stiffening. We find that shorter interplane bonds along [111] are significantly strengthened near the twinned region, from which the superstiff structure originates. Our discovery provides a novel step forward in the search for superstiff materials. PMID- 23933687 TI - The central CLOCK system and the stress axis in health and disease. PMID- 23933686 TI - Serum and glucocorticoid inducible kinase, metabolic syndrome, inflammation, and tumor growth. AB - Serum-and-glucocorticoid-inducible-kinase-1 (SGK1) is under regulation of several hormones, mediators and cell stressors. More specifically, SGK1 expression is particularly sensitive to glucocorticoids, mineralocorticoids, and TGFbeta. Moreover, SGK1 expression is exquisitely sensitive to hypertonicity, hyperglycemia, and ischemia. SGK1 is activated by insulin and growth factors via phosphatidylinositol-3-kinase, 3-phosphoinositide dependent-kinase PDK1, and mTOR. SGK1 up-regulates the Na+/K+-ATPase, a variety of carriers (e.g. NCC, NKCC, NHE1, NHE3, SGLT1, several amino acid transporters) and many ion channels (e.g. ENaC, SCN5A, TRPV4-6, Orai1/STIM1, ROMK, KCNE1/KCNQ1, GluR6, CFTR). SGK1 further up-regulates a number of enzymes (e.g. glycogen-synthase-kinase-3, ubiquitin ligase Nedd4-2), and transcription factors (e.g. forkhead-transcription-factor FOXO3a, beta-catenin, nuclear-factor-kappa-B NFkappaB). SGK1 sensitive functions contribute to regulation of epithelial transport, excitability, degranulation, matrix protein deposition, coagulation, platelet aggregation, migration, cell proliferation, and apoptosis. Apparently, SGK1 is not required for housekeeping functions, as the phenotype of SGK1 knockout mice is mild. However, excessive SGK1 expression and activity participates in the pathophysiology of several disorders, including hypertension, obesity, diabetes, thrombosis, stroke, inflammation, autoimmune disease, fibrosis, and tumor growth. A SGK1 gene variant (prevalence ~3-5% prevalence in Caucasians, ~10% in Africans) predisposes to hypertension, stroke, obesity, and type 2 diabetes. Moreover, excessive salt intake and/or excessive release of glucocorticoids, mineralocorticoids, and TGFbeta up-regulates SGK1 expression thus predisposing to SGK1-related diseases. PMID- 23933688 TI - The guidelines issued by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine regarding the induction of ovulation with metformin in patients with the polycystic ovary syndrome potentially require reconsideration. AB - In 2007, the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) issued guidelines in Thessaloniki regarding the use of metformin and clomiphene for the induction of ovulation in patients with anovulatory polycystic ovary syndrome (PCOS). According to these guidelines, the use of metformin should be limited to patients with impaired glucose tolerance and should be interrupted well before the administration of clomiphene, thus restricting the use of metformin to a minority of patients with PCOS. More recent data suggest that these guidelines potentially require reconsideration. Indeed, metformin appears to be useful in patients with PCOS who have a body mass index within the normal range and present with infertility due to anovulation. Moreover, the combination of metformin with clomiphene appears to be the best treatment choice in patients with PCOS who are resistant to clomiphene, i.e. it should precede the administration of gonadotropins. In addition, the administration of metformin reduces the incidence and severity of ovarian hyperstimulation syndrome when given to patients with PCOS who undergo multiple ovulation induction for in vitro fertilization and have a high risk for this syndrome. However, it should be emphasized that more studies are needed to support the above arguments and, more importantly, to determine the factors that predict the success of ovulation induction. PMID- 23933689 TI - Insulin action in morbid obesity: a focus on muscle and adipose tissue. AB - The aim of this review is to summarize the mechanisms underlying insulin resistance in morbid obesity. Glucose regulation by insulin depends on the suppression of endogenous glucose production and stimulation of glucose disposal. In morbid obesity, glucose production by the liver is increased. Moreover, the sensitivity of glucose metabolism to insulin is impaired both in muscle (due to defects in insulin-stimulated glucose utilization and decreased blood flow) and in adipose tissue (due to decreased blood flow). However, recent studies suggest that expanded total fat mass becomes a major consumer of glucose providing a sink for glucose and compensating for insulin resistance. Metabolism and immunity are closely linked. Bearing in mind the crosstalk between inflammatory pathways and the insulin signaling cascade, adipose tissue derived cytokines may represent a link between inflammation and metabolic signals and mediate, at least in part, insulin resistance. Adipose tissue plays a crucial role by buffering daily influx of dietary fat, suppressing the release of non-esterified fatty acids into the circulation and increasing triacylglycerol clearance. However, in morbid obesity there is an impairment of the normal ability of adipose tissue to buffer fatty acids, despite hyperinsulinemia. Lipotoxicity gradually impairs insulin action in the liver and muscle, aggravating insulin resistance. PMID- 23933690 TI - Incretins and bone: evolving concepts in nutrient-dependent regulation of bone turnover. AB - Postprandial variation of bone turnover markers and the closed relationship between bone remodeling and nutrient supply has been extensively studied in the past few years, but the underlying pathophysiologic mechanisms remain largely unknown. Recent studies have shown that the acute regulation of bone turnover induced by feeding is probably mediated by gastrointestinal (GI) peptides. The greater response of bone remodeling during oral versus intravenous glucose administration and the inhibition of this response after administration of octreotide, that inhibits the release of GI peptides, further support the existence of a gutbone axis. Glucose-dependent insulinotropic peptide and glucagon-like peptides-1 and -2 are released from K and L cells of the gastrointestinal tract, respectively, and are considered the main mediators of the postprandial response of bone turnover. In this review we outline the most recent evidence that demonstrates the role of incretins in nutrient-dependent regulation of bone metabolism. Further elucidation of the underlying mechanisms can be exploited therapeutically in the future. PMID- 23933691 TI - Androgen receptors in early and castration resistant prostate cancer: friend or foe? PMID- 23933692 TI - The corticotropin releasing factor system in the liver: expression, actions and possible implications in hepatic physiology and pathology. AB - The corticotropin-releasing factor (CRF) system plays a crucial regulatory role in the adaptation to exogenous and endogenous stress stimuli, as well as homeostasis. Apart from the central nervous system (CNS), the members of this neuropeptide family extend their actions in the periphery, where they may affect various body systems independently, stimulating peripheral CRF receptors via vagal and/or autocrine/paracrine pathways. Here, we review all findings concerning the expression and role of the CRF system in human liver, but also in other species. Direct and indirect regulatory data are also analyzed in order to draw conclusions about possible physiological/pathophysiological implications. Although data supporting any clinical significance are still limited and further research in the field is necessary, scientific interest in the CRF system is particularly active, with multiple ongoing clinical studies evaluating the activity of CRF ligands in medical conditions involving other organs. Thus, new knowledge with therapeutic potential appears to be steadily accumulating. PMID- 23933693 TI - Eating habits and factors affecting food choice of adolescents living in rural areas. AB - OBJECTIVE: To establish factors that affect food choices among adolescents living in rural areas and to identify their food choices. DESIGN: A random sample of adolescents living in a Greek rural area (n=382) aged 12-18 years were individually interviewed. Food consumption was assessed by a semi-quantitative food-frequency questionnaire and adherence to the Mediterranean diet was evaluated using the KIDMED questionnaire. Information was collected regarding self-perceived body size, dieting, dietary knowledge, parental control, meal and snack frequency, eating out of home, eating takeaways and precooked meals, eating from the school canteen. RESULTS: Body image concerns, dieting, education about food, parental control, maternal education level and eating with family and peers are factors that were found to affect food choices in this group of Greek adolescents. The adherence to the Mediterranean diet was low (KIDMED index was 4.5+/-2.7). Regular family meals at home were frequent in this group and 99% of the adolescents ate lunch daily at home. Eating out with peers and eating from the school canteen was related with higher consumption of 'junk type of food'. Girls and younger adolescents and those whose mothers had a higher education level seem to make healthier choices. CONCLUSIONS: Factors such as personal issues, family and peer pressure significantly affect food choices among adolescents living in a Greek rural area and highlight the importance of implementing multilevel strategies to promote healthy eating among adolescents. PMID- 23933694 TI - Factors influencing the outcome of microsurgical transsphenoidal surgery for pituitary adenomas: a study on 184 patients. AB - OBJECTIVE: Evaluation of factors influencing the outcome of microsurgical transsphenoidal surgery in patients harbouring pituitary adenomas as well as of the efficacy and safety of this procedure. DESIGN: A total of 184 consecutive patients with pituitary adenomas, undergoing microsurgical transsphenoidal resection of their lesions from March 2004 to June 2011, were prospectively studied. Extent of tumour resection and disease remission were defined according to recently established radiological and hormonal consensus criteria. RESULTS: The study included 97 nonfunctioning and 87 functioning adenomas. A gross-total removal, as documented on postoperative imaging, was achieved in 67.4% of all patients. Residual tumour after surgery was detected in 37.1% of patients with nonfunctioning adenomas. The remission rates for patients with functioning adenomas, as documented by the last endocrinological evaluation, were 54.9% for growth hormone-secreting, 69.5% for adrenocorticotropin hormone-secreting, 72.7% for prolactin-secreting and 100% for thyroid-stimulating hormone-secreting, with two recurrences in patients with Cushing's disease. Multivariate analysis showed that factors influencing surgical outcome were cavernous sinus invasion, large tumour diameter (>=25 mm) and reoperation for the nonfunctioning adenomas, and cavernous sinus invasion as well as large tumour diameter (>=25 mm) for the functioning adenomas. In the latter cohort, predictors for endocrinological remission were maximum tumour diameter (<=20 mm) and reoperation. Postoperative complications were present in 3.3% of the cases. One patient developed epistaxis, two hemorrhage at the surgical field, one postoperative rhinorrhea, one postoperative permanent diabetes insipidus and one postoperative panhypopituitarism. CONCLUSIONS: Microsurgical transsphenoidal surgery is an effective and safe treatment in all patients with pituitary adenomas, except for prolactinomas responsive to medical therapy. PMID- 23933695 TI - Association of physical activity and sedentary lifestyle patterns with obesity and cardiometabolic comorbidities in Greek adults: data from the National Epidemiological Survey. AB - OBJECTIVE: To investigate the association between physical activity (PA) and sedentary lifestyle (SL) patterns with overweight (OW), obesity (OB), abdominal obesity (AO) and cardiometabolic comorbidities in Greek adults based on data from the National Epidemiological Survey for the prevalence of obesity. DESIGN: Cross sectional epidemiological survey. Participants were selected via stratified sampling. 17,887 men and women, 20-70 years old, underwent anthropometric measurements for the estimation of OW, OB and AO prevalence. Assessment of PA, SL patterns and metabolic comorbidities was performed using an in-home questionnaire allowing self-evaluation of diverse activities and self-report for the presence of hypercholesterolemia (HCE), type 2 diabetes mellitus (T2DM) or hypertension (HTN). RESULTS: In men, even small amounts of walking were associated with decreased risk of being OW and AO, while larger amounts were associated with decreased risk of being OB. In women, engagement in entertainment activities for more than 4 hours per week was associated with less risk of being OW. Concerning cardiometabolic comorbidities, substantial improvement was evident mainly for men, e.g. signfiicantly reduced risk for HCE, T2DM and HTN by frequent engagement in exercise. On the other hand, frequent TV watching and long hours of office work significantly increased the risk of HCE and HTN in men. CONCLUSIONS: In Greek adults, and men in particular, walking activity was significantly associated with lower risk for obesity. In addition, frequent exercise and less sedentary behaviour were associated with reduced risk for cardiometabolic factors, mainly hypercholesterolemia and hypertension. PMID- 23933696 TI - The effect of prolonged aerobic exercise on serum adipokine levels during an ultra-marathon endurance race. AB - OBJECTIVE: To evaluate the effect of prolonged intensive aerobic exercise and acute energy deficit (180 km ultra-marathon race) on serum leptin, adiponectin, resistin and visfatin levels and their association and interaction with serum cortisol and insulin levels in highly trained ultra-endurance runners. DESIGN: The study included 17 highly trained ultra-endurance male athletes (mean age 51.29+/-6.84 years and body mass index (BetaMUIota) 23.51+/-1.90) participating in the 5th Olympian Race held in Greece on May 2010. Anthropometric values were assessed; Serum cortisol, insulin, leptin, adiponectin, resistin and visfatin levels were measured at baseline, post-exercise and ~20 hours after the end of the race. RESULTS: All hormonal values of the post-exercise and recovery status were corrected for plasma volume changes. The estimated energy deficit during the ultra-endurance event was about 5000 Kcal. At the end of the race serum resistin levels were elevated (p<0.001) and serum leptin levels were reduced (p<0.001) and failed to reach pre-exercise levels, although showing a tendency towards restoration. No significant changes were noted in serum adiponectin and visfatin levels. CONCLUSIONS: Ultra-endurance aerobic exercise and acute negative energy balance lead to an up-regulation of serum resistin levels and a down-regulation of serum leptin levels. PMID- 23933697 TI - Laparoscopic vs. open abdominal surgery in male pigs: marked differences in cortisol and catecholamine response depending on the size of surgical incision. AB - OBJECTIVE: Minimally invasive operations, such as laparoscopic cholecystectomy and adrenalectomy, result in a more rapid recovery of normal function, less physiological disturbances and less stress to the organism than similar open operations. The purpose of this study was to determine the stress response associated with minimally invasive abdominal surgery compared to conventional small or large incision laparotomy. METHODS: We compared the responses of the stress hormones cortisol and the catecholamines adrenaline and noradrenaline to elective conventional and laparoscopic cholecystectomy and unilateral adrenalectomy in male pigs. Blood samples were taken from all animals at the same time, one day before surgery, at the beginning of the operation, every 15 minutes during surgery and on the first postoperative morning. RESULTS: Plasma adrenaline and noradrenaline concentrations were significantly lower in both cholecystectomies (p<0.05) and adrenalectomies (p<0.01) during laparoscopic than during open surgery. Plasma cortisol levels were significantly lower in laparoscopic than in open adrenalectomies both during surgery and on postoperative day one (p<0.05), while no major differences in cortisol levels were observed between laparoscopic and open cholecystectomies. Thus, the stress related benefit of laparoscopic surgery depended on the size of the surgical incision in the conventional operation. CONCLUSION: Laparoscopic surgery was associated with less surgical stress than open surgery and this difference was accentuated as the surgical abdominal wall trauma increased. PMID- 23933698 TI - Microvessel density and VEGF expression in pituitaries of pregnant women. AB - OBJECTIVE: In pregnant women, the pituitary is enlarged and the prolactin (PRL) secreting cells increase in size and number. This PRL cell hyperplasia is associated with hyperprolactinemia. The aim of the present work was to investigate adenohypophysial vascularization and immunoexpression of vascular endothelial growth factor (VEGF) in pituitaries of pregnant and post-partum women and compare the results with age-matched adenohypophyses of nonpregnant women who had no endocrine diseases. DESIGN: Pituitaries (n=18) obtained by autopsy from female patients of reproductive age who had died during pregnancy, after abortion or during post-partum were immunostained for CD-34 and VEGF using the streptavidinbiotin- peroxidase complex method. RESULTS: The results showed that microvessel densities and VEGF immunoexpression in the adenohypophyses of pregnant and post-partum women were similar to those found in the control pituitaries. CONCLUSION: It can be concluded that pituitary enlargement and PRL cell hyperplasia in pregnant women may occur without neovascularization and increased VEGF immunoexpression. PMID- 23933699 TI - Euthyroid Graves' orbitopathy and incidental papillary thyroid microcarcinoma. AB - Euthyroid Graves' orbitopathy (GO) combined with incidental papillary thyroid microcarcinoma has rarely been reported. CASE REPORT: A 61-year-old Caucasian woman initially presented with progressive fatigue, exophthalmos, and thyroid function tests within normal limits. She underwent thyroidectomy, was found to have two incidental papillary thyroid microcarcinomas, and received radioactive iodine ablation to eliminate thyroid antigen. In addition to following her eye disease, TSH-receptor antibodies, thyroid stimulating immunoglobulins, and serum thyroglobulin measurements were recorded, demonstrating no evidence of thyroid cancer at four-year follow-up. At first, she had mild GO, developing into moderate-to-severe GO, and at 4 years she had Hertel measurements of 20 mm in both eyes. CONCLUSION: This report underscores the difficulty of managing GO even when thyroid function is normal(ized) and thyroid antigen exposure has been minimized. In addition, it illustrates why antithyroidal antibodies should be considered in cases of concomitant papillary thyroid cancer, as thyroid cells can be stimulated not only by TSH but also by TSH-receptor stimulating antibodies. PMID- 23933700 TI - A thymic carcinoid tumour causing Zollinger-Ellison and Cushing's syndromes due to ectopic ACTH and gastrin secretion. PMID- 23933701 TI - Acrodysostosis associated with hypercalcemia. AB - An 18-year-old man was admitted to the clinic complaining of deterioration in the function of his hands and feet. The clinical examination revealed that his movements were clumsy and that he had disproportionally short limbs. In addition, he also had facial abnormalities of frontal bossing, hypertelorism, maxillary hypoplasia, broad low nasal bridge, short upturned nose with anteverted nostrils and triangular mouth. All extremities appeared short with stubby fingers and toes and with broad hands and wrinkling of the dorsal skin. Chromosomal analysis showed a normal (46, XY) karyotype. X-ray studies revealed broad, short metacarpals and phalanges with cone-shaped epiphyses and brachycdactyly and a diagnosis of peripheral dysostosis was confirmed by the characteristic radiographic appearance of the hands. Serum calcium and alkaline phosphatase levels were high, parathormone (PTH) was low, but 25 (OH) Vitamin D, albumin, and 24 hour urine calcium levels were in the normal range. Based on these findings, a diagnosis of acrodysostosis associated with hypercalcemia was made. To the best of our knowledge, this represents the first description of this syndrome. PMID- 23933702 TI - Iodine-131 administration and risk of cancer: "appearances can be deceptive". PMID- 23933703 TI - More on the acute transient thyroid swelling following needle biopsy. PMID- 23933704 TI - Insights from simulations into the mechanism of human topoisomerase I: explanation for a seeming controversy in experiments. AB - Human topoisomerase-I is a vital enzyme involved in cellular regulation of DNA supercoiling. We extend our previous work on wild type enzyme [13] to study how different enzyme mutants with various parts of the protein clamped by disulfide mutations affect DNA rotation. Three different mutants have been simulated; they are clamped enzyme-DNA systems in which the disulfide bridge is formed by replacing His367 and Ala499, Gly365 and Ser534, and, respectively, Leu429 and Lys436 with Cys pairs. The first of these mutants, a 'distally clamped' enzyme, mimics the experimental study of Carey et al. [11], which reports DNA rotation within the clamped enzyme. The second one, a 'proximal clamp', mimics the study of Woo et al. [12], who do not observe DNA rotation. The third is a newly suggested mutant that clamps the hinge for protein opening; we use it to test a hypothesis on negative supercoil relaxation. Our simulations show that the helical domain alpha5 totally melts in relaxation of positive supercoils when the enzyme is proximally clamped, while it preserves its structure very well within the distally clamped one. Moreover, a distally clamped protein permits DNA rotations in both directions, while the proximal clamp allows rotations only for negatively supercoiled DNA. These observations reconcile the two seemingly contradictory experimental findings, suggesting that subtle changes in the location of the disulfide bridge alter the mechanism significantly. PMID- 23933705 TI - Anti-tumor activity of obinutuzumab and rituximab in a follicular lymphoma 3D model. AB - Follicular lymphomas (FLs) account for 35-40% of all adult lymphomas. Treatment typically involves chemotherapy combined with the anti-CD20 monoclonal antibody (MAb) rituximab (RTX). The development of the type II anti-CD20 MAb obinutuzumab (GA101) aims to further improve treatment. Here, using FL cells we show that RTX and GA101 display a similar activity on RL cells cultured in 2D. However, 2D culture cannot mimic tumor spatial organization and conventional 2D models may not reflect the effects of antibodies as they occur in vivo. Thus, we created a non-Hodgkin's lymphoma (NHL) 3D culture system, termed multicellular aggregates of lymphoma cells (MALC), and used it to compare RTX and GA101 activity. Our results show that both antibodies display greater activity towards FL cells in 3D culture compared with 2D culture. Moreover, we observed that in the 3D model GA101 was more effective than RTX both in inhibiting MALC growth through induction of (lysosomal) cell death and senescence and in inhibiting intracellular signaling pathways, such as mammalian target of rapamycin, Akt, PLCgamma (Phospholipase C gamma) and Syk. Altogether, our study demonstrates that spatial organization strongly influences the response to antibody treatment, supporting the use of 3D models for the testing of therapeutic agents in NHL. PMID- 23933706 TI - PSA-nadir at 1 year as a sound contemporary prognostic factor for low-dose-rate iodine-125 seeds brachytherapy. AB - OBJECTIVES: To identify predictors of outcomes in patients with localized prostate cancer treated with iodine-125 brachytherapy in a longitudinal uncontrolled study. METHODS: Between 2000 and 2011, 560 histologically confirmed patients were treated with brachytherapy of whom 305 with >=24-month follow-up and localized tumor were evaluated after exclusion of those locally advanced and under androgen ablation. RESULTS: Patients' mean age was 63.93 years (44-88), mean pretreatment prostate-specific antigen (PSA) was 6.34 ng/mL (0.67-33.09), overall median follow-up was 75.35 months (24-158.37), biochemical recurrence occurred in 17 patients (5.57 %), cancer-specific survival was 100 %, and overall survival was 98.03 %. At multivariate analyses, only PSA-nadir at 1 year and age were related to disease-free survival: To each unit of PSA-nadir, the risk increases 87.3 %-OR 1.87 (p < 0.001; 95 % CI 1.31-2.67), and risk was 4.7 times higher for those under 50 years (vs. >70)-OR 4.69 (p = 0.04; 95 % CI 1.39-18.47). Best cutoff for PSA-nadir at one year was 0.285 (AUC = 0.78; p < 0.001; 95 % CI 0.68-0.89). Kaplan-Meier analysis confirmed PSA-nadir (p < 0.001) as prognostic, while D'Amico's classification failed (p = 0.24). No grade 3 or 4 complication was reported, and only 31.4 % of patients had grade 2 urinary or rectal toxicity. PSA bounce >=0.4 ng/mL occurred in 18.4 % with no impact on biochemical recurrence. CONCLUSIONS: Half (50.49 %) of patients in the scenario of localized prostate cancer treated with iodine-125 brachytherapy reach PSA-nadir at 1 year <0.285, recognized as a key independent prognostic factor. PMID- 23933707 TI - Controlling periodontal bone levels with multiple LED irradiations. AB - Because a single exposure to light-emitting diode (LED) irradiation at 660 nm only demonstrated a 3-day biostimulatory effect in recovering periodontal bone level (PBL), this study sought to evaluate whether the periodontal effect could be extended through the use of multiple LED irradiations. Experimental periodontitis was developed unilaterally in 48 Sprague-Dawley rats after the placement of a silk ligature plus Porphyromonas gingivalis lipopolysaccharide injections. The animals were divided into four groups (no irradiation, a single irradiation, or two or three irradiations per week) and exposed to LED light irradiation at a wavelength of 660 +/- 25 nm and energy density of 10 J/cm(2) after debridement and detoxification. The animals were euthanized after 7 or 14 days, and the effect of irradiation was evaluated using micro-computed tomography and histology. By day 7, PBL was significantly reduced (p < 0.05), with significantly reduced inflammation (p < 0.05) and gingival hyperplasia (p < 0.001), in the animals receiving three irradiations per week. At day 14, the reduction in gingival hyperplasia was still significant (p < 0.05), and collagen matrix deposition and realignment appeared to be accelerated in the animals receiving three irradiations per week, despite a lack of significant difference in PBL. The treatment regimen receiving three LED light irradiations per week apparently extended the effects in reducing PBL and inflammation to 7 days. The inclusion of additional inflammation control measures or the addition of bioactive signals to mediate the repairing process is necessary to maintain long term periodontal stability. PMID- 23933708 TI - [Perspectives for development of German urology]. PMID- 23933709 TI - [Urological moulages: forgotten three-dimensional documents between university collections and panopticum -- a dying presentation form even in urological museology]. AB - The use of wax models traces its roots back to antiquity and appears to have reached the peak of perfection in the eighteenth century especially in Italy. From the beginning of the nineteenth century wax models and moulages were used in the new medical specialties, such as dermatology or urology depending on a new model of visualization in natural sciences. The moulage passed from local use into international acceptance with the institutionalization of the medical specialties and increase in scientific communication in the second half of the nineteenth century. By the 1970s moulages had all but lost their pre-eminent position as teaching and visual aids to depict dermatological and venereal diseases Unfortunately urology was not mentioned in the field of history of medicine or ethnic studies. PMID- 23933710 TI - [Ferdinand Eisenberger research scholarships 2013]. PMID- 23933716 TI - On translation of antibody drug conjugates efficacy from mouse experimental tumors to the clinic: a PK/PD approach. AB - Objectives of the present investigation were: (1) to compare three literature reported tumor growth inhibition (TGI) pharmacodynamic (PD) models and propose an optimal new model that best describes the xenograft TGI data for antibody drug conjugates (ADC), (2) to translate efficacy of the ADC Trastuzumab-emtansine (T DM1) from mice to patients using the optimized PD model, and (3) to apply the translational strategy to predict clinically efficacious concentrations of a novel in-house anti-5T4 ADC, A1mcMMAF. First, the performance of all four of the PD models (i.e. 3 literature reported + 1 proposed) was evaluated using TGI data of T-DM1 obtained from four different xenografts. Based on the estimates of the pharmacodynamic/pharmacokinetic (PK/PD) modeling, a secondary parameter representing the efficacy index of the drug was calculated, which is termed as the tumor static concentration (TSC). TSC values derived from all four of the models were compared with each other, and with literature reported values, to assess the performance of these models. Subsequently, using the optimized PK/PD model, PD parameters obtained from different cell lines, human PK, and the proposed translational strategy, clinically efficacious doses of T-DM1 were projected. The accuracy of projected efficacious dose range for T-DM1 was verified by comparison with the clinical doses. Aforementioned strategy was then applied to A1mcMMAF for projecting its efficacious concentrations in clinic. TSC values for A1mcMMAF, obtained by fitting TGI data from 4 different xenografts with the proposed PK/PD model, were estimated to range from 0.6 to 11.5 MUg mL-1. Accordingly, the clinically efficacious doses for A1mcMMAF were projected retrospectively. All in all, the improved PD model and proposed translational strategy presented here suggest that appropriate correction for the clinical exposure and employing the TSC criterion can help translate mouse TGI data to predict first in human doses of ADCs. PMID- 23933717 TI - The spectrum of congenital heart disease and outcomes after surgical repair among children with Turner syndrome: a single-center review. AB - Turner syndrome (TS), a genetic abnormality affecting 1 in 2,500 people, is commonly associated with congenital heart disease (CHD). However, the surgical outcomes for TS patients have not been well described. This study reviewed the spectrum of CHD in TS at the authors' center. The authors report outcomes after coarctation of the aorta (CoA) repair or staged palliation of hypoplastic left heart syndrome (HLHS) and then compare the surgical outcomes with those of non-TS patients undergoing like repair. This retrospective chart review was conducted at the Children's Hospital of Wisconsin from 1999 to 2011. Of the 173 patients with TS, 77 (44.5 %) were found to have CHD. Left-sided obstructive lesions were the most common. However, the spectrum of CHD was wide and included systemic and pulmonary venous abnormalities as well as abnormalities of the coronary arteries. In the comparative analysis of CoA repair, the TS patients younger than 60 days had longer aortic cross-clamp times (24 vs. 16 min; p = 0.001) and longer hospital stays (12 vs. 6 days; p <= 0.0001) than the non-TS patients. At the follow-up assessment after 8.8 +/- 9.1 years, 17 % of the TS patients had hypertension, but no patient had required reintervention, and no deaths had occurred. Finally, three of the four TS patients with HLHS died within the first year. The spectrum of CHD within TS is wide and not limited to bicuspid aortic valve or CoA. Additionally, patients with TS undergoing CoA repair may have a more challenging early postoperative course but experience outcomes similar to those of non-TS patients. Finally, patients who have TS combined with HLHS remain a challenging population with generally poor survival. PMID- 23933719 TI - Antifungal activity of ZnO nanoparticles and their interactive effect with a biocontrol bacterium on growth antagonism of the plant pathogen Fusarium graminearum. AB - Fungal plant pathogens such as Fusarium graminearum cause severe global economic losses in cereals crops, and current control measures are limited. This work addresses the potential for ZnO nanoparticles (NPs) and biocontrol bacteria to be used in plant fungal control strategies. Growth of F. graminearum was significantly (p = 0.05) inhibited by inclusion of the NPs in a mung bean broth agar and in sand. Suspension in mung bean broth medium modified the surface charge, dissolution, and aggregation state of the ZnO NPs, in comparison to processes occurring in water suspension. The ZnO NPs were significantly more inhibitory to fungal growth than micro-sized particles of ZnO, although both types of particles released similar levels of soluble Zn, indicating size dependent toxicity of the particles. Zn ions produced dose-dependent inhibition, noticeable at the level of soluble Zn released from NPs after seven-day suspension in medium; inhibitory levels caused acidification of the growth medium. Transfer of fungal inoculum after exposure to the ZnO NPs to fresh medium did not indicate adaptation to the stress because growth was still inhibited by the NPs. The ZnO NPs did not prevent metabolites from a biocontrol bacterium, Pseudomonas chlororaphis O6, from inhibiting Fusarium growth: no synergism was observed in the mung bean agar. Because other studies find that soil amendment with ZnO NPs required high doses for inhibition of plant growth, the findings of pathogen growth control reported in this paper open the possibility of using ZnO NP-based formulations to complement existing strategies for improving crop health in field settings. PMID- 23933718 TI - Can the "seek, test, treat, and retain" strategy be effective in France? PMID- 23933720 TI - Occult hepatitis B virus infection in Korean patients with isolated anti-HBc. AB - Serological detection of isolated anti-hepatitis B core antibody (anti-HBc) can occur in various scenarios, but the most clinically relevant situation is occult hepatitis B virus (HBV) infection (OBI). The purpose of this study was to evaluate the prevalence and clinical relevance of isolated anti-HBc and of OBI with isolated anti-HBc from an unselected hospital population. A total of 14,253 patients referred for hepatitis B surface antigen (HBsAg)/anti-HBs testing were classified into either the Health Promotion Center (HPC) group or the patient group. For patients who were negative for both HBsAg and anti-HBs, an anti-HBc test was additionally performed. An HBV DNA real-time PCR test was performed on isolated anti-HBc patients, and their demographic and clinical data were reviewed. The measured prevalence of isolated anti-HBc and OBI in isolated anti HBc patients was 5.9 % and 4.7 %, respectively. Prevalence was higher in males, elderly people, and the patient group than in females, the younger, and the HPC group, respectively. In most cases, the levels of HBV DNA load were very low (less than 200 IU/mL), and most cases of OBI presented without liver disease or history of HBV infection. The prevalence of isolated anti-HBc and OBI are affected by the methods of detection, subject population, and constituent factors such as sex and age. Although detection of HBV DNA does not always indicate infectivity, highly sensitive standardized HBV DNA tests are needed in clinical settings to exclude the possibility of OBI, especially in the advanced age group. PMID- 23933721 TI - Dinosaur energetics: setting the bounds on feasible physiologies and ecologies. AB - The metabolic status of dinosaurs has long been debated but remains unresolved as no consistent picture has emerged from a range of anatomical and isotopic evidence. Quantitative analysis of dinosaur energetics, based on general principles applicable to all vertebrates, shows that many features of dinosaur lifestyle are compatible with a physiology similar to that of extant lizards, scaled up to dinosaur body masses and temperatures. The analysis suggests that sufficient metabolic scope would have been available to support observed dinosaur growth rates and allow considerable locomotor activity, perhaps even migration. Since at least one dinosaur lineage evolved true endothermy, this study emphasizes there was no single dinosaur physiology. Many small theropods were insulated with feathers and appear to have been partial or full endotherms. Uninsulated small taxa, and all juveniles, presumably would have been ectothermic, with consequent diurnal and seasonal variations in body temperature. In larger taxa, inertial homeothermy would have resulted in warm and stable body temperatures but with a basal metabolism significantly below that of extant mammals or birds of the same size. It would appear that dinosaurs exhibited a range of metabolic levels to match the broad spectrum of ecological niches they occupied. PMID- 23933722 TI - Energy landscapes shape animal movement ecology. AB - The metabolic costs of animal movement have been studied extensively under laboratory conditions, although frequently these are a poor approximation of the costs of operating in the natural, heterogeneous environment. Construction of "energy landscapes," which relate animal locality to the cost of transport, can clarify whether, to what extent, and how movement properties are attributable to environmental heterogeneity. Although behavioral responses to aspects of the energy landscape are well documented in some fields (notably, the selection of tailwinds by aerial migrants) and scales (typically large), the principles of the energy landscape extend across habitat types and spatial scales. We provide a brief synthesis of the mechanisms by which environmentally driven changes in the cost of transport can modulate the behavioral ecology of animal movement in different media, develop example cost functions for movement in heterogeneous environments, present methods for visualizing these energy landscapes, and derive specific predictions of expected outcomes from individual- to population- and species-level processes. Animals modulate a suite of movement parameters (e.g., route, speed, timing of movement, and tortuosity) in relation to the energy landscape, with the nature of their response being related to the energy savings available. Overall, variation in movement costs influences the quality of habitat patches and causes nonrandom movement of individuals between them. This can provide spatial and/or temporal structure to a range of population- and species level processes, ultimately including gene flow. Advances in animal-attached technology and geographic information systems are opening up new avenues for measuring and mapping energy landscapes that are likely to provide new insight into their influence in animal ecology. PMID- 23933723 TI - When unreliable cues are good enough. AB - In many species, nongenetic phenotypic variation helps mitigate risk associated with an uncertain environment. In some cases, developmental cues can be used to match phenotype to environment-a strategy known as predictive plasticity. When environmental conditions are entirely unpredictable, generating random phenotypic diversity may improve the long-term success of a lineage-a strategy known as diversified bet hedging. When partially reliable information is available, a well adapted developmental strategy may strike a balance between the two strategies. We use information theory to analyze a model of development in an uncertain environment, where cue reliability is affected by variation both within and between generations. We show that within-generation variation in cues decreases the reliability of cues without affecting their fitness value. This transpires because the optimal balance of predictive plasticity and diversified bet hedging is unchanged. However, within-generation variation in cues does change the developmental mechanisms used to create that balance: developmental sensitivity to such cues not only helps match phenotype to environment but also creates phenotypic diversity that may be useful for hedging bets against environmental change. Understanding the adaptive role of developmental sensitivity thus depends on a proper assessment of both the predictive power and the structure of variation in environmental cues. PMID- 23933724 TI - Spatially explicit conditions for waterborne pathogen invasion. AB - Waterborne pathogens cause many possibly lethal human diseases. We derive the condition for pathogen invasion and subsequent disease outbreak in a territory with specific, space-inhomogeneous characteristics (hydrological, ecological, demographic, and epidemiological). The criterion relies on a spatially explicit model accounting for the density of susceptible and infected individuals and the pathogen concentration in a network of communities linked by human mobility and the water system. Pathogen invasion requires that a dimensionless parameter, the dominant eigenvalue of a generalized reproductive matrix J0, be larger than unity. Conditions for invasion are studied while crucial parameters (population density distribution, contact and water contamination rates, pathogen growth rates) and the characteristics of the networks (connectivity, directional transport, water retention times, mobility patterns) are varied. We analyze both simple, prototypical test cases and realistic landscapes, in which optimal channel networks mimic the water systems and gravitational models describe human mobility. Also, we show that the dominant eigenvector of J0 effectively portrays the geography of epidemic outbreaks, that is, the areas of the studied territory that will be initially affected by an epidemic. This is important for planning an efficient spatial allocation of interventions (e.g., improving sanitation and providing emergency aid and medicines). PMID- 23933725 TI - The relative importance of predation risk and water temperature in maintaining Bergmann's rule in a marine ectotherm. AB - Bergmann's rule-an increase in body size with latitude-correlates with latitudinal declines in ambient temperature and predation risk, but relatively few studies simultaneously explore the relative importance of these factors. Along temperate Atlantic shorelines, the isopod Idotea balthica from high latitudes are 53% longer on average than isopods from low latitudes. When reared at 6 degrees -24 degrees C, juveniles increased growth and development rates with temperature. Because the increase in growth rate with temperature outstripped increases in development rate, female size at maturity increased with temperature. This thermal sensitivity of growth cannot account for the latitudinal pattern in body size. Within temperature treatments, females from low latitudes reached sexual maturity at younger ages and at a smaller size than did females from higher latitudes. This shift in life-history strategy is predicted by latitudinal declines in predation pressure, which we tested using field tethering experiments. Overall, isopods at low latitudes had a 44% greater mortality risk from daytime predators relative to isopods at higher latitudes. We conclude that a latitudinal gradient in predation risk, not temperature, is principally responsible for Bergmann's rule in I. balthica. Increases in body size during future warming of oceans may be constrained by local patterns of predation risk. PMID- 23933726 TI - Adaptive phenotypic diversification along a temperature-depth gradient. AB - Theoretical models suggest that sympatric speciation along environmental gradients might be common in nature. Here we present the first data-based model of evolutionary diversification along a continuous environmental gradient. On the basis of genetic analyses, it has been suggested that a pair of coregonid fishes (Coregonus spp.) in a postglacial German lake originated by sympatric speciation. Within this lake, the two species segregate vertically and show metabolic adaptations to, as well as behavioral preferences for, correspondingly different temperatures. We test the plausibility of the hypothesis that this diversifying process has been driven by adaptations to different thermal microhabitats along the lake's temperature-depth gradient. Using an adaptive-dynamics model that is calibrated with empirical data and allows the gradual evolution of a quantitative trait describing optimal foraging temperature, we show that under the specific environmental conditions in the lake, evolutionary branching of a hypothetical ancestral population into two distinct phenotypes may have occurred. We also show that the resultant evolutionary diversification yields two stably coexisting populations with trait values and depth distributions that are in agreement with those currently observed in the lake. We conclude that divergent thermal adaptations along the temperature-depth gradient might have brought about the two species observed today. PMID- 23933727 TI - Cohort dynamics give rise to alternative stable community states. AB - Many ecological systems can exhibit alternative stable states (ASS), which implies that ecological communities may diverge depending on their initial state, despite identical environmental conditions. Here we present a new mechanism that can cause ASS in competition systems. Using a physiologically structured model of competing populations, representing Baltic Sea sprat and herring and their resources, we show how cohort-driven population cycles may result in priority effects leading to ASS. Similar mechanisms could, depending on mortality level, also result in a "resident strikes back" phenomenon. We argue that the prerequisites for the occurrence of ASS in our model system, that is, communities with competing populations exhibiting cohort cycles and variation in size at maturation, may be common in ecological systems. PMID- 23933728 TI - Synchronized dynamics of Tipula paludosa metapopulation in a southwestern Scotland agroecosystem: linking pattern to process. AB - Synchronization of population fluctuations at disjoint habitats has been observed in many studies, but its mechanisms often remain obscure. Synchronization may appear as a result of either interhabitat dispersal or regionally correlated environmental stochastic factors, the latter being known as the Moran effect. In this article, we consider the population dynamics of a common agricultural pest insect, Tipula paludosa, on a fragmented habitat by analyzing data derived from a multiannual survey of its abundance in 38 agricultural fields in southwestern Scotland. We use cross-correlation coefficients and show that there is a considerable synchronization between different populations across the whole area. The correlation strength exhibits an intermittent behavior, such that close populations can be virtually uncorrelated, but populations separated by distances up to approximately 150 km can have a cross-correlation coefficient close to one. To distinguish between the effects of stochasticity and dispersal, we then calculate a time-lagged cross-correlation coefficient and show that it possesses considerably different properties to the nonlagged one. In particular, the time lagged correlation coefficient shows a clear directional dependence. The distribution of the time-lagged correlations with respect to the bearing between the populations has a striking similarity to the distribution of wind velocities, which we regard as evidence of long-distance wind-assisted dispersal. PMID- 23933729 TI - The contributions of premating and postmating selection episodes to total selection in sex-role-reversed Gulf pipefish. AB - Empirical studies of sexual selection often focus on events occurring either before or after mating but rarely both and consequently may fail to discern the relative magnitudes and interactions of premating and postmating episodes of selection. Here, we simultaneously quantify premating and postmating selection in the sex-role-reversed Gulf pipefish by using a microsatellite-based analysis of parentage in experimental populations. Female pipefish exhibited an opportunity for selection (I) of 1.64, which was higher than that of males (0.35). Decompositions of I and the selection differential on body size showed that over 95% of the selection on females arose from the premating phase. We also found evidence for a trade-off between selection phases, where multiply mating females had significantly lower offspring survivorship compared to singly mated females. In males, variance in relative fitness arose mainly from the number of eggs received per copulation and a small number of males who failed to mate. Overall, our study exemplifies a general approach for the decomposition of total selection into premating and postmating phases to understand the interplay among components of natural and sexual selection that conspire to shape sexually selected traits. PMID- 23933730 TI - Quantifying behavioral changes in territorial animals caused by sudden population declines. AB - Although territorial animals are able to maintain exclusive use of certain regions of space, movement data from neighboring individuals often suggest overlapping home ranges. To explain and unify these two aspects of animal space use, we use recently developed mechanistic models of collective animal movement. We apply our approach to a natural experiment on an urban red fox (Vulpes vulpes) population that underwent a rapid decline in population density due to a sarcoptic mange epizooty. By extracting details of movement and interaction strategies from location data, we show how foxes alter their behavior, taking advantage of sudden population-level changes by acquiring areas vacated due to neighbor mortality, while ensuring territory boundaries remain contiguous. The rate of territory border movement increased eightfold as the population declined and the foxes' response time to neighboring scent reduced by a third. By demonstrating how observed, fluctuating territorial patterns emerge from movements and interactions of individual animals, our results give the first data validated, mechanistic explanation of the elastic disc hypothesis, proposed nearly 80 years ago. PMID- 23933731 TI - Speciation rates decline through time in individual-based models of speciation and extinction. AB - A well-documented pattern in the fossil record is a long-term decline in the origination rate of new taxa after diversity rebounds from a mass extinction. The mechanisms for this pattern remain elusive. In this article, we investigate the macroevolutionary predictions of an individual-based birth-death model (BDI model) where speciation and extinction rates emerge from population dynamics. We start with the simplest neutral model in which every individual has the same per capita rates of birth, death, and speciation. Although the prediction of the simplest neutral model agrees qualitatively with the fossil pattern, the predicted decline in per-species speciation rates is too fast to explain the long term trend in fossil data. We thus consider models with variation among species in per capita rates of speciation and a suite of alternative assumptions about the heritability of speciation rate. The results show that interspecific variation in per capita speciation rate can induce differences among species in their ability to resist extinction because a low speciation rate confers a small but important demographic advantage. As a consequence, the model predicts an appropriately slow temporal decline in speciation rates, which provides a mechanistic explanation for the fossil pattern. PMID- 23933732 TI - Nearest-neighbor interactions, habitat fragmentation, and the persistence of host pathogen systems. AB - Spatial interactions are known to promote stability and persistence in enemy victim interactions if instability and extinction occur in well-mixed settings. We investigate the effect of spatial interactions in the opposite case, where populations can persist in well-mixed systems. A stochastic agent-based model of host-pathogen dynamics is considered that describes nearest-neighbor interactions in an undivided habitat. Contrary to previous notions, we find that in this setting, spatial interactions in fact promote extinction. The reason is that, in contrast to the mass-action system, the outcome of the nearest-neighbor model is governed by dynamics in small "local neighborhoods." This is an abstraction that describes interactions in a minimal grid consisting of an individual plus its nearest neighbors. The small size of this characteristic scale accounts for the higher extinction probabilities. Hence, nearest-neighbor interactions in a continuous habitat lead to outcomes reminiscent of a fragmented habitat, which is underlined further with a metapopulation model that explicitly assumes habitat fragmentation. Beyond host-pathogen dynamics, axiomatic modeling shows that our results hold for generic enemy-victim interactions under specified assumptions. These results are used to interpret a set of published experiments that provide a first step toward model testing and are discussed in the context of the literature. PMID- 23933733 TI - Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects. AB - The importance of mitochondrial fatty acid beta-oxidation (FAO) as a glucose sparing process is illustrated by patients with inherited defects in FAO, who may present with life-threatening fasting-induced hypoketotic hypoglycemia. It is unknown why peripheral glucose demand outpaces hepatic gluconeogenesis in these patients. In this study, we have systematically addressed the fasting response in long-chain acyl-CoA dehydrogenase-deficient (LCAD KO) mice. We demonstrate that the fasting-induced hypoglycemia in LCAD KO mice was initiated by an increased glucose requirement in peripheral tissues, leading to rapid hepatic glycogen depletion. Gluconeogenesis did not compensate for the increased glucose demand, which was not due to insufficient hepatic glucogenic capacity but rather caused by a shortage in the supply of glucogenic precursors. This shortage in supply was explained by a suppressed glucose-alanine cycle, decreased branched-chain amino acid metabolism and ultimately impaired protein mobilization. We conclude that during fasting, FAO not only serves to spare glucose but is also indispensable for amino acid metabolism, which is essential for the maintenance of adequate glucose production. PMID- 23933734 TI - Depletion of extracellular signal-regulated kinase 1 in mice with cardiomyopathy caused by lamin A/C gene mutation partially prevents pathology before isoenzyme activation. AB - Mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins cause dilated cardiomyopathy with variable muscular dystrophy. These mutations enhance mitogen-activated protein kinase signaling in the heart and pharmacological inhibition of extracellular signal-regulated kinase (ERK) 1 and 2 improves cardiac function in Lmna(H222P/H222P) mice. In the current study, we crossed mice lacking ERK1 to Lmna(H222P/H222P) mice and examined cardiac performance and survival. Male Lmna(H222P/H222P)/Erk1(-/-) mice lacking ERK1 had smaller left ventricular end systolic diameters and increased fractional shortening (FS) at 16 weeks of age than Lmna(H222P/H222P/)Erk1(+/+) mice. Their mean survival was also significantly longer. However, the improved cardiac function was abrogated at 20 weeks of age concurrent with an increased activity of ERK2. Lmna(H222P/H222P)/Erk1(-/-) mice treated with an inhibitor of ERK1/2 activation had smaller left ventricular diameters and increased FS at 20 weeks of age. These results provide genetic evidence that ERK1 and ERK2 contribute to the development of cardiomyopathy caused by LMNA mutations and reveal interplay between these isoenzymes in maintaining a combined pathological activity in heart. PMID- 23933735 TI - Congenital myopathy is caused by mutation of HACD1. AB - Congenital myopathies are heterogeneous inherited diseases of muscle characterized by a range of distinctive histologic abnormalities. We have studied a consanguineous family with congenital myopathy. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous non-sense mutation in 3 hydroxyacyl-CoA dehydratase 1 (HACD1) in affected individuals. The mutation results in non-sense mediated decay of the HACD1 mRNA to 31% of control levels in patient muscle and completely abrogates the enzymatic activity of dehydration of 3-hydroxyacyl-CoA, the third step in the elongation of very long-chain fatty acids (VLCFAs). We describe clinical findings correlated with a deleterious mutation in a gene not previously known to be associated with congenital myopathy in humans. We suggest that the mutation in the HACD1 gene causes a reduction in the synthesis of VLCFAs, which are components of membrane lipids and participants in physiological processes, leading to congenital myopathy. These data indicate that HACD1 is necessary for muscle function. PMID- 23933736 TI - Myc inhibition impairs autophagosome formation. AB - Autophagy, a major clearance route for many long-lived proteins and organelles, has long been implicated in cancer development. Myc is a proto-oncogene often found to be deregulated in many cancers, and thus is an attractive target for design of cancer therapy. Therefore, understanding the relationship between anti Myc strategies and autophagy will be important for development of effective therapy. Here, we show that Myc depletion inhibits autophagosome formation and impairs clearance of autophagy substrates. Myc suppression has an inhibitory effect on autophagy via reduction of c-Jun N-terminal kinase 1 (JNK1) and B-cell lymphoma 2 (Bcl2) phosphorylation. Additionally, the decrease in JNK1 phosphorylation observed with Myc knockdown is associated with a reduction in ROS production. Our data suggest that targeting Myc in cancer therapy might have the additional benefit of inhibiting autophagy in the case of therapy resistance associated with chemotherapy-induced autophagy. PMID- 23933737 TI - Genome-wide association study identifies ZFHX1B as a susceptibility locus for severe myopia. AB - Severe myopia (defined as spherical equivalent < -6.0 D) is a predominant problem in Asian countries, resulting in substantial morbidity. We performed a meta analysis of four genome-wide association studies (GWAS), all of East Asian descent totaling 1603 cases and 3427 controls. Two single nucleotide polymorphisms (SNPs) (rs13382811 from ZFHX1B [encoding for ZEB2] and rs6469937 from SNTB1) showed highly suggestive evidence of association with disease (P < 1 * 10(-7)) and were brought forward for replication analysis in a further 1241 severe myopia cases and 3559 controls from a further three independent sample collections. Significant evidence of replication was observed, and both SNP markers surpassed the formal threshold for genome-wide significance upon meta analysis of both discovery and replication stages (P = 5.79 * 10(-10), per-allele odds ratio (OR) = 1.26 for rs13382811 and P = 2.01 * 10(-9), per-allele OR = 0.79 for rs6469937). The observation at SNTB1 is confirmatory of a very recent GWAS on severe myopia. Both genes were expressed in the human retina, sclera, as well as the retinal pigmented epithelium. In an experimental mouse model for myopia, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for Zfhx1b and Sntb1. These new data advance our understanding of the molecular pathogenesis of severe myopia. PMID- 23933738 TI - Length-dependent CTG.CAG triplet-repeat expansion in myotonic dystrophy patient derived induced pluripotent stem cells. AB - Myotonic dystrophy type 1 (DM1) is an inherited dominant muscular dystrophy caused by expanded CTG.CAG triplet repeats in the 3' untranslated region of the DMPK1 gene, which produces a toxic gain-of-function CUG RNA. It has been shown that the severity of disease symptoms, age of onset and progression are related to the length of the triplet repeats. However, the mechanism(s) of CTG.CAG triplet-repeat instability is not fully understood. Herein, induced pluripotent stem cells (iPSCs) were generated from DM1 and Huntington's disease patient fibroblasts. We isolated 41 iPSC clones from DM1 fibroblasts, all showing different CTG.CAG repeat lengths, thus demonstrating somatic instability within the initial fibroblast population. During propagation of the iPSCs, the repeats expanded in a manner analogous to the expansion seen in somatic cells from DM1 patients. The correlation between repeat length and expansion rate identified the interval between 57 and 126 repeats as being an important length threshold where expansion rates dramatically increased. Moreover, longer repeats showed faster triplet-repeat expansion. However, the overall tendency of triplet repeats to expand ceased on differentiation into differentiated embryoid body or neurospheres. The mismatch repair components MSH2, MSH3 and MSH6 were highly expressed in iPSCs compared with fibroblasts, and only occupied the DMPK1 gene harboring longer CTG.CAG triplet repeats. In addition, shRNA silencing of MSH2 impeded CTG.CAG triplet-repeat expansion. The information gained from these studies provides new insight into a general mechanism of triplet-repeat expansion in iPSCs. PMID- 23933739 TI - Neck weakness is a potent prognostic factor in sporadic amyotrophic lateral sclerosis patients. AB - OBJECTIVE: To clarify the emergence of muscle weakness in regions of the body that affect survival, and deterioration in activities of daily living (ADL) in amyotrophic lateral sclerosis (ALS) patients. METHODS: We conducted a multicentre based prospective cohort study of patients with ALS. We enrolled 401 sporadic patients with ALS. Death or the introduction of invasive ventilation was defined as the primary endpoint, and the time to five clinical markers of ADL deterioration associated with bulbar paralysis or limb weakness were defined as ADL milestones. Muscle weakness was assessed in the neck flexor muscles; the bilateral abductors of the shoulders; the bilateral wrist extensor muscles; the bilateral flexor muscles of the hips; and the bilateral ankle dorsiflexion muscles. We performed Cox proportional hazards regression analyses for the primary endpoint and the five ADL milestones, adjusting for known covariate prognostic factors for ALS. RESULTS: The Medical Research Council (MRC) score for the neck flexors was the most significant prognostic factor for the primary endpoint (HR 0.74, p<0.001), loss of speech (HR 0.66, p<0.001), and loss of swallowing function (HR 0.73, p<0.001), and was one of the significant prognostic factors for loss of upper limb function, difficulty turning in bed, and loss of walking ability (p=0.001, 0.002, and 0.008, respectively). The MRC score for the neck flexors was also a significant prognostic factor for covariates of the previously reported prognostic factors. CONCLUSIONS: Neck weakness is an independent prognostic factor for survival and deterioration in ADL in Patients with ALS. PMID- 23933740 TI - Association of silent lacunar infarct with brain atrophy and cognitive impairment. AB - OBJECTIVE: Silent lacunar infarct (SLI) is associated with cognitive decline and linked to an increased risk of stroke and dementia. We examined the association of SLI with MRI measures of cortical thickness, subcortical and lateral ventricular shapes and cognition in 285 ethnic Chinese elderly. METHODS: SLI, cortical thickness, shapes of subcortical and ventricular structures were quantified using MRI. The cognitive performance was assessed using comprehensive neuropsychological tests. Linear regression was used to examine associations among SLI, brain measures and cognition. RESULTS: SLI was associated with atrophy in multiple subcortical structures, ventricular enlargement and widespread cortical thinning. Both SLI and atrophy were independently related to poorer performance in attention, memory and language domains. Only SLI was associated with visuomotor speed and executive function, while atrophy mediated the association between SLI and visuoconstruction. CONCLUSIONS: Our findings support a vascular contribution to neurodegeneration and cognitive impairment. PMID- 23933741 TI - Impaired perfusion modifies the relationship between blood pressure and stroke risk in major cerebral artery disease. AB - OBJECTIVE: Blood pressure (BP) lowering may increase stroke risk in patients with symptomatic major cerebral artery disease and impaired perfusion. To investigate the relationships among BP, impaired perfusion and stroke risk. METHODS: We retrospectively analysed data from 130 non-disabled, medically treated patients with either symptomatic extracranial carotid occlusion or intracranial stenosis or occlusion of the carotid artery or middle cerebral arteries. All patients had baseline haemodynamic measurements with (15)O-gas positron emission tomography and were followed for 2 years or until stroke recurrence or death. RESULTS: There was a negative linear relationship between systolic BP (SBP) and risk of stroke in the territory of the diseased artery. The 2-year incidence of ischaemic stroke in the territory in patients with normal SBP (<130 mm Hg, 5/32 patients) was significantly higher than in patients with high SBP (2/98, p<0.005). Multivariate analysis revealed that normal SBP and impaired perfusion were independently associated with increased risk of stroke in the previously affected territory, while risk of stroke elsewhere was positively correlated with SBP. Overall, high total stroke risk was observed at lower BP in patients with impaired perfusion and at higher BPs in patients without (interaction, p<0.01). Overall, the relationship between SBP and total stroke recurrence was J-shaped. CONCLUSIONS: Impaired perfusion modified the relationship between blood pressure and stroke risk, although this study had limitations including the retrospective analysis, the potentially biased sample, the small number of critical events and the fact that BP was measured only as a snapshot in clinic. PMID- 23933742 TI - Acid-base and electrochemical properties of manganese meso(ortho- and meta-N ethylpyridyl)porphyrins: voltammetric and chronocoulometric study of protolytic and redox equilibria. AB - Growing interest in redox-active compounds as therapeutics for oxidative stress related diseases led to the design of metalloporphyrins as some of the most potent functional SOD-mimics. Herein we report a detailed electrochemical study of the protolytic and redox equilibria of manganese ortho and meta substituted N ethylpyridyl porphyrins (MnPs), MnTE-2-PyP(5+) and MnTE-3-PyP(5+), in aqueous solutions. The electrochemical parameters of redox processes for all experimentally available species have been determined, as well as their diffusion coefficients and estimated sizes of aqueous cavities. The results indicate that possible changes of the intracellular acidity cannot affect the antioxidant activity of MnPs in vivo, since no change in the E(Mn(III)P/Mn(II)P) values was observed below pH 10. Furthermore, the results confirm that both of these MnPs can be efficient redox scavengers of peroxynitrite (ONOO(-)), another major damaging species in vivo. This can occur by either single-electron reduction or two-electron reduction of ONOO(-), involving either the Mn(IV)P/Mn(III)P redox couple or Mn(IV)P/Mn(II)P redox couple. In addition to kred(ONOO(-)) reported previously, the thermodynamic parameters calculated herein imply a strong and identical driving force for the reaction of both ortho and meta isomeric MnPs with ONOO(-). An enlargement of both Mn(III)P complexes upon an increase of the solution pH was also observed and attributed to the reduction of positive charge on the central ion caused by deprotonation of the axial water molecules. This expansion of aqueous cavities suggests the formation of a solvent cage and the increased lipophilicity of Mn(III)P complexes caused by increased electron density on the Mn ion. PMID- 23933743 TI - Stress response of some lactic acid bacteria isolated from Romanian artisan dairy products. AB - Understanding the mechanisms of stress response and adaptation to stress in the case of lactic acid bacteria (LAB), especially in the case of strains with functional properties, is very important when such strains are potential candidates for starter cultures or probiotics. In this context, our study shows the response of some LAB [four exopolysaccharide (EPS)-producing strains and one strain with potential probiotic effect] to the stresses induced by low and high incubation temperatures, acidity, NaCl, and bile salts, often encountered during the technological processes in food or during the passage through the human gastro-intestinal tract. The strains were able to grow at temperatures up to 40 degrees C (the mesophilic strains) and 47 degrees C (the thermophilic strain), in medium with an initial pH of at least 4.0 (Lactobacillus acidophilus IBB801), or in the presence of NaCl up to 10% (Weissella confusa/cibaria 38.2), or bile salts up to 0.2% (L. acidophilus IBB801). The protein and isoenzyme patterns of the strains subjected to various stress conditions presented several differences compared with the control patterns, among which the overexpression of some proteins of about 50-60 kDa, differences in the bands intensity in the case of the intracellular enzymes, or the complete loss of some of these bands. The best survival to low pH values and high temperatures was observed for strain L. acidophilus IBB801, the candidate probiotic strain. The EPS production of the four tested strains was, in general, directly related to the growth, the highest yields being obtained when strains were incubated at 24 degrees C. PMID- 23933744 TI - Dietary probiotic supplementation (Shewanella putrefaciens Pdp11) modulates gut microbiota and promotes growth and condition in Senegalese sole larviculture. AB - Probiotic supplementation in fish aquaculture has significantly increased in the last decade due to its beneficial effect on fish performance. Probiotic use at early stages of fish development may contribute to better face metamorphosis and weaning stress. In the present work, we studied the influence of Shewanella putrefaciens Pdp11 supplementation on growth, body composition and gut microbiota in Senegalese sole (Solea senegalensis) during larval and weaning development. S. putrefaciens Pdp11 was incorporated using Artemia as live vector (2.5 * 107 cfu mL-1) and supplied to sole specimens in a co-feeding regime (10-86 DAH) by triplicate. Probiotic addition promoted early metamorphosis and a significantly higher growth in length at 24 DAH larvae. S. putrefaciens Pdp11 also modulated gut microbiota and significantly increased protein content and DHA/EPA ratios in sole fry (90 DAH). This nutritional enhancement is considered especially important after weaning, where significantly higher growth in length and weight was observed in probiotic fish. Moreover, a less heterogeneous fish size in length was detected since metamorphosis till the end of weaning, being of interest for sole aquaculture production. After weaning, fish showed significantly higher growth (length and weight) and less variable lengths in fish when supplemented with probiotics. Both the enhancement of nutritional condition and the decrease in size variability associated with probiotic addition are highly interesting for sole aquaculture production. PMID- 23933745 TI - Convergent synthesis and cellular uptake of multivalent cell penetrating peptides derived from Tat, Antp, pVEC, TP10 and SAP. AB - Cell penetrating peptides (CPP) are peptides of 10 to 30 residues derived from natural translocating proteins. Multivalency is known to enhance cellular uptake for the Tat peptide and closely related polycationic sequences. To test whether multivalency effects on cellular uptake might also occur with other CPP types, we prepared multivalent versions of the strongly cationic Tat, the amphipathic sequences Antp, pVEC and TP10, and the polyproline helix SAP by convergent thioether ligation of the linear CPP onto multivalent scaffolds, and evaluated their uptake in HeLa and CHO cells, intracellular localization, cytotoxicity and hemolysis. While multivalency did not increase the cellular uptake of pVEC or SAP, multivalency effects on uptake comparable to Tat were observed with TP10 and Antp, which are attributable to their polycationic nature. The efficient synthetic protocol for these divalent CPP and their localization in the cytoplasm suggest that CPP might be useful for application in cargo delivery into cells. PMID- 23933746 TI - Journal of Parkinson's Disease--an excellent first year and a new sister. PMID- 23933747 TI - Amphetamine-induced dyskinesia in the transplanted hemi-Parkinsonian mouse. AB - The transplantation of dopamine-rich tissue into the putamen of patients with Parkinson's disease shows much potential for use as a therapeutic strategy. However, a number of grafted individuals subsequently developed a set of abnormal involuntary movements (AIMs), unrelated to the dyskinesia caused by L-DOPA treatment, which have been termed graft-induced dyskinesia. Given the small number of patients, pre-clinical modeling of graft-induced dyskinesia in animal models will be critical to determine the underlying mechanisms and amelioration potential of this technique. Here we show that abnormal involuntary movements of the limbs, trunk and face can be observed in transplanted hemi-parkinsonian mice following amphetamine administration, similar to those previously described to model graft-induced dyskinesias in rats. C57Bl6 and CD1 mice were first rendered hemi-parkinsonian with 6-hydroxydopamine, treated with L-DOPA for 21 days until dyskinetic, and then transplanted with a single cell suspension of embryonic ventral mesencephalon (VM E12.5) tissue from corresponding strains into the denervated striatum. At 16 weeks post-transplantation, a single injection of amphetamine-elicited dyskinesia in a subgroup of mice of both strains, behavioural pattern not observed pre-transplantation. The number of surviving dopaminergic cells in the graft did not differ between those that developed AIMs and those that did not. The movements were phenotypically comparable to those seen in the rat model and parallels can be drawn to the human form of the movements, although the mouse model maybe less reproducible than the rat equivalent. This mouse model will facilitate assessment of graft-induced dyskinesia with mouse-derived stem cell lines and exploration of mechanisms using transgenic mice in future studies. PMID- 23933748 TI - Tuned thalamic excitation is amplified by visual cortical circuits. AB - Cortical neurons in thalamic recipient layers receive excitation from the thalamus and the cortex. The relative contribution of these two sources of excitation to sensory tuning is poorly understood. We optogenetically silenced the visual cortex of mice to isolate thalamic excitation onto layer 4 neurons during visual stimulation. Thalamic excitation contributed to a third of the total excitation and was organized in spatially offset, yet overlapping, ON and OFF receptive fields. This receptive field structure predicted the orientation tuning of thalamic excitation. Finally, both thalamic and total excitation were similarly tuned to orientation and direction and had the same temporal phase relationship to the visual stimulus. Our results indicate that tuning of thalamic excitation is unlikely to be imparted by direction- or orientation-selective thalamic neurons and that a principal role of cortical circuits is to amplify tuned thalamic excitation. PMID- 23933749 TI - Suppression of eIF2alpha kinases alleviates Alzheimer's disease-related plasticity and memory deficits. AB - Expression of long-lasting synaptic plasticity and long-term memory requires protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2 alpha-subunit (eIF2alpha). Elevated phosphorylation of eIF2alpha has been observed in the brains of Alzheimer's disease patients and Alzheimer's disease model mice. Therefore, we tested whether suppressing eIF2alpha kinases could alleviate synaptic plasticity and memory deficits in Alzheimer's disease model mice. Genetic deletion of eIF2alpha kinase PERK prevented enhanced phosphorylation of eIF2alpha and deficits in protein synthesis, synaptic plasticity and spatial memory in mice that express familial Alzheimer's disease-related mutations in APP and PSEN1. Similarly, deletion of another eIF2alpha kinase, GCN2, prevented impairments of synaptic plasticity and defects in spatial memory exhibited by the Alzheimer's disease model mice. Our findings implicate aberrant eIF2alpha phosphorylation as a previously unidentified molecular mechanism underlying Alzheimer's disease-related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for treatment of individuals with Alzheimer's disease. PMID- 23933750 TI - Linear transformation of thalamocortical input by intracortical excitation. AB - Neurons in thalamorecipient layers of sensory cortices integrate thalamocortical and intracortical inputs. Although we know that their functional properties can arise from the convergence of thalamic inputs, intracortical circuits could also be involved in thalamocortical transformations of sensory information. We silenced intracortical excitatory circuits with optogenetic activation of parvalbumin-positive inhibitory neurons in mouse primary visual cortex and compared visually evoked thalamocortical input with total excitation in the same layer 4 pyramidal neurons. We found that intracortical excitatory circuits preserved the orientation and direction tuning of thalamocortical excitation, with a linear amplification of thalamocortical signals of about threefold. The spatial receptive field of thalamocortical input was slightly elongated and was expanded by intracortical excitation in an approximately proportional manner. Thus, intracortical excitatory circuits faithfully reinforce the representation of thalamocortical information and may influence the size of the receptive field by recruiting additional inputs. PMID- 23933752 TI - Intracortical multiplication of thalamocortical signals in mouse auditory cortex. AB - Cortical processing of sensory information begins with the transformation of thalamically relayed signals. We optogenetically silenced intracortical circuits to isolate thalamic inputs to layer 4 neurons and found that intracortical excitation linearly amplified thalamocortical responses underlying frequency and direction selectivity, with spectral range and tuning preserved, and prolonged the response duration. This signal pre-amplification and prolongation enhanced the salience of thalamocortically relayed information and ensured its robust, faithful and more persistent representation. PMID- 23933754 TI - Similarity-based machine learning methods for predicting drug-target interactions: a brief review. AB - Computationally predicting drug-target interactions is useful to select possible drug (or target) candidates for further biochemical verification. We focus on machine learning-based approaches, particularly similarity-based methods that use drug and target similarities, which show relationships among drugs and those among targets, respectively. These two similarities represent two emerging concepts, the chemical space and the genomic space. Typically, the methods combine these two types of similarities to generate models for predicting new drug-target interactions. This process is also closely related to a lot of work in pharmacogenomics or chemical biology that attempt to understand the relationships between the chemical and genomic spaces. This background makes the similarity-based approaches attractive and promising. This article reviews the similarity-based machine learning methods for predicting drug-target interactions, which are state-of-the-art and have aroused great interest in bioinformatics. We describe each of these methods briefly, and empirically compare these methods under a uniform experimental setting to explore their advantages and limitations. PMID- 23933751 TI - The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy. AB - Compelling evidence indicates that two autosomal recessive Parkinson's disease genes, PINK1 (PARK6) and Parkin (PARK2), cooperate to mediate the autophagic clearance of damaged mitochondria (mitophagy). Mutations in the F-box domain containing protein Fbxo7 (encoded by PARK15) also cause early-onset autosomal recessive Parkinson's disease, by an unknown mechanism. Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy. Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy. In Drosophila, ectopic overexpression of Fbxo7 rescued loss of Parkin, supporting a functional relationship between the two proteins. Parkinson's disease-causing mutations in Fbxo7 interfered with this process, emphasizing the importance of mitochondrial dysfunction in Parkinson's disease pathogenesis. PMID- 23933753 TI - Lineage-specific laminar organization of cortical GABAergic interneurons. AB - In the cerebral cortex, pyramidal cells and interneurons are generated in distant germinal zones, and so the mechanisms that control their precise assembly into specific microcircuits remain an enigma. Here we report that cortical interneurons labeled at the clonal level do not distribute randomly but rather have a strong tendency to cluster in the mouse neocortex. This behavior is common to different classes of interneurons, independently of their origin. Interneuron clusters are typically contained within one or two adjacent cortical layers, are largely formed by isochronically generated neurons and populate specific layers, as revealed by unbiased hierarchical clustering methods. Our results suggest that different progenitor cells give rise to interneurons populating infra- and supragranular cortical layers, which challenges current views of cortical neurogenesis. Thus, specific lineages of cortical interneurons seem to be produced to primarily mirror the laminar structure of the cerebral cortex, rather than its columnar organization. PMID- 23933755 TI - Slit2 expression and its correlation with subcellular localization of beta catenin in gastric cancer. AB - Gastric cancer is the fourth most common cancer worldwide. Several signaling pathways are involved in gastric cancer development and progression. Slit2 was recently found to be involved in cancer; however, its expression pattern in gastric cancer has not been discovered yet. In the present study, we investigated the expression of Slit2 in human gastric cancer and its correlation with the expression and subcellular localization of beta-catenin. Immunohistochemistry (IHC) staining revealed that Slit2 was highly expressed in human gastric cancer tissues, while it was low or weakly expressed in normal gastric tissues. The differences in clinicopathological features between different groups were determined using Pearson's chi2 test. Slit2 levels were significantly associated with differentiation, Lauren's classification, lymph node metastasis and TNM staging. Slit2 levels were positively correlated with beta-catenin level in gastric cancer tissues and cell lines. High levels of Slit2 were correlated with the membrane localization of beta-catenin, and low levels of Slit2 were correlated with nuclear translocation of beta-catenin in both gastric cancer tissues and cell lines assayed by IHC and immunofluorescence staining, respectively. Our data suggest that Slit2 was highly expressed in gastric cancer patients with less advanced clinicopathological features. Slit2 levels were correlated with beta-catenin level and subcellular localization. PMID- 23933756 TI - Novel metabolic drugs and blood pressure: implications for the treatment of obese hypertensive patients? AB - Hypertension and obesity often coexist, exposing patients to cardiovascular and metabolic risks, particularly type 2 diabetes mellitus. Moreover, obesity may render hypertensive patients treatment resistant. We review how drugs recently approved for obesity or type 2 diabetes mellitus treatment affect blood pressure. The weight-reducing drug lorcaserin induces modest reductions in body weight while slightly improving blood pressure. The fixed low-dose topiramate/phentermine combinations elicit larger reductions in body weight and blood pressure. Concomitant improvements in glucose metabolism, adiposity, and blood pressure differentiate the first clinically available SGLT2 inhibitor dapagliflozin from other oral antidiabetic drugs. Yet, the mechanisms through which metabolic drugs affect blood pressure and their interaction with antihypertensive drugs are poorly understood. Blood pressure-lowering effects of metabolic drugs could be exploited in the clinical management of obese hypertensive patients with and without type 2 diabetes mellitus, particularly in patients with difficult to control arterial hypertension. PMID- 23933757 TI - Early engraftment and full-donor chimerism after single-cord blood plus third party donor dual transplantation in patients with high-risk acute leukemia. PMID- 23933758 TI - Pre-transplant risk factors for cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia after hematopoietic cell transplantation. AB - Cryptogenic organizing pneumonia (COP), previously known as bronchiolitis obliterans organizing pneumonia (BOOP), is a significant complication after allogeneic hematopoietic SCT (HCT). However, the pathogenesis of this complication has not yet been elucidated. Therefore, we identified the pre transplant risk factors for the development of COP/BOOP using the Japan transplant registry database between 2005 and 2009. Among 9550 eligible recipients, 193 experienced COP/BOOP (2%). HLA disparity (odds ratio (OR) 1.51, P=0.05), female-to-male HCT (OR 1.53, P=0.023), and PBSC transplant (OR 1.84, P=0.0076) were significantly associated with an increased risk of COP/BOOP. On the other hand, BU-based myeloablative conditioning (OR 0.52, P=0.033), or fludarabine-based reduced-intensity conditioning (OR 0.50, P=0.0011) in comparison with a TBI-based regimen and in vivo T-cell depletion (OR 0.46, P=0.055) were associated with a lower risk. Of the 193 patients with COP/BOOP, 77 died, including non-relapse death in 46 (59%). Pulmonary failure and fatal infection accounted for 41% (n=19) and 26% (n=12) of the non-relapse death. Allogeneic immunity and conditioning toxicity could be associated with COP/BOOP. Prospective studies are required to elucidate the true risk factors for COP/BOOP and to develop a prophylactic approach. PMID- 23933759 TI - High-dose melphalan produces favorable response in a patient with multiple myeloma and coexisting essential thrombocythemia with JAK2 mutation. PMID- 23933760 TI - Myeloablative T cell-depleted alloSCT with early sequential prophylactic donor lymphocyte infusion is an efficient and safe post-remission treatment for adult ALL. AB - The prognosis of adult patients with ALL remains unsatisfactory. AlloSCT is associated with a beneficial GVL response mediated by donor T cells. However, GVHD results in substantial mortality and long-term morbidity. T-cell depletion (TCD) of the graft reduces the severity of GVHD, but is associated with an increased relapse rate after alloSCT. Therefore, early sequential donor lymphocyte infusion (DLI) is likely to be necessary for a successful GVL reaction. Twenty-five adult ALL patients (10 Ph(+)ALL) were eligible for early DLI after initial disease control with myeloablative TCD-alloSCT in first CR (CR1), if active GVHD was absent at 3-6 months after alloSCT. Patients with a sibling donor or an unrelated donor were scheduled for 3.0 * 10(6) CD3(+) cells/kg or 1.5 * 10(6) CD3(+) cells/kg, respectively, at 6 months after alloSCT. Three patients died before evaluation (one early relapse). Five patients had active GVHD. Fourteen of the remaining seventeen patients received DLI (median time-to-DLI: 185 days). Overall, only 17% required long-term systemic immunosuppression for GVHD. With a median follow-up after TCD-alloSCT of 50 months, 2-year survival probability was 68% (95% confidence interval (CI) 49 87%). In conclusion, myeloablative TCD-alloSCT with early sequential DLI is an efficient and safe post-remission treatment for adult ALL patients in CR1. PMID- 23933761 TI - EBV-driven relapse of peripheral T-cell lymphoma, masquerading as a post transplant lymphoproliferative disorder following allo-SCT. PMID- 23933762 TI - Human parvovirus B19 in pediatric and adult recipients of allogeneic hematopoietic stem cell transplantation. PMID- 23933764 TI - Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML. AB - Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) can cure patients with AML in CR. However, relapse after RIC allo-HCT may indicate heterogeneity in the stringency of CR. Strict definition of CR requires no evidence of leukemia by both morphologic and flow cytometric criteria. We re-evaluated 85 AML patients receiving RIC allo-HCT in CR to test if a strict definition of CR had direct implications for the outcome. These patients had leukemia immunophenotype documented at diagnosis and analyzed at allo-HCT. Eight (9.4%) had persistent leukemia by flow cytometric criteria at allo-HCT. The patients with immunophenotypic persistent leukemia had a significantly increased relapse (hazard ratio (HR): 3.7; 95% confidence interval (CI): 1.3-10.3, P=0.01) and decreased survival (HR: 2.9; 95% CI: 1.3-6.4, P<0.01) versus 77 patients in CR by both morphology and flow cytometry. However, the pre allo-HCT bone marrow (BM) blast count (that is, 0-4%) was not significantly associated with risks of relapse or survival. These data indicate the presence of leukemic cells, but not the BM blast count affects survival. A strict morphologic and clinical lab flow cytometric definition of CR predicts outcomes after RIC allo-HCT, and therefore is critical to achieve at transplantation. PMID- 23933763 TI - Single-cell T-cell receptor-beta analysis of HLA-A*2402-restricted CMV- pp65 specific cytotoxic T-cells in allogeneic hematopoietic SCT. AB - Cellular immunity is important for the control of CMV infection after allogeneic hematopoietic cell transplantation (Allo-HCT). However, the actual in vivo dynamics of CMV-specific cytotoxic T cell (CMV-CTL) clones are still unclear. We conducted clone monitoring of tetramer(+) CMV-CTLs in HLA-A*2402-positive donor patient pairs, using a direct single-cell analysis that enabled the simultaneous identification and quantification of CTL clones. Clone dynamics were assessed in three cases with or without CMV reactivation. In Case-1 without CMV reactivation, despite the long-term use of systemic steroid, dominant clones of Donor-1 persisted and remained dominant. The CMV-CTLs at 1 year after Allo-HCT included a high proportion of CD45RA(+)CCR7(-) effector and CD27(-)CD57(+)mature T cells. On the other hand, in Cases-2 and -3 with CMV reactivation, novel clones appeared and became dominant during the follow-up. Their CMV-CTLs included more CD27(+) immature T cells at 1 year after Allo-HCT. With regard to clonotypes, HLA-A*2402 restricted CMV-CTLs tended to select BV7 and BJ1-1 genes for complementarity determining region 3 (CDR3) of T-cell receptor (TCR)-beta. Specific amino-acid sequences of CDR3 of TCR-beta were found in each case. Patterns of clone reconstitution and phenotype would be different according to CMV reactivation. In vivo clone monitoring of CMV-CTLs could provide insight into the mechanism of immunological reconstitution following Allo-HCT. PMID- 23933765 TI - Depletion of naive T cells using clinical grade magnetic CD45RA beads: a new approach for GVHD prophylaxis. AB - Depletion of naive T cells from donor leukapheresis products (LPs) aims at the reduction of alloreactivity, while preserving memory T-cell reactivity (for example, to pathogens). This study established the immunomagnetic depletion procedure under clean room conditions using CD45RA beads and analyzed LPs of six donors for cell composition and functional immune responses. CD45RA depletion resulted in 3.4-4.7 log (median 4.4) reduction of CD45RA(+) T cells, thereby eliminating naive and late effector T cells. B cells were also completely removed, whereas significant proportions of NK cells, monocytes and granulocytes persisted. CD45RA-depleted LPs contained effector and central memory CD4(+) and CD8(+) T cells that showed sustained IFN-gamma secretion to CMV, EBV, Aspergillus and Candida Ags. Alloreactivity was measured in MLRs between donors with complete HLA-mismatch. Alloreactive CD8(+) T cells were strongly reduced (median >1-log) upon CD45RA depletion, whereas alloreactive CD4(+) T cells persisted in significant numbers. In conclusion, clinical grade depletion of CD45RA(+) naive T cells from donor LPs is feasible and highly efficient. The depleted products show sustained CD4(+) and CD8(+) T-cell reactivity to pathogens and effectively reduced CD8-mediated alloreactivity. Prophylactic and preemptive infusions after allogeneic SCT may improve T-cell reconstitution and pathogen-specific immunosurveillance, along with lower risk of inducing GVHD. PMID- 23933766 TI - Factors associated with regular HIV testing among a sample of US MSM with HIV negative main partners. AB - : HIV transmission is common within men who have sex with men (MSM) couples; despite recommendations that MSM who engage in risky sexual behaviors get tested biannually/annually, little is known about the testing patterns of MSM while in a current primary relationship. This study compared demographic and relationship characteristics of groups of MSM with different testing patterns while in their primary relationships and assessed which factors were associated with regular or irregular testing. Two hundred seventy-five HIV-negative male couples/550 MSM were recruited online to complete a survey in 2011. Since the start of their relationship, 21% of MSM tested for HIV every 3, 4, or 6 months; 29% tested once a year; 30% tested only when they felt at risk for HIV; and 20% never tested for HIV. Bivariate analyses indicated that men who had never been tested while in their relationship were younger, less educated, had greater trust in their partner, and were less likely to be in a couple that had 1 or both men having had sex with someone else. In the multivariate analyses, testing at regular intervals was associated with higher education, having a sexual agreement, being in a couple that had 1 or both men having had sex with someone else, and having lower faith in trust toward the main partner. Findings suggest that many MSM's testing behaviors while in their primary relationship do not align with their risk profile. Trust seems to be a barrier to regular HIV testing, which may be addressed by encouraging MSM to negotiate clear sexual agreements with their primary partner. PMID- 23933767 TI - Social network characteristics and HIV risk among African American, Asian/Pacific Islander, and Latino men who have sex with men. AB - OBJECTIVES: To examine how social networks influence HIV risk among US racial/ethnic minority men who have sex with men (MSM) and whether the associations of social network characteristics with risk vary by race/ethnicity. METHODS: A chain-referral sample of 403 African American, 393 Asian/Pacific Islander, and 400 Latino MSM recruited in Los Angeles County, California, completed a questionnaire, which asked about their egocentric social networks, safer sex peer norms, and male anal intercourse partners. HIV-nonconcordant partnerships were those reported by respondents as serodisconcordant or where self and/or partner serostatus was unknown. RESULTS: Overall, 26% of the sample reported HIV-nonconcordant unprotected anal intercourse (UAI) with a nonprimary male partner in the previous 6 months. In a generalized estimating equation (GEE) logistic model that controlled for race/ethnicity, age, nativity, incarceration history, and HIV status, being in a more dense network was associated with less HIV-nonconcordant UAI [adjusted odds ratio (AOR) = 0.92, 95% confidence interval (CI): 0.86 to 0.99, P = 0.0467]. In addition, the effect of safer sex peer norms on HIV-nonconcordant UAI was moderated by ego-alter closeness (P = 0.0021). Safer sex peer norms were protective among those reporting "medium" or "high" ego-alter closeness (AOR = 0.70, 95% CI: 0.52 to 0.95, P = 0.0213 and AOR = 0.48, 95% CI: 0.35 to 0.66, P < 0.0001, respectively), but not among those reporting "low" ego alter closeness (AOR = 0.96, 95% CI: 0.63 to 1.46, P = 0.8333). The effects of density, closeness, and norms on HIV-nonconcordant UAI did not differ by race/ethnicity. CONCLUSIONS: The significant association of social network characteristics with UAI point to network-level factors as important loci for both ongoing research and HIV prevention interventions among US MSM of color. PMID- 23933768 TI - Changes in plasma viral load and penile viral shedding after circumcision among HIV-positive men in Kisumu, Kenya. AB - BACKGROUND: We conducted a prospective cohort study of HIV-positive men aged 18 35 years in Kisumu, Kenya to determine if medical circumcision of ART-naive HIV positive men leads to increased viral load and penile viral shedding. METHODS: From 108 HIV-positive men circumcised by forceps-guided method and followed up weekly for 6 weeks, 29 men were evaluated for penile viral shedding. HIV-1 RNA was measured in plasma from 19 men and in penile lavage samples from 29 men. Samples were collected before circumcision and at weekly intervals for 6 weeks or until the circumcision wound was healed. CD4 T-cell counts from 102 HIV-positive men were determined at baseline and at 2 weeks thereafter. Wounds with healthy scar, no scab or opening, and no suture tracks were deemed healed. RESULTS: Among 65 ART-naive men, mean CD4 T-cell count increased from 417 cells per cubic millimeter at baseline to 456 cells per cubic millimeter after 2 weeks (P = 0.04), but did not change in the 37 men on ART (P = 0.81). There was no change in HIV plasma viral load (P = 0.36), but penile viral shedding rose significantly within 1 week after circumcision then declined to undetectable levels by 6 weeks (multivariate analysis of variance; P < 0.001). In 28 of 29 men (96.6%), there was no detectable viral shedding after certification of wound healing. CONCLUSIONS: Medical circumcision among ART-naive HIV-infected men results in a transitory rise in penile viral shedding before complete wound healing, which should pose no additional risk of HIV transmission if men adhere to 6 weeks postcircumcision sexual abstinence and use condoms consistently. PMID- 23933769 TI - Association of depression, anxiety, and suicidal ideation with high-risk behaviors among men who inject drugs in Delhi, India. AB - BACKGROUND: Sharing of needles and syringes and unprotected sex remain a common practice among people who inject drugs (PWID) in India and are important drivers of new HIV infections. Whether engagement in risk behaviors among PWID is associated with symptoms of common mental disorders in India is unknown. METHODS: We analyzed the data collected in April and May of 2012 from a community-based sample of 420 PWID in Delhi using time location sampling. Self-report symptom scales were used to measure the severity of symptoms of depression (Patient Health Questionnaire 9) and anxiety (Generalized Anxiety Disorder scale 2) within the preceding 2 weeks. We assessed the presence of suicidal thoughts within the past 12 months. RESULTS: PWID with severe depressive symptoms and those with suicidal thoughts were 4 and 2 times more likely to share needles/syringes, respectively. PWID experiencing suicidal thoughts had 82% more female sexual partners and were 5 times more likely to have had unprotected sex at last sex with a paid female partner. Conversely, symptoms of anxiety were associated with a 30% decrease in the likelihood of needle/syringe sharing and a 70% decrease in the likelihood of unprotected sex at last sex with a paid female partner. CONCLUSIONS: We found a high prevalence of symptoms of depression, anxiety, and suicidal ideation among men who inject drugs in Delhi and that depression and suicidal ideation are independently positively associated with HIV risk behaviors, whereas anxiety is associated with a reduction in such behaviors. Ameliorating mental health problems among PWID in India may aid in reducing HIV infections. PMID- 23933770 TI - Is "educational advantage" advantageous? PMID- 23933771 TI - Protocols for protection of human participants: a comparison of five countries. AB - Research ethics protocols relating to human participants were compared across five countries, namely, Australia, Azerbaijan, Iran, the Philippines, and South Africa. These countries were considered to be geographically and culturally diverse, as well as representing both developed and developing countries. The extent to which the research participant is protected across cultures and countries was investigated, with particular focus on the use of informed consent procedures. It was argued that current ethical guidelines and practices fail to ensure the protection of the most vulnerable participants within these cultures. Informed consent mechanisms also often fail to consider cultural differences in self-concept, understanding of research methods, and power differences between researchers and participants. Discussion of these ethical challenges and recommendations for research ethics development within these cultures and countries are discussed. PMID- 23933772 TI - Giving consent without getting informed: a cross-cultural issue in research ethics. AB - Informed consent forms (ICFs) maintain the integrity of research ethics and preserve participants' rights. Using cross-sectional online survey data on sexuality and sexual practices of private university students from Lebanon, this paper questions whether participants thoroughly read ICFs, and whether time taken to read ICFs is associated with data completeness. A total of 2,534 surveys were completed; a median time of 18.66 seconds was taken to read the 815-word ICF; 65% of participants consented within the first 30 seconds and 90% in less than the minimum predicted time (2.7 minutes). Our data indicates potential participant neglect of ICFs, raising the question of whether participants who endorse an informed consent form are truly informed of the study objectives and their rights. PMID- 23933773 TI - A comparative analysis of the governance and use of residual dried blood spots from state newborn screening programs and neonatal biobanks. AB - In contrast to prior research, which has focused mainly on legislative content, this study aimed to characterize the current governance structures and procedures used by state newborn screening programs in the United States regarding the research use of residual dried blood spots. Content analysis was performed on newborn screening laws, program policies, survey responses, and online material, and was compared to information from two neonatal biobanks. Important differences between newborn screening programs and neonatal biobanks included the types of permissible research with blood spots, the evaluation criteria used for research requests, and characteristics of the research proposal reviewers. These findings can inform ongoing policy conversations with respect to the governance and use of residual dried blood spots. PMID- 23933774 TI - Sustaining engagement and partnership: model of enhancing cultural capital among nonaffiliated IRB members. AB - Although federal regulations require the presence of at least one nonaffiliated member on the roster of an institutional review board (IRB), little research exists about how to foster their participation and satisfaction. Guided by principles of justice and diversity, the Kaiser Permanente Southern California IRB adapted the sociological concept of "cultural capital" to develop training and support with its nonaffiliated IRB members. Using in-depth qualitative interviews with four past and current nonaffiliated IRB members, we describe how our initial and ongoing activities enhanced their ability to analyze, communicate, and complete the ethical review of research. This case study is situated in the gaps of existing research about nonaffiliated IRB members by providing insights into how to sustain their engagement while protecting the rights of research volunteers, particularly from vulnerable communities. PMID- 23933775 TI - Patients' rights: a hospital survey in South Egypt. AB - We examined the awareness of and practices regarding patients' rights in one of the general hospitals in South Egypt. This cross-sectional study incorporated a convenience sample of the hospitalized patients and their companions (N = 292), as well as the actively working medical care providers (MCPs) at the time of data collection, 72 physicians and 48 nurses. Pretested structured questionnaires inquired about the way in which patients' rights are perceived by and exercised through the lived experiences of the sample group. An in-depth interview about patient rights' practices was conducted with the study hospital's highest-level manager. Three quarters of the patients and companions did not know about the list of patients' rights, compared to about half of the physicians and nurses- 77%, 44%, and 48% respectively. Among those patients and companions who were knowledgeable about the list of patients' rights, mass media was their main source of knowledge, about eight times greater than their next source, placards on the hospital wall. The proportion of the physicians who stated undergraduate curriculum as a source of their knowledge was almost half that of the nurses. Strategies to promote awareness among MCPs, and to ensure effective supervision from both the Ministry of Health and local managers, should precede mass community patients' rights awareness efforts. PMID- 23933776 TI - Critical illness research involving collection of genomic data: the conundrum posed by low levels of genomic literacy among surrogate decision makers for critically ill patients. AB - Critical illness clinical trials that entail genomic data collection pose unique challenges. In this qualitative study, we found that surrogate decision makers (SDMs) for critically ill individuals, such as those who would be approached for study participation, appeared to have a limited grasp of genomic principles. We argue that low levels of genomic literacy should neither preclude nor be in conflict with the conduct of ethically rigorous clinical trials. PMID- 23933777 TI - How IRBs view and make decisions about social risks. AB - Whether and how IRBs assess social risks remains unclear, with little empirical investigation. I contacted leaders of 60 IRBs, and interviewed IRB leaders from 34 (response rate = 55%) and additionally, 12 members and administrators. IRBs struggle to assess and balance social risks and benefits, and vary in whether, how, and how much to do so, and how to balance these against individual risks/benefits. Risks to a group affect individuals within it. Hence, social risks can include indirect individual risks, raising ambiguities. Dilemmas emerge: e.g., how much responsibility researchers and IRBs have for addressing broader health inequities. These data, the first to examine how IRBs make decisions about social risks, reveal how IRBs face critical challenges, dilemmas, and ambiguities. PMID- 23933778 TI - Perceived discomfort levels in healthy children participating in vaccine research. AB - When assessing the risks of a research protocol, review boards need to consider not only the possible harms but also the expected discomfort levels caused by the various study procedures. However, data on how children experience various study procedures are scarce. This study assessed perceived discomfort levels in 671 healthy children aged 0-2 years under-going vaccinations, venipunctures, and nasopharyngeal swab taking. In half of the study participants, venipunctures caused a moderate or high level of discomfort (49%). Corresponding figures for nasopharyngeal swabbing and vaccinations were 28% and 12%, respectively. Within the reported age group, increasing age was related with higher discomfort levels. In a majority of cases for all study procedures, the perceived levels of discomfort met the parents' expectations. PMID- 23933780 TI - Educational advantage. AB - This issue of JERHRE examines informed consent requirements as they arise in diverse countries and cultures, and in relation to level of risk of the research and vulnerability of the potential participants. It also examines issues of literacy as they affect informed consent. And it examines whether research participants want to be informed. Adequate informed consent is a statement that is meaningful and understandable by the particular research participant and that allows the participant free choice regarding participation. The way in which an adequate consent procedure is administered must, by definition, depend on the level of literacy of the potential research participants, and the nature and values of the culture of the potential participants. An implication of these requirements is that Western consent procedures are likely to violate ethical standards when employed in non-Western cultures. Educational activities presented below will enable readers to consolidate their knowledge and understanding of these issues. Written informed consent statements are not valid for use with research participants who lack literacy. The level of literacy required depends on the complexity of the research topic. In Clough et al., we find that cultural differences in self-concept, understanding of research methods, level of education, and deference to researchers challenge researchers to modify standard consent procedures to render them valid in some cultural contexts. In Abou Zeina et al., we find an even more complex problem of communicating patients' rights to illiterate patients in an Egyptian public hospital: not only can they not read, but they consider "patients' rights" as the least of their problems. In Iverson et al., we find still different issues concerning the scientific literacy of surrogate decision makers for critically ill patients. And in Ghandour et al., we find in Lebanon, within a very large sample of socioeconomically diverse students, a virtually total lack of interest in being informed before participating in a survey on a highly sensitive topic. For those of us who would unthinkingly impose standard Western consent procedures on everyone, these four articles may have much to teach us. PMID- 23933781 TI - A series of eIF4E alleles at the Bc-3 locus are associated with recessive resistance to Clover yellow vein virus in common bean. AB - Clover yellow vein virus (ClYVV) is capable of causing severe damage to common bean (Phaseolus vulgaris L.) production worldwide. The snap bean market class is particularly vulnerable because infection may lead to distortion and necrosis of the fresh green pods and rejection of the harvest. Three putatively independent recessive genes (cyv, desc, bc-3) have been reported to condition resistance to ClYVV; however, their allelic relationships have not been resolved. We identified, evaluated, and characterized the phenotypic and molecular genetic variation present in 21 informative common bean genotypes for resistance to ClYVV. Allelism testing phenotypes from multiple populations provided clear evidence that the three genes were a series of recessive alleles at the Bc-3 locus that condition unique potyvirus strain- and species-specific resistance spectra. Candidate gene analysis revealed complete association between the recessive resistance alleles and unique patterns of predicted amino acid substitutions in P. vulgaris eukaryotic translation initiation factor 4E (PveIF4E). This led to the discovery and characterization of two novel PveIF4E alleles associated with resistance to ClYVV, PveIF4E (3) , and PveIF4E (4) . We developed KASPar allele-specific SNP genotyping assays and demonstrated their ability to accurately detect and differentiate all of the PveIF4E haplotypes present in the germplasm, allelism testing, and in three separate segregating populations. The results contribute to an enhanced understanding and accessibility of the important potyvirus resistance conditioned by recessive alleles at Bc-3. The KASPar assays should be useful to further enable germplasm exploration, allelic discrimination, and marker-assisted introgression of bc-3 alleles in common bean. PMID- 23933782 TI - High false-negative proportion of intraoperative histological examination as a serious problem for clinical application of sentinel node biopsy for early gastric cancer: final results of the Japan Clinical Oncology Group multicenter trial JCOG0302. AB - BACKGROUND: To evaluate the feasibility and accuracy of diagnosis using sentinel node (SN) biopsy in T1 gastric cancer, a multicenter trial was conducted by the Japan Clinical Oncology Group (JCOG). METHODS: Sentinel node biopsy with indocyanine green (ICG) was performed in patients with T1 gastric cancer. Green stained nodes (GNs), representing SNs, were removed first, and gastrectomy with lymphadenectomy was then performed. GNs in one plane (with the largest dimension) were histologically examined intraoperatively by frozen section with hematoxylin and eosin (H&E) stain. All harvested lymph nodes (GNs and non-GNs) were histologically examined by paraffin section after surgery. The primary endpoint was to determine the proportion of false negatives, which was defined as the number of patients with negative GNs by frozen section divided by those with positive GNs and/or positive non-GNs by paraffin section. The sample size was set at 1,550, based on the expected and threshold value as 5 and 10 % in the proportion of false negatives. RESULTS: Accrual was suspended when 440 patients were enrolled because the proportion of false negatives was high. In the primary analysis, the proportion of false negatives was 46 % (13/28) after a learning period with 5 patients for each institution. Seven of 13 patients had nodal metastases outside the lymphatic basin. False negatives remained at 14 % (4/28) even by examining additional sections of GNs by paraffin section. CONCLUSIONS: The proportion of false negatives was much higher than expected. Intraoperative histological examination using only one plane is not an appropriate method for clinical application of SN biopsy in gastric cancer surgery. PMID- 23933784 TI - Long-term results of hepatic resection for non-colorectal, non-neuroendocrine liver metastasis. AB - BACKGROUND/AIMS: The significance of surgical resection for non-colorectal non neuroendocrine tumor liver metastasis (NCNNLM) remains controversial. The present study sought to clarify the long-term outcomes of surgical resection for NCNNLM and prognostic factors after hepatectomy in a single institution. METHODOLOGY: From 1993 to 2009, 145 patients underwent hepatectomy for NCNNLM. The primary sites of the hepatic tumors were gastrointestinal carcinoma in 80 cases, breast in 30, genitourinary in 12, gastrointestinal stromal tumor in 11, and miscellaneous in 12. RESULTS: The cumulative 1-, 3-, and 5-year overall survival rates of those who underwent hepatectomy for NCNNLM were 83.9, 55.4, and 41.0%, respectively, with median overall survival times of 41.8 months. Multivariate analysis revealed that postoperative complication was the only independent poor prognostic factor impacting on survival. Postoperative morbidity and mortality rate were 17.9% and 1.4%. There are 38 cases survived more than 5 years including 21 patients without remnant tumors due to the repeat hepatic and/or pulmonary resection for recurrence. A total of 32 patients survived without tumor and without any kinds of chemotherapy in the latest condition. CONCLUSIONS: Hepatectomy for NCNNLM may be beneficial and might relieve patients from excursive chemotherapy in selected patients. Meticulous surgery avoiding complication may enhance the outcome. PMID- 23933785 TI - Clinical value of serum CA19-9 as a prognostic factor for the ampulla of Vater carcinoma. AB - BACKGROUND/AIMS: Ampulla of Vater carcinoma is a relatively rare digestive tract tumor; postoperative prognostic factors have been well studied. However, any indicator of preoperative prognosis remains poorly identified. This study aims to identify serum tumor markers as preoperative prognostic factors and other variables as postoperative prognostic factors for ampulla of Vater carcinoma. METHODOLOGY: This study retrospectively analyzed data from 26 patients undergoing pancreaticoduodenectomy (PD), including pylorus preserving PD for ampulla of Vater carcinoma between April 1993 and December 2006. The main outcome measures were survival rates of patients with and without high levels of CA19-9 and CEA. RESULTS: Patients with high levels of CA19-9 (n = 12) had significantly higher survival rates than those without (n = 14) (p = 0.0027). High levels of CEA did not influence cumulative survival rates (p = 0.4522). Histopathological classification was an independent predictor of poor survival rates; patients with well differentiated adenocarcinoma (n = 18) had significantly higher survival rates than those with moderate to poorly differentiated tumors (n = 12) (p = 0.0280). Other factors such as tumor size, lymph node metastasis (p = 0.4006), or invasion of pancreas (p = 0.1156), duodenum (p = 0.0.3723), vein (p = 0.4331), and lymph vessel (p = 0.8606), and perineural invasion (p = 0.0.8765) were not an independent indicators of poor survival rate. CONCLUSIONS: The results of our study indicated that high levels of CA19-9 and histopathological classification were significant independent predictors of poor survival rates for the ampulla of Vater carcinoma. PMID- 23933786 TI - Liver function test by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging with consideration of intrahepatic regional differences. AB - BACKGROUND/AIMS: To accurately quantify liver function using gadolinium ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA)-enhanced MR imaging. METHODOLOGY: A total of 105 patients with suspicion of a hepatic tumor (Child-Pugh scores: 5 in 56, 6 in 26, 7 in 20, and 8 in 3) who underwent Gd-EOB DTPA-enhanced MR imaging and an indocyanine green retention rate at 15 min (ICG R15) evaluation were retrospectively analyzed. The hepatobiliary images were taken at 20 min after Gd-EOB-DTPA injection. The quantitative liver-spleen contrast ratio (Q-LSC) was measured by calculating the signal intensity of the spleen and 12 intrahepatic points consisting of each central zone (near the porta hepatis) and peripheral zone (near the subcapsular zone) in the two main liver lobes. RESULTS: Each averaged Q-LSC of six points in the central zone or right lobe was significantly higher than that in the peripheral zone or left lobe regardless of hepatic function. The mean Q-LSC of the 12 points was significantly correlated with the ICG-R15 and significantly decreased with elevation of the Child-Pugh score. CONCLUSIONS: The hepatic enhancement by Gd-EOB-DTPA is influenced by zonal and lobar differences. This method with consideration of regional differences is valid for estimation of liver function by Gd-EOB-DTPA enhanced MR imaging. PMID- 23933787 TI - Appraisal of simultaneous laparoscopic splenectomy and hepatic resection in the treatment of hepatocellular carcinoma with hypersplenic thrombocytopenia. AB - BACKGROUND/AIMS: The management of hepatocellular carcinoma with hypersplenic thrombocytopenia remains controversial, because of the high surgical morbidity and mortality. Splenectomy has been reported to be useful for patients with hypersplenic thrombocytopenia, but the timing and route of splenectomy and hepatic resection remains unclear. This report evaluated the efficacy of laparoscopic surgery for simultaneous splenectomy and hepatic resection in the treatment of hepatocellular carcinoma with hypersplenic thrombocytopenia. METHODOLOGY: Among 65 patients with hypersplenic thrombocytopenia who underwent hepatic resection for hepatocellular carcinoma, 20 patients underwent simultaneous splenectomy and hepatic resection. Initially, ten patients underwent the procedure by conventional laparotomy (open group) and ten patients underwent by laparoscopy (laparoscopic group). The clinicopathological results from the two groups were compared retrospectively. RESULTS: The blood loss in the laparoscopic group was significantly less and the postoperative morbidity rate in the laparoscopic group was lower than that in the open group. The duration of the postoperative hospital stay in the laparoscopic group was significantly shorter and rate of patients administered interferon in the laparoscopic group was significantly higher than that in open group. CONCLUSIONS: Simultaneous splenectomy and hepatic resection under laparoscopy is a safe and useful in the treatment of hepatocellular carcinoma with hypersplenic thrombocytopenia. PMID- 23933788 TI - Decreased expression of SOX9 in intraductal papillary mucinous neoplasms of the bile duct. AB - BACKGROUND/AIMS: SOX9 is an important transcription factor required for development and has been implicated in several types of malignant tumor. Our recent study showed that SOX9 played an important role in multi-step carcinogenesis in cases of intraductal papillary mucinous tumor of the pancreas (IPMN-P). This study aimed to investigate the expression of SOX9 in cases of intraductal papillary mucinous tumor of the bile duct (IPMN-B). METHODOLOGY: SOX9 expression was immunohistochemically evaluated in the tumor and corresponding normal bile-duct epithelium of seven IPMN-B patients. RESULTS: In all cases, SOX9 expression in the IPMN-B was low compared with the normal biliary epithelium. CONCLUSIONS: This study demonstrated that SOX9 expression may indicate a link between IPMN-B and IPMN-P. SOX9 may also have potential as a therapeutic target and/or prognostic marker in IPMN-B. PMID- 23933789 TI - Management of abdominal compartment syndrome in severe acute pancreatitis patients with early continuous veno-venous hemofiltration. AB - BACKGROUND/AIMS: The present study investigates whether early continuous veno venous hemofiltration (CVVH) is effective for decreasing intra-abdominal pressure (IAP) and serum TNF-alpha in abdominal compartment syndrome (ACS) patients of severe acute pancreatitis (SAP), and to study the correlation between IAP and serum TNF-alpha level. METHODOLOGY: Twenty-five ACS patients of SAP were treated in the ICU and underwent CVVH. IAP and blood level of TNF-alpha were measured daily to investigate their time-course of changes and the correlation between the two parameters. RESULTS: IAP on admission to the ICU was high (22.9+/-2.1 mmHg). The IAP was significantly lower (17.2+/-2.2 mmHg; p <0.01) 24 h after initiation of CVVH, and thereafter decreased rapidly. Mean the blood level of TNF-alpha was high (59.9+/-18.2 ng/L) on admission. However, it significantly decreased (41.1+/ 12.8 ng/L; p <0.01) 24 h after initiation of CVVH, and subsequently decreased. There was a significant positive correlation between blood level of TNF-alpha and IAP (r = 0.53, p <0.01). CONCLUSIONS: CVVH significantly decreased IAP and TNF alpha in ACS patients of SAP. TNF-alpha was significantly correlated with IAP, suggesting that TNF-alpha may play an important role in the pathogenesis of ACS. Early CVVH can improve vascular permeability through elimination of cytokines such as TNF-alpha, and thereby decrease interstitial edema to lower IAP and should be applied in the early stages of ACS. PMID- 23933790 TI - Endoscopic drainage treatment of pancreatic pseudocysts. AB - BACKGROUND/AIMS: This study presents the experience of its authors with endoscopic drainage treatment of pancreatic pseudocysts. The first part of the study offers a literature overview of the basic knowledge of pancreatic pseudocysts. The authors gradually deal with the individual types of pancreatic pseudocysts, the clinical picture, complications and diagnostics. Within the bounds of differential diagnostics the authors stress mainly the necessity of differentiating pancreatic pseudocysts from cystic tumors and benign cysts. Special attention is dedicated to various modalities of pancreatic pseudocyst treatment. The second part of the study presents the authors' own results of the endoscopic drainage treatment of pancreatic pseudocysts. METHODOLOGY: Results of endoscopic drainage treatment of pancreatic pseudocysts, which is one of significant possibilities of treatment of these conditions, are presented. RESULTS: This method was used to treat 33 patients (24 men and 9 women) from September 2007 to March 2009. Endoscopic drainage of pancreatic pseudocysts was performed four times transduodenally and 29 times transgastrically, of which 6 cases were under endosonographic guidance and 27 cases by a duodenoscopy after endosonographic targeting. CONCLUSIONS: The authors conclude that endoscopic drainage is an effective method of pancreatic pseudocyst treatment. PMID- 23933791 TI - [OCT for diagnosis of diabetic retinopathy]. PMID- 23933792 TI - [Optic nerve neuritis]. AB - Optic nerve neuritis is one of the most important differential diagnoses of visual loss in young and middle aged adults. The prognosis in terms of functional outcome is generally good. The diagnosis of optic neuritis is clinical. Steroids can reduce the recovery time but do not affect the long-term functional outcome. Magnetic resonance imaging (MRI) is the most important investigation for assessing an associated risk of multiple sclerosis. Optical coherence tomography (OCT) contributes additional details on the course and functional outcome of optic neuritis. In the future OCT may additionally contribute to the relationship between optic neuritis and possible associated multiple sclerosis. PMID- 23933794 TI - Follow-up regarding inappropriate and cloned clinical histories on radiology request forms for sick children. PMID- 23933793 TI - Hypertension after kidney transplantation: a pathophysiologic approach. AB - Post-transplant hypertension is associated with decreased graft and patient survival and cardiovascular morbidity. Unfortunately, post-transplant hypertension is often poorly controlled. Important risk factors include immunosuppressive medications, complications of the transplant surgery, delayed graft function, rejection, and donor and recipient risk factors. The effects of immunosuppressive medications are multifactorial including increased vascular and sympathetic tone and salt and fluid retention. The immunosuppressive agents most commonly associated with hypertension are glucocorticoids and calcineurin inhibitors. Drug therapy for hypertension should be based on the comorbidities and pathophysiology. Evidence-based approaches to defining and treating hypertension in renal transplant recipients are predominantly extrapolated from large-scale studies performed in the general population. Thus, there continues to be a need for larger studies examining the pathophysiology, diagnosis and treatment of hypertension in renal transplant recipients. PMID- 23933795 TI - Stimulation of primary osteoblasts with ATP induces transient vinculin clustering at sites of high intracellular traction force. AB - Adenosine 5'-triphosphate (ATP), released in response to mechanical and inflammatory stimuli, induces the dynamic and asynchronous protrusion and subsequent retraction of local membrane structures in osteoblasts. The molecular mechanisms involved in the ligand-stimulated herniation of the plasma membrane are largely unknown, which prompted us to investigate whether the focal-adhesion protein vinculin is engaged in the cytoskeletal alterations that underlie the ATP induced membrane blebbing. Using time-lapse fluorescence microscopy of primary bovine osteoblast-like cells expressing green fluorescent protein-tagged vinculin, we found that stimulation of cells with 100 MUM ATP resulted in the transient and rapid clustering of recombinant vinculin in the cell periphery, starting approximately 100 s after addition of the nucleotide. The ephemeral nature of the vinculin clusters was made evident by the brevity of their mean assembly and disassembly times (66.7 +/- 13.3 s and 99.0 +/- 6.6 s, respectively). Traction force vector maps demonstrated that the vinculin-rich clusters were localized predominantly at sites of high traction force. Intracellular calcium measurements showed that the ligand-induced increase in [Ca(2+)]i clearly preceded the clustering of vinculin, since [Ca(2+)]i levels returned to normal within 30 s of exposure to ATP, indicating that intracellular calcium transients trigger a cascade of signalling events that ultimately result in the incorporation of vinculin into membrane-associated focal aggregates. PMID- 23933796 TI - Histomorphological evaluation of maternal and neonatal distal airspaces after maternal intake of nanoparticulate titanium dioxide: an experimental study in Wistar rats. AB - This study was performed to determine the histomorphological alterations occurring in maternal and neonatal pulmonary distal airspaces of Wistar rats after maternal administration of titanium dioxide nanoparticles (TiO2 NPs). Thirty adult pregnant rats (150-250 g) and their offspring were used in this study. Pregnant rats were randomly divided into control (n = 15) and TiO2 NP treated (n = 15) groups. A suspension of TiO2 NPs in phosphate-buffered saline was given orally to the treated group (0.1 ml/10 g body weight once daily) from days 6 to 12 of gestation. At term, maternal and neonatal lungs were collected and processed for energy-dispersive X-ray (EDX) and histological analysis. The mean linear intercept (MLI) and airspace wall thickness were measured by a stereological procedure with image analysis to assess alveolarization. EDX analysis demonstrated the presence of TiO2 in maternal and neonatal lungs. The lungs of TiO2 NP-treated mothers revealed evidence of pneumocytic apoptosis, abnormal lamellar inclusions, and macrophage and inflammatory cell infiltrates. Significant thinning of alveolar septa was detected in the treated rats (p < 0.001), but the MLI was constant in both groups (p = 0.207). Neonatal lungs from treated mothers revealed deficient septation, thickened mesenchyme between the saccules, pneumocytic apoptosis, atypical lamellar inclusions, and macrophage infiltration. The thickness of the primary septa was significantly increased (p = 0.001) with no significant change in MLI (p = 0.579) compared with the control group. In conclusion, TiO2 NPs were detected in maternal and neonatal lungs after oral intake by pregnant rats. The pulmonary response manifested as inflammatory lesions and delayed saccular development in neonates. PMID- 23933798 TI - The molecular characterisation of a Sida-infecting begomovirus from Jamaica. AB - The complete DNA sequence of both genome components of a new begomovirus (Sida golden mosaic Buckup virus-[Jamaica:St. Elizabeth:2004]; SiGMBuV-[JM:SE:04]) was determined from a field-infected Sida sp. sample from Buckup, St. Elizabeth, Jamaica. Phylogenetically, both genome components of SiGMBuV-[JM:SE:04] are most closely related to malvaceous weed-infecting Floridian and Mexican begomoviruses. Its DNA-B is a recombinant molecule, the majority of which was derived from a virus resembling Sida yellow mosaic Yucatan virus-[Mexico:Yucatan:2005] (SiYMYuV [MX:Yuc:05]), while nucleotides 43-342 were derived from a virus resembling Sida golden mosaic virus-[United States of America:Florida] (SiGMV-[US:Flo]). Symptomatic infectivity of our cloned SiGMBuV-[JM:SE:04] components was confirmed in Nicotiana benthamiana. PMID- 23933797 TI - Effect of air pollution and racism on ethnic differences in respiratory health among adolescents living in an urban environment. AB - Recent studies suggest that stress can amplify the harm of air pollution. We examined whether experience of racism and exposure to particulate matter with an aerodynamic diameter of less than 2.5 um and 10 um (PM2.5 and PM10) had a synergistic influence on ethnic differences in asthma and lung function across adolescence. Analyses using multilevel models showed lower forced expiratory volume (FEV1), forced vital capacity (FVC) and lower rates of asthma among some ethnic minorities compared to Whites, but higher exposure to PM2.5, PM10 and racism. Racism appeared to amplify the relationship between asthma and air pollution for all ethnic groups, but did not explain ethnic differences in respiratory health. PMID- 23933799 TI - DDQ-promoted direct transformation of benzyl hydrocarbons to amides via tandem reaction of the CDC reaction and Beckmann rearrangement. AB - An atom-efficient and transition metal-free approach to amides from the corresponding benzyl hydrocarbons through C-H and C-C bond cleavage has been developed. Mechanistic studies have shown that a DDQ-promoted cross dehydrogenative coupling (CDC) reaction with subsequent oxidation and rearrangement are involved in this transformation. PMID- 23933800 TI - LOXL2 expression is associated with invasiveness and negatively influences survival in breast cancer patients. AB - Lysyl oxidase-like 2 (LOXL2) is associated with invasiveness and metastasis in breast cancer. We analyzed the prognostic impact of LOXL2 for breast cancer patients and investigated the role of LOXL2 in breast cancer cell lines. Immunohistochemical study of LOXL2 expression was done in samples from 309 patients. Survival analysis was performed using log-rank test and Cox regression hazard model. After identification of LOXL2 expression in breast cancer cell lines, we performed matrigel invasion and wound-healing assays with LOXL2 silenced cell lines. In the human study, LOXL2 was expressed in 16.2 % of patients. Comparing the LOXL2-positive versus negative groups, there was a significantly higher proportion of estrogen receptor-negative patients (54.0 vs. 37.0 %, respectively; p = 0.029) and triple-negative patients (34.0 vs. 18.0 %; p = 0.022) in the positive group. In multivariate analysis for overall survival and metastasis-free survival, positive LOXL2 was demonstrated as a poor prognostic factor (HR 2.27 and 2.10, respectively). In vitro study indicated that LOXL2 silencing induces a mesenchymal-epithelial transition-like process in basal cell lines (MDA-MB-231 and BT549) associated with decreased invasive and migratory properties. These clinical and preclinical data confirm that higher LOXL2 expression is associated with invasiveness of basal-like breast cancer cells and lower survival of breast cancer patients. Our results suggest the clinical value of LOXL2 as a therapeutic target in breast cancer. PMID- 23933801 TI - Exploring novel targets of basal-like breast carcinoma by comparative gene profiling and mechanism analysis. AB - The heterogeneity of breast cancer makes its diagnosis and treatment far from being optimal. Analysis of traditional pathological and prognostic markers based on immunohistochemistry (IHC) is inadequate in elucidating the inherent heterogeneity of breast cancer, especially basal-like breast carcinoma (BLBC) which displays complex and unique epidemiological, phenotypic, and molecular features with distinctive relapse patterns and poor clinical outcomes. Gene expression profiling opened an avenue in research as independent predictors by classifying breast cancers into discrete groups with prognostic references, but it is not cost-effective in clinical application. It is necessary to develop an effective predictive gene list from gene profiling to optimize the treatment with traditional markers. In this report, we analyzed the correlation between IHC and gene profiling of breast cancer with an emphasis on the BLBC, highlighting the potential discovery of diagnostic markers and cellular mechanisms that may guide the development of BLBC-targeted therapy. Random forest-based classification and PAM50 gene-sets were used in the comparison analysis of traditional prognostic markers including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and microarray profiles. An intrinsic 40-gene set was developed to classify breast cancer subtypes, and genes expression differentiations were used to explore the different mechanisms between the BLBC and non-BLBC subtypes based on the comparison of clinicopathological markers and microarray profiling. Pathways and DNA repairs were analyzed to evaluate the biological mechanisms in BLBC and other breast cancer subtypes. It is reasonable to define BLBC as those tumors that are negative for ER, PR, and HER2 by IHC for their accordance with gene expression profiles. Focal adhesion kinase, ERBB, and their signaling pathways may play crucial role in BLBC. The intrinsic 40-gene set can be used to classify breast cancer and help to optimize therapeutic management of BLBC. PMID- 23933803 TI - Evaluation of a fully covered self-expanding metal stent with flared ends in malignant biliary obstruction: a multicenter study. AB - BACKGROUND AND AIMS: Limited data are available regarding fully covered metal stents in the management of malignant distal biliary strictures. The aim of this study was to evaluate the safety of a fully covered self-expanding metal stent (FCSEMS) with flared ends, in treating malignant biliary strictures. We report our long-term retrospective analysis from 6 centers. METHODS: A total of 260 patients (142 males, median age 68 y) underwent endoscopic retrograde cholangiopancreatography with placement of FCSEMS (WallFlex; Boston Scientific, Natick, MA) for the palliation of obstructive jaundice in the setting of pancreatic adenocarcinoma (169), metastatic disease (36), cholangiocarcinoma (23), ampullary cancer (19), or other (13). Patients were evaluated clinically in follow-up and biochemical tests of liver function were obtained. Data were recorded for the following variables: patient survival, duration of stent patency, the need for subsequent biliary intervention, and complications. RESULTS: A total of 266 FCSEMS were placed in 260 patients. There was a median survival of 100 days (range, 7 to 531 d). There was a mean follow-up of 134+/-118 days (range, 4 to 519 d). Biliary decompression was successful in 252 patients (97%). At the end of the study period, 121 were alive with a patent stent, 65 patients died with a patent stent, 40 patients were successfully bridged to surgery, 8 patients had their patent stent removed and had no need for further stenting, and 18 patients were lost to follow-up. Five patients who had a successfully placed FCSEMS were considered a failure due to the following reason: migration (2), cholangitis (1), stent occlusion (1), and removal for management of proximal biliary obstruction (1). Two additional patients experienced migration that did not require FCSEMS removal or replacement. Stent replacement was required in 10 patients, of whom 6 had a second FCSEMS placed. The remaining 4 were in the failure group and underwent replacement with either uncovered stents or plastic stents. Other complications, managed conservatively, included pain (2), postendoscopic retrograde cholangiopancreatography pancreatitis (4), fever (1), retroperitoneal perforation (1), and postsphincterotomy bleeding (1). The mean patency duration was 328 days (SE 19.04). The patency percentage was 83% at 3 months, 63% at 6 months, and 48.5% at 12 months. CONCLUSIONS: In the management of malignant distal biliary strictures, the fully covered WallFlex stent has acceptable patency and complication rates. Further long-term prospective data are required to confirm this observation. PMID- 23933804 TI - PCR amplification of the hrcV gene through specific primers for detecting Pseudomonas syringae pathovars. AB - Pseudomonas syringae pathovars are important pathogens among phytopathogenic bacteria causing a variety of diseases in plants. These pathogens can rapidly disseminate in a large area leading to infection and destruction of plants. To prevent the incidence of the bacteria, appropriate detection methods should be employed. Routinely serological tests, being time-consuming and costly, are exploited to detect these pathogens in plants, soil, water and other resources. Over the recent years, DNA-based detection approaches which are stable, rapid, specific and reliable have been developed and sequence analysis of various genes are widely utilized to identify different strains of P. syringe. However, the greatest limitation of these genes is inability to detect numerous pathovars of P. syringae. Herein, by using bioinformatic analysis, we found the hrcV gene located at pathogenicity islands of bacterial genome with the potential of being used as a new marker for phylogenetic detection of numerous pathovars of P. syringae. Following design of specific primers to hrcV, we amplified a 440 bp fragment. Of 13 assayed pathovars, 11 were detected. Also, through experimental procedures and bioinformatic analysis it was revealed that the designed primers have the capacity to detect 19 pathovars. Our findings suggest that hrcV could be used as a gene with the merit of detecting more pathovars of P. syringae in comparison with other genes used frequently for detection purposes. PMID- 23933805 TI - Rhizobacterium-mediated growth promotion and expression of stress enzymes in Glycine max L. Merrill against Fusarium wilt upon challenge inoculation. AB - Wilt disease of soybean caused by a very common soil-borne fungus, Fusarium oxysporum is one of the most destructive diseases of the crop. The aim of the present study was to characterize plant growth-promotion activities and induced resistance of a rhizobacterial strain for the soybean plant against F. oxysporum. Rhizobacterium strain SJ-5 exhibited plant growth-promotion characteristics and antagonistic activity against the test pathogen on dual plate assay. It was identified as a Carnobacterium sp. A 950 bp PCR product was amplified from Carnobacterium sp. strain SJ-5, using zwittermicin A self-resistance gene specific primers (zmaR). The strain produced indole 3-acetic acid (19 MUg/ml) in the presence of salt stress and exhibited growth in Dworkin and Foster salt medium amended with 1-aminocyclopropane-1-carboxylate (ACC) through ACC deaminase activity (277 nmol/mg/h) as compared to the control. Strain seeds treated with the strain significantly enhanced the quorum of healthy plants after challenge inoculation at 14 days after seeding. An increase in the activity of stress enzymes after challenge inoculation with the test pathogen is reported. Treatment with the bacterium resulted in an increase in the chlorophyll content in the leaves in comparison with challenge-inoculated plants. PMID- 23933806 TI - Determination of antimicrobial properties of picaridin and DEET against a broad range of microorganisms. AB - Insect repellents are topically applied to the skin and clothing of human and pet to keep flies, mosquitoes, and ticks away. Two important repellents, N,N-diethyl meta-toluamide (DEET) and Picaridin, have been widely used since their discovery. Although repellency and toxicological effects of DEET and Picaridin on human being and insects are well documented without understanding molecular mechanisms, there have been no attempts to study their effects on microorganisms up to now. In the current study, DEET and Picaridin have been investigated for their antimicrobial characteristics against a broad range of microorganisms including bacteria, yeast, and fungi for the first time. They exhibited considerable antibacterial, anticandidal and antifungal properties. Even though bacteria was found to be more sensitive to Picaridin, yeast and fungi were more susceptible to DEET. Antimicrobial properties of these two repellents will increase the usage and application areas of the products containing DEET and Picaridin. PMID- 23933807 TI - Changes in soil microbial community structure with planting years and cultivars of tree peony (Paeonia suffruticosa). AB - To understand the effects of planting tree peony (Paeonia suffruticosa) on soil microbial community structure, soil samples were collected from the tree peony gardens with three peony cultivars and three planting years, and adjacent wasteland at Luoyang, Henan Province of China. Soil microbial communities were analyzed by the polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) of partial 16S rDNA and sequencing methods. With the succeeding development of tree peony garden ecosystems, soil pH, organic C, total P, and available P increased. Soil total N, the cell numbers of bacteria, fungi, and actinomycetes, the Shannon's diversity index (H), richness (S), and Evenness (E(H)) first showed an increasing trend after wasteland was reclaimed and then a decreasing trend became apparent after 5 years of planting. Principal component analysis based on DGGE banding patterns showed that the microbial community structures were influenced by tree peony cultivars and planting years, and the influences of planting years were greater than those of tree peony cultivars. Sequence analysis of the DGGE bands revealed that the dominant bacteria in tree peony garden soils belonged to Proteobacteria, Bacteroidetes, Actinobacteria, Firmicutes, Acidobacteria, Planctomycetes, Euryarchaeota, and Unclassified bacteria. Moreover, some bacteria closely related to Bradyrhizobium, Sphingopyxis, Novosphingobium, and Sphingomonas, which have been associated with nitrogen fixation and recalcitrant compounds degradation, disappeared with the increasing planting years of tree peony. The bacteria had similarity of 100% compared with Pseudomonas mandelii which was a denitrifying bacteria, and increased gradually with increasing planting years of tree peony. PMID- 23933808 TI - Do wheelchairs spread pathogenic bacteria within hospital walls? AB - Transmission of nosocomial pathogens has been linked to transient colonization of health care workers, medical devices and other constituents of patients' environment. In this paper we present our findings concerning the presence of pathogenic bacteria on wheelchairs, and the possibility that wheelchairs constitute a reservoir of these bacteria and a means of spreading them. In this work we examined four wheelchairs, each from a different location: the internal medicine ward, the emergency department, the general surgery ward and wheelchair stockpile of the transportation unit of the hospital. The samples were collected and cultured on different media. Bacterial identification and antimicrobial sensitivity testing were carried out using accepted practices in the microbiology laboratory. We found that wheelchairs are contaminated with several pathogenic bacteria, among them antibiotic-resistant strains such as MRSA, Pseudomonas aeruginosa, Acinetobacter baumanni etc. Since there is no specific guideline protocol that deals with disinfection and cleaning frequency of wheelchairs in hospitals, we suggest each hospital to write one. PMID- 23933809 TI - Blastocystis sp. subtype 3 triggers higher proliferation of human colorectal cancer cells, HCT116. AB - Blastocystis sp. is a commonly found intestinal microorganism and was reported to cause many nonspecific gastrointestinal symptoms. Various subtypes have been previously reported, and the pathogenicity of different subtypes of Blastocystis is unclear and remains as a controversial issue. A recent study has shown that the Blastocystis antigen isolated from an unknown subtype could facilitate the proliferation of colon cancer cells. Current study was conducted to compare the effect of solubilized antigen isolated from five different subtypes of Blastocystis on colon cancer cells, HCT116. A statistically significant proliferation of these cells was observed when exposed to 1.0 MUg/ml solubilized antigen isolated from subtype 3 Blastocystis (37.22%, p < 0.05). Real-time polymerase chain reaction demonstrated the upregulation of Th2 cytokines especially transforming growth factor beta in subtype 3-treated cancer cells (p < 0.01, 3.71-fold difference). Of interest, subtype 3 Blastocystis antigen also caused a significantly higher upregulation of cathepsin B (subtypes 1 and 2, p < 0.01; subtypes 4 and 5, p < 0.001; 6.71-fold difference) which lead to the postulation that it may enhance the exacerbation of existing colon cancer cells by weakening the cellular immune response. The dysregulation of IFN-gamma and p53 expression also suggest Blastocystis as a proponent of carcinogenesis. Therefore, it is very likely for subtype 3 Blastocystis to have higher pathogenic potential as it caused an increased propagation of cancer cells and substantial amount of inflammatory reaction compared to other subtypes. PMID- 23933810 TI - Density of environmental Acanthamoeba and their responses to superheating disinfection. AB - Exposure to viable Acanthamoeba may cause fatal encephalitis and blinding keratitis in humans. Quantification of environmental Acanthamoeba by a reliable analytical assay is essential to assess the risk of human exposure and efficacy of control measures (e.g., superheating). Two DNA binding dyes (ethidium monoazide (EMA) and propidium monoazide) coupled with real-time quantitative PCR (qPCR) were tested for the ability in selectively quantifying viable Acanthamoeba castellanii. This newly developed qPCR assay was applied to determine the density of environmental Acanthamoeba and disinfection efficacy of superheating. Results showed qPCR with 2.3 MUg/mL EMA performed optimal with a great linearity (R (2) = 0.98) and a wide range of detection (5-1.5 * 10(5) cells). EMA-qPCR analyses on water samples collected from cooling towers, eyewash stations, irrigated farmlands, and various wastewater treatment stages further showed viable Acanthamoeba density from nondetectable level to 6.3 * 10(5) cells/L. Superheating A. castellanii at 75-95 degrees C for 20 min revealed significant reductions in both EMA-qPCR and qPCR detectable Acanthamoeba target sequences with an adverse association between heating temperature and qPCR-determined DNA quantity (r = -0.76 to -0.93, p < 0.0001). Moreover, A. castellanii trophozoites were more sensitive to superheat stress than the cells being encysted for 6 and 13 d (p < 0.05). This is the first study to quantify environmental Acanthamoeba and characterize their responses to superheating by EMA-qPCR. The quantitative data provided in this study facilitate to understand better the relative risk for human exposed to viable Acanthamoeba and the efficacy of superheating against Acanthamoeba. PMID- 23933811 TI - Coping with uncertainty: integrating physiology, behavior, and evolutionary ecology in a changing world. AB - The world is rapidly changing, and is exhibiting increased variability in environmental conditions. One of the grand challenges of current biology is to understand how, and predict which species will be able to cope with uncertain environments. The goal of this symposium was to explore how integrating physiological mechanisms with behavior and evolutionary ecology can help us understand how organisms cope with uncertainty. Here, we briefly review core principles that emerged in the symposium and topics covered by the presenters. Ecological studies can benefit from considering physiological mechanisms as these mechanisms may indicate constraints and trade-offs. In addition, considering the entire phenotype in an integrated way (the phenome) may reveal how different traits may trade-off or affect each other. Finally, considering the range of phenotypic plasticity is critical in exploring how organisms may cope with uncertainty via plasticity and/or adaptive evolution. PMID- 23933812 TI - Negative regulation of lncRNA GAS5 by miR-21. AB - In addition to protein-coding genes, the human genome makes a large amount of noncoding RNAs, including microRNAs and long noncoding RNAs (lncRNAs). Both microRNAs and lncRNAs have been shown to have a critical role in the regulation of cellular processes such as cell growth and apoptosis, as well as cancer progression and metastasis. Although it is well known that microRNAs can target a large number of protein-coding genes, little is known whether microRNAs can also target lncRNAs. In the present study, we determine whether miR-21 can regulate lncRNA expression. Using the lncRNA RT-PCR (reverse transcription-polymerase chain reaction) array carrying 83 human disease-related lncRNAs, we show that miR 21 is capable of suppressing the lncRNA growth arrest-specific 5 (GAS5). This negative correlation between miR-21 and GAS5 is also seen in breast tumor specimens. Of interest, GAS5 can also repress miR-21 expression. Whereas ectopic expression of GAS5 suppresses, GAS5-siRNA increases miR-21 expression. Importantly, there is a putative miR-21-binding site in exon 4 of GAS5; deletion of the miR-21-binding site abolishes this activity. Experiments with in vitro cell culture and xenograft mouse model suggest that GAS5 functions as a tumor suppressor. We further show that the biotin-labeled GAS5-RNA probe is able to pull down the key component (AGO2) of the RNA-induced silencing complex (RISC) and we subsequently identify miR-21 in this GAS5-RISC complex, implying that miR 21 and GAS5 may regulate each other in a way similar to the microRNA-mediated silencing of target mRNAs. Together, these results suggest that miR-21 targets not only tumor-suppressive protein-coding genes but also lncRNA GAS5. PMID- 23933813 TI - Autophagy and genomic integrity. AB - DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the damage. Autophagy, a lysosome-dependent degradation pathway that is activated by stressful situations such as starvation and oxidative stress, regulates cell fate after DNA damage and also has a pivotal role in the maintenance of nuclear and mitochondrial genomic integrity. Here, we review important evidence regarding the role played by autophagy in preventing genomic instability and tumorigenesis, as well as in micronuclei degradation. Several pathways governing autophagy activation after DNA injury and the influence of autophagy upon the processing of genomic lesions are also discussed herein. In this line, the mechanisms by which several proteins participate in both DDR and autophagy, and the importance of this crosstalk in cancer and neurodegeneration will be presented in an integrated fashion. At last, we present a hypothetical model of the role played by autophagy in dictating cell fate after genotoxic stress. PMID- 23933814 TI - TNFR1 determines progression of chronic liver injury in the IKKgamma/Nemo genetic model. AB - Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, as well as cancer. Deletion of NF-kappaB essential modulator in hepatocytes (IKKgamma/Nemo) causes spontaneous progression of TNF-mediated chronic hepatitis to hepatocellular carcinoma (HCC). Thus, we analyzed the role of death receptors including TNFR1 and TRAIL in the regulation of cell death and the progression of liver injury in IKKgamma/Nemo-deleted livers. We crossed hepatocyte-specific IKKgamma/Nemo knockout mice (Nemo(Deltahepa)) with constitutive TNFR1(-/-) and TRAIL(-/-) mice. Deletion of TNFR1, but not TRAIL, decreased apoptotic cell death, compensatory proliferation, liver fibrogenesis, infiltration of immune cells as well as pro inflammatory cytokines, and indicators of tumor growth during the progression of chronic liver injury. These events were associated with diminished JNK activation. In contrast, deletion of TNFR1 in bone-marrow-derived cells promoted chronic liver injury. Our data demonstrate that TNF- and not TRAIL signaling determines the progression of IKKgamma/Nemo-dependent chronic hepatitis. Additionally, we show that TNFR1 in hepatocytes and immune cells have different roles in chronic liver injury-a finding that has direct implications for treating chronic liver disease. PMID- 23933815 TI - Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells. AB - Many cancer entities and their associated cell line models are highly heterogeneous in their responsiveness to apoptosis inducers and, despite a detailed understanding of the underlying signaling networks, cell death susceptibility currently cannot be predicted reliably from protein expression profiles. Here, we demonstrate that an integration of quantitative apoptosis protein expression data with pathway knowledge can predict the cell death responsiveness of melanoma cell lines. By a total of 612 measurements, we determined the absolute expression (nM) of 17 core apoptosis regulators in a panel of 11 melanoma cell lines, and enriched these data with systems-level information on apoptosis pathway topology. By applying multivariate statistical analysis and multi-dimensional pattern recognition algorithms, the responsiveness of individual cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or dacarbazine (DTIC) could be predicted with very high accuracy (91 and 82% correct predictions), and the most effective treatment option for individual cell lines could be pre-determined in silico. In contrast, cell death responsiveness was poorly predicted when not taking knowledge on protein-protein interactions into account (55 and 36% correct predictions). We also generated mathematical predictions on whether anti-apoptotic Bcl-2 family members or x linked inhibitor of apoptosis protein (XIAP) can be targeted to enhance TRAIL responsiveness in individual cell lines. Subsequent experiments, making use of pharmacological Bcl-2/Bcl-xL inhibition or siRNA-based XIAP depletion, confirmed the accuracy of these predictions. We therefore demonstrate that cell death responsiveness to TRAIL or DTIC can be predicted reliably in a large number of melanoma cell lines when investigating expression patterns of apoptosis regulators in the context of their network-level interplay. The capacity to predict responsiveness at the cellular level may contribute to personalizing anti cancer treatments in the future. PMID- 23933816 TI - ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence. AB - Werner syndrome (WS) results from dysfunction of the WRN protein, and is associated with premature aging and early death. Here we report that loss of WRN function elicits accumulation of the Yes-associated protein (YAP protein), a major effector of the Hippo tumor suppressor pathway, both experimentally and in WS-derived fibroblasts. YAP upregulation correlates with slower cell proliferation and accelerated senescence, which are partially mediated by the formation of a complex between YAP and the PML protein, whose activity promotes p53 activation. The ATM kinase is necessary for YAP and PML accumulation in WRN depleted cells. Notably, the depletion of either YAP or PML partially impairs the induction of senescence following WRN loss. Altogether, our findings reveal that loss of WRN activity triggers the activation of an ATM-YAP-PML-p53 axis, thereby accelerating cellular senescence. The latter has features of SASP (senescence associated secretory phenotype), whose protumorigenic properties are potentiated by YAP, PML and p53 depletion. PMID- 23933817 TI - Characterization of novel MPS1 inhibitors with preclinical anticancer activity. AB - Monopolar spindle 1 (MPS1), a mitotic kinase that is overexpressed in several human cancers, contributes to the alignment of chromosomes to the metaphase plate as well as to the execution of the spindle assembly checkpoint (SAC). Here, we report the identification and functional characterization of three novel inhibitors of MPS1 of two independent structural classes, N-(4-{2-[(2 cyanophenyl)amino][1,2,4]triazolo[1,5-a]pyridin-6-yl}phenyl)-2-phenylacetamide (Mps-BAY1) (a triazolopyridine), N-cyclopropyl-4-{8-[(2-methylpropyl)amino]-6 (quinolin-5-yl)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2a) and N-cyclopropyl 4-{8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2b) (two imidazopyrazines). By selectively inactivating MPS1, these small inhibitors can arrest the proliferation of cancer cells, causing their polyploidization and/or their demise. Cancer cells treated with Mps-BAY1 or Mps-BAY2a manifested multiple signs of mitotic perturbation including inefficient chromosomal congression during metaphase, unscheduled SAC inactivation and severe anaphase defects. Videomicroscopic cell fate profiling of histone 2B-green fluorescent protein expressing cells revealed the capacity of MPS1 inhibitors to subvert the correct timing of mitosis as they induce a premature anaphase entry in the context of misaligned metaphase plates. Hence, in the presence of MPS1 inhibitors, cells either divided in a bipolar (but often asymmetric) manner or entered one or more rounds of abortive mitoses, generating gross aneuploidy and polyploidy, respectively. In both cases, cells ultimately succumbed to the mitotic catastrophe-induced activation of the mitochondrial pathway of apoptosis. Of note, low doses of MPS1 inhibitors and paclitaxel (a microtubular poison) synergized at increasing the frequency of chromosome misalignments and missegregations in the context of SAC inactivation. This resulted in massive polyploidization followed by the activation of mitotic catastrophe. A synergistic interaction between paclitaxel and MPS1 inhibitors could also be demonstrated in vivo, as the combination of these agents efficiently reduced the growth of tumor xenografts and exerted superior antineoplastic effects compared with either compound employed alone. Altogether, these results suggest that MPS1 inhibitors may exert robust anticancer activity, either as standalone therapeutic interventions or combined with microtubule-targeting chemicals. PMID- 23933818 TI - GRIN2A mutations cause epilepsy-aphasia spectrum disorders. AB - Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes. We identified four probands with GRIN2A variants that segregated with the disorder in their families. Notably, all four families presented with EAS, accounting for 9% of epilepsy-aphasia cases. We did not detect pathogenic variants in GRIN2A in other epileptic encephalopathies (n = 475) nor in probands with benign childhood epilepsy with centrotemporal spikes (n = 81). We report the first monogenic cause, to our knowledge, for EAS. GRIN2A mutations are restricted to this group of cases, which has important ramifications for diagnostic testing and treatment and provides new insights into the pathogenesis of this debilitating group of conditions. PMID- 23933819 TI - Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. AB - Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 * 10( 18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE. PMID- 23933820 TI - GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. AB - Epileptic encephalopathies are severe brain disorders with the epileptic component contributing to the worsening of cognitive and behavioral manifestations. Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and continuous spike and waves during slow-wave sleep syndrome (CSWSS) represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology. They show electroclinical overlap with rolandic epilepsy (the most frequent childhood focal epilepsy) and can be viewed as different clinical expressions of a single pathological entity situated at the crossroads of epileptic, speech, language, cognitive and behavioral disorders. Here we demonstrate that about 20% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy often associated with speech impairment can have a genetic origin sustained by de novo or inherited mutations in the GRIN2A gene (encoding the N-methyl-D-aspartate (NMDA) glutamate receptor alpha2 subunit, GluN2A). The identification of GRIN2A as a major gene for these epileptic encephalopathies provides crucial insights into the underlying pathophysiology. PMID- 23933823 TI - Recent developments in septic bursitis. AB - Septic bursitis is a disease that can be difficult to distinguish from aseptic bursitis. There are no definitive treatment guidelines. The optimal duration of antibiotic therapy is not defined. Most of the cases are due to infection with Staphylococcus aureus, although many other pathogens can also cause this infection. The optimal management includes early recognition and prompt initiation of appropriate antibiotic therapy. Surgical management may be necessary, and complications can arise from open procedures. Endoscopic bursectomy may be considered for patients requiring surgical debridement. This approach may lead to decreased morbidity in those requiring surgical intervention. PMID- 23933822 TI - Territorial inequalities in management and conformity to clinical guidelines for sarcoma patients: an exhaustive population-based cohort analysis in the Rhone Alpes region. AB - BACKGROUND: Sarcomas are rare cancers with great variability in clinical and histopathological presentation. The main objective of clinical practice guidelines (CPGs) is to standardize diagnosis and treatment. METHODS: From March 2005 to February 2007, all patients diagnosed with localized sarcoma in the Rhone Alpes region were included in a cohort-based study, to evaluate the compliance of sarcoma management with French guidelines in routine practice and to identify predictive factors for compliance with CGPs. RESULTS: 634 (71 %) patients with localized sarcoma satisfying the inclusion criteria were included out of 891 newly diagnosed sarcomas. Taking into account initial diagnosis until follow-up, overall conformity to CPGs was only 40 % [95 % confidence interval (CI) = 36-44], ranging from 54 % for gastrointestinal stromal tumor to 36 % for soft tissue sarcoma and 42 % for bone sarcoma. In multivariate analysis, primary tumor type [relative risk (RR) = 4.42, 95 % CI = 2.79-6.99, p < 0.001], dedicated multidisciplinary staff before surgery (RR = 4.19, 95 % CI = 2.39-7.35, p < 0.001) and management in specialized hospitals (RR = 3.71, 95 % CI = 2.43-5.66, p < 0.001) were identified as unique independent risk factors for conformity to CPGs for overall treatment sequence. CONCLUSIONS: With only 40 % of total conformity to CPGs, the conclusions support the improvement of initial sarcoma management and its performance in specialized centres or within specialized dedicated networks. PMID- 23933824 TI - Procalcitonin for antibiotic treatment in intensive care unit patients. AB - Procalcitonin (PCT), a 116-aminoacids prohormone, has been substantially studied over the last 2 decades in the field of sepsis. Disappointingly low sensitivity values led to the abandonment of the concept of it as a diagnostic tool and then to its being considered more as a prognostic marker with a good correlation with severe infection. Later on, growing concerns about multidrug-resistant bacteria in the ICU environment and about the cost and side effects of antibiotics suggested that PCT might prove to be a valuable asset in stewardship programs. Numerous but hardly comparable randomized controlled trials assessing either initiation or deescalation in ICU patients have been published. Stewardship encompassing PCT should focus on the latter, because of the high negative predictive value of this biomarker. However, there still would be safety concerns if a systematic implementation of PCT were to be considered in daily stewardship programs in the ICU, especially in extra-thoracic sepsis. PMID- 23933827 TI - The evolution and function of vessel and pit characters with respect to cavitation resistance across 10 Prunus species. AB - Various structure-function relationships regarding drought-induced cavitation resistance of secondary xylem have been postulated. These hypotheses were tested on wood of 10 Prunus species showing a range in P50 (i.e., the pressure corresponding to 50% loss of hydraulic conductivity) from -3.54 to -6.27 MPa. Hydraulically relevant wood characters were quantified using light and electron microscopy. A phylogenetic tree was constructed to investigate evolutionary correlations using a phylogenetically independent contrast (PIC) analysis. Vessel grouping characters were found to be most informative in explaining interspecific variation in P50, with cavitation-resistant species showing more solitary vessels than less resistant species. Co-evolution between vessel-grouping indices and P50 was reported. P50 was weakly correlated with the shape of the intervessel pit aperture, but not with the total intervessel pit membrane area per vessel. A negative correlation was found between P50 and intervessel pit membrane thickness, but this relationship was not supported by the PIC analysis. Cavitation resistance has co-evolved with vessel grouping within Prunus and was mainly influenced by the spatial distribution of the vessel network. PMID- 23933825 TI - Isolation and characterization of Brachyspira spp. including "Brachyspira hampsonii" from lesser snow geese (Chen caerulescens caerulescens) in the Canadian Arctic. AB - Brachyspira is associated with diarrhea and colitis in pigs, and control of these pathogens is complicated by their complex ecology. Identification of wildlife reservoirs of Brachyspira requires the discrimination of colonized animals and those simply contaminated through environmental exposure. Lesser snow geese (Chen caerulescens caerulescens) were sampled in the Canadian arctic during the summer of 2011, and cloacal swabs were cultured on selective media. Brachyspira isolates were obtained from 15/170 (8.8 %) samples, and 12/15 isolates were similar to isolates previously recovered from pigs, including "Brachyspira hampsonii", a recently characterized species associated with dysentery-like disease in pigs in North America. A pilot inoculation study with one strongly beta-hemolytic B. hampsonii isolate resulted in fecal shedding of the isolate by inoculated pigs for up to 14 days post-inoculation, but no severe clinical disease. Results of this study indicate that lesser snow geese can be colonized by Brachyspira strains that can also colonize pigs. Millions of lesser snow geese (C. caerulescens caerulescens) travel through the major pork-producing areas of Canada and the USA during their annual migration, making them a potential factor in the continental distribution of these bacteria. PMID- 23933826 TI - Co-transduction of ribosomal protein L23 enhances the therapeutic efficacy of adenoviral-mediated p53 gene transfer in human gastric cancer. AB - Induction of murine double minute 2 (MDM2) expression is thought to be a determinant of resistance to p53 gene therapy for cancer. Previous studies have revealed that ribosomal protein L23 (RPL23) inhibits MDM2-mediated p53 degradation through direct binding to MDM2. In addition, ectopically expressed RPL23 was reported to interact with MDM2 in both the nucleus and cytoplasm, by which RPL23 indirectly inhibited MDM2-p53 binding. Based on the known molecular properties of the RPL23 protein, it was speculated that co-transduction of RPL23 may protect wild-type p53 protein from MDM2-mediated inactivation and, thus, improve the effect of delivering therapeutic exogenous p53. To test this hypothesis, we constructed a bicistronic adenoviral vector expressing both the RPL23 and p53 genes (Ad-RPL23/p53) and compared its tumor-suppressor activity in human gastric cancer with that of a single gene vector for p53 (Ad-p53). In the in vivo and in vitro experiments, we observed that treatment with Ad-RPL23/p53 resulted in a stronger antitumor response compared to that obtained using Ad-p53. Moreover, the antitumor response of the bicistronic adenovirus was obtained not only in MGC803 cells (endogenous mutant p53) but also in MKN45 cells (endogenous wild-type p53) which were initially resistant to p53 gene transfer, indicating that co-transduction of RPL23 also expanded the utility of p53 gene therapy. Furthermore, in an orthotopic nude mouse model of human gastric cancer, we found that the survival benefit was greater after Ad-RPL23/p53 treatment than after Ad p53. Taken together, the data presented here demonstrate that co-transduction of RPL23 enhances the therapeutic efficacy of adenoviral-mediated p53 gene transfer in models of human gastric cancer and support the use of this strategy for cancer treatment. PMID- 23933828 TI - Ultrasonic spectroscopy allows a rapid determination of the relative water content at the turgor loss point: a comparison with pressure-volume curves in 13 woody species. AB - The turgor loss point (TLP), which is considered a threshold for many physiological processes, may be useful in plant-breeding programs or for the selection of reforestation species. Obtaining TLP through the standard pressure volume (p-v) curve method in a large set of species is highly time-consuming and somewhat subjective. To solve this problem, we present an objective and a less time-consuming technique based on the leaf resonance able to calculate the relative water content (RWC) at TLP (RWCTLP). This method uses air-coupled broadband ultrasonic spectroscopy to obtain the sigmoidal relation between RWC and the standardized resonant frequency (f/fo). For the 13 species measured, the inflexion point of the RWC-f/fo relationship ( ) was not statistically different from the value of RWC at the TLP obtained with the p-v curves (RWCTLP p-v). PMID- 23933829 TI - Seasonal and inter-annual dynamics of growth, non-structural carbohydrates and C stable isotopes in a Mediterranean beech forest. AB - Seasonal and inter-annual dynamics of growth, non-structural carbohydrates (NSC) and carbon isotope composition (delta(13)C) of NSC were studied in a beech forest of Central Italy over a 2-year period characterized by different environmental conditions. The net C assimilated by forest trees was mainly used to sustain growth early in the season and to accumulate storage carbohydrates in trunk and root wood in the later part of the season, before leaf shedding. Growth and NSC concentration dynamics were only slightly affected by the reduced soil water content (SWC) during the drier year. Conversely, the carbon isotope analysis on NSC revealed seasonal and inter-annual variations of photosynthetic and post carboxylation fractionation processes, with a significant increase in delta(13)C of wood and leaf soluble sugars in the drier summer year than in the wetter one. The highly significant correlation between delta(13)C of leaf soluble sugars and SWC suggests a decrease of the canopy C isotope discrimination and, hence, an increased water-use efficiency with decreasing soil water availability. This may be a relevant trait for maintaining an acceptable plant water status and a relatively high C sink capacity during dry seasonal periods. Our results suggest a short- to medium-term homeostatic response of the Collelongo beech stand to variations in water availability and solar radiation, indicating that this Mediterranean forest was able to adjust carbon-water balance in order to prevent C depletion and to sustain plant growth and reserve accumulation during relatively dry seasons. PMID- 23933830 TI - Within-twig leaf distribution patterns differ among plant life-forms in a subtropical Chinese forest. AB - In theory, plants can alter the distribution of leaves along the lengths of their twigs (i.e., within-twig leaf distribution patterns) to optimize light interception in the context of the architectures of their leaves, branches and canopies. We hypothesized that (i) among canopy tree species sharing similar light environments, deciduous trees will have more evenly spaced within-twig leaf distribution patterns compared with evergreen trees (because deciduous species tend to higher metabolic demands than evergreen species and hence require more light), and that (ii) shade-adapted evergreen species will have more evenly spaced patterns compared with sun-adapted evergreen ones (because shade-adapted species are generally light-limited). We tested these hypotheses by measuring morphological traits (i.e., internode length, leaf area, lamina mass per area, LMA; and leaf and twig inclination angles to the horizontal) and physiological traits (i.e., light-saturated net photosynthetic rates, Amax; light saturation points, LSP; and light compensation points, LCP), and calculated the 'evenness' of within-twig leaf distribution patterns as the coefficient of variation (CV; the higher the CV, the less evenly spaced leaves) of within-twig internode length for 9 deciduous canopy tree species, 15 evergreen canopy tree species, 8 shade adapted evergreen shrub species and 12 sun-adapted evergreen shrub species in a subtropical broad-leaved rainforest in eastern China. Coefficient of variation was positively correlated with large LMA and large leaf and twig inclination angles, which collectively specify a typical trait combination adaptive to low light interception, as indicated by both ordinary regression and phylogenetic generalized least squares analyses. These relationships were also valid within the evergreen tree species group (which had the largest sample size). Consistent with our hypothesis, in the canopy layer, deciduous species (which were characterized by high LCP, LSP and Amax) had more even leaf distribution patterns than evergreen species (which had low LCP, LSP and Amax); shade-adapted evergreen species had more even leaf distribution patterns than sun-adapted evergreen species. We propose that the leaf distribution pattern (i.e., 'evenness' CV, which is an easily measured functional trait) can be used to distinguish among life-forms in communities similar to the one examined in this study. PMID- 23933831 TI - Association of loblolly pine xylem development gene expression with single nucleotide polymorphisms. AB - Variation in the expression of genes with putative roles in wood development was associated with single-nucleotide polymorphisms (SNPs) using a population of loblolly pine (Pinus taeda L.) that included individuals from much of the native range. Association studies were performed using 3938 SNPs and expression data obtained using quantitative real-time polymerase chain reaction (PCR) (qRT-PCR) for 106 xylem development genes in 400 clonally replicated loblolly pine individuals. A general linear model (GLM) approach, which takes the underlying population structure into consideration, was used to discover significant associations. After adjustment for multiple testing using a false discovery rate correction, 88 statistically significant associations (Q<0.05) were observed for 80 SNPs with the expression data of 33 xylem development genes. Thirty SNPs caused nonsynonymous mutations, 18 resulted in synonymous mutations, 11 were in 3' untranslated regions (UTRs), 1 was in a 5' UTR and 20 were in introns. Using AraNet, we found that Arabidopsis genes with high similarity to the loblolly pine genes involved in 21 of the 88 statistically significant associations are connected in functional gene networks. Comparisons of gene expression values revealed that in most cases the average expression in plants homozygous for the rare SNP allele was lower than that of plants that were heterozygous or homozygous for the abundant allele. Although there are association studies of SNPs and expression profiles for humans, Arabidopsis and white spruce, to the best of our knowledge, this is the first example of such an association genetic study in pines. Functional validation of these associations will lead to a deeper understanding of the molecular basis of phenotypic differences in wood development among individuals in conifer populations. PMID- 23933832 TI - Spleen-preserving distal pancreatectomy: perioperative and long-term outcome analysis. AB - BACKGROUND/AIMS: Despite the emphasis on its role, the spleen has commonly been removed in distal pancreatectomy. We aimed to evaluate the efficacy of spleen salvage during distal pancreatectomy for patients with benign and borderline malignant tumors. METHODOLOGY: 82 patients underwent distal pancreatectomy with splenectomy (DPS) and 78 patients underwent spleen-preserving distal pancreatectomy (SPDP). Medical records were retrospectively reviewed. RESULTS: There were no significant differences in demographics, final diagnoses estimated blood loss, intraoperative transfusion and operative time between the two groups. More perioperative complications occurred in DPS group than in the SPDP group (p = 0.0344). Consequently, postoperative hospital stay was significantly shorter in SPDP group than in DPS group (p = 0.0273). On the follow-up survey, episodes of common cold or flu were apparently more frequent in the DPS group (p = 0.047). More patients in the DPS group felt fatigue (p = 0.0481) and poorer health condition (p = 0.0371). Less newly developed (p = 0.0193) and aggravated diabetes mellitus (p = 0.0361) were also observed in SPDP group. CONCLUSIONS: In addition to frequent higher-grade complications, and prolonged hospital stays, DPS appeared to result in poorer health condition based on follow-up survey. Even an effort to preserve adult spleen in distal pancreatectomy is worthwhile. PMID- 23933833 TI - Brown adipose tissue thermogenesis in humans. AB - The prevalence of obesity and type 2 diabetes is at epidemic proportions. Classical interventions aimed at targeting obesity, such as reducing energy intake or increasing exercise, are often not effective over the long term. In contrast to white adipocytes, which store energy, brown adipocytes generate heat via mitochondrial uncoupling protein 1, thereby acting as a defence against hypothermia and, potentially, obesity. In this issue of Diabetologia, Admiraal et al compare brown adipose tissue activation during cold exposure between two different ethnic groups: South Asians and Europids. The prevalence of abdominal obesity and type 2 diabetes differs among various ethnic groups and decreased BAT metabolic activity could be one causal factor. As yet, the clinical impact of this 'rediscovered' organ is largely unknown, but has potential as a drug target for obesity. PMID- 23933821 TI - Genetic relationship between five psychiatric disorders estimated from genome wide SNPs. AB - Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 +/- 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 +/- 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 +/- 0.06 s.e.), and ADHD and major depressive disorder (0.32 +/- 0.07 s.e.), low between schizophrenia and ASD (0.16 +/- 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders. PMID- 23933834 TI - beta2-Adrenergic receptor agonist administration promotes counter-regulatory responses and recovery from hypoglycaemia in rats. AB - AIMS/HYPOTHESIS: We have previously reported that local activation of beta2 adrenergic receptors (B2ARs) in the ventromedial hypothalamus (VMH) enhances hypoglycaemic counter-regulation. This study examines whether peripheral delivery of a selective B2AR agonist could also promote counter-regulatory responses and thereby has potential therapeutic value to limit hypoglycaemia risk. METHODS: Conscious male Sprague-Dawley rats received an intra-arterial injection of the B2AR specific agonist, formoterol, or a control solution either before a hyperinsulinaemic-hypoglycaemic clamp study or immediately before recovery from insulin-induced hypoglycaemia. In addition, the capacity of a VMH-targeted microinjection of a B2AR antagonist to limit the anti-insulin effect of the B2AR agonist was assessed. RESULTS: Systemic delivery of B2AR agonist markedly reduced the exogenous glucose infusion rate (GIR) required during the hypoglycaemic clamp study. This effect was mediated by blockade of insulin's inhibitory effect on endogenous glucose production. Local blockade of B2ARs within the VMH using a specific antagonist partially diminished the effect of systemic activation of B2ARs during hypoglycaemia at least in part by diminishing the adrenaline (epinephrine) response to hypoglycaemia. Peripheral B2AR agonist injection also enhanced glucose recovery from insulin-induced hypoglycaemia. CONCLUSIONS/INTERPRETATION: Systemic B2AR agonist administration acts to limit insulin-induced hypoglycaemia by offsetting insulin's inhibitory effect on hepatic glucose production. This effect appears to be predominately mediated via a direct effect on liver B2ARs, but a small stimulatory effect on B2ARs within the VMH cannot be excluded. Our data suggest that formoterol may have therapeutic value to limit the risk of hypoglycaemia in patients with diabetes. PMID- 23933835 TI - Metformin action in human hepatocytes: coactivation of atypical protein kinase C alters 5'-AMP-activated protein kinase effects on lipogenic and gluconeogenic enzyme expression. AB - AIMS/HYPOTHESIS: Atypical protein kinase C (aPKC) levels and activity are elevated in hepatocytes of individuals with type 2 diabetes and cause excessive increases in the levels of lipogenic and gluconeogenic enzymes; aPKC inhibitors largely correct these aberrations. Metformin improves hepatic gluconeogenesis by activating 5'-AMP-activated protein kinase (AMPK). However, metformin also activates aPKC in certain tissues; in the liver, this activation could amplify diabetic aberrations and offset the positive effects of AMPK. In this study, we examined whether metformin activates aPKC in human hepatocytes and the metabolic consequences of any such activation. METHODS: We compared protein kinase activities and alterations in lipogenic and gluconeogenic enzyme levels during activity of the AMPK activators metformin and AICAR, relative to those of an aPKC iota inhibitor, in hepatocytes from non-diabetic and type 2 diabetic human organ donors. RESULTS: Metformin and 5-aminoimidazole-4-carboxamide-1-beta-4 ribofuranoside (AICAR) activated aPKC at concentrations comparable with those required for AMPK activation. Moreover, both agents increased lipogenic enzyme levels by an aPKC-dependent mechanism. Thus, whereas insulin- and diabetes dependent increases in lipogenic enzyme levels were reversed by aPKC inhibition, such levels were increased in hepatocytes from non-diabetic donors and remained elevated in hepatocytes from diabetic donors following metformin and AICAR treatment. In addition, whereas aPKC inhibition diminished gluconeogenic enzyme levels in the absence and presence of insulin in hepatocytes from both non diabetic and diabetic donors, metformin and AICAR increased gluconeogenic enzyme levels in hepatocytes from non-diabetic individuals, but nevertheless diminished gluconeogenic enzyme levels in insulin-treated hepatocytes from diabetic donors. CONCLUSIONS/INTERPRETATION: Metformin and AICAR activate aPKC together with AMPK in human hepatocytes. Activation of aPKC increases lipogenic enzyme levels and alters gluconeogenic enzyme levels, and therefore appears to offset the positive effects of AMPK. PMID- 23933836 TI - [New aspects on biomechanics of the cornea in keratoconus]. AB - Keratoconus is a bilateral, progressive, non-inflammatory corneal degeneration characterized by a conical protrusion of the cornea which leads to marked corneal thinning thereby inducing severe visual impairment due to increasingly irregular astigmatism. Current corneal imaging technology provides an accurate anatomical and topographical analysis of the cornea which is the 'gold standard for the diagnosis of keratoconus and preoperative screening in refractive surgery. Until recently evaluation of corneal biomechanics was feasible only in vitro as the technology required for in vivo analysis was not available. However, in recent years methods have been developed which enable an accurate in vivo analysis of corneal biomechanics thereby enhancing the early detection of keratoconus and improving the safety profile of corneal refractive procedures. PMID- 23933837 TI - [Bilateral papilledema, unilateral loss of vision and abducens nerve palsy]. AB - A 35-year-old woman complained of headache, reduced visual acuity, restricted visual field in the right eye and blindness in the left eye. The examination of the retina showed papilledema and peripapillary hemorrhages in both eyes. Magnetic resonance imaging (MRI) revealed a sinus thrombosis. Despite modern imaging technologies sinus thrombosis is an often overlooked, life-threatening disease and needs immediate treatment in order to avoid long-term consequences. An ophthalmological examination can be pioneering as it leads to further imaging. PMID- 23933838 TI - [Intraocular lens as a drug delivery device]. AB - The development of an intraocular lens (IOL) as a drug delivery device has been the purpose of numerous preclinical studies and might become a future technology in cataract surgery. There are three techniques of pharmacological IOL modification: surface modification (coating), optic modification (soaking) or haptic modification with a slow-release-system. The therapeutic goals are endophthalmitis, postoperative inflammation and posterior capsule opacification. PMID- 23933839 TI - [Validation of an automatic test system for sterile testing of amniotic membranes]. AB - PURPOSE: The use of cryopreserved amniotic membranes for the treatment of diseases and injuries of the surface of the eye is an established procedure in ophthalmological surgery. Before clinical use of cryopreserved amniotic membranes (AM) a careful testing for microbial contamination is essential to ensure a safe application. In this study the use of the BacT/Alert(r) test system was evaluated for screening of microbial growth in AMs. MATERIALS AND METHODS: Minced fresh and cryopreserved AMs (approximately 5 * 5 cm in size) were injected with 10 ml of balanced salt solution in separate culture media test bottles and 10 ml of cryopreservation medium bacterial and fungal test strains according to European Union (EU) regulations were applied to test the performance of the system. Approximately 10-100 colony forming units were applied on the samples prior to injection in the corresponding test bottles. Bottles were incubated at 37 degrees C for 7 days. Positive controls contained only balanced salt solution and the test strains while negative controls contained the test material without microbial test strains. RESULTS: Growth of the test strains was detected in all inoculated samples from non-processed and cryopreserved AM within the 7-day incubation period. In samples of the cryopreservation medium only growth of the fungus Candida albicans could be detected. CONCLUSIONS: The automated BacT/Alert test system is suitable for testing of microbial safety of amniotic membranes but not for testing the cryopreservation medium in clinical practice according to EU regulations. PMID- 23933840 TI - Characterization of polarity development through 2- and 3-D imaging during the initial phase of microspore embryogenesis in Brassica napus L. AB - Isolated microspores of B. napus in culture change their developmental pathway from gametophytic to sporophytic and form embryo-like structures (ELS) upon prolonged heat shock treatment (5 days at 32 degrees C). ELS express polarity during the initial days of endosporic development. In this study, we focussed on the analysis of polarity development of ELS without suspensor. Fluorescence microscopy and 3-D confocal laser scanning microscopy (CLSM) without tissue interfering enabled us to get a good insight in the distribution of nuclei, mitochondria and endoplasmic reticulum (ER), the architecture of microtubular (MT) cytoskeleton and the places of 5-bromo-2'-deoxy-uridine (BrdU) incorporation in successive stages of microspore embryogenesis. Scanning electron microscopy (SEM) analysis revealed, for the first time, the appearance of a fibrillar extracellular matrix-like structure (ECM-like structure) in androgenic embryos without suspensor. Two types of endosporic development were distinguished based upon the initial location of the microspore nucleus. The polarity of dividing and growing cells was recognized by the differential distributions of organelles, by the organization of the MT cytoskeleton and by the visualization of DNA synthesis in the cell cycle. The directional location of nuclei, ER, mitochondria and starch grains in relation to the MTs configurations were early polarity indicators. Both exine rupture and ECM-like structure on the outer surfaces of ELS are supposed to stabilize ELS's morphological polarity. As the role of cell polarity during early endosporic microspore embryogenesis in apical-basal cell fate determination remains unclear, microspore culture system provides a powerful in vitro tool for studying the developmental processes that take place during the earliest stages of plant embryogenesis. PMID- 23933841 TI - Impact of Let's Go! 5-2-1-0: a community-based, multisetting childhood obesity prevention program. AB - OBJECTIVE: Document the impact of Let's Go!, a multisetting community-based childhood obesity prevention program on participants in 12 communities in Maine. METHODS: The study used repeated random telephone surveys with 800 parents of children to measure awareness of messages and child behaviors. Surveys were conducted in schools, child care programs, and afterschool programs to track changes in policies and environments. RESULTS: Findings show improvements from 2007 to 2011: Children consuming fruits and vegetables increased from 18%, 95% CI [15, 21], to 26% [23, 30] (p < .001); children limiting sugary drinks increased from 63% [59, 67] to 69% [65, 73] (p = .011); and parent awareness of the program grew from 10% [7, 12] to 47% [43, 51] (p < .001). Participating sites implemented widespread changes to promote healthy behaviors. CONCLUSIONS: A multisetting, community-based intervention with a consistent message can positively impact behaviors that lead to childhood obesity. PMID- 23933842 TI - Topical review: sluggish cognitive tempo: research findings and relevance for pediatric psychology. AB - OBJECTIVE: To summarize recent research on sluggish cognitive tempo (SCT) and consider the potential relevance of SCT for the field of pediatric psychology. METHODS: Literature review. RESULTS: Recent empirical evidence shows SCT symptoms consisting of sluggish/sleepy and daydreamy behaviors to be distinct from Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms. SCT is associated with psychosocial functioning in children and adolescents, including internalizing symptoms, social withdrawal, and, possibly, academic impairment. CONCLUSIONS: The recent findings reviewed suggest that SCT is an important construct for pediatric psychologists to be aware of and may also be directly useful for the research and practice of pediatric psychology. PMID- 23933843 TI - Photophysics of indole-2-carboxylic acid (I2C) and indole-5-carboxylic acid (I5C): heavy atom effect. AB - In this study the effect of carboxylic group substitution in the 2 and 5 position of indole ring on the photophysics of the parent indole chromophore has been studied. The photophysical parameters crucial in triplet state decay mechanism of aqueous indole-2-carboxylic acid (I2C) and indole-5-carboxylic acid (I5C) have been determined applying our previously proposed methodology based on the heavy atom effect and fluorescence and phosphorescence decay kinetics [Kowalska-Baron et al., 2012]. The determined time-resolved phosphorescence spectra of I2C and I5C are red-shifted as compared to that of the parent indole. This red-shift was especially evident in the case of I2C and may indicate the possibility of hydrogen bonded complex formation incorporating carbonyl CO, the NH group of I2C and, possibly, surrounding water molecules. The possibility of the excited state charge transfer process and the subsequent electronic charge redistribution in such a hydrogen bonded complex may also be postulated. The resulting stabilization of the I2C triplet state is manifested by its relatively long phosphorescence lifetime in aqueous solution (912 MUs). The relatively short phosphorescence lifetime of I5C (56 MUs) may be the consequence of more effective ground-state quenching of I5 C triplet state. This hypothesis may be strengthened by the significantly larger value of the determined rate constant of I5C triplet state quenching by its ground-state (4.4 * 10(8)M(-1)s(-1)) as compared to that for indole (6.8 * 10(7)M(-1)s(-1)) and I2C (2.3 * 10(7)M(-1)s(-1)). The determined bimolecular rate constant for triplet state quenching by iodide [Formula: see text] is equal to 1 * 10(4)M(-1)s(-1); 6 * 10(3)M(-1)s(-1) and 2.7 * 10(4)M(-1)s(-1) for indole, I2 C and I5 C, respectively. In order to obtain a better insight into iodide quenching of I2C and I5C triplet states in aqueous solution, the temperature dependence of the bimolecular rate constants for iodide quenching of the triplet states has been expressed in Arrhenius form. The linearity of the obtained Arrhenius plots clearly indicated the existence of one temperature-dependent non-radiative process for the de-excitation of I2C and I5C triplet state in the presence of iodide. This process may be attributed to the solute-quenching by iodide and, most probably, proceeds via reversibly formed exciplex. The activation energies obtained from linear Arrhenius plots (1.89 kcal/mol for I5 C; 2.55 kcal/mol for I2 C) are smaller as compared to that for diffusion controlled reactions in aqueous solution (about 4 kcal/mol), which may indicate the great importance of the electrostatic interactions between solute and iodide ions in lowering the energy barrier needed for the formation of the triplet-quencher complex. Based on the theoretical predictions (at the DFT(CAM B3LYP)/6-31+G(d,p) level of theory) and careful analysis of the obtained FTIR spectra it may be concluded that in the solid state I2 C and I5 C molecules form associates by intermolecular NH . . . OC and OH . . . OC hydrogen bonding interactions, whereas the existence of intramolecular NH . . . OC interactions in the solid state of I2C and I5C is highly unlikely. PMID- 23933844 TI - Labeling of human hepatocellular carcinoma cells by hexamethylene diamine modified fluorescent carbon dots. AB - Fluorescent carbon dots (CDs) were synthesized by a solvothermal method with glucose as carbon source and surface-modified with 1,6-hexamethylene diamine. In this hybrid CDs, the modification played important role for improving the fluorescent performance by introducing nitrogenous compound to passivate CD's surface, making the CDs emit strong fluorescence. The as-prepared CDs were linked with mouse anti-human Alpha fetoprotein (AFP) antibody and goat anti-mouse immunoglobulin (IgG) to directly and indirectly label fixed human hepatocellular carcinoma cells, respectively. The cytotoxicity of these CDs were also tested using the human hepatocellular carcinoma cells. No apparent cytotoxicity was observed, which suggested the potential application of the as-prepared CDs in bioimaging. PMID- 23933845 TI - Amygdalin analogues inhibit IFN-gamma signalling and reduce the inflammatory response in human epidermal keratinocytes. AB - Peptide T (PT), an octapeptide fragment located in the V2 region of the HIV-1 gp120-coating protein, appears to be beneficial in the treatment of psoriasis. Our previous investigations suggest that keratinocytes play a key role in conditioning the therapeutic effects of PT in psoriasis. The aim of this study was to explore the effects of PT and the peptidomimetic natural products, Dhurrin and Prunasin, on the expression of the IL-6, IL-8, IL-23, HSP70 and ICAM-1 on IFN gamma and TNF-alpha-NHEK activated cells. Moreover, we analysed the interference of PT and its analogues through STAT-3 activation. Our results show that the analogues tested exhibit the beneficial biological effects of PT, suggesting the primary role of keratinocytes upon which PT and the peptidomimetics act directly, by reducing proinflammatory responses. Its reduction appears to be important for therapeutic approach in psoriasis pathogenesis. PMID- 23933847 TI - Bradycardia in the athlete: don't always blame the autonomic system! PMID- 23933846 TI - Honokiol inhibits tumor necrosis factor-alpha-stimulated rat aortic smooth muscle cell proliferation via caspase- and mitochondrial-dependent apoptosis. AB - This study aims to investigate the effects of honokiol on proliferation, cell cycle, and apoptosis in tumor necrosis factor (TNF)-alpha-induced rat aortic smooth muscle cells (RASMCs). We found that honokiol treatment showed potent inhibitory effects on TNF-alpha-induced RASMC proliferation, which were associated with G0/G1 cell cycle arrest and downregulation of cell cycle-related proteins, including cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2 and CDK4. Furthermore, honokiol treatment led to the release of cytochrome c into cytosol and a loss of mitochondrial membrane potential (DeltaPsim), as well as a decrease in the expression of Bcl-2 and an increase in the expression of Bax. Treatment with honokiol also reduced TNF-alpha-induced phosphorylation of p38, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase. Taken together, our results suggest that honokiol suppresses TNF-alpha-stimulated RASMC proliferation via caspase- and mitochondria-dependent apoptosis and highlight the therapeutic potential of honokiol in the prevention of cardiovascular diseases. PMID- 23933848 TI - Apparent delay in tachycardia detection due to ventricular pacing: what is the mechanism? PMID- 23933849 TI - Risk of syncope during work. AB - AIMS: Little is known regarding the overall prevalence of syncope in a population of workers and the risk of occurrence during working time. METHODS AND RESULTS: A total of 452 consecutive workers (mean age: 46 +/- 9 years) were invited to answer an anonymous questionnaire. They had been employed for 22 +/- 10 years for a total of 9765 years worked. In the cohort, 160 subjects (35%) reported a total of 465 episodes of syncope during their lives; 64 (14%) suffered a syncopal episode after the start of employment, but only 26 (5.7%) reported syncope at work, 7 (1.5%) having had 2 episodes, and 1 (0.2%) 3 episodes (total: 36 episodes). The risk of syncope during work was 4.6 times higher for those who had a prior history of syncope [18 of 138 (13%)] than for those who did not [8 of 314 (3%), P = 0.001]. The occurrence of syncope during work for the patients with a history of syncope was one syncopal episode in every 99 years worked and for those who had already had an episode during work, one episode in every 16 years worked. Only one patient experienced minor trauma as a consequence of syncope during work and three were referred to the emergency department. All patients continued their employment without any problems. CONCLUSION: The prevalence of syncope during work is low and its impact is benign. The probability of syncope during work is higher for subjects with a history of syncope. PMID- 23933851 TI - Paradoxical thromboembolic stroke during extraction of a recalled St Jude Medical Riata defibrillator lead with conductor externalization. AB - Recalled St Jude Medical Riata leads have a high rate of insulation failures with potential thrombogenic externalized conductors. We report a paradoxical thromboembolic stroke through a persistent foramen ovale during extraction of a lead with externalization. We suggest mandatory transesophageal echocardiography prior to extraction to screen for lead-related thrombosis and routes of right-to left shunting to reduce risk of thromboembolic complications. PMID- 23933850 TI - Asymptomatic brain lesions following laserballoon-based pulmonary vein isolation. AB - AIMS: Laserballoon-based pulmonary vein isolation (PVI) for the treatment of atrial fibrillation (AF) has proven safe and effective. Silent brain lesions after AF ablation detected on magnetic resonance imaging (MRI) have been described for several technologies, but its incidence following laserballoon PVI is unknown. The current study sought to assess the incidence of new asymptomatic brain lesions in patients undergoing laserballoon-based PVI. METHODS AND RESULTS: Patients referred for PVI underwent pre- and post-procedural MRI of the brain. A total of 86 patients were enroled into the study (laserballoon group: 44 patients, 15 female, age 63 +/- 9 years, left atrial (LA) diameter 43 +/- 5 mm; cryoballoon group: 20 patients, 6 female, age 61 +/- 9 years, LA diameter 41 +/- 4 mm; and irrigated radiofrequency (RF) group: 22 patients, 11 female, age 64 +/- 8 years, LA diameter 43 +/- 6 mm). There was no statistically significant difference between the groups with regard to new asymptomatic brain lesions detected on post-procedural MRI: 5 of 44 (11.4%) patients in the laserballoon group, 1 of 20 (5.0%) patients in the cryoballoon group, and 4 of 22 (18.2%) patients in the irrigated RF group, respectively. In the laserballoon group, one additional patient with a new cerebral lesion experienced transient diplopia. In a multivariate regression model the only risk factor for asymptomatic new lesions was the CHA2DS2VASc score. CONCLUSION: Following laserballoon-based PVI, new asymptomatic brain lesions were detected in 11.4% of patients. A higher CHA2DS2VASc score, but not the ablation technology utilized, was the only associated risk factor. PMID- 23933852 TI - The effect of radiotherapy beam energy on modern cardiac devices: an in vitro study. AB - AIMS: Radiotherapy (RT) for malignancies can harm pacemakers (PMs) and implantable cardioverter-defibrillators (ICDs). There is some evidence that, besides cumulative dose, the damaging radiation effects increase with beam energy. The aim of this study was to determine whether modern PMs and ICDs are more sensitive to high-energy than to low-energy photon beams. METHODS AND RESULTS: Two groups of unused PMs and explanted ICDs (five PMs and one ICD in each) were subjected to irradiations in a phantom with 6 and 18 megavolt (MV) photons, respectively. The devices were exposed to radiation at doses of 2 gray (Gy) daily to simulate two clinical scenarios with the PM/ICD in the RT field. A cumulative dose of 150 Gy was given to each device, corresponding to approximately twice the therapeutic dose. In the 6 MV group, one episode of PM malfunction was detected after reaching 150 Gy. In the 18 MV group, a total of 14 episodes of malfunction were detected starting at 30 Gy in all five PMs. No episodes appeared in the ICD, at the respective treatment groups. This corresponded to a hazard ratio of 9.11 [~95% confidence interval (CI): 1.04 79.69] by Cox regression analysis between the two groups. In a repeated measures logistic regression model comparing the incidence rate of malfunctions, the odds ratio was 18.29 (~95% CI: 1.52-219.41). CONCLUSION: Photon beam energy plays a considerable role in inducing implantable cardiac device malfunctions. Low-energy RT may be safer in PM/ICD patients despite relatively high radiation dose to the device. PMID- 23933853 TI - Spontaneous electrodeposition of gold and platinum complexes through a coronene adlayer on Au(111). AB - The electrodeposition of gold and platinum complexes at the electrochemical interfaces on the coronene-modified Au(111) surface was investigated. Scanning tunneling microscopy revealed the spontaneous deposition of gold and platinum complexes, suggesting that the coronene adlayer plays an important role in the electroreduction of these complexes. PMID- 23933855 TI - The effect of statins on circulating endothelial progenitor cells in humans: a systematic review. AB - Numerous clinical trials have demonstrated early reductions in cardiovascular events occurring independently of the lipid-lowering effects of statins. These pleiotropic effects have been attributed to antiinflammatory properties, to atherosclerotic plaque stabilization, and more recently to mobilization of endothelial progenitor cells (EPCs). Our aim was to evaluate the evidence supporting statin-induced EPC mobilization in humans. We, therefore, performed a computerized literature search and systematic review of randomized trials to determine the effect of statin therapy and statin dosing on circulating EPC numbers. Our literature search identified 10 studies including 479 patients which met inclusion criteria with publication dates ranging from 2005 to 2011. Seven studies compared statin to nonstatin regimens whereas 3 studied low versus high dose statin therapy. Reported increases in EPC number ranged from 25.8% to 223.5% with a median reported increase of 70.2% when compared to nonstatin regimens with 7 of 10 studies reporting significant increases. Considerable heterogeneity exists in regard to patient population, statin regimens, and the definition of an EPC within the identified studies. In conclusion, randomized studies in humans suggest that statin therapy mobilizes EPCs into the circulation. Larger randomized studies using uniform definitions are needed to definitively establish this effect. PMID- 23933857 TI - Prevertebral paraspinal inflammation presenting with acute abdominal pain. AB - CT or MRI evaluation as a further diagnostic modality may be recommended in a patient showing vague clinical manifestation in the second order when patients present with subjective discomfort and simple and initial radiological modalities do not show any specific abnormal findings. PMID- 23933858 TI - Atypical presentation of postoperative faecal peritonitis in an elderly patient. AB - A 90-year-old Caucasian man was admitted for an elective sigmoid colectomy having been recently diagnosed with colon cancer. He first presented following a 3-month history of per rectal bleeding. Flexible sigmoidoscopy demonstrated a 4 cm lesion in the proximal sigmoid colon. A biopsy confirmed adenocarcinoma. A CT colonoscopy demonstrated no further colonic lesions and staging CT demonstrated no evidence of metastasis. On postoperative day 7, patient had symptoms of nausea and vomiting. On examination, he had a tender right iliac fossa, sluggish bowel sounds but no evidence of guarding or rebound tenderness. He had no fever with a white cell count 5.8*109/L and C reactive protein 58 mg/L. Chest X-ray showed air under the diaphragm. CT abdomen and pelvis was performed on postoperative day 8 showing a moderate amount of abdominal free fluid and air beneath the anterior abdominal wall. Subsequent laparotomy revealed gangrenous anastomotic disruption and faecal peritonitis. Abdominal washout and terminal colostomy performed. Good postoperative recovery was seen. PMID- 23933859 TI - Radiological diagnosis of a small bowel perforation secondary to toothpick ingestion. AB - A 77-year-old edentulous man presented to the accident and emergency department with a sudden onset of sharp right-sided abdominal pain. The patient reported a change in his bowel habit with constipation over a 6 month period but did not report any significant choking event or ingestion of a foreign body in the preceding months. On examination the patient was maximally tender with guarding over McBurneys point. CT scan showed an abnormal segment of distal ileum with a 3 cm high attenuation focus which had penetrated the bowel wall. At laparotomy the patient was found to have a perforation of his distal ileum caused by an ingested toothpick. Patients wearing dental plates or dentures are at higher risk of toothpick ingestion due to impaired palatal sensation. CT scanning, in the appropriate setting, may aid diagnosis and lower operator risk of sharp related injury at the time of operation. PMID- 23933860 TI - Syncope: there is more than haemodynamic failure. AB - Convulsive syncopes may be particularly difficult to differentiate from epileptic seizures. Recurrent syncopes are caused by autonomic or non-autonomic failure. In this report, we present a 22-year-old woman who was misdiagnosed as epileptic and whose first symptoms during neurocardiogenic syncope occurred prior to asystole. The patient sensed her aura and reached for the alarm button 2 s before a cardiac asystole was documented in the ECG. We conclude that so far unspecified autonomic mechanisms play a significant role in our patient leading to the symptoms of dizziness and nausea heralding her attacks prior to the occurrence of asystole. PMID- 23933861 TI - Gluteal compartment syndrome with severe rhabdomyolysis. AB - Gluteal compartment syndrome is a rare entity but a recognised complication of prolonged immobilisation. It can present as renal failure as a result of severe rhabdomyolysis and can lead to sepsis and death. We report a case of gluteal compartment syndrome in a 25-year-old man who was found unconscious following intoxication with alcohol and cocaine of an unknown duration. He presented with tense tight left buttock swelling, right thigh swelling, cold immobile extremeties and acute renal failure. Immediate left gluteal, thigh and calf fasciotomy resulting in an improvement of lower limb and renal function. PMID- 23933863 TI - Partial priapism. AB - With only 34 prior cases in world literature, partial priapism (PP), also called partial segmental thrombosis of the corpus cavernosum, is a rare urological condition. The aetiology and treatment of PP is still unclear, but bicycle riding, trauma, drug usage, sexual intercourse, haematological diseases and alpha blockers have been associated with PP. In this case report and world literature review, we describe the case of a 50-year-old man suffering from PP after ingesting 100 mg of sildenafil. The patient was treated with a surgical incision for corpus cavernosum and clot evacuation, as a conservative treatment of PP was not feasible due to severe pain and unresponsiveness to analgesics. PMID- 23933864 TI - Bilateral cystoid macular oedema and cotton wool spots associated with Henoch Schonlein purpura. AB - We report a case of a male patient having bilateral cystoid macular oedema and cotton wool spots associated with Henoch-Schonlein purpura. He presented with decreased vision bilaterally measuring 0.2 (6/9.5) on the right and 0.5 (6/19) on the left. He has chronic hypertension with blood pressure averaging 150/90. His blood pressure was raised at 180/110 and with treatment reduced to 164/99. There were no other signs of malignant hypertensive retinopathy. He was treated with oral prednisolone and noticed a significant improvement the following day. An objective measurement performed 2 days later was -0.10 (6/4.8) bilaterally with resolution of macular oedema. PMID- 23933865 TI - Hypothyroidism and acute kidney injury: an unusual association. AB - Association between severe hypothyroidism and acute kidney injury (AKI) is rare. A 40-year-old woman presented with 15 days history of generalised muscle pain, weakness, weight gain and oedema. MEDICAL HISTORY: hypertension and hypothyroidism. PHYSICAL EXAMINATION: dry skin, peripheral/periorbital oedema, slow thought and speaking, thyroid increased. Laboratory examinations: high levels of creatine kinase , creatinine, uric acid and lactate dehydrogenase. Free T4 was very low (<0.3 ng/dL) and thyroid-stimulating hormone was high (21.7 uIU/mL). Urinalysis showed haem pigment without haematuria. We performed the diagnosis of AKI secondary to hypothyroidism-induced rhabdomyolysis. Intravenous fluids were started, urinary alkalisation and increased l-thyroxine dose replacement. On the day after admission, forced diuresis with furosemide was introduced leading to a progressive improvement of symptoms. Although hypothyroidism and AKI is unusual, it should be suspected in patients presenting decrease of renal function and high creatine kinase in the absence of other causes of rhabdomyolysis. PMID- 23933866 TI - Classic neuroimaging, the bird's eye view in Wilson's disease. PMID- 23933867 TI - A longitudinal person-centered examination of nonsuicidal self-injury among university students. AB - Little is known about the development and maintenance of nonsuicidal self-injury (NSSI) over time; however, identifying individuals at risk for NSSI onset or its recurrent engagement is of critical importance for developing effective prevention and intervention strategies. To address this important gap in the literature, we used a person-centered approach to study patterns of change among self-injurers (i.e., new beginners, recovered injurers, relapsers, desisters, and persistent injurers). Undergraduate students (N = 666, 71.1 % female, M age = 19.15) from a mid-sized Canadian university participated in the two-wave study (assessments were 1 year apart). Participants completed the Inventory of Statements about Self-Injury (ISAS, Klonsky and Glenn in J Psychopathol Behav Assess 31:215-219, 2009) at Time 1, and a measure of past year NSSI frequency 1 year later. Participants also completed several measures of psychosocial risk (e.g., problem behaviors, problems with parents) at both time points. Consistent with Nock's (Ann Rev Clin Psychol 6:339-363, 2010) model on the development of NSSI over time, individuals who continued to engage in NSSI across the university years (i.e., persistent injurers) reported greater levels of psychosocial risk as compared to those in the other groups. Moreover, a discriminant function analysis revealed that new beginners, relapsed injurers, and persistent injurers were differentiated from recovered injurers and desisters by increases over time in problem behaviors, problems with parents, internalizing behaviors, and suicidal ideation. Our findings provide new insight into the course of NSSI engagement across the university years, and offer clinicians ways to discriminate among individuals with varying longitudinal patterns of NSSI (i.e., on measures of psychosocial risk, and motivations to stop self-injuring). PMID- 23933868 TI - Vitamin D status among older community dwelling men living in a sunny country and associations with lifestyle factors: the Concord Health and Ageing in Men Project, Sydney, Australia. AB - OBJECTIVES: Inadequate vitamin D status (25-hydroxyvitamin D (25(OH)D) concentrations <50 nmol/L) is an increasingly important public health issue in Australia. The aim of this analysis is to describe 25(OH)D levels in community dwelling men aged >=70 years in Sydney, Australia, and to determine associations between serum 25(OH)D levels and socioeconomic and lifestyle factors. DESIGN: A population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study conducted in Sydney between January 2005 and May 2007. PARTICIPANTS: 1659 non institutionalised men aged >=70 years. METHODS: The cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study conducted in Sydney between January 2005 and May 2007. Participants included 1659 community dwelling men who were interviewed and had clinical assessments. Main outcome measurements included serum 25(OH)D levels measured in blood samples using a radioimmunoassay kit (DiaSorin Inc., Stillwater, MN). Covariates included age, socioeconomic measures, season of blood sample, physical activity, sun exposure, vitamin D supplement use, cigarette smoking status, alcohol consumption, obesity and measures of health. RESULTS: Prevalence of vitamin D insufficiency was 43.0%; highest in winter (55.5%) and spring (53.9%), and was associated with season (winter and spring), low physical activity, avoidance of sun exposure, current smoking and obesity, even after adjustment for confounding factors. CONCLUSION: Inadequate vitamin D status is highly prevalent among Australian older men and is associated with specific lifestyle factors. These findings emphasize the need to screen and monitor 25(OH)D levels in this population group, despite living in a sunny country such as Australia. PMID- 23933869 TI - The short-form mini-nutritional assessment is as effective as the full-mini nutritional assessment in predicting follow-up 4-year mortality in elderly Taiwanese. AB - OBJECTIVE: To compare the mortality-predictive ability of the full- and short form (SF) Mini Nutritional Assessment (MNA). DESIGN: A prospective cohort study. SETTING: Population-representative sample. PARTICIPANTS: 2872 >=65-year old men and women. MEASUREMENTS: The study analyzed 1999 and 2003 datasets of the Taiwan Longitudinal Survey on Aging (TLSA). Subjects were graded for nutritional status with the full-MNA and MNA-SF of a Taiwanese-specific version (T2, containing calf circumference instead of BMI) at baseline (1999) and tracked their survival status for 4 years. Mortality-predictive abilities of the full-MNA and MNA-SF were compared using Cox regression analysis and Net Reclassification Improvement (NRI). RESULTS: The full-MNA and MNA-SF have comparable abilities in predicting follow-up 4-year mortality risk according to the hazard ratios (all p<0.001) and Akaike information criterion (AIC). It also showed a slight improvement (not significant) if the full-MNA in a predictive model was replaced by the MNA-SF (NRI=0.09%, p=0.956). CONCLUSION: The MNA-SF has at least comparable or even slightly better ability in predicting follow-up 4-year mortality risk of elderly Taiwanese. Results suggest that MNA-SF with calf circumference may possess some basic characteristics of a comprehensive and universal geriatric screening scale. PMID- 23933870 TI - Garlic intake is an independent predictor of endothelial function in patients with ischemic stroke. AB - OBJECTIVES: To investigate the effects of garlic on endothelial function in patients with ischemic stroke (ISS). DESIGN: Cross-sectional study. PARTICIPANTS: 125 Chinese patients with prior ISS due to athero-thrombotic disease were recruited from the outpatient clinics during July 2005 to December 2006. MEASUREMENTS: Daily allium vegetable intake (including garlic, onions, Chinese chives and shallots) was ascertained by means of a validated food frequency questionnaire for Chinese and brachial artery flow-mediated dilatation (FMD) was measured using high-resolution ultrasound in all subjects. RESULTS: The mean age of the study population was 65.9+/-11.1 years and 69% were males. Mean allium vegetable intake and garlic intake of the study population was 7.5+/-12.7g/day and 2.9+/-8.8g/day respectively. Their mean FMD was 2.6+/-2.3%. Daily intake of total allium vegetable (r=0.36, P<0.01) and garlic (r=0.34, P<0.01) significantly correlated with FMD. Using the median daily allium intake as cut-off (3.37g/day), patients with a low allium intake <3.37g/day was noted to have a lower FMD compared to those with a normal allium intake (2.1+/-2.1% versus 3.0+/-2.4%, P<0.05). After adjusting for confounding factors, multi-variate analysis identified that daily allium vegetable (B=0.05, 95% confidence interval: 0.02, 0.09, P<0.01) and garlic (B=0.07, 95% confidence interval: 0.02, 0.12, P<0.01) intake, but not onions, Chinese chives and shallots were independent predictors for changes in FMD in patients with ISS. CONCLUSIONS: Daily garlic intake is an independent predictor of endothelial function in patients with ISS and may play a role in the secondary prevention of atherosclerotic events. PMID- 23933871 TI - Nutritional status of community-dwelling elderly with newly diagnosed Alzheimer's disease: prevalence of malnutrition and the relation of various factors to nutritional status. AB - OBJECTIVES: To determine the prevalence of malnutrition and its relation to various factors in community-dwelling elderly with newly diagnosed Alzheimer's disease (AD). DESIGN: Retrospective cross-sectional study. SETTING: Memory clinic in a rural part of the Netherlands. PARTICIPANTS: 312 Community-dwelling AD patients, aged 65 years or older, were included. MEASUREMENTS: At the time the diagnosis AD was made, socio-demographic characteristics and data on nutritional status (Mini Nutritional Assessment (MNA)), cognitive function (Mini Mental State Examination (MMSE), Cambridge Cognitive Examination (Camcog)), functional status (Interview for Deterioration in Daily Living Activities in Dementia (IDDD), Barthel Index (BI)) and behaviour (Revised Memory and Behaviour Problems Checklist (RMBPC)) were assessed. Characteristics of well-nourished patients (MNA score >23.5) were compared to characteristics of patients at risk of malnutrition (MNA score 17-23.5). Linear regression analysis was performed to assess the effect of various factors on nutritional status. RESULTS: The prevalence of malnutrition was 0% and 14.1% was at risk of malnutrition. AD patients at risk of malnutrition were more impaired in basic and complex daily functioning than well nourished AD patients (median IDDD score 41.5 [25th -75th percentile 38.8-48.0] versus median IDDD score 40.0 [25th -75th percentile 37.0-43.0], p = 0.028). The degree of impairment in basic and complex daily functioning (IDDD) was independently related to nutritional status (MNA) (p = 0.001, B = -0.062). CONCLUSION: One in seven community-dwelling elderly with newly diagnosed AD is at risk of malnutrition. The degree of impairment in daily functioning is independently related to nutritional status. Therefore, assessment of the nutritional status should be included in the comprehensive assessment of AD patients. The relation between daily functioning, nutritional status and AD warrants further investigation. PMID- 23933872 TI - Designing pharmaceutical trials for sarcopenia in frail older adults: EU/US Task Force recommendations. AB - An international task force of academic and industry leaders in sarcopenia research met on December 5, 2012 in Orlando, Florida to develop guidelines for designing and executing randomized clinical trials of sarcopenia treatments. The Task Force reviewed results from previous trials in related disease areas to extract lessons relevant to future sarcopenia trials, including practical issues regarding the design and conduct of trials in elderly populations, the definition of appropriate target populations, and the selection of screening tools, outcome measures, and biomarkers. They discussed regulatory issues, the challenges posed by trials of different types of interventions, and the need for standardization and harmonization. The Task Force concluded with recommendations for advancing the field toward better clinical trials. PMID- 23933873 TI - How to design nutritional intervention trials to slow cognitive decline in apparently healthy populations and apply for efficacy claims: a statement from the International Academy on Nutrition and Aging Task Force. AB - Interventions are crucial as they offer simple and inexpensive public health solutions that will be useful over the long term use. A Task Force on designing trials of nutritional interventions to slow cognitive decline in older adults was held in Toulouse in September 2012. The aim of the Task Force was to bring together leading experts from academia, the food industry and regulatory agencies to determine the best trial designs that would enable us to reach our goal of maintaining or improving cognitive function in apparently healthy aging people. An associated challenge for this Task Force was to determine the type of trials required by the Public Food Agencies for assessing the impact of nutritional compounds in comparison to well established requirements for drug trials. Although the required quality of the study design, rationale and statistical analysis remains the same, the studies designed to show reduction of cognitive decline require a long duration and the objectives of this task force was to determine best design for these trials. Two specific needs were identified to support trials of nutritional interventions: 1- Risk- reduction strategies are needed to tackle the growing burden of cognitive decline that may lead to dementia, 2- Innovative study designs are needed to improve the quality of these studies. PMID- 23933874 TI - Guidance synthesis. Medical research for and with older people in Europe: proposed ethical guidance for good clinical practice: ethical considerations. AB - INTRODUCTION: In Europe the population is ageing rapidly. Older people are taking many medicinal products daily and these may not necessarily be suitable for them. Publications show that older patients are underrepresented in clinical trials, especially those over 75 years, with multiple co-morbidities, concomitant treatments and/or frailty. This document provides a summary of recommendations on ethical aspects of clinical trials with older people, who may in some cases be considered a vulnerable patient population. The EFGCP's Geriatric Medicine Working Party (GMWP) has developed this guidance to promote such research and to support health care professionals in their efforts. ETHICAL, SCOPE AND CONTEXT: The definition of a geriatric patient is reviewed. Frail and vulnerable patients, who are a minority of geriatric patients, should be included whenever it is relevant. The legal context is described. THE PROCESS OF INFORMED CONSENT: All adults should be presumed capable of consent, unless proven otherwise; informed consent must be sought for all older people who are able to consent. A simple, short and easy-to-understand information sheet and consent form will contribute to improving the readability and understanding of the older participant. A participant guide and the use of a simple tool to ensure decision making capacity, are recommended. Whenever older people are unable to consent, their assent should be sought systematically using adequate information, in addition to seeking the consent of their legal or authorised representative as appropriate. ETHICS COMMITTEES: Research ethics committees need internal and/or external geriatric expertise to balance the benefits and risks of research in older people and to appreciate and recognise their autonomy. DESIGN AND ANALYSES: Design and Analyses should be adapted to the objectives with appropriate outcomes and are not different from other clinical trials. CONCLUSIONS: The absence of proper recruitment or insufficient presence of older patients in clinical development plans for new medicinal products is detrimental; there is a need to improve evidence-based knowledge, understanding and management of their conditions and treatment. The aim of this guidance is to facilitate clinical research for and with the older patient population. The long version of the guidance will be available on the EFGCP's website: www.efgcp.be/. PMID- 23933875 TI - Looking for frailty in community-dwelling older persons: the Gerontopole Frailty Screening Tool (GFST). AB - The frailty syndrome is a pre-disability condition suitable to be targeted by preventive interventions against disability. In order to identify frail older persons at risk of negative outcomes, general practitioners must be provided with an easy and quick screening tool for detecting frailty without special effort. In the present paper, we present the screening tool for frailty that the Gerontopole of Toulouse (France) has developed and implemented in primary care in the region with the collaboration of the Department of Family Medicine of the University of Toulouse. The Gerontopole Frailty Screening Tool (GFST) is designed to be administered to persons aged >=65 years with no physical disability and acute clinical disease. It is composed by an initial questionnaire aimed at attracting the general practitioner's attention to very general signs and/or symptoms suggesting the presence of an underlying frailty status. Then, in a second section, the general practitioner expresses his/her own view about the frailty status of the individual. The clinical judgment of the general practitioner is finally retained for determining the eventual presence of frailty. Preliminary data document that almost everyone (95.2%) of the 442 patients referred to the Gerontopole frailty clinic by general practitioners using the GFST indeed presents a condition of (pre-)frailty according to the criteria proposed by Fried and colleagues in the Cardiovascular Health Study. The use of the GFST may help at raising awareness about the importance of identifying frailty, training healthcare professionals at the detection of the syndrome, and developing preventive interventions against disabling conditions. PMID- 23933876 TI - The mediating effects of depressive symptoms on nutritional status of older adults in long-term care facilities. AB - OBJECTIVE: To test whether depressive symptoms mediate the effects of activities of daily living (ADLs) on nutritional status of older adults living in long-term care (LTC) facilities in Taiwan. DESIGN: A cross-sectional study. SETTING: Seventy-three community-based LTC facilities in northern Taiwan. PARTICIPANTS: This study sampled 306 adults ranging in age from 65 to 97 years who were free of acute infection or disease and who were able to communicate. MEASUREMENTS: Nutritional status was assessed by the Mini-Nutritional Assessment (MNA) scale and depressive symptoms were assessed by the short form of the Geriatric Depressive Scale (GDS-SF). RESULTS: MNA scores revealed that 65% of the subjects were at risk for malnutrition (17 to 23.5 points). In addition, depressive symptoms partially mediated the relationship between ADLs and nutritional status, with 10.7% of the effect of depressive symptoms on nutritional status going through the mediator. CONCLUSION: Interventions to reduce depressive symptoms among institutionalized older adults should focus on improving nutritional status rather than promoting ADLs, which are believed to be difficult to change. PMID- 23933877 TI - In vitro efficacy of synthetic skin repellent IR3535 on head lice (Pediculus capitis). AB - In in vitro tests, skin repellent IR3535, applied in the form of the Diffusil H Prevental product in an aerosol bomb (active compound 20%), killed 100% of head lice (females and males) and nymphs 2 and 3, when directly sprayed at a dose of 0.94 mg of the active compound per square centimeter. Crawling lice exposed for 1 min on the filter paper impregnated by the same concentration showed no effort to suck blood 30 min after exposition. Twenty hours later, their mortality rate was 11 %. After the lice had been exposed for approximately 1 min (until they actively left the area) on 5 cm round areas of skin of test persons treated with the repellent at a mean total dose of 23.3 mg of active compound, they showed no effort to suck blood on the clean skin of other test person either immediately after exposure or 30 min later. Their mortality after 20 h ranged from 59 to 16%, depending on the time elapsed from skin treatment (10 min to 27 h). PMID- 23933879 TI - From tip to base: parallel proteomic and phosphoproteomic analyses of successive stages of maize leaf development. PMID- 23933878 TI - Mosquito larvicidal activity of thymol from essential oil of Coleus aromaticus Benth. against Culex tritaeniorhynchus, Aedes albopictus, and Anopheles subpictus (Diptera: Culicidae). AB - Diseases transmitted by blood-feeding mosquitoes, such as dengue fever, dengue hemorrhagic fever, Japanese encephalitis, malaria, and filariasis, are increasing in prevalence, particularly in tropical and subtropical zones. To control mosquitoes and mosquito-borne diseases, which have a worldwide health and economic impacts, synthetic insecticide-based interventions are still necessary, particularly in situations of epidemic outbreak and sudden increases of adult mosquitoes. However, the indiscriminate use of conventional insecticides is fostering multifarious problems like widespread development of insecticide resistance, toxic hazards to mammals, undesirable effects on nontarget organisms, and environmental pollution. The aim of this research was to evaluate the toxicity of mosquito larvicidal activity of essential oil from Coleus aromaticus and its pure isolated constituent thymol against larvae of Culex tritaeniorhynchus, Aedes albopictus, and Anopheles subpictus. The chemical composition of the essential oil was analyzed using gas chromatography-mass spectroscopy. A total of 14 components of the essential oil of C. aromaticus were identified. The major chemical components identified were thymol (82.68%), terpinen-4-ol (3.2%), and trans-Caryophyllene (3.18%). Twenty-five early third instar larvae of C. tritaeniorhynchus, A. albopictus, and A. subpictus were exposed and assayed in the laboratory. Thymol and essential oil were tested in concentrations of 10, 20, 30, 40, and 50 and 30, 60, 90, 120, and 150 ppm, respectively. The larval mortality was observed after 24 h of treatment. The thymol had a significant toxic effect against early third-stage larvae of C. tritaeniorhynchus, A. albopictus, and A. subpictus with an LC50 values of 28.19, 24.83, and 22.06 MUg/mL respectively, whereas the essential oil of C. aromaticus had an LC50 values of 72.70, 67.98, and 60.31 MUg/mL, respectively. No mortality was observed in controls. The Chi-square values were significant at p < 0.05 level. The result indicated that the essential oil of C. aromaticus and the isolated constituent have a potential for use in control of C. tritaeniorhynchus, A. albopictus, and A. subpictus larvae and could be useful in search of newer, safer, and more effective natural compounds as larvicides. PMID- 23933880 TI - The WKRY6 transcription factor is a key player in a multifaceted defense against arsenate. PMID- 23933881 TI - Parallel proteomic and phosphoproteomic analyses of successive stages of maize leaf development. AB - We performed large-scale, quantitative analyses of the maize (Zea mays) leaf proteome and phosphoproteome at four developmental stages. Exploiting the developmental gradient of maize leaves, we analyzed protein and phosphoprotein abundance as maize leaves transition from proliferative cell division to differentiation to cell expansion and compared these developing zones to one another and the mature leaf blade. Comparison of the proteomes and phosphoproteomes suggests a key role for posttranslational regulation in developmental transitions. Analysis of proteins with cell wall- and hormone related functions illustrates the utility of the data set and provides further insight into maize leaf development. We compare phosphorylation sites identified here to those previously identified in Arabidopsis thaliana. We also discuss instances where comparison of phosphorylated and unmodified peptides from a particular protein indicates tissue-specific phosphorylation. For example, comparison of unmodified and phosphorylated forms of PINFORMED1 (PIN1) suggests a tissue-specific difference in phosphorylation, which correlates with changes in PIN1 polarization in epidermal cells during development. Together, our data provide insights into regulatory processes underlying maize leaf development and provide a community resource cataloging the abundance and phosphorylation status of thousands of maize proteins at four leaf developmental stages. PMID- 23933882 TI - Heat shock-induced fluctuations in clock and light signaling enhance phytochrome B-mediated Arabidopsis deetiolation. AB - Moderately warm constant ambient temperatures tend to oppose light signals in the control of plant architecture. By contrast, here we show that brief heat shocks enhance the inhibition of hypocotyl growth induced by light perceived by phytochrome B in deetiolating Arabidopsis thaliana seedlings. In darkness, daily heat shocks transiently increased the expression of pseudo-response regulator7 (PRR7) and PRR9 and markedly enhanced the amplitude of the rhythms of late elongated hypocotyl (LHY) and circadian clock associated1 (CCA1) expression. In turn, these rhythms gated the hypocotyl response to red light, in part by changing the expression of phytochrome interacting FACTOR4 (PIF4) and PIF5. After light exposure, heat shocks also reduced the nuclear abundance of constitutive photomorphogenic1 (COP1) and increased the abundance of its target elongated hypocotyl5 (HY5). The synergism between light and heat shocks was deficient in the prr7 prr9, lhy cca1, pif4 pif5, cop1, and hy5 mutants. The evening element (binding site of LHY and CCA1) and G-box promoter motifs (binding site of PIFs and HY5) were overrepresented among genes with expression controlled by both heat shock and red light. The heat shocks experienced by buried seedlings approaching the surface of the soil prepare the seedlings for the impending exposure to light by rhythmically lowering LHY, CCA1, PIF4, and PIF5 expression and by enhancing HY5 stability. PMID- 23933883 TI - Epigenetics and genetics: global profiling in maize inbred lines examines variation in DNA methylation. PMID- 23933885 TI - Death in the nervous system: JNK signaling in junk clearance. PMID- 23933884 TI - Jasmonate regulates the inducer of cbf expression-C-repeat binding factor/DRE binding factor1 cascade and freezing tolerance in Arabidopsis. AB - The inducer of cbf expression (ICE)-C-repeat binding factor/DRE binding factor1 (CBF/DREB1) transcriptional pathway plays a critical role in modulating cold stress responses in Arabidopsis thaliana. Dissecting crucial upstream regulatory signals or components of the ICE-CBF/DREB1 cascade will enhance our understanding of plant cold-tolerance mechanisms. Here, we show that jasmonate positively regulates plant responses to freezing stress in Arabidopsis. Exogenous application of jasmonate significantly enhanced plant freezing tolerance with or without cold acclimation. By contrast, blocking endogenous jasmonate biosynthesis and signaling rendered plants hypersensitive to freezing stress. Consistent with the positive role of jasmonate in freezing stress, production of endogenous jasmonate was triggered by cold treatment. In addition, cold induction of genes acting in the CBF/DREB1 signaling pathway was upregulated by jasmonate. Further investigation revealed that several jasmonate ZIM-domain (JAZ) proteins, the repressors of jasmonate signaling, physically interact with ICE1 and ICE2 transcription factors. JAZ1 and JAZ4 repress the transcriptional function of ICE1, thereby attenuating the expression of its regulon. Consistent with this, overexpression of JAZ1 or JAZ4 represses freezing stress responses of Arabidopsis. Taken together, our study provides evidence that jasmonate functions as a critical upstream signal of the ICE-CBF/DREB1 pathway to positively regulate Arabidopsis freezing tolerance. PMID- 23933886 TI - dsDNA ASCs for caspase 8-mediated apoptosis. PMID- 23933887 TI - Autophagic cell death RIPs into tumors. PMID- 23933889 TI - Ovarian cancer survival: steady improvement, despite rhetoric to the contrary. PMID- 23933888 TI - Checkpoint modulation in melanoma: an update on ipilimumab and future directions. AB - Ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody, was the first therapy demonstrated to improve overall survival in melanoma. Since ipilimumab's approval by the FDA in 2011, a wealth of data has amassed, helping clinicians to optimize its use. We have learned how to mitigate the adverse effects of ipilimumab, identified its effects in melanoma subpopulations such as those with brain metastases, uveal melanoma, and mucosal melanoma, discovered potential biomarkers of activity, and investigated its use in combination with other therapeutic modalities. These discoveries have paved the way for rapid development of second-generation immunomodulatory antibodies such as inhibitors of the programmed cell death 1 receptor axis. These new agents hold promise as monotherapy, but perhaps the greatest allure lies in the possibility of combining these agents in synergistic multidrug regimens. PMID- 23933890 TI - Overestimation of the risk of progression to end-stage renal disease in the poor prognosis' group according to the 2002 Japanese histological classification for immunoglobulin A nephropathy. AB - BACKGROUND: The current (2012) histological classification of immunoglobulin A nephropathy was established using a case-control study of 287 patients. However, the risk of progression to end-stage renal disease (ESRD) has not been validated for the previous (2002) classification. This study aimed to determine whether the previous classification could identify the risk of long-term renal outcome through re-analysis of the 2012 cohort. METHODS: On the basis of the 2002 classification, namely 'good prognosis', 'relatively good prognosis', 'relatively poor prognosis', and 'poor prognosis', we examined the clinical data at the time of biopsy, the correlation between the 2002 classification and long-term renal outcomes, and a patient-by-patient correlation between the 2002 and 2012 classification systems. This was performed by analyzing samples from the 287 patients used to establish the 2012 classification. RESULTS: The rate of decline of estimated glomerular filtration rate was greater and the odds ratio of progression to ESRD was higher in the 'poor prognosis' group. In contrast, the odds ratio for renal death was comparable between the groups described as 'relatively poor prognosis' and 'relatively good prognosis' in the 2002 classification. Many patients in the 2002 classification were classified with a lower histological grade in the current classification, but none were classified with a higher grade. CONCLUSIONS: The 2002 classification could also identify the risk of progression to ESRD. However, it was overestimated for patients in the 'poor prognosis' group in the 2002 classification, as that group included patients with milder histological damage. PMID- 23933891 TI - Salt-sensitive hypertension in mitochondrial superoxide dismutase deficiency is associated with intra-renal oxidative stress and inflammation. AB - BACKGROUND: Renal interstitial inflammation and oxidative stress are invariably present and play a key role in the pathogenesis of hypertension in experimental animals. Mitochondria are the major source of reactive oxygen species (ROS). ROS generated in the mitochondria are normally contained by the mitochondrial antioxidant system including manganese superoxide dismutase (MnSOD). We have previously shown that a high salt diet causes hypertension in MnSOD-deficient (MnSOD(+/-)) mice but not in wild-type mice. The present study was undertaken to determine the effect of a high salt diet on oxidative and inflammatory pathways in the kidneys of MnSOD(+/-) mice compared to the wild-type mice. METHODS: Wild type (MnSOD(+/+)) and MnSOD(+/-) mice were randomized to receive a regular or a high salt diet for 4 months. Tail arterial pressure was measured and timed urine collection was obtained. The animals were then euthanized and the kidneys were harvested and processed for histological examination and Western blot analyses. RESULTS: In confirmation of our earlier study, a high salt diet resulted in a significant rise in arterial pressure and urinary albumin excretion in MnSOD(+/-) mice. This was accompanied by upregulation of NAD(P)H oxidase subunits, activation of nuclear factor kappa B, and elevation of PAI-1, iNOS, oxidized LDL receptor, and CD36 in the kidneys of the MnSOD(+/-) mice fed the high salt diet. In contrast, consumption of a high salt diet did not significantly alter blood pressure, urine protein excretion, or the measured oxidative and inflammatory mediators in the wild-type mice. CONCLUSION: Salt-induced hypertension in MnSOD(+/-) mice is associated with activation of intra-renal inflammatory and ROS generating pathways. PMID- 23933893 TI - Are motivation deficits underestimated in patients with ADHD? A review of the literature. AB - AIMS: Attention-deficit/hyperactivity disorder (ADHD) is characterized by impaired inhibition, inattention, and altered sensitivity to rewards. Behavioral studies support the presence of motivational disturbances as a distinct component of ADHD. Functional magnetic resonance imaging is a technology now used to research the brain circuitry underlying motivation. These studies indicate that individuals with ADHD exhibit hyporesponsitivity of the dopamine neurons in the ventral and dorsal striata in response to rewarding stimuli. Our article reviews the research examining interactions between external motivation and the responses of individuals with ADHD, from both neurobiologic and clinical perspectives. METHODS: A PubMed search of studies written in English between 2000 and 2012 with keywords ADHD and motivation was conducted. RESULTS: Motivational processes are examined using behavioral and neurobiologic paradigms. Behavioral studies show altered processing of reinforcement and incentives in children with ADHD. These children respond more impulsively to rewards and choose small, immediate rewards over larger, delayed incentives. Interestingly, a high intensity of reinforcement is effective in improving task performance in children with ADHD. Pharmacotherapy may also improve task persistence in these children. CONCLUSION: Previous studies suggest that a clinical approach using interventions to improve motivational processes in patients with ADHD may improve outcomes as children with ADHD transition into adolescence and adulthood. PMID- 23933894 TI - The impact of obesity on benign and malignant urologic conditions. AB - Obesity, defined as a body mass index >= 30 kg/m2 in adults by the National Institutes of Health, is associated with an increased risk for a number of health conditions, including hypertension, unfavorable lipid level, and diabetes mellitus. During the past 2 decades of the twentieth century, the prevalence of obesity has increased in the United States. In 2009 to 2010, 36% of adults were obese, including 41 million women and > 37 million men. In addition, the prevalence of metabolic syndrome (MetS), which is a constellation of interrelated cardiac risk factors including visceral obesity, impaired insulin action (ie, insulin resistance), atherogenic dyslipidemia, endothelial dysfunction, and systemic inflammation, has been increasing in the United States. More recently, there has been greater interest in the effects of obesity and MetS on a variety of benign and malignant urologic conditions. Obesity/MetS has been shown to have an effect on urolithiasis; benign prostatic hyperplasia and lower urinary tract symptoms; female incontinence and pelvic prolapse; male hypogonadism; and male sexual function and infertility. These urologic diseases have a considerable impact on patients' quality of life. From a urologic cancer standpoint, obesity/MetS has been demonstrated to play a role in prostate cancer and in renal cell cancer; its role in bladder cancer remains ill defined. Furthermore, dietary or lifestyle modifications may improve outcomes in many of these urologic disease processes. Thus, it is imperative for physicians to understand these relationships in order to better screen obese patients and be aware of the potential impact of weight loss on affected benign and malignant urologic conditions. PMID- 23933892 TI - Inflammation-induced interstitial migration of effector CD4+ T cells is dependent on integrin alphaV. AB - Leukocytes must traverse inflamed tissues to effectively control local infection. Although motility in dense tissues seems to be integrin independent and based on actomyosin-mediated protrusion and contraction, during inflammation, changes to the extracellular matrix (ECM) may necessitate distinct motility requirements. Indeed, we found that the interstitial motility of T cells was critically dependent on Arg-Gly-Asp (RGD)-binding integrins in the inflamed dermis. Inflammation-induced deposition of fibronectin was functionally linked to higher expression of integrin alphaV on effector CD4+ T cells. By intravital multiphoton imaging, we found that the motility of CD4+ T cells was dependent on alphaV expression. Selective blockade or knockdown of alphaV arrested T helper type 1 (TH1) cells in the inflamed tissue and attenuated local effector function. Our data demonstrate context-dependent specificity of lymphocyte movement in inflamed tissues that is essential for protective immunity. PMID- 23933895 TI - Integrating health information technology and electronic health records into the management of fibromyalgia. AB - Fibromyalgia (FM) is a widespread chronic pain condition that represents a significant economic burden for patients and health care systems. Effective treatment of FM requires a multidisciplinary management strategy that incorporates pharmacologic and nonpharmacologic therapy. Steps such as reducing the time to diagnosis and improving treatment decisions can result in significant cost savings and improved patient outcomes. An FM management framework, based on patient education and goal setting, has emphasized the need for ongoing care of patients with FM. In this article, we discuss how this framework could be further improved through the use of health information technology, including electronic health records. Health information technology/electronic health records can be incorporated at every stage of patient care, from initial presentation to diagnosis, through to making treatment decisions and maintaining ongoing patient management. This can lead to a number of potential benefits for patients with FM (by improving their level of care), primary care providers (by creating greater efficiencies), and the health care system (by reducing costs). Ultimately, the treatment and care of patients with FM need be no more burdensome to primary care providers than any other chronic illness. Through the greater efficiencies and optimized treatment approaches facilitated by health information technology/electronic health records, it should be possible to drive best practice care for patients with FM and improve patient outcomes. PMID- 23933896 TI - Attention-deficit/hyperactivity disorder in a chronic care paradigm. AB - The prevalence and disease burden of adult attention-deficit/hyperactivity disorder (ADHD) suggests that primary care physicians (PCPs) have an opportunity to improve the functioning and quality of life of a significant number of adult patients. The American Academy of Pediatrics provides evidence-based clinical practice guidelines that recognize ADHD as a chronic condition, and a large proportion of children with ADHD continue to meet diagnostic criteria as adults. Therefore, the management of ADHD should incorporate principles common to the management of other chronic conditions, including proactive planning for continuity of treatment across the life span and integrated, multidisciplinary health care teams for optimal disease management. This article describes a clinical approach whereby adult ADHD is treated within a chronic care paradigm that prominently features the involvement of the PCP. If PCPs envision ADHD as a chronic illness, similar to asthma or diabetes, they may be less likely to refer individuals to be managed by specialists, and more likely to see their role in coordinating and monitoring adult ADHD care, knowing when and how to bring other resources into play, and when and how to educate patients. PMID- 23933897 TI - Discovery of asymptomatic Krukenberg tumors diagnosed during caesarean section: therapy with hyperthermic intraperitoneal chemotherapy. AB - We report a case of the discovery of asymptomatic Krukenberg tumors in a 37-year old woman in the 37th week of pregnancy during caesarean section. Subsequent gastroscopy revealed an adenocarcinoma of the stomach as the primary tumor site. The patient was treated with hyperthermic intraperitoneal chemotherapy (HIPEC). Tumor surgery (Partial parietal peritonectomy and partial gastrectomy) and HIPEC treatment were successful, with no complications found during follow-up. Use of HIPEC seems to be a promising option after radical surgery, including its use in patients with gastric tumors that are in advanced stages, and use in patients who have tumors with poor prognoses, such as Krukenberg tumors. PMID- 23933898 TI - Clopidogrel, prasugrel, or ticagrelor? a practical guide to use of antiplatelet agents in patients with acute coronary syndromes. AB - Aspirin is a cornerstone of therapy in the treatment of patients with acute coronary syndromes (ACS). However, dual antiplatelet therapy reduces the risk of stent thrombosis and cardiovascular events compared with aspirin alone in the treatment of patients with ACS. Recently, there has been debate as to which antiplatelet agent should be added to aspirin in the ACS treatment regimen. This review summarizes the pharmacologic and clinical data comparing clopidogrel, prasugrel, and ticagrelor, and provides a practical guide to clinicians for determining which antiplatelet to use for patients with ACS. PMID- 23933899 TI - Novel oral anticoagulants: a review of new agents. AB - Until recently, warfarin had been one of the only treatment options for long-term anticoagulation of patients with atrial fibrillation, venous thromboembolism, or other medical conditions that require chronic anticoagulation. A main concern when treating patients with anticoagulants is balancing the benefits of preventing a thromboembolic event with the risks of bleeding events. The US Food and Drug Administration recently approved 2 new oral anticoagulants, dabigatran and rivaroxaban, for stroke prevention in patients with atrial fibrillation, and is currently reviewing a drug application for a third new oral anticoagulant, apixaban. These new anticoagulants do not require strict and frequent laboratory monitoring, dosing adjustments, or dietary restrictions, and they incur fewer drug-drug interactions than warfarin. However, these new medications do not have specific reversal agents, may require dosage adjustment based on patient renal function, and lack clinical data regarding their long-term safety and efficacy. The 2012 American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for antithrombotic therapy and prevention of thrombosis include recommendations for dabigatran, rivaroxaban, and apixaban for certain indications. Each of the 3 novel oral anticoagulants has specific pharmacokinetic and pharmacodynamic properties that may make them suitable agents for use in specific patient populations. Knowledge of dosing, drug-drug interactions, monitoring parameters, and clinical considerations for each of these new medications will help clinicians decide for which patients they may be best suited to replace conventional therapy with warfarin. PMID- 23933901 TI - Challenges in the transition of care for adolescents with attention deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is often considered a childhood disorder. However, in those diagnosed with ADHD as children, inattention, impulsivity, and hyperactivity can persist into adulthood, causing significant functional impairment and emotional distress, even if the condition no longer meets diagnostic criteria. This review examines the developmental and psychosocial factors to consider in adolescents with ADHD and the strategies that facilitate the transition from pediatric to adult care. Our findings are based on PubMed database searches conducted on November 29, 2011, that identified articles pertaining to ADHD and continuity or transition in medical care for adolescents published in English within the 5-year period preceding this date. Adolescents with ADHD face specific burdens associated with transitioning into adulthood that can impede the achievement of academic and occupational goals. The main finding of the literature review was that ADHD treatment rates decline sharply from childhood through young adulthood, despite the fact that functional impairment often persists. Moreover, although psychosocial therapy can play an important role in resolving functional difficulties and encouraging patient adherence to pharmacotherapy, the existing literature focuses mainly on pharmacotherapy as first-line treatment for ADHD. Therefore, careful, advanced planning to ensure continuity of medical and psychiatric care is essential. This planning involves the pediatric service that has been providing care, the adult service that will assume the responsibility of providing care, the young person with ADHD, and the family. Although recommendations for planning initiatives have been developed by a variety of professional organizations, they do not seem to be routinely implemented for the transition of ADHD care. Such careful advanced transition planning can ensure continuity of treatment, encourage treatment adherence, and help young individuals adjust to new life circumstances and avoid negative educational, social, and vocational results. Guidelines designed to facilitate this transition of care may be helpful. PMID- 23933902 TI - A Canadian study of the cost-effectiveness of apixaban compared with enoxaparin for post-surgical venous thromboembolism prevention. AB - BACKGROUND: Occurrence of a venous thromboembolism (VTE) in patients undergoing major orthopedic surgery who are not given thromboprophylactic therapy presents considerable danger to patient medical outcomes and a significant economic burden to the health care system at large. Apixaban is a direct factor Xa inhibitor that has been shown in clinical trial use to safely reduce the composite of VTE and mortality rates in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA); however, the cost-effectiveness of apixaban treatment in Canadian settings has not been studied. Our study evaluated the cost effectiveness of apixaban compared with enoxaparin as VTE preventive therapy in patients undergoing elective THA or TKA in Canada. METHODS: An economic model, including both a decision-tree component and a Markov model, was created. The decision tree considered VTE, bleeding, and mortality incidence that occurred in patients within 90 days post-surgery using data from the Apixaban Versus Enoxaparin for Thromboprophylaxis After Knee or Hip Replacement (ADVANCE) trials, which compared apixaban therapy with 30-mg twice daily and 40-mg daily enoxaparin treatment. The Markov model provided the option to simulate events that may occur over the long term, such as recurrent VTE and post-thrombotic syndrome. Outcomes during the short-term phase directly impact the risk of events occurring during the long-term phase (5 years post-surgery). RESULTS: The results of our analysis indicated that apixaban is dominant (ie, more effective and less expensive) than enoxaparin in treating patients undergoing THA and TKA. There were fewer occurrences of VTEs, bleeding events, recurrent VTEs, and post-thrombotic syndrome events in the TKA population with apixaban therapy. Similar results were seen in patients undergoing THA, with the exception of bleeding events, which were more common with apixaban treatment. Savings of $180 to $270 per patient are expected with apixaban treatment compared with enoxaparin treatment, and health outcomes in general are better with apixaban use. Sensitivity analyses yielded consistent results across the THA and TKA populations. CONCLUSION: : This is the first economic evaluation of apixaban use for VTE thromboprophylaxis in the Canadian setting, and our study results show apixaban to be a cost-effective treatment alternative to preventive treatment with enoxaparin. PMID- 23933900 TI - Risks, management, and monitoring of combination opioid, benzodiazepines, and/or alcohol use. AB - The concurrent use of opioids, benzodiazepines (BZDs), and/or alcohol poses a formidable challenge for clinicians who manage chronic pain. While the escalating use of opioid analgesics for the treatment of chronic pain and the concomitant rise in opioid-related abuse and misuse are widely recognized trends, the contribution of combination use of BZDs, alcohol, and/or other sedative agents to opioid-related morbidity and mortality is underappreciated, even when these agents are used appropriately. Patients with chronic pain who use opioid analgesics along with BZDs and/or alcohol are at higher risk for fatal/nonfatal overdose and have more aberrant behaviors. Few practice guidelines for BZD treatment are readily available, especially when they are combined clinically with opioid analgesics and other central nervous system-depressant agents. However, coadministration of these agents produces a defined increase in rates of adverse events, overdose, and death, warranting close monitoring and consideration when treating patients with pain. To improve patient outcomes, ongoing screening for aberrant behavior, monitoring of treatment compliance, documentation of medical necessity, and the adjustment of treatment to clinical changes are essential. In this article, we review the prevalence and pharmacologic consequences of BZDs and/or alcohol use among patients with pain on chronic opioid therapy, as well as the importance of urine drug testing, an indispensable tool for therapeutic drug monitoring, which helps to ensure the continued safety of patients. Regardless of risk or known aberrant drug-related behaviors, patients on chronic opioid therapy should periodically undergo urine drug testing to confirm adherence to the treatment plan. PMID- 23933903 TI - Not all angiotensin-converting enzyme inhibitors are equal: focus on ramipril and perindopril. AB - Angiotensin-converting enzyme (ACE) inhibitors are a heterogeneous class, varying in pharmacologic properties, which have different therapeutic impacts on patient profiles, including lipophilicity, tissue-ACE binding, duration of action, half life, and increased bradykinin availability. Among the ACE inhibitor class, the agent perindopril, in particular, has pleiotropic effects that are not equally shared by other ACE inhibitors, including bradykinin site selectivity and subsequent enhancement of nitric oxide and inhibition of endothelial cell apoptosis. Moreover, there is a large amount of evidence to suggest that perindopril therapy may reduce cardiovascular event rates in patients, yet perindopril is rarely prescribed in the United States. Ramipril is another ACE inhibitor with both a favorable clinical profile and impressive outcomes data. Our review compares the pharmacologic and trial data among perindopril, ramipril, and other ACE inhibitors. In patients with or at high risk for coronary heart disease who do not have heart failure, or in patients with heart failure with preserved ejection fraction, perindopril should be among the preferred treatment agents in the ACE inhibitor class. Ramipril has an impressive track record of improving cardiovascular outcomes, too, and should be considered a preferred agent among the ACE inhibitor class. PMID- 23933904 TI - Evidence-based approach to dyspepsia: from Helicobacter pylori to functional disease. AB - Patients with dyspepsia may present with associated complaints of abdominal pain, bloating, fullness, acid reflux, and epigastric tenderness on examination. The evaluation of patients with dyspepsia includes taking a comprehensive history and performing a physical examination. Although taking a patient history has its limitations in making an accurate diagnosis, it is useful in guiding the selection of subsequent diagnostic tests. Differential diagnoses of dyspepsia are best addressed using an anatomical approach. Patients with chronic dyspepsia lasting > 1 month should be evaluated for the presence of alarm features. Alarm features mandate an upper gastrointestinal endoscopy examination, as these may be suggestive of a malignancy. In patients without alarm features, a Helicobacter pylori test-and-treat strategy is cost-effective if the prevalence of H. pylori infection is high. Tests for H. pylori infection can be divided into non-invasive and minimally invasive tests. Many different antibiotic combination therapies (eg, triple therapy, quadruple therapy, levofloxacin-based therapy, sequential therapy, concomitant therapy, and probiotics with eradication therapy) are now available for the eradication of H. pylori infection. In patients who are symptomatic without an organic pathology, functional dyspepsia and other causes of abdominal pain need to be considered. Functional dyspepsia is best managed using a multifaceted approach by establishing a good physician-patient relationship, dietary and lifestyle interventions, medical therapy, psychotherapy, and the use of psychotropic medications. This review rationalizes the current-day recommendations for the evaluation and management of patients with dyspepsia in a clinical setting. PMID- 23933905 TI - Efficacy of metadoxine extended release in patients with predominantly inattentive subtype attention-deficit/hyperactivity disorder. AB - OBJECTIVES: To compare the effects of metadoxine extended release (ER) with those of placebo on inattentive (IA) versus hyperactive-impulsive (H-I) symptoms and predominantly inattentive (PI) versus combined type (CT) subtype in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: This was a 1:1 randomized, double-blind, parallel-design study of metadoxine ER 1400 mg/day for 6 weeks in 120 adults with ADHD. Efficacy measures were baseline to end-of treatment changes in Conners' Adult ADHD Rating Scale-Investigator Rated (CAARS INV) Total ADHD Symptoms scores with adult ADHD prompts, the Test of Variables of Attention ADHD scores, and response rates (>= 25% or >= 40% improvement in CAARS INV Total ADHD Symptoms score). RESULTS: There was a significant decrease in CAARS-INV Total ADHD Symptoms scores in patients with ADHD-PI taking metadoxine ER (40%) compared with those taking placebo (21%) (P < 0.05), while the decrease for patients with ADHD-CT was not significant (27% vs 26%). Similarly, there was a significant decrease in IA scores in patients with ADHD-PI (metadoxine ER, 50% vs placebo, 23%; P < 0.005), while the change in patients with ADHD-CT was not significant. There was no significant difference in percent decreases seen in H-I scores for patients with PI or ADHD-CT. Significantly higher response rates at both cutoffs (ie, 25% and 45% improvement) were seen in the metadoxine ER group compared with the placebo group in CAARS-INV Total ADHD Symptoms scores in patients with ADHD-PI, but not those with ADHD-CT. Test of Variables of Attention ADHD scores were significantly decreased in the metadoxine ER group compared with the placebo group for patients with ADHD-PI, but not those with ADHD-CT. CONCLUSION: These data suggest that metadoxine ER is selectively efficacious for treating IA symptoms in adults with ADHD-PI. TRIAL REGISTRATION: www.ClinicalTrials.gov identifier NCT01243242. PMID- 23933906 TI - Evidence-based guidance for the management of postherpetic neuralgia in primary care. AB - This article aims to help primary care physicians negotiate gaps in current guidelines for postherpetic neuralgia (PHN). The objectives of this article are to: 1) briefly review the available guidelines and identify their strengths and weaknesses; 2) review the gaps in the guidelines; 3) review new data that were not included in the most recent guidelines; 4) provide expert opinion on how the new data and current guidelines can be used to make treatment decisions; and 5) review several important dimensions of care (eg, tolerability, dosing) and provide guidance. In general, all guidelines recognize the alpha2delta ligands, tricyclic antidepressants (TCAs), opioids, and tramadol as efficacious systemic options, with topical lidocaine serving as an efficacious nonsystemic approach for localized PHN treatment. The first-line treatment options typically recommended in the guidelines are alpha2delta ligands and TCAs, while opioids and tramadol are often recommended as second- or third-line options. Since the latest guidelines were published, newer agents (eg, topical capsaicin [8%] patch and gastroretentive gabapentin) have met the standard as first-line therapy with the publication of >= 1 randomized controlled trial. However, gabapentin enacarbil has not met this standard due to a lack of a published randomized controlled trial in PHN. PMID- 23933907 TI - Multifunctional graphene oxide-TiO2-Ag nanocomposites for high performance water disinfection and decontamination under solar irradiation. AB - Multifunctional nanocomposites (GO-TiO2-Ag) integrating 2D GO sheets, 1D TiO2 nanorods and 0D Ag nanoparticles were synthesized via a facile two-phase method and characterized by various analytical techniques including TEM, EDS and XRD. The GO-TiO2-Ag nanocomposites demonstrate remarkably enhanced photocatalytic activities in degrading AO 7 and phenol under solar irradiation compared with GO TiO2 and GO-Ag. They also exhibit excellent intrinsic antibacterial activity toward Escherichia coli, as well as significantly enhanced photo-biocidal capability over GO-TiO2 and GO-Ag. Through systematically investigating the influence of Ag content in the nanocomposites for their photocatalytic activities, it indicates that the optimal Ag content in the GO-TiO2-Ag nanocomposites varies for dye degradation and for phenol/bacterial degradation with different mechanisms. The superior photocatalytic activities under solar irradiation and the easy recovery make the GO-TiO2-Ag nanocomposites a good promising candidate for water purification. PMID- 23933908 TI - Loss of COP1 expression determines poor prognosisin patients with gastric cancer. AB - Previous studies have suggested conflicting roles for the E3 ubiquitin ligase COP1 in tumorigenesis, providing evidence that both the oncoprotein c-Jun and the tumor suppressor p53 may be COP1 targets. In the present study, we focused on the clinical significance of COP1 expression in gastric cancer cases and analyzed the malignant behavior of COP1-knockdown gastric cancer cells in vitro. We analyzed COP1 expression in cancer lesions and the corresponding normal mucosa to demonstrate the clinical significance of COP1 expression in 133 cases of gastric cancer. We also investigated the relationship between COP1 expression and cell proliferation and the association of COP1 with c-Jun transcriptional target genes, such as MMP1, MMP7 and MMP10. The expression of COP1 mRNA was significantly lower in gastric cancer tissues compared to the corresponding normal mucosa (P=0.049). In multivariate analysis for overall survival, we found that COP1 expression was an independent prognostic factor in gastric cancer. Knockdown of COP1 expression in the gastric cancer cell lines MKN-45 and NUGC4 promoted proliferation, and significant associations between COP1 expression and MMP1, MMP7 and MMP10 were also observed in knockdown assays. In conclusion, the present study suggests that loss of COP1 expression may be a novel indicator for the biological aggressiveness in gastric cancer. PMID- 23933909 TI - Inflammation, carcinogenesis and neurodegeneration studies in transgenic animal models for polyamine research. AB - Natural polyamines (PA) are cationic molecules affecting cell growth and proliferation. An association between increased polyamine biosynthesis and inflammation-induced carcinogenesis has been recognised. On the other hand, there are indications that inflammatory stimuli can up-regulate polyamine catabolism and that altered polyamine metabolism could affect pro- and anti-inflammatory cytokines. Since the polyamine content is strictly related to cell growth, a consistent number of evidences relate polyamine metabolism dysfunction with cancer. The increase of polyamine levels in malignant and proliferating cells attracted the interest of scientists during last decades, addressing polyamine depletion as a new strategy to inhibit carcinogenesis. Several studies suggest that PA also play an important role in neurodegeneration, but the mechanisms by which they participate in neuronal death are still unclear. Furthermore, the role of endogenous PA in normal brain functioning is yet to be elucidated. The consequences of an alteration of polyamine metabolism have also been approached in vivo with the use of transgenic animals overexpressing or devoid of some enzymes involved in polyamine metabolism. In the present work we review the experimental investigation carried out on inflammation, cancerogenesis and neurodegeneration using transgenic animals engineered as models for polyamine research. PMID- 23933910 TI - The synergistic therapeutic effect of hepatocyte growth factor and granulocyte colony-stimulating factor on pulmonary hypertension in rats. AB - Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary arterial pressure and vascular resistance. Despite advances in therapy for PAH, its treatment and prognosis remain poor. We aimed to investigate whether the transplantation of bone marrow mesenchymal stem cells (MSCs) overexpressing hepatocyte growth factor (HGF), alone or in combination with granulocyte colony-stimulating factor (G-CSF), attenuates the development of experimental monocrotaline (MCT)-induced PAH. Three weeks after MCT administration, rats were divided into the following groups: (1) untreated (PAH); (2) HGF treated; (3) MSCs administered; (4) HGF-MSCs treated; and (5) HGF-MSCs plus G-CSF treated. After 3 weeks, hemodynamic changes, histomorphology, and angiogenesis were evaluated. To elucidate the molecular mechanisms of vascular remodeling and angiogenesis, serum levels of transforming growth factor (TGF) beta and endothelin-1 (ET-1) were measured, and the gene and protein expression levels of vascular cell adhesion molecule-1 (VCAM-1) and matrix metalloproteinase 9 (MMP-9) were determined. Compared with the PAH, MSC, and G-CSF groups, the HGF and HGF+G-CSF groups exhibited significantly reduced right ventricular hypertrophy and mean pulmonary arterial pressure (P < 0.05). Histologically, vessel muscularization or thickening and collagen deposition were also significantly decreased (P < 0.05). The number of vessels in the HGF+G-CSF group was higher than that in the other groups (P < 0.05). The TGF-beta and ET-1 concentrations in the plasma of pulmonary hypertensive rats were markedly lower in the HGF and HGF+G-CSF groups (P < 0.05). Furthermore, HGF induced the expression of VCAM-1, and HGF treatment together with G-CSF synergistically stimulated MMP-9 expression. Transplanted HGF-MSCs combined with G-CSF potentially offer synergistic therapeutic benefit for the treatment of PAH. PMID- 23933911 TI - Butyrylcholinesterase and gamma-glutamyltransferase activities and oxidative stress markers are altered in metabolic syndrome, but are not affected by body mass index. AB - Metabolic syndrome (MetS) leads to changes in enzymatic activities, oxidative and inflammatory parameters. Adenosine deaminase (ADA), dipeptidyl peptidase IV (DPP IV), butyrylcholinesterase (BuChE) and gamma-glutamyltransferase (gamma-GT) activities, C-reactive protein (hsCRP) and nitric oxide levels (NOx), as well as oxidative stress markers were analyzed in 39 subjects with MetS and 48 controls. Also, the influence of body mass index (BMI) and anthropometric measurements were evaluated. Disturbances in antioxidant defenses and higher gamma-GT and BuChE activities, NOx and hsCRP levels were observed in subjects with MetS. These findings remained associated with MetS after adjustment for BMI, except for hsCRP. ADA was correlated with age, insulin levels and HOMA-IR index in MetS. DPP IV and total cholesterol (TC), BuChE activity and TC, and VIT C and hsCRP levels also were correlated. The analyzed parameters may reflect the inflammatory state of the MetS, and could contribute to prevention and control of various aspects of this syndrome. PMID- 23933912 TI - Antidepressant and anticonvulsant effects of exercise in a rat model of epilepsy and depression comorbidity. AB - The bidirectional comorbidity between epilepsy and depression is associated with severe challenges for treatment efficacy and safety, often resulting in poor prognosis and outcome for the patient. We showed previously that rats selectively bred for depression-like behaviors (SwLo rats) also have increased limbic seizure susceptibility compared with their depression-resistant counterparts (SwHi rats). In this study, we examined the therapeutic efficacy of voluntary exercise in our animal model of epilepsy and depression comorbidity. We found that chronic wheel running significantly increased both struggling duration in the forced swim test and latency to pilocarpine-induced limbic motor seizure in SwLo rats but not in SwHi rats. The antidepressant and anticonvulsant effects of exercise were associated with an increase in galanin mRNA specifically in the locus coeruleus of SwLo rats. These results demonstrate the beneficial effects of exercise in a rodent model of epilepsy and depression comorbidity and suggest a potential role for galanin. PMID- 23933913 TI - Comparison of two models of hemispheric specialization with unilaterally lesioned patients: material-specific impairment vs response-bias distortion. AB - Validity of two models of hemispheric specialization was compared. The "material specific impairment" model was radicalized as postulating that left hemisphere (LH) lesions impair processing of verbal material and that right hemisphere (RH) lesions impair processing of visuospatial material, independently of response bias distortions. The "response-bias distortion" model was radicalized as postulating that LH lesions distort response style toward omissiveness and that RH lesions distort response style toward commissiveness, regardless of material specific impairments. Participants had comparable left (N=27) or right (N=24) hemisphere cortical lesions having occurred between birth and early adolescence. Four cognitive neuropsychological tests were adjusted to optimize applicability and comparability of the two theoretical models: Rey Complex Figure, Kimura's Recurring Figures, the Story Recall subtest of the Children's Memory Scale, and the California Verbal Learning Test. Both models significantly, independently, and equally distinguished the LH from the RH patients. Both these forms of hemispheric specialization seemed to be implemented very early in life and very rigidly. Intrahemispheric lesion sites, e.g., frontal vs nonfrontal, held no significant relation to the effects described above. PMID- 23933914 TI - Art and epilepsy surgery. AB - The impact of health and disease has led many artists to depict these themes for thousands of years. Specifically, epilepsy has been the subject of many famous works, likely because of the dramatic and misunderstood nature of the clinical presentation. It often evokes religious and even mythical processes. Epilepsy surgical treatment has revolutionized the care of selected patients and is a relatively recent advance. Epilepsy surgery has been depicted in very few artistic works. The first portrait showing a potential surgical treatment for patients with epilepsy was painted in the 12th century. During the Renaissance, Bosch famously provided artistic commentary on traditional beliefs in "The stone of madness". Several of these works demonstrate a surgeon extracting a stone from a patient's head, at one time believed to be the source of all "folly", including epileptic seizures, psychosis, intellectual disability, depression, and a variety of other illnesses. There are some contemporary art pieces including themes around epilepsy surgery, all of them depicting ancient Inca Empire procedures such as trepanning. This article reviews the most relevant artistic works related with epilepsy surgery and also its historical context at the time the work was produced. We also present a painting from the Mexican artist Eduardo Urbano Merino that represents the patient's journey through refractory epilepsy, investigations, and ultimately recovery. Through this work, the artist intends to communicate hope and reassurance to patients going through this difficult process. PMID- 23933916 TI - A one-pot and in situ synthesis of CuS-graphene nanosheet composites with enhanced peroxidase-like catalytic activity. AB - CuS-graphene nanosheet (GNS) composites with well-defined morphology have been successfully fabricated via a simple one-pot hydrothermal route by using thioacetamide (TAA) as both the sulfur source and reducing agent. The as-prepared CuS-GNS composites with an appropriate content of graphene exhibited an even higher peroxidase-like catalytic activity than pristine CuS nanoparticles in acetate buffer solution (pH = 4.0), which provided a facile method for the colorimetric detection of hydrogen peroxide (H2O2). It was calculated that H2O2 could be detected as low as 1.2 MUM (S/N = 3) with a wide linear range from 2.0 to 20.0 MUM (R(2) = 0.992), indicating that the as-prepared catalyst as an artificial peroxidase is promising for application in biosensors and environmental monitoring. PMID- 23933915 TI - Responsibility without legal authority? Tackling alcohol-related health harms through licensing and planning policy in local government. AB - BACKGROUND: The power to influence many social determinants of health lies within local government sectors that are outside public health's traditional remit. We analyse the challenges of achieving health gains through local government alcohol control policies, where legal and professional practice frameworks appear to conflict with public health action. METHODS: Current legislation governing local alcohol control in England and Wales is reviewed and analysed for barriers and opportunities to implement effective population-level health interventions. Case studies of local government alcohol control practices are described. RESULTS: Addressing alcohol-related health harms is constrained by the absence of a specific legal health licensing objective and differences between public health and legal assessments of the relevance of health evidence to a specific place. Local governments can, however, implement health-relevant policies by developing local evidence for alcohol-related health harms; addressing cumulative impact in licensing policy statements and through other non-legislative approaches such as health and non-health sector partnerships. Innovative local initiatives-for example, minimum unit pricing licensing conditions-can serve as test cases for wider national implementation. CONCLUSIONS: By combining the powers available to the many local government sectors involved in alcohol control, alcohol-related health and social harms can be tackled through existing local mechanisms. PMID- 23933917 TI - Association of preoperative obstructive jaundice with postoperative infectious complications following pancreaticoduodenectomy. AB - BACKGROUND/AIMS: The aim of this study was to evaluate the effects of obstructive jaundice on Infectious Complications of the patients who underwent pancreaticoduodenectomy. METHODOLOGY: One-hundred and sixteen consecutive patients without preoperative biliary drainage underwent pancreaticoduodenectomy from January 2006 to April 2010 and their data of post-operative complication were analyzed. Different level of bilirubin and different times of jaundice on infectious complications of the patients underwent pancreaticoduodenectomy were analysis. RESULTS: Patients with severe jaundice (Total bilirubin >=5 mg/dL; n = 55), had a higher incidence in subsequent infectious complications than the patients with total bilirubin level of less than 5 mg/dL (n = 61) (36.06% vs. 56.36%, p <0.05). The patients with preoperative TB level of 5 or more sub classified according to the duration of jaundice. However, two groups without statistical significance in terms of post-operative complications. There were no significant differences in post-operative mortality rate among the different groups. CONCLUSIONS: The elevated serum bilirubin increases the rate of infectious complications of the patients underwent pancreaticoduodeneotomy. PMID- 23933918 TI - Effectiveness of laparoscopic subtotal cholecystectomy: perioperative and long term postoperative results. AB - BACKGROUND/AIMS: We analyzed perioperative and long-term postoperative data to determine the effectiveness of laparoscopic subtotal cholecystectomy (LSC). METHODOLOGY: 89 LSCs done at our center were classified into 3 groups according to the operative procedure required to treat severe cholecystitis. Perioperative and long-term postoperative results were then compared with standard laparoscopic cholecystectomy (s-LC). RESULTS: Operative time was longer and postoperative CRP level was higher for LSC. Significantly more bleeding and longer operative times were seen only in the LSC-II subgroup, and average postoperative hospital stay was longer only in the LSC-III subgroup. As for long-term (1.5 to 8 years) postoperative results, 3 of 26 LSC-III cases had a relapse of cholecystolithiasis in remnant gallbladder tissue 2 years or later after initial surgery. CONCLUSIONS: There were no serious intraoperative complications such as the bile duct injury, and a smaller proportion of procedures were intraoperatively converted to open laparotomy. It is considered that LSC is a safe, useful surgical procedure to the patients in whom the neck of the gallbladder is anatomically unclear due to cholecystitis or fibrosis although patients undergoing LSC-III should be monitored for cholecystolithiasis in remnant gallbladder tissue. LSC is often the procedure of choice for patients. PMID- 23933919 TI - Effects of biliary drainage on the intestinal barrier function in obstructive jaundice. AB - BACKGROUND/AIMS: Despite advances in preoperative evaluation and postoperative care, intervention, especially surgery, for relief of obstructive jaundice still carries high morbidity and mortality rates. In obstructive jaundice, intestinal barrier dysfunction has been postulated to be a key factor contributing to high postoperative morbidity and mortality rates. Since surgery in patients with jaundice is thought to increase the risk of postoperative complications, preoperative biliary drainage (PBD) was introduced to improve the postoperative outcome. To date, whether biliary drainage should be routinely performed in patients with jaundice undergoing a pancreatoduodenectomy remains controversial, and the effect of biliary drainage on the intestinal barrier function in obstructive jaundice remains unknown. RESULTS: Biliary drainage is almost exclusively associated with beneficial results, such as improved intestinal barrier function in experimental models. However, clinical data in this field are limited, indirect and remain controversial. Most importantly, routine PBD will result in a highly procedure-related complication rate and an increase in operative infectious complications. CONCLUSIONS: PBD should not be performed routinely, unless further improved PBD techniques would become available in clinical studies. Future studies should focus on PBD techniques, and then on the effects of biliary drainage on intestinal mucosa in obstructive jaundice in clinical. PMID- 23933920 TI - Estrogen-induced cholestasis: pathogenesis and therapeuticimplications. AB - Cholestasis syndromes characterised by impairment of bile formation and secretion arecaused by many diseases. Estrogen-induced cholestasis among the cholestasis syndromes is a very common form. Based on the molecular studies of bile formation and transportation, a significant advancement has been achieved in understanding the mechanism of the disease. Estrogen can inhibit bile acids transportation from hepatocytes into bile canaliculi by interfering with the bile salt export pump and multidrug resistance-associated transporter 2 as well. It also inhibits Na+ taurocholate cotransporting polypeptide and Na+-independent organic anion transporting polypeptides in the basolateral membrane of hepatocytes to interfere with the uptake of bile acids. Thus, co-treatment strategy can be considered which combines nuclear receptor inducers and cAMP enhancer to increase bile acids transporters activities, and the agents to reduce serum estrogen concentration and its receptor binding, and to reduce bile acids in enterohepatic circulation. PMID- 23933921 TI - Predictive value of serum CEA, CA19-9 and CA125 in diagnosis of colorectal liver metastasis in Chinese population. AB - BACKGROUND/AIMS: Liver metastases are associated with poor prognosis in patients with colorectal cancer (CRC). The objective of this study is to determine the possible indicators in identifying the predictive value of serum CEA, CA19-9 and CA-125 in diagnosis of liver metastases from CRC in the Chinese population. METHODOLOGY: We randomly selected 101 CRC patients with liver metastases and 81 patients without liver metastases. Several clinical pathological factors were analyzed for the correlation with liver metastases. The predictive value of CEA, CA19-9 and CA-125 for liver metastases from CRC was evaluated. RESULTS: There was no significant difference in gender, age, hepatitis B history, serum AFP level or lesion location. Patients with liver metastases had a tendency to have higher serum CEA, CA19-9 and CA-125 level. Multivariate analysis revealed that serum CEA level (p<0.001), CA19-9 level (p<0.001) and CA-125 level (p=0.001) were independent prognostic predictors for liver metastases. Combination of CEA, CA19 9 and CA-125 can enhance their sensitivity in diagnosis of synchronous and metachronous liver metastases. Serum CA19-9 level, combined test of CA19-9 and CA 125, combined test of triple markers have higher sensitivities in synchronous metastasis than those in metachronous metastasis. CONCLUSIONS: Combination test would enhance the sensitivities of serum CEA, CA19-9 and CA-125 levels, which are important in predicting liver metastases from CRC in the Chinese population, either synchronous or metachronous. PMID- 23933922 TI - Liver regeneration in the first week after living donor liver transplantation: evaluation with sonography. AB - BACKGROUND/AIMS: Liver regeneration is a crucial issue after adult-to-adult living donor liver transplantation A-ALDLT. Several studies have shown the rapid enlargement of liver size 3 months after surgery but how the liver regenerate in the first postoperative week remains unknown. The purpose of our study was to investigate liver regeneration in the first postoperative week using sonography. METHODOLOGY: Twenty pairs of donors and recipients undergone A-ALDLT were enrolled between March 2007 and January 2008. A linear regression was done to determine the relationship between the preoperative donor liver volumetric measurements by CT and ultrasound. The volume of graft liver was obtained by water bath during surgery and by ultrasound daily in the first postoperative week. RESULTS: Liver volume of the 20 donors measured by CT and ultrasound were 1367.8+/-193.7cm3 and 1281.1+/-149.3cm3, respectively. The sonographic measurement correlated well with that of CT (r=0.93, p <0.0001). The mean volume of ex vivo graft livers was 595+/-193.7cm3. Hepatic volume increased sharply, by 42.31% at postoperative day one and 93.5% at postoperative day seven. CONCLUSIONS: Sonographic measurement of liver volume is accurate. Bedside ultrasound is a useful ancillary test to assess liver regeneration in early postoperative days. Liver regenerated vigorously in A-ALDLT recipients in the first postoperative week. PMID- 23933923 TI - Perioperative nutriture in esophageal cancer patients undergoing esophagectomy. AB - BACKGROUND/AIMS: Postoperative complications after thoracic esophagectomy are common and sometimes life-threatening. Optimized perioperative nutrition is essential for patient well-being and recovery. In this paper, we assessed the effects of perioperative parenteral nutrition on the nutritional status of thoracic esophagectomy patients. METHODOLOGY: The nutritional status of 25 patients, undergoing either 2- or 3-field lymph node dissection, was evaluated from one day before surgery until 14 days after. Respiratory quotient and energy expenditure were measured by indirect calorimetry. Nitrogen balance was measured as the difference between urophanic and intake nitrogen. We also measured nitrogen loss, total cholesterol, cholinesterase, total protein, rapid turnover protein, and biomarkers that included prealbumin, transferrin, and retinol binding protein. RESULTS: We observed significant and negative differences between pre- and postoperative calorie intake, caloric balance, respiratory quotient, nitrogen loss, nitrogen balance, total cholesterol, cholinesterase, total protein, and retinol-binding protein. On postoperative days 1-3, calorie intake was insufficient and caloric balance became negative and significantly lower than that before surgery. CONCLUSIONS: Parenteral nutrition provides insufficient nutrients to thoracic esophagectomy patients. Preoperative nutrition and early postoperative enteral nutrition in combination with parenteral nutrition may improve nutritional status, particularly in the early stages after surgery. PMID- 23933924 TI - Liver transplantation treating the patient with hepatic failure associated with sorafenib treatment: report of a case. AB - For the first time ever, sorafenib-induced hepatic failure has been cured by liver transplantation. A 54-year-old man, he underwent surgery for papillary carcinoma of thyroid gland two years ago. After two years follow up, a left neck lymph node metastasis was found and he was treated with sorafenib (800 mg/day). However, two days later, hepatic failure associated with sorafenib developed and he was treated with liver transplantation. The donor was a victim of road accident. Even though hepatic failure associated with sorafenib treatment is rare, the possible development of hepatic failure in patients undergoing sorafenib treatment must be kept in mind. PMID- 23933925 TI - POSSUM and P-POSSUM for risk assessment in general surgery in the elderly. AB - BACKGROUND/AIMS: The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) and Portsmouth POSSUM (P-POSSUM) use preoperative and intraoperative factors to evaluate risk. We examined our surgical results to investigate predictive factors for morbidity and mortality, and evaluate the accuracy of the POSSUM and P-POSSUM. METHODOLOGY: Patients (n = 593) aged >=80 years, undergoing general surgical procedures were enrolled. Logistic regression analysis was used to determine the independent predictors. The predicted outcomes using POSSUM and P-POSSUM were also compared with actual outcomes. RESULTS: Physiological score (PS) and operative severity score (OS) were independent predictors of morbidity and mortality. Using POSSUM, the observed/expected (O/E) morbidity ratio was 1.44 and O/E mortality ratio was 0.98. Using P-POSSUM, the O/E mortality ratio was 1.0. CONCLUSIONS: Even though POSSUM tended to underestimate the morbidity rate, POSSUM and P-POSSUM accurately predicted the mortality rate after general surgical procedures. PMID- 23933926 TI - Existence of microscopic residual viable lesions in patients with colorectal liver metastases after chemotherapy. AB - BACKGROUND/AIMS: Hepatic metastases from the colorectal carcinoma frequently recur after resection and microscopic residual cancer lesions (RCL) could be important in the development of recurrence. The aim of our study was to investigate an existence of microscopic RCL after modern chemotherapy and its correlation with the preoperative CT imaging. METHODOLOGY: Thirteen patients who underwent liver resection for colorectal liver metastases (CRM) after preoperative chemotherapy were studied. Resected hepatic specimens were stained with an antibody against carcinoembryonic antigen to detect microscopic RCL, which were defined as discrete microscopic cancerous lesions surrounding the dominant metastases. Also, we evaluated the correlation between the outline of CRM based on CT finding and the detection of microscopic RCLs around CRM. RESULTS: RCL were found immunohistochemically in 10 patients (77.8%). There are one patient whose RCL was most distant from the main tumor more than 10 mm. The presence of microscopic RCL was associated with the irregular outline of CRM (2/13, 15.4%) compared with regular CRM (11/13, 84.6%). CONCLUSIONS: To plan hepatectomy for CRM after chemotherapy, the possible existence of microscopic RCL should be taken into account. In addition, irregular shape tumor on CT should have wider surgical margin than 10 mm. PMID- 23933927 TI - Elevated C-reactive protein is associated with the tumor depth of invasion but not with disease recurrence in stage II and III colorectal cancer. AB - BACKGROUND/AIMS: We previously demonstrated that elevated serum C-reactive protein (CRP) level is associated with depth of tumor invasion in operable colorectal cancer. There is also increasing evidence to show that raised CRP concentration is associated with poor survival in patients with colorectal cancer. The purpose of this study was to investigate the correlation between preoperative CRP concentrations and short-term disease recurrence in cases with stage II and III colorectal cancer. METHODOLOGY: Of the 224 cases with resected colorectal cancer, 55 patients with TNM stage II and 50 with stage III were analyzed in this study. The clinical features were reviewed according to the CRP level, and statistical analysis was performed. In cases with stage II and III, 11 and 6 of which had elevated serum CRP (>=10mg/L), respectively. Recurrence-free interval was defined as the interval from surgery to the time disease recurrence was diagnosed. Among the cases with stage II and III colorectal cancer, 4 and 10 had recurrent disease. RESULTS: Among various clinicopathological characteristics, depth of tumor invasion was independently associated with preoperative elevation of CRP in stage II and III colorectal cancer in multivariate subgroup analysis. However, recurrence-free interval by Kaplan-Meier curves did not differ significantly among patients with preoperative CRP concentrations. CONCLUSIONS: Our results suggest that elevated serum CRP level is associated with depth of tumor, but not with recurrent disease in stage II and III colorectal cancer. PMID- 23933928 TI - Synchronous colorectal liver metastasis in patients without node metastasis: possibility of localized liver metastasis. AB - BACKGROUND/AIMS: The liver is the most common distant site of metastasis from colorectal cancer and is often the only organ affected. We hypothesized that whether distant disease is localized in the liver or is a more systemic disease, may be important in the prognosis of patients with synchronous liver metastasis. The purpose of this study was to investigate the possibility of localized liver metastasis in cases with colorectal synchronous liver metastasis and without lymph node involvement. METHODOLOGY: Three hundred and twenty-five consecutive patients who underwent colorectal resection were identified for inclusion in this study, of which 24 cases with synchronous liver metastasis were detected. Of these, 11 who underwent curative simultaneous surgical resection of primary tumor and liver metastases were analyzed in this study. The clinical and pathological features of these cases were reviewed. RESULTS: Of the 11 patients with synchronous liver metastasis from colorectal cancer, 4 had disease recurrence, but none of those without regional node involvement had disease recurrence. In the multivariate analysis, only regional node metastases were significantly associated with disease recurrence. Recurrence-free interval by Kaplan-Meier curves differed significantly among patients with positive regional nodes. CONCLUSIONS: Our results imply that synchronous liver metastasis without regional lymph node metastasis is localized disease. PMID- 23933929 TI - Tissue concentrations of antibiotics given prophylactically during colorectal cancer surgery. AB - BACKGROUND/AIMS: This study was designed to clarify the pharmacokinetics of prophylactically administered cefmetazole in serum, intestinal tissue, and subcutaneous adipose tissue in patients who underwent surgery for colorectal cancer. METHODOLOGY: Cefmetazole sodium (1 g) was given intravenously during the induction of anesthesia, followed by a 1-g dose after 3 hours. Blood samples were taken at the start of surgery, immediately before administration of the additional dose of cefmetazole, at the time of lesion resection, and at the time of wound closure. Tissue samples were obtained immediately after lesion resection and at the time of wound closure. Concentrations of cefmetazole in serum and tissue were measured by high performance liquid chromatography using an internal standard for calibration. Minimum inhibitory concentrations (MIC80) of cefmetazole for Escherichia coli, Klebsiella pneumoniae, and Bacteroides fragilis were measured, and pharmacokinetics were evaluated. RESULTS: In subcutaneous adipose tissue, cefmetazole concentrations were maintained higher than the MIC80's for E. coli and K. pneumoniae, but were low in all patients regardless of the time of measurement. CONCLUSIONS: The low transition rate of cefmetazole into subcutaneous adipose tissue indicates the need for additional measures, such as high-pressure washing of the subcutaneous wound tissue. PMID- 23933930 TI - The effect of polysaccharide k with S-1 based chemotherapy in advanced gastric cancer. AB - BACKGROUND/AIMS: Polysaccharide K (PSK) is widely used in Japan as a biological response modifier for cancer patients. We investigated the effects of PSK with S 1 based chemotherapy for advanced gastric cancer patients in immune response. METHODOLOGY: Nine advanced gastric cancer patients who underwent chemotherapy at the University of Tokushima were included in this study. In all patients, 3g PSK was received orally and S-1 based chemotherapy for 2 weeks alternately for 8 weeks. Serial changes in immunological parameters (Foxp3, Natural killer (NK), CD4/CD8) were monitored. RESULTS: The levels of Foxp3 at 8 weeks was significantly decreased compared with 2 weeks (4.26% vs. 3.11%). In NK activity at 8 weeks was significantly increased compared with 2 weeks (27% vs. 47%). CONCLUSIONS: These results of this study suggested that chemotherapy with PSK improved the immune response in advanced gastric cancer patients. Especially Foxp3 was concerned in this mechanism. PMID- 23933931 TI - Transarterial chemoembolization for patients with unresectable hepatocellular carcinoma: a retrospective study of a 5-year experience in a single institution. AB - BACKGROUND/AIMS: Transarterial chemoembolization (TACE) is the mainstay of management for patients with unresectable hepatocellular carcinoma (HCC). The aim of this study is to evaluate the survival rates of patients with unresectable HCC following TACE performed in a single center. METHODOLOGY: The authors retrospectively assessed the electronic medical records of 512 patients in whom HCC was newly diagnosed from January 2008 to December 2012 at a single tertiary medical center. Patients with decompensated hepatic function were excluded. Hepatic artery infusion chemotherapy was performed using one drug or combinations of oxaliplatin, fluorouracil and doxorubicin. The primary endpoint of the study was overall survival (OS). Survival rates were calculated using Kaplan-Meier method. RESULTS: A total of 512 HCC patients (425 men and 87 women; mean age, 58.9 years; age range, 38.3-86.1 years) were treated with TACE in a single center. The overall survival rates at 1, 2, and 3 years were 62%, 43%, and 37%, respectively. The overall median survival time from the start of TACE treatment was 15 months. CONCLUSIONS: TACE is an effective minimally invasive therapy option for palliative treatment of HCC patients. PMID- 23933932 TI - An approach to the intra-thoracic inferior vena cava through the abdominal cavity preparing for total hepatic vascular exclusion by sagittal diaphragmotomy. AB - BACKGROUND/AIMS: For resection of advanced liver tumors with tumor thrombus/invasion extending into the intra-thoracic inferior vena cava (IVC) above the diaphragm as well as huge liver tumors located at the root of hepatic vein, an appropriate approach to the intra-thoracic IVC through the abdominal cavity is the key to control the intraoperative massive bleeding. METHODOLOGY: SURGICAL TECHNIQUE: The pericardium and diaphragm are separated by using fingers without injury of the pericardium. From just below the xiphoid process to the IVC, the diaphragm is vertically dissected without cutting the pericardium and doing median sternotomy. Then the intra-thoracic IVC is exposed easily and encircled with an umbilical tape. RESULTS: This technique was applied in four patients (hepatocellular carcinoma: n = 3, cholangiocellular carcinoma: n = 1). The mean patient's age was 69 (59-81) year old, and three were male. The median duration of surgery and blood loss was 490 min and 3600 mL, respectively. The median peaked aspartate aminotransferase and total bilirubin was 428 IU/mL and 2.75 mg/dL, respectively. The median duration of hospital stay was 22 days. CONCLUSIONS: This approach to intra-thoracic IVC through the abdominal cavity is very beneficial and helpful for many liver surgeons. PMID- 23933933 TI - Long term recurrence analysis post drug eluting bead (deb) chemoembolization for hepatocellular carcinoma (hcc). AB - BACKROUND-AIMS: To determine long term outcomes, regarding recurrence and survival, in patients with HCC that achieved complete response after initial treatment with drug eluting beads (DEB) using DC Bead loaded with doxorubicin (DEB-DOX). METHODOLOGY: Forty-five patients with HCC, not suitable for curative treatments that exhibited complete response (EASL criteria) to initial DEB-DOX treatment were retrospectively analyzed after a median follow up period of 63 months. Child-Pugh class was A/B (62.2/37.8%) and mean lesion diameter 5.36 +/- 1.1 cm. Lesion morphology was one dominant <=5cm (53.3%), one dominant >5cm (31.1%) and multifocal (15.6%). RESULTS: At 5 years, overall survival was 62.2% and recurrence-free survival 8.9%. All deaths that occurred were related to tumor progression (31.1%) or complications of underlying liver disease (28.9%). Median time of initial recurrence from baseline treatment was 18 months (range 8-52). When recurrence occurred, a mean time interval between additional DEB-DOX procedures less than 9 months was correlated to a poorer prognosis (p=0.025). Multivariate analysis identified Child-Pugh class at baseline (p=0.048), combined therapy of recurrences with local ablation (p=0.03) and number of DEB-DOX procedures (p=0.037) as significant prognostic factors of 5-year survival. Lesion morphology displayed significance for recurrence-free survival (p=0.014). Child Pugh class at baseline, additional local ablation, pattern of initial recurrence and initial sum of recurrent tumor diameters all displayed statistical significance for post-recurrence survival (median 40 months), with the first two variables maintaining statistical significance in multivariate analysis (p=0.015 and p=0.014 respectively). CONCLUSION: Initial complete response to DEB-DOX ensures a favorable prognosis. However, management of recurrent tumors, which occur frequently mostly as new lesions, and preservation of underlying liver function appear to play a key role in prolonging survival. PMID- 23933934 TI - A splenic volume increase due to preoperative chemotherapy may impair the long term outcome after hepatectomy in patients with initially non-optimally resectable colorectal cancer liver metastases. AB - BACKGROUND/AIMS: In patients with colorectal cancer liver metastases (CRCLM), chemotherapy-associated hepatotoxicity (CAH) has been shown to be associated with splenomegaly. The aim of the present study was to investigate whether a higher splenic volume increase (SVI) after preoperative chemotherapy was associated with a worse long-term outcome after hepatectomy in patients with CRCLM. METHODOLOGY: Between 2007 and 2012, there were 36 patients who received preoperative chemotherapy based on a diagnosis of initially non-optimally resectable synchronous CRCLM. The splenic volume was measured by CT-volumetry before preoperative chemotherapy and 12 weeks after the start of the chemotherapy. Long term outcome was analyzed in these patients. RESULTS: The overall survival was significantly shorter in the SVI >=30% group than in the SVI <30% group (3-year survival = 52% vs. 28%, p <0.05). The disease-free survival was also significantly shorter in the SVI >=30% group than in the SVI <30% group (Median = 11 vs. 6 months, p <0.05). The survival after recurrence was significantly shorter in the SVI >=30% group than in the SVI <30% group (Median = 12.0 vs. 18 months, p<0.05). CONCLUSIONS: In patients with non-optimally resectable CRCLM, the SVI during the first 12 weeks of preoperative chemotherapy may be a significant predictor of the long-term survival after hepatectomy. PMID- 23933935 TI - A comprehensive study of the safety of using anti-hepatitis B core (Hbc) positive subjects in living donor liver transplants. AB - BACKGROUND/AIMS: In recent years, only few reports have addressed the safety of using living donors with a positive anti-Hepatitis B Core (HBc) antibody for liver transplants. Most reports have focused on short-term complications, short term changes in liver function and regeneration of remnant liver. Long term follow-up data, quality of life and overall laboratory tests variations have not been appropriately studied. In our study, we aim to comprehensively investigate the safety of using anti-HBc-positive subjects in living donor liver transplants (LDLT). METHODOLOGY: From March 2003 to March 2008, a total of 60 of LDLT cases were studied. All cases were right lobe transplants. Thirty donors with a positive anti-HBc were included in one group (group 1). The other 30 donors with a negative anti-HBc were included in Group 2. Preoperative parameters, intra operative data, postoperative short- and long-term complications, laboratory tests and quality of life after surgery were compared. RESULTS: Preoperative demographic data, intra-operative data and graft size comparisons from both groups showed non-significant differences. Anti-HBc-positive donors (9 cases; 30%) showed more complications than negative donors (7 cases; 23.3%). However, the increase did not reach statistical significance (p = 0.563). The quality of life, postoperative serum Transaminase levels, prothrombin times and routine blood values showed non-significant differences. Anti-HBc positive donors showed higher levels of total bilirubin (TB), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within the first 7 postoperative days. Nonetheless, all levels showed similar values for both groups in the days immediately following surgery. All indexes returned to normal levels, thirty days after surgery. However, a persistently decreased platelet count was observed in both groups. CONCLUSIONS: A positive serological test result for anti-HBc should not be considered as an absolute contraindication for LDLT. However, these cases require more caution than negative donors. PMID- 23933936 TI - HCC and its microenvironment. AB - BACKGROUND/AIMS: Thrombocytopenia has been reported to be a surrogate for cirrhosis, but the HCC phenotypes associated with and without cirrhosis are not well studied. To compare characteristics of HCC patients with and without associated thrombocytosis. METHODOLOGY: Records were examined of a cohort of 668 biopsy-proven and randomly presenting unresectable HCC patients, who were dichotomized for presence (platelets <125 x 109/L) or absence (platelets 125-400 x 109/L) of thrombocytopenia. RESULTS: Patients with normal platelets had larger tumors, more tumor nodules and longer survival than in the thrombocytopenia group. They also had more normal total plasma bilirubin, albumin and prothrombin times, yet had higher GGTP, ALKP and AFP levels. CONCLUSIONS: Thrombocytopenia in association with HCC occurs in patients with smaller tumor sizes, worse liver function and poorer survival, supporting the importance of host factors and liver micro-environment in HCC patients and the likelihood of two pathways for HCC development. PMID- 23933937 TI - Novel syngeneic liver hapten protein compounds play different roles in pathogenesis of autoimmune hepatitis in the C57BL/6 mouse. AB - BACKGROUND/AIMS: The autoimmune hepatitis (AIH) model in C57BL/6 mice with syngeneic hapten S100 and adjuvant injected intraperitoneally has been designed to elucidate the pathogenesis of AIH. Three separate hapten peak proteins, peak I, peak II and peak III, could be derived from S100, but little is understood their roles on the development of AIH. This study aims to learn more about these roles on pathogenesis of AIH. METHODOLOGY: Novel AIH C57BL/6 mouse models were developed by weekly immunization by intraperitoneal injection with syngeneic S100 liver proteins and the three separated hapten peak proteins emulsified covalently in complete Freund's adjuvant (CFA) for 4 weeks and sacrificed for liver histopathological study. Additionally, TNF-alpha and INF-gamma in culture supernatants of spleen lymphocytes of healthy C57BL/6 mice cultured together with S100 plus CFA for 48 hours were detected, and the T-lymphocytes proliferative response after stimulation with crude S100, peak I, II or III proteins were also assessed. RESULTS: Data showed that hepatitis induced by CFA+S100 was accompanied with more severe inflammation characterized by diffusely distributed liver necrosis and enhanced lymphocyte infiltration in portal tracts, while hepatitis induced by peak I+CFA was characterized by mass lymphocyte infiltration, occasional isolated liver necrosis and many acidophilic bodies, which was more similar to autoimmune hepatitis; hepatitis induced by peak II+CFA was characterized by massive liver necrosis and mild lymphocyte infiltration; hepatitis induced by peak III+CFA was characterized by mild inflammation with isolated acidophilic bodies or dotted hepatocellular necrosis. TNF-alpha, INF gamma from culture supernatants were increased, and T-lymphocyte proliferative response stimulated with peak I protein significantly increased compared with those stimulated with crude S100, peak II or III proteins. CONCLUSIONS: Syngenic S100 liver protein and its three separated hapten proteins have different roles in the pathogenesis of AIH, and peak I protein may be important in its development. PMID- 23933938 TI - Long-term (>=2 yr) efficacy of vitamin E for non-alcoholic steatohepatitis. AB - BACKGROUND/AIMS: Vitamin E is one of the most promising treatments for non alcoholic steatohepatitis (NASH). However, the long-term efficacy of this treatment remains unknown. METHODOLOGY: We retrospectively examined 17 patients with biopsy-proven NASH who received vitamin E at a dose of 300 mg/day for >=2 yr, and underwent second liver biopsies after treatment. Variables were compared between patients with (group R) and without (group NR) fibrosis regression. RESULTS: The median interval between basal and second liver biopsies was 2.4 yr (range, 2.0-5.8 yr). Overall, transaminase activities, insulin resistance index, and hepatic fibrosis markers were significantly improved. Although histological steatosis, inflammation, and fibrosis did not change after treatment, liver fibrosis improved in seven patients (41.2%), progressed in five (29.4%), and remained unchanged in five (29.4%). At baseline, subjects in group R (n = 7) were more likely to have diabetes, insulin resistance, and severe fibrosis compared to those in group NR (n = 10). Lower NAFLD activity score and larger decrease of ALT and insulin resistance after treatment were observed in group R compared with group NR. CONCLUSIONS: Two years or longer treatment can be expected to ameliorate NASH fibrosis, especially in those whose serum transaminase activities and insulin resistance can be improved. PMID- 23933940 TI - Transition of serum alkaline phosphatase isoenzymes during liver regeneration in humans. AB - BACKGROUND/AIMS: Serum alkaline phosphatase (ALP) levels tend to increase after hepatectomy, however, no previous examinations have yet focused on the relationship between liver regeneration and the individual ALP isoenzymes levels. METHODOLOGY: Forty living liver transplantation donors who underwent hemi hepatectomy were herein investigated. We evaluated the serum ALP levels and ALP isoenzyme levels preoperatively and postoperatively. The liver regeneration rate (LRR) was calculated using volumetry. According to the LRR, we divided the donors into two groups, consisting of a high regeneration group (HG) and a low regeneration group (LG). RESULTS: The total serum ALP levels increased gradually after hepatectomy and peaked on postoperative days (POD) 14. ALP-1 was not detected in any donor preoperatively; however it was detected after hepatectomy, peaking on POD 7. The serum ALP-2 level increased after hepatectomy, reaching a peak level on POD 14. The ALP-2 levels gradually increased after hepatectomy and reached peak levels on POD 14 in both groups. However, the ALP-2 level on POD 14 was significantly higher in HG than LG. CONCLUSIONS: The serum ALP- 2 levels after POD 14 might therefore be a useful indicator of favorable liver regeneration following hepatectomy, especially in patients who have a normal liver function. PMID- 23933939 TI - Biomarkers and prognosis after R0 resection of colorectal liver metastases. AB - BACKGROUND: Evaluation of biomarkers and clinical factors associated with cancer specific survival after curative resection for colorectal cancer liver metastases (LM). METHODOLOGY: All patients who had an R0 resection for LM between 2000-2006 were reviewed. Clinical and histological data were assessed; p53 expression was studied by IHC. ERCC1 codon 118 and XRCC1 codon 399 were analyzed by PCR-RFLP using BsrDI and HpaII, respectively. RESULTS: Out of 119 patients included (80 synchronous LM (67.2%), median number 2 (1-18)), 104 patients (87.4%) received chemotherapy before recurrence; 60 patients (50.4%) had a p53 negative tumor. ERCC1 distribution was: 31(26%) AAC/AAC, 44(37%) AAC/AAT and 44(37%) AAT/AAT. XRCC1 distribution was: 46(39%) CGG/CGG, 53(44.9%) CGG/CAG and 19(16.1%) CAG/CAG. Three and 5-years disease free survival (DFS) and overall survival (OS) were 31%, 22.7%, 77.4%, and 66.6%, respectively. Node ratio >0.2 (p = 0.0042), LM number >3 (p <0.0001), bilobar localization (p = 0.0074) and preoperative chemotherapy (p = 0.0036) were associated with a shorter DFS. None of the biomarkers was found to influence DFS. In multivariate analysis, a number of LM >3 was the only independent factor. No factor was found to influence OS. CONCLUSIONS: The studied biomarkers had no significant impact on prognosis. For routine practice, clinical factors remain the only usable available tools. PMID- 23933941 TI - Performance status is an important prognostic factor in second line treatment of pancreaticobiliary adenocarcinoma. AB - BACKGROUND/AIMS: To define the factors related with disease control and survival in patients with pancreaticobiliary adenocarcinoma treated with second-line therapy. METHODOLOGY: We retropectively reviewed the data of 39 pancreaticobiliary adenocarcinoma patients treated with second-line chemotherapy between 2000 and 2012. Age, gender, origin of tumor, location of tumor, stage at diagnosis, Eastern Cooperative Oncology Group (ECOG) performance status, progression site, progression free survival (PFS) for first-line therapy, disease control at first-line therapy and chemotherapy protocols are analyzed for disease control rate, PFS and overall survival (OS). RESULTS: Disease control was recorded in 21 (53.8%) patients (20 stable disease, 1 partial response). Disease control rate was higher in patients with good performance status (p=0.03). Disease control at first-line therapy was not a predictor of disease control at second-line (p=0.6). Response to first-line therapy and other prognostic factors was not related with disease control. Progression free survival and OS was significantly longer in patients with good ECOG performance status (0-1) (p=0.01, p=0.006). Choice of chemotherapy (single agent or combination) and other factors did not have any impact on PFS and OS. In multivariate analysis; disease control was independent prognostic factor for both PFS and OS (p<0.001), (p<0.001). CONCLUSIONS: Disease control and performance status are two important prognostic factors. Chemotherapy regimen has no impact on disease control and survival. Salvage chemotherapy can be considered for patients with good performance status whether they are resistant to first-line therapy or not. PMID- 23933942 TI - In vitro effects of lapatinib with gemcitabine for pancreatic cancer cells. AB - BACKGROUND/AIMS: We investigated whether lapatinib plus gemcitabine has synergistic or antagonistic effects on the pancreatic cancer cell lines MiaPaca-2 and PANC-1. Furthermore, the changes of gemcitabine sensitivity-related genes by lapatinib treatment were examined. METHODOLOGY: The effects of lapatinib, gemcitabine, and combined treatment with both agents on cell viability were examined by methyl thiazolyl tetrazolium analysis. Synergy between lapatinib and gemcitabine was assessed by median effect analysis. The mRNA amounts of human equilibrative nucleoside transporter (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit M1 (RRM1) genes were measured by quantitative real-time polymerase chain reaction in cells exposed to lapatinib for 48 h, as compared with untreated cells. RESULTS: No synergistic effects were observed with combined treatment in either cell line. In contrast, antagonistic effects occurred on MiaPaca-2 cells with the two agents. Specific changes in gemcitabine sensitivity-related genes induced by lapatinib were not detected in either MiaPaca-2 or PANC-1. CONCLUSIONS: Lapatinib may not enhance the anti-tumor effects of gemcitabine for pancreatic cancer. PMID- 23933943 TI - One layer end-to-side pancreaticojejunostomy using reinforcing suture on the pancreatic stump. AB - BACKGROUND/AIMS: Pancreaticoduodenectomy is associated with a high incidence of postoperative morbidity, and pancreatic fistulas are the most important complication. We therefore designed a modified method of pancreaticojejunostomy using reinforcing suture on the pancreatic stump. METHODOLOGY: The procedure is performed as follow: first, insert a soft rubber catheter into the pancreatic duct, then make reinforcing sutures with 3-0 vicryl. These sutures are parallel to the cut edge of the pancreatic stump, and 5mm from the cut edge. The whole layer of jejunum is sewed to the pancreas including the reinforcing sutures. RESULTS: Between July 2002 and November 2011, 52 consecutive cases of pancreaticoduodenectomy were performed using this method. We used The International Study Group for Pancreatic Surgery (ISGPS) severity grading for postoperative pancreatic fistula (POPF) and delayed gastric emptying (DGE). There was 1 grade A fistula (1.9%), 16 grade B fistulas (30.8%), and 2 grade C fistulas (3.8%). CONCLUSIONS: This method of one layer anastomosis is straightforward and practicable; hence it saves operative time, and is not much affected by lack of familiarity with the surgical technique. Even if it does not actually prevent pancreatic fistula formation, it does prevent the life-threatening complete breakdown of the pancreaticojejunostomy. PMID- 23933944 TI - Phase II study on combined intravenous and intra-arterial chemotherapy with gemcitabine and mitomycin C in patients with advanced pancreatic cancer. AB - BACKGROUND/AIMS: This prospective phase II study on a combination of intraarterial (i.a.) and systemic chemotherapy was performed to test whether regional chemotherapy may overcome the chemoresistance of pancreatic cancer. METHODOLOGY: One treatment cycle consisted of an i.a. infusion through an angiographic catheter into the celiac artery of 8.5mg/m2 mitomycin C (MMC) and 500 mg/m2 gemcitabine on days 1 and 22, and intravenous infusions of 500 mg/m2 gemcitabine on days 8 and 15. Study-endpoints were overall survival and tumor response as measured by computed tomography (CT). Treatment was continued until disease progression or complete remission on CT. RESULTS: Thirty-seven treatment cycles were performed in 17 patients. The most frequent side effects were hematological with 18 episodes of grade III/IV toxicities. According to radiographic and tumor marker criteria, four (24%) and seven patients (41%), respectively, demonstrated an objective response. The median actual progression free and overall survivals were 4.6 and 9.1 months, respectively. Patients without distant metastases had a longer median survival (15 months) than those with distant metastases (7.1 months, p = 0.037). CONCLUSIONS: This combination treatment was well tolerated and resulted in tumor response rates, median overall and progression-free survival times superior to systemic gemcitabine chemotherapy, and comparable to the more toxic FOLFIRINOX regimen. PMID- 23933945 TI - The clinical significance of HER-2 and NF-KB expression in gastric cancer. AB - BACKGROUND/AIMS: To investigate the expression of human epidermal growth factor 2 (HER-2) and Nuclear factor-Kb (NF-KB) in gastric cancer, and the relation of these two parameters with stage, grade and metastasis of gastric cancer. METHODOLOGY: The serum level of HER-2 in 75 gastric cancer patients and control participants were determined by enzyme-linked immunosorbent assay (ELISA) kits. Expression of HER-2 and NF-KB protein were detected by immunohistochemical staining (SP method) of paraffin-embedded tissues in 75 tumors (observed group) and 22 normal gastric specimens. The clinical pathological data was statistically analyzed. RESULTS: Serum HER-2 level were significantly increased in study group compared with those in the control group (p<0.001). The HER-2 level of 8.2 ng/mL as the cutoff value has a 79% sensitivity and an 82% specificity for predicting gastric cancer. The positive rate of HER-2 and NF-KB in the observed group was 24.00% (18/75) and 62.67% (47/75) respectively. The expression of HER-2 and NF-KB were not correlated with age and gender, but with stage, grade and metastasis (p<0.05). The expression of NF-KB was correlated with tumor size (p<0.05), while HER-2 was not (p<0.05). When HER-2 was positive, N F-KB had a positive rate of 94.44% (17/18), but a positive rate of 52.63% (30/57) when HER-2 was negative. Expression of NF-KB in gastric cancer tissue was correlated with HER-2 expression (X2 = 8.514, p<0.01). CONCLUSIONS: These data suggest that the expression of NF KB in gastric cancer tissue is correlated with HER-2 expression, and they may play a very important role in the progress of gastric cancer. PMID- 23933946 TI - Usefulness of endoscopic submucosal dissection for type I gastric carcinoid tumors compared with endoscopic mucosal resection. AB - BACKGROUND/AIMS: Gastric carcinoid tumors (GCTs) often extends into the submucosa, and are therefore difficult to resect completely by using conventional endoscopic mucosal resection (EMR). Endoscopic submucosal dissection (ESD) allows en bloc resection of submucosal gastrointestinal lesions. Therefore, ESD may be a feasible method for complete resection of GCT. Our purpose is to clarify the usefulness of ESD for treatment of type I GCT. METHODOLOGY: Between 1998 and 2011, EMR or ESD was performed for 13 lesions in 12 patients with type I GCTs. Among the 13 GCTs, 6 were resected using EMR, and 7 were removed using ESD. RESULTS: All lesions were histologically classified as Grade 1. The depth of invasion was the mucosa for 1 lesion and the submucosa for 12 lesions. The horizontal margins of excision were negative for all lesions; however, the vertical margins were positive in 4 lesions (66.7%) in the EMR group and no lesions (0%) in the ESD group. CONCLUSIONS: The results of this study suggest that ESD for small type I GCT is better to achieve complete resection than conventional EMR. ESD would be an effective technique for the treatment of small type I GCT. PMID- 23933947 TI - Totally laparoscopic vs. laparoscopically assisted distal gastrectomy for gastric cancer: a meta-analysis. AB - BACKGROUND/AIMS: Laparoscopic surgery has become common in the treatment of gastric cancer due to the improvement of both techniques and devices for laparoscopic surgery. This study compares totally laparoscopic distal gastrectomy (TLDG) with laparoscopically assisted distal gastrectomy (LADG) implemented by experienced laparoscopic surgeons. METHODOLOGY: Studies and relevant literature regarding the formation of LADG vs. TLDG were searched in PubMed, Embase and WanFang database. Operative time, bleeding volume, number of retrieved lymph nodes, time to first flatus, duration of postoperative hospitalization and postoperative complications in LADG and TLDG were pooled and compared using a meta-analysis. The odds ratios (ORs) and weighted mean different (WMD) were calculated with 95% confidence intervals (CIs) to evaluate the influence of TLDG. RESULTS: Five recent studies including 652 patients in total were included in this meta-analysis. These studies demonstrated that compared with LADG, TLDG has less bleeding (p <0.05), shorter time to first flatus (p <0.05), and lower rates of postoperative complications (p <0.01). The operation time, the mean number of lymph nodes retrieved and duration of postoperative hospitalization were not statistically significant (p >0.05). CONCLUSIONS: Compared with LADG, TLDG can significantly reduce bleeding, time to first flatus and rates of postoperative complications. Therefore, it was considered a useful technique for patients with gastric cancer. PMID- 23933948 TI - Menstrual and reproductive characteristics and breast density in young women. AB - PURPOSE: Breast density is strongly related to breast cancer risk, but determinants of breast density in young women remain largely unknown. METHODS: Associations of reproductive and menstrual characteristics with breast density measured by magnetic resonance imaging were evaluated in a cross-sectional study of 176 healthy women, 25-29 years old, using linear mixed effects models. RESULTS: Parity was significantly inversely associated with breast density. In multivariable adjusted models that included non-reproductive variables, mean percent dense breast volume (%DBV) decreased from 20.5 % in nulliparous women to 16.0 % in parous women, while mean absolute dense breast volume (ADBV) decreased from 85.3 to 62.5 cm(3). Breast density also was significantly inversely associated with the age women started using hormonal contraceptives, whereas it was significantly positively associated with duration of hormonal contraceptive use. In adjusted models, mean %DBV decreased from 21.7 % in women who started using hormones at 12-17 years of age to 14.7 % in those who started using hormones at 22-28 years of age, while mean ADBV decreased from 86.2 to 53.7 cm(3). The age at which women started using hormonal contraceptives and duration of hormone use were inversely correlated, and mean %DBV increased from 15.8 % in women who used hormones for not more than 2.0 years to 22.0 % in women who used hormones for more than 8 years, while mean ADBV increased from 61.9 to 90.4 cm(3) over this interval. CONCLUSIONS: Breast density in young women is inversely associated with parity and the age women started using hormonal contraceptives but positively associated with duration of hormone use. PMID- 23933949 TI - Understanding the relationship between social support and physical and mental well-being among jail detainees living with HIV. AB - Inmates face a disproportionate burden of HIV. This study sought to explore the relationship between social support and physical and mental well-being and the possibility that housing stability moderates this relationship among jail detainees living with HIV. Data for this cross-sectional analysis come from 438 clients who underwent a structured interview. Results indicate a significant positive relationship between social support and both types of well-being (ps < .05); the experience of homelessness was associated with less mental well-being (p < .01). There was no evidence of moderation. Results highlight the importance of social support and economic considerations in understanding well-being among HIV+ jail detainees. PMID- 23933950 TI - An exploration of the perceptions and experiences of living with chronic anorexia nervosa while an inpatient on an Eating Disorders Unit: an Interpretative Phenomenological Analysis (IPA) study. AB - Chronic anorexia nervosa (cAN) is a challenging presentation for the clinician. Motivation to recover is low, and outcomes are often poor. Within this study. six participants, currently in treatment, were interviewed. These interview transcripts were analysed using Interpretative Phenomenological Analysis. The results highlighted five superordinate themes resulted from the analysis and these referred to the following points: (1) 'making sense of AN', (2) 'experience of treatment/treatment', (3) 'interpersonal relationships', (4) 'battling with anorexia' and (5) 'staff pessimism in the treatment of cAN'. These results highlighted how the self is entwined with anorexia nervosa and thus making it incredibly difficult to perceive a life without cAN. PMID- 23933951 TI - Lack of institutional support entails disruption in cortisol awakening response in caregivers of people with high-functioning autism. AB - Several studies have found disruptions in cortisol awakening response in informal caregivers. Institutional support may modulate these effects, and this study analyses how the health of caregivers is affected when institutional support is provided for families of people with high-functioning autism. Self-reported health, depression and cortisol awakening response were analysed in three groups: supported caregivers, non-supported caregivers and non-caregivers. Non-supported caregivers presented higher somatic symptoms and lower cortisol awakening response than the supported caregiver and non-caregiver groups. A high number of somatic symptoms and low functionality of offspring were related to a lower cortisol awakening response only in the non-supported caregiver group. These findings demonstrate the importance of institutional support for improving the health of caregivers. PMID- 23933952 TI - Implanted islets in the anterior chamber of the eye are prone to autoimmune attack in a mouse model of diabetes. AB - AIMS/HYPOTHESIS: Type 1 diabetes is an autoimmune disease resulting from the destruction of insulin-producing beta cells. Along with advances in generating replacement beta cells for treating diabetes, there is also increasing demand for non-invasive tools to evaluate the recurrence of autoimmune attack on transplanted tissue. Here, we examined the anterior chamber of the eye as a potential islet transplant site, and also evaluated whether in vivo imaging of the islets transplanted in the eye could enable real-time visualisation of autoimmune processes underway in the pancreas. METHODS: Syngeneic islet equivalents were transplanted into the eye or kidney capsule of streptozotocin induced diabetic C57BL/6 mice to compare islet dose (25-125 islet equivalents) and function across transplant sites. Autoimmune attack of syngeneic islets was evaluated in the pancreas and eye tissues of NOD and NOD-severe combined immunodeficient (SCID) mice given diabetogenic splenocytes. RESULTS: Islet transplantation in the eye decreased fasting plasma glucose levels and increased weight gain and survival in an islet-dose-dependent manner. Even 50 islets in the eye reduced blood glucose levels, whereas >= 200 islets were required in the kidney for a similar effect. Autoimmune destruction of pancreatic islets in the eye mirrored that in the pancreas and could be visualised in real time by non invasive imaging. CONCLUSIONS/INTERPRETATION: We found that far fewer islets were required to restore normoglycaemia when transplanted into the anterior chamber of the eye vs the kidney capsule. However, our results suggest that islets are not protected against autoimmune attack in the eye, making this a suitable site for visualising autoimmune processes against transplanted tissue. PMID- 23933953 TI - Glucocorticoid treatment impairs microvascular function in healthy men in association with its adverse effects on glucose metabolism and blood pressure: a randomised controlled trial. AB - AIMS/HYPOTHESIS: Glucocorticoids (GCs) are widely used anti-inflammatory agents that frequently induce side effects, including insulin resistance, diabetes and hypertension. Here, we investigated the contribution of microvascular dysfunction to the development of these adverse effects in healthy men. METHODS: In a randomised, placebo-controlled, dose-response intervention study, 32 healthy normoglycaemic men (age: 21 +/- 2 years; BMI: 21.9 +/- 1.7 kg/m(2)) were allocated to receive prednisolone 30 mg once daily (n = 12), prednisolone 7.5 mg once daily (n = 12) or placebo (n = 8) for 2 weeks using block randomisation. A central office performed the treatment allocation, and medication was dispersed by the hospital pharmacy that was also blinded. Treatment allocation was kept in concealed envelopes. Participants, study personnel conducting the measures and assessing the outcome were blinded to group assignment. The study was conducted at a university hospital. Primary endpoint was prednisolone-induced changes in microvascular function, which was assessed by capillary microscopy. Insulin sensitivity was determined by hyperinsulinaemic-euglycaemic clamp and postprandial glycaemic excursions by standardised meal tests. RESULTS: Compared with placebo, prednisolone 7.5 mg and 30 mg decreased insulin-stimulated capillary recruitment by 9 +/- 4% and 17 +/- 3%, respectively (p < 0.01). In addition, prednisolone 7.5 mg and 30 mg reduced insulin sensitivity (M value) by 11.4 +/- 4.5 MUmol kg(-1) min(-1) and -25.1 +/- 4.1 MUmol kg(-1) min(-1) (p < 0.001) and increased postprandial glucose levels by 11 +/- 5% and 27 +/- 9% (p < 0.001), respectively. Only high-dose prednisolone increased systolic blood pressure (6 +/- 1.2 mmHg, p = 0.006). Prednisolone-induced changes in insulin stimulated capillary recruitment were associated with insulin sensitivity (r = +0.76; p < 0.001), postprandial glucose concentrations (r = -0.52; p < 0.03) and systolic blood pressure (r = -0.62; p < 0.001). Prednisolone increased resistin concentrations, which were negatively related to insulin-stimulated capillary recruitment (r = -0.40; p = 0.03). No effects were noted on adiponectin and leptin concentrations. Prednisolone treatment was well tolerated; none of the participants left the study. CONCLUSIONS/INTERPRETATION: Prednisolone-induced impairment of insulin-stimulated capillary recruitment was paralleled by insulin resistance, increased postprandial glucose levels, hypertension and increased circulating resistin concentrations in healthy men. We propose that GC-induced impairments of microvascular function may contribute to the adverse effects of GC treatment on glucose metabolism and blood pressure. TRIAL REGISTRATION: isrctn.org ISRTCN 78149983. FUNDING: The study was funded by the Dutch Top Institute Pharma T1-106. PMID- 23933954 TI - Use of a reactive transport model to describe reductive dechlorination (RD) as a remediation design tool: application at a CAH-contaminated site. AB - In this paper, a numerical model is presented that is capable of describing the complex set of biochemical processes that occur in chlorinated aliphatic hydrocarbon (CAH)-contaminated groundwater when an exogenous electron donor is added. The reactive pattern is based on the degradation pathways of both chlorinated ethanes and ethenes, and it includes electron donor production (H2 and acetate) from the fermentation of an organic substrate as well as rate limiting processes related to electron acceptor competition. Coupling of the kinetic model to a convection-dispersion module is described. The calibration phase was carried out using data obtained at a real CAH-contaminated site in the north of Italy. Model simulations of different application scenarios are presented to draw general conclusions on the effectiveness of reductive dechlorination (RD) as a possible cleanup strategy. Early outcomes indicate that cleanup targets can only be achieved if source longevity is reduced. Therefore, metabolic RD is expected to produce beneficial effects because it is known to induce bioenhanced degradation and transformation of CAHs. PMID- 23933955 TI - Occurrence and fate of perfluorinated acids in two wastewater treatment plants in Shanghai, China. AB - Perfluorinated acids (PFAs) have drawn much attention due to their environmental persistence, ubiquitous existence, and bioaccumulation potential. The discharge of wastewater effluent from municipal wastewater treatment plants (WWTPs) is a significant source of PFAs to the environment. In this study, wastewater and sludge samples were collected from two WWTPs in Shanghai, China, to investigate the contamination level and fate of PFAs in different stages of processing. The total concentrations of PFAs (?PFAs) in influent from plants A and B were 2,452 and 292 ng L(-1), respectively. Perfluoropentanoic acid (1,520 +/- 80 ng L(-1) in plant A and 89.2 +/- 12.1 ng L(-1) in plant B) was the predominant PFA in influent waters, followed by perfluorooctanoic acid. The concentration of ?PFAs ranged from 75.0 to 126.0 ng g(-1) dry weight in sludge samples from plant B, with perfluorooctanesulfonic acid as the predominant contaminant. The concentrations and fate of PFAs in different WWTPs vary. The ?PFAs entering plant A decreased significantly in the final effluent of activated sludge process, while that in plant B increased significantly in the final effluent of sequencing batch reactor system. The concentration changes could be due to the sorption onto sludge, or the degradation of PFAs precursors. PMID- 23933956 TI - Integrated evaluation of aerogenic pollution by air-transported heavy metals (Pb, Cd, Ni, Zn, Mn and Cu) in the analysis of the main deposit media. AB - The composition of the ambient air is constantly changing; therefore, the monitoring of ambient air quality to detect the changes caused by aerogenic pollutants makes the essential part of general environmental monitoring. To achieve more effective improvement of the ambient air quality, the Directive 2008/50/EC on 'Ambient Air Quality and Cleaner Air for Europe' was adopted by the European Parliament and the European Council. It informed the public and enterprises about a negative effect of pollution on humans, animals and plants, as well as about the need for monitoring aerogenic pollutants not only at the continuous monitoring stations but also by using indicator methods, i.e. by analysing natural deposit media. The problem of determining the relationship between the accumulation level of pollutants by a deposit medium and the level of air pollution and its risks is constantly growing in importance. The paper presents a comprehensive analysis of the response of the main four deposit media, i.e. snow cover, soil, pine bark and epigeic mosses, to the long-term pollution by aerogenic pollutants which can be observed in the area of oil refinery influence. Based on the quantitative expressions of the amounts of the accumulated pollutants in the deposit media, the territory of the oil refinery investigated in this paper has been referred to the areas of mild or moderate pollution. PMID- 23933957 TI - Health-reception of newly arrived documented migrants in Europe--why, whom, what and how? PMID- 23933958 TI - Comparing performance of indirect and direct laryngoscopes for nasotracheal intubation in patients with ankylosing spondylitis. PMID- 23933959 TI - Nasotracheal intubation and advantages of videolaryngoscopy. PMID- 23933960 TI - Infratentorial neurosurgery is an independent risk factor for respiratory failure and death in patients undergoing intracranial tumor resection. AB - BACKGROUND: Respiratory failure and death are devastating outcomes in the postoperative period. Patients undergoing neurosurgical procedures experience a greater frequency of respiratory failure compared with other surgical specialties. Resection of infratentorial mass lesions may be associated with an even higher risk because of several unique factors. Our objectives were: (1) to determine the incidence of postoperative respiratory failure and death in the neurosurgical population; and (2) to determine whether infratentorial procedures are associated with a higher risk compared with supratentorial procedures. METHODS: We retrospectively analyzed the American College of Surgeons National Surgical Quality Improvement Program database to identify patients undergoing intracranial tumor resection. The primary outcome was a composite of reintubation within 30 days, failure to wean from mechanical ventilation within 48 hours, and death within 30 days after surgery. We examined the association between the surgical site and the outcomes using multivariate logistic regression. RESULTS: A total of 1699 patients met inclusion criteria (79% supratentorial and 21% infratentorial). The primary outcome occurred in 3.8% of supratentorial procedures and 6.6% of infratentorial procedures (P=0.02). Infratentorial tumor resection was independently associated with the composite outcome in the final model (odds ratio, 1.75; 95% confidence interval, 1.03-2.99; P=0.04) with the strongest association seen between infratentorial site and death (odds ratio, 2.44; 95% confidence interval, 1.23-4.87; P=0.01). CONCLUSIONS: Infratentorial neurosurgery is an independent risk factor for respiratory failure and death in patients undergoing intracranial tumor resection. Mortality is an important contributor to this risk and should be a focus for future research. PMID- 23933961 TI - An unusual pressure-time curve. PMID- 23933962 TI - Genomic comparison of Salmonella typhimurium DT104 with non-DT104 strains. AB - DT104 emerged as a new branch of Salmonella typhimurium with resistance to multiple antimicrobials. To reveal some general genomic features of DT104 for clues of evolutionary events possibly associated with the emergence of this relatively new type of this pathogen, we mapped 11 independent DT104 strains and compared them with non-DT104 S. typhimurium strains. We found that all 11 DT104 strains contained three insertions absent in non-DT104 strains, i.e., the previously reported ST104, ST104B and ST64B. However, SGI-1, a genomic island known to be responsible for DT104 multidrug resistance, was not present in all DT104 strains examined in this study: one DT104 strain did not contain SGI-1 but carried a 144 kb plasmid, suggesting possible evolutionary relationships between the two DNA elements in the development of antimicrobial resistance. PMID- 23933963 TI - It's not how much you play, but how much you enjoy the game: the longitudinal associations between adolescents' self-esteem and the frequency versus enjoyment of involvement in sports. AB - The frequency of involvement in sports often has been concurrently and longitudinally associated with higher self-esteem. The interpretation of this association consistently has been framed as involvement in sports leading to higher levels of self-esteem over time (i.e., socialization effect), although no studies have tested whether higher levels of self-esteem lead to increased involvement in sports over time (i.e., selection effect). Another important aspect of involvement in sports that may be related to self-esteem is the degree to which youth enjoy sports. However, this aspect has received much less attention. To address these gaps in the literature, we first examined the bidirectional effects between self-esteem and the frequency of involvement in sports with 1,492 adolescents (50.8 % female; 92.4 % Canadian-born) over 4 years. Higher levels of self-esteem predicted greater involvement in sports over time, but greater involvement in sports did not predict higher levels of self-esteem over time, offering support only for selection effects. We then tested the bidirectional effects between the enjoyment of sports and self-esteem and found evidence of both socialization and selection effects. Specifically, greater enjoyment of sports predicted higher self-esteem over time, and higher self esteem predicted greater enjoyment of sports over time. These novel findings suggest that adolescents with higher self-esteem play sports more frequently and enjoy sports more than adolescents with lower self-esteem. In addition, the degree to which adolescents enjoy sports may be more important for increasing self-esteem than the frequency with which adolescents play sports. PMID- 23933965 TI - Single-port video-assisted thoracoscopic lobectomy with pulmonary artery reconstruction. AB - Despite the advances in video-assisted thoracoscopic surgery (VATS), vascular reconstruction of the pulmonary artery (PA) is still infrequently performed by thoracic surgeons because of the technical difficulties and the increased operative risk during thoracoscopy. The few published reports have been performed by using 3-4 incisions. We present the first report of a pulmonary artery reconstruction procedure performed by a single-incision VATS technique. A 73-year old male patient was operated on by the thoracoscopic approach through a single 4 cm incision with no rib spreading. The postoperative recovery was uneventful. PMID- 23933964 TI - Lung perfusion and ventilation during implantation of left ventricular assist device as a strategy to avoid postoperative pulmonary complications and right ventricular failure. AB - Right ventricular failure is a major contributor to increased morbidity and mortality in patients undergoing left ventricular assist device implantation. Cardiopulmonary bypass is associated with increased pulmonary ischaemia and pulmonary vascular resistance. Continuous pulmonary perfusion and ventilation represents an emerging strategy for pulmonary protection during cardiac surgery. We hypothesize that this technique may have a pivotal role in reducing postoperative right ventricular dysfunction in high-risk patients undergoing LVAD placement. PMID- 23933966 TI - Spectral correlation analysis of amyloid beta plaque inhomogeneity from double staining experiments. AB - A spectral correlation algorithm for the analysis of hyperspectral fluorescence images is proposed by Ellingsen et al. [J. Biomed. Opt. 18, 020501 (2013)]. Here, it is applied to the analysis of double-stained Abeta amyloid plaques being related to the Alzheimer's disease (AD). Sections of APP/PS1 AD mice model brains are double stained with luminescent-conjugated oligothiophenes, known to bind to amyloid protein deposits. Hyperspectral fluorescence images of the brain sections are recorded and by applying the correlation algorithm the spectral inhomogeneity of the double-stained samples is mapped in terms of radial distribution and spectral content. To further investigate the progression of Abeta amyloid plaque formation, 19 AD mice of different ages up to 23 months are characterized, enabling a statistical analysis of the plaque heterogeneity. In accordance with recent findings by Nystrom et al. [ACS Chem. Biol. 8, 1128-1133 (2013)], the spectral distribution within Abeta plaques is found to vary with age throughout the lifespan of the mouse. With the new correlation algorithm, it is possible to quantify the spectral abundance of the two stains depending on the relative distance from the plaque center and mouse age. Thus, we demonstrate the use of the correlation analysis approach in double-staining experiments and how it is possible to relate these to structural/spectral changes in biological samples. PMID- 23933967 TI - Multispectral imaging in the extended near-infrared window based on endogenous chromophores. AB - To minimize the problem with scattering in deep tissues while increasing the penetration depth, we explored the feasibility of imaging in the relatively unexplored extended near infrared (exNIR) spectral region at 900 to 1400 nm with endogenous chromophores. This region, also known as the second NIR window, is weakly dominated by absorption from water and lipids and is free from other endogenous chromophores with virtually no autofluorescence. To demonstrate the applicability of the exNIR for bioimaging, we analyzed the optical properties of individual components and biological tissues using an InGaAs spectrophotometer and a multispectral InGaAs scanning imager featuring transmission geometry. Based on the differences in spectral properties of tissues, we utilized ratiometric approaches to extract spectral characteristics from the acquired three dimensional "datacube". The obtained images of an exNIR transmission through a mouse head revealed sufficient details consistent with anatomical structures. PMID- 23933968 TI - Detection and quantification of enzymatically active prostate-specific antigen in vivo. AB - Assays for blood levels of prostate-specific antigen (PSA), performed in prostate cancer detection, measure mostly inactive/complexed PSA and do not provide information regarding enzymatically active PSA, which is biologically more relevant. Thus, we designed and synthesized an enzymatically cleavable peptide sequence labeled with near-infrared (NIR) fluorophores (ex/em 740/770 nm) and coupled it to a pharmacokinetic modifier designed to improve its plasma kinetics. In its native state, the agent, PSA750 FASTTM (PSA750), is optically quenched (>95%) and only becomes fluorescent upon cleavage by active PSA, yielding a significant increase in signal. This activation is highly selective for PSA relative to a large panel of disease-relevant enzymes. Active PSA was detected in tumor frozen sections using PSA750 and this activity was abolished in the presence of the inhibitor, alpha-1 anti-chymotrypsin. In vivo imaging of tumor bearing mice using fluorescence molecular tomography demonstrated a significantly higher fluorescent signal in PSA+ LNCaP tumors as compared to PSA- prostate cancer 3 tumors (13.0+/-3.7 versus 2.8+/-0.8 pmol, p=0.023). Ex vivo imaging of tumor sections confirms PSA750-derived NIR signal localization in nonvascular tissue. This is the first report that demonstrates the feasibility and effectiveness of noninvasive, real time, fluorescence molecular imaging of PSA enzymatic activity in prostate cancer. PMID- 23933969 TI - Metabolic phenotyping of diabetic nephropathy. AB - Diabetic nephropathy is the most serious complication of type 1 diabetes. There is no treatment to protect the kidneys from poorly controlled diabetes, and therefore prevention of the initial metabolic insults is currently the only effective approach to reducing the high mortality related to diabetic nephropathy. Metabolic phenotyping brings us one step closer to understanding the unique set of regulatory perturbations that predispose to kidney injury and paves the way for multiparametric risk assessment. PMID- 23933970 TI - Genetic and pharmacokinetic determinants of response to transdermal nicotine in white, black, and Asian nonsmokers. AB - The aim of the study was to examine genetic, pharmacokinetic, and demographic factors that influence sensitivity to nicotine in never-smokers. Sixty never smokers, balanced for gender and race (white, black, and Asian), wore 7-mg nicotine skin patches for up to 8 h. Serial plasma nicotine concentrations and subjective and cardiovascular effects were measured, and genetic variation in the CYP2A6 gene, encoding the primary enzyme responsible for nicotine metabolism, was assessed. Nicotine toxicity requiring patch removal developed in nine subjects and was strongly associated with rate of increase and peak concentrations of plasma nicotine. Toxicity and subjective and cardiovascular effects of nicotine were associated with the presence of reduced-function CYP2A6 alleles, presumably reflecting slow nicotine metabolic inactivation. This study has implications for understanding individual differences in responses to nicotine medications, particularly when they are used for treating medical conditions in nonsmokers, and possibly in vulnerability to developing nicotine dependence. PMID- 23933971 TI - Cometabolism of microbes and host: implications for drug metabolism and drug induced toxicity. AB - The recognition of the gut microbial-mammalian metabolic axis and its implications in human metabolic disease opens a new window to understanding the contribution of the gut microbiome to drug metabolism and drug-induced toxicity. The integrative omics approaches, including pharmacometabonomics and metagenomics, have demonstrated great promise for characterizing xenobiotic interventions that are associated with wide variation in efficacy or toxicity in humans, as well as for predicting individual response and susceptibility to toxicity. PMID- 23933972 TI - TFcheckpoint: a curated compendium of specific DNA-binding RNA polymerase II transcription factors. AB - SUMMARY: Gene regulatory network assembly and analysis requires high-quality knowledge sources that cover functional aspects of the various components of the gene regulatory machinery. A multiplicity of resources exists with information about mammalian transcription factors (TFs); yet, only few of these provide sufficiently accurate classifications of the functional roles of individual TFs, or standardized evidence that would justify the information on which these functional classifications are based. We compiled the list of all putative TFs from nine different resources, ignored factors such as general TFs, mediator complexes and chromatin modifiers, and for the remaining factors checked the available literature for references that support their function as a true sequence-specific DNA-binding RNA polymerase II TF (DbTF). The results are available in the TFcheckpoint database, an exhaustive collection of TFs annotated according to experimental and other evidence on their function as true DbTFs. TFcheckpoint.org provides a high-quality and comprehensive knowledge source for genome-scale regulatory network studies. AVAILABILITY: The TFcheckpoint database is freely available at www.tfcheckpoint.org PMID- 23933973 TI - Analysis of base-pairing probabilities of RNA molecules involved in protein-RNA interactions. AB - MOTIVATION: Understanding the details of protein-RNA interactions is important to reveal the functions of both the RNAs and the proteins. In these interactions, the secondary structures of the RNAs play an important role. Because RNA secondary structures in protein-RNA complexes are variable, considering the ensemble of RNA secondary structures is a useful approach. In particular, recent studies have supported the idea that, in the analysis of RNA secondary structures, the base-pairing probabilities (BPPs) of RNAs (i.e. the probabilities of forming a base pair in the ensemble of RNA secondary structures) provide richer and more robust information about the structures than a single RNA secondary structure, for example, the minimum free energy structure or a snapshot of structures in the Protein Data Bank. However, there has been no investigation of the BPPs in protein-RNA interactions. RESULTS: In this study, we analyzed BPPs of RNA molecules involved in known protein-RNA complexes in the Protein Data Bank. Our analysis suggests that, in the tertiary structures, the BPPs (which are computed using only sequence information) for unpaired nucleotides with intermolecular hydrogen bonds (hbonds) to amino acids were significantly lower than those for unpaired nucleotides without hbonds. On the other hand, no difference was found between the BPPs for paired nucleotides with and without intermolecular hbonds. Those findings were commonly supported by three probabilistic models, which provide the ensemble of RNA secondary structures, including the McCaskill model based on Turner's free energy of secondary structures. PMID- 23933974 TI - Depression in cognitive impairment. AB - Depression and cognitive disorders, including dementia and mild cognitive impairment, are common in the elderly. Depression is also a common feature of cognitive impairment although the symptoms of depression in cognitive impairment differ from depression without cognitive impairment. Pre-morbid depression approximately doubles the risk of subsequent dementia. There are two predominant, though not mutually exclusive, constructs linking pre-morbid depression to subsequent cognitive impairment: Alzheimer's pathology and the vascular depression hypothesis. When evaluating a patient with depression and cognitive impairment, it is important to obtain caregiver input and to evaluate for alternative etiologies for depressive symptoms such as delirium. We recommend a sequential approach to the treatment of depression in dementia patients: (1) a period of watchful waiting for milder symptoms, (2) psychosocial treatment program, (3) a medication trial for more severe symptoms or failure of psychosocial interventions, and (4) possible ECT for refractory symptoms. PMID- 23933975 TI - Globalization and cognitive enhancement: emerging social and ethical challenges for ADHD clinicians. AB - Globalization of ADHD and the rise of cognitive enhancement have raised fresh concerns about the validity of ADHD diagnosis and the ethics of stimulant drug treatment. We review the literature on these two emerging phenomena, with a focus on the corresponding social, scientific and ethical debates over the universality of ADHD and the use of stimulant drug treatments in a global population of children and adolescents. Drawing on this literature, we reflect on the importance of ethically informed, ecologically sensitive clinical practices in relation to ADHD diagnosis and treatment. PMID- 23933976 TI - A review of recent literature employing electroencephalographic techniques to study the pathophysiology, phenomenology, and treatment response of schizophrenia. AB - Clinical experience and research findings suggest that schizophrenia is a disorder comprised of multiple genetic and neurophysiological subtypes with differential response to treatment. Electroencephalography (EEG) is a non invasive, inexpensive and useful tool for investigating the neurobiology of schizophrenia and its subtypes. EEG studies elucidate the neurophysiological mechanisms potentially underlying clinical symptomatology. In this review article recent advances in applying EEG to study pathophysiology, phenomenology, and treatment response in schizophrenia are discussed. Investigative strategies employed include: analyzing quantitative EEG (QEEG) spectral power during the resting state and cognitive tasks; applying machine learning methods to identify QEEG indicators of diagnosis and treatment response; and using the event-related brain potential (ERP) technique to characterize the neurocognitive processes underlying clinical symptoms. Studies attempting to validate potential EEG biomarkers of schizophrenia and its symptoms, which could be useful in assessing familial risk and treatment response, are also reviewed. PMID- 23933977 TI - The comorbidity between depression and diabetes. AB - Comorbidity of depression and diabetes is common, and each disorder has a negative impact on the outcome of the other. The direction of causality is not certain as each disorder seems to act as both a risk factor and consequence for the other in longitudinal studies. This bidirectional association is possibly mediated by shared environmental and genetic risk factors. Comorbid depression is associated with reduced adherence to medication and self-care management, poor glycaemic control, increased health care utilization, increased costs and elevated risk of complications, as well as mortality in patients with diabetes. Psychological and pharmacological interventions are shown to be effective in improving depression symptoms; however, collaborative care programs that simultaneously manage both disorders seem to be most effective in improving diabetes-related outcomes. PMID- 23933978 TI - Consensual sadomasochistic sex (BDSM): the roots, the risks, and the distinctions between BDSM and violence. AB - When practiced consensually, sadomasochistic sex is being increasingly accepted as an alternative sexuality. Here I suggest the possible evolutionary roots of the preferences, draw distinctions between violent, abusive and "healthy" practitioners' partnership, provide clear behavioural markers of the respective situations, and underline some specific problems connected to this sexual preference. Some of the problems are well-known in the community of its practitioners, although they have not yet been described in medical nor scientific sources. PMID- 23933979 TI - Unique case of latent left ventricular obstruction in Takayasu arteritis. PMID- 23933980 TI - Unusual cause of acquired RBBB. PMID- 23933981 TI - Endothelial TWIK-related potassium channel-1 (TREK1) regulates immune-cell trafficking into the CNS. AB - The blood-brain barrier (BBB) is an integral part of the neurovascular unit (NVU). The NVU is comprised of endothelial cells that are interconnected by tight junctions resting on a parenchymal basement membrane ensheathed by pericytes, smooth muscle cells and a layer of astrocyte end feet. Circulating blood cells, such as leukocytes, complete the NVU. BBB disruption is common in several neurological diseases, but the molecular mechanisms involved remain largely unknown. We analyzed the role of TWIK-related potassium channel-1 (TREK1, encoded by KCNK2) in human and mouse endothelial cells and the BBB. TREK1 was downregulated in endothelial cells by treatment with interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Blocking TREK1 increased leukocyte transmigration, whereas TREK1 activation had the opposite effect. We identified altered mitogen-activated protein (MAP) kinase signaling, actin remodeling and upregulation of cellular adhesion molecules as potential mechanisms of increased migration in TREK1-deficient (Kcnk2(-/-)) cells. In Kcnk2(-/-) mice, brain endothelial cells showed an upregulation of the cellular adhesion molecules ICAM1, VCAM1 and PECAM1 and facilitated leukocyte trafficking into the CNS. Following the induction of experimental autoimmune encephalomyelitis (EAE) by immunization with a myelin oligodendrocyte protein (MOG)35-55 peptide, Kcnk2(-/-) mice showed higher EAE severity scores that were accompanied by increased cellular infiltrates in the central nervous system (CNS). The severity of EAE was attenuated in mice given the amyotrophic lateral sclerosis drug riluzole or fed a diet enriched with linseed oil (which contains the TREK-1 activating omega-3 fatty acid alpha-linolenic acid). These beneficial effects were reduced in Kcnk2( /-) mice, suggesting TREK-1 activating compounds may be used therapeutically to treat diseases related to BBB dysfunction. PMID- 23933982 TI - Local proliferation dominates lesional macrophage accumulation in atherosclerosis. AB - During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall. The observation that circulating monocytes give rise to lesional macrophages has reinforced the concept that monocyte infiltration dictates macrophage buildup. Recent work has indicated, however, that macrophage accumulation does not depend on monocyte recruitment in some inflammatory contexts. We therefore revisited the mechanism underlying macrophage accumulation in atherosclerosis. In murine atherosclerotic lesions, we found that macrophages turn over rapidly, after 4 weeks. Replenishment of macrophages in these experimental atheromata depends predominantly on local macrophage proliferation rather than monocyte influx. The microenvironment orchestrates macrophage proliferation through the involvement of scavenger receptor A (SR-A). Our study reveals macrophage proliferation as a key event in atherosclerosis and identifies macrophage self-renewal as a therapeutic target for cardiovascular disease. PMID- 23933983 TI - FGF21 contributes to neuroendocrine control of female reproduction. AB - Preventing reproduction during nutritional deprivation is an adaptive process that is conserved and essential for the survival of species. In mammals, the mechanisms that inhibit fertility during starvation are complex and incompletely understood. Here we show that exposure of female mice to fibroblast growth factor 21 (FGF21), a fasting-induced hepatokine, mimics infertility secondary to starvation. Mechanistically, FGF21 acts on the suprachiasmatic nucleus (SCN) in the hypothalamus to suppress the vasopressin-kisspeptin signaling cascade, thereby inhibiting the proestrus surge in luteinizing hormone. Mice lacking the FGF21 co-receptor, beta-Klotho, in the SCN are refractory to the inhibitory effect of FGF21 on female fertility. Thus, FGF21 defines an important liver neuroendocrine axis that modulates female reproduction in response to nutritional challenge. PMID- 23933985 TI - Low Reynolds number suspension gravity currents. AB - The extension of a gravity current in a lock-exchange problem, proceeds as square root of time in the viscous-buoyancy phase, where there is a balance between gravitational and viscous forces. In the presence of particles however, this scenario is drastically altered, because sedimentation reduces the motive gravitational force and introduces a finite distance and time at which the gravity current halts. We investigate the spreading of low Reynolds number suspension gravity currents using a novel approach based on the Lattice-Boltzmann (LB) method. The suspension is modeled as a continuous medium with a concentration-dependent viscosity. The settling of particles is simulated using a drift flux function approach that enables us to capture sudden discontinuities in particle concentration that travel as kinematic shock waves. Thereafter a numerical investigation of lock-exchange flows between pure fluids of unequal viscosity, reveals the existence of wall layers which reduce the spreading rate substantially compared to the lubrication theory prediction. In suspension gravity currents, we observe that the settling of particles leads to the formation of two additional fronts: a horizontal front near the top that descends vertically and a sediment layer at the bottom which aggrandises due to deposition of particles. Three phases are identified in the spreading process: the final corresponding to the mutual approach of the two horizontal fronts while the laterally advancing front halts indicating that the suspension current stops even before all the particles have settled. The first two regimes represent a constant and a decreasing spreading rate respectively. Finally we conduct experiments to substantiate the conclusions of our numerical and theoretical investigation. PMID- 23933984 TI - FGF21 regulates metabolism and circadian behavior by acting on the nervous system. AB - Fibroblast growth factor 21 (FGF21) is a hepatokine that acts as a global starvation signal to modulate fuel partitioning and metabolism and repress growth; however, the site of action of these diverse effects remains unclear. FGF21 signals through a heteromeric cell-surface receptor composed of one of three FGF receptors (FGFR1c, FGFR2c or FGFR3c) in complex with beta-Klotho, a single-pass transmembrane protein that is enriched in metabolic tissues. Here we show that in addition to its known effects on peripheral metabolism, FGF21 increases systemic glucocorticoid levels, suppresses physical activity and alters circadian behavior, which are all features of the adaptive starvation response. These effects are mediated through beta-Klotho expression in the suprachiasmatic nucleus of the hypothalamus and the dorsal vagal complex of the hindbrain. Mice lacking the gene encoding beta-Klotho (Klb) in these regions are refractory to these effects, as well as those on metabolism, insulin and growth. These findings demonstrate a crucial role for the nervous system in mediating the diverse physiologic and pharmacologic actions of FGF21. PMID- 23933986 TI - Generic instabilities in a fluid membrane coupled to a thin layer of ordered active polar fluid. AB - We develop an effective two-dimensional coarse-grained description for the coupled system of a planar fluid membrane anchored to a thin layer of polar ordered active fluid below. The macroscopic orientation of the active fluid layer is assumed to be perpendicular to the attached membrane. We demonstrate that activity or nonequilibrium drive of the active fluid makes such a system generically linearly unstable for either signature of a model parameter [Formula: see text] [Formula: see text] that characterises the strength of activity. Depending upon boundary conditions and within a range of the model parameters, underdamped propagating waves may be present in our model. We discuss the phenomenological significance of our results. PMID- 23933987 TI - Droplets on liquids and their journey into equilibrium. AB - The morphological path of droplets on a liquid substrate towards equilibrium is investigated experimentally and theoretically. The droplets emerge in the late stage of a dewetting process of short chained polystyrene (PS) dewetting from liquid polymethyl-methacrylate (PMMA). The three-dimensional droplet profiles are obtained experimentally by combining the in situ imaged PS/air interface during equilibration and the ex situ imaged PS/PMMA interface after removal of the PS by a selective solvent. Numerically the transient drop shapes are calculated by solving the thin-film equation in lubrication approximation using the experimentally determined input parameter like viscosity, film thickness and surface tensions. The numerically obtained droplet morphologies and time scales agree very well with the experimental drop shapes. An unexpected observation is that droplets with identical volumes synchronise their motion and become independent of the initial geometry long time before equilibrium is reached. PMID- 23933988 TI - Composite contact of binary lipid membranes. AB - Upon adhesion, binary lipid membranes may retain their structural identity but they may also undergo partial fusion promoted by microscopic phase separation of the components. In membranes composed of cylindrical and inverted conical lipids, a partially fused contact zone may consist of inverted micelles sandwiched between two monolayers. We theoretically analyze the elastic properties of such a composite contact zone. We calculate its bending moduli and we show that they may be considerably larger than the moduli of a phase-nonseparated double bilayer. The main mechanism responsible for the enhanced rigidity of the composite contact structure is the increased separation of the two monolayers caused by the presence of water in the inverted micelles. PMID- 23933989 TI - Symmetry, topology and faceting in bicontinuous lyotropic crystals. AB - Phase diagrams of phytantriol/ethanol/water and phytantriol/DSPG/ethanol/water systems are explored and experiments on facetings of Pn3m-in-L1 and Im3m-in-L1 crystals are performed. Observed crystal habits do not agree with the Friedel Donnay-Harker rules. We argue that this paradox can be explained in terms of constraints imposed on Pn3m/L1 and Im3m/L1 interfaces by the bicontinuous topology of the cubic phases. We point out that when free edges of the surfactant bilayer are prohibited at these interfaces, the two labyrinthes separated by the bilayer cannot anymore be equivalent. The corresponding [Formula: see text] and [Formula: see text] symmetry breakings are unveiled by the abnormal facetings. PMID- 23933990 TI - Stable transformation of ferns using spores as targets: Pteris vittata and Ceratopteris thalictroides. AB - Ferns (Pteridophyta) are very important members of the plant kingdom that lag behind other taxa with regards to our understanding of their genetics, genomics, and molecular biology. We report here, to our knowledge, the first instance of stable transformation of fern with recovery of transgenic sporophytes. Spores of the arsenic hyperaccumulating fern Pteris vittata and tetraploid 'C-fern Express' (Ceratopteris thalictroides) were stably transformed by Agrobacterium tumefaciens with constructs containing the P. vittata actin promoter driving a GUSPlus reporter gene. Reporter gene expression assays were performed on multiple tissues and growth stages of gametophytes and sporophytes. Southern-blot analysis confirmed stable transgene integration in recovered sporophytes and also confirmed that no plasmid from A. tumefaciens was present in the sporophyte tissues. We recovered seven independent transformants of P. vittata and four independent C. thalictroides transgenics. Inheritance analyses using beta glucuronidase (GUS) histochemical staining revealed that the GUS transgene was stably expressed in second generation C. thalictroides sporophytic tissues. In an independent experiment, the gusA gene that was driven by the 2* Cauliflower mosaic virus 35S promoter was bombarded into P. vittata spores using biolistics, in which putatively stable transgenic gametophytes were recovered. Transformation procedures required no tissue culture or selectable marker genes. However, we did attempt to use hygromycin selection, which was ineffective for recovering transgenic ferns. This simple stable transformation method should help facilitate functional genomics studies in ferns. PMID- 23933991 TI - An NAC transcription factor controls ethylene-regulated cell expansion in flower petals. AB - Cell expansion is crucial for plant growth. It is well known that the phytohormone ethylene functions in plant development as a key modulator of cell expansion. However, the role of ethylene in the regulation of this process remains unclear. In this study, 2,189 ethylene-responsive transcripts were identified in rose (Rosa hybrida) petals using transcriptome sequencing and microarray analysis. Among these transcripts, an NAC (for no apical meristem [NAM], Arabidopsis transcription activation factor [ATAF], and cup-shaped cotyledon [CUC])-domain transcription factor gene, RhNAC100, was rapidly and dramatically induced by ethylene in the petals. Interestingly, accumulation of the RhNAC100 transcript was modulated by ethylene via microRNA164-dependent posttranscriptional regulation. Overexpression of RhNAC100 in Arabidopsis (Arabidopsis thaliana) substantially reduced the petal size by repressing petal cell expansion. By contrast, silencing of RhNAC100 in rose petals using virus induced gene silencing significantly increased petal size and promoted cell expansion in the petal abaxial subepidermis (P < 0.05). Expression analysis showed that 22 out of the 29 cell expansion-related genes tested exhibited changes in expression in RhNAC100-silenced rose petals. Moreover, of those genes, one cellulose synthase and two aquaporin genes (Rosa hybrida Cellulose Synthase2 and R. hybrida Plasma Membrane Intrinsic Protein1;1/2;1) were identified as targets of RhNAC100. Our results suggest that ethylene regulates cell expansion by fine-tuning the microRNA164/RhNAC100 module and also provide new insights into the function of NAC transcription factors. PMID- 23933993 TI - Silencing tankyrase and telomerase promotes A549 human lung adenocarcinoma cell apoptosis and inhibits proliferation. AB - Telomeres are the end structures of chromosomes in mammalian cells; they play a pivotal role in maintaining the stability of the chromosome and become shorter with each cell division. However, several types of tumor cells express telomerase in very high levels to overcome this crisis and achieve the ability to proliferate endlessly. The telomerase inhibitors can partly inhibit tumor cell proliferation and promote apoptosis, but their roles are only limited. Tankyrase is a poly(ADP-ribose) polymerase which has synergistic effect on telomerase, and is expressed in lung cancer cells in high levels. In the present study, antisense oligonucleotides of telomerase (ashTERT) and tankyrase (asTANKS) were used as specific inhibitors to silence the expression of target genes in A549 human lung adenocarcinoma cells by transfection. The results showed that ashTERT and asTANKS suppressed the expression of telomerase and tankyrase significantly; both inhibited the activity of telomerase and the combination group achieved better effect, but only ashTERT shortened the length of telomeres, asTANKS did not. Further studies showed that ashTERT and asTANKS-promoted A549 apoptosis was not mediated by downregulation of the expression of the anti-apoptotic gene BCL-2 or upregulation of the expression of the pro-apoptotic gene BAX, but by adjusting the two isoforms proportion of myeloid cell leukemia-1 (MCL-1) which can interact with tankyrase directly. MCL-1short (MCL-1S), a pro-apoptotic gene, increased more than MCL-1Long (MCL-1L) which is an anti-apoptotic gene, leading to A549 cell apoptosis and a similar result was obtained in nude mice in vivo. The present study suggests that combination of the inhibitors of telomerase and tankyrase can be used as a strategy for the treatment of lung cancer in humans. PMID- 23933994 TI - Taurine chloramine produced from taurine under inflammation provides anti inflammatory and cytoprotective effects. AB - Taurine is one of the most abundant non-essential amino acid in mammals and has many physiological functions in the nervous, cardiovascular, renal, endocrine, and immune systems. Upon inflammation, taurine undergoes halogenation in phagocytes and is converted to taurine chloramine (TauCl) and taurine bromamine. In the activated neutrophils, TauCl is produced by reaction with hypochlorite (HOCl) generated by the halide-dependent myeloperoxidase system. TauCl is released from activated neutrophils following their apoptosis and inhibits the production of inflammatory mediators such as, superoxide anion, nitric oxide, tumor necrosis factor-alpha, interleukins, and prostaglandins in inflammatory cells at inflammatory tissues. Furthermore, TauCl increases the expressions of antioxidant proteins, such as heme oxygenase 1, peroxiredoxin, thioredoxin, glutathione peroxidase, and catalase in macrophages. Thus, a central role of TauCl produced by activated neutrophils is to trigger the resolution of inflammation and protect macrophages and surrounding tissues from being damaged by cytotoxic reactive oxygen metabolites overproduced during inflammation. This is achieved by attenuating further production of proinflammatory cytokines and reactive oxygen metabolites and also by increasing the levels of antioxidant proteins that are able to scavenge and diminish the production of cytotoxic oxygen metabolites. These findings suggest that TauCl released from activated neutrophils may be involved in the recovery processes of cells affected by inflammatory oxidative stresses and thus TauCl could be used as a potential physiological agent to control pathogenic symptoms of chronic inflammatory diseases. PMID- 23933995 TI - Light and sucrose up-regulate the expression level of Arabidopsis cystathionine gamma-synthase, the key enzyme of methionine biosynthesis pathway. AB - The sulfur-containing essential amino acid methionine controls the level of important metabolites and processes in plants. In addition, methionine levels limit the nutritional quality of many crop plants. The level of methionine is regulated mainly by cystathionine gamma-synthase (CGS), the first enzyme committed to its biosynthesis. Within our efforts to reveal factors that regulate CGS and methionine content in plants, we have analyzed how light regulates the transcript and protein level of Arabidopsis CGS (AtCGS). The expression of AtCGS is up-regulated in the light and reduced in the dark, independent of the diurnal cycle. Using tobacco plants overexpressing AtCGS, we have found that the light sensitive motives of the AtCGS gene are found within the coding sequence of AtCGS and not in its promoter, terminator or the untranslated regions of the gene. Sucrose can partially mimic the effect of light in dark grown plants while the addition of nitrogen and sulfur sources does not have any effect. The kinetics of the changes in the expression level of AtCGS suggest that its level can be maintained during extended darkness, or even when the sucrose content is reduced, such as during abiotic stresses. The up-regulation of AtCGS by light is in agreement with previous studies showing that other enzymes regulating the level of the carbon/amino skeleton and the sulfur group of Met, are up-regulated by light. The results indicate that light and dark participate in the regulation of the carbon/amino skeleton flux in the synthesis of amino acids of the aspartate family. PMID- 23933992 TI - Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics. AB - The anti-CD20 antibody rituximab (RTX; Rituxan(r), MabThera(r)) was the first anti-cancer antibody approved by the US Food and Drug Administration in 1997 and it is now the most-studied unconjugated therapeutic antibody. The knowledge gained over the past 15 y on the pharmacodynamics (PD) of this antibody has led to the development of a new generation of anti-CD20 antibodies with enhanced efficacy in vitro. Studies on the pharmacokinetics (PK) properties and the effect of factors such as tumor load and localization, antibody concentration in the circulation and gender on both PK and clinical response has allowed the design of optimized schedules and novel routes of RTX administration. Although clinical results using newer anti-CD20 antibodies, such as ofatumumab and obinutuzumab, and novel administration schedules for RTX are still being evaluated, the knowledge gained so far on RTX PK and PD should also be relevant for other unconjugated monoclonal antibody therapeutics, and will be critically reviewed here. PMID- 23933996 TI - Doctors, patients and the racial mortality gap. AB - Research in the health sciences reports persistent racial differences in health care access, utilization, and outcomes. This study investigates three potential sources of these disparities - differential quality of care, physician discrimination, and patient response to therapy. It uses a unique panel dataset of physician-patient encounters, the resulting medication therapies and the patients' adherence to those medical recommendations. Equalizing access to quality health care will not erase the racial differences in mortality among chronically ill patients. Targeted programs aimed at improving adherence with medication therapy among disadvantaged groups must be an integral part of any policy aimed at achieving equality in health outcomes. PMID- 23933997 TI - An investigation of the "jumping to conclusions" data-gathering bias and paranoid thoughts in Asperger syndrome. AB - The existence of a data-gathering bias, in the form of jumping to conclusions, and links to paranoid ideation was investigated in Asperger syndrome (AS). People with AS (N = 30) were compared to a neurotypical control group (N = 30) on the Reading the Mind in the Eyes and the Beads tasks, with self-report measures of depression, general anxiety, social anxiety, self-consciousness and paranoid ideation. The AS group performed less well than the control group on the Reading the Mind in the Eyes Task with regard to accuracy but responded more quickly and tended to make decisions on the basis of less evidence on the Beads Task with 50 % demonstrating a clear 'jumping to conclusions bias', whereas none of the control group showed such a bias. Depression and general anxiety were associated with paranoid ideation but not data-gathering style, which was contrary to expectation. PMID- 23933999 TI - Self assembly of three-dimensional Lu2O3:Eu3+ inverse opal photonic crystals, their modified emissions and dual-functional refractive index sensing. AB - In this study, Lu2O3:Eu(3+) inverse-opal-photonic crystals (IOPCs) with controllable lattice constants were fabricated using a polymethylmethacrylate (PMMA) template. The modification effect of PC on the (5)D0-(7)F(J) and (5)D1 (7)F(J) (J = 1-6) transitions were systemically studied by emission spectra, luminescent dynamics and the temperature-dependence. It is significant to observe that the increase of (5)D0-(7)F(J) radiative lifetime for Eu(3+) ions (30%) in contrast to the reference sample was mainly due to modulation of the effective refractive index, rather than the density of optical states. The spontaneous decay rate in (5)D1 increased linearly with the decreasing lattice constants, which was due to the change in (5)D1-(5)D0 nonradiative relaxation of the IOPC samples. The temperature quenching of Eu(3+) ions in the IOPCs could be suppressed considerably more than the reference. On this basis, dual functional refractive index detection with infiltrated solutions was realized by monitoring the variation in the photonic stop band (PSB) and the lifetime of (5)D0-(7)F2 transition of the Lu2O3:Eu(3+) IOPCs. This work shows that the Lu2O3:Eu(3+) IOPCs present highly modified photoluminescence properties and are promising candidates for dual-functional refractive index sensing application. PMID- 23933998 TI - Coping, daily hassles and behavior and emotional problems in adolescents with high-functioning autism/Asperger's Disorder. AB - Although daily hassles and coping are associated with behavior and emotional problems in non-clinical populations, few studies have investigated these relationships in individuals with high-functioning autism/Asperger's Disorder (HFASD). This study examined the relationships between daily hassles, coping and behavior and emotional problems in adolescents with HFASD. Thirty-one adolescents with HFASD completed questionnaires assessing their coping and behavior and emotional problems, and completed an Ecological Momentary Assessment run via a mobile phone application on their coping and daily hassles. Parents completed questionnaires of the adolescents' daily hassles, coping, and behavior and emotional problems. The disengagement coping style was associated with significantly higher levels of behavior and emotional problems regardless of respondent or methodology, suggesting it may be a valuable target for intervention. PMID- 23934000 TI - Research funding and authorship: does grant winning count towards authorship credit? AB - It is unclear whether or not grant winning should count towards authorship credit in the sciences. In this paper, I argue that under certain circumstances grant winning can count for credit as an author on subsequent works. It is a mistake to think that grant winning is always irrelevant to the correct attribution of authorship. PMID- 23934001 TI - Nativity disparities in late-stage diagnosis and cause-specific survival among Hispanic women with invasive cervical cancer: an analysis of Surveillance, Epidemiology, and End Results data. AB - PURPOSE: While cervical cancer screening and risk behaviors have been found to vary among US- and foreign-born Hispanic women, many cancer epidemiology studies have conceptualized Hispanics as a homogenous group. Here, we examine differences in cervical cancer stage at diagnosis and survival among Hispanic women by nativity. METHODS: We use data from the Surveillance, Epidemiology, and End Results program, 1998-2008. Nativity was based on place of birth and was categorized as US versus foreign born. Distant and regional tumors were classified as late stage, while local tumors were classified as early stage. RESULTS: Forty-seven percent of cases of invasive cervical cancer among Hispanics were diagnosed at a late stage, and over half of invasive cervical cancer cases were among foreign-born women. Foreign-born Hispanic women were significantly more likely than US-born Hispanics to have late-stage diagnosis, after adjusting for age at diagnosis and tumor histology (adjusted odds ration = 1.09, p value = 0.003). There was heterogeneity in the association between nativity and survival by stage at diagnosis. Among cases with early-stage diagnosis, survival was poorer among foreign-born versus US-born Hispanics after adjusting for age at diagnosis, histology, and cancer-directed therapy [adjusted hazard ratios (HR) = 1.31, p value = 0.030]. However, among cases with late-stage diagnosis, survival was better among foreign-born Hispanics (adjusted HR = 0.81, p value < 0.001). CONCLUSIONS: We hypothesize that nativity differences in survival may be indicative of diverse risk, screening, and treatment profiles. Given such differences, it may be inappropriate to aggregate Hispanics as a single group for cervical cancer research. PMID- 23934002 TI - The Change Questionnaire predicts change in hazardous tobacco and alcohol use. AB - INTRODUCTION: Assessing motivation for change is deemed an important step in the treatment process that allows further refinement of the intervention in motivational interviewing (MI) and brief MI (BMI) adaptations. During MI (and BMI) sessions, motivation for change is expressed by the client as "change talk", i.e. all statements inclined toward or away from change. We tested the predictive validity of the Change Questionnaire, a 12-item instrument assessing motivation to change, on hazardous tobacco and alcohol use. METHODS: As part of the baseline measurements for a randomized controlled trial on multi-substance BMI at the Lausanne recruitment center (army conscription is mandatory in Switzerland for males at age 20, and thus provides a unique opportunity to address a non-clinical and largely representative sample of young men), 213 participants completed the questionnaire on tobacco and 95 on alcohol and were followed-up six months later. The overall Change Questionnaire score and its six subscales (Desire, Ability, Reasons, Need, Commitment, and Taking steps) were used as predictors of hazardous tobacco use (defined as daily smoking) and hazardous alcohol use (defined as more than one occasion with six standard drinks or more per month, and/or more than 21 standard drinks per week) in bivariate logistic regression models at follow-up. RESULTS: Higher overall Change scores were significant predictors of decreased risk for hazardous tobacco (odds ratio [OR] = 0.83, p = 0.046) and alcohol (OR = 0.76, p = 0.03) use. Several sub-dimensions were associated with the outcomes in bivariate analyses. Using a principal components analysis to reduce the number of predictors for multivariate models, we obtained two components. 'Ability to change' was strongly related to change in hazardous tobacco use (OR = 0.54, p < 0.001), the second we interpreted as 'Other change language dimensions' and which was significantly related to change in hazardous alcohol use (OR = 0.81, p = 0.05). CONCLUSIONS: The present findings lend initial support for the predictive validity of the Change Questionnaire on hazardous tobacco and alcohol use, making it an interesting and potentially useful tool for assessing motivation to change among young males. PMID- 23934003 TI - Primary care patient characteristics associated with completion of 6-month buprenorphine treatment. AB - BACKGROUND: Opioid addiction is prevalent in the United States. Detoxification followed by behavioral counseling (abstinence-only approach) leads to relapse to opioids in most patients. An alternative approach is substitution therapy with the partial opioid receptor agonist buprenorphine, which is used for opioid maintenance in the primary care setting. This study investigated the patient characteristics associated with completion of 6-month buprenorphine/naloxone treatment in an ambulatory primary care office. METHODS: A retrospective chart review of 356 patients who received buprenorphine for treatment of opioid addiction was conducted. Patient characteristics were compared among completers and non-completers of 6-month buprenorphine treatment. RESULTS: Of the 356 patients, 127 (35.7%) completed 6-month buprenorphine treatment. Completion of treatment was associated with counseling attendance and having had a past injury. CONCLUSIONS: Future research needs to investigate the factors associated with counseling that influenced this improved outcome. Patients with a past injury might suffer from chronic pain, suggesting that buprenorphine might produce analgesia in addition to improving addiction outcome in these patients, rendering them more likely to complete 6-month buprenorphine treatment. Further research is required to test this hypothesis. Combination of behavioral and medical treatment needs to be investigated for primary care patients with opioid addiction and chronic pain. PMID- 23934004 TI - Hookah, cigarette, and marijuana use: a prospective study of smoking behaviors among first-year college women. AB - Better understanding of the temporal sequence of hookah, cigarette, and marijuana use will help to inform smoking prevention efforts. To address this gap in the literature, we assessed all three of these smoking behaviors in a sample of 424 first-year college women. Using a longitudinal design, we investigated whether hookah use predicts initiating/resuming cigarette and/or initiating marijuana use, and whether cigarette and/or marijuana use predicts initiating hookah use. Participants (67% White, M age = 18.1 years) completed nine monthly surveys. The initial (i.e., baseline) survey assessed demographics, sensation-seeking, impulsivity, and pre-college substance use. Follow-up surveys assessed past-month substance use; outcomes were initiating/resuming cigarette use, initiating marijuana use, and initiating hookah use during the first year of college. We controlled for sensation-seeking, impulsivity, binge drinking, and other smoking behaviors in our multivariate logistic regression models. The results showed that (a) pre-college hookah use predicted initiating/resuming cigarette use; (b) pre college marijuana use predicted initiation of hookah tobacco smoking; and (c) pre college cigarette use predicted neither hookah nor marijuana initiation. The findings highlight the co-occurrence of smoking behaviors as well as the need for bundling preventive interventions so that they address hookah, cigarette, and marijuana use. PMID- 23934005 TI - Associations between coping, affect, and social support among low-income African American smokers. AB - OBJECTIVE: Previous research has documented disparities in smoking cessation between African Americans and Caucasians. Many low-income African American smokers face a range of circumstances that may inhibit effective coping during quit attempts, yet previous research has not considered factors that influence coping in this population. This study examined (a) affect (positive and negative) and (b) perceived social support in association with coping strategies. METHODS: The baseline assessment of African American smokers (N = 168) enrolled in a randomized controlled trial included the Positive and Negative Affect Schedule, the Multidimensional Scale of Perceived Social Support, and the Brief COPE. A factor analysis of the Brief COPE resulted in two factors, adaptive and maladaptive strategies. RESULTS: Participants were mostly single (64%), women (61%), with >=12 years of education (68%), and low-income. They were middle aged (M = 46.1, SD = 8.7), smoked 21.8 (SD = 13.3) cigarettes/day for 24.3 (SD = 11) years, and were moderately nicotine dependent. Results demonstrated that adaptive coping was positively correlated with positive affect and social support. Maladaptive coping was positively correlated with negative affect, and inversely related to positive affect and social support. Multivariate analyses revealed that positive affect and social support were independently associated with adaptive coping strategies. In contrast, maladaptive coping was independently associated with negative affect, but not social support. CONCLUSIONS: Interventions that harness positive resources, such as social support and positive mood, may facilitate adaptive coping. Also, addressing negative affect among low-income African American smokers may be important to reduce maladaptive coping strategies. PMID- 23934006 TI - A comprehensive examination of hookah smoking in college students: use patterns and contexts, social norms and attitudes, harm perception, psychological correlates and co-occurring substance use. AB - The practice of waterpipe smoking (hookah) has rapidly increased in popularity among young adults yet burgeoning research suggests that its use is associated with nicotine dependence and other negative smoking-related health consequences. Moreover, descriptive studies indicate that consumers may hold the belief that hookah smoking is safer than smoking cigarettes. The current study extended previous work by conducting a comprehensive assessment of patterns and contexts of hookah use, psychological correlates of use, co-occurring substance use as well as social norms and health perceptions surrounding the practice. Participants were 143 ethnically diverse undergraduate students at a large urban US university. Approximately half of the sample (48%) reported life-time use of hookah and 22% reported use within the past 30days. Relative to cigarette smoking, hookah smoking was associated with less perceived harm and addiction potential and higher social approval. Participants who reported life-time hookah use, as compared to those who did not, perceived less associated harm, had a greater number of friends who had tried and approved of hookah, were more likely to use cigarettes, marijuana, and alcohol and in higher frequencies and quantities and were at higher risk for problem tobacco and alcohol use. Among participants who were not current smokers, those with hookah experience were more likely to endorse intent to try a cigarette soon. Hookah users did not differ from non-users on measures of trait anxiety, depression and impulsivity though they were more likely to drink alcohol for coping, social and enhancement purposes than non-users. Implications are discussed for public health initiatives to educate young adults about the potential consequences of hookah smoking. PMID- 23934007 TI - Exposure to estrogenic chemicals induces ectopic expression of vtg in the testis of rainbowfish, Melanotaenia fluviatilis. AB - Vitellogenin (Vtg) is the major egg-yolk precursor protein in oviparous organisms normally synthesised only in mature females. In males and juveniles, the vtg gene, although present, is silent, but its hepatic expression may be activated by xenoestrogens. Surprisingly, its induction and potential consequences in non hepatic tissues remain unexplored. Here we test the hepatic and testicular response of vtg expression in adult male rainbowfish Melanotaenia fluviatilis exposed to either 1, 3, 5 MUg/L 17beta-estradiol or 100, 500 MUg/L 4-n nonylphenol for 24-96 h. Significant increase in the expression level of vtg mRNA in the liver and testes of exposed males was observed. The early (24 h), sensitive and reliable detection of the vtg induction using qPCR demonstrates the assay's robustness to monitor xenobiotic exposure particularly in smaller fish like rainbowfish, an emerging indicator species. Whilst, the ectopic induction of vtg mRNA in testes suggests a more complex Vtg pathway. PMID- 23934008 TI - Thigh muscle volume in relation to age, sex and femur volume. AB - Secular changes and intra-individual differences in body shape and size can confound cross-sectional studies of muscle ageing. Normalising muscle mass to height squared is often suggested as a solution for this. We hypothesised that normalisation of muscle volume to femur volume may be a better way of determining the extent of muscle lost with ageing (sarcopenia). Thigh and femur muscle volumes were measured from serial magnetic resonance imaging sections in 20 recreationally active young men (mean age 22.4 years), 25 older men (72.3 years), 18 young women (22.1 years) and 28 older women (72.0 years). There were no age related differences in femur volume. The relationship between thigh muscle volume and femur volume (R (2) = 0.76; exponent of 1.12; P < 0.01) was stronger than that with height (R (2) = 0.49; exponent of 3.86; P < 0.01) in young participants. For young subjects, the mean muscle/bone ratios were 16.0 and 14.6 for men and women, respectively. For older men and women, the mean ratios were 11.6 and 11.5, respectively. The Z score for the thigh muscle/bone volume ratio relative to young subjects was -2.2 +/- 0.7 for older men and -1.4 +/- 0.8 for older women. The extent of sarcopenia judged by the muscle/bone ratio was approximately twice that determined when normalising to height squared. These data suggest that the muscle/bone ratio captures the intra-individual loss of muscle mass during ageing, and that the age-related loss of muscle mass may be underestimated when normalised to height squared. The quadriceps seems relatively more affected by ageing than other thigh muscles. PMID- 23934009 TI - HLA-DPB1*04:01 allele is associated with non-obstructive azoospermia in Japanese patients. AB - Azoospermia is defined by absence of sperm in the semen and can either be caused by obstruction of the seminal tract (obstructive azoospermia) or by defects in spermatogenesis (non-obstructive azoospermia, NOA). Previous studies reported that specific alleles and single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region were associated with NOA in East Asians. We attempt to expand upon previous findings by genotyping more HLA genes and to replicate SNP associations by focusing on Japanese NOA patients. HLA typing of six genes (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) was done on 355 NOA patients using SSO-Luminex assay while genotyping of two previously reported SNPs (rs498422 and rs3129878) was done on 443 patients and 544 fertile males using TaqMan assay. Association between the HLA alleles and SNP with NOA was assessed with Chi squared and logistic regression tests. We found that HLA-DPB1*04:01 [corrected p value, P(c) 7.13 * 10(-6); odds ratio (OR) 2.52], DRB1*13:02 (P(c) 4.93 * 10(-4), OR 1.97), DQB1*06:04 (P(c) 8.94 * 10(-4), OR 1.91) and rs3129878 (p value 3.98 * 10(-4); OR 1.32) showed significant association with NOA, however, these loci are in linkage disequilibrium with each other. The conditional logistic regression tests showed that DPB1*04:01 is independently associated with NOA, confirming the involvement of the HLA region in the etiology of NOA in Japanese patients. PMID- 23934010 TI - Laterally spreading tumors of the colorectum: clinicopathologic features and malignant potential by macroscopic morphology. AB - BACKGROUND/AIMS: Laterally spreading tumors (LSTs) are being increasingly reported nowadays. The aims of this study were to analyze the clinicopathologic characteristics and to identify the risk factors of malignancy in patients with LSTs by morphological subclassification. PATIENTS AND METHODS: The authors retrospectively reviewed 326 LSTs (287 patients). Patient characteristics, endoscopic findings, and histologic findings were analyzed. Endoscopic findings were subdivided into homogeneous, mixed nodular, flat elevated, and pseudo depressed subtypes. The clinicopathological features of these subtypes were compared. RESULTS: Of the 287 patients treated, 173 (50.3 %) were male and overall mean patient age was 65 +/- 10 years (ranged 35 to 83 year). Of the 326 LSTs diagnosed, 116 (35.6 %) were homogeneous and 102 (31.3 %) were flat elevated subtype. The location was significantly different among morphological subtype. Tumors of the mixed nodular subtype were significantly larger than the tumors of the other three subtypes (p = 0.00). Of the 326 lesions, 279 underwent endoscopic mucosal resection (granular type 88.1 % (177/201)/nongranular type 81.6 % (102/125)). Two hundred forty-nine lesions (76.4 %) were resected en bloc, and 45 lesions (13.8 %) were resected using the piecemeal technique. Piecemeal resection was significantly more common for the pseudo-depressed subtype (27.0 %, p = 0.00). The overall malignancy rate on a lesion basis was 8.6 %. The malignancy rate increased with lesion size and was higher for the pseudo-depressed (24.3 %) and the mixed nodular subtype (14.1 %). Submucosal invasion was noted for 16 % of pseudo-depressed lesions, and this was significantly higher than the invasion rates of the other subtypes (p = 0.06). By multivariate analysis, morphologic subtype, especially the pseudo-depressed or mixed nodular subtype and size larger than 20 mm were risk factor of malignancy. CONCLUSIONS: The clinicopathological features of laterally spreading tumors differ with respect to macroscopic morphology, and the risk of malignant transformation is significantly higher for the mixed nodular or pseudo-depressed subtypes and lesion larger than 20 mm. Careful consideration is required when choosing a treatment modality, and lesions of the mixed nodular and pseudo-depressed subtypes should be completely removed. PMID- 23934011 TI - Differential diagnosis of colorectal polyps with respect to similar capabilities of white light colonoscopy and narrow-band imaging. AB - PURPOSE: The responses of polyps to light essentially determine the diagnostic capability of an endoscopy system in differentiating adenomas from hyperplastic polyps. Compared with white light colonoscopy (WLC), narrow-band imaging (NBI) is expected to improve the diagnostic capability. The diagnostic capabilities of WLC and NBI are evaluated and compared based on the polyp responses. METHODS: The following WLC and NBI images were retrospectively reviewed and categorized: 195 images and polyps (89 WLC, 106 NBI) with the best visual quality were categorized in the best image group (BG), and 484 images of 242 polyps (both WLC and NBI) were categorized in the paired image group (PG). For each reflection of light used for WLC or NBI, the polyp responses were objectively expressed as reflection features. The reflection features were then used to establish a classification model for identifying adenomas. The diagnostic capability of reflection feature or classification model was measured by the area under the receiver operating characteristic curve (AUC). RESULTS: In both image groups, the diverse and heterogeneous features of the polyp responses enabled accurate identification of adenomas, regardless of the light source used for WLC and NBI. For differential diagnosis of adenomas and hyperplastic polyps, the WLC and NBI did not significantly differ in BG (AUC, 0.905 and 0.922, respectively; P = 0.690) or in PG (AUC, 0.782 and 0. 769, respectively; P = 0.755). CONCLUSIONS: Using WLC and NBI as classification models is effective in differential diagnosis of colorectal polyps and exhibited similar capabilities. PMID- 23934012 TI - Genetic and molecular biological characterization of two homologous cheR genes from Leptospira interrogans. AB - The Leptospira interrogans genome encodes two copies of cheR genes and each of them is able to complement for the swarming defective phenotype of Escherichia coli cheR null mutant RP1254 to certain extent, while over-expression of either of them inhibits the swarming of the chemotactic wild-type E. coli strain, RP437. Therefore, both CheR1 and CheR2 ought to bear the methyltransferase activities, although CheR1 has only one instead of two conserved basic amino acid residues located on the positively charged face of alpha2-helix. When this residue as well as the Lys48 and Arg55 of CheR2 was mutated, none of the CheRs was able to maintain aforementioned complementation functions, suggesting their critical roles in recognition of methyl-accepting chemotaxis proteins similar to that of E. coli. Demonstrated by microarray assay, the expression of cheR1 in L. interrogans cultured at 28 degrees C in Ellinghausen-McCullough-Johnson-Harris medium was significantly lower than the average transcription level of all other genes, while the transcription of cheR2 was significantly higher than that of cheR1 in accordance with real-time reverse transcriptase-polymerase chain reaction assay. Tandem MS-MS data mining for the proteome of the same culture detected 16 peptides derived from CheR2 but none from CheR1. Therefore, although both genes were shown to be functional in E. coli, the structurally more conserved CheR2 rather than CheR1 might be the major functional component of L. interrogans chemotaxis adaptation system under our laboratory culture conditions. PMID- 23934013 TI - Polyamines induce adaptive responses in water deficit stressed cucumber roots. AB - The aim of this study was to investigate the effect of exogenous polyamines (PAs) on the membrane status and proline level in roots of water stressed cucumber (Cucumis sativus cv. Dar) seedlings. It was found that water shortage resulted in an increase of membrane injury, lipoxygenase (LOX) activity, lipid peroxidation and proline concentration in cucumber roots during progressive dehydration. PA pretreatment resulted in a distinct reduction of the injury index, and this effect was reflected by a lower stress-evoked LOX activity increase and lipid peroxide levels at the end of the stress period. In contrast, PA-supplied stressed roots displayed a higher proline accumulation. The presented results suggest that exogenous PAs are able to alleviate water deficit-induced membrane permeability and diminish LOX activity. Observed changes were accompanied by an accumulation of proline, suggesting that the accumulation of this osmolyte might be another possible mode of action for PAs to attain higher membrane stability, and in this way mitigate water deficit effects in roots of cucumber seedlings. PMID- 23934014 TI - Thermographic investigation of tumor size, and its correlation to tumor relative temperature, in mice with transplantable solid breast carcinoma. AB - Treating cancer is one of the major challenges of modern medicine. Since mice models are an important tool in cancer treatment research, it is required to assess murine tumor development. Existing methods for investigating tumor development are either high cost and limited by their availability or suffer from low accuracy and reproducibility. In order to overcome these drawbacks, thermography may be used. DA3 breast cancer carcinoma tumors in 12 Balb/c mice were thermally imaged and monitored for a period of several weeks. Eight mice were treated with diffusing alpha emitters radiation therapy (DaRT) wires, while four were treated with inert wires. For large tumors, the area was estimated by analyzing thermal images and was found to be in correlation with manual caliper measurements. In addition, the correlation between tumor area and relative temperatures was calculated and compared to previous works. Temperature differences were larger for tumors treated with DaRT wires than tumors with inert wires. These correlations can be used to assist in tumor size estimation and reveal information regarding its metabolic state. Overall, thermography was shown to be a promising tool for assessing tumor development with the additional advantages of being nonradiative and potentially providing indication of intratumoral biological processes. PMID- 23934015 TI - Localized cell stiffness measurement using axial movement of an optically trapped microparticle. AB - A simple optical tweezers design is proposed to manipulate particles in the axial direction and estimate particle position with nanometer sensitivity. Balb3T3 cell is probed using two different-sized particles, and the localized cell stiffness is evaluated using Hertz model. A series of experiments are performed to obtain the necessary parameters for the cell stiffness computation: particle displacement, trapping stiffness, force exertion, and cell deformation. The computed cell stiffness measurements are 17 and 40 Pa using 4 MUm- and 2 MUm sized particles, respectively. Results suggest that the proposed optical tweezers scheme can measure the stiffness of a particular cell locale using Hertz model, offering insights about how cells respond to outside mechanical stimulus. PMID- 23934016 TI - Plasma osteopontin concentrations in patients with cutaneous melanoma. AB - An effective circulating tumour marker is needed for melanoma especially with the advent of targeted therapies. Gene expression studies examining primary melanomas have shown that increased expression of osteopontin (SPP1) is associated with poor prognosis. Studies subsequently reported higher blood levels in melanoma patients with metastatic disease than those without. This study was designed to determine whether osteopontin plasma concentrations in disease-free patients after initial treatment predict survival. An enzyme-linked immunosorbent assay (ELISA) was used to measure osteopontin levels in stored plasma samples (N=215) from participants in the Leeds Melanoma Cohort. AJCC stage at sampling was statistically significant associated with osteopontin levels (p=0.03). Participants with untreated stage IV disease at sampling (n=10) had higher median osteopontin levels compared to those with treated stage I-III disease (n=158) (p<0.001) confirming previous findings. There was a trend for increased risk of death with increasing osteopontin levels but this was not statistically significant. If a level of 103.14 ng/ml (95th centile of healthy controls) was taken as the upper end of the normal range then 2.5% of patients with treated stage I-III (4/110), 17.6% of patients with untreated stage III (3/17) and 30% of patients with untreated stage IV disease (3/10) had higher levels. These findings suggest that plasma osteopontin levels warrant investigation as a tumour marker in a larger study in which the significance of change in levels over time should be studied in relation to detectable disease recurrence. PMID- 23934017 TI - Motor skill learning is associated with diffusion characteristics of white matter in individuals with chronic stroke. AB - BACKGROUND AND PURPOSE: Imaging advances allow investigation of white matter after stroke; a growing body of literature has shown links between diffusion based measures of white matter microstructure and motor function. However, the relationship between these measures and motor skill learning has not been considered in individuals with stroke. The aim of this study was to investigate the relationships between posttraining white matter microstructural status, as indexed by diffusion tensor imaging within the ipsilesional posterior limb of the internal capsule (PLIC), and learning of a novel motor task in individuals with chronic stroke. METHODS: A total of 13 participants with chronic stroke and 9 healthy controls practiced a visuomotor pursuit task across 5 sessions. Change in motor behavior associated with learning was indexed by comparing baseline performance with a delayed retention test. Fractional anisotropy (FA) indexed at the retention test was the primary diffusion tensor imaging-derived outcome measure. RESULTS: In individuals with chronic stroke, we discovered an association between posttraining ipsilesional PLIC FA and the magnitude of change associated with motor learning; hierarchical multiple linear regression analyses revealed that the combination of age, time poststroke, and ipsilesional PLIC FA posttraining was associated with motor learning-related change (R = 0.649; P = 0.02). Baseline motor performance was not related to posttraining ipsilesional PLIC FA. DISCUSSION AND CONCLUSIONS: Diffusion characteristics of posttraining ipsilesional PLIC were linked to the magnitude of change in skilled motor behavior. These results imply that the microstructural properties of regional white matter indexed by diffusion behavior may be an important factor to consider when determining potential response to rehabilitation in persons with stroke. VIDEO ABSTRACT AVAILABLE: (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A59) for more insights from the authors. PMID- 23934018 TI - Elevated risk of adverse obstetric outcomes in pregnant women with depression. AB - In this study, we evaluated the association between prenatal depression symptoms adverse birth outcomes in African-American women. We conducted a retrospective cohort study of 261 pregnant African-American women who were screened with the Edinburgh Postnatal Depression Scale (EPDS) at their initial prenatal visit. Medical records were reviewed to assess pregnancy and neonatal outcomes, specifically preeclampsia, preterm birth, intrauterine growth retardation, and low birth weight. Using multivariable logistic regression models, an EPDS score >=10 was associated with increased risk for preeclampsia, preterm birth, and low birth weight. An EPDS score >=10 was associated with increased risk for intrauterine growth retardation, but after controlling for behavioral risk factors, this association was no longer significant. Patients who screen positive for depression symptoms during pregnancy are at increased risk for multiple adverse birth outcomes. In a positive, patient-rated depression screening at the initial obstetrics visit, depression is associated with increased risk for multiple adverse birth outcomes. Given the retrospective study design and small sample size, these findings should be confirmed in a prospective cohort study. PMID- 23934019 TI - Attempted application of bioengineered/biosynthetic supporting matrices with phosphatidylinositol-trisphosphate-enhancing substances to organ culture of human primordial follicles. AB - PURPOSE: To improve human primordial follicle culture. METHODS: Thin or thick ovarian slices were cultured on alginate scaffolds or in PEG-fibrinogen hydrogels with or without bpV (pic), which prevents the conversion of phosphatidylinositol trisphosphate (PIP3) to phosphatidylinositol-bisphosphate (PIP2) or 740Y-P which converts PIP2 to PIP3. Follicular growth was evaluated by follicular counts, Ki67 immunohistochemistry, and 17beta-estradiol (E2) levels. RESULTS: BpV (pic) had a destructive effect on cultured follicles. Thawed-uncultured samples had more primordial follicles than samples cultured in basic medium and fewer developing follicles than samples cultured in PEG-fibrinogen hydrogels with 740Y-P. There were more atretic follicles in samples cultured on alginate scaffolds than in PEG fibrinogen hydrogels, and in samples cultured in PEG-fibrinogen hydrogels with 740Y-P than in PEG-fibrinogen hydrogels with basic medium. Ki67 staining was higher in PEG-fibrinogen hydrogels than on alginate scaffolds. E2 levels were higher in thick than in thin slices. CONCLUSIONS: PEG-fibrinogen hydrogels appear to have an advantage over alginate scaffolds for culturing human primordial follicles. Folliculogenesis is not increased in the presence of substances that enhance PIP3 production or with thin rather than thick sectioning. PMID- 23934020 TI - The combination of pronuclear and blastocyst morphology: a strong prognostic tool for implantation potential. AB - PURPOSE: To (i) investigate a possible association between different features of pronuclear (PN) morphology and different features of blastocyst morphology, (ii) evaluate the combination of PN and blastocyst morphologies as a predictive factor for ICSI outcomes and (iii) identify possible contributing factors to poor PN morphology. METHODS: This study included 908 normally fertilised zygotes reaching full blastocyst stage, obtained from 350 patients undergoing ICSI cycles, in which the implantations rates were 0 % or 100 %. The influence of PN morphology on blastocyst morphology and on the rates of pregnancy and miscarriage was investigated. Embryos were graded and split into three groups, taking into consideration both the PN and the blastocyst status. The pregnancy rate was compared among these groups. RESULTS: Inner cell mass (ICM) alterations were correlated with the number of nucleolar precursor bodies (NPB), while trophectoderm alterations were correlated with the size of the pronuclei and the distribution of the NPB. The distribution of the NPB had an impact on the chances of pregnancy. A significant difference was observed among the groups regarding the pregnancy rate. The maternal age, number of aspirated follicles and number of retrieved oocytes influenced the incidence of PN defects. CONCLUSIONS: These findings suggest that a lower oocyte yield may lead to higher-quality PN zygotes. In addition, different PN features may influence further embryo development, especially the quality of the blastocyst. Moreover, the association between PN and blastocyst morphology may be used as a prognostic tool for implantation. PMID- 23934021 TI - Association of progesterone receptor gene polymorphism with male infertility and clinical outcome of ICSI. AB - PURPOSE: To investigate the association of Progesterone Receptor (PR) gene variations and male infertility METHODS: DNA extraction, PCR and sequencing of PR gene, PROGINS insertion by PCR. Association of the variations with seminal parameters and outcomes of ICSI. RESULTS: Four known SNPs in the PR gene were identified in the study of which three (rs3740753, rs1042838, rs104283) were co inherited and in complete linkage disequilibrium with the PROGINS Alu insertion. There were no differences in their frequencies between fertile and infertile males. The rs2020880 was found at a very low frequency only in the controls but not in the infertile subjects. The sperm counts, fertilization rate, embryo quality or pregnancy rates were not different in individuals with or without PROGINS allele. CONCLUSION: PR gene alterations are not associated with male infertility or ICSI outcome. PMID- 23934022 TI - AE37 peptide vaccination in prostate cancer: a 4-year immunological assessment updates on a phase I trial. AB - In our recent phase I trial, we demonstrated that the AE37 vaccine is safe and induces HER-2/neu-specific immunity in a heterogeneous population of HER-2/neu (+) prostate cancer patients. Herein, we tested whether one AE37 boost can induce long-lasting immunological memory in these patients. Twenty-three patients from the phase I study received one AE37 boost 6-month post-primary vaccinations. Local/systemic toxicities were evaluated following the booster injection. Immunological responses were monitored 1-month (long-term booster; LTB) and 3 year (long-term immunity; LTI) post-booster by delayed-type hypersensitivity, IFN gamma ELISPOT and proliferation assays. Regulatory T cell (Treg) frequencies, plasma transforming growth factor-beta (TGF-beta) and indoleamine 2,3-deoxygenase (IDO) activity levels were also determined at the same time points. The AE37 booster was safe and well tolerated. Immunological monitoring revealed vaccine specific long-term immunity in most of the evaluated patients during both LTB and LTI, although individual levels of immunity during LTI were decreased compared with those measured 3 years earlier during LTB. This was paralleled with increased Tregs, TGF-beta levels and IDO activity. One AE37 booster generated long-term immunological memory in HER-2/neu (+) prostate cancer patients, which was detectable 3 years later, albeit with a tendency to decline. Boosted patients had favorable clinical outcome in terms of overall and/or metastasis-free survival compared with historical groups with similar clinical characteristics at diagnosis. We suggest that more boosters and/or concomitant disarming of suppressor circuits may be necessary to sustain immunological memory, and therefore, further studies to optimize the AE37 booster schedule are warranted. PMID- 23934023 TI - Abnormal myelination in the spinal cord of PTPalpha-knockout mice. AB - PTPalpha interacts with F3/contactin to form a membrane-spanning co-receptor complex to transduce extracellular signals to Fyn tyrosine kinase. As both F3 and Fyn regulate myelination, we investigated a role for PTPalpha in this process. Here, we report that both oligodendrocytes and neurons express PTPalpha that evenly distributes along myelinated axons of the spinal cord. The ablation of PTPalpha in vivo leads to early formation of transverse bands that are mainly constituted by F3 and Caspr along the axoglial interface. Notably, PTPalpha deficiency facilitates abnormal myelination and pronouncedly increases the number of non-landed oligodendrocyte loops at shortened paranodes in the spinal cord. Small axons, which are normally less myelinated, have thick myelin sheaths in the spinal cord of PTPalpha-null animals. Thus, PTPalpha may be involved in the formation of axoglial junctions and ensheathment in small axons during myelination of the spinal cord. PMID- 23934024 TI - Cell adhesion molecules take you home: cell adhesion in axon guidance and neural circuit assembly. PMID- 23934025 TI - Risk assessment of vegetables irrigated with arsenic-contaminated water. AB - Arsenic (As) contaminated water is used in South Asian countries to irrigate food crops, but the subsequent uptake of As by vegetables and associated human health risk is poorly understood. We used a pot trial to determine the As uptake of four vegetable species (carrot, radish, spinach and tomato) with As irrigation levels ranging from 50 to 1000 MUg L(-1) and two irrigation techniques, non-flooded (70% field capacity for all studied vegetables), and flooded (110% field capacity initially followed by aerobic till next irrigation) for carrot and spinach only. Only the 1000 MUg As L(-1) treatment showed a significant increase of As concentration in the vegetables over all other treatments (P < 0.05). The distribution of As in vegetable tissues was species dependent; As was mainly found in the roots of tomato and spinach, but accumulated in the leaves and skin of root crops. There was a higher concentration of As in the vegetables grown under flood irrigation relative to non-flood irrigation. The trend of As bioaccumulation was spinach > tomato > radish > carrot. The As concentration in spinach leaves exceeded the Chinese maximum permissible concentration for inorganic As (0.05 MUg g(-1) fresh weight) by a factor of 1.6 to 6.4 times. No other vegetables recorded an As concentration that exceeded this threshold. The USEPA parameters hazard quotient and cancer risk were calculated for adults and adolescents. A hazard quotient value greater than 1 and a cancer risk value above the highest target value of 10(-4) confirms potential risk to humans from ingestion of spinach leaves. In our study, spinach presents a direct risk to human health where flood irrigated with water containing an arsenic concentration greater than 50 MUg As L(-1). PMID- 23934027 TI - Immune regulation by CD52-expressing CD4 T cells. AB - T-cell regulation by CD52-expressing CD4 T cells appears to operate by two different and possibly synergistic mechanisms. The first is by its release from the cell surface of CD4 T cells that express high levels of CD52 that then binds to the inhibitory sialic acid-binding immunoglobulin-like lectins-10 (Siglec-10) receptor to attenuate effector T-cell activation by impairing phosphorylation of T-cell receptor associated lck and zap-70. The second mechanism appears to be by crosslinkage of the CD52 molecules by an as yet unidentified endogenous ligand that is mimicked by a bivalent anti-CD52 antibody that results in their expansion. PMID- 23934026 TI - Non-celiac gluten sensitivity: questions still to be answered despite increasing awareness. AB - Recently, the increasing number of patients worldwide who are sensitive to dietary gluten without evidence of celiac disease or wheat allergy has contributed to the identification of a new gluten-related syndrome defined as non celiac gluten sensitivity. Our knowledge regarding this syndrome is still lacking, and many aspects of this syndrome remain unknown. Its pathogenesis is heterogeneous, with a recognized pivotal role for innate immunity; many other factors also contribute, including low-grade intestinal inflammation, increased intestinal barrier function and changes in the intestinal microbiota. Gluten and other wheat proteins, such as amylase trypsin inhibitors, are the primary triggers of this syndrome, but it has also been hypothesized that a diet rich in fermentable monosaccharides and polyols may elicit its functional gastrointestinal symptoms. The epidemiology of this condition is far from established; its prevalence in the general population is highly variable, ranging from 0.63% to 6%. From a clinical point of view, non-celiac gluten sensitivity is characterized by a wide array of gastrointestinal and extraintestinal symptoms that occur shortly after the ingestion of gluten and improve or disappear when gluten is withdrawn from the diet. These symptoms recur when gluten is reintroduced. Because diagnostic biomarkers have not yet been identified, a double-blind placebo-controlled gluten challenge is currently the diagnostic method with the highest accuracy. Future research is needed to generate more knowledge regarding non-celiac gluten sensitivity, a condition that has global acceptance but has only a few certainties and many unresolved issues. PMID- 23934028 TI - Translating translational research: mouse models of human disease. PMID- 23934029 TI - Regulatory roles of dermal type 2 innate lymphoid cells. PMID- 23934030 TI - Persistent structural disease is the most common cause of repeat hip preservation surgery. AB - BACKGROUND: Hip preservation surgery has become more commonplace, yet when it fails, it is unclear why it does so. Understanding failed procedures should lead to improved surgical results. QUESTIONS/PURPOSES: The purposes of this study were to (1) characterize patients undergoing hip preservation surgery after prior procedures; (2) compare demographics, hip pain, and function in patients with prior procedures with those undergoing primary surgery; (3) determine the types of previous procedures and the reasons for secondary surgery; and (4) report the procedure profile of the secondary surgeries. METHODS: A prospective, multicenter hip preservation database of 2263 patients (2386 surgery cases) was reviewed to identify 352 patients (359 hips, 15% of the total) who had prior surgery. Patient demographics, type of previous surgery, diagnostic categories, clinical scores, and type of secondary procedure were recorded. RESULTS: For patients undergoing secondary surgery, the average age was 23 years and 70% were female. Hip pain and function were similar between patients undergoing primary and secondary surgery. The previous surgical approaches were open in 52% and hip arthroscopy in 48%. In the femoroacetabular impingement and adult acetabular dysplasia subgroups, hip arthroscopy was the most common previous surgical approach (86% and 64%, respectively). Inadequately corrected structural disease was the most common reason for secondary surgery. Femoral osteochondroplasty and acetabular reorientation were the most common secondary procedures. CONCLUSIONS: Inadequately corrected structural disease (femoroacetabular impingement or acetabular dysplasia) was commonly associated with the need for secondary hip preservation surgery. Although we do not have data to identify other technical failures, the available data suggest primary treatments should encompass comprehensive deformity correction when indicated. PMID- 23934031 TI - The judgment defense in medical malpractice. PMID- 23934032 TI - The importance of outcome measurement in orthopaedics. PMID- 23934033 TI - In Memoriam: George Cierny, III MD (1947-2013). PMID- 23934034 TI - ACGME and ABOS changes for the orthopaedic surgery PGY-1 (intern) year. PMID- 23934035 TI - CORR Insights(r): distribution of locally delivered antimicrobials is limited by cortical bone: a pilot study. PMID- 23934036 TI - Onsager's Wien effect on a lattice. AB - The second Wien effect describes the nonlinear, non-equilibrium response of a weak electrolyte in moderate to high electric fields. Onsager's 1934 electrodiffusion theory, along with various extensions, has been invoked for systems and phenomena as diverse as solar cells, surfactant solutions, water splitting reactions, dielectric liquids, electrohydrodynamic flow, water and ice physics, electrical double layers, non-ohmic conduction in semiconductors and oxide glasses, biochemical nerve response and magnetic monopoles in spin ice. In view of this technological importance and the experimental ubiquity of such phenomena, it is surprising that Onsager's Wien effect has never been studied by numerical simulation. Here we present simulations of a lattice Coulomb gas, treating the widely applicable case of a double equilibrium for free charge generation. We obtain detailed characterization of the Wien effect and confirm the accuracy of the analytical theories as regards the field evolution of the free charge density and correlations. We also demonstrate that simulations can uncover further corrections, such as how the field-dependent conductivity may be influenced by details of microscopic dynamics. We conclude that lattice simulation offers a powerful means by which to model and investigate system specific corrections to the Onsager theory, and thus constitutes a valuable tool for detailed theoretical studies of the numerous practical applications of the second Wien effect. PMID- 23934037 TI - Quantitative assessment of myocardial strain with displacement encoding with stimulated echoes MRI in patients with coronary artery disease. AB - To determine the diagnostic performance and reproducibility of strain assessment with displacement encoding with stimulated echoes (DENSE) cardiovascular magnetic resonance (CMR) in identifying contractile abnormalities in myocardial segments with late gadolinium enhancement (LGE). DENSE CMR was obtained on short-axis planes of the left ventricle (LV) in 24 patients with suspected coronary artery disease. e1 and e2 strains of LV wall were quantified. Cine MRI was acquired to determine percent systolic wall thickening (%SWT), followed by (LGE) CMR. The diagnostic performance of e1, e2 and %SWT for predicting the presence of LGE was evaluated by receiver operating characteristics (ROC) analysis. Myocardial scar on LGE CMR was observed in 91 (24 %) of 384 segments. The area under ROC curve for predicting the segments with LGE was 0.874 by e1, 0.916 by e2 and 0.828 by %SWT (p = 0.001 between e2 and %SWT). Excellent inter-observer reproducibility was found for strain [Intraclass correlation coefficient (ICC) = 0.962 for e1, 0.955 for e2] as compared with %SWT (ICC = 0.790). DENSE CMR can be performed as a part of routine CMR study and allows for quantification of myocardial strain with high inter-observer reproducibility. Myocardial strain, especially e2 is useful in detecting altered abnormal systolic contraction in the segments with myocardial scar. PMID- 23934038 TI - Simultaneous quantitative determination of six active components in traditional Chinese medicinal preparation Cerebralcare Granule(r) by RP-HPLC coupled with diode array detection for quality control. AB - A simple, accurate and reliable method for the simultaneous separation and determination of six active components (protocatechuic acid, chlorogenic acid, caffeic acid, paeoniflorin, ferulic acid and rosmarinic acid) in traditional Chinese medicinal preparation Cerebralcare Granule((r)) (CG) was developed using reverse-phase high-performance liquid chromatography coupled with diode array detector detection. The chromatographic separation was performed on a Hypersil GOLD C18 column with aqueous formic acid (0.1%, v/v) and acetonitrile as mobile phase at a flow rate of 0.2 ml/min at 30 degrees C. Because of the different UV characteristics of these components, change detection wavelength method was used for quantitative analysis. All of the analytes showed good linearity (r > 0.9992). The established method showed good precision and relative standard deviations (%) for intra-day and inter-day variations of 0.15-1.81 and 0.11 1.98%, respectively. The validated method was successfully applied to the simultaneously determination of six active components in CG from different batches. PMID- 23934039 TI - Analysis of major constituents in Fructus aurantii-Magnolia bark decoction by UPLC-PDA. AB - A ultraperformance liquid chromatography (UPLC)-photodiode array (PDA) detection method was established for the simultaneous determination of seven constituents in Fructus aurantii-Magnolia bark decoction: naringin, hesperidin, neohesperidin, narirutin, meranzin hydrate, honokiol and magnolol. These were separated in <17 min using a C18 column with gradient elution using (a) acetonitrile, (b) water and (c) acetic acid at a flow rate of 0.3 mL/min, and with a PDA detector. All calibration curves showed good linear regression (r(2) > 0.9992) within the test ranges. The method was validated for specificity, accuracy, precision and limits of detection. The proposed method was found to be suitable for the quality assessment of the formula. PMID- 23934040 TI - Neuronal circuits in the hypothalamus controlling gonadotrophin-releasing hormone release: the neuroanatomical projections of kisspeptin neurons. AB - The hypothalamus regulates the key hormonal signalling events essential for reproduction and fertility in mammals. The gonadotrophin-releasing hormone (GnRH) neurons are the principal neurons of the complex neuronal network that co ordinates multiple internal homeostatic and external factors necessary for fertility. Kisspeptin neurons are one of the major regulators of GnRH neuronal activity, but the ways in which kisspeptin neurons, located in the arcuate nucleus (ARN) and rostral periventricular area of the third ventricle (RP3V), control GnRH neurons are poorly understood. This study focused on the use of anterograde and retrograde tracing techniques to establish the neuronal projection patterns of kisspeptin cells in the female mouse brain. Both anterograde and retrograde tracing studies highlight the complexity of the kisspeptin neuronal system and indicate that both ARN and RP3V kisspeptin neurons may participate in a variety of limbic functions. In relationship to the GnRH neuronal network, these investigations demonstrate that rostral ARN kisspeptin neurons may also project to GnRH neuronal cell bodies. However, we found no anatomical evidence to suggest that kisspeptin neurons innervate GnRH nerve terminals in the external layer of the median eminence. These studies provide a neuroanatomical framework for the further elucidation of the functions of the ARN and RP3V kisspeptin neuron populations. PMID- 23934041 TI - Changes in the number of CD8+ T lymphocytes in the peripheral blood of patients with various autoimmune diseases after autologous hematopoietic stem cell transplantations and their relations to the survival times. AB - The changes in the number of CD8+ T lymphocytes were studied before (0 day) and then 30 days after the autologous hematopoietic stem cell transplantations (AHSCT) in 14 therapy refractory patients with autoimmune diseases. The years of survival and the clinical states were also evaluated. The number of CD8+ T cells was determined by an hematologic automat and by flow cytometry. Longer than 5 year survival times were found in 6 cases, whereas there was no progression (improvement) in 2 cases, and 4 patients were lost. The increase in the number of CD8+ cytotoxic T cells was gradual in the first 2 months and reached the significantly highest values among all subtypes of lymphocytes. It was of a special interest that in all the 4 patients who died, the numbers of CD8+ T cells were less than 150/MUl on the 30th day after AHSCT, whereas all the 10 patients with a higher cell number survived. These results suggest that the early monitoring of the number (not only the ratio) of regenerating CD8+ T cells in the peripheral blood can be a useful and quantitative laboratory measurement after AHSCT, and it has a significant relation also to the survival times of transplanted patients. PMID- 23934042 TI - [Symptomatic calcification of the lateral collateral knee ligament]. AB - We describe a case of symptomatic calcification of the lateral collateral knee ligament in a 53-year-old female patient. The calcification became extremely painful and increased in size and it was decided to resect the calcification operatively because of pain progression. After operative resection of the deposits the patient is currently free of complaints and relapse-free after 4.5 years. In the literature four cases of calcification of the medial collateral ligament are described which were also successfully treated by operative resection. PMID- 23934043 TI - [RETRACTED ARTICLE: Occupation-related findings in patients with degenerative disc disease of the lumbar spine : Investigation of assessment relevant questions of the occupational disease number 2108 by descriptive representation of the data from the German spinal study]. PMID- 23934044 TI - Effects of CD40 ligation combined with chemotherapy drugs on human breast cancer cell lines. AB - OBJECTIVE: To investigate the influence of recombinant human CD40 ligand (rhCD40L) on the biological behaviour of breast cancer cells. METHODS: MDA-MB-23l and MDA-MB-435 treated with rhCD40L were observed for changes in the cell cycle, in membrane proteins, and in mRNA levels of B cell lymphoma-extra-large (Bcl-xl), Bcl-2 associated X protein (Bax) and regulated upon activation, normal T cell expressed and secreted (RANTES). Effects of rhCD40L on cell proliferation in the presence or absence of interferon (IFN)-gamma (500 IU/ml) and/or doxorubicin (20 ng/ml) were also determined. RESULTS: rhCD40L dose-dependently inhibited cell proliferation. Combination of rhCD40L with IFN-gamma or doxorubicin potentiated the inhibitory activity. After treatment, an increase in cells entering the G1 phase of the cell cycle was observed, with a significant decrease in the number entering the S phase. Levels of several membrane proteins including CD95L and CD120a were also increased. Reverse transcription-polymerase chain reaction revealed an increase in the Bax/Bcl-xl mRNA ratio and an increase in RANTES. CONCLUSION: rhCD40L treatment of breast cancer cells mediates a variety of anti tumour effects, not only by direct cytotoxic activity but also by upregulation of adhesion molecules, co-stimulators and cytokines to rectify T cell immunity. PMID- 23934045 TI - Application of parecoxib in post-uvulopalatopharyngoplasty analgesia. AB - OBJECTIVE: To investigate the postoperative analgesic effects of parecoxib for uvulopalatopharyngoplasty (UPPP). METHODS: Patients with obstructive sleep apnoea syndrome who underwent UPPP were randomly divided into two groups. In group A, the incision-local block was performed with 5 ml of 0.5% ropivacaine injected subcutaneously before the end of surgery, then 20 ml of physiological saline was injected intravenously every 12 h for 2 days. In group B, in addition to the incision-local block, 40 mg parecoxib was injected intravenously 30 min before the end of UPPP and 40 mg parecoxib was injected intravenously every 12 h for 2 days. Postoperative pain was measured using a visual analogue scale (VAS). Adverse reactions were recorded. RESULTS: A total of 40 patients were randomized (n = 20 per group). Under resting conditions, the mean +/- SD VAS pain scores were significantly higher in group A compared with group B at 24 h and 48 h after UPPP (24 h 4.0 +/- 0.8 versus 2.6 +/- 0.6; 48 h 3.8 +/- 0.7 versus 2.4 +/- 0.5; respectively). Under swallowing conditions, the mean +/- SD VAS pain scores were significantly higher in group A compared with group B at 8 h, 24 h and 48 h after UPPP. Postoperative adverse reactions were similar in the two groups. CONCLUSION: Intravenous parecoxib combined with incision-local ropivacaine provided effective postoperative analgesia for patients with obstructive sleep apnoea syndrome, undergoing UPPP. PMID- 23934046 TI - Rocuronium reversed by sugammadex versus mivacurium during high-risk eye surgery: an institutional anaesthetic practice evaluation. AB - OBJECTIVE: This institutional anaesthetic practice evaluation compared patient safety with respect to residual neuromuscular blockade (NMB) at the time of tracheal extubation in patients undergoing high-risk eye surgery. METHODS: Two muscle relaxation regimens were compared: rocuronium administered via intravenous (i.v.) bolus dosing combined with reversal through sugammadex at end of surgery (group R/S; 17 patients); mivacurium administered via continuous i.v. infusion without antagonization (group M; 22 patients). Train-of-four (TOF) monitoring determined the depth of NMB. RESULTS: The TOF ratio at the time of tracheal extubation was greater in group R/S (median 1.03) than in group M (median 0.62). Time from end of surgery to tracheal extubation was not significantly different. The surgeons were 100% satisfied with the working conditions provided under both relaxation regimens. CONCLUSIONS: Residual postoperative curarization at the time of extubation was frequently observed in group M, whereas there was complete recovery in group R/S. Reversal of NMB by sugammadex provides an additional safety dimension to patient care and should thus be considered especially for those at risk of airway complications or aspiration, in addition to frail patients. PMID- 23934047 TI - The effect of blood glucose regulation on the presence of opportunistic Demodex folliculorum mites in patients with type 2 diabetes mellitus. AB - OBJECTIVES: To measure the rate of Demodex folliculorum mite infestation in patients with type 2 diabetes mellitus and to investigate if it was related to blood glucose control. METHODS: Patients with type 2 diabetes were classified according to their glycosylated haemoglobin (HbA(1c)) level into two groups: a well controlled blood glucose group (HbA(1c) <= 7%) and a poorly controlled blood glucose group (HbA(1c) > 7%). A standardized skin surface biopsy method was used to determine if the patients had D. folliculorum infestation (>5 mites/cm2 of skin). RESULTS: A total of 69 patients (38 female) were enrolled in the study. Seventeen (24.6%) patients had D. folliculorum infestation. There were no significant differences in age, sex or body mass index between patients with and without D. folliculorum infestations. A significantly higher proportion of patients with poor blood glucose control had D. folliculorum infestation compared with patients with well controlled blood glucose. CONCLUSIONS: These current findings suggest that poor blood glucose regulation increases the susceptibility to D. folliculorum mite infestation in patients with type 2 diabetes. PMID- 23934048 TI - Differential splicing across immune system lineages. AB - Alternative splicing (AS) allows increased diversity and orthogonal regulation of the transcriptional products of mammalian genomes. To assess the distribution and variation of alternative splicing across cell lineages of the immune system, we comprehensively analyzed RNA sequencing and microarray data generated by the Immunological Genome Project Consortium. AS is pervasive: 60% of genes showed frequent AS isoforms in T or B lymphocytes, with 7,599 previously unreported isoforms. Distinct cell specificity was observed, with differential exon skipping in 5% of genes otherwise coexpressed in both B and T cells. The distribution of isoforms was mostly all or none, suggesting on/off switching as a frequent mode of AS regulation in lymphocytes. From the identification of differential exon use in the microarray data, clustering of exon inclusion/exclusion patterns across all Immunological Genome Project cell types showed that ~70% of AS exons are distributed along a common pattern linked to lineage differentiation and cell cycling. Other AS events distinguished myeloid from lymphoid cells or affected only a small set of exons without clear lineage specificity (e.g., Ptprc). Computational analysis predicted specific associations between AS exons and splicing regulators, which were verified by detection of the hnRPLL/Ptprc connection. PMID- 23934050 TI - [Biosimilars : Current state of the build up to series production]. AB - When patents expire, usually after 10 years in Germany, generic medicines routinely enter the market in place of conventional medications leading to significant reductions in prices. Currently the first biologicals are approaching patent expiry. Because of the biochemical complexities truly identical imitators are unrealistic. On the other hand, there is high socioeconomic pressure towards reduced cost of biologicals. In response to this situation the European Medicines Agency (EMA) has released a highly differentiated guidance document for the approval process of biosimilars. Biosimilars, which are already reality in other areas have to remain within a narrow biochemical variability corridor and are subsequently required to show bioequivalence to the reference product in both efficacy and safety in at least one large clinical phase III trial. In addition, post-marketing surveillance programs are mandatory in order to identify potential low frequency safety issues. In contrast to the "intended copies" used in some third world countries without such rigorous clinical testing the EMA-approved biosimilars are expected to have almost identical efficacy and safety as the reference medications. It is not yet clear how the use of specific biosimilars can be tracked and how uncontrolled exchange can be avoided. Nevertheless, biosimilars in rheumatology are likely to be available in the near future. PMID- 23934049 TI - Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition. AB - Antifolates, folate analogs that inhibit vitamin B9 (folic acid)-using cellular enzymes, have been used over several decades for the treatment of cancer and inflammatory diseases. Cellular uptake of the antifolates in clinical use occurs primarily via widely expressed facilitative membrane transporters. More recently, human folate receptors (FRs), high affinity receptors that transport folate via endocytosis, have been proposed as targets for the specific delivery of new classes of antifolates or folate conjugates to tumors or sites of inflammation. The development of specific, FR-targeted antifolates would be accelerated if additional biophysical data, particularly structural models of the receptors, were available. Here we describe six distinct crystallographic models that provide insight into biological trafficking of FRs and distinct binding modes of folate and antifolates to these receptors. From comparison of the structures, we delineate discrete structural conformations representative of key stages in the endocytic trafficking of FRs and propose models for pH-dependent conformational changes. Additionally, we describe the molecular details of human FR in complex with three clinically prevalent antifolates, pemetrexed (also Alimta), aminopterin, and methotrexate. On the whole, our data form the basis for rapid design and implementation of unique, FR-targeted, folate-based drugs for the treatment of cancer and inflammatory diseases. PMID- 23934051 TI - [Comorbidities in psoriatic arthritis]. AB - Psoriatic arthritis occurs almost exclusively together with psoriasis (of the skin). Thus, psoriasis-associated diseases or comorbidities are also seen in psoriatic arthritis patients. Among the clinically most relevant comorbidities are cardiovascular diseases and their risk factors, namely smoking, obesity and the metabolic syndrome. Moreover, psychological conditions and osteoporosis should also be considered. The link between psoriasis, psoriatic arthritis and its comorbidities has been established based on epidemiological studies; however, at least for the cardiovascular comorbidities, the association can be explained based on novel insights into the pathogenesis of atherosclerosis. For the practising physician it is important to take into account the aspect of comorbidity to come to an optimal treatment decision in each individual case. Clinical decision-making is complicated further by the fact that comorbidity necessitates comedication which again influence the choice of treatment. PMID- 23934052 TI - [Urological comorbidities in patients with rheumatoid arthritis : literature review]. AB - Patients with rheumatoid arthritis (RA) have an increased risk of urolithiasis which is further negatively impacted by a reduced bone density. Interstitial cystitis also tends to occur more often in patients with rheumatic diseases. The high incidence of bacterial urogenital infections is influenced by the use of immunomodulating drugs. Many RA patients have to undergo numerous tests until a diagnosis is reached and are then treated as outpatients on a tightly controlled schedule. Despite a closely controlled rheumatological follow-up, urological screening and determination of a baseline prostate-specific antigen (PSA) value (in men over 45 years old) should not be neglected. In patients with an increased risk of renal and bladder neoplasms or when such a diagnosis is known, the benefit of long-term use of high doses of non-steroidal anti-inflammatory drugs (NSAID, aspirin type) should be carefully weighed up with a risk profile and after specialist urological assessment. Patients who suffer from sexual dysfunction due to physical limitations and prolonged medical therapy should undergo urological and gynecological assessment to exclude contributing causes. The use of aphrodisiacs and erection-enhancing drugs (e.g. PDE5 inhibitors, local injection with prostaglandins and vacuum therapy) require prior approval by a medical specialist and also cardiovascular stability. Acute urinary retention is more common in chronic inflammatory musculoskeletal diseases. PMID- 23934053 TI - [Core set of behavioral recommendations for patients with ankylosing spondylitis]. AB - OBJECTIVES: Patients with ankylosing spondylitis (AS) can contribute to a favorable disease course by their own behaviour and environmental adaptations. However, no standardized consensus recommendations on patient behavior and adaptations exist, neither internationally nor nationally. The aim of this study was to establish a core set of recommendations concerning favorable patient behavior to be given to patients with AS by rheumatologists. METHODS: An extended literature research in the scientific and patient-oriented literature revealed 70 recommendations. These recommendations were evaluated and ranked by importance at a meeting of the Ankylosing Spondylitis International Federation (ASIF, 26 participants from 13 countries) in November 2011. The remaining 59 recommendations were extensively discussed, supplemented, partially reworded, condensed and those with the highest priority were selected by consensus at a seminar of local branch leaders of the AS patient organization in Germany (Deutsche Vereinigung Morbus Bechterew) in March 2012 (80 participants, 95% patients with AS). RESULTS: The core set encompasses 1) a general statement on living with AS and 2) recommendations in the areas of sitting position, walking, sleeping, at work, exercising, sports and recreational activities, diet and life style, sexuality and pregnancy, fall prevention, car driving and membership in an AS-specific patient organization. The selected recommendations received agreement by 80-100% of the patients. Some recommendations (e.g. fall prevention and car driving) are more relevant to patients with advanced and usually longstanding disease, i.e. with advanced ankylosis or osteoporosis. CONCLUSIONS: For the first time a core set of recommendations for the behavior of patients with AS was created in collaboration with many persons affected by the disease. Patients with AS should receive these recommendations from their rheumatologists, ideally early in the disease course. The German version of this core set is presented in this article. PMID- 23934054 TI - Gastroprotective effect of standardized extract of Amukkara choornam on experimental gastric ulcer in rats. AB - Amukkara choornam ethanolic extract (ACE) was investigated for phytochemical screening, content of total phenolics and flavonoids, in vitro radical scavenging activity (RSA), quantification of various antiulcer marker compounds (i.e., eugenol, piperine, trans-caryophyllene, and withaferine A) by a validated HPTLC method, and evaluated for its in vivo gastroprotective ability against ethanol (EtOH)-induced and pylorus ligation (PL)-induced ulcer models in rats. Phytochemical screening revealed the presence of flavonoids, saponins, phenols, bitter principles, and steroids. Total phenolic and flavonoid content was found to be 61.12 +/- 0.72 mg GAE/g of ACE and 24.06 +/- 1.07 mg RE/g of ACE, respectively; this was found to be very high in plant extracts showing very good antioxidant and antiulcerogenic effect. RSA of ACE appeared significantly (p < 0.05) lower than that of ascorbic acid (AA), but higher than that of ranitidine (RAN). In vivo the pretreatment of rats with RAN (100 mg/kg) and 50, 100, and 200 mg/kg doses of ACE significantly reduced the ulcer index in a dose-dependant manner in both the models by blocking lipid peroxidation and by significant increases in superoxide dismutase and catalase activity. But rats treated with AA (200 mg/kg) did not have any effect on the ulcer induced by EtOH or PL as it has very good in vitro and in vivo antioxidant activity. HPTLC analysis showed the presence of 0.198 +/- 0.01 MUg/g, 0.754 +/- 0.06 mg/g, 3.50 +/- 0.04, and 0.854 +/- 0.04 MUg/g of eugenol, piperine, trans-caryophyllene, and withaferine A per gram of Amukkara choornam (AC). So the antiulcerogenic activity of ACE might be due to a possible synergistic antioxidant, supported by the holistic approach of polyherbal formulations, i.e., systematism, multi-target and multi-channel owing to their complex chemical constituents and antihistaminic-like effects. PMID- 23934055 TI - Local injection of a single dose of simvastatin augments osteoporotic bone mass in ovariectomized rats. AB - The aim of this study was to evaluate the effects and explore the mechanism of a local injection of a single dose of simvastatin as a strategy to strengthen target bone. Simvastatin was injected into the femurs (5 or 10 mg) or caudal vertebrae (1 or 2 mg) of ovariectomized rats, with an equal volume of vehicle injected as a control. Bone mineral density (BMD), bone microstructure and strength were evaluated at 1 and 5 months post-injection for the femurs and at 12 days post-injection for the vertebrae. Bone mass, adipocyte numbers and Runx2 expression were also examined using histology and immunohistochemistry. Compared with controls, simvastatin significantly increased BMD, bone volume fraction (BV/TV), improved bone microstructural parameters and bone strength in the femurs at both time points (all P < 0.01). Simvastatin-treated femurs contained fewer adipocytes and a higher Runx2 expression. For the caudal vertebrae, simvastatin significantly improved BV/TV, bone microstructures, and bone strength (all P < 0.01) as compared with controls. In conclusion, local injection of a single dose of simvastatin induces early onset and long-lasting bone augmentation in osteoporotic bone, significantly improving BMD, and bone microstructure and biomechanical strength. Simvastatin induces Runx2 expression, which may function to induce osteogenesis and inhibit adipogenesis as an underlying mechanism to augment bone mass. PMID- 23934056 TI - Effects of angiotensin-converting enzyme inhibitor, captopril, on bone of mice with streptozotocin-induced type 1 diabetes. AB - There are contradictory results about the effect of angiotensin-converting enzyme inhibitors (ACEIs) on bone. This study was performed to address the skeletal renin-angiotensin system (RAS) activity and the effects of the ACEI, captopril, on the bone of streptozotocin-induced type 1 diabetic mice. Histochemical assessment on bone paraffin sections was conducted by Safranin O staining and tartrate-resistant acid phosphatase staining. Micro-computed tomography was performed to analyze bone biological parameters. Gene and protein expression were determined by real-time polymerase chain reaction and immunoblotting, respectively. Type 1 diabetic mice displayed osteopenia phenotype and captopril treatment showed no osteoprotective effects in diabetic mice as shown by the reduction of bone mineral density, trabecular thickness and bone volume/total volume. The mRNA expression of ACE and renin receptor, and the protein expression of renin and angiotensin II were markedly up-regulated in the bone of vehicle treated diabetic mice compared to those of non-diabetic mice, and these molecular changes of skeletal RAS components were effectively inhibited by treatment with captopril. However, treatment with captopril significantly elevated serum tartrate-resistant acid phosphatase 5b levels, reduced the ratio of osteoprotegerin/receptor activator of nuclear factor-kappaB ligand expression, increased carbonic anhydrase II mRNA expression and the number of matured osteoclasts and decreased transforming growth factor-beta and osteocalcin mRNA expression in the tibia compared to those of diabetic mice. The present study demonstrated that the use of the ACEI, captopril, has no beneficial effect on the skeletal biological properties of diabetic mice. However, this could be attributed, at least partially, to its suppression of osteogenesis and stimulation of osteoclastogenesis, even though it could effectively inhibit high activity of local RAS in the bone of diabetic mice. PMID- 23934057 TI - GIS as a community engagement tool: developing a plan to reduce infant mortality risk factors. AB - This article describes how a community coalition focusing on maternal and child health engages community participation through the use of geographic information systems (GIS) mapping, developing strategies that culminate in the implementation of a service delivery plan to improve birth outcomes. Vital statistics data from 2007 to 2009 was analyzed by zip code in Pinellas County Florida to produce choropleth thematic maps using ArcGIS for 3 year rolling average infant deaths and single year percentages for prematurity. The maps were presented at the organization's annual coalition meeting to discuss risk areas, changes over time in the selected indicators and solicit community feedback on how to best target issues addressing infant mortality and prematurity. The maps identified new zip codes of concern for prematurity in addition to known high risk zip codes for both infant mortality and prematurity. The community identified changes in demographic composition and changes in housing patterns, such as new mobile home areas, in the high risk areas. In response, the community assisted the Coalition in developing a holistic plan addressing risk factors affecting birth outcomes by expanding current services, hiring a nutritionist, and contracting a health navigator. When compared to tables and charts, a visual depiction of a neighborhood by recognizable zip codes is a useful tool to help community decision makers better visualize public health concerns and interpret trends based on local knowledge. Public health professionals should use this community knowledge to interpret research results and implement strategies to improve birth outcomes. PMID- 23934058 TI - Combining fragment homology modeling with molecular dynamics aims at prediction of Ca2+ binding sites in CaBPs. AB - The family of calcium-binding proteins (CaBPs) consists of dozens of members and contributes to all aspects of the cell's function, from homeostasis to learning and memory. However, the Ca2+-binding mechanism is still unclear for most of CaBPs. To identify the Ca2+-binding sites of CaBPs, this study presented a computational approach which combined the fragment homology modeling with molecular dynamics simulation. For validation, we performed a two-step strategy as follows: first, the approach is used to identify the Ca2+-binding sites of CaBPs, which have the EF-hand Ca2+-binding site and the detailed binding mechanism. To accomplish this, eighteen crystal structures of CaBPs with 49 Ca2+ binding sites are selected to be analyzed including calmodulin. The computational method identified 43 from 49 Ca2+-binding sites. Second, we performed the approach to large-conductance Ca2+-activated K+ (BK) channels which don't have clear Ca2+-binding mechanism. The simulated results are consistent with the experimental data. The computational approach may shed some light on the identification of Ca2+-binding sites in CaBPs. PMID- 23934059 TI - Landscape characterization integrating expert and local spatial knowledge of land and forest resources. AB - In many developing countries, political documentation acknowledges the crucial elements of participation and spatiality for effective land use planning. However, operative approaches to spatial data inclusion and representation in participatory land management are often lacking. In this paper, we apply and develop an integrated landscape characterization approach to enhance spatial knowledge generation about the complex human-nature interactions in landscapes in the context of Zanzibar, Tanzania. We apply an integrated landscape conceptualization as a theoretical framework where the expert and local knowledge can meet in spatial context. The characterization is based on combining multiple data sources in GIS, and involves local communities and their local spatial knowledge since the beginning into the process. Focusing on the expected information needs for community forest management, our characterization integrates physical landscape features and retrospective landscape change data with place-specific community knowledge collected through participatory GIS techniques. The characterization is established in a map form consisting of four themes and their synthesis. The characterization maps are designed to support intuitive interpretation, express the inherently uncertain nature of the data, and accompanied by photographs to enhance communication. Visual interpretation of the characterization mediates information about the character of areas and places in the studied local landscape, depicting the role of forest resources as part of the landscape entity. We conclude that landscape characterization applied in GIS is a highly potential tool for participatory land and resource management, where spatial argumentation, stakeholder communication, and empowerment are critical issues. PMID- 23934061 TI - Local farmers' perceptions of climate change and local adaptive strategies: a case study from the Middle Yarlung Zangbo River Valley, Tibet, China. AB - Climate change affects the productivity of agricultural ecosystems. Farmers cope with climate change based on their perceptions of changing climate patterns. Using a case study from the Middle Yarlung Zangbo River Valley, we present a new research framework that uses questionnaire and interview methods to compare local farmers' perceptions of climate change with the adaptive farming strategies they adopt. Most farmers in the valley believed that temperatures had increased in the last 30 years but did not note any changes in precipitation. Most farmers also reported sowing and harvesting hulless barley 10-15 days earlier than they were 20 years ago. In addition, farmers observed that plants were flowering and river ice was melting earlier in the season, but they did not perceive changes in plant germination, herbaceous vegetation growth, or other spring seasonal events. Most farmers noticed an extended fall season signified by delays in the freezing of rivers and an extended growing season for grassland vegetation. The study results showed that agricultural practices in the study area are still traditional; that is, local farmers' perceptions of climate change and their strategies to mitigate its impacts were based on indigenous knowledge and their own experiences. Adaptive strategies included adjusting planting and harvesting dates, changing crop species, and improving irrigation infrastructure. However, the farmers' decisions could not be fully attributed to their concerns about climate change. Local farming systems exhibit high adaptability to climate variability. Additionally, off-farm income has reduced the dependence of the farmers on agriculture, and an agricultural subsidy from the Chinese Central Government has mitigated the farmers' vulnerability. Nevertheless, it remains necessary for local farmers to build a system of adaptive climate change strategies that combines traditional experience and indigenous knowledge with scientific research and government polices as key factors. PMID- 23934062 TI - Callose and cellulose synthase gene expression analysis from the tight cluster to the full bloom stage and during early fruit development in Malus * domestica. AB - Apple (Malus * domestica) is an economically important temperate fruit-bearing crop which belongs to the family of Rosaceae and its pomaceous fruit is one of the most commonly cultivated. Several studies have demonstrated that the cell wall plays a pivotal role during flower and fruit development. It takes active part in pollen tube growth and contributes to determine the fruit firmness trait through the action of cell wall-related enzymes (i.e. polygalacturonase and pectinmethylesterase). We have investigated the expression of callose and cellulose synthase genes during flowering from tight cluster to anthesis and during early fruit development in domesticated apple. We also link the changes observed in gene expression to the profile of soluble non-structural carbohydrates at different developmental stages of flowers/fruitlets and to the qualitative results linked to wall polysaccharides' composition obtained through near-infrared spectroscopy. This work represents an important addition to the study of tree physiology with respect to the analysis of the expression of callose and cellulose synthase genes during flower and early fruit development in domesticated apple. PMID- 23934063 TI - Cardiac spectrum, cytogenetic analysis and thyroid profile of 418 children with Down syndrome from South India: a cross-sectional study. AB - OBJECTIVE: To describe the spectrum of congenital heart disease in children with Down syndrome and their cytogenetic profile (and that of parents of those with translocation), and thyroid profile. METHODS: A cross sectional study was conducted in 418 consecutive patients with Down syndrome attending the Department of Pediatric Genetics from a tertiary care centre in Kerala with a comprehensive Pediatric Cardiac Program, from November 2005 through April 2012. All children were offered cytogenetic analysis and were subjected to echocardiography. Parental karyotyping was offered for children with translocation type of Down syndrome. The thyroid profiles of all children were checked at the first visit and once every 6 mo during follow up. RESULTS: Congenital heart disease was present in 256 (63.4 %) of 404 children with Down syndrome. Ventricular septal defect (72; 28.1 %) was the commonest, followed by atrio-ventricular septal defect (70; 27.3 %) and patent ductus arteriosus (43; 16.8 %). Surgical correction was accomplished in 104 (40.6 %) with excellent intermediate-term outcomes. Three hundred eighty seven of 418 children (92.6 %) underwent cytogenetic tests. The abnormalities included non-disjunction (340, 87.8 %), translocation (33, 8.5 %) and mosaicism (12, 3.1 %). Hypothyroidism was detected in 57 children (13.6 %). CONCLUSIONS: The prevalence of congenital heart disease in children with Down syndrome in Kerala is the highest reported (63.4 %). Ventricular septal defect is the most common heart disease in the present study. The results highlight the changing attitudes of families towards the surgical correction of congenital heart disease in children with Down syndrome. Prevalence of hypothyroidism in Down syndrome in Kerala is 13.6 %. PMID- 23934064 TI - Does cluster-root activity benefit nutrient uptake and growth of co-existing species? AB - Species that inhabit phosphorus- (P) and micronutrient-impoverished soils typically have adaptations to enhance the acquisition of these nutrients, for example cluster roots in Proteaceae. However, there are several species co occurring in the same environment that do not produce similar specialised roots. This study aims to investigate whether one of these species (Scholtzia involucrata) can benefit from the mobilisation of P or micronutrients by the cluster roots of co-occurring Banksia attenuata, and also to examine the response of B. attenuata to the presence of S. involucrata. We conducted a greenhouse experiment, using a replacement series design, where B. attenuata and S. involucrata shared a pot at proportions of 2:0, 1:2 and 0:4. S. involucrata plants grew more in length, were heavier and had higher manganese (Mn) concentrations in their young leaves when grown next to one individual of B. attenuata and one individual of S. involucrata than when grown with three conspecifics. All S. involucrata individuals were colonised by arbuscular mycorrhizal fungi, and possibly Rhizoctonia. Additionally, P concentration was higher in the young leaves of B. attenuata when grown with another B. attenuata than when grown with two individuals of S. involucrata, despite the smaller size of the S. involucrata individuals. Our results demonstrate that intraspecific competition was stronger than interspecific competition for S. involucrata, but not for B. attenuata. We conclude that cluster roots of B. attenuata facilitate the acquisition of nutrients by neighbouring shrubs by making P and Mn more available for their neighbours. PMID- 23934066 TI - Downregulation of melanocyte-specific facultative melanogenesis by 4-hydroxy-3 methoxycinnamaldehyde acting as a cAMP antagonist. PMID- 23934065 TI - Transcription factor/microRNA axis blocks melanoma invasion program by miR-211 targeting NUAK1. AB - Melanoma is one of the deadliest human cancers, responsible for approximately 80% of skin cancer mortalities. The aggressiveness of melanoma is due to its capacity to proliferate and rapidly invade surrounding tissues, leading to metastases. A recent model suggests melanoma progresses by reversibly switching between proliferation and invasion transcriptional signatures. Recent studies show that cancer cells are more sensitive to microRNA (miRNA) perturbation than are non cancer cells; however, the roles of miRNAs in melanoma plasticity remain unexplored. Here, we use the gene expression profiles of melanoma and normal melanocytes to characterize the transcription factor-miRNA relationship that modulates the proliferative and invasive programs of melanoma. We identified two sets of miRNAs that likely regulate these programs. Interestingly, one of the miRNAs involved in melanoma invasion is miR-211, a known target of the master regulator microphthalmia-associated transcription factor (MITF). We demonstrate that miR-211 contributes to melanoma adhesion by directly targeting a gene, NUAK1. Inhibition of miR-211 increases NUAK1 expression and decreases melanoma adhesion, whereas upregulation of miR-211 restores adhesion through NUAK1 repression. This study defines the MITF/miR-211 axis that inhibits the invasive program by blocking adhesion. Furthermore, we have identified NUAK1 as a potential target for the treatment of metastatic melanoma. PMID- 23934067 TI - Sweeping lymph node micrometastases off their feet: an engineered model to evaluate natural killer cell mediated therapeutic intervention of circulating tumor cells that disseminate to the lymph nodes. AB - Approximately 90% of cancer related deaths are due to metastasis. Cells from the primary tumor can metastasize through either the vascular or lymphatic circulation. Cancer cells in circulation are called circulating tumor cells (CTCs) and it has been shown that bone marrow is a niche for homing of blood borne CTCs from several epithelial tumors. Cancer cells found in bone marrow are termed disseminated tumor cells (DTCs). Likewise, CTCs in the lymphatic circulation are more often seeded in the sentinel lymph nodes (SLN) that drain the tumor. Micrometastases (<2 mm) occur after the arrest and implantation of DTCs in lymph nodes over time. This paper presents a cell culture platform termed microbubbles formed in polydimethylsiloxane (PDMS) from a microfabricated silicon wafer for mimicking lymph node micrometastases. We cultured lymph node seeking cancer cells in microbubbles to evaluate the efficacy of natural killer (NK) mediated therapy for targeting lymph node micrometastasis. The microbubble platform consists of an array of microcavities that provides a unique microenvironment for mimicking the deep cortical unit of the lymph nodes. We show that cancer cells cultured in microbubbles with therapeutic NK cells undergo apoptosis after 24 h in culture. Since lymph node metastases are prevalent across several types of cancer, this platform may be useful for developing improved cancer therapies for targeting lymph node micrometastases. PMID- 23934068 TI - A new isolate from Fusarium proliferatum (AUF-2) for efficient nitrilase production. AB - A fungal isolate from Fusarium proliferatum strain AUF-2 has been found to have a high nitrilase activity (>= 1,000 U/l culture). The present work describes optimization of growth conditions and production medium to achieve maximum nitrilase production. The most effective carbon and nitrogen sources for nitrilase production were glucose and sodium nitrate, respectively. epsilon Caprolactam was found to be the best inducer for maximum nitrilase production with 80 g/l wet cell biomass and 26 U/g nitrilase activity. An overall nitrilase activity of >= 2,000 U/l culture was obtained in this study, which is one of the best activities reported so far in any Fusarium strain. Chemo-profiling has shown that the strain is versatile in its ability to hydrolyze both aliphatic as well as aromatic nitriles. Efforts are being made to use the strain for biotransformation of pharmaceutical substrates. PMID- 23934069 TI - Monitoring of PQQ-dependent glucose dehydrogenase substrate specificity for its potential use in biocatalysis and bioanalysis. AB - Substrate specificity of 2,7,9-tricarboxypyrroloquinoline quinone (PQQ)-dependent glucose dehydrogenase was investigated in biosensor arrangement for understanding the suitability and the limitations of its use in bioanalysis and bioproduction of chemicals. The study demonstrated a very broad substrate specificity of biosensor utilising soluble form of PQQ-dependent glucose dehydrogenase. Nineteen saccharides out of 31 were oxidised by the sensor. Investigation confirmed strong importance of hydroxyl configuration in the positions 2 and 5 of oxidised saccharides. The broad specificity suggests that the PQQ-dependent glucose dehydrogenase could be utilised for analysis of other sugars than glucose in food samples for various production processes and for biofuel cells. In addition, the results showed that the substrate specificity of enzymes can be effectively and generally studied by biosensor arrangement for research purposes. This layout utilising immobilised enzyme allowed performing comprehensive study using a small amount of enzymes and thus saving the costs and time. PMID- 23934070 TI - Knockdown of neurokinin-1 receptor expression by small interfering RNA prevents the development of allergic rhinitis in rats. AB - OBJECTIVE AND DESIGN: This study is aimed at exploring the role of neurokinin-1 receptor (NK-1R) in the development of allergic rhinitis (AR) in rats. METHODS: Sprague-Dawley rats were sensitized and challenged with ovalbumin to induce AR. The rats were treated intranasally with saline, control, or NK-1R-specific small interfering RNA (siRNA) before and during the challenge period. The numbers of sneezes and nose rubs and amount of nasal secretion in individual rats were measured. The levels of NK-1R expression in the nasal mucosal tissues after the last challenge were determined. The numbers of eosinophils in the collected nasal lavage fluid and the levels of serum interleukin (IL)-5 in individual rats were determined. RESULTS: The levels of NK-1R expression in the nasal mucosal tissues of the AR rats that had been treated with saline or control siRNA were significantly higher than those in the healthy controls and the rats treated with NK-1R-specific siRNA, demonstrating NK-1R silencing. Furthermore, knockdown of NK 1R expression significantly reduced the amounts of sneezing, nose rubbing, and nasal secretions in AR rats. Knockdown of NK-1R expression also significantly eliminated eosinophil infiltration in the nasal tissues and reduced the levels of serum IL-5 in rats. CONCLUSIONS: Knockdown of NK-1R expression decreased allergic inflammation in nasal mucosal tissues and alleviated the allergic rhinitis symptoms, suggesting that NK-1R may be a critical mediator of the development of AR. PMID- 23934072 TI - Prior robust empirical Bayes inference for large-scale data by conditioning on rank with application to microarray data. AB - Empirical Bayes methods have been extensively used for microarray data analysis by modeling the large number of unknown parameters as random effects. Empirical Bayes allows borrowing information across genes and can automatically adjust for multiple testing and selection bias. However, the standard empirical Bayes model can perform poorly if the assumed working prior deviates from the true prior. This paper proposes a new rank-conditioned inference in which the shrinkage and confidence intervals are based on the distribution of the error conditioned on rank of the data. Our approach is in contrast to a Bayesian posterior, which conditions on the data themselves. The new method is almost as efficient as standard Bayesian methods when the working prior is close to the true prior, and it is much more robust when the working prior is not close. In addition, it allows a more accurate (but also more complex) non-parametric estimate of the prior to be easily incorporated, resulting in improved inference. The new method's prior robustness is demonstrated via simulation experiments. Application to a breast cancer gene expression microarray dataset is presented. Our R package rank.Shrinkage provides a ready-to-use implementation of the proposed methodology. PMID- 23934071 TI - Inhibition of TRPM7 channels prevents proliferation and differentiation of human lung fibroblasts. AB - OBJECTIVE: Transient receptor potential melastatin 7 (TRPM7) is involved in both normal physiological processes and pathology of various diseases. The purpose of this study was to explore the function and underlying mechanisms of TRPM7 channels in human lung fibroblast (MRC5) proliferation and differentiation induced by transforming growth factor beta1 (TGF-beta1) in vitro. MATERIALS AND METHODS: We determined the expression of TRPM7 in MRC5 cells in response to TGF beta1 treatment in vitro. Chemical inhibitors (Gd(3+) and 2-APB) and specific siRNA for TRPM7 were used to study the role of TRPM7 in MRC5 cell proliferation and differentiation. The phosphorylation of Akt was determined by Western blotting. RESULTS: The expression of TRPM7 was significantly potentiated in response to TGF-beta1. Co-incubation of MRC5 cells with Gd(3+), 2-APB or TRPM7 siRNA decreased cell proliferation and differentiation. Furthermore, we found that suppression of TRPM7 channels also reduced the p-Akt in MRC5 cells induced by TGF-beta1. We conclude that suppression of TRPM7 channels may decrease fibroblast proliferation and differentiation stimulated by TGF-beta1 in vitro and this is associated with Akt phosphorylation. PMID- 23934073 TI - Development of a dendritic cell vaccine encoding multiple cytotoxic T lymphocyte epitopes targeting hepatitis C virus. AB - The aim of the present study was to develop a dendritic cell (DC) vaccine encoding hepatitis C virus (HCV) multiple cytotoxic T lymphocyte (CTL) epitopes that can stimulate T cell responses in vitro, and can be used for immunization in vivo. DCs were infected with recombinant replication-defective adenoviruses (Ads) expressing 2 HCV sequences fused with green fluorescent protein (GFP) and FLAG tags. One sequence (sequence 1) contained the HCV CTL epitopes, NS4B 1793-1801 and P7 774-782, as well as the HCV Th epitope, NS3 1248-1261. A second sequence (sequence 2) was the positive epitope control which contained HCV core 35-44, core 132-140 and NS3 1248-1261. The efficiency of infection was detected by flow cytometry and the expression of HCV epitopes in the DCs was confirmed by RT-PCR and western blot analysis. Ad infection significantly enhanced DC maturation and interleukin (IL)-12p70 production, resulting in T cell proliferation and increased interferon-gamma secretion. The CTLs stimulated by Ad-infected DCs specifically killed Huh7.5 human hepatoma cells. The recombinant Ad-expressing multiple CTL HCV epitopes effectively infected the DCs in vitro and promoted T cell antiviral immune responses, thereby laying the foundation for the development of anti-HCV DC vaccines. PMID- 23934075 TI - Exercise-induced myalgia may limit the cardiovascular benefits of statins. AB - The positive health benefits of statins extend beyond the cardiovascular and include increased flow mediated dilation, decreased atrial fibrillation, modest antihypertensive effects and reduced risks of malignancies. Prominent among the statin side-effects are myalgia and muscular weakness, which may be associated with a rise in circulating creatine kinase values. In increasing severity and decreasing incidence, the statin-induced muscle related conditions are myalgia, myopathy with elevated creatine kinase (CK) levels with or without symptoms, and rhabdomyolysis. Statin use may increase CK levels without decreasing average muscle strength or exercise performance. In one large study, only about 2 % had myalgia that could be attributed to statin use. A novel current hypothesis is that statins optimize cardiac mitochondrial function but impair the vulnerable skeletal muscle by inducing different levels of reactive oxygen species (ROS) in these two sites. In an important observational study, both statins and exercise reduced the adverse outcomes of cardiovascular disease, and the effects were additive. The major unresolved problem is that either can cause muscular symptoms with elevation of blood creatine kinase levels. There is, as yet, no clearly defined outcomes based policy to deal with such symptoms from use of either statins or exercise or both. A reasonable practical approach is to assess the creatine kinase levels, and if elevated to reduce the statin dose or the intensity of exercise. PMID- 23934074 TI - Expression of a Clostridium perfringens genome-encoded putative N-acetylmuramoyl L-alanine amidase as a potential antimicrobial to control the bacterium. AB - Clostridium perfringens is a gram-positive, spore-forming anaerobic bacterium that plays a substantial role in non-foodborne human, animal, and avian diseases as well as human foodborne disease. Previously discovered C. perfringens bacteriophage lytic enzyme amino acid sequences were utilized to identify putative prophage lysins or autolysins by BLAST analyses encoded by the genomes of C. perfringens isolates. A predicted N-acetylmuramoyl-L-alanine amidase or MurNAc-LAA (also known as peptidoglycan aminohydrolase, NAMLA amidase, NAMLAA, amidase 3, and peptidoglycan amidase; EC 3.5.1.28) was identified that would hydrolyze the amide bond between N-acetylmuramoyl and L-amino acids in certain cell wall glycopeptides. The gene encoding this protein was subsequently cloned from genomic DNA of a C. perfringens isolate by polymerase chain reaction, and the gene product (PlyCpAmi) was expressed to determine if it could be utilized as an antimicrobial to control the bacterium. By spot assay, lytic zones were observed for the purified amidase and the E. coli expression host cellular lysate containing the amidase gene. Turbidity reduction and plate counts of C. perfringens cultures were significantly reduced by the expressed protein and observed morphologies for cells treated with the amidase appeared vacuolated, non intact, and injured compared to the untreated cells. Among a variety of C. perfringens strains, there was little gene sequence heterogeneity that varied from 1 to 21 nucleotide differences. The results further demonstrate that it is possible to discover lytic proteins encoded in the genomes of bacteria that could be utilized to control bacterial pathogens. PMID- 23934076 TI - Allele-specific detection of single mRNA molecules in situ. AB - We describe a method for fluorescence in situ identification of individual mRNA molecules, allowing quantitative and accurate measurement, in single cells, of allele-specific transcripts that differ by only a few nucleotides. By using a combination of allele-specific and non-allele-specific probe libraries, we achieve >95% detection accuracy. We investigate the allele-specific stochastic expression of Nanog, which encodes a pluripotency factor, in murine embryonic stem cells. PMID- 23934077 TI - STED nanoscopy combined with optical tweezers reveals protein dynamics on densely covered DNA. AB - Dense coverage of DNA by proteins is a ubiquitous feature of cellular processes such as DNA organization, replication and repair. We present a single-molecule approach capable of visualizing individual DNA-binding proteins on densely covered DNA and in the presence of high protein concentrations. Our approach combines optical tweezers with multicolor confocal and stimulated emission depletion (STED) fluorescence microscopy. Proteins on DNA are visualized at a resolution of 50 nm, a sixfold resolution improvement over that of confocal microscopy. High temporal resolution (<50 ms) is ensured by fast one-dimensional beam scanning. Individual trajectories of proteins translocating on DNA can thus be distinguished and tracked with high precision. We demonstrate our multimodal approach by visualizing the assembly of dense nucleoprotein filaments with unprecedented spatial resolution in real time. Experimental access to the force dependent kinetics and motility of DNA-associating proteins at biologically relevant protein densities is essential for linking idealized in vitro experiments with the in vivo situation. PMID- 23934078 TI - Cytochrome c and superoxide: a reply. AB - In his comments, W.H. Koppenol criticizes our article with respect to our conclusions and procedures. In this answer, we respond in detail to his objections, demonstrating that the approaches used are commonly accepted in the literature and that he makes a number of assumptions regarding our proposed mechanism that are not justified. Our study is thus a contribution to the ongoing investigation of the behavior of cytochrome c. PMID- 23934079 TI - What we talk about when we talk about nuclear actin. AB - In the cytoplasm, actin filaments form crosslinked networks that enable eukaryotic cells to transport cargo, change shape, and move. Actin is also present in the nucleus but, in this compartment, its functions are more cryptic and controversial. If we distill the substantial literature on nuclear actin down to its essentials, we find four, recurring, and more-or-less independent, claims: (1) crosslinked networks of conventional actin filaments span the nucleus and help maintain its structure and organize its contents; (2) assembly or contraction of filaments regulates specific nuclear events; (3) actin monomers moonlight as subunits of chromatin remodeling complexes, independent of their ability to form filaments; and (4) modified actin monomers or oligomers, structurally distinct from canonical, cytoskeletal filaments, mediate nuclear events by unknown mechanisms. We discuss the evidence underlying these claims and as well as their strengths and weaknesses. Next, we describe our recent work, in which we built probes specific for nuclear actin and used them to describe the form and distribution of actin in somatic cell nuclei. Finally, we discuss how different forms of nuclear actin may play different roles in different cell types and physiological contexts. PMID- 23934080 TI - System identification of evoked mechanomyogram from abductor pollicis brevis muscle in isometric contraction. AB - The purpose of this study is to verify the applicability of a sixth-order model to the mechanomyogram (MMG) system of the parallel-fibered muscle, which was identified from the MMG of the pennation muscle. The median nerve was stimulated, and an MMG and torque of the abductor pollicis brevis muscle were measured. The MMGs were detected with either a capacitor microphone or an acceleration sensor. The transfer functions between stimulation and the MMG and between stimulation and torque were identified by the singular value decomposition method. The torque and the MMG, which were detected with a capacitor microphone, DMMG, were approximated with a second- and a third-order model, respectively. The natural frequency of the torque, reflecting longitudinal mechanical characteristics, did not show a significant difference from that of the DMMG. The MMG detected with an acceleration sensor was approximated with a fourth-order model. The natural frequencies of the AMMG reflecting the muscle and subcutaneous tissue in the transverse direction were obtained. Both DMMG and AMMG have to be measured to investigate the model of the MMG system for parallel-fibered muscle. The MMG system of parallel-fibered muscle was also modeled with a sixth-order model. PMID- 23934082 TI - A novel crosstalk between two major protein degradation systems: regulation of proteasomal activity by autophagy. AB - Eukaryotes have two major intracellular protein degradation pathways, namely the ubiquitin-proteasome system (UPS) and autophagy. Inhibition of proteasomal activities has been previously shown to induce autophagy, indicating a coordinated and complementary relationship between these two systems. However, little is known about the regulation of the UPS by autophagy. In this study, we showed for the first time that proteasomes were activated in response to pharmacological inhibition of autophagy as well as disruption of autophagy related genes by RNA interference under nutrient-deficient conditions in cultured human colon cancer cells. The induction was evidenced by the increased proteasomal activities and the upregulation of proteasomal subunits, including the proteasome beta5 subunit, PSMB5. Co-inhibition of the proteasome and autophagy also synergistically increased the accumulation of polyubiquitinated proteins. Collectively, our findings suggest that proteasomes are activated in a compensatory manner for protein degradation upon autophagy inhibition. Our studies unveiled a novel regulatory mechanism between the two protein degradation pathways. PMID- 23934081 TI - Trafficking of mRNAs containing ALREX-promoting elements through nuclear speckles. AB - In vertebrates, the majority of mRNAs that encode secreted, membrane-bound or mitochondrial proteins contain RNA elements that activate an alternative mRNA nuclear export (ALREX) pathway. Here we demonstrate that mRNAs containing ALREX promoting elements are trafficked through nuclear speckles. Although ALREX promoting elements enhance nuclear speckle localization, additional features within the mRNA largely drive this process. Depletion of two TREX-associated RNA helicases, UAP56 and its paralog URH49, or inhibition of the TREX-associated nuclear transport factor, TAP, not only inhibits ALREX, but also appears to trap these mRNAs in nuclear speckles. mRNAs that contain ALREX-promoting elements associate with UAP56 in vivo. Finally, we demonstrate that mRNAs lacking a poly(A)-tail are not efficiently exported by the ALREX pathway and show enhanced association with nuclear speckles. Our data suggest that within the speckle, ALREX-promoting elements, in conjunction with the poly(A)-tail, likely stimulate UAP56/URH49 and TAP dependent steps that lead to the eventual egress of the export-competent mRNP from these structures. PMID- 23934083 TI - Cell-free supernatants obtained from fermentation of cheese whey hydrolyzates and phenylpyruvic acid by Lactobacillus plantarum as a source of antimicrobial compounds, bacteriocins, and natural aromas. AB - Cheese whey hydrolyzates supplemented with phenylpyruvic acid (PPA) and commercial nutrients can be efficiently metabolized by Lactobacillus plantarum CECT-221 to biosynthesize some compounds with attractive applications in the food market. The main metabolites of cell-free extracts were antimicrobial compounds such as phenyllactic acid (PLA) and lactic acid (LA). The production of PLA by L. plantarum CECT-221 was evaluated in the Man-Rogosa-Sharpe broth supplemented with two biosynthetic precursors: phenylalanine or PPA. Using 30.5 mM PPA, the microorganism increased sevenfold the concentration of PLA producing 16.4 mM PLA in 46 h. A concentration of 40 mM PPA was a threshold to avoid substrate inhibition. The biosynthesis of whey hydrolyzates as a carbon source was enhanced by fed-batch fermentation of PPA; the average productivity of PLA increased up to 45.4 +/- 3.02 mM after 120 h with a product yield of 0.244 mM mM(-1); meanwhile, LA reached 26.1 +/- 1.3 g L(-1) with a product yield of 0.72 g g(-1). Cell-free fed-batch extracts charged in wells showed bacteriocin activity with halos of 7.49 +/- 1.44 mm in plates inoculated with Carnobacterium piscicola and antimicrobial activity against Staphylococcus aureus (11.54 +/- 1.14 mm), Pseudomonas aeruginosa (10.17 +/- 2.46 mm), Listeria monocytogenes (7.75 +/- 1.31 mm), and Salmonella enterica (3.60 +/- 1.52 mm). Additionally, the analysis of the volatile composition of the headspace of this cell-free extract revealed that L. plantarum is a potential producer for natural aromas, such as acetophenone, with high price in the market. This is the first report of PLA production from cheese whey and PPA. The extracts showed bacteriocin activity and potential to be applied as an antimicrobial in the elaboration of safer foods. PMID- 23934084 TI - Inhibition of RAGE signaling through the intracellular delivery of inhibitor peptides by PEI cationization. AB - The receptor for advanced glycation end products (RAGE) is a multi-ligand cell surface receptor and a member of the immunoglobulin superfamily. RAGE is involved in a wide range of inflammatory, degenerative and hyper-proliferative disorders which span over different organs by engaging diverse ligands, including advanced glycation end products, S100 family proteins, high-mobility group protein B1 (HMGB1) and amyloid beta. We previously demonstrated that the cytoplasmic domain of RAGE is phosphorylated upon the binding of ligands, enabling the recruitment of two distinct pairs of adaptor proteins, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and myeloid differentiation protein 88 (MyD88). This engagement allows the activation of downstream effector molecules, and thereby mediates a wide variety of cellular processes, such as inflammatory responses, apoptotic cell death, migration and cell growth. Therefore, inhibition of the binding of TIRAP to RAGE may abrogate intracellular signaling from ligand activated RAGE. In the present study, we developed inhibitor peptides for RAGE signaling (RAGE-I) by mimicking the phosphorylatable cytosolic domain of RAGE. RAGE-I was efficiently delivered into the cells by polyethylenimine (PEI) cationization. We demonstrated that RAGE-I specifically bound to TIRAP and abrogated the activation of Cdc42 induced by ligand-activated RAGE. Furthermore, we were able to reduce neuronal cell death induced by an excess amount of S100B and to inhibit the migration and invasion of glioma cells in vitro. Our results indicate that RAGE-I provides a powerful tool for therapeutics to block RAGE mediated multiple signaling. PMID- 23934085 TI - Histone post-translational modifications regulate autophagy flux and outcome. AB - Autophagy is an evolutionarily conserved process in eukaryotes by which cytoplasmic components including macromolecules and organelles are degraded by the lysosome/vacuole. Autophagy is implicated in a number of physiological processes important for human health and disease. Although primarily cytoprotective, autophagy can also contribute to cell death; it is thus important to understand what distinguishes the life or death decision in autophagic cells. Despite the fact that the execution of autophagy includes a unique set of cytoplasmic events, nuclear events, in particular transcriptional programs, have emerged as an important regulator of this process. In addition, a critical linkage was recently unveiled between specific histone posttranslational modifications and the transcriptional regulation of autophagy-related genes, which initiates a regulatory feedback loop, and serves as a key determinant of survival versus death responses upon autophagy induction. PMID- 23934086 TI - Effect of topical application of melatonin to the gingiva on salivary osteoprotegerin, RANKL and melatonin levels in patients with diabetes and periodontal disease. AB - This cross-section study was designed to assess the effect of topical application of melatonin to the gingiva on salivary RANKL, osteoprotegrin (OPG) and melatonin levels as well as plasma melatonin in 30 patients with diabetes and periodontal disease and in a control group of 30 healthy subjects. Salivary RANKL and OPG were measured by enzyme-linked immunosorbent assay and salivary and plasma melatonin by radioimmunoassay using commercial kits. Periodontograms were performed using the Florida Probe((r)). Diabetic patients were treated with topical application of melatonin (1% orabase cream formula) once daily for 20 days. Patients with diabetes showed significantly higher mean levels of salivary RANKL than healthy subjects as well as significantly lower values of salivary OPG and salivary and plasma melatonin. After treatment with melatonin, there was a statistically significant decrease of the gingival index, pocket depth and salivary levels of RANKL, and a significant rise in salivary values of OPG. Changes of salivary OPG levels before and after topical melatonin treatment correlated significantly with changes in the gingival index and pocket depth. Treatment with topical melatonin was associated with an improvement in the gingival index and pocket depth, a reduction in salivary concentrations of RANKL and increase in salivary concentrations of OPG, which indicates that melatonin has a favorable effect in slowing osteoclastogenesis, improving the quality of alveolar bone and preventing the progression of periodontal disease. PMID- 23934087 TI - Influence of background on natural tooth colour coordinates: an in vivo evaluation. AB - The aim of this study was to evaluate the influence of different backgrounds on spectrophotometric colour values of natural teeth. Twenty volunteers (10 males and 10 females) with a mean age of 25 years and 9 months (+/-3 years and 2 months) were each subjected to 4 spectrophotometric measurements of their upper right central incisor. Each sample was measured with alternatively black, 50% grey, white or no background (positive control). DeltaE medians ranged from 0.9 to 5.9. All artificial backgrounds presented significant differences (p < 0.05) when compared to values obtained without any background. No significant differences were observed between black and 50% grey background (p > 0.05). If an artificial background needs to be used, as for example when performing in vitro studies, preference should be given to a black background as it approaches best the clinical situation (i.e. no background). Even if no statistically significant differences were found when compared with the grey background, the black background should be preferred due to its lower DeltaE medians, standard deviation as well as lower minimum and maximum values. PMID- 23934088 TI - Evaluation of the effectiveness of an in-office bleaching system and the effect of potassium nitrate as a desensitizing agent. AB - The aims of the study were to evaluate by spectrophotometer the in vivo colour changes resulting from the application of an in-office tooth bleaching system containing 28% H2O2 by light-emitting diode (LED) activation and to determine whether the application of 5% potassium nitrate 30 min before bleaching decreased tooth sensitivity. Thirty-two individuals were assigned randomly to two groups (n = 16). Group A received 5% potassium nitrate as a desensitizing agent 30 min before bleaching with 28% hydrogen peroxide activated by LED. Group B received glycerin as a placebo and the same bleaching protocol was applied. The colour of the right central incisor of each patient was measured visually and by spectrophotometer before bleaching, immediately thereafter, 15 days and 3 months later. Differences in L* a* b* values were tested with a repeated measures analysis of variance (ANOVA). Differences in DeltaEpsilon values were tested with ANOVA statistical analysis at a 0.05 level of significance. Significant (p < 0.05) differences were detected in L*, as well as in b* values, between initial (I) and post bleaching (PB) and between initial (I) and 3 months post-op. In contrast, there was no significant difference between PB and 3 months post-op. The a* values showed no statistically significant differences among the different time points. Tooth sensitivity decreased significantly when potassium nitrate was applied. In-office bleaching system gave quantitatively stable results over a 3 month period. Tooth sensitivity was reduced significantly, when a desensitizing agent was applied 30 min before treatment, but the efficacy of bleaching decreased. PMID- 23934089 TI - Overexpression of beta-NGF promotes differentiation of bone marrow mesenchymal stem cells into neurons through regulation of AKT and MAPK pathway. AB - Bone marrow stromal stem cells (BMSCs) are fibroblastic in shape and capable of self-renewal and have the potential for multi-directional differentiation. Nerve growth factor (NGF), a homodimeric polypeptide, plays an important role in the nervous system by supporting the survival and growth of neural cells, regulating cell growth, promoting differentiation into neuron, and neuron migration. Adenoviral vectors are DNA viruses that contain 36 kb of double-stranded DNA allowing for transmission of the genes to the host nucleus but not inserting them into the host chromosome. The present study aimed to investigate the induction efficiency and differentiation of neural cells from BMSCs by beta-NGF gene transfection with recombinant adenoviral vector (Ad-beta-NGF) in vitro. The results of immunochemical assay confirmed the induced cells as neuron cells. Moreover, flow cytometric analysis, Annexin-V-FITC/PI, and BrdU assay revealed that chemical inducer beta-mercaptoethanol (beta-met) triggered apoptosis of BMSCs, as evidenced by inhibition of DNA fragmentation, nuclear condensation, translocation of phospholipid phosphatidylserine, and activation of caspase-3. Furthermore, the results of western blotting showed that beta-met suppressed AKT signaling pathway and regulated the MAPKs during differentiation of BMSCs. In contrast, Ad-beta-NGF effectively induced the differentiation of BMSCs without causing any cytopathic phenomenon and apoptotic cell death. Moreover, Ad-beta-NGF recovered the expression level of phosphorylated AKT and MAPKs in cells exposed to chemical reagents. Taken together, these results suggest that beta-NGF gene transfection promotes the differentiation of BMSCs into neurons through regulation of AKT and MAPKs signaling pathways. PMID- 23934091 TI - A distinct subgroup of cardiomyopathy patients characterized by transcriptionally active cardiotropic erythrovirus and altered cardiac gene expression. AB - Recent studies have detected erythrovirus genomes in the hearts of cardiomyopathy and cardiac transplant patients. Assessment of the functional status of viruses may provide clinically important information beyond detection of the viral genomes. Here, we report transcriptional activation of cardiotropic erythrovirus to be associated with strongly altered myocardial gene expression in a distinct subgroup of cardiomyopathy patients. Endomyocardial biopsies (EMBs) from 415 consecutive cardiac erythrovirus (B19V)-positive patients with clinically suspected cardiomyopathy were screened for virus-encoded VP1/VP2 mRNA indicating transcriptional activation of the virus, and correlated with cardiac host gene expression patterns in transcriptionally active versus latent infections, and in virus-free control hearts. Transcriptional activity was detected in baseline biopsies of only 66/415 patients (15.9 %) harbouring erythrovirus. At the molecular level, significant differences between cardiac B19V-positive patients with transcriptionally active versus latent virus were revealed by expression profiling of EMBs. Importantly, latent B19V infection was indistinguishable from controls. Genes involved encode proteins of antiviral immune response, B19V receptor complex, and mitochondrial energy metabolism. Thus, functional mapping of erythrovirus allows definition of a subgroup of B19V-infected cardiomyopathy patients characterized by virus-encoded VP1/VP2 transcripts and anomalous host myocardial transcriptomes. Cardiac B19V reactivation from latency, as reported here for the first time, is a key factor required for erythrovirus to induce altered cardiac gene expression in a subgroup of cardiomyopathy patients. Virus genome detection is insufficient to assess pathogenic potential, but additional transcriptional mapping should be incorporated into future pathogenetic and therapeutic studies both in cardiology and transplantation medicine. PMID- 23934090 TI - Hepatitis B virus X (HBx) play an anti-apoptosis role in hepatic progenitor cells by activating Wnt/beta-catenin pathway. AB - Increasing evidence has shown that normal stem cells may act as cancer-initiating cells and contribute to the development and progression of cancer. HBx has a close relationship with hepatocellular carcinoma, however, the role of HBx in hepatic progenitor cells (HPCs) is poorly understood. In this study, we sought to determine the role of HBx in regulating HPCs apoptosis and the underlying molecular mechanism(s) using HPCs derived from mouse fetal liver. The apoptotic ratio of HPCs infected with adenovirus-expressing HBx (Ad-HBx) was examined using flow cytometry. Results showed that the Ad-HBx treatment led to substantially decreased apoptotic ratio of HPCs, as confirmed by the Hoechst 33342 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL). Possible alterations of relative proteins were examined using Western blot and real-time PCR assays. The HBx expression in HPCs increased the expression levels of Bcl2 and Mcl1 while decreasing the expression levels of Bax and cleaved caspase-9 and -3. In addition, the mRNA and protein expression levels of beta catenin were both increased. The beta-catenin protein were mainly accumulated in cytoplasm and tended to transfer into cell nucleus after Ad-HBx treatment. The over-expression of beta-catenin decreased the apoptotic ratio of HPCs and inhibited the expression of cleaved caspase-9 and -3 while blocking beta-catenin expression resulted in the opposite results. Taken together, our results strongly suggested that the HBx protein may inhibits apoptosis of hepatic progenitor cells, at least in part by activating the WNT/beta-catenin pathway. This provided a new insight into the molecular mechanism of HBx-mediated live carcinogenesis. PMID- 23934092 TI - The Shilla growth guidance technique for early-onset spinal deformities at 2-year follow-up: a preliminary report. AB - BACKGROUND: The Shilla growth guidance technique has been developed to treat spinal deformities without the necessity of repeated operative lengthenings. The dual stainless steel rods are fixed to the corrected apex of the curve by pedicle screws with limited fusion about the apex. Vertebral growth occurs in a cephalad and caudad direction through extraperiosteally placed sliding pedicle screws. A retrospective review of patients treated with the Shilla growth guidance technique for early-onset spinal deformity was performed to study patients with >2-year follow-up and describe outcome parameters. METHODS: From a cohort of 38 patients, 10 patients with a mean age of 7 + 6 years were identified as qualifying for 2-year follow-up inclusion. RESULTS: The average preoperative curve of 70.5 degrees was corrected to 27 degrees at 6 weeks follow-up and maintained at 2-year follow-up. The space available for lung improved an average of 13%. Truncal height (C7 to S1) increased an average of 12%. One patient required rod revision, 1 required rod change to a smaller size rod, and 1 required rod replacement. Two patients required wound debridement for low-grade infection in the early-postoperative period for a total of 5 procedures beyond the index correction. No patient had changes neurologically as a result of surgery. Patients were braced for the first 3 months postoperatively while the fusion was incorporating then not thereafter. CONCLUSIONS: At 2-year follow-up, the Shilla procedure has allowed children correction of their spinal deformity with an acceptable complication rate and ability to grow brace free without repeated trips to the operating room for lengthenings. These patients would have had 49 scheduled lengthening procedures after their initial correction if treated by conventional distraction growing rod methods. LEVEL OF EVIDENCE: IV case series of therapeutic study investigating results of treatment. PMID- 23934093 TI - Venous thromboembolism in children: preliminary results of a survey of POSNA members. AB - BACKGROUND: The term venous thromboembolism (VTE) includes deep venous thrombosis of the extremity and pulmonary embolism, a potentially fatal clinical entity. Although the prevalence of VTE may be lower in children compared with adults, recent reports suggest a possible rise in this diagnosis among pediatric patients, especially in association with certain risk factors. We assessed the clinical experience and practice of members of the Pediatric Orthopaedic Society of North America (POSNA) related to VTE among their pediatric patients. METHODS: A 36-question online survey was sent to all 636 active POSNA members. The proportion of surgeons who had encountered at least 1 child with VTE and the respondents' practice of using thromboprophylaxis in children (<18 y old) was assessed. The relationship of responders' experience with VTE among pediatric patients with various practice characteristics was evaluated. RESULTS: The response rate was 56% (354/636). More than half (55%) [95% confidence interval (CI), 50%-60%] of the respondents could recall at least 1 (median, 2 cases/member) pediatric patient with deep venous thrombosis and 29% (95% CI, 24% 34%) could recall >=1 child with pulmonary embolism. Approximately one quarter (23%) (95% CI, 18%-27%) of all respondents reported never using mechanical prophylaxis and almost one half (45%) (95% CI, 40%-50%) of respondents reported never using pharmacologic prophylaxis against VTE in children. Only 16% (95% CI, 12%-20%) of the respondents had a thromboprophylaxis protocol for pediatric patients. Respondent characteristics such as being in clinical practice <5 years (P=0.01) and having a surgical volume of <100 cases/y (P=0.03) were associated with a lower likelihood of encountering a pediatric patient with VTE. CONCLUSIONS: More than half of responding active POSNA members reported having come across at least 1 case of VTE among pediatric patients during their practice. The routine use of VTE prophylaxis for children is uncommon among pediatric orthopaedists. Further studies aimed at determining the prevalence of VTE and developing specific guidelines for prophylaxis among pediatric patients seeking orthopaedic care are warranted. LEVEL OF EVIDENCE: IV. PMID- 23934095 TI - Gas/liquid sensing via chemotaxis of Euglena cells confined in an isolated micro aquarium. AB - We demonstrate on-chip gas/liquid sensing by using the chemotaxis of live bacteria (Euglena gracilis) confined in an isolated micro-aquarium, and gas/liquid permeation through porous polydimethylsiloxane (PDMS). The sensing chip consisted of one closed micro-aquarium and two separated bypass microchannels along the perimeter of the micro-aquarium. Test gas/liquid and reference samples were introduced into the two individual microchannels separately, and the gas/liquid permeated through the PDMS walls and dissolved in the micro-aquarium water, resulting in a chemical concentration gradient in the micro-aquarium. By employing the closed micro-aquarium isolated from sample flows, we succeeded in measuring the chemotaxis of Euglena for a gas substance quantitatively, which cannot be achieved with the conventional flow-type or hydro gel-type microfluidic devices. We found positive (negative) chemotaxis for CO2 concentrations below (above) 15%, with 64 ppm as the minimum concentration affecting the cells. We also observed chemotaxis for ethanol and H2O2. By supplying culture medium via the microchannels, the Euglena culture remained alive for more than 2 months. The sensing chip is thus useful for culturing cells and using them for environmental toxicity/nutrition studies by monitoring their motion. PMID- 23934096 TI - Optical generation of excitonic valley coherence in monolayer WSe2. AB - As a consequence of degeneracies arising from crystal symmetries, it is possible for electron states at band-edges ('valleys') to have additional spin-like quantum numbers. An important question is whether coherent manipulation can be performed on such valley pseudospins, analogous to that implemented using true spin, in the quest for quantum technologies. Here, we show that valley coherence can be generated and detected. Because excitons in a single valley emit circularly polarized photons, linear polarization can only be generated through recombination of an exciton in a coherent superposition of the two valley states. Using monolayer semiconductor WSe2 devices, we first establish the circularly polarized optical selection rules for addressing individual valley excitons and trions. We then demonstrate coherence between valley excitons through the observation of linearly polarized luminescence, whose orientation coincides with that of the linearly polarized excitation, for any given polarization angle. In contrast, the corresponding photoluminescence from trions is not observed to be linearly polarized, consistent with the expectation that the emitted photon polarization is entangled with valley pseudospin. The ability to address coherence, in addition to valley polarization, is a step forward towards achieving quantum manipulation of the valley index necessary for coherent valleytronics. PMID- 23934097 TI - Quantum interference in plasmonic circuits. AB - Surface plasmon polaritons (plasmons) are a combination of light and a collective oscillation of the free electron plasma at metal/dielectric interfaces. This interaction allows subwavelength confinement of light beyond the diffraction limit inherent to dielectric structures. As a result, the intensity of the electromagnetic field is enhanced, with the possibility to increase the strength of the optical interactions between waveguides, light sources and detectors. Plasmons maintain non-classical photon statistics and preserve entanglement upon transmission through thin, patterned metallic films or weakly confining waveguides. For quantum applications, it is essential that plasmons behave as indistinguishable quantum particles. Here we report on a quantum interference experiment in a nanoscale plasmonic circuit consisting of an on-chip plasmon beamsplitter with integrated superconducting single-photon detectors to allow efficient single plasmon detection. We demonstrate a quantum-mechanical interaction between pairs of indistinguishable surface plasmons by observing Hong Ou-Mandel (HOM) interference, a hallmark non-classical interference effect that is the basis of linear optics-based quantum computation. Our work shows that it is feasible to shrink quantum optical experiments to the nanoscale and offers a promising route towards subwavelength quantum optical networks. PMID- 23934098 TI - ARSH 1: Reproductive and sexual health problems of adolescents and young adults: a cross sectional community survey on knowledge, attitude and practice. AB - OBJECTIVE: To understand the problems faced and the difference in knowledge, attitude and practice of young people across the age group of 10-24 y on reproductive and sexual health issues and to get their suggestions regarding adolescent care services. METHODS: This cross sectional community survey involving three districts in Kerala was conducted among adolescents and young adults of 10-24 y using a population proportion to sample size technique. RESULTS: The main problems faced by the young people between 10 and 24 y of age were financial, substance abuse in family, poor academic performance, difference of opinion, disease in self/family, mental problems, lack of talent, strict parents, difficulty in mingling, love failure, broken family, loneliness and problems at school/office in the descending order. As the age advances higher percentage of both boys (43.4%) and girls (61.7%) discuss reproductive sexual health issues among themselves. There was a statistically significant difference in personal hygiene practices like changing napkins/cloths more than once a day (94.3%), cleaning genital organs with soap every day (71.7%), washing after urination (69.2%), washing from front to back after defecation (62.2%) and washing hands with soap after defecation (73.2%) between 10-14, 15-19, and 20-24 y age group with higher percentages in the older groups. In order to make the service more useful, more of the older group participants suggested giving information on adolescent services to parents, adolescents and society as a whole by creating better societal acceptance and keeping confidentiality in service delivery. CONCLUSIONS: This study has shown an overall inadequacy in reproductive health knowledge in all age groups, but increasing knowledge gain and better attitude and practices on reproductive and sexual health as the age increases. The suggestions made by the group regarding need for adolescent reproductive sexual health (ARSH) and counseling services with privacy and confidentiality ensured, is useful for planning ARSH services under National Rural Health Mission. PMID- 23934099 TI - ARSH 9: Lower reproductive tract infections among unmarried girls (15-24 y) - a clinic based validation study. AB - OBJECTIVE: To compare clinical and laboratory diagnosis of lower reproductive tract infections (RTIs) in a clinic setting, among unmarried adolescents and young adults between 15 and 24 y and to validate clinical diagnosis of lower RTIs against the microbiological diagnosis as gold standard. METHODS: A structured questionnaire was administered among the participants to assess symptoms of lower reproductive tract infections and associated known risk factors. A qualified gynecologist conducted the visual inspection of the external genitalia for any clinical evidence of lower RTIs and took cotton tipped swab from the vulva (outside the hymen) for laboratory examination. The swabs were examined by a qualified Laboratory Technician for evidence of candidiasis, and bacterial vaginosis. RESULTS: Out of the total of 427 unmarried girls enrolled in the study, 344 (80.6%) belonged to the age group 15-19 y and 83 (19.4%) to 20-24 y. The results of this clinic based study validating clinical diagnosis against laboratory diagnosis as gold standard have shown 62.69% sensitivity, 97.78% specificity, 0.76 positive predictive value, 0.96 negative predictive value and 92.27 overall accuracy. CONCLUSIONS: The results of this clinic based study on unmarried adolescent lower reproductive tract infections validating clinical diagnosis against laboratory diagnosis as gold standard have shown a high 0.96 negative predictive value, suggesting that external genital examination is enough to rule out lower reproductive tract infections among unmarried adolescents. PMID- 23934094 TI - Of mice and men: molecular genetics of congenital heart disease. AB - Congenital heart disease (CHD) affects nearly 1 % of the population. It is a complex disease, which may be caused by multiple genetic and environmental factors. Studies in human genetics have led to the identification of more than 50 human genes, involved in isolated CHD or genetic syndromes, where CHD is part of the phenotype. Furthermore, mapping of genomic copy number variants and exome sequencing of CHD patients have led to the identification of a large number of candidate disease genes. Experiments in animal models, particularly in mice, have been used to verify human disease genes and to gain further insight into the molecular pathology behind CHD. The picture emerging from these studies suggest that genetic lesions associated with CHD affect a broad range of cellular signaling components, from ligands and receptors, across down-stream effector molecules to transcription factors and co-factors, including chromatin modifiers. PMID- 23934100 TI - Common hematological disorders in children. AB - It is common for primary care physicians to be faced with children with hematological disorders in everyday practice. The article seeks to provide realistic information for the first-contact physician in handling common hematological diseases in children. Practical step-wise approach to understanding and investigating anemia and bleeding disorders is illustrated. Requirement of iron in normal children and management of iron deficiency anemia (IDA) and thalassemia is explained. The gold standard for IDA continues to be ferrous sulphate which has good bioavailability and is inexpensive. There is emerging concept of delayed clamping of umbilical cord at birth, particularly in regions with widespread IDA, to augment iron stores in infancy. Typical case scenarios of children with immune thrombocytopenia (ITP) and hemophilia are provided to facilitate the understanding of management in day to day practice. The vital role of the medical practitioner in shared care of patients with acute lymphoblastic leukemia and febrile neutropenia is emphasized. A risk based treatment algorithm for febrile neutropenia is provided. PMID- 23934101 TI - Successful hypothermia treatment of hypoxic-ischemic encephalopathy in a neonate with epidermolysis bullosa. AB - Despite advances in the neonatal care, hypoxic ischemic encephalopathy in late preterm and term infants remains an important cause of morbidity and mortality. There is lack of data on the application of therapeutic hypothermia in the existence of severe skin lesions. Epidermolysis bullosa is a rare group of inherited conditions which causes blisters in skin and mucosal membranes. In this report, the authors describe a successful whole-body hypothermia treatment of severe hypoxic ischemic encephalopathy in a term newborn with dystrophic epidermolysis bullosa. They observed that therapeutic hypothermia may also be given in newborns with dystrophic epidermolysis bullosa without any complications. PMID- 23934102 TI - A label-free immunosensor for determination of salbutamol based on localized surface plasmon resonance biosensing. AB - We developed a localized surface plasmon resonance (LSPR)-based label-free optical biosensor for detection of salbutamol (Sal). Hollow gold nanoparticles (HGNs) which deposited on transparent indium tin oxide (ITO) film coated glass was used to sensing platform. Antibody against Sal was immobilized on HGN surface to recognize the target Sal molecules. Thus, the change of LSPR peak was proportional to the concentration of Sal in the solution. The experimental results demonstrated that the LSPR immunosensor possessed a good sensitivity and a high selectivity for Sal. The detection range for Sal was from 0.05 to 0.8 MUg/mL with a correlation coefficient of 0.996. The biosensor was applied for the detection for Sal in spiked animal feed and pork liver samples, and the recoveries were in the range of 97-105 %. Therefore, it is expected that this approach may offer a new method in designing label-free LSPR immunosensor for detection of small molecules. PMID- 23934103 TI - Lanthanum-induced neurotoxicity: solving the riddle of its involvement in cognitive impairment? AB - The conclusion of a series of recent reports highlights the significant neurotoxic effects that rare earth elements, such as lanthanum (La), can have during neurodevelopment. These findings are, herein, combined and presented using a simplified schematic overview that provides a putative solution to the riddle of La-induced cognitive impairment. Our commentary also highlights potential targets for further investigations into the mechanisms which underpin La-induced neurotoxicity, with a focus on the crucial role of the hippocampus. Within this context, a central role for the cyclic-adenosine monophosphate signalling pathway is proposed. PMID- 23934104 TI - Validating the 5Fs mnemonic for cholelithiasis: time to include family history. AB - BACKGROUND: The time-honoured mnemonic of '5Fs' is a reminder to students that patients with upper abdominal pain and who conform to a profile of 'fair, fat, female, fertile and forty' are likely to have cholelithiasis. We feel, however, that a most important 'F'-that for 'family history'-is overlooked and should be introduced to enhance the value of a useful aide memoire. METHODS: To assess the usefulness of each of the existing factors of a popular mnemonic, 398 patients admitted with upper abdominal pain between March 2009 and April 2010 were studied. The clinical features expressed in the cholelithiasis mnemonic in patients with sonographic evidence of cholelithiasis were compared with those of patients without. FINDINGS: In the cholelithiasis group, significantly more patients were women (150/198 (75.8%) vs 111/200 (55.5%), p<0.001), fair (144/198 (62.9%) vs 54/200 (32.1%), (p<0.001)), fertile (135/198 (68.2%) vs 50/200 (25%) (p<0.001)) and had a body mass index >30 (56/198 (28.3%) vs 19/200 (9.5%) (p<0.001)) compared with controls; but age over 40 years did not predict cholelithiasis (82/198 (41.4%) vs 79/200 (39.5%) (p=0.697)). In the cholelithiasis group, 78/198 (39.4%) had a family history in at least one first degree relative, compared with 27/200 (13.5%) of controls, (p<0.001). Where the phenotypic elements of the history existed in combination, that patient was found to be at an increased risk of cholelithiasis. INTERPRETATION: Our study found that the validated 'students' 5Fs' mnemonic retains a role in clinical diagnosis of patients suspected of cholelithiasis but the factor 'familial' should be substituted for 'forty' in recognition of the role of inheritance and the changing demographics of gallstone incidence. PMID- 23934105 TI - Isolation and characterization of a thermostable esterase from a metagenomic library. AB - A novel esterase gene was isolated by functional screening of a metagenomic library prepared from an activated sludge sample. The gene (est-XG2) consists of 1,506 bp with GC content of 74.8 %, and encodes a protein of 501 amino acids with a molecular mass of 53 kDa. Sequence alignment revealed that Est-XG2 shows a maximum amino acid identity (47 %) with the carboxylesterase from Thermaerobacter marianensis DSM 12885 (YP_004101478). The catalytic triad of Est-XG2 was predicted to be Ser192-Glu313-His412 with Ser92 in a conserved pentapeptide (GXSXG), and further confirmed by site-directed mutagenesis. Phylogenetic analysis suggested Est-XG2 belongs to the bacterial lipase/esterase family VII. The recombinant Est-XG2, expressed and purified from Escherichia coli, preferred to hydrolyze short and medium length p-nitrophenyl esters with the best substrate being p-nitrophenyl acetate (K(m) and k(cat) of 0.33 mM and 36.21 s-1, respectively). The purified enzyme also had the ability to cleave sterically hindered esters of tertiary alcohols. Biochemical characterization of Est-XG2 revealed that it is a thermophilic esterase that exhibits optimum activity at pH 8.5 and 70 degrees C. Est-XG2 had moderate tolerance to organic solvents and surfactants. The unique properties of Est-XG2, high thermostability and stability in the presence of organic solvents, may render it a potential candidate for industrial applications. PMID- 23934106 TI - Recombinant TIMP-1-GPI inhibits growth of fibrosarcoma and enhances tumor sensitivity to doxorubicin. AB - Fibrosarcomas show a high incidence of recurrence and general resistance to apoptosis. Limiting tumor regrowth and increasing their sensitivity to chemotherapy and apoptosis represent key issues in developing more effective treatments of these tumors. Tissue inhibitor of metalloproteinase 1 (TIMP-1) broadly blocks matrix metalloproteinase (MMP) activity and can moderate tumor growth and metastasis. We previously described generation of a recombinant fusion protein linking TIMP-1 to glycosylphophatidylinositol (GPI) anchor (TIMP-1-GPI) that efficiently directs the inhibitor to cell surfaces. In the present report, we examined the effect of TIMP-1-GPI treatment on fibrosarcoma biology. Exogenously applied TIMP-1-GPI efficiently incorporated into surface membranes of human HT1080 fibrosarcoma cells. It inhibited their proliferation, migration, suppressed cancer cell clone formation, and enhanced apoptosis. Doxorubicin, the standard chemotherapeutic drug for fibrosarcoma, was tested alone or in combination with TIMP-1-GPI. In parallel, the influence of treatment on HT1080 side population cells (exhibiting tumor stem cell-like characteristics) was investigated using Hoechst 33342 staining. The sequential combination of TIMP-1 GPI and doxorubicin showed more than additive effects on apoptosis, while TIMP-1 GPI treatment alone effectively decreased "stem-cell like" side population cells of HT1080. TIMP-1-GPI treatment was validated using HT1080 fibrosarcoma murine xenografts. Growing tumors treated with repeated local injections of TIMP-1-GPI showed dramatically inhibited fibrosarcoma growth and reduced angiogenesis. Intraoperative peritumoral application of GPI-anchored TIMP-1 as an adjuvant to surgery may help maintain tumor control by targeting microscopic residual fibrosarcoma cells and increasing their sensitivity to chemotherapy. PMID- 23934107 TI - Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy. AB - The blood system is maintained by a small pool of haematopoietic stem cells (HSCs), which are required and sufficient for replenishing all human blood cell lineages at millions of cells per second throughout life. Megakaryocytes in the bone marrow are responsible for the continuous production of platelets in the blood, crucial for preventing bleeding--a common and life-threatening side effect of many cancer therapies--and major efforts are focused at identifying the most suitable cellular and molecular targets to enhance platelet production after bone marrow transplantation or chemotherapy. Although it has become clear that distinct HSC subsets exist that are stably biased towards the generation of lymphoid or myeloid blood cells, we are yet to learn whether other types of lineage-biased HSC exist or understand their inter-relationships and how differently lineage-biased HSCs are generated and maintained. The functional relevance of notable phenotypic and molecular similarities between megakaryocytes and bone marrow cells with an HSC cell-surface phenotype remains unclear. Here we identify and prospectively isolate a molecularly and functionally distinct mouse HSC subset primed for platelet-specific gene expression, with enhanced propensity for short- and long-term reconstitution of platelets. Maintenance of platelet biased HSCs crucially depends on thrombopoietin, the primary extrinsic regulator of platelet development. Platelet-primed HSCs also frequently have a long-term myeloid lineage bias, can self-renew and give rise to lymphoid-biased HSCs. These findings show that HSC subtypes can be organized into a cellular hierarchy, with platelet-primed HSCs at the apex. They also demonstrate that molecular and functional priming for platelet development initiates already in a distinct HSC population. The identification of a platelet-primed HSC population should enable the rational design of therapies enhancing platelet output. PMID- 23934108 TI - Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF driven cancers. AB - KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. Conversely, potent inhibition of active, phosphorylated MEK is required for strong inhibition of the MAPK pathway in BRAF mutant tumours, resulting in superior efficacy in this genotype with GDC-0973 (also known as cobimetinib), a MEK inhibitor currently in phase III clinical trials. Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK. These inhibitors are currently being evaluated in clinical trials to determine whether improvements in therapeutic index within KRAS versus BRAF preclinical models translate to improved clinical responses in patients. PMID- 23934109 TI - Evolutionary implications of a third lymphocyte lineage in lampreys. AB - Jawed vertebrates (gnathostomes) and jawless vertebrates (cyclostomes) have different adaptive immune systems. Gnathostomes use T- and B-cell antigen receptors belonging to the immunoglobulin superfamily. Cyclostomes, the lampreys and hagfish, instead use leucine-rich repeat proteins to construct variable lymphocyte receptors (VLRs), two types of which, VLRA and VLRB, are reciprocally expressed by lymphocytes resembling gnathostome T and B cells. Here we define another lineage of T-cell-like lymphocytes that express the recently identified VLRC receptors. Both VLRC(+) and VLRA(+) lymphocytes express orthologues of genes that gnathostome gammadelta and alphabeta T cells use for their differentiation, undergo VLRC and VLRA assembly and repertoire diversification in the 'thymoid' gill region, and express their VLRs solely as cell-surface proteins. Our findings suggest that the genetic programmes for two primordial T-cell lineages and a prototypic B-cell lineage were already present in the last common vertebrate ancestor approximately 500 million years ago. We propose that functional specialization of distinct T-cell-like lineages was an ancient feature of a primordial immune system. PMID- 23934110 TI - Interactome map uncovers phosphatidylserine transport by oxysterol-binding proteins. AB - The internal organization of eukaryotic cells into functionally specialized, membrane-delimited organelles of unique composition implies a need for active, regulated lipid transport. Phosphatidylserine (PS), for example, is synthesized in the endoplasmic reticulum and then preferentially associates--through mechanisms not fully elucidated--with the inner leaflet of the plasma membrane. Lipids can travel via transport vesicles. Alternatively, several protein families known as lipid-transfer proteins (LTPs) can extract a variety of specific lipids from biological membranes and transport them, within a hydrophobic pocket, through aqueous phases. Here we report the development of an integrated approach that combines protein fractionation and lipidomics to characterize the LTP-lipid complexes formed in vivo. We applied the procedure to 13 LTPs in the yeast Saccharomyces cerevisiae: the six Sec14 homology (Sfh) proteins and the seven oxysterol-binding homology (Osh) proteins. We found that Osh6 and Osh7 have an unexpected specificity for PS. In vivo, they participate in PS homeostasis and the transport of this lipid to the plasma membrane. The structure of Osh6 bound to PS reveals unique features that are conserved among other metazoan oxysterol binding proteins (OSBPs) and are required for PS recognition. Our findings represent the first direct evidence, to our knowledge, for the non-vesicular transfer of PS from its site of biosynthesis (the endoplasmic reticulum) to its site of biological activity (the plasma membrane). We describe a new subfamily of OSBPs, including human ORP5 and ORP10, that transfer PS and propose new mechanisms of action for a protein family that is involved in several human pathologies such as cancer, dyslipidaemia and metabolic syndrome. PMID- 23934112 TI - Preparation of pre-cut corneas from fresh donated whole globes for Descemet's stripping automated keratoplasty: 3-year results at the Central Eye Bank of Iran. AB - To describe the technique and the results of the preparation of pre-cut corneas for Descemet's stripping automated endothelial keratoplasty (DSAEK) during a 3 year period at the Central Eye Bank of Iran (CEBI). The method of preparation of pre-cut corneas from donated whole globes at the CEBI is described and the frequency and percentage of pre-cut corneas prepared for DSAEK, between April 2009 and March 2012, are specified. Moreover, post-operative reports are reviewed for any complaints about using pre-cut tissues for DSAEK. Out of the 1,518 donated whole globes appropriate for DSAEK, 1,478 (97.4 %) pre-cut corneas were successfully prepared. The method of preparation failed in 40 (2.6 %) cases. Based on the eye bank post-operative reports, thickness of pre-cut tissues for DSAEK was deemed unacceptable in only 6 (0.4 %) cases prior to surgery; five of these were too thick and one was too thin. Preparation of pre-cut corneas, for DSAEK from donated whole globes, in the CEBI is a safe and easy method, with very good preservation of endothelial cells after the preparation of the pre-cut corneas and reduced risks from corneal manipulation. PMID- 23934113 TI - Treatment of visceral aneurysm using multilayer stent: two-year follow-up results in five consecutive patients. AB - PURPOSE: The present study was performed to analyze the midterm results (five consecutive patients, 2-year follow-up) of the endovascular management of visceral artery aneurysms using the Cardiatis Multilayer Flow Modulator (CMFM) (Cardiatis, Isnes, Belgium), a self-expandable stent. MATERIALS AND METHODS: From August 2009 to January 2011, we implanted five CMFMs in five patients (all men; mean age 73 years) to treat two common hepatic artery aneurysms, one celiac trunk aneurysm, one splenic artery aneurysm, and one superior mesenteric artery aneurysm (diameter 25-81 mm). The primary end point was technical success. The secondary end point was stent patency, absence of aneurysm rupture or reperfusion, and shrinking of the sac at 6-, 12-, and 24-month follow-up using computed tomography angiography. Follow-up ranged from 24 to 48 months (mean 31.2). RESULTS: Technical success was achieved in all patients. Complete exclusion of the aneurysm with sac shrinking was achieved in two patients. Two stents became occluded at 6- and 24-month follow-up, respectively; both patients were asymptomatic and were not retreated. One patient developed sac reperfusion due to incomplete aneurysm exclusion. CONCLUSION: Long-term results in a wider population are needed to validate the effectiveness of the CMFM. PMID- 23934114 TI - Safety and efficacy of a circumferential clip-based vascular closure device in cirrhotic and coagulopathic patients with hepatocellular carcinoma after doxorubicin drug-eluting beads transarterial chemoembolization. AB - PURPOSE: This study was designed to investigate the safety and efficacy of the circumferential clip-based (StarClose) vascular closure device (VCD) in coagulopathic and cirrhotic patients with hepatocellular carcinoma (HCC) after doxorubicin drug-eluting beads transarterial chemoembolization (DEB TACE). METHODS: Consecutive cirrhotic patients with HCC, who underwent DEB TACE from November 2009 to February 2012, were included in the study. Based on platelet count (PC) and international normalized ratio (INR), these patients were further divided into group A (PC >= 150 k/dl), B (PC = 50-149 k/dl), C (PC < 50 k/dl), D (INR <= 1.2), E (INR = 1.21-1.5), and F (INR > 1.5). StarClose VCD was attempted in each case. Technical success was defined as complete hemostasis achieved within 3 min after the closure. Periprocedural complications were studied. RESULTS: A total of 350 DEB TACEs were performed in 195 patients (mean age 61.6 years, SD 9.1). StarClose VCD was attempted in all cases. StarClose device was not deployed in 2.2 % (8/350) of cases due to improper femoral punctures and severe atherosclerotic disease. Technical success rate was 97.1 % (332/342). All groups (A-F) were similar in age, sex, body mass index, and technical success rate (P > 0.05). Minor complications occurred after 1.8 % (6/342) of cases. VCD was repeatedly used in 92 patients with 96.2 % (230/239) of technical success rate. There was no major complication related to VCD. There was no access site infection, leg ischemia, and pseudoaneurysm or symptomatic groin hematoma. CONCLUSIONS: Circumferential clip based (StarClose) arterial closure device achieved effective and rapid hemostasis after DEB TACE with minimal complications in cirrhotic patients with HCC and coagulopathy. StarClose deployment and reaccess in patients with PC < 50 k/dl and INR > 1.2 are safe and effective. PMID- 23934111 TI - De novo mutations in epileptic encephalopathies. AB - Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ~4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 * 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 * 10(-10) and P = 7.8 * 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10( 8)), as has been reported previously for autism spectrum disorders. PMID- 23934115 TI - Ultrasound-guided transhepatic radiofrequency ablation of renal tumors: a safe and effective approach. AB - PURPOSE: This study was designed to determine the feasibility and safety of ultrasound-guided transhepatic radiofrequency ablation (RFA) of masses in the right kidney. METHODS: Between June 2001 and December 2011, 18 patients who underwent transhepatic renal RFA procedures to treat 19 tumors were retrospectively identified. Complications (Clavien-Dindo classification system) and local tumor control were evaluated for all patients. RESULTS: Median maximal diameter of the treated renal tumors was 1.9 (range 1.1-4.3) cm. No major complication developed during any of the procedures. No hepatic tumor seeding was identified during imaging follow-up. There was a single technical failure (5.3%). Median cross-sectional imaging follow-up was 28 (range 3-121) months. Primary technique failure (local recurrence) occurred in 1 of the 16 tumors with follow up imaging (5.3%). CONCLUSIONS: Percutaneous ultrasound-guided transhepatic RFA of renal neoplasms is technically feasible, effective, and associated with a low rate of complications. The transhepatic approach may allow safe ablation of renal tumors that would otherwise be difficult to treat. PMID- 23934116 TI - Th1 not Th17 cells drive spontaneous MS-like disease despite a functional regulatory T cell response. AB - Multiple sclerosis is considered a disease of complex autoimmune etiology, yet there remains a lack of consensus as to specific immune effector mechanisms. Recent analyses of experimental autoimmune encephalomyelitis, the common mouse model of multiple sclerosis, have investigated the relative contribution of Th1 and Th17 CD4 T cell subsets to initial autoimmune central nervous system (CNS) damage. However, inherent in these studies are biases influenced by the adjuvant and toxin needed to break self-tolerance. We investigated spontaneous CNS disease in a clinically relevant, humanized, T cell receptor transgenic mouse model. Mice develop spontaneous, ascending paralysis, allowing unbiased characterization of T cell immunity in an HLA-DR15-restricted T cell repertoire. Analysis of naturally progressing disease shows that IFNgamma(+) cells dominate disease initiation with IL-17(+) cells apparent in affected tissue only once disease is established. Tregs accumulate in the CNS but are ultimately ineffective at halting disease progression. However, ablation of Tregs causes profound acceleration of disease, with uncontrolled infiltration of lymphocytes into the CNS. This synchronous, severe disease allows characterization of the responses that are deregulated in exacerbated disease: the correlation is with increased CNS CD4 and CD8 IFNgamma responses. Recovery of the ablated Treg population halts ongoing disease progression and Tregs extracted from the central nervous system at peak disease are functionally competent to regulate myelin specific T cell responses. Thus, in a clinically relevant mouse model of MS, initial disease is IFNgamma driven and the enhanced central nervous system responses unleashed through Treg ablation comprise IFNgamma cytokine production by CD4 and CD8 cells, but not IL-17 responses. PMID- 23934117 TI - LOX-1, a new marker of risk and prognosis in coronary artery disease? AB - The development of atherosclerosis is caused by the accumulation of lipid, inflammatory cytokine production, and the large amount of inflammatory cells in the arterial wall. It is now established that the presence of oxidized low density lipoproteins (ox-LDL) has an important role in the pathogenesis of the disease. There are many scavenger receptors for ox-LDL, among which LOX-1 seems to be important for the induction of endothelial dysfunction and the other subsequent events that lead to the formation of atheromatous plaque. Our findings indicate the presence of a regulatory role induced by the presence of ox-LDL on LOX-1 through the amplification of IL-6 synthesis. This mechanism contributes to the upregulation of the ORL-1 gene expression in presence of risk factors. Many authors have shown the possibility to use LOX-1 as a good marker for the diagnosis and prognosis of coronary artery disease because it is easy to measure and more sensitive than other markers commonly used in the routine of laboratory medicine. PMID- 23934118 TI - Response of rat lung tissue to short-term hyperoxia: a proteomic approach. AB - An inspiratory oxygen fraction of 1.0 is often required to avoid hypoxia both in many pre- and in-hospital situations. On the other hand, hyperoxia may lead to deleterious consequences (cell growth inhibition, inflammation, and apoptosis) for numerous tissues including the lung. Whereas clinical effects of hyperoxic lung injury are well known, its impact on the expression of lung proteins has not yet been evaluated sufficiently. The aim of this study was to analyze time dependent alterations of protein expression in rat lung tissue after short-term normobaric hyperoxia (NH). After approval of the local ethics committee for animal research, N = 36 Wistar rats were randomized into six different groups: three groups with NH with exposure to 100 % oxygen for 3 h and three groups with normobaric normoxia (NN) with exposure to room air (21 % oxygen). After the end of the experiments, lungs were removed immediately (NH0 and NN0), after 3 days (NH3 and NN3) and after 7 days (NH7 and NN7). Lung lysates were analyzed by two dimensional gel electrophoresis (2D-GE) followed by peptide mass fingerprinting using mass spectrometry. Statistical analysis was performed with Delta 2D (DECODON GmbH, Greifswald, Germany; ANOVA, Bonferroni correction, p < 0.01). Biological functions of differential regulated proteins were studied using functional network analysis (Ingenuity Pathways Analysis, IPA). pO2 was significantly higher in NH-groups compared to NN-groups (581 +/- 28 vs. 98 +/- 12 mmHg; p < 0.01), all other physiological parameters did not differ. Expression of 14 proteins were significantly altered: two proteins were up-regulated and 12 proteins were down-regulated. Even though NH was comparatively short termed, significant alterations in lung protein expression could be demonstrated up to 7 days after hyperoxia. The identified proteins indicate an association with cell growth inhibition, regulation of apoptosis, and approval of structural cell integrity. PMID- 23934119 TI - Preeclampsia: a link between trophoblast dysregulation and an antiangiogenic state. AB - A 24-year-old nulliparous woman developed mildly elevated blood pressure (140 150/90-100 mmHg) without proteinuria (20 mg protein in a 24-hour urine collection) at 306/7 weeks of gestation. The fetus was small for gestational age (estimated fetal weight under the fifth percentile). At 325/7 weeks of gestation, the patient complained of epigastric pain, blood pressure was 180/110 mmHg, proteinuria was documented (780 mg protein in a 24-hour urine collection), schistocytes were detected in the peripheral smear, platelet count was 60,000 cells per mm3, and serum glutamic oxaloacetic transaminase was 234 U/l. The patient was diagnosed with severe preeclampsia/HELLP syndrome. Antenatal steroids were administered to induce fetal lung maturity. She and her family want to know the causes of this condition, what treatment is available, and whether there are any long-term implications of this diagnosis. PMID- 23934122 TI - Linking MLL and the HGF-MET signaling pathway in liver cancer. AB - Mixed-lineage leukemia (MLL; also known as myeloid/lymphoid), the human homolog of trithorax in Drosophila, is a transcriptional coactivator that plays an essential role during early development and hematopoiesis. Furthermore, MLL is critically involved in the epigenetic regulation of cell cycle, senescence, DNA damage, and stem cell self-renewal. Chromosomal aberrations of MLL in acute leukemias are well documented, but the role of this gene in solid malignancies remains unclear. In this issue of the JCI, Takeda et al. describe a novel epigenetic link between MLL and the HGF-MET signaling pathway conferring invasive and metastatic properties to hepatocellular carcinoma cells. PMID- 23934124 TI - alpha-Ketoglutarate regulates acid-base balance through an intrarenal paracrine mechanism. AB - Paracrine communication between different parts of the renal tubule is increasingly recognized as an important determinant of renal function. Previous studies have shown that changes in dietary acid-base load can reverse the direction of apical alpha-ketoglutarate (alphaKG) transport in the proximal tubule and Henle's loop from reabsorption (acid load) to secretion (base load). Here we show that the resulting changes in the luminal concentrations of alphaKG are sensed by the alphaKG receptor OXGR1 expressed in the type B and non-A-non-B intercalated cells of the connecting tubule (CNT) and the cortical collecting duct (CCD). The addition of 1 mM alphaKG to the tubular lumen strongly stimulated Cl(-)-dependent HCO(3)(-) secretion and electroneutral transepithelial NaCl reabsorption in microperfused CCDs of wild-type mice but not Oxgr1(-/-) mice. Analysis of alkali-loaded mice revealed a significantly reduced ability of Oxgr1( /-) mice to maintain acid-base balance. Collectively, these results demonstrate that OXGR1 is involved in the adaptive regulation of HCO(3)(-) secretion and NaCl reabsorption in the CNT/CCD under acid-base stress and establish alphaKG as a paracrine mediator involved in the functional coordination of the proximal and the distal parts of the renal tubule. PMID- 23934123 TI - HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma. AB - HGF signals through its cognate receptor, MET, to orchestrate diverse biological processes, including cell proliferation, cell fate specification, organogenesis, and epithelial-mesenchymal transition. Mixed-lineage leukemia (MLL), an epigenetic regulator, plays critical roles in cell fate, stem cell, and cell cycle decisions. Here, we describe a role for MLL in the HGF-MET signaling pathway. We found a shared phenotype among Mll(-/-), Hgf(-/-), and Met(-/-) mice with common cranial nerve XII (CNXII) outgrowth and myoblast migration defects. Phenotypic analysis demonstrated that MLL was required for HGF-induced invasion and metastatic growth of hepatocellular carcinoma cell lines. HGF-MET signaling resulted in the accumulation of ETS2, which interacted with MLL to transactivate MMP1 and MMP3. ChIP assays demonstrated that activation of the HGF-MET pathway resulted in increased occupancy of the MLL-ETS2 complex on MMP1 and MMP3 promoters, where MLL trimethylated histone H3 lysine 4 (H3K4), activating transcription. Our results present an epigenetic link between MLL and the HGF-MET signaling pathway, which may suggest new strategies for therapeutic intervention. PMID- 23934125 TI - Antigen-activated dendritic cells ameliorate influenza A infections. AB - Influenza A viruses cause significant morbidity and mortality worldwide. There is a need for alternative or adjunct therapies, as resistance to currently used antiviral drugs is emerging rapidly. We tested ligand epitope antigen presentation system (LEAPS) technology as a new immune-based treatment for influenza virus infection in a mouse model. Influenza-J-LEAPS peptides were synthesized by conjugating the binding ligand derived from the beta2 microglobulin chain of the human MHC class I molecule (J-LEAPS) with 15 to 30 amino acid-long peptides derived from influenza virus NP, M, or HA proteins. DCs were stimulated with influenza-J-LEAPS peptides (influenza-J-LEAPS) and injected intravenously into infected mice. Antigen-specific LEAPS-stimulated DCs were effective in reducing influenza virus replication in the lungs and enhancing survival of infected animals. Additionally, they augmented influenza-specific T cell responses in the lungs and reduced the severity of disease by limiting excessive cytokine responses, which are known to contribute to morbidity and mortality following influenza virus infection. Our data demonstrate that influenza-J-LEAPS-pulsed DCs reduce virus replication in the lungs, enhance survival, and modulate the protective immune responses that eliminate the virus while preventing excessive cytokines that could injure the host. This approach shows promise as an adjunct to antiviral treatment of influenza virus infections. PMID- 23934126 TI - Melanoma immunotherapy using mature DCs expressing the constitutive proteasome. AB - BACKGROUND: Many cancers, including melanoma, exclusively express constitutive proteasomes (cPs) and are unable to express immunoproteasomes (iPs). In contrast, mature DCs used for immunotherapy exclusively express iPs. Since proteasomes generate peptides presented by HLA class I molecules, we hypothesized that mature melanoma antigen-loaded DCs engineered to process antigens through cPs would be superior inducers of antimelanoma immunity in vivo. METHODS: Subjects with metastatic melanoma were vaccinated with mature DCs transfected with RNAs encoding melanoma antigens MART1, MAGE-3, gp100, and tyrosinase. These DCs were derived from monocytes that were untransfected (Arm A; n = 4), transfected with control siRNA (Arm B; n = 3), or transfected with siRNAs targeting the 3 inducible iP subunits (Arm C; n = 5). RESULTS: Vaccination stimulated antigen specific T cell responses in all subjects, which peaked after 3-4 vaccinations, but remained elevated in Arm C subjects. Also in Arm C, circulating melanoma cell levels (as detected by quantitative PCR) fell, and T cell lytic activity against autologous melanoma was induced. In HLA-A2+ subjects, CD8+ T cells that bound tetramers loaded with cP-derived melanoma antigenic peptides were found in the peripheral blood only in Arm C subjects. Of 2 subjects with active disease (both in Arm C), one had a partial clinical response, while the other, who exhibited diffuse dermal and soft tissue metastases, had a complete response. CONCLUSION: These results suggest that the efficacy of melanoma DC-based immunotherapy is enhanced when tumor antigen-loaded DCs used for vaccination express cPs. TRIAL REGISTRATION: Clinicaltrials.gov NCT00672542. FUNDING: Duke Clinical Research Institute/Duke Translational Medicine Institute, Duke Melanoma Consortium, and Duke University Department of Surgery. PMID- 23934127 TI - Maternal cholestasis during pregnancy programs metabolic disease in offspring. AB - The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring. PMID- 23934128 TI - WAVE1 mediates suppression of phagocytosis by phospholipid-derived DAMPs. AB - Clearance of invading pathogens is essential to preventing overwhelming inflammation and sepsis that are symptomatic of bacterial peritonitis. Macrophages participate in this innate immune response by engulfing and digesting pathogens, a process called phagocytosis. Oxidized phospholipids (OxPL) are danger-associated molecular patterns (DAMPs) generated in response to infection that can prevent the phagocytic clearance of bacteria. We investigated the mechanism underlying OxPL action in macrophages. Exposure to OxPL induced alterations in actin polymerization, resulting in spreading of peritoneal macrophages and diminished uptake of E. coli. Pharmacological and cell-based studies showed that an anchored pool of PKA mediates the effects of OxPL. Gene silencing approaches identified the A-kinase anchoring protein (AKAP) WAVE1 as an effector of OxPL action in vitro. Chimeric Wave1(-/-) mice survived significantly longer after infection with E. coli and OxPL treatment in vivo. Moreover, we found that endogenously generated OxPL in human peritoneal dialysis fluid from end-stage renal failure patients inhibited phagocytosis via WAVE1. Collectively, these data uncover an unanticipated role for WAVE1 as a critical modulator of the innate immune response to severe bacterial infections. PMID- 23934129 TI - Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia. AB - During human pregnancy, a subset of placental cytotrophoblasts (CTBs) differentiates into cells that aggressively invade the uterus and its vasculature, anchoring the progeny and rerouting maternal blood to the placenta. In preeclampsia (PE), CTB invasion is limited, reducing placental perfusion and/or creating intermittent flow. This syndrome, affecting 4%-8% of pregnancies, entails maternal vascular alterations (e.g., high blood pressure, proteinuria, and edema) and, in some patients, fetal growth restriction. The only cure is removal of the faulty placenta, i.e., delivery. Previously, we showed that defective CTB differentiation contributes to the placental component of PE, but the causes were unknown. Here, we cultured CTBs isolated from PE and control placentas for 48 hours, enabling differentiation and invasion. In various severe forms of PE, transcriptomics revealed common aberrations in CTB gene expression immediately after isolation, including upregulation of SEMA3B, which resolved in culture. The addition of SEMA3B to normal CTBs inhibited invasion and recreated aspects of the PE phenotype. Additionally, SEMA3B downregulated VEGF signaling through the PI3K/AKT and GSK3 pathways, effects that were observed in PE CTBs. We propose that, in severe PE, the in vivo environment dysregulates CTB gene expression; the autocrine actions of the upregulated molecules (including SEMA3B) impair CTB differentiation, invasion and signaling; and patient-specific factors determine the signs. PMID- 23934131 TI - Kaempferol inhibits IL-1beta-induced proliferation of rheumatoid arthritis synovial fibroblasts and the production of COX-2, PGE2 and MMPs. AB - Inflammatory cytokines, matrix metalloproteinases (MMPs) and cyclooxygenase (COX) 2 released from rheumatoid arthritis synovial fibroblasts (RASFs) are involved in the destruction of both articular bone and cartilage. Kaempferol has been reported to act as an antioxidant and anti-inflammatory agent by inhibiting nitric oxide synthase and COX enzymes. The aim of the present study was to determine the effects of kaempferol on the interleukin-1beta (IL-1beta)-induced proliferation of RASFs and the production of MMPs, COX and prostaglandin E2 (PGE2) by RASFs. The proliferation of the RASFs stimulated with IL-1beta and treated with/without kaempferol was evaluated by CCK-8 assay. The expression of MMPs, TIMP metallopeptidase inhibitor-1 (TIMP-1), COXs, PGE2 and that of intracellular MAPK signaling molecules, including p-ERK, p-p38, p-JNK and nuclear factor-kappaB (NF-kappaB) was examined by immunoblotting or semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and ELISA under the conditions described above. Kaempferol inhibited the proliferation of both unstimulated and IL-1beta-stimulated RASFs, as well as the mRNA and protein expression of MMP-1, MMP-3, COX-2 and PGE2 induced by IL-1beta. Kaempferol also inhibited the phosphorylation of ERK-1/2, p38 and JNK, as well as the activation of NF-kappaB induced by IL-1beta. These results indicate that kaempferol inhibits synovial fibroblast proliferation, as well as the production of and MMPs, COX-2 and PGE2, which is involved in articular inflammation and destruction in rheumatoid arthritis (RA). Our data suggest that kaempferol may be a novel therapeutic agent for the treatment of RA. PMID- 23934132 TI - Accelerated hypofractionated whole-breast irradiation with concomitant daily boost in early breast cancer. AB - OBJECTIVES: The aim of this study is to evaluate the feasibility and the related toxicity of hypofractionated whole-breast irradiation with a concomitant daily boost in early breast cancer women not eligible for accelerated partial-breast irradiation. METHODS: Twenty-seven patients received 46 Gy to the whole breast in 20 fractions/4 weeks with 2.3 Gy/fraction plus an additional concomitant daily boost of 0.4 Gy to the tumor bed, giving a total dose of 54 Gy (EQD2=60 Gy). The cosmetic outcome was assessed according to the European Organization for Research and Treatment of Cancer and Radiation Therapy Oncology Group grading system. RESULTS: Three months after the end of radiotherapy, 59.2% and 40.7% of patients showed grade 0 skin toxicity and grade 1 skin toxicity, respectively. After 6 months, 70.4% and 29.6% of patients showed grade 0 and grade 1 skin toxicity. After 1 year, grade 0 skin toxicity was found in 77.7% of the patients and grade 1 skin toxicity in 22.2% of the patients. After 18 months, grade 0 skin toxicity was found in 92.6% and grade 1 skin toxicity in 7.4% of the patients. After a median follow-up of 24 months, all patients showed excellent cosmetic results with minimal breast edema and minimal skin changes. There have been no local relapses to date. CONCLUSION: The accelerated hypofractionated schedule with a concomitant boost appears to be an acceptable alternative to the traditional longer schedule, with low local toxicity and excellent to good short-term cosmetic results, although a much longer follow-up is needed to assess the local control rate. PMID- 23934130 TI - Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure. AB - Chronic cannabis exposure can lead to cerebellar dysfunction in humans, but the neurobiological mechanisms involved remain incompletely understood. Here, we found that in mice, subchronic administration of the psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), activated cerebellar microglia and increased the expression of neuroinflammatory markers, including IL-1beta. This neuroinflammatory phenotype correlated with deficits in cerebellar conditioned learning and fine motor coordination. The neuroinflammatory phenotype was readily detectable in the cerebellum of mice with global loss of the CB1 cannabinoid receptor (CB1R, Cb1(-/-) mice) and in mice lacking CB1R in the cerebellar parallel fibers, suggesting that CB1R downregulation in the cerebellar molecular layer plays a key role in THC-induced cerebellar deficits. Expression of CB2 cannabinoid receptor (CB2R) and Il1b mRNA was increased under neuroinflammatory conditions in activated CD11b-positive microglial cells. Furthermore, administration of the immunosuppressant minocycline or an inhibitor of IL-1beta receptor signaling prevented the deficits in cerebellar function in Cb1(-/-) and THC-withdrawn mice. Our results suggest that cerebellar microglial activation plays a crucial role in the cerebellar deficits induced by repeated cannabis exposure. PMID- 23934133 TI - Emerging therapies in multiple myeloma. AB - The treatment of multiple myeloma has evolved significantly over the past 2 decades due to the use of high-dose chemotherapy and autologous stem cell transplantation, and the subsequent introduction of the immunomodulatory agents (thalidomide and lenalidomide) and the proteasome inhibitor (bortezomib). The median overall survival of multiple myeloma patients has increased significantly with patients younger than age 50 years experiencing a 10-year survival rate of around 40%. However, despite the increased effectiveness of the first-line agents, the majority of patients will eventually relapse and become drug resistant. Promising novel therapies have recently emerged and are being used to treat relapsed and refractory patients. This review will cover the clinical data regarding these emergent therapies that include new generation of proteasome inhibitors (carfilzomib, ixazomib, oprozomib, and marizomib), immunomodulatory drugs (pomalidomide), monoclonal antibodies (elotuzumab and daratumumab), signal transduction modulator (perifosine), and histone deacetylase inhibitors (vorinostat and panobinostat). PMID- 23934134 TI - Gemcitabine Adjuvant Therapy for Resected Pancreatic Cancer: A Meta-analysis. AB - Gemcitabine (GEM) is an approved treatment for unresectable pancreatic cancer; however, its role in treating resected pancreatic cancer is less clear. The aim of this study was to investigate the evidence of the role of adjuvant GEM therapy on survival in resected pancreatic cancer. Four phase III randomized trials of adjuvant GEM in patients with resected pancreatic cancer were identified and the hazard ratio (HR) for overall survival were used in this meta-analysis; 2 studies compared GEM treatment with best supportive care and 2 studies with 5 fluorouracil/folinic acid therapy. The pooled data (n=2017 patients) indicated that the overall survival data were homogenous among the studies (Q=4.371; I=31.37%; P=0. 224). The combined HR significantly favors GEM over the other treatments. The overall HR was 0.88 (range, 0. 720 to 0.940; P=0.014). The results indicate that GEM prolongs overall survival compared with other treatments after the resection of pancreatic cancer. PMID- 23934136 TI - Sleep, attention, and executive functioning in children with attention deficit/hyperactivity disorder. AB - The objective of this study was to investigate potential relationships between two measures of sleep impairments (i.e., sleep duration and sleep efficiency [SE]) and attention and executive functioning in children with attention deficit/hyperactivity disorder (ADHD). Parents of 43 children (mean age = 10 +/- 1.8 years) with ADHD completed sleep and behavioral questionnaires. Children also wore a wrist actigraph for seven nights and were subsequently assessed with the Conners' continuous performance test (CPT)-2. A significant relationship was found between lower SE and increased variability in reaction time on the CPT. Shorter sleep duration was associated with a range of executive functioning problems as reported by the parents. The relationships between sleep duration and the executive functioning measures held even after controlling for age, gender, and use of medication, but not the relationships with SE. These results suggest that sleep quantity is an important correlate of executive functioning in children with ADHD. PMID- 23934135 TI - Multiple Endocrine Disruption by the MET/ALK Inhibitor Crizotinib in Patients With Non-small Cell Lung Cancer. AB - OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogenous group of disorders that can be subclassified based upon molecular characterization. Anaplastic lymphoma kinase translocation and MET aberrations occur in a subset of NSCLC. Anaplastic lymphoma kinase/MET have been shown to be inhibited by the small molecule tyrosine kinase inhibitor crizotinib. Recently, crizotinib was shown to decrease testosterone in males. Herein, we describe the effects of crizotinib on multiple hormonal axes. MATERIALS AND METHODS: Seven consecutive patients with NSCLC who were receiving crizotinib as part of their standard care were evaluated for hormonal disruptions. RESULTS: Primary hypogonadism was detected in 4/5 of males, whereas mildly elevated prolactin was observed in 4/7 patients. Hypocalcemia was observed in 3/7 patients. Interestingly, 5/7 patients had elevated levels of insulin-like growth factor-1 (IGF-1) levels, and the remaining 2 individuals had levels that were near the upper limits of the normal range. CONCLUSIONS: Because of cellular cross-talk between MET and IGF-1 signaling, elevated IGF-1 levels induced by crizotinib treatment may have implications for long-term drug efficacy. Furthermore, this finding suggests a potential avenue of therapeutic synergy, namely coordinate inhibition of the MET and IGF-1 signaling pathways. Finally, as crizotinib has been recently approved, it is prudent to check hormone and calcium biomarkers and correct noted deficiencies for improved outcomes and quality of life. PMID- 23934138 TI - 1H, 15N, and 13C chemical shift assignments for the winged helix domains of two archeal MCM C-termini. AB - High-fidelity replication guarantees the stable inheritance of genetic information stored in the DNA of living organisms. The minichromosome maintenance (MCM) complex functions as replicative DNA-unwinding helicase and has been identified as one key player in the replication process of archea and eukarya. Despite the availability of considerable structural information on archeal MCMs, such information was missing for their C-terminal domain. In order to obtain more detailed structural information, we assigned the NMR chemical shifts for backbone and side chain nuclei for the MCM C-terminal winged helix domains of the archeal species Methanothermobacter thermautrophicus and Sulfolobus solfataricus. PMID- 23934137 TI - Tobacco smoke exposure during pregnancy increases maternal blood lead levels affecting neonate birth weight. AB - To assess the effect of lead exposure from cigarette smoke on fetal growth, blood lead concentrations were measured using inductively coupled plasma mass spectrometry in 150 healthy pregnant women. Mean lead concentrations in plasma and whole blood were significantly higher in the smoking group compared with the nonsmoking group in each trimester of pregnancy (p < 0.001). Logistic regression analysis showed the highest impact of the number of cigarettes smoked per day for serum lead concentration (beta = 0.238; p < 0.05), while in whole blood, it was duration of smoking before conception (beta = 0.297; p < 0.001). Birth weight of the smoking mothers' infants was significantly lower (mean +/- SEM, 3,192 +/- 50.8 and 3,569 +/- 49.6 g, respectively; p < 0.001) and negatively correlated with lead levels in plasma (r = -0.38; p < 0.001) and in whole blood (r = -0.27; p < 0.001). Therefore, it is suggested that smoking during pregnancy increases lead concentrations in maternal blood. Fetal exposure to low doses of lead in utero may be a serious risk factor causing lower birth weight. PMID- 23934139 TI - Solid-state NMR sequential assignments of the amyloid core of Sup35pNM. AB - Sup35pNM represents the N-terminal and middle (M) domains of the yeast Saccharomyces cerevisiae prion Sup35p. This fragment is commonly used for structural and functional studies of Sup35p. We here present a solid-state NMR study of fibrils formed by this fragment and show that sequential assignments can be obtained for the rigid and well-ordered parts of the protein using 3D spectroscopy. We describe in detail the sequential assignment of the 22 residues yielding strong, narrow signals with chemical shifts that correspond mostly to beta-sheet secondary-structured amino acids that form the fibril core. PMID- 23934140 TI - Resolution of hypertropia with correction of intermittent exotropia. AB - PURPOSE: We describe the spontaneous resolution of hypertropia in a subset of patients with preoperative exotropia and hypertropia, who underwent surgery for intermittent exotropia alone. DESIGN: This was a retrospective case series. METHODS: The charts were reviewed of 17 patients who underwent surgical correction for an intermittent exotropia, who additionally were noted on preoperative exam to have greater than 5 prism dioptres of vertical deviation in primary position. Patients were excluded if they had prior strabismus surgery, dissociated vertical deviation, and paretic or restrictive deviations. RESULTS: All patients were documented to have complete resolution of any vertical deviation in any field of gaze. This effect was noted to persist. CONCLUSIONS: We propose that the measured distance hypertropia, which is coincident with intermittent exotropia, even with the appearance of superior oblique dysfunction or inferior oblique overaction, is not created by a true vertical or cyclovertical muscle imbalance. Further, that the reduction of the hypertropia at near fixation predicts its resolution with horizontal muscle surgery. Therefore, vertical surgery should not be performed to address the coincident vertical deviation in these patients. PMID- 23934141 TI - Sources of variation in quantitative computed tomography of the lung. AB - The goal of quantitative analysis of computed tomography (CT) scans is to understand the anatomic structure that is responsible for the physiological function of the lung. The gold standard for structural analysis requires the examination of tissue, which is not practical in most studies. Quantitative CT allows valuable information on lung structure to be obtained without removal of tissue from the body, thereby aiding longitudinal studies on chronic lung diseases. This review briefly discusses CT analysis of the lung and some of the sources of variation that can cause differences in the CT metrics used for analysis of lung disease. Although there are many sources of variation, this review will show that, if the study is properly designed to take into account these variations and if the CT scanner is properly calibrated, valuable information can be obtained from CT scans that should allow us to study the pathogenesis of lung disease and the effect of treatment. PMID- 23934142 TI - Development of quantitative computed tomography lung protocols. AB - The purpose of this review article is to review the process of developing optimal computed tomography (CT) protocols for quantitative lung CT (QCT). In this review, we discuss the following important topics: QCT-derived metrics of lung disease; QCT scanning protocols; quality control; and QCT image processing software. We will briefly discuss several QCT-derived metrics of lung disease that have been developed for the assessment of emphysema, small airway disease, and large airway disease. The CT scanning protocol is one of the most important elements in a successful QCT. We will provide a detailed description of the current move toward optimizing the QCT protocol for the assessment of chronic obstructive pulmonary disorder and asthma. Quality control of CT images is also a very important part of the QCT process. We will discuss why it is necessary to use CT scanner test objects (phantoms) to provide frequent periodic checks on the CT scanner calibration to ensure precise and accurate CT numbers. We will discuss the use of QCT image processing software to segment the lung and extract the desired QCT metrics of lung disease. We will discuss the practical issues of using this software. The data obtained from the image processing software are then combined with those from other clinical examinations, health status questionnaires, pulmonary physiology, and genomics to increase our understanding of obstructive lung disease and improve our ability to design new therapies for these diseases. PMID- 23934143 TI - Expert opinion: how can quantitative CT benefit patients with COPD and idiopathic interstitial pneumonias? PMID- 23934144 TI - Solicitations in GP, nurse and pharmacist prescriber consultations: an observational study. AB - BACKGROUND: The opening solicitation is a key element of the primary care consultation as it enables patients to express their ideas, concerns and expectations that can lead to improved patient outcomes. However, in practice, this may not always occur. With nurses and pharmacists now able to prescribe, this research explored the opening solicitation in a multi-professional context. OBJECTIVE: To compare the nature, frequency and response to opening solicitations used in consultations with nurse prescribers (NPs), pharmacist prescribers (PPs) and GPs. METHODS: An observational study using audio-recordings of NP, PP and GP patient consultations in 36 primary care practices in southern England. Between 7 13 prescriber-patient consultations were recorded per prescriber. A standardized pro forma based upon previous research was used to assess recordings. RESULTS: Five hundred and thirty-three patient consultations (213 GPs, 209 NPs, 111 PPs) were audio-recorded with 51 prescribers. Across the prescribing groups, pharmacists asked fewer opening solicitations, while GPs used more open questions than NPs and PPs. The mean number of patient agenda items was 1.3 with more items in GP consultations. Patients completed their opening agenda in 20% of consultations, which was unaffected by professional seen. Redirection of the patient's agenda occurred at 24 seconds (mean). CONCLUSION: All prescribers should be encouraged to use more open questions and ask multiple solicitations throughout the consultation. This is likely to result in greater expression of patients' concerns and improved patient outcomes. PMID- 23934145 TI - Formation of superoxide anion and carbon-centered radicals by photosystem II under high light and heat stress-EPR spin-trapping study. AB - In this study, electron paramagnetic resonance spin-trapping spectroscopy was used to study the light-induced production of superoxide anion (O2 (*-)) and carbon-centered (R(*)) radicals by Photosystem II (PSII). It is evidenced here that exposure of PSII membranes to high light (2,000 MUmol photons m(-2) s(-1)) or heat (47 degrees C) treatments prior to the illumination suppressed O2 (*-) production, while R(*) was formed. Formation of R(*) in the both high light- and heat-treated PSII membranes was enhanced by DCMU. Removal of molecular oxygen by glucose/glucose oxidase/catalase system and O2 (*-) scavenging by exogenous superoxide dismutase completely suppressed carbon-centered radical formation. It is proposed here that the oxidation of polyunsaturated fatty acids and amino acids by O2 (*-) on the electron acceptor side of PSII results in the formation of R(*), known to initiate a cascade reaction leading to the lipid peroxidation and protein degradation, respectively. PMID- 23934146 TI - The differently expressed proteins in MSCs of degenerative scoliosis. AB - PURPOSE: Degenerative scoliosis (DS) is an important degenerative lumbar disease causing spinal dysfunction. The true reason or pathogenesis of DS is still unknown. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are the stem/progenitor cells of the osteoblasts. The diseases associated with osteogenesis could be caused by abnormality of the MSCs. The purpose of this study was to find the differential proteins expressed in MSCs of patients with DS. METHODS: We collected and cultured the MSCs from 12 DS patients and 12 age- and gender-matched patients with lumbar spinal stenosis. Then the MSC samples were analyzed with 2D-DIGE and MALDI-TOF-MS to find the differential proteins which were further validated by Western blot. RESULTS: We found 115 spots that were differently expressed in the MSC of DS patients with 2D-DIGE, and 44 proteins were identified from samples of DS and control using MALDI-TOF-MS. Of these proteins, PIAS2, NDUFA2, and TRIM 68, which were up-regulated in DS more than 4 times were validated by Western blot. CONCLUSIONS: The information obtained with this proteomics analysis will be useful in understanding the pathophysiology of DS. Further investigations on the functioning pathway, the specificity and the mechanism of these proteins will be carried out. PMID- 23934147 TI - Do meta-analyses reveal time-dependent differences between the clinical outcomes achieved by microfracture and autologous chondrocyte implantation in the treatment of cartilage defects of the knee? AB - PURPOSE: To test the hypothesis that autologous chondrocyte implantation (ACI) has a better treatment effect than microfracture (MF), and increasing superiority over the years, when performed under similar patient-specific and defect-specific conditions. METHODS: We scanned four electronic databases for controlled clinical trials or controlled prospective observational studies. We conducted random effects meta-analyses of equivalent data using standardized mean differences as the outcome measure of choice at 1, 2, and 5-year follow-up. We assessed heterogeneity with the I (2) index and publication bias with funnel plots and Kendall's tests. RESULTS: Our literature search revealed six study populations (nine papers) which satisfied our eligibility criteria. Overall, 399 patients aged between 16 and 60 years with 1-10 cm(2) chondral defects were available. The MF and the ACI study groups were well matched regarding patient baseline characteristics. For all papers, microfracture was performed according to Steadman, whereas three generations of ACI were applied. When all were combined, non-significant superiority of ACI over MF was revealed; surprisingly, this superiority decreased over the years. However, our meta-analyses combining solely second and third-generation ACI revealed significant standardized differences, becoming smaller over the years, but always representing a large effect. Nevertheless, our approximate estimate of the difference between the treatment effects provoked by second and third-generation ACI and by MF is not indicative of clinically relevant superiority of ACI over MF at 5-year follow-up. CONCLUSIONS: Both series of meta-analyses (combining either all ACI modifications or solely the second and third generations of ACI) suggest that the treatment effects resulting from ACI and MF converge over the years. PMID- 23934148 TI - Bidirectional processing of pri-miRNAs with branched terminal loops by Arabidopsis Dicer-like1. AB - MicroRNAs (miRNAs) originate from primary transcripts (pri-miRNAs) with characteristic stem-loop structures, and their accurate processing is required for the production of functional miRNAs. Here, using the pri-miR-166 family in Arabidopsis thaliana as a paradigm, we report the crucial role of pri-miRNA terminal loops in miRNA biogenesis. We found that multibranched terminal loops in pri-miR-166s substantially suppress miR-166 expression in vivo. Unlike canonical processing of pri-miRNAs, terminal loop-branched pri-miRNAs can be processed by Dicer-like 1 (DCL1) complexes bidirectionally from base to loop and from loop to base, resulting in productive and abortive processing of miRNAs, respectively. In both cases, DCL1 complexes canonically cut pri-miRNAs at a distance of 16-17 bp from a reference single-stranded loop region. DCL1 also adjusts processing sites toward an internal loop through its helicase domain. These results provide new insight into the poorly understood processing mechanism of pri-miRNAs with complex secondary structures. PMID- 23934150 TI - The N-terminal acetylation of Sir3 stabilizes its binding to the nucleosome core particle. AB - The N-terminal acetylation of Sir3 is essential for heterochromatin establishment and maintenance in yeast, but its mechanism of action is unknown. The crystal structure of the N-terminally acetylated BAH domain of Saccharomyces cerevisiae Sir3 bound to the nucleosome core particle reveals that the N-terminal acetylation stabilizes the interaction of Sir3 with the nucleosome. Additionally, we present a new method for the production of protein-nucleosome complexes for structural analysis. PMID- 23934149 TI - Single-cell RNA-Seq profiling of human preimplantation embryos and embryonic stem cells. AB - Measuring gene expression in individual cells is crucial for understanding the gene regulatory network controlling human embryonic development. Here we apply single-cell RNA sequencing (RNA-Seq) analysis to 124 individual cells from human preimplantation embryos and human embryonic stem cells (hESCs) at different passages. The number of maternally expressed genes detected in our data set is 22,687, including 8,701 long noncoding RNAs (lncRNAs), which represents a significant increase from 9,735 maternal genes detected previously by cDNA microarray. We discovered 2,733 novel lncRNAs, many of which are expressed in specific developmental stages. To address the long-standing question whether gene expression signatures of human epiblast (EPI) and in vitro hESCs are the same, we found that EPI cells and primary hESC outgrowth have dramatically different transcriptomes, with 1,498 genes showing differential expression between them. This work provides a comprehensive framework of the transcriptome landscapes of human early embryos and hESCs. PMID- 23934151 TI - The Mll2 branch of the COMPASS family regulates bivalent promoters in mouse embryonic stem cells. AB - Promoters of many developmentally regulated genes, in the embryonic stem cell state, have a bivalent mark of H3K27me3 and H3K4me3, proposed to confer precise temporal activation upon differentiation. Although Polycomb repressive complex 2 is known to implement H3K27 trimethylation, the COMPASS family member responsible for H3K4me3 at bivalently marked promoters was previously unknown. Here, we identify Mll2 (KMT2b) as the enzyme catalyzing H3K4 trimethylation at bivalentlymarked promoters in embryonic stem cells. Although H3K4me3 at bivalent genes is proposed to prime future activation, we detected no substantial defect in rapid transcriptional induction after retinoic acid treatment in Mll2-depleted cells. Our identification of the Mll2 complex as the COMPASS family member responsible for H3K4me3 marking bivalent promoters provides an opportunity to reevaluate and experimentally test models for the function of bivalency in the embryonic stem cell state and in differentiation. PMID- 23934152 TI - Nalpha-acetylated Sir3 stabilizes the conformation of a nucleosome-binding loop in the BAH domain. AB - In Saccharomyces cerevisiae, acetylation of the Sir3 N terminus is important for transcriptional silencing. This covalent modification promotes the binding of the Sir3 BAH domain to the nucleosome, but a mechanistic understanding of this phenomenon is lacking. By X-ray crystallography, we show here that the acetylated N terminus of Sir3 does not interact with the nucleosome directly. Instead, it stabilizes a nucleosome-binding loop in the BAH domain. PMID- 23934153 TI - Structure of the p300 catalytic core and implications for chromatin targeting and HAT regulation. AB - CBP and p300 are histone acetyltransferases (HATs) that associate with and acetylate transcriptional regulators and chromatin. Mutations in their catalytic 'cores' are linked to genetic disorders, including cancer. Here we present the 2.8-A crystal structure of the catalytic core of human p300 containing its bromodomain, CH2 region and HAT domain. The structure reveals that the CH2 region contains a discontinuous PHD domain interrupted by a RING domain. The bromodomain, PHD, RING and HAT domains adopt an assembled configuration with the RING domain positioned over the HAT substrate-binding pocket. Disease mutations that disrupt RING attachment led to upregulation of HAT activity, thus revealing an inhibitory role for this domain. The structure provides a starting point for understanding how chromatin-substrate targeting and HAT regulation are coupled and why mutations in the p300 core lead to dysregulation. PMID- 23934154 TI - Myosin II in mechanotransduction: master and commander of cell migration, morphogenesis, and cancer. AB - Mechanotransduction encompasses the role of mechanical forces in controlling cell behavior by activating signal transduction pathways. Most forces at a cellular level are caused by myosin II, which contracts and cross-links actin. Myosin II dependent forces are transmitted through the actin cytoskeleton to molecular endpoints that promote specific cellular outcomes, e.g., cell proliferation, adhesion, or migration. For example, most adhesive and migratory phenomena are mechanically linked by a molecular clutch comprised of mechanosensitive scaffolds. Myosin II activation and mechanosensitive molecular mechanisms are finely tuned and spatiotemporally integrated to coordinate morphogenetic events during development. Mechanical events dependent on myosin II also participate in tumor cell proliferation, invasion, and metastatic dissemination. Specifically, tumor cells alter the mechanical properties of the microenvironment to create favorable conditions for proliferation and/or dissemination. These observations position myosin II-dependent force generation and mechanotransduction at the crossroads between normal development and cancer. PMID- 23934155 TI - Osteoblast-adipocyte lineage plasticity in tissue development, maintenance and pathology. AB - Osteoblasts and adipocytes share a common precursor in adult bone marrow and there is a degree of plasticity between the two cell lineages. This has important implications for the etiology of not only osteoporosis but also several other diseases involving an imbalance between osteoblasts and adipocytes. Understanding the process of differentiation of osteoblasts and adipocytes and their trans differentiation is crucial in order to identify genes and other factors that may contribute to the pathophysiology of such diseases. Several transcriptional regulators have been shown to control osteoblast and adipocyte differentiation and function. Regulation of cell commitment occurs at the level of the progenitor cell through cross talk between complex signaling pathways and epigenetic mechanisms such as DNA methylation, chromatin remodeling, and microRNAs. Here we review the complex precursor cell microenvironment controlling osteoblastogenesis and adipogenesis during tissue development, maintenance, and pathology. PMID- 23934156 TI - Advances in culture and manipulation of human pluripotent stem cells. AB - Recent advances in the understanding of pluripotent stem cell biology and emerging technologies to reprogram somatic cells to a stem cell-like state are helping bring stem cell therapies for a range of human disorders closer to clinical reality. Human pluripotent stem cells (hPSCs) have become a promising resource for regenerative medicine and research into early development because these cells are able to self-renew indefinitely and are capable of differentiation into specialized cell types of all 3 germ layers and trophoectoderm. Human PSCs include embryonic stem cells (hESCs) derived from the inner cell mass of blastocyst-stage embryos and induced pluripotent stem cells (hiPSCs) generated via the reprogramming of somatic cells by the overexpression of key transcription factors. The application of hiPSCs and the finding that somatic cells can be directly reprogrammed into different cell types will likely have a significant impact on regenerative medicine. However, a major limitation for successful therapeutic application of hPSCs and their derivatives is the potential xenogeneic contamination and instability of current culture conditions. This review summarizes recent advances in hPSC culture and methods to induce controlled lineage differentiation through regulation of cell-signaling pathways and manipulation of gene expression as well as new trends in direct reprogramming of somatic cells. PMID- 23934157 TI - Estrogen aggravates iodoacetate-induced temporomandibular joint osteoarthritis. AB - Temporomandibular joint osteoarthritis (TMJOA) is clinically characterized by female preponderance, with a female-to-male ratio of more than 2:1; however, the underlying mechanism remains obscure. We examined the effects of estrogen on TMJOA induced by monosodium iodoacetate. Female rats were randomly and equally divided into 5 groups: control, sham-ovariectomized, and ovariectomized rats treated, respectively, with 17beta-estradiol (E2) at doses of 0 ug, 20 ug, and 80 ug/day until the end of the experiment. After induction of TMJOA, TMJs were evaluated by histopathology and microCT, and the expression of Fas, FasL, caspase 3, and caspase 8 was evaluated by real-time polymerase chain-reaction or immunohistochemistry. Another 5 groups of female rats were used to evaluate the effect of estrogen receptor antagonist ICI 182780 on E2 effects on TMJOA, when injected intraperitoneally into the control, sham-ovariectomized, and 80-ug-E2 treated groups. We found that E2 potentiated cartilage degradation and subchondral bone erosion in iodoacetate-induced TMJOA. E2 also potentiated mRNA expression of Fas, FasL, caspase 3, and caspase 8 in the condylar cartilage. Moreover, the estrogen receptor antagonist partially blocked E2 effects on TMJOA. These findings suggest that E2 could aggravate TMJOA, which may be an important mechanism underlying the sexual dimorphism of TMJOA. PMID- 23934158 TI - Quantitative bioimaging of platinum in polymer embedded mouse organs using laser ablation ICP-MS. AB - A novel quantification approach for tissue imaging using laser ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) based on tissue embedding in cold-curing resins (Technovit 7100) is presented. With respect to massive side effects on cisplatin, the platinum distribution at different time intervals after cisplatin treatment of mice was determined quantitatively in different tissues including cochlea, testis and kidney. For this purpose, cold curing resin blocks spiked with different amounts of platinum acetyl acetonate prior to curing were ablated after sectioning at 5 MUm thickness and were analysed using ICP-MS after microwave digestion. High spatial resolution and limits of detection in the low ppb range (8 MUg kg(-1)) were achieved using a simple and efficient sample preparation. External calibration using the Technovit 7100 standards proved to yield precise and reproducible quantification results. The distribution and retention behaviour of cisplatin in the organs was investigated using the new calibration method. PMID- 23934160 TI - Chlorine and sodium chemical shift imaging during acute stroke in a rat model at 9.4 Tesla. AB - OBJECT: A triple-resonant coil setup with an (1)H linear resonator and a double tuned (23)Na/(35)Cl surface coil was used to study the evolution of T 2 (*) and M 0 for (35)Cl and (23)Na in a rat stroke model during the acute phase at 9.4 Tesla. MATERIALS AND METHODS: In vivo measurements were performed 1.5-7 h after onset of stroke (n = 2), ten days after onset (n = 1) and on a healthy control rat by a chemical shift imaging sequence. Measurement times were 15 min ((23)Na) and 57 min ((35)Cl). RESULTS: The relaxation times ten days after onset [T 2 (*) = 14.3 +/- 1.8 ms ((23)Na) and 6.0 +/- 1.3 ms ((35)Cl)] are clearly prolonged in comparison to a healthy rat [T 2 (*) = 4.8 +/- 0.6 ms ((23)Na) and 2.1 +/- 0.3 ms ((35)Cl)] and the acute phase [T 2 (*) = 5.6 +/- 0.2 ms ((23)Na) and 1.9 +/- 0.1 ms ((35)Cl)]. CONCLUSION: M 0 in the infarcted region clearly rises later and slower for chlorine than for sodium. To the best of our knowledge, these are the first combined proton, sodium, and chlorine measurements in an animal stroke model during the acute phase. PMID- 23934159 TI - Fetal blood flow velocimetry by phase-contrast MRI using a new triggering method and comparison with Doppler ultrasound in a sheep model: a pilot study. AB - OBJECT: We present the first study demonstrating the feasibility of antenatal blood flow velocimetry performing ECG triggered phase-contrast (PC)-MRI in the fetal aorta by using a newly developed Doppler ultrasound trigger. MATERIALS AND METHODS: Five pregnant sheep carrying singleton fetuses (gestational age 121 days) were anesthetized to undergo fetal 2D PC-MRI in the fetal descending aorta (1.5 T) using a newly developed MR-compatible Doppler ultrasound trigger for fetal cardiac triggering. Inter-operator variability was assessed for PC-MR measurements and reproducibility was tested by repeated scans in one fetus. Inter modality comparison was performed by Doppler ultrasound velocimetry. RESULTS: Fetal cardiac triggering was possible in all examinations. PC-MR velocimetry revealed a mean inter-operator variability of 3 +/- 5%. Average peak systolic flow velocities of 62.5 +/- 4.4 cm/s were in good agreement with Doppler ultrasound measurements of 62.0 +/- 9.2 cm/s (p (Lord's U test) ? 0.05). CONCLUSION: Fetal PC-MR velocimetry was successfully performed using the newly developed MR-compatible Doppler ultrasound trigger for intrauterine fetal cardiac triggering, demonstrating high inter-operator and inter-modality agreement. This new method has the high potential for alternative assessment of hemodynamic decompensation of the fetal circulation. PMID- 23934161 TI - An L-Arginine supplement improves broiler hypertensive response and gut function in broiler chickens reared at high altitude. AB - An experiment was carried out to examine the effects of supplemental dietary arginine (ARG) on growth, hypertensive response, and gut function in broilers reared at high altitude (2,100 m). A total of 120 day-old male broilers (Cobb 500) were divided equally into two treatment groups. Treatments included a control basal diet composed of corn and soybean meal and an experimental diet to which an L-ARG supplement was added at 10 g/kg. The trial lasted for 42 days. There were no treatment differences with regard to feed intake, body weight gain, or feed conversion ratio. However ARG supplementation did increase the plasma concentration of nitric oxide, a potent vasodilator (P<0.05), and attenuated indices of pulmonary hypertension as reflected by reductions in the hematocrit and the right to total ventricular weight ratio (P<0.05). Significantly enhanced intestinal mucosal development was observed in broilers receiving ARG supplement when compared with controls (P<0.05), suggesting that ARG supplementation increased the absorptive surface area of the jejunum and ileum. In conclusion, broiler diets supplemented with ARG beneficially improved pulmonary hemodynamics and appeared to enhance gut function. PMID- 23934162 TI - Climate as a driver of phenological change in southern seabirds. AB - Seabirds are one of the most threatened groups of birds globally and, overall, their conservation status is deteriorating rapidly. Southern hemisphere countries are over-represented in the number of species of conservation concern yet long term phenological data on seabirds in the southern hemisphere is limited. A better understanding of the implications of changes in the marine and terrestrial environments to seabird species is required in order to improve their management and conservation status. Here we conducted a meta-analysis of the phenological drivers and trends among southern hemisphere seabirds. Overall there was a general trend towards later phenological events over time (34 % of all data series, N = 47; 67 % of all significant trends), though this varied by taxa and location. The strongest trends towards later events were for seabirds breeding in Australia, the Laridae (gulls, noddies, terns) and migratory southern polar seabirds. In contrast, earlier phenologies were more often observed for the Spheniscidae (penguins) and for other seabirds breeding in the Antarctic and subantarctic. Phenological changes were most often associated with changes in oceanographic conditions, with sea-ice playing an important role for more southerly species. For some species in some locations, such as the Little Penguin Eudyptula minor in south-eastern Australia, warmer oceans projected under various climate change scenarios are expected to correspond to increased seabird productivity, manifested through earlier breeding, heavier chicks, an increased chance of double brooding, at least in the short-term. PMID- 23934163 TI - Biomat development in soil treatment units for on-site wastewater treatment. AB - We provide a simple mathematical model of the bioremediation of contaminated wastewater leaching into the subsoil below a septic tank percolation system. The model comprises a description of the percolation system's flows, together with equations describing the growth of biomass and the uptake of an organic contaminant concentration. By first rendering the model dimensionless, it can be partially solved, to provide simple insights into the processes which control the efficacy of the system. In particular, we provide quantitative insight into the effect of a near surface biomat on subsoil permeability; this can lead to trench ponding, and thus propagation of effluent further down the trench. Using the computed vadose zone flow field, the model can be simply extended to include reactive transport of other contaminants of interest. PMID- 23934164 TI - In vivo arrhythmogenicity of the marine biotoxin azaspiracid-2 in rats. AB - Azaspiracids (AZAs) are marine biotoxins produced by the dinoflagellate Azadinium spinosum that accumulate in several shellfish species. Azaspiracid poisoning episodes have been described in humans due to ingestion of AZA-contaminated seafood. Therefore, the contents of AZA-1, AZA-2 and AZA-3, the best-known analogs of the group, in shellfish destined to human consumption have been regulated by food safety authorities of many countries to protect human health. In vivo and in vitro toxicological studies have described effects of AZAs at different cellular levels and on several organs, however, AZA target remains unknown. Very recently, AZAs have been demonstrated to block the hERG cardiac potassium channel. In this study, we explored the potential cardiotoxicity of AZA 2 in vivo. The effects of AZA-2 on rat electrocardiogram (ECG) and cardiac biomarkers were evaluated for cardiotoxicity signs besides corroborating the hERG blocking activity of AZA-2. Our results demonstrated that AZA-2 does not induce QT interval prolongation on rat ECGs in vivo, in spite of being an in vitro blocker of the hERG cardiac potassium channel. However, AZA-2 alters the heart electrical activity causing prolongation of PR intervals and the appearance of arrhythmias. More studies will be needed to clarify the mechanism by which AZA-2 causes these ECG alterations; however, the potential cardiotoxicity of AZAs demonstrated in this in vivo study should be taken into consideration when evaluating the possible threat that these toxins pose to human health, mainly for individuals with pre-existing cardiovascular disease when regulated toxin limits are exceeded. PMID- 23934165 TI - Impact of MALDI-TOF will be highly dependent on the clinician. PMID- 23934166 TI - Managing transmission of carbapenem-resistant enterobacteriaceae in healthcare settings: a view from the trenches. AB - In 2011, the National Institutes of Health Clinical Center experienced a cluster of infection and colonization caused by carbapenem-resistant Klebsiella pneumoniae among profoundly immunocompromised inpatients. This manuscript describes the approach and interventions that were implemented in an attempt to curtail the cluster. Interventions employed included engagement of all stakeholders involved in care of at-risk patients; detailed and frequent communication with hospital staff about issues relating to the outbreak; aggressive microbial surveillance; use of techniques that facilitate rapid identification of resistant organisms; rapid characterization of resistance mechanisms; whole-genome sequencing of outbreak isolates to characterize the spread and to investigate mechanisms of healthcare-associated spread; implementation of enhanced contact precautions for all infected or colonized patients; geographic and personnel cohorting; daily chlorhexidine gluconate baths; dedicating equipment to be used solely for cohorted patients and aggressive decontamination of equipment that had to be reused on uncohorted patients; monitoring adherence to infection control precautions, including unwavering attention to adherence to appropriate hand hygiene procedures; and attention to the details of environmental decontamination. In addition, the manuscript discusses some of the challenges associated with managing such an event, as well as a few of the unanticipated consequences associated with the aftermath of the case cluster. PMID- 23934167 TI - Absence of the superior mesenteric artery in an adult and a new classification method for superior-inferior mesenteric arterial variations. AB - PURPOSE: This paper aims to report the complete absence of the superior mesenteric artery (SMA) in an adult and to propose a new classification method for the superior-inferior mesenteric arterial variations (SIMAV). METHODS: A 69 year-old female was referred for abdominal pain and change of stool habits and characteristics. Multi-detector computed tomography (MDCT) was performed. Based on the CT findings of the patient and previous reports on the abnormalities of the superior-inferior mesenteric arteries, attempt was made to propose a new classification method for SIMAV. RESULTS: MDCT with enhancement revealed complete absence of SMA and compensatory dilation of the inferior mesenteric artery (IMA). Aneurysm of the splenic artery and both inferior phrenic arteries aberrantly arising from the aorta at the same level of the celiac trunk were also noted. Based on our case and literature reports, we were able to propose a new classification method for SIMAV. Without considering the relationship with the celiac arteries, SIMAV can be divided into 4 types. Type I is the normal type or "textbook" type. In type II, SMA is defective and in type III, IMA is defective. In type IV, there is an aberrant middle mesenteric artery (MMA). CONCLUSIONS: Complete absence of SMA is extremely rare. However, awareness of such a variation is of great importance during operations for rectal and sigmoid cancer. In such patients, ligation of the trunk of IMA, which is the only artery for the entire intestine, will lead to disastrous consequence. The new classification method may be helpful in the scientific and systematic description of SIMAV. PMID- 23934168 TI - Methodological challenges in the use of hip-specific composite outcomes: linking measurements from hip fracture trials to the International Classification of Functioning, Disability and Health Framework. AB - INTRODUCTION: The prevalence of hip-specific outcome measures in randomized trials reflects what directs our outcome assessment following a hip fracture. The present study provides an overview on the most commonly-used hip-specific outcome instruments used for postoperative assessment of hip fracture with respect to their covered contents. This can facilitate the selection of appropriate items for specific purposes in clinical as well as research settings. METHODS: We used the International Classification of Functioning, Disability and Health (ICF) model to distinguish concepts within the instrument. All items from the questionnaires were categorized into one of three categories using the ICF linking rules for a standardized approach. The hip-specific composites measures were also compared to other types of prevalent measures: generic and patient based instruments. RESULTS: All of the items in the instruments could be mapped to the ICF. We report the highest frequency of ICF activity and participation (71%) within the Harris hip score (HHS) which is similar to the frequency of ICF content found in the generic measures (82%). Hip-specific composites focused mostly on walking and moving long and short distances, while in patient-reported measures there was a concentration on the concept of sensation of pain and pain in body parts. DISCUSSION AND CONCLUSION: The prevalent use of the HHS, over the other hip-specific instruments, could be attributed to its likeness in concept to other generic measures. The dominance of the ICF category of activity and participation reflects what is important to clinicians treating a hip fracture. Composite scores remain problematic as they cut across different ICF concepts. As long as the popularity of composite scoring systems continues, an overall score may not represent the true patient preferences and concerns in clinical trials. Future studies could apply the results from this study for the creation of an ICF category-based item banking or investigators could operationalize the ICF categories within these candidate measures for specific interventions. PMID- 23934169 TI - Six percent hydroxyethyl starch 130/0.4 (Voluven(r)) versus 5% human serum albumin for volume replacement therapy during elective open-heart surgery in pediatric patients. AB - BACKGROUND: Although 5% albumin (human serum albumin [HSA]) is widely used in cardiac surgery children, synthetic colloids may provide a valuable alternative. This study compared 6% hydroxyethyl starch (HES) 130/0.4 with HSA for volume replacement in this population. METHODS: The study was a two-center, randomized, controlled, parallel-group, double-blind trial performed in children aged 2-12 yr undergoing elective surgery for congenital heart disease under extracorporeal circulation. The primary objective was to demonstrate equivalence between HES and HSA with regard to the total volume of colloid infusion for intraoperative volume replacement including priming of the extracorporeal circuitery. RESULTS: In the per-protocol population, mean volume of colloid required until end of surgery was (mean +/- SD) 36.6 +/- 11.8 ml/kg body weight in the HES group (N = 29) and 37.0 +/- 11.9 ml/kg body weight in the HSA group (N = 26; ratio of means HES/HSA = 0.98 [95% CI, 0.84-1.16]). Intraoperative fluid balance was less positive in the HES group (P = 0.047). No difference was found regarding hemodynamics, the use of vasoactive and inotropic drugs. Blood loss, erythrocytes transfusion, and renal function were not different between groups. The incidence of adverse events up to postoperative day 28 did not differ between the groups. CONCLUSIONS: In pediatric cardiac surgery, HES showed equivalence to HSA with regard to volume replacement therapy in children aged from 2 to 12 yr. Although there was no suggestion of an imbalance of safety measures between HES and HSA, the study was not powered to provide any firm conclusions about safety of tetrastarch in this population. PMID- 23934170 TI - Capsosiphon fulvescens glycoprotein reduces AGS gastric cancer cell migration by downregulating transforming growth factor-beta1 and integrin expression. AB - Seaweeds are commonly used as functional foods and drugs. A glycoprotein (GP) from the green alga Capsosiphon fulvescens (Cf) has been reported to have antitumor activity toward various cancer cells. We previously observed that Cf-GP induced different pathways of apoptosis in AGS human gastric cancer cells. Transforming growth factor (TGF)-beta1 plays an important role in cancer cell migration. Increased TGF-beta1 levels increase the expression of the small GTPases and activate the FAK/PI3K/AKT pathways, resulting in the upregulation of integrin receptor proteins, which mediate the attachment of cells to surrounding tissues, cells or extracellular matrix. Thus, the inhibition of TGF-beta1 signaling would downregulate integrin expression and thereby effectively decrease cell growth and migration. In the present study, we determined the effect of Cf GP treatment on the proliferation, migration and apoptosis of AGS human gastric cancer cells. To investigate the mechanism by which Cf-GP exerts its anticancer actions, we examined the effect of Cf-GP on the expression levels of TGF-beta1, FAK, PI3K, AKT, the small GTPases and integrins in AGS cells. Our findings indicate that Cf-GP inhibits AGS cell proliferation and migration by downregulating integrin expression via the TGF-beta1-activated FAK/PI3K/AKT pathways. These results suggest that Cf-GP may be an important factor in the development of functional foods and therapeutic agents. PMID- 23934171 TI - Classification of type 2 diabetes rats based on urine amino acids metabolic profiling by liquid chromatography coupled with tandem mass spectrometry. AB - An analytical method for quantifying underivatized amino acids (AAs) in urine samples of rats was developed by using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Classification of type 2 diabetes rats was based on urine amino acids metabolic profiling. LC-MS/MS analysis was applied through chromatographic separation and multiple reactions monitoring (MRM) transitions of MS/MS. Multivariate profile-wide predictive models were constructed using partial least squares discriminant analysis (PLS-DA) by SIMAC-P 11.5 version software package and hierarchical cluster analysis (HCA) by SPSS 18.0 version software. Some amino acids in urine of rats have significant change. The results of the present study prove that this method could perform the quantification of free AAs in urine of rats by using LC-MS/MS. In summary, the PLS-DA and HCA statistical analysis in our research were preferable to differentiate healthy rats and type 2 diabetes rats by the quantification of AAs in their urine samples. In addition, comparing with health group the seven increased amino acids in urine of type 2 rats were returned to normal under the treatment of acarbose. PMID- 23934172 TI - Rapid detection of bacteria in urine samples by the "three-plug-injection" method using capillary electrophoresis. AB - This study explored a method that can rapidly detect bacteria in urine samples for the auxiliary determination of urinary tract infections (UTIs). Urine samples from patients with UTIs (230 cases) were obtained using aseptic technique. The urine biochemical assay was then carried out using an automated urine analyzer for all the urine samples. Bacterial species were identified by a combination of bacterial culture technique, morphological observation and the BACT-IST microbial identification/susceptibility analysis system. The most common seven species of bacteria in the study included Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter cloacae, Enterococcus faecalis, Staphylococcus aureus and Staphylococcus epidermidis. Bacterial samples were suspended in sample buffer solutions and separated by the "three-plug-injection" method using capillary electrophoresis (CE). Each species of bacteria appeared as a bacterial peak. The mixture of the seven species also provided only one peak. Further analysis showed that the concentration limit for the "three-plug injection" method is 10(6) colony forming units (CFU)/mL, and there is a good linear relationship between the peak height and bacterial concentration (R(2)=0.99). The effect of urine composition on CE results was also investigated. The results showed that urine composition, i.e., proteins, white blood cells (WBCs) and red blood cells (RBCs), affected the peak retention time but could not affect the separation of bacteria. The results demonstrated that the bacteria in urine samples can be detected within 10min by the "three-plug-injection" method using CE. The "three-plug-injection" method is therefore suitable for the rapid detection of organisms in clinical urine samples from UTIs. PMID- 23934173 TI - High throughput liquid chromatography-tandem mass spectrometry assay for mercapturic acids of acrolein and crotonaldehyde in cigarette smokers' urine. AB - 3-Hydroxypropylmercapturic acid (3-HPMA) and 3-hydroxy-1-methylpropylmercapturic acid (HMPMA) are urinary metabolites of the toxicants acrolein and crotonaldehyde, respectively. Virtually all human urine samples contain these metabolites, resulting from the action of glutathione-S-transferases on acrolein and crotonaldehyde, which are lipid peroxidation products, environmental and dietary contaminants, and constituents of cigarette smoke. We have developed a high throughput liquid chromatography-tandem mass spectrometry method for quantitative analysis of 3-HPMA and HMPMA in large numbers of small urine samples, as would be required in molecular epidemiology and clinical studies relating levels of these metabolites to cancer risk. Solid-phase extraction on mixed mode reverse phase-anion exchange 96-well plates provided sufficient purification for LC-MS/MS analysis, which was performed by auto-injection using a 96-well format, and resulted in clean, readily interpretable chromatograms, with detection limits of 4.5pmol/mL urine for 3-HPMA and 3.5pmol/mL urine for HMPMA. Accuracy was 92% for 3-HPMA and 97% for HMPMA while inter-day precision was 9.1% (coefficient of variation) for 3-HPMA and 11.0% for HMPMA. The method was applied to more than 2600 urine samples from smokers; mean levels of 3-HPMA and HMPMA were 4800+/-5358 (S.D.)pmol/mL and 3302+/-3341pmol/mL, respectively. PMID- 23934174 TI - Viability, proliferation and phenotype maintenance in cryopreserved human iliac apophyseal chondrocytes. AB - Cryopreservation preserves cells at low temperature and creates a reserve for future use while executing the clinical translation. Unlike articular chondrocyte, cryopreservation protocol and its outcome are not described in iliac apophyseal chondrocytes, a potential source of chondrocytes in cartilage engineering. This study for the first time describes the cryopreservation of human iliac apophyseal chondrocytes. Four cartilage samples were procured from iliac crests of children undergoing hip surgery after consent. The total chondrocyte yield was divided into two groups. First group was grown as monolayer while second group was cryopreserved following the slow cooling method in the medium containing 10 % Dimethyl sulfoxide for 3 months. Group two cells were also grown as a monolayer following thawing. Viability, time to confluence, population doubling time and phenotype maintenance were compared for both the groups. Viability was 65.75 % after 3 months of cryopreservation at -196 degrees C, as compared to 94.19 % for fresh chondrocytes (p = 0.001). Fresh and cryopreserved cells reached confluence on 10th and 15th day of culture respectively. Population doubling time was significantly more in fresh than cryopreserved chondrocytes on 10th (p = 0.0006) and 15th day (p = 0.0002) in culture. Both fresh and cryopreserved cells maintain their chondrocyte phenotype as assessed by immunocytochemistry. Relative gene expression by real time polymerase chain reaction showed similar upregulation of mRNA of Collagen 2, SOX 9, Aggrecan and Collagen 1 in cryopreserved chondrocyte as compared to fresh chondrocyte. Iliac apophyseal chondrocytes cryopreserved for 3 months maintained the phenotype successfully 2 weeks after thawing in culture. The viability and proliferation rates after thawing were adequate for a clinical translation of these cells. PMID- 23934175 TI - cMYC expression in infiltrating gliomas: associations with IDH1 mutations, clinicopathologic features and outcome. AB - Gliomas are among the most frequent adult primary brain tumors. Mutations in IDH1, a metabolic enzyme, strongly correlate with secondary glioblastomas and increased survival. cMYC is an oncogene also implicated in aberrant metabolism, but its prognostic impact remains unclear. Recent genotyping studies also showed SNP variants near the cMYC gene locus, associate with an increased risk for development of IDH1/2 mutant gliomas suggesting a possible interaction between cMYC and IDH1. We evaluated nuclear cMYC protein levels and IDH1 (R132H) by immunohistochemistry in patients with oligodendroglioma/oligoastrocytomas (n = 20), astrocytomas (grade II) (n = 19), anaplastic astrocytomas (n = 21) or glioblastomas (n = 111). Of 158 tumors with sufficient tissue, 110 (70 %) showed nuclear cMYC immunopositivity--most frequent (95 %, chi(2) p = 0.0248) and intense (mean 1.33, ANOVA p = 0.0179) in anaplastic astrocytomas versus glioblastomas (63 %) or low grade gliomas (74 %). cMYC expression associated with younger age as well as p53 immunopositivity (OR = 3.6, p = 0.0332) and mutant IDH1 (R132H) (OR = 7.4, p = 0.06) among malignant gliomas in our cohort. Independent analysis of the publically available TCGA glioblastoma dataset confirmed our strong association between cMYC and mutant IDH1 expression. Both IDH1 (R132H) and cMYC protein expression were associated with improved overall survival by univariate analysis. However, cMYC co-expression associated with shortened time to malignant transformation and overall survival among IDH1 (R132H) mutants in both univariate and multivariate analyses. In summary, our findings suggest that cMYC may be associated with a unique clinicopathologic and biologic group of infiltrating gliomas and help mediate the malignant transformation of IDH1 mutant gliomas. PMID- 23934176 TI - MicroRNA-based strategy to mitigate the risk of gain-of-function influenza studies. AB - Recent gain-of-function studies in influenza A virus H5N1 strains revealed that as few as three-amino-acid changes in the hemagglutinin protein confer the capacity for viral transmission between ferrets. As transmission between ferrets is considered a surrogate indicator of transmissibility between humans, these studies raised concerns about the risks of gain-of-function influenza A virus research. Here we present an approach to strengthen the biosafety of gain-of function influenza experiments. We exploit species-specific endogenous small RNAs to restrict influenza A virus tropism. In particular, we found that the microRNA miR-192 was expressed in primary human respiratory tract epithelial cells as well as in mouse lungs but absent from the ferret respiratory tract. Incorporation of miR-192 target sites into influenza A virus did not prevent influenza replication and transmissibility in ferrets, but did attenuate influenza pathogenicity in mice. This molecular biocontainment approach should be applicable beyond influenza A virus to minimize the risk of experiments involving other pathogenic viruses. PMID- 23934177 TI - Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. AB - Progress in adoptive T-cell therapy for cancer and infectious diseases is hampered by the lack of readily available, antigen-specific, human T lymphocytes. Pluripotent stem cells could provide an unlimited source of T lymphocytes, but the therapeutic potential of human pluripotent stem cell-derived lymphoid cells generated to date remains uncertain. Here we combine induced pluripotent stem cell (iPSC) and chimeric antigen receptor (CAR) technologies to generate human T cells targeted to CD19, an antigen expressed by malignant B cells, in tissue culture. These iPSC-derived, CAR-expressing T cells display a phenotype resembling that of innate gammadelta T cells. Similar to CAR-transduced, peripheral blood gammadelta T cells, the iPSC-derived T cells potently inhibit tumor growth in a xenograft model. This approach of generating therapeutic human T cells 'in the dish' may be useful for cancer immunotherapy and other medical applications. PMID- 23934178 TI - High-throughput profiling of off-target DNA cleavage reveals RNA-programmed Cas9 nuclease specificity. AB - The RNA-programmable Cas9 endonuclease cleaves double-stranded DNA at sites complementary to a 20-base-pair guide RNA. The Cas9 system has been used to modify genomes in multiple cells and organisms, demonstrating its potential as a facile genome-engineering tool. We used in vitro selection and high-throughput sequencing to determine the propensity of eight guide-RNA:Cas9 complexes to cleave each of 10(12) potential off-target DNA sequences. The selection results predicted five off-target sites in the human genome that were confirmed to undergo genome cleavage in HEK293T cells upon expression of one of two guide RNA:Cas9 complexes. In contrast to previous models, our results show that guide RNA:Cas9 specificity extends past a 7- to 12-base-pair seed sequence. Our results also suggest a tradeoff between activity and specificity both in vitro and in cells as a shorter, less-active guide RNA is more specific than a longer, more active guide RNA. High concentrations of guide-RNA:Cas9 complexes can cleave off target sites containing mutations near or within the PAM that are not cleaved when enzyme concentrations are limiting. PMID- 23934179 TI - Associations between depressive symptoms, self-efficacy, eating styles, exercise and body mass index in women. AB - This article explores cross-sectional associations between depressive symptoms and body mass index (BMI) in women working in schools in the Greater New Orleans area. Self-efficacy for eating and exercise, eating styles, and exercise are examined as potential pathways. This is a secondary data analysis of 743 women who were participating in a workplace wellness randomized controlled trial to address environmental factors influencing eating and exercise behaviors using baseline data prior to the intervention. BMI was the primary outcome examined. Path analysis suggested that increased depressive symptoms were associated with increased BMI in women. Indirect effects of depressive symptoms on BMI were found for increased healthy eating self-efficacy, increased emotional eating, and decreased exercise self-efficacy. The association between greater healthy eating self efficacy and BMI was unexpected, and may indicate a suppressor effect of eating self-efficacy in the relationship between depressive symptoms and BMI in women. The findings suggest the importance of depressive symptoms to BMI in women. Targets for interventions to reduce BMI include targeting depressive symptoms and related sequelae including self-efficacy for exercise, and emotional eating. Further investigation of eating self-efficacy and BMI are recommended with particular attention to both efficacy for health eating and avoidance of unhealthy foods. PMID- 23934180 TI - Motivational interviewing with primary care populations: a systematic review and meta-analysis. AB - This meta-analysis synthesized the findings from randomized controlled trials (RCTs) of motivational interviewing (MI) for health behavior outcomes within primary care populations. Published and unpublished RCTs were identified using databases and online listservs. Studies were synthesized by outcome subgroup and meta-regression analyses were conducted to determine potential moderators accounting for heterogeneity within samples. Mean effect sizes ranged from .07 to .47; significant effect sizes were found for the adherence subgroup of studies (p = .04) and all outcomes combined (p = .02). Professional credentials of intervention deliverer were found to significantly moderate the association between MI and effect size in substance use subgroup (p = .0005) and all outcomes combined (p = .004). Mean effect sizes were largest in outcomes related to weight loss, blood pressure, and substance use. MI appears to be useful in clinical settings and as few as 1 MI session may be effective in enhancing readiness to change and action directed towards reaching health behavior-change goals. PMID- 23934181 TI - Crossing boundaries and identification processes. AB - This article provides a commentary on seven papers published in a special issue led by J. Dahinden and T. Zittoun in this journal. The papers explore social polarisation, boundary making, inter-group dialogue and migrants' movement between groups in the context of religion. The exploration is undertaken from different disciplinary backgrounds and in various countries across Europe as well as in Australia. A critical engagement is developed with some of the key issues raised by the papers. This engagement begins by drawing on critiques of 'groupism' and then proceeds to consider the role played by process, power, knowledge and governmentality in the context of both time and space. The discussion is supported by illustrations from the case studies provided by the papers. The discussion also links issues raised by the papers to developments within Britain over time and in urban space, which involve the state, Muslim community representatives and the everyday practices of Muslim citizens in London, particularly those concerned with the body. PMID- 23934182 TI - Impact of hyperhomocysteinemia on breast cancer initiation and progression: epigenetic perspective. AB - Our recent study showing association of hyperhomocysteinemia and hypomethioninemia in breast cancer and other studies indicating association of hyperhomocysteinemia with metastasis and development of drug resistance in breast cancer cells treated with homocysteine lead us to hypothesize that homocysteine might modulate the expression of certain tumor suppressors, i.e., RASSF1, RARbeta1, CNND1, BRCA1, and p21, and might influence prognostic markers such as BNIP3 by inducing epigenetic alteration. To demonstrate this hypothesis, we have treated MCF-7 and MDA-MB-231 cells with different doses of homocysteine and observed dose-dependent inhibition of BRCA1 and RASSF1, respectively. In breast cancer tissues, we observed the following expression pattern: BNIP3 > BRCA1 > RARbeta1 > CCND1 > p21 > RASSF1. Hyperhomocysteinemia was positively associated with BRAC1 hypermethylation both in breast cancer tissue and corresponding peripheral blood. Peripheral blood CpG island methylation of BRCA1 in all types of breast cancer and methylation of RASSF1 in ER/PR-negative breast cancers showed positive correlation with total plasma homocysteine. The methylation of RASSF1 and BRCA1 was associated with breast cancer initiation as well as progression, while BRCA1 methylation was associated with DNA damage. Vitamin B12 showed inverse association with the methylation at both the loci. RFC1 G80A and cSHMT C1420T variants showed positive association with methylation at both the loci. Genetic variants influencing remethylation step were associated positively with BRCA1 methylation and inversely with RASSF1 methylation. GCPII C1561T variant showed inverse association with BRCA1 methylation. We found good correlation of BRAC1 (r = 0.90) and RASSF1 (0.92) methylation pattern between the breast cancer tissue and the corresponding peripheral blood. To conclude, elevated homocysteine influences methionine dependency phenotype of breast cancer cells and is associated with breast cancer progression by epigenetic modulation of RASSF1 and BRCA1. PMID- 23934183 TI - Asiatic acid inhibits adipogenic differentiation of bone marrow stromal cells. AB - Bone marrow mesenchymal stromal cells (BMSCs) are the common precursors for both osteoblasts and adipocytes. With aging, BMSC osteoblast differentiation decreases whereas BMSC differentiation into adipocytes increases, resulting in increased adipogenesis and bone loss. In the present study, we investigated the effect of asiatic acid (AA) on adipocytic differentiation of BMSCs. AA inhibited the adipogenic induction of lipid accumulation, activity of glycerol-3-phosphate dehydrogenase, and expression of marker genes in adipogenesis: peroxisome proliferation-activated receptor (PPAR)gamma, adipocyte fatty acid-binding protein (ap) 2, and adipsin. Further, we found that AA did not alter clonal expansion rate and expression of C/EBPbeta, upstream key regulator of PPARgamma, and binding activity of C/EBPbeta to PPARgamma promoter was not affected by AA as well. These findings suggest that AA may modulate differentiation of BMSCs to cause a lineage shift away from the adipocytes, and inhibition of PPARgamma by AA is through C/EBPbeta-independent mechanisms. Thus, AA could be a potential candidate for a novel drug against osteoporosis. PMID- 23934184 TI - Severity illness scoring systems for early identification and prediction of in hospital mortality in patients with suspected sepsis presenting to the emergency department. AB - The in-hospital mortality of patients with severe sepsis and septic shock (SSSS) is high. In this study we examined the diagnostic and prognostic accuracy of the emergency severity index (ESI), the modified early warning score (MEWS), and the mortality in emergency department (ED) sepsis (MEDS) score. This is a single centre, prospective and observational study of 151 consecutive patients presenting to the ED of the Nuremberg Hospital with suspected sepsis (age 68.3 +/ 18 years, 54.3 % men, 45 % with SSSS, in-hospital mortality of SSSS: 27.8 %). In this study, 37.7 % of the studied patients had a urinary tract infection (n = 57/151), 33.8 % a pneumonia (n = 51/151), 8.6 % an acute abdominal infection (n = 13/151), and in 12.6 % the focus of infection was not further specified or identifiable (n = 19/151). The diagnostic and prognostic accuracy was analyzed by means of the receiver operating characteristic (ROC) curve. The areas under curve (AUC) in terms of diagnostic accuracy were 0.609, 0.641, and 0.778 for the ESI, MEWS, and MEDS score respectively. The AUCs concerning prognostic accuracy were 0.617, 0.642, and 0.871 for ESI, MEWS, and MEDS score respectively.By using the MEDS score systematically, critically ill patients with sepsis could be detected in the ED. Finally, the MEDS score provides the basis for a risk adjusted disposition management that follows objective criteria. PMID- 23934185 TI - Postoperative quality of life after two different methods of tonsillectomy. AB - BACKGROUND AND OBJECTIVES: Tonsillectomy is a very painful procedure. Pain may be severe, and patients are often unable to perform in school or eat regular food for a number of days after the surgery. The aim of this study was to compare the quality of life after undergoing two different surgical techniques of tonsillectomy, harmonic scalpel and classic tonsillectomy with bipolar cauterization. DESIGN AND SETTING: Prospective randomized double-blind, clinical trial study conducted in the ENT Department, Dr. Josip Bencevic General Hospital, Slavonski Brod, Croatia. PATIENTS AND METHODS: Data were collected, according to the type of operation, on pain persistence and intensity and returning to normal eating with tonsillectomy patients during the first seven postoperative days. Group A consisted of 50 children submitted to classic tonsillectomy with bipolar cauterization, while group B included 50 children operated on using the harmonic scalpel. Data on pain intensity were obtained using pain measuring scales adjusted to children's age (Faces scales, visual analog scale). The first day of normal oral food intake was recorded. RESULTS: The analysis of variance revealed that the grade of pain significantly differs by a surgical technique employed, and that it significantly varied over the first seven postoperative days. The pain was more severe after undergoing the harmonic scalpel technique and children started to eat later compared with the classic tonsillectomy. CONCLUSION: The classic tonsillectomy method with bipolar cauterization is the method of choice due to lower postoperative pain levels and sooner normal eating. The quality of life is better after undergoing the classic tonsillectomy method. PMID- 23934187 TI - Oncogenic PAK4 regulates Smad2/3 axis involving gastric tumorigenesis. AB - The alteration of p21-activated kinase 4 (PAK4) and transforming growth factor beta (TGF-beta) signaling effector Smad2/3 was detected in several types of tumors, which acts as oncogenic factor and tumor suppressor, but the relationship between these events has not been explored. Here, we demonstrate that PAK4 interacts with and modulates phosphorylation of Smad2/3 via both kinase-dependent and kinase-independent mechanisms, which attenuate Smad2/3 axis transactivation and TGF-beta-mediated growth inhibition in gastric cancer cells. First, PAK4 interaction with Smad2/3, which is independent of PAK4 kinase activity, blocks TGF-beta1-induced phosphorylation of Smad2 Ser465/467 or Smad3 Ser423/425 and the consequent activation. In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin-proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. Interestingly, PAK4 expression correlates negatively with phospho-Ser465/467 Smad2 but positively with phospho Ser465 Smad2 in gastric cancer tissues. Furthermore, the expressions of HGF, phospho-Ser474 PAK4 and phospho-Ser465 Smad2 are markedly increased in gastric cancer tissues, and the expression of Smad2 is decreased in gastric cancer tissues. Our results document an oncogenic role of PAK4 in repression of Smad2/3 transactivation that involved in tumorigenesis, and suggest PAK4 as a potential therapeutic target for gastric cancer. PMID- 23934186 TI - The Yin and Yang of Toll-like receptors in cancer. AB - Recognition of non-self molecular patterns by pattern recognition receptors is a cornerstone of innate immunity. Toll-like receptors (TLRs) exert a key role in recognizing pathogen-associated molecular patterns (PAMPs) but have also been implicated in the recognition of damage-associated molecular patterns (DAMPs). As such, TLRs regulate a wide range of biological responses including inflammatory and immune responses during carcinogenesis. The high expression of TLRs by antigen-presenting cells, including dendritic cells, and their ability to induce antitumor mediators such as type I interferon has led to efforts to utilize TLR agonists in tumor therapy in order to convert the often tolerant immune response toward antitumor responses. However, TLRs are also increasingly recognized as regulators of tumor-promoting inflammation and promoters of tumor survival signals. Here, we will review in detail the dichotomous role of TLRs in tumor biology, focusing on relevant TLR-dependent pro- and antitumor pathways, and discuss clinical applications of TLR-targeted therapies for tumor prevention and treatment. PMID- 23934189 TI - PTRF/cavin-1 neutralizes non-caveolar caveolin-1 microdomains in prostate cancer. AB - Caveolin-1 has a complex role in prostate cancer and has been suggested to be a potential biomarker and therapeutic target. As mature caveolin-1 resides in caveolae, invaginated lipid raft domains at the plasma membrane, caveolae have been suggested as a tumor-promoting signaling platform in prostate cancer. However, caveola formation requires both caveolin-1 and cavin-1 (also known as PTRF; polymerase I and transcript release factor). Here, we examined the expression of cavin-1 in prostate epithelia and stroma using tissue microarray including normal, non-malignant and malignant prostate tissues. We found that caveolin-1 was induced without the presence of cavin-1 in advanced prostate carcinoma, an expression pattern mirrored in the PC-3 cell line. In contrast, normal prostate epithelia expressed neither caveolin-1 nor cavin-1, while prostate stroma highly expressed both caveolin-1 and cavin-1. Utilizing PC-3 cells as a suitable model for caveolin-1-positive advanced prostate cancer, we found that cavin-1 expression in PC-3 cells inhibits anchorage-independent growth, and reduces in vivo tumor growth and metastasis in an orthotopic prostate cancer xenograft mouse model. The expression of alpha-smooth muscle actin in stroma along with interleukin-6 (IL-6) in cancer cells was also decreased in tumors of mice bearing PC-3-cavin-1 tumor cells. To determine whether cavin-1 acts by neutralizing caveolin-1, we expressed cavin-1 in caveolin-1-negative prostate cancer LNCaP and 22Rv1 cells. Caveolin-1 but not cavin-1 expression increased anchorage-independent growth in LNCaP and 22Rv1 cells. Cavin-1 co expression reversed caveolin-1 effects in caveolin-1-positive LNCaP cells. Taken together, these results suggest that caveolin-1 in advanced prostate cancer is present outside of caveolae, because of the lack of cavin-1 expression. Cavin-1 expression attenuates the effects of non-caveolar caveolin-1 microdomains partly via reduced IL-6 microenvironmental function. With circulating caveolin-1 as a potential biomarker for advanced prostate cancer, identification of the molecular pathways affected by cavin-1 could provide novel therapeutic targets. PMID- 23934188 TI - miR-137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin-resistant neuroblastoma cells. AB - Chemotherapy is the most common treatment for cancer. However, multidrug resistance (MDR) remains a major obstacle to effective chemotherapy, limiting the efficacy of both conventional chemotherapeutic and novel biologic agents. The constitutive androstane receptor (CAR), a xenosensor, is a key regulator of MDR. It functions in xenobiotic detoxification by regulating the expression of phase I drug-metabolizing enzymes and ATP-binding cassette (ABC) transporters, whose overexpression in cancers and whose role in drug resistance make them potential therapeutic targets for reducing MDR. MicroRNAs (miRNAs) are endogenous negative regulators of gene expression and have been implicated in most cellular processes, including drug resistance. Here, we report the inversely related expression of miR-137 and CAR in parental and doxorubicin-resistant neuroblastoma cells, wherein miR-137 is downregulated in resistant cells. miR-137 overexpression resulted in downregulation of CAR protein and mRNA (via mRNA degradation); it sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis and increased G2-phase cell cycle arrest) and reduced the in vivo growth rate of neuroblastoma xenografts. We observed similar results in cellular models of hepatocellular and colon cancers, indicating that the doxorubicin-sensitizing effect of miR-137 is not tumor type specific. Finally, we show for the first time a negative feedback loop whereby miR-137 downregulates CAR expression and CAR downregulates miR-137 expression. Hypermethylation of the miR-137 promoter and negative regulation of miR-137 by CAR contribute in part to reduced miR-137 expression and increased CAR and MDR1 expression in doxorubicin-resistant neuroblastoma cells. These findings demonstrate that miR-137 is a crucial regulator of cancer response to doxorubicin treatment, and they identify miR-137 as a highly promising target to reduce CAR driven doxorubicin resistance. PMID- 23934190 TI - COL11A1 promotes tumor progression and predicts poor clinical outcome in ovarian cancer. AB - Biomarkers that predict disease progression might assist the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. Here, we investigated the role of collagen type XI alpha 1 (COL11A1) in cell invasiveness and tumor formation and the prognostic impact of COL11A1 expression in ovarian cancer. Microarray analysis suggested that COL11A1 is a disease progression-associated gene that is linked to ovarian cancer recurrence and poor survival. Small interference RNA-mediated specific reduction in COL11A1 protein levels suppressed the invasive ability and oncogenic potential of ovarian cancer cells and decreased tumor formation and lung colonization in mouse xenografts. A combination of experimental approaches, including real-time RT-PCR, casein zymography and chromatin immunoprecipitation (ChIP) assays, showed that COL11A1 knockdown attenuated MMP3 expression and suppressed binding of Ets-1 to its putative MMP3 promoter-binding site, suggesting that the Ets-1-MMP3 axis is upregulated by COL11A1. Transforming growth factor (TGF)-beta (TGF-beta1) treatment triggers the activation of smad2 signaling cascades, leading to activation of COL11A1 and MMP3. Pharmacological inhibition of MMP3 abrogated the TGF-beta1-triggered, COL11A1-dependent cell invasiveness. Furthermore, the NF-YA binding site on the COL11A1 promoter was identified as the major determinant of TGF-beta1-dependent COL11A1 activation. Analysis of 88 ovarian cancer patients indicated that high COL11A1 mRNA levels are associated with advanced disease stage. The 5-year recurrence-free and overall survival rates were significantly lower (P=0.006 and P=0.018, respectively) among patients with high expression levels of tissue COL11A1 mRNA compared with those with low expression. We conclude that COL11A1 may promote tumor aggressiveness via the TGF-beta1-MMP3 axis and that COL11A1 expression can predict clinical outcome in ovarian cancer patients. PMID- 23934191 TI - LIM domain kinases as potential therapeutic targets for neurofibromatosis type 2. AB - Neurofibromatosis type 2 (NF2) is caused by mutations in the NF2 gene that encodes a tumor-suppressor protein called merlin. NF2 is characterized by formation of multiple schwannomas, meningiomas and ependymomas. Merlin loss-of function is associated with increased activity of Rac and p21-activated kinases (PAKs) and deregulation of cytoskeletal organization. LIM domain kinases (LIMK1 and 2) are substrate for Cdc42/Rac-PAK and modulate actin dynamics by phosphorylating cofilin at serine-3. This modification inactivates the actin severing and depolymerizing activity of cofilin. LIMKs also translocate into the nucleus and regulate cell cycle progression. Significantly, LIMKs are overexpressed in several tumor types, including skin, breast, lung, liver and prostate. Here we report that mouse Schwann cells (MSCs) in which merlin function is lost as a result of Nf2 exon2 deletion (Nf2(DeltaEx2)) exhibited increased levels of LIMK1, LIMK2 and active phospho-Thr508/505-LIMK1/2, as well as phospho Ser3-cofilin, compared with wild-type normal MSCs. Similarly, levels of LIMK1 and 2 total protein and active phosphorylated forms were elevated in human vestibular schwannomas compared with normal human Schwann cells (SCs). Reintroduction of wild-type NF2 into Nf2(DeltaEx2) MSC reduced LIMK1 and LIMK2 levels. We show that pharmacological inhibition of LIMK with BMS-5 decreased the viability of Nf2(DeltaEx2) MSCs in a dose-dependent manner, but did not affect viability of control MSCs. Similarly, LIMK knockdown decreased viability of Nf2(DeltaEx2) MSCs. The decreased viability of Nf2(DeltaEx2) MSCs was not due to caspase dependent or -independent apoptosis, but rather due to inhibition of cell cycle progression as evidenced by accumulation of cells in G2/M phase. Inhibition of LIMKs arrests cells in early mitosis by decreasing aurora A activation. Our results suggest that LIMKs are potential drug targets for NF2 and tumors associated with merlin deficiency. PMID- 23934192 TI - A high-throughput screen identifies PARP1/2 inhibitors as a potential therapy for ERCC1-deficient non-small cell lung cancer. AB - Excision repair cross-complementation group 1 (ERCC1) is a DNA repair enzyme that is frequently defective in non-small cell lung cancer (NSCLC). Although low ERCC1 expression correlates with platinum sensitivity, the clinical effectiveness of platinum therapy is limited, highlighting the need for alternative treatment strategies. To discover new mechanism-based therapeutic strategies for ERCC1 defective tumours, we performed high-throughput drug screens in an isogenic NSCLC model of ERCC1 deficiency and dissected the mechanism underlying ERCC1-selective effects by studying molecular biomarkers of tumour cell response. The high throughput screens identified multiple clinical poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors, such as olaparib (AZD-2281), niraparib (MK-4827) and BMN 673, as being selective for ERCC1 deficiency. We observed that ERCC1 deficient cells displayed a significant delay in double-strand break repair associated with a profound and prolonged G2/M arrest following PARP1/2 inhibitor treatment. Importantly, we found that ERCC1 isoform 202, which has recently been shown to mediate platinum sensitivity, also modulated PARP1/2 sensitivity. A PARP1/2 inhibitor-synthetic lethal siRNA screen revealed that ERCC1 deficiency was epistatic with homologous recombination deficiency. However, ERCC1-deficient cells did not display a defect in RAD51 foci formation, suggesting that ERCC1 might be required to process PARP1/2 inhibitor-induced DNA lesions before DNA strand invasion. PARP1 silencing restored PARP1/2 inhibitor resistance in ERCC1 deficient cells but had no effect in ERCC1-proficient cells, supporting the hypothesis that PARP1 might be required for the ERCC1 selectivity of PARP1/2 inhibitors. This study suggests that PARP1/2 inhibitors as a monotherapy could represent a novel therapeutic strategy for NSCLC patients with ERCC1-deficient tumours. PMID- 23934193 TI - Pleiotropic effect of somatic mutations in the E2F subunit DP-1 gene in human cancer. AB - Transcription factor E2F-1 and its interaction with pRb provide a key point of control in cell proliferation. E2F-1 participates in both cell cycle progression and apoptosis, and in cells exists with a DP dimerization partner protein, the most prominent being DP-1. By mining the tumor tissue and cancer cell line encyclopedia genomic databases, we identified the first somatic mutations in the DP-1 gene and describe 53 distinct mutation events here. The mutations are mostly missense mutations, but also include nonsense and frame-shift mutations that result in truncated DP-1 derivatives. Mutation occurs throughout the DP-1 gene but generally leaves protein dimerization activity intact. This allows the mutant derivatives to affect the properties of the E2F-1/DP-1 heterodimer through a transdominant mechanism, which changes the DNA binding, transcriptional activation and pRb-binding properties of the heterodimer. In particular, many DP 1 mutants were found to impair E2F-1-dependent apoptosis. Our results establish that somatic mutations in DP-1 uncouple normal control of the E2F pathway, and thus define a new mechanism that could contribute to aberrant proliferation in tumor cells. PMID- 23934195 TI - Abstract and proportional myoelectric control for multi-fingered hand prostheses. AB - Powered hand prostheses with many degrees of freedom are moving from research into the market for prosthetics. In order to make use of the prostheses' full functionality, it is essential to study efficient ways of high dimensional myoelectric control. Human subjects can rapidly learn to employ electromyographic (EMG) activity of several hand and arm muscles to control the position of a cursor on a computer screen, even if the muscle-cursor map contradicts directions in which the muscles would act naturally. But can a similar control scheme be translated into real-time operation of a dexterous robotic hand? We found that despite different degrees of freedom in the effector output, the learning process for controlling a robotic hand was surprisingly similar to that for a virtual two dimensional cursor. Control signals were derived from the EMG in two different ways, with a linear and a Bayesian filter, to test how stable user intentions could be conveyed through them. Our analysis indicates that without visual feedback, control accuracy benefits from filters that reject high EMG amplitudes. In summary, we conclude that findings on myoelectric control principles, studied in abstract, virtual tasks can be transferred to real-life prosthetic applications. PMID- 23934196 TI - [Exercise training in heart failure]. AB - In patients with chronic but stable heart failure (HF) exercise training is a recommended and widely accepted adjunct to an evidence-based management involving pharmacological and non-pharmacological therapies. Various pathophysiological mechanisms, such as central hemodynamics, vasculature, ventilation, skeletal muscle function as well as neurohormonal activation and inflammation are responsible for exercise intolerance described in HF patients. There is sufficient and growing evidence that exercise training in HF with reduced (HFrEF) and with preserved ejection fraction (HFpEF) is effective in improving exercise capacity, HF symptoms and quality of life. The positive effects of exercise training in HF are mediated by an improvement of central hemodynamics, endothelial function, inflammatory markers, neurohumoral activation, as well as skeletal muscle structure and function. In contrast to convincing data from a large meta-analysis, the large HF-ACTION study (Heart Failure-A Controlled Trial Investigating Outcomes of exercise TraiNing) only demonstrated a modest improvement of all cause mortality and hospitalizations in HFrEF. Outcome data in HFpEF are lacking. Whether interval training incorporating variable and higher intensities or the addition of resistance exercise to a standard aerobic prescription is superior in improving clinical status of HF patients is currently being examined. Despite increasing validation of the potential of exercise training in chronic HF, challenges remain in the routine therapeutic application, including interdisciplinary management, financing of long-term exercise programs and the need to improve short-term and long-term adherence to exercise training. PMID- 23934197 TI - Gamma glutamyl transferase activity: relationship with thoracic aortic intima media thickness and inflammation. AB - OBJECTIVE: Increased serum gamma-glutamyl transferase (GGT) activity is known to be associated with atherosclerotic diseases. Thoracic aortic intima-media thickness (IMT) was reported as a marker of preclinical atherosclerosis. However, there is a lack of research directly examining the relationship between serum GGT activity and thoracic aortic IMT. Therefore, we aimed to investigate the association between serum GGT activity and thoracic aortic IMT. PATIENTS AND METHODS: The study population consisted of 329 patients without coronary artery disease, who underwent transesophageal echocardiography (TEE) examination for various indications from January 2011 to April 2013. GGT, high-sensitivity C reactive protein (hs-CRP) and other biochemical markers were measured in all patients. The patients were classified into tertiles according to their GGT activities (GGTlow < 19 U/l, GGTmid >= 19 U/l < 29 U/l, and GGThigh >= 29). RESULTS: The highest aortic IMT values were observed in the GGThigh group compared with the GGTmid and GGTlow groups (p < 0.05, for all). Also, aortic IMT values in the GGTmid group were higher than in the GGTlow group (p < 0.05). Multivariate regression analysis showed that GGT activity was independently associated with aortic IMT (beta = 0.487, p < 0.001) hs-CRP (beta = 0.282, p < 0.001), and triglyceride level (beta = 0.161, p = 0.007). CONCLUSION: The higher serum GGT concentrations within the "normal" range were associated with a greater IMT of the thoracic aorta. GGT activity may be a predictor of the extent of subclinical aortic atherosclerosis assessed with thoracic aortic IMT. PMID- 23934194 TI - Epithelial ovarian cancer experimental models. AB - Epithelial ovarian cancer (OvCa) is associated with high mortality and, as the majority (>75%) of women with OvCa have metastatic disease at the time of diagnosis, rates of survival have not changed appreciably over 30 years. A mechanistic understanding of OvCa initiation and progression is hindered by the complexity of genetic and/or environmental initiating events and lack of clarity regarding the cell(s) or tissue(s) of origin. Metastasis of OvCa involves direct extension or exfoliation of cells and cellular aggregates into the peritoneal cavity, survival of matrix-detached cells in a complex ascites fluid phase and subsequent adhesion to the mesothelium lining covering abdominal organs to establish secondary lesions containing host stromal and inflammatory components. Development of experimental models to recapitulate this unique mechanism of metastasis presents a remarkable scientific challenge, and many approaches used to study other solid tumors (for example, lung, colon and breast) are not transferable to OvCa research given the distinct metastasis pattern and unique tumor microenvironment (TME). This review will discuss recent progress in the development and refinement of experimental models to study OvCa. Novel cellular, three-dimensional organotypic, and ex vivo models are considered and the current in vivo models summarized. The review critically evaluates currently available genetic mouse models of OvCa, the emergence of xenopatients and the utility of the hen model to study OvCa prevention, tumorigenesis, metastasis and chemoresistance. As these new approaches more accurately recapitulate the complex TME, it is predicted that new opportunities for enhanced understanding of disease progression, metastasis and therapeutic response will emerge. PMID- 23934198 TI - Observation of the temporal crest canal in the mandibular ramus by cone beam computed tomography and macroscopic study. AB - PURPOSE: The mandibular ramus is regarded as a relatively safe zone for a sagittal splitting osteotomy or for harvesting bone during implant treatment. The only important anatomical structure is the mandibular canal. The mandible has some anatomical variants that need to be recognized, such as a bifid mandibular canal, a retromolar canal, and rarely a temporal crest canal (TCC). In this study, cadaver mandibles were used to evaluate the TCC in the mandibular ramus using cone beam computed tomography (CBCT). METHODS: Altogether, 90 sites on 48 mandibles from Japanese cadavers were examined in this study. The CBCT volumetric images were acquired for areas of 79 mm[Formula: see text] 71 mm. Three dimensional observation of the images was undertaken to estimate the frequency, position of the orifices, and canal continuity. The cadaver mandibles in which the TCCs were observed were dissected from the inner surface to confirm the contents. RESULTS: Five TCCs (5.6 %) were observed in 90 observation areas. At least one TCC was confirmed in four (8.3 %) of 48 mandibles. Two types of TCC were recognized. Dissection revealed that they contained neurovascular bundles. CONCLUSION: Three-dimensional diagnosis is essential prior to surgical procedures in the mandibular ramus because unexpected blood vessels may be present that may cause bleeding or complications during the surgery. PMID- 23934199 TI - Real life experience with alemtuzumab treatment of patients with lower-risk MDS and a hypocellular bone marrow. AB - Immunosuppressive therapy is a therapeutic option for selected low-risk myelodysplastic syndromes (MDS) patients. Besides standard treatment protocols that include ATG and CSA, the humanized CD52 antibody alemtuzumab has been shown to have efficacy in MDS treatment. We report our experience with alemtuzumab in nine MDS RCMD patients. All patients had a hypocellular bone marrow with a blast count <5 % and were classified as intermediate-1 according to the IPSS. We found a response in five patients (60 %); three patients achieved a complete remission 3 and 6 months after the treatment with alemtuzumab, and two patients showed a haematological improvement. Alemtuzumab was administered in a 10-mg dosage for 10 days. Treatment was well tolerated, and no severe side effects were observed. We could confirm the finding that the alemtuzumab is effective and save selected MDS patients. Due to the promising results, further studies, especially with regard to long-term survival and risk of leucemic progression should be initiated. PMID- 23934200 TI - A novel three-dimensional analysis of standardized bone defects by means of confocal scanner and micro-computed tomography. AB - OBJECTIVES: The aim of the study was to introduce a novel three-dimensional (3D) method to quantify the relative amount of different tissue components in bone substitute-treated defects by means of integration of confocal laser imaging into micro-computed tomography (MUCT) analysis. MATERIALS AND METHODS: One standardized semisaddle intraosseous defect was prepared in the mandibles of six minipigs and scanned by an optical scanner to capture the surface of the fresh defect in a 3D manner. Subsequently, all the defects were filled with a biphasic calcium phosphate material. The animals were divided into two groups of three animals each, which were allowed to heal for 3 and 8 weeks, respectively. MUCT analysis followed the two healing periods and was performed on all defect locations. The data from optical scanning and MUCT were used for three dimensional evaluation of bone formation, nonmineralized tissue ratio, and graft degradation. The integration of confocal laser scanning into MUCT analysis through a superimposition imaging procedure was conducted using the software Amira (Mercury Computer Systems, Chelmsford, MA, USA). RESULTS: The feasibility of combining the confocal imaging into MUCT data with regard to obtaining accurate 3D quantification was demonstrated. The amount of tissue components was identified and quantified in all the investigated samples. Quantitative analysis demonstrated that a significant increase in the amount of bone filling the defect was observed in vivo (p < 0.02) while a significant decrease in the amount of nonmineralized tissue occurred (p < 0.04). No difference in the amount of residual grafting material was detected between 3 and 8 weeks in vivo (p > 0.38). CONCLUSIONS: The combination of confocal imaging and micro-computed tomography techniques allows for analysis of different tissue types over time in vivo. This method has revealed to be a feasible alternative to current bone regeneration quantification methods. CLINICAL RELEVANCE: Assessment of bone formation in a large animal model is a key step in assessing the performance of new bone substitute materials. Reliable and accurate methods are needed for the analysis of the regenerative potential of new materials. PMID- 23934201 TI - Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy. AB - Covering 2005 to 2013. In this review recent progress in the development of heat shock proteins (Hsp90) in oncogenesis is illuminated. Particular emphasis is put on inhibitors such as geldanamycin and analogues that serve as a natural product show case. Hsp90 has emerged as an important target in cancer therapy and/or against pathogenic cells which elicit abnormal Hsp patterns. Competition for ATP by geldanamycin and related compounds abrogate the chaperone function of Hsp90. In this context, this account pursues three topics in detail: a) Hsp90 and its biochemistry, b) Hsp90 and its role in oncogenesis and c) strategies to create compound libraries of structurally complex inhibitors like geldanamycin on which SAR studies and the development of drugs that are currently in different stages of clinical testing rely. PMID- 23934202 TI - MRI after unicondylar knee arthroplasty: rotational alignment of components. AB - INTRODUCTION: This pilot study used magnet resonance imaging (MRI) to analyse the rotation of medial unicondylar knee arthroplasty (UKA) components and assessed how accurately the results could be reproduced. MATERIALS AND METHODS: Knee MRI using a special protocol to reduce metal artefact was performed in ten patients who had undergone medial UKA. Two independent investigators measured the rotation angle of femoral (zirconium) and tibial (cemented full-poly or cemented modular metal-backed) components applying different reference lines for the latter. Statistical analysis comprised tests for reliability, variance between measurement techniques, standard deviations and limits of agreement. RESULTS: For all methods tested, there was sufficient inter- and intra-observer reliability. Lowest variances were, however, found for the femoral epicondyles, for both femoral and tibial components. A tangent to the dorsal epicondyles of the tibia also gave reproducible results with low variances for the tibial component. DISCUSSION: Almost all applied measurement techniques were reproducible by statistical definition, although some of them resulted in substantial differences between both, observations and observers. A variance test helps to distinguish better between clinically useful and less accurate references. CONCLUSION: MRI allows good reproducible rotation analysis via the femoral epicondyles for both femoral and tibial UKA implants. For the tibia, the tibial tuberosity, the eminentia and the tibial epicondyles in particular were shown to be less reliable. The dorsal epicondyles seem to be most suitable for the tibial component. PMID- 23934203 TI - Detection of EGFR gene mutations in non-small cell lung cancer: lessons from a single-institution routine analysis of 1,403 tumor samples. AB - Activating mutations of the epidermal growth factor receptor (EGFR) in lung tumors are associated with a dramatic response to tyrosine kinase inhibitors. Therefore, routine analysis of pathological specimens is mandatory in clinical practice. We have prospectively tested tumors from Caucasian lung tumor patients between January 2010 and June 2012. DNA was extracted from formalin-fixed paraffin-embedded tissues following macrodissection. The p.L858R substitution was assessed by allele-specific PCR and exon 19 deletions by PCR and DNA fragment analysis. Using a robust process from patient sampling to screening methods, we analyzed samples from 1,403 patients. The EGFR status could be successfully determined for 1,322 patients. EGFR mutations were detected in 179 (13.5%) patients, with female and adenocarcinoma histology predominance. Mutated patients were significantly older than non-mutated patients. Similar mutation rates were obtained with primary tumors and metastases, and with surgical resection, bronchial biopsies, CT-guided needle biopsies and transbronchial needle aspiration. The sensitivity of our assays allowed us to detect EGFR mutations in samples poor (<10%) in tumor cells. Finally, the mutation rate was much higher in tumors expressing the TTF-1 antigen (145/820; 17.7%) than in TTF-1 negative tumors (3/218; 1.4%). The results obtained through routine analysis of more than 1,300 samples indicated that all types of specimen can be analyzed without any significant bias. TTF-1 immunostaining may be used to predict negative EGFR mutation status. PMID- 23934204 TI - Group A streptococcal emm type prevalence among symptomatic children in Cape Town and potential vaccine coverage. AB - The molecular epidemiology of group A streptococcal pharyngeal infections in children in the Vanguard Community of Cape Town revealed 26 emm types among 157 isolates from 742 subjects. Coverage of a 30-valent vaccine is predicted to be 95% of pharyngitis cases in this population at high risk of rheumatic fever. PMID- 23934205 TI - Teeth and tongue discoloration after linezolid treatment in children. AB - We describe 3 children who developed teeth and tongue discoloration while receiving intravenous linezolid for 2 to 3 weeks. Linezolid was coadministered with piperacillin-tazobactam or meropenem. Teeth and tongue discoloration was reversible with dental cleaning after discontinuation of linezolid. We review the published pediatric and adult cases regarding teeth and tongue discoloration after linezolid administration. PMID- 23934206 TI - Temporal trends in emergency department visits for bronchiolitis in the United States, 2006 to 2010. AB - BACKGROUND: To examine temporal trends in emergency departments (EDs) visits for bronchiolitis among US children between 2006 and 2010. METHODS: Serial, cross sectional analysis of the Nationwide Emergency Department Sample, a nationally representative sample of ED patients. We used International Classification of Diseases, Ninth Revision, Clinical Modification code 466.1 to identify children <2 years of age with bronchiolitis. Primary outcome measures were rate of bronchiolitis ED visits, hospital admission rate and ED charges. RESULTS: Between 2006 and 2010, weighted national discharge data included 1,435,110 ED visits with bronchiolitis. There was a modest increase in the rate of bronchiolitis ED visits, from 35.6 to 36.3 per 1000 person-years (2% increase; Ptrend = 0.008), due to increases in the ED visit rate among children from 12 months to 23 months (24% increase;Ptrend < 0.001). By contrast, there was a significant decline in the ED visit rate among infants (4% decrease; Ptrend < 0.001). Although unadjusted admission rate did not change between 2006 and 2010 (26% in both years), admission rate declined significantly after adjusting for potential patient- and ED-level confounders (adjusted odds ratio for comparison of 2010 with 2006, 0.84; 95% confidence interval: 0.76-0.93; P < 0.001). Nationwide ED charges for bronchiolitis increased from $337 million to $389 million (16% increase; Ptrend < 0.001), adjusted for inflation. This increase was driven by a rise in geometric mean of ED charges per case from $887 to $1059 (19% increase; Ptrend < 0.001). CONCLUSIONS: Between 2006 and 2010, we found a divergent temporal trend in the rate of bronchiolitis ED visits by age group. Despite a significant increase in associated ED charges, ED-associated hospital admission rates for bronchiolitis significantly decreased over this same period. PMID- 23934207 TI - Community-associated Staphylococcus aureus infections in otherwise healthy infants less than 60 days old. AB - Community-associated (CA)-Staphylococcus aureus (CA-methicillin-resistant S. aureus in 57%) infections were reviewed in 179 infants (0-60 days) from June 2006 to June 2011. CA-MSSA accounted for 16 of 44 (36%) in year 1 up to 12 of 25 (48%) in year 5 (P = 0.08). Abscess/cellulitis infections were more likely (P = 0.006) to be caused by CA-methicillin-resistant S. aureus (67%) versus other manifestations of infections (46%). Among 160 isolates, 13% were clindamycin resistant and 63% were USA300. PMID- 23934209 TI - 7,8-Dihydroxyflavone, a TrkB agonist, attenuates behavioral abnormalities and neurotoxicity in mice after administration of methamphetamine. AB - RATIONALE: It is widely recognized that methamphetamine (METH) induces behavioral abnormalities and dopaminergic neurotoxicity in the brain. Several lines of evidence suggest a role for brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), in METH-induced behavioral abnormalities. OBJECTIVE: In this study, we examined whether 7,8-dihydroxyflavone (7,8-DHF), a novel potent TrkB agonist, could attenuate behavioral abnormalities and dopaminergic neurotoxicity in mice after administration of METH. RESULTS: Pretreatment with 7,8-DHF (3.0, 10, or 30 mg/kg), but not the inactive TrkB compound, 5,7-dihydroxyflavone (5,7-DHF) (30 mg/kg), attenuated hyperlocomotion in mice after a single administration of METH (3.0 mg/kg), in a dose-dependent manner. The development of behavioral sensitization after repeated administration of METH (3.0 mg/kg/day, once daily for 5 days) was significantly attenuated by pretreatment with 7,8-DHF (10 mg/kg). Furthermore, pretreatment and subsequent administration of 7,8-DHF (10 mg/kg) attenuated the reduction of dopamine transporter (DAT) in the striatum after repeated administration of METH (3.0 mg/kg * 3 at 3-hourly intervals). Treatment with ANA-12 (0.5 mg/kg), a potent TrkB antagonist, blocked the protective effects of 7,8-DHF on the METH-induced reduction of DAT in the striatum. Moreover, 7,8-DHF attenuated microglial activation in the striatum after repeated administration of METH. CONCLUSIONS: These findings suggest that 7,8-DHF can ameliorate behavioral abnormalities as well as dopaminergic neurotoxicity in mice after administration of METH. It is likely, therefore, that TrkB agonists such as 7,8-DHF may prove to be potential therapeutic drugs for several symptoms associated with METH abuse in humans. PMID- 23934212 TI - Kinin-stimulated B1 receptor signaling depends on receptor endocytosis whereas B2 receptor signaling does not. AB - Kinins are potent pro-inflammatory peptides that act through two G protein coupled receptor subtypes, B1 (B1R) and B2 (B2R). Kinin-stimulated B2R signaling is often transient, whereas B1R signaling is sustained. This was confirmed by monitoring agonist-stimulated intracellular Ca(2+) mobilization in A10 smooth muscle cells expressing human wild-type B2R and B1R. We further studied the role of receptor membrane trafficking in receptor-mediated phosphoinositide (PI) hydrolysis in model HEK293 cell lines stably expressing the receptors. Treatment of cells with brefeldin A, to inhibit maturation of de novo synthesized receptors, or hypertonic sucrose, to inhibit receptor endocytosis, showed that the basal cell surface receptor turnover was considerably faster for B1R than for B2R. Inhibition of endocytosis, which stabilized B1R on the cell surface, inhibited B1R signaling, whereas B2R signaling was not perturbed. Signaling by a B1R construct in which the entire C-terminal domain was deleted remained sensitive to inhibition of receptor endocytosis, whereas signaling by a B1R construct in which this domain was substituted with the corresponding domain in B2R was not sensitive. B2R and B1R co-expression, which also appeared to stabilize B1R on the cell surface, presumably by receptor hetero-dimerization, also inhibited B1R signaling, whereas B2R signaling was slightly enhanced. Furthermore, the B2R-specific agonist bradykinin (BK) directed both receptors through a common endocytic pathway, whereas the B1R-specific agonist Lys desArg(9)-BK was unable to do so. These results suggest that B1R-mediated PI hydrolysis depends on a step in receptor endocytosis, whereas B2R-mediated PI hydrolysis does not. We propose that B1R uses at least part of the endocytic machinery to sustain agonist-promoted signaling. PMID- 23934213 TI - The distinct signaling regulatory roles in the cortical atrophy and cerebellar apoptosis of newborn Nbn-deficient mice. AB - Human Nijmegen breakage syndrome, caused by the hypomorphic mutation of Nbn gene, is a hereditary instability disease, characterized by chromosomal instability, immunodeficiency, radiosensitivity, cancer predisposition and microcephaly. To study the roles of Nbn protein in microcephaly, Nbn gene was specifically deleted in the central nervous system of mice by nestin-Cre targeting gene system (Frappart et al. in Nat Med 11:538-544, 2005). Strikingly, newborn Nbn-deficient mice exhibit the evident microcephalic cerebellum, which contributes to severe ataxia and balance deficiency. In this study, we first report that PI3K/AKT/mTOR signaling pathway that performs neurotrophic-protecting role in neuronal growth is significantly inhibited in newborn Nbn-deficient cortex and cerebellum. In addition, JNK signaling and ATR signaling are likely to converge to regulate the cerebellar apoptosis of newborn Nbn-deficient mice. PMID- 23934211 TI - The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders. AB - RATIONALE AND OBJECTIVES: Modafinil (MOD) and its R-enantiomer (R-MOD) are approved medications for narcolepsy and other sleep disorders. They have also been used, off-label, as cognitive enhancers in populations of patients with mental disorders, including substance abusers that demonstrate impaired cognitive function. A debated nonmedical use of MOD in healthy individuals to improve intellectual performance is raising questions about its potential abuse liability in this population. RESULTS AND CONCLUSIONS: MOD has low micromolar affinity for the dopamine transporter (DAT). Inhibition of dopamine (DA) reuptake via the DAT explains the enhancement of DA levels in several brain areas, an effect shared with psychostimulants like cocaine, methylphenidate, and the amphetamines. However, its neurochemical effects and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory. At variance with typical psychostimulants, MOD shows very low, if any, abuse liability, in spite of its use as a cognitive enhancer by otherwise healthy individuals. Finally, recent clinical studies have focused on the potential use of MOD as a medication for treatment of drug abuse, but have not shown consistent outcomes. However, positive trends in several result measures suggest that medications that improve cognitive function, like MOD or R MOD, may be beneficial for the treatment of substance use disorders in certain patient populations. PMID- 23934214 TI - Establishment of totipotency does not depend on Oct4A. AB - Oct4A is a core component of the regulatory network of pluripotent cells, and by itself can reprogram neural stem cells into pluripotent cells in mice and humans. However, its role in defining totipotency and inducing pluripotency during embryonic development is still unclear. We genetically eliminated maternal Oct4A using a Cre/loxP approach in mouse and found that the establishment of totipotency was not affected, as shown by the generation of live pups. After complete inactivation of both maternal and zygotic Oct4A expression, the embryos still formed Oct4-GFP- and Nanog-expressing inner cell masses, albeit non pluripotent, indicating that Oct4A is not a determinant for the pluripotent cell lineage separation. Interestingly, Oct4A-deficient oocytes were able to reprogram fibroblasts into pluripotent cells. Our results clearly demonstrate that, in contrast to its role in the maintenance of pluripotency, maternal Oct4A is not crucial for either the establishment of totipotency in embryos, or the induction of pluripotency in somatic cells using oocytes. PMID- 23934215 TI - Primary cilium migration depends on G-protein signalling control of subapical cytoskeleton. AB - In ciliated mammalian cells, the precise migration of the primary cilium at the apical surface of the cells, also referred to as translational polarity, defines planar cell polarity (PCP) in very early stages. Recent research has revealed a co-dependence between planar polarization of some cell types and cilium positioning at the surface of cells. This important role of the primary cilium in mammalian cells is in contrast with its absence from Drosophila melanogaster PCP establishment. Here, we show that deletion of GTP-binding protein alpha-i subunit 3 (Galphai3) and mammalian Partner of inscuteable (mPins) disrupts the migration of the kinocilium at the surface of cochlear hair cells and affects hair bundle orientation and shape. Inhibition of G-protein function in vitro leads to kinocilium migration defects, PCP phenotype and abnormal hair bundle morphology. We show that Galphai3/mPins are expressed in an apical and distal asymmetrical domain, which is opposite and complementary to an aPKC/Par-3/Par-6b expression domain, and non-overlapping with the core PCP protein Vangl2. Thus G-protein dependent signalling controls the migration of the cilium cell autonomously, whereas core PCP signalling controls long-range tissue PCP. PMID- 23934216 TI - Tissue damage detection by osmotic surveillance. AB - How tissue damage is detected to induce inflammatory responses is unclear. Most studies have focused on damage signals released by cell breakage and necrosis. Whether tissues use other cues in addition to cell lysis to detect that they are damaged is unknown. We find that osmolarity differences between interstitial fluid and the external environment mediate rapid leukocyte recruitment to sites of tissue damage in zebrafish by activating cytosolic phospholipase a2 (cPLA2) at injury sites. cPLA2 initiates the production of non-canonical arachidonate metabolites that mediate leukocyte chemotaxis through a 5-oxo-ETE receptor (OXE R). Thus, tissues can detect damage through direct surveillance of barrier integrity, with cell swelling probably functioning as a pro-inflammatory intermediate in the process. PMID- 23934217 TI - Volar dislocation of index and middle finger carpometacarpal joints: a case report. PMID- 23934218 TI - Agreement between SPECT V/Q scan and CT angiography in patients with high clinical suspicion of PE. AB - OBJECTIVE: To track agreement between single positron emission computed tomography (SPECT) V/Q and CT angiography in patients with high clinical suspicion of pulmonary embolism (PE). If significant agreement occurs, a case could be made for more frequent use of chest radiography followed by SPECT V/Q scanning given its lower risk profile. INTRODUCTION: Diagnosis of PE can be difficult. CT pulmonary angiography (CTA) is the preferred initial test, but may be indeterminate, is a significant source of ionizing radiation, and is contraindicated in renal insufficiency. SPECT ventilation/perfusion imaging (V/Q) is therefore preferred in certain patients. METHODS: Two thousand nine hundred and twenty patients admitted to a tertiary care hospital in New York City were screened and 100 consecutive high-risk patients who required both CTA and V/Q for an initial indeterminate or negative imaging test despite a high pre-test probability were identified. The agreement between these tests was evaluated. RESULTS: There was no significant agreement between CTA and V/Q when positive, negative and indeterminate results were included (K = 0.18, SE = 0.09, p = 0.051). However, in the presence of a positive finding on either test, there was substantial agreement between the two (K = 0.62, SE = 0.27, p = 0.02). In 30 cases in which CTA was indeterminate, V/Q was diagnostic 93 % of the time. In 12 cases in which V/Q was indeterminate, CTA was diagnostic 83 % of the time and negative in 100 % of those cases. CONCLUSION: In the presence of an indeterminate CTA in patients with high clinical suspicion of PE, SPECT V/Q often provides a diagnosis. PMID- 23934219 TI - Heat-induced formation of nitrogen oxides in water. AB - It was found by the fluorimetric method using 2,3-diaminonaphthalene that moderate heating of water (60-80 degrees C, for up to 4 h) leads to the fixation of atmospheric nitrogen with the formation of nitrite. The kinetic parameters of this process were determined. The energy of activation of [Formula: see text]formation was estimated to be 139 kJ/mol. It was found that the amount of nitrite formed depends on the concentration of dissolved oxygen and nitrogen. It was shown by two independent methods (Griess reagent/VCl3 and 2,3 diaminonaphthalene/nitrate reductase) that heating of water (80 degrees C, 1 h) results in the formation of nitrate; with the use of the fluorescent probe dihydrorhodamine 123, the generation of nitrogen dioxide (peroxynitrite) was revealed. Nitrite, nitrate, and nitrogen dioxide are formed in water upon heating in approximately equal amounts. A scheme of reactions proceeding with bidistilled water by the action of heat with the formation of nitrogen oxides is proposed. PMID- 23934220 TI - Yoga for rheumatic diseases: a systematic review. AB - OBJECTIVE: To evaluate the quality of evidence and the strength of recommendation for yoga as an ancillary intervention in rheumatic diseases. METHODS: Medline/PubMed, Scopus, the Cochrane Library and IndMED were searched through February 2013. Randomized controlled trials (RCTs) comparing yoga with control interventions in patients with rheumatic diseases were included. Two authors independently assessed the risk of bias using the Cochrane Back Review Group risk of bias tool. The quality of evidence and the strength of the recommendation for or against yoga were graded according to the GRADE recommendations. RESULTS: Eight RCTs with a total of 559 subjects were included; two RCTs had a low risk of bias. In two RCTs on FM syndrome, there was very low evidence for effects on pain and low evidence for effects on disability. In three RCTs on OA, there was very low evidence for effects on pain and disability. Based on two RCTs, very low evidence was found for effects on pain in RA. No evidence for effects on pain was found in one RCT on CTS. No RCT explicitly reported safety data. CONCLUSION: Based on the results of this review, only weak recommendations can be made for the ancillary use of yoga in the management of FM syndrome, OA and RA at this point. PMID- 23934221 TI - Trajectories of functional limitation in early rheumatoid arthritis and their association with mortality. AB - OBJECTIVE: This study aimed to identify subgroups with distinct trajectories of functional (HAQ) progression over 10 years following diagnosis of RA and identify baseline characteristics associated with the trajectories and their prognostic value for mortality. METHODS: Between 1986 and 1998, 1460 patients with RA symptoms <2 years and prior to disease-modifying treatment (DMARDs) were recruited to an inception cohort (Early RA Study). Standard clinical, functional and laboratory assessments were performed at presentation and annually. Deaths were tracked by the National Health Service Central Register. Growth mixture modelling was used to identify distinct trajectories of HAQ score progression and survival analysis employed to compare all-cause mortality across the trajectory classes. RESULTS: Four HAQ score progression classes were identified: moderate increasing (46%), low stable (6%), moderate stable (28%) and high stable (20%). Only the moderate-increasing class exhibited an accelerated decline in function over normal ageing. Compared with the moderate-increasing class, individuals with high-stable HAQ scores were more likely to be female, have more severe disease and other coexistent conditions. Low-stable class patients were more likely to be male and report less pain. The high-stable class had increased risk of mortality compared with the moderate-increasing class after adjusting for potential confounding factors, whereas low-stable and moderate-stable classes were at reduced mortality risk. CONCLUSION: The effect of RA on function is set within the first few years and is affected by comorbidity. Identifying distinct groups of patients may help to target those at greater risk of poor functional outcome and mortality. PMID- 23934222 TI - Fanconi anemia signaling network regulates the spindle assembly checkpoint. AB - Fanconi anemia (FA) is a heterogenous genetic disease with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy. Furthermore, we discovered that FA proteins differentially localize to key structures of the mitotic apparatus in a cell cycle-dependent manner. The essential role of the FA pathway in mitosis offers a mechanistic explanation for the aneuploidy and malignant transformation known to occur after disruption of FA signaling. Collectively, our findings provide insight into the genetically unstable cancers resulting from inactivation of the FA/BRCA pathway. PMID- 23934223 TI - Exploring the perceived changes and the reasons why expected outcomes were not obtained in individual levels in a successful regional palliative care intervention trial: an analysis for interpretations. AB - CONTEXT: The Japan Outreach Palliative Care Trial of Integrated Model (OPTIM) study, a mixed-methods study to evaluate the effects of a comprehensive regional palliative care program, revealed that the program provided broad positive outcomes at the regional level: increased home death, palliative care use, patient- and family-reported qualities of care, and health care professionals' difficulties. Not all participants however obtained positive outcomes and thus exploring the reasons why expected outcomes were observed in individual levels could be of value. AIMS: The primary aims were to explore why expected outcomes were not obtained in individual participants, and the perceived changes in daily practices of physicians and nurses were explored. SUBJECTS AND METHODS: Postintervention questionnaire survey on 857 patients, 1,137 bereaved family members, 706 physicians, and 2,236 nurses were analyzed. RESULTS: The reasons for not achieving home deaths included unexpected rapid deterioration, caregivers unavailable, concerns about adequate responses to sudden changes, and physical symptoms uncontrolled, while lack of physician availability at home and lack of information from physicians were less frequently reported. The reasons for not receiving specialized palliative care services were the lack of recommendations from physicians and no information about palliative care services. The reason for evaluating the quality of palliative care as not high was that clinicians tried to relieve symptoms, but there were limited effects and insufficient time. Many physicians and nurses reported that they became more aware of palliative care, that the availability of palliative care specialists and knowledge about palliative care improved, and that they cooperated with other regional health care providers more easily. CONCLUSION: The OPTIM study seemed to succeed in optimizing physician availability at home, improves physician information about home care, achieved maximum efforts to relieve patient distress by clinicians, and increased communication among regional health care professionals. To achieve further better outcomes, multiple interventions to the health care system to be performed on the basis of a comprehensive regional palliative care program are proposed. PMID- 23934224 TI - Managing brain metastases patients with and without radiotherapy: initial lessonsfrom a team-based consult service through a multidisciplinary integrated palliative oncology clinic. AB - PURPOSE: A new ambulatory consultative clinic with integrated assessments by palliative care, radiation oncology, and allied health professionals was introduced to (1) assess patients with brain metastases at a regional comprehensive cancer center and (2) inform and guide patients on management strategies, including palliative radiotherapy, symptom control, and end-of-life care issues. We conducted a quality assurance study to inform clinical program development. METHODS: Between January 2011 and May 2012, 100 consecutive brain metastases patients referred and assessed through a multidisciplinary clinic were evaluated for baseline characteristics, radiotherapy use, and supportive care decisions. Overall survival was examined by known prognostic groups. Proportion of patients receiving end-of-life radiotherapy (death within 30 and 14 days of brain radiotherapy) was used as a quality metric. RESULTS: The median age was 65 years, with non-small cell lung cancer (n = 38) and breast cancer (n = 23) being the most common primary cancers. At least 57 patients were engaged in advance care planning discussions at first consult visit. In total, 75 patients eventually underwent brain radiotherapy, whereas 25 did not. The most common reasons for nonradiotherapy management were patient preference and rapid clinical deterioration. Overall survival for prognostic subgroups was consistent with literature reports. End-of-life brain radiotherapy was observed in 9 % (death within 30 days) and 1 % (within 14 days) of treated patients. CONCLUSIONS: By integrating palliative care expertise to address the complex needs of patients with newly diagnosed brain metastases, end-of-life radiotherapy use appears acceptable and improved over historical rates at our institution. An appreciable proportion of patients are not suitable for palliative brain radiotherapy or opt against this treatment option, but the team approach involving nurses, palliative care experts, allied health, and clinical oncologists facilitates patient centered decision making and transition to end-of-life care. PMID- 23934225 TI - Can the LANSS scale be used to classify pain in chronic cancer pain trials? AB - PURPOSE: The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale was developed to differentiate pain of predominantly neuropathic or nociceptive origin. The aim of this study was to determine whether the LANSS scale was an appropriate tool to classify pain in a trial of patients with advanced cancer and chronic refractory pain. METHODS: Clinician assessment of pain type (neuropathic or nociceptive) was used to determine the sensitivity and specificity of LANSS scores in 112 trial participants. Those classified as "mixed" or of uncertain aetiology were excluded. We undertook several analyses in an attempt to improve the LANSS scale and better diagnose pain type for our specific dataset. RESULTS: There was strong association between the LANSS score and a diagnosis of neuropathic versus nociceptive pain, p < 0.001. When the clinical assessment was compared with the LANSS scale, the overall accuracy was 94 % (79/84). The 5 false negatives and no false positives resulted in a sensitivity of 0.86 (0.70, 0.95), specificity of 1 (0.93, 1), positive predictive value of 1 (0.88, 1) and negative predictive value of 0.91 (0.80, 0.97). The negative likelihood ratio was 0.14 (0, 0.32). The scale had good discriminant and construct validity. Reliability was assessed via internal consistency with Cronbach's alpha = 0.76, similar to that of the original validation study (alpha = 0.74). None of the new scales developed was better at differentiating pain type. CONCLUSIONS: The LANSS scale predicted well for pain type in a cancer population and is a useful tool for classifying pain in cancer pain trials. PMID- 23934226 TI - A brief couples' workshop for improving sexual experiences after prostate cancer treatment: a feasibility study. AB - PURPOSE: The most difficult survivorship issue reported by prostate cancer patients is the dramatic changes in their sexual relationships. The purpose of this study was to investigate the feasibility of a workshop designed to improve patients' and partners' sexual relationships. METHOD: Participants attended one 3.5-h workshop. A total of three separate workshops were held over a 12-month period. Patients and partners complete the Sexual Functioning Questionnaire (SFQ) prior, 2 months following, and if couples registered early enough, 2 months before the workshop. Change scores were calculated. RESULTS: Over the three workshops, 77 participants attended. All targets were met for feasibility and acceptability. Patients and partners both demonstrated significant gains on the medical impact subscale of the SFQ, and partners also demonstrated significant gains in sexual interest, problems, and total sexual function. CONCLUSIONS: The results suggest that attending one 3.5-h workshop that is offered every 4 months is feasible and acceptable to patients and their partners. Furthermore, the SFQ proves to be a sensitive assessment instrument of sexual function for patients and their partners. PMID- 23934227 TI - Friction coefficient dependence on electrostatic tribocharging. AB - Friction between dielectric surfaces produces patterns of fixed, stable electric charges that in turn contribute electrostatic components to surface interactions between the contacting solids. The literature presents a wealth of information on the electronic contributions to friction in metals and semiconductors but the effect of triboelectricity on friction coefficients of dielectrics is as yet poorly defined and understood. In this work, friction coefficients were measured on tribocharged polytetrafluoroethylene (PTFE), using three different techniques. As a result, friction coefficients at the macro- and nanoscales increase many fold when PTFE surfaces are tribocharged, but this effect is eliminated by silanization of glass spheres rolling on PTFE. In conclusion, tribocharging may supersede all other contributions to macro- and nanoscale friction coefficients in PTFE and probably in other insulating polymers. PMID- 23934229 TI - Discrete modeling of dynamics of zooplankton community at the different stages of an antropogeneous eutrophication. AB - Mathematical modeling is a convenient way for characterization of complex ecosystems. This approach was applied to study the dynamics of zooplankton in Lake Sevan (Armenia) at different stages of anthropogenic eutrophication with the use of a novel method called discrete modeling of dynamical systems with feedback (DMDS). Simulation demonstrated that the application of this method helps in characterization of inter- and intra-component relationships in a natural ecosystem. This method describes all possible pairwise inter-component relationships like "plus-plus," "minus-minus," "plus-minus," "plus-zero," "minus zero," and "zero-zero" that occur in most ecosystems. Based on the results, a working hypothesis was formulated. It was found that the sensitivity to weak external influence in zooplanktons was the greatest during the mid period of eutrophication in Lake Sevan, whereas in the final stages of eutrophication, an outbreak in the biomass production of cyanobacteria was evident. To support this approach, a weak external disturbance in the form of magnetic storm was used to see its effect on species Daphnia longispina sevanica. A statistically significant correlation between the frequency of magnetic storms and the number of this species was revealed and an increase in the number of toxic cyanobacteria species as a consequence of eutrophication. This paper, for the first time, suggests a DMDS method, to diagnose impact of anthropogenic eutrophication on environment. PMID- 23934228 TI - Generating hypoimmunogenic human embryonic stem cells by the disruption of beta 2 microglobulin. AB - Immune rejection hinders the application of human embryonic stem cells (hESCs) in transplantation therapy. Human leukocyte antigens (HLAs) on the cell surface are the major cause of graft rejection. In this study, we generated HLA class I deficient hESCs via disruption of beta 2-microglobulin (beta2m), the light chain of HLA Class I. We found that HLA class I proteins were not present on the cell surface of beta2m-null hESCs. These cells showed the same pluripotency as wildtype hESCs and demonstrated hypoimmunogenicity. Thus, HLA class I-deficient hESCs might serve as an unlimited cell source for the generation of universally compatible "off-the-shelf" cell grafts, tissues or organs in the future. PMID- 23934230 TI - Reversible adaptive trees. AB - We describe reversible adaptive trees, a class of stochastic algorithms modified from the formerly described adaptive trees. They evolve in time a finite subset of an ambient Euclidean space of any dimension, starting from a seed point and, accreting points to the evolving set, they grow branches towards a target set which can depend on time. In contrast with plain adaptive trees, which were formerly proven to have strong convergence properties to a static target, the points of reversible adaptive trees are removed from the tree when they have not been used recently enough in a path from the root to an accreted point. This, together with a straightening process performed on the branches, permits the tree to follow some moving targets and still remain adapted to it. We then discuss in what way one can see such reversible trees as a model for a qualitative property of resilience, which leads us to discuss qualitative modeling. PMID- 23934231 TI - Alemtuzumab induced complete remission of romidepsin-refractory large cell transformation of mycosis fungoides. PMID- 23934232 TI - Pulmonary congestion due to hypothyroidism and nephrotic syndrome induced by cold agglutinins. PMID- 23934234 TI - Functional MRI studies in non-CNS cancers. AB - With increasing survival, cognitive problems after systemic treatment for non-CNS cancers are a growing concern. Functional magnetic resonance imaging (fMRI) is a noninvasive neuroimaging technique that has the potential to uncover the neural circuitry underlying cognitive problems after systemic treatment in cancer patients. Here, we provide an in depth review of the 14 fMRI studies that have been published to date on potential neurotoxic side effects of systemic treatment for non-CNS cancers. Cross-sectional studies in breast cancer survivors show a consistent pattern of hypoactivation in prefrontal and parietal brain regions during various executive functioning tasks 5 to 10 years after completion of adjuvant chemotherapy that are sometimes associated with worse cognitive performance compared to cancer-specific or no-cancer controls. These findings suggest reduced neural functioning as a result of chemotherapy in brain regions that support cognitive functioning. With regard to episodic memory, hypoactivation at encoding is followed by hyperactivation at retrieval, suggestive of impairments in memory encoding that are compensated by neural hyperactivation to perform adequate memory retrieval. Prospective studies of executive functioning and episodic memory show a more complex picture of hypo- and hyperactivation that is possibly due to various counteracting mechanisms relatively shortly after chemotherapy. Two small studies in prostate cancer patients, finally, provide preliminary evidence for reduced activation in task relevant brain regions after androgen deprivation therapy, suggestive of reduction of neural function. Statistical correction for multiple comparisons in the reviewed studies is typically quite lenient. We suggest that future studies should preferably include larger sample sizes to allow proper statistical correction for multiple comparisons and include comprehensive neurocognitive tests and multimodal MRI to facilitate the interpretation of the observed fMRI findings. PMID- 23934233 TI - Apolipoprotein E gene polymorphism influences aggressive behavior in prostate cancer cells by deregulating cholesterol homeostasis. AB - High circulating cholesterol and its deregulated homeostasis may facilitate prostate cancer progression. Genetic polymorphism in Apolipoprotein (Apo) E, a key cholesterol regulatory protein may effect changes in systemic cholesterol levels. In this investigation, we determined whether variants of the Apo E gene can trigger defective intracellular cholesterol efflux, which could promote aggressive prostate cancer. ApoE genotypes of weakly (non-aggressive), moderate and highly tumorigenic (aggressive) prostate cancer cell lines were characterized, and we explored whether the ApoE variants were associated with tumor aggressiveness generated by intra-cellular cholesterol imbalance, using the expression of caveolin-1 (cav-1), a pro-malignancy surrogate of cholesterol overload. Restriction isotyping of ApoE isoforms revealed that the non-aggressive cell lines carried ApoE epsilon3/epsilon3 or epsilon3/epsilon4 alleles, while the aggressive cell lines carried the Apoepsilon2/epsilon4 alleles. Our data suggest a contrast between the non-aggressive and the aggressive prostate cancer cell lines in the pattern of cholesterol efflux and cav-1 expression. Our exploratory results suggest a relationship between prostate aggressiveness, ApoE isoforms and cholesterol imbalance. Further investigation of this relationship may elucidate the molecular basis for considering cholesterol as a risk factor of aggressive prostate tumors, and underscore the potential of the dysfunctional ApoE2/E4 isoform as a biomarker of aggressive disease. PMID- 23934235 TI - Effect of sub-inhibitory antibacterial stress on bacterial surface properties and biofilm formation. AB - Sub-inhibitory concentrations of antibacterial compounds do not effectively interfere with bacterial growth and only impart stress on them. Bacteria may react to external stress by abandoning planktonic life and form biofilms as the latter life-form offers superior resistance. This study on the effect of norfloxacin on biofilm formation by Staphylococcus aureus and Pseudomonas aeruginosa found that biofilm formation is enhanced under sub-inhibitory stress. Studies have reported increase in biofilm formation under the influence of external stress. In addition, the physicochemical properties of bacteria (i.e. zeta potential and contact angle) in the presence of antibacterial compounds were determined and its effect on initial attachment of bacteria to surfaces was examined. Single cell AFM force spectroscopy measurements were carried out to model the detachment force once the transient attachment takes place. The results indicate that once bacteria breach the physiochemical free energy barrier and come in direct contact with a surface, specific molecular interactions occur and detachment demands more energy than physicochemical forces alone can explain, especially at relatively higher separation distances. PMID- 23934236 TI - Functional diversity of organic molecule enzyme cofactors. AB - Covering up to 2013. Cofactor-dependent enzymes which need small organic molecule cofactors to accomplish enzymatic activity are widespread. The number of newly discovered reactions within cofactor-dependent enzyme families increases continuously. A knowledge based categorization of cofactors with respect to their chemical properties shows that within enzymes they are not used for the catalysis of singular types of reactions and functionalities. Therefore, in many cases an unambiguous and narrow classification does not seem sufficient. Rather, the functional diversity of cofactors found in enzymes represents variations around specific themes with regard to a catalysed reaction and the cofactor chemistry. Furthermore, organic cofactor molecules are also used for non-enzymatic functions. Two representative cofactors are exemplarily discussed in detail, thiamin diphosphate (ThDP) as a self-sufficient cofactor and S-adenosyl-L methionine (SAM), as both a catalytic and building-block-delivering cofactor. A further synopsis on selected examples of organic cofactors emphasizes the discovery and application of new enzymatic activities based on the cofactor dependent chemistry and shows how bioinspired synthesis approaches expand catalytic and non-catalytic synthesis applications beyond natural solutions. PMID- 23934237 TI - Impact of oral antipsychotic medication adherence on healthcare resource utilization among schizophrenia patients with Medicare coverage. AB - Nonadherence to antipsychotic medications is widespread and compromises the outcome of patients with schizophrenia. Using the MarketScan Medicare claims database, this study examined the impact of medication adherence on healthcare utilization among Medicare insured schizophrenia patients. The study population was separated into two cohorts defined by medication adherence, one with a medication possession ratio (MPR) >=0.7 (high adherence) and the other with a MPR <0.7(low adherence). Of the 354 patients identified, 126 (36 %) had high adherence (mean +/- SD MPR 0.94 +/- 0.09) and 228 (64 %) had low adherence (MPR 0.24 +/- 0.19). All cause hospitalizations (0.68 vs. 0.44; p = 0.015) and length of stay (LOS) (7.0 vs. 2.6 days; p = 0.005), and relapse hospitalizations (0.22 vs. 0.11; p = 0.028) and LOS (3.2 vs. 0.7 days; p = 0.027) were greater among patients with low adherence. Low adherent Medicare insured patients with schizophrenia require significantly more inpatient care and represent a patient population in which effective interventions are needed to improve disease management. PMID- 23934238 TI - Cervical metastases of squamous cell carcinoma of the maxilla: a retrospective study of 25 years. AB - OBJECTIVES: Squamous cell carcinomas (SCCs) of the maxilla are relatively rare; therefore, only little data is available regarding the frequency of cervical metastasis (CM) and therapy strategies. Most authors only undertake clinical observation of the lymph nodes. The aim of this retrospective study was to evaluate the manner of metastasis in SCC of the maxilla. MATERIALS AND METHODS: All patient records from 1987 to 2011 were scanned for SCC of the maxilla. Patients with SCC limited to the maxilla were comprised. The cases were analyzed regarding tumor node metastasis staging system and any special occurrences in the follow-up time such as tumor recurrence, metastasis, and exitus letalis. Classification and staging were performed according to the 2003 UICC system. RESULTS: One hundred thirty-eight patients were comprised of 36 % females and 64 % males (average age, 66 years; women, 71 years; men, 63 years). The average follow-up time was 43 months (range, 0-195). Fifty-eight percent smoked or declared regular consumption of alcohol. About 50 % of the patients had an advanced tumor stage (III-IV). At the time of the primary diagnosis, 38 % of the patients had CM. There is an increased risk for CM occurrence with increasing tumor size and grading and a tumor localized in the postcanine region. Contralateral CM arises frequently in T4 tumors and tumors localized in the postcanine region. CONCLUSION: The data exhibit aggressive regional metastatic behavior of SCC of the maxilla. CLINICAL RELEVANCE: Therefore, surgical treatment of the draining lymphatic system as a primary management strategy is recommended for patients with SCC of the maxilla. PMID- 23934239 TI - A comparison of pregnancy rate before and after the administration of HCG in intrauterine insemination. AB - PURPOSE: Intrauterine insemination (IUI) is one of the first treatments of infertility. In natural cycles, women conceive when an intercourse takes place during a 6-day period ending on the day of ovulation. The current practice in IUI cycles is to perform IUI 24-36 h after the HCG administration, when the ovulation already took place. In this study, HCG was administered after IUI, which more closely resembles the fertilization process in natural cycles. The aim of the present study is to compare the fertility rates in an IUI protocol in women who took an HCG injection before and after the IUI. METHODS: This study was conducted on 100 infertile couples who referred to the infertility research center of Shahid Sadoughi University of Medical Sciences. They were divided into two groups: HCG injection before IUI and HCG injection after IUI. The main outcome measure was the result of a beta HCG test that was done two weeks after the IUI; if it was positive, transvaginal sonography would be performed in the seventh week for clinical confirmation of pregnancy. RESULTS: The analysis included 50 cycles with HCG administered before and 50 cycles with HCG administered after the IUI. The pregnancy rates were 10 and 12 % (P = 0.85), respectively. Independent factor affected the cycle outcome was the time of infertility. CONCLUSION: HCG administration after IUI brought about no improvement in the pregnancy rate. Therefore, HCG can be administered either before or after IUI. PMID- 23934240 TI - Perinatal outcomes of immigrant women of Turkish, Middle Eastern and North African origin in Berlin, Germany: a comparison of two time periods. AB - PURPOSE: Publications based on data from perinatal health registries reported worse perinatal health outcomes among women of Turkish origin. The aim of this study was to compare the perinatal outcomes of women of German and Turkish origin in Berlin in two time periods and to analyze if the situation among the women of Turkish origin has improved over time. METHODS: Datasets of all singleton deliveries from Berlin hospitals for the time periods 1993-1997 (n = 144,600) and 2003-2007 (n = 147,559) were used. Incidence rates resp. prevalences of perinatal health outcomes were computed for women of German and a group of immigrant women mostly of Turkish origin stratified for 'parity' and 'having a partner'. Logistic regression models were computed to test for a change in the odds for adverse perinatal outcomes over time. RESULTS: The chances for adverse perinatal outcomes were decreasing in the later time period for most measures. For stillbirth, preterm birth and congenital malformations, no differences between women of Turkish and German origin could be found. Differences exist in the utilization of perinatal health care and in the risk for anemia. Among women of Turkish origin, the chance for being anemic is even higher in 2003-2007 compared to 1993-1997. CONCLUSIONS: The perinatal health measures of women of Turkish origin have improved over time. The lower utilization rates of antenatal health care could be the expression of barriers to access the health care for pregnant women with migration background as offered in Germany. A risk group which needs a special focus by health care providers are women without a partner, irrespective of their origin. PMID- 23934241 TI - Inflammatory bowel disease and preterm delivery. AB - BACKGROUND: The association between inflammatory bowel disease (IBD) and preterm delivery is controversial. Study size, quality, and design have been inconsistent, making it difficult to assess the relationship between IBD and preterm delivery. OBJECTIVE: Utilizing a systematic search of Pubmed for all relevant literature, this review seeks to clarify the correlation between IBD and preterm delivery and to assess the impact of disease activity and medication usage on this outcome. RESULTS: The available evidence is inadequate to make any robust claims about the association between IBD and preterm delivery. IBD in pregnant women may represent a risk for preterm delivery, and it is probable that IBD activity augments this risk. Many of the medications used to treat IBD also have a correlation with preterm delivery. CONCLUSIONS: While an association between IBD and preterm delivery may exist, further well-designed prospective studies are necessary to determine how the course and management of disease may impact this outcome. PMID- 23934242 TI - Prospective evaluation of 3T MRI findings for primary adnexal lesions and comparison with the final histological diagnosis. AB - PURPOSE: We prospectively investigated the diagnostic accuracy of magnetic resonance imaging (MRI) at 3.0 Tesla (3T) for the detection of suspected primary adnexal masses in a large cohort of patients. METHODS: This prospective clinical study included 223 patients with suspected gynaecological disease who were referred for 3T MRI assessments before laparoscopy or laparotomy. Fifty-nine patients were excluded. All detected adnexal pathologies on MRI were categorized into the four groups (endometric cysts, teratomas, benign tumours and malignant tumours). Histological findings were used as the comparative reference standard. As measures to detect or rule out primary adnexal masses, accuracy, sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) were determined by lesion-based evaluations. RESULTS: The reference standard method detected 141 primary adnexal lesions in 125 patients. The areas under the receiver operating characteristic curve of the lesion-based evaluations for endometric cysts, teratomas, benign lesions and malignant lesions were 92.8, 93.6, 95.1 and 94.4 %. Lesion-based evaluation yielded an accuracy of 90.3 %, sensitivity of 92.7 %, specificity of 89.3 %, PPV of 77.6 % and NPV of 96.8 % in differentiating malignancies from non-malignant lesions. The diagnostic value of 3T MRI for detecting malignancies was superior to that for benign tumours. CONCLUSIONS: 3T MRI well categorize the characteristics of primary adnexal lesions and may be a reliable modality for distinguishing malignancies from benign tumours. PMID- 23934243 TI - Uterine artery pseudoaneurysm: a master of deception. PMID- 23934244 TI - Operative time required to perform sacrospinous ligament suspension. PMID- 23934245 TI - Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion. AB - Although there have been numerous advances in our understanding of how apicomplexan parasites such as Toxoplasma gondii enter host cells, many of the signaling pathways and enzymes involved in the organization of invasion mediators remain poorly defined. We recently performed a forward chemical-genetic screen in T. gondii and identified compounds that markedly enhanced infectivity. Although molecular dissection of invasion has benefited from the use of small-molecule inhibitors, the mechanisms underlying induction of invasion by small-molecule enhancers have never been described. Here we identify the Toxoplasma ortholog of human APT1, palmitoyl protein thioesterase-1 (TgPPT1), as the target of one class of small-molecule enhancers. Inhibition of this uncharacterized thioesterase triggered secretion of invasion-associated organelles, increased motility and enhanced the invasive capacity of tachyzoites. We demonstrate that TgPPT1 is a bona fide depalmitoylase, thereby establishing an important role for dynamic and reversible palmitoylation in host-cell invasion by T. gondii. PMID- 23934247 TI - Myroides guanonis sp. nov., isolated from prehistoric paintings. AB - A novel psychrotolerant, strictly aerobic, non-motile, rod-shaped bacterial strain, designated IM13(T), was isolated from a sample taken from prehistoric guano paintings in Magura Cave, northwest Bulgaria and subjected to a polyphasic taxonomic study. Strain IM13(T) formed yellow colonies on LB agar plates and was Gram-staining-negative, heterotrophic and alkalitolerant. It grew optimally at pH 7.5 and 30 degrees C in the absence of NaCl. Phylogenetic analysis of the whole 16S rRNA gene revealed that strain IM13(T) branched with representatives of the genus Myroides with sequence similarity of 93-94 % with other species of the genus. The novel isolate contained iso-C15 : 0 (49.1 %), iso-C17 : 1omega9c (18.2 %) and iso-C17 : 0 3-OH (14.0 %) as dominant fatty acids. The DNA G+C content of strain IM13(T) was 33.5 mol%. Based on phylogenetic inference and phenotypic characteristics, it was concluded that strain IM13(T) represents a novel species of the genus Myroides, for which the name Myroides guanonis sp. nov. is proposed. The type strain is IM13(T) ( = DSM 26542(T) = NBIMCC 8736(T)). PMID- 23934246 TI - Spontaneous activation of [FeFe]-hydrogenases by an inorganic [2Fe] active site mimic. AB - Hydrogenases catalyze the formation of hydrogen. The cofactor ('H-cluster') of [FeFe]-hydrogenases consists of a [4Fe-4S] cluster bridged to a unique [2Fe] subcluster whose biosynthesis in vivo requires hydrogenase-specific maturases. Here we show that a chemical mimic of the [2Fe] subcluster can reconstitute apo hydrogenase to full activity, independent of helper proteins. The assembled H cluster is virtually indistinguishable from the native cofactor. This procedure will be a powerful tool for developing new artificial H2-producing catalysts. PMID- 23934248 TI - Pseudoruegeria haliotis sp. nov., isolated from the gut of the abalone Haliotis discus hannai. AB - A novel Gram-negative, aerobic, non-motile and rod-shaped bacterium, designated strain WM67(T), was isolated from the gut of an abalone (Haliotis discus hannai) collected from the northern coast of Jeju Island in Korea. Phylogenetic analyses based on the 16S rRNA gene sequence indicated that strain WM67(T) clustered in the genus Pseudoruegeria, and the highest sequence similarity was shared with Pseudoruegeria lutimaris (98.0 % similarity to the type strain). Optimal growth of the isolate occurred at 30 degrees C, pH 7-8 and with 1 % (w/v) NaCl. The major cellular fatty acids were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and C16 : 0. Ubiquinone Q-10 was the major respiratory quinone. The polar lipids of strain WM67(T) comprised phosphatidylserine, phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, an unidentified glycolipid and three unidentified lipids. The genomic DNA G+C content was 66.5 mol%. DNA-DNA hybridization indicated <17 % genomic relatedness to other members of the genus Pseudoruegeria. The physiological, biochemical, chemotaxonomic and genotypic analyses indicated that strain WM67(T) represents a novel species of Pseudoruegeria, for which the name Pseudoruegeria haliotis sp. nov. is proposed. The type strain is WM67(T) ( = KACC 17214(T) = JCM 18872(T)). PMID- 23934249 TI - Fretibacter rubidus gen. nov., sp. nov., isolated from seawater. AB - A brick-red-coloured, curved-rod-shaped, prostheca-bearing and non-motile bacterial strain, designated JC2236(T), was isolated from a seawater sample of Jeju Island, Republic of Korea. 16S rRNA gene sequence analysis indicated that this strain belongs to the family Hyphomonadaceae and represents a distinct phyletic line that reflects a novel genus status within a clade containing the genera Litorimonas, Hellea, Robiginitomaculum and Algimonas. The predominant isoprenoid quinone (Q10) and polar lipid profile (phosphatidylglycerol, glucuronopyranosyl diglyceride and monoglycosyl diglyderide) were in line with those of most members of the family. However, the DNA G+C content (49.3 mol%), the abundance of C16 : 0, the requirement of sea salts for growth and absence of cell motility differentiated strain JC2236(T) from other closely related genera. Overall enzyme traits also demonstrated that the novel strain is not closely affiliated with any of the previously described genera. Thus, based on data from the present polyphasic taxonomic study, strain JC2236(T) is considered to represent a novel species of a new genus belonging to the family Hyphomonadaceae, for which the name Fretibacter rubidus gen. nov., sp. nov. is proposed. The type strain of Fretibacter rubidus is JC2236(T) ( = KACC 16935(T) = JCM 15585(T)). PMID- 23934250 TI - Nibribacter koreensis gen. nov., sp. nov., isolated from estuarine water. AB - A Gram-reaction-negative, rod-shaped, non-motile, red-pigmented bacterium, designated strain GSR3061(T), was isolated from a water sample of the Mangyung estuary enclosed by the Saemangeum Embankment in JEOLlabuk-do of South Korea, and characterized using a polyphasic approach. 16S rRNA gene sequence analysis of strain GSR3061(T) indicated that the isolate belonged to the phylum Bacteroidetes and exhibited similarity levels of 94.7 % to Rufibacter tibetensis NRRL B 51285(T), 92.4 % to Adhaeribacter terreus KACC 14257(T) and 91.9 % to Pontibacter korlensis KACC 15371(T). Growth was observed at 15-40 degrees C and pH 6.5-9.5. The major cellular fatty acids of the novel strain were summed feature 4 (comprising iso-C17 : 1 I and/or anteiso-C17 : 1 B), iso-C15 : 0, C17 : 1omega6c and iso-C16 : 1 H. Flexirubin-type pigments were absent. The DNA G+C content of strain GSR3061(T) was 44.9 mol% and the major quinone was MK-7. The polar lipid profile consisted mainly of phosphatidylethanolamine; three unidentified lipids, two unknown aminolipids, two unknown phospholipids, an unknown aminophospholipid and an unknown glycolipid were also present. On the basis of the evidence presented, it is concluded that strain GSR3061(T) represents a novel species of a new genus, for which the name Nibribacter koreensis gen. nov., sp. nov. is proposed. The type strain of Nibribacter koreensis is GSR3061(T) ( = KACC 16450(T) = JCM 17917(T)). PMID- 23934251 TI - Rhodotorula portillonensis sp. nov., a basidiomycetous yeast isolated from Antarctic shallow-water marine sediment. AB - During the characterization of the mycobiota associated with shallow-water marine environments from Antarctic sea, a novel pink yeast species was isolated. Sequence analysis of the D1/D2 domain of the LSU rDNA gene and 5.8S-ITS regions revealed that the isolated yeast was closely related to Rhodotorula pallida CBS 320(T) and Rhodotorula benthica CBS 9124(T). On the basis of morphological, biochemical and physiological characterization and phylogenetic analyses, a novel basidiomycetous yeast species, Rhodotorula portillonensis sp. nov., is proposed. The type strain is Pi2(T) ( = CBS 12733(T) = CECT 13081(T)) which was isolated from shallow-water marine sediment in Fildes Bay, King George Island, Antarctica. PMID- 23934252 TI - Kurtzmanomyces shapotouensis sp. nov., an anamorphic, basidiomycetous yeast isolated from desert soil crusts. AB - Two yeast strains isolated from soil crusts in the Shapotou region of Tengger Desert (north-western China) were grouped in the genus Kurtzmanomyces based on morphological characteristics. rRNA gene sequence analyses (including the D1/D2 domain of the large subunit rRNA gene and internal transcribed spacer region) indicated that these two strains represented a novel species of the genus Kurtzmanomyces, for which the name Kurtzmanomyces shapotouensis sp. nov. is proposed (type strain: CPCC 300020(T) = DSM 26579(T) = CBS 12707(T)). The MycoBank number of the novel species is MB 804959. PMID- 23934253 TI - DNA-DNA hybridization study of strains of Chryseobacterium, Elizabethkingia and Empedobacter and of other usually indole-producing non-fermenters of CDC groups IIc, IIe, IIh and IIi, mostly from human clinical sources, and proposals of Chryseobacterium bernardetii sp. nov., Chryseobacterium carnis sp. nov., Chryseobacterium lactis sp. nov., Chryseobacterium nakagawai sp. nov. and Chryseobacterium taklimakanense comb. nov. AB - The taxonomic classification of 182 phenotypically similar isolates was evaluated using DNA-DNA hybridization and 16S rRNA gene sequence analysis. These bacterial isolates were mainly derived from clinical sources; all were Gram-negative non fermenters and most were indole-producing. Phenotypically, they resembled species from the genera Chryseobacterium, Elizabethkingia or Empedobacter or belonged to CDC groups IIc, IIe, IIh and IIi. Based on these analyses, four novel species are described: Chryseobacterium bernardetii sp. nov. (type strain NCTC 13530(T) = CCUG 60564(T) = CDC G229(T)), Chryseobacterium carnis sp. nov. (type strain NCTC 13525(T) = CCUG 60559(T) = CDC G81(T)), Chryseobacterium lactis sp. nov. (type strain NCTC 11390(T) = CCUG 60566(T) = CDC KC1864(T)) and Chryseobacterium nakagawai sp. nov. (type strain NCTC 13529(T) = CCUG 60563(T) = CDC G41(T)). The new combination Chryseobacterium taklimakanense comb. nov. (type strain NCTC 13490(T) = X-65(T) = CCTCC AB 208154(T) = NRRL B-51322(T)) is also proposed to accommodate the reclassified Planobacterium taklimakanense. PMID- 23934254 TI - On-command drug release from nanochains inhibits growth of breast tumors. AB - PURPOSE: To evaluate the ability of radiofrequency (RF)-triggered drug release from a multicomponent chain-shaped nanoparticle to inhibit the growth of an aggressive breast tumor. METHODS: A two-step solid phase chemistry was employed to synthesize doxorubicin-loaded nanochains, which were composed of three iron oxide nanospheres and one doxorubicin-loaded liposome assembled in a 100-nm-long linear nanochain. The nanochains were tested in the 4T1-LUC-GFP orthotopic mouse model, which is a highly aggressive breast cancer model. The 4T1-LUC-GFP cell line stably expresses firefly luciferase, which allowed the non-invasive in vivo imaging of tumor response to the treatment using bioluminescence imaging (BLI). RESULTS: Longitudinal BLI imaging showed that a single nanochain treatment followed by application of RF resulted in an at least 100-fold lower BLI signal compared to the groups treated with nanochains (without RF) or free doxorubicin followed by RF. A statistically significant increase in survival time of the nanochain-treated animals followed by RF (64.3 days) was observed when compared to the nanochain-treated group without RF (35.7 days), free doxorubicin-treated group followed by RF (38.5 days), and the untreated group (30.5 days; n=5 animals per group). CONCLUSIONS: These studies showed that the combination of RF and nanochains has the potential to effectively treat highly aggressive cancers and prolong survival. PMID- 23934255 TI - Biocompatible glycol chitosan-coated gold nanoparticles for tumor-targeting CT imaging. AB - PURPOSE: The application of gold nanoparticles (AuNPs) in biomedical field was limited due to the low stability in the biological condition. Herein, to enhance stability and tumor targeting ability of AuNPs, their surface was modified with biocompatible glycol chitosan (GC) and the in vivo biodistribution of GC coated AuNPs (GC-AuNPs) were studied through computed tomography (CT). METHODS: Polymer coated gold nanoparticles were produced using GC as a reducing agent and a stabilizer. Their feasibility in biomedical application was explored through CT in tumor-bearing mice. RESULTS: Stability of gold nanoparticles increased in the physiological condition due to the GC coating layer on the surface. Tomographic images of tumor were successfully obtained in the tumor-xenografted animal model when the GC-AuNPs were used as a CT contrast agent. The tumor targeting property of the gold nanoparticles was due to the properties of GC because GC-AuNPs were accumulated in the tumor, while most of heparin-coated nanoparticles were found in the liver and spleen. CONCLUSIONS: The polymer properties on the surface played an important role in the behavior of gold nanoparticles in the biological condition and the enhanced stability and tumor targeting property of nanoparticles were inherited from GC on the surface. PMID- 23934256 TI - Radioiodinated hypericin: its biodistribution, necrosis avidity and therapeutic efficacy are influenced by formulation. AB - PURPOSE: To study whether formulation influences biodistribution, necrosis avidity and tumoricidal effects of the radioiodinated hypericin, a necrosis avid agent for a dual-targeting anticancer radiotherapy. METHODS: Iodine-123- and 131 labeled hypericin ((123)I-Hyp and (131)I-Hyp) were prepared with Iodogen as oxidant, and formulated in dimethyl sulfoxide (DMSO)/PEG400 (polyethylene glycol 400)/water (25/60/15, v/v/v) or DMSO/saline (20:80, v/v). The formulations with excessive Hyp were optically characterized. Biodistribution, necrosis avidity and tumoricidal effects were studied in rats (n = 42) without and with reperfused liver infarction and implanted rhabdomyosarcomas (R1). To induce tumor necrosis, R1-rats were pre-treated with a vascular disrupting agent. Magnetic resonance imaging, tissue-gamma counting, autoradiography and histology were used. RESULTS: The two formulations differed significantly in fluorescence and precipitation. (123)I-Hyp/Hyp in DMSO/PEG400/water exhibited high uptake in necrosis but lower concentration in the lung, spleen and liver (p < 0.01). Tumor volumes of 0.9 +/- 0.3 cm(3) with high radioactivity (3.1 +/- 0.3% ID/g) were detected 6 days post treatment. By contrast, (131)I-Hyp/Hypin DMSO/saline showed low uptake in necrosis but high retention in the spleen and liver (p < 0.01). Tumor volumes reached 2.6 +/- 0.7 cm(3) with low tracer accumulation (0.1 +/- 0.04%ID/g). CONCLUSIONS: The formulation of radioiodinated hypericin/hypericin appears crucial for its physical property, biodistribution, necrosis avidity and tumoricidal effects. PMID- 23934257 TI - The frontline clinical manager identifying direct reports' level of practice. AB - Patricia Benner applied the Dreyfus Model of Skill Acquisition to describe and interpret skill acquisition and clinical judgment in nursing practice. Operational definitions for the 5 levels of her original Novice to Expert Theory were used by the study participants in a large Midwestern pediatric hospital to self-identify their level of practice. The frontline clinical managers of these direct care registered nurses (RNs) used the same tool to rate their direct reports. The aim of this portion of a larger study was to determine if the clinical manager's perception of their direct reports was the same as that of the RNs. The results of this study are being used by one study unit's clinical managers as the basis for implementing the Hersey and Blanchard Situational Leadership Model. The clinical managers work with their direct reports depending on the level of practice and the details of the task to be performed. One example is creating therapeutic relationships with each other and with families to ensure a safe environment for all. PMID- 23934258 TI - Synthesis and biological evaluation of 1,2,4-triazole and 1,3,4-thiadiazole derivatives as potential cytotoxic agents. AB - A series of new 3-amino-5-sulfanyl-1,2,4-triazole and 2-amino-5-sulfanyl-1,3,4 thiadiazole derivatives have been synthesized and their cytotoxicities were evaluated on a panel of human cancer cell lines (BxPC-3, H1975, SKOV-3, A875, HCT116, etc.). The best one (compound 5m) exhibited activities with IC50 values ranging from 0.04 to 23.6 uM against nine human cancer cell lines. Further biological evaluation indicated that DNA replication was blocked by treatment with compound 5m in HCT116 cells. PMID- 23934260 TI - "CAPABILITY" and "Genetic testing in emerging economies" (GenTEE). PMID- 23934259 TI - Role of MT1 melatonin receptors in methamphetamine-induced locomotor sensitization in C57BL/6 mice. AB - RATIONALE: Melatonin modifies physiological and behavioral responses to psychostimulants, with the MT1 and MT2 melatonin receptors specifically implicated in facilitating methamphetamine (METH)-induced sensitization in melatonin-proficient mice. OBJECTIVE: The objective of the study is to assess differences in locomotor sensitization after a single dose of methamphetamine in low-melatonin-expressing C57BL/6 wild-type and MT1 receptor knockout (MT1KO) mice, comparing with melatonin-expressing C3H/HeN mice. METHODS: Mice received a vehicle or methamphetamine (1.2 mg/kg, i.p.) pretreatment (day 1) during the light (ZT5-9) or dark (ZT 19-21) periods in novel test arenas. Locomotor sensitization was assessed by methamphetamine challenge after an eight-day abstinence (day 9). TH protein expression was evaluated by immunofluorescence and Western blot analysis. RESULTS: Methamphetamine pretreatment induced statistically significant locomotor sensitization upon challenge after eight-day abstinence in C3H and C57 wild-type mice during the light period. The magnitude of sensitization in C57 mice was diminished in the dark period and completely abrogated in MT1KO mice. No differences were observed in tyrosine hydroxylase immunoreactivity in the mesolimbic dopamine system. Additional exposures to the test arenas after methamphetamine pretreatment (nights 2-6) enhanced sensitization. CONCLUSIONS: Deletion of the MT1 melatonin receptor abolishes sensitization induced by a single METH pretreatment. The magnitude of sensitization is also altered by time of day and contextual cues. We conclude that the MT1 melatonin receptor is emerging as a novel target of therapeutic intervention for drug abuse disorders. PMID- 23934261 TI - Molecular and cytogenetic changes in multi-drug resistant cancer cells and their influence on new compounds testing. AB - PURPOSE: Multi-drug resistance (MDR) is a major obstacle to successful cancer treatment. Therefore, in vitro models are necessary for the investigation of the phenotypic changes provoked by cytotoxic agents and more importantly for preclinical testing of new anticancer drugs. METHODS: We analyzed chromosomal, numerical, and structural changes after development of MDR, alterations in p53 and PTEN, single nucleotide polymorphisms (SNPs) in the mdr1 gene and corresponding protein expression of P-glycoprotein (P-gp) in three human MDR cancer cell lines: non-small cell lung carcinoma NCI-H460/R, colorectal carcinoma DLD1-TxR, and glioma U87-TxR. In addition, we explored how these molecular and phenotypic alterations influence the anticancer effect of new drugs. RESULTS: Cytogenetic analysis showed polyploidy reduction after development of MDR in U87 TxR. Losses of 6q in all resistant cancer cell lines and inactivation of p53 in U87-TxR and PTEN in DLD1-TxR were also revealed. Overexpression of P-gp was observed in all MDR cancer cell lines. We evaluated the anticancer activities and MDR reversal potential of Akt inhibitor GSK690693, Ras inhibitor Tipifarnib, and two P-gp inhibitors (jatrophane diterpenoids). Their effects vary due to the cell type differences, existence of MDR phenotype, presence of mdr1 SNP, and tumor suppressors' alterations. Tipifarnib and jatrophane diterpenoids significantly sensitized MDR cancer cells to paclitaxel. CONCLUSION: In conclusion, investigated MDR cancer cells obtained new molecular and cytogenetic characteristics that may serve as potential clinical prognostic markers. In addition, these MDR cancer cell lines present a valuable model for preclinical evaluation of new anticancer agents. PMID- 23934262 TI - Identification of two novel inhibitors of mTOR signaling pathway based on high content screening. AB - PURPOSE: Mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation and survival. Dysregulation of mTOR signaling pathway is closely involved in cancer development and chemotherapy resistance. Inhibitors of mTOR signaling pathway have been demonstrated to be attractive therapeutics for cancer therapy. In the present study, we aim to discover novel mTOR signaling pathway inhibitors from a natural compound library. METHODS: Inhibitors of mTOR signaling pathway were discovered via high content screen assay based on the subcellular localization of eukaryotic initiation factor 4E (eIF4E) in mouse embryonic fibroblast cells. Candidate compounds were further assessed in cancer cells. Phosphorylation levels of mTOR complexes downstream targets were analyzed using Western blot. Cell cytotoxicity and apoptosis were evaluated using MTS assay and flow cytometry, respectively. RESULTS: Two compounds, 1,4-O-diferuloylsecoisolariciresinol (IM-1) and Pierreione B (IM-2), were identified which induced significant nuclear translocation of eIF4E in a panel of cancer cells. Both of the compounds decreased the phosphorylation levels of p70 ribosomal protein S6 kinase (S6K) and eIF4E binding protein 1 (4E-BP1), resulting in cancer cell cytotoxicity and apoptosis. CONCLUSIONS: Via high content screen assay, two novel inhibitors of mTOR signaling, IM-1 and IM-2, were identified with strong anticancer activity. IM-1 and IM-2 could be potential candidates for anticancer therapeutics by targeting mTOR signaling pathway and as such warrants further exploration. PMID- 23934263 TI - Risk factors for delayed extubation in thoracic and lumbar spine surgery: a retrospective analysis of 135 patients. AB - PURPOSE: Extubation may be delayed after spine surgery mainly for the concerns of airway safety. Risk factors for delayed extubation in cervical spine surgery have been described to include prolonged surgery time and amount of crystalloids or blood transfused. To date, risk factors for delayed extubation in thoracic or lumbar spine surgery have not been investigated. We retrospectively reviewed 135 consecutive patients from 2006 to 2009 who underwent thoracic or lumbar spine surgery by one particular surgeon to identify risk factors for delayed extubation. METHODS: Data including patient factors, surgical time, anesthetic technique, blood loss, crystalloid and colloid administration, transfusion requirements, time to transfusion, and time to extubation were collected and analyzed. Delayed extubation was defined as the patient was not extubated in the operating room at completion of the surgery. RESULTS: One hundred and eight patients were extubated in the OR. Delayed extubation occurred in 27 patients. Delayed extubation was significantly related to total operative time (6.6 +/- 0.4 vs. 5.2 +/- 0.1 h), volume of crystalloid replacement (6,018 +/- 408 vs. 4,186 +/ 130 cm3), volume of total colloids infused (787 +/- 93 vs. 442 +/- 36 cm3), intraoperative blood transfused (3.7 +/- 0.5 vs. 0.7 +/- 0.1 units); blood loss (2,137 +/- 286 vs. 832 +/- 50 cm3), and time to starting blood transfusion (106 +/- 12 vs. 199 +/- 9 min). CONCLUSIONS: Our study suggests that intraoperative factors including prolonged surgical time, significant blood loss, larger volume of crystalloid and colloid infusion, and blood transfusion may be risk factors for delayed extubation following thoracic or lumbar spine surgery. Early blood transfusion may also increase the risk of delayed extubation. Patient factors did not affect extubation time. PMID- 23934264 TI - A great option for elderly patients with locally invasive bladder cancer, BOAI CDDP-radiation (OMC regimen). AB - We have developed a novel bladder preservation therapy, balloon-occluded arterial infusion (BOAI) of cisplatin/gemcitabine, concomitantly with hemodialysis, along with concurrent irradiation [the so-called 'OMC (Osaka Medical College) regimen']. The OMC regimen delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects, since more than 95% of free Pt was efficiently eliminated by hemodialysis, which enables short hospital stay. In this study, we investigated the efficiency of OMC regimen in patients aged over 70 years with muscle-invasive bladder cancer without metastasis. A total of 134 such patients were assigned to receive either the OMC regimen (n=89) or cystectomy (n=45). OMC regimen patients who failed to achieve CR underwent cystectomy, or secondary BOAI with gemcitabine (1,600 mg). The OMC regimen, which delivers an extremely high concentration of anticancer agent to the tumor site without systemic adverse effects, yielded CR in >91% (81/89) of patients. More than 96% (78/81) of the CR patients survived without recurrence with intact bladder after a mean follow-up of 164 (range 16-818) weeks. The 5- and 10-year bladder intact survival rates were 87.2 and 69.8%, and overall survival rates were 88.4 and 70.7% (vs. 59.9 and 33.3% for cystectomy, p=0.0002), respectively, although the median age in the OMC regimen group was significantly greater than in the cystectomy group (median, range = 77, 70-98 vs. 74, 70-89; p=0.0003). No patients suffered grade II or more severe toxicities; the oldest patient, aged 91 years, successfully completed this therapy. In conclusion, the OMC regimen is a useful bladder preservation strategy for elderly patients with locally invasive bladder cancer, not only in those for whom cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment and for whom palliation would otherwise seem the only option. PMID- 23934265 TI - Enhanced oxidation stability of quasi core-shell alloyed CdSeS quantum dots prepared through aqueous microwave synthesis technique. AB - Quasi core shell alloyed CdSeS quantum dots (QDs) have been prepared through a facile aqueous-phase route employing microwave irradiation technique. The optical spectroscopy and structure characterization evidenced the quasi core shell alloyed structures of CdSeS QDs. The X-ray diffraction patterns of the obtained CdSeS QDs displayed peak positions very close to those of bulk cubic CdS crystal structures and the result of X-ray photoelectron spectroscopy data re-confirmed the thick CdS shell on the CdSe core. The TEM images and HRTEM images of the CdSeS QDs ascertained the well-defined spherical particles and a relatively narrow size distribution. On the basis, the stability of the obtained QDs in an oxidative environment was also discussed using etching reaction by H2O2. The experiments result showed the as-prepared QDs present high tolerance towards H2O2, obviously superior to the commonly used CdTe QDs and core-shell CdTe/CdS QDs, which was attributed to the unique quasi core-shell CdSeS crystal structure and the small lattice mismatch between CdSe and CdS semiconductor materials. This assay provided insight to obtain high stable crystal structured semiconductor nanocrystals in the design and synthesis process. PMID- 23934267 TI - Gender-transformative interventions to reduce HIV risks and violence with heterosexually-active men: a review of the global evidence. AB - Emerging out of increased attention to gender equality within HIV and violence prevention programming has been an intensified focus on masculinities. A new generation of health interventions has attempted to shift norms of masculinity to be more gender equitable and has been termed "gender-transformative." We carried out a systematic review of gender-transformative HIV and violence prevention programs with heterosexually-active men in order to assess the efficacy of this programming. After reviewing over 2,500 abstracts in a systematic search, a total of 15 articles matched review criteria. The evidence suggests that gender transformative interventions can increase protective sexual behaviors, prevent partner violence, modify inequitable attitudes, and reduce STI/HIV, though further trials are warranted, particularly in establishing STI/HIV impacts. In the conclusion, we discuss the promises and limitations of gender-transformative work with men and make suggestions for future research focused on HIV and/or violence prevention. PMID- 23934266 TI - In vivo ectopic implantation model to assess human mesenchymal progenitor cell potential. AB - Clinical interest on human mesenchymal progenitor cells (hMPC) relies on their potential applicability in cell-based therapies. An in vitro characterization is usually performed in order to define MPC potency. However, in vitro predictions not always correlate with in vivo results and thus there is no consensus in how to really assess cell potency. Our goal was to provide an in vivo testing method to define cell behavior before therapeutic usage, especially for bone tissue engineering applications. In this context, we wondered whether bone marrow stromal cells (hBMSC) would proceed in an osteogenic microenvironment. Based on previous approaches, we developed a fibrin/ceramic/BMP-2/hBMSCs compound. We implanted the compound during only 2 weeks in NOD-SCID mice, either orthotopically to assess its osteoinductive property or subcutaneously to analyze its adequacy as a cell potency testing method. Using fluorescent cell labeling and immunohistochemistry techniques, we could ascertain cell differentiation to bone, bone marrow, cartilage, adipocyte and fibrous tissue. We observed differences in cell potential among different batches of hBMSCs, which did not strictly correlate with in vitro analyses. Our data indicate that the method we have developed is reliable, rapid and reproducible to define cell potency, and may be useful for testing cells destined to bone tissue engineering purposes. Additionally, results obtained with hMPCs from other sources indicate that our method is suitable for testing any potentially implantable mesenchymal cell. Finally, we propose that this model could successfully be employed for bone marrow niche and bone tumor studies. PMID- 23934268 TI - Geographical clustering of high risk sexual behaviors in "hot-spots" for HIV and sexually transmitted infections in Kwazulu-Natal, South Africa. AB - We investigated geographical variations of three sexually transmitted infections (STIs) namely chlamydia, gonorrhea and syphilis in the greater Durban area, so as to optimize intervention strategies. The study population was a cohort of sexually active women who consented to be screened in one of three biomedical studies conducted in Durban. A total of nine local regions collectively formed three clusters at screening, five of which were previously defined as HIV hot spots. STI cases were geo-coded at the census level based on residence at the time of screening. Spatial SaTScan Statistics software was employed to identify the areas with a disproportionate prevalence and incidence of STI infection when compared to the neighboring areas under study. Both prevalence and incidence of STIs were collectively clustered in several localized areas, and the majority of these locations overlapped with high HIV clusters and shared the same characteristics: younger age, not married/cohabitating and multiple sex partners. PMID- 23934269 TI - The LIVE Network: a music-based messaging program to promote ART adherence self management. AB - We developed and pilot-tested the efficacy, acceptability, and feasibility of a music program, The LIVE Network (LN), compared to standard care on outcomes of ART adherence, clinical indicators, and self-efficacy. The study was powered to detect differences at p < 0.1. We enrolled and followed 77 participants for 12 weeks (T3). Mean monthly pill counts (PC) declined over time in both groups. Although not significant, the LN had higher PC and a larger proportion had plasma antiretroviral trough levels within therapeutic range. The LN group did have significantly (p < 0.1) increased levels of adherence self-efficacy and decrease in viral loads. PMID- 23934270 TI - Associations between alcohol use, other psychosocial factors, structural factors and antiretroviral therapy (ART) adherence among South African ART recipients. AB - We examined whether alcohol use is associated with antiretroviral therapy (ART) adherence independently of structural and psychosocial factors among 304 male and female ART recipients in ART sites in Tshwane, South Africa. ART adherence was assessed by the CASE Adherence Index. Independent variables were demographic, structural, psycho-social, and alcohol use (AUDIT score) factors. In hierarchical multiple regression, demographic variables (Step 1) explained 4 % of variance in ART adherence (p <= 0.01). Variance explained increased to 16 % (p <= 0.001) after entering structural variables (Step 2); 19 % (p <= 0.001) after entering psychosocial variables (Step 3); and 24 % (p <= 0.001) after entering AUDIT score (Step 4). Alcohol use is independently associated with ART adherence. PMID- 23934271 TI - "Mini" gastric bypass: systematic review of a controversial procedure. AB - Mini gastric bypass is being explored by many bariatric surgeons as a standalone bariatric procedure. Several surgeons from different parts of the world have now published their extensive experience with this procedure. It appears to be an effective bariatric procedure with acceptable weight loss, co-morbidity resolution, and complication rates in the short and medium term. Its proponents claim that it is safer and easier than the gold standard Roux-en-Y gastric bypass. However, concerns with regard to symptomatic gastric or oesophageal biliary reflux requiring revisional surgery and long-term risk of gastric and oesophageal cancers persist. This paper reviews the published experience to date with this procedure and examines the surrounding controversy. PMID- 23934272 TI - Lower glycemic fluctuations early after bariatric surgery partially explained by caloric restriction. AB - BACKGROUND: We assessed the acute impact of laparoscopic Roux-en-Y gastric bypass (GBP) or sleeve gastrectomy (SG) compared to caloric-matched control group without surgery on glucose excursion in obese patients with type 2 diabetes, and examined if this was mediated by changes in insulin resistance, early insulin response or glucagon-like peptide (GLP)-1 levels. METHODS: Six-day subcutaneous continuous glucose monitoring (CGM) recordings were obtained from patients beginning 3 days before GBP (n = 11), SG (n = 10) or fasting in control group (n = 10). GLP-1, insulin and glucose were measured during 75 g oral glucose tolerance testing at the start and end of each CGM. RESULTS: Post-operative hyperglycaemia occurred after both surgeries in the first 6 h, with a more rapid decline in glycaemia after GBP (p < 0.001). Beyond 24 h post-operatively, continuous overlapping of net glycaemia action reduced from baseline after GBP (median [interquartile range]) 1.6 [1.2-2.4] to 1.0 [0.7-1.3] and after SG 1.4 [0.9-1.8] to 0.7 [0.7-1.0]; p < 0.05), similar to controls (2.2 [1.7-2.5] to 1.3 [0.8-2.8] p < 0.05). Higher log GLP-1 increment post-oral glucose occurred after GBP (mean +/- SE, 0.80 +/- 0.12 vs. 0.37 +/- 0.09, p < 0.05), but not after SG or control intervention. Among subgroup with baseline hyperglycaemia, a reduction in HOMA-IR followed GBP. Reduction in time and level of peak glucose and 2-h glucose occurred after both surgeries but not in controls. CONCLUSIONS: GBP and SG have a similar acute impact on reducing glycaemia to caloric restriction; however, with a superior impact on glucose tolerance. PMID- 23934273 TI - Incretin response to a standard test meal in a rat model of sleeve gastrectomy with diet-induced obesity. AB - BACKGROUND: Currently, the most effective treatment for obesity is bariatric surgery. Gastroduodenal bypass surgery produces sustained weight loss and improves glycemic control and insulin sensitivity. Previous studies have shown that sleeve gastrectomy (SG) produces similar results and implicate changes in incretin hormone release in these effects. METHODS: Male Sprague-Dawley rats were divided into four groups; lean control (lean), diet-induced obesity (DIO), DIO animals that had undergone SG (SG), and DIO animals that had undergone a sham operation (sham). RESULTS: After a 2-week recovery period, the incretin response to a standard test meal was measured. Blood sampling was performed in free-moving rats at various time points using chronic vascular access to the right jugular vein. There was a significant increase in the bodyweight of DIO animals fed a high-fat/high-sugar diet compared with the lean animals, which was reversed by SG. DIO caused an impairment of the GLP-1 response to a standard test meal, but not the GIP response. SG resulted in a dramatic increase in the GLP-1 response to a standard test meal but had no effect on the GIP response. CONCLUSIONS: A rapid rise in blood sugar was observed in the SG group following a standard test meal that was followed by reactive hypoglycemia. SG dramatically increases the GLP-1 response to a standard test meal but has no effect on GIP in a rat model of DIO. PMID- 23934274 TI - Adherence and weight loss outcomes in bariatric surgery: does cognitive function play a role? AB - Although bariatric surgery is the most effective intervention for severe obesity, a significant minority of participants fail to achieve or maintain optimal weight loss at extended follow-up. Accumulating evidence suggests that adherence to prescribed postoperative recommendations, including attendance at follow-up appointments and dietary and physical activity, is related to improved weight loss outcomes. However, adherence to these guidelines presents a significant challenge for many patients, potentially due in part to deficits in cognitive function. In this paper, we briefly examine current literature of adherence on postoperative weight loss outcomes, and review emerging evidence that the cognitive dysfunction present in a subset of obese individuals is related to weight loss outcomes following bariatric procedures. We then extend these findings, positing a role for cognitive function in moderating the relationship between adherence and postoperative outcomes. PMID- 23934275 TI - Long-term efficacy and safety of eculizumab in Japanese patients with PNH: AEGIS trial. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, progressive hematopoietic stem cell disorder characterized by chronic complement-mediated hemolysis leading to life-threatening complications and early mortality. Eculizumab, a humanized anti-C5 monoclonal antibody, inhibits terminal complement activation, reduces hemolysis, decreases the risk of thrombosis, and improves renal function and quality of life in PNH patients. The long-term efficacy and safety of eculizumab in Japanese patients were assessed in a 2-year extension to a 12-week, open-label study (AEGIS). Eculizumab treatment led to an immediate and sustained reduction in intravascular hemolysis (P < 0.001) and red blood cell transfusions (P = 0.0016) compared with baseline levels. There were no reports of thromboembolism during eculizumab treatment. The majority of patients had stable (56 %) or improved (41 %) renal function and an improved quality of life (P = 0.015), with sustained reductions in fatigue and dyspnea. Eculizumab was well tolerated; no deaths or serious hemolytic events were reported, and the rate of infections declined over time. There were no significant differences in the response to eculizumab in patients with or without bone marrow dysfunction. These results demonstrate that eculizumab is an effective, well-tolerated long-term treatment for Japanese PNH patients and leads to continued amelioration of some hemolytic complications. PMID- 23934276 TI - Multimode resistive switching in single ZnO nanoisland system. AB - Resistive memory has attracted a great deal of attention as an alternative to contemporary flash memory. Here we demonstrate an interesting phenomenon that multimode resistive switching, i.e. threshold-like, self-rectifying and ordinary bipolar switching, can be observed in one self-assembled single-crystalline ZnO nanoisland with base diameter and height ranging around 30 and 40 nm on Si at different levels of current compliance. Current-voltage characteristics, conductive atomic force microscopy (C-AFM), and piezoresponse force microscopy results show that the threshold-like and self-rectifying types of switching are controlled by the movement of oxygen vacancies in ZnO nanoisland between the C AFM tip and Si substrate while ordinary bipolar switching is controlled by formation and rupture of conducting nano-filaments. Threshold-like switching leads to a very small switching power density of 1 * 10(3) W/cm(2). PMID- 23934277 TI - Prolyl isomerase Pin1 negatively regulates the stability of SUV39H1 to promote tumorigenesis in breast cancer. AB - Pin1, a conserved eukaryotic peptidyl-prolyl cis/trans isomerase, has profound effects on numerous key-signaling molecules, and its deregulation contributes to disease, particularly cancer. Although Pin1-mediated prolyl isomerization of protein servers as a regulatory switch in signaling pathways, the significance of proline isomerase activity in chromatin modifying complex remains unclear. Here, we identify Pin1 as a key negative regulator for suppressor of variegation 3-9 homologue 1 (SUV39H1) stability, a major methyltransferase responsible for histone H3 trimethylation on Lys9 (H3K9me3). Pin1 interacts with SUV39H1 in a phosphorylation-dependent manner and promotes ubiquitination-mediated degradation of SUV39H1. Consequently, Pin1 reduces SUV39H1 abundance and suppresses SUV39H1 ability to induce H3K9me3. In contrast, depletion of Pin1 in cancer cells leads to elevated SUV39H1 expression, which subsequently increases H3K9me3, inhibiting tumorigenecity of cancer cells. In a xenograft model with 4T1 metastatic mouse breast carcinoma cells, Pin1 overexpression increases tumor growth, whereas SUV39H1 overexpression abrogates it. In human breast cancer patients, immunohistochemical staining shows that Pin1 levels are negatively correlated with SUV39H1 as well as H3K9me3 levels. Thus, Pin1-mediated reduction of SUV39H1 stability contributes to convey oncogenic signals for aggressiveness of human breast cancer, suggesting that Pin1 may be a promising drug target for anticancer therapy. PMID- 23934279 TI - Importin-7 mediates glucocorticoid receptor nuclear import and is impaired by oxidative stress, leading to glucocorticoid insensitivity. AB - Some patients with severe inflammatory disease fail to respond to glucocorticoids, and oxidative stress contributes to this insensitivity. Importin receptors are associated with nuclear translocation of the glucocorticoid receptor (GR), which is essential for glucocorticoid function. We hypothesized that importin-7 is central to GR nuclear translocation and glucocorticoid sensitivity. We investigated the effects of importin-7 siRNA on fluticasone propionate (FP)-induced GR nuclear localization and suppression of IL-1beta induced CXCL8 and the effects of hydrogen peroxide (H2O2) plus IL-1beta costimulation on importin-7 expression, function, and glucocorticoid responsiveness in a human macrophagecell line (U937). H2O2 significantly reduced FP-induced GR nuclear localization (3.4+/-0.51- vs. 5.7+/-0.85-fold increase, P<0.05) and suppression of IL-1beta-induced CXCL8 (62.3+/-2.3 vs. 85.1+/-7.0%, P<0.05). Knockdown of importin-7 by 38.4 +/- 11.5% (compared with control siRNA) significantly reduced FP-mediated GR nuclear localization (3.5+/-0.5- vs. 5.7+/ 0.85-fold increase, P<0.05) and suppression of IL-1beta-induced CXCL8 expression (40.2+/-16.1 vs. 68.4+/-3.0%, P<0.05). H2O2 plus IL-1beta had no direct effect on importin-7 but caused a significant loss (61.2+/-12.6% compared with baseline) of nuclear RanGTP, an essential cofactor for importin-7-mediated nuclear import of cargo proteins. The importin-7 complex is essential for glucocorticoid function, and the expression of its cofactor RanGTP is reduced during oxidative stress induced glucocorticoid insensitivity. PMID- 23934278 TI - A novel strategy for preserving renal grafts in an ex vivo setting: potential for enhancing the marginal donor pool. AB - Renal transplantation remains the best treatment option for patients with end stage renal failure. However, the shortage of renal grafts remains a big challenge. Renal graft ischemic injuries that occur before and after graft retrieval have a devastating effect on graft survival, especially on grafts from marginal donors. This study was conducted to assess the protective effect against ischemic injury of a preservative solution supplemented with xenon (Xe), when used on ex vivo kidney grafts in a rat renal transplant model, and to explore the underlying mechanisms in vitro. Lewis rat renal grafts were stored in Soltran preservative solution at 4 degrees C, saturated with nitrogen (N2) or Xe gas (70% Xe or N2, with 5% CO2 balanced with O2) for 24 or 48 h. Grafts stored in Xe saturated preservative solution demonstrated significantly less severe histopathologic changes, together with enhanced B-cell lymphoma (Bcl)-2 and heat shock protein (HSP)-70 expression. After engraftment in the Lewis rat recipient, renal function was significantly improved in the Xe-treated grafts, and macrophage infiltration and fibrosis were reduced. Xe exposure enhanced Bcl-2 and HSP-70 expression in human renal tubular epithelial (HK-2) cells and prevented mitochondrial and nuclear damage. The release of the apoptogenic factors cytochrome c, apoptosis-inducing factor (AIF), and proinflammatory high-mobility group protein B1 (HMGB-1) was effectively suppressed. This study thus demonstrated for the first time that Xe confers renoprotection on renal grafts ex vivo and is likely to stabilize cellular structure during ischemic insult. The current study has significant clinical implications, in which the use of Xe ex vivo could enhance the marginal donor pool of renal grafts by preventing graft loss due to ischemia. PMID- 23934280 TI - Vasoactive intestinal peptide regulates sinonasal mucociliary clearance and synergizes with histamine in stimulating sinonasal fluid secretion. AB - Mucociliary clearance (MCC) is the primary physical airway defense against inhaled pathogens and particulates. MCC depends on both proper fluid/mucus homeostasis and epithelial ciliary beating. Vasoactive intestinal peptide (VIP) is a neurotransmitter expressed in the sinonasal epithelium that is up-regulated in allergy. However, the effects of VIP on human sinonasal physiology are unknown, as are VIP's interactions with histamine, a major regulator of allergic disease. We imaged ciliary beat frequency, mucociliary transport, apical Cl(-) permeability, and airway surface liquid (ASL) height in primary human sinonasal air-liquid-interface cultures to investigate the effects of VIP and histamine. VIP stimulated an increase in ciliary beat frequency (EC50 0.5 MUM; maximal increase ~40% compared with control) and cystic fibrosis transmembrane conductance regulator (CFTR)-dependent and Na(+)K(+)2Cl(-) cotransporter dependent fluid secretion, all requiring cAMP/PKA signaling. Histamine activated Ca(2+) signaling that increased ASL height but not ciliary beating. Low concentrations of VIP and histamine had synergistic effects on CFTR-dependent fluid secretion, revealed by increased ASL heights. An up-regulation of VIP in histamine-driven allergic rhinitis would likely enhance mucosal fluid secretion and contribute to allergic rhinorrhea. Conversely, a loss of VIP-activated secretion in patients with CF may impair mucociliary transport, contributing to increased incidences of sinonasal infections and rhinosinusitis. PMID- 23934283 TI - Guarded response to AHVLA's tendering plans. PMID- 23934282 TI - Nitric oxide mediates coral bleaching through an apoptotic-like cell death pathway: evidence from a model sea anemone-dinoflagellate symbiosis. AB - Coral bleaching (involving the loss of symbiotic algae from the cnidarian host) is a major threat to coral reefs and appears to be mediated at the cellular level by nitric oxide (NO). In this study, we examined the specific role of NO in bleaching using the sea anemone Aiptasia pulchella, a model system for the study of corals. Exposure of A. pulchella to high-temperature shock (26-33 degrees C over <1 h) or an NO donor (S-nitrosoglutathione) resulted in significant increases in host caspase-like enzyme activity. These responses were reflected in the intensities of bleaching, which were significantly higher in heat- or NO treated specimens than in controls maintained in seawater at 26 degrees C. Notably, the inhibition of caspase-like activity prevented bleaching even in the presence of an NO donor or at elevated temperature. The additional use of an NO scavenger controlled for effects mediated by agents other than NO. We also exposed A. pulchella to a more ecologically relevant treatment (an increase from 26 to 33 degrees C over 6-7 d). Again, host NO synthesis correlated with the activation of caspase-like enzyme activity. Therefore, we conclude that NO's involvement in cnidarian bleaching arises through the regulation of host apoptotic pathways. PMID- 23934281 TI - The biophysical and molecular basis of intracellular pH sensing by Na+/H+ exchanger-3. AB - Epithelial Na(+)/H(+) exchanger-3 (NHE3) transport is fundamental for renal and intestinal sodium reabsorption. Cytoplasmic protons are thought to serve as allosteric modifiers of the exchanger and to trigger its transport through protein conformational change. This effect presupposes an intracellular pH (pHi) dependence of NHE3 activity, although the biophysical and molecular basis of NHE3 pHi sensitivity have not been defined. NHE3, when complexed with the calcineurin homologous protein-1 (CHP1), had a shift in pHi sensitivity (0.4 units) toward the acidic side in comparison with NHE3 alone, as measured by oscillating pH electrodes combined with whole-cell patch clamping. Indeed, CHP1 interaction with NHE3 inhibited NHE3 transport in a pHi -dependent manner. CHP1 binding to NHE3 also affected its acute regulation. Intracellular perfusion of peptide from the CHP1 binding region (or pHi modification to reduce the CHP1 amount bound to NHE3) was permissive and cooperative for dopamine inhibition of NHE3 but reversed that of adenosine. Thus, CHP1 interaction with NHE3 apparently establishes the exchanger set point for pHi, and modification in this set point is effective in the hormonal stimuli-mediated regulation of NHE3. CHP1 may serve as a regulatory cofactor for NHE3 conformational change, dependent on intracellular protonation. PMID- 23934284 TI - Proposals for electronic movement reporting system for sheep. PMID- 23934285 TI - Calls for a ban on the use of electric shock collars on dogs. PMID- 23934286 TI - Defra seeks views on maximum penalty for aggravated dog attacks. PMID- 23934287 TI - Triple launch event helps celebrate Veterinary Record's 125 years. PMID- 23934288 TI - Vets to be more involved in Red Tractor Assurance herd health planning. PMID- 23934289 TI - Equine health survey highlights the prevalence of lameness. PMID- 23934290 TI - Vet to be removed from the Register following convictions for fraud. PMID- 23934291 TI - Blanket acceptable for transporting injured dogs. PMID- 23934292 TI - Early-career fellowships in food safety. PMID- 23934293 TI - In the swim for AWF. PMID- 23934294 TI - Cold spring prolongs Nematodirus infective period in Northern Ireland. AB - Nematodirosis in lambs Jejunal haemorrhagic syndrome in a heifer Epitheliogenesis imperfecta in a bovine fetus Plant poisoning in cattle and sheep Abomasal emptying defect in a ewe Cholangiocellular carcinoma in a duck These are among matters discussed in the Northern Ireland animal disease surveillance quarterly report for April to June 2013. PMID- 23934295 TI - Emergence and spread of Schmallenberg virus. PMID- 23934296 TI - Absence of E coli O157:H7 in sheep and cattle faeces in North Wales. PMID- 23934297 TI - Emergence of severe porcine epidemic diarrhoea in pigs in the USA. PMID- 23934298 TI - Detection of Angiostrongylus vasorum in red foxes in Scotland. PMID- 23934299 TI - [Brachioradialis rerouting for restoration of forearm supination or pronation]. AB - OBJECTIVE: Improvement of active forearm supination or pronation. Reduction of paralytic pronation or supination posture. INDICATIONS: Disability or impairment of active supination or pronation due to cerebral palsy, obstetric palsy or traumatic brachial plexus palsy, quadriplegia or paralysis from other causes. CONTRAINDICATIONS: Inadequate passive range of motion of forearm supination or pronation. Insufficient power of brachioradialis muscle < M4. Insufficient rehabilitation after conservative treatment or neurosurgical intervention with possible improvement of supination or pronation. Lack of patient's cooperation and compliance. SURGICAL TECHNIQUE: Exposure and mobilisation of brachioradialis muscle. Division of brachioradialis tendon distally with Z-plasty. Passing distal tendon through the interosseus space in dorsal to palmar direction for restoration of supination respectively in palmar to dorsal direction for restoration of pronation. Suturing both tendon ends. POSTOPERATIVE MANAGEMENT: Management includes an above elbow cast with the elbow in 70 degrees flexion for 4 weeks. Then active physiotherapy to learn new brachioradialis muscle function for supination or pronation over 1-1.5 years. If needed dynamic orthesis. RESULTS: Ozkan et al. performed brachioradialis rerouting to restore supination in 5 children between 4 and 14 years with pronation deformity and to restore pronation in 4 children aged 5-9 years with supination deformity. Mean active gain for supination was 81 degrees (40-140 degrees ). Active pronation improved from 28 to 49 degrees (30-75 degrees ; Ozkan et al., J Hand Surg Br 29:263-268, 2004; Ozkan et al., J Hand Surg Am 29:22-27, 2004). Between April 2006 and January 2011 we used this technique in 4 patients aged 7-26 years (mean 14 years). Three patients could be followed up. One patient had preoperative a fixed pronation deformity of the forearm in 80 degrees pronation. In this case active range of motion could be improved to 80/30/0 degrees pronation/supination. One patient improved from preoperative 0/0/90 degrees pronation/supination to 30/0/90 degrees postoperatively. In one case no functional improvement of forearm rotation could be achieved in long-term follow-up. No functional loss in forearm rotation to the opposite direction or of the elbow function was observed. Mean follow-up time was 51 months (21-77 months). PMID- 23934300 TI - Mechanisms on electrical breakdown strength increment of polyethylene by acetophenone and its analogues addition: a theoretical study. AB - A theoretical investigation is completed on the mechanism of electrical breakdown strength increment of polyethylene. It is shown that it is one of the most important factors for increasing electrical breakdown strength of polyethylene through keto-enol isomerization of acetophenone and its analogues at the ground state S0 and the lowest triplet state T1. The minimum structures and transition states of the keto- and the enol-tautomer of acetophenone and its analogues at the S0 and T1 states are obtained at the B3LYP/6-311+G(d,p) level, as well as the harmonic vibration frequencies of the equilibrium geometries and the minimum energy path (MEP) by the intrinsic reaction coordinate (IRC) theory at the same level. The two C-C bond cleavage reaction channels have been identified in acetophenone. The calculated results show that the energy barriers of keto-enol isomerization of acetophenone and its analogues at S0 and T1 states are much smaller than the average C-C bond energy of polyethylene, and the acetophenone doping or bond linked into polyethylene can increase the electrical breakdown strength and inhibit polyethylene electrical tree initiation and aging. PMID- 23934301 TI - Influence of quantum dots on the aromaticity of thiosalicylic acid. AB - When ligands are coordinated to quantum dots (QDs), the ring current of the ligand strongly influences the applications of the QDs, for example in solar cell technology. The Raman spectrum of the ligand can be used to probe and identify ions or measure ion concentrations. Here, we investigated, using a theoretical method, the aromaticities and Raman spectra of CdTe, CdSe, and CdS QDs coordinated with thiosalicylic acid ligands. We found that the aromaticity of the benzene ring in free thiosalicylic acid increased when it was used as a QD ligand. The ring currents of the benzene rings in the CdTe-ligand, CdSe-ligand, and CdS-ligand systems were stronger than the ring current of the benzene ring in free thiosalicylic acid; in other words, the QDs influence the ring current--they enhance the electron transfer rate of the benzene ring. We also discovered that the CdTe-ligand and CdSe-ligand systems have stronger ring currents than the CdS ligand system. The high electronegativity and vacant d orbital of the sulfur atom influence the ring current of the ligand in the CdS-ligand system. Further, the Raman spectrum of free thiosalicylic acid was different from the spectra of the ligands in the QD-ligand systems: the Raman spectra of COO(-) in each QD-ligand system was enhanced compared with that of the COO(-) in free thiosalicylic acid. PMID- 23934302 TI - Ammonium adsorption on Bronsted acidic centers on low-index vanadium pentoxide surfaces. AB - Vanadium-based catalysts are used in many technological processes, among which the removal of nitrogen oxides (NOx) from waste gases is one of the most important. The chemical reaction responsible for this selective catalytic reaction (SCR) is based on the reduction of NOx molecules to N2, and a possible reductant in this case is pre-adsorbed NH3. In this paper, NH3 adsorption on Bronsted OH acid centers on low-index surfaces of V2O5 (010, 100, 001) is studied using a theoretical DFT method with a gradient-corrected functional (RPBE) in the embedded cluster approximation model. The results of the calculations show that ammonia molecules are spontaneously stabilized on all low-index surfaces of the investigated catalyst, with adsorption energies ranging from -0.34 to -2 eV. Two different mechanisms of ammonia adsorption occur: the predominant mechanism involves the transfer of a proton from a surface OH group and the stabilization of ammonia as an NH4 (+) cation bonded to surface O atom(s), while an alternative mechanism involves the hydrogen bonding of NH3 to a surface OH moiety. The latter binding mode is present only in cases of stabilization over a doubly coordinated O(2) center at a (100) surface. The results of the calculations indicate that a nondirectional local electrostatic interaction with ammonia approaching a surface predetermines the mode of stabilization, whereas hydrogen-bonding interactions are the main force stabilizing the adsorbed ammonia. Utilizing the geometric features of the hydrogen bonds, the overall strength of these interactions was quantified and qualitatively correlated (R = 0.93) with the magnitude of the stabilization effect (i.e., the adsorption energy). PMID- 23934303 TI - Theory meets practice: the localization of wraparound services for youth with serious emotional disturbance. AB - This study identified statewide variation in implementation of wraparound for children on the severe emotional disturbance (SED) Waiver in Kansas. SED Waivers allow Community Mental Health Centers (CMHC) to offer an array of community-based services to high risk youth. Qualitative methods, including interviews, reviews of charts and billing records, and a survey, were employed. Stratified random sampling was used to select seven CMHCs, and random sampling was used to select individual cases for interviews. Although CMHCs shared similar wraparound philosophy and service initiation processes, each developed their own localized wraparound model within the confines of Medicaid eligibility and documentation rules. Eight models for wraparound team composition were identified. Findings demonstrate implementation of wraparound with fidelity to a central model is difficult on a large scale. The balance of standardized wraparound practices, localized innovations, and agency compliance with Medicaid is essential for optimizing children's mental health services. PMID- 23934304 TI - Change patterns of homeless individuals with mental illness: a multiple case study. AB - This multiple case study illuminates the individual change trajectories of four homeless men with mental illnesses who participated in a manualized life skills intervention to improve housing retention. Readiness-to-change, life skills knowledge and trauma symptoms were measured at baseline, post-intervention and at 3-6 months follow-up. Cluster analysis identified two patterns of readiness-to change: engaged and pre-engaged. Change is non-linear and baseline readiness is not necessary to benefit from the intervention. Examining individuals' lives in context illuminated the change process and demonstrated that varied patterns can lead to successful outcomes for housing stability and community reintegration. PMID- 23934305 TI - Ultrathin graphitic carbon nitride nanosheets: a low-cost, green, and highly efficient electrocatalyst toward the reduction of hydrogen peroxide and its glucose biosensing application. AB - In this communication, we demonstrate for the first time that ultrathin graphitic carbon nitride (g-C3N4) nanosheets can serve as a low-cost, green, and highly efficient electrocatalyst toward the reduction of hydrogen peroxide. We further demonstrate its application for electrochemical glucose biosensing in both buffer solution and human serum medium with a detection limit of 11 MUM and 45 MUM, respectively. PMID- 23934306 TI - Recent advances in biosensor based endotoxin detection. AB - Endotoxins also referred to as pyrogens are chemically lipopolysaccharides habitually found in food, environment and clinical products of bacterial origin and are unavoidable ubiquitous microbiological contaminants. Pernicious issues of its contamination result in high mortality and severe morbidities. Standard traditional techniques are slow and cumbersome, highlighting the pressing need for evoking agile endotoxin detection system. The early and prompt detection of endotoxin assumes prime importance in health care, pharmacological and biomedical sectors. The unparalleled recognition abilities of LAL biosensors perched with remarkable sensitivity, high stability and reproducibility have bestowed it with persistent reliability and their possible fabrication for commercial applicability. This review paper entails an overview of various trends in current techniques available and other possible alternatives in biosensor based endotoxin detection together with its classification, epidemiological aspects, thrust areas demanding endotoxin control, commercially available detection sensors and a revolutionary unprecedented approach narrating the influence of omics for endotoxin detection. PMID- 23934307 TI - Root-derived CLE glycopeptides control nodulation by direct binding to HAR1 receptor kinase. AB - Leguminous plants establish a symbiosis with rhizobia to enable nitrogen fixation in root nodules under the control of the presumed root-to-shoot-to-root negative feedback called autoregulation of nodulation. In Lotus japonicus, autoregulation is mediated by CLE-RS genes that are specifically expressed in the root, and the receptor kinase HAR1 that functions in the shoot. However, the mature functional structures of CLE-RS gene products and the molecular nature of CLE-RS/HAR1 signalling governed by these spatially distant components remain elusive. Here we show that CLE-RS2 is a post-translationally arabinosylated glycopeptide derived from the CLE domain. Chemically synthesized CLE-RS glycopeptides cause significant suppression of nodulation and directly bind to HAR1 in an arabinose chain and sequence-dependent manner. In addition, CLE-RS2 glycopeptide specifically produced in the root is found in xylem sap collected from the shoot. We propose that CLE-RS glycopeptides are the long sought mobile signals responsible for the initial step of autoregulation of nodulation. PMID- 23934308 TI - Reply to Nation et al. PMID- 23934309 TI - The urgent need for clear and accurate information on the polymyxins. PMID- 23934310 TI - Adherence and discontinuation of oral hormonal therapy in patients with hormone receptor positive breast cancer. AB - BACKGROUND: Oral treatment in women with breast cancer has been increasingly used. However, a potentially negative side of oral medication is poor patient adherence and/or discontinuation, which reduces the treatment effectiveness, accelerating progression of the disease and reducing the patient survival rate. AIM OF THE REVIEW: To compare the rates of adherence and/or discontinuation and the methodologies used to assess these outcomes. It was conducted an integrative review of original articles published from 2000 to 2012, in which their primary outcome was to quantify medication adherence and/or discontinuation of oral hormonal therapy in patients with hormone receptor positive breast cancer. METHODS: Original studies were searched in the PubMed/MEDLINE, Scopus, Embase and SciELO databases. The Medical Subject Heading was used to define descriptors. The descriptor "breast neoplasms" was used in all combinations. Each of the descriptors "medication adherence" and "patient compliance" were combined with each of the following descriptors "tamoxifen", "aromatase inhibitors", "selective estrogen receptor modulators", or the terms "letrozole", "anastrozole", and "exemestane". RESULTS: Twenty-four original articles were included. Our study showed a wide range of adherence and discontinuation rates, ranging from 45-95.7 and 12-73 %, respectively. Regarding the methodological development of the selected articles, a high prevalence (87.5 %) of prospective and/or retrospective longitudinal studies was found. In addition, there was a high prevalence of studies using a database (70.8 %). Among some of the studies, it was shown that patient adherence to hormonal therapy gradually reduces, while discontinuation increases during the treatment. CONCLUSIONS: It was observed a great diversity among rates of adherence and/or discontinuation of hormonal therapy for breast cancer, which may be due to a lack of methodology standardization. Therefore, adequate and validated methods to ensure reliability of the results and allow comparison in the literature are needed. Furthermore, adherence decreases and discontinuation increases over time, suggesting the need for patient continuous education and a pharmacotherapeutic follow up by health professionals to improve these clinical outcomes. PMID- 23934311 TI - Health-related quality of life in gout: a systematic review. AB - OBJECTIVES: To identify the instruments that have been used to measure health related quality of life (HRQOL) in gout and assess their clinimetric properties, determine the distribution of HRQOL in gout and identify factors associated with poor HRQOL. METHODS: Medline, CINAHL, EMBASE and PsycINFO were searched from inception to October 2012. Search terms pertained to gout, health or functional status, clinimetric properties and HRQOL. Study data extraction and quality assessment were performed by two independent reviewers. RESULTS: From 474 identified studies, 22 met the inclusion criteria. Health Assessment Questionnaire Disability Index (HAQ-DI) and Short Form 36 (SF-36) were most frequently used and highest rated due to robust construct and concurrent validity, despite high floor and ceiling effects. The Gout Impact Scale had good content validity. Gout had a greater impact on physical HRQOL compared to other domains. Both gout-specific features (attack frequency and intensity, intercritical pain and number of joints involved) and comorbid disease were associated with poor HRQOL. Evidence for objective features such as tophi and serum uric acid was less robust. Limitations of existing studies include cross sectional design, recruitment from specialist clinic settings and frequent use of generic instruments. CONCLUSION: Most studies have used the generic HAQ-DI and SF 36. Gout-specific characteristics and comorbidities contribute to poor HRQOL. There is a need for a cohort study in primary care (where most patients with gout are treated) to determine which factors predict changes in HRQOL over time. This will enable those at risk of deterioration to be identified and better targeted for treatment. PMID- 23934312 TI - Mesenteric vasculitis in active systemic lupus erythematosus causing diffuse abdominal pain. PMID- 23934313 TI - Long-term efficacy and safety of pre-emptive maintenance therapy with rituximab in granulomatosis with polyangiitis: results from a single centre. AB - OBJECTIVE: Rituximab (RTX) is an anti-CD20 antibody used successfully in granulomatosis with polyangiitis (GPA) for induction and maintenance of remission. Our study aims to evaluate the long-term efficacy and safety of chronic pre-emptive RTX therapy in GPA. METHODS: Retrospective study of 35 GPA patients treated with RTX between April 2004 and September 2011 for active disease and maintenance. RTX was initiated as two 1 g infusions 2 weeks apart and thereafter 2 g of RTX was readministered annually. Patients were followed for 47 (2-88) months. They received a median RTX dose of 8 g (2-13) over 5 (1-10) rounds. RESULTS: All patients had a clinical response, but nine relapses were recorded (flare rate of 6.6/100 patient-years). At last visit, 13 patients (37%) had discontinued RTX mainly due to hypogammaglobulinaemia (57%). Nine patients (26%) had severe infections (infection rate of 6.6/100 patient-years) and 10 patients (29%) had chronic infections. Risks factors for severe infections are a high cumulative dose of CYC, low CD4 cell count and a significant drop in total immunoglobulins after the first RTX round. Risks factors for chronic infections are low IgG level during RTX maintenance and possibly the cumulative RTX dose. CONCLUSION: Long-term pre-emptive RTX maintenance was efficacious in reducing the risk for relapse but was discontinued in one-third of the patients. The patients' net state of immunodeficiency under RTX changes over time as low immunoglobulin serum levels increased the risk for infections. PMID- 23934314 TI - Power and sample size calculations for Mendelian randomization studies using one genetic instrument. AB - Mendelian randomization, which is instrumental variable analysis using genetic variants as instruments, is an increasingly popular method of making causal inferences from observational studies. In order to design efficient Mendelian randomization studies, it is essential to calculate the sample sizes required. We present formulas for calculating the power of a Mendelian randomization study using one genetic instrument to detect an effect of a given size, and the minimum sample size required to detect effects for given levels of significance and power, using asymptotic statistical theory. We apply the formulas to some example data and compare the results with those from simulation methods. Power and sample size calculations using these formulas should be more straightforward to carry out than simulation approaches. These formulas make explicit that the sample size needed for Mendelian randomization study is inversely proportional to the square of the correlation between the genetic instrument and the exposure and proportional to the residual variance of the outcome after removing the effect of the exposure, as well as inversely proportional to the square of the effect size. PMID- 23934315 TI - [Association of ischemic and hemorrhagic cerebral stroke due to severe envenomation by the Sahara horned viper (Cerastes cerastes)]. AB - Viper envenomation can cause complex disorders of hemostasis. These disorders usually lead to hemorrhagic syndrome. The occurrence of thrombosis is exceptional. This case report describes a severe envenomation by the Saharan horned viper (Cerastes cerastes), complicated by unusual brain injuries: hemorrhagic and ischemic stroke. The physiopathologic link between this serious toxic coagulopathy and the multitude of toxins in the venom of Cerastes cerastes is highlighted. PMID- 23934316 TI - Phlebotomine sand flies from Madagascar (Diptera: Psychodidae). VIII--Phlebotomus (Anaphlebotomus) vincenti n. sp. AB - A new species of Phlebotomine sand fly (Diptera: Psychodidae) is described from Mikea Forest in the southwest of Madagascar: Phlebotomus vincenti n. sp. It is temporarily classified in the subgenus Anaphlebotomus according to its spermathecal organization, similar to those of P. berentiensis, P. fertei and P. vaomalalae, previously classified in the subgenus Anaphlebotomus referring to on male genitalia morphology. An original trumpet-like dilatation on the distal part of the spermathecal ducts individualizes P. vincenti n. sp. from the other Malagasy species. Moreover, the second internal transcribed spacer (ITS2) sequences strongly individualises P. vincenti n. sp. from the other Malagasy Phlebotomus. PMID- 23934317 TI - New treatment strategies for HPV-positive head and neck cancer. AB - Epidemiological studies show an increasing incidence of human papilloma virus associated oropharyngeal cancer. HPV-positive head and neck squamous cell carcinoma (HNSCC) is recognized as a special subgroup of HNSCC. Because HPV positive patients are often younger and have an outstanding prognosis, long-term toxicities of therapy have become an important issue. Current clinical trials focus on a reduction of treatment-related toxicity and the development of HPV specific therapies. New treatment strategies include a dose reduction of radiotherapy, the use of cetuximab instead of cisplatin for chemoradiation and transoral robotic surgery (TORS). Increasing comprehension of the molecular background of HPV-associated HNSCC has also lead to more specific treatment attempts including immunotherapeutic strategies. Whereas recently published data shed light on immune mechanisms resulting in a tolerogenic niche for HPV and HPV associated HNSCC, other studies focus on specific vaccination of HPV-positive HNSCC. This study will summarize current therapy approaches and illustrate ongoing clinical trials in the field of HPV-positive HNSCC. PMID- 23934318 TI - Recombinant human histidine triad nucleotide-binding protein 1 attenuates liver fibrosis induced by carbon tetrachloride in rats. AB - It is currently thought that the transforming growth factor-beta (TGF-beta)/Smad signaling pathway acts as a central pathway leading to liver fibrosis, and that the aberrant Wnt/beta-catenin signaling pathway also plays a vital role in the development of liver fibrosis. There is evidence that the histidine triad nucleotide-binding protein 1 (Hint1) was capable of inhibiting these two pathways. However, little data regarding the effects of Hint1 on liver fibrosis exists. Thus, we sought to investigate whether the recombinant human Hint1 protein (rhHint1) was capable of attenuating liver fibrosis induced by carbon tetrachloride (CCl4) in rats and the possible underlying mechanism(s) of action. In the present study, purified rhHint1 was obtained using genetic engineering technology. Liver fibrosis was induced in male Sprague-Dawley (SD) rats by the subcutaneous injection of CCl4. The rats were randomly divided into the normal control, the liver fibrosis model and the rhHint1 (doses, 50 and 100 ug/kg) treated groups. Following four weeks of treatment, the rhHint1-treated rats exhibited significantly reduced liver fibrosis upon histopathological analysis and lower levels of hydroxyproline. Furthermore, rhHint1 inhibited the expression of alpha-smooth muscle actin (alpha-SMA) in the liver tissues. Additionally, rhHint1 lowered the gene expression levels of TGF-beta1/Smad3 and beta catenin/cyclin D1, whereas it increased the gene expression levels of Smad7. In conclusion, the results of this study indicated that rhHint1 is capable of attenuating CCl4-induced liver fibrosis by simultaneously targeting multiple pathogenic pathways, which may be developed as a new treatment for liver fibrosis. PMID- 23934321 TI - The association between the expression of solute carrier transporters and the prognosis of pancreatic cancer. AB - OBJECTIVES: The aim of this study was to investigate the prognostic significance of fourteen anticancer drug-relevant solute carrier transporters (SLCs) in pancreatic cancer in the context of clinical-pathological characteristics and the KRAS mutation status of tumors. METHODS: Tumors and non-neoplastic pancreatic tissues were obtained from 32 histologically verified patients with pancreatic ductal adenocarcinoma. The transcript profile of SLCs was assessed using quantitative real-time PCR. KRAS mutations in exon 2 were assessed by high resolution melting analysis and confirmed by sequencing. RESULTS: SLC22A3 and SLC22A18 were upregulated and SLC22A1, SLC22A2, SLC22A11, SLC28A1, SLC28A3 and SLC29A1 were downregulated when compared with non-neoplastic pancreatic tissues. Moreover, significantly lower levels of SLC22A1, SLC22A11 and SLC29A1 were found in tumors with angioinvasion. There was also a significantly higher transcript level of SLC28A1 in tumors with regional lymph nodes affected by metastasis. The study found that a high expression of SLC28A1 was significantly associated with poor overall survival in unselected patients. In contrast, a high expression of SLC22A3 or SLC29A3 was significantly associated with longer overall survival in patients treated with nucleoside analogs. Protein expression of SLC22A1, SLC22A3 and SLC29A3 in tumor tissues of patients with pancreatic carcinoma was observed by immunoblotting for the first time. Finally, SLC levels were not found to be associated with KRAS mutation status in exon 2. CONCLUSIONS: This study identified a number of associations of transcript levels of SLCs with prognosis of pancreatic cancer patients. PMID- 23934319 TI - A five-day progesterone plus eCG-based fixed-time AI protocol improves fertility over spontaneous estrus in high-producing dairy cows under heat stress. AB - This study compared the efficiency of a five-day or standard (nine-day) progesterone-based regimen combined with equine chorionic gonadotrophin (eCG) in a fixed-time AI (FTAI) protocol for dairy cows. The data examined were derived from 3577 inseminations conducted in three dairy herds. Animals with no estrus signs detected over 21 days were randomly assigned to a PRID-9 or PRID-5 group. Cows in each group received a progesterone intravaginal device (PRID) for 9 or 5 days, respectively, PGF(2alpha) and eCG on PRID removal, and GnRH 48 h later. Fixed-time AI was performed 12 h after the GnRH dose. Cows artificially inseminated following spontaneous estrus during the study period were considered as controls. Based on the odds ratio, the likelihoods of animals in PRID-9 in the warm (conception rate [CR] of 22.3%) and cool (32% CR) periods, and control animals in the warm period (26.6% CR) becoming pregnant were reduced (by factors of 0.6, 0.3 and 0.4, respectively) compared with the control animals in the cool period (CR of 43.7%). The risk of a twin pregnancy was higher (51.4%) for cystic PRID-9 cows (by a factor of 3.6) and lower (9.9%) for cyclic PRID-5 animals (by a factor of 0.4) compared with the PRID-9 cyclic cows. These findings indicate that the proposed protocol achieves similar results during the cool or warm season to those obtained when AI is conducted at spontaneous estrus during the cool season. In addition, PRID-5 reduced twin pregnancy compared with PRID-9. PMID- 23934320 TI - Vitamin A deprivation affects the progression of the spermatogenic wave and initial formation of the blood-testis barrier, resulting in irreversible testicular degeneration in mice. AB - The blood testis-barrier (BTB) is essential for maintaining homeostasis in the seminiferous epithelium. Although many studies have reported that vitamin A (VA) is required for the maintenance of spermatogenesis, the relationships between the BTB, spermatogenesis and VA have not been elucidated. In this study, we analyzed BTB assembly and spermatogenesis in the testes of mice fed the VA-deficient (VAD) diet from the prepubertal period to adulthood. During the prepubertal period, no changes were observed in the initiation and progression of the first spermatogenic wave in mice fed the VAD diet. However, the numbers of preleptotene/leptotene spermatocytes derived from the second spermatogenic wave onwards were decreased, and initial BTB formation was also delayed, as evidenced by the decreased expression of mRNAs encoding BTB components and VA signaling molecules. From 60 days postpartum, mice fed the VAD diet exhibited apoptosis of germ cells, arrest of meiosis, disruption of the BTB, and dramatically decreased testis size. Furthermore, vacuolization and calcification were observed in the seminiferous epithelium of adult mice fed the VAD diet. Re-initiation of spermatogenesis by VA replenishment in adult mice fed the VAD diet rescued BTB assembly after when the second spermatogenic wave initiated from the arrested spermatogonia reached the preleptotene/leptotene spermatocytes. These results suggested that BTB integrity was regulated by VA metabolism with meiotic progression and that the impermeable BTB was required for persistent spermatogenesis rather than meiotic initiation. In conclusion, consumption of the VAD diet led to critical defects in spermatogenesis progression and altered the dynamics of BTB assembly. PMID- 23934322 TI - New fronts in the adjuvant treatment of GIST. AB - PURPOSE: To review the prognostic factors and stratification systems used to determine the need for adjuvant therapy in the treatment of gastrointestinal stromal tumors (GIST), and to review recent clinical advances in investigation of the efficacy and safety of adjuvant imatinib mesylate treatment. METHODS: Recent data from clinical trials of various durations of adjuvant imatinib in GIST are reviewed, with emphasis on key results from the Phase III American College of Surgeons Oncology Group (ACOSOG) Z9001 trial and the Scandinavian Sarcoma Group XVIII/Arbeitsgemeinschaft Internistische Onkologie (SSGXVIII/AIO) trial. RESULTS: Complete surgical resection remains the standard of treatment for localized GISTs; however, disease recurrence occurs in up to 50 % of patients who undergo complete resection. The ACOSOG Z9001 trial established that 1 year of adjuvant imatinib reduces the risk of recurrence in patients with resected GIST. The SSGXVIII/AIO trial further demonstrated that 3-year adjuvant imatinib improves both recurrence-free survival and overall survival compared with 1-year therapy in patients at high risk of recurrence after surgery. Considering risk factors associated with tumor recurrence is essential for identifying the patients who are most likely to benefit from adjuvant imatinib. CONCLUSIONS: Although the optimal duration of adjuvant therapy remains to be determined, results from these pivotal trials provide firm evidence that adjuvant imatinib improves recurrence free survival and improved overall survival of patients in the SSGXVIII/AIO trial. Ongoing studies may shed further light on the benefits and harms of adjuvant therapy, as well as the most appropriate patient candidates for adjuvant imatinib treatment. PMID- 23934323 TI - Antitumor efficacy, toxicity and pharmacokinetics of 9-nitrocamptothecin: role of lactone ratio. AB - PURPOSE: Since the carboxylate form could be regarded as a possible "source" of lactone form, the optimum ratio of lactone should be determined for the administration of camptothecin (CPT) analogues such as 9-nitrocamptothecin (9 NC). METHODS: 9-NC solutions with different lactone ratios (100, 75, 50, 25 and 0 %) were obtained by the change of pH. The resultant 9-NC solution and corresponding blank solvent were intravenously injected to mice to evaluate toxicity. The S180 tumor-bearing mice were intravenously administered 9-NC solutions with different lactone ratios, and the antitumor efficacy and toxicity were compared. The tissue distribution of lactone and total (the total of lactone and carboxylate forms) 9-NC was also investigated as a function of lactone ratio. RESULTS: Toxicity of 9-NC was found to be increased with the increase in lactone ratio. The tumor inhibitory rates of 9-NC solution were determined to be 64.17, 60.43, 42.78, 41.71 and 8.60 % for 100, 75, 50, 25 and 0 % lactone ratio, respectively. The lactone stability of 9-NC in most tissues was found to be higher than in plasma. In tumor and plasma, whether for lactone or total 9-NC AUC values, there was no difference between 100 and 75 % groups. CONCLUSIONS: Although carboxylate form of CPTs is inactive, the administration of carboxylate form in an appropriate ratio is active as a result of its conversion to lactone form in vivo. PMID- 23934324 TI - Bispectral index predicts deaths within 2 weeks in coma patients, a better predictor than serum neuron-specific enolase or S100 protein. AB - PURPOSE: We assessed the ability of bispectral index (BIS) to predict clinical outcome (dead or alive within 2 weeks). METHODS: In total, 90 coma patients with severe brain injuries underwent BIS monitoring, and serum neuron-specific enolase (NSE) and S100 protein levels were assayed within the first 3 days of admission. Receiver operator characteristic (ROC) curve analysis was used to assess the performance of BIS values for predicting death within 2 weeks. A cutoff value was calculated using the Youden index. RESULTS: A significant negative correlation was found between BIS value and serum NSE and S100 levels. The area under the curve for BIS value was 0.841 (p < 0.001, 95 % CI = 0.751-0.931), and higher than for NSE (0.713) (p = 0.002, 95 % CI = 0.582-0.844) or S100 (0.790) (p < 0.001, 95 % CI = 0.680-0.899). The optimal cutoff of BIS was 32.5. Serum NSE and S100 protein levels and the mortality rate were significantly lower in patients with a BIS value >32.5 than in patients with a BIS value <=32.5. CONCLUSIONS: Bispectral index values may reflect degree of brain injury, and BIS is an objective and noninvasive monitoring method for helping clinicians to predict death in patients with a BIS value <=32.5. PMID- 23934325 TI - Visual assessment method of angular performance in medical liquid-crystal displays by use of the ANG test pattern: effect of ambient illuminance and effectiveness of modified scoring. AB - A visual assessment method of the angular performance in medical liquid-crystal displays (LCDs) by use of the "ANG test pattern" was proposed by Badano and the International Electrotechnical Commission. Our goals were to examine the effect of ambient illuminance on the visual assessment, and to investigate whether our modified visual assessment (with the ANG test pattern) can be used instead of the conventional assessment based on luminance measurements. As the ambient illuminance increased, the original scores obtained with the visual assessment decreased. The modified score of the visual assessment was in reasonable agreement with the results of the luminance-based assessment. We conclude that the visual assessment with the ANG test pattern should be performed in a room with constant ambient illuminance, and the modified visual assessment could have the potential to be used instead of the luminance-based assessment for quality assurance of medical LCDs. PMID- 23934326 TI - An overview of genetic counseling in Cuba. AB - This brief report provides an overview of the history and current status of genetic services in Cuba. In 1971, the University of Medical Sciences of Havana began to train doctors in medical genetics according to the medicine development plan in Cuba. With the aim of introducing genetic services to the population, two main issues were identified: the impact of neural tube defects as a cause of infantile mortality, and a founder effect resulting in a high frequency of sickle cell anemia, which increased the mortality rate and impacted the quality of peoples' lives. The impact of consanguinity is variable; it depends on the isolation of the population, with rates of 1 to 11% in different regions for first and second cousin marriages. From 1981, the services of medical genetics began to expand to the entire country, according to a government directive, and the need to design a program for the specialty became evident. From 1995 to 2000, two Masters-level programs were designed by professors of the Department of Medical Genetics, University of Medical Sciences of Havana, and authorized by the Ministry of Higher Education. One program in medical genetics was designed for physicians with other specialties, and the second program was designed to train professionals to become genetic counselors. The majority of graduates from the latter program are working at the primary level of healthcare. PMID- 23934327 TI - Alpha-1 couples: interpersonal and intrapersonal predictors of spousal communication and stress. AB - Couples often discuss genetic test results, and then manage their implications together. This interdependence can lead to common, shared experiences, similar intrapersonal processes to manage shared stressors, or interpersonal influences between spouses, leading to different outcomes. This study sought to reveal the intracouple, intrapersonal, and interpersonal influences of genetic stigma and negative feelings on spousal communication and perceived stress with 50 couples in which one spouse is a member of a genetic disease registry. The results were analyzed with dyadic analysis, including multilevel modeling. The findings showed that registered members and their spouses were not statistically different in their mean levels of perceived genetic stigma, negative feelings about alpha-1 antitrypsin deficiency (AATD), conversations with each other about the AATD test results, and their perceived stress. The findings also showed that their intracouple consistencies were not high, and their intrapersonal and interpersonal influences on communication and stress differed. The social implications of genetic research at the interpersonal level are discussed. PMID- 23934329 TI - Adjuvant therapy after resection of brain metastases. Frameless image-guided LINAC-based radiosurgery and stereotactic hypofractionated radiotherapy. AB - BACKGROUND: Tumor bed stereotactic radiosurgery (SRS) after resection of brain metastases is a new strategy to delay or avoid whole-brain irradiation (WBRT) and its associated toxicities. This retrospective study analyzes results of frameless image-guided linear accelerator (LINAC)-based SRS and stereotactic hypofractionated radiotherapy (SHRT) as adjuvant treatment without WBRT. MATERIALS AND METHODS: Between March 2009 and February 2012, 44 resection cavities in 42 patients were treated with SRS (23 cavities) or SHRT (21 cavities). All treatments were delivered using a stereotactic LINAC. All cavities were expanded by >= 2 mm in all directions to create the clinical target volume (CTV). RESULTS: The median planning target volume (PTV) for SRS was 11.1 cm(3). The median dose prescribed to the PTV margin for SRS was 17 Gy. Median PTV for SHRT was 22.3 cm(3). The fractionation schemes applied were: 4 fractions of 6 Gy (5 patients), 6 fractions of 4 Gy (6 patients) and 10 fractions of 4 Gy (10 patients). Median follow-up was 9.6 months. Local control (LC) rates after 6 and 12 months were 91 and 77 %, respectively. No statistically significant differences in LC rates between SRS and SHRT treatments were observed. Distant brain control (DBC) rates at 6 and 12 months were 61 and 33 %, respectively. Overall survival (OS) at 6 and 12 months was 87 and 63.5 %, respectively, with a median OS of 15.9 months. One patient treated by SRS showed symptoms of radionecrosis, which was confirmed histologically. CONCLUSION: Frameless image guided LINAC-based adjuvant SRS and SHRT are effective and well tolerated local treatment strategies after resection of brain metastases in patients with oligometastatic disease. PMID- 23934328 TI - Receptor trafficking and the regulation of synaptic plasticity by SUMO. AB - Timely and efficient information transfer at synapses is fundamental to brain function. Synapses are highly dynamic structures that exhibit long-lasting activity-dependent alterations to their structure and transmission efficiency, a phenomenon termed synaptic plasticity. These changes, which occur through alterations in presynaptic release or in the trafficking of postsynaptic receptor proteins, underpin the formation and stabilisation of neural circuits during brain development, and encode, process and store information essential for learning, memory and cognition. In recent years, it has emerged that the ubiquitin-like posttranslational modification SUMOylation is an important mediator of several aspects of neuronal and synaptic function. Through orchestrating synapse formation, presynaptic release and the trafficking of postsynaptic receptor proteins during forms of synaptic plasticity such as long term potentiation, long-term depression and homeostatic scaling, SUMOylation is being increasingly appreciated to play a central role in neurotransmission. In this review, we outline key discoveries in this relatively new field, provide an update on recent progress regarding the targets and consequences of protein SUMOylation in synaptic function and plasticity, and highlight key outstanding questions regarding the roles of protein SUMOylation in the brain. PMID- 23934331 TI - Improvement of infrared single-photon detectors absorptance by integrated plasmonic structures. AB - Plasmonic structures open novel avenues in photodetector development. Optimized illumination configurations are reported to improve p-polarized light absorptance in superconducting-nanowire single-photon detectors (SNSPDs) comprising short- and long-periodic niobium-nitride (NbN) stripe-patterns. In OC-SNSPDs consisting of ~quarter-wavelength dielectric layer closed by a gold reflector the highest absorptance is attainable at perpendicular incidence onto NbN patterns in P orientation due to E-field concentration at the bottom of nano-cavities. In NCAI SNSPDs integrated with nano-cavity-arrays consisting of vertical and horizontal gold segments off-axis illumination in S-orientation results in polar-angle independent perfect absorptance via collective resonances in short-periodic design, while in long-periodic NCAI-SNSPDs grating-coupled surface waves promote EM-field transportation to the NbN stripes and result in local absorptance maxima. In NCDAI-SNSPDs integrated with nano-cavity-deflector-array consisting of longer vertical gold segments large absorptance maxima appear in 3p-periodic designs due to E-field enhancement via grating-coupled surface waves synchronized with the NbN stripes in S-orientation, which enable to compensate fill-factor related retrogression. PMID- 23934330 TI - NFkappaB attenuates IL-5 production and upregulates T-box transcription factors in Th2-like T cells. AB - IL-5 plays important roles in eosinophil differentiation, expansion, and recruitment. The regulation of IL-5 seems critical for the treatment of eosinophil-mediated allergic reactions. However, the precise mechanisms for IL-5 regulation remain unknown. In this study, we investigated how IL-5 production is regulated. The transduction of GATA-3 into a murine T cell hybridoma resulted in acquiring the ability to produce IL-5 in response to an antigenic stimulus like Th2 cells. This production was dependent on the cAMP-PKA pathway, but not on p38 activation. Transduction of NIK largely impaired IL-5 production. RelA and RelB similarly impaired IL-5 production. RelA decreased not only IL-5 protein amount but mRNA. RelA also inhibited Il5-luciferase reporter activity. The transduction of GATA-3 decreased the expression of Tbx21 and Eomes, but the additional transduction of RelA abrogated the decreased expression of GATA-3-induced Tbx21 and Eomes. Furthermore, the transduction of T-bet or Eomes into the GATA-3 transduced T cell hybridoma impaired IL-5 production. These results suggested that strong enhancement of the NFkappaB pathway downregulates IL-5 production and upregulates T-box protein expression to shift an immune response from Th2 to inflammatory Th1. PMID- 23934332 TI - Case of radiologically multicentric but genetically identical multiple glioblastomas. AB - Surgery was performed in a 65-year-old male patient with malignant gliomas at two locations in the left and right cerebral hemispheres that showed no apparent continuity in imaging studies. Slight differences in histopathological appearance were seen between the tumors, and multicentric malignant glioma was diagnosed. Detailed genetic examination showed both the left- and right-side tumors to be of the IDH-1 wild type with a p53 mutation at the same locus. Whole genome analysis by comparative genomic hybridization revealed many of the same mutations to be present in both tumors. The O(6)-methylguanine-methyltransferase promoter in both cases was unmethylated, and the genetic profiles of both showed them to be homologous tumors. They were therefore inferred to be multiple gliomas from the same clone. There have been occasional reports of multicentric gliomas classified by diagnostic imaging. This report discusses the need to examine tumor origin by genomic profiling. PMID- 23934334 TI - Micropatterned substrates coated with neuronal adhesion molecules for high content study of synapse formation. AB - Studying the roles of different proteins and the mechanisms involved in synaptogenesis is hindered by the complexity and heterogeneity of synapse types, and by the spatial and temporal unpredictability of spontaneous synapse formation. Here we demonstrate a robust and high-content method to induce selectively presynaptic or postsynaptic structures at controlled locations. Neurons are cultured on micropatterned substrates comprising arrays of micron scale dots coated with various synaptogenic adhesion molecules. When plated on neurexin-1beta-coated micropatterns, neurons expressing neuroligin-1 exhibit specific dendritic organization and selective recruitment of the postsynaptic scaffolding molecule PSD-95. Furthermore, functional AMPA receptors are trapped at neurexin-1beta dots, as revealed by live-imaging experiments. In contrast, neurons plated on SynCAM1-coated substrates exhibit strongly patterned axons and selectively assemble functional presynapses. N-cadherin coating, however, is not able to elicit synapses, indicating the specificity of our system. This method opens the way to both fundamental and therapeutic studies of various synaptic systems. PMID- 23934336 TI - The renin-angiotensin system meets the hallmarks of cancer. AB - The hallmarks of cancer are described as the distinctive and complementary capacities that cells must acquire during the multistep development of becoming a cancer cell that allow them to survive, proliferate and disseminate. The renin angiotensin system (RAS) was first discovered and extensively studied in the physiological regulation of systemic arterial pressure. RAS signalling increases cell proliferation in malignancy by directly affecting tumour and stromal cells and by indirectly modulating the growth of vascular cells during angiogenesis. We aim to describe and give a general view of how the RAS is involved in several hallmarks of cancer and how this could open a window to several interesting treatments. PMID- 23934335 TI - Does a calculated "NAFLD fibrosis score" reliably negate the need for liver biopsy in patients undergoing bariatric surgery? AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) represents the most common cause of chronic liver disease in the USA. Biopsy has been the standard for determining fibrosis but is invasive, costly, and associated with risk. Previous studies report a calculated "NAFLD fibrosis scores" (cNFS) as a means to overcome the need for biopsy. We compared cNFS versus biopsy-pathological scoring for patients undergoing bariatric surgery. METHODS: We retrospectively reviewed patients with available preoperative labs and patient information undergoing Roux en-Y gastric bypass (RYGBP) surgery at a single institution over a 5.5-year period. Biopsy samples were blind scored by a single hepatopathologist and compared with scores calculated using a previously reported cNFS. RESULTS: Of the 225 patients that met the inclusion criteria, the mean body mass index was 44.6 +/- 5.4 kg/m(2) and 85 % were female. Using the cNFS, 39.6 % of patients were categorized into low fibrosis, 52 % indeterminate, and 8.4 % high fibrosis groups. Analysis of fibrosis by pathology scoring demonstrated 2 of 89 (2.2 %) and 7 of 110 (3.4 %) had significant fibrosis in the low and intermediate groups, respectively. Conversely, in the high fibrosis group calculated by cNFS, only 6 of 19 (31.6 %) exhibited significant fibrosis by pathology scoring. CONCLUSIONS: No definitive model for accurately predicting presence of NAFLD and fibrosis currently exits. Furthermore, under no circumstances should a clinical "NAFLD fibrosis score" replace liver biopsy at this time for RYGBP patients. PMID- 23934337 TI - Influence of delignification efficiency with alkaline peroxide on the digestibility of furfural residues for bioethanol production. AB - Furfural residues (FR), the abundant lignocellulosic residues from commercial furfural production, were delignified with alkaline peroxide process and then taken as substrates for ethanol production by simultaneous saccharification and fermentation (SSF). It was apparent that the delignification efficiency was increased with higher chemical addition and temperature, reaching the maximum removal (73.5%) of lignin. The widespread accessible-cellulose in FR favored the enzymatic hydrolysis and achieved the considerable bioconversion (75.7% with 5 FPU+10 IU/g substrate). The delignification process increased the relative glucose content and then the bioconversion efficiency, closely relating to the increased specific surface area. As the cellulose contents were higher than 60%, the final conversions conversely fell to around 75%, probably due to the insufficient utilization of all active cellulose with low enzyme cocktails addition. Although the SSF bioconversion slightly decreased as the elevated amount of fermentable cellulose, the maximum of ethanol concentration (16.9 g/L) was expectedly obtained. PMID- 23934338 TI - Cell growth and accumulation of polyhydroxyalkanoates from CO2 and H2 of a hydrogen-oxidizing bacterium, Cupriavidus eutrophus B-10646. AB - Synthesis of polyhydroxyalkanoates (PHAs) by a new strain of Cupriavidus - Cupriavidus eutrophus B-10646 - was investigated under autotrophic growth conditions. Under chemostat, at the specific flow rate D=0.1h(-1), on sole carbon substrate (CO2), with nitrogen, sulfur, phosphorus, potassium, and manganese used as growth limiting elements, the highest poly(3-hydroxybutyrate) [P(3HB)] yields were obtained under nitrogen deficiency. In batch autotrophic culture, in the fermenter with oxygen mass transfer coefficient 0.460 h(-1), P(3HB) yields reached 85% of dry cell weight (DCW) and DCW reached 50 g/l. Concentrations of supplementary PHA precursor substrates (valerate, hexanoate, gamma-butyrolactone) and culture conditions were varied to produce, for the first time under autotrophic growth conditions, PHA ter- and tetra-polymers with widely varying major fractions of 3-hydroxybutyrate, 4-hydroxybutyrate, 3-hydroxyvalerate, and 3 hydroxyhexanoate monomer units. Investigation of the high-purity PHA specimens showed significant differences in their physicochemical and physicomechanical properties. PMID- 23934339 TI - Microbial community shifts and biogas conversion computation during steady, inhibited and recovered stages of thermophilic methane fermentation on chicken manure with a wide variation of ammonia. AB - The thermophilic methane fermentation of chicken manure (10% TS) was investigated within a wide range of ammonia. Microbiological analysis showed significant shifts in Archaeal and Bacterial proportions with VFA accmulation and CH4 formation before and after inhibition. VFA accumulated sharply with lower methane production, 0.29 L/g VS, than during the steady stage, 0.32 L/g VS. Biogas production almost ceased with the synergy inhibition of TAN (8000 mg/L) and VFA (25,000 mg/L). Hydrogenotrophic Methanothermobacter thermautotrophicus str. was the dominate archaea with 95% in the inhibition stage and 100% after 40 days recovery compared to 9.3% in the steady stage. Aceticlastic Methanosarcina was not encountered with coincided phenomenal of high VFA in the inhibition stage as well as recovery stage. Evaluation of the microbial diversity and functional bacteria indicated the dominate phylum of Firmicutes were 94.74% and 84.4% with and without inhibition. The microbial community shifted significantly with elevated ammonia concentration affecting the performance. PMID- 23934340 TI - Development of year 2020 goals for the National HIV/AIDS Strategy for the United States. AB - In July, 2010, President Barack Obama released the National HIV/AIDS Strategy (NHAS). The NHAS set forth ambitious goals for the year 2015. These goals were potentially achievable had the appropriate level of resources been invested; however, investment at the necessary scale has not been made and the 2015 goals now may well be out of reach. Therefore, we propose that an updated NHAS be developed with goals for the year 2020 clearly articulated. For the purposes of fostering discussion on this important topic, we propose bold yet achievable quantitative 2020 goals based on previously published economic and mathematical modeling analyses. PMID- 23934341 TI - Prevalence of knowledge and use of the female condom in South Africa. AB - Male condoms remain a key tool in preventing the spread of HIV and the female condom (FC) holds similar potential. Using data collected through a national cross-sectional population survey that was conducted in 2008, this report investigated the national prevalence of FC knowledge and use by sexually active males and females (n = 7,727) over the age of 15 years in South Africa, followed by a closer examination of the sexually active female population alone. Though knowledge of the FC among sexually active females over the age of 15 years (n = 4,551) was relatively high at 77.75 %, use was low at 7.16 %. The present study found statistically significant associations between knowledge or use of the FC and several demographic variables for females in South Africa. Having heard of the FC was consistently associated with locality, province, age, education level, marital status, and employment status. Use of the FC, however, was only associated with province and age group. Many demographic groups exhibited a high prevalence of knowledge but a low level of use; or conversely, a low prevalence of knowledge but a high level of use compared to their counterparts. Our findings support the need for a rigorous campaign to promote the use of FCs by women and also to increase their availability in public health sector facilities such as government clinics and hospitals in order to improve the chance of women using the FC, a cost-effective device that has the potential to protect both their rights and lives. PMID- 23934342 TI - Effect of CLC-2 on the cytoskeleton in human trabecular meshwork cells. AB - The chloride channel protein 2 (CLC-2) is important in maintaining the volume of trabecular meshwork cells by adjusting the outflow of aqueous solutions and maintaining the fluid balance. However, little is known concerning the functions of CLC-2 in the cytoskeleton, specifically in human trabecular meshwork (HTM) cells. In the present study, two CLC-2 specific siRNAs (siRNA1 and siRNA2) that target CLC-2 mRNA were designed. The siRNAs were transfected into the HTM cells and the results showed that siRNA1 in particular decreased the expression of CLC 2 by ~45%. Furthermore, an siRNA1-mediated CLC-2 knockdown significantly reconstructed the actin cytoskeleton and formed cross-linked actin networks. In addition, the downregulation of the expression of CLC-2 was associated with increased TGF-beta and Smad2 activities in the HTM cells following 24 h of transfection. In conclusion, these results suggest that CLC-2 knockdown promotes trabecular meshwork cytoskeletal disorders and may activate the TGF-beta/Smad signaling pathway. Thus, CLC-2 may be a promising and potential novel therapeutic strategy for combating primary open-angle glaucoma. PMID- 23934343 TI - Interactions between soybean ABA receptors and type 2C protein phosphatases. AB - The plant hormone abscisic acid (ABA) plays important roles in regulating plant growth, development, and responses to environmental stresses. Proteins in the PYR/PYL/RCAR family (hereafter referred to as PYLs) are known as ABA receptors. Since most studies thus far have focused on Arabidopsis PYLs, little is known about PYL homologs in crop plants. We report here the characterization of 21 PYL homologs (GmPYLs) in soybean. Twenty-three putative GmPYLs can be found from soybean genome sequence and categorized into three subgroups. GmPYLs interact with AtABI1 and two GmPP2Cs in diverse manners. A lot of the subgroup I GmPYLs interact with PP2Cs in an ABA-dependent manner, whereas most of the subgroup II and III GmPYLs bind to PP2Cs in an ABA-independent manner. The subgroup III GmPYL23, which cannot interact with any of the tested PP2Cs, differs from other GmPYLs. The CL2/gate domain is crucial for GmPYLs-PP2Cs interaction, and a mutation in the conserved proline (P109S) abolishes the interaction between GmPYL1 and AtABI1. Furthermore, the ABA dependence of GmPYLs-PP2Cs interactions are partially correlated with two amino acid residues preceding the CL2/gate domain of GmPYLs. We also show that GmPYL1 interacts with AtABI1 in an ABA dependent manner in plant cells. Three GmPYLs differentially inhibit AtABI1 and GmPP2C1 in an ABA-dependent or -enhanced manner in vitro. In addition, ectopically expressing GmPYL1 partially restores ABA sensitivity of the Arabidopsis triple mutant pyr1/pyl1/pyl4. Taken together, our results suggest that soybean GmPYLs are ABA receptors that function by interacting and inhibiting PP2Cs. PMID- 23934344 TI - Inhibition of microbial growth by carbon nanotube networks. AB - In the last years carbon nanotubes have attracted increasing attention for their potential applications in the biomedical field as diagnostic and therapeutic nano tools. Here we investigate the antimicrobial activity of different fully characterized carbon nanotube types (single walled, double walled and multi walled) on representative pathogen species: Gram-positive Staphylococcus aureus, Gram-negative Pseudomonas aeruginosa and the opportunistic fungus Candida albicans. Our results show that all the carbon nanotube types possess a highly significant antimicrobial capacity, even though they have a colony forming unit capacity and induction of oxidative stress in all the microbial species to a different extent. Moreover, scanning electron microscopy analysis revealed that the microbial cells were wrapped or entrapped by carbon nanotube networks. Our data taken together suggest that the reduced capacity of microbial cells to forming colonies and their oxidative response could be related to the cellular stress induced by the interactions of pathogens with the CNT network. PMID- 23934345 TI - 6-demethoxynobiletin, a nobiletin-analog citrus flavonoid, enhances extracellular signal-regulated kinase phosphorylation in PC12D cells. AB - We previously demonstrated that nobiletin, a polymethoxylated flavone isolated from citrus peels, has the potential to improve cognitive dysfunction in patients with Alzheimer's disease (AD). Recent studies suggest that the generation of intraneuronal amyloid-beta (Abeta) oligomers is an early event in the pathogenesis of AD. Abeta oligomers cause deficits in the regulation of the extracellular signal-regulated kinase (ERK) signaling which is critical for consolidation of the memory. Our previous studies revealed that nobiletin activated ERK signaling and subsequent cyclic AMP response element-dependent transcription. In this study, the effects of five nobiletin analogs, 6 demethoxynobiletin, tangeretin, 5-demethylnobiletin, sinensetin, and 6 demethoxytangeretin, isolated from citrus peels were assessed on ERK phosphorylation in PC12D cells, and the structure-activity relationships were examined. PC12D cells were treated with nobiletin or its analogs, and the cell extracts were analyzed by Western blotting using an antibody specific to phosphorylated ERK. 6-Demethoxynobiletin markedly enhanced ERK phosphorylation in a concentration-dependent manner. These results may be useful in developing drugs and functional foods using citrus peels for the treatment of dementia including AD. PMID- 23934346 TI - Identification of the risk factors associated with hypocalcemia induced by denosumab. AB - Denosumab, a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor-kappaB ligand, inhibits the activation of osteoclasts. Some clinical trials have shown that denosumab suppresses bone resorption in patients with advanced cancer, but hypocalcemia has been reported as a serious adverse effect after the administration of denosumab. It is difficult to predict hypocalcemia in such cases because the risk factors for denosumab-induced hypocalcemia have not been reported. Accordingly, the aim of the present study was to identify the risk factors for hypocalcemia induced by denosumab. We retrospectively reviewed the records of patients who had received denosumab at Tokushima University Hospital between April 2012 and May 2013. Fifty-three patients were analyzed and eleven patients had hypocalcemia after administration of denosumab. Univariate logistic regression analysis revealed that the patients who had not been administered zoledronic acid before receiving denosumab or had lower creatinine clearance (CCr) appeared to have a higher risk of hypocalcemia (p<0.05). The cut off value of CCr was 50.4 mL/min calculated by receiver operator characteristics curves. Moreover, multivariate logistic regression analysis revealed that non-administration of zoledronic acid (odds ratio 10.43, p<0.05) and CCr less than 50.0 mL/min (odds ratio 5.90, p<0.05) were independent risk factors for denosumab-induced hypocalcemia. These findings provide useful information regarding the monitoring of hypocalcemia in patients receiving denosumab. PMID- 23934347 TI - Assessment of natural and anthropogenic radioactivity levels in soils, rocks and water in the vicinity of Chirano Gold Mine in Ghana. AB - Studies have been carried out within and around the operational area of the Chirano Gold Mine Ltd of Ghana to ascertain the baseline radioactivity levels of naturally occurring radioactive materials as well as artificial radionuclides in the surface and underground mines. The analysis was carried out by using gamma spectrometry to quantify the radionuclides of interest, namely (238)U, (232)Th, (137)Cs and (40)K in soil, ore, waste rock and water samples. The average activity concentrations of (238)U, (232)Th, (40)K and (137)Cs in the soil/rock samples were 9.79+/-5.39, 9.18+/-7.06, 237.40+/-144.34 and 0.64+/-0.57 Bq kg(-1), respectively. For the water samples, the average activity concentrations were 0.86+/-0.67, 0.97+/-1.33 and 9.05+/-10.45 Bq l(-1) for (226)Ra, (232)Th and (40)K, respectively. The total annual effective dose to the public was estimated to be 0.13 mSv, which is below the International Commission on Radiological Protection recommended level of 1 mSv for public exposure control. The study also assessed the elemental concentrations of U, Th and K in the soil/rock samples from the gold mine and surrounding communities. The average concentrations of the U, Th and K were 0.82+/-0.48, 2.18+/-1.77 ug g(-1) and 0.77+/-0.47 %, respectively. The concentrations of U, Th and K were variable in soil and rock samples taken from different locations in the study area with values varying in the range 0.28-2.21, 0.24-6.50 ug g(-1) and 0.28-1.87 %, respectively. The concentrations of U, Th and K are far lower than the world average values but comparable with the range of similar studies for different countries. The concentration values of gross-alpha and gross-beta for all the water samples were below the Ghana Standards Authority and World Health Organisation recommended guideline values for drinking water quality. The results obtained in this study also show that radiation levels are within the natural background radiation levels found in the literature and compare well with those of similar studies for other countries including Ghana. PMID- 23934348 TI - Posterior approach lumbar and thoracolumbar hemivertebra resection in congenital scoliosis in children under 10 years of age: results with 3 years mean follow up. AB - INTRODUCTION: The authors present 15 cases of congenital scoliosis with lumbar or thoracolumbar hemivertebra in children under 10 years of age (mean age at the time of surgery was 5.5 years). Patients were treated by posterior hemivertebra resection and pedicle screws two levels stabilization or three or more levels stabilization in the case of deformity above or under hemivertebra or for severe curve deformities. MATERIALS AND METHODS: All operated patients had worsening curves; mean follow up was 40 months. The mean scoliosis curve value was 44 degrees Cobb, and reduced to a mean 11 degrees Cobb after surgery. The mean segmental kyphosis value was 19.7 degrees Cobb, and reduced to a mean -1.8 degrees Cobb after surgery. We did not consider total dorsal kyphosis value as all hemivertebras treated were at lumbar or thoracic lumbar level. No major complications emerged (infections, instrumentation mobilization or failure, neurological or vascular impairment) and only one pedicle fracture occurred. RESULTS: Our findings show that the hemivertebra resection with posterior approach instrumentation is an effective procedure, which has led to significant advances in congenital deformity control, which include excellent frontal and sagittal correction, excellent stability, short segment arthrodesis, low neurological impairment risk, and no necessity for further anterior surgery. CONCLUSION: Surgery should be considered as soon as possible in order to avoid severe deformity and the use of long segment arthrodesis. The youngest patient we treated, with a completed dossier at the end the follow up was 24 months old at the time of surgery; the youngest patient treated by this procedure was 18 months old at the time of surgery. PMID- 23934349 TI - Top-down analysis of 30-80 kDa proteins by electron transfer dissociation time-of flight mass spectrometry. AB - Electron transfer dissociation (ETD)-based top-down mass spectrometry (MS) is the method of choice for in-depth structure characterization of large peptides, small and medium-sized proteins, and non-covalent protein complexes. Here, we describe the performance of this approach for structural analysis of intact proteins as large as the 80 kDa serotransferrin. Current time-of-flight (TOF) MS technologies ensure adequate resolution and mass accuracy to simultaneously analyze intact 30 80 kDa protein ions and the complex mixture of their ETD product ions. Here, we show that ETD TOF MS is efficient and may provide extensive sequence information for unfolded and highly charged (around 1 charge/kDa) proteins of ~30 kDa and structural motifs embedded in larger proteins. Sequence regions protected by disulfide bonds within intact non-reduced proteins oftentimes remain uncharacterized due to the low efficiency of their fragmentation by ETD. For serotransferrin, reduction of S-S bonds leads to significantly varied ETD fragmentation pattern with higher sequence coverage of N- and C-terminal regions, providing a complementary structural information to top-down analysis of its oxidized form. PMID- 23934350 TI - Current strategies of blood doping detection. AB - During the last 30 years, the artificial increase of red blood cell volume ("blood doping") has changed the level of performance in all endurance sports. Many doping scandals have shown the extent of the problem. The detection of blood doping relies on two different approaches: the direct detection of exogenous manipulating substances (erythropoietic stimulants) or red cells (homologous transfusion) and the indirect detection, where not the doping substance or technique itself, but its effect on certain biomarkers is measured. Whereas direct detection using standard laboratory procedures such as isoelectric focusing can identify erythropoietic stimulants, homologous blood transfusion is identified through mismatches in minor blood group antigens by flow cytometry. Indirect methods such as the athlete biological passport are the only means to detect autologous transfusion and may also be used for the detection of erythropoietic stimulants or homologous transfusion. New techniques to unmask blood doping include the use of high-throughput 'omics' technologies (proteomics/metabolomics) and the combination of different biomarkers with the help of mathematical approaches. Future strategies should aim at improving the use of the available data and resources by applying pattern recognition algorithms to recognize suspicious athletes and, on the basis of these findings, use the appropriate testing method. Different types of information should be combined in the quest for a forensic approach to anti-doping. PMID- 23934351 TI - The role of caffeine in otorhinolaryngology: guilty as charged? AB - Caffeine is implicated as causing or aggravating numerous otorhinolaryngological conditions, including tinnitus, Meniere's disease, laryngopharyngeal reflux, globus pharyngeus and dysphonia. We address caffeine's effects in such conditions and to determine whether such implications are founded. The defined search limits of data sources included human trials and either randomised control trials, meta analyses, editorials, letters, clinical trials, case reports, comments or journal articles over the last 40 years. MEDLINE, EMBASE and CINAHL databases were searched using 'otorhinolaryngological diseases' and 'caffeine' as a duplicate filter. PubMed databases were searched using 'caffeine' in combination with 'tinnitus', 'Meniere's', 'vertigo', 'motion sickness', 'imbalance', 'vestibular migraine', 'voice', 'vocal hygiene', 'reflux', 'ear', 'nose', 'throat' and 'head neck cancer', respectively. Searches were not limited to the English language. MEDLINE, EMBASE and CINAHL database searches identified 417 papers. Of these, 200 abstracts were chosen for further scrutiny, following which 30 full manuscripts were chosen for full review. The PubMed database search identified 275 abstracts of which 33 were reviewed. Of the total 692 studies searched, 63 studies were reviewed and 36 were finally used. At present, there is little evidence in the literature to support the notion that caffeine causes or aggravates otorhinolaryngological conditions. In tinnitus, its withdrawal may actually worsen symptoms whereas in motion sickness, there is some clinical evidence for its benefit. More research is needed into the role caffeine plays in otorhinolaryngological conditions to allow clinicians to give informed advice to their patients. PMID- 23934352 TI - Time-related transcriptome analysis of B. subtilis 168 during growth with glucose. AB - Gene expression in Bacillus subtilis from late exponential to stationary phase was monitored by DNA microarrays with samples taken from the culture in LB broth with glucose supplement to prevent sporulation. Three major patterns of gene expression as revealed in this study were consistent to the expression profiling of PerR/Spx regulons and three major sigma factors-SigA, SigB, and SigW. Expression of most SigA-dependent house-keeping genes was significantly decreased and remained at low levels in the stationary phase. The sigB gene and additional genes of the SigB regulon for stress response exhibited a distinct pattern of transient induction with a peak in transition phase. The majority of induced genes after cessation of SigB-dependent surge were subjected to regulation by SigW, PerR, and Spx in response to oxidative stress. No induction of spo0A and skfA regulons supports the suppression of sporulation and cannibalism processes in the stationary phase by glucose supplement. In summary, these results depicted complicated strategies by cells to adapt changes from the fast growing exponential phase toward the stationary phase. The absence of programmed cell death and sporulation greatly facilitated data analysis and the identification of distinct expression patterns in the stationary phase of growth in B. subtilis. PMID- 23934353 TI - Identification of intracellular bacteria in adenoid and tonsil tissue specimens: the efficiency of culture versus fluorescent in situ hybridization (FISH). AB - Monocyte/macrophage cells from human nasopharyngeal lymphoid tissue can be a source of bacteria responsible for human chronic and recurrent upper respiratory tract infection. Detection and characterization of pathogens surviving intracellularly could be a key element in bacteriological diagnosis of the infections as well as in the study on interactions between bacteria and their host. The present study was undertaken to assess the possibility of isolation of viable bacteria from the cells expressing monocyte/macrophage marker CD14 in nasopharyngeal lymphoid tissue. Overall, 74 adenotonsillectomy specimens (adenoids and tonsils) from 37 children with adenoid hypertrophy and recurrent infections as well as 15 specimens from nine children with adenoid hypertrophy, which do not suffer from upper respiratory tract infections (the control group), were studied. The suitability of immunomagnetic separation for extraction of CD14(+) cells from lymphoid tissue and for further isolation of the intracellular pathogens has been shown. The coexistence of living pathogens including Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pyogenes with the bacteria representing normal nasopharyngeal microbiota inside CD14(+) cells was demonstrated. Twenty-four strains of these pathogens from 32.4 % of the lysates of CD14(+) cells were isolated. Concurrently, the fluorescent in situ hybridization (FISH) with a universal EUB388, and the species-specific probes demonstrated twice more often the persistence of these bacterial species in the lysates of CD14(+) cells than conventional culture. Although the FISH technique appears to be more sensitive than traditional culture in the intracellular bacteria identification, the doubts on whether the bacteria are alive, and therefore, pathogenic would still exist without the strain cultivation. PMID- 23934354 TI - Comparison between the short-term results of onlay and sublay mesh placement in the management of uncomplicated para-umbilical hernia: a prospective randomized study. AB - PURPOSE: The aim of this study was to compare between the short-term results of onlay and sublay mesh placement in the prosthetic repair of uncomplicated para umbilical hernia (PUH). METHODS: Eighty patients with a defect size ranging from 4 to 10 cm were prospectively randomized to either the onlay group (40 patients) or the sublay group (40 patients). The operative time, postoperative complications and short-term recurrence were reported. RESULTS: There were no statistically significant differences between both study groups as regards the patients' demographics, associated co-morbidities and mean defect size. The median operative time was significantly shorter in the onlay group compared to that in the sublay group (52 vs. 91 min respectively, p < 0.001). No statistically significant difference was found in the daily median pain score throughout the first postoperative week. The time required to remove the suction drain was significantly shorter in the sublay group compared to that in the onlay group (3 vs. 7 days respectively, p < 0.001).Complications were encountered in 4 patients (10%) in the onlay group compared to 3 patients (7.5%) in the sublay group (p = 1.000). Superficial wound infection was encountered in 1 patient (2.5%) in the sublay group, Seroma was encountered in 2 patients (5%) in the onlay group, Deep vein thrombosis was encountered in 1 patient (2.5%) in the onlay group, Chest infection was encountered in 2 patients (5%) in the sublay group compared to 1 patient (2.5%) in the onlay group. Throughout the 22 months median follow-up duration (range 6-42 months), 2 recurrences (5%) were encountered in either study group. CONCLUSIONS: Both techniques are safe, efficient and are associated with comparable complication and recurrence rates. PMID- 23934355 TI - Non-crosslinked porcine-derived acellular dermal matrix for the management of complex ventral abdominal wall hernias: a report of 45 cases. AB - PURPOSE: Ventral abdominal wall hernias are common and repair is frequently associated with complications and recurrence. Although non-crosslinked intact porcine-derived acellular dermal matrix (PADM) has been used successfully in the repair of complex ventral hernias, there is currently no consensus regarding the type of mesh and surgical techniques to use in these patients. This report provides added support for PADM use in complex ventral hernias. METHODS: In a consecutive series of adult patients (2008-2011), complex ventral abdominal wall hernias (primary and incisional) were repaired with PADM by a single surgeon. Patient comorbidities, repair procedures, and postoperative recovery, recurrence, and complications were noted. RESULTS: Forty-four patients (mean age, 57.5 years) underwent 45 single-stage ventral abdominal wall hernia repairs (3 primary; 42 incisional). Previously placed synthetic mesh was removed in 17 cases. In 40 cases, primary fascial closure was achieved; in 5 cases, PADM was used as a bridge. Vacuum-assisted closure (VAC) was used for 38/45 cases: 19 closed incisions, 16 cases using the "French fry" technique, and 3 cases with open incisions. Mean hospital stay was 8.2 days (range, 3-32) and mean follow-up was 17 months (range, 1-48). There were 4 (8.9 %) hernia recurrences, 3 requiring additional repair and 1 requiring PADM explantation. There were 3 (6.7 %) skin dehiscences, 4 (8.9 %) deep wound infections requiring drainage, and 5 (11.1 %) seromas (4 self-limited, 1 requiring drainage). CONCLUSIONS: Non-crosslinked intact PADM yielded favorable early outcomes when used to repair complex ventral abdominal wall hernias in high-risk patients. PMID- 23934356 TI - Repair of symptomatic perineal hernia with a titanium mesh. AB - PURPOSE: Surgical repair of symptomatic perineal hernia is challenging, especially via a perineal approach with limited exposure of the hernia sac. Furthermore, insecure fixation of autologous or synthetic materials to bony structures often results in recurrence. Here, we describe the application of a titanium mesh for perineal hernia repair. METHODS: We performed hernia repair with a thin titanium mesh via a perineal approach in three patients who developed secondary perineal hernia following abdominoperineal resection. After the hernia sac was isolated and dissected, the titanium mesh was molded and placed over the ischium and coccyx to support the pelvic floor. RESULTS: No major complications occurred, and all three patients were free of recurrence at follow-up after 73, 109, and 6 months, respectively. The patients experienced slight pain in the perineal region when sitting, which resolved within 6 months. CONCLUSION: Our successful preliminary results indicate that a titanium mesh is useful for perineal hernia repair by the perineal approach, as it can provide rigid support for the pelvic floor by its entire surface while ensuring stability without any fixation. PMID- 23934357 TI - The association of SCGB3A2 polymorphisms with the risk of Graves' disease: a meta analysis. AB - The aim of this study is to assess the association of the SCGB3A2 -112G>A promoter polymorphism with Graves' disease(GD) using a meta-analysis. Relevant studies were identified using PubMed and EMBASE electronic databases. A meta analysis of relevant studies was performed. This meta-analysis included four case control studies, containing 6,913 GD cases (Caucasian 3904, Han 3009) and 7,185 controls(Caucasian 4155, Han 3030). The combined results showed a significant difference in genotype distribution (-112A/G) between GD and control populations (A vs. G P = 1.53 * 10(-7); GG vs. AA+AG P = 6.78 * 10(-9)). Meta-analysis was performed using a fixed-effects model. Under the dominant model (GG/AA + GA), the AA and GA genotypes were significantly associated with GD (pooled OR = 1.24, 95 % CI 1.12-1.37). When the two European studies are combined, the AA and GA genotypes were also significantly associated with GD (pooled OR = 1.29, 95 % CI 1.20-1.39). This meta-analysis suggests that SCGB3A2 polymorphism at positions 112G>A was associated with GD both in Chinese and Caucasian population. PMID- 23934358 TI - Relationships of serum soluble E-selectin concentration with insulin sensitivity and metabolic flexibility in lean and obese women. AB - The markers of endothelial dysfunction, including soluble E-selectin (sE selectin), are related to insulin resistance, which is associated with metabolic inflexibility, i.e., impaired stimulation of carbohydrate oxidation and impaired inhibition of lipid oxidation by insulin. Endothelial dysfunction may also be important in the metabolic syndrome. The aim of our study was to analyze the association of sE-selectin with insulin sensitivity and metabolic flexibility in lean and obese women. We examined 22 lean women (BMI < 25 kg m(-2)) and 26 overweight or obese women (BMI > 25 kg m(-2)) with normal glucose tolerance. A hyperinsulinemic euglycemic clamp and indirect calorimetry were performed. An increase in the respiratory exchange ratio in response to insulin was used as a measure of metabolic flexibility. Obese women had lower insulin sensitivity (P < 0.01), higher plasma sE-selectin (P = 0.007), and higher the metabolic syndrome total Z-score (MS Z-score) (P < 0.0001). Insulin sensitivity was negatively correlated with sE-selectin level (r = -0.24, P = 0.04). sE-selectin was associated with the rate of carbohydrate oxidation at the baseline state (r = 0.31, P = 0.007) and was negatively correlated with metabolic flexibility (r = 0.34, P = 0.003). MS Z-score correlated positively with sE-selectin level and negatively with metabolic flexibility and insulin sensitivity (r = 0.49, P < 0.0001, r = -0.29, P = 0.04, r = -0.51, P < 0.0001, respectively). In multiple regression analysis we observed that the relationship between metabolic flexibility and sE-selectin (beta = -0.36; P = 0.004) was independent of the other evaluated factors. Our data suggest that endothelial dysfunction as assessed by plasma sE-selectin is associated with metabolic flexibility, inversely and independently of the other estimated factors. PMID- 23934359 TI - Indoor particle counts during Asian dust events under everyday conditions at an apartment in Japan. AB - OBJECTIVE: Asian dust storms originating from arid regions of Mongolia and China are a well-known springtime phenomenon throughout East Asia. Evidence is increasing for the adverse health effects caused by airborne desert dust inhalation. Given that people spend approximately 90 % of their time indoors, indoor air quality is a significant concern. The present study aimed to examine the influence of outdoor particulate matter (PM) levels on indoor PM levels during Asian dust events under everyday conditions. METHODS: We simultaneously monitored counts of particles larger than 0.3, 0.5, 1, 2, and 5 MUm using two direct-reading instruments (KC-01D1 airborne particle counter; Rion), one placed in an apartment room and another on the veranda, under everyday conditions before and during an Asian dust event. We also examined how indoor particle counts were affected by opening a window, crawling, and air purifier use. RESULTS: An Asian dust event on 24 April 2012 caused 50- and 20-fold increases in PM counts in outdoor and indoor air, respectively. A window open for 10 min resulted in a rapid increase of indoor PM counts up to 70 % of outside levels that did not return to baseline levels after 3 h. An air purifier rapidly reduced PM counts for all particle sizes measured. CONCLUSIONS: It is important to account for occupant behavior, such as window-opening and air purifier use, when estimating residential exposure to particulate matter. PMID- 23934360 TI - Single nucleotide polymorphisms in the mitochondrial displacement loop and age-at onset of renal cell carcinoma. AB - The accumulation of single nucleotide polymorphisms (SNPs) in the displacement loop (D-loop) of mitochondrial DNA (mtDNA) has been described in various types of cancers, and their association with cancer risk and disease outcome has been extensively identified. In the present study, we investigated the association between age-at-onset and SNPs in the mitochondrial D-loop using a population based series of renal cell carcinoma(RCC). The SNP sites of nucleotides 16293A/G were identified for their association with age-at-onset using the log-rank test. The age-at-onset of patients with the minor allele G genotype was significantly lower than that of patients with the A genotype at the 16293 site (p < 0.001). Genetic polymorphisms in the D-loop are predictive markers of age-at-onset in RCC patients. Accordingly, the analysis of genetic polymorphisms in the mitochondrial D-loop may help identify RCC patient subgroups at high risk of early onset. PMID- 23934361 TI - Compartmentalization and metabolic channeling for multienzymatic biosynthesis: practical strategies and modeling approaches. AB - : The construction of efficient enzyme complexes for multienzymatic biosynthesis is of increasing interest in order to achieve maximum yield and to minimize the interference due to shortcomings that are typical for straightforward one-pot multienzyme catalysis. These include product or intermediate feedback inhibition, degeneration, and diffusive losses of reaction intermediates, consumption of co factors, and others. The main mechanisms in nature to tackle these effects in transient or stable protein associations are the formation of metabolic channeling and microcompartments, processes that are desirable also for multienzymatic biosynthesis in vitro. This chapter provides an overview over two main aspects. First, numerous recent strategies for establishing compartmentalized multienzyme associations and constructed synthetic enzyme complexes are reviewed. Second, the computational methods at hand to investigate and optimize such associations systematically, especially with focus on large multienzyme complexes and metabolic channeling, are discussed. Perspectives on future studies of multienzymatic biosynthesis concerning compartmentalization and metabolic channeling are presented. PMID- 23934362 TI - Biosensors based on enzyme inhibition. AB - The present chapter describes the use of biosensors based on enzyme inhibition as analytical tools. The parameters that affect biosensor sensitivity, such as the amount of immobilized enzyme, incubation time, and immobilization type, were critically evaluated, highlighting how the knowledge of enzymatic kinetics can help researchers optimize the biosensor in an easy and fast manner. The applications of these biosensors demonstrating their wide application have been reported. The objective of this survey is to give a critical description of biosensors based on enzyme inhibition, of their assembly, and their application in the environmental, food, and pharmaceutical fields. PMID- 23934363 TI - Therapeutic human cells: manufacture for cell therapy/regenerative medicine. AB - : Human primary cells (e.g. adult stem cells) as well as differentiated cells, including those of the immune system, have been found to be therapeutically useful and free of ethical concerns. Several products have received market authorization and numerous promising clinical trials are underway. We believe that such primary therapeutic cells will dominate the market for cell therapy applications for the foreseeable future. Consequently, production of such cellular products warrants attention and needs to be a fully controlled pharmaceutical process. Thus, where possible, such production should change from manufacture towards a truly scalable industrialized process for both allogeneic and autologous products. Here, we discuss manufacturing aspects of both autogeneic and allogeneic products, review the field, and provide historical context. PMID- 23934364 TI - Pulse oximetry screening for critical congenital heart defects in newborn infants: should it be routine? AB - Screening with pulse oximetry for critical congenital heart defects is the subject of much recent debate. This review will explore the recent evidence for screening and discuss how implementation of screening might be best achieved. PMID- 23934365 TI - Birth weight and longitudinal growth in infants born below 32 weeks' gestation: a UK population study. AB - OBJECTIVE: To describe birth weight and postnatal weight gain in a contemporaneous population of babies born <32 weeks' gestation, using routinely captured electronic clinical data. DESIGN: Anonymised longitudinal weight data from 2006 to 2011. SETTING: National Health Service neonatal units in England. METHODS: Birth weight centiles were constructed using the LMS method, and longitudinal weight gain was summarised as mean growth curves for each week of gestation until discharge, using SITAR (Superimposition by Translation and Rotation) growth curve analysis. RESULTS: Data on 103 194 weights of 5009 babies born from 22-31 weeks' gestation were received from 40 neonatal units. At birth, girls weighed 6.6% (SE 0.4%) less than boys (p<0.0001). For babies born at 31 weeks' gestation, weight fell after birth by an average of 258 g, with the nadir on the 8th postnatal day. The rate of weight gain then increased to a maximum of 28.4 g/d or 16.0 g/kg/d after 3 weeks. Conversely for babies of 22 to 28 weeks' gestation, there was on average no weight loss after birth. At all gestations, babies tended to cross weight centiles downwards for at least 2 weeks. CONCLUSIONS: In very preterm infants, mean weight crosses centiles downwards by at least two centile channel widths. Postnatal weight loss is generally absent in those born before 29 weeks, but marked in those born later. Assigning an infant's target centile at birth is potentially harmful as it requires rapid weight gain and should only be done once weight gain has stabilised. The use of electronic data reflects contemporary medical management. PMID- 23934367 TI - Selective contacts drive charge extraction in quantum dot solids via asymmetry in carrier transfer kinetics. AB - Colloidal quantum dot solar cells achieve spectrally selective optical absorption in a thin layer of solution-processed, size-effect tuned, nanoparticles. The best devices built to date have relied heavily on drift-based transport due to the action of an electric field in a depletion region that extends throughout the thickness of the quantum dot layer. Here we study for the first time the behaviour of the best-performing class of colloidal quantum dot films in the absence of an electric field, by screening using an electrolyte. We find that the action of selective contacts on photovoltage sign and amplitude can be retained, implying that the contacts operate by kinetic preferences of charge transfer for either electrons or holes. We develop a theoretical model to explain these experimental findings. The work is the first to present a switch in the photovoltage in colloidal quantum dot solar cells by purposefully formed selective contacts, opening the way to new strategies in the engineering of colloidal quantum dot solar cells. PMID- 23934366 TI - Association between facility characteristics and the process of care delivered to patients with hepatitis C virus infection. AB - BACKGROUND: Available data suggest problems in the process of care provided to patients with chronic hepatitis C (HCV). However, the solutions to these problems are less obvious. Healthcare facility factors are potentially modifiable and may enhance process quality in HCV treatment. METHODS: We evaluated the relationship between the process of HCV care and facility factors including number of weekly half-day HCV clinics per 1,000 HCV patients, HCV-specific quality-improvement initiatives, and administrative service of the HCV clinic (gastroenterology, infectious disease, primary care) for a cohort of 34,258 patients who sought care in 126 Veterans Affairs facilities during 2003-2006. We measured HCV care on the basis of 23 HCV-specific process measures capturing pretreatment (seven measures), preventive and/or comorbid (seven measures), and treatment and treatment monitoring care (nine measures). RESULTS: Patients seen at a facility with >8 half-day clinics were 52 % more likely to receive overall indicated care (OR 1.52, 95 % CI 1.13-2.05). Patients seen at a facility with >3 HCV quality improvement initiatives were more likely to receive better preventive and/or comorbid care (OR 1.32, 95 % CI 1.00-1.74). Compared with patients in facilities with no dedicated HCV clinic, patients at facilities with gastroenterology-based clinics received better pretreatment care (OR 1.36, 95 % CI 1.01-1.85) and more antiviral treatment (OR 1.45, 95 % CI 1.06-1.97) whereas those at facilities with infectious disease-based or primary care-based clinics received better preventive and/or comorbid care (OR 1.59, 95 % CI 1.06-2.39 and 1.84, 95 % CI 1.21-2.79 respectively). CONCLUSION: Several facility factors affected the process of HCV care. These factors may serve as targets for quality-improvement efforts. PMID- 23934369 TI - How the Internet is changing gambling: findings from an Australian Prevalence Survey. AB - Interactive gambling as a regulated activity, coupled with easy accessibility to offshore providers represents a new mode and format of gambling superimposed on traditional land-based opportunities. This paper aimed to investigate the prevalence of gambling among Australian adults and the relationship between various gambling activities and interactive modes of access. A second aim was to compare interactive and non-interactive gamblers in terms of socio-demographic characteristics, attitudes and beliefs about gambling and gambling participation. In a nationally representative telephone survey, 15,006 Australian adults completed measures assessing past 12-month gambling participation and a sub sample completed questions about interactive gambling and beliefs. The majority of participants (64.3 %) reported gambling at least once, with 8.1 % having gambled online. Interactive gamblers gambled on a greater number of activities overall and more frequently. Interactive gamblers were more likely to be male, younger, have home Internet access, participate in more forms of gambling and have higher gambling expenditure. Almost half of the interactive gamblers preferred land-based gambling although a small proportion also noted a number of disadvantages of interactive gambling. This study shows that the nature of gambling participation is shifting with interactive gambling having a significant and growing impact on overall gambling involvement. PMID- 23934368 TI - College student beliefs about wagering: an evaluation of the adolescent gambling expectancies survey. AB - Expectancy theory posits that decisions to engage in a given behavior are closely tied to expectations of the outcome of that behavior. Gambling outcome expectancies have predicted adolescent gambling and gambling problems. When high school students' outcome expectancies were measured by Wickwire et al. (Psychol Addict Behav 24(1):75-88 2010), the Adolescent Gambling Expectancy Survey (AGES) revealed five categories of expectancies that were each predictive of gambling frequency and pathology. The present study aimed to explore if the AGES could be successfully replicated with college students. When administered to a diverse college student population, factor analyses identified five factors similar to those found in the high school sample. Several factors of the AGES were also found to predict gambling frequency and gambling problems for college students. Gambling frequency and gambling activity preference were also addressed. PMID- 23934370 TI - Overall gambling behaviors and gambling treatment needs among a statewide sample of drug treatment clients in Ohio. AB - Casino gambling in Ohio became available for the first time in May 2012. This gambling expansion led the Ohio substance abuse monitoring (OSAM) Network, Ohio's drug abuse surveillance system that collects drug trend data on an ongoing basis, to amend its protocol in June 2011 to include collection of data related to problem and pathological gambling to inform current treatment and prevention needs. OSAM collected gambling data from July 2011 to June 2012 via focus group interviews of 714 drug users recruited from alcohol and other drug (AOD) treatment programs throughout Ohio. Participants who reported gambling during the past 6 months (N = 412) completed the South Oaks gambling screen. This study found a prevalence estimate of 12.1 % for probable pathological gambling among its statewide sample. Sizeable proportions of participants reported that they gambled more when using AOD (23.5 %) and used more AOD when gambling (19.4 %). A majority of study participants (59.2 %) reported participation in at least one type of gambling during the past 6 months, and of those participants, only 22.2 % reported ever having been asked about gambling while receiving AOD treatment services, with just 12.5 % reporting ever having had gambling treatment services offered to them. Men were 4.1 times more likely to screen positive for probable pathological gambling than women; non-Whites were 61.0 % more likely to screen positive than Whites. Findings presented in this report have the potential to help shape and strengthen problem and pathological gambling prevention and treatment measures in Ohio. PMID- 23934371 TI - Thin and thick target PIXE analyses to assess the mechanism of Cu2+ removal by Egeria densa. AB - In this work the PIXE technique was used to study the mechanism of metal sorption by dead biomass. Several batch copper-sorption experiments were performed by using Egeria densa biomass. PIXE measurements were performed in solid and liquid samples. Element concentrations in biosorbent samples were determined using the Clara software. Based on the mass balance among the major elements in the liquid and solid phases before and after the Cu-removal experiments, an ion exchange process is suggested as the main mechanism. PMID- 23934372 TI - Research and evidence-based care: it takes a village. PMID- 23934373 TI - Disease burden and the family circle. PMID- 23934374 TI - High-frequency and noncontact low-frequency ultrasound therapy for venous leg ulcer treatment: a randomized, controlled study. AB - Ultrasound therapy can be utilized to manage chronic wounds, including venous leg ulcers (VLUs). A randomized, controlled clinical study was conducted to compare the effectiveness of standard treatment and standard treatment plus either high frequency ultrasound (HFU) or noncontact low-frequency ultrasound (NCLFU) on VLU outcomes. Ninety (90) outpatients (47 men, 43 women, average age 38.3 [SD 11.5] years) were randomized into the standard care (n = 30), HFU (n = 30), or NCLFU group (n = 30). Standard care included multilayered compression bandaging (40 mm Hg of pressure at the ankle graduated to 17 mm Hg to 20 mm Hg below the knee), nonadherent dressing, and regular debridement. Standard care dressing changes and ultrasound therapy were provided three times per week for 3 months or until healed. HFU delivers high-intensity (0.5-1 W/cm2), high-frequency (1-3 MHz) ultrasound for 5 to 10 minutes; and NCLFU delivers low-intensity (0.1-0.8 W/cm2), low-frequency (40 kHz) ultrasound for 4-10 minutes. After 3 months, patients continued to be followed until healed. Wound size, wound pain, and lower leg edema were assessed at baseline and after 2 and 4 months. Data were analyzed using Student's t-test, ANOVA, chi-square, or Fisher's exact test. P <0.05 was considered significant. Initial wound measurements were 9.60 cm2 (SD 5.54), 9.86 cm2 (SD 3.95), and 10.01 cm2 (SD 4.58) for the standard treatment, HFU, and NCLFU groups, respectively; after 4 months, measurements were 4.28 cm2 (SD 2.80), 3.23 cm2 (SD 2.39), and 2.72 cm2 (SD 2.16), a statically significant difference (P = 0.04). All wounds were healed after an average of 8.50 (SD 2.17), 6.86 (SD 2.04), and 6.65 (SD 1.59) months in the standard treatment, HFU, and NCLFU groups, respectively (P = 0.001). Differences in the amount of edema and pain rating scores were also significant at the 4-month, follow-up visit (P <0.05). Outcomes of both methods of ultrasound therapy were better than standard care alone, and some differences between the two ultrasound therapy groups were observed, but they were not statistically significant. PMID- 23934375 TI - A randomized, controlled clinical pilot study comparing three types of compression therapy to treat venous leg ulcers in patients with superficial and/or segmental deep venous reflux . AB - Compression therapy--including inelastic, elastic, and intermittent pneumatic compression--is the standard of care for venous ulcers (VLUs) and chronic venous insufficiency, but there is no consensus in the literature regarding the most effective type of compression therapy. A prospective, randomized, clinical pilot study was conducted among 70 patients with unilateral VLUs treated in a hospital dermatology department in Poland to compare three types of compression therapy (intermittent pneumatic compression, stockings, and short-stretch bandages) in persons with superficial deep venous reflux alone or combined with the segmental variety. Study endpoints were change in ulcer dimensions and proportions healed. Patients with superficial or combined superficial and deep vein insufficiency were randomly allocated to receive one of the three therapies (one of each vein type for each treatment option, six groups total). All patients received saline soaked gauze dressings along with micronized purified flavonoid fraction, diosmin, hesperidin, and Daflon 500 once daily. Compression treatments were changed or pneumatic compression provided daily for 15 days. Wound size reduction and percentage of wounds healed were significantly higher in groups receiving intermittent pneumatic compression or stockings than in groups using short stretch bandages (for percentage change of ulcer surface area, P = 0.02; for healing rates P = 0.01). These results warrant additional randomized controlled clinical studies with a larger sample size and longer patient follow-up. PMID- 23934376 TI - A laboratory study examining the impact of linen use on low-air-loss support surface heat and water vapor transmission rates. AB - Layers of linens are frequently placed under patients to manage moisture and/or assist with positioning immobile patients, including persons placed on a therapeutic surface because they are at risk for developing pressure ulcers. Because skin microclimate is believed to affect pressure ulcer risk, some therapeutic surfaces are designed to manage skin temperature and humidity (microclimate management). The purpose of this study was to measure the effects of linens and underpads on a low-air-loss (LAL) surface's ability to disperse heat and evaporate moisture. Underpads and transfer sheet combinations (grouped by three common linen functions: immobility, moisture management, and immobility and moisture management) were tested using the sweating guarded hot plate method, which allows for the measurement of the evaporative capacity (g H2O/m2*hour) and the total rate of heat withdrawal (Watts/m2) associated with nine different linen configurations placed on the support surface. Total heat withdrawal and evaporative capacity of the LAL surface with a fitted sheet only was used for comparison (P <0.05) Compared with fitted sheet only, heat withdrawal was significantly reduced by five of eight combinations, and evaporative moisture reduction was significantly reduced by six of eight linen combinations (P <0.05). All combinations that included plastic-containing underpads significantly reduced the surface's ability to dissipate heat and evaporate moisture, and use of the maximum number of layers (nine) reduced heat withdrawal to the level of a static, nonLAL surface. The results of this study suggest that putting additional linens or underpads on LAL surfaces may adversely affect skin temperature and moisture, thereby reducing the pressure ulcer prevention potential of these surfaces. Additional studies to examine the effect of linens and underpads as well as microclimate management strategies on pressure ulcer risk are needed. PMID- 23934377 TI - Thyroid dysfunction in children with Down syndrome: a literature review. AB - INTRODUCTION: This article is an evidence-based review of thyroid disease in children with Down syndrome, including a comparison between various professional guidelines for the management of thyroid disease in children with Down syndrome. Aspects of thyroid disease which are discussed include: congenital hypothyroidism; autoimmune thyroid disease; subclinical hypothyroidism; and hyperthyroidism. The national professional guidelines of Ireland, the United Kingdom, the United States of America, Australia and Canada are reviewed and compared. MATERIALS AND METHODS: A literature search was conducted using Medline and PubMed. Search terms included 'Down syndrome' and 'thyroid disease', 'hypothyroidism', 'hyperthyroidism', 'subclinical hypothyroidism'. RESULTS: Eighty-nine articles were retrieved and reviewed for inclusion. The guidelines on the medical management of children with Down syndrome of five expert groups have also been retrieved and reviewed for this discussion. These various guidelines offer largely similar advice regarding frequency of thyroid function tests, with only Ireland and the UK testing less frequently than annually. Only the United Kingdom and Irish Down Syndrome Medical Interest Group guidelines suggest testing for thyroid antibodies at every thyroid screen. None of the guidelines offer suggestions on the optimal course of action to pursue after the discovery of subclinical hypothyroidism. CONCLUSION: In conclusion, more evidence is required regarding the optimal course of treatment for subclinical hypothyroidism. Such evidence may be best obtained by conducting a prospective randomized control trial. PMID- 23934378 TI - Alcohol consumption in pregnancy: results from the general practice setting. AB - BACKGROUND: There is no established safe level of alcohol consumption in pregnancy. Studies from Ireland have consistently shown lower abstention and higher binge drinking rates in pregnancy than other countries, indicating a high potential for foetal alcohol-related disorders. There has been little research on alcohol in pregnancy in primary care. AIMS: To determine the prevalence of alcohol consumption amongst pregnant women attending their GP for antenatal care, and to compare this to use in the year prior to conception. METHODS: Prospective cross-sectional study was carried out in fifteen teaching practices in the greater Dublin area. Women were recruited at their antenatal visits. Data were gathered by self-completed questionnaire in the practice, or researcher administered telephone questionnaire. The questionnaire was based on the AUDIT, a WHO-validated data collection instrument designed for use in primary care. RESULTS: Two hundred and forty valid questionnaires were returned (80 % recruitment rate). Alcohol intake and binge drinking levels were much lower during pregnancy compared to the year prior to pregnancy (p < 0.001). There was a marked reduction in the prevalence of alcohol use in pregnancy compared to previous research. Over 97 % drink no more than once a week, including almost two thirds of women who abstain totally from alcohol in pregnancy. Non-pregnant Irish women drink alcohol more frequently, and with higher rates of binge drinking, than women of other nationalities. CONCLUSIONS: Primary care is a suitable setting to research alcohol use in pregnancy. Alcohol use in pregnancy in Ireland has decreased markedly compared to previous research from this jurisdiction. PMID- 23934380 TI - Forward mandibular positioning enhances the expression of Ang-1 and Ang-2 in rabbit condylar chondrocytes. AB - Functional appliances correct dental malocclusion, partly by exerting an indirect mechanical stimulus on the condylar cartilage, initiating novel bone formation in the condyle. Angiopoietin is involved in the angiogenesis associated with novel bone formation. This study aimed to determine the expression of angiopoietin (Ang)-1 and -2 following forward mandibular positioning (FMP) in the condylar chondrocytes of rabbits. Sixty rabbits (age, 8 weeks) were randomly allocated to the experimental and control groups (n=30 per group). In the experimental group, FMP was induced by a functional appliance. Five rabbits from the experimental group and the control group were sacrificed following 3 days and 1, 2, 4, 8 and 12 weeks, respectively. The right temporomandibular joints (TMJs) were collected and the expression of Ang-1 and -2 was evaluated by immunohistochemical staining. The expression of Ang-1 increased at day 3 and reached a peak at 2 weeks, whereas Ang-2 reached maximal expression 4 weeks after FMP. Subsequently, the expression of Ang-1 and -2 gradually decreased. Thus, FMP enhanced the expression of Ang-1 and Ang-2 in condylar cartilage, which is related to angiogenesis in the process of endochondral ossification. PMID- 23934379 TI - Photon activation therapy: a Monte Carlo study on dose enhancement by various sources and activation media. AB - In the present study, a number of brachytherapy sources and activation media were simulated using MCNPX code and the results were analyzed based on the dose enhancement factor values. Furthermore, two new brachytherapy sources (131Cs and a hypothetical 170Tm) were evaluated for their application in photon activation therapy (PAT). 125I, 103Pd, 131Cs and hypothetical 170Tm brachytherapy sources were simulated in water and their dose rate constant and the radial dose functions were compared with previously published data. The sources were then simulated in a soft tissue phantom which was composed of Ag, I, Pt or Au as activation media uniformly distributed in the tumour volume. These simulations were performed using the MCNPX code, and dose enhancement factor (DEF) was obtained for 7, 18 and 30 mg/ml concentrations of the activation media. Each source, activation medium and concentration was evaluated separately in a separate simulation. The calculated dose rate constant and radial dose functions were in agreement with the published data for the aforementioned sources. The maximum DEF was found to be 5.58 for a combination of the 170Tm source with 30 mg/ml concentration of I. The DEFs for 131Cs and 170Tm sources for all the four activation media were higher than those for other sources and activation media. From this point of view, these two sources can be more useful in photon activation therapy with photon emitter sources. Furthermore, 131Cs and 170Tm brachytherapy sources can be proposed as new options for use in the field of PAT. PMID- 23934381 TI - CT-guided injection technique into intervertebral discs in the ovine lumbar spine. AB - PURPOSE: Disc injection to create intervertebral (IVD) disc degeneration (IVDD) has been reported in ovine models, but the techniques have not been thoroughly described. The current ex vivo study aimed to evaluate a computed tomography (CT) guided injection technique into IVDs in the ovine lumbar spine. METHODS: Insertion of needles into the nucleus pulposus was assessed by gross anatomic dissection in two lumbar segments (group A), and injection of liquid within the disc was assessed by discography in six segments (group B). RESULTS: The pathway of the needle was simulated on computer after an initial CT scan, followed by control of the insertion process via a laser beam and monitoring scans. In group A, 20 insertions were assessed and 17 needles (85 %) were successfully positioned in the nucleus pulposus. In group B of 30 injections, the rate of success was 90 %. CONCLUSIONS: The current study provides useful clinical information that will help surgeons working with an ovine model for research on IVDD. This model could also be useful to train less experienced surgeons or radiologists to disc injection. This CT-guided injection seems to offer several advantages such as ease of use, good success rate and safety to important nervous and vascular structures. PMID- 23934383 TI - Elevated serum uric acid in nondiabetic people mark pro-inflammatory state and HDL dysfunction and independently predicts coronary disease. AB - We explored the association of serum uric acid (UA) concentrations with pro inflammatory state and high-density lipoprotein (HDL) dysfunction. UA tertiles in tracked 1,508 nondiabetic participants were analyzed cross-sectionally for associations with inflammation biomarkers and protective proteins over a mean follow-up of 4.9 years for incident coronary heart disease (CHD) using Cox proportional hazards regression. In the absence of metabolic syndrome (MetS), UA tertiles significantly distinguished, in each sex, increasing categories of three MetS components (inflammation/oxidation markers, apolipoprotein (apo)B) and (inversely) current smoking (but not protective proteins such as HDL, apoA-I, and adiponectin). Distinctions attenuated in the presence of MetS. Linear regression model revealed fasting triglycerides (1.86 mg/dl variance), male sex, and gamma glutamyl transferase and age as covariates of UA levels in women. In Cox analysis, incident CHD (n = 137) was predicted by mid and upper UA tertile in men alone at significant hazard ratios of 2.7, additively to conventional risk factors. Elevated serum UA levels, linked to triglycerides, mark in nondiabetic people pro-inflammatory state, and, notably, HDL dysfunction. CHD risk is independently predicted by elevated UA levels in nondiabetic men and is modulated by MetS and gender. PMID- 23934384 TI - Turkish lupusPRO: cross-cultural validation study for lupus. AB - LupusPRO is a disease-targeted patient-reported outcome measure that was developed and validated from and among US patients with systemic lupus erythematosus (SLE). We herein report the results of the cross-cultural adaptation and validation study of the Turkish translated version of the LupusPRO. Turkish LupusPRO and the Medical Outcomes Study Short Form (SF-36) (Turkish) were administered to the Turkish lupus patients. Disease activity was ascertained using the physician global assessment (PGA), Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI), and flare (defined by LFA-Lupus Foundation of America). Disease damage was assessed with Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). Also, second Turkish LupusPRO tests were given to the patients to be completed within 2 3 days and sent back to us. Internal consistency reliability, test-retest reliability, and convergent and criterion validity (against disease activity or health status) were tested. All reported p values are two-tailed. The conceptual framework of the LupusPRO was evaluated using confirmatory factor analysis appropriate for categorical data. One hundred two SLE subjects (94 % women) were enrolled. The median (IQR) age and mean disease duration (+/-SD) were 38.5 (18) years and 60.3 (+/-56.3) months, respectively. The mean +/- SD, SLEDAI, and SDI scores were 3.1 +/- 3.7 and 0.52 +/- 0.75, respectively. There were 25 patients who had flares at the time of study. Forty-two patients with no change in their health status completed and sent back the second LupusPRO test and were included in the test-retest analysis. Test-retest reliability of LupusPRO domains ranged from 0.87 to 0.97, while internal consistency reliability of the domains ranged from 0.63 to 0.94. Convergent validity with corresponding domains of SF-36 was present. Health-related quality-of-life domains performed well against disease activity measures (PGA, total SLEDAI, LFA flare, and SF-6D-overall health status), establishing its criterion validity. Item-to-factor loadings representing the hypothesized item-to-scale relationships were satisfactory. The model fit for the hypothesized item-to-scale relationships was also satisfactory. The Turkish version of the LupusPRO is valid and appears to perform comparably to the English and Spanish language versions. It can be used as a patient-reported outcome parameter in clinical trials, as well as longitudinal studies for testing responsiveness to change. PMID- 23934385 TI - The impact of conventional DMARD and biological therapies on CD4+ cell subsets in rheumatoid arthritis: a follow-up study. AB - Rheumatoid arthritis (RA) is an autoimmune disease characterized by abnormal prevalence of Th1, Th2, Th17, and regulatory (Treg) subsets. Some data suggest that these subsets are influenced by anti-RA agents. Follow-up studies monitoring T cell phenotype in response to therapy are limited. We investigated the alteration of CD4+ T cell subset distribution after the initiation of disease modifying antirheumatic drug (DMARD) (with glucocorticosteroid (GCS) and methotrexate (MTX)) and anti-TNFalpha therapy. We enrolled 19 treatment naive (early) RA patients and initiated GCS (in a dose of 16 mg/day for 4 weeks; then 8 mg/day). MTX, 10 mg/week, was started at week 4. We also enrolled 32 RA patients unresponsive to DMARD and initiated anti-TNFalpha therapy: adalimumab (ADA), 40 mg/2 weeks, n = 12; etanercept (ETA), 50 mg/weeks, n = 12; or infliximab (IFX) on week 0, 2, and 6, 3 mg/kg bw, n = 8. Blood was taken before and 4 and 8 weeks after the initiation of therapy. Ten volunteers served as controls. The T cell phenotype was assessed with flow cytometry. In early RA, Th1, Th2, and Th17 prevalence was higher, while Treg prevalence was lower than normal. GCS alone decreased Th2 prevalence. GCS + MTX decreased Th17 prevalence. Immune phenotype in unresponsive RA before anti-TNF therapy was as in early RA. Four and 8 weeks after initiating anti-TNF therapy, Th1 prevalence was higher than baseline in ETA or IFX, while it was stable in ADA groups. Th2 prevalence was higher than normal in ADA or IFX, while normalized in ETA group. In each group, Treg prevalence increased, while Th17 prevalence was at the baseline. The proinflammatory immune phenotype is normalized only under GCS + MTX combination in early RA. Anti TNFalpha therapy exhibit marked effects on all the cell populations investigated (except Th17); some slight differences in this action exist between ADA, ETA, and IFX therapy. PMID- 23934386 TI - Factors associated with methotrexate dosing and therapeutic decisions in veterans with rheumatoid arthritis. AB - The purpose of this study is to explore patient factors associated with differences in methotrexate (MTX) dosing and to compare patient factors and MTX dosing patterns between those who remained on MTX monotherapy and those who were switched or had additional therapy. A retrospective cohort of 7,017 patients with newly diagnosed rheumatoid arthritis (RA) was identified in the United States Department of Veterans Affairs administrative databases between 1 October 1999 and 30 September 2009. Regression analyses were used to study the association of MTX start and maximum dose attained with various patient characteristics and compare differences between groups who had therapeutic change (having switched to or added another anti-rheumatic agent or having steroids increased by 2.5 mg of prednisone or equivalent) with those remaining on MTX monotherapy. Abnormal serum creatinine (>1.5 mg/dL) was associated lower start and peak MTX doses (p < 0.01). Older RA patients were less likely to attain peak MTX dose of 15 mg or more (p < 0.01). Males and patients 75 and older (compared with <45) had lower risk of therapeutic change (hazard ratio, [HR] 0.80, 95 % confidence interval [CI] 0.72 0.90, and HR 0.42, 95% CI 0.42-0.36-0.50, respectively). Patients who attained higher peak MTX dose had lower risk of therapeutic change compared with those dosed at less than 15 mg/week (HR 0.85, 95% CI 0.77-0.92 for 15 to <20 and HR 0.79, 95% CI 0.72-0.86 for 20 or more). Injectable MTX use conferred lower risk of therapeutic change (HR 0.64, 95% CI 0.52-0.78). Two thirds did not attain a maximum MTX dose of 20 mg/week or more before therapeutic change occurred. Older age and renal insufficiency were barriers to the use of higher MTX maximum dosages. Use of injectable MTX and higher maximum MTX dose were independently associated with higher likelihood to remain on MTX monotherapy. Further studies are needed to explore targeted interventions that may optimize MTX dosing to improve success rates of MTX monotherapy. PMID- 23934387 TI - Palpation versus ultrasound-guided corticosteroid injections and short-term effect in the distal radioulnar joint disorder: a randomized, prospective single blinded study. AB - The aim of this study was to conduct a randomized, prospective single-blinded clinical study on the mid-term benefits and accuracy rate of the ultrasound (US) guided versus palpation-guided intra-articular (IA) injections for the treatment of distal radioulnar joint (DRUJ) disorder. Subjects with DRUJ disorder (n = 60) were randomly assigned to undergo US-guided or palpation-guided IA injection. Primary outcomes were measured with Disability of the Arm, Shoulder, and Hand questionnaire (DASH) and secondary outcomes included Verbal Numeric Pain Scale (VNS), Modified Mayo Wrist Score (MMWS), range of motion (ROM), and accuracy rate between two groups; 1.25 mL of mixed material (0.5 ml Omnipaque + 1 % lidocaine 0.25 ml + triamcinolone 20 mg 0.5 ml) was injected into the intra-articular space of the DRUJ. Treatment effects were assessed by using VNS, DASH, MMWS, and passive ROM of the DRUJ (supination, pronation from neutral) before the injections and at 1, 3, and 6 months after the injections. After the US-guided and palpation-guided IA injection into DRUJ, a radiographic image was taken to determine whether the injected material had reached the IA space or infiltrated into the soft tissue. US-guided IA injections showed significantly higher accuracy (100 %) than palpation-guided IA injections (75.8 %) in DRUJ. VNS, DASH, MMWS, and ROM were improved at 1, 3, and 6 months in both groups. There was no significant difference in clinical outcomes between the group receiving US-guided injections and the group receiving palpation-guided injections. US-guided IA injection showed significantly higher accuracy than palpation-guided IA injection in the DRUJ, and corticosteroid IA injections were effective in improving of the pain of patients with DRUJ disorder during 6 months of follow-up. PMID- 23934389 TI - Small reentrant atrial tachycardia adjacent to left aortic sinus of valsalva. PMID- 23934388 TI - Perspectives of the relationship between IL-7 and autoimmune diseases. AB - Interleukin (IL)-7 is one of the IL-2 family cytokines comprised of IL-2, IL-4, IL-7, IL-9, IL-15, as well as IL-21. IL-7 is mainly secreted by stroma cells in primary lymphoid tissues, playing an essential role in the program of T cell development. Recently, studies have revealed that physiological function exerted by immunocytes can be influenced by aberrant IL-7 signaling, which is common in abnormal autoimmunity regulation. There is also increasing evidence that IL-7 is involved in several autoimmune diseases, such as rheumatoid arthritis, type I diabetes, multiple sclerosis and systemic lupus erythematosus, etc. Targeting components in IL-7 signaling pathways may have potential significance for treating numerous autoimmune diseases. In this review, we therefore summarize our current understandings regarding the relationship between IL-7 and autoimmune diseases so as to render more valuable information on this kind of research. PMID- 23934390 TI - A new class of drug for pulmonary arterial hypertension. Can a Rho-kinase inhibitor break the stagnation in treating it? PMID- 23934391 TI - An emission model tracking the life cycle pathways of human pharmaceuticals in Korea. AB - OBJECTIVES: Pharmaceuticals in the environment are of growing public health concern. The main objectives of this study were to develop a new emission estimation model, identify factors critical to reducing emission, and demonstrate the model's applicability for screening and priority setting. METHODS: A new emission estimation model was developed covering the life cycle pathways of pharmaceuticals from supply to discharge into surface water. The emission estimates of the model were assessed by coupling with SimpleBox to give predicted concentrations and by comparing the predicted concentrations with measured concentrations in Korean surface waters for five selected pharmaceuticals (acetaminophen, cephradine, ibuprofen, mefenamic acid, and naproxen). RESULTS: The sensitivity analysis revealed that the biodegradation rate in the sewage treatment plant and the excretion rate of pharmaceuticals were the most important factors influencing the emission rate. The uncertainty of the emission estimate was found to increase with increases in the value of the emission estimate. Once the intrinsic properties of a pharmaceutical (excretion rate, biodegradation rate, and removal rate by sludge separation) were given, the patient behavior parameters, such as participation in a Take-back program and rate of administration, were determined to have a strong influence on the emission estimate. In our study, the predicted and measured concentrations agreed with each other within one order of magnitude. Several management implications were drawn from the analysis of model outcomes. CONCLUSIONS: The model outcomes, alone or in combination with toxicity data, may potentially be used for the purposes of screening, priority setting, and the design of management programs. PMID- 23934392 TI - Microextraction by packed sorbents combined with surface-enhanced Raman spectroscopy for determination of musk ketone in river water. AB - Microextraction by packed sorbents (MEPS) combined with Surface-enhanced Raman spectroscopy (SERS) was investigated, and applied to the determination of musk ketone (MK) in river water samples. The full MEPS-SERS method includes analyte enrichment by MEPS preconcentration with C18 sorbent followed by SERS detection supported by silver nanoparticles. An eluent drop containing the analyte is deposited directly from the MEPS syringe on a CaF2 glass plate. When the drop has dried, a specific volume of silver nanoparticles solution is added on it before each SERS measurement. Several experimental variables were studied in depth; under the optimum experimental conditions MK can be extracted from a 500 MUL sample with recoveries in the range 47-63 %. The limit of detection was 0.02 mg L(-1) and the relative standard deviation 15.2 % (n = 4). Although not investigated in this work, the proposed method might be suitable for in-situ monitoring, because of the portability of the Raman spectrometer used. PMID- 23934393 TI - A highly sensitive europium nanoparticle-based lateral flow immunoassay for detection of chloramphenicol residue. AB - A europium nanoparticle-based lateral flow immunoassay for highly sensitive detection of chloramphenicol residue was developed. The detection result could be either qualitatively resolved with naked eye or quantitatively analyzed with the assistance of a digital camera. In the qualitative mode, the limit of detection (LOD) was found to be 0.25 ng/mL. In the quantitative mode, the half-maximal inhibition concentration (IC50) was determined to be 0.45 ng/mL and the LOD can reach an ultralow level of 0.03 ng/mL, which is ~100 times lower than that of the conventional colloidal gold-based lateral flow immunoassay. Potential application of the established method was demonstrated by analyzing representative cow milk samples. PMID- 23934394 TI - Insulin-like growth factor-I (IGF-I) misuse in athletes and potential methods for detection. AB - To athletes, insulin-like growth factor-I (IGF-I) is an attractive performance enhancing drug, particularly as an alternative to growth hormone (GH) because IGF I mediates many of the anabolic actions of GH. IGF-I has beneficial effects on muscle protein synthesis and glycogen storage that could enhance performance in several sporting disciplines. Recombinant human IGF-I (rhIGF-I) is used in clinical practice, but a variety of IGF-I compounds and IGF-I analogues are also advertised on the internet and many have been available on the black market for several years. Although methods for detecting GH misuse are now well established and there have been several cases in which athletes have tested positive for GH, no test is yet in place for detecting IGF-I misuse. The GH-2004 research group has been investigating methods for detection of IGF-I misuse and a test is being developed on the basis of the principles of the successful GH-2000 marker method, in which markers from the IGF axis and markers of collagen and bone turnover are used to detect GH misuse. Commercial immunoassays for these markers have been validated for anti-doping purposes but new methods, including IGF-I measurement by use of mass spectrometry, should improve the performance of the tests and help in the detection of athletes who are doping with these peptide hormones. PMID- 23934395 TI - A new label-free approach for the determination of reaction rates in oxidative footprinting experiments. AB - Hydroxyl radical-mediated oxidative footprinting coupled to mass spectrometric analysis is an attractive technique for protein surface mapping, conformational changes monitoring, and protein-ligand interfaces mapping in solution. In this technique, a protein is oxidized by in situ-generated hydroxy radicals and the site and rate of oxidation can be determined by proteolysis followed by mass spectrometric analysis. Changes in peptide oxidation rate can then be correlated to the changes in solvent exposure, and information about conformational changes or interaction domains can be obtained. The method relies, therefore, on the accurate measurements of peptide oxidation rate. Here, we describe a new label free method to determine the oxidation rate of peptides that is based on the consumption of the unoxidized peptide instead of measuring the formation of oxidized peptides. The reaction rate thus obtained presents a better linearity and lower variation when compared to the traditional method. The label-free method is also simpler to implement and automation can be achieved through label free quantitation software. PMID- 23934396 TI - Automated quantitative analysis of lipid accumulation and hydrolysis in living macrophages with label-free imaging. AB - The accumulation of lipids in macrophages is a key factor that promotes the formation of atherosclerotic lesions. Several methods such as biochemical assays and neutral lipid staining have been used for the detection of lipids in cells. However, a method for real-time quantitative assessment of the lipid content in living macrophages has yet to be shown, particularly for its kinetic process with drugs, due to the lack of suitable tools for non-invasive chemical detection. Here we demonstrate label-free real-time monitoring of lipid droplets (LDs) in living macrophages by using coherent anti-Stokes Raman scattering (CARS) microscopy. In addition, we have established an automated image analysis method based on maximum entropy thresholding (MET) to quantify the cellular lipid content. The result of CARS image analysis shows a good correlation (R(2) > 0.9) with the measurement of biochemical assay. Using this method, we monitored the processes of lipid accumulation and hydrolysis in macrophages. We further characterized the effect of a lipid hydrolysis inhibitor (diethylumbelliferyl phosphate, DEUP) and determined the kinetic parameters such as the inhibition constant, K(i). Our work demonstrates that the automated quantitative analysis method is useful for the studies of cellular lipid metabolism and has potential for preclinical high-throughput screening of therapeutic agents related to atherosclerosis and lipid-associated disorders. PMID- 23934397 TI - Hyperspectral unmixing of Raman micro-images for assessment of morphological and chemical parameters in non-dried brain tumor specimens. AB - Hyperspectral unmixing is an unsupervised algorithm to calculate a bilinear model of spectral endmembers and abundances of components from Raman images. Thirty nine Raman images were collected from six glioma brain tumor specimens. The tumor grades ranged from astrocytoma WHO II to glioblastoma multiforme WHO IV. The abundance plots of the cell nuclei were processed by an image segmentation procedure to determine the average nuclei size, the number of nuclei, and the fraction of nuclei area. The latter two morphological parameters correlated with the malignancy. A combination of spectral unmixing and non-negativity constrained linear least squares fitting is introduced to assess chemical parameters. First, endmembers of the most abundant and most dissimilar components were defined that represent all data sets. Second, the content of the obtained components' proteins, nucleic acids, lipids, and lipid to protein ratios were determined in all Raman images. Except for the protein content, all chemical parameters correlated with the malignancy. We conclude that the morphological and chemical information offer new ways to develop Raman-based classification approaches that can complement diagnosis of brain tumors. The role of non-linear Raman modalities to speed-up image acquisition is discussed. PMID- 23934399 TI - Carbohydrate-actuated nanofluidic diode: switchable current rectification in a nanopipette. AB - Nanofluidic structures share many properties with ligand-gated ion channels. However, actuating ion conductance in artificial systems is a challenge. We have designed a system that uses a carbohydrate-responsive polymer to modulate ion conductance in a quartz nanopipette. The cationic polymer, a poly(vinylpyridine) quaternized with benzylboronic acid groups, undergoes a transition from swollen to collapsed upon binding to monosaccharides. As a result, the current rectification in nanopipettes can be reversibly switched depending on the concentration of monosaccharides. Such molecular actuation of nanofluidic conductance may be used in novel sensors and drug delivery systems. PMID- 23934401 TI - Delta neutrophil index as a marker for differential diagnosis between flare and infection in febrile systemic lupus erythematosus patients. AB - Fever is a common symptom of systemic lupus erythematosus (SLE), and because of this it is difficult to discriminate between SLE flare and infection. The delta neutrophil index (DNI), automatically determined by the ADVIA 2120 electronic cell analyzer, has been reported to reflect the fraction of circulating immature granulocytes and to be associated with the presence of infection. In this study, we investigated the utility of DNI in discriminating infections from SLE flares in febrile SLE patients. In total, 111 episodes in 92 febrile SLE patients were reviewed. The infection group showed significantly higher white blood cell counts, neutrophil counts, C-reactive protein and procalcitonin than the SLE flare group. Complement (C)3 and C4 levels were decreased significantly in the SLE flare group. Patients in the SLE flare group had significantly lower DNI than those in both infection groups, with or without bacteremia. In a multivariate logistic regression analysis, only DNI was a significant independent factor for the presence of infection (odds ratio (OR): 18.9). When we selected a DNI value of 2.8% as the cutoff for infection, SLE patients with DNI >= 2.8% were found to be at higher risk for infection than those with DNI <2.8% (relative risk 8.48 fold). Our data suggest that DNI may be a marker to differentiate infections from SLE flares in febrile SLE patients. PMID- 23934400 TI - NtERF32: a non-NIC2 locus AP2/ERF transcription factor required in jasmonate inducible nicotine biosynthesis in tobacco. AB - Nicotine biosynthesis in tobacco (Nicotiana tabacum L.) is highly regulated by jasmonic acid (JA). Two nuclear loci, A and B (renamed NIC1 and NIC2) have been identified that mediate JA-inducible nicotine formation and total alkaloid accumulation. NIC2 was recently shown to be a cluster of seven genes encoding Apetala2/Ethylene-Response Factor (AP2/ERF)-domain transcription factors (TFs) in Group IX of the tobacco AP2/ERF family. Here we report the characterization of several NtERF TF genes that are not within the NIC2 locus, but required for methyl JA (MeJA)-induced nicotine biosynthesis. Expression of NtERF1, NtERF32, and NtERF121 is rapidly induced (<30 min) by MeJA treatment. All three of these TFs specifically bind the GCC box-like element of the GAG motif required for MeJA induced transcription of NtPMT1a, a gene encoding putrescine N-methyltransferase, the first committed step in the synthesis of the nicotine pyrrolidine ring. Ectopic overexpression of NtERF32 increases expression of NtPMT1a in vivo and elevates total alkaloid contents, whereas RNAi-mediated knockdown of NtERF32 reduces the mRNA levels of multiple genes in the nicotine biosynthetic pathway including NtPMT1a and quinolinate phosphoribosyltransferase (NtQPT2), and lowers nicotine and total alkaloid levels. We conclude that NtERF32 and related ERF genes are important non-NIC2 locus associated transcriptional regulators of nicotine and total alkaloid formation. PMID- 23934402 TI - Systemic lupus erythematosus (SLE) in the eastern region of Saudi Arabia. A comparative study. AB - This retrospective study aimed to collect data related to the clinical manifestations and laboratory investigations of systemic lupus erythematosus (SLE) patients in the eastern part of Saudi Arabia, in one of the tertiary-care centers, King Fahd Hospital Al-Hasa, and to compare it with other regions of Saudi Arabia. Forty-six patients fulfilling the American College of Rheumatology 1997 criteria (ACR) were collected over a period from January 2004 to December 2008. The results showed an average age of onset of 26.17 (+/-9.17). The most common clinical features were nonspecific constitutional symptoms (fever, fatigue and malaise) seen in 44 patients (95.7%). Musculoskeletal features seen were mostly arthralgias (91.3%) and arthritis (76.1%). Nephritis was seen in 58.7% and hypertension in 52.2%. Mucocutaneous involvement included oral ulcers (71.7%), hair loss (65.2%), butterfly rashes (67.4%), photosensitivity (47.8%) and discoid lupus (13%). Neurologic manifestations showed psychosis in 17.4%, depression in 15.2% and headache in 28.3%. The most common hematologic presentation was leukopenia (58.7%) followed by hemolytic anemia and anemia of chronic disease (47.8%). Antinuclear antibodies were positive in 44 (95.7%), anti-dsDNA in 38 (42.6%), anti-Ro SSA and La SSB in 38 (82.6%). Anticardiolipin antibodies and lupus anticoagulant were positive in eight (17.4%). Low complement levels (C3 and C4) were seen in 41 (89.1%) of the patients with active disease. The drugs used in treatment were NSAIDs (100%), antimalarials (97.8%), steroids (100%), intermittent cyclophosphamide and other immunosuppressive drugs (71.7%). We found that the age of onset and sex distributions were different from other areas of Saudi Arabia, while clinical manifestations were the same as in other areas. The prognosis of lupus was good overall despite the multi-organ involvement. However, further studies based on larger number of patients are needed. PMID- 23934404 TI - [Superior results after fast track recovery versus standard care following liver resection : results of a randomized clinical trial]. PMID- 23934403 TI - [Sequelae of severe injuries : consequences for trauma rehabilitation]. AB - Consequences of accidents are found not only in physical but also in psychological and social areas. The quality of life of severely injured patients is significantly reduced compared with the normal population even years after the trauma. Subjective experiences of severely injured patients during and after hospitalization have a major impact on the subsequent quality of life. Knowledge of these factors is essential for the planning, organization and implementation of rehabilitation after severe injury. The phase model of rehabilitation after trauma requires early initiation of therapy even during acute treatment as so called early rehabilitation. After a specialized post-acute rehabilitation additional therapeutic options are often required. Besides pain management the focus lies especially in work-related rehabilitation and psychological support which is also decisive for the success of rehabilitation of accident victims. For severely injured patients it is important to provide sufficient support, e.g. through a case manager which does not end with discharge from the rehabilitation facility. The aim of all efforts is reintegration into the working and social environment and the best possible quality of life. PMID- 23934405 TI - [Percutaneous drainage alone as therapy of perforated sigmoid colon diverticulitis : critical comments]. PMID- 23934406 TI - [Current treatment and outcome of esophageal perforation in adults : systematic review and meta-analysis of 75 studies]. PMID- 23934407 TI - A full-sunlight-driven photocatalyst with super long-persistent energy storage ability. AB - A major drawback of traditional photocatalysts like TiO2 is that they can only work under illumination, and the light has to be UV. As a solution for this limitation, visible-light-driven energy storage photocatalysts have been developed in recent years. However, energy storage photocatalysts that are full sunlight-driven (UV-visible-NIR) and possess long-lasting energy storage ability are lacking. Here we report, a Pt-loaded and hydrogen-treated WO3 that exhibits a strong absorption at full-sunlight spectrum (300-1,000 nm), and with a super-long energy storage time of more than 300 h to have formaldehyde degraded in dark. In this new material system, the hydrogen treated WO3 functions as the light harvesting material and energy storage material simultaneously, while Pt mainly acts as the cocatalyst to have the energy storage effect displayed. The extraordinary full-spectrum absorption effect and long persistent energy storage ability make the material a potential solar-energy storage and an effective photocatalyst in practice. PMID- 23934409 TI - [Congratulations on your birthday, dear Mr. Dietel!]. PMID- 23934408 TI - The neurological wake-up test does not alter cerebral energy metabolism and oxygenation in patients with severe traumatic brain injury. AB - BACKGROUND: The neurological wake-up test (NWT) is used to monitor the level of consciousness in patients with traumatic brain injury (TBI). However, it requires interruption of sedation and may elicit a stress response. We evaluated the effects of the NWT using cerebral microdialysis (MD), brain tissue oxygenation (PbtiO2), jugular venous oxygen saturation (SjvO2), and/or arterial-venous difference (AVD) for glucose, lactate, and oxygen in patients with severe TBI. METHODS: Seventeen intubated TBI patients (age 16-74 years) were sedated using continuous propofol infusion. All patients received intracranial pressure (ICP) and cerebral perfusion pressure (CPP) monitoring in addition to MD, PbtiO2 and/or SjvO2. Up to 10 days post-injury, ICP, CPP, PbtiO2 (51 NWTs), MD (49 NWTs), and/or SjvO2 (18 NWTs) levels during propofol sedation (baseline) and NWT were compared. MD was evaluated at a flow rate of 1.0 MUL/min (28 NWTs) or the routine 0.3 MUL/min rate (21 NWTs). RESULTS: The NWT increased ICP and CPP levels (p < 0.05). Compared to baseline, interstitial levels of glucose, lactate, pyruvate, glutamate, glycerol, and the lactate/pyruvate ratio were unaltered by the NWT. Pathological SjvO2 (<50 % or >71 %; n = 2 NWTs) and PbtiO2 (<10 mmHg; n = 3 NWTs) values were rare at baseline and did not change following NWT. Finally, the NWT did not alter the AVD of glucose, lactate, or oxygen. CONCLUSIONS: The NWT induced stress response resulted in increased ICP and CPP levels although it did not negatively alter focal neurochemistry or cerebral oxygenation in TBI patients. PMID- 23934410 TI - [Gene expression analysis in breast cancer. A new diagnostic tool in pathology]. AB - Molecular biomarker analysis is increasingly being used as a basis for individualized therapy selection. In breast cancer established standard biomarkers are hormone receptors, HER2 and if indicated Ki67. In particular for hormone receptor positive, HER2 negative tumors, gene expression analysis provides additional information on proliferation and hormone receptor signalling. The results of the gene expression tests can be used to identify patients with a very good prognosis under an exclusive endocrine therapy. This group of patients can then be treated without conventional chemotherapy. The EndoPredict assay was validated in two large cohorts from clinical studies of the Austrian breast cancer study group (ABCSG). Furthermore, using a round robin test, the test method was established in several German institutes of molecular pathology. The EndoPredict assay can be carried out in local institutes of pathology and offers additional information to existing standard prognostic parameters. PMID- 23934411 TI - Inhibition of ATR kinase with the selective inhibitor VE-821 results in radiosensitization of cells of promyelocytic leukaemia (HL-60). AB - We compared the effects of inhibitors of kinases ATM (KU55933) and ATR (VE-821) (incubated for 30 min before irradiation) on the radiosensitization of human promyelocyte leukaemia cells (HL-60), lacking functional protein p53. VE-821 reduces phosphorylation of check-point kinase 1 at serine 345, and KU55933 reduces phosphorylation of check-point kinase 2 on threonine 68 as assayed 4 h after irradiation by the dose of 6 Gy. Within 24 h after gamma-irradiation with a dose of 3 Gy, the cells accumulated in the G2 phase (67 %) and the number of cells in S phase decreased. KU55933 (10 MUM) did not affect the accumulation of cells in G2 phase and did not affect the decrease in the number of cells in S phase after irradiation. VE-821 (2 and 10 MUM) reduced the number of irradiated cells in the G2 phase to the level of non-irradiated cells and increased the number of irradiated cells in S phase, compared to irradiated cells not treated with inhibitors. In the 144 h interval after irradiation with 3 Gy, there was a considerable induction of apoptosis in the VE-821 group (10 MUM). The repair of the radiation damage, as observed 72 h after irradiation, was more rapid in the group exposed solely to irradiation and in the group treated with KU55933 (80 and 77 % of cells, respectively, were free of DSBs), whereas in the group incubated with 10 MUM VE-821, there were only 61 % of cells free of DSBs. The inhibition of kinase ATR with its specific inhibitor VE-821 resulted in a more pronounced radiosensitizing effect in HL-60 cells as compared to the inhibition of kinase ATM with the inhibitor KU55933. In contrast to KU55933, the VE-821 treatment prevented HL-60 cells from undergoing G2 cell cycle arrest. Taken together, we conclude that the ATR kinase inhibition offers a new possibility of radiosensitization of tumour cells lacking functional protein p53. PMID- 23934413 TI - Geography lessons: scrutinizing state-by-state differences in inpatient gastroparesis care. PMID- 23934412 TI - Diagnostic stringency and healthcare needs in patients with biliary dyskinesia. AB - AIM: We have recently shown an increase in cholecystectomies for biliary dyskinesia. Based on these results, we hypothesized that diagnostic criteria are less stringently applied which may contribute to ongoing resource utilization. METHODS: Using billing codes, patients seen for biliary dyskinesia were identified and data were extracted from the electronic medical record to confirm the diagnosis, obtain demographic and clinical data and assess resource utilization 1 year prior to and after cholecystectomy. RESULTS: A total of 972 patients were identified, with 894 undergoing cholecystectomy. In 259 patients, symptoms had started <3 months prior to evaluation. Functional gallbladder imaging revealed a mean gallbladder ejection fraction of 23.1 +/- 0.7 %; of the patients undergoing surgery, 116 had a normal gallbladder ejection fraction. Sufficient up data for pre- and post-operative assessment of resource utilization was available for 368 patients. Emergency room (ER) visits decreased from 0.86 +/ 0.07 to 0.69 +/- 0.03 (P < 0.05), while hospitalization rates remained unchanged after surgery. Patients not meeting consensus criteria for the diagnosis of biliary dyskinesia were more likely to use opioids and have ER visits prior to and after cholecystectomy. Using multiple logistic regression benzodiazepine use, migraine history and prior ER visits independently predicted postoperative resource utilization. CONCLUSIONS: Our data demonstrate that a significant number of patients undergo cholecystectomy for biliary dyskinesia, even though they do not meet currently accepted diagnostic criteria. While healthcare resource utilization drops within the first year after surgery, ER visits and hospitalizations remain common, suggesting a more limited benefit of surgical approaches in these patients. PMID- 23934414 TI - Intravenous albumin shortens the duration of hospitalization for patients with hypoalbuminemia and bleeding peptic ulcers: a pilot study. AB - BACKGROUND: Patients with hypoalbuminemia have an increased risk of ulcer rebleeding and longer length of hospitalization. AIMS: This study aimed to test whether intravenous albumin can decrease the incidence of rebleeding or shorten the duration of hospitalization in patients with bleeding peptic ulcers and hypoalbuminemia. METHODS: Sixty-two patients with bleeding peptic ulcers and Rockall scores >= 6 were prospectively enrolled after having received endoscopic therapy. The enrolled patients were divided into a normal albumin group (serum albumin >= 3 g/dL, n = 39) or an intervention group (<3 g/dL, n = 23) to receive a 3-day course of omeprazole infusion and 25-day oral esomeprazole. Patients (n = 29) with bleeding ulcers and hypoalbuminemia who received the same dose of intravenous and oral omeprazole but did not receive albumin therapy were enrolled from a previous study as the control group. In the intervention group, patients received albumin infusion (10 g q8h) for 1 day (serum albumin levels 2.5-2.9 g/dL) and 2 days (<2.5 g/dL), respectively. RESULTS: The 28-day cumulative rebleeding rates were similar between the intervention group and the control group (39.1 vs. 42.3 %, p = 0.99). The intervention group had a shorter duration of hospitalization (9 vs. 15 days, p = 0.02) than cohort controls. The risk of rebleeding developed after discharge were similar (normal albumin group vs. intervention group vs. control group, 1/5 [20 %] vs. 2/9 [22.2 %] vs. 1/11 [9.1 %], p = 0.7). CONCLUSIONS: Albumin administration shortens the duration of hospitalization for patients with peptic ulcer bleeding and hypoalbuminemia, but does not decrease the incidence of rebleeding. PMID- 23934415 TI - Identification of genes and candidate agents associated with pancreatic cancer. AB - Pancreatic cancer is a malignant neoplasm originating from transformed cells arising in tissues forming the pancreas. A major challenge in current cancer research is biological interpretation of complexity of cancer somatic mutation profiles. It has been suggested that several molecular alterations may play important roles in pancreatic carcinogenesis. In this study, by using the GSE28735 affymetrix microarray data accessible from Gene Expression Omnibus (GEO) database, we identified differentially expressed genes (DEGs) between paired pancreatic cancer tissues and adjacent nontumor tissues, followed the protein protein interaction of the DEGs. Our study identified thousands of DEGs involved in regulation of cell cycle and apoptosis in progression of pancreatic cancer. Sp1 was predicted to be the major regulator by transcription factors analysis. From the protein-protein interaction networks, we found that Tk1 might play an important role in the progression of pancreatic cancer. Finally, we predicted candidate agents, including tomatidine and nialamide, which may be used as drugs to treat pancreatic cancer. In conclusion, our data provide a comprehensive bioinformatics analysis of genes and pathways which may be involved in the progression of pancreatic cancer. PMID- 23934416 TI - Perception of affective and linguistic prosody: an ALE meta-analysis of neuroimaging studies. AB - Prosody refers to the melodic and rhythmic aspects of speech. Two forms of prosody are typically distinguished: 'affective prosody' refers to the expression of emotion in speech, whereas 'linguistic prosody' relates to the intonation of sentences, including the specification of focus within sentences and stress within polysyllabic words. While these two processes are united by their use of vocal pitch modulation, they are functionally distinct. In order to examine the localization and lateralization of speech prosody in the brain, we performed two voxel-based meta-analyses of neuroimaging studies of the perception of affective and linguistic prosody. There was substantial sharing of brain activations between analyses, particularly in right-hemisphere auditory areas. However, a major point of divergence was observed in the inferior frontal gyrus: affective prosody was more likely to activate Brodmann area 47, while linguistic prosody was more likely to activate the ventral part of area 44. PMID- 23934418 TI - ADAM33 protein expression and the mechanics of airway smooth muscle cells are highly correlated in ovalbumin-sensitized rats. AB - A disintegrin and metalloproteinase 33 (ADAM33) has been identified as an asthma susceptibility gene; however, the role of ADAM33 in the pathogenesis and progression of asthma remains to be elucidated. As ADAM33 is predominantly expressed in airway smooth muscle cells (ASMCs), it is feasible to investigate whether ADAM33 protein expression is correlated with ASMC mechanics that are ultimately responsible for airway hyperresponsiveness in asthma. To determine this, Sprague Dawley rats were sensitized with ovalbumin (OVA) for up to 12 weeks to simulate asthma symptoms. Subsequently, ASMCs were isolated from the rats and cultured in vitro. The protein expression of ADAM33 and cytoskeletal proteins (including F-actin and vinculin), cell stiffness and contractility, as well as traction force were measured. The results demonstrated that compared with the non sensitized rats, the protein expression of ADAM33 in ASMCs from the OVA sensitized rats increased in a time-dependent manner, reaching a maximum level at 4 weeks of sensitization and gradually subsiding as OVA sensitization continued (P<0.001). The cell stiffness, traction force and expression of vinculin and F actin changed similarly, resulting in a positive correlation with ADAM33 protein expression (Pearson's correlation coefficient, 0.864, 0.716, 0.774 and 0.662, respectively; P=0.1-0.3). The in vivo results of OVA-induced ADAM33 protein expression and its association with the mechanics of ASMCs suggested that ADAM33 is a mediator of ASMC dysfunction in asthma, and may provide a rationale for the therapeutic targeting of ADAM33 in the treatment of asthma. PMID- 23934417 TI - Neural correlates of a computerized attention modification program in anxious subjects. AB - Computerized attention modification is a relatively new and empirically validated treatment approach for different types of anxiety disorders. However, its neural basis and processes involved are poorly understood. This study examined the effect of a one-time application of an attention modification program (AMP) on neural substrates underlying emotion processing in individuals with high social anxiety. Fourteen individuals with elevated social anxiety symptoms completed an emotional face processing task during functional magnetic resonance imaging before and after AMP, and were subsequently exposed to a laboratory stressor. Results revealed the following: First, there was attenuated activation from pre- to post-AMP in the bilateral amygdala, bilateral insula and subgenual anterior cingulate cortex. Second, post-AMP, individuals exhibited increased activation in several regions of the prefrontal cortex (PFC). Third, those individuals with greater enhancement of ventromedial PFC activation after AMP showed diminished attentional allocation for threat and attenuated anxiety reactivity to the stressor. We conclude that AMP exerts effects that are similar to those previously reported for standard anxiolytics; however, it also appears to foster deployment of top-down brain processes aimed to regulate anxiety. PMID- 23934419 TI - NCDs: can healthy synergies replace fatal interactions? AB - A growing global movement argues for health to take center stage in the post-2015 sustainable human development agenda, building on the Millennium Development Goals and improving measurement of outcomes and equity. Considered key is the urgent need to effectively stem chronic noncommunicable diseases (NCDs). The reasoning is straightforward and yet addresses the interactive complexities of NCD impact and the potential synergies to reduce it: NCDs constitute the most important, if until recently neglected, pandemic of our era. They accounted for over 65% of global deaths and 54% of the global disease burden in 2010.[1,2] Such a negative "contribution" -including the sequelae of disability and alarming costs of treatment for multimorbidities associated with aging populations worldwide-jeopardizes sustainable human development. PMID- 23934420 TI - Sounding the alarm on chronic kidney disease in farming communities: Maria Isabel Rodriguez MD. Minister of health, El Salvador. Interview by Conner Gorry. AB - In April 2013, a consortium of regional health ministries, nongovernmental organizations, aid agencies, clinical specialists and researchers from diverse sectors convened in San Salvador to discuss the epidemic of chronic kidney disease of unknown or non-traditional causes (CKDu) plaguing agricultural communities in Central America and beyond. The three-day meeting, where presentation of research on the clinical and epidemiological characteristics of CKDu roused significant debate, led the Pan American Health Organization to declare CKDu "a pressing and serious health problem [which] represents a burden for families, communities, health systems and society as a whole."[1] This High level Meeting on Chronic Kidney Disease of Non-Traditional Causes in Central America (24-26 April) followed several international meetings at which Dr Maria Isabel Rodriguez, El Salvador's Minister of Health, presented studies on the disease burden in her country, where end-stage renal disease is the leading cause of hospital deaths. She outlined results of original scientific research by Dr Carlos Orantes (first published in MEDICC Review), that described an "elevated prevalence of chronic kidney disease, chronic renal failure and risk factors" among the patients studied, noting that "the most common [form] was chronic kidney disease of unknown cause, associated with neither diabetes nor hypertension."[2] In this interview with MEDICC Review, Dr Rodriguez discussed the gravity of the problem in Salvadoran agricultural communities; the importance of CKDu research in other countries; and the urgent need for intersectoral action and active community participation to confront and control the epidemic. PMID- 23934421 TI - Prognostic factors in hemodialysis patients: experience of a Havana hospital. AB - INTRODUCTION: Knowledge of prognostic factors in end-stage renal disease patients has improved dialysis management and methods for reducing morbidity and mortality, underlining the importance of identification, prevention and control of these factors. OBJECTIVE: Identify factors affecting prognosis (survival or death) in hemodialysis patients at the Medical-Surgical Research Center in Havana over a ten-year period. METHODS: Descriptive, prospective study of 81 end-stage renal disease patients who received hemodialysis at the Medical-Surgical Research Center from 1995 to 2004. Prognostic factors were identified at initiation of and during dialysis treatment, using chi square, t test, McNemar test, Kaplan Meier analysis, log-rank test and Cox regression model, with significance threshold set at p <0.05. RESULTS: Hypertension and diabetes were the leading causes of end stage renal disease. Six patients were referred late. Mean survival was 4.4 years; with survival of 86.6%, 54.7% and 26.6% at one, three and five years respectively. Factors predictive of decreased survival that were most frequent at initiation of hemodialysis were hypertension and chronic anemia (both present in 95.9% of cases); malnutrition, hypoalbuminemia, cardiovascular disease and chronic liver disease increased during treatment while hypertension decreased. In multivariate analysis, prognostic factors that significantly predicted decreased survival were hypertension, inadequate vascular access and diabetes. Patients aged >= 60 years and those with malnutrition, hypoalbuminemia, anemia, cardiovascular disease or liver disease had lower survival figures at the end of the study period. Leading causes of death were infections (45.2%) and cardiovascular disease (41.9%); the latter was present in 93.5% of deaths, independent of underlying cause of death. CONCLUSIONS: Survival of hemodialysis patients diminished at five years. Some negative predictive factors are present at initiation of hemodialysis, such as diabetes, hypertension and chronic anemia; others increased later, including malnutrition, hypoalbuminemia, cardiovascular disease and liver disease. PMID- 23934422 TI - Spatiotemporal analysis of lung cancer incidence and case fatality in Villa Clara Province, Cuba. AB - INTRODUCTION: Cancer has historically been a main cause of death in Cuba, with lung cancer the number one cause of cancer death in both sexes. Cancer morbidity and mortality rates are the basic measures of cancer impact in the community. Cancer mortality has been one of the major applications of geographic analysis and has made important progress in recent decades thanks to access to mortality statistics and to development and availability of geographic information systems. Cuba does not have a strong tradition of etiologic research using spatial analysis. High levels of lung cancer morbidity and mortality in Villa Clara and growing interest in spatial analysis as an epidemiologic tool motivated this study. OBJECTIVE: To identify spatial and/or spatiotemporal clusters of lung cancer morbidity and case fatality in the province of Villa Clara, and to demonstrate the value of cluster analysis as an epidemiologic tool. METHODS: Descriptive observational study based on administrative data, using the technique of space-time scan statistics. The study focused on new cases diagnosed in 2004 and case-fatality for those cases through 2009. Variables used were: cases diagnosed, deaths, date of diagnosis, date of death, municipality and Cartesian geocoding for each municipality. RESULTS: The study identified significant spatial and spatiotemporal clusters of greater than expected lung cancer incidence (municipalities of Encrucijada, Camajuani, Cifuentes, Sagua la Grande, Caibarien and Santa Clara) and case fatality (Encrucijada, Camajuani, Cifuentes, Sagua la Grande, Caibarien, Santa Clara, Placetas and Manicaragua). CONCLUSIONS: Although the results are not explanatory, the spatial and spatiotemporal patterns of excess lung cancer risk and case-fatality can support hypothesis generation for research and eventual interventions for targeted prevention and management. PMID- 23934423 TI - Contribution of genome-environment interaction to pre-eclampsia in a Havana Maternity Hospital. AB - INTRODUCTION: Pre-eclampsia is a major cause of morbidity and mortality during pregnancy worldwide and is among the leading causes of maternal mortality in Cuba. It is a complex, multifactoral disease, in which interaction of genetic and environmental factors should not be overlooked if the goal is proper risk assessment to support personalized preventive genetic counseling and more effective prenatal care to prevent pregnancy complications. OBJECTIVE: Determine the contribution to pre-eclampsia of interaction between a predisposing genome and adverse environmental factors in pregnant women in a Havana maternity hospital. METHODS: This was the exploratory phase of a hospital-based case control study, using January 2007-December 2009 patient records from the Eusebio Hernandez University Hospital, a provincial maternity hospital in Havana. Eighty pregnant women diagnosed with pre-eclampsia and 160 controls were studied. The main variables were age, parity, nutritional status (measured by BMI), alcohol use, tobacco use, and history of pre-eclampsia in relatives of the pregnant woman (proband) or of her partner. Pearson chi square and Fisher exact test were used to assess statistical significance of associations between variables and odds ratio as a measure of association strength. Familial aggregation was studied and a case-control design used to assess gene-environment interaction, using multiplicative and additive models. RESULTS: Among the environmental risk factors studied, alcohol showed the strongest effect on pre-eclampsia risk (OR 3.87, 95% CI 1.64-9.13). Familial pre-eclampsia clustering was observed; risk was increased for both first-degree (OR 2.43, 95% CI 1.62-3.73) and second-degree (OR 1.89, 95% CI 1.34-2.68) relatives as well as for husband's relatives (OR 2.32, 95% CI 1.40 3.86). There was evidence of interaction between alcohol consumption and family history. CONCLUSIONS: Familial aggregation of the disorder was demonstrated, the first Cuban epidemiological evidence of genetic and enviromental contributions to pre-eclampsia risk. Familial clustering among the husband's relatives demonstrates the fetal genome's importance in genesis of pre-eclampsia. The interaction of environmental risk factors with genetic ones produces increased pre-eclampsia risk, compared to expectations based on independent action of these variables. KEYWORDS Pre-eclampsia, toxemia of pregnancy, pregnancy outcome, environment, genetics, genome-environment interaction, genetic epidemiology, Cuba. PMID- 23934424 TI - Predicting mortality from head injury: experience of Sancti Spiritus Province, Cuba. AB - INTRODUCTION: Better prognostic classification of patients who are severely injured or in critical condition has been associated with reduced case fatality from traumatic brain injury. OBJECTIVE: Determine the value of admission results (clinical, laboratory and imaging) and severity scales, for predicting mortality in traumatic brain injury patients. METHODS: A cross-sectional study of traumatic brain injury patients was conducted at the Sancti Spiritus Provincial General Teaching Hospital in 2009 and 2010; the study population included all 16 traumatic brain injury patients who died during the period, plus 31 who survived to discharge. The following independent variables were used: Glasgow Coma Scale, Glasgow Coma Scale motor score, pupil reaction to light, blood glucose, respiratory distress, systolic blood pressure, hemoglobin, and lesions detectable on cranial computed tomography. Associations between independent and dependent variables (death or survival to discharge) were analyzed using the chi-square test and, for cells with expected values of <5, the Fisher exact test. Odds ratios and 95% confidence intervals were calculated. RESULTS: Of 47 patients, 20 (42.6%) were aged >60 years and 32 (68.1%) were male. Parameters associated with higher mortality identified were: Glasgow Coma Scale score <= 8 (OR 47.25, 95% CI 6.26-483.3, p <0.001) and Glasgow Coma Scale motor score <= 3 (OR 28.00, 95% CI 4.20-220.2, p <0.001); absence of pupil reaction (OR = 8.40, 95% CI 1.20-73.35, p <0.001), respiratory distress (OR = 47.25, 95% CI 1.85-85.92, p <0.0014), blood glucose >8.8 mmol/L (OR = 7.26, CI 1.28-46.18, p <0.001), subdural hematoma (OR 20.25, 95% CI 3.55-136.65, p <0.001) and multiple injuries detected by cranial computed tomography (OR = 29.25, 95% CI 4.64-228.43, p <0.001). CONCLUSIONS: The study confirmed value in Sancti Spiritus Province of the following for predicting mortality in head injury patients: Glasgow Coma Scale score <= 8, Glasgow Coma Scale motor score <= 3, blood glucose >8.8 mmol/L, absence of pupil reaction to light, respiratory distress, and presence of multiple injuries detected in cranial computed tomography. No prognostic value was demonstrated for low hemoglobin values or abnormal blood pressure. PMID- 23934425 TI - Sex education for children and adolescents with type 1 diabetes in Camaguey province, Cuba. AB - Education at the community level is indispensable for control of chronic non communicable diseases and comprehensive patient care, with diabetes mellitus a case in point. The need is even more pronounced for type 1 diabetes, affecting children and adolescents. Families of diabetic adolescents naturally worry about vulnerability to sexually transmitted diseases, which create risks for glycemic control and the adolescent's health. We felt compelled to explore the issue of sexuality in diabetes education for adolescents, because education can do more than help maintain metabolic control; it can contribute to keeping diabetic children and adolescents on a healthy developmental curve, when combined with the other pillars of diabetes management. Accordingly, we carried out an educational intervention to increase type 1 diabetic adolescents' knowledge of sexuality and sexually transmitted infections. Participants were 20 adolescents in Camaguey Province's central clinic for type 1 diabetes patients. A six-session educational program was developed and implemented. Responses to a questionnaire before and after the program revealed that prior to the intervention only 3 of 20 participants (15%) demonstrated satisfactory knowledge of the material covered (>= 70%), increasing to 20 (100%) after completion of the program. PMID- 23934426 TI - Care for pregnant diabetics in Cuba: achievements and challenges. AB - Establishment, progressive development, expansion and organization of Cuba's National Comprehensive Diabetes and Pregnancy Program is described, including changes in related health services since 1959. Currently implemented throughout the country, the Program is supervised by a working group and addresses diabetic women's reproductive health and care during pregnancy. The importance of preconception care for diabetic women is emphasized, as well as the need to increase Program uptake nationally, including screening for gestational diabetes in primary care. PMID- 23934427 TI - Are increased chronic diseases a potential legacy of Cuba's special period? AB - Cuba is the only country I know to erect a monument to the egg....and so it should. Located on Havana's Fifth Avenue, the simple sculpture pays homage to the salva vida-literally the life saver of many a Cuban family, particularly in the 1990s. Those were the worst years of what was euphemistically called the "Special Period," when the economy careened ever downward, reeling from the loss of 85% of Cuba's aid and trade in the post-Soviet era. PMID- 23934428 TI - Efficient and bright organic light-emitting diodes on single-layer graphene electrodes. AB - Organic light-emitting diodes are emerging as leading technologies for both high quality display and lighting. However, the transparent conductive electrode used in the current organic light-emitting diode technologies increases the overall cost and has limited bendability for future flexible applications. Here we use single-layer graphene as an alternative flexible transparent conductor, yielding white organic light-emitting diodes with brightness and efficiency sufficient for general lighting. The performance improvement is attributed to the device structure, which allows direct hole injection from the single-layer graphene anode into the light-emitting layers, reducing carrier trapping induced efficiency roll-off. By employing a light out-coupling structure, phosphorescent green organic light-emitting diodes exhibit external quantum efficiency >60%, while phosphorescent white organic light-emitting diodes exhibit external quantum efficiency >45% at 10,000 cd m(-2) with colour rendering index of 85. The power efficiency of white organic light-emitting diodes reaches 80 lm W(-1) at 3,000 cd m(-2), comparable to the most efficient lighting technologies. PMID- 23934429 TI - Cadmium increases catechol 2,3-dioxygenase activity in Variovorax sp. 12S, a metal-tolerant and phenol-degrading strain. AB - A Gram-negative bacterium, designated as strain 12S, was isolated from a heavy metal-polluted soil. According to the biochemical characteristics, FAME analysis, and 16S rRNA gene sequence analysis, the isolated strain was identified as Variovorax sp. 12S. In the presence of 0.1 mM cadmium, 12S was able to completely utilize up to 1.5 mM of phenol as the sole carbon and energy source in an MSM TRIS medium. Degradation of phenol was accompanied by a slow bacterial growth rate and an extension of the lag phase. The cells grown on phenol showed catechol 2,3-dioxygenase (C23O) activity. The activity of C23O from 12S cultivated in medium with Cd(2+) was almost 20 % higher than in the control. Since environmental contamination with aromatic compounds is often accompanied by the presence of heavy metals, Variovorax sp. 12S and its C23O appear to be very powerful and useful tools in the biotreatment of wastewaters and soil decontamination. PMID- 23934430 TI - An overview of carbon materials for flexible electrochemical capacitors. AB - Under the background of the quick development of lightweight, flexible, and wearable electronic devices in our society, a flexible and highly efficient energy management strategy is needed for their counterpart energy-storage systems. Among them, flexible electrochemical capacitors (ECs) have been considered as one of the most promising candidates because of their significant advantages in power and energy densities, and unique properties of being flexible, lightweight, low-cost, and environmentally friendly compared with current energy storage devices. In a common EC, carbon materials play an irreplaceable and principal role in its energy-storage performance. Up till now, most progress towards flexible ECs technologies has mostly benefited from the continuous development of carbon materials. As a result, in view of the dual remarkable highlights of ECs and carbon materials, a summary of recent research progress on carbon-based flexible EC electrode materials is presented in this review, including carbon fiber (CF, consisting of carbon microfiber-CMF and carbon nanofiber-CNF) networks, carbon nanotube (CNT) and graphene coatings, CNT and/or graphene papers (or films), and freestanding three-dimensional (3D) flexible carbon-based macroscopic architectures. Furthermore, some promising carbon materials for great potential applications in flexible ECs are introduced. Finally, the trends and challenges in the development of carbon-based electrode materials for flexible ECs and their smart applications are analyzed. PMID- 23934431 TI - [Diagnosis of otolith disorders in routine otolaryngology]. AB - Nowadays, specific and reproducible side-separated neurotologic testing of all vestibular receptors is possible. Assessment of saccular function by measuring cervical vestibular-evoked myogenic potentials (cVEMP) is well established. Reliable screening tests exist for the isolated assessment of utricular function. These tests can be performed even in less well-equipped surroundings to generate information regarding a possible partial dysfunction of the otolith organs. Apart from assessing the functionality of the semicircular canals by caloric irrigation and the head impulse test, screening for otolith disorders should be part of a comprehensive modern vestibular examination. Neurofeedbacktraining is an effective therapy in the treatment of otholith disorders. PMID- 23934432 TI - Impact of cross-linking and drying method on drug delivery performance of casein pectin microparticles. AB - Pectin is a heteropolysaccharide which has been investigated for the development of colon-specific drug delivery systems. Polymers have been associated with pectin to reduce its aqueous solubility and improve the performance of drug delivery systems. Pectin-casein interaction is widely known in food research, but it has not been fully considered by pharmaceutical scientists. Thus, this study investigated the potential of casein-pectin microparticles as a drug delivery system and clarified the impact of cross-linking and drying methods on the in vitro release of indomethacin (IND) or acetaminophen (PCT) from microparticles. Microparticles were prepared by coacervation and dried by spray or spouted bed methods. Drug recovery, in vitro drug release, size, morphology, and the thermal and diffractometric properties of dried microparticles were determined. Spray dried non-cross-linked microparticles were able to prolong IND release, and pectin was still degraded by pectinolytic enzymes. On the other hand, glutaraldehyde cross-linking prevented the enzymatic breakdown of pectin without improving IND release. Spouted bed drying reduced IND recovery from all microparticles when compared with spray drying, thus the successful spouted bed drying of microparticles depends on the chemical characteristics of both the drug and the polymer. Release data from PCT microparticles suggested that the microparticle formulation should be improved to bring about a more efficient delivery of water-soluble drugs. In conclusion, casein-pectin microparticles show great potential as a drug delivery system because casein reduces the water solubility of pectin. The drying method and cross-linking process had significant effects on the in vitro performance of these microparticles. PMID- 23934433 TI - The preparation and evaluation of water-soluble SKLB610 nanosuspensions with improved bioavailability. AB - The aim of the study was to investigate the potential of nanosuspension to enhance the bioavailability of SKLB610 (Biopharmaceutical Classification System class II drug), a bioactive anticancer compound synthesized in our labs. SKLB610 nanosuspensions were prepared using wet media milling. Physicochemical characteristics of the nanosuspensions were evaluated, including particle size and distribution, dissolution, transmission electron microscopy, atomic force microscopy, thermogravimetric analysis, and X-ray powder diffractometry. The dissolution rate of SKLB610 was greatly improved in nanosuspensions, compared to crude SKLB610. Pharmacokinetic studies in rats demonstrated that the oral bioavailability of SKLB610 in nanosuspension (89.4%) was 2.6-fold higher than in coarse suspension (34.1%). Stabilizer type, milling time, and milling speed had a significant effect on particle size of the SKLB610 nanosuspensions. Nanosuspensions effectively improved the dissolution rate and bioavailability of the water-insoluble drug SKLB610 by reducing the compound particle size to the nanoscale and employing a proper formulation. PMID- 23934434 TI - Synthesis of a smart gold nano-vehicle for liver specific drug delivery. AB - Targeting drug formulations to specific tissues and releasing the bioactive content in response to a certain stimuli remains a significant challenge in the field of biomedical science. We have developed a nanovehicle that can be used to deliver "drugs" to "specific" tissues. For this, we have simultaneously modified the surface of the nanovehicle with "drugs" and "tissue-specific ligands". The "tissue-specific ligands" will target the nanovehicle to the correct tissue and release the "drug" of interest in response to specific stimuli. We have synthesised a "lactose surface-modified gold nanovehicle" to target liver cells and release the model fluorescent drug (coumarin derivative) in response to the differential glutathione concentration (between blood plasma and liver cells). Lactose is used as the liver-specific targeting ligand given the abundance of L galactose receptors in hepatic cells. The coumarin derivative is used as a fluorescent tag as well as a linker for the attachment of various biologically relevant molecules. The model delivery system is compatible with a host of different ligands and hence could be used to target other tissues as well in future. The synthesised nanovehicle was found to be non-toxic to cultured human cell lines even at elevated non-physiological concentrations as high as 100 MUg/mL. We discover that the synthesised gold-based nanovehicle shows considerable stability at low extracellular glutathione concentrations; however coumarin is selectively released at high hepatic glutathione concentration. PMID- 23934435 TI - Promoter hypermethylation-mediated down-regulation of RUNX3 gene in human brain tumors. AB - BACKGROUND: The Runx family proteins, including RUNX3, are tissue-restricted transcription factors and play role in neuronal development and tumorigenesis. RUNX3 has an important role in glioblastoma (GBM) tumorigenesis because of its promoter hypermethylation. AIM: We aimed to evaluate the methylation-mediated expression regulation of RUNX3 gene in brain tumors. PATIENTS AND METHODS: Cases of meningiomas WHO grade III (3), anaplastic astrocytomas (3), diffuse astrocytoma (3), and GBM (12) were recruited into this study. Real-time quantitative PCR was performed for analyses of DNA promoter methylation and analyses of methylation-mediated expression status of RUNX3 gene was performed by real-time quantitative RT-PCR. RESULTS: There was no significant difference between methylated and unmethylated quantitative ratio of RUNX3 gene promoter region and also no significant difference in relative ratio of RUNX3 gene expression in brain tumor groups. Methylated and unmethylated ratio in anaplastic astrocytoma, diffuse astrocytoma, GBM, meningioma (WHO grade III) and in all groups were; 1.44, 1.09, 1.51, 1.52 and 1.43, respectively. One allele was found methylated necessarily. No methylation was detected in one case of GBM group and one case of anaplastic astrocytoma group. There was no unmethylated promoter in one of the GBM cases. There were significant differences between relative ratio of RUNX3 gene expression and methylated/unmethylated ratio rates for all cases (p = 0.001) and GBM groups (p = 0.041). CONCLUSION: This study overemphasized the RUNX3 gene importance in brain tumors, due to the existence of at least one methylated allele. PMID- 23934436 TI - Tinzaparin safety and efficacy in pregnancy. AB - BACKGROUND: Unfractionated heparin has largely been replaced by low molecular weight heparin in the treatment and prevention of thrombosis and recurrent miscarriage in pregnancy. There is little information, however, about the efficacy and safety of tinzaparin, which has the advantage of being administered as a single daily dose. AIMS: To evaluate the safety and efficacy of tinzaparin use in pregnancy. METHODS: We retrospectively reviewed the medical records of women who were prescribed tinzaparin during pregnancy and the puerperium in our hospitals from January 2000 to December 2008. Tinzaparin was given as a single daily prophylactic dose for women with a history of venous thromboembolism (VTE) or recurrent miscarriage and as a single daily therapeutic dose for women diagnosed with VTE. The primary outcomes recorded were thrombosis, bleeding, allergy and thrombocytopenia. RESULTS: One hundred and forty-nine women aged between 17 and 44 years received tinzaparin in pregnancy and the puerperium over the study period. The dose administered was therapeutic in 21 (14 %) cases and prophylactic in all others. VTE recurred in three women who had a history of VTE (3.6 %). Antepartum and postpartum haemorrhage occurred in 9.7 and 5 % of cases, respectively and two women developed thrombocytopenia but their platelets remained above 100,000/ml. Fifty-seven women (38 %) had regional anaesthesia without complication. CONCLUSION: Our study demonstrates a safety profile for tinzaparin in pregnancy that is equivalent to other low molecular weight heparins with the advantage of single daily dosing. PMID- 23934437 TI - Strong temporal variation over one Saturnian year: from Voyager to Cassini. AB - Here we report the combined spacecraft observations of Saturn acquired over one Saturnian year (~29.5 Earth years), from the Voyager encounters (1980-81) to the new Cassini reconnaissance (2009-10). The combined observations reveal a strong temporal increase of tropic temperature (~10 Kelvins) around the tropopause of Saturn (i.e., 50 mbar), which is stronger than the seasonal variability (~a few Kelvins). We also provide the first estimate of the zonal winds at 750 mbar, which is close to the zonal winds at 2000 mbar. The quasi-consistency of zonal winds between these two levels provides observational support to a numerical suggestion inferring that the zonal winds at pressures greater than 500 mbar do not vary significantly with depth. Furthermore, the temporal variation of zonal winds decreases its magnitude with depth, implying that the relatively deep zonal winds are stable with time. PMID- 23934438 TI - High fidelity simulation effectiveness in nursing students' transfer of learning. AB - BACKGROUND: Members of nursing faculty are utilizing interactive teaching tools to improve nursing student's clinical judgment; one method that has been found to be potentially effective is high fidelity simulation (HFS). The purpose of this time series design study was to determine whether undergraduate nursing students were able to transfer knowledge and skills learned from classroom lecture and a HFS clinical to the traditional clinical setting. METHOD: Students (n=42) were observed and rated on their ability to perform a respiratory assessment. The observations and ratings took place at the bedside, prior to a respiratory lecture, following the respiratory lecture, and following simulation clinical. RESULTS: The findings indicated that there was a significant difference (p=0.000) in transfer of learning demonstrated over time. CONCLUSIONS: Transfer of learning was demonstrated and the use of HFS was found to be an effective learning and teaching method. Implications of results are discussed. PMID- 23934439 TI - Clinical and radiological outcomes following microscopic decompression utilizing tubular retractor or conventional microscopic decompression in lumbar spinal stenosis with a minimum of 10-year follow-up. AB - Satisfactory short- and mid-term results have been observed following microscopic decompression with tubular retractor (MDT) and conventional microscopic decompression (CMD) in lumbar spinal stenosis (LSS). It is not yet clear which surgical procedure is the optimal treatment for LSS, especially in long-term follow-up period. To the best of our knowledge, there is no comparative study analyzing the clinical-radiological outcomes of MDT and CMD over a 10-year follow up periods. The purpose of this study was to evaluate and compare clinical and radiological outcomes of MDT and CMD over a 10-year follow-up period in patients with LSS. Of total 121 patients, 102 patients (53 MDT and 49 CMD) were followed for at least 10 years following MDT and CMD for LSS. We retrospectively reviewed surgical results and clinical outcomes based on the visual analogue scale, McNab's criteria, and the Oswestry Disability Index, and radiological analysis results with the parameters, including the change of disk height and intervertebral distance, obtained preoperatively and 3- and 6-month, and 1-, 6-, and 10-year postoperatively. There was no significant difference in patient demographics between the two groups. Five patients (two in MDT, three in CMD) required re-operation for re-stenotic change of the affected segment. The number of patients requiring re-operation was not significantly different between the two groups (p > 0.05). No statistically significant differences were observed between the groups in a long-term follow-up period after a 3-month follow-up (p > 0.05). However, in the acute postoperative phase of <3-month postoperatively, MDT appears to result in less postoperative pain and better clinical outcomes compared with the CMD. In conclusion, despite relatively small sample size with retrospective design, our study suggested that MDT appears to result in less postoperative pain and better clinical outcomes in the acute postoperative period of <3 months, but both MDT and CMD were no significant differences in clinical and radiological outcomes after that time. PMID- 23934440 TI - A comparison of the functional and radiological results of Paris plaster cast and ulnar gutter splint in the conservative treatment of fractures of the fifth metacarpal. AB - AIM: In the treatment protocol of fractures of the fifth metacarpal, closed reduction and immobilization is generally recommended. This study aimed to compare the radiological and functional results of short-arm plaster cast and a forearm U-splint. PATIENTS AND METHODS: Between January 2011 and June 2012, the study comprised a total of 122 cases with 64 (52.4%) in the cast group and 58 (47.6%) in the splint group. The cases were 92 (75.4%) males and 30 (24.6%) females with a mean age of 30.56 +/- 12.27 years (range 10-66 years). Two groups were formed according to the surgical treatment plans of the two surgeons who were to follow up the patients. RESULTS: No statistically significant difference was found between the groups in terms of age, duration of the cast or splint and follow-up period (p > 0.05). The grip strength of Group A was determined as 90.38 +/- 1.77% of the healthy side and Group B as 90.58 +/- 1.65%. No statistically significant difference was seen between the groups in respect of grip strength (p > 0.05). The degree of dorsal angulation pre-application, post-application and after removal of the groups showed no statistically significant difference between the groups (p > 0.05). CONCLUSION: No superiority was seen in the clinical and radiological results of the two different treatment protocols applied to fractures of the fifth metacarpal. However, when the complications created by a plaster cast and pressure wounds are taken into consideration, the application of a short-arm U-splint can be said to be a better option. PMID- 23934442 TI - Responses of human hip abductor muscles to lateral balance perturbations during walking. AB - Lateral stability during gait is of utmost importance to maintain balance. This was studied on human subjects walking on a treadmill who were given 100-ms perturbations of known magnitude and timing with respect to the gait cycle by means of a computer-controlled pneumatic device. This method has the advantage that the same perturbations can be given at different phases of the stride cycle, thereby allowing an analysis of the phase dependency of the responses in the primary muscles involved. After an inward push, e.g., a push toward the left during right stance, the left foot in the step to follow is placed more to the left (outward strategy). The hypothesis was that this movement is caused by automatic unvoluntary muscle activity. This turned out to be the case: the abduction movement follows EMG responses in the left abductor muscle, gluteus medius, in response to the push. Two responses, with latencies of 100 and 170 ms, and a late reaction >270 ms can be discerned. All three responses are phase dependent; they show facilitation in swing and no response in stance, in contrast to the normal walking activity (background). This independence of the background activity suggests a premotoneuronal gating of these responses, reminiscent of phase-dependent modulation of electrically elicited reflexes. It is concluded that facilitating pathways are opened independent of normal background activation to enable appropriate actions to restore balance after a mediolateral perturbation. PMID- 23934441 TI - Saccade reaction time asymmetries during task-switching in pursuit tracking. AB - We investigate how smooth pursuit eye movements affect the latencies of task switching saccades. Participants had to alternate their foveal vision between a continuous pursuit task in the display center and a discrete object discrimination task in the periphery. The pursuit task was either carried out by following the target with the eyes only (ocular) or by steering an on-screen cursor with a joystick (oculomanual). We measured participants' saccadic reaction times (SRTs) when foveal vision was shifted from the pursuit task to the discrimination task and back to the pursuit task. Our results show asymmetries in SRTs depending on the movement direction of the pursuit target: SRTs were generally shorter in the direction of pursuit. Specifically, SRTs from the pursuit target were shorter when the discrimination object appeared in the motion direction. SRTs to pursuit were shorter when the pursuit target moved away from the current fixation location. This result was independent of the type of smooth pursuit behavior that was performed by participants (ocular/oculomanual). The effects are discussed in regard to asymmetries in attention and processes that suppress saccades at the onset of pursuit. PMID- 23934443 TI - Hurting, helping, or neutral? The effects of parental permissiveness toward adolescent drinking on college student alcohol use and problems. AB - To enhance prevention efforts to reduce college drinking, parents have been identified as an important source of influence that can be modified with brief interventions. Research suggests parental permissiveness toward drinking in adolescence is positively related to college student drinking, though existing studies have not comprehensively accounted for potential confounders (e.g., parental drinking). The present study used propensity modeling to estimate the effects of pre-college parental permissiveness on college student drinking and consequences while accounting for an inclusive range of confounders. A random sample of 1,518 incoming students at a large university completed baseline measures of parental permissiveness and a list of confounders (e.g., parental drinking, family history). At follow-up 15 months later, participants reported on their drinking and alcohol-related consequences. To control for potential confounders, individuals were weighted based on their propensity scores to obtain less biased estimates of the effects of parental permissiveness on drinking and consequences. Analyses revealed parental permissiveness was consistently and positively associated with college drinking and consequences when the confounders were not accounted for, but these effects were attenuated after weighting. Parents' allowance of drinking was not related to college drinking or consequences after weighting. Students' perceived parental limits for consumption were related to drinking and consequences in the weighted models. Prevention efforts may benefit from targeting parents' communication of acceptable limits for alcohol consumption. PMID- 23934444 TI - A regulatory variant in CYP2E1 affects the risk of lung squamous cell carcinoma. AB - Cytochrome P450 2E1 (CYP2E1), an ethanol-inducible enzyme, has been shown to metabolically activate various carcinogens, which is critical for the development of cancers. It has been demonstrated that CYP2E1 polymorphisms alter the transcriptional activity. However, studies on the association between CYP2E1 1239G>C polymorphism and non-small cell lung cancer have reported conflicting results. Thus, the gain of the present study was to investigate whether CYP2E1 1239G>C polymorphism is associated with the development of non-small cell lung cancer in Chinese population. A case-control study was conducted in which CYP2E1 1239G>C polymorphism was analyzed in 526 Chinese patients with non-small cell lung cancer and 526 age-matched healthy controls by polymerase chain reaction restriction fragment length polymorphism. Odds ratios were estimated by multivariate logistic regression. A meta-analysis was conducted to evaluate the association of CYP2E1 -1239G>C polymorphism with the risk of lung cancer in Chinese population by calculating pooled odds ratio (OR). For CYP2E1 -1239G>C polymorphism, -1239C allele carriers (OR = 0.67; 95% confidence interval (CI) = 0.51-0.87; P = 0.002) were associated with a decreased risk of non-small cell lung cancer when compared with -1239GG homozygotes. In the group analyses by pathological types, for lung squamous cell carcinoma and other types, the ORs of the C allele carriers were 0.60 (95% CI = 0.41-0.88; P = 0.009) and 0.54 (95% CI = 0.30-0.99; P = 0.045). In the group analysis of smoking status, the OR for the 1239C allele-containing genotype was higher than that for -1239GG genotype (OR = 0.57; 95% CI = 0.40-0.81; P = 0.002) among smokers, but not among nonsmokers. Moreover, when the risk associated with CYP2E1 polymorphism was further evaluated within strata of <25 and >=25 pack-years smoked, this effect between susceptible genotypes and smoking was mostly evident among light smokers (<25 pack-years) with OR of 0.42 (95% CI 0.23-0.79), but not among heavy smokers with OR of 0.87 (95% CI 0.53-1.43). In the group analyses by TNM stage, there was no significant difference between CYP2E1 -1239G>C polymorphism and the risk of non-small cell lung cancer. Meta-analysis data also showed that the carriers of CYP2E1 -1239C allele had a protect effect on the risk of lung cancer in Chinese with overall OR of 0.77 (95% CI 0.66-0.90). CYP2E1 -1239G>C polymorphism was associated with a decreased risk of development of non-small cell lung cancer in Chinese patients. The association displays a manner of gene-environment interaction between this polymorphism and smoking status. PMID- 23934445 TI - Pravastatin slows the progression of heart failure by inhibiting the c-Jun N terminal kinase-mediated intrinsic apoptotic signaling pathway. AB - Tumor necrosis factor-alpha (TNF-alpha) and c-Jun N-terminal kinases (JNKs) are known to be associated with apoptosis and are important in cardiac remodeling. It remains to be determined whether statins inhibit cardiac remodeling through interfering with TNF-alpha-JNK-related signaling pathways. This study was designed to investigate the effect of pravastatin on the progression of hypertrophy to heart failure in transverse aortic constriction (TAC) and the associations with TNF-alpha-JNK signaling. Either pravastatin (5 or 20 mg/kg/day) or vehicle was orally administered to male C57BL/6J mice with TAC. Cardiac remodeling and left ventricular hemodynamics, as well as JNK-dependent apoptotic signals were analyzed 4 weeks following TAC. Neonatal rat cardiomyocytes were cultured to investigate the effect of pravastatin on TNF-alpha-induced JNK related apoptotic signals. Notably, pravastatin reduced the heart/body weight and lung/body weight ratios. In addition, a decrease of left ventricular (LV) echocardiographic dimensions, an increase of LV fractional shortening and diastolic index, a reduction of JNK activity, caspase-12 and Bax were observed in the pravastatin-treated groups. The TNF-alpha-induced phosphorylation of JNK and upregulation of caspase-12 and Bax in cultured cardiomyocytes was inhibited by pravastatin. These results indicated that pravastatin attenuates cardiac remodeling by inhibiting JNK-dependent pro-apoptotic signaling. PMID- 23934447 TI - WITHDRAWN:Pharmacokinetics and Pharmacodynamics of a Novel Amoxicillin/Sulbactam/Prednisolone Intramammary Infusion in Lactating Cows after Repeated Administrations. AB - Ahead of Print article withdrawn by publisher. PMID- 23934446 TI - Carcinosarcoma in a white Rhinoceros (Ceratotherium simum simum). AB - In Rhinocerotidae, there are very few reports of tumors and no reports of a mixed tumor. This paper reports the case of a male 33-year-old southern white rhinoceros. Grossly, there were two masses in the coelomic cavity and solid nodules in the liver. Histologically, all tumors had a biphasic pattern that consisted of malignant epithelial cells (cytokeratin- and E-cadherin-positive) and non-epithelial cells (vimentin-positive) with cartilage. In this case, the prostate could not be identified, and instead, the largest tumor mass was present at that site. Furthermore, since structures regarded as the prostate duct remained in this tumor, we considered that this tumor was very likely to be of prostate gland origin. This case is the first report of carcinosarcoma in Rhinocerotidae. PMID- 23934448 TI - Effects of fluoride on metamorphosis, thyroid and skeletal development in Bufo gargarizans tadpoles. AB - This study examined the effects of chronic fluoride exposure on metamorphosis, thyroid and skeletal development in tadpoles of Chinese Toad, Bufo gargarizans. The tadpoles were exposed to fluoride concentrations either at 0, 1, 5, 10, or at 50 mg L(-1) from Gosner stage 26 to Gosner stage 42. Body weight, total length and percentage of tadpoles reaching metamorphosis climax were recorded, and thyroid histological examinations were employed. In addition, mRNA expression of both deiodinase type 2 (D2) and deiodinase type 3 (D3) was analyzed by using RT PCR and skeletal systems were investigated by using double-staining methodology at stage 42. Results showed that total length and body weight were unaffected by fluoride exposure at all concentrations while metamorphosis was strongly inhibited only by 50 mg L(-1) fluoride. Histomorphological measurements showed the percentage of colloid depletion in thyroid gland increased significantly, while the average diameter of follicles was significantly shorter at 50 mg L(-1) concentration. In addition, fluoride at 5 mg L(-1) can stimulate bone mineralization, while fluoride at 50 mg L(-1) can retard deposition of calcium. In conclusion, our study suggests that 50 mg L(-1) fluoride could damage follicular cells in thyroid gland and induce a sharp reduction in thyroid hormone probably through the up-regulation of D3 mRNA expression, and these influences on thyroid system may delay metamorphosis as well as ossification in bone tissue by inhibiting calcium deposition. PMID- 23934450 TI - Alterations of sodium and potassium channels of RGCs in RCS rat with the development of retinal degeneration. AB - All know that retinitis pigmentosa (RP) is a group of hereditary retinal degenerative diseases characterized by progressive dysfunction of photoreceptors and associated with progressive cells loss; nevertheless, little is known about how rods and cones loss affects the surviving inner retinal neurons and networks. Retinal ganglion cells (RGCs) process and convey visual information from retina to visual centers in the brain. The healthy various ion channels determine the normal reception and projection of visual signals from RGCs. Previous work on the Royal College of Surgeons (RCS) rat, as a kind of classical RP animal model, indicated that, at late stages of retinal degeneration in RCS rat, RGCs were also morphologically and functionally affected. Here, retrograde labeling for RGCs with Fluorogold was performed to investigate the distribution, density, and morphological changes of RGCs during retinal degeneration. Then, patch clamp recording, western blot, and immunofluorescence staining were performed to study the channels of sodium and potassium properties of RGCs, so as to explore the molecular and proteinic basis for understanding the alterations of RGCs membrane properties and firing functions. We found that the resting membrane potential, input resistance, and capacitance of RGCs changed significantly at the late stage of retinal degeneration. Action potential could not be evoked in a part of RGCs. Inward sodium current and outward potassium current recording showed that sodium current was impaired severely but only slightly in potassium current. Expressions of sodium channel protein were impaired dramatically at the late stage of retinal degeneration. The results suggested that the density of RGCs decreased, process ramification impaired, and sodium ion channel proteins destructed, which led to the impairment of electrophysiological functions of RGCs and eventually resulted in the loss of visual function. PMID- 23934449 TI - Induction of Kruppel-like factor 4 expression in reactive astrocytes following ischemic injury in vitro and in vivo. AB - Kruppel-like factor 4 (KLF4) is a transcription factor with diverse and cell type specific functions and is associated with a variety of pathophysiological processes. Recently, it has been proposed that the regulation of KLF4 is critical to neuronal differentiation and that neural progenitors overexpressing KLF4 take on a glial identity. The present study aimed to determine whether KLF4 is involved in the astroglial reaction induced by ischemia-reperfusion injury in the brain. No specific KLF4 immunoreactivity was observed in resting astrocytes of the control hippocampus, but significant induction was detected in reactive astrocytes preferentially located in the CA1 and dentate hilar regions of the hippocampus following transient forebrain ischemia. Astroglial KLF4 expression was induced in the nuclei and cytoplasm within 3 days of ischemia and persisted for at least 4 weeks. This pattern was reproduced in an in vitro astrogliosis model of rat primary cortical astrocytes exposed to oxygen-glucose deprivation (OGD). Furthermore, immunoblot assay showed that nuclear and cytosolic extracts from cortical astrocytes subjected to OGD had significantly higher levels of KLF4 protein compared to normoxic extracts. Thus, our data demonstrate that KLF4 expression was induced in astroglia by ischemic injury both in vivo and in vitro, suggesting that KLF4 may act as a transcription factor linked to the regulation of the astroglial reaction following ischemic injury. PMID- 23934452 TI - Are we expecting too much from the diffusion-weighted MRI? PMID- 23934451 TI - Loss of function of Slc20a2 associated with familial idiopathic Basal Ganglia calcification in humans causes brain calcifications in mice. AB - Familial idiopathic basal ganglia calcification (FIBGC) is a neurodegenerative disorder with neuropsychiatric and motor symptoms. Deleterious mutations in SLC20A2, encoding the type III sodium-dependent phosphate transporter 2 (PiT2), were recently linked to FIBGC in almost 50% of the families reported worldwide. Here, we show that knockout of Slc20a2 in mice causes calcifications in the thalamus, basal ganglia, and cortex, demonstrating that reduced PiT2 expression alone can cause brain calcifications. PMID- 23934453 TI - Histopathologic evaluation of anti-ulcerogenic effect of montelukast in indomethacin-induced experimental ulcer model. AB - BACKGROUND/AIMS: The effects of anti-ulcerogenic drugs are dependent on the increase in prostaglandin production and reduction in leukotriene production in the gastric mucosa. Montelukast is an anti-asthmatic drug, a selective reversible cysteinyl leukotriene D4 receptor antagonist. In this study, we aimed to evaluate the anti-ulcerogenic effect of montelukast and to investigate the relationship between its anti-ulcerogenic effect and polymorphonuclear leukocyte infiltration in the gastric tissues. MATERIALS AND METHODS: Male Sprague-Dawley rats were separated into five groups. Distilled water (control group), famotidine (40 mg/kg), and montelukast (5, 10 and 20 mg/kg) were given orally (gavage). Thirty minutes later, indomethacin (25 mg/kg) was administered to all the groups. Six hours later, the animals were sacrificed by decapitation. The ulcer indexes for each stomach and the ulcer inhibition rates for each group were calculated, and the stomachs were later evaluated histopathologically (polymorphonuclear leukocyte infiltration). RESULTS: Ulcer inhibition rates were as follows: famotidine 96.14% and montelukast 59.96%, 72.65% and 76.97% (5, 10 and 20 mg/kg, respectively). Montelukast (10 and 20 mg/kg) showed effects similar to those of famotidine histopathologically. CONCLUSIONS: In this study, it was observed that there was a relationship between the anti-ulcerogenic effect of montelukast and polymorphonuclear leukocyte infiltration in the gastric mucosa, and montelukast behaved as an anti-ulcerogenic drug both macroscopically and microscopically. PMID- 23934454 TI - Relationship between continuous use of low-dose enteric-coated aspirin and gastrointestinal injuries in patients with gastrointestinal hemorrhage. AB - BACKGROUND/AIMS: Gastrointestinal disorders are important side effects of aspirin therapy, even if the low-dose enteric-coated form is administered. The aim of the current study was to present the upper and lower endoscopic features of patients with gastrointestinal hemorrhage using low-dose enteric-coated aspirin. MATERIALS AND METHODS: This prospective study was conducted among 633 consecutive patients with gastrointestinal hemorrhage who admitted to our tertiary referral hospital for endoscopy assessment. Patients were divided into two groups as low-dose aspirin users (n=168) and non-aspirin users (n=495). Aspirin users included those who were taking 80-100 mg of enteric-coated aspirin per day. RESULTS: Ulcer lesions were found in 78 patients in the aspirin user group and in 113 patients in the control group. Prevalence of duodenal ulcer was statistically similar between the two groups; however, gastric ulcer was seen more in the aspirin-user group. The use of low-dose aspirin could strongly predict gastric ulcers in the patients examined by endoscopy (p<0.001). Overall prevalence of peptic ulcer disease in those with confirmed Helicobacter pylori infection was significantly higher than in non-infected ones (p<0.001). The presence of this infection was strongly associated with peptic ulcer disease in the aspirin-user group (p<0.001). Multivariable analysis also demonstrated that the use of aspirin had a main triggering effect on short-term mortality following gastrointestinal endoscopy (p=0.003). CONCLUSIONS: Low-dose enteric-coated aspirin causes significant gastric endoscopic lesions and even predicts mortality due to progression of gastrointestinal disorders. PMID- 23934455 TI - Expression and significance of IGF-2, PCNA, MMP-7, and alpha-actin in gastric carcinoma with Lauren classification. AB - BACKGROUND/AIMS: By detecting the expression and distribution of insulin-like growth factor-2, proliferating cell nuclear antigen, and matrix metalloproteinase 7 in cancer cells and the expression of alpha-actin in interstitial myofibroblasts, we studied their differences and their relationship in intestinal type and diffuse type gastric cancer with Lauren classification. MATERIALS AND METHODS: Clinical and pathological data of 50 patients with gastric adenocarcinoma who underwent primary surgical resection between 2003 and 2008 in Qianfoshan Hospital were collected. The cancer was classified as intestinal or diffuse type with Lauren classification. Immunohistochemical technique was used to detect the protein expression of insulin-like growth factor-2, proliferating cell nuclear antigen, matrix metalloproteinase-7, and alpha-actin in both gastric cancer tissue and normal gastric mucosa. RESULTS: The expression of insulin-like growth factor-2, proliferating cell nuclear antigen, matrix metalloproteinase-7, and alpha-actin in the gastric tissue was significantly higher than in the normal gastric mucosa. Insulin-like growth factor-2 was mainly expressed in the nucleus in diffuse gastric cancer and in the cytoplasm in intestinal type. The expression of insulin-like growth factor-2 in the nucleus was correlated with depth of tumor invasion, lymph node metastasis and staging. Proliferating cell nuclear antigen and matrix metalloproteinase-7 showed higher expression in diffuse than in intestinal type gastric cancer. The overexpression of proliferating cell nuclear antigen was relevant to lymph node metastasis in gastric cancer. The overexpression of matrix metalloproteinase-7 was relevant to invasion, lymph node metastasis, distant metastasis, and staging in gastric cancer. There was no significant difference in alpha-actin expression between the intestinal type and diffuse type gastric cancer. The overexpression of alpha-actin was relevant to cancer invasion and lymph node metastasis. CONCLUSIONS: The expression patterns of insulin-like growth factor-2 and the expression intensity of proliferating cell nuclear antigen and matrix metalloproteinase-7 were significantly different between diffuse type and intestinal type gastric cancer cells, but the expression pattern and intensity of the interstitial myofibroblast marker showed no significant difference. The clinical pathology distinction between intestinal type and diffuse type gastric cancer may be due mainly to the change in the genetic structure and the phenotype of epithelial cells, and interstitial myofibroblasts and cancer cells jointly promote the invasion and metastasis of gastric cancer. PMID- 23934456 TI - Pneumonia and mortality after percutaneous endoscopic gastrostomy insertion. AB - BACKGROUND/AIMS: Percutaneous endoscopic gastrostomy feeding provides enteral nutrition to patients with neurological dysphagia. Thirty-day mortality rates of 4-26% have been reported, with pneumonia being the common cause post-percutaneous endoscopic gastrostomy insertion. MATERIALS AND METHODS: This retrospective analysis of percutaneous endoscopic gastrostomy tube insertions in Malta (January 2008 - June 2010) compares the incidence of pneumonia in patients fed through a nasogastric tube versus in those fed via a percutaneous endoscopic gastrostomy tube. We analyzed the indications, poor prognostic factors and mortality for percutaneous endoscopic gastrostomy insertion. RESULTS: Ninety-seven patients underwent percutaneous endoscopic gastrostomy insertion. Fifty-four patients received nasogastric feeds before percutaneous endoscopic gastrostomy feeds. Patients on nasogastric feeds developed 32 episodes of pneumonia over a total of 7884 days of feeds (1 every 246 days). Patients with percutaneous endoscopic gastrostomy feeds after a period of nasogastric feeds developed 48 pneumonia episodes over 36,238 days (1 every 755 days). Patients with percutaneous endoscopic gastrostomy feeds without previous nasogastric feeds developed 28 pneumonia episodes over 23,983 days (1 every 856 days), and this was statistically significant (chi 2 test p value <0.005). Forty-seven patients had died at the time of data collection, with 29 patients dying from pneumonia. One week mortality was 3%, 30-day mortality was 8% and 1-year mortality was 39%. All patients dying within the first week and 50% of those dying within 30 days of the procedure died following pneumonia. CONCLUSIONS: There was a statistically significant decrease in the number of pneumonia episodes among patients receiving percutaneous endoscopic gastrostomy feeds versus nasogastric feeds. However, pneumonia is still the major cause of death among percutaneous endoscopic gastrostomy patients. PMID- 23934457 TI - Decrease in gastric cancer susceptibility by MTHFR C677T polymorphism in Ardabil Province, Iran. AB - BACKGROUND/AIMS: Gastric cancer, as the fourth most frequent malignancy worldwide, has the highest rate among cancer-related disorders in Ardabil province, located in North-West Iran. Methylene tetrahydrofolate reductase is one of the cancer susceptibility genes with considerable polymorphisms. Methylene tetrahydrofolate reductase C677T leads to a decrease of about 30% in its product activity and is reported to have an effect on cancer susceptibility. MATERIALS AND METHODS: Methylene tetrahydrofolate reductase C677T genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism on peripheral blood DNA from 76 gastric cancer patients and 91 healthy controls. The statistical significance was calculated by logistic regression analysis. RESULTS: The mean age was 64.2+/-11.1 and 62.1+/-9.8 years for cases and controls, respectively. Among tumors, 35.5% were diffuse type and others were intestinal. The frequency of genotypes was 61.8%, 32.9%, and 5.3% among cases and 45.1%, 50.6%, and 4.4% among controls for Ala/Ala, Ala/Val, and Val/Val, respectively. CT heterozygotes had lower susceptibility to gastric cancer (p=0.02). This relationship of significance was detected considering gender and age. CONCLUSIONS: It was found that T allele has a protective association with age in the Ardabil province. PMID- 23934458 TI - Prevalence of celiac disease in patients with type 1 diabetes mellitus in the south of Iran. AB - BACKGROUND/AIMS: Celiac disease is a chronic enteropathy caused by hypersensitivity to gluten. An increased prevalence of celiac disease has been found in children with diabetes mellitus type 1. The large differences in the frequency of celiac disease in different countries show a great regional variability. Our aim was to detect the prevalence of celiac disease in diabetes mellitus type 1 children among southern Iranians. MATERIALS AND METHODS: A prospective study was conducted on 83 diabetes mellitus type 1 children from the south of Iran. They were tested for the presence of anti-tissue transglutaminase immunoglobulin A antibody and total immunoglobulin A level. The patients testing immunoglobulin A anti-tissue transglutaminase-positive were offered small bowel biopsy. RESULTS: Eighty-three children with diabetes mellitus type 1 (49 females, 34 males) aged 10.38+/-4.7 years were enrolled. None of the patients was immunoglobulin A deficient. Twelve diabetic children had a high titer of anti tissue transglutaminase immunoglobulin A (14.4%). In four patients, biopsy was in favor of celiac disease (4.8%). CONCLUSIONS: Our study showed that the prevalence of celiac disease in diabetes mellitus type 1 children in Iran is more than in America and Europe but similar to that observed in Turkey. The age of the patient and duration of disease had an effect on this prevalence, and more studies should be done to determine the effects of ethnic, genetic and environmental factors such as diet to identify the reasons for these differences. PMID- 23934459 TI - The preliminary experience in simultaneous treatment of rectal cancer and synchronous liver metastases with laparoscopy. AB - BACKGROUND/AIMS: There is no consensus for laparoscopy first in patients with rectal cancer and synchronous liver metastases, whose metastases are confined to the liver. This study aimed to evaluate its indications for one-stage surgery in laparoscopy. MATERIALS AND METHODS: Eighteen patients with rectal cancer and synchronous liver metastases, who had undergone laparoscopic colorectal resection and simultaneous treatment for liver metastases, were retrospectively reviewed. RESULTS: Concomitant with laparoscopic colorectal resection, eight patients received liver resection simultaneously; 10 patients underwent a variety of down staging management including local ablation, right hepatic portal vein ligation, and implantation of chemotherapy pumps into the hepatic artery. The colo anal/rectal anastomoses were performed with a stapler or "pull-though" mode though the anus. Three patients underwent two-stage liver resection following tumor down-staging. Median survival time was 22.3 months. CONCLUSIONS: Laparoscopy approach for rectal cancer and synchronous liver metastases is feasible in selected patients. Colon pull-through anastomosis was a potential method to avoid abdominal incision and decrease the risk of anastomotic leakage. It is worth further investigation regarding its advantages over traditional modalities with a prospective randomized controlled study. PMID- 23934460 TI - PPAR-alpha agonist treatment increases trefoil factor family-3 expression and attenuates apoptosis in the liver tissue of bile duct-ligated rats. AB - BACKGROUND/AIMS: Peroxisome proliferators-activated receptor alpha activation modulates cholesterol metabolism and suppresses bile acid synthesis. The trefoil factor family comprises mucin-associated proteins that increase the viscosity of mucins and help protect epithelial linings from insults. We evaluated the effect of short-term administration of fenofibrate, a peroxisome proliferators activated receptor alpha agonist, on trefoil factor family-3 expression, degree of apoptosis, generation of free radicals, and levels of proinflammatory cytokines in the liver tissue of bile duct-ligated rats. MATERIALS AND METHODS: Forty male Wistar rats were randomly divided into four groups: 1 = sham operated, 2 = bile duct ligation, 3 = bile duct-ligated + vehicle (gum Arabic), and 4 = bile duct ligated + fenofibrate (100 mg/kg/day). All rats were sacrificed on the 7 th day after obtaining blood samples and liver tissue. Liver function tests, tumor necrosis factor-alpha and interleukin 1 beta in serum, and trefoil factor family 3 mRNA expression, degree of apoptosis (TUNEL) and tissue malondialdehyde (malondialdehyde, end-product of lipid peroxidation by reactive oxygen species) in liver tissue were evaluated. RESULTS: Fenofibrate administration significantly reduced serum total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and tumor necrosis factor-alpha and interleukin-1beta levels. Apoptosis and malondialdehyde were significantly reduced in the fenofibrate group. Trefoil factor family-3 expression increased with fenofibrate treatment in bile duct-ligated rats. CONCLUSIONS: The peroxisome proliferators-activated receptor alpha agonist fenofibrate significantly increased trefoil factor family-3 expression and decreased apoptosis and lipid peroxidation in the liver and attenuated serum levels of proinflammatory cytokines in bile duct-ligated rats. Further studies are needed to determine the protective role of fenofibrate in human cholestatic disorders. PMID- 23934461 TI - Transarterial chemoembolization for treatment of hepatocellular carcinoma: A single center experience. AB - BACKGROUND/AIMS: We aimed to determine the effect of transarterial chemoembolization treatment on survival in patients with hepatocellular carcinoma and to investigate the efficacy and tolerability of two different transarterial chemoembolization procedures, conventional transarterial chemoembolization and drug-eluting beads, in these patients. MATERIALS AND METHODS: A total of 40 patients with hepatocellular carcinoma treated with transarterial chemoembolization between January 2007 and March 2011 were included. Thirty-seven patients had Child-Pugh class A and the remaining 3 had class B. Intra-arterial administration of doxorubicin with lipiodol-based conventional transarterial chemoembolization or drug-eluting beads-transarterial chemoembolization was performed. Eighty sessions were performed with a median of 2 sessions. Sixteen patients were treated with conventional transarterial chemoembolization and 11 with drug-eluting beads-based transarterial chemoembolization, and 13 were treated with both treatment procedures in separate sessions. Primary outcome was defined as patient survival after treatment. RESULTS: The median follow-up was 19 months. The median overall survival of patients was 23.2 months. The survival of patients with Child-Pugh class A was significantly better than that of patients with class B (24 vs 6 months, p=0.004). No statistically significant difference in survival was observed between conventional transarterial chemoembolization and drug-eluting beads-based transarterial chemoembolization treatments (p>0.05). Baseline low serum albumin level (p=0.003) and the presence of portal vein thrombosis (p=0.011) negatively affected patient survival. Side effects of conventional transarterial chemoembolization and drug-eluting beads-based transarterial chemoembolization were similar. CONCLUSIONS: Based on the results of this study and in comparison with the findings in the literature, transarterial chemoembolization treatment was seen to improve overall survival and provide better outcome in selected patients with hepatocellular carcinoma. No differences in survival or side effects were observed between the two transarterial chemoembolization treatment modalities. PMID- 23934462 TI - The role of diffusion-weighted examination in non-polyploid gallbladder malignancies: A preliminary study. AB - BACKGROUND/AIMS: The aim of the present study was to investigate the diagnostic value of diffusion-weighted magnetic resonance imaging in gallbladder malignancies, which are typically diagnosed during surgery because the radiologic findings are similar to those of cholecystitis-caused diffuse thickening of the gallbladder wall. MATERIALS AND METHODS: Seven patients with gallbladder malignancies and nine patients with benign gallbladder pathology were included in this study. In one of the patients with a malignancy, a lesion was determined on the porcelain gallbladder; in another patient, acute myeloblastic leukemia had infiltrated the gallbladder, causing the diffuse wall thickening. Five subjects had a primary malignant gallbladder. The view of the bladder wall was evaluated visually in increasing b values. Apparent diffusion coefficient measurements were obtained from at least three sites of the bladder wall in each patient, and the results of the measurements were analyzed after comparing the malignant and benign groups. In the malignant group, the results of the radiological outcomes were compared with histological examinations. In the benign group, cholecystitis was diagnosed by observing normalization of the bladder wall thickening via surgery or medical treatment. RESULTS: There was a statistically significant difference in apparent diffusion coefficient levels between the malignant group, which caused diffuse thickening of the gallbladder wall, and the benign group (Student t test, p<0.01). CONCLUSIONS: According to this preliminary study, observation of distinct brightness of the gallbladder wall in diffusion-weighted examination with a high b value is a significant finding in terms of diffuse gallbladder malignancy. A value below the 0.86 mm 2 /sn cut-off was significant for malignancy in apparent diffusion coefficient mapping. PMID- 23934463 TI - The value of diffusion-weighted magnetic resonance imaging in the differential diagnosis in diffuse bowel wall thickening. AB - BACKGROUND/AIMS: We aimed to investigate the value of diffusion-weighted magnetic resonance imaging in the differentiation of benign-malignant diffuse bowel wall thickening (scirrhous colon carcinoma) and to discuss the diagnostic importance and potential use of apparent diffusion coefficient measurements. MATERIALS AND METHODS: A total of 41 patients (32 males, 9 females; mean age, 57 years) with diffuse bowel wall thickening diagnosed on computed tomography were included in this study. The magnetic resonance imaging was performed on a 1.5 T scanner (Siemens-Espree). Changes in the signal intensity of the lesions were determined by their appearance in images at b800 s/mm 2 , and apparent diffusion coefficient values were also calculated. Lesions were classified in two groups according to the presence of hyperintensity on b800 images and results of endoscopic biopsies. The differences in mean apparent diffusion coefficient values between the two groups were compared with the Mann-Whitney U test, and threshold values were determined with receiver operating characteristic curve analysis. RESULTS: The difference between the mean apparent diffusion coefficient values of benign and malignant groups was statistically significant, and the apparent diffusion coefficient values of benign lesions were significantly higher than of malignant lesions (p<0.05). By using a cut-off value of 1.21 x 10-3mm2 /s, apparent diffusion coefficient had a sensitivity of 100%, specificity of 87.3%, and accuracy of 89.3% in the discrimination of malignant colorectal pathologies. With the visual assessment of the diffusion weighted images and the measurement of apparent diffusion coefficient values, malignant and benign lesions could be differentiated, with 100% sensitivity, 89.2% specificity, and 90.4% accuracy. Although some benign lesions were interpreted as malignant,no malignant lesion was determined as benign in the visual assessment. CONCLUSIONS: Diffusion weighted magnetic resonance imaging and apparent diffusion coefficient values together can successfully differentiate malignant from benign diffuse bowel wall thickening. PMID- 23934464 TI - Endoscopic submucosal dissection for early esophageal cancer associated with achalasia. AB - Esophageal achalasia is often associated with esophageal cancer. However, in many cases, esophageal cancer tends to be found in an advanced stage, with a poor prognosis. However, early-stage cancer was detected recently due to the advances in endoscopic instruments. In those cases, it is important to facilitate successful treatment by endoscopic submucosal dissection. We analyzed a total of six cases of esophageal cancer with achalasia in four patients treated with endoscopic submucosal dissection. Three features common to all six cases had a bearing on how endoscopic submucosal dissection was performed. First, esophageal dilatation and diminished peristalsis facilitated the performance of successful endoscopic submucosal dissection. Second, the esophageal wall was thickened, primarily with muscular tissue. Third, the submucosal layer contained abundant blood vessels that made it difficult to minimize bleeding during dissection. Those findings suggest that endoscopic submucosal dissection for early esophageal cancer associated with achalasia is a safe and potentially curative procedure. It is important, therefore, to detect esophageal cancer early. PMID- 23934465 TI - Primary liposarcoma of the stomach. AB - Sarcomas represent less than 1% of adult solid malignancies and are rarely seen in the gastrointestinal tract. Here, we report a 59-year-old female with a well differentiated liposarcoma of the stomach. This is the first case in the literature in which endoscopic ultrasound proved to be a diagnostic tool for gastric liposarcoma. PMID- 23934466 TI - Cystic duct cyst: Report of one case. AB - Cystic duct cyst is an extremely rare anomaly. The classification developed by Tadoni is used for the other bile duct anomalies, but cystic duct cysts are excluded from this classification. In this case report, acute pancreatitis was diagnosed based on the clinical and laboratory findings of the patient, who presented with a complaint of nonspecific abdominal pain. Cystic duct cyst was determined with magnetic resonance cholangiopancreatography performed after determination of a cystic lesion on the neck of the gallbladder by abdominal ultrasonography. Cystic duct cyst is an extremely rare anomaly, and advanced examination is required for the diagnosis. PMID- 23934467 TI - Groove (paraduodenal) pancreatitis: Report of two cases. AB - "Groove" pancreatitis is a rare segmental form of chronic pancreatitis that involves the area located between the common bile duct, head of the pancreas and duodenum. It is more common in middle-aged males who have a history of alcohol abuse. The differential diagnosis varies from anatomic variants to malignancies. The most relevant differential diagnosis of groove pancreatitis is adenocarcinoma of the head of the pancreas. Most of the cases were diagnosed after pancreatic resection. Thus, the correct diagnosis of this rarely seen disease is very important to avoid unnecessary tests or procedures and to determine the definitive treatment. PMID- 23934468 TI - Hepatic hydrothorax in the absence of ascites in a child with autoimmune hepatitis: Successful management with octreotide and pleurodesis. AB - Hepatic hydrothorax is a rare complication of liver cirrhosis and portal hypertension. It carries a diagnostic and therapeutic difficulty especially if occurring in the absence of ascites. We report a nine-year-old child with autoimmune hepatitis type 1, who presented with a right-sided hepatic hydrothorax in the absence of ascites. The patient was treated successfully with diuretics, octreotide and pleurodesis together with immunosuppressive therapy for autoimmune hepatitis. There was no recurrence of effusion after a long follow-up duration. In conclusion, hepatic hydrothorax should be considered in the differential diagnosis of pleural effusion occurring in children with cirrhotic liver, whether associated with ascites or not. Octreotide as a splanchnic vasoconstrictor can be used in establishing the diagnosis and in the treatment of hepatic hydrothorax. The need for liver transplantation in such patients may be avoided when the liver disease can be treated specifically. PMID- 23934469 TI - Very rare coexistence of hypertrophic cardiomyopathy and achalasia. PMID- 23934470 TI - A high chromogranin A: Is it always a tumor? PMID- 23934471 TI - Mesenteric Meckel's diverticulum. PMID- 23934472 TI - Mesenteric localization of Meckel's diverticulum. PMID- 23934473 TI - A case of intestinal obstruction due to ileocecal tuberculosis. PMID- 23934474 TI - Cirrhosis and intestinal B-cell lymphoma: two entities that are rarely associated with celiac disease. PMID- 23934475 TI - Lymphoma-like presentation of hepatocellular carcinoma. PMID- 23934476 TI - Heat illness: predictors of hospital admissions among emergency department visits Georgia, 2002-2008. AB - Heat-related illnesses (HRI) are the most frequent cause of environmental exposure-related injury treated in US emergency departments (ED). While most individuals with HRI evaluated in EDs are discharged to home, understanding predictors of individuals hospitalized with HRI may help public health practitioners and medical providers identify high risk groups who would benefit from educational outreach. We analyzed data collected by the Georgia Department of Public Health, Office of Health Indicators for Planning, regarding ED and hospital discharges for HRI, as identified by ICD-9 codes, between 2002 and 2008 to determine characteristics of individuals receiving care in EDs. Temperature data from CDC's Environmental Public Health Tracking Network were linked to the dataset to determine if ED visits occurred during an extreme heat event (EHE). A multivariable logistic regression model was developed to determine characteristics predicting hospitalization versus ED discharge using demographic characteristics, comorbid conditions, socioeconomic status, the public health district of residence, and the presence of an EHE. Men represented the majority of ED visits (75 %) and hospitalizations (78 %). In the multivariable model, the odds of admission versus ED discharge with an associated HRI increased with age among both men and women, and odds were higher among residents of specific public health districts, particularly in the southern part of the state. Educational efforts targeting the specific risk groups identified by this study may help reduce the burden of hospitalization due to HRI in the state of Georgia. PMID- 23934477 TI - Short tandem repeat analysis of host's hepatocellular carcinoma by laser microdissection confirms the validity of safety procedures in liver transplantation: a forensic case. AB - BACKGROUND: To limit the chimerism typical of transplanted organs, which constantly reveals mixed profiles, laser microdissection (LCM) has been hypothesized as a valid tool in comparison with manual dissection. CASE REPORT: A 42-year-old man with end-stage HBV/HDV liver cirrhosis and single hepatocellular carcinoma (HCC) underwent liver transplantation. Four months later hepatic nodules were diagnosed. The histological investigation showed an HCC. Despite therapy, the man died as a result of metastatic carcinoma 9 months later. On behalf of the public prosecutor, we performed short tandem repeat analysis on the hepatic nodules to determine whether the carcinoma had originated from the transplanted liver. CONCLUSIONS: The manually dissected samples revealed a high degree of chimerism that did not allow a clear diagnosis. Instead, the detected chimerism was very low in the microdissected samples, where the tumor origin was clearly diagnosable as a recurrence of the recipient's primitive HCC. Accordingly, the application of LCM improved the quality of the results leading to an exclusion of medical liability profiles, confirming the high quality safety procedure of the Italian system in solid organ transplantation, and showing at the same time how useful this technique may be in selected forensic cases. PMID- 23934478 TI - Gastrointestinal manifestations of Behcet's disease in Japan: a study of 43 patients. AB - We analyzed the clinical gastrointestinal (GI) characteristics of Behcet's disease (BD) patients in Japan. We retrospectively reviewed the clinical charts of 412 patients who fulfilled the 1987 Japanese criteria for BD and were treated in two university hospitals from July 1991 to December 2007. Forty-three patients (10.4 %) had BD-related GI lesions, which were shown by imaging examinations. Median age at BD diagnosis and onset of GI episodes were 29.6 and 31.0 years, respectively. The patients suffered from abdominal pain (30/43) and GI bleeding (18/43), while they had lower frequency of eye involvement and higher incidence of arthritis and vascular involvement than BD patients without GI lesions. The lesions were prevalent in the ileum (32/43) followed by cecum (21/43) and esophagus (9/43). The patients were treated with mesalazine and sulfasalazine (41/43), corticosteroids (32/43), immunosuppressants (13/43), and infliximab for 7 patients having refractory lesions, while 10 patients had surgical operation. Two patients died due to non-GI events during the observation. The diagnosis of BD was often difficult because of lack of eye involvement. Surgery is required for some patients in spite of intensive immunosuppressive therapies. Appropriate use of anti-TNF agents may be promising for the GI involvement. PMID- 23934480 TI - [Congratulations to Prof. Dr. Jurgen Scholmerich on the occasion of his 65th birthday]. PMID- 23934479 TI - [Tumor-induced hypercalcemia]. AB - Hypercalcemia is in many cases a symptom of advanced stage malignant diseases due to increased resorption and reduced secretion. A slightly increased hypercalcemia is mostly asymptomatic but high calcium levels are associated with neurological, gastrointestinal, cardiac and renal symptoms. Important diagnostic tools are the determination of serum albumin and ionized calcium levels. Therapeutic intervention depends on the clinical symptoms as well as calcium levels. Furthermore, increase over time and duration of hypercalcemia has to be taken into account. The principles of treatment are sufficient fluid replacement and maintaining adequate diuresis. In addition, calcitonin, bisphosphonates and steroids are effective and widely used to decrease plasma calcium levels. PMID- 23934481 TI - Bacillus oceani sp. nov., a new slightly halophilic bacterium, isolated from a deep sea sediment environment. AB - A strictly aerobic, Gram-stain positive, slightly halophilic strain, designated SCSIO 04524(T), was isolated from a deep sea sediment sample collected from the northern South China Sea at a depth of 3415 m. The isolate slightly embedded into the medium after 72 h incubation at 30 degrees C. Growth was found to occur on media with 0-10 % NaCl but extremely weak growth occurred without supplying NaCl. The predominant menaquinone was determined to be MK-7. The major cellular fatty acid identified was iso-C15:0. The diagnostic polar lipids were determined to be diphosphatidylglycerol, phosphatidyl methylethanolamine, phosphatidylethanolamine and phosphatidylglycerol. The genomic DNA G+C content was determined to be 38 mol%. 16S rRNA gene sequences analysis showed that this strain had the highest similarities with Bacillus carboniphilus JCM 9731(T) (94.7 %) and Bacillus endophyticus 2DT(T) (94.3 %). Phylogenetic analysis revealed that strain SCSIO 04524(T) formed a distinct lineage with Bacillus chungangensis CAU 348(T) and B. carboniphilus JCM 9731(T). Physiological characteristics including utilization of sole nitrogen and carbon sources, and chemotaxonomic properties of cellular fatty acids and polar lipids could readily distinguish strain SCSIO 04524(T) from its most closely related species. Based on this polyphasic taxonomic data, a new species, Bacillus oceani sp. nov., is proposed, with the type strain SCSIO 04524(T) (=DSM 26213(T) = KCTC 33077(T)). PMID- 23934482 TI - NF-kappaB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype. AB - Patients with triple-negative breast cancer display the highest rates of early relapse of all patients with breast cancer. The basal-like subtype, a subgroup of triple-negative breast cancer, exhibits high levels of constitutively active NF kappaB signalling. Here we show that NF-kappaB activation, induced by inflammatory cytokines or by epigenetically dysregulated NIK expression, cell autonomously upregulates JAG1 expression in non-cancer stem cells. This upregulation stimulates NOTCH signalling in cancer stem cells in trans, leading to an expansion of cancer stem cell populations. Among breast cancers, the NF kappaB-dependent induction of JAG1 and the NOTCH-dependent expansion of the cancer stem cell population occur only in the basal-like subtype. Collectively, our results indicate that NF-kappaB has a non-cell-autonomous role in regulating cancer stem cell populations by forming intratumoural microenvironments composed of JAG1-expressing non-cancer stem cells with a basal-like subtype. PMID- 23934483 TI - Surface plasmon resonance induced excellent solar control for VO2@SiO2 nanorods based thermochromic foils. AB - Transition-metal oxide nanocrystals are novel candidates for being used as the hosts of localized surface plasmon resonance because they exhibit fascinating properties arising from the unique characteristics of their outer-d valence electrons. VO2(M) nanocrystal is well-known due to its reversible metal-insulator transition (MIT) temperature near room temperature (~68 degrees C) corresponding to the appearance/disappearance of localized surface plasmon resonance across the MIT. In this study, a microemulsion-based method was introduced to synthesize VO2(M)@SiO2 nanoparticles which were applied to prepare VO2-based thermochromic foils owing to a strong and tunable surface plasmon resonance in the metallic state. The optical transmittance spectra demonstrates that the employment of surface plasmon resonance in VO2-based thermochromic foils greatly improves their solar regulating efficiency up to 18.54%, and provides an unprecedented insight in optimizing VO2-based thermochromic windows for solar control. PMID- 23934484 TI - Mercury methylation by the methanogen Methanospirillum hungatei. AB - Methylmercury (MeHg), a neurotoxic substance that accumulates in aquatic food chains and poses a risk to human health, is synthesized by anaerobic microorganisms in the environment. To date, mercury (Hg) methylation has been attributed to sulfate- and iron-reducing bacteria (SRB and IRB, respectively). Here we report that a methanogen, Methanospirillum hungatei JF-1, methylated Hg in a sulfide-free medium at comparable rates, but with higher yields, than those observed for some SRB and IRB. Phylogenetic analyses showed that the concatenated orthologs of the Hg methylation proteins HgcA and HgcB from M. hungatei are closely related to those from known SRB and IRB methylators and that they cluster together with proteins from eight other methanogens, suggesting that these methanogens may also methylate Hg. Because all nine methanogens with HgcA and HgcB orthologs belong to the class Methanomicrobia, constituting the late evolving methanogenic lineage, methanogenic Hg methylation could not be considered an ancient metabolic trait. Our results identify methanogens as a new guild of Hg-methylating microbes with a potentially important role in mineral poor (sulfate- and iron-limited) anoxic freshwater environments. PMID- 23934485 TI - The periplasmic HrpB1 protein from Xanthomonas spp. binds to peptidoglycan and to components of the type III secretion system. AB - The plant-pathogenic bacterium Xanthomonas campestris pv. vesicatoria employs a type III secretion (T3S) system to translocate bacterial effector proteins into eukaryotic host cells. The membrane-spanning secretion apparatus consists of 11 core components and several associated proteins with yet unknown functions. In this study, we analyzed the role of HrpB1, which was previously shown to be essential for T3S and the formation of the extracellular T3S pilus. We provide experimental evidence that HrpB1 localizes to the bacterial periplasm and binds to peptidoglycan, which is in agreement with its predicted structural similarity to the putative peptidoglycan-binding domain of the lytic transglycosylase Slt70 from Escherichia coli. Interaction studies revealed that HrpB1 forms protein complexes and binds to T3S system components, including the inner membrane protein HrcD, the secretin HrcC, the pilus protein HrpE, and the putative inner rod protein HrpB2. The analysis of deletion and point mutant derivatives of HrpB1 led to the identification of amino acid residues that contribute to the interaction of HrpB1 with itself and HrcD and/or to protein function. The finding that HrpB1 and HrpB2 colocalize to the periplasm and both interact with HrcD suggests that they are part of a periplasmic substructure of the T3S system. PMID- 23934486 TI - Detection of Escherichia coli O157 by peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) and comparison to a standard culture method. AB - Despite the emergence of non-O157 Shiga toxin-producing Escherichia coli (STEC) infections, E. coli serotype O157 is still the most commonly identified STEC in the world. It causes high morbidity and mortality and has been responsible for a number of outbreaks in many parts of the world. Various methods have been developed to detect this particular serotype, but standard bacteriological methods remain the gold standard. Here, we propose a new peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) method for the rapid detection of E. coli O157. Testing on 54 representative strains showed that the PNA probe is highly sensitive and specific to E. coli O157. The method then was optimized for detection in food samples. Ground beef and unpasteurized milk samples were artificially contaminated with E. coli O157 concentrations ranging from 1 * 10( 2) to 1 * 10(2) CFU per 25 g or ml of food. Samples were then preenriched and analyzed by both the traditional bacteriological method (ISO 16654:2001) and PNA FISH. The PNA-FISH method performed well in both types of food matrices with a detection limit of 1 CFU/25 g or ml of food samples. Tests on 60 food samples have shown a specificity value of 100% (95% confidence interval [CI], 82.83 to 100), a sensitivity of 97.22% (95% CI, 83.79 to 99.85%), and an accuracy of 98.33% (CI 95%, 83.41 to 99.91%). Results indicate that PNA-FISH performed as well as the traditional culture methods and can reduce the diagnosis time to 1 day. PMID- 23934488 TI - Monitoring the metabolic state of fungal hyphae and the presence of melanin by nonlinear spectral imaging. AB - Label-free nonlinear spectral imaging microscopy (NLSM) records two-photon excited fluorescence emission spectra of endogenous fluorophores within the specimen. Here, NLSM is introduced as a novel, minimally invasive method to analyze the metabolic state of fungal hyphae by monitoring the autofluorescence of NAD(P)H and flavin adenine dinucleotide (FAD). Moreover, the presence of melanin was analyzed by NLSM. NAD(P)H, FAD, and melanin were used as biomarkers for freshness of mushrooms of Agaricus bisporus (white button mushroom) that had been stored at 4 degrees C for 0 to 17 days. During this period, the mushrooms did not show changes in morphology or color detectable by eye. In contrast, FAD/NAD(P)H and melanin/NAD(P)H ratios increased over time. For instance, these ratios increased from 0.92 to 2.02 and from 0.76 to 1.53, respectively, at the surface of mushroom caps that had been harvested by cutting the stem. These ratios were lower under the skin than at the surface of fresh mushrooms (0.78 versus 0.92 and 0.41 versus 0.76, respectively), indicative of higher metabolism and lower pigment formation within the fruiting body. Signals were different not only between tissues of the mushroom but also between neighboring hyphae. These data show that NLSM can be used to determine the freshness of mushrooms and to monitor the postharvest browning process at an early stage. Moreover, these data demonstrate the potential of NLSM to address a broad range of fundamental and applied microbiological processes. PMID- 23934489 TI - Microbial contents of vacuum cleaner bag dust and emitted bioaerosols and their implications for human exposure indoors. AB - Vacuum cleaners can release large concentrations of particles, both in their exhaust air and from resuspension of settled dust. However, the size, variability, and microbial diversity of these emissions are unknown, despite evidence to suggest they may contribute to allergic responses and infection transmission indoors. This study aimed to evaluate bioaerosol emission from various vacuum cleaners. We sampled the air in an experimental flow tunnel where vacuum cleaners were run, and their airborne emissions were sampled with closed face cassettes. Dust samples were also collected from the dust bag. Total bacteria, total archaea, Penicillium/Aspergillus, and total Clostridium cluster 1 were quantified with specific quantitative PCR protocols, and emission rates were calculated. Clostridium botulinum and antibiotic resistance genes were detected in each sample using endpoint PCR. Bacterial diversity was also analyzed using denaturing gradient gel electrophoresis (DGGE), image analysis, and band sequencing. We demonstrated that emission of bacteria and molds (Penicillium/Aspergillus) can reach values as high as 1E5 cell equivalents/min and that those emissions are not related to each other. The bag dust bacterial and mold content was also consistent across the vacuums we assessed, reaching up to 1E7 bacterial or mold cell equivalents/g. Antibiotic resistance genes were detected in several samples. No archaea or C. botulinum was detected in any air samples. Diversity analyses showed that most bacteria are from human sources, in keeping with other recent results. These results highlight the potential capability of vacuum cleaners to disseminate appreciable quantities of molds and human-associated bacteria indoors and their role as a source of exposure to bioaerosols. PMID- 23934487 TI - Prevalence of hemolysin genes and comparison of ehxA subtype patterns in Shiga toxin-producing Escherichia coli (STEC) and non-STEC strains from clinical, food, and animal sources. AB - Shiga toxin-producing Escherichia coli (STEC) belonging to certain serogroups (e.g., O157 and O26) can cause serious conditions like hemolytic-uremic syndrome (HUS), but other strains might be equally pathogenic. While virulence factors, like stx and eae, have been well studied, little is known about the prevalence of the E. coli hemolysin genes (hlyA, ehxA, e-hlyA, and sheA) in association with these factors. Hemolysins are potential virulence factors, and ehxA and hlyA have been associated with human illness, but the significance of sheA is unknown. Hence, 435 E. coli strains belonging to 62 different O serogroups were characterized to investigate gene presence and phenotypic expression of hemolysis. We further investigated ehxA subtype patterns in E. coli isolates from clinical, animal, and food sources. While sheA and ehxA were widely distributed, e-hlyA and hlyA were rarely found. Most strains (86.7%) were hemolytic, and significantly more hemolytic (95%) than nonhemolytic strains (49%) carried stx and/or eae (P < 0.0001). ehxA subtyping, as performed by using PCR in combination with restriction fragment length polymorphism analysis, resulted in six closely related subtypes (>94.2%), with subtypes A/D being eae-negative STECs and subtypes B, C, E, and F eae positive. Unexpectedly, ehxA subtype patterns differed significantly between isolates collected from different sources (P < 0.0001), suggesting that simple linear models of exposure and transmission need modification; animal isolates carried mostly subtypes A/C (39.3%/42.9%), food isolates carried mainly subtype A (81.9%), and clinical isolates carried mainly subtype C (66.4%). Certain O serogroups correlated with particular ehxA subtypes: subtype A with O104, O113, and O8; B exclusively with O157; C with O26, O111, and O121. PMID- 23934490 TI - Fecal shedding of zoonotic food-borne pathogens by wild rodents in a major agricultural region of the central California coast. AB - Recent outbreaks of food-borne illness associated with the consumption of produce have increased concern over wildlife reservoirs of food-borne pathogens. Wild rodents are ubiquitous, and those living close to agricultural farms may pose a food safety risk should they shed zoonotic microorganisms in their feces near or on agricultural commodities. Fecal samples from wild rodents trapped on 13 agricultural farms (9 produce, 3 cow-calf operations, and 1 beef cattle feedlot) in Monterey and San Benito Counties, CA, were screened to determine the prevalence and risk factors for shedding of several food-borne pathogens. Deer mice (Peromyscus maniculatus) were the most abundant rodent species trapped (72.5%). Cryptosporidium species (26.0%) and Giardia species (24.2%) were the predominant isolates from rodent feces, followed by Salmonella enterica serovars (2.9%) and Escherichia coli O157:H7 (0.2%). Rodent trap success was significantly associated with detection of Salmonella in rodent feces, while farm type was associated with fecal shedding of Cryptosporidium and Giardia. Seasonal shedding patterns were evident, with rodents trapped during the spring and summer months being significantly less likely to be shedding Cryptosporidium oocysts than those trapped during autumn. Higher rodent species diversity tended to correlate with lower fecal microbial prevalence, and most spatiotemporal pathogen clusters involved deer mice. Rodents in the study area posed a minimal risk as environmental reservoirs of E. coli O157:H7, but they may play a role in environmental dissemination of Salmonella and protozoa. Rodent control efforts that potentially reduce biodiversity may increase pathogen shedding, possibly through promotion of intraspecific microbial transmission. PMID- 23934491 TI - Comparative genomic and transcriptomic analyses reveal habitat differentiation and different transcriptional responses during pectin metabolism in Alishewanella species. AB - Alishewanella species are expected to have high adaptability to diverse environments because they are isolated from different natural habitats. To investigate how the evolutionary history of Alishewanella species is reflected in their genomes, we performed comparative genomic and transcriptomic analyses of A. jeotgali, A. aestuarii, and A. agri, which were isolated from fermented seafood, tidal flat sediment, and soil, respectively. Genomic islands with variable GC contents indicated that invasion of prophage and transposition events occurred in A. jeotgali and A. agri but not in A. aestuarii. Habitat differentiation of A. agri from a marine environment to a terrestrial environment was proposed because the species-specific genes of A. agri were similar to those of soil bacteria, whereas those of A. jeotgali and A. aestuarii were more closely related to marine bacteria. Comparative transcriptomic analysis with pectin as a sole carbon source revealed different transcriptional responses in Alishewanella species, especially in oxidative stress-, methylglyoxal detoxification-, membrane maintenance-, and protease/chaperone activity-related genes. Transcriptomic and experimental data demonstrated that A. agri had a higher pectin degradation rate and more resistance to oxidative stress under pectin-amended conditions than the other 2 Alishewanella species. However, expression patterns of genes in the pectin metabolic pathway and of glyoxylate bypass genes were similar among all 3 Alishewanella species. Our comparative genomic and transcriptomic data revealed that Alishewanella species have evolved through horizontal gene transfer and habitat differentiation and that pectin degradation pathways in Alishewanella species are highly conserved, although stress responses of each Alishewanella species differed under pectin culture conditions. PMID- 23934492 TI - mhpT encodes an active transporter involved in 3-(3-hydroxyphenyl)propionate catabolism by Escherichia coli K-12. AB - Escherichia coli K-12 utilizes 3-(3-hydroxyphenyl)propionate (3HPP) as a sole carbon and energy source. Among the genes in its catabolic cluster in the genome, mhpT was proposed to encode a hypothetical transporter. Since no transporter for 3HPP uptake has been identified, we investigated whether MhpT is responsible for 3HPP uptake. MhpT fused with green fluorescent protein was found to be located at the periphery of cells by confocal microscopy, consistent with localization to the cytoplasmic membrane. Gene knockout and complementation studies clearly indicated that mhpT is essential for 3HPP catabolism in E. coli K-12 W3110 at pH 8.2. Uptake assays with (14)C-labeled substrates demonstrated that strain W3110 and strain W3110DeltamhpT containing recombinant MhpT specifically transported 3HPP but not benzoate, 3-hydroxybenzoate, or gentisate into cells. Energy dependence assays suggested that MhpT-mediated 3HPP transport was driven by the proton motive force. The change of Ala-272 of MhpT to a histidine, surprisingly, resulted in enhanced transport activity, and strain W3110DeltamhpT containing the MhpT A272H mutation had a slightly higher growth rate than the wild-type strain at pH 8.2. Hence, we demonstrated that MhpT is a specific 3HPP transporter and vital for E. coli K-12 W3110 growth on this substrate under basic conditions. PMID- 23934493 TI - Development of a tunable wide-range gene induction system useful for the study of streptococcal toxin-antitoxin systems. AB - Despite the plethora of genetic tools that have been developed for use in Streptococcus mutans, the S. mutans genetic system still lacks an effective gene induction system exhibiting low basal expression and strong inducibility. Consequently, we created two hybrid gene induction cassettes referred to as Xyl S1 and Xyl-S2. Both Xyl-S cassettes are xylose inducible and controlled by the Bacillus megaterium xylose repressor. The Xyl-S cassettes each demonstrated >600 fold-increased reporter activity in the presence of 1.2% (wt/vol) xylose. However, the Xyl-S1 cassette yielded a much higher maximum level of gene expression, whereas the Xyl-S2 cassette exhibited much lower uninduced basal expression. The cassettes also performed similarly in Streptococcus sanguinis and Streptococcus gordonii, which suggests that they are likely to be useful in a variety of streptococci. We demonstrate how both Xyl-S cassettes are particularly useful for the study of toxin-antitoxin (TA) modules using both the previously characterized S. mutans mazEF TA module and a previously uncharacterized HicAB TA module in S. mutans. HicAB TA modules are widely distributed among bacteria and archaea, but little is known about their function. We show that HicA serves as the toxin component of the module, while HicB serves as the antitoxin. Our results suggest that, in contrast to that of typical TA modules, HicA toxicity in S. mutans is modest at best. The implications of these results for HicAB function are discussed. PMID- 23934494 TI - X-ray absorption near-edge structure (XANES) spectroscopy study of the interaction of silver ions with Staphylococcus aureus, Listeria monocytogenes, and Escherichia coli. AB - Silver ions are widely used as antibacterial agents, but the basic molecular mechanism of this effect is still poorly understood. X-ray absorption near-edge structure (XANES) spectroscopy at the Ag LIII, S K, and P K edges reveals the chemical forms of silver in Staphylococcus aureus and Escherichia coli (Ag(+) treated). The Ag LIII-edge XANES spectra of the bacteria are all slightly different and very different from the spectra of silver ions (silver nitrate and silver acetate), which confirms that a reaction occurs. Death or inactivation of bacteria was observed by plate counting and light microscopy. Silver bonding to sulfhydryl groups (Ag-S) in cysteine and Ag-N or Ag-O bonding in histidine, alanine, and DL-aspartic acid was detected by using synthesized silver-amino acids. Significantly lower silver-cysteine content, coupled with higher silver histidine content, in Gram-positive S. aureus and Listeria monocytogenes cells indicates that the peptidoglycan multilayer could be buffering the biocidal effect of silver on Gram-positive bacteria, at least in part. Bonding of silver to phosphate groups was not detected. Interaction with DNA or proteins can occur through Ag-N bonding. The formation of silver-cysteine can be confirmed for both bacterial cell types, which supports the hypothesis that enzyme-catalyzed reactions and the electron transport chain within the cell are disrupted. PMID- 23934495 TI - Novel cultivation-based approach to understanding the miscellaneous crenarchaeotic group (MCG) archaea from sedimentary ecosystems. AB - The uncultured miscellaneous crenarchaeotic group (MCG) archaea comprise one of the most abundant microbial groups in the Earth's subsurface environment. However, very little information is available regarding the lifestyle, physiology, and factors controlling the distribution of members of this group. We established a novel method using both cultivation and molecular techniques, including a pre-PCR propidium monoazide treatment, to investigate viable members of the MCG in vitro. Enrichment cultures prepared from estuarine sediment were provided with one of a variety of carbon substrates or cultivation conditions and incubated for 3 weeks. Compared with the samples from time zero, there was an order-of-magnitude increase in the number of MCG 16S rRNA genes in almost all cultures, indicating that MCG archaea are amenable to in vitro cultivation. None of the tested substrates or conditions significantly stimulated growth of MCG archaea more than the basal medium alone; however, glycerol (0.02%) had a significantly inhibitory effect (P < 0.05). Diversity analysis of populations resulting from four culture treatments (basal medium, addition of amino acids, H2 CO2 as the gas phase, or initial aerobic conditions) revealed that the majority of viable MCG archaea were affiliated with the MCG-8 and MCG-4 clusters. There were no significant differences in MCG diversity between these treatments, also indicating that some members of MCG-4 and MCG-8 are tolerant of initially oxic conditions. The methods outlined here will be useful for further investigation of MCG archaea and comparison of substrates and cultivation conditions that influence their growth in vitro. PMID- 23934496 TI - Behavior of Yersinia enterocolitica in the presence of the bacterivorous Acanthamoeba castellanii. AB - Free-living protozoa play an important role in the ecology and epidemiology of human-pathogenic bacteria. In the present study, the interaction between Yersinia enterocolitica, an important food-borne pathogen, and the free-living amoeba Acanthamoeba castellanii was studied. Several cocultivation assays were set up to assess the resistance of Y. enterocolitica to A. castellanii predation and the impact of environmental factors and bacterial strain-specific characteristics. Results showed that all Y. enterocolitica strains persist in association with A. castellanii for at least 14 days, and associations with A. castellanii enhanced survival of Yersinia under nutrient-rich conditions at 25 degrees C and under nutrient-poor conditions at 37 degrees C. Amoebae cultivated in the supernatant of one Yersinia strain showed temperature- and time-dependent permeabilization. Intraprotozoan survival of Y. enterocolitica depended on nutrient availability and temperature, with up to 2.8 log CFU/ml bacteria displaying intracellular survival at 7 degrees C for at least 4 days in nutrient-rich medium. Transmission electron microscopy was performed to locate the Yersinia cells inside the amoebae. As Yersinia and Acanthamoeba share similar ecological niches, this interaction identifies a role of free-living protozoa in the ecology and epidemiology of Y. enterocolitica. PMID- 23934497 TI - U(VI) reduction by diverse outer surface c-type cytochromes of Geobacter sulfurreducens. AB - Early studies with Geobacter sulfurreducens suggested that outer-surface c-type cytochromes might play a role in U(VI) reduction, but it has recently been suggested that there is substantial U(VI) reduction at the surface of the electrically conductive pili known as microbial nanowires. This phenomenon was further investigated. A strain of G. sulfurreducens, known as Aro-5, which produces pili with substantially reduced conductivity reduced U(VI) nearly as well as the wild type, as did a strain in which the gene for PilA, the structural pilin protein, was deleted. In order to reduce rates of U(VI) reduction to levels less than 20% of the wild-type rates, it was necessary to delete the genes for the five most abundant outer surface c-type cytochromes of G. sulfurreducens. X ray absorption near-edge structure spectroscopy demonstrated that whereas 83% +/- 10% of the uranium associated with wild-type cells correspond to U(IV) after 4 h of incubation, with the quintuple mutant, 89% +/- 10% of uranium was U(VI). Transmission electron microscopy and X-ray energy dispersion spectroscopy revealed that wild-type cells did not precipitate uranium along pili as previously reported, but U(IV) was precipitated at the outer cell surface. These findings are consistent with those of previous studies, which have suggested that G. sulfurreducens requires outer-surface c-type cytochromes but not pili for the reduction of soluble extracellular electron acceptors. PMID- 23934498 TI - Functional identification of rubber oxygenase (RoxA) in soil and marine myxobacteria. AB - The rubber oxygenase (RoxA) of Xanthomonas sp. strain 35Y (RoxA(Xsp)) is so far the only known extracellular c-type diheme cytochrome that is able to cleave poly(cis-1,4-isoprene). All other rubber-degrading bacteria described are Gram positive and employ a nonheme protein (latex-clearing protein [Lcp]) for the postulated primary attack of polyisoprene. Here, we identified RoxA orthologs in the genomes of Haliangium ochraceum, Myxococcus fulvus, Corallococcus coralloides, and Chondromyces apiculatus. The roxA orthologs of H. ochraceum (RoxA(Hoc)), C. coralloides BO35 (RoxA(Cco)), and M. fulvus (RoxA(Mfu)) were functionally expressed in a DeltaroxA Xanthomonas sp. 35Y background. All RoxA orthologs oxidatively cleaved polyisoprene, as revealed by restoration of clearing-zone formation and detection of 12-oxo-4,8-dimethyltrideca-4,8-diene-1 al (ODTD) as a cleavage product. RoxA(Xsp), RoxA(Mfu), and RoxA(Cco) were purified and biochemically characterized. The optimal temperature of RoxA(Cco) and RoxA(Mfu) was between 22 and 30 degrees C. All RoxA orthologs as isolated showed an oxidized UV-visible spectrum. Chemical reduction of RoxA(Cco) and RoxA(Mfu) indicated the presence of two slightly different heme centers with absorption maxima between 549 and 553 nm, similar to RoxA(Xsp). Sequence analysis and modeling of the three-dimensional structures of the RoxA orthologs revealed a high degree of similarity to the recently solved RoxA(Xsp) structure and included several conserved residues, notably, W302, F317, and a MauG motif at about H517. Lcp-like sequences were not detected in the genomes of the Xanthomonas sp. 35Y, H. ochraceum, M. fulvus, and C. coralloides. No RoxA orthologs were found in Gram positive bacteria, and this first description of functional RoxA in Gram-negative bacteria other than Xanthomonas proves that RoxA is more common among rubber degraders than was previously assumed. PMID- 23934499 TI - Microgradients of pH do not occur around Lactococcus colonies in a model cheese. AB - Lactococci inoculated into cheese grow as colonies producing lactic acid. The pH microgradients were investigated around colonies in a complex food such as cheese. The results, obtained using a nondestructive technique, demonstrated that pH microgradients did not occur regardless of the acidification kinetics and the size of the colony. PMID- 23934501 TI - Functional and expression analysis of the metal-inducible dmeRF system from Rhizobium leguminosarum bv. viciae. AB - A gene encoding a homolog to the cation diffusion facilitator protein DmeF from Cupriavidus metallidurans has been identified in the genome of Rhizobium leguminosarum UPM791. The R. leguminosarum dmeF gene is located downstream of an open reading frame (designated dmeR) encoding a protein homologous to the nickel- and cobalt-responsive transcriptional regulator RcnR from Escherichia coli. Analysis of gene expression showed that the R. leguminosarum dmeRF genes are organized as a transcriptional unit whose expression is strongly induced by nickel and cobalt ions, likely by alleviating the repressor activity of DmeR on dmeRF transcription. An R. leguminosarum dmeRF mutant strain displayed increased sensitivity to Co(II) and Ni(II), whereas no alterations of its resistance to Cd(II), Cu(II), or Zn(II) were observed. A decrease of symbiotic performance was observed when pea plants inoculated with an R. leguminosarum dmeRF deletion mutant strain were grown in the presence of high concentrations of nickel and cobalt. The same mutant induced significantly lower activity levels of NiFe hydrogenase in microaerobic cultures. These results indicate that the R. leguminosarum DmeRF system is a metal-responsive efflux mechanism acting as a key element for metal homeostasis in R. leguminosarum under free-living and symbiotic conditions. The presence of similar dmeRF gene clusters in other Rhizobiaceae suggests that the dmeRF system is a conserved mechanism for metal tolerance in legume endosymbiotic bacteria. PMID- 23934500 TI - Environmental surveillance of human parechoviruses in sewage in The Netherlands. AB - The circulation of human parechoviruses (HPeVs) in the population was studied by environmental surveillance comprising of molecular analyses of sewage samples (n = 89) that were collected from 15 different locations in The Netherlands. Samples were taken from sewage originating from schools (n = 9) or from parts of municipalities (n = 6) during the Dutch school year 2010-2011. At 13/15 locations HPeV1, HPeV3, or HPeV6 RNA was detected at least once; however, sequence diversity did not reflect associations in time or place. A higher percentage of positives was observed in the samples originating from the municipalities. It was demonstrated that HPeV circulated in the studied population to a higher extent than would be expected from the current knowledge on infections predominating in young children. PMID- 23934502 TI - Medial humeral condyle fractures in adolescents: treatment and complications. AB - The very rare isolated medial humeral condyle fractures in children and adolescents pose significant problems to orthopedic surgeons such as ulnar nerve injury, trochlear irregularities, fishtail deformity and motion loss. Six adolescent boys with displaced medial humeral condyle fractures with an average age of 14.8 (range 12-17) were included in this study. Patients were followed-up with a mean of 39.8 months (range 21-72). In three patients, there were clinical signs of ulnar nerve dysfunction at initial presentation. Of these, two had only mild hypoesthesia on the ulnar side. The other patient had sensory and motor loss of ulnar nerve at initial presentation complicated by hypothenar atrophy and anhydrosis during follow-up. Complete recovery was seen in this patient only at 2 years. One patient without a neurologic compliant at initial presentation developed mild hypoesthesia on the ulnarly innervated areas postoperatively with complete resolution. Medial skin incision was used for open reduction and internal fixation. No signs of gross morphologic damage were seen on the nerve. The symptoms resolved postoperatively in 3 months time in three of the patients, but in the remaining one, it took 2 years for complete resolution of the symptoms. Also, trochlear irregularity and fishtail deformity were seen on radiographs of two different patients. In all but one patients, motion loss ranging from 10 degrees to 20 degrees was evident on physical examination. The most important finding of this study revealed that transient ulnar nerve dysfunction was seen two-thirds of the patients in this series than any other series reported previously. In three series, only one case of ulnar nerve injury was reported from a total of 19 patients. A possible explanation for such a difference may be the older age in this series. PMID- 23934503 TI - Rotational malalignment after closed intramedullary nailing of femoral shaft fractures and its influence on daily life. AB - BACKGROUND: Any intraoperative rotational malalignment during intramedullary nailing (IMN) of femoral shaft fractures will become permanent. We hypothesized that rotational malalignment of the femur and its compensatory biomechanics may induce problems in the hip, knee, patellofemoral and ankle joints. We purposed to clarify the influence of a femoral rotational malalignment of >=10 degrees on daily activities. METHODS: Twenty-four femoral shaft fracture patients treated with closed antegrade IMN were included. At last follow-up, to reveal any rotational malalignment, computerized tomography (CT) scans of both femurs (injured and uninjured sides) were examined. The patient groups with or without CT-detected true rotational malalignment >=10 degrees were compared with respect to the activity scores. RESULTS: Ten of the 24 patients (41.7%) had a CT-detected true rotational malalignment of >=10 degrees compared with the unaffected side. The AOFAS scores were 100.00 for all of the patients. LKS, WOMAC knee, and WOMAC hip scores were significantly decreased in the patients with rotational malalignment compared to those without. Patients without rotational malalignment tolerated climbing stairs significantly better than those with rotational malalignment. Patients who could not tolerate climbing stairs were consistently complaining of anterior knee pain. CONCLUSIONS: A femoral rotational malalignment of >=10 degrees is symptomatic for the patients, and the hip, knee, and patellofemoral joints were affected. Because of the possibly altered joint loadings and biomechanics, these could render patients prone to degenerative joint disease. In addition, due to the high rates of rotational malalignment after femoral shaft fracture and consequent malpractice claims, it is important for surgeons to be more aware of rotational alignment during surgery. PMID- 23934504 TI - Treatment of mental hypochondriasis: a case report. AB - Hypochondriasis is characterized by intensive fears of serious disease. Most patients with hypochondriasis worry about physical diseases like cancer, although in rare cases, patients report severe fears of mental disorders (e.g., schizophrenia), a phenomenon described in the literature as mental hypochondriasis. However, little is known about this rare subtype of hypochondriasis and experts have questioned whether mental hypochondriasis has much in common with the type of hypochondriasis in which somatic diseases are the focus of preoccupation. This paper presents, a case report of a woman with a fear of schizophrenia, which was treated with cognitive therapy. This patient fulfills the DSM-IV criteria of hypochondriasis and exhibits many characteristics (e.g., selective attention, safety behavior) considered to be maintaining factors in well-established cognitive-behavioral models of hypochondriasis. Cognitive treatment strategies for hypochondriasis (e.g., attention training, behavioral experiments) also proved effective in this case of mental hypochondriasis. PMID- 23934505 TI - Internal Mammary Sentinel Node Biopsy in Breast Cancer. Is it Indicated? AB - Axillary sentinel node (A-SN) biopsy is a standard procedure in breast cancer surgery. Sampling of intenal mammary sentinel nodes (IM-SN) is not performed routinly, although it is also considered an important prognostic factor of breast cancer. The role of this latter procedure was investigated in cases of IM-SN visualized on lymphoscintigraphy. Between January 2001 and June 2012 1542 patients with clinically node negative operable primary breast cancer had sentinel node biopsy (SNB). Both axillary and IM-SN were sampled (whenever detected), based on lymphoscintigraphy, intraoperative gamma probe detection and blu dye mapping. Lymphoscintigraphy showed IM-SN in 83 cases. IM-SN biopsy (IM SNB) was succesfull in 77 patients (93%). A total of 86 IM-SNs were removed. IM SN involvement was identified in 14 cases, representing 18% of patients who underwent IM-SNB. This included macrometastases (MAC) in 5 cases, micrometastases (MIC) in 2 cases, isolated tumor cells (ITC) in 7 cases. No significant differences were found between patients with and without IM-SN involvement in terms of age, tumor location, tumor size, axillary involvement, tumor grade or estrogen receptor status. The IM-SN involvement has lead to new therapeutic indications in 2 cases (2.6%), both of them due to MAC in the IM-SN: in 1 case change in chemotherapy and in 1 case change in radiotherapy, with the addition of iradiation of the internal mammary chain. Based on this series and information from the literature, we conclude that the indication for an IM-SNB procedure is very limited and its routine use should not be recommended. PMID- 23934506 TI - Genetic parameters for milk urea concentration and milk traits in Polish Holstein Friesian cows. AB - Milk urea concentration (MU) used by dairy producers for management purposes can be affected by selection for milk traits. To assess this problem, genetic parameters for MU in Polish Holstein-Friesian cattle were estimated for the first three lactations. The genetic correlation of MU with milk production traits, lactose percentage, fat to protein ratio (FPR) and somatic cell score (SCS) were computed with two 5-trait random regression test-day models, separately for each lactation. Data used for estimation (159,044 daily observations) came from 50 randomly sampled herds. (Co)variance components were estimated with the Bayesian Gibbs sampling method. The coefficient of variation for MU in all three parities was high (40-41 %). Average daily heritabilities of MU were 0.22 for the first parity and 0.21 for the second and third lactations. Average genetic correlations for different days in milk in the first three lactations between MU and other traits varied. They were small and negative for protein percentage (from -0.24 to -0.11) and for SCS (from -0.14 to -0.09). The weakest genetic correlation between MU and fat percentage, and between MU and lactose percentage were observed (from 0.10 to 0.10). Negative average genetic correlation with the fat to protein ratio was observed only in the first lactation (-0.14). Genetic correlations with yield traits were positive and ranged from low to moderate for protein (from 0.09 to 0.33), fat (from 0.16 to 0.35) and milk yield (from 0.20 to 0.42). These results suggest that the selection on yield traits and SCS tends to increase MU slightly. PMID- 23934507 TI - Tunable Dirac fermion dynamics in topological insulators. AB - Three-dimensional topological insulators are characterized by insulating bulk state and metallic surface state involving relativistic Dirac fermions which are responsible for exotic quantum phenomena and potential applications in spintronics and quantum computations. It is essential to understand how the Dirac fermions interact with other electrons, phonons and disorders. Here we report super-high resolution angle-resolved photoemission studies on the Dirac fermion dynamics in the prototypical Bi2(Te,Se)3 topological insulators. We have directly revealed signatures of the electron-phonon coupling and found that the electron disorder interaction dominates the scattering process. The Dirac fermion dynamics in Bi2(Te3-xSex) topological insulators can be tuned by varying the composition, x, or by controlling the charge carriers. Our findings provide crucial information in understanding and engineering the electron dynamics of the Dirac fermions for fundamental studies and potential applications. PMID- 23934508 TI - Mechanism for full-length RNA processing of Arabidopsis genes containing intragenic heterochromatin. AB - Genomes of higher eukaryotes contain many transposable elements, which often localize within the transcribed regions of active genes. Although intragenic transposable elements can be silenced to form heterochromatin, the impact of intragenic heterochromatin on transcription and RNA processing remains largely unexplored. Here we show using a flowering plant, Arabidopsis, that full-length transcript formation over intragenic heterochromatin depends on a protein named IBM2 (Increase in Bonsai Methylation 2), which has a Bromo-Adjacent Homology domain and an RNA recognition motif. Mutation of ibm2 triggers premature termination of transcripts with 3' RNA processing around intragenic heterochromatin at loci including the H3K9 demethylase gene IBM1. The need for IBM2 is circumvented in variant alleles that lack the heterochromatic domain. Our results reveal a mechanism that masks deleterious effects of intragenic heterochromatin, providing evolutionary sources for genetic and epigenetic variations. PMID- 23934509 TI - Controversy and consensus on the management of patients with pseudomyxoma peritonei. AB - OPINION STATEMENT: Pseudomyxoma peritonei and peritoneal carcinomatosis derived from appendiceal epithelial tumors are controversial entities from classification to treatment. For the former entity, multiple classification systems have been attempted to distinguish indolent from more aggressive subtypes. The treatment of the low grade variants is managed with serial cytoreduction surgery, with data indicating possible, but unproven, benefit from heated intraperitoneal chemotherapy (HIPEC). There is no consensus on the role of cytoreduction and HIPEC for the management of the more aggressive histologic variants and peritoneal carcinomatosis. Currently, we believe systemic chemotherapy is the standard of care for patients with the high grade variants and peritoneal carcinomatosis. PMID- 23934511 TI - Recent advances in treatment of primary central nervous system lymphoma. AB - OPINION STATEMENT: Therapeutic options are limited in primary central nervous system lymphoma (PCNSL) with no uniform consensus on optimal management and few published, randomized trials. High-dose methotrexate in combination with other chemotherapeutic agents forms the mainstay of treatment. There hasn't been much progress beyond high-dose methotrexate in this disease, and although results from trials using high-dose chemotherapy and autologous stem-cell transplant seem promising, these need to be further validated. Moreover, the role of whole brain radiation in the upfront setting remains to be determined. However, international efforts in this direction are underway, with ongoing randomized trials in newly diagnosed PCNSL, more research on the molecular pathogenesis and biomarkers, and the use of novel agents in salvage therapy. There also is emphasis on quality of life parameters and neurocognitive status. Future treatment options should optimize high-efficacy rates while minimizing the risk of neurotoxicity. PMID- 23934512 TI - Chemokine CCL2 induces apoptosis in cortex following traumatic brain injury. AB - The chemokine C-C motif ligand 2 (CCL2) is an important mediator of neuroinflammation. Released in response to acute injury, ischemia, and neurodegenerative disease, CCL2 binds primarily to the G-protein-coupled chemokine C-C motif receptor 2 (CCR2) to recruit inflammatory cells to sites of tissue damage. Inflammation is thought to have both beneficial and deleterious consequences following traumatic brain injury (TBI), so we investigated CCL2-CCR2 signaling during the post-TBI period to assess possible neurodegenerative and protective actions. Local TBI in adult rat cortex was induced by Feeney's weight drop method, and the expression of CCL2 and CCR2 in the tissue around the contusion site was measured by real-time quantitative PCR. Both CCL2 and CCR2 mRNA levels were increased markedly for at least 10 days after injury, peaking on day 3. The CCL2 protein was mainly co-localized with the astroglial marker glial fibrillary acidic protein and CCR2 protein with the neuronal nuclear marker NeuN as revealed by double immunofluorescence staining. A selective CCR2 antagonist, RS504393, reduced TUNEL staining, a marker of apoptosis, and improved performance in the Morris water maze 3 days post-TBI, suggesting that CCL2-CCR2 signaling has deleterious effects on neuronal survival and learning. Targeting the CCL2-CCR2 pathway may provide a novel therapeutic approach for the treatment of TBI. PMID- 23934510 TI - Targeting the immune system in the treatment of non-small-cell lung cancer. AB - OPINION STATEMENT: Non-small-cell lung cancer (NSCLC) remains the most common cause of cancer-related death worldwide. Traditional cytotoxic agents and their attendant toxicities have remained the mainstay of systemic therapy for this disease, until now. With the identification of novel molecular and immune cancer specific aberrancies, molecular agents and immunotherapies have garnered increasing attention as attractive targets, with the potential for improved outcomes while mitigating systemic toxicities seen with traditional cytotoxic agents. Despite a longstanding interest in immunotherapy for the treatment of NSCLC, results of prior studies of therapeutic vaccines have failed to show durable or convincingly meaningful clinical responses. However, newer trials of therapeutic vaccines and checkpoint inhibitors have yielded more promising results. In particular, the checkpoint inhibitors targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway have shown meaningful clinical responses with manageable toxicities. Large phase III studies are underway, the results of which have the potential to revolutionize the way in which we care for patients with NSCLC. More studies also are needed to investigate the potentially synergistic effects of traditional and immune-based therapies. Given their unique antineoplastic effects, novel immune specific clinical endpoints also are actively being investigated. PMID- 23934514 TI - Cytotoxic effects of crocin on MOLT-4 human leukemia cells. AB - BACKGROUND: Among various naturally occurring compounds which have been extracted from Crocus sativus, crocin has shown different pharmacological effects i.e. neuroprotection and anti-tumor activity. METHODS: Here, crocin effects on human T cell leukemia cell line, MOLT-4, were evaluated. In this study, we examined the effects of 24 and 48 h of crocin treatment (50, 250 and 500 uM) on the viability of MOLT-4 cell line. Moreover, probable apoptotic/necrotic outcomes, reactive oxygen species (ROS) production variations along with crocin treatment consequences on DNA, were investigated. RESULTS: Results from MTT assay demonstrated that 48-h crocin treatment at 500 uM, significantly reduced cell viability (p<0.01). DNA fragmentation was recorded to be significantly increased at higher doses of crocin following 24 and 48 h (p<0.01). According to our results, while apoptosis was detected at all concentrations, necrosis detected at the highest dose, only. In comparison with control, ROS production was reduced at 50 and 250 uM. CONCLUSIONS: In accordance with previous reports, crocin exhibited mild cytotoxic effects on a leukemia cell line which might be mediated through the increase of DNA fragmentation. PMID- 23934515 TI - Impact of relaxation training according to the Yoga In Daily Life(r) system on anxiety after breast cancer surgery. AB - The purpose of this pilot study was to gather information on the immediate and short-term effects of relaxation training according to the Yoga In Daily Life(r) (YIDL(r)) system on anxiety of breast cancer patients. The YIDL(r) system is a holistic system being practised and taught worldwide and has been proven to be highly effective in the prevention and treatment of various diseases. The system aims to establish physical, mental, spiritual, and social health. Thirty-two patients at the Institute for Oncology Ljubljana were randomized to the experimental (n=16) and to the control groups (n=16). Both groups received the same standard physiotherapy for 1 week, while the experimental group additionally received 1-hour group relaxation training session according to the YIDL(r) system per day. At discharge, the experimental group was issued with audiocassette recordings containing similar instructions for relaxation training to be practiced for 3 weeks individually at home. Anxiety measures were obtained by blinded assessors using standardized questionnaires. The results indicate that relaxation training according to the YIDL(r) system could be a useful clinical physiotherapy intervention for breast cancer patients experiencing anxiety. PMID- 23934516 TI - Exposure assessment, chemical characterization and source identification of PM2.5 for school children and industrial downwind residents in Guangzhou, China. AB - To assess the exposure doses of PM(2.5) and to investigate its chemical components for the subpopulation (i.e., school children and industrial downwind residents), simultaneous sampling of indoor and outdoor PM(2.5) was conducted at an elementary school close to traffic arteries and a residence located in the downwind area of a steel plant in metropolitan Guangzhou in 2010. Chemical components, i.e., organic carbon, elemental carbon and 6 water soluble ions were analyzed in PM(2.5). A survey was also conducted to investigate the time-activity patterns of the school children and the industrial downwind residents. Indoor and outdoor PM(2.5) were 63.2 +/- 20.1 and (76.7 +/- 35.8) MUg/m(3) at the school, and 118.8 +/- 44.7 and 125.7 +/- 57.1 MUg/m(3) in the community, respectively. Indoor PM(2.5) was found to be highly related to outdoor sources, and stationary sources were the significant contributors to PM(2.5) at both sites. The daily average doses of PM(2.5) for the school children at the school (D(children)) and the industrial downwind residents in the community (D(residents)) were (7.6 +/- 1.9) and (36.1 +/- 36.8) MUg/kg-day, respectively. The daily average doses of particulate organic mass and SO(4)(2-) were the two most abundant chemical components in PM(2.5). PM(2.5) exposure for the school children was contributed by indoor and outdoor environments by 48.8 and 51.2 %, respectively; for the industrial downwind residents, the contributions were 66.0 and 34.0 %, respectively. Age and body weight were significantly and negatively correlated with D(children), while age, body weight and education level were significantly and negatively correlated with D(residents); gender was not a significant factor at both cases. PMID- 23934517 TI - The effect of race/ethnicity on gestational weight gain. AB - Minority women are gaining more weight than recommended during pregnancy. This study aimed to determine the risk of excessive gestational weight gain (GWG) in Hispanic and Black women compared to non-Hispanic women in Colorado. A retrospective cohort study of all birth records from 2007 to 2010 in Colorado was conducted. The primary outcome was GWG, and the exposure was race/ethnicity. Covariates were marital status, education, intensity of prenatal care, age, parity, tobacco use, alcohol use and years in the US. Chi square and multiple logistic regression was performed. 230,698 records were analyzed. Half of the Hispanic and Black women began their pregnancy overweight or obese. Hispanic women had a 0.84 (95% CI 0.8-0.9) and Black women had a 0.95 (95% CI 0.9-1.0) risk of excessive GWG than NHW women. Pre-pregnancy weight is an independent risk for adverse outcomes. The study findings provide healthcare providers focal points in preconception health care and programming. PMID- 23934518 TI - Validation of Arabic and English versions of the ARSMA-II Acculturation Rating Scale. AB - To translate and adapt the Acculturation Rating Scale of Mexican-Americans II (ARSMA-II) for Arab Americans. A multistage translation process followed by a pilot and a large study. The translated and adapted versions, Acculturation Rating Scale for Arabic Americans-II Arabic and English (ARSAA-IIA, ARSAA-IIE), were validated in a sample of 297 Arab Americans. Factor analyses with principal axis factoring extractions and direct oblimin rotations were used to identify the underlying structure of ARSAA-II. Factor analysis confirmed the underlying structure of ARSAA-II and produced two interpretable factors labeled as 'Attraction to American Culture' (AAmC) and 'Attraction to Arabic Culture' (AArC). The Cronbach's alphas of AAmC and AArC were .89 and .85 respectively. Findings support ARSAA-II A & E to assess acculturation among Arab Americans. The emergent factors of ARSAA-II support the theoretical structure of the original ARSMA-II tool and show high internal consistency. PMID- 23934519 TI - Neuroborreliosis and CNS lymphoma: what is the nexus? PMID- 23934520 TI - Autophagy is a key feature in the pathogenesis of systemic sclerosis. AB - Autophagosomes are formed during autophagy, which is activated by hypoxia and starvation. Autophagy is important for mast cell degranulation. We hypothesized that autophagy is a key feature in the pathogenesis of systemic sclerosis (SSc). We examined SSc clinical features and mast cell density across the presence and severity of autophagy. Skin punch biopsy was performed on 33 SSc patients and 6 healthy controls (HC). Autophagy was evaluated by immunofluorescence on paraffin sections using LC3-FITC staining on these patients. The intensity of staining and mast cell density was examined across clinical features in 19 of the SSc patients. Presence of autophagosome formation was assessed by EM in 17 of the SSc patients and 4 HC. In our SSc study population, 29 of subjects were female and 23 were limited cutaneous. Twenty-nine of 33 SSc patients had autophagy by LC3-FITC staining. Intensity of staining decreased with longer duration of SSc (p = 0.09) and RP (p = 0.10). Bloating and distention differed across level of intensity staining (Wilcoxon signed-rank test, p = 0.05), with the greatest levels among those with moderate intensity. On EM, autophagosome formation was present in 16 of 17 SSc patients and no HC. All SSc patients had perivascular mast cells. Autophagy was present in 29 of 33 SSc patients, and none of our HC suggesting importance in pathogenesis. Autophagy staining was greater among those with shorter duration of SSc. Bloating and distention were higher in patients with moderate autophagy staining. Perivascular mast cells were present in all SSc patients. The role of autophagy in vasculopathy and mast cell activation in SSc warrants further studies. PMID- 23934521 TI - Psychological factors at work and musculoskeletal disorders: a one year prospective study. AB - The etiology of musculoskeletal disorders is complex, with physical and psychosocial working conditions playing an important role. This study aimed to determine the relationship between psychosocial work conditions, such as psychological job demands, decision latitude, social support and job insecurity and musculoskeletal complains (MSCs) and (repetitive strain injuries (RSIs) in a 1-year prospective study. The job content questionnaire, the Nordic musculoskeletal questionnaire and provocation tests were used to study 725 employees aged 20-70 years. Pain in the lower back (58 % of subjects), neck (57 %), wrists/hands (47 %) and upper back (44 %) was most frequent. The carpal tunnel syndrome (CTS) (33.6 %), rotator cuff tendinitis (15.4 %), Guyon's canal syndrome (13.4 %), lateral epicondylitis (7.6 %), medial epicondylitis (5.3 %), tendinitis of forearm-wrist extensors (7.8 %) and tendinitis of forearm-wrist flexors (7.3 %) were the most frequent RSIs. Logistic analysis showed that increased psychological job demands statistically significantly increased the probability of lateral and medial epicondylitis, and increased control (decision latitude) statistically significantly decreased the risk of CTS. There was no relationship between job insecurity, social support and the studied RSIs. Psychosocial factors at work predict prevalence of MSCs and RSIs, irrespectively of demographic factors, e.g., age or gender, and organizational and physical factors. PMID- 23934523 TI - [Development of drugs to treat autoimmune disease - from biologics to small molecules]. PMID- 23934522 TI - The value of pattern capillary changes and antibodies to predict the development of systemic sclerosis in patients with primary Raynaud's phenomenon. AB - The aim of this study is to assess the prognostic value of major provisional criteria for the development of systemic sclerosis (SSc) in primary Raynaud's phenomenon (RP) patients. We retrospectively studied the chart of 497 patients with primary RP in whom anticentromere (ACA) and antitopoisomerase I (ATA) antibodies tests and a capillary reading were available. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratios (LHR+), negative likelihood ratios (LHR-), odds ratio (OR), and area under the receiver operating characteristics curve (AUC) of those criteria were assessed to predict the development of SSc. During the average follow-up of 2.3 +/- 1.9 years, 159 (32 %) patients evolved to SSc, 245 (49.3 %) evolved to other connective tissue diseases, and 93 (18.7 %) patients did not progress. The SSc pattern predicted SSc satisfactorily (LHR+ 4.12, LHR- 0.07, OR 63, AUC 0.819; P < 0.001). ACA were not significantly associated with the development of SSc (LHR+ 1.19, LHR- 0.9, OR 1.32, AUC 0.538, P = 0.156). ATA were significantly associated with the development of SSc (LHR+ 9.32, LHR- 0.67, OR 15.13, AUC 0.777; P < 0.001). Both SSc pattern and ACA or ATA were significantly associated with the development of SSc (LHR+ 2.98, LHR- 0.70, OR 4.2, AUC 0.674; P < 0.001 vs. LHR+ 16, LHR- 0.68, OR 24, AUC 0.819; P < 0.001, respectively). SSc pattern or ATA as independent risk factors, as well as following two parameters together (SSc pattern and ATA or SSc pattern and ACA) were good predictors for the development of SSc. PMID- 23934524 TI - [Kinase inhibitors as an approach to autoimmune disease treatment]. PMID- 23934525 TI - [Proteasome inhibitor for antibody-mediated disease therapy]. PMID- 23934526 TI - [Target identification of novel orally active anti-inflammatory compounds]. PMID- 23934527 TI - [Imaging analyses of ion channel-molecule functions]. PMID- 23934528 TI - [Indoleamine 2,3-dioxygenase 1 modulates the immuneresponse; the new therapeutic targets of this drug]. PMID- 23934529 TI - [Innovation by TaNeDS (Take a New challenge of Drug diScovery) collaborative drug discovery project]. PMID- 23934530 TI - [Injuries to the upper extremities. Clavicular shaft fracture]. PMID- 23934531 TI - [Reverse shoulder arthroplasty for primary fracture treatment. Displaced three and four part fractures of the proximal humerus in the elderly patient]. AB - The treatment of comminuted three and four part fractures of the proximal humerus in elderly patients with degenerative rotator cuff tears is challenging. Primary reverse total shoulder arthroplasty (RSA) is an alternative; however, functional outcome is still unclear due to a lack of study results. The aim of this study was to examine the functional results of RSA and to compare them with the results after reconstruction and locking plate osteosynthesis 1 year after surgery.In this study 24 patients (mean age: 77.9+/-9.1 years) underwent RSA as primary treatment for three and four part fractures of the proximal humerus with either head split or rotator cuff tears >Bateman type II. The results obtained at 3, 6 and 12 months follow-up included shoulder range of motion (ROM), Constant score, age-adjusted and gender-adjusted Constant score and as a percentage when compared to the uninjured side. Data were compared to patients of matching age, gender and fracture pattern from a prospectively collected database of 526 patients treated by locking plate osteosynthesis.The mean shoulder ROM 1 year after surgery was 105+/-29 degrees flexion, 99+/-31 degrees abduction, 22+/-23 degrees external rotation and 65+/-26 degrees internal rotation. In 6 patients flexion-abduction was >130 degrees . The mean Constant score (CS) 1 year postoperatively was 62.4+/ 14, age and gender normalized CS was 79.2+/-20.5, CS compared to the uninjured side was 76.1% and there were no significant differences to matched individuals treated by open reduction and internal fixation using locking plates (p=0.360). There were no infections, dislocations, vascular or neural disorders and surgical revision was not necessary in any patient. RSA should be considered as an appropriate alternative for the primary treatment of comminuted three and four part fractures of the proximal humerus with head split or large rotator cuff tears in elderly patients. Although RSA can provide immediate shoulder stability for elderly patients with severe shoulder injuries, primary RSA needs investigation with regards to long-term outcome. PMID- 23934532 TI - [Endoprosthetics of acute radial head fractures]. AB - Radial head arthroplasty is the treatment of choice for non-reconstructble radial head fractures. Solid prostheses made of metal or pyocarbon can restore valgus stability of the elbow independent of design or stem fixation. Short-term and mid term results show mostly good to excellent results without any evident differences between the different prosthesis philosophies. In order to obtain good results it is important to implant the prosthesis correctly without overfilling and to judge concomitant ligament injuries correctly. This article discusses the anatomical and biomechanical basis of radial head arthroplasty as well as the surgical technique and radiological diagnosis of overfilling. PMID- 23934533 TI - [Fracture endoprosthesis of distal humerus fractures]. AB - The treatment of choice for fractures of the distal humerus is double plate osteosynthesis. Due to anatomical preshaped angle stable plates the primary stability and management of soft tissues has been improved. However, osteoporotic comminuted fractures in the elderly are often not amenable to stable osteosynthesis and total elbow arthroplasty has been established as an alternative therapy. Although complication rates have been reduced, complications of total elbow arthroplasty are still much more frequent than in total hip replacement. Furthermore, patients are advised not to exceed a weight bearing of 5 kg. Therefore, the indications for elbow arthroplasty must be evaluated very strictly and should be reserved for comminuted distal humeral fractures in the elderly with poor bone quality that are not amenable to stable osteosynthesis or for simple fractures in cases of preexisting symptomatic osteoarthritis. This article introduces and discusses modern concepts of elbow arthroplasty, such as modular convertible prosthesis systems, hemiarthroplasty and radial head replacement in total elbow arthroplasty. PMID- 23934534 TI - [Mono- versus polyaxial locking plates]. AB - Conventional plate osteosynthesis is undergoing a period of transition. The concept of locking plate osteosynthesis is of special importance. Monoaxial locking plate osteosynthesis has shown promising results (rapid bone healing via callus, minimal soft tissue irritation, advantageous in osteoporosis). Some implants allow for polyaxial locking. The first results of comparative studies concerning biomechanics and clinical outcome of mono- versus polyaxial locking plates are presented. PMID- 23934535 TI - [Remuneration for orthopedic and trauma surgery in the German diagnosis-related groups (DRG) system. Current development and future needs]. PMID- 23934536 TI - Computed fractional flow reserve (FFTCT) derived from coronary CT angiography. AB - Recent advances in image-based modeling and computational fluid dynamics permit the calculation of coronary artery pressure and flow from typically acquired coronary computed tomography (CT) scans. Computed fractional flow reserve is the ratio of mean coronary artery pressure divided by mean aortic pressure under conditions of simulated maximal coronary hyperemia, thus providing a noninvasive estimate of fractional flow reserve (FFRCT) at every point in the coronary tree. Prospective multicenter clinical trials have shown that computed FFRCT improves diagnostic accuracy and discrimination compared to CT stenosis alone for the diagnosis of hemodynamically significant coronary artery disease (CAD), when compared to invasive FFR as the reference gold standard. This promising new technology provides a combined anatomic and physiologic assessment of CAD in a single noninvasive test that can help select patients for invasive angiography and revascularization or best medical therapy. Further evaluation of the clinical effectiveness and economic implications of noninvasive FFRCT are now being explored. PMID- 23934538 TI - Probiotic supplementation in mothers of very low birth weight infants. AB - OBJECTIVE: Oral probiotic supplementation reduces the risk of necrotizing enterocolitis (NEC) in preterm infants. Concerns about safety and purity of probiotic preparations have limited their use in preterm infants. The authors administered probiotic bacteria to mothers of preterm infants, thereby avoiding the risks of direct exposure of infants to probiotic bacteria. DESIGN: This prospective, randomized, double blind, placebo-controlled trial at the Tel Aviv Medical Center (June 2007-November 2009) examined the effects of maternal oral probiotic supplementation on the incidence of NEC, death, and sepsis in very low birth weight (VLBW) infants fed with maternal breast milk. Mothers were assigned to supplementation with Lactobacillus acidophilus and Bifidobacteria lactis 2 * 10(E) [DOSAGE ERROR CORRECTED] CFU/d or to placebo starting from 1 to 3 days postpartum. The primary outcome measures were NEC, sepsis, and death. RESULTS: In total 49 mothers of 58 VLBW infants were recruited. A total of 25 infants were in the probiotic group and 33 in the placebo group. The overall incidence of Bell stage II to III NEC was 12%, with an incidence of 4% in the infants of the probiotic group and 18.2% in the placebo group (p = 0.12), respectively. Sepsis and mortality rates were similar. CONCLUSION: Postpartum maternal supplementation with probiotic bacteria may decrease the incidence of NEC in breastfed infants. PMID- 23934537 TI - CXCR4+ and FLK-1+ identify circulating cells associated with improved cardiac function in patients following myocardial infarction. AB - The biomarkers CXCR4/FLK-1 select cardiac progenitors from a stem cell pool in experimental models. However, the translational value of these cells in human ischemic heart disease is unknown. Here, flow-cytometry identified CD45( )/CXCR4(+)/FLK-1(+) cells in 30 individuals without ischemic heart disease and 33 first-time acute myocardial infarction (AMI) patients. AMI patients had higher CD45(-)/CXCR4(+)/FLK-1(+) cell-load at 48-h and 3- and 6-months post-AMI (p = 0.003,0.04,0.04, respectively) than controls. Cardiovascular risk factors and left ventricular (LV) ejection fraction were not associated with cell-load. 2D speckle-tracking strain echocardiography assessment of LV systolic function showed improvement in longitudinal strain and dyssynchrony during follow-up associated with longitudinal increases in and higher 48-h post-AMI CD45( )/CXCR4(+)/FLK-1(+) cell-load (r = -0.525, p = 0.025; r = -0.457, p = 0.029, respectively). In conclusion, CD45(-)/CXCR4(+)/FLK-1(+) cells are present in adult human circulation, increased in AMI and associated with improved LV systolic function. Thus, CD45(-)/CXCR4(+)/FLK-1(+) cells may provide a diagnostic tool to follow cardiac regenerative capacity and potentially serve as a prognostic marker in AMI. PMID- 23934539 TI - A history of prior preeclampsia as a risk factor for preterm birth. AB - OBJECTIVE: The objectives of this study are to evaluate the frequency and type of preterm birth (PTB) in women with prior preeclampsia and to compare neonatal outcomes between spontaneous PTB (SPTB) and medically indicated PTB (IPTB) groups. STUDY DESIGN: A secondary analysis of data in women with prior preeclampsia enrolled in a multicenter randomized trial for preeclampsia prevention. Delivery indications were categorized as SPTB and IPTB. Primary outcomes were rates of SPTB and IPTB by gestational age (GA). The rates of composite respiratory morbidity and neonatal intensive care unit (NICU) admission were compared between the PTB groups. RESULTS: Of the 606 pregnancies studied, 142 (23%) pregnancies were delivered at < 37 weeks: 67 (47%) pregnancies were caused by SPTB and 75 (53%) pregnancies were caused by IPTB. Of those who delivered preterm, 89 (63%) were in the late preterm period. The overall rate of the composite neonatal morbidity was 23%. The rates of composite neonatal morbidity, NICU admission, and perinatal death were not different between the groups. The frequency of small for gestational age (SGA) infants was higher in the IPTB group as compared with the SPTB group (21.3 vs. 1.4%, p = 0.01). CONCLUSION: Women with prior preeclampsia are at high risk for PTB (SPTB and IPTB), particularly late PTB, as well as increased risk for SGA. PMID- 23934540 TI - Applicability of standard parameters in diagnostics of primary open-angle glaucoma. AB - BACKGROUND: The aim of this study was to evaluate the sensitivity, specificity, and likelihood ratio of standard diagnostic parameters C/D, NFI, and MD and their applicability in diagnostics of primary open-angle glaucoma. MATERIAL AND METHODS: This study included 194 subjects (371 eyes), ages 30 to 65 years old, who underwent full ophthalmologic examination and HRT, GDx, and FDT examinations. The values of C/D, NFI, and MD diagnostic parameters were determined. The data were statistically evaluated to determine their sensitivity, specificity, and likelihood ratio. RESULTS: Values of the positive and negative likelihood ratios were C/D (11.471 and 0.159), NFI (3.739 and 0.152), and MD (6.323 and 0.309), respectively. CONCLUSIONS: The C/D parameter showed the highest sensitivity and specificity, as well as high positive likelihood ratio and near-zero negative likelihood ratio. The NFI and MD parameters showed lower likelihood ratios and their applicability for the diagnosis of primary open-angle glaucoma is limited. PMID- 23934541 TI - The antiferromagnetic structures of IrMn3 and their influence on exchange-bias. AB - We have determined the magnetic structures of single-crystal thin-films of IrMn3 for the crystallographic phases of chemically-ordered L12, and for chemically disordered face-centred-cubic, which is the phase typically chosen for information-storage devices. For the chemically-ordered L12 thin-film, we find the same triangular magnetic structure as reported for the bulk material. We determine the magnetic structure of the chemically-disordered face-centred-cubic alloy for the first time, which differs from theoretical predictions, with magnetic moments tilted away from the crystal diagonals towards the face-planes. We study the influence of these two antiferromagnetic structures on the exchange bias properties of an epitaxial body-centred-cubic Fe layer showing that magnetization reversal mechanism and bias-field in the ferromagnetic layer is altered significantly. We report a change of reversal mechanism from in-plane nucleation of 90 degrees domain-walls when coupled to the newly reported cubic structure towards a rotational process, including an out-of-plane magnetization component when coupled to the L12 triangular structure. PMID- 23934542 TI - Short- and long-term results of laparoscopic surgery for transverse colon cancer. AB - PURPOSES: We investigated the feasibility of laparoscopic surgery for transverse colon cancer (TCC) by examining the results of this procedure, and comparing the short- and long-term outcomes with those for right-sided and sigmoid colon cancer (OSCC). METHODS: The subjects consisted of 117 patients with TCC. Their complications, forms of recurrence and disease-free and 5-year survival rates were compared to those of 564 patients with OSCC. RESULTS: There were no significant between-group differences in the patient background. The average length of the operation in the TCC group was 215 min and that in the OSCC group was 184 min (p < 0.05). There were also no significant between-group differences in the average blood loss, which was 83.9 and 70.5 g, respectively. No significant difference was observed between groups by stage in terms of the disease-free survival rates, which were 94.4 and 79.1 % for stage II and III in the TCC group, and 92.4 and 78.8 % for stage II and III in the OSCC group. The incidence of intraoperative and postoperative complications was low, and the five year survival rate was favorable. As favorable results of laparoscopic colectomy (LAC) for TCC were also obtained at other sites in a multicenter randomized controlled trial, LAC is expected to become a standard therapy for TCC. PMID- 23934544 TI - Comparative advantages and limitations of the basic metrology methods applied to the characterization of nanomaterials. AB - Fabrication of modern nanomaterials and nanostructures with specific functional properties is both scientifically promising and commercially profitable. The preparation and use of nanomaterials require adequate methods for the control and characterization of their size, shape, chemical composition, crystalline structure, energy levels, pathways and dynamics of physical and chemical processes during their fabrication and further use. In this review, we discuss different instrumental methods for the analysis and metrology of materials and evaluate their advantages and limitations at the nanolevel. PMID- 23934543 TI - Role of maca (Lepidium meyenii) consumption on serum interleukin-6 levels and health status in populations living in the Peruvian Central Andes over 4000 m of altitude. AB - Lepidium meyenii (Maca) is a plant that grows at over 4,000 m above sea level in the central Peruvian Andes. The hypocotyls of this plant are traditionally consumed for their nutritional and medicinal properties. The aim of this study was to determine the health status based on a health related quality of life (HRQL) questionnaire (SF-20) and serum levels of interleukin 6 (IL-6) in subjects that are maca consumers. For this, a cross-sectional study was designed to be performed in 50 subjects from Junin (4,100 m): 27 subjects were maca consumers and 23 were non-consumers. The SF-20 survey is used to obtain a summary measure of health status. The stand up from a chair and sit down (SUCSD) test (to assess lower-extremity function), hemoglobin measurement, blood pressure, sexual hormone levels, serum IL-6 levels and the score of chronic mountain sickness (CMS) were evaluated. Testosterone/estradiol ratio (P <0.05), IL-6 (P < 0.05) and CMS score were lower, whereas the health status score was higher, in maca consumers when compared to non-consumers (P < 0.01). A greater proportion of maca consumers successfully completed the SUCSD test compared to non-consumers (P < 0.01), showing a significant association with lower values of serum IL-6 (P < 0.05). In conclusion, consumption of maca was associated with low serum IL-6 levels and in turn with better health status scores in the SF-20 survey and low chronic mountain sickness scores. PMID- 23934546 TI - Intra-individual reaction time variability and all-cause mortality over 17 years: a community-based cohort study. AB - BACKGROUND: very few studies have examined the association between intra individual reaction time variability and subsequent mortality. Furthermore, the ability of simple measures of variability to predict mortality has not been compared with more complex measures. METHOD: a prospective cohort study of 896 community-based Australian adults aged 70+ were interviewed up to four times from 1990 to 2002, with vital status assessed until June 2007. From this cohort, 770 790 participants were included in Cox proportional hazards regression models of survival. Vital status and time in study were used to conduct survival analyses. The mean reaction time and three measures of intra-individual reaction time variability were calculated separately across 20 trials of simple and choice reaction time tasks. Models were adjusted for a range of demographic, physical health and mental health measures. RESULTS: greater intra-individual simple reaction time variability, as assessed by the raw standard deviation (raw SD), coefficient of variation (CV) or the intra-individual standard deviation (ISD), was strongly associated with an increased hazard of all-cause mortality in adjusted Cox regression models. The mean reaction time had no significant association with mortality. CONCLUSION: intra-individual variability in simple reaction time appears to have a robust association with mortality over 17 years. Health professionals such as neuropsychologists may benefit in their detection of neuropathology by supplementing neuropsychiatric testing with the straightforward process of testing simple reaction time and calculating raw SD or CV. PMID- 23934545 TI - Loss of PPARgamma expression in mammary secretory epithelial cells creates a pro breast tumorigenic environment. AB - Breast cancer is the leading cause of new cancer diagnoses among women. Using peroxisome proliferator-activated receptor (PPAR)gamma((+/-)) mice, we showed normal expression of PPARgamma was critical to stop 7,12 dimethylbenz[a]anthracene (DMBA)-induced breast tumorigenesis. PPARgamma is expressed in many breast cell types including mammary secretory epithelial (MSE) cells. MSEs proliferate as required during pregnancy, and undergo apoptosis or reversible transdifferentiation during involution once lactation is complete. Thus, MSE-specific loss of PPARgamma was hypothesized to enhance DMBA-mediated breast tumorigenesis. To test this, MSE cell-specific PPARgamma knockout (PPARgamma-MSE KO) and control (PPARgamma-WT) mice were generated, mated and allowed to nurse for three days. One week after involution, dams were treated with DMBA to initiate breast tumors, and randomized on week 7 to continue receiving a normal chow diet (DMBA Only: PPARgamma-WT, n = 15; PPARgamma-MSE KO, n = 25) or one supplemented with a PPARgamma activating drug (DMBA + ROSI: PPARgamma-WT, n = 17; PPARgamma-MSE KO, n = 24), and monitored for changes in breast tumor outcomes. PPARgamma-MSE KOs had significantly lower overall survival and decreased mammary tumor latency as compared to PPARgamma-WT controls. PPARgamma activation significantly reduced DMBA-mediated malignant mammary tumor volumes irrespective of genotype. MSE-specific PPARgamma loss resulted in decreased mammary gland expression of PTEN and Bax, increased superoxide anion production, and elevated serum eotaxin and RANTES, creating a protumorigenic environment. Moreover, PPARgamma activation in MSEs delayed mammary tumor growth in part by down-regulating Cox-1, Cox-2 and cyclin D1. Collectively, these studies highlight a protective role of MSE-specific PPARgamma during breast tumorigenesis, and support a novel chemotherapeutic role of PPARgamma activation in breast cancer. PMID- 23934547 TI - Direct analysis in real time mass spectrometry (DART-MS) of ionic liquids. AB - Direct analysis in real time mass spectrometry (DART-MS) was used to analyze ionic liquids (ILs) containing either imidazolium or phosphonium cations combined with different types of inorganic and organic anions. Ionic liquids were directly inserted into the ionization source using a glass probe without dissolution into organic solvents. Mass spectra of the ILs were collected in both positive and negative mode with a linear ion-trap instrument. The intact cation of the compound was typically the dominant peak in positive mass spectra and cluster ion formation was present. Some individual anions were not readily observed in the negative mass spectra (based on the type of anion); however, the mass difference of adjacent cluster ions equal the mass of a complete IL and the anion mass could be verified by subtracting the known cation mass. The degree and intensity of the cluster ion formations was found to be dependent on the nature of the specific ILs as well as the DART temperature gas stream. PMID- 23934548 TI - Thermally accelerated oxidative degradation of quercetin using continuous flow kinetic electrospray-ion trap-time of flight mass spectrometry. AB - Thermally accelerated oxidative degradation of aqueous quercetin at pH 5.9 and 7.4 was kinetically measured using an in-house built online continuous flow device made of concentric capillary tubes, modified to fit to the inlet of an electrospray ionization-ion trap-time-of-flight-mass spectrometer (ESI-IT-TOF MS). Time-resolved mass spectral measurements ranging from 2 to 21 min were performed in the negative mode to track intermediate degradation products and to evaluate the degradation rate of the deprotonated quercetin ion, [Q-H](-). Upon heating solutions in the presence of dissolved oxygen, degradation of [Q-H](-) was observed and was accelerated by an increase in pH and temperature. Regardless of the condition, the same degradation pathways were observed. Degradation mechanisms and structures were determined using higher order tandem mass spectrometry (up to MS(3)) and high mass accuracy. The observed degradation mechanisms included oxidation, hydroxylation, and ring-cleavage by nucleophilic attack. A chalcan-trione structure formed by C-ring opening after hydroxylation at C2 was believed to be a precursor for other degradation products, formed by hydroxylation at the C2, C3, and C4 carbons from attack by nucleophilic species. This resulted in A-type and B-type ions after cross-ring cleavage of the C-ring. Based on time of appearance and signal intensity, nucleophilic attack at C3 was the preferred degradation pathway, which generated 2,4,6-trihydroxymandelate and 2,4,6-trihydroxyphenylglyoxylate ions. Overall, 23 quercetin-related ions were observed. PMID- 23934549 TI - Is there a role for probiotics in the prevention or treatment of food allergy? AB - A balanced gut microbiota is crucial for the development of healthy immunoregulation and gut barrier function to allow brisk immune responses to pathogens and systemic hyporesponsiveness to harmless antigens such as food. Although the first allergic disease to manifest itself, atopic eczema, is not equivalent to food allergy, pre- and postnatal administration of specific probiotic strains has emerged as a promising tool for the prevention of this condition, with potential implications for food allergy development. For food allergy proper, however, we lack markers and risk factors and mechanisms, i.e., targets for preventive measures. The focus here is therefore on the treatment. Indeed, the potential of specific probiotic strains to alleviate food allergy resides in their ability to modify antigens, repair gut barrier functions, balance altered microbiota, and restore local and systemic immune regulation. In patients with multiple food allergies, induction of oral tolerance by specific probiotics continues to attract research interest. PMID- 23934550 TI - The relationship between advances in understanding the microbiome and the maturing hygiene hypothesis. AB - Expanding knowledge about an interaction of the bacterial colonization with pathogenic and non-pathogenic bacteria and the human immune system leads to speculation on potential effects on health and disease. Recent advances in sequencing technologies and new bioinformatic possibilities now allow investigating the microbes that colonize the human gut, skin and airways in more detail. In light of the hygiene hypothesis, the impact of the microbial composition of individuals with allergic sensitization and/or atopic diseases, i.e., allergic asthma or atopic eczema, were investigated in several clinical trials. Altered diversity of gut microbiota during infancy as well as colonization with specific pathogenic and apathogenic bacteria has been linked with an elevated risk for allergy. There are ongoing attempts to establish intervention strategies aimed at modifying initial colonization patterns in early life. While results from animal models, in-vitro data and epidemiological studies encourage the concept of a relationship between the microbiome and the development of allergic diseases, the transfer of these findings to intervention strategies still seems to be a major challenge. PMID- 23934552 TI - Small for gestational age and low birth weight term admissions to a tertiary perinatal centre in northern Queensland, Australia. AB - Northern Queensland is unique in that the proportion of Aboriginal and Torres Straits Islander (ATSI) communities is higher than the rest of Australia. The aim of this study was to describe the characteristics of term admissions of low birth weight (LBW; birth weight < 2,500 g) and small for gestational age (SGA; birth weight < 10th centile) infants to a neonatal unit. All term infants (>37 weeks of gestation) with LBW and/or SGA admitted to the neonatal unit over the last 10 years (2002-2011) were identified and the percentage calculated. Ethnicity was determined by the mother and that information was recorded in the patient's medical record. The average percentage of LBW ATSI infants was 20.2 +/- 5.7%, which was significantly higher (almost double) compared with the percentage of LBW non-ATSI infants (10.2 +/- 1.9%; p < 0.001). The average percentage of SGA ATSI infants was also significantly higher than the percentage of SGA non-ATSI infants (31.8 +/- 6.0 vs. 18.6 +/- 2.8%, respectively; p < 0.001). The mean percentage of LBW indigenous infants admitted to the neonatal unit was significantly higher than non-ATSI infants. PMID- 23934551 TI - Effect of Janus kinase 3 on the peptide transporters PEPT1 and PEPT2. AB - The tyrosine kinase Janus kinase 3 (JAK3) contributes to signaling regulating the proliferation and apoptosis of lymphocytes and tumor cells. Replacement of lysine by alanine in the catalytic subunit yields the inactive (K851A)JAK3 mutant that underlies severe combined immune deficiency. The gain-of-function mutation (A572V)JAK3 is found in acute megakaryoplastic leukemia and T cell lymphoma. The excessive nutrient demand of tumor cells requires upregulation of transporters in the cell membrane including peptide transporters PEPT1 and PEPT2. The carriers further accomplish intestinal peptide transport. Little is known about signaling regulating peptide transport. The present study explored whether PEPT1 and PEPT2 are upregulated by JAK3. PEPT1 or PEPT2 was expressed in Xenopus oocytes with or without additional expression of JAK3, and electrogenic peptide (glycine-glycine) transport was determined by dual-electrode voltage clamp. PEPT2-HA membrane protein abundance was analyzed by chemiluminescence. Intestinal electrogenic peptide transport was estimated from peptide-induced current in Ussing chamber experiments. In PEPT1- and PEPT2-expressing oocytes, but not in water-injected oocytes, the dipeptide gly-gly generated an inward current, which was significantly increased following coexpression of JAK3. The effect of JAK3 on PEPT1 was mimicked by (A568V)JAK3 but not by (K851A)JAK3. JAK3 increased maximal peptide-induced current in PEPT1-expressing oocytes but rather decreased apparent affinity of the carrier. Coexpression of JAK3 enhanced the PEPT2-HA protein abundance in the cell membrane. In JAK3- and PEPT1-expressing oocytes, peptide induced current was blunted by the JAK3 inhibitor WHI-P154, 4-[(3'-bromo-4' hydroxyphenyl)amino]-6,7-dimethoxyquinazoline (22 MUM). In intestinal segments gly-gly generated a current which was significantly smaller in JAK3-deficient mice (jak3-/-) than in wild-type mice (jak3+/+). In conclusion, JAK3 is a powerful regulator of peptide transporters PEPT1 and PEPT2. PMID- 23934553 TI - Up-regulation of Alzheimer's disease-associated proteins may cause enflurane anesthesia induced cognitive decline in aged rats. AB - Isoflurane anesthesia can cause post-operative cognitive dysfunction in elderly patients. As an isomer of isoflurane, enflurane may also account for cognitive dysfunction. However, the mechanism of enflurane-induced cognitive dysfunction remains obscure. In this study, we investigated the effects of enflurane anesthesia on cognitive function and the possible roles of beta-amyloid protein and phosphorylated tau protein in response to enflurane anesthesia in aged rats. After intraperitoneal injection of enflurane, the Morris water maze and the step down passive avoidance tests were conducted to test the cognitive ability and memory. The enflurane group showed prolonged escape latency, extended space exploration time and increased number of errors at early stage after enflurane anesthesia, suggesting that enflurane should be responsible for the impairment of cognition in aged rats. In addition, we analyzed the expression level of beta amyloid and phosphorylation level of tau in the hippocampus by immunoblotting. Interestingly, the levels of beta-amyloid and phosphorylated tau in the hippocampus increased significantly at early stage and then restored to pre anesthetic levels. Taken together, our results suggest that increasing of beta amyloid and phosphorylation of tau are important to cause cognitive decline in aged rats during initial stage after enflurane anesthesia. PMID- 23934555 TI - Micellar electrokinetic chromatography of graphene and chemically modified graphenes with dodecylbenzenesulfonate. AB - Graphene and chemically modified graphenes were resolved by micellar electrokinetic chromatography (MEKC) using sodium dodecylbenzenesulfonate (SDBS) as a micelle matrix. Graphene was successfully dispersed in a micellar solution, and a consecutive and broad signal was obtained by the MEKC with a 20 mmol dm-3 aqueous SDBS solution for Graphene Nanoplatelets. Chemically oxidized graphene was less retained to the micelle than the Graphene Nanoplatelets by the proposed MEKC, and they were resolved with each other. PMID- 23934554 TI - Fine mapping of type 1 diabetes regions Idd9.1 and Idd9.2 reveals genetic complexity. AB - Nonobese diabetic (NOD) mice congenic for C57BL/10 (B10)-derived genes in the Idd9 region of chromosome 4 are highly protected from type 1 diabetes (T1D). Idd9 has been divided into three protective subregions (Idd9.1, 9.2, and 9.3), each of which partially prevents disease. In this study we have fine-mapped the Idd9.1 and Idd9.2 regions, revealing further genetic complexity with at least two additional subregions contributing to protection from T1D. Using the NOD sequence from bacterial artificial chromosome clones of the Idd9.1 and Idd9.2 regions as well as whole-genome sequence data recently made available, sequence polymorphisms within the regions highlight a high degree of polymorphism between the NOD and B10 strains in the Idd9 regions. Among numerous candidate genes are several with immunological importance. The Idd9.1 region has been separated into Idd9.1 and Idd9.4, with Lck remaining a candidate gene within Idd9.1. One of the Idd9.2 regions contains the candidate genes Masp2 (encoding mannan-binding lectin serine peptidase 2) and Mtor (encoding mammalian target of rapamycin). From mRNA expression analyses, we have also identified several other differentially expressed candidate genes within the Idd9.1 and Idd9.2 regions. These findings highlight that multiple, relatively small genetic effects combine and interact to produce significant changes in immune tolerance and diabetes onset. PMID- 23934556 TI - Solvent-dependent assembly of discrete and continuous CoCl2 adamantane-based ligand complexes: observations by CSI-mass spectrometry and X-ray crystallography. AB - Discrete and continuous coordination structures were obtained in single crystals of CoCl2 and an adamantane-based bidentate ligand bearing imidazolyl groups, depending on the methanol concentration in a methanol-chloroform mixture. Single crystal X-ray structure analysis revealed that the metal centers exhibited a tetrahedral geometry in the discrete complex and an octahedral geometry in the continuous metal complex. Conventional analytical methods, including UV-vis and NMR spectroscopy, could not identify those two complexes in solution. In contrast, cold-spray ionization mass spectrometry could detect differences between the discrete complex and the continuous metal complex, and ion peaks due to continuous ligand adducts were found only in the spectrum of the continuous metal complex. PMID- 23934557 TI - Amino acid precursors from a simulated lower atmosphere of titan: experiments of cosmic ray energy source with 13C- and 18O-stable isotope probing mass spectrometry. AB - The organic haze of aerosols that shrouds the Saturnian moon Titan has previously been studied by both observations and laboratory simulation experiments. Here we report the abiotic formation of amino acid precursors in complex organic molecules during experimental simulation of the environment near Titan's surface with proton irradiation. Pyrolysis of the organic molecules formed in the simulated Titan atmosphere by proton irradiation at 600 degrees C yielded compounds that contained HCN and NH3 (m/z = 27 and 17). These experimental results are consistent with the molecular information obtained by pyrolysis gas chromatography/mass spectrometry (pyrolysis GC/MS) of samples collected by the Huygens probe to Titan. Scanning electron microscopy (SEM) and three-dimensional atomic force microscopy (AFM) images of the irradiation products reveal nanometer scale filaments and globules in complex amorphous structures (approximately 1000 Da). Isotope probing experiments by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) show that oxygen atoms were incorporated into the racemic amino acids by hydrolysis of 18O-labeled water. We suggest that the amino acid precursors possibly formed after water hydrolysis, as suggested in a previous observational study (C. A. Griffith, T. Owen, T. R. Geballe, J. Rayner, and P. Rannou, Science, 2003, 300, 628). We propose that cosmic rays are a significant and effective energy source for producing complex organics and amino acid precursors in Titan's atmospheric haze. PMID- 23934558 TI - Chromatographic behavior of selenoproteins in rat serum detected by inductively coupled plasma mass spectrometry. AB - Two major selenoproteins are present in mammalian serum: extracellular glutathione peroxidase (eGPx) and selenoprotein P (Sel P). The chromatographic behaviors of the two serum selenoproteins were compared in four rodent species, and the selenoproteins in rat serum were identified by measuring enzyme activity and Western blotting. The selenoproteins in rat serum showed a specific chromatographic behavior. In particular, rat eGPx was eluted faster than eGPxs of the other rodent species, although the amino-acid sequences of the rodent species were identical. The elution profiles of Se in rat serum obtained by inductively coupled plasma tandem mass spectrometry (ICP-MS-MS) and ICP-MS were compared. The tandem quadrupoles and the O2 reaction/collision gas completely removed severe interferences with the Se speciation originating from the plasma source and the biological sample matrix. ICP-MS-MS under the O2 mass shift mode gave us more accurate abundance ratios of Se than ICP-MS. PMID- 23934559 TI - Multi-element analysis by portable total reflection X-ray fluorescence spectrometer. AB - Multi-element solutions containing the 11 elements S, K, Sc, V, Mn, Co, Cu, Ga, As, Br and Y were analyzed by a portable total reflection X-ray fluorescence (TXRF) spectrometer. The excitation parameters (glancing angle, operational voltage and current) and sample amount were optimized for the portable TXRF in order to realize the smallest possible detection limits for all elements. The excitation parameter dependencies of the fluorescence signal and background for the detected elements are explained in detail. Background contributed by the sample carrier is also discussed. Consequently, nine elements were detectable at sub-nanogram levels in a single measurement of 10 min under the optimal experimental conditions. The portable TXRF spectrometer was found to be suitable for simultaneous multi-element analysis with low detection limits. The features of high sensitivity, small sample amount required, and fast detection of a wide range of elements make the portable TXRF a valuable tool in various applications, such as field studies in environmental and geological investigations. PMID- 23934560 TI - Lateral flow immunoassay with the signal enhanced by gold nanoparticle aggregates based on polyamidoamine dendrimer. AB - In order to amplify the signal in a gold nanoparticle-based lateral flow immunoassay, a simple and sensitive method utilizing gold nanoparticle aggregates as a colored reagent formed with a polyamidoamine dendrimer was developed. The results were compared with that achieved by employing the individual nanoparticles used in the conventional lateral flow immunoassay. Under the optimized experimental conditions, a detection limit of 0.1 ng mL-1 for rabbit immunoglobulin G was achieved, which is almost 20-fold lower than that of the traditional method using individual gold nanoparticles. We believe that this simple, practical bioassay platform will be of interest for use in areas such as disease diagnostics, pathogen detection, and quality monitoring of food and water. PMID- 23934561 TI - Determining the concentration of procalcitonin using a magnetic particles-based chemiluminescence assay for the clinical diagnosis of sepsis. AB - Our objective is to develop an assay based on magnetic particles (MPs) to determine the concentration of procalcitonin (PCT) using a chemiluminescence immunoassay (CLIA). Fluorescein isothiocyanate (FITC) and N-(aminobutyl)-N (ethylisoluminol) (ABEI) were used to label two different anti-procalcitonin (PCT) monoclonal antibodies. The labeled antibodies, the PCT antigen, and the anti-FITC antibody-coated MPs formed a double-sandwiched immunocomplex. The measured relative light units (RLUs) of ABEI in the substrate solution were directly proportional to the amount of PCT present in the samples. The proposed method was linear to 600 ng/mL with a detection limit of 0.03 ng/mL. The coefficient of variation (CV) was <5% and <6% for the intra- and inter-assay precision, respectively. The average recoveries were between 95 and 107%. The linearity-dilution effect gave a linear correlation coefficient of 0.9912. This proposed assay provided an alternative method to quantitatively measure PCT in serum for the diagnosis of sepsis. PMID- 23934562 TI - Simple preparation of green fluorescent protein conjugated with beta-cyclodextrin in a site specific manner. AB - We have site-directedly linked a green fluorescent protein (GFP) variant and a beta-cyclodextrin (beta-CD) with a simple method to develop a basic complex for sophisticated supramolecules. We have confirmed beta-CD grafting on GFP with several methods including matrix-assisted laser desorption/ionization linear time of-flight mass spectrometry (MALDI-TOF MS) without protease digestion and characterized the complex as well. In consideration of the resulting properties, the product we plainly and efficiently obtained could have applications related to sensing devices and drug delivery systems. PMID- 23934563 TI - Indirect chemiluminescence-based determination of catecholamines in pharmaceutical formulations by furandicarboxylate derivative as a novel blue fluorescer in peroxyoxalate-H2O2 system. AB - A novel, simple, cheap, and high sensitivity batch chemiluminescent method for the determination of catecholamine drugs, epinephrine (E), dopamine (DA) and methyldopa (MD) at microgram levels in pharmaceutical formulations is described. The method is based on a chemiluminescence (CL) system arising from the reaction of bis(2,4,6-trichlorophenyl) oxalate (TCPO) with H2O2 in the presence of a novel fluorescer, furandicarboxylate, and is proposed as a new analytical method for the determination of catecholamines. The method is based on the inhibition of CL emission by DA and its enhancement by E and MD. Under optimal conditions, good linear ranges were obtained, 0.5 - 12.7, 0.06 - 1.83 and 0.069 - 3.52 MUg/mL with detection limits of 0.30, 0.03 and 0.04 MUg/mL (S/N = 3) for DA, E and MD, respectively. Moreover, a pooled-intermediate model was used to determine the kinetic parameters of CL with and without catecholamines and a possible CL mechanism was discussed. PMID- 23934564 TI - Speciation analysis of ultratrace chromium in water by on-line reaction/concentration/separation method using a cation-exchange column. AB - A cation-exchange column (TSK IC-Cation, 4.6 mm i.d., 10 mm) was used as a reaction/concentration/separation medium in an HPLC system. Cr(VI) and 1,5 diphenylcarbazide (DPC) were on-line mixed and reacted in a flow tube. When the reagents flowed into the column, both DPC and the complex were concentrated on the column, and the higher DPC concentration accelerated the remaining Cr(VI) to quickly complete the reaction with the DPC on the column. After the complexation and preconcentration, the complex and the extra DPC were eluted by a mixed solution containing lanthanum chloride and 1-propanol. The absorbance of the Cr(III)-DPCO complex at 540 nm was continuously monitored. In addition, the dissolved Cr(III) could be oxidized to Cr(VI) by 185-nm irradiation using a low pressure ultraviolet (UV) lamp for 8 min, and then analyzed by the present method as total chromium, thus the quantitative speciation analysis of Cr(III) and Cr(VI) was realized. In the range of 1 ng dm-3 - 100 MUg dm-3 Cr(VI) concentration, the calibration curve was linear. The analytical time was 8 min for Cr(VI) and 24 min for total Cr. The detection limit (3sigma) of the method was 0.6 ng dm-3 for Cr(VI) and 0.8 ng dm-3 for total chromium when using a 3.9 cm3 water sample. The present method could be successfully applied to the speciation analysis of dissolved chromium in natural water, and the leaching test of Cr(III) and Cr(VI) from stainless steel. PMID- 23934565 TI - Application of online preconcentration affinity capillary electrophoresis method to glycans labeled with 8-aminonaphthalene-1,3,6-trisulfonic acid using blue light emitting diode-induced fluorescence detection. AB - An online preconcentration technique, large volume sample stacking with an electroosmotic flow pump, was combined with partial filling affinity capillary electrophoresis (PFACE) to create a highly sensitive analysis of the interaction of glycoprotein-derived oligosaccharides with plant lectins. Oligosaccharides were derivatized with 8-aminonaphthalene-1,3,6-trisulfonic acid (ANTS) for use in a blue light emitting diode-induced fluorescence detection capillary electrophoresis system. ANTS-labeled oligosaccharides were delivered to an entire neutrally coated capillary, and lectin solution was then hydrodynamically introduced from the outlet of the capillary as a short plug. When negative voltage was then applied, a low concentration sample solution caused a significant flow by electroosmosis from anode to cathode and the ANTS-labeled oligosaccharides moved quickly towards the anode and concentrated in the lectin phase. Finally, when the electroosmotic flow became negligible, ANTS-labeled saccharides passed through the lectin plug and were detected at the anodic end. The sensitivity was enhanced by a factor of roughly 200 compared to typical hydrodynamic injection (13.8 kPa, 5 s). PMID- 23934566 TI - Homogeneous liquid-liquid extraction (HoLLE) via flotation combined with gas chromatography-flame ionization detection as a very simple, rapid and sensitive method for the determination of fenitrothion in water samples. AB - Homogeneous liquid-liquid extraction via flotation assistance (HoLLE-FA) and gas chromatography-flame ionization detection (GC-FID) was presented for the extraction and determination of fenitrothion in water samples. In this work, a rapid, simple and efficient HoLLE-FA method was developed based on applying low density organic solvents without employing centrifugation. A special extraction cell was designed to facilitate the collection of low-density solvent extraction in the determination of fenitrothion in water samples. The water sample solution was added into an extraction cell that contained an appropriate mixture of extraction and homogeneous solvents. By using air flotation, the organic solvent was collected at the conical part of the designed cell. Under the optimum conditions, the method performance was studied in terms of the linear dynamic range (LDR from 1.0 up to 100 MUg L-1), linearity (r2 > 0.998), and precision (repeatability < 8.0%). Also, limit of detection (LOD) of 0.4 MUg L-1 was obtained for fenitrothion. The applicability of the HoLLE-FA method was evaluated by the extraction and determination of fenitrothion in three different water samples. PMID- 23934567 TI - 13C and 27Al NMR study of complexation between aluminium ion and simple dicarboxylic acids under an acidic condition: new peak assignments of 27Al NMR spectra of mixed solutions of Al3+ and simple dicarboxylic acids. AB - Due to a consideration of Al detoxicification by simple carboxylic acid, the interaction between aluminium ion (Al3+) and three dicarboxylic acids (oxalic acid (OX), malonic acid (MA) and succinic acid (SU)) under an acidic condition was investigated using 13C and 27Al NMR techniques. Based on deconvolution of the 27Al NMR spectra and quantitative 13C NMR spectra, the structure of each complex was elucidated. Especially, we focused on the peak assignments of 27Al NMR spectra by combining of the results of quantitative 13C NMR spectra. In the OX system, the peak at 16 ppm in the 27Al NMR spectrum originates from Al(OX)33- and Al(OX)2-, and the ratio of each complex depends on the OX/Al molar ratio. In the MA system, the three complexes (Al(MA)2-, Al(MA)33- and Al(MA)+) are represented in the peak at 2 ppm in the 27Al NMR spectrum. The assignment of peaks in the 27Al NMR spectra in this study differs from those described in previous papers. PMID- 23934568 TI - A novel approach to identifying the elemental composition of individual residue particles retained in single snow crystals. AB - This study was carried out to describe the chemical characteristics of individual residual particles in hexagonal snow crystals, which can provide a clue to the aerosol removal mechanism during snowfall. In the present study, to collect snow crystal individually and to identify the elemental composition of individual residues retained in a hexagonal crystal, an orchestration of the replication technique and micro-particle induced X-ray emission (micro-PIXE) analysis was carried out. Information concerning the elemental compositions and their abundance in the snow crystals showed a severe crystal-to-crystal fluctuation. The residues retained in the hexagonal snow crystals were dominated primarily by mineral components, such as silica and calcium. Based on the elemental mask and the spectrum of micro-PIXE, it was possible to presume the chemical inner structure as well as the elemental mixing state in and/or on the individual residues retained in single snow crystals. PMID- 23934569 TI - Electrochemical determination of celecoxib on a graphene based carbon ionic liquid electrode modified with gold nanoparticles and its application to pharmaceutical analysis. AB - A graphene-based carbon ionic liquid electrode modified with gold nanoparticles was fabricated. The electrochemical response of the modified electrode toward celecoxib was studied by means of cyclic voltammetry and differential pulse voltammetry. The structural morphology of the modified electrode was characterized by a scanning electron microscopy technique and electrochemical impedance spectroscopy. The prepared electrode showed excellent electrocatalytic activity in the reduction of celecoxib in a phosphate buffer solution, leading to remarkable enhancements in the corresponding peak currents and lowering of the peak potential. The advantages are related to the unique properties of graphene and gold nanoparticles such as a large surface area and increased electron transfer abilities. Differential pulse voltammetry was applied to the quantitative determination. The calibration curve was linear in the concentration range of 0.5 to 15 MUM and the detection limit was about 0.2 MUM (Sb/N = 3). The proposed electrochemical sensor was successfully applied to the determination of celecoxib in real samples. PMID- 23934571 TI - The active form of goat insulin-like peptide 3 (INSL3) is a single-chain structure comprising three domains B-C-A, constitutively expressed and secreted by testicular Leydig cells. AB - Relaxin-like factor (RLF), also called insulin-like peptide 3 (INSL3), is a member of the insulin/relaxin gene family and is produced by testicular Leydig cells. While the understanding of its effects is growing, very little is known about the structural and functional properties of native INSL3. Here, we demonstrate that native INSL3 isolated from goat testes is a single-chain structure with full biological activity, and is constitutively expressed and secreted by Leydig cells. Using a series of chromatography steps, native INSL3 was highly purified as a single 12-kDa peak as revealed by SDS-PAGE. MS/MS analysis provided 81% sequence coverage and revealed a distinct single-chain structure consisting of the B-, C-, and A-domains deduced previously from the INSL3 cDNA sequence. Moreover, the N-terminal peptide was six amino acid residues longer than predicted. Native INSL3 exhibited full bioactivity in HEK-293 cells expressing the receptor for INSL3. Immunoelectron microscopy and Western blot analysis revealed that INSL3 was secreted by Leydig cells through the constitutive pathway into blood and body fluids. We conclude, therefore, that goat INSL3 is constitutively secreted from Leydig cells as a B-C-A single-chain structure with full biological activity. PMID- 23934572 TI - Relationship between condensed tannin structures and their ability to precipitate feed proteins in the rumen. AB - BACKGROUND: Tannins can bind to and precipitate protein by forming insoluble complexes resistant to fermentation and with a positive effect on protein utilisation by ruminants. Three protein types, Rubisco, rapeseed protein and bovine serum albumin (a single high-molecular weight protein), were used to test the effects of increasing concentrations of structurally different condensed tannins on protein solubility/precipitation. RESULTS: Protein type (PT) influenced solubility after addition of condensed tannins (P < 0.001) in the order: Rubisco < rapeseed < BSA (P < 0.05). The type of condensed tannin (CT) affected protein solubility (P = 0.001) with a CT * PT interaction (P = 0.001). Mean degree of polymerisation, proportions of cis- versus trans-flavanol subunits or prodelphinidins versus procyanidins among CTs could not explain precipitation capacities. Increasing tannin concentration decreased protein solubility (P < 0.001) with a PT * CT concentration interaction. The proportion of low-molecular weight rapeseed proteins remaining in solution increased with CT concentration but not with Rubisco. CONCLUSIONS: Results of this study suggest that PT and CT type are both of importance for protein precipitation but that the CT structures investigated did not allow identification of parameters that contribute most to precipitation. It is possible that the three-dimensional structures of tannins and proteins may be more important factors in tannin-protein interactions. PMID- 23934573 TI - Aripiprazole increases NADPH level in PC12 cells: the role of NADPH oxidase. AB - In aripiprazole-treated PC12 cells, we previously showed that the mitochondrial membrane potential (Deltapsim) was rather increased in spite of lowered cytochrome c oxidase activity. To address these inconsistent results, we focused the NADPH generation by glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway (PPP), to titrate reactive oxygen species (ROS) that results in the Deltapsim maintenance. G6PD may be also involved in another inconsistent result of lowered intracellular lactate level in aripiprazole-treated PC12 cells, because PPP competes glucose-6-phosphate with the glycolytic pathway, resulting in the downregulation of glycolysis. Therefore, we assayed intracellular amounts of NADPH, ROS, and the activities of the enzymes generating or consuming NADPH (G6PD, NADP(+)-dependent isocitrate dehydrogenase, NADP(+)-dependent malic enzyme, glutathione reductase, and NADPH oxidase [NOX]) and estimated glycolysis in 50 MUM aripiprazole-, clozapine-, and haloperidol treated PC12 cells. NADPH levels were enhanced only in aripiprazole-treated ones. Only haloperidol increased ROS. However, the enzyme activities did not show significant changes toward enhancing NADPH level except for the aripiprazole induced decrease in NOX activity. Thus, the lowered NOX activity could have contributed to the aripiprazole-induced increase in the NADPH level by lowering ROS generation, resulting in maintained Deltapsim. Although the aforementioned assumption was invalid, the ratio of fructose-1,6-bisphosphate to fructose-6 phosphate was decreased by all antipsychotics examined. Pyruvate kinase activity was enhanced only by aripiprazole. In summary, these observations indicate that aripiprazole possibly possesses the pharmacological superiority to clozapine and haloperidol in the ROS generation and the adjustment of glycolytic pathway. PMID- 23934574 TI - Inhibition of NF-kappaB transcriptional activation in HepG2 cells by diterpenoids from the soft coral Sinularia maxima. AB - Anti-inflammatory transcriptional effects of nineteen compounds (1-19) from the soft coral Sinularia maxima were evaluated using NF-kappaB luciferase and reverse transcriptase polymerase chain reaction. Compounds 1, 2, 4, 8, 15, 17, and 18 significantly inhibited TNFalpha-induced NF-kappaB transcriptional activity in HepG2 cells in a dose-dependent manner, with IC50 values ranging from 15.81 +/- 2.29 to 29.10 +/- 1.54 MUM. Furthermore, the transcriptional inhibitory function of these compounds was confirmed by a decrease in intercellular adhesion molecule 1 and inducible nitric oxide synthase gene expression levels in HepG2 cells. These results provide a scientific rationale for the use of the soft coral S. maxima warrant further studies to develop new agents for the prevention and treatment of inflammatory. PMID- 23934576 TI - The difficulty of letting go: moderators of the deactivation of completed intentions. AB - Recent studies showed that prospective memory (PM) intentions might not be deactivated directly after completion. The residual activation leads to aftereffects which are reflected as interference in performance when former PM cues of old intentions are interspersed in the new task (i.e., intention deactivation failure, Walser et al., J Exp Psychol Learn Mem Cogn 38(4):1030 1044, 2012). In the present study, we investigated potential mechanisms that might support the deactivation process of completed intentions by manipulating the task demands (e.g., working memory load) between intention completion and measurement of aftereffects. Aftereffects on repeated PM-cue trials were found when working memory load was low (control condition), but were reduced when available resources were sparse (working memory load condition). When participants were asked to reflect upon the to-be-deactivated PM cue, subsequent aftereffects were increased. Further, overall aftereffects were larger for participants low in self-reported action control. Results show that the nature of the filler-task activity determines whether the representation of the completed intention is destabilized (working memory load) or strengthened (intention reflection). The (at least partial) overwriting of completed intention representations by new working memory task representations seems therefore to reflect a supporting factor for the deactivation of completed intentions. PMID- 23934577 TI - Molecular mechanisms of moraxella catarrhalis-induced otitis media. AB - Moraxella catarrhalis is a Gram-negative bacterium, exclusively present in humans and a leading causative agent of otitis media (OM) in children. Most children (80 %) experience at least one episode of OM by their third birthday and half suffer multiple episodes of infection. Over the last 10 years, increased evidence suggests that M. cat possesses multiple virulence factors which can be carried through biologically active outer membrane vesicles (OMVs) that are themselves able to activate host-immune responses. It has also been noted that multiple toll like receptors are responsible for M. cat recognition. This review is intended to summarize the key findings and progress in recent years of the molecular mechanisms of M. cat-induced otitis media with particular emphasis on adhesion, invasion, and activation of the host immune system, biofilm formation, and vaccine development. PMID- 23934578 TI - Preparation of reduced graphene oxide by infrared irradiation induced photothermal reduction. AB - We present a green and scalable route toward the formation of reduced graphene oxide (r-GO) by photothermal reduction induced by infrared (IR) irradiation, utilizing a bathroom IR lamp as the source of IR light. Thermogravimetric analysis, Raman, Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy confirm the reduction of r-GO by IR light. Ultraviolet-visible infrared spectra indicate that adsorption of IR light by original GO films is less than that of UV and visible light; but when GO is exposed to IR light, its adsorption of IR light increases very rapidly with time. The influence of the power density of the IR light on the structure and properties of r-GO was investigated. At high IR power density, the reduction reaction was so fierce that r-GO became highly porous due to the rapid degassing and exfoliation of GO sheets. The r-GO powder revealed good performance as the anode material for lithium ion batteries. At relatively low IR power density, the reduction process was found to be mild but relatively slow. Crack-free and uniform conductive r-GO thin films with a volume conductivity of 1670 S m(-1) were then prepared by two step IR irradiation, i.e. first at low IR power density and then at high IR power density. Moreover, the r-GO films were also observed to exhibit obvious and reversible IR light-sensing behavior. PMID- 23934580 TI - The 21st century benefits of smoking cessation in Europe. PMID- 23934579 TI - A meta-analysis of prospective studies of coffee consumption and mortality for all causes, cancers and cardiovascular diseases. AB - Several prospective studies considered the relation between coffee consumption and mortality. Most studies, however, were underpowered to detect an association, since they included relatively few deaths. To obtain quantitative overall estimates, we combined all published data from prospective studies on the relation of coffee with mortality for all causes, all cancers, cardiovascular disease (CVD), coronary/ischemic heart disease (CHD/IHD) and stroke. A bibliography search, updated to January 2013, was carried out in PubMed and Embase to identify prospective observational studies providing quantitative estimates on mortality from all causes, cancer, CVD, CHD/IHD or stroke in relation to coffee consumption. A systematic review and meta-analysis was conducted to estimate overall relative risks (RR) and 95 % confidence intervals (CI) using random-effects models. The pooled RRs of all cause mortality for the study-specific highest versus low (<=1 cup/day) coffee drinking categories were 0.88 (95 % CI 0.84-0.93) based on all the 23 studies, and 0.87 (95 % CI 0.82 0.93) for the 19 smoking adjusting studies. The combined RRs for CVD mortality were 0.89 (95 % CI 0.77-1.02, 17 smoking adjusting studies) for the highest versus low drinking and 0.98 (95 % CI 0.95-1.00, 16 studies) for the increment of 1 cup/day. Compared with low drinking, the RRs for the highest consumption of coffee were 0.95 (95 % CI 0.78-1.15, 12 smoking adjusting studies) for CHD/IHD, 0.95 (95 % CI 0.70-1.29, 6 studies) for stroke, and 1.03 (95 % CI 0.97-1.10, 10 studies) for all cancers. This meta-analysis provides quantitative evidence that coffee intake is inversely related to all cause and, probably, CVD mortality. PMID- 23934581 TI - Re: Rautenberg O, Kociszewski J, Welter J, Kuszka A, Eberhard J, Viereck V. Ultrasound and early tape mobilization--a practical solution for treating postoperative voiding dysfunction. PMID- 23934583 TI - High-efficiency polymer light-emitting devices with robust phosphorescent platinum(II) emitters containing tetradentate dianionic O^N^C^N ligands. AB - [Pt(O(?) N(?) C(?) N)]-type complexes are used as single emitters in solution processed PLEDs with maximum EQEs of 15.55% for green and 12.73% for white devices, which are the highest values ever achieved for PLEDs based on Pt(ii) complexes. PMID- 23934582 TI - Impact of distal median neuropathy on handwriting performance for patients with carpal tunnel syndrome in office and administrative support occupations. AB - PURPOSE: This study investigates the handwriting performance of patients with carpal tunnel syndrome (CTS) and healthy controls in office and administrative support occupations, adopting both biomechanical and functional perspectives. This work also explores how surgical intervention altered the performance of the CTS patients. METHODS: Fourteen CTS patients and 14 control subjects were recruited to complete a self-reported survey and participate in sensory tests, hand strength, dexterity and handwriting tasks using a custom force acquisition pen along with motion capture technology. Based on the results of these, the sensory measurements, along with functional and biomechanical parameters, were used to determine the differences between the groups and also reveal any improvements that occurred in the CTS group after surgical intervention. RESULTS: The CTS patients showed significantly poorer hand sensibility and dexterity than the controls, as well as excessive force exertion of the digits and pen tip, and less efficient force adjustment ability during handwriting. After surgery and sensory recovery, the hand dexterity and pen tip force of the CTS patients improved significantly. The force adjustment abilities of the digits also increased, but these changes were not statistically significant. CONCLUSIONS: This study provides the objective measurements and novel apparatus that can be used to determine impairments in the handwriting abilities of office or administrative workers with CTS. The results can also help clinicians or patients to better understand the sensory-related deficits in sensorimotor control of the hand related to CTS, and thus develop and implement more suitable training or adaptive protocols. PMID- 23934584 TI - Senescent human periodontal ligament fibroblasts after replicative exhaustion or ionizing radiation have a decreased capacity towards osteoblastic differentiation. AB - Loss of teeth increases with age or after genotoxic treatments, like head and neck radiotherapy, due to periodontium breakdown. Periodontal ligament fibroblasts represent the main cell type in this tissue and are crucial for the maintenance of homeodynamics and for its regeneration. Here, we have studied the characteristics of human periodontal ligament fibroblasts (hPDLF) that became senescent after replicative exhaustion or after exposure to ionizing radiation, as well as their ability for osteoblastic differentiation. We found that senescent hPDLF express classical markers of senescence, as well as a catabolic phenotype, as shown by the decrease in collagen type I and the increase of MMP-2 expression. In addition, we observed a considerably decreased expression of the major transcription factor for osteoblastic differentiation, i.e. Runx2, a down regulation which was found to be p53-dependent. In accordance to the above, senescent cells have a significantly decreased alkaline phosphatase gene expression and activity, as well as a reduced ability for osteoblastic differentiation, as found by Alizarin Red staining. Interestingly, cells from both type of senescence express similar characteristics, implying analogous functions in vivo. In conclusion, senescent hPDLF express a catabolic phenotype and express a significantly decreased ability towards an osteoblastic differentiation, thus probably affecting tissue development and integrity. PMID- 23934586 TI - [Intracerebral hemorrhage: is rapid, intensive lowering of blood pressure effective?--rapid, intensive lowering of blood pressure is not hazardous and possibly beneficial]. PMID- 23934587 TI - [Hospital-acquired infections--tribute to high-performance medicine]. PMID- 23934585 TI - Physical exercise is associated with less neurocognitive impairment among HIV infected adults. AB - Neurocognitive impairment (NCI) remains prevalent in HIV infection. Randomized trials have shown that physical exercise improves NCI in non-HIV-infected adults, but data on HIV-infected populations are limited. Community-dwelling HIV-infected participants (n = 335) completed a comprehensive neurocognitive battery that was utilized to define both global and domain-specific NCI. Participants were divided into "exercise" (n = 83) and "no exercise" (n = 252) groups based on whether they self-reported engaging in any activity that increased heart rate in the last 72 h or not. We also measured and evaluated a series of potential confounding factors, including demographics, HIV disease characteristics, substance use and psychiatric comorbidities, and physical functioning. Lower rates of global NCI were observed among the exercise group (15.7 %) as compared to those in the no exercise group (31.0 %; p < 0.01). A multivariable logistic regression controlling for potential confounds (i.e., education, AIDS status, current CD4+ lymphocyte count, self-reported physical function, current depression) showed that being in the exercise group remained significantly associated with lower global NCI (odds ratio = 2.63, p < 0.05). Similar models of domain-specific NCI showed that exercise was associated with reduced impairment in working memory (p < 0.05) and speed of information processing (p < 0.05). The present findings suggest that HIV-infected adults who exercise are approximately half as likely to show NCI as compared to those who do not. Future longitudinal studies might be best suited to address causality, and intervention trials in HIV-infected individuals will determine whether exercise can prevent or ameliorate NCI in this population. PMID- 23934588 TI - [Compliance with national guidelines for the prevention of central venous catheter-associated-infections in German intensive care units]. AB - BACKGROUND AND OBJECTIVE: Aim of the survey was to determine the compliance with national guidelines for the prevention of central venous catheter (CVC) associated bloodstream infection in German intensive care units (ICUs). METHODS: Within the pan-European PROHIBIT (Prevention of Hospital Infections by Intervention and Training) survey on infection control an online-questionnaire was answered by German ICU staff. Questions concerned insertion and handling of CVC. Continuous data are presented in median including interquartile range (IQR); categorical parameters are summarized by percentage. RESULTS: Ninety-two percent of ICUs created local guidelines for the prevention of CVC-associated sepsis according to national guidelines. Eleven percent did not provide educational sessions for health care workers concerning sepsis prevention routinely. The subclavian vein was the favored insertion site in 17 % of ICUs. A standardized approach for daily assessment of the need of the CVC was established in 39 % of ICUs. Impregnated (antiseptic or antibiotic) CVCs were used by every fourth ICU. Single-use vials were not used as single-use vials by a third of ICUs. CONCLUSION: There are still many German ICUs in which national guidelines are not implemented. Training of staff is necessary to raise awareness for prevention measures and to contribute to a good quality of patient care. PMID- 23934589 TI - [Deficits in central venous catheter associated bloodstream infection]. AB - BACKGROUND AND OBJECTIVE: Intensive care units (ICUs) with high rates of central venous catheter (CVC) -associated bloodstream infections (BSI) were invited to implement a bundle on BSI prevention during an educational programme which was created by the German national reference center for surveillance of nosocomial infections (NRZ). Training of health care workers (HCWs) was the main component and will be presented in the following. METHODS: The intervention was realized by local infection control staff from April 2006 to March 2007. Modules were lecture, script and poster. Before the intervention HCWs completed an anonymous multiple choice questionnaire about BSI prevention measures. Lectures could be modified in accordance to the ICUs knowledge of prevention measures. Processes and CVC-BSI rates were surveyed and analysed before and after the intervention and also during an additional 24-months follow-up period. RESULTS: Thirty-two ICUs with 1,622 HCWs realized the intervention. Knowledge of BSI prevention of 1,251 HCWs was assessed. Knowledge gaps could predominantly be shown for the favored insertion site and the changing intervals of intravenous tubing for aqueous infusions. One third of HCWs said that a daily CVC's dressing change was indicated. After the intervention ICUs showed a significant decrease in the pooled CVC-BSI rate. ICUs showed a significant decrease of the pooled CVC-BSI rate during the follow-up. CONCLUSION: In this first assessment of more than 1,200 HCWs' knowledge of BSI prevention in German ICUs knowledge gaps could be identified. During the 12-months intervention the implementation of evidence based IC recommendations improved and the pooled CVC-BSI rate decreased significantly. PMID- 23934590 TI - [Effectiveness of a hospital-wide educational programme for infection control to reduce the rate of health-care associated infections and related sepsis (ALERTS)- methods and interim results]. AB - BACKGROUND AND AIM: Health care associated infections (HAIs) are one of the most frequent complications of hospital care, associated with increased morbidity, mortality and considerable extra costs for the health care system. The overarching objective of the ALERTS study is to demonstrate the feasibility of a hospitalwide programme to reduce the burden of HAIs and related sepsis of at least 20 %. METHODS: Prospective, quasi-experimental study covering all acute care units (27 general wards, 4 ICUs, overall 809 beds) at Jena University Hospital. Surveillance for HAIs is performed by computerized antibiotic monitoring in patients with risk factors for HAIs (i. e. intravenous and urinary catheters, surgery) on a daily basis. Following the first surveillance period a multifaceted, pragmatic infection control programme, aimed at proper hand hygiene and bundles for the prevention of the four most common HAIs will be implemented. Subsequently, a second surveillance period lasting 18 months will be conducted to measure the effect of the infection control programme, starting in May 2013. RESULTS: Interim results for the first surveillance period (09/2011 to 08/2012) are presented. During this period, 30,631 patients were admitted to the participating departments. According to CDC definitions we identified 1,637 HAIs, resulting in an overall incidence of 5.3 %. Based on clinical evaluation only, irrespective of the CDC definitions, an additional 944 HAIs were detected (overall HAI rate, 8.4 % [n =2581]). A substantial proportion of patients had HAI associated severe sepsis or septic shock (lower respiratory tract infection, n = 279 [37 %]; surgical site infection, n = 114 [25 %]; primary sepsis, n = 110 [32 %]; urinary tract infection, n = 46 [8 %]; other, n = 87 [22 %]). CONCLUSION: Our numbers reveal that a high number of HAIs are missed using CDC-definitions and therefore the magnitude of the problem might be underestimated. Furthermore, a high percentage of HAIs progress from localized infection to severe sepsis or septic shock, requiring ICU treatment. PMID- 23934591 TI - [Peripheral venous catheter-related E. faecalis sepsis with fatal outcome]. AB - HISTORY AND ADMISSION FINDINGS: A 82 year-old man was admitted with a facial Herpes zoster reactivation and a zoster-related meningoencephalitis. He was treated with Aciclovir over a peripheral venous catheter that was placed in the right elbow pit. The meningoencephalitis subsided without neurological deficits, but the patient developed a catheter-associated phlebitis. An oral cephalosporin was prescribed and the patient discharged. After developing a fever and general discomfort he was readmitted to hospital three days later. INVESTIGATIONS: A 3 * 3 cm abscess in the elbow pit was incised and drained, but no swab or blood cultures were taken. When the patient's condition got worse an echocardiogram was ordered. It showed vegetations on the aortic and mitral valves as well as on the cardiac pacemaker wires. TREATMENT AND COURSE: Blood cultures were positive for Enterococcus faecalis. Although a therapy with vancomycin and ampicillin was started, the patient's condition impaired. Surgical valve replacement was initiated, but the patient expired 5 weeks later due to septic multi-organ failure. CONCLUSION: The danger of peripheral venous catheter infections is frequently underrated, early identification of the causing pathogen, sensitivity testing and proper antibiotic treatment are of tremendous importance. Clinical sings of sepsis must under no circumstances be overlooked. PMID- 23934592 TI - [Prevention of catheter-related bloodstream infections: avoiding mistakes]. PMID- 23934593 TI - [Prevention of sepsis after splenectomy]. PMID- 23934594 TI - [Pneumococcal vaccine]. PMID- 23934595 TI - Fusariosis, a complex infection caused by a high diversity of fungal species refractory to treatment. AB - In recent years the number of opportunistic invasive fusariosis has increased significantly, the main factors involved in these infections being reviewed here. In spite of the extensive literature published the advances in the management of disseminated fusariosis have been very poor and it remains a severe infection, refractory to treatment and with a high mortality rate. There are no ideal therapies and the presence of neutropenia has a critical part to play in the outcome of the infection. At least 70 species have been involved in fusariosis. Fusarium solani species complex is responsible for nearly 60% of the cases and F. oxysporum species complex for approximately 20% of them. Most of the infections are caused by four species, i.e. F. petroliphilum, F. keratoplasticum and other two unnamed phylogenetic species. The efficacy of amphotericin B and voriconazole, the most used antifungal drugs, for treating invasive fusariosis are controversial but in general the percentage of patients cured in the different clinical trials is low. Infections by Fusarium verticillioides seem to have the best prognosis. The recent release of complete genome sequences of the most clinically relevant species and the emergence of fungal genomics offer excellent opportunities for examining the multifactorial processes of Fusarium pathogenicity. Using knockout mutants of genes encoding sequence-specific proteins, several virulence factors have been characterized. PMID- 23934596 TI - Is colonoscopy necessary in cases of infection by Streptococcus bovis biotype II? AB - The association of colorectal neoplasia (CRN) with Streptococcus bovis biotype I (SBI) infection is well recognized. However, this is not the case for Streptococcus bovis biotype II (SBII). We conducted this study in order to analyze the relationship between SBII and CRN. We analyzed all cases of bacteremia due to SBI (n = 99) and SBII (n = 36) diagnosed in our hospital (during the period 1988-2011) that were followed up with colonoscopy. In addition, we reviewed the literature (during the period 1982-2011) to select all cases of infection of SB that had undergone colonoscopy or other adequate form of colorectal examination. A multivariate analysis was performed to detect CRN risk factors in patients infected with SB. From the 223 cases of SB infection included in the analysis (135 from our institution and 88 from the literature review), 159 were due to SBI and 64 were caused by SBII. As compared with SBI, the SBII cases had a lower frequency of CRN (27 % vs. 67 %, p <0.001), advanced adenomas (8 % vs. 29 %, p <0.01), and carcinomas (6 % vs. 21 %, p <0.01). In a multivariate analysis, and after adjusting for age, sex, type of infection, and biotype, SBII infection was not associated with CRN: odds ratio (OR) = 0.17; 95 % confidence interval (CI) = 0.09 to 0.33. The only factor independently associated with CRN was SBI infection: OR = 5.7; 95 % CI = 3.0 to 10.9. The prevalence of CRN in patients infected with SBII is significantly lower than patients with SBI and does not appear to be higher than the CRN prevalence among the general population. PMID- 23934597 TI - Screening human genes for small alterations performing an enzymatic cleavage mismatched analysis (ECMA) protocol. AB - Many human diseases are caused by small alterations in the genes and in the majority of cases sophisticated protocols are required for their detection. In this study we estimated the efficacy of an enzymatic protocol, which using a new mismatch-specific DNA plant endonuclease from celery (CEL family) recognizes and cleaves mismatched alleles between mutant and normal PCR products. The protocol was standardized on a variety of known mutations, in 11 patients with cystic fibrosis (CF), Fabry's disease (FD), steroid 21-hydroxylase deficiency (21-HD), and Duchenne/Becker muscular dystrophy (DMD/BMD). The method does not require special equipment, labeling or standardization for every PCR product, since conditions of heteroduplex formation and enzyme digestion are universal for all products. The results showed that the method is rapid, effective, safe, reliable, and very simple, as the mutations are visualized on agarose or nusieve/agarose gels. The protocol was furthermore evaluated in three DMD patients with the detection of three alterations, which after sequencing, were characterized as disease causative mutations. The proposed assay, which was applied for the first time in a variety of monogenic disorders, indicates that point mutation identification is feasible in any conventional molecular lab even for cases where other techniques have failed. PMID- 23934598 TI - The prevalence and pathological correlates of orthostatic hypotension and its subtypes when measured using beat-to-beat technology in a sample of older adults living in the community. AB - BACKGROUND: beat-to-beat technology is increasingly used for investigating orthostatic intolerance (OI) but the prevalence of orthostatic hypotension (OH) diagnosed with this technology is unclear. OBJECTIVES: (i) to use beat-to-beat technology to define the prevalence of OH, (ii) to investigate the pathological correlates of OH, (iii) to report the diversity of postural BP responses. METHODS: cross-sectional study of adults >= 65 years. BP responses to a 3-min head-up tilt were analysed. RESULTS: of 326 participants, 203(62.3%) were females. The median (IQR) age was 73 (70-78). One hundred and ninety-one (58.6%) met standard (20 mmHg systolic/10 mmHg diastolic) criteria for OH. The prevalence was higher in females (60.1% F versus 56.1% M); 47% were arteriolar subtype, 33% were venular, 9% were mixed and 11.0% could not be classified. Morphological analysis identified 102 subjects with 'small drop, overshoot', 131 with 'medium drop, slow recovery' and 31 with 'large drop, nonrecovery'. Those with OH had a lower BMI (P = 0.02), a higher resting heart rate (P = 0.005), were more likely to take a psychotropic (P = 0.02), have vertigo (P = 0.004) and report OI (P = 0.02). The 95th centile for the duration of systolic BP (SYSBP) decay >20 mmHg was 175 s and the slope of systolic BP decay was 4.75 mmHg/s. The 5th centile for percentage recovery of SYSBP was 81.4%. CONCLUSION: (i) beat-to-beat methods identify a higher prevalence of OH than sphygmomanometry, (ii) the pathological correlates of OH diagnosed in this manner are similar to those described for sphygmomanometry, (iii) there is a diverse pattern of orthostatic BP decay that could be used in future research to predict adverse outcomes in OH. PMID- 23934599 TI - Role of rapid sequence whole-body MRI screening in SDH-associated hereditary paraganglioma families. AB - Patients with germline mutations in one of the SDH genes are at substantially increased risk of developing paragangliomas, pheochromocytomas (pheos), and other tumors (all combined referred to as SDH-related tumors). However, limited data exist on screening in SDH mutation carriers and no studies have evaluated whole body MRI as a screening tool in asymptomatic patients. This was a single-center observational study. We evaluated the results of screening in 37 SDH carriers who underwent 45 whole-body MRIs and 47 biochemical tests. Screening included annual biochemical testing (catecholamines, metanephrines and chromogranin A) and biennial or annual rapid sequence whole-body MRI from the base of the skull to the pelvis beginning at age 10 years old. Six tumors (paragangliomas of the organ of Zuckerkandl, the aortocaval/vas deferens, of the carotid body times three, and a renal cell carcinoma) were diagnosed in five patients. In total, 13.5 % of all patients screened were diagnosed with SDH-related tumors. Whole-body MRI missed one tumor, while biochemical testing was normal in five patients with SDH-related tumors. The sensitivity of whole-body MRI was 87.5 % and the specificity was 94.7 %, while the sensitivity of biochemical testing was 37.5 % and the specificity was 94.9 %. Whole-body MRI had a higher sensitivity for SDH-related tumors than biochemical testing in patients undergoing screening due to their SDHB or SDHC mutation status. Whole-body MRI reduces radiation exposure compared to computed tomography scan and time compared to dedicated MRI of the head/neck, thorax, and abdomen/pelvis. PMID- 23934600 TI - Does and should breast cancer genetic counselling include lifestyle advice? AB - To optimally inform counselees about their and their relatives' risks, information about lifestyle risk factors, e.g. physical activity and alcohol consumption, might be discussed in breast cancer genetic counselling. This study explored whether lifestyle was discussed, on whose initiative, whether information and/or advice was given, and whether discussion of lifestyle was related to counselees' characteristics and their causal attributions. First and follow-up consultations with 192 consecutive counselees for breast cancer genetic counselling were videotaped and coded for discussion of lifestyle topics. Counselees completed web-based questionnaires before the initial and after the final consultation. With 52 (27%) counselees lifestyle was discussed, either in the first, or the final consultation, or both. Counselees mostly raised the topic (60%). Counsellors provided information about lifestyle risk factors to 19% and lifestyle advice to 6% of the counselees. Discussion of lifestyle was not associated with counselees' characteristics or causal attributions. Post counselling, more affected counselees considered lifestyle as a cause of their breast cancer (29%) compared to pre-counselling (15%; p = 0.003). Information and advice about lifestyle risk factors was infrequently provided, both with breast cancer unaffected and affected counselees and with those who did and did not consider their lifestyle as a cause of their breast cancer. Modifiable lifestyle factors could be discussed more frequently to optimally inform counselees about possible ways to reduce their risk. Counsellors should be educated about effects of lifestyle and research should be conducted on how to best integrate lifestyle information in breast cancer genetic counselling. PMID- 23934601 TI - Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome. AB - Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan-Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45%), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56% for males and 87% for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype-phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype phenotype associations could not be identified. PMID- 23934602 TI - Getting stuck in the blues: persistence of mental health problems in Australia. AB - Do episodes of mental health (MH) problems cause future MH problems, and if yes, how strong are these dynamics? We quantify the degree of persistence in MH problems using nationally representative, longitudinal data from Australia and system generalized method of moments (GMM), and correlated random effects approaches are applied to separate true from spurious state dependence. Our results suggest only a moderate degree of persistence in MH problems when assuming that persistence is constant across the MH distribution once individual specific heterogeneity is accounted for. However, individuals who fell once below a threshold that indicates an episode of depression are up to five times more likely to experience such a low score again a year later, indicating a strong element of state dependence in depression. Low income is a strong risk factor in state dependence for both men and women, which has important policy implications. PMID- 23934604 TI - Novel alkoxide cluster topologies featuring rare seesaw geometry at transition metal centers. AB - Caution! Chemists playing: Novel clusters of the form [M2Li2Cl2(OR)4] featuring rare seesaw geometry at the transition metal centers were synthesized for M=Cr Co. The use of sterically hindering alkoxide ligands, as well as the inclusion of lithium ions in the structures enforces this highly unusual configuration. PMID- 23934605 TI - Ulnar nerve morbidity as a long-term complication of pediatric supracondylar humeral fracture. AB - BACKGROUND: Supracondylar humeral fractures are common in children. We studied long-term ulnar nerve symptoms secondary to these fractures and analyzed the treatment for ulnar neuropathy. MATERIALS AND METHODS: The cohort included 91 patients with a supracondylar humeral fracture in childhood, on average 12 years previously, in the geographic catchment area. All the cases were reexamined in regard to ulnar nerve morbidity. Cases with secondary ulnar neuropathy were treated nonoperatively and operatively. RESULTS: Ulnar neuropathy was present in four cases (4.4 %). They all had suffered from a dislocated fracture, and they had been operated primarily. Another three patients had slight ulnar nerve symptoms. Hence, the total prevalence of secondary ulnar nerve morbidity was 7.7 %. A jumping nerve was seen in 9.9 %; 51.6 % had a diminished axial angle. CONCLUSIONS: We report a defined pattern of long-term ulnar nerve morbidity after pediatric supracondylar humeral fracture. The prevalence of neuropathy is alarming in the young population (<25 years of age). PMID- 23934606 TI - First human experience of thermal arterial closure. AB - OBJECTIVES: This study was designed to evaluate the efficacy and safety of the CardioDex arterial closure device, which is a novel femoral artery closure device used following percutaneous cardiac catheterization. BACKGROUND: Current devices utilized to achieve hemostasis of the femoral artery following percutaneous cardiac catheterization include collagen plug and suture mediated devices, but are associated with significant vascular complications. The CardioDex closure device utilizes thermal energy to cause collagen shrinking and swelling and thereby, achieve hemostasis. METHODS: The device was evaluated in a prospective nonrandomized single-center trial with patients undergoing 6F invasive cardiac procedures. Femoral artery puncture closure was performed immediately at completion of the procedure, followed by 3-4 minutes of manual compression. Time to hemostasis (TTH), time to ambulation (TTA), and short-term clinical follow-up data were collected. RESULTS: A total of 34 patients including 21 diagnostic and 13 interventional cases were evaluated. The median TTH was 3 min in diagnostic and 4 min in interventional cases. TTH was independent of activated clotting time (ACT). The median TTA was 2.75 hr and 3.37 hr in diagnostic and interventional groups, respectively. There were no major adverse events identified at 1 week and 30 day follow up. CONCLUSIONS: This first in human clinical experience with the CardioDex closure device demonstrates that in the small cohort studied, it is safe and effective in diagnostic cardiac catheterization and also in interventional cases on mild anticoagulation (mean ACT = 188 sec). It has the advantage of leaving no foreign material in the body following use. PMID- 23934607 TI - Alterations in the EGFR pathway coincide in colorectal cancer and impact on prognosis. AB - Alterations of the downstream effectors of the epidermal growth factor receptor (EGFR) are common events in colorectal cancer (CRC) carcinogenesis. Since EGFR serves as a target for therapy and some downstream effectors of EGFR have predictive and prognostic impact, reliable information on the frequency and concordance of alterations in the signaling pathway has become clinically significant. We, therefore, determined the frequency and coincidence of mutations in the EGFR pathway. We also analyzed the concordance of these alterations between primary tumor and distant metastases. Furthermore, we assessed their prognostic relevance for the development of metastasis. Mutations of KRAS exon 2, BRAF exons 11 and 15, AKT exon 3, and PIK3CA exons 9 and 20 were analyzed by pyrosequencing in 171 primary CRC samples as well as in 63 corresponding metastases. Furthermore, the expression of PTEN and EGFR was assessed by immunohistochemistry. Of the 171 tumors investigated, 60.2 % showed mutations in one or more genes of pathways downstream of EGFR. KRAS exon 2 and BRAF exon 15 mutations were detected in 40.9 and 11.1 % of cases, respectively, and were mutually exclusive. Mutations in exons 9 and 20 of the PIK3CA gene (18.7 %) largely overlapped with exon 2 KRAS mutations (16 of 32 cases; 50.0 %) and, to a lesser extent, with exon 15 mutations of BRAF (2 of 32 cases; 6.3 %). Only one case had simultaneous mutations of AKT exon 3 (0.6 %) and BRAF exon 15. Mutation analysis for KRAS exon 2, BRAF exon 15, PIK3CA exon 20, and AKT exon 3 in primary tumors and in their corresponding metastases revealed 100 % concordance. In one case, a PIK3CA exon 9 mutation in the primary tumor could not be detected in the matched distant metastases (kappa = 0.9). Three different scores were applied for the evaluation of EGFR immunohistochemistry, and the range of positive cases varied between 8.8 and 52.6 %. Loss of PTEN expression was detected in 38.6 %. Although the expression of both markers does coincide with KRAS exon 2, BRAF exon 15, AKT exon 3, and PIK3CA exons 9 and 20 mutations, high discordance rates were found. The presence of at least one alteration in downstream effectors of the EGFR pathway was associated with a higher rate of distant metastases (p = 0.002). PIK3CA exons 9 and 20 mutations overlap with KRAS exon 2 and BRAF exon 15 mutations, and BRAF exon 15 and AKT exon 3 mutations co-occur in a single tumor, whereas KRAS exon 2 and BRAF exon 15 mutations are mutually exclusive. This suggests that mutations in the PIK3CA/PTEN/AKT branch of the EGFR pathway are less important than those of the RAS/RAF/MAPK branch for the progression of CRC. We found no difference in the mutational status of KRAS exon 2, BRAF exon 15, and AKT exon 3 between primary tumor and distant metastasis, validating both for diagnostic purposes. PIK3CA exons 9 and 20 mutations can be discordant between primary tumor and distant metastasis, and therefore, the lesion which is targeted for therapy should be tested. Protein expression of PTEN and EGFR using current protocols yields highly discordant results, and better standardization is needed before these markers can be used for diagnostic purposes. PMID- 23934608 TI - The mid p-value in exact tests for Hardy-Weinberg equilibrium. AB - OBJECTIVE: Exact tests for Hardy-Weinberg equilibrium are widely used in genetic association studies. We evaluate the mid p-value, unknown in the genetics literature, as an alternative for the standard p-value in the exact test. METHOD: The type 1 error rate and the power of the exact test are calculated for different sample sizes, significance levels, minor allele counts and degrees of deviation from equilibrium. Three different p-value are considered: the standard two-sided p-value, the doubled one-sided p-value and the mid p-value. Practical implications of using the mid p-value are discussed with HapMap datasets and a data set on colon cancer. RESULTS: The mid p-value is shown to have a type 1 error rate that is always closer to the nominal level, and to have better power. Differences between the standard p-value and the mid p-value can be large for insignificant results, and are smaller for significant results. The analysis of empirical databases shows that the mid p-value uncovers more significant markers, and that the equilibrium null distribution is not tenable for both databases. CONCLUSION: The standard exact p-value is overly conservative, in particular for small minor allele frequencies. The mid p-value ameliorates this problem by bringing the rejection rate closer to the nominal level, at the price of occasionally exceeding the nominal level. PMID- 23934609 TI - General power and sample size calculations for high-dimensional genomic data. AB - In the design of microarray or next-generation sequencing experiments it is crucial to choose the appropriate number of biological replicates. As often the number of differentially expressed genes and their effect sizes are small and too few replicates will lead to insufficient power to detect these. On the other hand, too many replicates unnecessary leads to high experimental costs. Power and sample size analysis can guide experimentalist in choosing the appropriate number of biological replicates. Several methods for power and sample size analysis have recently been proposed for microarray data. However, most of these are restricted to two group comparisons and require user-defined effect sizes. Here we propose a pilot-data based method for power and sample size analysis which can handle more general experimental designs and uses pilot-data to obtain estimates of the effect sizes. The method can also handle chi2 distributed test statistics which enables power and sample size calculations for a much wider class of models, including high-dimensional generalized linear models which are used, e.g., for RNA-seq data analysis. The performance of the method is evaluated using simulated and experimental data from several microarray and next-generation sequencing experiments. Furthermore, we compare our proposed method for estimation of the density of effect sizes from pilot data with a recent proposed method specific for two group comparisons. PMID- 23934610 TI - A graphical model method for integrating multiple sources of genome-scale data. AB - Making effective use of multiple data sources is a major challenge in modern bioinformatics. Genome-wide data such as measures of transcription factor binding, gene expression, and sequence conservation, which are used to identify binding regions and genes that are important to major biological processes such as development and disease, can be difficult to use together due to the different biological meanings and statistical distributions of the heterogeneous data types, but each can provide valuable information for understanding the processes under study. Here we present methods for integrating multiple data sources to gain a more complete picture of gene regulation and expression. Our goal is to identify genes and cis-regulatory regions which play specific biological roles. We describe a graphical mixture model approach for data integration, examine the effect of using different model topologies, and discuss methods for evaluating the effectiveness of the models. Model fitting is computationally efficient and produces results which have clear biological and statistical interpretations. The Hedgehog and Dorsal signaling pathways in Drosophila, which are critical in embryonic development, are used as examples. PMID- 23934611 TI - Bayseian genomic models for the incorporation of pathway topology knowledge into association studies. AB - Pathway topology and relationships between genes have the potential to provide information for modeling effects of mRNA gene expression on complex traits. For example, researchers may wish to incorporate the prior belief that "hub" genes (genes with many neighbors) are more likely to influence the trait. In this paper, we propose and compare six Bayesian pathway-based prior models to incorporate pathway topology information into association analyses. Including prior information regarding the relationships among genes in a pathway was effective in somewhat improving detection rates for genes associated with complex traits. Through an extensive set of simulations, we found that when hub (central) effects are expected, the diagonal degree model is preferred; when spoke (edge) effects are expected, the spatial power model is preferred. When there is no prior knowledge about the location of the effect genes in the pathway (e.g., hub versus spoke model), it is worthwhile to apply multiple models, as the model with the best DIC is not always the one with the best detection rate. We also applied the models to pharmacogenomic studies for the drugs gemcitabine and 6 mercaptopurine and found that the diagonal degree model identified an association between 6-mercaptopurine response and expression of the gene SLC28A3, which was not detectable using the model including no pathway information. These results demonstrate the value of incorporating pathway information into association analyses. PMID- 23934612 TI - Improving the efficiency of genomic selection. AB - We investigate two approaches to increase the efficiency of phenotypic prediction from genome-wide markers, which is a key step for genomic selection (GS) in plant and animal breeding. The first approach is feature selection based on Markov blankets, which provide a theoretically-sound framework for identifying non informative markers. Fitting GS models using only the informative markers results in simpler models, which may allow cost savings from reduced genotyping. We show that this is accompanied by no loss, and possibly a small gain, in predictive power for four GS models: partial least squares (PLS), ridge regression, LASSO and elastic net. The second approach is the choice of kinship coefficients for genomic best linear unbiased prediction (GBLUP). We compare kinships based on different combinations of centring and scaling of marker genotypes, and a newly proposed kinship measure that adjusts for linkage disequilibrium (LD). We illustrate the use of both approaches and examine their performances using three real-world data sets with continuous phenotypic traits from plant and animal genetics. We find that elastic net with feature selection and GBLUP using LD adjusted kinships performed similarly well, and were the best-performing methods in our study. PMID- 23934613 TI - Haloacylation of the quintuple-bonded group VI metal amidinate dimers and disproportionation of acyl groups to form carbynes. PMID- 23934614 TI - Human intestinal microbiota and type 1 diabetes. AB - The role of intestinal microbiota in immune-mediated diseases, such as type 1 diabetes, has deservedly received a lot of attention. Evidently, changes in the intestinal microbiota are associated with type 1 diabetes as demonstrated by recent studies. Children with beta-cell autoimmunity have shown low abundance of butyrate-producing bacteria and increase in the abundance of members of the Bacteroidetes phylum in fecal microbiota. These alterations could explain increased gut permeability, subclinical small intestinal inflammation, and dysregulation of oral tolerance in type 1 diabetes. However, these studies do not provide evidence of the causative role of the gut microbiota in the development of beta-cell autoimmunity, yet. In animal models, the composition of gut microbiota modulates the function of both innate and adaptive immunity, and intestinal bacteria are regulators of autoimmune diabetes. Thus, prevention of type 1 diabetes could, in the future, be based on the interventions targeted to the gut microbiota. PMID- 23934615 TI - Selective co-stimulation of pudendal afferents enhances bladder activation and improves voiding efficiency. AB - AIMS: Clinical application of pudendal nerve (PN) afferent stimulation to restore bladder emptying in persons with neurological disorders requires increased stimulation-evoked voiding efficiencies (VEs). We tested the hypothesis that selective co-stimulation of multiple PN branches, either bilateral dorsal nerve of the penis (DNP) stimulation or selective stimulation of both the cranial sensory nerve (CSN) and DNP, will evoke larger reflex bladder contractions and result in higher VEs than stimulation of any single afferent pathway alone. METHODS: We measured the strength of bladder contractions, threshold volumes, and VEs produced by unilateral and bilateral stimulation of the DNP as well as singular and selective unilateral co-stimulation of the DNP and CSN in cats anesthetized with alpha-chloralose. RESULTS: Co-stimulation of afferent pathways generated significantly larger isovolumetric bladder contractions and evoked contractions at lower threshold volumes than individual stimulation. Co stimulation of pudendal afferents also suppressed dyssynergic activity in the external anal sphincter produced by low frequency individual stimulation. VE was significantly improved with co-stimulation (172 +/- 6% of distention evoked volumes) over individual stimulation (141 +/- 6%). CONCLUSIONS: Both types of co stimulation evoked larger bladder contractions and increased VE over individual branch PN afferent stimulation and distention-evoked voiding. The decreased threshold volumes required for reflex bladder activation and increased VEs with co-stimulation support the use of stimulation of multiple individual stimulation evoked reflexes to improve voiding efficiency. PMID- 23934616 TI - The proinflammatory peptide substance P promotes blood-brain barrier breaching by breast cancer cells through changes in microvascular endothelial cell tight junctions. AB - Neuropeptide substance P (SP) has been implicated in inflammation, pain, depression and breast cancer cell (BCC) growth. Here, we examined the role of SP in trafficking of BCCs (human MDA-MB-231 and MDA-MB-231BrM2 cells) across the blood-brain barrier (BBB) and brain microvascular endothelial cells (BMECs) using in vitro and in vivo models. SP was secreted from BCCs and mediated adhesion and transmigration of BCCs across human BMECs (HBMECs) in vitro. SP induced activation of HBMECs, leading to secretion of Tumor Necrosis Factor alpha (TNF alpha) and angiopoietin-2 (Ang-2) from HBMECs, resulting in changes in localization and distribution of tight junction (TJ) ZO-1 (tight junction protein zonula occludins-1) and claudin-5 structures as well as increased permeability of HBMECs. Using spontaneous breast cancer metastasis mouse model (syngeneic) of GFP 4T1-BrM5 mammary tumor cells administered into mammary fat pads of Balb/c mice, SP inhibitor spantide III inhibited in vivo changes in permeability of the BBB and BMEC-TJs ZO-1 and claudin-5 structures as well as decreased tumor cell colonization in brain. Thus, SP secreted from BCCs induces transmigration of BCCs across the BBB, leading to activation of BMECs and secretion of TNF-alpha and Ang 2, resulting in BBB impairment and colonization of tumor cells in brain. Therefore, therapies based on SP inhibition in combination with other therapies may prevent breaching of the BBB by BCCs and their colonization in brain. PMID- 23934617 TI - Estimating glomerular filtration rate in centenarians: comparison of the chronic kidney disease epidemiology collaboration (CKD-EPI) and modification of diet in renal disease (MDRD) study equations. PMID- 23934618 TI - National trends in hospitalization from indwelling urinary catheter complications, 2001-2010. AB - PURPOSE: The purpose of this study is to investigate national trends in hospitalization from indwelling urinary catheters complications from 2001 to 2010. MATERIALS AND METHODS: The Healthcare Utilization Project Nationwide Inpatient Sample database was analyzed for this study. We examine hospitalization rates, patient demographics, hospital stays, insurance provider, hospital type, geographic location, and septicemia rates of patients hospitalized for indwelling urinary catheter complications from 2001 to 2010. RESULTS: Hospitalization from indwelling urinary catheters almost quadrupled from 11,742 in 2001 to 40,429 in 2010. The increases have been due to patients who are older and predominantly male compared to all hospitalization. The "national bill" increased from $213 million to $1.3 billion (a factor of 6) after adjusting for inflation. Most patients had urinary tract infections, 77 % in 2001 and 87 % in 2010. Septicemia in indwelling urinary catheter hospitalization patients has increased from 21 % in 2001 to 40 % in 2010. In 2010, secondary diseases associated with hospitalization due to indwelling urinary catheters included urinary tract infections (86.5 %), adverse effects of medical care (61.9 %), bacterial infection (48.6 %), and septicemia (40.3 %). CONCLUSIONS: Hospitalization due to indwelling urinary catheter complications has almost quadrupled from 11,742 in 2001 to 40,429 in 2010, and the majority of patients had urinary tract infections. Septicemia is of particular concern since rates have almost doubled (from 21 to 40 % over the period) in these patients. The specific medical indication for urinary catheters used postoperatively should be scrutinized, and the duration of placement should be minimized to reduce future complication rates. PMID- 23934619 TI - Management and outcome in hepatorenal syndrome: need for renal replacement therapy in non-transplanted patients. AB - PURPOSE: Hepatorenal syndrome (HRS) type I is a devastating complication of decompensated cirrhosis. Liver transplantation (LT) offers an excellent survival, and renal replacement therapy (RRT) may be useful until transplantation is available. The survival benefit of RRT in the absence of LT is thought to be short and its benefit in these patients is unknown. To investigate this, we studied the outcome of different therapies (pharmacological, RRT, and LT) in patients with type 1 HRS. METHODS: Medical records (2005-2009) of all cirrhotic patients admitted to our facility with abnormal renal function were reviewed. Patients with preexisting renal disease, diagnosis other than type I HRS, or those without long-term follow-up were excluded. RESULTS: Of 380 patients reviewed, 30 were studied. Nineteen (63.3 %) patients underwent liver transplantation. No difference in baseline liver or renal parameters was noted between those who were or were not transplanted. A decreased mortality was noted (5.3 vs. 64.6 %; p = 0.0005) compared to patients who were not transplanted during the study follow-up median period of 7.8 [CI 1.9-34] months. Among non transplanted patients, no differences in median survival (8.8 vs. 6.5 months; p = 0.62) or in other parameters studied were found in those patients who received RRT compared to those who did not. Similarly, no survival difference was found comparing those who did or did not receive pharmacological therapy without transplant. CONCLUSION: In type I HRS, LT offers better survival. Among patients who do not receive LT, RRT does not provide an improved survival benefit. PMID- 23934620 TI - Emergency hospital admissions attributable to infective complications of prostate biopsy despite appropriate prophylaxis: need for additional infection prevention strategies? AB - PURPOSE: To report the incidence of emergency admissions attributable to infective complications of transrectal ultrasound-guided prostate biopsy (TGB) and evaluate appropriateness of antimicrobial prophylaxis. METHODS: Retrospective cross-sectional study of patients undergoing TGB at the North West London Hospitals in 2009-2011. Demographic information of patients who had emergency admission within 30 days of TGB, length of hospital stay and microbiology results were obtained from the hospital's information system, medical records and laboratory information system. All patients received ciprofloxacin and amikacin prophylaxis. RESULTS: 1,419 TGB were performed in 1,276 patients. Forty-eight (3.3 %) patients had emergency admissions. Thirty-three (2.3 %) admissions were due to complications from TGB, while 15 (1 %) were for unrelated reasons. 30/33 (90 %, overall 2.1 %) of admissions from TGB complications were due to confirmed infections or systemic inflammatory response syndrome (SIRS). The rest were admitted with urinary retention. Admission rates due to TGB complications and infection/SIRS remained consistent over the 3 years (2009: TGB complications-2 %, TGB infection/SIRS-1.8 %; 2010: TGB complications-2.4 %, TGB infections/SIRS-2.2 %; 2011: TGB complications-2.6 %, TGB infection/SIRS-2.4 %; P > 0.05). All 11 cases with bacteraemia were caused by ciprofloxacin-resistant but amikacin susceptible E. coli. CONCLUSIONS: We observed a consistent rate of emergency admissions for complications following TGB; 90 % of these were due to infections. Ciprofloxacin-resistant but amikacin-sensitive E. coli was isolated in all bacteriologically confirmed infections. These results suggest that infective complications of TGB cannot be altogether eliminated despite appropriate antimicrobial prophylaxis. Therefore, additional strategies for reduction in biopsy-related admissions due to infections have to be considered. PMID- 23934622 TI - Stereoselective synthesis of highly functionalized nitrocyclopropanes through the organocatalyic Michael-addition-initiated cyclization of bromonitromethane and beta,gamma-unsaturated alpha-ketoesters. AB - A highly diastereo- and enantioselective cyclopropanation of beta,gamma unsaturated alpha-ketoesters with bromonitromethane has been successfully developed through a domino Michael-addition/intramolecular-alkylation strategy. Acceptable yields (up to 89%) and enantioselectivities (up to 96% ee) have been obtained. PMID- 23934621 TI - The effects of alcohol on the pharmacokinetics and pharmacodynamics of the selective mu-opioid receptor antagonist GSK1521498 in healthy subjects. AB - The mu-opioid system has a key role in hedonic and motivational processes critical to substance addiction. However, existing mu-opioid antagonists have had limited success as anti-addiction treatments. GSK1521498 is a selective and potent mu-opioid antagonist being developed for the treatment of overeating and substance addictions. In this study, 28 healthy participants were administered single doses of GSK1521498 20 mg, ethanol 0.5 g/kg body weight, or both in combination, in a double blind placebo controlled four-way crossover design. The primary objective was to determine the risk of significant adverse pharmacodynamic and pharmacokinetic (PK) interactions. The effects of GSK1521498 on hedonic and consummatory responses to alcohol and the attentional processing of alcohol-related stimuli, and their modulation by the OPRM1 A118G polymorphism were also explored. GSK1521498 20 mg was well tolerated alone and in combination with ethanol. There were mild transient effects of GSK1521498 on alertness and mood that were greater when it was combined with ethanol. These effects were not of clinical significance. There were no effects of GSK1521498 on reaction time, hedonic or consummatory responses. These findings provide encouraging safety and PK data to support continued development of GSK1521498 for the treatment of alcohol addiction. PMID- 23934623 TI - Hypothetical proteins present during recovery phase of radiation resistant bacterium Deinococcus radiodurans are under purifying selection. AB - Deinococcus radiodurans has an unusual capacity to recover from intense doses of ionizing radiation. The DNA repair proteins of this organism play an important role in repairing the heavily damaged DNA by employing a novel mechanism of DNA double-strand break repair. An earlier report stated that genes of many of these repair proteins are under positive selection implying that these genes have a tendency to mutate, which in turn provides selective advantage to this bacterium. Several "hypothetical proteins" are also present during the recovery phase and some of them have also been shown for their roles in radiation resistance. Therefore, we tested the selection pressure on the genes encoding these poorly characterized proteins. Our results show that a number of "hypothetical proteins" present during the repair phase have structural adaptations compared to their orthologs and the genes encoding them as well as those for the DNA repair proteins present during this phase are under purifying selection. Evidence of purifying selection in these hypothetical proteins suggests that certain novel characteristics among these proteins are conserved and seem to be under functional constraints to perform important functions during recovery process after gamma radiation damage. PMID- 23934624 TI - Ultrasound-assisted extraction with LC-TOF/MS identification and LC-UV determination of imazamox and its metabolites in leaves of wheat plants. AB - INTRODUCTION: imazamox is a herbicide used in many legominous and cereal crops. There are few methods in the literature for determination of imazamox and its metabolites in plants because of the lack of commercial standards or owing to expensive and/or complex synthesis. OBJECTIVE: To develop a method based on liquid chromatography and ultraviolet absorption detection for simultaneous determination of imazamox and its metabolites in plants. METHODS: Sample preparation was based on ultrasound-assisted extraction (70 W power and duty cycle of 0.7 s/s for 10 min) with subsequent filtration of the extracts and clean up and concentration prior to chromatographic separation and detection at 240 nm. The chromatographic analysis was completed in 30 min using a Luna(r) HILIC column. Identification and confirmatory analysis of the presence of imazamox and its metabolites in extracts from treated plants was performed by LC-TOF/MS in high resolution mode for precursor ions. The metabolites were quantified using a surrogate approach based on an imazamox standard. The method was validated by analysing wheat samples treated with 200 g per hectare of active ingredient imazamox. RESULTS: The linear dynamic range of the calibration curve was within 0.27-600 ug/mL, with a correlation coefficient of 0.998 and precision--studied at 0.1 and 2 ug/mL--of 2.9% and 5.0% for repeatability, and 4.7% and 6.9% for reproducibility, respectively. CONCLUSION: The analytical characteristics of the method make it recommendable for evaluating the metabolism of imazamox in plants. PMID- 23934625 TI - Influence of Mg doping on the morphology and optical properties of ZnO films for enhanced H2 sensing. AB - Highly oriented ZnO and Mg doped ZnO thin films were fabricated on Al2 O3 substrate by sputtering at room temperature. The effect of Mg doping on the structural, optical, and morphological properties of ZnO film was investigated. The intensity of (002) peak in X-ray diffraction measurements revealed the influence of Mg doping on the crystallinity and orientation of ZnO film. Photoluminescence (PL) results show that the Ultraviolet (UV) emission peak was shifted to lower wavelength side for Mg:ZnO film indicating the possibility for quantum confinement. UV-vis-NIR optical absorption revealed an improvement in optical transmittance from 70 to 85%, and corresponding optical band gap from 3.25 to 3.54 eV. Atomic force microscope (AFM) images revealed the nano-size particulate microstructure of the films. The surface topography of Mg doped ZnO film confirmed decreased grain size with large surface roughness and increased surface area, favorable for sensing. Pure ZnO and Mg doped ZnO film were used as active layer and tested for its sensing performance to hydrogen. Compared to undoped ZnO, 22 at.% Mg doped ZnO film showed much higher sensor response to H2 at a concentration as low as 200 ppm and at a lower operating temperature of 180 degrees C. A linear sensor response was observed for H2 concentration in the range of 100-500 ppm. PMID- 23934626 TI - International survey on the management of esophageal atresia. AB - INTRODUCTION: Because many aspects of the management of esophageal atresia (EA) are still controversial, we evaluated the practice patterns of this condition across Europe. METHODS: A survey was completed by 178 delegates (from 45 [27 European] countries; 88% senior respondents) at the EUPSA-BAPS 2012. RESULTS: Approximately 66% of respondents work in centers where more than five EA repairs are performed per year. Preoperatively, 81% of respondents request an echocardiogram, and only 43% of respondents routinely perform preoperative bronchoscopy. Approximately 94% of respondents prefer an open approach, which is extrapleural in 71% of respondents. There were no differences in use of thoracoscopy between Europeans (10%) and non-Europeans (11%, p = nonsignificant). Approximately 60% of respondents measure the gap intraoperatively. A transanastomotic tube (90%) and chest drain (69%) are left in situ. Elective paralysis is adopted by 56% of respondents mainly for anastomosis tension (65%). About 72% of respondents routinely request a contrast study on postoperative day 7 (2-14). Approximately 54% of respondents use parenteral nutrition, 40% of respondents start transanastomotic feeds on postoperative day 1, and 89% of respondents start oral feeds after postoperative day 5. Pure EA: 46% of respondents work in centers that repair two or more than two pure EA a year. About 60% of respondents opt for delayed primary anastomosis at 3 months (1-12 months) with gastrostomy formation without esophagostomy. Anastomosis is achieved with open approach by 85% of respondents. About 47% of respondents attempt elongation of esophageal ends via Foker technique (43%) or with serial dilations with bougies (41%). Approximately 67% of respondents always attempt an anastomosis. Gastric interposition is the commonest esophageal substitution. CONCLUSION: Many aspects of EA management are lacking consensus. Minimally invasive repair is still sporadic. We recommend establishment of an EA registry. PMID- 23934628 TI - Sticker-type Alq(3)-based OLEDs based on printable ultrathin substrates in periodically anchored and suspended configurations. AB - Introducing two-dimensional post arrays and a water-soluble sacrificial layer between an ultrathin substrate and a handling substrate provides controllability of the interfacial adhesion in a stable manner. The periodically anchored and suspended configuration after the chemical etching process facilitates the development of, for example, printable Alq3 -based OLEDs that can be attached to unconventional surfaces. PMID- 23934627 TI - Bcr-Abl activates AURKA and AURKB in chronic myeloid leukemia cells via AKT signaling. AB - This study explored molecular mechanisms by which Bcr-Abl induced expression of Aurora kinase A and B (AURKA and AURKB) in chronic myeloid leukemia cells. Lentiviral transduction of Bcr-Abl into either Ba/F3 or CD34(+) hematopoietic stem/progenitor cells potently increased levels of AURKA and AURKB in association with phosphorylation of AKT and stimulated their proliferation. Bcr-Abl-mediated expression of AURKA and AURKB were decreased in CD34(+) HSPCs when AKT was inactivated by an shRNA against AKT, suggesting that Bcr-Abl induced expression of AURKA and AURKB via AKT signaling. MLN8237, an inhibitor of AURKA, significantly inhibited the proliferation of freshly isolated CD34(+) CML cells in a dose-dependent manner as measured by colony forming assay. Importantly, inhibition of AURKA in CD34(+) leukemia cells freshly isolated from individuals with blast crisis of CML with Bcr-Abl T315I mutant (n = 2) by MLN8237 significantly impaired the engraftment of these cells in severely immunocompromised mice and decreased the weight of spleens. Taken together, Bcr Abl induces expression of AURKA and AURKB at least in part via AKT. Inhibition of AURKA could be useful to overcome imatinib-resistance mediated by Bcr-Abl mutants. PMID- 23934630 TI - fMRI reliability: influences of task and experimental design. AB - As scientists, it is imperative that we understand not only the power of our research tools to yield results, but also their ability to obtain similar results over time. This study is an investigation into how common decisions made during the design and analysis of a functional magnetic resonance imaging (fMRI) study can influence the reliability of the statistical results. To that end, we gathered back-to-back test-retest fMRI data during an experiment involving multiple cognitive tasks (episodic recognition and two-back working memory) and multiple fMRI experimental designs (block, event-related genetic sequence, and event-related m-sequence). Using these data, we were able to investigate the relative influences of task, design, statistical contrast (task vs. rest, target vs. nontarget), and statistical thresholding (unthresholded, thresholded) on fMRI reliability, as measured by the intraclass correlation (ICC) coefficient. We also utilized data from a second study to investigate test-retest reliability after an extended, six-month interval. We found that all of the factors above were statistically significant, but that they had varying levels of influence on the observed ICC values. We also found that these factors could interact, increasing or decreasing the relative reliability of certain Task * Design combinations. The results suggest that fMRI reliability is a complex construct whose value may be increased or decreased by specific combinations of factors. PMID- 23934632 TI - Recommendations regarding the rabbit posterolateral spinal fusion model. PMID- 23934631 TI - Volume-to-creatinine clearance ratio in patients undergoing coronary angiography with or without percutaneous coronary intervention: implications of varying definitions of contrast-induced nephropathy. AB - OBJECTIVES: Whether predicting the risk of early serum creatinine rise using the ratio of the volume of contrast media administered to the estimated creatinine clearance (V/CrCl) is applicable to the broader definition of contrast-induced nephropathy (CIN) (>=0.5 mg/dL absolute and/or 25% relative increase from baseline serum creatinine) is unknown. BACKGROUND: A V/CrCl >=4 has been proven to predict the risk of >=0.5 mg/dL postprocedural absolute rise in serum creatinine. METHODS: A total of 722 patients undergoing coronary angiography +/- percutaneous coronary intervention (PCI) between March 2011 and October 2011 with paired serum creatinine determinations at preprocedure and within 72-hr postprocedure were analyzed. The V/CrCl ratio was calculated by dividing the volume of contrast received by the patient's creatinine clearance. CIN using different definitions was termed as CINnarrow (rise in serum creatinine >=0.5 mg/dL) and CINbroad (rise in serum creatinine >=0.5 mg/dL and/or >=25% increase in baseline serum creatinine). RESULTS: The mean age was 66 +/- 11 years and the mean baseline serum creatinine was 1.1 +/- 0.8 mg/dL. Patients with V/CrCl >=4 were significantly older and more frequently underwent ad hoc PCI compared with those with V/CrCl <4. CINnarrow and CINbroad were observed in 13 versus 3% (P < 0.001) and 23 versus 11% (P < 0.001) of patients with or without V/CrCl >=4, respectively. After statistical adjustment, a V/CrCl ratio >=4 remained significantly associated with the risk of both CINnarrow [adjusted OR 3.5, 95% confidence intervals (95% CI) 1.7-7.3; P < 0.001] and CINbroad (adjusted OR 2.5, 95% 1.6-3.9; P < 0.001). CONCLUSIONS: A volume-to-creatinine clearance ratio >=4 significantly predicts the risk of early postprocedural rise in serum creatinine regardless of the CIN definition adopted. PMID- 23934633 TI - Synthesis of constrained head-to-tail cyclic tetrapeptides by an imine-induced ring-closing/contraction strategy. PMID- 23934634 TI - Improved field free line magnetic particle imaging using saddle coils. AB - Magnetic particle imaging (MPI) is a novel tracer-based imaging method detecting the distribution of superparamagnetic iron oxide (SPIO) nanoparticles in vivo in three dimensions and in real time. Conventionally, MPI uses the signal emitted by SPIO tracer material located at a field free point (FFP). To increase the sensitivity of MPI, however, an alternative encoding scheme collecting the particle signal along a field free line (FFL) was proposed. To provide the magnetic fields needed for line imaging in MPI, a very efficient scanner setup regarding electrical power consumption is needed. At the same time, the scanner needs to provide a high magnetic field homogeneity along the FFL as well as parallel to its alignment to prevent the appearance of artifacts, using efficient radon-based reconstruction methods arising for a line encoding scheme. This work presents a dynamic FFL scanner setup for MPI that outperforms all previously presented setups in electrical power consumption as well as magnetic field quality. PMID- 23934635 TI - A rare case of osteogenesis imperfecta combined with complete tooth loss. AB - Osteogenesis imperfecta (OI) is a heritable disorder of the connective tissue characterized by blue sclerae, osteoporosis and bone fragility. Dentinogenesis imperfecta type I is commonly seen in OI patients, but other dental impairments, such as tooth agenesis or complete tooth loss, are rarely reported for these patients. Here, we report the case of a 37-year-old female Chinese OI patient who experienced complete tooth loss before puberty. The patient has a family history of OI and her father has a history of tooth loss. She showed obvious OI phenotypes, including a dwarfed stature, blue sclerae, scoliosis, pigeon chest and a history of fractures. Tooth loss began at the age of 6 years and continued until complete tooth loss at 20 years; this occurred in the absence of dental decay, gum disease, accidents or drug usage. Radiological studies revealed osteoporosis of the lower limbs and an underdeveloped scapula. Type I collagen gene analysis identified a known c.2314G>A (p.Gly772Ser) substitution in the COL1A2 gene, which we suggest affects the interaction between type I collagen and extracellular matrix proteins, including cartilage oligomeric matrix protein, phosphophoryn and SPARC (secreted protein acidic and rich in cysteine). In silico prediction indicated a relatively mild effect of the mutation, so it is conceivable that the severity of the clinical phenotype may result from additional mutations in candidate genes responsible for abnormal dental phenotypes in this family. To our knowledge, this is the first report of an OI patient with a phenotype of complete tooth loss at a young age. PMID- 23934636 TI - Hypercalcemia and osteolytic lesions as presenting symptoms of acute lymphoblastic leukemia in childhood. The use of zoledronic acid and review of the literature. AB - Hypercalcemia is rare in children with etiology different from adults. We report an 11.5-year-old boy with developmental delay that presented with difficulty in walking and vomiting. Laboratory investigations revealed hypercalcemia (Ca 13.8 mg/dL) with low serum parathormone, normal full blood count and no circulating blasts. Osteolytic lesions were discovered on radiological survey. Bone marrow examination was consistent with the diagnosis of common B acute lymphoblastic leukemia (ALL). Hypercalcemia was successfully treated with zoledronic acid. Hypercalcemia is a rare but well-recognized complication of ALL, usually present at the time of initial diagnosis. We reviewed the literature and analyzed the clinical and laboratory data in 36 cases of childhood ALL presenting with hypercalcemia. In conclusion, hypercalcemia alone or combined with osteolytic lesions can be the only presenting symptom of ALL in children. PMID- 23934637 TI - Glycemic control in familial vs. sporadic type 1 diabetes patients over 5 years. AB - BACKGROUND: Studies have shown that familial type 1 diabetes patients (FTID) have less severe metabolic derangement at presentation compared to sporadic patients (ST1D), but data on long-term metabolic control are lacking. OBJECTIVE/HYPOTHESIS: (1) FT1D will have less severe presentation and better HbA1c over 5 years compared to ST1D; (2) HbA1c in the offspring will correlate with parent HbA1c in parent-offspring group; and (3) HbA1c of the second affected sibling (SP2) will correlate with the first affected sibling (SP1) in sib-pairs. METHODS: Cohort of 33 parent-offspring and 19 sib-pairs; controls included 33 sporadic subjects matched by age, sex, ethnicity, puberty, and insulin regimen. Paired t-test and Pearson's correlation were used for statistical analysis. RESULTS: At diagnosis, mean age in FT1D vs. matched ST1D (7.7+/-4.9 vs. 7.6+/-4.5 years), mean HbA1c (9.6% vs. 10.7%), HCO3 (21 vs. 18 meq/L), glucose (428 vs. 463 mg/dL) and pH (7.35 vs. 7.36; p=ns) were not different. At 5 years, HbA1c (8.9% vs. 8.8%; p=0.81), clinic visits (12 vs. 12.5, p=0.68) and emergency room visits (0.48 vs. 0.24, p=0.10) were not different. In affected siblings, only HCO3 was different (SP1:18 vs. SP2: 24 meq/L; p<0.01). HbA1c for SP2 correlated positively with SP1 (r=0.67, p<0.01). Offspring HbA1c correlated positively with affected parents (9.3% vs. 8.6%, r=0.57, p=0.18) but was not significant. CONCLUSION: Metabolic control at diagnosis and at 5 years was similar in FT1D and ST1D. In sib-pairs, the second affected sibling had milder clinical presentation compared to the first affected sibling. PMID- 23934638 TI - Hypothalamic hamartoma associated with central precocious puberty and growth hormone deficiency. AB - Hypothalamic hamartomas (HHs) are tumors generally associated with isolated central precocious puberty (CPP). To our knowledge, we report a unique case of a girl with HH associated with CPP and growth hormone deficiency. This case highlights the complex interaction between HHs and the hypothalamic-pituitary gonadal axis. It also emphasizes the value of close follow-up of growth velocity in these patients even after treatment of the CPP. PMID- 23934639 TI - Iatrogenic acute pancreatitis due to hypercalcemia in a child with pseudohypoparathyroidism. AB - Pancreatitis due to hypercalcemia is very rare in children, and its pathogenetic role is still debated. The following report describes a case of acute pancreatitis secondary to hypercalcemia in a 6-year-old boy with pseudohypoparathyroidism treated with calcium and vitamin D. Pseudohypoparathyroidism is characterized by parathormone (PTH) resistance, high PTH levels and hypocalcemia which need to be corrected with calcium and vitamin D supplementation. The patient was admitted for severe abdominal pain and vomiting associated with high plasma amylase, lipase and calcium levels. Hypercalcemia due to vitamin D and calcium overtreatment was probably responsible for the acute pancreatitis in this case. High serum calcium levels seem to sensitize patients to pancreatitis, even if the mechanism through which it happens is not completely understood. Moreover, the importance of concomitant predisposing factors, either acquired or especially genetic, needs to be further defined. Even though a rare occurance in childhood, hypercalcemia should be considered as a cause of pancreatitis and it should be examined together with the other etiologies that may contribute to the development of this disease. PMID- 23934640 TI - Hypocalcemia in a paediatric case: from the clinical features to diagnosis. AB - Pseudohypoparathyroidism refers to end-organ resistance that primarily impairs the renal actions of parathyroid hormone (PTH), a key regulator of calcium homeostasis. Its diagnosis is complex because of the multiple variants of this entity, and more so because intravenous PTH is not available for the Ellsworth Howard test. We report a symptomatic paediatric case of hypocalcaemia, the clinical features of which, and the course after treatment, suggest that it is most probably a case of pseudohypoparathyroidism type Ib. PMID- 23934641 TI - Homozygosity for a DTDST mutation in a child with multiple epiphyseal dysplasia. AB - BACKGROUND: Multiple epiphyseal dysplasia (MED) is one of the common hereditary osteochondrodysplasias. Mutations in diastrophic dysplasia sulfate transporter gene (DTDST) result in recessive MED. OBJECTIVE: To investigate the possible gene mutation in a recessive MED patient. SUBJECTS: A boy with typical clinical features of recessive MED and his parents. METHODS: Clinical and radiological evaluations, DTDST gene sequence analysis, and sulfate uptake assay were performed on the patient and his parents. RESULTS: The patient showed typical symptoms of recessive MED. The radiological evaluation confirmed dysplasia in multiple epiphysis of the patient, while his parents did not show the similar clinical and radiological features. Gene sequence showed the patient was homozygous of A2092T (T689S) mutation, while his parents were both of heterozygous of the same mutation. No such mutation in DTDST gene was found in 81 normal control individuals. The patient showed reduced sulfate uptake ability in dermal fibroblast compared with his parents and normal controls. CONCLUSION: The homozygous A2092T (T689S) mutation could be one of the mutations in the DTDST gene causing MED. PMID- 23934642 TI - Thiosulfate in urine: new hope or new failure of a biomarker for prostate cancer? PMID- 23934643 TI - Evaluation of the N Latex free light chain assay in the diagnosis and monitoring of AL amyloidosis. AB - BACKGROUND: We compared a novel assay for free light chain (FLC) quantitation based on monoclonal antibodies (N-Latex, Siemens, Germany) to the established polyclonal antibody-based assay (FreeliteTM, The Binding Site, UK) in AL amyloidosis. METHODS: Sixty-two diagnostic samples were analysed on a BNII nephelometer, 32 of which also had a post-treatment sample. RESULTS: In the diagnostic samples: for AL of kappa type, the median involved FLC (iFLC) was significantly lower by the N-Latex assay (289 vs. 667 mg/L, p=0.0002) whereas for lambda AL the values were similar (148 vs. 161 mg/L, p=0.84). Measurable disease, defined as a difference between involved and uninvolved FLC (dFLC) >50 mg/L was present in 82% by the N-Latex assay compared to 89% by the FreeliteTM assay. For diagnostic sensitivity, the FLC ratio was normal in 21% (95% CI 12%-33%) and 15% (95% CI 7%-26%) of patients by the N-Latex and FreeliteTM assays, respectively. The combination of serum and urine immunofixation electrophoresis with either FLC assay allowed identification of the amyloidogenic clone in 98% producing comparable sensitivity. For the monitoring samples the median reduction in dFLC was 68% for the N-Latex assay and 77% for the FreeliteTM assay (p=0.04). This led to some differences in assigning response categories. Partial response as assigned by both assays predicted overall survival (N-Latex p=0.0015, FreeliteTM p=0.022). CONCLUSIONS: There are differences between FLC as measured by the N Latex and FreeliteTM assays, but overall the two assays have similar diagnostic sensitivity. Disease response calculated by both assays predicts survival but more clinical validation is required. PMID- 23934645 TI - The molecular biology of genetic-based epilepsies. AB - Epilepsy is one of the most common neurological disorders characterized by abnormal electrical activity in the central nervous system. The clinical features of this disorder are recurrent seizures, difference in age onset, type, and frequency, leading to motor, sensory, cognitive, psychic, or autonomic disturbances. Since the discovery of the first monogenic gene mutation in 1995, it is proposed that genetic factor plays an important role in the mechanism of epilepsy. Genes discovered in idiopathic epilepsies encode for ion channel or neurotransmitter receptor proteins, whereas syndromes with epilepsy as a main feature are caused by genes that are involved in functions such as cortical development, mitochondrial function, and cell metabolism. The identification of these monogenic epilepsy-causing genes provides new insight into the pathogenesis of epilepsies. Although most of the identified gene mutations present a monogenic inheritance, most of idiopathic epilepsies are complex genetic diseases exhibiting a polygenic or oligogenic inheritance. This article reviews recent genetic and molecular progresses in exploring the pathogenesis of epilepsy, with special emphasis on monogenic epilepsy-causing genes, including voltage-gated channels (Na(+), K(+), Ca(2+), Cl(-), and HCN), ligand-gated channels (nicotinic acetylcholine and GABAA receptors), non-ion channel genes as well as the mitochondrial DNA genes. These progresses have improved our understanding of the complex neurological disorder. PMID- 23934644 TI - The proform of glia cell line-derived neurotrophic factor: a potentially biologically active protein. AB - Growing evidences have revealed that the proforms of several neurotrophins including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3), by binding to p75 neurotrophin receptor and sortilin, could induce neuronal apoptosis and are implicated in the pathogenesis of various neurodegenerative diseases. The glial cell line-derived neurotrophic factor (GDNF), one of the most potent useful neurotrophic factors for the treatment of Parkinson's disease (PD), is firstly synthesized as the proform (proGDNF) like other neurotrophin NGF, BDNF, and NT3. However, little is known about proGDNF expression and secretion under physiological as well as pathological states in vivo or in vitro. In this study, we investigated the expression profile and dynamic changes of proGDNF in brains of aging and PD animal models, with the interesting finding that proGDNF was a predominant form of GDNF with molecular weight of about 36 kDa by reducing and nonreducing immunoblots in adult brains and was unregulated in the aging, lipopolysaccharide (LPS), and 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) insult. We further provided direct evidence that accompanied activation of primary astrocytes as well as C6 cell line induced by LPS stimulation, proGDNF was increasingly synthesized and released as the uncleaved form in cell culture. Taken together, our results strongly suggest that proGDNF may be a biologically active protein and has specific effects on the cells close to its secreting site, and a potentially important role of proGDNF signaling in the brains, in the glia-neuronal interaction or in the pathogenesis of PD, should merit further investigation. PMID- 23934646 TI - Neuroprotection by monocarbonyl dimethoxycurcumin C: ameliorating the toxicity of mutant TDP-43 via HO-1. AB - Mutation of TAR DNA-binding protein-43 (TDP-43) was detected in familiar and sporadic amyotrophic lateral sclerosis, and pathological TDP-43 was identified in the frontotemporal lobar degeneration. The neuroprotective functions of curcumin derivatives were assessed in motor neurons transfected with mutant TDP-43. We found that curcumin derivatives reduced the levels of TDP-43 fragments. Furthermore, we evaluated these compounds on the cellular model that the cells were transfected with TDP-25. We found that the expression level and aggregate formation of TDP-25 were significantly reduced by monocarbonyl dimethoxycurcumin C (Compound C). To study on the neuroprotective functions of curcumin derivatives, the neuroblastoma-spinal cord-34 cells transfected with mutant TDP 43 were assessed by the level of lactate dehydrogenase (LDH) and malondialdehyde bisdimethyl acetal (MDA) that were involved in the oxidative stress. We found that Compound C ameliorated the damage of mutant TDP-43 by reducing the level of MDA and LDH. Furthermore, heme oxygenase-1 (HO-1) was induced by Compound C significantly higher than other compounds. Znpp, which is known an inhibitor of HO-1, dramatically interfered with the function of Compound C. In addition, Compound C was tested in vivo, and HO-1 was significantly upregulated at the hippocampus. These findings suggest that Compound C, which degrades TDP-43 fragment and strengthens the antioxidant ability by HO-1, is a promising agent for TDP-43 proteinopathy. PMID- 23934647 TI - alpha-Synuclein is involved in manganese-induced ER stress via PERK signal pathway in organotypic brain slice cultures. AB - Overexposure to manganese (Mn) has been known to induce neuronal damage involving endoplasmic reticulum (ER) stress. However, the exact mechanism of Mn-induced ER stress is unclear. Increasing evidence suggested that the overexpression of alpha synuclein played a critical role in Mn-induced neurotoxicity. To explore whether the occurrence of ER stress was associated with alpha-synuclein overexpression, we made the rat brain slices model of silencing alpha-synuclein using short interference RNA. After non-silencing alpha-synuclein slices were treated with Mn (0-400 MUM) for 24 h, there was a dose-dependent increase in apoptotic rates of cells and levels of lactate dehydrogenase in the culture medium. Moreover, there was a dose-dependent increase in the protein expression of 78, 94-kDa glucose regulated protein (GRP78/94), C/EBP homologous protein (CHOP), and caspase-12. Moreover, PKR-like ER kinase (PERK) phosphorylation, PERK-mediated phosphorylation of eIF2a, and ATF4 expression also increased. Inositol-requiring enzyme 1 (IRE1) activation and X-box-binding protein-1 (Xbp1) mRNA splicing increased. Activating transcription factor 6 p90 levels did not change. However, after silencing alpha-synuclein slices were treated with 400 MUM Mn for 24 h, there was a significant decrease in the expression of GRP78/94, CHOP, and caspase 12 compared with 400 MUM Mn-treated non-silencing alpha-synuclein slices. Furthermore, PERK phosphorylation, PERK-mediated phosphorylation of eIF2a, and ATF4 mRNA expression also decreased. However, IRE1 phosphorylation and Xbp1 mRNA splicing did not change. The findings revealed that Mn induced ER stress via activation of PERK and IRE1 signaling pathways and subsequent apoptosis in cultured slices. Moreover, alpha-synuclein protein was associated with Mn-induced activation of PERK signaling pathway. PMID- 23934649 TI - Serum concentrations of perfluorinated alkyl acids and their associations with diet and personal characteristics among Swedish adults. AB - SCOPE: In this study, food is suggested as a major source of human exposure to perfluorinated alkyl acids (PFAA). We investigated relations between serum levels of PFAA in adults and diet/lifestyle factors nationwide in Sweden. METHODS AND RESULTS: In 2010-2011, adults (18-80 years, N = 270) recorded their diet for 4 days and answered a food frequency questionnaire. PFAA were measured in blood serum as well as v-3 fatty acids in plasma phospholipids as a biomarker for fish consumption. Higher levels of PFAA were associated with male sex, increased age, and higher education. Women reporting full breastfeeding for >=12 months had 32 44% lower levels of perfluorooctane sulfonate, perfluorooctanoic acid, and perfluorohexane sulfonate than women who never nursed their infants full-time. Serum perfluorooctane sulfonate, perfluorononanoic acid, perfluorodecanoic acid, and perfluoroundecanoic acid were positively related to n-3 fatty acids in plasma (partial r = 0.19-0.34, p <= 0.05). CONCLUSION: The relatively strong correlations between biomarkers of fish consumption and certain PFAA suggest that PFAA exposure should be taken into account in health risk and benefit assessment of fish consumption. Breastfeeding appears to be a major source of elimination of certain PFAA among women, and consequently PFAA exposure of nursed infants could be significant. PMID- 23934648 TI - C9ORF72 mutations in neurodegenerative diseases. AB - Recent works have demonstrated an expansion of the GGGGCC hexanucleotide repeat in the first intron of chromosome 9 open reading frame 72 (C9ORF72), encoding an unknown C9ORF72 protein, which was responsible for an unprecedented large proportion of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases of European ancestry. C9ORF72 is expressed in most tissues including the brain. Emerging evidence has demonstrated that C9ORF72 mutations could reduce the level of C9ORF72 variant 1, which may influence protein expression and the formation of nuclear RNA foci. The spectrum of mutations is broad and provides new insight into neurological diseases. Clinical manifestations of diseases related with C9ORF72 mutations can vary from FTD, ALS, primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), Huntington disease-like syndrome (HDL syndrome), to Alzheimer's disease. In this article, we will review the brief characterizations of the C9ORF72 gene, the expansion mutations, the related disorders, and their features, followed by a discussion of the deficiency knowledge of C9ORF72 mutations. Based on the possible pathological mechanisms of C9ORF72 mutations in ALS and FTD, we can find new targets for the treatment of C9ORF72 mutation-related diseases. Future studies into the mechanisms, taking into consideration the discovery of those disorders, will significantly accelerate new discoveries in this field, including targeting identification of new therapy. PMID- 23934650 TI - Three-Degree-of-Freedom MR-Compatible Multisegment Cardiac Catheter Steering Mechanism. AB - This paper presents a novel MR-compatible 3-DOF cardiac catheter steering mechanism. The catheter's steerable structure is tendon driven and consists of miniature deflectable, helical segments created by a precise rapid prototyping technique. The created catheter prototype has an outer diameter of 9 Fr (3 mm) and a steerable distal end that can be deflected in a 3-D space via four braided high-tensile Spectra fiber tendons. Any longitudinal twist commonly observed in helical structures is compensated for by employing clockwise (CW) and counter clockwise (CCW) helical segments in an alternating fashion. A 280 MUm flexible carbon fiber rod is used as a backbone in a central channel to improve the structure's steering and positioning repeatability. In addition to the backbone, a carbon fiber tube can be inserted into the structure to a varying amount capable of changing the structure's forcibility and, thus, providing a means to change the curvature and to modify the deflectable length of the catheter leading to an extension of reachable points in the catheter-tip workspace. A unique feature of this helical segment structure is that the stiffness can be further adjusted by appropriately tensioning tendons simultaneously. An experimental study has been conducted examining the catheter-tip trajectory in a 3-D space and its positioning repeatability using a 5-DOF magnetic coil tracking system. Furthermore, MRI experiments in a 1.5-T scanner confirmed the MR-compatibility of the catheter prototype. The study shows that the proposed concept for catheter steering has great potential to be employed for robotically steered and MR-guided cardiac catheterization. PMID- 23934651 TI - Robust endoscope motion estimation via an animated particle filter for electromagnetically navigated endoscopy. AB - Electromagnetically navigated endoscopy, which is increasingly applied in endoscopic interventions, utilizes an electromagnetic sensor attached at the endoscope tip to measure the endoscope movements and to navigate the endoscope in the region of interest in the body. Due to patient motion and magnetic field distortion, sensor electromagnetic tracking (EMT) measurement inaccuracy and dynamic jitter errors remain challenging for electromagnetic navigation. This paper proposes a new tracking framework of an animated particle filter that integrates adaptive particle swarm optimization into a generic particle filter to significantly boost electromagnetic trackers. We validate our method on a dynamic phantom and compare it to state-of-the-art EMT methods. Our experimental results demonstrate the effectiveness and robustness of our method, which provides position and orientation accuracy of 2.48 mm, 4.69 degrees that significantly outperformed previous methods at least with tracking error of 4.19 mm, 7.75 degrees . The tracking smoothness was improved from 4.09 mm, 3.37 degrees to 1.84 mm, 2.52 degrees . Our method successfully tackled the particle impoverishment better than standard particle filters. PMID- 23934652 TI - Serrated polyps: clinical implications and future directions. AB - Serrated polyps were once thought to have no clinical implications with regards to the development of colorectal cancer (CRC). Over the past several years, published data have enabled clinicians to develop a better understanding of these lesions. The serrated pathway associated with these lesions involves an epigenetic mechanism characterized by abnormal hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes. It is often associated with BRAF mutations and may account for 15-35% of all CRC. This pathway may also play a major role in proximal neoplasia and missed cancer. There are three distinct subtypes of serrated neoplasia; hyperplastic (70% of all serrated polyps), sessile serrated adenoma/polyp (SSA/P) (25%) and traditional serrated adenoma (<2%). The last two forms are considered to be precursors for CRC. SSA/P are associated with synchronous CRC especially if the polyps are large (>=1 cm), multiple, or if they are in the proximal colon. Lesions containing serrated neoplasia are usually flat or sessile, may be large, and occasionally have a mucous cap. Serrated lesions provide many challenges for the clinician and may be difficult to detect and completely remove. Furthermore, pathologists may misclassify SSA/P as HP. For the first time, the Multi-Society Task Force guidelines for colorectal polyp surveillance have included the management of serrated lesions in their published recommendations. In addition, an expert panel has also recently issued recommendations regarding serrated neoplasia. In this article, we provide the reader with a summary as well as the latest developments regarding serrated colonic lesions. PMID- 23934653 TI - Persistent diarrhea: still a serious public health problem in developing countries. AB - Diarrhea is still responsible for high rates of morbidity and mortality in children under 5 years of age. The prolongation of the acute episode may cause digestive and absorptive malfunction and, consequently, malnutrition, raising the risk of death. The objective of this review is to supply the most recent knowledge in the field of persistent diarrhea and to contribute to the decrease of its incidence. Some possible etiologic agents may be involved, including viruses, bacteria, and parasites. Treatment must be addressed to avoid malabsorption of the nutrients of the diet, associated with replacement of the hydroelectrolytic losses, to prevent its prolongation. In the great majority of the episodes, antibiotics are not indicated. Breastfeeding, introduction of safe dietary strategies to prevent protein-energy malnutrition, and improvement of sanitary conditions and hygiene are measures to be promoted with the objective of decreasing the morbidity/mortality of the diarrheic disease in children less than 5 years of age. PMID- 23934654 TI - Role of bed nucleus of the stria terminalis and amygdala AMPA receptors in the development and expression of context conditioning and sensitization of startle by prior shock. AB - A core symptom of post-traumatic stress disorder is hyper-arousal-manifest in part by increases in the amplitude of the acoustic startle reflex. Gewirtz et al. (Prog Neuropsychopharmacol Biol Psychiatry 22:625-648, 1998) found that, in rats, persistent shock-induced startle increases were prevented by pre-test electrolytic lesions of the bed nucleus of the stria terminalis (BNST). We used reversible inactivation to determine if similar effects reflect actions on (a) BNST neurons themselves versus fibers-of-passage, (b) the development versus expression of such increases, and (c) associative fear versus non-associative sensitization. Twenty-four hours after the last of three shock sessions, startle was markedly enhanced when rats were tested in a non-shock context. These increases decayed over the course of several days. Decay was unaffected by context exposure, and elevated startle was restored when rats were tested for the first time in the original shock context. Thus, both associative and non associative components could be measured under different conditions. Pre-test intra-BNST infusions of the AMPA receptor antagonist NBQX (3 MUg/side) blocked the non-associative (as did infusions into the basolateral amygdala) but not the associative component, whereas pre-shock infusions disrupted both. NBQX did not affect baseline startle or shock reactivity. These results indicate that AMPA receptors in or very near to the BNST are critical for the expression and development of non-associative shock-induced startle sensitization, and also for context fear conditioning, but not context fear expression. More generally, they suggest that treatments targeting the BNST may be clinically useful for treating trauma-related hyper-arousal and perhaps for retarding its development. PMID- 23934656 TI - Synthesis of 9-oxononanoic acid, a precursor for biopolymers. AB - Polymers based on renewable resources have become increasingly important. The natural functionalization of fats and oils enables an easy access to interesting monomeric building blocks, which in turn transform the derivative biopolymers into high-performance materials. Unfortunately, interesting building blocks of medium-chain length are difficult to obtain by traditional chemical means. Herein, a biotechnological pathway is established that could provide an environmentally suitable and sustainable alternative. A multiple enzyme two-step one-pot process efficiently catalyzed by a coupled 9S-lipoxygenase (St-LOX1, Solanum tuberosum) and 9/13-hydroperoxide lyase (Cm-9/13HPL, Cucumis melo) cascade reaction is proposed as a potential route for the conversion of linoleic acid into 9-oxononanoic acid, which is a precursor for biopolymers. Lipoxygenase catalyzes the insertion of oxygen into linoleic acid through a radical mechanism to give 9S-hydroperoxy-octadecadienoic acid (9S-HPODE) as a cascade intermediate, which is subsequently cleaved by the action of Cm-9/13HPL. This one-pot process afforded a yield of 73 % combined with high selectivity. The best reaction performance was achieved when lipoxygenase and hydroperoxide lyase were applied in a successive rather than a simultaneous manner. Green leaf volatiles, which are desired flavor and fragrance products, are formed as by-products in this reaction cascade. Furthermore, we have investigated the enantioselectivity of 9/13-HPLs, which exhibited a strong preference for 9S-HPODE over 9R-HPODE. PMID- 23934655 TI - Cell-type specific increases in female hamster nucleus accumbens spine density following female sexual experience. AB - Female sexual behavior is an established model of a naturally motivated behavior which is regulated by activity within the mesolimbic dopamine system. Repeated activation of the mesolimbic circuit by female sexual behavior elevates dopamine release and produces persistent postsynaptic alterations to dopamine D1 receptor signaling within the nucleus accumbens. Here we demonstrate that sexual experience in female Syrian hamsters significantly increases spine density and alters morphology selectively in D1 receptor-expressing medium spiny neurons within the nucleus accumbens core, with no corresponding change in dopamine receptor binding or protein expression. Our findings demonstrate that previous life experience with a naturally motivated behavior has the capacity to induce persistent structural alterations to the mesolimbic circuit that can increase reproductive success and are analogous to the persistent structural changes following repeated exposure to many drugs of abuse. PMID- 23934657 TI - Novel proteomic approach (PUNCH-P) reveals cell cycle-specific fluctuations in mRNA translation. AB - Monitoring protein synthesis is essential to our understanding of gene expression regulation, as protein abundance is thought to be predominantly controlled at the level of translation. Mass-spectrometric and RNA sequencing methods have been recently developed for investigating mRNA translation at a global level, but these still involve technical limitations and are not widely applicable. In this study, we describe a novel system-wide proteomic approach for direct monitoring of translation, termed puromycin-associated nascent chain proteomics (PUNCH-P), which is based on incorporation of biotinylated puromycin into newly synthesized proteins under cell-free conditions followed by streptavidin affinity purification and liquid chromatography-tandem mass spectrometry analysis. Using PUNCH-P, we measured cell cycle-specific fluctuations in synthesis for >5000 proteins in mammalian cells, identified proteins not previously implicated in cell cycle processes, and generated the first translational profile of a whole mouse brain. This simple and economical technique is broadly applicable to any cell type and tissue, enabling the identification and quantification of rapid proteome responses under various biological conditions. PMID- 23934660 TI - Application limits and data correction in number of molecules and brightness analysis. AB - Number of molecules and Brightness (N&B) has been proposed for measuring the molecular brightness and number of fluorophores in time-sequence of images, in live cells. If the fluorescently tagged-proteins are mobile in the illumination volume, the stoichiometry of their oligomers can be derived from the increase of the brightness of the fluorescent dyes due to clustering. We examine aspects concerning extra-fluctuation effects induced by cell shifts and photobleaching, which yield large overestimates of the clusters size and sub-unit counts. We develop an offline corrective approach consisting in frame re-alignment and boxcar filtering for recovering precision of the analysis. Using simulations we derive general criteria for approaching this analysis, and assess the application limits of the corrective procedure. We tested the approach in extreme experimental conditions (few pixels, large extra-variance perturbations), in which we analyzed the minimal increases of brightness as that expected between a monomeric and dimeric GPI-mEGFP constructs. We show how most of the perturbing effects can be abolished, and obtain the correct the brightness of GPI-mEGFP monomers and dimers. PMID- 23934662 TI - OCT predicts VEGF levels in human eyes. PMID- 23934658 TI - Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. AB - Senescence is a stable proliferation arrest, associated with an altered secretory pathway, thought to promote tumor suppression and tissue aging. While chromatin regulation and lamin B1 down-regulation have been implicated as senescence effectors, functional interactions between them are poorly understood. We compared genome-wide Lys4 trimethylation on histone H3 (H3K4me3) and H3K27me3 distributions between proliferating and senescent human cells and found dramatic differences in senescence, including large-scale domains of H3K4me3- and H3K27me3 enriched "mesas" and H3K27me3-depleted "canyons." Mesas form at lamin B1 associated domains (LADs) in replicative senescence and oncogene-induced senescence and overlap DNA hypomethylation regions in cancer, suggesting that pre malignant senescent chromatin changes foreshadow epigenetic cancer changes. Hutchinson-Gilford progeria syndrome fibroblasts (mutant lamin A) also show evidence of H3K4me3 mesas, suggesting a link between premature chromatin changes and accelerated cell senescence. Canyons mostly form between LADs and are enriched in genes and enhancers. H3K27me3 loss is correlated with up-regulation of key senescence genes, indicating a link between global chromatin changes and local gene expression regulation. Lamin B1 reduction in proliferating cells triggers senescence and formation of mesas and canyons. Our data illustrate profound chromatin reorganization during senescence and suggest that lamin B1 down-regulation in senescence is a key trigger of global and local chromatin changes that impact gene expression, aging, and cancer. PMID- 23934661 TI - Dual tasking and balance in those with central and peripheral vision loss. AB - PURPOSE: To investigate the effects of a secondary task on standing balance in patients with glaucoma or AMD compared with age-similar control subjects. METHODS: Twelve AMD, 12 glaucoma, and 12 control participants underwent posturography under two standing conditions (eyes open on a firm or foam-rubber surface) and two tasks: quiet standing and undertaking a mental arithmetic task. Center of foot-pressure average displacement (root mean square [RMS]; in millimeters) was calculated. RESULTS: The mean (SD) age of the participants in each group was as follows: controls 66.2 (6.4) years, glaucoma 69.2 (4.3) years, and AMD 72.2 (5.3) years. There were significant differences in RMS between controls and AMD patients when undertaking the mental arithmetic task standing on the firm surface (mean difference [SE]: 2.8 [0.8] mm, P = 0.005). There were significant differences between controls and AMD patients when undertaking the mental arithmetic task on the foam surface, with the difference between controls and glaucoma patients approaching significance (mean difference [SE]: control versus AMD = 3.1 [0.9] mm, P = 0.005; control versus glaucoma = 2.2 [0.9] mm, P = 0.06). CONCLUSIONS: Postural instability increases with the addition of a secondary task in older persons, which may put them at greater risk of falls. Patients with central losses exhibit greater instability with the addition of a secondary task, particularly during somatosensory perturbations. The negative effects of secondary tasks on balance control in those with peripheral visual losses become more apparent under somatosensory perturbations. PMID- 23934663 TI - A Framework for Inter-Subject Prediction of Functional Connectivity From Structural Networks. AB - Functional connections between brain regions are supported by structural connectivity. Both functional and structural connectivity are estimated from in vivo magnetic resonance imaging and offer complementary information on brain organization and function. However, imaging only provides noisy measures, and we lack a good neuroscientific understanding of the links between structure and function. Therefore, inter-subject joint modeling of structural and functional connectivity, the key to multimodal biomarkers, is an open challenge. We present a probabilistic framework to learn across subjects a mapping from structural to functional brain connectivity. Expanding on our previous work [1], our approach is based on a predictive framework with multiple sparse linear regression. We rely on the randomized LASSO to identify relevant anatomo-functional links with some confidence interval. In addition, we describe resting-state functional magnetic resonance imaging in the setting of Gaussian graphical models, on the one hand imposing conditional independences from structural connectivity and on the other hand parameterizing the problem in terms of multivariate autoregressive models. We introduce an intrinsic measure of prediction error for functional connectivity that is independent of the parameterization chosen and provides the means for robust model selection. We demonstrate our methodology with regions within the default mode and the salience network as well as, atlas-based cortical parcellation. PMID- 23934659 TI - Cisplatin causes cell death via TAB1 regulation of p53/MDM2/MDMX circuitry. AB - The interdependence of p53 and MDM2 is critical for proper cell survival and cell death and, when altered, can lead to tumorigenesis. Mitogen-activated protein kinase (MAPK) signaling pathways function in a wide variety of cellular processes, including cell growth, migration, differentiation, and death. Here we discovered that transforming growth factor beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1), an activator of TAK1 and of p38alpha, associates with and inhibits the E3 ligase activity of MDM2 toward p53 and its homolog, MDMX. Depletion of TAB1 inhibits MDM2 siRNA-mediated p53 accumulation and p21 induction, partially rescuing cell cycle arrest induced by MDM2 ablation. Interestingly, of several agents commonly used as DNA-damaging therapeutics, only cell death caused by cisplatin is mitigated by knockdown of TAB1. Two mechanisms are required for TAB1 to regulate apoptosis in cisplatin-treated cells. First, p38alpha is activated by TAB1 to phosphorylate p53 N-terminal sites, leading to selective induction of p53 targets such as NOXA. Second, MDMX is stabilized in a TAB1-dependent manner and is required for cell death after cisplatin treatment. Interestingly TAB1 levels are relatively low in cisplatin-resistant clones of ovarian cells and in ovarian patient's tumors compared with normal ovarian tissue. Together, our results indicate that TAB1 is a potential tumor suppressor that serves as a functional link between p53-MDM2 circuitry and a key MAPK signaling pathway. PMID- 23934664 TI - Evaluation and comparison of current fetal ultrasound image segmentation methods for biometric measurements: a grand challenge. AB - This paper presents the evaluation results of the methods submitted to Challenge US: Biometric Measurements from Fetal Ultrasound Images, a segmentation challenge held at the IEEE International Symposium on Biomedical Imaging 2012. The challenge was set to compare and evaluate current fetal ultrasound image segmentation methods. It consisted of automatically segmenting fetal anatomical structures to measure standard obstetric biometric parameters, from 2D fetal ultrasound images taken on fetuses at different gestational ages (21 weeks, 28 weeks, and 33 weeks) and with varying image quality to reflect data encountered in real clinical environments. Four independent sub-challenges were proposed, according to the objects of interest measured in clinical practice: abdomen, head, femur, and whole fetus. Five teams participated in the head sub-challenge and two teams in the femur sub-challenge, including one team who tackled both. Nobody attempted the abdomen and whole fetus sub-challenges. The challenge goals were two-fold and the participants were asked to submit the segmentation results as well as the measurements derived from the segmented objects. Extensive quantitative (region-based, distance-based, and Bland-Altman measurements) and qualitative evaluation was performed to compare the results from a representative selection of current methods submitted to the challenge. Several experts (three for the head sub-challenge and two for the femur sub-challenge), with different degrees of expertise, manually delineated the objects of interest to define the ground truth used within the evaluation framework. For the head sub-challenge, several groups produced results that could be potentially used in clinical settings, with comparable performance to manual delineations. The femur sub challenge had inferior performance to the head sub-challenge due to the fact that it is a harder segmentation problem and that the techniques presented relied more on the femur's appearance. PMID- 23934665 TI - On Artifact-Free Projection Overlaps in Multi-Pinhole Tomographic Imaging. AB - In multi-pinhole SPECT, overlapping the projections from different pinholes has been used to increase sensitivity. However, the prevailing view is that the overall quality of the reconstructed image is not improved by the overlaps in the projections. It is often stated in literatures that overlaps introduce ambiguous information, which can lead to nonuniqueness of solution for the inverse problem, and thus artifacts are introduced in the reconstructed image. On the other hand, contrary to the prevailing view, a recent study on slit-slat collimators shows that artifacts can be removed with the "help" of an extra complete nonoverlapped projection data set. In this paper, two types of artifact-free projection overlaps are defined in general, and the criteria for designing artifact-free multi-pinhole systems with overlaps are proposed. It is shown that once the criteria are satisfied, the solution of the inverse problem is unique, and thus no artifact is expected in the reconstructed image. Via extensive simulation study, various artifact-free overlapping multi-pinhole systems are designed and validated. It is shown that overlaps in the artifact-free systems can improve contrast-to-noise ratio (CNR). With a proper design, the CNR for an artifact-free overlapping system can be significantly higher than that for the corresponding nonoverlapping system. The improved image quality is also confirmed with noisy reconstructions. PMID- 23934666 TI - General synthesis and physicochemical characterisation of a series of peptide mimic lysine-based amino-functionalised lipids. AB - A series of novel malonic acid diamides (second generation) with two long hydrophobic alkyl chains and an alkaline polar head group was synthesised and characterised as a new class of amino-functionalised lipids. These peptide-mimic lipids are suitable for polynucleotide transfer. The lipids bear a novel backbone consisting of a lysine unit and a malonic acid unit. Six different head-group structures, which vary in size and number of amino groups that can be protonated, were attached to the backbone structure. Furthermore, different alkyl chains were used to build the lipophilic part (namely tetradecyl, hexadecyl, and oleyl). Phase transitions of the new compounds in aqueous dispersions at pH 10 were analysed and discussed in terms of head group and alkyl chain variations. The shape and size of the formed aggregates of selected lipid dispersions were investigated by dynamic light scattering and transmission electron microscopy. PMID- 23934669 TI - Elimination reactions of esters in the biosynthesis of polyketides and ribosomal peptides. PMID- 23934670 TI - Diastolic Timed Vibrator: Noninvasive Pre-Hospitalization Treatment of Acute Coronary Ischemia. AB - The speed of intervention is one of the major factors in increasing the survival rate of patients suffering from acute coronary ischemia. The two principal techniques currently in use: pharmacological and interventional, can be employed to re-canalize coronary arteries, but the former is slow acting and often leads to incomplete reperfusion, while the latter requires specialized personnel in a hospital with a cardiac catheterization laboratory. In this paper, we introduce a novel method intended for pre-hospitalization treatment of patients with acute coronary ischemia that can be safely applied by a minimally trained individual prior to or during patient transportation to hospital. It consists in applying low frequency mechanical vibrations to the left intercostal space of patient's chest during diastole of the heart cycle, to induce vibrations of the heart and thus of the coronary arteries. Mechanical vibrations stimulate mixing of blood which improves drug delivery to the occlusion site, applies mechanical force on the clot leading to its faster dissolution and finally acts as a strong vasodilator in case of spasms. We introduce the principle of operation and the architecture of the Diastolic Timed Vibrator (DTV), including a custom ECG processing algorithm, vibration pattern generator and active braking methods. Experimental results demonstrate the functionality of the DTV device and pave way for in-vivo tests necessary for clinical confirmation of the proposed method. PMID- 23934671 TI - Bio-Inspired Asynchronous Pixel Event Tricolor Vision Sensor. AB - This article investigates the potential of the first ever prototype of a vision sensor that combines tricolor stacked photo diodes with the bio-inspired asynchronous pixel event communication protocol known as Address Event Representation (AER). The stacked photo diodes are implemented in a 22 * 22 pixel array in a standard STM 90 nm CMOS process. Dynamic range is larger than 60 dB and pixels fill factor is 28%. The pixels employ either simple pulse frequency modulation (PFM) or a Time-to-First-Spike (TFS) mode. A heuristic linear combination of the chip's inherent pseudo colors serves to approximate RGB color representation. Furthermore, the sensor outputs can be processed to represent the radiation in the near infrared (NIR) band without employing external filters, and to color-encode direction of motion due to an asymmetry in the update rates of the different diode layers. PMID- 23934673 TI - Spanish version of the Children's Somatization Inventory: factorial structure and psychometric properties in a community sample. AB - BACKGROUND: The Children's Somatization Inventory (CSI) has proved to be a suitable measure to assess somatic symptoms in pediatric patients, but additional research was needed to evaluate its psychometric properties in community populations. PURPOSE: The objective of the present study was to examine psychometric properties and factorial structure of the instrument among a nonclinical sample of Spanish children. METHOD: The 24-item version of the CSI and two self-report measures of anxiety and depression were administered to 1,111 Spanish children aged 8 to 12. RESULTS: Exploratory analysis suggested a factorial structure composed of three factors: pseudoneurologic symptoms, gastrointestinal symptoms, and pain. Due to confirmatory analysis indicating a poor fit for the three-factor model, two alternative models were tested. A six item single factor identified in a previous study with an American community sample showed the best fit (RMSEA = 0.04; GFI = 0.99; AGFI = 0.98; CFI = 0.98; chi(2)/gl = 2.71). The internal consistency for the six-item version was acceptable (omega = .71), and the construct validity with anxiety (r = .53) and depression (r = .38) measures was adequate. CONCLUSION: The six-item version of the CSI demonstrated to be a reliable measure for assessing somatization symptoms in Spanish children. PMID- 23934674 TI - Fuzzy Filtering With Randomly Occurring Parameter Uncertainties, Interval Delays, and Channel Fadings. AB - In this paper, the Hinfinity fuzzy filtering problem is investigated for a class of discrete-time Takagi-Sugeno (T-S) fuzzy systems with randomly occurring uncertainties and randomly occurring interval time-varying delays, as well as channel fadings. A sequence of random variables obeying the Bernoulli distribution is utilized to govern the randomly occurring uncertainties and probabilistic interval time-varying delays. Simultaneously, the Rice fading model is employed to describe the phenomena of channel fadings by setting different values of the channel coefficients. Our attention is focused on the design of an Hinfinity fuzzy filter such that the filtering error dynamics is exponentially mean-square stable and the disturbance rejection attenuation is constrained to a given level by means of the Hinfinity-performance index. In the presence of the randomly occurring phenomena, sufficient conditions are derived, via stochastic analysis and Lyapunov functional approach, for the existence of desired filter ensuring both the exponential mean-square stability and the prescribed Hinfinity performance. The filter parameters can be obtained by solving a convex optimization problem via the semidefinite program method. Finally, a numerical example is utilized to illustrate the usefulness and effectiveness of the proposed design technique. PMID- 23934675 TI - Comparing the performance of expert user heuristics and an integer linear program in aircraft carrier deck operations. AB - Planning operations across a number of domains can be considered as resource allocation problems with timing constraints. An unexplored instance of such a problem domain is the aircraft carrier flight deck, where, in current operations, replanning is done without the aid of any computerized decision support. Rather, veteran operators employ a set of experience-based heuristics to quickly generate new operating schedules. These expert user heuristics are neither codified nor evaluated by the United States Navy; they have grown solely from the convergent experiences of supervisory staff. As unmanned aerial vehicles (UAVs) are introduced in the aircraft carrier domain, these heuristics may require alterations due to differing capabilities. The inclusion of UAVs also allows for new opportunities for on-line planning and control, providing an alternative to the current heuristic-based replanning methodology. To investigate these issues formally, we have developed a decision support system for flight deck operations that utilizes a conventional integer linear program-based planning algorithm. In this system, a human operator sets both the goals and constraints for the algorithm, which then returns a proposed schedule for operator approval. As a part of validating this system, the performance of this collaborative human automation planner was compared with that of the expert user heuristics over a set of test scenarios. The resulting analysis shows that human heuristics often outperform the plans produced by an optimization algorithm, but are also often more conservative. PMID- 23934676 TI - Long term efficacy of radioiodine treatment in hyperthyroidism. AB - OBJECTIVES: Radioiodine is the mainstay of the treatment of thyroid hyperfunction. However, it is difficult to apply the appropriate amount of radioidone to achieve optimal efficacy with the least possible adverse effects. Results of the investigation on the efficacy of a relatively new protocol for radioiodine treatment of hyperthyroidism are reported. DESIGN: A retrospective evaluation of data from 326 patients with a mean average follow-up of 5.7 (1.0 11.7) years was performed. 64% of these patients suffered from Graves' disease and 36% had uni- or multinodular toxic goitre. RESULTS: In Graves' disease, the recurrence rate was 5% 1 year after the treatment, and that remained the same after 5 years. In toxic goitre, these rates were 6 and 7%, respectively. After 5 years 70% of the patients with autonomous adenomas were euthyroid, while 78% of the Graves patients developed hypothyroidism and 17% showed euthyroid state. A relationship between the lack of normalisation of thyroid-stimulating hormone levels after radioiodine treatment and the increased recurrence of late hyperthyroidism has also been established in patients with Graves's disease. CONCLUSION: Compared to the available data published in the literature, the success rate of the treatment is fairly high confirming the effectiveness of our protocol. PMID- 23934677 TI - Functional significance of the novel H-RAS gene mutation M72I in a patient with medullary thyroid cancer. AB - Medullary thyroid cancer (MTC) accounts for around 5-10% of all thyroid cancers. Though usually sporadic, 1 in 4 cases are of genetic origin, with germinal mutations in the RET proto-oncogene in familial forms and somatic mutations both in RET and in the RAS family genes in sporadic ones.This study aimed to characterize a rare H-RAS sequence variant -M72I- in a patient with sporadic MTC, focusing on its functional significance.Mutation analysis was performed for the RET, N-RAS, K-RAS and H-RAS genes by direct sequencing. Western blot analysis was done on 4 thyroid tissues from 1 patient carrying the M72I mutation in H-RAS, 1 with the Q61R mutation in H-RAS, 1 with no RET, H-RAS, K-RAS or N-RAS gene mutations, and 1 normal thyroid, using different antibodies against Erk1/2, phospho-Erk1/2 (Thr202/Tyr204), Akt and phospho-Akt (Ser473). Large-scale molecular dynamics simulations were completed for H-RAS wt and H-RAS M72I.Western blot analysis demonstrated that both MAPK and PI3K/Akt pathways were activated in the MTC patient carrying the M72I variant. In silico results showed conformational changes in H-RAS that could influence its activation by Sos and phosphate binding. Results of molecular dynamics were consistent with Western blot experiments.The M72I mutation may contribute effectively to proliferation and survival signaling throughout the MAPK and PI3K/Akt pathways. This work underscores the importance of studying genetic alterations that may lead to carcinogenesis. PMID- 23934678 TI - Structural vascular disease in Africans: Performance of ethnic-specific waist circumference cut points using logistic regression and neural network analyses: The SABPA study. AB - A recently proposed model for waist circumference cut points (RPWC), driven by increased blood pressure, was demonstrated in an African population. We therefore aimed to validate the RPWC by comparing the RPWC and the Joint Statement Consensus (JSC) models via Logistic Regression (LR) and Neural Networks (NN) analyses. Urban African gender groups (N=171) were stratified according to the JSC and RPWC cut point models. Ultrasound carotid intima media thickness (CIMT), blood pressure (BP) and fasting bloods (glucose, high density lipoprotein (HDL) and triglycerides) were obtained in a well-controlled setting. The RPWC male model (LR ROC AUC: 0.71, NN ROC AUC: 0.71) was practically equal to the JSC model (LR ROC AUC: 0.71, NN ROC AUC: 0.69) to predict structural vascular -disease. Similarly, the female RPWC model (LR ROC AUC: 0.84, NN ROC AUC: 0.82) and JSC model (LR ROC AUC: 0.82, NN ROC AUC: 0.81) equally predicted CIMT as surrogate marker for structural vascular disease. Odds ratios supported validity where prediction of CIMT revealed -clinical -significance, well over 1, for both the JSC and RPWC models in African males and females (OR 3.75-13.98). In conclusion, the proposed RPWC model was substantially validated utilizing linear and non linear analyses. We therefore propose ethnic-specific WC cut points (African males, >=90 cm; -females, >=98 cm) to predict a surrogate marker for structural vascular disease. PMID- 23934679 TI - The impact of fasting during Ramadan on the glycemic control of patients with type 2 diabetes mellitus. AB - BACKGROUND: Millions of Muslims fast from dawn until dusk during the annual Islamic holy month of Ramadan. Most of the studies evaluating biochemical changes in diabetic patients during Ramadan showed little changes in the glycemic control. In this study, our aim was to assess the impact of fasting during Ramadan on glycemic control in patients with type 2 diabetes. METHODS AND DESIGN: We examined 122 patients with type 2 diabetes (82 female, 40 male, age 56.93 +/- 9.57 years) before and after the Ramadan. 66.4% of the patients were treated with oral antidiabetic (OAD) alone, 6.5% with a combination of insulin plus OAD and 19.7% with insulin alone. 88 of 122 patients fasted during Ramadan (26.98 +/- 5.93 days). Weight, body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose (FPG), postprandial glucose (PPG), fructosamine, HbA1c, fasting insulin and lipid parameters were measured. RESULTS: The frequencies of both severe hyperglycemia and hypoglycemia were higher in the fasting group, but the difference was not significant (p=0.18). Weight, BMI, waist circumference, blood pressure, FPG (143.38 +/- 52.04 vs. 139.31 +/- 43.47 mg/dl) PPG (213.40 +/- 98.56 vs. 215.66+109.31 mg/dl), fructosamine (314.18 +/- 75.40 vs. 314.49 +/- 68.36 umol/l), HbA1c (6.33 +/- 0.98 vs. 6.22 +/- 0.92%) and fasting insulin (12.61 +/- 8.94 vs. 10.51 +/- 6.26 uU/ml) were unchanged in patients who fasted during Ramadan. Microalbuminuria significantly decreased during Ramadan (132.85 +/- 197.11 vs. 45.03 +/- 73.11 mg/dl). CONCLUSIONS: In this study, we concluded that fasting during Ramadan did not worsen the glycemic control of patients with type 2 diabetes. PMID- 23934680 TI - Low fructose and low salt diets increase mitochondrial DNA in white blood cells of overweight subjects. AB - OBJECTIVE: To evaluate the effect of sodium and fructose restriction on mitochondrial DNA (mtDNA) content and systemic oxidative stress in a sample of overweight and pre hypertensive subjects. MATERIAL/METHODS: Data and blood samples were collected from 36 overweight and pre hypertensive patients randomly assigned to either an isocaloric (with respect to baseline) low sodium-fructose diet or an isocaloric low sodium diet. Patients were followed for 8 weeks. We measured mitochondrial DNA (mtDNA) content from peripheral blood white cells by Real-time PCR and plasma malondialdehyde (MDA) and 2,4-dinitrophenylhydrazine (DNPH) as markers of reactive oxygen species (ROS). RESULTS: Compared to baseline, at week 8 there was a continued and significant increase in mtDNA in both the low sodium diet group [2.4 vs. 13.1 (relative copy number), p<0.05] and the low sodium diet-fructose group (1.9 vs. 147.2, p<0.05). By week 8 there was a continued decrease in plasma DNPH levels in the low sodium diet group (4.6 vs. 2.6, p<0.05) and in the low sodium diet-fructose group (5.8 vs. 2.2, p<0.05). No significant differences were found with MDA. CONCLUSION: Our studies suggest that simple dietary measures such as reducing salt with or without restricting fructose can increase mtDNA and improve markers of oxidative stress. PMID- 23934681 TI - Oroxylin A has therapeutic potential in acute myelogenous leukemia by dual effects targeting PPARgamma and RXRalpha. AB - Oroxylin A (OA) is a flavonoid derived from a Chinese herb that has previously been reported to inhibit the proliferation of several cancer cell lines. It is found that OA significantly inhibited the growth of myeloid leukemia cell lines and as xenografts in immunodeficient mice and primary blasts from acute myelogenous leukemia (AML) patients. Furthermore, OA-induced cell cycle arrest and differentiation were observed in OA-treated AML cell lines. OA-induced increase of CD11b/CD14 expression was reversed by GW9662, a specific PPARgamma inhibitor, or transient transfection with PPARgamma siRNA. Docking study showed OA bound to ligand-binding domain of PPARgamma via forming hydrogen bonds with Arg288 and Leu340 sites. Results of fluorescence polarization-based ligand assay verified PPARgamma-binding activity of OA, and in OA-treated cells, intranuclear accumulation and increased binding activity of PPARgamma to PPRE were detected. We also found that GW9662 attenuated OA-induced upregulation of C/EBPbeta, an important regulator of leukemic differentiation, and p21, which is a potent inhibitor of CDKs that can inhibit phosphorylation of Rb by cyclin D1-CDK4 complexes. Moreover, our results showed that OA displayed synergistic effects with all-trans retinoic acid and VD3 in part related to reduction of intranuclear phosphorylated RXRalpha that has been reported to block nuclear receptor/RXRalpha heterodimer transcriptional activity. This reduction of phosphorylated RXRalpha was associated with inhibition of the specific upstream MAP kinase ERK1/2. We suggest that OA may provide a novel complement to AML treatment by its dual effects of augmenting PPARgamma activity and sensitizing nuclear receptors to specific ligands. PMID- 23934682 TI - Determination of zeranol and its metabolites in bovine muscle and liver by a chemiluminescence enzyme immunoassay: compared to an ultraperformance liquid chromatography tandem mass spectroscopy method. AB - A chemiluminescent enzyme immunoassay (CLEIA) was compared to an ultraperformance liquid chromatography tandem mass spectroscopy (UPLC-MS/MS) procedure for the analysis of zeranol and its metabolites in bovine tissue samples. Apparent recoveries from fortified samples by both methods were comparable at 0.5-4.0 ug/kg and a significant correlation was obtained. For CLEIA analysis, hapten mimicking the analyte was first synthesized and conjugated with the carrier protein bovine serum albumin as the immunogen to produce monoclonal antibody. The obtained antibody showed extensive cross-reactivity toward zeranol metabolites (zearalanone). The limit of detection of CLEIA and UPLC-MS/MS was 0.05 ug/kg and 0.5 ug/kg, respectively. Recoveries of both methods for fortified samples were higher than 75.0% with the coefficient of variation less than 15%. These results indicated that the combination of screening with CLEIA and confirmation with UPLC MS/MS for zeranol and its metabolites would be a reliable method for a large number of bovine samples. PMID- 23934683 TI - Selenium alters miRNA profile in an intestinal cell line: evidence that miR-185 regulates expression of GPX2 and SEPSH2. AB - SCOPE: Intake of the essential micronutrient selenium (Se) has health implications. This work addressed whether some effects of Se on gene expression are exerted through microRNAs (miRNA). METHODS AND RESULTS: Human colon adenocarcinoma cells (Caco-2) were grown in Se-deficient or Se-adequate medium for 72 h. RNA was extracted and subjected to analysis of 737 miRNA using microarray technology. One hundred and forty-five miRNA were found to be expressed in Caco-2 cells. Twelve miRNA showed altered expression after Se depletion: miR-625, miR-492, miR-373*, miR-22, miR-532-5p, miR-106b, miR-30b, miR 185, miR-203, miR1308, miR-28-5p, miR-10b. These changes were validated by quantitative real-time PCR (RT-qPCR). Transcriptomic analysis showed that Se depletion altered expression of 50 genes including selenoproteins GPX1, SELW, GPX3, SEPN1, SELK, SEPSH2 and GPX4. Pathway analysis identified arachidonic acid metabolism, glutathione metabolism, oxidative stress, positive acute phase response proteins and respiration of mitochondria as Se-sensitive pathways. Bioinformatic analysis identified 13 transcripts as targets for the Se-sensitive miRNA; three were predicted to be recognised by miR-185. Silencing of miR-185 increased GPX2 and SEPSH2 expression. CONCLUSIONS: We propose that miR-185 plays a role in up-regulation of GPX2 and SEPHS2 expression. In the case of SEPHS2 this may contribute to maintaining selenoprotein synthesis. The data indicate that micronutrient supply can regulate the cell miRNA expression profile. PMID- 23934684 TI - Complex temporal decay: a complete analysis. AB - Relaxation dynamics is universal in science and engineering; its study serves to parameterize a system's response and to help identify a microscopic model of the processes involved. When measured data for a phenomenon cannot be fitted using one exponential, the choice of an alternative function to describe the decay becomes nontrivial. Here, we contrast two different, but fundamentally related approaches to fitting nontrivial decay curves; exponential decomposition and the gamma probability density function. PMID- 23934685 TI - Reduction of central venous line-associated bloodstream infection rates by using a chlorhexidine-containing dressing. AB - PURPOSE: The reduction of central venous line (CVL)-associated bloodstream infections (CLABSIs) is generally advocated. However, despite implementing infection prevention recommendations, CLABSI rates remain high at some institutions. Therefore, a chlorhexidine-containing dressing should be assessed for its potential for infection reduction, adverse events (AEs) and practicability. METHODS: The number of CVLs, CVL days, CLABSIs and CLABSI rates with regard to the kind of dressing (standard vs. chlorhexidine-containing) were documented from November 2010 to may 2012 (1,298 patients with 12,220 CVL days) at two intensive care units (ICUs) and compared to historical controls. The practicability and safety of the chlorhexidine-containing dressing and reasons for not using this dressing were assessed. RESULTS: Forty CLABSIs occurred in 34 patients, resulting in a significantly lower overall CLABSI rate in patients with the chlorhexidine-containing dressing [1.51/1,000 CVL days; confidence interval (CI): 0.75-2.70] compared to patients with the standard dressing (5.87/1,000 CVL days; CI: 3.93-8.43; p < 0.0001). The CLABSI rate in historical controls receiving the standard dressing was 6.2/1,000 CVL days. The main reason for not using chlorhexidine-containing dressing was bleeding at the insertion site. AEs occurred in five patients and represented self-healing skin macerations (3 cases) and superficial skin necrosis (2 cases). CONCLUSIONS: In case of high CLABSI rates despite the implementation of standard recommendations, our findings suggest that a chlorhexidine-containing dressing safely decreases CLABSI rates. PMID- 23934686 TI - Platelet-derived growth factor B induces senescence and transformation in normal human fibroblasts. AB - Normal cells enter a senescent state upon aberrant oncogenic signals and this response inhibits tumor initiation and progression. It is now well admitted that intracellular and membrane localized oncogenes can illicit oncogene induced senescence. However, the effect of mitogenic growth factor on cellular senescence is so far largely unknown. Here we show that normal human dermal fibroblasts display a complex response to Platelet derived growth factor B (PDGFB) expression. Indeed, PDGFB expression induces, in the same cell population, both senescence and cellular transformation. Remarkably both populations are sustained with passages suggesting that transformed cells eventually enter a senescent state. This senescence state is p53 dependent as inhibiting the p53 pathway blocks the ability of PDGFB to induce senescence and results in strong cellular transformation increase upon PDGFB expression. The relevance of these observations is supported by the fact that human dermatofibrosarcoma protuberans, skin tumors arising from constitutive PDGFB production with little aggressiveness, also display some senescence hallmarks. Together these data support the view that PDGFB, a mitogenic growth factor, has a limited ability to induce senescence. We propose that this low level of senescence might decrease the transforming ability of this factor without totally abolishing it. PMID- 23934687 TI - Expression of FGF19 in human embryonic stem cells. PMID- 23934688 TI - Conductive, monodisperse polyaniline nanofibers of controlled length using well defined cylindrical block copolymer micelles as templates. AB - Stable colloidal dispersions of polyaniline (PAni) nanofibers with controlled lengths from about 200 nm-1.1 MUm and narrow length distributions (Lw/Ln < 1.04; Lw = weight average micelle length, Ln = number average micelle length) were prepared through the template-directed synthesis of PAni using monodisperse, solution-self-assembled, cylindrical, block copolymer micelles as nanoscale templates. These micelles were prepared through a crystallization-driven living self-assembly method from a poly(ferrocenyldimethylsilane)-b-poly(2 vinylpyridine) block copolymer (PFS25 -b-P2VP425). This material was initially self-assembled in iPrOH to form cylindrical micelles with a crystalline PFS core and a P2VP corona and lengths of up to several micrometers. Sonication of this sample then yielded short cylinders with average lengths of 90 nm and a broad length distribution (Lw/Ln = 1.32). Cylindrical micelles of PFS25 -b-P2VP425 with controlled lengths and narrow length distributions (Lw/Ln < 1.04) were subsequently prepared using thermal treatment at specific temperatures between 83.5 and 92.0 degrees C using a 1D self-seeding process. These samples were then employed in the template-directed synthesis of PAni nanofibers through a two-step procedure, where the micellar template was initially stabilised by deposition of an oligoaniline coating followed by addition of a polymeric acid dopant, resulting in PAni nanofibers in the emeraldine salt (ES) state. The ES-PAni nanofibers were shown to be conductive by scanning conductance microscopy, whereas the precursor PFS25-b-P2VP425 micelle templates were found to be dielectric in character. PMID- 23934690 TI - Correcting reproductive health disparities in women: an opportunity to improve the health of future generations. PMID- 23934691 TI - Racial and ethnic health disparities in reproductive medicine: an evidence-based overview. AB - Racial and ethnic health disparities in reproductive medicine exist across the life span and are costly and burdensome to our healthcare system. Reduction and ultimate elimination of health disparities is a priority of the National Institutes of Health who requires reporting of race and ethnicity for all clinical research it supports. Given the increasing rates of admixture in our population, the definition and subsequent genetic significance of self-reported race and ethnicity used in health disparity research is not straightforward. Some groups have advocated using self-reported ancestry or carefully selected single nucleotide polymorphisms, also known as ancestry informative markers, to sort individuals into populations. Despite the limitations in our current definitions of race and ethnicity in research, there are several clear examples of health inequalities in reproductive medicine extending from puberty and infertility to obstetric outcomes. We acknowledge that socioeconomic status, education, insurance status, and overall access to care likely contribute to the differences, but these factors do not fully explain the disparities. Epigenetics may provide the biologic link between these environmental factors and the transgenerational disparities that are observed. We propose an integrated view of health disparities across the life span and generations focusing on the metabolic aspects of fetal programming and the effects of environmental exposures. Interventions aimed at improving nutrition and minimizing adverse environmental exposures may act synergistically to reverse the effects of these epigenetic marks and improve the outcome of our future generations. PMID- 23934693 TI - Racial disparities in pubertal development. AB - The question of whether or not children, particularly girls, are entering puberty earlier than they did in the past has been a concern in both the medical community and the general population. A secular trend analysis of the current data on pubertal timing in boys and girls is limited by variations in the study design, the population assessed, and the methods used to determine pubertal development. These differences present a challenge when interpreting the available data, especially when comparing multiple studies. The influence of race on pubertal timing and development had not been assessed before the 1970s. The purpose of this article is to review the reported variations in pubertal timing among different racial/ethnic groups. Data suggest African American girls enter puberty earlier and reach menarche earlier than Caucasian and Hispanic girls. In addition, the trend toward earlier timing of puberty seems to be occurring faster in African American girls compared with Caucasian girls over the past 25 years. While the mechanism and understanding of the cause of racial disparities in pubertal development remain to be discerned, genetic and/or environmental factors may play a role and require further investigation. PMID- 23934694 TI - Disparities in obstetrical outcomes in ART pregnancies compared with natural conceptions. AB - Health disparities are observed in all fields of medicine and reproductive health is not immune to this phenomenon. The incidence of women using infertility treatments to conceive is increasing. Women undergoing assisted reproduction appear to be at increased risk of adverse outcomes, and minority women tend to be at even greater risk. This article examines several adverse obstetrical outcomes including preterm birth, congenital malformations, and preeclampsia among women receiving infertility treatments compared with those who conceive spontaneously. It will further examine societal costs associated with these procedures. PMID- 23934692 TI - Do in utero events contribute to current health disparities in reproductive medicine? AB - Health disparities exist in reproductive medicine as discussed in detail in the subsequent articles of this issue; however, in most cases, the exact cause of these differences is unknown. Some of these disparities can be linked to environmental exposures such as alcohol and other hazardous toxic exposures (polycarbonate, pesticides, nicotine) in adults. In addition, low socioeconomic status, behavioral risk factors, and lack of education have been linked to poor obstetric and reproductive outcomes in minority groups. Aside from these various environmental exposures later in life, there is evidence that adverse events in utero could contribute to poor reproductive outcome in specific minority groups. We will focus on the developmental origins of health and disease as a possible causal mechanism for health disparities in reproductive diseases, as this perspective may suggest tractable solutions of how to address and eliminate these health disparities. PMID- 23934695 TI - Disparities in contraceptive access and provision. AB - Even though contraceptive coverage expands under the Patient Protection and Affordable Care Act, reducing disparities in contraceptive access and provision requires that all providers assess their patient's reproductive life plans and that health systems work to minimize institutional and socioeconomic barriers. In this article, the challenges of providing equal access to contraceptive care, as well as recommendations for encouraging the use of effective contraception among all reproductive age women are reviewed. PMID- 23934696 TI - Ethnic differences in assisted reproductive technologies outcomes. AB - Disparities in assisted reproductive technologies (ARTs) outcomes have been identified among ethnic minorities when compared with their Caucasian counterparts. Minority ethnicity has been shown to be an independent predictor of lower clinical pregnancy and live birth rates in many studies. In this article, we seek to summarize the most recent literature on ethnic difference reported within ART outcomes. We will discuss potential reasons behind these disparities and further explore independent predictors and associations between ethnicity and ART success. PMID- 23934697 TI - Racial and ethnic differences in physiology and clinical symptoms of polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders and affects approximately 5 to 10% of women of reproductive age. There exists substantial variation of physical stigmata and clinical symptoms among women, but PCOS has been known to be associated with irregular periods, infertility, increased pregnancy complications, as well as nonreproductive health problems arising from its association with the metabolic syndrome. Over the years, there have been various consensus statements regarding the diagnostic criteria, but the varying pronouncements suggest that the underlying cause is still not well understood and may be multifaceted. Importantly, the interaction of genetic predisposition and local environment is possibly responsible for the heterogeneity of phenotypes seen; it has been demonstrated that there is substantial ethnic and racial variation in the clinical presentations among PCOS patients and related individuals may vary in appearance based on nutritional and other aspects of locale. The differences in phenotype and clinical symptoms of PCOS related to the clinical, hormonal, and metabolic characteristics among various ethnic backgrounds, including Hispanics, African Americans, Asians, and Indians, need to be considered when assessing and treating these individuals. Future research must address the importance of interactions between genotype and the environment. PMID- 23934699 TI - Racial and ethnic differences in the physiology and clinical symptoms of menopause. AB - More than 4 million menopausal women are from ethnic minority groups. Over the past 25 years, recognition of the importance of social, emotional, and physical changes of midlife to women's long-term health and well-being has emerged. Multiple factors influence how a woman perceives menopausal changes and what she addresses as associated symptoms. Factors such as educational level to socioeconomic status, health-related factors, stress, and marital status influence these choices. Increasingly, researchers are reporting on the impact of race and ethnicity on menopausal symptoms. Understanding similarities and differences among women's perceptions, attitudes, and expectations surrounding menopause improves delivery of culturally appropriate care and promotes lifestyles that may decrease symptoms and increase quality of life. Historically, the majority of the research in this area has been conducted in Western countries with clinical samples of women predominantly from European backgrounds. Thus, this population has shaped the emerging clinical picture of the midlife menopausal transition. Recently, studies of non-European women, both in the United States and internationally, indicate significant variations in their experiences during this transition, but these cultural differences have not broadened the understanding of the meaning of this universal experience. To date, there are still large knowledge gaps in race, ethnic, and cultural differences in menopausal health. The content of this review summarizes the current body of knowledge on racial differences in the menopause experience. PMID- 23934700 TI - Identification of malate dehydrogenase 2 as a target protein of the HIF-1 inhibitor LW6 using chemical probes. PMID- 23934698 TI - Racial and ethnic differences in the pathogenesis and clinical manifestations of uterine leiomyoma. AB - Uterine leiomyomas are the most common benign gynecologic condition. The prevalence is three times more common among women of African ethnicity. Disparity in this disease is evidenced by earlier age of onset, greater severity of symptoms, and different response to treatment. Although the pathogenesis of disease development is not completely known, growing evidence focuses on investigating the molecular mechanisms in disease development and the influence of ethnicity. Variation in the expression levels or function of estrogen and progesterone receptors, polymorphism of genes involved in estrogen synthesis and/or metabolism (COMT, CYP17), retinoic acid nuclear receptors (retinoid acid receptor-alpha, retinoid X receptor-alpha), and aberrant expression of micro-RNAs (miRNAs) are some of the molecular mechanisms that may be involved. Nutritional factors, such as vitamin D deficiency, might also contribute to the higher incidence in dark skinned populations who are also commonly suffer from hypovitaminosis D. Culture and environmental difference might have a role in disease development. Further analysis and better understanding of these mechanisms will provide insight into the molecular basis of racial disparities in leiomyoma formation and will help to develop new innovations in leiomyoma treatment. PMID- 23934701 TI - Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma. AB - Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been recently investigated in several cancer types, but their respective clinical significance remains to be determined. In our prospective study, we compared the detection rate and the prognostic value of these two circulating biomarkers in patients with metastatic uveal melanoma. GNAQ/GNA11 mutations were characterized in archived tumor tissue. Using a highly sensitive and mutation-specific bidirectional pyrophosphorolysis-activated polymerization (bi-PAP) technique, GNAQ c.626A>T, GNAQ c.626A>C and GNA11 c.626A>T copy numbers were quantified in plasma from 12 mL of blood. CTCs were detected at the same time in 7.5 mL of blood by the CellSearch technique. Patient characteristics and outcome were prospectively collected. CTCs (>=1) were detected in 12 of the 40 included patients (30%, range 1-20). Among the 26 patients with known detectable mutations, ctDNA was detected and quantified in 22 (84%, range 4-11,421 copies/mL). CTC count and ctDNA levels were associated with the presence of miliary hepatic metastasis (p = 0.004 and 0.03, respectively), with metastasis volume (p = 0.005 and 0.004) and with each other (p < 0.0001). CTC count and ctDNA levels were both strongly associated with progression-free survival (p = 0.003 and 0.001) and overall survival (p = 0.0009 and <0.0001). In multivariate analyses, ctDNA appeared to be a better prognostic marker than CTC. In conclusion, ctDNA and CTC are correlated and both have poor prognostic significance. CTC detection can be performed in every patient but, in patients with detectable mutations, ctDNA was more frequently detected than CTC and has possibly more prognostic value. PMID- 23934702 TI - A Gel Filtration-Based Method for the Purification of Infectious Rotavirus Particles for Environmental Research Applications. AB - This article describes a rapid method for purifying infectious rotavirus particles from cell culture for environmental research. The method is based on size-exclusion chromatography using TOSOH TSKgel(r) G5000PWXL-CP with a TSKgel(r) Size Exclusion G2500PWxl guard column, set up on an AKTA Explorer10. Four peaks were identified from the chromatogram and the corresponding fractions were collected and analysed by electron microscopy, 1-step quantitative reverse transcription polymerase chain reaction (RT-PCR) and qNano measurement. Infectivity potential of the recovered virus particles was determined using cell culture. Our analysis reveals that the first fraction contains majority of the intact triple-layered infectious virions while the other three fractions contain mixtures of empty capsids and intact infectious virions. Our results also indicate that there is a gross overestimation of rotaviruses in crude extracts due to encapsidated RNA in the order of 2.3 * 1011 particles and we note that estimates by qNano are similarly skewed (1.36 * 1013 particle) possibly due to empty capsids and cellular debris. In summary we present a method for purification (~12 h) of rotaviruses for a more robust and accurate quantification of virus size, surface charge and particle concentration in environmental contexts. PMID- 23934703 TI - Hepatitis B virus infection in clustering of infection in families with unfavorable prognoses in northwest China. AB - Hepatitis B virus (HBV) infection and its associated liver diseases have characteristics of familial clustering in China. However, the reasons for this are not understood fully. To address this issue, the prevalence HBV infection and the characteristics of unfavorable prognoses in clustering of infection in families in northwest China were investigated. Families with clustering of infection and unfavorable prognoses were enrolled, and general information and serum samples were collected. The clinical features and sequelae of HBV infection were compared among the blood relatives (including the first-, second-, and third degree blood relatives) and spouses using the chi-square test or Fisher's exact test. A total of 102 clusterings of infection families with unfavorable prognoses were interviewed. In the first-, second-, and third-degree blood relatives and spouses, the prevalences of cirrhosis of the liver were 29.2%, 11.9%, and 8.7%, respectively, while those of hepatocellular carcinoma (HCC) were 21.8%, 1.4%, and 4.3%, respectively (P<0.05). The mean ages of the onset of cirrhosis of the liver in the first-, second-, and third-degree blood relatives and spouses were 57 +/- 9.91, 47 +/- 9.96, 38 +/- 10.35, and 57 +/- 8.49 years, respectively, while the mean ages of the onset of HCC were 60 +/- 7.92, 49 +/- 8.57, 41 +/- 3.54, and 50 +/- 0 years, respectively, (P<0.05). The first-, second-, and third-degree blood relatives from clustering of infection in families with unfavorable prognoses had prevalences of cirrhosis or HCC in descending order of relationship. The findings suggest that genetic factors may be associated with a familial tendency for cirrhosis of the liver and HCC. PMID- 23934704 TI - Methods to calculate the heat index as an exposure metric in environmental health research. AB - BACKGROUND: Environmental health research employs a variety of metrics to measure heat exposure, both to directly study the health effects of outdoor temperature and to control for temperature in studies of other environmental exposures, including air pollution. To measure heat exposure, environmental health studies often use heat index, which incorporates both air temperature and moisture. However, the method of calculating heat index varies across environmental studies, which could mean that studies using different algorithms to calculate heat index may not be comparable. OBJECTIVE AND METHODS: We investigated 21 separate heat index algorithms found in the literature to determine a) whether different algorithms generate heat index values that are consistent with the theoretical concepts of apparent temperature and b) whether different algorithms generate similar heat index values. RESULTS: Although environmental studies differ in how they calculate heat index values, most studies' heat index algorithms generate values consistent with apparent temperature. Additionally, most different algorithms generate closely correlated heat index values. However, a few algorithms are potentially problematic, especially in certain weather conditions (e.g., very low relative humidity, cold weather). To aid environmental health researchers, we have created open-source software in R to calculate the heat index using the U.S. National Weather Service's algorithm. CONCLUSION: We identified 21 separate heat index algorithms used in environmental research. Our analysis demonstrated that methods to calculate heat index are inconsistent across studies. Careful choice of a heat index algorithm can help ensure reproducible and consistent environmental health research. PMID- 23934705 TI - The single-nucleotide polymorphism (GPX4c718t) in the glutathione peroxidase 4 gene influences endothelial cell function: interaction with selenium and fatty acids. AB - SCOPE: Selenium (Se) is incorporated into selenoproteins as selenocysteine, which requires structures in the 3'-untranslated region (3'-UTR) of selenoprotein mRNAs. The functional consequences of a single nucleotide polymorphism (SNP) within the 3'-UTR of the selenoprotein GPX4 gene (GPX4c718t) was assessed in human umbilical vein endothelial cells (HUVECs) and monocytes from human volunteers. METHODS AND RESULTS: HUVEC and monocytes homozygous for the T- or C variant of the GPX4c718t SNP were assessed for monocyte-endothelial cell adhesion, expression of VCAM-1 and sensitivity to oxidative challenge. Interaction of the SNP with Se and different PUFA and effects on selenoprotein expression were also investigated. HUVEC and monocytes homozygous for the T variant showed elevated adhesion levels compared to cells of the C-variant. This effect was modified by Se and PUFA. HUVEC homozygous for the T-variant showed elevated levels of VCAM-1 protein in the presence of arachidonic acid, were more sensitive to oxidative challenge and showed Se-dependant changes in lipid peroxide levels and expression of additional selenoproteins. CONCLUSION: These findings demonstrate functional effects of the GPX4c718t SNP in endothelial cells and may suggest that individuals with the TT genotype have impaired endothelial function and are at greater risk of vascular disease compared to individuals with the CC genotype. PMID- 23934706 TI - Mechanical and morphological aspects of the calcaneal tendon of mdx mice at 21 days of age. AB - A relationship between compromised muscles and other tissues has been demonstrated in mdx mouse, an animal model studied for understanding of Duchenne muscular dystrophy. The hypothesis is that changes in the calcaneal tendon of mdx mice occur previous to the onset of rigorous and most marked episodes of muscle degeneration, which start suddenly after 21 days of life. Thus, this study aimed to identify possible alterations in the calcaneal tendon of mdx mouse at 21 days of age. Control and mdx tendons were submitted to mechanical tensile testing, quantification of hydroxyproline, and staining with toluidine blue and picrosirius red. Hydroxyproline content was similar between mdx and control groups. The control tendon presented higher mechanical strength (load, stress, and elastic modulus) and its morphological analysis showed a larger number of round fibroblasts, nuclei with well-decondensed chromatin, and slightly metachromatic well-stained cytoplasmic material, different from that observed in mdx tendons. The results suggest that the absence of dystrophin in mdx mouse can provoke directly or indirectly alterations in the mechanical properties and morphology of the calcaneal tendon. PMID- 23934708 TI - Sympathetic vasomotor tone is associated with depressive symptoms in young females: a potential link between depression and cardiovascular disease. AB - BACKGROUND: Although increased sympathetic nervous system (SNS) activity is commonly associated with major depressive disorder (MDD) and cardiovascular disease (CVD), a biomarker linking these two entities remains elusive. We therefore evaluated the relationship between depressive symptoms and cardiovascular modulation by heart rate variability (HRV), brachial blood pressure (BP), ambulatory BP (ABP), and low frequency component of systolic BP variability (LFSBP), a surrogate of sympathetic vasomotor tone. We hypothesized that LFSBP would be the strongest predictor of depressive symptoms compared with HRV and BP measurements. METHODS: Eighty young healthy female subjects (20.51 +/- 2.82 years) were evaluated for depressive symptoms using the Center for Epidemiologic Studies Depression Scale (CES-D). Data collection was conducted after a 10-minute resting period. Beat-to-beat BPs were recorded for 5-minute at baseline (BASE) followed by a 3-minute cold pressor test (CPT). ABP was obtained for 24 hours. RESULTS: Hierarchical multiple regression analyses indicated that LFSBP at BASE was a stronger predictor of CES-D variance than BP and HRV indices, with LFSBP uniquely accounting for 8.1% of variance in CES-D scores during laboratory beat-by-beat BP assessments and 44.7% in ABP assessments. Individuals with acute depression scores (n = 12; CES-D >= 16) had significantly higher (P < 0.001) mean LFSBP values (6.66 +/- 2.54 mm Hg(2)) than the remaining sample (3.32 +/- 2.2 mm Hg(2)), whereas no other significant differences were detected in any of the other cardiovascular variables. Cardiovascular responses to CPT did not predict CES-D scores. CONCLUSIONS: These findings suggest that LFSBP could be a biomarker of neurovascular functioning with potential clinical implications for understanding the interaction between MDD and CVD. PMID- 23934707 TI - AT1 receptors prevent salt-induced vascular dysfunction in isolated middle cerebral arteries of 2 kidney-1 clip hypertensive rats. AB - BACKGROUND: Elevated blood pressure, elevated angiotensin II (ANG II), and ANG II suppression with high salt (HS) diet all contribute to vascular dysfunction. This study investigated the interplay of HS diet and vascular function in a high renin model of hypertension. METHODS: Male Sprague-Dawley rats were subjected to 2 kidney-1 clip (2K1C) Goldblatt hypertension for 4 weeks and compared with sham operated controls. RESULTS: Middle cerebral arteries (MCA) of 2K1C rats and sham operated controls fed normal salt (NS; 0.4% NaCl) diet dilated in response to acetylcholine (ACh) and reduced partial pressure of oxygen (PO2). Switching to HS (4% NaCl) diet for 3 days to reduce plasma renin activity (PRA) eliminated vasodilation to ACh and reduced PO2 in sham-operated controls, with no effect on vasodilation in 2K1C rats. AT1 receptor blockade (losartan, 20 mg/kg/day; 1 week) eliminated vasodilator responses to ACh and reduced PO2 in 2K1C rats fed NS or HS diet. ANG II infusion (5 ng/kg/min, intravenous) for 3 days to prevent salt induced reductions in plasma ANG II restored vascular relaxation in MCA of sham operated controls fed HS diet. Copper/zinc superoxide dismutase expression and total superoxide dismutase activity were significantly higher in arteries of 2K1C rats fed HS diet vs. sham-operated controls. CONCLUSIONS: These results suggest that the sustained effects of elevated ANG II levels in 2K1C hypertension maintain endothelium-dependent vasodilatation via AT1 receptor-mediated preservation of antioxidant defense mechanisms despite significant elevations in blood pressure and salt-induced suppression of PRA. PMID- 23934709 TI - Prevalence of resistant hypertension and eligibility for catheter-based renal denervation in hypertensive outpatients. AB - BACKGROUND: Studies of endovascular renal denervation (RDN) have demonstrated significant blood pressure reduction in eligible patients with resistant hypertension. These trials have used stringent inclusion and exclusion criteria in patient enrollment, potentially selecting for a small subset of patients with resistant hypertension. In this study, we examined the changes in estimated prevalence of resistant hypertension when using increasingly stringent definitions of resistant hypertension in a fixed population and assessed the generalizability of RDN when applying study criteria to a community-based hypertensive population. METHODS: A retrospective chart review was done of hypertensive outpatients. Four increasingly stringent interpretations of the American Heart Association definition of resistant hypertension were used to calculate prevalence estimates. Patients eligible for RDN were identified using criteria from SYMPLICITY HTN-3. Demographic and clinical characteristics were compared. RESULTS: We identified 1,756 hypertensive outpatients; 55.0% were male, 53.9% were white, and subjects had a mean age of 66.6 +/- 12.5 years and a body mass index (BMI) of 30.1 +/- 10.7 kg/m(2). Only 14 (0.8%) were eligible for RDN. Among these patients, 10 (71.4%) were female and all were black, with a mean age of 69.9 +/- 8.8 and BMI of 35.7 +/- 6.6. Congestive heart failure was more common in patients eligible for RDN. CONCLUSIONS: Patients eligible for RDN based on published studies represent an exceedingly small proportion of the total hypertensive population. Further studies are necessary to determine if the benefits of RDN can be generalized to a broader range of hypertensive patients than those included in previous trials. PMID- 23934710 TI - Vibrational spectroscopy as a rapid quality control method for Melaleuca alternifolia cheel (tea tree oil). AB - INTRODUCTION: Tea tree oil (TTO) is an important commercial oil which has found application in the flavour, fragrance and cosmetic industries. The quality is determined by the relative concentration of its major constituents: 1,8-cineole, terpinen-4-ol, alpha-terpineol, alpha-terpinene, terpinolene, gamma-terpinene and limonene. Gas chromatography coupled to mass spectrometry (GC-MS) is traditionally used for qualitative and quantitative analyses but is expensive and time consuming. OBJECTIVE: To evaluate the use of vibrational spectroscopy in tandem with chemometric data analysis as a fast and low-cost alternative method for the quality control of TTO. METHODS: Spectral data were acquired in both the mid-infrared (MIR) and near infrared (NIR) wavelength regions and reference data obtained using GC-MS with flame ionisation detection (FID). Principal component analysis (PCA) was used to investigate the data by observing clustering and identifying outliers. Partial least squares (PLS) multivariate calibration models were constructed for the quantification of the seven major constituents. RESULTS: High correlation coefficients (R(2) ) of >= 0.75 were obtained for the seven major compounds and 1,8-cineole showed the best correlation coefficients for both MIR and NIR data (R(2) = 0.97 and 0.95, respectively). Low values were obtained for the root mean square error of estimation (RMSEE) and root mean square error of prediction (RMSEP) values thereby confirming accuracy. CONCLUSION: The accurate prediction of the external dataset after introduction into the models confirmed that both MIR and NIR spectroscopy are valuable methods for quantification of the major compounds of TTO when compared with the reference data obtained using GC-MS. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 23934712 TI - Acute lung injury. PMID- 23934711 TI - Contribution of microRNA 24-3p and Erk1/2 to interleukin-6-mediated plasma cell survival. AB - Plasma cells can survive for long periods and continuously secrete protective antibodies, but plasma cell production of autoantibodies or transformation to tumor cells is detrimental. Plasma cell survival depends on exogenous factors from the surrounding microenvironment, and largely unknown intracellular mediators that regulate cell homeostasis. Here we investigated the contribution of the microRNA 24-3p (miR-24-3p) to the survival of human plasma cells under the influence of IL-6 and SDF-1alpha (stromal cell derived factor 1), both of which are bone marrow survival niche mediators. Deep sequencing revealed a strong expression of miR-24-3p in primary B cells, plasma blasts, plasma cells, and in plasmacytoma cells. In vitro studies using primary cells and the plasmacytoma cell line RPMI-8226 revealed that (i) expression of miR-24-3p mediates plasma cell survival, (ii) miR-24-3p is upregulated by IL-6 and SDF-1alpha, (iii) IL-6 mediates cell survival under ER stress conditions via miR-24-3p expression, and (iv) IL-6-induced miR-24-3p expression depends on the activity of the MAP kinase Erk1/2. These results suggest a direct connection between an external survival signal and an intracellular microRNA in regulating plasma cell survival. miR-24 3p could therefore be a promising target for new therapeutic strategies for autoimmune and allergic diseases and for multiple myeloma. PMID- 23934713 TI - A new definition for the acute respiratory distress syndrome. AB - Similar to other syndromes, patients are defined as having acute respiratory distress syndrome (ARDS) when they meet prespecified diagnostic criteria. These criteria have evolved over time, having gained and lost complexity, but the core principles have remained remarkably similar over the past 45 years. The specific diagnostic criteria allow clinicians and investigators to reliably identify patients with the syndrome of ARDS. ARDS is a form of acute diffuse lung injury occurring in patients with a predisposing risk factor. Lung injury is characterized by inflammation leading to increased endothelial and epithelial permeability and loss of aerated lung tissue resulting in hypoxemia and bilateral radiographic opacities on chest radiography. Additional physiological derangements include increased venous admixture and physiological dead space along with decreased respiratory system compliance. The corresponding pathological findings are lung edema, inflammation, hyaline membranes, and alveolar hemorrhage (i.e., diffuse alveolar damage). This article discusses the evolution of the definition of ARDS to the new Berlin definition of ARDS proposed in 2012 and its novel iterative refinement. PMID- 23934714 TI - Emerging pharmacological therapies for prevention and early treatment of acute lung injury. AB - Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are serious complications of acute illness and injury, associated with an inpatient mortality of up to 40%. Despite considerable basic science and clinical research, therapeutic options for established ALI are limited. Survivors of ARDS are often faced with poor health-related quality of life, depressive-anxiety disorders, cognitive deficits, and financial strain. An attractive approach toward managing ALI lies in its prevention and early treatment. In addition to improving recognition of at-risk patients, it is necessary to identify novel treatments targeting the pathways that may prevent or ameliorate lung injury. The rationale and animal and clinical evidence for aspirin, systemic and inhaled steroids, beta agonists, renin-angiotensin axis blockers, statins, peroxisome proliferator agonist receptor ligands, curcumin, and inhaled heparin are included in this narrative review. Randomized, controlled trials are currently being designed and implemented to address their efficacy in populations at risk for ALI. PMID- 23934715 TI - Genetic heterogeneity and risk of acute respiratory distress syndrome. AB - Genetic variation explains some of the observed heterogeneity in patients' risk for developing the acute respiratory distress syndrome (ARDS). Although the lack of extant family pedigrees for ARDS precludes an estimate of heritability of the syndrome, ARDS may function as a pattern of response to injury or infection, traits that exhibit strong heritability. A total of 34 genes have now been reported to influence ARDS susceptibility, the majority of which arose as candidate genes based on the current pathophysiological understanding of ARDS, with particular focus on inflammation and endothelial or epithelial injury. In addition, novel candidate genes have emerged from agnostic genetic approaches, including genome-wide association studies, orthologous gene expression profiling across animal models of lung injury, and human peripheral blood gene expression data. The genetic risk for ARDS seems to vary both by ancestry and by the subtype of ARDS, suggesting that both factors may be valid considerations in clinical trial design. PMID- 23934717 TI - Treatment of acute lung injury: current and emerging pharmacological therapies. AB - As a syndrome of injurious pulmonary inflammation resulting in deranged respiratory physiology, acute lung injury affords numerous potential therapeutic targets. Two main pharmacological treatment strategies have arisen-the attempted inhibition of excessive inflammation or the manipulation of the resulting physiological derangement causing respiratory failure. Additionally, such interventions may allow the delivery of less injurious mechanical ventilation. An emerging approach is the use of cell-based therapy, which, rather than inhibiting the inflammatory process, seeks to convert it from an injurious process to a reparative one. This review outlines previous, current, and emerging pharmacological therapies for acute lung injury. PMID- 23934716 TI - Viral pathogens and acute lung injury: investigations inspired by the SARS epidemic and the 2009 H1N1 influenza pandemic. AB - Acute viral pneumonia is an important cause of acute lung injury (ALI), although not enough is known about the exact incidence of viral infection in ALI. Polymerase chain reaction-based assays, direct fluorescent antigen (DFA) assays, and viral cultures can detect viruses in samples from the human respiratory tract, but the presence of the virus does not prove it to be a pathogen, nor does it give information regarding the interaction of viruses with the host immune response and bacterial flora of the respiratory tract. The severe acute respiratory syndrome (SARS) epidemic and the 2009 H1N1 influenza pandemic provided a better understanding of how viral pathogens mediate lung injury. Although the viruses initially infect the respiratory epithelium, the relative role of epithelial damage and endothelial dysfunction has not been well defined. The inflammatory host immune response to H1N1 infection is a major contributor to lung injury. The SARS coronavirus causes lung injury and inflammation in part through actions on the nonclassical renin angiotensin pathway. The lessons learned from the pandemic outbreaks of SARS coronavirus and H1N1 capture key principles of virally mediated ALI. There are pathogen-specific pathways underlying virally mediated ALI that converge onto a common end pathway resulting in diffuse alveolar damage. In terms of therapy, lung protective ventilation is the cornerstone of supportive care. There is little evidence that corticosteroids are beneficial, and they might be harmful. Future therapeutic strategies may be targeted to specific pathogens, the pathogenetic pathways in the host immune response, or enhancing repair and regeneration of tissue damage. PMID- 23934718 TI - Novel modes of mechanical ventilation. AB - The overarching goal of positive pressure mechanical ventilation is to provide adequate gas exchange support while not causing harm. Indeed, positive pressure mechanical ventilators are only support technologies, not therapeutic technologies. As such they cannot be expected to "cure" disease; they can only "buy time" for other therapies (including the patient's own defenses) to work.Conventional approaches to positive pressure ventilation involve applying ventilatory patterns mimicking normal ones through either masks or artificial airways. This is usually done with modes of support incorporating assist/control breath-triggering mechanisms, gas delivery patterns governed by either a set flow or pressure, and breath cycling based on either a set volume, a set inspiratory time, or a set flow. Often this support includes positive end-expiratory pressure and supplemental oxygen. In recent decades several novel or unconventional approaches to providing mechanical ventilatory support have been introduced. For these to be considered of value, however, it would seem reasonable that they address important clinical challenges and be shown to improve important clinical outcomes (e.g., mortality, duration of ventilation, sedation needs, complications). This article focuses on challenges facing clinicians in providing mechanical ventilatory support and assesses several novel approaches introduced over the last 2 decades in the context of these challenges. PMID- 23934720 TI - Clinical trial design in acute lung injury--issues and controversies. AB - The evolution of scientific investigation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is replete with examples of effective bench to-bedside transitions, pioneering research methodology, and international collaboration. This article highlights for clinicians a selection of challenges and controversies of clinical trial design in ALI and ARDS. A section on Patient Selection highlights controversial trade-offs between homogeneous and heterogeneous study populations. A section on Clinical Protocols covers blinding, process-of-care interventions, usual-care control groups, and standardized protocols for adjunctive care. The third section discusses the quest for ideal Study Outcomes. The final section presents Interpretation Controversies, such as early stopping of clinical trials. PMID- 23934719 TI - The role for invasive monitoring in acute lung injury. AB - Because acute lung injury (ALI) may arise from diverse and heterogeneous clinical insults, monitoring strategies for patients with ALI are heterogeneous as well. This review divides the monitoring strategies for ALI into three distinct phases. The "at-risk phase" is the period in which patients are at risk for ALI, and interventions may be applied to minimize or eliminate this risk. The "ALI phase" is the period during which ALI has occurred and requires attentive clinical management. The "resolution phase" is the period defined by resolution of ALI and successful discontinuation of mechanical ventilation. These phases are arbitrary, but they provide a useful framework for discussing the temporal changes in patient condition and monitoring goals in ALI.Invasive hemodynamic monitoring has specific roles in each phase of therapy for patients with ALI: pre-ALI, peri-ALI, and post-ALI. The primary goals are to optimize fluid resuscitation to prevent organ dysfunction, including ALI, and if ALI occurs to additional optimize fluid balance vis-a-vis the lung. By judicious application of invasive hemodynamic monitoring, particularly in its more modern iterations, clinicians can optimize the ebb and flow phases common to critically ill patients. This is vitally important given our current and growing understanding of the relationship between fluid balance and important clinical outcomes, multiple organ dysfunction syndrome, and mortality. PMID- 23934721 TI - Lung-injured patients do not need a specialized rehabilitation program: ICUAW as a case study. AB - An episode of critical illness is transformative. Patients suffer important new nerve, brain, and muscle injury. The spectrum of morbidity varies according to individual risks, but prevalent disabilities transcend diagnostic groupings. In the context of intensive care unit-acquired weakness (ICUAW), each patient who enters the ICU will begin to degrade muscle through upregulation of different proteolytic pathways, and, although the inciting stimulus, or its magnitude, may differ somewhat across patients, the result is the same. This argues for an approach to rehabilitation that is etiologically neutral and based on an understanding of molecular pathophysiology that can be mapped to functional outcome and tailored to individual need. PMID- 23934723 TI - Biomarkers of ALI/ARDS: pathogenesis, discovery, and relevance to clinical trials. AB - Despite the high incidence and poor prognosis of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), it remains challenging to identify patients who are at highest risk of developing these syndromes, differentiate these syndromes from other causes of acute respiratory failure, and accurately prognosticate once the diagnosis is made. The identification and validation of biological markers of ALI has the potential to ameliorate these challenges by facilitating studies of therapies aimed at prevention, identifying patients more accurately that have ALI so they can benefit from evidence-based therapies and enrollment in clinical trials, and determining which patients are unlikely to have a positive outcome to guide therapeutic choices and trials of experimental rescue therapies. This article reviews the current state of biomarker research in ALI/ARDS. New methodologies for identification of novel biomarkers of ALI, including metabolomics, proteomics, gene expression, and genetic studies are also discussed. PMID- 23934722 TI - Cost and health care utilization in ARDS--different from other critical illness? AB - Costs of care in the intensive care unit are a frequent target for concern in the current health care system. Utilization of critical care services in the United States is increasing and will continue to do so. Acute respiratory distress syndrome (ARDS) is a common and important complication of critical illness. Patients with ARDS frequently have long hospitalizations and consume a significant amount of health care resources. Many patients are discharged with functional limitations and high susceptibility to new complications that require significant additional health care resources. There is increasing literature on the cost-effectiveness of the treatment of ARDS, and despite its high costs, treatment remains a cost-effective intervention by current societal standards. However, when ARDS leads to prolonged mechanical ventilation, treatment becomes less cost-effective. Current research seeks to find interventions that lead to reductions in duration of mechanical ventilation and intensive care unit (ICU) length of stay. Limited reductions in ICU length of stay have benefits for the patient, but they do not lead to significant reductions in overall hospital costs. Early discharge to post-acute care facilities can reduce hospital costs but are unlikely to decrease costs for an entire episode of illness. Improved effectiveness of communication between clinicians and patients or their surrogates could help avoid costly interventions with poor expected outcomes. PMID- 23934724 TI - [Religious/spiritual well-being in mentally ill persons: a comparison of anxious/depressives, addicts and healthy controls]. AB - OBJECTIVE: The aim of this study is to investigate different dimensions of religiosity and spirituality among psychiatric in-patients. The study examines differences between addictive (ICD 10: F1x) and anxious/depressive (ICD 10: F3x/F4x) patients and considers the main implications for treatment. METHOD: Differences in dimensions of religious/spiritual well-being (RSWB) between addictive (n = 389) and anxious/depressive patients (n = 200) are investigated, also by comparison to a control group (n = 1,500). Furthermore dimensions of RSWB are related to personality factors and different psychiatric parameters within the psychiatric groups. RESULTS: The psychiatric groups show a lower amount of overall RSWB (p < 0.001) than the healthy controls. Furthermore, dimensions of RSWB turned out to be negatively correlated with several psychiatric symptoms. CONCLUSIONS: Based on these results we emphasize religious/spiritual issues within psychiatric treatment. Moreover, there may be a strong potential of the RSWB dimensions such as "Hope" or "Forgiveness" as positive therapeutic factors in psychiatric treatment. PMID- 23934725 TI - Substituent effects on the decomposition of chemiluminescent tricyclic aromatic dioxetanes. AB - Three tricyclic 1,2-dioxetane derivatives, 1a, 2a and 3a were synthesized from their corresponding 1,4-dioxin acenaphthylene compounds, 1, 2 and 3, by reaction with singlet-oxygen ((1) O2 ) in dichloromethane. Evidence for the formation of the dioxetanes 1a, 2a and 3a is provided by the chemiluminescence (CL) that corresponds to the emission from the electronically excited diesters 1b*, 2b* and 3b*, which are decomposed thermally from the dioxetanes 1a, 2a and 3a, respectively. The highly strained 1,2-dioxetane ring decomposes from a twisted geometry by simultaneous cleavages of the O-O and C-C bonds, producing the electronically excited diester that emits CL. It was observed that the CL from compound 2a is red-shifted relative to that of compounds 1a and 3a suggesting a higher degree of stabilization for the excited state by the electron-donating methoxy group. Also, a study of the solvent effect on fluorescence shows a significant red-shift in compound 2b, indicating a more polar excited state. The kinetics of the thermal decomposition of the 1,2-dioxetanes clearly demonstrate that the CL characteristics of compound 2a are quite different from those of compounds, 1a and 3a. These results are consistent with the proposed intramolecular chemically initiated electron exchange luminescence (CIEEL) mechanism which is triggered by the electron-donating group of compound 2a. PMID- 23934726 TI - A multiclass likelihood ratio approach for genetic risk prediction allowing for phenotypic heterogeneity. AB - The translation of human genome discoveries into health practice is one of the major challenges in the coming decades. The use of emerging genetic knowledge for early disease prediction, prevention, and pharmacogenetics will advance genome medicine and lead to more effective prevention/treatment strategies. For this reason, studies to assess the combined role of genetic and environmental discoveries in early disease prediction represent high priority research projects, as manifested in the multiple risk prediction studies now underway. However, the risk prediction models formed to date lack sufficient accuracy for clinical use. Converging evidence suggests that diseases with the same or similar clinical manifestations could have different pathophysiological and etiological processes. When heterogeneous subphenotypes are treated as a single entity, the effect size of predictors can be reduced substantially, leading to a low-accuracy risk prediction model. The use of more refined subphenotypes facilitates the identification of new predictors and leads to improved risk prediction models. To account for the phenotypic heterogeneity, we have developed a multiclass likelihood-ratio approach, which simultaneously determines the optimum number of subphenotype groups and builds a risk prediction model for each group. Simulation results demonstrated that the new approach had more accurate and robust performance than existing approaches under various underlying disease models. The empirical study of type II diabetes (T2D) by using data from the Genes and Environment Initiatives suggested heterogeneous etiology underlying obese and nonobese T2D patients. Considering phenotypic heterogeneity in the analysis leads to improved risk prediction models for both obese and nonobese T2D subjects. PMID- 23934727 TI - Copper-catalyzed enantioselective Henry reaction of enals and subsequent iodocyclization: stereoselective construction of chiral azatricyclic frameworks. PMID- 23934729 TI - Identification of molecular crystals capable of undergoing an acyl-transfer reaction based on intermolecular interactions in the crystal lattice. AB - Investigation of the intermolecular acyl-transfer reactivity in molecular crystals of myo-inositol orthoester derivatives and its correlation with crystal structures enabled us to identify the essential parameters to support efficient acyl-transfer reactions in crystals: 1) the favorable geometry of the nucleophile (-OH) and the electrophile (C-O) and 2) the molecular assembly, reinforced by C H???pi interactions, which supports a domino-type reaction in crystals. These parameters were used to identify another reactive crystal through a data-mining study of the Cambridge Structural Database. A 2:1 co-crystal of 2,3-naphthalene diol and its di-p-methylbenzoate was selected as a potentially reactive crystal and its reactivity was tested by heating the co-crystals in the presence of solid sodium carbonate. A facile intermolecular p-toluoyl group transfer was observed as predicted. The successful identification of reactive crystals opens up a new method for the detection of molecular crystals capable of exhibiting acyl transfer reactivity. PMID- 23934730 TI - Ten renal arteries found in a 51-year-old man during multidetector computed tomography (MDCT) angiography. PMID- 23934728 TI - Rapamycin extends life- and health span because it slows aging. AB - Making headlines, a thought-provocative paper by Neff, Ehninger and coworkers claims that rapamycin extends life span but has limited effects on aging. How is that possibly possible? And what is aging if not an increase of the probability of death with age. I discuss that the JCI paper actually shows that rapamycin slows aging and also extends lifespan regardless of its direct anti-cancer activities. Aging is, in part, MTOR-driven: a purposeless continuation of developmental growth. Rapamycin affects the same processes in young and old animals: young animals' traits and phenotypes, which continuations become hyperfunctional, harmful and lethal later in life. PMID- 23934731 TI - Epstein-Barr virus induction of the Hedgehog signalling pathway imposes a stem cell phenotype on human epithelial cells. AB - Nasopharyngeal carcinoma (NPC) is a cancer common in southern China and South East Asia that is causally linked to Epstein-Barr virus (EBV) infection. Here, we demonstrate that NPC displays frequent dysregulation of the Hedgehog (HH) pathway, a pathway implicated in the maintenance of stem cells, but whose aberrant activation in adult tissues can lead to cancer. Using authentic EBV positive carcinoma-derived cell lines and nasopharyngeal epithelial cell lines latently infected with EBV as models for NPC in vitro, we show that EBV activates the HH signalling pathway through autocrine induction of SHH ligand. Moreover, we find that constitutive engagement of the HH pathway induces the expression of a number of stemness-associated genes and imposes stem-like characteristics on EBV infected epithelial cells in vitro. Using epithelial cells expressing individual EBV latent genes detected in NPC, we show that EBNA1, LMP1, and LMP2A are all capable of inducing SHH ligand and activating the HH pathway, but only LMP1 and LMP2A are able to induce expression of stemness-associated marker genes. Our findings not only identify a role for dysregulated HH signalling in NPC oncogenesis, but also provide a novel rationale for therapeutic intervention. PMID- 23934732 TI - Diagnostic value of a "wide-range" quantitative nested real-time PCR assay for varicella zoster virus myelitis. AB - Myelitis is one of the rarest neurological complications of varicella zoster virus (VZV) infection. In this study, the authors remodeled the "wide-range" quantitative nested real-time (QNRT) polymerase chain reaction (PCR) assay to quantitatively detect a small amount of VZV-DNA in cerebrospinal fluid (CSF). For use as a specific internal control "calibrator," an original mutation-VZV (MZ) plasmid was developed. The initial copy number of VZV-DNA in CSF specimens was measured by the amplification rate of the MZ-plasmid. For 17 consecutive CSF specimens collected from three elderly patients with VZV myelitis, the diagnostic value of the wide-range QNRT-PCR assay was evaluated and compared with other conventional PCR assays and enzyme immunoassay (EIA). The MZ-plasmid demonstrated statistically uniform amplifications (F=1.016) against a wide range (1-100,000) of copy numbers of mimic VZV-DNA. The wide-range QNRT-PCR assay quantitatively and rapidly (within 48 hr) detected 5,863, 3,052, 958, and 6,721 copies/ml of VZV DNA in the CSF specimens collected from all patients in the acute phase. Additionally, there was a significant difference (*P=0.023) in the copy number of VZV-DNA between before and after acyclovir treatment. Other conventional single PCR assays all revealed negative results, but were nevertheless time-consuming (7 days). The IgG EIA-value for VZV was continually elevated throughout the clinical course of all patients. The MZ-plasmid was thus regarded as an appropriate "calibrator" in the wide-range QNRT-PCR assay. This assay is a novel, rapid, accurate, quantitative, and highly sensitive technique, and will contribute as a reliable and useful clinical examination for the rapid diagnosis of VZV infection to central nervous system. PMID- 23934733 TI - Is the relationship between prenatal exposure to PCB-153 and decreased birth weight attributable to pharmacokinetics? AB - BACKGROUND: A recent meta-analysis based on data from > 7,000 pregnancies reported an association between prenatal polychlorinated biphenyl (PCB)-153 exposure and reduced birth weight. Gestational weight gain, which is associated negatively with PCB levels in maternal and cord blood, and positively with birth weight, could substantially confound this association. OBJECTIVE: We sought to estimate the influence of gestational weight gain on the association between PCB 153 exposure and birth weight using a pharmacokinetic model. METHODS: We modified a recently published pharmacokinetic model and ran Monte Carlo simulations accounting for variability in physiologic parameters and their correlations. We evaluated the pharmacokinetic model by comparing simulated plasma PCB-153 levels during pregnancy to serial measurements in 10 pregnant women from another study population. We estimated the association between simulated plasma PCB-153 levels and birth weight using linear regression models. RESULTS: The plasma PCB-153 level profiles generated with the pharmacokinetic model were comparable to measured levels in 10 pregnant women. We estimated a 118-g decrease in birth weight (95% CI: -129, -106 g) for each 1-MUg/L increase in simulated cord plasma PCB-153, compared with the 150-g decrease estimated based on the previous meta analysis. The estimated decrease in birth weight was reduced to -6 g (95% CI: 18, 6 g) when adjusted for simulated gestational weight gain. CONCLUSION: Our findings suggest that associations previously noted between PCB levels and birth weight may be attributable to confounding by maternal weight gain during pregnancy. PMID- 23934734 TI - Leonidas Zervas award lecture: abiotic ligands for new quaternary architectures of peptides and proteins. AB - This review is the result of a kind invitation to provide a report on the basis of the Leonidas Zervas award lecture at the 32nd European Peptide Society in Athens, Greece, September 2012. The lecture covered several topics including contributions toward new methods for the assembly of peptides and chemical modification of proteins. The present review will focus on another topic from the Zervas lecture, namely, our recent efforts at creating new, artificial architectures for the organization of the quaternary structure of proteins. Crucially, this is achieved with abiotic ligands and not protein surface engineering. This concept was demonstrated for the important biopharmaceutical peptide insulin, by using both abiotic metal ion binding ligands and perfluoroalkyl chains. PMID- 23934735 TI - Denervation and castration effects on the cross-sectional area of pubococcygeus muscle fibers in male rats. AB - The number of fibers in skeletal muscles changes little through life; however, the cross-sectional area of its fibers is modified as result of denervation and in some muscles by castration. The pubococcygeus muscle (Pcm) participates in micturition and ejaculatory processes and its fibers cross-sectional area is reduced in castrated rats, but denervation effects remained unknown. Here, we used a model in which unilateral denervation of this muscle in gonadally intact and castrated male rats, allowed us to explore the neural and gonadal hormone effects on the cross-sectional area of its fibers. Denervation significantly reduced the mean cross-sectional area values; likewise, the percentage distribution of its fibers. We found that castration had a greater effect than denervation. Castration resulted in a lack of fibers from 2,000 to 3,999 MUm(2) , while in denervation it was from 2,500 to 3,999 MUm(2) . It was interpreted that the castration effect was due to a lack of the direct gonadal hormone effect on muscle fibers, and to a reduction of the indirect hormonal action in its neuromuscular complex. In denervated Pcm of gonadally intact animals these effects were present; however, in denervated but castrated animals these were absent. Thus, combined surgeries resulted in the lowest mean cross-sectional area values with a restricted fiber distribution from 500 to 1,499 MUm(2) . In conclusion, the study in this important muscle showed that cross-sectional area of its fibers depends on neural and direct/indirect gonadal hormone effects. PMID- 23934737 TI - Effects of ellagitannin-rich berries on blood lipids, gut microbiota, and urolithin production in human subjects with symptoms of metabolic syndrome. AB - Ellagitannins are polyphenols abundant in strawberries, raspberries, and cloudberries. The effects of a mixture of these berries were studied in a randomized controlled trial with subjects having symptoms of metabolic syndrome. The study focused on serum lipid profiles, gut microbiota, and ellagitannin metabolites. The results indicate that bioavailability of ellagitannins appears to be dependent on the composition of gut microbiota. PMID- 23934736 TI - Genome-wide association study of a heart failure related metabolomic profile among African Americans in the Atherosclerosis Risk in Communities (ARIC) study. AB - Both the prevalence and incidence of heart failure (HF) are increasing, especially among African Americans, but no large-scale, genome-wide association study (GWAS) of HF-related metabolites has been reported. We sought to identify novel genetic variants that are associated with metabolites previously reported to relate to HF incidence. GWASs of three metabolites identified previously as risk factors for incident HF (pyroglutamine, dihydroxy docosatrienoic acid, and X 11787, being either hydroxy-leucine or hydroxy-isoleucine) were performed in 1,260 African Americans free of HF at the baseline examination of the Atherosclerosis Risk in Communities (ARIC) study. A significant association on chromosome 5q33 (rs10463316, MAF = 0.358, P-value = 1.92 * 10(-10) ) was identified for pyroglutamine. One region on chromosome 2p13 contained a nonsynonymous substitution in N-acetyltransferase 8 (NAT8) was associated with X 11787 (rs13538, MAF = 0.481, P-value = 1.71 * 10(-23) ). The smallest P-value for dihydroxy docosatrienoic acid was rs4006531 on chromosome 8q24 (MAF = 0.400, P value = 6.98 * 10(-7) ). None of the above SNPs were individually associated with incident HF, but a genetic risk score (GRS) created by summing the most significant risk alleles from each metabolite detected 11% greater risk of HF per allele. In summary, we identified three loci associated with previously reported HF-related metabolites. Further use of metabolomics technology will facilitate replication of these findings in independent samples. PMID- 23934738 TI - Sticky platelet syndrome. AB - Sticky platelet syndrome (SPS) is a thrombophilic thrombocytopathy with familial occurrence and autosomal dominant trait, characterized by an increased in vitro platelet aggregation in response to low concentrations of adenosine diphosphate (ADP) and/or epinephrine (EPI). According to aggregation pattern, three types of the syndrome can be identified (hyperresponse after both reagents, Type I; EPI alone, Type II; ADP alone, Type III). Clinically, the syndrome is associated with both venous and arterial thrombosis. In pregnant women, complications such as fetal growth retardation and fetal loss have been reported. The first thrombotic event usually occurs before 40 years of age and without prominent acquired risk factors. Antiplatelet drugs generally represent adequate treatment. The use of other antithrombotics is usually ineffective and may result in the recurrence of thrombosis. In most patients, low doses of antiplatelet drugs (acetylsalicylic acid, 80-100 mg/d) lead to normalization of hyperaggregability. Combination of SPS with other thrombophilic disorders has been described. Despite several studies investigating platelet glycoproteins' role in platelets' activation and aggregation, the precise defect responsible for the syndrome remains unknown. The aim of this review is to summarize authors' own experience about SPS and the clinical data indexed in selected databases of medical literature (PubMed and Scopus). PMID- 23934739 TI - Detection of VIM-34, a novel VIM-1 variant identified in the intercontinental ST15 Klebsiella pneumoniae clone. PMID- 23934740 TI - Insertion sequence IS18 mediates overexpression of blaOXA-257 in a carbapenem resistant Acinetobacter bereziniae isolate. PMID- 23934741 TI - Molecular mechanism of prion protein oligomerization at atomic resolution. AB - Prion protein oligomerization: Despite the crucial role of oligomers during prion protein (PrP) pathogenesis the molecular mechanism of their formation has remained largely elusive. A 2D time-resolved NMR study which made it possible to characterize the oligomerization kinetics with unprecedented site-specificity is reported. PMID- 23934742 TI - Current place of monoamine oxidase inhibitors in the treatment of depression. AB - This paper reviews the discovery and history of the use of irreversible monoamine oxidase (MAO) inhibitors (MAOIs) such as phenelzine, tranylcypromine and isocarboxazid, as well as the second generation selective and reversible MAOIs such as the MAO-A inhibitor, moclobemide and the MAO-B inhibitor, selegiline. Data for review were identified from a literature search of OvidSP Medline and PsycInfo performed in July 2012, using the subject terms and keywords of 'monoamine oxidase inhibitors', 'major depression', 'depressive disorder' and 'depression (emotion)'. The search was limited to papers published in the English language and from 2007 onward only. Irreversible MAOIs have the potential to treat the most challenging mood disorder patients including those with treatment resistant depression, atypical depression and bipolar depression. Unfortunately, the use of irreversible MAOIs has been declining sharply due to lack of marketing and the excessive fears of clinicians. Moreover, few clinicians now have any experience, let alone comfort, in prescribing this class of antidepressants. The newer MAOIs are available as another option for the treatment of major depression but have not replaced the irreversible MAOIs for the specific sub-types of depression for which they are now recommended in most consensus guidelines and treatment algorithms. The pharmacology, drug interactions and dietary recommendations associated with the use of MAOIs are reviewed. With the appropriate dietary restrictions and attention to potential drug interactions with serotonin and noradrenaline agents this class of drugs can be used effectively and safely. The MAOIs still represent an important element in our therapeutic armamentarium. Despite recommendations by opinion leaders and consensus guidelines for the use of MAOIs in specific sub-types of depression, the prescription rate of MAOIs is far less than expected and is decreasing. The "bad reputation" and the lack of industry support for this class of agents (especially the irreversible MAOIs) must be overcome in order to continue to provide a potentially useful treatment for a very vulnerable yet substantial sub population of mood disorder patients. PMID- 23934743 TI - Adipose tissue derived stromal stem cell therapy in murine ConA-derived hepatitis is dependent on myeloid-lineage and CD4+ T-cell suppression. AB - Mesenchymal stromal stem cells (MSCs) are an attractive therapeutic model for regenerative medicine due to their pluripotency. MSCs are used as a treatment for several inflammatory diseases, including hepatitis. However, the detailed immunopathological impact of MSC treatment on liver disease, particularly for adipose tissue derived stromal stem cells (ADSCs), has not been described. Here, we investigated the immuno-modulatory effect of ADSCs on hepatitis using an acute ConA C57BL/6 murine hepatitis model. i.v. administration of ADSCs simultaneously or 3 h post injection prevented and treated ConA-induced hepatitis. Immunohistochemical analysis revealed higher numbers of CD11b(+), Gr-1(+), and F4/80(+) cells in the liver of ConA-induced hepatitis mice was ameliorated after the administration of ADSCs. Hepatic expression of genes affected by ADSC administration indicated tissue regeneration-related biological processes, affecting myeloid-lineage immune-mediating Gr-1(+) and CD11b(+) cells. Pathway analysis of the genes expressed in ADSC-treated hepatic inflammatory cells revealed the possible involvement of T cells and macrophages. TNF-alpha and IFN gamma expression was downregulated in hepatic CD4(+) T cells isolated from hepatitis livers co-cultured with ADSCs. Thus, the immunosuppressive effect of ADSCs in a C57BL/6 murine ConA hepatitis model was dependent primarily on the suppression of myeloid-lineage cells and, in part, of CD4(+) T cells. PMID- 23934744 TI - Overcoming treatment resistance in acute promyelocytic leukemia and beyond. PMID- 23934746 TI - Tuning the dispersibility of carbon nanostructures from organophilic to hydrophilic: towards the preparation of new multipurpose carbon-based hybrids. AB - The hydroxyphenyl derivatives of carbon nanostructures (graphene and carbon nanotubes) can be easily transformed into highly organophilic or hydrophilic derivatives by using the ionic interactions between the phenolic groups and oleylamine or tetramethylammonium hydroxide, respectively. The products were finely dispersed in homo-polymers or block co-polymers to create homogeneous carbon-based nanocomposites and were used as nanocarriers for the dispersion and protection of strongly hydrophobic compounds, such as large aromatic chromophores or anticancer drugs in aqueous solutions. PMID- 23934747 TI - A randomized comparison between records made with an anesthesia information management system and by hand, and evaluation of the Hawthorne effect. AB - PURPOSE: Anesthesia information management system (AIMS) technology is designed to facilitate high-quality anesthetic recordkeeping. We examined the hypothesis that no difference exists between AIMS and handwritten anesthetic records in regard to the completeness of important information contained as text data. We also investigated the effect of observational research on the completeness of anesthesiologists' recordkeeping. METHODS: As part of a larger randomized controlled trial, participants were randomized to produce 400 anesthetic records, either handwritten (n = 200) or using an AIMS (n = 200). Records were assessed against a 32-item checklist modified from a clinical guideline. Intravenous agent and bolus recordings were quantified, and data were compared between handwritten and AIMS records. Records produced with intensive research observation during the initial phase of the study (n = 200) were compared with records produced with reduced intensity observation during the final phase of the study (n = 200). RESULTS: The AIMS records were more complete than the handwritten records (mean difference 7.1%; 95% confidence interval [CI] 5.6 to 8.6%; P < 0.0001), with higher completion rates for six individual items on the checklist (P < 0.0001). Drug annotation data were equal between arms. The records completed early in the study, during a period of more intense observation, were more thorough than subsequent records (87.3% vs 81.6%, respectively; mean difference 5.7%; 95% CI 4.2 to 7.3%; P < 0.0001). CONCLUSIONS: The AIMS records were more complete than the handwritten records for 32 predefined items. The potential of observational research to influence professional behaviour in an anesthetic context was confirmed. This trial was registered at the Australian New Zealand Clinical Trials Registry No 12608000068369. PMID- 23934748 TI - Mechanistic insights into the scale-up of the roller compaction process: a practical and dimensionless approach. AB - Although the roller compaction process appears simple, efforts to quantitatively model the process have proven challenging because of complex material behavior in the feeding and compaction zones. To date, implementation of roller compaction models to experimental work has been limited because these models typically require large experimental data sets or obscure input parameters that are difficult to obtain experimentally. In this work, an alternative approach has been established, expanding upon a widely used roller compaction model, Johanson's model, to enable its incorporation into a daily workflow. The proposed method requires only standard, routinely measured parameters as inputs. An excellent correlation between simulated and experimental results has been achieved for placebo and active blends up to 22% (w/w) drug load. Furthermore, a dimensionless relationship between key process parameters and final compact properties was elucidated. This dimensionless parameter, referred to as the modified Bingham number (Bm *), highlights the importance of balancing yield and viscous stresses during roller compaction to achieve optimal output properties. By maintaining a constant ratio of yield-to-viscous stresses, as indicated by a constant Bm *, consistent products were attained between two scales of operation. Bm * was shown to provide guidance toward determining the design space for formulation development, as well as to facilitate scale-up development. PMID- 23934749 TI - Crystal structures of alpha-dioxygenase from Oryza sativa: insights into substrate binding and activation by hydrogen peroxide. AB - alpha-Dioxygenases (alpha-DOX) are heme-containing enzymes found predominantly in plants and fungi, where they generate oxylipins in response to pathogen attack. alpha-DOX oxygenate a variety of 14-20 carbon fatty acids containing up to three unsaturated bonds through stereoselective removal of the pro-R hydrogen from the alpha-carbon by a tyrosyl radical generated via the oxidation of the heme moiety by hydrogen peroxide (H2 O2 ). We determined the X-ray crystal structures of wild type alpha-DOX from Oryza sativa, the wild type enzyme in complex with H2 O2 , and the catalytically inactive Y379F mutant in complex with the fatty acid palmitic acid (PA). PA binds within the active site cleft of alpha-DOX such that the carboxylate forms ionic interactions with His-311 and Arg-559. Thr-316 aids in the positioning of carbon-2 for hydrogen abstraction. Twenty-five of the twenty eight contacts made between PA and residues lining the active site occur within the carboxylate and first eight carbons, indicating that interactions within this region of the substrate are responsible for governing selectivity. Comparison of the wild type and H2 O2 structures provides insight into enzyme activation. The binding of H2 O2 at the distal face of the heme displaces residues His-157, Asp-158, and Trp-159 ~ 2.5 A from their positions in the wild type structure. As a result, the Odelta2 atom of Asp-158 interacts with the Ca atom in the calcium binding loop, the side chains of Trp-159 and Trp-213 reorient, and the guanidinium group of Arg-559 is repositioned near Tyr-379, poised to interact with the carboxylate group of the substrate. PMID- 23934750 TI - Polymorphisms in the SCD1 gene are associated with indices of stearoyl CoA desaturase activity and obesity: a prospective study. AB - SCOPE: The serum fatty acid (FA) composition is influenced by dietary fat and the endogenous production of FAs. Stearoyl CoA desaturase 1 (SCD1) is the rate limiting enzyme catalyzing the synthesis of MUFAs from saturated FAs. Variations in SCD1 activity have been associated with obesity, diabetes, or inflammation. We evaluated the associations between genetic variation of the SCD1 gene, SCD1 activity, intake of oil, and obesity in a population-based prospective study in southern Spain. METHODS AND RESULTS: We collected phenotypic, metabolic, nutritional, and genetic information. The type of dietary fat was assessed from samples of cooking oil taken from the participants' kitchens and analyzed by GC. A total of nine single nucleotide polymorphisms (SNPs) of the SCD1 gene were analyzed by SNPlex technology. We found a significant association between SCD1 genetic variation and enzyme activity in four of nine polymorphisms studied. An interaction between rs10883463 and olive oil intake on the [18:1/18:0] desaturase index was found (p = 0.009). We also showed that genetic variations in the SCD1 gene were associated with obesity. CONCLUSION: Our results show a relationship between genetic variation of the SCD1 gene, enzyme activity, and the risk of obesity, an association that is not independent of the type of oil consumed. PMID- 23934751 TI - A shrinkage method for testing the Hardy-Weinberg equilibrium in case-control studies. AB - Testing for the Hardy-Weinberg equilibrium (HWE) is often used as an initial step for checking the quality of genotyping. When testing the HWE for case-control data, the impact of a potential genetic association between the marker and the disease must be controlled for otherwise the results may be biased. Li and Li [2008] proposed a likelihood ratio test (LRT) that accounts for this potential genetic association and it is more powerful than the commonly used control-only chi2 test. However, the LRT is not efficient when the marker is independent of the disease, and also requires numerical optimization to calculate the test statistic. In this article, we propose a novel shrinkage test for assessing the HWE. The proposed shrinkage test yields higher statistical power than the LRT when the marker is independent of or weakly associated with the disease, and converges to the LRT when the marker is strongly associated with the disease. In addition, the proposed shrinkage test has a closed form and can be easily used to test the HWE for large datasets that result from genome-wide association studies. We compare the performance of the shrinkage test with existing methods using simulation studies, and apply the shrinkage test to a genome-wide association dataset for Alzheimer's disease. PMID- 23934752 TI - Platelet-type von Willebrand disease: new insights into the molecular pathophysiology of a unique platelet defect. AB - Compared with coagulation factor defects, little attention is given to defects of platelet function as causes of rare bleeding disorders. Platelet-type von Willebrand disease (PT-VWD) is an autosomal dominant bleeding disorder and is unique among platelet disorders because it is characterized by platelet hyperresponsiveness rather than decreased function. The disease is caused by gain of-function mutations in the platelet GP1BA gene, which codes for the platelet von Willebrand factor (VWF) receptor, GPIbalpha. Only five mutations (four missense and one deletion) have so far been reported. Affected patients suffer from mild to moderate mucocutaneous bleeding, low VWF activity compared with antigen, decreased high-molecular-weight VWF multimers, variable degree of thrombocytopenia and typically platelet aggregation in response to low concentrations of ristocetin. All reported PT-VWD missense mutations occur within the R-loop of GPIbalpha and it was speculated that the introduction of short branched chain mutations such as Val in PT-VWD stabilized the extended beta hairpin. Examination of this theory by surveying all the available GPIbalpha structures showed that a distinct conformation predominates for the R-loop when GPIbalpha is not bound to VWF-A1 and this provides the framework of a new hypothesis for the molecular basis of PT-VWD. Worldwide efforts to improve diagnosis of PT-VWD continue, and international systematic studies are required to further our understanding of the phenotype and the influence of the hyperresponsive GPIbalpha beyond hemostasis. PMID- 23934753 TI - Building a parent iridabenzene structure from acetylene and dichloromethane on an iridium center. AB - Parenthood: The reaction of [TpIr(C2H4)2] (1) (Tp=hydrotris(pyrazolyl)borate) with acetylene in CH2 Cl2 affords a 1:1 mixture of the "parent" metallabenzene 2 (that is, all the ring carbon centers are CH units) and the beta-Cl substituted vinyl species 3. Generation of 2 is by the coupling of an iridacyclopentadiene (formed from two acetylene molecules at the Ir center) with the dichloromethane derived chlorocarbene ":C(H)Cl" and a subsequent alpha-Cl elimination event. PMID- 23934754 TI - Apoptotic cells enhance sphingosine-1-phosphate receptor 1 dependent macrophage migration. AB - The lipid sphingosine-1-phosphate (S1P) is a chemokine for a variety of immune cells including lymphocytes and monocytes. Migration toward S1P is determined by the S1P receptor expression profile, with S1PR1/3 (where S1PR is S1P receptor) stimulating and S1PR2 attenuating migration. However, the impact and physiological significance of S1P-induced migration of macrophages is largely unclear. We observed that alternative activation of human macrophages, by IL-4 or apoptotic cells (ACs), enhanced S1PR1 expression. Moreover, ACs provoked macrophage migration toward S1P in an S1PR1-dependent manner as confirmed by pharmacological receptor inhibition and S1PR1-deficient murine macrophages. In a mouse model of resolving peritoneal inflammation, F4/80-driven deletion of S1PR1 reduced postinflammatory macrophage emigration from inflammatory sites. S1PR1 expression on macrophages might, therefore, be relevant for restoring tissue homeostasis during the resolution of inflammation. PMID- 23934755 TI - Efficient lookup table using a linear function of inverse distance squared. AB - The major bottleneck in molecular dynamics (MD) simulations of biomolecules exist in the calculation of pairwise nonbonded interactions like Lennard-Jones and long range electrostatic interactions. Particle-mesh Ewald (PME) method is able to evaluate long-range electrostatic interactions accurately and quickly during MD simulation. However, the evaluation of energy and gradient includes time consuming inverse square roots and complementary error functions. To avoid such time-consuming operations while keeping accuracy, we propose a new lookup table for short-range interaction in PME by defining energy and gradient as a linear function of inverse distance squared. In our lookup table approach, densities of table points are inversely proportional to squared pair distances, enabling accurate evaluation of energy and gradient at small pair distances. Regardless of the inverse operation here, the new lookup table scheme allows fast pairwise nonbonded calculations owing to efficient usage of cache memory. PMID- 23934756 TI - Improving apoptotic responses to targeted therapy. PMID- 23934757 TI - High charge delocalization and conjugation in oligofuran molecular wires. AB - The extent of charge delocalization and of conjugation in oligofurans and oligothiophenes was studied by using mixed valence systems comprising oligofurans and oligothiophenes capped at both ends by ferrocenyl redox units. Using electrochemical, spectral, and computational tools, we find strong charge delocalization in ferrocene-capped oligofurans which was stronger than in the corresponding oligothiophene systems. Spectroscopic studies suggest that the electronic coupling integral (H(ab)) is roughly 30-50 % greater for oligofuran bridged systems, indicating better energy matching between ferrocene units and oligofurans. The distance decay constant (damping factor), beta, is similar for oligofurans (0.066 A(-1)) and oligothiophenes (0.070 A(-1)), which suggests a similar extent of delocalization in the bridge, despite the higher HOMO-LUMO gap in oligofurans. Computational studies indicate a slightly larger extent of delocalization in furan-bridged systems compared with thiophene-bridged systems, which is consistent with oligofurans being significantly more rigid and less aromatic than oligothiophenes. High charge delocalization in oligofurans, combined with the previously reported strong fluorescence, high mobility, and high rigidity of oligofuran-based materials makes them attractive candidates for organic electronic applications. PMID- 23934758 TI - Observed octameric assembly of a Plasmodium yoelii peroxiredoxin can be explained by the replacement of native "ball-and-socket" interacting residues by an affinity tag. AB - Peroxiredoxins (Prxs) are ubiquitous and efficient antioxidant enzymes crucial for redox homeostasis in most organisms, and are of special importance for disease-causing parasites that must protect themselves against the oxidative weapons of the human immune system. Here, we describe reanalyses of crystal structures of two Prxs from malaria parasites. In addition to producing improved structures, we provide normalizing explanations for features that had been noted as unusual in the original report of these structures (Qiu et al., BMC Struct Biol 2012;12:2). Most importantly, we provide evidence that the unusual octameric assembly seen for Plasmodium yoelii Prx1a is not physiologically relevant, but arises because the structure is not of authentic P. yoelii Prx1a, but a variant we designate PyPrx1a(N*) that has seven native N-terminal residues replaced by an affinity tag. This N-terminal modification disrupts a previously unrecognized, hydrophobic "ball-and-socket" interaction conserved at the B-type dimer interface of Prx1 subfamily enzymes, and is accommodated by a fascinating two-residue "beta slip" type register shift in the beta-strand association at a dimer interface. The resulting change in the geometry of the dimer provides a simple explanation for octamer formation. This study illustrates how substantive impacts can occur in protein variants in which native residues have been altered. PMID- 23934759 TI - EINVis: a visualization tool for analyzing and exploring genetic interactions in large-scale association studies. AB - Epistasis (gene-gene interaction) detection in large-scale genetic association studies has recently drawn extensive research interests as many complex traits are likely caused by the joint effect of multiple genetic factors. The large number of possible interactions poses both statistical and computational challenges. A variety of approaches have been developed to address the analytical challenges in epistatic interaction detection. These methods usually output the identified genetic interactions and store them in flat file formats. It is highly desirable to develop an effective visualization tool to further investigate the detected interactions and unravel hidden interaction patterns. We have developed EINVis, a novel visualization tool that is specifically designed to analyze and explore genetic interactions. EINVis displays interactions among genetic markers as a network. It utilizes a circular layout (specially, a tree ring view) to simultaneously visualize the hierarchical interactions between single nucleotide polymorphisms (SNPs), genes, and chromosomes, and the network structure formed by these interactions. Using EINVis, the user can distinguish marginal effects from interactions, track interactions involving more than two markers, visualize interactions at different levels, and detect proxy SNPs based on linkage disequilibrium. EINVis is an effective and user-friendly free visualization tool for analyzing and exploring genetic interactions. It is publicly available with detailed documentation and online tutorial on the web at http://filer.case.edu/yxw407/einvis/. PMID- 23934760 TI - Proenergetic effects of resveratrol in the murine neuronal cell line Neuro2a. AB - SCOPE: Energy deficit is a common characteristic of neurodegenerative disorders, including Alzheimer's disease. Adenosine monophosphate activated protein kinase (AMPK) is a key enzyme maintaining energy balance by regulating the cellular uptake of glucose, beta-oxidation of fatty acids, and expression of glucose transporter 4. Since resveratrol has been shown to increase the activity of AMPK, we hypothesized that it might influence energy metabolism in a model neuron-like cell line, murine Neuro2a cells. METHODS AND RESULTS: Resveratrol caused an elevation of adenosine triphosphate (ATP) and guanosine triphosphate (GTP) in a dose-dependent manner. The highest ATP and GTP levels achieved by treatment with resveratrol were 70.3 +/- 8.2 nmol/mg protein (1.9-fold of control) and 27.2 +/- 4.0 nmol/mg protein (1.7-fold of control), respectively, when cells were treated with 100 MUM resveratrol for 6 h. Interestingly, increases in the total sum of all adenine nucleotides were found upon addition of resveratrol. Despite these increases in ATP, GTP, and the total adenine nucleotide pool, resveratrol treatment led to a decrease in glucose consumption and lactate release, suggesting that resveratrol does not increase energy production (e.g. via AMPK kinase activation) but rather inhibits energy-consuming processes. CONCLUSION: Resveratrol increases the levels of ATP and GTP, but without creating an additional glucose demand. PMID- 23934764 TI - Genomic vagabonds: endogenous retroviruses and placental evolution. PMID- 23934763 TI - Kinase inhibitor therapy in CML: it's what's inside that counts. PMID- 23934762 TI - Psychosocial approaches to participation in BRCA1/2 genetic risk assessment among African American women: a systematic review. AB - Breast cancer is a significant health concern for African American women. Nonetheless, uptake of genetic risk assessment (including both genetic counseling and testing) for breast cancer gene mutations among these populations remains low. This paper systematically reviews cognitive (i.e., beliefs) and affective (i.e., emotions) factors influencing BRCA1/2 genetic risk assessment among African American women as well as psychosocial interventions to facilitate informed decision making in this population. A systematic search of CINAHL, PubMed, and PsycINFO was undertaken, yielding 112 published studies. Of these, 18 met the eligibility criteria. African American woman are likely to participate in genetic risk assessment if they are knowledgeable about cancer genetics, perceive a high risk of developing breast cancer, have low expectancies of stigmatization from medical professionals, view themselves as independent from family, and have fatalistic beliefs and a future temporal orientation. Anticipated negative affective responses, such as an inability to "handle" the results of testing, are barriers to uptake. Specific perceptions, beliefs, and emotional factors are associated with genetic risk assessment among African American women. Understanding these factors is key in the development of interventions to facilitate informed decision making in this population. PMID- 23934761 TI - Patient compliance based on genetic medicine: a literature review. AB - For this literature review, medical literature data bases were searched for studies on patient compliance after genetic risk assessment. The review focused on conditions where secondary or tertiary preventive options exist, namely cancer syndromes (BRCA-related cancer, HNPCC/colon cancer), hemochromatosis, thrombophilia, smoking cessation, and obesity. As a counterpart, patient compliance was assessed regarding medication adherence and medical advice in some of the most epidemiologically important conditions (including high blood pressure, metabolic syndrome, and coronary heart disease) after receiving medical advice based on nongenetic risk information or a combination of genetic and nongenetic risk information. In the majority of studies based on genetic risk assessments, patients were confronted with predictive rather than diagnostic genetic profiles. Most of the studies started from a knowledge base around 10 years ago when DNA testing was at an early stage, limited in scope and specificity, and costly. The major result is that overall compliance of patients after receiving a high-risk estimate from genetic testing for a given condition is high. However, significant behavior change does not take place just because the analyte is "genetic." Many more factors play a role in the complex process of behavioral tuning. Without adequate counseling and guidance, patients may interpret risk estimates of predictive genetic testing with an increase in fear and anxiety. PMID- 23934765 TI - Butterfly-shaped pentanuclear dysprosium single-molecule magnets. AB - Two new "butterfly-shaped" pentanuclear dysprosium(III) clusters, [Dy5(MU3 OH)3(opch)6(H2O)3]?3 MeOH?9 H2O (1) and [Dy5(MU3 OH)3(Hopch)2(opch)4(MeOH)(H2O)2]?(ClO4)2?6 MeOH?4 H2O (2), which were based on the heterodonor-chelating ligand o-vanillin pyrazine acylhydrazone (H2opch), have been successfully synthesized by applying different reaction conditions. Single crystal X-ray diffraction analysis revealed that the butterfly-shaped cores in both compounds were comparable. However, their magnetic properties were drastically different. Indeed, compound 1 showed dual slow-relaxation processes with a transition between them that corresponded to energy gaps (Delta) of 8.1 and 37.9 K and pre-exponential factors (tau0) of 1.7*10(-5) and 9.7*10(-8) s for the low- and high-temperature domains, respectively, whilst only a single relaxation process was noted for compound 2 (Delta = 197 K, tau0 = 3.2*10(-9) s). These significant disparities are most likely due to the versatile coordination of the H2opch ligands with particular keto-enol tautomerism, which alters the strength of the local crystal field and, hence, the nature or direction of the easy axes of anisotropic dysprosium ions. PMID- 23934766 TI - The tricky task of nitrate/nitrite antiport. AB - Subtle differences: Two recent crystal structures have provided the first insight into nitrate/nitrite exchangers (example shown with bound nitrite), which are crucial to bacterial metabolism. A direct comparison of the structures reveals how the proteins can distinguish between their highly similar substrates and translate this into a conformational change to translocate ions across the membrane. PMID- 23934768 TI - Modeling the physiological factors that affect drug delivery from a nipple shield delivery system to breastfeeding infants. AB - An apparatus was designed to mimic lactation from a human breast. It was used to determine the influence of milk fat content and flow rate, and suction pulse rate of a breastfeeding infant upon the release of a model compound from a nipple shield delivery system (NSDS). The NSDS would be worn by a mother to deliver drugs and nutrients to her infant during breastfeeding. Sulforhodamine B dye (SB) was used as model compound and formulated as a dispersible tablet to be placed within the NSDS. Increasing suction pulse rate from 30 to 120 pulses/min clearly correlated with increased cumulative release of SB for the same volume of milk passed through the NSDS. No distinct correlation was found between flow rates (1, 5, and 8 mL/min) and SB release, possibly because of competing factors controlling release rate at different flow rates. A highly similar SB release rate into two fat content fluids (2.9 and 4.2 wt %) was observed for identical flow conditions. This proof of concept study outlines a novel method to mimic lactation from a breast, and future studies will lead to effective methods to identify key physiological factors that influence drug release from a NSDS. PMID- 23934769 TI - An analysis of the prognostic value of IDH1 (isocitrate dehydrogenase 1) mutation in Polish glioma patients. AB - BACKGROUND AND OBJECTIVE: IDH1 (isocitrate dehydrogenase 1) is a potential biomarker and drug target. Genomic and epigenetic data on astrocytoma have demonstrated that the IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Furthermore, recent studies have also indicated that a mutant IDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. As the presence of the p.R132H mutation in the IDH1 gene seems to be a more powerful prognostic marker than O(6) methylguanine-DNA methyltransferase promoter status, we evaluated the presence of IDH1 mutation in Polish patients with astrocytoma, glioblastoma, oligoastrocytoma, ganglioglioma, oligodendroglioma, and ependymoma. METHODS: The IDH1 mutation status at codon 132 was determined using a mouse monoclonal antibody specific for the R132H mutation, direct sequencing, and Co-amplification at Lower Denaturation Temperature (COLD) polymerase chain reaction (PCR) high resolution melting-curve analysis (HRM). RESULTS: Wild-type (WT) IDH1 was detected in cases with a World Health Organization (WHO) grade I astrocytoma. The IDH1 c.G395A; p.R132H mutation was observed in 56 and 94 % of grade II and grade III astrocytoma cases, respectively. Significant differences in the median overall survival were observed in astrocytoma patients grouped on the basis of the presence of IDH1 mutation: survival was 24 months longer in grade II astrocytoma and 12 months longer in glioblastoma. Overall survival was compared between grade II astrocytoma patients with low or high expression of the mutant protein. Interestingly, lower R132H expression correlated with better overall survival. CONCLUSION: Our results indicate the usefulness of assessing the R132H IDH1 mutation in glioma patients: the presence or absence of the R132H mutation can help pathologists to distinguish pilocytic astrocytomas (IDH1 WT) from diffuse ones (R132H IDH1/WT). Moreover, low IDH1 p.R132H expression was related to better prognosis. This clinical implication appears to be important for personalization of prognosis and treatment by oncologists. PMID- 23934771 TI - Urolithiasis associated with atazanavir may mask a metabolic 'channelling' bias. PMID- 23934770 TI - Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing. AB - OBJECTIVES: The introduction of two new non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the past 5 years and the identification of novel NNRTI associated mutations have made it necessary to reassess the extent of phenotypic NNRTI cross-resistance. METHODS: We analysed a dataset containing 1975, 1967, 519 and 187 genotype-phenotype correlations for nevirapine, efavirenz, etravirine and rilpivirine, respectively. We used linear regression to estimate the effects of RT mutations on susceptibility to each of these NNRTIs. RESULTS: Sixteen mutations at 10 positions were significantly associated with the greatest contribution to reduced phenotypic susceptibility (>=10-fold) to one or more NNRTIs, including: 14 mutations at six positions for nevirapine (K101P, K103N/S, V106A/M, Y181C/I/V, Y188C/L and G190A/E/Q/S); 10 mutations at six positions for efavirenz (L100I, K101P, K103N, V106M, Y188C/L and G190A/E/Q/S); 5 mutations at four positions for etravirine (K101P, Y181I/V, G190E and F227C); and 6 mutations at five positions for rilpivirine (L100I, K101P, Y181I/V, G190E and F227C). G190E, a mutation that causes high-level nevirapine and efavirenz resistance, also markedly reduced susceptibility to etravirine and rilpivirine. K101H, E138G, V179F and M230L mutations, associated with reduced susceptibility to etravirine and rilpivirine, were also associated with reduced susceptibility to nevirapine and/or efavirenz. CONCLUSIONS: The identification of novel cross-resistance patterns among approved NNRTIs illustrates the need for a systematic approach for testing novel NNRTIs against clinical virus isolates with major NNRTI-resistance mutations and for testing older NNRTIs against virus isolates with mutations identified during the evaluation of a novel NNRTI. PMID- 23934773 TI - Endoplasmic reticulum stress in adipose tissue determines postprandial lipoprotein metabolism in metabolic syndrome patients. AB - SCOPE: Our aim was to ascertain whether the quality and quantity of fat in the diet may influence the ER stress at the postprandial state in adipose tissue by analyzing the gene expression of chaperones, folding enzymes, and activators of the UPR. METHODS AND RESULTS: A randomized, controlled trial conducted within the LIPGENE study assigned 39 MetS patients to one of four diets: high-SFA (HSFA; 38% energy (E) from fat, 16% E as SFA), high MUFA (HMUFA; 38% E from fat, 20% E as MUFA), and two low-fat, high-complex carbohydrate (LFHCC; 28% E from fat) diets supplemented with 1.24 g/day of long-chain n-3 PUFA or placebo for 12 wk each. A fat challenge reflecting the same fatty acid composition as the original diets was conducted post intervention. sXBP-1 is induced in the postprandial state irrespective of the diet consumed (p < 0.001). BiP increases postprandially after consumption of diets HMUFA (p = 0.006), LFHCC (p = 0.028), and LFHCC n-3 (p = 0.028). Postprandial mRNA expression levels of CRL, CNX, PDIA3, and GSTP1 in AT did not differ between the different types of diets. CONCLUSION: Our results suggest that upregulation of the unfolded protein response at the postprandial state may represent an adaptive mechanism to counteract diet-induced stress. PMID- 23934772 TI - Exhaustive comparison and classification of ligand-binding surfaces in proteins. AB - Many proteins function by interacting with other small molecules (ligands). Identification of ligand-binding sites (LBS) in proteins can therefore help to infer their molecular functions. A comprehensive comparison among local structures of LBSs was previously performed, in order to understand their relationships and to classify their structural motifs. However, similar exhaustive comparison among local surfaces of LBSs (patches) has never been performed, due to computational complexity. To enhance our understanding of LBSs, it is worth performing such comparisons among patches and classifying them based on similarities of their surface configurations and electrostatic potentials. In this study, we first developed a rapid method to compare two patches. We then clustered patches corresponding to the same PDB chemical component identifier for a ligand, and selected a representative patch from each cluster. We subsequently exhaustively as compared the representative patches and clustered them using similarity score, PatSim. Finally, the resultant PatSim scores were compared with similarities of atomic structures of the LBSs and those of the ligand-binding protein sequences and functions. Consequently, we classified the patches into ~ 2000 well-characterized clusters. We found that about 63% of these clusters are used in identical protein folds, although about 25% of the clusters are conserved in distantly related proteins and even in proteins with cross-fold similarity. Furthermore, we showed that patches with higher PatSim score have potential to be involved in similar biological processes. PMID- 23934775 TI - Superconductivity with Rashba spin-orbit coupling and magnetic field. AB - Two-dimensional electron systems at oxide interfaces are often influenced by a Rashba type spin-orbit coupling, which is tunable by a transverse electric field. Ferromagnetism near the interface can simultaneously induce strong local magnetic fields. This combination of spin-orbit coupling and magnetism leads to asymmetric two-sheeted Fermi surfaces, on which either intra- or inter-band pairing is favored. The superconducting order parameters are derived within a microscopic pairing model realizing both the Bardeen-Cooper-Schrieffer superconductor with inter-band pairing and a mixed parity state with finite-momentum intra-band pairing. We present a phase diagram for the superconducting groundstates and analyze the density of states, the spectra, and the momentum distribution functions of the different phases. The results are discussed in the context of superconductivity and ferromagnetism at LaAlO3-SrTiO3 interfaces and superconductors with broken inversion symmetry. PMID- 23934774 TI - Structural and mutational analyses of Aes, an inhibitor of MalT in Escherichia coli. AB - The acyl esterase Aes effectively inhibits the transcriptional activity of MalT the central activator of maltose and maltodextrin utilizing genes in Escherichia coli. To provide better insight into the nature of the interaction between Aes and MalT, we determined two different crystal structures of Aes-in its native form and covalently modified by a phenylmethylsulfonyl moiety at its active site serine. Both structures show distinct space groups and were refined to a resolution of 1.8 A and 2.3 A, respectively. The overall structure of Aes resembles a canonical alpha/beta-hydrolase fold, which is extended by a funnel like cap structure that forms the substrate-binding site. The catalytic triad of Aes, comprising residues Ser165, His292, and Asp262, is located at the bottom of this funnel. Analysis of the crystal-packing contacts of the two different space groups as well as analytical size-exclusion chromatography revealed a homodimeric arrangement of Aes. The Aes dimer adopts an antiparallel contact involving both the hydrolase core and the cap, with its twofold axis perpendicular to the largest dimension of Aes. To identify the surface area of Aes that is responsible for the interaction with MalT, we performed a structure-based alanine-scanning mutagenesis to pinpoint Aes residues that are significantly impaired in MalT inhibition, but still exhibit wild-type expression and enzymatic activity. These residues map to a shallow slightly concave surface patch of Aes at the opposite site of the dimerization interface and indicate the surface area that interacts with MalT. PMID- 23934776 TI - Determination of newly synthesized lipoic acid-niacin dimer in rat plasma by UPLC/electrospray ionization tandem mass spectrometry: assay development, validation and application to a pharmacokinetic study. AB - A simple, sensitive and specific ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed to determine the newly synthesized compound lipoic acid-niacin dimer (N2L) in plasma. Plasma samples were precipitated by methanol using tetrahydropalmatine as internal standard. Chromatographic separation was achieved on an Acquity BEH C18 (2.1 * 50 mm i.d., 1.7 um) column; the mobile phase contains methanol and buffer solution (water with 0.5% formic acid and 10 mmol/L ammonium acetate). Multiple reaction monitoring (m/z 353.9 -> 148.6 for N2L and m/z 356.0 -> 192.0 for internal standard) was performed for detection and quantification. The method was validated to be rapid, specific, accurate and precise over the concentration range of 1-750 ng/mL; N2L was not stable on the bench-top or during freeze-freeze thaw cycles in plasma, but was stable in the stock solution and after preparation in the autosampler for 24 h. The utility of the assay was confirmed by pharmacokinetic study of N2L in rats. PMID- 23934778 TI - Nanosilver-decorated TiO2 nanofibers coated with a SiO2 layer for enhanced light scattering and localized surface plasmons in dye-sensitized solar cells. AB - Enhanced harvesting of visible light is vital to the development of highly efficient dye-sensitized solar cells (DSSCs). Nanosilver-decorated TiO2 nanofibers (Ag@TiO2 NFs) were synthesized by depositing chemically reduced Ag ions onto the surface of electrospun TiO2 nanofibers (TiO2 NFs). The prepared Ag@TiO2 NFs were coated with SiO2 (SiO2@Ag@TiO2 NFs) by using PVP as coupling agent for protecting corrosion of Ag nanoparticle by I(-)/I3(-) solution. The fabricated SiO2@Ag@TiO2 NFs demonstrated a synergistic effect of light scattering and surface plasmons, leading to an enhanced light absorption. Moreover, an anode consisting of SiO2@Ag@TiO2 NFs incorporating TiO2 nanoparticles (NPs) increased light harvesting without substantially sacrificing dye attachment. The power conversion efficiency increased from 6.8 to 8.7 % for a thick film (10 MUm), that is, 28 %. These results suggest that SiO2@Ag@TiO2 NFs are promising materials for enhanced light absorption in dye-sensitized solar cells. PMID- 23934780 TI - Outcomes after endoscopic port surgery for spontaneous intracerebral hematomas. AB - BACKGROUND: Spontaneous intracerebral hemorrhages (ICHs) cause significant morbidity and mortality. Traditional open surgical management strategies offer limited benefit except for the most superficial hemorrhages in select patients. Recent reports suggest that endoscopic approaches may improve outcomes, particularly for deep subcortical hemorrhages. However, the management of these patients remains controversial. We reviewed our experience using endoscopic port surgery to identify characteristics that may predict acceptable outcomes. MATERIALS AND METHODS: We completed a retrospective chart and imaging review of patients who underwent endoscopic port surgery for evacuation of spontaneous ICH at a single center. Data were gathered regarding patient demographics, hemorrhage locations, operative findings, and clinical outcomes. RESULTS: From 2007 to 2011, 18 patients underwent evacuation of spontaneous intracerebral hematomas using an endoscopic port. The mean age in years was 62 years (range, 43-84 years). Six of 18 patients (33%) died before discharge, and 2 others (11%) died after at least 1 month of survival. Of 12 initial survivors, all were discharged to a rehabilitation or nursing facility. Complete hematoma evacuation was achieved in 7 of 18 patients, with the remaining 11 having a partial evacuation. The patients who died (n = 6) before discharge were statistically more likely to have a left sided hemorrhage, partial evacuation, or older age than the survivors; death at least 1 month after evacuation was additionally associated with greater preoperative hematoma volumes. CONCLUSIONS: Our series demonstrates that endoscopic port surgery for acute intracerebral hematoma evacuation has the ability to achieve significant decompression of large and deep-seated hematomas. Patient age, extent of evacuation, laterality, and preoperative hematoma volume appear to influence patient outcome. Most overall outcomes remain poor. Future studies are necessary to determine if surgical evacuation is in fact superior to best medical treatment and if so, to validate, refute, or further identify characteristics that define surgical candidates. PMID- 23934779 TI - Enhancement of oral bioavailability of E804 by self-nanoemulsifying drug delivery system (SNEDDS) in rats. AB - Indirubin and its derivatives have been shown to interrupt the cell cycle by inhibiting cyclin-dependent kinases, explaining their long-time use in traditional Chinese medicine for the treatment of chronic myelocytic leukemia. A potent derivative of indirubin, indirubin-3'-oxime 2,3-dihydroxypropyl ether (E804), has been shown to block the Src-Stat3 and Src-Stat5 signaling pathway in human cancer cells, inducing apoptosis. The anticancer effects of E804, however, cannot be easily examined in vivo because of its poor water solubility and low absorption. The aim of this study was to develop and evaluate a self nanoemulsifying drug delivery system (SNEDDS) containing E804 for enhancing its solubility and bioavailability. Solubility of E804 was determined in various vehicles, and pseudoternary phase diagram was used to evaluate the self emulsifying existence area. The SNEDDS composed of Capmul MCM (oil), Solutol HS 15 (surfactant), and polyethylene glycol 400 (cosurfactant) on the ratio of 20.5:62.5:16 loaded 1.5% of E804. The particle size of droplets was found to be 16.8 and 140 nm, and SNEDDS was stable after freeze-thaw cycles and upon dilution in HCl 0.1 N and pH 7.4 HBSS++. The ability of formulation for absorption enhancement was studied in rats in vivo after oral administration. The results showed that the developed SNEDDS increased the E804 bioavailability 984.23% compared with the aqueous suspension. Our studies for the first time show that the developed SNEDDS can be used as a possible formulation for E804 to improve its solubility and oral bioavailability. PMID- 23934781 TI - Identification of subgroups of schizophrenia patients with changes in either immune or growth factor and hormonal pathways. AB - Schizophrenia is a heterogeneous disorder normally diagnosed using the Diagnostic and Statistical Manual of Mental Disorders criteria. However, these criteria do not necessarily reflect differences in underlying molecular abnormalities of the disorder. Here, we have used multiplexed immunoassay analyses to measure immune molecules, growth factors, and hormones important to schizophrenia in acutely ill antipsychotic-naive patients (n = 180) and matched controls (n = 398). We found that using the resulting molecular profiles, we were capable of separating schizophrenia patients into 2 significantly distinct subgroups with predominant molecular abnormalities in either immune molecules or growth factors and hormones. These molecular profiles were tested using an independent cohort, and this showed the same separation into 2 subgroups. This suggests that distinct abnormalities occur in specific molecular pathways in schizophrenia patients. This may be of relevance for intervention studies that specifically target particular molecular mechanisms and could be a first step to further define the complex schizophrenia syndrome based on molecular profiles. PMID- 23934782 TI - Sparsely populated residue conformations in protein structures: revisiting "experimental" Ramachandran maps. AB - The Ramachandran map clearly delineates the regions of accessible conformational (phi-psi) space for amino acid residues in proteins. Experimental distributions of phi, psi values in high-resolution protein structures, reveal sparsely populated zones within fully allowed regions and distinct clusters in apparently disallowed regions. Conformational space has been divided into 14 distinct bins. Residues adopting these relatively rare conformations are presented and amino acid propensities for these regions are estimated. Inspection of specific examples in a completely "arid", fully allowed region in the top left quadrant establishes that side-chain and backbone interactions may provide the energetic compensation necessary for populating this region of phi-psi space. Asn, Asp, and His residues showed the highest propensities in this region. The two distinct clusters in the bottom right quadrant which are formally disallowed on strict steric considerations correspond to the gamma turn (C7 axial) conformation (Bin 12) and the i + 1 position of Type II' beta turns (Bin 13). Of the 516 non-Gly residues in Bin 13, 384 occupied the i + 1 position of Type II' beta turns. Further examination of these turn segments revealed a high propensity to occur at the N-terminus of helices and as a tight turn in beta hairpins. The beta strand helix motif with the Type II' beta turn as a connecting element was also found in as many as 57 examples. PMID- 23934783 TI - Reassessing buried surface areas in protein-protein complexes. AB - The buried surface area (BSA), which measures the size of the interface in a protein-protein complex may differ from the accessible surface area (ASA) lost upon association (which we call DSA), if conformation changes take place. To evaluate the DSA, we measure the ASA of the interface atoms in the bound and unbound states of the components of 144 protein-protein complexes taken from the Protein-Protein Interaction Affinity Database of Kastritis et al. (2011). We observe differences exceeding 20%, and a systematic bias in the distribution. On average, the ASA calculated in the bound state of the components is 3.3% greater than in their unbound state, and the BSA, 7% greater than the DSA. The bias is observed even in complexes where the conformation changes are small. An examination of the bound and unbound structures points to a possible origin: local movements optimize contacts with the other component at the cost of internal contacts, and presumably also the binding free energy. PMID- 23934784 TI - Plasma kinetic of ingested essential amino acids in healthy elderly people. AB - The purpose of this study was to investigate whether the documented difficulties of physiological amounts of essential amino acids (EAAs) (7 g) to induce protein synthesis could be reflected in a simple method adaptable to a clinical setting. Sixteen healthy individuals, nine elderly (75.3 +/- 3.5 years), and seven young (28 +/- 2.5 years) were enrolled in the study. Five minutes before EAA ingestion (baseline) and 20, 40, 60, 90, 120, 180 min after EAA ingestion, venous blood samples were taken from the ante-cubital vein to determine the concentrations of EAAs (MUmol/L). The results show that plasma EAA increases were significantly higher in old than in young persons at the considered time points (from p < 0.004 to p < 0.001) (unpaired Student t test). However, the velocity rate of the increasing was slower in old subjects than in young group. The study shows that EAAs ingestion by old subject is associated with reduced muscle EAA uptake. PMID- 23934785 TI - Possible s+/--wave pairing evidenced by midgap surface bound states in Fe pnictide superconductors. AB - A phenomenological theory of tunneling spectroscopy for Fe-pnictide superconductors is developed by taking into consideration asymmetric interface scattering between particle and holes. It is shown that, consistent with anti phase s(+/-)-wave pairing, appreciable zero-energy surface bound states exist on the [100] surface of Fe-pnictide superconductors. However, in contrast to the [110] bound states in d-wave cuprate superconductors, these bound states arise as a result of non-conservation of momentum perpendicular to the interface for tunneling electrons and the s(+/-) pairing, and hence they can only exist in a small window (~ +/- 6 degrees ) in the orientation of edges near the [100] direction. Our results explain why a zero-bias conductance peak is often observed in tunneling spectroscopy and why, when it disappears, two coherent peaks show up. These results provide unambiguous signals to test for possible s(+/-)-wave pairing in Fe-pnictide superconductors. PMID- 23934786 TI - Development of structural complexity by liquid-crystal self-assembly. AB - Since the discovery of the liquid-crystalline state of matter 125 years ago, this field has developed into a scientific area with many facets. This Review presents recent developments in the molecular design and self-assembly of liquid crystals. The focus is on new exciting soft-matter structures distinct from the usually observed nematic, smectic, and columnar phases. These new structures have enhanced complexity, including multicompartment and cellular structures, periodic and quasiperiodic arrays of spheres, and new emergent properties, such as ferroelctricity and spontaneous achiral symmetry-breaking. Comparisons are made with developments in related fields, such as self-assembled monolayers, multiblock copolymers, and nanoparticle arrays. Measures of structural complexity used herein are the size of the lattice, the number of distinct compartments, the dimensionality, and the logic depth of the resulting supramolecular structures. PMID- 23934787 TI - Alkaline earth metallocenes coordinated with ester pendants: synthesis, structural characterization, and application in metathesis reactions. AB - A variety of ester-substituted cyclopentadiene derivatives have been synthesized by one-pot reactions of 1,4-dilithio-1,3-butadienes, CO, and acid chlorides. Direct deprotonation of the ester-substituted cyclopentadienes with Ae[N(SiMe3 )2 ]2 (Ae=Ca, Sr, Ba) efficiently generated members of a new class of heavier alkaline earth (Ca, Sr, Ba) metallocenes in good to excellent yields. Single crystal X-ray structural analysis demonstrated that these heavier alkaline earth metallocenes incorporated two intramolecularly coordinated ester pendants and multiply-substituted cyclopentadienyl ligands. The corresponding transition metal metallocenes, such as ferrocene derivatives and half-sandwich cyclopentadienyl tricarbonylrhenium complexes, could be generated highly efficiently by metathesis reactions. The multiply-substituted cyclopentadiene ligands bearing an ester pendant, and the corresponding heavier alkaline earth and transition-metal metallocenes, may have further applications in coordination chemistry, organometallic chemistry, and organic synthesis. PMID- 23934788 TI - Dearomatizing conjugate addition to quinolinyl amidines for the synthesis of dehaloperophoramidine through tandem arylation and allylation. PMID- 23934789 TI - The impact of blood on liver metabolite profiling - a combined metabolomic and proteomic approach. AB - Metabolomics has entered the well-established omic sciences as it is an indispensable information resource to achieve a global picture of biological systems. The aim of the present study was to estimate the influence of blood removal from mice liver as part of sample preparation for metabolomic and proteomic studies. For this purpose, perfused mice liver tissue (i.e. with blood removed) and unperfused mice liver tissue (i.e. containing blood) were compared by two-dimensional gas chromatography time of flight mass spectrometry (GC * GC TOFMS) for the metabolomic part, and by liquid chromatography tandem mass spectrometry (LC-MS/MS) for the proteomic part. Our data showed significant differences between the unperfused and perfused liver tissue samples. Furthermore, we also observed an overlap of blood and tissue metabolite profiles in our data, suggesting that the perfusion of liver tissue prior to analysis is beneficial for an accurate metabolic profile of this organ. PMID- 23934790 TI - Foetal and postnatal equine articular cartilage development: magnetic resonance imaging and polarised light microscopy. AB - Adult articular cartilage (AC) has a well described multizonal collagen structure. Knowledge of foetal AC organisation and development may provide a prototype for cartilage repair strategies, and improve understanding of structural changes in developmental diseases such as osteochondrosis (OC). The objective of this study was to describe normal development of the spatial architecture of the collagen network of equine AC using 1.5 T magnetic resonance imaging (MRI) and polarised light microscopy (PLM), at sites employed for cartilage repair studies or susceptible to OC. T2-weighted fast-spin echo (FSE) sequences and PLM assessment were performed on distal femoral epiphyses of equine foetuses, foals and adults. Both MRI and PLM revealed an early progressive collagen network zonal organisation of the femoral epiphyses, beginning at 4 months of gestation. PLM revealed that the collagen network of equine foetal AC prior to birth was already organised into an evident anisotropic layered structure that included the appearance of a dense tangential zone in the superficial AC in the youngest specimens, with the progressive development of an underlying transitional zone. A third, increasingly birefringent, radial layer developed in the AC from 6 months of gestation. Four laminae were observed on the MR images in the last third of gestation. These included not only the AC but also the superficial growth plate of the epiphysis. These findings provide novel data on normal equine foetal cartilage collagen development, and may serve as a template for cartilage repair studies in this species or a model for developmental studies of OC. PMID- 23934792 TI - Angle and frequency dependence of self-energy from spin fluctuation mediated d wave pairing for high temperature superconductors. AB - We investigated the characteristics of spin fluctuation mediated superconductivity employing the Eliashberg formalism. The effective interaction between electrons was modeled in terms of the spin susceptibility measured by inelastic neutron scattering experiments on single crystal La(2-x)Sr(x)CuO4 superconductors. The diagonal self-energy and off-diagonal self-energy were calculated by solving the coupled Eliashberg equation self-consistently for the chosen spin susceptibility and tight-binding dispersion of electrons. The full momentum and frequency dependence of the self-energy is presented for optimally doped, overdoped, and underdoped LSCO cuprates in a superconductive state. These results may be compared with the experimentally deduced self-energy from ARPES experiments. PMID- 23934791 TI - Protein models: the Grand Challenge of protein docking. AB - Characterization of life processes at the molecular level requires structural details of protein-protein interactions (PPIs). The number of experimentally determined protein structures accounts only for a fraction of known proteins. This gap has to be bridged by modeling, typically using experimentally determined structures as templates to model related proteins. The fraction of experimentally determined PPI structures is even smaller than that for the individual proteins, due to a larger number of interactions than the number of individual proteins, and a greater difficulty of crystallizing protein-protein complexes. The approaches to structural modeling of PPI (docking) often have to rely on modeled structures of the interactors, especially in the case of large PPI networks. Structures of modeled proteins are typically less accurate than the ones determined by X-ray crystallography or nuclear magnetic resonance. Thus the utility of approaches to dock these structures should be assessed by thorough benchmarking, specifically designed for protein models. To be credible, such benchmarking has to be based on carefully curated sets of structures with levels of distortion typical for modeled proteins. This article presents such a suite of models built for the benchmark set of the X-ray structures from the Dockground resource (http://dockground.bioinformatics.ku.edu) by a combination of homology modeling and Nudged Elastic Band method. For each monomer, six models were generated with predefined C(alpha) root mean square deviation from the native structure (1, 2, ..., 6 A). The sets and the accompanying data provide a comprehensive resource for the development of docking methodology for modeled proteins. PMID- 23934794 TI - New opportunities for immobilization of enzymes. AB - In this chapter, as a general introduction, we summarize our personal point of view on immobilization technique in order to prepare optimal and cost-effective biocatalysts. Special attention is paid to the improvement of enzyme properties via immobilization techniques. From the stabilization by multipoint covalent attachment to the generation of hydrophilic environments via post-immobilization techniques are here discussed. Immobilization techniques, a necessary tool to reuse enzyme, have to be simple and, if possible, may become a very powerful tool to greatly improve properties of every kind of enzymes: monomeric, multimeric, stable, labile, poorly selective, etc. PMID- 23934793 TI - Crystal structure of the Alpha subunit PAS domain from soluble guanylyl cyclase. AB - Soluble guanylate cyclase (sGC) is a heterodimeric heme protein of ~ 150 kDa and the primary nitric oxide receptor. Binding of NO stimulates cyclase activity, leading to regulation of cardiovascular physiology and providing attractive opportunities for drug discovery. How sGC is stimulated and where candidate drugs bind remains unknown. The alpha and beta sGC chains are each composed of Heme Nitric Oxide Oxygen (H-NOX), Per-ARNT-Sim (PAS), coiled-coil and cyclase domains. Here, we present the crystal structure of the alpha1 PAS domain to 1.8 A resolution. The structure reveals the binding surfaces of importance to heterodimer function, particularly with respect to regulating NO binding to heme in the beta1 H-NOX domain. It also reveals a small internal cavity that may serve to bind ligands or participate in signal transduction. PMID- 23934796 TI - Glutaraldehyde-mediated protein immobilization. AB - In this chapter, we describe different approaches for the utilization of glutaraldehyde in protein immobilization. First, we focus on the covalent attachment of proteins to glutaraldehyde-activated matrixes. We describe conditions for the synthesis of such supports and provide an example of the immobilization and stabilization of fructosyltransferase. We also describe how glutaraldehyde may be used for the cross-linking of protein-protein aggregates and protein adsorbed onto amino-activated matrixes. In these cases, glutaraldehyde bridges either two lysine groups from different proteic molecules or a lysine from the protein structure and an amine group from the support. Examples of cross-linking are given for the immobilization of DAAO on different amino-activated supports. PMID- 23934795 TI - Immobilization of enzymes: a literature survey. AB - The term immobilized enzymes refers to "enzymes physically confined or localized in a certain defined region of space with retention of their catalytic activities, and which can be used repeatedly and continuously." Immobilized enzymes are currently the subject of considerable interest because of their advantages over soluble enzymes. In addition to their use in industrial processes, the immobilization techniques are the basis for making a number of biotechnology products with application in diagnostics, bioaffinity chromatography, and biosensors. At the beginning, only immobilized single enzymes were used, after 1970s more complex systems including two-enzyme reactions with cofactor regeneration and living cells were developed. The enzymes can be attached to the support by interactions ranging from reversible physical adsorption and ionic linkages to stable covalent bonds. Although the choice of the most appropriate immobilization technique depends on the nature of the enzyme and the carrier, in the last years the immobilization technology has increasingly become a matter of rational design. As a consequence of enzyme immobilization, some properties such as catalytic activity or thermal stability become altered. These effects have been demonstrated and exploited. The concept of stabilization has been an important driving force for immobilizing enzymes. Moreover, true stabilization at the molecular level has been demonstrated, e.g., proteins immobilized through multipoint covalent binding. PMID- 23934797 TI - Immobilization of enzymes on monofunctional and heterofunctional epoxy-activated supports. AB - The immobilization of proteins on epoxy activated supports is discussed in this chapter. Immobilization on epoxy supports is carried out as a two-step mechanism: in the first step the adsorption of the protein is promoted and in the second step the intramolecular covalent linkage among epoxy groups and nucleophiles of the protein is produced. Based on this mechanism of the need of a first adsorption of the protein on the support, different epoxy supports are described. The different supports are able to immobilize proteins through different orientations being obtained catalysts with different properties of activity, stability, and selectivity. PMID- 23934798 TI - Stabilization of enzymes by multipoint covalent immobilization on supports activated with glyoxyl groups. AB - Stabilization of enzymes via immobilization techniques is a valuable approach in order to convert a necessary protocol (immobilization) into a very interesting tool to improve key enzyme properties (stabilization). Multipoint covalent attachment of each immobilized enzyme molecule may promote a very interesting stabilizing effect. The relative distances among all enzyme residues involved in immobilization has to remain unaltered during any conformational change induced by any distorting agent. Amino groups are very interesting nucleophiles placed on protein surfaces. The immobilization of enzyme through the region having the highest amount of amino groups (Lys residues) is key for a successful stabilization. Glyoxyl groups are small aliphatic aldehydes that form very unstable Schiff's bases with amino groups and they do not seem to be useful for enzyme immobilization at neutral pH. However, under alkaline conditions, glyoxyl supports are able to immobilize enzymes via a first multipoint covalent immobilization through the region having the highest amount of Lysine groups. Activation of supports with a high surface density of glyoxyl groups and the performance of very intense enzyme-support multipoint covalent attachments are here described. PMID- 23934799 TI - Oriented covalent immobilization of enzymes on heterofunctional-glyoxyl supports. AB - Novel heterofunctional glyoxyl-agarose supports were prepared. These supports contained the maximal concentration of glyoxyl groups to promote maximization of covalent immobilization and groups' capability to adsorb proteins by various mechanisms (e.g., ionic exchange, metal-chelate formation). Immobilization on various supports makes it possible to orientate and rigidify an enzyme in various regions of its surface. The use of different heterofunctional supports allowed for obtaining catalysts with different activity, stability, and selectivity properties. PMID- 23934800 TI - Reversible covalent immobilization of enzymes via disulfide bonds. AB - This enzyme immobilization approach involves the formation of disulfide (-S-S-) bonds with the support. Thus, enzymes bearing exposed nonessential thiol (SH) groups can be immobilized onto thiol-reactive supports provided with reactive disulfides or disulfide oxides under mild conditions. The great potential advantage of this approach is the reversibility of the bonds formed between the activated solid phase and the thiol-enzyme, because the bound protein can be released with an excess of a low-molecular-weight thiol (e.g., dithiothreitol [DTT]). This is of particular interest when the enzyme degrades much faster than the adsorbent, which can be reloaded afterwards. The possibility of reusing the polymeric support after inactivation of the enzyme may be of interest for the practical use of immobilized enzymes in large-scale processes in industry, where their use has often been hampered by the high cost of the support material. Disulfide oxides (thiolsulfinate or thiolsulfonate groups) can be introduced onto a wide variety of support materials with different degrees of porosity and with different mechanical resistances. Procedures are given for the preparation of thiol-activated solid phases and the covalent attachment of thiol-enzymes to the support material via disulfide bonds. The possibility of reusing the polymeric support is also shown. PMID- 23934801 TI - Immobilization of Candida rugosa lipase on superparamagnetic Fe3O4 nanoparticles for biocatalysis in low-water media. AB - A simple immobilization method for Candida rugosa lipase on superparamagnetic Fe3O4 nanoparticles is described. The Fe3O4 nanoparticles were coated with PEI and Candida rugosa lipase was adsorbed on these particles via electrostatic interactions. The immobilization resulted in marginal simultaneous purification. However, the immobilized preparation showed 110* higher transesterification activity in low-water media. It was also efficient in kinetic resolution of (+/-) 1-phenylethanol with eep of 99 % and E = 412 within 24 h. PMID- 23934802 TI - Immobilization of enzymes by bioaffinity layering. AB - Bioaffinity immobilization exploits the affinity of the enzyme to a macro (affinity ligand). Such a macro-(affinity ligand) could be a lectin, a water soluble polymer, or a bioconjugate of a water-soluble polymer and the appropriate affinity ligand. Successive layering of the enzyme and the macro-(affinity ligand) on a matrix allows deposition of a large amount of enzyme activity on a small surface. Illustrative protocols show affinity layering of a pectinase and horseradish peroxidase on Concanavalin A-agarose and Concanavalin A-Sephadex matrices, respectively. PMID- 23934803 TI - Immobilization of enzymes on magnetic beads through affinity interactions. AB - The development of enzyme immobilization techniques that will not affect catalytic activity and conformation is an important research task. Affinity tags that are present or added at a specific position far from the active site in the structure of the native enzyme could be used to create strong affinity bonds between the protein structure and a surface functionalized with the complementary affinity ligand. These immobilization techniques are based on affinity interactions between biotin and (strept)avidin molecules, lectins and sugars, or metal chelate and histidine tag. Recent developments involve immobilization of tagged enzymes onto magnetic nanoparticles. These supports can improve the performance of immobilized biomolecules in analytical assay because magnetic beads provide a relative large numbers of binding sites for biochemical reactions resulting in faster assay kinetics. This chapter describes immobilization procedures of tagged enzymes onto various magnetic beads. PMID- 23934804 TI - Tips for the functionalization of nanoparticles with antibodies. AB - Multiple antibody immobilization methodologies have been developed for several applications including affinity chromatography, immunosensing, and drug delivery. Most of them have been carried out without considering the orientation of the antigen binding site of the antibody, or after the chemical modification of the antibody. An efficient immobilization to improve the biological activity of the antibody is one of the key fundamental issues to pursue. A simple and effective methodology for well-oriented covalently immobilization of antibodies on nanoparticles is reported in this chapter. PMID- 23934805 TI - Design and characterization of functional nanoparticles for enhanced bio performance. AB - Recent years have witnessed the rapid development of inorganic nanomaterials for medical applications. At present, nanomedicines-nanoparticles (NPs) destined for therapy or diagnosis purposes-can be found in a number of medical applications including therapeutics (either self-therapeutics or drug carriers) and diagnosis agents (e.g., contrast agents for imaging or transducers in biosensors). Pushing the limits of nanotechnology towards enhanced nanomedicines will surely help to reduce side effects of traditional treatments and to achieve earlier diagnosis. As for all medical approaches, the ultimate aim of nanomedicine is improving the well-being of patients. However, mixing nanomaterials with biological components such as fluids, living cells, and tissues does not always result as expected. The interplay between engineered nanomaterials and biological components is influenced by complex interactions which make predicting their biological fate and performance a nontrivial issue. Indeed, the structural integrity and the a priori function of nanomaterials can change dramatically due to unwanted nano-bio interactions. For medical applications in particular, any new nanomaterial has to be exhaustively studied when it comes in close contact with biological fluids and living cells or organisms. The motivation is clear: first, many unwanted effects can be turned on unexpectedly (e.g., leakage of toxic ions, ROS production, and sequestration by the phagocytic system) and second, their purpose as therapeutic or diagnostic agent can be lost as they are transferred to the desired working environment. This chapter aims to highlight key factors that should be taken into account when choosing and characterizing such functional materials for a given application, with a view to minimizing unwanted nano-bio interactions, rather than providing an exhaustive compilation of recent work. We hope that both early stage and experienced researchers will find it valuable for designing nanoparticles for enhanced bio-performance. PMID- 23934806 TI - Immobilization of enzymes on ethynyl-modified electrodes via click chemistry. AB - This paper describes a novel, simple, and versatile protocol for covalent immobilization of enzyme on electrode. The immobilization method is based on the combination of diazonium salt electrografting and click chemistry. The ethynyl terminated monolayers are obtained by diazonium salt electrografting, then, in the presence of copper (I) catalyst, the ethynyl modified surfaces reacts efficiently and rapidly with enzyme bearing an azide function (azido-enzyme), thus forming a covalent 1,2,3-triazole linkage by means of click chemistry. The ethynyl-terminated film preserves the activity of the immobilized enzyme. The click chemistry along with binary film of diazonium salts offers a variety of good characteristics including high sensitivity, good repeatability and reusability, rapid response and long term stability of the system. Thus, because of the chemoselective reactivity and quantitative yield of the click reaction, an ethynyl-terminated monolayer can be treated as a general platform for obtaining reliable coverage of a wide range of azido-terminated species of interest for various sensing applications. PMID- 23934807 TI - Modification of carbon nanotube electrodes with 1-pyrenebutanoic acid, succinimidyl ester for enhanced bioelectrocatalysis. AB - Conductive materials functionalized with redox enzymes provide bioelectronic architectures with application to biological fuel cells and biosensors. Effective electron transfer between the enzyme (biocatalyst) and the conductive materials is imperative for function. Various nanostructured carbon materials are common electrode choices for these applications as both the materials' inherent conductivity and physical integrity aids optimal performance. The following chapter presents a method for the use of carbon nanotube buckypaper as a conductive architecture suitable for biocatalyst functionalization. In order to securely attach the biocatalyst to the carbon nanotube surface, the conductive buckypaper is modified with the heterobifunctional cross-linker, 1-pyrenebutanoic acid, succinimidyl ester. The technique effectively tethers the enzyme to the carbon nanotube which enhances bioelectrocatalysis, preserves the conductive nature of the carbon surface, and facilities direct electron transfer between the catalyst and material interface. The approach is demonstrated using phenol oxidase (laccase) and pyrroloquinoline quinone-dependent glucose dehydrogenase PQQ-GDH, as representative biocatalysts. PMID- 23934808 TI - Enzyme immobilization by entrapment within a gel network. AB - This chapter provides a detailed description of the three immobilization methods based on the biomolecules entrapment into polymer matrices. The poly (vinyl alcohol) bearing styrylpyridinium groups (PVA-SbQ), a soluble pre-polymer bearing photo-cross-linkable groups, has widely been used to entrap enzymes, and several bioassays based on this immobilization matrix have been reported. Similarly, immobilization of enzymes via sol-gel has been described in this chapter. Sol-gel process is based on the ability to form solid metal or semi-metal oxides via the aqueous process of hydrolytically labile precursors. Enzymes can also be entrapped in an agarose gel. Contrary to synthetic polymers such as polyacrylamide, this matrix is biocompatible, non-toxic, provides natural microenvironment to the enzyme and also gives sufficient accessibility to electrons to shuttle between the enzyme and the electrode. The entrapment strategies are easy-to-perform, and permit to deposit enzyme, mediators, and additives in the same sensing layer. Moreover, the activity of the enzyme is preserved during the immobilization process, as biological element is not modified. Biosensors based on physically entrapped enzymes are often characterized by increased operational and storage stability. PMID- 23934809 TI - Practical protocols for lipase immobilization via sol-gel techniques. AB - Lipases can be efficiently entrapped in the pores of hydrophobic silicates by a simple and cheap sol-gel process in which a mixture of a hydrophobic alkylsilane RSi(OCH3)3 and Si(OCH3)4 is hydrolyzed under basic conditions in the presence of the enzyme. Additives such as isopropanol, polyvinyl alcohol, cyclodextrins, ionic liquids or surfactants enhance the efficiency of this type of lipase immobilization. The main area of application of these heterogeneous biocatalysts concerns esterification or transesterification in organic solvents, ionic liquids, or supercritical carbon dioxide. Rate enhancements (relative to the traditional use of lipase powders) of several orders of magnitude have been observed, in addition to higher thermal stability. The lipase-immobilizates are particularly useful in the kinetic resolution of chiral esters, enantioselectivity often being higher than what is observed when using the commercial forms of these lipases (powder or classical immobilizates). Thus, due to the low price of sol-gel entrapment, the excellent performance of the lipase immobilizates, and the ready recyclability, the method is industrially viable. PMID- 23934811 TI - High activity preparations of lipases and proteases for catalysis in low water containing organic solvents and ionic liquids. AB - Simple precipitation of enzymes has shown impressive catalytic efficiencies in organic solvents. In asmuch as these can be recovered after the reaction, these can be viewed as immobilized preparations just like more extensively used cross linked enzyme aggregates (CLEAs). This chapter describes three protocols which use these enzyme precipitated and rinsed with propanol/some other appropriate organic solvent. The first two protocols show their applications in ionic liquids for a transesterification reaction and a kinetic resolution. The third protocol presumably incorporates an "imprinting" effect so that the precipitates are now able to efficiently catalyze transesterification of tributyrin with tertiary alcohols. PMID- 23934810 TI - Improving lipase activity by immobilization and post-immobilization strategies. AB - One important parameter for the application of lipase catalysts in chemical industries is the specific activity displayed towards natural or unnatural substrates. Different strategies to enhance the lipase activity have been described. The immobilization of lipases on hydrophobic supports by interfacial adsorption at low ionic strength permitted the hyper-activation of these enzymes by fixing the open conformation of the lipase on the hydrophobic support. Improvements of activity from 1.2- up to 20-fold with respect to the initial one have been observed for lipases from different sources. A second strategy was based on the presence of additives, in particular surfactants or ionic liquids, with hydrophobic character to enhance the activity of lipases immobilized on macroporous supports up to eightfold and even more than 100-fold in some cases for soluble lipases. Finally, a third strategy to improve the activity in immobilized lipases was based on a site-directed chemical modification of the protein by glycosylation on the enzyme N-terminal group or on a unique reactive cysteine of the enzyme by disulfide exchange using different tailor-made disulfide activated activated polymers. PMID- 23934812 TI - Biomedical applications of immobilized enzymes: an update. AB - Immobilized enzymes have been widely studied during the last few decades. Biocatalyst systems may work as biosensors or may be used for the treatment of different diseases. This chapter presents different attempts to immobilize enzymes in the biomedical field, particularly the use of prolidase and superoxide dismutase as two examples of this approach. Although this chapter focuses on liposomes and nanoparticles for the entrapment of these enzymes, the methods detailed here could be adapted for the immobilization of other enzymes with therapeutic purposes. PMID- 23934813 TI - Immobilization of whole cells by chemical vapor deposition of silica. AB - Effective entrapment of whole bacterial cells onto solid-phase materials can significantly improve bioprocessing and other biotechnology applications. Cell immobilization allows integration of biocatalysts in a manner that maintains long term cell viability and typically enhances process output. A wide variety of functionalized materials have been explored for microbial cell immobilization, and specific advantages and limitations were identified. The method described here is a simple, versatile, and scalable one-step process for the chemical vapor deposition of silica to encapsulate and stabilize viable, whole bacterial cells. The immobilized bacterial population is prepared and captured at a predefined physiological state so as to affix bacteria with a selected metabolic or catalytic capability to compatible materials and surfaces. Immobilization of Shewanella oneidensis to carbon electrodes and immobilization of Acinetobacter venetianus to adsorbent mats are described as model systems. PMID- 23934814 TI - Encapsulation of cells in alginate gels. AB - Cell microencapsulation is based on the immobilization of cells for continuous release of therapeutics. This approach has been tested in the treatment of many diseases and several clinical trials have been performed. Factors such as the choice of cells to be encapsulated, the biomaterial used, and the procedure for carrying out the capsules are important issues when implementing this technology.This book chapter makes a comprehensive description of alginate, the most frequently employed biomaterial, passing by its structure, the extraction and treatment, and finishing with the process of gelation. It also describes the various modifications that can be carried out to allow the interaction between the alginate and the integrin receptors of encapsulated cells. The main microencapsulation technologies are presented as well as how 100 MUm alginate Poly-L-Lysine-alginate microcapsules can be fabricated with Flow-focusing technology. PMID- 23934815 TI - Microalgal immobilization methods. AB - In this review, methods for the most common microalgal immobilization procedures are gathered and described. Passive (due to natural adherence of cells to surfaces) and active immobilization methods should be distinguished. Among active immobilization methods, calcium alginate entrapment is the most widely used method if living cells are intended to be immobilized, due to the chemical, optical, and mechanical characteristics of this substance. Immobilization in synthetic foams, immobilization in agar and carrageenan as well as immobilization in silica-based matrix or filters are also discussed and described. Finally, some considerations on the use of flocculation for microalgae are mentioned. PMID- 23934816 TI - Therapeutic applications of encapsulated cells. AB - The synergy of some promising advances in the fields of cell therapy and biomaterials together with improvements in the fabrication of more refined and tailored microcapsules for drug delivery have triggered the progress of cell encapsulation technology. Cell microencapsulation involves immobilizing the transplanted cells within a biocompatible scaffold surrounded by a membrane in attempt to isolate the cells from the host immune attack and enhance or prolong their function in vivo. This technology represents one strategy which aims to overcome the present difficulties related to local and systemic controlled release of drugs and growth factors as well as to organ graft rejection and thus the requirements for use of immunomodulatory protocols or immunosuppressive drugs. This chapter gives an overview of the current situation of cell encapsulation technology as a controlled drug delivery system, and the essential requirements of the technology, some of the therapeutic applications, the challenges, and the future directions under investigation are highlighted. PMID- 23934817 TI - Whole cell entrapment techniques. AB - Microbial whole cells are efficient, ecological, and low-cost catalysts that have been successfully applied in the pharmaceutical, environmental, and alimentary industries, among others. Microorganism immobilization is a good way to carry out the bioprocess under preparative conditions. The main advantages of this methodology lie in their high operational stability, easy upstream separation and bioprocess scale-up feasibility. Cell entrapment is the most widely used technique for whole cell immobilization. This technique-in which the cells are included within a rigid network-is porous enough to allow the diffusion of substrates and products, protects the selected microorganism from the reaction medium, and has high immobilization efficiency (100 % in most cases). PMID- 23934818 TI - Rapid access to dibenzohelicenes and their functionalized derivatives. AB - Spiraling up: Easy access to dibenzo[5]-, dibenzo[6]-, and dibenzo[7]helicenes as well as their functionalized derivatives includes Sonogashira and Suzuki-Miyaura couplings, desilylation, and [2+2+2] alkyne cycloisomerization. The simplicity of this non-photochemical approach combined with the potential for helicity control favors dibenzohelicenes over the parent helicenes for practical applications. PMID- 23934819 TI - Neurocognitive pattern analysis reveals classificatory hierarchy of attention deficits in schizophrenia. AB - Attention deficits, among other cognitive deficits, are frequently observed in schizophrenia. Although valid and reliable neurocognitive tasks have been established to assess attention deficits in schizophrenia, the hierarchical value of those tests as diagnostic discriminants on a single-subject level remains unclear. Thus, much research is devoted to attention deficits that are unlikely to be translated into clinical practice. On the other hand, a clear hierarchy of attention deficits in schizophrenia could considerably aid diagnostic decisions and may prove beneficial for longitudinal monitoring of therapeutic advances. To propose a diagnostic hierarchy of attention deficits in schizophrenia, we investigated several facets of attention in 86 schizophrenia patients and 86 healthy controls using a set of established attention tests. We applied state-of the-art machine learning algorithms to determine attentive test variables that enable an automated differentiation between schizophrenia patients and healthy controls. After feature preranking, hypothesis building, and hypothesis validation, the polynomial support vector machine classifier achieved a classification accuracy of 90.70% +/- 2.9% using psychomotor speed and 3 different attention parameters derived from sustained and divided attention tasks. Our study proposes, to the best of our knowledge, the first hierarchy of attention deficits in schizophrenia by identifying the most discriminative attention parameters among a variety of attention deficits found in schizophrenia patients. Our results offer a starting point for hierarchy building of schizophrenia-associated attention deficits and contribute to translating these concepts into diagnostic and therapeutic practice on a single-subject level. PMID- 23934820 TI - Torsional dynamics of thioflavin T in room-temperature ionic liquids: an effect of heterogeneity of the medium. AB - The ultrafast excited-state dynamics of a fibril binding dye, thioflavin T (ThT), has been studied in two room-temperature ionic liquids (RTILs): 1-Butyl-1 methylpyrrolidinium bis(trifluoromethylsulfonyl)imide and methyltrioctylammonium bis(trifluoromethylsulfonyl)imide. Previously, in most studies, it was observed that the excited-state dynamics of the ThT dye were dependent on the viscosity of the medium. In our study, by using RTILs, we have demonstrated that the excited state dynamics of ThT are not only viscosity dependent, but also dependent on the heterogeneous nature of the medium. The effect of structural heterogeneity present in neat RTILs on the excited-state dynamics of ThT was observed. For both RTILs, excitation wavelength dependency on the emission properties of ThT was observed. PMID- 23934821 TI - Air-stable, dinuclear and tetranuclear sigma,pi-acetylide gold(I) complexes and their catalytic implications. AB - Two for one gold: Factors governing the formation of isolable digold(I) sigma,pi acetylide complexes are given (see scheme), indicating the general tendency of phosphine-Au(I) precatalysts to form this type of complexes, which are involved as reaction intermediates in gold(I)-catalyzed reactions. Mechanistic insights into the intermolecular hydroamination of aniline and terminal alkynes catalyzed by gold(I) have shown the role of a fluxional, cationic sigma,pi-digold alkynide complex as one of the intermediates in the formation of imines. PMID- 23934822 TI - Reproducibility of choroidal thickness measurements in healthy Turkish subjects. AB - PURPOSE: To assess intraobserver and interobserver reproducibility of the measurement of choroidal thickness by using enhanced depth imaging optical coherence tomography (EDI-OCT). METHODS: A prospective, cross-sectional study was performed at Gazi University Ophthalmology Department. The macular areas of the right eyes of 110 healthy volunteers with no ophthalmic or systemic disease were recruited. Choroidal thickness was measured at the fovea and at 1000-um intervals from the foveal center in both temporal and nasal directions. Each examiner measured choroidal thickness 30 days after the first measurement to assess intraobserver variability. Interobserver and intraobserver reproducibility were described by intraclass correlation coefficient (ICC) and coefficient of variation (CV). RESULTS: The mean age was 44.0 +/- 14.7 years (range 18-70 years). The mean choroidal thickness at the fovea was 315.5 +/- 78.6. All the parameters evaluated were highly reproducible. Intraobserver CV of choroidal thickness measurements ranged from 24.76% to 35.74%, and the CV of subfoveal choroidal thickness was 24.92. The intraobserver and interobserver intraclass correlation coefficient was greater than 0.90 for all the parameters. Repeatability was slightly better at locations not exceeding 400 um. CONCLUSIONS: Choroidal thickness measurements obtained by EDI-OCT showed good repeatability for healthy Turkish subjects; EDI-OCT examinations of choroid are reliable in healthy eyes. PMID- 23934823 TI - Monthly intravitreal bevacizumab for macular edema after iodine-125 plaque radiotherapy of uveal melanoma. AB - PURPOSE: To examine the efficacy of monthly injections of intravitreal bevacizumab (IVB) for macular edema after iodine-125 plaque radiotherapy of uveal melanoma. METHODS: We studied 36 patients with macular edema after plaque radiotherapy of uveal melanoma in this noncomparative, interventional case series. All eyes were treated with 4 monthly injections of IVB. Central macular thickness (CMT) and best-corrected visual acuity (BCVA) were measured before each injection and 4-6 months after the first injection. The main outcome measures were change in CMT and BCVA. RESULTS: At 4-6 months following the first IVB, 20 eyes (56%) had decreased CMT, 11 eyes (31%) had stable CMT, and 5 eyes (14%) had increased CMT. The mean change in CMT and the mean percent change in CMT at 4-6 months compared to baseline were -91 um (-20%) in all eyes, -174 um (-37%) in the group with decreased macular thickness, -14 um (-3%) in the group with stable macular thickness, and +69 um (+17%) in the group with increased macular thickness. At 4-6 months, 15 eyes (42%) had increased BCVA, 16 eyes (44%) had stable BCVA, and 5 eyes (14%) had decreased BCVA. An increase in CMT was seen between the fourth monthly IVB injection and the final evaluation at 4-6 months after the first injection in all 3 groups of our study. CONCLUSIONS: At 4-6 months following the first injection, 4 monthly injections of IVB in eyes with macular edema after plaque radiotherapy of uveal melanoma decreased macular edema in 56% and improved BCVA in 42% of the treated eyes. PMID- 23934824 TI - Intraocular pressure elevation after vitrectomy for various vitreoretinal disorders. AB - PURPOSE: To determine the incidence of and risk factors for intraocular pressure (IOP) elevation in the immediate postoperative period after vitrectomy for various vitreoretinal disorders. METHODS: A prospective study was performed in 228 consecutive patients with various vitreoretinal disorders. The IOP was measured before surgery, at the end of surgery, and at 5 hours and 1 day after surgery using Tono-Pen XL. The IOP at the end of surgery was adjusted to 15.0 +/- 2.0 mm Hg. RESULTS: Intraocular pressure elevation (>25 mm Hg) was found in 55 (24.1%) and 52 (22.8%) patients at 5 hours and 1 day postoperatively, respectively. The IOP at 5 hours was significantly lower in patients with macular hole (MH) than in those with diabetic macular edema, proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy, or rhegmatogenous retinal detachment (RD). The IOP at 1 day was significantly higher in patients with PDR and RD than in those with MH and epiretinal membrane. Multiple regression analysis revealed that IOP at 5 hours postoperatively had a significant correlation with the number of laser photocoagulation, preoperative IOP, combined cataract surgery, and 20-gauge vitrectomy. The IOP at 1 day postoperatively was significantly associated with these 4 parameters as well as the severity of postoperative vitreous hemorrhage and use of expanding gas tamponade. CONCLUSIONS: Intraocular pressure elevation was found in approximately one quarter of cases within 1 day following vitrectomy. The risk factors for IOP elevation included number of laser photocoagulation, combined cataract surgery, severity of postoperative vitreous hemorrhage, and use of expanding gas tamponade. PMID- 23934825 TI - Visual impairment and spectacle use in schoolchildren in rural and urban regions in Beijing. AB - PURPOSE: To determine prevalence and associations of visual impairment and frequency of spectacle use among grade 1 and grade 4 students in Beijing. METHODS: This school-based, cross-sectional study included 382 grade 1 children (age 6.3 +/- 0.5 years) and 299 grade 4 children (age 9.4 +/- 0.7 years) who underwent a comprehensive eye examination including visual acuity, noncycloplegic refractometry, and ocular biometry. RESULTS: Presenting visual acuity (mean 0.04 +/- 0.17 logMAR) was associated with younger age (p = 0.002), hyperopic refractive error (p<0.001), and male sex (p = 0.03). Presenting visual impairment (presenting visual acuity <=20/40 in the better eye) was found in 44 children (prevalence 6.64 +/- 1.0% [95% confidence interval (CI) 4.74, 8.54]). Mean best corrected visual acuity (right eyes -0.02 +/- 0.04 logMAR) was associated with more hyperopic refractive error (p = 0.03) and rural region of habitation (p<0.001). The prevalence of best-corrected visual impairment (best-corrected visual acuity <=20/40 in the better eye) was 2/652 (0.30 +/- 0.21% [95% CI 0.00, 0.72]). Undercorrection of refractive error was present in 53 children (7.99 +/- 1.05%) and was associated with older age (p = 0.003; B 0.53; OR 1.71 [95% CI 1.20, 2.42]), myopic refractive error (p = 0.001; B -0.72; OR 0.49 [95% CI 0.35, 0.68]), and longer axial length (p = 0.002; B 0.74; OR 2.10 [95% CI 1.32, 3.32]). Spectacle use was reported for 54 children (8.14 +/- 1.06%). Mean refractive error of the worse eyes of these children was -2.09 +/- 2.88 D (range -7.38 to +7.25 D). CONCLUSIONS: Factors associated with presenting visual impairment were older age, myopic refractive error, and higher maternal education level. Despite a prevalence of myopia of 33% in young schoolchildren in Greater Beijing, prevalence of best-corrected visual impairment (0.30% +/- 0.21%), presenting visual impairment (6.64% +/- 1.0%), and undercorrection of refractive error (7.99% +/- 1.05%) were relatively low. PMID- 23934826 TI - Combined ab externo and ab interno revision of failed filtering blebs with adjunctive mitomycin C. AB - PURPOSE: To report the results of combined ab externo and ab interno revision with mitomycin C (MMC) of failed filtering blebs in glaucoma patients. METHODS: Glaucoma patients with a failed trabeculectomy who had undergone internal and external revision with MMC in the last 6 years with at least 12 months of follow up were considered. All study patients followed the same protocol in the operating room: injection of 0.2 mL of MMC (0.4 mg/mL) 2 cm lateral from the bleb followed by internal revision with an iris spatula and external revision with a 26-G * 1/2" needle. Success was defined as an intraocular pressure (IOP) >=6 mm Hg and <=18 mm Hg with (qualified) or without (absolute) any ocular hypotensive drugs. RESULTS: The study included 25 eyes of 22 glaucoma patients. Mean age was 65.2 +/- 10.5 years. Mean follow-up was 26.9 +/- 10.3 months. The IOP was reduced from 24.5 +/- 6.0 mm Hg preoperatively to 10.0 +/- 3.3 mm Hg at the last visit (p<0.001). The number of ocular hypotensive medications was reduced from 1.8 +/- 1.0 to 0.2 +/- 0.6 (p<0.001). There was no change in visual acuity (0.83 +/- 0.75 vs 0.83 +/- 0.74, p = 0.7). Three patients developed choroidal detachment, another eye had a transient hypotony with maculopathy, and 2 patients developed cataract. Absolute success was achieved in 80% of eyes, and qualified success in 16% of eyes. CONCLUSIONS: Combined ab externo and ab interno revision with MMC can be an effective technique to revitalize failed filtering blebs in glaucoma patients with minimal complications. PMID- 23934827 TI - Formulation of probabilistic models of protein structure in atomic detail using the reference ratio method. AB - We propose a method to formulate probabilistic models of protein structure in atomic detail, for a given amino acid sequence, based on Bayesian principles, while retaining a close link to physics. We start from two previously developed probabilistic models of protein structure on a local length scale, which concern the dihedral angles in main chain and side chains, respectively. Conceptually, this constitutes a probabilistic and continuous alternative to the use of discrete fragment and rotamer libraries. The local model is combined with a nonlocal model that involves a small number of energy terms according to a physical force field, and some information on the overall secondary structure content. In this initial study we focus on the formulation of the joint model and the evaluation of the use of an energy vector as a descriptor of a protein's nonlocal structure; hence, we derive the parameters of the nonlocal model from the native structure without loss of generality. The local and nonlocal models are combined using the reference ratio method, which is a well-justified probabilistic construction. For evaluation, we use the resulting joint models to predict the structure of four proteins. The results indicate that the proposed method and the probabilistic models show considerable promise for probabilistic protein structure prediction and related applications. PMID- 23934828 TI - Sulfoximines: a neglected opportunity in medicinal chemistry. AB - Innovation has frequently been described as the key to drug discovery. However, in the daily routine, medicinal chemists often tend to stick to the functional groups and structural elements they know and love. Blockbuster cancer drug Velcade (bortezomib), for example, was rejected by more than 50 companies, supposedly because of its unusual boronic acid function (as often repeated: "only a moron would put boron in a drug!"). Similarly, in the discovery process of the pan-CDK inhibitor BAY 1000394, the unconventional proposal to introduce a sulfoximine group into the lead series also led to sneers and raised eyebrows, since sulfoximines have seldom been used in medicinal chemistry. However, it was the introduction of the sulfoximine group that finally allowed the fundamental issues of the project to be overcome, culminating in the identification of the clinical sulfoximine pan-CDK inhibitor BAY 1000394. This Minireview provides an overview of a widely neglected opportunity in medicinal chemistry--the sulfoximine group. PMID- 23934829 TI - Culturing fetal precursor cells using free floating serum-free conditions. AB - The propagation of neural precursors in culture is an essential tool for the study of the signaling matrix that regulates their proliferation, self-renewal, and generation of terminally differentiated progeny. Neural precursors can be expanded in vitro using both adherent and non-adherent culture protocols. The culture of fetal human neural precursors in the absence of serum as free-floating clusters of cells termed neurospheres is described here. PMID- 23934831 TI - Isolate and culture precursor cells from the adult periventricular area. AB - Due to the complexity of the NSC niche organization, the lack of specific NSC markers and the difficulty of long-term tracking these cells and their progeny in vivo the functional properties of the endogenous NSCs remain largely unexplored. These limitations have led to the development of methodologies to efficiently isolate, expand, and differentiate NSCs ex vivo. We describe here the peculiarities of the neurosphere assay (NSA) as a methodology that allows to efficiently isolate, expand, and differentiate somatic NSCs derived from the adult forebrain periventricular region while preserving proliferation, self renewal, and multipotency, the main attributes that provide their functional identification. PMID- 23934830 TI - In vitro expansion of fetal neural progenitors as adherent cell lines. AB - In vitro studies of neural progenitors isolated from the developing mouse have provided important insights into intrinsic and extrinsic pathways that control their behavior. However, use of primary cultures or neurospheres established from fetal tissues in cell population-based assays can be compromised by cellular heterogeneity. A complementary approach that addresses this issue is the establishment of adherent clonal neural stem (NS) cell lines. Here I describe protocols and troubleshooting advice for establishing adherent NS cell lines from the mouse fetal forebrain. NS cells grow as pure cultures in defined serum-free conditions as adherent monolayers and are therefore amenable to chemical/genetic screens, biochemical studies, and population-based analysis of gene expression or transcriptional regulation (e.g. RNA-Seq and ChIP-Seq). NS cell lines therefore represent a tractable cellular model system to explore the molecular and cellular biology of neural stem cell self-renewal and differentiation. Similar protocols can be extended to rat and human embryos, as well as human brain tumors. PMID- 23934832 TI - Culturing and expansion of precursor cells from the adult hippocampus. AB - It is now well established that a resident population of neural precursor cells continues to generate new neurons in the adult hippocampus throughout life. Numerous studies have suggested that these newborn neurons preferentially participate in the functional hippocampal circuitry that leads to enhancement of learning, cognition and mood. Therefore, understanding the molecular mechanisms that regulate the activity of these endogenous precursor cells is paramount to develop novel regenerative strategies for the treatment of neurological and psychiatric disorders. The neurosphere assay has been instrumental in discovering the presence of stem and precursor cell population from several brain regions. In this chapter, we describe this assay to specifically isolate and culture neural stem and precursor cell populations from the adult hippocampus of mice. In addition, we provide methods to conduct detailed assays to examine their functional properties such as proliferation, self-renewal, and differentiation. PMID- 23934833 TI - Isolate and culture neural stem cells from the mouse adult spinal cord. AB - Whereas neural stem cells and their niches have been extensively studied in the brain, little is known on these cells, their environment and their function in the adult spinal cord. Adult spinal cord neural stem cells are located in a complex niche surrounding the central canal and these cells expressed genes which are specifically expressed in the caudal central nervous system (CNS). In depth characterization of these cells in vivo and in vitro will provide interesting clues on the possibility to utilize this endogenous cell pool to treat spinal cord damages. We describe here a procedure to derive and culture neural spinal cord stem cells from adult mice using the neurosphere method. PMID- 23934834 TI - Culturing and expansion of "clinical grade" precursors cells from the fetal human central nervous system. AB - NSCs have been demonstrated to be very useful in grafts into the mammalian central nervous system to investigate the exploitation of NSC for the therapy of neurodegenerative disorders in animal models of neurodegenerative diseases. To push cell therapy in CNS on stage of clinical application, it is necessary to establish a continuous and standardized, clinical grade (i.e., produced following the good manufacturing practice guidelines) human neural stem cell lines. In this chapter, we illustrate some of the protocols routinely used into our GMP cell bank for the production of "clinical grade" human neural stem cell lines. PMID- 23934835 TI - Isolating and culturing of precursor cells from the adult human brain. AB - Adult neural precursor cells are an essential part of the brain, and a focus of two decades of intense research (Ming and Song, Neuron 70:687-702, 2011). Even though adult human stem/progenitor cells have been identified early on (Kirschenbaum et al., Cereb Cortex 4:576-589, 1994; Eriksson et al., Nat Med 4:1313-1317, 1998), progress in the field of adult human neurogenesis has been slow. The reasons for this may be more advanced neighboring fields of pluripotent stem cell research, and lacking study material as well as well-established and standardized protocols. Furthermore, adult precursor cells in humans seem to have greater potential than in rodents (Walton et al., Development 133:3671-3681, 2006). This may be attributed to species differences in astrocyte development and diversity (Oberheim et al., Neurosci 29:3276-3287, 2009). In this chapter, we provide a guideline for adult human brain tissue dissociation, be it from biopsy or autopsy specimens. This is by no means the only way of culturing adult neural precursor cells, but it may help in streamlining research on this fascinating topic, as well as help introducing others into this field. We describe our methodology for establishing and maintaining long-term cultures from white and grey matter, as well as a simple protocol for differentiating these cells. PMID- 23934836 TI - Isolation and culture of precursor cells from the adult human spinal cord. AB - Our group recently provided evidence for the presence of neural stem cells and/or progenitor cells in the adult human spinal cord. In this chapter, we review materials and methods to harvest high-quality samples of thoracolumbar, lumbar, and sacral adult human spinal cord from brain-dead patients who had agreed to donate their bodies to science for therapeutic and scientific advances. The methods to culture precursor cells from the adult human spinal cord are also described. PMID- 23934837 TI - Isolation and enrichment of defined neural cell populations from heterogeneous neural stem cell progeny. AB - The renewable source of neural stem cells (NSCs) with multi-lineage differentiation capability towards neurons, astrocytes, and oligodendrocytes represent an ideal supply for cell therapy of central nervous system (CNS) diseases. In spite of this, the clinical use of NSCs is hampered by heterogeneity, poor neuronal cell yield, predominant astrocytic differentiation of NSC progeny and possible uncontrolled proliferation, and tumor formation upon transplantation. The ability to generate highly enriched and defined neural cell populations from the renewable source of NSCs might overcome many of these impediments and pave the way towards their successful clinical applications. Here, we describe a simple method for NSC differentiation and subsequent purification of neuronal progenitor cells, taking advantage of size and granularity differences between neuronal cells and other NSC progeny. This highly enriched neuronal cell population provides an invaluable source of cells for both in vitro and in vivo studies. PMID- 23934839 TI - Enumerating stem cell frequency: neural colony forming cell assay. AB - Recent reports have highlighted several parameters of the neurosphere culture or assay system which render it unreliable as a quantitative in vitro assay for measuring neural stem cell (NSC) frequency. The single-step semi-solid based assay, the Neural Colony Forming Cell (NCFC) assay is an assay which was developed to overcome some of the limitations of the neurospheres assay in terms of accurately measuring NSC numbers. The NCFC assay allows the discrimination between NSCs and progenitors by the size of colonies they produce (i.e. their proliferative potential). The NCFC assay and other improved tissue culture tools offer further advances in the promising application of NSCs for therapeutic use. PMID- 23934838 TI - Isolation of adult stem cells from the human olfactory mucosa. AB - The olfactory mucosa, located in the nasal cavity, is the only nervous tissue that is exposed to the external environment and easily accessible in every living individual. In addition, this organ is home of a continuing neurogenesis that is sustained by a large population of stem cells. Here, we describe a method for biopsying olfactory mucosa from human nasal cavities and isolating multipotent adult stem cells that can be used to either identify biomarkers in brain disorders or repair the pathological/traumatized nervous system. PMID- 23934840 TI - Flow cytometry of neural cells. AB - Flow cytometry is an advanced group of techniques for counting and quantifying microscopic particles such as cells, chromosomes, or functionalized beads. These approaches employ sophisticated optical and fluidic components to detect scattered light and fluorescent signals from cells as they sequentially pass an interrogation point. Cytometry plays a crucial role in the diagnosis of immunological disorders and cancers, and is a mainstay technique in basic research settings such as hematology, cell biology, and biomolecular screening. However, in spite of the breadth of applications spanning many fields, flow cytometry in neuroscience has been largely unexploited and has seen only a steady increase in interest until recent years. This is rather surprising as the potential of flow cytometry in neuroscience applications was recognized in the early 1980s as the technology was evolving. PMID- 23934841 TI - Neonatal transplant in hypoxic injury. AB - Hypoxic-ischemic encephalopathy in neonates often causes long-term disabilities. Stem cell therapy may be a successful treatment for HIE. Neurogenic astrocytes with characteristics of neural stem cells (NSCs) can be cultured as adherent monolayers. Following reintroduction into the NSC niche of both neonatal and adult hosts, these astrocytes can be induced to generate neuronal progeny in vitro and in vivo. Thus, neurogenic astrocytes represent promising candidates for cell replacement therapy in HIE. Such an approach requires optimized cell cultivation protocols as well as extensive testing of donor cells to assess their capacity for engraftment, survival, and integration in the HIE animal models. In this chapter, we describe methods of generating the HIE model, generating and culturing monolayer neurogenic astrocytes, and transplanting these cells into HIE animal models. PMID- 23934842 TI - Isolation and purification of self-renewable human neural stem cells for cell therapy in experimental model of ischemic stroke. AB - Human embryonic stem cells (hESCs) are pluripotent with a strong self-renewable ability making them a virtually unlimited source of neural cells for structural repair in neurological disorders. Currently, hESCs are one of the most promising cell sources amenable for commercialization of off-shelf cell therapy products. However, along with this strong proliferative capacity of hESCs comes the tumorigenic potential of these cells after transplantation. Thus, the isolation and purification of a homogeneous, population of neural stem cells (hNSCs) are of paramount importance to avoid tumor formation in the host brain. This chapter describes the isolation, neuralization, and long-term perpetuation of hNSCs derived from hESCs through use of specific mitogenic growth factors and the preparation of hNSCs for transplantation in an experimental model of stroke. Additionally, we describe methods to analyze the stroke and size of grafts using magnetic resonance imaging and Osirix software, and neuroanatomical tracing procedures to study axonal remodeling after stroke and cell transplantation. PMID- 23934843 TI - Transplantation of fetal midbrain dopamine progenitors into a rodent model of Parkinson's disease. AB - Cell therapy is a promising experimental treatment for Parkinson's disease (PD). It is based on the idea that new dopamine neurons transplanted directly into the forebrain of the patient can structurally and functionally compensate for those lost to the disease in order to restore motor function. While there is a highly active field of research focused on the development of stem cell-based procedures, fetal tissue remains the "gold standard" as a safe and reliable source of dopamine neuron progenitors capable of structural and functional integration with existing motor circuitry following transplantation. This chapter describes the basic procedures for preparation of dopamine progenitor rich cell suspensions of ventral mesencephalon as well as implantation into the unilateral 6-hydroxydopamine model of PD and assessment of functional impact according to drug-induced rotational behavior. The description assumes a basic knowledge of animal handling and stereotaxic surgical procedures in rodents. PMID- 23934844 TI - Distribution of neural precursor cells in the adult mouse brain. AB - Since its inception in 1992 [Reynolds and Weiss, Science 255:1707-10, 1992], the neurosphere assay (NSA) has proven an exceptionally useful tool in detecting neural stem cells (NSCs) in both the developing and adult mammalian brain. To date, over 1,300 manuscripts have been published employing the assay, attesting to the robustness of the assay, and its ease of use. However, a brief survey of the literature demonstrates that the number of primary neurospheres generated from essentially the same anatomical region (i.e., the periventricular region of the rostral lateral ventricle) ranges between 150 and 936 [Gritti et al., J Neurosci 22:437-445, 2002; Tropepe et al., J Neurosci 17:7850-59, 1997; Doetsch et al., Cell 97:703-16, 1999; Enwere et al., J Neurosci 24:8354-65, 2004]. Indeed, in our hands we typically generate approximately 1,800 primary spheres when harvesting tissue from the same region. PMID- 23934845 TI - Identifying neural progenitor cells in the adult human brain. AB - The discovery, in 1998, that the adult human brain contains at least two populations of progenitor cells and that progenitor cells are upregulated in response to a range of degenerative brain diseases has raised hopes for their use in replacing dying brain cells. Since these early findings the race has been on to understand the biology of progenitor cells in the human brain and they have now been isolated and studied in many major neurodegenerative diseases. Before these cells can be exploited for cell replacement purposes it is important to understand how to: (1) find them, (2) label them, (3) determine what receptors they express, (4) isolate them, and (5) examine their electrophysiological properties when differentiated. In this chapter we have described the methods we use for studying progenitor cells in the adult human brain and in particular the tissue processing, immunohistochemistry, autoradiography, progenitor cell culture, and electrophysiology on brain cells. The Neurological Foundation of New Zealand Human Brain Bank has been receiving human tissue for approximately 20 years during which time we have developed a number of unique ways to examine and isolate progenitor cells from resected surgical specimens as well as from postmortem brain tissue. There are ethical and technical considerations that are unique to working with human brain tissue and these, as well as the processing of this tissue and the culturing of it for the purpose of studying progenitor cells, are the topic of this chapter. PMID- 23934846 TI - Clinical trials for the treatment of spinal cord injury: not so simple. AB - The fast pace of research in stem cell biology and regenerative medicine is feeding hopes of the scientific community and the public that a new revolution in treatments is upon us. There are increasing numbers of examples of stem cell therapies that are effective in treating animal injuries and diseases. There is an expectation that stem cell transplantation will soon be commonplace in the human clinic, especially with the beginnings of clinical trials of embryonic stem cell transplantation for bone repair, spinal cord injury, macular degeneration, Stargardt's disease, and Batten's disease. This may be an appropriate point at which to review our experiences in moving from the lab to the clinic to initiate a Phase I clinical trial of autologous olfactory ensheathing cells in spinal cord injured humans. PMID- 23934847 TI - Thermal or nonthermal? That is the question for ultrafast spin switching in GdFeCo. AB - GdFeCo is among the most interesting magnets for producing laser-induced femtosecond magnetism, where light can switch its spin moment from one direction to another. This paper aims to set a criterion for the thermal/nonthermal mechanism: we propose to use the Fermi-Dirac distribution function as a reliable criterion. A precise value for the thermalization time is needed, and through a two-level model, we show that since there is no direct connection between the laser helicity and the definition of thermal/nonthermal processes, the helicity is a poor criterion for differentiating a thermal from a nonthermal process. In addition, we propose a four-site model system (Gd2Fe2) for investigating the transient ferromagnetic ordering between Gd and Fe ions. We find that states of two different kinds can allow such an ordering. One state is a pure ferromagnetic state with ferromagnetic ordering among all the ions, and the other is the short ranged ferromagnetic ordering of a pair of Gd and Fe ions. PMID- 23934848 TI - The effect of thinning and clear-cut on changes in the relative abundance of root feeding beetle (Coleoptera: Curculionidae) in Pinus taeda plantations in central Alabama and Georgia. AB - BACKGROUND: Root-feeding beetles, particularly Hylastes spp., Hylobius pales Herbst and Pachylobius picivorus Germar, increase in abundance in stressed forest stands and vector Grosmannia and Leptographium spp. fungi, which contribute to southern pine decline (SPD) in the southeastern United States. This study examined changes in the relative abundance of root-feeding beetles in response to mechanical thinning and clear-cut of even-age loblolly pine (Pinus taeda L.) stands in central Alabama and Georgia every 2 weeks during a 30 month study in 2009-2012. RESULTS: The most abundant bark beetles were Hylastes salebrosus Eichhoff, H. porculus Erichson and H. tenuis Eichhoff. The relative abundance of the Hylastes spp. significantly increased after thinning treatments at all five sites. An initial decrease in Hylastes spp. occurred in response to clear-cut in some plots, but they typically recovered 2 months later and were stable for the remainder of the study. CONCLUSION: This study reports on the relative abundance responses of pathogen-vectoring root-feeding beetles to a thinning and clear-cut treatment in P. taeda stands. Thinning treatments conducted during the summer and winter may increase the relative abundance of Hylastes spp., vectors of Leptographium and Grosmannia spp., which are known to contribute to SPD by triggering plants to release defensive volatile compounds. PMID- 23934849 TI - Aspirate from human stented native coronary arteries vs. saphenous vein grafts: more endothelin but less particulate debris. AB - Stent implantation into atherosclerotic coronary arteries releases particulate debris and soluble substances that contribute to impaired microvascular perfusion. Here we addressed the potential for microvascular obstruction in patients with stenotic native right coronary arteries (nRCA) compared with saphenous vein grafts on right coronary arteries (SVG-RCA). We enrolled symptomatic, male patients with stable angina pectoris and a flow-limiting stenosis in their nRCA or SVG-RCA (n = 18/18). Plaque volume and composition were analyzed using intravascular ultrasound before stent implantation. Coronary aspirate was retrieved during stent implantation under protection with a distal occlusion/aspiration device and divided into particulate debris and plasma. The release of catecholamines, endothelin, serotonin, thromboxane B2, and tumor necrosis factor-alpha was measured. The response of rat mesenteric arteries with intact (+E) and denuded (-E) endothelium to aspirate plasma (without and with selective endothelin receptor blockade) was normalized to that by potassium chloride (KClmax = 100%). Plaque volume and composition were not different between nRCA and SVG-RCA. There was less particulate debris (65 +/- 8 vs. 146 +/- 23 mg; P < 0.05) and more endothelin release (5.8 +/- 0.8 vs. 1.3 +/- 0.7 pg/ml; P < 0.05) in nRCA than in SVG-RCA, whereas the release of the other mediators was not different. Aspirate from nRCA induced stronger vasoconstriction than that from SVG-RCA [nRCA, 78 +/- 6% (+E)/84 +/- 5% (-E); SVG-RCA, 59 +/- 6% (+E)/68 +/- 3% (-E); P < 0.05 nRCA vs. SVG-RCA], which was attenuated by a nonspecific endothelin and a specific endothelin receptor A antagonist. Thus coronary aspirate from stented nRCA is characterized by less debris but more endothelin and stronger vasoconstrictor response than that from SVG-RCA. PMID- 23934850 TI - Cathepsin G deficiency decreases complexity of atherosclerotic lesions in apolipoprotein E-deficient mice. AB - Cathepsin G is a serine protease with a broad range of catalytic activities, including production of angiotensin II, degradation of extracellular matrix and cell-cell junctions, modulation of chemotactic responses, and induction of apoptosis. Cathepsin G mRNA expression is increased in human coronary atheroma vs. the normal vessel. To assess whether cathepsin G modulates atherosclerosis, cathepsin G knockout (Cstg(-/-)) mice were bred with apolipoprotein E knockout (Apoe(-/-)) mice to obtain Ctsg(+/-)Apoe(-/-) and Ctsg(+/+)Apoe(-/-) mice. Heterozygous cathepsin G deficiency led to a 70% decrease in cathepsin G activity in bone marrow cells, but this reduced activity did not impair generation of angiotensin II in bone marrow-derived macrophages (BMDM). Atherosclerotic lesions were compared in male Cstg(+/-)Apoe(-/-) and Cstg(+/+)Apoe(-/-) mice after 8 wk on a high-fat diet. Plasma cholesterol levels and cholesterol distribution within serum lipoprotein fractions did not differ between genotypes nor did the atherosclerotic lesion areas in either the aortic root or aortic arch. Cstg(+/ )Apoe(-/-) mice, however, showed a lower percentage of complex lesions within the aortic root and a smaller number of apoptotic cells compared with Cstg(+/+)Apoe( /-) littermates. Furthermore, apoptotic Cstg(-/-) BMDM were more efficiently engulfed by phagocytic BMDM than were apoptotic Ctsg(+/+) BMDM. Thus cathepsin G activity may impair efferocytosis, which could lead to an accumulation of lesion associated apoptotic cells and the accelerated progression of early atherosclerotic lesions to more complex lesions in Apoe(-/-) mice. PMID- 23934851 TI - Disruption of phase synchronization between blood pressure and muscle sympathetic nerve activity in postural vasovagal syncope. AB - Withdrawal of muscle sympathetic nerve activity (MSNA) may not be necessary for the precipitous fall of peripheral arterial resistance and arterial pressure (AP) during vasovagal syncope (VVS). We tested the hypothesis that the MSNA-AP baroreflex entrainment is disrupted before VVS regardless of MSNA withdrawal using the phase synchronization between blood pressure and MSNA during head-up tilt (HUT) to measure reflex coupling. We studied eight VVS subjects and eight healthy control subjects. Heart rate, AP, and MSNA were measured during supine baseline and at early, mid, late, and syncope stages of HUT. Phase synchronization indexes, measuring time-dependent differences between MSNA and AP phases, were computed. Directionality indexes, indicating the influence of AP on MSNA (neural arc) and MSNA on AP (peripheral arc), were computed. Heart rate was greater in VVS compared with control subjects during early, mid, and late stages of HUT and significantly declined at syncope (P = 0.04). AP significantly decreased during mid, late, and syncope stages of tilt in VVS subjects only (P = 0.001). MSNA was not significantly different between groups during HUT (P = 0.700). However, the phase synchronization index significantly decreased during mid and late stages in VVS subjects but not in control subjects (P < .001). In addition, the neural arc was significantly affected more than the peripheral arc before syncope. In conclusion, VVS is accompanied by a loss of the synchronous AP MSNA relationship with or without a loss in MSNA at faint. This provides insight into the mechanisms behind the loss of vasoconstriction and drop in AP independent of MSNA at the time of vasovagal faint. PMID- 23934852 TI - Autonomic modulation of repolarization instability in patients with heart failure prone to ventricular tachycardia. AB - QT variability (QTV) signifies repolarization lability, and increased QTV is a risk predictor for sudden cardiac death. The aim of the present study was to investigate the role of autonomic nervous system activity on QTV. This study was performed in 29 subjects: 10 heart failure (HF) patients with spontaneous ventricular tachycardia [HFVT(+)], 10 HF patients without spontaneous VT [HFVT( )], and 9 subjects with structurally normal hearts (HNorm). The beat-to-beat QT interval was measured on 3-min records of surface ECGs at baseline and during interventions (atrial pacing and esmolol, isoprenaline, and atropine infusion). Variability in QT intervals was expressed as the SD of all QT intervals (SDQT). The ratio of the SDQT to SD of RR intervals (SDRR) was calculated as an index of QTV normalized to heart rate variability. There was a trend toward a higher baseline SDQT-to-SDRR ratio in the HFVT(+) group compared with the HFVT(-) and HNorm groups (P = 0.09). SDQT increased significantly in the HFVT(+) and HFVT(-) groups compared with the HNorm group during fixed-rate atrial pacing (P = 0.008). Compared with baseline, isoprenaline infusion increased SDQT in HNorm subjects (P = 0.02) but not in HF patients. SDQT remained elevated in the HFVT(+) group relative to the HNorm group despite acute beta-adrenoceptor blockade with esmolol (P = 0.02). In conclusion, patients with HF and spontaneous VT have larger fluctuations in beat-to-beat QT intervals. This appears to be a genuine effect that is not solely a consequence of heart rate variation. The effect of acute autonomic nervous system modulation on QTV appears to be limited in HF patients. PMID- 23934853 TI - SERCA Cys674 sulphonylation and inhibition of L-type Ca2+ influx contribute to cardiac dysfunction in endotoxemic mice, independent of cGMP synthesis. AB - The goal of this study was to identify the cellular mechanisms responsible for cardiac dysfunction in endotoxemic mice. We aimed to differentiate the roles of cGMP [produced by soluble guanylyl cyclase (sGC)] versus oxidative posttranslational modifications of Ca(2+) transporters. C57BL/6 mice [wild-type (WT) mice] were administered lipopolysaccharide (LPS; 25 MUg/g ip) and euthanized 12 h later. Cardiomyocyte sarcomere shortening and Ca(2+) transients (DeltaCai) were depressed in LPS-challenged mice versus baseline. The time constant of Ca(2+) decay (tauCa) was prolonged, and sarcoplasmic reticulum Ca(2+) load (CaSR) was depressed in LPS-challenged mice (vs. baseline), indicating decreased activity of sarco(endo)plasmic Ca(2+)-ATPase (SERCA). L-type Ca(2+) channel current (ICa,L) was also decreased after LPS challenge, whereas Na(+)/Ca(2+) exchange activity, ryanodine receptors leak flux, or myofilament sensitivity for Ca(2+) were unchanged. All Ca(2+)-handling abnormalities induced by LPS (the decrease in sarcomere shortening, DeltaCai, CaSR, ICa,L, and tauCa prolongation) were more pronounced in mice deficient in the sGC main isoform (sGCalpha1(-/-) mice) versus WT mice. LPS did not alter the protein expression of SERCA and phospholamban in either genotype. After LPS, phospholamban phosphorylation at Ser(16) and Thr(17) was unchanged in WT mice and was increased in sGCalpha1(-/-) mice. LPS caused sulphonylation of SERCA Cys(674) (as measured immunohistochemically and supported by iodoacetamide labeling), which was greater in sGCalpha1(-/-) versus WT mice. Taken together, these results suggest that cardiac Ca(2+) dysregulation in endotoxemic mice is mediated by a decrease in L type Ca(2+) channel function and oxidative posttranslational modifications of SERCA Cys(674), with the latter (at least) being opposed by sGC-released cGMP. PMID- 23934854 TI - Peripheral delta-opioid receptors attenuate the exercise pressor reflex. AB - In rats with ligated femoral arteries, the exercise pressor reflex is exaggerated, an effect that is attenuated by stimulation of peripheral MU-opioid receptors on group IV metabosensitive afferents. In contrast, delta-opioid receptors are expressed mostly on group III mechanosensitive afferents, a finding that prompted us to determine whether stimulation of these opioid receptors could also attenuate the exaggerated exercise pressor reflex in "ligated" rats. We found femoral arterial injection of [D-Pen2,D-Pen5]enkephalin (DPDPE; 1.0 MUg), a delta-opioid agonist, significantly attenuated the pressor and cardioaccelerator components of the exercise pressor reflex evoked by hindlimb muscle contraction in both rats with ligated and patent femoral arteries. DPDPE significantly decreased the pressor responses to muscle mechanoreflex activation, evoked by tendon stretch, in ligated rats only. DPDPE (1.0 MUg) had no effect in either group on the pressor and cardioaccelerator responses to capsaicin (0.2 MUg), which primarily stimulates group IV afferents. DPDPE (1.0 MUg) had no effect on the pressor and cardioaccelerator responses to lactic acid (24 mM), which stimulates group III and IV afferents, in rats with patent femoral arteries but significantly decreased the pressor response in ligated rats. Western blots revealed the amount of protein comprising the delta-opioid receptor was greater in dorsal root ganglia innervating hindlimbs with ligated femoral arteries than in dorsal root ganglia innervating hindlimbs with patent femoral arteries. Our findings support the hypothesis that stimulation of delta-opioid receptors on group III afferents attenuated the exercise pressor reflex. PMID- 23934855 TI - Shear stress modulates VCAM-1 expression in response to TNF-alpha and dietary lipids via interferon regulatory factor-1 in cultured endothelium. AB - Dyslipidemia is a primary risk factor for cardiovascular disease, but the specific mechanisms that determine the localization of atherosclerotic plaques in arteries are not well defined. Triglyceride-rich lipoproteins (TGRL) isolated from human plasma after a high-fat meal modulate TNF-alpha-induced VCAM-1 expression in cultured human aortic endothelial cells (HAECs) via an interferon regulatory factor (IRF)-1-dependent transcriptional mechanism. We examined whether fluid shear stress acts as a mediator of IRF-1-dependent VCAM-1 expression in response to cytokine and dietary lipids. IRF-1 and VCAM-1 were examined by immunofluorescence in TNF-alpha-stimulated HAEC monolayers exposed to TGRL and a linear gradient of shear stress ranging from 0 to 16 dyn/cm(2) in a microfluidic device. Shear stress alone modulated TNF-alpha-induced VCAM-1 expression, eliciting a 150% increase at low shear stress (2 dyn/cm(2)) and a 70% decrease at high shear stress (12 dyn/cm(2)) relative to static. These differences correlated with a 60% increase in IRF-1 expression under low shear stress and a 40% decrease under high shear stress. The addition of TGRL along with cytokine activated a fourfold increase in VCAM-1 expression and a twofold increase in IRF-1 expression. The combined effect of shear stress and TGRL on the upregulation of membrane VCAM-1 was abolished by transfection of HAECs with IRF-1 specific small interfering RNA. In a healthy swine model, elevated levels of endothelial IRF-1 were also observed within atherosusceptible regions of the aorta by Western blot analysis and immunohistochemistry, implicating arterial hemodynamics in the regulation of IRF-1 expression. These data demonstrate direct roles for fluid shear stress and postprandial TGRL from human serum in the regulation of IRF-1 expression and downstream inflammatory responses in HAECs. PMID- 23934856 TI - Diverse regulation of IP3 and ryanodine receptors by pentazocine through sigma1 receptor in cardiomyocytes. AB - Although pentazocine binds to sigma1-receptor (sigma1R) with high affinity, the physiological relevance of its binding remains unclear. We first confirmed that sigma1R stimulation with pentazocine rescues contractile dysfunction following pressure overload (PO)-induced cardiac hypertrophy ovariectomized (OVX) female rats. In in vivo studies, vehicle, pentazocine (0.5-1.0 mg/kg ip), and NE-100 (1.0 mg/kg po), a sigma1R antagonist, were administered for 4 wk (once daily) starting from the onset of aortic banding after OVX. We also examined antihypertrophic effects of pentazocine (0.5-1 MUM) in cultured cardiomyocytes exposed to angiotensin II. Pentazocine administration significantly inhibited PO induced cardiac hypertrophy and rescued hypertrophy-induced impairment of cardiac dysfunctions such as left ventricular end-diastolic pressure, left ventricular developed pressure, and left ventricular contraction and relaxation (+/-dp/dt) rates. Coadministration of NE-100 with pentazocine eliminated pentazocine-induced amelioration of heart dysfunction. Interestingly, pentazocine administration inhibited PO-induced sigma1R reduction and inositol-1,4,5-trisphosphate (IP3) receptor type 2 (IP3R2) upregulation in heart. Therefore, the reduced mitochondrial ATP production following PO was restored by pentazocine administration. Furthermore, we found that sigma1R binds to the ryanodine receptor (RyR) in addition to IP3 receptor (IP3R) in cardiomyocytes. The sigma1R/RyR complexes were decreased following OVX-PO and restored by pentazocine administration. We noticed that pentazocine inhibits the ryanodine-induced Ca(2+) release from sarcoplasmic reticulum (SR) in cultured cardiomyocytes. Taken together, the stimulation of sigma1R by pentazocine rescues cardiac dysfunction by restoring IP3R-mediated mitochondrial ATP production and by suppressing RyR mediated Ca(2+) leak from SR in cardiomyocytes. PMID- 23934857 TI - Mechanistic insight into prolonged electromechanical delay in dyssynchronous heart failure: a computational study. AB - In addition to the left bundle branch block type of electrical activation, there are further remodeling aspects associated with dyssynchronous heart failure (HF) that affect the electromechanical behavior of the heart. Among the most important are altered ventricular structure (both geometry and fiber/sheet orientation), abnormal Ca(2+) handling, slowed conduction, and reduced wall stiffness. In dyssynchronous HF, the electromechanical delay (EMD), the time interval between local myocyte depolarization and myofiber shortening onset, is prolonged. However, the contributions of the four major HF remodeling aspects in extending EMD in the dyssynchronous failing heart remain unknown. The goal of this study was to determine the individual and combined contributions of HF-induced remodeling aspects to EMD prolongation. We used MRI-based models of dyssynchronous nonfailing and HF canine electromechanics and constructed additional models in which varying combinations of the four remodeling aspects were represented. A left bundle branch block electrical activation sequence was simulated in all models. The simulation results revealed that deranged Ca(2+) handling is the primary culprit in extending EMD in dyssynchronous HF, with the other aspects of remodeling contributing insignificantly. Mechanistically, we found that abnormal Ca(2+) handling in dyssynchronous HF slows myofiber shortening velocity at the early-activated septum and depresses both myofiber shortening and stretch rate at the late-activated lateral wall. These changes in myofiber dynamics delay the onset of myofiber shortening, thus giving rise to prolonged EMD in dyssynchronous HF. PMID- 23934858 TI - Apurinic/apyrimidinic endonucelase 1 maintains adhesion of endothelial progenitor cells and reduces neointima formation. AB - Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that processes DNA-repair function and controls cellular response to oxidative stress. Endothelial progenitor cells (EPCs) are recruited to oxidative stress-rich injured vascular walls and positively contribute to vascular repair and endothelialization. We hypothesized that APE1 functions for EPCs-mediated inhibition of neointima formation in injured vasculature. EPCs isolated from bone marrow cells of C57BL6 mice (12-16 wk old) were able to survive in the presence of hydrogen peroxide (H2O2; up to 1,000 MUM) due to the highly expressed reactive oxygen species (ROS) scavengers. However, adhesion capacity of EPCs was significantly inhibited by H2O2 (100 MUM) even though an intracellular ROS was retained at small level. An APE1-selective inhibitor or RNA interference-mediated knockdown of endogenous APE1 in EPCs aggravated the H2O2-mediated inhibition of EPCs-adhesion. In contrast, when APE1 was overexpressed in EPCs using an adenovirus harboring the APE1 gene (APE-EPCs), adhesion was significantly improved during oxidative stress. To examine in vivo effects of APE1 in EPCs, APE EPCs were transplanted via the tail vein after wire-mediated injury of the mouse femoral artery. The number of adherent EPCs at injured vascular walls and the vascular repair effect of EPCs were enhanced in APE-EPCs compared with control EPCs. Among the cellular functions of EPCs, adhesion is especially sensitive to oxidative stress. APE1 enhances in vivo vascular repair effects of EPCs in part through the maintenance of adhesion properties of EPCs. APE1 may be a novel and useful target gene for effective cellular transplantation therapy. PMID- 23934859 TI - Microvascular function in younger adults with obesity and metabolic syndrome: role of oxidative stress. AB - Older adults with cardiovascular disease exhibit microvascular dysfunction and increased levels of reactive oxygen species (ROS). We hypothesized that microvascular impairments begin early in the disease process and can be improved by scavenging ROS. Forearm blood flow (Doppler ultrasound) was measured in 45 young (32 +/- 2 yr old) adults (n = 15/group) classified as lean, obese, and metabolic syndrome (MetSyn). Vasodilation in response to endothelial (ACh) and vascular smooth muscle [nitroprusside (NTP) and epoprostenol (Epo)] agonists was tested before and after intra-arterial infusion of ascorbic acid to scavenge ROS. Vasodilation was assessed as a rise in relative vascular conductance (ml.min( 1).dl(-1).100 mmHg(-1)). ACh and NTP responses were preserved (P = 0.825 and P = 0.924, respectively), whereas Epo responses were lower in obese and MetSyn adults (P < 0.05) than in lean controls. Scavenging of ROS via infusion of ascorbic acid resulted in an increase in ACh-mediated (P < 0.001) and NTP-mediated (P < 0.001) relative vascular conductance across all groups, suggesting that oxidative stress influences vascular responsiveness in adults with and without overt cardiovascular disease risk. Ascorbic acid had no effect on Epo-mediated vasodilation (P = 0.267). These results suggest that obese and MetSyn adults exhibit preserved endothelium-dependent vasodilation with reduced dependence on prostacyclin and are consistent with an upregulation of compensatory vascular control mechanisms. PMID- 23934860 TI - Substrate-dependent dynamics of UDP-galactopyranose mutase: Implications for drug design. AB - Trypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical disease that represents one of the major health challenges of the Latin American countries. Successful efforts were made during the last few decades to control the transmission of this disease, but there is still no treatment for the 10 million adults in the chronic phase of the disease. In T. cruzi, as well as in other pathogens, the flavoenzyme UDP-galactopyranose mutase (UGM) catalyzes the conversion of UDP-galactopyranose to UDP-galactofuranose, a precursor of the cell surface beta-galactofuranose that is involved in the virulence of the pathogen. The fact that UGM is not present in humans makes inhibition of this enzyme a good approach in the design of new Chagas therapeutics. By performing a series of computer simulations of T. cruzi UGM in the presence or absence of an active site ligand, we address the molecular details of the mechanism that controls the uptake and retention of the substrate. The simulations suggest a modular mechanism in which each moiety of the substrate controls the flexibility of a different protein loop. Furthermore, the calculations indicate that interactions with the substrate diphosphate moiety are especially important for stabilizing the closed active site. This hypothesis is supported with kinetics measurements of site-directed mutants of T. cruzi UGM. Our results extend our knowledge of UGM dynamics and offer new alternatives for the prospective design of drugs. PMID- 23934861 TI - Nucleoside analogues with a 1,3-diene-Fe(CO)3 substructure: stereoselective synthesis, configurational assignment, and apoptosis-inducing activity. AB - The synthesis and stereochemical assignment of two classes of iron-containing nucleoside analogues, both of which contain a butadiene-Fe(CO)3 substructure, is described. The first type of compounds are Fe(CO)3-complexed 3'-alkenyl-2',3' dideoxy-2',3'-dehydro nucleosides (2,5-dihydrofuran derivatives), from which the second class of compounds is derived by formal replacement of the ring oxygen atom by a CH2 group (carbocyclic nucleoside analogues). These compounds were prepared in a stereoselective manner through the metal-assisted introduction of the nucleobase. Whilst the furanoid intermediates were prepared from carbohydrates (such as methyl-glucopyranoside), the carbocyclic compounds were obtained by using an intramolecular Pauson-Khand reaction. Stereochemical assignments based on NMR and CD spectroscopy were confirmed by X-ray structural analysis. Biological investigations revealed that several of the complexes exhibited pronounced apoptosis-inducing properties (through an unusual caspase 3 independent but ROS-dependent pathway). Furthermore, some structure-activity relationships were identified, also as a precondition for the design and synthesis of fluorescent and biotin-labeled conjugates. PMID- 23934862 TI - PSA enzymatic activity: a new biomarker for assessing prostate cancer aggressiveness. AB - BACKGROUND: With the advent of widespread prostate-specific antigen (PSA) testing in recent decades, prostate cancer (PCa) has emerged as the most frequently diagnosed non-skin cancer among men in the U.S. and Europe. Greater screening rates coupled with improved detection methods have caused a controversial upsurge in the number of men undergoing prostate biopsy and subsequent treatment. However, current diagnostic techniques generally suffer from limited ability to identify which seemingly indolent cancers are biologically aggressive. METHODS: We collected prostatic fluid from 778 post-radical prostatectomy specimens and randomly selected samples from both the clinically confirmed aggressive (n = 50) and non-aggressive (n = 50) prostate cancer populations. We measured the level of proteolytic enzyme activity of PSA (aPSA) in each sample and used receiver operating characteristic (ROC) analysis to correlate aPSA levels with prostate cancer aggressiveness. RESULTS: We found aPSA in prostatic fluid to be inversely proportional to disease stage, such that patients with the most aggressive PCa have on average significantly reduced aPSA compared to those with less aggressive disease. Significantly, our results suggest that many (22% in our study population) of the diagnosed patients with non-aggressive PCa could have averted or delayed radical prostatectomy. CONCLUSIONS: Given the high level of debate surrounding PSA screening effectiveness [3-5] and the recent U.S. Preventative Services Task Force recommendation to discontinue PSA screening [6], our results provide renewed hope that a clinical monitoring tool may emerge that truly refines PCa treatment decision-making. PMID- 23934863 TI - Comprehensive and accurate Ab initio energy surface of simple alanine peptides. AB - Secondary structures for AcAla(n)NH(2) (n=2-4) peptides have been analyzed by means of ab initio MP2, CCSD(T), and DFT-B3PW91 methods using large basis sets and including implicit hydration effects and thermal corrections. In addition to the classical "pure" right-handed 3(10)- and alpha-helices, left-handed polyproline II, inverse gamma-turn, and fully extended conformations, a large number of "mixed" structures obtained by combining characteristic phi/psi angles of each residue in every way have been found. All mixed structures are energetically accessible and can be present at significant levels in aqueous solution. Furthermore, they represent the way through which hierarchical unfolding of 3(10)- and alpha-helices or nonhierarchical polyproline II to fully extended transitions occur. Computational results are in qualitative agreement with the large amount of experimental data for simpler polyalanines and provide significant insight into their thermodynamic properties and how these can be modulated by interactions with solvent. PMID- 23934864 TI - Nicotinic acetylcholine receptor agonists: a milestone for modern crop protection. AB - The destruction of crops by invertebrate pests is a major threat against a background of a continuously rising demand in food supply for a growing world population. Therefore, efficient crop protection measures in a vast range of agricultural settings are of utmost importance to guarantee sustainable yields. The discovery of synthetic agonists selectively addressing the nicotinic acetylcholine receptors (nAChRs), located in the central nervous system of insects, for use as insecticides was a major milestone in applied crop protection research. These compounds, as a result of their high target specificity and versatility in application methods, opened a new innovative era in the control of some of the world's most devastating insect pests. These insecticides also contributed massively to extending our knowledge of the biochemistry of insect nicotinic acetylcholine receptors. The global economic success of synthetic nAChR agonists as insecticides renders the nicotinic acetylcholine receptor still one of the most attractive target sites for exploration in insecticide discovery. PMID- 23934865 TI - Expanding the frontiers of protein-protein modeling: from docking and scoring to binding affinity predictions and other challenges. AB - In addition to protein-protein docking, this CAPRI edition included new challenges, like protein-water and protein-sugar interactions, or the prediction of binding affinities and DeltaDeltaG changes upon mutation. Regarding the standard protein-protein docking cases, our approach, mostly based on the pyDock scheme, submitted correct models as predictors and as scorers for 67% and 57% of the evaluated targets, respectively. In this edition, available information on known interface residues hardly made any difference for our predictions. In one of the targets, the inclusion of available experimental small-angle X-ray scattering (SAXS) data using our pyDockSAXS approach slightly improved the predictions. In addition to the standard protein-protein docking assessment, new challenges were proposed. One of the new problems was predicting the position of the interface water molecules, for which we submitted models with 20% and 43% of the water-mediated native contacts predicted as predictors and scorers, respectively. Another new problem was the prediction of protein-carbohydrate binding, where our submitted model was very close to being acceptable. A set of targets were related to the prediction of binding affinities, in which our pyDock scheme was able to discriminate between natural and designed complexes with area under the curve = 83%. It was also proposed to estimate the effect of point mutations on binding affinity. Our approach, based on machine learning methods, showed high rates of correctly classified mutations for all cases. The overall results were highly rewarding, and show that the field is ready to move forward and face new interesting challenges in interactomics. PMID- 23934866 TI - Prior housing conditions and sleep loss may affect recovery from brain injury in rats: a pilot study. AB - The purpose of this study is to understand the effect of combat-associated conditions such as sleep deprivation (SD) on subsequent traumatic brain injury (TBI). Prior to TBI (or sham surgery) induced by controlled cortical impact (CCI), rats were housed singly in chambers that prevented rapid eye movement sleep or allowed unrestricted sleep (no SD). Sensorimotor function was tested pre SD and retested on postoperative days (PDs) 4, 7, and 14. Two additional control groups were housed socially prior to either CCI or sham surgery. CCI resulted in immediate performance deficits on sensorimotor tasks. The PD on which performance returned to baseline depended on preinjury conditions. Overall, preinjury SD+CCI resulted in an earlier recovery than no SD+CCI, and the no SD+CCI group (housed singly under conditions comparable with the SD group) recovered slower than all other groups. These data are the first to raise the possibility that recovery of sensorimotor function following TBI is affected by preinjury conditions. The data suggest that preinjury SD 24 h in duration may result in faster recovery and that novel or social isolation conditions may impede recovery. Thus, the combat environment may contribute to complexities associated with TBIs common in U.S. servicemembers. PMID- 23934867 TI - Driving simulator performance of veterans from the Iraq and Afghanistan wars. AB - Driving simulator performance was examined in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) Veterans to objectively evaluate driving abilities among this cohort who self-report poorer driving safety postdeployment. OIF/OEF Veterans (n = 25) and age- and education-matched civilian controls (n = 25) participated in a 30 min driving simulator assessment that measured the frequency of minor, moderate, and severe driving errors. Frequency of errors in specific content domains (speed regulation, positioning, and signaling) was also calculated. All participants answered questions about number of lifetime traffic "warnings," moving violation tickets, and accidents. Veterans completed the Posttraumatic Stress Disorder (PTSD) Checklist-Military Version. On the driving simulator assessment, Veterans committed more minor, moderate, severe, and speeding errors and reported poorer lifetime driving records than the civilian control group. Exploratory analyses revealed an association between increasing errors on the driving simulator with increasing symptoms of PTSD, although statistically this correlation did not reach significance. These findings suggest that Veterans perform more poorly on an objective evaluation of driving safety and that the presence of PTSD could be associated with worse performance on this standardized driving simulator assessment. PMID- 23934868 TI - Use of group treatment among case managers in Department of Veterans Affairs supported housing program. AB - Because the predominant supported housing model includes individual intensive community-based case management, use of group treatments in supported housing has not been adequately studied. This study examined practices and attitudes about groups among case managers in the Department of Housing and Urban Development Department of Veterans Affairs Supportive Housing (HUD-VASH) program. We examined national administrative HUD-VASH data and an online survey of case managers from eight sites in the New England region, where dissemination of a new group-based model is in progress. Compared with other sites nationally, sites in the New England region had more group contacts, possibly reflecting the dissemination project. Among the New England sites (n = 8), administrative data showed that a higher percentage of group contacts was associated with a greater number of clients served and with more contacts per client. Although case manager survey data (n = 55) showed generally positive attitudes about using groups, particularly about the potential effectiveness of groups and peer support, greater reported use of groups was not associated with more positive attitudes about groups. These findings suggest providing group treatments in supported housing programs may help case managers stay connected to clients and case managers appear receptive to using groups, though further research is needed. PMID- 23934869 TI - Patient repositioning and pressure ulcer risk--monitoring interface pressures of at-risk patients. AB - Repositioning patients regularly to prevent pressure ulcers and reduce interface pressures is the standard of care, yet prior work has found that standard repositioning does not relieve all areas of at-risk tissue in nondisabled subjects. To determine whether this holds true for high-risk patients, we assessed the effectiveness of routine repositioning in relieving at-risk tissue of the perisacral area using interface pressure mapping. Bedridden patients at risk for pressure ulcer formation (n = 23, Braden score <18) had their perisacral skin-bed interface pressures recorded every 30 s while they received routine repositioning care for 4-6 h. All participants had specific skin areas (206 +/- 182 cm(2)) that exceeded elevated pressure thresholds for >95% of the observation period. Thirteen participants were observed in three distinct positions (supine, turned left, turned right), and all had specific skin areas (166 +/- 184 cm(2)) that exceeded pressure thresholds for >95% of the observation period. At-risk patients have skin areas that are likely always at risk throughout their hospital stay despite repositioning. Healthcare providers are unaware of the actual tissue relieving effectiveness (or lack thereof) of their repositioning interventions, which may partially explain why pressure ulcer mitigation strategies are not always successful. Relieving at-risk tissue is a necessary part of pressure ulcer prevention, but the repositioning practice itself needs improvement. PMID- 23934870 TI - Role of sensory and motor intensity of electrical stimulation on fibroblastic growth factor-2 expression, inflammation, vascularization, and mechanical strength of full-thickness wounds. AB - Electrical stimulation (ES) profoundly affects angiogenesis by modulating the production of angiogenic factors. We evaluated the effect of sensory (direct current, 600 microamperes) and motor (monophasic pulse current, 2.5 to 3 milliamperes, 300-microsecond pulse duration, 100 Hz) intensities of cathodal current on the release of fibroblastic growth factor-2 (FGF-2) at the wound site and also the biomechanical and histological properties of healed skin. Ninety-six male, Sprague-Dawley rats were randomly assigned into one control and two experimental groups. A full-thickness skin incision was made on the dorsal region of each animal. The experimental groups received 10 sessions of ES (sensory or motor) for 1 hour per day every other day. The results showed that FGF-2 levels in the sensory group were significantly greater than in the other groups on the third day. In the motor group, FGF-2 levels were significantly decreased compared with the control group. There were no significant differences between the normalized ultimate strength and stiffness in the groups, but they tended to be higher in the motor ES group. We conclude that the application of sensory ES during the early stage of wound healing may have a beneficial effect on wound healing by inducing the release of angiogenic factors and decreasing the duration of the inflammation phase. PMID- 23934872 TI - Long-term activity in and among persons with transfemoral amputation. AB - Although physical limitations associated with transfemoral amputation (TFA) have been studied in laboratory settings, little is known about habitual activity within free-living environments. A retrospective analysis of 12 mo of step activity data was performed to quantify activity levels, variations, and patterns in 17 adults with unilateral TFA. Yearly, seasonal, and monthly average daily step counts and coefficients of variation (CoVs) were examined to characterize mobility. Analysis by Medicare Functional Classification Level (MFCL) was performed to explore relationships between clinical classification and performance. Subjects averaged 1,540 prosthetic steps/day, and activity generally increased with MFCL. Activity between MFCL-2 and -3 subjects was not significantly different, suggesting that ability to engage in habitual physical activity may be similar for these groups. Relative variation (CoV) was 0.65 across subjects but was lower for those with higher activity levels. No significant differences in CoV by group were detected. Marked seasonal and monthly patterns in activity were identified. Warmer seasons and months generally promoted higher activity, but peak temperatures and humidity depressed activity. Results suggest that persons with TFA are greatly limited in regards to activity. Further, large variations within and between subjects may challenge the interpretation of step activity gathered over short periods of time. PMID- 23934871 TI - Muscle activity during stance phase of walking: comparison of males with transfemoral amputation with osseointegrated fixations to nondisabled male volunteers. AB - A recent development in prosthetics is the osseointegrated fixation (OF), with improvements in comfort, fatigue, hip movement, and ease of prosthetic attachment reported. However, little information is available regarding muscle function. This study reports on selected gait parameters of the residual limb during the stance phase of level overground walking, focusing on muscle activity. Five males with transfemoral amputation (TFA) with OFs were recruited. Ground reaction force (GRF), lower-limb kinematics, and surface electromyography (sEMG) from residual limb muscles were recorded. sEMG data were also collected from a group of 10 nondisabled male subjects. Interstance variability of gait parameters was assessed by coefficient of multiple correlations. Repeatability of GRF and hip kinematics was high, whereas repeatability of the sEMG was low for four of the five individuals with TFA. Interstance variability of the sEMG for gluteus medius (GMED) was significantly greater in the group with TFA. The main difference in sEMG between the groups was the phase, with GMED and adductor magnus displaying greater differences than their counterparts in the nondisabled group. Results demonstrate that muscles in the residual limb retain aspects of their previous functional pattern. PMID- 23934873 TI - Bilateral electromyogram response latency following platform perturbation in unilateral transtibial prosthesis users: influence of weight distribution and limb position. AB - Appropriate muscular response following an external perturbation is essential in preventing falls. Transtibial prosthesis users lack a foot-ankle complex and associated sensorimotor structures on the side with the prosthesis. The effect of this lack on rapid responses of the lower limb to external surface perturbations is unknown. The aim of the present study was to compare electromyogram (EMG) response latencies of otherwise healthy, unilateral, transtibial prosthesis users (n = 23, mean +/- standard deviation [SD] age = 48 +/- 14 yr) and a matched control group (n = 23, mean +/- SD age = 48 +/- 13 yr) following sudden support surface rotations in the pitch plane (toes-up and toes-down). Perturbations were elicited in various weight-bearing and limb-perturbed conditions. The results indicated that transtibial prosthesis users have delayed responses of multiple muscles of the lower limb following perturbation, both in the intact and residual limbs. Weight-bearing had no influence on the response latency in the residual limb, but did on the intact limb. Which limb received the perturbation was found to influence the muscular response, with the intact limb showing a significantly delayed response when the perturbation was received only on the side with a prosthesis. These delayed responses may represent an increased risk of falling for individuals who use transtibial prostheses. PMID- 23934874 TI - Cycling exercise to resist electrically stimulated antagonist increases oxygen uptake in males: pilot study. AB - A hybrid training system (HTS) has been developed as the combined application of electrical stimulation (ES) and volitional contractions (VC), using electrically stimulated eccentric antagonist muscle contractions as a resistance to voluntary agonist muscle contractions. The purpose of the present study is to compare the metabolic cost between cycling exercise using HTS as added resistance (HTC) and unloaded cycling exercise (ULC). Twelve male subjects exercised on a leg cycle ergometer. After 5 min rest and 5 min warm up, they performed ULC for 5 min or HTC for 5 min. During rest and each exercise, the steady state of oxygen uptake (VO2), carbon dioxide output (VCO2), expired ventilation (VE), respiratory exchange ratio (RER), and heart rate (HR) were measured. The values of VO2, VCO2, VE, and HR during HTC were significantly greater than during ULC (p < 0.05). Relative VO2 was 16.7% +/- 2.1% of peak VO2 during ULC, and it was 21.1% +/- 3.4% during HTC. However, there was no significant difference in RER between ULC and HTC. These findings indicate that the combined application of VC and ES could lead to a greater increase in metabolic cost. HTS seems to be applicable as a resistance of motion. PMID- 23934875 TI - Changes in passive ankle stiffness and its effects on gait function in people with chronic stroke. AB - Mechanical impedance of the ankle is known to influence key aspects of ankle function. We investigated the effects of robot-assisted ankle training in people with chronic stroke on the paretic ankle's passive stiffness and its relationship to overground gait function. Over 6 wk, eight participants with residual hemiparetic deficits engaged in a visuomotor task while seated that required dorsiflexion (DF) or plantar flexion (PF) of their paretic ankle with an ankle robot ("anklebot") assisting as needed. Passive ankle stiffness (PAS) was measured in both the trained sagittal and untrained frontal planes. After 6 wk, the PAS decreased in both DF and PF and reverted into the variability of age matched controls in DF. Changes in PF PAS correlated strongly with gains in paretic step lengths (Spearman rho = -0.88, p = 0.03) and paretic stride lengths (Spearman rho = -0.82, p = 0.05) during independent floor walking. Moreover, baseline PF PAS were correlated with gains in paretic step lengths (Spearman rho = 0.94, p = 0.01), paretic stride lengths (Spearman rho = 0.83, p = 0.05), and single-support stance duration (Spearman rho = 0.94, p = 0.01); and baseline eversion PAS were correlated with gains in cadence (Spearman rho = -0.88, p = 0.03). These findings suggest that ankle robot-assisted, visuomotor-based, isolated ankle training has a positive effect on paretic ankle PAS that strongly influences key measures of gait function. PMID- 23934876 TI - Evaluating psychoacoustic measures for establishing presence of tinnitus. AB - The Department of Veterans Affairs (VA) considers tinnitus a disability. Veterans can claim tinnitus as a "service-connected" disability if the tinnitus is thought to be connected to military service. The VA adjudicates each claim and determines whether reasonable evidence exists to support it. Currently, determining the presence of tinnitus is based on subjective reporting-objective measures do not exist. The aim of this study was to develop and document a test for detecting the presence/absence of tinnitus with high confidence. Using our computer-automated, self-guided tinnitus evaluation system, we conducted three phases of testing to compare psychoacoustic measures of tinnitus between participants with versus without tinnitus. Phase 1 measures included loudness match, pitch match, minimum masking level, residual inhibition, Bekesy, and forced-choice double staircase. Phases 2 and 3 measures were chosen based on results of the previous phase. The number of tests and time of testing decreased during each successive phase. Differences were seen between groups; most notably, higher low-frequency loudness matches and higher median pitch matches were observed for participants with tinnitus. Results of this study suggest that further efforts can produce a defined psychoacoustic test battery for identifying the presence/absence of tinnitus. PMID- 23934877 TI - Hearing aid effectiveness after aural rehabilitation: individual versus group trial results. AB - We designed this noninferiority randomized trial to determine (1) if group hearing aid fitting visits and group hearing aid follow-up visits were at least as effective as individual visits in terms of hearing-related function (measured with the Inner Effectiveness of Auditory Rehabilitation [EAR] scale) and adherence, and (2) if group visits were less costly over the 6 mo post-fitting period. For 644 participants randomized to receive their hearing aid visits in an individual or group format at the Department of Veterans Affairs Puget Sound Health Care System, 6 mo outcomes showed no significant differences in Inner EAR scores between individual and group fitting (p = 0.53) or follow-up (p = 0.11), or in the number of hours per day hearing aids were worn between individual and group fitting (p = 0.90) or follow-up (p = 0.24). We found significantly higher cost for individual compared with group fitting (p < 0.001) and follow-up (p < 0.001). We conclude that outcomes for group hearing aid fitting and hearing aid follow-up visits were not inferior to individual hearing aid fitting and follow up visits, with group fitting and follow-up visits yielding cost savings. PMID- 23934878 TI - Early and innovative symptomatic care to improve quality of life of ALS patients at Cleveland VA ALS Center. PMID- 23934879 TI - Nematicidal metabolites from roots of Stellera chamaejasme against Bursaphelenchus xylophilus and Bursaphelenchus mucronatus. AB - BACKGROUND: Bursaphelenchus xylophilus, the causal agent of pine wilt disease, severely damages pine forests, and Bursaphelenchus mucronatus, a species related to B. xylophilus, is weakly pathogenic. Because the use of synthetic pesticides to control pine wilt disease has raised concerns for human and environmental health, a search for useful botanically based compounds is needed. RESULTS: The ethyl acetate layer from an ethanol extract of Stellera chamaejasme L. roots showed significant nematicidal activity against B. xylophilus and B. mucronatus, with LC50 values of 169.7 and 37.7 ug mL(-1), respectively, at 72 h. Further purification of the active layer yielded eight effective nematicidal compounds, which were identified by mass and nuclear magnetic resonance spectral data. Among the eight bioactive compounds, chamaejasmenin C induced the highest mortality against B. xylophilus, with an LC50 value of 2.7 uM at 72 h, and chamaechromone exhibited strong nematicidal activity against B. mucronatus, with an LC50 value of 0.003 uM at 72 h. CONCLUSION: The nematicidal metabolites from S. chamaejasme roots could be used as lead compounds for developing botanically based nematicides for the management of pine wilt disease. PMID- 23934880 TI - Accumulation of spontaneous mutations in the ciliate Tetrahymena thermophila. AB - Knowledge of the rate and fitness effects of mutations is essential for understanding the process of evolution. Mutations are inherently difficult to study because they are rare and are frequently eliminated by natural selection. In the ciliate Tetrahymena thermophila, mutations can accumulate in the germline genome without being exposed to selection. We have conducted a mutation accumulation (MA) experiment in this species. Assuming that all mutations are deleterious and have the same effect, we estimate that the deleterious mutation rate per haploid germline genome per generation is U=0.0047 (95% credible interval: 0.0015, 0.0125), and that germline mutations decrease fitness by s=11% when expressed in a homozygous state (95% CI: 4.4%, 27%). We also estimate that deleterious mutations are partially recessive on average (h=0.26; 95% CI: -0.022, 0.62) and that the rate of lethal mutations is <10% of the deleterious mutation rate. Comparisons between the observed evolutionary responses in the germline and somatic genomes and the results from individual-based simulations of MA suggest that the two genomes have similar mutational parameters. These are the first estimates of the deleterious mutation rate and fitness effects from the eukaryotic supergroup Chromalveolata and are within the range of those of other eukaryotes. PMID- 23934881 TI - Rare variants in hypermutable genes underlie common morphology and growth traits in wild Saccharomyces paradoxus. AB - Understanding the molecular basis of common traits is a primary challenge of modern genetics. One model holds that rare mutations in many genetic backgrounds may often phenocopy one another, together explaining the prevalence of the resulting trait in the population. For the vast majority of phenotypes, the role of rare variants and the evolutionary forces that underlie them are unknown. In this work, we use a population of Saccharomyces paradoxus yeast as a model system for the study of common trait variation. We observed an unusual, flocculation and invasive-growth phenotype in one-third of S. paradoxus strains, which were otherwise unrelated. In crosses with each strain in turn, these morphologies segregated as a recessive Mendelian phenotype, mapping either to IRA1 or to IRA2, yeast homologs of the hypermutable human neurofibromatosis gene NF1. The causal IRA1 and IRA2 haplotypes were of distinct evolutionary origin and, in addition to their morphological effects, associated with hundreds of stress-resistance and growth traits, both beneficial and disadvantageous, across S. paradoxus. Single gene molecular genetic analyses confirmed variant IRA1 and IRA2 haplotypes as causal for these growth characteristics, many of which were independent of morphology. Our data make clear that common growth and morphology traits in yeast result from a suite of variants in master regulators, which function as a mutation-driven switch between phenotypic states. PMID- 23934882 TI - Negative functional interaction between cell integrity MAPK pathway and Rho1 GTPase in fission yeast. AB - Rho1 GTPase is the main activator of cell wall glucan biosynthesis and regulates actin cytoskeleton in fungi, including Schizosaccharomyces pombe. We have obtained a fission yeast thermosensitive mutant strain carrying the rho1-596 allele, which displays reduced Rho1 GTPase activity. This strain has severe cell wall defects and a thermosensitive growth, which is partially suppressed by osmotic stabilization. In a global screening for rho1-596 multicopy suppresors the pmp1+ gene was identified. Pmp1 is a dual specificity phosphatase that negatively regulates the Pmk1 mitogen-activated protein kinase (MAPK) cell integrity pathway. Accordingly, elimination of Pmk1 MAPK partially rescued rho1 596 thermosensitivity, corroborating the unexpected antagonistic functional relationship of these genes. We found that rho1-596 cells displayed increased basal activation of the cell integrity MAPK pathway and therefore were hypersensitive to MgCl2 and FK506. Moreover, the absence of calcineurin was lethal for rho1-596. We found a higher level of calcineurin activity in rho1-596 than in wild-type cells, and overexpression of constitutively active calcineurin partially rescued rho1-596 thermosensitivity. All together our results suggest that loss of Rho1 function causes an increase in the cell integrity MAPK activity, which is detrimental to the cells and turns calcineurin activity essential. PMID- 23934883 TI - Genome-wide prediction of traits with different genetic architecture through efficient variable selection. AB - In genome-based prediction there is considerable uncertainty about the statistical model and method required to maximize prediction accuracy. For traits influenced by a small number of quantitative trait loci (QTL), predictions are expected to benefit from methods performing variable selection [e.g., BayesB or the least absolute shrinkage and selection operator (LASSO)] compared to methods distributing effects across the genome [ridge regression best linear unbiased prediction (RR-BLUP)]. We investigate the assumptions underlying successful variable selection by combining computer simulations with large-scale experimental data sets from rice (Oryza sativa L.), wheat (Triticum aestivum L.), and Arabidopsis thaliana (L.). We demonstrate that variable selection can be successful when the number of phenotyped individuals is much larger than the number of causal mutations contributing to the trait. We show that the sample size required for efficient variable selection increases dramatically with decreasing trait heritabilities and increasing extent of linkage disequilibrium (LD). We contrast and discuss contradictory results from simulation and experimental studies with respect to superiority of variable selection methods over RR-BLUP. Our results demonstrate that due to long-range LD, medium heritabilities, and small sample sizes, superiority of variable selection methods cannot be expected in plant breeding populations even for traits like FRIGIDA gene expression in Arabidopsis and flowering time in rice, assumed to be influenced by a few major QTL. We extend our conclusions to the analysis of whole genome sequence data and infer upper bounds for the number of causal mutations which can be identified by LASSO. Our results have major impact on the choice of statistical method needed to make credible inferences about genetic architecture and prediction accuracy of complex traits. PMID- 23934884 TI - Imprints of natural selection along environmental gradients in phenology-related genes of Quercus petraea. AB - We explored single nucleotide polymorphism (SNP) variation in candidate genes for bud burst from Quercus petraea populations sampled along gradients of latitude and altitude in Western Europe. SNP diversity was monitored for 106 candidate genes, in 758 individuals from 32 natural populations. We investigated whether SNP variation reflected the clinal pattern of bud burst observed in common garden experiments. We used different methods to detect imprints of natural selection (FST outlier, clinal variation at allelic frequencies, association tests) and compared the results obtained for the two gradients. FST outlier SNPs were found in 15 genes, 5 of which were common to both gradients. The type of selection differed between the two gradients (directional or balancing) for 3 of these 5. Clinal variations were observed for six SNPs, and one cline was conserved across both gradients. Association tests between the phenotypic or breeding values of trees and SNP genotypes identified 14 significant associations, involving 12 genes. The results of outlier detection on the basis of population differentiation or clinal variation were not very consistent with the results of association tests. The discrepancies between these approaches may reflect the different hierarchical levels of selection considered (inter- and intrapopulation selection). Finally, we obtained evidence for convergent selection (similar for gradients) and clinal variation for a few genes, suggesting that comparisons between parallel gradients could be used to screen for major candidate genes responding to natural selection in trees. PMID- 23934885 TI - A novel approach to estimating heterozygosity from low-coverage genome sequence. AB - High-throughput shotgun sequence data make it possible in principle to accurately estimate population genetic parameters without confounding by SNP ascertainment bias. One such statistic of interest is the proportion of heterozygous sites within an individual's genome, which is informative about inbreeding and effective population size. However, in many cases, the available sequence data of an individual are limited to low coverage, preventing the confident calling of genotypes necessary to directly count the proportion of heterozygous sites. Here, we present a method for estimating an individual's genome-wide rate of heterozygosity from low-coverage sequence data, without an intermediate step that calls genotypes. Our method jointly learns the shared allele distribution between the individual and a panel of other individuals, together with the sequencing error distributions and the reference bias. We show our method works well, first, by its performance on simulated sequence data and, second, on real sequence data where we obtain estimates using low-coverage data consistent with those from higher coverage. We apply our method to obtain estimates of the rate of heterozygosity for 11 humans from diverse worldwide populations and through this analysis reveal the complex dependency of local sequencing coverage on the true underlying heterozygosity, which complicates the estimation of heterozygosity from sequence data. We show how we can use filters to correct for the confounding arising from sequencing depth. We find in practice that ratios of heterozygosity are more interpretable than absolute estimates and show that we obtain excellent conformity of ratios of heterozygosity with previous estimates from higher coverage data. PMID- 23934886 TI - Empirical complexities in the genetic foundations of lethal mutagenesis. AB - From population genetics theory, elevating the mutation rate of a large population should progressively reduce average fitness. If the fitness decline is large enough, the population will go extinct in a process known as lethal mutagenesis. Lethal mutagenesis has been endorsed in the virology literature as a promising approach to viral treatment, and several in vitro studies have forced viral extinction with high doses of mutagenic drugs. Yet only one empirical study has tested the genetic models underlying lethal mutagenesis, and the theory failed on even a qualitative level. Here we provide a new level of analysis of lethal mutagenesis by developing and evaluating models specifically tailored to empirical systems that may be used to test the theory. We first quantify a bias in the estimation of a critical parameter and consider whether that bias underlies the previously observed lack of concordance between theory and experiment. We then consider a seemingly ideal protocol that avoids this bias mutagenesis of virions-but find that it is hampered by other problems. Finally, results that reveal difficulties in the mere interpretation of mutations assayed from double-strand genomes are derived. Our analyses expose unanticipated complexities in testing the theory. Nevertheless, the previous failure of the theory to predict experimental outcomes appears to reside in evolutionary mechanisms neglected by the theory (e.g., beneficial mutations) rather than from a mismatch between the empirical setup and model assumptions. This interpretation raises the specter that naive attempts at lethal mutagenesis may augment adaptation rather than retard it. PMID- 23934887 TI - Genotype imputation reference panel selection using maximal phylogenetic diversity. AB - The recent dramatic cost reduction of next-generation sequencing technology enables investigators to assess most variants in the human genome to identify risk variants for complex diseases. However, sequencing large samples remains very expensive. For a study sample with existing genotype data, such as array data from genome-wide association studies, a cost-effective approach is to sequence a subset of the study sample and then to impute the rest of the study sample, using the sequenced subset as a reference panel. The use of such an internal reference panel identifies population-specific variants and avoids the problem of a substantial mismatch in ancestry background between the study population and the reference population. To efficiently select an internal panel, we introduce an idea of phylogenetic diversity from mathematical phylogenetics and comparative genomics. We propose the "most diverse reference panel", defined as the subset with the maximal "phylogenetic diversity", thereby incorporating individuals that span a diverse range of genotypes within the sample. Using data both from simulations and from the 1000 Genomes Project, we show that the most diverse reference panel can substantially improve the imputation accuracy compared to randomly selected reference panels, especially for the imputation of rare variants. The improvement in imputation accuracy holds across different marker densities, reference panel sizes, and lengths for the imputed segments. We thus propose a novel strategy for planning sequencing studies on samples with existing genotype data. PMID- 23934888 TI - Predicting functionally informative mutations in Escherichia coli BamA using evolutionary covariance analysis. AB - The essential outer membrane beta-barrel protein BamA forms a complex with four lipoprotein partners BamBCDE that assembles beta-barrel proteins into the outer membrane of Escherichia coli. Detailed genetic studies have shown that BamA cycles through multiple conformations during substrate assembly, suggesting that a complex network of residues may be involved in coordinating conformational changes and lipoprotein partner function. While genetic analysis of BamA has been informative, it has also been slow in the absence of a straightforward selection for mutants. Here we take a bioinformatic approach to identify candidate residues for mutagenesis using direct coupling analysis. Starting with the BamA paralog FhaC, we show that direct coupling analysis works well for large beta-barrel proteins, identifying pairs of residues in close proximity in tertiary structure with a true positive rate of 0.64 over the top 50 predictions. To reduce the effects of noise, we designed and incorporated a novel structured prior into the empirical correlation matrix, dramatically increasing the FhaC true positive rate from 0.64 to 0.88 over the top 50 predictions. Our direct coupling analysis of BamA implicates residues R661 and D740 in a functional interaction. We find that the substitutions R661G and D740G each confer OM permeability defects and destabilize the BamA beta-barrel. We also identify synthetic phenotypes and cross suppressors that suggest R661 and D740 function in a similar process and may interact directly. We expect that the direct coupling analysis approach to informed mutagenesis will be particularly useful in systems lacking adequate selections and for dynamic proteins with multiple conformations. PMID- 23934889 TI - TORC1 signaling is governed by two negative regulators in fission yeast. AB - The target of rapamycin (TOR) is a highly conserved protein kinase that regulates cell growth and metabolism. Here we performed a genome-wide screen to identify negative regulators of TOR complex 1 (TORC1) in Schizosaccharomyces pombe by isolating mutants that phenocopy Deltatsc2, in which TORC1 signaling is known to be up-regulated. We discovered that Deltanpr2 displayed similar phenotypes to Deltatsc2 in terms of amino acid uptake defects and mislocalization of the Cat1 permease. However, Deltanpr2 and Deltatsc2 clearly showed different phenotypes in terms of rapamycin supersensitivity and Isp5 transcription upon various treatments. Furthermore, we showed that Tor2 controls amino acid homeostasis at the transcriptional and post-transcriptional levels. Our data reveal that both Npr2 and Tsc2 negatively regulate TORC1 signaling, and Npr2, but not Tsc2, may be involved in the feedback loop of a nutrient-sensing pathway. PMID- 23934891 TI - Overcompensation in response to herbivory in Arabidopsis thaliana: the role of glucose-6-phosphate dehydrogenase and the oxidative pentose-phosphate pathway. AB - That some plants benefit from being eaten is counterintuitive, yet there is now considerable evidence demonstrating enhanced fitness following herbivory (i.e., plants can overcompensate). Although there is evidence that genetic variation for compensation exists, little is known about the genetic mechanisms leading to enhanced growth and reproduction following herbivory. We took advantage of the compensatory variation in recombinant inbred lines of Arabidopsis thaliana, combined with microarray and QTL analyses to assess the molecular basis of overcompensation. We found three QTL explaining 11.4, 10.1, and 26.7% of the variation in fitness compensation, respectively, and 109 differentially expressed genes between clipped and unclipped plants of the overcompensating ecotype Columbia. From the QTL/microarray screen we uncovered one gene that plays a significant role in overcompensation: glucose-6-phosphate-1-dehydrogenase (G6PDH1). Knockout studies of Transfer-DNA (T-DNA) insertion lines and complementation studies of G6PDH1 verify its role in compensation. G6PDH1 is a key enzyme in the oxidative pentose-phosphate pathway that plays a central role in plant metabolism. We propose that plants capable of overcompensating reprogram their transcriptional activity by up-regulating defensive genes and genes involved in energy metabolism and by increasing DNA content (via endoreduplication) with the increase in DNA content feeding back on pathways involved in defense and metabolism through increased gene expression. PMID- 23934890 TI - Architectural and functional diversity of polycomb group response elements in Drosophila. AB - Polycomb group response elements (PREs) play an essential role in gene regulation by the Polycomb group (PcG) repressor proteins in Drosophila. PREs are required for the recruitment and maintenance of repression by the PcG proteins. PREs are made up of binding sites for multiple DNA-binding proteins, but it is still unclear what combination(s) of binding sites is required for PRE activity. Here we compare the binding sites and activities of two closely linked yet separable PREs of the Drosophila engrailed (en) gene, PRE1 and PRE2. Both PRE1 and PRE2 contain binding sites for multiple PRE-DNA-binding proteins, but the number, arrangement, and spacing of the sites differs between the two PREs. These differences have functional consequences. Both PRE1 and PRE2 mediate pairing sensitive silencing of mini-white, a functional assay for PcG repression; however, PRE1 requires two binding sites for Pleiohomeotic (Pho), whereas PRE2 requires only one Pho-binding site for this activity. Furthermore, for full pairing-sensitive silencing activity, PRE1 requires an AT-rich region not found in PRE2. These two PREs behave differently in a PRE embryonic and larval reporter construct inserted at an identical location in the genome. Our data illustrate the diversity of architecture and function of PREs. PMID- 23934892 TI - Spargel/dPGC-1 is a new downstream effector in the insulin-TOR signaling pathway in Drosophila. AB - Insulin and target of rapamycin (TOR) signaling pathways converge to maintain growth so a proportionate body form is attained. Insufficiency in either insulin or TOR results in developmental growth defects due to low ATP level. Spargel is the Drosophila homolog of PGC-1, which is an omnipotent transcriptional coactivator in mammals. Like its mammalian counterpart, Spargel/dPGC-1 is recognized for its role in energy metabolism through mitochondrial biogenesis. An earlier study demonstrated that Spargel/dPGC-1 is involved in the insulin-TOR signaling, but a comprehensive analysis is needed to understand exactly which step of this pathway Spargel/PGC-1 is essential. Using genetic epistasis analysis, we demonstrated that a Spargel gain of function can overcome the TOR and S6K mediated cell size and cell growth defects in a cell autonomous manner. Moreover, the tissue-restricted phenotypes of TOR and S6k mutants are rescued by Spargel overexpression. We have further elucidated that Spargel gain of function sets back the mitochondrial numbers in growth-limited TOR mutant cell clones, which suggests a possible mechanism for Spargel action on cells and tissue to attain normal size. Finally, excess Spargel can ameliorate the negative effect of FoxO overexpression only to a limited extent, which suggests that Spargel does not share all of the FoxO functions and consequently cannot significantly rescue the FoxO phenotypes. Together, our observation established that Spargel/dPGC-1 is indeed a terminal effector in the insulin-TOR pathway operating below TOR, S6K, Tsc, and FoxO. This led us to conclude that Spargel should be incorporated as a new member of this growth-signaling pathway. PMID- 23934894 TI - Journal of Parkinson's disease. PMID- 23934895 TI - The most cited Parkinson's disease researchers - a personal perspective. PMID- 23934893 TI - Precise and heritable genome editing in evolutionarily diverse nematodes using TALENs and CRISPR/Cas9 to engineer insertions and deletions. AB - Exploitation of custom-designed nucleases to induce DNA double-strand breaks (DSBs) at genomic locations of choice has transformed our ability to edit genomes, regardless of their complexity. DSBs can trigger either error-prone repair pathways that induce random mutations at the break sites or precise homology-directed repair pathways that generate specific insertions or deletions guided by exogenously supplied DNA. Prior editing strategies using site-specific nucleases to modify the Caenorhabditis elegans genome achieved only the heritable disruption of endogenous loci through random mutagenesis by error-prone repair. Here we report highly effective strategies using TALE nucleases and RNA-guided CRISPR/Cas9 nucleases to induce error-prone repair and homology-directed repair to create heritable, precise insertion, deletion, or substitution of specific DNA sequences at targeted endogenous loci. Our robust strategies are effective across nematode species diverged by 300 million years, including necromenic nematodes (Pristionchus pacificus), male/female species (Caenorhabditis species 9), and hermaphroditic species (C. elegans). Thus, genome-editing tools now exist to transform nonmodel nematode species into genetically tractable model organisms. We demonstrate the utility of our broadly applicable genome-editing strategies by creating reagents generally useful to the nematode community and reagents specifically designed to explore the mechanism and evolution of X chromosome dosage compensation. By developing an efficient pipeline involving germline injection of nuclease mRNAs and single-stranded DNA templates, we engineered precise, heritable nucleotide changes both close to and far from DSBs to gain or lose genetic function, to tag proteins made from endogenous genes, and to excise entire loci through targeted FLP-FRT recombination. PMID- 23934897 TI - On the addition of aryl radicals to graphene: the importance of nonbonded interactions. AB - Dispersion-corrected density functional theory is utilized to study the addition of aryl radicals to perfect and defective graphene. Although the perfect sheet shows a low reactivity against aryl diazonium salts, the agglomeration of these groups and the addition onto defect sites improves the feasibility of the reaction by increasing binding energies per aryl group up to 27 kcal mol(-1). It is found that if a single phenyl radical interacts with graphene, the covalent and noncovalent additions have similar binding energies, but in the particular case of the nitrophenyl group, the adsorption is stronger than the chemisorption. The single vacancy shows the largest reactivity, increasing the binding energy per aryl group by about 80 kcal mol(-1). The zigzag edge ranks second, enhancing the reactivity 5.4 times with respect to the perfect sheet. The less reactive defect site is the Stone-Wales type, but even in this case the addition of an isolated aryl radical is exergonic. The arylation process is favored if the groups are attached nearby and on different sublattices. This is particularly true for the ortho and para positions. However, the enhancement of the binding energies decreases quickly if the distance between the two aryl radicals is increased, thereby making the addition on the perfect sheet difficult. A bandgap of 1-2 eV can be opened on functionalization of the graphene sheets with aryl radicals, but for certain configurations the sheet can maintain its semimetallic character even if there is one aryl radical per eight carbon atoms. At the highest level of functionalization achieved, that is, one aryl group per five carbon atoms, the bandgap is 1.9 eV. Regarding the effect of using aryl groups with different substituents, it is found that they all induce the same bandgap and thus the presence of NO(2), H, or Br is not relevant for the alteration of the electronic properties. Finally, it is observed that the presence of tetrafluoroborate can induce metallic character in graphene. PMID- 23934896 TI - An automated approach to network features of protein structure ensembles. AB - Network theory applied to protein structures provides insights into numerous problems of biological relevance. The explosion in structural data available from PDB and simulations establishes a need to introduce a standalone-efficient program that assembles network concepts/parameters under one hood in an automated manner. Herein, we discuss the development/application of an exhaustive, user friendly, standalone program package named PSN-Ensemble, which can handle structural ensembles generated through molecular dynamics (MD) simulation/NMR studies or from multiple X-ray structures. The novelty in network construction lies in the explicit consideration of side-chain interactions among amino acids. The program evaluates network parameters dealing with topological organization and long-range allosteric communication. The introduction of a flexible weighing scheme in terms of residue pairwise cross-correlation/interaction energy in PSN Ensemble brings in dynamical/chemical knowledge into the network representation. Also, the results are mapped on a graphical display of the structure, allowing an easy access of network analysis to a general biological community. The potential of PSN-Ensemble toward examining structural ensemble is exemplified using MD trajectories of an ubiquitin-conjugating enzyme (UbcH5b). Furthermore, insights derived from network parameters evaluated using PSN-Ensemble for single-static structures of active/inactive states of beta2-adrenergic receptor and the ternary tRNA complexes of tyrosyl tRNA synthetases (from organisms across kingdoms) are discussed. PSN-Ensemble is freely available from http://vishgraph.mbu.iisc.ernet.in/PSN-Ensemble/psn_index.html. PMID- 23934898 TI - Trochanteric non-union following revision hip replacement is associated with a poor functional outcome: a matched, case-control study. AB - The aim of this study was to determine the functional outcome in patients with a trochanteric non-union following revision total hip replacement. Twenty-five consecutive patients with a unilateral, trochanteric non-union were individually matched for age, sex, body mass index and duration of follow-up to two control groups: 1) 25 patients who had a primary total hip replacement ('primary controls'); and 2) 25 patients who had a revision total hip replacement ('revision controls'). At a mean follow up of approximately four years, the Harris hip score (HHS) for the cases was significantly worse compared to the primary control group (p<0.0001) and the revision control group (p<0.0001), with an overall 'poor' outcome in over half of the patients. The physical component of the Short Form-12 (SF-12) score was also significantly worse for the cases compared to the primary control group (p = 0.001), while the difference in the mental component approached significance (p = 0.057). There was no difference in the SF-12 scores between the cases and the revision control group (p = 0.1 and p = 0.4, respectively). A non-union of the greater trochanter is associated with a poor functional outcome following revision total hip replacement. PMID- 23934899 TI - The human hip joint and its long-term load intake--how x-ray density distribution mirrors bone strength. AB - The aim of this study was to gain information about the topographical distribution of the mechanical strength of the subchondral bone plate of the hip joint and evaluate the correlation to its density distribution. Our intention was to describe a method of visualising and monitoring the long-term load intake of the hip using conventional CT-data in a way which might be applied in clinical practice. We examined the lunate surface of the acetabulum (facies lunata) and femoral head in 25 cases, looking at the density of the subchondral bone plate by computed tomography osteoabsorptiometry (CT-OAM) and determined its mechanical strength by indentation testing using an osteo-penetrometer. The resulting distribution patterns were matched and statistically analysed, showing an inhomogeneous but regular and reproducible distribution of mineralisation and mechanical strength throughout the joint surface. Maximal density was found anterosuperiorly and near the rim of the facies lunata and in the superior area of the femoral head. For each specimen a correlation of density and strength (r(2) = 0.77 - 0.97) was found (p<0.01). The density distribution pattern shown by CT-OAM allows conclusions to be drawn about the distribution of strength and therefore the long term load intake within the subchondral bone plate of the hip. Using conventional CT-data, the method can be used in the clinical setting for evaluation and monitoring. PMID- 23934900 TI - Prevention of venous thromboembolic events following femoroacetabular osteoplasty: aspirin is enough for most. AB - BACKGROUND: As hip-preservation surgery is performed in a particularly young and active group of patients, the knowledge accrued in the fields of hip arthroplasty and hip fracture care regarding postoperative thromboprophylaxis cannot be extrapolated to this patient population. Recommendations based on the evidence for each particular surgical procedure and population is desirable. For these reasons, the purpose of our study is to describe the rate of clinically relevant venous thromboembolism (VTE) and anticoagulation-related complications observed in patients undergoing hip-preservation surgery through mini-open femoracetabular osteoplasty (FAO) with a formal postoperative thromboprophylaxis protocol of aspirin dosing. METHODS: A prospective case series of 407 consecutive FAO procedures in 375 patients of mean age 34.5 +/- 11.1 years (range 15-62 years) were followed six weeks post operatively to document the presence of clinically relevant VTE as well as major bleeding events, as defined by the most recent American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. All patients were given aspirin 325 mg by mouth daily for two to four weeks. RESULTS: There was one case of distal DVT in a 31-year-old male with no specific risk factors. No cases of pulmonary embolism were observed. There were no major bleeding events or reoperations due to postsurgical haematoma. There were no deaths. The crude incidence of clinically relevant VTE was 1 per 407 procedures (0.25%). CONCLUSION: Aspirin is a safe and effective modality to provide thromboprophylaxis in patients undergoing hip-preservation surgery. The rate of VTE that we observed is, thus far, the lowest in comparison to other published series of hip preservation surgery that specifically focused on this complication. PMID- 23934901 TI - A cost-utility analysis of a comprehensive orthogeriatric care for hip fracture patients, compared with standard of care treatment. AB - BACKGROUND: The economic burden associated with hip fractures calls for the investigation of innovative new cost-utility forms of organisation and integration of services for these patients. OBJECTIVE: To carry out a cost utility analysis integrating epidemiological and economic aspects for hip fracture patients treated within a comprehensive orthogeriatric model (COGM) of care, as compared with standard of care model (SOCM). DESIGN: A demonstration study conducted in a major tertiary medical centre, operating both a COGM ward and standard orthopaedic and rehabilitation wards. METHODS: Data was collected on the clinical outcomes and health care costs of the two different treatment modalities, in order to calculate the absolute cost and disability-adjusted life years (DALY) ratio. RESULTS: The COGM model used 23% fewer resources per patient ($14,919 vs. $19,363) than the SOCM model and to avert 0.226 additional DALY per patient, mainly as a result of lower 1-year mortality rates among COGM patients (14.8% vs. 17.3%). CONCLUSION: A comprehensive ortho-geriatric care modality is more cost-effective, providing additional quality-adjusted life years (QALY) while using fewer resources compared with standard of care approach. The results should assist health policy-makers in optimising healthcare use and healthcare planning. PMID- 23934902 TI - Measuring limb length discrepancy using pelvic radiographs: the most reproducible method. AB - Leg length inequality following total hip replacement remains common. In an effort to reduce this occurrence, surgeons undertake pre-operative measurements, templating and use various forms of intraoperative measurements, including computer navigation. This study aims to delineate which measurement technique is most appropriate for measuring leg length inequality from a pelvic radiograph. Three observers took a total of 9600 measurements from 100 pelvic radiographs. Four lines were constructed on each of the radiographs, bisecting the acetabular teardrops, ischial spines, inferior sacroiliac joint and inferior obturator foramen. Measurements were taken from these lines to the most prominent medial point on the lesser trochanter and to the tip of the greater trochanter. The effect of pelvic positioning was also assessed using radiographs of a synthetic pelvis and femur. Intra-observer and inter-observer variability were calculated. Measuring from the inferior aspect of the ischial tuberosities to the most prominent medial point on the lesser trochanter appears to be the best method for measuring LLD however large error margin still exist, even when corrected for magnification errors. PMID- 23934903 TI - Successful treatment of isolated, partial thickness ligamentum teres (LT) tears with debridement and capsulorrhaphy. AB - BACKGROUND: To determine if the addition of anterior capsular tightening to the treatment of partial ligamentum teres (LT) tears by debridement will diminish the recurrence rate of symptoms due to LT retears. METHOD: A prospective case series, including all patients treated for an isolated LT tear from June 2009 to August 2011. Arthroscopically the tear was debrided using radiofrequency (RF) and the joint capsule was tightened using either RF or suture plication. All the patients were prospectively assessed with the Modified Harris Hip Score (MHHS) and the Non Arthritic Hip Score (NAHS). A total of 1574 hip arthroscopies were performed from June 2009 to November 2011. Isolated partial LT tears, were found in 27 hips (26 patients). The average age was 24.4 years (range 12-45). There were 24 females and two males. RESULTS: Over an average follow-up period of 32 months (range 23 49), MHHS and NAHS preoperative outcome scores improved significantly. No revision surgery was required for a recurrent tear. CONCLUSION: Debridement of partial thickness LT tears, with additional anterior capsule tightening, has been shown to lead to improvents in MHHS and NAHS, with no recurrence of symptoms due to LT retear in the short to medium term. PMID- 23934904 TI - Surveillance of Arc2f polyethylene after 15 years of implantation. AB - BACKGROUND: To investigate the behavior of Arc2f polyethylene (PE) component after a minimum of 15 years post implantation and its possible reasons for failure. METHODS: Between January 1988 and March 1995, 557 cementless total hip arthroplasties were performed in 578 patients. A total of 435 patients (450 hips) were followed up for 18.6 years (range 15-22). RESULTS: At 10 years follow-up no cup needed revision surgery. After 15 years of implantation, we observed massive PE wear in 140 cups (31%) with large osteolytic lesions. A revision procedure was performed in all cases. Exchange only of the PE liner was sufficient in 78 cases, whilst in 59 the cup was also revised. PE insert thickness and the type of prosthetic head were found to be related to PE wear. CONCLUSIONS: We postulate that the massive failure seen is attributed to the manufacturing of the PE insert. We advocate following all patients that have an implant lasting a decade after implantation for routine monitoring to identify those at risk for accelerated PE wear. PMID- 23934905 TI - Reliability of the six-minute walk test after total hip arthroplasty. AB - BACKGROUND: Walking ability is a crucial component of lower extremity function. Assessment of walking after total hip arthroplasty (THA) provides important information about the healing process. Walking endurance, an important functional component of walking, can be reliably measured with the 6-minute walk test (6 mWT). Even though the 6 mWT is commonly used in patients with THA, its reliability has never been reported for this patient population. The aim of this study is to assess the reliability of the test-retest 6 mWT after THA. METHODS: Thirty-four patients with THA performed two test trials on the same day, separated by a one hour seated rest. To assess reliability, intra-class correlation coefficient (ICC(2,1)), standard error of measurement (SEM), and smallest real difference (SRD) were calculated. RESULTS: The 6 mWT showed a high reliability. The patients walked 3.71 metres more at the end of the second 6 mWT in comparison with the first test. The ICC(2,1) (AS(95)), SEM (m), SEM(95) (m) and SRD(95) (m) were 0.96 (0.92), 3.67, 7.19, and 10.17 m respectively. CONCLUSIONS: Reliability of the 6 mWT was high in patients with THA. The 6 mWT is a simple and sensitive method to measure the functional performance in patients with THA in the clinical setting. Moreover, clinicians and researchers can use the 6 mWT to quantify even small changes in functional performance after THA. PMID- 23934906 TI - Hip shape and long-term hip function: a study of patients with in-situ fixation for slipped capital femoral epiphysis. AB - Slipped capital femoral epiphysis (SCFE) is a rare adolescent hip disease that leads to a hip shape abnormality. Typical treatment involves in-situ fixation. It is not known if the degree of initial hip shape abnormality associated with SCFE has a significant effect on long-term hip function. A cohort of patients aged 18 50 who had undergone in-situ fixation for SCFE from 1970 onwards in our institution provided IHOT-33 (hip function) outcome data. Frog lateral radiographs from the time of surgery were used to measure radiological hip shape using both Southwick angle and alpha angle. There were 38 patients (46 hips) SCFE patients who met the eligibility criteria. We obtained follow-up data for 32 patients (38 hips), 83% follow-up. Ten patients (20 hips) had bilateral SCFE. The mean follow-up was 12.7 years (95% CI 10.7-14.7). 32 patients matched for age and sex who had no history of SCFE provided control IHOT-33 outcome data. There was a significant difference (p<0.05) in long-term hip function between patients undergoing in-situ fixation for SCFE and the control population (mean IHOT-33 scores of 71.8 and 95.8 respectively). There was no significant (p>0.05) correlation between long-term hip function and Southwick angle or lateral alpha angle. The initial severity of hip shape abnormality due to SCFE was not a strong predictor of long-term hip function. Other extraneous factors not related to hip shape may have an equally if not more important role to play in the subsequent long-term outcome of SCFE. PMID- 23934907 TI - Metal ion trend may be more predictive for malfunctioning metal-on-metal implants than a single measurement. AB - Forty-eight unilateral hip resurfacing arthroplasty patients were evaluated for cobalt and chromium levels. The metal ion trend of 42 well-functioning patients was compared with six sub-optimal functioning patients. Median metal ion levels were significantly higher for the sub-optimal group. For the well-functioning implants, the percentage of patients with increasing cobalt/chromium levels between two consecutive time-intervals ('risers') gradually decreased from 90/86% (0-3 months) to 22/22% (24-36 months). The percentage of patients with increasing metal ion levels was higher in the sub-optimal group. The median absolute increase of this 'risers' subgroup was significantly lower for the well functioning group at 12-24 months. Sub-optimal functioning MoM implants have a different metal ion trend than well-functioning implants, a higher chance of 'risers' and a larger absolute increase in time. PMID- 23934908 TI - Cyclometalation of aryl-substituted phosphinines through C-H-bond activation: a mechanistic investigation. AB - A series of 2,4,6-triarylphosphinines were prepared and investigated in the base assisted cyclometalation reaction using [Cp*IrCl2]2 (Cp* = 1,2,3,4,5 pentamethylcyclopentadienyl) as the metal precursor. Insight in the mechanism of the C-H bond activation of phosphinines as well as in the regioselectivity of the reaction was obtained by time-dependent (31)P{(1)H} NMR spectroscopy. At room temperature, 2,4,6-triarylphosphinines instantaneously open the Ir-dimer and coordinate in an eta(1)-fashion to the metal center. Upon heating, a dissociation step towards free ligand and an Ir-acetate species is observed and proven to be a first-order reaction with an activation energy of DeltaEA = 56.6 kJ mol(-1) found for 2,4,6-triphenylphosphinine. Electron-donating substituents on the ortho phenyl groups of the phosphorus heterocycle facilitate the subsequent cyclometalation reaction, indicating an electrophilic C-H activation mechanism. The cyclometalation reaction turned out to be very sensitive to steric effects as even small substituents can have a large effect on the regioselectivity of the reaction. The cyclometalated products were characterized by means of NMR spectroscopy and in several cases by single-crystal X-ray diffraction. Based on the observed trends during the mechanistic investigation, a concerted base assisted metalation-deprotonation (CMD) mechanism, which is electrophilic in nature, is proposed. PMID- 23934909 TI - Intravenous administration of human umbilical cord blood-derived AC133+ endothelial progenitor cells in rat stroke model reduces infarct volume: magnetic resonance imaging and histological findings. AB - Endothelial progenitor cells (EPCs) hold enormous therapeutic potential for ischemic vascular diseases. Previous studies have indicated that stem/progenitor cells derived from human umbilical cord blood (hUCB) improve functional recovery in stroke models. Here, we examined the effect of hUCB AC133+ EPCs on stroke development and resolution in a middle cerebral artery occlusion (MCAo) rat model. Since the success of cell therapies strongly depends on the ability to monitor in vivo the migration of transplanted cells, we also assessed the capacity of magnetic resonance imaging (MRI) to track in vivo the magnetically labeled cells that were administered. Animals were subjected to transient MCAo and 24 hours later injected intravenously with 10(7) hUCB AC133+ EPCs. MRI performed at days 1, 7, and 14 after the insult showed accumulation of transplanted cells in stroke-affected hemispheres and revealed that stroke volume decreased at a significantly higher rate in cell-treated animals. Immunohistochemistry analysis of brain tissues localized the administered cells in the stroke-affected hemispheres only and indicated that these cells may have significantly affected the magnitude of endogenous proliferation, angiogenesis, and neurogenesis. We conclude that transplanted cells selectively migrated to the ischemic brain parenchyma, where they exerted a therapeutic effect on the extent of tissue damage, regeneration, and time course of stroke resolution. PMID- 23934910 TI - Enhancing in vivo survival of adipose-derived stromal cells through Bcl-2 overexpression using a minicircle vector. AB - Tissue regeneration using progenitor cell-based therapy has the potential to aid in the healing of a diverse range of pathologies, ranging from short-gut syndrome to spinal cord lesions. However, there are numerous hurdles to be overcome prior to the widespread application of these cells in the clinical setting. One of the primary barriers to effective stem cell therapy is the hostile environment that progenitor cells encounter in the clinical injury wound setting. In order to promote cellular survival, stem cell differentiation, and participation in tissue regeneration, relevant cells and delivery scaffolds must be paired with strategies to prevent cell death to ensure that these cells can survive to form de novo tissue. The Bcl-2 protein is a prosurvival member of a family of proteins that regulate the mitochondrial pathway of apoptosis. Using several strategies to overexpress the Bcl-2 protein, we demonstrated a decrease in the mediators of apoptosis in vitro and in vivo. This was shown through the use of two different clinical tissue repair models. Cells overexpressing Bcl-2 not only survived within the wound environment at a statistically significantly higher rate than control cells, but also increased tissue regeneration. Finally, we used a nonintegrating minicircle technology to achieve this in a potentially clinically applicable strategy for stem cell therapy. PMID- 23934911 TI - Direct-to-consumer stem cell marketing and regulatory responses. AB - There is a large, poorly regulated international market of putative stem cell products, including transplants of processed autologous stem cells from various tissues, cell processing devices, cosmetics, and nutritional supplements. Despite the absence of rigorous scientific research in the form of randomized clinical trials to support the routine use of such products, the market appears to be growing and diversifying. Very few stem cell biologics have passed regulatory scrutiny, and authorities in many countries, including the United States, have begun to step up their enforcement activities to protect patients and the integrity of health care markets. PMID- 23934912 TI - An anion-modulated three-way supramolecular switch that selectively binds dihydrogen phosphate, H2PO4-. PMID- 23934913 TI - Is the bovine lysosomal phospholipase B-like protein an amidase? AB - The main function of lysosomal proteins is to degrade cellular macromolecules. We purified a novel lysosomal protein to homogeneity from bovine kidneys. By gene annotation, this protein is defined as a bovine phospholipase B-like protein 1 (bPLBD1) and, to better understand its biological function, we solved its structure at 1.9 A resolution. We showed that bPLBD1 has uniform noncomplex-type N-glycosylation and that it localized to the lysosome. The first step in lysosomal protein transport, the initiation of mannose-6-phosphorylation by a N acetylglucosamine-1-phosphotransferase, requires recognition of at least two distinct lysines on the protein surface. We identified candidate lysines by analyzing the structural and sequentially conserved N-glycosylation sites and lysines in bPLBD1 and in the homologous mouse PLBD2. Our model suggests that N408 is the primarily phosphorylated glycan, and K358 a key residue for N acetylglucosamine-1-phosphotransferase recognition. Two other lysines, K334 and K342, provide the required second site for N-acetylglucosamine-1 phosphotransferase recognition. bPLBD1 is an N-terminal nucleophile (Ntn) hydrolase. By comparison with other Ntn-hydrolases, we conclude that the acyl moiety of PLBD1 substrate must be small to fit the putative binding pocket, whereas the space for the rest of the substrate is a large open cleft. Finally, as all the known substrates of Ntn-hydrolases have amide bonds, we suggest that bPLBD1 may be an amidase or peptidase instead of lipase, explaining the difficulty in finding a good substrate for any members of the PLBD family. PMID- 23934914 TI - Pseudoexfoliation syndrome: don't brush it off. PMID- 23934915 TI - Is FapyG mutagenic?: Evidence from the DFT study. AB - 2,6-diamino-4-oxo-5-formamidopyrimidine (FapyG) is an oxidatively damaged product of guanine (G), which is mainly formed through metabolic processes that produce OH radicals. It has been proposed that in bacterial cells, FapyG retains the coding properties of G, and is, therefore, not mutagenic. However, in mammalian cells, FapyG induces G to thymine (T) mutation more dominantly than another ubiquitous oxidative lesion, that is, 8-oxoguanine (8-oxoG). The exact reasons for these coding properties of FapyG are not properly understood. In order to rationalize the cause of FapyG-mediated mutagenesis, all of the possible base pair interactions of FapyG with cytosine (C), adenine (A), and T, in both anti- and syn- conformations, are studied in detail by using density functional theory (DFT). The effects of solvation on the coding properties of FapyG are also evaluated. We demonstrate that the anti-FapyG:C base pair has the highest binding energy, and that the base-pair alignment is similar to that of the normal G:C base pair. Therefore, insertion of C opposite anti-FapyG is preferred over the other DNA bases. This could be the reason for the non-mutagenic behavior of FapyG in bacterial cells. However, as the binding patterns and energies of anti-FpyG:A and syn-FapyG:A base pairs are similar, and these are also similar to those of the T:A base pair, mammalian polymerases may not distinguish between FapyG and T. As a result, A would be mistakenly inserted opposite either anti-FapyG or syn FapyG, resulting in G to T transverse mutation. PMID- 23934916 TI - Animal models of gastrointestinal problems in Parkinson's disease. AB - Gastrointestinal (GI) symptoms are being increasingly recognized as early, common, and severe features of Parkinson's disease (PD), and they are important determinants of quality of life and disability throughout the disease course. In addition, the concept that GI symptoms could represent "pre-motor" PD has been hotly debated and has recently become a driving force for investigations into the pathophysiology and neuropathology of PD. Clinical data has been supported by many pathological studies demonstrating alpha-synuclein neuritic pathology and neuronal loss in central and peripheral areas relevant to GI function. As understanding has matured concerning the impact of GI dysmotility on patients and its potential relationship to incipient PD, behavioral and neuropathological examination of the GI tract has become a critical aspect of evaluation and validation of PD animal models. This review will briefly summarize GI symptoms and neuropathology in PD important to model in animals, behavioral and neuropathological examination of the GI tract in animals, and the current state of modeling parkinsonian GI dysfunction in animal model systems. PMID- 23934917 TI - Aberrant dopamine transmission and cognitive dysfunction in animal models of Parkinson's disease. AB - Due to the relative success of therapeutic interventions aimed at treating the overt motor symptoms evident in Parkinson's disease (PD), a greater appreciation of the non-motor aspects of the disease has emerged in recent time. Indeed, evidence suggests that impairments in emotional processing, behavioural control and cognitive function may emerge early in the onset of the disease. Decades of experimental research have seen the development of diverse animal models, all of which have aimed to mimic the characteristic features of the disease process including the dopaminergic neural cell loss, the molecular neuropathology and the concomitant behavioural impairments. The following review provides an overview of the use of animal, particularly rodent, models in the quest to obtain a greater understanding of the role of corticostriatal dopamine in cognitive and neuropsychiatric functions. Given the limitations of using the available rodent models of PD, including altered motor and motivational function, it has become necessary to employ a range of techniques to eke out the precise function of this neurotransmitter in corticostriatal function. Combinations of lesion and pharmacological studies have allowed the assessment of dopamine depletion and precise receptor populations in the learning or expression of a range of executive functions, which has gained us considerable insight into the relationship between the neuropathology that occurs in PD and the resulting impairments in cognitive and neuropsychiatric function. PMID- 23934918 TI - Bicycle sign for differential diagnosis of parkinsonism: is it of use in a hilly country like Japan? AB - The loss of the ability to cycle after disease onset, the so-called "bicycle sign", has been proposed as a new red flag for atypical parkinsonism. However, actual environments or situations for bicycling differ from one country to another, raising the question of whether "bicycle sign" could be universally applicable. The present study suggested that "bicycle sign" could contribute to earlier and better differential diagnosis of parkinsonism in a hilly country like Japan. PMID- 23934919 TI - Mitochondrial dysfunction in skin fibroblasts from a Parkinson's disease patient with an alpha-synuclein triplication. AB - Mitochondrial dysfunction has been frequently implicated in the neurodegenerative process that underlies Parkinson's disease (PD), but the basis for this impairment is not fully understood. The goal of this study was to investigate the effects of alpha-synuclein (alpha-syn) gene multiplication on mitochondrial function in human tissue. To investigate this question, human fibroblasts were taken from a patient with parkinsonism carrying a triplication in the alpha-syn gene. Unexpectedly, the cells showed a significant decrease in cell growth compared to matched healthy controls. With regard to mitochondrial function, alpha-syn triplication fibroblasts exhibited a 39% decrease in ATP production, a 40% reduction in mitochondrial membrane potential, and a 49% reduction in complex I activity. Furthermore, they proved to be more sensitive to the effects of the nigrostrial toxicant paraquat compared to controls. Finally, siRNA knockdown of alpha-syn resulted in a partial rescue of mitochondrial impairment and reduction of paraquat-induced cell toxicity, suggesting that alpha-syn plays a causative role for mitochondrial dysfunction in these patient-derived peripheral skin fibroblasts. PMID- 23934920 TI - Measurement properties of the SF-12 health survey in Parkinson's disease. AB - The 12-item Short-Form Health Survey (SF-12) is an abbreviated version of the SF 36, one of the most widely used patient-reported health outcome rating scales. Similar to the SF-36, it yields summary scores of physical and mental health (PCS and MCS, respectively). However, SF-36 derived PCS and MCS scores have not been found valid in neurological disorders such as Parkinson's disease (PD). Here we used modern psychometric methodology (Rasch analysis) to test the SF-12 in PD, and explored the appropriateness of a total SF-12 score representing overall health. SF-12 data from 150 non-demented people with PD (56% men; mean age/PD duration, 70/5 years) were analyzed regarding Rasch model fit for the PCS, MCS, as well as for the full SF-12. Data showed some signs of misfit to the Rasch model for all three scales (overall item-trait interaction, P >= 0.003; reliability, >= 0.85). For example, all scales exhibited signs of dependency between item responses, and the PCS measured with relatively low precision. Model fit (but not measurement precision) was improved following deletion of one PCS and one MCS item (overall item-trait interaction, P >= 0.387; reliability, >= 0.82). These observations suggest that the SF-12 can be used as a coarse health survey tool in PD and that a total SF-12 may be useful as a measure of overall health. However, its appropriateness as an outcome measure can be questioned and it is somewhat unclear exactly what the derived scores represent. As such, the SF 12 should probably be considered an assessment tool (or index) rather than a measurement instrument. PMID- 23934921 TI - Chronic subcutaneous infusion therapy with apomorphine in advanced Parkinson's disease compared to conventional therapy: a real life study of non motor effect. AB - BACKGROUND: Apomorphine infusion therapy remains under-used and there are no comparative studies of motor and non-motor effects of apomorphine infusion. METHODS: In this paper we report preliminary results from an ongoing clinical observational "real life" surveillance-based study focused on effects of this therapy on non-motor symptoms and health-related quality of life in a group of patients on apomorphine. RESULTS: Apomorphine infusion led to highly significant improvements in UPDRS 3 (p = 0.0003), UPDRS 4 (p = 0.0003), PDQ-8 (Parkinson's disease questionnaire, p = 0.001) and NMSS total (non motor symptoms scale, p = 0.0003). Furthermore, apomorphine was tolerated in patients with visual hallucinations, illusions and paranoid ideations while significant improvement in specific non-motor symptoms such as hyperhidrosis, nocturia, urgency of micturition, and fatigue was recorded. Levodopa equivalent dose decreased significantly (1077.81 +/- 446.26 to 458.75 +/- 282.29, p < 0.0001) and a large effect size of intervention was noted. In an untreated group no such improvement was noted. The number needed to treat (NNT) for improvement >1 SEM in the Apo group was calculated and was lower than 2 for >1 SEM improvement of UPDRS 3, NMSS, and PDQ-8 total scores. CONCLUSIONS: This pilot observational study suggests that non-motor effects are evident with apomorphine therapy and patients suitable for apomorphine deteriorate in the absence of therapy. PMID- 23934923 TI - Use of cleavable coordinating rings as protective groups in the synthesis of a rotaxane with an axis that incorporates more chelating groups than threaded macrocycles. AB - A new methodology allowing preparation of a linear "unsaturated" [3]rotaxane consisting of an axis incorporating more coordination sites than threaded rings was developed. It was based on the preliminary synthesis of a "saturated" [5]rotaxane consisting of a four-chelating site axis threaded through four macrocyclic components, two of them being cleavable rings incorporating a lactone function and the two others being "secure" non-cleavable rings. The stoppering reaction was based on click chemistry. Subsequently, cleavage and removal of the two lactone-containing macrocycles from the [5]rotaxane in basic medium afforded the desired "unsaturated" [3]rotaxane in quantitative yield. PMID- 23934922 TI - Generation of ferric iron links oxidative stress to alpha-synuclein oligomer formation. AB - BACKGROUND: Synucleinopathies such as Parkinson's disease are characterized by the deposition of aggregated alpha-synuclein in affected brain areas. As genes involved in mitochondrial function, mitochondrial toxins, and age-related mitochondrial impairment have been implicated in Parkinson's disease pathogenesis, an increase in reactive oxygen species resulting from mitochondrial dysfunction has been speculated to induce alpha-synuclein aggregation. In vitro, pore-forming, SDS-resistant alpha-synuclein oligomers are formed in presence of ferric iron and may represent an important toxic particle species. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the interplay of reactive oxygen species, antioxidants and iron oxidation state in regard to alpha-synuclein aggregation using confocal single particle fluorescence spectroscopy, Phenanthroline spectrometry and thiobarbituric acid reactive substances assay. We found that the formation of alpha-synuclein oligomers in presence of Fe3+ is due to a direct interaction. In contrast, oxidizing agents and hydroxyl radicals generated in the Fenton reaction did not directly affect alpha-synuclein oligomerization. However, reactive oxygen species could enhance aggregation via oxidation of ferrous to ferric iron when iron ions were present. CONCLUSIONS/SIGNIFICANCE: Our data thus indicate that oxidative stress affects alpha-synuclein aggregation via oxidation of iron to the ferric state. This provides a new perspective on the role of mitochondrial toxins and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. PMID- 23934924 TI - Mechanical ventilation-induced apoptosis in newborn rat lung is mediated via FasL/Fas pathway. AB - Mechanical ventilation induces pulmonary apoptosis and inhibits alveolar development in preterm infants, but the molecular basis for the apoptotic injury is unknown. The objective was to determine the signaling mechanism(s) of ventilation (stretch)-induced apoptosis in newborn rat lung. Seven-day-old rats were ventilated with room air for 24 h using moderate tidal volumes (8.5 ml/kg). Isolated fetal rat lung epithelial and fibroblast cells were subjected to continuous cyclic stretch (5, 10, or 17% elongation) for up to 12 h. Prolonged ventilation significantly increased the number of apoptotic alveolar type II cells (i.e., terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling and anti-cleaved caspase-3 immunochemistry) and was associated with increased expression of the apoptotic mediator Fas ligand (FasL). Fetal lung epithelial cells, but not fibroblasts, subjected to maximal (i.e., 17%, but not lesser elongation) cyclic stretch exhibited increased apoptosis (i.e., nuclear fragmentation and DNA laddering), which appeared to be mediated via the extrinsic pathway (increased expression of FasL and cleaved caspase-3, -7, and -8). The intrinsic pathway appeared not to be involved [minimal mitochondrial membrane depolarization (JC-1 flow analysis) and no activation of caspase-9]. Universal caspases inhibition and neutralization of FasL abrogated the stretch-induced apoptosis. Prolonged mechanical ventilation induces apoptosis of alveolar type II cells in newborn rats and the mechanism appears to involve activation of the extrinsic death pathway via the FasL/Fas system. PMID- 23934927 TI - Death of the (traveling) salesman: primates do not show clear evidence of multi step route planning. AB - Several comparative studies have linked larger brain size to a fruit-eating diet in primates and other animals. The general explanation for this correlation is that fruit is a complex resource base, consisting of many discrete patches of many species, each with distinct nutritional traits, the production of which changes predictably both within and between seasons. Using this information to devise optimal spatial foraging strategies is among the most difficult problems to solve in all of mathematics, a version of the famous Traveling Salesman Problem. Several authors have suggested that primates might use their large brains and complex cognition to plan foraging strategies that approximate optimal solutions to this problem. Three empirical studies have examined how captive primates move when confronted with the simplest version of the problem: a spatial array of equally valuable goals. These studies have all concluded that the subjects remember many food source locations and show very efficient travel paths; some authors also inferred that the subjects may plan their movements based on considering combinations of three or more future goals at a time. This analysis re-examines critically the claims of planned movement sequences from the evidence presented. The efficiency of observed travel paths is largely consistent with use of the simplest of foraging rules, such as visiting the nearest unused "known" resource. Detailed movement sequences by test subjects are most consistent with a rule that mentally sums spatial information from all unused resources in a given trial into a single "gravity" measure that guides movements to one destination at a time. PMID- 23934926 TI - Soluble guanylate cyclase modulates alveolarization in the newborn lung. AB - Nitric oxide (NO) regulates lung development through incompletely understood mechanisms. NO controls pulmonary vascular smooth muscle cell (SMC) differentiation largely through stimulating soluble guanylate cyclase (sGC) to produce cGMP and increase cGMP-mediated signaling. To examine the role of sGC in regulating pulmonary development, we tested whether decreased sGC activity reduces alveolarization in the normal and injured newborn lung. For these studies, mouse pups with gene-targeted sGC-alpha1 subunit truncation were used because we determined that they have decreased pulmonary sGC enzyme activity. sGC alpha1 knockout (KO) mouse pups were observed to have decreased numbers of small airway structures and lung volume compared with wild-type (WT) mice although lung septation and body weights were not different. However, following mild lung injury caused by breathing 70% O2, the sGC-alpha1 KO mouse pups had pronounced inhibition of alveolarization, as evidenced by an increase in airway mean linear intercept, reduction in terminal airway units, and decrease in lung septation and alveolar openings, as well as reduced somatic growth. Because cGMP regulates SMC phenotype, we also tested whether decreased sGC activity reduces lung myofibroblast differentiation. Cellular markers revealed that vascular SMC differentiation decreased, whereas myofibroblast activation increased in the hyperoxic sGC-alpha1 KO pup lung. These results indicate that lung development, particularly during hyperoxic injury, is impaired in mouse pups with diminished sGC activity. These studies support the investigation of sGC-targeting agents as therapies directed at improving development in the newborn lung exposed to injury. PMID- 23934925 TI - Cigarette smoke and CFTR: implications in the pathogenesis of COPD. AB - Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder consisting of chronic bronchitis and/or emphysema. COPD patients suffer from chronic infections and display exaggerated inflammatory responses and a progressive decline in respiratory function. The respiratory symptoms of COPD are similar to those seen in cystic fibrosis (CF), although the molecular basis of the two disorders differs. CF is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding a chloride and bicarbonate channel (CFTR), leading to CFTR dysfunction. The majority of COPD cases result from chronic oxidative insults such as cigarette smoke. Interestingly, environmental stresses including cigarette smoke, hypoxia, and chronic inflammation have also been implicated in reduced CFTR function, and this suggests a common mechanism that may contribute to both the CF and COPD. Therefore, improving CFTR function may offer an excellent opportunity for the development of a common treatment for CF and COPD. In this article, we review what is known about the CF respiratory phenotype and discuss how diminished CFTR expression-associated ion transport defects may contribute to some of the pathological changes seen in COPD. PMID- 23934928 TI - Characterizing the binding of annexin V to a lipid bilayer using molecular dynamics simulations. AB - Annexins play critical roles in membrane organization, membrane trafficking and vesicle transport. The family members share the ability to bind to membranes with high affinities, but the interactions between annexins and membranes remain unclear. Here, using long-time molecular dynamics simulations, we provide detailed information for the binding of an annexin V trimer to a POPC/POPS lipid bilayer. Calcium ions function as bridges between several negatively charged residues of annexin V and the oxygen atoms of lipids. The preferred calcium bridges are those formed via the carboxyl oxygen atoms of POPS lipids. H-bonds and hydrophobic interactions formed by several critical residues have also been observed in the annexin-membrane interface. The annexin-membrane binding causes small changes of annexin trimer structures, while has significant effects on lipid bilayer structures. The lipid bilayer shows a bent shape and forms a concave region in the annexin-membrane interaction interface, which provides an atomic-level evidence to support the view that annexins could disturb the stability of lipids and bend membranes. This study provides insights into the commonly occurring PS-dependent and calcium-dependent binding of proteins to membranes. PMID- 23934929 TI - Oxidative trifluoromethylation of unactivated olefins: an efficient and practical synthesis of alpha-trifluoromethyl-substituted ketones. PMID- 23934930 TI - Endovascular repair of symptomatic hemodialysis access graft pseudoaneurysms. AB - AIM: Repeated needle punctures of arteriovenous hemodialysis grafts can lead to the development of pseudoaneurysms. As they enlarge, graft pseudoaneurysms are associated with significant morbidity and require treatment. We present our single-center experience using stent grafts in selected patients to exclude symptomatic hemodialysis graft pseudoaneurysms. MATERIALS AND METHODS: Between March 2007 and December 2010, 11 consecutive patients (7 men and 4 women, mean age 57 years) underwent percutaneous endovascular repair of symptomatic hemodialysis access graft pseudoaneurysms. Indications for treatment were rapidly enlarging pseudoaneurysm in 5 patients, high venous pressures, limb edema and pseudoaneurysm in 3, skin breakdown over the pseudoaneurysm site in 2 and acute rupture and bleeding in 1 patient. No patient was lost to follow-up. RESULTS: Technical success across the 11 patients was 90.9%. The patient who presented with rupture required ligation of the access due to continuous bleeding after stent graft insertion. Balloon angioplasty of a separate hemodynamically significant stenosis at the time of stent graft insertion was performed in 7 of 11 (63.6%) patients. The primary access patency rates were 72.7% (95% CI of 0.390 0.939) at 3 months and 36.4% (95% CI 0.109-0.692) at 6 months. Secondary access patency rates were 72.7% at 6 months (95% CI 0.233-0.832). There were no procedure-related complications. Mean follow-up was 9 months (range 2-29 months). CONCLUSIONS: Endovascular treatment of symptomatic hemodialysis graft pseudoaneurysms is safe and effective with similar patency rates to surgical approaches. Importantly, this approach allows aggressive management of associated access circuit stenoses at the same time and avoids interval tunneled dialysis line insertion. PMID- 23934931 TI - Creation of autogenous radial cephalic direct wrist access for hemodialysis in the elderly using microsurgery. AB - PURPOSE: Guidelines recommend autogenous radial-cephalic AV fistula (RCAVF) as the first choice for hemodialysis. Concern has been raised that this is not suitable in the elderly. We assessed the results of microsurgery for RCAVF creation comparatively in patients older and younger than 70 years. METHODS: We prospectively followed 126 patients for three years. After systematic clinical and ultrasound assessment, a RCAVF was created using a surgical microscope. Patency was assessed immediately, at one week, one month and one year. Outcomes were recorded and stratified into two groups: <70y and >70y. RESULTS: RCAVF was created in 75.4% and 70.8% of the <70y and >70y groups, respectively. Incidence of early failure was 11% (<70y) and 13% (>70y). Primary and secondary patency at one year was 67% and 84% (<70y) versus 63% and 80% (>70y). CONCLUSIONS: Microsurgery enabled the creation of RCAVF in >70y with acceptable risk of failure and slight differences by comparison with <70y. Older age should not preclude RCAVF creation. PMID- 23934932 TI - Analysis and correction of crosstalk effects in pathway analysis. AB - Identifying the pathways that are significantly impacted in a given condition is a crucial step in understanding the underlying biological phenomena. All approaches currently available for this purpose calculate a P-value that aims to quantify the significance of the involvement of each pathway in the given phenotype. These P-values were previously thought to be independent. Here we show that this is not the case, and that many pathways can considerably affect each other's P-values through a "crosstalk" phenomenon. Although it is intuitive that various pathways could influence each other, the presence and extent of this phenomenon have not been rigorously studied and, most importantly, there is no currently available technique able to quantify the amount of such crosstalk. Here, we show that all three major categories of pathway analysis methods (enrichment analysis, functional class scoring, and topology-based methods) are severely influenced by crosstalk phenomena. Using real pathways and data, we show that in some cases pathways with significant P-values are not biologically meaningful, and that some biologically meaningful pathways with nonsignificant P values become statistically significant when the crosstalk effects of other pathways are removed. We describe a technique able to detect, quantify, and correct crosstalk effects, as well as identify independent functional modules. We assessed this novel approach on data from four experiments involving three phenotypes and two species. This method is expected to allow a better understanding of individual experiment results, as well as a more refined definition of the existing signaling pathways for specific phenotypes. PMID- 23934933 TI - Intensive induction chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue for young children newly diagnosed with central nervous system atypical teratoid/rhabdoid tumors: the Head Start III experience. AB - BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) is a rare embryonal neoplasm of early childhood with dismal outcome and no current uniformly accepted treatment. Given its highly aggressive nature and predilection for dissemination at diagnosis, intensive multimodal therapy is required. MATERIALS AND METHODS: Nineteen children with newly diagnosed CNS AT/RT were treated on the head start (HS) III protocol. Treatment consisted of surgical resection, 5 cycles of induction chemotherapy, followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR). Irradiation was given following recovery from consolidation based on patient age, disease extent at diagnosis, and treatment response to induction. RESULTS: Nineteen children (median age of 14 months) were treated on HS III between 2003 and 2009. Only four finished induction and three proceeded to consolidation. There are presently four survivors at 40, 42, 46, and 79 months from study enrollment. Eleven patients experienced tumor progression at a median time to progression of 4.1 months of whom 10 died with a median time from progression to death of 2.6 months. Five toxic deaths occurred, three of them while on the study. The 3-year event-free survival (EFS) and overall survival (OS) for the whole group was 21 +/- 9% and 26 +/- 10%, respectively. Five patients received irradiation at progression with only one long-term survivor. CONCLUSION: A minority of children with CNS AT/RT treated on HS III may be long term survivors without irradiation. More effective therapies are desperately needed. PMID- 23934934 TI - Occupation-based family-centered therapy approach for young children with feeding problems in South Korea; a case study. AB - Documenting the effectiveness of an occupation-based family-centered therapy approach, when providing therapy for a young child with feeding problems, is needed in a culture such as Korea, which has a strong medical model of service. A case study was conducted involving a 16-month-old boy with feeding problems. An occupation-based family-centered therapy approach was carried out for 10 weeks. The results indicated that this approach addressed the physical components of the child's feeding problems and also the parent-child bonding, which together improved the overall family dynamics. Although these results may stimulate clinicians to consider an alternative approach to a medical model, further research with a larger sample is needed to provide sufficient evidence for therapists to shift to a new service delivery model. PMID- 23934935 TI - Influence of age and type of underlying disease on complications related to home enteral nutrition: a single Italian center experience. AB - BACKGROUND: No data about the influence of age and underlying diseases on home enteral nutrition (HEN)-related complications are reported in the literature. Herein, we retrospectively investigated this issue by analyzing HEN-related complications in a cohort of consecutive patients grouped according to the underlying disease and age. MATERIAL AND METHODS: We reviewed the medical records of 101 patients referring to our team in 2007-2010 to obtain patients' demographic data, age, nutrition status, duration of HEN treatment, and type of HEN-related complications. They were divided in cancer and neurologic patients and subgrouped on the basis of their age. HEN-related complications were expressed as complication rates. RESULTS: Patients with neurological diseases suffered a significantly higher number of complications as compared with cancer patients (P = .04). Age did not significantly influence complication rates. The mechanical complications were the most frequent. The majority of HEN-related complications were resolved at home. CONCLUSION: Our data strongly suggest that HEN-related complications are influenced by underlying diseases and not by age. In neurologic patients, dementia, loss of autonomy, and the different therapies administered by PEG probably play an important role in increasing the number of HEN-related complications as compared with cancer patients. The most frequent complications can be managed at home, reducing the costs of hospitalizations and discomfort for the patient. PMID- 23934936 TI - Weighted subtraction in 3D ultrashort echo time (UTE) imaging for visualization of short T2 tissues of the knee. AB - BACKGROUND: Ultrashort echo time (UTE) image to directly visualize short T2 tissues requires postprocessing for the suppression of the surrounding long T2 tissues in a clinical magnetic resonance imaging (MRI) scanner. Weighted subtraction of UTE images with an optimal weighting factor could provide high positive contrast with adequate suppression. PURPOSE: To demonstrate in-vivo UTE MRI with weighted subtractions of dual echo UTE imaging using a 3 T clinical MRI and to determine the optimal weighting factors through the analyses of signal-to noise ratios (SNRs) and contrast-to-noise ratios (CNRs). MATERIAL AND METHODS: Forty-seven consecutive knee MR including dual echo 3D UTE sequence (TE of 70 us and 3.82 ms) were reviewed. Seven patients with normal findings in the knee MR were included in the current study. For variably weighted subtraction images, the initial UTE image was rescaled relative to that of the second echo image with weighting factors from 0.1 to 4.0. Thirty-five pairs of the ROI measurements of the UTE image and second long echo images were repeated after 2 weeks. For quantitative assessment, SNR and CNR were measured from the ROIs on the patellar tendon, cartilage, cortical bone, meniscus, and infrapatellar fat pad. Intra observer agreement was assessed by using both Cohen's Kappa and Bland-Altman approach. RESULTS: The short T2 tissue could be visualized with adequate suppression on the subtraction images. Considering the CNRs and SNRs, the optimal ranges of the weighting factors could be suggested: 0.3 for the tendon, 0.4 for the cortical bone, and 1.0 for the meniscus. The 35 paired measurements showed excellent agreement with statistical significance (P < 0.05). CONCLUSION: The 3D UTE MRI provides imaging of short T2 tissues which cannot be visualized by conventional MRI. Using weighted subtractions with optimal weighting values, each tissue can be optimally depicted by overcoming the reduced T2 contrast. PMID- 23934937 TI - Accuracy of a freehand sculpting tool for unicondylar knee replacement. AB - BACKGROUND: Unicondylar knee replacement is technically challenging and malalignment of the implant components is one of the factors that results in high failure rates. Surgical robotics with navigation is emerging as a potential solution to improve the accuracy of implant placement. METHODS: The accuracy of performing unicondylar knee replacement using a freehand sculpting, semi-active robotic tool was investigated using 20 synthetic femurs and tibia. Resultant femoral and tibial implant placement was compared to the planned implant position. RESULTS: The maximum rotational error was 3.2(o) and RMS angular error was 1.46(o) across all orientations, for both the tibia and femoral implants. The maximum translational error was 1.18 mm and the RMS translational error across all directions was 0.61 mm. CONCLUSIONS: The freehand sculpting tool produced accurate implant placement with small errors comparable to those reported by other robotic-assistive devices on the market for unicondylar knee replacement. PMID- 23934938 TI - Growth of Au@Ag core-shell pentatwinned nanorods: tuning the end facets. AB - Au@Ag core-shell nanorods with tunable end facets are obtained by coating Au bipyramids (BPs) with Ag. The resultant nanorods exhibit a pentatwinned crystal structure with tips terminated with either {110} or {111} facets. The control over the end facets is achieved by varying the capping agents and tuning the reduction rate of Ag. Specifically, when Ag is reduced slowly, Au@Ag nanorods with flat {110} end facets are formed with cetyltrimethylammonium bromide (CTAB) as the capping agent. If CTAB is replaced with cetyltrimethylammonium chloride (CTAC), Au@Ag nanorods with tips terminated with {111} facets are obtained. However, at a high Ag reduction rate, dumbbell-shaped Au@Ag nanorods are formed, with either CTAB or CTAC as the capping agent. The morphological evolution of the nanorods in each case is closely followed and a growth mechanism is proposed. PMID- 23934939 TI - Outcomes of Prolonged Exposure therapy for veterans with posttraumatic stress disorder. AB - Prolonged Exposure (PE) is an evidenced-based psychotherapy for posttraumatic stress disorder (PTSD) that is being disseminated nationally within the U.S. Department of Veterans Affairs (VA) with promising initial results. Empirical evidence, however, regarding the effectiveness of PE for treatment of PTSD in military veterans is limited. Building on previous treatment outcome research, the current study investigated the effectiveness of PE in a diverse veteran sample. One-hundred fifteen veterans were enrolled in PE at an urban VA medical center and its surrounding outpatient clinics. PTSD and depression symptoms as well as quality of life were measured before and after treatment. Several baseline patient characteristics were examined as predictors of treatment response. Eighty-four participants completed treatment. Participants experienced a 42% reduction in PTSD symptoms, a 31% reduction in depression symptoms, and an increase in quality of life following PE. Veterans not prescribed psychotropic medication reported greater PTSD symptom reduction than veterans prescribed such medication. The implications of these results for treatment programs targeting PTSD in veterans are discussed. PMID- 23934940 TI - Stable electron donor-acceptor nanohybrids by interfacing n-type TCAQ with p-type single-walled carbon nanotubes. PMID- 23934941 TI - A comparative study of variable selection methods in the context of developing psychiatric screening instruments. AB - The development of screening instruments for psychiatric disorders involves item selection from a pool of items in existing questionnaires assessing clinical and behavioral phenotypes. A screening instrument should consist of only a few items and have good accuracy in classifying cases and non-cases. Variable/item selection methods such as Least Absolute Shrinkage and Selection Operator (LASSO), Elastic Net, Classification and Regression Tree, Random Forest, and the two-sample t-test can be used in such context. Unlike situations where variable selection methods are most commonly applied (e.g., ultra high-dimensional genetic or imaging data), psychiatric data usually have lower dimensions and are characterized by the following factors: correlations and possible interactions among predictors, unobservability of important variables (i.e., true variables not measured by available questionnaires), amount and pattern of missing values in the predictors, and prevalence of cases in the training data. We investigate how these factors affect the performance of several variable selection methods and compare them with respect to selection performance and prediction error rate via simulations. Our results demonstrated that: (1) for complete data, LASSO and Elastic Net outperformed other methods with respect to variable selection and future data prediction, and (2) for certain types of incomplete data, Random Forest induced bias in imputation, leading to incorrect ranking of variable importance. We propose the Imputed-LASSO combining Random Forest imputation and LASSO; this approach offsets the bias in Random Forest and offers a simple yet efficient item selection approach for missing data. As an illustration, we apply the methods to items from the standard Autism Diagnostic Interview-Revised version. PMID- 23934942 TI - Benzofurazane as a new redox label for electrochemical detection of DNA: towards multipotential redox coding of DNA bases. AB - Benzofurazane has been attached to nucleosides and dNTPs, either directly or through an acetylene linker, as a new redox label for electrochemical analysis of nucleotide sequences. Primer extension incorporation of the benzofurazane modified dNTPs by polymerases has been developed for the construction of labeled oligonucleotide probes. In combination with nitrophenyl and aminophenyl labels, we have successfully developed a three-potential coding of DNA bases and have explored the relevant electrochemical potentials. The combination of benzofurazane and nitrophenyl reducible labels has proved to be excellent for ratiometric analysis of nucleotide sequences and is suitable for bioanalytical applications. PMID- 23934943 TI - Optically active conjugated polymer from solvent chirality transfer polymerization in monoterpenes. AB - Disubstituted acetylene monomers [1,2-diphenylacetylenes (DPAs: DPA-pC1, DPA-mC1, DPA-pC8); 1-phenyl-2-hexylacetylene (PHA-pC1)] are tested for asymmetric polymerization in chiral monoterpenes used as solvents and compared with the corresponding monosubstituted acetylene monomer [1-phenylacetylene (PA-pC1)]. DPA pC1 containing a trimethylsilyl group in the para-position of the phenyl ring produces an optically active polymer with a large Cotton effect, despite the absence of a stereogenic center. The polymer sample obtained by polymerization in 87% ee (-)-alpha-pinene shows the strongest CD signal (gCD value at 385 nm: ~3.2 * 10-3). The Cotton bands of the polymers obtained in (-)- and (+)-alpha-pinenes show the opposite sign in the CD signals. Theoretical calculations show that only the cis-cisoid model adopts a helical conformation. A time-correlated single photon counting experiment shows that the emission of the chiral polymer originates from a virtually single excited species with a 98% component fraction. This polymer solution does not show any significant decrease in gCD value over a wide temperature range of 20 to 80 degrees C. No noticeable decrease in the gCD value is detected when the polymer solution is kept at relatively low temperatures for a prolonged period (35 d). In contrast, the other polymers show no CD signal. PMID- 23934944 TI - Quality improvements in resident mobility care: using person- and relationship centered frameworks. AB - PURPOSE OF THE STUDY: Research is needed to demonstrate the application of person and relationship-centered care to nursing home practice. This article aimed to find a suitable person/relationship-centered framework to assist with mobility care practice improvements in nursing homes. DESIGN AND METHOD: The authors discuss the task of mobility care, the nature of person- and relationship centered care, and the significance of such approaches to mobility care. The Senses Framework (Nolan, Davies, Ryan, & Keady, 2008) is employed to develop mobility care practice improvement objectives. RESULTS: The objectives are used to evaluate outcomes from 2 hypothetical scenarios to illustrate the possible value of the Senses Framework. IMPLICATIONS: The Senses Framework facilitated development of objectives for mobility care practice improvement that considers the needs of all stakeholders. PMID- 23934945 TI - Cryoplasty for peripheral arterial disease. AB - BACKGROUND: Percutaneous balloon angioplasty is an endovascular technique for restoring blood flow through an artery that has become narrowed or blocked by atherosclerosis. Narrowing of the artery following angioplasty (restenosis) is the major cause of long-term failure. Cryoplasty offers a different approach to improving long-term angioplasty results. It combines the dilation force of balloon angioplasty with cooling of the vessel wall. This systematic review evaluated cryoplasty in peripheral arterial disease and provides focus for further research in the field. This is an update of a review first published in 2007. OBJECTIVES: To assess the efficacy of, and complications associated with, cryoplasty for maintaining patency in the iliac, femoropopliteal and crural arteries in the short and medium term. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2012) and CENTRAL (2012, Issue 10). Trial databases were searched for ongoing or unpublished studies. We also searched the reference lists of relevant articles. SELECTION CRITERIA: All randomised controlled trials in which participants with peripheral arterial disease (PAD) of the lower limbs, or lower limb bypass graft stenoses, were randomised to cryoplasty with or without another procedure versus a procedure without cryoplasty were considered. This included trials where all participants received angioplasty and the randomisation was for cryoplasty versus no cryoplasty and trials where cryoplasty was used as an adjunct to conventional treatment (for example stenting) against a control. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed, assessed and selected trials, extracted data and assessed risk of bias. MAIN RESULTS: Seven trials (six primary cryoplasty and one adjunctive cryoplasty trial) with a combined total of 478 patients were included in this review. The trials reported patency and restenosis either by participant, lesion or vessel location. Follow-up ranged from 30 days to three years.Target lesion patency measured at various time points in two primary cryoplasty trials showed no statistically significant difference between the treatment groups. The adjunctive cryoplasty study showed that cryoplasty was associated with improved patency only at six months (OR 5.37, 95% CI 1.09 to 26.49, n = 90).Restenosis measured per patient (two primary cryoplasty trials) showed no statistically significant difference between the treatments. Restenosis measured by lesion (two primary cryoplasty trials) showed a statistically significant difference only within 24 hours of the procedure (OR 0.08, 95% CI 0.04 to 0.18, n = 192) favouring cryoplasty.Need for re-intervention was not significantly different in primary cryoplasty trial participants (per participant: OR 0.27, 95% CI 0.05 to 1.52, n = 241, I(2) = 89%; per lesion: OR 0.59, 95% CI 0.06 to 5.69, n = 307, I(2) = 94%). The adjunctive cryoplasty trial did not report on need for intervention.Immediate success of procedure (within 24 hours) was not significantly different in primary cryoplasty trial participants (per participant: OR 1.63, 95% CI 0.14 to 19.55, n = 340, I(2) = 95%; per lesion: OR 1.81, 95% CI 0.19 to 17.36, n = 397, I(2) = 90%). The adjunctive cryoplasty trial reported 100% success.Limb loss, deaths from all causes and the risk of complications immediately after treatment showed no statistically significant differences between the treatments. AUTHORS' CONCLUSIONS: The benefit of cryoplasty over conventional angioplasty cannot be established as the number of randomised controlled trials is small and their quality is not sufficiently high. The technical success and primary patency rates seen in these trials are inconsistent and do not necessarily suggest a future role for cryoplasty in the treatment of PAD, but they cannot be reliably interpreted. Currently there are insufficient data to support the routine use of cryoplasty over conventional balloon angioplasty in the treatment of PAD. PMID- 23934946 TI - One-shot scleroembolization: a new technique for the treatment of varicose veins disease of lower extremities. Preliminary results. AB - OBJECTIVE: The aim of this article is to present a new technique for minimally invasive treatment of varicose veins disease of lower extremities. METHODS: One shot scleroembolization is a new technique designed for the treatment of varicose veins of the lower extremities, which associates a mechanical interruption of the sapheno-femoral junction to classic sclerotherapy with no need for surgery or anesthesia. This is achieved with the combined use of a coil positioned in the terminal portion of the great saphenous vein and a foamed sclerosant drug. RESULTS: At three months' follow-up no complications have been observed. The great saphenous vein was still occluded in all patients (nine out of nine). CONCLUSIONS: One-shot scleroembolization seems to be an effective technique for the treatment of varicose veins disease in outpatients, with the advantage of causing little distress to the patient. PMID- 23934947 TI - A general, practical palladium-catalyzed cyanation of (hetero)aryl chlorides and bromides. AB - Playing it safe: The nontoxic cyanide source K4 [Fe(CN)6].3H2O can be used for the cyanation of (hetero)aryl halides. The application of palladacycle catalysts prevents poisoning during catalyst formation, thereby allowing for low catalyst loadings, fast reaction times, and wide heterocyclic substrate scope. PMID- 23934948 TI - Propensity score-based diagnostics for categorical response regression models. AB - For binary or categorical response models, most goodness-of-fit statistics are based on the notion of partitioning the subjects into groups or regions and comparing the observed and predicted responses in these regions by a suitable chi squared distribution. Existing strategies create this partition based on the predicted response probabilities, or propensity scores, from the fitted model. In this paper, we follow a retrospective approach, borrowing the notion of balancing scores used in causal inference to inspect the conditional distribution of the predictors, given the propensity scores, in each category of the response to assess model adequacy. We can use this diagnostic under both prospective and retrospective sampling designs, and it may ascertain general forms of misspecification. We first present simple graphical and numerical summaries that can be used in a binary logistic model. We then generalize the tools to propose model diagnostics for the proportional odds model. We illustrate the methods with simulation studies and two data examples: (i) a case-control study of the association between cumulative lead exposure and Parkinson's disease in the Boston, Massachusetts, area and (ii) and a cohort study of biomarkers possibly associated with diabetes, from the VA Normative Aging Study. PMID- 23934949 TI - Joint segmentation and named entity recognition using dual decomposition in Chinese discharge summaries. AB - OBJECTIVE: In this paper, we focus on three aspects: (1) to annotate a set of standard corpus in Chinese discharge summaries; (2) to perform word segmentation and named entity recognition in the above corpus; (3) to build a joint model that performs word segmentation and named entity recognition. DESIGN: Two independent systems of word segmentation and named entity recognition were built based on conditional random field models. In the field of natural language processing, while most approaches use a single model to predict outputs, many works have proved that performance of many tasks can be improved by exploiting combined techniques. Therefore, in this paper, we proposed a joint model using dual decomposition to perform both the two tasks in order to exploit correlations between the two tasks. Three sets of features were designed to demonstrate the advantage of the joint model we proposed, compared with independent models, incremental models and a joint model trained on combined labels. MEASUREMENTS: Micro-averaged precision (P), recall (R), and F-measure (F) were used to evaluate results. RESULTS: The gold standard corpus is created using 336 Chinese discharge summaries of 71 355 words. The framework using dual decomposition achieved 0.2% improvement for segmentation and 1% improvement for recognition, compared with each of the two tasks alone. CONCLUSIONS: The joint model is efficient and effective in both segmentation and recognition compared with the two individual tasks. The model achieved encouraging results, demonstrating the feasibility of the two tasks. PMID- 23934950 TI - Leveraging electronic healthcare record standards and semantic web technologies for the identification of patient cohorts. AB - BACKGROUND: The secondary use of electronic healthcare records (EHRs) often requires the identification of patient cohorts. In this context, an important problem is the heterogeneity of clinical data sources, which can be overcome with the combined use of standardized information models, virtual health records, and semantic technologies, since each of them contributes to solving aspects related to the semantic interoperability of EHR data. OBJECTIVE: To develop methods allowing for a direct use of EHR data for the identification of patient cohorts leveraging current EHR standards and semantic web technologies. MATERIALS AND METHODS: We propose to take advantage of the best features of working with EHR standards and ontologies. Our proposal is based on our previous results and experience working with both technological infrastructures. Our main principle is to perform each activity at the abstraction level with the most appropriate technology available. This means that part of the processing will be performed using archetypes (ie, data level) and the rest using ontologies (ie, knowledge level). Our approach will start working with EHR data in proprietary format, which will be first normalized and elaborated using EHR standards and then transformed into a semantic representation, which will be exploited by automated reasoning. RESULTS: We have applied our approach to protocols for colorectal cancer screening. The results comprise the archetypes, ontologies, and datasets developed for the standardization and semantic analysis of EHR data. Anonymized real data have been used and the patients have been successfully classified by the risk of developing colorectal cancer. CONCLUSIONS: This work provides new insights in how archetypes and ontologies can be effectively combined for EHR driven phenotyping. The methodological approach can be applied to other problems provided that suitable archetypes, ontologies, and classification rules can be designed. PMID- 23934951 TI - A critical appraisal of a meta-analysis comparing transcatheter closure of PFO versus medical therapy. PMID- 23934952 TI - Preparation of functionalized indoles and azaindoles by the intramolecular copper mediated carbomagnesiation of ynamides. AB - Variations on a theme: A mild and general intramolecular copper-mediated carbomagnesiation procedure for the synthesis of functionalized indoles as well as 4-, 5-, 6-, and 7-azaindoles starts from readily available ynamides. Subsequent reactions with various electrophiles provides polyfunctional N heterocycles in good yields. PMID- 23934953 TI - Tandem synthesis of benzo[b]carbazoles and their photoluminescent properties. AB - 5 H-Benzo[b]carbazoles were prepared through a tandem reaction between 2-ethynyl N-triphenylphosphoranylidene anilines and alpha-diazoketones through ketenimine intermediates in moderate-to-good yields. By using this approach, benzo[b]benzo[5,6]indolo[3,2-h]carbazoles, fluoreno[9,1-ab]carbazoles, and fluoreno[9,1-ab]fluoreno[1',9':5,6,7]indolo[3,2-h]carbazoles were constructed in one pot. Moreover, the resulting products emitted light within the range 410-521 nm, with quantum yields of up to 62 %. PMID- 23934955 TI - Palladium-catalyzed intermolecular asymmetric allylic dearomatization reaction of naphthol derivatives. AB - Baring all: The title reaction provides beta-naphthalenones bearing an all-carbon quaternary center in good to excellent yields, as well as excellent chemo- and enantioselectivity. PMID- 23934954 TI - Effective targeting of chronic myeloid leukemia initiating activity with the combination of arsenic trioxide and interferon alpha. AB - Imatinib is the standard of care in chronic meloid leukemia (CML) therapy. However, imatinib is not curative since most patients who discontinue therapy relapse indicating that leukemia initiating cells (LIC) are resistant. Interferon alpha (IFN) induces hematologic and cytogenetic remissions and interestingly, improved outcome was reported with the combination of interferon and imatinib. Arsenic trioxide was suggested to decrease CML LIC. We investigated the effects of arsenic and IFN on human CML cell lines or primary cells and the bone marrow retroviral transduction/transplantation murine CML model. In vitro, the combination of arsenic and IFN inhibited proliferation and activated apoptosis. Importantly, arsenic and IFN synergistically reduced the clonogenic activity of primary bone marrow cells derived from CML patients. Finally, in vivo, combined interferon and arsenic treatment, but not single agents, prolonged the survival of primary CML mice. Importantly, the combination severely impaired engraftment into untreated secondary recipients, with some recipients never developing the disease, demonstrating a dramatic decrease in CML LIC activity. Arsenic/IFN effect on CML LIC activity was significantly superior to that of imatinib. These results support further exploration of this combination, alone or with imatinib aiming at achieving CML eradication rather than long-term disease control. PMID- 23934956 TI - Drug-coated balloon treatment of coronary artery disease: a position paper of the Italian Society of Interventional Cardiology. AB - Drug-coated balloons are a new tool for the treatment of patients with coronary artery disease. The main feature of this technology is a rapid and homogenous transfer of an antiproliferative drug (paclitaxel) to the vessel wall just at the time of balloon inflation, when neointimal proliferation, in response to angioplasty, is the highest. Moreover, drug-coated balloons share adjuntive advantages over stents: the absence of permanent scaffold and polymer, the respect of the original coronary anatomy, and limited inflammatory stimuli, thereby allowing for short-term dual antiplatelet therapy. To this day, a lot of devices are available in the market, with limited scientific data for the vast majority of them. Thus, the Italian scientific society of interventional cardiologists GISE decided to coordinate the efforts of a group of reknown experts on the field, in order to obtain a Position Paper on the correct use of drug-coated balloons in all the settings of coronary artery disease, giving a class of indication to each one, based on the clinical evidence. This Position Paper represents a quick reference for operators, investigators, and manufactures to promote the understanding and the correct use of the drug-coated balloon technology in everyday clinical practice. PMID- 23934957 TI - Directly deposited quantum dot solids using a colloidally stable nanoparticle ink. AB - We develop a photovoltaic colloidal quantum dot ink that allows for lossless, single-step coating of large areas in a manufacturing-compatible process. Our materials strategy involves a solution-phase ligand exchange to transport compatible linkers that yield 1-thioglycerol-capped PbS quantum dots in dimethyl sulfoxide with a photoluminescence quantum yield of 24%. A proof-of-principle solar cell made from the ink exhibits 2.1% power conversion efficiency. PMID- 23934958 TI - Tripterygium wilfordii Hook F (a traditional Chinese medicine) for primary nephrotic syndrome. AB - BACKGROUND: Tripterygium wilfordii Hook F (TwHF), a traditional Chinese herbal medicine used as an immunosuppressive agent, has been prescribed in China for patients with primary nephrotic syndrome (NS) for more than two decades. Although patients with primary NS in China have benefited from TwHF treatment, its properties have not yet been fully understood. OBJECTIVES: To assess the benefits and harms of TwHF for patients with primary NS. SEARCH METHODS: We searched the Cochrane Renal Group's specialised register (August 2012), Cochrane Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 8), EMBASE (1966 to August 2012), and MEDLINE (1966 to August 2012). We also searched CBM (Chinese Biological Medical Database) (1978 to November 2010), CNKI (Chinese National Knowledge Infrastructure) (1979 to November 2010), VIP (ChongQing WeiPu Chinese Science and Technology Periodical Database) (1989 to November 2010), WanFang Database (1980 to November 2010), and reference lists of articles (6 November 2010). SELECTION CRITERIA: Only randomised controlled trials (RCTs) were included. Two standardised preparations of TwHF were investigated: ethanol-ethyl acetate extract and chloroform-methanol extract. All other TwHF preparations were excluded because of reported toxicities. Other traditional Chinese herbal medicines were also excluded. All included RCTs had a follow-up of at least three months. DATA COLLECTION AND ANALYSIS: Data extraction and risk of bias assessment were undertaken independently by two authors. Where details of randomised sequence generation and allocation concealment were absent or inadequately reported, we contacted original study investigators for verification and details of the procedure. For dichotomous outcomes (remission and drug-related adverse events) we used risk ratio (RR) with 95% confidence intervals (95% CI) and mean difference (MD) for continuous outcomes (urinary protein excretion, serum albumin and serum creatinine). MAIN RESULTS: Ten studies enrolling 630 participants were included. Overall, the quality of evidence was suboptimal due to the small number of included studies enrolling small numbers of participants; short follow-up in each study; only a few studies in each comparison category; and major concerns with methodological bias. Four studies (293 participants) contributed to the comparison of TwHF versus non-TwHF. TwHF significantly increased complete remission (RR 1.46, 95% CI 1.18 to 1.80) and complete or partial remission (RR 1.26, 95% CI 1.10 to 1.44) without escalating the adverse events profile at the last follow-up (12 to 16 months). Four studies (223 participants) compared TwHF with prednisone. There were no statistically significant differences between complete remission, partial remission, and complete or partial remission. Two studies (114 participants) contributed to the comparison of TwHF versus cyclophosphamide (CPA) at the last follow-up (3 to 12 months). There were no statistically significant differences between complete, partial, or complete or partial remission. One study (46 participants) reported TwHF was associated with a significantly lower serum creatinine compared with CPA (MD -14.00 MUmol/L, 95% CI -26.43 to -1.57). No serious adverse events of TwHF were observed. One study (37 participants) reported TwHF was associated with a significantly lower risk of psychosis when compared to prednisone (RR 0.11, 95% CI 0.01 to 0.75), and two studies showed a significantly lower risk of hair loss with TwHF when compared to CPA ((2 studies, 114 participants): RR 0.11, 95% CI 0.02 to 0.59). AUTHORS' CONCLUSIONS: TwHF may have an add-on effect on remission in patients with primary NS. There was insufficient evidence to assess if TwHF was as effective as prednisone or CPA. More methodologically sound and sufficiently powered studies, with adequate follow-up would help to better inform management options for the use of TwHF for primary NS. TwHF should be further directly compared with other widely used immunosuppressive agents after the superiority over placebo or no treatment has been clearly established. PMID- 23934959 TI - Transient, asymptomatic, fluctuating bradycardia with oral ziprasidone in an older woman. PMID- 23934960 TI - Human linear growth trajectory defined. AB - OBJECTIVES: The purpose of this study was to assess the applicability of a simple mathematical formula for prediction of individual child linear growth. The formula describes a square root dependence of height on age with only two constants, k and C. METHODS: Retrospective serial height measurements of 137 healthy children (61 female), who attended clinic in the Pediatrics Department at the University of California, San Francisco were used. For each child, two of the initial measurements and their corresponding measurement times were used to determine the values of k and C. By substituting the determined values of k and C into the formula, the formula was then used to predict the trajectory of the child's growth. RESULTS: The 137 children were comprised of 20% Hispanic, 23% African-American, 27% Caucasian and 30% Asian. The formula predicted growth trajectories of 136 out of the 137 children with minimal discrepancies between the measured data and the corresponding predicted data. The mean of the discrepancies was 0.8 cm. CONCLUSIONS: Our proposed formula is very easy to use and predicts individual child growth with high precision irrespective of gender or ethnicity. The formula will be a valuable tool for studying human growth and possibly growths of other animals. PMID- 23934961 TI - Synthesis of a new series of phosphonylated 1,2,3-triazoles as acyclic analogs of ribavirin. AB - A novel series of phosphonylated 1,2,3-triazoles as structural acyclic analogs of ribavirin, in which the 1,2,3-triazole ring was substituted at C4' with COOMe, CONH2, CONHOH, and CH2 NHBoc groups, were synthesized from diethyl azidomethyl-, 2-azidoethyl-, 3-azidopropyl-, 4-azidobutyl-, 2-azido-1-hydroxyethyl-, 3-azido-2 hydroxypropyl-, 2-azidoethoxymethyl- and 2-azidoethoxyethylphosphonate. The efficient synthesis of diethyl azidomethylphosphonate from diethyl 4 nitrobenzenesulfonylmethylphosphonate employing the in situ formed azides is described. All synthesized compounds were evaluated in vitro for their inhibitory activity against a broad variety of RNA and DNA viruses. No antiviral activity was observed at 100 uM. Only compound 13g exhibited inhibitory effects on the proliferation of HeLa cells (IC50=169+/-45 uM). PMID- 23934962 TI - Justification of CT examinations in young adults and children can be improved by education, guideline implementation and increased MRI capacity. AB - OBJECTIVE: To determine whether the justification of CT examinations performed on young patients can be improved by various interventions and whether these have an effect on the total number of CTs performed. METHODS: Specific interventions education, guideline implementation and increased MRI capacity-were introduced at the Oulu University Hospital, Oulu, Finland, following a previous study demonstrating unjustified use of CT examination in young patients. In the present study, the justification of 177 CT examinations of the lumbar and cervical spine, head, abdomen, nasal sinuses and trauma performed on patients aged under 35 years in 2009 was analysed retrospectively by looking at requests and corresponding patient files. The indications of the examinations were compared with the referral guidelines recommended by the European Commission. Results from our previously published similar study carried out before the interventions were used as a reference. RESULTS: The proportion of justified CT examinations increased from 71% (141/200) in 2005 to 87% (154/177) in 2009 (p<0.001), and in the lumbar spine group from 23% (7/30) to 81% (22/27) (p<0.001). In the case of most of the unjustified examinations, MRI could have been performed instead. The total number of CT examinations carried out on young patients decreased by 7% (p=0.012) and in the lumbar spine group by 79% (p<0.001). CONCLUSION: The implemented interventions decreased the number of CT examinations performed on young patients, and the justification of the examinations improved significantly. ADVANCES IN KNOWLEDGE: This study demonstrates that it is possible to reduce the number of various CT examinations and to improve their justification in young patients by regular education, guideline implementation and increased MRI capacity. PMID- 23934963 TI - Effective dose to staff members in a positron emission tomography/CT facility using zirconium-89. AB - OBJECTIVE: Positron emission tomography (PET) using zirconium-89 ((89)Zr) is complicated by its complex decay scheme. In this study, we quantified the effective dose from (89)Zr and compared it with fluorine-18 fludeoxyglucose ((18)F-FDG). METHODS: Effective dose distribution in a PET/CT facility in Riyadh was calculated by Monte Carlo simulations using MCNPX. The positron bremsstrahlung, the annihilation photons, the delayed gammas from (89)Zr and those emissions from (18)F-FDG were modelled in the simulations but low-energy characteristic X-rays were ignored. RESULTS: On the basis of injected activity, the dose from (89)Zr was higher than that of (18)F-FDG. However, the dose per scan from (89)Zr became less than that from (18)F-FDG near the patient, owing to the difference in injected activities. In the corridor and control rooms, the (89)Zr dose was much higher than (18)F-FDG, owing to the difference in attenuation by the shielding materials. CONCLUSION: The presence of the high energy photons from (89)Zr-labelled immuno-PET radiopharmaceuticals causes a significantly higher effective dose than (18)F-FDG to the staff outside the patient room. Conversely, despite the low administered activity of (89)Zr, it gives rise to a comparable or even lower dose than (18)F-FDG to the staff near the patient. This interesting result raises apparently contradictory implications in the radiation protection considerations of a PET/CT facility. ADVANCES IN KNOWLEDGE: To the best of our knowledge, radiation exposure to staff and public in the PET/CT unit using (89)Zr has not been investigated. The ultimate output of this study will lead to the optimal design of the facility for routine use of (89)Zr. PMID- 23934964 TI - K-edge ratio method for identification of multiple nanoparticulate contrast agents by spectral CT imaging. AB - OBJECTIVE: Recently introduced energy-sensitive X-ray CT makes it feasible to discriminate different nanoparticulate contrast materials. The purpose of this work is to present a K-edge ratio method for differentiating multiple simultaneous contrast agents using spectral CT. METHODS: The ratio of two images relevant to energy bins straddling the K-edge of the materials is calculated using an analytic CT simulator. In the resulting parametric map, the selected contrast agent regions can be identified using a thresholding algorithm. The K edge ratio algorithm is applied to spectral images of simulated phantoms to identify and differentiate up to four simultaneous and targeted CT contrast agents. RESULTS: We show that different combinations of simultaneous CT contrast agents can be identified by the proposed K-edge ratio method when energy sensitive CT is used. In the K-edge parametric maps, the pixel values for biological tissues and contrast agents reach a maximum of 0.95, whereas for the selected contrast agents, the pixel values are larger than 1.10. The number of contrast agents that can be discriminated is limited owing to photon starvation. For reliable material discrimination, minimum photon counts corresponding to 140 kVp, 100 mAs and 5-mm slice thickness must be used. CONCLUSION: The proposed K edge ratio method is a straightforward and fast method for identification and discrimination of multiple simultaneous CT contrast agents. ADVANCES IN KNOWLEDGE: A new spectral CT-based algorithm is proposed which provides a new concept of molecular CT imaging by non-iteratively identifying multiple contrast agents when they are simultaneously targeting different organs. PMID- 23934965 TI - Biphasic and monophasic repair: comparative implications for biologically equivalent dose calculations in pulsed dose rate brachytherapy of cervical carcinoma. AB - OBJECTIVE: To consider the implications of the use of biphasic rather than monophasic repair in calculations of biologically-equivalent doses for pulsed dose-rate brachytherapy of cervix carcinoma. METHODS: Calculations are presented of pulsed-dose-rate (PDR) doses equivalent to former low-dose-rate (LDR) doses, using biphasic vs monophasic repair kinetics, both for cervical carcinoma and for the organ at risk (OAR), namely the rectum. The linear-quadratic modelling calculations included effects due to varying the dose per PDR cycle, the dose reduction factor for the OAR compared with Point A, the repair kinetics and the source strength. RESULTS: When using the recommended 1 Gy per hourly PDR cycle, different LDR-equivalent PDR rectal doses were calculated depending on the choice of monophasic or biphasic repair kinetics pertaining to the rodent central nervous and skin systems. These differences virtually disappeared when the dose per hourly cycle was increased to 1.7 Gy. This made the LDR-equivalent PDR doses more robust and independent of the choice of repair kinetics and alpha/beta ratios as a consequence of the described concept of extended equivalence. CONCLUSION: The use of biphasic and monophasic repair kinetics for optimised modelling of the effects on the OAR in PDR brachytherapy suggests that an optimised PDR protocol with the dose per hourly cycle nearest to 1.7 Gy could be used. Hence, the durations of the new PDR treatments would be similar to those of the former LDR treatments and not longer as currently prescribed. ADVANCES IN KNOWLEDGE: Modelling calculations indicate that equivalent PDR protocols can be developed which are less dependent on the different alpha/beta ratios and monophasic/biphasic kinetics usually attributed to normal and tumour tissues for treatment of cervical carcinoma. PMID- 23934966 TI - Unusual inherent electrochemistry of graphene oxides prepared using permanganate oxidants. AB - Graphene and graphene oxides are materials of significant interest in electrochemical devices such as supercapacitors, batteries, fuel cells, and sensors. Graphene oxides and reduced graphenes are typically prepared by oxidizing graphite in strong mineral acid mixtures with chlorate (Staudenmaier, Hofmann) or permanganate (Hummers, Tour) oxidants. Herein, we reveal that graphene oxides pose inherent electrochemistry, that is, they can be oxidized or reduced at relatively mild potentials (within the range +/-1 V) that are lower than typical battery potentials. This inherent electrochemistry of graphene differs dramatically from that of the used oxidants. Graphene oxides prepared using chlorate exhibit chemically irreversible reductions, whereas graphene oxides prepared through permanganate-based methods exhibit very unusual inherent chemically reversible electrochemistry of oxygen-containing groups. Insight into the electrochemical behaviour was obtained through cyclic voltammetry, chronoamperometry, and X-ray photoelectron spectroscopy experiments. Our findings are of extreme importance for the electrochemistry community as they reveal that electrode materials undergo cyclic changes in charge/discharge cycles, which has strong implications for energy-storage and sensing devices. PMID- 23934968 TI - High-efficiency hybrid solar cells based on polymer/PbSx Se1-x nanocrystals benefiting from vertical phase segregation. AB - Solution-processed hybrid solar cells employing a low band-gap polymer and PbSx Se1-x alloy nanocrystals, achieving a record high PCE of 5.50% and an optimal FF of 67% are presented. The remarkable device efficiency can be attributed to the high-performance active materials, the optimal polymer/NCs ratio and, more importantly, the vertical donor/(donor:acceptor)/acceptor structure which benefits charge dissociation and transport. PMID- 23934967 TI - Gene expression profile of A549 cells from tissue of 4D model predicts poor prognosis in lung cancer patients. AB - The tumor microenvironment plays an important role in regulating cell growth and metastasis. Recently, we developed an ex vivo lung cancer model (four dimensional, 4D) that forms perfusable tumor nodules on a lung matrix that mimics human lung cancer histopathology and protease secretion pattern. We compared the gene expression profile (Human OneArray v5 chip) of A549 cells, a human lung cancer cell line, grown in a petri dish (two-dimensional, 2D), and of the same cells grown in the matrix of our ex vivo model (4D). Furthermore, we obtained gene expression data of A549 cells grown in a petri dish (2D) and matrigel (three dimensional, 3D) from a previous study and compared the 3D expression profile with that of 4D. Expression array analysis showed 2,954 genes differentially expressed between 2D and 4D. Gene ontology (GO) analysis showed upregulation of several genes associated with extracellular matrix, polarity and cell fate and development. Moreover, expression array analysis of 2D vs. 3D showed 1,006 genes that were most differentially expressed, with only 36 genes (4%) having similar expression patterns as observed between 2D and 4D. Finally, the differential gene expression signature of 4D cells (vs. 2D) correlated significantly with poor survival in patients with lung cancer (n = 1,492), while the expression signature of 3D vs. 2D correlated with better survival in lung cancer patients with lung cancer. As patients with larger tumors have a worse rate of survival, the ex vivo 4D model may be a good mimic of natural progression of tumor growth in lung cancer patients. PMID- 23934969 TI - Metabolic syndrome does not impact long-term survival in patients with acute myocardial infarction after successful percutaneous coronary intervention with drug-eluting stents. AB - OBJECTIVE: This study aimed to evaluate long-term survival according to the presence of metabolic syndrome (MS) in patients with acute myocardial infarction (AMI) undergoing successful percutaneous coronary intervention (PCI) with drug eluting stents (DES). BACKGROUND: Despite the significance of coronary reperfusion in AMI, the prognostic impact of MS has been investigated under inconsistent reperfusion therapy in AMI patients. METHODS AND RESULTS: Three-year clinical outcomes, including all-cause death and the composite of cardiac death or myocardial infarction, were evaluated according to MS status for 963 patients with AMI treated with successful PCI with DES. This study included 494 subjects with MS (51%) and 469 subjects without MS (49%). The incidence of multivessel disease and the mean number of implanted stents were significantly higher in patients with MS than in patients with non-MS. The occurrence of all-cause death (5.9% vs. 6.4%, P = 0.789) and the composite outcomes (5.1% vs. 6.2%, P = 0.485) did not differ significantly between patients with and without MS. Cox regression models revealed that MS had no significant impact on all-cause death (hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.55-1.52; P = 0.726) or the composite outcomes (HR 0.81; 95% CI 0.48-1.39; P = 0.448). Obesity was associated with a decreased risk of all-cause death and the composite outcomes among all MS components. CONCLUSIONS: No difference was observed in long-term survival according to the presence of MS in patients with AMI after successful PCI with DES. This suggests that reperfusion therapy using PCI with DES is equally beneficial in patients AMI with and without MS. PMID- 23934970 TI - Long-range distances in amyloid fibrils of alpha-synuclein from PELDOR spectroscopy. PMID- 23934971 TI - Telephone counselling for smoking cessation. AB - BACKGROUND: Telephone services can provide information and support for smokers. Counselling may be provided proactively or offered reactively to callers to smoking cessation helplines. OBJECTIVES: To evaluate the effect of proactive and reactive telephone support via helplines and in other settings to help smokers quit. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialised Register for studies of telephone counselling, using search terms including 'hotlines' or 'quitline' or 'helpline'. Date of the most recent search: May 2013. SELECTION CRITERIA: randomized or quasi-randomised controlled trials in which proactive or reactive telephone counselling to assist smoking cessation was offered to smokers or recent quitters. DATA COLLECTION AND ANALYSIS: One author identified and data extracted trials, and a second author checked them. The main outcome measure was the risk ratio for abstinence from smoking after at least six months follow-up. We selected the strictest measure of abstinence, using biochemically validated rates where available. We considered participants lost to follow-up to be continuing smokers. Where trials had more than one arm with a less intensive intervention we used only the most similar intervention without the telephone component as the control group in the primary analysis. We assessed statistical heterogeneity amongst subgroups of clinically comparable studies using the I2 statistic. We considered trials recruiting callers to quitlines separately from studies recruiting in other settings. Where appropriate, we pooled studies using a fixed-effect model. We used a meta-regression to investigate the effect of differences in planned number of calls, selection for motivation, and the nature of the control condition (self help only, minimal intervention, pharmacotherapy) in the group of studies recruiting in non-quitline settings. MAIN RESULTS: Seventy-seven trials met the inclusion criteria. Some trials were judged to be at risk of bias in some domains but overall we did not judge the results to be at high risk of bias. Among smokers who contacted helplines, quit rates were higher for groups randomized to receive multiple sessions of proactive counselling (nine studies, > 24,000 participants, risk ratio (RR) for cessation at longest follow-up 1.37, 95% confidence interval (CI) 1.26 to 1.50). There was mixed evidence about whether increasing the number of calls altered quit rates but most trials used more than two calls. Three studies comparing different counselling approaches during a single quitline contact did not detect significant differences. Of three studies that tested the provision of access to a hotline two detected a significant benefit and one did not.Telephone counselling not initiated by calls to helplines also increased quitting (51 studies, > 30,000 participants, RR 1.27; 95% CI 1.20 to 1.36). In a meta regression controlling for other factors the effect was estimated to be slightly larger if more calls were offered, and in trials that specifically recruited smokers motivated to try to quit. The relative extra benefit of counselling was smaller when it was provided in addition to pharmacotherapy (usually nicotine replacement therapy) than when the control group only received self-help material or a brief intervention.A further eight studies were too diverse to contribute to meta-analyses and are discussed separately. Two compared different intensities of counselling, both of which detected a dose response; one of these detected a benefit of multiple counselling sessions over a single call for people prescribed bupropion. The others tested a variety of interventions largely involving offering telephone counselling as part of a referral or systems change and none detected evidence of effect. AUTHORS' CONCLUSIONS: Proactive telephone counselling aids smokers who seek help from quitlines. Telephone quitlines provide an important route of access to support for smokers, and call-back counselling enhances their usefulness. There is limited evidence about the optimal number of calls. Proactive telephone counselling also helps people who receive it in other settings. There is some evidence of a dose response; one or two brief calls are less likely to provide a measurable benefit. Three or more calls increase the chances of quitting compared to a minimal intervention such as providing standard self-help materials, or brief advice, or compared to pharmacotherapy alone. PMID- 23934973 TI - Thermal methane activation by a binary V-Nb transition-metal oxide cluster cation: a further example for the crucial role of oxygen-centered radicals. AB - The heteronuclear transition-metal oxide cluster activates methane: VNbO5(+) reacts with CH4 under ambient conditions via hydrogen-atom transfer (HAT), thus providing an interesting prototype example of room-temperature methane activation by a binary transition-metal oxide cluster. PMID- 23934972 TI - STAT3 inhibition sensitizes colorectal cancer to chemoradiotherapy in vitro and in vivo. AB - Increased activity of signal transducer and activator of transcription 3 (STAT3) is common in human malignancies, including colorectal cancers (CRCs). We have recently reported that STAT3 gene expression correlates with resistance of CRC cell lines to 5-fluorouracil (5-FU)-based chemoradiotherapy (CT/RT). This is of considerable clinical importance, because a large proportion of rectal cancers are resistant to preoperative multimodal treatment. To test whether STAT3 contributes to CT/RT-resistance, we first confirmed that STAT3 protein expression correlated positively with increasing resistance. While STAT3 was not constitutively active, stimulation with interleukin-6 (IL-6) resulted in remarkably higher expression levels of phosphorylated STAT3 in CT/RT-resistant cell lines. A similar result was observed when we determined IL-6-induced expression levels of phosphorylated STAT3 following irradiation. Next, STAT3 was inhibited in SW480 and SW837 using siRNA, shRNA and the small-molecule inhibitor STATTIC. Successful silencing and inhibition of phosphorylation was confirmed using Western blot analysis and a luciferase reporter assay. RNAi-mediated silencing as well as STATTIC treatment resulted in significantly decreased clonogenic survival following exposure to 3 uM of 5-FU and irradiation in a dose dependent manner, with dose-modifying factors of 1.3-2.5 at a surviving fraction of 0.37. Finally, STAT3 inhibition led to a profound CT/RT-sensitization in a subcutaneous xenograft model, with a significantly delayed tumor regrowth in STATTIC-treated mice compared with control animals. These results highlight a potential role of STAT3 in mediating treatment resistance and provide first proof of concept that STAT3 represents a promising novel molecular target for sensitizing resistant rectal cancers to CT/RT. PMID- 23934974 TI - PHOTO QUIZ. A 40-year-old woman from a native Indian community with non-Hodgkin lymphoma and hemoptysis. Diagnosis: pulmonary paragonimiasis. PMID- 23934981 TI - Rebuttal: "a critical appraisal of a meta-analysis comparing transcatheter closure of PFO versus medical therapy". PMID- 23934984 TI - Scientific Working Group for Forensic Toxicology (SWGTOX) standard practices for method validation in forensic toxicology. PMID- 23934982 TI - Antimicrobial therapy for chronic bacterial prostatitis. AB - BACKGROUND: Chronic bacterial prostatitis (CBP) is frequently diagnosed in men of fertile age, and is characterized by a disabling array of symptoms, including pain in the pelvic area (for example, perineum, testicles), voiding symptoms (increased frequency and urgency, also at night; pain or discomfort at micturition), and sexual dysfunction. Cure of CBP can be attempted by long-term therapy with antibacterial agents, but relapses are frequent. Few antibacterial agents are able to distribute to the prostatic tissue and achieve sufficient concentrations at the site of infection. These agents include fluoroquinolones, macrolides, tetracyclines and trimethoprim. After the introduction of fluoroquinolones into clinical practice, a number of studies have been performed to optimize the antimicrobial treatment of CBP, and to improve eradication rates and symptom relief. OBJECTIVES: To assess and compare the efficacy and harm of antimicrobial treatments for chronic bacterial prostatitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), EMBASE, other national or international databases and abstracts from conference proceedings on 8 August 2012. SELECTION CRITERIA: We included all randomized controlled comparisons of one antimicrobial agent versus placebo or one or more comparator antimicrobial agents, combined or not with non antimicrobial drugs. We also included trials comparing different doses, treatment durations, dosing frequencies, or routes of administration of antimicrobial agents. We excluded studies in which patients were not diagnosed according to internationally recommended criteria, or were not subjected to lower urinary tract segmented tests. DATA COLLECTION AND ANALYSIS: Study data were extracted independently by two review authors. Study outcomes were microbiological efficacy (pathogen eradication), clinical efficacy (symptom cure or improvement, or symptom scores) at test-of-cure visits or at follow-up, or both, and adverse effects of therapy. Secondary outcomes included microbiological recurrence rates.Statistical analysis was performed using a fixed-effect model for microbiological outcomes and a random-effects model for clinical outcomes and adverse effects. The results were expressed as risk ratios for dichotomous outcomes (with 95% confidence intervals) or as standardized mean differences for continuous or non-dichotomous variables. MAIN RESULTS: We identified 18 studies, enrolling a total of 2196 randomized patients. The oral fluoroquinolones ciprofloxacin, levofloxacin, lomefloxacin, ofloxacin and prulifloxacin were compared. There were no significant differences in clinical or microbiological efficacy or in the rate of adverse effects between these fluoroquinolones. In chlamydial prostatitis, (i) azithromycin showed improved eradication rates and clinical cure rates compared to ciprofloxacin, with no significant differences regarding adverse effects; (ii) azithromycin was equivalent to clarithromycin, both microbiologically and clinically; (iii) prulifloxacin appeared to improve clinical symptoms, but not eradication rates, compared to doxycycline. In ureaplasmal prostatitis, the comparisons ofloxacin versus minocycline and azithromycin versus doxycycline showed similar microbiological, clinical and toxicity profiles. AUTHORS' CONCLUSIONS: The microbiological and clinical efficacy, as well as the adverse effect profile, of different oral fluoroquinolones are comparable. No conclusions can be drawn regarding the optimal treatment duration of fluoroquinolones in the treatment of CBP caused by traditional pathogens.Alternative antimicrobial agents tested for the treatment of CBP caused by traditional pathogens are co-trimoxazole, beta-lactams and tetracyclines, but no conclusive evidence can be drawn regarding the role of non fluoroquinolone antibiotics in the treatment of CBP caused by traditional pathogens.In patients with CBP caused by obligate intracellular pathogens, macrolides showed higher microbiological and clinical cure rates compared to fluoroquinolones. PMID- 23934989 TI - Measuring the health-related quality of life and sexual functioning of patients with rectal cancer: does type of treatment matter? AB - The literature on the health-related quality of life (HRQOL) after rectal cancer is growing, however, a comparison between patients with nonadvanced disease (NAD), locally advanced rectal cancer (LARC), locally recurrent rectal cancer (LRRC) and a normative population has not been made. Data on the sexual functioning of patient groups is also scarce. We compared (i) the HRQOL of patients with NAD, LARC, or LRRC, with a special focus on sexual functioning and (ii) the HRQOL of the three treatment groups with a normative population. The EORTC QLQ-C30 and QLQ-CR38 were completed by 80 patients with NAD, 292 LARC patients and 67 LRRC patients. The normative population (n = 350) completed the EORTC QLQ-C30 and the Sexual Functioning and Sexual Enjoyment scales of the CR38. LRRC patients reported a lower Physical Function, Social Function, Future Perspective, Sexual Functioning and more Pain compared with LARC and NAD patients. Also, LRRC patients had a worse Body image than NAD patients and a lower Male Sexual Functioning than LARC patients. More than 75% of men and 50% of women were sexually active preoperative, compared with less than 50% and less than 35% postoperative. Male LRRC patients had more problems with erectile or ejaculatory functioning and felt less masculine than NAD or LARC patients. Women did not differ on Lubrication, Dyspareunia and Body Image. About 10% of patients used aids in order to improve erectile functioning (men) or lubrication (women). The treatment groups reported a lower HRQOL and sexual functioning compared with the normative population. PMID- 23934990 TI - Surviving another influenza threat. PMID- 23934991 TI - Progression of anal high-grade squamous intraepithelial lesions to invasive anal cancer among HIV-infected men who have sex with men. AB - The incidence of anal cancer is elevated in human immunodeficiency virus (HIV) infected men-who-have-sex-with-men (MSM) compared to the general population. Anal high-grade squamous intraepithelial lesions (HSIL) are common in HIV-infected MSM and the presumed precursors to anal squamous cell cancer; however, direct progression of HSIL to anal cancer has not been previously demonstrated. The medical records were reviewed of 138 HIV-infected MSM followed up at the University of California, San Francisco, who developed anal canal or perianal squamous cancer between 1997 and 2011. Men were followed up regularly with digital anorectal examination (DARE), high-resolution anoscopy (HRA) and HRA guided biopsy. Although treatment for HSIL and follow-up were recommended, not all were treated and some were lost to follow-up. Prevalent cancer was found in 66 men. Seventy-two HIV-infected MSM developed anal cancer while under observation. In 27 men, anal cancer developed at a previously biopsied site of HSIL. An additional 45 men were not analyzed in this analysis due to inadequate documentation of HSIL in relation to cancer location. Of the 27 men with documented progression to cancer at the site of biopsy-proven HSIL, 20 men progressed from prevalent HSIL identified when first examined and seven men from incident HSIL. Prevalent HSIL progressed to cancer over an average of 57 months compared to 64 months for incident HSIL. Most men were asymptomatic, and cancers were detected by DARE. Anal HSIL has clear potential to progress to anal cancer in HIV-infected MSM. Early diagnosis is facilitated by careful follow-up. Carefully controlled studies evaluating efficacy of screening for and treatment of HSIL to prevent anal cancer are needed. PMID- 23934992 TI - Myocardial fibrosis as a key determinant of left ventricular remodeling in idiopathic dilated cardiomyopathy: a contrast-enhanced cardiovascular magnetic study. AB - BACKGROUND: In idiopathic dilated cardiomyopathy, there are scarce data on the influence of late gadolinium enhancement (LGE) assessed by cardiovascular magnetic resonance on left ventricular (LV) remodeling. METHODS AND RESULTS: Fifty-eight consecutive patients with idiopathic dilated cardiomyopathy underwent baseline clinical, biohumoral, and instrumental workup. Medical therapy was optimized after study enrollment. Cardiovascular magnetic resonance was used to assess ventricular volumes, function, and LGE extent at baseline and 24-month follow-up. LV reverse remodeling (RR) was defined as an increase in LV ejection fraction >=10 U, combined with a decrease in LV end-diastolic volume >=10% at follow-up. DeltaLGE extent was the difference in LGE extent between follow-up and baseline. LV-RR was observed in 22 patients (38%). Multivariate regression analysis showed that the absence of LGE at baseline cardiovascular magnetic resonance was a strong predictor of LV-RR (odds ratio, 10.857 [95% confidence interval, 1.844-63.911]; P=0.008) after correction for age, heart rate, New York Heart Association class, LV volumes, and LV and right ventricular ejection fractions. All patients with baseline LGE (n=26; 45%) demonstrated LGE at follow up, and no patient without baseline LGE developed LGE at follow-up. In LGE positive patients, there was an increase in LGE extent over time (P=0.034), which was inversely related to LV ejection fraction variation (Spearman rho, -0.440; P=0.041). Five patients showed an increase in LGE extent >75th percentile of DeltaLGE extent, and among these none experienced LV-RR and 4 had a decrease in LV ejection fraction >=10 U at follow-up. CONCLUSIONS: In patients with idiopathic dilated cardiomyopathy, the absence of LGE at baseline is a strong independent predictor of LV-RR at 2-year follow-up, irrespective of the initial clinical status and the severity of ventricular dilatation and dysfunction. The increase in LGE extent during follow-up was associated with progressive LV dysfunction. PMID- 23934993 TI - A unique Au-Ag-Au triangular motif in a trimetallic halonium dication: silver incorporation in a gold(I) catalyst. AB - As a result of explorations into the solution chemistry of silver/gold mixtures, a unique diphosphine trimetallic chloronium dication was discovered that incorporates silver-arene chelation and a triangular mixed gold/silver core in the solid state. Notably, it was isolated from a Celite prefiltered solution initially thought to be silver-free. The crystal structure also incorporates the coordination to silver of one fluorine atom of one SbF6(-) counterion. The structure was compared to two new, but well-precedented, phosphine digold chloride cations. DFT calculations supported significant silver-halide and silver arene interactions in the mixed gold/silver complex and metallophilic interactions in all three complexes. Comparison of computed data revealed that the omegaB97X-D functional, which has a long-range corrected hybrid with atom atom dispersion corrections, gave a better fit to the experimental data compared with the PBE0 functional, which has previously failed to capture aurophilic interactions. Preliminary studies support the presence of the mixed gold/silver structure in solution. PMID- 23934995 TI - Expression plasmids for use in Candida glabrata. AB - We describe a series of CEN/ARS episomal plasmids containing different Candida glabrata promoters, allowing for a range of constitutive or regulated expression of proteins in C. glabrata. The set of promoters includes three constitutive promoters (EGD2pr, HHT2pr, PDC1pr), two macrophage/phagocytosis-induced promoters (ACO2pr, LYS21pr), and one nutritionally regulated promoter (MET3pr). Each promoter was cloned into two plasmid backbones that differ in their selectable marker, URA3, or the dominant-selectable NAT1 gene, which confers resistance to the drug nourseothricin. Expression from the 12 resulting plasmids was assessed using GFP as a reporter and flow cytometry or quantitative reverse-transcription polymerase chain reaction to assess expression levels. Together this set of plasmids expands the toolkit of expression vectors available for use with C. glabrata. PMID- 23934994 TI - The C-terminal residues of Saccharomyces cerevisiae Mec1 are required for its localization, stability, and function. AB - Mec1, a member of the phosphoinositide three-kinase-related kinase (PIKK) family of proteins, is involved in the response to replicative stress and DNA damage and in telomere maintenance. An essential 30 to 35 residue, the FATC domain is found at the C-terminus of all PIKK family members. To investigate the roles of the C terminal residues of Mec1, we characterized alleles of Saccharomyces cerevisiae mec1 that alter the FATC domain. A change of the terminal tryptophan to alanine resulted in temperature-sensitive growth, sensitivity to hydroxyurea, and diminished kinase activity in vitro. Addition of a terminal glycine or deletion of one, two, or three residues resulted in loss of cell viability and kinase function. Each of these Mec1 derivatives was less stable than wild-type Mec1, eluted abnormally from a size exclusion column, and showed reduced nuclear localization. We identified rpn3-L140P, which encodes a component of the 19S proteasomal regulatory particle of the 26S proteasome, as a suppressor of the temperature-sensitive growth caused by mec1-W2368A. The rpn3-L140P allele acted in a partially dominant fashion. It was not able to suppress the inviability of the C-terminal truncations or additions or the hydroxyurea sensitivity of mec1 W2368A. The rpn3-L140P allele restored Mec1-W2368A to nearly wild-type protein levels at 37 degrees , an effect partially mimicked by the proteasome inhibitor MG-132. Our study supports a role for the C-terminus in Mec1 folding and stability, and suggests a role for the proteasome in regulating Mec1 levels. PMID- 23934996 TI - A deep intronic mutation in the ankyrin-1 gene causes diminished protein expression resulting in hemolytic anemia in mice. AB - Linkage between transmembrane proteins and the spectrin-based cytoskeleton is necessary for membrane elasticity of red blood cells. Mutations of the proteins that mediate this linkage result in various types of hemolytic anemia. Here we report a novel N-ethyl-N-nitrosourea-induced mutation of ankyrin-1, named hema6, which causes hereditary spherocytosis in mice through a mild reduction of protein expression. The causal mutation was traced to a single nucleotide transition located deep into intron 13 of gene Ank1. In vitro minigene splicing assay revealed two abnormally spliced transcripts containing cryptic exons from fragments of Ank1 intron 13. The inclusion of cryptic exons introduced a premature termination codon, which leads to nonsense-mediated decay of the mutant transcripts in vivo. Hence, in homozygous mice, only wild-type ankyrin-1 is expressed, albeit at 70% of the level in wild-type mice. Heterozygotes display a similar hereditary spherocytosis phenotype stemming from intermediate protein expression level, indicating the haploinsufficiency of the mutation. Weakened linkage between integral transmembrane protein, band 3, and underlying cytoskeleton was observed in mutant mice as the result of reduced high-affinity binding sites provided by ankyrin-1. Hema6 is the only known mouse mutant of Ank1 allelic series that expresses full-length canonical ankyrin-1 at a reduced level, a fact that makes it particularly useful to study the functional impact of ankyrin-1 quantitative deficiency. PMID- 23934997 TI - Schizosaccharomyces japonicus yeast poised to become a favorite experimental organism for eukaryotic research. AB - Both budding yeast Saccharomyces cerevisiae and fission yeast Schizosaccahromyces pombe have been very popular organisms used for biological research with eukaryotes for many decades. Judging from the fission yeast Schizosaccharomyces japonicus DNA sequence determined 2 years ago, this species is evolutionarily very much unrelated to the commonly used yeasts for research. Indicating evolutionary divergence, the S. japonicus makes 8-spored asci and mitosis occurs with a partial breakdown of nuclear membrane whereas the other yeasts make 4 spored asci and cells divide without nuclear breakdown. The commonly used yeast species exhibit a generation time between 1.5 and 2.0 hr, and their genetic cross takes a period of more than 7 working d. As described here, a generation time of only 63 min and meiotic analysis completed in just 2.5 d, the S. japonicus fission yeast is predicted to become a choice organism for future research on the biology of eukaryotes. PMID- 23934998 TI - A large-scale behavioral screen to identify neurons controlling motor programs in the Drosophila brain. AB - Drosophila is increasingly used for understanding the neural basis of behavior through genetically targeted manipulation of specific neurons. The primary approach in this regard has relied on the suppression of neuronal activity. Here, we report the results of a novel approach to find and characterize neural circuits by expressing neuronal activators to stimulate subsets of neurons to induce behavior. Classical electrophysiological studies demonstrated that stimulation of command neurons could activate neural circuits to trigger fixed action patterns. Our method was designed to find such command neurons for diverse behaviors by screening flies in which random subsets of brain cells were activated. We took advantage of the large collection of Gal4 lines from the NP project and crossed 835 Gal4 strains with relatively limited Gal4 expression in the brain to flies carrying a UAS transgene encoding TRPM8, a cold-sensitive ion channel. Low temperatures opened the TRPM8 channel in Gal4-expressing cells, leading to their excitation, and in many cases induced overt behavioral changes in adult flies. Paralysis was reproducibly observed in the progeny of crosses with 84 lines, whereas more specific behaviors were induced with 24 other lines. Stimulation performed using the heat-activated channel, TrpA1, resulted in clearer and more robust behaviors, including flight, feeding, and egg-laying. Through follow-up studies starting from this screen, we expect to find key components of the neural circuits underlying specific behaviors, thus providing a new avenue for their functional analysis. PMID- 23934999 TI - Mono and dual cofactor dependence of human cystathionine beta-synthase enzyme variants in vivo and in vitro. AB - Any two individuals differ from each other by an average of 3 million single nucleotide polymorphisms. Some polymorphisms have a functional impact on cofactor using enzymes and therefore represent points of possible therapeutic intervention through elevated-cofactor remediation. Because most known disease-causing mutations affect protein stability, we evaluated how the in vivo impact caused by single amino acid substitutions in a prototypical enzyme of this type compared with physical characteristics of the variant enzymes in vitro. We focused on cystathionine beta-synthase (CBS) because of its clinical relevance in homocysteine metabolism and because some variants of the enzyme are clinically responsive to increased levels of its B6 cofactor. Single amino-acid substitutions throughout the CBS protein caused reduced function in vivo, and a subset of these altered sensitivity to limiting B6-cofactor. Some of these B6 sensitive substitutions also had altered sensitivity to limiting heme, another CBS cofactor. Limiting heme resulted in reduced incorporation of heme into these variants, and subsequently increased protease sensitivity of the enzyme in vitro. We hypothesize that these alleles caused a modest, yet significant, destabilization of the native state of the protein, and that the functional impact of the amino acid substitutions caused by these alleles can be influenced by cofactor(s) even when the affected amino acid is distant from the cofactor binding site. PMID- 23935001 TI - Estimating the excess of inappropriate prescriptions of anti-dopaminergic anti emetics during acute gastroenteritis epidemics in France. AB - PURPOSE: Anti-dopaminergic anti-emetics (ADA) use for the treatment of nausea associated with gastroenteritis (GE) can be considered inappropriate, as their effects are not supported by evidence of clinical efficacy and can potentially induce serious adverse events. OBJECTIVE: This study quantifies the suboptimal consumption of ADA attributable to seasonal GE epidemics in France and its cost. METHODS: GE epidemiological data were collected and transmitted by the general practitioners (GPs) of Sentinelles network. Epidemic periods were identified by periodic regression. Drug sales data were obtained from pharmacies, and costs data were obtained from the French National Social Security. The ADA use and costs incurred by seasonal GE epidemics were calculated. RESULTS: During the epidemic periods considered in this study, the median age of patients seen by GPs for GE was 24 years old. During each epidemic, a sale increase by 14% for domperidone, by 15% for metoclopramide and 30% for metopimazine was observed. The average cost attributable to seasonal GE epidemic was 5,030,000 Euros, of which 2,160,000 Euros were incurred by the French National Social Security. CONCLUSION: Linking epidemiological databases helped to identify and quantify inappropriate ADA prescriptions. GE treatment guidelines should be disseminated more widely. PMID- 23935000 TI - Cytoplasmic male sterility contributes to hybrid incompatibility between subspecies of Arabidopsis lyrata. AB - In crosses between evolutionarily diverged populations, genomic incompatibilities may result in sterile hybrids, indicating evolution of reproductive isolation. In several plant families, crosses within a population can also lead to male sterile progeny because of conflict between the maternally and biparentally inherited genomes. We examined hybrid fertility between subspecies of the perennial outcrossing self-incompatible Lyrate rockcress (Arabidopsis lyrata) in large reciprocal F2 progenies and three generations of backcrosses. In one of the reciprocal F2 progenies, almost one-fourth of the plants were male-sterile. Correspondingly, almost one-half of the plants in one of the four reciprocal backcross progenies expressed male sterility. In an additional four independent F2 and backcross families, three segregated male sterility. The observed asymmetrical hybrid incompatibility is attributable to male sterility factors in one cytoplasm, for which the other population lacks effective fertility restorers. Genotyping of 96 molecular markers and quantitative trait locus mapping revealed that only 60% of the plants having the male sterile cytoplasm and lacking the corresponding restorers were phenotypically male-sterile. Genotyping data showed that there is only one restorer locus, which mapped to a 600-kb interval at the top of chromosome 2 in a region containing a cluster of pentatricopeptide repeat genes. Male fertility showed no trade-off with seed production. We discuss the role of cytoplasm and genomic conflict in incipient speciation and conclude that cytoplasmic male sterility-lowering hybrid fitness is a transient effect with limited potential to form permanent reproductive barriers between diverged populations of hermaphrodite self-incompatible species. PMID- 23935002 TI - Predicting apple (cv. Elshof) postharvest dry matter and soluble solids content with near infrared spectroscopy. AB - BACKGROUND: Fruit dry matter (DM) and soluble solids content (SSC) are primarily composed of carbohydrate and are standard parameters for assessing quality. Near infrared spectroscopy provides potential for non-destructive fruit quality analysis but the collinearity between DM and SSC is an issue for prediction. Shorter wavelength spectra have been used for the prediction of fruit DM and SSC, but radiation between 1000 and 2500 nm may be suitable for distinguishing between the two forms of carbohydrate. RESULTS: Spectra and DM and SSC samples were taken for a total of 450 'Elshof' apples 30, 58 and 93 days after harvest. Regression models were built using the interval partial least squares method. Prediction models for DM and SSC for each day yielded R2 values between 0.63 and 0.86 and residual predictive deviations (RPDs) between 1.7 and 2.7 for DM, and R2 = 0.76 0.85 and RPDs = 2.2-2.6 for SSC. CONCLUSION: Model RPD values were not high enough for general quantitative predictions, although they compare well to previous work. Certain factors affected model success, including changes in fruit physiology over time and the range of reference data. The complexity of absorbance spectra for DM and SSC plus their strong correlation suggests that prediction models cannot easily distinguish between soluble and non-soluble forms of carbohydrate. PMID- 23935003 TI - Automatic detection of adverse events to predict drug label changes using text and data mining techniques. AB - PURPOSE: The aim of this study was to assess the impact of automatically detected adverse event signals from text and open-source data on the prediction of drug label changes. METHODS: Open-source adverse effect data were collected from FAERS, Yellow Cards and SIDER databases. A shallow linguistic relation extraction system (JSRE) was applied for extraction of adverse effects from MEDLINE case reports. Statistical approach was applied on the extracted datasets for signal detection and subsequent prediction of label changes issued for 29 drugs by the UK Regulatory Authority in 2009. RESULTS: 76% of drug label changes were automatically predicted. Out of these, 6% of drug label changes were detected only by text mining. JSRE enabled precise identification of four adverse drug events from MEDLINE that were undetectable otherwise. CONCLUSIONS: Changes in drug labels can be predicted automatically using data and text mining techniques. Text mining technology is mature and well-placed to support the pharmacovigilance tasks. PMID- 23935005 TI - Is greater temperature change within a day associated with increased emergency hospital admissions for heart failure? AB - BACKGROUND: Although the seasonal variation and the effect of cold temperature on heart failure (HF) morbidity have been well documented, it is unknown whether the temperature variation within a day, that is, diurnal temperature range (DTR), is an independent risk factor for HF. We hypothesized that large DTR might be a source of additional environmental stress and, therefore, a risk factor for HF exacerbation. We aimed to test the association between DTR and HF hospitalization and to examine the effect modifiers, such as age, sex, and season. METHODS AND RESULTS: We collected daily meteorologic data and emergency HF hospital admissions from 2000 to 2007 in Hong Kong. We used Poisson regression models to fit the relationship between daily DTR and emergency HF hospitalizations, after adjusting for the time trend, seasonality, mean temperature, humidity, and levels of outdoor air pollution. We confirmed the seasonal variation of HF with peak hospital admissions in winter in Hong Kong. The adverse effects of DTR on emergency HF admissions were observed on the current day and lasted for the following several days. Every 1 degrees C increase of DTR at lag0 corresponded to 0.86% (95% confidence interval, 0.31%-1.43%) increment of emergency hospital admissions for HF. DTR exhibited significantly greater effect in the cool season, and on female and elderly patients. CONCLUSIONS: Greater temperature change within a day was associated with increased emergency hospital admissions for HF. Health policymakers and hospitals may want to take into account the increased demand of specific facilities for susceptive population in winter with greater daily temperature variations. PMID- 23935006 TI - Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. AB - BACKGROUND: We investigated the protective effects of mitochondrial-targeted antioxidant and protective peptides, Szeto-Schiller (SS) 31 and SS20, on cardiac function, proteomic remodeling, and signaling pathways. METHODS AND RESULTS: We applied an improved label-free shotgun proteomics approach to evaluate the global proteomics changes in transverse aortic constriction (TAC)-induced heart failure and the associated signaling pathway changes using ingenuity pathway analysis. We found that 538 proteins significantly changed after TAC, which mapped to 53 pathways. The top pathways were in the categories of actin cytoskeleton, mitochondrial function, intermediate metabolism, glycolysis/gluconeogenesis, and citrate cycle. Concomitant treatment with SS31 ameliorated the congestive heart failure phenotypes and mitochondrial damage induced by TAC, in parallel with global attenuation of mitochondrial proteome changes, with an average of 84% protection of mitochondrial and 69% of nonmitochondrial protein changes. This included significant amelioration of all the ingenuity pathway analysis noted above. SS20 had only modest effects on heart failure and this tracked with only partial attenuation of global proteomics changes; furthermore, actin cytoskeleton pathways were significantly protected in SS20, whereas mitochondrial and metabolic pathways essentially were not. CONCLUSIONS: This study elucidates the signaling pathways significantly changed in pressure-overload-induced heart failure. The global attenuation of TAC-induced proteomic alterations by the mitochondrial-targeted peptide SS31 suggests that perturbed mitochondrial function may be an upstream signal to many of the pathway alterations in TAC and supports the potential clinical application of mitochondrial-targeted peptide drugs for the treatment heart failure. PMID- 23935007 TI - The Arabidopsis floral repressor BFT delays flowering by competing with FT for FD binding under high salinity. AB - Soil salinity is one of the most serious agricultural problems that significantly reduce crop yields in the arid and semi-arid regions. It influences various phases of plant growth and developmental processes, such as seed germination, leaf and stem growth, and reproductive propagation. Salt stress delays the onset of flowering in many plant species. We have previously reported that the Arabidopsis BROTHER OF FT AND TFL1 (BFT) acts as a floral repressor under salt stress. However, the molecular mechanisms underlying the BFT function in the salt regulation of flowering induction is unknown. In this work, we found that BFT delays flowering under high salinity by competing with FLOWERING LOCUS T (FT) for binding to the FD transcription factor. The flowering time of FD-deficient fd-2 mutant was insensitive to high salinity. BFT interacts with FD in the nucleus via the C-terminal domain of FD, which is also required for the interaction of FD with FT, and interferes with the FT-FD interaction. These observations indicate that BFT constitutes a distinct salt stress signaling pathway that modulates the function of the FT-FD module and possibly provides an adaptation strategy that fine-tunes photoperiodic flowering under high salinity. PMID- 23935008 TI - STOP2 activates transcription of several genes for Al- and low pH-tolerance that are regulated by STOP1 in Arabidopsis. AB - The zinc-finger protein STOP1 (sensitive to proton rhizotoxicity 1) regulates transcription of multiple genes critical for tolerance to aluminum (Al) and low pH in Arabidopsis. We evaluated the contributions of genes that are suppressed in the stop1 mutant to Al- and low pH-tolerance using T-DNA-inserted disruptants, and transgenic stop1 mutants expressing each of the suppressed genes. STOP2, a STOP1 homolog, partially recovered Al- and low pH-tolerance by recovering the expression of genes regulated by STOP1. Growth and root tip viability under proton stress were partially rescued in the STOP2-complemented line. STOP2 localized in the nucleus and regulated transcription of two genes (PGIP1 and PGIP2) associated with cell wall stabilization at low pH. GUS assays revealed that STOP1 and STOP2 showed similar cellular expression in the root. However, the expression level of STOP2 was much lower than that of STOP1. In a STOP1 promoter::STOP2-complemented line, Al tolerance was slightly recovered, concomitant with the recovery of expression of ALS3 (aluminum sensitive 3) and AtMATE (Arabidopsis thaliana multidrug and toxic compound extrusion), while the expression of AtALMT1 (aluminum-activated malate transporter 1) was not recovered. These analyses indicated that STOP2 is a physiologically minor isoform of STOP1, but it can activate expression of some genes regulated by STOP1. PMID- 23935009 TI - Molecular mechanisms of ethylene-auxin interaction. PMID- 23935004 TI - Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia. AB - OBJECTIVE: Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. DESIGN: We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92*10(-4) was used to determine statistical significance of the associations. RESULTS: Two correlated SNPs- rs10090154 and rs4242382--in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74*10(-5)), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. CONCLUSIONS: This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24. PMID- 23935010 TI - Signaling at the root surface: the role of cutin monomers in mycorrhization. PMID- 23935011 TI - Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma controlled, phase IIIb study. AB - BACKGROUND: Patients experiencing major bleeding while taking vitamin K antagonists require rapid vitamin K antagonist reversal. We performed a prospective clinical trial to compare nonactivated 4-factor prothrombin complex concentrate (4F-PCC) with plasma for urgent vitamin K antagonist reversal. METHODS AND RESULTS: In this phase IIIb, multicenter, open-label, noninferiority trial, nonsurgical patients were randomized to 4F-PCC (containing coagulation factors II, VII, IX, and X and proteins C and S) or plasma. Primary analyses examined whether 4F-PCC was noninferior to plasma for the coprimary end points of 24-hour hemostatic efficacy from start of infusion and international normalized ratio correction (<=1.3) at 0.5 hour after end of infusion. The intention-to treat efficacy population comprised 202 patients (4F-PCC, n=98; plasma, n=104). Median (range) baseline international normalized ratio was 3.90 (1.8-20.0) for the 4F-PCC group and 3.60 (1.9-38.9) for the plasma group. Effective hemostasis was achieved in 72.4% of patients receiving 4F-PCC versus 65.4% receiving plasma, demonstrating noninferiority (difference, 7.1% [95% confidence interval, -5.8 to 19.9]). Rapid international normalized ratio reduction was achieved in 62.2% of patients receiving 4F-PCC versus 9.6% receiving plasma, demonstrating 4F-PCC superiority (difference, 52.6% [95% confidence interval, 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start (P<0.02). The safety profile (adverse events, serious adverse events, thromboembolic events, and deaths) was similar between groups; 66 of 103 (4F-PCC group) and 71 of 109 (plasma group) patients experienced >=1 adverse event. CONCLUSIONS: 4F-PCC is an effective alternative to plasma for urgent reversal of vitamin K antagonist therapy in major bleeding events, as demonstrated by clinical assessments of bleeding and laboratory measurements of international normalized ratio and factor levels. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00708435. PMID- 23935012 TI - Four-factor prothrombin complex concentrate for urgent reversal of vitamin K antagonists in patients with major bleeding. PMID- 23935013 TI - Long-term effects of secondary prevention on cognitive function in stroke patients. AB - BACKGROUND: Limited long-term follow-up data exist on the impact of appropriate secondary prevention therapies on cognitive function in patients after first-ever stroke. The aim of this study is to determine the effect of secondary prevention of vascular events on cognitive function after stroke. METHODS AND RESULTS: Data were collected between 1995 and 2011 (n=4413) from the community-based South London Stroke Register covering an inner-city multiethnic source population of 271 817 inhabitants. Modified Poisson regression models were constructed to adjust for cognitive function status at 3 months, demographic and socioeconomic characteristics, case mix, stroke subtype, vascular risk factors, disability, and stroke recurrence. In patients with ischemic strokes without a history of atrial fibrillation (AF), there was a reduced risk of cognitive impairment associated with the use of different prevention treatments: (1) antihypertensives (relative risk, 0.7 [95% confidence interval, 0.57-0.82] for diuretics; relative risk, 0.8 [95% confidence interval, 0.64-0.98] for angiotensin-converting enzyme inhibitors; and relative risk, 0.7 [95% confidence interval, 0.55-0.81] for their combination), (2) a combination of aspirin and dipyridamole (relative risk, 0.8 [95% confidence interval, 0.68-1.01]), and (3) statin (relative risk, 0.9 [95% confidence interval, 0.76-1.06]) when clinically indicated. Protective effects against cognitive impairment were also observed in patients on the combination of antihypertensives, antithrombotic agents, and lipid-lowering drugs (relative risk, 0.55 [95% confidence interval, 0.40-0.77]). No significant associations were noted between poststroke cognitive impairment and antihypertensives among hemorrhagic stroke patients. CONCLUSIONS: Appropriate vascular risk management was associated with a long-term reduced risk of cognitive impairment. Focus on optimal preventive drug therapy of vascular risk factors and management should be supported. PMID- 23935014 TI - I've had a good life, what's left is a bonus: factor analysis of the Mental Adjustment to Cancer Scale in a palliative care population. AB - BACKGROUND: The Mental Adjustment to Cancer Scale is an assessment tool commonly used to measure coping in cancer patients, which characterises adaptive coping under the label of 'fighting spirit'. AIM: This study explores adaptation in patients with advanced cancer, by examining the factor structure of the Mental Adjustment to Cancer Scale. Further aims were to examine associations between types of coping and psychological outcomes measured at the same time (time 1) and 4 weeks after referral to palliative care services (time 2). DESIGN: A cross sectional study with a follow-up assessment 4 weeks later. Factor analysis examined the structure of the Mental Adjustment to Cancer Scale at time 1. SETTING/PARTICIPANTS: A total of 275 patients with advanced cancer receiving palliative care, of whom 193 took part at follow-up. RESULTS: This study provided evidence for the internal consistency and validity of a new scale of 'acceptance and positivity' for use in advanced cancer patients. Patients with a desire for hastened death had lower acceptance and positivity, and patients with higher global quality of life reported a higher level. Social support was positively associated with acceptance and positivity. Higher scores on the acceptance and positivity scale were associated with reduced odds of a desire for hastened death at time 2. CONCLUSION: Adaptation to advanced cancer differs from adaptation to early stage cancer, comprising a general acceptance of the illness and trying to make the most of the time that is left. Individuals with low social support were less likely to evidence appropriate adaptation to their illness. PMID- 23935015 TI - Research on psychological and social factors in palliative care: an invited commentary. AB - BACKGROUND: Psychosocial factors are a major determinant of well-being in patients with advanced disease. However, the development of valid and reliable measures of meaningful and relevant outcomes and randomized controlled trials to assess the impact of novel interventions are relatively recent accomplishments. AIM: To discuss significant developments in psychosocial research, including work of the author, in palliative populations and to identify areas where uncertainty and controversy persist. DESIGN: The impact of systematic research on psychosocial factors in palliative care over the past four decades is discussed. Particular attention is paid to the development of relevant measures of psychological outcomes and to the results of pilot studies and randomized controlled trials of psychosocial interventions. RESULTS: A variety of factors, including methodological limitations, protective attitudes of health-care providers, and the progressive deterioration of patients with terminal disease, have presented obstacles to psychosocial research in palliative care. The more recent development of valid and reliable measures of psychological distress and psychological well-being has significantly advanced research in the field. Pilot studies and randomized controlled trials of psychosocial interventions have yielded promising results, although the demonstrated impact on primary outcomes in these studies has typically been modest. CONCLUSION: Psychosocial research in palliative care has grown in rigor and volume over the past several decades, and a variety of novel interventions have been developed and evaluated. However, the findings from this research have only begun to have an impact on clinical practice in palliative care. PMID- 23935016 TI - A Markov multistate analysis of the relationship between performance status and death among an ambulatory population of cancer patients. AB - BACKGROUND: The relationship between performance status and death among cancer patients has been of increasing interest over the past years. However, few studies have implemented statistical models that adequately capture the longitudinal nature of performance status assessments collected under intermittent observation. AIM: The main research aims were to examine the association between performance status and death and to determine the probability of deterioration in performance status over time. DESIGN: This was a population based longitudinal study among adult outpatients diagnosed with cancer. Throughout their observation period, all patients were repeatedly assessed for performance status using an 11-point scale with a score of 100 being the best, 10 being the worst and 0 representing death. A Markov multistate model accounting for intermittent observation was implemented in which each score represented a distinct state in the model. RESULTS: The cohort consisted of 27,739 patients with over 157,000 assessments. The rate of transition to death increases with a quadratic trend as performance status declines. The 1-month and 3-month probability of deterioration also increases with a quadratic trend as performance status declines. The relative rate of transition to death decreases as we compare lower scores (relative rate = 2.20 for comparing scores 90 vs 100 and relative rate = 1.23 for comparing scores 10 vs 20). CONCLUSION: There is a significant relationship between performance status and rate of transition to death. The Markov multistate model provides a comprehensive understanding of the shape of this relationship, which facilitates the interpretation of performance status and provides strength in its use as a prognostic tool in a clinical setting. PMID- 23935017 TI - Observations of professional-patient relationships: a mixed-methods study exploring whether familiarity is a condition for nurses' provision of psychosocial support. AB - BACKGROUND: There is a popular belief that the professional-patient relationship is a prerequisite in the provision of psychosocial support. Studies suggest that professionals must know, or be familiar with, a patient in order to effectively provide psychosocial support. AIM: To examine the association between familiarity and the provision of psychosocial care by professionals. DESIGN: A mixed-methods study involving participant observation, interviews and organisational and documentary analysis was conducted over 8 months in an inpatient hospice setting. PARTICIPANTS: In total, 38 nurses (registered and auxiliary) and 47 patients were included in a maximum variation sampling strategy. Data were analysed using both qualitative and quantitative techniques. RESULTS: The data disconfirm the belief that familiarity is either a necessary or sufficient condition for the provision of psychosocial support. Nurses familiar with patients did not necessarily respond to patients' psychosocial needs, and nurses with no prior contact with the patient immediately dealt with psychosocial needs. CONCLUSION: Psychosocial support can be provided on a patient's first contact with a clinician and does not rely on building a professional-patient relationship. This suggests that high quality psychosocial care can be provided in the short time frame available to palliative care clinicians. PMID- 23935018 TI - Identification of a novel erythroid-specific enhancer for the ALAS2 gene and its loss-of-function mutation which is associated with congenital sideroblastic anemia. AB - Erythroid-specific 5-aminolevulinate synthase (ALAS2) is the rate-limiting enzyme for heme biosynthesis in erythroid cells, and a missense mutation of the ALAS2 gene is associated with congenital sideroblastic anemia. However, the gene responsible for this form of anemia remains unclear in about 40% of patients. Here, we identify a novel erythroid-specific enhancer of 130 base pairs in the first intron of the ALAS2 gene. The newly identified enhancer contains a cis acting element that is bound by the erythroid-specific transcription factor GATA1, as confirmed by chromatin immunoprecipitation analysis in vivo and by electrophoretic mobility shift assay in vitro. A promoter activity assay in K562 human erythroleukemia cells revealed that the presence of this 130-base pair region increased the promoter activity of the ALAS2 gene by 10-15-fold. Importantly, two mutations, each of which disrupts the GATA-binding site in the enhancer, were identified in unrelated male patients with congenital sideroblastic anemia, and the lower expression level of ALAS2 mRNA in bone marrow erythroblasts was confirmed in one of these patients. Moreover, GATA1 failed to bind to each mutant sequence at the GATA-binding site, and each mutation abolished the enhancer function on ALAS2 promoter activity in K562 cells. Thus, a mutation at the GATA-binding site in this enhancer may cause congenital sideroblastic anemia. These results suggest that the newly identified intronic enhancer is essential for the expression of the ALAS2 gene in erythroid cells. We propose that the 130-base pair enhancer region located in the first intron of the ALAS2 gene should be examined in patients with congenital sideroblastic anemia in whom the gene responsible is unknown. PMID- 23935019 TI - Characteristic phenotypes associated with congenital dyserythropoietic anemia (type II) manifest at different stages of erythropoiesis. AB - Congenital dyserythropoietic anemia type II is an autosomally recessive form of hereditary anemia caused by SEC23B gene mutations. Patients exhibit characteristic phenotypes including multinucleate erythroblasts, erythrocytes with hypoglycosylated membrane proteins and an apparent double plasma membrane. Despite ubiquitous expression of SEC23B, the effects of mutations in this gene are confined to the erythroid lineage and the basis of this erythroid specificity remains to be defined. In addition, little is known regarding the stage at which the disparate phenotypes of this disease manifest during erythropoiesis. We employ an in vitro culture system to monitor the appearance of the defining phenotypes associated with congenital dyserythropoietic anemia type II during terminal differentiation of erythroblasts derived from small volumes of patient peripheral blood. Membrane protein hypoglycosylation was detected by the basophilic stage, preceding the onset of multinuclearity in orthochromatic erythroblasts that occurs coincident with the loss of secretory pathway proteins including SEC23A during erythropoiesis. Endoplasmic reticulum remnants were observed in nascent reticulocytes of both diseased and healthy donor cultures but were lost upon further maturation of normal reticulocytes, implicating a defect of ER clearance during reticulocyte maturation in congenital dyserythropoietic anemia type II. We also demonstrate distinct isoform and species-specific expression profiles of SEC23 during terminal erythroid differentiation and identify a prolonged expression of SEC23A in murine erythropoiesis compared to humans. We propose that SEC23A is able to compensate for the absence of SEC23B in mouse erythroblasts, providing a basis for the absence of phenotype within the erythroid lineage of a recently described SEC23B knockout mouse. PMID- 23935020 TI - Myeloma plasma cells alter the bone marrow microenvironment by stimulating the proliferation of mesenchymal stromal cells. AB - Multiple myeloma is an incurable hematologic cancer characterized by the clonal proliferation of malignant plasma cells within the bone marrow. Numerous studies suggest that the myeloma plasma cells occupy and alter the stromal tissue of the bone marrow as a means of enhancing their survival and growth. However, the nature and magnitude of the changes to the stromal cell tissue remain to be determined. In this study, we used mesenchymal stromal cell and osteoblast related cell surface marker expression (STRO-1 and alkaline phosphatase, respectively) and flow cytometry to enumerate mesenchymal stromal cell and osteoblast numbers in bone marrow recovered from myeloma patients at the time of diagnosis. Using this approach, we identified an increase in the number of STRO-1 positive colony forming mesenchymal stromal cells and a concomitant decrease in alkaline phophatase osteoblasts. Notably, this increase in mesenchymal stromal cell numbers correlated closely with plasma cell burden at the time of diagnosis. In addition, in comparison with the osteoblast population, the STRO-1+ mesenchymal stromal cell population was found to express higher levels of plasma cell- and osteoclast-activating factors, including RANKL and IL-6, providing a mechanism by which an increase in mesenchymal stromal cells may promote and aid the progression of myeloma. Importantly, these findings were faithfully replicated in the C57BL/KaLwRij murine model of myeloma, suggesting that this model may present a unique and clinically relevant system in which to identify and therapeutically modulate the bone microenvironment and, in turn, alter the progression of myeloma disease. PMID- 23935021 TI - Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study. AB - Myeloid leukemia of Down syndrome has a better prognosis than sporadic pediatric acute myeloid leukemia. Most cases of myeloid leukemia of Down syndrome are characterized by additional cytogenetic changes besides the constitutional trisomy 21, but their potential prognostic impact is not known. We, therefore, conducted an international retrospective study of clinical characteristics, cytogenetics, treatment, and outcome of 451 children with myeloid leukemia of Down syndrome. All karyotypes were centrally reviewed before assigning patients to subgroups. The overall 7-year event-free survival for the entire cohort was 78% (+/- 2%), with the overall survival rate being 79% (+/- 2%), the cumulative incidence of relapse 12% (+/- 2%), and the cumulative incidence of toxic death 7% (+/- 1%). Outcome estimates showed large differences across the different cytogenetic subgroups. Based on the cumulative incidence of relapse, we could risk-stratify patients into two groups: cases with a normal karyotype (n=103) with a higher cumulative incidence of relapse (21%+/- 4%) than cases with an aberrant karyotype (n=255) with a cumulative incidence of relapse of 9% (+/- 2%) (P=0.004). Multivariate analyses revealed that white blood cell count >= 20 * 10(9)/L and age >3 years were independent predictors for poor event-free survival, while normal karyotype independently predicted inferior overall survival, event-free survival, and relapse-free survival. In conclusion, this study showed large differences in outcome within patients with myeloid leukemia of Down syndrome and identified novel prognostic groups that predicted clinical outcome and hence may be used for stratification in future treatment protocols. PMID- 23935022 TI - Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. AB - Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in one of 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%), including patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pre-treated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full-dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities. PMID- 23935023 TI - Monocyte count at diagnosis is a prognostic parameter in diffuse large B-cell lymphoma: results from a large multicenter study involving 1191 patients in the pre- and post-rituximab era. AB - In this study we assessed the prognostic significance of absolute monocyte count and selected the best cut-off value at diagnosis in a large cohort of patients with diffuse large B-cell lymphoma. Data were retrieved for therapy-naive patients with diffuse large B-cell lymphoma followed in Israel and Italy during 1993-2010. A final cohort of 1017 patients was analyzed with a median follow up of 48 months and a 5-year overall survival rate of 68%. The best absolute monocyte count cut-off level was 630/mm(3) and the 5-year overall survival for patients with counts below this cut-off was 71%, whereas it was 59% for those with a count >630 mm(3) (P=0.0002). Of the 1017 patients, 521 (51%) were treated with chemo-immunotherapy, and in this cohort, using multivariate analysis, elevated monocyte count retained a negative prognostic value even when adjusted for International Prognostic Index (HR1.54, P=0.009). This large study shows that a simple parameter such as absolute monocyte count (>630/mm(3)) can easily be used routinely in the evaluation of newly diagnosed diffuse large B-cell lymphoma to identify high-risk patients with a worse survival in the rituximab era. PMID- 23935025 TI - A phylogenetic overview of the antrodia clade (Basidiomycota, Polyporales). AB - Phylogenetic relationships among members of the antrodia clade were investigated with molecular data from two nuclear ribosomal DNA regions, LSU and ITS. A total of 123 species representing 26 genera producing a brown rot were included in the present study. Three DNA datasets (combined LSU-ITS dataset, LSU dataset, ITS dataset) comprising sequences of 449 isolates were evaluated with three different phylogenetic analyses (maximum likelihood, maximum parsimony, Bayesian inference). We present a phylogenetic overview of the five main groups recovered: the fibroporia, laetiporus, postia, laricifomes and core antrodia groups. Not all of the main groups received strong support in the analyses, requiring further research. We were able to identify a number of well supported clades within the main groups. PMID- 23935024 TI - Alternative donor hematopoietic stem cell transplantation for mature lymphoid malignancies after reduced-intensity conditioning regimen: similar outcomes with umbilical cord blood and unrelated donor peripheral blood. AB - We have reported encouraging results of unrelated cord blood transplantation for patients with lymphoid malignancies. Whether those outcomes are comparable to matched unrelated donor transplants remains to be defined. We studied 645 adult patients with mature lymphoid malignancies who received an allogeneic unrelated donor transplant using umbilical cord blood (n=104) or mobilized peripheral blood stem cells (n=541) after a reduced-intensity conditioning regimen. Unrelated cord blood recipients had more refractory disease. Median follow-up time was 30 months. Neutrophil engraftment (81% vs. 97%, respectively; P<0.0001) and chronic graft-versus-host disease (26% vs. 52%; P=0.0005) were less frequent after unrelated cord blood than after matched unrelated donor, whereas no differences were observed in grade II-IV acute graft-versus-host disease (29% vs. 32%), non relapse mortality (29% vs. 28%), and relapse or progression (28% vs. 35%) at 36 months. There were also no significant differences in 2-year progression-free survival (43% vs. 58%, respectively) and overall survival (36% vs. 51%) at 36 months. In a multivariate analysis, no differences were observed in the outcomes between the two stem cell sources except for a higher risk of neutrophil engraftment (hazard ratio=2.12; P<0.0001) and chronic graft-versus-host disease (hazard ratio 2.10; P=0.0002) after matched unrelated donor transplant. In conclusion, there was no difference in final outcomes after transplantation between umbilical cord blood and matched unrelated donor transplant. Umbilical cord blood is a valuable alternative for patients with lymphoid malignancies lacking an HLA-matched donor, being associated with lower risk of chronic graft versus-host disease. PMID- 23935026 TI - Spores do travel. AB - Model calculations are presented on the horizontal dispersal distance of basidiospores from their source (any typical agaric). The results are compared to old and recent experimental data obtained by sampling on sticky microscope slides placed on soil. I argue that such experimental data alone are insufficient to determine the dispersion kernel because of sampling paucity: Only a minor fraction of the released spores is sampled, and the fate of the rest is unknown. Spore dispersal is determined largely by wind, whereas deposition may be due predominantly to wash-out by rainfall. PMID- 23935027 TI - Genomewide analysis of polysaccharides degrading enzymes in 11 white- and brown rot Polyporales provides insight into mechanisms of wood decay. AB - To degrade the polysaccharides, wood-decay fungi secrete a variety of glycoside hydrolases (GHs) and carbohydrate esterases (CEs) classified into various sequence-based families of carbohydrate-active enzymes (CAZys) and their appended carbohydrate-binding modules (CBM). Oxidative enzymes, such as cellobiose dehydrogenase (CDH) and lytic polysaccharide monooxygenase (LPMO, formerly GH61), also have been implicated in cellulose degradation. To examine polysaccharide degrading potential between white- and brown-rot fungi, we performed genomewide analysis of CAZys and these oxidative enzymes in 11 Polyporales, including recently sequenced monokaryotic strains of Bjerkandera adusta, Ganoderma sp. and Phlebia brevispora. Furthermore, we conducted comparative secretome analysis of seven Polyporales grown on wood culture. As a result, it was found that genes encoding cellulases belonging to families GH6, GH7, GH9 and carbohydrate-binding module family CBM1 are lacking in genomes of brown-rot polyporales. In addition, the presence of CDH and the expansion of LPMO were observed only in white-rot genomes. Indeed, GH6, GH7, CDH and LPMO peptides were identified only in white rot polypores. Genes encoding aldose 1-epimerase (ALE), previously detected with CDH and cellulases in the culture filtrates, also were identified in white-rot genomes, suggesting a physiological connection between ALE, CDH, cellulase and possibly LPMO. For hemicellulose degradation, genes and peptides corresponding to GH74 xyloglucanase, GH10 endo-xylanase, GH79 beta-glucuronidase, CE1 acetyl xylan esterase and CE15 glucuronoyl methylesterase were significantly increased in white-rot genomes compared to brown-rot genomes. Overall, relative to brown-rot Polyporales, white-rot Polyporales maintain greater enzymatic diversity supporting lignocellulose attack. PMID- 23935028 TI - London 2012 Paralympic swimming: passive drag and the classification system. AB - BACKGROUND: The key difference between the Olympic and Paralympic Games is the use of classification systems within Paralympic sports to provide a fair competition for athletes with a range of physical disabilities. In 2009, the International Paralympic Committee mandated the development of new, evidence based classification systems. This study aims to assess objectively the swimming classification system by determining the relationship between passive drag and level of swimming-specific impairment, as defined by the current swimming class. METHODS: Data were collected on participants at the London 2012 Paralympic Games. The passive drag force of 113 swimmers (classes 3-14) was measured using an electro-mechanical towing device and load cell. Swimmers were towed on the surface of a swimming pool at 1.5 m/s while holding their most streamlined position. RESULTS: Passive drag ranged from 24.9 to 82.8 N; the normalised drag (drag/mass) ranged from 0.45 to 1.86 N/kg. Significant negative associations were found between drag and the swimming class (tau = -0.41, p < 0.01) and normalised drag and the swimming class (tau = -0.60, p < 0.01). The mean difference in drag between adjacent classes was inconsistent, ranging from 0 N (6 vs 7) to 11.9 N (5 vs 6). Reciprocal Ponderal Index (a measure of slenderness) correlated moderately with normalised drag (r(P) = -0.40, p < 0.01). CONCLUSIONS: Although swimmers with the lowest swimming class experienced the highest passive drag and vice versa, the inconsistent difference in mean passive drag between adjacent classes indicates that the current classification system does not always differentiate clearly between swimming groups. PMID- 23935031 TI - Phylogenetic and phylogenomic overview of the Polyporales. AB - We present a phylogenetic and phylogenomic overview of the Polyporales. The newly sequenced genomes of Bjerkandera adusta, Ganoderma sp., and Phlebia brevispora are introduced and an overview of 10 currently available Polyporales genomes is provided. The new genomes are 39 500 000-49 900 00 bp and encode for 12 910-16 170 genes. We searched available genomes for single-copy genes and performed phylogenetic informativeness analyses to evaluate their potential for phylogenetic systematics of the Polyporales. Phylogenomic datasets (25, 71, 356 genes) were assembled for the 10 Polyporales species with genome data and compared with the most comprehensive dataset of Polyporales to date (six-gene dataset for 373 taxa, including taxa with missing data). Maximum likelihood and Bayesian phylogenetic analyses of genomic datasets yielded identical topologies, and the corresponding clades also were recovered in the 373-taxa dataset although with different support values in some datasets. Three previously recognized lineages of Polyporales, antrodia, core polyporoid and phlebioid clades, are supported in most datasets, while the status of the residual polyporoid clade remains uncertain and certain taxa (e.g. Gelatoporia, Grifola, Tyromyces) apparently do not belong to any of the major lineages of Polyporales. The most promising candidate single-copy genes are presented, and nodes in the Polyporales phylogeny critical for the suprageneric taxonomy of the order are identified and discussed. PMID- 23935032 TI - Health wash in Helsinki. PMID- 23935033 TI - Plasma protein denaturation with graded heat exposure. AB - During cardiopulmonary bypass (CPB), perfusion at tepid temperatures (33-35 degrees C) is recommended to avoid high temperature cerebral hyperthermia during and after the operation. However, the ideal temperature for uncomplicated adult cardiac surgery is an unsettled question. Typically, the heat exchanger maximum temperature is monitored between 40-42 degrees C to prevent denaturation of plasma proteins, but studies have not been performed to make these conclusions. Therefore, our hypothesis was to determine the temperature in which blood plasma protein degradation occurs after 2 hours of heat exposure. As a result, blood plasma proteins were exposed to heat in the 37-50 degrees C range for 2 hours. Plasma protein samples were loaded onto an 8-12% gradient gel for SDS-PAGE and low molecular weight plasma protein degradation was detected with graded heat exposure. Protein degradation was first detected between 43-45 degrees C of heat exposure. This study supports the practice of monitoring the heat exchanger between 40-42 degrees C to prevent denaturation of plasma proteins. PMID- 23935034 TI - Aortic arch replacement with a beating heart: a simple method using continuous 3 way perfusion. AB - We describe a simplified 3-way perfusion strategy that could be used in complex aortic procedures, which ensures continuous end-organ perfusion and minimizes the potential risks of cardiac, cerebral and peripheral ischaemic complications. PMID- 23935035 TI - Commentary on: Plasma protein denaturation with heat exposure. PMID- 23935037 TI - In vivo imaging of prostate cancer using [68Ga]-labeled bombesin analog BAY86 7548. AB - PURPOSE: A novel [(68)Ga]-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide (BAY86-7548) having high affinity to bombesin receptor subtype II to detect primary and metastatic prostate carcinoma using positron emission tomography/computed tomography (PET/CT) was synthesized and evaluated for prostate cancer. EXPERIMENTAL DESIGN: In this first human study with BAY86-7548, 14 men scheduled for radical prostatectomy (n = 11) or with biochemical recurrence after surgery or hormonal therapy (n = 3) were enrolled. The patients received an intravenous injection of BAY86-7548 followed by over 60 minute dynamic imaging of prostate gland (n = 10) and/or subsequent whole-body imaging (n = 14). The visual assessment of PET/CT images included evaluation of intraprostatic (12 subsextants) and pelvic nodal uptake of BAY86-7548 in 11 surgical patients and detection of potential metastatic foci in all patients. In patients with biochemical recurrence, results were compared with those of either [(11)C]-acetate (n = 2) or [(18)F]-fluoromethylcholine (n = 1) PET/CT. RESULTS: We found a sensitivity, specificity, and accuracy of 88%, 81% and 83%, respectively, for detection of primary PCa and sensitivity of 70% for metastatic lymph nodes using histology as gold standard. BAY86-7548 correctly detected local recurrence in prostate bed and showed nodal relapse in accordance with [(11)C] acetate PET/CT in 2 patients with biochemical relapse. In the third hormone refractory patient, BAY86-7548 failed to show multiple bone metastases evident on [(18)F]-fluoromethylcholine PET/CT. CONCLUSION: BAY86-7548 PET/CT is a promising molecular imaging technique for detecting intraprostatic prostate cancer. PMID- 23935036 TI - Predicting response to bevacizumab in ovarian cancer: a panel of potential biomarkers informing treatment selection. AB - PURPOSE: The aim of this study was to identify and validate novel predictive and/or prognostic serum proteomic biomarkers in patients with epithelial ovarian cancer (EOC) treated as part of the phase III international ICON7 clinical trial. EXPERIMENTAL DESIGN: ICON7 was a phase III international trial in EOC which showed a modest but statistically significant benefit in progression-free survival (PFS) with the addition of bevacizumab to standard chemotherapy. Serum samples from 10 patients who received bevacizumab (five responders and five nonresponders) were analyzed by mass spectrometry to identify candidate biomarkers. Initial validation and exploration by immunoassay was undertaken in an independent cohort of 92 patients, followed by a second independent cohort of 115 patients (taken from across both arms of the trial). RESULTS: Three candidate biomarkers were identified: mesothelin, fms-like tyrosine kinase-4 (FLT4), and alpha1-acid glycoprotein (AGP). Each showed evidence of independent prognostic potential when adjusting for high-risk status in initial (P < 0.02) and combined (P < 0.01) validation cohorts. In cohort I, individual biomarkers were not predictive of bevacizumab benefit; however, when combined with CA-125, a signature was developed that was predictive of bevacizumab response and discriminated benefit attributable to bevacizumab better than clinical characteristics. The signature showed weaker evidence of predictive ability in validation cohort II, but was still strongly predictive considering all samples (P = 0.001), with an improvement in median PFS of 5.5 months in signature positive patients in the experimental arm compared with standard arm. CONCLUSIONS: This study shows a discriminatory signature comprising mesothelin, FLT4, AGP, and CA-125 as potentially identifying those patients with EOC more likely to benefit from bevacizumab. These results require validation in further patient cohorts. PMID- 23935038 TI - Ponatinib--a step forward in overcoming resistance in chronic myeloid leukemia. AB - With the current therapy, the improvement in survival of patient with early chronic phase chronic myelogenous leukemia (CML) is unrivaled by that of any other leukemia. In fact, extrapolation of the survival curves may suggest that life expectancy of patients who achieve and maintain predetermined milestones may not differ from that of the age-matched healthy adults. The main reasons for such success are the presence of a well-defined molecular target, the BCR-ABL oncogene, necessary and sufficient for the initiation and propagation of CML, and the powerful and selective agents that inhibit it. Five U.S. Food and Drug Administration (FDA)-approved tyrosine kinase inhibitors (TKI), each with unique activities and toxicity profiles, allow for individualized patient care. Despite the remarkable responses of most patients, a small but significant fraction of patients develops clinical resistance to the TKIs, some of which is attributed to the BCR-ABL kinase domain mutations affecting TKI binding and activity. The recently approved third-generation TKI ponatinib showed remarkable activity in the patients with multi-TKI-resistant disease. Particularly impressive was its efficacy in patients with T315I mutation that is resistant to all other TKIs. In lieu of the current emphasis on achieving earlier and more profound responses and excellent activity of ponatinib in the refractory setting, its optimal position among the available armamentarium of agents is being established. PMID- 23935039 TI - Socio-economic differences in healthcare access from a welfare system perspective, Italy: 2007-2010. AB - Inequalities between poorer and wealthier people in accessing healthcare services have been widely studied, but the mechanisms generating them are still to be fully understood. Among these, there is still a lack of evidence of relationships between health prevention/health promotion policies, welfare systems and social differences. We analysed 68 201 females from the PASSI Italian surveillance system for the years 2007-2010. The prevalence of women undergoing Pap testing was used as an example of access to preventive services. An odds ratio gradient was found with regard to different welfare system clusters: the probability of undergoing a screening test is higher for more advanced welfare systems. A strong association was found between having received a letter from the local health unit and having undergone the screening test. Significant differences still exist between high- and low-income women and their access to Italian preventive public services. As we expected, social determinants play an important role in health disparities, as these are also strongly influenced by typologies of welfare systems and by health policies. PMID- 23935040 TI - Functionally essential interaction between Yersinia YscO and the T3S4 domain of YscP. AB - The type III secretion (T3S) system is essential to the virulence of a large number of Gram-negative bacterial pathogens, including Yersinia. YscO is required for T3S in Yersinia and is known to interact with several other T3S proteins, including the chaperone SycD and the needle length regulator YscP. To define which interactions of YscO are required for T3S, we pursued model-guided mutagenesis: three conserved and surface-exposed regions of modeled YscO were targeted for multiple alanine substitutions. Most of the mutations abrogated T3S and did so in a recessive manner, consistent with a loss of function. Both functional and nonfunctional YscO mutant proteins interacted with SycD, indicating that the mutations had not affected protein stability. Likewise, both functional and nonfunctional versions of YscO were exclusively intrabacterial. Functional and nonfunctional versions of YscO were, however, distinguishable with respect to interaction with YscP. This interaction was observed only for wild type YscO and a T3S-proficient mutant of YscO but not for the several T3S deficient mutants of YscO. Evidence is presented that the YscO-YscP interaction is direct and that the type III secretion substrate specificity switch (T3S4) domain of YscP is sufficient for this interaction. These results provide evidence that the interaction of YscO with YscP, and in particular the T3S4 domain of YscP, is essential to type III secretion. PMID- 23935041 TI - Evidence for benzylsuccinate synthase subtypes obtained by using stable isotope tools. AB - We studied the benzylsuccinate synthase (Bss) reaction mechanism with respect to the hydrogen-carbon bond cleavage at the methyl group of toluene by using different stable isotope tools. Lambda values (slopes of linear regression curves for carbon and hydrogen discrimination) for two-dimensional compound-specific stable isotope analysis (2D-CSIA) of toluene activation by Bss-containing cell extracts (in vitro studies) were found to be similar to previously reported data from analogous experiments with whole cells (in vivo studies), proving that Lambda values generated by whole cells are caused by Bss catalysis. The Bss enzymes of facultative anaerobic bacteria produced smaller Lambda values than those of obligate anaerobes. In addition, a partial exchange of a single deuterium atom in benzylsuccinate with hydrogen was observed in experiments with deuterium-labeled toluene. In this study, the Bss enzymes of the tested facultative anaerobes showed 3- to 8-fold higher exchange probabilities than those for the enzymes of the tested obligate anaerobic bacteria. The phylogeny of the Bss variants, determined by sequence analyses of BssA, the gene product corresponding to the alpha subunit of Bss, correlated with the observed differences in Lambda values and hydrogen exchange probabilities. In conclusion, our results suggest subtle differences in the reaction mechanisms of Bss isoenzymes of facultative and obligate anaerobes and show that the putative isoenzymes can be differentiated by 2D-CSIA. PMID- 23935042 TI - Structure-function analysis of MurJ reveals a solvent-exposed cavity containing residues essential for peptidoglycan biogenesis in Escherichia coli. AB - Gram-negative bacteria such as Escherichia coli build a peptidoglycan (PG) cell wall in their periplasm using the precursor known as lipid II. Lipid II is a large amphipathic molecule composed of undecaprenyl diphosphate and a disaccharide-pentapeptide that PG-synthesizing enzymes use to build the PG sacculus. During PG biosynthesis, lipid II is synthesized at the cytoplasmic face of the inner membrane and then flipped across the membrane. This translocation of lipid II must be assisted by flippases thought to shield the disaccharide pentapeptide as it crosses the hydrophobic core of the membrane. The inner membrane protein MurJ is essential for PG biogenesis and homologous to known and putative flippases of the MOP (multidrug/oligo-saccharidyl-lipid/polysaccharide) exporter superfamily, which includes flippases that translocate undecaprenyl diphosphate-linked oligosaccharides across the cytoplasmic membranes of bacteria. Consequently, MurJ has been proposed to function as the lipid II flippase in E. coli. Here, we present a three-dimensional structural model of MurJ generated by the I-TASSER server that suggests that MurJ contains a solvent-exposed cavity within the plane of the membrane. Using in vivo topological studies, we demonstrate that MurJ has 14 transmembrane domains and validate features of the MurJ structural model, including the presence of a solvent-exposed cavity within its transmembrane region. Furthermore, we present functional studies demonstrating that specific charged residues localized in the central cavity are essential for function. Together, our studies support the structural homology of MurJ to MOP exporter proteins, suggesting that MurJ might function as an essential transporter in PG biosynthesis. PMID- 23935043 TI - Staphylococcus aureus mutants lacking the LytR-CpsA-Psr family of enzymes release cell wall teichoic acids into the extracellular medium. AB - The LytR-CpsA-Psr (LCP) proteins are thought to transfer bactoprenol-linked biosynthetic intermediates of wall teichoic acid (WTA) to the peptidoglycan of Gram-positive bacteria. In Bacillus subtilis, mutants lacking all three LCP enzymes do not deposit WTA in the envelope, while Staphylococcus aureus Deltalcp mutants display impaired growth and reduced levels of envelope phosphate. We show here that the S. aureus Deltalcp mutant synthesized WTA yet released ribitol phosphate polymers into the extracellular medium. Further, Deltalcp mutant staphylococci no longer restricted the deposition of LysM-type murein hydrolases to cell division sites, which was associated with defects in cell shape and increased autolysis. Mutations in S. aureus WTA synthesis genes (tagB, tarF, or tarJ2) inhibit growth, which is attributed to the depletion of bactoprenol, an essential component of peptidoglycan synthesis (lipid II). The growth defect of S. aureus tagB and tarFJ mutants was alleviated by inhibition of WTA synthesis with tunicamycin, whereas the growth defect of the Deltalcp mutant was not relieved by tunicamycin treatment or by mutation of tagO, whose product catalyzes the first committed step of WTA synthesis. Further, sortase A-mediated anchoring of proteins to peptidoglycan, which also involves bactoprenol and lipid II, was not impaired in the Deltalcp mutant. We propose a model whereby the S. aureus Deltalcp mutant, defective in tethering WTA to the cell wall, cleaves WTA synthesis intermediates, releasing ribitol phosphate into the medium and recycling bactoprenol for peptidoglycan synthesis. PMID- 23935044 TI - Control of the Escherichia coli sialoregulon by transcriptional repressor NanR. AB - NanR, one of >8,500 GntR superfamily helix-turn-helix transcriptional regulators, controls expression of the genes required for catabolism of sialic acids in Escherichia coli. It is predicted to do the same in related bacteria harboring orthologs of nanR. The sialic acids are a family of over 40 naturally occurring nine-carbon keto-sugar acids found mainly in the animal lineage, which includes starfish to humans in the deuterostome lineage. Sialic acids function in development, immunity, protein localization and stability, and homeostasis. They also serve as microbial carbon and nitrogen sources and ligands for cell recognition during host colonization. The importance of microbial sialic acid metabolism for host-microbe interactions has made it a target for therapeutic development. Exploiting this target depends on understanding sialometabolic pathways in a wide range of evolutionarily distinct bacteria. Here, we show by transcriptome, genetic, and biochemical analyses that the most common sialic acid, N-acetylneuraminate, induces the nanATEK-yhcH, yjhATS (nanCMS), and yjhBC operons by directly inactivating NanR, converting the predominantly dimeric form of the repressor to an inactive monomer of approximately 30-kDa. Additionally, other results identify critical amino acid residues and nucleotides in the regulator and operator, respectively. The combined results better define how sialic acids, acting through NanR, affect the metabolic flux of an important group of host-derived metabolites. Thus, E. coli serves as a valuable model for understanding sialocatabolic pathways in bacteria. PMID- 23935045 TI - Nitrite reductase NirBD is induced and plays an important role during in vitro dormancy of Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis is one of the strongest reducers of nitrate among all mycobacteria. Reduction of nitrate to nitrite, mediated by nitrate reductase (NarGHJI) of M. tuberculosis, is induced during the dormant stage, and the enzyme has a respiratory function in the absence of oxygen. Nitrite reductase (NirBD) is also functional during aerobic growth when nitrite is the sole nitrogen source. However, the role of NirBD-mediated nitrite reduction during the dormancy is not yet characterized. Here, we analyzed nitrite reduction during aerobic growth as well as in a hypoxic dormancy model of M. tuberculosis in vitro. When nitrite was used as the sole nitrogen source in the medium, the organism grew and the reduction of nitrite was evident in both hypoxic and aerobic cultures of M. tuberculosis. Remarkably, the hypoxic culture of M. tuberculosis, compared to the aerobic culture, showed 32- and 4-fold-increased expression of nitrite reductase (NirBD) at the transcription and protein levels, respectively. More importantly, a nirBD mutant of M. tuberculosis was unable to reduce nitrite and compared to the wild-type (WT) strain had a >2-log reduction in viability after 240 h in the Wayne model of hypoxic dormancy. Dependence of M. tuberculosis on nitrite reductase (NirBD) was also seen in a human macrophage-based dormancy model where the nirBD mutant was impaired for survival compared to the WT strain. Overall, the increased expression and essentiality of nitrite reductase in the in vitro dormancy models suggested that NirBD-mediated nitrite reduction could be critical during the persistent stage of M. tuberculosis. PMID- 23935046 TI - Characterization of IntA, a bidirectional site-specific recombinase required for conjugative transfer of the symbiotic plasmid of Rhizobium etli CFN42. AB - Site-specific recombination occurs at short specific sequences, mediated by the cognate recombinases. IntA is a recombinase from Rhizobium etli CFN42 and belongs to the tyrosine recombinase family. It allows cointegration of plasmid p42a and the symbiotic plasmid via site-specific recombination between attachment regions (attA and attD) located in each replicon. Cointegration is needed for conjugative transfer of the symbiotic plasmid. To characterize this system, two plasmids harboring the corresponding attachment sites and intA were constructed. Introduction of these plasmids into R. etli revealed IntA-dependent recombination events occurring at high frequency. Interestingly, IntA promotes not only integration, but also excision events, albeit at a lower frequency. Thus, R. etli IntA appears to be a bidirectional recombinase. IntA was purified and used to set up electrophoretic mobility shift assays with linear fragments containing attA and attD. IntA-dependent retarded complexes were observed only with fragments containing either attA or attD. Specific retarded complexes, as well as normal in vivo recombination abilities, were seen even in derivatives harboring only a minimal attachment region (comprising the 5-bp central region flanked by 9- to 11 bp inverted repeats). DNase I-footprinting assays with IntA revealed specific protection of these zones. Mutations that disrupt the integrity of the 9- to 11 bp inverted repeats abolish both specific binding and recombination ability, while mutations in the 5-bp central region severely reduce both binding and recombination. These results show that IntA is a bidirectional recombinase that binds to att regions without requiring neighboring sequences as enhancers of recombination. PMID- 23935047 TI - ppGpp metabolism is involved in heterocyst development in the cyanobacterium Anabaena sp. strain PCC 7120. AB - When deprived of a combined-nitrogen source in the growth medium, the filamentous cyanobacterium Anabaena sp. PCC 7120 (Anabaena) can form heterocysts capable of nitrogen fixation. The process of heterocyst differentiation takes about 20 to 24 h, during which extensive metabolic and morphological changes take place. Guanosine tetraphosphate (ppGpp) is the signal of the stringent response that ensures cell survival by adjusting major cellular activities in response to nutrient starvation in bacteria, and ppGpp accumulates at the early stage of heterocyst differentiation (J. Akinyanju, R. J. Smith, FEBS Lett. 107:173-176, 1979; J Akinyanju, R. J. Smith, New Phytol. 105:117-122, 1987). Here we show that all1549 (here designated relana) in Anabaena, homologous to relA/spoT, is upregulated in response to nitrogen deprivation and predominantly localized in vegetative cells. The disruption of relana strongly affects the synthesis of ppGpp, and the resulting mutant, all1549Omegasp/sm, fails to form heterocysts and to grow in the absence of a combined-nitrogen source. This phenotype can be complemented by a wild-type copy of relana. Although the upregulation of hetR is affected in the mutant, ectopic overexpression of hetR cannot rescue the phenotype. However, we found that the mutant rapidly loses its viability, within a time window of 3 to 6 h, following the deprivation of combined nitrogen. We propose that ppGpp plays a major role in rebalancing the metabolic activities of the cells in the absence of the nitrogen source supply and that this regulation is necessary for filament survival and consequently for the success of heterocyst differentiation. PMID- 23935048 TI - Diverse functions for six glycosyltransferases in Caulobacter crescentus cell wall assembly. AB - The essential process of peptidoglycan synthesis requires two enzymatic activities, transpeptidation and transglycosylation. While the PBP2 and PBP3 transpeptidases perform highly specialized functions that are widely conserved, the specific roles of different glycosyltransferases are poorly understood. For example, Caulobacter crescentus encodes six glycosyltransferase paralogs of largely unknown function. Using genetic analyses, we found that Caulobacter glycosyltransferases are primarily redundant but that PbpX is responsible for most of the essential glycosyltransferase activity. Cells containing PbpX as their sole glycosyltransferase are viable, and the loss of pbpX leads to a general defect in the integrity of the cell wall structure even in the presence of the other five glycosyltransferases. However, neither PbpX nor any of its paralogs is required for the specific processes of cell elongation or division, while the cell wall synthesis required for stalk biogenesis is only partially disrupted in several of the glycosyltransferase mutants. Despite their genetic redundancy, Caulobacter glycosyltransferases exhibit different subcellular localizations. We suggest that these enzymes have specialized roles and normally function in distinct subcomplexes but retain the ability to substitute for one another so as to ensure the robustness of the peptidoglycan synthesis process. PMID- 23935049 TI - The putative enoyl-coenzyme A hydratase DspI is required for production of the Pseudomonas aeruginosa biofilm dispersion autoinducer cis-2-decenoic acid. AB - In the present study, we report the identification of a putative enoyl-coenzyme A (CoA) hydratase/isomerase that is required for synthesis of the biofilm dispersion autoinducer cis-2-decenoic acid in the human pathogen Pseudomonas aeruginosa. The protein is encoded by PA14_54640 (PA0745), named dspI for dispersion inducer. The gene sequence for this protein shows significant homology to RpfF in Xanthomonas campestris. Inactivation of dspI was shown to abolish biofilm dispersion autoinduction in continuous cultures of P. aeruginosa and resulted in biofilms that were significantly greater in thickness and biomass than those of the parental wild-type strain. Dispersion was shown to be inducible in dspI mutants by the exogenous addition of synthetic cis-2-decenoic acid or by complementation of DeltadspI in trans under the control of an arabinose-inducible promoter. Mutation of dspI was also shown to abolish cis-2-decenoic acid production, as revealed by gas chromatography-mass spectrometry (GC-MS) analysis of cell-free spent culture medium. The transcript abundance of dspI correlated with cell density, as determined by quantitative reverse transcriptase (RT) PCR. This regulation is consistent with the characterization of cis-2-decenoic acid as a cell-to-cell communication molecule that regulates biofilm dispersion in a cell density-dependent manner. PMID- 23935050 TI - Interaction of Streptococcus mutans YidC1 and YidC2 with translating and nontranslating ribosomes. AB - The YidC/OxaI/Alb3 family of membrane proteins is involved in the biogenesis of integral membrane proteins in bacteria, mitochondria, and chloroplasts. Gram positive bacteria often contain multiple YidC paralogs that can be subdivided into two major classes, namely, YidC1 and YidC2. The Streptococcus mutans YidC1 and YidC2 proteins possess C-terminal tails that differ in charges (+9 and + 14) and lengths (33 and 61 amino acids). The longer YidC2 C terminus bears a resemblance to the C-terminal ribosome-binding domain of the mitochondrial OxaI protein and, in contrast to the shorter YidC1 C terminus, can mediate the interaction with mitochondrial ribosomes. These observations have led to the suggestion that YidC1 and YidC2 differ in their abilities to interact with ribosomes. However, the interaction with bacterial translating ribosomes has never been addressed. Here we demonstrate that Escherichia coli ribosomes are able to interact with both YidC1 and YidC2. The interaction is stimulated by the presence of a nascent membrane protein substrate and abolished upon deletion of the C-terminal tail, which also abrogates the YidC-dependent membrane insertion of subunit c of the F1F0-ATPase into the membrane. It is concluded that both YidC1 and YidC2 interact with ribosomes, suggesting that the modes of membrane insertion by these membrane insertases are similar. PMID- 23935051 TI - Identification and characterization of RibN, a novel family of riboflavin transporters from Rhizobium leguminosarum and other proteobacteria. AB - Rhizobia are symbiotic bacteria able to invade and colonize the roots of legume plants, inducing the formation of nodules, where bacteria reduce atmospheric nitrogen (N2) to ammonia (NH3). Riboflavin availability influences the capacity of rhizobia to survive in the rhizosphere and to colonize roots. In this study, we identified the RL1692 gene of Rhizobium leguminosarum downstream of a flavin mononucleotide (FMN) riboswitch. RL1692 encodes a putative transmembrane permease with two EamA domains. The presence of an FMN riboswitch regulating a transmembrane protein is usually observed in riboflavin transporters, suggesting that RL1692 may be involved in riboflavin uptake. The product of RL1692, which we named RibN, is conserved in members of the alpha-, beta-, and gammaproteobacteria and shares no significant identity with any riboflavin transporter previously identified. In this work, we show that RibN is localized in the membrane cellular fraction and its expression is downregulated by riboflavin. By heterologous expression in a Brucella abortus mutant auxotrophic for riboflavin, we demonstrate that RibN possesses flavin transport activity. Similarly, we also demonstrate that RibN orthologues from Ochrobactrum anthropi and Vibrio cholerae (which lacks the FMN riboswitch) are able to transport riboflavin. An R. leguminosarum ribN null mutant exhibited lower nodule occupancy levels in pea plants during symbiosis assays. Thus, we propose that RibN and its homologues belong to a novel family of riboflavin transporters. This work provides the first experimental description of riboflavin transporters in Gram-negative bacteria. PMID- 23935052 TI - Deciphering the interplay between two independent functions of the small RNA regulator SgrS in Salmonella. AB - Bacterial dual-function small RNAs regulate gene expression by RNA-RNA base pairing and also code for small proteins. SgrS is a dual-function small RNA in Escherichia coli and Salmonella that is expressed under stress conditions associated with accumulation of sugar-phosphates, and its activity is crucial for growth during stress. The base-pairing function of SgrS regulates a number of mRNA targets, resulting in reduced uptake and enhanced efflux of sugars. SgrS also encodes the SgrT protein, which reduces sugar uptake by a mechanism that is independent of base pairing. While SgrS base-pairing activity has been characterized in detail, little is known about how base pairing and translation of sgrT are coordinated. In the current study, we utilized a series of mutants to determine how translation of sgrT affected the efficiency of base pairing dependent regulation and vice versa. Mutations that abrogated sgrT translation had minimal effects on base-pairing activity. Conversely, mutations that impaired base-pairing interactions resulted in increased SgrT production. Furthermore, while ectopic overexpression of sgrS mutant alleles lacking only one of the two functions rescued cell growth under stress conditions, the SgrS base-pairing function alone was indispensable for growth rescue when alleles were expressed from the native locus. Collectively, the results suggest that during stress, repression of sugar transporter synthesis via base pairing with sugar transporter mRNAs is the first priority of SgrS. Subsequently, SgrT is made and acts on preexisting transporters. The combined action of these two functions produces an effective stress response. PMID- 23935053 TI - Mapping of the SecA signal peptide binding site and dimeric interface by using the substituted cysteine accessibility method. AB - SecA is an ATPase nanomotor critical for bacterial secretory protein translocation. Secretory proteins carry an amino-terminal signal peptide that is recognized and bound by SecA followed by its transfer across the SecYEG translocon. While this process is crucial for the onset of translocation, exactly where the signal peptide interacts with SecA is unclear. SecA protomers also interact among themselves to form dimers in solution, yet the oligomeric interface and the residues involved in dimerization are unknown. To address these issues, we utilized the substituted cysteine accessibility method (SCAM); we generated a library of 23 monocysteine SecA mutants and probed for the accessibility of each mutant cysteine to maleimide-(polyethylene glycol)2-biotin (MPB), a sulfhydryl-labeling reagent, both in the presence and absence of a signal peptide. Dramatic differences in MPB labeling were observed, with a select few mutants located at the preprotein cross-linking domain (PPXD), the helical wing domain (HWD), and the helical scaffold domain (HSD), indicating that the signal peptide binds at the groove formed between these three domains. The exposure of this binding site is varied under different conditions and could therefore provide an ideal mechanism for preprotein transfer into the translocon. We also identified residues G793, A795, K797, and D798 located at the two-helix finger of the HSD to be involved in dimerization. Adenosine-5'-(gamma-thio) triphosphate (ATPgammaS) alone and, more extensively, in conjunction with lipids and signal peptides strongly favored dimer dissociation, while ADP supports dimerization. This study provides key insight into the structure-function relationships of SecA preprotein binding and dimer dissociation. PMID- 23935054 TI - The MerR-like regulator BrlR impairs Pseudomonas aeruginosa biofilm tolerance to colistin by repressing PhoPQ. AB - While the MerR-like transcriptional regulator BrlR has been demonstrated to contribute to Pseudomonas aeruginosa biofilm tolerance to antimicrobial agents known as multidrug efflux pump substrates, the role of BrlR in resistance to cationic antimicrobial peptides (CAP), which is based on reduced outer membrane susceptibility, is not known. Here, we demonstrate that inactivation of brlR coincided with increased resistance of P. aeruginosa to colistin, while overexpression of brlR resulted in increased susceptibility. brlR expression correlated with reduced transcript abundances of phoP, phoQ, pmrA, pmrB, and arnC. Inactivation of pmrA and pmrB had no effect on the susceptibility of P. aeruginosa biofilms to colistin, while inactivation of phoP and phoQ rendered biofilms more susceptible than the wild type. The susceptibility phenotype of DeltaphoP biofilms to colistin was comparable to that of P. aeruginosa biofilms overexpressing brlR. BrlR was found to directly bind to oprH promoter DNA of the oprH-phoPQ operon. BrlR reciprocally contributed to colistin and tobramycin resistance in P. aeruginosa PAO1 and CF clinical isolates, with overexpression of brlR resulting in increased tobramycin MICs and increased tobramycin resistance but decreased colistin MICs and increased colistin susceptibility. The opposite trend was observed upon brlR inactivation. The difference in susceptibility to colistin and tobramycin was eliminated by combination treatment of biofilms with both antibiotics. Our findings establish BrlR as an unusual member of the MerR family, as it not only functions as a multidrug transport activator, but also acts as a repressor of phoPQ expression, thus suppressing colistin resistance. PMID- 23935055 TI - A novel protein protects bacterial iron-dependent metabolism from nitric oxide. AB - Reactive nitrogen species (RNS), in particular nitric oxide (NO), are toxic to bacteria, and bacteria have mechanisms to allow growth despite this stress. Understanding how bacteria interact with NO is essential to understanding bacterial physiology in many habitats, including pathogenesis; however, many targets of NO and enzymes involved in NO resistance remain uncharacterized. We performed for the first time a metabolomic screen on NO-treated and -untreated bacteria to define broadly the effects of NO on bacterial physiology, as well as to identify the function of NnrS, a previously uncharacterized enzyme involved in defense against NO. We found many known and novel targets of NO. We also found that iron-sulfur cluster enzymes were preferentially inhibited in a strain lacking NnrS due to the formation of iron-NO complexes. We then demonstrated that NnrS is particularly important for resistance to nitrosative stress under anaerobic conditions. Our data thus reveal the breadth of the toxic effects of NO on metabolism and identify the function of an important enzyme in alleviating this stress. PMID- 23935056 TI - Version 6 of the consensus yeast metabolic network refines biochemical coverage and improves model performance. AB - Updates to maintain a state-of-the art reconstruction of the yeast metabolic network are essential to reflect our understanding of yeast metabolism and functional organization, to eliminate any inaccuracies identified in earlier iterations, to improve predictive accuracy and to continue to expand into novel subsystems to extend the comprehensiveness of the model. Here, we present version 6 of the consensus yeast metabolic network (Yeast 6) as an update to the community effort to computationally reconstruct the genome-scale metabolic network of Saccharomyces cerevisiae S288c. Yeast 6 comprises 1458 metabolites participating in 1888 reactions, which are annotated with 900 yeast genes encoding the catalyzing enzymes. Compared with Yeast 5, Yeast 6 demonstrates improved sensitivity, specificity and positive and negative predictive values for predicting gene essentiality in glucose-limited aerobic conditions when analyzed with flux balance analysis. Additionally, Yeast 6 improves the accuracy of predicting the likelihood that a mutation will cause auxotrophy. The network reconstruction is available as a Systems Biology Markup Language (SBML) file enriched with Minimium Information Requested in the Annotation of Biochemical Models (MIRIAM)-compliant annotations. Small- and macromolecules in the network are referenced to authoritative databases such as Uniprot or ChEBI. Molecules and reactions are also annotated with appropriate publications that contain supporting evidence. Yeast 6 is freely available at http://yeast.sf.net/ as three separate SBML files: a model using the SBML level 3 Flux Balance Constraint package, a model compatible with the MATLAB(r) COBRA Toolbox for backward compatibility and a reconstruction containing only reactions for which there is experimental evidence (without the non-biological reactions necessary for simulating growth). Database URL: http://yeast.sf.net/ PMID- 23935057 TI - metabolicMine: an integrated genomics, genetics and proteomics data warehouse for common metabolic disease research. AB - Common metabolic and endocrine diseases such as diabetes affect millions of people worldwide and have a major health impact, frequently leading to complications and mortality. In a search for better prevention and treatment, there is ongoing research into the underlying molecular and genetic bases of these complex human diseases, as well as into the links with risk factors such as obesity. Although an increasing number of relevant genomic and proteomic data sets have become available, the quantity and diversity of the data make their efficient exploitation challenging. Here, we present metabolicMine, a data warehouse with a specific focus on the genomics, genetics and proteomics of common metabolic diseases. Developed in collaboration with leading UK metabolic disease groups, metabolicMine integrates data sets from a range of experiments and model organisms alongside tools for exploring them. The current version brings together information covering genes, proteins, orthologues, interactions, gene expression, pathways, ontologies, diseases, genome-wide association studies and single nucleotide polymorphisms. Although the emphasis is on human data, key data sets from mouse and rat are included. These are complemented by interoperation with the RatMine rat genomics database, with a corresponding mouse version under development by the Mouse Genome Informatics (MGI) group. The web interface contains a number of features including keyword search, a library of Search Forms, the QueryBuilder and list analysis tools. This provides researchers with many different ways to analyse, view and flexibly export data. Programming interfaces and automatic code generation in several languages are supported, and many of the features of the web interface are available through web services. The combination of diverse data sets integrated with analysis tools and a powerful query system makes metabolicMine a valuable research resource. The web interface makes it accessible to first-time users, whereas the Application Programming Interface (API) and web services provide convenient data access and tools for bioinformaticians. metabolicMine is freely available online at http://www.metabolicmine.org Database URL: http://www.metabolicmine.org. PMID- 23935059 TI - Financial incentives are spurring growth of electronic health records. PMID- 23935058 TI - Preventing sexual abusers of children from reoffending: systematic review of medical and psychological interventions. AB - OBJECTIVE: To evaluate the effectiveness of current medical and psychological interventions for individuals at risk of sexually abusing children, both in known abusers and those at risk of abusing. DESIGN: Systematic review of interventions designed to prevent reoffending among known abusers and prevention for individuals at risk of sexually abusing children. Randomised controlled trials and prospective observational studies were eligible. Primary outcomes were arrests, convictions, breaches of conditions, and self reported sexual abuse of children after one year or more. RESULTS: After review of 1447 abstracts, we retrieved 167 full text studies, and finally included eight studies with low to moderate risk of bias. We found weak evidence for interventions aimed at reducing reoffending in identified sexual abusers of children. For adults, evidence from five trials was insufficient regarding both benefits and risks with psychological treatment and pharmacotherapy. For adolescents, limited evidence from one trial suggested that multisystemic therapy prevented reoffence (relative risk 0.18, 95% confidence interval 0.04 to 0.73); lack of adequate research prevented conclusions about effects of other treatments. Evidence was also inadequate regarding effectiveness of treatment for children with sexual behavioural problems in the one trial identified. Finally, we found no eligible research on preventive methods for adults and adolescents who had not sexually abused children but were at higher risk of doing so (such as those with paedophilic sexual preference). CONCLUSION: There are major weaknesses in the scientific evidence, particularly regarding adult men, the main category of sexual abusers of children. Better coordinated and funded high quality studies including several countries are urgently needed. Until conclusive evidence is available, realistic clinical strategies might involve reduction of specific risk factors for sex crimes, such as sexual preoccupation, in abusers at risk of reoffending. PMID- 23935060 TI - Reinventing clinical commissioning groups. PMID- 23935061 TI - GPs should have more oversight of out of hours care, say leaders. PMID- 23935062 TI - The curious case of 600 extra deaths a week. PMID- 23935063 TI - Refugees in South Sudan to receive pneumococcal vaccine after delays over price. PMID- 23935064 TI - Regulation of microRNA expression by rifampin in human hepatocytes. AB - Rifampin causes drug interactions by altering hepatic drug metabolism. Because microRNAs (miRNAs) have been shown to regulate genes involved in drug metabolism, we determined the effect of rifampin on the expression of hepatic miRNAs. Primary human hepatocytes from seven subjects were treated with rifampin, and the expression of miRNA and cytochrome P450 (P450) mRNAs was measured by TaqMan assays and RNA-seq, respectively. Rifampin induced the expression of 10 clinically important and 13 additional P450 genes and repressed the expression of 9 other P450 genes (P < 0.05). Rifampin induced the expression of 33 miRNAs and repressed the expression of 35 miRNAs (P < 0.05). Several of these changes were highly negatively correlated with the rifampin-induced changes in the expression of their predicted target P450 mRNAs, supporting the possibility of miRNA-induced regulation of P450 mRNA expression. In addition, several other miRNA changes were positively correlated with the changes in P450 mRNA expression, suggesting similar regulatory mechanisms. Despite the interindividual variability in the rifampin effects on miRNA expression, principal components analysis clearly separated the rifampin-treated samples from the controls. In conclusion, rifampin treatment alters miRNA expression patterns in human hepatocytes, and some of the changes were correlated with the rifampin-induced changes in expression of the P450 mRNAs they are predicted to target. PMID- 23935065 TI - Characterization of monocarboxylate transporter 6: expression in human intestine and transport of the antidiabetic drug nateglinide. AB - Monocarboxylate transporter (MCT) 6, encoded by SLC16A5, is a member of the monocarboxylate transporter family. Nateglinide, an oral hypoglycemic agent, quickly reaches the maximal serum concentration after its premeal administration. Although the functional existence of uptake systems for nateglinide in the intestine has been demonstrated, these transport systems have not yet been identified at the molecular level. The aim of this study was to demonstrate the localization of MCT6 in the human small intestine and characterize the transport properties of nateglinide via MCT6. Immunohistochemical analysis of the human small intestine revealed that anti-MCT6 antiserum stained the luminal side of the epithelial cells. When expressed in Xenopus laevis oocytes, MCT6-mediated uptake of [(14)C]nateglinide was sensitive to extracellular pH and membrane potential. Furthermore, the K(t) value of nateglinide (45.9 MUM) for MCT6 was lower than those previously reported in Caco-2 cells and rat intestinal brush-border membrane vesicles. In addition, probenecid, fluorescein, valproic acid, and salicylic acid, which are inhibitors of nateglinide uptake in Caco-2 cells and rat intestine, did not inhibit the uptake of nateglinide via MCT6. These results suggest that MCT6 may play a role in the intestinal absorption of nateglinide, although other transporters are also likely involved. PMID- 23935066 TI - Epigenetic regulation of ADME-related genes: focus on drug metabolism and transport. AB - Epigenetic regulation of gene expression refers to heritable factors that are functionally relevant genomic modifications but that do not involve changes in DNA sequence. Examples of such modifications include DNA methylation, histone modifications, noncoding RNAs, and chromatin architecture. Epigenetic modifications are crucial for packaging and interpreting the genome, and they have fundamental functions in regulating gene expression and activity under the influence of physiologic and environmental factors. Recently, epigenetics has become one of the fastest-growing areas of science and has now become a central issue in biologic studies of development and disease pathogenesis. The interest in epigenetics is also true for studies of drug metabolism and transport. In this issue of Drug Metabolism and Disposition, a series of articles is presented to demonstrate the role of epigenetic factors in regulating the expression of genes involved in drug absorption, distribution, metabolism, and excretion in organ development, tissue-specific gene expression, sexual dimorphism, and in the adaptive response to xenobiotic exposure, both therapeutic and toxic. The articles also demonstrate that, in addition to genetic polymorphisms, epigenetics may also contribute to wide interindividual variations in drug metabolism and transport. Identification of functionally relevant epigenetic biomarkers in human specimens has the potential to improve prediction of drug responses based on patient's epigenetic profiles. PMID- 23935067 TI - BlackOPs: increasing confidence in variant detection through mappability filtering. AB - Identifying variants using high-throughput sequencing data is currently a challenge because true biological variants can be indistinguishable from technical artifacts. One source of technical artifact results from incorrectly aligning experimentally observed sequences to their true genomic origin ('mismapping') and inferring differences in mismapped sequences to be true variants. We developed BlackOPs, an open-source tool that simulates experimental RNA-seq and DNA whole exome sequences derived from the reference genome, aligns these sequences by custom parameters, detects variants and outputs a blacklist of positions and alleles caused by mismapping. Blacklists contain thousands of artifact variants that are indistinguishable from true variants and, for a given sample, are expected to be almost completely false positives. We show that these blacklist positions are specific to the alignment algorithm and read length used, and BlackOPs allows users to generate a blacklist specific to their experimental setup. We queried the dbSNP and COSMIC variant databases and found numerous variants indistinguishable from mapping errors. We demonstrate how filtering against blacklist positions reduces the number of potential false variants using an RNA-seq glioblastoma cell line data set. In summary, accounting for mapping caused variants tuned to experimental setups reduces false positives and, therefore, improves genome characterization by high-throughput sequencing. PMID- 23935068 TI - Contributions of the RAD51 N-terminal domain to BRCA2-RAD51 interaction. AB - RAD51 DNA strand exchange protein catalyzes the central step in homologous recombination, a cellular process fundamentally important for accurate repair of damaged chromosomes, preservation of the genetic integrity, restart of collapsed replication forks and telomere maintenance. BRCA2 protein, a product of the breast cancer susceptibility gene, is a key recombination mediator that interacts with RAD51 and facilitates RAD51 nucleoprotein filament formation on single stranded DNA generated at the sites of DNA damage. An accurate atomistic level description of this interaction, however, is limited to a partial crystal structure of the RAD51 core fused to BRC4 peptide. Here, by integrating homology modeling and molecular dynamics, we generated a structure of the full-length RAD51 in complex with BRC4 peptide. Our model predicted previously unknown hydrogen bonding patterns involving the N-terminal domain (NTD) of RAD51. These interactions guide positioning of the BRC4 peptide within a cavity between the core and the NTDs; the peptide binding separates the two domains and restricts internal dynamics of RAD51 protomers. The model's depiction of the RAD51-BRC4 complex was validated by free energy calculations and in vitro functional analysis of rationally designed mutants. All generated mutants, RAD51(E42A), RAD51(E59A), RAD51(E237A), RAD51(E59A/E237A) and RAD51(E42A/E59A/E237A) maintained basic biochemical activities of the wild-type RAD51, but displayed reduced affinities for the BRC4 peptide. Strong correlation between the calculated and experimental binding energies confirmed the predicted structure of the RAD51-BRC4 complex and highlighted the importance of RAD51 NTD in RAD51-BRCA2 interaction. PMID- 23935069 TI - DNA hybridization kinetics: zippering, internal displacement and sequence dependence. AB - Although the thermodynamics of DNA hybridization is generally well established, the kinetics of this classic transition is less well understood. Providing such understanding has new urgency because DNA nanotechnology often depends critically on binding rates. Here, we explore DNA oligomer hybridization kinetics using a coarse-grained model. Strand association proceeds through a complex set of intermediate states, with successful binding events initiated by a few metastable base-pairing interactions, followed by zippering of the remaining bonds. But despite reasonably strong interstrand interactions, initial contacts frequently dissociate because typical configurations in which they form differ from typical states of similar enthalpy in the double-stranded equilibrium ensemble. Initial contacts must be stabilized by two or three base pairs before full zippering is likely, resulting in negative effective activation enthalpies. Non-Arrhenius behavior arises because the number of base pairs required for nucleation increases with temperature. In addition, we observe two alternative pathways pseudoknot and inchworm internal displacement-through which misaligned duplexes can rearrange to form duplexes. These pathways accelerate hybridization. Our results explain why experimentally observed association rates of GC-rich oligomers are higher than rates of AT- rich equivalents, and more generally demonstrate how association rates can be modulated by sequence choice. PMID- 23935070 TI - Targeted resequencing of HIV variants by microarray thermodynamics. AB - Within a single infected individual, a virus population can have a high genomic variability. In the case of HIV, several mutations can be present even in a small genomic window of 20-30 nucleotides. For diagnostics purposes, it is often needed to resequence genomic subsets where crucial mutations are known to occur. In this article, we address this issue using DNA microarrays and inputs from hybridization thermodynamics. Hybridization signals from multiple probes are analysed, including strong signals from perfectly matching (PM) probes and a large amount of weaker cross-hybridization signals from mismatching (MM) probes. The latter are crucial in the data analysis. Seven coded clinical samples (HIV-1) are analyzed, and the microarray results are in full concordance with Sanger sequencing data. Moreover, the thermodynamic analysis of microarray signals resolves inherent ambiguities in Sanger data of mixed samples and provides additional clinically relevant information. These results show the reliability and added value of DNA microarrays for point-of-care diagnostic purposes. PMID- 23935071 TI - G-rich VEGF aptamer with locked and unlocked nucleic acid modifications exhibits a unique G-quadruplex fold. AB - The formation of a single G-quadruplex structure adopted by a promising 25 nt G rich vascular endothelial growth factor aptamer in a K(+) rich environment was facilitated by locked nucleic acid modifications. An unprecedented all parallel stranded monomeric G-quadruplex with three G-quartet planes exhibits several unique structural features. Five consecutive guanine residues are all involved in G-quartet formation and occupy positions in adjacent DNA strands, which are bridged with a no-residue propeller-type loop. A two-residue D-shaped loop facilitates inclusion of an isolated guanine residue into the vacant spot within the G-quartet. The remaining two G-rich tracts of three residues each adopt parallel orientation and are linked with edgewise and propeller loops. Both 5' with 3 nt and 3' with 4 nt overhangs display well-defined conformations, with latter adopting a basket handle topology. Locked residues contribute to thermal stabilization of the adopted structure and formation of structurally pre organized intermediates that facilitate folding into a single G-quadruplex. Understanding the impact of chemical modifications on folding, thermal stability and structural polymorphism of G-quadruplexes provides means for the improvement of vascular endothelial growth factor aptamers and advances our insights into driving nucleic acid structure by locking or unlocking the conformation of sugar moieties of nucleotides in general. PMID- 23935072 TI - A three-state model for the regulation of telomerase by TERRA and hnRNPA1. AB - Telomeres, the physical ends of eukaryotic chromosomes, are transcribed into telomeric repeat-containing RNA (TERRA), a large non-coding RNA, which forms an integral part of telomeric heterochromatin. In vitro, naked TERRA molecules are efficient inhibitors of human telomerase, base-pairing via their 5'-UUAGGG-3' repeats with the template sequence of telomerase RNA, in addition to contacting the telomerase reverse transcriptase protein subunit. In vivo, however, TERRA mediated inhibition of telomerase can be prevented by unknown mechanisms. Also, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) has been implicated in telomere length control. In vivo, TERRA is partially associated with hnRNPA1, and hnRNPA1 is also detected at telomeres. We demonstrate that on binding of TERRA, hnRNPA1 can alleviate the TERRA-mediated inhibition of telomerase. However, when in excess over TERRA, hnRNPA1 becomes itself an inhibitor of telomere extension, on binding of the telomeric DNA substrate. Yet, hnRNPA1 has no notable direct effects on the telomerase catalysis. Our in vitro results suggest that TERRA mediated telomerase inhibition may be prevented by hnRNPA1 in vivo. Telomere extension by telomerase may require balanced levels of TERRA and hnRNPA1 at telomeres. Thus, TERRA and hnRNPA1 can function as a bimolecular regulator to turn telomerase and the telomere on and off. PMID- 23935073 TI - A specific N-terminal extension of the 8 kDa domain is required for DNA end bridging by human PolMU and Pollambda. AB - Human DNA polymerases mu (Polu) and lambda (Pollambda) are X family members involved in the repair of double-strand breaks in DNA during non-homologous end joining. Crucial abilities of these enzymes include bridging of the two 3' single stranded overhangs and trans-polymerization using one 3' end as primer and the other as template, to minimize sequence loss. In this context, we have studied the importance of a previously uncharacterised sequence ('brooch'), located at the N-terminal boundary of the Polbeta-like polymerase core, and formed by Tyr(141), Ala(142), Cys(143), Gln(144) and Arg(145) in Polu, and by Trp(239), Val(240), Cys(241), Ala(242) and Gln(243) in Pollambda. The brooch is potentially implicated in the maintenance of a closed conformation throughout the catalytic cycle, and our studies indicate that it could be a target of Cdk phosphorylation in Polu. The brooch is irrelevant for 1 nt gap filling, but of specific importance during end joining: single mutations in the conserved residues reduced the formation of two ended synapses and strongly diminished the ability of Polu and polymerase lambda to perform non-homologous end joining reactions in vitro. PMID- 23935074 TI - In-gel probing of individual RNA conformers within a mixed population reveals a dimerization structural switch in the HIV-1 leader. AB - Definitive secondary structural mapping of RNAs in vitro can be complicated by the presence of more than one structural conformer or multimerization of some of the molecules. Until now, probing a single structure of conformationally flexible RNA molecules has typically relied on introducing stabilizing mutations or adjusting buffer conditions or RNA concentration. Here, we present an in-gel SHAPE (selective 2'OH acylation analysed by primer extension) approach, where a mixed structural population of RNA molecules is separated by non-denaturing gel electrophoresis and the conformers are individually probed within the gel matrix. Validation of the technique using a well-characterized RNA stem-loop structure, the HIV-1 trans-activation response element, showed that authentic structure was maintained and that the method was accurate and highly reproducible. To further demonstrate the utility of in-gel SHAPE, we separated and examined monomeric and dimeric species of the HIV-1 packaging signal RNA. Extensive differences in acylation sensitivity were seen between monomer and dimer. The results support a recently proposed structural switch model of RNA genomic dimerization and packaging, and demonstrate the discriminatory power of in-gel SHAPE. PMID- 23935077 TI - Natural language processing: algorithms and tools to extract computable information from EHRs and from the biomedical literature. PMID- 23935075 TI - Upstream mononucleotide A-repeats play a cis-regulatory role in mammals through the DICER1 and Ago proteins. AB - A-repeats are the simplest form of tandem repeats and are found ubiquitously throughout genomes. These mononucleotide repeats have been widely believed to be non-functional 'junk' DNA. However, studies in yeasts suggest that A-repeats play crucial biological functions, and their role in humans remains largely unknown. Here, we showed a non-random pattern of distribution of sense A- and T-repeats within 20 kb around transcription start sites (TSSs) in the human genome. Different distributions of these repeats are observed upstream and downstream of TSSs. Sense A-repeats are enriched upstream, whereas sense T-repeats are enriched downstream of TSSs. This enrichment directly correlates with repeat size. Genes with different functions contain different lengths of repeats. In humans, tissue specific genes are enriched for short repeats of <10 bp, whereas housekeeping genes are enriched for long repeats of >=10 bp. We demonstrated that DICER1 and Argonaute proteins are required for the cis-regulatory role of A-repeats. Moreover, in the presence of a synthetic polymer that mimics an A-repeat, protein binding to A-repeats was blocked, resulting in a dramatic change in the expression of genes containing upstream A-repeats. Our findings suggest a length dependent cis-regulatory function of A-repeats and that Argonaute proteins serve as trans-acting factors, binding to A-repeats. PMID- 23935078 TI - President's column: operational informatics--expanding the scope of our discipline. PMID- 23935076 TI - Systems biology of Ewing sarcoma: a network model of EWS-FLI1 effect on proliferation and apoptosis. AB - Ewing sarcoma is the second most frequent pediatric bone tumor. In most of the patients, a chromosomal translocation leads to the expression of the EWS-FLI1 chimeric transcription factor that is the major oncogene in this pathology. Relative genetic simplicity of Ewing sarcoma makes it particularly attractive for studying cancer in a systemic manner. Silencing EWS-FLI1 induces cell cycle alteration and ultimately leads to apoptosis, but the exact molecular mechanisms underlying this phenotype are unclear. In this study, a network linking EWS-FLI1 to cell cycle and apoptosis phenotypes was constructed through an original method of network reconstruction. Transcriptome time-series after EWS-FLI1 silencing were used to identify core modulated genes by an original scoring method based on fitting expression profile dynamics curves. Literature data mining was then used to connect these modulated genes into a network. The validity of a subpart of this network was assessed by siRNA/RT-QPCR experiments on four additional Ewing cell lines and confirmed most of the links. Based on the network and the transcriptome data, CUL1 was identified as a new potential target of EWS-FLI1. Altogether, using an original methodology of data integration, we provide the first version of EWS-FLI1 network model of cell cycle and apoptosis regulation. PMID- 23935079 TI - Sublingual immunotherapy improves symptoms of allergical rhinoconjunctivitis and asthma. PMID- 23935080 TI - Short sleep duration is associated with increased BMI in adolescents over time. PMID- 23935081 TI - Limited impact of omega-3 fatty acids in patients with multiple cardiovascular risk factors. PMID- 23935082 TI - Use of non-steroidal anti-inflammatory drugs (NSAIDs) as immunomodulatory agents. PMID- 23935083 TI - Time for the NHS to stop trying to build large scale IT systems? PMID- 23935084 TI - Learning lessons from a hidden success of the NHS national programme for IT. PMID- 23935085 TI - Rehabilitation after stroke. Financial implications for survivors of stroke. PMID- 23935086 TI - Mechanism based treatments for anaemia in advanced cancer. PMID- 23935087 TI - Polypill. Faulty logic justifies aspirin use for primary prevention of cardiovascular disease. PMID- 23935088 TI - Private patient options. Many NHS centres offering self funded in vitro fertilisation are poor performers. PMID- 23935089 TI - Improving the safety of patients in England. PMID- 23935090 TI - NIH and family of Henrietta Lacks reach agreement on access to HeLa genome. PMID- 23935091 TI - Camels could be the source of MERS coronavirus, research finds. PMID- 23935092 TI - Epicardial wave mapping in human long-lasting persistent atrial fibrillation: transient rotational circuits, complex wavefronts, and disorganized activity. AB - OBJECTIVES: To characterize the nature of atrial fibrillation (AF) activation in human persistent AF (PerAF) using modern tools including activation, directionality analyses, complex-fractionated electrogram, and spectral information. BACKGROUND: The mechanism of PerAF in humans is uncertain. METHODS AND RESULTS: High-density epicardial mapping (128 electrodes/6.75 cm(2)) of the posterior LA wall (PLAW), LA and RA appendage (LAA, RAA), and RSPV-LA junction was performed in 18 patients with PerAF undergoing open heart surgery. Continuous 10 s recordings were analysed offline. Activation patterns were characterized into four subtypes (i) wavefronts (broad or multiple), (ii) rotational circuits (>=2 rotations of 360 degrees ), (iii) focal sources with centrifugal activation of the entire mapping area, or (iv) disorganized activity [isolated chaotic activation(s) that propagate <=3 bipoles or activation(s) that occur as isolated beats dissociated from the activation of adjacent bipole sites]. Activation at a total of 36 regions were analysed (14 PLAW, 3 RSPV-LA, 12 LAA, and 7 RAA) creating a database of 2904 activation patterns. In the majority of maps, activation patterns were highly heterogeneous with multiple unstable activation patterns transitioning from one to another during each recording. A mean of 3.8 +/- 1.6 activation subtypes was seen per map. The most common patterns seen were multiple wavefronts (56.2 +/- 32%) and disorganized activity (24.2 +/- 30.3%). Only 2 of 36 maps (5.5%) showed a single stable activation pattern throughout the 10-s period. These were stable planar wavefronts. Three transient rotational circuits were observed. Two of the transient circuits were located in the posterior left atrium, while the third was located on the anterior surface of the LAA. Focal activations accounted for 11.3 +/- 14.2% of activations and were all short-lived (<=2 beats), with no site demonstrating sustained focal activity. CONCLUSION: Human long-lasting PerAF is characterized by heterogeneous and unstable patterns of activation including wavefronts, transient rotational circuits, and disorganized activity. PMID- 23935093 TI - A meta-analysis of cognitive-based behaviour change techniques as interventions to improve medication adherence. AB - OBJECTIVE: To describe and evaluate the use of cognitive-based behaviour change techniques as interventions to improve medication adherence. DESIGN: Systematic review and meta-analysis of interventions to improve medication adherence. DATA SOURCES: Search of the MEDLINE, EMBASE, PsycINFO, CINAHL and The Cochrane Library databases from the earliest year to April 2013 without language restriction. References of included studies were also screened to identify further relevant articles. REVIEW METHODS: We used predefined criteria to select randomised controlled trials describing a medication adherence intervention that used Motivational Interviewing (MI) or other cognitive-based techniques. Data were extracted and risk of bias was assessed by two independent reviewers. We conducted the meta-analysis using a random effects model and Hedges' g as the measure of effect size. RESULTS: We included 26 studies (5216 participants) in the meta-analysis. Interventions most commonly used MI, but many used techniques such as aiming to increase the patient's confidence and sense of self-efficacy, encouraging support-seeking behaviours and challenging negative thoughts, which were not specifically categorised. Interventions were most commonly delivered from community-based settings by routine healthcare providers such as general practitioners and nurses. An effect size (95% CI) of 0.34 (0.23 to 0.46) was calculated and was statistically significant (p < 0.001). Heterogeneity was high with an I(2) value of 68%. Adjustment for publication bias generated a more conservative estimate of summary effect size of 0.21 (0.08 to 0.33). The majority of subgroup analyses produced statistically non-significant results. CONCLUSIONS: Cognitive-based behaviour change techniques are effective interventions eliciting improvements in medication adherence that are likely to be greater than the behavioural and educational interventions largely used in current practice. Subgroup analyses suggest that these interventions are amenable to use across different populations and in differing manners without loss of efficacy. These factors may facilitate incorporation of these techniques into routine care. PMID- 23935094 TI - SLP-76 sterile alpha motif (SAM) and individual H5 alpha helix mediate oligomer formation for microclusters and T-cell activation. AB - Despite the importance of the immune adaptor SLP-76 in T-cell immunity, it has been unclear whether SLP-76 directly self-associates to form higher order oligomers for T-cell activation. In this study, we show that SLP-76 self associates in response to T-cell receptor ligation as mediated by the N-terminal sterile alpha motif (SAM) domain. SLP-76 co-precipitated alternately tagged SLP 76 in response to anti-CD3 ligation. Dynamic light scattering and fluorescent microscale thermophoresis of the isolated SAM domain (residues 1-78) revealed evidence of dimers and tetramers. Consistently, deletion of the SAM region eliminated SLP-76 co-precipitation of itself, concurrent with a loss of microcluster formation, nuclear factor of activated T-cells (NFAT) transcription, and interleukin-2 production in Jurkat or primary T-cells. Furthermore, the H5 alpha helix within the SAM domain contributed to self-association. Retention of H5 in the absence of H1-4 sufficed to support SLP-76 self-association with smaller microclusters that nevertheless enhanced anti-CD3-driven AP1/NFAT transcription and IL-2 production. By contrast, deletion of the H5 alpha helix impaired self-association and anti-CD3 induced AP1/NFAT transcription. Our data identified for the first time a role for the SAM domain in mediating SLP-76 self association for T-cell function. PMID- 23935095 TI - Autoimmunity against INS-IGF2 protein expressed in human pancreatic islets. AB - Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain, and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine the expression of INS-IGF2 in human pancreatic islets and autoantibodies in newly diagnosed children with type 1 diabetes and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared with donors with either type 2 diabetes (p = 0.006) or high HbA1c levels (p < 0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed patients with type 1 diabetes (n = 304) compared with healthy controls (n = 355; p < 0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain, and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody-binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes. PMID- 23935096 TI - Sphingosine kinase 1 regulates tumor necrosis factor-mediated RANTES induction through p38 mitogen-activated protein kinase but independently of nuclear factor kappaB activation. AB - Sphingosine kinase 1 (SK1) produces the pro-survival sphingolipid sphingosine 1 phosphate and has been implicated in inflammation, proliferation, and angiogenesis. Recent studies identified TRAF2 as a sphingosine 1-phosphate target, implicating SK1 in activation of the NF-kappaB pathway, but the functional consequences of this connection on gene expression are unknown. Here, we find that loss of SK1 potentiates induction of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted; also known as CCL5) in HeLa cells stimulated with TNF-alpha despite RANTES induction being highly dependent on the NF-kappaB pathway. Additionally, we find that SK1 is not required for TNF induced IKK phosphorylation, IkappaB degradation, nuclear translocation of NF kappaB subunits, and transcriptional NF-kappaB activity. In contrast, loss of SK1 prevented TNF-induced phosphorylation of p38 MAPK, and inhibition of p38 MAPK, like SK1 knockdown, also potentiates RANTES induction. Finally, in addition to RANTES, loss of SK1 also potentiated the induction of multiple chemokines and cytokines in the TNF response. Taken together, these data identify a potential and novel anti-inflammatory function of SK1 in which chemokine levels are suppressed through SK1-mediated activation of p38 MAPK. Furthermore, in this system, activation of NF-kappaB is dissociated from SK1, suggesting that the interaction between these pathways may be more complex than currently thought. PMID- 23935097 TI - A highly selective dual insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an extracellular signal-regulated kinase (ERK) inhibitor. AB - Dual inhibitors of the closely related receptor tyrosine kinases insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) are promising therapeutic agents in cancer. Here, we report an unusually selective class of dual inhibitors of IGF-1R and IR identified in a parallel screen of known kinase inhibitors against a panel of 300 human protein kinases. Biochemical and structural studies indicate that this class achieves its high selectivity by binding to the ATP-binding pocket of inactive, unphosphorylated IGF-1R/IR and stabilizing the activation loop in a native-like inactive conformation. One member of this compound family was originally reported as an inhibitor of the serine/threonine kinase ERK, a kinase that is distinct in the structure of its unphosphorylated/inactive form from IR/IGF-1R. Remarkably, this compound binds to the ATP-binding pocket of ERK in an entirely different conformation to that of IGF-1R/IR, explaining the potency against these two structurally distinct kinase families. These findings suggest a novel approach to polypharmacology in which two or more unrelated kinases are inhibited by a single compound that targets different conformations of each target kinase. PMID- 23935098 TI - Agonist-dependent endocytosis of gamma-aminobutyric acid type A (GABAA) receptors revealed by a gamma2(R43Q) epilepsy mutation. AB - GABA-gated chloride channels (GABAARs) trafficking is involved in the regulation of fast inhibitory transmission. Here, we took advantage of a gamma2(R43Q) subunit mutation linked to epilepsy in humans that considerably reduces the number of GABAARs on the cell surface to better understand the trafficking of GABAARs. Using recombinant expression in cultured rat hippocampal neurons and COS 7 cells, we showed that receptors containing gamma2(R43Q) were addressed to the cell membrane but underwent clathrin-mediated dynamin-dependent endocytosis. The gamma2(R43Q)-dependent endocytosis was reduced by GABAAR antagonists. These data, in addition to a new homology model, suggested that a conformational change in the extracellular domain of gamma2(R43Q)-containing GABAARs increased their internalization. This led us to show that endogenous and recombinant wild-type GABAAR endocytosis in both cultured neurons and COS-7 cells can be amplified by their agonists. These findings revealed not only a direct relationship between endocytosis of GABAARs and a genetic neurological disorder but also that trafficking of these receptors can be modulated by their agonist. PMID- 23935099 TI - Discovery of novel irreversible inhibitors of interleukin (IL)-2-inducible tyrosine kinase (Itk) by targeting cysteine 442 in the ATP pocket. AB - IL-2-inducible tyrosine kinase (Itk) plays a key role in antigen receptor signaling in T cells and is considered an important target for anti-inflammatory drug discovery. In order to generate inhibitors with the necessary potency and selectivity, a compound that targeted cysteine 442 in the ATP binding pocket and with an envisaged irreversible mode of action was designed. We incorporated a high degree of molecular recognition and specific design features making the compound suitable for inhaled delivery. This study confirms the irreversible covalent binding of the inhibitor to the kinase by x-ray crystallography and enzymology while demonstrating potency, selectivity, and prolonged duration of action in in vitro biological assays. The biosynthetic turnover of the kinase was also examined as a critical factor when designing irreversible inhibitors for extended duration of action. The exemplified Itk inhibitor demonstrated inhibition of both TH1 and TH2 cytokines, was additive with fluticasone propionate, and inhibited cytokine release from human lung fragments. Finally, we describe an in vivo pharmacodynamic assay that allows rapid preclinical development without animal efficacy models. PMID- 23935100 TI - Interleukin-4 induces senescence in human renal carcinoma cell lines through STAT6 and p38 MAPK. AB - Interleukin (IL)-4, originally identified as a lymphocyte growth factor, can directly inhibit growth of certain tumor cell types. We reported previously that IL-4 induced cell cycle arrest in G1 phase through an increase in p21(WAF1/CIP1) expression in human renal cell carcinoma (RCC) cell lines. In the present study, we investigated the underlying mechanism of IL-4-induced growth inhibition. In four of six human RCC cell lines, including Caki-1, A498, SNU482, and SNU228, IL 4 induced cellular senescence as demonstrated by enlarged and flattened morphology, increased granularity, and senescence-associated-beta-galactosidase (SA-beta-gal) staining. Signal tranducer and activator of transcription 6 (STAT6) and p38 MAPK were found to mediate IL-4-induced growth inhibition and cellular senescence. Both of these molecules were activated by 10 min after IL-4 treatment, and inhibition of their activity or expression prevented growth suppression and cellular senescence induced by IL-4. Inhibiting or silencing either STAT6 or p38 MAPK alone partially reduced the effect of IL-4, whereas inhibiting or silencing both molecules exerted an additive effect and almost completely abrogated the effect of IL-4. Thus STAT6 and p38 MAPK appeared to independently mediate IL-4-induced growth inhibition and cellular senescence. The p21(WAF1/CIP1) up-regulation that accompanied growth inhibition and cellular senescence by IL-4 was also attenuated additively when p38 MAPK and STAT6 were silenced. Taken together, these results show that IL-4 induces cellular senescence through independent signaling pathways involving STAT6 and p38 MAPK in some human RCC cell lines. PMID- 23935101 TI - Noncanonical control of vasopressin receptor type 2 signaling by retromer and arrestin. AB - The vasopressin type 2 receptor (V2R) is a critical G protein-coupled receptor (GPCR) for vertebrate physiology, including the balance of water and sodium ions. It is unclear how its two native hormones, vasopressin (VP) and oxytocin (OT), both stimulate the same cAMP/PKA pathway yet produce divergent antinatriuretic and antidiuretic effects that are either strong (VP) or weak (OT). Here, we present a new mechanism that differentiates the action of VP and OT on V2R signaling. We found that vasopressin, as opposed to OT, continued to generate cAMP and promote PKA activation for prolonged periods after ligand washout and receptor internalization in endosomes. Contrary to the classical model of arrestin-mediated GPCR desensitization, arrestins bind the VP-V2R complex yet extend rather than shorten the generation of cAMP. Signaling is instead turned off by the endosomal retromer complex. We propose that this mechanism explains how VP sustains water and Na(+) transport in renal collecting duct cells. Together with recent work on the parathyroid hormone receptor, these data support the existence of a novel "noncanonical" regulatory pathway for GPCR activation and response termination, via the sequential action of beta-arrestin and the retromer complex. PMID- 23935102 TI - A ruler protein in a complex for antiviral defense determines the length of small interfering CRISPR RNAs. AB - Small RNAs undergo maturation events that precisely determine the length and structure required for their function. CRISPRs (clustered regularly interspaced short palindromic repeats) encode small RNAs (crRNAs) that together with CRISPR associated (cas) genes constitute a sequence-specific prokaryotic immune system for anti-viral and anti-plasmid defense. crRNAs are subject to multiple processing events during their biogenesis, and little is known about the mechanism of the final maturation step. We show that in the Staphylococcus epidermidis type III CRISPR-Cas system, mature crRNAs are measured in a Cas10.Csm ribonucleoprotein complex to yield discrete lengths that differ by 6-nucleotide increments. We looked for mutants that impact this crRNA size pattern and found that an alanine substitution of a conserved aspartate residue of Csm3 eliminates the 6-nucleotide increments in the length of crRNAs. In vitro, recombinant Csm3 binds RNA molecules at multiple sites, producing gel-shift patterns that suggest that each protein binds 6 nucleotides of substrate. In vivo, changes in the levels of Csm3 modulate the crRNA size distribution without disrupting the 6 nucleotide periodicity. Our data support a model in which multiple Csm3 molecules within the Cas10.Csm complex bind the crRNA with a 6-nucleotide periodicity to function as a ruler that measures the extent of crRNA maturation. PMID- 23935103 TI - Five conditions commonly used to down-regulate tor complex 1 generate different physiological situations exhibiting distinct requirements and outcomes. AB - Five different physiological conditions have been used interchangeably to establish the sequence of molecular events needed to achieve nitrogen-responsive down-regulation of TorC1 and its subsequent regulation of downstream reporters: nitrogen starvation, methionine sulfoximine (Msx) addition, nitrogen limitation, rapamycin addition, and leucine starvation. Therefore, we tested a specific underlying assumption upon which the interpretation of data generated by these five experimental perturbations is premised. It is that they generate physiologically equivalent outcomes with respect to TorC1, i.e. its down regulation as reflected by TorC1 reporter responses. We tested this assumption by performing head-to-head comparisons of the requirements for each condition to achieve a common outcome for a downstream proxy of TorC1 inactivation, nuclear Gln3 localization. We demonstrate that the five conditions for down-regulating TorC1 do not elicit physiologically equivalent outcomes. Four of the methods exhibit hierarchical Sit4 and PP2A phosphatase requirements to elicit nuclear Gln3-Myc(13) localization. Rapamycin treatment required Sit4 and PP2A. Nitrogen limitation and short-term nitrogen starvation required only Sit4. G1 arrest correlated, long-term nitrogen starvation and Msx treatment required neither PP2A nor Sit4. Starving cells of leucine or treating them with leucyl-tRNA synthetase inhibitors did not elicit nuclear Gln3-Myc(13) localization. These data indicate that the five commonly used nitrogen-related conditions of down-regulating TorC1 are not physiologically equivalent and minimally involve partially differing regulatory mechanisms. Further, identical requirements for Msx treatment and long term nitrogen starvation raise the possibility that their effects are achieved through a common regulatory pathway with glutamine, a glutamate or glutamine metabolite level as the sensed metabolic signal. PMID- 23935104 TI - The transcription factor Twist1 limits T helper 17 and T follicular helper cell development by repressing the gene encoding the interleukin-6 receptor alpha chain. AB - Cytokine responsiveness is a critical component of the ability of cells to respond to the extracellular milieu. Transcription factor-mediated regulation of cytokine receptor expression is a common mode of altering responses to the external environment. We identify the transcription factor Twist1 as a component of a STAT3-induced feedback loop that controls IL-6 signals by directly repressing Il6ra. Human and mouse T cells lacking Twist1 have an increased ability to differentiate into Th17 cells. Mice with a T cell-specific deletion of Twist1 demonstrate increased Th17 and T follicular helper cell development, early onset experimental autoimmune encephalomyelitis, and increased antigen-specific antibody responses. Thus, Twist1 has a critical role in limiting both cell mediated and humoral immunity. PMID- 23935105 TI - Specialization among iron-sulfur cluster helicases to resolve G-quadruplex DNA structures that threaten genomic stability. AB - G-quadruplex (G4) DNA, an alternate structure formed by Hoogsteen hydrogen bonds between guanines in G-rich sequences, threatens genomic stability by perturbing normal DNA transactions including replication, repair, and transcription. A variety of G4 topologies (intra- and intermolecular) can form in vitro, but the molecular architecture and cellular factors influencing G4 landscape in vivo are not clear. Helicases that unwind structured DNA molecules are emerging as an important class of G4-resolving enzymes. The BRCA1-associated FANCJ helicase is among those helicases able to unwind G4 DNA in vitro, and FANCJ mutations are associated with breast cancer and linked to Fanconi anemia. FANCJ belongs to a conserved iron-sulfur (Fe S) cluster family of helicases important for genomic stability including XPD (nucleotide excision repair), DDX11 (sister chromatid cohesion), and RTEL (telomere metabolism), genetically linked to xeroderma pigmentosum/Cockayne syndrome, Warsaw breakage syndrome, and dyskeratosis congenita, respectively. To elucidate the role of FANCJ in genomic stability, its molecular functions in G4 metabolism were examined. FANCJ efficiently unwound in a kinetic and ATPase-dependent manner entropically favored unimolecular G4 DNA, whereas other Fe-S helicases tested did not. The G4-specific ligands Phen-DC3 or Phen-DC6 inhibited FANCJ helicase on unimolecular G4 ~1000-fold better than bi- or tetramolecular G4 DNA. The G4 ligand telomestatin induced DNA damage in human cells deficient in FANCJ but not DDX11 or XPD. These findings suggest FANCJ is a specialized Fe-S cluster helicase that preserves chromosomal stability by unwinding unimolecular G4 DNA likely to form in transiently unwound single stranded genomic regions. PMID- 23935106 TI - Active glutaminase C self-assembles into a supratetrameric oligomer that can be disrupted by an allosteric inhibitor. AB - The phosphate-dependent transition between enzymatically inert dimers into catalytically capable tetramers has long been the accepted mechanism for the glutaminase activation. Here, we demonstrate that activated glutaminase C (GAC) self-assembles into a helical, fiber-like double-stranded oligomer and propose a molecular model consisting of seven tetramer copies per turn per strand interacting via the N-terminal domains. The loop (321)LRFNKL(326) is projected as the major regulating element for self-assembly and enzyme activation. Furthermore, the previously identified in vivo lysine acetylation (Lys(311) in humans, Lys(316) in mouse) is here proposed as an important down-regulator of superoligomer assembly and protein activation. Bis-2-(5-phenylacetamido-1,3,4 thiadiazol-2-yl)ethyl sulfide, a known glutaminase inhibitor, completely disrupted the higher order oligomer, explaining its allosteric mechanism of inhibition via tetramer stabilization. A direct correlation between the tendency to self-assemble and the activity levels of the three mammalian glutaminase isozymes was established, with GAC being the most active enzyme while forming the longest structures. Lastly, the ectopic expression of a fiber-prone superactive GAC mutant in MDA-MB 231 cancer cells provided considerable proliferative advantages to transformed cells. These findings yield unique implications for the development of GAC-oriented therapeutics targeting tumor metabolism. PMID- 23935107 TI - Mechanism and regulation of mycobactin fatty acyl-AMP ligase FadD33. AB - Mycobacterial siderophores are critical components for bacterial virulence in the host. Pathogenic mycobacteria synthesize iron chelating siderophores named mycobactin and carboxymycobactin to extract intracellular macrophage iron. The two siderophores differ in structure only by a lipophilic aliphatic chain attached on the epsilon-amino group of the lysine mycobactin core, which is transferred by MbtK. Prior to acyl chain transfer, the lipophilic chain requires activation by a specific fatty acyl-AMP ligase FadD33 (also known as MbtM) and is then loaded onto phosphopantetheinylated acyl carrier protein (holo-MbtL) to form covalently acylated MbtL. We demonstrate that FadD33 prefers long chain saturated lipids and initial velocity studies showed that FadD33 proceeds via a Bi Uni Uni Bi ping-pong mechanism. Inhibition experiments suggest that, during the first half-reaction (adenylation), fatty acid binds first to the free enzyme, followed by ATP and the release of pyrophosphate to form the adenylate intermediate. During the second half-reaction (ligation), holo-MbtL binds to the enzyme followed by the release of products AMP and acylated MbtL. In addition, we characterized a post-translational regulation mechanism of FadD33 by the mycobacterial protein lysine acetyltransferase in a cAMP-dependent manner. FadD33 acetylation leads to enzyme inhibition, which can be reversed by the NAD(+) dependent deacetylase, MSMEG_5175 (DAc1). To the best of our knowledge, this is the first time that bacterial siderophore synthesis has been shown to be regulated via post-translational protein acetylation. PMID- 23935108 TI - Genetic and morphological structure of a spruce hybrid (Picea sitchensis x P. glauca) zone along a climatic gradient. AB - PREMISE OF THE STUDY: Historic colonization and contemporary evolutionary processes contribute to patterns of genetic variation and differentiation among populations. However, separating the respective influences of these processes remains a challenge, particularly for natural hybrid zones, where standing genetic variation may result from evolutionary processes both preceding and following contact, influencing the evolutionary trajectory of hybrid populations. Where adaptation to novel environments may be facilitated by interspecific hybridization, teasing apart these processes will have practical implications for forest management in changing environments. METHODS: We evaluated the neutral genetic architecture of the Picea sitchensis (Sitka spruce) * P. glauca (white spruce) hybrid zone along the Nass and Skeena river valleys in northwestern British Columbia using chloroplast, mitochondrial, and nuclear microsatellite markers, in combination with cone morphological traits. KEY RESULTS: Sitka spruce mitotype "capture", evidenced by this species dominating the maternal lineage, is consistent with earlier colonization of the region by Sitka spruce. This "capture" differs from the spatial distribution of chloroplast haplotypes, indicating pollen dispersal and its contribution to geographic structure. Genetic ancestry, based on nuclear markers, was strongly influenced by climate and geography. Highly parallel results for replicate transects along environmental gradients provide support for the bounded hybrid superiority model of hybrid zone maintenance. * CONCLUSIONS: This broad-scale analysis of neutral genetic structure indicates the importance of historic and contemporary gene flow, environmental selection, and their interaction in shaping neutral genetic variation within this hybrid zone, informative to seed transfer development and reforestation for future climates. PMID- 23935109 TI - Bacterial endophytes enhance competition by invasive plants. AB - PREMISE OF THE STUDY: Invasive plants can alter soil microbial communities and profoundly alter ecosystem processes. In the invasive grass Sorghum halepense, these disruptions are consequences of rhizome-associated bacterial endophytes. We describe the effects of N2-fixing bacterial strains from S. halepense (Rout and Chrzanowski, 2009) on plant growth and show that bacteria interact with the plant to alter soil nutrient cycles, enabling persistence of the invasive. * METHODS: We assessed fluxes in soil nutrients for ~4 yr across a site invaded by S. halepense. We assayed the N2-fixing bacteria in vitro for phosphate solubilization, iron chelation, and production of the plant-growth hormone indole 3-acetic acid (IAA). We assessed the plant's ability to recruit bacterial partners from substrates and vertically transmit endophytes to seeds and used an antibiotic approach to inhibit bacterial activity in planta and assess microbial contributions to plant growth. * KEY RESULTS: We found persistent alterations to eight biogeochemical cycles (including nitrogen, phosphorus, and iron) in soils invaded by S. halepense. In this context, three bacterial isolates solubilized phosphate, and all produced iron siderophores and IAA in vitro. In growth chamber experiments, bacteria were transmitted vertically, and molecular analysis of bacterial community fingerprints from rhizomes indicated that endophytes are also horizontally recruited. Inhibiting bacterial activity with antibiotics resulted in significant declines in plant growth rate and biomass, with pronounced rhizome reductions. * CONCLUSIONS: This work suggests a major role of endophytes on growth and resource allocation of an invasive plant. Indeed, bacterial isolate physiology is correlated with invader effects on biogeochemical cycles of nitrogen, phosphate, and iron. PMID- 23935110 TI - A total evidence approach to understanding phylogenetic relationships and ecological diversity in Selaginella subg. Tetragonostachys. AB - PREMISE OF THE STUDY: Several members of Selaginella are renowned for their ability to survive extreme drought and "resurrect" when conditions improve. Many of these belong to subgenus Tetragonostachys, a group of ~45 species primarily found in North and Central America, with substantial diversity in the Sonoran and Chihuahuan Deserts. We evaluated the monophyly and the age of subgenus Tetragonostachys and assess how drought tolerance contributed to the evolution of this clade. METHODS: Our study included most Tetragonostachys species, using plastid and nuclear sequences, fossil and herbarium records, and climate variables to describe the species diversity, phylogenetic relationships, divergence times, and climatic niche evolution in the subgenus. KEY RESULTS: We found that subgenus Tetragonostachys forms a monophyletic group sister to Selaginella lepidophylla and may have diverged from other Selaginella because of a Gondwanan-Laurasian vicariance event ca. 240 mya. The North American radiation of Tetragonostachys appears to be much more recent and to have occurred during the Early Cretaceous-late Paleocene interval. We identified two significant and nested ecological niche shifts during the evolution of Tetragonostachys associated with extreme drought tolerance and a more recent shift to cold climates. Our analyses suggest that drought tolerance evolved in the warm deserts of southwest North America and may have been advantageous for colonization of cold and dry boreal climates. CONCLUSIONS: Our investigation provides a foundation for future research addressing the genomics of ecological niche evolution and the potential role of reticulate evolution in Selaginella subgenus Tetragonostachys. PMID- 23935111 TI - Climate drives vein anatomy in Proteaceae. AB - PREMISE OF STUDY: The mechanisms by which plants tolerate water deficit are only just becoming clear. One key factor in drought tolerance is the ability to maintain the capacity to conduct water through the leaves in conditions of water stress. Recent work has shown that a simple feature of the leaf xylem cells, the cube of the thickness of cell walls divided by the lumen width (t/b)(3), is strongly correlated with this ability. METHODS: Using ecologically, phylogenetically, and anatomically diverse members of Proteaceae, we tested the relationships between (t/b)(3) and climate, leaf mass per unit area, leaf area, and vein density. To test relationships at high phylogenetic levels (mostly genus), we used phylogenetic and nonphylogenetic single and multiple regressions based on data from 50 species. We also used 14 within-genus species pairs to test for relationships at lower phylogenetic levels. KEY RESULTS: All analyses revealed that climate, especially mean annual precipitation, was the best predictor of (t/b)(3). The variation in (t/b)(3) was driven by variation in both lumen diameter and wall thickness, implying active control of these dimensions. Total vein density was weakly related to (t/b)(3) but unrelated to either leaf area or climate. CONCLUSIONS: We conclude that xylem reinforcement is a fundamental adaptation for water stress tolerance and, among evergreen woody plants, drives a strong association between rainfall and xylem anatomy. The strong association between (t/b)(3) and climate cannot be explained by autocorrelation with other aspects of leaf form and anatomy that vary along precipitation gradients. PMID- 23935112 TI - Increased seed survival and seedling emergence in a polyploid plant invader. AB - PREMISE OF THE STUDY: Because seeds have essential functions in the life cycle of plants, even subtle changes in their characteristics may have important demographic consequences. In this study, we examined whether potential changes in seed characteristics as a result of polyploidy or postintroduction evolution may have contributed to the invasion of Centaurea stoebe (Asteraceae). This plant occurs as diploid and tetraploid cytotypes in its native range in Europe, whereas only tetraploids have been found and become invasive in North America. Specific comparisons among these three "geo-cytotypes" allow us to explore hypotheses of preadaptation resulting from polyploidy (European diploids vs. European tetraploids) and postintroduction evolution (European tetraploids vs. North American tetraploids). METHODS: Using seeds collected from plants of each geo cytotype grown in a common maternal environment, we compared seed mass, morphology (achene and pappus size), dispersal potential (falling velocity, seed roughness), survival, germination, and seedling emergence in a combination of laboratory, greenhouse and field experiments. KEY RESULTS: We found increased seed mass in North American tetraploids compared with European tetraploids. Seed morphology and dispersal potential were largely similar in all geo-cytotypes. Seed survival under field conditions was higher in native and invasive tetraploids compared with diploids. Germination in the laboratory was similar among all geo-cytotypes, but seedling emergence under field conditions was higher in invasive tetraploids than in the other geo-cytotypes. CONCLUSIONS: Our findings suggest that a combination of preadaptation due to polyploidy (increased seed survival) and further postintroduction evolution in North American tetraploids (increased seed mass and seedling emergence) may have contributed to their invasion. PMID- 23935113 TI - Inside the root microbiome: bacterial root endophytes and plant growth promotion. AB - Bacterial root endophytes reside in a vast number of plant species as part of their root microbiome, with some being shown to positively influence plant growth. Endophyte community structure (species diversity: richness and relative abundances) within the plant is dynamic and is influenced by abiotic and biotic factors such as soil conditions, biogeography, plant species, microbe-microbe interactions and plant-microbe interactions, both at local and larger scales. Plant-growth-promoting bacterial endophytes (PGPBEs) have been identified, but the predictive success at positively influencing plant growth in field conditions has been limited. Concurrent to the development of modern molecular techniques, the goal of predicting an organism's ability to promote plant growth can perhaps be realized by more thorough examination of endophyte community dynamics. This paper reviews the drivers of endophyte community structure relating to plant growth promotion, the mechanisms of plant growth promotion, and the current and future use of molecular techniques to study these communities. PMID- 23935114 TI - Growth habit of the late Paleozoic rhizomorphic tree-lycopsid family Diaphorodendraceae: phylogenetic, evolutionary, and paleoecological significance. AB - PREMISE OF THE STUDY: Rhizomorphic lycopsids evolved the tree habit independently of all other land plants. Newly discovered specimens allow radical revision of our understanding of the growth architectures of the extinct Paleozoic sister genera Synchysidendron and Diaphorodendron. METHODS: Detailed descriptions of six remarkable adpression specimens from the Pennsylvanian of the USA and three casts from the late Mississippian of Scotland are used to revise and reanalyze a previously published morphological cladistic matrix and to reinterpret their remarkable growth forms. KEY RESULTS: Contrary to previous assertions, Synchysidendron resembled Diaphorodendron in having a distinct and relatively complex growth habit that emphasized serially homologous, closely spaced, deciduous lateral branches at the expense of reduced monocarpic crown branches. Lateral branches originated through several strongly anisotomous dichotomies before producing during extended periods large numbers of Achlamydocarpon strobili. The comparatively large diameter of abscission scars remaining on the main trunk and the emergence of branches above the horizontal plane suggest that the lateral branch systems were robust. Lateral branches were borne in two opposite rows on the main trunk and continued upward into an isotomously branched, determinate crown; their striking distichous arrangement caused preferred orientation of fallen trunks on bedding planes. CONCLUSIONS: This discovery identifies the plagiotropic growth habit, dominated by serial lateral branches, as ubiquitous in the Diaphorodendraceae and also as unequivocally primitive within Isoetales s.l., a conclusion supported by both the revised morphological cladistic analysis and relative first appearances of taxa in the fossil record. Previously assumed complete homology between crown branching in Lepidodendraceae and that of all earlier-divergent genera requires reassessment. Saltational phenotypic transitions via modification of key developmental switches remains the most credible explanation for architectural evolution in the group. The resulting architecture allowed Diaphorodendraceae to co-dominate disturbed, clastic, equatorial wetlands from the Asbian to the Early Permian. PMID- 23935115 TI - ss-siRNAs allele selectively inhibit ataxin-3 expression: multiple mechanisms for an alternative gene silencing strategy. AB - Single-stranded silencing RNAs (ss-siRNAs) provide an alternative approach to gene silencing. ss-siRNAs combine the simplicity and favorable biodistribution of antisense oligonucleotides with robust silencing through RNA interference (RNAi). Previous studies reported potent and allele-selective inhibition of human huntingtin expression by ss-siRNAs that target the expanded CAG repeats within the mutant allele. Mutant ataxin-3, the genetic cause of Machado-Joseph Disease, also contains an expanded CAG repeat. We demonstrate here that ss-siRNAs are allele-selective inhibitors of ataxin-3 expression and then redesign ss-siRNAs to optimize their selectivity. We find that both RNAi-related and non-RNAi-related mechanisms affect gene expression by either blocking translation or affecting alternative splicing. These results have four broad implications: (i) ss-siRNAs will not always behave similarly to analogous RNA duplexes; (ii) the sequences surrounding CAG repeats affect allele-selectivity of anti-CAG oligonucleotides; (iii) ss-siRNAs can function through multiple mechanisms and; and (iv) it is possible to use chemical modification to optimize ss-siRNA properties and improve their potential for drug discovery. PMID- 23935117 TI - Tagetitoxin inhibits transcription by stabilizing pre-translocated state of the elongation complex. AB - Transcription elongation consists of repetition of the nucleotide addition cycle: phosphodiester bond formation, translocation and binding of the next nucleotide. Inhibitor of multi-subunit RNA polymerase tagetitoxin (TGT) enigmatically slows down addition of nucleotides in a sequence-dependent manner, only at certain positions of the template. Here, we show that TGT neither affects chemistry of RNA synthesis nor induces backward translocation, nor competes with the nucleoside triphosphate (NTP) in the active center. Instead, TGT increases the stability of the pre-translocated state of elongation complex, thus slowing down addition of the following nucleotide. We show that the extent of inhibition directly depends on the intrinsic stability of the pre-translocated state. The dependence of translocation equilibrium on the transcribed sequence results in a wide distribution (~1-10(3)-fold) of inhibitory effects of TGT at different positions of the template, thus explaining sequence-specificity of TGT action. We provide biochemical evidence that, in pre-translocated state, TGT stabilizes folded conformation of the Trigger Loop, which inhibits forward and backward translocation of the complex. The results suggest that Trigger Loop folding in the pre-translocated state may serve to reduce back-tracking of the elongation complex. Overall, we propose that translocation may be a limiting and highly regulated step of RNA synthesis. PMID- 23935116 TI - Robust gene silencing mediated by antisense small RNAs in the pathogenic protist Entamoeba histolytica. AB - RNA interference uses small RNAs (sRNA), which target genes for sequence-specific silencing. The parasite Entamoeba histolytica contains an abundant repertoire of 27 nt antisense (AS) sRNA with 5'-polyphosphate termini, but their roles in regulating gene expression have not been well established. We demonstrate that a gene-coding region to which large numbers of AS sRNAs map can serve as a 'trigger' and silence the gene fused to it. Silencing is mediated by generation of AS sRNAs with 5'-polyphosphate termini that have sequence specificity to the fused gene. The mechanism of silencing is independent of the placement of the trigger relative to the silenced gene but is dependent on the sRNA concentration to the trigger. Silencing requires transcription of the trigger-gene fusion and is maintained despite loss of the trigger plasmid. We used this approach to silence multiple amebic genes, including an E. histolytica Myb gene, which is upregulated during oxidative stress response. Silencing of the EhMyb gene decreased parasite viability under oxidative stress conditions. Thus, we have developed a new tool for genetic manipulation in E. histolytica with many advantages over currently available technologies. Additionally, these data shed mechanistic insights into a eukaryotic RNA interference pathway with many novel aspects. PMID- 23935118 TI - Torsionally constrained DNA for single-molecule assays: an efficient, ligation free method. AB - Controlled twisting of individual, double-stranded DNA molecules provides a unique method to investigate the enzymes that alter DNA topology. Such twisting requires a single DNA molecule to be torsionally constrained. This constraint is achieved by anchoring the opposite ends of the DNA to two separate surfaces via multiple bonds. The traditional protocol for making such DNA involves a three-way ligation followed by gel purification, a laborious process that often leads to low yield both in the amount of DNA and the fraction of molecules that is torsionally constrained. We developed a simple ligation-free procedure for making torsionally constrained DNA via polymerase chain reaction (PCR). This PCR protocol used two 'megaprimers', 400-base-pair long double-stranded DNA that were labelled with either biotin or digoxigenin. We obtained a relatively high yield of gel-purified DNA (~500 ng/100 ul of PCR reaction). The final construct in this PCR-based method contains only one labelled strand in contrast to the traditional construct in which both strands of the DNA are labelled. Nonetheless, we achieved a high yield (84%) of torsionally constrained DNA when measured using an optical trap-based DNA-overstretching assay. This protocol significantly simplifies the application and adoption of torsionally constrained assays to a wide range of single-molecule systems. PMID- 23935121 TI - Universal digital high-resolution melt: a novel approach to broad-based profiling of heterogeneous biological samples. AB - Comprehensive profiling of nucleic acids in genetically heterogeneous samples is important for clinical and basic research applications. Universal digital high resolution melt (U-dHRM) is a new approach to broad-based PCR diagnostics and profiling technologies that can overcome issues of poor sensitivity due to contaminating nucleic acids and poor specificity due to primer or probe hybridization inaccuracies for single nucleotide variations. The U-dHRM approach uses broad-based primers or ligated adapter sequences to universally amplify all nucleic acid molecules in a heterogeneous sample, which have been partitioned, as in digital PCR. Extensive assay optimization enables direct sequence identification by algorithm-based matching of melt curve shape and Tm to a database of known sequence-specific melt curves. We show that single-molecule detection and single nucleotide sensitivity is possible. The feasibility and utility of U-dHRM is demonstrated through detection of bacteria associated with polymicrobial blood infection and microRNAs (miRNAs) associated with host response to infection. U-dHRM using broad-based 16S rRNA gene primers demonstrates universal single cell detection of bacterial pathogens, even in the presence of larger amounts of contaminating bacteria; U-dHRM using universally adapted Lethal-7 miRNAs in a heterogeneous mixture showcases the single copy sensitivity and single nucleotide specificity of this approach. PMID- 23935122 TI - Yin and Yang of disease genes and death genes between reciprocally scale-free biological networks. AB - Biological networks often show a scale-free topology with node degree following a power-law distribution. Lethal genes tend to form functional hubs, whereas non lethal disease genes are located at the periphery. Uni-dimensional analyses, however, are flawed. We created and investigated two distinct scale-free networks; a protein-protein interaction (PPI) and a perturbation sensitivity network (PSN). The hubs of both networks exhibit a low molecular evolutionary rate (P < 8 * 10(-12), P < 2 * 10(-4)) and a high codon adaptation index (P < 2 * 10(-16), P < 2 * 10(-8)), indicating that both hubs have been shaped under high evolutionary selective pressure. Moreover, the topologies of PPI and PSN are inversely proportional: hubs of PPI tend to be located at the periphery of PSN and vice versa. PPI hubs are highly enriched with lethal genes but not with disease genes, whereas PSN hubs are highly enriched with disease genes and drug targets but not with lethal genes. PPI hub genes are enriched with essential cellular processes, but PSN hub genes are enriched with environmental interaction processes, having more TATA boxes and transcription factor binding sites. It is concluded that biological systems may balance internal growth signaling and external stress signaling by unifying the two opposite scale-free networks that are seemingly opposite to each other but work in concert between death and disease. PMID- 23935120 TI - Topoisomerase II regulates yeast genes with singular chromatin architectures. AB - Eukaryotic topoisomerase II (topo II) is the essential decatenase of newly replicated chromosomes and the main relaxase of nucleosomal DNA. Apart from these general tasks, topo II participates in more specialized functions. In mammals, topo IIalpha interacts with specific RNA polymerases and chromatin-remodeling complexes, whereas topo IIbeta regulates developmental genes in conjunction with chromatin remodeling and heterochromatin transitions. Here we show that in budding yeast, topo II regulates the expression of specific gene subsets. To uncover this, we carried out a genomic transcription run-on shortly after the thermal inactivation of topo II. We identified a modest number of genes not involved in the general stress response but strictly dependent on topo II. These genes present distinctive functional and structural traits in comparison with the genome average. Yeast topo II is a positive regulator of genes with well-defined promoter architecture that associates to chromatin remodeling complexes; it is a negative regulator of genes extremely hypo-acetylated with complex promoters and undefined nucleosome positioning, many of which are involved in polyamine transport. These findings indicate that yeast topo II operates on singular chromatin architectures to activate or repress DNA transcription and that this activity produces functional responses to ensure chromatin stability. PMID- 23935119 TI - Genome-wide single-cell-level screen for protein abundance and localization changes in response to DNA damage in S. cerevisiae. AB - An effective response to DNA damaging agents involves modulating numerous facets of cellular homeostasis in addition to DNA repair and cell-cycle checkpoint pathways. Fluorescence microscopy-based imaging offers the opportunity to simultaneously interrogate changes in both protein level and subcellular localization in response to DNA damaging agents at the single-cell level. We report here results from screening the yeast Green Fluorescent Protein (GFP) fusion library to investigate global cellular protein reorganization on exposure to the alkylating agent methyl methanesulfonate (MMS). Broad groups of induced, repressed, nucleus- and cytoplasm-enriched proteins were identified. Gene Ontology and interactome analyses revealed the underlying cellular processes. Transcription factor (TF) analysis identified principal regulators of the response, and targets of all major stress-responsive TFs were enriched amongst the induced proteins. An unexpected partitioning of biological function according to the number of TFs targeting individual genes was revealed. Finally, differential modulation of ribosomal proteins depending on methyl methanesulfonate dose was shown to correlate with cell growth and with the translocation of the Sfp1 TF. We conclude that cellular responses can navigate different routes according to the extent of damage, relying on both expression and localization changes of specific proteins. PMID- 23935123 TI - Mus81 nuclease and Sgs1 helicase are essential for meiotic recombination in a protist lacking a synaptonemal complex. AB - Mus81 resolvase and Sgs1 helicase have well-established roles in mitotic DNA repair. Moreover, Mus81 is part of a minor crossover (CO) pathway in the meiosis of budding yeast, plants and vertebrates. The major pathway depends on meiosis specific synaptonemal complex (SC) formation, ZMM proteins and the MutLgamma complex for CO-directed resolution of joint molecule (JM)-recombination intermediates. Sgs1 has also been implicated in this pathway, although it may mainly promote the non-CO outcome of meiotic repair. We show in Tetrahymena, that homologous chromosomes fail to separate and JMs accumulate in the absence of Mus81 or Sgs1, whereas deletion of the MutLgamma-component Mlh1 does not affect meiotic divisions. Thus, our results are consistent with Mus81 being part of an essential, if not the predominant, CO pathway in Tetrahymena. Sgs1 may exert functions similar to those in other eukaryotes. However, we propose an additional role in supporting homologous CO formation by promoting homologous over intersister interactions. Tetrahymena shares the predominance of the Mus81 CO pathway with the fission yeast. We propose that in these two organisms, which independently lost the SC during evolution, the basal set of mitotic repair proteins is sufficient for executing meiotic recombination. PMID- 23935124 TI - Associations of age and sex with the clinical outcome and incubation period of Shiga toxin-producing Escherichia coli O104:H4 infections, 2011. AB - We pooled data on adults who reported diarrhea or developed life-threatening hemolytic uremic syndrome (HUS) in any of 6 closed cohorts from 4 countries (1 cohort each in Denmark, France, and Sweden and 3 in Germany) that were investigated during a large outbreak of Shiga toxin-producing Escherichia coli (STEC) O104:H4 infection in 2011. Logistic regression and Weibull regression for interval censored data were used to assess the relation of age and sex with clinical outcome and with incubation period. Information on the latter was used in a nonparametric back-projection context to estimate when adult cases reported in Germany were exposed to STEC O104:H4. Overall, data from 119 persons (median age, 49 years; 80 women) were analyzed. Bloody diarrhea and HUS were recorded as the most severe outcome for 44 and 26 individuals, respectively. Older age was significantly associated with bloody diarrhea but not with HUS. Woman had nonsignificantly higher odds for bloody diarrhea (odds ratio = 1.81) and developing HUS (odds ratio = 1.83) than did men. Older participants had a statistically significantly reduced incubation period. The shortest interval that included 75% of exposures in adults spanned only 12 days and preceded outbreak detection. In conclusion, the frequency of bloody diarrhea but not of HUS and the length of the incubation period depended on the age of individuals infected with STEC O104:H4. A large number of people were exposed to STEC O104:H4 for a short period of time. PMID- 23935127 TI - Determinants of serum T4 and T3 at the time of diagnosis in nosological types of thyrotoxicosis: a population-based study. AB - OBJECTIVE: To characterize thyroid hormone levels at the time of diagnosis in the nosological types of thyrotoxicosis diagnosed in the population and to analyze determinants for serum thyroxine (T4) and tri-iodothyronine (T3). DESIGN: Population-based study of thyrotoxicosis at disease onset. METHODS: In the period 1997-2000, we prospectively identified all patients diagnosed with incident primary overt thyrotoxicosis in a Danish population cohort and classified patients into ten well-defined nosological types of disease (n=1082). Untreated levels of serum T3, T4, and T3:T4 ratio were compared and related to sex, age, level of iodine deficiency, smoking status, alcohol intake, iodine supplement use, co-morbidity, and TSH receptor antibodies (TRAbs) in multivariate models. RESULTS: Graves' disease (GD) patients had much higher levels of T3 and higher T3:T4 ratio at diagnosis compared with other thyrotoxic patients, but with a profound negative association between hormone levels and age. In GD, patients diagnosed in the area with more severe iodine deficiency had lower levels of T3 and T4. TRAb-negative GD patients had biochemically mild thyrotoxicosis. Higher age was also associated with lower degree of biochemical thyrotoxicosis in nodular toxic goiter. We found no association between serum T3 and T4 and sex, smoking habits, iodine supplements, alcohol intake, or co-morbidity in any type of thyrotoxicosis. CONCLUSIONS: The study gives new insight into the hormonal presentation of thyrotoxicosis and showed that young age, positive TRAb levels, but also residency in the area with higher iodine intake was positively associated with biochemical disruption in GD. PMID- 23935126 TI - Nucleotide precursors prevent folic acid-resistant neural tube defects in the mouse. AB - Closure of the neural tube during embryogenesis is a crucial step in development of the central nervous system. Failure of this process results in neural tube defects, including spina bifida and anencephaly, which are among the most common birth defects worldwide. Maternal use of folic acid supplements reduces risk of neural tube defects but a proportion of cases are not preventable. Folic acid is thought to act through folate one-carbon metabolism, which transfers one-carbon units for methylation reactions and nucleotide biosynthesis. Hence suboptimal performance of the intervening reactions could limit the efficacy of folic acid. We hypothesized that direct supplementation with nucleotides, downstream of folate metabolism, has the potential to support neural tube closure. Therefore, in a mouse model that exhibits folic acid-resistant neural tube defects, we tested the effect of specific combinations of pyrimidine and purine nucleotide precursors and observed a significant protective effect. Labelling in whole embryo culture showed that nucleotides are taken up by the neurulating embryo and incorporated into genomic DNA. Furthermore, the mitotic index was elevated in neural folds and hindgut of treated embryos, consistent with a proposed mechanism of neural tube defect prevention through stimulation of cellular proliferation. These findings may provide an impetus for future investigations of supplemental nucleotides as a means to prevent a greater proportion of human neural tube defects than can be achieved by folic acid alone. PMID- 23935128 TI - Elevated hepatic chemerin mRNA expression in human non-alcoholic fatty liver disease. AB - OBJECTIVE: Adipose tissue-derived factors link non-alcoholic fatty liver disease (NAFLD) with obesity, which has also been reported for circulating chemerin. On the other hand, hepatic chemerin and chemokine-like receptor 1 (CMKLR1) mRNA expression has not yet been studied in an extensively characterized patient collective. DESIGN: This study was cross-sectional and experimental in design. METHODS: Liver tissue samples were harvested from 47 subjects and histologically examined according to the NAFLD activity score (NAS). The concentrations of chemerin and CMKLR1 were measured using semi-quantitative real-time PCR, and the concentration of serum chemerin was measured using ELISA. To evaluate potential effects of chemerin and CMKLR1, cultured primary human hepatocytes (PHHs) were exposed to selected metabolites known to play a role in NAFLD (insulin, glucagon, palmitoic acid, and interleukin-6 (IL6)). RESULTS: Chemerin and CMKLR1 mRNA levels were elevated in the human liver. Their expression was correlated with the NAS (R(2)=0.543; P<0.001 and R(2)=0.355; P=0.014 respectively) and was significantly elevated in patients with definite non-alcoholic steatohepatitis (NASH) (P<0.05 respectively). Linear regression analysis confirmed an independent association of liver fibrosis, steatosis, inflammation, and hepatocyte ballooning with hepatic chemerin mRNA expression (P<0.05 respectively). The expression of hepatic chemerin and CMKLR1 was correlated with the measures of obesity (P<0.05). The incubation of PHHs with IL6 significantly increased the expression of CMKLR1 mRNA (P=0.027), while that of chemerin remained unaffected (P>0.05). None of the other metabolites showed an influence (P>0.05). CONCLUSION: This is the first study to show that chemerin mRNA expression is significantly elevated in the liver of NASH patients and that CMKLR1 expression is upregulated in liver inflammation, whereby IL6 could play a causal role. PMID- 23935125 TI - Biological sex affects the neurobiology of autism. AB - In autism, heterogeneity is the rule rather than the exception. One obvious source of heterogeneity is biological sex. Since autism was first recognized, males with autism have disproportionately skewed research. Females with autism have thus been relatively overlooked, and have generally been assumed to have the same underlying neurobiology as males with autism. Growing evidence, however, suggests that this is an oversimplification that risks obscuring the biological base of autism. This study seeks to answer two questions about how autism is modulated by biological sex at the level of the brain: (i) is the neuroanatomy of autism different in males and females? and (ii) does the neuroanatomy of autism fit predictions from the 'extreme male brain' theory of autism, in males and/or in females? Neuroanatomical features derived from voxel-based morphometry were compared in a sample of equal-sized high-functioning male and female adults with and without autism (n = 120, n = 30/group). The first question was investigated using a 2 * 2 factorial design, and by spatial overlap analyses of the neuroanatomy of autism in males and females. The second question was tested through spatial overlap analyses of specific patterns predicted by the extreme male brain theory. We found that the neuroanatomy of autism differed between adult males and females, evidenced by minimal spatial overlap (not different from that occurred under random condition) in both grey and white matter, and substantially large white matter regions showing significant sex * diagnosis interactions in the 2 * 2 factorial design. These suggest that autism manifests differently by biological sex. Furthermore, atypical brain areas in females with autism substantially and non-randomly (P < 0.001) overlapped with areas that were sexually dimorphic in neurotypical controls, in both grey and white matter, suggesting neural 'masculinization'. This was not seen in males with autism. How differences in neuroanatomy relate to the similarities in cognition between males and females with autism remains to be understood. Future research should stratify by biological sex to reduce heterogeneity and to provide greater insight into the neurobiology of autism. PMID- 23935129 TI - The serum 25-hydroxyvitamin D response to vitamin D supplementation is related to genetic factors, BMI, and baseline levels. AB - OBJECTIVE: The serum 25-hydroxyvitamin D (25(OH)D) level is not only dependent on vitamin D intake and production in the skin but also dependent on genetic factors. Thus, in large genome-wide association studies, it has been shown that single nucleotide polymorphisms (SNPs) in the vitamin D binding protein (DBP), as well as in enzymes related to activation or degradation of vitamin D and its metabolites, are as important for the serum 25(OH)D level as the effect of season. How these SNPs affect the serum 25(OH)D response to vitamin D supplementation is uncertain. DESIGN AND METHODS: Data were pooled from three randomized controlled trials where 40, 000 IU vitamin D/week was given for 6 months. Serum 25(OH)D was measured before and at the end of the intervention, and the subjects were genotyped for SNPs related to the serum 25(OH)D level. RESULTS: Baseline 25(OH)D levels were significantly related to SNPs in the DBP and CYP2R1 genes. Those with SNPs associated with the lowest baseline 25(OH)D levels also had the smallest increase (delta) after supplementation. Those with the lowest baseline serum 25(OH)D (without regard to genotypes) had the highest increase (delta) after supplementation. Subjects with high BMI had lowest baseline 25(OH)D levels and also the smallest increase (delta) after supplementation. CONCLUSIONS: The serum 25(OH)D response to supplementation depends on genes, baseline level, and BMI. However, whether this is clinically important or not depends on the therapeutic window of vitamin D, an issue that is still not settled. PMID- 23935130 TI - Polymorphisms of TCF7L2 gene in South Brazilian women with polycystic ovary syndrome: a cross-sectional study. AB - OBJECTIVE: To assess whether TCF7L2 single nucleotide polymorphisms rs7903146 C/T and rs11196236 C/T are associated with polycystic ovary syndrome (PCOS) in South Brazilian women. DESIGN: Cross-sectional study. METHODS: Two hundred PCOS patients and 102 non-hirsute, ovulatory controls were genotyped by real-time PCR. Haplotypes were constructed from the combination of both polymorphisms. Frequencies were inferred using the PHASE 2.1.1 software. RESULTS AND CONCLUSIONS: The distribution of rs7903146 (PCOS, 54.4% CC; 28.5% CT; 17.1% TT; controls, 51.0% CC; 37.0% CT; 12.0% TT) and rs11196236 (PCOS, 4.3% CC; 33.5% CT; 62.2% TT; controls, 3.2% CC; 35.5% CT; 61.3% TT) was similar between the groups. rs7903146 and rs11196236 were not in linkage disequilibrium (|D'|=0.34; r(2)=0.07). PCOS participants were younger, with higher age-adjusted BMI, waist circumference, blood pressure, triglycerides, insulin, homeostasis model assessment index to estimate insulin resistance and total testosterone, and lower HDL-C and sex hormone binding globulin vs controls. In PCOS, no differences between genotypes and haplotypes were found for clinical and metabolic variables. However, for each T (rs7903146) and T (rs11196236) allele added to the haplotypes, a variation of 5.87 cm in waist (P trend=0.01), 10.7 mg/dl in total cholesterol (P trend=0.03), and 10.3 mg/dl in LDL-C (P trend=0.01) was recorded. TCF7L2 variants are probably not implicated in PCOS development in South Brazilian women. PMID- 23935131 TI - GH therapy and cancer risk in hypopituitarism: what we know from human studies. AB - It has been difficult to identify factors that affect the risk of cancer, but we know that people are at higher risk as they get older, or if they have a strong family history of cancer. The potential influence of environmental and behavioral factors remains poorly understood. Early population-based and case-control studies suggested that higher serum levels of IGF1 could be associated with increased cancer risk. Since GH therapy increases IGF1 levels, concern has been raised regarding its potential role as a cancer initiation factor. Experimental evidence and some clinical studies showed that when GH/IGF1 secretion or action was inhibited, a decreased incidence and rate of progression of cancers occurred. However, human populations comprise a garden variety of genotypes that respond differently to the same kind of exposures. Human population studies frequently reveal only very small effects to these exposures. So, are GH and cancer guilty by association? After more than 20 years, leukemia, a major safety issue initially believed associated with GH treatment in children with GH deficiency (GHD), has not been confirmed but the risk of second malignancies in patients previously treated with irradiation has been detected or confirmed through the National Cooperative Growth Study. Overall, this large study confirmed the favorable overall safety profile of GH therapy in children with GHD, and also highlighted specific populations at potential risk. The risk of secondary malignancy following radiotherapy is surely related to radiotherapy more than GH therapy that may increase growth but is less likely to start the oncogenic process. In GH-deficient adults treated with GH, observational studies (KIMS, HypoCCS) have shown that when IGF1 levels were targeted within normal age-related reference ranges, the occurrence of malignancies was not higher than in the general population. PMID- 23935132 TI - Primary cilia and renal cysts: does length matter? PMID- 23935136 TI - The problem with the DSM-5 is the DSM not the 5. PMID- 23935133 TI - Voices across the fence: commonality, difference and respectful practice across a half century of change. AB - OBJECTIVE: To describe changes that have occurred in the field of indigenous mental health over the last 50 years. CONCLUSIONS: The last half-century has seen major advances in psychiatry and in the roles and capacities of the Royal Australian and New Zealand College of Psychiatrists. Over the same period, Aboriginal and Torres Strait Islander Australia has been transformed by social and political forces that have brought both benefits and disappointments to Indigenous Australians. Indigenous mental health has evolved from a marginal interest in an 'exotic' area to a recognised field with its own issues, competencies and training needs. In this paper, two College Fellows consider these decades of change, presenting their reflections through voices that reflect different vantages despite a common destination. PMID- 23935137 TI - Comparison of suicide rates in Sri Lanka during and after the civil war. PMID- 23935138 TI - Suicide prediction and prevention. PMID- 23935139 TI - Psychotropic drug-regimen changes between community treatment orders. PMID- 23935140 TI - Success in psychiatry training programs. PMID- 23935153 TI - Diagnostic performance of hyperaemic myocardial blood flow index obtained by dynamic computed tomography: does it predict functionally significant coronary lesions? AB - AIMS: The severity of coronary artery narrowing is a poor predictor of functional significance, in particular in intermediate coronary lesions (30-70% diameter narrowing). The aim of this work was to compare the performance of a quantitative hyperaemic myocardial blood flow (MBF) index derived from adenosine dynamic computed tomography perfusion (CTP) imaging with that of visual CT coronary angiography (CTCA) and semi-automatic quantitative CT (QCT) in the detection of functionally significant coronary lesions in patients with stable chest pain. METHODS AND RESULTS: CTCA and CTP were performed in 80 patients (210 analysable coronary vessels) referred to invasive coronary angiography (ICA). The MBF index (mL/100 mL/min) was computed using a model-based parametric deconvolution method. The diagnostic performance of the MBF index in detecting functionally significant coronary lesions was compared with visual CTCA and QCT. Coronary lesions with invasive fractional flow reserve of <=0.75 were defined as functionally significant. The optimal cut-off value of the MBF index to detect functionally significant coronary lesions was 78 mL/100 mL/min. On a vessel-territory level, the MBF index had a larger area under the curve (0.95; 95% confidence interval [95% CI]: 0.92-0.98) compared with visual CTCA (0.85; 95% CI: 0.79-0.91) and QCT (0.89; 95% CI: 0.84-0.93) (both P-values <0.001). In the analysis restricted to intermediate coronary lesions, the specificity of visual CTCA (69%) and QCT (77%) could be improved by the subsequent use of the MBF index (89%). CONCLUSION: In this proof-of-principle study, the MBF index performed better than visual CTCA and QCT in the identification of functionally significant coronary lesions. The MBF index had additional value beyond CTCA anatomy in intermediate coronary lesions. This may have a potential to support patient management. PMID- 23935155 TI - The cost-effectiveness of temozolomide in the adjuvant treatment of newly diagnosed glioblastoma in the United States. AB - BACKGROUND: The objective of this work was to determine the cost-effectiveness of temozolomide compared with that of radiotherapy alone in the adjuvant treatment of newly diagnosed glioblastoma. Temozolomide is the only chemotherapeutic agent to have demonstrated a significant survival benefit in a randomized clinical trial. Our analysis builds on earlier work by incorporating caregiver time costs and generic temozolomide availability. It is also the first analysis applicable to the US context. METHODS: A systematic literature review was conducted to collect relevant data. Transition probabilities were calculated from randomized controlled trial data comparing temozolomide plus radiotherapy with radiotherapy alone. Direct costs were calculated from charges reported by the Mayo Clinic. Utilities were obtained from a previous cost-utility analysis. Using these data, a Markov model with a 1-month cycle length and 5-year time horizon was constructed. RESULTS: The addition of brand Temodar and generic temozolomide to the standard radiotherapy regimen was associated with base-case incremental cost effectiveness ratios of $102 364 and $8875, respectively, per quality-adjusted life-year. The model was most sensitive to the progression-free survival associated with the use of only radiotherapy. CONCLUSIONS: Both the brand and generic base-case estimates are cost-effective under a willingness-to-pay threshold of $150 000 per quality-adjusted life-year. All 1-way sensitivity analyses produced incremental cost-effectiveness ratios below this threshold. We conclude that both the brand Temodar and generic temozolomide are cost-effective treatments for newly diagnosed glioblastoma within the US context. However, assuming that the generic product produces equivalent quality of life and survival benefits, it would be significantly more cost-effective than the brand option. PMID- 23935156 TI - Reply to "association between radiation dose to neuronal progenitor cell niches and temporal lobes and performance on neuropsychological testing in children: a prospective study" by Redmond et al. PMID- 23935154 TI - Cells with intense EGFR staining and a high nuclear to cytoplasmic ratio are specific for infiltrative glioma: a useful marker in neuropathological practice. AB - BACKGROUND: The differential diagnosis between infiltrative glioma (IG) and benign or curable glial lesions, such as gliosis, pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor, ganglioglioma, or demyelinating disease, may be challenging for the pathologist because specific markers are lacking. Recently, we described a strong EGFR immunolabelling pattern in cells with a high nuclear to cytoplasmic ratio that enables the discrimination of low-grade IG from gliosis. The aim of this study was to extend our observation to high-grade glioma to assess whether EGFR expression pattern is of value in the discrimination of all IG from noninfiltrative glial lesions (NIG), including gliosis, benign tumors, and demyelinating disease. METHODS: One hundred one IG and 58 NIG were compared for immunohistochemical expression of EGFR with use of an antibody that recognizes an epitope in the extracellular domain of both EGFRwt and EGFRvIII. Highly EGFR-positive cells with a high nuclear to cytoplasmic ratio were isolated and further characterized. RESULTS: Cells with intense EGFR staining and a high nuclear to cytoplasmic ratio were significantly associated with the diagnosis of IG (P < .0001). The sensitivity and specificity of this staining pattern for the diagnosis of IG were 95% and 100%, respectively. EGFR expression was independent of IDH1 mutations and EGFR amplification. Finally, we showed that these particular cells displayed the phenotype and properties of glial progenitors and coexpressed CXCR4, a marker of invasiveness. CONCLUSIONS: We demonstrate that cells with intense EGFR staining and a high nuclear to cytoplasmic ratio are specific criteria for the diagnosis of IG, irrespective of grade, histological subtype, and progression pathway, and their identification represents a tool to discriminate IG from benign or curable glial lesions. PMID- 23935157 TI - Predictive accuracy of triage nurses evaluation in risk stratification of syncope in the emergency department. AB - BACKGROUND: Syncope is a common clinical problem that accounts for 1-3% of all emergency department (ED) visits. Its prognosis is extremely variable with a 1 year mortality that may reach 30%. There are no available data about the accuracy of nursing triage in identifying high-risk syncope. The aim of our study was to evaluate the predictive accuracy of nursing triage in identifying high-risk syncope. METHODS: We conducted a retrospective study on 678 consecutive patients who presented with syncope at four EDs. For each patient, nursing triage, comorbidities, clinical features and adverse events that occurred both in the ED and at 10-day follow-up were assessed. Adverse events included death, readmission to ED, need for major therapeutic procedures, cardiopulmonary resuscitation, intensive care unit admittance, acute antiarrhythmic therapy and major causes of syncope identified during the ED evaluation. Predictive accuracy of nursing triage was evaluated. RESULTS: We observed a total of 55 (8.1%) adverse events. Eight of them (9.4%) occurred among the 85 patients who were identified as high priority by nursing triage. Sensitivity (Sn) and specificity (Sp) of urgent nursing triage in identifying adverse outcomes in the ED (19 patients) were 21% (95% CI 3% to 39%) and 88% (95% CI 85% to 90%), while the positive likelihood ratio (LR+) and negative likelihood ratio (LR-) were 1.7 and 0.9, respectively. Sn and Sp for 10-day adverse events were 15% (95% CI 5% to 24%) and 88% (95% CI 85% to 90%), respectively, with a LR+ of 1.18 and a LR- of 0.98. CONCLUSIONS: Nursing triage was characterised by a low predictive accuracy in identifying high risk individuals. PMID- 23935158 TI - Glutamate and migraine: from Ikeda to the 21st century. PMID- 23935159 TI - Ictal epileptic headache: moving forward. Reply to Cianchetti et al. PMID- 23935160 TI - Barriers to the effective use of medico-legal findings in sexual assault cases worldwide. AB - Despite the increasing implementation of standardized rape kits across jurisdictions, the medico-legal findings generated by these tools are often not related to positive criminal justice outcomes. Given that there has been no global investigation of the factors that might impede their successful use in cases of sexual assault, we conducted a review of relevant scholarly and "grey" literature from industrialized and less-developed regions. One key theme to emerge from the analysis concerned certain problematic practices and behaviors of professional groups involved in the various stages of the post-sexual assault process. We found that a lack of competence in handling sexual assault cases, contempt for women who have been victimized, and corruption among some forensic examiners, police, scientists, and legal personnel often have shaped the collection, processing, analysis, and use of medico-legal evidence. We discuss recent initiatives and future directions for research that might serve to address these issues. PMID- 23935161 TI - Feasibility trial of a Spanish-language multimedia educational intervention. AB - BACKGROUND: Hispanic cancer patients are underrepresented in clinical trials; research suggests lack of knowledge and language barriers contribute to low accrual. Multimedia materials offer advantages to Hispanic populations because they have high acceptability, are easy to disseminate, and can be viewed with family. PURPOSE: Hispanic cancer patients and caregivers participated in focus groups to aid in developing a Spanish-language multimedia intervention to educate Hispanic cancer patients about clinical trials. We explored the feasibility of delivering the intervention in medical oncology clinics. METHODS: A total of 35 patients were randomized to either the multimedia intervention group (n = 18) or a control group (n = 17) who were asked to read the National Cancer Institute's Spanish-language clinical trials brochure. Self-reported data on knowledge about and attitudes toward clinical trials, self-efficacy for participating in a clinical trial, intention to participate in a clinical trial if asked, and receptivity to information about a clinical trial were collected at baseline and 10 days later. RESULTS: Delivery of the multimedia presentation in oncology clinics was feasible. The intervention group had more knowledge about clinical trials at follow-up than the control group; scores for intention to participate in a clinical trial by participants in the intervention group increased from 3.8 to 4.0 of a possible 5, but declined in the control group from 4.5 to 4.1. No statistically significant difference was detected between groups in scores for attitudes or self-efficacy for making a decision to participate in a clinical trial. LIMITATIONS: Our sample size was inadequate to identify differences between the informational methods. Although all patients were asked about their willingness to participate in a clinical trial, this decision was hypothetical. In addition, the study was conducted with a sample of Spanish-speaking Hispanic cancer patients at a comprehensive cancer center in Florida. Thus, the results may not generalize to other Hispanic populations. CONCLUSION: In the pilot project, we demonstrated the feasibility of delivering multimedia information to patients in medical oncology clinics. Because delivery in a clinical setting was found to be feasible, a larger study should be conducted to evaluate the efficacy of the multimedia intervention with respect to promoting accrual of Hispanic patients to clinical trials. PMID- 23935162 TI - An audit strategy for time-to-event outcomes measured with error: application to five randomized controlled trials in oncology. AB - BACKGROUND: Measurement error in time-to-event end points complicates interpretation of treatment effects in clinical trials. Non-differential measurement error is unlikely to produce large bias [1]. When error depends on treatment arm, bias is of greater concern. Blinded-independent central review (BICR) of all images from a trial is commonly undertaken to mitigate differential measurement-error bias that may be present in hazard ratios (HRs) based on local evaluations. Similar BICR and local evaluation HRs may provide reassurance about the treatment effect, but BICR adds considerable time and expense to trials. METHODS: We describe a BICR audit strategy [2] and apply it to five randomized controlled trials to evaluate its use and to provide practical guidelines. The strategy requires BICR on a subset of study subjects, rather than a complete-case BICR, and makes use of an auxiliary-variable estimator. RESULTS: When the effect size is relatively large, the method provides a substantial reduction in the size of the BICRs. In a trial with 722 participants and a HR of 0.48, an average audit of 28% of the data was needed and always confirmed the treatment effect as assessed by local evaluations. More moderate effect sizes and/or smaller trial sizes required larger proportions of audited images, ranging from 57% to 100% for HRs ranging from 0.55 to 0.77 and sample sizes between 209 and 737. LIMITATIONS: The method is developed for a simple random sample of study subjects. In studies with low event rates, more efficient estimation may result from sampling individuals with events at a higher rate. CONCLUSION: The proposed strategy can greatly decrease the costs and time associated with BICR, by reducing the number of images undergoing review. The savings will depend on the underlying treatment effect and trial size, with larger treatment effects and larger trials requiring smaller proportions of audited data. PMID- 23935169 TI - Randomized clinical trials: the double edged sword. PMID- 23935163 TI - CT density analysis of the medial cuneiform. AB - BACKGROUND: A cannulated lag screw inserted through the medial cuneiform into the base of the second metatarsal is often utilized to reduce the diastasis and aid healing of Lisfranc injuries. Also procedures such as a midfoot or a Lapidus arthrodesis require adequate implant-bone purchase in the medial cuneiform. The medial cuneiform contains cancellous bone of varying density. Knowledge of density variation may be helpful for implant usage and manufacturing of area specific implants. METHODS: In 60 randomly selected patients, mean computed tomography (CT) intensity in Hounsfield units was measured at 12 sampled locations within the medial cuneiform and served as a proxy for bone density. The patients' age, gender, and race were recorded. An analysis of variance (ANOVA) assessed the effect of age, gender, race, and sample site on bone density. Statistical testing assumed 95% level of confidence. RESULTS: ANOVA showed age, gender, and sample site had significant effects (P < .001) on bone density, though race had no significant effect (P = .28). The distal-dorsal-lateral (DDL) site was significantly denser than all other sites (P < .001) except the middle dorsal-lateral (MDL) (P = .53). The proximal-plantar-lateral (PPL) site was significantly less dense than all other sites (P < .001) except the middle plantar-lateral/medial and the proximal-plantar-medial sites (P < .14). A general trend of density increasing in the distal and dorsal directions was evident, and within the dorsal sites there was a trend of increasing density in the lateral direction. CONCLUSION: This is the first study to date to measure density of the medial cuneiform using living subjects. The sample size of 60 patients was also the largest of any study measuring density of this bone. We conclude that the densest area of the medial cuneiform is the most anterior, dorsal, and lateral portion. CLINICAL RELEVANCE: The findings of this study may indicate the most optimal area for implant purchase in the medial cuneiform when reducing the diastasis between the base of the second metatarsal and medial cuneiform and for stabilization of the medial column. PMID- 23935170 TI - Eight o'clock ROCK! PMID- 23935172 TI - Author's response to letter on number needed to treat in COPD: exacerbations versus pneumonias. PMID- 23935173 TI - Author's response: co-trimoxazole treatment in idiopathic pulmonary fibrosis. PMID- 23935174 TI - Commentary: the British Thoracic Society guideline on pulmonary rehabilitation in adults. AB - The first British Thoracic Society guideline on pulmonary rehabilitation in adults is published in the accompanying Thorax supplement. Focusing on delivery of a quality pulmonary rehabilitation service, the evidenced-based guideline encompasses recommendations on the composition of the service, referral of patients and who benefits, the expected patient-related outcome measures and markers, pulmonary rehabilitation following exacerbations, the post rehabilitation period and areas requiring further research. In this commentary, we introduce the guideline and discuss pulmonary rehabilitation in the wider context of chronic disease management of respiratory patients. PMID- 23935176 TI - Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. AB - OBJECTIVE: We aimed to investigate the possible association between SCN2A mutations and early-onset epileptic encephalopathies (EOEEs). METHODS: We recruited a total of 328 patients with EOEE, including 67 patients with Ohtahara syndrome (OS) and 150 with West syndrome. SCN2A mutations were examined using high resolution melt analysis or whole exome sequencing. RESULTS: We found 14 novel SCN2A missense mutations in 15 patients: 9 of 67 OS cases (13.4%), 1 of 150 West syndrome cases (0.67%), and 5 of 111 with unclassified EOEEs (4.5%). Twelve of the 14 mutations were confirmed as de novo, and all mutations were absent in 212 control exomes. A de novo mosaic mutation (c.3976G>C) with a mutant allele frequency of 18% was detected in one patient. One mutation (c.634A>G) was found in transcript variant 3, which is a neonatal isoform. All 9 mutations in patients with OS were located in linker regions between 2 transmembrane segments. In 7 of the 9 patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia. All 15 of the patients with novel SCN2A missense mutations had intractable seizures; 3 of them were seizure-free at the last medical examination. All patients showed severe developmental delay. CONCLUSIONS: Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions. PMID- 23935178 TI - In situ evidence of JC virus control by CD8+ T cells in PML-IRIS during HIV infection. AB - OBJECTIVE: To determine the pathophysiologic features of progressive multifocal leukoencephalopathy (PML) associated with immune reconstitution inflammatory syndrome (PML-IRIS) in HIV-infected patients. METHODS: In a cross-sectional study, we retrospectively analyzed 11 HIV-infected patients with a firm diagnosis of PML-IRIS. Brain biopsies were collected from 5 patients and their histopathologic features were compared to those of 4 HIV-infected patients with classic PML. RESULTS: PML-IRIS developed soon after initiation of antiretroviral therapy in late-presenting HIV-infected patients. The lesions from the 5 biopsied PML-IRIS patients were characterized by a reduction in the density of JC virus (JCV)-infected cells when compared to the 4 patients with PML (11.1 +/- 3.2/mm2 vs 51.2 +/- 4.3/mm2, p = 0.01). Comparing the 5 patients with PML-IRIS vs the 4 patients with PML, this correlated with an increased accumulation of CD8+ T cells (818.2 +/- 192.8/mm2 vs 52.5 +/- 10.6/mm2, p = 0.01), CD20+ B cells (33.4 +/- 13.5/mm2 vs 0.5 +/- 0.5/mm2, p = 0.01), and CD138+ plasma cells (177 +/- 84.1/mm2 vs 0.25 +/- 0.25/mm2, p = 0.01), while the number of CD68+ macrophages/microglia did not differ. The ratio between CD8+ T cells and JCV-infected cells was 70 times higher in the 5 patients with PML-IRIS. These findings indicate a clear relationship between an enhanced recruitment of CD8+ T cells and the associated control of the JCV infection. CONCLUSIONS: Our data provide in situ evidence that PML-IRIS brain lesions are enriched in cytotoxic CD8+ T cells that engage JCV infected oligodendrocytes. This leads to a better control of JCV dissemination, but at the cost of oligodendrocyte cell death and demyelination. PMID- 23935177 TI - Neuropathologic basis of white matter hyperintensity accumulation with advanced age. AB - OBJECTIVE: To determine which vascular pathology measure most strongly correlates with white matter hyperintensity (WMH) accumulation over time, and whether Alzheimer disease (AD) neuropathology correlates with WMH accumulation. METHODS: Sixty-six older persons longitudinally followed as part of an aging study were included for having an autopsy and >1 MRI scan, with last MRI scan within 36 months of death. Mixed-effects models were used to examine the associations between longitudinal WMH accumulation and the following neuropathologic measures: myelin pallor, arteriolosclerosis, microvascular disease, microinfarcts, lacunar infarcts, large-vessel infarcts, atherosclerosis, neurofibrillary tangle rating, and neuritic plaque score. Each measure was included one at a time in the model, adjusted for duration of follow-up and age at death. A final model included measures showing an association with p < 0.1. RESULTS: Mean age at death was 94.5 years (5.5 SD). In the final mixed-effects models, arteriolosclerosis, myelin pallor, and Braak score remained significantly associated with increased WMH accumulation over time. In post hoc analysis, we found that those with Braak score 5 or 6 were more likely to also have high atherosclerosis present compared with those with Braak score 1 or 2 (p = 0.003). CONCLUSION: Accumulating white matter changes in advanced age are likely driven by small-vessel ischemic disease. Additionally, these results suggest a link between AD pathology and white matter integrity disruption. This may be due to wallerian degeneration secondary to neurodegenerative changes. Alternatively, a shared mechanism, for example ischemia, may lead to both vascular brain injury and neurodegenerative changes of AD. The observed correlation between atherosclerosis and AD pathology supports the latter. PMID- 23935179 TI - Relations of arterial stiffness and endothelial function to brain aging in the community. AB - OBJECTIVE: To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging. METHODS: Stroke- and dementia-free Framingham Offspring Study participants (n = 1,587, 61 +/- 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998-2001) and brain MRI and cognition (1999-2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory delayed recall, respectively). RESULTS: Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p < 0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p < 0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p < 0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p > 0.05). CONCLUSIONS: Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes. PMID- 23935180 TI - Acute late-onset encephalopathy after radiotherapy: an unusual life-threatening complication. AB - Unusual late-onset complications of brain irradiation, characterized by reversible neurologic focal signs, seizures, and MRI alterations, have recently been reported and classified as stroke-like migraine attacks after radiation therapy (SMART)(1) and peri-ictal pseudoprogression (PIPG).(2.) PMID- 23935181 TI - Cigarette excise tax structure and cigarette prices: evidence from the global adult tobacco survey and the U.S. National Adult Tobacco Survey. AB - INTRODUCTION: The importance of tobacco tax structure in determining the relative prices of different tobacco products and brands has become increasingly recognized. The structuring of tobacco tax across products and brands within a country can impact the variability of prices within a country, shaping consumption and influencing tobacco users' incentives to switch down to cheaper alternatives in response to tax and price increases. METHODS: Brand-specific data on the average prices paid for the top 5 cigarette brands in 13 countries were obtained from the Global Adult Tobacco Survey, and for the United States, data were obtained from the National Adult Tobacco Survey. The variability of cigarette prices paid across brands was analyzed in the context of each country's tobacco tax structure. RESULTS: Countries with simpler cigarette tax structures, particularly those that emphasize specific taxes and do not involve tier-based taxes, exhibit less variability in the prices smokers pay for cigarettes across brands. CONCLUSIONS: Increases in cigarette taxes in countries with simpler tax structures will be more effective in reducing cigarette smoking and its health and economic consequences than comparable tax increases in countries where tax structures are more complicated and there are greater opportunities for switching to cheaper brands in order to avoid a tax increase. PMID- 23935182 TI - Sustained reduction of nicotine craving with real-time neurofeedback: exploring the role of severity of dependence. AB - BACKGROUND: Neurofeedback delivered via real-time functional magnetic resonance imaging (rtfMRI) is a promising therapeutic technique being explored to facilitate self-regulation of craving in nicotine-dependent cigarette smokers. The current study examined the role of nicotine-dependence severity and the efficacy of multiple visits of neurofeedback from a single region of interest (ROI) in the anterior cingulate cortex (ACC) on craving reduction. METHODS: Nine nicotine-dependent cigarette smokers participated in three rtfMRI visits that examined cue-induced craving and brain activation. Severity of nicotine dependence was assessed with the Fagerstrom Test for Nicotine Dependence. When viewing smoking-related images with instructions to "crave," patient-tailored ROIs were generated in the vicinity of the ACC. Activity levels from the ROI were fed back while participants viewed smoking cues with the instruction to reduce craving. RESULTS: Neurofeedback from a single ROI in the ACC led to consistent decreases in self-reported craving and activation in the ACC across the three visits. Dependence severity predicted response to neurofeedback at Visit 3. CONCLUSIONS: This study builds upon previous rtfMRI studies on the regulation of nicotine craving in demonstrating that feedback from the ACC can reduce activation to smoking cues across three separate visits. Individuals with lower nicotine-dependence severity were more successful in reducing ACC activation over time. These data highlight the need to consider dependence severity in developing more individualized neurofeedback methods. PMID- 23935187 TI - Galectin LEC-1 plays a defensive role against damage due to oxidative stress in Caenorhabditis elegans. AB - LEC-1 is a major galectin in Caenorhabditis elegans and contains two carbohydrate recognition domains (CRDs), N-CRD and C-CRD. To determine the role of LEC-1, we examined the phenotypes of a mutant C. elegans strain lacking lec-1. We observed negligible differences in embryogenesis, morphogenesis and egg laying at 20 degrees C between the mutant and the wild-type. Furthermore, the life spans of the mutant and the wild-type were equivalent at either 20 degrees C or 25 degrees C. However, the lec-1 mutant showed a greater susceptibility to H2O2 and paraquat than the wild-type. This result suggests an increased susceptibility to oxidative stress, with the phenotypes being similar to those of lec-10 deletion mutants as previously described. To understand the molecular mechanism underlying this phenotype, C. elegans proteins bound by either the LEC-1 N-CRD or C-CRD were isolated and identified using a nano liquid chromatography-tandem mass spectrometry technique. MIG-6 was identified as a major binding partner of LEC-1 with both N- and C-CRD. From these results and previous reports, we speculate that interaction of LEC-1 and MIG-6 in the pharynx may affect susceptibility to paraquat and that LEC-10 has different functions from LEC-1 in regulating H2O2 and paraquat resistance in the intestine. PMID- 23935188 TI - Global warming comes to tobacco control. PMID- 23935190 TI - CCR7 plays no appreciable role in trafficking of central memory CD4 T cells to lymph nodes. AB - CCR7-/- mice exhibit profound anomalies in lymph node and spleen architecture, which complicates the study of CCR7-mediated T cell trafficking in vivo. To circumvent this problem, we established in vivo models in which wild-type and CCR7-/- populations coexist within mice possessing normal lymphoid organs and must compete for developmental niches within the tissues of these mice. Under the conditions we have created in vivo, we find the entry of memory CD4 T cells into lymph nodes from the blood to be independent of CCR7. Thus, the central memory CD4 T cells that traffic though lymph nodes, which are often defined by their expression of CCR7, do not appear to gain any competitive homing advantage by expressing this receptor. Furthermore, in contrast to cutaneous dendritic cell populations, we found that CCR7 deficiency had no appreciable effect on the exit of CD4 T cells from inflamed skin. Finally, we found that wild-type and CCR7-/- precursors were equally represented within the major thymic subpopulations, despite previous findings that CCR7 plays a role in seeding the thymus from bone marrow-derived T cell precursors. PMID- 23935191 TI - Parental dietary fat intake alters offspring microbiome and immunity. AB - Mechanisms underlying modern increases in prevalence of human inflammatory diseases remain unclear. The hygiene hypothesis postulates that decreased microbial exposure has, in part, driven this immune dysregulation. However, dietary fatty acids also influence immunity, partially through modulation of responses to microbes. Prior reports have described the direct effects of high fat diets on the gut microbiome and inflammation, and some have additionally shown metabolic consequences for offspring. Our study sought to expand on these previous observations to identify the effects of parental diet on offspring immunity using mouse models to provide insights into challenging aspects of human health. To test the hypothesis that parental dietary fat consumption during gestation and lactation influences offspring immunity, we compared pups of mice fed either a Western diet (WD) fatty acid profile or a standard low-fat diet. All pups were weaned onto the control diet to specifically test the effects of early developmental fat exposure on immune development. Pups from WD breeders were not obese or diabetic, but still had worse outcomes in models of infection, autoimmunity, and allergic sensitization. They had heightened colonic inflammatory responses, with increased circulating bacterial LPS and muted systemic LPS responsiveness. These deleterious impacts of the WD were associated with alterations of the offspring gut microbiome. These results indicate that parental fat consumption can leave a "lard legacy" impacting offspring immunity and suggest inheritable microbiota may contribute to the modern patterns of human health and disease. PMID- 23935192 TI - Shark IgW C region diversification through RNA processing and isotype switching. AB - Sharks and skates represent the earliest vertebrates with an adaptive immune system based on lymphocyte Ag receptors generated by V(D)J recombination. Shark B cells express two classical Igs, IgM and IgW, encoded by an early, alternative gene organization consisting of numerous autonomous miniloci, where the individual gene cluster carries a few rearranging gene segments and one C region, MU or omega. We have characterized eight distinct Ig miniloci encoding the nurse shark omega H chain. Each cluster consists of VH, D, and JH segments and six to eight C domain exons. Two interspersed secretory exons, in addition to the 3' most C exon with tailpiece, provide the gene cluster with the ability to generate at least six secreted isoforms that differ as to polypeptide length and C domain combination. All clusters appear to be functional, as judged by the capability for rearrangement and absence of defects in the deduced amino acid sequence. We previously showed that IgW VDJ can perform isotype switching to MU C regions; in this study, we found that switching also occurs between omega clusters. Thus, C region diversification for any IgW VDJ can take place at the DNA level by switching to other omega or MU C regions, as well as by RNA processing to generate different C isoforms. The wide array of pathogens recognized by Abs requires different disposal pathways, and our findings demonstrate complex and unique pathways for C effector function diversity that evolved independently in cartilaginous fishes. PMID- 23935193 TI - Induction of functional human macrophages from bone marrow promonocytes by M-CSF in humanized mice. AB - Engraftment of human CD34+ hematopoietic stem/progenitor cells into immunodeficient mice leads to robust reconstitution of human T and B cells but not monocytes and macrophages. To identify the cause underlying the poor monocyte and macrophage reconstitution, we analyzed human myeloid cell development in humanized mice and found that it was blocked at the promonocyte stage in the bone marrow. Expression of human M-CSF or GM-CSF by hydrodynamic injection of cytokine encoding plasmid completely abolished the accumulation of promonocytes in the bone marrow. M-CSF promoted the development of mature monocytes and tissue resident macrophages whereas GM-CSF did not. Moreover, correlating with an increased human macrophages at the sites of infection, M-CSF-treated humanized mice exhibited an enhanced protection against influenza virus and Mycobacterium infection. Our study identifies the precise stage at which human monocyte/macrophage development is blocked in humanized mice and reveals overlapping and distinct functions of M-CSF and GM-CSF in human monocyte and macrophage development. The improved reconstitution and functionality of monocytes/macrophages in the humanized mice following M-CSF expression provide a superior in vivo system to investigate the role of macrophages in physiological and pathological processes. PMID- 23935194 TI - Death receptor-independent activation-induced cell death in human melanoma antigen-specific MHC class I-restricted TCR-engineered CD4 T cells. AB - Engaging CD4 T cells in antitumor immunity has been quite challenging, especially in an Ag-specific manner, because most human solid tumors usually do not express MHC class II molecules. We have recently shown that human CD4 T cells engineered to express a human melanoma-associated antigenic epitope, MART-127-35, specific MHC class I-restricted transgenic TCR function as polyfunctional effectors that can exhibit a helper as well as cytolytic effector function, in an epitope specific and MHC class I-restricted manner (Chhabra et al. 2008. J. Immunol. 181: 1063-1070; Ray et al. 2010. Clin. Immunol. 136: 338-347). TCR-engineered (TCReng) CD4 T cells therefore have translational potential, and clinical trials with MHC class I TCReng CD4 T cells are under way. In this study, we show that although TCReng CD4 T cells could be useful in cancer immunotherapy, they are also susceptible to epitope-specific activation-induced cell death (AICD). We also show that the AICD in TCReng CD4 T cells is a death receptor-independent process and that JNK and p53 play critical roles in this process as pharmacological inhibitors targeting JNK activation and p-53-mediated transcription-independent mitochondria-centric death cascade rescued a significant fraction of TCReng CD4 T cells from undergoing AICD without affecting their effector function. Our data offer novel insights toward AICD in TCReng CD4 T cells and identify several potential targets to interfere with this process. PMID- 23935195 TI - Plasma cell homeostasis: the effects of chronic antigen stimulation and inflammation. AB - Long-lived plasma cells (LLPCs) that maintain humoral immunity to previously encountered Ags occupy a compartment in the bone marrow (BM). The rules and mechanisms by which cells enter (and leave) this compartment are poorly understood. We looked at what happens to the LLPC compartment and to plasma cell lifespan in general, in situations in which Ag stimulation and/or inflammation persist. We find that chronic Ag supply causes the generation of short-lived plasma cells in the local lymphoid organ, at the expense of any LLPC production. Furthermore, we find that inflammation caused by infection (mediated via TNF alpha) causes a dramatic mobilization of LLPCs from the BM, with a concomitant reduction in circulating Ab levels against previously immunized Ags. These data are discussed in the context of the capacity of the BM LLPC compartment and competition for entry to it. PMID- 23935196 TI - Neuromyelitis optica IgG causes placental inflammation and fetal death. AB - Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS and affects women of childbearing age. Most patients with NMO have circulating Abs, termed NMO-IgG, against the astrocytic water channel protein aquaporin-4. In the CNS, NMO-IgG causes complement-mediated astrocyte damage, inflammatory cell infiltration, and myelin loss. In this study, we show that aquaporin-4 is expressed in the syncytiotrophoblast of human and mouse placenta. Placental aquaporin-4 expression is high during mid-gestation and progressively decreases with advancing pregnancy. Intraperitoneally injected NMO-IgG binds mouse placental aquaporin-4, activates coinjected human complement, and causes inflammatory cell infiltration into the placenta and placental necrosis. There was no damage to maternal organs that express aquaporin-4, including the brain, spinal cord, kidneys, and skeletal muscle. In control experiments, no placentitis was found in mice injected with NMO-IgG without complement, non-NMO-IgG with human complement, or in aquaporin-4 null mice injected with NMO-IgG and human complement. The infiltrating cells were primarily neutrophils with a few scattered eosinophils and macrophages. NMO-IgG and human complement-induced placentitis caused fetal death, but some fetuses were born normal when lower amounts of NMO-IgG and human complement were injected. Sivelestat, a neutrophil elastase inhibitor, and aquaporumab, a nonpathogenic IgG that competes with NMO IgG for aquaporin-4 binding, significantly reduced NMO-IgG and human complement induced placentitis and fetal death. Our data suggest that NMO-IgG can cause miscarriage, thus challenging the concept that NMO affects only the CNS. These findings have implications for the management of NMO during pregnancy. PMID- 23935198 TI - Alendronate attenuates eosinophilic airway inflammation associated with suppression of Th2 cytokines, Th17 cytokines, and eotaxin-2. AB - Bisphosphonates (BPs) have been widely used to treat osteoporosis. They act by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. This resembles the action of statins, whose immune-modulating effect has recently been highlighted. In contrast, the effect of BPs on immune responses has not been elucidated well. In this study, we examined the effect of alendronate (ALN), a nitrogen-containing BP, on allergic airway inflammation in a mouse model. BALB/c mice were sensitized twice with OVA and challenged three times with nebulized OVA to induce eosinophilic airway inflammation. ALN was administered by an intragastric tube before each inhalation. ALN strongly suppressed airway eosinophilia and Th2, as well as Th17 cytokine production in the lung. ALN also attenuated eotaxin-2 production in the lung. Immunohistochemistry demonstrated that the major cell source of eotaxin-2 was peribronchial/perivascular macrophages, and flow cytometrical studies confirmed that ALN decreased eotaxin-2 expression in these macrophages. Furthermore, ALN attenuated eotaxin-2 production from mouse pleural macrophages and human monocyte/macrophage-like THP-1 cells in vitro. These results suggest that ALN suppressed Ag-induced airway responses in the mouse model. The suppression of eotaxin-2 production from macrophages appears to be one of ALN's immunomodulatory effects, whereas the mechanism by which ALN suppressed Th2 and Th17 responses could not be fully elucidated in this study. Although a clinical study should be conducted, ALN could be a novel therapeutic option for asthma. PMID- 23935199 TI - Oropharyngeal group A streptococcal colonization disrupts latent Epstein-Barr virus infection. AB - Epstein-Barr virus (EBV) infects >90% of the human population within the first 2 decades of life and establishes reversible latent infection in B cells. The stimuli that lead to switching from latent to lytic EBV infection in vivo are still elusive. Group A streptococci (GAS) are a common cause of bacterial pharyngotonsillitis in children and adolescents and colonize the tonsils and pharynx of up to 20% of healthy children. Thus, concomitant presence of EBV and GAS in the same individual is frequent. Here, we show that EBV carriers who are colonized with GAS shed EBV particles in higher numbers in their saliva, compared with EBV carriers not colonized with GAS. Messenger RNA levels of the master lytic regulatory EBV gene BZLF1 were more frequently detected in tonsils from EBV carriers colonized with GAS than from EBV carriers not colonized. Heat-killed GAS, potentially mimicking GAS colonization, elicited lytic EBV in latently infected lymphoblastoid cell lines (LCLs) partially via Toll-like receptor 2 triggering, as did purified GAS peptidoglycan. Thus, colonization by GAS might benefit EBV by increasing the EBV load in saliva and thereby enhancing the likelihood of EBV spread to other hosts. PMID- 23935197 TI - Type I IFNs downregulate myeloid cell IFN-gamma receptor by inducing recruitment of an early growth response 3/NGFI-A binding protein 1 complex that silences ifngr1 transcription. AB - The ability of type I IFNs to increase susceptibility to certain bacterial infections correlates with downregulation of myeloid cell surface IFNGR, the receptor for the type II IFN (IFN-gamma), and reduced myeloid cell responsiveness to IFN-gamma. In this study, we show that the rapid reductions in mouse and human myeloid cell surface IFNGR1 expression that occur in response to type I IFN treatment reflect a rapid silencing of new ifngr1 transcription by repressive transcriptional regulators. Treatment of macrophages with IFN-beta reduced cellular abundance of ifngr1 transcripts as rapidly and effectively as actinomycin D treatment. IFN-beta treatment also significantly reduced the amounts of activated RNA polymerase II (pol II) and acetylated histones H3 and H4 at the ifngr1 promoter and the activity of an IFNGR1-luc reporter construct in macrophages. The suppression of IFNGR1-luc activity required an intact early growth response factor (Egr) binding site in the proximal ifngr1 promoter. Three Egr proteins and two Egr/NGFI-A binding (Nab) proteins were found to be expressed in bone macrophages, but only Egr3 and Nab1 were recruited to the ifngr1 promoter upon IFN-beta stimulation. Knockdown of Nab1 in a macrophage cell line prevented downregulation of IFNGR1 and prevented the loss of acetylated histones from the ifngr1 promoter. These data suggest that type I IFN stimulation induces a rapid recruitment of a repressive Egr3/Nab1 complex that silences transcription from the ifngr1 promoter. This mechanism of gene silencing may contribute to the anti inflammatory effects of type I IFNs. PMID- 23935200 TI - Fc gamma receptor 3B (FCGR3B-c.233C>A-rs5030738) polymorphism modifies the protective effect of malaria specific antibodies in Ghanaian children. AB - Immunoglobulin G (IgG) cross-linking with Fc gamma receptor IIIB (FcgammaRIIIB) triggers neutrophil degranulation, releasing reactive oxygen species with high levels associated with protection against malaria. The FCGR3B-c.233C>A polymorphism thought to influence the interaction between IgG and FcgammaRIIIB was recently associated with malaria. We studied the statistical interaction between glutamate rich protein antibodies and FCGR3B-c.233C>A genotypes on risk of malaria in a cohort of Ghanaian children. The absolute risk of malaria decreased more rapidly with increasing antibody levels for 233AA/AC individuals compared with 233CC children. This genotype related effect modification may significantly influence malaria sero-epidemiological and vaccine trial studies. PMID- 23935201 TI - Avian-origin influenza A(H7N9) infection in influenza A(H7N9)-affected areas of China: a serological study. AB - Serological surveillance conducted in areas of an outbreak of influenza A(H7N9) infection in China found no seropositivity for antibodies specific for avian origin influenza A(H7N9) among 1129 individuals of the general population, whereas >6% of 396 poultry workers were positive (on the basis of a hemagglutination inhibition titer of >= 80) for this subtype, confirming that infected poultry is the principal source of human infections and that subclinical infections are possible. Fourteen days after symptom onset, elevated levels of antibodies to A(H7N9) were found in 65.8% of patients (25/38) who survived but in only 28.6% of those (2/7) who died, suggesting that the presence of antibodies may improve clinical outcome in infected patients. PMID- 23935202 TI - Importance of toxin A, toxin B, and CDT in virulence of an epidemic Clostridium difficile strain. AB - Clostridium difficile infection is the main cause of healthcare-acquired diarrhea in the developed world. In addition to the main virulence factors toxin A and B, epidemic, PCR Ribotype 027 strains, such as R20291, produce a third toxin, CDT. To develop effective medical countermeasures, it is important to understand the importance of each toxin. Accordingly, we created all possible combinations of isogenic toxin mutants of R20291 and assessed their virulence. We demonstrated that either toxin A or toxin B alone can cause fulminant disease in the hamster infection model and present tantalizing data that C. difficile toxin may also contribute to virulence. PMID- 23935203 TI - Viruses detected among sporadic cases of parotitis, United States, 2009-2011. AB - BACKGROUND: Sporadic cases of parotitis are generally assumed to be mumps, which often requires a resource-intensive public health response. This project surveyed the frequency of viruses detected among such cases. METHODS: During 2009-2011, 8 jurisdictions throughout the United States investigated sporadic cases of parotitis. Epidemiologic information, serum, and buccal and oropharyngeal swabs were collected. Polymerase chain reaction methods were used to detect a panel of viruses. Anti-mumps virus immunoglobulin M (IgM) antibodies were detected using a variety of methods. RESULTS: Of 101 specimens, 38 were positive for a single virus: Epstein-Barr virus (23), human herpesvirus (HHV)-6B (10), human parainfluenza virus (HPIV)-2 (3), HPIV-3 (1), and human bocavirus (1). Mumps virus, enteroviruses (including human parechovirus), HHV-6A, HPIV-1, and adenoviruses were not detected. Early specimen collection did not improve viral detection rate. Mumps IgM was detected in 17% of available specimens. Patients in whom a virus was detected were younger, but no difference was seen by sex or vaccination profile. No seasonal patterns were identified. CONCLUSIONS: Considering the timing of specimen collection, serology results, patient vaccination status, and time of year may be helpful in assessing the likelihood that a sporadic case of parotitis without laboratory confirmation is mumps. PMID- 23935204 TI - Faster progression to AIDS and AIDS-related death among seroincident individuals infected with recombinant HIV-1 A3/CRF02_AG compared with sub-subtype A3. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) is divided into subtypes and circulating recombinant forms (CRFs) but the impact of subtype/CRF on disease progression is not fully understood. METHODS: We determined the HIV-1 subtype/CRF of 152 seroincident individuals from Guinea-Bissau, based on the C2-V3 region of env. Disease progression was measured as time from estimated seroconversion to AIDS and AIDS-related death. Hazard ratios (HRs) were calculated using a Cox proportional hazard model, adjusting for gender and age at seroconversion. RESULTS: The major subtypes/CRFs identified were CRF02_AG (53%), A3 (29%), and A3/02 (a recombinant of A3 and CRF02_AG) (13%). Infection with A3/02 was associated with a close to 3-fold increased risk of AIDS and AIDS-related death compared to A3 (HR = 2.6 [P = 0.011] and 2.9 [P = 0.032], respectively). The estimated time from seroconversion to AIDS and AIDS-related death was 5.0 and 8.0 years for A3/02, 6.2 and 9.0 years for CRF02_AG, and 7.2 and 11.3 years for A3. CONCLUSION: Our results show that there are differences in disease progression between HIV-1 A-like subtypes/CRFs. Individuals infected with A3/02 have among the fastest progression rates to AIDS reported to date. Determining the HIV-1 subtype of infected individuals could be important in the management of HIV-1 infections. PMID- 23935205 TI - Influenza A virus impairs control of Mycobacterium tuberculosis coinfection through a type I interferon receptor-dependent pathway. AB - Influenza followed by severe acute bacterial pneumonia is a major cause of mortality worldwide. Several mechanisms account for this enhanced susceptibility, including increased production of type I interferon (IFN). In individuals infected with Mycobacterium tuberculosis, the influence of acute viral infections on tuberculosis progression is unclear. We show that prior exposure of mice to influenza A virus, followed by M. tuberculosis infection, leads to enhanced mycobacterial growth and decreased survival. Following M. tuberculosis/influenza virus coinfection, mycobacterial growth is enhanced by a type I IFN signaling pathway. Our findings highlight the detrimental influence influenza virus infection can have before or during M. tuberculosis infection. PMID- 23935206 TI - Poorer survival of male breast cancer compared with female breast cancer patients may be due to biological differences. AB - OBJECTIVE: The objective of the study was to compare disease-free survival and overall survival in a group of matched males and females with breast cancer, and to analyze possible treatment- and gender-related differences. METHODS: We retrospectively analyzed the data of 150 operable male breast cancer patients treated in our hospital from December 1980 to June 2012. Each male breast cancer patient recorded in the database was matched with two female breast cancer patients of equal stage. Prognosis in terms of disease-free survival and overall survival was evaluated. RESULTS: The mean age at diagnosis was 58.6 +/- 9.7 years for males and 57.2 +/- 10.3 years for females. The median follow-up was 69 months for males and 81 months for females. Significant differences were identified for tumor location, hormone receptor status, molecular subtypes and hormone therapy between the two groups. Monofactorial analysis demonstrated that tumor size, lymph node state, American Joint Committee on Cancer stage, molecular subtypes and adjuvant chemotherapy treatment were prognostic factors in male breast cancer patients. The 5- and 10-year disease-free survival rates were 65.6 and 40.1% for males, and 74.9 and 51.5% for females, respectively. The 5- and 10-year overall survival rates were 72.9 and 53.9% for males, and 83.2 and 68.5% for females, respectively. There was significantly difference in disease-free survival and overall survival between the two matched groups (P = 0.002). CONCLUSIONS: Male breast cancer patients had inferior outcome despite of equal stage in comparison with matched female breast cancer patients, which demonstrates that biological differences may contribute to the worse prognosis. PMID- 23935207 TI - Neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy for poor-risk rectal cancer: N-SOG 03 Phase II trial. AB - OBJECTIVE: This Phase II trial was designed to evaluate the safety and efficacy of neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy in patients with poor-risk rectal cancer. METHODS: Patients with magnetic resonance imaging-defined poor-risk rectal cancer received neoadjuvant oxaliplatin and capecitabine and bevacizumab followed by total mesorectal excision or more extensive surgery. RESULTS: Between February 2010 and December 2011, 32 patients were enrolled in this study. The completion rate of the scheduled chemotherapy was 91%. Reasons for withdrawal were refusal to continue therapy in two patients and disease progression in one, with two of these three patients not undergoing surgery. Among the 29 patients who completed the scheduled chemotherapy, one refused surgery within 8 weeks after the completion of chemotherapy, which was the period stipulated by the protocol, and another had rectal perforation, requiring urgent laparotomy. As a result, the completion rate of this experimental treatment was 84%. Of the 30 patients who underwent surgery, the R0 resection rate was 90% and a postoperative complication occurred in 43%. A pathological complete response was observed in 13% and good tumor regression was exhibited in 37%. CONCLUSIONS: Neoadjuvant oxaliplatin and capecitabine plus bevacizumab for poor-risk rectal cancer caused a high rate of anastomotic leakage and experienced a case with perforation during chemotherapy, both of which were bevacizumab-related toxicity. Although the short-term results with the completion rate of 84.4% and the pathological complete response rate of 13.3% were satisfactory, we have to reconsider the necessity of bevacizumab in neoadjuvant chemotherapy (UMIN number, 000003507). PMID- 23935209 TI - Sword, Shield and Buoys: A History of the NATO Sub-Committee on Oceanographic Research, 1959-1973. AB - In the late 1950s the North-Atlantic Treaty Organization (NATO) made a major effort to fund collaborative research between its member states. One of the first initiatives following the establishment of the alliance's Science Committee was the creation of a sub-group devoted to marine science: the Sub-committee on Oceanographic Research.This paper explores the history of this organization, charts its trajectory over the 13 years of its existence, and considers its activities in light of NATO's naval defence strategies. In particular it shows how the alliance's naval commands played a key role in the sub-committee's creation due to the importance of oceanographic research in the tracking of enemy submarines. The essay also scrutinizes the reasons behind the committee's dissolution, with a special focus on the changing landscape of scientific collaboration at NATO. The committee's fall maps onto a more profound shift in the alliance's research agenda, including the re-organization of defence research and the rise of environmentalism. PMID- 23935210 TI - Computing the partition function, ensemble averages, and density of states for lattice spin systems by sampling the mean. AB - An algorithm to approximately calculate the partition function (and subsequently ensemble averages) and density of states of lattice spin systems through non Monte-Carlo random sampling is developed. This algorithm (called the sampling-the mean algorithm) can be applied to models where the up or down spins at lattice nodes interact to change the spin states of other lattice nodes, especially non Ising-like models with long-range interactions such as the biological model considered here. Because it is based on the Central Limit Theorem of probability, the sampling-the-mean algorithm also gives estimates of the error in the partition function, ensemble averages, and density of states. Easily implemented parallelization strategies and error minimizing sampling strategies are discussed. The sampling-the-mean method works especially well for relatively small systems, systems with a density of energy states that contains sharp spikes or oscillations, or systems with little a priori knowledge of the density of states. PMID- 23935211 TI - Acculturation of Personality: A Three-Culture Study of Japanese, Japanese Americans, and European Americans. AB - The present study tests the hypothesis that involvement with a new culture instigates changes in personality of immigrants that result in (a) better fit with the norms of the culture of destination and (b) reduced fit with the norms of the culture of origin. Participants were 40 Japanese first-generation immigrants to the United States, 57 Japanese monoculturals, and 60 U.S. monoculturals. All participants completed the Jackson Personality Inventory (JPI) as a measure of the Big Five; immigrants completed the Japanese American Acculturation Scale. Immigrants' fits with the cultures of destination and origin were calculated by correlating Japanese American mothers' patterns of ratings on the Big Five with the average patterns of ratings of European Americans and Japanese on the same personality dimensions. Japanese Americans became more "American" and less "Japanese" in their personality as they reported higher participation in the U.S. culture. The results support the view that personality can be subject to cultural influence. PMID- 23935208 TI - G protein-coupled receptor kinase-3-deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses. AB - Chemokine receptor interactions coordinate leukocyte migration in inflammation. Chemokine receptors are GPCRs that when activated, are phosphorylated by GRKs to turn off G protein-mediated signaling yet recruit additional signaling machinery. Recently, GRK3 was identified as a negative regulator of CXCL12/CXCR4 signaling that is defective in human WHIM syndrome. Here, we report that GRK3-/- mice exhibit numerous features of human WHIM, such as impaired CXCL12-mediated desensitization, enhanced CXCR4 signaling to ERK activation, altered granulocyte migration, and a mild myelokathexis. Moreover, GRK3-/- protects mice from two acute models of inflammatory arthritis (K/BxN serum transfer and CAIA). In these granulocyte-dependent disease models, protection of GRK3-/- mice is mediated by retention of cells in the marrow, fewer circulating granulocytes in the peripheral blood, and reduced granulocytes in the joints during active inflammation. In contrast to WHIM, GRK3-/- mice have minimal hypogammaglobulinemia and a peripheral leukocytosis with increased lymphocytes and absent neutropenia. Thus, we conclude that the loss of GRK3-mediated regulation of CXCL12/CXCR4 signaling contributes to some, but not all, of the complete WHIM phenotype and that GRK3 inhibition may be beneficial in the treatment of inflammatory arthritis. PMID- 23935212 TI - Barriers to Implementing Individualized Substance Abuse Treatment: Qualitative Findings from the CASPAR Replication Studies. AB - Problem-to-services matching is critical to patient-centered care. Further, the extent to which substance abuse treatment is individualized to meet specific client needs is a key predictor of success and represents "best practice" in substance abuse treatment. The CASPAR Resource Guide, an electronic database of local free and low-cost services, is an evidence-based tool designed to help counselors easily and quickly provide offsite referrals to services not available in most community treatment programs to increase problem-to-service matching. This paper examines system-level barriers to using the CASPAR Resource Guide among 30 counselors and 21 site directors across 16 sites in two different studies. Results from qualitative implementation analyses found that key program components needed to support the implementation of this evidence-based practice (e.g., individualized treatment planning, individual treatment sessions, and individual counselor supervision) were lacking, which jeopardized successful adoption of the CASPAR research interventions and prompted a redesign of the studies in order to enhance each program's ability to support individualized care. PMID- 23935213 TI - Fluorine-Containing Taxoid Anticancer Agents and Their Tumor-Targeted Drug Delivery. AB - A long-standing problem of conventional chemotherapy is the lack of tumor specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Consequently, various "molecularly targeted cancer therapies" have been developed for use in specific cancers, including tumor-targeting drug delivery systems. In general, such a drug delivery system consists of a tumor recognition moiety and a cytotoxic "warhead" connected through a "smart" linker to form a conjugate. When a multi-functionalized nanomaterial is used as the vehicle, a "Trojan Horse" approach can be used for mass delivery of cytotoxic "warheads" to maximize the efficacy. Exploitation of the special properties of fluorine has proven successful in the development of new and effective biochemical tools as well as therapeutic agents. Fluorinated congeners can also serve as excellent probes for the investigation of biochemical mechanisms. 19F-NMR can provide unique and powerful tools for mechanistic investigations in chemical biology. This account presents our recent progress, in perspective, on the molecular approaches to the design and development of novel tumor-targeted drug delivery systems for new generation chemotherapy by exploiting the unique nature of fluorine. PMID- 23935214 TI - Parental Financial Assistance and Young Adults' Relationships With Parents and Well-Being. AB - Drawing on data from the National Longitudinal Study of Adolescent Health, this study examined the impact of parental financial assistance on young adults' relationships with parents and well-being. Conditional change models were estimated to evaluate the effects of parental financial assistance reported in Wave 3 (ages 18 - 26) and Wave 4 (ages 24 - 32) of the study. The results (Ns ranged from 9,128 to 13,389 across outcomes) indicated that financial assistance was positively associated with changes in depressive symptoms and closeness to both mothers and fathers in both periods. Changes in self-esteem were less robustly linked to parental financial assistance. Although the observed pattern with respect to parent - child relations held regardless of the progress young people had made in the transition to adulthood, the effects for well-being, which were also relatively small in magnitude, did not. In particular, changes in depressive symptoms associated with financial assistance were concentrated among individuals occupying adult social roles. PMID- 23935215 TI - High-pressure synthesis and characterization of the first cerium fluoride borate CeB2O4F. AB - CeB2O4F is the first cerium fluoride borate, which is exclusively built up of one dimensional, infinite chains of condensed trigonal-planar [BO3]3- groups. This new cerium fluoride borate was synthesized under high-pressure/high-temperature conditions of 0.9 GPa and 1450 degrees C in a Walker-type multianvil apparatus. The compound crystallizes in the orthorhombic space group Pbca (No. 61) with eight formula units and the lattice parameters a=821.63(5), b=1257.50(9), c=726.71(6) pm, V=750.84(9) A3, R1=0.0698, and wR2=0.0682 (all data). The structure exhibits a 9+1 coordinated cerium ion, one three-fold coordinated fluoride ion and a one-dimensional chain of [BO3]3- groups. Furthermore, IR spectroscopy, Electron Micro Probe Analysis and temperature-dependent X-ray powder diffraction measurements were performed. PMID- 23935216 TI - Nanoporous gold as a solid support for protein immobilization and development of an electrochemical immunoassay for prostate specific antigen and carcinoembryonic antigen. AB - Nanoporous gold (NPG) was utilized as a support for immobilizing alkaline phosphatase (ALP) conjugated to monoclonal antibodies against either prostate specific antigen (PSA) or carcinoembryonic antigen (CEA). The antibody-ALP conjugates were coupled to self-assembled monolayers of lipoic acid and used in direct kinetic assays. Using the enzyme substrate p-aminophenylphosphate, the product p-aminophenol was detected by its oxidation near 0.1 V (vs. Ag|AgCl) using square wave voltammetry. The difference in peak current arising from oxidation of p-aminophenol before and after incubation with biomarker increased with biomarker concentration. The response to these two biomarkers was linear up to 10 ng mL-1 for CEA and up to 30 ng mL-1 for PSA. The effect of interference on the PSA assay was studied using bovine serum albumin (BSA) as a model albumin protein. The effect of interference from a serum matrix was examined for the PSA assay using newborn calf serum. A competitive version of the immunoassay using antigen immobilized onto the NPG surface was highly sensitive at lower antigen concentration. Estimates of the surface coverage of the antibody-ALP conjugates on the NPG surface are presented. PMID- 23935217 TI - Portage and Path Dependence. AB - We examine portage sites in the U.S. South, Mid-Atlantic, and Midwest, including those on the fall line, a geomorphological feature in the southeastern U.S. marking the final rapids on rivers before the ocean. Historically, waterborne transport of goods required portage around the falls at these points, while some falls provided water power during early industrialization. These factors attracted commerce and manufacturing. Although these original advantages have long since been made obsolete, we document the continuing importance of these portage sites over time. We interpret these results as path dependence and contrast explanations based on sunk costs interacting with decreasing versus increasing returns to scale. PMID- 23935218 TI - A penalized likelihood approach to estimate within-household contact networks from egocentric data. AB - Acute infectious diseases are transmitted over networks of social contacts. Epidemic models are used to predict the spread of emergent pathogens and compare intervention strategies. Many of these models assume equal probability of contact within mixing groups (homes, schools, etc.), but little work has inferred the actual contact network, which may influence epidemic estimates. We develop a penalized likelihood method to infer contact networks within households, a key area for disease transmission. Using egocentric surveys of contact behavior in Belgium, we estimate within-household contact networks for six different age compositions. Our estimates show dependency in contact behavior and vary substantively by age composition, with fewer contacts occurring in older households. Our results are relevant for epidemic models used to make policy recommendations. PMID- 23935219 TI - Migration, Remittances, and Educational Stratification among Blacks in Apartheid and Post-Apartheid South Africa. AB - This paper extends previous work on family structure and children's education by conceptualizing migration as a distinct form of family disruption that reduces parental input but brings substantial economic benefits through remittances. It examines the multiple and countervailing effects of migration on schooling in the context of substantial migration and limited educational opportunities for Blacks in South Africa. The receipt of remittances substantially increases Black children's school attendance, but has no such effect for Whites. The effect for Blacks is in part attributable to improved household economic conditions that increase household educational spending and reduce the demand for child labor. We also find a negative effect of parental absence due to migration, but it is largely cushioned by inflows of remittances. Sensitivity analyses using propensity score methods and contextual fixed-effect modeling suggest that the beneficial effect of remittances is relatively robust. We find further that remittances help ameliorate inter-familial socioeconomic inequality in schooling. Finally, we evaluate possible temporal changes and show that the positive and equalizing effects of remittances persisted during and after the apartheid regime. We conclude that labor migration and remittances, as institutionalized family strategies adopted by many Blacks, help reconfigure structural opportunities in the educational stratification process in South Africa. PMID- 23935220 TI - Falling Further Behind? Child Support Arrears and Fathers' Labor Force Participation. AB - This study examines how child support arrears affect fathers' labor force participation. It relies on longitudinal data from the Fragile Families and Child Well-Being Study. Findings from analyses of these data suggest that child support arrears result in declines in average weeks worked in the formal labor market in subsequent time periods. These findings are driven by the behaviors of fathers who had relatively high amounts of arrears and no income in the previous year and are mostly robust to tests for selection into no work or low levels of work by fathers. Findings also suggest that arrears obligations that are low relative to income result in increases in the probability that fathers engage in any formal work. Arrears are not statistically significantly related to informal labor force participation. This study highlights both intended and unintended consequences of the growth in arrears under current child support enforcement policies. PMID- 23935221 TI - Synthesis and characterization of 2-substituted bornane pharmacophores for novel cannabinergic ligands. AB - Analogously to the fenchyl and adamantyl groups, the bornyl and epimeric isobornyl groups are compact lipophilic substituents that can be incorporated into drug design to improve pharmacological or physicochemical properties. Methods are reported for the synthesis and characterization of 2-substituted norbornanes and bornanes that can serve as novel cannabinergic ligand intermediates. PMID- 23935222 TI - Improved synthesis of N1-substituted orotic acid derivatives. AB - An improved method for the synthesis of N1-substituted orotic acid derivatives is reported. The method involves sequential incorporation of nitrogen atoms to the pyrimidine structure from simple starting materials and thus allows the synthesis of N1-substituted orotic acid derivatives with single 15N label at either N-1 or N-3. PMID- 23935223 TI - Simplified synthesis of individual stereoisomers of the 4-hydroxynonenal adducts of deoxyguanosine. AB - We previously reported the synthesis of the 1,N2-deoxyguanosine adducts of 4 hydroxynonenal, an important product of lipid peroxidation, which involved the nucleophilic aromatic substitution reaction of an O6-protected-2-fluoroinosine with 4-amino-1,2,5-trihydroxydecanal followed by periodate oxidation of the vicinal diol.3 An improved synthesis of the amino triols has been developed. The syn and anti diasteromers of a key intermediate, 4-nitro-5-hydroxy-1-decene, were synthesized by a Henry reaction and separated; each diastereomer was further separated into individual enantiomers by chiral supercritical fluid chromatography. Of note, dihydroxylation of the terminal olefin under conventional conditions with catalytic OsO4 and a tertiary amine oxide as the stoichiometric oxidant led to scrambling of stereochemistry at C4. The scrambling was not observed when t-butylhydroperoxide was used as the oxidant. PMID- 23935224 TI - An efficient procedure for the preparation of natural products bearing the 2-(2 phenylethyl)chromone skeleton. AB - Several 2-(2-phenylethyl)chromones have been shown to possess neuroprotective activity. However, limited synthetic methods have been disclosed to construct the 2-(2-phenylethyl)chromone skeleton. Herein we report a straightforward 3-step preparation of five naturally occurring 2-(2-phenylethyl)chromones utilizing the Claisen condensation as the key step. PMID- 23935225 TI - Estimation of water retention parameters from nuclear magnetic resonance relaxation time distributions. AB - [1] For characterizing water flow in the vadose zone, the water retention curve (WRC) of the soil must be known. Because conventional WRC measurements demand much time and effort in the laboratory, alternative methods with shortened measurement duration are desired. The WRC can be estimated, for instance, from the cumulative pore size distribution (PSD) of the investigated material. Geophysical applications of nuclear magnetic resonance (NMR) relaxometry have successfully been applied to recover PSDs of sandstones and limestones. It is therefore expected that the multiexponential analysis of the NMR signal from water-saturated loose sediments leads to a reliable estimation of the WRC. We propose an approach to estimate the WRC using the cumulative NMR relaxation time distribution and approximate it with the well-known van-Genuchten (VG) model. Thereby, the VG parameter n, which controls the curvature of the WRC, is of particular interest, because it is the essential parameter to predict the relative hydraulic conductivity. The NMR curves are calibrated with only two conventional WRC measurements, first, to determine the residual water content and, second, to define a fixed point that relates the relaxation time to a corresponding capillary pressure. We test our approach with natural and artificial soil samples and compare the NMR-based results to WRC measurements using a pressure plate apparatus and to WRC predictions from the software ROSETTA. We found that for sandy soils n can reliably be estimated with NMR, whereas for samples with clay and silt contents higher than 10% the estimation fails. This is the case when the hydraulic properties of the soil are mainly controlled by the pore constrictions. For such samples, the sensitivity of the NMR method for the pore bodies hampers a plausible WRC estimation. Citation: Costabel, S., and U. Yaramanci (2013), Estimation of water retention parameters from nuclear magnetic resonance relaxation time distributions, Water Resour. Res., 49, 2068-2079, doi:10.1002/wrcr.20207. PMID- 23935226 TI - INFORMAL SOCIAL SUPPORT AND DEPRESSION AMONG AFRICAN AMERICAN MEN WHO HAVE SEX WITH MEN. AB - Men who have sex with men (MSM) experience greater mental health problems as compared with heterosexual populations. Informal social support plays a critical role in emotional well-being. The primary goal of this article is to examine the relationship between depressive symptoms and received social support from family, friends, and sex partners within the social network from a sample of 188 African American MSM in Baltimore, Maryland. We found that receiving emotional support from a family member or a sex partner was associated with reduced odds of having depressive symptoms. Receiving financial support from a family member or a friend was associated with increased odds of having depressive symptoms. The results suggest the importance of emotional support provided by family and sex partner in mental health and the potential value of training African American MSM in skills to enhance the quality of the relationships. PMID- 23935228 TI - Photochromic copolymers containing 3-indolylfulgides/indolylfulgimides: synthesis and photochemical properties in toluene and as films. AB - Photochromic indolylfulgimides covalently attached to polymers have beneficial properties for optical switching. A 3-indolylfulgide and two 3-indolylfulgimides with one or two polymerizable styrene groups attached on the nitrogen atom(s) were synthesized. Copolymerization with methyl methacrylate (MMA) provided linear copolymers (one styrene group) or a cross-linked copolymer (two styrene groups). The properties of the monomers and copolymers in toluene or as thin films were characterized. The new copolymers were photochromic (reversible Z-to-C isomerization), absorbed visible light, and revealed good thermal and photochemical stability. At room temperature, all copolymer films showed no loss of absorbance after 5 weeks. At 80 degrees C in either toluene or as films, the Z-forms copolymers were less stable than the C-form copolymers, which showed little or no degradation after 400 h. The degradation rate due to repeated ring closing - ring opening cycles was less than 3% per 100 cycles. The cross-linked copolymer showed photochemical stability comparable to monomeric fulgides in toluene, <1% per 100 cycles. In general, the properties of the linear and cross linked copolymers were similar to the corresponding monomers in toluene. In films, the conformations of the Z-form were restricted due to the matrix indicating that the preparation of films from the C-form is advantageous. PMID- 23935227 TI - Boys' and Girls' Relational and Physical Aggression in Nine Countries. AB - Distinguishing between relational and physical aggression has become a key feature of many developmental studies in North America and Western Europe, but very little information is available on relational and physical aggression in more diverse cultural contexts. This study examined the factor structure of, associations between, and gender differences in relational and physical aggression in China, Colombia, Italy, Jordan, Kenya, the Philippines, Sweden, Thailand, and the United States. Children ages 7-10 years (N = 1,410) reported on their relationally and physically aggressive behavior. Relational and physical aggression shared a common factor structure across countries. In all nine countries, relational and physical aggression were significantly correlated (average r = .49). Countries differed in the mean levels of both relational and physical aggression that children reported using and with respect to whether children reported using more physical than relational aggression or more relational than physical aggression. Boys reported being more physically aggressive than girls across all nine countries; no consistent gender differences emerged in relational aggression. Despite mean-level differences in relational and physical aggression across countries, the findings provided support for cross country similarities in associations between relational and physical aggression as well as links between gender and aggression. PMID- 23935229 TI - Trials and Tribulations: The 'Use' (and 'Misuse') of Evidence in Public Policy. AB - Randomized controlled trials (RCTs) are increasingly playing a central role in shaping policy for development. By comparison, social experimentation has not driven the great transformation of welfare within the developed world. This introduces a range of issues for those interested in the nature of research evidence for making policy. In this article we will seek a greater understanding of why the RCT is increasingly seen as the 'gold standard' for policy experiments in low- and middle-income countries (LMICs), but not in the more advanced liberal democracies, and we will explore the implications of this. One objection to the use of RCTs, however can be cost, but implementing policies and programmes without good evidence or a good understanding of their effectiveness is unlikely to be a good use of resources either. Other issues arise. Trials are often complex to run and ethical concerns often arise in social 'experiments' with human subjects. However, rolling out untested policies may also be morally objectionable. This article sheds new light on the relationship between evidence and evaluation in public policy in both the global north and developing south. It also tackles emerging issues concerning the 'use' and 'misuse' of evidence and evaluation within public policy. PMID- 23935230 TI - Longitudinal tests on the influence of achievement goals on effort and intrinsic interest in the workplace. AB - This study investigates whether four types of achievement goals-mastery-approach, mastery-avoidance, performance-approach, and performance-avoidance-influence effort and intrinsic interest at work. Cross-lagged panel analyses were applied to data from a two-wave survey conducted on 57 newly hired Japanese police officers. The results showed that performance-approach goals had significant positive influences on effort and intrinsic interest. In contrast, performance avoidance goals had significant negative impacts on the abovementioned two outcome variables. Longitudinal effects were observed when the influence of competence expectancy was controlled. These results highlight the benefits of performance-approach goals and the costs associated with performance-avoidance goals in the workplace. PMID- 23935231 TI - Neural Correlates of Three Neurocognitive Intervention Strategies: A Preliminary Step Towards Personalized Treatment for Psychological Disorders. AB - Brain-based behavioral interventions targeting specific neurocognitive mechanisms show initial promise in the treatment of emotional disorders, but personalization of such approaches will be facilitated if brain targets are empirically established. As a preliminary step, we conducted a proof-of-concept study to test whether particular emotion regulatory neural circuitry can be differentially targeted by specific neurocognitive tasks, and whether these tasks effectively inhibit amygdala activity. Eleven healthy individuals underwent an idiographic sadness and guilt induction. Brain response was measured via fMRI during 4 subsequent emotion regulation conditions: fixation, cognitive reappraisal (selected to target the ventrolateral prefrontal cortex), working memory practice (selected to target the dorsolateral prefrontal cortex), and visual distraction (Tetris; selected to target occipital cortex). In whole-brain comparisons to fixation, hypotheses were upheld. Reappraisal uniquely activated left ventrolateral prefrontal cortex, working memory practice uniquely activated left dorsolateral prefrontal cortex, and Tetris uniquely activated bilateral occipitoparietal cortex, activations that were largely robust at the single subject level. All tasks inhibited amygdala activity relative to fixation. Data support examining whether repeated exposure to these tasks in psychiatric patients affects neural abnormalities implicated in emotional disorders. Ideally, psychiatric treatment will be accelerated by matching specific treatments to patients with specific neural profiles. PMID- 23935232 TI - An adaptive truncated product method for combining dependent p-values. AB - We propose an adaptive truncated product method that facilitates the selection of the truncation point among a set of candidates. To efficiently estimate the distribution of the proposed method when the p-values are correlated, we develop a single-layer bootstrap procedure. PMID- 23935233 TI - Using Discrete-time Event History Fertility Models to Simulate Total Fertility Rates and Other Fertility Measures. AB - Event history models, also known as hazard models, are commonly used in analyses of fertility. One drawback of event history models is that the conditional probabilities (hazards) estimated by event history models do not readily translate into summary measures, particularly for models of repeatable events, like childbirth. In this paper, we describe how to translate the results of discrete-time event history models of all births into well-known summary fertility measures: simulated age- and parity-specific fertility rates, parity progression ratios (PPRs), and the total fertility rate (TFR). The method incorporates all birth intervals, but permits the hazard functions to vary across parities. It also can simulate values for groups defined by both fixed and time varying covariates, such as marital or employment life histories. We demonstrate the method using an example from the National Survey of Family Growth (NSFG) and provide an accompanying data file and Stata program. PMID- 23935234 TI - A Longitudinal Examination of Risk and Protective Factors Associated with Drug Use and Unsafe Sex among Young African American Females. AB - This study prospectively examined associations among multiple theoretically informed risk (e.g., depression, sexual sensation seeking, and risky peers norms) and protective factors (e.g., social support, STI knowledge, and refusal to have sex self efficacy) on unsafe sex among 715 African American adolescent females aged 15-21 who participated in an STI/HIV prevention intervention. Generalized estimating equation models were used to assess associations between baseline characteristics and sexual risk over a 12-month follow up period. Overall risk in this population was high: at baseline, nearly a third of women reported sex under the influence of alcohol or substances; >= 2 partners for vaginal sex, and casual sex partners in the 60 days prior to baseline, and nearly 75% of those reporting vaginal sex used condoms inconsistently. In multivariable analysis, when risk and protective factors were simultaneously considered, higher levels of sexual sensation seeking were associated with having multiple sex partners and inconsistent condom use. Greater perception of risky peer norms was associated with a higher risk of having sex under the influence of alcohol or drugs. In addition, higher sex refusal self-efficacy was protective against having multiple; casual; and concurrent sex partners. Incorporating these salient factors into prevention programs may be critical to the development of targeted interventions for this population. PMID- 23935235 TI - Not all risk taking behavior is bad: Associative sensitivity predicts learning during risk taking among high sensation seekers. AB - Risk taking behavior can be both adaptive and maladaptive depending on context. The majority of studies of risk taking, however, focus on clinical populations and dangerous or harmful risk taking. Individual differences in learning during risk taking are rarely examined in relation to task performance. The present study examined risk taking and associated outcomes in an exploration-based instrumental learning task (Balloon Emotional Learning Task; BELT), which presented a series of balloons in which participants pump up for points. Consistent with prior work, sensation seeking predicted increased risk taking behavior. Importantly, however, a significant interaction between sensation seeking and associative sensitivity, an attentional construct defined as the frequency and remoteness of automatic cognitive activity, was found. Specifically, among individuals high in sensation seeking, associative sensitivity predicted fewer balloon explosions and an increase in points earned on the balloon condition with the most potential feedback driven learning. Thus, these findings suggest that sensation seekers are a heterogeneous group, and secondary traits such as associative sensitivity moderate behavior such as risk taking and learning according to context. PMID- 23935236 TI - Hispanic heterogeneity and environmental injustice: Intra-ethnic patterns of exposure to cancer risks from traffic-related air pollution in Miami. PMID- 23935237 TI - Continental estimates of forest cover and forest cover changes in the dry ecosystems of Africa between 1990 and 2000. AB - AIM: This study provides regional estimates of forest cover in dry African ecoregions and the changes in forest cover that occurred there between 1990 and 2000, using a systematic sample of medium-resolution satellite imagery which was processed consistently across the continent. LOCATION: The study area corresponds to the dry forests and woodlands of Africa between the humid forests and the semi arid regions. This area covers the Sudanian and Zambezian ecoregions. METHODS: A systematic sample of 1600 Landsat satellite imagery subsets, each 20 km * 20 km in size, were analysed for two reference years: 1990 and 2000. At each sample site and for both years, dense tree cover, open tree cover, other wooded land and other vegetation cover were identified from the analysis of satellite imagery, which comprised multidate segmentation and automatic classification steps followed by visual control by national forestry experts. RESULTS: Land cover and land-cover changes were estimated at continental and ecoregion scales and compared with existing pan-continental, regional and local studies. The overall accuracy of our land-cover maps was estimated at 87%. Between 1990 and 2000, 3.3 million hectares (Mha) of dense tree cover, 5.8 Mha of open tree cover and 8.9 Mha of other wooded land were lost, with a further 3.9 Mha degraded from dense to open tree cover. These results are substantially lower than the 34 Mha of forest loss reported in the FAO's 2010 Global Forest Resources Assessment for the same period and area. MAIN CONCLUSIONS: Our method generates the first consistent and robust estimates of forest cover and change in dry Africa with known statistical precision at continental and ecoregion scales. These results reduce the uncertainty regarding vegetation cover and its dynamics in these previously poorly studied ecosystems and provide crucial information for both science and environmental policies. PMID- 23935238 TI - Distress Tolerance Scale: A Confirmatory Factor Analysis Among Daily Cigarette Smokers. AB - The present investigation evaluated the factor structure of the Distress Tolerance Scale (DTS; Simons and Gaher 2005) among a sample of 173 (54.9% males) daily cigarette smokers (M=16.64 cigarettes per day, SD=7.83). Comparison of a single higher-order model and a hierarchical multidimensional model was conducted using confirmatory factor analyses (CFA). In addition, evaluation of the internal consistency and convergent and discriminant validity of the better-fitting model was completed. CFA of the DTS indicated a single second-order factor of distress tolerance, and four lower-order factors including Tolerance, Appraisal, Absorption, and Regulation; each factor demonstrated acceptable levels of internal consistency. In addition, the DTS displayed good convergent and discriminant validity with theoretically relevant smoking and affect variables. Results are discussed in terms of explicating the latent structure of distress tolerance, as measured by the DTS, within the context of smoking research. PMID- 23935239 TI - The Relevance of Age of Onset to the Psychopathology of Social Phobia. AB - The present study aimed to examine the relevance of age of onset to the psychopathology of social phobia using a large clinical sample of 210 patients with social phobia. The two most common periods of onset were during adolescence (ages 14-17) and early childhood (prior to age 10). Structural regression modeling was used to test predictions that early onset social phobia would be associated with greater severity of the disorder, stronger current symptoms of depression and anxiety, greater functional impairment, and more pronounced levels of emotional disorder vulnerabilities (e.g., neuroticism/behavioral inhibition, extraversion, perceptions of control). Logistic regression was used to evaluate relationships between age of onset and the presence of acute and chronic stress at the time of onset. Results showed that earlier age of social phobia onset was associated with stronger current psychopathology, functional impairment, and emotional disorder vulnerabilities, and that later age of onset predicted the presence of an acutely stressful event around the time of disorder emergence. These results are discussed in regard to their clinical implications and congruence with prominent etiological models of the emotional disorders. PMID- 23935240 TI - Predictors of discrepancies between informants' ratings of preschool-aged children's behavior: An examination of ethnicity, child characteristics, and family functioning. AB - The present study examined predictors of discrepancies between mothers', fathers', and teachers' ratings of 3-year-old children's hyperactivity, attention problems, and aggression. Participants were families of 196 3-year-old children who took part in child and family assessments. Ethnicity was one of the most consistent predictors of discrepancies. African American mothers and fathers were more likely to rate their children's hyperactivity, attention problems, and aggression lower than teachers. In contrast, Latina mothers were more likely to rate their children as more hyperactive and inattentive than teachers. ADHD/ODD diagnoses, parental depression, number of children, and children's pre-academic skills were also predictive of discrepancies for some measures for some informants. These findings provide insight into factors that may contribute to informant discrepancies in ratings of preschool children. PMID- 23935241 TI - A Biochip with a 3D microfluidic architecture for trapping white blood cells. AB - We present a microfluidic biochip for trapping single white blood cells (WBCs). The novel biochip, microfabricated using standard surface micromachining processes, consists of an array of precisely engineered microholes that confine single cells in a tight, three dimensional space and mechanically immobilize them. A high (> 87%) trapping efficiency was achieved when WBC-containing samples were delivered to the biochip at the optimal pressure of 3 psi. The biochip can efficiently trap up to 7,500 cells, maintaining a high trapping efficiency even when the number of cells is extremely low (~200 cells). We believe that the developed biochip can be used as a standalone unit in a biology/clinical lab for trapping WBCs as well as other cell types and imaging them using a standard fluorescent microscope at the single cell level. Furthermore, it can be integrated with other miniaturized optical modules to construct a portable platform for counting a wide variety of cells and therefore it can be an excellent tool for monitoring human diseases at the point-of-care. PMID- 23935242 TI - Relation and interactions among reading fluency and competence for adult education learners. AB - Statistical analyses of data from an academically diverse sample of 276 adult basic and secondary education learners extends understanding of the relation of and interactions between oral reading fluency and reading competence indices. Significant interactions between total word rate and word error rate that differed in relation to two measures of reading competence suggest that adult literacy instructors should emphasize fluency instruction to a greater or lesser degree depending on whether the major goal of instruction is academic reading (e.g., being able to comprehend a textbook) or functional reading (e.g., being able to fill out a job application). PMID- 23935244 TI - Characterising cytokine gene expression signatures in patients with severe sepsis. AB - INTRODUCTION: Severe sepsis in humans may be related to an underlying profound immune suppressive state. We investigated the link between gene expression of immune regulatory cytokines and the range of illness severity in patients with infection and severe sepsis. METHODS: A prospective observational study included 54 ICU patients with severe sepsis, 53 patients with infection without organ failure, and 20 healthy controls. Gene expression in peripheral blood mononuclear cells (PBMC) was measured using real-time polymerase chain reaction. RESULTS: Infection differed from health by decreased expression of the IL2, and IL23 and greater expression of IL10 and IL27. Severe sepsis differed from infection by having decreased IL7, IL23, IFN gamma , and TNF alpha gene expression. An algorithm utilising mRNA copy number for TNF alpha , IFN gamma , IL7, IL10, and IL23 accurately distinguished sepsis from severe sepsis with a receiver operator characteristic value of 0.88. Gene expression was similar with gram-positive and gram-negative infection and was similar following medical and surgical severe sepsis. Severity of organ failure was associated with serum IL6 protein levels but not with any index of cytokine gene expression in PBMCs. CONCLUSIONS: Immune regulatory cytokine gene expression in PBMC provides a robust method of modelling patients' response to infection. PMID- 23935245 TI - Toll-like receptor 9 promotes cardiac inflammation and heart failure during polymicrobial sepsis. AB - BACKGROUND: Aim was to elucidate the role of toll-like receptor 9 (TLR9) in cardiac inflammation and septic heart failure in a murine model of polymicrobial sepsis. METHODS: Sepsis was induced via colon ascendens stent peritonitis (CASP) in C57BL/6 wild-type (WT) and TLR9-deficient (TLR9-D) mice. Bacterial load in the peritoneal cavity and cardiac expression of inflammatory mediators were determined at 6, 12, 18, 24, and 36 h. Eighteen hours after CASP cardiac function was monitored in vivo. Sarcomere length of isolated cardiomyocytes was measured at 0.5 to 10 Hz after incubation with heat-inactivated bacteria. RESULTS: CASP led to continuous release of bacteria into the peritoneal cavity, an increase of cytokines, and differential regulation of receptors of innate immunity in the heart. Eighteen hours after CASP WT mice developed septic heart failure characterised by reduction of end-systolic pressure, stroke volume, cardiac output, and parameters of contractility. This coincided with reduced cardiomyocyte sarcomere shortening. TLR9 deficiency resulted in significant reduction of cardiac inflammation and a sustained heart function. This was consistent with reduced mortality in TLR9-D compared to WT mice. CONCLUSIONS: In polymicrobial sepsis TLR9 signalling is pivotal to cardiac inflammation and septic heart failure. PMID- 23935243 TI - LOX-1, OxLDL, and atherosclerosis. AB - Oxidized low-density lipoprotein (OxLDL) contributes to the atherosclerotic plaque formation and progression by several mechanisms, including the induction of endothelial cell activation and dysfunction, macrophage foam cell formation, and smooth muscle cell migration and proliferation. Vascular wall cells express on their surface several scavenger receptors that mediate the cellular effects of OxLDL. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the main OxLDL receptor of endothelial cells, and it is expressed also in macrophages and smooth muscle cells. LOX-1 is almost undetectable under physiological conditions, but it is upregulated following the exposure to several proinflammatory and proatherogenic stimuli and can be detected in animal and human atherosclerotic lesions. The key contribution of LOX-1 to the atherogenic process has been confirmed in animal models; LOX-1 knockout mice exhibit reduced intima thickness and inflammation and increased expression of protective factors; on the contrary, LOX-1 overexpressing mice present an accelerated atherosclerotic lesion formation which is associated with increased inflammation. In humans, LOX 1 gene polymorphisms were associated with increased susceptibility to myocardial infarction. Inhibition of the LOX-1 receptor with chemicals or antisense nucleotides is currently being investigated and represents an emerging approach for controlling OxLDL-LOX-1 mediated proatherogenic effects. PMID- 23935246 TI - Systemic immune activation leads to neuroinflammation and sickness behavior in mice. AB - Substantial evidence indicates an association between clinical depression and altered immune function. Systemic administration of bacterial lipopolysaccharide (LPS) is commonly used to study inflammation-associated behavioral changes in rodents. In these experiments, we tested the hypothesis that peripheral immune activation leads to neuroinflammation and depressive-like behavior in mice. We report that systemic administration of LPS induced astrocyte activation in transgenic GFAP-luc mice and increased immunoreactivity against the microglial marker ionized calcium-binding adapter molecule 1 in the dentate gyrus of wild type mice. Furthermore, LPS treatment caused a strong but transient increase in cytokine levels in the serum and brain. In addition to studying LPS-induced neuroinflammation, we tested whether sickness could be separated from depressive like behavior by evaluating LPS-treated mice in a panel of behavioral paradigms. Our behavioral data indicate that systemic LPS administration caused sickness and mild depressive-like behavior. However, due to the overlapping time course and mild effects on depression-related behavior per se, it was not possible to separate sickness from depressive-like behavior in the present rodent model. PMID- 23935247 TI - Inhibitory effect of herbal remedy PERVIVO and anti-inflammatory drug sulindac on L-1 sarcoma tumor growth and tumor angiogenesis in Balb/c mice. AB - Anticancer activity of many herbs was observed for hundreds of years. They act as modifiers of biologic response, and their effectiveness may be increased by combining multiple herbal extracts . PERVIVO, traditional digestive herbal remedy, contains some of them, and we previously described its antiangiogenic activity. Numerous studies documented anticancer effects of nonsteroidal anti inflammatory drugs. We were the first to show that sulindac and its metabolites inhibit angiogenesis. In the present paper the combined in vivo effect of multicomponent herbal remedy PERVIVO and nonsteroidal anti-inflammatory drug sulindac on tumor growth, tumor angiogenesis, and tumor volume in Balb/c mice was studied. These effects were checked after grafting cells collected from syngeneic sarcoma L-1 tumors into mice skin. The strongest inhibitory effect was observed in experimental groups treated with PERVIVO and sulindac together. The results of our investigation showed that combined effect of examined drugs may be the best way to get the strongest antiangiogenic and antitumor effect. PMID- 23935248 TI - Parthenolide is neuroprotective in rat experimental stroke model: downregulating NF-kappaB, phospho-p38MAPK, and caspase-1 and ameliorating BBB permeability. AB - Inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Parthenolide (PN) has been proved to elicit a wide range of biological activities through its anti-inflammatory action in the treatment of migraine, arthritis, and atherosclerosis. To decide whether this effect applies to ischemic injury in brain, we therefore investigate the potential neuroprotective role of PN and the underlying mechanisms. Male Sprague Dawley rats were randomly divided into Saline, Vehicle, and PN groups and a permanent middle cerebral artery occlusion (MCAO) model was used. PN administered intraperitoneally immediately after cerebral ischemia and once daily on the following days. At time points after MCAO, neurological deficit, infarct volume, and brain water content were measured. Immunohistochemistry, western blot and RT PCR were used to analyze the expression of NF- kappa B and caspase-1 in ischemic brain tissue. Phospho-p38MAPK and claudin-5 were detected by western blot. The results indicated that PN dramatically ameliorated neurological deficit, brain water content, and infarct volume, downregulated NF- kappa B, phospho-p38MAPK, and caspase-1 expressions, and upregulated claudin-5 expression in ischemic brain tissue. CONCLUSIONS: PN protected the brain from damage caused by MCAO; this effect may be through downregulating NF- kappa B, phosho-p38MAPK, and caspase-1 expressions and ameliorating BBB permeability. PMID- 23935249 TI - Regulation and prognostic relevance of symmetric dimethylarginine serum concentrations in critical illness and sepsis. AB - In systemic inflammation and sepsis, endothelial activation and microvascular dysfunction are characteristic features that promote multiorgan failure. As symmetric dimethylarginine (SDMA) impacts vascular tension and integrity via modulating nitric oxide (NO) pathways, we investigated circulating SDMA in critical illness and sepsis. 247 critically ill patients (160 with sepsis, 87 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) and on day 7, in comparison to 84 healthy controls. SDMA serum levels were significantly elevated in critically ill patients at admission to ICU compared to controls and remained stably elevated during the first week of ICU treatment. The highest SDMA levels were found in patients with sepsis. SDMA levels closely correlated with disease severity scores, biomarkers of inflammation, and organ failure (renal, hepatic, and circulatory). We identified SDMA serum concentrations at admission as an independent prognostic biomarker in critically ill patients not only for short-term mortality at the ICU but also for unfavourable long-term survival. Thus, the significant increase of circulating SDMA in critically ill patients indicates a potential pathogenic involvement in endothelial dysfunction during sepsis and may be useful for mortality risk stratification at the ICU. PMID- 23935252 TI - Diagnostic value of dynamics serum sCD163, sTREM-1, PCT, and CRP in differentiating sepsis, severity assessment, and prognostic prediction. AB - OBJECTIVE: To describe the dynamics changes of sCD163, soluble serum triggering receptor expressed on myeloid cells-1 (sTREM-1), procalcitonin (PCT), and C reactive protein (CRP) during the course of sepsis, as well as their outcome prediction. PATIENTS AND METHODS: An SIRS group (30 cases) and a sepsis group (100 cases) were involved in this study. Based on a 28-day survival, the sepsis was further divided into the survivors' and nonsurvivors' groups. Serum sTREM-1, sCD163, PCT, CRP, and WBC counts were tested on days 1, 3, 5, 7, 10, and 14. RESULTS: On the ICU admission, the sepsis group displayed higher levels of sTREM 1, sCD163, PCT, and CRP than the SIRS group (P < 0.05). Although PCT and sTREM-1 are good markers to identify severity, sTREM-1 is more reliable, which proved to be a risk factor related to sepsis. During a 14-day observation, sCD163, sTREM-1, PCT, and SOFA scores continued to climb among nonsurvivors, while their WBC and CRP went down. Both sCD163 and SOFA scores are risk factors impacting the survival time. CONCLUSION: With regard to sepsis diagnosis and severity, sTREM-1 is more ideal and constitutes a risk factor. sCD163 is of a positive value in dynamic prognostic assessment and may be taken as a survival-impacting risk factor. PMID- 23935251 TI - Cellular and molecular mediators of neuroinflammation in the pathogenesis of Parkinson's disease. AB - Neuroinflammation is a host-defense mechanism associated with restoration of normal structure and function of the brain and neutralization of an insult. Increasing neuropathological and biochemical evidence from the brains of individuals with Parkinson's disease (PD) provides strong evidence for activation of neuroinflammatory pathways. Microglia, the resident innate immune cells, may play a major role in the inflammatory process of the diseased brain of patients with PD. Although microglia forms the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly affect neurons by releasing various molecular mediators such as inflammatory cytokines (tumor necrosis factor- alpha , interleukin [IL]-6, and IL-1 beta ), nitric oxide, prostaglandin E2, and reactive oxygen and nitrogen species. Moreover, recent studies have reported that activated microglia phagocytose not only damaged cell debris but also intact neighboring cells. This phenomenon further supports their active participation in self-enduring neuronal damage cycles. As the relationship between PD and neuroinflammation is being studied, there is a realization that both cellular and molecular mediators are most likely assisting pathological processes leading to disease progression. Here, we discuss mediators of neuroinflammation, which are known activators released from damaged parenchyma of the brain and result in neuronal degeneration in patients with PD. PMID- 23935253 TI - VEGF in the crosstalk between human adipocytes and smooth muscle cells: depot specific release from visceral and perivascular adipose tissue. AB - Adipose tissue secrets adipokines and fatty acids, which may contribute to obesity-associated vascular dysfunction and cardiovascular risk. This study investigated which factors are responsible for the synergistic effect of adipokine and oleic acid- (OA-) induced proliferation of human vascular smooth muscle cells (VSMC). Adipocyte-conditioned medium (CM) from human adipocytes induces proliferation of VSMC in correlation to its vascular endothelial growth factor (VEGF) content. CM increases VEGF-receptor (VEGF-R) 1 and 2 expression and VEGF secretion of VSMC, while OA only stimulates VEGF secretion. VEGF neutralization abrogates CM- and OA-induced proliferation and considerably reduces proliferation induced by CM and OA in combination. VEGF release is higher from visceral adipose tissue (VAT) of obese subjects compared to subcutaneous adipose tissue (SAT) and VAT from lean controls. Furthermore, VEGF release from VAT correlates with its proliferative effect. Perivascular adipose tissue (PAT) from type 2 diabetic patients releases significantly higher amounts of VEGF and induces stronger proliferation of VSMC as compared to SAT and SAT/PAT of nondiabetics. In conclusion, VEGF is mediating CM-induced proliferation of VSMC. As this adipokine is released in high amounts from VAT of obese patients and PAT of diabetic patients, VEGF might link adipose tissue inflammation to increased VSMC proliferation. PMID- 23935250 TI - Possible involvement of TLRs and hemichannels in stress-induced CNS dysfunction via mastocytes, and glia activation. AB - In the central nervous system (CNS), mastocytes and glial cells (microglia, astrocytes and oligodendrocytes) function as sensors of neuroinflammatory conditions, responding to stress triggers or becoming sensitized to subsequent proinflammatory challenges. The corticotropin-releasing hormone and glucocorticoids are critical players in stress-induced mastocyte degranulation and potentiation of glial inflammatory responses, respectively. Mastocytes and glial cells express different toll-like receptor (TLR) family members, and their activation via proinflammatory molecules can increase the expression of connexin hemichannels and pannexin channels in glial cells. These membrane pores are oligohexamers of the corresponding protein subunits located in the cell surface. They allow ATP release and Ca(2+) influx, which are two important elements of inflammation. Consequently, activated microglia and astrocytes release ATP and glutamate, affecting myelinization, neuronal development, and survival. Binding of ligands to TLRs induces a cascade of intracellular events leading to activation of several transcription factors that regulate the expression of many genes involved in inflammation. During pregnancy, the previous responses promoted by viral infections and other proinflammatory conditions are common and might predispose the offspring to develop psychiatric disorders and neurological diseases. Such disorders could eventually be potentiated by stress and might be part of the etiopathogenesis of CNS dysfunctions including autism spectrum disorders and schizophrenia. PMID- 23935255 TI - Individual Differences in Base Rate Neglect: A Fuzzy Processing Preference Index. AB - Little is known about individual differences in integrating numeric base-rates and qualitative text in making probability judgments. Fuzzy-Trace Theory predicts a preference for fuzzy processing. We conducted six studies to develop the FPPI, a reliable and valid instrument assessing individual differences in this fuzzy processing preference. It consists of 19 probability estimation items plus 4 "M Scale" items that distinguish simple pattern matching from "base rate respect." Cronbach's Alpha was consistently above 0.90. Validity is suggested by significant correlations between FPPI scores and three other measurers: "Rule Based" Process Dissociation Procedure scores; the number of conjunction fallacies in joint probability estimation; and logic index scores on syllogistic reasoning. Replicating norms collected in a university study with a web-based study produced negligible differences in FPPI scores, indicating robustness. The predicted relationships between individual differences in base rate respect and both conjunction fallacies and syllogistic reasoning were partially replicated in two web-based studies. PMID- 23935254 TI - Making a Case for Treatment Integrity as a Psychosocial Treatment Quality Indicator for Youth Mental Health Care. AB - Measures of treatment integrity are needed to advance clinical research in general and are viewed as particularly relevant for dissemination and implementation research. Although some efforts to develop such measures are underway, a conceptual and methodological framework will help guide these efforts. The purpose of this article is to demonstrate how frameworks adapted from the psychosocial treatment, therapy process, healthcare, and business literatures can be used to address this gap. We propose that components of treatment integrity (i.e., adherence, differentiation, competence, alliance, client involvement) pulled from the treatment technology and process literatures can be used as quality indicators of treatment implementation and thereby guide quality improvement efforts in practice settings. Further, we discuss how treatment integrity indices can be used in feedback systems that utilize benchmarking to expedite the process of translating evidence-based practices to service settings. PMID- 23935256 TI - Agriscience Student Engagement in Scientific Inquiry: Representations of Scientific Processes and Nature of Science. AB - Students' experiences with science integrated into agriscience courses contribute to their developing epistemologies of science. The purpose of this case study was to gain insight into the implementation of scientific inquiry in an agriscience classroom. Also of interest was how the tenets of the nature of science were reflected in the students' experiments. Participants included an agriscience teacher and her fifteen students who were conducting plant experiments to gain insight into the role of a gene disabled by scientists. Data sources included classroom observations, conversations with students, face-to-face interviews with the teacher, and students' work. Analysis of the data indicated that the teacher viewed scientific inquiry as a mechanical process with little emphasis on the reasoning that typifies scientific inquiry. Students' participation in their experiments also centered on the procedural aspects of inquiry with little attention to scientific reasoning. There was no explicit attention to the nature of science during the experiments, but the practice implied correct, incorrect, and underdeveloped conceptions of the nature of science. Evidence from the study suggests a need for collaboration between agriscience and science teacher educators to design and conduct professional development focused on scientific inquiry and nature of science for preservice and practicing teachers. PMID- 23935257 TI - Predator and prey activity levels jointly influence the outcome of long-term foraging bouts. AB - Consistent interindividual differences in behavior (i.e., "behavioral types") may be a key factor in determining the outcome of species interactions. Studies that simultaneously account for the behavioral types of individuals in multiple interacting species, such as predator-prey systems, may be particularly strong predictors of ecological outcomes. Here, we test the predator-prey locomotor crossover hypothesis, which predicts that active predators are more likely to encounter and consume prey with the opposing locomotor tendency. We test this hypothesis using intraspecific behavioral variation in both a predator and prey species as predictors of foraging outcomes. We use the old field jumping spider, Phidippus clarus (Araneae, Salticidae), and the house cricket, Acheta domesticus (Orthoptera, Gryllidae), as a model predator-prey system in laboratory mesocosm trials. Stable individual differences in locomotor tendencies were identified in both P. clarus and A. domesticus, and the outcome of foraging bouts depended neither on the average activity level of the predator nor on the average activity level of prey. Instead, an interaction between the activity level of spiders and crickets predicted spider foraging success and prey survivorship. Consistent with the locomotor crossover hypothesis, predators exhibiting higher activity levels consumed more prey when in an environment containing low-activity prey items and vice versa. This study highlights 1) the importance of intraspecific variation in determining the outcome of predator-prey interactions and 2) that acknowledging behavioral variation in only a single species may be insufficient to characterize the performance consequences of intraspecific trait variants. PMID- 23935258 TI - Short-Run Prosocial Behavior in Response to Receiving Corrections and Affirmations in Three Therapeutic Communities. AB - Therapeutic communities (TC s) have a strong record of maintaining a high quality social climate on prison units. One possible reason for this is the system of mutual monitoring among TC residents, based on the assumption that peer affirmation of behavior in accord with TC norms and peer correction of behavior contrary to TC norms will lead to increased resident prosocial behavior. Laboratory experiments have demonstrated that such peer monitoring can lead to cooperation, but there has been no quantitative test of this hypothesis in an actual TC. In this article we test this assumption by using the affirmations that residents of three different TCs send as a measure of prosocial behavior following the reception of peer affirmations and corrections. At all three facilities residents send more affirmations following the reception of both affirmations and corrections, with this relationship being stronger and longer lasting after receiving affirmations. No other variable consistently predicts the number of affirmations that residents send to peers. These findings imply that mutual monitoring among TC residents can lead to increased levels of prosocial behavior within the facility, and that prosocial behavior in response to peer affirmations plays a key role. PMID- 23935260 TI - Intradiverticular ampulla of vater: personal experience at ERCP. AB - Introduction. Conflicting results have been reported about the true impact of intradiverticula ampulla (IA) on the technical success and complication rate of endoscopic retrograde cholangiopancreatography (ERCP). Patients. A total of 500 patients who underwent ERCP were divided into two groups according to the presence (group A, 81 patients) or absence (group B, 419 patients) of IA. Success rate, difficulty at cannulation, findings at ERCP, and procedure-related complications were retrospectively reviewed. Results. Successful cannulation was achieved in 100% of group A patients compared to 98% of group B patients (P = ns). There was a significant difference in the type of cannulation that was routinary in group B (P < 0.05), while requiring guidewire in group A (P < 0.05). Cholangitis (P < 0.05), microstones (P < 0.01), dilated common bile duct without stones (P < 0.01), stone recurrence (P < 0.01), and transient postprocedure hyperamylasemia (P < 0.01) were more frequently observed in group A. There was no significant difference in complication rate between both groups. Conclusions. The finding of an IA at ERCP should not be considered a predictor for failed cannulation. IA is associated with post-ERCP transient hyperamylasemia and is a risk factor for biliary stone disease and its recurrence. PMID- 23935259 TI - Pregnancy and susceptibility to infectious diseases. AB - To summarize the literature regarding susceptibility of pregnant women to infectious diseases and severity of resulting disease, we conducted a review using a PubMed search and other strategies. Studies were included if they reported information on infection risk or disease outcome in pregnant women. In all, 1454 abstracts were reviewed, and a total of 85 studies were included. Data were extracted regarding number of cases in pregnant women, rates of infection, risk factors for disease severity or complications, and maternal outcomes. The evidence indicates that pregnancy is associated with increased severity of some infectious diseases, such as influenza, malaria, hepatitis E, and herpes simplex virus (HSV) infection (risk for dissemination/hepatitis); there is also some evidence for increased severity of measles and smallpox. Disease severity seems higher with advanced pregnancy. Pregnant women may be more susceptible to acquisition of malaria, HIV infection, and listeriosis, although the evidence is limited. These results reinforce the importance of infection prevention as well as of early identification and treatment of suspected influenza, malaria, hepatitis E, and HSV disease during pregnancy. PMID- 23935261 TI - Clinical Application and Outcomes of Over the Scope Clip Device: Initial US Experience in Humans. AB - Background. OTSCs are now available in the US for various indications. Methods. Retrospective review of OTSCs used from January 2011 to April 2012. Results. Twenty-four patients underwent placement of 28 OTSCs. Indications included postsurgical fistula, perforations, anastomotic leak, prophylactic closure after EMR, postpolypectomy bleeding, tracheoesophageal fistula, and jejunostomy site leak. Instruments used to grasp the tissue were dedicated (bidirectional forceps or tripronged device) and nondedicated devices (rat/alligator forceps or suction). Success was higher with nondedicated devices (12.5% versus 86.5%, P = 0.0004). Overall, OTSC was effective in 15/27 procedures. Defect closure was complete in 12/21. Mean followup was 2.9 months (1-8 m). Mean defect size was 10 mm (5-25 mm). A trend towards higher success was noted in defects <10 mm compared to defects >10 mm (90% versus 60%; P = 0.36). No difference was noted in closure of fresh (<72 hrs) versus chronic defects (>1 month) (75% versus 67%). There were no complications. Conclusion. The OTSC provides a safe alternative to manage fistula, perforation, and bleeding. No significant difference was seen for closure of early fistula or perforations as compared to chronic fistula. Rat tooth forceps or suction was superior to the dedicated devices. PMID- 23935262 TI - POWER ANALYSIS FOR COMPLEX MEDIATIONAL DESIGNS USING MONTE CARLO METHODS. AB - Applied researchers often include mediation effects in applications of advanced methods such as latent variable models and linear growth curve models. Guidance on how to estimate statistical power to detect mediation for these models has not yet been addressed in the literature. We describe a general framework for power analyses for complex mediational models. The approach is based on the well known technique of generating a large number of samples in a Monte Carlo study, and estimating power as the percentage of cases in which an estimate of interest is significantly different from zero. Examples of power calculation for commonly used mediational models are provided. Power analyses for the single mediator, multiple mediators, three-path mediation, mediation with latent variables, moderated mediation, and mediation in longitudinal designs are described. Annotated sample syntax for Mplus is appended and tabled values of required sample sizes are shown for some models. PMID- 23935263 TI - Incretins in type 2 diabetes mellitus: cardiovascular and anti-atherogenic effects beyond glucose lowering. AB - Type 2 diabetes mellitus is the most outspreading disease of the western world and it provides cardiovascular disease. During the past decade new drug categories were added to the already existing ones. Perhaps, the most outstanding, as promising, too, are glucagon-like peptide-1(GLP-1) analogues, which pinpointed at the incretin hormone system, targeting mainly at the postprandial hyperglycemia.It seemed that these novel drugs have beneficial effects on ischemic heart, heart failure,blood pressure, even on lipids and body weight in type 2 diabetics, considering them not only as another glucose lowering agent. A lot of recent studies investigate the potential relationship between GLP 1 and its possible cardioprotective and anti-atherogenic effects in type 2 diabetes and the present review discusses these effects of GLP-1. PMID- 23935264 TI - The new biology: a bridge to clinical cardiology. AB - The recent advances in the biological research have produced new biological disciplines with clinical applications in medicine and cardiology. The integration of multilevel biological data and the connection with the clinical practice reveal the potential of personalized medicine and nanotechnology with future implications for prognosis, diagnosis and management. In the post-genomic time period the new disciplines, systems biology, synthetic biology and translational medicine are emerging as significant research areas in biology and medicine with extension in the field of clinical medicine and cardiology. These disciplines, with their predictive, preventive and therapeutic potential, are formulating the concept of personalized management, with patient's energetic involvement and participation in the diagnosis and treatment. Personalized medicine and cardiology, using biomarkers as health and disease indicators, encourage drug development and direct towards a better molecular comprehension of disease processes. PMID- 23935265 TI - Pulmonary microvascular permeability and gas exchange in patients with syndrome X. AB - AIM: This clinical study was planned to assess pulmonary microvascular permeability in patients with Syndrome X (SX) by using a functional imaging tool, technetium-99m-diethyltriaminepentaaceticacid ((99m)Tc-DTPA) lung clearance scintigraphy, and the pulmonary functions test, which includes diffusion capacity of the lung for carbon monoxide (DLCO). METHODS: The study population consisted of 22 non-smoker subjects divided into two groups. First group comprised 12 patients (4 male, 8 female, mean age: 48+/-4 years, range 36 to 65) with SX. Ten healthy subject (4 men, 6 female, mean age: 45+/-3 years, range 34 to 58) were served as control group. Volumetric pulmonary functions, including DLCO were also performed before lung scintigraphy. Alveolar epithelial permeability was assessed by measuring the pulmonary clearance of an inhaled (99m)Tc-DTPA using a gamma camera. RESULTS: Spirometric data was comparable in both groups. Although volumetric pulmonary measurements were similar, DLCO values of SX patients were lower than those in control (20.9+/-1.7 ml/min/mmHg vs. 27.8+/-1.3 ml/min/mmHg, p=0.002). The mean clearance rate of (99m)Tc-DTPA in control subjects was 106+/-6 min, and this value was lower than patients with SX (179+/-19 min; p=0.0001). CONCLUSION: We conclude that lung is a target organ for SX. The pulmonary gas exchange and microvascular permeability, which is measured by (99m)Tc-DTPA scintigraphy, are restricted without change of volumetric pulmonary functions in patients with SX. PMID- 23935266 TI - Serum antioxidant status among young, middle-aged and elderly people before and after antioxidant rich diet. AB - BACKGROUND: The influence of factors such as age, sex, life style and smoking on oxidative stress status of the organism remains unclear. There is evidence that dietary intake of antioxidants is thought to enforce the organism ability to counteract free radicals. Administration of synthetic antioxidants as dietary supplements does not seem to have the same beneficial effect as consumption of the same antioxidants as part of food ingredients. This work focuses on the investigation of age and diet effects on oxidative stress and examines the hypotheses of their significant influence. METHODS: Blood samples of 146 volunteers, were collected and allocated in three age groups. All volunteers completed a questionnaire concerning home and working environmental conditions, special habits and dietary preferences. We implemented a thirty days diet rich in antioxidants in 55 volunteers. Antioxidant activity was estimated before and after the special diet by measuring the influence of serum in oxidation of ABTS by the ferryl myoglobinhydrogen peroxide system. RESULTS: Our findings showed unexpected lower serum total antioxidant capacity (TAC) in younger people (ages 18-35 yrs) 79%, compared to middle aged and elderly individuals and a large increase 62% in serum TAC of all age-groups after the one-month special diet. CONCLUSION: These results imply that a diet rich in antioxidants based on antioxidant rich food consumption and not on single antioxidants administration, can increase the antioxidant status of the organism and offer better health. The total serum antioxidant status increases with age and this fact should be taken into account when TAC is measured in different diseases. PMID- 23935267 TI - The attitudes of surgeons concerning preoperative smoking cessation: a questionnaire study*. AB - BACKGROUND: The purpose of this study was to evaluate the attitudes and behavior of surgeons regarding preoperative smoking cessation. METHODS: A total of 109 anonymous questionnaires were distributed to non-vascular surgeons in our hospital, inquiring about their smoking attitudes, their smoking cessation advice practices, whether they appreciated the benefits of preoperative smoking cessation, and their knowledge of smoking cessation methods. RESULTS: Eighty questionnaires (from 51 resident doctors and 29 academic staff) were returned (response rate: 73.40%). Of the surgeons, 17.50% were current smokers. Although 40% of the surgeons surveyed believed that preoperative smoking cessation reduces postoperative complications, 31.2% of the surgeons (25/63) had given smoking cessation advice at least to 1 patient in the last month. Most of the resident doctors (39.2%) advised smoking cessation within a month; prior to surgery however, the academic staff (27.6%) advised cessation immediately before the operation (p=0.038). There was a significant difference between academic sfaff and resident doctors concerning the method to increase a patient's chance of quitting (p=0.045), even among current smokers (p=0.049). CONCLUSION: The surgeons who participated in the questionnaire were aware that smoking cessation improves outcome, but most of them did not appreciate that providing brief advice, referring to cessation services, or prescribing nicotine replacement therapy (NRT) may be of benefit in helping patients to quit. It is necessary to educate surgeons about the scale of the benefit and the efficacy of smoking cessation interventions or to set up systematic frameworks to offer smoking cessation advice to preoperative patients who smoke. PMID- 23935268 TI - A perspective from the practice of swaddling by Turkish mothers. AB - AIM: The purpose of this study was to investigate the practice of swaddling by Turkish mothers residing in different areas of the country (rural or urban), and determine to their level of knowledge on its positive and negative effects on children's health. MATERIAL AND METHODS: A total of 632 mothers with an infant aged 0-3 months who presented to our University Hospital volunteered their participation and 598 mothers were included in the study. The study was based on a questionnaire form given to the mothers. RESULTS: Two hundred eighty three (283) mothers swaddled their infants (47.3 %), while 315 mothers did not swaddle (52.7%). The mothers that swaddled their baby cited tradition ("That's what I learned from my elders") as the most common reason (38%) for swaddling. The most important reason (32%) for not swaddling was the mothers' belief "that it would prevent normal development". CONCLUSION: In Turkey, the swaddling tends to decrease with the increase of maternal education level and socio-economic situation.The level of Turkish mother's knowledge about beneficial and adverse effect of swaddling were insufficient.We think that the information about properly swaddling should be given to mothers In order to benefit from it's positive effects and at the same time and avoid its adverse effects. PMID- 23935269 TI - Association of glomerular filtration rate and inflammation with left ventricular hypertrophy in chronic kidney disease patients. AB - BACKGROUND: Although left ventricular hypertrophy (LVH) is an independent predictor of mortality in patients with end stage renal disease, few have examined its prevalence before the initiation of dialysis. The aim of this study was to investigate the relationship between LVH, estimated glomerular filtration rate (GFR), and inflammatory markers in patients with chronic kidney disease (CKD). METHODS: Forty-one CKD patients (18 women, 23 men, mean age 53+/-17 years) with an estimated GFR between 15 and 59 mL/min (mean 34.2 mL/min) were enrolled and the following tests performed: routine serum biochemical analyses, high sensitivity C-reactive protein (hs-CRP), fibrinogen, ferritin, and homocysteine, and left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS). RESULTS: LVH was diagnosed in 32/41 patients (78%). CKD patients with LVH (n=32) had significantly higher hs-CRP (p=0.012), fibrinogen (p=0.031), and lower serum albumin (p=0.028) levels than those without LVH (n=9). In all patients, LVMI correlated positively with hs-CRP (r=0.483, p=0.002) and serum fibrinogen (r=0.426, p=0.015). Estimated GFR correlated positively with LVEF (r=0.414, p=0.007) and LVFS (r=0.376, p=0.018). CONCLUSIONS: Important positive associations exist between markers of inflammation and LVMI in patients with CKD. In addition to hs-CRP, elevated fibrinogen may portend the development of LVH in patients with CKD who are not yet on dialysis. PMID- 23935270 TI - A comparison of the effects of losartan and ramipril on blood pressure, renal volume and progression in polycystic kidney disease: A 5-Year follow-up. AB - BACKGROUND: The major cause of hereditary renal failure is autosomal dominant polycystic kidney disease (ADPKD). Many factors affect renal progression in these patients. Among these, hypertension and an increase in renal volume are interrelated in terms of their effects on renal progression. We aimed to investigate the effects of losartan and ramipril on renal volume and progression in patients with ADPKD. MATERIALS AND METHODS: Data from 18 hypertensive patients with ADPKD were evaluated. Eleven of the 18 hypertensive patients were on losartan and 7 on ramipril treatment. Demographic parameters, use of antihypertensives and other medications, the course of blood pressure (BP), biochemical parameters, creatinine clearance (CrCL), findings at computed tomography and renal volume were recorded at baseline and at 1 and 5 years. RESULTS: Target BP values were maintained over 5 years. The annual decrease in CrCL was 1.33 mL/min in the losartan group compared with 6.59 mL/min in the ramipril group. There was no significant difference between the groups in terms of annual decrease in CrCL. Annual increase in renal volume was 252.04 cm3 in the losartan group and 167.36 cm3 in the ramipril group. There was no significant difference between the groups in terms of the increase in renal volumes at 1 and 5 years. CONCLUSION: Our study demonstrated that losartan and ramipril provided effective BP control. In addition, the results of our study demonstrated that despite the increase in renal volume, losartan and ramipril may have regressed renal progression via other factors. PMID- 23935271 TI - Twenty four-hour ambulatory blood pressure monitoring and lipid levels before, 3, 6 and 12 months after the onset of hemodialysis in chronic kidney disease patients: a pilot study. AB - BACKGROUND: Twenty four-hour ambulatory blood pressure (BP) monitoring (ABPM) is being increasingly used to evaluate the effectiveness of antihypertensive medications. We aimed to to investigate the incidence of "non-dippers" in ESRD patients before, as well after the initiation of hemodialysis, to evaluate whether start of hemodialysis is associated with a reduction in the use of antihypertensive drugs, and to correlate 24-hour ABPM with serum lipid levels, the use of lipid-lowering drugs (statins) and the development of the Metabolic Syndrome (MetS) in these patients. METHODS: Thirty patients scheduled to initiate hemodialysis (glomerular filtration rate <15 ml/min/1.73m(2)) were prospectively recruited. Twenty four-hour ABPM and lipid levels were recorded before (T0), as well as 3 (T1), 6 (T2) and 12 (T3) months after hemodialysis onset. RESULTS: A progressively significant (p=0.025) decrease in the use of antihypertensive medications was observed in 26 of 30 patients throughout the study, whereas the remaining four patients were not hypertensive during the same period. There was a progressive increase in the use of statins for the management of dyslipidemia (p=0.015). This increase in statin use was coupled with an increase in the prevalence of the MetS in the study population (p=0.040). Patients with daily BP <135/85 mm Hg had a lower incidence of new MetS compared with patients with daily BP >135/85 mm Hg (p=0.053). CONCLUSIONS: Patients initializing hemodialysis demonstrate a progressively increased incidence of dyslipidemia and MetS, as well as a reduction in the use of antihypertensive drugs. Optimal management of BP and dyslipidemias is essential to reduce the high cardiovascular morbidity and mortality rates in this high-risk population. PMID- 23935272 TI - Thyroid surgery with harmonic focus, ligasure precise and conventional technique: a retrospective case-matched study. AB - BACKGROUND: New surgical technologies have been introduced in thyroid surgery, to achieve vessel sealing and hemostasis. The aim of the study was to examine their effectiveness and compare the outcome of total thyroidectomy using the Harmonic FocusTM, the LigaSure(r) Precise and the conventional technique of suture ligation. METHODS: A retrospective case-matched study of all total thyroidectomies between October 2008 through May 2010 was conducted. Patients (n=240) underwent total thyroidectomy using three different methods; the Harmonic FocusTM (Group F, n=80), the LigaSure Precise(r) (Group L, n=80) and the conventional technique of suture ligation (Group C, n=80). RESULTS: No significant differences were identified between the 3 groups in terms of demographics, thyroid gland weight, pathologic diagnosis, preoperative and postoperative calcium levels, postoperative complications, duration of hospital stay, and final outcome. The operative time was shorter with Harmonic Focus(r) by about 15%. Statistical analysis revealed a statistically significant difference between operations with F (62.7+/-14.1 minutes) and C (72.7+/-13.6minutes) with (p=0.019). CONCLUSION: Both devices were safe and efficient. A significant reduction of the operative time was found with Harmonic Focus(r) compared to the other two techniques with no statistically significant differences in postoperative complications in the 3 groups. PMID- 23935273 TI - Non steroidal antiinflammatory drugs may be harmful to normal kidneys: experimental surgery model*. AB - BACKGROUND AND AIM: The exact effect of analgesics on normal kidneys is not known yet. We aimed to evaluate the impression of non steroidal antiinflammatory drugs (NSAID) used post-operatively on kidneys, in rat (tracheotomy) model. METHODS: Twenty-five non-uremic male wistar albino rats were included. For 18 rats, tracheotomy was performed and divided into two groups. First group, NSAID (diclofenac 10 mg/kg/day intramuscular (im)) (NSAID, n=8); second group isotonic (im)(Control, n=10) were administered for a week. For third group (Histological control,n=7) in order to evaluate normal histology neither surgery nor medication were applied. At the end (7th day), 24 hours urine collected then, blood samples were taken by intracardiac punction and were sacrified. One of the kidneys fixed for histological evaluation, the other was preserved for the measurements of tissue enzyme levels. Lipid peroxidation products and antioxidant enzyme levels were measured both from plasma and renal tissues. Histologically inflammation, regeneration, degeneration assessed semiquatitativelly and immunohistochemical dyes were applied. RESULTS: Hemoglobin thiobarbituric acid reactive substance level indicating the increase of lipid peroxidation in NSAID group was higher than control group (673+/-204 vs.373+/-27nmol/gHb respectively, p>0.05). Superoxide dismutase (one of the antioxidant enzymes responsible for reduction of reactive oxygen substances) and serum nitrate levels were lower in NSAID groups (700+/-68 vs.1371+/-164U/gHb and 26+/-4.4 vs.50.8+/-6.8 umol/mL respectively, p<0.05).Although tissue levels were parallel to plasma levels but the difference wasn't significant. In histological assessment degeneration was present only in NSAID group (1.3+/-0.6 vs.0.0+/-0, p<0.05). Inflammation were lower than the control group (0.8+/-0.4 vs.1.2+/-0.2, p>0.05). Cyclooxygenase-2 expression was disappeared in NSAID group. CONCLUSIONS: NSAIDs mostly used post-operatively for analgesia, may cause unfavorable effects on kidneys by oxidative stress. PMID- 23935274 TI - Lateralized olfactory difference in patients with a nasal septal deviation before and after septoplasty*. AB - BACKGROUND: Patients with a smell disorder and less often, healthy people, exhibit an olfactory difference between the two sides of the nose. Higher olfactory thresholds are correlated with the obstructed side of a nasal septal deviation (NSD). With this prospective study we sought to investigate if a NSD compromises the olfactory identification. MATERIALS AND METHODS: Thirty patients with nasal obstruction due to a NSD were recruited. The patients were listed for primary septoplasty with or without radiofrequency reduction of the inferior turbinates. Pre- and postoperatively, patients were assessed by visual analogue scales for symptoms and by the bilateral nasal spirometry (nasal partitioning ratio-NPR) for the side/degree of obstruction. Olfactory identification was tested separately for each nasal cavity by means of the 12 item Sniffin Sticks test (12-SS test) and a 3-point difference between the nasal sides was considered significant. RESULTS: The mean age of patients (25 males/5 females) was 33 years (range 17-52). No complications or anosmia were reported postoperatively. Subjective hyposmia, nasal obstruction and the NPR were reduced (p<0.001). Significant lateralized differences were present in 20% and 13% of patients before and after septoplasty respectively; the change was not significant (p=0.754). Patients with a significant lateralized olfactory difference had a greater NPR pre- (p=0.031) but not postoperatively (p=0.783). The sides of obstruction and worst olfactory performance did not differ in these patients before surgery. CONCLUSIONS: Olfactory identification may be compromised on the convex side of a large NSD. Post-operatively, patients exhibit a lateralised smell identification difference as often as healthy people. The effect of a clinically significant NSD on the different aspects of olfactory performance warrants further study. PMID- 23935275 TI - An Evaluation of European Countries' Health Systems through Distance Based Analysis. AB - INTRODUCTION: The issue of evaluating the efficiency of health systems has been elaborated upon frequently. Since "health" is a multi-faceted concept, many variables of different measurement units must be included in its analysis; consequently, this presents a great obstacle for researchers to overcome. MATERIALS AND METHODS: A novel statistical approach for evaluating the efficiency of organizational units is here proposed, which can also be easily applied to the health sector. For these purposes, the health status of the 27 countries belonging to the European Union has been examined by employing a statistical Ivanovic-Jeremic Distance Based Analysis (DBA) on various health indicators. RESULTS: The subsequent outcome of the Distance Based Analysis has shown that Cyprus and Ireland have a most efficient health system sectors. Greece also has exceptional indicators of health service, yet health on the individual level is not comparable. LIMITATIONS: Since it synthesizes many variables into an efficiency score, a DBA can be easily applied to other regions/countries. However, the choice of input and output variables can be considered to be potential limitations since a different choice of variables may cause different efficiency scores for the countries selected. CONCLUSIONS: A DBA approach contributes significantly to the efficiency in the field of research measurement. This analysis can be additionally performed alongside DEA and SFA methods, as a new measure of efficiency. PMID- 23935276 TI - Diagnosis and management of congenital neonatal chylous ascites. AB - BACKGROUND: Congenital chylous ascites is a rare condition that constitutes a challenge for the physician. It is defined as the accumulation of chyle into the peritoneal cavity in infants younger than 3 months. This condition is often refractory to therapy and it is responsible for serious malnutrition and immunological deficiency because of the loss of proteins and lymphocytes. MATERIAL AND METHODS: Four cases of congenital neonatal chylous ascites, were treated by our staff during the last two years. One case was treated conservatively and three with laparotomy. Two of them had intraabdominal cysts that were excised and one was treated with ligation of the left lumbar lymphatic trunk and cisterna chyli and the use of fibrin glue. RESULTS: All four cases were treated successfully. On follow up tests no one showed recurrence of the ascites. All children, except the one that treated conservatively and also had other problems due to prematurity, are growing up normally. CONCLUSIONS: Congenital chylous ascites is a complex condition. Its diagnostic evaluation is difficult and its therapy of long duration. Conservative treatment is in most cases the initial choice, but when it fails, exploratory laparotomy could provide a successful alternative. PMID- 23935277 TI - Perforated endometrial appendicitis in pregnancy. AB - BACKGROUND: Endometriosis is a common disorder in women of reproductive age. A rare localization is the appendix, which, in most cases, is an incidental finding during appendectomies. The incidence of symptomatic appendiceal endometriosis or endometrial appendicitis might be increased in pregnancy. Moreover, endometrial appendicitis in pregnancy is more likely to present in an advanced stage, given the physiologic changes characterizing the gravid abdomen. MATERIALS AND METHODS: Description of a case of a pregnant woman presenting to the A&E with acute peritonitis attributable to advanced appendicitis. She underwent emergency laparotomy with appendectomy. The biopsy specimen was examined by the pathology laboratory of the same hospital. RESULTS: The laparotomy revealed perforated appendicitis. The histopathology report described acute endometrial appendicitis. PMID- 23935278 TI - Diagnosis of dialysis leak in children on peritoneal dialysis using radionuclide technique. AB - Dialysis leak from the peritoneal cavity into various tissue planes, most often into subcutaneous tissue around a previous surgical incision or trough umbilical hernia is known complication of continuous ampulatory peritoneal dialysis (CAPD). This complication leads to bed ultrafiltration and compromise the peritoneal dialysis. Usually computed tomogtaphy (CT) makes the diagnosis of dialysate leakage. However there are other techniques that have been shown useful in particulars occasions. Peritoneoscintigraphy is an underestimated noninvasive technique for diagnosis of dialysate leakage. We refer a 9-year-old girl who was on CAPD for 2 years and presented with genitals oedema and failure of ultrafiltration. Using peritoneoscintigraphy we diagnosed leakage of dialysate in subcutaneous tissue through umbilical hernia. CT has proved this finding. We conclude that the peritoneoscintigraphy is an instrumental technique to identify the causes of genital edema in patients on peritoneal dialysis. PMID- 23935279 TI - Is hypertension a manifestation of the nutcracker phenomenon/syndrome? Case report and brief review of the literature. AB - Hypertension has been rarely reported in patients with the nutcracker phenomenon/syndrome. We describe a young male adult where a computed tomography angiography provided evidence of left renal vein dilatation, probably due to its compression through the angle between the aorta and the superior mesenteric artery, during the evaluation for secondary hypertension. As there were no other signs for secondary hypertension, we proceeded with a venography of the inferior vena cava and the renal veins that revealed mild anatomical findings compatible with the so called nutcracker phenomenon/syndrome. Blood levels of renin and aldosterone and renocaval pressure gradient from these sites were between normal limits. As there were coexisting anatomical and clinical findings (hypertension), nutcracker syndrome might have been claimed. However, no causal links could be established and these findings should be considered only as a coincidence. PMID- 23935280 TI - An unusual characteristic "flower-like" pattern: flash suppressor burns. AB - The case on contact shots from firearms with a flash suppressor is rare. When a rifle fitted with a flash suppressor is fired, the emerging soot-laden gas in the barrel escapes from the slits of the flash suppressor. If the shot is contact or near contact, the flash suppressor will produce a characteristic "flower-like" pattern of seared, blackened zones around the entrance. This paper presents the injury pattern of the flash suppressor in a 29-year-old man who committed suicide with a G3 automatic infantry rifle. PMID- 23935281 TI - Pediatric Oncology Pathology: another important area for prevention. PMID- 23935282 TI - Molecularly targeted drugs for the treatment of cancer: oral complications and pathophysiology. AB - BACKGROUND: Targeted cancer therapy is a new approach for the treatment of cancer. It involves a specific molecular target, mainly a receptor that serves as a target for monoclonal antibodies or tyrosine kinase inhibitors. Side-effects of these new regimens are described to be mild, compared to those of classical chemotherapy. There is a lack in the documentation and understanding of oral complications related to molecularly targeted drugs. METHODS: In this review, we tried to make a systematic review of the databases Pubmed and Scopus, using "targeted cancer therapy" and "oral", or "mucositis", or "stomatitis", or "bleeding", or "hemorrhage" as search terms. Specific drug name searches were not conducted. The search yielded 97 results. Only articles related to EGFR and VEGFR inhibition were selected. Finally 13 articles met the criteria. RESULTS are discussed and possible pathogenetic mechanisms for the complications of targeted cancer therapy regimens are presented. RESULTS: It appears that the most serious side-effect is mucositis/stomatitis that may affect the whole gastrointestinal tract. It rarely results in treatment discontinuation. Reduced saliva secretion, xerostomia and dysphagia can be severe with some regimens and interfere with food uptake. Osteonecrosis, wound healing impairment, spontaneous gingival bleeding and dysgeusia were also reported. CONCLUSIONS: Considering these data it is obvious that symptoms related to cancer treatment should be considered in the context of the holistic management of patients. Oral complications should not be ignored but recorded during physical examination, because they may significantly impair daily activities and patients' quality of life. PMID- 23935283 TI - Eosinophilic Esophagitis: update on treatment approaches. AB - Epsilonosinophilic esophagitis (EoE) is a clinical entity with continuously increasing incidence in children and adults. Diet therapy and corticosteroids are the most important therapeutic interventions currently used, while new therapies are being developed, based on the research of the disease mechanisms. In this review we assess the results of the latest clinical trials on management of patients with EoE, and the advances in the development of novel drug therapies. Hippokratia 2012; 16 (3): 200-204. PMID- 23935284 TI - Depression in diabetes mellitus: a comprehensive review. AB - Although the prevalence of a mental disorder, in general, in patients with diabetes mellitus is regarded to be comparable to the general population, an increased prevalence of depressive disorders, often comorbid with anxiety, has been reported in patients with diabetes mellitus. The co-occurrence of depression in diabetes is attributed to a variety of factors, including the psychological and psychosocial impact of the disease, a potential common genetic susceptibility and common pathophysiological abnormalities involving neuroimmunological and neuroendocrinical pathways, as well as microvascular brain lesions due to diabetes mellitus. However, issues concerning pathogenesis and causality of this high co-occurrence are not fully determined yet. Still, the presence of depression in patients with diabetes mellitus is of vast importance, as it is usually associated with poor disease control, adverse health outcomes and quality of life impairment. This article aims to provide a comprehensive review of epidemiological findings, clinical considerations and management strategies concerning depression in patients with diabetes mellitus. PMID- 23935285 TI - Oral Mucositis: understanding the pathology and management. AB - Oral Mucositis is a common complication of cancer therapy which may limit the completion of treatment and affect the quality of life of the patient. As we have come to understand its pathogenesis new developments in its management and prevention have allowed us minimize this side effect. PMID- 23935286 TI - Association of tumor necrosis factor-alpha gene polymorphism (-308) and obstructive sleep apnea-hypopnea syndrome. AB - BACKGROUND AND AIM: Elevated serum tumor necrosis factor-alpha (TNF-alpha) concentra-tion and a polymorphism of the TNF-alpha gene at the position -308 in the promoter region are associated with obstructive sleep apnea-hypopnea syndrome (OSAHS). We aimed to determine the association of this polymorphism with OSAHS in Greek patients. PATIENTS AND METHODS: A blood sample was obtained from 220 patients clinicaly diagnosed with OSAHS and 319 normal controls. TNF-alpha genotype was determined from nucleus-containing cells from whole blood using a PCR method. RESULTS: The results demonstrated that the distribution of alleles was significantly dif-ferent when comparing the OSAHS patients group to the healthy controls. The appearance of AA (p=0.04) and AG (p<0.001) genotypes was significantly greater in OSAHS patients (8.6% and 32.7%, respectively) compared to the healthy control group (4.4% and 26.3%, respectively). Correspondingly, the appearance of the GG genotype was significantly lower in OSAHS patients compared to healthy controls (53.6% vs 69.3%). The A and G allele appeared at a frequency of 27.5% and 72.5% respectively in the OSAHS groups, and 17.6% and 82.4% in the control group respectively. CONCLUSIONS: The distribution of genotypes and alleles of the single nucleotide polymorphism of TNF-alpha (-308) of OSAHS patients varies from healthy controls. PMID- 23935287 TI - Benign epilepsy with centro-temporal spikes (BECTS): relationship between unilateral or bilateral localization of interictal stereotyped focal spikes on EEG and the effectiveness of anti-epileptic medication. AB - BACKGROUND AND AIM: Benign epilepsy with centro-temporal spikes (BECTS) is one of the most frequent epileptic syndromes in children. It is placed among the idiopathic localization-related epilepsies. However, the relationship between unilateral or bilateral localization of interictal stereotyped focal spikes on electroencephalogram (EEG) and the effectiveness of anti-epileptic drugs has not been studied yet. PATIENTS AND METHODS: We studied 55 neurodevelopmentally normal children who had been diagnosed with BECTS. Children were subdivided into two groups, based on EEG findings: Group A comprised 30 children with unilateral findings on EEG and Group B 25 children with bilateral findings on EEG. All patients in the present study were started on an anti-epileptic medication after the third seizure (Sodium Valproate, Carbamazepine, Oxcarbazepine) and we studied the response to medications. RESULTS: Children with bilateral findings on EEG had the same response to treatment with either Sodium Valproate or Carbamazepine or Oxcarbazepine. Other side, children with unilateral findings on EEG corresponded best to Carbamazepine or Oxcarbazepine. CONCLUSIONS: Children diagnosed with BECTS and bilateral discharges on EEG have good response to treatment with either Sodium Valproate or Carbamazepine or Oxcarbazepine. PMID- 23935288 TI - Reliability and concurrent validity of the adapted Greek version of the Scoliosis Research Society-22r Questionnaire. A cross-sectional study performed on conservatively treated patients. AB - BACKGROUND: The Scoliosis Research Society-22r Questionnaire (SRS-22r) is a questionnaire assessing the health related quality of life of patients with scoliosis. Aim of this study was to evaluate the validity and reliability of the Greek Version of the SRS-22r in patients suffering from scoliosis who were treated conservatively. METHODS: The (translated and adapted) Greek versions of the SRS-22r together with the previously validated Short Form-36 questionnaire were mailed to 117 patients suffering from idiopathic scoliosis. Two weeks later, the Greek SRS-22r was mailed to the same patients once again. The internal consistency, reproducibility and concurrent validity were assessed. RESULTS: Factor analysis revealed a five-factor structure. The study demonstrated high Cronbach alpha coefficients for all but the 'Satisfaction with management' domain, when compared with the original questionnaire. Intraclass correlation was excellent regarding every domain of the SRS-22r. Concerning concurrent validity, one domain had excellent (r=0.75-1), thirteen domains good (r=0.50-0.75) and 16 domains moderate correlations (r=0.25-0.50) when compared with the relevant domains of the SF-36 questionnaire. CONCLUSIONS: This Greek Version of the SRS 22r outcome instrument is a validated questionnaire which can be used to evaluate Greek-speaking patients suffering from Idiopathic Scoliosis who are being treated conservatively. PMID- 23935289 TI - Different fatty acid composition of serum phospholipids of small and appropriate for gestational age preterm infants and of milk from their mothers. AB - BACKGROUND: Placental supply of fatty acids (FA) is essential for normal foetal development but in premature infants this supply is interrupted. To investigate the association of intrautrine growth restriction with serum phospholipid and breast milk FA composition, we compared preterm infants small for gestational age (SGA) and matched appropriate for gestational age (AGA), and their mothers' milk during the first 4 weeks of postnatal life. METHODS: Sera from 11 SGA and 12 AGA infants born 34-36 weeks of gestation were collected at birth, 14(th) and 28(th) day, and breast milk on 14(th) and 28(th) day after birth. FA composition was analyzed by gas chromatography. RESULTS: Preterm SGA infants had significantly lower oleic, total monounsaturated FA (MUFA), docosahexaenoic acid (DHA) and n-3 polyunsaturated FA (PUFA) and higher levels of stearic and linoleic acid at birth than AGA infants (p<0.05). DHA was significantly lower, whereas docosatetraenoic and docosapentaenoic acids were higher in SGA infants after 28 days. Mothers of AGA infants had markedly lower levels of MUFA and higher levels of total and n-6 PUFA in their breast milk. CONCLUSION: SGA infants have altered serum phospholipid FA composition at birth and during their first month of life, probably due to inadequate transplacental supply and activity of desaturase system. RESULTS on human milk suggest that pregnancies with AGA or SGA would later influence breast milk FA composition. PMID- 23935290 TI - Evaluation of nutritional parameters of hemodialysis patients. AB - BACKGROUND: This study was performed to investigate nutritional parameters of hemodialysis patients by using anthropometric and biochemical measurements. METHODS: Data from the last 6 months of 22 adult hemodialysis patients with a mean age of 61 +/- 14 years were analyzed retrospectively. Dialysis vintage, normalized protein catabolic rate (nPCR), serum biochemical parameters, mid arm muscle circumference (MAMC) were determined as mean and standard deviation. Correlations between the variables were computed by coefficient p of Pearson. RESULTS: We found significant positive correlations: age of patients versus C reactive protein, MAMC versus LDL-Cholesterol, MAMC versus body mass index, albumin versus hemoglobin. There were also significant negative correlations: age versus serum creatinine, age versus albumin, age versus intact parathyroid hormone (iPTH), dialysis vintage versus MAMC. CONCLUSION: In conclusion, age seem to be negatively associated with iPTH and albumin. As dialysis vintage increases, muscle mass seems to decrease. PMID- 23935291 TI - The effects of omega 3 fatty acid supplementation on brain tissue oxidative status in aged wistar rats. AB - BACKGROUND: The omega 3 fatty acids play an important role in many physiological processes. Their effect is well documented in neurodegenerative diseases and inflammatory diseases. Also, aging as a biophysiological process could be influenced by eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) components of fish oil. However there are not many studies showing the effect of PUFA (polyunsaturated FA) suplementation in eldery brain functions and the response to oxidative strees. The aim of this study was to investigate the effects of dietary omega-3 fatty acid supplementation on levels of lipid peroxidation and oxidant/antioxidant status of brain tissue in aged (24 months old) Wistar rats. METHODS: Animals were divided in two groups. Control group (n=8) was fed with standard laboratory food and received water ad libitum. Treated group (n=8) was also fed with standard laboratory food, water ad libitum and received fish oil capsules (EPA+DHA) for 6 weeks. Daily dose was 30mg EPA and 45mg DHA (capsules: 200mg EPA and 300mg DHA; in-house method). At the end of treatment animals were sacrificed and brains were collected and frozen on -80oC. The levels of lipid peroxidation (malondialdehyde - MDA), activity of catalase (CAT) and activity of superoxide dismutase (SOD) were examined in cerebral cortex. Catalase activity was determined by measuring the decrease in absorbance (H2O2 degradation) at 240 nm for 3 min and expressed as U/mg protein. Total SOD (superoxide dismutase) activity was performed at room temperature according to the method of Misra and Fridovich. The extent of lipid peroxidation (LPO) was estimated as the concentration of thiobarbituric acid reactive product malondialdehyde (MDA) by using the method of Aruoma et al. The incorporation of fatty acids in cellular membranes was confirmed by gas chromatography. RESULTS: Our results showed that lipid peroxidation significantly decreased in treated animal group, where MDA concentration was 0.38+/-0.001 vs. 0.43+/-0.001 nM/ml (p<0.05) in control. However SOD activity increased significantly in treated animal group 1.57+/-0.24 vs. 4.12+/-0.15 U/gHb/L (p<0.01) in control. CAT activity decreased in treated group but not significantly. CONCLUSION: Incorporation of omega-3 fatty acids after their supplementation had beneficial effects on brain tissue. Omega-3 fatty acids increased activity of SOD and decreased lipid peroxidation. Changes in oxidative/antioxidative balance are a result of EPA and DHA effects on lipids and enzymes of antioxidative system. PMID- 23935292 TI - A retrospective study of angiographic ally determined anomalous coronary arteries in 12,844 subjects in Thrace region of Turkey. AB - BACKGROUND: Congenital anomalies of the coronary arteries are rarely encountered in patients undergoing cardiac catheterization. In patients undergoing coronary angioplasty or cardiac surgery, angiographic recognition of coronary anomalies is important for the proper management of these patients. METHOD: We retrospectively reviewed the records of 12,844 patients who had previously undergone coronary angiography in the catheterization laboratory of Trakya University Cardiology Department over the past 14 years. We tried to investigate the presence of a variety of coronary anomalies in these patients to determine the prevalence of various types of anomalies and their anatomic variation in a selected population of the European part of Turkey. The potential association between coronary atherosclerosis and congenital coronary anomalies was also investigated. RESULTS: Among these patients, 95 patients were found to have major coronary anomalies that predominantly comprised anomalous aortic origin of coronary arteries. Among the major anomalies, anomalous aortic origin of the left circumflex (LCX) artery from the right sinus of Valsalva or right coronary artery (RCA) was found to be the the most prevalent (46 out of 95 patients) outnumbering the second most common anomaly that was anomalous aortic origin of the RCA (32 out of 95 patients). In the present study, the incidence of major coronary arterial anomaly was found to be 0.74 %. However, only about one third of the patients (31 out of 95, 32.6%) with major anomaly had significant coronary atherosclerotic lesions among whom nine were found to involve the LCX artery with a posterior course. CONCLUSION: The incidence of congenital coronary anomalies in a selected population of the European part of Turkey is similar to those of other populations. Congenital coronary anomalies generally present as isolated anomalies and are not associated with an increased risk of coronary atherosclerosis in this series. Cardiologists and surgeons should be familiar with these entities for the proper management of patients undergoing cardiac surgery or coronary angioplasty. PMID- 23935293 TI - Prevalence of thrombophilic mutations in patients with unprovoked thromboembolic disease. A comparative analysis regarding arterial and venous disease. AB - BACKGROUND: Thromboembolic disease (TED) represents one of the main reasons of morbitity and mortality in Western World. Venous and arterial thrombotic disorders have long been viewed as separate pathophysiological entities. However, in recent times the separate nature of arterial and venous thrombotic events has been challenged. Although inherited thrombophilia's predominant clinical manifestation is venous thrombosis, its contribution to arterial thrombosis remains controversial. Purpose of the study was to evaluate the prevalence of the most common thrombophilic mutations, FV Leiden G1691A-FVL and FII G20210A-PTM and to assess the differences between venous, arterial and mixed thrombotic events. Testing for polymorphism MTHFR C677T and antithrombin, protein C and protein S was also performed. Correlations with dyslipidemia, smoking, obesity, homocysteine and antiphospholipid antibodies were made. METHODS: 515 patients with unprovoked TED, 263 males, median age 44 years, were studied. Patients were divided into three groups: 258 with venous thrombosis (group A), 239 with arterial (group B) and 18 with mixed episodes (group C). All patients were interviewed regarding family history of TED, origin, smoking and dyslipidemia. Body mass index (BMI) had been calculated. Molecular assessment of the FVL, PTM and MTHFR C677T was performed. Antithrombin, protein C, protein S, APCR, homocysteine, antiphospholipid antibodies and lipid profile were also measured. RESULTS: The population studied was homogenous among three groups as regards age (p=0.943), lipid profile (p=0.271), BMI (p=0.506), homocysteine (p=0.177), antiphospholipid antibodies (p=0.576), and positive family history (p=0.099). There was no difference in the prevalence of FVL between venous and arterial disease (p=0.440). Significant correlation of PTM with venous TED was found (p=0.001). The number of positive and negative for MTHFR presented statistically significant difference with a support in arterial disease (p=0.05). Moreover, a 2-fold increase in the risk of venous thrombosis in FVL positive patients (odds ratio: 2.153) and a positive correlation of homocysteine levels with MTHFR C677T (p<0.001) was found. CONCLUSIONS: Correlation of PTM with venous thrombosis was established. Analysis showed no difference in prevalence of FVL between venous and arterial thrombosis, indicating that FVL might be a predisposing factor for arterial disease. A significant increase in MTHFR C677T prevalence in arterial disease was found. In conclusion, young patients with unprovoked arterial disease should undergo evaluation for thrombophilic genes. Identification of these mutations is important in the overall assessment and management of patients at high risk. Findings will influence the decisions of stratified approaches for antithrombotic therapy either primary or secondary thromboprophylaxis, the duration of therapy, the potential for avoiding clinical thrombosis by risk factor modification and the genetic counselling of family members. However, further studies are needed to clarify the nature of the association regarding venous and arterial thrombotic events. PMID- 23935294 TI - Risk factors of obesity in a cohort of 1001 Cypriot adults: An epidemiological study. AB - BACKGROUND AND AIMS: To measure the prevalence of overweight and obesity in adults in the Republic of Cyprus, and to evaluate and relate possible obesity risk factors of the adult Cypriot population. METHODS: This is an epidemiological cross-sectional study on a stratified random sample of 1001 (48.5% males-51.5% females) subjects, aged 18-80 years old. Anthropometric, biochemical, and dietary/lifestyle characteristics included in the study. RESULTS: The prevalence of overweight (Ow) and obesity (Ob) was 46.9% and 28.8% for males and 26% and 27% for females, respectively. Overweight and obese subjects were found to have statistically significant higher levels of Body Mass Index (p<0.001), Waist circumference (p<0.001), Total serum cholesterol (p<0.001), Low density lipoprotein (p<0.005), Glucose (p<0.007) and Triglycerides (p<0.001) compared to normal peers. In addition, Ow and Ob participants consumed significantly lower levels of fruits and vegetables (p<0.001), exercised less time/d (p<0.001) and smoke more cigarettes/d (p<0.001), compared to normal subjects, respectively. In multiple regression analysis of factors associated with overweight and obesity, Waist Circumference (beta: 1.132, p<0.001), Glucose (beta: 0.892, p<0.045), alcohol consumption (beta: 0.563, p<0.001), and exercise levels (beta: -0.444, p<0.001), were the most significant ones. CONCLUSION: The prevalence of overweight and obesity is very high in Cypriot adults. The current study also revealed a significant positive relation of Ow and Ob with waist circumference, high blood glucose levels and increased consumption of alcohol and a negative one with decreased levels of exercise. PMID- 23935295 TI - Inappropriately repeated lipid tests in a tertiary hospital in Greece: the magnitude and cost of the phenomenon. AB - BACKGROUND: Demand and costs of laboratory testing are increasing worldwide. It seems that a considerable proportion of the tests requested do not follow the published guidelines. Tests comprising the lipid profile are advised for the entire population, as determinants of cardiovascular risk. Published guidelines exist for different groups of the population. This study is an attempt to assess the volume and the cost of the excessive demand for laboratory measurements of lipids concerning inpatients of a tertiary teaching hospital in Athens, Greece. METHODS: Tests were characterized as inappropriate through revision of guidelines for lipid measurement. The demand for laboratory measurement of lipid blood levels was studied by collecting data from the hospital's test result database. The study was conducted during the trimester October to December 2008 and 20,698 tests from 3,279 inpatients were reviewed+9. RESULTS: The results of this study are consistent with international observations showing a significant percentage of clinically inappropriate laboratory tests and the consequent financial burden. The inappropriately repeated lipid tests during the trimester reached the number of 7,938 costing ? 12,680 to the hospital. Almost half of the inpatients were tested more than twice a month. CONCLUSIONS: Physicians' behavior is an important factor, as is derived by certain profiles of the wards studied. Guidelines are not followed when ordering lipid tests. Curtailing of these excessive laboratory tests has been shown to be feasible using cheap strategies and will yield considerable benefits for patients and hospitals alike. PMID- 23935296 TI - Peritonitis due to uncommon gram-positive pathogens in children undergoing peritoneal dialysis. AB - Peritonitis is still the main complication of peritoneal dialysis (PD) in children. Staphylococcus, especially Staphylococcus epidermidis and Staphylococcus aureus, are the predominant species isolated, followed by Streptococcus spp. and by far by gram-negative bacteria and fungi. We describe three cases of PD-related peritonitis in pediatric patients due to uncommon gram positive pathogens, which were treated with intraperitoneal antibiotic agents. PMID- 23935297 TI - Solitary fibrous tumours: unusual aspects of a rare disease. AB - BACKGROUND: In literature there are only a few descriptions of the typical presentation of solitary fibrous tumours (SFT) and only a few case reports showing its unusual clinical and radiological features. METHODS: We retrospectively evaluated the computed tomography scans of 36 patients presenting with a histological diagnosis of SFT between 1998 and 2008. RESULTS: We present five cases of SFT with an atypical clinical presentation and radiological features. CONCLUSIONS: SFT can occasionally present with unusual radiological features making a differential diagnosis difficult. Even thought imaging plays a fundamental role in the initial diagnostic approach, final diagnosis in only confirmed by biopsy and histology. PMID- 23935298 TI - Psychosis following stab brain injury by a billiard stick. AB - Traumatic brain injury sometimes can lead to psychotic disorder which resembles schizophrenia. We report a 17-year-old boy, admitted to psychiatric department for psychotic symptomatology. He had suffered penetrating craniocerebral injury after stabbing by a billiard stick, three years earlier. On admission, he expressed delusions with paranoid and religious content. The magnetic resonance imaging of the brain showed a 10 cm large tubular area of posttraumatic encephalomalacia of the left hemisphere, whereas the electroencephalography revealed slow left temporal activity. The patient's recovery was uneventful with clozapine at a dosage of 100 mg daily. This case shows the diagnostic challenge in differentiation between schizophrenia and psychotic disorder due to traumatic brain injury. The authors emphasise the importance of imaging of the brain, especially magnetic resonance, in establishing the diagnosis of psychotic disorder due to traumatic brain injury. PMID- 23935299 TI - Giant transmural lipoma of the sigmoid colon. AB - Lipomas of the colon are relatively rare benign tumors of mesenchymatic origin. They are usually asymptomatic but as they become larger they can cause symptoms including abdominal pain, diarrhea, nausea, constipation, haematochezia, loss of body weight, anemia or even intussusception and colonic obstruction. We present a 52 year old male patient who visited the emergency room complaining of constipation, rectal bleeding, mucus in stools and a palpable rectal mass. Colonoscopy revealed a polypoid mass of the sigmoid colon lying about 30 cm from the anal verge. Sigmoidectomy was performed. The postoperative recovery was uneventful and he was discharged five days later. At follow up a month after surgery the patient was asymptomatic. The pathological examination revealed a transmural tumor of the sigmoid colon measuring a 9x5x2.5cm and histologically compatible with a lipoma. PMID- 23935300 TI - Gastric schwannoma: a case report and literature review. AB - Schwannomas are generally benign, slow growing tumors, which can originate from any nerve that has a Schwann cell sheath. Digestive tract schwannomas are rare and are usually asymptomatic. We present the case of a 48-year-old woman with a symptomatic submucosal tumour of the gastric antrum. The patient underwent partial gastrectomy and the histological and immunohistochemical findings of the resected specimen established the diagnosis of schwannoma. PMID- 23935301 TI - Idiopathic acute transverse myelitis: Complete recovery after intravenous immunoglobulin. AB - Idiopathic acute transverse myelitis is a focal inflammatory disorder of the spinal cord of unknown etiology diagnosed according to established criteria. As it occurs rarely in children herein we report a case of a 4 year old boy who developed clinical and radiological manifestations of myelitis, 10 days after a recent respiratory tract infection. Diagnostic workup failed to reveal a causative factor. After the administration of corticosteroids a clinical deterioration was observed and intravenous immunoglobulin was administered. Symptoms resolved within a 48-hour period, suggesting an immune-mediated pathogenetic mechanism. PMID- 23935302 TI - Pulmonary tuberculosis in an adult patient with tetralogy of Fallot. PMID- 23935303 TI - Honey and its protective role against oxidation of human low density lipoproteins and total serum lipoproteins. PMID- 23935304 TI - The current role of radiotherapy in "Bilateral exophthalmos in Grave's Disease". PMID- 23935305 TI - Cells and pumps: Mechanical support and cellular therapy emerge as a realistic alternative to heart transplantation. PMID- 23935307 TI - Mechanisms responsible for the emergence of carbapenem resistance in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen associated with a range of nosocomial infections. This microorganism is noted for its intrinsic resistance to antibiotics and for its ability to acquire genes encoding resistance determinants. Among the beta-lactam antibiotics, carbapenems with antipseudomonal activity are important agents for the therapy of infections due to P. aeruginosa. The development of carbapenem resistance among P. aeruginosa strains is multifactorial. Plasmid or integron-mediated carbapenemases, increased expression of efflux systems, reduced porin expression and increased chromosomal cephalosporinase activity have all been defined as contributory factors. Phenotypic tests and molecular techniques are used for the characterization of the resistance determinants. The isolation of carbapenem resistant strains is alarming and requires the implementation of strict infection control measures in order to prevent the spread of carbapenemase encoding genes to unrelated clones or to other bacterial species. PMID- 23935308 TI - Is brain death diagnosis in newborns feasible? AB - Brain death as the irreversible and permanent loss of cerebral and brainstem function, is relatively uncommon among newborns who need life support. It is considered the result of an acute and irreversible central nervous system insult. Asphyxia, severe intracranial hemorrhage and infection are the most common causes of brain death in children. BD diagnosis is usually based on clinical criteria. Because of major differences of brain function in this age group, brain death should be established with extreme caution. Comparative to adults' longer observational periods (at least 24 hours apart) and specific neurodiagnostic tests, by at least two expert physicians, are needed to ascertain an irreversible loss of brain function. The objective of this article is to present current guidelines for BD determination in newborns and to refer their application in Greece. PMID- 23935306 TI - Differential diagnosis of hyperkalemia: an update to a complex problem. AB - Hyperkalemia is a relative common and sometimes life threatening electorlyte disorder. Although its symptomatic treatment is relatively easy, since precise therapeutic algorithms are available, its differential diagnosis is more complicated. The present review aims to unfold the differential diagnosis of hypekalemia using a pathophysiological, albeit clinically useful, approach. The basic elements of potassium homeostasis are provided, the causes of hyperkalemia are categorized and analysed and finally the required for the diferrential diagnosis laboratory tests are mentioned. PMID- 23935309 TI - Moving toward the utilization of all donated liver grafts. The "b-list" concept. AB - The number of available liver grafts is not sufficient to meet the current demand. A significant number of patients succumb before they receive a liver graft. However, approximately 10% of marginal livers are considered unsuitable for donation and are discarded. Calculating the primary non-function probability for any given liver graft can be performed using prognostic tools, such as the Donor Risk Index and the Eurotransplant Donor Risk Index. On the other hand, mortality on the waiting list, which is sometimes more than 15% per year of enlistment, directly correlates with its size, the graft supply and the gravity of the potential recipients' clinical condition. Up to 30% of the potential recipients will never receive a graft. The purpose of this invited commentary is to examine whether the literature supports the utilization of the marginal liver grafts that would otherwise be discarded. It appears that there is sufficient evidence in favor of the development of a "B-list" for potential liver graft recipients. It should comprise all of the candidates who were definitely removed from the primary waiting list or were never included. The potential "B-list" recipients should only be eligible to receive grafts that would otherwise be discarded, i.e., "B-livers". Enrollment in a "B-list" might not only increase the overall patient survival (enlisted and transplanted combined) but might also improve candidate quality of life by maintaining their hope for a cure. PMID- 23935310 TI - Burkholderia cenocepacia bacteremia without respiratory colonization in an adult intensive care unit: epidemiological and molecular investigation of an outbreak. AB - BACKGROUND: To investigate an outbreak of Burkholderia cenocepacia bacteremia. Observational study and chart review in a multidisciplinary adult Intensive Care Unit (ICU) at a tertiary care hospital. METHODS: Patients' demographic variables, comorbid conditions, ICU admission diagnosis, disease severity and outcome were analyzed. In case-patients, time and possible sources of bacteremia, molecular assays, antimicrobial susceptibility and response to therapy were also recorded. RESULTS: During a 9-month period, 30 episodes of B. cenocepacia bacteremia were diagnosed in 21 patients. Median time for a positive blood culture was 9 days after admission. None of the case-patients had respiratory colonization prior to onset of bacteremia. Pathogen was susceptible to meropenem, piperacillin/tazobactam, ciprofloxacin and trimethoprim /sulphamethoxazole. Surveillance involved environmental and patient/personnel cultures. All samples were negative for B. cenocepacia. However, extensive assessment revealed lapses in infection control procedures. PFGE molecular typing showed that all isolates were indistinguishable. Prior surgery and septic shock on ICU admission were significantly more frequent among case-patients. These patients needed significantly prolonged mechanical ventilation, central venous catheterization and ICU hospitalization. All patients responded to antimicrobial therapy and the attributed mortality was zero. Complete elimination of the outbreak was achieved only after strict enforcement of infection control policies and ICU disinfection. CONCLUSION: The outbreak influenced ICU morbidity but it did not affect mortality. Although extensive environmental investigations failed to identify the source of infection, B.cenocepacia disappeared after implementation of control measures. Effective outbreak elimination cannot be limited to offending reservoir removal but needs to extend to efficient infection control practices. PMID- 23935311 TI - Stroboscopy for benign laryngeal pathology in evidence based health care. AB - BACKGROUND AND AIMS: Voice disorders are common. The aim of this study is to evaluate the diagnostic value of stroboscopy for voice disorders related with benign pathology and apply results in evidence based health care. METHODS: Prospective study. Tertiary care hospital. Voice Clinic. One hundred and fifty consecutive patients with an initial diagnosis of benign laryngeal disease or dysphonia of no clarified cause (normal laryngoscopy) were examined stroboscopically and studied prospectively until a final diagnosis was reached. Sixty-six men, eighty women and four children met the selection criteria for the study and had adequate follow-up. The initial laryngoscopic diagnosis was compared to the stroboscopic diagnosis. The diagnostic value of stroboscopy was rated at a scale of 0 to 3. A score 3 describes the diagnostic value of stroboscopy in the cases where the stroboscopic examination resulted to a change of the therapeutic modality offered to the patient. RESULTS: For one third of the study's population the diagnostic value of stroboscopy was very significant, since it established the laryngeal pathology responsible for the voice disorder (28.8%) and for a small number of patients it changed the choice of treatment (4.7%). For about one third of the cases (32.2%) stroboscopy offered additional information regarding the cause of dysphonia. The diagnostic value of stroboscopy correlated with the type of laryngeal pathology. CONCLUSIONS: Patients expected to benefit from stroboscopic examination are patients with small lesions of the vocal fold edge, dysphonic patients with unremarkable indirect laryngoscopy, and professional voice users. PMID- 23935312 TI - Bioimpedance and echocardiography used interchangeably in volume comparison of dialysis patients. AB - BACKGROUND: Euvolemia is a major issue in chronic kidney disease. The present study compares cardiac condition and volume status in peritoneal dialysis (PD) and hemodialysis (HD) patients and points out importance of volume control. METHODS: From a single-center center, 81 PD and 89 HD patients were enrolled. Echocardiography and body composition analysis using bioimpedance spectroscopy (BIS) technique were performed. Overhydration (OH) and extracellular water (ECW) in liters and OH/ECW % were used as volume indices. RESULTS: Patients were younger (47.6+/-14. 5 and 53.1+/-11.8 years, p< 0.05), daily urine volume higher (1068+/-926 vs 290+/-444 ml, p <0.001) and dialysis vintage was shorter (30.1+/ 18.6 vs 53.6+/-35.4 months, p<0.001), systolic blood pressure was lower (127.5+/ 15.4 vs 140.3+/-18.9 mmHg, p<0.001) in PD than HD group respectively. Volume indices were (OH, OH/ECW %, ECW/height, ECW to Intracellular Water ratios (E/I) (p<0.05)) significantly higher in HD patients compared to PD patients. Over all 66 of 170 patients (39%) had OH/ECW % <5 and OH/ECW % ratio was positively correlated with Left atrium index (R(2):0.105, p<0.05). Interventricular septum diameter and Left ventricular mass index (1.41+/-0.24 and 159.6+/-48.2 vs. 1.27+/ 0.17 cm and 115.8+/-37 g/m(2), p<0.001) were increased in HD than in PD group. After multivariate adjustment OH/ECW increased with: HD and diabetic patients. LVH increased with: HD group, OH/ECW (%) and SBP significantly. CONCLUSION: Overhydration was more common among HD. Excess fluid may lead adverse effect in organ functions especially cardiac condition. This indicates that the current clinical and technical tools to achieve euvolemia are insufficient and that an additional tool, such as BIS, could be useful in the diagnosis of overhydration. PMID- 23935314 TI - Virologic response and resistance to lamivudine in patients with chronic hepatitis B: a ten-year retrospective analysis. AB - BACKGROUND: Emergence of resistance was recognized shortly after the introduction of lamivudine. This 10 year retrospective study investigates resistance to lamivudine and the modifications of antiviral strategies required. PATIENTS AND METHODS: Two hundred and nine patients were treated with lamivudine. Sixty seven out of 209 patients were excluded from the present study. HBVDNA was tested using the PCR assay and genotypic resistance was performed using the direct PCR sequencing. RESULTS: In the 125 patients initially treated with lamivudine monotherapy: Alpha) 48 (38.4%) patients with a mean time of 63.6+/-26.2 months under lamivudine treatment have normal ALT levels with negative (19%) or low (<1X102) HBVDNA levels, 10% developed cirrhosis, 1 HCC and 6% cleared HBsAg. Beta) Resistance was developed in 61.60% patients within 45+/-23.84 months of lamivudine treatment. These patients were: 1) either switched to adefovir (9), entecavir (2) or tenofovir (2) or adefovir was added to lamivudine (21) for a short time and then they were switched to adefovir alone. Six out of 34 patients developed cirrhosis and 4 HCC while on treatment. 2) or adefovir was added-on to lamivudine (43). In 39 out of 43 treatment is ongoing while on virological response. No one developed cirrhosis or HCC. C) Seventeen patients received de novo combination therapy with lamivudine and adefovir and 2 out of 17 (11.7%) showed resistance to adefovir after 24 months of therapy. CONCLUSIONS: Our results showed that a) approximately 38.4% of patients maintain viral suppression more than 5 years of lamivudine treatment and b) rescue therapy with add-on adefovir to ongoing lamivudine, seems to be a better treatment strategy associated with long term benefit regarding disease complications. PMID- 23935313 TI - Effects of alternate fasting or very low calorie diet and low calorie diet on metabolic syndrome in severely obese patients. AB - BACKGROUND AND AIM: Weight loss improves the metabolic syndrome (MetS) features and related clinical abnormalities in obese subjects. The aim of this study was to assess the effects of a non-surgical therapeutic program on the MetS in severely obese patients. PATIENTS AND METHODS: Sixty-four extremely obese patients were involved in the therapeutic program, which consisted of two alternating phases: the three-week therapeutic fasting or semi-fasting in hospital conditions and the low calorie diet with dosed physical activity in outpatient conditions. At the baseline we measured: anthropometric parameters, blood pressure and lipid profile. Subjects underwent an oral glucose tolerance test and insulin resistance/sensitivity was evaluated by the homeostasis model assessment and the oral glucose insulin sensitivity. After weight reduction by at least 10%, all mentioned assessments were repeated. RESULTS: None of the patients had significant adverse effects. Forty-one patients aged 43.0+/-11.5 years completed the study. The mean weight loss was 27 kg or 18% of the initial weight (p<0.01), which was followed by a significant decrease of the insulin resistance, the overall prevalence of MetS (32%) and all MetS parameters, without the significant change in high-density lipoprotein. This weight loss pogram substantially improves the MetS in extremely obese patients. CONCLUSION: The tailored alternating either fasting or semi- fasting should be considered as an optional approach to manage extreme obesity and related metabolic abnormality. PMID- 23935315 TI - Trimebutine as a potential antimicrobial agent: a preliminary in vitro approach. AB - AIM: The aim of this preliminary study was to investigate the in vitro effect of "non-antibiotic" trimebutine against reference strains Staphylococcus aureus ATCC 29213, ATCC 25923, Escherichia coli ATCC 25922, ATCC 35218, Pseudomonas aeruginosa ATCC 27853 and Enterococcus faecalis ATCC 29212; microbiota that are potentially involved in the pathophysiology of post-infectious functional gastrointestinal disorders. METHODS: Trimebutine activity was assessed by the broth microdilution method according to Clinical and Laboratory Standards Institute recommendations against reference strains S. aureus ATCC 29213 and ATCC 25923, E. coli ATCC 25922 and ATCC 35218, P. aeruginosa ATCC 27853 and E. faecalis ATCC 29212. Bactericidal activity of the compound was determined by spreading a 10 MUL aliquot on Mueller-Hinton agar from each dilution showing non visible growth. All tests were carried out in triplicate. RESULTS: Trimebutine was active against all strains tested presenting with MIC ranging from 1024 to 4000 mg/L. MIC and MBC were similar for E. coli ATCC 25922 and P. aeruginosa ATCC 27853 whereas for Gram-positive isolates and E. coli ATCC 35218 the MBC was higher. CONCLUSIONS: We demonstrated the in vitro bacteriostatic/bactericidal activity of trimebutine against bacteria frequently colonizing the gastrointestinal tract and potentially involved in human gastrointestinal infections that might trigger post-infectious functional gastrointestinal disorders. PMID- 23935316 TI - A three-year Performance Evaluation of the NHS Hospitals in Greece. AB - PURPOSE: The purpose of this study was to access the performance of 117 Greek National Health System (NHS) hospitals for the year 2011, to compare the findings with the results from similar studies of the previous years (2009 and 2010) and to investigate the changes during the last three years of financial crisis. METHOD: An input-oriented Data Envelopment Analysis was used to measure three indicators, technical, pure technical and scale efficiency indicators. Data was collected from the reports of the web-based facility (ESY.net) which was developed by the General Secretary of Ministry of Health and Social Solidarity. The input variables were the number of physicians, the number of nurses and other personnel, the number of beds and expenditures of every hospital. The output variables were the number of inpatient and outpatient visits. Hospitals were categorized into three size groups. RESULTS: Between the years 2009-2011, all hospitals, especially middle-sized hospitals showed performance improvement on all three indicators. Specific problems were noticed mainly in large-sized hospitals. The technical efficiency of Large-sized hospitals was estimated at 80%, of Middle-sized hospitals at 82% and of Small hospitals-Health Care Centres at 89%. Pure technical and scale efficiency varied between satisfactory levels throughout the study period. CONCLUSION: Comparing the 2009-2011 data, an improvement of technical efficiency in NHS hospitals has been achieved up to 100%, mainly in the middle-sized hospitals. Specifically, an increase of best practice hospitals has been noted, especially in the middle and small-sized hospitals, when certain units were added the technical efficiency reached over 80%. The consequences of the spending-cuts and the constant reforms appear to have a positive effect on hospitals' efficiency. PMID- 23935317 TI - Zinc status in patients with chronic renal failure on conservative and peritoneal dialysis treatment. AB - BACKGROUND AND AIM: The physiological mechanisms regulating zinc homeostasis in humans have been elucidated and described, but the knowledge of zinc status and zinc distribution in the tissues and in the different biological compartments of patients with conservatively treated chronic renal failure (CRF) and on peritoneal dialysis is still insufficient. This investigation examines and compares zinc content in urine, erythrocytes, plasma, and outflow dialysis solution in a group of continuous ambulatory peritoneal dialysis (CAPD) patients, a group of patients with CRF on conservative treatment and in healthy controls. MATERIAL AND METHODS: Data from the last 6 months of 22 adult hemodialysis patients with a mean age of 61 +/- 14 years were analyzed retrospectively. Dialysis vintage, normalized protein catabolic rate (nPCR), serum biochemical parameters, mid arm muscle circumference (MAMC) were determined as mean and standard deviation. Correlations between the variables were computed by coefficient p of Pearson. RESULTS AND CONCLUSION: In patients on CAPD treatment (group 3) compared to healthy controls (group 1) plasma zinc level was diminished (r<0.05), while erythrocyte zinc elevated (r<0.01). The investigation found out difference between plasma, erythrocyte and urine levels of zinc between the patients with chronic renal failure (group 2) on conservative treatment and those treated by CAPD (group 3), which proves, that continuous ambulatory peritoneal dialysis influences redistribution of zinc in human organism "per se". PMID- 23935318 TI - Retinol Binding Protein 4 in children with Inflammatory Bowel Disease: a negative correlation with the disease activity. AB - OBJECTIVES: Retinol Binding Protein-4 (RBP-4), the action of which was initially thought to be only the transport of vitamin A, is a major circulating adipocytokine involved in the inflammation. We evaluated the serum RBP-4 levels in children with inflammatory bowel disease (IBD) and correlated them with transthyretin (TTR), inflammation markers, disease activity, and body mass index (BMI). DESIGN: In 41 children of mean age 11.9 +/- 3.6 years (range 5-17.7 y) with IBD (19 with Crohn's disease (CD) and 22 with Ulcerative colitis (UC) serum RBP-4, TTR, Amyloid A (SAA), C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), disease activity and BMI were prospectively determined and compared with those of 42 matched controls. RESULTS: No difference in the RBP-4 and TTR serum levels, between patients and controls as well as between active and remission state of the disease was noticed. A negative correlation of serum RBP-4 with the disease activity, SAA and ESR and a positive correlation with TTR was found, but no significant correlation with CRP or BMI was found. Inflammation markers were significantly increased in patients compared to controls and had a positive correlation with the disease activity. CONCLUSIONS: RBP-4 negatively correlated with disease activity of children with IBD probably indicating a protective anti-inflammatory mechanism of action in addition to transport of vitamin A. PMID- 23935319 TI - Intramyocardial implantation of autologous bone marrow-derived stem cells combined with coronary artery bypass grafting in patients with ischemic cardiomyopathy: a pilot study. AB - BACKGROUND: Ischemic cardiomyopathy has the distinctiveness of irreversible myocardial damage with scar tissue formation and mainly impaired perfusion of the remaining viable myocardium. We present results of the first series of patients with severe ischemic cardiomyopathy managed in our institution with intramyocardial implantation of autologous bone marrow stem cells at the time of coronary artery bypass grafting. The aim is to evaluate feasibility and safety of the procedure in our institution. PATIENTS AND METHODS: Nine patients with severe ischemic cardiomyopathy scheduled for elective coronary artery bypass grafting were managed with concurrent intramyocardial autologous bone marrow stem cells injection in pre-defined viable peri-infarct areas that showed poor perfusion and could not be grafted. Detailed mapping of infracted and hibernating myocardial segments was performed in all patients with single photon emission computed tomography segmental analysis. RESULTS: There was no perioperative 30-day mortality. Improvement was evident in left ventricular ejection fraction which was increased significantly from 31.3% preoperatively to 42.4%, 46.6% and 52.5% at 3, 6 and 12 months respectively. Postoperative thallium scintigraphy revealed increased perfusion in myocardial segments corresponding to areas of stem cell injection and a net reduction in the estimated infarct size at 6 and 12 months in 5/8 (62.5%) patients. CONCLUSIONS: Preliminary data from this pilot study show that intramyocardial administration of bone marrow stem cells in patients undergoing coronary bypass grafting for ischemic cardiomyopathy is safe and associated with an improvement in left ventricular function and enhanced reperfusion of non-viable myocardial territories. PMID- 23935320 TI - Wernicke's encephalopathy and anabolic steroid drug abuse. Is there any possible relation? AB - Wernicke's encephalopathy is a reversible, neurologic disorder due to thiamine deficiency which is mainly related to chronic alcohol abuse. We report a case of a young male patient, who was bodybuilder and anabolic drug user, in whom encephalopathy was diagnosed after a short medical course in the ICU after a major upper gastrointestinal bleeding (Mallory-Weiss syndrome) and hypovolemic shock. His clinical condition was typical for Wernicke's encephalopathy and although neuroimaging tests were not indicative, the patient received thiamine supplement therapy, which resulted in rapid clinical improvement. The diagnosis was based only on clinical sings and anabolic drug abuse was considered as a possible predisposing factor for the manifestation of the syndrome. PMID- 23935321 TI - Management of a patient with Opalski's syndrome in intensive care unit and mini review of the literature. AB - Stroke syndromes include a variety of syndromes with often overlapping clinical presentations. When ipsilateral hemiplegia is associated with symptoms of a lateral medullary syndrome, it corresponds to the submedullary syndrome of Opalski. A 72-year-old woman presented with sudden onset of headache, gait disturbance, and recurrent vomiting. Her clinical status gradually deteriorated and she was admitted to the intensive care unit where a variety of problems, related to her diagnosis (Opalski syndrome), were managed. PMID- 23935322 TI - Distal ischemia induced by vascular access for hemodialysis - a case report. AB - Arteriovenous fistulas for hemodialysis may cause significant local and general changes in the bloodstream. Vascular access-induced ischemia is a rare but very serious complication which, if not treated in time, can lead to tissue necrosis. We describe a 66 year-old man with symptoms of distal limb ischemia caused by an arteriovenous fistula for hemodialysis. PMID- 23935323 TI - Fleshy palmaris longus muscle - a cadaveric finding and its clinical significance: a case report. AB - INTRODUCTION: Palmaris longus variations may include complete agenesis, variation in the location and form of the fleshy portion, aberrancy in attachment, duplication or triplication, accessory tendinous slips, replacing elements of similar form or position. Description of case: An anomalous palmaris longus muscle was found in the right upper extremity of a 63 year-old male cadaver. The muscle was totally fleshy without a long insertion tendon. Its origin was normal, the belly was rather broad and long, fusiform at the upper half and unipennate at the lower half of the forearm, and it was toggled into a short and thick tendon. At its insertion the tendon was split forming a second thinner tendon. The thick tendon was inserted into the flexor retinaculum and the thinner one into the palmar aponeurosis. The muscle compressed the median nerve although no related symptoms were reported on the cadaver's medical history. DISCUSSION: This variation is of clinical importance because it may cause carpal tunnel syndrome or difficulties in image interpretation by radiologists. In addition the palmaris longus muscle is an anatomical landmark for operations at the forearm and wrist and its tendon can be used as a graft. PMID- 23935324 TI - Community acquired quinolone-resistant Escherichia coli pyelonephritis complicated with multiple renal abscesses: a case report. AB - Acute pyelonephritis is a potentially organ-damaging and life-threatening infection. A 37-year old woman was admitted to Intensive Care Unit in septic shock and multi-organ failure due to acute pyelonephritis with systemic bacterial dissemination caused by a quinolone-resistant Escherichia coli. The patient, a previously healthy woman, reported recurrent episodes of urinary tract infection in the previous 3 years, which were treated with quinolones. Treatment course with broad-spectrum antimicrobial agents reversed her septic shock and multi organ failure. However, pyelonephritis progressed to intrarenal and perirenal abscesses formation. The patient fully recovered after surgical removal of the infected kidney. PMID- 23935325 TI - H275Y oseltamivir resistant Influenza A (H1N1) strains in northern Greece during the post pandemic influenza season 2010-2011. PMID- 23935326 TI - Development of type 2 diabetes after gestational diabetes mellitus. PMID- 23935327 TI - Late abdominal wall inflammatory mass mimicking drain site recurrence after rectal cancer surgery. PMID- 23935328 TI - Splenic emboli owing to left ventricle mural thrombus: an unusual cause of acute abdominal pain. PMID- 23935329 TI - Successful treatment with Rituximab in a patient with life-threatening resistant Thrombotic Thrombopenic Purpura. PMID- 23935330 TI - Ilio-femoral by-pass in a patient with heparin-induced thrombocytopaenia (HIT). PMID- 23935331 TI - Pacemaker infection due to Brucella Melitensis. PMID- 23935332 TI - Radiation Therapy in Chloroma: A promising palliative manipulation. PMID- 23935333 TI - Ovarian metastasis from breast invasive ductal carcinoma. PMID- 23935334 TI - Laparoscopic Gastric Plication: Its pitfalls and intrigues. PMID- 23935335 TI - (18)F-FDG PET and PET/CT for the diagnosis of diabetic foot osteomyelitis. PMID- 23935336 TI - Body composition in multiple sclerosis. AB - Multiple sclerosis affects central nervous system leading to disability. Among other complications the deterioration of body composition is usually neglected and increases the risk for diseases such as coronary heart disease, non-insulin dependent diabetes mellitus, lipid abnormalities and bone loss leading to fractures in this population. Body mass index values, the effect of spasticity, the increased number of drugs used and the relationship between skeletal muscle and bone which interacts with impaired motor function leading to body composition alterations in multiple sclerosis are reviewed. PMID- 23935337 TI - Vasoactive intestinal Peptide inhaled agonists: potential role in respiratory therapeutics. AB - PURPOSE OF REVIEW: Vasoactive Intestinal Peptide (VIP) is a neuropeptide, expressed by lymphoid as well as neural cells, which has diverse effects on the cellular mediators of inflammation and immunity and is also a potent neurotransmitter. VIP seems to have a major role in the homeostasis of the respiratory system, while several studies, including clinical trials, suggest that VIP-inhaled agonists could be used in respiratory therapeutics. In this review, we provide an introduction to the field of VIP research geared to clinical and research pulmonologists. RECENT FINDINGS: As a neurotransmitter, VIP exerts a potent bronchodilatory and vasodilatory effect and also is supposed to induce the house-keeping mucus secretion by submucosal glands. On the other hand, it has immunomodulatory functions which include humoral immune response suppression, inhibition of vascular and bronchial remodeling and inflammation and attenuation of the cigarette smoke extract-induced apoptotic death of alveolar L2 cells. Recent research on a wide spectrum of lung diseases including asthma, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary hypertension, and sarcoidosis indicates a potential therapeutic role of a VIP agonist. Simultaneously, novel stabilized inhaled VIP agonists and drug delivery systems have been proposed as a promising candidate alternative drug with minimized side effects. These data are supported by the results of certain, limited clinical trials which have already been conducted. CONCLUSION: Ongoing research continues to clarify the immunomodulatory effects of VIP and to confirm animal findings with human studies. A major challenge for investigators will be to determine whether stabilized inhaled-VIP agonists could be used in respiratory therapeutics. PMID- 23935338 TI - Laboratory surveillance of influenza virus in children under 10 years old, in northern Greece, during 2004-2010. AB - OBJECTIVES: Influenza viruses constitute one of the most common pathogens that cause acute respiratory disease in children. The aim of this study is to present the contribution of influenza viruses to influenza-like illness (ILI) in children (aged<10 years old) in Northern Greece during six influenza seasons (2004-2010). MATERIALS AND METHODS: 1,242 pharyngeal swabs or/and washes from children younger than 10 years old, presented as ILI infections during the last six influenza seasons (2004-2005, 2005-2006, 2006-2007, 2007-2008, 2008-2009 and 2009-2010) were examined for influenza A and B by Real-time one step RT-PCR. RESULTS: Influenza viruses were detected in 431 (34.7%) of the 1,242 specimens. In a total of 372 specimens were positive for influenza A and 58 for influenza B. The majority of the infected young patients were 6-10 years old (51.9%). CONCLUSION: Our results show that in N. Greece, influenza viruses type A and B contribute to ILI presenting infections at a rate of 34.7 % in children younger than 10 years old. PMID- 23935339 TI - Epidemiology of community-acquired Mycoplasma Pneumoniae respiratory tract infections among hospitalized Chinese children, including relationships with meteorological factors. AB - BACKGROUND: Mycoplasma Pneumoniae (M. pneumoniae) is a common cause of respiratory tract infections (RTIs), especially in children. Combined diagnostic techniques have provided more reliable information about the epidemiology of infections by this pathogen. The relationship between M. pneumoniae RTIs and climatic conditions is not well documented in the literature. AIMS: To study the epidemiology of M. pneumoniae infections in hospitalized children with RTIs and its association with meteorological factors. METHODS: Samples were obtained from children with RTIs and tested for M. pneumoniae by PCR and ELISA. Meanwhile, meteorological factors were recorded. RESULTS: M. pneumoniae was identified in 11.02% of the 8,157 specimens. There were significant differences among the annual distribution of infections (chi(2) =130.13, P<0.0001) and among different seasons (chi(2) =93.59, P<0.0001). Of the total number of patients with M. pneumoniae infections, 14.5% were infected with more than one pathogen. M. pneumoniae infection strongly correlated with mean temperature. Children with a single M. pneumoniae infection had significantly higher neutrophil percentages and CRP levels than children with co-infections. CONCLUSIONS: M. pneumoniae is one of the most commonly held pathogens, according to the 5-year surveillance. M. pneumoniae infection has its own epidemic season, especially in the summer. Mean temperature is the main meteorological factor affecting the epidemiology of M. pneumoniae infections. PMID- 23935340 TI - Prevalence of Barrett's esophagus in Northern Greece: A Prospective Study (Barrett's esophagus). AB - BACKGROUND: Barrett's esophagus(BE) is a premalignant condition associated with chronic gastro-esophageal reflux disease (GERD). As only a small proportion of BE progresses to malignancy, it is important to study BE prevalence to prevent adenocarcinoma. MATERIALS AND METHODS: Between January 2007 and December 2010, all consecutive individuals who underwent routine upper endoscopy were prospectively recruited. Patients referred for GERD were excluded from the study. Clinical and endoscopic data were collected. RESULTS: A total of 1,990 patients (mean age 47.48+/-13.4 years; 52.8% males) were included. Of them, 496 (24.9%) reported GERD. Erosive esophagitis (EE) was found in 221 participants (11.1%, 193 patients with LA grade A and 28 patients with LA grade B). Overall 31 of 1494 participants not reporting reflux symptoms (2.07%) suffered from silent GERD. BE was diagnosed in 75 participants (3.77%), four (5.3%) with long-segment BE and 71 (94.7%) with short-segment BE. Low-grade dysplasia was noticed in 1 patient with long-segment BE. Hiatal hernia (HH) was found in 196 patients (9.8%), and mean HH length was 3.22 +/- 0.2 cm. BE was correlated to EE, GERD and the presence of HH (p= 0.0167, <0.001 and 0.017, respectively) whereas it was not associated with age, alcohol consumption and smoking (p= 0.057, 0.099 and 0.06, respectively). BE was not correlated with Helicobacter pylori infection (p=0.542). CONCLUSION: The prevalence of BE was 3.77% in a Greek population undergoing upper endoscopy not referred for GERD. Long-segment BE was very uncommon (0.2%) whereas 2.07% of patients not reporting symptoms suffered from silent GERD. PMID- 23935342 TI - Diagnosis and Genetic Counseling for Friedreich's Ataxia: A time for consideration of TP-PCR in an Indian Setup. AB - BACKGROUND AND INTRODUCTION: Expansion of GAA triplet repeats in the first intron of the frataxin gene causes Friedreich's ataxia. Genetic testing in such condition is important to initiate the appropriate genetic counseling for the family members. The conventional genetic tests used in the diagnosis of Friedreich's ataxia are southern blot, short and long PCR. Recently, triplet repeat primed polymerase chain reaction (TP-PCR) methodology was described in the diagnosis of Friedreich's ataxia, especially for detection of long repeats. Accurate genetic diagnosis of Friedreich's ataxia helps in differentiating it from other ataxias and helps provide appropriate genetic counseling for such families. Extended family screening and genetic counseling can prevent birth of children with Friedreich's ataxia in these families. MATERIALS AND METHODS: TP PCR was carried out in 37 samples obtained from Neurology clinic, Sanjay Gandhi Post Graduate Institute of Medical Sciences. The amplified products were subjected to genotyping on a ABI 310 genetic analyser. For heterozygosity, the samples were processed for short and long range PCR. RESULTS: A total of 37 samples of suspected cases of Friedreich ataxia were analysed. Of these, 81% samples were confirmed as Friedreich ataxia and 19% of samples were found to be negative for Friedreich's ataxia by TP-PCR. Extended family screening was done in 2 of the families. Among the 7 individuals screened, 4 were identified as carriers and genetic counseling was provided to them. CONCLUSIONS: This is first report from India which describes the molecular diagnosis of Friedreich's ataxia by TP-PCR, its utility in extended family screening and genetic counseling. It qualifies as a highly reliable, sensitive and robust technique that can easily be set up in any laboratory. PMID- 23935341 TI - Effectiveness of current teaching methods in Cardiology: the SKILLS (medical Students Knowledge Integration of Lower Level clinical Skills) study. AB - INTRODUCTION: The aim of the study is to assess reported changes in medical students' capacity to attain five basic cardiological clinical skills, following a one-month intensive cardiology course provisioned in the core curriculum. MATERIALS AND METHODS: An anonymous questionnaire comprising self reported performance in the five skills, namely 1) arterial blood pressure measurement, 2) cardiac auscultation, 3) electrocardiogram (ECG) carry out, 4) ECG interpretation and 5) defibrillation, was distributed to 177 fifth year students of the Athens Medical School upon initiating the cardiology course (pre-training group) and to 59 students matched for sex, age, year of study and training centre, following completion of the course (post training group). Comparison of pre- and post- training performance was evaluated using the chi(2) test. RESULTS: No change was noted with regards to blood pressure measurement, cardiac auscultation or defibrillation. By contrast, a statistically significant improvement was reported for ECG execution (54.3 versus 81.4%; p<0.001) and interpretation (from 33.1 to 89.8%; p<0.001). CONCLUSIONS: Improvement in the execution and interpretation of ECGs seems to be among the strengths of the cardiology training program. Further studies including larger samples from multiple medical schools and objective assessment of skill execution might facilitate accurate training evaluation and define opportunities for improvement. PMID- 23935343 TI - Is beverage intake related to overweight and obesity in school children? AB - BACKGROUND AND AIM: Recently, considerable attention has been given to beverage intake as a source of calories which may be linked to pediatric obesity. The purpose of our study was to evaluate the beverage intake in school children and adolescents aged 7 to 15 years old. METHODS: Six hundred and seven (607) out of 655 children participated in the study. One hundred percent fruit juice were classified those beverages that contain 100% fruit juice, without sweetener. Sweetened sugar beverages (SSBs) were included (fruit drinks sweetened fruit juice, fruit-flavored drink or drink that contained fruit juice in part, sweeten soft drinks, coffee, and tea). RESULTS: Around 84% of subjects consumed water while 81% of children who were included in the analysis consumed milk, 49.5% consumed 100% fruit juice, and 79.4 % SSBs. Whole milk was consumed by 40.9% of school children. Skim milk and 1% milk were consumed by 3.6% and 4.7% of the children, respectively. Children and adolescents consuming SSBs were 2.57 (95% CI: 1.06, 3.38) times more likely to become obese compared to normal peers. CONCLUSION: Sugar beverage drinks but not 100% fruit juices and milk are associated with obesity. Further studies investigating the relationship among beverage consumption, total energy intake, and development of overweight are needed. PMID- 23935344 TI - Risk factors associated with anemia among Serbian non-pregnant women 20 to 49 years old. A cross-sectional study. AB - BACKGROUND: Representative national data of prevalence of anemia and casual factors are missing for population group of reproductive aged non-pregnant females in Serbia. The purpose of the current study was to assess the prevalence and grades of anemia and its association with risk factors among non-pregnant women of childbearing age in Serbia. METHODS: Data were collected as part of the first "National Health Survey", a cross-sectional, multistage cluster survey, conducted on 677 households in Serbia. A total of 708 females 20-49-year-old were recruited. Socioeconomic, anthropometric, dietary and reproductive data have been collected and hemoglobin levels were determined. RESULTS: The overall prevalence of anemia was 27.7% (196/708) [95% Confidence Interval (CI), 24.5-31.1%], and more precisely mild (21.9%), moderate (5.1%) and severe (0.7%) anemia. Belgrade residential area [odds ratio 2.11 (95% CI 1.27-3.50), p=0.004], shortage of living space per person (<16m(2)) [2.18 (1.17-4.03), p=0.014], body mass index (<25) [1.55 (1.04-2.29), p=0.029], alcohol intake [0.52 (0.33-0.81), p=0.004], lack [2.48 (1.31-4.70), p=0.005] or fruit juice consumption 1-2 [2.76 (1.46 5.23), p=0.002] times a week and previously diagnosed, but treated [2.62 (1.29 5.35), p=0.008] or not treated [3.57 (1.71-7.45), p<0.001] anemia were independent predictors of low hemoglobin levels. Deficit of electricity supply and insufficient living space in households, increased risk of moderate anemia, while likelihood of being mild and moderately anemic, augmented with previously diagnosed but, treated or not treated anemia and lack or juice consumption 1-2 times a week. CONCLUSIONS: High prevalence of anemia among non-pregnant women and its association to casual factors needs continuous monitoring and control efforts for anemia in Serbia. PMID- 23935345 TI - Reduced total antioxidant status in postterm pregnancies. AB - BACKGROUND: The placenta is the major source of oxidative stress in normal human pregnancy. The placental tissue is typically functional in postterm pregnancies. We hypothesized that such pregnancies experience deteriorating oxidative balance and increasing oxidative stress. In this case-control study, our aim was to investigate the oxidative status in postterm pregnancies comparing with term by using total antioxidant status (TAS) measurement. METHODS: Fifty pregnant women who were in their 41st gestational week (GW) and whose labor had not yet started were selected for the study group. Fifty subjects whose spontaneous labor onset and who delivered before their 41st GW were included for control group. Venous blood samples were obtained from each participant before the onset of labor. A premixed reagent was used to obtain serum TAS measurements from the blood samples. The Mann-Whitney test was used to compare the groups. RESULTS: Age, gravity, and parity of the subjects were similar between the groups (p> 0.05). Body mass index (BMI) were statistically higher in postterm group (p =0.011). The median (interquartile range) TAS level was lower in the pregnancies beyond 41 weeks than term pregnancies [1.69 (0.12) mM vs 1.75 (0.20) mM, (p< 0.05)]. CONCLUSIONS: A lower total antioxidant status in past days pregnancy suggests an association with decreased oxidative status compared to term. It can be speculated that pregnancies beyond 41 weeks are associated with decreased oxidative stress and this may be play a role in the etiology of the prolonged pregnancy. PMID- 23935346 TI - Outcome of lung cancer patients admitted to the intensive care unit with acute respiratory failure. AB - BACKGROUND: Previous studies have shown that the outcome of lung cancer patients who were admitted to the Intensive Care Unit (ICU), especially those requiring mechanical ventilation, is extremely poor. The present study was conducted in order to assess the outcome of a recent cohort of lung cancer patients admitted to the ICU with acute respiratory failure. METHODS: A retrospective analysis of the medical records of 105 lung cancer patients who were admitted to the ICU between January 2008 and January 2011 was performed. Severity of illness on the first day of ICU admission was assessed using the acute physiology and chronic health evaluation (APACHE) II and the sequential organ failure assessment (SOFA) scoring systems. Associated organ failure was determined according to the Knaus criteria. RESULTS: Eighty four (80%) patients were diagnosed with non-small cell lung cancer, 14 (13.3%) with small cell lung cancer, one patient with mesothelioma, and in the remaining 6 patients, the type of lung cancer could not be determined. Significant factors on admission were APACHE II and SOFA scores, poor performance status and severe comorbidity. During ICU stay, the main risk factors for poor outcome were the long term mechanical ventilation duration, use of vasopressors, more than two organ system failures and septic condition. The overall ICU, hospital and 6-month mortality rates were 44.7% (47/105), 56.1% (59/105) and 77.1% (81/105) respectively. CONCLUSIONS: The present data show that the medical intensive care unit outcome of lung cancer patients is improving. Further studies of patients selected to ICU admission are needed to assess long term mortality, quality of life, ability to continue chemotherapy and economic cost. PMID- 23935347 TI - A comparison of the effects of topical green tea and lotus on facial sebum control in healthy humans. AB - BACKGROUND AND AIM: Green tea and lotus hold several synergistic antioxidant compounds. This investigation aimed to assess the efficacy of green tea and green tea plus lotus vs. placebo multiple emulsions in healthy adults for controlling casual sebum secretions. PARTICIPANTS AND METHODS: After signing informed consents, twenty-two participants were registered in a single-blinded, placebo controlled, split-face comparative study. Group 1 participants applied a multiple emulsion formulation with green tea extract while group 2 applied a multiple emulsion with green tea plus lotus extract in a 60 days treatment course. A non invasive photometric device (SebumeterTM) has been used for the measurement of casual sebum secretions on both sides of the face. RESULTS: Steady and statistically significant reductions in sebum secretions were noted for mono (green tea) and combined treatments (green tea plus lotus) compared to placebo treatment. However, irrespective of the concentration of extracts in active formulations, green tea plus lotus combined treatment produced statistically more sound results (two-tailed p value = 0.0002) than green tea alone (two-tailed p value = 0.0060) in a 60-days treatment course. CONCLUSIONS: RESULTS suggest that synergistic compounds in green tea and lotus could be a promising choice for cutaneous disorders where elevated sebum levels are involved in the pathophysiology of these disorders. PMID- 23935348 TI - Clinicopathologic characteristics and surgical treatment of solid pseudopapillary tumor of the pancreas. AB - BACKGROUND AND AIM: Solid pseudopapillary tumor (SPT) of the pancreas is a very rare neoplasm of low malignant potential that mostly affects young women. The aim of the present study is to report our experience in surgical treatment of SPT and review of the literature. MATERIAL AND METHODS: A retrospective review of three cases of SPT who were treated at our department during the last two years was performed. The clinicopathologic characteristics, surgical treatment, and prognosis are described in detail. RESULTS: Case 1 described an asymptomatic SPT in a pregnant woman. To the best of our knowledge, only one case of SPT in pregnancy has been reported in the literature. Case 2 described an SPT in the pancreatic tail causing splenic infarction, and a distal pancreatectomy combined with splenectomy was performed. Case 3 described an SPT in the pancreatic head, for which a pancreatoduodenectomy was successfully performed. All of the three patients were followed up for 10-22 months without recurrence or metastases after the initial surgery at the time of reporting. CONCLUSIONS: At present, radical resection is the treatment of choice for SPT. Enucleation can be performed for tumors with complete amicula. Distal pancreatectomy combined with or without splenectomy can be performed for pancreatic body and/or tail tumor, and pancreatoduodenectomy for pancreatic head tumor. The prognosis of SPT is good. PMID- 23935349 TI - Unilateral pulmonary artery agenesis: a case series. AB - BACKGROUND: Unilateral pulmonary artery agenesis (UPAA) is a rare congenital anomaly due to a malformation of the sixth aortic arch of the affected side during embryogenesis. The diagnosis is usually set at adolescence, however it can remain asymptomatic and late diagnosis is possible. DESCRIPTION: We present a case series of three female patients, aged 18, 49 and 68 years old, with history of recurrent respiratory tract infections, to whom the diagnosis of UPAA was set. They were admitted, due to hemoptysis and productive cough (case 1) or progressive dyspnea on exertion (cases 2 and 3). Chest X-ray was abnormal in all three cases, depicting shift of the mediastinal structures to the left and hypoplasia of the left lung while chest CT demonstrated absence of the left pulmonary artery. CONCLUSION: UPAA can remain asymptomatic and diagnosis in adult age is possible, usually after an abnormal chest radiograph. A number of additional imaging techniques are available to aid the diagnosis. Physicians should consider the possibility of undiagnosed UPAA in adults. PMID- 23935350 TI - Incorrect prescription of intravenous paracetamol in a pediatric patient. AB - Intravenous (IV) paracetamol is widely used for the treatment of pain and fever, when there is a clinical indication for an IV route. A 16-month-old girl weighing 12 kg had undergone anterior open reduction for developmental dysplasia of the hip. Twenty-four hours after the operation, IV paracetamol (Perfalgan(r) 10 mg/ml) infusion was started for the postoperative pain management. After 12 hours' infusion, she has developed nausea, vomiting and agitation. The liver function tests were found to be more than 10-fold elevated on the laboratory results. When the medication order was checked, it was shown that she had been administered paracetamol 5 times at a dose of 42 mg/kg (total: 2.5 g/30 hours or 168 mg/kg/24 hours). The patient was started on N-acetyl cysteine (NAC) therapy immediately. She was asymptomatic at the 36th hour of the NAC treatment and the liver function tests completely recovered over 15 days. Since the errors in the calculation of the dosage of IV paracetamol may lead to serious complications or even death, physicians should be careful not to miscalculate when preferring the IV form of the drug. PMID- 23935351 TI - A Case of Transient Ischemic Attack in a patient with Ulcerative Colitis. AB - Arterial stroke is a rare complication of Ulcerative Colitis (UC) and so far there are no guidelines for the treatment of stroke in these patients. The pathogenesis of thrombosis in UC remains uncertain. This case is one of the few published reports on the relationship between stroke associated with UC and the factor V Leiden mutation. PMID- 23935352 TI - Treatment of a patient with classical paroxysmal nocturnal hemoglobinuria and Budd-Chiari syndrome, with complement inhibitor eculizumab: Case Report. AB - Background. Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired clonal disorder of hematopoietic stem cells involving all blood cells. Erythrocytes have increased susceptibility to complement-mediated haemolysis. Thrombosis is the leading cause of mortality and follows episodes of acute hemolysis. Eculizumab, a monoclonal antibody blocking activation of complement C5 is currently used in the treatment of PNH. Recent results demonstrated that eculizumab effectively reduces thrombosis. Description of case. We present a 30-year-old male patient admitted with abdominal and lumbar pain. Thorough investigation revealed severe hemolytic anemia requiring transfusions and hepatosplenomegaly. Imaging findings were compatible with a Budd-Chiari syndrome. Flow cytometry confirmed the PNH diagnosis. Due to refractory ascites he underwent a transjugular intrahepatic portal-systemic shunt (TIPS) and eculizumab administration was started. Results. He has already completed three years of eculizumab treatment and he is transfusion independent. There is also a significant reduction in fatigue with improvement in his quality of life. Doppler scans of his TIPS persistently show it to be patent. Conclusions. Classical PNH patients with thrombosis and severe intravascular hemolysis are particularly challenging to manage. For these patients, eculizumab is a reasonable therapeutic option, expecting that by decreasing the risk for thrombosis, life expectancy may be increased. PMID- 23935353 TI - Cyclosporine therapy during pregnancy in a patient with beta-thalassemia major and autoimmune haemolytic anemia: a case report and review of the literature. AB - Recent advances in the management of hemoglobinopathies offer an improved potential for safe pregnancy with favourable outcome in patients with beta thalassemia major. Autoimmune diseases that are common in women at reproductive age might be fulminant and hardly manageable in pregnant women with thalassemia. Thus immunosuppressant drugs like cyclosporine A could be necessary in order to maintain good maternal and foetal health. We present a case report of a 35-year old woman with beta-thalassemia major, splenectomy, autoimmune hemolytic anemia and insulin treated diabetes mellitus who was treated with cyclosporine A during her pregnancy, and delivered a healthy male infant. First line therapy with steroids was ineffective, due to deregulation of diabetes mellitus. PMID- 23935354 TI - Cerebral venous thrombosis after high dose steroid in multiple sclerosis: a case report. AB - Cerebral venous thrombosis (CVT) is a clinical condition which is caused by the partial or complete occlusion of the dural sinuses and cerebral veins. Cases of associated CVT and multiple sclerosis (MS) have been reported and CVT development has been attributed to the previous lumbar puncture (LP) in majority of these cases. We report a case of 32-year-old woman with no previous history of recent LP, who developed CVT after high dose intravenous methylprednisolone and discuss the possible role of high dose steroids in development of CVT in MS patients. PMID- 23935355 TI - Hepatitis B reactivation in a patient with rheumatoid arthritis with antibodies to hepatitis B surface antigen treated with rituximab. AB - Hepatitis B virus (HBV) can still be found within the hepatocytes after its clearance and the control of viral replication depends on the immune response. However during immunosuppression, seroconversion of HBsAg has been described followed by disease reactivation. Hepatitis B virus reactivation represents an emerging cause of liver disease in patients undergoing treatment with biologic agents and in particular, by the use of rituximab (anti-CD20) and alemtuzumab (anti-CD52) that cause profound and long-lasting immunosuppression. We describe a case of a 64-year old female patient with rheumatoid arthritis and resolved HBV infection, who experienced a severe hepatitis B reactivation after the administration of rituximab. PMID- 23935356 TI - Diffuse subcutaneous emphysema after transperitoneal laparoscopic donor nephrectomy. PMID- 23935357 TI - Conservative treatment of a 7 week cervical ectopic pregnancy after intra-uterine insemination. PMID- 23935358 TI - Penile Kaposi's sarcoma in a HIV negative HHV-8 positive man. PMID- 23935359 TI - Identification of potential prognostic markers for knee osteoarthritis by serum proteomic analysis. AB - BACKGROUND: As osteoarthritis (OA) is a highly heterogeneous disease in terms of progression, establishment of prognostic biomarkers would be highly beneficial for treatment. The present study was performed to identify novel biomarkers capable of predicting the progression of knee OA. METHODS: A total of 69 plasma samples (OA patients undergoing radiographic progression, n = 25; nonprogression, n = 33; healthy donors, n = 11) were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), and ion peaks of interest were identified by liquid chromatography and matrix-assisted laser desorption/ionization (MALDI)-TOF MS. The identities of these proteins were further validated by immunoprecipitation combined with SELDI-TOF MS analysis. RESULTS: SELDI-TOF MS analysis indicated that the intensities of 3 ion peaks differed significantly between progressors and nonprogressors. Subsequent analyses indicated that these peaks corresponded to apolipoprotein C-I, C-III, and an N-terminal truncated form of transthyretin, respectively. The identities of these proteins were confirmed by the loss of ion peaks in SELDI-TOF MS spectra by immunoprecipitation using specific antibodies for the respective proteins. CONCLUSIONS: Three potential biomarkers were identified whose serum levels differed significantly between OA progressors and nonprogressors. These biomarkers are expected to be prognostic biomarkers for knee OA and to facilitate the development of novel disease-modifying treatments for OA. PMID- 23935360 TI - Revisiting keratoconus diagnosis and progression classification based on evaluation of corneal asymmetry indices, derived from Scheimpflug imaging in keratoconic and suspect cases. AB - PURPOSE: To survey the standard keratoconus grading scale (Pentacam(r)-derived Amsler-Krumeich stages) compared to corneal irregularity indices and best spectacle-corrected distance visual acuity (CDVA). PATIENTS AND METHODS: Two hundred and twelve keratoconus cases were evaluated for keratoconus grading, anterior surface irregularity indices (measured by Pentacam imaging), and subjective refraction (measured by CDVA). The correlations between CDVA, keratometry, and the Scheimpflug keratoconus grading and the seven anterior surface Pentacam-derived topometric indices - index of surface variance, index of vertical asymmetry, keratoconus index, central keratoconus index, index of height asymmetry, index of height decentration, and index of minimum radius of curvature - were analyzed using paired two-tailed t-tests, coefficient of determination (r(2)), and trendline linearity. RESULTS: The average +/- standard deviation CDVA (expressed decimally) was 0.626 +/- 0.244 for all eyes (range 0.10-1.00). The average flat meridian keratometry was (K1) 46.7 +/- 5.89 D; the average steep keratometry (K2) was 51.05 +/- 6.59 D. The index of surface variance and the index of height decentration had the strongest correlation with topographic keratoconus grading (P < 0.001). CDVA and keratometry correlated poorly with keratoconus severity. CONCLUSION: It is reported here for the first time that the index of surface variance and the index of height decentration may be the most sensitive and specific criteria in the diagnosis, progression, and surgical follow-up of keratoconus. The classification proposed herein may present a novel benchmark in clinical work and future studies. PMID- 23935361 TI - Adherence decision making in the everyday lives of emerging adults with type 1 diabetes. AB - PURPOSE: The purpose of this study was to explore motivations underlying nonadherent treatment decisions made by young adults with type 1 diabetes. METHODS: Eight emerging adults each completed a series of semi-structured interviews concerning their approaches to diabetes care, relationships with clinicians, and everyday activities and routines. A narrative thematic analysis was used to develop initial themes and refine them through continued data collection and review of the research literature. RESULTS: FIVE THEMES WERE IDENTIFIED AS MOTIVATING NONADHERENCE: (1) efforts to mislead health care providers, (2) adherence to alternative standards, (3) treatment fatigue and burnout, (4) social support problems, and (5) emotional and self-efficacy problems. CONCLUSION: Instances of nonadherence generally involved a combination of the five identified themes. Participants reporting nonadherence also described difficulties communicating with care providers regarding their treatment. Nonjudgmental communication between providers and emerging adults may be particularly important in promoting positive health outcomes in this population. PMID- 23935362 TI - Antitumor activity of docetaxel-loaded polymeric nanoparticles fabricated by Shirasu porous glass membrane-emulsification technique. AB - Docetaxel (DTX) has excellent efficiency against a wide spectrum of cancers. However, the current clinical formulation has limited its usage, as it causes some severe side effects. Various polymeric nanoparticles have thus been developed as alternative formulations of DTX, but they have been mostly fabricated on a laboratory scale. Previously, we synthesized a novel copolymer, poly(lactide)-D-alpha-tocopheryl polyethylene glycol 1000 succinate (PLA-TPGS), and found that it exhibited great potential in drug delivery with improved properties. In this study, we applied the Shirasu porous glass (SPG) membrane emulsification technique to prepare the DTX-loaded PLA-TPGS nanoparticles on a pilot scale. The effect of several formulation variables on the DTX-loaded nanoparticle properties, including particle size, zeta potential, and drug encapsulation efficiency, were investigated based on surfactant type and concentration in the aqueous phase, organic/aqueous phase volumetric ratio, membrane-pore size, transmembrane cycles, and operation pressure. The DTX-loaded nanoparticles were obtained with sizes of 306.8 +/- 5.5 nm and 334.1 +/- 2.7 nm (mean value +/- standard deviation), and drug-encapsulation efficiency of 81.8% +/- 4.5% and 64.5% +/- 2.7% for PLA-TPGS and poly(lactic-co-glycolic acid) (PLGA) nanoparticles, respectively. In vivo pharmacokinetic study exhibited a significant advantage of PLA-TPGS nanoparticles over PLGA nanoparticles and Taxotere. Drug-loaded PLA-TPGS nanoparticles exhibited 1.78-, 6.34- and 3.35-fold higher values for area under the curve, half-life, and mean residence time, respectively, compared with those of PLGA nanoparticles, and 2.23-, 13.2-, 8.51 fold higher than those of Taxotere, respectively. In vivo real-time distribution of nanoparticles was measured on tumor-bearing mice by near-infrared fluorescence imaging, which demonstrated that the PLA-TPGS nanoparticles achieved much higher concentration and longer retention in tumors than PLGA nanoparticles after intravenous injection. This is consistent with the pharmacokinetic behavior of the nanoparticles. The tumor-inhibitory effect of DTX-loaded nanoparticles was observed in vivo in an H22 tumor-bearing mice model via intravenous administration. This indicated that PLA-TPGS nanoparticles are a feasible drug delivery formulation with a pilot fabrication technique and have superior pharmacokinetic and anticancer effects compared to the commercially available Taxotere. PMID- 23935363 TI - Mechanism of enhanced oral absorption of hydrophilic drug incorporated in hydrophobic nanoparticles. AB - Hydroxysafflor yellow A (HSYA) is an effective ingredient of the Chinese herb Carthamus tinctorius L, which has high water solubility and low oral bioavailability. This research aims to develop a hydrophobic nanoparticle that can enhance the oral absorption of HSYA. Transmission electron microscopy and freeze-fracture replication transmission election microscopy showed that the HSYA nanoparticles have an irregular shape and a narrow size distribution. Zonula occludens 1 protein (ZO-1) labeling showed that the nanoparticles with different dilutions produced an opening in the tight junctions of Caco-2 cells without inducing cytotoxicity to the cells. Both enhanced uptake in Caco-2 cells monolayer and increased bioavailability in rats for HSYA nanoparticles indicated that the formulation could improve bioavailability of HSYA significantly after oral administration both in vitro and in vivo. PMID- 23935366 TI - Effective management of intractable neuropathic pain using an intrathecal morphine pump in a patient with acute transverse myelitis. AB - Transverse myelitis is a rare inflammatory myelopathy characterized by loss of motor and sensory function below the affected level of the spinal cord, and causes neurogenic bowel and bladder. Occasionally, it also causes neuropathic pain with spasticity. Traditional therapies for neuropathic pain are multiple, including multimodal analgesic regimens, antiepileptic or antidepressant medications, opioids, sympathetic blocks, and spinal cord stimulation. Persistent neuropathic pain can cause emotional distress by affecting sleep, work, recreation, and emotional well-being. Here we report the case of a patient suffering from intractable neuropathic pain following acute transverse myelitis that was not relieved by combinations of nonsteroidal anti-inflammatory, anti epileptic, antidepressant, and opioid medications, or by acupuncture. Implantation of an intrathecal morphine pump controlled the pain successfully without side effects, and enabled the patient to embark on intensive rehabilitation. The patient's muscle strength has improved significantly and the patient may soon be able to use a walker with minimal assistance. PMID- 23935364 TI - In vitro proliferation and osteogenic differentiation of mesenchymal stem cells on nanoporous alumina. AB - Cell adhesion, migration, and proliferation are significantly affected by the surface topography of the substrates on which the cells are cultured. Alumina is one of the most popular implant materials used in orthopedics, but few data are available concerning the cellular responses of mesenchymal stem cells (MSCs) grown on nanoporous structures. MSCs were cultured on smooth alumina substrates and nanoporous alumina substrates to investigate the interaction between surface topographies of nanoporous alumina and cellular behavior. Nanoporous alumina substrates with pore sizes of 20 nm and 100 nm were used to evaluate the effect of pore size on MSCs as measured by proliferation, morphology, expression of integrin beta1, and osteogenic differentiation. An MTT assay was used to measure cell viability of MSCs on different substrates, and determined that cell viability decreased with increasing pore size. Scanning electron microscopy was used to investigate the effect of pore size on cell morphology. Extremely elongated cells and prominent cell membrane protrusions were observed in cells cultured on alumina with the larger pore size. The expression of integrin beta1 was enhanced in MSCs cultured on porous alumina, revealing that porous alumina substrates were more favorable for cell growth than smooth alumina substrates. Higher levels of osteoblastic differentiation markers such as alkaline phosphatase, osteocalcin, and mineralization were detected in cells cultured on alumina with 100 nm pores compared with cells cultured on alumina with either 20 nm pores or smooth alumina. This work demonstrates that cellular behavior is affected by variation in pore size, providing new insight into the potential application of this novel biocompatible material for the developing field of tissue engineering. PMID- 23935365 TI - MicroRNA as therapeutic targets for treatment of depression. AB - Depression is a potentially life-threatening mental disorder affecting approximately 300 million people worldwide. Despite much effort, the molecular underpinnings of clinical depression remain poorly defined, and current treatments carry limited therapeutic efficacy and potentially burdensome side effects. Recently, small noncoding RNA molecules known as microRNA (miRNA) have gained prominence as a target for therapeutic intervention, given their capacity to regulate neuronal physiology. Further, mounting evidence suggests a prominent role for miRNA in depressive molecular signaling. Recent studies have demonstrated that dysregulation of miRNA expression occurs in animal models of depression, and in the post-mortem tissue of clinically depressed patients. Investigations into depression-associated miRNA disruption reveals dramatic effects on downstream targets, many of which are thought to contribute to depressive symptoms. Furthermore, selective serotonin reuptake inhibitors, as well as other antidepressant drugs, have the capacity to reverse aberrant depressive miRNA expression and their downstream targets. Given the powerful effects that miRNA have on the central nervous system transcriptome, and the aforementioned studies, there is a compelling rationale to begin to assess the potential contribution of miRNA to depressive etiology. Here, we review the molecular biology of miRNA, our current understanding of miRNA in relation to clinical depression, and the utility of targeting miRNA for antidepressant treatment. PMID- 23935368 TI - Thyroid Hormones and Cortisol Concentrations in Offspring are Influenced by Maternal Supranutritional Selenium and Nutritional Plane in Sheep. AB - To determine the effects of maternal supranutritional selenium (Se) supplementation and maternal nutritional plane on offspring growth potential, ewes were randomly assigned to 1 of 6 treatments in a 2 * 3 factorial arrangement [dietary Se (adequate Se; 9.5 MUg/kg body weight vs. high Se; 81.8 MUg/kg body weight initiated at breeding) and plane of nutrition [60%, 100%, or 140% of requirements; initiated on day 50 of gestation]]. Lambs were immediately removed from dams at birth and reared. Cortisol concentrations at birth were similar, but by 24 h, a relationship (P = 0.02) between maternal Se supplementation and nutritional plane on cortisol concentrations was observed in lambs. A sex of offspring * day of age interaction (P = 0.01) and a maternal Se supplementation * nutritional plane * day of age interaction (P = 0.04) was observed for thyroxine concentrations. Differences in growth may be influenced by thyroid hormone production early in neonatal life. PMID- 23935367 TI - Vitamin B1 Deficiency Does not Affect the Liver Concentrations of the Other Seven Kinds of B-Group Vitamins in Rats. AB - We aimed to determine the effects of vitamin B1 deficiency on vitamin contents of urine, liver, and blood. In the current study, rats were divided into 3 groups (n = 5, each group): the first was freely fed a complete diet (ad lib-fed control group); the second freely fed a vitamin B1-free diet (vitamin B1 deficient group); and the third pair-fed a complete diet with the same amounts of the vitamin B1 deficient group (pair-fed control group). The experimental period was for 15 days. The blood concentrations of vitamin B2, PLP, vitamin B12, folic acid, and biotin were lower in the pair-fed control than in the ad lib-fed control and those of nicotinamide and pantothenic acid were the same. We conclude that Vitamin B1 deficiency did not affect concentrations of the other B-group vitamins. PMID- 23935369 TI - Excess Vitamin Intake before Starvation does not Affect Body Mass, Organ Mass, or Blood Variables but Affects Urinary Excretion of Riboflavin in Starving Rats. AB - B-vitamins are important for producing energy from amino acids, fatty acids, and glucose. The aim of this study was to elucidate the effects of excess vitamin intake before starvation on body mass, organ mass, blood, and biological variables as well as on urinary excretion of riboflavin in rats. Adult rats were fed two types of diets, one with a low vitamin content (minimum vitamin diet for optimum growth) and one with a sufficient amount of vitamins (excess vitamin diet). Body mass, organ mass, and blood variables were not affected by excess vitamin intake before starvation. Interestingly, urinary riboflavin excretion showed a different pattern. Urine riboflavin in the excess vitamin intake group declined gradually during starvation, whereas it increased in the low vitamin intake group. Excess vitamin intake before starvation does not affect body mass, organ mass, or blood variables but does affect the urinary excretion of riboflavin in starving rats. PMID- 23935370 TI - High d(+)-fructose diet adversely affects testicular weight gain in weaning rats?protection by moderate d(+)-glucose diet. AB - The use of high D(+)-fructose corn syrup has increased over the past several decades in the developed countries, while overweight and obesity rates and the related diseases have risen dramatically. However, we found that feeding a high D(+)-fructose diet (80% D(+)-fructose as part of the diet) to weaning rats for 21 days led to reduced food intake (50% less, P < 0.0001) and thus delayed the weight gains in the body (40% less, P < 0.0001) and testes (40% less, P < 0.0001) compared to the no D(+)-fructose diet. We also challenged a minimum requirement of dietary D(+)-glucose for preventing the adverse effects of D(+)-fructose, such as lower food intake and reduction of body weight and testicular weight; the minimum requirement of D(+)-glucose was ~23% of the diet. This glucose amount may be the minimum requirement of exogenous glucose for reducing weight gain. PMID- 23935371 TI - Influence of acute coffee consumption on postprandial oxidative stress. AB - BACKGROUND: Coffee has been reported to be rich in antioxidants, with both acute and chronic consumption leading to enhanced blood antioxidant capacity. High-fat feeding is known to result in excess production of reactive oxygen and nitrogen species, promoting a condition of postprandial oxidative stress. METHODS: We tested the hypothesis that coffee intake following a high-fat meal would attenuate the typical increase in blood oxidative stress during the acute postprandial period. On 3 different occasions, 16 men and women consumed a high fat milk shake followed by either 16 ounces of caffeinated or decaffeinated coffee or bottled water. Blood samples were collected before and at 2 and 4 hours following intake of the milk shake and analyzed for triglycerides (TAG), malondialdehyde (MDA), hydrogen peroxide (H2O2), and Trolox equivalent antioxidant capacity (TEAC). RESULTS: Values for TAG and MDA (P < 0.001), as well as for H2O2 (P < 0.001), increased significantly following milk shake consumption, with values higher at 4 hours compared with 2 hours post consumption for TAG and H2O2 (P < 0.05). TEAC was unaffected by the milk shake consumption. Coffee had no impact on TAG, MDA, H2O2, or TEAC, with no condition or interaction effects noted for any variable (P > 0.05). CONCLUSIONS: Acute coffee consumption following a high-fat milk shake has no impact on postprandial oxidative stress. PMID- 23935372 TI - The role of fluorescence diagnosis in clinical practice. AB - Fluorescence diagnosis is a fast, easy, noninvasive, selective, and sensitive diagnostic tool for estimation of treatment results in oncology. In clinical practice the use of photodynamic diagnosis is focused on five targets: detection for prevention of malignant transformation precancerous changes, detection of neoplasmatic tissue in the early stages for fast removal, prevention of expansion and detection of recurrence of the cancer, monitoring therapy, and the possibility of excluding neoplasmatic disease. In this article, selected applications of fluorescence diagnosis at the Center for Laser Diagnostics and Therapy in Bytom, Poland, for each of these targets are presented. PMID- 23935373 TI - Critical analysis of the potential for targeting STAT3 in human malignancy. AB - The signal transducer and activator of transcription (STAT) family of proteins was originally discovered in the context of normal cell biology where they function to transduce intracellular and extracellular signals to the nucleus, ultimately leading to transcription of specific target genes and downstream phenotypic effects. It was quickly appreciated that the STATs, especially STAT3, play a fundamental role in human malignancy. In contrast to normal biology in which transient STAT3 signaling is strictly regulated by a tightly coordinated network of activators and deactivators, STAT3 is constitutively activated in human malignancies. Constitutive STAT3 signaling has been associated with many cancerous phenotypes across nearly all human cancers, including the upregulation of cell growth, proliferation, survival, and motility, among others. Studies involving candidate preclinical STAT3 inhibitors have further demonstrated that the reversal of these phenotypes results from pharmacologic or genetic inhibition of STAT3, suggesting that STAT3 may be a promising target for clinical interventions. Indeed, a Phase 0 clinical trial involving a STAT3 decoy oligonucleotide demonstrated that STAT3 is a drug-gable target in human tumors. Because of the ubiquity of overactive STAT3 in cancer, its role in promoting a wide variety of cancerous phenotypes, and the strong clinical and preclinical studies performed to date, STAT3 represents a promising target for the development of inhibitors for the treatment of human cancers. PMID- 23935375 TI - Effect of calcium channel blockers on incidence of diabetes: a meta-analysis. AB - AIMS: Insulin resistance and the progressive loss of beta-cell function are components of the fundamental pathophysiology of type II diabetes. A recent experimental study suggested that calcium channel blockers (CCBs) might inhibit beta-cell apoptosis, enhance beta-cell function, and prevent diabetes. The present meta-analysis examined the clinical effect of CCBs on the incidence of diabetes. METHODS: MEDLINE, EMBASE, ISI Web of Science, the Cochrane Library, and ClinicalTrials. gov were each searched for relevant articles published up to March 11, 2013. Randomized controlled trials (RCTs) with a follow-up period of at least 1-year were included. Identified articles were systematically reviewed, and those with pertinent data were selected for inclusion in a meta-analysis. RESULTS: We included ten RCTs in a meta-analysis. Of the 108,118 people with hypertension and no pre-existing diabetes, 7,073 (6.5%) cases of type II diabetes were reported. CCBs were associated with a higher incidence of diabetes than angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs; pooled risk ratios [95% confidence intervals]: 1.23 [1.01-1.51] and 1.27 [1.14-1.42], respectively) and a lower incidence compared with beta blockers or diuretics (0.83 [0.73-0.94] and 0.82 [0.69-0.98], respectively). The overall risk of diabetes among subjects taking CCBs was not significant (0.99 [0.85-1.15]). CONCLUSION: THE USE OF CCBS WAS NOT SIGNIFICANTLY ASSOCIATED WITH INCIDENT DIABETES COMPARED TO OTHER ANTIHYPERTENSIVE AGENTS: the association with diabetes was lowest for ACEIs and ARBs, followed by CCBs, beta blockers, and diuretics. Although CCBs can be safely used in hypertensive patients, it would be premature to advocate CCBs for the prevention or treatment of diabetes. PMID- 23935374 TI - Update on imatinib for gastrointestinal stromal tumors: duration of treatment. AB - Gastrointestinal stromal tumors (GISTs) are the most common sarcoma of the gastrointestinal tract, with transformation typically driven by activating mutations of c-KIT and less commonly platelet-derived growth factor receptor alpha (PDGFRA). Successful targeting of c-KIT and PDGFRA with imatinib, a tyrosine kinase inhibitor (TKI), has had a major impact in advanced GIST and as an adjuvant and neoadjuvant treatment. If treatment with imatinib fails, further lines of TKI therapy have a role, but disease response is usually only measured in months, so strategies to maximize the benefit from imatinib are paramount. Here, we provide an overview of the structure and signaling of c-KIT coupled with a review of the clinical trials of imatinib in GIST. In doing so, we make recommendations about the duration of imatinib therapy and suggest how best to utilize imatinib in order to improve patient outcomes in the future. PMID- 23935376 TI - Effect of tomato consumption on high-density lipoprotein cholesterol level: a randomized, single-blinded, controlled clinical trial. AB - INTRODUCTION: Epidemiologic evidence suggests that tomato-based products could reduce the risk of cardiovascular diseases. One of the main cardiovascular risk factors is low levels of high-density lipoprotein cholesterol (HDL-C). This study aimed to prospectively evaluate the effect of tomato consumption on HDL-C levels. SUBJECT AND METHODS: We conducted a randomized, single-blinded, controlled clinical trial. We screened 432 subjects with a complete lipid profile. Those individuals with low HDL-C (men <40 mg/dL and women <50 mg/dL) but normal triglyceride levels (<150 mg/dL) were included. Selected participants completed a 2-week run-in period on an isocaloric diet and then were randomized to receive 300 g of cucumber (control group) or two uncooked Roma tomatoes a day for 4 weeks. RESULTS: A total of 50 individuals (women = 41; 82%) with a mean age of 42 +/- 15.5 years and a mean body mass index of 27.6 +/- 5.0 kg/m(2) completed the study. A significant increase in HDL-C levels was observed in the tomato group (from 36.5 +/- 7.5 mg/dL to 41.6 +/- 6.9 mg/dL, P < 0.0001 versus the control group). After stratification by gender, the difference in HDL-C levels was only significant in women. The mean HDL-C increase was 5.0 +/- 2.8 mg/dL (range 1-12 mg/dL). Twenty patients (40%) finished the study with levels >40 mg/dL. A linear regression model that adjusted for those parameters that impact HDL-C levels (age, gender, waist-to-hip ratio, body mass index, fasting triglyceride concentration, simple sugars, alcohol, physical activity, and omega-3 consumption) showed an independent association between tomato consumption and the increase in HDL-C (r (2) = 0.69; P < 0.0001). CONCLUSION: Raw tomato consumption produced a favorable effect on HDL-C levels in overweight women. PMID- 23935377 TI - Effects of Phyllanthus emblica extract on endothelial dysfunction and biomarkers of oxidative stress in patients with type 2 diabetes mellitus: a randomized, double-blind, controlled study. AB - BACKGROUND: It has been reported that hyperglycemia can induce endothelial dysfunction via increased oxidative stress and that it plays a central role in the development of atherosclerosis and coronary heart disease. Phyllanthus emblica (Emblica officinalis, amla) is known for its antioxidant and antihyperlipidemic activity. The present study compared the effects of an aqueous extract of P. emblica (highly standardized by high-performance liquid chromatography to contain low molecular weight hydrolyzable tannins, ie, emblicanin A, emblicanin B, pedunculagin, and punigluconin) versus those of atorvastatin and placebo on endothelial dysfunction and biomarkers of oxidative stress in patients with type 2 diabetes. METHODS: Eligible patients were randomized to receive either P. emblica 250 mg twice daily, P. emblica 500 mg twice daily, atorvastatin 10 mg in the evening and matching placebo in the morning, or placebo twice daily for 12 weeks. The primary efficacy parameter was the change in endothelial function identified on salbutamol challenge at baseline and after 12 weeks of treatment. Secondary efficacy parameters were changes in biomarkers of oxidative stress (malondialdehyde, nitric oxide, and glutathione), high sensitivity C-reactive protein levels, the lipid profile, and glycosylated hemoglobin (HbA1c) levels. Laboratory safety parameters were measured at baseline and after 12 weeks of treatment. RESULTS: Eighty patients completed the study. Treatment with P. emblica 250 mg, P. emblica 500 mg, or atorvastatin 10 mg produced significant reductions in the reflection index (-2.25%+/-1.37% to 9.13%+/-2.56% versus -2.11%+/-0.98% to -10.04%+/-0.92% versus -2.68%+/-1.13% to 11.03%+/-3.93%, respectively), suggesting improvement in endothelial function after 12 weeks of treatment compared with baseline. There was a significant improvement in biomarkers of oxidative stress and systemic inflammation compared with baseline and placebo. Further, the treatments significantly improved the lipid profile and HbA1c levels compared with baseline and placebo. All treatments were well tolerated. CONCLUSION: Both atorvastatin and P. emblica significantly improved endothelial function and reduced biomarkers of oxidative stress and systemic inflammation in patients with type 2 diabetes mellitus, without any significant changes in laboratory safety parameters. PMID- 23935379 TI - Genetic variants associated with Crohn's disease. AB - Crohn's disease is an immune-related disorder characterized by inflammation of the gastrointestinal mucosa, which can occur in any area throughout the digestive tract. This life-long disease commonly presents with abdominal pain, diarrhea, vomiting, and weight loss. While the exact etiology of this disease is largely unknown, it is thought to arise from an interaction between microbial, immunological, and environmental factors in a genetically susceptible host, whereby the immune system attacks the intestine as it cross reacts against gut microbial antigens. The study of genetic variants associated with Crohn's disease has shed light on our understanding of disease pathophysiology. A large number of genetic variants identified in Crohn's disease are related to genes targeting microbial recognition and bacterial wall sensing, the most common being NOD2/CARD15 gene. This review will discuss the recent advance in our knowledge of genetic variants of this disease and how they influence the disease course and prognosis. PMID- 23935380 TI - Candidate genes of Waldenstrom's macroglobulinemia: current evidence and research. AB - Waldenstrom's macroglobulinemia (WM) is a relatively uncommon, indolent malignancy of immunoglobulin M-producing B cells. The World Health Organization classifies it as a lymphoplasmacytic lymphoma and patients typically present with anemia, hepatosplenomegaly and diffuse lymphadenopathies. Historically, the genetic characterization of the disease has been hampered by the relatively low proliferative rate of WM cells, thus making karyotyping challenging. The use of novel technologies such as fluorescence in situ hybridization, gene array, and whole genome sequencing has contributed greatly to establishing candidate genes in the pathophysiology of WM and to identifying potential treatment targets, such as L265P MYD88. The discovery of microRNAs and the recognition of epigenetics as a major modulatory mechanism of oncogene expression and/or oncosuppressor silencing have aided in further understanding the pathogenesis of WM. Once thought to closely resemble multiple myeloma, a cancer of terminally differentiated, immunoglobulin-secreting plasma cells, WM appears to genetically cluster with other indolent B-cell lymphomas such as chronic lymphocytic leukemia/small cell lymphoma. The relative high incidence of familial cases of WM and other B-cell malignancies has been helpful in identifying high-risk gene candidates. In this review, we focus on the established genes involved in the pathogenesis of WM, with special emphasis on the key role of derangement of the nuclear factor kappa B signaling pathway and epigenetic mechanisms. PMID- 23935381 TI - PALB2 and breast cancer: ready for clinical translation! AB - For almost two decades, breast cancer clinical genetics has operated in an environment where a heritable cause of breast cancer susceptibility is identified in the vast minority of women seeking advice about their personal and/or family history of breast and/or ovarian cancer. A new wave of genetic information is upon us that promises to provide an explanation for the greater proportion of current missing heritability of breast cancer. Whilst researchers refine bioinformatic and analytic methodology necessary to interpret the new genetic data, attention needs to be paid to defining appropriate and coordinated pathways for the translation of this information so that it can be applied in clinical genetic services for the benefit of the majority of women who currently have no explanation for their breast cancer susceptibility. The search for additional breast cancer susceptibility genes remains a very active area of research. Exhausting the power of linkage studies that identified BRCA1 and BRCA2, the research community moved to candidate gene studies that led to the identification of ATM, BRIP1, CHEK2, and PALB2 as so-called "moderate-risk" breast cancer susceptibility genes. Mutations in these genes are rare and although early reports suggested that, on average, they are associated with moderate risks of breast cancer; population-based studies have demonstrated that at least some mutations in these genes are associated with breast cancer risks that are comparable to the average risk associated with BRCA2 mutations. The search for additional breast cancer susceptibility genes has now moved onto research platforms applying massively parallel sequencing capable of sequencing whole human exomes and genomes in single instrument runs. These programs are identifying a large number of additional putative breast cancer susceptibility genes, many of which are currently undergoing validation. It is highly anticipated that the remaining missing heritability of breast cancer will be due to mutations in many different genes, each explaining a small proportion of the currently unexplained heritable breast cancer susceptibility. The characterization of PALB2 as a breast cancer susceptibility gene and subsequent research that has refined our understanding of the prevalence and penetrance of heritable mutations in PALB2 offers a precious opportunity to use the data as a model and develop modes of translation that would be appropriate for the anticipated volume of imminent new information. PMID- 23935383 TI - Nephrolithiasis in patients with inflammatory bowel disease in the community. AB - BACKGROUND: Inflammatory bowel disease (IBD) has been associated with renal stone formation. The objective of this study was to determine prospectively the prevalence of nephrolithiasis in a community-based population of patients with IBD and to analyze factors associated with renal calculus formation. METHODS: Screening renal ultrasound was performed in a well characterized cohort of patients seen between 2009 and 2012 at an IBD clinic. We enrolled 168 patients, including 93 with Crohn's disease and 75 with ulcerative colitis. Clinical and phenotypic variables associated with asymptomatic nephrolithiasis were determined. RESULTS: Nephrolithiasis was detected in 36 patients with Crohn's disease and in 28 patients with ulcerative colitis (38% for both). Although none of the patients had been previously hospitalized for symptomatic nephrolithiasis, nine with Crohn's disease and five with ulcerative colitis had recurrent urinary tract infections or hydronephrosis. In patients with Crohn's disease, ileocolonic (L3) disease was associated with a greater risk of nephrolithiasis than was ileal (L1) or colonic (L2) disease (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.8-7). Active ulcerative colitis (regardless of severity) represented a significant risk factor for formation of renal calculi (OR 4.2, 95% CI 1.1-15, P = 0.02). CONCLUSION: In surgery-naive patients with IBD in the community, asymptomatic nephrolithiasis is common and should be considered when renal dysfunction or infection is detected. PMID- 23935382 TI - Reduced life expectancy seen in hereditary diseases which predispose to early onset tumors. AB - There are several hereditary diseases that are a predisposition to early-onset tumors. These include syndromic conditions like neurofibromatosis 1 and 2, von Hippel-Lindau syndrome, Gorlin syndrome, multiple endocrine neoplasia, and familial adenomatous polyposis; and conditions which are usually not possible to diagnose clinically in a single individual, such as Lynch syndrome and BRCA1/2. Understanding of the mortality in hereditary cancer predisposing diseases is important for developing effective disease treatment programs. A number of studies have been undertaken to investigate the genetic predictors, prevalence and incidence, and treatment outcomes of these diseases; however, the majority examine only the most common of these diseases (eg, neurofibromatosis or BRCA), or look into postoperative survival. The mortality of individuals who are diagnosed with one of these hereditary diseases remains an area for investigation. This review is the first to attempt identification of studies investigating life expectancy in hereditary diseases which predispose to early onset tumors. PMID- 23935384 TI - Ethnic differences and socio-demographic predictors of illness perceptions, self management, and metabolic control of type 2 diabetes. AB - OBJECTIVES: This study investigated ethnic differences in diabetes-specific knowledge, illness perceptions, self-management, and metabolic control among black-African, black-Caribbean,and white-British populations with type 2 diabetes. The study also examined associations between demographic/disease characteristics and diabetes-specific knowledge, illness perceptions, self management, and metabolic control in each of the three ethnic groups. DESIGN: Cross-sectional. SETTING: Diabetes/retinal screening clinics in Hackney and Brent, London. METHODS: Black-African, black-Caribbean and white-British populations with type 2 diabetes were asked to participate. Questionnaires measuring demographic/disease characteristics, diabetes-specific knowledge, self management, and illness perceptions were used for data collection. Data for glycated hemoglobin (HbA1c) and microvascular complications were obtained from medical records. Ethnic differences in diabetes-related measures were estimated using analysis of variance/covariance. Multiple regression techniques were used to determine relationships between demographic/disease characteristics and measured diabetes-related outcomes. RESULTS: Three hundred and fifty-nine patients participated in the study. White-British participants had high diabetes specific knowledge compared to their black-African and black-Caribbean counterparts. Black-Africans reported better adherence to self-management recommendations than the other ethnic groups. Compared to the white-British patients, black-African and black-Caribbean participants perceived diabetes as a benign condition that could be cured. Educational status and treatment category were determinants of diabetes-specific knowledge in all three ethnic groups. However, different demographic/disease characteristics predicted adherence to self-management recommendations in each ethnic group. CONCLUSION: Clearly, there is disease (diabetes) knowledge-perception variation between different ethnic groups in the UK which may partly influence overall disease outcome. It is plausible to recommend screening, identifying, and dispelling misconceptions about diabetes among ethnic minority patients by health care professionals as well as emphasizing the importance of self-management in managing chronic diseases such as diabetes. PMID- 23935385 TI - Utility of the heated lidocaine/tetracaine patch in the treatment of pain associated with shoulder impingement syndrome: a pilot study. AB - INTRODUCTION: Pain control is an important first step in the treatment of shoulder impingement syndrome (SIS) because fear of pain must be removed as an obstacle to participation in an appropriate physical therapy program. METHODS: Adult patients with SIS-associated pain of at least 2 weeks' duration and who had an average pain score of >=4 on the zero- to ten-point Numeric Pain Rating Scale were eligible to enroll in this 2-week pilot study. Patients were treated with the heated lidocaine/tetracaine (70 mg/70 mg) patch (HLT patch) placed over the site of shoulder tenderness each morning and evening for a period of 2 to 4 hours. Average and worst pain during the previous 24 hours and shoulder range of motion were assessed at baseline and on Day 14. Results were expressed as change and percent change from baseline to Day 14. This pilot study was not powered for rigorous statistical analysis. RESULTS: Twenty patients (seven male, 13 female; average age 51.2 +/- 10.8 years [mean +/- standard deviation]) enrolled in this study, and 18 patients completed the protocol. The mean average pain score at baseline was 5.5 +/- 1.1 (range 4 to 8). In the per-protocol population, average and worst pain scores declined by 2.4 +/- 2.0 and 3.7 +/- 2.7 points, respectively. Two-thirds of the patients demonstrated a clinically meaningful >=30% decline in average pain score, and half of the patients demonstrated a >=50% decline in average pain score. Shoulder internal rotation increased by 29.7 degrees +/- 21.8 degrees and abduction increased by 40.0 degrees +/- 44.2 degrees . Application-site erythema was reported by ten patients at some time during the study. CONCLUSION: Patients treated with the HLT patch for 14 days demonstrated clinically meaningful improvement in pain intensity and range of motion. Further controlled research is necessary to characterize the efficacy and tolerability of the HLT patch in the treatment of SIS. PMID- 23935386 TI - Impact of an integrated intervention program on atorvastatin adherence: a randomized controlled trial. AB - BACKGROUND: This trial evaluated the effectiveness of an integrated intervention program that included a 3-to-5-minute nurse counseling session, copay relief cards, and a monthly newsletter on adherence to atorvastatin treatment. METHODS AND RESULTS: A prospective, integrated (composed of nurse counseling, adherence tip sheet, copay relief card, opportunity to enroll in 12-week cholesterol management program) randomized interventional study was designed involving patients >21 years of age who were prescribed atorvastatin at a large single specialty cardiovascular physician practice in Illinois from March 2010 to May 2011. Data from the practice's electronic medical record were matched/merged to IMS Health's longitudinal data. A total of 500 patients were enrolled (125 in the control arm; 375 in the intervention arm). After data linkage, 53 control patients and 155 intervention patients were included in the analysis. RESULTS: Mean age was 67.8 years (control) and 69.5 years (intervention); 67.9% and 58.7%, respectively, were male. The mean 6-month adherence rate was 0.82 in both arms. The mean proportion of days covered for both the new-user control and intervention groups was the same, averaging 0.70 day (standard deviation [SD], 0.27 day); for continuing users, the proportion of days covered for the control group was 0.83 (SD, 0.24) and for the intervention group was 0.84 (SD, 0.22). For continuing users, the control group had mean persistent days of 151.6 (SD, 50.2) compared with 150.9 days (SD, 50.9) for the intervention group. New users had fewer persistent days (control 111.4 days, SD, 69.6 days; intervention 112.0 days, SD, 58.8 days) compared with continuing users. The Cox proportional hazards model of the risk of discontinuation with index therapy was not significantly different between the intervention and control groups (hazard ratio 0.83, P = 0.55). CONCLUSION: The integrated intervention program did not significantly improve atorvastatin adherence relative to usual care in the studied patient population. PMID- 23935387 TI - Liposome bupivacaine (EXPAREL(r)) for extended pain relief in patients undergoing ileostomy reversal at a single institution with a fast-track discharge protocol: an IMPROVE Phase IV health economics trial. AB - BACKGROUND: Postoperative opioid use following ileostomy reversal procedures contributes to postoperative ileus. We assessed the impact of a liposome bupivacaine-based, opioid-sparing multimodal analgesia regimen versus a standard opioid-based analgesia regimen on postsurgical opioid use. We also assessed health economic outcomes in patients undergoing ileostomy reversal at our institution, which employs an enhanced recovery discharge protocol. METHODS: In this single-center, open-label study, patients undergoing ileostomy reversal received postsurgical pain therapy via multimodal analgesia that included a single intraoperative administration of liposome bupivacaine or opioid-based patient-controlled analgesia (PCA) with intravenous morphine or hydromorphone. Rescue analgesia (intravenous [IV] opioids and/or oral opioid + acetaminophen) was available to all patients. Primary efficacy measures included postsurgical opioid use, hospital length of stay (LOS), and hospitalization costs. Secondary measures included: time to first rescue opioid use; patient satisfaction with analgesia; additional medical intervention; and opioid-related adverse events. RESULTS: Forty-three patients were enrolled and met eligibility criteria (IV opioid PCA group = 20; liposome bupivacaine-based multimodal analgesia group = 23). Postsurgical opioid use was significantly less in the multimodal analgesia group compared with the IV opioid PCA group (mean [standard deviation]: 38 mg [46 mg] versus 68 mg [47 mg]; P = 0.004). Postsurgical LOS between-group differences (median: 3.0 days versus 3.8 days) and geometric mean hospitalization costs (US $6,611 versus US$6,790) favored the multimodal analgesic group but did not achieve statistical significance. Median time to first opioid use was 1.1 hours versus 0.7 hours in the multimodal analgesia and IV opioid PCA groups, respectively; P = 0.035. Two patients in the multimodal analgesia group and one in the IV opioid PCA group experienced opioid-related adverse events. CONCLUSION: A liposome bupivacaine-based multimodal analgesic regimen reduced postoperative opioid consumption in patients undergoing ileostomy reversal under a fast-track discharge protocol. A reduction of 21% in LOS (0.8 days) was noted which, although not statistically significant, may be considered clinically meaningful given the already aggressive fast-track discharge program. PMID- 23935389 TI - Is a bowel resection necessary for deep endometriosis with rectovaginal or colorectal involvement? AB - BACKGROUND: The purpose of this paper is to report the long-term results of surgery without bowel resection in patients suffering from deep infiltrating endometriosis with rectovaginal or colorectal involvement. METHODS: This retrospective observational study identified 42 patients suffering with deep infiltrating endometriosis who underwent surgery. Conservative surgery was performed in 23 women (only one of them with bowel resection), and 19 women underwent a hysterectomy and bilateral salpingo-oophorectomy (HBSO). In the conservative surgery group, a later HBSO was performed in eight patients as a second operation. Pregnancies, recurrences, reoperations, use of hormone replacement therapy, and outcomes during long-term follow-up were analyzed. RESULTS: The average follow-up duration was 7 +/- 5.7 years in conservative surgery cases. Only one patient was treated with sigmoid bowel resection in 1997 and had complications. In this conservative surgery group, 13 patients (56%) received medical treatment after surgery, 10 patients wanted to get pregnant (of whom seven [70%] were successful), and eight patients underwent a subsequent HBSO because of recurrent symptoms and/or endometrioma. Therefore, HBSO was performed in 27 patients, of whom 14 (51.8%) used hormone replacement therapy for 5.6 +/- 3.6 years. No recurrences or complications were observed in patients after HBSO with or without hormone replacement therapy. CONCLUSION: Good clinical results can be obtained by performing only conservative surgery and/or HBSO without bowel resection, an alternative that could reduce the number of colorectal resections that are performed very frequently nowadays. After HBSO, patients may use hormone replacement therapy for several years with total satisfaction and well-being. PMID- 23935388 TI - Impact of vulvovaginal health on postmenopausal women: a review of surveys on symptoms of vulvovaginal atrophy. AB - Several recent, large-scale studies have provided valuable insights into patient perspectives on postmenopausal vulvovaginal health. Symptoms of vulvovaginal atrophy, which include dryness, irritation, itching, dysuria, and dyspareunia, can adversely affect interpersonal relationships, quality of life, and sexual function. While approximately half of postmenopausal women report these symptoms, far fewer seek treatment, often because they are uninformed about hypoestrogenic postmenopausal vulvovaginal changes and the availability of safe, effective, and well-tolerated treatments, particularly local vaginal estrogen therapy. Because women hesitate to seek help for symptoms, a proactive approach to conversations about vulvovaginal discomfort would improve diagnosis and treatment. PMID- 23935390 TI - Data retention after a patient withdraws consent in clinical trials. AB - Patient retention is critically important in the conduct of a successful clinical trial. The power in numbers in multicenter trials is dependent on the completion of follow-up for every patient randomized. If at the end of a clinical trial, a significant number of randomized patients are missing outcome data, there will not be enough pool for data analyses to conclude a study based on its primary and secondary objectives. When patients who are either lost to follow-up or who withdraw consent during the clinical trial are eliminated from the data pool, they subsequently affect the power and the validity of conclusions derived from the clinical study. This paper aims to present current guidance on data retention for patients who have withdrawn consent from clinical trials. PMID- 23935391 TI - Recent developments in the surgical treatment of bone tumors and their impact on quality of life. PMID- 23935393 TI - Phase transition in NH4HSO4-porous glasses nanocomposites. AB - The results of investigations of porous glasses (PG) and porous glasses-ammonium hydrogen sulfate ferroelectric nanocomposites (AHS-PG) are presented. On the basis of dielectric and calorimetric measurements it was shown that in the AHS-PG nanocomposites with average pore size of 44, 68, 95, and 320 nm the anomalies of dielectric permittivity and specific heat similar to those in bulk crystals AHS are observed. An influence of the mean value of pores sizes on the ferroelectric phase transition temperatures of AHS nanocrystals embedded into the porous matrices was determined. It was shown that in AHS-PG dispersion of the dielectric permittivity is observed in both para- and ferro-electric phases and above room temperature AHS-PG nanocomposites exhibit the ionic conductivity. PMID- 23935394 TI - Electrochemically assisted fabrication of size-exclusion films of organically modified silica and application to the voltammetry of phospholipids. AB - Modification of electrodes with nm-scale organically modified silica films with pores diameters controlled at 10- and 50-nm is described. An oxidation catalyst, mixed-valence ruthenium oxide with cyano crosslinks or gold nanoparticles protected by dirhodium-substituted phosophomolybdate (AuNP-Rh2PMo11), was immobilized in the pores. These systems comprise size-exclusion films at which the biological compounds, phosphatidylcholine and cardiolipin, were electrocatalytically oxidized without interference from surface-active concomitants such as bovine serum albumin. 10-nm pores were obtained by adding generation-4 poly(amidoamine) dendrimer, G4-PAMAM, to a (CH3)3SiOCH3 sol. 50-nm pores were obtained by modifying a glassy carbon electrode (GC) with a sub monolayer film of aminopropyltriethoxylsilane, attaching 50-nm diameter poly(styrene sulfonate), PSS, spheres to the protonated amine, transferring this electrode to a (CH3)3SiOCH3 sol, and electrochemically generating hydronium at uncoated GC sites, which catalyzed ormosil growth around the PSS. Voltammetry of Fe(CN)63- and Ru(NH3)63+ demonstrated the absence of residual charge after removal of the templating agents. With the 50-nm system, the pore structure was sufficiently defined to use layer-by-layer electrostatic assembly of AuNP Rh2PMo11 therein. Flow injection amperometry of phosphatidylcholine and cardiolipin demonstrated analytical utility of these electrodes. PMID- 23935392 TI - Elastomeric Recombinant Protein-based Biomaterials. AB - Elastomeric protein-based biomaterials, produced from elastin derivatives, are widely investigated as promising tissue engineering scaffolds due to their remarkable properties including substantial extensibility, long-term stability, self-assembly, high resilience upon stretching, low energy loss, and excellent biological activity. These elastomers are processed from different sources of soluble elastin such as animal-derived soluble elastin, recombinant human tropoelastin, and elastin-like polypeptides into various forms including three dimensional (3D) porous hydrogels, elastomeric films, and fibrous electrospun scaffolds. Elastin-based biomaterials have shown great potential for the engineering of elastic tissues such as skin, lung and vasculature. In this review, the synthesis and properties of various elastin-based elastomers with their applications in tissue engineering are described. PMID- 23935395 TI - CXCL12/CXCR4 signal axis plays an important role in mediating bone morphogenetic protein 9-induced osteogenic differentiation of mesenchymal stem cells. AB - Mesenchymal progenitor stem cells (MPCs) are a group of bone marrow stromal progenitor cells processing osteogenic, chondrogenic, adipogenic and myogenic lineages differentiations. Previous studies have demonstrated that bone morphogeneic protein 9(BMP9) is one of the most osteogenic BMPs both in vitro and in vivo, however, the underlying molecular mechanism of osteogenesis induced by BMP9 is needed to be deep explored. Here, we used the recombinant adenoviruses assay to introduce BMP9 into C3H10T1/2 mesenchymal stem cells to elucidate the role of CXCL12/CXCR4 signal axis during BMP9-incuced osteogenic differentiation. The results showed that CXCL12 and CXCR4 expressions were down-regulated at the stage of BMP9-induced osteogenic differentiation, in a dose- and time-dependent. Pretreatment of C3H10T1/2 cells with CXCL12/CXCR4 could significantly affect the early and mid osteogenic markers alkaline phosphatase (ALP), osteocalcin (OCN), the transcription factors of Runx2, Osx, Plzf and Dlx5 expression, through activating the Smad, MAPK signaling pathway. Addition of exogenous CXCL12 did not affect the changes of the late osteogenic marker calcium deposition. Thus, our findings suggest a co-requirement of the CXCL12/CXCR4 signal axis in BMP9-induced the early- and mid-process of osteogenic differentiation of MSCs. PMID- 23935396 TI - Reciprocal interference between Lactobacillus spp. and Gardnerella vaginalis on initial adherence to epithelial cells. AB - Bacterial vaginosis (BV) is the most common vaginal disorder in women of child bearing age. It is widely accepted that the microbial switch from normal microflora to the flora commonly associated with BV is characterized by a decrease in vaginal colonization by specific Lactobacillus species together with an increase of G. vaginalis and other anaerobes. However, the order of events leading to the development of BV remains poorly characterized and it is unclear whether the decrease in lactobacilli is a cause or a consequence of the increase in the population density of anaerobes. Our goal was to characterize the interaction between two Gardnerella vaginalis strains, one of which was isolated from a healthy woman (strain 5-1) and the other from a woman diagnosed with BV (strain 101), and vaginal lactobacilli on the adherence to cervical epithelial cells. In order to simulate the transition from vaginal health to BV, the lactobacilli were cultured with the epithelial cells first, and then the G. vaginalis strain was introduced. We quantified the inhibition of G. vaginalis adherence by the lactobacilli and displacement of adherent lactobacilli by G. vaginalis. Our results confirmed that pathogenic G vaginalis 101 had a higher capacity for adhesion to the cervical epithelial cells than strain 5-1. Interestingly, strain 101 displaced L. crispatus but not L. iners whereas strain 5-1 had less of an effect and did not affect the two species differently. Furthermore, L. iners actually enhanced adhesion of strain 101 but not of strain 5-1. These results suggest that BV-causing G. vaginalis and L. iners do not interfere with one another, which may help to explain previous reports that women who are colonized with L. iners are more likely to develop BV. PMID- 23935397 TI - Increased expression of pattern recognition receptors and nitric oxide synthase in patients with endometriosis. AB - OBJECTIVE: Endometriosis is characterized by repeated inflammatory changes and serious adhesions, inducing innate and adaptive immune responses within the abdominal cavity. To assess these immune responses, we evaluated the levels of expression of Toll-like receptors (TLR)-1, -2, -4, -5, and -9; nucleotide-binding oligomerization domains (NOD)-1 and -2; interleukins-1beta, -6, -8, -10, and -12; interferon-gamma; tumor necrosis factor-alpha; inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS); and immunoglobulins (Igs) in patients with endometriosis. METHODS: The levels of TLRs, NODs, cytokines, and NOS mRNAs in peritoneal effusions were assessed by real time reverse transcription-polymerase chain reaction; and IgG, IgA and IgM concentrations were measured by enzyme linked immunosorbent assays (ELISA) in 40 patients with and 40 without endometriosis. Findings from the two groups were compared. RESULTS: We observed expression of all pattern recognition receptors (PRRs), cytokines, and NOS mRNAs and Igs in the effusion fluid of patients with and without endometriosis. The levels of TLR-2 and -9; NOD-1 and -2; iNOS and eNOS mRNAs and CA 125 were significantly higher in the endometriosis than in the non-endometriosis group (p<0.05 each). Moreover, PRR, cytokine, and NOS expression showed significant correlations (p<0.05). CONCLUSIONS: PRRs, cytokines, and NOS, which act cooperatively in the innate immune response, are closely associated with endometriosis. Increased expression of TLR-2, TLR -9, NOD-1, NOD-2, and NOS mRNA in peritoneal fluid may be associated with endometriosis. PMID- 23935398 TI - Comparison of the antialbuminuric effects of L-/N-type and L-type calcium channel blockers in hypertensive patients with diabetes and microalbuminuria: the study of assessment for kidney function by urinary microalbumin in randomized (SAKURA) trial. AB - OBJECTIVE: To clarify whether the L-/N-type calcium channel blocker (CCB) cilnidipine is more renoprotective than the L-type CCB amlodipine in patients with early-stage diabetic nephropathy. METHODS: In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of cilnidipine and amlodipine were examined in renin-angiotensin system (RAS) inhibitor-treated patients with hypertension (blood pressure [BP]: 130-180/80-110 mmHg), type 2 diabetes, and microalbuminuria (urinary albumin to creatinine [Cr] ratio [UACR]: 30-300 mg/g). RESULTS: Patients received cilnidipine (n = 179, final dose: 10.27 +/- 4.13 mg/day) or amlodipine (n = 186, 4.87 +/- 2.08 mg/day) for 12 months. Cilnidipine and amlodipine equally decreased BP. The UACR values for the cilnidipine and amlodipine groups were 111.50 +/- 138.97 and 88.29 +/- 63.45 mg/g, respectively, before treatment and 107.93 +/- 130.23 and 89.07 +/- 97.55 mg/g, respectively, after treatment. The groups showed similar changes for the natural logarithm of the UACR, serum Cr, and estimated glomerular filtration rate. CONCLUSIONS: Cilnidipine did not offer greater renoprotection than amlodipine in RAS inhibitor-treated hypertensive patients with type 2 diabetes and microalbuminuria. PMID- 23935399 TI - Clinicopathological implications of the expression of hypoxia-related proteins in gastric cancer. AB - OBJECTIVES: Tumor hypoxia confers poor prognosis of a wide range of solid tumors due to increased malignancy, increased likelihood of metastasis and treatment resistance. The aim of this study was to assess the significance of the expression of HIF-1alpha and HIF-1alpha-inducible proteins in gastric cancer and their impact on prognosis. MATERIALS AND METHODS: The expression of HIF-1alpha, GLUT-1, CA-9, and iNOS proteins was analyzed by immunohistochemistry in 193 gastric adenocarcinomas (GAs) and 20 normal gastric mucosa. RESULTS: HIF-1alpha, GLUT-1, CA-9 and iNOS were expressed in 52.3%, 43.0%, 57.0%, and 43.0% of GAs, respectively, which are higher than the normal counterparts except for CA-9. HIF 1alpha expression was positively correlated with the expression of GLUT-1, CA-9 and iNOS. GLUT-1 expression was higher in the intestinal type (p = 0.012); however, iNOS expression was higher in the less-differentiated type and the diffuse type (p = 0.006, p = 0.032, respectively). The expression of HIF-1alpha and GLUT-1 was significantly correlated with lymph node metastasis (p = 0.009, p = 0.008, respectively), while the expression of GLUT-1 and iNOS was significantly correlated with the depth of invasion and advanced stage (p = 0.044, p = 0.004; p = 0.009, p = 0.008, respectively). Overall survival was shorter in patients with GLUT-1 expression than in those without GLUT-1 expression, which was statistically significant by univariate analysis (p = 0.042). On multivariate analysis, however, stage was determined as the only independent prognostic marker (p < 0.001). CONCLUSIONS: Our data suggest that overexpression of HIF-1alpha, GLUT-1, and iNOS may play an important role in gastric cancer progression. GLUT-1 is a potential candidate for predicting patient survival. PMID- 23935400 TI - Which adverse events are related to health care during hospitalization in elderly inpatients? AB - BACKGROUND: Adverse events result in longer hospital stays and increase costs and mortality. We aimed to assess incidence of adverse events occurring during hospitalization in a post-emergency unit and to describe their characteristics. METHODS: All adverse events occurring in patients during their hospitalization in a post-emergency unit in a French university hospital (20 beds) were systematically and consecutively recorded from September 2009 to February 2011. Patients with adverse events were compared to up to three control patients, matched for date of admission +/- age in the same unit. RESULTS: We identified 56 patients with 64 adverse events, giving an incidence of 3.0/100 patients admitted/year. Fifty-one adverse events were drug-related. Patients had a median age of 82.5 years with a male/female ratio of 1/1.4. They presented a median Charlson score of 1 and the median number of medications was 6. The drugs most frequently involved in drug-related events were nervous system drugs (47%) and anti-infectives (22%). In multivariate analysis, a Charlson score >= 2 was associated with the occurrence of adverse events (OR 0.4; 95% CI [0.21 - 0.80]). CONCLUSIONS: Systematic recording showed that adverse events were not rare in a post-emergency unit. Patients with comorbid conditions were less likely to present an adverse event, possibly because of greater precautions taken by the medical team. PMID- 23935401 TI - Determining timing of hepatectomy for colorectal cancer with distant metastasis according to imaging-based tumor shrinkage ratio. AB - BACKGROUND: The optimal timing of surgical resection of liver metastasis remains controversial, and guidelines regarding the upper limits of operative indications have not yet been defined. Surgical indication for metastasis from colorectal cancer (CLM) based on results of preoperative chemotherapy and RNF8 was investigated. METHODS: Differences in CLM size on CT were evaluated as shrinkage rate/day by dividing tumor shrinkage rates by the interval in days between CT. Levels of RNF8 of resected colorectal cancer and CLM frozen specimen were detected. RESULTS: When the cut line for shrinkage rate at 12 weeks was set at 0.35%, disease-free survival was significantly better in patients with a shrinkage rate >0.35% vs. <=0.35% (p=0.003). RNF8 expression was significantly higher in Tis (p=0.001). In liver metastasis, RNF8 expression level was significantly lower in patients with partial response to FOLFOX than with stable disease, (p=0.017). CONCLUSIONS: A strategy of FOLFOX administration for 12 weeks to patients with low RNF8 expression and hepatectomy planned after 4 weeks rest may be accepted as the best therapeutic option for treating CLM. PMID- 23935402 TI - Arrhythmogenesis toxicity of aconitine is related to intracellular ca(2+) signals. AB - Aconitine is a well-known arrhythmogenic toxin and induces triggered activities through cardiac voltage-gated Na(+) channels. However, the effects of aconitine on intracellular Ca(2+) signals were previously unknown. We investigated the effects of aconitine on intracellular Ca(2+) signals in rat ventricular myocytes and explored the possible mechanism of arrhythmogenic toxicity induced by aconitine. Ca(2+) signals were evaluated by measuring L-type Ca(2+) currents, caffeine-induced Ca(2+) release and the expression of NCX and SERCA2a. Action potential and triggered activities were recorded by whole-cell patch-clamp techniques. In rat ventricular myocytes, the action potential duration was significantly prolonged by 1 uM aconitine. At higher concentrations (5 uM and 10 uM), aconitine induced triggered activities and delayed after-depolarizations (6 of 8 cases), which were inhibited by verapamil. Aconitine (1 uM) significantly increased the ICa-L density from 12.77 +/- 3.12 pA/pF to 18.98 +/- 3.89 pA/pF (n=10, p<0.01). The activation curve was shifted towards more negative potential, while the inactivation curve was shifted towards more positive potential by 1 MUM aconitine. The level of Ca(2+) release induced by 10 mM caffeine was markedly increased. Aconitine (1 uM) increased the expression of NCX, while SERCA2a expression was reduced. In conclusion, aconitine increased the cytosolic [Ca(2+)]i by accelerating ICa-L and changing the expression of NCX and SERCA2a. Then, the elevation of cytosolic [Ca(2+)]i induced triggered activities and delayed after-depolarizations. Arrhythmogenesis toxicity of aconitine is related to intracellular Ca(2+) signals. PMID- 23935404 TI - Transnational childrearing and the preservation of transnational identity in Brazzaville, Congo. AB - Drawing on ethnographic research conducted at two ends of an intra- Africa migration flow (Mali and the Republic of Congo), in this article I examine the role of childrearing practices in the maintenance of transnationalism. I consider different approaches to transnational childrearing by migrant parents and their reasons for adopting them, and delineate three common modes. The most widespread and socially validated approach is to send children home from Congo to their parents' places of origin, where child fostering is widespread, to be raised by relatives for long periods; this approach increases the durability of transnational ties. I use childrearing approaches as an analytical lens to demonstrate the complementarity of multiple forms of domestic organization, mobility and settlement in the intergenerational production and transmission of durable transnational identities. By arguing for greater focus on phenomena such as transnational childrearing, I seek to promote a broader conceptualization of transnationalism. PMID- 23935403 TI - Radiographic and tomographic analysis in patients with stickler syndrome type I. AB - OBJECTIVE: To further investigate the underlying pathology of axial and appendicular skeletal abnormalities such as painful spine stiffness, gait abnormalities, early onset osteoarthritis and patellar instability in patients with Stickler syndrome type I. Radiographic and tomographic analyses were organized. METHODS: From a series of Stickler syndrome patients followed from early life to late childhood. Ten patients (6 boys and four girls of different ethnic origins were consistent with the diagnosis of Stickler syndrome type I ). Phenotypic characterization was the baseline tool applied for all patients and genotypic correlation was performed on four families RESULTS: A constellation of axial abnormalities namely; anterolateral ossification of the anterior longitudinal spinal ligament with subsequent fusion of two cervical vertebrae, early onset Forestier disease (progressive spinal hyperostosis with subsequent vertebral fusion on top of bridging osteophytes and "Bamboo-like spine" resembling ankylosing spondylitis) and severe premature spine degeneration were evident. Appendicular abnormalities in connection with generalized epiphyseal dysplasia were the underlying aetiology in patients with Intoeing gait and femoral anteversion, early onset severe osteoarthritis of the weight bearing joint. Remarkable trochleo-patellar dysplasia secondary to severe osteoarthritis causing effectively the development of patellar instability was additional pathology. Mutation of COL2A1 has been confirmed as the causative gene for Stickler syndrome type I CONCLUSION: We concluded that conventional radiographs and the molecular determination of a COL2A1 in patients with (Stickler syndrome type I) are insufficient tools to explain the reasons behind the tremendous magnitude of axial and appendicular skeletal abnormalities. We were able to modify the criteria of the clinical phenotype as designated by Rose et al in accordance with the novel axial and appendicular criteria as emerged from within our current study. PMID- 23935405 TI - The Value of Clinical Needs Assessments for Point-of-Care Diagnostics. AB - Most entrepreneurial ventures fail long before the core technology can be brought to the marketplace because of disconnects in performance and usability measures such as accuracy, cost, complexity, assay stability, and time requirements between technology developers' specifications and needs of the end-users. By going through a clinical needs assessment (CNA) process, developers will gain vital information and a clear focus that will help minimize the risks associated with the development of new technologies available for use within the health care system. This article summarizes best practices of the principal investigators of the National Institute of Biomedical Imaging and Bioengineering point-of-care (POC) centers within the National Institute of Biomedical Imaging and Bioengineering POC Technologies Research Network. Clinical needs assessments are particularly important for product development areas that do not sufficiently benefit from traditional market research, such as grant-funded research and development, new product lines using cutting-edge technologies developed in start up companies, and products developed through product development partnerships for low-resource settings. The objectives of this article were to (1) highlight the importance of CNAs for development of POC devices, (2) discuss methods applied by POC Technologies Research Network for assessing clinical needs, and (3) provide a road map for future CNAs. PMID- 23935406 TI - The NIBIB Point of Care Technologies Research Network Center Themes and Opportunities for Exploratory POC Projects. AB - This article describes the new National Institute of Biomedical Imaging and Bioengineering Point-of-Care (POC) Technologies Research Network and its 4 Centers. The goal is to build expertise in development of integrated systems that address unmet POC testing clinical needs. Centers will work individually and also collectively as part of the national network to coordinate development, clinical evaluation, and reduction to practice of new POC devices. PMID- 23935407 TI - Acoustic velocity log numerical simulation and saturation estimation of gas hydrate reservoir in Shenhu area, South China Sea. AB - Gas hydrate model and free gas model are established, and two-phase theory (TPT) for numerical simulation of elastic wave velocity is adopted to investigate the unconsolidated deep-water sedimentary strata in Shenhu area, South China Sea. The relationships between compression wave (P wave) velocity and gas hydrate saturation, free gas saturation, and sediment porosity at site SH2 are studied, respectively, and gas hydrate saturation of research area is estimated by gas hydrate model. In depth of 50 to 245 m below seafloor (mbsf), as sediment porosity decreases, P wave velocity increases gradually; as gas hydrate saturation increases, P wave velocity increases gradually; as free gas saturation increases, P wave velocity decreases. This rule is almost consistent with the previous research result. In depth of 195 to 220 mbsf, the actual measurement of P wave velocity increases significantly relative to the P wave velocity of saturated water modeling, and this layer is determined to be rich in gas hydrate. The average value of gas hydrate saturation estimated from the TPT model is 23.2%, and the maximum saturation is 31.5%, which is basically in accordance with simplified three-phase equation (STPE), effective medium theory (EMT), resistivity log (Rt), and chloride anomaly method. PMID- 23935408 TI - Ultrasonic characterization of the fiber-matrix interfacial bond in aerospace composites. AB - The properties of advanced composites rely on the quality of the fiber-matrix bonding. Service-induced damage results in deterioration of bonding quality, seriously compromising the load-bearing capacity of the structure. While traditional methods to assess bonding are destructive, herein a nondestructive methodology based on shear wave reflection is numerically investigated. Reflection relies on the bonding quality and results in discernable changes in the received waveform. The key element is the "interphase" model material with varying stiffness. The study is an example of how computational methods enhance the understanding of delicate features concerning the nondestructive evaluation of materials used in advanced structures. PMID- 23935410 TI - Recognition of emotions in Mexican Spanish speech: an approach based on acoustic modelling of emotion-specific vowels. AB - An approach for the recognition of emotions in speech is presented. The target language is Mexican Spanish, and for this purpose a speech database was created. The approach consists in the phoneme acoustic modelling of emotion-specific vowels. For this, a standard phoneme-based Automatic Speech Recognition (ASR) system was built with Hidden Markov Models (HMMs), where different phoneme HMMs were built for the consonants and emotion-specific vowels associated with four emotional states (anger, happiness, neutral, sadness). Then, estimation of the emotional state from a spoken sentence is performed by counting the number of emotion-specific vowels found in the ASR's output for the sentence. With this approach, accuracy of 87-100% was achieved for the recognition of emotional state of Mexican Spanish speech. PMID- 23935409 TI - QPSO-based adaptive DNA computing algorithm. AB - DNA (deoxyribonucleic acid) computing that is a new computation model based on DNA molecules for information storage has been increasingly used for optimization and data analysis in recent years. However, DNA computing algorithm has some limitations in terms of convergence speed, adaptability, and effectiveness. In this paper, a new approach for improvement of DNA computing is proposed. This new approach aims to perform DNA computing algorithm with adaptive parameters towards the desired goal using quantum-behaved particle swarm optimization (QPSO). Some contributions provided by the proposed QPSO based on adaptive DNA computing algorithm are as follows: (1) parameters of population size, crossover rate, maximum number of operations, enzyme and virus mutation rate, and fitness function of DNA computing algorithm are simultaneously tuned for adaptive process, (2) adaptive algorithm is performed using QPSO algorithm for goal-driven progress, faster operation, and flexibility in data, and (3) numerical realization of DNA computing algorithm with proposed approach is implemented in system identification. Two experiments with different systems were carried out to evaluate the performance of the proposed approach with comparative results. Experimental results obtained with Matlab and FPGA demonstrate ability to provide effective optimization, considerable convergence speed, and high accuracy according to DNA computing algorithm. PMID- 23935411 TI - On a family of multivariate modified Humbert polynomials. AB - This paper attempts to present a multivariable extension of generalized Humbert polynomials. The results obtained here include various families of multilinear and multilateral generating functions, miscellaneous properties, and also some special cases for these multivariable polynomials. PMID- 23935412 TI - The use of the direct optimized probabilistic calculation method in design of bolt reinforcement for underground and mining workings. AB - The load-carrying system of each construction should fulfill several conditions which represent reliable criteria in the assessment procedure. It is the theory of structural reliability which determines probability of keeping required properties of constructions. Using this theory, it is possible to apply probabilistic computations based on the probability theory and mathematic statistics. Development of those methods has become more and more popular; it is used, in particular, in designs of load-carrying structures with the required level or reliability when at least some input variables in the design are random. The objective of this paper is to indicate the current scope which might be covered by the new method-Direct Optimized Probabilistic Calculation (DOProC) in assessments of reliability of load-carrying structures. DOProC uses a purely numerical approach without any simulation techniques. This provides more accurate solutions to probabilistic tasks, and, in some cases, such approach results in considerably faster completion of computations. DOProC can be used to solve efficiently a number of probabilistic computations. A very good sphere of application for DOProC is the assessment of the bolt reinforcement in the underground and mining workings. For the purposes above, a special software application-"Anchor"-has been developed. PMID- 23935413 TI - Weighted moments estimators of the parameters for the extreme value distribution based on the multiply type II censored sample. AB - We propose the weighted moments estimators (WMEs) of the location and scale parameters for the extreme value distribution based on the multiply type II censored sample. Simulated mean squared errors (MSEs) of best linear unbiased estimator (BLUE) and exact MSEs of WMEs are compared to study the behavior of different estimation methods. The results show the best estimator among the WMEs and BLUE under different combinations of censoring schemes. PMID- 23935414 TI - Metal complexes of macrocyclic schiff-base ligand: preparation, characterisation, and biological activity. AB - A new macrocyclic multidentate Schiff-base ligand Na4L consisting of two submacrocyclic units (10,21-bis-iminomethyl-3,6,14,17-tricyclo[17.3.1.1]tetracosa 1(23),2,6,8,10,12(24),13,17,19,21,-decaene-23,24-disodium) and its tetranuclear metal complexes with Mn(II), Co(II), Ni(II), Cu(II), and Zn(II) are reported. Na4L was prepared via a template approach, which is based on the condensation reaction of sodium 2,4,6-triformyl phenolate with ethylenediamine in mole ratios of 2 : 3. The tetranuclear macrocyclic-based complexes were prepared from the reaction of the corresponding metal chloride with the ligand. The mode of bonding and overall geometry of the compounds were determined through physicochemical and spectroscopic methods. These studies revealed tetrahedral geometries about Mn, Co, and Zn atoms. However, square planar geometries have been suggested for Ni(II) and Cu(II) complexes. Biological activity of the ligand and its metal complexes against Gram positive bacterial strain Staphylococcus aureus and Gram negative bacteria Escherichia coli revealed that the metal complexes become more potentially resistive to the microbial activities as compared to the free ligand. However, these metal complexes do not exhibit any effects on the activity of Pseudomonas aeruginosa bacteria. There is therefore no inhibition zone. PMID- 23935415 TI - A new developed airlift reactor integrated settling process and its application for simultaneous nitrification and denitrification nitrogen removal. AB - This study presented the performance of simultaneous nitrification and denitrification (SND) process using a new developed hybrid airlift reactor which integrated the activated sludge reaction process in the airlift reactor and the sludge settling separation process in the clarifier. The proposed reactor was started up successfully after 76 days within which the COD and total nitrogen removal rate can reach over 90% and 76.3%, respectively. The effects of different COD/N and DO concentrations on the performance of reactor were investigated. It was found that the influent COD/N maintained at 10 was sufficient for SND and the optimum DO concentration for SND was in the range of 0.5 to 0.8 mg L(-1). Batch test demonstrated that both macroscopic environment caused by the spatial DO concentration difference and microscopic environment caused by the stratification of activated sludge may be responsible for the SND process in the reactor. The hybrid airlift reactor can accomplish SND process in a single reactor and in situ automatic separation of sludge; therefore, it may serve as a promising reactor in COD and nitrogen removal fields. PMID- 23935416 TI - An improved marriage in honey bees optimization algorithm for single objective unconstrained optimization. AB - Marriage in honey bees optimization (MBO) is a metaheuristic optimization algorithm developed by inspiration of the mating and fertilization process of honey bees and is a kind of swarm intelligence optimizations. In this study we propose improved marriage in honey bees optimization (IMBO) by adding Levy flight algorithm for queen mating flight and neighboring for worker drone improving. The IMBO algorithm's performance and its success are tested on the well-known six unconstrained test functions and compared with other metaheuristic optimization algorithms. PMID- 23935417 TI - Evaluation of the effects of different surface configurations on stability of miniscrews. AB - INTRODUCTION: The aim of this study was to analyze the effects of screw design and force application on the stability of miniscrews, using RTT, SEM, and histomorphometric analyses. MATERIALS AND METHODS: Eighty cylindrical, self drilling, and Ti6Al4V alloy miniscrews (1,6 * 6 mm) were used. Four mini-screws were inserted in fibulas of each rabbit, and 115 G of force was immediately applied. Four miniscrews were inserted in the other fibula, on which no force was applied. Eight weeks after insertion, osseointegration between miniscrew and the surrounding bone was evaluated by the histomorphometric analyses, SEM, and RTT. Kruskal-Wallis and the paired t-tests were used for statistical analysis. RESULTS: Values obtained from Group I were significantly higher than those of the other loaded groups (P < .05). There were no differences in RTT scores among Groups II, III, and IV. Similar findings were also observed for unloaded mini screws. There was no significant difference between Groups I and I(C), while the differences between loaded and unloaded controls for each miniscrew were statistically significant. CONCLUSIONS: Immediate loading of miniscrews does not impair screw stability. Also, the diameter of miniscrew and more frequent thread pitches have a positive effect on stability; however, length of miniscrews does not have a significant effect on the stability. PMID- 23935418 TI - Healthy lifestyles of university students in China and influential factors. AB - This study was conducted to analyze to what extent university students exhibit healthy lifestyles and which sociodemographic variables influence healthy lifestyles. 4809 university students randomly selected were measured by use of the Healthy Lifestyle Scale for University Students questionnaire. When controlling for the other variables, the total healthy lifestyles score was predicted by gender, grade, father's level of education, and type of institution; exercise behaviour was partially predicted by gender, grade, type of institution, and family monthly income; regular behaviour was modulated by gender, grade, type of institution, family monthly income, and father's educational level; nutrition behaviour was partially affected by type of institution, family monthly income, and father's educational level; health risk behaviour was modulated by gender, mother's level of education, and family monthly income; health responsibility was modulated by gender, grade, type of institution, and father's educational level; social support was modulated by gender, grade, and father's educational level; stress management was modulated by gender, grade, type of institution, and mother's education level; life appreciation was modulated by grade, type of institution, and mother's educational level. These influences should be taken into account in designing interventions for specific socio-demographic profiles that might be at higher risk for certain behaviours. PMID- 23935419 TI - Nociceptive and histomorphometric evaluation of neural mobilization in experimental injury of the median nerve. AB - The carpal tunnel syndrome is the most common peripheral neuropathy in the upper limb, but its treatment with conservative therapies such as neural mobilization (NM) is still controversial. The aim of this study was to investigate the efficacy of the NM as treatment in a model of median nerve compression. 18 Wistar rats were subjected to compression of the median nerve in the right elbow proximal region. Were randomly divided into G1 (untreated), G2 (NM for 1 minute), and G3 (NM for 3 minutes). For treatment, the animals were anesthetized and the right forelimb received mobilization adapted to humans, on alternated days, from the 3rd to the 13th day postoperatively (PO), totaling six days of therapy. Nociception was assessed by withdrawal threshold, and after euthanasia histomorphometric analysis of the median nerve was performed. The nociceptive evaluation showed in G2 and G3 delay in return to baseline. Histomorphometric analysis showed no significant differences in the variables analyzed. It is concluded that the NM was not effective in reducing nociceptive sensation and did not alter the course of nerve regeneration. PMID- 23935420 TI - RhoA regulation of cardiomyocyte differentiation. AB - Earlier findings from our laboratory implicated RhoA in heart developmental processes. To investigate factors that potentially regulate RhoA expression, RhoA gene organisation and promoter activity were analysed. Comparative analysis indicated strict conservation of both gene organisation and coding sequence of the chick, mouse, and human RhoA genes. Bioinformatics analysis of the derived promoter region of mouse RhoA identified putative consensus sequence binding sites for several transcription factors involved in heart formation and organogenesis generally. Using luciferase reporter assays, RhoA promoter activity was shown to increase in mouse-derived P19CL6 cells that were induced to differentiate into cardiomyocytes. Overexpression of a dominant negative mutant of mouse RhoA (mRhoAN19) blocked this cardiomyocyte differentiation of P19CL6 cells and led to the accumulation of the cardiac transcription factors SRF and GATA4 and the early cardiac marker cardiac alpha -actin. Taken together, these findings indicate a fundamental role for RhoA in the differentiation of cardiomyocytes. PMID- 23935421 TI - Comparative analysis and systematic mapping of the labial sensilla in the Nepomorpha (Heteroptera: Insecta). AB - The present study provides new data concerning the morphology and distribution of the labial sensilla of 55 species of 12 nepomorphan families (Heteroptera: Nepomorpha) using the scanning electron microscope. On the labial tip, three morphologically distinct types of chemosensilla have been identified: two types of papillae sensilla and one type of peg-in-pit sensilla. Twenty-one morphologically distinct types of the mechanosensilla as well as two types of the trichoid sensilla (contact-chemoreceptive sensillum) have been identified on all labial segments in representatives of subfamilies. In Nepomorpha, morphological ground plan of the labial sensory structures is represented by an apical sensory field with 10-13 pairs of papillae sensilla and the peg-in-pit ones placed more laterally; numerous trichoid sensilla are placed on the IV segment; the chaetica sensilla are present and placed in groups or rows distributed along the labium near the labial groove on the dorsal side, and also several chaetica sensilla are unevenly scattered on the surface of that segment; the cupola and peg sensilla are numerous and evenly scattered on the fourth labial segment; the prioprerecptive sensilla, one pair is positioned on the dorsal side and on the fourth segment of the labium. The new apomorphical characters have been established for the labial sensilla in the Nepomorpha. PMID- 23935422 TI - Experimental studies of active and passive flow control techniques applied in a twin air-intake. AB - The flow control in twin air-intakes is necessary to improve the performance characteristics, since the flow traveling through curved and diffused paths becomes complex, especially after merging. The paper presents a comparison between two well-known techniques of flow control: active and passive. It presents an effective design of a vortex generator jet (VGJ) and a vane-type passive vortex generator (VG) and uses them in twin air-intake duct in different combinations to establish their effectiveness in improving the performance characteristics. The VGJ is designed to insert flow from side wall at pitch angle of 90 degrees and 45 degrees. Corotating (parallel) and counterrotating (V-shape) are the configuration of vane type VG. It is observed that VGJ has the potential to change the flow pattern drastically as compared to vane-type VG. While the VGJ is directed perpendicular to the side walls of the air-intake at a pitch angle of 90 degree, static pressure recovery is increased by 7.8% and total pressure loss is reduced by 40.7%, which is the best among all other cases tested for VGJ. For bigger-sized VG attached to the side walls of the air-intake, static pressure recovery is increased by 5.3%, but total pressure loss is reduced by only 4.5% as compared to all other cases of VG. PMID- 23935423 TI - Solubility and leaching risks of organic carbon in paddy soils as affected by irrigation managements. AB - Influence of nonflooding controlled irrigation (NFI) on solubility and leaching risk of soil organic carbon (SOC) were investigated. Compared with flooding irrigation (FI) paddies, soil water extractable organic carbon (WEOC) and dissolved organic carbon (DOC) in NFI paddies increased in surface soil but decreased in deep soil. The DOC leaching loss in NFI field was 63.3 kg C ha-1, reduced by 46.4% than in the FI fields. It indicated that multi-wet-dry cycles in NFI paddies enhanced the decomposition of SOC in surface soils, and less carbon moved downward to deep soils due to less percolation. That also led to lower SOC in surface soils in NFI paddies than in FI paddies, which implied that more carbon was released into the atmosphere from the surface soil in NFI paddies. Change of solubility of SOC in NFI paddies might lead to potential change in soil fertility and sustainability, greenhouse gas emission, and bioavailability of trace metals or organic pollutants. PMID- 23935424 TI - Reinforcement learning based artificial immune classifier. AB - One of the widely used methods for classification that is a decision-making process is artificial immune systems. Artificial immune systems based on natural immunity system can be successfully applied for classification, optimization, recognition, and learning in real-world problems. In this study, a reinforcement learning based artificial immune classifier is proposed as a new approach. This approach uses reinforcement learning to find better antibody with immune operators. The proposed new approach has many contributions according to other methods in the literature such as effectiveness, less memory cell, high accuracy, speed, and data adaptability. The performance of the proposed approach is demonstrated by simulation and experimental results using real data in Matlab and FPGA. Some benchmark data and remote image data are used for experimental results. The comparative results with supervised/unsupervised based artificial immune system, negative selection classifier, and resource limited artificial immune classifier are given to demonstrate the effectiveness of the proposed new method. PMID- 23935425 TI - New sensors and techniques for the structural health monitoring of propulsion systems. AB - The ability to monitor the structural health of the rotating components, especially in the hot sections of turbine engines, is of major interest to aero community in improving engine safety and reliability. The use of instrumentation for these applications remains very challenging. It requires sensors and techniques that are highly accurate, are able to operate in a high temperature environment, and can detect minute changes and hidden flaws before catastrophic events occur. The National Aeronautics and Space Administration (NASA), through the Aviation Safety Program (AVSP), has taken a lead role in the development of new sensor technologies and techniques for the in situ structural health monitoring of gas turbine engines. This paper presents a summary of key results and findings obtained from three different structural health monitoring approaches that have been investigated. This includes evaluating the performance of a novel microwave blade tip clearance sensor; a vibration based crack detection technique using an externally mounted capacitive blade tip clearance sensor; and lastly the results of using data driven anomaly detection algorithms for detecting cracks in a rotating disk. PMID- 23935426 TI - Radon natural radioactivity measurements for evaluation of primary pollutants. AB - Radon is naturally released from the soil into the surface layer of the atmosphere, and by monitoring the natural radioactivity data of radon and its shot-live decay products we can get valuable information about the dilution properties of the lower boundary layer. This paper explores the dispersion characteristics of the lower layer of the atmosphere in Lanzhou, China, and the close relationship with the patterns of primary pollutants' concentrations. Measurements were conducted from July 2007 to May 2008 at one station and a fifty day campaign was carried out at two stations in Lanzhou. The interpretation of radon radioactivity measurement showed that the measured atmospheric stability index (ASI) data at two stations in Lanzhou had statistically significant correlation, and well described the lower atmospheric layer mixing property in the area. The temporal trend of PM10 data was consistent with the temporal trend of ASI, with almost twice as high values in December than it in August. The results show that the ASI allows to highlight the dilution factor playing an important role in determining primary pollution events, and the mixing properties of the lower boundary layer is the key factor determining PM10 concentration in urban areas. PMID- 23935427 TI - Estimation model of soil freeze-thaw erosion in Silingco watershed wetland of Northern Tibet. AB - The freeze-thaw (FT) erosion is a type of soil erosion like water erosion and wind erosion. Limited by many factors, the grading evaluation of soil FT erosion quantities is not well studied. Based on the comprehensive analysis of the evaluation indices of soil FT erosion, we for the first time utilized the sensitivity of microwave remote sensing technology to soil moisture for identification of FT state. We established an estimation model suitable to evaluate the soil FT erosion quantity in Silingco watershed wetland of Northern Tibet using weighted summation method of six impact factors including the annual FT cycle days, average diurnal FT phase-changed water content, average annual precipitation, slope, aspect, and vegetation coverage. Finally, with the support of GIS, we classified soil FT erosion quantity in Silingco watershed wetland. The results showed that soil FT erosion are distributed in broad areas of Silingco watershed wetland. Different soil FT erosions with different intensities have evidently different spatial and geographical distributions. PMID- 23935428 TI - Nondestructive damage evaluation in ceramic matrix composites for aerospace applications. AB - Infrared thermography (IRT) and acoustic emission (AE) are the two major nondestructive methodologies for evaluating damage in ceramic matrix composites (CMCs) for aerospace applications. The two techniques are applied herein to assess and monitor damage formation and evolution in a SiC-fiber reinforced CMC loaded under cyclic and fatigue loading. The paper explains how IRT and AE can be used for the assessment of the material's performance under fatigue. IRT and AE parameters are specifically used for the characterization of the complex damage mechanisms that occur during CMC fracture, and they enable the identification of the micromechanical processes that control material failure, mainly crack formation and propagation. Additionally, these nondestructive parameters help in early prediction of the residual life of the material and in establishing the fatigue limit of materials rapidly and accurately. PMID- 23935429 TI - Application of particle swarm optimization algorithm in the heating system planning problem. AB - Based on the life cycle cost (LCC) approach, this paper presents an integral mathematical model and particle swarm optimization (PSO) algorithm for the heating system planning (HSP) problem. The proposed mathematical model minimizes the cost of heating system as the objective for a given life cycle time. For the particularity of HSP problem, the general particle swarm optimization algorithm was improved. An actual case study was calculated to check its feasibility in practical use. The results show that the improved particle swarm optimization (IPSO) algorithm can more preferably solve the HSP problem than PSO algorithm. Moreover, the results also present the potential to provide useful information when making decisions in the practical planning process. Therefore, it is believed that if this approach is applied correctly and in combination with other elements, it can become a powerful and effective optimization tool for HSP problem. PMID- 23935430 TI - Wellbore stability in oil and gas drilling with chemical-mechanical coupling. AB - Wellbore instability in oil and gas drilling is resulted from both mechanical and chemical factors. Hydration is produced in shale formation owing to the influence of the chemical property of drilling fluid. A new experimental method to measure diffusion coefficient of shale hydration is given, and the calculation method of experimental results is introduced. The diffusion coefficient of shale hydration is measured with the downhole temperature and pressure condition, then the penetration migrate law of drilling fluid filtrate around the wellbore is calculated. Furthermore, the changing rules of shale mechanical properties affected by hydration and water absorption are studied through experiments. The relationships between shale mechanical parameters and the water content are established. The wellbore stability model chemical-mechanical coupling is obtained based on the experimental results. Under the action of drilling fluid, hydration makes the shale formation softened and produced the swelling strain after drilling. This will lead to the collapse pressure increases after drilling. The study results provide a reference for studying hydration collapse period of shale. PMID- 23935431 TI - Reliable execution based on CPN and skyline optimization for Web service composition. AB - With development of SOA, the complex problem can be solved by combining available individual services and ordering them to best suit user's requirements. Web services composition is widely used in business environment. With the features of inherent autonomy and heterogeneity for component web services, it is difficult to predict the behavior of the overall composite service. Therefore, transactional properties and nonfunctional quality of service (QoS) properties are crucial for selecting the web services to take part in the composition. Transactional properties ensure reliability of composite Web service, and QoS properties can identify the best candidate web services from a set of functionally equivalent services. In this paper we define a Colored Petri Net (CPN) model which involves transactional properties of web services in the composition process. To ensure reliable and correct execution, unfolding processes of the CPN are followed. The execution of transactional composition Web service (TCWS) is formalized by CPN properties. To identify the best services of QoS properties from candidate service sets formed in the TCSW-CPN, we use skyline computation to retrieve dominant Web service. It can overcome that the reduction of individual scores to an overall similarity leads to significant information loss. We evaluate our approach experimentally using both real and synthetically generated datasets. PMID- 23935432 TI - Use of tissue culture techniques for producing virus-free plant in garlic and their identification through real-time PCR. AB - This study was performed for comparison of meristem culture technique with shoot tip culture technique for obtaining virus-free plant, comparison of micropropagation success of two different nutrient media, and determination of effectiveness of real-time PCR assay for the detection of viruses. Two different garlic species (Allium sativum and Allium tuncelianum) and two different nutrient media were used in this experiment. Results showed that Medium 2 was more successful compared to Medium 1 for both A. tuncelianum and A. sativum (Kastamonu garlic clone). In vitro plants obtained via meristem and shoot tip cultures were tested for determination of onion yellow dwarf virus (OYDV) and leek yellow stripe virus (LYSV) through real-time PCR assay. In garlic plants propagated via meristem culture, we could not detect any virus. OYDV and LYSV viruses were detected in plants obtained via shoot tip culture. OYDV virus was observed in amount of 80% and 73% of tested plants for A. tuncelianum and A. sativum, respectively. LYSV virus was found in amount of 67% of tested plants of A. tuncelianum and in amount of 87% of tested plants of A. sativum in this study. PMID- 23935433 TI - Immunity-based optimal estimation approach for a new real time group elevator dynamic control application for energy and time saving. AB - Nowadays, the increasing use of group elevator control systems owing to increasing building heights makes the development of high-performance algorithms necessary in terms of time and energy saving. Although there are many studies in the literature about this topic, they are still not effective enough because they are not able to evaluate all features of system. In this paper, a new approach of immune system-based optimal estimate is studied for dynamic control of group elevator systems. The method is mainly based on estimation of optimal way by optimizing all calls with genetic, immune system and DNA computing algorithms, and it is evaluated with a fuzzy system. The system has a dynamic feature in terms of the situation of calls and the option of the most appropriate algorithm, and it also adaptively works in terms of parameters such as the number of floors and cabins. This new approach which provides both time and energy saving was carried out in real time. The experimental results comparatively demonstrate the effects of method. With dynamic and adaptive control approach in this study carried out, a significant progress on group elevator control systems has been achieved in terms of time and energy efficiency according to traditional methods. PMID- 23935434 TI - Stress and temperature sensitivity of photonic crystals resonant cavity. AB - The temperature and stress characteristic of photonic band gap structure resonant cavities with square and graphite lattice have been studied by finite-difference time-domain method. The results show that the resonant cavities, both square and graphite lattice, have more and more resonant frequency with the cavity enlarging. And the curves between the resonant frequency and stress have better linearity. When the cavity enlarges enough, the curve between resonant frequency and temperature will become sectionalized line from nonlinear curve. Especially, the temperature sensitivity will be descending as the cavity is enlarging. Nevertheless, once some structures are put in the center of the cavity, the temperature sensitivity will be rising fast for this kind of cavity. Obviously, this character is convenient for us to achieve the specification measurement for temperature and stress. PMID- 23935435 TI - Sulfonic acid functionalized nano-gamma-Al2O3: a new, efficient, and reusable catalyst for synthesis of 3-substituted-2H-1,4-benzothiazines. AB - A simple and efficient synthetic protocol has been developed for the synthesis of 3-substituted-2H-1,4-benzothiazines by using a novel sulfonic acid functionalized nano-gamma-Al2O3 catalyst, devoid of corrosive acidic, and basic reagents. The developed method has the advantages of good to excellent yields, short reaction times, operational simplicity, and a recyclable catalyst. The catalyst can be prepared by a simple procedure from inexpensive and readily available nano-gamma Al2O3 and has been shown to be recoverable and reusable up to six cycles without any loss of activity. PMID- 23935436 TI - Level of anxiety, depression, self-esteem, social anxiety, and quality of life among the women with polycystic ovary syndrome. AB - INTRODUCTION: Polycystic ovary syndrome (PCOS) is a heterogeneous disease and many symptoms are seen with varying degrees. The aim of the present study was to determine which symptoms increased such problems as depression, anxiety, low self esteem, and social worry by classifying PCOS according to symptoms. METHODS: The study was carried out with two groups. The first group consisted of 86 patients who were diagnosed with PCOS and the second group consisted of 47 healthy volunteers. Liebowitz' Social Anxiety Scale, Rosenberg' Self-Esteem Scale, Short Form 36, Quality of Life Scale, Beck Anxiety Inventory, and Beck Depression Inventory were administered to each volunteer. RESULTS: Depression scores of infertile group were higher while anxiety scores of the obese group were bigger than other groups. It was the obesity group that received the smallest score in self-esteem and trust in people and the highest score in sensitiveness to criticism. The most affected group was oligomenorrhea-hirsutism group in terms of physical functioning, physical role function, pain, social functioning, emotional role function, and emotional well-being. CONCLUSION: We suggest that not only gynecologist but also a multidisciplinary team may examine these patients. PMID- 23935437 TI - Installation of an artificial vegetating island in oligomesotrophic Lake Paro, Korea. AB - After cut off of inflowing water, Lake Paro, an oligomesotrophic lake lost littoral zone, an important region for the aquatic ecosystem. For the first step of restoration, the artificial vegetation island was installed. The concentration of nutrients in lake water was not sufficient for the growth of macrophyte as total phosphate was ranged from 58 to 83 MUg L(-1). In order to overcome this problem, the hydrophobic substratum for bacterial attachment was selected as buoyant mat material of the artificial vegetation island. In this medium, total phosphate and total nitrogen were ranged from 190 to 1,060 MUg L(-1) and from 4.9 to 9.1 mg L(-1), respectively. These concentrations were high enough for macrophytes growth. After launching 1,800 m(2) of AVI in Lake Paro, the macrophytes, Iris pseudoacorus and Iris ensata, grew well after five years of launching without the addition of fertilizer. Furthermore, fishes were plentiful under the artificial vegetation island, and ducks were observed on the artificial vegetation island. Bacteria using sunlight as energy source and self-designed ecotechnology can be used as an alternative method for the restoration of disturbed littoral zone in oligo-mesotrophic lakes. PMID- 23935438 TI - Observational research on alcohol use and chronic disease outcome: new approaches to counter biases. AB - BACKGROUND: The frequently reported protective effects of moderate alcohol consumption in observational studies may be due to unadjusted bias. AIM: To examine two new approaches that account for unknown confounding factors and allow the application of intention-to-treat analysis. METHOD: This study used data from the 2008, 2009, and 2010 National Health Interview Surveys conducted in the United States. Unknown confounding effects were estimated through the association between parental alcohol use and health outcomes for children, because the presence of hypothetical physiological effects of alcohol can be ruled out for this association. In order to apply intention-to-treat analysis, previous alcohol use of former drinkers was obtained by using multiple imputations. Estimates with new adjustment approaches were compared with the traditional approach. RESULTS: The traditional analytical approach; appears to be consistent with findings from previous observational studies; when two further adjustment approaches were used, the "protective" effects of moderate drinking almost disappeared. CONCLUSION: Use of a proxy outcome to estimate and control residual confounding effects of alcohol use and application of the intention-to-treat principle could provide a more realistic estimation of the true effects of alcohol use on health outcomes in observational epidemiological studies. PMID- 23935439 TI - Iterative nearest neighborhood oversampling in semisupervised learning from imbalanced data. AB - Transductive graph-based semisupervised learning methods usually build an undirected graph utilizing both labeled and unlabeled samples as vertices. Those methods propagate label information of labeled samples to neighbors through their edges in order to get the predicted labels of unlabeled samples. Most popular semi-supervised learning approaches are sensitive to initial label distribution which happened in imbalanced labeled datasets. The class boundary will be severely skewed by the majority classes in an imbalanced classification. In this paper, we proposed a simple and effective approach to alleviate the unfavorable influence of imbalance problem by iteratively selecting a few unlabeled samples and adding them into the minority classes to form a balanced labeled dataset for the learning methods afterwards. The experiments on UCI datasets and MNIST handwritten digits dataset showed that the proposed approach outperforms other existing state-of-art methods. PMID- 23935440 TI - Inviscid and viscous interactions in subsonic corner flows. AB - A flap can be used as a high-lift device, in which a downward deflection results in a gain in lift at a given geometric angle of attack. To characterize the aerodynamic performance of a deflected surface in compressible flows, the present study examines a naturally developed turbulent boundary layer past the convex and concave corners. This investigation involves the analysis of mean and fluctuating pressure distributions. The results obtained indicate strong inviscid-viscous interactions. There are upstream expansion and downstream compression for the convex-corner flows, while the opposite trend is observed for the concave-corner flows. A combined flow similarity parameter, based on the small perturbation theory, is proposed to scale the flow characteristics in both subsonic convex- and concave-corner flows. PMID- 23935441 TI - Research on phthalic acid esters removal and its health risk evaluation by combined process for secondary effluent of wastewater treatment plant. AB - This paper analyses the treatment effect of the "coagulation-sedimentation-O3 biological sand filtration-GAC" combined process on phthalic acid esters in secondary effluent of municipal wastewater treatment plant and meanwhile evaluate its health risk. The results indicated that when the concentrations of DBP and DiOP in secondary effluent were at range of 0.41 mg/L-0.814 mg/L and 0.23 mg/L 0.36 mg/L, the average total removal rates of DBP and DiOP were 85.10% and 68.11%, and the average concentration of DBP and DiOP in effluent were 0.089 mg/L and 0.091 mg/L, respectively. The quality of the effluent met the requirement of the ornamental scenic environment water in The Quality of Urban Wastewater Recycling and Scenic Environment Water (GB/T 18921-2002), and the health risks of DBP and DiOP in effluent were at range of 1.99 * 10(-12) - 2.15 * 10(-12)/a and 1.48 * 10(-11) - 1.85 * 10(-11)/a, respectively, which is lower than the acceptable maximum risk level: 1.0 * 10(-6). PMID- 23935442 TI - Adsorption properties of low-cost biomaterial derived from Prunus amygdalus L. for dye removal from water. AB - The capability of Prunus amygdalus L. (almond) shell for dye removal from aqueous solutions was investigated and methyl orange was used as a model compound. The effects of operational parameters including pH, ionic strength, adsorbent concentration and mesh size, dye concentration, contact time, and temperature on the removal of dye were evaluated. The adsorption kinetics conformed to the pseudo-second-order kinetic model. The equilibrium data pointed out excellent fit to the Langmuir isotherm model with maximum monolayer adsorption capacity of 41.34 mg g(-1) at 293 K. Thermodynamic analysis proved a spontaneous, favorable, and exothermic process. It can be concluded that almond shell might be a potential low-cost adsorbent for methyl orange removal from aqueous media. PMID- 23935443 TI - Heuristic search for planning with different forced goal-ordering constraints. AB - Planning with forced goal-ordering (FGO) constraints has been proposed many times over the years, but there are still major difficulties in realizing these FGOs in plan generation. In certain planning domains, all the FGOs exist in the initial state. No matter which approach is adopted to achieve a subgoal, all the subgoals should be achieved in a given sequence from the initial state. Otherwise, the planning may arrive at a deadlock. For some other planning domains, there is no FGO in the initial state. However, FGO may occur during the planning process if certain subgoal is achieved by an inappropriate approach. This paper contributes to illustrate that it is the excludable constraints among the goal achievement operations (GAO) of different subgoals that introduce the FGOs into the planning problem, and planning with FGO is still a challenge for the heuristic search based planners. Then, a novel multistep forward search algorithm is proposed which can solve the planning problem with different FGOs efficiently. PMID- 23935444 TI - Characterization of urban runoff pollution between dissolved and particulate phases. AB - To develop urban stormwater management effectively, characterization of urban runoff pollution between dissolved and particulate phases was studied by 12 rainfall events monitored for five typical urban catchments. The average event mean concentration (AEMC) of runoff pollutants in different phases was evaluated. The AEMC values of runoff pollutants in different phases from urban roads were higher than the ones from urban roofs. The proportions of total dissolved solids, total dissolved nitrogen, and total dissolved phosphorus in total ones for all the catchments were 26.19%-30.91%, 83.29%-90.51%, and 61.54-68.09%, respectively. During rainfall events, the pollutant concentration at the initial stage of rainfall was high and then sharply decreased to a low value. Affected by catchments characterization and rainfall distribution, the highest concentration of road pollutants might appear in the later period of rainfall. Strong correlations were also found among runoffs pollutants in different phases. Total suspended solid could be considered as a surrogate for particulate matters in both road and roof runoff, while dissolved chemical oxygen demand could be regarded as a surrogate for dissolved matters in roof runoff. PMID- 23935445 TI - An adaptive Cauchy differential evolution algorithm for global numerical optimization. AB - Adaptation of control parameters, such as scaling factor (F), crossover rate (CR), and population size (NP), appropriately is one of the major problems of Differential Evolution (DE) literature. Well-designed adaptive or self-adaptive parameter control method can highly improve the performance of DE. Although there are many suggestions for adapting the control parameters, it is still a challenging task to properly adapt the control parameters for problem. In this paper, we present an adaptive parameter control DE algorithm. In the proposed algorithm, each individual has its own control parameters. The control parameters of each individual are adapted based on the average parameter value of successfully evolved individuals' parameter values by using the Cauchy distribution. Through this, the control parameters of each individual are assigned either near the average parameter value or far from that of the average parameter value which might be better parameter value for next generation. The experimental results show that the proposed algorithm is more robust than the standard DE algorithm and several state-of-the-art adaptive DE algorithms in solving various unimodal and multimodal problems. PMID- 23935446 TI - Promising new treatments for psoriasis. AB - Psoriasis is a chronic, proliferative, and inflammatory skin disease affecting 2 3% of the population and is characterized by red plaques with white scales. Psoriasis is a disease that can affect many aspects of professional and social life. Currently, several treatments are available to help control psoriasis such as methotrexate, ciclosporin, and oral retinoids. However, the available treatments are only able to relieve the symptoms and lives of individuals. The discovery of new immunological factors and a better understanding of psoriasis have turned to the use of immunological pathways and could develop new biological drugs against specific immunological elements that cause psoriasis. Biological drugs are less toxic to the body and more effective than traditional therapies. Thus, they should improve the quality of life of patients with psoriasis. This review describes new psoriasis treatments, which are on the market or currently in clinical trials that are being used to treat moderate-to-severe plaque psoriasis. In addition, this paper describes the characteristics and mechanisms in detail. In general, biological drugs are well tolerated and appear to be an effective alternative to conventional therapies. However, their effectiveness and long-term side effects need to be further researched. PMID- 23935447 TI - Two-tiered control of epithelial growth and autophagy by the insulin receptor and the ret-like receptor, stitcher. AB - Body size in Drosophila larvae, like in other animals, is controlled by nutrition. Nutrient restriction leads to catabolic responses in the majority of tissues, but the Drosophila mitotic imaginal discs continue growing. The nature of these differential control mechanisms that spare distinct tissues from starvation are poorly understood. Here, we reveal that the Ret-like receptor tyrosine kinase (RTK), Stitcher (Stit), is required for cell growth and proliferation through the PI3K-I/TORC1 pathway in the Drosophila wing disc. Both Stit and insulin receptor (InR) signaling activate PI3K-I and drive cellular proliferation and tissue growth. However, whereas optimal growth requires signaling from both InR and Stit, catabolic changes manifested by autophagy only occur when both signaling pathways are compromised. The combined activities of Stit and InR in ectodermal epithelial tissues provide an RTK-mediated, two-tiered reaction threshold to varying nutritional conditions that promote epithelial organ growth even at low levels of InR signaling. PMID- 23935448 TI - Anthranilate fluorescence marks a calcium-propagated necrotic wave that promotes organismal death in C. elegans. AB - For cells the passage from life to death can involve a regulated, programmed transition. In contrast to cell death, the mechanisms of systemic collapse underlying organismal death remain poorly understood. Here we present evidence of a cascade of cell death involving the calpain-cathepsin necrosis pathway that can drive organismal death in Caenorhabditis elegans. We report that organismal death is accompanied by a burst of intense blue fluorescence, generated within intestinal cells by the necrotic cell death pathway. Such death fluorescence marks an anterior to posterior wave of intestinal cell death that is accompanied by cytosolic acidosis. This wave is propagated via the innexin INX-16, likely by calcium influx. Notably, inhibition of systemic necrosis can delay stress-induced death. We also identify the source of the blue fluorescence, initially present in intestinal lysosome-related organelles (gut granules), as anthranilic acid glucosyl esters--not, as previously surmised, the damage product lipofuscin. Anthranilic acid is derived from tryptophan by action of the kynurenine pathway. These findings reveal a central mechanism of organismal death in C. elegans that is related to necrotic propagation in mammals--e.g., in excitotoxicity and ischemia-induced neurodegeneration. Endogenous anthranilate fluorescence renders visible the spatio-temporal dynamics of C. elegans organismal death. PMID- 23935449 TI - A temperature-responsive network links cell shape and virulence traits in a primary fungal pathogen. AB - Survival at host temperature is a critical trait for pathogenic microbes of humans. Thermally dimorphic fungal pathogens, including Histoplasma capsulatum, are soil fungi that undergo dramatic changes in cell shape and virulence gene expression in response to host temperature. How these organisms link changes in temperature to both morphologic development and expression of virulence traits is unknown. Here we elucidate a temperature-responsive transcriptional network in H. capsulatum, which switches from a filamentous form in the environment to a pathogenic yeast form at body temperature. The circuit is driven by three highly conserved factors, Ryp1, Ryp2, and Ryp3, that are required for yeast-phase growth at 37 degrees C. Ryp factors belong to distinct families of proteins that control developmental transitions in fungi: Ryp1 is a member of the WOPR family of transcription factors, and Ryp2 and Ryp3 are both members of the Velvet family of proteins whose molecular function is unknown. Here we provide the first evidence that these WOPR and Velvet proteins interact, and that Velvet proteins associate with DNA to drive gene expression. Using genome-wide chromatin immunoprecipitation studies, we determine that Ryp1, Ryp2, and Ryp3 associate with a large common set of genomic loci that includes known virulence genes, indicating that the Ryp factors directly control genes required for pathogenicity in addition to their role in regulating cell morphology. We further dissect the Ryp regulatory circuit by determining that a fourth transcription factor, which we name Ryp4, is required for yeast-phase growth and gene expression, associates with DNA, and displays interdependent regulation with Ryp1, Ryp2, and Ryp3. Finally, we define cis-acting motifs that recruit the Ryp factors to their interwoven network of temperature-responsive target genes. Taken together, our results reveal a positive feedback circuit that directs a broad transcriptional switch between environmental and pathogenic states in response to temperature. PMID- 23935450 TI - The Rho exchange factors Vav2 and Vav3 favor skin tumor initiation and promotion by engaging extracellular signaling loops. AB - The catalytic activity of GDP/GTP exchange factors (GEFs) is considered critical to maintain the typically high activity of Rho GTPases found in cancer cells. However, the large number of them has made it difficult to pinpoint those playing proactive, nonredundant roles in tumors. In this work, we have investigated whether GEFs of the Vav subfamily exert such specific roles in skin cancer. Using genetically engineered mice, we show here that Vav2 and Vav3 favor cooperatively the initiation and promotion phases of skin tumors. Transcriptomal profiling and signaling experiments indicate such function is linked to the engagement of, and subsequent participation in, keratinocyte-based autocrine/paracrine programs that promote epidermal proliferation and recruitment of pro-inflammatory cells. This is a pathology-restricted mechanism because the loss of Vav proteins does not cause alterations in epidermal homeostasis. These results reveal a previously unknown Rho GEF-dependent pro-tumorigenic mechanism that influences the biology of cancer cells and their microenvironment. They also suggest that anti-Vav therapies may be of potential interest in skin tumor prevention and/or treatment. PMID- 23935452 TI - Vav proteins' role in skin cancer. PMID- 23935451 TI - Mapping differentiation under mixed culture conditions reveals a tunable continuum of T cell fates. AB - Cell differentiation is typically directed by external signals that drive opposing regulatory pathways. Studying differentiation under polarizing conditions, with only one input signal provided, is limited in its ability to resolve the logic of interactions between opposing pathways. Dissection of this logic can be facilitated by mapping the system's response to mixtures of input signals, which are expected to occur in vivo, where cells are simultaneously exposed to various signals with potentially opposing effects. Here, we systematically map the response of naive T cells to mixtures of signals driving differentiation into the Th1 and Th2 lineages. We characterize cell state at the single cell level by measuring levels of the two lineage-specific transcription factors (T-bet and GATA3) and two lineage characteristic cytokines (IFN-gamma and IL-4) that are driven by these transcription regulators. We find a continuum of mixed phenotypes in which individual cells co-express the two lineage-specific master regulators at levels that gradually depend on levels of the two input signals. Using mathematical modeling we show that such tunable mixed phenotype arises if autoregulatory positive feedback loops in the gene network regulating this process are gradual and dominant over cross-pathway inhibition. We also find that expression of the lineage-specific cytokines follows two independent stochastic processes that are biased by expression levels of the master regulators. Thus, cytokine expression is highly heterogeneous under mixed conditions, with subpopulations of cells expressing only IFN-gamma, only IL-4, both cytokines, or neither. The fraction of cells in each of these subpopulations changes gradually with input conditions, reproducing the continuous internal state at the cell population level. These results suggest a differentiation scheme in which cells reflect uncertainty through a continuously tuneable mixed phenotype combined with a biased stochastic decision rather than a binary phenotype with a deterministic decision. PMID- 23935455 TI - "I'm not sure that I can figure out how to do that": Pursuit of work among people with mental illnesses leaving jail. AB - Restoring people with mental illnesses to community life after detention in jail is fraught with significant challenges. Many of these challenges mirror those faced by anyone else who has been detained in jail. Among these are the particular challenge of seeking gainful employment and financial support for day to-day life. This challenge is intensified when individuals return from jail to impoverished communities where employment prospects are already limited for residents, and where either a criminal record or a mental illness creates still additional barriers to work. To understand these barriers more fully, this study examined the process of seeking employment among people with mental illnesses leaving jail. Seventeen individuals with a history of mental health problems and with recent jail incarcerations were recruited from either a community based employment program or a mental health service setting. The informants were interviewed using life history interview techniques. Results show that connections to the paid workforce were tenuous at best for these respondents, both before and after their jail detention. While psychiatric symptoms, addiction, and the lack of productive social connections were individual-level factors that affected employment, the most pernicious impediments were rooted in policy, community structures, stigma and other social and economic realities.. If employment interventions are to have any traction at all in these settings, interventionists need to dig for innovative ways to address these factors, which are not complications, but bedrock realities that undergird all else. PMID- 23935453 TI - Stochastic cytokine expression induces mixed T helper cell States. AB - During eukaryotic development, the induction of a lineage-specific transcription factor typically drives differentiation of multipotent progenitor cells, while repressing that of alternative lineages. This process is often mediated by some extracellular signaling molecules, such as cytokines that can bind to cell surface receptors, leading to activation and/or repression of transcription factors. We explored the early differentiation of naive CD4 T helper (Th) cells into Th1 versus Th2 states by counting single transcripts and quantifying immunofluorescence in individual cells. Contrary to mutually exclusive expression of antagonistic transcription factors, we observed their ubiquitous co-expression in individual cells at high levels that are distinct from basal-level co expression during lineage priming. We observed that cytokines are expressed only in a small subpopulation of cells, independent from the expression of transcription factors in these single cells. This cell-to-cell variation in the cytokine expression during the early phase of T helper cell differentiation is significantly larger than in the fully differentiated state. Upon inhibition of cytokine signaling, we observed the classic mutual exclusion of antagonistic transcription factors, thus revealing a weak intracellular network otherwise overruled by the strong signals that emanate from extracellular cytokines. These results suggest that during the early differentiation process CD4 T cells acquire a mixed Th1/Th2 state, instructed by extracellular cytokines. The interplay between extracellular and intracellular signaling components unveiled in Th1/Th2 differentiation may be a common strategy for mammalian cells to buffer against noisy cytokine expression. PMID- 23935456 TI - Access to drugs for treatment of noncommunicable diseases. PMID- 23935457 TI - The growing problem of multidrug-resistant tuberculosis in North Korea. PMID- 23935458 TI - Recent shifts in global governance: implications for the response to non communicable diseases. PMID- 23935460 TI - Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments. AB - BACKGROUND: The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address. METHODS AND FINDINGS: We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria--most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation. CONCLUSIONS: By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice. Please see later in the article for the Editors' Summary. PMID- 23935459 TI - Factors affecting the delivery, access, and use of interventions to prevent malaria in pregnancy in sub-Saharan Africa: a systematic review and meta analysis. AB - BACKGROUND: Malaria in pregnancy has important consequences for mother and baby. Coverage with the World Health Organization-recommended prevention strategy for pregnant women in sub-Saharan Africa of intermittent preventive treatment in pregnancy (IPTp) and insecticide-treated nets (ITNs) is low. We conducted a systematic review to explore factors affecting delivery, access, and use of IPTp and ITNs among healthcare providers and women. METHODS AND RESULTS: We searched the Malaria in Pregnancy Library and Global Health Database from 1 January 1990 to 23 April 2013, without language restriction. Data extraction was performed by two investigators independently, and data was appraised for quality and content. Data on barriers and facilitators, and the effect of interventions, were explored using content analysis and narrative synthesis. We conducted a meta-analysis of determinants of IPTp and ITN uptake using random effects models, and performed subgroup analysis to evaluate consistency across interventions and study populations, countries, and enrolment sites. We did not perform a meta ethnography of qualitative data. Ninety-eight articles were included, of which 20 were intervention studies. Key barriers to the provision of IPTp and ITNs were unclear policy and guidance on IPTp; general healthcare system issues, such as stockouts and user fees; health facility issues stemming from poor organisation, leading to poor quality of care; poor healthcare provider performance, including confusion over the timing of each IPTp dose; and women's poor antenatal attendance, affecting IPTp uptake. Key determinants of IPTp coverage were education, knowledge about malaria/IPTp, socio-economic status, parity, and number and timing of antenatal clinic visits. Key determinants of ITN coverage were employment status, education, knowledge about malaria/ITNs, age, and marital status. Predictors showed regional variations. CONCLUSIONS: Delivery of ITNs through antenatal clinics presents fewer problems than delivery of IPTp. Many obstacles to IPTp delivery are relatively simple barriers that could be resolved in the short term. Other barriers are more entrenched within the overall healthcare system or socio-economic/cultural contexts, and will require medium- to long-term strategies. Please see later in the article for the Editors' Summary. PMID- 23935462 TI - Evaluation of prediction models for decision-making: beyond calibration and discrimination. AB - Lars Holmberg and Andrew Vickers discuss the importance of ensuring prediction models lead to better decision making in light of new research into breast, endometrial, and ovarian cancer risk by Ruth Pfeiffer and colleagues. Please see later in the article for the Editors' Summary. PMID- 23935461 TI - The influence of health systems on hypertension awareness, treatment, and control: a systematic literature review. AB - BACKGROUND: Hypertension (HT) affects an estimated one billion people worldwide, nearly three-quarters of whom live in low- or middle-income countries (LMICs). In both developed and developing countries, only a minority of individuals with HT are adequately treated. The reasons are many but, as with other chronic diseases, they include weaknesses in health systems. We conducted a systematic review of the influence of national or regional health systems on HT awareness, treatment, and control. METHODS AND FINDINGS: Eligible studies were those that analyzed the impact of health systems arrangements at the regional or national level on HT awareness, treatment, control, or antihypertensive medication adherence. The following databases were searched on 13th May 2013: Medline, Embase, Global Health, LILACS, Africa-Wide Information, IMSEAR, IMEMR, and WPRIM. There were no date or language restrictions. Two authors independently assessed papers for inclusion, extracted data, and assessed risk of bias. A narrative synthesis of the findings was conducted. Meta-analysis was not conducted due to substantial methodological heterogeneity in included studies. 53 studies were included, 11 of which were carried out in LMICs. Most studies evaluated health system financing and only four evaluated the effect of either human, physical, social, or intellectual resources on HT outcomes. Reduced medication co-payments were associated with improved HT control and treatment adherence, mainly evaluated in US settings. On balance, health insurance coverage was associated with improved outcomes of HT care in US settings. Having a routine place of care or physician was associated with improved HT care. CONCLUSIONS: This review supports the minimization of medication co-payments in health insurance plans, and although studies were largely conducted in the US, the principle is likely to apply more generally. Studies that identify and analyze complexities and links between health systems arrangements and their effects on HT management are required, particularly in LMICs. Please see later in the article for the Editors' Summary. PMID- 23935463 TI - Risk prediction for breast, endometrial, and ovarian cancer in white women aged 50 y or older: derivation and validation from population-based cohort studies. AB - BACKGROUND: Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer. METHODS AND FINDINGS: Using data on white, non Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health-AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96-1.04) for breast cancer and 1.08 (95% CI: 0.97-1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11-1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57-0.59), 0.59 (95% CI: 0.56 0.63), and 0.68 (95% CI: 0.66-0.70) for the breast, ovarian, and endometrial models, respectively. CONCLUSIONS: These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races. Please see later in the article for the Editors' Summary. PMID- 23935464 TI - Translating translational research into global health gains. PMID- 23935465 TI - Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection. AB - Conventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for cells within a range of responsiveness that allows the detection of foreign antigen without excessive responses to self. Regulatory T cells are thought to lie at the higher end of the spectrum of acceptable self-reactivity and play a crucial role in the control of autoimmunity and tolerance to innocuous antigens. While many studies have elucidated key elements influencing lineage commitment, we still lack a full understanding of how thymocytes integrate signals obtained by sampling self-peptides to make fate decisions. To address this problem, we apply stochastic models of signal integration by T cells to data from a study quantifying the development of the two lineages using controllable levels of agonist peptide in the thymus. We find two models are able to explain the observations; one in which T cells continually re-assess fate decisions on the basis of multiple summed proximal signals from TCR-pMHC interactions; and another in which TCR sensitivity is modulated over time, such that contact with the same pMHC ligand may lead to divergent outcomes at different stages of development. Neither model requires that T(conv) and T(reg) are differentially susceptible to deletion or that the two lineages need qualitatively different signals for development, as have been proposed. We find additional support for the variable sensitivity model, which is able to explain apparently paradoxical observations regarding the effect of partial and strong agonists on T(conv) and T(reg) development. PMID- 23935466 TI - 'HypothesisFinder:' a strategy for the detection of speculative statements in scientific text. AB - Speculative statements communicating experimental findings are frequently found in scientific articles, and their purpose is to provide an impetus for further investigations into the given topic. Automated recognition of speculative statements in scientific text has gained interest in recent years as systematic analysis of such statements could transform speculative thoughts into testable hypotheses. We describe here a pattern matching approach for the detection of speculative statements in scientific text that uses a dictionary of speculative patterns to classify sentences as hypothetical. To demonstrate the practical utility of our approach, we applied it to the domain of Alzheimer's disease and showed that our automated approach captures a wide spectrum of scientific speculations on Alzheimer's disease. Subsequent exploration of derived hypothetical knowledge leads to generation of a coherent overview on emerging knowledge niches, and can thus provide added value to ongoing research activities. PMID- 23935467 TI - Reconstruction and validation of a genome-scale metabolic model for the filamentous fungus Neurospora crassa using FARM. AB - The filamentous fungus Neurospora crassa played a central role in the development of twentieth-century genetics, biochemistry and molecular biology, and continues to serve as a model organism for eukaryotic biology. Here, we have reconstructed a genome-scale model of its metabolism. This model consists of 836 metabolic genes, 257 pathways, 6 cellular compartments, and is supported by extensive manual curation of 491 literature citations. To aid our reconstruction, we developed three optimization-based algorithms, which together comprise Fast Automated Reconstruction of Metabolism (FARM). These algorithms are: LInear MEtabolite Dilution Flux Balance Analysis (limed-FBA), which predicts flux while linearly accounting for metabolite dilution; One-step functional Pruning (OnePrune), which removes blocked reactions with a single compact linear program; and Consistent Reproduction Of growth/no-growth Phenotype (CROP), which reconciles differences between in silico and experimental gene essentiality faster than previous approaches. Against an independent test set of more than 300 essential/non-essential genes that were not used to train the model, the model displays 93% sensitivity and specificity. We also used the model to simulate the biochemical genetics experiments originally performed on Neurospora by comprehensively predicting nutrient rescue of essential genes and synthetic lethal interactions, and we provide detailed pathway-based mechanistic explanations of our predictions. Our model provides a reliable computational framework for the integration and interpretation of ongoing experimental efforts in Neurospora, and we anticipate that our methods will substantially reduce the manual effort required to develop high-quality genome-scale metabolic models for other organisms. PMID- 23935468 TI - Co-expression profiling of autism genes in the mouse brain. AB - Autism spectrum disorder (ASD) is one of the most prevalent and highly heritable neurodevelopmental disorders in humans. There is significant evidence that the onset and severity of ASD is governed in part by complex genetic mechanisms affecting the normal development of the brain. To date, a number of genes have been associated with ASD. However, the temporal and spatial co-expression of these genes in the brain remain unclear. To address this issue, we examined the co-expression network of 26 autism genes from AutDB (http://mindspec.org/autdb.html), in the framework of 3,041 genes whose expression energies have the highest correlation between the coronal and sagittal images from the Allen Mouse Brain Atlas database (http://mouse.brain-map.org). These data were derived from in situ hybridization experiments conducted on male, 56-day old C57BL/6J mice co-registered to the Allen Reference Atlas, and were used to generate a normalized co-expression matrix indicating the cosine similarity between expression vectors of genes in this database. The network formed by the autism-associated genes showed a higher degree of co-expression connectivity than seen for the other genes in this dataset (Kolmogorov-Smirnov P = 5*10-28). Using Monte Carlo simulations, we identified two cliques of co expressed genes that were significantly enriched with autism genes (A Bonferroni corrected P<0.05). Genes in both these cliques were significantly over-expressed in the cerebellar cortex (P = 1*10-5) suggesting possible implication of this brain region in autism. In conclusion, our study provides a detailed profiling of co-expression patterns of autism genes in the mouse brain, and suggests specific brain regions and new candidate genes that could be involved in autism etiology. PMID- 23935469 TI - Spatial stochastic dynamics enable robust cell polarization. AB - Although cell polarity is an essential feature of living cells, it is far from being well-understood. Using a combination of computational modeling and biological experiments we closely examine an important prototype of cell polarity: the pheromone-induced formation of the yeast polarisome. Focusing on the role of noise and spatial heterogeneity, we develop and investigate two mechanistic spatial models of polarisome formation, one deterministic and the other stochastic, and compare the contrasting predictions of these two models against experimental phenotypes of wild-type and mutant cells. We find that the stochastic model can more robustly reproduce two fundamental characteristics observed in wild-type cells: a highly polarized phenotype via a mechanism that we refer to as spatial stochastic amplification, and the ability of the polarisome to track a moving pheromone input. Moreover, we find that only the stochastic model can simultaneously reproduce these characteristics of the wild-type phenotype and the multi-polarisome phenotype of a deletion mutant of the scaffolding protein Spa2. Significantly, our analysis also demonstrates that higher levels of stochastic noise results in increased robustness of polarization to parameter variation. Furthermore, our work suggests a novel role for a polarisome protein in the stabilization of actin cables. These findings elucidate the intricate role of spatial stochastic effects in cell polarity, giving support to a cellular model where noise and spatial heterogeneity combine to achieve robust biological function. PMID- 23935470 TI - Efficient partitioning of memory systems and its importance for memory consolidation. AB - Long-term memories are likely stored in the synaptic weights of neuronal networks in the brain. The storage capacity of such networks depends on the degree of plasticity of their synapses. Highly plastic synapses allow for strong memories, but these are quickly overwritten. On the other hand, less labile synapses result in long-lasting but weak memories. Here we show that the trade-off between memory strength and memory lifetime can be overcome by partitioning the memory system into multiple regions characterized by different levels of synaptic plasticity and transferring memory information from the more to less plastic region. The improvement in memory lifetime is proportional to the number of memory regions, and the initial memory strength can be orders of magnitude larger than in a non partitioned memory system. This model provides a fundamental computational reason for memory consolidation processes at the systems level. PMID- 23935471 TI - Multi-study integration of brain cancer transcriptomes reveals organ-level molecular signatures. AB - We utilized abundant transcriptomic data for the primary classes of brain cancers to study the feasibility of separating all of these diseases simultaneously based on molecular data alone. These signatures were based on a new method reported herein--Identification of Structured Signatures and Classifiers (ISSAC)--that resulted in a brain cancer marker panel of 44 unique genes. Many of these genes have established relevance to the brain cancers examined herein, with others having known roles in cancer biology. Analyses on large-scale data from multiple sources must deal with significant challenges associated with heterogeneity between different published studies, for it was observed that the variation among individual studies often had a larger effect on the transcriptome than did phenotype differences, as is typical. For this reason, we restricted ourselves to studying only cases where we had at least two independent studies performed for each phenotype, and also reprocessed all the raw data from the studies using a unified pre-processing pipeline. We found that learning signatures across multiple datasets greatly enhanced reproducibility and accuracy in predictive performance on truly independent validation sets, even when keeping the size of the training set the same. This was most likely due to the meta-signature encompassing more of the heterogeneity across different sources and conditions, while amplifying signal from the repeated global characteristics of the phenotype. When molecular signatures of brain cancers were constructed from all currently available microarray data, 90% phenotype prediction accuracy, or the accuracy of identifying a particular brain cancer from the background of all phenotypes, was found. Looking forward, we discuss our approach in the context of the eventual development of organ-specific molecular signatures from peripheral fluids such as the blood. PMID- 23935472 TI - A mixture of delta-rules approximation to bayesian inference in change-point problems. AB - Error-driven learning rules have received considerable attention because of their close relationships to both optimal theory and neurobiological mechanisms. However, basic forms of these rules are effective under only a restricted set of conditions in which the environment is stable. Recent studies have defined optimal solutions to learning problems in more general, potentially unstable, environments, but the relevance of these complex mathematical solutions to how the brain solves these problems remains unclear. Here, we show that one such Bayesian solution can be approximated by a computationally straightforward mixture of simple error-driven 'Delta' rules. This simpler model can make effective inferences in a dynamic environment and matches human performance on a predictive-inference task using a mixture of a small number of Delta rules. This model represents an important conceptual advance in our understanding of how the brain can use relatively simple computations to make nearly optimal inferences in a dynamic world. PMID- 23935474 TI - Insertion of the Ca2+-independent phospholipase A2 into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations. AB - Group VI Ca2+-independent phospholipase A2 (iPLA2) is a water-soluble enzyme that is active when associated with phospholipid membranes. Despite its clear pharmaceutical relevance, no X-ray or NMR structural information is currently available for the iPLA2 or its membrane complex. In this paper, we combine homology modeling with coarse-grained (CG) and all-atom (AA) molecular dynamics (MD) simulations to build structural models of iPLA2 in association with a phospholipid bilayer. CG-MD simulations of the membrane insertion process were employed to provide a starting point for an atomistic description. Six AA-MD simulations were then conducted for 60 ns, starting from different initial CG structures, to refine the membrane complex. The resulting structures are shown to be consistent with each other and with deuterium exchange mass spectrometry (DXMS) experiments, suggesting that our approach is suitable for the modeling of iPLA2 at the membrane surface. The models show that an anchoring region (residues 710-724) forms an amphipathic helix that is stabilized by the membrane. In future studies, the proposed iPLA2 models should provide a structural basis for understanding the mechanisms of lipid extraction and drug-inhibition. In addition, the dual-resolution approach discussed here should provide the means for the future exploration of the impact of lipid diversity and sequence mutations on the activity of iPLA2 and related enzymes. PMID- 23935473 TI - Evolutionary evidence for alternative structure in RNA sequence co-variation. AB - Sequence conservation and co-variation of base pairs are hallmarks of structured RNAs. For certain RNAs (e.g. riboswitches), a single sequence must adopt at least two alternative secondary structures to effectively regulate the message. If alternative secondary structures are important to the function of an RNA, we expect to observe evolutionary co-variation supporting multiple conformations. We set out to characterize the evolutionary co-variation supporting alternative conformations in riboswitches to determine the extent to which alternative secondary structures are conserved. We found strong co-variation support for the terminator, P1, and anti-terminator stems in the purine riboswitch by extending alignments to include terminator sequences. When we performed Boltzmann suboptimal sampling on purine riboswitch sequences with terminators we found that these sequences appear to have evolved to favor specific alternative conformations. We extended our analysis of co-variation to classic alignments of group I/II introns, tRNA, and other classes of riboswitches. In a majority of these RNAs, we found evolutionary evidence for alternative conformations that are compatible with the Boltzmann suboptimal ensemble. Our analyses suggest that alternative conformations are selected for and thus likely play functional roles in even the most structured of RNAs. PMID- 23935475 TI - Information and efficiency in the nervous system--a synthesis. AB - In systems biology, questions concerning the molecular and cellular makeup of an organism are of utmost importance, especially when trying to understand how unreliable components--like genetic circuits, biochemical cascades, and ion channels, among others--enable reliable and adaptive behaviour. The repertoire and speed of biological computations are limited by thermodynamic or metabolic constraints: an example can be found in neurons, where fluctuations in biophysical states limit the information they can encode--with almost 20-60% of the total energy allocated for the brain used for signalling purposes, either via action potentials or by synaptic transmission. Here, we consider the imperatives for neurons to optimise computational and metabolic efficiency, wherein benefits and costs trade-off against each other in the context of self-organised and adaptive behaviour. In particular, we try to link information theoretic (variational) and thermodynamic (Helmholtz) free-energy formulations of neuronal processing and show how they are related in a fundamental way through a complexity minimisation lemma. PMID- 23935476 TI - Cell-cycle dependence of transcription dominates noise in gene expression. AB - The large variability in mRNA and protein levels found from both static and dynamic measurements in single cells has been largely attributed to random periods of transcription, often occurring in bursts. The cell cycle has a pronounced global role in affecting transcriptional and translational output, but how this influences transcriptional statistics from noisy promoters is unknown and generally ignored by current stochastic models. Here we show that variable transcription from the synthetic tetO promoter in S. cerevisiae is dominated by its dependence on the cell cycle. Real-time measurements of fluorescent protein at high expression levels indicate tetO promoters increase transcription rate ~2 fold in S/G2/M similar to constitutive genes. At low expression levels, where tetO promoters are thought to generate infrequent bursts of transcription, we observe random pulses of expression restricted to S/G2/M, which are correlated between homologous promoters present in the same cell. The analysis of static, single-cell mRNA measurements at different points along the cell cycle corroborates these findings. Our results demonstrate that highly variable mRNA distributions in yeast are not solely the result of randomly switching between periods of active and inactive gene expression, but instead largely driven by differences in transcriptional activity between G1 and S/G2/M. PMID- 23935477 TI - Quantifying cell fate decisions for differentiation and reprogramming of a human stem cell network: landscape and biological paths. AB - Cellular reprogramming has been recently intensively studied experimentally. We developed a global potential landscape and kinetic path framework to explore a human stem cell developmental network composed of 52 genes. We uncovered the underlying landscape for the stem cell network with two basins of attractions representing stem and differentiated cell states, quantified and exhibited the high dimensional biological paths for the differentiation and reprogramming process, connecting the stem cell state and differentiated cell state. Both the landscape and non-equilibrium curl flux determine the dynamics of cell differentiation jointly. Flux leads the kinetic paths to be deviated from the steepest descent gradient path, and the corresponding differentiation and reprogramming paths are irreversible. Quantification of paths allows us to find out how the differentiation and reprogramming occur and which important states they go through. We show the developmental process proceeds as moving from the stem cell basin of attraction to the differentiation basin of attraction. The landscape topography characterized by the barrier heights and transition rates quantitatively determine the global stability and kinetic speed of cell fate decision process for development. Through the global sensitivity analysis, we provided some specific predictions for the effects of key genes and regulation connections on the cellular differentiation or reprogramming process. Key links from sensitivity analysis and biological paths can be used to guide the differentiation designs or reprogramming tactics. PMID- 23935478 TI - Parameter trajectory analysis to identify treatment effects of pharmacological interventions. AB - The field of medical systems biology aims to advance understanding of molecular mechanisms that drive disease progression and to translate this knowledge into therapies to effectively treat diseases. A challenging task is the investigation of long-term effects of a (pharmacological) treatment, to establish its applicability and to identify potential side effects. We present a new modeling approach, called Analysis of Dynamic Adaptations in Parameter Trajectories (ADAPT), to analyze the long-term effects of a pharmacological intervention. A concept of time-dependent evolution of model parameters is introduced to study the dynamics of molecular adaptations. The progression of these adaptations is predicted by identifying necessary dynamic changes in the model parameters to describe the transition between experimental data obtained during different stages of the treatment. The trajectories provide insight in the affected underlying biological systems and identify the molecular events that should be studied in more detail to unravel the mechanistic basis of treatment outcome. Modulating effects caused by interactions with the proteome and transcriptome levels, which are often less well understood, can be captured by the time dependent descriptions of the parameters. ADAPT was employed to identify metabolic adaptations induced upon pharmacological activation of the liver X receptor (LXR), a potential drug target to treat or prevent atherosclerosis. The trajectories were investigated to study the cascade of adaptations. This provided a counter-intuitive insight concerning the function of scavenger receptor class B1 (SR-B1), a receptor that facilitates the hepatic uptake of cholesterol. Although activation of LXR promotes cholesterol efflux and -excretion, our computational analysis showed that the hepatic capacity to clear cholesterol was reduced upon prolonged treatment. This prediction was confirmed experimentally by immunoblotting measurements of SR-B1 in hepatic membranes. Next to the identification of potential unwanted side effects, we demonstrate how ADAPT can be used to design new target interventions to prevent these. PMID- 23935479 TI - Full design automation of multi-state RNA devices to program gene expression using energy-based optimization. AB - Small RNAs (sRNAs) can operate as regulatory agents to control protein expression by interaction with the 5' untranslated region of the mRNA. We have developed a physicochemical framework, relying on base pair interaction energies, to design multi-state sRNA devices by solving an optimization problem with an objective function accounting for the stability of the transition and final intermolecular states. Contrary to the analysis of the reaction kinetics of an ensemble of sRNAs, we solve the inverse problem of finding sequences satisfying targeted reactions. We show here that our objective function correlates well with measured riboregulatory activity of a set of mutants. This has enabled the application of the methodology for an extended design of RNA devices with specified behavior, assuming different molecular interaction models based on Watson-Crick interaction. We designed several YES, NOT, AND, and OR logic gates, including the design of combinatorial riboregulators. In sum, our de novo approach provides a new paradigm in synthetic biology to design molecular interaction mechanisms facilitating future high-throughput functional sRNA design. PMID- 23935480 TI - Signalling C-type lectins in antimicrobial immunity. PMID- 23935481 TI - Pertussis: challenges today and for the future. PMID- 23935482 TI - A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity. AB - Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4+ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing beta-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1beta, MIP-1alpha and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific beta-chemokine upregulation required new mRNA synthesis. The upregulation of beta chemokines was shown to be associated with a pronounced downmodulation of the HIV 1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i.e. CCR5 receptor down regulation). PMID- 23935483 TI - The viral chemokine MCK-2 of murine cytomegalovirus promotes infection as part of a gH/gL/MCK-2 complex. AB - Human cytomegalovirus (HCMV) forms two gH/gL glycoprotein complexes, gH/gL/gO and gH/gL/pUL(128,130,131A), which determine the tropism, the entry pathways and the mode of spread of the virus. For murine cytomegalovirus (MCMV), which serves as a model for HCMV, a gH/gL/gO complex functionally homologous to the HCMV gH/gL/gO complex has been described. Knock-out of MCMV gO does impair, but not abolish, virus spread indicating that also MCMV might form an alternative gH/gL complex. Here, we show that the MCMV CC chemokine MCK-2 forms a complex with the glycoprotein gH, a complex which is incorporated into the virion. We could additionally show that mutants lacking both, gO and MCK-2 are not able to produce infectious virus. Trans-complementation of these double mutants with either gO or MCK-2 showed that both proteins can promote infection of host cells, although through different entry pathways. MCK-2 has been extensively studied in vivo by others. It has been shown to be involved in attracting cells for virus dissemination and in regulating antiviral host responses. We now show that MCK-2, by forming a complex with gH, strongly promotes infection of macrophages in vitro and in vivo. Thus, MCK-2 may play a dual role in MCMV infection, as a chemokine regulating the host response and attracting specific target cells and as part of a glycoprotein complex promoting entry into cells crucial for virus dissemination. PMID- 23935484 TI - Genomic analysis of the Kiwifruit pathogen Pseudomonas syringae pv. actinidiae provides insight into the origins of an emergent plant disease. AB - The origins of crop diseases are linked to domestication of plants. Most crops were domesticated centuries--even millennia--ago, thus limiting opportunity to understand the concomitant emergence of disease. Kiwifruit (Actinidia spp.) is an exception: domestication began in the 1930s with outbreaks of canker disease caused by P. syringae pv. actinidiae (Psa) first recorded in the 1980s. Based on SNP analyses of two circularized and 34 draft genomes, we show that Psa is comprised of distinct clades exhibiting negligible within-clade diversity, consistent with disease arising by independent samplings from a source population. Three clades correspond to their geographical source of isolation; a fourth, encompassing the Psa-V lineage responsible for the 2008 outbreak, is now globally distributed. Psa has an overall clonal population structure, however, genomes carry a marked signature of within-pathovar recombination. SNP analysis of Psa-V reveals hundreds of polymorphisms; however, most reside within PPHGI-1 like conjugative elements whose evolution is unlinked to the core genome. Removal of SNPs due to recombination yields an uninformative (star-like) phylogeny consistent with diversification of Psa-V from a single clone within the last ten years. Growth assays provide evidence of cultivar specificity, with rapid systemic movement of Psa-V in Actinidia chinensis. Genomic comparisons show a dynamic genome with evidence of positive selection on type III effectors and other candidate virulence genes. Each clade has highly varied complements of accessory genes encoding effectors and toxins with evidence of gain and loss via multiple genetic routes. Genes with orthologs in vascular pathogens were found exclusively within Psa-V. Our analyses capture a pathogen in the early stages of emergence from a predicted source population associated with wild Actinidia species. In addition to candidate genes as targets for resistance breeding programs, our findings highlight the importance of the source population as a reservoir of new disease. PMID- 23935485 TI - A product of heme catabolism modulates bacterial function and survival. AB - Bilirubin is the terminal metabolite in heme catabolism in mammals. After deposition into bile, bilirubin is released in large quantities into the mammalian gastrointestinal (GI) tract. We hypothesized that intestinal bilirubin may modulate the function of enteric bacteria. To test this hypothesis, we investigated the effect of bilirubin on two enteric pathogens; enterohemorrhagic E. coli (EHEC), a Gram-negative that causes life-threatening intestinal infections, and E. faecalis, a Gram-positive human commensal bacterium known to be an opportunistic pathogen with broad-spectrum antibiotic resistance. We demonstrate that bilirubin can protect EHEC from exogenous and host-generated reactive oxygen species (ROS) through the absorption of free radicals. In contrast, E. faecalis was highly susceptible to bilirubin, which causes significant membrane disruption and uncoupling of respiratory metabolism in this bacterium. Interestingly, similar results were observed for other Gram-positive bacteria, including B. cereus and S. aureus. A model is proposed whereby bilirubin places distinct selective pressure on enteric bacteria, with Gram negative bacteria being protected from ROS (positive outcome) and Gram-positive bacteria being susceptible to membrane disruption (negative outcome). This work suggests bilirubin has differential but biologically relevant effects on bacteria and justifies additional efforts to determine the role of this neglected waste catabolite in disease processes, including animal models. PMID- 23935486 TI - Structural basis for native agonist and synthetic inhibitor recognition by the Pseudomonas aeruginosa quorum sensing regulator PqsR (MvfR). AB - Bacterial populations co-ordinate gene expression collectively through quorum sensing (QS), a cell-to-cell communication mechanism employing diffusible signal molecules. The LysR-type transcriptional regulator (LTTR) protein PqsR (MvfR) is a key component of alkyl-quinolone (AQ)-dependent QS in Pseudomonas aeruginosa. PqsR is activated by 2-alkyl-4-quinolones including the Pseudomonas quinolone signal (PQS; 2-heptyl-3-hydroxy-4(1H)-quinolone), its precursor 2-heptyl-4 hydroxyquinoline (HHQ) and their C9 congeners, 2-nonyl-3-hydroxy-4(1H)-quinolone (C9-PQS) and 2-nonyl-4-hydroxyquinoline (NHQ). These drive the autoinduction of AQ biosynthesis and the up-regulation of key virulence determinants as a function of bacterial population density. Consequently, PqsR constitutes a potential target for novel antibacterial agents which attenuate infection through the blockade of virulence. Here we present the crystal structures of the PqsR co inducer binding domain (CBD) and a complex with the native agonist NHQ. We show that the structure of the PqsR CBD has an unusually large ligand-binding pocket in which a native AQ agonist is stabilized entirely by hydrophobic interactions. Through a ligand-based design strategy we synthesized and evaluated a series of 50 AQ and novel quinazolinone (QZN) analogues and measured the impact on AQ biosynthesis, virulence gene expression and biofilm development. The simple exchange of two isosteres (OH for NH2) switches a QZN agonist to an antagonist with a concomitant impact on the induction of bacterial virulence factor production. We also determined the complex crystal structure of a QZN antagonist bound to PqsR revealing a similar orientation in the ligand binding pocket to the native agonist NHQ. This structure represents the first description of an LTTR antagonist complex. Overall these studies present novel insights into LTTR ligand binding and ligand-based drug design and provide a chemical scaffold for further anti-P. aeruginosa virulence drug development by targeting the AQ receptor PqsR. PMID- 23935488 TI - Enterovirus 71 binding to PSGL-1 on leukocytes: VP1-145 acts as a molecular switch to control receptor interaction. AB - Some strains of enterovirus 71 (EV71), but not others, infect leukocytes by binding to a specific receptor molecule: the P-selectin glycoprotein ligand-1 (PSGL-1). We find that a single amino acid residue within the capsid protein VP1 determines whether EV71 binds to PSGL-1. Examination of capsid sequences of representative EV71 strains revealed that the PSGL-1-binding viruses had either a G or a Q at residue 145 within the capsid protein VP1 (VP1-145G or Q), whereas PSGL-1-nonbinding viruses had VP1-145E. Using site-directed mutagenesis we found that PSGL-1-binding strains lost their capacity to bind when VP1-145G/Q was replaced by E; conversely, nonbinding strains gained the capacity to bind PSGL-1 when VP1-145E was replaced with either G or Q. Viruses with G/Q at VP1-145 productively infected a leukocyte cell line, Jurkat T-cells, whereas viruses with E at this position did not. We previously reported that EV71 binds to the N terminal region of PSGL-1, and that binding depends on sulfated tyrosine residues within this region. We speculated that binding depends on interaction between negatively charged sulfate groups and positively charged basic residues in the virus capsid. VP1-145 on the virus surface is in close proximity to conserved lysine residues at VP1-242 and VP1-244. Comparison of recently published crystal structures of EV71 isolates with either Q or E at VP1-145 revealed that VP1-145 controls the orientation of the lysine side-chain of VP1-244: with VP1-145Q the lysine side chain faces outward, but with VP1-145E, the lysine side chain is turned toward the virus surface. Mutation of VP1-244 abolished virus binding to PSGL-1, and mutation of VP1-242 greatly reduced binding. We propose that conserved lysine residues on the virus surface are responsible for interaction with sulfated tyrosine residues at the PSGL-1 N-terminus, and that VP1-145 acts as a switch, controlling PSGL-1 binding by modulating the exposure of VP1-244K. PMID- 23935487 TI - In vivo adaptation and persistence of Neisseria meningitidis within the nasopharyngeal mucosa. AB - Neisseria meningitidis (Nme) asymptomatically colonizes the human nasopharynx, yet can initiate rapidly-progressing sepsis and meningitis in rare instances. Understanding the meningococcal lifestyle within the nasopharyngeal mucosa, a phase of infection that is prerequisite for disease, has been hampered by the lack of animal models. Herein, we compare mice expressing the four different human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) that can bind the neisserial Opa protein adhesins, and find that expression of human CEACAM1 is necessary and sufficient to establish intranasal colonization. During infection, in vivo selection for phase variants expressing CEACAM1-specific Opa proteins occurs, allowing mucosal attachment and entry into the subepithelial space. Consistent with an essential role for Opa proteins in this process, Opa deficient meningococci were unable to colonize the CEACAM1-humanized mice. While simple Opa-mediated attachment triggered an innate response regardless of meningococcal viability within the inoculum, persistence of viable Opa-expressing bacteria within the CEACAM1-humanized mice was required for a protective memory response to be achieved. Parenteral immunization with a capsule-based conjugate vaccine led to the accumulation of protective levels of Nme-specific IgG within the nasal mucus, yet the sterilizing immunity afforded by natural colonization was instead conferred by Nme-specific IgA without detectable IgG. Considered together, this study establishes that the availability of CEACAM1 helps define the exquisite host specificity of this human-restricted pathogen, displays a striking example of in vivo selection for the expression of desirable Opa variants, and provides a novel model in which to consider meningococcal infection and immunity within the nasopharyngeal mucosa. PMID- 23935489 TI - Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls. AB - Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6 * 10-11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Delta32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size. PMID- 23935490 TI - The Salmonella type III effector SspH2 specifically exploits the NLR co-chaperone activity of SGT1 to subvert immunity. AB - To further its pathogenesis, S. Typhimurium delivers effector proteins into host cells, including the novel E3 ubiquitin ligase (NEL) effector SspH2. Using model systems in a cross-kingdom approach we gained further insight into the molecular function of this effector. Here, we show that SspH2 modulates innate immunity in both mammalian and plant cells. In mammalian cell culture, SspH2 significantly enhanced Nod1-mediated IL-8 secretion when transiently expressed or bacterially delivered. In addition, SspH2 also enhanced an Rx-dependent hypersensitive response in planta. In both of these nucleotide-binding leucine rich repeat receptor (NLR) model systems, SspH2-mediated phenotypes required its catalytic E3 ubiquitin ligase activity and interaction with the conserved host protein SGT1. SGT1 has an essential cell cycle function and an additional function as an NLR co chaperone in animal and plant cells. Interaction between SspH2 and SGT1 was restricted to SGT1 proteins that have NLR co-chaperone function and accordingly, SspH2 did not affect SGT1 cell cycle functions. Mechanistic studies revealed that SspH2 interacted with, and ubiquitinated Nod1 and could induce Nod1 activity in an agonist-independent manner if catalytically active. Interestingly, SspH2 in vitro ubiquitination activity and protein stability were enhanced by SGT1. Overall, this work adds to our understanding of the sophisticated mechanisms used by bacterial effectors to co-opt host pathways by demonstrating that SspH2 can subvert immune responses by selectively exploiting the functions of a conserved host co-chaperone. PMID- 23935492 TI - Understanding human variation in infectious disease susceptibility through clinical and cellular GWAS. PMID- 23935491 TI - Blocking TLR7- and TLR9-mediated IFN-alpha production by plasmacytoid dendritic cells does not diminish immune activation in early SIV infection. AB - Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-alpha that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-alpha, albeit at low levels. pDC mediate a marked but transient IFN alpha response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-alpha response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-alpha production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-alpha production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-alpha production may not reduce HIV-associated immunopathology. PMID- 23935493 TI - Prion replication occurs in endogenous adult neural stem cells and alters their neuronal fate: involvement of endogenous neural stem cells in prion diseases. AB - Prion diseases are irreversible progressive neurodegenerative diseases, leading to severe incapacity and death. They are characterized in the brain by prion amyloid deposits, vacuolisation, astrocytosis, neuronal degeneration, and by cognitive, behavioural and physical impairments. There is no treatment for these disorders and stem cell therapy therefore represents an interesting new approach. Gains could not only result from the cell transplantation, but also from the stimulation of endogenous neural stem cells (NSC) or by the combination of both approaches. However, the development of such strategies requires a detailed knowledge of the pathology, particularly concerning the status of the adult neurogenesis and endogenous NSC during the development of the disease. During the past decade, several studies have consistently shown that NSC reside in the adult mammalian central nervous system (CNS) and that adult neurogenesis occurs throughout the adulthood in the subventricular zone of the lateral ventricle or the Dentate Gyrus of the hippocampus. Adult NSC are believed to constitute a reservoir for neuronal replacement during normal cell turnover or after brain injury. However, the activation of this system does not fully compensate the neuronal loss that occurs during neurodegenerative diseases and could even contribute to the disease progression. We investigated here the status of these cells during the development of prion disorders. We were able to show that NSC accumulate and replicate prions. Importantly, this resulted in the alteration of their neuronal fate which then represents a new pathologic event that might underlie the rapid progression of the disease. PMID- 23935494 TI - Viperin regulates cellular lipid metabolism during human cytomegalovirus infection. AB - Human cytomegalovirus (HCMV) has been shown to induce increased lipogenesis in infected cells, and this is believed to be required for proper virion envelopment. We show here that this increase is a consequence of the virus induced redistribution of the host protein viperin to mitochondria and its capacity to interact with and block the function of the mitochondrial trifunctional protein (TFP), the enzyme that mediates fatty acid-beta-oxidation. The resulting decrease in cellular ATP levels activates the enzyme AMP-activated protein kinase (AMPK), which induces expression of the glucose transporter GLUT4, resulting in increased glucose import and translocation to the nucleus of the glucose-regulated transcription factor ChREBP. This induces increased transcription of genes encoding lipogenic enzymes, increased lipid synthesis and lipid droplet accumulation, and generation of the viral envelope. Viperin dependent lipogenesis is required for optimal production of infectious virus. We show that all of these metabolic outcomes can be replicated by direct targeting of viperin to mitochondria in the absence of HCMV infection, and that the motif responsible for Fe-S cluster binding by viperin is essential. The data indicate that viperin is the major effector underlying the ability of HCMV to regulate cellular lipid metabolism. PMID- 23935495 TI - Discovery of anthelmintic drug targets and drugs using chokepoints in nematode metabolic pathways. AB - Parasitic roundworm infections plague more than 2 billion people (1/3 of humanity) and cause drastic losses in crops and livestock. New anthelmintic drugs are urgently needed as new drug resistance and environmental concerns arise. A "chokepoint reaction" is defined as a reaction that either consumes a unique substrate or produces a unique product. A chokepoint analysis provides a systematic method of identifying novel potential drug targets. Chokepoint enzymes were identified in the genomes of 10 nematode species, and the intersection and union of all chokepoint enzymes were found. By studying and experimentally testing available compounds known to target proteins orthologous to nematode chokepoint proteins in public databases, this study uncovers features of chokepoints that make them successful drug targets. Chemogenomic screening was performed on drug-like compounds from public drug databases to find existing compounds that target homologs of nematode chokepoints. The compounds were prioritized based on chemical properties frequently found in successful drugs and were experimentally tested using Caenorhabditis elegans. Several drugs that are already known anthelmintic drugs and novel candidate targets were identified. Seven of the compounds were tested in Caenorhabditis elegans and three yielded a detrimental phenotype. One of these three drug-like compounds, Perhexiline, also yielded a deleterious effect in Haemonchus contortus and Onchocerca lienalis, two nematodes with divergent forms of parasitism. Perhexiline, known to affect the fatty acid oxidation pathway in mammals, caused a reduction in oxygen consumption rates in C. elegans and genome-wide gene expression profiles provided an additional confirmation of its mode of action. Computational modeling of Perhexiline and its target provided structural insights regarding its binding mode and specificity. Our lists of prioritized drug targets and drug-like compounds have potential to expedite the discovery of new anthelmintic drugs with broad-spectrum efficacy. PMID- 23935496 TI - Three-dimensional normal human neural progenitor tissue-like assemblies: a model of persistent varicella-zoster virus infection. AB - Varicella-zoster virus (VZV) is a neurotropic human alphaherpesvirus that causes varicella upon primary infection, establishes latency in multiple ganglionic neurons, and can reactivate to cause zoster. Live attenuated VZV vaccines are available; however, they can also establish latent infections and reactivate. Studies of VZV latency have been limited to the analyses of human ganglia removed at autopsy, as the virus is strictly a human pathogen. Recently, terminally differentiated human neurons have received much attention as a means to study the interaction between VZV and human neurons; however, the short life-span of these cells in culture has limited their application. Herein, we describe the construction of a model of normal human neural progenitor cells (NHNP) in tissue like assemblies (TLAs), which can be successfully maintained for at least 180 days in three-dimensional (3D) culture, and exhibit an expression profile similar to that of human trigeminal ganglia. Infection of NHNP TLAs with cell-free VZV resulted in a persistent infection that was maintained for three months, during which the virus genome remained stable. Immediate-early, early and late VZV genes were transcribed, and low-levels of infectious VZV were recurrently detected in the culture supernatant. Our data suggest that NHNP TLAs are an effective system to investigate long-term interactions of VZV with complex assemblies of human neuronal cells. PMID- 23935497 TI - Rab18 binds to hepatitis C virus NS5A and promotes interaction between sites of viral replication and lipid droplets. AB - Hepatitis C virus (HCV) is a single-stranded RNA virus that replicates on endoplasmic reticulum-derived membranes. HCV particle assembly is dependent on the association of core protein with cellular lipid droplets (LDs). However, it remains uncertain whether HCV assembly occurs at the LD membrane itself or at closely associated ER membranes. Furthermore, it is not known how the HCV replication complex and progeny genomes physically associate with the presumed sites of virion assembly at or near LDs. Using an unbiased proteomic strategy, we have found that Rab18 interacts with the HCV nonstructural protein NS5A. Rab18 associates with LDs and is believed to promote physical interaction between LDs and ER membranes. Active (GTP-bound) forms of Rab18 bind more strongly to NS5A than a constitutively GDP-bound mutant. NS5A colocalizes with Rab18-positive LDs in HCV-infected cells, and Rab18 appears to promote the physical association of NS5A and other replicase components with LDs. Modulation of Rab18 affects genome replication and possibly also the production of infectious virions. Our results support a model in which specific interactions between viral and cellular proteins may promote the physical interaction between membranous HCV replication foci and lipid droplets. PMID- 23935498 TI - An anti-human ICAM-1 antibody inhibits rhinovirus-induced exacerbations of lung inflammation. AB - Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ~90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM 1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo. PMID- 23935499 TI - Rational design of a live attenuated dengue vaccine: 2'-o-methyltransferase mutants are highly attenuated and immunogenic in mice and macaques. AB - Dengue virus is transmitted by Aedes mosquitoes and infects at least 100 million people every year. Progressive urbanization in Asia and South-Central America and the geographic expansion of Aedes mosquito habitats have accelerated the global spread of dengue, resulting in a continuously increasing number of cases. A cost effective, safe vaccine conferring protection with ideally a single injection could stop dengue transmission. Current vaccine candidates require several booster injections or do not provide protection against all four serotypes. Here we demonstrate that dengue virus mutants lacking 2'-O-methyltransferase activity are highly sensitive to type I IFN inhibition. The mutant viruses are attenuated in mice and rhesus monkeys and elicit a strong adaptive immune response. Monkeys immunized with a single dose of 2'-O-methyltransferase mutant virus showed 100% sero-conversion even when a dose as low as 1,000 plaque forming units was administrated. Animals were fully protected against a homologous challenge. Furthermore, mosquitoes feeding on blood containing the mutant virus were not infected, whereas those feeding on blood containing wild-type virus were infected and thus able to transmit it. These results show the potential of 2'-O methyltransferase mutant virus as a safe, rationally designed dengue vaccine that restrains itself due to the increased susceptibility to the host's innate immune response. PMID- 23935500 TI - Malaria parasite-synthesized heme is essential in the mosquito and liver stages and complements host heme in the blood stages of infection. AB - Heme metabolism is central to malaria parasite biology. The parasite acquires heme from host hemoglobin in the intraerythrocytic stages and stores it as hemozoin to prevent free heme toxicity. The parasite can also synthesize heme de novo, and all the enzymes in the pathway are characterized. To study the role of the dual heme sources in malaria parasite growth and development, we knocked out the first enzyme, delta-aminolevulinate synthase (ALAS), and the last enzyme, ferrochelatase (FC), in the heme-biosynthetic pathway of Plasmodium berghei (Pb). The wild-type and knockout (KO) parasites had similar intraerythrocytic growth patterns in mice. We carried out in vitro radiolabeling of heme in Pb-infected mouse reticulocytes and Plasmodium falciparum-infected human RBCs using [4-(14)C] aminolevulinic acid (ALA). We found that the parasites incorporated both host hemoglobin-heme and parasite-synthesized heme into hemozoin and mitochondrial cytochromes. The similar fates of the two heme sources suggest that they may serve as backup mechanisms to provide heme in the intraerythrocytic stages. Nevertheless, the de novo pathway is absolutely essential for parasite development in the mosquito and liver stages. PbKO parasites formed drastically reduced oocysts and did not form sporozoites in the salivary glands. Oocyst production in PbALASKO parasites recovered when mosquitoes received an ALA supplement. PbALASKO sporozoites could infect mice only when the mice received an ALA supplement. Our results indicate the potential for new therapeutic interventions targeting the heme-biosynthetic pathway in the parasite during the mosquito and liver stages. PMID- 23935501 TI - Clostridium difficile 027/BI/NAP1 encodes a hypertoxic and antigenically variable form of TcdB. AB - The Clostridium difficile exotoxin, TcdB, which is a major virulence factor, varies between strains of this pathogen. Herein, we show that TcdB from the epidemic BI/NAP1/027 strain of C. difficile is more lethal, causes more extensive brain hemorrhage, and is antigenically variable from TcdB produced by previously studied strains of this pathogen (TcdB003). In mouse intoxication assays, TcdB from a ribotype 027 strain (TcdB027) was at least four fold more lethal than TcdB003. TcdB027 caused a previously undescribed brain hemorrhage in mice and this correlated with a heightened sensitivity of brain microvascular endothelial cells to the toxin. TcdB003 and TcdB027 also differed in their antigenic profiles and did not share cross-neutralizing epitopes in a major immunogenic region of the protein. Solid phase humoral mapping of epitopes in the carboxy-terminal domains (CTD) of TcdB027 and TcdB003 identified 11 reactive epitopes that varied between the two forms of TcdB, and 13 epitopes that were shared or overlapping. Despite the epitope differences and absence of neutralizing epitopes in the CTD of TcdB027, a toxoid form of this toxin primed a strong protective response. These findings indicate TcdB027 is a more potent toxin than TcdB003 as measured by lethality assays and pathology, moreover the sequence differences between the two forms of TcdB alter antigenic epitopes and reduce cross-neutralization by antibodies targeting the CTD. PMID- 23935502 TI - The late endosomal HOPS complex anchors active G-protein signaling essential for pathogenesis in magnaporthe oryzae. AB - In Magnaporthe oryzae, the causal ascomycete of the devastating rice blast disease, the conidial germ tube tip must sense and respond to a wide array of requisite cues from the host in order to switch from polarized to isotropic growth, ultimately forming the dome-shaped infection cell known as the appressorium. Although the role for G-protein mediated Cyclic AMP signaling in appressorium formation was first identified almost two decades ago, little is known about the spatio-temporal dynamics of the cascade and how the signal is transmitted through the intracellular network during cell growth and morphogenesis. In this study, we demonstrate that the late endosomal compartments, comprising of a PI3P-rich (Phosphatidylinositol 3-phosphate) highly dynamic tubulo-vesicular network, scaffold active MagA/GalphaS, Rgs1 (a GAP for MagA), Adenylate cyclase and Pth11 (a non-canonical GPCR) in the likely absence of AKAP-like anchors during early pathogenic development in M. oryzae. Loss of HOPS component Vps39 and consequently the late endosomal function caused a disruption of adenylate cyclase localization, cAMP signaling and appressorium formation. Remarkably, exogenous cAMP rescued the appressorium formation defects associated with VPS39 deletion in M. oryzae. We propose that sequestration of key G-protein signaling components on dynamic late endosomes and/or endolysosomes, provides an effective molecular means to compartmentalize and control the spatio temporal activation and rapid downregulation (likely via vacuolar degradation) of cAMP signaling amidst changing cellular geometry during pathogenic development in M. oryzae. PMID- 23935503 TI - Distinct binding and immunogenic properties of the gonococcal homologue of meningococcal factor h binding protein. AB - Neisseria meningitidis is a leading cause of sepsis and meningitis. The bacterium recruits factor H (fH), a negative regulator of the complement system, to its surface via fH binding protein (fHbp), providing a mechanism to avoid complement mediated killing. fHbp is an important antigen that elicits protective immunity against the meningococcus and has been divided into three different variant groups, V1, V2 and V3, or families A and B. However, immunisation with fHbp V1 does not result in cross-protection against V2 and V3 and vice versa. Furthermore, high affinity binding of fH could impair immune responses against fHbp. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae, designated as Gonococcal homologue of fHbp (Ghfp) which we show is a promising vaccine candidate for N. meningitidis. We demonstrate that Gfhp is not expressed on the surface of the gonococcus and, despite its high level of identity with fHbp, does not bind fH. Substitution of only two amino acids in Ghfp is sufficient to confer fH binding, while the corresponding residues in V3 fHbp are essential for high affinity fH binding. Furthermore, immune responses against Ghfp recognise V1, V2 and V3 fHbps expressed by a range of clinical isolates, and have serum bactericidal activity against N. meningitidis expressing fHbps from all variant groups. PMID- 23935504 TI - A novel role for pro-coagulant microvesicles in the early host defense against streptococcus pyogenes. AB - Previous studies have shown that stimulation of whole blood or peripheral blood mononuclear cells with bacterial virulence factors results in the sequestration of pro-coagulant microvesicles (MVs). These particles explore their clotting activity via the extrinsic and intrinsic pathway of coagulation; however, their pathophysiological role in infectious diseases remains enigmatic. Here we describe that the interaction of pro-coagulant MVs with bacteria of the species Streptococcus pyogenes is part of the early immune response to the invading pathogen. As shown by negative staining electron microscopy and clotting assays, pro-coagulant MVs bind in the presence of plasma to the bacterial surface. Fibrinogen was identified as a linker that, through binding to the M1 protein of S. pyogenes, allows the opsonization of the bacteria by MVs. Surface plasmon resonance analysis revealed a strong interaction between pro-coagulant MVs and fibrinogen with a KD value in the nanomolar range. When performing a mass spectrometry-based strategy to determine the protein quantity, a significant up regulation of the fibrinogen-binding integrins CD18 and CD11b on pro-coagulant MVs was recorded. Finally we show that plasma clots induced by pro-coagulant MVs are able to prevent bacterial dissemination and possess antimicrobial activity. These findings were confirmed by in vivo experiments, as local treatment with pro coagulant MVs dampens bacterial spreading to other organs and improved survival in an invasive streptococcal mouse model of infection. Taken together, our data implicate that pro-coagulant MVs play an important role in the early response of the innate immune system in infectious diseases. PMID- 23935505 TI - IL-1beta suppresses innate IL-25 and IL-33 production and maintains helminth chronicity. AB - Approximately 2 billion people currently suffer from intestinal helminth infections, which are typically chronic in nature and result in growth retardation, vitamin A deficiency, anemia and poor cognitive function. Such chronicity results from co-evolution between helminths and their mammalian hosts; however, the molecular mechanisms by which these organisms avert immune rejection are not clear. We have found that the natural murine helminth, Heligmosomoides polygyrus bakeri (Hp) elicits the secretion of IL-1beta in vivo and in vitro and that this cytokine is critical for shaping a mucosal environment suited to helminth chronicity. Indeed in mice deficient for IL-1beta (IL-1beta(-/-)), or treated with the soluble IL-1betaR antagonist, Anakinra, helminth infection results in enhanced type 2 immunity and accelerated parasite expulsion. IL-1beta acts to decrease production of IL-25 and IL-33 at early time points following infection and parasite rejection was determined to require IL-25. Taken together, these data indicate that Hp promotes the release of host-derived IL-1beta that suppresses the release of innate cytokines, resulting in suboptimal type 2 immunity and allowing pathogen chronicity. PMID- 23935506 TI - Post-translational control of IL-1beta via the human papillomavirus type 16 E6 oncoprotein: a novel mechanism of innate immune escape mediated by the E3 ubiquitin ligase E6-AP and p53. AB - Infections with high-risk human papillomaviruses (HPVs) are causally involved in the development of anogenital cancer. HPVs apparently evade the innate immune response of their host cells by dysregulating immunomodulatory factors such as cytokines and chemokines, thereby creating a microenvironment that favors malignancy. One central key player in the immune surveillance interactome is interleukin-1 beta (IL-1beta) which not only mediates inflammation, but also links innate and adaptive immunity. Because of its pleiotropic physiological effects, IL-1beta production is tightly controlled on transcriptional, post translational and secretory levels. Here, we describe a novel mechanism how the high-risk HPV16 E6 oncoprotein abrogates IL-1beta processing and secretion in a NALP3 inflammasome-independent manner. We analyzed IL-1beta regulation in immortalized keratinocytes that harbor the HPV16 E6 and/or E7 oncogenes as well as HPV-positive cervical tumor cells. While in primary and in E7-immortalized human keratinocytes the secretion of IL-1beta was highly inducible upon inflammasome activation, E6-positive cells did not respond. Western blot analyses revealed a strong reduction of basal intracellular levels of pro-IL-1beta that was independent of dysregulation of the NALP3 inflammasome, autophagy or lysosomal activity. Instead, we demonstrate that pro-IL-1beta is degraded in a proteasome-dependent manner in E6-positive cells which is mediated via the ubiquitin ligase E6-AP and p53. Conversely, in E6- and E6/E7-immortalized cells pro-IL-1beta levels were restored by siRNA knock-down of E6-AP and simultaneous recovery of functional p53. In the context of HPV-induced carcinogenesis, these data suggest a novel post-translational mechanism of pro-IL-1beta regulation which ultimately inhibits the secretion of IL-1beta in virus-infected keratinocytes. The clinical relevance of our results was further confirmed in HPV positive tissue samples, where a gradual decrease of IL-1beta towards cervical cancer could be discerned. Hence, attenuation of IL-1beta by the HPV16 E6 oncoprotein in immortalized cells is apparently a crucial step in viral immune evasion and initiation of malignancy. PMID- 23935507 TI - Gene * physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry. AB - Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS * physical activity interaction effect estimate (Pinteraction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction = 0.014 vs. n = 71,611, Pinteraction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction = 0.003) and the SEC16B rs10913469 (Pinteraction = 0.025) variants showed evidence of SNP * physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal. PMID- 23935508 TI - RBM5 is a male germ cell splicing factor and is required for spermatid differentiation and male fertility. AB - Alternative splicing of precursor messenger RNA (pre-mRNA) is common in mammalian cells and enables the production of multiple gene products from a single gene, thus increasing transcriptome and proteome diversity. Disturbance of splicing regulation is associated with many human diseases; however, key splicing factors that control tissue-specific alternative splicing remain largely undefined. In an unbiased genetic screen for essential male fertility genes in the mouse, we identified the RNA binding protein RBM5 (RNA binding motif 5) as an essential regulator of haploid male germ cell pre-mRNA splicing and fertility. Mice carrying a missense mutation (R263P) in the second RNA recognition motif (RRM) of RBM5 exhibited spermatid differentiation arrest, germ cell sloughing and apoptosis, which ultimately led to azoospermia (no sperm in the ejaculate) and male sterility. Molecular modelling suggested that the R263P mutation resulted in compromised mRNA binding. Within the adult mouse testis, RBM5 localises to somatic and germ cells including spermatogonia, spermatocytes and round spermatids. Through the use of RNA pull down coupled with microarrays, we identified 11 round spermatid-expressed mRNAs as putative RBM5 targets. Importantly, the R263P mutation affected pre-mRNA splicing and resulted in a shift in the isoform ratios, or the production of novel spliced transcripts, of most targets. Microarray analysis of isolated round spermatids suggests that altered splicing of RBM5 target pre-mRNAs affected expression of genes in several pathways, including those implicated in germ cell adhesion, spermatid head shaping, and acrosome and tail formation. In summary, our findings reveal a critical role for RBM5 as a pre-mRNA splicing regulator in round spermatids and male fertility. Our findings also suggest that the second RRM of RBM5 is pivotal for appropriate pre-mRNA splicing. PMID- 23935509 TI - Reassembly of nucleosomes at the MLH1 promoter initiates resilencing following decitabine exposure. AB - Hypomethylating agents reactivate tumor suppressor genes that are epigenetically silenced in cancer. Inevitably these genes are resilenced, leading to drug resistance. Using the MLH1 tumor suppressor gene as a model, we showed that decitabine-induced re-expression was dependent upon demethylation and eviction of promoter nucleosomes. Following decitabine withdrawal, MLH1 was rapidly resilenced despite persistent promoter demethylation. Single molecule analysis at multiple time points showed that gene resilencing was initiated by nucleosome reassembly on demethylated DNA and only then was followed by remethylation and stable silencing. Taken together, these data establish the importance of nucleosome positioning in mediating resilencing of drug-induced gene reactivation and suggest a role for therapeutic targeting of nucleosome assembly as a mechanism to overcome drug resistance. PMID- 23935510 TI - Oxidative stress and replication-independent DNA breakage induced by arsenic in Saccharomyces cerevisiae. AB - Arsenic is a well-established human carcinogen of poorly understood mechanism of genotoxicity. It is generally accepted that arsenic acts indirectly by generating oxidative DNA damage that can be converted to replication-dependent DNA double strand breaks (DSBs), as well as by interfering with DNA repair pathways and DNA methylation. Here we show that in budding yeast arsenic also causes replication and transcription-independent DSBs in all phases of the cell cycle, suggesting a direct genotoxic mode of arsenic action. This is accompanied by DNA damage checkpoint activation resulting in cell cycle delays in S and G2/M phases in wild type cells. In G1 phase, arsenic activates DNA damage response only in the absence of the Yku70-Yku80 complex which normally binds to DNA ends and inhibits resection of DSBs. This strongly indicates that DSBs are produced by arsenic in G1 but DNA ends are protected by Yku70-Yku80 and thus invisible for the checkpoint response. Arsenic-induced DSBs are processed by homologous recombination (HR), as shown by Rfa1 and Rad52 nuclear foci formation and requirement of HR proteins for cell survival during arsenic exposure. We show further that arsenic greatly sensitizes yeast to phleomycin as simultaneous treatment results in profound accumulation of DSBs. Importantly, we observed a similar response in fission yeast Schizosaccharomyces pombe, suggesting that the mechanisms of As(III) genotoxicity may be conserved in other organisms. PMID- 23935511 TI - A network of HMG-box transcription factors regulates sexual cycle in the fungus Podospora anserina. AB - High-mobility group (HMG) B proteins are eukaryotic DNA-binding proteins characterized by the HMG-box functional motif. These transcription factors play a pivotal role in global genomic functions and in the control of genes involved in specific developmental or metabolic pathways. The filamentous ascomycete Podospora anserina contains 12 HMG-box genes. Of these, four have been previously characterized; three are mating-type genes that control fertilization and development of the fruit-body, whereas the last one encodes a factor involved in mitochondrial DNA stability. Systematic deletion analysis of the eight remaining uncharacterized HMG-box genes indicated that none were essential for viability, but that seven were involved in the sexual cycle. Two HMG-box genes display striking features. PaHMG5, an ortholog of SpSte11 from Schizosaccharomyces pombe, is a pivotal activator of mating-type genes in P. anserina, whereas PaHMG9 is a repressor of several phenomena specific to the stationary phase, most notably hyphal anastomoses. Transcriptional analyses of HMG-box genes in HMG-box deletion strains indicated that PaHMG5 is at the hub of a network of several HMG-box factors that regulate mating-type genes and mating-type target genes. Genetic analyses revealed that this network also controls fertility genes that are not regulated by mating-type transcription factors. This study points to the critical role of HMG-box members in sexual reproduction in fungi, as 11 out of 12 members were involved in the sexual cycle in P. anserina. PaHMG5 and SpSte11 are conserved transcriptional regulators of mating-type genes, although P. anserina and S. pombe diverged 550 million years ago. Two HMG-box genes, SOX9 and its upstream regulator SRY, also play an important role in sex determination in mammals. The P. anserina and S. pombe mating-type genes and their upstream regulatory factor form a module of HMG-box genes analogous to the SRY/SOX9 module, revealing a commonality of sex regulation in animals and fungi. PMID- 23935512 TI - A dual role for SOX10 in the maintenance of the postnatal melanocyte lineage and the differentiation of melanocyte stem cell progenitors. AB - During embryogenesis, the transcription factor, Sox10, drives the survival and differentiation of the melanocyte lineage. However, the role that Sox10 plays in postnatal melanocytes is not established. We show in vivo that melanocyte stem cells (McSCs) and more differentiated melanocytes express SOX10 but that McSCs remain undifferentiated. Sox10 knockout (Sox10(fl); Tg(Tyr::CreER)) results in loss of both McSCs and differentiated melanocytes, while overexpression of Sox10 (Tg(DctSox10)) causes premature differentiation and loss of McSCs, leading to hair graying. This suggests that levels of SOX10 are key to normal McSC function and Sox10 must be downregulated for McSC establishment and maintenance. We examined whether the mechanism of Tg(DctSox10) hair graying is through increased expression of Mitf, a target of SOX10, by asking if haploinsufficiency for Mitf (Mitf(vga9) ) can rescue hair graying in Tg(DctSox10) animals. Surprisingly, Mitf(vga9) does not mitigate but exacerbates Tg(DctSox10) hair graying suggesting that MITF participates in the negative regulation of Sox10 in McSCs. These observations demonstrate that while SOX10 is necessary to maintain the postnatal melanocyte lineage it is simultaneously prevented from driving differentiation in the McSCs. This data illustrates how tissue-specific stem cells can arise from lineage-specified precursors through the regulation of the very transcription factors important in defining that lineage. PMID- 23935513 TI - The role of interruptions in polyQ in the pathology of SCA1. AB - At least nine dominant neurodegenerative diseases are caused by expansion of CAG repeats in coding regions of specific genes that result in abnormal elongation of polyglutamine (polyQ) tracts in the corresponding gene products. When above a threshold that is specific for each disease the expanded polyQ repeats promote protein aggregation, misfolding and neuronal cell death. The length of the polyQ tract inversely correlates with the age at disease onset. It has been observed that interruption of the CAG tract by silent (CAA) or missense (CAT) mutations may strongly modulate the effect of the expansion and delay the onset age. We have carried out an extensive study in which we have complemented DNA sequence determination with cellular and biophysical models. By sequencing cloned normal and expanded SCA1 alleles taken from our cohort of ataxia patients we have determined sequence variations not detected by allele sizing and observed for the first time that repeat instability can occur even in the presence of CAG interruptions. We show that histidine interrupted pathogenic alleles occur with relatively high frequency (11%) and that the age at onset inversely correlates linearly with the longer uninterrupted CAG stretch. This could be reproduced in a cellular model to support the hypothesis of a linear behaviour of polyQ. We clarified by in vitro studies the mechanism by which polyQ interruption slows down aggregation. Our study contributes to the understanding of the role of polyQ interruption in the SCA1 phenotype with regards to age at disease onset, prognosis and transmission. PMID- 23935514 TI - Hepatocyte growth factor signaling in intrapancreatic ductal cells drives pancreatic morphogenesis. AB - In a forward genetic screen for regulators of pancreas development in zebrafish, we identified donut(s908) , a mutant which exhibits failed outgrowth of the exocrine pancreas. The s908 mutation leads to a leucine to arginine substitution in the ectodomain of the hepatocyte growth factor (HGF) tyrosine kinase receptor, Met. This missense mutation impedes the proteolytic maturation of the receptor, its trafficking to the plasma membrane, and diminishes the phospho-activation of its kinase domain. Interestingly, during pancreatogenesis, met and its hgf ligands are expressed in pancreatic epithelia and mesenchyme, respectively. Although Met signaling elicits mitogenic and migratory responses in varied contexts, normal proliferation rates in donut mutant pancreata together with dysmorphic, mislocalized ductal cells suggest that met primarily functions motogenically in pancreatic tail formation. Treatment with PI3K and STAT3 inhibitors, but not with MAPK inhibitors, phenocopies the donut pancreatic defect, further indicating that Met signals through migratory pathways during pancreas development. Chimera analyses showed that Met-deficient cells were excluded from the duct, but not acinar, compartment in the pancreatic tail. Conversely, wild-type intrapancreatic duct and "tip cells" at the leading edge of the growing pancreas rescued the donut phenotype. Altogether, these results reveal a novel and essential role for HGF signaling in the intrapancreatic ducts during exocrine morphogenesis. PMID- 23935515 TI - Dietary restriction induced longevity is mediated by nuclear receptor NHR-62 in Caenorhabditis elegans. AB - Dietary restriction (DR) extends lifespan in a wide variety of species, yet the underlying mechanisms are not well understood. Here we show that the Caenorhabditis elegans HNF4alpha-related nuclear hormone receptor NHR-62 is required for metabolic and physiologic responses associated with DR-induced longevity. nhr-62 mediates the longevity of eat-2 mutants, a genetic mimetic of dietary restriction, and blunts the longevity response of DR induced by bacterial food dilution at low nutrient levels. Metabolic changes associated with DR, including decreased Oil Red O staining, decreased triglyceride levels, and increased autophagy are partly reversed by mutation of nhr-62. Additionally, the DR fatty acid profile is altered in nhr-62 mutants. Expression profiles reveal that several hundred genes induced by DR depend on the activity of NHR-62, including a putative lipase required for the DR response. This study provides critical evidence of nuclear hormone receptor regulation of the DR longevity response, suggesting hormonal and metabolic control of life span. PMID- 23935516 TI - The bHLH subgroup IIId factors negatively regulate jasmonate-mediated plant defense and development. AB - Plants have evolved sophisticated systems for adaptation to their natural habitat. In response to developmental and environmental cues, plants produce and perceive jasmonate (JA) signals, which induce degradation of JASMONATE-ZIM-Domain (JAZ) proteins and derepress the JAZ-repressed transcription factors to regulate diverse aspects of defense responses and developmental processes. Here, we identified the bHLH subgroup IIId transcription factors (bHLH3, bHLH13, bHLH14 and bHLH17) as novel targets of JAZs. These bHLH subgroup IIId transcription factors act as transcription repressors and function redundantly to negatively regulate JA responses. The quadruple mutant bhlh3 bhlh13 bhlh14 bhlh17 showed severe sensitivity to JA-inhibited root growth and JA-induced anthocyanin accumulation, and exhibited obvious increase in JA-regulated plant defense against pathogen infection and insect attack. Transgenic plants overexpressing bHLH13 or bHLH17 displayed reduced JA responses. Furthermore, these bHLH factors functioned as transcription repressors to antagonize the transcription activators, such as MYC2 and the WD-repeat/bHLH/MYB complex, through binding to their target sequences. Coordinated regulation of JA responses by transcription activators and repressors would benefit plants by allowing fine regulation of defense and development, and survival in their frequently changing environment. PMID- 23935517 TI - Pattern dynamics in adaxial-abaxial specific gene expression are modulated by a plastid retrograde signal during Arabidopsis thaliana leaf development. AB - The maintenance and reformation of gene expression domains are the basis for the morphogenic processes of multicellular systems. In a leaf primordium of Arabidopsis thaliana, the expression of FILAMENTOUS FLOWER (FIL) and the activity of the microRNA miR165/166 are specific to the abaxial side. This miR165/166 activity restricts the target gene expression to the adaxial side. The adaxial and abaxial specific gene expressions are crucial for the wide expansion of leaf lamina. The FIL-expression and the miR165/166-free domains are almost mutually exclusive, and they have been considered to be maintained during leaf development. However, we found here that the position of the boundary between the two domains gradually shifts from the adaxial side to the abaxial side. The cell lineage analysis revealed that this boundary shifting was associated with a sequential gene expression switch from the FIL-expressing (miR165/166 active) to the miR165/166-free (non-FIL-expressing) states. Our genetic analyses using the enlarged fil expression domain2 (enf2) mutant and chemical treatment experiments revealed that impairment in the plastid (chloroplast) gene expression machinery retards this boundary shifting and inhibits the lamina expansion. Furthermore, these developmental effects caused by the abnormal plastids were not observed in the genomes uncoupled1 (gun1) mutant background. This study characterizes the dynamic nature of the adaxial-abaxial specification process in leaf primordia and reveals that the dynamic process is affected by the GUN1-dependent retrograde signal in response to the failure of plastid gene expression. These findings advance our understanding on the molecular mechanism linking the plastid function to the leaf morphogenic processes. PMID- 23935518 TI - A moonlighting enzyme links Escherichia coli cell size with central metabolism. AB - Growth rate and nutrient availability are the primary determinants of size in single-celled organisms: rapidly growing Escherichia coli cells are more than twice as large as their slow growing counterparts. Here we report the identification of the glucosyltransferase OpgH as a nutrient-dependent regulator of E. coli cell size. During growth under nutrient-rich conditions, OpgH localizes to the nascent septal site, where it antagonizes assembly of the tubulin-like cell division protein FtsZ, delaying division and increasing cell size. Biochemical analysis is consistent with OpgH sequestering FtsZ from growing polymers. OpgH is functionally analogous to UgtP, a Bacillus subtilis glucosyltransferase that inhibits cell division in a growth rate-dependent fashion. In a striking example of convergent evolution, OpgH and UgtP share no homology, have distinct enzymatic activities, and appear to inhibit FtsZ assembly through different mechanisms. Comparative analysis of E. coli and B. subtilis reveals conserved aspects of growth rate regulation and cell size control that are likely to be broadly applicable. These include the conservation of uridine diphosphate glucose as a proxy for nutrient status and the use of moonlighting enzymes to couple growth rate-dependent phenomena to central metabolism. PMID- 23935519 TI - Mechanisms of protein sequence divergence and incompatibility. AB - Alignments of orthologous protein sequences convey a complex picture. Some positions are utterly conserved whilst others have diverged to variable degrees. Amongst the latter, many are non-exchangeable between extant sequences. How do functionally critical and highly conserved residues diverge? Why and how did these exchanges become incompatible within contemporary sequences? Our model is phosphoglycerate kinase (PGK), where lysine 219 is an essential active-site residue completely conserved throughout Eukaryota and Bacteria, and serine is found only in archaeal PGKs. Contemporary sequences tested exhibited complete loss of function upon exchanges at 219. However, a directed evolution experiment revealed that two mutations were sufficient for human PGK to become functional with serine at position 219. These two mutations made position 219 permissive not only for serine and lysine, but also to a range of other amino acids seen in archaeal PGKs. The identified trajectories that enabled exchanges at 219 show marked sign epistasis - a relatively small loss of function with respect to one amino acid (lysine) versus a large gain with another (serine, and other amino acids). Our findings support the view that, as theoretically described, the trajectories underlining the divergence of critical positions are dominated by sign epistatic interactions. Such trajectories are an outcome of rare mutational combinations. Nonetheless, as suggested by the laboratory enabled K219S exchange, given enough time and variability in selection levels, even utterly conserved and functionally essential residues may change. PMID- 23935520 TI - Recombination dynamics of a human Y-chromosomal palindrome: rapid GC-biased gene conversion, multi-kilobase conversion tracts, and rare inversions. AB - The male-specific region of the human Y chromosome (MSY) includes eight large inverted repeats (palindromes) in which arm-to-arm similarity exceeds 99.9%, due to gene conversion activity. Here, we studied one of these palindromes, P6, in order to illuminate the dynamics of the gene conversion process. We genotyped ten paralogous sequence variants (PSVs) within the arms of P6 in 378 Y chromosomes whose evolutionary relationships within the SNP-defined Y phylogeny are known. This allowed the identification of 146 historical gene conversion events involving individual PSVs, occurring at a rate of 2.9-8.4*10(-4) events per generation. A consideration of the nature of nucleotide change and the ancestral state of each PSV showed that the conversion process was significantly biased towards the fixation of G or C nucleotides (GC-biased), and also towards the ancestral state. Determination of haplotypes by long-PCR allowed likely co conversion of PSVs to be identified, and suggested that conversion tract lengths are large, with a mean of 2068 bp, and a maximum in excess of 9 kb. Despite the frequent formation of recombination intermediates implied by the rapid observed gene conversion activity, resolution via crossover is rare: only three inversions within P6 were detected in the sample. An analysis of chimpanzee and gorilla P6 orthologs showed that the ancestral state bias has existed in all three species, and comparison of human and chimpanzee sequences with the gorilla outgroup confirmed that GC bias of the conversion process has apparently been active in both the human and chimpanzee lineages. PMID- 23935521 TI - The mating competence of geographically diverse Leishmania major strains in their natural and unnatural sand fly vectors. AB - Invertebrate stages of Leishmania are capable of genetic exchange during their extracellular growth and development in the sand fly vector. Here we explore two variables: the ability of diverse L. major strains from across its natural range to undergo mating in pairwise tests; and the timing of the appearance of hybrids and their developmental stage associations within both natural (Phlebotomus duboscqi) and unnatural (Lutzomyia longipalpis) sand fly vectors. Following co infection of flies with parental lines bearing independent drug markers, doubly drug resistant hybrid progeny were selected, from which 96 clonal lines were analyzed for DNA content and genotyped for parent alleles at 4-6 unlinked nuclear loci as well as the maxicircle DNA. As seen previously, the majority of hybrids showed '2n' DNA contents, but with a significant number of '3n' and one '4n' offspring. In the natural vector, 97% of the nuclear loci showed both parental alleles; however, 3% (4/150) showed only one parental allele. In the unnatural vector, the frequency of uniparental inheritance rose to 10% (27/275). We attribute this to loss of heterozygosity after mating, most likely arising from aneuploidy which is both common and temporally variable in Leishmania. As seen previously, only uniparental inheritance of maxicircle kDNA was observed. Hybrids were recovered at similar efficiencies in all pairwise crosses tested, suggesting that L. major lacks detectable 'mating types' that limit free genetic exchange. In the natural vector, comparisons of the timing of hybrid formation with the presence of developmental stages suggest nectomonads as the most likely sexually competent stage, with hybrids emerging well before the first appearance of metacyclic promastigotes. These studies provide an important perspective on the prevalence of genetic exchange in natural populations of L. major and a guide for experimental studies to understand the biology of mating. PMID- 23935523 TI - Computational identification of diverse mechanisms underlying transcription factor-DNA occupancy. AB - ChIP-based genome-wide assays of transcription factor (TF) occupancy have emerged as a powerful, high-throughput method to understand transcriptional regulation, especially on a global scale. This has led to great interest in the underlying biochemical mechanisms that direct TF-DNA binding, with the ultimate goal of computationally predicting a TF's occupancy profile in any cellular condition. In this study, we examined the influence of various potential determinants of TF-DNA binding on a much larger scale than previously undertaken. We used a thermodynamics-based model of TF-DNA binding, called "STAP," to analyze 45 TF ChIP data sets from Drosophila embryonic development. We built a cross-validation framework that compares a baseline model, based on the ChIP'ed ("primary") TF's motif, to more complex models where binding by secondary TFs is hypothesized to influence the primary TF's occupancy. Candidates interacting TFs were chosen based on RNA-SEQ expression data from the time point of the ChIP experiment. We found widespread evidence of both cooperative and antagonistic effects by secondary TFs, and explicitly quantified these effects. We were able to identify multiple classes of interactions, including (1) long-range interactions between primary and secondary motifs (separated by <=150 bp), suggestive of indirect effects such as chromatin remodeling, (2) short-range interactions with specific inter-site spacing biases, suggestive of direct physical interactions, and (3) overlapping binding sites suggesting competitive binding. Furthermore, by factoring out the previously reported strong correlation between TF occupancy and DNA accessibility, we were able to categorize the effects into those that are likely to be mediated by the secondary TF's effect on local accessibility and those that utilize accessibility-independent mechanisms. Finally, we conducted in vitro pull-down assays to test model-based predictions of short-range cooperative interactions, and found that seven of the eight TF pairs tested physically interact and that some of these interactions mediate cooperative binding to DNA. PMID- 23935524 TI - Genetic mapping of specific interactions between Aedes aegypti mosquitoes and dengue viruses. AB - Specific interactions between host genotypes and pathogen genotypes (G*G interactions) are commonly observed in invertebrate systems. Such specificity challenges our current understanding of invertebrate defenses against pathogens because it contrasts the limited discriminatory power of known invertebrate immune responses. Lack of a mechanistic explanation, however, has questioned the nature of host factors underlying G*G interactions. In this study, we aimed to determine whether G*G interactions observed between dengue viruses and their Aedes aegypti vectors in nature can be mapped to discrete loci in the mosquito genome and to document their genetic architecture. We developed an innovative genetic mapping strategy to survey G*G interactions using outbred mosquito families that were experimentally exposed to genetically distinct isolates of two dengue virus serotypes derived from human patients. Genetic loci associated with vector competence indices were detected in multiple regions of the mosquito genome. Importantly, correlation between genotype and phenotype was virus isolate specific at several of these loci, indicating G*G interactions. The relatively high percentage of phenotypic variation explained by the markers associated with G*G interactions (ranging from 7.8% to 16.5%) is consistent with large-effect host genetic factors. Our data demonstrate that G*G interactions between dengue viruses and mosquito vectors can be assigned to physical regions of the mosquito genome, some of which have a large effect on the phenotype. This finding establishes the existence of tangible host genetic factors underlying specific interactions between invertebrates and their pathogens in a natural system. Fine mapping of the uncovered genetic loci will elucidate the molecular mechanisms of mosquito-virus specificity. PMID- 23935525 TI - Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in fabry disease. AB - Fabry disease (FD) is an X-linked hereditary defect of glycosphingolipid storage caused by mutations in the gene encoding the lysosomal hydrolase alpha galactosidase A (GLA, alpha-gal A). To date, over 400 mutations causing amino acid substitutions have been described. Most of these mutations are related to the classical Fabry phenotype. Generally in lysosomal storage disorders a reliable genotype/phenotype correlation is difficult to achieve, especially in FD with its X-linked mode of inheritance. In order to predict the metabolic consequence of a given mutation, we combined in vitro enzyme activity with in vivo biomarker data. Furthermore, we used the pharmacological chaperone (PC) 1 deoxygalactonojirimycin (DGJ) as a tool to analyse the influence of individual mutations on subcellular organelle-trafficking and stability. We analysed a significant number of mutations and correlated the obtained properties to the clinical manifestation related to the mutation in order to improve our knowledge of the identity of functional relevant amino acids. Additionally, we illustrate the consequences of different mutations on plasma lyso-globotriaosylsphingosine (lyso-Gb3) accumulation in the patients' plasma, a biomarker proven to reflect the impaired substrate clearance caused by specific mutations. The established system enables us to provide information for the clinical relevance of PC therapy for a given mutant. Finally, in order to generate reliable predictions of mutant GLA defects we compared the different data sets to reveal the most coherent system to reflect the clinical situation. PMID- 23935526 TI - Cited1 deficiency suppresses intestinal tumorigenesis. AB - Conditional deletion of Apc in the murine intestine alters crypt-villus architecture and function. This process is accompanied by multiple changes in gene expression, including upregulation of Cited1, whose role in colorectal carcinogenesis is unknown. Here we explore the relevance of Cited1 to intestinal tumorigenesis. We crossed Cited1 null mice with Apc(Min/+) and AhCre(+)Apc(fl/fl) mice and determined the impact of Cited1 deficiency on tumour growth/initiation including tumour multiplicity, cell proliferation, apoptosis and the transcriptome. We show that Cited1 is up-regulated in both human and murine tumours, and that constitutive deficiency of Cited1 increases survival in Apc(Min/+) mice from 230.5 to 515 days. However, paradoxically, Cited1 deficiency accentuated nearly all aspects of the immediate phenotype 4 days after conditional deletion of Apc, including an increase in cell death and enhanced perturbation of differentiation, including of the stem cell compartment. Transcriptome analysis revealed multiple pathway changes, including p53, PI3K and Wnt. The activation of Wnt through Cited1 deficiency correlated with increased transcription of beta-catenin and increased levels of dephosphorylated beta catenin. Hence, immediately following deletion of Apc, Cited1 normally restrains the Wnt pathway at the level of beta-catenin. Thus deficiency of Cited1 leads to hyper-activation of Wnt signaling and an exaggerated Wnt phenotype including elevated cell death. Cited1 deficiency decreases intestinal tumourigenesis in Apc(Min/+) mice and impacts upon a number of oncogenic signaling pathways, including Wnt. This restraint imposed by Cited1 is consistent with a requirement for Cited1 to constrain Wnt activity to a level commensurate with optimal adenoma formation and maintenance, and provides one mechanism for tumour repression in the absence of Cited1. PMID- 23935528 TI - Integrative modeling of eQTLs and cis-regulatory elements suggests mechanisms underlying cell type specificity of eQTLs. AB - Genetic variants in cis-regulatory elements or trans-acting regulators frequently influence the quantity and spatiotemporal distribution of gene transcription. Recent interest in expression quantitative trait locus (eQTL) mapping has paralleled the adoption of genome-wide association studies (GWAS) for the analysis of complex traits and disease in humans. Under the hypothesis that many GWAS associations tag non-coding SNPs with small effects, and that these SNPs exert phenotypic control by modifying gene expression, it has become common to interpret GWAS associations using eQTL data. To fully exploit the mechanistic interpretability of eQTL-GWAS comparisons, an improved understanding of the genetic architecture and causal mechanisms of cell type specificity of eQTLs is required. We address this need by performing an eQTL analysis in three parts: first we identified eQTLs from eleven studies on seven cell types; then we integrated eQTL data with cis-regulatory element (CRE) data from the ENCODE project; finally we built a set of classifiers to predict the cell type specificity of eQTLs. The cell type specificity of eQTLs is associated with eQTL SNP overlap with hundreds of cell type specific CRE classes, including enhancer, promoter, and repressive chromatin marks, regions of open chromatin, and many classes of DNA binding proteins. These associations provide insight into the molecular mechanisms generating the cell type specificity of eQTLs and the mode of regulation of corresponding eQTLs. Using a random forest classifier with cell specific CRE-SNP overlap as features, we demonstrate the feasibility of predicting the cell type specificity of eQTLs. We then demonstrate that CREs from a trait-associated cell type can be used to annotate GWAS associations in the absence of eQTL data for that cell type. We anticipate that such integrative, predictive modeling of cell specificity will improve our ability to understand the mechanistic basis of human complex phenotypic variation. PMID- 23935527 TI - The Wilms tumor gene, Wt1, is critical for mouse spermatogenesis via regulation of sertoli cell polarity and is associated with non-obstructive azoospermia in humans. AB - Azoospermia is one of the major reproductive disorders which cause male infertility in humans; however, the etiology of this disease is largely unknown. In the present study, six missense mutations of WT1 gene were detected in 529 human patients with non-obstructive azoospermia (NOA), indicating a strong association between WT1 mutation and NOA. The Wilms tumor gene, Wt1, is specifically expressed in Sertoli cells (SCs) which support spermatogenesis. To examine the functions of this gene in spermatogenesis, Wt1 was deleted in adult testis using Wt1(flox) and Cre-ER(TM) mice strains. We found that inactivation of Wt1 resulted in massive germ cell death and only SCs were present in most of the seminiferous tubules which was very similar to NOA in humans. In investigating the potential mechanism for this, histological studies revealed that the blood testis barrier (BTB) was disrupted in Wt1 deficient testes. In vitro studies demonstrated that Wt1 was essential for cell polarity maintenance in SCs. Further studies found that the expression of cell polarity associated genes (Par6b and E cadherin) and Wnt signaling genes (Wnt4, Wnt11) were downregulated in Wt1 deficient SCs, and that the expression of Par6b and E-cadherin was regulated by Wnt4. Our findings suggest that Wt1 is important in spermatogenesis by regulating the polarity of SCs via Wnt signaling pathway and that WT1 mutation is one of the genetic causes of NOA in humans. PMID- 23935529 TI - Transposon domestication versus mutualism in ciliate genome rearrangements. AB - Ciliated protists rearrange their genomes dramatically during nuclear development via chromosome fragmentation and DNA deletion to produce a trimmer and highly reorganized somatic genome. The deleted portion of the genome includes potentially active transposons or transposon-like sequences that reside in the germline. Three independent studies recently showed that transposase proteins of the DDE/DDD superfamily are indispensible for DNA processing in three distantly related ciliates. In the spirotrich Oxytricha trifallax, high copy-number germline-limited transposons mediate their own excision from the somatic genome but also contribute to programmed genome rearrangement through a remarkable transposon mutualism with the host. By contrast, the genomes of two oligohymenophorean ciliates, Tetrahymena thermophila and Paramecium tetraurelia, encode homologous PiggyBac-like transposases as single-copy genes in both their germline and somatic genomes. These domesticated transposases are essential for deletion of thousands of different internal sequences in these species. This review contrasts the events underlying somatic genome reduction in three different ciliates and considers their evolutionary origins and the relationships among their distinct mechanisms for genome remodeling. PMID- 23935530 TI - The conditional nature of genetic interactions: the consequences of wild-type backgrounds on mutational interactions in a genome-wide modifier screen. AB - The phenotypic outcome of a mutation cannot be simply mapped onto the underlying DNA variant. Instead, the phenotype is a function of the allele, the genetic background in which it occurs and the environment where the mutational effects are expressed. While the influence of genetic background on the expressivity of individual mutations is recognized, its consequences on the interactions between genes, or the genetic network they form, is largely unknown. The description of genetic networks is essential for much of biology; yet if, and how, the topologies of such networks are influenced by background is unknown. Furthermore, a comprehensive examination of the background dependent nature of genetic interactions may lead to identification of novel modifiers of biological processes. Previous work in Drosophila melanogaster demonstrated that wild-type genetic background influences the effects of an allele of scalloped (sd), with respect to both its principal consequence on wing development and its interactions with a mutation in optomotor blind. In this study we address whether the background dependence of mutational interactions is a general property of genetic systems by performing a genome wide dominant modifier screen of the sd(E3) allele in two wild-type genetic backgrounds using molecularly defined deletions. We demonstrate that ~74% of all modifiers of the sd(E3) phenotype are background-dependent due in part to differential sensitivity to genetic perturbation. These background dependent interactions include some with qualitative differences in the phenotypic outcome, as well as instances of sign epistasis. This suggests that genetic interactions are often contingent on genetic background, with flexibility in genetic networks due to segregating variation in populations. Such background dependent effects can substantially alter conclusions about how genes influence biological processes, the potential for genetic screens in alternative wild-type backgrounds identifying new loci that contribute to trait expression, and the inferences of the topology of genetic networks. PMID- 23935531 TI - Origin and functional diversification of an amphibian defense peptide arsenal. AB - The skin secretion of many amphibians contains an arsenal of bioactive molecules, including hormone-like peptides (HLPs) acting as defense toxins against predators, and antimicrobial peptides (AMPs) providing protection against infectious microorganisms. Several amphibian taxa seem to have independently acquired the genes to produce skin-secreted peptide arsenals, but it remains unknown how these originated from a non-defensive ancestral gene and evolved diverse defense functions against predators and pathogens. We conducted transcriptome, genome, peptidome and phylogenetic analyses to chart the full gene repertoire underlying the defense peptide arsenal of the frog Silurana tropicalis and reconstruct its evolutionary history. Our study uncovers a cluster of 13 transcriptionally active genes, together encoding up to 19 peptides, including diverse HLP homologues and AMPs. This gene cluster arose from a duplicated gastrointestinal hormone gene that attained a HLP-like defense function after major remodeling of its promoter region. Instead, new defense functions, including antimicrobial activity, arose by mutation of the precursor proteins, resulting in the proteolytic processing of secondary peptides alongside the original ones. Although gene duplication did not trigger functional innovation, it may have subsequently facilitated the convergent loss of the original function in multiple gene lineages (subfunctionalization), completing their transformation from HLP gene to AMP gene. The processing of multiple peptides from a single precursor entails a mechanism through which peptide-encoding genes may establish new functions without the need for gene duplication to avoid adaptive conflicts with older ones. PMID- 23935532 TI - ATM release at resected double-strand breaks provides heterochromatin reconstitution to facilitate homologous recombination. AB - Non-homologous end-joining (NHEJ) and homologous recombination (HR) represent the two main pathways for repairing DNA double-strand breaks (DSBs). During the G2 phase of the mammalian cell cycle, both processes can operate and chromatin structure is one important factor which determines DSB repair pathway choice. ATM facilitates the repair of heterochromatic DSBs by phosphorylating and inactivating the heterochromatin building factor KAP-1, leading to local chromatin relaxation. Here, we show that ATM accumulation and activity is strongly diminished at DSBs undergoing end-resection during HR. Such DSBs remain unrepaired in cells devoid of the HR factors BRCA2, XRCC3 or RAD51. Strikingly, depletion of KAP-1 or expression of phospho-mimic KAP-1 allows repair of resected DSBs in the absence of BRCA2, XRCC3 or RAD51 by an erroneous PARP-dependent alt NHEJ process. We suggest that DSBs in heterochromatin elicit initial local heterochromatin relaxation which is reversed during HR due to the release of ATM from resection break ends. The restored heterochromatic structure facilitates HR and prevents usage of error-prone alternative processes. PMID- 23935533 TI - Calpain-6 deficiency promotes skeletal muscle development and regeneration. AB - Calpains are Ca(2+)-dependent modulator Cys proteases that have a variety of functions in almost all eukaryotes. There are more than 10 well-conserved mammalian calpains, among which eutherian calpain-6 (CAPN6) is unique in that it has amino acid substitutions at the active-site Cys residue (to Lys in humans), strongly suggesting a loss of proteolytic activity. CAPN6 is expressed predominantly in embryonic muscles, placenta, and several cultured cell lines. We previously reported that CAPN6 is involved in regulating microtubule dynamics and actin reorganization in cultured cells. The physiological functions of CAPN6, however, are still unclear. Here, to elucidate CAPN6's in vivo roles, we generated Capn6-deficient mice, in which a lacZ expression cassette was integrated into the Capn6 gene. These Capn6-deficient mouse embryos expressed lacZ predominantly in skeletal muscles, as well as in cartilage and the heart. Histological and biochemical analyses showed that the CAPN6 deficiency promoted the development of embryonic skeletal muscle. In primary cultured skeletal muscle cells that were induced to differentiate into myotubes, Capn6 expression was detected in skeletal myocytes, and Capn6-deficient cultures showed increased differentiation. Furthermore, we found that CAPN6 was expressed in the regenerating skeletal muscles of adult mice after cardiotoxin-induced degeneration. In this experimental system, Capn6-deficient mice exhibited more advanced skeletal-muscle regeneration than heterozygotes or wild-type mice at the same time point. These results collectively showed that a loss of CAPN6 promotes skeletal muscle differentiation during both development and regeneration, suggesting a novel physiological function of CAPN6 as a suppressor of skeletal muscle differentiation. PMID- 23935534 TI - Genome wide association identifies novel loci involved in fungal communication. AB - Understanding how genomes encode complex cellular and organismal behaviors has become the outstanding challenge of modern genetics. Unlike classical screening methods, analysis of genetic variation that occurs naturally in wild populations can enable rapid, genome-scale mapping of genotype to phenotype with a medium throughput experimental design. Here we describe the results of the first genome wide association study (GWAS) used to identify novel loci underlying trait variation in a microbial eukaryote, harnessing wild isolates of the filamentous fungus Neurospora crassa. We genotyped each of a population of wild Louisiana strains at 1 million genetic loci genome-wide, and we used these genotypes to map genetic determinants of microbial communication. In N. crassa, germinated asexual spores (germlings) sense the presence of other germlings, grow toward them in a coordinated fashion, and fuse. We evaluated germlings of each strain for their ability to chemically sense, chemotropically seek, and undergo cell fusion, and we subjected these trait measurements to GWAS. This analysis identified one gene, NCU04379 (cse-1, encoding a homolog of a neuronal calcium sensor), at which inheritance was strongly associated with the efficiency of germling communication. Deletion of cse-1 significantly impaired germling communication and fusion, and two genes encoding predicted interaction partners of CSE1 were also required for the communication trait. Additionally, mining our association results for signaling and secretion genes with a potential role in germling communication, we validated six more previously unknown molecular players, including a secreted protease and two other genes whose deletion conferred a novel phenotype of increased communication and multi-germling fusion. Our results establish protein secretion as a linchpin of germling communication in N. crassa and shed light on the regulation of communication molecules in this fungus. Our study demonstrates the power of population-genetic analyses for the rapid identification of genes contributing to complex traits in microbial species. PMID- 23935535 TI - Distinct SUMO ligases cooperate with Esc2 and Slx5 to suppress duplication mediated genome rearrangements. AB - Suppression of duplication-mediated gross chromosomal rearrangements (GCRs) is essential to maintain genome integrity in eukaryotes. Here we report that SUMO ligase Mms21 has a strong role in suppressing GCRs in Saccharomyces cerevisiae, while Siz1 and Siz2 have weaker and partially redundant roles. Understanding the functions of these enzymes has been hampered by a paucity of knowledge of their substrate specificity in vivo. Using a new quantitative SUMO-proteomics technology, we found that Siz1 and Siz2 redundantly control the abundances of most sumoylated substrates, while Mms21 more specifically regulates sumoylation of RNA polymerase-I and the SMC-family proteins. Interestingly, Esc2, a SUMO-like domain-containing protein, specifically promotes the accumulation of sumoylated Mms21-specific substrates and functions with Mms21 to suppress GCRs. On the other hand, the Slx5-Slx8 complex, a SUMO-targeted ubiquitin ligase, suppresses the accumulation of sumoylated Mms21-specific substrates. Thus, distinct SUMO ligases work in concert with Esc2 and Slx5-Slx8 to control substrate specificity and sumoylation homeostasis to prevent GCRs. PMID- 23935536 TI - Loss of a conserved tRNA anticodon modification perturbs cellular signaling. AB - Transfer RNA (tRNA) modifications enhance the efficiency, specificity and fidelity of translation in all organisms. The anticodon modification mcm(5)s(2)U(34) is required for normal growth and stress resistance in yeast; mutants lacking this modification have numerous phenotypes. Mutations in the homologous human genes are linked to neurological disease. The yeast phenotypes can be ameliorated by overexpression of specific tRNAs, suggesting that the modifications are necessary for efficient translation of specific codons. We determined the in vivo ribosome distributions at single codon resolution in yeast strains lacking mcm(5)s(2)U. We found accumulations at AAA, CAA, and GAA codons, suggesting that translation is slow when these codons are in the ribosomal A site, but these changes appeared too small to affect protein output. Instead, we observed activation of the GCN4-mediated stress response by a non-canonical pathway. Thus, loss of mcm(5)s(2)U causes global effects on gene expression due to perturbation of cellular signaling. PMID- 23935537 TI - The yeast environmental stress response regulates mutagenesis induced by proteotoxic stress. AB - Conditions of chronic stress are associated with genetic instability in many organisms, but the roles of stress responses in mutagenesis have so far been elucidated only in bacteria. Here, we present data demonstrating that the environmental stress response (ESR) in yeast functions in mutagenesis induced by proteotoxic stress. We show that the drug canavanine causes proteotoxic stress, activates the ESR, and induces mutagenesis at several loci in an ESR-dependent manner. Canavanine-induced mutagenesis also involves translesion DNA polymerases Rev1 and Polzeta and non-homologous end joining factor Ku. Furthermore, under conditions of chronic sub-lethal canavanine stress, deletions of Rev1, Polzeta, and Ku-encoding genes exhibit genetic interactions with ESR mutants indicative of ESR regulating these mutagenic DNA repair processes. Analyses of mutagenesis induced by several different stresses showed that the ESR specifically modulates mutagenesis induced by proteotoxic stress. Together, these results document the first known example of an involvement of a eukaryotic stress response pathway in mutagenesis and have important implications for mechanisms of evolution, carcinogenesis, and emergence of drug-resistant pathogens and chemotherapy resistant tumors. PMID- 23935539 TI - Letter from the editor. PMID- 23935538 TI - In vivo bypass of 8-oxodG. AB - 8-oxoG is one of the most common and mutagenic DNA base lesions caused by oxidative damage. However, it has not been possible to study the replication of a known 8-oxoG base in vivo in order to determine the accuracy of its replication, the influence of various components on that accuracy, and the extent to which an 8-oxoG might present a barrier to replication. We have been able to place a single 8-oxoG into the Saccharomyces cerevisiae chromosome in a defined location using single-strand oligonucleotide transformation and to study its replication in a fully normal chromosome context. During replication, 8-oxoG is recognized as a lesion and triggers a switch to translesion synthesis by Pol eta, which replicates 8-oxoG with an accuracy (insertion of a C opposite the 8-oxoG) of approximately 94%. In the absence of Pol eta, template switching to the newly synthesized sister chromatid is observed at least one third of the time; replication of the 8-oxoG in the absence of Pol eta is less than 40% accurate. The mismatch repair (MMR) system plays an important role in 8-oxoG replication. Template switching is blocked by MMR and replication accuracy even in the absence of Pol eta is approximately 95% when MMR is active. These findings indicate that in light of the overlapping mechanisms by which errors in 8-oxoG replication can be avoided in the cell, the mutagenic threat of 8-oxoG is due more to its abundance than the effect of a single lesion. In addition, the methods used here should be applicable to the study of any lesion that can be stably incorporated into synthetic oligonucleotides. PMID- 23935540 TI - Correspondence: cefdinir and red stool. PMID- 23935541 TI - GASTRO-HEP News. PMID- 23935544 TI - Highlights From the New ACG Guidelines for the Diagnosis and Management of GERD. PMID- 23935542 TI - Optimizing Diagnostic Yield for EUS-Guided Sampling of Solid Pancreatic Lesions: A Technical Review. AB - Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has a higher diagnostic accuracy for pancreatic cancer than other techniques. This article will review the current advances and considerations for optimizing diagnostic yield for EUS-guided sampling of solid pancreatic lesions. Preprocedural considerations include patient history, confirmation of appropriate indication, review of imaging, method of sedation, experience required by the endoscopist, and access to rapid on-site cytologic evaluation. New EUS imaging techniques that may assist with differential diagnoses include contrast-enhanced harmonic EUS, EUS elastography, and EUS spectrum analysis. FNA techniques vary, and multiple FNA needles are now commercially available; however, neither techniques nor available FNA needles have been definitively compared. The need for suction depends on the lesion, and the need for a stylet is equivocal. No definitive endosonographic finding can predict the optimal number of passes for diagnostic yield. Preparation of good smears and communication with the cytopathologist are essential to optimize yield. PMID- 23935545 TI - Training model for endoscopic ultrasound-guided fine-needle aspiration of lymph nodes. PMID- 23935546 TI - Protease inhibitor therapy post-liver transplantation in the treatment of hepatitis C virus infection. PMID- 23935543 TI - Environmental risk factors for inflammatory bowel disease. AB - Crohn's disease (CD) and ulcerative colitis (UC) are chronic immunologically mediated diseases that often have a relapsing-remitting course in young persons. Genetic-risk polymorphisms explain less than one third of the heritability of disease. Epidemiologic and laboratory data suggest that environmental factors play a significant role in influencing the risk and natural history of disease. Smoking is the most widely and consistently described risk factor. It, however, increases the risk of CD while conferring protection against UC. The gut microbiome is a key component in the development of inflammatory bowel disease (IBD). Several external factors potentially exert an effect by influencing the composition of the gut microbiome or disrupting the intestinal barrier. These external influences include the use of antibiotics or nonsteroidal anti inflammatory drugs and the presence of enteric infections. Data on diet have been inconsistent, but high fiber intake, particularly of soluble fiber, appears to protect against CD, whereas protein intake may increase disease risk. Vitamin D may also play an important protective role, particularly in patients with CD. Neurobehavioral factors, such as stress and depression, also influence the risk of IBD. Systematic and rigorous studies of environmental exposures in the management of IBD are needed. In particular, studies of whether environmental factors can be modified to reduce the likelihood of relapse or improve patient outcomes would be valuable. PMID- 23935547 TI - Antibiotic use and the risk of Crohn's disease. PMID- 23935548 TI - Giant hepatic hemangioma masquerading as a gastric subepithelial tumor. PMID- 23935549 TI - Differential diagnoses and diagnostic troubleshooting of upper abdominal masses. PMID- 23935550 TI - Letter from the editor. PMID- 23935551 TI - Office-based management of fecal incontinence. AB - Fecal incontinence (FI) is a devastating disorder that is more prevalent than previously realized. FI is the involuntary loss of stool. Many factors contribute to the pathophysiology of FI, including advanced age, bowel irregularity, parity, and obesity. A detailed history and focused rectal examination are important to making the diagnosis and determining contributing causes. Although multiple diagnostic studies are available to assess the cause of FI, specific guidelines that delineate when testing should be done do not exist. Clinicians must weigh the risk, benefit, and burden of testing against the need for empiric treatment. All types of FI are initially managed in the same way, which includes lifestyle modification to reduce bowel derangements, improved access to toileting, and initiation of a bulking regimen to improve stool consistency. If initial conservative management fails, pharmaco-logic agents, biofeedback, or surgery may be indicated. PMID- 23935553 TI - EUS-Guided Drainage of Pancreatic Fluid Collections Using Fully Covered Self Expandable Metal Stents. PMID- 23935552 TI - The effect of liver transplantation for primary sclerosing cholangitis on disease activity in patients with inflammatory bowel disease. AB - Immunosuppressive therapies are indicated following liver transplantation (LT) to prevent graft loss through rejection, and these same agents also may have a role in the management of inflammatory bowel disease (IBD). The aims of this study were to examine the effects of immunosuppression following LT on IBD activity and to identify markers of IBD control post-LT in patients with IBD who underwent LT for primary sclerosing cholangitis (PSC). A retrospective analysis of all adult patients with a pre-LT diagnosis of IBD who underwent LT for PSC over a 15-year period was performed. The primary outcome was IBD activity based on symptomatology and endoscopic assessment. Secondary outcomes included recipient mortality and post-LT development of colorectal cancer or small bowel lymphoma. A total of 105 patients underwent LT for PSC, and IBD was diagnosed in 27 (26%) pre LT. Patients were followed for a mean of 88.5 months. Fourteen (52%) patients had stable IBD, 6 (22%) had worsening disease, and 7 (26%) had clinical improvement after LT. Colorectal cancer developed in 2 (7%) patients, and small bowel lymphoma developed in 1 (4%) patient. The absence of additional maintenance therapy for IBD was found to be associated with good outcome for IBD control. The use of either infliximab (Remicade, Janssen Biotech) or corticosteroids to control IBD post-LT was associated with poor outcome. Most patients with PSC and IBD had a stable course of IBD post-LT. The need for infliximab or additional or prolonged corticosteroids after LT appears to be a surrogate marker of aggressive disease. PMID- 23935554 TI - Update on the use of radiofrequency ablation for treatment of barrett esophagus. PMID- 23935555 TI - The Low FODMAP Diet for Treatment of Irritable Bowel Syndrome and Other Gastrointestinal Disorders. PMID- 23935556 TI - Diagnosis, prognosis, and management of primary sclerosing cholangitis. PMID- 23935557 TI - Optimizing biologic therapy for treatment of inflammatory bowel disease. PMID- 23935558 TI - Reversible pseudoachalasia in a patient with laparoscopic adjustable gastric banding. PMID- 23935560 TI - Gastro-hep news: highlights from digestive disease week. PMID- 23935559 TI - Should the lap band be removed to treat pseudoachalasia? PMID- 23935561 TI - High gene flow in epiphytic ferns despite habitat loss and fragmentation. AB - Tropical montane forests suffer from increasing fragmentation and replacement by other types of land-use such as coffee plantations. These processes are known to affect gene flow and genetic structure of plant populations. Epiphytes are particularly vulnerable because they depend on their supporting trees for their entire life-cycle. We compared population genetic structure and genetic diversity derived from AFLP markers of two epiphytic fern species differing in their ability to colonize secondary habitats. One species, Pleopeltis crassinervata, is a successful colonizer of shade trees and isolated trees whereas the other species, Polypodium rhodopleuron, is restricted to forests with anthropogenic separation leading to significant isolation between populations. By far most genetic variation was distributed within rather than among populations in both species, and a genetic admixture analysis did not reveal any clustering. Gene flow exceeded by far the benchmark of one migrant per generation to prevent genetic divergence between populations in both species. Though populations are threatened by habitat loss, long-distance dispersal is likely to support gene flow even between distant populations, which efficiently delays genetic isolation. Consequently, populations may rather be threatened by ecological consequences of habitat loss and fragmentation. PMID- 23935562 TI - Controlled dispensing and mixing of pico- to nanoliter volumes using on-demand droplet-based microfluidics. AB - We present an integrated droplet-on-demand microfluidic platform for dispensing, mixing, incubating, extracting and analyzing by mass spectrometry pico- to nanoliter-sized droplets. All of the functional components are successfully integrated for the first time into a monolithic microdevice. Droplet generation is accomplished using computer-controlled pneumatic valves. Controlled actuation of valves for different aqueous streams enables accurate dosing and rapid mixing of reagents within droplets in either the droplet generation area or in a region of widening channel cross-section. Following incubation, which takes place as droplets travel in the oil stream, the droplet contents are extracted to an aqueous channel for subsequent ionization at an integrated nanoelectrospray emitter. Using the integrated platform, rapid enzymatic digestions of a model protein were carried out in droplets and detected on-line by nanoelectrospray ionization mass spectrometry. PMID- 23935563 TI - Temporal features of adult neurogenesis: differences and similarities across mammalian species. AB - Production of new neurons continues throughout life in most invertebrates and vertebrates like crustaceans, fishes, reptiles, birds, and mammals including humans. Most studies have been carried out on rodent models and demonstrated that adult neurogenesis is located mainly in two structures, the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ). If adult neurogenesis is well preserved throughout evolution, yet there are however some features which differ between species. The present review proposes to target similarities and differences in the mechanism of mammalian adult neurogenesis by comparing selected species including humans. We will highlight the cellular composition and morphological organization of the SVZ in primates which differs from that of rodents and may be of functional relevance. We will particularly focus on the dynamic of neuronal maturation in rodents, primates, and humans but also in sheep which appears to be an interesting model due to its similarities with the primate brain. PMID- 23935564 TI - 5-HT3 and 5-HT4 antagonists inhibit peristaltic contractions in guinea-pig distal colon by mechanisms independent of endogenous 5-HT. AB - Recent studies have shown that endogenous serotonin is not required for colonic peristalsis in vitro, nor gastrointestinal (GI) transit in vivo. However, antagonists of 5-Hydroxytryptamine (5-HT) receptors can inhibit peristalsis and GI-transit in mammals, including humans. This raises the question of how these antagonists inhibit GI-motility and transit, if depletion of endogenous 5-HT does not cause any significant inhibitory changes to either GI-motility or transit? We investigated the mechanism by which 5-HT3 and 5-HT4 antagonists inhibit distension-evoked peristaltic contractions in guinea-pig distal colon. In control animals, repetitive peristaltic contractions of the circular muscle were evoked in response to fixed fecal pellet distension. Distension-evoked peristaltic contractions were unaffected in animals with mucosa and submucosal plexus removed, that were also treated with reserpine (to deplete neuronal 5-HT). In control animals, peristaltic contractions were blocked temporarily by ondansetron (1-10 MUM) and SDZ-205-557 (1-10 MUM) in many animals. Interestingly, after this temporary blockade, and whilst in the continued presence of these antagonists, peristaltic contractions recovered, with characteristics no different from controls. Surprisingly, similar effects were seen in mucosa-free preparations, which had no detectable 5-HT, as detected by mass spectrometry. In summary, distension-evoked peristaltic reflex contractions of the circular muscle layer of the guinea-pig colon can be inhibited temporarily, or permanently, in the same preparation by selective 5-HT3 and 5-HT4 antagonists, depending on the concentration of the antagonists applied. These effects also occur in preparations that lack any detectable 5-HT. We suggest caution should be exercised when interpreting the effects of 5-HT3 and 5-HT4 antagonists; and the role of endogenous 5-HT, in the generation of distension-evoked colonic peristalsis. PMID- 23935566 TI - Learning and memory in zebrafish larvae. AB - Larval zebrafish possess several experimental advantages for investigating the molecular and neural bases of learning and memory. Despite this, neuroscientists have only recently begun to use these animals to study memory. However, in a relatively short period of time a number of forms of learning have been described in zebrafish larvae, and significant progress has been made toward their understanding. Here we provide a comprehensive review of this progress; we also describe several promising new experimental technologies currently being used in larval zebrafish that are likely to contribute major insights into the processes that underlie learning and memory. PMID- 23935567 TI - Neuroanatomical differences in visual, motor, and language cortices between congenitally deaf signers, hearing signers, and hearing non-signers. AB - WE INVESTIGATED EFFECTS OF SIGN LANGUAGE USE AND AUDITORY DEPRIVATION FROM BIRTH ON THE VOLUMES OF THREE CORTICAL REGIONS OF THE HUMAN BRAIN: the visual cortex surrounding the calcarine sulcus in the occipital lobe; the language-related cortex in the inferior frontal gyrus (pars triangularis and pars opercularis); and the motor hand region in the precentral gyrus. The study included 25 congenitally deaf participants and 41 hearing participants (of which 16 were native sign language users); all were right-handed. Deaf participants exhibited a larger calcarine volume than hearing participants, which we interpret as the likely result of cross-modal compensation and/or dynamic interactions within sensory neural networks. Deaf participants also had increased volumes of the pars triangularis bilaterally compared to hearing signers and non-signers, which we interpret is related to the increased linguistic demands of speech processing and/or text reading for deaf individuals. Finally, although no statistically significant differences were found in the motor hand region for any of the groups, the deaf group was leftward asymmetric, the hearing signers essentially symmetric and the hearing non-signers were rightward asymmetric - results we interpret as the possible result of activity-dependent change due to life-long signing. The brain differences we observed in visual, motor, and language-related areas in adult deaf native signers provide evidence for the plasticity available for cognitive adaptation to varied environments during development. PMID- 23935569 TI - The importance of Open Access publishing in the field of Linguistics for spreading scholarly knowledge and preserving languages diversity in the era of the economic financial crisis. PMID- 23935568 TI - Comodulation of dopamine and serotonin on prefrontal cortical rhythms: a theoretical study. AB - The prefrontal cortex (PFC) is implicated to play an important role in cognitive control. Abnormal PFC activities and rhythms have been observed in some neurological and neuropsychiatric disorders, and evidences suggest influences from the neuromodulators dopamine (DA) and serotonin (5-HT). Despite the high level of interest in these brain systems, the combined effects of DA and 5-HT modulation on PFC dynamics remain unknown. In this work, we build a mathematical model that incorporates available experimental findings to systematically study the comodulation of DA and 5-HT on the network behavior, focusing on beta and gamma band oscillations. Single neuronal model shows pyramidal cells with 5-HT1A and 2A receptors can be non-monotonically modulated by 5-HT. Two-population excitatory-inhibitory type network consisting of pyramidal cells with D1 receptors can provide rich repertoires of oscillatory behavior. In particular, 5 HT and DA can modulate the amplitude and frequency of the oscillations, which can emerge or cease, depending on receptor types. Certain receptor combinations are conducive for the robustness of the oscillatory regime, or the existence of multiple discrete oscillatory regimes. In a multi-population heterogeneous model that takes into account possible combination of receptors, we demonstrate that robust network oscillations require high DA concentration. We also show that selective D1 receptor antagonists (agonists) tend to suppress (enhance) network oscillations, increase the frequency from beta toward gamma band, while selective 5-HT1A antagonists (agonists) act in opposite ways. Selective D2 or 5-HT2A receptor antagonists (agonists) can lead to decrease (increase) in oscillation amplitude, but only 5-HT2A antagonists (agonists) can increase (decrease) the frequency. These results are comparable to some pharmacological effects. Our work illustrates the complex mechanisms of DA and 5-HT when operating simultaneously through multiple receptors. PMID- 23935565 TI - Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses. AB - Autism spectrum disorder (ASD) is a group of developmental disabilities characterized by impairments in social interaction and communication and restricted and repetitive interests/behaviors. Advances in human genomics have identified a large number of genetic variations associated with ASD. These associations are being rapidly verified by a growing number of studies using a variety of approaches, including mouse genetics. These studies have also identified key mechanisms underlying the pathogenesis of ASD, many of which involve synaptic dysfunctions, and have investigated novel, mechanism-based therapeutic strategies. This review will try to integrate these three key aspects of ASD research: human genetics, animal models, and potential treatments. Continued efforts in this direction should ultimately reveal core mechanisms that account for a larger fraction of ASD cases and identify neural mechanisms associated with specific ASD symptoms, providing important clues to efficient ASD treatment. PMID- 23935570 TI - FOXP2 gene and language development: the molecular substrate of the gestural origin theory of speech? PMID- 23935571 TI - Essentials of psychoanalytic process and change: how can we investigate the neural effects of psychodynamic psychotherapy in individualized neuro-imaging? AB - The paper focuses on the essentials of psychoanalytic process and change and the question of how the neural correlates and mechanisms of psychodynamic psychotherapy can be investigated. The psychoanalytic approach aims at enabling the patient to "remember, repeat, and work through" concerning explicit memory. Moreover, the relationship between analyst and patient establishes a new affective configuration which enables a reconstruction of the implicit memory. If psychic change can be achieved it corresponds to neuronal transformation. Individualized neuro-imaging requires controlling and measuring of variables that must be defined. Two main methodological problems can be distinguished: the design problem addresses the issue of how to account for functionally related variables in an experimentally independent way. The translation problem raises the question of how to bridge the gaps between different levels of the concepts presupposed in individualized neuro-imaging (e.g., the personal level of the therapist and the client, the neural level of the brain). An overview of individualized paradigms, which have been used until now is given, including Operationalized Psychodynamic Diagnosis (OPD-2) and the Maladaptive Interpersonal Patterns Q-Start (MIPQS). The development of a new paradigm that will be used in fMRI experiments, the "Interpersonal Relationship Picture Set" (IRPS), is described. Further perspectives and limitations of this new approach concerning the design and the translation problem are discussed. PMID- 23935572 TI - The effects of mental practice in neurological rehabilitation; a systematic review and meta-analysis. AB - OBJECTIVE: To investigate the beneficial and adverse effects of a mental practice intervention on activities, cognition, and emotion in patients after stroke, patients with Parkinson's disease or multiple sclerosis. METHODS: Electronic databases PubMed/Medline, PEDro, Science Direct, Cochrane Library, PsycINFO, Rehadat, Embase, and Picarta were searched until June 2012. Fourteen randomized controlled trials in stroke and two randomized controlled trials in Parkinson's disease were included, representing 491 patients (421 with stroke). No randomized controlled trials in multiple sclerosis were identified. The methodologic quality of the included trials was assessed with the Amsterdam-Maastricht-Consensus-List (AMCL). Information on study characteristics and outcomes was summarized and evidence for effects described. Data from individual studies in stroke with same outcome measures were pooled. RESULTS: The included 16 randomized controlled trials were heterogeneous and methodologic quality varied. Ten trials reported significant effects in favor of mental practice in patients with stroke (n = 9) and Parkinson's disease (n = 1). In six studies mental practice had similar effects as therapy as usual (n = 5 in stroke and n = 1 in Parkinson's disease). Of six performed meta-analyses with identical measures in stroke studies only two showed significant effects of mental practice: short-term improvement of arm-hand ability (ARAT: SMD 0.62; 95% CI: 0.05 to 1.19) and improvement of performance of activities (NRS: SMD 0.9; 95% CI: 0.04 to 1.77). Five studies found effects on cognition (e.g., effects on attention, plan actions in unfamiliar surroundings) and four reported observed side-effects, both positive (e.g., might increase motivation and arousal and reduce depression) and negative (e.g., diminished concentration, irritation). CONCLUSIONS: Mental practice might have positive effects on performance of activities in patients with neurological diseases, but this review reports less positive results than earlier published ones. Strengths and limitations of past studies are pointed out. Methodologic recommendations for future studies are given. PMID- 23935574 TI - Mutations at the SLC20A2 gene and brain resilience in families with idiopathic basal ganglia calcification ("Fahr's disease"). PMID- 23935573 TI - The dorsal attentional system in oculomotor learning of predictive information. AB - The dorsal attentional network is known for its role in directing top-down visual attention toward task-relevant stimuli. This goal-directed nature of the dorsal network makes it a suitable candidate for processing and extracting predictive information from the visual environment. In this review we briefly summarize some of the findings that delineate the neural substrates that contribute to predictive learning at both levels within the dorsal attentional system: including the frontal eye field (FEF) and posterior parietal cortex (PPC). We also discuss the similarities and differences between these two regions when it comes to learning predictive information. The current findings from the literature suggest that the FEFs may be more involved in top-down spatial attention, whereas the parietal cortex is involved in processing task-relevant attentional influences driven by stimulus salience, both contribute to the processing of predictive cues at different time points. PMID- 23935575 TI - The significance of the subplate for evolution and developmental plasticity of the human brain. AB - The human life-history is characterized by long development and introduction of new developmental stages, such as childhood and adolescence. The developing brain had important role in these life-history changes because it is expensive tissue which uses up to 80% of resting metabolic rate (RMR) in the newborn and continues to use almost 50% of it during the first 5 postnatal years. Our hominid ancestors managed to lift-up metabolic constraints to increase in brain size by several interrelated ecological, behavioral and social adaptations, such as dietary change, invention of cooking, creation of family-bonded reproductive units, and life-history changes. This opened new vistas for the developing brain, because it became possible to metabolically support transient patterns of brain organization as well as developmental brain plasticity for much longer period and with much greater number of neurons and connectivity combinations in comparison to apes. This included the shaping of cortical connections through the interaction with infant's social environment, which probably enhanced typically human evolution of language, cognition and self-awareness. In this review, we propose that the transient subplate zone and its postnatal remnant (interstitial neurons of the gyral white matter) probably served as the main playground for evolution of these developmental shifts, and describe various features that makes human subplate uniquely positioned to have such a role in comparison with other primates. PMID- 23935576 TI - MEG reveals a fast pathway from somatosensory cortex to occipital areas via posterior parietal cortex in a blind subject. AB - Cross-modal activity in visual cortex of blind subjects has been reported during performance of variety of non-visual tasks. A key unanswered question is through which pathways non-visual inputs are funneled to the visual cortex. Here we used tomographic analysis of single trial magnetoencephalography (MEG) data recorded from one congenitally blind and two sighted subjects after stimulation of the left and right median nerves at three intensities: below sensory threshold, above sensory threshold and above motor threshold; the last sufficient to produce thumb twitching. We identified reproducible brain responses in the primary somatosensory (S1) and motor (M1) cortices at around 20 ms post-stimulus, which were very similar in sighted and blind subjects. Time-frequency analysis revealed strong 45-70 Hz activity at latencies of 20-50 ms in S1 and M1, and posterior parietal cortex Brodmann areas (BA) 7 and 40, which compared to lower frequencies, were substantially more pronounced in the blind than the sighted subjects. Critically, at frequencies from alpha-band up to 100 Hz we found clear, strong, and widespread responses in the visual cortex of the blind subject, which increased with the intensity of the somatosensory stimuli. Time-delayed mutual information (MI) revealed that in blind subject the stimulus information is funneled from the early somatosensory to visual cortex through posterior parietal BA 7 and 40, projecting first to visual areas V5 and V3, and eventually V1. The flow of information through this pathway occurred in stages characterized by convergence of activations into specific cortical regions. In sighted subjects, no linked activity was found that led from the somatosensory to the visual cortex through any of the studied brain regions. These results provide the first evidence from MEG that in blind subjects, tactile information is routed from primary somatosensory to occipital cortex via the posterior parietal cortex. PMID- 23935577 TI - Dorsolateral prefrontal transcranial magnetic stimulation in patients with major depression locally affects alpha power of REM sleep. AB - Sleep alterations are among the most important disabling manifestation symptoms of Major Depression Disorder (MDD). A critical role of sleep importance is also underlined by the fact that its adjustment has been proposed as an objective marker of clinical remission in MDD. Repetitive transcranial magnetic stimulation (rTMS) represents a relatively novel therapeutic tool for the treatment of drug resistant depression. Nevertheless, besides clinical evaluation of the mood improvement after rTMS, we have no clear understanding of what are the neurophysiological correlates of such treatment. One possible marker underlying the clinical outcome of rTMS in MDD could be cortical changes on wakefulness and sleep activity. The aim of this open-label study was to evaluate the efficacy of a sequential bilateral rTMS treatment over the dorsolateral prefrontal cortex (DLPFC) to improve the mood in MDD patients, and to determine if rTMS can induce changes on the sleep structure, and if those changes can be used as a surrogate marker of the clinical state of the patient. Ten drug-resistant depressed patients participated to ten daily sessions of sequential bilateral rTMS with a low-frequency TMS (1 Hz) over right-DLPFC and a subsequent high-frequency (10 Hz) TMS over left-DLPFC. The clinical and neurophysiological effects induced by rTMS were evaluated, respectively by means of the Hamilton Depression Rating Scale (HDRS), and by comparing the sleep pattern modulations and the spatial changes of EEG frequency bands during both NREM and REM sleep, before and after the real rTMS treatment. The sequential bilateral rTMS treatment over the DLPFC induced topographical-specific decrease of the alpha activity during REM sleep over left DLPFC, which is significantly associated to the clinical outcome. In line with the notion of a left frontal hypoactivation in MDD patients, the observed local decrease of alpha activity after rTMS treatment during the REM sleep suggests that alpha frequency reduction could be considered as a marker of up-regulation of cortical activity induced by rTMS, as well as a surrogate neurophysiological correlate of the clinical outcome. PMID- 23935578 TI - Combining functional magnetic resonance imaging with transcranial electrical stimulation. AB - Transcranial electrical stimulation (tES) is a neuromodulatory method with promising potential for basic research and as a therapeutic tool. The most explored type of tES is transcranial direct current stimulation (tDCS), but also transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) have been shown to affect cortical excitability, behavioral performance and brain activity. Although providing indirect measure of brain activity, functional magnetic resonance imaging (fMRI) can tell us more about the global effects of stimulation in the whole brain and what is more, on how it modulates functional interactions between brain regions, complementing what is known from electrophysiological methods such as measurement of motor evoked potentials. With this review, we aim to present the studies that have combined these techniques, the current approaches and discuss the results obtained so far. PMID- 23935579 TI - On the application of quantitative EEG for characterizing autistic brain: a systematic review. AB - Autism-Spectrum Disorders (ASD) are thought to be associated with abnormalities in neural connectivity at both the global and local levels. Quantitative electroencephalography (QEEG) is a non-invasive technique that allows a highly precise measurement of brain function and connectivity. This review encompasses the key findings of QEEG application in subjects with ASD, in order to assess the relevance of this approach in characterizing brain function and clustering phenotypes. QEEG studies evaluating both the spontaneous brain activity and brain signals under controlled experimental stimuli were examined. Despite conflicting results, literature analysis suggests that QEEG features are sensitive to modification in neuronal regulation dysfunction which characterize autistic brain. QEEG may therefore help in detecting regions of altered brain function and connectivity abnormalities, in linking behavior with brain activity, and subgrouping affected individuals within the wide heterogeneity of ASD. The use of advanced techniques for the increase of the specificity and of spatial localization could allow finding distinctive patterns of QEEG abnormalities in ASD subjects, paving the way for the development of tailored intervention strategies. PMID- 23935580 TI - Three ways in which midline regions contribute to self-evaluation. AB - An integration of existing research and newly conducted psychophysiological interaction (PPI) connectivity analyses suggest a new framework for understanding the contribution of midline regions to social cognition. Recent meta-analyses suggest that there are no midline regions that are exclusively associated with self-processing. Whereas medial prefrontal cortex (MPFC) is broadly modulated by self-processing, subdivisions within MPFC are differentially modulated by the evaluation of close others (ventral MPFC: BA 10/32) and the evaluation of other social targets (dorsal MPFC: BA 9/32). The role of DMPFC in social cognition may also be less uniquely social than previously thought; it may be better characterized as a region that indexes certainty about evaluation rather than previously considered social mechanisms (i.e., correction of self-projection). VMPFC, a region often described as an important mediator of socioemotional significance, may instead perform a more cognitive role by reflecting the type of information brought to bear on evaluations of people we know well. Furthermore, the new framework moves beyond MPFC and hypothesizes that two other midline regions, ventral anterior cingulate cortex (VACC: BA 25) and medial orbitofrontal cortex (MOFC: BA 11), aid motivational influences on social cognition. Despite the central role of motivation in psychological models of self-perception, neural models have largely ignored the topic. Positive connectivity between VACC and MOFC may mediate bottom-up sensitivity to information based on its potential for helping us evaluate ourselves or others the way we want. As connectivity becomes more positive with striatum and less positive with middle frontal gyrus (BA 9/44), MOFC mediates top-down motivational influences by adjusting the standards we bring to bear on evaluations of ourselves and other people. PMID- 23935581 TI - HDDM: Hierarchical Bayesian estimation of the Drift-Diffusion Model in Python. AB - The diffusion model is a commonly used tool to infer latent psychological processes underlying decision-making, and to link them to neural mechanisms based on response times. Although efficient open source software has been made available to quantitatively fit the model to data, current estimation methods require an abundance of response time measurements to recover meaningful parameters, and only provide point estimates of each parameter. In contrast, hierarchical Bayesian parameter estimation methods are useful for enhancing statistical power, allowing for simultaneous estimation of individual subject parameters and the group distribution that they are drawn from, while also providing measures of uncertainty in these parameters in the posterior distribution. Here, we present a novel Python-based toolbox called HDDM (hierarchical drift diffusion model), which allows fast and flexible estimation of the the drift-diffusion model and the related linear ballistic accumulator model. HDDM requires fewer data per subject/condition than non-hierarchical methods, allows for full Bayesian data analysis, and can handle outliers in the data. Finally, HDDM supports the estimation of how trial-by-trial measurements (e.g., fMRI) influence decision-making parameters. This paper will first describe the theoretical background of the drift diffusion model and Bayesian inference. We then illustrate usage of the toolbox on a real-world data set from our lab. Finally, parameter recovery studies show that HDDM beats alternative fitting methods like the chi(2)-quantile method as well as maximum likelihood estimation. The software and documentation can be downloaded at: http://ski.clps.brown.edu/hddm_docs/ PMID- 23935582 TI - Effects of hemochromatosis and transferrin gene mutations on peripheral iron dyshomeostasis in mild cognitive impairment and Alzheimer's and Parkinson's diseases. AB - Deregulation of iron metabolism has been observed in patients with neurodegenerative diseases. We have carried out a molecular analysis investigating the interaction between iron specific gene variants [transferrin (TF, P589S), hemochromatosis (HFE) C282Y and (H63D)], iron biochemical variables [iron, Tf, ceruloplasmin (Cp), Cp:Tf ratio and % of Tf saturation (% Tf-sat)] and apolipoprotein E (APOE) gene variants in 139 Alzheimer's disease (AD), 27 Mild Cognitive Impairment (MCI), 78 Parkinson's disease (PD) patients and 139 healthy controls to investigate mechanisms of iron regulation or toxicity. No difference in genetic variant distributions between patients and controls was found in our Italian sample, but the stratification for the APOEepsilon4 allele revealed that among the APOEepsilon4 carriers was higher the frequency of those carriers of at least a mutated TF P589S allele. Decreased Tf in both AD and MCI and increased Cp:Tf ratio in AD vs. controls were detected. A multinomial logistic regression model revealed that increased iron and Cp:Tf ratio and being man instead of woman increased the risk of having PD, that increased values of Cp:Tf ratio corresponded to a 4-fold increase of the relative risk of having MCI, while higher Cp levels were protective for PD and MCI. Our study has some limitations: the small size of the samples, one ethnic group considered, the rarity of some alleles which prevent the statistical power of some genetic analysis. Even though they need confirmation in larger cohorts, our data suggest the hypothesis that deregulation of iron metabolism, in addition to other factors, has some effect on the PD disease risk. PMID- 23935583 TI - Conservation of 5-HT1A receptor-mediated autoinhibition of serotonin (5-HT) neurons in mice with altered 5-HT homeostasis. AB - Firing activity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is controlled by inhibitory somatodendritic 5-HT1A autoreceptors. This autoinhibitory mechanism is implicated in the etiology of disorders of emotion regulation, such as anxiety disorders and depression, as well as in the mechanism of antidepressant action. Here, we investigated how persistent alterations in brain 5-HT availability affect autoinhibition in two genetically modified mouse models lacking critical mediators of serotonergic transmission: 5-HT transporter knockout (Sert-/-) and tryptophan hydroxylase-2 knockout (Tph2-/-) mice. The degree of autoinhibition was assessed by loose-seal cell-attached recording in DRN slices. First, application of the 5-HT1A-selective agonist R(+)-8-hydroxy-2 (di-n-propylamino)tetralin showed mild sensitization and marked desensitization of 5-HT1A receptors in Tph2-/- mice and Sert-/- mice, respectively. While 5-HT neurons from Tph2-/- mice did not display autoinhibition in response to L tryptophan, autoinhibition of these neurons was unaltered in Sert-/- mice despite marked desensitization of their 5-HT1A autoreceptors. When the Tph2-dependent 5 HT synthesis step was bypassed by application of 5-hydroxy-L-tryptophan (5-HTP), neurons from both Tph2-/- and Sert-/- mice decreased their firing rates at significantly lower concentrations of 5-HTP compared to wildtype controls. Our findings demonstrate that, as opposed to the prevalent view, sensitivity of somatodendritic 5-HT1A receptors does not predict the magnitude of 5-HT neuron autoinhibition. Changes in 5-HT1A receptor sensitivity may rather be seen as an adaptive mechanism to keep autoinhibition functioning in response to extremely altered levels of extracellular 5-HT resulting from targeted inactivation of mediators of serotonergic signaling. PMID- 23935584 TI - Is the VO2max that we measure really maximal? PMID- 23935585 TI - Language influences on numerical development-Inversion effects on multi-digit number processing. AB - In early numerical development, children have to become familiar with the Arabic number system and its place-value structure. The present review summarizes and discusses evidence for language influences on the acquisition of the highly transparent structuring principles of digital-Arabic digits by means of its moderation through the transparency of the respective language's number word system. In particular, the so-called inversion property (i.e., 24 named as "four and twenty" instead of "twenty four") was found to influence number processing in children not only in verbal but also in non-verbal numerical tasks. Additionally, there is first evidence suggesting that inversion-related difficulties may influence numerical processing longitudinally. Generally, language-specific influences in children's numerical development are most pronounced for multi digit numbers. Yet, there is currently only one study on three-digit number processing for German-speaking children. A direct comparison of additional new data from Italian-speaking children further corroborates the assumption that language impacts on cognitive (number) processing as inversion-related interference was found most pronounced for German-speaking children. In sum, we conclude that numerical development may not be language-specific but seems to be moderated by language. PMID- 23935586 TI - Design and evaluation of the computer-based training program Calcularis for enhancing numerical cognition. AB - This article presents the design and a first pilot evaluation of the computer based training program Calcularis for children with developmental dyscalculia (DD) or difficulties in learning mathematics. The program has been designed according to insights on the typical and atypical development of mathematical abilities. The learning process is supported through multimodal cues, which encode different properties of numbers. To offer optimal learning conditions, a user model completes the program and allows flexible adaptation to a child's individual learning and knowledge profile. Thirty-two children with difficulties in learning mathematics completed the 6-12-weeks computer training. The children played the game for 20 min per day for 5 days a week. The training effects were evaluated using neuropsychological tests. Generally, children benefited significantly from the training regarding number representation and arithmetic operations. Furthermore, children liked to play with the program and reported that the training improved their mathematical abilities. PMID- 23935587 TI - Perceptual load and early selection: an effect of attentional engagement? PMID- 23935588 TI - Proposal of a Nonlinear Interaction of Person and Situation (NIPS) model. AB - Marshall and Brown (2006) proposed a Traits as Situational Sensitivities (TASS) Model, which implies a systematic person * situation interaction. We review this model and show that it suffers from several limitations. We extend and modify the model in order to obtain a symmetric pattern of levels and effects for both person and situation factors. Our suggestions result in a general Nonlinear Interaction of Person and Situation (NIPS) Model. The NIPS model bears striking similarities to the Rasch model. Based on the symmetric nature of the NIPS model, we generalize the concept of weak and strong situations to individuals and propose the concepts of weak and strong persons. Finally, we discuss psychological mechanisms that might explain the NIPS pattern and offer ideas for future research. PMID- 23935590 TI - The stability-plasticity dilemma: investigating the continuum from catastrophic forgetting to age-limited learning effects. PMID- 23935589 TI - Recurrent temporal networks and language acquisition-from corticostriatal neurophysiology to reservoir computing. AB - One of the most paradoxical aspects of human language is that it is so unlike any other form of behavior in the animal world, yet at the same time, it has developed in a species that is not far removed from ancestral species that do not possess language. While aspects of non-human primate and avian interaction clearly constitute communication, this communication appears distinct from the rich, combinatorial and abstract quality of human language. So how does the human primate brain allow for language? In an effort to answer this question, a line of research has been developed that attempts to build a language processing capability based in part on the gross neuroanatomy of the corticostriatal system of the human brain. This paper situates this research program in its historical context, that begins with the primate oculomotor system and sensorimotor sequencing, and passes, via recent advances in reservoir computing to provide insight into the open questions, and possible approaches, for future research that attempts to model language processing. One novel and useful idea from this research is that the overlap of cortical projections onto common regions in the striatum allows for adaptive binding of cortical signals from distinct circuits, under the control of dopamine, which has a strong adaptive advantage. A second idea is that recurrent cortical networks with fixed connections can represent arbitrary sequential and temporal structure, which is the basis of the reservoir computing framework. Finally, bringing these notions together, a relatively simple mechanism can be built for learning the grammatical constructions, as the mappings from surface structure of sentences to their meaning. This research suggests that the components of language that link conceptual structure to grammatical structure may be much simpler that has been proposed in other research programs. It also suggests that part of the residual complexity is in the conceptual system itself. PMID- 23935591 TI - Brain response to primary blast wave using validated finite element models of human head and advanced combat helmet. AB - Blast-induced traumatic brain injury has emerged as a "signature injury" in combat casualty care. Present combat helmets are designed primarily to protect against ballistic and blunt impacts, but the current issue with helmets is protection concerning blasts. In order to delineate the blast wave attenuating capability of the Advanced Combat Helmet (ACH), a finite element (FE) study was undertaken to evaluate the head response against blast loadings with and without helmet using a partially validated FE model of the human head and ACH. Four levels of overpressures (0.27-0.66 MPa) from the Bowen's lung iso-damage threshold curves were used to simulate blast insults. Effectiveness of the helmet with respect to head orientation was also investigated. The resulting biomechanical responses of the brain to blast threats were compared for human head with and without the helmet. For all Bowen's cases, the peak intracranial pressures (ICP) in the head ranged from 0.68 to 1.8 MPa in the coup cortical region. ACH was found to mitigate ICP in the head by 10-35%. Helmeted head resulted in 30% lower average peak brain strains and product of strain and strain rate. Among three blast loading directions with ACH, highest reduction in peak ICP (44%) was due to backward blasts whereas the lowest reduction in peak ICP and brain strains was due to forward blast (27%). The biomechanical responses of a human head to primary blast insult exhibited directional sensitivity owing to the different geometry contours and coverage of the helmet construction and asymmetric anatomy of the head. Thus, direction-specific tolerances are needed in helmet design in order to offer omni-directional protection for the human head. The blasts of varying peak overpressures and durations that are believed to produce the same level of lung injury produce different levels of mechanical responses in the brain, and hence "iso-damage" curves for brain injury are likely different than the Bowen curves for lung injury. PMID- 23935592 TI - Breaking bad news to a prospective cross-sectional sample of patients' relatives in a nigerian neurosurgical service. AB - OBJECTIVES: Breaking of medical bad news is anecdotally deemed culturally unacceptable, even intolerable, to native Africans. We explored this hypothesis among a cohort of relatives of patients who had difficult neurosurgical diagnoses in an indigenous practice. MATERIALS AND METHODS: A semi-structured, interviewer administered questionnaire was used in a cross-sectional survey among a consecutive cohort of surrogates/relatives of concerned patients. Their opinion and preferences regarding the full disclosure of the grave neurosurgical diagnoses, and prognoses, of their wards were analyzed. RESULTS: A total of 114 patients' relatives, 83 (72.8%) females, were sampled. They were mainly young adults, mean age 40.2 (SD 14.2) years; 57% had only basic literacy education; but the majority, 97%, declared themselves to have serious religious commitments. Ninety nine percent of the study participants deemed it desirable that either they or the patients concerned be told the bad news; 80.7% felt that this is best done with both patients and relations in attendance; 3.5% felt only the patients need be told. These preferences are similar to those expressed by the patients themselves in an earlier study. But a nearly significant greater proportion of patients' relatives (15 vs 5%, p = 0.06) would rather be the only ones to be told the patients' bad news. CONCLUSION: This data-driven study showed that contrary to anecdotal belief about them, a cohort of native Nigerian-African surrogates of neurosurgical patients was well disposed to receiving, and appeared able to handle well, the full disclosure of difficult medical diagnostic/prognostic information. PMID- 23935593 TI - Review of Levetiracetam as a First Line Treatment in Status Epilepticus in the Adult Patients - What Do We Know so Far? AB - With the advent of new antiepileptic drugs comes the potential for significant advances in the emergent management of status epilepticus. Traditional antiepileptic drugs possess side effect profiles that may limit their clinical utility or lead to increased patient morbidity or mortality. The relatively recent development of levetiracetam shows promise for effective control of acute status epilepticus in adults, but current objective data of its use as a first line agent for control of status is quite limited. This paper serves to examine existing literature while considering levetiracetam as a first-line therapy in status in the adult patient population. Although existing studies are narrow in their scope, the present data lay a substantial foundation for further investigation of levetiracetam as a primary therapy in acute status epilepticus. PMID- 23935594 TI - New insights into the evolutionary history of biological nitrogen fixation. AB - Nitrogenase, which catalyzes the ATP-dependent reduction of dinitrogen (N2) to ammonia (NH3), accounts for roughly half of the bioavailable nitrogen supporting extant life. The fundamental requirement for fixed forms of nitrogen for life on Earth, both at present and in the past, has led to broad and significant interest in the origin and evolution of biological N2 fixation. One key question is whether the limited availability of fixed nitrogen was a factor in life's origin or whether there were ample sources of fixed nitrogen produced by abiotic processes or delivered through the weathering of bolide impact materials to support this early life. If the latter, the key questions become what were the characteristics of the environment that precipitated the evolution of this oxygen sensitive process, when did this occur, and how was its subsequent evolutionary history impacted by the advent of oxygenic photosynthesis and the rise of oxygen in the Earth's biosphere. Since the availability of fixed sources of nitrogen capable of supporting early life is difficult to glean from the geologic record, there are limited means to get direct insights into these questions. Indirect insights, however, can be gained through phylogenetic studies of nitrogenase structural gene products and additional gene products involved in the biosynthesis of the complex metal-containing prosthetic groups associated with this enzyme complex. Insights gained from such studies, as reviewed herein, challenge traditional models for the evolution of biological nitrogen fixation and provide the basis for the development of new conceptual models that explain the stepwise evolution of this highly complex life sustaining process. PMID- 23935595 TI - Presence and diversity of anammox bacteria in cold hydrocarbon-rich seeps and hydrothermal vent sediments of the Guaymas Basin. AB - Hydrothermally active sediments are highly productive, chemosynthetic areas which are characterized by the rapid turnover of particulate organic matter under extreme conditions in which ammonia is liberated. These systems might be suitable habitats for anaerobic ammonium oxidizing (anammox) bacteria but this has not been investigated in detail. Here we report the diversity and abundance of anammox bacteria in sediments that seep cold hydrocarbon-rich fluids and hydrothermal vent areas of the Guaymas Basin in the Cortes Sea using the unique functional anammox marker gene, hydrazine synthase (hzsA). All clones retrieved were closely associated to the "Candidatus Scalindua" genus. Phylogenetic analysis revealed two distinct clusters of hzsA sequences (Ca. Scalindua hzsA cluster I and II). Comparison of individual sequences from both clusters showed that several of these sequences had a similarity as low as 76% on nucleotide level. Based on the analysis of this phylomarker, a very high interspecies diversity within the marine anammox group is apparent. Absolute numbers of anammox bacteria in the sediments samples were determined by amplification of a 257 bp fragment of the hszA gene in a qPCR assay. The results indicate that numbers of anammox bacteria are generally higher in cold hydrocarbon-rich sediments compared to the vent areas and the reference zone. Ladderanes, lipids unique to anammox bacteria were also detected in several of the sediment samples corroborating the hzsA analysis. Due to the high concentrations of reduced sulfur compounds and its potential impact on the cycling of nitrogen we aimed to get an indication about the key players in the oxidation of sulfide in the Guaymas Basin sediments using the alpha subunit of the adenosine-5'-phosphosulfate (APS) reductase (aprA). Amplification of the aprA gene revealed a high number of gammaproteobacterial aprA genes covering the two sulfur-oxidizing bacteria aprA lineages as well as sulfate-reducers. PMID- 23935596 TI - Antimicrobial resistance in commensal Escherichia coli isolated from animals at slaughter. AB - Monitoring of antimicrobial resistance in commensal Escherichia coli (N = 3430) isolated from slaughtered broilers, laying hens, turkeys, swine, and cattle in Poland has been run between 2009 and 2012. Based on minimal inhibitory concentration (MIC) microbiological resistance to each of 14 tested antimicrobials was found reaching the highest values for tetracycline (43.3%), ampicillin (42.3%), and ciprofloxacin (39.0%) whereas the lowest for colistin (0.9%), cephalosporins (3.6 / 3.8%), and florfenicol (3.8%). The highest prevalence of resistance was noted in broiler and turkey isolates, whereas it was rare in cattle. That finding along with resistance patterns specific to isolation source might reflect antimicrobial consumption, usage preferences or management practices in specific animals. Regression analysis has identified changes in prevalence of microbiological resistance and shifts of MIC values. Critically important fluoroquinolone resistance was worrisome in poultry isolates, but did not change over the study period. The difference (4.7%) between resistance to ciprofloxacin and nalidixic acid indicated the scale of plasmid-mediated quinolone resistance. Cephalosporin resistance were found in less than 3.8% of the isolates but an increasing trends were observed in poultry and MIC shift in the ones from cattle. Gentamycin resistance was also increasing in E. coli of turkey and cattle origin although prevalence of streptomycin resistance in laying hens decreased considerably. Simultaneously, decreasing MIC for phenicols observed in cattle and layers isolates as well as tetracycline values in E. coli from laying hens prove that antimicrobial resistance is multivariable phenomenon not only directly related to antimicrobial usage. Further studies should elucidate the scope of commensal E. coli as reservoirs of resistance genes, their spread and possible threats for human and animal health. PMID- 23935598 TI - Beyond the antigen receptor: editing the genome of T-cells for cancer adoptive cellular therapies. AB - Recent early stage clinical trials evaluating the adoptive transfer of patient CD8(+) T-cells re-directed with antigen receptors recognizing tumors have shown very encouraging results. These reports provide strong support for further development of the therapeutic concept as a curative cancer treatment. In this respect combining the adoptive transfer of tumor-specific T-cells with therapies that increase their anti-tumor capacity is viewed as a promising strategy to improve treatment outcome. The ex vivo genetic engineering step that underlies T cell re-direction offers a unique angle to combine antigen receptor delivery with the targeting of cell-intrinsic pathways that restrict T-cell effector functions. Recent progress in genome editing technologies such as protein- and RNA-guided endonucleases raise the possibility of disrupting gene expression in T-cells in order to enhance effector functions or to bypass tumor immune suppression. This approach would avoid the systemic administration of compounds that disrupt immune homeostasis, potentially avoiding autoimmune adverse effects, and could improve the efficacy of T-cell based adoptive therapies. PMID- 23935600 TI - The critical amplifying role of increasing atmospheric moisture demand on tree mortality and associated regional die-off. PMID- 23935599 TI - Immune parameters to consider when choosing T-cell receptors for therapy. AB - T-cell receptor (TCR) therapy has arrived as a realistic treatment option for many human diseases. TCR gene therapy allows for the mass redirection of T-cells against a defined antigen while high affinity TCR engineering allows for the creation of a new class of soluble drugs. However, deciding which TCR blueprint to take forward for gene therapy or engineering is difficult. More than one quintillion TCR combinations can be generated by somatic recombination and we are only now beginning to appreciate that not all are functionally equal. TCRs can exhibit high or low degrees of HLA-restricted cross-reactivity and alloreact against one or a combination of HLA alleles. Identifying TCR candidates with high specificity and minimal cross-reactivity/alloreactivity footprints before engineering is obviously highly desirable. Here we will summarize what we currently know about TCR biology with regard to immunoengineering. PMID- 23935597 TI - Do Natural T Regulatory Cells become Activated to Antigen Specific T Regulatory Cells in Transplantation and in Autoimmunity? AB - Antigen specific T regulatory cells (Treg) are often CD4(+)CD25(+)FoxP3(+) T cells, with a phenotype similar to natural Treg (nTreg). It is assumed that nTreg cannot develop into an antigen specific Treg as repeated culture with IL-2 and a specific antigen does not increase the capacity or potency of nTreg to promote immune tolerance or suppress in vitro. This has led to an assumption that antigen specific Treg mainly develop from CD4(+)CD25(-)FoxP3(-) T cells, by activation with antigen and TGF-beta in the absence of inflammatory cytokines such as IL-6 and IL-1beta. Our studies on antigen specific CD4(+)CD25(+) T cells from animals with tolerance to an allograft, identified that the antigen specific and Treg are dividing, and need continuous stimulation with specific antigen T cell derived cytokines. We identified that a variety of cytokines, especially IL-5 and IFN gamma but not IL-2 or IL-4 promoted survival of antigen specific CD4(+)CD25(+)FoxP3(+) Treg. To examine if nTreg could be activated to antigen specific Treg, we activated nTreg in culture with either IL-2 or IL-4. Within 3 days, antigen specific Treg are activated and there is induction of new cytokine receptors on these cells. Specifically nTreg activated by IL-2 and antigen express the interferon-gamma receptor (IFNGR) and IL-12p70 (IL-12Rbeta2) receptor but not the IL-5 receptor (IL-5Ralpha). These cells were responsive to IFN-gamma or IL-12p70. nTreg activated by IL-4 and alloantigen express IL-5Ralpha not IFNGR or IL-12p70Rbeta2 and become responsive to IL-5. These early activated antigen specific Treg, were respectively named Ts1 and Ts2 cells, as they depend on Th1 or Th2 responses. Further culture of Ts1 cells with IL-12p70 induced Th1-like Treg, expressing IFN-gamma, and T-bet as well as FoxP3. Our studies suggest that activation of nTreg with Th1 or Th2 responses induced separate lineages of antigen specific Treg, that are dependent on late Th1 and Th2 cytokines, not the early cytokines IL-2 and IL-4. PMID- 23935601 TI - The physiological resilience of fern sporophytes and gametophytes: advances in water relations offer new insights into an old lineage. AB - Ferns are some of the oldest vascular plants in existence and they are the second most diverse lineage of tracheophytes next to angiosperms. Recent efforts to understand fern success have focused on the physiological capacity and stress tolerance of both the sporophyte and the gametophyte generations. In this review, we examine these insights through the lens of plant water relations, focusing primarily on the form and function of xylem tissue in the sporophyte, as well as the tolerance to and recovery from drought and desiccation stress in both stages of the fern life cycle. The absence of secondary xylem in ferns is compensated by selection for efficient primary xylem composed of large, closely arranged tracheids with permeable pit membranes. Protection from drought-induced hydraulic failure appears to arise from a combination of pit membrane traits and the arrangement of vascular bundles. Features such as tracheid-based xylem and variously sized megaphylls are shared between ferns and more derived lineages, and offer an opportunity to compare convergent and divergent hydraulic strategies critical to the success of xylem-bearing plants. Fern gametophytes show a high degree of desiccation tolerance but new evidence shows that morphological attributes in the gametophytes may facilitate water retention, though little work has addressed the ecological significance of this variation. We conclude with an emergent hypothesis that selection acted on the physiology of both the sporophyte and gametophyte generations in a synchronous manner that is consistent with selection for drought tolerance in the epiphytic niche, and the increasingly diverse habitats of the mid to late Cenozoic. PMID- 23935603 TI - A perspective on photoperiodic phloem-mobile signals that control development. AB - Phloem-mobile signals that are regulated by day length activate both flowering and tuber formation. Both signaling processes have numerous elements in common. In this review, FLOWERING LOCUS T and the three signals currently implicated in controlling tuberization, SP6A, miR172, and the StBEL5 complex, are discussed with a focus on their functional roles, their mechanisms of long-distance transport, and their possible interactions. PMID- 23935604 TI - Mammalian miRNA curation through next-generation sequencing. AB - Characteristic small RNA biogenesis processing patterns are used for the discovery of novel microRNAs (miRNAs) from next-generation sequencing data. Here, we highlight and discuss key criteria for mammalian - specifically human - miRNA database curation based on small RNA sequencing data. Sequence reads obtained from small RNA cDNA libraries are aligned to reference genomic regions, and miRNA genes are revealed by their distinct read length and bimodal read frequency distribution, the predicted secondary structure of the deduced miRNA stem-loop precursor molecule, and, to a lesser degree, based on evolutionary conservation of small RNAs from other vertebrates. Properly curated miRNA databases are an important resource for investigators interested in miRNA biology, diagnostics, and therapeutics. PMID- 23935602 TI - A contribution to the study of plant development evolution based on gene co expression networks. AB - Phototrophic eukaryotes are among the most successful organisms on Earth due to their unparalleled efficiency at capturing light energy and fixing carbon dioxide to produce organic molecules. A conserved and efficient network of light dependent regulatory modules could be at the bases of this success. This regulatory system conferred early advantages to phototrophic eukaryotes that allowed for specialization, complex developmental processes and modern plant characteristics. We have studied light-dependent gene regulatory modules from algae to plants employing integrative-omics approaches based on gene co expression networks. Our study reveals some remarkably conserved ways in which eukaryotic phototrophs deal with day length and light signaling. Here we describe how a family of Arabidopsis transcription factors involved in photoperiod response has evolved from a single algal gene according to the innovation, amplification and divergence theory of gene evolution by duplication. These modifications of the gene co-expression networks from the ancient unicellular green algae Chlamydomonas reinhardtii to the modern brassica Arabidopsis thaliana may hint on the evolution and specialization of plants and other organisms. PMID- 23935606 TI - Skin Disorders among Elder Patients in a Referral Center in Northern Iran (2011). AB - Background. Geriatric health care has become a worldwide concern, but a few statistical studies were carried out about skin diseases in this age group. In this study, we set out to determine the frequency as well as the age and gender distribution of dermatological diseases in geriatric patients. Materials and Methods. In a cross-sectional study, all patients over 60 years who were accepted to department of dermatology in north of Iran participated in this study. Baseline information and clinical examination were done by a group of dermatologists. Biopsy, Pathological and laboratory methods were used in order to confirm the diagnosis. Results. 440 patients were accepted to the department that 232 patients were male (52.7%). Benign neoplasm was as the common skin disease among patients (65%), followed by erythemo-squamous (35.3%) and precancerous lesions (26.1%). The most common precancerous lesion was actinic keratosis (24.3%). BCC by 8.8% was the most prevalent skin carcinoma. Pruritus was the common problem in other dermatological disease (22%). Conclusion. Skin disorders especially precancerous lesion are among those important health problems in elderly patients in this geographic area. Increasing general awareness about risk factors of these diseases and doing more researches in other regions are highly recommended. PMID- 23935605 TI - Strategic cognitive sequencing: a computational cognitive neuroscience approach. AB - We address strategic cognitive sequencing, the "outer loop" of human cognition: how the brain decides what cognitive process to apply at a given moment to solve complex, multistep cognitive tasks. We argue that this topic has been neglected relative to its importance for systematic reasons but that recent work on how individual brain systems accomplish their computations has set the stage for productively addressing how brain regions coordinate over time to accomplish our most impressive thinking. We present four preliminary neural network models. The first addresses how the prefrontal cortex (PFC) and basal ganglia (BG) cooperate to perform trial-and-error learning of short sequences; the next, how several areas of PFC learn to make predictions of likely reward, and how this contributes to the BG making decisions at the level of strategies. The third models address how PFC, BG, parietal cortex, and hippocampus can work together to memorize sequences of cognitive actions from instruction (or "self-instruction"). The last shows how a constraint satisfaction process can find useful plans. The PFC maintains current and goal states and associates from both of these to find a "bridging" state, an abstract plan. We discuss how these processes could work together to produce strategic cognitive sequencing and discuss future directions in this area. PMID- 23935607 TI - Autologous Serum Skin Test versus Autologous Plasma Skin Test in Patients with Chronic Spontaneous Urticaria. AB - Previous studies indicate that 25-45% of chronic urticaria patients have an autoimmune etiology. Autologous serum skin test (ASST) and autologous plasma skin test (APST) are simple tests for diagnosing chronic autoimmune urticaria (CAU). However, there are still some questions about the specificity of these tests. This study consisted of 50 patients with chronic spontaneous urticaria (CSU) and 50 sex- and age-matched healthy individuals aged 18 years, and older. A total of 31 (62%) patients and 5 (10%) control patients had positive ASST; 21 (42%) patients and 3 (6%) control patients had positive APST. Statistically significant differences were noted in ASST and APST positivity between the patient and control groups (ASST P < 0.001; APST P < 0.001). Thirteen (26%) patients and 5 (10%) control patients had antithyroglobulin antibodies or antithyroid peroxidase antibody positivity. No statistically significant differences were noted in thyroid autoantibodies between the patient and control groups (anti-TG P = 0.317; anti-TPO P = 0.269). We consider that the ASST and APST can both be used as in vivo tests for the assessment of autoimmunity in the etiology of CSU and that thyroid autoantibodies should be checked even when thyroid function tests reveal normal results in patients with CSU. PMID- 23935608 TI - Antireflux endoluminal therapies: past and present. AB - The basic principle of antireflux procedures employing endoscopic intervention aims to create a mechanical barrier to prevent primary pathophysiology in gastroesophageal reflux disease (GERD). We review, highlight, and discuss the past and present status of endoluminal therapy. Currently, there are 3 commonly employed anti-reflux endoluminal procedures: fundoplication or suturing techniques (EndoCinch, NDO, and EsophyX), intramural injection or implant techniques (enhancing lower esophageal sphincter (LES) volume and/or strengthening compliance of the LES-Enteryx and Gatekeeper), and radiofrequency ablation of LES and cardia. EndoCinch plication requires further study and modification of technique before it can be recommended because of durability issues. Esophynx, the transoral incisionless fundoplication, may reduce hiatal hernias and increase LES length. Preliminary studies have shown promising reduction in symptoms and medication use but evidence concerning safety and long term durability is still pending. The safety issue with injection technique is the main concern as evident from the incidences of implant withdrawals after reported major adverse events. Future research with cautious monitoring is required before any new implant material can be recommended for commercial application. Radiofrequency ablation therapy is regaining popularity in treating refractory symptoms despite PPI use due to improved efficacy, durability, and safety after years of refinement of protocol. PMID- 23935609 TI - Prediction and treatment of difficult cases in colorectal endoscopic submucosal dissection. AB - Purpose. The aim of this study was to examine the characteristics of difficult cases and the learning curve in colorectal endoscopic submucosal dissection (ESD). Methods. We studied 518 colorectal tumors treated by ESD. Patients were divided into 2 groups such as the difficult ESD group and non-difficult ESD group in view of procedure time and procedure speed, respectively. The clinical features in each group were analyzed, and we also examined cases with severe fibrosis. Furthermore, we divided all cases into 5 periods according to experience of ESDs and investigated the rates of difficult and perforation cases. Results. In view of both procedure time and procedure speed, there were significant differences about mean tumor size, rates of severe fibrosis and perforation, and en bloc resection rate between the two groups. Severe fibrosis was detected in protruding tumors >40 mm in diameter. With respect to the learning curve, the rate of difficult and perforation cases decreased significantly in the late periods compared to the first period. Conclusions. Large tumor size, high rates of severe fibrosis and perforation, and low rate of en bloc resection are related with difficult ESD cases. The increasing of experiences can decrease the rate of difficult cases and perforation. PMID- 23935611 TI - Implementation of endoscopic submucosal dissection for early colorectal neoplasms in Sweden. AB - Objectives. Endoscopic submucosal dissection (ESD) is an effective method for en bloc removal of large colorectal tumors in Japan, but this technique is not yet widely established in western countries. The purpose here was to report the experience of implementing colorectal ESD in Sweden. Methods. Twenty-nine patients with primarily nonmalignant and early colorectal neoplasms considered to be too difficult to remove en bloc with EMR underwent ESD. Five cases of invasive cancer underwent ESD due to high comorbidity excluding surgical intervention or as an unexpected finding. Results. The median age of the patients was 74 years. The median tumor size was 26 mm (range 11-89 mm). The median procedure time was 142 min (range 57-291 min). En bloc resection rate was 72% and the R0 resection rate was 69%. Two perforations occurred amounting to a perforation rate of 6.9%. Both patients with perforation could be managed conservatively. One bleeding occurred during ESD but no postoperative bleeding was observed. Conclusion. Our data confirms that ESD is an effective method for en bloc resection of large colorectal adenomas and early cancers. This study demonstrates that implementation of colorectal ESD is feasible in Sweden after proper training, careful patient selection, and standardization of the ESD procedure. PMID- 23935610 TI - Current advances in the diagnosis and treatment of nonerosive reflux disease. AB - Nonerosive reflux disease (NERD) is a distinct pattern of gastroesophageal reflux disease (GERD). It is defined as a subcategory of GERD characterized by troublesome reflux-related symptoms in the absence of esophageal mucosal erosions/breaks at conventional endoscopy. In clinical practice, patients with reflux symptoms and negative endoscopic findings are markedly heterogeneous. The potential explanations for the symptom generation in NERD include microscopic inflammation, visceral hypersensitivity (stress and sleep), and sustained esophageal contractions. The use of 24-hour esophageal impedance and pH monitoring gives further insight into reflux characteristics and symptom association relevant to NERD. The treatment choice of NERD still relies on acid suppression therapy. Initially, patients can be treated by a proton pump inhibitor (PPI; standard dose, once daily) for 2-4 weeks. If initial treatment fails to elicit adequate symptom control, increasing the PPI dose (standard dose PPI twice daily) is recommended. In patients with poor response to appropriate PPI treatment, 24-hour esophageal impedance and pH monitoring is indicated to differentiate acid-reflux-related NERD, weakly acid-reflux-related NERD (hypersensitive esophagus), nonacid-reflux-related NERD, and functional heartburn. The response is less effective in NERD as compared with erosive esophagitis. PMID- 23935612 TI - Labisia pumila Upregulates Peroxisome Proliferator-Activated Receptor Gamma Expression in Rat Adipose Tissues and 3T3-L1 Adipocytes. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated transcription factor that regulates lipid and glucose metabolism. We investigated the effects of Labisia pumila (LP) standardized water extract on PPARgamma transcriptional activity in adipocytes in vitro and in vivo. We used a rat model of dihydrotestosterone- (DHT-) induced polycystic ovary syndrome (PCOS), a condition characterized by insulin resistance. At 9 weeks of age, the PCOS rats were randomly subdivided into two groups: PCOS-LP (50 mg/kg/day of LP) and PCOS-control (1 mL of deionised water) for 4-5 weeks on the same schedule. Real-time RT-PCR was performed to determine the PPARgamma mRNA levels. LP upregulated PPARgamma mRNA level by 40% in the PCOS rats. Western blot analysis further demonstrated the increased PPARgamma protein levels in parallel with upregulation in mRNA. These observations were further proven by adipocytes culture. Differentiated 3T3-L1 adipocytes were treated with final concentration of 100 MU g/mL LP and compared to untreated control and 10 MU M of rosiglitazone (in type of thiazolidinediones). LP increased PPARgamma expressions at both mRNA and protein levels and enhanced the effect of glucose uptake in the insulin-resistant cells. The data suggest that LP may ameliorate insulin resistance in adipocytes via the upregulation of PPARgamma pathway. PMID- 23935614 TI - Cell matrix remodeling ability shown by image spatial correlation. AB - Extracellular matrix (ECM) remodeling is a critical step of many biological and pathological processes. However, most of the studies to date lack a quantitative method to measure ECM remodeling at a scale comparable to cell size. Here, we applied image spatial correlation to collagen second harmonic generation (SHG) images to quantitatively evaluate the degree of collagen remodeling by cells. We propose a simple statistical method based on spatial correlation functions to determine the size of high collagen density area around cells. We applied our method to measure collagen remodeling by two breast cancer cell lines (MDA-MB-231 and MCF-7), which display different degrees of invasiveness, and a fibroblast cell line (NIH/3T3). We found distinct collagen compaction levels of these three cell lines by applying the spatial correlation method, indicating different collagen remodeling ability. Furthermore, we quantitatively measured the effect of Latrunculin B and Marimastat on MDA-MB-231 cell line collagen remodeling ability and showed that significant collagen compaction level decreases with these treatments. PMID- 23935615 TI - Clinical Validation of a Highly Sensitive GC-MS Platform for Routine Urine Drug Screening and Real-Time Reporting of up to 212 Drugs. AB - An important role of the clinical toxicology laboratory is to provide continuous diagnostic testing for patients with altered mental status and for other medical indications. To meet these needs, we have developed a new Gas Chromatography-Mass Spectrometry (GC-MS) platform that facilitates routine screening and automated reporting of 212 drugs by laboratory technologists around the clock without the need to sign out by an on-site mass spectrometry-trained toxicologist. The platform uses a programmable temperature vaporizer (PTV) injector for large sample volume injection and the free software Automated Mass Spectral Deconvolution and Identification System (AMDIS) for data reduction and spectral matching that facilitates rapid library searching and analyte identification. Method comparison with 118 patient samples demonstrated that this platform and data searching algorithm independently provided improvements in sensitivity compared to an established GC-MS platform. Further examination of the role of the data processing software and the in-house databases used in the established versus the new platform demonstrated that the improved analytical sensitivity of the new platform was attributed to both the technical superiority of the new GC MS instrumentation and the use of AMDIS in conjunction with the newly generated in-house library for data processing. PMID- 23935613 TI - Entry, Retention, and Virological Suppression in an HIV Cohort Study in India: Description of the Cascade of Care and Implications for Reducing HIV-Related Mortality in Low- and Middle-Income Countries. AB - HIV treatment, care, and support programmes in low- and middle-income countries have traditionally focused more on patients remaining in care after the initiation of antiretroviral therapy (ART) than on earlier stages of care. This study describes the cumulative retention from HIV diagnosis to the achievement of virological suppression after ART initiation in an HIV cohort study in India. Of all patients diagnosed with HIV, 70% entered into care within three months. 65% of patients ineligible for ART at the first assessment were retained in pre-ART care. 67% of those eligible for ART initiated treatment within three months. 30% of patients who initiated ART died or were lost to followup, and 82% achieved virological suppression in the last viral load determination. Most attrition occurred the in pre-ART stages of care, and it was estimated that only 31% of patients diagnosed with HIV engaged in care and achieved virological suppression after ART initiation. The total mortality attributable to pre-ART attrition was considerably higher than the mortality for not achieving virological suppression. This study indicates that early entry into pre-ART care along with timely initiation of ART is more likely to reduce HIV-related mortality compared to achieving virological suppression. PMID- 23935616 TI - Factors that affect the false-negative outcomes of fine-needle aspiration biopsy in thyroid nodules. AB - Background. The purpose of this study was to assess the factors that affect the false-negative outcomes of fine-needle aspiration biopsies (FNABs) in thyroid nodules. Methods. Thyroid nodules that underwent FNAB and surgery between August 2005 and January 2012 were analyzed. FNABs were taken from the suspicious nodules regardless of nodule size. Results. Nodules were analyzed in 2 different groups: Group 1 was the false-negatives (n = 81) and Group 2 was the remaining true positives, true-negatives, and false-positives (n = 649). A cytopathologist attended in 559 (77%) of FNAB procedures. There was a positive correlation between the nodule size and false-negative rates, and the absence of an interpreting cytopathologist for the examination of the FNAB procedure was the most significant parameter with a 76-fold increased risk of false-negative results. Conclusion. The contribution of cytopathologists extends the time of the procedure, and this could be a difficult practice in centres with high patient turnovers. We currently request the contribution of a cytopathologist for selected patients whom should be followed up without surgery. PMID- 23935617 TI - Physical fitness in children with type 1 diabetes measured with six-minute walk test. AB - Aim/Hypothesis. To examine whether children with DMT1 are less physically fit than healthy children and to assess whether an elevated level of HbA1c was associated with decreased physical fitness among children with diabetes. Methods. The study was conducted using case-control methodology. The cases were 100 children with T1DM, 7-17,9 years. Study subjects underwent a 6MWT, where distance measured, heart rate, and oxygen saturation was recorded. Results. Results of the 6MWT for children with T1DM and controls were 601.3 +/- 86.1 meters versus 672.1 +/- 60.6 meters, respectively (P < 0.001). The cases were divided into two subgroups, one with HbA1c levels >8% and one with HbA1c <8%. Results for both groups were inferior to the controls (P < 0.001). The posttest pulse rate in all subjects was higher than the pretest pulse rate (P < 0.001). Pulse oxygen levels were lower than controls at the pretest measurement (P < 0.001), and for both cases and controls, pulse oxygen levels decreased after test (P = 0.004). However, the change in oxygen saturation did not differ between the groups (P = 0.332). Conclusions. Children with T1D are less fit than matched controls. The level of HbA1c did not affect the physical fitness of children with T1D. PMID- 23935618 TI - The impact of endocrine disruptors on endocrine targets. PMID- 23935619 TI - Determinants of hypovitaminosis d in pregnant women and their newborns in a sunny region. AB - Introduction. This study aims to assess the factors associated with 25-hydroxy vitamin D (25(OH)D) levels in pregnant women and their newborns in a sunny region. Materials and Methods. This cross-sectional study was conducted in 2012 in Isfahan, Iran. It comprised 100 nulliparous singleton pregnant women, selected by random cluster sampling. Laboratory tests were assessed before delivery in mothers and after delivery in their infants' umbilical cord blood. The P for trend of variables was assessed across the air quality index (AQI) quartiles. The associations of AQI and 25(OH)D were assessed by multiple linear regression after adjustment for age, body mass index, and dietary intake. Results. Sera of 98 mothers and an equal number of newborns were analyzed. The median (interquartile range, IQR) of serum 25(OH)D of mothers and neonates was 15.1(12.6, 18.2) ng/mL in mothers and 15.7(12.0, 18.1) ng/mL in neonates, respectively. AQI had an inverse association with serum 25(OH)D (Beta = -0.58, P = 0.04). The corresponding figure was also inverse and significant for newborns (Beta (SE)= 0.51(0.04), P = 0.01). Conclusion. The independent inverse association of 25(OH)D with air quality can explain the high prevalence of hypovitaminosis D in pregnant women living in this sunny region. PMID- 23935620 TI - Long-term results after treatment of very low-, low-, and high-risk thyroid cancers in a combined setting of thyroidectomy and radio ablation therapy in euthyroidism. AB - Introduction. Differentiated thyroid cancer treatment usually consists of thyroidectomy and radio ablation in hypothyroidism 4-6 weeks after surgery. Replacing hypothyroidism by recombinant human thyroid stimulating hormone can facilitate radio ablation in euthyroidism within one week after surgery. The outcome of this approach was investigated. Methods. This is a prospective randomized trial to compare thyroidectomy and radio ablation within a few days after preconditioning with recombinant human thyroid stimulating hormone versus thyroidectomy and radio ablation separated by four weeks of L-T4 withdrawal. Tumors were graded into very low-, low- , or high-risk tumors. Recurrence-free survival was confirmed at follow-up controls by neck ultrasound and serum thyroglobulin. Suspected tumor recurrence was treated by additional radio ablation or surgery. Quality-of-life questionnaires with additional evaluation of job performance and sick-leave time were used in all patients. Results. Radio ablation in euthyroidism in quick succession after thyroidectomy did not lead to higher tumor recurrence rates of differentiated thyroid cancers in any risk category and was significantly advantageous with respect to quality-of-life (P < 0.001), sick-leave time (P < 0.001), and job performance (P = 0.002). Conclusion. Recombinant human thyroid stimulating hormone can be used safely and with good efficacy to allow radio ablation under sustained euthyroidism within one week after thyroidectomy. PMID- 23935621 TI - Complementary roles of orexin and melanin-concentrating hormone in feeding behavior. AB - Transcribed within the lateral hypothalamus, the neuropeptides orexin/hypocretin (OX) and melanin-concentrating hormone (MCH) both promote palatable food intake and are stimulated by palatable food. While these two neuropeptides share this similar positive relationship with food, recent evidence suggests that this occurs through different albeit complementary effects on behavior, with OX promoting food seeking and motivation for palatable food and MCH functioning during ongoing food intake, reinforcing the consumption of calorically dense foods. Further differences are evident in their effects on physiological processes, which are largely opposite in nature. For example, activation of OX receptors, which is neuronally excitatory, promotes waking, increases energy expenditure, and enhances limbic dopamine levels and reward. In contrast, activation of MCH receptors, which is neuronally inhibitory, promotes paradoxical sleep, enhances energy conservation, reduces limbic dopamine, and increases depressive behavior. This review describes these different effects of the neuropeptides, developing the hypothesis that they stimulate the consumption of palatable food through excessive seeking in the case of OX and through excessive energy conservation in the case of MCH. It proposes that OX initiates food intake and subsequently stimulates MCH which then acts to prolong the consumption of palatable, energy-dense food. PMID- 23935623 TI - Human Calmodulin-Like Protein CALML3: A Novel Marker for Normal Oral Squamous Mucosa That Is Downregulated in Malignant Transformation. AB - Oral cancer is often diagnosed only at advanced stages due to a lack of reliable disease markers. The purpose of this study was to determine if the epithelial specific human calmodulin-like protein (CALML3) could be used as marker for the various phases of oral tumor progression. Immunohistochemical analysis using an affinity-purified CALML3 antibody was performed on biopsy-confirmed oral tissue samples representing these phases. A total of 90 tissue specimens were derived from 52 patients. Each specimen was analyzed in the superficial and basal mucosal cell layers for overall staining and staining of cellular subcompartments. CALML3 was strongly expressed in benign oral mucosal cells with downregulation of expression as squamous cells progress to invasive carcinoma. Based on the Cochran Armitage test for trend, expression in the nucleus and at the cytoplasmic membrane significantly decreased with increasing disease severity. Chi-square test showed that benign tissue specimens had significantly more expression compared to dysplasia/CIS and invasive specimens. Dysplasia/CIS tissue had significantly more expression than invasive tissue. We conclude that CALML3 is expressed in benign oral mucosal cells with a statistically significant trend in downregulation as tumorigenesis occurs. CALML3 may thus be a sensitive new marker for oral cancer screening. PMID- 23935622 TI - Endoscopic Detection of Early Esophageal Squamous Cell Carcinoma in Patients with Achalasia: Narrow-Band Imaging versus Lugol's Staining. AB - Chromoendoscopy with Lugol's staining remains the gold standard technique for detecting superficial SCC. An alternative technique, such as narrow-band imaging (NBI), for "optical staining" would be desirable, since NBI is a simpler technique and has no known complications. In this study, we compare NBI without magnification and chromoendoscopy with Lugol's staining for detecting high-grade dysplasia and intramucosal esophageal squamous cell carcinoma (SCC) in patients with achalasia. This was a prospective observational study of 43 patients with achalasia referred to the Gastrointestinal Endoscopy Unit of the Hospital of Clinics, Sao Paulo, University Medical School, Brazil, from October 2006 to February 2007. Conventional examinations with white light, NBI, and Lugol staining were consecutively performed, and the suspected lesions were mapped, recorded, and sent for biopsy. The results of the three methods were compared regarding sensitivity, specificity, accuracy, positive predictive value, negative predictive value, positive likelihood value, and negative likelihood value. Of the 43 patients, one was diagnosed with esophageal squamous cell carcinoma, and it was detected by all of the methods. NBI technology without magnification has high sensitivity and negative predictive value for detecting superficial esophageal squamous cell carcinoma, and it has comparable results with those obtained with Lugol's staining. PMID- 23935624 TI - Clinical outcome following oral potentially malignant disorder treatment: a 100 patient cohort study. AB - Oral potentially malignant disorders (PMDs) are at risk of transforming to invasive squamous cell carcinoma (SCC), but controversy exists over their management and the precise role of interventional treatment. In this study, a cohort of 100 patients presenting with new, single oral dysplastic PMD lesions were followed for up to 10 years following laser excision. PMDs presented primarily as homogeneous leukoplakias on floor of mouth and ventrolateral tongue sites and showed mainly high-grade dysplasia following analysis of excision specimens. Sixty-two patients were disease-free at the time of the most recent followup, whilst 17 experienced same site PMD recurrence, 14 developed further PMDs at new sites, 5 underwent same site malignant transformation, and 2 developed SCC at new oral sites. Whilst laser excision is an effective therapeutic tool in PMD management, prolonged patient followup and active mucosal surveillance together with clear definitions of clinical outcomes are all essential prerequisites for successful interventional management. Multicentre, prospective, and randomised trials of PMD treatment intervention are urgently required to determine optimal management strategies. PMID- 23935625 TI - Utilization of N-bromosuccinimide as a brominating agent for the determination of sumatriptan succinate in bulk drug and tablets. AB - One titrimetric and two spectrophotometric methods which are simple, sensitive, and economic are described for the determination of sumatriptan succinate (STS) in bulk drug and in tablet dosage form using N-bromosuccinimide (NBS) as a brominating agent. In titrimetry, aqueous solution of STS is treated with a measured excess of NBS in acetic acid medium, and after the bromination of STS is judged to be complete, the unreacted NBS is determined iodometrically (method A). Spectrophotometric methods entail addition of a known excess of NBS in acid medium followed by the determination of residual NBS by its reaction with excess iodide, and the liberated iodine (I3 (-)) is either measured at 370 nm (method B) or liberated iodine is reacted with starch followed by the measurement of the blue colored starch-iodine complex at 570 nm (method C). Titrimetric method is applicable over range 1.0-10.0 mg STS (method A), and the reaction stoichiometry is found to be 1 : 3 (STS : NBS). The spectrophotometric methods obey Beer's law for concentration range 0.6-15.0 MU g mL(-1) (method B) and 0.2-4.0 MU g mL(-1) (method C). The calculated apparent molar absorptivity values were found to be 2.10 * 10(4) and 7.44 * 10(4) L mol(-1) cm(-1), for method B and method C, respectively. PMID- 23935626 TI - Expression of Tra2 beta in Cancer Cells as a Potential Contributory Factor to Neoplasia and Metastasis. AB - The splicing regulator proteins SRSF1 (also known as ASF/SF2) and SRSF3 (also known as SRP20) belong to the SR family of proteins and can be upregulated in cancer. The SRSF1 gene itself is amplified in some cancer cells, and cancer associated changes in the expression of MYC also increase SRSF1 gene expression. Increased concentrations of SRSF1 protein promote prooncogenic splicing patterns of a number of key regulators of cell growth. Here, we review the evidence that upregulation of the SR-related Tra2 beta protein might have a similar role in cancer cells. The TRA2B gene encoding Tra2 beta is amplified in particular tumours including those of the lung, ovary, cervix, stomach, head, and neck. Both TRA2B RNA and Tra2 beta protein levels are upregulated in breast, cervical, ovarian, and colon cancer, and Tra2 beta expression is associated with cancer cell survival. The TRA2B gene is a transcriptional target of the protooncogene ETS-1 which might cause higher levels of expression in some cancer cells which express this transcription factor. Known Tra2 beta splicing targets have important roles in cancer cells, where they affect metastasis, proliferation, and cell survival. Tra2 beta protein is also known to interact directly with the RBMY protein which is implicated in liver cancer. PMID- 23935627 TI - Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance. AB - Overexpression of human epidermal growth factor receptor (HER-2) occurs in 20-30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant Delta16HER-2 (results from exon 16 skipping) increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention) and p100 (results from intron 15 retention) inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. "Individualised" strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets. PMID- 23935628 TI - A Prevalence Study of Hearing Loss among Primary School Children in the South East of Iran. AB - Hearing impairment substantially affects child's ability to normally acquire the spoken language. Such negative effects create problems for the child not only in terms of communication but also in terms of achievement in school as well as social and emotional growth. The aim of this research is to study the prevalence of hearing disorders and its relationship to age and gender among primary school students of Zahedan, Iran. In this cross-sectional and descriptive analytical study, 1500 students from elementary schools were screened for hearing loss. The selection of samples was performed using multistage sampling method. Primary information was obtained through direct observation, otoscopy, and audiometric and tympanometric screenings. Data was obtained and analyzed via ANOVA test. Statistical analysis showed a significant correlation between the age and the prevalence of middle ear abnormal function. Conductive hearing loss in males and females was 8.8% and 7.1%, respectively. In addition, 1% and 0.7% of male and female students, respectively, suffered from sensorineural hearing loss. Results indicated that 20.2% of students of elementary schools in Zahedan needed medical treatment for their problems. Therefore, it is recommended that the hearing screening of school-age children should be included in annual school health programs in this region. PMID- 23935629 TI - Management of globus pharyngeus. AB - Globus pharyngeus is a common ENT condition. This paper reviews the current evidence on globus and gives a rational guide to the management of patients with globus. The aetiology of globus is still unclear though most ENT surgeons believe that reflux whether acidic or not plays a significant role. Though proton pump inhibitors are used extensively in practice, there is little evidence to support their efficacy. Most patients with globus can be discharged after simple office investigations. The role of pepsin-induced laryngeal injury is an exciting concept that needs further study. Given the benign nature of globus pharyngeus, in most cases, reassurance rather than treatment or extensive investigation with rigid oesophagoscopy or contrast swallows is all that is needed. We need more research into the aetiology of globus. PMID- 23935630 TI - The Clinical Role of HPV Testing in Primary and Secondary Cervical Cancer Screening. AB - Traditional population-based cervical screening programs, based on cytology, have successfully reduced the burden of cervical cancer. Nevertheless limitations remain and new screening methods are emerging. Despite vaccination against the 2 most oncogenic types (HPV 16/18), cervical cancer screening will have to continue as an essential public health strategy. As the acquisition of an HR-HPV infection is critical in the progression to (pre-)cancerous cervical lesions, recent research has focused on HR-HPV detection. The sensitivity of HPV testing in primary and secondary prevention outweighs that of cytology, at the cost of slightly lower specificity. Although most of the HR-HPV infections are cleared after conization, new evidence from numerous studies encourages the implementation of HR-HPV testing and genotyping to improve posttreatment surveillance. An HR-HPV test 6 months after conization is a promising useful clinical marker to detect persistence and prevent progression. This review highlights the clinical role of HPV testing in primary and secondary cervical cancer screening. PMID- 23935631 TI - Female genital mutilation/cutting: the secret world of women as seen by men. AB - Efforts aimed at the abandonment of Female Genital Mutilation/Cutting (FGM/C) in the communities where it is deeply rooted have extensively considered and addressed women's perceptions on the issue, leaving those of men barely acknowledged. Although the practice is generally confined to the secret world of women, it does not mean that men cannot be influential. Indeed, men can play an important role in prevention. In order to address this gap, and having as background an extensive ethnographic field work, a transversal descriptive study was designed to explore Gambian men's knowledge and attitudes towards FGM/C, as well as related practices in their family/household. Results show ethnic identity, more than religion, as the decisive shaping factor on how men conceive and value FGM/C. The greater support towards the practice is found among traditionally practicing groups. A substantial proportion of men intend to have it performed on their daughters, although reporting a low involvement in the decision making process, with very few taking alone the final decision. Only a minority is aware of FGM/C health consequences, but those who understand its negative impact on the health and well-being of girls and women are quite willing to play a role in its prevention. PMID- 23935632 TI - The oncoplacental gene placenta-specific protein 1 is highly expressed in endometrial tumors and cell lines. AB - Placenta-specific protein 1 (PLAC1) is a small secreted protein expressed exclusively in trophoblast cells in the mammalian placenta. PLAC1 is expressed early in gestation and is maintained throughout. It is thought to function in trophoblast invasion of the uterine epithelium and, subsequently, to anchor the placenta to the epithelium. In recent years, evidence has accumulated that PLAC1 is also expressed in a variety of human solid tumors, notably in breast cancers. We demonstrate for the first time that PLAC1 is ubiquitously expressed in tumors originating in uterine epithelium. Further, we find that PLAC1 expression is significantly higher in the more advanced, more aggressive endometrial serous adenocarcinomas and carcinosarcomas relative to endometrioid adenocarcinomas by more than 6-fold and 16-fold, respectively. We also show that PLAC1 is simultaneously transcribed from two promoters but that, in all cases, the more distal P1 promoter dominates the more proximal P2 promoter. While the function of the two PLAC1 promoters and their regulation are as yet unknown, overall expression data suggest that PLAC1 may serve as a biomarker for endometrial cancer as well as a potential prognostic indicator. PMID- 23935633 TI - Eosinophilic pleural effusion: a rare complication of extracorporeal shock wave lithotripsy. AB - Background. Extracorporeal shock wave lithotripsy has been widely used to treat renal stones. The procedure is relatively safe with minor complications. Case. The patient is a 32-year-old man who presented with left sided pleural effusion after extracorporeal shock wave lithotripsy. Results. The pleural effusion study revealed an exudative fluid rich in eosinophils (30%). So, the diagnosis of eosinophilic pleural effusion as a complication of lithotripsy was made. Conclusion. Extracorporeal shock wave lithotripsy should be regarded as an etiology of unexplained eosinophilic pleural effusion after this procedure. PMID- 23935634 TI - Emergency liver resection with staplers for spontaneous liver haemorrhage in a patient receiving anticoagulant therapy. AB - Introduction. Emergency liver resection during active bleeding in a patient who takes anticoagulant therapy is a complicated and high-risk surgery. Aim. We described a technique that is combination of staplers, total hepatic vascular occlusion, and hemostatic agent (TachoSil) application for safe and quick hepatectomy. Patient and Method. A 72-year-old woman who uses warfarin regularly due to valvuloplasty admitted emergency unit with abdominal pain and shock. At admission, her hemoglobin, hematocrit, and INR values were 5.2 g/dL, 14.9%, and 6.7, respectively. Radiologic evaluation revealed abdominal free fluid and a liver lesion on segments V, VI, and VII. Emergency laparotomy was required. There was an active bleeding from a liver hematoma that could not be controlled by packing, and an urgent hepatic resection was required. Under total hepatic vascular occlusion, segments V, VI, and VII were resected with endoscopic nonvascular staplers. Cut surface of the liver was coagulated with bipolar cautery and covered with a hemostatic material. Results. Hepatectomy took six minutes, and the duration of surgery was 80 minutes. There was no complication and no transfusion required after surgery, and the patient was discharged on 8th day, uneventfully. Conclusion. Emergency hepatectomy with staplers, under vascular control with hemostatic agents, provided a rapid and safe surgery. PMID- 23935635 TI - Specific Oral Tolerance Induction Using IFN-Gamma in 2 Cases of Food-Dependent Exercise-Induced Anaphylaxis. AB - Anaphylaxis induced by exercise after the intake of certain foods is referred to as food-dependent exercise-induced anaphylaxis (FDEIA). Only the preventive medication such as oral sodium cromoglycate and oral combined cetirizine montelukast was tried in FDEIA. Specific oral tolerance induction (SOTI) using IFN-gamma was tried in 2 cases of FDEIA for wheat. Merely, exercise accompanied every treatment just after the intake of allergenic foods during treatment. Patients acquired tolerance for wheat in both cases successfully. After treatment, two patients take wheat in their food living freely. Conclusively, SOTI using IFN-gamma was effective as the causative treatment for allergenic foods in FDEIA. PMID- 23935636 TI - Colonization of a Central Venous Catheter by the Hyaline Fungus Fusarium solani Species Complex: A Case Report and SEM Imaging. AB - The incidence of opportunistic infections by filamentous fungi is increasing partly due to the widespread use of central venous catheters (CVC), indwelling medical devices, and antineoplastic/immunosuppressive drugs. The case of a 13 year-old boy under treatment for acute lymphoblastic leukemia is presented. The boy was readmitted to the Pediatric Ward for intermittent fever of unknown origin. Results of blood cultures drawn from peripheral venous sites or through the CVC were compared. CVC-derived bottles (but not those from peripheral veins) yielded hyaline fungi that, based on morphology, were identified as belonging to the Fusarium solani species complex. Gene amplification and direct sequencing of the fungal ITS1 rRNA region and the EF-1alpha gene confirmed the isolate as belonging to the Fusarium solani species complex. Portions of the CVC were analyzed by scanning electron microscopy. Fungi mycelia with long protruding hyphae were seen into the lumen. The firm adhesion of the fungal formation to the inner surface of the catheter was evident. In the absence of systemic infection, catheter removal and prophylactic voriconazole therapy were followed by disappearance of febrile events and recovery. Thus, indwelling catheters are prone to contamination by environmental fungi. PMID- 23935637 TI - Silicate Urolithiasis during Long-Term Treatment with Zonisamide. AB - Silicate urinary calculi are rare in humans, with an incidence of 0.2% of all urinary calculi. Most cases were related to excess ingestion of silicate, typically by taking magnesium trisilicate as an antacid for peptic ulcers over a long period of time; however, there also existed unrelated cases, whose mechanism of development remains unclear. On the other hand, zonisamide, a newer antiepileptic drug, is one of the important causing agents of iatrogenic urinary stones in patients with epilepsy. The supposed mechanism is that zonisamide induces urine alkalinization and then promotes crystallization of urine components such as calcium phosphate by inhibition of carbonate dehydratase in renal tubular epithelial cells. Here, we report a case of silicate urolithiasis during long-term treatment with zonisamide without magnesium trisilicate intake and discuss the etiology of the disease by examining the silicate concentration in his urine. PMID- 23935638 TI - Wernicke's Encephalopathy: An Unusual Consequence of the Acquired Immune Deficiency Syndrome-Case Report and Literature Review. AB - Introduction. Wernicke's encephalopathy is a well-described syndrome characterized by the classic triad of confusion, ataxia, and ophthalmoplegia. Wernicke's encephalopathy results from thiamine (vitamin B1) deficiency. Common causes include alcoholism and gastric disorders. Wernicke's has been described in patients with acquired immune deficiency syndrome (AIDS); however, given these patients' immunosuppressed state, the diagnosis of Wernicke's encephalopathy is not apparent. Case Presentation. A 31-year-old previously healthy male presented to the ER complaining of progressive dyspnea. Workup revealed HIV/AIDS and PCP pneumonia. He was treated and improved. On day 14 he became confused and developed nystagmus and ataxia. Considering his immunocompromised state, infectious and neoplastic etiologies topped the differential diagnosis. CT head was negative. Lumbar puncture was unremarkable. Brain MRI revealed increased T2 signal in the medial thalamus bilaterally. Intravenous thiamine was administered resulting in resolution of symptoms. Discussion. The classic triad of Wernicke's encephalopathy occurs in 10% of cases. When immunosuppressed patients develop acute neurologic symptoms infectious or neoplastic etiologies must be excluded. However, given the relative safety of thiamine supplementation, there should be a low threshold for initiating therapy in order to reverse the symptoms and prevent progression to Korsakoff dementia, which is permanent. PMID- 23935639 TI - A case of reed syndrome with a novel mutation in the fumarate hydratase gene. AB - Reed syndrome is a heritable cancer predisposition syndrome that can easily be missed due to its simple presentation of tender red papules. We present a young female with a history of uterine fibroids who presented to the dermatology clinic with several painful pink papules that had been previously evaluated by multiple physicians. Biopsy results were diagnostic for cutaneous leiomyomas, raising clinical suspicion for Reed syndrome. She was found to have a novel heterozygote mutation in her fumarate hydratase gene, supporting the diagnosis. This case demonstrates the importance of rendering a proper workup for seemingly innocent skin complaints as they could be associated with an underlying malignancy. Despite the fact that up to 16% of patients can develop aggressive type 2 papillary renal cell carcinoma, there are currently no consensus guidelines on screening or patient management. PMID- 23935640 TI - Emerging therapeutic strategies for targeting chronic myeloid leukemia stem cells. AB - Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI) therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML) that have the potential to target CML stem cells and potentially provide cure for CML. PMID- 23935641 TI - Systematic Review into Diagnostics for Post-Kala-Azar Dermal Leishmaniasis (PKDL). AB - Identification of post-kala-azar dermal leishmaniasis (PKDL) is important due to the long and toxic treatment and the fact that PKDL patients may serve as a reservoir for visceral leishmaniasis (VL). We summarized the published literature about the accuracy of diagnostic tests for PKDL. We searched Medline for eligible studies investigating the diagnostic accuracy of any test for PKDL. Study quality was assessed using QUADAS-2. Data were extracted from 21 articles including 43 separate studies. Twenty-seven studies evaluated serological tests (rK39 dipstick, ELISA, DAT, and leishmanin tests), six studies molecular tests, eight microscopy, and two cultures. Only a few of these studies reported a valid estimate of diagnostic accuracy, as most were case-control designs or used a reference standard with low sensitivity. The included studies were very heterogeneous, for example, due to a large variety of reference standards used. Hence, no summary estimates of sensitivity or specificity could be made. We recommend well-designed diagnostic accuracy trials that evaluate, side-by-side, all currently available diagnostics, including clinical symptoms, serological, antigen, molecular, and parasitological tests and possible use of statistical modelling to evaluate diagnostics when there is no suitable gold standard. PMID- 23935643 TI - The prevalence of very frequent physical fighting among boys and girls in 27 countries and cities: regional and gender differences. AB - OBJECTIVE: Using nationally representative data, this study examined the prevalence of very frequent physical fighting (>=12 times per year) among youth in 27 countries and cities. Frequent physical fighting has rarely been reported in the previous literature despite the implications for research and practice. METHODS: Analyses were based on the Global School-based Student Health Survey (2003-2008) and the 2009 US Youth Risk Behavior Survey. Multinomial regression analyses were conducted to determine gender differences in frequent fighting. Countries were categorized into five regions (Sub-Saharan Africa, Central and South America, Asia, Eastern Mediterranean, and the United States), and one-way ANOVA tests were used to determine regional differences. RESULTS: The prevalence of frequent fighting was highest in Zambia (7.7%) and lowest in Myanmar (0.5%). Gender differences were found in 20 countries, with boys being more likely to report frequent fighting than girls. The prevalence of frequent fighting varied by region (F(3,22) = 4.78, P = .01), with the Eastern Mediterranean having a significantly higher prevalence of frequent fighting than Asia (P < .01). CONCLUSION: The prevalence of frequent fighting varies by gender in many countries and varies across world regions. More cross-national research is needed to better understand the sociocultural context of frequent fighting and to inform youth violence prevention efforts. PMID- 23935642 TI - Antimicrobial peptides: versatile biological properties. AB - Antimicrobial peptides are diverse group of biologically active molecules with multidimensional properties. In recent past, a wide variety of AMPs with diverse structures have been reported from different sources such as plants, animals, mammals, and microorganisms. The presence of unusual amino acids and structural motifs in AMPs confers unique structural properties to the peptide that attribute for their specific mode of action. The ability of these active AMPs to act as multifunctional effector molecules such as signalling molecule, immune modulators, mitogen, antitumor, and contraceptive agent makes it an interesting candidate to study every aspect of their structural and biological properties for prophylactic and therapeutic applications. In addition, easy cloning and recombinant expression of AMPs in heterologous plant host systems provided a pipeline for production of disease resistant transgenic plants. Besides these properties, AMPs were also used as drug delivery vectors to deliver cell impermeable drugs to cell interior. The present review focuses on the diversity and broad spectrum antimicrobial activity of AMPs along with its multidimensional properties that could be exploited for the application of these bioactive peptides as a potential and promising drug candidate in pharmaceutical industries. PMID- 23935644 TI - Comparative assessment of particulate air pollution exposure from municipal solid waste incinerator emissions. AB - BACKGROUND: Research to date on health effects associated with incineration has found limited evidence of health risks, but many previous studies have been constrained by poor exposure assessment. This paper provides a comparative assessment of atmospheric dispersion modelling and distance from source (a commonly used proxy for exposure) as exposure assessment methods for pollutants released from incinerators. METHODS: Distance from source and the atmospheric dispersion model ADMS-Urban were used to characterise ambient exposures to particulates from two municipal solid waste incinerators (MSWIs) in the UK. Additionally an exploration of the sensitivity of the dispersion model simulations to input parameters was performed. RESULTS: The model output indicated extremely low ground level concentrations of PM10, with maximum concentrations of <0.01 MU g/m(3). Proximity and modelled PM10 concentrations for both MSWIs at postcode level were highly correlated when using continuous measures (Spearman correlation coefficients ~ 0.7) but showed poor agreement for categorical measures (deciles or quintiles, Cohen's kappa coefficients <= 0.5). CONCLUSION: To provide the most appropriate estimate of ambient exposure from MSWIs, it is essential that incinerator characteristics, magnitude of emissions, and surrounding meteorological and topographical conditions are considered. Reducing exposure misclassification is particularly important in environmental epidemiology to aid detection of low-level risks. PMID- 23935645 TI - Disparities of food availability and affordability within convenience stores in Bexar County, Texas. AB - The American Diabetes Association (ADA) recommends healthful food choices; however, some geographic areas are limited in the types of foods they offer. Little is known about the role of convenience stores as viable channels to provide healthier foods in our "grab and go" society. The purposes of this study were to (1) identify foods offered within convenience stores located in two Bexar County, Texas, ZIP Codes and (2) compare the availability and cost of ADA recommended foods including beverages, produce, grains, and oils/fats. Data were analyzed from 28 convenience store audits performed in two sociodemographically diverse ZIP Codes in Bexar County, Texas. Chi-squared tests were used to compare food availability, and t-tests were used to compare food cost in convenience stores between ZIP Codes. A significantly larger proportion of convenience stores in more affluent areas offered bananas (chi (2) = 4.17, P = 0.003), whole grain bread (chi (2) = 8.33, P = 0.004), and baked potato chips (chi (2) = 13.68, P < 0.001). On average, the price of diet cola (t = -2.12, P = 0.044) and certain produce items (e.g., bananas, oranges, tomatoes, broccoli, and cucumber) was significantly higher within convenience stores in more affluent areas. Convenience stores can play an important role to positively shape a community's food environment by stocking healthier foods at affordable prices. PMID- 23935646 TI - The immune factors involved in the pathogenesis, diagnosis, and treatment of Sjogren's syndrome. AB - Sjogren's syndrome (SS) is a systemic, autoimmune disorder characterized by salivary insufficiency and lymphocytic infiltration of the exocrine glands. Even though the mechanism of its pathology and progression has been researched ever since its discovery, the roles of different parts of immune system remain inconclusive. There is no straightforward and simple theory for the pathogenesis and diagnosis of Sjogren's syndrome because of the multiple kinds and functions of autoantibodies, changing proportion of different T-lymphocyte subsets with the progression of disease, unsuspected abilities of B lymphocytes discovered recently, crosstalk between cytokines connecting the factors mentioned previously, and genetic predisposition that contributes to the initiation of this disease. On the other hand, the number of significant reports and open-label studies of B-cell depletion therapy showing clinical efficacy in sjogren's syndrome has continued to accumulate, which provides a promising future for the patients. In a word, further elucidation of the role of different components of the immune system will open avenues for better diagnosis and treatment of SS, whose current management is still mainly supportive. PMID- 23935647 TI - Correlation of increased blood levels of GITR and GITRL with disease severity in patients with primary Sjogren's syndrome. AB - Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is a type I transmembrane protein belonging to the TNFR superfamily. After activated by its ligand GITRL, GITR could influence the activity of effector and regulatory T cells, participating in the development of several autoimmune and inflammatory diseases included rheumatoid arthritis and autoimmune thyroid disease. We previously reported that serum GITRL levels are increased in systemic lupus erythematosus (SLE) patients compared with healthy controls (HC). Here, we tested serum soluble GITR (sGITR) and GITRL levels in 41 primary Sjogren's syndrome (pSS) patients and 29 HC by ELISA and correlated sGITR and GITRL levels with clinical and laboratory variables. GITR and GITRL expression in labial salivary glands was detected by immunohistochemistry. pSS patients had significantly increased serum levels of sGITR and GITRL compared with controls (GITR: 5.66 +/- 3.56 ng/mL versus 0.50 +/- 0.31 ng/mL; P < 0.0001; GITRL: 6.17 +/ 7.10 ng/mL versus 0.36 +/- 0.28 ng/mL; P < 0.0001). Serum sGITR and GITRL levels were positively correlated with IgG (GITRL: r = 0.6084, P < 0.0001; sGITR: r = 0.6820, P < 0.0001) and ESR (GITRL: r = 0.8315, P < 0.0001; sGITR: r = 0.7448, P < 0.0001). Moreover, GITR and GITRL are readily detected in the lymphocytic foci and periductal areas of the LSGs. In contrast, the LSGs of HC subjects did not express GITR or GITRL. Our findings indicate the possible involvement of GITR GITRL pathway in the pathogenesis of pSS. Further studies may facilitate the development of targeting this molecule pathway for the treatment of pSS. PMID- 23935648 TI - Structural and antigenic definition of hepatitis C virus E2 glycoprotein epitopes targeted by monoclonal antibodies. AB - Hepatitis C virus (HCV) is the major cause of chronic liver disease as well as the major indication for liver transplantation worldwide. Current standard of care is not completely effective, not administrable in grafted patients, and burdened by several side effects. This incomplete effectiveness is mainly due to the high propensity of the virus to continually mutate under the selective pressure exerted by the host immune response as well as currently administered antiviral drugs. The E2 envelope surface glycoprotein of HCV (HCV/E2) is the main target of the host humoral immune response and for this reason one of the major variable viral proteins. However, broadly cross-neutralizing monoclonal antibodies (mAbs) directed against HCV/E2 represent a promising tool for the study of virus-host interplay as well as for the development of effective prophylactic and therapeutic approaches. In the last few years many anti-HCV/E2 mAbs have been evaluated in preclinical and clinical trials as possible candidate antivirals, particularly for administration in pre- and post-transplant settings. In this review we summarize the antigenic and structural characteristics of HCV/E2 determined through the use of anti-HCV/E2 mAbs, which, given the absence of a crystal structure of this glycoprotein, represent currently the best tool available. PMID- 23935649 TI - The importance of C4d in biopsies of kidney transplant recipients. AB - Antibody-mediated rejection (AMR) is highly detrimental to the prolonged survival of transplanted kidneys. C4d has been regarded as a footprint of AMR tissue damage, and the introduction of C4d staining in daily clinical practice aroused an ever-increasing interest in the role of antibody-mediated mechanisms in allograft rejection. Despite the general acceptance of the usefulness of C4d in the identification of acute AMR, the data for C4d staining in chronic AMR is variable. The presence of C4d in the majority of the biopsies with features of chronic antibody-mediated rejection is reported, but this rejection without C4d staining is observed as well, suggesting that C4d is specific but not sensitive. Further studies on AMR with positive C4d staining in biopsy specimens are really important, as well as the study of novel routine markers that may participate in the pathogenesis of this process. PMID- 23935652 TI - Inflammatory chemokine expression via Toll-like receptor 3 signaling in normal human mesangial cells. AB - The innate and adaptive immune systems have been reported to play an important role in the pathogenesis of glomerular diseases. Since viral infections may trigger the development of inflammatory renal disease or the worsening of preexisting renal disease, recent studies have focused on the involvement of toll like receptors (TLRs) and their signaling pathways in the inflammatory processes of glomerular cells. Viral double-stranded RNA (dsRNA) can activate not only TLR3 located within intracellular endosomes but also retinoic-acid-inducible-gene-I- (RIG-I-) like helicase receptors located within the cytosol. RIG-I and melanoma differentiation-associated gene 5 (MDA5) are members of the RNA helicase family in the cytosol, and both act as pathogen recognition receptors. The activation of TLRs and their downstream immune responses can be induced by both infectious pathogens and noninfectious stimuli such as endogenous ligands, and this mechanism may be involved in the pathogenesis of autoimmune renal diseases. However, there are few data on the interaction between TLR3, MDA5, and RIG-I in autoimmune glomerular diseases. Based on our recent experimental studies using cultured normal human mesangial cells (MCs), we found that novel TLR3-mediated signaling pathways in MCs may be involved in the pathogenesis of glomerular diseases. In the present paper, we summarize our recent findings. PMID- 23935651 TI - Neonatal host defense against Staphylococcal infections. AB - Preterm infants are especially susceptible to late-onset sepsis that is often due to Gram-positive bacterial infections resulting in substantial morbidity and mortality. Herein, we will describe neonatal innate immunity to Staphylococcus spp. comparing differences between preterm and full-term newborns with adults. Newborn innate immunity is distinct demonstrating diminished skin integrity, impaired Th1-polarizing responses, low complement levels, and diminished expression of plasma antimicrobial proteins and peptides, especially in preterm newborns. Characterization of distinct aspects of the neonatal immune response is defining novel approaches to enhance host defense to prevent and/or treat staphylococcal infection in this vulnerable population. PMID- 23935650 TI - The Interplay between the bone and the immune system. AB - In the last two decades, numerous scientists have highlighted the interactions between bone and immune cells as well as their overlapping regulatory mechanisms. For example, osteoclasts, the bone-resorbing cells, are derived from the same myeloid precursor cells that give rise to macrophages and myeloid dendritic cells. On the other hand, osteoblasts, the bone-forming cells, regulate hematopoietic stem cell niches from which all blood and immune cells are derived. Furthermore, many of the soluble mediators of immune cells, including cytokines and growth factors, regulate the activities of osteoblasts and osteoclasts. This increased recognition of the complex interactions between the immune system and bone led to the development of the interdisciplinary osteoimmunology field. Research in this field has great potential to provide a better understanding of the pathogenesis of several diseases affecting both the bone and immune systems, thus providing the molecular basis for novel therapeutic strategies. In these review, we reported the latest findings about the reciprocal regulation of bone and immune cells. PMID- 23935653 TI - The Korean Mistletoe (Viscum album coloratum) Extract Has an Antiobesity Effect and Protects against Hepatic Steatosis in Mice with High-Fat Diet-Induced Obesity. AB - This study investigates the inhibitory effects of Korean mistletoe extract (KME) on adipogenic factors in 3T3-L1 cells and obesity and nonalcoholic fatty liver disease (NAFLD) in mice fed a high-fat diet. Male C57Bl/6 mice fed a high-fat diet were treated with KME (3 g/kg/day) for 15 weeks for the antiobesity and NAFLD experiments. Body weight and daily food intake were measured regularly during the experimental period. The epididymal pad was measured and liver histology was observed. The effects of KME on thermogenesis and endurance capacity were measured. The effects of KME on adipogenic factors were examined in 3T3-L1 cells. Body and epididymal fat pad weights were reduced in KME-treated mice, and histological examination showed an amelioration of fatty liver in KME treated mice, without an effect on food consumption. KME potently induces mitochondrial activity by activating thermogenesis and improving endurance capacity. KME also inhibited adipogenic factors in vitro. These results demonstrate the inhibitory effects of KME on obesity and NAFLD in mice fed a high fat diet. The effects appear to be mediated through an enhanced mitochondrial activity. Therefore, KME may be an effective therapeutic candidate for treating obesity and fatty liver caused by a high-fat diet. PMID- 23935654 TI - Low Frequency Electroacupuncture Alleviated Spinal Nerve Ligation Induced Mechanical Allodynia by Inhibiting TRPV1 Upregulation in Ipsilateral Undamaged Dorsal Root Ganglia in Rats. AB - Neuropathic pain is an intractable problem in clinical practice. Accumulating evidence shows that electroacupuncture (EA) with low frequency can effectively relieve neuropathic pain. Transient receptor potential vanilloid type 1 (TRPV1) plays a key role in neuropathic pain. The study aimed to investigate whether neuropathic pain relieved by EA administration correlates with TRPV1 inhibition. Neuropathic pain was induced by right L5 spinal nerve ligation (SNL) in rats. 2 Hz EA stimulation was administered. SNL induced mechanical allodynia in ipsilateral hind paw. SNL caused a significant reduction of TRPV1 expression in ipsilateral L5 dorsal root ganglia (DRG), but a significant up-regulation in ipsilateral L4 and L6 DRGs. Calcitonin gene-related peptide (CGRP) change was consistent with that of TRPV1. EA alleviated mechanical allodynia, and inhibited TRPV1 and CGRP overexpressions in ipsilateral L4 and L6 DRGs. SNL did not decrease pain threshold of contralateral hind paw, and TRPV1 expression was not changed in contralateral L5 DRG. 0.001, 0.01 mg/kg TRPV1 agonist 6'-IRTX fully blocked EA analgesia in ipsilateral hind paw. 0.01 mg/kg 6'-IRTX also significantly decreased pain threshold of contralateral paw. These results indicated that inhibition of TRPV1 up-regulation in ipsilateral adjacent undamaged DRGs contributed to low frequency EA analgesia for mechanical allodynia induced by spinal nerve ligation. PMID- 23935656 TI - A longitudinal study of the reliability of acupuncture deqi sensations in knee osteoarthritis. AB - Deqi is one of the core concepts in acupuncture theory and encompasses a range of sensations. In this study, we used the MGH Acupuncture Sensation Scale (MASS) to measure and assess the reliability of the sensations evoked by acupuncture needle stimulation in a longitudinal clinical trial on knee osteoarthritis (OA) patients. The Knee injury and Osteoarthritis Outcome Score (KOOS) was used as the clinical outcome. Thirty OA patients were randomized into one of three groups (high dose, low dose, and sham acupuncture) for 4 weeks. We found that, compared with sham acupuncture, real acupuncture (combining high and low doses) produced significant improvement in knee pain (P = .025) and function in sport (P = .049). Intraclass correlation analysis showed that patients reliably rated 11 of the 12 acupuncture sensations listed on the MASS and that heaviness was rated most consistently. Overall perceived sensation (MASS Index) (P = .014), ratings of soreness (P = .002), and aching (P = .002) differed significantly across acupuncture groups. Compared to sham acupuncture, real acupuncture reliably evoked stronger deqi sensations and led to better clinical outcomes when measured in a chronic pain population. Our findings highlight the MASS as a useful tool for measuring deqi in acupuncture research. PMID- 23935655 TI - Case series of an intraoral balancing appliance therapy on subjective symptom severity and cervical spine alignment. AB - Objective. The objective of this study was to investigate the effect of a holistic intraoral appliance (OA) on cervical spine alignment and subjective symptom severity. Design. An observational study on case series with holistic OA therapy. Setting. An outpatient clinic for holistic temporomandibular joint (TMJ) therapy under the supervision of the Pain Center, CHA Biomedical center, CHA University. Subjects. Ambulatory patients presenting with diverse chief complaints in the holistic TMJ clinic. Main Measures. Any immediate change in the curvature of cervical spine and the degree of atlantoaxial rotation was investigated in the images of simple X-ray and computed tomography of cervical spine with or without OA. Changes of subjective symptom severity were also analyzed for the holistic OA therapy cases. Results. A total of 59 cases were reviewed. Alignment of upper cervical spine rotation showed an immediate improvement (P < 0.001). Changes of subjective symptom severity also showed significant improvement (P < 0.05). Conclusion. These cases revealed rudimentary clinical evidence that holistic OA therapy may be related to an alleviated symptom severity and an improved cervical spinal alignment. These results show that further researches may warrant for the holistic TMJ therapy. PMID- 23935658 TI - Infectious diseases physicians' attitudes and practices related to complementary and integrative medicine: results of a national survey. AB - Background. Complementary and alternative medicine (CAM) and integrative medicine (IM) modalities are widely used by patients, including those with infectious diseases (ID). Methods. One thousand randomly selected ID practitioners were surveyed. The survey was divided into domains related to familiarity and recommendation, beliefs and attitudes, and use of CAM/IM modalities. Results. The response rate was 31%. ID physicians were most familiar with vitamin and mineral supplementation (83%), massage (80%), acupuncture (79%), chiropractic (77%), yoga (74%), and herbal medicine (72%). ID physicians most recommended vitamin and mineral supplementation (80%) and massage (62%). Yoga, meditation, and acupuncture were recommended by 52%, 45%, and 46%, respectively. Drug interactions, clinical research, and knowledge of CAM/IM modalities were factors that were considered a major influence. Almost 80% of respondents indicated an interest in IM versus 11% for CAM. Most respondents (75%) felt that IM modalities are useful, and more than 50% believed that they could directly affect the immune system or disease process. Conclusion. ID physicians expressed a markedly greater interest for IM versus CAM. They appear to be familiar and willing to recommend some CAM/IM modalities and see a role for these in the management of certain infectious diseases. Data regarding clinical efficacy and safety appear to be important factors. PMID- 23935657 TI - Acupuncture for Depression: Patterns of Diagnosis and Treatment within a Randomised Controlled Trial. AB - Background. In a large randomised controlled trial of acupuncture, counselling, or usual care for depression, we document the acupuncture intervention and explore the relationship between traditional acupuncture diagnosis and outcome. Methods. Patients who were continuing to experience depression were recruited from primary care to the ACUDep trial (n = 755). Practitioners documented for each patient the traditional Chinese medicine diagnosis, the points needled, and additional components of the treatment, such as lifestyle advice, as recommended by the STRICTA guidelines. Results. Over an 18-month period, 23 acupuncturists delivered 2741 treatments to 266 patients, an average of 10 sessions per patient. The primary and secondary zang fu syndromes were identified for 99% of patients. When combining primary and secondary diagnoses, there was a predominant Liver Qi Stagnation cluster (66% of patients) and a Spleen Deficiency cluster (34%). Practitioners sought de qi responses 96% of the time. Lifestyle advice was given to 66% of patients, most commonly dietary. When comparing patient outcomes, no significant differences were found between the two main syndrome clusters. Conclusion. In this large-scale trial, our documentation of diagnosis and treatment provides a useful snapshot of common patterns that patients present with when continuing to experience depression after consulting in primary care. PMID- 23935659 TI - Characterizing acupuncture de qi in mild cognitive impairment: relations with small-world efficiency of functional brain networks. AB - As an intermediate state between normal aging and dementia, mild cognitive impairment (MCI) became a hot topic and early treatments can improve disease prognosis. Acupuncture is shown to have possible effect in improving its cognitive defect. However, the underlying neural mechanism of acupuncture and relations between De Qi and different needling depths are still elusive. The present study aimed to explore how acupuncture can exert effect on the reorganization of MCI and to what extent needling depths, associating with De Qi sensations, can influence the acupuncture effects for MCI treatment. Our results presented that MCI patients exhibited losses of small-world attributes indicated by longer characteristic path lengths and larger clustering coefficients, compared with healthy controls. In addition, acupuncture with deep needling can induce much stronger and a wide range of De Qi sensations both in intensity and prevalence. Acupuncture with deep needling showed modulatory effect to compensate the losses of small-world attributes existed in MCI patients while acupuncture with superficial needling did not. Furthermore, acupuncture with deep needling enhanced the nodal centrality primarily in the abnormal regions of MCI including the hippocampus, postcentral cortex as well as anterior cingulate cortex. This study provides evidence to understand neural mechanism underlying acupuncture and the key role of De Qi for MCI treatment. PMID- 23935660 TI - Activation of MITF by Argan Oil Leads to the Inhibition of the Tyrosinase and Dopachrome Tautomerase Expressions in B16 Murine Melanoma Cells. AB - Argan (Argania spinosa L.) oil has been used for centuries in Morocco as cosmetic oil to maintain a fair complexion and to cure skin pimples and chicken pox pustules scars. Although it is popular, the scientific basis for its effect on the skin has not yet been established. Here, the melanogenesis regulatory effect of argan oil was evaluated using B16 murine melanoma cells. Results of melanin assay using B16 cells treated with different concentrations of argan oil showed a dose-dependent decrease in melanin content. Western blot results showed that the expression levels of tyrosinase (TYR), tyrosinase-related protein 1 (TRP1), and dopachrome tautomerase (DCT) proteins were decreased. In addition, there was an increase in the activation of MITF and ERK1/2. Real-time PCR results revealed a downregulation of Tyr, Trp1, Dct, and Mitf mRNA expressions. Argan oil treatment causes MITF phosphorylation which subsequently inhibited the transcription of melanogenic enzymes, TYR and DCT. The inhibitory effect of argan oil on melanin biosynthesis may be attributed to tocopherols as well as the synergistic effect of its components. The results of this study provide the scientific basis for the traditionally established benefits of argan oil and present its therapeutic potential against hyperpigmentation disorders. PMID- 23935661 TI - Bidens pilosa L. (Asteraceae): Botanical Properties, Traditional Uses, Phytochemistry, and Pharmacology. AB - There are 230 to 240 known Bidens species. Among them, Bidens pilosa is a representative perennial herb, globally distributed across temperate and tropical regions. B. pilosa has been traditionally used in foods and medicines without obvious adverse effects. Despite significant progress in phytochemical and biological analyses of B. pilosa over the past few years, comprehensive and critical reviews of this plant are anachronistic or relatively limited in scope. The present review aims to summarize up-to-date information on the phytochemistry, pharmacology, and toxicology of B. pilosa from the literature. In addition to botanical studies and records of the traditional use of B. pilosa in over 40 diseases, scientific studies investigating the potential medicinal uses of this species and its constituent phytochemicals for a variety of disorders are presented and discussed. The structure, bioactivity, and likely mechanisms of action of B. pilosa and its phytochemicals are emphasized. Although some progress has been made, further rigorous efforts are required to investigate the individual compounds isolated from B. pilosa to understand and validate its traditional uses and develop clinical applications. The present review provides preliminary information and gives guidance for further basic and clinical research into this plant. PMID- 23935662 TI - Cytotoxicity and pharmacogenomics of medicinal plants from traditional korean medicine. AB - Aim. The present study was designed to investigate the cytotoxicity of a panel of 280 Korean medicinal plants belonging to 73 families and 198 species against human CCRF-CEM leukemia cells. Selected phytochemicals were investigated in more detail for their mode of action. Methods. The resazurin assay was used to determine cytotoxicity of the plant extracts. Microarray-based mRNA expression profiling, COMPARE, and hierarchical cluster analyses were applied to identify which genes correlate with sensitivity or resistance to selected phytochemicals of the Korean plants. Results. The results of the resazurin assay showed that cytotoxicity extracts tested at 10 MU g/mL from 13 samples inhibited proliferation more than 50% (IC50 < 10 MU g/mL) and the most active plants are Sedum middendorffianum (15.33%) and Lycoris radiata (17.61%). Out of 13 selected phytochemicals from these plants, hopeaphenol and deoxynarciclasine were the most cytotoxic ones. Genes from various functional groups (transcriptional or translational regulation, signal transduction, cellular proliferation, intracellular trafficking, RNA metabolism, endoplasmic/sarcoplasmic reticulum function, etc.) were significantly correlated with response of tumor cell lines to these two compounds. Conclusion. The results provide evidence on the possible use of selected Korean medicinal plants and chemical constituents derived from them for the treatment of tumors. PMID- 23935663 TI - Deqi sensations of transcutaneous electrical nerve stimulation on auricular points. AB - Deqi sensation, a psychophysical response characterized by a spectrum of different needling sensations, is essential for Chinese acupuncture clinical efficacy. Previous research works have investigated the component of Deqi response upon acupuncture on acupoints on the trunk and limbs. However, the characteristics of Deqi sensations of transcutaneous electrical nerve stimulation (TENS) on auricular points are seldom reported. In this study, we investigated the individual components of Deqi during TENS on auricular concha area and the superior scapha using quantitative measurements in the healthy subjects and depression patients. The most striking characteristics of Deqi sensations upon TENS on auricular points were tingling, numbness, and fullness. The frequencies of pressure, warmness, heaviness, and soreness were relatively lower. The dull pain and coolness are rare. The characteristics of Deqi were similar for the TENS on concha and on the superior scapha. PMID- 23935664 TI - The Synthetic Compound Norcantharidin Induced Apoptosis in Mantle Cell Lymphoma In Vivo and In Vitro through the PI3K-Akt-NF- kappa B Signaling Pathway. AB - This study aimed to elucidate the antitumor activity of norcantharidin (NCTD) against human mantle cell lymphoma (MCL). Cell proliferation and apoptosis were examined by MTS and flow cytometry. Caspase-3, -8, and -9 activities were detected with a colorimetric caspase protease assay. Apoptotic proteins-including PARP, cyclin D1, Bcl-2 family proteins, XIAP, and cIAP I-were studied by western blot. The phosphoinositide 3 kinase (PI3K) inhibitor LY294002 was used to investigate the involvement of the PI3K/Akt signaling pathway. In vivo studies were performed using Z138 cell xenografts in nude mice. NCTD inhibited proliferation and induced apoptosis of Z138 and Mino cells, both in vitro and in vivo. PI3Kp110 alpha and p-Akt expressions were downregulated by NCTD treatment. NCTD downregulated NF- kappa B activity by preventing NF- kappa B phosphorylation and nuclear translocation. This effect was correlated with the suppression of NF- kappa B-regulated gene products, such as cyclin D1, BAX, survivin, Bcl-2, XIAP, and cIAP. This phenomenon was blocked by the PI3K inhibitor LY294002. Our results demonstrated that NCTD can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the PI3K/Akt/NF- kappa B signaling pathway. NCTD may have therapeutic and/or adjuvant therapeutic applications in the treatment of MCL. PMID- 23935665 TI - The Ameliorating Effect of Steamed and Fermented Codonopsis lanceolata on Scopolamine-Induced Memory Impairment in Mice. AB - Codonopsis lanceolata (Campanulaceae) have been traditionally used to treat lung inflammatory diseases, such as asthma, tonsillitis, and pharyngitis. The present study was performed to evaluate the cognitive-enhancing effects of steamed and fermented C. lanceolata in scopolamine-induced memory impairments in mice. Cognitive abilities were determined by the Morris water maze and passive avoidance tests. Mice orally received fermented C. lanceolata extract at doses of 100, 300, or 500 mg/kg body weight. Fermented C. lanceolata extract (500 mg/kg body weight, p.o.) significantly shortened the escape latency times that were increased by scopolamine on the 4th day of trial sessions in the Morris water maze task. In addition, it exerted longer step-through latency times than those of the scopolamine-treated group in the passive avoidance test. Furthermore, the neuroprotective effects of fermented C. lanceolata extract on glutamate-induced neurocytotoxicity were investigated in HT22 cells. Fermented C. lanceolata extract showed a relative protection ratio of 59.62% at 500 MU g/mL. In conclusion, fermented C. lanceolata extract ameliorated scopolamine-induced memory impairments, exerted neuroprotective effects, and improved activity compared to that found with original C. lanceolata. Further study will be required to investigate the mechanisms underlying this cognitive-enhancing activity. PMID- 23935666 TI - History of bioelectrical study and the electrophysiology of the primo vascular system. AB - Background. Primo vascular system is a new anatomical structure whose research results have reported the possibility of a new circulatory system similar to the blood vascular system and cells. Electrophysiology, which measures and analyzes bioelectrical signals tissues and cells, is an important research area for investigating the function of tissues and cells. The bioelectrical study of the primo vascular system has been reported by using modern techniques since the early 1960s by Bonghan Kim. This paper reviews the research result of the electrophysiological study of the primo vascular system for the discussion of the circulatory function. We hope it would help to study the electrophysiology of the primo vascular system for researchers. This paper will use the following exchangeable expressions: Kyungrak system = Bonghan system = Bonghan circulatory system = primo vascular system = primo system; Bonghan corpuscle = primo node; Bonghan duct = primo vessel. We think that objective descriptions of reviewed papers are more important than unified expressions when citing the papers. That said, this paper will unify the expressions of the primo vascular system. PMID- 23935667 TI - "Intensity-response" effects of electroacupuncture on gastric motility and its underlying peripheral neural mechanism. AB - The aim of this study was to explore the "intensity-response" relationship between EAS and the effect of gastric motility of rats and its underlying peripheral neural mechanism by employing ASIC3 knockout (ASIC3-/-), TRPV1 knockout (TRPV1-/-), and C57BL/6 mice. For adult male Sprague-Dawley (n = 18) rats, the intensities of EAS were 0.5, 1, 3, 5, 7, and 9 mA, respectively. For mice (n = 8 in each group), only 1 mA was used, by which C fiber of the mice can be activated. Gastric antrum motility was measured by intrapyloric balloon. Gastric motility was facilitated by EAS at ST36 and inhibited by EAS at CV12. The half maximal facilitation intensity of EAS at ST36 was 2.1-2.3 mA, and the half maximal inhibitory intensity of EAS at CV12 was 2.8 mA. In comparison with C57BL/6 mice, the facilitatory effect of ST36 and inhibitive effect of CV12 in ASIC3-/- mice decreased, but the difference was not statistically significant (P > 0.05). However, these effects in TRPV1-/- mice decreased significantly (P < 0.001). The results indicated that there existed an "intensity-response" relationship between EAS and the effect of gastric motility. TRPV1 receptor was involved in the regulation of gastric motility of EAS. PMID- 23935668 TI - Cervical coupling motion characteristics in healthy people using a wireless inertial measurement unit. AB - Objective. The objectives were to show the feasibility of a wireless microelectromechanical system inertial measurement unit (MEMS-IMU) to assess the time-domain characteristics of cervical motion that are clinically useful to evaluate cervical spine movement. Methods. Cervical spine movements were measured in 18 subjects with wireless IMUs. All rotation data are presented in the Euler angle system. Amount of coupling motions was evaluated by calculating the average angle ratio and the maximum angle ratio of the coupling motion to the primary motion. Reliability is presented with intraclass correlation coefficients (ICC). Results. Entire time-domain characteristics of cervical motion were measured with developed MEMS-IMU system. Cervical range of motion (CROM) and coupling motion range were measured with high ICCs. The acquired data and calculated parameters had similar tendency with the previous studies. Conclusions. We evaluated cervical motion with economic system using a wireless IMU of high reliability. We could directly measure the three-dimensional cervical motion in degrees in realtime. The characteristics measured by this system may provide a diagnostic basis for structural or functional dysfunction of cervical spine. This system is also useful to demonstrate the effectiveness of any intervention such as conventional medical treatment, and Korean medical treatment, exercise therapy. PMID- 23935669 TI - Gene Expression Profile of the A549 Human Non-Small Cell Lung Carcinoma Cell Line following Treatment with the Seeds of Descurainia sophia, a Potential Anticancer Drug. AB - Descurainia sophia has been traditionally used in Korean medicine for treatment of diverse diseases and their symptoms, such as cough, asthma, and edema. Our previous results showed that ethanol extract of the seeds of D. sophia (EEDS) has a potent cytotoxic effect on human cancer cells. In this study, we reveal the molecular events that are induced by EEDS treatment in A549 human lung cancer cells. The dose-dependent effect of EEDS on gene expression was measured via a microarray analysis. Gene ontology and pathway analyses were performed to identify functional involvement of genes regulated by EEDS. From gene expression analyses, two major dose-dependent patterns were observed after EEDS treatment. One pattern consisted of 1,680 downregulated genes primarily involved in metabolic processes (FDR < 0.01). The second pattern consisted of 1,673 upregulated genes primarily involved in signaling processes (FDR < 0.01). Pathway activity analyses revealed that the metabolism-related pathways and signaling related pathways were regulated by the EEDS in dose-dependent and reciprocal manners. In conclusion, the identified biphasic regulatory mechanism involving activation of signaling pathways may provide molecular evidence to explain the inhibitory effect of EEDS on A549 cell growth. PMID- 23935670 TI - A review of the phytochemistry and pharmacological activities of raphani semen. AB - The dried ripe seed of Raphanus sativus L., commonly known as radish seed (or Raphani Semen), is used as traditional Chinese medicine (TCM) to treat constipation, chronic tracheitis, and hypertension. The major active compounds in Raphani Semen are alkaloids, glucosinolates, brassinosteroids, and flavonoids. Fatty acids are its main nutritional contents. Raphani Semen has been demonstrated to have beneficial effects on hypertension, obesity, diabetes mellitus, constipation, and cough. So far, there is no report about the adverse/toxic effects of this herb on humans. However, Raphani Semen processed by roasting was reported to exhibit some adverse effects on mice. Additionally, erucic acid, the main fatty acid in Raphani Semen, was shown to enhance the toxicity of doxorubicin. Thus, Raphani Semen has a potential risk of causing toxicity and drug interaction. In summary, Raphani Semen is a valuable TCM herb with multiple pharmacological effects. More studies on Raphani Semen could help better understand its pharmacological mechanisms so as to provide clear scientific evidence to explain its traditional uses, to identify its therapeutic potential on other diseases, and to understand its possible harmful effects. PMID- 23935671 TI - Ginsenoside RK3 Prevents Hypoxia-Reoxygenation Induced Apoptosis in H9c2 Cardiomyocytes via AKT and MAPK Pathway. AB - Reperfusion therapy is widely utilized for acute myocardial infarction (AMI), but further injury induced by rapidly initiating reperfusion of the heart is often encountered in clinical practice. Ginsenoside RK3 (RK3) is reportedly present in the processed Radix notoginseng that is often used as a major ingredient of the compound preparation for ischemic heart diseases. This study aimed to investigate the possible protective effect of RK3 against hypoxia-reoxygenation (H/R) induced H9c2 cardiomyocytes damage and its underlying mechanisms. Our results showed that RK3 pretreatment caused increased cell viability and decreased levels of LDH leakage compared with the H/R group. Moreover, RK3 pretreatment inhibited cell apoptosis, as evidenced by decreased caspase-3 activity, TUNEL-positive cells, and Bax expression, as well as increased Bcl-2 level. Further mechanism investigation revealed that RK3 prevented H9c2 cardiomyocytes injury and apoptosis induced by H/R via AKT/Nrf-2/HO-1 and MAPK pathways. These observations indicate that RK3 has the potential to exert cardioprotective effects against H/R injury, which might be of great importance to clinical efficacy for AMI treatment. PMID- 23935672 TI - Isoflavonoid-Rich Flemingia macrophylla Extract Attenuates UVB-Induced Skin Damage by Scavenging Reactive Oxygen Species and Inhibiting MAP Kinase and MMP Expression. AB - In this study, we investigated the antioxidant activity and anti-photoaging properties of an extract of Flemingia macrophylla, a plant rich in isoflavonoid content. Pretreatment of fibroblasts with Flemingia macrophylla extract (FME) inhibited elastase activity, promoted the protein expression of type I procollagen, and attenuated the phosphorylation of mitogen-activated protein (MAP) kinase and the protein expression of matrix-metalloproteinase- (MMP-) 1, 3, and 9. The IC50 values were 2.1 MU g/mL for DPPH radical scavenging ability, 366.8 MU g/mL for superoxide anion scavenging ability, 178.9 MU g/mL for hydrogen peroxide scavenging ability, and 230.9 MU g/mL for hydroxyl radical scavenging ability. Also, exposure of erythrocytes to various concentrations of FME (50-500 MU g/mL) resulted in a dose- and time-dependent inhibition of AAPH induced hemolysis. In human fibroblasts, FME at 10 MU g/mL was shown to be a potent scavenger of UV-induced reactive oxygen species (ROS). The antioxidant and anti-photoaging properties of FME make it an ideal anti-intrinsic aging and anti photoaging agent. PMID- 23935673 TI - Renal Protective Role of Xiexin Decoction with Multiple Active Ingredients Involves Inhibition of Inflammation through Downregulation of the Nuclear Factor kappaB Pathway in Diabetic Rats. AB - In Chinese medicine, Xiexin decoction (XXD) has been used for the clinical treatment of diabetes for at least 1700 years. The present study was conducted to investigate the effective ingredients of XXD and their molecular mechanisms of antidiabetic nephropathy in rats. Rats with diabetes induced by high-fat diet and streptozotocin were treated with XXD extract for 12 weeks. XXD significantly improved the glucolipid metabolism disorder, attenuated albuminuria and renal pathological changes, reduced renal advanced glycation end-products, inhibited receptor for advanced glycation end-product and inflammation factors expression, suppressed renal nuclear factor- kappa B pathway activity, and downregulated renal transforming growth factor- beta 1. The concentrations of multiple components in plasma from XXD were determined by liquid chromatography and tandem mass spectrometry. Pharmacokinetic/pharmacodynamic analysis using partial least square regression revealed that 8 ingredients of XXD were responsible for renal protective effects via actions on multiple molecular targets. Our study suggests that the renal protective role of XXD with multiple effective ingredients involves inhibition of inflammation through downregulation of the nuclear factor- kappa B pathway, reducing renal advanced glycation end-products and receptor for advanced glycation end-product in diabetic rats. PMID- 23935674 TI - Protective Effect of Punica granatum L. against Serum/Glucose Deprivation-Induced PC12 Cells Injury. AB - The discovery and development of natural products with potent antioxidant, anti inflammatory, and antiapoptotic properties have been one of the most interesting and promising approaches in the search for the treatment of many neurodegenerative diseases including ischemic stroke. Serum/glucose deprivation (SGD) has served as an excellent in vitro model for the understanding of the molecular mechanisms of neuronal damage during ischemia and for the development of neuroprotective drugs against ischemia-induced brain injury. Recent studies suggested that pomegranate (Punica granatum L.) or its active constituents exert pharmacological actions such as antioxidant, anti-inflammatory, and neuroprotective properties. Therefore, in this study we investigated the possible protective effects of different extracts of pomegranate against SGD-induced PC12 cells injury. Initially, the cells were pretreated with different concentrations of pulp hydroalcoholic extract (PHE), pulp aqueous extract (PAE) and pomegranate juice (PJ) for 2 h and then deprived of serum/glucose (SGD) for 6 and 12 h. SGD caused a significant reduction in cell viability (measured by the MTT assay) after 6 and 12 h, as compared with control cells (P < 0.001). Pretreatment with PHE, PAE, and PJ significantly and concentration-dependently increased cell viability following SGD insult for 6 and 12 h. A significant increase in DNA damage (measured by the comet assay) was seen in nuclei of cells following SGD for 12 h (P < 0.001). In control groups, no significant difference was seen in DNA damage between PHE, PAE, and PJ-pretreated and vehicle-pretreated PC12 cells (P > 0.05). PHE, PAE, and PJ pretreatment resulted in a significant decrease in DNA damage following ischemic insult (P < 0.001). This suppression of DNA damage by PHE, PAE and PJ was found to be concentration dependent. These data indicate that there is a cytoprotective property in PHE, PAE, and PJ under SGD condition in PC12 cells, suggesting that pomegranate has the potential to be used as a new therapeutic strategy for neurodegenerative disorders. PMID- 23935676 TI - Antiviral Protein of Momordica charantia L. Inhibits Different Subtypes of Influenza A. AB - The new antiviral activity of the protein extracted from Momordica charantia was determined with different subtypes of influenza A. The protein was purified from the seed of M. charantia using an anion exchanger and a Fast Protein Liquid Chromatography (FPLC) system. At the concentration of 1.401 mg/mL, the protein did not exhibit cytotoxicity in Madin-Darby canine kidney cells (MDCK) but inhibited 1 * 10(5) FFU influenza A/PR/8/34 H1N1 virus at 56.50%, 65.72%, and 100% inhibition by the protein treated before the virus (pretreated), the protein treated alongside with the virus (simultaneously treated), and the protein treated after the virus (posttreated) during incubation, respectively. Using 5, 25, and 100 TCID50 of influenza A/New Caledonia/20/99 H1N1, A/Fujian/411/01 H3N2 and A/Thailand/1(KAN-1)/2004 H5N1, the IC50 was calculated to be 100, 150, and 200; 75, 175, and 300; and 40, 75, and 200 MU g/mL, respectively. Our present finding indicated that the plant protein inhibited not only H1N1 and H3N2 but also H5N1 subtype. As a result of the broad spectrum of its antiviral activity, this edible plant can be developed as an effective therapeutic agent against various and even new emerging subtypes of influenza A. PMID- 23935675 TI - In Vitro Antileishmanial Activity of Essential Oil of Vanillosmopsis arborea (Asteraceae) Baker. AB - The search for new immunopharmacological chemical agents to treat various diseases caused by bacteria, fungi, and protozoa, such as leishmaniasis, for example, has led to the exploration of potential products from plant species and their main active ingredients. Antimonial drugs are the current treatment for leishmaniasis. These drugs cause major side effects and frequent discontinuation of treatment. In this study, we evaluated the in vitro leishmanicidal activity of essential oil of Vanillosmopsis arborea (VAEO) and its major compound alpha bisabolol against Leishmania amazonensis. The essential oil and alpha -bisabolol showed activity against promastigotes (IC50 7.35 and 4.95 MU g/mL resp.) and intracellular amastigotes (IC50 12.58 and 10.70 MU g/mL, resp.). Neither product showed any cytotoxicity on treated macrophages. The ultrastructural analysis of promastigotes incubated with VAEO or alpha -bisabolol at 30 MU g/mL, showed morphological changes with the accumulation of vesicles electrodense lipid inclusions. The results give evidence that both VAEO and alpha -bisabolol have potential as new therapeutic agents against leishmaniasis. PMID- 23935677 TI - Qi-shen-yi-qi dripping pills for the secondary prevention of myocardial infarction: a randomised clinical trial. AB - Background. Several types of drugs have been recommended for the secondary prevention of myocardial infarction (MI). However, these conventional strategies have several limitations, such as low adherence, high cost, and side effects during long time use. Novel approaches to this problem are still needed. This trial aimed to test the effectiveness and safety of Qi-Shen-Yi-Qi Dripping Pills (QSYQ), a multi-ingredient Chinese patent medicine, for the secondary prevention of MI. Methods and Findings. A total of 3505 eligible patients were randomly assigned to QSYQ group (1746 patients) or aspirin group (1759). Patients took their treatments for 12 months. The final follow-up visit took place 6 months after the end of the trial drugs. The 12-month and 18-month estimated incidences of the primary outcome were 2.98% and 3.67%, respectively, in the QSYQ group. The figures were 2.96% and 3.81% in the aspirin group. No significant difference was identified between the groups. Conclusions. This trial did not show significant difference of primary and secondary outcomes between aspirin and QSYQ in patients who have had an MI. Though inconclusive, the result suggests that QSYQ has similar effects to aspirin in the secondary prevention of MI. PMID- 23935678 TI - An exploration of the needling depth in acupuncture: the safe needling depth and the needling depth of clinical efficacy. AB - Objective. To explore the existing scientific information regarding safe needling depth of acupuncture points and the needling depth of clinical efficacy. Methods. We searched the PubMed, EMBASE, Cochrane, Allied and Complementary Medicine (AMED), The National Center for Complementary and Alternative Medicine (NCCAM), and China National Knowledge Infrastructure (CNKI) databases to identify relevant monographs and related references from 1991 to 2013. Chinese journals and theses/dissertations were hand searched. Results. 47 studies were recruited and divided into 6 groups by measuring tools, that is, MRI, in vivo evaluation, CT, ultrasound, dissected specimen of cadavers, and another group with clinical efficacy. Each research was analyzed for study design, definition of safe depth, and factors that would affect the measured depths. Depths of clinical efficacy were discussed from the perspective of de-qi and other clinical observations. Conclusions. Great inconsistency in depth of each point measured from different subject groups and tools exists. The definition of safe depth should be established through standardization. There is also lack of researches to compare the clinical efficacy. A well-designed clinical trial selecting proper measuring tools to decide the actual and advisable needling depth for each point, to avoid adverse effects or complications and promote optimal clinical efficacy, is a top priority. PMID- 23935679 TI - Combination of Chinese Herbal Medicines and Conventional Treatment versus Conventional Treatment Alone in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention (5C Trial): An Open-Label Randomized Controlled, Multicenter Study. AB - Aims. To evaluate the efficacy of Chinese herbal medicines (CHMs) plus conventional treatment in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). Methods and Results. Participants (n = 808) with ACS who underwent PCI from thirteen hospitals of mainland China were randomized into two groups: CHMs plus conventional treatment group (treatment group) or conventional treatment alone group (control group). All participants received conventional treatment, and participants in treatment group additionally received CHMs for six months. The primary endpoint was the composite of cardiac death, nonfatal recurrent MI, and ischemia-driven revascularization. Secondary endpoint was the composite of readmission for ACS, stroke, or congestive heart failure. The safety endpoint involved occurrence of major bleeding events. The incidence of primary endpoint was 2.7% in treatment group versus 6.2% in control group (HR, 0.43; 95% CI, 0.21 to 0.87; P = 0.015). The incidence of secondary endpoint was 3.5% in treatment group versus 8.7% in control group (HR, 0.39; 95% CI, 0.21 to 0.72; P = 0.002). No major bleeding events were observed in any participant. Conclusion. Treatment with CHMs plus conventional treatment further reduced the occurrence of cardiovascular events in patients with ACS after PCI without increasing risk of major bleeding. PMID- 23935680 TI - Sargassum fulvellum Protects HaCaT Cells and BALB/c Mice from UVB-Induced Proinflammatory Responses. AB - Ultraviolet (UV) radiation has been reported to induce cutaneous inflammation such as erythema and edema via induction of proinflammatory enzymes and mediators. Sargassum fulvellum is a brown alga of Sargassaceae family which has been demonstrated to exhibit antipyretic, analgesic, antiedema, antioxidant, antitumor, fibrinolytic, and hepatoprotective activities. The purpose of this study is to investigate anti-inflammatory effects of ethylacetate fraction of ethanol extract of Sargassum fulvellum (SFE-EtOAc) in HaCaT keratinocytes and BALB/c mice. In HaCaT cells, SFE-EtOAc effectively inhibited UVB-induced cytotoxicity (60 mJ/cm(2)) and the expression of proinflammatory proteins such as cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS). Furthermore, SFE-EtOAc significantly reduced UVB induced production of proinflammatory mediators including prostaglandin E2 (PGE2) and nitric oxide (NO). In BALB/c mice, topical application of SFE-EtOAc prior to UVB irradiation (200 mJ/cm(2)) effectively suppressed the UVB-induced protein expression of COX-2, iNOS, and TNF-alpha and subsequently attenuated generation of PGE2 and NO as well. In another experiment, SFE-EtOAc pretreatment suppressed UVB-induced reactive oxygen species production and exhibited an antioxidant potential by upregulation of antioxidant enzymes such as catalase and Cu/Zn superoxide dismutase in HaCaT cells. These results suggest that SFE-EtOAc could be an effective anti-inflammatory agent protecting against UVB irradiation induced skin damages. PMID- 23935681 TI - Chinese herbal medicine banxiaxiexin decoction treating diabetic gastroparesis: a systematic review of randomized controlled trials. AB - Objective. To assess the current clinical evidence of Banxiaxiexin decoction for diabetic gastroparesis (DGP). Methods. Electronic databases were searched until December 2012. No language limitations were applied. We included RCTs using Banxiaxiexin decoction/modified Banxiaxiexin decoction for DGP. No restriction for the control group except acupuncture. Applying clinical effective rate as the main outcome index. Data extraction, analyses and quality assessment were conducted according to the Cochrane review standards. Results. 16 RCTs involving 1302 patients were finally identified, and the methodological quality was evaluated as generally low. The data showed that the effect of Banxiaxiexin decoction (BXXD) for DGP was superior to the control group (n = 1302, RR 1.23, 95% CI 1.17 to 1.29, Z = 8.04, P < 0.00001). Only one trial recorded adverse events, no obvious adverse event occurred. Conclusions. Banxiaxiexin decoction could regain the gastric emptying rate and improve diabetic gastrointestinal symptoms. However, the methodological quality of included studies is low, and long term efficacy and safety are still uncertain, which indicates that the findings above should be read with caution. Thereby, well-designed, large-scale, and high-quality randomized controlled clinical trials with scientific rigor are warranted for stronger evidence in future research. PMID- 23935683 TI - Composition and Antioxidant Activity of Geopropolis Collected by Melipona subnitida (Jandaira) Bees. AB - An investigation of the geopropolis collected by Melipona subnitida (jandaira) stingless bee led to the isolation and characterization of two phenylpropanoids, 6-O-p-coumaroyl-D-galactopyranose (1) and 6-O-cinnamoyl-1-O-p-coumaroyl- beta -D glucopyranose (2), and seven flavonoids, 7-O-methyl-naringenin (3), 7-O-methyl aromadendrin (4), 7,4'-di-O-methyl aromadendrin (5), 4'-O-methyl kaempferol (6), 3-O-methyl quercetin (7), 5-O-methyl aromadendrin (8), and 5-O-methyl kaempferol (9). The structure of the new phenylpropanoid (1) was established from IR, LC-ESI MS, and NMR spectral data, including 2D NMR experiments. The extract and fractions demonstrated significant antioxidant activity in DPPH, ABTS, and beta carotene/linoleic acid tests. PMID- 23935682 TI - Effect of Dietary Cocoa Tea (Camellia ptilophylla) Supplementation on High-Fat Diet-Induced Obesity, Hepatic Steatosis, and Hyperlipidemia in Mice. AB - Recent studies suggested that green tea has the potential to protect against diet induced obesity. The presence of caffeine within green tea has caused limitations. Cocoa tea (Camellia ptilophylla) is a naturally decaffeinated tea plant. To determine whether cocoa tea supplementation results in an improvement in high-fat diet-induced obesity, hyperlipidemia and hepatic steatosis, and whether such effects would be comparable to those of green tea extract, we studied six groups (n = 10) of C57BL/6 mice that were fed with (1) normal chow (N); (2) high-fat diet (21% butterfat + 0.15% cholesterol, wt/wt) (HF); (3) a high-fat diet supplemented with 2% green tea extract (HFLG); (4) a high-fat diet supplemented with 4% green tea extract (HFHG); (5) a high-fat diet supplemented with 2% cocoa tea extract (HFLC); and (6) a high-fat diet supplemented with 4% cocoa tea extract (HFHC). From the results, 2% and 4% dietary cocoa tea supplementation caused a dose-dependent decrease in (a) body weight, (b) fat pad mass, (c) liver weight, (d) total liver lipid, (e) liver triglyceride and cholesterol, and (f) plasma lipids (triglyceride and cholesterol). These data indicate that dietary cocoa tea, being naturally decaffeinated, has a beneficial effect on high-fat diet-induced obesity, hepatomegaly, hepatic steatosis, and elevated plasma lipid levels in mice, which are comparable to green tea. The present findings have provided the proof of concept that dietary cocoa tea might be of therapeutic value and could therefore provide a safer and cost effective option for patients with diet-induced metabolic syndrome. PMID- 23935684 TI - The Evaluation of CP-001 (a Standardized Herbal Mixture of Houttuynia cordata, Rehmannia glutinosa, Betula platyphylla, and Rubus coreanus) for Cytochrome P450 Related Herb-Drug Interactions. AB - In the present study, the effect of CP-001, a standardized herbal mixture of Houttuynia cordata, Rehmannia glutinosa, Betula platyphylla, and Rubus coreanus, on cytochrome P450 (CYP) enzyme-mediated drug metabolism was investigated in vitro to evaluate the potential for herb-drug interactions. CP-001 was tested at concentrations of 1, 3, 10, 30, and 100 MU g/mL. A CYP-specific substrate mixture was incubated with CP-001 in human liver microsomes, and the metabolites generated by each CYP-specific metabolic reaction were measured by liquid chromatography-tandem mass spectrometry. CP-001 seemed to slightly inhibit some CYP isozymes, but the IC50 values for all CYP isozymes were greater than 100 MU g/mL. Furthermore, CP-001 did not exhibit time-dependent CYP inhibitory activities, indicating that it does not act as a mechanism-based inactivator of CYP enzymes. In conclusion, the effects of CP-001 on CYP isozyme activities were negligible at the concentrations tested. Therefore, the likelihood of herbal mixture-drug interaction is considered minimal. PMID- 23935685 TI - Effects of Moxibustion Temperature on Blood Cholesterol Level in a Mice Model of Acute Hyperlipidemia: Role of TRPV1. AB - Objectives. To compare the effects of moxibustion at two different temperatures (38 degrees C and 46 degrees C) on the blood cholesterol level in a mice model of acute hyperlipidemia, to detect the different expression levels of transient receptor potential vanilloid subfamily 1 (TRPV1) in the dorsal root ganglions of the wild mice, and to explore the correlation between TRPV1 and moxibustion's cholesterol-lowering effects. Method. Two different mice models were used: C57BL/6J wild type (WT) and TRPV1 gene knockout (TRPV1-/-). Each model was randomly divided into control group and model group with three subgroups after acute hyperlipidemia was established: model control group, 38 degrees C moxibustion group, and 46 degrees C moxibustion group. The mice in 38 degrees C group and 46 degrees C group were subject to moxibustion. After the therapy, the cholesterol concentration in serum was measured, and the expression of TRPV1 was quantified. Results. In WT mice, moxibustion caused a decrease in blood cholesterol level and upregulation of TRPV1 at the mRNA level, which was significantly greater in the 46 degrees C group. In contrast, in TRPV1-/- mice, the differences of cholesterol-lowering effects of moxibustion were lost. Conclusions. Temperature is one of the important factors affecting the effects of moxibustion, and the cholesterol -lowering effect of moxibustion is related to the activation of TRPV1. PMID- 23935686 TI - Visualized characterization for cerebral response of acupuncture deqi: paradox underway. AB - Acupuncture as an oriental natural healing therapy with prolonged history has been extensively utilized in the management of great numbers of disorders. Deqi, a renowned acupuncture needling sensation, is profoundly regarded as the predictor and also the prerequisite of a preferable acupuncture treatment efficacy. Till now, there is still no consistency being reached towards the mechanism of acupuncture Deqi as a result of the discrepancy for publicly acknowledged evidence. Recent visualized research on Deqi using modern technologies has demonstrated possible central mechanism towards it. However, there is a conspicuous paradox underway in the research of cerebral response to acupuncture Deqi. This paper provided a view of up-to-date studies using visualized tools to characterize the brain response to acupuncture Deqi, such as functional magnetic resonance imaging (fMRI) and positron emission tomography/computed tomography (PET/CT). The paradox was extruded to highlight certain reasons from a TCM view. It is hypothesized that acupoints located at different dermal sites, state of participant, and needling manipulation can all contribute to the current paradox. Hence, further studies on acupuncture Deqi should pay more attention to the strategy of experiment design with generalized measurement, valid sham control methods, and more to subjects in diseased condition. PMID- 23935687 TI - Dried Ginger (Zingiber officinalis) Inhibits Inflammation in a Lipopolysaccharide Induced Mouse Model. AB - Objectives. Ginger rhizomes have a long history of human use, especially with regards to their anti-inflammatory properties. However, the mechanisms by which ginger acts on lipopolysaccharide-(LPS-)induced inflammation have not yet been identified. We investigated the anti-inflammatory effects of dried Zingiber officinalis (DZO) on LPS-induced hepatic injury. Methods. ICR mice were given a DZO water extract (100, 1000 mg/kg) orally for three consecutive days. On the third day, they were administered by LPS intraperitoneally. To investigate the anti-inflammatory effects of DZO, histological, cytokine expression, and protein factor analyses were performed. Results. Oral administration of DZO significantly reduced pathological changes in the liver and proinflammatory cytokines including interferon-(IFN-) gamma and interleukin-(IL-)6 in the serum. In addition, DZO inhibited LPS-induced NF- kappa B activation by preventing degradation of the I kappa B- alpha , as well as the phosphorylation of ERK1/2, SAPK/JNK, and p38 MAPKs. These were associated with a decrease in the expression of inducible nitric oxide synthase (iNOS) and cyclooxyenase-2 (COX-2). Conclusions. Our data provide evidence for the hepatoprotective mechanisms of DZO as an anti inflammatory effect. Furthermore, use of DZO to treat could provide therapeutic benefits in clinical settings. PMID- 23935688 TI - Specific Dioscorea Phytoextracts Enhance Potency of TCL-Loaded DC-Based Cancer Vaccines. AB - Dioscorea tuber phytoextracts can confer immunomodulatory activities ex vivo and improve regeneration of bone marrow cells in vivo. In present study, we evaluated specific Dioscorea phytoextracts for use ex vivo as a bone-marrow-derived dendritic cell- (DC-) based vaccine adjuvant for cancer immunotherapy. Fractionated Dioscorea extracts (DsII) were assayed for their effect on maturation and functions of DC ex vivo and antimelanoma activity of DC-based vaccine in vivo. The phytoextract from 50-75% ethanol-precipitated fraction of Dioscorea alata var. purpurea Tainung no. 5 tuber, designated as DsII-TN5, showed a strong augmentation of tumor cell lysate- (TCL-) loaded DC-mediated activation of T-cell proliferation. DsII-TN5 stimulated the expression of CD40, CD80, CD86, and IL-1 beta in TCL-loaded DCs and downregulated the expression of TGF- beta 1. DC vaccines prepared by a specific schema (TCL (2 h) + LPS (22 h)) showed the strongest antitumor activity. DsII-TN5 as a DC vaccine adjuvant showed strong antimelanoma activity and reduced myeloid-derived suppressor cell (MDSC) population in tested mice. DsII-TN5 can also activate DCs to enhance Th1- and Th17-related cytokine expressions. Biochemical analysis showed that DsII-TN5 consists mainly of polysaccharides containing a high level (53%) of mannose residues. We suggest that DsII-TN5 may have potential for future application as a potent, cost-effective adjuvant for DC-based cancer vaccines. PMID- 23935689 TI - Pathological Changes in Internal Organs after Blocking Low Hydraulic Resistance Channels along the Stomach Meridian in Pigs. AB - Objective. The correlation between meridians and organs (Zang-fu) is an important aspect of meridian theory. The objective of this paper is to investigate the pathological changes in the organs resulting from blocking low hydraulic resistance channel (LHRC) along the stomach meridian by injecting gel in pigs so as to offer some insight into the correlation between meridians and internal organs. Methods. Four white piglets and twelve black minipigs were divided into four batches and were observed in different periods. Each batch included two pairs of pigs and each pair matched two pigs with similar conditions among which gel was injected into 6~8 low hydraulic resistance points along the the stomach meridian in the experimental pig and the same amount of saline was injected into the same points in the control pig. The state of stomach and intestine was observed 6~10 weeks after the blocking model was developed. Results. The results showed that there were bloated stomach or/and intestine in all the experimental pigs while there were normal states in seven control pigs except one dead during the experiment. Conclusion. The findings confirmed that the blockage of LHRC along the stomach meridian can influence the state of stomach and intestine, leading to a distension on stomach or/and intestine. PMID- 23935690 TI - Trypanocidal activity of thioamide-substituted imidazoquinolinone: electrochemical properties and biological effects. AB - Three thioamide-substituted imidazoquinolinone, which possess a heterocyclic center similar to tryptanthrin and are named C1, C2, and C3, were studied regarding (a) their in vitro anti-Trypanosoma cruzi activity, (b) their cytotoxicity and electrochemical behaviour, and (c) their effect on cell viability, redox state, and mitochondrial function. The assayed compounds showed a significant activity against the proliferative forms, but only C1 showed activity on the trypomastigote form (for C1, IC50 epi = 1.49 MUM; IC50 amas = 1.74 MUM; and IC50 try = 34.89 MUM). The presence of an antioxidant compound such as ascorbic acid or dithiotreitol induced a threefold increase in the antiparasitic activity, whereas glutathione had a dual effect depending on its concentration. Our results indicate that these compounds, which exhibited low toxicity to the host cells, can be reduced inside the parasite by means of the pool of low molecular weight thiols, causing oxidative stress and parasite death by apoptosis. The antiparasitic activity of the compounds studied could be explained by a loss of the capacity of the antioxidant defense system of the parasite to keep its intracellular redox state. C1 could be considered a good candidate for in vivo evaluation. PMID- 23935691 TI - Modulation of the expression of the proinflammatory IL-8 gene in cystic fibrosis cells by extracts deriving from olive mill waste water. AB - A persistent recruitment of neutrophils in the bronchi of cystic fibrosis (CF) patients contributes to aggravate the airway tissue damage, suggesting the importance of modulating the expression of chemokines, including IL-8 during the management of the CF patients. Polyphenols rich extracts derived from waste water from olive mill, obtained by a molecular imprinting approach, have been investigated in order to discover compounds able to reduce IL-8 expression in human bronchial epithelial cells (IB3-1 cells), derived from a CF patient with a DeltaF508/W1282X mutant genotype and stimulated with TNF-alpha. Initially, electrophoretic mobility shift assays (EMSAs) were performed to determine whether the different active principles were able to inhibit the binding between transcription factor (TF) NF-kappaB and DNA consensus sequences. Among different representative active principles present in the extract, three compounds were selected, apigenin, oleuropein, and cyanidin chloride, which displayed remarkable activity in inhibiting NF-kappaB/DNA complexes. Utilizing TNF-alpha-treated IB3-1 cells as experimental model system, we demonstrated that apigenin and cyanidin chloride are able to modulate the expression of the NF-kappaB-regulated IL-8 gene, while oleuropein showed no effect in regulating the expression of the gene IL-8. PMID- 23935692 TI - Efficacy and safety of a chinese herbal formula (invigorating kidney and strengthening spleen) in chronic hepatitis B virus carrier: results from a multicenter, randomized, double-blind, and placebo-controlled trial. AB - A Chinese Herbal Formula (CHF) has acquired a certain therapeutic effect on chronic HBV infection. To assess the efficacy and safety of CHF on HBV replication in chronic HBV carriers, we performed a randomized, double-blind, and placebo-controlled trial involving patients from 16 centers. A total of 300 confirmed chronic HBV carriers were randomized at baseline in a ratio of 2 : 1 to receive either CHF or placebo for 52 weeks. The results showed that a greater proportion of CHF than placebo treated patients achieved virological response at week 52; the mean decline of serum HBsAg levels in the CHF group dropped more obviously than that in the control group at all stages of the treatment; however, the rates of HBeAg loss and seroconversion had no difference between the two groups. Meanwhile, were presented significant increases in IFN- gamma ; IL-2 levels and reductions in IL-4 and IL-10 levels in the treatment group compared to the control group at week 52. There were no drug-related serious adverse events. In conclusion, the treatment with 52-week CHF is safe and effective in inhibiting HBV replication in chronic HBV carriers. The ability of the compound to modulate host immune function probably contributed to this effect. PMID- 23935693 TI - Curative Effects of Thiacremonone against Acetaminophen-Induced Acute Hepatic Failure via Inhibition of Proinflammatory Cytokines Production and Infiltration of Cytotoxic Immune Cells and Kupffer Cells. AB - High doses of acetaminophen (APAP; N-acetyl-p-aminophenol) cause severe hepatotoxicity after metabolic activation by cytochrome P450 2E1. This study was undertaken to examine the preventive effects of thiacremonone, a compound extracted from garlic, on APAP-induced acute hepatic failure in male C57BL/6J. Mice received with 500 mg/kg APAP after a 7-day pretreatment with thiacremonone (10-50 mg/kg). Thiacremonone inhibited the APAP-induced serum ALT and AST levels in a dose-dependent manner, and markedly reduced the restricted area of necrosis and inflammation by administration of APAP. Thiacremonone also inhibited the APAP induced depletion of intracellular GSH, induction of nitric oxide, and lipid peroxidation as well as expression of P450 2E1. After APAP injection, the numbers of Kupffer cells, natural killer cells, and cytotoxic T cells were elevated, but the elevated cell numbers in the liver were reduced in thiacremonone pretreated mice. The expression levels of I-309, M-CSF, MIG, MIP-1 alpha , MIP-1 beta , IL 7, and IL-17 were increased by APAP treatment, which were inhibited in thiacremonone pretreated mice. These data indicate that thiacremonone could be a useful agent for the treatment of drug-induced hepatic failure and that the reduction of cytotoxic immune cells as well as proinflammatory cytokine production may be critical for the prevention of APAP-induced acute liver toxicity. PMID- 23935694 TI - The improvement of emotion and attention regulation after a 6-week training of focused meditation: a randomized controlled trial. AB - Self-regulatory trainings can be an effective complementary treatment for mental health disorders. We investigated the effects of a six-week-focused meditation training on emotion and attention regulation in undergraduates randomly allocated to a meditation, a relaxation, or a wait-list control group. Assessment comprised a discrimination task that investigates the relationship between attentional load and emotional processing and self-report measures. For emotion regulation, results showed greater reduction in emotional interference in the low attentional load condition in meditators, particularly compared to relaxation. Only meditators presented a significant association between amount of weekly practice and the reduction in emotion interference in the task and significantly reduced image ratings of negative valence and arousal, perceived anxiety and difficulty during the task, and state and trait-anxiety. For attention regulation, response bias during the task was analyzed through signal detection theory. After training, meditation and relaxation significantly reduced bias in the high attentional load condition. Importantly, there was a dose-response effect on general bias: the lowest in meditation, increasing linearly across relaxation and wait-list. Only meditators reduced omissions in a concentrated attention test. Focused meditation seems to be an effective training for emotion and attention regulation and an alternative for treatments in the mental health context. PMID- 23935695 TI - Auricular acupuncture with laser. AB - Auricular acupuncture is a method which has been successfully used in various fields of medicine especially in the treatment of pain relief. The introduction of lasers especially low-level lasers into medicine brought besides the already existing stimulation with needles and electricity an additional technique to auricular acupuncture. This literature research looks at the historical background, the development and the anatomical and neurological aspects of auricular acupuncture in general and auricular laser acupuncture in detail. Preliminary scientific findings on auricular acupuncture with laser have been described in detail and discussed critically in this review article. The results of the studies have shown evidence of the effect of auricular laser acupuncture. However, a comparison of these studies was impossible due to their different study designs. The most important technical as well as study parameters were described in detail in order to give more sufficient evidence and to improve the quality of future studies. PMID- 23935696 TI - Comorbidity of depression and anxiety: association with poor quality of life in type 1 and 2 diabetic patients. AB - BACKGROUND: Diabetes is associates with depression and impairment in Quality of Life (QoL). OBJECTIVE: The objective is to define the frequencies of depressive and anxiety symptoms in a sample of patients diagnosed with type 1 and 2 diabetes, the amount of impairment of QoL and the weight of depression and anxiety in determining the QoL in such of patients. METHODS: A total of 210 patients were divided into two groups (type 1 and type 2). Patients completed the HADS and WHOQoL-bref. RESULTS: Groups showed a high prevalence of anxiety (type 1 = 60%, type 2 = 43.8%) and depression (type 1 = 52.4%, type 2 = 38.1%), both measures were significantly higher (p < 0.05) in diabetes type 1 patients. Type 1 patients also showed a QoL in the overall assessment and the physical, psychological and social relations domains. In both Type 1 and 2 diabetes poor QoL was found associated by anxiety and depression comorbidity. CONCLUSION: In overall diabetes patients depression and anxiety seems to be a determinant of poor QoL. PMID- 23935697 TI - Which drug for which patient? Is there a fluoxetine responding versus a bupropion responding personality profile? AB - This paper proposes that a certain premorbid personality type - that of hard driving, achievement-oriented, often exercise-oriented individuals - correlates with bupropion response; conversely, patients without these premorbid traits and whose depression is marked by mood swings, irritability and rumination are likely fluoxetine responders. The authors developed the Fluoxetine Bupropion Assessment Scale (FBAS), a 10-question, self-administered rating scale, to assess these traits and hypothesized that its use would improve outcomes. A Marriage and Family Therapist (MFT) and a Registered Nurse/Nurse Practitioner (RN/NP) retrospectively reviewed 72 charts from one psychiatrist's office for two time periods: before and after the psychiatrist utilized the questionnaire to guide antidepressant selection (33 charts before and 39 charts after). Raters were blinded to the theory and to the treatment time period. On the basis of clinical information in the charts, they formulated Clinical Global Impression assessments of treatment response in patients with Beck Depression Inventory scores >=17 who were not on either drug at the time of intake, and who were prescribed either fluoxetine or bupropion. The data were in the direction of better results in the FBAS-guided group, particularly after adjusting for age, gender and marital status (efficacy p = 0.087). When global improvement data were combined into three groups describing treatment response (improved, minimal to no improvement, and worse) there were statistically significant better results (p = 0.047) in the FBAS-guided treatment group. Revision and validation of the questionnaire and a larger, randomized study seem indicated. PMID- 23935699 TI - Bayesian method with spatial constraint for retinal vessel segmentation. AB - A Bayesian method with spatial constraint is proposed for vessel segmentation in retinal images. The proposed model makes the assumption that the posterior probability of each pixel is dependent on posterior probabilities of their neighboring pixels. An energy function is defined for the proposed model. By applying the modified level set approach to minimize the proposed energy function, we can identify blood vessels in the retinal image. Evaluation of the developed method is done on real retinal images which are from the DRIVE database and the STARE database. The performance is analyzed and compared to other published methods using a number of measures which include accuracy, sensitivity, and specificity. The proposed approach is proved to be effective on these two databases. The average accuracy, sensitivity, and specificity on the DRIVE database are 0.9529, 0.7513, and 0.9792, respectively, and for the STARE database 0.9476, 0.7147, and 0.9735, respectively. The performance is better than that of other vessel segmentation methods. PMID- 23935700 TI - The influence of the specimen shape and loading conditions on the parameter identification of a viscoelastic brain model. AB - The mechanical properties of brain under various loadings have been reported in the literature over the past 50 years. Step-and-hold tests have often been employed to characterize viscoelastic and nonlinear behavior of brain under high rate shear deformation; however, the identification of brain material parameters is typically performed by neglecting the initial strain ramp and/or by assuming a uniform strain distribution in the brain samples. Using finite element (FE) simulations of shear tests, this study shows that these simplifications have a significant effect on the identified material properties in the case of cylindrical human brain specimens. Material models optimized using only the stress relaxation curve under predict the shear force during the strain ramp, mainly due to lower values of their instantaneous shear moduli. Similarly, material models optimized using an analytical approach, which assumes a uniform strain distribution, under predict peak shear forces in FE simulations. Reducing the specimen height showed to improve the model prediction, but no improvements were observed for cubic samples with heights similar to cylindrical samples. Models optimized using FE simulations show the closest response to the test data, so a FE-based optimization approach is recommended in future parameter identification studies of brain. PMID- 23935702 TI - Bayesian hierarchical modeling for categorical longitudinal data from sedation measurements. AB - We investigate a Bayesian hierarchical model for the analysis of categorical longitudinal data from sedation measurement for Magnetic Resonance Imaging (MRI) and Computerized Tomography (CT). Data for each patient is observed at different time points within the time up to 60 min. A model for the sedation level of patients is developed by introducing, at the first stage of a hierarchical model, a multinomial model for the response, and then subsequent terms are introduced. To estimate the model, we use the Gibbs sampling given some appropriate prior distributions. PMID- 23935701 TI - Research on calculation of the IOL tilt and decentration based on surface fitting. AB - The tilt and decentration of intraocular lens (IOL) result in defocussing, astigmatism, and wavefront aberration after operation. The objective is to give a method to estimate the tilt and decentration of IOL more accurately. Based on AS OCT images of twelve eyes from eight cases with subluxation lens after operation, we fitted spherical equation to the data obtained from the images of the anterior and posterior surfaces of the IOL. By the established relationship between IOL tilt (decentration) and the scanned angle, at which a piece of AS-OCT image was taken by the instrument, the IOL tilt and decentration were calculated. IOL tilt angle and decentration of each subject were given. Moreover, the horizontal and vertical tilt was also obtained. Accordingly, the possible errors of IOL tilt and decentration existed in the method employed by AS-OCT instrument. Based on 6-12 pieces of AS-OCT images at different directions, the tilt angle and decentration values were shown, respectively. The method of the surface fitting to the IOL surface can accurately analyze the IOL's location, and six pieces of AS-OCT images at three pairs symmetrical directions are enough to get tilt angle and decentration value of IOL more precisely. PMID- 23935703 TI - Computational methods in neuroengineering. PMID- 23935704 TI - Optimisation of ionic models to fit tissue action potentials: application to 3D atrial modelling. AB - A 3D model of atrial electrical activity has been developed with spatially heterogeneous electrophysiological properties. The atrial geometry, reconstructed from the male Visible Human dataset, included gross anatomical features such as the central and peripheral sinoatrial node (SAN), intra-atrial connections, pulmonary veins, inferior and superior vena cava, and the coronary sinus. Membrane potentials of myocytes from spontaneously active or electrically paced in vitro rabbit cardiac tissue preparations were recorded using intracellular glass microelectrodes. Action potentials of central and peripheral SAN, right and left atrial, and pulmonary vein myocytes were each fitted using a generic ionic model having three phenomenological ionic current components: one time-dependent inward, one time-dependent outward, and one leakage current. To bridge the gap between the single-cell ionic models and the gross electrical behaviour of the 3D whole-atrial model, a simplified 2D tissue disc with heterogeneous regions was optimised to arrive at parameters for each cell type under electrotonic load. Parameters were then incorporated into the 3D atrial model, which as a result exhibited a spontaneously active SAN able to rhythmically excite the atria. The tissue-based optimisation of ionic models and the modelling process outlined are generic and applicable to image-based computer reconstruction and simulation of excitable tissue. PMID- 23935705 TI - A local region of interest imaging method for electrical impedance tomography with internal electrodes. AB - Electrical Impedance Tomography (EIT) is a very attractive functional imaging method despite the low sensitivity and resolution. The use of internal electrodes with the conventional reconstruction algorithms was not enough to enhance image resolution and accuracy in the region of interest (ROI). We propose a local ROI imaging method with internal electrodes developed from careful analysis of the sensitivity matrix that is designed to reduce the sensitivity of the voxels outside the local region and optimize the sensitivity of the voxel inside the local region. We perform numerical simulations and physical measurements to demonstrate the localized EIT imaging method. In preliminary results with multiple objects we show the benefits of using an internal electrode and the improved resolution due to the local ROI image reconstruction method. The sensitivity is further increased by allowing the surface electrodes to be unevenly spaced with a higher density of surface electrodes near the ROI. Also, we analyse how much the image quality is improved using several performance parameters for comparison. While these have not yet been studied in depth, it convincingly shows an improvement in local sensitivity in images obtained with an internal electrode in comparison to a standard reconstruction method. PMID- 23935706 TI - Healthy Eating Strategies in the Workplace. AB - PURPOSE: There is a clear link between dietary behavior and a range of chronic diseases, and overweight and obesity constitute an indirect risk in relation to these diseases. The worksite is a central venue for influencing dietary behavior. The purpose of this paper is to provide an overview of workplace influences on worker dietary patterns. DESIGN/METHODOLOGY/APPROACH: The paper reviews the evidence of the effectiveness of dietary health promotion, and provides a brief overview of appropriate theoretical frameworks to guide intervention design and evaluation. The findings are illustrated through research examples. FINDINGS: Through case studies and published research, it is found that workplace dietary interventions are generally effective, especially fruit and vegetable interventions. There is less consistent evidence on the long term effectiveness of workplace weight management interventions, underscoring the need for further research in this area. This paper also reports evidence that changes in the work environment, including through health and safety programs, may contribute to enhancing the effectiveness of workplace health promotion, including dietary interventions. Organizational factors such as work schedule may also influence dietary patterns. The social ecological model, the social contextual model and political process approach are presented as exemplar conceptual models that may be useful when designing or assessing the effects of workplace health promotion. ORIGINALITY/VALUE: Using the worksite as setting for influencing health by influencing dietary patterns holds considerable promise and may be instrumental in reducing workers' risk of chronic diseases. PMID- 23935707 TI - Impulse response and Modulation Transfer Function analysis for Shift-And-Add and Back Projection image reconstruction algorithms in Digital Breast Tomosynthesis (DBT). AB - Breast cancer is second only to lung cancer as the leading cause of non preventable cancer death in women. Digital Breast Tomosynthesis (DBT) is a promising technique to improve early breast cancer detection. In this paper, we present the impulse response and Modulation Transfer Function (MTF) analysis to quantitatively compare Shift-And-Add (SAA) and point-by-point Back Projection (BP) three-dimensional image reconstruction algorithms in DBT. A Filtered Back Projection (FBP) deblurring algorithm based on point-by-point BP was used to demonstrate deblurred tomosynthesis images. PMID- 23935709 TI - Mucinous cystadenocarcinoma of the appendix in which contrast-enhanced ultrasonography was useful for assessing blood flow in a focal nodular lesion in the tumor cavity: A case report. AB - A 63-year-old woman was admitted to hospital with pain in the right lower quadrant. Abdominal computed tomography (CT) revealed a 60-mm cystic mass at a site corresponding to the appendix. The mass wall on the appendicular ostium was thickened and enhanced by contrast, while calcification was observed in the mass wall on the appendicular tip. No projection was observed in the mass cavity. On abdominal ultrasonography (US), the mass wall on the appendicular ostium was thickened and projections were observed at two sites in the mass cavity. On contrast-enhanced US (CEUS), only one of these projections was enhanced. Based on the thickened and contrast-enhanced wall of the mass on the appendicular ostium on CT and US, as well as the contrast enhancement of a projection on US, the mass was diagnosed as mucinous cystadenocarcinoma of the appendix. Ileocecal resection was subsequently performed on day 10. A detailed examination of the surgical specimen revealed carcinoma cells in the mass wall on the appendicular ostium. The contrast-enhanced projection was identified as granulation tissue that had grown to come into contact with the tumor, while the non-contrast-enhanced projection was identified as solidified mucus. US enabled successful visualization of projections in the mass cavity that were not visible on abdominal CT. CEUS also proved useful for assessing blood flow in these projections. PMID- 23935708 TI - Trends in overweight and obesity over 22 years in a large adult population: the HUNT Study, Norway. AB - Some reports indicate that the obesity epidemic may be slowing down or halting. We followed body mass index (BMI) and waist circumference (WC) in a large adult population in Norway (n = 90 000) from 1984-1986 (HUNT1) through 1995-1997 (HUNT2) to 2006-2008 (HUNT3) to study whether this is occurring in Norway. Height and weight were measured with standardized and identical methods in all three surveys; WC was also measured in HUNT2 and HUNT3. In the three surveys, mean BMI increased from 25.3 to 26.5 and 27.5 kg m-2 in men and from 25.1 to 26.2 and 26.9 kg m-2 in women. Increase in prevalence of obesity (BMI >= 30 kg m-2) was greater in men (from 7.7 to 14.4 and 22.1%) compared with women (from 13.3 to 18.3 and 23.1%). In contrast, women had a greater increase in abdominal obesity (WC >= 102 cm for men and WC >= 88 cm for women). There was a continuous shift in the distribution curve of BMI and WC to the right, demonstrating that the increase in body weight was occurring in all weight groups, but the increase of obesity was greatest in the youngest age groups. Our data showed no signs of a halt in the increase of obesity in this representative Norwegian population. PMID- 23935710 TI - Non-invasive monitoring of blood pressure using the Philips Intellivue MP50 monitor cannot replace invasive blood pressure techniques in surgery patients under general anesthesia. AB - The Philips Intellivue MP50 monitor provides a method for non-invasive, near continuous blood pressure (BP) monitoring and is designed to be an alternative to direct intra-arterial BP (IABP) measurement. However, no studies have specifically compared non-invasive and invasive BP measurements using the monitor. The present retrospective study observed 515 patients undergoing surgery with general anesthesia, whose invasive (intra-radial, femoral or dorsalis pedis artery) and non-invasive (oscillometric) BP (NIBP) were monitored simultaneously using the monitor. These data were analyzed using correlations, regressions and Bland-Altman plots. The patients were placed in a supine position during surgery. The correlation data for invasive BP and NIBP measurements were: for intra-radial measurements, r2=0.51 (bias and precision, 11.04+/-15.22 and 14.76+/-11.64 mmHg, respectively) for systolic BP (SBP) and r2=0.27 (6.17+/-11.95 and 9.77+/-9.25 mmHg, respectively) for diastolic BP (DBP); for intra-femoral measurements: r2=0.57 (14.79+/-14.55 and 17.15+/-11.68 mmHg, respectively) for SBP and r2=0.45 (4.12+/-9.70 and 7.49+/-7.40 mmHg, respectively) for DBP; and for intra-dorsalis pedis measurements: r2=0.33 (13.00+/-16.81 and 17.34+/-12.28 mmHg, respectively) for SBP and r2=0.30 (0.17+/-11.27 and 8.44+/-7.46 mmHg, respectively) for DBP. According to this data, the NIBP measured by the Philips Intellivue MP50 monitor showed low positive correlations and poor agreement with the IABP, as calculated by Bland-Altman analysis. Therefore, the use of oscillometric BP measured by the monitor in surgery patients under general anesthesia is not generally recommended. PMID- 23935711 TI - Arrival time parametric imaging of the hemodynamic balance changes between the hepatic artery and the portal vein during deep inspiration, using Sonazoid enhanced ultrasonography: A case of Budd-Chiari syndrome. AB - This case report concerns a 40-year-old male who had previously been treated for an esophageal varix rupture, at the age of 30 years. The medical examination at that time revealed occlusion of the inferior vena cava in the proximity of the liver, leading to the diagnosis of the patient with Budd-Chiari syndrome. The progress of the patient was therefore monitored in an outpatient clinic. The patient had no history of drinking or smoking, but had suffered an epileptic seizure in 2004. The patient's family history revealed nothing of note. In February 2012, color Doppler ultrasonography (US) revealed a change in the blood flow in the right portal vein branch, from hepatopetal to hepatofugal, during deep inspiration. Arrival time parametric imaging (At-PI), using Sonazoid enhanced US, was subsequently performed to examine the deep respiration-induced changes observed in the hepatic parenchymal perfusion. US images captured during deep inspiration demonstrated hepatic parenchymal perfusion predominantly in red, indicating that the major blood supply was the hepatic artery. During deep expiration, the portal venous blood flow remained hepatopetal, and hepatic parenchymal perfusion was displayed predominantly in yellow, indicating that the portal vein was the major source of the blood flow. The original diagnostic imaging results were reproduced one month subsequently by an identical procedure. At-PI enabled an investigation into the changes that were induced in the hepatic parenchymal perfusion by a compensatory mechanism involving the hepatic artery. These changes occurred in response to a reduction in the portal venous blood flow, as is observed in the arterialization of hepatic blood flow that is correlated with the progression of chronic hepatitis C. It has been established that the peribiliary capillary plexus is important in the regulation of hepatic arterial blood flow. However, this case demonstrated that the peribiliary capillary plexus also regulates acute changes in portal venous blood flow, in addition to the chronic reduction in blood flow that is observed in patients with chronic hepatitis C. PMID- 23935712 TI - An implantable electrical stimulator used for peripheral nerve rehabilitation in rats. AB - This study evaluated an implantable electrical stimulator using a sciatic nerve injury animal model, and ethological, electrophysiological and histological assessments. Forty Sprague-Dawley rats were used in the study, and were subjected to crushing of the right sciatic nerve with a micro-vessel clamp. Electrical stimulators were implanted in twenty of the rats (the implantation group), while the remaining twenty rats were assigned to the control group. At three and six weeks following the surgery, the sciatic nerve function index (SFI) and the motor nerve conduction velocity (MCV) were demonstrated to be significantly higher in the implantation group compared with the control group (P<0.05). Histological analysis, using hematoxylin and eosin (H&E) staining, showed the typical pathological atrophy, and an assessment of the nerve that had been crushed revealed distal axonal breakdown in the control group. These results suggest that the implantable electrical stimulator was effective, and was suitable for implantation in a Sprague-Dawley rat model. PMID- 23935713 TI - Renoprotective activity of sivelestat in severe acute pancreatitis in rats. AB - Acute pancreatitis, affecting 382,014 individuals annually in China, is life threatening in its severe form. Since acute pancreatitis-associated morbidity or mortality is attributable mainly to functional failure of the vital organs, significant research efforts have focused on the identification of novel agents with potential organ-protective properties in the hope of developing approaches to improve the outcome of acute pancreatitis. In a previous study, we demonstrated that sivelestat, a specific inhibitor of neutrophil elastase (NE), is effective in protecting against lung failure in rats with taurocholate-induced acute pancreatitis. As part of the analyses extended from that study, the present study aimed to evaluate the role of sivelestat in the protection against acute pancreatitis-associated renal injury. Renal histopathology and major renal function parameters were analyzed in renal tissue and blood specimens collected from rats with acute pancreatitis induced by the surgical administration of sodium taurocholate in the presence or absence of sivelestat treatment and in sham-operated control rats at various time-points. The extended analyses demonstrated that: i) sodium taurocholate induced apparent renal injury and dysfunction manifested by histological anomalies, including vacuolization and apoptosis of the cells of the tubular epithelial lining in the kidney, as well as biochemical aberrations in the blood (increases in levels of blood urea nitrogen, creatinine and tumor necrosis factor-alpha) and renal tissue (robust increases in NE activity and induced neutrophil chemoattractant-1 levels); and ii) sivelestat treatment effectively attenuated all taurocholate-induced histological anomalies and biochemical aberrations. These observations strongly suggest that the NE inhibitor, sivelestat, is effective in protecting against acute pancreatitis associated renal injury. PMID- 23935714 TI - Primary testicular diffuse large B-cell lymphoma: A case report focusing on touch imprint cytology and a non-germinal center B-cell-like phenotype. AB - Primary diffuse large B-cell lymphoma (DLBCL) of the testis is a rare subtype of testicular tumor. While the histomorphology of testicular DLBCL is well described, a paucity of information in the literature exists with regard to the cytological diagnosis of this subtype of tumor. Touch imprint specimens were obtained from a testicular DLBCL occurring in a 64-year-old man. The cytological features of imprints were compared with the results obtained from histological and immunohistochemical examinations. Smears obtained from the touch imprints exhibited a high cellular yield consisting of discretely arranged monomorphic large cells with irregular nuclear membranes, scant cytoplasm and conspicuous nucleoli. Histologically, the tumor consisted of discohesive neoplastic lymphocytes that infiltrated diffusely and produced a wide separation of intact seminiferous tubules. Diffuse, intense immunostaining for CD45, CD20, MUM1 and Ki 67 led to the diagnosis of primary DLBCL of the testis with a non-germinal center B-cell-like phenotype. Careful observation of the touch imprint specimens of testicular DLBCL revealed a high cellularity with a predominant single-cell pattern of monomorphic cells demonstrating irregular nuclear membranes and conspicuous nucleoli. In addition, DLBCL is capable of developing in the testis and forming a predominantly discohesive cell population, suggesting the presence of a lymphoid malignancy. Thus, it may be possible to detect morphological features that are characteristic of DLBCL using imprint cytology. To the best of our knowledge, this is the first study reporting the diagnosis of testicular DLBCL using touch imprint cytology. PMID- 23935715 TI - Evaluation of Helicobacter pylori eradication and drug therapy in patients with functional dyspepsia. AB - The aim of this study was to assess the effect of Helicobactor pylori (H. pylori) infection and drug therapy on functional dyspepsia (FD) symptoms and gastrointestinal eosinophil count. In this study, 215 continuous FD patients fulfilling Rome III criteria were enrolled. The patients were divided into a H. pylori-positive group and a H. pylori-negative group. The H. pylori-positive group was divided into H. pylori-eradicated and H. pylori-uneradicated groups following H. pylori-eradication treatment, and the H. pylori-negative group was randomly divided into esomeprazole and teprenone treatment groups. The symptom scores of the esomeprazole group were significantly lower compared with those of the teprenone group at week 6 but not at baseline and week 2. Compared with the H. pylori-uneradicated group, eosinophil counts in the antrum and body were significantly reduced in the H. pylori-eradicated group at week 6. The number of gastric eosinophil clusters was significantly higher in the H. pylori-positive group than in the H. pylori-negative group. Eradication was associated with gastric eosinophil counts but did not affect duodenal eosinophil levels. Neither esomeprazole nor teprenone treatments reduced eosinophil levels in the stomach and duodenum of H. pylori-negative patients. PMID- 23935716 TI - Comparison of fixed- and mobile-bearing total knee arthroplasty with a mean five year follow-up: A meta-analysis. AB - Controversy exists regarding the clinical and radiological differences in outcomes between fixed-bearing (FB) and mobile-bearing (MB) total knee arthroplasties (TKAs) at the mid- or long-term follow-up. We therefore conducted a meta-analysis and systematic review of randomized controlled trials (RCTs) that have evaluated FB and MB TKAs. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Medline and Embase. The data, including demographic information, methodological quality, duration of follow-up, clinical and radiographical outcomes, patient preferences and complications, were extracted. The methodological quality of the studies was assessed in accordance with the guidelines presented in the Cochrane Handbook for Systematic Reviews of Interventions. Nine trials, studying 1,821 knees, were eligible for data extraction and meta-analysis. The Knee Society score and the maximum knee flexion demonstrated no difference between the FB and MB groups (P=0.47 and P=0.72, respectively). Similarly, no difference was revealed between the groups for radiological outcomes or general health results. An increased number of high-quality RCTs with long-term follow-ups are required to validate the results. PMID- 23935717 TI - Effect of Lycopersicon esculentum extract on apoptosis in the rat cerebellum, following prenatal and postnatal exposure to an electromagnetic field. AB - The expansion of mobile phone technology has raised concerns regarding the effect of 900-MHz electromagnetic field (EMF) exposure on the central nervous system. At present, the developing human brain is regularly exposed to mobile telephones, pre- and postnatally. Several studies have demonstrated the acute effects of EMF exposure during pre- or postnatal periods; however, the chronic effects of EMF exposure are less understood. Thus, the aim of the present study was to determine the chronic effects of EMF on the pre- and postnatal rat cerebellum. The control group was maintained in the same conditions as the experimental groups, without the exposure to EMF. In the EMF1 group, the rats were exposed to EMF during pre- and postnatal periods (until postnatal day 80). In the EMF2 group, the rats were also exposed to EMF pre- and postnatally; in addition, however, they were provided with a daily oral supplementation of Lycopersicon esculentum extract (~2 g/kg). The number of caspase-3-labeled Purkinje neurons and granule cells present in the rats in the control and experimental groups were then counted. The neurodegenerative changes were studied using cresyl violet staining, and these changes were evaluated. In comparison with the control animals, the EMF1 group demonstrated a significant increase in the number of caspase-3-labeled Purkinje neurons and granule cells present in the cerebellum (P<0.001). However, in comparison with the EMF1 group, the EMF2 group exhibited significantly fewer caspase-3-labeled Purkinje neurons and granule cells in the cerebellum. In the EMF1 group, the Purkinje neurons were revealed to have undergone dark neuron degenerative changes. However, the presence of dark Purkinje neurons was reduced in the EMF2 group, compared with the EMF1 group. The results indicated that apoptosis and neurodegeneration in rats exposed to EMF during pre- and postnatal periods may be reduced with Lycopersicon esculentum extract therapy. PMID- 23935718 TI - Prognostic factors for survival of patients with nasopharyngeal carcinoma following conventional fractionation radiotherapy. AB - This study aimed to investigate the risk factors influencing the prognosis of patients receiving conventional fractionation radiotherapy. A retrospective analysis of clinical data from 100 patients with nasopharyngeal carcinoma receiving radiotherapy was conducted. The Chi-square test was used to screen the relevant factors and Cox multiple-factor analysis was used to investigate the risk factors influencing the survival of patients. One-factor analysis results revealed that tumor stage, tumor diameter, prescription dose completion and radiotherapy regularity are related to the prognosis of nasopharyngeal carcinoma and multiple-factor analysis results revealed that tumor stage, radiotherapy dose and radiotherapy regularity are independent risk factors influencing prognosis. The prognosis of patients with nasopharyngeal carcinoma receiving radiotherapy is related to tumor progression and an adequate dose of regular radiotherapy improves the prognosis of patients. PMID- 23935719 TI - Case report of emergency repair of injury to the great vessels of the clavicular region by coated endovascular stent implantation. AB - The subclavian artery leaves the thoracic cage at the outer margin of the first rib, where it becomes the axillary artery. Rupture and hemorrhage of the subclavian artery may result in ischemia and necrosis of the upper limb, brachial plexus injury, and even hemorrhagic shock or mortality. A patient with an injury to the proximal segment of the axillary artery underwent emergency repair using a coated endovascular stent graft. The patient was followed up for 13 months and examined using CT imaging, B-mode ultrasonography and electromyography to evaluate stent function and brachial plexus recovery. The endovascular stent graft remained correctly positioned and patent, extending across the injured part of the vessel. Neurolysis at 3 months after injury was effective in restoring the majority of the brachial plexus function. The coated endovascular stent graft was effective in treating the acute injury to the great vessels in the clavicular region. Follow-up of brachial plexus function is important and secondary neurolysis should be performed if necessary. PMID- 23935720 TI - Effect of ouabain on myocardial remodeling in rats. AB - The aim of this study was to investigate the effect of ouabain (EO) on myocardial remodeling. Twenty-two adult male Sprague-Dawley rats were randomly divided into two groups: the rats in the EO group (n=12) were intraperitoneally injected with EO daily and those in the control group (n=10) were injected with physiological saline daily. After 8 weeks the rats were sacrificed. The ultrastructural changes in the myocardium were observed. The expression levels of voltage-gated potassium channel 4.2 (KV4.2) were detected by real-time quantitative reverse transcription polymerase chain reaction. The effects of EO on the myocardial action potential and transient potassium efflux (Ito) were measured by patch clamping. The systolic blood pressure (SBP) of 10 of the 12 rats in the EO group, designated as the EO-sensitive (OS) rats, began to increase from the fifth week of treatment and was significantly higher compared with that of the control group 6 weeks later (P<0.01). The remaining 2 rats in the EO group that presented no increase in SBP following 8 weeks of treatment (P>0.05) were designated as EO-resistant (OR) rats. Pathological ultrastructural changes were significant in the apical mid-myocardium of the OS rats. No significant differences in KV4.2 expression were observed among the OS, OR and control rats. The patch clamp results revealed that EO prolongs the action potential duration, reduces Ito and triggers the electrical remodeling of the myocardium. EO induces a blood pressure increase and triggers structural and electrical remodeling. PMID- 23935721 TI - Clinical features and magnetic resonance image analysis of 15 cases of demyelinating leukoencephalopathy induced by levamisole. AB - The aim of this study was to explore the diagnostic value of magnetic resonance imaging (MRI) for levamisole-induced demyelinating leukoencephalopathy. The clinical features and MRI findings of 15 patients with levamisole-induced demyelinating leukoencephalopathy were retrospectively analyzed. The abnormality rate of the patients was demonstrated to be 100% by MRI, and scattered multiple cerebral foci were observed in all of the patients. The majority of the foci were located at the centrum ovale, peri-lateral cerebral ventricles and basal ganglia, while the remainder were located in the brain stem and cerebellum, as well as in the white matter regions of the temporal, frontal, apical and occipital lobes. In addition, mottling and ring-shaped enhancements were observed. The study demonstrated that MRI effectively displays demyelinating leukoencephalopathy, and that the combination of MRI with the medical history of the patient is of significance for the early diagnosis, differentiation and treatment of demyelinating leukoencephalopathy. PMID- 23935722 TI - An unusual dermoid cyst in subcutaneous tissue of the mastoid region: A case report. AB - Dermoid cysts of the head and neck are rare lesions. An unusual dermoid cyst in the subcutaneous tissue of the mastoid region is easily confused with lymph node abnormalities; therefore, diagnosis and treatment are often challenging. We describe a 22-year-old male with an unusual dermoid cyst in the subcutaneous tissue of the mastoid region whose only complaint was a retroauricular lump, which was similar to an intumescent retroauricular lymph node. Final diagnosis was confirmed by pathological examination of the surgically removed specimen. A dermoid cyst in the subcutaneous tissue of the mastoid region is rare and may be misdiagnosed as a retroauricular lymph node. A lump may be the only presenting symptom without hearing loss and vertigo complaints. Complete excision of the tumor must be ensured and pathological analysis is important for the diagnosis. PMID- 23935723 TI - Association between metabolic syndrome and the development of non-alcoholic fatty liver disease. AB - The aim of this study was to examine the effects of metabolic syndrome (MS) and the number of MS components on the development of non-alcoholic fatty liver disease (NAFLD). A total of 1,343 males and 574 females aged >=50 years without NAFLD at baseline were included. Information on lifestyle, including alcohol use and personal history, was collected by face-to-face interviews. Biochemical parameters were assayed using fasting blood samples. NAFLD was diagnosed by abdominal ultrasonography. During follow-up at an average of 4.8 years, 223 patients developed NAFLD. Following adjustment for multiple covariates, age was an independent protective predictor [hazard ratio (HR), 0.96; 95% confidence interval (CI), 0.95-0.98], while the independent risk predictors were obesity (HR, 2.81; 95% CI, 2.14-3.69), higher triglycerides (HR, 2.56; 95% CI, 1.95-3.32) and alanine aminotransferase (HR, 1.004; 95% CI, 1.000-1.008). Participants with a diagnosis of MS had a significantly increased risk of developing NAFLD (HR, 3.17; 95% CI, 2.42-4.14). A greater number of MS components was significantly associated with a higher risk of NAFLD (all adjusted P for trend <0.001). Compared with those without any components of MS, participants with only one component of MS had a 3.6-fold higher risk of developing NAFLD (adjusted HR, 3.64; 95% CI, 1.50-8.88). The diagnosis and the number of components of MS were prospectively associated with the risk of developing NAFLD. Even in those with only one component of MS, the risk increased by 2.6-fold compared with that for the individuals without any components, suggesting a beneficial effect of intervention at the very early stage of MS on the prevention of NAFLD. PMID- 23935724 TI - Genotype distribution and the relative risk factors for human papillomavirus in Urumqi, China. AB - The aim of this study was to investigate human papillomavirus (HPV) infection and HPV genotype distributions in Urumqi, Xinjiang, China. The related risk factors for high-risk HPV infection was also analyzed. A stratified cluster sampling method was used for the population-based cervical cancer screening of women aged 18-69 years in the Urumqi Saybagh district. Exfoliated cervical cell samples were collected for liquid-based cytology detection and HPV genotyping DNA microarrays. Education level, number of sexual partners, condom use and occupation were used in the multivariate analysis model. The HPV infection rate of women working in service industries was significantly higher compared with those of white-collar workers, community residents and migrant workers. The 35-44-year-old migrant worker group had the highest HPV infection rates among all of the groups in the three different age ranges. The number of marriages, education level, smoking history, number of abortions, use of condoms, number of sexual partners, number of sexual partners in the past five years and occupation were all associated with female HPV infection rate (P<0.05). The 35-44-year-old women were the age group with the highest HPV infection rate. The HPV infection rate of females in service industries was the highest. Education level and condom use were protective factors of HPV infection, while the number of sexual partners and occupation were risk factors for HPV infection. PMID- 23935725 TI - Cavernous hemangioma of the testis mimicking a testicular teratoma. AB - In this study we report a case of cavernous hemangioma of the testis, which mimicked a testicular teratoma. A 42-year-old male presented with a left testicular swelling that had arisen suddenly and been present for three months. Scrotal ultrasound revealed a hypoechoic mass with several calcifications in the left testicle. The mass demonstrated blood flow in the color Doppler mode. A radical orchiectomy was performed. Pathological evaluation revealed a testicular cavernous hemangioma with thrombus organization and calcification. PMID- 23935726 TI - Correlation between anxiety-depression status and cytokines in diarrhea predominant irritable bowel syndrome. AB - The aim of this study was to investigate the correlation between anxiety depression status and cytokines in diarrhea-predominant irritable bowel syndrome (IBS-D). IBS-D patients were divided into an anxiety-depression IBS-D group and a non-anxiety-depression IBS-D group. Patients without IBS, anxiety or depression were selected as the control group. Scoring was performed using the self-rating anxiety scale (SAS) and self-rating depression scale (SDS). Levels of IL-1beta and IL-10 in the blood and sigmoid colon mucosa were detected, and the proportions of IL-1beta- and IL-10-positive cells in the sigmoid colon mucosa were determined. The results demonstrated that the SDS and SAS scores in the IBS D group were significantly higher than those in the control group (P<0.05). The levels of IL-1beta in the blood and sigmoid colon mucosa and the proportion of IL 1beta-positive cells in the sigmoid colon mucosa in the IBS-D group were significantly higher than those in the control group (P<0.05). The levels of IL 10 in the blood and sigmoid colon mucosa and the proportion of IL-10-positive cells in the IBS-D group were significantly lower than those in the control group (P<0.05). The levels of IL-1beta in the blood and sigmoid colon mucosa and the proportion of IL-1beta-positive cells in the anxiety-depression IBS-D group were significantly higher than those in the non-anxiety-depression IBS-D group, and the levels of IL-10 and the proportion of IL-10-positive cells in the anxiety depression IBS-D group were significantly lower than those in the non-anxiety depression IBS-D group (P<0.05). Anxiety-depression status may cause the IL-1beta and IL-10 levels in IBS patients to change and result in an imbalance of the proinflammatory and anti-inflammatory cytokines, leading to the occurrence or aggravation of IBS. PMID- 23935727 TI - Expression and correlation of Twist and gelatinases in breast cancer. AB - Altered expression of Twist, matrix metalloproteinase (MMP)-2 and MMP-9 proteins has been identified in various types of human cancers. However, the correlation between Twist and these gelatinases in breast cancer remains unclear. In this study, immunohistochemical analysis of Twist, MMP-2 and MMP-9 expression was performed on tissue microarrays from 200 breast cancer cases. The association of Twist and gelatinase expression with clinicopathological factors and patient survival was analyzed. Altered expression of Twist, MMP-2 and MMP-9 proteins was observed in breast cancer tissue. The positive rates of Twist, MMP-2 and MMP-9 protein expression were 75.5, 97.0 and 96.0%, respectively. Increased expression of Twist was positively correlated with the status of axillary lymph node metastasis and higher tumor-node-metastasis (TNM) stage (P<0.01). Moreover, increased expression of Twist was correlated with poor overall survival (OS) and post-operative relapse-free survival (RFS), compared with those for the patients with reduced expression levels of Twist (P<0.05, P<0.01). The expression of MMP-2 and MMP-9 was positively correlated with Twist expression (P<0.001). Our results indicate that Twist may play an important role in the invasion, metastasis and prognosis of breast cancer. Additionally, our results suggest that Twist may be a regulator of gelatinases (MMP-2 and MMP-9). PMID- 23935728 TI - Long-term facial nerve function following facial reanimation after translabyrinthine vestibular schwannoma surgery: A comparison between sural grafting and VII-XII anastomosis. AB - The aim of this study was to compare the recovery of long-term facial nerve function between patients who received sural grafts and those who underwent hypoglossal-facial anastomosis techniques following translabyrinthine vestibular schwannoma surgery. This study included 25 patients with vestibular schwannomas treated with translabyrinthine tumor removal. All patients had large tumors with a mean tumor size of 3.12 cm. Of these patients, six had progressive tumor enlargement symptoms and had been treated previously with stereotactic irradiation. Preoperatively, all patients had normal facial functions, and total tumor removal with a translabyrinthine approach was achieved in all cases. During surgery, the facial nerve was interrupted in all 25 patients. Two types of facial reanimation were performed. Sural grafts were placed in 13 patients and hypoglossal-facial (VII-XII) anastomosis was performed in the other 12. Facial nerve function and surgical outcomes were observed upon discharge, in the short term (one year following surgery), and in the long term (three years following surgery). Total facial paresis was observed in all patients upon discharge. In the sural graft group, House-Brackmann grade III facial function was achieved in four patients upon short-term evaluation and in ten upon long-term evaluation, while House-Brackmann grade IV facial function was achieved in nine patients upon short-term evaluation and three in the long term. In the VII-XII anastomosis group, House-Brackmann grade III facial function was achieved in two patients in the short term and eight in the long term, and House-Brackmann grade IV facial function was achieved in ten patients in the short term and four in the long term. There was a statistically significant difference in the facial recovery results between the short- and long-term follow-up periods. The sural graft group exhibited a marked improvement in results compared with the VII-XII anastomosis group, but no statistically significant difference in facial function was observed between the two facial reanimation groups at either the short- or long term follow-up. In the sural graft group, synkinesia, noted in three patients, was the most frequently observed complication. Claudication was common upon discharge (four patients), but diminished during follow-up. Disarticulation was the most common complication in the VII-XII anastomosis group (five patients); numbness of the tongue was the second most common complication (four patients). None of the patients developed dysphagia. Facial reanimation is an effective procedure for the surgical rehabilitation of static and dynamic facial nerve functions. Significant improvement in facial nerve function may occur more than three years after surgery. Despite morbidities such as synkinesia, the sural graft technique demonstrates greater improvements in facial nerve function than VII-XII anastomosis in the short and long term following surgery, but this conclusion requires confirmation by larger studies with a greater number of patients. PMID- 23935729 TI - Correlation between inflammatory factors and post-stroke pneumonia in diabetic patients. AB - Pneumonia is the most common cause of mortality in stroke patients and it has been demonstrated to contribute to mortality and poor functional outcome following stroke in the majority of clinical studies. The risk of infection may be attributed to stroke-induced immunodepression syndrome (SIDS). Cytokine production is increased in SIDS. However, the correlation between biomarkers and the risk of post-stroke pneumonia in patients with diabetes mellitus is not clear. The aim of this study was to determine the correlation between pneumonia and the levels of C-reactive protein (CRP) and interleukin-6 (IL-6), as well as to identify early predictors of pneumonia in acute ischemic stroke patients with diabetes mellitus. Additionally, we investigated the impact of pneumonia on functional outcome after 1 month. A total of 106 ischemic stroke patients with diabetes mellitus who were admitted after the onset of symptoms were included in the study. They were divided into two groups, the pneumonia and non-pneumonia groups. CRP, IL-6, white blood cells (WBCs), mean body temperature and National Institutes of Health Stroke Scale (NIHSS) score were measured at the time of admission. The modified Rankin Scale score was assessed at 30 days. The levels of IL-6, CRP and WBCs, as well as mean body temperature were significantly higher in the patients with pneumonia than in the patients without pneumonia. There were also significant differences between the pneumonia and non-pneumonia groups in age, admission NIHSS score, length of hospital stay and dysphagia. Pneumonia patients had worse outcomes compared with patients without pneumonia at 1 month. Age, NIHSS score and dysphagia were significantly associated with pneumonia. WBCs and mean body temperature were not significant predictors of pneumonia. Older patients with more severe ischemic stroke are more susceptible to the development of pneumonia during the stay in hospital. Pneumonia contributes to poor functional outcome. IL-6, CRP, age, NIHSS score and dysphagia may predict the occurrence of pneumonia on the day of stroke symptom onset. PMID- 23935730 TI - Clinical analysis and prognostic significance of hepatitis B virus infections for diffuse large B-cell lymphoma with or without rituximab therapy. AB - The aim of this study was to analyze the clinical features of hepatitis B surface antigen (HBsAg)-positive and negative diffuse large B-cell lymphomas (DLBCLs) and to compare the outcomes and serum hepatitis B virus (HBV)-DNA loads of patients treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimens with rituximab (RCHOP) or without. A total of 451 DLBCL patients, of which 90 were HBsAg-positive and 361 were HBsAg-negative, were retrospectively reviewed. We compared onset age, gender, Ann Arbor stage, international prognostic index (IPI), lactate dehydrogenase (LDH) and beta2-microglobulin (beta2-M) levels, as well as overall survival (OS) rates and HBV-DNA loads under CHOP or RCHOP regimens. The OS rate of the HBsAg-positive DLBCL patients was significantly lower than that of HBsAg-negative DLBCL patients and the HBsAg positive DLBCL patients had an earlier median onset age. HBsAg-positive DLBCL patients had poorer OS rates compared with HBsAg-negative patients (62.2% HBsAg positive vs. 76.2% HBsAg-negative, P=0.018). HBsAg-positive DLBCL patients with HBV-DNA loads >103 cps/ml during chemotherapy had significantly lower OS rates than those with lower HBV-DNA loads (48.4% HBV-DNA elevated vs. 71.2% HBV-DNA normal, P=0.037). HBsAg-positive DLBCL patients treated with RCHOP had a significantly higher OS rate (79.6%) compared with the 41 CHOP-treated patients (43.9%; P<0.001). HBsAg-positive DLBCL patients with an earlier median onset age and elevated HBV-DNA during chemotherapy had poorer prognoses. HBsAg and HBV-DNA during chemotherapy may be used as prognostic indicators for patients with DLBCL. Rituximab improves the outcome of HBsAg-positive DLBCL patients when administered in combination with anti-viral lamivudine. PMID- 23935731 TI - Comparison of magnetic resonance enterography, capsule endoscopy and gastrointestinal radiography of children with small bowel Crohn's disease. AB - The aim of this study was to compare magnetic resonance enterography (MRE) findings with those of video capsule endoscopy (VCE) or conventional gastrointestinal radiography (CGR) in pediatric patients with small bowel Crohn's disease. A total of 55 cases of small bowel Crohn's disease that were diagnosed through clinical, laboratory, surgical and histopathological findings were reviewed. Prior to the examination, children suspected of having other types of diseases of the small intestinal were identified. The pulse sequences included coronal T2-true-fast imaging with steady-state precession (TrueFISP) images, navigation axial and coronal T1-weighted images, T2-weighted fat-suppressed images and coronal fat-suppressed three-dimensional gradient-echo images, immediately followed by contrast-enhanced axial and coronal T1-weighted fat suppressed images. Findings from MRE were compared with those of VCE (n=39) and CGR (n=37). MRE results exhibited a number of features characteristic to small bowel Crohn's disease, including wall thickening, mesenteric fibrofatty changes and mesenteric vasculature changes. VCE, MRE and CGR demonstrated sensitivities of 94.6, 85.7 and 71.1% with specificities of 72.7, 70 and 40%; accuracies of 89.6, 82.2 and 61.1%; positive predictive values of 92.1, 90.9 and 59.6%; and negative predictive values of 80, 58.3 and 40%, respectively. VCE depicted mucosal pathologies missed by MRE in three patients. MRE revealed 83 extraenteric findings in 55 patients and CGR was able to show the dynamic evolution of the gastrointestinal function. MRE is a simple, safe, non-invasive and effective method for evaluating small bowel Crohn's disease. VCE allows visualization and readily characterizes subtle mucosal lesions missed by MRE, whereas MRE yields additional mural, perienteric and extraenteric information. However, oral barium CGR utilizes radiation, which is not suitable for repeated use in children. PMID- 23935732 TI - Correlation between serum high-mobility group box-1 levels and high-sensitivity C reactive protein and troponin I in patients with coronary artery disease. AB - The aim of this study was to evaluate the correlation between levels of serum high-mobility group box-1 (HMGB1) and high-sensitivity C-reactive protein (hs CRP) and cardiac troponin I in patients with coronary artery disease. The levels of serum HMGB1, hs-CRP and cardiac troponin I were measured in 98 patients with coronary artery disease and in 30 healthy subjects. The correlation between serum HMGB1 levels and hs-CRP and cardiac troponin I levels was analyzed. Serum HMGB1 levels in patients with coronary artery disease were higher compared with those in healthy volunteers (63.5+/-15.29 vs. 21.98+/-4.33 MUg/l; P<0.01). Serum HMGB1 levels in patients with acute myocardial infarction were higher compared with those in patients with unstable and stable angina pectoris (77.53+/-6.86 vs. 63.67+/-8.6 and 44.39+/-9.01 MUg/l, respectively; both P<0.01). The levels of HMGB1 were positively correlated with hs-CRP and cardiac troponin I levels (r=0.657 and 0.554, respectively; both P<0.01) in patients with coronary artery disease. In conclusion, serum HMGB1 levels were elevated in patients with coronary artery disease, particularly in those with acute myocardial infarction. The levels of HMGB1 were correlated with the levels of hs-CRP and cardiac troponin I. PMID- 23935733 TI - Network pharmacology-based prediction of the multi-target capabilities of the compounds in Taohong Siwu decoction, and their application in osteoarthritis. AB - Taohong Siwu decoction (THSWD), a formulation prescribed in traditional Chinese medicine (TCM), has been widely used in the treatment of osteoarthritis (OA). TCM has the potential to prevent diseases, such as OA, in an integrative and holistic manner. However, the system-level characterization of the drug-target interactions of THSWD has not been elucidated. In the present study, we constructed a novel modeling system, by integrating chemical space, virtual screening and network pharmacology, to investigate the molecular mechanism of action of THSWD. The chemical distribution of the ligand database and the potential compound prediction demonstrated that THSWD, as a natural combinatorial chemical library, comprises abundant drug-like and lead-like compounds that may act as potential inhibitors for a number of important target proteins associated with OA. Moreover, the results of the 'compound-target network' analysis demonstrated that 19 compounds within THSWD were correlated with more than one target, whilst the maximum degree of correlation for the compounds was seven. Furthermore, the 'target-disease network' indicated that THSWD may potentially be effective against 69 diseases. These results may aid in the understanding of the use of THSWD as a multi-target therapy in OA. Moreover, they may be useful in establishing other pharmacological effects that may be brought about by THSWD. The in silico method used in this study has the potential to advance the understanding of the molecular mechanisms of TCM. PMID- 23935735 TI - A clinical trial report of autologous bone marrow-derived mesenchymal stem cell transplantation in patients with spinal cord injury. AB - Spinal cord injury (SCI) is a severe neurological disease. An effective strategy for the treatment of SCI is urgently required. Stem cell transplantation has emerged as a viable therapeutic option with great potential for restoring neurological function lost following SCI. From 2009 to 2010, a total of 20 SCI patients were enrolled in a clinical trial by Wuhan Hongqiao Brain Hospital; all patients completed and signed informed consent prior to autologous bone marrow derived mesenchymal stem cell transplantation. Analysis of subsequent treatment results indicated significant improvements in sensory, motor and autonomic nerve function as assessed by the American Spinal Injury Association's impairment scale. Thirty days after transplantation, a total of 15 patients (75%) demonstrated improvement, including four of the eight patients (50%) with grade A SCI, three of the four patients (75%) with grade B injury and all eight patients (100%) with grade C injury. The most common adverse events, fever and headache, disappeared within 24-48 h without treatment. PMID- 23935734 TI - 64-Slice spiral CT perfusion combined with vascular imaging of acute ischemic stroke for assessment of infarct core and penumbra. AB - The aim of this study was to determine the value of computed tomography perfusion (CTP) parameters, including cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) and time-to-peak (TP), in a clinical study of patients with stroke. Additionally, we determined which parameter or combination of parameters are reliable in detecting the presence of an infarct and penumbra. CTP was performed within 24 h of the onset of symptoms in 20 patients with possible stroke. Magnetic resonance imaging (MRI) was performed 3-7 days later and the threshold of the CTP was adjusted according to the results to provide CT images that correlated with the MRI; the MRI results were taken as the gold standard. CBV, CBF and TP contrast agent enhancement were calculated using the CT results. The CTP results were compared with the MRI findings. All CTP parameters were reliable in detecting the penumbra (P<0.001). In these parameters, changes of MTT were the most useful. CTP revealed various changes in CBF, CBV, MTT and TP in ischemic areas. CTP parameters were also reliable in detecting the infarct core (P<0.001). We determined that when detecting the penumbra, all CTP parameters are reliable, and when detecting cerebral ischemia, a combination of parameters should be used. PMID- 23935736 TI - Comparison of two different double-plate fixation methods with olecranon osteotomy for intercondylar fractures of the distal humeri of young adults. AB - Although several studies have demonstrated good results with open reduction and internal fixation of intercondylar fractures of the distal humerus, few have specifically addressed the results of such surgical fixation in young adults. The purpose of this study was to compare the clinical outcomes in patients with intercondylar fractures of the distal humerus treated using two different double plating methods. Twenty-five patients with distal humeral fractures classified as type C according to the Association for Osteosynthesis/Association for the Study of Internal Fixation (AO/ASIF) classification system, who were admitted to the Second Hospital Affiliated to Anhui Medical University (Hefei, China) from October 2008 to October 2011, were included in the study. The patients were treated with two different double-plate fixation and olecranon osteotomy methods. Thirteen patients were treated by perpendicular plating (group I) and twelve patients by Y-shaped double-plating in the coronal plane (group II). All the patients were followed up for 12-38 months, with an average of 19.2+/-7.1 months in group I and 18.3+/-4.0 months in group II. All the osteotomies and fractures had healed by the final follow-up. Complications developed in 4 patients in group I and 3 patients in group II. According to the Mayo Elbow Performance Scores (MEPS), 84.6% of patients in group I and 83.3% in group II had excellent or good scores. No significant differences were identified between the clinical outcomes of the two plating methods. The olecranon osteotomy approach with double-plate fixation is a good choice for the surgical treatment of type C intercondylar fractures in young adult distal humeri. The two plating methods provide solid fixation, permit early rehabilitation and result in satisfactory clinical outcomes. PMID- 23935737 TI - Posterior internal fixation plus vertebral bone implantation under navigational aid for thoracolumbar fracture treatment. AB - The aim of this study was to investigate the method of posterior thoracolumbar vertebral pedicle screw reduction and fixation combined with vertebral bone implantation via the affected vertebral body under navigational aid for the treatment of thoracolumbar fractures. The efficacy of the procedure was also measured. Between June 2005 and March 2011, posterior thoracolumbar vertebral pedicle screw reduction and fixation plus artificial bone implantation via the affected vertebral pedicle under navigational aid was used to treat 30 patients with thoracolumbar fractures, including 18 males and 12 females, ranging in age from 21 to 57 years. Compared with the values prior to surgery, intraspinal occupation, vertebral height ratio and Cobb angle at the follow-up were significantly improved. At the long-term follow-up, the postoperative Cobb angle loss was <1 degrees and the anterior vertebral body height loss was <2 mm. Posterior thoracolumbar vertebral pedicle screw reduction and fixation combined with vertebral bone implantation via the affected vertebral body under navigational aid may increase the accuracy and safety of surgery, and it is an ideal method of internal implantation. Bone implantation via the affected vertebral body may increase vertebral stability. PMID- 23935738 TI - Efficacy and safety of percutaneous microwave coagulation therapy followed by 125I seed brachytherapy for VX2 hepatic tumors in a rabbit model. AB - The aim of this study was to evaluate the efficacy and safety of percutaneous microwave coagulation therapy (PMCT) followed by 125I seed brachytherapy for VX2 liver cancer in rabbits. Eighty New Zealand rabbits were injected with suspensions of VX2 tumor cells to create an animal model. The rabbits were randomly divided into 4 groups (n=20); the control, PMCT, 125I seed brachytherapy and combination groups. Group A was treated with PMCT at 40 W for 120 sec, group B was treated with 125I seed brachytherapy and group C was treated with PMCT followed by 125I seed brachytherapy. Group D were not treated and served as the control group. At 21 days after treatment, the rabbits were sacrificed for pathological assessment. The complete tumor necrosis rate was 19 out of 20 tumors (95%) in group C, 6 (30%) in group A, 0 (0%) in group B and 0 (0%) in the control group. The complete tumor necrosis rate was observed to be significantly different between groups C and A, and between groups C and B (P<0.01). No intraheptic metastasis occurred in group C, compared with an incidence of 7 (35%) in group A, 2 (10%) in group B and 20 (100%) in the control group. Between groups C and A, and between groups C and D, the intraheptic metastasis rate was statistically significant (P<0.01). PMCT followed by 125I seed brachytherapy increased the rate of carcinoma necrosis and decreased carcinoma metastasis in the VX2 rabbit model. This combined treatment is a safe, effective and minimally invasive therapeutic option for liver cancer. PMID- 23935739 TI - Intramuscular schwannoma of the musculocutaneous nerve: An uncommon clinical presentation. AB - A schwannoma is a benign peripheral nerve sheath tumor composed exclusively of Schwann cells. A major-nerve schwannoma with an intramuscular location is an extremely rare condition. We present a rare case of intramuscular schwannoma originating from the musculocutaneous nerve in a 71-year-old female. The patient presented with a 7-month history of a slowly growing, painless mass in the medial aspect of the proximal upper arm. Magnetic resonance imaging revealed an oval shaped intramuscular soft tissue mass with iso-signal intensity relative to skeletal muscle on T1-weighted images and high signal intensity on T2-weighted images. A rim of fat surrounding the mass, suggesting the split-fat sign, was also observed. The tumor was completely enucleated using an intracapsular technique. Histological examination confirmed the diagnosis of schwannoma consisting of Antoni A and B areas. There was no immediate neurological deficit following surgery. The patient had no evidence of local recurrence and no neurological deficit at final follow-up. To the best of our knowledge, this is the first report of musculocutaneous nerve schwannoma within the coracobrachialis muscle. PMID- 23935740 TI - Correlation analysis of prognostic and pathological features of patients with chronic sinusitis and nasal polyps following endoscopic surgery. AB - The aim of this study was to evaluate the therapeutic value of pathological indicators to predict the efficacy of endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis (CRS) with nasal polyps. A total of 53 patients with CRS with nasal polyps, who had undergone endoscopic surgery at least one year before, were surveyed for their clinical symptoms. Surgical specimen biopsies were consulted and related pathological indicators were measured. The association between the main symptoms of CRS with nasal polyps following ESS and pathological indicators were statistically analyzed. The main symptoms of patients with CRS with nasal polyps following ESS were nasal congestion, thick nasal discharge, rhinorrhea or sneezing. Goblet cells are associated with the symptoms of sneezing and thick nasal discharge, pathological gland formation is associated with dizziness, and the degree of tissue edema is associated with post-nasal discharge (P<0.05). Pathological indicators aid the prediction of the efficacy of nasal ESS in patients with CRS with nasal polyps. PMID- 23935741 TI - Regulation of synoviocyte activity by resveratrol in rats with adjuvant arthritis. AB - The aim of this study was to investigate the preventive effects of resveratrol (Res) on rats with adjuvant arthritis (AA) and the mechanism(s) of action. An AA model was established by injection of Freund's complete adjuvant (FCA). Vascular endothelial growth factor (VEGF) was visualized in joint specimens using immunohistochemistry. IL-1beta and TNF-alpha production in synoviocytes was determined by radioimmunoassay (RIA). The mRNA expression of IL-1beta and TNF alpha was observed in synoviocytes using the reverse transcription (RT)-PCR method. The synoviocytes of the AA model were stimulated by Res or treated with the protein kinase C (PKC) inhibitor chelerythrine prior to stimulation. The expression of phosphorylated ERK1/2 (p-ERK1/2) was detected by western blotting. Res was able to reduce the elevated levels of IL-1beta and TNF-alpha, and inhibit the mRNA expression of IL-1beta and TNF-alpha in the synoviocytes of the AA model rats. VEGF expression in the Res-treated group was significantly lowered. The protein expression levels of p-ERK1/2 were significantly higher in the Res treated group compared with those of the model group, while p-ERK1/2 was markedly lower in the group pretreated with chelerythrine. Res has a therapeutic effect on AA rats, which may be correlated with its immunoregulatory actions, and may activate p-ERK1/2 in synoviocytes via PKC. PMID- 23935742 TI - Changes in ADF/destrin expression in the development of hair cells following Atoh1-induced ectopic regeneration. AB - The aim of this study was to investigate the effects of actin depolymerizing factor (ADF)/destrin and position changes of kinetosomes in the development of hair cells following Atoh1-induced ectopic regeneration in the basilar membrane of mice. We observed through immunofluorescence at various time-points the expression of ADF/destrin and the specific kinetosome marker, gamma-tubulin, in hair cells following ectopic regeneration induced by adenovirus transfection, overexpression of Atoh1 and in vitro culture. Changes of ADF/destrin distribution and kinetosome position during in vitro culture of new hair cells [Myo7a(+)] following Atoh1-induced ectopic regeneration are consistent with the changes in ADF/destrin expression and the polar migration of kinetosomes in hair cells of the cochlear sensory epithelium in normal development. ADF/destrin is involved in the development of the auditory epithelium and the development and structural rearrangement of ectopically regenerated hair cells in mammals. The kinetosomes of hair cells following Atoh1-induced ectopic regeneration show positional changes in vitro at different time-points. PMID- 23935743 TI - Effect of folic acid and vitamin B12 on the expression of PPARgamma, caspase-3 and caspase-8 mRNA in the abdominal aortas of rats with hyperlipidemia. AB - Hyperlipidemia may lead to endothelial injury, due to its effects on homocysteine and vascular endothelial growth factor in the serum, and the mRNA expression levels of peroxisome proliferator-activated receptor-gamma (PPARgamma), and caspase-3 and -8 in the vascular wall. In order to prevent and mitigate the high fat state that results from endothelial injury, this study examined the effect of folic acid (FA) and vitamin B12 (VB12) on the expression of PPARgamma and caspase 3 and -8 mRNA in the abdominal aortas of rats with hyperlipidemia. Sixty 4-week old healthy male Sprague Dawley rats were randomly divided into five groups (each n=12): the normal control (NC), high-fat diet (HL), FA, VB12 and FA+VB12 groups. Following one week of adaptive feeding, the FA, VB12 and FA+VB12 groups were subject to the intraperitoneal injection of FA (0.5 mg/day), VB12 (0.05 mg/day) and FA+VB12 (0.5 mg/day and 0.05 mg/day), respectively, while fed a high-fat diet. The rats in the NC group were injected intraperitoneally with 0.9% NaCl solution (0.5 ml/day) and fed a normal diet, whereas those in the HL group were fed a high-fat diet only. A reverse transcription-polymerase chain reaction (RT PCR) assay demonstrated that at the end of week 12, the FA treatment had effectively increased the PPARgamma mRNA level, while reducing the caspase-3 and 8 mRNA levels, compared with the high-fat diet treatment (P<0.05). The effect of FA on the expression of PPARgamma and caspase-3 and -8 was enhanced when used in combination with VB12 (P<0.05). These results revealed that the application of FA, alone or in combination with VB12, improves and mitigates the high-fat state that results from endothelial injury. PMID- 23935744 TI - Qing Hua Chang Yin attenuates lipopolysaccharide-induced inflammatory response in human intestinal cells by inhibiting NF-kappaB activation. AB - Ulcerative colitis (UC) is a major form of inflammatory bowel disease (IBD), which is tightly regulated by the nuclear factor kappaB (NF-kappaB) pathway. Thus, the suppression of NF-kappaB signaling may provide a promising strategy for the treatment of UC. Qing Hua Chang Yin (QHCY) is a traditional Chinese formulation, which has been used for a number of years to clinically treat UC. However, little is known with regard to its anti-inflammatory properties. In the present study, lipopolysaccharide (LPS)-stimulated Caco-2 cells were used as an in vitro inflammatory model of the human intestinal epithelium to evaluate the anti-inflammatory effects of QHCY and its underlying molecular mechanisms. We observed that QHCY inhibited the inflammatory response in intestinal epithelial cells as it significantly and concentration-dependently reduced the LPS-induced secretion of pro-inflammatory TNF-alpha and IL-8 in Caco-2 cells. Furthermore, QHCY treatment inhibited the phosphorylation of IkappaB and the nuclear translocation of NF-kappaB in Caco-2 cells in a concentration-dependent manner, indicating that QHCY suppressed the activation of the NF-kappaB signaling pathway. Collectively, our results suggest that the inhibition of NF-kappaB mediated inflammation may constitute a potential mechanism by which QHCY treats UC. PMID- 23935745 TI - Application of acellular dermal xenografts in full-thickness skin burns. AB - The aim of this study was to explore the clinical value of the porcine acellular dermal xenograft (ADX) in combination with autologous split-thickness skin and pure autologous split-thickness skin grafting applied in deep full-thickness burns and scar wounds. A total of 30 patients with deep burns were randomly divided into experimental and control groups following escharectomy. The patients were separately treated with porcine acellular dermal xenograft (ADX) in combination with autologous split-thickness skin and pure autologous split thickness skin graft. The wound healing was observed routinely and the scores were evaluated using Vancouver scar scale at different times following transplant surgery. The samples of cograft regions and the control group (pure transplant split-thickness skin autograft) were observed using light microscopy and electron microscopy, and the follow-up results were recorded. No conspicuous rejections on the cograft wound surface were observed. Compared with the control group, the cograft wounds were smooth, presented no scar contracture and exhibited good skin elasticity and recovery of the joint function. The cografted skin combined well and displayed a clear and continuous basal membrane, as well as gradually combined skin structure, a mature stratum corneum, downward extended rete pegs, a mainly uniform dermal collagen fiber structure, regular alignment, and fewer blood capillaries. Clear desmosome cograft regions were identified among heckle cells, as well as a clear and continuous basal membrane. The cografted skin of the combined split-thickness autograft and the acellular heterologous (porcine) dermal matrix showed an improved shape and functional recovery compared with the pure split-thickness skin autograft. The combination of the meshed ADX and the split-thickness skin autograft applied in deep full-thickness burns and scar wounds may induce tissue regeneration via dermis aiming. This method also has superior shape and functional recovery, and has an extensive clinical application value. PMID- 23935747 TI - Aspirin inhibits human telomerase activation in unstable carotid plaques. AB - The activation of telomerase in unstable plaques is an important factor in atherosclerosis, and may be predictive of the risk of cerebrovascular diseases. Human telomerase reverse transcriptase (hTERT) is a subunit of telomerase that is essential for telomerase activation. The aim of the present study was to investigate whether aspirin inhibits the activation of telomerase and hTERT in unstable carotid plaques. Polymorphonuclear neutrophils (PMNs) derived from carotid plaques were isolated from the washing medium of angioplasty balloons, while circulating PMNs, isolated from arterial blood, served as the controls. A polymerase chain reaction-based telomeric repeat amplification protocol (TRAP) enzyme-linked immunosorbent assay (ELISA) was used to measure the telomerase activity in the cells following treatment with aspirin. The mRNA and protein expression of hTERT were detected by a reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis, respectively. The results revealed that the atherosclerotic plaques were positive for telomerase activity, and that aspirin inhibited the telomerase activity of the PMNs derived from the plaques. In addition, aspirin was demonstrated to inhibit the mRNA and protein expression of hTERT through the suppression of hTERT transcriptional activity; however, it had no inhibitory effect on the telomerase activity of the circulating PMNs. Thus, the activation of telomerase in resident PMNs is critical in the instability of carotid plaques. The upregulation of telomerase and hTERT during the progression of atherosclerosis may indicate a role for telomerase in the vascular remodeling that occurs during atherogenesis. Aspirin was demonstrated to inhibit the activation of telomerase via an hTERT-dependent manner in the PMN cells of unstable carotid plaques, and thus hTERT may be considered as a target in the treatment of cerebrovascular diseases. PMID- 23935746 TI - Antioxidant and anti-inflammatory effects of Astragalus polysaccharide on EA.hy926 cells. AB - The aim of this study was to explore the role of astragalus polysaccharide (APS) in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm children using an established BPD cell model. EA.hy926 cell cultures were divided into three groups: the air group as the blank control, the hyperoxia group as the experimental control and the APS group (2.5 mg/ml). The production of superoxide dismutase (SOD), malondialdehyde (MDA) and reactive oxygen species (ROS) were analyzed by biochemical assays. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were used to detect the RNA and protein expression levels of inflammatory cytokines, including interleukin (IL)-8, intercellular adhesion molecule 1 (ICAM-1) and nuclear factor (NF)-kappaB p65. Compared with the hyperoxia group, the ROS and MDA levels of the APS group were significantly reduced. By contrast, SOD production was significantly increased. The expression of IL-8, ICAM-1 and NF-kappaB p65 in the APS group was downregulated. APS acts as an antioxidant by stimulating SOD production while inhibiting lipid peroxidation in the EA.hy926 cells. Furthermore, this study demonstrated that APS retards the inflammatory response, as shown by the reduced expression of NF-kappaB p65, IL-8 and ICAM-1 when APS was added. PMID- 23935748 TI - Construction of HCC-targeting artificial miRNAs using natural miRNA precursors. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, particularly in developing countries. Despite the achievements in clinical therapeutics, the HCC mortality rate remains high. A number of artificial microRNA (amiRNA)-based HCC gene therapy studies have demonstrated significant inhibition of invasion and induction of apoptosis of HCC cancer cells, indicating that this type of therapy may be a promising alternative to current therapeutics. Since the structure of the amiRNA precursor in the specific intracellular environment is critical for the processing to mature amiRNA, a precursor structure that may be efficiently processed is desired. In this study, we constructed amiRNAs targeting firefly luciferase with the precursor structures of six HCC-abundant microRNAs: miR-18a, miR-21, miR-192, miR-221, miR-222 and miR 224, and evaluated the processing efficiency of these amiRNAs in the HCC cell lines Hep3B and HepG2 using a luciferase reporter system. The results demonstrated that these amiRNA precursors are capable of being expressed in HCC cells, with the miR-221 precursor-based amiRNA exhibiting the most efficient inhibition on firefly luciferase at the levels of mRNA and protein activity. This finding provides a basis for constructing HCC-targeting amiRNAs with potent processing efficiency using the precursor structure of miR-221. PMID- 23935749 TI - A novel classification to guide total hip arthroplasty for adult acetabular dysplasia. AB - In the field of hip arthroplasties, the secondary fixation of the implants depends directly on the quality of the primary stability. A good acetabular fit and metaphyseal filling between the prostheses and implants improve the initial stabilization, and optimize the transmission of forces to the bone. A precise knowledge of the three-dimensional acetabular or femoral shape is essential to the selection of adapted implants. A total of 63 patients diagnosed with developmental dysplasia were analyzed by three-dimensional computed tomography (3DCT), and the preoperative radiographic and 3DCT images were used to assess the acetabular/femoral deformities and variations of the hips. All joints were classified as Crowe type I, and bilateral measurements were taken for 10 patients. The acetabular abnormalities were classified according to the type of deficiency and the section angles of the acetabulum, with 26 hips (36%) classified as an anterior deficiency, 13 hips (18%) as a posterior deficiency and 34 hips (46%) as a lateral deficiency. The femoral side deformities were divided into three types according to the anteversion angle of the femur. A gradual increase in anteversion angle led to secondary rotational anomalies, and a narrowing of the canal at the isthmus. A total of 35 hips (48%) were classified as an F1 type deficiency, femur anteversion angle (FAVA) <30 degrees ; 32 hips (44%) as F2-type, 30 degrees <= FAVA <=40 degrees , with mild abnormalities of the femoral canal rotation and the diameter of the isthmus; and 6 hips (8%) as F3 type, FAVA >40 degrees , with significant abnormalities of the femoral canal rotation and the diameter of the isthmus. This novel classification for adult acetabular dysplasia may provide a useful guide for surgery, and enable an improved selection of a suitable prosthesis. PMID- 23935750 TI - Thrombocytopenia induces multiple intracranial hemorrhages in patients with severe burns: A review of 16 cases. AB - The aim of this study was to explore the etiology and diagnosis of multiple intracranial hemorrhages (ICHs) following severe burns, with a retrospective review of 16 cases of severe burns further complicated by multiple ICHs. Using cranial CT scans of the brains, we identified that all patients presented with low platelet counts and coagulation abnormalities prior to intracranial hemorrhaging. Following conventional treatment and various supporting treatments, five cases succumbed following a progressive reduction in blood platelet levels and the ICHs were cured in 11 cases following the restoration of normal platelet levels. We conclude that low platelet counts and coagulation abnormalities may cause multiple ICHs following severe burns and early diagnosis and treatment is the key to successful treatment. PMID- 23935751 TI - Preventive effect of resistant starch on activated carbon-induced constipation in mice. AB - The aim of this study was to investigate the effects of resistant starch (RS) on activated carbon-induced constipation in ICR mice. ICR mice were fed on diet containing 15% RS of type RS2, RS3 or RS4 for 9 days. Gastrointestinal transit, defecation time and intestinal tissue histopathological sections, as well as motilin (MTL), gastrin (Gas), endothelin (ET), somatostatin (SS), acetylcholinesterase (AChE), substance P (SP) and vasoactive intestinal peptide (VIP) levels in serum were used to evaluate the preventive effects of RS on constipation. Bisacodyl, a laxative drug, was used as a positive control. The time to the first black stool defecation for normal, control, bisacodyl-treated (100 mg/kg, oral administration) and RS2-, RS3- and RS4-treated mice was 78, 208, 109, 181, 144 and 173 min, respectively. Following the consumption of RS2, RS3 and RS4 or the oral administration of bisacodyl (100 mg/kg), the gastrointestinal transit was reduced to 37.7, 52.1, 39.3 and 87.3%, respectively, of the transit in normal mice, respectively. Histopathological sections of intestinal tissue also underscored the protective effect of RS3. The serum levels of MTL, Gas, ET, AChE, SP and VIP were significantly increased and the serum levels of SS were reduced in the mice treated with RS compared with those in the untreated control mice (P<0.05). These results demonstrate that RS has preventive effects on mouse constipation and RS3 demonstrated the best functional activity. PMID- 23935752 TI - Removal of impacted esophageal foreign bodies with a dual-channel endoscope: 19 cases. AB - There have been few reports concerning the endoscopic removal of impacted esophageal foreign bodies from patients. The objective of this study was to evaluate the effectiveness of dual-channel endoscopy in managing foreign-body ingestions in patients. A total of 19 patients with foreign-body ingestions between September 2008 and July 2011 were selected from the Digestive Endoscope Center in Lishui, a typical middle-sized city in China. The patients underwent endoscopy following admission. The impacted foreign bodies were successfully removed from 18 patients without complications using a dual-channel endoscope. One patient underwent surgery for an ingested denture following the failure of the endoscopic removal method. This study demonstrates that dual-channel endoscopic management may be a useful option for removing ingested foreign bodies from the esophagus. PMID- 23935753 TI - Needle-free injection of 5-aminolevulinic acid in photodynamic therapy for the treatment of condylomata acuminata. AB - The external application of 5-aminolevulinic acid (ALA) in photodynamic therapy (PDT) results in a shallow penetration depth in thick or extensive condylomata acuminata (CA) lesions, thus demonstrating a poor therapeutic effect for those patients. To compare the efficacy of needle-free injection with external application of ALA in PDT for the treatment of CA, 160 CA patients with thick or extensive warts received ALA-PDT by means of external application or needle-free injection of ALA, respectively. The complete response (CR) rate and recurrence rate in the two groups were analyzed. The CR rate after the first treatment in the needle-free injection group (68.8%) was significantly higher compared with that in the external application group (52.5%; P=0.035). The recurrence rates in the needle-free injection group and external application group were 4.1 and 15.4%, respectively (P=0.022). The needle-free injection of ALA increases the therapeutic effect of PDT for CA patients with thick or extensive lesions. It shortens the treatment time and reduces the recurrence rate, and has great potential in the treatment of CA. PMID- 23935754 TI - Effects of the surface characteristics of nanoporous titanium oxide films on Ti 24Nb-4Zr-8Sn alloy on the initial adhesion of osteoblast-like MG-63 cells. AB - The aim of the present study was to investigate the effects of the surface characteristics of nanoporous titanium oxide films, formed by anodization on Ti 24Nb-4Zr-8Sn (Ti2448) alloy, on the early adhesion of osteoblast-like MG-63 cells. Nanoporous titanium oxide films with two different pore sizes (30 and 90 nm) were formed by anodization in NH4F solution on Ti2448 alloy. The surface roughness of the nanoporous titanium oxide films was determined using a Surftest Formtracer and field emission scanning electron microscopy (FESEM). Cell viability was evaluated at different time points using the 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. To investigate the regulatory mechanisms involved in the focal adhesion of osteoblasts to Ti2448 alloy, we quantified the expression levels of integrin beta1 and paxillin mRNAs on the nanoporous titanium oxide films during early osteoblast adhesion using real-time RT-PCR. Samples with a 30-nm nanoporous film exhibited a greater number of overlapping microporous structures with microprojections compared with the 90-nm nanoporous film samples. The MTT assay indicated that cell viability on the 30-nm nanoporous surface following 24 and 48 h of cell culture was higher than those observed on the unanodized control and 90-nm nanoporous surfaces. Integrin beta1 mRNA expression levels on the 30-nm nanoporous surface following cell culture for 48 h were also significantly higher compared with those on the unanodized control and 90-nm nanoporous surfaces. The results demonstrated that a 30-nm nanoporous titanium oxide film on Ti2448 alloy may provide the optimum bioactive implant surface for the initial adhesion of osteoblasts. PMID- 23935755 TI - Stimulation of insulin secretion by large-dose oral arginine administration in healthy adults. AB - The effects of large-dose oral arginine administration on the secretion of insulin by islet beta-cells in healthy adults were determined. Eight non-obese healthy volunteers with normal glucose tolerance participated randomly in tests with four stages (with an interval of at least 3 days): the 300 ml purified water stage (PWS), the 75 g glucose stage (GSS), the 30 g arginine stage (ARS) and the 75 g glucose with 30 g arginine stage (GAS). Venous blood samples were collected to detect the concentrations of glucose and insulin at baseline (0) and at 15, 30, 45, 60 and 120 min after drug administration. The glucose and insulin levels were steady in the PWS. The remaining three stages had similarly shaped insulin concentration-time curves, which differed from that of the PWS. The peak concentration of blood insulin and the net incremental area under the curve of blood insulin in the GSS, ARS and GAS were significantly higher compared with those in the PWS (P<0.05). In the ARS, the glucose levels remained stable; however, the net incremental area under the curve for blood insulin in the ARS was much lower compared with that in the GSS or GAS (P<0.05). Large-dose oral arginine administration may slightly stimulate insulin secretion by islet beta cells in healthy adults with normal glucose tolerance in a manner that is independent of glucose concentration. PMID- 23935756 TI - Evaluation of remifentanil anesthesia for off-pump coronary artery bypass grafting surgery using heart rate variability. AB - Heart rate variability (HRV) was used in the present study to evaluate a target controlled approach compared with a constant-rate infusion for remifentanil anesthesia during off-pump coronary artery bypass grafting (OP-CABG) surgery. A total of 65 patients with American Society of Anesthesiologists (ASA) physical status II or III, who were aged 60-85 years and scheduled for OP-CABG, were selected for the study. All patients were administered an intramuscular premedication of 10 mg morphine and 0.3 mg scopolamine. In group I, remifentanil was infused using a target-controlled approach at 1.5-5.0 ng/ml, and in group II, remifentanil was infused at a constant-rate of 0.05-1.0 MUg/kg/min and at additional single increments of 1 MUg/kg when appropriate. The heart rate and other hemodynamic monitoring indices of the patients, including the mean arterial pressure, central venous pressure, pulmonary artery pressure and pulmonary capillary wedge pressure, were monitored at various time points, including prior to induction (T0), at extubation (performed intraoperatively; T7) and at 24 h post-surgery. The HRV indices, including total power (TP), low frequency (LF) and the LF/high frequency (HF) ratio of power (LF/HF), were reduced following induction at T0 and remained low at 24 h post-surgery. At T5 (right coronary or left circumflex artery anastomosis) and T7 (tracheal extubation), all the HRV indices, with the exception of the HF power, were significantly increased (P<0.05). Additionally, the TP, LF and LF/HF values in group II were higher at T5 compared with those in group I (P<0.05). Remifentanil target-controlled infusion is superior to constant-rate infusion in suppressing the stress response during OP-CABG, maintaining the balance of the cardiac autonomic nervous system and promoting the recovery of the autonomic function following surgery. PMID- 23935757 TI - Takotsubo cardiomyopathy recurrence with left ventricular apical ballooning following isolated right ventricular involvement: A case report. AB - We report a case of Takotsubo cardiomyopathy, which involved the right ventricle at first presentation and demonstrated involvement of the left ventricle during recurrence. The patient was admitted to Kyung Hee University Hospital due to a left hip fracture, which was considered a result of physical stress. Complete recovery was confirmed by echocardiography prior to recurrence. The cause of the second event was surgery for the left hip fracture. Recurrence of Takotsubo cardiomyopathy at various cardiac locations provides evidence against the existing hypotheses that variants of Takotsubo cardiomyopathy are associated with anatomically different distributions of cardiac adrenergic receptors, the degree of stimulation by sympathetic activity and different susceptibilities to such sympathetic stimulation. PMID- 23935758 TI - Progesterone attenuates cerebral edema in neonatal rats with hypoxic-ischemic brain damage by inhibiting the expression of matrix metalloproteinase-9 and aquaporin-4. AB - The aim of this study was to investigate the effects of progesterone (PROG) on blood-brain barrier (BBB) permeability, cerebral edema and the expression of matrix metalloproteinase-9 (MMP-9) and aquaporin-4 (AQP-4) in neonatal rats with hypoxic-ischemic brain damage (HIBD) and to explore the mechanism of its neuroprotective effect. Sixty 7-day-old Wistar rats were divided into sham surgery, hypoxic ischemia (HI) and drug prophylaxis (PROG) groups. HIBD animal models were established. All the animals were sacrificed after 24 h. The BBB was assessed using Evans blue. Cerebral moisture capacity was determined using the dry-wet method. MMP-9 was detected in the brain tissues using enzyme-linked immunosorbent assay. The expression of AQP-4 and MMP-9 in the cerebral cortex was observed using immunohistochemistry and real-time polymerase chain reaction. The MMP-9 levels in the cortex, BBB permeability, cerebral moisture capacity and expression of AQP-4 and MMP-9 in the HI group were significantly higher compared with those in the sham surgery group (P<0.01), and they were significantly lower in the drug prophylaxis group compared with those in the HI group (P<0.05). In conclusion, PROG reduces BBB damage and cerebral edema and inhibits MMP-9 generation to protect rat brains against HIBD. The protective effect of PROG may be correlated with downregulated expression of AQP-4 and MMP-9 in the cerebral cortex. PMID- 23935759 TI - Comparison of optic nerve morphology in eyes with glaucoma and eyes with non arteritic anterior ischemic optic neuropathy by Fourier domain optical coherence tomography. AB - The aim of this study was to compare the optic nerve head (ONH) and peripapillary retinal nerve fiber layer (RNFL) thickness in eyes with glaucoma and non arteritic anterior ischemic neuropathy (NAION) by Fourier domain optical coherence tomography (FDOCT), and to evaluate the diagnostic capability of FDOCT in glaucoma and NAION. This study included 26 eyes with glaucoma (36.6%), 15 eyes with NAION (21.1%) and 30 eyes of normal subjects (42.3%). Those with the following conditions were excluded; a visual field defect greater than one hemifield, spherical equivalent (SE) more than +/-6 D, or the onset of NAION within 6 months. FDOCT was used to analyze the characteristics of ONH and RNFL thickness. Among the three groups of subjects, glaucomatous eyes had the largest cup area and cup volume, and the smallest rim area, rim volume and disc volume (P<0.05). NAION eyes had the smallest cup area and cup volume (P<0.05), but their rim area, rim volume and disc volume were comparable to those of control eyes (P>0.05). The cup-to-disc (C/D) ratio was increased in glaucomatous eyes but reduced in NAION eyes compared with control eyes. Glaucomatous eyes had the greatest loss of RNFL thickness in the temporal upper (TU), superior temporal (ST) and temporal lower (TL) regions (P<0.05), whereas NAION eyes had the smallest RNFL thickness in the superior nasal (SN) and nasal upper (NU) regions (P<0.05). The areas under the receiver operator characteristic curve (AROCs) of the temporal, superior and inferior RNFL in glaucomatous eyes were greater compared with that of the disc area (P<0.05). In addition, the AROCs of the temporal, superior and inferior RNFL were higher compared with that of nasal RNFL (P<0.05). The AROCs of all parameters for NAION were not significantly different, with the exception of superior, nasal superior and inferior temporal RNFL (P<0.05). In conclusion, FDOCT is able to detect quantitative differences in the optic disc morphology and RNFL thickness between glaucomatous and NAION eyes. These differences may provide new insights into the clinical characteristics and diagnosis of the two diseases. PMID- 23935760 TI - Analgesic effects of the COX-2 inhibitor parecoxib on surgical pain through suppression of spinal ERK signaling. AB - Cyclooxygenase (COX)-2 inhibitors are widely used for postoperative pain control in clinical practice. However, it is unknown whether spinal sensitization is involved in the analgesic effects of COX-2 inhibitors on surgical pain. Extracellular signal-regulated kinase (ERK) in the spinal cord is implicated in various types of pain, including surgical pain. The present study investigated the role of spinal ERK signaling in the analgesic effect of the COX-2 inhibitor parecoxib on surgical pain. Surgical pain was produced in rats by surgical incision of the hind paw. Phosphorylated (p)-ERK1/2 expression was determined by immunohistochemistry. Pain hypersensitivity was evaluated by measuring the paw withdrawal threshold using the von Frey test. The selective COX-2 inhibitor parecoxib was delivered 20 min before or 20 min after the incision by intraperitoneal injection. Pretreatment with parecoxib markedly attenuated the pain hypersensitivity induced by incision. However, post-treatment with parecoxib produced minimal analgesic effects. Parecoxib inhibited the increase in spinal p ERK expression following surgical incision. The present study thus suggests that the COX-2 inhibitor parecoxib exerts its analgesic effect on surgical pain through the inhibition of neuronal ERK activation in the spinal cord. COX-2 inhibitor delivery prior to surgery has more potent analgesic effects, suggesting the advantage of preventive analgesia for post-operative pain control. PMID- 23935761 TI - Health Technology Assessment - science or art? AB - The founding disciplines of HTA are clearly scientific, and have been firmly based among the natural sciences. However, common definitions of HTA indicate that HTA is something more than the "pure application of science". This article investigates whether this "something" also makes HTA an art. The question of whether HTA is a science or an art is pursued in two specific and historically rich directions. The first is whether HTA is an art in the same way that medicine is described as an art. It has been argued extensively that medicine is based on two different and partly incompatible cultures, i.e., the natural sciences and humanities. Medicine is based on disciplines within the natural sciences, while its value judgments have been placed in the humanities camp. This dichotomy is present in HTA as well, and the first part of the investigation illustrates how HTA is an art in terms of its inherent and constitutive value-judgments. The second part of the science/art-scrutiny leads us to the ancient (Hippocratic) concept of art, techne, where we find an etymological and a conceptual link between HTA and art. It demonstrates HTA is not an arbitrary process, even though it involves value judgments and relates complex decision making processes. As an art (techne) HTA has a specific subject matter, requires inquiry and mastery of general rational principles, and is oriented to a specific end. In conclusion, the science-or-art-question makes sense in two specific perspectives, illustrating that HTA is a science based art. This has implications for the practice of HTA, for its education, and for the status of its results. PMID- 23935762 TI - The effectiveness of occupational therapy for persons with moderate and severe dementia. AB - An occupational therapy tailored for persons concerned with moderate to severe dementia is effective. Occupational therapy applies in a targeted manner activities as therapeutic measure. Aim is a high quality of life in everyday life - also without drugs. Mental capacity and independence in daily routine shall be maintained as long as possible. Occupational therapy can be more cost-effective than medical treatment because it reduces the nursing expenditures. PMID- 23935763 TI - The Organizational Health of Urban Elementary Schools: School Health and Teacher Functioning. AB - This study examined the factor structure of the Organizational Health Inventory Elementary version (OHI-E; Hoy, Tarter, & Kottkamp, 1991) in a sample of 203 teachers working in 19 high-poverty, urban schools and the association of organizational school health with teacher efficacy, teacher stress, and job satisfaction. Results indicated a similar factor structure of the OHI-E as compared with the population of schools in the original sample (Hoy et al., 1991), and that specific components of organizational health, such as a positive learning environment, are associated with teacher efficacy, stress, and satisfaction. Overall, teachers' relations with their peers, their school leadership, and their students appear especially critical in high-poverty, urban schools. Recommendations for research and practice related to improving high poverty, urban schools are presented. PMID- 23935764 TI - Interaction between sex and apolipoprotein e genetic background in a murine model of intracerebral hemorrhage. AB - Emerging evidence suggests sex and apolipoprotein E (APOE) genotype separately modify outcomes after intracerebral hemorrhage (ICH). We test the hypothesis that an interaction exists between sex and APOE polymorphism in modifying outcomes after ICH and is altered by administration of exogenous apoE-mimetic peptide. To define the effects of sex and APOE polymorphism in ICH, we created collagenase induced ICH in male and female APOETR mice (targeted replacement mice homozygous for APOE3 or APOE4 alleles; n=12/group) and assessed performance on Rotarod (RR) and Morris water maze (MWM). To evaluate hematoma formation, we used hematoxylin and eosin staining at 24 h after injury (n=8/group). Using separate cohorts (n=12/group), apoE-mimetic peptide (COG1410 at 2 mg/kg) was administered after ICH, and mice were assessed by RR and MWM. Female mice outperformed male mice via RR and MWM by over 190% improvement through 7 days (RR) and 32 days (MWM) of testing after ICH (p<0.01). Female APOE3TR mice demonstrated improved function compared with all other groups (p<0.05) without any difference in hematoma volume at 24 h after injury in any group. Administration of a therapeutic apoE-mimetic peptide improved RR latencies through 7 days after ICH in male and female APOE4TR mice and MWM latencies over days 28-32 after ICH in male APOE4TR mice (p<0.05). Sex and APOE polymorphism influence functional outcomes in our murine model of ICH. Moreover, administration of exogenous apoE-mimetic peptide after injury differentially modifies the interaction between sex and APOE polymorphism. PMID- 23935765 TI - Computed tomography-based centrilobular emphysema subtypes relate with pulmonary function. AB - INTRODUCTION: Centrilobular emphysema (CLE) is recognized as low attenuation areas (LAA) with centrilobular pattern on high-resolution computed tomography (CT). However, several shapes of LAA are observed. Our preliminary study showed three types of LAA in CLE by CT-pathologic correlations. This study was performed to investigate whether the morphological features of LAA affect pulmonary functions. MATERIALS AND METHODS: A total of 73 Japanese patients with stable CLE (63 males, 10 females) were evaluated visually by CT and classified into three subtypes based on the morphology of LAA including shape and sharpness of border; patients with CLE who shows round or oval LAA with well-defined border (Subtype A), polygonal or irregular-shaped LAA with ill-defined border (Subtype B), and irregular-shaped LAA with ill-defined border coalesced with each other (Subtype C). CT score, pulmonary function test and smoking index were compared among three subtypes. RESULTS: Twenty (27%), 45 (62%) and 8 cases (11%) of the patients were grouped into Subtype A, Subtype B and Subtype C, respectively. In CT score and smoking index, both Subtype B and Subtype C were significantly higher than Subtype A. In FEV1%, Subtype C was significantly lower than both Subtype A and Subtype B. In diffusing capacity of lung for carbon monoxide, Subtype B was significantly lower than Subtype A. CONCLUSION: The morphological differences of LAA may relate with an airflow limitation and alveolar diffusing capacity. To assess morphological features of LAA may be helpful for the expectation of respiratory function. PMID- 23935766 TI - Impact of blood cultures on the changes of treatment in hospitalized patients with community-acquired pneumonia. AB - BACKGROUND: Initial blood cultures (BCs) with severe community-acquired pneumonia (CAP) are warranted. However, other than severity, the specific contributing factors that affect the decision to change antimicrobial agents have not been evaluated previously. METHODS: Consecutive adults with CAP hospitalized between January 2008 and December 2010 were assessed retrospectively. We enrolled those who were over 18 years old with typical symptoms of pneumonia and with an infiltrate consistent with pneumonia, from which 2 sets of BCs were obtained. Those who had been immunocompromised, hospitalized, or prescribed antibiotics in the past 30 days were excluded. We retrospectively assessed the factors contributing to the change in antimicrobial agents as well as the frequency of these changes in the enrolled patients based on the initial BC results. RESULTS: In total, 793 patients with initial diagnosis of CAP were admitted; 399 met the inclusion criteria. Among them, 386 were made definitive diagnosis of CAP after admission (the remaining 13 were made alternative diagnosis [non-pneumonia illnesses]). BC results were positive in 17 (4.4%) out of 386 CAP patients, among whom antimicrobial therapy was changed based on the BC results in 8 (2.1%) (Pneumonia Severity Index [PSI] grade IV; 2, PSI grade V; 6). Alternative diagnosis after admission was contributing factors for changing antimicrobial agents based on the positive blood culture results. CONCLUSIONS: The use of BCs should be limited to patients with very severe cases. It would be helpful to find alternative diagnosis and modify treatment. PMID- 23935768 TI - Employment Status, Quality of Matching, and Retirement in Korea: Evidence from Korean Longitudinal Study of Aging. AB - This paper explores the differing probabilities of retirement for self-employed and wage-and-salary workers. It finds self-employed workers are less likely to retire than wage-and-salary ones, and that differences in retirement incomes, health, productivity, job characteristics, and compulsory retirement practices do not explain the disparity. The difference between self-employed and wage-and salary workers in the quality of matching between the job and the worker (i.e., between required and desired amount of work) explains the later retirement of the self-employed. We note the implications of these findings for labor-force participation at older ages and how policies might boost employment of the elderly. PMID- 23935767 TI - Decreased exhaled nitric oxide levels in patients with mitochondrial disorders. AB - BACKGROUND: Nitric oxide (NO) deficiency may occur in mitochondrial disorders (MD) and can contribute to the pathogenesis of the disease. It is difficult and invasive to measure systemic nitric oxide. NO is formed in the lungs and can be detected in expired air. Currently, hand-held fractional exhaled nitric oxide (FeNO) measurement devices are available enabling a fast in-office analysis of this non-invasive test. It was postulated that FeNO levels might be reduced in MD. METHODS: Sixteen subjects with definite MD by modified Walker criteria (4 to 30 years of age) and sixteen healthy control subjects of similar age, race and body mass index (BMI) underwent measurement of FeNO in accordance with the American Thoracic Society guidelines. RESULTS: Sixteen patient-control pairs were recruited. The median FeNO level was 6.5 ppm (IQR: 4-9.5) and 10.5 ppm (IQR: 8 20.5) in the MD and control groups, respectively. In 13 pairs (81%), the FeNO levels were lower in the MD cases than in the matched controls (p=0.021). Eleven (69%) cases had very low FeNO levels (<=7ppm) compared to only 1 control (p=0.001). All cases with enzymatic deficiencies in complex I had FeNO <=7ppm. CONCLUSIONS: Single-breath exhaled nitric oxide recordings were decreased in patients with MD. This pilot study suggests that hand-held FeNO measurements could be an attractive non-invasive indicator of MD. In addition, measurement of FeNO could be used as a parameter to monitor therapeutic response in this population. PMID- 23935769 TI - Significance of p16 in Site-specific HPV Positive and HPV Negative Head and Neck Squamous Cell Carcinoma. AB - Expression of p16INK4A (p16 positive) is highly correlated with human papilloma virus (HPV) infection in head and neck squamous cell carcinoma (HNSCC), however, p16-positivity is not limited to HPV positive tumors and therefore, not a perfect surrogate for HPV. p16 survival outcomes are best documented for the oropharyngeal site (OP); non-OP sites such as the oral cavity (OC), larynx, and hypopharynx (HP) are understudied. The goal of this study was to evaluate p16 in the context of HPV16 and examine p16 survival outcomes in HPV16 positive and HPV16 negative site-specific HNSCC. p16 and HPV16 status were determined by immunohistochemistry and qPCR respectively, on 80 primary HNSCC from four sites: OC, OP, larynx and HP. p16 expression was different across sites (p<0.001), was more frequent in OP than non-OP sites (p<0.0001), and was different between Caucasian Americans (CA) and African Americans (AA) (p=0.031), similar to HPV (p=0.013). p16 was associated with marital status (p=0.008) and smoking (p=0.014). p16 positive patients had improved survival (similar to HPV16 positive cases). Patients with p16 negative/HPV16 negative status had the worst survival for all sites combined as well as for OP. p16 status is an important prognostic indicator in both OPSCC and non-OPSCC and the p16 positive/HPV16 negative group is likely a distinct subgroup lacking any HPV genotype. Cohorts with larger representations of non-OP sites examining multiple molecular markers will be key to deciphering and dissecting out p16's role as a useful prognostic indicator when assessed in combination with HPV status. PMID- 23935770 TI - On the Validity of the Rapid Estimate of Adult Literacy in Medicine (REALM) Scale as a Measure of Health Literacy. AB - Originally developed to measure the literacy level of patients, the Rapid Estimate of Adult Literacy in Medicine (REALM) scale is one of the most widely used instruments to measure the construct of health literacy. This article critically examines the validity of the REALM as a measure of health literacy. Logical analysis of content coverage led to the conclusion that scores on the REALM should not be used to make inferences about a person's level of health literacy. Rather, the REALM should be used to make inferences about the ability of a person to read and pronounce health related terms. Evidence from an analysis of a sample of 1,037 respondents to the REALM with a cancer diagnosis supports the quality of the REALM as a measure of reading and pronunciation ability. Other uses of the REALM in health literacy research are discussed. PMID- 23935771 TI - FIELD NOTES: PEOPLE, PROGRAMS, & POLICIES Farmers' Market Produce Delivery Program for Mitigating Nutritional Risk in Older Adults. AB - Community-dwelling older adults in disadvantaged neighborhoods may face nutritional risks not mitigated by existing programs. The Senior Market Basket Program, administered by nonprofit organization P.E.E.R., Inc., is a unique approach to serving community-dwelling senior adults and a valuable model for integrating targeted social services into local food systems. The program ensures access to fresh produce during the growing season for a defined target population. PMID- 23935801 TI - Topographic hub maps of the human structural neocortical network. AB - Hubs within the neocortical structural network determined by graph theoretical analysis play a crucial role in brain function. We mapped neocortical hubs topographically, using a sample population of 63 young adults. Subjects were imaged with high resolution structural and diffusion weighted magnetic resonance imaging techniques. Multiple network configurations were then constructed per subject, using random parcellations to define the nodes and using fibre tractography to determine the connectivity between the nodes. The networks were analysed with graph theoretical measures. Our results give reference maps of hub distribution measured with betweenness centrality and node degree. The loci of the hubs correspond with key areas from known overlapping cognitive networks. Several hubs were asymmetrically organized across hemispheres. Furthermore, females have hubs with higher betweenness centrality and males have hubs with higher node degree. Female networks have higher small-world indices. PMID- 23935816 TI - Diagnosis of Barmah Forest virus infection by a nested real-time SYBR green RT PCR assay. AB - Barmah Forest virus (BFV) is a mosquito borne (+) ssRNA alphavirus found only in Australia. It causes rash, myalgia and arthralgia in humans and is usually diagnosed serologically. We developed a real-time PCR assay to detect BFV in an effort to improve diagnosis early in the course of infection. The limit of detection was 16 genome equivalents with a specificity of 100%. Fifty five serum samples from BFV-infected patients were tested by the PCR. 52 of 53 antibody positive samples were PCR negative. Two culture-positive (neutralizing antibody negative) samples were positive on first round PCR, while one sample (IgM and neutralizing antibody strongly positive, IgG negative) was positive on second round PCR, suggesting that viral RNA is detectable and transiently present in early infection. PCR can provide results faster than culture, is capable of high throughput and by sequencing the PCR product strain variants can be characterized. PMID- 23935817 TI - Short-term effect of El Nino-Southern Oscillation on pediatric hand, foot and mouth disease in Shenzhen, China. AB - Hand, foot and mouth disease (HFMD) was an emerging viral infectious disease in recent years in Shenzhen. The underlying risk factors have not yet been systematically examined. This study analyzed the short-term effect of El Nino Southern Oscillation on pediatric HFMD in Shenzhen, China. Daily count of HFMD among children aged below 15 years old, Southern Oscillation Index (SOI), and weather variables were collected to construct the time series. A distributed lag non-linear model was applied to investigate the effect of daily SOI on pediatric HFMD occurrence during 2008-2010. We observed an acute effect of SOI variation on HFMD occurrence. The extremely high SOI (SOI = 45, with 0 as reference) was associated with increased HFMD, with the relative risk (RR) being 1.66 (95% Confidence Interval [CI]: 1.34-2.04). Further analyses of the association between HFMD and daily mean temperature and relative humidity supported the correlation between pediatric HFMD and SOI. Meteorological factors might be important predictors of pediatric HFMD occurrence in Shenzhen. PMID- 23935818 TI - Computer-assisted teaching of skin flap surgery: validation of a mobile platform software for medical students. AB - The purpose of this study was to develop and validate a multimedia software application for mobile platforms to assist in the teaching and learning process of design and construction of a skin flap. Traditional training in surgery is based on learning by doing. Initially, the use of cadavers and animal models appeared to be a valid alternative for training. However, many conflicts with these training models prompted progression to synthetic and virtual reality models. Fifty volunteer fifth- and sixth-year medical students completed a pretest and were randomly allocated into two groups of 25 students each. The control group was exposed for 5 minutes to a standard text-based print article, while the test group used multimedia software describing how to fashion a rhomboid flap. Each group then performed a cutaneous flap on a training bench model while being evaluated by three blinded BSPS (Brazilian Society of Plastic Surgery) board-certified surgeons using the OSATS (Objective Structured Assessment of Technical Skill) protocol and answered a post-test. The text-based group was then tested again using the software. The computer-assisted learning (CAL) group had superior performance as confirmed by checklist scores (p<0.002), overall global assessment (p = 0.017) and post-test results (p<0.001). All participants ranked the multimedia method as the best study tool. CAL learners exhibited better subjective and objective performance when fashioning rhomboid flaps as compared to those taught with standard print material. These findings indicate that students preferred to learn using the multimedia method. PMID- 23935819 TI - Novel 5' untranslated region directed blockers of iron-regulatory protein-1 dependent amyloid precursor protein translation: implications for down syndrome and Alzheimer's disease. AB - We reported that iron influx drives the translational expression of the neuronal amyloid precursor protein (APP), which has a role in iron efflux. This is via a classic release of repressor interaction of APP mRNA with iron-regulatory protein 1 (IRP1) whereas IRP2 controls the mRNAs encoding the L- and H-subunits of the iron storage protein, ferritin. Here, we identified thirteen potent APP translation blockers that acted selectively towards the uniquely configured iron responsive element (IRE) RNA stem loop in the 5' untranslated region (UTR) of APP mRNA. These agents were 10-fold less inhibitory of 5'UTR sequences of the related prion protein (PrP) mRNA. Western blotting confirmed that the 'ninth' small molecule in the series selectively reduced neural APP production in SH-SY5Y cells at picomolar concentrations without affecting viability or the expression of alpha-synuclein and ferritin. APP blocker-9 (JTR-009), a benzimidazole, reduced the production of toxic Abeta in SH-SY5Y neuronal cells to a greater extent than other well tolerated APP 5'UTR-directed translation blockers, including posiphen, that were shown to limit amyloid burden in mouse models of Alzheimer's disease (AD). RNA binding assays demonstrated that JTR-009 operated by preventing IRP1 from binding to the IRE in APP mRNA, while maintaining IRP1 interaction with the H-ferritin IRE RNA stem loop. Thus, JTR-009 constitutively repressed translation driven by APP 5'UTR sequences. Calcein staining showed that JTR-009 did not indirectly change iron uptake in neuronal cells suggesting a direct interaction with the APP 5'UTR. These studies provide key data to develop small molecules that selectively reduce neural APP and Abeta production at 10-fold lower concentrations than related previously characterized translation blockers. Our data evidenced a novel therapeutic strategy of potential impact for people with trisomy of the APP gene on chromosome 21, which is a phenotype long associated with Down syndrome (DS) that can also cause familial Alzheimer's disease. PMID- 23935820 TI - Pathogen-host associations and predicted range shifts of human monkeypox in response to climate change in central Africa. AB - Climate change is predicted to result in changes in the geographic ranges and local prevalence of infectious diseases, either through direct effects on the pathogen, or indirectly through range shifts in vector and reservoir species. To better understand the occurrence of monkeypox virus (MPXV), an emerging Orthopoxvirus in humans, under contemporary and future climate conditions, we used ecological niche modeling techniques in conjunction with climate and remote sensing variables. We first created spatially explicit probability distributions of its candidate reservoir species in Africa's Congo Basin. Reservoir species distributions were subsequently used to model current and projected future distributions of human monkeypox (MPX). Results indicate that forest clearing and climate are significant driving factors of the transmission of MPX from wildlife to humans under current climate conditions. Models under contemporary climate conditions performed well, as indicated by high values for the area under the receiver operator curve (AUC), and tests on spatially randomly and non-randomly omitted test data. Future projections were made on IPCC 4(th) Assessment climate change scenarios for 2050 and 2080, ranging from more conservative to more aggressive, and representing the potential variation within which range shifts can be expected to occur. Future projections showed range shifts into regions where MPX has not been recorded previously. Increased suitability for MPX was predicted in eastern Democratic Republic of Congo. Models developed here are useful for identifying areas where environmental conditions may become more suitable for human MPX; targeting candidate reservoir species for future screening efforts; and prioritizing regions for future MPX surveillance efforts. PMID- 23935821 TI - Development and evaluation of an algorithm for the computer-assisted segmentation of the human hypothalamus on 7-Tesla magnetic resonance images. AB - Post mortem studies have shown volume changes of the hypothalamus in psychiatric patients. With 7T magnetic resonance imaging this effect can now be investigated in vivo in detail. To benefit from the sub-millimeter resolution requires an improved segmentation procedure. The traditional anatomical landmarks of the hypothalamus were refined using 7T T1-weighted magnetic resonance images. A detailed segmentation algorithm (unilateral hypothalamus) was developed for colour-coded, histogram-matched images, and evaluated in a sample of 10 subjects. Test-retest and inter-rater reliabilities were estimated in terms of intraclass correlation coefficients (ICC) and Dice's coefficient (DC). The computer-assisted segmentation algorithm ensured test-retest reliabilities of ICC>=.97 (DC>=96.8) and inter-rater reliabilities of ICC>=.94 (DC = 95.2). There were no significant volume differences between the segmentation runs, raters, and hemispheres. The estimated volumes of the hypothalamus lie within the range of previous histological and neuroimaging results. We present a computer-assisted algorithm for the manual segmentation of the human hypothalamus using T1-weighted 7T magnetic resonance imaging. Providing very high test-retest and inter-rater reliabilities, it outperforms former procedures established at 1.5T and 3T magnetic resonance images and thus can serve as a gold standard for future automated procedures. PMID- 23935815 TI - The age-specific quantitative effects of metabolic risk factors on cardiovascular diseases and diabetes: a pooled analysis. AB - BACKGROUND: The effects of systolic blood pressure (SBP), serum total cholesterol (TC), fasting plasma glucose (FPG), and body mass index (BMI) on the risk of cardiovascular diseases (CVD) have been established in epidemiological studies, but consistent estimates of effect sizes by age and sex are not available. METHODS: We reviewed large cohort pooling projects, evaluating effects of baseline or usual exposure to metabolic risks on ischemic heart disease (IHD), hypertensive heart disease (HHD), stroke, diabetes, and, as relevant selected other CVDs, after adjusting for important confounders. We pooled all data to estimate relative risks (RRs) for each risk factor and examined effect modification by age or other factors, using random effects models. RESULTS: Across all risk factors, an average of 123 cohorts provided data on 1.4 million individuals and 52,000 CVD events. Each metabolic risk factor was robustly related to CVD. At the baseline age of 55-64 years, the RR for 10 mmHg higher SBP was largest for HHD (2.16; 95% CI 2.09-2.24), followed by effects on both stroke subtypes (1.66; 1.39-1.98 for hemorrhagic stroke and 1.63; 1.57-1.69 for ischemic stroke). In the same age group, RRs for 1 mmol/L higher TC were 1.44 (1.29-1.61) for IHD and 1.20 (1.15-1.25) for ischemic stroke. The RRs for 5 kg/m(2) higher BMI for ages 55-64 ranged from 2.32 (2.04-2.63) for diabetes, to 1.44 (1.40-1.48) for IHD. For 1 mmol/L higher FPG, RRs in this age group were 1.18 (1.08-1.29) for IHD and 1.14 (1.01-1.29) for total stroke. For all risk factors, proportional effects declined with age, were generally consistent by sex, and differed by region in only a few age groups for certain risk factor-disease pairs. CONCLUSION: Our results provide robust, comparable and precise estimates of the effects of major metabolic risk factors on CVD and diabetes by age group. PMID- 23935822 TI - Involvement of TRPM2 in peripheral nerve injury-induced infiltration of peripheral immune cells into the spinal cord in mouse neuropathic pain model. AB - Recent evidence suggests that transient receptor potential melastatin 2 (TRPM2) expressed in immune cells plays an important role in immune and inflammatory responses. We recently reported that TRPM2 expressed in macrophages and spinal microglia contributes to the pathogenesis of inflammatory and neuropathic pain aggravating peripheral and central pronociceptive inflammatory responses in mice. To further elucidate the contribution of TRPM2 expressed by peripheral immune cells to neuropathic pain, we examined the development of peripheral nerve injury induced neuropathic pain and the infiltration of immune cells (particularly macrophages) into the injured nerve and spinal cord by using bone marrow (BM) chimeric mice by crossing wildtype (WT) and TRPM2-knockout (TRPM2-KO) mice. Four types of BM chimeric mice were prepared, in which irradiated WT or TRPM2-KO recipient mice were transplanted with either WT-or TRPM2-KO donor mouse-derived green fluorescence protein-positive (GFP(+)) BM cells (TRPM2(BM+/Rec+), TRPM2(BM /Rec+), TRPM2(BM+/Rec-), and TRPM2(BM-/Rec-) mice). Mechanical allodynia induced by partial sciatic nerve ligation observed in TRPM2(BM+/Rec+) mice was attenuated in TRPM2(BM-/Rec+), TRPM2(BM+/Rec-), and TRPM2(BM-/Rec-) mice. The numbers of GFP(+) BM-derived cells and Iba1/GFP double-positive macrophages in the injured sciatic nerve did not differ among chimeric mice 14 days after the nerve injury. In the spinal cord, the number of GFP(+) BM-derived cells, particularly GFP/Iba1 double-positive macrophages, was significantly decreased in the three TRPM2-KO chimeric mouse groups compared with TRPM2(BM+/Rec+) mice. However, the numbers of GFP(-)/Iba1(+) resident microglia did not differ among chimeric mice. These results suggest that TRPM2 plays an important role in the infiltration of peripheral immune cells, particularly macrophages, into the spinal cord, rather than the infiltration of peripheral immune cells into the injured nerves and activation of spinal-resident microglia. The spinal infiltration of macrophages mediated by TRPM2 may contribute to the pathogenesis of neuropathic pain. PMID- 23935823 TI - Sex and breed-dependent organ development and metabolic responses in foetuses from lean and obese/leptin resistant swine. AB - The present study aimed to determine the effects of breed and sex on growth patterns and metabolic features of advanced-pregnancy foetuses exposed to the same environmental conditions. Thus, at Day 62 of pregnancy, swine foetuses from an obese breed with leptin resistance (Iberian breed) were compared to lean crossbred foetuses (25% Large White *25% Landrace *50% Pietrain). There were differential developmental patterns in foetuses with leptin resistance, mainly a higher relative weight of the brain resembling "brain-sparing effect". Prioritization of brain growth may be protective for the adequate growth and postnatal survival of the Iberian individuals, an ancient breed reared in extensive semi-feral conditions for centuries. There were also clear sex-related differences in foetal development and metabolism in the Iberian breed. Female Iberian foetuses were similar in size and weight to male littermates but had a significantly higher relative liver to body weight ratio resembling "liver sparing effect" and a trend for a higher relative intestine to body ratio. Moreover, the availability of triglycerides, cholesterol and IL-6 in female Iberian foetuses was similar to that of lean crossbred foetuses. Overall, these features may favour a better postnatal survival and development of females, the sex more critical for the species survival. These findings set the basis for future translational studies aimed at increasing the knowledge on the interaction between genetic and environmental factors in the early programming of the adult phenotype. PMID- 23935825 TI - Do bodily expressions compete with facial expressions? Time course of integration of emotional signals from the face and the body. AB - The decoding of social signals from nonverbal cues plays a vital role in the social interactions of socially gregarious animals such as humans. Because nonverbal emotional signals from the face and body are normally seen together, it is important to investigate the mechanism underlying the integration of emotional signals from these two sources. We conducted a study in which the time course of the integration of facial and bodily expressions was examined via analysis of event-related potentials (ERPs) while the focus of attention was manipulated. Distinctive integrating features were found during multiple stages of processing. In the first stage, threatening information from the body was extracted automatically and rapidly, as evidenced by enhanced P1 amplitudes when the subjects viewed compound face-body images with fearful bodies compared with happy bodies. In the second stage, incongruency between emotional information from the face and the body was detected and captured by N2. Incongruent compound images elicited larger N2s than did congruent compound images. The focus of attention modulated the third stage of integration. When the subjects' attention was focused on the face, images with congruent emotional signals elicited larger P3s than did images with incongruent signals, suggesting more sustained attention and elaboration of congruent emotional information extracted from the face and body. On the other hand, when the subjects' attention was focused on the body, images with fearful bodies elicited larger P3s than did images with happy bodies, indicating more sustained attention and elaboration of threatening information from the body during evaluative processes. PMID- 23935824 TI - YjcC, a c-di-GMP phosphodiesterase protein, regulates the oxidative stress response and virulence of Klebsiella pneumoniae CG43. AB - This study shows that the expression of yjcC, an in vivo expression (IVE) gene, and the stress response regulatory genes soxR, soxS, and rpoS are paraquat inducible in Klebsiella pneumoniae CG43. The deletion of rpoS or soxRS decreased yjcC expression, implying an RpoS- or SoxRS-dependent control. After paraquat or H2O2 treatment, the deletion of yjcC reduced bacterial survival. These effects could be complemented by introducing the DeltayjcC mutant with the YjcC expression plasmid pJR1. The recombinant protein containing only the YjcC-EAL domain exhibited phosphodiesterase (PDE) activity; overexpression of yjcC has lower levels of cyclic di-GMP. The yjcC deletion mutant also exhibited increased reactive oxygen species (ROS) formation, oxidation damage, and oxidative stress scavenging activity. In addition, the yjcC deletion reduced capsular polysaccharide production in the bacteria, but increased the LD50 in mice, biofilm formation, and type 3 fimbriae major pilin MrkA production. Finally, a comparative transcriptome analysis showed 34 upregulated and 29 downregulated genes with the increased production of YjcC. The activated gene products include glutaredoxin I, thioredoxin, heat shock proteins, chaperone, and MrkHI, and proteins for energy metabolism (transporters, cell surface structure, and transcriptional regulation). In conclusion, the results of this study suggest that YjcC positively regulates the oxidative stress response and mouse virulence but negatively affects the biofilm formation and type 3 fimbriae expression by altering the c-di-GMP levels after receiving oxidative stress signaling inputs. PMID- 23935827 TI - Elevated frequency of cataracts in birds from chernobyl. AB - BACKGROUND: Radiation cataracts develop as a consequence of the effects of ionizing radiation on the development of the lens of the eye with an opaque lens reducing or eliminating the ability to see. Therefore, we would expect cataracts to be associated with reduced fitness in free-living animals. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the incidence of lens opacities typical of cataracts in more than 1100 free-living birds in the Chernobyl region in relation to background radiation. The incidence of cataracts increased with level of background radiation both in analyses based on a dichotomous score and in analyses of continuous scores of intensity of cataracts. The odds ratio per unit change in the regressor was 0.722 (95% CI 0.648, 0.804), which was less than odds ratios from investigations of radiation cataracts in humans. The relatively small odds ratio may be due to increased mortality in birds with cataracts. We found a stronger negative relationship between bird abundance and background radiation when the frequency of cataracts was higher, but also a direct effect of radiation on abundance, suggesting that radiation indirectly affects abundance negatively through an increase in the frequency of cataracts in bird populations, but also through direct effects of radiation on other diseases, food abundance and interactions with other species. There was no increase in incidence of cataracts with increasing age, suggesting that yearlings and older individuals were similarly affected as is typical of radiation cataract. CONCLUSIONS/SIGNIFICANCE: These findings suggest that cataracts are an under estimated cause of morbidity in free-living birds and, by inference, other vertebrates in areas contaminated with radioactive materials. PMID- 23935826 TI - Characteristics of an environmentally monitored prolonged type 2 vaccine derived poliovirus shedding episode that stopped without intervention. AB - Vaccine derived poliovirus (VDPV) type 2 strains strongly divergent from the corresponding vaccine strain, Sabin 2, were repeatedly isolated from sewage in Slovakia over a period of 22 months in 2003-2005. Cell cultures of stool specimens from known immune deficient patients and from an identified putative source population of 500 people failed to identify the potential excretor(s) of the virus. The occurrence of VDPV in sewage stopped without any intervention. No paralytic cases were reported in Slovakia during the episode. According to a GenBank search and similarity plotting-analysis, the closest known relative of the first isolate PV2/03/SVK/E783 through all main sections of the genome was the type 2 poliovirus Sabin strain, with nucleotide identities in 5'UTR, P1, P2, P3, and 3'UTR parts of the genome of 88.6, 85.9, 87.3, 88.5, and 94.0 percent, respectively. Phenotypic properties of selected Slovakian aVDPV strains resembled those of VDPV strains isolated from immune deficient individuals with prolonged PV infection (iVDPV), including antigenic changes and moderate neurovirulence in the transgenic mouse model. One hundred and two unique VP1 coding sequences were determined from VDPV strains isolated from 34 sewage specimens. Nucleotide differences from Sabin 2 in the VP1 coding region ranged from 12.5 to 15.6 percent, and reached a maximum of 9.6 percent between the VDPV strains under study. Most of the nucleotide substitutions were synonymous but as many as 93 amino acid positions out of 301 in VP1 showed substitutions. We conclude that (1) individuals with prolonged poliovirus infection are not as rare as suggested by the studies on immune deficient patients known to the health care systems and (2) genetic divergence of VDPV strains may remain extensive during years long replication in humans. PMID- 23935828 TI - The GPVI-Fc fusion protein Revacept improves cerebral infarct volume and functional outcome in stroke. AB - OBJECTIVES: We examined the effect of Revacept, an Fc fusion protein which is specifically linked to the extracellular domain of glycoprotein VI (GPVI), on thrombus formation after vessel wall injury and on experimental stroke in mice. BACKGROUND: Several antiplatelet drugs for the treatment of myocardial infarction or ischemic stroke with potent anti-ischemic effects have been developed, but all incur a significant risk of bleeding. METHODS: Platelet adhesion and thrombus formation after endothelial injury was monitored in the carotid artery by intra vital fluorescence microscopy. The morphological and clinical consequences of stroke were investigated in a mouse model with a one hour-occlusion of the middle cerebral artery. RESULTS: Thrombus formation was significantly decreased after endothelial injury by 1 mg/kg Revacept i.v., compared to Fc only. 1 mg/kg Revacept i.v. applied in mice with ischemic stroke immediately before reperfusion significantly improved functional outcome, cerebral infarct size and edema compared to Fc only. Also treatment with 10 mg/kg rtPA was effective, and functional outcome was similar in both treatment groups. The combination of Revacept with rtPA leads to increased reperfusion compared to treatment with either agent alone. In contrast to rtPA, however, there were no signs of increased intracranial bleeding with Revacept. Both rtPA and Revacept improved survival after stroke compared to placebo treatment. Revacept and vWF bind to collagen and Revacept competitively prevented the binding of vWF to collagen. CONCLUSIONS: Revacept reduces arterial thrombus formation, reduces cerebral infarct size and edema after ischemic stroke, improves functional and prognostic outcome without intracranial bleeding. Revacept not only prevents GPVI-mediated, but probably also vWF-mediated platelet adhesion and aggregate formation. Therefore Revacept might be a potent and safe tool to treat ischemic complications of stroke. PMID- 23935829 TI - Serum uric acid and non-alcoholic fatty liver disease in non-diabetic Chinese men. AB - Increased serum uric acid (SUA) levels may be involved in the development of non alcoholic fatty liver disease (NAFLD) in men presenting with metabolic syndrome (MetS) and/or insulin resistance. We aimed to determine the independent relationship between SUA and NAFLD in non-diabetic Chinese male population, and to explore the determinants of SUA levels among indexes of adiposity, lipid, and genotypes pertaining to triglycerides metabolism, inflammation, oxidative stress, and SUA concentrations. A total of 1440 men, classified depending on the presence of ultrasonographically detected NAFLD, underwent a complete healthy checkup program. Genotypes were extracted from our previously established genome-wide association study database. After adjusting for age, smoking, drinking, body mass index, homeostasis model assessment of insulin resistance, C-reactive protein, creatinine, alanine aminotransferase (ALT) and components of metabolic syndrome, the odds ratio for NAFLD, comparing the highest with the lowest SUA quartile, was 2.81 (95% confidence interval 1.66-4.76). A stepwise multivariate linear regression analysis (R(2) = 0.238, P<0.001) retained age, waist circumference, serum creatinine, triglycerides, the Q141K variant in ABCG2 (rs2231142) and NAFLD as significant predictors of SUA levels (all P<0.001). Besides, ALT and Met196Arg variant in TNFRSF1B (rs1061622) additionally associated with SUA among individuls with NAFLD. Our data suggest that in Chinese men, elevated SUA is significantly associated with NAFLD, independent of insulin resistance and other metabolic disorders, such as central obesity or hypertriglyceridemia. Meanwhile, among subjects with NAFLD, index of liver damage, such as elevated ALT combined with genetic susceptibility to inflammation associated with increased SUA levels. PMID- 23935830 TI - If we share data, will anyone use them? Data sharing and reuse in the long tail of science and technology. AB - Research on practices to share and reuse data will inform the design of infrastructure to support data collection, management, and discovery in the long tail of science and technology. These are research domains in which data tend to be local in character, minimally structured, and minimally documented. We report on a ten-year study of the Center for Embedded Network Sensing (CENS), a National Science Foundation Science and Technology Center. We found that CENS researchers are willing to share their data, but few are asked to do so, and in only a few domain areas do their funders or journals require them to deposit data. Few repositories exist to accept data in CENS research areas.. Data sharing tends to occur only through interpersonal exchanges. CENS researchers obtain data from repositories, and occasionally from registries and individuals, to provide context, calibration, or other forms of background for their studies. Neither CENS researchers nor those who request access to CENS data appear to use external data for primary research questions or for replication of studies. CENS researchers are willing to share data if they receive credit and retain first rights to publish their results. Practices of releasing, sharing, and reusing of data in CENS reaffirm the gift culture of scholarship, in which goods are bartered between trusted colleagues rather than treated as commodities. PMID- 23935831 TI - Development of molecular resources for an intertidal clam, Sinonovacula constricta, using 454 transcriptome sequencing. AB - BACKGROUND: The razor clam Sinonovacula constricta is a benthic intertidal bivalve species with important commercial value. Despite its economic importance, knowledge of its transcriptome is scarce. Next generation sequencing technologies offer rapid and efficient tools for generating large numbers of sequences, which can be used to characterize the transcriptome, to develop effective molecular markers and to identify genes associated with growth, a key breeding trait. RESULTS: Total RNA was isolated from the mantle, gill, liver, siphon, gonad and muscular foot tissues. High-throughput deep sequencing of S. constricta using 454 pyrosequencing technology yielded 859,313 high-quality reads with an average read length of 489 bp. Clustering and assembly of these reads produced 16,323 contigs and 131,346 singletons with average lengths of 1,376 bp and 458 bp, respectively. Based on transcriptome sequencing, 14,615 sequences had significant matches with known genes encoding 147,669 predicted proteins. Subsequently, previously unknown growth-related genes were identified. A total of 13,563 microsatellites (SSRs) and 13,634 high-confidence single nucleotide polymorphism loci (SNPs) were discovered, of which almost half were validated. CONCLUSION: De novo sequencing of the razor clam S. constricta transcriptome on the 454 GS FLX platform generated a large number of ESTs. Candidate growth factors and a large number of SSRs and SNPs were identified. These results will impact genetic studies of S. constricta. PMID- 23935832 TI - LabTrove: a lightweight, web based, laboratory "blog" as a route towards a marked up record of work in a bioscience research laboratory. AB - BACKGROUND: The electronic laboratory notebook (ELN) has the potential to replace the paper notebook with a marked-up digital record that can be searched and shared. However, it is a challenge to achieve these benefits without losing the usability and flexibility of traditional paper notebooks. We investigate a blog based platform that addresses the issues associated with the development of a flexible system for recording scientific research. METHODOLOGY/PRINCIPAL FINDINGS: We chose a blog-based approach with the journal characteristics of traditional notebooks in mind, recognizing the potential for linking together procedures, materials, samples, observations, data, and analysis reports. We implemented the LabTrove blog system as a server process written in PHP, using a MySQL database to persist posts and other research objects. We incorporated a metadata framework that is both extensible and flexible while promoting consistency and structure where appropriate. Our experience thus far is that LabTrove is capable of providing a successful electronic laboratory recording system. CONCLUSIONS/SIGNIFICANCE: LabTrove implements a one-item one-post system, which enables us to uniquely identify each element of the research record, such as data, samples, and protocols. This unique association between a post and a research element affords advantages for monitoring the use of materials and samples and for inspecting research processes. The combination of the one-item one-post system, consistent metadata, and full-text search provides us with a much more effective record than a paper notebook. The LabTrove approach provides a route towards reconciling the tensions and challenges that lie ahead in working towards the long-term goals for ELNs. LabTrove, an electronic laboratory notebook (ELN) system from the Smart Research Framework, based on a blog-type framework with full access control, facilitates the scientific experimental recording requirements for reproducibility, reuse, repurposing, and redeployment. PMID- 23935833 TI - Are all placebo effects equal? Placebo pills, sham acupuncture, cue conditioning and their association. AB - Placebo treatments and healing rituals have been used to treat pain throughout history. The present within-subject crossover study examines the variability in individual responses to placebo treatment with verbal suggestion and visual cue conditioning by investigating whether responses to different types of placebo treatment, as well as conditioning responses, correlate with one another. Secondarily, this study also examines whether responses to sham acupuncture correlate with responses to genuine acupuncture. Healthy subjects were recruited to participate in two sequential experiments. Experiment one is a five-session crossover study. In each session, subjects received one of four treatments: placebo pills (described as Tylenol), sham acupuncture, genuine acupuncture, or no treatment rest control condition. Before and after each treatment, paired with a verbal suggestion of positive effect, each subject's pain threshold, pain tolerance, and pain ratings to calibrated heat pain were measured. At least 14 days after completing experiment one, all subjects were invited to participate in experiment two, during which their analgesic responses to conditioned visual cues were tested. Forty-eight healthy subjects completed experiment one, and 45 completed experiment two. The results showed significantly different effects of genuine acupuncture, placebo pill and rest control on pain threshold. There was no significant association between placebo pills, sham acupuncture and cue conditioning effects, indicating that individuals may respond to unique healing rituals in different ways. This outcome suggests that placebo response may be a complex behavioral phenomenon that has properties that comprise a state, rather than a trait characteristic. This could explain the difficulty of detecting a signature for "placebo responders." However, a significant association was found between the genuine and sham acupuncture treatments, implying that the non specific effects of acupuncture may contribute to the analgesic effect observed in genuine acupuncture analgesia. PMID- 23935834 TI - Prevalence of chronic conditions in Australia. AB - OBJECTIVES: To estimate prevalence of chronic conditions among patients seeing a general practitioner (GP), patients attending general practice at least once in a year, and the Australian population. DESIGN SETTING AND PARTICIPANTS: A sub-study of the BEACH (Bettering the Evaluation and Care of Health) program, a continuous national study of general practice activity conducted between July 2008 and May 2009. Each of 290 GPs provided data for about 30 consecutive patients (total 8,707) indicating diagnosed chronic conditions, using their knowledge of the patient, patient self-report, and patient's health record. MAIN OUTCOME MEASURES: Estimates of prevalence of chronic conditions among patients surveyed, adjusted prevalence in patients who attended general practice at least once that year, and national population prevalence. RESULTS: Two-thirds (66.3%) of patients surveyed had at least one chronic condition: most prevalent being hypertension (26.6%), hyperlipidaemia (18.5%), osteoarthritis (17.8%), depression (13.7%), gastro oesophageal reflux disease (11.6%), asthma (9.5%) and Type 2 diabetes (8.3%). For patients who attended general practice at least once, we estimated 58.8% had at least one chronic condition. After further adjustment we estimated 50.8% of the Australian population had at least one chronic condition: hypertension (17.4%), hyperlipidaemia (12.7%), osteoarthritis (11.1%), depression (10.5%) and asthma (8.0%) being most prevalent. CONCLUSIONS: This study used GPs to gather information from their knowledge, the patient, and health records, to provide prevalence estimates that overcome weaknesses of studies using patient self report or health record audit alone. Our results facilitate examination of primary care resource use in management of chronic conditions and measurement of prevalence of multimorbidity in Australia. PMID- 23935835 TI - Preconditioning with associated blocking of Ca2+ inflow alleviates hypoxia induced damage to pancreatic beta-cells. AB - OBJECTIVE: Beta cells of pancreatic islets are susceptible to functional deficits and damage by hypoxia. Here we aimed to characterize such effects and to test for and pharmacological means to alleviate a negative impact of hypoxia. METHODS AND DESIGN: Rat and human pancreatic islets were subjected to 5.5 h of hypoxia after which functional and viability parameters were measured subsequent to the hypoxic period and/or following a 22 h re-oxygenation period. Preconditioning with diazoxide or other agents was usually done during a 22 h period prior to hypoxia. RESULTS: Insulin contents decreased by 23% after 5.5 h of hypoxia and by 61% after a re-oxygenation period. Preconditioning with diazoxide time-dependently alleviated these hypoxia effects in rat and human islets. Hypoxia reduced proinsulin biosynthesis ((3)H-leucine incorporation into proinsulin) by 35%. Preconditioning counteracted this decrease by 91%. Preconditioning reduced hypoxia-induced necrosis by 40%, attenuated lowering of proteins of mitochondrial complexes I-IV and enhanced stimulation of HIF-1-alpha and phosphorylated AMPK proteins. Preconditioning by diazoxide was abolished by co-exposure to tolbutamide or elevated potassium (i.e. conditions which increase Ca(2+) inflow). Preconditioning with nifedipine, a calcium channel blocker, partly reproduced effects of diazoxide. Both diazoxide and nifedipine moderately reduced basal glucose oxidation whereas glucose-induced oxygen consumption (tested with diazoxide) was unaffected. Preconditioning with diaxoxide enhanced insulin contents in transplants of rat islets to non-diabetic rats and lowered hyperglycemia vs. non-preconditioned islets in streptozotocin-diabetic rats. Preconditioning of human islet transplants lowered hyperglycemia in streptozotocin-diabetic nude mice. CONCLUSIONS: 1) Prior blocking of Ca(2+) inflow associates with lesser hypoxia-induced damage, 2) preconditioning affects basal mitochondrial metabolism and accelerates activation of hypoxia-reactive and potentially protective factors, 3) results indicate that preconditioning by K(+) ATP-channel openers has therapeutic potential for islet transplantations. PMID- 23935837 TI - An in vitro expansion system for generation of human iPS cell-derived hepatic progenitor-like cells exhibiting a bipotent differentiation potential. AB - Hepatoblasts, hepatic stem/progenitor cells in liver development, have a high proliferative potential and the ability to differentiate into both hepatocytes and cholangiocytes. In regenerative medicine and drug screening for the treatment of severe liver diseases, human induced pluripotent stem (iPS) cell-derived mature functional hepatocytes are considered to be a potentially good cell source. However, induction of proliferation of these cells is difficult ex vivo. To circumvent this problem, we generated hepatic progenitor-like cells from human iPS cells using serial cytokine treatments in vitro. Highly proliferative hepatic progenitor-like cells were purified by fluorescence-activated cell sorting using antibodies against CD13 and CD133 that are known cell surface markers of hepatic stem/progenitor cells in fetal and adult mouse livers. When the purified CD13(high)CD133(+) cells were cultured at a low density with feeder cells in the presence of suitable growth factors and signaling inhibitors (ALK inhibitor A-83 01 and ROCK inhibitor Y-27632), individual cells gave rise to relatively large colonies. These colonies consisted of two types of cells expressing hepatocytic marker genes (hepatocyte nuclear factor 4alpha and alpha-fetoprotein) and a cholangiocytic marker gene (cytokeratin 7), and continued to proliferate over long periods of time. In a spheroid formation assay, these cells were found to express genes required for mature liver function, such as cytochrome P450 enzymes, and secrete albumin. When these cells were cultured in a suitable extracellular matrix gel, they eventually formed a cholangiocytic cyst-like structure with epithelial polarity, suggesting that human iPS cell-derived hepatic progenitor-like cells have a bipotent differentiation ability. Collectively these data indicate that this novel procedure using an in vitro expansion system is useful for not only liver regeneration but also for the determination of molecular mechanisms that regulate liver development. PMID- 23935836 TI - Analysis of PALB2 gene in BRCA1/BRCA2 negative Spanish hereditary breast/ovarian cancer families with pancreatic cancer cases. AB - BACKGROUND: The PALB2 gene, also known as FANCN, forms a bond and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer and 3-4% of familial pancreatic cancer. The goal of this study was to determine the prevalence of PALB2 mutations in a population of BRCA1/BRCA2 negative breast cancer patients selected from either a personal or family history of pancreatic cancer. METHODS: 132 non BRCA1/BRCA2 breast/ovarian cancer families with at least one pancreatic cancer case were included in the study. PALB2 mutational analysis was performed by direct sequencing of all coding exons and intron/exon boundaries, as well as multiplex ligation-dependent probe amplification. RESULTS: Two PALB2 truncating mutations, the c.1653T>A (p.Tyr551Stop) previously reported, and c.3362del (p.Gly1121ValfsX3) which is a novel frameshift mutation, were identified. Moreover, several PALB2 variants were detected; some of them were predicted as pathological by bioinformatic analysis. Considering truncating mutations, the prevalence rate of our population of BRCA1/2-negative breast cancer patients with pancreatic cancer is 1.5%. CONCLUSIONS: The prevalence rate of PALB2 mutations in non-BRCA1/BRCA2 breast/ovarian cancer families, selected from either a personal or family pancreatic cancer history, is similar to that previously described for unselected breast/ovarian cancer families. Future research directed towards identifying other gene(s) involved in the development of breast/pancreatic cancer families is required. PMID- 23935838 TI - A proline-hinge alters the characteristics of the amphipathic alpha-helical AMPs. AB - HP (2-20) is a 19-aa, amphipathic, alpha-helical peptide with antimicrobial properties that was derived from the N-terminus of Helicobacter pylori ribosomal protein L1. We previously showed that increasing the net hydrophobicity of HP (2 20) by substituting Trp for Gln(17) and Asp(19) (Anal 3) increased the peptide's antimicrobial activity. In hydrophobic medium, Anal 3 forms an amphipathic structure consisting of an N-terminal random coil region (residues 2-5) and an extended helical region (residues 6-20). To investigate the structure-activity relationship of Anal 3, we substituted Pro for Glu(9) (Anal 3-Pro) and then examined the new peptide's three-dimensional structure, antimicrobial activity and mechanism of action. Anal 3-Pro had an alpha-helical structure in the presence of trifluoroethanol (TFE) and sodium dodecyl sulfate (SDS). NMR spectroscopic analysis of Anal 3-Pro's tertiary structure in SDS micelles confirmed that the kink potential introduced by Pro(10) was responsible for the helix distortion. We also found that Anal 3-Pro exhibited about 4 times greater antimicrobial activity than Anal 3. Fluorescence activated flow cytometry and confocal fluorescence microscopy showed that incorporating a Pro-hinge into Anal 3 markedly reduced its membrane permeability so that it accumulated in the cytoplasm without remaining in the cell membrane. To investigate the translocation mechanism, we assessed its ability to release of FITC-dextran. The result showed Anal 3-Pro created a pore <1.8 nm in diameter, which is similar to buforin II. Notably, scanning electron microscopic observation of Candida albicans revealed that Anal 3-Pro and buforin II exert similar effects on cell membranes, whereas magainin 2 exerts a different, more damaging, effect. In addition, Anal 3-Pro assumed a helix-hinge-helix structure in the presence of biological membranes and formed micropores in both bacterial and fungal membranes, through which it entered the cytoplasm and tightly bound to DNA. These results indicate that the bending region of Anal 3- Pro peptide is prerequisite for effective antibiotic activity and may facilitate easy penetration of the lipid bilayers of the cell membrane. PMID- 23935839 TI - Association of preexisting drug-resistance mutations and treatment failure in hepatitis B patients. AB - The role of preexisting minority drug-resistance mutations in treatment failure has not been fully understood in chronic hepatitis B patients. To understand mechanisms of drug resistance, we analyzed drug-resistance mutations in 46 treatment-failure patients and in 29 treatment-naive patients and determined linkage patterns of the drug-resistance mutations in individual viral genomes using a highly sensitive parallel allele-specific sequencing (PASS) method. Lamivudine resistance (LAMr) mutations were predominant in treatment-failure patients, irrespective of the inclusion of LAM in the regimen. The primary LAMr mutations M204V and M204I were detected in 100% and 30% of the treatment-failure patients, respectively. Two secondary LAMr mutations (L180M and V173L) were also found in most treatment-failure patients (87% and 78%, respectively). The linkages containing these three mutations dominated the resistant viruses. Importantly, minority LAMr mutations present in <2% of the viral population were detected in 83% of the treatment-naive patients. Moreover, the low-frequency same linked LAMr mutations (<0.15%) were detected in 24% of the treatment-naive patients. Our results demonstrate that the selection of preexisting minority linked LAMr mutations may be an important mechanism for the rapid development of LAM resistance, caution the continuous use of LAM to treat drug-experienced and naive hepatitis B patients, and underline the importance of the detection of minority single and linked drug-resistance mutations before initiating antiviral therapy. PMID- 23935840 TI - Menthol binding and inhibition of alpha7-nicotinic acetylcholine receptors. AB - Menthol is a common compound in pharmaceutical and commercial products and a popular additive to cigarettes. The molecular targets of menthol remain poorly defined. In this study we show an effect of menthol on the alpha7 subunit of the nicotinic acetylcholine (nACh) receptor function. Using a two-electrode voltage clamp technique, menthol was found to reversibly inhibit alpha7-nACh receptors heterologously expressed in Xenopus oocytes. Inhibition by menthol was not dependent on the membrane potential and did not involve endogenous Ca(2+) dependent Cl(-) channels, since menthol inhibition remained unchanged by intracellular injection of the Ca(2+) chelator BAPTA and perfusion with Ca(2+) free bathing solution containing Ba(2+). Furthermore, increasing ACh concentrations did not reverse menthol inhibition and the specific binding of [(125)I] alpha-bungarotoxin was not attenuated by menthol. Studies of alpha7- nACh receptors endogenously expressed in neural cells demonstrate that menthol attenuates alpha7 mediated Ca(2+) transients in the cell body and neurite. In conclusion, our results suggest that menthol inhibits alpha7-nACh receptors in a noncompetitive manner. PMID- 23935841 TI - Crucial residue involved in L-lactate recognition by human monocarboxylate transporter 4 (hMCT4). AB - BACKGROUND: Monocarboxylate transporters (MCTs) transport monocarboxylates such as lactate, pyruvate and ketone bodies. These transporters are very attractive therapeutic targets in cancer. Elucidations of the functions and structures of MCTs is necessary for the development of effective medicine which targeting these proteins. However, in comparison with MCT1, there is little information on location of the function moiety of MCT4 and which constituent amino acids govern the transport function of MCT4. The aim of the present work was to determine the molecular mechanism of L-lactate transport via hMCT4. EXPERIMENTAL APPROACH: Transport of L-lactate via hMCT4 was determined by using hMCT4 cRNA-injected Xenopus laevis oocytes. hMCT4 mediated L-lactate uptake in oocytes was measured in the absence and presence of chemical modification agents and 4,4' diisothiocyanostilbene-2,2'-disulphonate (DIDS). In addition, L-lactate uptake was measured by hMCT4 arginine mutants. Immunohistochemistry studies revealed the localization of hMCT4. RESULTS: In hMCT4-expressing oocytes, treatment with phenylglyoxal (PGO), a compound specific for arginine residues, completely abolished the transport activity of hMCT4, although this abolishment was prevented by the presence of L-lactate. On the other hand, chemical modifications except for PGO treatment had no effect on the transport activity of hMCT4. The transporter has six conserved arginine residues, two in the transmembrane spanning domains (TMDs) and four in the intracellular loops. In hMCT4-R278 mutants, the uptake of L-lactate is void of any transport activity without the alteration of hMCT4 localization. CONCLUSIONS: Our results suggest that Arg-278 in TMD8 is a critical residue involved in substrate, L-lactate recognition by hMCT4. PMID- 23935842 TI - Factors determining forest diversity and biomass on a tropical volcano, Mt. Rinjani, Lombok, Indonesia. AB - Tropical volcanoes are an important but understudied ecosystem, and the relationships between plant species diversity and compositional change and elevation may differ from mountains created by uplift, because of their younger and more homogeneous soils. We sampled vegetation over an altitudinal gradient on Mt. Rinjani, Lombok, Indonesia. We modeled alpha- (plot) and beta- (among plot) diversity (Fisher's alpha), compositional change, and biomass against elevation and selected covariates. We also examined community phylogenetic structure across the elevational gradient. We recorded 902 trees and shrubs among 92 species, and 67 species of ground-cover plants. For understorey, subcanopy and canopy plants, an increase in elevation was associated with a decline in alpha-diversity, whereas data for ground-cover plants suggested a hump-shaped pattern. Elevation was consistently the most important factor in determining alpha-diversity for all components. The alpha-diversity of ground-cover vegetation was also negatively correlated with leaf area index, which suggests low light conditions in the understorey may limit diversity at lower elevations. Beta-diversity increased with elevation for ground-cover plants and declined at higher elevations for other components of the vegetation. However, statistical power was low and we could not resolve the relative importance to beta-diversity of different factors. Multivariate GLMs of variation in community composition among plots explained 67.05%, 27.63%, 18.24%, and 19.80% of the variation (deviance) for ground-cover, understorey, subcanopy and canopy plants, respectively, and demonstrated that elevation was a consistently important factor in determining community composition. Above-ground biomass showed no significant pattern with elevation and was also not significantly associated with alpha-diversity. At lower elevations communities had a random phylogenetic structure, but from 1600 m communities were phylogenetically clustered. This suggests a greater role of environmental filtering at higher elevations, and thus provides a possible explanation for the observed decline in diversity with elevation. PMID- 23935843 TI - Effect of licochalcone A on growth and properties of Streptococcus suis. AB - Streptococcus suis (S.suis) is an important emerging worldwide pig pathogen and zoonotic agent with rapid evolution of virulence and drug resistance. In this study, we wanted to investigate the effect of licochalcone A on growth and properties of Streptococcus suis. The antimicrobial activity of licochalcone A was tested by growth inhibition assay and the minimal inhibitory concentrations (MICs) also were determined. The effect of licochalcone A on S.suis biofilm formation was characterized by crystal violet staining. The effect of licochalcone A on suilysin secretion was evaluated by titration of hemolytic activity. To understand the antimicrobial effect, gene expression profile of S.suis treated by licochalcone A was analyzed by DNA microarray. Our results demonstrated that licochalcone A showed antimicrobial activity on S.suis with MICs of 4 ug/ml for S.suis serotype 2 strains and 8 ug/ml for S.suis serotype 7 strains. Biofilm formation was inhibited by 30-40% in the presence of licochalcone A (3 ug/ml) and suilysin secretion was also significantly inhibited in the presence of licochalcone A (1.5 ug/ml). The gene expression profile of S.suis in the presence of licochalcone A showed that 132 genes were differentially regulated, and we analyzed the regulated genes in the aspect of the bacterial cell cycle control. Among the deregulated genes, the genes responsible for the mass doubling was increased expression, but the genes responsible for DNA replication and cell division were inhibited the expression. So, we think the regulation of the cell cycle genes might provide a mechanistic understanding of licochalcone A mediated antimicrobial effect against S.suis. PMID- 23935844 TI - Kallikrein transduced mesenchymal stem cells protect against anti-GBM disease and lupus nephritis by ameliorating inflammation and oxidative stress. AB - Previously we have shown that kallikreins (klks) play a renoprotective role in nephrotoxic serum induced nephritis. In this study, we have used mesenchymal stem cells (MSCs) as vehicles to deliver klks into the injured kidneys and have measured their therapeutic effect on experimental antibody induced nephritis and lupus nephritis. Human KLK-1 (hKLK1) gene was transduced into murine MSCs using a retroviral vector to generate a stable cell line, hKLK1-MSC, expressing high levels of hKLK1. 129/svj mice subjected to anti-GBM induced nephritis were transplanted with 10(6) hKLK1-MSCs and hKLK1 expression was confirmed in the kidneys. Compared with vector-MSCs injected mice, the hKLK1-MSCs treated mice showed significantly reduced proteinuria, blood urea nitrogen (BUN) and ameliorated renal pathology. Using the same strategy, we treated lupus-prone B6.Sle1.Sle3 bicongenic mice with hKLK1-MSCs and demonstrated that hKLK1-MSCs delivery also attenuated lupus nephritis. Mechanistically, hKLK1-MSCs reduced macrophage and T-lymphocyte infiltration into the kidney by suppressing the expression of inflammation cytokines. Moreover, hKLK1 transduced MSCs were more resistant to oxidative stress-induced apoptosis. These findings advance genetically modified MSCs as potential gene delivery tools for targeting therapeutic agents to the kidneys in order to modulate inflammation and oxidative stress in lupus nephritis. PMID- 23935845 TI - An index for characterization of natural and non-natural amino acids for peptidomimetics. AB - Bioactive peptides and peptidomimetics play a pivotal role in the regulation of many biological processes such as cellular apoptosis, host defense, and biomineralization. In this work, we develop a novel structural matrix, Index of Natural and Non-natural Amino Acids (NNAAIndex), to systematically characterize a total of 155 physiochemical properties of 22 natural and 593 non-natural amino acids, followed by clustering the structural matrix into 6 representative property patterns including geometric characteristics, H-bond, connectivity, accessible surface area, integy moments index, and volume and shape. As a proof of-principle, the NNAAIndex, combined with partial least squares regression or linear discriminant analysis, is used to develop different QSAR models for the design of new peptidomimetics using three different peptide datasets, i.e., 48 bitter-tasting dipeptides, 58 angiotensin-converting enzyme inhibitors, and 20 inorganic-binding peptides. A comparative analysis with other QSAR techniques demonstrates that the NNAAIndex method offers a stable and predictive modeling technique for in silico large-scale design of natural and non-natural peptides with desirable bioactivities for a wide range of applications. PMID- 23935846 TI - The role of Cancer-Testis antigens as predictive and prognostic markers in non small cell lung cancer. AB - BACKGROUND: Cancer-Testis Antigens (CTAs) are immunogenic proteins that are poor prognostic markers in non-small cell lung cancer (NSCLC). We investigated expression of CTAs in NSCLC and their association with response to chemotherapy, genetic mutations and survival. METHODS: We studied 199 patients with pathological N2 NSCLC treated with neoadjuvant chemotherapy (NAC; n = 94), post operative observation (n = 49), adjuvant chemotherapy (n = 47) or unknown (n = 9). Immunohistochemistry for NY-ESO-1, MAGE-A and MAGE-C1 was performed. Clinicopathological features, response to neoadjuvant treatment and overall survival were correlated. DNA mutations were characterized using the Sequenom Oncocarta panel v1.0. Affymetrix data from the JBR.10 adjuvant chemotherapy study were obtained from a public repository, normalised and mapped for CTAs. RESULTS: NY-ESO-1 was expressed in 50/199 (25%) samples. Expression of NY-ESO-1 in the NAC cohort was associated with significantly increased response rates (P = 0.03), but not overall survival. In the post-operative cohort, multivariate analyses identified NY-ESO-1 as an independent poor prognostic marker for those not treated with chemotherapy (HR 2.61, 95% CI 1.28-5.33; P = 0.008), whereas treatment with chemotherapy and expression of NY-ESO-1 was an independent predictor of improved survival (HR 0.267, 95% CI 0.07-0.980; P = 0.046). Similar findings for MAGE-A were seen, but did not meet statistical significance. Independent gene expression data from the JBR.10 dataset support these findings but were underpowered to demonstrate significant differences. There was no association between oncogenic mutations and CTA expression. CONCLUSIONS: NY-ESO-1 was predictive of increased response to neoadjuvant chemotherapy and benefit from adjuvant chemotherapy. Further studies investigating the relationship between these findings and immune mechanisms are warranted. PMID- 23935847 TI - Variations in alveolar partial pressure for carbon dioxide and oxygen have additive not synergistic acute effects on human pulmonary vasoconstriction. AB - The human pulmonary vasculature constricts in response to hypercapnia and hypoxia, with important consequences for homeostasis and adaptation. One function of these responses is to direct blood flow away from poorly-ventilated regions of the lung. In humans it is not known whether the stimuli of hypercapnia and hypoxia constrict the pulmonary blood vessels independently of each other or whether they act synergistically, such that the combination of hypercapnia and hypoxia is more effective than the sum of the responses to each stimulus on its own. We independently controlled the alveolar partial pressures of carbon dioxide (Paco 2) and oxygen (Pao 2) to examine their possible interaction on human pulmonary vasoconstriction. Nine volunteers each experienced sixteen possible combinations of four levels of Paco 2 (+6, +1, -4 and -9 mmHg, relative to baseline) with four levels of Pao 2 (175, 100, 75 and 50 mmHg). During each of these sixteen protocols Doppler echocardiography was used to evaluate cardiac output and systolic tricuspid pressure gradient, an index of pulmonary vasoconstriction. The degree of constriction varied linearly with both Paco 2 and the calculated haemoglobin oxygen desaturation (1-So2). Mixed effects modelling delivered coefficients defining the interdependence of cardiac output, systolic tricuspid pressure gradient, ventilation, Paco 2 and So2. No interaction was observed in the effects on pulmonary vasoconstriction of carbon dioxide and oxygen (p>0.64). Direct effects of the alveolar gases on systolic tricuspid pressure gradient greatly exceeded indirect effects arising from concurrent changes in cardiac output. PMID- 23935848 TI - Silencing BRE expression in human umbilical cord perivascular (HUCPV) progenitor cells accelerates osteogenic and chondrogenic differentiation. AB - BRE is a multifunctional adapter protein involved in DNA repair, cell survival and stress response. To date, most studies of this protein have been focused in the tumor model. The role of BRE in stem cell biology has never been investigated. Therefore, we have used HUCPV progenitor cells to elucidate the function of BRE. HUCPV cells are multipotent fetal progenitor cells which possess the ability to differentiate into a multitude of mesenchymal cell lineages when chemically induced and can be more easily amplified in culture. In this study, we have established that BRE expression was normally expressed in HUCPV cells but become down-regulated when the cells were induced to differentiate. In addition, silencing BRE expression, using BRE-siRNAs, in HUCPV cells could accelerate induced chondrogenic and osteogenic differentiation. Hence, we postulated that BRE played an important role in maintaining the stemness of HUCPV cells. We used microarray analysis to examine the transcriptome of BRE-silenced cells. BRE silencing negatively regulated OCT4, FGF5 and FOXO1A. BRE-silencing also altered the expression of epigenetic genes and components of the TGF-beta/BMP and FGF signaling pathways which are crucially involved in maintaining stem cell self renewal. Comparative proteomic profiling also revealed that BRE-silencing resulted in decreased expressions of actin-binding proteins. In sum, we propose that BRE acts like an adaptor protein that promotes stemness and at the same time inhibits the differentiation of HUCPV cells. PMID- 23935849 TI - Function and X-ray crystal structure of Escherichia coli YfdE. AB - Many food plants accumulate oxalate, which humans absorb but do not metabolize, leading to the formation of urinary stones. The commensal bacterium Oxalobacter formigenes consumes oxalate by converting it to oxalyl-CoA, which is decarboxylated by oxalyl-CoA decarboxylase (OXC). OXC and the class III CoA transferase formyl-CoA:oxalate CoA-transferase (FCOCT) are widespread among bacteria, including many that have no apparent ability to degrade or to resist external oxalate. The EvgA acid response regulator activates transcription of the Escherichia coli yfdXWUVE operon encoding YfdW (FCOCT), YfdU (OXC), and YfdE, a class III CoA-transferase that is ~30% identical to YfdW. YfdW and YfdU are necessary and sufficient for oxalate-induced protection against a subsequent acid challenge; neither of the other genes has a known function. We report the purification, in vitro characterization, 2.1-A crystal structure, and functional assignment of YfdE. YfdE and UctC, an orthologue from the obligate aerobe Acetobacter aceti, perform the reversible conversion of acetyl-CoA and oxalate to oxalyl-CoA and acetate. The annotation of YfdE as acetyl-CoA:oxalate CoA transferase (ACOCT) expands the scope of metabolic pathways linked to oxalate catabolism and the oxalate-induced acid tolerance response. FCOCT and ACOCT active sites contain distinctive, conserved active site loops (the glycine-rich loop and the GNxH loop, respectively) that appear to encode substrate specificity. PMID- 23935850 TI - Affect and the brain's functional organization: a resting-state connectivity approach. AB - The question of how affective processing is organized in the brain is still a matter of controversial discussions. Based on previous initial evidence, several suggestions have been put forward regarding the involved brain areas: (a) right lateralized dominance in emotional processing, (b) hemispheric dominance according to positive or negative valence, (c) one network for all emotional processing and (d) region-specific discrete emotion matching. We examined these hypotheses by investigating intrinsic functional connectivity patterns that covary with results of the Positive and Negative Affective Schedule (PANAS) from 65 participants. This approach has the advantage of being able to test connectivity rather than activation, and not requiring a potentially confounding task. Voxelwise functional connectivity from 200 regions-of-interest covering the whole brain was assessed. Positive and negative affect covaried with functional connectivity involving a shared set of regions, including the medial prefrontal cortex, the anterior cingulate, the visual cortex and the cerebellum. In addition, each affective domain had unique connectivity patterns, and the lateralization index showed a right hemispheric dominance for negative affect. Therefore, our results suggest a predominantly right-hemispheric network with affect-specific elements as the underlying organization of emotional processes. PMID- 23935851 TI - A novel role for Tm7sf2 gene in regulating TNFalpha expression. AB - We have explored the role of Tm7sf2 gene, which codifies for 3beta-hydroxysterol Delta14-reductase, an endoplasmic reticulum resident protein, in the sensitivity to endoplasmic reticulum stress and in the resulting inflammatory response. We used mouse embryonic fibroblasts, derived from Tm7sf2(+/+) and Tm7sf2(-/-) mice, to determine the in vitro effects of thapsigargin on NF-kappaB activation. Our results show that the Tm7sf2 gene controls the launch of the unfolded protein response and presides an anti-inflammatory loop thus its absence correlates with NF-kappaB activation and TNFalpha up-regulation. Our data also show that Tm7sf2 gene regulates liver X receptor activation and its absence inhibits LXR signalling. By expressing the hTm7sf2 gene in KO MEFs and observing a reduced NF kappaB activation, we have confirmed that Tm7sf2 gene is linked to NF-kappaB activation. Finally we used genetically modified mice in an in vivo model of ER stress and of inflammation. Our results show a significant increase in renal TNFalpha expression after tunicamycin exposure and in the oedematogenic response in Tm7sf2(-/-) mice. In conclusion, we have shown that the Tm7sf2 gene, to date involved only in cholesterol biosynthesis, also controls an anti-inflammatory loop thereby confirming the existence of cross talk between metabolic pathways and inflammatory response. PMID- 23935852 TI - Refining HIV risk: the modifying effects of youth, gender and education among people who inject drugs in Poland. AB - OBJECTIVE: The goal of this study was to examine specific factors placing young (aged <30) women who inject drugs at higher risk for HIV, and to establish the need for targeted interventions within this population. METHODS: A national cross sectional sero-survey was conducted in 2004-2005 in six regions in Poland. A snowball sample of ever-injectors was recruited from drug treatment facilities and the surrounding community. Log-binomial regression was used to estimate adjusted prevalence ratios (PRs). RESULTS: A total of 491 injection drug users younger than 30 were recruited, of whom 159 were women and 332 were men. The prevalence of HIV was 16.4% and 9.6% among women and men, respectively. In multivariate analysis, young female injectors whose education terminated at the primary level were more likely to be HIV-positive compared to males with a similar level of education (PR = 3.34, 95% CI = 1.86-6.00) and more highly educated women (PR = 4.16, 95% CI = 2.21-7.82). CONCLUSIONS: This study confirms an elevated risk of HIV among under-educated young women. Suggestions for specific interventions to reduce HIV transmission are presented. Additional research is needed to quantify the differential distribution of risk behaviors which amplify their likelihood of transmission. PMID- 23935854 TI - Repeated evolution of fungal cultivar specificity in independently evolved ant plant-fungus symbioses. AB - Some tropical plant species possess hollow structures (domatia) occupied by ants that protect the plant and in some cases also provide it with nutrients. Most plant-ants tend patches of chaetothyrialean fungi within domatia. In a few systems it has been shown that the ants manure the fungal patches and use them as a food source, indicating agricultural practices. However, the identity of these fungi has been investigated only in a few samples. To examine the specificity and constancy of ant-plant-fungus interactions we characterised the content of fungal patches in an extensive sampling of three ant-plant symbioses (Petalomyrmex phylax/Leonardoxa africana subsp. africana, Aphomomyrmex afer/Leonardoxa africana subsp. letouzeyi and Tetraponera aethiops/Barteria fistulosa) by sequencing the Internal Transcribed Spacers of ribosomal DNA. For each system the content of fungal patches was constant over individuals and populations. Each symbiosis was associated with a specific, dominant, primary fungal taxon, and to a lesser extent, with one or two specific secondary taxa, all of the order Chaetothyriales. A single fungal patch sometimes contained both a primary and a secondary taxon. In one system, two founding queens were found with the primary fungal taxon only, one that was shown in a previous study to be consumed preferentially. Because the different ant-plant symbioses studied have evolved independently, the high specificity and constancy we observed in the composition of the fungal patches have evolved repeatedly. Specificity and constancy also characterize other cases of agriculture by insects. PMID- 23935855 TI - Genetic polymorphism of human Y chromosome and risk factors for cardiovascular diseases: a study in WOBASZ cohort. AB - Genetic variants of Y chromosome predispose to hypertension in rodents, whereas in humans the evidence is conflicting. Our purpose was to study the distribution of a panel of Y chromosome markers in a cohort from a cross-sectional population based study on the prevalence of cardiovascular risk factors in Poland (WOBASZ study). The HindIII, YAP Y chromosome variants, previously shown to influence blood pressure, lipid traits or height, as well as SNPs defining main Y chromosome haplogroups, were typed in 3026, 2783 and 2652 samples, respectively. In addition, 4 subgroups (N~100 each) representing extremes of LDL concentration or blood pressure (BP) were typed for a panel of 17 STRs. The HindIII and YAP polymorphism were not associated with any of the studied traits. Analysis of the haplogroup distribution showed an association between higher HDL level and hg I M170 (P = 0.02), higher LDL level and hg F*(xI-M170, J2-M172, K-M9) (P = 0.03) and lower BMI and hg N3-Tat (P = 0.04). Analysis of STRs did not show statistically significant differences. Since all these associations lost statistical significance after Bonferroni correction, we conclude that a major role of Y chromosome genetic variation (defined by HindIII, YAP or main Y chromosome haplogroups) in determining cardiovascular risk in Poles is unlikely. PMID- 23935853 TI - Early phase of plasticity-related gene regulation and SRF dependent transcription in the hippocampus. AB - Hippocampal organotypic cultures are a highly reliable in vitro model for studying neuroplasticity: in this paper, we analyze the early phase of the transcriptional response induced by a 20 uM gabazine treatment (GabT), a GABA-Ar antagonist, by using Affymetrix oligonucleotide microarray, RT-PCR based time course and chromatin-immuno-precipitation. The transcriptome profiling revealed that the pool of genes up-regulated by GabT, besides being strongly related to the regulation of growth and synaptic transmission, is also endowed with neuro protective and pro-survival properties. By using RT-PCR, we quantified a time course of the transient expression for 33 of the highest up-regulated genes, with an average sampling rate of 10 minutes and covering the time interval [10?90] minutes. The cluster analysis of the time-course disclosed the existence of three different dynamical patterns, one of which proved, in a statistical analysis based on results from previous works, to be significantly related with SRF dependent regulation (p-value<0.05). The chromatin immunoprecipitation (chip) assay confirmed the rich presence of working CArG boxes in the genes belonging to the latter dynamical pattern and therefore validated the statistical analysis. Furthermore, an in silico analysis of the promoters revealed the presence of additional conserved CArG boxes upstream of the genes Nr4a1 and Rgs2. The chip assay confirmed a significant SRF signal in the Nr4a1 CArG box but not in the Rgs2 CArG box. PMID- 23935856 TI - T cells induce pre-metastatic osteolytic disease and help bone metastases establishment in a mouse model of metastatic breast cancer. AB - Bone metastases, present in 70% of patients with metastatic breast cancer, lead to skeletal disease, fractures and intense pain, which are all believed to be mediated by tumor cells. Engraftment of tumor cells is supposed to be preceded by changes in the target tissue to create a permissive microenvironment, the pre metastatic niche, for the establishment of the metastatic foci. In bone metastatic niche, metastatic cells stimulate bone consumption resulting in the release of growth factors that feed the tumor, establishing a vicious cycle between the bone remodeling system and the tumor itself. Yet, how the pre metastatic niches arise in the bone tissue remains unclear. Here we show that tumor-specific T cells induce osteolytic bone disease before bone colonization. T cells pro-metastatic activity correlate with a pro-osteoclastogenic cytokine profile, including RANKL, a master regulator of osteoclastogenesis. In vivo inhibition of RANKL from tumor-specific T cells completely blocks bone loss and metastasis. Our results unveil an unexpected role for RANKL-derived from T cells in setting the pre-metastatic niche and promoting tumor spread. We believe this information can bring new possibilities for the development of prognostic and therapeutic tools based on modulation of T cell activity for prevention and treatment of bone metastasis. PMID- 23935857 TI - Decreased external skeletal robustness in schoolchildren--a global trend? Ten year comparison of Russian and German data. AB - OBJECTIVES: Obesity and a reduced physical activity are global developments. Physical activity affects the external skeletal robustness which decreased in German children. It was assumed that the negative trend of decreased external skeletal robustness can be found in other countries. Therefore anthropometric data of Russian and German children from the years 2000 and 2010 were compared. METHODS: Russian (2000/2010 n = 1023/268) and German (2000/2010 n = 2103/1750) children aged 6-10 years were investigated. Height, BMI and external skeletal robustness (Frame-Index) were examined and compared for the years and the countries. Statistical analysis was performed by Mann-Whitney-Test. RESULTS: Comparison 2010 and 2000: In Russian children BMI was significantly higher; boys were significantly taller and exhibited a decreased Frame-Index (p = .002) in 2010. German boys showed significantly higher BMI in 2010. In both sexes Frame Index (p = .001) was reduced in 2010. Comparison Russian and German children in 2000: BMI, height and Frame-Index were different between Russian and German children. German children were significantly taller but exhibited a lower Frame Index (p<.001). Even German girls showed a significantly higher BMI. Comparison Russian and German children in 2010: BMI and Frame-Index were different. Russian children displayed a higher Frame-Index (p<.001) compared with Germans. CONCLUSIONS: In Russian children BMI has increased in recent years. Frame-Index is still higher in Russian children compared with Germans however in Russian boys Frame-Index is reduced. This trend and the physical activity should be observed in the future. PMID- 23935858 TI - Evolution of primary HIV drug resistance in a subtype C dominated epidemic in Mozambique. AB - OBJECTIVE: In Mozambique, highly active antiretroviral treatment (HAART) was introduced in 2004 followed by decentralization and expansion, resulting in a more than 20-fold increase in coverage by 2009. Implementation of HIV drug resistance threshold surveys (HIVDR-TS) is crucial in order to monitor the emergence of transmitted viral resistance, and to produce evidence-based recommendations to support antiretroviral (ARV) policy in Mozambique. METHODS: World Health Organization (WHO) methodology was used to evaluate transmitted drug resistance (TDR) in newly diagnosed HIV-1 infected pregnant women attending ante natal clinics in Maputo and Beira to non-nucleoside reverse transcriptase inhibitors (NNRTI), nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI). Subtypes were assigned using REGA HIV-1 subtyping tool and phylogenetic trees constructed using MEGA version 5. RESULTS: Although mutations associated with resistance to all three drug were detected in these surveys, transmitted resistance was analyzed and classified as <5% in Maputo in both surveys for all three drug classes. Transmitted resistance to NNRTI in Beira in 2009 was classified between 5-15%, an increase from 2007 when no NNRTI mutations were found. All sequences clustered with subtype C. CONCLUSIONS: Our results show that the epidemic is dominated by subtype C, where the first-line option based on two NRTI and one NNRTI is still effective for treatment of HIV infection, but intermediate levels of TDR found in Beira reinforce the need for constant evaluation with continuing treatment expansion in Mozambique. PMID- 23935859 TI - Molecular dynamics simulations of sonic hedgehog-receptor and inhibitor complexes and their applications for potential anticancer agent discovery. AB - The sonic hedgehog (Shh) signaling pathway is necessary for a variety of development and differentiation during embryogenesis as well as maintenance and renascence of diverse adult tissues. However, an abnormal activation of the signaling pathway is related to various cancers. In this pathway, the Shh signaling transduction is facilitated by binding of Shh to its receptor protein, Ptch. In this study, we modeled the 3D structure of functionally important key loop peptides of Ptch based on homologous proteins. Using this loop model, the molecular interactions between the structural components present in the pseudo active site of Shh and key residues of Ptch was investigated in atomic level through molecular dynamics (MD) simulations. For the purpose of developing inhibitor candidates of the Shh signaling pathway, the Shh pseudo-active site of this interface region was selected as a target to block the direct binding between Shh and Ptch. Two different structure-based pharmacophore models were generated considering the key loop of Ptch and known inhibitor-induced conformational changes of the Shh through MD simulations. Finally two hit compounds were retrieved through a series of virtual screening combined with molecular docking simulations and we propose two hit compounds as potential inhibitory lead candidates to block the Shh signaling pathway based on their strong interactions to receptor or inhibitor induced conformations of the Shh. PMID- 23935860 TI - Evaluation of phage display discovered peptides as ligands for prostate-specific membrane antigen (PSMA). AB - The aim of this study was to identify potential ligands of PSMA suitable for further development as novel PSMA-targeted peptides using phage display technology. The human PSMA protein was immobilized as a target followed by incubation with a 15-mer phage display random peptide library. After one round of prescreening and two rounds of screening, high-stringency screening at the third round of panning was performed to identify the highest affinity binders. Phages which had a specific binding activity to PSMA in human prostate cancer cells were isolated and the DNA corresponding to the 15-mers were sequenced to provide three consensus sequences: GDHSPFT, SHFSVGS and EVPRLSLLAVFL as well as other sequences that did not display consensus. Two of the peptide sequences deduced from DNA sequencing of binding phages, SHSFSVGSGDHSPFT and GRFLTGGTGRLLRIS were labeled with 5-carboxyfluorescein and shown to bind and co-internalize with PSMA on human prostate cancer cells by fluorescence microscopy. The high stringency requirements yielded peptides with affinities KD~1 uM or greater which are suitable starting points for affinity maturation. While these values were less than anticipated, the high stringency did yield peptide sequences that apparently bound to different surfaces on PSMA. These peptide sequences could be the basis for further development of peptides for prostate cancer tumor imaging and therapy. PMID- 23935862 TI - Improved inference of gene regulatory networks through integrated Bayesian clustering and dynamic modeling of time-course expression data. AB - Inferring gene regulatory networks from expression data is difficult, but it is common and often useful. Most network problems are under-determined--there are more parameters than data points--and therefore data or parameter set reduction is often necessary. Correlation between variables in the model also contributes to confound network coefficient inference. In this paper, we present an algorithm that uses integrated, probabilistic clustering to ease the problems of under determination and correlated variables within a fully Bayesian framework. Specifically, ours is a dynamic Bayesian network with integrated Gaussian mixture clustering, which we fit using variational Bayesian methods. We show, using public, simulated time-course data sets from the DREAM4 Challenge, that our algorithm outperforms non-clustering methods in many cases (7 out of 25) with fewer samples, rarely underperforming (1 out of 25), and often selects a non clustering model if it better describes the data. Source code (GNU Octave) for BAyesian Clustering Over Networks (BACON) and sample data are available at: http://code.google.com/p/bacon-for-genetic-networks. PMID- 23935861 TI - Analysis of 953 human proteins from a mitochondrial HEK293 fraction by complexome profiling. AB - Complexome profiling is a novel technique which uses shotgun proteomics to establish protein migration profiles from fractionated blue native electrophoresis gels. Here we present a dataset of blue native electrophoresis migration profiles for 953 proteins by complexome profiling. By analysis of mitochondrial ribosomal complexes we demonstrate its potential to verify putative protein-protein interactions identified by affinity purification-mass spectrometry studies. Protein complexes were extracted in their native state from a HEK293 mitochondrial fraction and separated by blue native gel electrophoresis. Gel lanes were cut into gel slices of even size and analyzed by shotgun proteomics. Subsequently, the acquired protein migration profiles were analyzed for co-migration via hierarchical cluster analysis. This dataset holds great promise as a comprehensive resource for de novo identification of protein-protein interactions or to underpin and prioritize candidate protein interactions from other studies. To demonstrate the potential use of our dataset we focussed on the mitochondrial translation machinery. Our results show that mitoribosomal complexes can be analyzed by blue native gel electrophoresis, as at least four distinct complexes. Analysis of these complexes confirmed that 24 proteins that had previously been reported to co-purify with mitoribosomes indeed co-migrated with subunits of the mitochondrial ribosome. Co-migration of several proteins involved in biogenesis of inner mitochondrial membrane complexes together with mitoribosomal complexes suggested the possibility of co-translational assembly in human cells. Our data also highlighted a putative ribonucleotide complex that potentially contains MRPL10, MRPL12 and MRPL53 together with LRPPRC and SLIRP. PMID- 23935863 TI - Prediction of disease causing non-synonymous SNPs by the Artificial Neural Network Predictor NetDiseaseSNP. AB - We have developed a sequence conservation-based artificial neural network predictor called NetDiseaseSNP which classifies nsSNPs as disease-causing or neutral. Our method uses the excellent alignment generation algorithm of SIFT to identify related sequences and a combination of 31 features assessing sequence conservation and the predicted surface accessibility to produce a single score which can be used to rank nsSNPs based on their potential to cause disease. NetDiseaseSNP classifies successfully disease-causing and neutral mutations. In addition, we show that NetDiseaseSNP discriminates cancer driver and passenger mutations satisfactorily. Our method outperforms other state-of-the-art methods on several disease/neutral datasets as well as on cancer driver/passenger mutation datasets and can thus be used to pinpoint and prioritize plausible disease candidates among nsSNPs for further investigation. NetDiseaseSNP is publicly available as an online tool as well as a web service: http://www.cbs.dtu.dk/services/NetDiseaseSNP. PMID- 23935864 TI - Protein profiling in hepatocellular carcinoma by label-free quantitative proteomics in two west African populations. AB - BACKGROUND: Hepatocellular Carcinoma is the third most common cause of cancer related death worldwide, often diagnosed by measuring serum AFP; a poor performance stand-alone biomarker. With the aim of improving on this, our study focuses on plasma proteins identified by Mass Spectrometry in order to investigate and validate differences seen in the respective proteomes of controls and subjects with LC and HCC. METHODS: Mass Spectrometry analysis using liquid chromatography electro spray ionization quadrupole time-of-flight was conducted on 339 subjects using a pooled expression profiling approach. ELISA assays were performed on four significantly differentially expressed proteins to validate their expression profiles in subjects from the Gambia and a pilot group from Nigeria. Results from this were collated for statistical multiplexing using logistic regression analysis. RESULTS: Twenty-six proteins were identified as differentially expressed between the three subject groups. Direct measurements of four; hemopexin, alpha-1-antitrypsin, apolipoprotein A1 and complement component 3 confirmed their change in abundance in LC and HCC versus control patients. These trends were independently replicated in the pilot validation subjects from Nigeria. The statistical multiplexing of these proteins demonstrated performance comparable to or greater than ALT in identifying liver cirrhosis or carcinogenesis. This exercise also proposed preliminary cut offs with achievable sensitivity, specificity and AUC statistics greater than reported AFP averages. CONCLUSIONS: The validated changes of expression in these proteins have the potential for development into high-performance tests usable in the diagnosis and or monitoring of HCC and LC patients. The identification of sustained expression trends strengthens the suggestion of these four proteins as worthy candidates for further investigation in the context of liver disease. The statistical combinations also provide a novel inroad of analyses able to propose definitive cut-offs and combinations for evaluation of performance. PMID- 23935865 TI - Detection of VEGF-A(xxx)b isoforms in human tissues. AB - Vascular Endothelial Growth Factor-A (VEGF-A) can be generated as multiple isoforms by alternative splicing. Two families of isoforms have been described in humans, pro-angiogenic isoforms typified by VEGF-A165a, and anti-angiogenic isoforms typified by VEGF-A165b. The practical determination of expression levels of alternative isoforms of the same gene may be complicated by experimental protocols that favour one isoform over another, and the use of specific positive and negative controls is essential for the interpretation of findings on expression of the isoforms. Here we address some of the difficulties in experimental design when investigating alternative splicing of VEGF isoforms, and discuss the use of appropriate control paradigms. We demonstrate why use of specific control experiments can prevent assumptions that VEGF-A165b is not present, when in fact it is. We reiterate, and confirm previously published experimental design protocols that demonstrate the importance of using positive controls. These include using known target sequences to show that the experimental conditions are suitable for PCR amplification of VEGF-A165b mRNA for both q-PCR and RT-PCR and to ensure that mispriming does not occur. We also provide evidence that demonstrates that detection of VEGF-A165b protein in mice needs to be tightly controlled to prevent detection of mouse IgG by a secondary antibody. We also show that human VEGF165b protein can be immunoprecipitated from cultured human cells and that immunoprecipitating VEGF-A results in protein that is detected by VEGF-A165b antibody. These findings support the conclusion that more information on the biology of VEGF-A165b isoforms is required, and confirm the importance of the experimental design in such investigations, including the use of specific positive and negative controls. PMID- 23935866 TI - Factors controlling the redox potential of ZnCe6 in an engineered bacterioferritin photochemical 'reaction centre'. AB - Photosystem II (PSII) of photosynthesis has the unique ability to photochemically oxidize water. Recently an engineered bacterioferritin photochemical 'reaction centre' (BFR-RC) using a zinc chlorin pigment (ZnCe6) in place of its native heme has been shown to photo-oxidize bound manganese ions through a tyrosine residue, thus mimicking two of the key reactions on the electron donor side of PSII. To understand the mechanism of tyrosine oxidation in BFR-RCs, and explore the possibility of water oxidation in such a system we have built an atomic-level model of the BFR-RC using ONIOM methodology. We studied the influence of axial ligands and carboxyl groups on the oxidation potential of ZnCe6 using DFT theory, and finally calculated the shift of the redox potential of ZnCe6 in the BFR-RC protein using the multi-conformational molecular mechanics-Poisson-Boltzmann approach. According to our calculations, the redox potential for the first oxidation of ZnCe6 in the BRF-RC protein is only 0.57 V, too low to oxidize tyrosine. We suggest that the observed tyrosine oxidation in BRF-RC could be driven by the ZnCe6 di-cation. In order to increase the efficiency of tyrosine oxidation, and ultimately oxidize water, the first potential of ZnCe6 would have to attain a value in excess of 0.8 V. We discuss the possibilities for modifying the BFR-RC to achieve this goal. PMID- 23935867 TI - Flow cytometric quantification of all phases of the cell cycle and apoptosis in a two-color fluorescence plot. AB - An optimal technology for cell cycle analysis would allow the concomitant measurement of apoptosis, G0, G1, S, G2 and M phases in combination with cell surface phenotyping. We have developed an easy method in flow cytometry allowing this discrimination in an only two-color fluorescent plot. It is based on the concomitant use of 7-amino-actinomycin D and the antibodies anti-Ki67 and anti phospho(Ser10)-histone H3, both conjugated to Alexa Fluor(r)488 to discriminate G0 and M phases, respectively. The method is particularly valuable in a clinical setting as verified in our laboratory by analyzing human leukemic cells from marrow samples or after exposure to cell cycle modifiers. PMID- 23935868 TI - Mapping of quantitative trait loci underlying cold tolerance in rice seedlings via high-throughput sequencing of pooled extremes. AB - Low temperature is a major limiting factor in rice growth and development. Mapping of quantitative trait loci (QTLs) controlling cold tolerance is important for rice breeding. Recent studies have suggested that bulked segregant analysis (BSA) combined with next-generation sequencing (NGS) can be an efficient and cost effective way for QTL mapping. In this study, we employed NGS-assisted BSA to map QTLs conferring cold tolerance at the seedling stage in rice. By deep sequencing of a pair of large DNA pools acquired from a very large F3 population (10,800 individuals), we obtained ~450,000 single nucleotide polymorphisms (SNPs) after strict screening. We employed two statistical methods for QTL analysis based on these SNPs, which yielded consistent results. Six QTLs were mapped on chromosomes 1, 2, 5, 8 and 10. The three most significant QTLs on chromosomes 1, 2 and 8 were validated by comparison with previous studies. Two QTLs on chromosomes 2 and 5 were also identified previously, but at the booting stage rather than the seedling stage, suggesting that some QTLs may function at different developmental stages, which would be useful for cold tolerance breeding in rice. Compared with previously reported QTL mapping studies for cold tolerance in rice based on the traditional approaches, the results of this study demonstrated the advantages of NGS-assisted BSA in both efficiency and statistical power. PMID- 23935869 TI - The carbohydrate sensitive rat as a model of obesity. AB - BACKGROUND: Sensitivity to obesity is highly variable in humans, and rats fed a high fat diet (HFD) are used as a model of this inhomogeneity. Energy expenditure components (basal metabolism, thermic effect of feeding, activity) and variations in substrate partitioning are possible factors underlying the variability. Unfortunately, in rats as in humans, results have often been inconclusive and measurements usually made after obesity onset, obscuring if metabolism was a cause or consequence. Additionally, the role of high carbohydrate diet (HCD) has seldom been studied. METHODOLOGY/FINDINGS: Rats (n=24) were fed for 3 weeks on HCD and then 3 weeks on HFD. Body composition was tracked by MRI and compared to energy expenditure components measured prior to obesity. RESULTS: 1) under HFD, as expected, by adiposity rats were variable enough to be separable into relatively fat resistant (FR) and sensitive (FS) groups, 2) under HCD, and again by adiposity, rats were also variable enough to be separable into carbohydrate resistant (CR) and sensitive (CS) groups, the normal body weight of CS rats hiding viscerally-biased fat accumulation, 3) HCD adiposity sensitivity was not related to that under HFD, and both HCD and HFD adiposity sensitivities were not related to energy expenditure components (BMR, TEF, activity cost), and 4) only carbohydrate to fat partitioning in response to an HCD test meal was related to HCD-induced adiposity. CONCLUSIONS/SIGNIFICANCE: The rat model of human obesity is based on substantial variance in adiposity gains under HFD (FR/FS model). Here, since we also found this phenomenon under HCD, where it was also linked to an identifiable metabolic difference, we should consider the existence of another model: the carbohydrate resistant (CR) or sensitive (CS) rat. This new model is potentially complementary to the FR/FS model due to relatively greater visceral fat accumulation on a low fat high carbohydrate diet. PMID- 23935870 TI - Impact of HIV-associated conditions on mortality in people commencing anti retroviral therapy in resource limited settings. AB - OBJECTIVES: To identify associations between specific WHO stage 3 and 4 conditions diagnosed after ART initiation and all cause mortality for patients in resource-limited settings (RLS). DESIGN, SETTING: Analysis of routine program data collected prospectively from 25 programs in eight countries between 2002 and 2010. SUBJECTS, PARTICIPANTS: 36,664 study participants with median ART follow-up of 1.26 years (IQR 0.55-2.27). OUTCOME MEASURES: Using a proportional hazards model we identified factors associated with mortality, including the occurrence of specific WHO clinical stage 3 and 4 conditions during the 6-months following ART initiation. RESULTS: There were 2922 deaths during follow-up (8.0%). The crude mortality rate was 5.41 deaths per 100 person-years (95% CI: 5.21-5.61). The diagnosis of any WHO stage 3 or 4 condition during the first 6 months of ART was associated with increased mortality (HR: 2.21; 95% CI: 1.97-2.47). After adjustment for age, sex, region and pre-ART CD4 count, a diagnosis of extrapulmonary cryptococcosis (aHR: 3.54; 95% CI: 2.74-4.56), HIV wasting syndrome (aHR: 2.92; 95%CI: 2.21 -3.85), non-tuberculous mycobacterial infection (aHR: 2.43; 95% CI: 1.80-3.28) and Pneumocystis pneumonia (aHR: 2.17; 95% CI 1.80 3.28) were associated with the greatest increased mortality. Cerebral toxoplasmosis, pulmonary and extra-pulmonary tuberculosis, Kaposi's sarcoma and oral and oesophageal candidiasis were associated with increased mortality, though at lower rates. CONCLUSIONS: A diagnosis of certain WHO stage 3 and 4 conditions is associated with an increased risk of mortality in those initiating ART in RLS. This information will assist initiatives to reduce excess mortality, including prioritization of resources for diagnostics, therapeutic interventions and research. PMID- 23935871 TI - The transcriptional cofactor MCAF1/ATF7IP is involved in histone gene expression and cellular senescence. AB - Cellular senescence is post-mitotic or oncogene-induced events combined with nuclear remodeling. MCAF1 (also known as hAM or ATF7IP), a transcriptional cofactor that is overexpressed in various cancers, functions in gene activation or repression, depending on interacting partners. In this study, we found that MCAF1 localizes to PML nuclear bodies in human fibroblasts and non-cancerous cells. Interestingly, depletion of MCAF1 in fibroblasts induced premature senescence that was characterized by cell cycle arrest, SA-beta-gal activity, and senescence-associated heterochromatic foci (SAHF) formation. Under this condition, core histones and the linker histone H1 significantly decreased at both mRNA and protein levels, resulting in reduced nucleosome formation. Consistently, in activated Ras-induced senescent fibroblasts, the accumulation of MCAF1 in PML bodies was enhanced via the binding of this protein to SUMO molecules, suggesting that sequestration of MCAF1 to PML bodies promotes cellular senescence. Collectively, these results reveal that MCAF1 is an essential regulator of cellular senescence. PMID- 23935873 TI - Optimal designs of the median run length based double sampling X chart for minimizing the average sample size. AB - Designs of the double sampling (DS) X chart are traditionally based on the average run length (ARL) criterion. However, the shape of the run length distribution changes with the process mean shifts, ranging from highly skewed when the process is in-control to almost symmetric when the mean shift is large. Therefore, we show that the ARL is a complicated performance measure and that the median run length (MRL) is a more meaningful measure to depend on. This is because the MRL provides an intuitive and a fair representation of the central tendency, especially for the rightly skewed run length distribution. Since the DS X chart can effectively reduce the sample size without reducing the statistical efficiency, this paper proposes two optimal designs of the MRL-based DS X chart, for minimizing (i) the in-control average sample size (ASS) and (ii) both the in control and out-of-control ASSs. Comparisons with the optimal MRL-based EWMA X and Shewhart X charts demonstrate the superiority of the proposed optimal MRL based DS X chart, as the latter requires a smaller sample size on the average while maintaining the same detection speed as the two former charts. An example involving the added potassium sorbate in a yoghurt manufacturing process is used to illustrate the effectiveness of the proposed MRL-based DS X chart in reducing the sample size needed. PMID- 23935872 TI - Computed tomography measurement of rib cage morphometry in emphysema. AB - BACKGROUND: Factors determining the shape of the human rib cage are not completely understood. We aimed to quantify the contribution of anthropometric and COPD-related changes to rib cage variability in adult cigarette smokers. METHODS: Rib cage diameters and areas (calculated from the inner surface of the rib cage) in 816 smokers with or without COPD, were evaluated at three anatomical levels using computed tomography (CT). CTs were analyzed with software, which allows quantification of total emphysema (emphysema%). The relationship between rib cage measurements and anthropometric factors, lung function indices, and %emphysema were tested using linear regression models. RESULTS: A model that included gender, age, BMI, emphysema%, forced expiratory volume in one second (FEV1)%, and forced vital capacity (FVC)% fit best with the rib cage measurements (R(2) = 64% for the rib cage area variation at the lower anatomical level). Gender had the biggest impact on rib cage diameter and area (105.3 cm(2); 95% CI: 111.7 to 98.8 for male lower area). Emphysema% was responsible for an increase in size of upper and middle CT areas (up to 5.4 cm(2); 95% CI: 3.0 to 7.8 for an emphysema increase of 5%). Lower rib cage areas decreased as FVC% decreased (5.1 cm(2); 95% CI: 2.5 to 7.6 for 10 percentage points of FVC variation). CONCLUSIONS: This study demonstrates that simple CT measurements can predict rib cage morphometric variability and also highlight relationships between rib cage morphometry and emphysema. PMID- 23935874 TI - Fast association tests for genes with FAST. AB - Gene-based tests of association can increase the power of a genome-wide association study by aggregating multiple independent effects across a gene or locus into a single stronger signal. Recent gene-based tests have distinct approaches to selecting which variants to aggregate within a locus, modeling the effects of linkage disequilibrium, representing fractional allele counts from imputation, and managing permutation tests for p-values. Implementing these tests in a single, efficient framework has great practical value. Fast ASsociation Tests (Fast) addresses this need by implementing leading gene-based association tests together with conventional SNP-based univariate tests and providing a consolidated, easily interpreted report. Fast scales readily to genome-wide SNP data with millions of SNPs and tens of thousands of individuals, provides implementations that are orders of magnitude faster than original literature reports, and provides a unified framework for performing several gene based association tests concurrently and efficiently on the same data. AVAILABILITY: https://bitbucket.org/baderlab/fast/downloads/FAST.tar.gz, with documentation at https://bitbucket.org/baderlab/fast/wiki/Home. PMID- 23935875 TI - Lack of association of MiR-34b/c polymorphism (rs4938723) with hepatocellular carcinoma: a meta-analysis. AB - BACKGROUND: Previous studies have focused on the association of miR-34 family members with carcinogenesis of many cancers, including hepatocellular carcinoma (HCC). It has been suggested that miR-34b/c polymorphism (rs4938723) is associated with susceptibility to HCC. In the present study, we performed a meta analysis to systematically summarize the possible association between rs4938723 and the risk for HCC. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a search of case-control studies on the associations of rs4938723 with susceptibility to HCC in PubMed, EMBASE, ISI Web of Science, Cochrane Central Register of Controlled Trials, ScienceDirect, Wiley Online Library, Wangfang database in China, and Chinese National Knowledge Infrastructure databases. Data from eligible studies were extracted for meta-analysis. HCC risk associated with rs4938723 was estimated by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). 3 studies on rs4938723 were included in our meta-analysis. Our results showed that neither allele frequency nor genotype distribution of the rs4938723 was associated with risk for HCC in all genetic models. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests that rs4938723 is not associated with the risk of HCC. Well-designed studies with larger sample size and more ethnic groups are required to further validate the results. PMID- 23935876 TI - NF-kappaB regulates mesenchymal transition for the induction of non-small cell lung cancer initiating cells. AB - The epithelial-to-mesenchymal transition (EMT) is a de-differentiation process that has been implicated in metastasis and the generation of cancer initiating cells (CICs) in solid tumors. To examine EMT in non-small cell lung cancer (NSCLC), we utilized a three dimensional (3D) cell culture system in which cells were co-stimulated with tumor necrosis factor alpha (TNF) and transforming growth factor beta (TGFbeta). NSCLC spheroid cultures display elevated expression of EMT master-switch transcription factors, TWIST1, SNAI1/Snail1, SNAI2/Slug and ZEB2/Sip1, and are highly invasive. Mesenchymal NSCLC cultures show CIC characteristics, displaying elevated expression of transcription factors KLF4, SOX2, POU5F1/Oct4, MYCN, and KIT. As a result, these putative CIC display a cancer "stem-like" phenotype by forming lung metastases under limiting cell dilution. The pleiotropic transcription factor, NF-kappaB, has been implicated in EMT and metastasis. Thus, we set out to develop a NSCLC model to further characterize the role of NF-kappaB activation in the development of CICs. Here, we demonstrate that induction of EMT in 3D cultures results in constitutive NF kappaB activity. Furthermore, inhibition of NF-kappaB resulted in the loss of TWIST1, SNAI2, and ZEB2 induction, and a failure of cells to invade and metastasize. Our work indicates that NF-kappaB is required for NSCLC metastasis, in part, by transcriptionally upregulating master-switch transcription factors required for EMT. PMID- 23935877 TI - Searching for synergies: matrix algebraic approaches for efficient pair screening. AB - Functionally interacting perturbations, such as synergistic drugs pairs or synthetic lethal gene pairs, are of key interest in both pharmacology and functional genomics. However, to find such pairs by traditional screening methods is both time consuming and costly. We present a novel computational-experimental framework for efficient identification of synergistic target pairs, applicable for screening of systems with sizes on the order of current drug, small RNA or SGA (Synthetic Genetic Array) libraries (>1000 targets). This framework exploits the fact that the response of a drug pair in a given system, or a pair of genes' propensity to interact functionally, can be partly predicted by computational means from (i) a small set of experimentally determined target pairs, and (ii) pre-existing data (e.g. gene ontology, PPI) on the similarities between targets. Predictions are obtained by a novel matrix algebraic technique, based on cyclical projections onto convex sets. We demonstrate the efficiency of the proposed method using drug-drug interaction data from seven cancer cell lines and gene gene interaction data from yeast SGA screens. Our protocol increases the rate of synergism discovery significantly over traditional screening, by up to 7-fold. Our method is easy to implement and could be applied to accelerate pair screening for both animal and microbial systems. PMID- 23935878 TI - Insulin sensitivity from preschool to school age in patients with severe obesity. AB - BACKGROUND: Insulin sensitivity decreases at puberty transition, but little information has been provided on its earlier time-course. Aim of the present study was to describe the time-course of insulin sensitivity in severely obese children at the transition from preschool to school age. RESEARCH DESIGN AND METHODS: Retrospective study of a cohort of 47 severely obese [Body Mass Index (BMI) >=99 degrees percentile] preschoolers evaluated twice, once between 2 and 6 years of age, and once before age 8. Glucose tolerance, Whole Body Insulin Sensitivity Index (WBISI), Insulinogenic Index (IGI); beta-cell demand index (BCDI) and Insulin Secretion-Sensitivity Index 2 (ISSI-2) were longitudinally estimated during the oral glucose tolerance test. RESULTS: After a median follow up of 2.23 (1-4.52) y, obese patients showed significant decrease in WBISI (p<0.0001), and increase in fasting (p = 0.005) and 2 h glucose (2HG, p = 0.001). One child in preschool age and 4 school age children presented with 2HG between 7.8-11.1 mmol/l. Best predictors of WBISI, 2HG and BCDI in the school age were changes in BMI z-score (R(2) = 0.309; p = 0.002; beta = -0.556), ISSI-2 (R(2) = 0.465; p<0.0001; beta = -0.682), and BMI z-score (R(2) = 0.246; p = 0.008; 0.496), respectively. CONCLUSIONS: In morbidly obese children, insulin sensitivity seems to decline even before pubertal transition, but changes in total adiposity can only partially explain this variation. PMID- 23935879 TI - Using synthetic biology to distinguish and overcome regulatory and functional barriers related to nitrogen fixation. AB - Biological nitrogen fixation is a complex process requiring multiple genes working in concert. To date, the Klebsiella pneumoniae nif gene cluster, divided into seven operons, is one of the most studied systems. Its nitrogen fixation capacity is subject to complex cascade regulation and physiological limitations. In this report, the entire K. pneumoniae nif gene cluster was reassembled as operon-based BioBrick parts in Escherichia coli. It provided ~100% activity of native K. pneumoniae system. Based on the expression levels of these BioBrick parts, a T7 RNA polymerase-LacI expression system was used to replace the sigma(54)-dependent promoters located upstream of nif operons. Expression patterns of nif operons were critical for the maximum activity of the recombinant system. By mimicking these expression levels with variable-strength T7-dependent promoters, ~42% of the nitrogenase activity of the sigma(54)-dependent nif system was achieved in E. coli. When the newly constructed T7-dependent nif system was challenged with different genetic and physiological conditions, it bypassed the original complex regulatory circuits, with minor physiological limitations. Therefore, we have successfully replaced the nif regulatory elements with a simple expression system that may provide the first step for further research of introducing nif genes into eukaryotic organelles, which has considerable potentials in agro-biotechnology. PMID- 23935880 TI - Identification of genome-wide copy number variations among diverse pig breeds using SNP genotyping arrays. AB - Copy number variations (CNVs) are important forms of genetic variation complementary to SNPs, and can be considered as promising markers for some phenotypic and economically important traits or diseases susceptibility in domestic animals. In the present study, we performed a genome-wide CNV identification in 14 individuals selected from diverse populations, including six types of Chinese indigenous breeds, one Asian wild boar population, as well as three modern commercial foreign breeds. We identified 63 CNVRs in total, which covered 9.98 Mb of polymorphic sequence and corresponded to 0.36% of the genome sequence. The length of these CNVRs ranged from 3.20 to 827.21 kb, with an average of 158.37 kb and a median of 97.85 kb. Functional annotation revealed these identified CNVR have important molecular function, and may play an important role in exploring the genetic basis of phenotypic variability and disease susceptibility among pigs. Additionally, to confirm these potential CNVRs, we performed qPCR for 12 randomly selected CNVRs and 8 of them (66.67%) were confirmed successfully. CNVs detected in diverse populations herein are essential complementary to the CNV map in the pig genome, which provide an important resource for studies of genomic variation and the association between various economically important traits and CNVs. PMID- 23935881 TI - Hypovitaminosis D is independently associated with metabolic syndrome in obese patients. AB - BACKGROUND: Metabolic syndrome (MS) and hypovitaminosis D represent two of the most diffuse condition worldwide, reaching pandemic proportions in industrialized countries, and are both strongly associated with obesity. This study set out to evaluate the presence of an independent association between hypovitaminosis D and MS in an adult population of obese subjects with/without MS. METHODS: We recruited 107 consecutive obese subjects, 61 with MS (age(mean+/-SD) 45.3+/-13.3 years, BMI(mean+/-SD): 43.1+/-8.3 kg/m(2)) and 46 without MS (age: 41.8+/-11.5, p = n.s., BMI:41.6+/-6.5 kg/m(2), p = n.s.) comparable for sex, BMI, waist circumference and body fat mass, evaluated by bioimpedentiometry. 25(OH) vitamin D3 levels were measured by colorimetric method. Insulin resistance was estimated by fasting blood insulin, HOMA-IR and ISI. RESULTS: Serum 25(OH)D3 levels were significantly lower in MS obese patients than in obese subjects without MS (median(range) 13.5(3.3-32) vs 17.4(5.1-37.4), p<0.007). Low 25(OH)D3 levels correlated with glycaemia (p<0.007), phosphate (p<0.03), PTH (p<0.003) and the MS (p<0.001). Multivariate model confirmed that low 25(OH)D3 levels were associated with the diagnosis of MS in obese patients independently from gender, age, serum PTH and body fat mass. After stratifying the study population according to 25(OH)D3 concentrations, patients in the lowest quartile showed a markedly increased prevalence of MS compared to those in the highest quartile (OR = 4.1, CI 1.2-13.7, p = 0.02). CONCLUSIONS: A powerful association exists between hypovitaminosis D and MS in obese patients independently from body fat mass and its clinical correlates. This indicates that the association between low 25(OH) D3 levels and MS is not merely induced by vitamin D deposition in fat tissue and reinforces the hypothesis that hypovitaminosis D represent a crucial independent determinant of MS. PMID- 23935882 TI - Pseudoxanthoma elasticum: cardiac findings in patients and Abcc6-deficient mouse model. AB - BACKGROUND: Pseudoxanthoma elasticum (PXE), caused by mutations in the ABCC6 gene, is a rare multiorgan disease characterized by the mineralization and fragmentation of elastic fibers in connective tissue. Cardiac complications reportedly associated with PXE are mainly based on case reports. METHODS: A cohort of 67 PXE patients was prospectively assessed. Patients underwent physical examination, electrocardiogram, transthoracic echocardiography, cardiac magnetic resonance imaging (CMR), treadmill testing, and perfusion myocardial scintigraphy (SPECT). Additionally, the hearts of a PXE mouse models (Abcc6(-/-)) and wild type controls (WT) were analyzed. RESULTS: Three patients had a history of proven coronary artery disease. In total, 40 patients underwent exercise treadmill tests, and 28 SPECT. The treadmill tests were all negative. SPECT showed mild perfusion abnormalities in two patients. Mean left ventricular (LV) dimension and function values were within the normal range. LV hypertrophy was found in 7 (10.4%) patients, though the hypertrophy etiology was unknown for 3 of those patients. Echocardiography revealed frequent but insignificant mitral and tricuspid valvulopathies. Mitral valve prolapse was present in 3 patients (4.5%). Two patients exhibited significant aortic stenosis (3.0%). While none of the functional and histological parameters diverged significantly between the Abcc6( /-) and WT mice groups at age of 6 and 12 months, the 24-month-old Abcc6(-/-) mice developed cardiac hypertrophy without contractile dysfunction. CONCLUSIONS: Despite sporadic cases, PXE does not appear to be associated with frequent cardiac complications. However, the development of cardiac hypertrophy in the 24 month-old Abcc6(-/-) mice suggests that old PXE patients might be prone to developing late cardiopathy. PMID- 23935883 TI - Characterization of colonizing Staphylococcus aureus isolated from surgical wards' patients in a Nigerian university hospital. AB - In contrast to developed countries, only limited data on the prevalence, resistance and clonal structure of Staphylococcus aureus are available for African countries. Since S. aureus carriage is a risk factor for postoperative wound infection, patients who had been hospitalized in surgical wards in a Nigerian University Teaching Hospital were screened for S. aureus carriage. All S. aureus isolates were genotyped (spa, agr) and assigned to multilocus sequence types (MLST). Species affiliation, methicillin-resistance, and the possession of pyrogenic toxin superantigens (PTSAg), exfoliative toxins (ETs) and Panton Valentine Leukocidin (PVL) were analyzed. Of 192 patients screened, the S. aureus carrier rate was 31.8 % (n = 61). Of these isolates, 7 (11.5%) were methicillin resistant (MRSA). The isolates comprised 24 spa types. The most frequent spa types were t064, t084, t311, and t1931, while the most prevalent MLST clonal complexes were CC5 and CC15. The most frequent PTSAg genes detected were seg/sei (41.0%) followed by seb (29.5%), sea (19.7%), seh (14.7%) and sec (11.5). The difference between the possession of classical and newly described PTSAg genes was not significant (63.9% versus 59.0% respectively; P = 0.602). PVL encoding genes were found in 39.3% isolates. All MRSA isolates were PVL negative, SCCmec types I and VI in MLST CC 5 and CC 30, respectively. Typing of the accessory gene regulator (agr) showed the following distribution: agr group 1 (n = 20), group II (n = 17), group III (n = 14) and group IV (n = 10). Compared to European data, enterotoxin gene seb and PVL-encoding genes were more prevalent in Nigerian methicillin-susceptible S. aureus isolates, which may therefore act as potential reservoir for PVL and PTSAg genes. PMID- 23935884 TI - Overexpression of high mobility group A1 protein in human uveal melanomas: implication for prognosis. AB - There is increasing evidence that the high mobility group A1 (HMGA1) protein, which functions as a transcriptional master regulator, plays critical roles in tumor progression. We evaluated HMGA1 expression in 89 primary uveal melanomas (UM) by immunohistochemistry to determine the clinicopathological and prognostic value of HMGA1 in UM after adjusting for other prognostic variables. Nuclear expression of HMGA1 was detected in 44% UMs. High expression levels of HMGA1 were more frequent in UMs with high levels of epithelioid cell pattern, mitoses count, and Ki67 labeling index (P = 0.025, P<0.0001, P = 0.0018; respectively), and HMGA1 expression levels were directly correlated with Ki67 labeling indexes and mitoses counts (R = 0.31, P <0.0001; R = 0.27, P<0.0068; respectively). High expression of HMGA1 was also independently associated with an increased risk of distant metastases as determined using the Cox proportional hazards regression model (multivariate hazard ratio: 3.44; 95% confidence interval: 1.56-7.60; log rank P = 0.0022). Moreover, high HMGA1 expression was associated with shorter UM specific survival (multivariate hazard ratio: 2.41; 95% confidence interval: 1.10 5.53; log rank P = 0.041). These findings suggest that high levels of HMGA1 are associated with adverse clinical outcomes in UM patients and that further evaluation of HMGA1 as a potential therapeutic target in UM is warranted. PMID- 23935886 TI - A preliminary study of the heating effect of the Tibetan Plateau. AB - The immense and towering Tibetan Plateau acts as a heating source and, thus, deeply shapes the climate of the Eurasian continent and even the whole world. However, due to the scarcity of meteorological observation stations and very limited climatic data, little is quantitatively known about the heating effect of the plateau and its implications. This paper firstly collects climate data (2001 2007) from 109 observation stations and MODIS-based estimated monthly mean temperature data in the plateau and the neighboring Sichuan Basin, and conducts correlation and simple linear regression to reveal the altitudinal pattern of temperature. Then, according to the linear relationships of temperature and altitude for each month, it compares air temperature differences on the same elevation between the main plateau and surrounding mountains and the Sichuan Basin so as to quantify the heating effect and discuss its implication on timberline of the plateau. The results show that: 1) the heating effect of the plateau is significant. The temperature of the main plateau area was higher than that of free air on the same elevation above the neighboring areas; on the elevation of 4500 m (the main plateau), temperature is 1-6 degrees C higher in the main Plateau than over the Sichuan Basin for different months and 5.9-10.7 degrees C higher than in the Qilian Mountains in the northeastern corner of the plateau. 2) Even at altitudes of 5000-6000 m in the main Plateau, there are 4 months with a mean temperature above 0 degrees C. The mean temperature of the warmest month (July) can reach 10 degrees C at about 4600-4700 m. This may help explain why the highest timberline in the northern hemisphere is on the southeastern Tibetan Plateau. PMID- 23935885 TI - Tobacco smoking and its association with illicit drug use among young men aged 15 24 years living in urban slums of Bangladesh. AB - BACKGROUND: Tobacco smoking (TS) and illicit drug use (IDU) are of public health concerns especially in developing countries, including Bangladesh. This paper aims to (i) identify the determinants of TS and IDU, and (ii) examine the association of TS with IDU among young slum dwellers in Bangladesh. METHODOLOGY/PRINCIPAL FINDINGS: Data on a total of 1,576 young slum dwellers aged 15-24 years were extracted for analysis from the 2006 Urban Health Survey (UHS), which covered a nationally representative sample of 13,819 adult men aged 15-59 years from slums, non-slums and district municipalities of six administrative regions in Bangladesh. Methods used include frequency run, Chi-square test of association and multivariable logistic regression. The overall prevalence of TS in the target group was 42.3%, of which 41.4% smoked cigarettes and 3.1% smoked bidis. The regression model for TS showed that age, marital status, education, duration of living in slums, and those with sexually transmitted infections were significantly (p<0.001 to p<0.05) associated with TS. The overall prevalence of IDU was 9.1%, dominated by those who had drug injections (3.2%), and smoked ganja (2.8%) and tari (1.6%). In the regression model for IDU, the significant (p<0.01 to p<0.10) predictors were education, duration of living in slums, and whether infected by sexually transmitted diseases. The multivariable logistic regression (controlling for other variables) revealed significantly (p<0.001) higher likelihood of IDU (OR = 9.59, 95% CI = 5.81-15.82) among users of any form of TS. The likelihood of IDU increased significantly (p<0.001) with increased use of cigarettes. CONCLUSIONS/SIGNIFICANCE: Certain groups of youth are more vulnerable to TS and IDU. Therefore, tobacco and drug control efforts should target these groups to reduce the consequences of risky lifestyles through information, education and communication (IEC) programs. PMID- 23935887 TI - Application of structural equation models for elucidating the ecological drivers of Anopheles sinensis in the three gorges reservoir. AB - OBJECTIVE: To identify the major ecological drivers for malaria vector density using the structural equation model (SEM) in the Three Gorges Reservoir. METHOD: An 11-year longitudinal surveillance of malaria vector as well as its related ecological factors was carried out in the Three Gorges Reservoir. The Delphi method was used to identify associated ecological factors. The structural equation model was repeatedly corrected and improved by the corrected index, combined with the actual situation. The final model was defined by relative simplicity, best fitting as well as the practicality. RESULT: The final model indicated that the direct effects of temperature, livestock, humidity, and breeding on the vector were 0.015, -0.228, 0.450, 0.516 respectively, their total effects on the vector were 0.359, -0.112, 0.850, and 0.043 through different pathways. CONCLUSION: SEM was effective and convenient in elucidating the mechanism by which malaria vector dynamics operated in this study. It identified that the breeding had the highest direct effect on vector and played a key role for mediating effect of temperature and humidity. PMID- 23935888 TI - Cardiotrophin-1 induces matrix metalloproteinase-1 in human aortic endothelial cells. AB - Rupture of an atherosclerotic plaque is a key event in the development of cardiovascular disorders, in which matrix metalloproteinase-1 (MMP-1) plays a crucial role by degradation of extracellular matrix resulting in plaque instability. Cardiotrophin-1 (CT-1), a member of interleukin-6-type proinflammatory cytokines, has potent cardiovascular actions and is highly expressed in vascular endothelium, however its role in atherosclerosis has not been fully elucidated to date. The present study was designed to investigate whether CT-1 induces MMP-1 in human aortic endothelial cells (HAECs). Ribonuclease protection assay demonstrated that MMP-1 gene level in HAECs was enhanced by the treatment of CT-1 in a dose- and time-dependent manner. Immunocytochemical staining, Western immunoblot analysis and enzyme-linked immunosorbent assay revealed that CT-1 augmented MMP-1 protein synthesis and secretion. MMP-1 activity assay revealed that MMP-1 present in the supernatant of HAECs was exclusively precursor form. Casein zymography disclosed proteolytic activity in the supernatant of HAECs, which was enhanced by CT-1 treatment. Furthermore, pharmacological inhibitor study indicated the important roles of extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen-activated protein (MAP) kinase, c-Jun N-terminal kinase (JNK) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways in mediating CT-1 induced MMP-1 gene and protein expression. These data reveal for the first time that CT-1 induces the proteolytic potential in HAECs by upregulating MMP-1 expression through ERK1/2, p38 MAP kinase, JNK and JAK/STAT pathways, and suggest that CT-1 may play an important role in the pathophysiology of atherosclerosis and plaque instability. PMID- 23935889 TI - Disruption of calcium homeostasis in cardiomyocytes underlies cardiac structural and functional changes in severe sepsis. AB - Sepsis, a major cause of morbidity/mortality in intensive care units worldwide, is commonly associated with cardiac dysfunction, which worsens the prognosis dramatically for patients. Although in recent years the concept of septic cardiomyopathy has evolved, the importance of myocardial structural alterations in sepsis has not been fully explored. This study offers novel and mechanistic data to clarify subcellular events that occur in the pathogenesis of septic cardiomyopathy and myocardial dysfunction in severe sepsis. Cultured neonatal mice cardiomyocytes subjected to serum obtained from mice with severe sepsis presented striking increment of [Ca(2+)]i and calpain-1 levels associated with decreased expression of dystrophin and disruption and derangement of F-actin filaments and cytoplasmic bleb formation. Severe sepsis induced in mice led to an increased expression of calpain-1 in cardiomyocytes. Moreover, decreased myocardial amounts of dystrophin, sarcomeric actin, and myosin heavy chain were observed in septic hearts associated with depressed cardiac contractile dysfunction and a very low survival rate. Actin and myosin from the sarcomere are first disassembled by calpain and then ubiquitinated and degraded by proteasome or sequestered inside specialized vacuoles called autophagosomes, delivered to the lysosome for degradation forming autophagolysosomes. Verapamil and dantrolene prevented the increase of calpain-1 levels and preserved dystrophin, actin, and myosin loss/reduction as well cardiac contractile dysfunction associated with strikingly improved survival rate. These abnormal parameters emerge as therapeutic targets, which modulation may provide beneficial effects on future vascular outcomes and mortality in sepsis. Further studies are needed to shed light on this mechanism, mainly regarding specific calpain inhibitors. PMID- 23935891 TI - Genotype directed therapy in murine mismatch repair deficient tumors. AB - The PI3K/AKT/mTOR pathway has frequently been found activated in human tumors. We show that in addition to Wnt signaling dysfunction, the PI3K/AKT/mTOR pathway is often upregulated in mouse Msh2(-/-) initiated intestinal tumors. NVP-BEZ235 is a dual PI3K/mTOR inhibitor toxic to many cancer cell lines and currently involved in clinical trials. We have treated two mouse models involving Msh2 that develop small intestinal and/or colonic tumors with NVP-BEZ235, and a subset of animals with NVP-BEZ235 and MEK inhibitor ADZ4266. The disease phenotype has been followed with pathology, (18)F FDG PET imaging, and endoscopy. Intestinal adenocarcinomas are significantly decreased in multiplicity by both drug regimens. The majority of tumors treated with combined therapy regress significantly, while a small number of highly progressed tumors persist. We have examined PTEN, AKT, MEK 1&2, MAPK, S6K, mTOR, PDPK1, and Cyclin D1 and find variable alterations that include downregulation of PTEN, upregulation of AKT and changes in its phosphorylated forms, upregulation of pMEK 1&2, p42p44MAPK, pS6K, and Cyclin D1. Apoptosis has been found intact in some tumors and not in others. Our data indicate that NVP-BEZ235 alone and in combination with ADZ4266 are effective in treating a proportion of colorectal cancers, but that highly progressed resistant tumors grow in the presence of the drugs. Pathways upregulated in some resistant tumors also include PDPK1, suggesting that metabolic inhibitors may also be useful in treating these tumors. PMID- 23935890 TI - Potential capacity of aptamers to trigger immune activation in human blood. AB - Target specific short single-stranded DNA (ssDNA) molecules, called aptamers, are auspicious ligands for numerous in vivo applications. However, aptamers are synthetic molecules, which might be recognized by the immune cells in vivo and induce an activation of the innate immune system. Thus, immune activation potential of synthetic ssDNA oligonucleotides (ODNs) was determined using a well established closed-loop circulation model. Fresh human blood was incubated at 37 degrees C for 2 or 4 hours with ssDNA ODNs (SB_ODN) or CpG ODN as positive control. Transcriptional changes were determined by microarray analyses. Blood samples containing SB_ODN demonstrated after 4 hours a significant regulation of 295 transcripts. Amongst others, CCL8, CXCL10, CCL7 and CXCL11 were highest regulated genes. Gene Ontology terms and KEGG pathway analyses exhibited that the differentially expressed genes belong to the transcripts that are regulated during an immune and inflammatory response, and were overrepresented in TLR signaling pathway. This study shows for the first time the potential of aptamers to activate immune system after systemic application into the human blood. Thus, we highly recommend performing of these preclinical tests with potential aptamer based therapeutics. PMID- 23935892 TI - Effects of Bacillus amyloliquefaciens FZB42 on lettuce growth and health under pathogen pressure and its impact on the rhizosphere bacterial community. AB - The soil-borne pathogen Rhizoctonia solani is responsible for crop losses on a wide range of important crops worldwide. The lack of effective control strategies and the increasing demand for organically grown food has stimulated research on biological control. The aim of the present study was to evaluate the rhizosphere competence of the commercially available inoculant Bacillus amyloliquefaciens FZB42 on lettuce growth and health together with its impact on the indigenous rhizosphere bacterial community in field and pot experiments. Results of both experiments demonstrated that FZB42 is able to effectively colonize the rhizosphere (7.45 to 6.61 Log 10 CFU g(-1) root dry mass) within the growth period of lettuce in the field. The disease severity (DS) of bottom rot on lettuce was significantly reduced from severe symptoms with DS category 5 to slight symptom expression with DS category 3 on average through treatment of young plants with FZB42 before and after planting. The 16S rRNA gene based fingerprinting method terminal restriction fragment length polymorphism (T-RFLP) showed that the treatment with FZB42 did not have a major impact on the indigenous rhizosphere bacterial community. However, the bacterial community showed a clear temporal shift. The results also indicated that the pathogen R. solani AG1-IB affects the rhizosphere microbial community after inoculation. Thus, we revealed that the inoculant FZB42 could establish itself successfully in the rhizosphere without showing any durable effect on the rhizosphere bacterial community. PMID- 23935893 TI - SIMS: a hybrid method for rapid conformational analysis. AB - Proteins are at the root of many biological functions, often performing complex tasks as the result of large changes in their structure. Describing the exact details of these conformational changes, however, remains a central challenge for computational biology due the enormous computational requirements of the problem. This has engendered the development of a rich variety of useful methods designed to answer specific questions at different levels of spatial, temporal, and energetic resolution. These methods fall largely into two classes: physically accurate, but computationally demanding methods and fast, approximate methods. We introduce here a new hybrid modeling tool, the Structured Intuitive Move Selector (sims), designed to bridge the divide between these two classes, while allowing the benefits of both to be seamlessly integrated into a single framework. This is achieved by applying a modern motion planning algorithm, borrowed from the field of robotics, in tandem with a well-established protein modeling library. sims can combine precise energy calculations with approximate or specialized conformational sampling routines to produce rapid, yet accurate, analysis of the large-scale conformational variability of protein systems. Several key advancements are shown, including the abstract use of generically defined moves (conformational sampling methods) and an expansive probabilistic conformational exploration. We present three example problems that sims is applied to and demonstrate a rapid solution for each. These include the automatic determination of "active" residues for the hinge-based system Cyanovirin-N, exploring conformational changes involving long-range coordinated motion between non sequential residues in Ribose-Binding Protein, and the rapid discovery of a transient conformational state of Maltose-Binding Protein, previously only determined by Molecular Dynamics. For all cases we provide energetic validations using well-established energy fields, demonstrating this framework as a fast and accurate tool for the analysis of a wide range of protein flexibility problems. PMID- 23935895 TI - What took them so long? Explaining PhD delays among doctoral candidates. AB - A delay in PhD completion, while likely undesirable for PhD candidates, can also be detrimental to universities if and when PhD delay leads to attrition/termination. Termination of the PhD trajectory can lead to individual stress, a loss of valuable time and resources invested in the candidate and can also mean a loss of competitive advantage. Using data from two studies of doctoral candidates in The Netherlands, we take a closer look at PhD duration and delay in doctoral completion. Specifically, we address the question: Is it possible to predict which PhD candidates will experience delays in the completion of their doctorate degree? If so, it might be possible to take steps to shorten or even prevent delay, thereby helping to enhance university competitiveness. Moreover, we discuss practical do's and don'ts for universities and graduate schools to minimize delays. PMID- 23935894 TI - Molecular and functional characterization of odorant-binding protein genes in an invasive vector mosquito, Aedes albopictus. AB - Aedes albopictus is a major vector of dengue and Chikungunya viruses. Olfaction plays a vital role in guiding mosquito behaviors and contributes to their ability to transmit pathogens. Odorant-binding proteins (OBPs) are abundant in insect olfactory tissues and involved in the first step of odorant reception. While comprehensive descriptions are available of OBPs from Aedes aegypti, Culex quinquefasciatus and Anopheles gambiae, only a few genes from Ae. albopictus have been reported. In this study, twenty-one putative AalbOBP genes were cloned using their homologues in Ae. aegypti to query an Ae. albopictus partial genome sequence. Two antenna-specific OBPs, AalbOBP37 and AalbOBP39, display a remarkable similarity in their overall folding and binding pockets, according to molecular modeling. Binding affinity assays indicated that AalbOBP37 and AalbOBP39 had overlapping ligand affinities and are affected in different pH condition. Electroantennagrams (EAG) and behavioral tests show that these two genes were involved in olfactory reception. An improved understanding of the Ae. albopictus OBPs is expected to contribute to the development of more efficient and environmentally-friendly mosquito control strategies. PMID- 23935896 TI - Genome array of hair follicle genes in lambskin with different patterns. AB - Hu sheep lambskin comes from a specific breed of sheep of China. Hu sheep are considered a protected breed by the Chinese government. The hair follicles of these sheep have three types of waves, large, medium, and small. There are only few histological reports of Hu sheep lambskin, and there are no modern molecular or biological studies, so the molecular mechanisms underlying the formation of hair follicles with different patterns are not currently known. The aim of this article was to study the molecular mechanism of the formation of these types of hair follicles in Hu sheep. Histological and microscopic analysis indicated that the number of follicles with small waves was not significantly higher than the number of follicles with large waves (P>0.05). The diameters of primary and secondary small-wave follicles were significantly smaller than those of large wave follicles (P<0.05; P<0.01). The ratio between the number primary follicles and the number of secondary follicles was significantly higher among small-wave follicles than among large-wave follicles (P<0.05). Differentially expressed genes in the skin tissue were screened using an Agilent gene chip and RT-PCR. Differential expression analysis revealed 3 groups of large waves and small waves; 1067, 2071, and 3879 differentially expressed genes; and 137 genes common to all 3 groups. Differentially expressed genes were classified using gene ontology. They were found to be mainly involved in cell differentiation, proliferation, apoptosis, growth, immune response, and ion transport. RT-PCR results of 4 differentially expressed genes were consistent with gene chip results. Combined with related literature, our results suggest that BMP7, MMP2, SNAI1, SFXN1, CDKNIC, MT3, and POU1F1 may have important effects on the formation of large-wave and small-wave hair follicles. This study may enrich knowledge of hair follicle development, and may identify the genes responsible for the formation of hair follicles with different patterns. PMID- 23935897 TI - Orthosteric binding of rho-Da1a, a natural peptide of snake venom interacting selectively with the alpha1A-adrenoceptor. AB - rho-Da1a is a three-finger fold toxin from green mamba venom that is highly selective for the alpha1A-adrenoceptor. This toxin has atypical pharmacological properties, including incomplete inhibition of (3)H-prazosin or (125)I-HEAT binding and insurmountable antagonist action. We aimed to clarify its mode of action at the alpha1A-adrenoceptor. The affinity (pKi 9.26) and selectivity of rho-Da1a for the alpha1A-adrenoceptor were confirmed by comparing binding to human adrenoceptors expressed in eukaryotic cells. Equilibrium and kinetic binding experiments were used to demonstrate that rho-Da1a, prazosin and HEAT compete at the alpha1A-adrenoceptor. rho-Da1a did not affect the dissociation kinetics of (3)H-prazosin or (125)I-HEAT, and the IC50 of rho-Da1a, determined by competition experiments, increased linearly with the concentration of radioligands used, while the residual binding by rho-Da1a remained stable. The effect of rho-Da1a on agonist-stimulated Ca(2+) release was insurmountable in the presence of phenethylamine- or imidazoline-type agonists. Ten mutations in the orthosteric binding pocket of the alpha1A-adrenoceptor were evaluated for alterations in rho-Da1a affinity. The D106(3.32)A and the S188(5.42)A/S192(5.46)A receptor mutations reduced toxin affinity moderately (6 and 7.6 times, respectively), while the F86(2.64)A, F288(6.51)A and F312(7.39)A mutations diminished it dramatically by 18- to 93-fold. In addition, residue F86(2.64) was identified as a key interaction point for (125)I-HEAT, as the variant F86(2.64)A induced a 23-fold reduction in HEAT affinity. Unlike the M1 muscarinic acetylcholine receptor toxin MT7, rho-Da1a interacts with the human alpha1A adrenoceptor orthosteric pocket and shares receptor interaction points with antagonist (F86(2.64), F288(6.51) and F312(7.39)) and agonist (F288(6.51) and F312(7.39)) ligands. Its selectivity for the alpha1A-adrenoceptor may result, at least partly, from its interaction with the residue F86(2.64), which appears to be important also for HEAT binding. PMID- 23935898 TI - Evidence that personal genome testing enhances student learning in a course on genomics and personalized medicine. AB - An emerging debate in academic medical centers is not about the need for providing trainees with fundamental education on genomics, but rather the most effective educational models that should be deployed. At Stanford School of Medicine, a novel hands-on genomics course was developed in 2010 that provided students the option to undergo personal genome testing as part of the course curriculum. We hypothesized that use of personal genome testing in the classroom would enhance the learning experience of students. No data currently exist on how such methods impact student learning; thus, we surveyed students before and after the course to determine its impact. We analyzed responses using paired statistics from the 31 medical and graduate students who completed both pre-course and post course surveys. Participants were stratified by those who did (N = 23) or did not (N = 8) undergo personal genome testing. In reflecting on the experience, 83% of students who underwent testing stated that they were pleased with their decision compared to 12.5% of students who decided against testing (P = 0.00058). Seventy percent of those who underwent personal genome testing self-reported a better understanding of human genetics on the basis of having undergone testing. Further, students who underwent personal genome testing demonstrated an average 31% increase in pre- to post-course scores on knowledge questions (P = 3.5*10( 6)); this was significantly higher (P = 0.003) than students who did not undergo testing, who showed a non-significant improvement. Undergoing personal genome testing and using personal genotype data in the classroom enhanced students' self reported and assessed knowledge of genomics, and did not appear to cause significant anxiety. At least for self-selected students, the incorporation of personal genome testing can be an effective educational tool to teach important concepts of clinical genomic testing. PMID- 23935900 TI - Age differences in the neuroelectric adaptation to meaningful sounds. AB - Much of what we know regarding the effect of stimulus repetition on neuroelectric adaptation comes from studies using artificially produced pure tones or harmonic complex sounds. Little is known about the neural processes associated with the representation of everyday sounds and how these may be affected by aging. In this study, we used real life, meaningful sounds presented at various azimuth positions and found that auditory evoked responses peaking at about 100 and 180 ms after sound onset decreased in amplitude with stimulus repetition. This neural adaptation was greater in young than in older adults and was more pronounced when the same sound was repeated at the same location. Moreover, the P2 waves showed differential patterns of domain-specific adaptation when location and identity was repeated among young adults. Background noise decreased ERP amplitudes and modulated the magnitude of repetition effects on both the N1 and P2 amplitude, and the effects were comparable in young and older adults. These findings reveal an age-related difference in the neural processes associated with adaptation to meaningful sounds, which may relate to older adults' difficulty in ignoring task irrelevant stimuli. PMID- 23935899 TI - Causal inference regarding infectious aetiology of chronic conditions: a systematic review. AB - BACKGROUND: The global burden of disease has shifted from communicable diseases in children to chronic diseases in adults. This epidemiologic shift varies greatly by region, but in Europe, chronic conditions account for 86% of all deaths, 77% of the disease burden, and up to 80% of health care expenditures. A number of risk factors have been implicated in chronic diseases, such as exposure to infectious agents. A number of associations have been well established while others remain uncertain. METHODS AND FINDINGS: We assessed the body of evidence regarding the infectious aetiology of chronic diseases in the peer-reviewed literature over the last decade. Causality was assessed with three different criteria: First, the total number of associations documented in the literature between each infectious agent and chronic condition; second, the epidemiologic study design (quality of the study); third, evidence for the number of Hill's criteria and Koch's postulates that linked the pathogen with the chronic condition. We identified 3136 publications, of which 148 were included in the analysis. There were a total of 75 different infectious agents and 122 chronic conditions. The evidence was strong for five pathogens, based on study type, strength and number of associations; they accounted for 60% of the associations documented in the literature. They were human immunodeficiency virus, hepatitis C virus, Helicobacter pylori, hepatitis B virus, and Chlamydia pneumoniae and were collectively implicated in the aetiology of 37 different chronic conditions. Other pathogens examined were only associated with very few chronic conditions (<= 3) and when applying the three different criteria of evidence the strength of the causality was weak. CONCLUSIONS: Prevention and treatment of these five pathogens lend themselves as effective public health intervention entry points. By concentrating research efforts on these promising areas, the human, economic, and societal burden arising from chronic conditions can be reduced. PMID- 23935901 TI - Using complete genome comparisons to identify sequences whose presence accurately predicts clinically important phenotypes. AB - In clinical settings it is often important to know not just the identity of a microorganism, but also the danger posed by that particular strain. For instance, Escherichia coli can range from being a harmless commensal to being a very dangerous enterohemorrhagic (EHEC) strain. Determining pathogenic phenotypes can be both time consuming and expensive. Here we propose a simple, rapid, and inexpensive method of predicting pathogenic phenotypes on the basis of the presence or absence of short homologous DNA segments in an isolate. Our method compares completely sequenced genomes without the necessity of genome alignments in order to identify the presence or absence of the segments to produce an automatic alignment of the binary string that describes each genome. Analysis of the segment alignment allows identification of those segments whose presence strongly predicts a phenotype. Clinical application of the method requires nothing more that PCR amplification of each of the set of predictive segments. Here we apply the method to identifying EHEC strains of E. coli and to distinguishing E. coli from Shigella. We show in silico that with as few as 8 predictive sequences, if even three of those predictive sequences are amplified the probability of being EHEC or Shigella is >0.99. The method is thus very robust to the occasional amplification failure for spurious reasons. Experimentally, we apply the method to screening a set of 98 isolates to distinguishing E. coli from Shigella, and EHEC from non-EHEC E. coli strains and show that all isolates are correctly identified. PMID- 23935902 TI - Cemented versus uncemented hemiarthroplasty for femoral neck fractures in elderly patients: a meta-analysis. AB - OBJECTIVE: Controversy still exists regarding using cemented or uncemented hemiarthroplasty for femoral neck fractures in elderly patients. The aim of this study is to compare the effectiveness and safety of the two surgical techniques in femoral neck fracture patients over 70 years old. METHODS: We searched PUBMED, EMBASE, Cochrane Library, CNKI and VIP Database from inception to December 2012 for relevant randomized controlled trials (RCTs). Outcomes of interest include postoperative hip function, residue pain, complication rates, mortality, reoperation rate, operation time and intraoperative blood loss. Odds ratios (OR) and weighted mean differences (WMD) from each trial were pooled using random effects model or fixed-effects model given on the heterogeneity of the included studies. RESULTS: 7 RCTs involving 1,125 patients (1,125 hips) were eligible for meta-analysis. Our results demonstrate that cemented hemiarthroplasty is associated with better postoperative hip function (OR = 0.48, 95% CI, 0.31-0.76; P = 0.002), lower residual pain (OR = 0.43, 95%CI, 0.29-0.64; P<0.0001), less implant-related complications (OR = 0.15, 95%CI, 0.09-0.26; P<0.00001) and longer operation time (WMD = 7.43 min, 95% CI, 5.37-9.49 min; P<0.00001). No significant difference was observed between the two groups in mortality, cardiovascular and cerebrovascular complications, local complications, general complications, reoperation rate and intraoperative blood loss. CONCLUSIONS: Compared with uncemented hemiarthroplasty, the existing evidence indicates that cemented hemiarthroplasty can achieve better hip function, lower residual pain and less implant-related complications with no increased risk of mortality, cardiovascular and cerebrovascular complications, general complications, local complications and reoperation rate in treating elderly patients with femoral neck fractures. PMID- 23935903 TI - Assumptions and properties of limiting pathway models for analysis of epistasis in complex traits. AB - For most complex traits, results from genome-wide association studies show that the proportion of the phenotypic variance attributable to the additive effects of individual SNPs, that is, the heritability explained by the SNPs, is substantially less than the estimate of heritability obtained by standard methods using correlations between relatives. This difference has been called the "missing heritability". One explanation is that heritability estimates from family (including twin) studies are biased upwards. Zuk et al. revisited overestimation of narrow sense heritability from twin studies as a result of confounding with non-additive genetic variance. They propose a limiting pathway (LP) model that generates significant epistatic variation and its simple parametrization provides a convenient way to explore implications of epistasis. They conclude that over-estimation of narrow sense heritability from family data ('phantom heritability') may explain an important proportion of missing heritability. We show that for highly heritable quantitative traits large phantom heritability estimates from twin studies are possible only if a large contribution of common environment is assumed. The LP model is underpinned by strong assumptions that are unlikely to hold, including that all contributing pathways have the same mean and variance and are uncorrelated. Here, we relax the assumptions that underlie the LP model to be more biologically plausible. Together with theoretical, empirical, and pragmatic arguments we conclude that in outbred populations the contribution of additive genetic variance is likely to be much more important than the contribution of non-additive variance. PMID- 23935904 TI - Quantifying biomass changes of single CD8+ T cells during antigen specific cytotoxicity. AB - Existing approaches that quantify cytotoxic T cell responses rely on bulk or surrogate measurements which impede the direct identification of single activated T cells of interest. Single cell microscopy or flow cytometry methodologies typically rely on fluorescent labeling, which limits applicability to primary cells such as human derived T lymphocytes. Here, we introduce a quantitative method to track single T lymphocyte mediated cytotoxic events within a mixed population of cells using live cell interferometry (LCI), a label-free microscopy technique that maintains cell viability. LCI quantifies the mass distribution within individual cells by measuring the phase shift caused by the interaction of light with intracellular biomass. Using LCI, we imaged cytotoxic T cells killing cognate target cells. In addition to a characteristic target cell mass decrease of 20-60% over 1-4 h following attack by a T cell, there was a significant 4-fold increase in T cell mass accumulation rate at the start of the cytotoxic event and a 2-3 fold increase in T cell mass relative to the mass of unresponsive T cells. Direct, label-free measurement of CD8+ T and target cell mass changes provides a kinetic, quantitative assessment of T cell activation and a relatively rapid approach to identify specific, activated patient-derived T cells for applications in cancer immunotherapy. PMID- 23935905 TI - In vitro characterization of the anti-bacterial activity of SQ109 against Helicobacter pylori. AB - The most evident challenge to treatment of Helicobacter pylori, a bacterium responsible for gastritis, peptic ulcers and gastric cancer, is the increasing rate of resistance to all currently used therapeutic antibiotics. Thus, the development of novel therapies is urgently required. N-geranyl-N'-(2-adamantyl) ethane-1, 2-diamine (SQ109) is an ethylene diamine-based antitubercular drug that is currently in clinical trials for the treatment of tuberculosis (TB). Previous pharmacokinetic studies of SQ109 revealed that persistently high concentrations of SQ109 remain in the stomach 4 hours post oral administration in rats. This finding, combined with the need for new anti-Helicobacter therapies, prompted us to define the in vitro efficacy of SQ109 against H. pylori. Liquid broth micro dilution was used for susceptibility studies to determine the antimicrobial activity of SQ109 against a total of 6 laboratory strains and 20 clinical isolates of H. pylori; the clinical isolates included a multi-drug resistant strain. All strains tested were susceptible to SQ109 with MIC and MBC ranges of 6 10 uM and 50-60 uM, respectively. SQ109 killing kinetics were concentration- and time-dependent. SQ109 killed H. pylori in 8-10 h at 140 uM (2MBCs) or 4-6 h at 200 uM (~3MBCs). Importantly, though the kinetics of killing were altered, SQ109 retained potent bactericidal activity against H. pylori at low pH. Additionally, SQ109 demonstrated robust thermal stability and was effective at killing slow growing or static bacteria. In fact, pretreatment of cultures with a bacteriostatic concentration of chloramphenicol (Cm) synergized the effects of typically bacteriostatic concentrations of SQ109 to the level of five-logs of bacterial killing. A molar-to-molar comparison of the efficacy of SQ109 as compared to metronidazole (MTZ), amoxicillin (AMX), rifampicin (RIF) and clarithromycin (CLR), revealed that SQ109 was superior to MTZ, AMX and RIF but not to CLR. Finally, the frequency of resistance to SQ109 was low and electron microscopy studies revealed that SQ109 interacted with bacterial inner membrane and cytoplasmic content(s). Collectively, our in vitro data demonstrate that SQ109 is an effective monotherapy against susceptible and multi-drug resistant strains of H. pylori and may be useful alone or in combination with other antibiotics for development as a new class of anti-Helicobacter drugs. PMID- 23935907 TI - Chiral hydroxylation at the mononuclear nonheme Fe(II) center of 4-(S) hydroxymandelate synthase--a structure-activity relationship analysis. AB - (S)-Hydroxymandelate synthase (Hms) is a nonheme Fe(II) dependent dioxygenase that catalyzes the oxidation of 4-hydroxyphenylpyruvate to (S)-4-hydroxymandelate by molecular oxygen. In this work, the substrate promiscuity of Hms is characterized in order to assess its potential for the biosynthesis of chiral alpha-hydroxy acids. Enzyme kinetic analyses, the characterization of product spectra, quantitative structure activity relationship (QSAR) analyses and in silico docking studies are used to characterize the impact of substrate properties on particular steps of catalysis. Hms is found to accept a range of alpha-oxo acids, whereby the presence of an aromatic substituent is crucial for efficient substrate turnover. A hydrophobic substrate binding pocket is identified as the likely determinant of substrate specificity. Upon introduction of a steric barrier, which is suspected to obstruct the accommodation of the aromatic ring in the hydrophobic pocket during the final hydroxylation step, the racemization of product is obtained. A steady state kinetic analysis reveals that the turnover number of Hms strongly correlates with substrate hydrophobicity. The analysis of product spectra demonstrates high regioselectivity of oxygenation and a strong coupling efficiency of C-C bond cleavage and subsequent hydroxylation for the tested substrates. Based on these findings the structural basis of enantioselectivity and enzymatic activity is discussed. PMID- 23935906 TI - Pro-inflammatory flagellin proteins of prevalent motile commensal bacteria are variably abundant in the intestinal microbiome of elderly humans. AB - Some Eubacterium and Roseburia species are among the most prevalent motile bacteria present in the intestinal microbiota of healthy adults. These flagellate species contribute "cell motility" category genes to the intestinal microbiome and flagellin proteins to the intestinal proteome. We reviewed and revised the annotation of motility genes in the genomes of six Eubacterium and Roseburia species that occur in the human intestinal microbiota and examined their respective locus organization by comparative genomics. Motility gene order was generally conserved across these loci. Five of these species harbored multiple genes for predicted flagellins. Flagellin proteins were isolated from R. inulinivorans strain A2-194 and from E. rectale strains A1-86 and M104/1. The amino-termini sequences of the R. inulinivorans and E. rectale A1-86 proteins were almost identical. These protein preparations stimulated secretion of interleukin-8 (IL-8) from human intestinal epithelial cell lines, suggesting that these flagellins were pro-inflammatory. Flagellins from the other four species were predicted to be pro-inflammatory on the basis of alignment to the consensus sequence of pro-inflammatory flagellins from the beta- and gamma- proteobacteria. Many fliC genes were deduced to be under the control of sigma(28). The relative abundance of the target Eubacterium and Roseburia species varied across shotgun metagenomes from 27 elderly individuals. Genes involved in the flagellum biogenesis pathways of these species were variably abundant in these metagenomes, suggesting that the current depth of coverage used for metagenomic sequencing (3.13-4.79 Gb total sequence in our study) insufficiently captures the functional diversity of genomes present at low (<=1%) relative abundance. E. rectale and R. inulinivorans thus appear to synthesize complex flagella composed of flagellin proteins that stimulate IL-8 production. A greater depth of sequencing, improved evenness of sequencing and improved metagenome assembly from short reads will be required to facilitate in silico analyses of complete complex biochemical pathways for low-abundance target species from shotgun metagenomes. PMID- 23935908 TI - A 3-dimensional trimeric beta-barrel model for Chlamydia MOMP contains conserved and novel elements of Gram-negative bacterial porins. AB - Chlamydia trachomatis is the most prevalent cause of bacterial sexually transmitted diseases and the leading cause of preventable blindness worldwide. Global control of Chlamydia will best be achieved with a vaccine, a primary target for which is the major outer membrane protein, MOMP, which comprises ~60% of the outer membrane protein mass of this bacterium. In the absence of experimental structural information on MOMP, three previously published topology models presumed a16-stranded barrel architecture. Here, we use the latest beta barrel prediction algorithms, previous 2D topology modeling results, and comparative modeling methodology to build a 3D model based on the 16-stranded, trimeric assumption. We find that while a 3D MOMP model captures many structural hallmarks of a trimeric 16-stranded beta-barrel porin, and is consistent with most of the experimental evidence for MOMP, MOMP residues 320-334 cannot be modeled as beta-strands that span the entire membrane, as is consistently observed in published 16-stranded beta-barrel crystal structures. Given the ambiguous results for beta-strand delineation found in this study, recent publications of membrane beta-barrel structures breaking with the canonical rule for an even number of beta-strands, findings of beta-barrels with strand exchanged oligomeric conformations, and alternate folds dependent upon the lifecycle of the bacterium, we suggest that although the MOMP porin structure incorporates canonical 16-stranded conformations, it may have novel oligomeric or dynamic structural changes accounting for the discrepancies observed. PMID- 23935909 TI - Activation of Wnt/beta-catenin pathway in monocytes derived from chronic kidney disease patients. AB - Patients with chronic kidney disease (CKD) have significantly increased morbidity and mortality resulting from infections and cardiovascular diseases. Since monocytes play an essential role in host immunity, this study was directed to explore the gene expression profile in order to identify differences in activated pathways in monocytes relevant to the pathophysiology of atherosclerosis and increased susceptibility to infections. Monocytes from CKD patients (stages 4 and 5, estimated GFR <20 ml/min/1.73 m(2)) and healthy donors were collected from peripheral blood. Microarray gene expression profile was performed and data were interpreted by GeneSpring software and by PANTHER tool. Western blot was done to validate the pathway members. The results demonstrated that 600 and 272 genes were differentially up- and down regulated respectively in the patient group. Pathways involved in the inflammatory response were highly expressed and the Wnt/beta-catenin signaling pathway was the most significant pathway expressed in the patient group. Since this pathway has been attributed to a variety of inflammatory manifestations, the current findings may contribute to dysfunctional monocytes in CKD patients. Strategies to interfere with this pathway may improve host immunity and prevent cardiovascular complications in CKD patients. PMID- 23935910 TI - Targeting imperfect vaccines against drug-resistance determinants: a strategy for countering the rise of drug resistance. AB - The growing prevalence of antimicrobial resistance in major pathogens is outpacing discovery of new antimicrobial classes. Vaccines mitigate the effect of antimicrobial resistance by reducing the need for treatment, but vaccines for many drug-resistant pathogens remain undiscovered or have limited efficacy, in part because some vaccines selectively favor pathogen strains that escape vaccine induced immunity. A strain with even a modest advantage in vaccinated hosts can have high fitness in a population with high vaccine coverage, which can offset a strong selection pressure such as antimicrobial use that occurs in a small fraction of hosts. We propose a strategy to target vaccines against drug resistant pathogens, by using resistance-conferring proteins as antigens in multicomponent vaccines. Resistance determinants may be weakly immunogenic, offering only modest specific protection against resistant strains. Therefore, we assess here how varying the specific efficacy of the vaccine against resistant strains would affect the proportion of drug-resistant vs. -sensitive strains population-wide for three pathogens--Streptococcus pneumoniae, Staphylococcus aureus, and influenza virus--in which drug resistance is a problem. Notably, if such vaccines confer even slightly higher protection (additional efficacy between 1% and 8%) against resistant variants than sensitive ones, they may be an effective tool in controlling the rise of resistant strains, given current levels of use for many antimicrobial agents. We show that the population-wide impact of such vaccines depends on the additional effect on resistant strains and on the overall effect (against all strains). Resistance-conferring accessory gene products or resistant alleles of essential genes could be valuable as components of vaccines even if their specific protective effect is weak. PMID- 23935911 TI - Whole cell screen for inhibitors of pH homeostasis in Mycobacterium tuberculosis. AB - Bacterial pathogens like Mycobacterium tuberculosis (Mtb) encounter acidic microenvironments in the host and must maintain their acid-base homeostasis to survive. A genetic screen identified two Mtb strains that cannot control intrabacterial pH (pHIB) in an acidic environment; infection with either strain led to severe attenuation in mice. To search for additional proteins that Mtb requires to survive at low pH, we introduced a whole-cell screen for compounds that disrupt pHIB, along with counter-screens that identify ionophores and membrane perturbors. Application of these methods to a natural product library identified four compounds of interest, one of which may inhibit novel pathway(s). This approach yields compounds that may lead to the identification of pathways that allow Mtb to survive in acidic environments, a setting in which Mtb is resistant to most of the drugs currently used to treat tuberculosis. PMID- 23935913 TI - Efficient sampling in fragment-based protein structure prediction using an estimation of distribution algorithm. AB - Fragment assembly is a powerful method of protein structure prediction that builds protein models from a pool of candidate fragments taken from known structures. Stochastic sampling is subsequently used to refine the models. The structures are first represented as coarse-grained models and then as all-atom models for computational efficiency. Many models have to be generated independently due to the stochastic nature of the sampling methods used to search for the global minimum in a complex energy landscape. In this paper we present EdaFold(AA), a fragment-based approach which shares information between the generated models and steers the search towards native-like regions. A distribution over fragments is estimated from a pool of low energy all-atom models. This iteratively-refined distribution is used to guide the selection of fragments during the building of models for subsequent rounds of structure prediction. The use of an estimation of distribution algorithm enabled EdaFold(AA) to reach lower energy levels and to generate a higher percentage of near-native models. [Formula: see text] uses an all-atom energy function and produces models with atomic resolution. We observed an improvement in energy driven blind selection of models on a benchmark of EdaFold(AA) in comparison with the [Formula: see text] AbInitioRelax protocol. PMID- 23935912 TI - Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience. AB - PURPOSE: Rapid advances in the understanding of cancer biology have transformed drug development thus leading to the approval of targeted therapies and to the development of molecular tests to select patients that will respond to treatments. KRAS status has emerged as a negative predictor of clinical benefit from anti-EGFR antibodies in colorectal cancer, and anti-EGFR antibodies use was limited to KRAS wild type tumors. In order to ensure wide access to tumor molecular profiling, the French National Cancer Institute (INCa) has set up a national network of 28 regional molecular genetics centers. Concurrently, a nationwide external quality assessment for KRAS testing (MOKAECM) was granted to analyze reproducibility and costs. METHODS: 96 cell-line DNAs and 24 DNA samples from paraffin embedded tumor tissues were sent to 40 French laboratories. A total of 5448 KRAS results were collected and analyzed and a micro-costing study was performed on sites for 5 common methods by an independent team of health economists. RESULTS: This work provided a baseline picture of the accuracy and reliability of KRAS analysis in routine testing conditions at a nationwide level. Inter-laboratory Kappa values were >0.8 for KRAS results despite differences detection methods and the use of in-house technologies. Specificity was excellent with only one false positive in 1128 FFPE data, and sensitivity was higher for targeted techniques as compared to Sanger sequencing based methods that were dependent upon local expertise. Estimated reagent costs per patient ranged from ?5.5 to ?19.0. CONCLUSION: The INCa has set-up a network of public laboratories dedicated to molecular oncology tests. Our results showed almost perfect agreements in KRAS testing at a nationwide level despite different testing methods ensuring a cost-effective equal access to personalized colorectal cancer treatment. PMID- 23935914 TI - The relative expression of Mig6 and EGFR is associated with resistance to EGFR kinase inhibitors. AB - The sensitivity of only a few tumors to anti-epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) can be explained by the presence of EGFR tyrosine kinase (TK) domain mutations. In addition, such mutations were rarely found in tumor types other than lung, such as pancreatic and head and neck cancer. In this study we sought to elucidate mechanisms of resistance to EGFR targeted therapies in tumors that do not harbor TK sensitizing mutations in order to identify markers capable of guiding the decision to incorporate these drugs into chemotherapeutic regimens. Here we show that EGFR activity was markedly decreased during the evolution of resistance to the EGFR tyrosine kinase inhibitor (TKI) erlotinib, with a concomitant increase of mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR through the upregulation of the PI3K-AKT pathway. EGFR activity, which was more accurately predicted by the ratio of Mig6/EGFR, highly correlated with erlotinib sensitivity in panels of cancer cell lines of different tissue origins. Blinded testing and analysis in a prospectively followed cohort of lung cancer patients treated with gefitinib alone demonstrated higher response rates and a marked increased in progression free survival for patients with a low Mig6/EGFR ratio (approximately 100 days, P = 0.01). PMID- 23935915 TI - Ineffectiveness of reverse wording of questionnaire items: let's learn from cows in the rain. AB - OBJECTIVE: We examined the effectiveness of reverse worded items as a means of reducing or preventing response bias. We first distinguished between several types of response bias that are often confused in literature. We next developed arguments why reversing items is probably never a good way to address response bias. We proposed testing whether reverse wording affects response bias with item level data from the Multidimensional Fatigue Inventory (MFI-20), an instrument that contains reversed worded items. METHODS: With data from 700 respondents, we compared scores on items that were similar with respect either to content or to direction of wording. Psychometric properties of sets of these items worded in the same direction were compared with sets consisting of both straightforward and reversed worded items. RESULTS: We did not find evidence that ten reverse-worded items prevented response bias. Instead, the data suggest scores were contaminated by respondent inattention and confusion. CONCLUSIONS: Using twenty items, balanced for scoring direction, to assess fatigue did not prevent respondents from inattentive or acquiescent answering. Rather, fewer mistakes are made with a 10-item instrument with items posed in the same direction. Such a format is preferable for both epidemiological and clinical studies. PMID- 23935916 TI - An exact relationship between invasion probability and endemic prevalence for Markovian SIS dynamics on networks. AB - Understanding models which represent the invasion of network-based systems by infectious agents can give important insights into many real-world situations, including the prevention and control of infectious diseases and computer viruses. Here we consider Markovian susceptible-infectious-susceptible (SIS) dynamics on finite strongly connected networks, applicable to several sexually transmitted diseases and computer viruses. In this context, a theoretical definition of endemic prevalence is easily obtained via the quasi-stationary distribution (QSD). By representing the model as a percolation process and utilising the property of duality, we also provide a theoretical definition of invasion probability. We then show that, for undirected networks, the probability of invasion from any given individual is equal to the (probabilistic) endemic prevalence, following successful invasion, at the individual (we also provide a relationship for the directed case). The total (fractional) endemic prevalence in the population is thus equal to the average invasion probability (across all individuals). Consequently, for such systems, the regions or individuals already supporting a high level of infection are likely to be the source of a successful invasion by another infectious agent. This could be used to inform targeted interventions when there is a threat from an emerging infectious disease. PMID- 23935917 TI - Aberrant expression of Beclin-1 and LC3 correlates with poor prognosis of human hypopharyngeal squamous cell carcinoma. AB - BACKGROUND: Beclin-1, a key regulator of autophagy. Microtubule-associated protein 1 light chain 3 (LC3), is involved in autophagsome formation during autophagy. The autophagic genes beclin-1 and LC3 paly an important role in the development and progression of tumor. This study was designed to investigate the expression of beclin-1 and LC3 and to clarify their clinical significance in hypopharyngeal squamous cell carcinoma (HSCC). METHODS: Eighty-two surgical hypopharyngeal squamous cell carcinoma specimens and fifty-four adjacent non cancerous mucosal epithelial tissues were obtained. Beclin-1 and LC3-II expression was examined by immunohistochemistry, real-time RT-PCR and Western blotting assays. Correlations with patient clinical characteristics and overall survival were evaluated. RESULTS: Beclin-1 was positively expressed in 42.7% (35/82) of HSCC specimens (adjacent non-cancerous tissues, 79.6%, 43/54; P<0.0001). Furthermore, 41.5% (34/82) of HSCC specimens exhibited high LC3 immunoreactivity (adjacent non-cancerous tissues, 74.1%, 40/54; P=0.0002). Beclin 1 and LC3-II mRNA transcript levels were significantly lower in HSCCs than in paired non-cancerous tissues (P<0.0001, P=0.0001, respectively). Similarly, western blotting assays showed that beclin-1 and LC3-II were markedly decreased in HSCCs (P=0.02, P=0.004, respectively). A positive correlation was observed between the mRNA transcript levels of beclin-1 and LC3-II in HSCCs (r=0.51, P<0.0001; 95%CI: 0.273 to 0.689). Beclin-1 and LC3 expression were significantly correlated with T categories, differentiation and lymph node metastasis. Negative beclin-1 immunoreactivity and low LC3 expression were associated with poorer overall survival in HSCC patients (P<0.0001, P=0.0145, respectively). Multivariate analysis revealed that beclin-1 was an independent prognositic factor for overall survival. CONCLUSION: Beclin-1 and LC3-II are downregulated in HSCCs and their aberrant expression correlates with poor prognosis of HSCCs. PMID- 23935918 TI - Grasping the changes seen in older adults when reaching for objects of varied texture. AB - Old age is associated with reduced mobility of the hand. To investigate age related decline when reaching-to-lift an object we used sophisticated kinematic apparatus to record reaches carried out by healthy older and younger participants. Three objects of different widths were placed at three different distances, with objects having either a high or low friction surface (i.e. rough or slippery). Older participants showed quantitative differences to their younger counterparts - movements were slower and peak speed did not scale with object distance. There were also qualitative differences with older adults showing a greater propensity to stop the hand and adjust finger position before lifting objects. The older participants particularly struggled to lift wide slippery objects, apparently due to an inability to manipulate their grasp to provide the level of precision necessary to functionally enclose the object. These data shed light on the nature of age related changes in reaching-to-grasp movements and establish a powerful technique for exploring how different product designs will impact on prehensile behavior. PMID- 23935919 TI - Effects of MICA expression on the prognosis of advanced non-small cell lung cancer and the efficacy of CIK therapy. AB - OBJECTIVE: To investigate the clinical significance of the expression of MHC class I chain-related gene A (MICA) in patients with advanced non-small cell lung cancer and explore the relationship between MICA expression and the efficacy of cytokine-induced killer cell (CIK) therapy for treating advanced non-small cell lung cancer. METHODS: We obtained data on 222 patients with advanced non-small cell lung cancer, including data on MICA expression, age, gender, ECOG score, pathological type, stage, treatment history (including 38 patients who were given autologous CIK cell infusion), and overall survival (OS). MICA expression in lung cancer tissue was evaluated by immunohistochemical staining. Analyses of MICA expression, and CIK therapy association with survival outcomes were performed using Cox proportional models, Kaplan-Meier methods, and the log-rank test. RESULT: s MICA was expressed in both membrane and cytoplasm. MICA expression correlated with the stage of lung cancer, ECOG score, gender and age. Multivariate COX regression analysis showed that the expression of MICA was an independent prognostic factor of advanced non-small cell lung cancer (p = 0.002). In subgroup analysis, we divided the 222 patients into CIK and control groups. In the CIK group, the medium OS (mOS) of patients with a high expression of MICA was longer than in those with low expression of MICA (27 months vs. 13 months). In the control group, the mOS in patients with a high expression of MICA was shorter than in patients with low MICA expression (9 months vs. 18 months). COX regression analysis showed that the MICA expression affects the effect of CIK therapy (p<0.0001). CONCLUSION: 1) The high expression of MICA is one of the indicators of a poor prognosis for advanced non-small cell lung cancer patients. 2) The high expression of MICA might be one of the predictive factors for successful CIK therapy. PMID- 23935920 TI - An acetylcholinesterase antibody-based quartz crystal microbalance for the rapid identification of spinal ventral and dorsal roots. AB - Differences in the levels of acetylcholinesterase (AChE) in ventral and dorsal spinal roots can be used to differentiate the spinal nerves. Although many methods are available to assay AChE, a rapid and sensitive method has not been previously developed. Here, we describe an antibody-based quartz crystal microbalance (QCM) assay and its application for the quantification of AChE in the solutions of ventral and dorsal spinal roots. The frequency variation of the QCM device corresponds to the level of AChE over a wide dynamic range (0.5-10 ug/ml), which is comparable to the response range of the ELISA method. The frequency shift caused by the ventral roots is 3-fold greater than that caused by the dorsal roots. The antibody-based QCM sensor was stable across many successive replicate samples, and the method required less than 10 min, including the AChE extraction and analysis steps. This method is a rapid and convenient means for the quantification of AChE in biological samples and may be applicable for distinguishing the ventral and dorsal roots during surgical operations. PMID- 23935921 TI - Activation of AMPK inhibits cholera toxin stimulated chloride secretion in human and murine intestine. AB - Increased intestinal chloride secretion through chloride channels, such as the cystic fibrosis transmembrane conductance regulator (CFTR), is one of the major molecular mechanisms underlying enterotoxigenic diarrhea. It has been demonstrated in the past that the intracellular energy sensing kinase, the AMP activated protein kinase (AMPK), can inhibit CFTR opening. We hypothesized that pharmacological activation of AMPK can abrogate the increased chloride flux through CFTR occurring during cholera toxin (CTX) mediated diarrhea. Chloride efflux was measured in isolated rat colonic crypts using real-time fluorescence imaging. AICAR and metformin were used to activate AMPK in the presence of the secretagogues CTX or forskolin (FSK). In order to substantiate our findings on the whole tissue level, short-circuit current (SCC) was monitored in human and murine colonic mucosa using Ussing chambers. Furthermore, fluid accumulation was measured in excised intestinal loops. CTX and forskolin (FSK) significantly increased chloride efflux in isolated colonic crypts. The increase in chloride efflux could be offset by using the AMPK activators AICAR and metformin. In human and mouse mucosal sheets, CTX and FSK increased SCC. AICAR and metformin inhibited the secretagogue induced rise in SCC, thereby confirming the findings made in isolated crypts. Moreover, AICAR decreased CTX stimulated fluid accumulation in excised intestinal segments. The present study suggests that pharmacological activation of AMPK effectively reduces CTX mediated increases in intestinal chloride secretion, which is a key factor for intestinal water accumulation. AMPK activators may therefore represent a supplemental treatment strategy for acute diarrheal illness. PMID- 23935922 TI - Leprosy association with low MASP-2 levels generated by MASP2 haplotypes and polymorphisms flanking MAp19 exon 5. AB - BACKGROUND: The gene MASP2 (mannan-binding lectin (MBL)-associated serine protease 2) encodes two proteins, MASP-2 and MAp19 (MBL-associated protein of 19 kDa), bound in plasma to MBL and ficolins. The binding of MBL/MASP-2 and ficolin/MASP-2 complexes to microorganisms activates the lectin pathway of complement and may increase the ingestion of intracellular pathogens such as Mycobacterium leprae. METHODS: We haplotyped 11 MASP2 polymorphisms with multiplex sequence-specific PCR in 219 Brazilian leprosy patients (131 lepromatous, 29 borderline, 21 tuberculoid, 14 undetermined, 24 unspecified), 405 healthy Brazilians and 291 Danish blood donors with previously determined MASP-2 and MAp19 levels. We also evaluated MASP-2 levels in further 46 leprosy patients and 69 Brazilian controls. RESULTS: Two polymorphisms flanking exon 5 of MASP2 were associated with a dominant effect on high MASP-2 levels and an additive effect on low MAp19 levels. Patients presented lower MASP-2 levels (P = 0.0012) than controls. The frequency of the p.126L variant, associated with low MASP-2 levels (below 200 ng/mL), was higher in the patients (P = 0.0002, OR = 4.92), as was the frequency of genotypes with p.126L (P = 0.00006, OR = 5.96). The *1C2-l [AG] haplotype, which harbors p.126L and the deficiency-causing p.439H variant, has a dominant effect on the susceptibility to the disease (P = 0.007, OR = 4.15). Genotypes composed of the *2B1-i and/or *2B2A-i haplotypes, both associated with intermediate MASP-2 levels (200-600 ng/mL), were found to be protective against the disease (P = 0.0014, OR = 0.6). Low MASP-2 levels (P = 0.022), as well as corresponding genotypes with *1C2-l and/or *2A2-l but without *1B1-h or *1B2-h, were more frequent in the lepromatous than in other patients (P = 0.008, OR = 8.8). CONCLUSIONS: In contrast with MBL, low MASP-2 levels increase the susceptibility to leprosy in general and to lepromatous leprosy in particular. MASP2 genotypes and MASP-2 levels might thus be of prognostic value for leprosy progression. PMID- 23935923 TI - Molecular threading: mechanical extraction, stretching and placement of DNA molecules from a liquid-air interface. AB - We present "molecular threading", a surface independent tip-based method for stretching and depositing single and double-stranded DNA molecules. DNA is stretched into air at a liquid-air interface, and can be subsequently deposited onto a dry substrate isolated from solution. The design of an apparatus used for molecular threading is presented, and fluorescence and electron microscopies are used to characterize the angular distribution, straightness, and reproducibility of stretched DNA deposited in arrays onto elastomeric surfaces and thin membranes. Molecular threading demonstrates high straightness and uniformity over length scales from nanometers to micrometers, and represents an alternative to existing DNA deposition and linearization methods. These results point towards scalable and high-throughput precision manipulation of single-molecule polymers. PMID- 23935924 TI - Cortical presynaptic control of dorsal horn C-afferents in the rat. AB - Lamina 5 sensorimotor cortex pyramidal neurons project to the spinal cord, participating in the modulation of several modalities of information transmission. A well-studied mechanism by which the corticospinal projection modulates sensory information is primary afferent depolarization, which has been characterized in fast muscular and cutaneous, but not in slow-conducting nociceptive skin afferents. Here we investigated whether the inhibition of nociceptive sensory information, produced by activation of the sensorimotor cortex, involves a direct presynaptic modulation of C primary afferents. In anaesthetized male Wistar rats, we analyzed the effects of sensorimotor cortex activation on post tetanic potentiation (PTP) and the paired pulse ratio (PPR) of dorsal horn field potentials evoked by C-fiber stimulation in the sural (SU) and sciatic (SC) nerves. We also explored the time course of the excitability changes in nociceptive afferents produced by cortical stimulation. We observed that the development of PTP was completely blocked when C-fiber tetanic stimulation was paired with cortex stimulation. In addition, sensorimotor cortex activation by topical administration of bicuculline (BIC) produced a reduction in the amplitude of C-fiber responses, as well as an increase in the PPR. Furthermore, increases in the intraspinal excitability of slow-conducting fiber terminals, produced by sensorimotor cortex stimulation, were indicative of primary afferent depolarization. Topical administration of BIC in the spinal cord blocked the inhibition of C-fiber neuronal responses produced by cortical stimulation. Dorsal horn neurons responding to sensorimotor cortex stimulation also exhibited a peripheral receptive field and responded to stimulation of fast cutaneous myelinated fibers. Our results suggest that corticospinal inhibition of nociceptive responses is due in part to a modulation of the excitability of primary C-fibers by means of GABAergic inhibitory interneurons. PMID- 23935925 TI - NVP-LDE225, a potent and selective SMOOTHENED antagonist reduces melanoma growth in vitro and in vivo. AB - Melanoma is one of the most aggressive cancers and its incidence is increasing worldwide. So far there are no curable therapies especially after metastasis. Due to frequent mutations in members of the mitogen-activated protein kinase (MAPK) signaling pathway, this pathway is constitutively active in melanoma. It has been shown that the SONIC HEDGEHOG (SHH)-GLI and MAPK signaling pathway regulate cell growth in many tumors including melanoma and interact with each other in the regulation of cell proliferation and survival. Here we show that the SHH-GLI pathway is active in human melanoma cell lines as they express downstream target of this pathway GLI1. Expression of GLI1 was significantly higher in human primary melanoma tissues harboring BRAF(V600E) mutation than those with wild type BRAF. Pharmacologic inhibition of BRAF(V600E) in human melanoma cell lines resulted in decreased expression of GLI1 thus demonstrating interaction of SHH GLI and MAPK pathways. Inhibition of SHH-GLI pathway by the novel small molecule inhibitor of smoothened NVP-LDE225 was followed by inhibition of cell growth and induction of apoptosis in human melanoma cell lines, interestingly with both BRAF(V600E) and BRAF(Wild Type) status. NVP-LDE225 was potent in reducing cell proliferation and inducing tumor growth arrest in vitro and in vivo, respectively and these effects were superior to the natural compound cyclopamine. Finally, we conclude that inhibition of SHH-GLI signaling pathway in human melanoma by the specific smoothened inhibitor NVP-LDE225 could have potential therapeutic application in human melanoma even in the absence of BRAF(V600E) mutation and warrants further investigations. PMID- 23935926 TI - Effects of thyroxine exposure on osteogenesis in mouse calvarial pre-osteoblasts. AB - The incidence of craniosynostosis is one in every 1,800-2500 births. The gene environment model proposes that if a genetic predisposition is coupled with environmental exposures, the effects can be multiplicative resulting in severely abnormal phenotypes. At present, very little is known about the role of gene environment interactions in modulating craniosynostosis phenotypes, but prior evidence suggests a role for endocrine factors. Here we provide a report of the effects of thyroid hormone exposure on murine calvaria cells. Murine derived calvaria cells were exposed to critical doses of pharmaceutical thyroxine and analyzed after 3 and 7 days of treatment. Endpoint assays were designed to determine the effects of the hormone exposure on markers of osteogenesis and included, proliferation assay, quantitative ALP activity assay, targeted qPCR for mRNA expression of Runx2, Alp, Ocn, and Twist1, genechip array for 28,853 targets, and targeted osteogenic microarray with qPCR confirmations. Exposure to thyroxine stimulated the cells to express ALP in a dose dependent manner. There were no patterns of difference observed for proliferation. Targeted RNA expression data confirmed expression increases for Alp and Ocn at 7 days in culture. The genechip array suggests substantive expression differences for 46 gene targets and the targeted osteogenesis microarray indicated 23 targets with substantive differences. 11 gene targets were chosen for qPCR confirmation because of their known association with bone or craniosynostosis (Col2a1, Dmp1, Fgf1, 2, Igf1, Mmp9, Phex, Tnf, Htra1, Por, and Dcn). We confirmed substantive increases in mRNA for Phex, FGF1, 2, Tnf, Dmp1, Htra1, Por, Igf1 and Mmp9, and substantive decreases for Dcn. It appears thyroid hormone may exert its effects through increasing osteogenesis. Targets isolated suggest a possible interaction for those gene products associated with calvarial suture growth and homeostasis as well as craniosynostosis. PMID- 23935928 TI - NaOH-debittering induces changes in bacterial ecology during table olives fermentation. AB - Limited information is available on the impact of the NaOH treatment on table olive fermentations, and for this reason a polyphasic approach has been adopted here to investigate its effect on the fermentation dynamics and bacterial biodiversity. The microbial counts of the main groups involved in the transformation have not shown any differences, apart from a more prompt start of the fermentation when the olives were subjected to the NaOH treatment. The data produced by culture-independent analyses highlighted that the fermentation of table olives not treated with NaOH is the result of the coexistence of two different ecosystems: the surface of the olives and the brines. A sodium hydroxide treatment not only eliminates this difference, but also affects the bacterial ecology of the olives to a great extent. As proved by high-throughput sequencing, the fermentation of the olives not treated with NaOH was characterized by the presence of halophilic bacteria, which were substituted by Lactobacillus at the later stages of the fermentation, while enterobacteria were dominant when the olives were treated with sodium hydroxide. Higher biodiversity was found for Lactobacillus plantarum isolated during untreated fermentation. Different biotypes were found on the olive surface and in the brines. When the debittering process was carried out, a decrease in the number of L. plantarum biotypes were observed and those originating from the surface of the olive did not differentiate from the ones present in the brines. PMID- 23935927 TI - Elimination of metastatic melanoma using gold nanoshell-enabled photothermal therapy and adoptive T cell transfer. AB - Ablative treatments such as photothermal therapy (PTT) are attractive anticancer strategies because they debulk accessible tumor sites while simultaneously priming antitumor immune responses. However, the immune response following thermal ablation is often insufficient to treat metastatic disease. Here we demonstrate that PTT induces the expression of proinflammatory cytokines and chemokines and promotes the maturation of dendritic cells within tumor-draining lymph nodes, thereby priming antitumor T cell responses. Unexpectedly, however, these immunomodulatory effects were not beneficial to overall antitumor immunity. We found that PTT promoted the infiltration of secondary tumor sites by CD11b(+)Ly-6G/C(+) myeloid-derived suppressor cells, consequently failing to slow the growth of poorly immunogenic B16-F10 tumors and enhancing the growth of distant lung metastases. To exploit the beneficial effects of PTT activity against local tumors and on antitumor immunity whilst avoiding the adverse consequences, we adoptively transferred gp100-specific pmel T cells following PTT. The combination of local control by PTT and systemic antitumor immune reactivity provided by adoptively transferred T cells prevented primary tumor recurrence post-ablation, inhibited tumor growth at distant sites, and abrogated the outgrowth of lung metastases. Hence, the combination of PTT and systemic immunotherapy prevented the adverse effects of PTT on metastatic tumor growth and optimized overall tumor control. PMID- 23935929 TI - Downregulation of SPARC expression inhibits the invasion of human trophoblast cells in vitro. AB - Successful pregnancy depends on the precise regulation of extravilloustrophoblast (EVT) invasion into the uterine decidua. SPARC (secreted protein acidic and rich in cysteine) is a matricellular glycoprotein that plays critical roles in the pathologies associated with obesity and diabetes, as well as tumorigenesis. The objective of this study was to investigate the role of SPARC in the process of trophoblast invasion which shares many similarities with tumor cell invasion. By Western blot, higher expression of SPARC was observed in mouse brain, ovary and uterus compared to other mouse tissues. Immunohistochemistry analysis revealed a spatio-temporal expression of SPARC in mouse uterus in the periimplantation period. At the implantation site of d8 pregnancy, SPARC mainly accumulated in the secondary decidua zone (SDZ), trophoblast cells and blastocyst. The expression of SPARC was also detected in human placental villi and trophoblast cell lines. In a Matrigel invasion assay, we found SPARC-specific RNA interference significantly reduced the invasion of human extravilloustrophoblast HTR8/SVneo cells. Microarray analysis revealed that SPARC depletion upregulated the expression of interleukin 11 (IL11), KISS1, insulin-like growth factor binding protein 4 (IGFBP4), collagen type I alpha 1 (COLIA1), matrix metallopeptidase 9 (MMP9), and downregulated the expression of the alpha polypeptide of chorionic gonadotropin (CGA), MMP1, gap junction protein alpha 1 (GJA1), et al. The gene array result was further validated by qRT-PCR and Western blot. The present data indicate that SPARC may play an important role in the regulation of normal placentation by promoting the invasion of trophoblast cells into the uterine decidua. PMID- 23935930 TI - Plasma 25-hydroxyvitamin D and its genetic determinants in relation to incident myocardial infarction and stroke in the European prospective investigation into cancer and nutrition (EPIC)-Germany study. AB - Circulating 25-hydroxyvitamin D (25(OH)D) has been associated with cardiovascular disease (CVD) risk in observational studies. Also, SNPs to explain variation in 25(OH)D have been identified by genome-wide association studies. Detection of direct associations between SNPs that significantly affect 25(OH)D and CVD risk would indicate a causal role of vitamin D, as reverse causation could be excluded and confounding could be better controlled. Thus, a combined analysis of candidate SNPs in relation to circulating 25(OH)D and CVD risk was carried out. A case-cohort study within the EPIC-Germany study was conducted comprising a randomly drawn subcohort of 2,132 subjects (57.9% women, mean age: 50.6 years) and incident cases of myocardial infarction (n=559) and stroke (n=471) that occurred during a mean follow-up duration of 7.6 years. 25(OH)D concentrations were measured by LC-MS/MS in baseline plasma samples. Additionally, eight candidate SNPs were assayed. Associations between 25(OH)D, SNPs and the risks of myocardial infarction and stroke were assessed by multivariable regression analyses. Mean 25(OH)D level was 47.2 nmol/L in the subcohort. Four SNPs were associated with 25(OH)D (p<0.05). In subjects with 25(OH)D levels <25 nmol/L, the risks of CVD as composite endpoint (Hazard Ratio: 1.53, 95% confidence interval: 1.12-2.09), myocardial infarction, and stroke were significantly increased compared to subjects with levels >= 50 nmol/L, while no significant linear associations were observed. A SNP score was not related to the risks of total CVD (Hazard Ratio: 1.0, 95% confidence interval: 0.71-1.42), myocardial infarction, or stroke. The same was true concerning single SNPs. Given the lack of association between SNPs and the risks of stroke and myocardial infarction, the present findings do not point to a major causal role of vitamin D in the development of these diseases. However, a detection of modest associations between genetic markers and CVD risk in larger consortia cannot be ruled out. PMID- 23935931 TI - Abnormal pre-attentive arousal in young children with autism spectrum disorder contributes to their atypical auditory behavior: an ERP study. AB - Auditory sensory modulation difficulties and problems with automatic re-orienting to sound are well documented in autism spectrum disorders (ASD). Abnormal preattentive arousal processes may contribute to these deficits. In this study, we investigated components of the cortical auditory evoked potential (CAEP) reflecting preattentive arousal in children with ASD and typically developing (TD) children aged 3-8 years. Pairs of clicks ('S1' and 'S2') separated by a 1 sec S1-S2 interstimulus interval (ISI) and much longer (8-10 sec) S1-S1 ISIs were presented monaurally to either the left or right ear. In TD children, the P50, P100 and N1c CAEP components were strongly influenced by temporal novelty of clicks and were much greater in response to the S1 than the S2 click. Irrespective of the stimulation side, the 'tangential' P100 component was rightward lateralized in TD children, whereas the 'radial' N1c component had higher amplitude contralaterally to the stimulated ear. Compared to the TD children, children with ASD demonstrated 1) reduced amplitude of the P100 component under the condition of temporal novelty (S1) and 2) an attenuated P100 repetition suppression effect. The abnormalities were lateralized and depended on the presentation side. They were evident in the case of the left but not the right ear stimulation. The P100 abnormalities in ASD correlated with the degree of developmental delay and with the severity of auditory sensory modulation difficulties observed in early life. The results suggest that some rightward lateralized brain networks that are crucially important for arousal and attention re-orienting are compromised in children with ASD and that this deficit contributes to sensory modulation difficulties and possibly even other behavioral deficits in ASD. PMID- 23935932 TI - Adiponectin inhibits neutrophil phagocytosis of Escherichia coli by inhibition of PKB and ERK 1/2 MAPK signalling and Mac-1 activation. AB - Full length adiponectin is a potent immune modulatory adipokine, impacting upon the actions of several immune cells. Neutrophil oxidative burst has been shown to decrease in response to adiponectin, and we speculated that it could have other effects on neutrophil function. Here we report that adiponectin reduces the phagocytic ability of human neutrophils, decreasing significantly the ingestion of opsonised E. coli by these cells in whole blood (p<0.05) and as isolated neutrophils (p<0.05). We then determined the mechanisms involved. We observed that the activation of Mac-1, the receptor engaged in complement-mediated phagocytosis, was decreased by adiponectin in response to E. coli stimulation. Moreover, treatment of neutrophils with adiponectin prior to incubation with E. coli significantly inhibited signalling through the PI3K/PKB and ERK 1/2 pathways, with a parallel reduction of F-actin content. Studies with pharmacological inhibitors showed that inhibition of PI3K/PKB, but not ERK 1/2 signalling was able to prevent the activation of Mac-1. In conclusion, we propose that adiponectin negatively affects neutrophil phagocytosis, reducing the uptake of E. coli and inhibiting Mac-1 activation, the latter by blockade of the PI3K/PKB signal pathway. PMID- 23935933 TI - Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation. AB - Compound A possesses glucocorticoid receptor (GR)-dependent anti-inflammatory properties. Just like classical GR ligands, Compound A can repress NF-kappaB mediated gene expression. However, the monomeric Compound A-activated GR is unable to trigger glucocorticoid response element-regulated gene expression. The heat shock response potently activates heat shock factor 1 (HSF1), upregulates Hsp70, a known GR chaperone, and also modulates various aspects of inflammation. We found that the selective GR modulator Compound A and heat shock trigger similar cellular effects in A549 lung epithelial cells. With regard to their anti inflammatory mechanism, heat shock and Compound A are both able to reduce TNF stimulated IkappaBalpha degradation and NF-kappaB p65 nuclear translocation. We established an interaction between Compound A-activated GR and Hsp70, but remarkably, although the presence of the Hsp70 chaperone as such appears pivotal for the Compound A-mediated inflammatory gene repression, subsequent novel Hsp70 protein synthesis is uncoupled from an observed CpdA-induced Hsp70 mRNA upregulation and hence obsolete in mediating CpdA's anti-inflammatory effect. The lack of a Compound A-induced increase in Hsp70 protein levels in A549 cells is not mediated by a rapid proteasomal degradation of Hsp70 or by a Compound A induced general block on translation. Similar to heat shock, Compound A can upregulate transcription of Hsp70 genes in various cell lines and BALB/c mice. Interestingly, whereas Compound A-dependent Hsp70 promoter activation is GR dependent but HSF1-independent, heat shock-induced Hsp70 expression alternatively occurs in a GR-independent and HSF1-dependent manner in A549 lung epithelial cells. PMID- 23935934 TI - Functional characterization of stromal osteopontin in melanoma progression and metastasis. AB - BACKGROUND: Recent studies demonstrated that not only tumor derived- but stroma derived factors play crucial role in cancer development. Osteopontin (OPN) is a secreted non-collagenous, sialic acid rich, chemokine-like phosphoglycoprotein that facilitates cell-matrix interactions and promotes tumor progression. Elevated level of OPN has been shown in melanoma patient and predicted as a prognostic marker. Recent reports have indicated that stroma-derived OPN are involved in regulating stem cell microenvironment and pre-neoplastic cell growth. However, the function of stroma derived OPN in regulation of side population (SP) enrichment leading to melanoma growth, angiogenesis and metastasis is not well studied and yet to be the focus of intense investigation. METHODOLOGY/PRINCIPAL FINDINGS: In this study, using melanoma model, in wild type and OPN knockout mice, we have demonstrated that absence of host OPN effectively curbs melanoma growth, angiogenesis and metastasis. Melanoma cells isolated from tumor of OPN wild type (OPN(+/+)) mice exhibited more tumorigenic feature as compared to the parental cell line or cells isolated from the tumors of OPN KO (OPN(-/-)) mice. Furthermore, host OPN induces VEGF, ABCG2 and ERK1/2 expression and activation in B16-WT cells. We report for the first time that stroma derived OPN regulates SP phenotype in murine melanoma cells. Moreover, loss in and gain of function studies demonstrated that stroma-derived OPN regulates SP phenotype specifically through ERK2 activation. CONCLUSIONS: This study establish at least in part, the molecular mechanism underlying the role of host OPN in melanoma growth and angiogenesis, and better understanding of host OPN-tumor interaction may assist the advancement of novel therapeutic strategy for the management of malignant melanoma. PMID- 23935935 TI - The LuWD40-1 gene encoding WD repeat protein regulates growth and pollen viability in flax (Linum Usitatissimum L.). AB - As a crop, flax holds significant commercial value for its omega-3 rich oilseeds and stem fibres. Canada is the largest producer of linseed but there exists scope for significant yield improvements. Implementation of mechanisms such as male sterility can permit the development of hybrids to assist in achieving this goal. Temperature sensitive male sterility has been reported in flax but the leakiness of this system in field conditions limits the production of quality hybrid seeds. Here, we characterized a 2,588 bp transcript differentially expressed in male sterile lines of flax. The twelve intron gene predicted to encode a 368 amino acid protein has five WD40 repeats which, in silico, form a propeller structure with putative nucleic acid and histone binding capabilities. The LuWD40-1 protein localized to the nucleus and its expression increased during the transition and continued through the vegetative stages (seed, etiolated seedling, stem) while the transcript levels declined during reproductive development (ovary, anthers) and embryonic morphogenesis of male fertile plants. Knockout lines for LuWD40-1 in flax failed to develop shoots while overexpression lines showed delayed growth phenotype and were male sterile. The non-viable flowers failed to open and the pollen grains from these flowers were empty. Three independent transgenic lines overexpressing the LuWD40-1 gene had ~80% non-viable pollen, reduced branching, delayed flowering and maturity compared to male fertile genotypes. The present study provides new insights into a male sterility mechanism present in flax. PMID- 23935936 TI - Systemic transplantation of human umbilical cord derived mesenchymal stem cells educated T regulatory cells improved the impaired cognition in AbetaPPswe/PS1dE9 transgenic mice. AB - Alzheimer's disease (AD) is one of most prevalent dementias, which is characterized by the deposition of extracellular amyloid-beta protein (Abeta) and the formation of neurofibrillary tangles within neurons. Although stereotaxic transplantation of mesenchymal stem cells (MSCs) into the hippocampus of AD animal model as immunomodulatory cells has been suggested as a potential therapeutic approach to prevent the progress of AD, it is invasive and difficult for clinical perform. Systemic and central nervous system inflammation play an important role in pathogenesis of AD. T regulatory cells (Tregs) play a crucial role in maintaining systemic immune homeostasis, indicating that transplantation of Tregs could prevent the progress of the inflammation. In this study, we aimed to evaluate whether systemic transplantation of purified autologous Tregs from spleens of AbetaPPswe/PS1dE9 double-transgenic mice after MSCs from human umbilical cords (UC-MSCs) education in vitro for 3 days could improve the neuropathology and cognition deficits in AbetaPPswe/PS1dE9 double-transgenic mice. We observed that systemic transplantation of autologous Tregs significantly ameliorate the impaired cognition and reduced the Abeta plaque deposition and the levels of soluble Abeta, accompanied with significantly decreased levels of activated microglia and systemic inflammatory factors. In conclusion, systemic transplantation of autologous Tregs may be an effective and safe intervention to prevent the progress of AD. PMID- 23935937 TI - Structural and logical analysis of a comprehensive hedgehog signaling pathway to identify alternative drug targets for glioma, colon and pancreatic cancer. AB - Hedgehog is an evolutionarily conserved developmental pathway, widely implicated in controlling various cellular responses such as cellular proliferation and stem cell renewal in human and other organisms, through external stimuli. Aberrant activation of this pathway in human adult stem cell line may cause different types of cancers. Hence, targeting this pathway in cancer therapy has become indispensable, but the non availability of detailed molecular interactions, complex regulations by extra- and intra-cellular proteins and cross talks with other pathways pose a serious challenge to get a coherent understanding of this signaling pathway for making therapeutic strategy. This motivated us to perform a computational study of the pathway and to identify probable drug targets. In this work, from available databases and literature, we reconstructed a complete hedgehog pathway which reports the largest number of molecules and interactions to date. Using recently developed computational techniques, we further performed structural and logical analysis of this pathway. In structural analysis, the connectivity and centrality parameters were calculated to identify the important proteins from the network. To capture the regulations of the molecules, we developed a master Boolean model of all the interactions between the proteins and created different cancer scenarios, such as Glioma, Colon and Pancreatic. We performed perturbation analysis on these cancer conditions to identify the important and minimal combinations of proteins that can be used as drug targets. From our study we observed the under expressions of various oncoproteins in Hedgehog pathway while perturbing at a time the combinations of the proteins GLI1, GLI2 and SMO in Glioma; SMO, HFU, ULK3 and RAS in Colon cancer; SMO, HFU, ULK3, RAS and ERK12 in Pancreatic cancer. This reconstructed Hedgehog signaling pathway and the computational analysis for identifying new combinatory drug targets will be useful for future in-vitro and in-vivo analysis to control different cancers. PMID- 23935938 TI - MHC class IIB exon 2 polymorphism in the Grey partridge (Perdix perdix) is shaped by selection, recombination and gene conversion. AB - Among bird species, the most studied major histocompatibility complex (MHC) is the chicken MHC. Although the number of studies on MHC in free-ranging species is increasing, the knowledge on MHC variation in species closely related to chicken is required to understand the peculiarities of bird MHC evolution. Here we describe the variation of MHC class IIB (MHCIIB) exon 2 in a population of the Grey partridge (Perdix perdix), a species of high conservation concern throughout Europe and an emerging galliform model in studies of sexual selection. We found 12 alleles in 108 individuals, but in comparison to other birds surprisingly many sites show signatures of historical positive selection. Individuals displayed between two to four alleles both on genomic and complementary DNA, suggesting the presence of two functional MHCIIB loci. Recombination and gene conversion appear to be involved in generating MHCIIB diversity in the Grey partridge; two recombination breakpoints and several gene conversion events were detected. In phylogenetic analysis of galliform MHCIIB, the Grey partridge alleles do not cluster together, but are scattered through the tree instead. Thus, our results indicate that the Grey partridge MHCIIB is comparable to most other galliforms in terms of copy number and population polymorphism. PMID- 23935939 TI - Paeoniflorin inhibits pulmonary artery smooth muscle cells proliferation via upregulating A2B adenosine receptor in rat. AB - Paeoniflorin (PF), which is the main active ingredient in the root of Paeonia Radix, has many pharmacological effects. Here, we investigated the effect of PF on rat pulmonary artery smooth muscle cells (PASMCs) under hypoxic conditions and explored the mechanisms of the effects. The anti-proliferative effect of PF increased in a dose dependent manner. At the highest dose (20 MUmol/L), the anti proliferative effect of PF peaked at 24 h after administration. However, the selective A2B adenosine receptor (A2BAR) antagonist MRS1754 abolished it. PF increased A2BAR mRNA levels from 0.0763+/-0.0067 of beta-actin mRNA levels (hypoxia group) to 0.1190+/-0.0139 (P<0.05) measured by Real Time Reverse Transcription-Polymerase Chain Reaction. A2BAR protein expression measured by Western Blot was also increased. PF inhibited the proliferation of PASMCs by blocking cell cycle progression in the S phase. These data indicated that activation of A2BAR might be involved in the anti-proliferative effect of PF on PASMCs under hypoxic conditions. The results suggested that a new mechanism of PF could be relevant to the management of clinical hypoxic pulmonary hypertension. PMID- 23935940 TI - Versatile and simple approach to determine astrocyte territories in mouse neocortex and hippocampus. AB - BACKGROUND: Besides their neuronal support functions, astrocytes are active partners in neuronal information processing. The typical territorial structure of astrocytes (the volume of neuropil occupied by a single astrocyte) is pivotal for many aspects of glia-neuron interactions. METHODS: Individual astrocyte territorial volumes are measured by Golgi impregnation, and astrocyte densities are determined by S100beta immunolabeling. These data are compared with results from conventionally applied methods such as dye filling and determination of the density of astrocyte networks by biocytin loading. Finally, we implemented our new approach to investigate age-related changes in astrocyte territories in the cortex and hippocampus of 5- and 21-month-old mice. RESULTS: The data obtained by our simplified approach based on Golgi impregnation were compared to previously published dye filling experiments, and yielded remarkably comparable results regarding astrocyte territorial volumes. Moreover, we found that almost all coupled astrocytes (as indicated by biocytin loading) were immunopositive for S100beta. A first application of this new experimental approach gives insight in age-dependent changes in astrocyte territorial volumes. They increased with age, while cell densities remained stable. In 5-month-old mice, the overlap factor was close to 1, revealing little or no interdigitation of astrocyte territories. However, in 21-month-old mice, the overlap factor was more than 2, suggesting that processes of adjacent astrocytes interdigitate. CONCLUSION: Here we verified the usability of a simple, versatile method for assessing astrocyte territories and the overlap factor between adjacent territories. Second, we found that there is an age-related increase in territorial volumes of astrocytes that leads to loss of the strict organization in non-overlapping territories. Future studies should elucidate the physiological relevance of this adaptive reaction of astrocytes in the aging brain and the methods presented in this study might be a powerful tool to do so. PMID- 23935941 TI - Metabolomics and in-silico analysis reveal critical energy deregulations in animal models of Parkinson's disease. AB - Parkinson's disease (PD) is a multifactorial disease known to result from a variety of factors. Although age is the principal risk factor, other etiological mechanisms have been identified, including gene mutations and exposure to toxins. Deregulation of energy metabolism, mostly through the loss of complex I efficiency, is involved in disease progression in both the genetic and sporadic forms of the disease. In this study, we investigated energy deregulation in the cerebral tissue of animal models (genetic and toxin induced) of PD using an approach that combines metabolomics and mathematical modelling. In a first step, quantitative measurements of energy-related metabolites in mouse brain slices revealed most affected pathways. A genetic model of PD, the Park2 knockout, was compared to the effect of CCCP, a mitochondrial uncoupler [corrected]. Model simulated and experimental results revealed a significant and sustained decrease in ATP after CCCP exposure, but not in the genetic mice model. In support to data analysis, a mathematical model of the relevant metabolic pathways was developed and calibrated onto experimental data. In this work, we show that a short-term stress response in nucleotide scavenging is most probably induced by the toxin exposure. In turn, the robustness of energy-related pathways in the model explains how genetic perturbations, at least in young animals, are not sufficient to induce significant changes at the metabolite level. PMID- 23935942 TI - Nemo-like kinase associated with proliferation and apoptosis by c-Myb degradation in breast cancer. AB - Nemo-like kinase (NLK), a mediator of the Wnt signaling pathway, binds directly to c-Myb, leading to its phosphorylation, ubiquitination and proteasome-dependent degradation. NLK was significantly downregulated in the breast cancer tissues compared to corresponding normal tissues. NLK expression was negatively correlated with c-Myb expression. NLK suppressed proliferation, induced apoptosis and mediated c-Myb degradation in MCF-7 cells via a mechanism that seems to involve c-myc and Bcl2. These findings might provide a novel target for therapeutic intervention in patients with breast cancer. PMID- 23935943 TI - Prenatal exposure to dexamethasone in the mouse alters cardiac growth patterns and increases pulse pressure in aged male offspring. AB - Exposure to synthetic glucocorticoids during development can result in later cardiovascular and renal disease in sheep and rats. Although prenatal glucocorticoid exposure is associated with impaired renal development, less is known about effects on the developing heart. This study aimed to examine the effects of a short-term exposure to dexamethasone (60 hours from embryonic day 12.5) on the developing mouse heart, and cardiovascular function in adult male offspring. Dexamethasone (DEX) exposed fetuses were growth restricted compared to saline treated controls (SAL) at E14.5, but there was no difference between groups at E17.5. Heart weights of the DEX fetuses also tended to be smaller at E14.5, but not different at E17.5. Cardiac AT1aR, Bax, and IGF-1 mRNA expression was significantly increased by DEX compared to SAL at E17.5. In 12-month-old offspring DEX exposure caused an increase in basal blood pressure of ~3 mmHg. In addition, DEX exposed mice had a widened pulse pressure compared to SAL. DEX exposed males at 12 months had an approximate 25% reduction in nephron number compared to SAL, but no difference in cardiomyocyte number. Exposure to DEX in utero appears to adversely impact on nephrogenesis and heart growth but is not associated with a cardiomyocyte deficit in male mice in adulthood, possibly due to compensatory growth of the myocardium following the initial insult. However, the widened pulse pressure may be indicative of altered vascular compliance. PMID- 23935944 TI - O-GlcNAcylation-inducing treatments inhibit estrogen receptor alpha expression and confer resistance to 4-OH-tamoxifen in human breast cancer-derived MCF-7 cells. AB - O-GlcNAcylation (addition of N-acetyl-glucosamine on serine or threonine residues) is a post-translational modification that regulates stability, activity or localization of cytosolic and nuclear proteins. O-linked N-acetylgluocosmaine transferase (OGT) uses UDP-GlcNAc, produced in the hexosamine biosynthetic pathway to O-GlcNacylate proteins. Removal of O-GlcNAc from proteins is catalyzed by the beta-N-Acetylglucosaminidase (OGA). Recent evidences suggest that O GlcNAcylation may affect the growth of cancer cells. However, the consequences of O-GlcNAcylation on anti-cancer therapy have not been evaluated. In this work, we studied the effects of O-GlcNAcylation on tamoxifen-induced cell death in the breast cancer-derived MCF-7 cells. Treatments that increase O-GlcNAcylation (PUGNAc and/or glucosoamine) protected MCF-7 cells from death induced by tamoxifen. In contrast, inhibition of OGT expression by siRNA potentiated the effect of tamoxifen on cell death. Since the PI-3 kinase/Akt pathway is a major regulator of cell survival, we used BRET to evaluate the effect of PUGNAc+glucosamine on PIP3 production. We observed that these treatments stimulated PIP3 production in MCF-7 cells. This effect was associated with an increase in Akt phosphorylation. However, the PI-3 kinase inhibitor LY294002, which abolished the effect of PUGNAc+glucosamine on Akt phosphorylation, did not impair the protective effects of PUGNAc+glucosamine against tamoxifen-induced cell death. These results suggest that the protective effects of O-GlcNAcylation are independent of the PI-3 kinase/Akt pathway. As tamoxifen sensitivity depends on the estrogen receptor (ERalpha) expression level, we evaluated the effect of PUGNAc+glucosamine on the expression of this receptor. We observed that O GlcNAcylation-inducing treatment significantly reduced the expression of ERalpha mRNA and protein, suggesting a potential mechanism for the decreased tamoxifen sensitivity induced by these treatments. Therefore, our results suggest that inhibition of O-GlcNAcylation may constitute an interesting approach to improve the sensitivity of breast cancer to anti-estrogen therapy. PMID- 23935945 TI - Decreased expression of AZGP1 is associated with poor prognosis in primary gastric cancer. AB - BACKGROUND: 2-Zinc-glycoprotein 1 (AZGP1) is a multidisciplinary protein that participates in many important functions in the human body, including fertilization, immunoregulation and lipid mobilization. Recently, it has been shown that AZGP1 is also involved in carcinogenesis and tumor differentiation. In this study, we investigated the expression levels and prognostic value of AZGP1 in primary gastric cancers. METHODS AND RESULTS: We examined the expression of AZGP1 in 35 paired cancerous and matched adjacent noncancerous gastric mucosa tissues by real-time quantitative RT-PCR (qRT-PCR) and western blotting. Furthermore, we analyzed AZGP1 expression in 248 patients who underwent resection procedures between 2005 and 2007 using immunohistochemistry. The relationships between the AZGP1 expression levels, the clinicopathological factors, and patient survival were investigated. AZGP1 expression was significantly reduced at both the mRNA (P = 0.023) and protein levels (P = 0.019) in tumor tissue samples, compared with expression in matched adjacent non-tumor tissue samples. The immunohistochemical staining data showed that AZGP1 expression was significantly decreased in 52.8% (131/248) of gastric adenocarcinoma cases. Clinicopathological analysis showed that the reduced expression of AZGP1 was significantly correlated with tumor location (P = 0.011), histological grade (P = 0.005) and T stage (P = 0.008). Kaplan-Meier survival curves revealed that the reduced expression of AZGP1 was associated with a poor prognosis in gastric adenocarcinoma patients (P = 0.009). Multivariate Cox analysis identified AZGP1 expression was an independent prognostic factor for overall survival of gastric adenocarcinoma patients (HR = 1.681, 95% CI = 1.134-2.494, P = 0.011). CONCLUSIONS: Our study suggests that AZGP1 might serve as a candidate tumor suppressor and a potential prognostic biomarker in gastric carcinogenesis. PMID- 23935946 TI - Phytoplankton growth and microzooplankton grazing in the subtropical Northeast Atlantic. AB - Dilution experiments were performed to estimate phytoplankton growth and microzooplankton grazing rates during two Lagrangian surveys in inner and eastern locations of the Eastern North Atlantic Subtropical Gyre province (NAST-E). Our design included two phytoplankton size fractions (0.2-5 um and >5 um) and five depths, allowing us to characterize differences in growth and grazing rates between size fractions and depths, as well as to estimate vertically integrated measurements. Phytoplankton growth rates were high (0.11-1.60 d(-1)), especially in the case of the large fraction. Grazing rates were also high (0.15-1.29 d( 1)), suggesting high turnover rates within the phytoplankton community. The integrated balances between phytoplankton growth and grazing losses were close to zero, although deviations were detected at several depths. Also, O2 supersaturation was observed up to 110 m depth during both Lagrangian surveys. These results add up to increased evidence indicating an autotrophic metabolic balance in oceanic subtropical gyres. PMID- 23935947 TI - The critical period hypothesis in second language acquisition: a statistical critique and a reanalysis. AB - In second language acquisition research, the critical period hypothesis (cph) holds that the function between learners' age and their susceptibility to second language input is non-linear. This paper revisits the indistinctness found in the literature with regard to this hypothesis's scope and predictions. Even when its scope is clearly delineated and its predictions are spelt out, however, empirical studies-with few exceptions-use analytical (statistical) tools that are irrelevant with respect to the predictions made. This paper discusses statistical fallacies common in cph research and illustrates an alternative analytical method (piecewise regression) by means of a reanalysis of two datasets from a 2010 paper purporting to have found cross-linguistic evidence in favour of the cph. This reanalysis reveals that the specific age patterns predicted by the cph are not cross-linguistically robust. Applying the principle of parsimony, it is concluded that age patterns in second language acquisition are not governed by a critical period. To conclude, this paper highlights the role of confirmation bias in the scientific enterprise and appeals to second language acquisition researchers to reanalyse their old datasets using the methods discussed in this paper. The data and R commands that were used for the reanalysis are provided as supplementary materials. PMID- 23935949 TI - The embedding problem for markov models of nucleotide substitution. AB - Continuous-time Markov processes are often used to model the complex natural phenomenon of sequence evolution. To make the process of sequence evolution tractable, simplifying assumptions are often made about the sequence properties and the underlying process. The validity of one such assumption, time homogeneity, has never been explored. Violations of this assumption can be found by identifying non-embeddability. A process is non-embeddable if it can not be embedded in a continuous time-homogeneous Markov process. In this study, non embeddability was demonstrated to exist when modelling sequence evolution with Markov models. Evidence of non-embeddability was found primarily at the third codon position, possibly resulting from changes in mutation rate over time. Outgroup edges and those with a deeper time depth were found to have an increased probability of the underlying process being non-embeddable. Overall, low levels of non-embeddability were detected when examining individual edges of triads across a diverse set of alignments. Subsequent phylogenetic reconstruction analyses demonstrated that non-embeddability could impact on the correct prediction of phylogenies, but at extremely low levels. Despite the existence of non-embeddability, there is minimal evidence of violations of the local time homogeneity assumption and consequently the impact is likely to be minor. PMID- 23935948 TI - Haploinsufficiency of akt1 prolongs the lifespan of mice. AB - There is increasing evidence that nutrient-sensing machinery is critically involved in the regulation of aging. The insulin/insulin-like growth factor-1 signaling pathway is the best-characterized pathway with an influence on longevity in a variety of organisms, ranging from yeast to rodents. Reduced expression of the receptor for this pathway has been reported to prolong the lifespan; however, the underlying mechanisms are largely unknown. Here we show that haploinsufficiency of Akt1 leads to an increase of the lifespan in mice. Akt1 (+/-) mice had a lower body weight than their littermates with less fat mass and normal glucose metabolism. Ribosomal biogenesis and the mitochondrial DNA content were significantly reduced in these mice, along with a decrease of oxidative stress. Consistent with the results obtained in mice, inhibition of Akt 1 promoted longevity in nematodes (Caenorhabditis elegans), whereas activation of Akt-1 shortened the lifespan. Inhibition of Akt-1 led to a decrease of ribosomal gene expression and the mitochondrial DNA content in both human cells and nematodes. Moreover, deletion of ribosomal gene expression resulted in a decrease of the mitochondrial DNA content and normalized the lifespan shortened by Akt-1 activation in nematodes. These results suggest that an increase of mitochondrial amount and energy expenditure associated with enhanced protein synthesis accelerates both aging and the onset of age-associated diseases. PMID- 23935951 TI - Exploring the mode of action of bioactive compounds by microfluidic transcriptional profiling in mycobacteria. AB - Most candidate anti-bacterials are identified on the basis of their whole cell anti-bacterial activity. A critical bottleneck in the early discovery of novel anti-bacterials is tracking the structure activity relationship (SAR) of the novel compounds synthesized during the hit to lead and lead optimization stage. It is often very difficult for medicinal chemists to visualize if the novel compounds synthesized for understanding SAR of a particular scaffold have similar molecular mechanism of action (MoA) as that of the initial hit. The elucidation of the molecular MoA of bioactive inhibitors is critical. Here, a new strategy and routine assay for MoA de-convolution, using a microfluidic platform for transcriptional profiling of bacterial response to inhibitors with whole cell activity has been presented. First a reference transcriptome compendium of Mycobacterial response to various clinical and investigational drugs was built. Using feature reduction, it was demonstrated that subsets of biomarker genes representative of the whole genome are sufficient for MoA classification and deconvolution in a medium-throughput microfluidic format ultimately leading to a cost effective and rapid tool for routine antibacterial drug-discovery programs. PMID- 23935950 TI - Dopaminergic neuronal imaging in genetic Parkinson's disease: insights into pathogenesis. AB - OBJECTIVES: To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease. METHODS: A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. The right:left asymmetry index and striatal asymmetry index was calculated. RESULTS: Scans were available from 37 cases of monogenetic Parkinson's disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). The asymmetry of radioligand uptake for Parkinson's disease with GBA or LRRK2 mutations was greater than that for Parkinson's disease with alpha synuclein, PINK1 or Parkin mutations. CONCLUSIONS: The asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss. PMID- 23935952 TI - DNA repair deficiency as a susceptibility marker for spontaneous lymphoma in golden retriever dogs: a case-control study. AB - There is accumulating evidence that an individual's inability to accurately repair DNA damage in a timely fashion may in part dictate a predisposition to cancer. Dogs spontaneously develop lymphoproliferative diseases such as lymphoma, with the golden retriever (GR) breed being at especially high risk. Mechanisms underlying such breed susceptibility are largely unknown; however, studies of heritable cancer predisposition in dogs may be much more straightforward than similar studies in humans, owing to a high degree of inbreeding and more limited genetic heterogeneity. Here, we conducted a pilot study with 21 GR with lymphoma, 20 age-matched healthy GR and 20 age-matched healthy mixed-breed dogs (MBD) to evaluate DNA repair capability following exposure to either ionizing radiation (IR) or the chemical mutagen bleomycin. Inter-individual variation in DNA repair capacity was evaluated in stimulated canine lymphoctyes exposed in vitro utilizing the G2 chromosomal radiosensitivity assay to quantify clastogen-induced chromatid-type aberrations (gaps and breaks). Golden retrievers with lymphoma demonstrated elevated sensitivity to induction of chromosome damage following either challenge compared to either healthy GR or MBD at multiple doses and time points. Using the 75(th) percentile of chromatid breaks per 1,000 chromosomes in the MBD population at 4 hours post 1.0 Gy IR exposure as a benchmark to compare cases and controls, GR with lymphoma were more likely than healthy GR to be classified as "sensitive" (odds ratio = 21.2, 95% confidence interval 2.3-195.8). Furthermore, our preliminary findings imply individual (rather than breed) susceptibility, and suggest that deficiencies in heritable factors related to DNA repair capabilities may be involved in the development of canine lymphoma. These studies set the stage for larger confirmatory studies, as well as candidate-based approaches to probe specific genetic susceptibility factors. PMID- 23935953 TI - Computational and experimental insights into the mechanism of substrate recognition and feedback inhibition of protoporphyrinogen oxidase. AB - Protoporphyrinogen IX oxidase (PPO; EC 1.3.3.4) is an essential enzyme catalyzing the last common step in the pathway leading to heme and chlorophyll biosynthesis. Great interest in PPO inhibitors arises from both its significance to agriculture and medicine. However, the discovery of PPO inhibitors with ultrahigh potency and selectivity is hampered due to lack of structural and mechanistic understanding about the substrate recognition, which remains a longstanding question central in porphyrin biology. To understand the mechanism, a novel binding model of protogen (protoporphyrinogen IX, the substrate) was developed through extensive computational simulations. Subsequently, amino acid residues that are critical for protogen binding identified by computational simulations were substituted by mutagenesis. Kinetic analyses of these mutants indicated that these residues were critical for protogen binding. In addition, the calculated free energies of protogen binding with these mutants correlated well with the experimental data, indicating the reasonability of the binding model. On the basis of this novel model, the fundamental mechanism of substrate recognition was investigated by performing potential of mean force (PMF) calculations, which provided an atomic level description of conformational changes and pathway intermediates. The free energy profile revealed a feedback inhibition mechanism of proto (protoporphyrin IX, the product), which was also in agreement with experimental evidence. The novel mechanistic insights obtained from this study present a new starting point for future rational design of more efficient PPO inhibitors based on the product bound PPO structure. PMID- 23935954 TI - Genome-wide association mapping for identification of quantitative trait loci for rectal temperature during heat stress in Holstein cattle. AB - Heat stress compromises production, fertility, and health of dairy cattle. One mitigation strategy is to select individuals that are genetically resistant to heat stress. Most of the negative effects of heat stress on animal performance are a consequence of either physiological adaptations to regulate body temperature or adverse consequences of failure to regulate body temperature. Thus, selection for regulation of body temperature during heat stress could increase thermotolerance. The objective was to perform a genome-wide association study (GWAS) for rectal temperature (RT) during heat stress in lactating Holstein cows and identify SNPs associated with genes that have large effects on RT. Records on afternoon RT where the temperature-humidity index was >=78.2 were obtained from 4,447 cows sired by 220 bulls, resulting in 1,440 useable genotypes from the Illumina BovineSNP50 BeadChip with 39,759 SNP. For GWAS, 2, 3, 4, 5, and 10 adjacent SNP were averaged to identify consensus genomic regions associated with RT. The largest proportion of SNP variance (0.07 to 0.44%) was explained by markers flanking the region between 28,877,547 and 28,907,154 bp on Bos taurus autosome (BTA) 24. That region is flanked by U1 (28,822,883 to 28,823,043) and NCAD (28,992,666 to 29,241,119). In addition, the SNP at 58,500,249 bp on BTA 16 explained 0.08% and 0.11% of the SNP variance for 2- and 3-SNP analyses, respectively. That contig includes SNORA19, RFWD2 and SCARNA3. Other SNPs associated with RT were located on BTA 16 (close to CEP170 and PLD5), BTA 5 (near SLCO1C1 and PDE3A), BTA 4 (near KBTBD2 and LSM5), and BTA 26 (located in GOT1, a gene implicated in protection from cellular stress). In conclusion, there are QTL for RT in heat-stressed dairy cattle. These SNPs could prove useful in genetic selection and for identification of genes involved in physiological responses to heat stress. PMID- 23935955 TI - Tissue-specific epigenetic modifications in root apical meristem cells of Hordeum vulgare. AB - Epigenetic modifications of chromatin structure are essential for many biological processes, including growth and reproduction. Patterns of DNA and histone modifications have recently been widely studied in many plant species, although there is virtually no data on the spatial and temporal distribution of epigenetic markers during plant development. Accordingly, we have used immunostaining techniques to investigate epigenetic modifications in the root apical meristem of Hordeum vulgare. Histone H4 acetylation (H4K5ac), histone H3 dimethylation (H3K4me2, H3K9me2) and DNA methylation (5mC) patterns were established for various root meristem tissues. Distinct levels of those modifications were visualised in the root cap, epidermis, cortex and vascular tissues. The lateral root cap cells seem to display the highest level of H3K9me2 and 5mC. In the epidermis, the highest level of 5mC and H3K9me2 was detected in the nuclei from the boundary of the proximal meristem and the elongation zone, while the vascular tissues were characterized by the highest level of H4K5ac. Some of the modified histones were also detectable in the cytoplasm in a highly tissue-specific manner. Immunolocalisation of epigenetic modifications of chromatin carried out in this way, on longitudinal or transverse sections, provides a unique topographic context within the organ, and will provide some answers to the significant biological question of tissue differentiation processes during root development in a monocotyledon plant species. PMID- 23935956 TI - Genome wide association analysis of a founder population identified TAF3 as a gene for MCHC in humans. AB - The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5-10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene. The association was replicated in two cohorts (rs1887582, P = 4.25E-09). TAF3 encodes a transcription cofactor that participates in core promoter recognition complex, and is involved in zebrafish and mouse erythropoiesis. We show here that TAF3 is required for transcription of the SPTA1 gene, encoding alpha spectrin, one of the proteins that link the plasma membrane to the actin cytoskeleton. Mutations in SPTA1 are responsible for hereditary spherocytosis, a monogenic disorder of MCHC, as well as for the normal MCHC level. Based on our results, we propose that TAF3 is required for normal erythropoiesis in human and that it might have a role in controlling the ratio between hemoglobin (Hb) and cell volume and in the dynamics of RBC maturation in healthy individuals. Finally, TAF3 represents a potential candidate or a modifier gene for disorders of red cell membrane. PMID- 23935957 TI - Nbn and atm cooperate in a tissue and developmental stage-specific manner to prevent double strand breaks and apoptosis in developing brain and eye. AB - Nibrin (NBN or NBS1) and ATM are key factors for DNA Double Strand Break (DSB) signaling and repair. Mutations in NBN or ATM result in Nijmegen Breakage Syndrome and Ataxia telangiectasia. These syndromes share common features such as radiosensitivity, neurological developmental defects and cancer predisposition. However, the functional synergy of Nbn and Atm in different tissues and developmental stages is not yet understood. Here, we show in vivo consequences of conditional inactivation of both genes in neural stem/progenitor cells using Nestin-Cre mice. Genetic inactivation of Atm in the central nervous system of Nbn deficient mice led to reduced life span and increased DSBs, resulting in increased apoptosis during neural development. Surprisingly, the increase of DSBs and apoptosis was found only in few tissues including cerebellum, ganglionic eminences and lens. In sharp contrast, we showed that apoptosis associated with Nbn deletion was prevented by simultaneous inactivation of Atm in developing retina. Therefore, we propose that Nbn and Atm collaborate to prevent DSB accumulation and apoptosis during development in a tissue- and developmental stage-specific manner. PMID- 23935958 TI - Reconstruction of cellular signal transduction networks using perturbation assays and linear programming. AB - Perturbation experiments for example using RNA interference (RNAi) offer an attractive way to elucidate gene function in a high throughput fashion. The placement of hit genes in their functional context and the inference of underlying networks from such data, however, are challenging tasks. One of the problems in network inference is the exponential number of possible network topologies for a given number of genes. Here, we introduce a novel mathematical approach to address this question. We formulate network inference as a linear optimization problem, which can be solved efficiently even for large-scale systems. We use simulated data to evaluate our approach, and show improved performance in particular on larger networks over state-of-the art methods. We achieve increased sensitivity and specificity, as well as a significant reduction in computing time. Furthermore, we show superior performance on noisy data. We then apply our approach to study the intracellular signaling of human primary nave CD4(+) T-cells, as well as ErbB signaling in trastuzumab resistant breast cancer cells. In both cases, our approach recovers known interactions and points to additional relevant processes. In ErbB signaling, our results predict an important role of negative and positive feedback in controlling the cell cycle progression. PMID- 23935959 TI - Acute effects of modafinil on brain resting state networks in young healthy subjects. AB - BACKGROUND: There is growing debate on the use of drugs that promote cognitive enhancement. Amphetamine-like drugs have been employed as cognitive enhancers, but they show important side effects and induce addiction. In this study, we investigated the use of modafinil which appears to have less side effects compared to other amphetamine-like drugs. We analyzed effects on cognitive performances and brain resting state network activity of 26 healthy young subjects. METHODOLOGY: A single dose (100 mg) of modafinil was administered in a double-blind and placebo-controlled study. Both groups were tested for neuropsychological performances with the Raven's Advanced Progressive Matrices II set (APM) before and three hours after administration of drug or placebo. Resting state functional magnetic resonance (rs-FMRI) was also used, before and after three hours, to investigate changes in the activity of resting state brain networks. Diffusion Tensor Imaging (DTI) was employed to evaluate differences in structural connectivity between the two groups. Protocol ID: Modrest_2011; NCT01684306; http://clinicaltrials.gov/ct2/show/NCT01684306. PRINCIPAL FINDINGS: Results indicate that a single dose of modafinil improves cognitive performance as assessed by APM. Rs-fMRI showed that the drug produces a statistically significant increased activation of Frontal Parietal Control (FPC; p<0.04) and Dorsal Attention (DAN; p<0.04) networks. No modifications in structural connectivity were observed. CONCLUSIONS AND SIGNIFICANCE: Overall, our findings support the notion that modafinil has cognitive enhancing properties and provide functional connectivity data to support these effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT01684306 http://clinicaltrials.gov/ct2/show/NCT01684306. PMID- 23935960 TI - Extended result reading window in lateral flow tests detecting exposure to Onchocerca volvulus: a new technology to improve epidemiological surveillance tools. AB - Onchocerciasis is a neglected tropical disease caused by infection with the parasite Onchocerca volvulus (Ov). An estimated 180 million people are at risk for Ov infection, and 37 million people are infected, mostly in Africa. A lateral flow-based assay to detect human IgG4 antibodies to the Ov-specific antigen Ov-16 was developed as a rapid tool to detect exposure to Ov. The test, when performed on 449 sera specimens from patients with microfiladermia and Ov-negative patients, has a sensitivity of 89.1% (95% confidence interval: 86.2%-92.0%), and specificity of 97% (95% confidence interval: 95.4%-98.6%). Because the intended use of the test is for surveillance, it is highly desirable to have a stable, long-lasting result. An extended read window is thus desirable for a high-volume, busy workflow and facilitates post-surveillance quality assurance. The main restriction on achieving an extended read window for this assay was the erythrocyte lysis that can alter the signal-to-noise ratio, especially in those with low IgG4 levels (weak positives). We describe a test housing that incorporates a user-independent feature driven by assay fluid and an expanding wick that detaches the blood separation membrane from the nitrocellulose used in the assay, but before hemolysis occurs. We demonstrated material functionality at extreme operational conditions (37 degrees C, 80% relative humidity) and a read window of a minimum of 70 days. The fluid-driven assay device performs equally as well with whole blood as with plasma, as demonstrated with 100 spiked clinical specimens (with a correlation coefficient of 0.96). We show a novel, inexpensive, and simple approach to actuating the detachment of the blood separation membrane from the nitrocellulose test with no impact on the performance characteristics of the test. PMID- 23935961 TI - High-sensitivity C-reactive protein and risk of sepsis. AB - BACKGROUND: Conventional C-reactive protein assays have been used to detect or guide the treatment of acute sepsis. The objective of this study was to determine the association between elevated baseline high-sensitivity C-reactive protein (hsCRP) and the risk of future sepsis events. METHODS: We studied data from 30,239 community dwelling, black and white individuals, age >=45 years old enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Baseline hsCRP and participant characteristics were determined at the start of the study. We identified sepsis events through review of hospital records. Elevated hsCRP was defined as values >3.0 mg/L. Using Cox regression, we determined the association between elevated hsCRP and first sepsis event, adjusting for sociodemographic factors (age, sex, race, region, education, income), health behaviors (tobacco and alcohol use), chronic medical conditions (coronary artery disease, diabetes, dyslipidemia, hypertension, chronic kidney disease, chronic lung disease) and statin use. RESULTS: Over the mean observation time of 5.7 years (IQR 4.5-7.1), 974 individuals experienced a sepsis event, and 11,447 (37.9%) had elevated baseline hsCRP (>3.0 mg/L). Elevated baseline hsCRP was independently associated with subsequent sepsis (adjusted HR 1.56; 95% CI 1.36-1.79), adjusted for sociodemographics, health behaviors, chronic medical conditions and statin use. CONCLUSION: Elevated baseline hsCRP was associated with increased risk of future sepsis events. hsCRP may help to identify individuals at increased risk for sepsis. PMID- 23935962 TI - Circulating microRNA profiling identifies a subset of metastatic prostate cancer patients with evidence of cancer-associated hypoxia. AB - MicroRNAs (miRNAs) are small (~22 nucleotide) non-coding RNAs that regulate a myriad of biological processes and are frequently dysregulated in cancer. Cancer associated microRNAs have been detected in serum and plasma and hold promise as minimally invasive cancer biomarkers, potentially for assessing disease characteristics in patients with metastatic disease that is difficult to biopsy. Here we used miRNA profiling to identify cancer-associated miRNAs that are differentially expressed in sera from patients with metastatic castration resistant prostate cancer (mCRPC) as compared to healthy controls. Of 365 miRNAs profiled, we identified five serum miRNAs (miR-141, miR-200a, miR-200c, miR-210 and miR-375) that were elevated in cases compared to controls across two independent cohorts. One of these, miR-210, is a known transcriptional target of the hypoxia-responsive HIF-1alpha signaling pathway. Exposure of cultured prostate cancer cells to hypoxia led to induction of miR-210 and its release into the extracellular environment. Moreover, we found that serum miR-210 levels varied widely amongst mCRPC patients undergoing therapy, and correlated with treatment response as assessed by change in PSA. Our results suggest that (i) cancer-associated hypoxia is a frequent, previously under-appreciated characteristic of mCRPC, and (ii) serum miR-210 may be further developed as a predictive biomarker in patients with this distinct disease biology. PMID- 23935963 TI - Latitudinal diversity gradients in New World bats: are they a consequence of niche conservatism? AB - The increase in species diversity from the Poles to the Equator is a major biogeographic pattern, but the mechanisms underlying it remain obscure. Our aim is to contribute to their clarification by describing the latitudinal gradients in species richness and in evolutionary age of species of New World bats, and testing if those patterns may be explained by the niche conservatism hypothesis. Maps of species ranges were used to estimate species richness in a 100 x 100 km grid. Root distances in a molecular phylogeny were used as a proxy for the age of species, and the mean root distance of the species in each cell of the grid was estimated. Generalised additive models were used to relate latitude with both species richness and mean root distance. This was done for each of the three most specious bat families and for all Chiroptera combined. Species richness increases towards the Equator in the whole of the Chiroptera and in the Phyllostomidae and Molossidae, families that radiated in the tropics, but the opposite trend is observed in the Vespertilionidae, which has a presumed temperate origin. In the whole of the Chiroptera, and in the three main families, there were more basal species in the higher latitudes, and more derived species in tropical areas. In general, our results were not consistent with the predictions of niche conservatism. Tropical niche conservatism seems to keep bat clades of tropical origin from colonizing temperate zones, as they lack adaptations to survive cold winters, such as the capacity to hibernate. However, the lower diversity of Vespertilionidae in the Neotropics is better explained by competition with a diverse pre-existing community of bats than by niche conservatism. PMID- 23935964 TI - Lung macrophages contribute to house dust mite driven airway remodeling via HIF 1alpha. AB - HIF-1alpha is a transcription factor that is activated during hypoxia and inflammation and is a key regulator of angiogenesis in vivo. During the development of asthma, peribronchial angiogenesis is induced in response to aeroallergens and is thought to be an important feature of sustained chronic allergic inflammation. Recently, elevated HIF-1alpha levels have been demonstrated in both the lung tissue and bronchoalveolar lavage of allergic patients, respectively. Therefore, we investigated the role of HIF-1alpha on the development of angiogenesis and inflammation following acute and chronic allergen exposure. Our data shows that intranasal exposure to house dust mite (HDM) increases the expression of HIF-1alpha in the lung, whilst reducing the expression of the HIF-1alpha negative regulators, PHD1 and PHD3. Blockade of HIF 1alpha in vivo, significantly decreased allergic inflammation and eosinophilia induced by allergen, due to a reduction in the levels of IL-5 and Eotaxin-2. Importantly, HIF-1alpha blockade significantly decreased levels of VEGF-A and CXCL1 in the lungs, which in turn led to a profound decrease in the recruitment of endothelial progenitor cells and a reduction of peribronchial angiogenesis. Furthermore, HDM or IL-4 treatment of primary lung macrophages resulted in significant production of both VEGF-A and CXCL1; inhibition of HIF-1alpha activity abrogated the production of these factors via an up-regulation of PHD1 and PHD3. These findings suggest that novel strategies to reduce the expression and activation of HIF-1alpha in lung macrophages may be used to attenuate allergen-induced airway inflammation and angiogenesis through the modulation of VEGF-A and CXCL1 expression. CLINICAL RELEVANCE: This study provides new insights into the role of HIF-1alpha in the development of peribronchial angiogenesis and inflammation in a murine model of allergic airway disease. These findings indicate that strategies to reduce activation of macrophage derived HIF-1alpha may be used as a target to improve asthma pathology. PMID- 23935965 TI - Adaptive plasticity in wild field cricket's acoustic signaling. AB - Phenotypic plasticity can be adaptive when phenotypes are closely matched to changes in the environment. In crickets, rhythmic fluctuations in the biotic and abiotic environment regularly result in diel rhythms in density of sexually active individuals. Given that density strongly influences the intensity of sexual selection, we asked whether crickets exhibit plasticity in signaling behavior that aligns with these rhythmic fluctuations in the socio-sexual environment. We quantified the acoustic mate signaling behavior of wild-caught males of two cricket species, Gryllus veletis and G. pennsylvanicus. Crickets exhibited phenotypically plastic mate signaling behavior, with most males signaling more often and more attractively during the times of day when mating activity is highest in the wild. Most male G. pennsylvanicus chirped more often and louder, with shorter interpulse durations, pulse periods, chirp durations, and interchirp durations, and at slightly higher carrier frequencies during the time of the day that mating activity is highest in the wild. Similarly, most male G. veletis chirped more often, with more pulses per chirp, longer interpulse durations, pulse periods, and chirp durations, shorter interchirp durations, and at lower carrier frequencies during the time of peak mating activity in the wild. Among-male variation in signaling plasticity was high, with some males signaling in an apparently maladaptive manner. Body size explained some of the among-male variation in G. pennsylvanicus plasticity but not G. veletis plasticity. Overall, our findings suggest that crickets exhibit phenotypically plastic mate attraction signals that closely match the fluctuating socio-sexual context they experience. PMID- 23935966 TI - Selection of multiarmed spiral waves in a regular network of neurons. AB - Formation and selection of multiarmed spiral wave due to spontaneous symmetry breaking are investigated in a regular network of Hodgkin-Huxley neuron by changing the excitability and imposing spatial forcing currents on the neurons in the network. The arm number of the multiarmed spiral wave is dependent on the distribution of spatial forcing currents and excitability diversity in the network, and the selection criterion for supporting multiarmed spiral waves is discussed. A broken spiral segment is measured by a short polygonal line connected by three adjacent points (controlled nodes), and a double-spiral wave can be developed from the spiral segment. Multiarmed spiral wave is formed when a group of double-spiral waves rotate in the same direction in the network. In the numerical studies, a group of controlled nodes are selected and spatial forcing currents are imposed on these nodes, and our results show that l-arm stable spiral wave (l = 2, 3, 4,...8) can be induced to occupy the network completely. It is also confirmed that low excitability is critical to induce multiarmed spiral waves while high excitability is important to propagate the multiarmed spiral wave outside so that distinct multiarmed spiral wave can occupy the network completely. Our results confirm that symmetry breaking of target wave in the media accounts for emergence of multiarmed spiral wave, which can be developed from a group of spiral waves with single arm under appropriate condition, thus the potential formation mechanism of multiarmed spiral wave in the media is explained. PMID- 23935967 TI - Predilection of segmental glomerulosclerosis lesions for the glomerulotubular junction area in type 1 diabetic patients: a novel mapping method. AB - The location of segmental glomerular lesions in relation to the vascular or tubular pole may have diagnostic or prognostic significance. We have developed a model-based method to estimate the distance from a glomerular lesion to a given landmark (vascular or tubular pole) or the glomerular center and applied this to biopsies from 5 microalbuminuric, 5 normoalbuminuric and 7 proteinuric type 1 diabetic patients and 5 normal controls. The distance from each glomerular adhesion to the glomerulotubular junction was measured and divided by the glomerular radius, allowing comparability among different glomeruli, assuming a spherical shape for Bowman's capsule, an assumption which was validated. The frequency of adhesions in 6 glomerular zones with equal height (zone I adjacent to the glomerulotubular junction and zones II-VI progressively farther away) was determined: 59% of adhesions were in zone I, 15% in zone II, 16% in zone III, 7% in zone IV and 3% in zone VI (adjacent to the hilus). In glomeruli with only one adhesion, 82% of these were in zone I. This new method accurately localizes segmental lesions within glomeruli and revealed a marked predilection in type 1 diabetic patients for segmental sclerosis to develop at the glomerulotubular junction. PMID- 23935968 TI - Making sense of a new transport system: an ethnographic study of the Cambridgeshire Guided Busway. AB - An increase in public transport use has the potential to contribute to improving population health, and there is growing interest in innovative public transport systems. Yet how new public transport infrastructure is experienced and integrated (or not) into daily practice is little understood. We investigated how the Cambridgeshire Guided Busway, UK, was used and experienced in the weeks following its opening, using the method of participant observation (travelling on the busway and observing and talking to passengers) and drawing on Normalization Process Theory to interpret our data. Using excerpts of field notes to support our interpretations, we describe how the ease with which the new transport system could be integrated into existing daily routines was important in determining whether individuals would continue to use it. It emerged that there were two groups of passengers with different experiences and attitudes. Passengers who had previously travelled frequently on regular bus services did not perceive the new system to be an improvement; consequently, they were frustrated that it was differentiated from and not coherent with the regular system. In contrast, passengers who had previously travelled almost exclusively by car appraised the busway positively and perceived it to be a novel and superior form of travel. Our rich qualitative account highlights the varied and creative ways in which people learn to use new public transport and integrate it into their everyday lives. This has consequences for the introduction and promotion of future transport innovations. It is important to emphasise the novelty of new public transport, but also the ways in which its use can become ordinary and routine. Addressing these issues could help to promote uptake of other public transport interventions, which may contribute to increasing physical activity and improving population health. PMID- 23935969 TI - Ixabepilone administered weekly or every three weeks in HER2-negative metastatic breast cancer patients; a randomized non-comparative phase II trial. AB - To explore the activity and safety of two schedules of ixabepilone, as first line chemotherapy, in patients with metastatic breast cancer previously treated with adjuvant chemotherapy, a randomized non-comparative phase II study was conducted. From November 2008 until December 2010, 64 patients were treated with either ixabepilone 40 mg/m(2) every 3 weeks (Group A, 32 patients) or ixabepilone 20 mg/m(2) on days 1, 8 and 15 every 4 weeks (Group B, 32 patients). Overall response rate (the primary end point) was 47% in Group A and 50% in Group B. The most frequent severe adverse events were neutropenia (32% vs. 23%), metabolic disturbances (29% vs. 27%) and sensory neuropathy (12% vs. 27%). Two patients in Group A and 3 in Group B developed febrile neutropenia. After a median follow-up of 22.7 months, median progression-free survival (PFS) was 9 months in Group A and 12 months in Group B. Median survival was 26 months in Group A, whereas it was not reached in Group B. Multiple genetic and molecular markers were examined in tumor and peripheral blood DNA, but none of them was associated with ORR or drug toxicity. Favorable prognostic markers included: the T-variants of ABCB1 SNPs c.2677G/A/T, c.1236C/T and c.3435C/T, as well as high MAPT mRNA and Tau protein expression, which were all associated with the ER/PgR-positive phenotype; absence of TopoIIa; and, an interaction between low TUBB3 mRNA expression and Group B. Upon multivariate analysis, tumor ER-positivity was a favorable (p = 0.0092) and TopoIIa an unfavorable (p = 0.002) prognostic factor for PFS; PgR positivity was favorable (p = 0.028) for survival. In conclusion, ixabepilone had a manageable safety profile in both the 3-weekly and weekly schedules. A number of markers identified in the present trial appear to deserve further evaluation for their prognostic and/or predictive value in larger multi-arm studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00790894. PMID- 23935970 TI - Cost-effectiveness comparison of Genechip and conventional drug susceptibility test for detecting multidrug-resistant tuberculosis in China. AB - BACKGROUND: Genechip (CapitalBio, Beijing, China) is a system for diagnosing resistance to rifampin and isoniazid, which shows high efficiency in detecting drug-resistant tuberculosis. Here, we firstly evaluated the costs of Genechip for detecting the drug susceptibility of Mycobacterium tuberculosis, compared to conventional drug susceptibility test (DST) in laboratories in China. METHODOLOGY/PRINCIPAL FINDINGS: Data on the costs of the two tests were collected at four hospitals. Costs were calculated using the essential factor cost calculation method. The costs of diagnosing a single case of multidrug-resistant tuberculosis (MDR-TB) using Genechip and DST were US$22.38 and $53.03, respectively. Taking into account the effect on costs from failure of a certain number of tests to accurately diagnose MDR-TB, the costs of Genechip and DST increased by 17.65% and 5.22%, respectively. The cost of both tests decreased with the increasing prevalence of MDR-TB disease, and the cost of Genechip at a sensitivity of more than 50% was lower than that of DST. When price of Genechip was varied to 50%, 80%, 150%, and 200% of the original price, the cost of Genechip at sensitivities of more than 30%, 40%, 60%, and 70%, respectively, was also lower than that of DST. CONCLUSIONS/SIGNIFICANCE: This study showed that Genechip was a more cost-effective method of diagnosing MDR-TB compared to conventional DST. PMID- 23935971 TI - Note onset deviations as musical piece signatures. AB - A competent interpretation of a musical composition presents several non-explicit departures from the written score. Timing variations are perhaps the most important ones: they are fundamental for expressive performance and a key ingredient for conferring a human-like quality to machine-based music renditions. However, the nature of such variations is still an open research question, with diverse theories that indicate a multi-dimensional phenomenon. In the present study, we consider event-shift timing variations and show that sequences of note onset deviations are robust and reliable predictors of the musical piece being played, irrespective of the performer. In fact, our results suggest that only a few consecutive onset deviations are already enough to identify a musical composition with statistically significant accuracy. We consider a mid-size collection of commercial recordings of classical guitar pieces and follow a quantitative approach based on the combination of standard statistical tools and machine learning techniques with the semi-automatic estimation of onset deviations. Besides the reported results, we believe that the considered materials and the methodology followed widen the testing ground for studying musical timing and could open new perspectives in related research fields. PMID- 23935972 TI - Spatial clustering of all-cause and HIV-related mortality in a rural South African population (2000-2006). AB - BACKGROUND: Sub-Saharan Africa bears a disproportionate burden of HIV infection. Knowledge of the spatial distribution of HIV outcomes is vital so that appropriate public health interventions can be directed at locations most in need. In this regard, spatial clustering analysis of HIV-related mortality events has not been performed in a rural sub-Saharan African setting. METHODOLOGY AND RESULTS: Kulldorff's spatial scan statistic was used to identify HIV-related and all-cause mortality clusters (p<0.05) in a population-based demographic surveillance survey in rural KwaZulu Natal, South Africa (2000-2006). The analysis was split pre (2000-2003) and post (2004-2006) rollout of antiretroviral therapy, respectively. Between 2000-2006 a total of 86,175 resident individuals >=15 years of age were under surveillance and 5,875 deaths were recorded (of which 2,938 were HIV-related) over 343,060 person-years of observation (crude all cause mortality rate 17.1/1000). During both time periods a cluster of high HIV related (RR = 1.46/1.51, p = 0.001) and high all-cause mortality (RR = 1.35/1.38, p = 0.001) was identified in peri-urban communities near the National Road. A consistent low-risk cluster was detected in the urban township in both time periods (RR = 0.60/0.39, p = 0.003/0.005) and in the first time period (2000 2003) a large cluster of low HIV-related and all-cause mortality in a remote rural area was identified. CONCLUSIONS: HIV-related and all-cause mortality exhibit strong spatial clustering tendencies in this population. Highest HIV related mortality and all-cause mortality occurred in the peri-urban communities along the National Road and was lowest in the urban township and remote rural communities. The geography of HIV-related mortality corresponded closely to the geography of HIV prevalence, with the notable exception of the urban township where high HIV-related mortality would have been expected on the basis of the high HIV prevalence. Our results suggest that HIV treatment and care programmes should be strengthened in easy-to-reach high density, peri-urban populations near National Roads where both HIV-related and all-cause mortality are highest. PMID- 23935973 TI - A single argonaute gene participates in exogenous and endogenous RNAi and controls cellular functions in the basal fungus Mucor circinelloides. AB - The mechanism of RNAi is well described in metazoans where it plays a role in diverse cellular functions. However, although different classes of endogenous small RNAs (esRNAs) have been identified in fungi, their biological roles are poorly described due, in part, to the lack of phenotype of mutants affected in the biogenesis of these esRNAs. Argonaute proteins are one of the key components of the RNAi pathways, in which different members of this protein family participate in the biogenesis of a wide repertoire of esRNAs molecules. Here we identified three argonaute genes of the fungus Mucor circinelloides and investigated their participation in exogenous and endogenous RNAi. We found that only one of the ago genes, ago-1, is involved in RNAi during vegetative growth and is required for both transgene-induced RNA silencing and the accumulation of distinct classes of esRNAs derived from exons (ex-siRNAs). Classes I and II ex siRNAs bind to Ago-1 to control mRNA accumulation of the target protein coding genes. Class III ex-siRNAs do not specifically bind to Ago-1, but requires this protein for their production, revealing the complexity of the biogenesis pathways of ex-siRNAs. We also show that ago-1 is involved in the response to environmental signals, since vegetative development and autolysis induced by nutritional stress are affected in ago-1(-) M. circinelloides mutants. Our results demonstrate that a single Ago protein participates in the production of different classes of esRNAs that are generated through different pathways. They also highlight the role of ex-siRNAs in the regulation of endogenous genes in fungi and expand the range of biological functions modulated by RNAi. PMID- 23935974 TI - P45 forms a complex with FADD and promotes neuronal cell survival following spinal cord injury. AB - Fas-associated death domain (DD) adaptor (FADD), a member of the DD superfamily, contains both a DD and a death effector domain (DED) that are important in mediating FAS ligand-induced apoptotic signaling. P45 is a unique member of the DD superfamily in that it has a domain with sequence and structural characteristics of both DD and DED. We show that p45 forms a complex with FADD and diminishes Fas-FADD mediated death signaling. The DED of FADD is required for the complex formation with p45. Following spinal cord injury, transgenic mice over-expressing p45 exhibit increased neuronal survival, decreased retraction of corticospinal tract fibers and improved functional recovery. Understanding p45 mediated cellular and molecular mechanisms may provide insights into facilitating nerve regeneration in humans. PMID- 23935975 TI - Altered white matter architecture in BDNF met carriers. AB - Brain-derived neurotrophic factor (BDNF) modulates the pruning of synaptically silent axonal arbors. The Met allele of the BDNF gene is associated with a reduction in the neurotrophin's activity-dependent release. We used diffusion weighted imaging to construct structural brain networks for 36 healthy subjects with known BDNF genotypes. Through permutation testing we discovered clear differences in connection strength between subjects carrying the Met allele and those homozygotic for the Val allele. We trained a Gaussian process classifier capable of identifying the subjects' allelic group with 86% accuracy and high predictive value. In Met carriers structural connectivity was greatly increased throughout the forebrain, particularly in connections corresponding to the anterior and superior corona radiata as well as corticothalamic and corticospinal projections from the sensorimotor, premotor, and prefrontal portions of the internal capsule. Interhemispheric connectivity was also increased via the corpus callosum and anterior commissure, and extremely high connectivity values were found between inferior medial frontal polar regions via the anterior forceps. We propose that the decreased availability of BDNF leads to deficits in axonal maintenance in carriers of the Met allele, and that this produces mesoscale changes in white matter architecture. PMID- 23935976 TI - A prospective study of bone marrow hematopoietic and mesenchymal stem cells in type 1 Gaucher disease patients. AB - Gaucher disease (GD) is an autosomal recessive disorder characterized by lysosomal glucocerebrosidase (GBA) deficiency leading to hematological and skeletal manifestations. Mechanisms underlying these symptoms have not yet been elucidated. In vivo, bone marrow (BM) mesenchymal stem cells (MSCs) have important role in the regulation of bone mass and in the support of hematopoiesis, thus representing potential candidate that could contribute to the disease. GBA deficiency may also directly impair hematopoietic stem/progenitors cells (HSPCs) intrinsic function and induce hematological defect. In order to evaluate the role of BM stem cells in GD pathophysiology, we prospectively analyzed BM-MSCs and HSPCs properties in a series of 10 patients with type 1 GD. GBA activity was decreased in all tested cell subtypes. GD-MSCs had an impaired growth potential, morphological and cell cycle abnormalities, decreased capacities to differentiate into osteoblasts. Moreover, GD-MSCs secreted soluble factors that stimulated osteoclasts resorbing activities. In vitro and in vivo primitive and mature hematopoiesis were similar between patients and controls. However, GD-MSCs had a lower hematopoietic supportive capacity than those from healthy donors. These data suggest that BM microenvironment is altered in GD and that MSCs are key components of the manifestations observed in GD. PMID- 23935977 TI - A novel approach to accounting for loss to follow-up when estimating the relationship between CD4 Count at ART initiation and mortality. AB - BACKGROUND: While CD4 strongly predicts mortality on antiretroviral therapy (ART), estimates from programmatic data suffer from incomplete patient outcomes. METHODS: We conducted a pooled analysis of one-year mortality data on ART accounting for lost patients. We identified articles reporting one-year mortality by ART initiation CD4 count. We estimated the average mortality among those lost as the value that maximizes the fit of a regression of the natural log of mortality on the natural log of the imputed mean CD4 count in each band. RESULTS: We found 20 studies representing 64,426 subjects and 51 CD4 observations. Without correcting for losses, one-year mortality was >4.8% for all CD4 counts <200 cells/mm(3). When searching over different values for mortality among those lost, the best fitting model occurs at 60% mortality. In this model, those with a CD4<=200 had a one-year mortality above 8.7, while those with a CD4>500 had a one year mortality <6.8%. Comparing those starting ART at 500 vs. 50, one-year mortality risk was reduced by 54% (6.8 vs. 12.5%). Regardless of CD4 count, mortality was substantially higher than when assuming no mortality among those lost, ranging from a 23-94% increase. CONCLUSIONS: Our best fitting regression estimates that every 10% increase in CD4 count at initiation is associated with a 2.8% decline in one-year mortality, including those lost. Our study supports the health benefits of higher thresholds for CD4 count initiation and suggests that reports of programmatic ART outcomes can and should adjust results for mortality among those lost. PMID- 23935978 TI - Contrasting fish behavior in artificial seascapes with implications for resources conservation. AB - Artificial reefs are used by many fisheries managers as a tool to mitigate the impact of fisheries on coastal fish communities by providing new habitat for many exploited fish species. However, the comparison between the behavior of wild fish inhabiting either natural or artificial habitats has received less attention. Thus the spatio-temporal patterns of fish that establish their home range in one habitat or the other and their consequences of intra-population differentiation on life-history remain largely unexplored. We hypothesize that individuals with a preferred habitat (i.e. natural vs. artificial) can behave differently in terms of habitat use, with important consequences on population dynamics (e.g. life history, mortality, and reproductive success). Therefore, using biotelemetry, 98 white seabream (Diplodus sargus) inhabiting either artificial or natural habitats were tagged and their behavior was monitored for up to eight months. Most white seabreams were highly resident either on natural or artificial reefs, with a preference for the shallow artificial reef subsets. Connectivity between artificial and natural reefs was limited for resident individuals due to great inter-habitat distances. The temporal behavioral patterns of white seabreams differed between artificial and natural reefs. Artificial-reef resident fish had a predominantly nocturnal diel pattern, whereas natural-reef resident fish showed a diurnal diel pattern. Differences in diel behavioral patterns of white seabream inhabiting artificial and natural reefs could be the expression of realized individual specialization resulting from differences in habitat configuration and resource availability between these two habitats. Artificial reefs have the potential to modify not only seascape connectivity but also the individual behavioral patterns of fishes. Future management plans of coastal areas and fisheries resources, including artificial reef implementation, should therefore consider the potential effect of habitat modification on fish behavior, which could have key implications on fish dynamics. PMID- 23935979 TI - Hepatitis C virus infection influences the S-methadone metabolite plasma concentration. AB - BACKGROUND AND OBJECTIVES: Heroin-dependent patients typically contract hepatitis C virus (HCV) at a disproportionately high level due to needle exchange. The liver is the primary target organ of HCV infection and also the main organ responsible for drug metabolism. Methadone maintenance treatment (MMT) is a major treatment regimen for opioid dependence. HCV infection may affect methadone metabolism but this has rarely been studied. In our current study, we aimed to test the hypothesis that HCV may influence the methadone dosage and its plasma metabolite concentrations in a MMT cohort from Taiwan. METHODS: A total of 366 MMT patients were recruited. The levels of plasma hepatitis B virus (HBV), HCV, human immunodeficiency virus (HIV) antibodies (Ab), liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were measured along with the urine morphine concentration and amphetamine screening. RESULTS: Of the 352 subjects in our cohort with HCV test records, 95% were found to be positive for plasma anti-HCV antibody. The liver functional parameters of AST (Wilcoxon Rank-Sum test, P = 0.02) and ALT (Wilcoxon Rank-Sum test, P = 0.04), the plasma methadone concentrations (Wilcoxon Rank-Sum test, P = 0.043) and the R-enantiomer of methadone concentrations (Wilcoxon Rank-Sum test, P = 0.032) were significantly higher in the HCV antibody-positive subjects than in the HCV antibody-negative patients, but not the S-EDDP/methadone dose ratio. The HCV levels correlated with the methadone dose (beta= 14.65 and 14.13; P = 0.029 and 0.03) and the S-EDDP/methadone dose ratio (beta= -0.41 and -0.40; P = 0.00084 and 0.002) in both univariate and multivariate regression analyses. CONCLUSIONS: We conclude that HCV may influence the methadone dose and plasma S-EDDP/methadone dose ratio in MMT patients in this preliminary study. PMID- 23935980 TI - Rivermouth alteration of agricultural impacts on consumer tissue delta(15)N. AB - Terrestrial agricultural activities strongly influence riverine nitrogen (N) dynamics, which is reflected in the delta(15)N of riverine consumer tissues. However, processes within aquatic ecosystems also influence consumer tissue delta(15)N. As aquatic processes become more important terrestrial inputs may become a weaker predictor of consumer tissue delta(15)N. In a previous study, this terrestrial-consumer tissue delta(15)N connection was very strong at river sites, but was disrupted by processes occurring in rivermouths (the 'rivermouth effect'). This suggested that watershed indicators of N loading might be accurate in riverine settings, but could be inaccurate when considering N loading to the nearshore of large lakes and oceans. In this study, the rivermouth effect was examined on twenty-five sites spread across the Laurentian Great Lakes. Relationships between agriculture and consumer tissue delta(15)N occurred in both upstream rivers and at the outlets where rivermouths connect to the nearshore zone, but agriculture explained less variation and had a weaker effect at the outlet. These results suggest that rivermouths may sometimes be significant sources or sinks of N, which would cause N loading estimates to the nearshore zone that are typically made at discharge gages further upstream to be inaccurate. Identifying definitively the controls over the rivermouth effect on N loading (and other nutrients) will require integration of biogeochemical and hydrologic models. PMID- 23935981 TI - Lineage analysis of the late otocyst stage mouse inner ear by transuterine microinjection of a retroviral vector encoding alkaline phosphatase and an oligonucleotide library. AB - The mammalian inner ear subserves the special senses of hearing and balance. The auditory and vestibular sensory epithelia consist of mechanically sensitive hair cells and associated supporting cells. Hearing loss and balance dysfunction are most frequently caused by compromise of hair cells and/or their innervating neurons. The development of gene- and cell-based therapeutics will benefit from a thorough understanding of the molecular basis of patterning and cell fate specification in the mammalian inner ear. This includes analyses of cell lineages and cell dispersals across anatomical boundaries (such as sensory versus nonsensory territories). The goal of this study was to conduct retroviral lineage analysis of the embryonic day 11.5(E11.5) mouse otic vesicle. A replication defective retrovirus encoding human placental alkaline phosphatase (PLAP) and a variable 24-bp oligonucleotide tag was microinjected into the E11.5 mouse otocyst. PLAP-positive cells were microdissected from cryostat sections of the postnatal inner ear and subjected to nested PCR. PLAP-positive cells sharing the same sequence tag were assumed to have arisen from a common progenitor and are clonally related. Thirty five multicellular clones consisting of an average of 3.4 cells per clone were identified in the auditory and vestibular sensory epithelia, ganglia, spiral limbus, and stria vascularis. Vestibular hair cells in the posterior crista were related to one another, their supporting cells, and nonsensory epithelial cells lining the ampulla. In the organ of Corti, outer hair cells were related to a supporting cell type and were tightly clustered. By contrast, spiral ganglion neurons, interdental cells, and Claudius' cells were related to cells of the same type and could be dispersed over hundreds of microns. These data contribute new information about the developmental potential of mammalian otic precursors in vivo. PMID- 23935982 TI - RhoA is essential for maintaining normal megakaryocyte ploidy and platelet generation. AB - RhoA plays a multifaceted role in platelet biology. During platelet development, RhoA has been proposed to regulate endomitosis, proplatelet formation, and platelet release, in addition to having a role in platelet activation. These processes were previously studied using pharmacological inhibitors in vitro, which have potential drawbacks, such as non-specific inhibition or incomplete disruption of the intended target proteins. Therefore, we developed a conditional knockout mouse model utilizing the CRE-LOX strategy to ablate RhoA, specifically in megakaryocytes and in platelets to determine its role in platelet development. We demonstrated that deleting RhoA in megakaryocytes in vivo resulted in significant macrothrombocytopenia. RhoA-null megakaryocytes were larger, had higher mean ploidy, and exhibited stiff membranes with micropipette aspiration. However, in contrast to the results observed in experiments relying upon pharmacologic inhibitors, we did not observe any defects in proplatelet formation in megakaryocytes lacking RhoA. Infused RhoA-null megakaryocytes rapidly released platelets, but platelet levels rapidly plummeted within several hours. Our evidence supports the hypothesis that changes in membrane rheology caused infused RhoA-null megakaryocytes to prematurely release aberrant platelets that were unstable. These platelets were cleared quickly from circulation, which led to the macrothrombocytopenia. These observations demonstrate that RhoA is critical for maintaining normal megakaryocyte development and the production of normal platelets. PMID- 23935983 TI - Cognitive and clinical dysfunction, altered MEG resting-state networks and thalamic atrophy in multiple sclerosis. AB - The relation between pathological findings and clinical and cognitive decline in Multiple Sclerosis remains unclear. Here, we tested the hypothesis that altered functional connectivity could provide a missing link between structural findings, such as thalamic atrophy and white matter lesion load, and clinical and cognitive dysfunction. Resting-state magnetoencephalography recordings from 21 MS patients and 17 gender- and age matched controls were projected onto atlas-based regions of-interest using beamforming. Average functional connectivity was computed for each ROI and literature-based resting-state networks using the phase-lag index. Structural measures of whole brain and thalamic atrophy and lesion load were estimated from MRI scans. Global analyses showed lower functional connectivity in the alpha2 band and higher functional connectivity in the beta band in patients with Multiple Sclerosis. Additionally, alpha2 band functional connectivity was lower for the patients in two resting-state networks, namely the default mode network and the visual network. Higher beta band functional connectivity was found in the default mode network and in the temporo-parietal network. Lower alpha2 band functional connectivity in the visual network was related to lower thalamic volumes. Beta band functional connectivity correlated positively with disability scores, most prominently in the default mode network, and correlated negatively with cognitive performance in this network. These findings illustrate the relationship between thalamic atrophy, altered functional connectivity and clinical and cognitive dysfunction in MS, which could serve as a bridge to understand how neurodegeneration is associated with altered functional connectivity and subsequently clinical and cognitive decline. PMID- 23935984 TI - Inter-individual difference in the effect of mirror reflection-induced visual feedback on phantom limb awareness in forearm amputees. AB - OBJECTIVE: To test whether the phantom limb awareness could be altered by observing mirror reflection-induced visual feedback (MVF) in unilateral forearm amputees. METHODS: Ten unilateral forearm amputees were asked to perform bilateral (intact and phantom) synchronous wrist motions with and without MVF. During wrist motion, electromyographic activities in the extensor digitorum longus (EDL) and flexor carpi radialis muscles (FCR) were recorded with bipolar electrodes. Degree of wrist range of motion (ROM) was also recorded by electrogoniometry attached to the wrist joint of intact side. Subjects were asked to answer the degree of attainment of phantom limb motion using a visual analog scale (VAS: ranging from 0 (hard) to 10 (easy)). RESULTS: VAS and ROM were significantly increased by utilizing MVF, and the extent of an enhancement of the VAS and wrist ROM was positively correlated (r = 0.72, p<0.05). Although FCR EMG activity also showed significant enhancement by MVF, this was not correlated with the changes of VAS and ROM. Interestingly, while we found negative correlation between EDL EMG activity and wrist ROM, MVF generally affected to be increasing both EDL EMG and ROM. CONCLUSIONS: Although there was larger extent of variability in the effect of MVF on phantom limb awareness, MVF has a potential to enhance phantom limb awareness, in case those who has a difficulty for the phantom limb motion. The present result suggests that the motor command to the missing limb can be re-activated by an appropriate therapeutic strategy such as mirror therapy. PMID- 23935985 TI - Development of an epidermal growth factor derivative with EGFR blocking activity. AB - The members of the epidermal growth factor (EGF)/ErbB family are prime targets for cancer therapy. However, the therapeutic efficiency of the existing anti-ErbB agents is limited. Thus, identifying new molecules that inactivate the ErbB receptors through novel strategies is an important goal on cancer research. In this study we have developed a shorter form of human EGF (EGFt) with a truncated C-terminal as a novel EGFR inhibitor. EGFt was designed based on the superimposition of the three-dimensional structures of EGF and the Potato Carboxypeptidase Inhibitor (PCI), an EGFR blocker previously described by our group. The peptide was produced in E. coli with a high yield of the correctly folded peptide. EGFt showed specificity and high affinity for EGFR but induced poor EGFR homodimerization and phosphorylation. Interestingly, EGFt promoted EGFR internalization and translocation to the cell nucleus although it did not stimulate the cell growth. In addition, EGFt competed with EGFR native ligands, inhibiting the proliferation of cancer cells. These data indicate that EGFt may be a potential EGFR blocker for cancer therapy. In addition, the lack of EGFR mediated growth-stimulatory activity makes EGFt an excellent delivery agent to target toxins to tumours over-expressing EGFR. PMID- 23935986 TI - Dysregulation of mitochondrial quality control processes contribute to sarcopenia in a mouse model of premature aging. AB - Mitochondrial DNA (mtDNA) mutations lead to decrements in mitochondrial function and accelerated rates of these mutations has been linked to skeletal muscle loss (sarcopenia). The purpose of this study was to investigate the effect of mtDNA mutations on mitochondrial quality control processes in skeletal muscle from animals (young; 3-6 months and older; 8-15 months) expressing a proofreading deficient version of mtDNA polymerase gamma (PolG). This progeroid aging model exhibits elevated mtDNA mutation rates, mitochondrial dysfunction, and a premature aging phenotype that includes sarcopenia. We found increased expression of the mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and its target proteins, nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (Tfam) in PolG animals compared to wild-type (WT) (P<0.05). Muscle from older PolG animals displayed higher mitochondrial fission protein 1 (Fis1) concurrent with greater induction of autophagy, as indicated by changes in Atg5 and p62 protein content (P<0.05). Additionally, levels of the Tom22 import protein were higher in PolG animals when compared to WT (P<0.05). In contrast, muscle from normally-aged animals exhibited a distinctly different expression profile compared to PolG animals. Older WT animals appeared to have higher fusion (greater Mfn1/Mfn2, and lower Fis1) and lower autophagy (Beclin-1 and p62) compared to young WT suggesting that autophagy is impaired in aging muscle. In conclusion, muscle from mtDNA mutator mice display higher mitochondrial fission and autophagy levels that likely contribute to the sarcopenic phenotype observed in premature aging and this differs from the response observed in normally-aged muscle. PMID- 23935987 TI - A mutation in mouse Pak1ip1 causes orofacial clefting while human PAK1IP1 maps to 6p24 translocation breaking points associated with orofacial clefting. AB - Orofacial clefts are among the most common birth defects and result in an improper formation of the mouth or the roof of the mouth. Monosomy of the distal aspect of human chromosome 6p has been recognized as causative in congenital malformations affecting the brain and cranial skeleton including orofacial clefts. Among the genes located in this region is PAK1IP1, which encodes a nucleolar factor involved in ribosomal stress response. Here, we report the identification of a novel mouse line that carries a point mutation in the Pak1ip1 gene. Homozygous mutants show severe developmental defects of the brain and craniofacial skeleton, including a median orofacial cleft. We recovered this line of mice in a forward genetic screen and named the allele manta-ray (mray). Our findings prompted us to examine human cases of orofacial clefting for mutations in the PAK1IP1 gene or association with the locus. No deleterious variants in the PAK1IP1 gene coding region were recognized, however, we identified a borderline association effect for SNP rs494723 suggesting a possible role for the PAK1IP1 gene in human orofacial clefting. PMID- 23935988 TI - Intra-peritoneal hyperthermia combining alpha-galactosylceramide in the treatment of ovarian cancer. AB - The purpose of this study was to investigate the anti-tumor effect and potential mechanisms of i.p. hyperthermia in combination with alpha-galactosylceramide (alpha-GalCer) for the treatment of ovarian cancer. In this study, immuno competent tumor models were established using murine ovarian cancer cell lines and treated with i.p. hyperthermia combining alpha-GalCer. Th1/Th2 cytokine expression profiles in the serum, NK cell cytotoxicity and phagocytic activities of dendritic cells (DCs) were assayed. We also analyzed the number of CD8(+)/IFN gamma(+) tumor specific cytotoxic T cells, as well as the tumor growth based on depletion of lymphocyte sub-population. Therapeutic effect on those ovarian tumors was monitored by a non-invasive luminescent imaging system. Intra peritoneal hyperthermia induced significant pro-inflammatory cytokines expression, and sustained the response of NK and DCs induced by alpha-GalCer treatment. The combination treatment enhanced the cytotoxic T lymphocyte (CTL) immune response in two mouse ovarian cancer models. This novel treatment modality by combination of hyperthermia and glycolipid provides a pronounced anti-tumor immune response and better survival. In conclusion, intra-peritoneal hyperthermia enhanced the pro-inflammatory cytokine secretion and phagocytic activity of DCs stimulated by alpha-GalCer. The subsequent CTL immune response induced by alpha GalCer was further strengthened by combining with i.p. hyperthermia. Both innate and adaptive immunities were involved and resulted in a superior therapeutic effect in treating the ovarian cancer. PMID- 23935989 TI - Fibrotic remodeling of the extracellular matrix through a novel (engineered, dual function) antibody reactive to a cryptic epitope on the N-terminal 30 kDa fragment of fibronectin. AB - Fibrosis is characterized by excessive accumulation of scar tissue as a result of exaggerated deposition of extracellular matrix (ECM), leading to tissue contraction and impaired function of the organ. Fibronectin (Fn) is an essential component of the ECM, and plays an important role in fibrosis. One such fibrotic pathology is that of proliferative vitreoretinopathy (PVR), a sight-threatening complication which develops as a consequence of failure of surgical repair of retinal detachment. Such patients often require repeated surgeries for retinal re attachment; therefore, a preventive measure for PVR is of utmost importance. The contractile membranes formed in PVR, are composed of various cell types including the retinal pigment epithelial cells (RPE); fibronectin is an important constituent of the ECM surrounding these cells. Together with the vitreous, fibronectin creates microenvironments in which RPE cells proliferate. We have successfully developed a dual-action, fully human, fibronectin-specific single chain variable fragment antibody (scFv) termed Fn52RGDS, which acts in two ways: i) binds to cryptic sites in fibronectin, and thereby prevents its self polymerization/fibrillogenesis, and ii) interacts with the cell surface receptors, ie., integrins (through an attached "RGD" sequence tag), and thereby blocks the downstream cell signaling events. We demonstrate the ability of this antibody to effectively reduce some of the hallmark features of fibrosis- migration, adhesion, fibronectin polymerization, matrix metalloprotease (MMP) expression, as well as reduction of collagen gel contraction (a model of fibrotic tissue remodeling). The data suggests that the antibody can be used as a rational, novel anti-fibrotic candidate. PMID- 23935990 TI - Influence of initial treatment modality on long-term control of chronic idiopathic urticaria. AB - BACKGROUND: Chronic idiopathic urticaria (CIU) is a common cutaneous disorder but the influence of initial treatment modality on long-term control is not known. The aim of this study was to evaluate clinical features, and the influence of initial treatment modality on long-term control. METHODS AND RESULTS: 641 CIU patients were enrolled from the allergy clinic in a tertiary referral hospital. Disease duration, aggravating factors and treatment modality at each visit were evaluated. Times required to reach a controlled state were analyzed according to initial treatment modality, using Kaplan-Meier survival curves, the Cox proportional-hazards model, and propensity scores. Female to male ratio was 1.7: 1; mean age at onset was 40.5 years. The most common aggravating factors were food (33.5%), stress (31.5%) and fatigue (21.6%). Most patients (82.2%) used H1 antihistamines alone as initial treatment while 17% used a combination treatment with oral corticosteroids. There was no significant difference in the time taken to reach a controlled state between patients treated with single vs multiple H1 antihistamines or between those who received H1-antihistamine monotherapy vs. a combination therapy with oral corticosteroids. CONCLUSION: The time required to control CIU is not reduced by use of multiple H1-antihistamines or oral corticosteroids in the initial treatment. PMID- 23935991 TI - Adaptation of pelage color and pigment variations in Israeli subterranean blind mole rats, Spalax ehrenbergi [corrected]. AB - BACKGROUND: Concealing coloration in rodents is well established. However, only a few studies examined how soil color, pelage color, hair-melanin content, and genetics (i.e., the causal chain) synergize to configure it. This study investigates the causal chain of dorsal coloration in Israeli subterranean blind mole rats, Spalax ehrenbergi. METHODS: We examined pelage coloration of 128 adult animals from 11 populations belonging to four species of Spalax ehrenbergi superspecies (Spalax galili, Spalax golani, Spalax carmeli, and Spalax judaei) and the corresponding coloration of soil samples from the collection sites using a digital colorimeter. Additionally, we quantified hair-melanin contents of 67 animals using HPLC and sequenced the MC1R gene in 68 individuals from all four mole rat species. RESULTS: Due to high variability of soil colors, the correlation between soil and pelage color coordinates was weak and significant only between soil hue and pelage lightness. Multiple stepwise forward regression revealed that soil lightness was significantly associated with all pelage color variables. Pelage color lightness among the four species increased with the higher southward aridity in accordance to Gloger's rule (darker in humid habitats and lighter in arid habitats). Darker and lighter pelage colors are associated with darker basalt and terra rossa, and lighter rendzina soils, respectively. Despite soil lightness varying significantly, pelage lightness and eumelanin converged among populations living in similar soil types. Partial sequencing of the MC1R gene identified three allelic variants, two of which were predominant in northern species (S. galili and S. golani), and the third was exclusive to southern species (S. carmeli and S. judaei), which might have caused the differences found in pheomelanin/eumelanin ratio. CONCLUSION/SIGNIFICANCE: Darker dorsal pelage in darker basalt and terra rossa soils in the north and lighter pelage in rendzina and loess soils in the south reflect the combined results of crypsis and thermoregulatory function following Gloger's rule. PMID- 23935992 TI - A role for MeCP2 in switching gene activity via chromatin unfolding and HP1gamma displacement. AB - Methyl-CpG-binding protein 2 (MeCP2) is generally considered to act as a transcriptional repressor, whereas recent studies suggest that MeCP2 is also involved in transcription activation. To gain insight into this dual function of MeCP2, we assessed the impact of MeCP2 on higher-order chromatin structure in living cells using mammalian cell systems harbouring a lactose operator and reporter gene-containing chromosomal domain to assess the effect of lactose repressor-tagged MeCP2 (and separate MeCP2 domains) binding in living cells. Our data reveal that targeted binding of MeCP2 elicits extensive chromatin unfolding. MeCP2-induced chromatin unfolding is triggered independently of the methyl cytosine-binding domain. Interestingly, MeCP2 binding triggers the loss of HP1gamma at the chromosomal domain and an increased HP1gamma mobility, which is not observed for HP1alpha and HP1beta. Surprisingly, MeCP2-induced chromatin unfolding is not associated with transcriptional activation. Our study suggests a novel role for MeCP2 in reorganizing chromatin to facilitate a switch in gene activity. PMID- 23935993 TI - MiR-146a regulates SOD2 expression in H2O2 stimulated PC12 cells. AB - SOD2 (superoxide dismutase 2) is one of the endogenous antioxidant enzymes that protect against reactive oxygen species. While explorations of SOD2 expression regulation are mainly focused on transcriptional and post-translational activation, there are few reports about the post-transcriptional regulation of SOD2. MicroRNAs (miRNAs) are 21nt-25nt (nucleotide) small noncoding RNAs that have emerged as indispensable regulators of gene expression. Here we show that miR-146a, a widely expressed miRNA, is up-regulated by H2O2-induced stress. By sequence analysis we found a binding site for miR-146a in the sod2 mRNA 3'UTR, and a luciferase reporter assay confirmed that miR-146a can interact with this sod2 regulatory region. Our results further show that miR-146a could down regulate the SOD2 protein expression, and antisense-miR-146a could reverse the decrease of both the SOD2 level and cell viability in H2O2 treated PC12 cells. In conclusion, here we have identified a novel function of miR-146a in the post transcriptional regulation of SOD2 expression. PMID- 23935994 TI - FGFR1OP tagSNP but not CCR6 polymorphisms are associated with Vogt-Koyanagi Harada syndrome in Chinese Han. AB - BACKGROUND: Polymorphisms of the CC chemokine receptor 6 (CCR6) and FGFR10P tagSNP (locus close to CCR6) at 6q27 have recently been reported to be associated with the susceptibility to several immune-related diseases. This study was designed to determine the association of CCR6 and FGFR10P (tag)SNPs with Vogt Koyanagi-Harada (VKH) syndrome, an autoimmune disease directed against melanocytes, in two independent Chinese Han populations. METHODOLOGY/PRINCIPAL FINDINGS: A total of 601 VKH patients and 725 healthy controls from two Chinese Han populations were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. Hardy-Weinberg equilibrium was tested using the chi(2) test. Genotype frequencies were estimated by direct counting. Allele and genotype frequencies were compared between patients and controls using the chi(2) test. The frequency of the A allele of rs2301436 was significantly higher both in Cohort 1 and Cohort 2 as compared with two separate controls (P = 0.044; P = 0.049, respectively). The significance was lost after Bonferroni correction in both cohorts (Pc = 0.516; Pc = 0.392, respectively). The frequency of the A allele was significantly higher in the combined patient group as compared with all controls before and after Bonferroni correction (P = 0.005, Pc = 0.025). The genotype and allele frequencies of rs3093024, rs6902119, rs3093023 and rs968334 were not different between patients with VKH and healthy controls based on analysis either for both cohorts or for the patients and controls in total. Analysis according to extra ocular clinical findings including headache, alopecia and poliosis, vitiligo and tinnitus did not show any association of the five polymorphisms with these parameters. CONCLUSION: These results suggest that the rs2301436 tagSNP of FGFR10P is positively associated with susceptibility to VKH syndrome in the tested Chinese Han populations. No association was found for the tested CCR6 SNPs. PMID- 23935995 TI - Are cellulosome scaffolding protein CipC and CBM3-containing protein HycP, involved in adherence of Clostridium cellulolyticum to cellulose? AB - Clostridium cellulolyticum, a mesophilic anaerobic bacterium, produces highly active enzymatic complexes called cellulosomes. This strain was already shown to bind to cellulose, however the molecular mechanism(s) involved is not known. In this context we focused on the gene named hycP, encoding a 250-kDa protein of unknown function, containing a Family-3 Carbohydrate Binding Module (CBM3) along with 23 hyaline repeat modules (HYR modules). In the microbial kingdom the gene hycP is only found in C. cellulolyticum and the very close strain recently sequenced Clostridium sp BNL1100. Its presence in C. cellulolyticum guided us to analyze its function and its putative role in adhesion of the cells to cellulose. The CBM3 of HycP was shown to bind to crystalline cellulose and was assigned to the CBM3b subfamily. No hydrolytic activity on cellulose was found with a mini protein displaying representative domains of HycP. A C. cellulolyticum inactivated hycP mutant strain was constructed, and we found that HycP is neither involved in binding of the cells to cellulose nor that the protein has an obvious role in cell growth on cellulose. We also characterized the role of the cellulosome scaffolding protein CipC in adhesion of C. cellulolyticum to cellulose, since cellulosome scaffolding protein has been proposed to mediate binding of other cellulolytic bacteria to cellulose. A second mutant was constructed, where cipC was inactivated. We unexpectedly found that CipC is only partly involved in binding of C. cellulolyticum to cellulose. Other mechanisms for cellulose adhesion may therefore exist in C. cellulolyticum. In addition, no cellulosomal protuberances were observed at the cellular surface of C. cellulolyticum, what is in contrast to reports from several other cellulosomes producing strains. These findings may suggest that C. cellulolyticum has no dedicated molecular mechanism to aggregate the cellulosomes at the cellular surface. PMID- 23935996 TI - Genetic variants in hormone-related genes and risk of breast cancer. AB - Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk. PMID- 23935997 TI - Lower respiratory tract infections associated with rhinovirus during infancy and increased risk of wheezing during childhood. A cohort study. AB - BACKGROUND AND OBJECTIVES: Although association between respiratory syncytial virus infection and later asthma development has been established, little is known about the role of other respiratory viruses. Rhinovirus was considered a mild pathogen of the upper respiratory tract but current evidence suggests that rhinovirus is highly prevalent among children with lower respiratory tract infections (LRTI). The aim of the study was to evaluate whether LRTI hospitalization associated with rhinovirus during infancy was associated with an increased risk of wheezing - a proxy measure of asthma - during childhood. METHODS: During a 12 months period, all infants <1 year admitted to Manhica District Hospital with symptoms of LRTI who survived the LRTI episode, were enrolled in the study cohort. Nasopharyngeal aspirates were collected on admission for viral determination and study infants were classified according to presence or not of rhinovirus. The study cohort was passively followed-up at the Manhica District Hospital for up to 4 years and 9 months to evaluate the association between LRTI associated with rhinovirus in infancy and wheezing during childhood. FINDINGS AND CONCLUSIONS: A total of 220 infants entered the cohort; 25% of them had rhinovirus detected during the LRTI episode as opposed to 75% who tested negative for rhinovirus. After adjusting for sex and age and HIV infection at recruitment, infants hospitalized with LRTI associated with rhinovirus had higher incidence of subsequent visits with wheezing within the year following hospitalization [Rate ratio=1.68, (95% confidence interval=1.02 2.75); Wald test p-value = 0.039]. No evidence of increased incidence rate of visits with wheezing was observed for the remaining follow-up period. Our data suggest a short term increased risk of wheezing after an initial episode of LRTI with RV. PMID- 23935998 TI - Structure-dynamics relationships in bursting neuronal networks revealed using a prediction framework. AB - The question of how the structure of a neuronal network affects its functionality has gained a lot of attention in neuroscience. However, the vast majority of the studies on structure-dynamics relationships consider few types of network structures and assess limited numbers of structural measures. In this in silico study, we employ a wide diversity of network topologies and search among many possibilities the aspects of structure that have the greatest effect on the network excitability. The network activity is simulated using two point-neuron models, where the neurons are activated by noisy fluctuation of the membrane potential and their connections are described by chemical synapse models, and statistics on the number and quality of the emergent network bursts are collected for each network type. We apply a prediction framework to the obtained data in order to find out the most relevant aspects of network structure. In this framework, predictors that use different sets of graph-theoretic measures are trained to estimate the activity properties, such as burst count or burst length, of the networks. The performances of these predictors are compared with each other. We show that the best performance in prediction of activity properties for networks with sharp in-degree distribution is obtained when the prediction is based on clustering coefficient. By contrast, for networks with broad in-degree distribution, the maximum eigenvalue of the connectivity graph gives the most accurate prediction. The results shown for small ([Formula: see text]) networks hold with few exceptions when different neuron models, different choices of neuron population and different average degrees are applied. We confirm our conclusions using larger ([Formula: see text]) networks as well. Our findings reveal the relevance of different aspects of network structure from the viewpoint of network excitability, and our integrative method could serve as a general framework for structure-dynamics studies in biosciences. PMID- 23936000 TI - Longer leukocyte telomeres are associated with ultra-endurance exercise independent of cardiovascular risk factors. AB - Telomere length is recognized as a marker of biological age, and shorter mean leukocyte telomere length is associated with increased risk of cardiovascular disease. It is unclear whether repeated exposure to ultra-endurance aerobic exercise is beneficial or detrimental in the long-term and whether it attenuates biological aging. We quantified 67 ultra-marathon runners' and 56 apparently healthy males' leukocyte telomere length (T/S ratio) using real-time quantitative PCR. The ultra-marathon runners had 11% longer telomeres (T/S ratio) than controls (ultra-marathon runners: T/S ratio = 3.5+/-0.68, controls: T/S ratio = 3.1+/-0.41; beta = 0.40, SE = 0.10, P = 1.4*10(-4)) in age-adjusted analysis. The difference remained statistically significant after adjustment for cardiovascular risk factors (P = 2.2*10(-4)). The magnitude of this association translates into 16.2+/-0.26 years difference in biological age and approximately 324-648bp difference in leukocyte telomere length between ultra-marathon runners and healthy controls. Neither traditional cardiovascular risk factors nor markers of inflammation/adhesion molecules explained the difference in leukocyte telomere length between ultra-marathon runners and controls. Taken together these data suggest that regular engagement in ultra-endurance aerobic exercise attenuates cellular aging. PMID- 23935999 TI - A network integration approach to predict conserved regulators related to pathogenicity of influenza and SARS-CoV respiratory viruses. AB - Respiratory infections stemming from influenza viruses and the Severe Acute Respiratory Syndrome corona virus (SARS-CoV) represent a serious public health threat as emerging pandemics. Despite efforts to identify the critical interactions of these viruses with host machinery, the key regulatory events that lead to disease pathology remain poorly targeted with therapeutics. Here we implement an integrated network interrogation approach, in which proteome and transcriptome datasets from infection of both viruses in human lung epithelial cells are utilized to predict regulatory genes involved in the host response. We take advantage of a novel "crowd-based" approach to identify and combine ranking metrics that isolate genes/proteins likely related to the pathogenicity of SARS CoV and influenza virus. Subsequently, a multivariate regression model is used to compare predicted lung epithelial regulatory influences with data derived from other respiratory virus infection models. We predicted a small set of regulatory factors with conserved behavior for consideration as important components of viral pathogenesis that might also serve as therapeutic targets for intervention. Our results demonstrate the utility of integrating diverse 'omic datasets to predict and prioritize regulatory features conserved across multiple pathogen infection models. PMID- 23936001 TI - Melittin suppresses HIF-1alpha/VEGF expression through inhibition of ERK and mTOR/p70S6K pathway in human cervical carcinoma cells. AB - OBJECTIVE: Melittin (MEL), a major component of bee venom, has been associated with various diseases including arthritis, rheumatism and various cancers. In this study, the anti-angiogenic effects of MEL in CaSki cells that were responsive to the epidermal growth factor (EGF) were examined. METHODOLOGY/PRINCIPAL FINDINGS: MEL decreased the EGF-induced hypoxia-inducible factor-1alpha (HIF-1alpha) protein and significantly regulated angiogenesis and tumor progression. We found that inhibition of the HIF-1alpha protein level is due to the shortened half-life by MEL. Mechanistically, MEL specifically inhibited the EGF-induced HIF-1alpha expression by suppressing the phosphorylation of ERK, mTOR and p70S6K. It also blocked the EGF-induced DNA binding activity of HIF-1alpha and the secretion of the vascular endothelial growth factor (VEGF). Furthermore, the chromatin immunoprecipitation (ChIP) assay revealed that MEL reduced the binding of HIF-1alpha to the VEGF promoter HRE region. The anti-angiogenesis effects of MEL were confirmed through a matrigel plus assay. CONCLUSIONS: MEL specifically suppressed EGF-induced VEGF secretion and new blood vessel formation by inhibiting HIF-1alpha. These results suggest that MEL may inhibit human cervical cancer progression and angiogenesis by inhibiting HIF-1alpha and VEGF expression. PMID- 23936002 TI - A comparison of Aggregatibacter actinomycetemcomitans (Aa) virulence traits in a rat model for periodontal disease. AB - Our aim was to explore the effects of Cytolethal Distending toxin (Cdt) in a well established rat model of periodontal disease where leukotoxin (LtxA) was thought to have no known effect. In vitro studies, were used to assess CdtB activity using Aa Leukotoxin as a negative control. These studies showed that both CdtB and LtxA (unexpectedly) exerted significant effects on CD4(+) T cells. As a result we decided to compare the effects of these two prominent Aa virulence factors on bone loss using our rat model of Aa-induced periodontitis. In this model, Aa strains, mutant in cdtB and ltxA, were compared to their parent non mutant strains and evaluated for colonization, antibody response to Aa, bone loss and disease. We found that bone loss/disease caused by the ltxA mutant strain, in which cdtB was expressed, was significantly less (p<0.05) than that due to the wild type strain. On the other hand, the disease caused by cdtB mutant strain, in which ltxA was expressed, was not significantly different from the wild type strain. This data indicates that Aa LtxA exerts a greater effect on bone loss than Cdt in this rat model of periodontal disease and supports the utility of this model to dissect specific virulence factors as they relate to immunopathology in studies of Aa-induced disease. PMID- 23936004 TI - Very long-chain acyl-CoA synthetase 3: overexpression and growth dependence in lung cancer. AB - Lung cancer is the leading cause of cancer deaths worldwide. In the United States, only one in six lung cancer patients survives five years after diagnosis. These statistics may improve if new therapeutic targets are identified. We previously reported that an enzyme of fatty acid metabolism, very long-chain acyl CoA synthetase 3 (ACSVL3), is overexpressed in malignant glioma, and that depleting glioblastoma cells of ACSVL3 diminishes their malignant properties. To determine whether ACSVL3 expression was also increased in lung cancer, we studied tumor histologic sections and lung cancer cell lines. Immunohistochemical analysis of normal human lung showed moderate ACSVL3 expression only in bronchial epithelial cells. In contrast, all of 69 different lung tumors tested, including adeno-, squamous cell, large cell, and small cell carcinomas, had robustly elevated ACSVL3 levels. Western blot analysis of lung cancer cell lines derived from these tumor types also had significantly increased ACSVL3 protein compared to normal bronchial epithelial cells. Decreasing the growth rate of lung cancer cell lines did not change ACSVL3 expression. However, knocking down ACSVL3 expression by RNA interference reduced cell growth rates in culture by 65-76%, and the ability of tumor cells to form colonies in soft agar suspension by 65 80%. We also conducted studies to gain a better understanding of the biochemical properties of human ACSVL3. ACSVL3 mRNA was detected in many human tissues, but the expression pattern differed somewhat from that of the mouse. The enzyme activated long- and very long-chain saturated fatty acid substrates, as well as long-chain mono- and polyunsaturated fatty acids to their respective coenzyme A derivatives. Endogenous human ACSVL3 protein was found in a punctate subcellular compartment that partially colocalized with mitochondria as determined by immunofluorescence microscopy and subcellular fractionation. From these studies, we conclude that ACSVL3 is a promising new therapeutic target in lung cancer. PMID- 23936003 TI - Porcine reproductive and respiratory syndrome virus nonstructural protein 4 induces apoptosis dependent on its 3C-like serine protease activity. AB - Porcine reproductive and respiratory syndrome (PRRS) is a highly contagious disease in pigs caused by PRRS virus (PRRSV). Although PRRSV infection-induced cell apoptosis has been established, the related viral protein is still unknown. Here, we reported that PRRSV nonstructural protein 4 (nsp4) was a critical apoptosis inducer. Nsp4 could activate caspase-3, -8, and -9. Using truncated constructs without different domains in nsp4, we demonstrated that the full length of nsp4 structure was required for its apoptosis-inducing activity. Furthermore, using site-directed mutagenesis to inactivate the 3C-like serine protease activity of nsp4, we showed that nsp4-induced apoptosis was dependent on its serine protease activity. The ability of nsp4 to induce apoptosis was significantly impaired by His39, Asp64, and Ser118 mutations, suggesting that His39, Asp64, and Ser118 were essential for nsp4 to trigger apoptosis. In conclusion, our present work showed that PRRSV nsp4 could induce apoptosis in host cells and might be partially responsible for the apoptosis induced by PRRSV infection. PRRSV 3C-like protease-mediated apoptosis represents the first report in the genus Arterivirus, family Arteriviridae. PMID- 23936005 TI - Current analogues of future climate indicate the likely response of a sensitive montane tropical avifauna to a warming world. AB - Among birds, tropical montane species are likely to be among the most vulnerable to climate change, yet little is known about how climate drives their distributions, nor how to predict their likely responses to temperature increases. Correlative models of species' environmental niches have been widely used to predict changes in distribution, but direct tests of the relationship between key variables, such as temperature, and species' actual distributions are few. In the absence of historical data with which to compare observations and detect shifts, space-for-time substitutions, where warmer locations are used as analogues of future conditions, offer an opportunity to test for species' responses to climate. We collected density data for rainforest birds across elevational gradients in northern and southern subregions within the Australian Wet Tropics (AWT). Using environmental optima calculated from elevational density profiles, we detected a significant elevational difference between the two regions in ten of 26 species. More species showed a positive (19 spp.) than negative (7 spp.) displacement, with a median difference of ~80.6 m across the species analysed that is concordant with that expected due to latitudinal temperature differences (~75.5 m). Models of temperature gradients derived from broad-scale climate surfaces showed comparable performance to those based on in situ measurements, suggesting the former is sufficient for modeling impacts. These findings not only confirm temperature as an important factor driving elevational distributions of these species, but also suggest species will shift upslope to track their preferred environmental conditions. Our approach uses optima calculated from elevational density profiles, offering a data-efficient alternative to distribution limits for gauging climate constraints, and is sensitive enough to detect distribution shifts in this avifauna in response to temperature changes of as little as 0.4 degrees. We foresee important applications in the urgent task of detecting and monitoring impacts of climate change on montane tropical biodiversity. PMID- 23936006 TI - A twin-cysteine motif in the V2 region of gp120 is associated with SIV envelope trimer stabilization. AB - The V1 and V2 variable regions of the primate immunodeficiency viruses contribute to the trimer association domain of the gp120 exterior envelope glycoprotein. A pair of V2 cysteine residues at 183 and 191 ("twin cysteines") is present in several simian immunodeficiency viruses, human immunodeficiency virus type 2 (HIV 2) and some SIV(cpz) lineages, but not in HIV-1. To examine the role of this potentially disulfide-bonded twin-cysteine motif, the cysteine residues in the SIVmac239 envelope glycoproteins were individually and pairwise substituted by alanine residues. All of the twin-cysteine mutants exhibited decreases in gp120 association with the Env trimer, membrane-fusing activity, and ability to support virus entry. Thus, the twin-cysteine motif plays a role in Env trimer stabilization in SIV and may do so in HIV-2 and some SIV(cpz) as well. This implies that HIV-1 lost the twin-cysteines, and may have relatively unstable Env trimers compared to SIV and HIV-2. PMID- 23936007 TI - Tuning of thioredoxin redox properties by intramolecular hydrogen bonds. AB - Thioredoxin-like proteins contain a characteristic C-x-x-C active site motif and are involved in a large number of biological processes ranging from electron transfer, cellular redox level maintenance, and regulation of cellular processes. The mechanism for deprotonation of the buried C-terminal active site cysteine in thioredoxin, necessary for dissociation of the mixed-disulfide intermediate that occurs under thiol/disulfide mediated electron transfer, is not well understood for all thioredoxin superfamily members. Here we have characterized a 8.7 kD thioredoxin (BC3987) from Bacillus cereus that unlike the typical thioredoxin appears to use the conserved Thr8 side chain near the unusual C-P-P-C active site to increase enzymatic activity by forming a hydrogen bond to the buried cysteine. Our hypothesis is based on biochemical assays and thiolate pKa titrations where the wild type and T8A mutant are compared, phylogenetic analysis of related thioredoxins, and QM/MM calculations with the BC3987 crystal structure as a precursor for modeling of reduced active sites. We suggest that our model applies to other thioredoxin subclasses with similar active site arrangements. PMID- 23936009 TI - Simple and versatile molecular method of copy-number measurement using cloned competitors. AB - Variations and alterations of copy numbers (CNVs and CNAs) carry disease susceptibility and drug responsiveness implications. Although there are many molecular methods to measure copy numbers, sensitivity, reproducibility, cost, and time issues remain. In the present study, we were able to solve those problems utilizing our modified real competitive PCR method with cloned competitors (mrcPCR). First, the mrcPCR for ERBB2 copy number was established, and the results were comparable to current standard methods but with a shorter assay time and a lower cost. Second, the mrcPCR assays for 24 drug-target genes were established, and the results in a panel of NCI-60 cells were comparable to those from real-time PCR and microarray. Third, the mrcPCR results for FCGR3A and the FCGR3B CNVs were comparable to those by the paralog ratio test (PRT), but without PRT's limitations. These results suggest that mrcPCR is comparable to the currently available standard or the most sensitive methods. In addition, mrcPCR would be invaluable for measurement of CNVs in genes with variants of similar structures, because combination of the other methods is not necessary, along with its other advantages such as short assay time, small sample amount requirement, and applicability to all sequences and genes. PMID- 23936008 TI - Nucleic acid scavenging polymers inhibit extracellular DNA-mediated innate immune activation without inhibiting anti-viral responses. AB - Toll-like receptor (TLR) family members, 3, 7 and 9 are key components in initiation and progression of autoimmune disorders such as systemic lupus erythematosus (SLE). These TLRs are often referred to as nucleic acid-sensing TLRs based on their ability to recognize DNAs or RNAs produced by pathogens or damaged cells. During autoimmune disease progression these receptors recognize self nucleic acids as well as self nucleic acid-containing complexes and contribute to inflammatory cytokine production and subsequent enhancement of serum autoantibody levels. We have recently discovered that nucleic-acid scavenging polymers (NASPs) can neutralize the proinflammatory effects of nucleic acids. Here, we begin to explore what effects such NASPs have on normal immune function. We show that such NASPs can inhibit TLR activation without affecting nucleic acid-independent T cell activation. Moreover, we observe that stimulation of immune cells by encapsulated nucleic acids, such as those found in viral particles, is unaffected by NASPs. Thus NASPs only limit the activation of the immune system by accessible extra-cellular nucleic acid and do not engender non specific immune suppression. These important findings suggest that NASPs represent a new approach toward anti-inflammatory drug development as these agents can potentially be utilized to block overt autoimmune disorders and inflammation while allowing normal immune responses to occur. PMID- 23936010 TI - 4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation. AB - Recent studies have proposed that n-3 polyunsaturated fatty acids (n-3 PUFAs) have direct antioxidant and anti-inflammatory effects in vascular tissue, explaining their cardioprotective effects. However, the molecular mechanisms are not yet fully understood. We tested whether n-3 PUFAs showed antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcriptional factor for antioxidant genes. C57BL/6 or Nrf2(-/-) mice were fed a fish-oil diet for 3 weeks. Fish-oil diet significantly increased the expression of heme oxygenase-1 (HO-1), and endothelium-dependent vasodilation in the aorta of C57BL/6 mice, but not in the Nrf2(-/-) mice. Furthermore, we observed that 4-hydroxy hexenal (4-HHE), an end-product of n-3 PUFA peroxidation, was significantly increased in the aorta of C57BL/6 mice, accompanied by intra aortic predominant increase in docosahexaenoic acid (DHA) rather than that in eicosapentaenoic acid (EPA). Human umbilical vein endothelial cells were incubated with DHA or EPA. We found that DHA, but not EPA, markedly increased intracellular 4-HHE, and nuclear expression and DNA binding of Nrf2. Both DHA and 4-HHE also increased the expressions of Nrf2 target genes including HO-1, and the siRNA of Nrf2 abolished these effects. Furthermore, DHA prevented oxidant-induced cellular damage or reactive oxygen species production, and these effects were disappeared by an HO-1 inhibitor or the siRNA of Nrf2. Thus, we found protective effects of DHA through Nrf2 activation in vascular tissue, accompanied by intra vascular increases in 4-HHE, which may explain the mechanism of the cardioprotective effects of DHA. PMID- 23936011 TI - Glycogen phosphorylase inhibitor N-(3,5-dimethyl-Benzoyl)-N'-(beta-D glucopyranosyl)urea improves glucose tolerance under normoglycemic and diabetic conditions and rearranges hepatic metabolism. AB - Glycogen phosphorylase (GP) catalyzes the breakdown of glycogen and largely contributes to hepatic glucose production making GP inhibition an attractive target to modulate glucose levels in diabetes. Hereby we present the metabolic effects of a novel, potent, glucose-based GP inhibitor (KB228) tested in vitro and in vivo under normoglycemic and diabetic conditions. KB228 administration enhanced glucose sensitivity in chow-fed and obese, diabetic mice that was a result of higher hepatic glucose uptake. Besides improved glucose sensitivity, we have observed further unexpected metabolic rearrangements. KB228 administration increased oxygen consumption that was probably due to the overexpression of uncoupling protein-2 (UCP2) that was observed in animal and cellular models. Furthermore, KB228 treatment induced mammalian target of rapamycin complex 2 (mTORC2) in mice. Our data demonstrate that glucose based GP inhibitors are capable of reducing glucose levels in mice under normo and hyperglycemic conditions. Moreover, these GP inhibitors induce accommodation in addition to GP inhibition--such as enhanced mitochondrial oxidation and mTORC2 signaling--to cope with the glucose influx and increased glycogen deposition in the cells, however the molecular mechanism of accommodation is unexplored. PMID- 23936012 TI - Gap junctions are essential for generating the correlated spike activity of neighboring retinal ganglion cells. AB - Neurons throughout the brain show spike activity that is temporally correlated to that expressed by their neighbors, yet the generating mechanism(s) remains unclear. In the retina, ganglion cells (GCs) show robust, concerted spiking that shapes the information transmitted to central targets. Here we report the synaptic circuits responsible for generating the different types of concerted spiking of GC neighbors in the mouse retina. The most precise concerted spiking was generated by reciprocal electrical coupling of GC neighbors via gap junctions, whereas indirect electrical coupling to a common cohort of amacrine cells generated the correlated activity with medium precision. In contrast, the correlated spiking with the lowest temporal precision was produced by shared synaptic inputs carrying photoreceptor noise. Overall, our results demonstrate that different synaptic circuits generate the discrete types of GC correlated activity. Moreover, our findings expand our understanding of the roles of gap junctions in the retina, showing that they are essential for generating all forms of concerted GC activity transmitted to central brain targets. PMID- 23936013 TI - Effects of a foot placement constraint on use of motor equivalence during human hopping. AB - Humans can robustly locomote over complex terrains even while simultaneously attending to other tasks such as accurate foot placement on the ground. We investigated whether subjects would exploit motor redundancy across the joints of the leg to stabilize overall limb kinematics when presented with a hopping task that constrained foot placement position. Subjects hopped in place on one leg (2.2 Hz) while having to place their foot into one of three target sizes upon landing (0.250, 0.063, 0.010 m(2)). As takeoff and landing angles are critical to this task performance, we hypothesized smaller target sizes would increase the need to stabilize (i.e., make more consistent) the leg orientation through motor equivalent combinations of segment angles. As it was not critical to the targeting task, we hypothesized no changes for leg length stabilization across target size. With smaller target sizes, we saw total segment angle variance increase due to greater signal-dependent noise associated with an increased activation of leg extensor muscles (medial and lateral gastrocnemius, vastus medialis, vastus lateralis and rectus femoris). At smaller target sizes, more segment angle variance was aligned to kinematic deviations with the goal of maintaining leg orientation trajectory. We also observed a decrease in the variance structure for stabilizing leg length at the smallest target conditions. This trade-off effect is explained by the nearly orthogonal relationship between the two goal-equivalent manifolds for leg length vs. leg orientation stabilization. Our results suggest humans increasingly rely on kinematic redundancy in their legs to achieve robust, consistent locomotion when faced with novel conditions that constrain performance requirements. These principles may generalize to other human locomotor gaits and provide important insights into the control of the legs during human walking and running. PMID- 23936014 TI - Is obstructive sleep apnea associated with cardiovascular and all-cause mortality? AB - BACKGROUND: Studies have reported inconsistent findings regarding the association between obstructive sleep apnea (OSA) and future risks of cardiovascular and all cause mortality. We conducted a meta-analysis to investigate whether OSA is an independent predictor for future cardiovascular and all-cause mortality using prospective observational studies. METHODS: Electronic literature databases (Medline and Embase) were searched for prospective observational studies published prior to December 2012. Only observational studies that assessed baseline OSA and future risk of cardiovascular and all-cause mortality were selected. Pooled hazard risk (HR) and corresponding 95% confidence intervals (CI) were calculated for categorical risk estimates. Subgroup analyses were based on the severity of OSA. RESULTS: Six studies with 11932 patients were identified and analyzed, with 239 reporting cardiovascular mortality, and 1397 all-cause mortality. Pooled HR of all-cause mortality was 1.19 (95% CI, 1.00 to 1.41) for moderate OSA and 1.90 (95% CI, 1.29 to 2.81) for severe OSA. Pooled HR of cardiovascular mortality was 1.40 (95% CI, 0.77 to 2.53) for moderate OSA and 2.65 (95% CI, 1.82 to 3.85) for severe OSA. There were no differences in cardiovascular mortality in continuous positive airway pressure (CPAP) treatment compared with healthy subjects (HR 0.82; 95% CI, 0.50 to 1.33). CONCLUSIONS: Severe OSA is a strong independent predictor for future cardiovascular and all cause mortality. CPAP treatment was associated with decrease cardiovascular mortality. PMID- 23936016 TI - Fuzzy nonlinear proximal support vector machine for land extraction based on remote sensing image. AB - Currently, remote sensing technologies were widely employed in the dynamic monitoring of the land. This paper presented an algorithm named fuzzy nonlinear proximal support vector machine (FNPSVM) by basing on ETM(+) remote sensing image. This algorithm is applied to extract various types of lands of the city Da'an in northern China. Two multi-category strategies, namely "one-against-one" and "one-against-rest" for this algorithm were described in detail and then compared. A fuzzy membership function was presented to reduce the effects of noises or outliers on the data samples. The approaches of feature extraction, feature selection, and several key parameter settings were also given. Numerous experiments were carried out to evaluate its performances including various accuracies (overall accuracies and kappa coefficient), stability, training speed, and classification speed. The FNPSVM classifier was compared to the other three classifiers including the maximum likelihood classifier (MLC), back propagation neural network (BPN), and the proximal support vector machine (PSVM) under different training conditions. The impacts of the selection of training samples, testing samples and features on the four classifiers were also evaluated in these experiments. PMID- 23936015 TI - Effective coverage for antiretroviral therapy in a Ugandan district with a decentralized model of care. AB - INTRODUCTION: While increasing access to antiretroviral therapy (ART) is reported from many African countries, data on effective coverage particular from settings without external support or research remains scarce. We examined and report effective coverage data from a public ART program in rural Uganda. METHODS: We conducted a retrospective cohort study at all ART-providing governmental health facilities in Iganga District, Eastern Uganda. Based on all HIV patients registered between April 2004 and September 2009 (n = 4775), we assessed indicators of program performance and determined rates of retention and Cox proportional hazards for attrition. Effective ART coverage was calculated using projections (SPECTRUM software) adapted to the district demographic structure and number of people receiving ART. RESULTS: By September 2009, district public sector effective ART coverage was 10.3% for adults and 1.9% for children. After a median follow-up of 26.9 months, overall ART retention was 54.7%. The probability of retention was 0.72 (95% confidence interval (CI) 0.69-0.75) at 12 and 0.58 (CI 0.54-0.62) at 36 months after ART initiation. Individual health facilities differed considerably regarding performance indicators and retention. Overall, 198 (16.9%) individual files of 1171 registered ART patients were lost. Young adult age (15-24 years) had a higher risk of attrition (HR 2.1, CI 1.4-3.2) as well as WHO stage I (HR 4.8, CI 1.9-11.8) and WHO stage IV (HR 2.5, CI 1.3-4.7). An interval >=6 weeks between HIV testing and ART initiation was associated with a reduced risk (HR 0.6, CI 0.47-0.78). CONCLUSION: Compared to reported national data effective ART coverage in Iganga District was low. Intensified efforts to improve access, retention in care, and quality of documentation are urgently needed. Children and young adults require special attention in the program. PMID- 23936017 TI - Gene expression-based biomarkers for Anopheles gambiae age grading. AB - Information on population age structure of mosquitoes under natural conditions is fundamental to the understanding of vectorial capacity and crucial for assessing the impact of vector control measures on malaria transmission. Transcriptional profiling has been proposed as a method for predicting mosquito age for Aedes and Anopheles mosquitoes, however, whether this new method is adequate for natural conditions is unknown. This study tests the applicability of transcriptional profiling for age-grading of Anopheles gambiae, the most important malaria vector in Africa. The transcript abundance of two An. gambiae genes, AGAP009551 and AGAP011615, was measured during aging under laboratory and field conditions in three mosquito strains. Age-dependent monotonic changes in transcript levels were observed in all strains evaluated. These genes were validated as age-grading biomarkers using the mark, release and recapture (MRR) method. The MRR method determined a good correspondence between actual and predicted age, and thus demonstrated the value of age classifications derived from the transcriptional profiling of these two genes. The technique was used to establish the age structure of mosquito populations from two malaria-endemic areas in western Kenya. The population age structure determined by the transcriptional profiling method was consistent with that based on mosquito parity. This study demonstrates that the transcription profiling method based on two genes is valuable for age determination of natural mosquitoes, providing a new approach for determining a key life history trait of malaria vectors. PMID- 23936018 TI - Malaria prevalence, spatial clustering and risk factors in a low endemic area of Eastern Rwanda: a cross sectional study. AB - BACKGROUND: Rwanda reported significant reductions in malaria burden following scale up of control intervention from 2005 to 2010. This study sought to; measure malaria prevalence, describe spatial malaria clustering and investigate for malaria risk factors among health-centre-presumed malaria cases and their household members in Eastern Rwanda. METHODS: A two-stage health centre and household-based survey was conducted in Ruhuha sector, Eastern Rwanda from April to October 2011. At the health centre, data, including malaria diagnosis and individual level malaria risk factors, was collected. At households of these Index cases, a follow-up survey, including malaria screening for all household members and collecting household level malaria risk factor data, was conducted. RESULTS: Malaria prevalence among health centre attendees was 22.8%. At the household level, 90 households (out of 520) had at least one malaria-infected member and the overall malaria prevalence for the 2634 household members screened was 5.1%. Among health centre attendees, the age group 5-15 years was significantly associated with an increased malaria risk and a reported ownership of >=4 bednets was significantly associated with a reduced malaria risk. At the household level, age groups 5-15 and >15 years and being associated with a malaria positive index case were associated with an increased malaria risk, while an observed ownership of >=4 bednets was associated with a malaria risk protective effect. Significant spatial malaria clustering among household cases with clusters located close to water- based agro-ecosystems was observed. CONCLUSIONS: Malaria prevalence was significantly higher among health centre attendees and their household members in an area with significant household spatial malaria clustering. Circle surveillance involving passive case finding at health centres and proactive case detection in households can be a powerful tool for identifying household level malaria burden, risk factors and clustering. PMID- 23936019 TI - Long-term effects of ionizing radiation on gene expression in a zebrafish model. AB - Understanding how initial radiation injury translates into long-term effects is an important problem in radiation biology. Here, we define a set of changes in the transcription profile that are associated with the long-term response to radiation exposure. The study was performed in vivo using zebrafish, an established radiobiological model organism. To study the long-term response, 24 hour post-fertilization embryos were exposed to 0.1 Gy (low dose) or 1.0 Gy (moderate dose) of whole-body gamma radiation and allowed to develop for 16 weeks. Liver mRNA profiles were then analyzed using the Affymetrix microarray platform, with validation by quantitative PCR. As a basis for comparison, 16-week old adults were exposed at the same doses and analyzed after 4 hours. Statistical analysis was performed in a way to minimize the effects of multiple comparisons. The responses to these two treatment regimes differed greatly: 360 probe sets were associated primarily with the long-term response, whereas a different 2062 probe sets were associated primarily with the response when adults of the same age were irradiated 4 hours before exposure. Surprisingly, a ten-fold difference in radiation dose (0.1 versus 1.0 Gy) had little effect. Analysis at the gene and pathway level indicated that the long-term response includes the induction of cytokine and inflammatory regulators and transcription and growth factors. The acute response includes the induction of p53 target genes and modulation of the hypoxia-induced transcription factor-C/EBP axis. Results help define genes and pathways affected in the long-term, low and moderate dose radiation response and differentiate them from those affected in an acute response in the same tissue. PMID- 23936020 TI - The teacher, the physician and the person: exploring causal connections between teaching performance and role model types using directed acyclic graphs. AB - BACKGROUND: In fledgling areas of research, evidence supporting causal assumptions is often scarce due to the small number of empirical studies conducted. In many studies it remains unclear what impact explicit and implicit causal assumptions have on the research findings; only the primary assumptions of the researchers are often presented. This is particularly true for research on the effect of faculty's teaching performance on their role modeling. Therefore, there is a need for robust frameworks and methods for transparent formal presentation of the underlying causal assumptions used in assessing the causal effects of teaching performance on role modeling. This study explores the effects of different (plausible) causal assumptions on research outcomes. METHODS: This study revisits a previously published study about the influence of faculty's teaching performance on their role modeling (as teacher-supervisor, physician and person). We drew eight directed acyclic graphs (DAGs) to visually represent different plausible causal relationships between the variables under study. These DAGs were subsequently translated into corresponding statistical models, and regression analyses were performed to estimate the associations between teaching performance and role modeling. RESULTS: The different causal models were compatible with major differences in the magnitude of the relationship between faculty's teaching performance and their role modeling. Odds ratios for the associations between teaching performance and the three role model types ranged from 31.1 to 73.6 for the teacher-supervisor role, from 3.7 to 15.5 for the physician role, and from 2.8 to 13.8 for the person role. CONCLUSIONS: Different sets of assumptions about causal relationships in role modeling research can be visually depicted using DAGs, which are then used to guide both statistical analysis and interpretation of results. Since study conclusions can be sensitive to different causal assumptions, results should be interpreted in the light of causal assumptions made in each study. PMID- 23936021 TI - Minimal residual disease-based risk stratification in Chinese childhood acute lymphoblastic leukemia by flow cytometry and plasma DNA quantitative polymerase chain reaction. AB - Minimal residual disease, or MRD, is an important prognostic indicator in childhood acute lymphoblastic leukemia. In ALL-IC-BFM 2002 study, we employed a standardized method of flow cytometry MRD monitoring for multiple centers internationally using uniformed gating, and determined the relevant MRD-based risk stratification strategies in our local patient cohort. We also evaluated a novel method of PCR MRD quantitation using peripheral blood plasma. For the bone marrow flow MRD study, patients could be stratified into 3 risk groups according to MRD level using a single time-point at day-15 (Model I) (I-A: <0.1%, I-B: 0.1 10%, I-C: >10%), or using two time-points at day-15 and day-33 (Model II) (II-A: day-15<10% and day-33<0.01%, II-B: day-15 >= 10% or day-33 >= 0.01% but not both, II-C: day-15 >= 10% and day-33 >= 0.01%), which showed significantly superior prediction of relapse (p = .00047 and <0.0001 respectively). Importantly, patients with good outcome (frequency: 56.0%, event-free survival: 90.1%) could be more accurately predicted by Model II. In peripheral blood plasma PCR MRD investigation, patients with day-15-MRD >= 10(-4) were at a significantly higher risk of relapse (p = 0.0117). By multivariate analysis, MRD results from both methods could independently predict patients' prognosis, with 20-35-fold increase in risk of relapse for flow MRD I-C and II-C respectively, and 5.8-fold for patients having plasma MRD of >= 10(-4). We confirmed that MRD detection by flow cytometry is useful for prognostic evaluation in our Chinese cohort of childhood ALL after treatment. Moreover, peripheral blood plasma DNA MRD can be an alternative where bone marrow specimen is unavailable and as a less invasive method, which allows close monitoring. PMID- 23936022 TI - KMUP-1 suppresses RANKL-induced osteoclastogenesis and prevents ovariectomy induced bone loss: roles of MAPKs, Akt, NF-kappaB and calcium/calcineurin/NFATc1 pathways. AB - BACKGROUND: KMUP-1 is a xanthine derivative with inhibitory activities on the phosphodiesterase (PDE) 3,4 and 5 isoenzymes to suppress the degradation of cyclic AMP and cyclic GMP. However, the effects of KMUP-1 on osteoclast differentiation are still unclear. In this study, we investigated whether KMUP-1 inhibits osteoclastogenesis induced by RANKL in RAW 264.7 cells and bone loss induced by ovariectomy in mice, and the underlying mechanisms. PRINCIPAL FINDINGS: In vitro, KMUP-1 inhibited RANKL-induced TRAP activity, the formation of multinucleated osteoclasts and resorption-pit formation. It also inhibited key mediators of osteoclastogenesis including IL-1beta, IL-6, TNF-alpha and HMGB1. In addition, KMUP-1 inhibited RANKL-induced activation of signaling molecules (Akt, MAPKs, calcium and NF-kappaB), mRNA expression of osteoclastogensis-associated genes (TRAP, MMP-9, Fra-1, and cathepsin K) and transcription factors (c-Fos and NFATc1). Furthermore, most inhibitory effects of KMUP-1 on RANKL-mediated signal activations were reversed by a protein kinase A inhibitor (H89) and a protein kinase G inhibitor (KT5823). In vivo, KMUP-1 prevented loss of bone mineral content, preserved serum alkaline phosphate and reduced serum osteocalcin in ovariectomized mice. CONCLUSIONS: KMUP-1 inhibits RANKL-induced osteoclastogenesis in vitro and protects against ovariectomy-induced bone loss in vivo. These effects are mediated, at least in part, by cAMP and cGMP pathways. Therefore, KMUP-1 may have a role in pharmacologic therapy of osteoporosis. PMID- 23936023 TI - Heme oxygenase-1 and inflammation in experimental right ventricular failure on prolonged overcirculation-induced pulmonary hypertension. AB - Heme oxygenase (HO)-1 is a stress response enzyme which presents with cardiovascular protective and anti-inflammatory properties. Six-month chronic overcirculation-induced pulmonary arterial hypertension (PAH) in piglets has been previously reported as a model of right ventricular (RV) failure related to the RV activation of apoptotic and inflammatory processes. We hypothesized that altered HO-1 signalling could be involved in both pulmonary vascular and RV changes. Fifteen growing piglets were assigned to a sham operation (n = 8) or to an anastomosis of the left innominate artery to the pulmonary arterial trunk (n = 7). Six months later, hemodynamics was evaluated after closure of the shunt. After euthanasia of the animals, pulmonary and myocardial tissue was sampled for pathobiological evaluation. Prolonged shunting was associated with a tendency to decreased pulmonary gene and protein expressions of HO-1, while pulmonary gene expressions of interleukin (IL)-33, IL-19, intercellular adhesion molecule (ICAM) 1 and -2 were increased. Pulmonary expressions of constitutive HO-2 and pro inflammatory tumor necrosis factor (TNF)-alpha remained unchanged. Pulmonary vascular resistance (evaluated by pressure/flow plots) was inversely correlated to pulmonary HO-1 protein and IL-19 gene expressions, and correlated to pulmonary ICAM-1 gene expression. Pulmonary arteriolar medial thickness and PVR were inversely correlated to pulmonary IL-19 expression. RV expression of HO-1 was decreased, while RV gene expressions TNF-alpha and ICAM-2 were increased. There was a correlation between RV ratio of end-systolic to pulmonary arterial elastances and RV HO-1 expression. These results suggest that downregulation of HO-1 is associated to PAH and RV failure. PMID- 23936024 TI - Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors. AB - We previously reported that the expression of KIAA1199 in human colorectal tumors (benign and malignant) is markedly higher than that in the normal colonic mucosa. In this study, we investigated the functions of the protein encoded by this gene, which are thus far unknown. Immunostaining studies were used to reveal its subcellular localization, and proteomic and gene expression experiments were conducted to identify proteins that might interact with KIAA1199 and molecular pathways in which it might play roles. Using colon cancer cell lines, we showed that both endogenous and ectopically expressed KIAA1199 is secreted into the extracellular environment. In the cells, it was found mainly in the perinuclear space (probably the ER) and cell membrane. Both cellular compartments were also over-represented in lists of proteins identified by mass spectrometry as putative KIAA1199 interactors and/or proteins encoded by genes whose transcription was significantly changed by KIAA1199 expression. These proteomic and transcriptomic datasets concordantly link KIAA1199 to several genes/proteins and molecular pathways, including ER processes like protein binding, transport, and folding; and Ca(2+), G-protein, ephrin, and Wnt signaling. Immunoprecipitation experiments confirmed KIAA1199's interaction with the cell-membrane receptor ephrin A2 and with the ER receptor ITPR3, a key player in Ca(2+) signaling. By modulating Ca(2+) signaling, KIAA1199 could affect different branches of the Wnt network. Our findings suggest it may negatively regulate the Wnt/CTNNB1 signaling, and its expression is associated with decreased cell proliferation and invasiveness. PMID- 23936025 TI - The uncoordinated-5 homolog B (UNC5B) receptor increases myocardial ischemia reperfusion injury. AB - The UNC5 receptor family are chemorepulsive neuronal guidance receptors with additional functions outside the central nervous system. Previous studies have implicated that the UNC5B receptor influences the migration of leukocytes into sites of tissue inflammation. Given that this process is a critical step during the pathophysiology of myocardial ischemia followed by reperfusion (IR) we investigated the role of UNC5B during myocardial IR. In initial in-vitro experiments, the functional inhibition of UNC5B resulted in a significant reduction of chemotactic migration of neutrophils. In-vivo, using a model of acute myocardial ischemia in UNC5B(+/-) and wild type (WT) animals, we found a significant reduction of infarct sizes in UNC5B(+/-) animals. This was associated with significantly reduced levels of troponin-I and IL-6 in UNC5B(+/-) mice. The repression of UNC5B using siRNA and the functional inhibition of UNC5B significantly dampened the extent of myocardial IR injury. Following depletion of neutrophils, we were not able to observe any further reduction in infarct size through functional inhibition of UNC5B in WT and UNC5B(+/-) mice. In summary our studies demonstrate an important role for UNC5B during myocardial IR injury, and that UNC5B might be a potential therapeutic target to control reperfusion injury in the future. PMID- 23936027 TI - Predicting 7-day survival using heart rate variability in hospice patients with non-lung cancers. AB - BACKGROUND: A simple and accurate survival prediction tool can facilitate decision making processes for hospice patients with advanced cancers. The objectives of this study were to explore the association of cardiac autonomic functions and survival in patients with advanced cancer and to evaluate the prognostic value of heart rate variability (HRV) in 7-day survival prediction. METHODS: A prospective study was conducted on 138 patients with advanced cancer recruited from the hospice ward of a regional hospital in southern Taiwan. Information on functional status and symptom burden of the patients was recorded. Frequency-domain HRV was obtained for the evaluation of cardiac autonomic functions at admission. The end point of the study was defined as the survival status at day 7 after admission to the hospice ward. Multivariate logistic regression analyses were performed to evaluate the independent associations between HRV indices and survival of 7 days or less. RESULTS: The median survival time of the patients was 20 days (95% CI, 17-28 days). Results from the multivariate logistic regression analysis indicated that the natural logarithm transformed high-frequency power (lnHFP) of a value less than 2 (OR = 3.8, p = 0.008) and ECOG performance status of 3 or 4 (OR = 3.4, p = 0.023) were significantly associated with a higher risk of survival of 7 days or less. Receiver operating characteristic (ROC) curve analysis revealed that the area under the curve was 0.71 (95% CI, 0.61-0.81). CONCLUSIONS: In hospice patients with non-lung cancers, an lnHPF value below 2 at hospice admission was significantly associated with survival of 7 days or less. HRV might be used as a non-invasive and objective tool to facilitate medical decision making by improving the accuracy in survival prediction. PMID- 23936026 TI - microRNA-124 inhibits migration and invasion by down-regulating ROCK1 in glioma. AB - BACKGROUND: The extraordinary invasive capability is a major cause of treatment failure and tumor recurrence in glioma, however, the molecular and cellular mechanisms governing glioma invasion remain poorly understood. Evidence in other cell systems has implicated the regulatory role of microRNA in cell motility and invasion, which promotes us to investigate the biological functions of miR-124 in glioma in this regard. RESULTS: We have found that miR-124 is dramatically downregulated in clinical specimen of glioma and is negatively correlated with the tumor pathological grading in the current study. The cells transfected by miR 124 expression vector have demonstrated retarded cell mobility. Using a bioinformatics analysis approach, rho-associated coiled-coil containing protein kinase 1 (ROCK1), a well-known cell mobility-related gene, has been identified as the target of miR-124. A dual-luciferase reporter assay was used to confirm that miR-124 targeted directly the 3'UTR of ROCK1 gene and repressed the ROCK1 expression in U87MG human glioma cell line. Furthermore, experiments have shown that the decreased cell mobility was due to the actin cytoskeleton rearrangements and the reduced cell surface ruffle in U87MG glioma cells. These results are similar to the cellular responses of U87MG glioma cells to the treatment of Y 27632, an inhibitor of ROCK protein. Moreover, a constitutively active ROCK1 in miR-124 over-expressed glioma cells reversed the effects of miR-124. Our results revealed a novel mechanism that miR-124 inhibits glioma cells migration and invasion via ROCK1 downregulation. CONCLUSIONS: These results suggest that miR 124 may function as anti-migration and anti-invasion influence in glioma and provides a potential approach for developing miR-124-based therapeutic strategies for malignant glioma therapy. PMID- 23936028 TI - Loss of survivin in the prostate epithelium impedes carcinogenesis in a mouse model of prostate adenocarcinoma. AB - The inhibitor of apoptosis protein survivin is expressed in most cancers. Using the conditional PTEN deletion mouse model, we previously reported that survivin levels increase with prostate tumor growth. Here we evaluated the functional role of survivin in prostate tumor growth. First, we demonstrated that mice lacking the survivin gene in prostate epithelium were fertile and had normal prostate growth and development. We then serially, from about 10-56 weeks of age, evaluated histopathologic changes in the prostate of mice with PTEN deletion combined with survivin mono- or bi-allelic gene deletion. While within this time period most of the animals with wild-type or monoallelic survivin deletion developed adenocarcinomas, the most severe lesions in the biallelic survivin deleted mice were high-grade prostatic intra-epithelial neoplasia with distinct histopathology. Many atypical cells contained large hypertrophic cytoplasm and desmoplastic reaction in the prostatic intra-epithelial neoplasia lesions of this group was minimal until the late ages. A reduced proliferation index as well as apoptotic and senescent cells were detected in the lesions of mice with compound PTEN/survivin deficiency throughout the time points examined. Survivin deletion was also associated with reduced tumor expression of another inhibitor of apoptosis member, the X-linked inhibitor of apoptosis. Our findings suggest that survivin participates in the progression of prostatic intraepithelial neoplasia to adenocarcinoma, and that survivin interference at the prostatic intraepithelial neoplasia stages may be a potential therapeutic strategy to halt or delay further progression. PMID- 23936029 TI - Neurocognitive impairment in patients treated with protease inhibitor monotherapy or triple drug antiretroviral therapy. AB - BACKGROUND: In patients who remain virologically suppressed in plasma with triple drug ART a switch to protease inhibitor monotherapy maintains high rates of suppression; however it is unknown if protease inhibitor monotherapy is associated to a higher rate of neurocognitive impairment. METHODS: In this observational, cross-sectional study we included patients with plasma virological suppression (>= 1 year) without concomitant major neurocognitive confounders, currently receiving for >= 1 year boosted lopinavir or darunavir as monotherapy or as triple ART. Neurocognitive impairment was defined as per the 2007 consensus of the American Association of Neurology. The association between neurocognitive impairment and protease inhibitor monotherapy, adjusted by significant confounders, was analysed. RESULTS: Of the 191 included patients--triple therapy: 96, 1-2 years of monotherapy: 40 and >2 years of monotherapy: 55--proportions (95% CI) with neurocognitive impairment were: overall, 27.2% (20.9-33.6); triple therapy, 31.6% (22.1-41.0); short-term monotherapy, 25.0% (11.3-38.7); long-term monotherapy: 21.4% (10.5-32.3); p = 0.38. In all groups, neurocognitive impairment was mildly symptomatic or asymptomatic by self-report. There were not significant differences in Global Deficit Score by group. In the regression model confounding variables for neurocognitive impairment were years on ART, ethnicity, years of education, transmission category and the HOMA index. Adjusted by these variables the Odds Ratio (95% CI) for neurocognitive impairment of patients receiving short-term monotherapy was 0.85 (0.29-2.50) and for long-term monotherapy 0.40 (0.14-1.15). CONCLUSIONS: Compared to triple drug antiretroviral therapy, monotherapy with lopinavir/ritonavir or darunavir/ritonavir in patients with adequate plasma suppression was not associated with a higher rate of asymptomatic neurocognitive impairment than triple drug ART. PMID- 23936030 TI - Evaluation of the genotoxic and antigenotoxic effects of Chios mastic water by the in vitro micronucleus test on human lymphocytes and the in vivo wing somatic test on Drosophila. AB - Chios mastic gum, a plant-derived product obtained by the Mediterranean bush Pistacia lentiscus (L.) var. chia (Duham), has generated considerable interest because of its antimicrobial, anticancer, antioxidant and other beneficial properties. Its aqueous extract, called Chios mastic water (CMW), contains the authentic mastic scent and all the water soluble components of mastic. In the present study, the potential genotoxic activity of CMW, as well as its antigenotoxic properties against the mutagenic agent mitomycin-C (MMC), was evaluated by employing the in vitro Cytokinesis Block MicroNucleus (CBMN) assay and the in vivo Somatic Mutation And Recombination Test (SMART). In the former assay, lymphocytes were treated with 1, 2 and 5% (v/v) of CMW with or without MMC at concentrations 0.05 and 0.50 ug/ml. No significant micronucleus induction was observed by CMW, while co-treatment with MMC led to a decrease of the MMC-induced micronuclei, which ranged between 22.8 and 44.7%. For SMART, larvae were treated with 50 and 100% (v/v) CMW with or without MMC at concentrations 1.00, 2.50 and 5.00 ug/ml. It was shown that CMW alone did not modify the spontaneous frequencies of spots indicating lack of genotoxic activity. Tauhe simultaneous administration of MMC with 100% CMW led to considerable alterations of the frequencies of MMC-induced wing spots with the total mutant clones showing reduction between 53.5 and 74.4%. Our data clearly show a protective role of CMW against the MMC-induced genotoxicity and further research on the beneficial properties of this product is suggested. PMID- 23936031 TI - Molecular characterization of multidrug resistant hospital isolates using the antimicrobial resistance determinant microarray. AB - Molecular methods that enable the detection of antimicrobial resistance determinants are critical surveillance tools that are necessary to aid in curbing the spread of antibiotic resistance. In this study, we describe the use of the Antimicrobial Resistance Determinant Microarray (ARDM) that targets 239 unique genes that confer resistance to 12 classes of antimicrobial compounds, quaternary amines and streptothricin for the determination of multidrug resistance (MDR) gene profiles. Fourteen reference MDR strains, which either were genome, sequenced or possessed well characterized drug resistance profiles were used to optimize detection algorithms and threshold criteria to ensure the microarray's effectiveness for unbiased characterization of antimicrobial resistance determinants in MDR strains. The subsequent testing of Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae hospital isolates revealed the presence of several antibiotic resistance genes [e.g. belonging to TEM, SHV, OXA and CTX-M classes (and OXA and CTX-M subfamilies) of beta-lactamases] and their assemblages which were confirmed by PCR and DNA sequence analysis. When combined with results from the reference strains, ~25% of the ARDM content was confirmed as effective for representing allelic content from both Gram-positive and negative species. Taken together, the ARDM identified MDR assemblages containing six to 18 unique resistance genes in each strain tested, demonstrating its utility as a powerful tool for molecular epidemiological investigations of antimicrobial resistance in clinically relevant bacterial pathogens. PMID- 23936033 TI - A new long-lasting indoor residual formulation of the organophosphate insecticide pirimiphos methyl for prolonged control of pyrethroid-resistant mosquitoes: an experimental hut trial in Benin. AB - BACKGROUND: Indoor residual spraying (IRS) is widely used for malaria transmission control in sub-Saharan Africa. Resistance to pyrethroids in the mosquito Anopheles gambiae is a growing problem. There is an urgent need to develop long-lasting alternative insecticides to reduce selection pressure for pyrethroid resistance and to provide control with a single IRS application in countries with long transmission seasons. METHODS: Two capsule suspension formulations (CS) of the organophosphate pirimiphos methyl were evaluated as IRS treatments in experimental huts in an area of Benin where the mosquitoes Anopheles gambiae and Culex quinquefasciatus are resistant to pyrethroids but susceptible to organophosphates. The CS formulations were tested alongside an emulsifiable concentrate (EC) formulation of pirimiphos methyl and a CS formulation of the pyrethroid lambdacyhalothrin. RESULTS: The two CS formulations of pirimiphos methyl gave prolonged control of An. gambiae and Cx. quinquefasciatus. In cement huts application rates of 0.5 g/m(2) induced high mortality of An. gambiae for almost a year: overall mortality rates 87% (95% CI 82-91%) and 92% (95% CI 88-94%). In mud huts application rates of 1 g/m(2) induced high mortality of An. gambiae for 10 months: overall mortality rates 75% (95% CI 69-81%) and 76% (95% CI 68-83%). The EC formulation of pirimiphos methyl failed to control An. gambiae two months after spraying. The pyrethroid lambdacyhalothrin demonstrated prolonged residual activity in bioassay tests but failed to control pyrethroid resistant An. gambiae that entered the huts. Pirimiphos methyl CS was highly active against Culex quinquefasciatus and gave control for 10 months in cement huts and 6 months in mud huts. CONCLUSION: Pirimiphos methyl CS (Actellic 300 CS) applied at 1 g/m(2) shows great promise for providing prolonged control of pyrethroid-resistant An gambiae and for delaying pyrethroid resistance. An alternative to DDT, giving year-round transmission control in sub-Saharan Africa is now a realistic prospect. PMID- 23936032 TI - Integrated analysis of drug-induced gene expression profiles predicts novel hERG inhibitors. AB - Growing evidence suggests that drugs interact with diverse molecular targets mediating both therapeutic and toxic effects. Prediction of these complex interactions from chemical structures alone remains challenging, as compounds with different structures may possess similar toxicity profiles. In contrast, predictions based on systems-level measurements of drug effect may reveal pharmacologic similarities not evident from structure or known therapeutic indications. Here we utilized drug-induced transcriptional responses in the Connectivity Map (CMap) to discover such similarities among diverse antagonists of the human ether-a-go-go related (hERG) potassium channel, a common target of promiscuous inhibition by small molecules. Analysis of transcriptional profiles generated in three independent cell lines revealed clusters enriched for hERG inhibitors annotated using a database of experimental measurements (hERGcentral) and clinical indications. As a validation, we experimentally identified novel hERG inhibitors among the unannotated drugs in these enriched clusters, suggesting transcriptional responses may serve as predictive surrogates of cardiotoxicity complementing existing functional assays. PMID- 23936034 TI - Routine HIV testing among hospitalized patients in Argentina. is it time for a policy change? AB - INTRODUCTION: The Argentinean AIDS Program estimates that 110,000 persons are living with HIV/AIDS in Argentina. Of those, approximately 40% are unaware of their status, and 30% are diagnosed in advanced stages of immunosuppression. Though studies show that universal HIV screening is cost-effective in settings with HIV prevalence greater than 0.1%, in Argentina, with the exception of antenatal care, HIV testing is always client-initiated. OBJECTIVE: We performed a pilot study to assess the acceptability of a universal HIV screening program among inpatients of an urban public hospital in Buenos Aires. METHODS: Over a six month period, all eligible adult patients admitted to the internal medicine ward were offered HIV testing. Demographics, uptake rates, reasons for refusal and new HIV diagnoses were analyzed. RESULTS: Of the 350 admissions during this period, 249 were eligible and subsequently enrolled. The enrolled population was relatively old compared to the general population, was balanced on gender, and did not report traditional high risk factors for HIV infection. Only 88 (39%) reported prior HIV testing. One hundred and ninety (76%) patients accepted HIV testing. In multivariable analysis only younger age (OR 1.02; 95%CI 1.003-1.05) was independently associated with test uptake. Three new HIV diagnoses were made (undiagnosed HIV prevalence: 1.58%); none belonged to a most-at-risk population. CONCLUSIONS: Our findings suggest that universal HIV screening in this setting is acceptable and potentially effective in identifying undiagnosed HIV-infected individuals. If confirmed in a larger study, our findings may inform changes in the Argentinean HIV testing policy. PMID- 23936035 TI - Augmenting autophagy to treat acute kidney injury during endotoxemia in mice. AB - OBJECTIVE: To determine that 1) an age-dependent loss of inducible autophagy underlies the failure to recover from AKI in older, adult animals during endotoxemia, and 2) pharmacologic induction of autophagy, even after established endotoxemia, is of therapeutic utility in facilitating renal recovery in aged mice. DESIGN: Murine model of endotoxemia and cecal ligation and puncture (CLP) induced acute kidney injury (AKI). SETTING: Academic research laboratory. SUBJECTS: C57Bl/6 mice of 8 (young) and 45 (adult) weeks of age. INTERVENTION: Lipopolysaccharide (1.5 mg/kg), Temsirolimus (5 mg/kg), AICAR (100 mg/kg). MEASUREMENTS AND MAIN RESULTS: Herein we report that diminished autophagy underlies the failure to recover renal function in older adult mice utilizing a murine model of LPS-induced AKI. The administration of the mTOR inhibitor temsirolimus, even after established endotoxemia, induced autophagy and protected against the development of AKI. CONCLUSIONS: These novel results demonstrate a role for autophagy in the context of LPS-induced AKI and support further investigation into like interventions that have potential to alter the natural history of disease. PMID- 23936037 TI - Men's preferences for women's femininity in dynamic cross-modal stimuli. AB - Men generally prefer feminine women's faces and voices over masculine women's faces and voices, and these cross-modal preferences are positively correlated. Men's preferences for female facial and vocal femininity have typically been investigated independently by presenting soundless still images separately from audio-only vocal recordings. For the first time ever, we presented men with short video clips in which dynamic faces and voices were simultaneously manipulated in femininity/masculinity. Men preferred feminine men's faces over masculine men's faces, and preferred masculine men's voices over feminine men's voices. We found that men preferred feminine women's faces and voices over masculine women's faces and voices. Men's attractiveness ratings of both feminine and masculine faces were increased by the addition of vocal femininity. Also, men's attractiveness ratings of feminine and masculine voices were increased by the addition of facial femininity present in the video. Men's preferences for vocal and facial femininity were significantly and positively correlated when stimuli were female, but not when they were male. Our findings complement other evidence for cross modal femininity preferences among male raters, and show that preferences observed in studies using still images and/or independently presented vocal stimuli are also observed when dynamic faces and voices are displayed simultaneously in video format. PMID- 23936036 TI - The peripheral myeloid expansion driven by murine cancer progression is reversed by radiation therapy of the tumor. AB - Expansion of myeloid-lineage leukocytes in tumor-bearing mice has been proposed as a cause of systemic immunosuppression. We demonstrate that radiation therapy of tumors leads to a decline in myeloid cell numbers in the blood and a decrease in spleen size. The frequency of myeloid cells does not decline to the level seen in tumor-free mice: we demonstrate that metastatic disease can prevent myeloid cell numbers from returning to baseline, and that tumor recurrence from residual disease correlates with re-expansion of myeloid lineage cells. Radiation therapy results in increased proliferation of T cells in the spleen and while T cell responses to foreign antigens are not altered by tumor burden or myeloid cell expansion, responses to tumor-associated antigens are increased after radiation therapy. These data demonstrate that myeloid cell numbers are directly linked to primary tumor burden, that this population contracts following radiation therapy, and that radiation therapy may open a therapeutic window for immunotherapy of residual disease. PMID- 23936038 TI - BMP9 is a proliferative and survival factor for human hepatocellular carcinoma cells. AB - TGF-beta family members play a relevant role in tumorigenic processes, including hepatocellular carcinoma (HCC), but a specific implication of the Bone Morphogenetic Protein (BMP) subfamily is still unknown. Although originally isolated from fetal liver, little is known about BMP9, a BMP family member, and its role in liver physiology and pathology. Our results show that BMP9 promotes growth in HCC cells, but not in immortalized human hepatocytes. In the liver cancer cell line HepG2, BMP9 triggers Smad1,5,8 phosphorylation and inhibitor of DNA binding 1 (Id1) expression up- regulation. Importantly, by using chemical inhibitors, ligand trap and gene silencing approaches we demonstrate that HepG2 cells autocrinely produce BMP9 that supports their proliferation and anchorage independent growth. Additionally, our data reveal that in HepG2 cells BMP9 triggers cell cycle progression, and strikingly, completely abolishes the increase in the percentage of apoptotic cells induced by long-term incubation in low serum. Collectively, our data unveil a dual role for BMP9, both promoting a proliferative response and exerting a remarkable anti-apoptotic function in HepG2 cells, which result in a robust BMP9 effect on liver cancer cell growth. Finally, we show that BMP9 expression is increased in 40% of human HCC tissues compared with normal human liver as revealed by immunohistochemistry analysis, suggesting that BMP9 signaling may be relevant during hepatocarcinogenesis in vivo. Our findings provide new clues for a better understanding of BMPs contribution, and in particular BMP9, in HCC pathogenesis that may result in the development of effective and targeted therapeutic interventions. PMID- 23936039 TI - Structure of the SCAN domain of human paternally expressed gene 3 protein. AB - Human paternally expressed gene 3 protein (PEG3) is a large multi-domain entity with diverse biological functions, including acting as a transcription factor. PEG3 contains twelve Cys2-His2 type zinc finger domains, extended regions of predicted disorder and at the N-terminus a SCAN domain. PEG3 has been identified as partner of the E3 ubiquitin-protein ligase Siah1, an association we sought to investigate. An efficient bacterial recombinant expression system of the human PEG3-SCAN domain was prepared and crystals appeared spontaneously when the protein was being concentrated after purification. The structure was determined at 1.95 A resolution and reveals a polypeptide fold of five helices in an extended configuration. An extensive dimerization interface, using almost a quarter of the solvent accessible surface, and key salt bridge interactions explain the stability of the dimer. Comparison with other SCAN domains reveals a high degree of conservation involving residues that contribute to the dimer interface. The PEG3-SCAN domain appears to constitute an assembly block, enabling PEG3 homo- or heterodimerization to control gene expression in a combinatorial fashion. PMID- 23936040 TI - A mouse model of familial ALS has increased CNS levels of endogenous ubiquinol9/10 and does not benefit from exogenous administration of ubiquinol10. AB - Oxidative stress and mitochondrial impairment are the main pathogenic mechanisms of Amyotrophic Lateral Sclerosis (ALS), a severe neurodegenerative disease still lacking of effective therapy. Recently, the coenzyme-Q (CoQ) complex, a key component of mitochondrial function and redox-state modulator, has raised interest for ALS treatment. However, while the oxidized form ubiquinone10 was ineffective in ALS patients and modestly effective in mouse models of ALS, no evidence was reported on the effect of the reduced form ubiquinol10, which has better bioavailability and antioxidant properties. In this study we compared the effects of ubiquinone10 and a new stabilized formulation of ubiquinol10 on the disease course of SOD1(G93A) transgenic mice, an experimental model of fALS. Chronic treatments (800 mg/kg/day orally) started from the onset of disease until death, to mimic the clinical trials that only include patients with definite ALS symptoms. Although the plasma levels of CoQ10 were significantly increased by both treatments (from <0.20 to 3.0-3.4 ug/mL), no effect was found on the disease progression and survival of SOD1(G93A) mice. The levels of CoQ10 in the brain and spinal cord of ubiquinone10- or ubiquinol10-treated mice were only slightly higher (<=10%) than the endogenous levels in vehicle-treated mice, indicating poor CNS availability after oral dosing and possibly explaining the lack of pharmacological effects. To further examine this issue, we measured the oxidized and reduced forms of CoQ9/10 in the plasma, brain and spinal cord of symptomatic SOD1(G93A) mice, in comparison with age-matched SOD1(WT). Levels of ubiquinol9/10, but not ubiquinone9/10, were significantly higher in the CNS, but not in plasma, of SOD1(G93A) mice, suggesting that CoQ redox system might participate in the mechanisms trying to counteract the pathology progression. Therefore, the very low increases of CoQ10 induced by oral treatments in CNS might be not sufficient to provide significant neuroprotection in SOD1(G93A) mice. PMID- 23936041 TI - The weight of a guilty conscience: subjective body weight as an embodiment of guilt. AB - Guilt is an important social and moral emotion. In addition to feeling unpleasant, guilt is metaphorically described as a "weight on one's conscience." Evidence from the field of embodied cognition suggests that abstract metaphors may be grounded in bodily experiences, but no prior research has examined the embodiment of guilt. Across four studies we examine whether i) unethical acts increase subjective experiences of weight, ii) feelings of guilt explain this effect, and iii) whether there are consequences of the weight of guilt. Studies 1 3 demonstrated that unethical acts led to more subjective body weight compared to control conditions. Studies 2 and 3 indicated that heightened feelings of guilt mediated the effect, whereas other negative emotions did not. Study 4 demonstrated a perceptual consequence. Specifically, an induction of guilt affected the perceived effort necessary to complete tasks that were physical in nature, compared to minimally physical tasks. PMID- 23936042 TI - IL-10 gene polymorphisms and susceptibility to systemic lupus erythematosus: a meta-analysis. AB - BACKGROUND: A number of observational studies have been conducted to investigate the association of the IL-10 gene polymorphisms with systemic lupus erythematosus (SLE) susceptibility. However, their results are conflicting. METHOD: We searched published case-control studies on the IL-10 polymorphisms and SLE in PubMed, EMBASE and Chinese Biomedical Literature Database. A meta-analysis was conducted using a fixed-effect or random-effect model based on between-study heterogeneity. RESULTS: A total of 42 studies with 7948 cases and 11866 controls were included in this meta-analysis. Among Caucasians, the CA27 allele of the IL10.G microsatellites (OR 2.38, 95% CI 1.01-5.62), the G allele of the IL-10 -1082G/A polymorphism (G vs. A: OR 1.21, 95% CI 1.02-1.44; GG vs. AA: OR 1.45, 95% CI 1.16 1.82; GG+GA vs. AA: OR 1.16, 95% CI 1.03-1.29) and its associated haplotype 1082G/-819C/-592C (OR 1.25, 95% CI 1.10-1.42) were associated with increased SLE susceptibility without or with unimportant between-study heterogeneity. Removing studies deviating from Hardy-Weinberg equilibrium (HWE) hardly changed these results. Among Asians, the CA21 allele of the IL-10.G microsatellites (OR 1.28, 95% CI 1.02-1.60) and the -1082G/-819C/-592C haplotype (OR 1.24, 95% CI 1.00 1.53) were associated with increased SLE susceptibility, but with substantial between-study heterogeneity or sensitive to HWE status. Removing studies deviating from HWE also produced statistically significant associations of the IL 10 -1082G/A (GG vs. AA: OR 3.21, 95% CI 1.24-8.28; GG vs. AA+GA: OR 2.85, 95% CI 1.19-6.79) and -592C/A polymorphisms (CC+CA vs. AA: OR 0.69, 95% CI 0.51-0.94) with SLE among Asians. CONCLUSION: This meta-analysis showed that the IL10.G microsatellites, the IL-10 -1082G/A and -592C/A polymorphisms and the haplotype 1082G/-819C/-592C are associated with SLE susceptibility. Besides, this is the first time to report an association between the CA27 allele of the IL-10.G microsatellites and SLE among Caucasians. Further studies are needed to confirm these findings. PMID- 23936043 TI - Exome sequencing and linkage analysis identified tenascin-C (TNC) as a novel causative gene in nonsyndromic hearing loss. AB - In this study, a five-generation Chinese family (family F013) with progressive autosomal dominant hearing loss was mapped to a critical region spanning 28.54 Mb on chromosome 9q31.3-q34.3 by linkage analysis, which was a novel DFNA locus, assigned as DFNA56. In this interval, there were 398 annotated genes. Then, whole exome sequencing was applied in three patients and one normal individual from this family. Six single nucleotide variants and two indels were found co segregated with the phenotypes. Then using mass spectrum (Sequenom, Inc.) to rank the eight sites, we found only the TNC gene be co-segregated with hearing loss in 53 subjects of F013. And this missense mutation (c.5317G>A, p.V1773M ) of TNC located exactly in the critical linked interval. Further screening to the coding region of this gene in 587 subjects with nonsyndromic hearing loss (NSHL) found a second missense mutation, c.5368A>T (p. T1796S), co-segregating with phenotype in the other family. These two mutations located in the conserved region of TNC and were absent in the 387 normal hearing individuals of matched geographical ancestry. Functional effects of the two mutations were predicted using SIFT and both mutations were deleterious. All these results supported that TNC may be the causal gene for the hearing loss inherited in these families. TNC encodes tenascin-C, a member of the extracellular matrix (ECM), is present in the basilar membrane (BM), and the osseous spiral lamina of the cochlea. It plays an important role in cochlear development. The up-regulated expression of TNC gene in tissue repair and neural regeneration was seen in human and zebrafish, and in sensory receptor recovery in the vestibular organ after ototoxic injury in birds. Then the absence of normal tenascin-C was supposed to cause irreversible injuries in cochlea and caused hearing loss. PMID- 23936045 TI - Biomass and its allocation in relation to temperature, precipitation, and soil nutrients in Inner Mongolia grasslands, China. AB - AIM: Understanding and predicting ecosystem functioning such as biomass accumulation requires an accurate assessment of large-scale patterns of biomass distribution and partitioning in relation to climatic and soil environments. METHODS: We sampled above- and belowground biomass from 26 sites spanning 1500 km in Inner Mongolian grasslands, compared the difference in aboveground, belowground biomass and below-aboveground biomass ratio (AGB, BGB, and B/A, respectively) among meadow steppe, typical steppe, and desert steppe types. The relationships between AGB, BGB, B/A and climatic and soil environments were then examined. RESULTS: We found that AGB and BGB differed significantly among three types of grasslands while B/A did not differ. Structural equation model analyses indicated that mean annual precipitation was the strongest positive driver for AGB and BGB. AGB was also positively associated with soil organic carbon, whereas B/A was positively associated with total soil nitrogen. CONCLUSIONS: These results indicated that precipitation positively influence plant production in Inner Mongolian grasslands. Contrary to the prediction from the optimal partitioning hypothesis, biomass allocation to belowground increased with soil total nitrogen, suggesting that more productive sites may increase belowground allocation as an adaptive strategy to potentially high fire frequencies. PMID- 23936044 TI - Increased risk of active tuberculosis following acute kidney injury: a nationwide, population-based study. AB - BACKGROUND: Profound alterations in immune responses associated with uremia and exacerbated by dialysis increase the risk of active tuberculosis (TB). Evidence of the long-term risk and outcome of active TB after acute kidney injury (AKI) is limited. METHODS: This population-based-cohort study used claim records retrieved from the Taiwan National Health Insurance database. We retrieved records of all hospitalized patients, more than 18 years, who underwent dialysis for acute kidney injury (AKI) during 1999-2008 and validated using the NSARF data. Time dependent Cox proportional hazards model to adjust for the ongoing effect of end stage renal disease (ESRD) was conducted to predict long-term de novo active TB after discharge from index hospitalization. RESULTS: Out of 2,909 AKI dialysis patients surviving 90 days after index discharge, 686 did not require dialysis after hospital discharge. The control group included 11,636 hospital patients without AKI, dialysis, or history of TB. The relative risk of active TB in AKI dialysis patients, relative to the general population, after a mean follow-up period of 3.6 years was 7.71. Patients who did (hazard ratio [HR], 3.84; p<0.001) and did not (HR, 6.39; p<0.001) recover from AKI requiring dialysis had significantly higher incidence of TB than patients without AKI. The external validated data also showed nonrecovery subgroup (HR = 4.37; p = 0.049) had high risk of developing active TB compared with non-AKI. Additionally, active TB was associated with long-term all-cause mortality after AKI requiring dialysis (HR, 1.34; p = 0.032). CONCLUSIONS: AKI requiring dialysis seems to independently increase the long-term risk of active TB, even among those who weaned from dialysis at discharge. These results raise concerns that the increasing global burden of AKI will in turn increase the incidence of active TB. PMID- 23936046 TI - Role of a novel I1781T mutation and other mechanisms in conferring resistance to acetyl-CoA carboxylase inhibiting herbicides in a black-grass population. AB - BACKGROUND: Knowledge of the mechanisms of herbicide resistance is important for designing long term sustainable weed management strategies. Here, we have used an integrated biology and molecular approach to investigate the mechanisms of resistance to acetyl-CoA carboxylase inhibiting herbicides in a UK black-grass population (BG2). METHODOLOGY/PRINCIPAL FINDINGS: Comparison between BG2 phenotypes using single discriminant rates of herbicides and genotypes based on ACCase gene sequencing showed that the I1781L, a novel I1781T, but not the W2027C mutations, were associated with resistance to cycloxydim. All plants were killed with clethodim and a few individuals containing the I1781L mutation were partially resistant to tepraloxydim. Whole plant dose response assays demonstrated that a single copy of the mutant T1781 allele conferred fourfold resistance levels to cycloxydim and clodinafop-propargyl. In contrast, the impact of the I1781T mutation was low (Rf = 1.6) and non-significant on pinoxaden. BG2 was also characterised by high levels of resistance, very likely non-target site based, to the two cereal selective herbicides clodinafop-propargyl and pinoxaden and not to the poorly metabolisable cyclohexanedione herbicides. Analysis of 480 plants from 40 cycloxydim resistant black grass populations from the UK using two very effective and high throughput dCAPS assays established for detecting any amino acid changes at the 1781 ACCase codon and for positively identifying the threonine residue, showed that the occurrence of the T1781 is extremely rare compared to the L1781 allele. CONCLUSION/SIGNIFICANCE: This study revealed a novel mutation at ACCase codon position 1781 and adequately assessed target site and non-target site mechanisms in conferring resistance to several ACCase herbicides in a black-grass population. It highlights that over time the level of suspected non-target site resistance to some cereal selective ACCase herbicides have in some instances surpassed that of target site resistance, including the one endowed by the most commonly encountered I1781L mutation. PMID- 23936047 TI - When women deliver with no one present in Nigeria: who, what, where and so what? AB - With the current maternal mortality ratio (MMR) of 630/100,000 live births, Nigeria ranks among the nations with the highest mortality rates in the world. The use of skilled assistants during delivery has been identified a key predictor in the reduction of mortality rates in the world over. Not only are Nigerian women predominantly using unskilled attendants, one in five births are delivered with No One Present (NOP). We assessed who, what, where and the so what of this practice using 2008 Nigeria DHS (NDHS) data. The study revealed that the prevalence of NOP is highest in the northern part of Nigeria with 94% of all observed cases. Socio-demographic factors, including, women's age at birth, birth order, being Muslim, and region of residence, were positively associated with NOP deliveries. Mother's education, higher wealth quintiles, urban residence, decision-making autonomy, and a supportive environment for women's social and economic security were inversely associated with NOP deliveries. Women's autonomy and social standing were critical to choosing to deliver with skilled attendance, which were further amplified by economic prosperity. Women's' economic wellbeing is entwined with their feelings of independence and freedom. Programs that seek to improve the autonomy of women and their strategic participation in sound health seeking decisions will, most likely, yield better results with improvements in women's education, income, jobs, and property ownership. As a short term measure, the use of conditional cash transfer, proven to work in several countries, including 18 in sub-Saharan Africa, is recommended. Its use has the potential to reduce household budget constraint by lowering cost-related barriers associated with women's ability to demand and use life-saving services. Given the preponderance of NOP in the Northern region, the study suggests that interventions to eradicate NOP deliveries must initially focus this region as priority. PMID- 23936048 TI - Chronic hydrocephalus after experimental subarachnoid hemorrhage. AB - Chronic communicating hydrocephalus is a significant health problem affecting up to 20% of survivors of spontaneous subarachnoid hemorrhage (SAH). The development of new treatment strategies is hampered by the lack of well characterized disease models. This study investigated the incidence of chronic hydrocephalus by evaluating the temporal profile of intracranial pressure (ICP) elevation after SAH, induced by endovascular perforation in rats. Twenty-five adult male Sprague Dawley rats (260-320 g) were subjected to either endovascular perforation or sham surgery. Five animals died after SAH induction. At 7, 14 and 21 days after surgery ICP was measured by stereotaxic puncture of the cisterna magna in SAH (n=10) and SHAM (n=10) animals. On day 21 T-maze test was performed and the number of alterations and latency to decision was recorded. On day 23, samples were processed for histological analyses. The relative ventricle area was evaluated in coronal Nissl stained sections. On day 7 after surgery all animals showed normal ICP. The absolute ICP values were significantly higher in SAH compared to SHAM animals on day 21 (8.26+/-4.53 mmHg versus 4.38+/-0.95 mmHg) but not on day 14. Observing an ICP of 10 mmHg as cut-off, 3 animals showed elevated ICP on day 14 and another animal on day 21. The overall incidence of ICP elevation was 40% in SAH animals. On day 21, results of T-maze testing were significantly correlated with ICP values, i.e. animals with elevated ICP showed a lower number of alterations and a delayed decision. Histology yielded a significantly higher (3.59 fold increased) relative ventricle area in SAH animals with ICP elevation compared to SAH animals without ICP elevation. In conclusion, the current study shows that experimental SAH leads to chronic hydrocephalus, which is associated with ICP elevation, behavioral alterations and ventricular dilation in about 40% of SAH animals. PMID- 23936049 TI - Quantitative analysis of cell migration using optical flow. AB - Neural crest cells exhibit dramatic migration behaviors as they populate their distant targets. Using a line of zebrafish expressing green fluorescent protein (sox10:EGFP) in neural crest cells we developed an assay to analyze and quantify cell migration as a population, and use it here to characterize in detail the subtle defects in cell migration caused by ethanol exposure during early development. The challenge was to quantify changes in the in vivo migration of all Sox10:EGFP expressing cells in the visual field of time-lapse movies. To perform this analysis we used an Optical Flow algorithm for motion detection and combined the analysis with a fit to an affine transformation. Through this analysis we detected and quantified significant differences in the cell migrations of Sox10:EGFP positive cranial neural crest populations in ethanol treated versus untreated embryos. Specifically, treatment affected migration by increasing the left-right asymmetry of the migrating cells and by altering the direction of cell movements. Thus, by applying this novel computational analysis, we were able to quantify the movements of populations of cells, allowing us to detect subtle changes in cell behaviors. Because cranial neural crest cells contribute to the formation of the frontal mass these subtle differences may underlie commonly observed facial asymmetries in normal human populations. PMID- 23936050 TI - Risk factors of fecal toxigenic or non-toxigenic Clostridium difficile colonization: impact of Toll-like receptor polymorphisms and prior antibiotic exposure. AB - BACKGROUND: This study is to investigate the significance and risk factors of fecal toxigenic (tCdC) or non-toxigenic Clostridium difficile colonization (ntCdC) among hospitalized patients. METHODS: Adults admitted to medical wards in a district hospital between January 2011 and June 2012 were enrolled, and those with a history of colectomy, C. difficile fecal colonization or infection or receipt of either metronidazole or oral vancomycin within 3 months, were excluded. Stools collected within 48 hours after admission and every week during hospitalization were cultured for C. difficile. FINDINGS: Among the 441 enrolled patients, 84 (20.0%) had CdC at initial screening, including 58 (13.2%) with tCdC and 26 (6.8%) with ntCdC. Among patients with initial negative fecal screening for CdC, it took an average of 70.6 days or 66.5 days to develop tCdC or ntCdC during the study period. Finally 78 (17.7%) had tCdC and 34 (7.7%) had ntCdC. During the follow-up period, the patients with tCdC had a higher risk of CDAD (11/79, 14.1%) than those without CdC (3/328, 0.9%) and those with ntCdC (0/34, 0%) (P<0.001). In multivariate analysis, the TLR4 rs1927914 polymorphism (GG genotype) (odds ratio [OR] 4.4, 95% confidence interval [CI] 1.6-11.8, P = 0.003) and recent cefepime therapy (OR 5.3, 95% CI 2.1-13.2, P<0.001) were independently associated with tCdC, whereas recent cefuroxime (OR 11.7, 95% CI 2.3-60.2, P = 0.003) and glycopeptide therapy (OR 10.9, CI: 2.1-57.2, P = 0.005) associated with ntCdC. CONCLUSION: The incidence of CDAD is highest in patients with tCdC and lowest in patients with ntCdC, and the TLR4 rs1927914 polymorphism GG genotype and recent cefepime therapy were independently associated with tCdC. PMID- 23936051 TI - Identification of proteins enriched in rice egg or sperm cells by single-cell proteomics. AB - In angiosperms, female gamete differentiation, fertilization, and subsequent zygotic development occur in embryo sacs deeply embedded in the ovaries. Despite their importance in plant reproduction and development, how the egg cell is specialized, fuses with the sperm cell, and converts into an active zygote for early embryogenesis remains unclear. This lack of knowledge is partly attributable to the difficulty of direct analyses of gametes in angiosperms. In the present study, proteins from egg and sperm cells obtained from rice flowers were separated by one-dimensional polyacrylamide gel electrophoresis and globally identified by highly sensitive liquid chromatography coupled with tandem mass spectroscopy. Proteome analyses were also conducted for seedlings, callus, and pollen grains to compare their protein expression profiles to those of gametes. The proteomics data have been deposited to the ProteomeXchange with identifier PXD000265. A total of 2,138 and 2,179 expressed proteins were detected in egg and sperm cells, respectively, and 102 and 77 proteins were identified as preferentially expressed in egg and sperm cells, respectively. Moreover, several rice or Arabidopsis lines with mutations in genes encoding the putative gamete enriched proteins showed clear phenotypic defects in seed set or seed development. These results suggested that the proteomic data presented in this study are foundational information toward understanding the mechanisms of reproduction and early development in angiosperms. PMID- 23936052 TI - Risk factors for community-acquired urinary tract infections caused by ESBL producing enterobacteriaceae--a case-control study in a low prevalence country. AB - Community-acquired urinary tract infection (CA-UTI) is the most common infection caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, but the clinical epidemiology of these infections in low prevalence countries is largely unknown. A population based case-control study was conducted to assess risk factors for CA-UTI caused by ESBL-producing E. coli or K. pneumoniae. The study was carried out in a source population in Eastern Norway, a country with a low prevalence of infections caused by ESBL-producing Enterobacteriaceae. The study population comprised 100 cases and 190 controls with CA-UTI caused by ESBL producing and non-ESBL-producing E. coli or K. pneumoniae, respectively. The following independent risk factors of ESBL-positive UTIs were identified: Travel to Asia, The Middle East or Africa either during the past six weeks (Odds ratio (OR) = 21; 95% confidence interval (CI): 4.5-97) or during the past 6 weeks to 24 months (OR = 2.3; 95% CI: 1.1-4.4), recent use of fluoroquinolones (OR = 16; 95% CI: 3.2-80) and beta-lactams (except mecillinam) (OR = 5.0; 95% CI: 2.1-12), diabetes mellitus (OR = 3.2; 95% CI: 1.0-11) and recreational freshwater swimming the past year (OR = 2.1; 95% CI: 1.0-4.0). Factors associated with decreased risk were increasing number of fish meals per week (OR = 0.68 per fish meal; 95% CI: 0.51-0.90) and age (OR = 0.89 per 5 year increase; 95% CI: 0.82-0.97). In conclusion, we have identified risk factors that elucidate mechanisms and routes for dissemination of ESBL-producing Enterobacteriaceae in a low prevalence country, which can be used to guide appropriate treatment of CA-UTI and targeted infection control measures. PMID- 23936053 TI - Biochemical and biophysical characterization of the deadenylase CrCaf1 from Chlamydomonas reinhardtii. AB - The modulation of mRNA turnover has been increasingly recognized as a hotpoint for gene expression regulation at the post-transcriptional level. In eukaryotic cells, most mRNAs are degraded via the deadenylation-dependent pathway, in which the removal of the poly(A) tail is the initial and rate-limiting step. Caf1, a deadenylase specifically degrades poly(A) from the 3'-end, is highly conserved from yeast to mammalians. Caf1s in higher plants have been shown to be involved in plant development and stress response. However, little is known about the biochemical and biophysical properties of Caf1s in plants. In this research, we cloned the crcaf1 gene from Chlamydomonas reinhardtii and studied the properties of the recombinant proteins. The results showed that CrCaf1 was a deadenylase with conserved sequence motifs, structural features, and catalytic properties of the Caf1 family. CrCaf1 degraded poly(A) in a distributive mode with the optimal reacting conditions at pH 7 and 35 degrees C. CrCaf1 had similar activity when coordinated with Mg(2+) and Mn(2+), while the enzyme bound to Ca(2+) or Zn(2+) was almost inactivated. Zn(2+) could induce CrCaf1 aggregation with the disruption of the native structure, while Mg(2+), Mn(2+) and Ca(2+) could stabilize CrCaf1 against thermal denaturation by reducing protein aggregation. Among the various metal ions, Mn(2+) showed the strongest protective effect on CrCaf1 stability, implying that Mn(2+) might play a role in regulating CrCaf1 stability in the C. reinhardtii cells under some stressed conditions. These findings provide a starting point for further investigation of the physiological functions of CrCaf1 in C. reinhardtii. PMID- 23936054 TI - Lack of congruence in species diversity indices and community structures of planktonic groups based on local environmental factors. AB - The importance of analyzing the determinants of biodiversity and community composition by using multiple trophic levels is well recognized; however, relevant data are lacking. In the present study, we investigated variations in species diversity indices and community structures of the plankton taxonomic groups-zooplankton, rotifers, ciliates, and phytoplankton-under a range of local environmental factors in pond ecosystems. For each planktonic group, we estimated the species diversity index by using linear models and analyzed the community structure by using canonical correspondence analysis. We showed that the species diversity indices and community structures varied among the planktonic groups and according to local environmental factors. The observed lack of congruence among the planktonic groups may have been caused by niche competition between groups with similar trophic guilds or by weak trophic interactions. Our findings highlight the difficulty of predicting total biodiversity within a system, based upon a single taxonomic group. Thus, to conserve the biodiversity of an ecosystem, it is crucial to consider variations in species diversity indices and community structures of different taxonomic groups, under a range of local conditions. PMID- 23936055 TI - Re-imagining the future: repetition decreases hippocampal involvement in future simulation. AB - Imagining or simulating future events has been shown to activate the anterior right hippocampus (RHC) more than remembering past events does. One fundamental difference between simulation and memory is that imagining future scenarios requires a more extensive constructive process than remembering past experiences does. Indeed, studies in which this constructive element is reduced or eliminated by "pre-imagining" events in a prior session do not report differential RHC activity during simulation. In this fMRI study, we examined the effects of repeatedly simulating an event on neural activity. During scanning, participants imagined 60 future events; each event was simulated three times. Activation in the RHC showed a significant linear decrease across repetitions, as did other neural regions typically associated with simulation. Importantly, such decreases in activation could not be explained by non-specific linear time-dependent effects, with no reductions in activity evident for the control task across similar time intervals. Moreover, the anterior RHC exhibited significant functional connectivity with the whole-brain network during the first, but not second and third simulations of future events. There was also evidence of a linear increase in activity across repetitions in right ventral precuneus, right posterior cingulate and left anterior prefrontal cortex, which may reflect source recognition and retrieval of internally generated contextual details. Overall, our findings demonstrate that repeatedly imagining future events has a decremental effect on activation of the hippocampus and many other regions engaged by the initial construction of the simulation, possibly reflecting the decreasing novelty of simulations across repetitions, and therefore is an important consideration in the design of future studies examining simulation. PMID- 23936058 TI - Rapid quantification of methamphetamine: using attenuated total reflectance fourier transform infrared spectroscopy (ATR-FTIR) and chemometrics. AB - In Australia and increasingly worldwide, methamphetamine is one of the most commonly seized drugs analysed by forensic chemists. The current well-established GC/MS methods used to identify and quantify methamphetamine are lengthy, expensive processes, but often rapid analysis is requested by undercover police leading to an interest in developing this new analytical technique. Ninety six illicit drug seizures containing methamphetamine (0.1%-78.6%) were analysed using Fourier Transform Infrared Spectroscopy with an Attenuated Total Reflectance attachment and Chemometrics. Two Partial Least Squares models were developed, one using the principal Infrared Spectroscopy peaks of methamphetamine and the other a Hierarchical Partial Least Squares model. Both of these models were refined to choose the variables that were most closely associated with the methamphetamine % vector. Both of the models were excellent, with the principal peaks in the Partial Least Squares model having Root Mean Square Error of Prediction 3.8, R(2) 0.9779 and lower limit of quantification 7% methamphetamine. The Hierarchical Partial Least Squares model had lower limit of quantification 0.3% methamphetamine, Root Mean Square Error of Prediction 5.2 and R(2) 0.9637. Such models offer rapid and effective methods for screening illicit drug samples to determine the percentage of methamphetamine they contain. PMID- 23936057 TI - This examined life: the upside of self-knowledge for interpersonal relationships. AB - Although self-knowledge is an unquestioned good in many philosophical traditions, testing this assumption scientifically has posed a challenge because of the difficulty of measuring individual differences in self-knowledge. In this study, we used a novel, naturalistic, and objective criterion to determine individuals' degree of self-knowledge. Specifically, self-knowledge was measured as the congruence between people's beliefs about how they typically behave and their actual behavior as measured with unobtrusive audio recordings from daily life. We found that this measure of self-knowledge was positively correlated with informants' perceptions of relationship quality. These results suggest that self knowledge is interpersonally advantageous. Given the importance of relationships for our social species, self-knowledge could have great social value that has heretofore been overlooked. PMID- 23936056 TI - Activation of store-operated calcium entry in airway smooth muscle cells: insight from a mathematical model. AB - Intracellular Ca(2+) dynamics of airway smooth muscle cells (ASMC) mediate ASMC contraction and proliferation, and thus play a key role in airway hyper responsiveness (AHR) and remodelling in asthma. We evaluate the importance of store-operated Ca(2+) entry (SOCE) in these Ca(2+) dynamics by constructing a mathematical model of ASMC Ca(2+) signaling based on experimental data from lung slices. The model confirms that SOCE is elicited upon sufficient Ca(2+) depletion of the sarcoplasmic reticulum (SR), while receptor-operated [Ca(2+) entry (ROCE) is inhibited in such conditions. It also shows that SOCE can sustain agonist induced Ca(2+) oscillations in the absence of other [Ca(2+) influx. SOCE up regulation may thus contribute to AHR by increasing the Ca(2+) oscillation frequency that in turn regulates ASMC contraction. The model also provides an explanation for the failure of the SERCA pump blocker CPA to clamp the cytosolic Ca(2+) of ASMC in lung slices, by showing that CPA is unable to maintain the SR empty of Ca(2+). This prediction is confirmed by experimental data from mouse lung slices, and strongly suggests that CPA only partially inhibits SERCA in ASMC. PMID- 23936059 TI - Long QT interval in Turner syndrome--a high prevalence of LQTS gene mutations. AB - OBJECTIVES: QT-interval prolongation of unknown aetiology is common in Turner syndrome. This study set out to explore the presence of known long QT mutations in Turner syndrome and to examine the corrected QT-interval (QTc) over time and relate the findings to the Turner syndrome phenotype. METHODS: Adult women with Turner syndrome (n = 88) were examined thrice and 68 age-matched healthy controls were examined once. QTc was measured by one blinded reader (intra-reader variability: 0.7%), and adjusted for influence of heart rate by Bazett's (bQTc) and Hodges's formula (hQTc). The prevalence of mutations in genes related to Long QT syndrome was determined in women with Turner syndrome and a QTc >432.0 milliseconds (ms). Echocardiographic assessment of aortic valve morphology, 24 hour blood pressures and blood samples were done. RESULTS: The mean hQTc in women with Turner syndrome (414.0 +/- 25.5 ms) compared to controls (390.4 +/- 17.8 ms) was prolonged (p<0.001) and did not change over time (416.9 +/- 22.6 vs. 415.6 +/ 25.5 ms; p =0.4). 45,X karyotype was associated with increased hQTc prolongation compared to other Turner syndrome karyotypes (418.2 +/- 24.8 vs. 407.6 +/- 25.5 ms; p = 0.055). In women with Turner syndrome and a bQTc >432 ms, 7 had mutations in major Long QT syndrome genes (SCN5A and KCNH2) and one in a minor Long QT syndrome gene (KCNE2). CONCLUSION: There is a high prevalence of mutations in the major LQTS genes in women with TS and prolonged QTc. It remains to be settled, whether these findings are related to the unexplained excess mortality in Turner women. CLINICAL TRIAL REGISTRATION: NCT00624949. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol/sid/S0001FLI/se ectaction/View/ts/3/uid/U000099E. PMID- 23936060 TI - R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism. AB - Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH decapeptide sequence. This mutation was identified in a CpG islet in nine nCHH subjects from four unrelated families, giving evidence for a putative "hot spot". Interestingly, all the nCHH patients carry this mutation in heterozygosis that strikingly contrasts with the recessive inheritance associated with frame shift and non-sense mutations. Therefore, after exclusion of a second genetic event, a comprehensive functional characterization of the mutant R31C GnRH was undertaken. Using different cellular models, we clearly demonstrate a dramatic reduction of the mutant decapeptide capacity to bind GnRH-receptor, to activate MAPK pathway and to trigger inositol phosphate accumulation and intracellular calcium mobilization. In addition it is less able than wild type to induce lh-beta transcription and LH secretion in gonadotrope cells. Finally, the absence of a negative dominance in vitro offers a unique opportunity to discuss the complex in vivo patho-physiology of this form of nCHH. PMID- 23936061 TI - Erythropoietin protects epithelial cells from excessive autophagy and apoptosis in experimental neonatal necrotizing enterocolitis. AB - Neonatal necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of preterm infants. Increased intestinal epithelium permeability is an early event in NEC pathogenesis. Autophagy and apoptosis are induced by multiple stress pathways which may impact the intestinal barrier, and they have been associated with pathogenesis of diverse gastrointestinal diseases including inflammatory bowel disease. Using both in vitro and in vivo models, this study investigates autophagy and apoptosis under experimental NEC stresses. Furthermore this study evaluates the effect of erythropoietin (Epo), a component of breast milk previously shown to decrease the incidence of NEC and to preserve intestinal barrier function, on intestinal autophagy and apoptosis. It was found that autophagy and apoptosis are both rapidly up regulated in NEC in vivo as indicated by increased expression of the autophagy markers Beclin 1 and LC3II, and by evidence of apoptosis by TUNEL and cleaved caspase-3 staining. In the rat NEC experimental model, autophagy preceded the onset of apoptosis in intestine. In vitro studies suggested that Epo supplementation significantly decreased both autophagy and apoptosis via the Akt/mTOR signaling pathway and the MAPK/ERK pathway respectively. These results suggest that Epo protects intestinal epithelium from excessive autophagy and apoptosis in experimental NEC. PMID- 23936062 TI - Intelligently targeted drug delivery and enhanced antitumor effect by gelatinase responsive nanoparticles. AB - AIMS: The matrix metalloproteinase (MMP) 2/9, also known as collagenases IV and gelatinases A/B, play a key role in cancer invasion and metastasis. However, the clinical trials of the MMP inhibitors (MMPIs) ended up with disappointing results. In this paper, we synthesized a gelatinase-responsive copolymer (mPEG PCL) by inserting a gelatinase cleavable peptide (PVGLIG) between mPEG and PCL blocks of mPEG-PCL for anticancer drug delivery to make use of MMP2/9 as an intelligent target for drug delivery. MATERIALS AND METHODS: mPEG-pep-PCL copolymer was synthesized via ring-opening copolymerization and double-amidation. To evaluate whether Nanoparticles (NPs) prepared from this copolymer are superior to NPs prepared from mPEG-PCL, NPs prepared from mPEG-PCL copolymer were used as positive control. Docetaxel-loading NPs using mPEG-pep-PCL and mPEG-PCL were prepared by nano-precipitation method, mentioned as Gel-NPs and Con-NPs, respectively. The morphologic changes of the NPs after treatment with gelatinases were observed macroscopically by spectrophotometer and microscopically by transmission electron microscopy (TEM) and atomic force microscopy (AFM). The cellular uptake amount and cytotoxicity of Gel-NPs and Con-NPs, respectively, in cell lines with different levels of gelatinase expression were studied. Moreover, the cytotoxicity study on the primary cancer cells isolated from pericardial fluids from a patient with late-stage lung cancer was conducted. RESULTS: The Gel NPs aggregated in response to gelatinases, which was confirmed macroscopically and microscopically. The cellular uptake amount of Gel-NPs was correlated with the level of gelatinases. The in vitro antitumor effect of Gel-NPs was also correlated with the level of gelatinases and was superior to Taxotere (commercially available docetaxel) as well as the Con-NPs. The cytotoxicity study on the primary lung cancer cells also confirmed the effectiveness of Gel-NPs. CONCLUSION: The results in this study preliminarily demonstrated the effectiveness of gelatinase-responsive targeting strategy and the prospect of this intelligent nano-drug delivery system though further studies are needed. PMID- 23936063 TI - Molecular cloning and characterization of a surface-localized adhesion protein in Mycoplasma bovis Hubei-1 strain. AB - Mycoplasma bovis (M. bovis) is an important pathogen that causes various bovine diseases, such as mastitis in cows and pneumonia in calves. The surface proteins are generally thought to play a central role in the pathogenesis of this organism. We screened the entire genome of M. bovis Hubei-1 and discovered a gene named vpmaX that encodes the 25 kDa variable surface lipoprotein A (VpmaX). Sequence analysis revealed that VpmaX contains several repetitive units and a typical bacterial lipoprotein signal sequence. The vpmaX gene was cloned and expressed in E. coli to obtain recombinant VpmaX (rVpmaX). Western blot analysis using a rabbit antibody against rVpmaX demonstrated that VpmaX is a membrane protein. Immunostaining visualized via confocal laser scanning microscopy showed that rVpmaX was able to adhere to embryonic bovine lung cells (EBL), and this was also confirmed by a sandwich ELISA. In summary, a surface-localized adhesion protein was identified in M. bovis Hubei-1. PMID- 23936064 TI - Toward repurposing ciclopirox as an antibiotic against drug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae. AB - Antibiotic-resistant infections caused by gram-negative bacteria are a major healthcare concern. Repurposing drugs circumvents the time and money limitations associated with developing new antimicrobial agents needed to combat these antibiotic-resistant infections. Here we identified the off-patent antifungal agent, ciclopirox, as a candidate to repurpose for antibiotic use. To test the efficacy of ciclopirox against antibiotic-resistant pathogens, we used a curated collection of Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates that are representative of known antibiotic resistance phenotypes. We found that ciclopirox, at 5-15 ug/ml concentrations, inhibited bacterial growth regardless of the antibiotic resistance status. At these same concentrations, ciclopirox reduced growth of Pseudomonas aeruginosa clinical isolates, but some of these pathogens required higher ciclopirox concentrations to completely block growth. To determine how ciclopirox inhibits bacterial growth, we performed an overexpression screen in E. coli. This screen revealed that galE, which encodes UDP-glucose 4-epimerase, rescued bacterial growth at otherwise restrictive ciclopirox concentrations. We found that ciclopirox does not inhibit epimerization of UDP-galactose by purified E. coli GalE; however, DeltagalU, DeltagalE, DeltarfaI, or DeltarfaB mutant strains all have lower ciclopirox minimum inhibitory concentrations than the parent strain. The galU, galE, rfaI, and rfaB genes all encode enzymes that use UDP-galactose or UDP-glucose for galactose metabolism and lipopolysaccharide (LPS) biosynthesis. Indeed, we found that ciclopirox altered LPS composition of an E. coli clinical isolate. Taken together, our data demonstrate that ciclopirox affects galactose metabolism and LPS biosynthesis, two pathways important for bacterial growth and virulence. The lack of any reported fungal resistance to ciclopirox in over twenty years of use in the clinic, its excellent safety profiles, novel target(s), and efficacy, make ciclopirox a promising potential antimicrobial agent to use against multidrug-resistant problematic gram-negative pathogens. PMID- 23936065 TI - Modulation of Pleurodeles waltl DNA polymerase mu expression by extreme conditions encountered during spaceflight. AB - DNA polymerase u is involved in DNA repair, V(D)J recombination and likely somatic hypermutation of immunoglobulin genes. Our previous studies demonstrated that spaceflight conditions affect immunoglobulin gene expression and somatic hypermutation frequency. Consequently, we questioned whether PolMU expression could also be affected. To address this question, we characterized PolMU of the Iberian ribbed newt Pleurodeles waltl and exposed embryos of that species to spaceflight conditions or to environmental modifications corresponding to those encountered in the International Space Station. We noted a robust expression of PolMU mRNA during early ontogenesis and in the testis, suggesting that PolMU is involved in genomic stability. Full-length PolMU transcripts are 8-9 times more abundant in P. waltl than in humans and mice, thereby providing an explanation for the somatic hypermutation predilection of G and C bases in amphibians. PolMU transcription decreases after 10 days of development in space and radiation seem primarily involved in this down-regulation. However, space radiation, alone or in combination with a perturbation of the circadian rhythm, did not affect PolMU protein levels and did not induce protein oxidation, showing the limited impact of radiation encountered during a 10-day stay in the International Space Station. PMID- 23936067 TI - In vivo fluorescence imaging reveals the promotion of mammary tumorigenesis by mesenchymal stromal cells. AB - Mesenchymal stromal cells (MSCs) are multipotent adult stem cells which are recruited to the tumor microenvironment (TME) and influence tumor progression through multiple mechanisms. In this study, we examined the effects of MSCs on the tunmorigenic capacity of 4T1 murine mammary cancer cells. It was found that MSC-conditioned medium increased the proliferation, migration, and efficiency of mammosphere formation of 4T1 cells in vitro. When co-injected with MSCs into the mouse mammary fat pad, 4T1 cells showed enhanced tumor growth and generated increased spontaneous lung metastasis. Using in vivo fluorescence color-coded imaging, the interaction between GFP-expressing MSCs and RFP-expressing 4T1 cells was monitored. As few as five 4T1 cells could give rise to tumor formation when co-injected with MSCs into the mouse mammary fat pad, but no tumor was formed when five or ten 4T1 cells were implanted alone. The elevation of tumorigenic potential was further supported by gene expression analysis, which showed that when 4T1 cells were in contact with MSCs, several oncogenes, cancer markers, and tumor promoters were upregulated. Moreover, in vivo longitudinal fluorescence imaging of tumorigenesis revealed that MSCs created a vascularized environment which enhances the ability of 4T1 cells to colonize and proliferate. In conclusion, this study demonstrates that the promotion of mammary cancer progression by MSCs was achieved through the generation of a cancer-enhancing microenvironment to increase tumorigenic potential. These findings also suggest the potential risk of enhancing tumor progression in clinical cell therapy using MSCs. Attention has to be paid to patients with high risk of breast cancer when considering cell therapy with MSCs. PMID- 23936066 TI - Evaluation of mucosal and systemic immune responses elicited by GPI-0100- adjuvanted influenza vaccine delivered by different immunization strategies. AB - Vaccines for protection against respiratory infections should optimally induce a mucosal immune response in the respiratory tract in addition to a systemic immune response. However, current parenteral immunization modalities generally fail to induce mucosal immunity, while mucosal vaccine delivery often results in poor systemic immunity. In order to find an immunization strategy which satisfies the need for induction of both mucosal and systemic immunity, we compared local and systemic immune responses elicited by two mucosal immunizations, given either by the intranasal (IN) or the intrapulmonary (IPL) route, with responses elicited by a mucosal prime followed by a systemic boost immunization. The study was conducted in BALB/c mice and the vaccine formulation was an influenza subunit vaccine supplemented with GPI-0100, a saponin-derived adjuvant. While optimal mucosal antibody titers were obtained after two intrapulmonary vaccinations, optimal systemic antibody responses were achieved by intranasal prime followed by intramuscular boost. The latter strategy also resulted in the best T cell response, yet, it was ineffective in inducing nose or lung IgA. Successful induction of secretory IgA, IgG and T cell responses was only achieved with prime boost strategies involving intrapulmonary immunization and was optimal when both immunizations were given via the intrapulmonary route. Our results underline that immunization via the lungs is particularly effective for priming as well as boosting of local and systemic immune responses. PMID- 23936068 TI - Comprehensive phylogenetic reconstructions of African swine fever virus: proposal for a new classification and molecular dating of the virus. AB - African swine fever (ASF) is a highly lethal disease of domestic pigs caused by the only known DNA arbovirus. It was first described in Kenya in 1921 and since then many isolates have been collected worldwide. However, although several phylogenetic studies have been carried out to understand the relationships between the isolates, no molecular dating analyses have been achieved so far. In this paper, comprehensive phylogenetic reconstructions were made using newly generated, publicly available sequences of hundreds of ASFV isolates from the past 70 years. Analyses focused on B646L, CP204L, and E183L genes from 356, 251, and 123 isolates, respectively. Phylogenetic analyses were achieved using maximum likelihood and Bayesian coalescence methods. A new lineage-based nomenclature is proposed to designate 35 different clusters. In addition, dating of ASFV origin was carried out from the molecular data sets. To avoid bias, diversity due to positive selection or recombination events was neutralized. The molecular clock analyses revealed that ASFV strains currently circulating have evolved over 300 years, with a time to the most recent common ancestor (TMRCA) in the early 18(th) century. PMID- 23936069 TI - A mouse model for Candida glabrata hematogenous disseminated infection starting from the gut: evaluation of strains with different adhesion properties. AB - Adhesion to digestive mucosa is considered a crucial first step in the pathogenicity of invasive Candida infections. Candida glabrata disseminated infections predominantly start from the gut. A mouse model of disseminated infection starting from the gut was set up. Hematogenous dissemination was obtained after a low-protein diet followed by a regimen of cyclophosphamide methotrexate and an oral inoculation of the yeasts via the drinking water. The liver was the first organ infected (day 7 post-infection), and lethality was 100% at day 21 post-infection. This new mouse model was used to compare the mortality rate and fungal burden in deep organs induced by 5 strains exhibiting different levels of adhesion to enterocyte Caco-2 cells, as determined in a test on 36 C. glabrata strains. In this model, no statistical difference of lethality was demonstrated between the strains, and fungal burden varied in kidneys and lungs but without correlation with the level of adhesion to enterocytes. Further studies using the model developed here allow analysis of the crossing of the digestive mucosa by yeasts, and help relate this to yet-poorly understood adhesion phenotypes. PMID- 23936070 TI - GobyWeb: simplified management and analysis of gene expression and DNA methylation sequencing data. AB - We present GobyWeb, a web-based system that facilitates the management and analysis of high-throughput sequencing (HTS) projects. The software provides integrated support for a broad set of HTS analyses and offers a simple plugin extension mechanism. Analyses currently supported include quantification of gene expression for messenger and small RNA sequencing, estimation of DNA methylation (i.e., reduced bisulfite sequencing and whole genome methyl-seq), or the detection of pathogens in sequenced data. In contrast to previous analysis pipelines developed for analysis of HTS data, GobyWeb requires significantly less storage space, runs analyses efficiently on a parallel grid, scales gracefully to process tens or hundreds of multi-gigabyte samples, yet can be used effectively by researchers who are comfortable using a web browser. We conducted performance evaluations of the software and found it to either outperform or have similar performance to analysis programs developed for specialized analyses of HTS data. We found that most biologists who took a one-hour GobyWeb training session were readily able to analyze RNA-Seq data with state of the art analysis tools. GobyWeb can be obtained at http://gobyweb.campagnelab.org and is freely available for non-commercial use. GobyWeb plugins are distributed in source code and licensed under the open source LGPL3 license to facilitate code inspection, reuse and independent extensions http://github.com/CampagneLaboratory/gobyweb2-plugins. PMID- 23936071 TI - Characterization of cell subpopulations expressing progenitor cell markers in porcine cardiac valves. AB - Valvular interstitial cells (VICs) are the main population of cells found in cardiac valves. These resident fibroblastic cells play important roles in maintaining proper valve function, and their dysregulation has been linked to disease progression in humans. Despite the critical functions of VICs, their cellular composition is still not well defined for humans and other mammals. Given the limited availability of healthy human valves and the similarity in valve structure and function between humans and pigs, we characterized porcine VICs (pVICs) based on expression of cell surface proteins and sorted a specific subpopulation of pVICs to study its functions. We found that small percentages of pVICs express the progenitor cell markers ABCG2 (~5%), NG2 (~5%) or SSEA-4 (~7%), whereas another subpopulation (~5%) expresses OB-CDH, a type of cadherin expressed by myofibroblasts or osteo-progenitors. pVICs isolated from either aortic or pulmonary valves express most of these protein markers at similar levels. Interestingly, OB-CDH, NG2 and SSEA-4 all label distinct valvular subpopulations relative to each other; however, NG2 and ABCG2 are co-expressed in the same cells. ABCG2(+) cells were further characterized and found to deposit more calcified matrix than ABCG2(-) cells upon osteogenic induction, suggesting that they may be involved in the development of osteogenic VICs during valve pathology. Cell profiling based on flow cytometry and functional studies with sorted primary cells provide not only new and quantitative information about the cellular composition of porcine cardiac valves, but also contribute to our understanding of how a subpopulation of valvular cells (ABCG2(+) cells) may participate in tissue repair and disease progression. PMID- 23936072 TI - Roflumilast inhibits respiratory syncytial virus infection in human differentiated bronchial epithelial cells. AB - Respiratory syncytial virus (RSV) causes acute exacerbations in COPD and asthma. RSV infects bronchial epithelial cells (HBE) that trigger RSV associated lung pathology. This study explores whether the phosphodiesterase 4 (PDE4) inhibitor Roflumilast N-oxide (RNO), alters RSV infection of well-differentiated HBE (WD HBE) in vitro. WD-HBE were RSV infected in the presence or absence of RNO (0.1 100 nM). Viral infection (staining of F and G proteins, nucleoprotein RNA level), mRNA of ICAM-1, ciliated cell markers (digital high speed videomicroscopy, beta tubulin immunofluorescence, Foxj1 and Dnai2 mRNA), Goblet cells (PAS), mRNA of MUC5AC and CLCA1, mRNA and protein level of IL-13, IL-6, IL-8, TNFalpha, formation of H2O2 and the anti-oxidative armamentarium (mRNA of Nrf2, HO-1, GPx; total antioxidant capacity (TAC) were measured at day 10 or 15 post infection. RNO inhibited RSV infection of WD-HBE, prevented the loss of ciliated cells and markers, reduced the increase of MUC5AC and CLCA1 and inhibited the increase of IL-13, IL-6, IL-8, TNFalpha and ICAM-1. Additionally RNO reversed the reduction of Nrf2, HO-1 and GPx mRNA levels and consequently restored the TAC and reduced the H2O2 formation. RNO inhibits RSV infection of WD-HBE cultures and mitigates the cytopathological changes associated to this virus. PMID- 23936073 TI - Cardiac myosin binding protein-C plays no regulatory role in skeletal muscle structure and function. AB - Myosin binding protein-C (MyBP-C) exists in three major isoforms: slow skeletal, fast skeletal, and cardiac. While cardiac MyBP-C (cMyBP-C) expression is restricted to the heart in the adult, it is transiently expressed in neonatal stages of some skeletal muscles. However, it is unclear whether this expression is necessary for the proper development and function of skeletal muscle. Our aim was to determine whether the absence of cMyBP-C alters the structure, function, or MyBP-C isoform expression in adult skeletal muscle using a cMyBP-C null mouse model (cMyBP-C((t/t))). Slow MyBP-C was expressed in both slow and fast skeletal muscles, whereas fast MyBP-C was mostly restricted to fast skeletal muscles. Expression of these isoforms was unaffected in skeletal muscle from cMyBP C((t/t)) mice. Slow and fast skeletal muscles in cMyBP-C((t/t)) mice showed no histological or ultrastructural changes in comparison to the wild-type control. In addition, slow muscle twitch, tetanus tension, and susceptibility to injury were all similar to the wild-type controls. Interestingly, fMyBP-C expression was significantly increased in the cMyBP-C((t/t)) hearts undergoing severe dilated cardiomyopathy, though this does not seem to prevent dysfunction. Additionally, expression of both slow and fast isoforms was increased in myopathic skeletal muscles. Our data demonstrate that i) MyBP-C isoforms are differentially regulated in both cardiac and skeletal muscles, ii) cMyBP-C is dispensable for the development of skeletal muscle with no functional or structural consequences in the adult myocyte, and iii) skeletal isoforms can transcomplement in the heart in the absence of cMyBP-C. PMID- 23936075 TI - Family and neighbourhood socioeconomic inequalities in childhood trajectories of BMI and overweight: longitudinal study of Australian children. AB - BACKGROUND: Socioeconomic inequalities in longitudinal patterning of childhood overweight could cause marked differentials in total burden by adulthood. This study aims to determine timing and strength of the association between socioeconomic status (SES) and children's body mass index (BMI) in the pre- and primary school years, and to examine socioeconomic differences in overweight trajectories across childhood. METHODS: Participants were 4949 children from the Longitudinal Study of Australian Children. BMI was measured at four biennial waves starting at age 4-5 years in 2004. Developmental trajectories of childhood overweight were identified with latent class analyses. Composite variables of family and neighbourhood SES were used. RESULTS: Socioeconomic differences in mean BMI z-scores already present at age 4-5 more than doubled by age 10-11 years, reflecting decreasing mean BMI among advantaged rather than increasing means among disadvantaged children. Latent class analysis identified children with 'stable normal weight' (68%), and with 'persistent' (15%), 'late-onset' (14%), and 'resolving' overweight (3%). Risks of persistent and late-onset childhood overweight were highest among low SES families (e.g. most disadvantaged quintile: OR(persistent) = 2.51, 95%CI: 1.83-3.43), and only partly explained by birth weight and parental overweight. Relationships with neighbourhood SES were weaker and attenuated fully on adjustment for family SES. No socioeconomic gradient was observed for resolving overweight. CONCLUSIONS: Childhood has become the critical period when socioeconomic inequalities in overweight emerge and strengthen. Although targeting disadvantaged children with early overweight must be a top priority, the presence of childhood overweight even among less disadvantaged families suggests only whole-society approaches will eliminate overweight-associated morbidity. PMID- 23936074 TI - Telomeric repeats facilitate CENP-A(Cnp1) incorporation via telomere binding proteins. AB - The histone H3 variant, CENP-A, is normally assembled upon canonical centromeric sequences, but there is no apparent obligate coupling of sequence and assembly, suggesting that centromere location can be epigenetically determined. To explore the tolerances and constraints on CENP-A deposition we investigated whether certain locations are favoured when additional CENP-A(Cnp1) is present in fission yeast cells. Our analyses show that additional CENP-A(Cnp1) accumulates within and close to heterochromatic centromeric outer repeats, and over regions adjacent to rDNA and telomeres. The use of minichromosome derivatives with unique DNA sequences internal to chromosome ends shows that telomeres are sufficient to direct CENP-A(Cnp1) deposition. However, chromosome ends are not required as CENP A(Cnp1) deposition also occurs at telomere repeats inserted at an internal locus and correlates with the presence of H3K9 methylation near these repeats. The Ccq1 protein, which is known to bind telomere repeats and recruit telomerase, was found to be required to induce H3K9 methylation and thus promote the incorporation of CENP-A(Cnp1) near telomere repeats. These analyses demonstrate that at non-centromeric chromosomal locations the presence of heterochromatin influences the sites at which CENP-A is incorporated into chromatin and, thus, potentially the location of centromeres. PMID- 23936076 TI - A new omics data resource of Pleurocybella porrigens for gene discovery. AB - BACKGROUND: Pleurocybellaporrigens is a mushroom-forming fungus, which has been consumed as a traditional food in Japan. In 2004, 55 people were poisoned by eating the mushroom and 17 people among them died of acute encephalopathy. Since then, the Japanese government has been alerting Japanese people to take precautions against eating the P. porrigens mushroom. Unfortunately, despite efforts, the molecular mechanism of the encephalopathy remains elusive. The genome and transcriptome sequence data of P. porrigens and the related species, however, are not stored in the public database. To gain the omics data in P. porrigens, we sequenced genome and transcriptome of its fruiting bodies and mycelia by next generation sequencing. METHODOLOGY/PRINCIPAL FINDINGS: Short read sequences of genomic DNAs and mRNAs in P. porrigens were generated by Illumina Genome Analyzer. Genome short reads were de novo assembled into scaffolds using Velvet. Comparisons of genome signatures among Agaricales showed that P. porrigens has a unique genome signature. Transcriptome sequences were assembled into contigs (unigenes). Biological functions of unigenes were predicted by Gene Ontology and KEGG pathway analyses. The majority of unigenes would be novel genes without significant counterparts in the public omics databases. CONCLUSIONS: Functional analyses of unigenes present the existence of numerous novel genes in the basidiomycetes division. The results mean that the omics information such as genome, transcriptome and metabolome in basidiomycetes is short in the current databases. The large-scale omics information on P. porrigens, provided from this research, will give a new data resource for gene discovery in basidiomycetes. PMID- 23936077 TI - Multivoxel patterns in fusiform face area differentiate faces by sex and race. AB - Although prior research suggests that fusiform gyrus represents the sex and race of faces, it remains unclear whether fusiform face area (FFA)-the portion of fusiform gyrus that is functionally-defined by its preferential response to faces contains such representations. Here, we used functional magnetic resonance imaging to evaluate whether FFA represents faces by sex and race. Participants were scanned while they categorized the sex and race of unfamiliar Black men, Black women, White men, and White women. Multivariate pattern analysis revealed that multivoxel patterns in FFA-but not other face-selective brain regions, other category-selective brain regions, or early visual cortex-differentiated faces by sex and race. Specifically, patterns of voxel-based responses were more similar between individuals of the same sex than between men and women, and between individuals of the same race than between Black and White individuals. By showing that FFA represents the sex and race of faces, this research contributes to our emerging understanding of how the human brain perceives individuals from two fundamental social categories. PMID- 23936078 TI - Effects of mild cold shock (25 degrees C) followed by warming up at 37 degrees C on the cellular stress response. AB - Temperature variations in cells, tissues and organs may occur in a number of circumstances. We report here that reducing temperature of cells in culture to 25 degrees C for 5 days followed by a rewarming to 37 degrees C affects cell biology and induces a cellular stress response. Cell proliferation was almost arrested during mild hypothermia and not restored upon returning to 37 degrees C. The expression of cold shock genes, CIRBP and RBM3, was increased at 25 degrees C and returned to basal level upon rewarming while that of heat shock protein HSP70 was inversely regulated. An activation of pro-apoptotic pathways was evidenced by FACS analysis and increased Bax/Bcl2 and BclX(S/L) ratios. Concomitant increased expression of the autophagosome-associated protein LC3II and AKT phosphorylation suggested a simultaneous activation of autophagy and pro-survival pathways. However, a large proportion of cells were dying 24 hours after rewarming. The occurrence of DNA damage was evidenced by the increased phosphorylation of p53 and H2AX, a hallmark of DNA breaks. The latter process, as well as apoptosis, was strongly reduced by the radical oxygen species (ROS) scavenger, N-acetylcysteine, indicating a causal relationship between ROS, DNA damage and cell death during mild cold shock and rewarming. These data bring new insights into the potential deleterious effects of mild hypothermia and rewarming used in various research and therapeutical fields. PMID- 23936079 TI - 24h urinary sodium excretion and subsequent change in weight, waist circumference and body composition. AB - BACKGROUND: In the same period as the increasing obesity epidemic, there has been an increased consumption of highly processed foods with a high salt content, and a few studies have suggested that a diet with a high salt content may be associated with obesity. OBJECTIVE: To investigate the association between 24 h urinary sodium excretion and subsequent change in body weight (BW), waist circumference (WC), body fat (BF) and fat free mass (FFM) among adults. DESIGN: A longitudinal population study based on the Danish part of the MONICA project, with examinations in 1987-1988 and 1993-1994. Complete information on 24 h urinary sodium excretion along with repeated measures of obesity, as well as on potential confounders, was obtained from 215 subjects. Linear regression was used to examine the association between sodium excretion, as a measure of salt consumption, and subsequent changes in BW, WC, BF and FFM, and further evaluated by restricted cubic splines. Stepwise adjustments were made for selected covariates. RESULTS: Neither the crude nor the adjusted models showed any statistically significant associations between sodium excretion and change in BW or WC. Likewise, we found no significant association between sodium excretion and change in BF and FFM in the unadjusted models. However, after adjusting for potential baseline confounders and the concurrent BW change, we found a significant increase in BF of 0.24 kg (P = 0.015, CI: 0.05 to 0.43) per 100 mmol increase in 24 h urinary sodium excretion (equivalent to 6 g of salt), during the 6-year study period. Moreover, during the same period, we found a significant association with FFM of -0.21 kg (P = 0.041, CI: -0.40 to -0.01). CONCLUSIONS: These results suggest that a diet with a high salt content may have a negative influence on development in body composition by expanding BF and reducing FFM. PMID- 23936080 TI - Production and evaluation of a recombinant chimeric vaccine against clostridium botulinum neurotoxin types C and D. AB - Bovine botulism is a fatal disease that is caused by botulinum neurotoxins (BoNTs) produced by Clostridium botulinum serotypes C and D and that causes great economic losses, with nearly 100% lethality during outbreaks. It has also been considered a potential source of human food-borne illness in many countries. Vaccination has been reported to be the most effective way to control bovine botulism. However, the commercially available toxoid-based vaccines are difficult and hazardous to produce. Neutralizing antibodies targeted against the C-terminal fragment of the BoNT heavy chain (HC) are known to confer efficient protection against lethal doses of BoNTs. In this study, a novel recombinant chimera, consisting of Escherichia coli heat-labile enterotoxin B subunit (LTB), a strong adjuvant of the humoral immune response, fused to the HC of BoNT serotypes C and D, was produced in E. coli. Mice vaccinated with the chimera containing LTB and an equivalent molar ratio of the chimera without LTB plus aluminum hydroxide (Al(OH)3) developed 2 IU/mL of antitoxins for both serotypes. Guinea pigs immunized with the recombinant chimera with LTB plus Al(OH)3 developed a protective immune response against both BoNT/C (5 IU/mL) and BoNT/D (10 IU/mL), as determined by a mouse neutralization bioassay with pooled sera. The results achieved with guinea pig sera fulfilled the requirements of commercial vaccines for prevention of botulism, as determined by the Brazilian Ministry of Agriculture, Livestock and Food, Supply. The presence of LTB was essential for the development of a strong humoral immune response, as it acted in synergism with Al(OH)3. Thus, the vaccine described in this study is a strong candidate for the control of botulism in cattle. PMID- 23936081 TI - Environmental and parental influences on offspring health and growth in great tits (Parus major). AB - Sexual selection requires both that there is heritable variation in traits related to fitness, and that either some of this variation is linked to traits of the parents, and/or that there are direct benefits of choosing particular individuals as mates. This suggests that if direct benefits are important offspring performance should be predicted by traits of the rearing adults. But if indirect benefits are more significant offspring performance should be predicted by traits of the adults at the nest-of-origin. We conducted cross-fostering experiments in great tits (Parus major) over four years, in two of which we manipulated environmental conditions by providing supplemental food. In a third year, some nestlings were directly supplemented with carotenoids. Nestlings in broods whose rearing adults received supplemental food were heavier and had improved immune responses even when controlling for body mass. Nestling immune function was related to measures of the yellow plumage color of both the rearing male and the putative father. Nestling body mass was influenced by the coloration of both the rearing female and the genetic mother. Our results suggest that features of both their social and putative genetic parents influence nestling health and growth. From this it would appear that females could be gaining both direct and indirect benefits through mate choice of male plumage traits and that it would be possible for males to similarly gain through mate choice of female traits. PMID- 23936083 TI - Validation of blubber progesterone concentrations for pregnancy determination in three dolphin species and a porpoise. AB - Recent studies have validated the use of biopsies as a minimally invasive way to identify pregnant females in several species of wild cetaceans: Balaenapteraacutorostrata , Delphinusdelphis , Lissodelphisborealis, and Lagenorhynchusobliquidens. These studies found that progesterone (P4) concentrations quantified from blubber attached to biopsy samples is diagnostic of pregnancy. Here we examine a broader group of cetacean species in efforts to investigate how progesterone levels vary between species with respect to pregnancy status. We compared P4 concentrations in blubber collected from fishery bycatch and beach-stranded specimens for 40 females of known reproductive condition from Delphinuscapensis (n = 18), Stenellaattenuata (n = 8), S. longirostris (n = 6), and Phocoenoidesdalli (n = 8). The P4 concentrations were different (t = -7.1, p = 1.79E-08) between pregnant and non-pregnant animals in all species, with the mean blubber P4 concentration for pregnant animals 164 times higher than that of non-pregnant animals. There was no overlap in concentration levels between sexually immature or non-pregnant sexually mature animals and pregnant animals. No significant differences (F = 0.354, p = 0.559) were found between mature non-pregnant and immature D. capensis and Pdalli, suggesting P4 level is not indicative of maturity state in female delphinoids. P4 concentrations in relation to reproductive state were remarkably similar across species. All samples were analyzed with two different enzyme immunoassay kits to gauge assay sensitivity to measure progesterone in small samples, such as biopsies. With the technique now validated for these cetacean species, blubber P4 is a reliable diagnostic of pregnancies across multiple species, and thus expands the utility of this method to study reproduction in free-ranging cetaceans using biopsies. PMID- 23936082 TI - MEG correlates of learning novel objects properties in children. AB - Learning the functional properties of objects is a core mechanism in the development of conceptual, cognitive and linguistic knowledge in children. The cerebral processes underlying these learning mechanisms remain unclear in adults and unexplored in children. Here, we investigated the neurophysiological patterns underpinning the learning of functions for novel objects in 10-year-old healthy children. Event-related fields (ERFs) were recorded using magnetoencephalography (MEG) during a picture-definition task. Two MEG sessions were administered, separated by a behavioral verbal learning session during which children learned short definitions about the "magical" function of 50 unknown non-objects. Additionally, 50 familiar real objects and 50 other unknown non-objects for which no functions were taught were presented at both MEG sessions. Children learned at least 75% of the 50 proposed definitions in less than one hour, illustrating children's powerful ability to rapidly map new functional meanings to novel objects. Pre- and post-learning ERFs differences were analyzed first in sensor then in source space. Results in sensor space disclosed a learning-dependent modulation of ERFs for newly learned non-objects, developing 500-800 msec after stimulus onset. Analyses in the source space windowed over this late temporal component of interest disclosed underlying activity in right parietal, bilateral orbito-frontal and right temporal regions. Altogether, our results suggest that learning-related evolution in late ERF components over those regions may support the challenging task of rapidly creating new semantic representations supporting the processing of the meaning and functions of novel objects in children. PMID- 23936084 TI - T regulatory lymphocytes and endothelial function in pediatric obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a low-grade inflammatory disease affecting the cardiovascular and metabolic systems. Increasing OSA severity reduces T-regulatory lymphocytes (Tregs) in OSA children. Since Tregs modulate endothelial activation, and attenuate insulin resistance, we hypothesized that Tregs are associated with endothelial and metabolic dysfunction in pediatric OSA. METHODS: 50 consecutively recruited children (ages 4.8-12 years) underwent overnight polysomnography and fasting homeostatic model (HOMA) of insulin resistance was assessed. Percentage of Tregs using flow cytometry, and endothelial function, expressed as the time to peak occlusive hyperemia (Tmax), were examined. In a subgroup of children (n = 21), in vitro Treg suppression tests were performed. RESULTS: Circulating Tregs were not significantly associated with either BMI z score or HOMA. However, a significant inverse correlation between percentage of Tregs and Tmax emerged (p<0.0001, r = -0.56). A significant negative correlation between Tregs suppression and the sleep pressure score (SPS), a surrogate measure of sleep fragmentation emerged (p = 0.02, r = 0.51) emerged, but was not present with AHI. CONCLUSIONS: Endothelial function, but not insulin resistance, in OSA children is strongly associated with circulating Tregs and their suppressive function, and appears to correlate with sleep fragmentation. Thus, alterations in T cell lymphocytes may contribute to cardiovascular morbidity in pediatric OSA. PMID- 23936085 TI - Autotaxin signaling governs phenotypic heterogeneity in visceral and parietal mesothelia. AB - Mesothelia, which cover all coelomic organs and body cavities in vertebrates, perform diverse functions in embryonic and adult life. Yet, mesothelia are traditionally viewed as simple, uniform epithelia. Here we demonstrate distinct differences between visceral and parietal mesothelia, the most basic subdivision of this tissue type, in terms of gene expression, adhesion, migration, and invasion. Gene profiling determined that autotaxin, a secreted lysophospholipase D originally discovered as a tumor cell-motility-stimulating factor, was expressed exclusively in the more motile and invasive visceral mesothelia and at abnormally high levels in mesotheliomas. Gain and loss of function studies demonstrate that autotaxin signaling is indeed a critical factor responsible for phenotypic differences within mesothelia. Furthermore, we demonstrate that known and novel small molecule inhibitors of the autotaxin signaling pathway dramatically blunt migratory and invasive behaviors of aggressive mesotheliomas. Taken together, this study reveals distinct phenotypes within the mesothelial cell lineage, demonstrates that differential autotaxin expression is the molecular underpinning for these differences, and provides a novel target and lead compounds to intervene in invasive mesotheliomas. PMID- 23936086 TI - Algae as reservoirs for coral pathogens. AB - Benthic algae are associated with coral death in the form of stress and disease. It's been proposed that they release exudates, which facilitate invasion of potentially pathogenic microbes at the coral-algal interface, resulting in coral disease. However, the original source of these pathogens remains unknown. This study examined the ability of benthic algae to act as reservoirs of coral pathogens by characterizing surface associated microbes associated with major Caribbean and Indo-Pacific algal species/types and by comparing them to potential pathogens of two dominant coral diseases: White Syndrome (WS) in the Indo-Pacific and Yellow Band Disease (YBD) in the Caribbean. Coral and algal sampling was conducted simultaneously at the same sites to avoid spatial effects. Potential pathogens were defined as those absent or rare in healthy corals, increasing in abundance in healthy tissues adjacent to a disease lesion, and dominant in disease lesions. Potentially pathogenic bacteria were detected in both WS and YBD and were also present within the majority of algal species/types (54 and 100% for WS and YBD respectively). Pathogenic ciliates were associated only with WS and not YBD lesions and these were also present in 36% of the Indo-Pacific algal species. Although potential pathogens were associated with many algal species, their presence was inconsistent among replicate algal samples and detection rates were relatively low, suggestive of low density and occurrence. At the community level, coral-associated microbes irrespective of the health of their host differed from algal-associated microbes, supporting that algae and corals have distinctive microbial communities associated with their tissue. We conclude that benthic algae are common reservoirs for a variety of different potential coral pathogens. However, algal-associated microbes alone are unlikely to cause coral death. Initial damage or stress to the coral via other competitive mechanisms is most likely a prerequisite to potential transmission of these pathogens. PMID- 23936088 TI - Unit cost of medical services at different hospitals in India. AB - Institutional care is a growing component of health care costs in low- and middle income countries, but local health planners in these countries have inadequate knowledge of the costs of different medical services. In India, greater utilisation of hospital services is driven both by rising incomes and by government insurance programmes that cover the cost of inpatient services; however, there is still a paucity of unit cost information from Indian hospitals. In this study, we estimated operating costs and cost per outpatient visit, cost per inpatient stay, cost per emergency room visit, and cost per surgery for five hospitals of different types across India: a 57-bed charitable hospital, a 200 bed private hospital, a 400-bed government district hospital, a 655-bed private teaching hospital, and a 778-bed government tertiary care hospital for the financial year 2010-11. The major cost component varied among human resources, capital costs, and material costs, by hospital type. The outpatient visit cost ranged from Rs. 94 (district hospital) to Rs. 2,213 (private hospital) (USD 1 = INR 52). The inpatient stay cost was Rs. 345 in the private teaching hospital, Rs. 394 in the district hospital, Rs. 614 in the tertiary care hospital, Rs. 1,959 in the charitable hospital, and Rs. 6,996 in the private hospital. Our study results can help hospital administrators understand their cost structures and run their facilities more efficiently, and we identify areas where improvements in efficiency might significantly lower unit costs. The study also demonstrates that detailed costing of Indian hospital operations is both feasible and essential, given the significant variation in the country's hospital types. Because of the size and diversity of the country and variations across hospitals, a large-scale study should be undertaken to refine hospital costing for different types of hospitals so that the results can be used for policy purposes, such as revising payment rates under government-sponsored insurance schemes. PMID- 23936087 TI - Challenges in using cultured primary rodent hepatocytes or cell lines to study hepatic HDL receptor SR-BI regulation by its cytoplasmic adaptor PDZK1. AB - BACKGROUND: PDZK1 is a four PDZ-domain containing cytoplasmic protein that binds to a variety of membrane proteins via their C-termini and can influence the abundance, localization and/or function of its target proteins. One of these targets in hepatocytes in vivo is the HDL receptor SR-BI. Normal hepatic expression of SR-BI protein requires PDZK1 - <5% of normal hepatic SR-BI is seen in the livers of PDZK1 knockout mice. Progress has been made in identifying features of PDZK1 required to control hepatic SR-BI in vivo using hepatic expression of wild-type and mutant forms of PDZK1 in wild-type and PDZK1 KO transgenic mice. Such in vivo studies are time consuming and expensive, and cannot readily be used to explore many features of the underlying molecular and cellular mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: Here we have explored the potential to use either primary rodent hepatocytes in culture using 2D collagen gels with newly developed optimized conditions or PDZK1/SR-BI co-transfected cultured cell lines (COS, HEK293) for such studies. SR-BI and PDZK1 protein and mRNA expression levels fell rapidly in primary hepatocyte cultures, indicating this system does not adequately mimic hepatocytes in vivo for analysis of the PDZK1 dependence of SR-BI. Although PDZK1 did alter SR-BI protein expression in the cell lines, its influence was independent of SR-BI's C-terminus, and thus is not likely to occur via the same mechanism as that which occurs in hepatocytes in vivo. CONCLUSIONS/SIGNIFICANCE: Caution must be exercised in using primary hepatocytes or cultured cell lines when studying the mechanism underlying the regulation of hepatic SR-BI by PDZK1. It may be possible to use SR-BI and PDZK1 expression as sensitive markers for the in vivo-like state of hepatocytes to further improve primary hepatocyte cell culture conditions. PMID- 23936089 TI - Polymorphisms in DNA-repair genes in a cohort of prostate cancer patients from different areas in Spain: heterogeneity between populations as a confounding factor in association studies. AB - BACKGROUND: Differences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics. OBJECTIVE: To evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias. DESIGN SETTING AND PARTICIPANTS: A total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782), ERCC2 (rs13181), ERCC1 (rs11615), LIG4 (rs1805388, rs1805386), ATM (rs17503908, rs1800057) and P53 (rs1042522). The SNP genotyping was made in a Biotrove OpenArray(r) NT Cycler. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Comparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer. RESULTS AND LIMITATIONS: We observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics. CONCLUSION: Differences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack of validation of SNPs associated with radiation-induced toxicity, especially when extensive meta analysis with subjects from different countries are carried out. PMID- 23936090 TI - Rotigotine transdermal patch in Parkinson's disease: a systematic review and meta analysis. AB - BACKGROUND AND METHODS: The efficacy and safety of rotigotine transdermal patch in Parkinson's disease (PD) were studied in some clinical trials. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy, tolerability, and safety of rotigotine transdermal patch versus placebo in PD. RESULTS: Six randomized controlled trials (1789 patients) were included in this meta-analysis. As compared with placebo, the use of rotigotine resulted in greater improvements in Unified Parkinson's Disease Rating Scale activities of daily living score (weighted mean difference [WMD] -1.69, 95% confidence interval [CI] -2.18 to -1.19), motor score (WMD -3.86, 95% CI -4.86 to -2.86), and the activities of daily living and motor subtotal score (WMD -4.52, 95% CI -5.86 to -3.17). Rotigotine was associated with a significantly higher rate of withdrawals due to adverse events (relative risk [RR] 1.82, 95% CI 1.29 2.59), and higher rates of application site reactions (RR 2.92, 95% CI 2.29 3.72), vomiting (RR 5.18, 95% CI 2.25-11.93), and dyskinesia (RR 2.52, 95% CI 1.47-4.32) compared with placebo. No differences were found in the relative risks of headache, constipation, back pain, diarrhea, or serious adverse events. CONCLUSIONS: Our meta-analysis showed that the use of rotigotine can reduce the symptoms of PD. However, rotigotine was also associated with a higher incidence of adverse events, especially application site reactions, compared with placebo. PMID- 23936091 TI - Prevalence and phase variable expression status of two autotransporters, NalP and MspA, in carriage and disease isolates of Neisseria meningitidis. AB - Neisseria meningitidis is a human nasopharyngeal commensal capable of causing life-threatening septicemia and meningitis. Many meningococcal surface structures, including the autotransporter proteins NalP and MspA, are subject to phase variation (PV) due to the presence of homopolymeric tracts within their coding sequences. The functions of MspA are unknown. NalP proteolytically cleaves several surface-located virulence factors including the 4CMenB antigen NhbA. Therefore, NalP is a phase-variable regulator of the meningococcal outer membrane and secretome whose expression may reduce isolate susceptibility to 4CMenB induced immune responses. To improve our understanding of the contributions of MspA and NalP to meningococcal-host interactions, their distribution and phase variable expression status was studied in epidemiologically relevant samples, including 127 carriage and 514 invasive isolates representative of multiple clonal complexes and serogroups. Prevalence estimates of >98% and >88% were obtained for mspA and nalP, respectively, with no significant differences in their frequencies in disease versus carriage isolates. 16% of serogroup B (MenB) invasive isolates, predominately from clonal complexes ST-269 and ST-461, lacked nalP. Deletion of nalP often resulted from recombination events between flanking repetitive elements. PolyC tract lengths ranged from 6-15 bp in nalP and 6-14 bp in mspA. In an examination of PV status, 58.8% of carriage, and 40.1% of invasive nalP-positive MenB isolates were nalP phase ON. The frequency of this phenotype was not significantly different in serogroup Y (MenY) carriage strains, but was significantly higher in invasive MenY strains (86.3%; p<0.0001). Approximately 90% of MenB carriage and invasive isolates were mspA phase ON; significantly more than MenY carriage (32.7%) or invasive (13.7%) isolates. This differential expression resulted from different mode mspA tract lengths between the serogroups. Our data indicates a differential requirement for NalP and MspA expression in MenB and MenY strains and is a step towards understanding the contributions of phase-variable loci to meningococcal biology. PMID- 23936093 TI - Adverse respiratory health and hematological alterations among agricultural workers occupationally exposed to organophosphate pesticides: a cross-sectional study in North India. AB - BACKGROUND: Non-protective work practices followed by farm workers during spraying of pesticides lead to occupational exposure among them. OBJECTIVE: This study is designed to explore the respiratory health and hematological profile of agricultural workers occupationally exposed to OP pesticides. MATERIALS AND METHODS: A cross sectional study was undertaken among 166 pesticide sprayers working in mango orchards of Lucknow district in North India compared with 77 controls to assess the respiratory illness, lung functions, cholinesterase levels and hematological profile. A questionnaire based survey and clinical examination for respiratory health were conducted among study subjects. Lung function test was conducted among study subjects by using spirometer. Cholinesterase level as biomarker of OP pesticides and hematological profile of study subjects were investigated in the laboratory by following the standard protocols. RESULTS: Overall respiratory morbidity observed among exposed subjects was 36.75%. Symptoms for respiratory illness like dry cough, productive cough, wheezing, irritation of throat and blood stained sputum were found to be significantly more (p<0.05) among pesticide sprayers than controls. Lung function parameters viz. PEFR, FEV1, %PEFR predicted, %FEV1 predicted and FEV1/FVC were found to be significantly decreased (p<0.05) among pesticide sprayers as compared to controls. Exposure wise distribution of respiratory illness and lung functions among pesticide sprayers show that the exposure duration significantly elevates (p<0.05) the respiratory problems and significantly decreases (p<0.001) lung functions among pesticide sprayers. Activities of acetylcholinesterase and butyrylcholinesterase were found to be significantly depleted (p<0.001) among pesticide sprayers as compared to controls which show the exposure of OP pesticides among them. The hematological profile viz. RBC, WBC, monocytes, neutrophils, MCV, MCH, MCHC and platelet count were significantly altered (p<0.001) in pesticide sprayers than controls. CONCLUSION: This study shows that the unsafe occupational exposure of OP pesticides causes respiratory illness, decreased lung functions and hematological alterations among pesticide sprayers. PMID- 23936092 TI - VAR2CSA signatures of high Plasmodium falciparum parasitemia in the placenta. AB - Plasmodium falciparum infected erythrocytes (IE) accumulate in the placenta through the interaction between Duffy-binding like (DBL) domains of parasite encoded ligand VAR2CSA and chondroitin sulphate-A (CSA) receptor. Polymorphisms in these domains, including DBL2X and DBL3X, may affect their antigenicity or CSA binding affinity, eventually increasing parasitemia and its adverse effects on pregnancy outcomes. A total of 373 DBL2X and 328 DBL3X sequences were obtained from transcripts of 20 placental isolates infecting Mozambican women, resulting in 176 DBL2X and 191 DBL3X unique sequences at the protein level. Sequence alignments were divided in segments containing combinations of correlated polymorphisms and the association of segment sequences with placental parasite density was tested using Bonferroni corrected regression models, taking into consideration the weight of each sequence in the infection. Three DBL2X and three DBL3X segments contained signatures of high parasite density (P<0.003) that were highly prevalent in the parasite population (49-91%). Identified regions included a flexible loop that contributes to DBL3X-CSA interaction and two DBL3X motifs with evidence of positive natural selection. Limited antibody responses against signatures of high parasite density among malaria-exposed pregnant women could not explain the increased placental parasitemia. These results suggest that a higher binding efficiency to CSA rather than reduced antigenicity might provide a biological advantage to parasites with high parasite density signatures in VAR2CSA. Sequences contributing to high parasitemia may be critical for the functional characterization of VAR2CSA and the development of tools against placental malaria. PMID- 23936094 TI - Decrease of miR-202-3p expression, a novel tumor suppressor, in gastric cancer. AB - Emerging studies have indicated that microRNAs are involved in the development and progression of cancer. Here we found that miR-202-3p was frequently down regulated in gastric cancer tissues. Overexpression of miR-202-3p in gastric cancer cells MKN-28 and BGC-823, markedly suppressed cell proliferation and induced cell apoptosis both in vitro and in vivo. Furthermore, Gli1 expression was frequently positive in gastric cancer tissues and inversely correlated with miR-133b expression. We demonstrate that the transcriptional factor Gli1 was a target of miR-202-3p and plays an essential role as a mediator of the biological effects of miR-202-3p in gastric cancer. MiR-202-3p also inhibited the expression of gamma-catenin and BCL-2. Taken together, these findings suggest that miR-202 3p may function as a novel tumor suppressor in gastric cancer and its anti-tumor activity may attribute the direct targeting and inhibition of Gli1. PMID- 23936095 TI - Resistance development of cystic fibrosis respiratory pathogens when exposed to fosfomycin and tobramycin alone and in combination under aerobic and anaerobic conditions. AB - Although antibiotics from different classes are frequently prescribed in combination to prevent the development of resistance amongst Cystic Fibrosis (CF) respiratory pathogens, there is a lack of data as to the efficacy of this approach. We have previously shown that a 4:1 (w/w) combination of fosfomycin and tobramycin (F:T) has excellent activity against CF pathogens with increased activity under physiologically relevant anaerobic conditions. Therefore, the aim of this study was to determine whether F:T could delay or prevent the onset of resistance compared to either fosfomycin or tobramycin alone under aerobic and anaerobic conditions. The frequency of spontaneous mutants arising following exposure to fosfomycin, tobramycin and F:T was determined for clinical Pseudomonas aeruginosa and MRSA isolates under aerobic and anaerobic conditions. The effect of sub-inhibitory concentrations of fosfomycin, tobramycin and F:T on the induction of resistance was also investigated, with the stability of resistance and fitness cost associated with resistance assessed if it developed. P. aeruginosa and MRSA isolates had a lower frequency of spontaneous mutants to F:T compared to fosfomycin and tobramycin under both aerobic and anaerobic conditions. There was a maximum two-fold increase in F:T MICs when P. aeruginosa and MRSA isolates were passaged in sub-inhibitory F:T for 12 days. In contrast, sequential resistance to fosfomycin and tobramycin developed quickly (n = 3 days for both) after passage in sub-inhibitory concentrations. Once developed, both fosfomycin and tobramycin resistance was stable and not associated with a biological fitness cost to either P. aeruginosa or MRSA isolates. The results of this study suggest that F:T may prevent the development of resistance compared to fosfomycin or tobramycin alone under aerobic and physiologically relevant anaerobic conditions. F:T may be a potential treatment option in CF patients chronically colonised by MRSA and/or P. aeruginosa. PMID- 23936096 TI - Two coiled-coil domains of Chlamydia trachomatis IncA affect membrane fusion events during infection. AB - Chlamydia trachomatis replicates in a parasitophorous membrane-bound compartment called an inclusion. The inclusions corrupt host vesicle trafficking networks to avoid the degradative endolysosomal pathway but promote fusion with each other in order to sustain higher bacterial loads in a process known as homotypic fusion. The Chlamydia protein IncA (Inclusion protein A) appears to play central roles in both these processes as it participates to homotypic fusion and inhibits endocytic SNARE-mediated membrane fusion. How IncA selectively inhibits or activates membrane fusion remains poorly understood. In this study, we analyzed the spatial and molecular determinants of IncA's fusogenic and inhibitory functions. Using a cell-free membrane fusion assay, we found that inhibition of SNARE-mediated fusion requires IncA to be on the same membrane as the endocytic SNARE proteins. IncA displays two coiled-coil domains showing high homology with SNARE proteins. Domain swap and deletion experiments revealed that although both these domains are capable of independently inhibiting SNARE-mediated fusion, these two coiled-coil domains cooperate in mediating IncA multimerization and homotypic membrane interaction. Our results support the hypothesis that Chlamydia employs SNARE-like virulence factors that positively and negatively affect membrane fusion and promote infection. PMID- 23936097 TI - Allosteric inhibitors of the NS3 protease from the hepatitis C virus. AB - The nonstructural protein 3 (NS3) from the hepatitis C virus processes the non structural region of the viral precursor polyprotein in infected hepatic cells. The NS3 protease activity has been considered a target for drug development since its identification two decades ago. Although specific inhibitors have been approved for clinical therapy very recently, resistance-associated mutations have already been reported for those drugs, compromising their long-term efficacy. Therefore, there is an urgent need for new anti-HCV agents with low susceptibility to resistance-associated mutations. Regarding NS3 protease, two strategies have been followed: competitive inhibitors blocking the active site and allosteric inhibitors blocking the binding of the accessory viral protein NS4A. In this work we exploit the intrinsic Zn(+2)-regulated plasticity of the protease to identify a new type of allosteric inhibitors. In the absence of Zn(+2), the NS3 protease adopts a partially-folded inactive conformation. We found ligands binding to the Zn(+2)-free NS3 protease, trap the inactive protein, and block the viral life cycle. The efficacy of these compounds has been confirmed in replicon cell assays. Importantly, direct calorimetric assays reveal a low impact of known resistance-associated mutations, and enzymatic assays provide a direct evidence of their inhibitory activity. They constitute new low molecular-weight scaffolds for further optimization and provide several advantages: 1) new inhibition mechanism simultaneously blocking substrate and cofactor interactions in a non-competitive fashion, appropriate for combination therapy; 2) low impact of known resistance-associated mutations; 3) inhibition of NS4A binding, thus blocking its several effects on NS3 protease. PMID- 23936098 TI - Associations of organic produce consumption with socioeconomic status and the local food environment: Multi-Ethnic Study of Atherosclerosis (MESA). AB - Neighborhood characteristics, such as healthy food availability, have been associated with consumption of healthy food. Little is known about the influence of the local food environment on other dietary choices, such as the decision to consume organic food. We analyzed the associations between organic produce consumption and demographic, socioeconomic and neighborhood characteristics in 4,064 participants aged 53-94 in the Multi-Ethnic Study of Atherosclerosis using log-binomial regression models. Participants were classified as consuming organic produce if they reported eating organic fruits and vegetables either "sometimes" or "often or always". Women were 21% more likely to consume organic produce than men (confidence interval [CI]: 1.12-1.30), and the likelihood of organic produce consumption was 13% less with each additional 10 years of age (CI: 0.84-0.91). Participants with higher education were significantly more likely to consume organic produce (prevalence ratios [PR] were 1.05 with a high school education, 1.39 with a bachelor's degree and 1.68 with a graduate degree, with less than high school as the reference group [1.00]). Per capita household income was marginally associated with produce consumption (p = 0.06), with the highest income category more likely to consume organic produce. After adjustment for these individual factors, organic produce consumption was significantly associated with self-reported assessment of neighborhood produce availability (PR: 1.07, CI: 1.02-1.11), with an aggregated measure of community perception of the local food environment (PR: 1.08, CI: 1.00-1.17), and, to a lesser degree, with supermarket density (PR: 1.02: CI: 0.99-1.05). This research suggests that both individual-level characteristics and qualities of the local food environment are associated with having a diet that includes organic food. PMID- 23936099 TI - C5a regulates IL-12+ DC migration to induce pathogenic Th1 and Th17 cells in sepsis. AB - OBJECTIVE: It is well known that complement system C5a is excessively activated during the onset of sepsis. However, it is unclear whether C5a can regulate dentritic cells (DCs) to stimulate adaptive immune cells such as Th1 and Th17 in sepsis. METHODS: Sepsis was induced by cecal ligation and puncture (CLP). CLP induced sepsis was treated with anti-C5a or IL-12. IL-12(+)DC, IFNgamma(+)Th1, and IL-17(+)Th17 cells were analyzed by flow cytometry. IL-12 was measured by ELISA. RESULTS: Our studies here showed that C5a induced IL-12(+)DC cell migration from the peritoneal cavity to peripheral blood and lymph nodes. Furthermore, IL-12(+)DC cells induced the expansion of pathogenic IFNgamma(+)Th1 and IL-17(+)Th17 cells in peripheral blood and lymph nodes. Moreover, IL-12, secreted by DC cells in the peritoneal cavity, is an important factor that prevents the development of sepsis. CONCLUSION: Our data suggests that C5a regulates IL-12(+)DC cell migration to induce pathogenic Th1 and Th17 cells in sepsis. PMID- 23936100 TI - The C57BL/6J mouse exhibits sporadic congenital portosystemic shunts. AB - C57BL/6 mice are the most widely used strain of laboratory mice. Using in vivo proton Magnetic Resonance Spectroscopy ((1)H MRS), we have repeatedly observed an abnormal neurochemical profile in the brains of both wild-type and genetically modified mice derived from the C57BL/6J strain, consisting of a several fold increase in cerebral glutamine and two fold decrease in myo-inositol. This strikingly abnormal neurochemical "phenotype" resembles that observed in chronic liver disease or portosystemic shunting and appeared to be independent of transgene, origin or chow and was not associated with liver failure. As many as 25% of animals displayed the abnormal neurochemical profile, questioning the reliability of this model for neurobiology. We conducted an independent study to determine if this neurochemical profile was associated with portosystemic shunting. Our results showed that 100% of the mice with high brain glutamine displayed portosystemic shunting by concomitant portal angiography while all mice with normal brain glutamine did not. Since portosystemic shunting is known to cause alterations in gene expression in many organs including the brain, we conclude that portosystemic shunting may be the most significant problem associated with C57BL/6J inbreeding both for its effect on the central nervous system and for its systemic repercussions. PMID- 23936101 TI - Low cross-sex genetic correlation in carotenoid-based plumage traits in the blue tit nestlings (Cyanistes caeruleus). AB - In some bird species, both adult and juvenile individuals are often brightly coloured. It has been commonly assumed that identical plumage colouration present in both sexes results from strong intersexual genetic correlations in colour related traits. Here, we aimed at testing this hypothesis in juvenile individuals and looked at genetic parameters describing carotenoid-based colouration of blue tit nestlings in a wild population. To separate genetic and environmental sources of phenotypic variation we performed a cross-fostering experiment. Our analyses confirmed the existence of sexual dichromatism in blue tit nestlings and revealed a significant, although low, genetic component of carotenoid-based colouration. However, genetic effects are expressed differently across sexes as indicated by low cross-sex genetic correlations (rmf). Thus our results do not support the prediction of generally high rmf and suggest that intersexual constraints on the evolution of colouration traits may be weaker than expected. We hypothesise that observed patterns of genetic correlations result from sex-specific selective pressures acting on nestling plumage colouration. PMID- 23936102 TI - Identification and candidate gene analysis of a novel phytophthora resistance gene Rps10 in a Chinese soybean cultivar. AB - Resistance to Phytophthora sojae isolate PsMC1 was evaluated in 102 F2?3 families derived from a cross between the resistant soybean cultivar Wandou 15 and the susceptible cultivar Williams and genotyped using simple sequence repeat (SSR) markers. The segregation ratio of resistant, segregating, and susceptible phenotypes in the population suggested that the resistance in Wandou 15 was dominant and monogenic. Twenty-six polymorphic SSR markers were identified on soybean chromosome 17 (Molecular linkage group D2; MLG D2), which were linked to the resistance gene based on bulked segregation analysis (BSA). Markers Sattwd15 24/25 and Sattwd15-47 flanked the resistance gene at a distance of 0.5 cM and 0.8 cM, respectively. Two cosegregating markers, Sattwd15-28 and Sattwd15-32, were also screened in this region. This is the first Rps resistance gene mapped on chromosome 17, which is designated as Rps10. Eight putative genes were found in the mapped region between markers Sattwd15-24/25 and Sattwd15-47. Among them, two candidate genes encoding serine/threonine (Ser/Thr) protein kinases in Wandou 15 and Williams were identified and sequenced. And the differences in genomic sequence and the putative amino acid sequence, respectively, were identified within each candidate gene between Wandou 15 and Williams. This novel gene Rps10 and the linked markers should be useful in developing soybean cultivars with durable resistance to P. sojae. PMID- 23936103 TI - Unique and conserved microRNAs in wheat chromosome 5D revealed by next-generation sequencing. AB - MicroRNAs are a class of short, non-coding, single-stranded RNAs that act as post transcriptional regulators in gene expression. miRNA analysis of Triticum aestivum chromosome 5D was performed on 454 GS FLX Titanium sequences of flow sorted chromosome 5D with a total of 3,208,630 good quality reads representing 1.34x and 1.61x coverage of the short (5DS) and long (5DL) arms of the chromosome respectively. In silico and structural analyses revealed a total of 55 miRNAs; 48 and 42 miRNAs were found to be present on 5DL and 5DS respectively, of which 35 were common to both chromosome arms, while 13 miRNAs were specific to 5DL and 7 miRNAs were specific to 5DS. In total, 14 of the predicted miRNAs were identified in wheat for the first time. Representation (the copy number of each miRNA) was also found to be higher in 5DL (1,949) compared to 5DS (1,191). Targets were predicted for each miRNA, while expression analysis gave evidence of expression for 6 out of 55 miRNAs. Occurrences of the same miRNAs were also found in Brachypodium distachyon and Oryza sativa genome sequences to identify syntenic miRNA coding sequences. Based on this analysis, two other miRNAs: miR1133 and miR167 were detected in B. distachyon syntenic region of wheat 5DS. Five of the predicted miRNA coding regions (miR6220, miR5070, miR169, miR5085, miR2118) were experimentally verified to be located to the 5D chromosome and three of them : miR2118, miR169 and miR5085, were shown to be 5D specific. Furthermore miR2118 was shown to be expressed in Chinese Spring adult leaves. miRNA genes identified in this study will expand our understanding of gene regulation in bread wheat. PMID- 23936104 TI - Elevated carbon monoxide in the exhaled breath of mice during a systemic bacterial infection. AB - Blood is the specimen of choice for most laboratory tests for diagnosis and disease monitoring. Sampling exhaled breath is a noninvasive alternative to phlebotomy and has the potential for real-time monitoring at the bedside. Improved instrumentation has advanced breath analysis for several gaseous compounds from humans. However, application to small animal models of diseases and physiology has been limited. To extend breath analysis to mice, we crafted a means for collecting nose-only breath samples from groups and individual animals who were awake. Samples were subjected to gas chromatography and mass spectrometry procedures developed for highly sensitive analysis of trace volatile organic compounds (VOCs) in the atmosphere. We evaluated the system with experimental systemic infections of severe combined immunodeficiency Mus musculus with the bacterium Borrelia hermsii. Infected mice developed bacterial densities of ~10(7) per ml of blood by day 4 or 5 and in comparison to uninfected controls had hepatosplenomegaly and elevations of both inflammatory and anti-inflammatory cytokines. While 12 samples from individual infected mice on days 4 and 5 and 6 samples from uninfected mice did not significantly differ for 72 different VOCs, carbon monoxide (CO) was elevated in samples from infected mice, with a mean (95% confidence limits) effect size of 4.2 (2.8-5.6), when differences in CO2 in the breath were taken into account. Normalized CO values declined to the uninfected range after one day of treatment with the antibiotic ceftriaxone. Strongly correlated with CO in the breath were levels of heme oxygenase-1 protein in serum and HMOX1 transcripts in whole blood. These results (i) provide further evidence of the informativeness of CO concentration in the exhaled breath during systemic infection and inflammation, and (ii) encourage evaluation of this noninvasive analytic approach in other various other rodent models of infection and for utility in clinical management. PMID- 23936106 TI - Estimating age ratios and size of pacific walrus herds on coastal haulouts using video imaging. AB - During Arctic summers, sea ice provides resting habitat for Pacific walruses as it drifts over foraging areas in the eastern Chukchi Sea. Climate-driven reductions in sea ice have recently created ice-free conditions in the Chukchi Sea by late summer causing walruses to rest at coastal haulouts along the Chukotka and Alaska coasts, which provides an opportunity to study walruses at relatively accessible locations. Walrus age can be determined from the ratio of tusk length to snout dimensions. We evaluated use of images obtained from a gyro stabilized video system mounted on a helicopter flying at high altitudes (to avoid disturbance) to classify the sex and age of walruses hauled out on Alaska beaches in 2010-2011. We were able to classify 95% of randomly selected individuals to either an 8- or 3-category age class, and we found measurement based age classifications were more repeatable than visual classifications when using images presenting the correct head profile. Herd density at coastal haulouts averaged 0.88 walruses/m(2) (std. err. = 0.02), herd size ranged from 8,300 to 19,400 (CV 0.03-0.06) and we documented ~30,000 animals along ~1 km of beach in 2011. Within the herds, dependent walruses (0-2 yr-olds) tended to be located closer to water, and this tendency became more pronounced as the herd spent more time on the beach. Therefore, unbiased estimation of herd age-ratios will require a sampling design that allows for spatial and temporal structuring. In addition, randomly sampling walruses available at the edge of the herd for other purposes (e.g., tagging, biopsying) will not sample walruses with an age structure representative of the herd. Sea ice losses are projected to continue, and population age structure data collected with aerial videography at coastal haulouts may provide demographic information vital to ongoing efforts to understand effects of climate change on this species. PMID- 23936105 TI - Complete genes may pass from food to human blood. AB - Our bloodstream is considered to be an environment well separated from the outside world and the digestive tract. According to the standard paradigm large macromolecules consumed with food cannot pass directly to the circulatory system. During digestion proteins and DNA are thought to be degraded into small constituents, amino acids and nucleic acids, respectively, and then absorbed by a complex active process and distributed to various parts of the body through the circulation system. Here, based on the analysis of over 1000 human samples from four independent studies, we report evidence that meal-derived DNA fragments which are large enough to carry complete genes can avoid degradation and through an unknown mechanism enter the human circulation system. In one of the blood samples the relative concentration of plant DNA is higher than the human DNA. The plant DNA concentration shows a surprisingly precise log-normal distribution in the plasma samples while non-plasma (cord blood) control sample was found to be free of plant DNA. PMID- 23936107 TI - Overexpression of GmHsp90s, a heat shock protein 90 (Hsp90) gene family cloning from soybean, decrease damage of abiotic stresses in Arabidopsis thaliana. AB - Hsp90 is one of the most conserved and abundant molecular chaperones and is an essential component of the protective stress response; however, its roles in abiotic stress responses in soybean (Glycine max) remain obscure. Here, 12 GmHsp90 genes from soybean were identified and found to be expressed and to function differentially under abiotic stresses. The 12 GmHsp90 genes were isolated and named GmHsp90A1-GmHsp90A6, GmHsp90B1, GmHsp90B2, GmHsp90C1.1, GmHsp90C1.2, GmHsp90C2.1 and GmHsp90C2.2 based on their characteristics and high homology to other Hsp90s according to a new nomenclature system. Quantitative real-time PCR expression data revealed that all the genes exhibited higher transcript levels in leaves and could be strongly induced under heat, osmotic and salt stress but not cold stress. Overexpression of five typical genes (GmHsp90A2, GmHsp90A4, GmHsp90B1, GmHsp90C1.1 and GmHsp90C2.1) in Arabidopsis thaliana provided useful evidences that GmHsp90 genes can decrease damage of abiotic stresses. In addition, an abnormal accumulation of proline was detected in some transgenic Arabidopsis plants suggested overexpressing GmHsp90s may affect the synthesis and response system of proline. Our work represents a systematic determination of soybean genes encoding Hsp90s, and provides useful evidence that GmHsp90 genes function differently in response to abiotic stresses and may affect the synthesis and response system of proline. PMID- 23936108 TI - Enhanced nanomagnetic gene transfection of human prenatal cardiac progenitor cells and adult cardiomyocytes. AB - Magnetic nanoparticle-based gene transfection has been shown to be an effective, non-viral technique for delivery of both plasmid DNA and siRNA into cells in culture. It has several advantages over other non-viral delivery techniques, such as short transfection times and high cell viability. These advantages have been demonstrated in a number of primary cells and cell lines. Here we report that oscillating magnet array-based nanomagnetic transfection significantly improves transfection efficiency in both human prenatal cardiac progenitor cells and adult cardiomyocytes when compared to static magnetofection, cationic lipid reagents and electroporation, while maintaining high cell viability. In addition, transfection of adult cardiomyocytes was improved further by seeding the cells onto Collagen I-coated plates, with transfection efficiencies of up to 49% compared to 24% with lipid reagents and 19% with electroporation. These results demonstrate that oscillating nanomagnetic transfection far outperforms other non viral transfection techniques in these important cells. PMID- 23936109 TI - Fractalkine depresses cardiomyocyte contractility. AB - BACKGROUND: Our laboratory reported that male mice with cardiomyocyte-selective knockout of the prostaglandin E2 EP4 receptor sub-type (EP4 KO) exhibit reduced cardiac function. Gene array on left ventricles (LV) showed increased fractalkine, a chemokine implicated in heart failure. We therefore hypothesized that fractalkine is regulated by PGE2 and contributes to depressed contractility via alterations in intracellular calcium. METHODS: Fractalkine was measured in LV of 28-32 week old male EP4 KO and wild type controls (WT) by ELISA and the effect of PGE2 on fractalkine secretion was measured in cultured neonatal cardiomyocytes and fibroblasts. The effect of fractalkine on contractility and intracellular calcium was determined in Fura-2 AM-loaded, electrical field-paced cardiomyocytes. Cardiomyocytes (AVM) from male C57Bl/6 mice were treated with fractalkine and responses measured under basal conditions and after isoproterenol (Iso) stimulation. RESULTS: LV fractalkine was increased in EP4 KO mice but surprisingly, PGE2 regulated fractalkine secretion only in fibroblasts. Fractalkine treatment of AVM decreased both the speed of contraction and relaxation under basal conditions and after Iso stimulation. Despite reducing contractility after Iso stimulation, fractalkine increased the Ca(2+) transient amplitude but decreased phosphorylation of cardiac troponin I, suggesting direct effects on the contractile machinery. CONCLUSIONS: Fractalkine depresses myocyte contractility by mechanisms downstream of intracellular calcium. PMID- 23936110 TI - Soil particle heterogeneity affects the growth of a rhizomatous wetland plant. AB - Soil is commonly composed of particles of different sizes, and soil particle size may greatly affect the growth of plants because it affects soil physical and chemical properties. However, no study has tested the effects of soil particle heterogeneity on the growth of clonal plants. We conducted a greenhouse experiment in which individual ramets of the wetland plant Bolboschoenus planiculmis were grown in three homogeneous soil treatments with uniformly sized quartz particles (small: 0.75 mm, medium: 1.5 mm, or large: 3 mm), one homogeneous treatment with an even mixture of large and medium particles, and two heterogeneous treatments consisting of 16 or 4 patches of large and medium particles. Biomass, ramet number, rhizome length and spacer length were significantly greater in the treatment with only medium particles than in the one with only large particles. Biomass, ramet number, rhizome length and tuber number in the patchy treatments were greater in patches of medium than of large particles; this difference was more pronounced when patches were small than when they were large. Soil particle size and soil particle heterogeneity can greatly affect the growth of clonal plants. Thus, studies to test the effects of soil heterogeneity on clonal plants should distinguish the effects of nutrient heterogeneity from those of particle heterogeneity. PMID- 23936111 TI - A joint matrix completion and filtering model for influenza serological data integration. AB - Antigenic characterization based on serological data, such as Hemagglutination Inhibition (HI) assay, is one of the routine procedures for influenza vaccine strain selection. In many cases, it would be impossible to measure all pairwise antigenic correlations between testing antigens and reference antisera in each individual experiment. Thus, we have to combine and integrate the HI tables from a number of individual experiments. Measurements from different experiments may be inconsistent due to different experimental conditions. Consequently we will observe a matrix with missing data and possibly inconsistent measurements. In this paper, we develop a new mathematical model, which we refer to as Joint Matrix Completion and Filtering, for HI data integration. In this approach, we simultaneously handle the incompleteness and uncertainty of observations by assuming that the underlying merged HI data matrix has low rank, as well as carefully modeling different levels of noises in each individual table. An efficient blockwise coordinate descent procedure is developed for optimization. The performance of our approach is validated on synthetic and real influenza datasets. The proposed joint matrix completion and filtering model can be adapted as a general model for biological data integration, targeting data noises and missing values within and across experiments. PMID- 23936112 TI - Differential gene expression at the maternal-fetal interface in preeclampsia is influenced by gestational age. AB - Genome-wide transcription data of utero-placental tissue has been used to identify altered gene expression associated with preeclampsia (PE). As many women with PE deliver preterm, there is often a difference in gestational age between PE women and healthy pregnant controls. This may pose a potential bias since gestational age has been shown to dramatically influence gene expression in utero placental tissue. By pooling data from three genome-wide transcription studies of the maternal-fetal interface, we have evaluated the relative effect of gestational age and PE on gene expression. A total of 18,180 transcripts were evaluated in 49 PE cases and 105 controls, with gestational age ranging from week 14 to 42. A total of 22 transcripts were associated with PE, whereas 92 transcripts with gestational age (nominal P value <1.51*10(-6), Bonferroni adjusted P value <0.05). Our results indicate that gestational age has a great influence on gene expression both in normal and PE-complicated pregnancies. This effect might introduce serious bias in data analyses and needs to be carefully assessed in future genome-wide transcription studies. PMID- 23936113 TI - Handgrip strength predicts functional decline at discharge in hospitalized male elderly: a hospital cohort study. AB - Functional decline after hospitalization is a common adverse outcome in elderly. An easy to use, reproducible and accurate tool to identify those at risk would aid focusing interventions in those at higher risk. Handgrip strength has been shown to predict adverse outcomes in other settings. The aim of this study was to determine if handgrip strength measured upon admission to an acute care facility would predict functional decline (either incident or worsening of preexisting) at discharge among older Mexican, stratified by gender. In addition, cutoff points as a function of specificity would be determined. A cohort study was conducted in two hospitals in Mexico City. The primary endpoint was functional decline on discharge, defined as a 30-point reduction in the Barthel Index score from that of the baseline score. Handgrip strength along with other variables was measured at initial assessment, including: instrumental activities of daily living, cognition, depressive symptoms, delirium, hospitalization length and quality of life. All analyses were stratified by gender. Logistic regression to test independent association between handgrip strength and functional decline was performed, along with estimation of handgrip strength test values (specificity, sensitivity, area under the curve, etc.). A total of 223 patients admitted to an acute care facility between 2007 and 2009 were recruited. A total of 55 patients (24.7%) had functional decline, 23.46% in male and 25.6% in women. Multivariate analysis showed that only males with low handgrip strength had an increased risk of functional decline at discharge (OR 0.88, 95% CI 0.79-0.98, p = 0.01), with a specificity of 91.3% and a cutoff point of 20.65 kg for handgrip strength. Females had not a significant association between handgrip strength and functional decline. Measurement of handgrip strength on admission to acute care facilities may identify male elderly patients at risk of having functional decline, and intervene consequently. PMID- 23936114 TI - Estradiol regulation of nucleotidases in female reproductive tract epithelial cells and fibroblasts. AB - The use of topical and oral adenosine derivatives in HIV prevention that need to be maintained in tissues and cells at effective levels to prevent transmission prompted us to ask whether estradiol could influence the regulation of catabolic nucleotidase enzymes in epithelial cells and fibroblasts from the upper and lower female reproductive tract (FRT) as these might affect cellular TFV-DP levels. Epithelial cells and fibroblasts were isolated from endometrium (EM), endocervix (CX) and ectocervix (ECX) tissues from hysterectomy patients, grown to confluence and treated with or without estradiol prior to RNA isolation. The expression of nucleotidase (NT) genes was measurable by RT-PCR in epithelial cells and fibroblasts from all FRT tissues. To determine if sex hormones have the potential to regulate NT, we evaluated NT gene expression and NT biological activity in FRT cells following hormone treatment. Estradiol increased expression of Cytosolic 5' nucleotidase after 2 or 4 h in endometrial epithelial cells but not epithelial cells or fibroblasts from other sites. In studies using a modified 5' Nucleotidase biological assay for nucleotidases, estradiol increased NT activity in epithelial cells and fibroblasts from the EM, CX and ECX at 24 and 48 h. In related studies, HUVEC primary cells and a HUVEC cell line were unresponsive to estradiol in terms of nucleotidase expression or biological activity. Our findings of an increase in nucleotidase expression and biological activity induced by estradiol do not directly assess changes in microbicide metabolism. However, they do suggest that when estradiol levels are elevated during the menstrual cycle, FRT epithelial cells and fibroblasts from the EM, CX and ECX have the potential to influence microbicide levels that could enhance protection of HIV-target cells (CD4+T cells, macrophages and dendritic cells) throughout the FRT. PMID- 23936115 TI - Protective efficacy of VP1-specific neutralizing antibody associated with a reduction of viral load and pro-inflammatory cytokines in human SCARB2-transgenic mice. AB - Hand-foot-mouth diseases (HFMD) caused by enterovirus 71 (EV71) and coxsackievirus 16 (CVA16) in children have now become a severe public health issue in the Asian-Pacific region. Recently we have successfully developed transgenic mice expressing human scavenger receptor class B member 2 (hSCARB2, a receptor of EV71 and CVA16) as an animal model for evaluating the pathogenesis of enterovirus infections. In this study, hSCARB2-transgenic mice were used to investigate the efficacy conferred by a previously described EV71 neutralizing antibody, N3. A single injection of N3 effectively inhibited the HFMD-like skin scurfs in mice pre-infected with clinical isolate of EV71 E59 (B4 genotype) or prevented severe limb paralysis and death in mice pre-inoculated with 5746 (C2 genotype). This protection was correlated with remarkable reduction of viral loads in the brain, spinal cord and limb muscles. Accumulated viral loads and the associated pro-inflammatory cytokines were all reduced. The protective efficacy of N3 was not observed in animals challenged with CVA16. This could be due to dissimilarity sequences of the neutralizing epitope found in CVA16. These results indicate N3 could be useful in treating severe EV71 infections and the hSCARB2 transgenic mouse could be used to evaluate the protective efficacy of potential anti-enterovirus agent candidates. PMID- 23936116 TI - Expression and functional characterization of Xhmg-at-hook genes in Xenopus laevis. AB - High Mobility Group A proteins (HMGA1 and HMGA2) are architectural nuclear factors involved in development, cell differentiation, and cancer formation and progression. Here we report the cloning, developmental expression and functional analysis of a new multi-AT-hook factor in Xenopus laevis (XHMG-AT-hook) that exists in three different isoforms. Xhmg-at-hook1 and 3 isoforms, but not isoform 2, are expressed throughout the entire development of Xenopus, both in the maternal and zygotic phase. Localized transcripts are present in the animal pole in the early maternal phase; during the zygotic phase, mRNA can be detected in the developing central nervous system (CNS), including the eye, and in the neural crest. We show evidence that XHMG-AT-hook proteins differ from typical HMGA proteins in terms of their properties in DNA binding and in protein/protein interaction. Finally, we provide evidence that they are involved in early CNS development and in neural crest differentiation. PMID- 23936118 TI - Climatic correlates of tree mortality in water- and energy-limited forests. AB - Recent increases in tree mortality rates across the western USA are correlated with increasing temperatures, but mechanisms remain unresolved. Specifically, increasing mortality could predominantly be a consequence of temperature-induced increases in either (1) drought stress, or (2) the effectiveness of tree-killing insects and pathogens. Using long-term data from California's Sierra Nevada mountain range, we found that in water-limited (low-elevation) forests mortality was unambiguously best modeled by climatic water deficit, consistent with the first mechanism. In energy-limited (high-elevation) forests deficit models were only equivocally better than temperature models, suggesting that the second mechanism is increasingly important in these forests. We could not distinguish between models predicting mortality using absolute versus relative changes in water deficit, and these two model types led to different forecasts of mortality vulnerability under future climate scenarios. Our results provide evidence for differing climatic controls of tree mortality in water- and energy-limited forests, while highlighting the need for an improved understanding of tree mortality processes. PMID- 23936117 TI - Regulation of flagellar biogenesis by a calcium dependent protein kinase in Chlamydomonas reinhardtii. AB - Chlamydomonas reinhardtii, a bi-flagellated green alga, is a model organism for studies of flagella or cilia related activities including cilia-based signaling, flagellar motility and flagellar biogenesis. Calcium has been shown to be a key regulator of these cellular processes whereas the signaling pathways linking calcium to these cellular functions are less understood. Calcium-dependent protein kinases (CDPKs), which are present in plants but not in animals, are also present in ciliated microorganisms which led us to examine their possible functions and mechanisms in flagellar related activities. By in silico analysis of Chlamydomonas genome we have identified 14 CDPKs and studied one of the flagellar localized CDPKs--CrCDPK3. CrCDPK3 was a protein of 485 amino acids and predicted to have a protein kinase domain at the N-terminus and four EF-hand motifs at the C-terminus. In flagella, CrCDPK3 was exclusively localized in the membrane matrix fraction and formed an unknown 20 S protein complex. Knockdown of CrCDPK3 expression by using artificial microRNA did not affect flagellar motility as well as flagellar adhesion and mating. Though flagellar shortening induced by treatment with sucrose or sodium pyrophosphate was not affected in RNAi strains, CrCDPK3 increased in the flagella, and pre-formed protein complex was disrupted. During flagellar regeneration, CrCDPK3 also increased in the flagella. When extracellular calcium was lowered to certain range by the addition of EGTA after deflagellation, flagellar regeneration was severely affected in RNAi cells compared with wild type cells. In addition, during flagellar elongation induced by LiCl, RNAi cells exhibited early onset of bulbed flagella. This work expands new functions of CDPKs in flagellar activities by showing involvement of CrCDPK3 in flagellar biogenesis in Chlamydomonas. PMID- 23936119 TI - The rate of decline in small fibre function assessed using axon reflex-mediated neurogenic vasodilatation and the importance of age related centile values to improve the detection of clinical neuropathy. AB - BACKGROUND: The LDIflare technique (LDIflare) is a simple non-invasive test of small fibre function in dorsal foot skin involving skin heating and measuring the size of the resulting axon reflex-mediated vasodilator (flare) response using a laser Doppler imager (LDI). This study establishes age-related normative reference ranges for the test and determines the rate of decline in small fibre function per decade. Additionally, the potential value of using age related centiles rather than Receiver Operator Curves (ROC) was explored by comparison of the sensitivity and specificity of each analytic technique in identifying clinical neuropathy. METHODS: LDIflare areas were assessed in 94 healthy controls and 66 individuals with diabetes with (DN+, n = 31) and without clinical neuropathy (DN-, n = 35); neuropathy defined as a Neuropathy Disability Score >= 3. The age specific 5th centile values were used as the 'cut-offs' for the diagnosis of neuropathy from which sensitivity and specificity were calculated. RESULTS: There was a significant age dependant decrease in LDIflare size (r = 0.42, p<0.0001) with no significant gender differences. The LDIflare size reduced 0.56 cm(2) per decade which gives a percentage reduction of approximately 5.5% per decade. Using the normative 5th centiles as the cut-offs, the technique had a sensitivity of 77%, specificity of 90%, positive predictive value of 82% and negative predictive value of 87%.The ROC analysis gave a threshold of <3.66 cm(2) for the cut-off, resulting in a sensitivity of 75%, specificity of 85%, positive predictive value of 74% and negative predictive value of 86%. CONCLUSIONS: There is an age dependent decrease in small fibre function in the foot of 5.5% per decade. Both analytic techniques demonstrate good sensitivity and specificity for detecting clinical neuropathy but the technique based on age centiles offers better diagnostic accuracy and is therefore proposed as the method of choice. PMID- 23936120 TI - Blueberry peel extracts inhibit adipogenesis in 3T3-L1 cells and reduce high-fat diet-induced obesity. AB - This study examined the anti-obesity effect and mechanism of action of blueberry peel extracts (BPE) in 3T3-L1 cells and high-fat diet (HFD)-induced obese rats. The levels of lipid accumulation were measured, along with the changes in the expression of genes and proteins associated with adipocyte differentiation in 3T3 L1 cells. Evidenced by Oil-red O staining and triglyceride assay, BPE dose dependently inhibited lipid accumulation at concentrations of 0, 50, and 200 ug/ml. BPE decreased the expression of the key adipocyte differentiation regulator C/EBPbeta, as well as the C/EBPalpha and PPARgamma genes, during the differentiation of preadipocytes into adipocytes. Moreover, BPE down-regulated adipocyte-specific genes such as aP2 and FAS compared with control adipocytes. The specific mechanism mediating the effects of BP revealed that insulin stimulated phosphorylation of Akt was strongly decreased, and its downstream substrate, phospho-GSK3beta, was downregulated by BPE treatment in 3T3-L1 cells. Together, these data indicated that BP exerted anti-adipogenic activity by inhibiting the expression of PPARgamma and C/EBPbeta and the Akt signaling pathway in 3T3-L1 adipocytes. Next, we investigated whether BP extracts attenuated HFD-induced obesity in rats. Oral administration of BPE reduced HFD induced body weight gain significantly without affecting food intake. The epididymal or perirenal adipose tissue weights were lower in rats on an HFD plus BPE compared with the tissue weights of HFD-induced obese rats. Total cholesterol and triglyceride levels in the rats fed BPE were modestly reduced, and the HDL cholesterol level was significantly increased in HFD plus BP-fed rats compared with those of HFD-fed rats. Taken together, these results demonstrated an inhibitory effect of BP on adipogenesis through the down-regulation of C/EBPbeta, C/EBPalpha, and PPARgamma and the reduction of the phospho-Akt adipogenic factor in 3T3-L1 cells. Moreover, BPE reduced body weight gain and inhibited fat accumulation in an HFD-induced animal model of obesity. PMID- 23936122 TI - Quantifying policy options for reducing future coronary heart disease mortality in England: a modelling study. AB - AIMS: To estimate the number of coronary heart disease (CHD) deaths potentially preventable in England in 2020 comparing four risk factor change scenarios. METHODS AND RESULTS: Using 2007 as baseline, the IMPACTSEC model was extended to estimate the potential number of CHD deaths preventable in England in 2020 by age, gender and Index of Multiple Deprivation 2007 quintiles given four risk factor change scenarios: (a) assuming recent trends will continue; (b) assuming optimal but feasible levels already achieved elsewhere; (c) an intermediate point, halfway between current and optimal levels; and (d) assuming plateauing or worsening levels, the worst case scenario. These four scenarios were compared to the baseline scenario with both risk factors and CHD mortality rates remaining at 2007 levels. This would result in approximately 97,000 CHD deaths in 2020. Assuming recent trends will continue would avert approximately 22,640 deaths (95% uncertainty interval: 20,390-24,980). There would be some 39,720 (37,120-41,900) fewer deaths in 2020 with optimal risk factor levels and 22,330 fewer (19,850 24,300) in the intermediate scenario. In the worst case scenario, 16,170 additional deaths (13,880-18,420) would occur. If optimal risk factor levels were achieved, the gap in CHD rates between the most and least deprived areas would halve with falls in systolic blood pressure, physical inactivity and total cholesterol providing the largest contributions to mortality gains. CONCLUSIONS: CHD mortality reductions of up to 45%, accompanied by significant reductions in area deprivation mortality disparities, would be possible by implementing optimal preventive policies. PMID- 23936121 TI - Somato-motor haptic processing in posterior inner perisylvian region (SII/pIC) of the macaque monkey. AB - The posterior inner perisylvian region including the secondary somatosensory cortex (area SII) and the adjacent region of posterior insular cortex (pIC) has been implicated in haptic processing by integrating somato-motor information during hand-manipulation, both in humans and in non-human primates. However, motor-related properties during hand-manipulation are still largely unknown. To investigate a motor-related activity in the hand region of SII/pIC, two macaque monkeys were trained to perform a hand-manipulation task, requiring 3 different grip types (precision grip, finger exploration, side grip) both in light and in dark conditions. Our results showed that 70% (n = 33/48) of task related neurons within SII/pIC were only activated during monkeys' active hand-manipulation. Of those 33 neurons, 15 (45%) began to discharge before hand-target contact, while the remaining neurons were tonically active after contact. Thirty-percent (n = 15/48) of studied neurons responded to both passive somatosensory stimulation and to the motor task. A consistent percentage of task-related neurons in SII/pIC was selectively activated during finger exploration (FE) and precision grasping (PG) execution, suggesting they play a pivotal role in control skilled finger movements. Furthermore, hand-manipulation-related neurons also responded when visual feedback was absent in the dark. Altogether, our results suggest that somato-motor neurons in SII/pIC likely contribute to haptic processing from the initial to the final phase of grasping and object manipulation. Such motor related activity could also provide the somato-motor binding principle enabling the translation of diachronic somatosensory inputs into a coherent image of the explored object. PMID- 23936123 TI - New perspective on dextran sodium sulfate colitis: antigen-specific T cell development during intestinal inflammation. AB - CD4+ T cell responses against oral antigens can develop in inflammatory bowel disease (IBD) patients, which may modulate disease. Dextran sodium sulfate (DSS) colitis is commonly used to study IBD, however, it is not considered the best model in which to study T cell involvement in intestinal disease. Our aim was to determine if antigen-specific T cells could be induced during DSS colitis and if they could be detected after disease resolution. To induce antigen-specific T cells, the tracking antigen, ovalbumin (OVA), was administered orally during colitis initiation. Disease severity was monitored, and the antigen-reactivity of CD4+ T cells examined using CD69 expression. While OVA-directed, CD4+ Foxp3+ regulatory T cells could be detected in the spleens of both OVA-treated control and DSS mice, OVA-reactive, CD4+ Foxp3-T cells were only found in the OVA and DSS treated mice. These results indicate that during DSS colitis T cells develop that are specific against oral antigens, and they are found systemically after colitis resolution. This gives added depth and utility to the DSS model as well as a way to track T cells that are primed against luminal antigens. PMID- 23936125 TI - Mating increases neuronal tyrosine hydroxylase expression and selectively gates transmission of male chemosensory information in female mice. AB - Exposure to chemosensory signals from unfamiliar males can terminate pregnancy in recently mated female mice. The number of tyrosine hydroxylase-positive neurons in the main olfactory bulb has been found to increase following mating and has been implicated in preventing male-induced pregnancy block during the post implantation period. In contrast, pre-implantation pregnancy block is mediated by the vomeronasal system, and is thought to be prevented by selective inhibition of the mate's pregnancy blocking chemosignals, at the level of the accessory olfactory bulb. The objectives of this study were firstly to identify the level of the vomeronasal pathway at which selective inhibition of the mate's pregnancy blocking chemosignals occurs. Secondly, to determine whether a post-mating increase in tyrosine hydroxylase-positive neurons is observed in the vomeronasal system, which could play a role in preventing pre-implantation pregnancy block. Immunohistochemical staining revealed that mating induced an increase in tyrosine hydroxylase positive neurons in the arcuate hypothalamus of BALB/c females, and suppressed c-Fos expression in these neurons in response to mating male chemosignals. This selective suppression of c-Fos response to mating male chemosignals was not apparent at earlier levels of the pregnancy-blocking neural pathway in the accessory olfactory bulb or corticomedial amygdala. Immunohistochemical staining revealed an increase in the number of tyrosine hydroxylase-positive neurons in the accessory olfactory bulb of BALB/c female mice following mating. However, increased dopamine-mediated inhibition in the accessory olfactory bulb is unlikely to account for the prevention of pregnancy block to the mating male, as tyrosine hydroxylase expression did not increase in females of the C57BL/6 strain, which show normal mate recognition. These findings reveal an association of mating with increased dopaminergic modulation in the pregnancy block pathway and support the hypothesis that mate recognition prevents pregnancy block by suppressing the activation of arcuate dopamine release. PMID- 23936124 TI - Involvement of the clock gene Rev-erb alpha in the regulation of glucagon secretion in pancreatic alpha-cells. AB - Disruption of pancreatic clock genes impairs pancreatic beta-cell function, leading to the onset of diabetes. Despite the importance of pancreatic alpha cells in the regulation of glucose homeostasis and in diabetes pathophysiology, nothing is known about the role of clock genes in these cells. Here, we identify the clock gene Rev-erb alpha as a new intracellular regulator of glucagon secretion. Rev-erb alpha down-regulation by siRNA (60-70% inhibition) in alphaTC1 9 cells inhibited low-glucose induced glucagon secretion (p<0.05) and led to a decrease in key genes of the exocytotic machinery. The Rev-erb alpha agonist GSK4112 increased glucagon secretion (1.6 fold) and intracellular calcium signals in alphaTC1-9 cells and mouse primary alpha-cells, whereas the Rev-erb alpha antagonist SR8278 produced the opposite effect. At 0.5 mM glucose, alphaTC1-9 cells exhibited intrinsic circadian Rev-erb alpha expression oscillations that were inhibited by 11 mM glucose. In mouse primary alpha-cells, glucose induced similar effects (p<0.001). High glucose inhibited key genes controlled by AMPK such as Nampt, Sirt1 and PGC-1 alpha in alphaTC1-9 cells (p<0.05). AMPK activation by metformin completely reversed the inhibitory effect of glucose on Nampt-Sirt1-PGC-1 alpha and Rev-erb alpha. Nampt inhibition decreased Sirt1, PGC 1 alpha and Rev-erb alpha mRNA expression (p<0.01) and glucagon release (p<0.05). These findings identify Rev-erb alpha as a new intracellular regulator of glucagon secretion via AMPK/Nampt/Sirt1 pathway. PMID- 23936126 TI - Comparing the quality of crowdsourced data contributed by expert and non-experts. AB - There is currently a lack of in-situ environmental data for the calibration and validation of remotely sensed products and for the development and verification of models. Crowdsourcing is increasingly being seen as one potentially powerful way of increasing the supply of in-situ data but there are a number of concerns over the subsequent use of the data, in particular over data quality. This paper examined crowdsourced data from the Geo-Wiki crowdsourcing tool for land cover validation to determine whether there were significant differences in quality between the answers provided by experts and non-experts in the domain of remote sensing and therefore the extent to which crowdsourced data describing human impact and land cover can be used in further scientific research. The results showed that there was little difference between experts and non-experts in identifying human impact although results varied by land cover while experts were better than non-experts in identifying the land cover type. This suggests the need to create training materials with more examples in those areas where difficulties in identification were encountered, and to offer some method for contributors to reflect on the information they contribute, perhaps by feeding back the evaluations of their contributed data or by making additional training materials available. Accuracies were also found to be higher when the volunteers were more consistent in their responses at a given location and when they indicated higher confidence, which suggests that these additional pieces of information could be used in the development of robust measures of quality in the future. PMID- 23936127 TI - Genotypic and phenotypic characterisation of enteroaggregative Escherichia coli from children in Rio de Janeiro, Brazil. AB - Enteroaggregative Escherichia coli (EAEC) is a significant cause of diarrhoeal illness in both children and adults. Genetic heterogeneity and recovery of EAEC strains from both healthy and diseased individuals complicates our understanding of EAEC pathogenesis. We wished to establish if genetic or phenotypic attributes could be used to distinguish between strains asymptomatically colonising healthy individuals and those which cause disease. Genotypic screening of a collection of twenty four EAEC isolates from children with and without diarrhoea revealed no significant differences in the repertoire of putative virulence factors present in either group of strains. In contrast, EAEC strains from phylogroup A were more strongly associated with asymptomatic groups whereas strains from phylogroup D were more associated with cases of diarrhoea. Phenotypic screening revealed no differences in the ability of strains from either cohort of children to form biofilms, to adhere to and invade cells in tissue culture or to cause disease in the Caenorhabditis elegans model of infection. However, the latter assay did reveal significant reduction in nematode killing rates when specific virulence factors were deleted from human pathogenic strains. Our results suggest that current models of infection are not useful for distinguishing avirulent from pathogenic strains of EAEC but can be useful in studying the effect of specific virulence factors. PMID- 23936128 TI - Cep63 and cep152 cooperate to ensure centriole duplication. AB - Centrosomes consist of two centrioles embedded in pericentriolar material and function as the main microtubule organising centres in dividing animal cells. They ensure proper formation and orientation of the mitotic spindle and are therefore essential for the maintenance of genome stability. Centrosome function is crucial during embryonic development, highlighted by the discovery of mutations in genes encoding centrosome or spindle pole proteins that cause autosomal recessive primary microcephaly, including Cep63 and Cep152. In this study we show that Cep63 functions to ensure that centriole duplication occurs reliably in dividing mammalian cells. We show that the interaction between Cep63 and Cep152 can occur independently of centrosome localisation and that the two proteins are dependent on one another for centrosomal localisation. Further, both mouse and human Cep63 and Cep152 cooperate to ensure efficient centriole duplication by promoting the accumulation of essential centriole duplication factors upstream of SAS-6 recruitment and procentriole formation. These observations describe the requirement for Cep63 in maintaining centriole number in dividing mammalian cells and further establish the order of events in centriole formation. PMID- 23936129 TI - The Q175 mouse model of Huntington's disease shows gene dosage- and age-related decline in circadian rhythms of activity and sleep. AB - Sleep and circadian disruptions are commonly reported by patients with neurodegenerative diseases, suggesting these may be an endophenotype of the disorders. Several mouse models of Huntington's disease (HD) that recapitulate the disease progression and motor dysfunction of HD also exhibit sleep and circadian rhythm disruption. Of these, the strongest effects are observed in the transgenic models with multiple copies of mutant huntingtin gene. For developing treatments of the human disease, knock-in (KI) models offer advantages of genetic precision of the insertion and control of mutation copy number. Therefore, we assayed locomotor activity and immobility-defined sleep in a new model of HD with an expansion of the KI repeats (Q175). We found evidence for gene dose- and age dependent circadian disruption in the behavior of the Q175 line. We did not see evidence for loss of cells or disruption of the molecular oscillator in the master pacemaker, the suprachiasmatic nucleus (SCN). The combination of the precise genetic targeting in the Q175 model and the observed sleep and circadian disruptions make it tractable to study the interaction of the underlying pathology of HD and the mechanisms by which the disruptions occur. PMID- 23936130 TI - Social curiosity and gossip: related but different drives of social functioning. AB - The present online-questionnaire study examined two fundamental social behaviors, social curiosity and gossip, and their interrelations in an English (n = 218) and a German sample (n = 152). Analyses showed that both samples believed that they are less gossipy but more curious than their peers. Multidimensional SEM of self and trait conceptions indicated that social curiosity and gossip are related constructs but with different patterns of social functions. Gossip appears to serve predominantly entertainment purposes whereas social curiosity appears to be more driven by a general interest in gathering information about how other people feel, think, and behave and the need to belong. Relationships to other personality traits (N, E, O) provided additional evidence for divergent validity. The needs for gathering and disseminating social information might represent two interlinked but different drives of cultural learning. PMID- 23936131 TI - Transfected HEK293 cells expressing functional recombinant intercellular adhesion molecule 1 (ICAM-1)--a receptor associated with severe Plasmodium falciparum malaria. AB - Intercellular adhesion molecule 1 (ICAM-1) is a membrane-bound glycoprotein expressed on endothelial cells and cells of the immune system. Human ICAM-1 mediates adhesion and migration of leucocytes, and is implicated in inflammatory pathologies, autoimmune diseases and in many cancer processes. Additionally, ICAM 1 acts as receptor for pathogens like human rhinovirus and Plasmodium falciparum malaria parasites. A group of related P. falciparum erythrocyte membrane protein 1 (PfEMP1) domains, the DBLbeta, mediates ICAM-1 binding of P. falciparum infected erythrocytes. This ICAM-1-binding phenotype has been suggested to be involved in the development of cerebral malaria. However, more studies identifying cross-reactive antibody and ICAM-1-binding epitopes and the establishment of a clinical link between DBLbeta expression and e.g. cerebral malaria are needed before the DBLbeta domains can be put forward as vaccine candidates and go into clinical trials. Such studies require availability of functional recombinant ICAM-1 in large quantities. In this study, we compared recombinant ICAM-1 expressed in HEK293 and COS-7 cells with mouse myeloma NS0 ICAM-1 purchased from a commercial vendor in terms of protein purity, yield, fold, ability to bind DBLbeta, and relative cost. We present a HEK293 cell-based, high-yield expression and purification scheme for producing inexpensive, functional ICAM-1. ICAM-1 expressed in HEK293 is applicable to malaria research and can also be useful in other research fields. PMID- 23936132 TI - Oxidized phospholipids induce ceramide accumulation in RAW 264.7 macrophages: role of ceramide synthases. AB - Oxidized phospholipids (OxPLs), including 1-palmitoyl-2-glutaroyl-sn-glycero-3 phosphocholine (PGPC) and 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine (POVPC) are among several biologically active derivatives that are generated during oxidation of low-density lipoproteins (LDLs). These OxPLs are factors contributing to pro-atherogenic effects of oxidized LDLs (OxLDLs), including inflammation, proliferation and death of vascular cells. OxLDL also elicits formation of the lipid messenger ceramide (Cer) which plays a pivotal role in apoptotic signaling pathways. Here we report that both PGPC and POVPC are cytotoxic to cultured macrophages and induce apoptosis in these cells which is associated with increased cellular ceramide levels after several hours. In addition, exposure of RAW 264.7 cells to POVPC and PGPC under the same conditions resulted in a significant increase in ceramide synthase activity, whereas, acid or neutral sphingomyelinase activities were not affected. PGPC is not only more toxic than POVPC, but also a more potent inducer of ceramide formation by activating a limited subset of CerS isoforms. The stimulated CerS activities are in line with the C16-, C22-, and C24:0-Cer species that are generated under the influence of the OxPL. Fumonisin B1, a specific inhibitor of CerS, suppressed OxPL-induced ceramide generation, demonstrating that OxPL-induced CerS activity in macrophages is responsible for the accumulation of ceramide. OxLDL elicits the same cellular ceramide and CerS effects. Thus, it is concluded that PGPC and POVPC are active components that contribute to the capacity of this lipoprotein to elevate ceramide levels in macrophages. PMID- 23936133 TI - Donald's Ideotype and growth redundancy: a pot experimental test using an old and a modern spring wheat cultivar. AB - Human selection for high crop yield under water-limited conditions should have led modern cereal cultivars to invest less in root biomass, be it unconsciously. To test this hypothesis we conducted a pot experiment with two spring wheat cultivars, one old and one modern, both widely grown in the semi-arid regions of China. Using the replacement series method introduced by de Wit, we showed that the older landrace (Monkhead) was significantly more competitive than the more modern cultivar (92-46). However, when grown in pure stand, old Monkhead had grown root biomass 3.5 times modern 92-46, whereas modern 92-46 gained a 20% higher grain yield. We also found modern 92-46 significantly increased root biomass per plant and root allocation (i.e., root biomass/total individual biomass) as its frequency in mixtures decreased, whereas old Monkhead did not respond in a similar way. This result suggests that the roots of modern cultivars may have gained an ability to recognize neighboring root systems and show more plastic self-restraining response to intra-cultivar competition. PMID- 23936134 TI - Mechanism of protein kinetic stabilization by engineered disulfide crosslinks. AB - The impact of disulfide bonds on protein stability goes beyond simple equilibrium thermodynamics effects associated with the conformational entropy of the unfolded state. Indeed, disulfide crosslinks may play a role in the prevention of dysfunctional association and strongly affect the rates of irreversible enzyme inactivation, highly relevant in biotechnological applications. While these kinetic-stability effects remain poorly understood, by analogy with proposed mechanisms for processes of protein aggregation and fibrillogenesis, we propose that they may be determined by the properties of sparsely-populated, partially unfolded intermediates. Here we report the successful design, on the basis of high temperature molecular-dynamics simulations, of six thermodynamically and kinetically stabilized variants of phytase from Citrobacter braakii (a biotechnologically important enzyme) with one, two or three engineered disulfides. Activity measurements and 3D crystal structure determination demonstrate that the engineered crosslinks do not cause dramatic alterations in the native structure. The inactivation kinetics for all the variants displays a strongly non-Arrhenius temperature dependence, with the time-scale for the irreversible denaturation process reaching a minimum at a given temperature within the range of the denaturation transition. We show this striking feature to be a signature of a key role played by a partially unfolded, intermediate state/ensemble. Energetic and mutational analyses confirm that the intermediate is highly unfolded (akin to a proposed critical intermediate in the misfolding of the prion protein), a result that explains the observed kinetic stabilization. Our results provide a rationale for the kinetic-stability consequences of disulfide-crosslink engineering and an experimental methodology to arrive at energetic/structural descriptions of the sparsely populated and elusive intermediates that play key roles in irreversible protein denaturation. PMID- 23936135 TI - Functional analysis of Casein Kinase 1 in a minimal circadian system. AB - The Earth's rotation has driven the evolution of cellular circadian clocks to facilitate anticipation of the solar cycle. Some evidence for timekeeping mechanism conserved from early unicellular life through to modern organisms was recently identified, but the components of this oscillator are currently unknown. Although very few clock components appear to be shared across higher species, Casein Kinase 1 (CK1) is known to affect timekeeping across metazoans and fungi, but has not previously been implicated in the circadian clock in the plant kingdom. We now show that modulation of CK1 function lengthens circadian rhythms in Ostreococcustauri, a unicellular marine algal species at the base of the green lineage, separated from humans by ~1.5 billion years of evolution. CK1 contributes to timekeeping in a phase-dependent manner, indicating clock-mediated gating of CK1 activity. Label-free proteomic analyses upon overexpression as well as inhibition revealed CK1-responsive phosphorylation events on a set of target proteins, including highly conserved potentially clock-relevant cellular regulator proteins. These results have major implications for our understanding of cellular timekeeping and can inform future studies in any circadian organism. PMID- 23936136 TI - Zinc finger protein 148 is dispensable for primitive and definitive hematopoiesis in mice. AB - Hematopoiesis is regulated by transcription factors that induce cell fate and differentiation in hematopoietic stem cells into fully differentiated hematopoietic cell types. The transcription factor zinc finger protein 148 (Zfp148) interacts with the hematopoietic transcription factor Gata1 and has been implicated to play an important role in primitive and definitive hematopoiesis in zebra fish and mouse chimeras. We have recently created a gene-trap knockout mouse model deficient for Zfp148, opening up for analyses of hematopoiesis in a conventional loss-of-function model in vivo. Here, we show that Zfp148-deficient neonatal and adult mice have normal or slightly increased levels of hemoglobin, hematocrit, platelets and white blood cells, compared to wild type controls. Hematopoietic lineages in bone marrow, thymus and spleen from Zfp148 (gt/gt) mice were further investigated by flow cytometry. There were no differences in T-cells (CD4 and CD8 single positive cells, CD4 and CD8 double negative/positive cells) in either organ. However, the fraction of CD69- and B220-positive cells among lymphocytes in spleen was slightly lower at postnatal day 14 in Zfp148 (gt/gt) mice compared to wild type mice. Our results demonstrate that Zfp148-deficient mice generate normal mature hematopoietic populations thus challenging earlier studies indicating that Zfp148 plays a critical role during hematopoietic development. PMID- 23936137 TI - Divergence in olfactory host plant preference in D. mojavensis in response to cactus host use. AB - Divergence in host adaptive traits has been well studied from an ecological and evolutionary perspective, but identification of the proximate mechanisms underlying such divergence is less well understood. Behavioral preferences for host plants are often mediated by olfaction and shifts in preference may be accompanied by changes in the olfactory system. In this study, we examine the evolution of host plant preferences in cactophilic Drosophila mojavensis that feeds and breeds on different cacti throughout its range. We show divergence in electrophysiological responses and olfactory behavior among populations with host plant shifts. Specifically, significant divergence was observed in the Mojave Desert population that specializes on barrel cactus. Differences were observed in electrophysiological responses of the olfactory organs and in behavioral responses to barrel cactus volatiles. Together our results suggest that the peripheral nervous system has changed in response to different ecological environments and that these changes likely contribute to divergence among D. mojavensis populations. PMID- 23936138 TI - A novel prokaryotic promoter identified in the genome of some monopartite begomoviruses. AB - Geminiviruses are known to exhibit both prokaryotic and eukaryotic features in their genomes, with the ability to express their genes and even replicate in bacterial cells. We have demonstrated previously the existence of unit-length single-stranded circular DNAs of Ageratum yellow vein virus (AYVV, a species in the genus Begomovirus, family Geminiviridae) in Escherichia coli cells, which prompted our search for unknown prokaryotic functions in the begomovirus genomes. By using a promoter trapping strategy, we identified a novel prokaryotic promoter, designated AV3 promoter, in nts 762-831 of the AYVV genome. Activity assays revealed that the AV3 promoter is strong, unidirectional, and constitutive, with an endogenous downstream ribosome binding site and a translatable short open reading frame of eight amino acids. Sequence analyses suggested that the AV3 promoter might be a remnant of prokaryotic ancestors that could be related to certain promoters of bacteria from marine or freshwater environments. The discovery of the prokaryotic AV3 promoter provided further evidence for the prokaryotic origin in the evolutionary history of geminiviruses. PMID- 23936140 TI - Genetic architecture of delayed senescence, biomass, and grain yield under drought stress in cowpea. AB - The stay-green phenomenon is a key plant trait with wide usage in managing crop production under limited water conditions. This trait enhances delayed senescence, biomass, and grain yield under drought stress. In this study we sought to identify QTLs in cowpea (Vigna unguiculata) consistent across experiments conducted in Burkina Faso, Nigeria, Senegal, and the United States of America under limited water conditions. A panel of 383 diverse cowpea accessions and a recombinant inbred line population (RIL) were SNP genotyped using an Illumina 1536 GoldenGate assay. Phenotypic data from thirteen experiments conducted across the four countries were used to identify SNP-trait associations based on linkage disequilibrium association mapping, with bi-parental QTL mapping as a complementary strategy. We identified seven loci, five of which exhibited evidence suggesting pleiotropic effects (stay-green) between delayed senescence, biomass, and grain yield. Further, we provide evidence suggesting the existence of positive pleiotropy in cowpea based on positively correlated mean phenotypic values (0.34< r <0.87) and allele effects (0.07< r <0.86) for delayed senescence and grain yield across three African environments. Three of the five putative stay-green QTLs, Dro-1, 3, and 7 were identified in both RILs and diverse germplasm with resolutions of 3.2 cM or less for each of the three loci, suggesting that these may be valuable targets for marker-assisted breeding in cowpea. Also, the co-location of early vegetative delayed senescence with biomass and grain yield QTLs suggests the possibility of using delayed senescence at the seedling stage as a rapid screening tool for post-flowering drought tolerance in cowpea breeding. BLAST analysis using EST sequences harboring SNPs with the highest associations provided a genomic context for loci identified in this study in closely related common bean (Phaseolus vulgaris) and soybean (Glycine max) reference genomes. PMID- 23936141 TI - Regulation of the tumor suppressor PTEN through exosomes: a diagnostic potential for prostate cancer. AB - PTEN is a potent tumor-suppressor protein. Aggressive and metastatic prostate cancer (PC) is associated with a reduction or loss of PTEN expression. PTEN reduction often occurs without gene mutations, and its downregulation is not fully understood. Herein, we show that PTEN is incorporated in the cargo of exosomes derived from cancer cells. PTEN is not detected in exosomes derived from normal, noncancerous cells. We found that PTEN can be transferred to other cells through exosomes. In cells that have a reduction or complete loss of PTEN expression, the transferred PTEN is competent to confer tumor-suppression activity to acceptor cells. In PC patients, we show that PTEN is incorporated in the cargo of exosomes that circulate in their blood. Interestingly, normal subjects have no PTEN expression in their blood exosomes. Further, we found that the prostate-specific antigen (PSA) is incorporated in PC patients' and normal subjects' blood exosomes. These data suggest that exosomal PTEN can compensate for PTEN loss in PTEN deficient cells, and may have diagnostic value for prostate cancer. PMID- 23936139 TI - Mesoamerican origin and pre- and post-columbian expansions of the ranges of Acanthoscelides obtectus say, a cosmopolitan insect pest of the common bean. AB - An unprecedented global transfer of agricultural resources followed the discovery of the New World; one consequence of this process was that staple food plants of Neotropical origin, such as the common bean (Phaseolus vulgaris), soon expanded their ranges overseas. Yet many pests and diseases were also transported. Acanthoscelides obtectus is a cosmopolitan seed predator associated with P. vulgaris. Codispersal within the host seed seems to be an important determinant of the ability of A. obtectus to expand its range over long distances. We examined the phylogeographic structure of A. obtectus by (a) sampling three mitochondrial gene sequences (12s rRNA, 16s rRNA, and the gene that encodes cytochrome c oxidase subunit I (COI)) throughout most of the species' range and (b) exploring its late evolutionary history. Our findings indicate a Mesoamerican origin for the current genealogical lineages of A. obtectus. Each of the two major centers of genetic diversity of P. vulgaris (the Andes and Mesoamerica) contains a highly differentiated lineage of the bean beetle. Brazil has two additional, closely related lineages, both of which predate the Andean lineage and have the Mesoamerican lineage as their ancestor. The cosmopolitan distribution of A. obtectus has resulted from recent expansions of the two Brazilian lineages. We present additional evidence for both pre-Columbian and post-Columbian range expansions as likely events that shaped the current distribution of A. obtectus worldwide. PMID- 23936142 TI - A novel tumor suppressor function of glycine N-methyltransferase is independent of its catalytic activity but requires nuclear localization. AB - Glycine N-methyltransferase (GNMT), an abundant cytosolic enzyme, catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to glycine generating S-adenosylhomocysteine and sarcosine (N-methylglycine). This reaction is regulated by 5-methyltetrahydrofolate, which inhibits the enzyme catalysis. In the present study, we observed that GNMT is strongly down regulated in human cancers and is undetectable in cancer cell lines while the transient expression of the protein in cancer cells induces apoptosis and results in the activation of ERK1/2 as an early pro-survival response. The antiproliferative effect of GNMT can be partially reversed by treatment with the pan-caspase inhibitor zVAD-fmk but not by supplementation with high folate or SAM. GNMT exerts the suppressor effect primarily in cells originated from malignant tumors: transformed cell line of non-cancer origin, HEK293, was insensitive to GNMT. Of note, high levels of GNMT, detected in regenerating liver and in NIH3T3 mouse fibroblasts, do not produce cytotoxic effects. Importantly, GNMT, a predominantly cytoplasmic protein, was translocated into nuclei upon transfection of cancer cells. The presence of GNMT in the nuclei was also observed in normal human tissues by immunohistochemical staining. We further demonstrated that the induction of apoptosis is associated with the GNMT nuclear localization but is independent of its catalytic activity or folate binding. GNMT targeted to nuclei, through the fusion with nuclear localization signal, still exerts strong antiproliferative effects while its restriction to cytoplasm, through the fusion with nuclear export signal, prevents these effects (in each case the protein was excluded from cytosol or nuclei, respectively). Overall, our study indicates that GNMT has a secondary function, as a regulator of cellular proliferation, which is independent of its catalytic role. PMID- 23936143 TI - Mortality trends in women and men presenting with acute coronary syndrome: insights from a 20-year registry. AB - BACKGROUND: Coronary artery disease (CAD) is the leading cause of mortality worldwide. The present study evaluated the impact of gender in patients hospitalized with acute coronary syndromes (ACS) over a 20-year period in Qatar. METHODS: Data were collected retrospectively from the registry of the department of cardiology for all patients admitted with ACS during the study period (1991 2010) and were analyzed according to gender. RESULTS: Among 16,736 patients who were admitted with ACS, 14262 (85%) were men and 2474 (15%) were women. Cardiovascular risk factors were more prevalent among women in comparison to men. On admission, women presented mainly with non-ST-elevation ACS and were more likely to be undertreated with beta-blockers (BB), antiplatelet agents and reperfusion therapy in comparison to men. However, from 1999 through 2010, the use of aspirin, angiotensin-converting enzyme inhibitors and BB increased from 66% to 79%, 27% to 41% and 17% to 49%, respectively in women. In the same period, relative risk reduction for mortality was 64% in women and 51% in men. Across the 20-year period, the mortality rate decreased from 27% to 7% among the Middle Eastern Arab women. Multivariate logistic regression analysis showed that female gender was independent predictor of in-hospital mortality (odd ratio 1.51, 95% CI 1.27-1.79). CONCLUSIONS: Women presenting with ACS are high-risk population and their in-hospital mortality remains higher for all age groups in comparison to men. Although, substantial improvement in the hospital outcome has been observed, guidelines adherence and improvement in the hospital care have not yet been optimized. PMID- 23936144 TI - Default mode network in the effects of Delta9-Tetrahydrocannabinol (THC) on human executive function. AB - Evidence is increasing for involvement of the endocannabinoid system in cognitive functions including attention and executive function, as well as in psychiatric disorders characterized by cognitive deficits, such as schizophrenia. Executive function appears to be associated with both modulation of active networks and inhibition of activity in the default mode network. In the present study, we examined the role of the endocannabinoid system in executive function, focusing on both the associated brain network and the default mode network. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist Delta9-tetrahydrocannabinol (THC) on executive function in 20 healthy volunteers, using a continuous performance task with identical pairs. Task performance was impaired after THC administration, reflected in both an increase in false alarms and a reduction in detected targets. This was associated with reduced deactivation in a set of brain regions linked to the default mode network, including posterior cingulate cortex and angular gyrus. Less deactivation was significantly correlated with lower performance after THC. Regions that were activated by the continuous performance task, notably bilateral prefrontal and parietal cortex, did not show effects of THC. These findings suggest an important role for the endocannabinoid system in both default mode modulation and executive function. This may be relevant for psychiatric disorders associated with executive function deficits, such as schizophrenia and ADHD. PMID- 23936145 TI - Effect of socioeconomic status on mortality after bacteremia in working-age patients. A Danish population-based cohort study. AB - OBJECTIVES: To examine the effect of socioeconomic status (SES) on mortality in patients with bacteremia and the underlying factors that may mediate differences in mortality. METHODS: We conducted a population-based cohort study in two Danish regions. All patients 30 to 65 years of age with first time bacteremia from 2000 through 2008 were identified in a population-based microbiological bacteremia database (n = 8,653). Individual-level data on patients' SES (educational level and personal income) and comorbid conditions were obtained from public and medical registries. We used Cox regression to examine mortality within 30 days after bacteremia with and without cumulative adjustment for potential mediators. RESULTS: Bacteremia patients of low SES were more likely to live alone and be unmarried than patients of high SES. They also had more pre-existing comorbidity, more substance abuse, more Staphylococcus aureus and nosocomial infections, and more admissions to small nonteaching hospitals. Overall, 1,374 patients (15.9%) died within 30 days of follow-up. Patients of low SES had consistently higher mortality after bacteremia than those of high SES crude hazard ratio for low vs. high education, 1.38 [95% confidence interval (CI), 1.18-1.61]; crude hazard ratio for low-income vs. high-income tertile, 1.58 [CI, 1.39-1.80]. Adjustment for differences in social support, pre-existing comorbidity, substance abuse, place of acquisition of the infection, and microbial agent substantially attenuated the effect of SES on mortality (adjusted hazard ratio for low vs. high education, 1.15 [95% CI, 0.98-1.36]; adjusted hazard ratio for low-income vs. high-income tertile, 1.29 [CI, 1.12-1.49]). Further adjustment for characteristics of the admitting hospital had minimal effect on observed mortality differences. CONCLUSIONS: Low SES was strongly associated with increased 30-day mortality after bacteremia. Less social support, more pre existing comorbidity, more substance abuse, and differences in place of acquisition and agent of infection appeared to mediate much of the observed disparities in mortality. PMID- 23936146 TI - Biphasic functional regulation in hippocampus of rat with chronic cerebral hypoperfusion induced by permanent occlusion of bilateral common carotid artery. AB - BACKGROUND: Chronic cerebral hypoperfusion induced by permanent occlusion of the bilateral common carotid artery (BCCAO) in rats has been commonly used for the study of Alzheimer's disease and vascular dementia. Despite the apparent cognitive dysfunction in rats with BCCAO, the molecular markers or pathways involved in the pathological alternation have not been clearly identified. METHODS: Temporal changes (sham, 21, 35, 45, 55 and 70 days) in gene expression in the hippocampus of rats after BCCAO were measured using time-course microarray analysis. Gene Ontology (GO) and pathway analyses were performed to identify the functional involvement of temporally regulated genes in BCCAO. RESULTS: Two major gene expression patterns were observed in the hippocampus of rats after BCCAO. One pattern, which was composed of 341 early up-regulated genes after the surgical procedure, was dominantly involved in immune-related biological functions (false discovery rate [FDR]<0.01). Another pattern composed of 182 temporally delayed down-regulated genes was involved in sensory perception such as olfactory and cognition functions (FDR<0.01). In addition to the two gene expression patterns, the temporal change of GO and the pathway activities using all differentially expressed genes also confirmed that an immune response was the main early change, whereas sensory functions were delayed responses. Moreover, we identified FADD and SOCS3 as possible core genes in the sensory function loss process using text-based mining and interaction network analysis. CONCLUSIONS: The biphasic regulatory mechanism first reported here could provide molecular evidence of BCCAO-induced impaired memory in rats as well as mechanism of the development of vascular dementia. PMID- 23936147 TI - Downregulation of steroid receptor coactivator-2 modulates estrogen-responsive genes and stimulates proliferation of mcf-7 breast cancer cells. AB - The p160/Steroid Receptor Coactivators SRC-1, SRC-2/GRIP1, and SRC-3/AIB1 are important regulators of Estrogen Receptor alpha (ERalpha) activity. However, whereas the functions of SRC-1 and SRC-3 in breast tumourigenesis have been extensively studied, little is known about the role of SRC-2. Previously, we reported that activation of the cAMP-dependent protein kinase, PKA, facilitates ubiquitination and proteasomal degradation of SRC-2 which in turn leads to inhibition of SRC-2-coactivation of ERalpha and changed expression of the ERalpha target gene, pS2. Here we have characterized the global program of transcription in SRC-2-depleted MCF-7 breast cancer cells using short-hairpin RNA technology, and in MCF-7 cells exposed to PKA activating agents. In order to identify genes that may be regulated through PKA-induced downregulation of SRC-2, overlapping transcriptional targets in response to the respective treatments were characterized. Interestingly, we observed decreased expression of several breast cancer tumour suppressor genes (e.g., TAGLN, EGR1, BCL11b, CAV1) in response to both SRC-2 knockdown and PKA activation, whereas the expression of a number of other genes implicated in cancer progression (e.g., RET, BCAS1, TFF3, CXCR4, ADM) was increased. In line with this, knockdown of SRC-2 also stimulated proliferation of MCF-7 cells. Together, these results suggest that SRC-2 may have an antiproliferative function in breast cancer cells. PMID- 23936148 TI - Effect of folic acid supplementation on levels of circulating Monocyte Chemoattractant Protein-1 and the presence of intravascular ultrasound derived virtual histology thin-cap fibroatheromas in patients with stable angina pectoris. AB - BACKGROUND: Virtual Histology Intravascular Ultrasound (VH-IVUS) may be used to detect early signs of unstable coronary artery disease. Monocyte Chemoattractant Protein-1 (MCP-1) is linked with coronary atherosclerosis and plaque instability and could potentially be modified by folic acid treatment. METHODS: In a randomized, prospective study, 102 patients with stable angina pectoris (SAP) received percutaneous coronary intervention and established medical treatment as well as either homocysteine-lowering folic acid/vitamin B12 (+/- B6) or placebo (+/- B6) for 1 year before VH-IVUS was performed. The presence of VH-Thin-Cap Fibroatheroma (VH-TCFA) in non-intervened coronary vessels was registered and serum levels of MCP-1 were measured. The patients were subsequently followed for incident myocardial infarction (MI). RESULTS: Patients treated with folic acid/vitamin B12 had a geometric mean (SD) MCP-1 level of 79.95 (1.49) versus 86.00 (1.43) pg/mL for patients receiving placebo (p-value 0.34). VH-TCFA lesions were present in 7.8% of patients and did not differ between intervention arms (p value 0.47). Serum levels of MCP-1 were 1.46 (95% CI 1.12 to 1.92) times higher in patients with VH-TCFA lesions than in those without (p-value 0.005). Afterwards, patients were followed for median 2.1 years and 3.8% experienced a myocardial infarction (MI), which in post-hoc Cox regression analyses was independently predicted by both MCP-1 (P-value 0.006) and VH-TCFA (p-value 0.01). CONCLUSIONS: In patients with SAP receiving established medical treatment, folic acid supplementation is not associated with either presence of VH-TCFA or levels of MCP-1. MCP-1 is however associated with VH-TCFA, a finding corroborated by increased risk for future MI. ClinicalTrials.gov Identifier: NCT00354081. PMID- 23936149 TI - Potential reporting bias in fMRI studies of the brain. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) studies have reported multiple activation foci associated with a variety of conditions, stimuli or tasks. However, most of these studies used fewer than 40 participants. METHODOLOGY: After extracting data (number of subjects, condition studied, number of foci identified and threshold) from 94 brain fMRI meta-analyses (k = 1,788 unique datasets) published through December of 2011, we analyzed the correlation between individual study sample sizes and number of significant foci reported. We also performed an analysis where we evaluated each meta-analysis to test whether there was a correlation between the sample size of the meta-analysis and the number of foci that it had identified. Correlation coefficients were then combined across all meta-analyses to obtain a summary correlation coefficient with a fixed effects model and we combine correlation coefficients, using a Fisher's z transformation. PRINCIPAL FINDINGS: There was no correlation between sample size and the number of foci reported in single studies (r = 0.0050) but there was a strong correlation between sample size and number of foci in meta analyses (r = 0.62, p<0.001). Only studies with sample sizes <45 identified larger (>40) numbers of foci and claimed as many discovered foci as studies with sample sizes >= 45, whereas meta-analyses yielded a limited number of foci relative to the yield that would be anticipated from smaller single studies. CONCLUSIONS: These results are consistent with possible reporting biases affecting small fMRI studies and suggest the need to promote standardized large scale evidence in this field. It may also be that small studies may be analyzed and reported in ways that may generate a larger number of claimed foci or that small fMRI studies with inconclusive, null, or not very promising results may not be published at all. PMID- 23936150 TI - FTY720 treatment in the convalescence period improves functional recovery and reduces reactive astrogliosis in photothrombotic stroke. AB - BACKGROUND: The Sphingosine-1-phosphate (S1P) signaling pathway is known to influence pathophysiological processes within the brain and the synthetic S1P analog FTY720 has been shown to provide neuroprotection in experimental models of acute stroke. However, the effects of a manipulation of S1P signaling at later time points after experimental stroke have not yet been investigated. We examined whether a relatively late initiation of a FTY720 treatment has a positive effect on long-term neurological outcome with a focus on reactive astrogliosis, synapses and neurotrophic factors. METHODS: We induced photothrombotic stroke (PT) in adult C57BL/6J mice and allowed them to recover for three days. Starting on post stroke day 3, mice were treated with FTY720 (1 mg/kg b.i.d.) for 5 days. Behavioral outcome was observed until day 31 after photothrombosis and periinfarct cortical tissue was analyzed using tandem mass-spectrometry, TaqMan(r)analysis and immunofluorescence. RESULTS: FTY720 treatment results in a significantly better functional outcome persisting up to day 31 after PT. This is accompanied by a significant decrease in reactive astrogliosis and larger post synaptic densities as well as changes in the expression of vascular endothelial growth factor alpha (VEGF alpha). Within the periinfarct cortex, S1P is significantly increased compared to healthy brain tissue. CONCLUSION: Besides its known neuroprotective effects in the acute phase of experimental stroke, the initiation of FTY720 treatment in the convalescence period has a positive impact on long-term functional outcome, probably mediated through reduced astrogliosis, a modulation in synaptic morphology and an increased expression of neurotrophic factors. PMID- 23936151 TI - Identification of a Novel TECTA mutation in a Chinese DFNA8/12 family with prelingual progressive sensorineural hearing impairment. AB - Tectorial membrane, an extracellular matrix of the cochlea, plays a crucial role in the transmission of sound to the sensory hair cells. Alpha-tectorin is the most important noncollagenous component of the tectorial membrane and the otolith membrane in the maculae of the vestibular system. Defects in TECTA, the gene encodes alpha-tectorin, are cause of both dominant (DFNA8/12) and recessive (DFNB21) forms of deafness. Here, we report a three-generation Chinese family characterized by prelingual progressive sensorineural hearing impairment. We mapped the disease locus to chromosome 11q23-24 region, overlapping with the DFNA8/12 locus. Sequencing of candidate gene TECTA revealed a heterozygous c.5945C>A substitution in exon 19, causing amino acid substitution of Ala to Asp at a conservative position 1982. The A1982D substitution is consistent with hearing loss in this Chinese family and has not been found in 200 random control chromosomes. To our knowledge, this is the first TECTA mutation identified in Chinese population. Our data provides additional molecular and clinical information for establishing a better genotype-phenotype understanding of DFNA8/12. PMID- 23936152 TI - Pathoadaptive mutations in Salmonella enterica isolated after serial passage in mice. AB - How pathogenic bacteria adapt and evolve in the complex and variable environment of the host remains a largely unresolved question. Here we have used whole genome sequencing of Salmonella enterica serovar Typhimurium LT2 populations serially passaged in mice to identify mutations that adapt bacteria to systemic growth in mice. We found unique pathoadaptive mutations in two global regulators, phoQ and stpA, which increase the competitive indexes of the bacteria 3- to 5-fold. Also, all mouse-adapted lineages had changed the orientation of the hin invertable element, resulting in production of a FliC type of flagellum. Competition experiments in mice with locked flagellum mutants showed that strains expressing the FliC type of flagellum had a 5-fold increase in competitive index as compared to those expressing FljB type flagellum. Combination of the flagellum cassette inversion with the stpA mutation increased competitive indexes up to 20-fold. These experiments show that Salmonella can rapidly adapt to a mouse environment by acquiring a few mutations of moderate individual effect that when combined confer substantial increases in growth. PMID- 23936153 TI - Lack of genetic interaction between Tbx20 and Tbx3 in early mouse heart development. AB - Members of the T-box family of transcription factors are important regulators orchestrating the complex regionalization of the developing mammalian heart. Individual mutations in Tbx20 and Tbx3 cause distinct congenital heart abnormalities in the mouse: Tbx20 mutations result in failure of heart looping, developmental arrest and lack of chamber differentiation, while hearts of Tbx3 mutants progress further, loop normally but show atrioventricular convergence and outflow tract defects. The two genes have overlapping areas of expression in the atrioventricular canal and outflow tract of the heart but their potential genetic interaction has not been previously investigated. In this study we produced compound mutants to investigate potential genetic interactions at the earliest stages of heart development. We find that Tbx20; Tbx3 double heterozygous mice are viable and fertile with no apparent abnormalities, while double homozygous mutants are embryonic lethal by midgestation. Double homozygous mutant embryos display abnormal cardiac morphogenesis, lack of heart looping, expression patterns of cardiac genes and time of death that are indistinguishable from Tbx20 homozygous mutants. Prior to death, the double homozygotes show an overall developmental delay similar to Tbx3 homozygous mutants. Thus the effects of Tbx20 are epistatic to Tbx3 in the heart but Tbx3 is epistatic to Tbx20 with respect to developmental delay. PMID- 23936154 TI - Developmental gains in visuospatial memory predict gains in mathematics achievement. AB - Visuospatial competencies are related to performance in mathematical domains in adulthood, but are not consistently related to mathematics achievement in children. We confirmed the latter for first graders and demonstrated that children who show above average first-to-fifth grade gains in visuospatial memory have an advantage over other children in mathematics. The study involved the assessment of the mathematics and reading achievement of 177 children in kindergarten to fifth grade, inclusive, and their working memory capacity and processing speed in first and fifth grade. Intelligence was assessed in first grade and their second to fourth grade teachers reported on their in-class attentive behavior. Developmental gains in visuospatial memory span (d = 2.4) were larger than gains in the capacity of the central executive (d = 1.6) that in turn were larger than gains in phonological memory span (d = 1.1). First to fifth grade gains in visuospatial memory and in speed of numeral processing predicted end of fifth grade mathematics achievement, as did first grade central executive scores, intelligence, and in-class attentive behavior. The results suggest there are important individual differences in the rate of growth of visuospatial memory during childhood and that these differences become increasingly important for mathematics learning. PMID- 23936156 TI - Impact of genetic heterogeneity in polymerase of hepatitis B virus on dynamics of viral load and hepatitis B progression. AB - OBJECTIVE: The hepatitis B virus (HBV)-polymerase region overlaps pre-S/S genes with high epitope density and plays an essential role in viral replication. We investigated whether genetic variation in the polymerase region determined long term dynamics of viral load and the risk of hepatitis B progression in a population-based cohort study. METHODS: We sequenced the HBV-polymerase region using baseline plasma from treatment-naive individuals with HBV-DNA levels>=1000 copies/mL in a longitudinal viral-load study of participants with chronic HBV infection followed-up for 17 years, and obtained sequences from 575 participants (80% with HBV genotype Ba and 17% with Ce). RESULTS: Patterns of viral sequence diversity across phases (i.e., immune-tolerant, immune-clearance, non/low replicative, and hepatitis B e antigen (HBeAg)-negative hepatitis phases) of HBV infection, which were associated with viral and clinical features at baseline and during follow-up, were similar between HBV genotypes, despite greater diversity for genotype Ce vs. Ba. Irrespective of genotypes, however, HBeAg-negative participants had 1.5-to-2-fold higher levels of sequence diversity than HBeAg positive participants (P<0.0001). Furthermore, levels of viral genetic divergence from the population consensus sequence, estimated by numbers of nucleotide substitutions, were inversely associated with long-term viral load even in HBeAg negative participants. A mixed model developed through analysis of the entire HBV polymerase region identified 153 viral load-associated single nucleotide polymorphisms in overall and 136 in HBeAg-negative participants, with distinct profiles between HBV genotypes. These polymorphisms were most evident at sites within or flanking T-cell epitopes. Seven polymorphisms revealed associations with both enhanced viral load and a more than 4-fold increased risk of hepatocellular carcinoma and/or liver cirrhosis. CONCLUSIONS: The data highlight a role of viral genetic divergence in the natural course of HBV-infection. Interindividual differences in the long-term dynamics of viral load is not only associated with accumulation of mutations in HBV-polymerase region, but differences in specific viral polymorphisms which differ between genotypes. PMID- 23936155 TI - HIV DNA reservoir increases risk for cognitive disorders in cART-naive patients. AB - OBJECTIVES: Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14(+) enriched monocytes predicted cognitive impairment and brain injury. METHODS: We enrolled 61 cART-naive HIV infected Thais in a prospective study and measured HIV DNA in CD14(+) enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF). RESULTS: The mean (SD) age was 35 (6.9) years, CD4 T lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty eight of 61 met HAND criteria. The log10 CD14(+) HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14(+) HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions. INTERPRETATION: Reservoir burden of HIV DNA in monocyte-enriched (CD14(+)) peripheral blood cells increases risk for HAND in treatment-naive HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS. PMID- 23936157 TI - Population structure of mixed Mycobacterium tuberculosis infection is strain genotype and culture medium dependent. AB - BACKGROUND: Molecular genotyping methods have shown infection with more than one Mycobacterium tuberculosis strain genotype in a single sputum culture, indicating mixed infection. AIM: This study aimed to develop a PCR-based genotyping tool to determine the population structure of M. tuberculosis strain genotypes in primary Mycobacterial Growth Indicator Tubes (MGIT) and Lowenstein-Jensen (LJ) cultures to identify mixed infections and to establish whether the growth media influenced the recovery of certain strain genotypes. METHOD: A convenience sample of 206 paired MGIT and LJ M. tuberculosis cultures from pulmonary tuberculosis patients resident in Khayelitsha, South Africa were genotyped using an in-house PCR-based method to detect defined M. tuberculosis strain genotypes. RESULTS: The sensitivity and specificity of the PCR-based method for detecting Beijing, Haarlem, S-family, and LAM genotypes was 100%, and 75% and 50% for detecting the Low Copy Clade, respectively. Thirty-one (15%) of the 206 cases showed the presence of more than one M. tuberculosis strain genotype. Strains of the Beijing and Haarlem genotypes were significantly more associated with a mixed infection (on both media) when compared to infections with a single strain (Beijing MGIT p = 0.02; LJ, p<0.01) and (Haarlem: MGIT p<0.01; LJ, p = 0.01). Strains with the Beijing genotype were less likely to be with "other genotype" strains (p<0.01) while LAM, Haarlem, S-family and LCC occurred independently with the Beijing genotype. CONCLUSION: The PCR-based method was able to identify mixed infection in at least 15% of the cases. LJ media was more sensitive in detecting mixed infections than MGIT media, implying that the growth characteristics of M. tuberculosis on different media may influence our ability to detect mixed infections. The Beijing and Haarlem genotypes were more likely to occur in a mixed infection than any of the other genotypes tested suggesting pathogen pathogen compatibility. PMID- 23936158 TI - A computational model of lipopolysaccharide-induced nuclear factor kappa B activation: a key signalling pathway in infection-induced preterm labour. AB - Preterm birth is the single biggest cause of significant neonatal morbidity and mortality, and the incidence is rising. Development of new therapies to treat and prevent preterm labour is seriously hampered by incomplete understanding of the molecular mechanisms that initiate labour at term and preterm. Computational modelling provides a new opportunity to improve this understanding. It is a useful tool in (i) identifying gaps in knowledge and informing future research, and (ii) providing the basis for an in silico model of parturition in which novel drugs to prevent or treat preterm labour can be "tested". Despite their merits, computational models are rarely used to study the molecular events initiating labour. Here, we present the first attempt to generate a dynamic kinetic model that has relevance to the molecular mechanisms of preterm labour. Using published data, we model an important candidate signalling pathway in infection-induced preterm labour: that of lipopolysaccharide (LPS) -induced activation of Nuclear Factor kappa B. This is the first model of this pathway to explicitly include molecular interactions upstream of Nuclear Factor kappa B activation. We produced a formalised graphical depiction of the pathway and built a kinetic model based on ordinary differential equations. The kinetic model accurately reproduced published in vitro time course plots of Lipopolysaccharide-induced Nuclear Factor kappa B activation in mouse embryo fibroblasts. In this preliminary work we have provided proof of concept that it is possible to build computational models of signalling pathways that are relevant to the regulation of labour, and suggest that models that are validated with wet-lab experiments have the potential to greatly benefit the field. PMID- 23936159 TI - Entry and elimination of marine mammal Brucella spp. by hooded seal (Cystophora cristata) alveolar macrophages in vitro. AB - A high prevalence of Brucellapinnipedialis serology and bacteriology positive animals has been found in the Northeast Atlantic stock of hooded seal (Cystophoracristata); however no associated gross pathological changes have been identified. Marine mammal brucellae have previously displayed different infection patterns in human and murine macrophages. To investigate if marine mammal Brucella spp. are able to invade and multiply in cells originating from a presumed host species, we infected alveolar macrophages from hooded seal with a B. pinnipedialis hooded seal isolate. Hooded seal alveolar macrophages were also challenged with B. pinnipedialis reference strain (NCTC 12890) from harbor seal (Phocavitulina), B. ceti reference strain (NCTC 12891) from harbor porpoise (Phocoenaphocoena) and a B. ceti Atlantic white-sided dolphin (Lagenorhynchusacutus) isolate (M83/07/1), to evaluate possible species-specific differences. Brucella suis 1330 was included as a positive control. Alveolar macrophages were obtained by post mortem bronchoalveolar lavage of euthanized hooded seals. Phenotyping of cells in the lavage fluid was executed by flow cytometry using the surface markers CD14 and CD18. Cultured lavage cells were identified as alveolar macrophages based on morphology, expression of surface markers and phagocytic ability. Alveolar macrophages were challenged with Brucella spp. in a gentamicin protection assay. Following infection, cell lysates from different time points were plated and evaluated quantitatively for colony forming units. Intracellular presence of B. pinnipedialis hooded seal isolate was verified by immunocytochemistry. Our results show that the marine mammal brucellae were able to enter hooded seal alveolar macrophages; however, they did not multiply intracellularly and were eliminated within 48 hours, to the contrary of B. suis that showed the classical pattern of a pathogenic strain. In conclusion, none of the four marine mammal strains tested were able to establish a persistent infection in primary alveolar macrophages from hooded seal. PMID- 23936160 TI - MicroRNA-3906 regulates fast muscle differentiation through modulating the target gene homer-1b in zebrafish embryos. AB - A microRNA, termed miR-In300 or miR-3906, suppresses the transcription of myf5 through silencing dickkopf-related protein 3 (dkk3r/dkk3a) during early development when myf5 is highly transcribed, but not at late stages when myf5 transcription is reduced. Moreover, after 24 hpf, when muscle cells are starting to differentiate, Dkk3a could not be detected in muscle tissue at 20 hpf. To explain these reversals, we collected embryos at 32 hpf, performed assays, and identified homer-1b, which regulates calcium release from sarcoplasmic reticulum, as the target gene of miR-3906. We further found that either miR-3906 knockdown or homer-1b overexpression increased expressions of fmhc4 and atp2a1 of calcium dependent fast muscle fibrils, but not slow muscle fibrils, and caused a severe disruption of sarcomeric actin and Z-disc structure. Additionally, compared to control embryos, the intracellular calcium concentration ([Ca(2+)]i) of these treated embryos was increased as high as 83.9-97.3% in fast muscle. In contrast, either miR-3906 overexpression or homer-1b knockdown caused decreases of [Ca(2+)]i and, correspondingly, defective phenotypes in fast muscle. These defects could be rescued by inducing homer-1b expression at later stage. These results indicate that miR-3906 controls [Ca(2+)]i homeostasis in fast muscle through fine tuning homer-1b expression during differentiation to maintain normal muscle development. PMID- 23936162 TI - Improvement of pharmacokinetics behavior of apocynin by nitrone derivatization: comparative pharmacokinetics of nitrone-apocynin and its parent apocynin in rats. AB - Apocynin, a potent inhibitor of NADPH-oxidase, was widely studied for activities in diseases such as inflammation-mediated disorders, asthma and cardiovascular diseases. In our recent study, a novel nitrone derivative of apocynin, AN-1, demonstrated potent inhibition to oxidative injury and to high expression of gp91(phox) subunit of NADPH-oxidase induced by tert-butyl hydroperoxide (t-BHP) in RAW 264.7 macrophage cells, and displayed promising preclinical protective effect against lipopolysaccharide (LPS)-induced acute lung injury in rats. In this work, the pharmacokinetic behaviors of AN-1 in Sprague-Dawley rats with single intravenous and intragastric doses were investigated for further development. Furthermore, apocynin's pharmacokinetics remain lacking, even though its pharmacological action has been extensively evaluated. The pharmacokinetics of parent apocynin were also comparatively characterized. A simple HPLC method was developed and validated to determine both AN-1 and apocynin in rat plasma. The chromatographic separation was achieved on an Agilent HC-C18 column (250 mm*4.6 mm, 5 um) at an isocratic flow rate of 1.0 mL/min, with the mobile phase of methanol and water (53?47, v/v) and the UV detection set at 279 nm. Good linearity was established over the concentration range of 0.1-500 ug/mL for AN-1 and 0.2-100 ug/mL for apocynin. The absolute recovery, precision and accuracy were satisfactory. Compared with the parent compound apocynin, AN-1 yielded a much longer T1/2 (AN-1 179.8 min, apocynin 6.1 min) and higher AUC0-t (AN-1 61.89 mmol/L.min, apocynin 2.49 mmol/L.min) after equimolar intravenous dosing (0.302 mmol/kg). The absolute bioavailability of oral AN-1 was 78%, but that of apocynin was only 2.8%. The significant improvement of pharmacokinetic behavior might be accounted for the effective pharmacodynamic results we documented for the novel nitrone derivative AN-1. PMID- 23936161 TI - An experimental study on (131)I-CHIBA-1001: a radioligand for alpha7 nicotinic acetylcholine receptors. AB - OBJECTIVE: The alpha7 nicotinic acetylcholine receptors (nAChRs) play a vital role in the pathophysiology of neuropsychiatric diseases such as Alzheimer's disease and depression. However, there is currently no suitable positron emission tomography (PET) or Single-Photon Emission Computed Tomography (SPECT) radioligands for imaging alpha7 nAChRs in brain. Here our aim is to radiosynthesize a novel SPECT radioligand (131)I-CHIBA-1001 for whole body biodistribution study and in vivo imaging of alpha7 nAChRs in brain. METHOD: (131)I-CHIBA-1001 was radiosynthesized by chloramine-T method. Different conditions of reaction time and temperature were tested to get a better radiolabeling yield. Radiolabeling yield and radiochemical purities of (131)I CHIBA-1001 were analyzed by thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) system. Whole body biodistribution study was performed at different time points post injection of (131)I-CHIBA-1001 in KM mice. Monkey subject was used for in vivo SPECT imaging in brain. RESULT: The radiolabeling yield of (131)I-CHIBA-1001 reached 96% within 1.5~2.0 h at 90~95 degrees C. The radiochemical purity reached more than 99% after HPLC purification. (131)I-CHIBA-1001 was highly stable in saline and fresh human serum in room temperature and 37 degrees C separately. The biodistribution data of brain at 15, 30, and 60 min were 11.05+/-1.04%ID/g, 8.8+/-0.04%ID/g and 6.28+/ 1.13%ID/g, respectively. In experimental SPECT imaging, the distribution of radioactivity in the brain regions was paralleled with the distribution of alpha7 nAChRs in the monkey brain. Moreover, in the blocking SPECT imaging study, the selective alpha7 nAChR agonist SSR180711 blocked the radioactive uptake in the brain successfully. CONCLUSION: The CHIBA-1001 can be successfully radiolabeled with (131)I using the chloramine-T method. (131)I-CHIBA-1001 can successfully accumulate in the monkey brain and image the alpha7 acetylcholine receptors. (131)I-CHIBA-1001 can be a candidate for imagingalpha7 acetylcholine receptors, which will be of great value for the diagnosis and treatment of mental diseases. PMID- 23936163 TI - Identification and validation of human papillomavirus encoded microRNAs. AB - We report here identification and validation of the first papillomavirus encoded microRNAs expressed in human cervical lesions and cell lines. We established small RNA libraries from ten human papillomavirus associated cervical lesions including cancer and two human papillomavirus harboring cell lines. These libraries were sequenced using SOLiD 4 technology. We used the sequencing data to predict putative viral microRNAs and discovered nine putative papillomavirus encoded microRNAs. Validation was performed for five candidates, four of which were successfully validated by qPCR from cervical tissue samples and cell lines: two were encoded by HPV 16, one by HPV 38 and one by HPV 68. The expression of HPV 16 microRNAs was further confirmed by in situ hybridization, and colocalization with p16INK4A was established. Prediction of cellular target genes of HPV 16 encoded microRNAs suggests that they may play a role in cell cycle, immune functions, cell adhesion and migration, development, and cancer. Two putative viral target sites for the two validated HPV 16 miRNAs were mapped to the E5 gene, one in the E1 gene, two in the L1 gene and one in the LCR region. This is the first report to show that papillomaviruses encode their own microRNA species. Importantly, microRNAs were found in libraries established from human cervical disease and carcinoma cell lines, and their expression was confirmed in additional tissue samples. To our knowledge, this is also the first paper to use in situ hybridization to show the expression of a viral microRNA in human tissue. PMID- 23936164 TI - Information theoretically secure, enhanced Johnson noise based key distribution over the smart grid with switched filters. AB - We introduce a protocol with a reconfigurable filter system to create non overlapping single loops in the smart power grid for the realization of the Kirchhoff-Law-Johnson-(like)-Noise secure key distribution system. The protocol is valid for one-dimensional radial networks (chain-like power line) which are typical of the electricity distribution network between the utility and the customer. The speed of the protocol (the number of steps needed) versus grid size is analyzed. When properly generalized, such a system has the potential to achieve unconditionally secure key distribution over the smart power grid of arbitrary geometrical dimensions. PMID- 23936166 TI - Age and ethnic differences in volumetric breast density in new zealand women: a cross-sectional study. AB - Breast cancer incidence differs by ethnicity in New Zealand (NZ) with Maori (the indigenous people) women having the highest rates followed by Pakeha (people primarily of British/European descent), Pacific and Asian women, who experience the lowest rates. The reasons for these differences are unclear. Breast density, an important risk factor for breast cancer, has not previously been studied here. We used an automated system, VolparaTM, to measure breast density volume from the medio-lateral oblique view of digital mammograms, by age (<=50 years and >50 years) and ethnicity (Pakeha/Maori/Pacific/Asian) using routine data from the national screening programme: age; x-ray system and mammography details for 3,091 Pakeha, 716 Maori, 170 Pacific and 662 Asian (total n = 4,239) women. Linear regression of the natural logarithm of absolute and percent density values was used, back-transformed and expressed as the ratio of the geometric means. Covariates were age, x-ray system and, for absolute density, the natural log of the volume of non-dense tissue (a proxy for body mass index). Median age for Pakeha women was 55 years; Maori 53 years; and Pacific and Asian women, 52 years. Compared to Pakeha women (reference), Maori had higher absolute volumetric density (1.09; 95% confidence interval [95% CI] 1.03-1.15) which remained following adjustment (1.06; 95% CI 1.01-1.12) and was stronger for older compared to younger Maori women. Asian women had the greatest risk of high percentage breast density (1.35; 95% CI 1.27-1.43) while Pacific women in both the <=50 and >50 year age groups (0.78; 95% CI 0.66-0.92 and 0.81; 95% CI 0.71-0.93 respectively) had the lowest percentage breast density compared to Pakeha. As well as expected age differences, we found differential patterns of breast density by ethnicity consistent with ethnic differences seen in breast cancer risk. Breast density may be a contributing factor to NZ's well-known, but poorly explained, inequalities in breast cancer incidence. PMID- 23936167 TI - Refining susceptibility loci of chronic obstructive pulmonary disease with lung eqtls. AB - Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality worldwide. Recent genome-wide association studies (GWAS) have identified robust susceptibility loci associated with COPD. However, the mechanisms mediating the risk conferred by these loci remain to be found. The goal of this study was to identify causal genes/variants within susceptibility loci associated with COPD. In the discovery cohort, genome-wide gene expression profiles of 500 non-tumor lung specimens were obtained from patients undergoing lung surgery. Blood-DNA from the same patients were genotyped for 1,2 million SNPs. Following genotyping and gene expression quality control filters, 409 samples were analyzed. Lung expression quantitative trait loci (eQTLs) were identified and overlaid onto three COPD susceptibility loci derived from GWAS; 4q31 (HHIP), 4q22 (FAM13A), and 19q13 (RAB4B, EGLN2, MIA, CYP2A6). Significant eQTLs were replicated in two independent datasets (n = 363 and 339). SNPs previously associated with COPD and lung function on 4q31 (rs1828591, rs13118928) were associated with the mRNA expression of HHIP. An association between mRNA expression level of FAM13A and SNP rs2045517 was detected at 4q22, but did not reach statistical significance. At 19q13, significant eQTLs were detected with EGLN2. In summary, this study supports HHIP, FAM13A, and EGLN2 as the most likely causal COPD genes on 4q31, 4q22, and 19q13, respectively. Strong lung eQTL SNPs identified in this study will need to be tested for association with COPD in case control studies. Further functional studies will also be needed to understand the role of genes regulated by disease-related variants in COPD. PMID- 23936165 TI - P2X4 assembles with P2X7 and pannexin-1 in gingival epithelial cells and modulates ATP-induced reactive oxygen species production and inflammasome activation. AB - We have previously reported that Porphyromonas gingivalis infection of gingival epithelial cells (GEC) requires an exogenous danger signal such as ATP to activate an inflammasome and caspase-1, thereby inducing secretion of interleukin (IL)-1beta. Stimulation with extracellular ATP also stimulates production of reactive oxygen species (ROS) in GEC. However, the mechanism by which ROS is generated in response to ATP, and the role that different purinergic receptors may play in inflammasome activation, is still unclear. In this study, we revealed that the purinergic receptor P2X(4) is assembled with the receptor P2X(7) and its associated pore, pannexin-1. ATP induces ROS production through a complex consisting of the P2X(4), P2X(7), and pannexin-1. P2X(7)-mediated ROS production can activate the NLRP3 inflammasome and caspase-1. Furthermore, separate depletion or inhibition of P2X(4), P2X(7), or pannexin-1 complex blocks IL-1beta secretion in P. gingivalis-infected GEC following ATP treatment. However, activation via P2X(4) alone induces ROS generation but not inflammasome activation. These results suggest that ROS is generated through stimulation of a P2X(4)/P2X(7)/pannexin-1 complex, and reveal an unexpected role for P2X(4), which acts as a positive regulator of inflammasome activation during microbial infection. PMID- 23936168 TI - Exploring the sources of bacterial spoilers in beefsteaks by culture-independent high-throughput sequencing. AB - Microbial growth on meat to unacceptable levels contributes significantly to change meat structure, color and flavor and to cause meat spoilage. The types of microorganisms initially present in meat depend on several factors and multiple sources of contamination can be identified. The aims of this study were to evaluate the microbial diversity in beefsteaks before and after aerobic storage at 4 degrees C and to investigate the sources of microbial contamination by examining the microbiota of carcasses wherefrom the steaks originated and of the processing environment where the beef was handled. Carcass, environmental (processing plant) and meat samples were analyzed by culture-independent high throughput sequencing of 16S rRNA gene amplicons. The microbiota of carcass swabs was very complex, including more than 600 operational taxonomic units (OTUs) belonging to 15 different phyla. A significant association was found between beef microbiota and specific beef cuts (P<0.01) indicating that different cuts of the same carcass can influence the microbial contamination of beef. Despite the initially high complexity of the carcass microbiota, the steaks after aerobic storage at 4 degrees C showed a dramatic decrease in microbial complexity. Pseudomonas sp. and Brochothrix thermosphacta were the main contaminants, and Acinetobacter, Psychrobacter and Enterobacteriaceae were also found. Comparing the relative abundance of OTUs in the different samples it was shown that abundant OTUs in beefsteaks after storage occurred in the corresponding carcass. However, the abundance of these same OTUs clearly increased in environmental samples taken in the processing plant suggesting that spoilage-associated microbial species originate from carcasses, they are carried to the processing environment where the meat is handled and there they become a resident microbiota. Such microbiota is then further spread on meat when it is handled and it represents the starting microbial association wherefrom the most efficiently growing microbial species take over during storage and can cause spoilage. PMID- 23936169 TI - Women's satisfaction with body image before pregnancy and body mass index 4 years after delivery in the mothers of generation XXI. AB - BACKGROUND: Body image satisfaction (BIS) influences body weight regulation and may contribute to long-term healthier lifestyle after pregnancy. Thus, we aimed to assess the association between BIS before pregnancy and body mass index (BMI) 4 years after the index pregnancy. METHODS: As part of the follow-up of a birth cohort, 3612 women with prepregnancy BMI >18.5 kg/m(2) were reevaluated 4 years after the birth of a child. BIS was defined as the difference between perceived and ideal body size before pregnancy, assessed by Stunkard Silhouettes after birth. The associations of BIS with BMI change (continuous) and BMI classes at 4 years, based on measured weight and height, were estimated using linear and multinomial regression, respectively. RESULTS: Among women with normal prepregnancy BMI, those who felt too small, regarding their ideal, had a 0.25 kg/m(2) smaller increase in BMI within 4 years and a lower likelihood of becoming overweight or obese [multivariate-adjusted odds ratio (OR) = 0.63; 95% confidence interval (95%CI): 0.44-0.91 and OR = 0.21; 95%CI: 0.05-0.91, respectively) than those satisfied with body image. Feeling too large was associated with a 0.41 kg/m(2) larger increase in BMI and a higher risk of becoming overweight or obese (OR = 2.12; 95%CI:1.73-2.59 and OR = 3.42; 95%CI:2.02-5.79, respectively). A similar, non-significant, trend was observed for overweight women. Obese women who felt too large had a non-significant decrease in BMI. CONCLUSIONS: BIS plays a role in maternal body weight after delivery. Realistic body size goals may promote the motivation to lose weight and contribute to higher success in attaining them. PMID- 23936171 TI - IL-17A mediates early post-transplant lesions after heterotopic trachea allotransplantation in Mice. AB - Primary graft dysfunction (PGD) and bronchiolitis obliterans (BO) are the leading causes of morbidity and mortality after lung transplantation. Reports from clinical and rodent models suggest the implication of IL-17A in either PGD or BO. We took advantage of the heterotopic trachea transplantation model in mice to study the direct role of IL-17A in post-transplant airway lesions. Across full MHC barrier, early lesions were controlled in IL-17A(-/-) or anti-IL17 treated recipients. In contrast, IL-17A deficiency did not prevent subsequent obliterative airway disease (OAD). Interestingly, this early protection occurred also in syngeneic grafts and was accompanied by a decrease in cellular stress, as attested by lower HSP70 mRNA levels, suggesting the involvement of IL-17A in ischemia-reperfusion injury (IRI). Furthermore, persistence of multipotent CK14(+) epithelial stem cells underlined allograft protection afforded by IL-17A deficiency or neutralisation. Recipient-derived gammadelta(+) and CD4(+) T cells were the major source of IL-17A. However, lesions still occurred in the absence of each subset, suggesting a high redundancy between the innate and adaptive IL 17A producing cells. Notably, a double depletion significantly diminished lesions. In conclusion, this work implicated IL-17A as mediator of early post transplant airway lesions and could be considered as a potential therapeutic target in clinical transplantation. PMID- 23936170 TI - MiR-17 partly promotes hematopoietic cell expansion through augmenting HIF-1alpha in osteoblasts. AB - BACKGROUND: Hematopoietic stem cell (HSC) regulation is highly dependent on interactions with the marrow microenvironment, of which osteogenic cells play a crucial role. While evidence is accumulating for an important role of intrinsic miR-17 in regulating HSCs and HPCs, whether miR-17 signaling pathways are also necessary in the cell-extrinsic control of hematopoiesis hereto remains poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Using the immortalized clone with the characteristics of osteoblasts, FBMOB-hTERT, in vitro expansion, long-term culture initiating cell (LTC-IC) and non-obese diabetic/severe combined immunodeficient disease (NOD/SCID) mice repopulating cell (SRC) assay revealed that the ectopic expression of miR-17 partly promoted the ability of FBMOB-hTERT to support human cord blood (CB) CD34(+) cell expansion and maintain their multipotency. It also seemed that osteoblastic miR-17 was prone to cause a specific expansion of the erythroid lineage. Conversely, deficient expression of miR-17 partly inhibited the hematopoietic supporting ability of FBMOB-hTERT. We further identified that HIF-1alpha is responsible for, at least in part, the promoted hematopoietic supporting ability of FBMOB-hTERT caused by miR-17. HIF 1alpha expression is markedly enhanced in miR-17 overexpressed FBMOB-hTERT upon interaction with CB CD34(+) cells compared to other niche associated factors. More interestingly, the specific erythroid lineage expansion of CB CD34(+) cells caused by osteoblastic miR-17 was abrogated by HIF-1alpha knock down. CONCLUSION/SIGNIFICANCE: Our data demonstrated that CB CD34(+) cell expansion can be partly promoted by osteoblastic miR-17, and in particular, ectopic miR-17 can cause a specific expansion of the erythroid lineage through augmenting HIF-1alpha in osteoblasts. PMID- 23936172 TI - Identification and characterization of a novel Shigella flexneri serotype Yv in China. AB - Shigella flexneri is the major cause of bacterial shigellosis in developing countries. S. flexneri is divided into at least 19 serotypes, the majority of which are modifications of the same basic O-antigen by glucosylation and/or O acetylation of its sugar residues by phage encoded serotype-converting genes. Recently, a plasmid encoded phosphoethanolamine (PEtN) modification of the O antigen has been reported, which is responsible for the presence of the MASF IV-1 determinant and results in conversion of traditional serotypes X, 4a and Y to novel serotypes Xv, 4av and Yv, respectively. In this study, we characterized 19 serotype Yv strains isolated in China. A variant of the O-antigen phosphoethanolamine transferase gene opt (formerly called lpt-O) carried by a pSFxv_2-like plasmid was found in serotype Yv strains, which specifies the phosphorylation pattern on the O-antigen of this serotype. For the majority of the O-antigen units, the PEtN modification occurs on Rha(III), while for a minority, modifications occur on both Rha(II) and Rha(III). Serotype-specific gene detection and PFGE analysis suggested that these serotype Yv isolates were originated from serotypes Y, Xv and 2a by acquisition of an opt-carrying plasmid and/or inactivation of serotype-specific gene gtrII or gtrX. These data, combined with those of serotypes Xv and 4av reported earlier, demonstrate that the plasmid encoded PEtN modification is an important serotype conversion mechanism in S. flexneri, in addition to glucosylation and O-acetylation. PMID- 23936173 TI - Induction of premalignant host responses by cathepsin x/z-deficiency in Helicobacter pylori-infected mice. AB - Helicobacter pylori are responsible for the induction of chronic gastric inflammation progressing to atrophy, metaplasia, and gastric cancer. The overexpression of Cathepsin X/Z (Ctsz) in H. pylori-infected mucosa and gastric cancer is mediated predominantly by an augmented migration of ctsz(-/-)positive macrophages and the up-regulation of Ctsz in tumor epithelium. To explore the Ctsz-function in the context of chronic inflammation and the development of preneoplastic lesions, we used Ctsz-deficient mice in a H. pylori gastritis model. Ctsz (-/-) and wild-type (wt) mice were infected with H. pylori strain SS1. The mice were sacrificed at 24, 36, and 50 weeks post infection (wpi). The stomach was removed, and gastric strips were snap-frozen or embedded and stained with H&E. Tissue sections were scored for epithelial lesions and inflammation. Ki 67 and F4/80 immunostaining were used to measure epithelial cell proliferation and macrophage infiltration, respectively. The upregulation of compensating cathepsins and cytokines were confirmed by Western blotting and quantitative RT PCR. SS1-infected wt and ctsz (-/-) mice showed strong inflammation, foveolar hyperplasia, atrophy, and cystically-dilated glands. However, at 50 wpi, ctsz (-/ ) mice developed significantly more severe spasmolytic polypeptide-expressing metaplasia (SPEM), showed enhanced epithelial proliferation, and higher levels of infiltrating macrophages. Induction of cytokines was higher and significantly prolonged in ctsz (-/-) mice compared to wt. Ctsz deficiency supports H. pylori dependent development of chronic gastritis up to metaplasia, indicating a protective, but not proteolytic, function of Ctsz in inflammatory gastric disease. PMID- 23936174 TI - Non-motor and motor features in LRRK2 transgenic mice. AB - BACKGROUND: Non-motor symptoms are increasingly recognized as important features of Parkinson's disease (PD). LRRK2 mutations are common causes of familial and sporadic PD. Non-motor features have not been yet comprehensively evaluated in LRRK2 transgenic mouse models. OBJECTIVE: Using a transgenic mouse model overexpressing the R1441G mutation of the human LRRK2 gene, we have investigated the longitudinal correlation between motor and non-motor symptoms and determined if specific non-motor phenotypes precede motor symptoms. METHODOLOGY: We investigated the onset of motor and non-motor phenotypes on the LRRK2(R1441G) BAC transgenic mice and their littermate controls from 4 to 21 month-old using a battery of behavioral tests. The transgenic mutant mice displayed mild hypokinesia in the open field from 16 months old, with gastrointestinal dysfunctions beginning at 6 months old. Non-motor features such as depression and anxiety-like behaviors, sensorial functions (pain sensitivity and olfaction), and learning and memory abilities in the passive avoidance test were similar in the transgenic animals compared to littermate controls. CONCLUSIONS: LRRK2(R1441G) BAC transgenic mice displayed gastrointestinal dysfunction at an early stage but did not have abnormalities in fine behaviors, olfaction, pain sensitivity, mood disorders and learning and memory compared to non-transgenic littermate controls. The observations on olfaction and gastrointestinal dysfunction in this model validate findings in human carriers. These mice did recapitulate mild Parkinsonian motor features at late stages but compensatory mechanisms modulating the progression of PD in these models should be further evaluated. PMID- 23936175 TI - The use of structured imagery and dispositional measurement to assess situational use of mindfulness skills. AB - The recent proliferation of studies on mindfulness produced varying theoretical models, each based in part on how mindfulness is assessed. These models agree, however, that mindfulness encompasses moment-to-moment or situational experiences. Incongruence between dispositional and situational assessment would be problematic for theory and empirical research. In particular, it remains to be established whether situational measurement is an accurate method for mindfulness assessment and whether dispositional measures are able to accurately detect mindfulness skills in various situations. The association between dispositional and situational mindfulness processes (i.e., situational attention awareness and emotion acceptance) was examined in two studies. In Study 1 (N = 148), independent groups who reported high and low levels of dispositional mindfulness skills were compared on a continuous measure of situational mindfulness skills. In Study 2 (N = 317), dispositional mindfulness questionnaires were used to predict situational use of mindfulness skills. Results suggest not only that situational measures accurately detect use of mindfulness skills, but also that dispositional measures can predict one's use of situational mindfulness skills. Findings from both studies were consistent across both positive and negative situations. Moreover, neither neuroticism nor extraversion was shown to have a moderating effect on the relationship between dispositional and situational use of mindfulness skills. The implications of these findings for clinical practice and future investigations pertaining to measurement validity in this area are discussed. PMID- 23936176 TI - Using boreholes as windows into groundwater ecosystems. AB - Groundwater ecosystems remain poorly understood yet may provide ecosystem services, make a unique contribution to biodiversity and contain useful bio indicators of water quality. Little is known about ecosystem variability, the distribution of invertebrates within aquifers, or how representative boreholes are of aquifers. We addressed these issues using borehole imaging and single borehole dilution tests to identify three potential aquifer habitats (fractures, fissures or conduits) intercepted by two Chalk boreholes at different depths beneath the surface (34 to 98 m). These habitats were characterised by sampling the invertebrates, microbiology and hydrochemistry using a packer system to isolate them. Samples were taken with progressively increasing pumped volume to assess differences between borehole and aquifer communities. The study provides a new conceptual framework to infer the origin of water, invertebrates and microbes sampled from boreholes. It demonstrates that pumping 5 m(3) at 0.4-1.8 l/sec was sufficient to entrain invertebrates from five to tens of metres into the aquifer during these packer tests. Invertebrates and bacteria were more abundant in the boreholes than in the aquifer, with associated water chemistry variations indicating that boreholes act as sites of enhanced biogeochemical cycling. There was some variability in invertebrate abundance and bacterial community structure between habitats, indicating ecological heterogeneity within the aquifer. However, invertebrates were captured in all aquifer samples, and bacterial abundance, major ion chemistry and dissolved oxygen remained similar. Therefore the study demonstrates that in the Chalk, ecosystems comprising bacteria and invertebrates extend from around the water table to 70 m below it. Hydrogeological techniques provide excellent scope for tackling outstanding questions in groundwater ecology, provided an appropriate conceptual hydrogeological understanding is applied. PMID- 23936177 TI - A comparative study of clinicopathological features between chronic cholecystitis patients with and without Helicobacter pylori infection in gallbladder mucosa. AB - BACKGROUND: Helicobacter pylori has been isolated from 10%-20% of human chronic cholecystitis specimens but the characteristics of "Helicobacter pylori positive cholecystitis" remains unclear. This study aims to compare the clinicopathological features between chronic cholecystitis patients with and without Helicobacter pylori infection in gallbladder mucosa. METHODS: Three hundred and twenty-six chronic cholecystitis patients were divided into two groups according to whether Helicobacter pylori could be detected by culture, staining or PCR for Helicobacter 16s rRNA gene in gallbladder mucosa. Positive samples were sequenced for Helicobacter pylori-specific identification. Clinical parameters as well as pathological characteristics including some premalignant lesions and the expression levels of iNOS and ROS in gallbladder were compared between the two groups. RESULTS: Helicobacter pylori infection in gallbladder mucosa was detected in 20.55% of cholecystitis patients. These patients had a higher prevalence of acid regurgitation symptoms (p = 0.001), more histories of chronic gastritis (p = 0.005), gastric ulcer (p = 0.042), duodenal ulcer (p = 0.026) and higher presence of Helicobacter pylori in the stomach as compared to patients without Helicobacter pylori infection in the gallbladder mucosa. Helicobacter pylori 16s rRNA in gallbladder and gastric-duodenal mucosa from the same individual patient had identical sequences. Also, higher incidences of adenomyomatosis (p = 0.012), metaplasia (p = 0.022) and higher enhanced expressions of iNOS and ROS were detected in Helicobacter pylori infected gallbladder mucosa (p<0.05). CONCLUSIONS: Helicobacter pylori infection in gallbladder mucosa is strongly associated with Helicobacter pylori existed in stomach. Helicobacter pylori is also correlated with gallbladder premalignant lesions including metaplasia and adenomyomatosis. The potential mechanism might be related with higher ROS/RNS production but needs further investigation. PMID- 23936178 TI - Effect of antibiotics against Mycoplasma sp. on human embryonic stem cells undifferentiated status, pluripotency, cell viability and growth. AB - Human embryonic stem cells (hESCs) are self-renewing pluripotent cells that can differentiate into specialized cells and hold great promise as models for human development and disease studies, cell-replacement therapies, drug discovery and in vitro cytotoxicity tests. The culture and differentiation of these cells are both complex and expensive, so it is essential to extreme aseptic conditions. hESCs are susceptible to Mycoplasma sp. infection, which is hard to detect and alters stem cell-associated properties. The purpose of this work was to evaluate the efficacy and cytotoxic effect of Plasmocin(TM) and ciprofloxacin (specific antibiotics used for Mycoplasma sp. eradication) on hESCs. Mycoplasma sp. infected HUES-5 884 (H5 884, stable hESCs H5-brachyury promoter-GFP line) cells were effectively cured with a 14 days Plasmocin(TM) 25 ug/ml treatment (curative treatment) while maintaining stemness characteristic features. Furthermore, cured H5 884 cells exhibit the same karyotype as the parental H5 line and expressed GFP, through up-regulation of brachyury promoter, at day 4 of differentiation onset. Moreover, H5 cells treated with ciprofloxacin 10 ug/ml for 14 days (mimic of curative treatment) and H5 and WA09 (H9) hESCs treated with Plasmocin(TM) 5 ug/ml (prophylactic treatment) for 5 passages retained hESCs features, as judged by the expression of stemness-related genes (TRA1-60, TRA1-81, SSEA-4, Oct-4, Nanog) at mRNA and protein levels. In addition, the presence of specific markers of the three germ layers (brachyury, Nkx2.5 and cTnT: mesoderm; AFP: endoderm; nestin and Pax-6: ectoderm) was verified in in vitro differentiated antibiotic treated hESCs. In conclusion, we found that Plasmocin(TM) and ciprofloxacin do not affect hESCs stemness and pluripotency nor cell viability. However, curative treatments slightly diminished cell growth rate. This cytotoxic effect was reversible as cells regained normal growth rate upon antibiotic withdrawal. PMID- 23936179 TI - Transfer of a serial representation between two distinct tasks by rhesus macaques. AB - Do animals form task-specific representations, or do those representations take a general form that can be applied to qualitatively different tasks? Rhesus monkeys (Macaca mulatta) learned the ordering of stimulus lists using two different serial tasks, in order to test whether prior experience in each task could be transfered to the other, enhancing performance. The simultaneous chaining paradigm delivered rewards only after subjects responded in the correct order to all stimuli displayed on a touch sensitive video monitor. The transitive inference paradigm presented pairs of items and delivered rewards when subjects selected the item with the lower ordinal rank. After learning a list in one paradigm, subjects' knowledge of that list was tested using the other paradigm. Performance was enhanced from the very start of transfer training. Transitive inference performance was characterized by 'symbolic distance effects,' whereby the ordinal distance between stimuli in the implied list ordering was strongly predictive of the probability of a correct response. The patterns of error displayed by subjects in both tasks were best explained by a spatially coded representation of list items, regardless of which task was used to learn the list. Our analysis permits properties of this representation to be investigated without the confound of verbal reasoning. PMID- 23936180 TI - Hemispheric differences in corticospinal excitability and in transcallosal inhibition in relation to degree of handedness. AB - In this study, we examined hemispheric differences in corticospinal excitability and in transcallosal inhibition in a selected group of young adults (n = 34) grouped into three handedness categories (RH: strongly right-handed, n = 17; LH: strongly left-handed, n = 10; MH: mixed-handed, n = 7) based on laterality quotients (LQ) derived from the Edinburgh Handedness Inventory. Performance measures were also used to derive a laterality index reflecting right-left asymmetries in manual dexterity (Dextli) and in finger tapping speed (Speedli). Corticospinal excitability was assessed in each hemisphere by means of transcranial magnetic stimulation (TMS) using the first dorsal interosseus as the target muscle. TMS measures consisted of resting motor threshold (rMT), motor evoked potential (MEP) recruitment curve (RC) and the contralateral silent period (cSP) with the accompanying MEP facilitation. Hemispheric interactions were assessed by means of the ipsilateral silent period (iSP) to determine the onset latency and the duration of transcallosal inhibition (i.e., LTI and DTI). Analysis of hemispheric variations in measures of corticospinal excitability revealed no major asymmetries in relation to degrees of laterality or handedness, with the exception of a rightward increase in rMTs in the LH group. Similarly, no clear asymmetries were found when looking at hemispheric variations in measures of transcallosal inhibition. However, a large group effect was detected for LTI measures, which were found to be significantly shorter in the MH group than in either the LH or RH group. MH participants also tended to show longer DTI than the other participants. Further inspection of overall variations in LTI and DTI measures as a function of LQs revealed that both variables followed a non-linear relationship, which was best described by a 2(nd) order polynomial function. Overall, these findings provide converging evidence for a link between mixed handedness and more efficient interhemispheric communication when compared to either right- or left-handedness. PMID- 23936181 TI - Task and spatial frequency modulations of object processing: an EEG study. AB - Visual object processing may follow a coarse-to-fine sequence imposed by fast processing of low spatial frequencies (LSF) and slow processing of high spatial frequencies (HSF). Objects can be categorized at varying levels of specificity: the superordinate (e.g. animal), the basic (e.g. dog), or the subordinate (e.g. Border Collie). We tested whether superordinate and more specific categorization depend on different spatial frequency ranges, and whether any such dependencies might be revealed by or influence signals recorded using EEG. We used event related potentials (ERPs) and time-frequency (TF) analysis to examine the time course of object processing while participants performed either a grammatical gender-classification task (which generally forces basic-level categorization) or a living/non-living judgement (superordinate categorization) on everyday, real life objects. Objects were filtered to contain only HSF or LSF. We found a greater positivity and greater negativity for HSF than for LSF pictures in the P1 and N1 respectively, but no effects of task on either component. A later, fronto central negativity (N350) was more negative in the gender-classification task than the superordinate categorization task, which may indicate that this component relates to semantic or syntactic processing. We found no significant effects of task or spatial frequency on evoked or total gamma band responses. Our results demonstrate early differences in processing of HSF and LSF content that were not modulated by categorization task, with later responses reflecting such higher-level cognitive factors. PMID- 23936182 TI - Population-specific haplotype association of the postsynaptic density gene DLG4 with schizophrenia, in family-based association studies. AB - The post-synaptic density (PSD) of glutamatergic synapses harbors a multitude of proteins critical for maintaining synaptic dynamics. Alteration of protein expression levels in this matrix is a marked phenomenon of neuropsychiatric disorders including schizophrenia, where cognitive functions are impaired. To investigate the genetic relationship of genes expressed in the PSD with schizophrenia, a family-based association analysis of genetic variants in PSD genes such as DLG4, DLG1, PICK1 and MDM2, was performed, using Japanese samples (124 pedigrees, n = 376 subjects). Results showed a significant association of the rs17203281 variant from the DLG4 gene, with preferential transmission of the C allele (p = 0.02), although significance disappeared after correction for multiple testing. Replication analysis of this variant, found no association in a Chinese schizophrenia cohort (293 pedigrees, n = 1163 subjects) or in a Japanese case-control sample (n = 4182 subjects). The DLG4 expression levels between postmortem brain samples from schizophrenia patients showed no significant changes from controls. Interestingly, a five marker haplotype in DLG4, involving rs2242449, rs17203281, rs390200, rs222853 and rs222837, was enriched in a population specific manner, where the sequences A-C-C-C-A and G-C-C-C-A accumulated in Japanese (p = 0.0009) and Chinese (p = 0.0007) schizophrenia pedigree samples, respectively. However, this could not be replicated in case control samples. None of the variants in other examined candidate genes showed any significant association in these samples. The current study highlights a putative role for DLG4 in schizophrenia pathogenesis, evidenced by haplotype association, and warrants further dense screening for variants within these haplotypes. PMID- 23936183 TI - Branched-chain amino acid supplementation reduces oxidative stress and prolongs survival in rats with advanced liver cirrhosis. AB - Long-term supplementation with branched-chain amino acids (BCAA) is associated with prolonged survival and decreased frequency of development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis. However, the pharmaceutical mechanism underlying this association is still unclear. We investigated whether continuous BCAA supplementation increases survival rate of rats exposed to a fibrogenic agent and influences the iron accumulation, oxidative stress, fibrosis, and gluconeogenesis in the liver. Further, the effects of BCAA on gluconeogenesis in cultured cells were also investigated. A significant improvement in cumulative survival was observed in BCAA-supplemented rats with advanced cirrhosis compared to untreated rats with cirrhosis (P<0.05). The prolonged survival due to BCAA supplementation was associated with reduction of iron contents, reactive oxygen species production and attenuated fibrosis in the liver. In addition, BCAA ameliorated glucose metabolism by forkhead box protein O1 pathway in the liver. BCAA prolongs survival in cirrhotic rats and this was likely the consequences of reduced iron accumulation, oxidative stress and fibrosis and improved glucose metabolism in the liver. PMID- 23936184 TI - How about lunch? Consequences of the meal context on cognition and emotion. AB - Although research addresses the effects of a meal's context on food preference, the psychological consequences of meal situations are largely unexplored. We compared the cognitive and emotional effects of a restaurant meal eaten in the company of others to a solitary meal consumed in a plain office using pre- and post-tests analysis and controlling for the kind and amount of food consumed. Three tasks were conducted, measuring: (1) semantic memory (2) cognitive control and error monitoring, and (3) processing of emotional facial expressions. Covert processes in these tasks were assessed with event-related brain potentials. A mood rating questionnaire indicated a relaxation effect of the restaurant as compared to the plain meal situation. The restaurant meal increased sensitivity to threatening facial expressions and diminished cognitive control and error monitoring. No effects were observed for semantic memory. These findings provide the first experimental evidence that a restaurant meal with a social component may be more relaxing than a meal eaten alone in a plain setting and may reduce cognitive control. PMID- 23936186 TI - Land use changes and GHG emissions from tropical forest conversion by oil palm plantations in Riau Province, Indonesia. AB - Increasing prices and demand for biofuel and cooking oil from importer countries have caused a remarkable expansion of oil palm plantations in Indonesia. In this paper, we attempt to monitor the expansion of oil palm plantations on peat land and in tropical forests. We measure the GHG emissions from the land conversion activities at provincial scale. Using Landsat images from three different periods (1990s, 2000s and 2012), we classified LULC of the Riau Province, which is the largest oil palm producing region in Indonesia. A hybrid method of integration, generated by combining automatic processing and manual analysis, yields the best results. We found that the tropical rainforest cover decreased from ~63% in the 1990s to ~37% in the 2000s. By 2012, the remaining tropical rainforest cover was only ~22%. From the 1990s to the 2000s, conversion of forests and peat lands was the primary source of emissions, total CO2 emitted to the atmosphere was estimated at ~26.6 million tCO2.y(-1), with 40.62% and 59.38% of the emissions from conversion of peat lands and forests, respectively. Between 2000 and 2012, the total CO2 emitted to the atmosphere was estimated at ~5.2 million tCO2. y( 1), with 69.94% and 27.62% of the emissions from converted peat lands and converted forests, respectively. The results show that in the Riau Province, the oil palm industry boomed in the period from 1990 to 2000, with transformation of tropical forest and peat land as the primary source of emissions. The decrease of CO2 emissions in the period from 2000 to 2012 is possibly due to the enforcement of a moratorium on deforestation. PMID- 23936185 TI - Synchronous recruitment of epigenetic modifiers to endotoxin synergistically activated Tnf-alpha gene in acute kidney injury. AB - BACKGROUND: As a consequence of acute kidney injury (AKI), proximal tubular cells hyperrespond to endotoxin (lipopolysaccharide, LPS) by exaggerated renal Tnf alpha Production. This LPS hyperresponsiveness is transcriptionally mediated. The epigenetic pathways that control these responses are unknown. METHODS/FINDINGS: We applied multiplex chromatin immunoprecipitation platform (Matrix ChIP) to explore epigenetic pathways that underlie endotoxin hyperresponsiveness in the setting of preceding unilateral renal ischemia/reperfusion (I/R) in mouse AKI model. Endotoxin exposure after I/R resulted in enhanced transcription, manifested by hyperresponsive recruitment of RNA polymerase II (Pol II) at the Tnf-alpha gene. At this locus, LPS but not I/R increased levels of Pol II C terminal domain (CTD) phosho-serine2 &5 and induced dephosphorylation of the transcription-repressive histone H4 phospho-serine-1. In contrast, I/R but not LPS increased the transcription-permissive histone phosphorylation (H3 phospho serine-10, H3.3 phospho-serine-31) at the Tnf-alpha gene. In agreement with these observations, I/R but not LPS increased activity of cognate kinases (Erk1/2, Msk1/2 and Aurora A) at the Tnf-alpha locus. Cross-talk of histone phosphorylation and acetylation synergize to active gene expression. I/R and LPS increased histone acetylation. (H3K9/14Ac, H4K5/8/12/16Ac, H2KA5Ac, H2BK4/7Ac). Levels of some histone acetyltransferases at this gene (PCAF and MOF) were increased by I/R but not by LPS, while others were induced by either I/R or LPS and exhibited endotoxin hyperresponsive patterns (GCN5, CBP and p300). The adaptor protein 14-3-3 couples histone phosphorylation with acetylation, and tethers chromatin modifiers/transcription elongation factors to target genes. Both I/R and LPS increased levels of 14-3-3 and several chromatin/transcription modifiers (BRD4, BRG1, HP-1gamma and IKKalpha) at the Tnf-alpha gene, all exhibiting endotoxin hyperresponsive recruitment patterns similar to Pol II. CONCLUSIONS: Our results suggest that I/R and LPS differentially trigger phosphorylation (Pol II and histone) and acetylation (histone) epigenetic pathways that interact at the Tnf-alpha gene to generate endotoxin hyperresponse in AKI. PMID- 23936188 TI - Study on hydrological functions of litter layers in North China. AB - Canopy interception, throughfall, stemflow, and runoff have received considerable attention during the study of water balance and hydrological processes in forested ecosystems. Past research has either neglected or underestimated the role of hydrological functions of litter layers, although some studies have considered the impact of various characteristics of rainfall and litter on litter interception. Based on both simulated rainfall and litter conditions in North China, the effect of litter mass, rainfall intensity and litter type on the maximum water storage capacity of litter (S) and litter interception storage capacity (C) were investigated under five simulated rainfall intensities and four litter masses for two litter types. The results indicated: 1) the S values increased linearly with litter mass, and the S values of broadleaf litter were on average 2.65 times larger than the S values of needle leaf litter; 2) rainfall intensity rather than litter mass determined the maximum interception storage capacity (Cmax ); Cmax increased linearly with increasing rainfall intensity; by contrast, the minimum interception storage capacity (Cmin ) showed a linear relationship with litter mass, but a poor correlation with rainfall intensity; 3) litter type impacted Cmax and Cmin ; the values of Cmax and Cmin for broadleaf litter were larger than those of needle leaf litter, which indicated that broadleaf litter could intercepte and store more water than needle leaf litter; 4) a gap existed between Cmax and Cmin , indicating that litter played a significant role by allowing rainwater to infiltrate or to produce runoff rather than intercepting it and allowing it to evaporate after the rainfall event; 5) Cmin was always less than S at the same litter mass, which should be considered in future interception predictions. Vegetation and precipitation characteristics played important roles in hydrological characteristics. PMID- 23936187 TI - Conserved roles of the prion protein domains on subcellular localization and cell cell adhesion. AB - Analyses of cultured cells and transgenic mice expressing prion protein (PrP) deletion mutants have revealed that some properties of PrP -such as its ability to misfold, aggregate and trigger neurotoxicity- are controlled by discrete molecular determinants within its protein domains. Although the contributions of these determinants to PrP biosynthesis and turnover are relatively well characterized, it is still unclear how they modulate cellular functions of PrP. To address this question, we used two defined activities of PrP as functional readouts: 1) the recruitment of PrP to cell-cell contacts in Drosophila S2 and human MCF-7 epithelial cells, and 2) the induction of PrP embryonic loss- and gain-of-function phenotypes in zebrafish. Our results show that homologous mutations in mouse and zebrafish PrPs similarly affect their subcellular localization patterns as well as their in vitro and in vivo activities. Among PrP's essential features, the N-terminal leader peptide was sufficient to drive targeting of our constructs to cell contact sites, whereas lack of GPI-anchoring and N-glycosylation rendered them inactive by blocking their cell surface expression. Importantly, our data suggest that the ability of PrP to homophilically trans-interact and elicit intracellular signaling is primarily encoded in its globular domain, and modulated by its repetitive domain. Thus, while the latter induces the local accumulation of PrPs at discrete punctae along cell contacts, the former counteracts this effect by promoting the continuous distribution of PrP. In early zebrafish embryos, deletion of either domain significantly impaired PrP's ability to modulate E-cadherin cell adhesion. Altogether, these experiments relate structural features of PrP to its subcellular distribution and in vivo activity. Furthermore, they show that despite their large evolutionary history, the roles of PrP domains and posttranslational modifications are conserved between mouse and zebrafish. PMID- 23936189 TI - Rebmab200, a humanized monoclonal antibody targeting the sodium phosphate transporter NaPi2b displays strong immune mediated cytotoxicity against cancer: a novel reagent for targeted antibody therapy of cancer. AB - NaPi2b, a sodium-dependent phosphate transporter, is highly expressed in ovarian carcinomas and is recognized by the murine monoclonal antibody MX35. The antibody had shown excellent targeting to ovarian cancer in several early phase clinical trials but being murine the antibody's full therapeutic potential could not be explored. To overcome this impediment we developed a humanized antibody version named Rebmab200, expressed in human PER.C6(r) cells and cloned by limiting dilution. In order to select a clone with high therapeutic potential clones were characterized using a series of physicochemical assays, flow cytometry, real-time surface plasmon resonance, glycosylation analyses, immunohistochemistry, antibody dependent cell-mediated cytotoxicity, complement-dependent-cytotoxicity assays and quantitative PCR. Comparative analyses of Rebmab200 and MX35 monoclonal antibodies demonstrated that the two antibodies had similar specificity for NaPi2b by flow cytometry with a panel of 30 cell lines and maintained similar kinetic parameters. Robust and high producer cell clones potentially suitable for use in manufacturing were obtained. Rebmab200 antibodies were assessed by immunohistochemistry using a large panel of tissues including human carcinomas of ovarian, lung, kidney and breast origin. An assessment of its binding towards 33 normal human organs was performed as well. Rebmab200 showed selected strong reactivity with the tested tumor types but little or no reactivity with the normal tissues tested confirming its potential for targeted therapeutics strategies. The remarkable cytotoxicity shown by Rebmab200 in OVCAR-3 cells is a significant addition to the traits of stability and productivity displayed by the top clones of Rebmab200. Antibody-dependent cell-mediated toxicity functionality was confirmed in repeated assays using cancer cell lines derived from ovary, kidney and lung as targets. To explore use of this antibody in clinical trials, GMP production of Rebmab200 has been initiated. As the next step of development, Phase I clinical trials are now planned for translation of Rebmab200 into the clinic. PMID- 23936190 TI - Neuregulin upregulates microglial alpha7 nicotinic acetylcholine receptor expression in immortalized cell lines: implications for regulating neuroinflammation. AB - Neuregulin, previously known as ARIA, is a signaling protein involved in cell survival, synaptic plasticity, cell communication and differentiation. Neuregulin has also been described as a potent inducer of acetylcholine receptor transcription in muscle and although both neuregulin and acetylcholine have been individually described to have neuroprotective roles, their relationship in the cholinergic anti-inflammatory pathway of the brain has not been examined. Using three cell lines, BV-2, EOC-20 and RAW 264.7, we investigated the role that neuregulin signaling through the Erb family of tyrosine kinases may play in the anti-inflammatory process mediated by the alpha7 nicotinic acetylcholine receptors. Here we show that ErbB4 is expressed in all of our cell lines and is phosphorylated upon treatment with neuregulin. Neuregulin treatment further increases the expression of alpha7 nicotinic acetylcholine receptors in the microglial lines tested. Given the central role of alpha7 nicotinic acetylcholine receptors in regulating system inflammation we analyzed the expression of several pro-inflammatory cytokines in our system. Using ELISAs for TNF-alpha and IL-6 we show that treatment with NRG can produce a nearly a 33% decrease in the levels of tumor necrosis factor-alpha secreted by activated microglia and a nearly 88% decrease in IL-6. Given these results we propose a neuroprotective role for neuregulin wherein it modulates the expression of TNF-alpha and thus inflammation in the CNS via the upregulation of alpha7 nicotinic acetylcholine receptor expression in microglia in vitro. We suggest that the disregulation of neuregulin expression may be pivotal in neurological disorders characterized by inflammation. PMID- 23936191 TI - HSC-explorer: a curated database for hematopoietic stem cells. AB - HSC-Explorer (http://mips.helmholtz-muenchen.de/HSC/) is a publicly available, integrative database containing detailed information about the early steps of hematopoiesis. The resource aims at providing fast and easy access to relevant information, in particular to the complex network of interacting cell types and molecules, from the wealth of publications in the field through visualization interfaces. It provides structured information on more than 7000 experimentally validated interactions between molecules, bioprocesses and environmental factors. Information is manually derived by critical reading of the scientific literature from expert annotators. Hematopoiesis-relevant interactions are accompanied with context information such as model organisms and experimental methods for enabling assessment of reliability and relevance of experimental results. Usage of established vocabularies facilitates downstream bioinformatics applications and to convert the results into complex networks. Several predefined datasets (Selected topics) offer insights into stem cell behavior, the stem cell niche and signaling processes supporting hematopoietic stem cell maintenance. HSC-Explorer provides a versatile web-based resource for scientists entering the field of hematopoiesis enabling users to inspect the associated biological processes through interactive graphical presentation. PMID- 23936192 TI - S-nitrosoglutathione reductase inhibition regulates allergen-induced lung inflammation and airway hyperreactivity. AB - Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1) in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4(+) Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation. PMID- 23936193 TI - Gbeta-like CpcB plays a crucial role for growth and development of Aspergillus nidulans and Aspergillus fumigatus. AB - Growth, development, virulence and secondary metabolism in fungi are governed by heterotrimeric G proteins (G proteins). A Gbeta-like protein called Gib2 has been shown to function as an atypical Gbeta in Gpa1-cAMP signaling in Cryptococcus neoformans. We found that the previously reported CpcB (cross pathway control B) protein is the ortholog of Gib2 in Aspergillus nidulans and Aspergillus fumigatus. In this report, we further characterize the roles of CpcB in governing growth, development and toxigenesis in the two aspergilli. The deletion of cpcB results in severely impaired cellular growth, delayed spore germination, and defective asexual sporulation (conidiation) in both aspergilli. Moreover, CpcB is necessary for proper expression of the key developmental activator brlA during initiation and progression of conidiation in A. nidulans and A. fumigatus. Somewhat in accordance with the previous study, the absence of cpcB results in the formation of fewer, but not micro-, cleistothecia in A. nidulans in the presence of wild type veA, an essential activator of sexual development. However, the cpcB deletion mutant cleistothecia contain no ascospores, validating that CpcB is required for progression and completion of sexual fruiting including ascosporogenesis. Furthermore, unlike the canonical GbetaSfaD, CpcB is not needed for the biosynthesis of the mycotoxin sterigmatocystin (ST) as the cpcB null mutant produced reduced amount of ST with unaltered STC gene expression. However, in A. fumigatus, the deletion of cpcB results in the blockage of gliotoxin (GT) production. Further genetic analyses in A. nidulans indicate that CpcB may play a central role in vegetative growth, which might be independent of FadA- and GanB mediated signaling. A speculative model summarizing the roles of CpcB in conjunction with SfaD in A. nidulans is presented. PMID- 23936194 TI - Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode. AB - Human Pim1 kinase is a serine/threonine protein kinase that plays important biological roles in cell survival, apoptosis, proliferation, and differentiation. Moreover, Pim1 is up-regulated in various hematopoietic malignancies and solid tumors. Thus, Pim1 is an attractive target for cancer therapeutics, and there has been growing interest in developing small molecule inhibitors for Pim1. Here, we describe the crystal structure of Pim1 in complex with a newly developed pyrido[4,3-d]pyrimidine-derivative inhibitor (SKI-O-068). Our inhibitor exhibits a half maximum inhibitory concentration (IC50) of 123 (+/-14) nM and has an unusual binding mode in complex with Pim1 kinase. The interactions between SKI-O 068 and the Pim1 active site pocket residue are different from those of other scaffold inhibitor-bound structures. The binding mode analysis suggests that the SKI-O-068 inhibitor can be improved by introducing functional groups that facilitate direct interaction with Lys67, which aid in the design of an optimized inhibitor. PMID- 23936195 TI - Competence-independent activity of pneumococcal EndA [corrected] mediates degradation of extracellular dna and nets and is important for virulence. AB - Membrane surface localized endonuclease EndA of the pulmonary pathogen Streptococcus pneumoniae (pneumococcus) is required for both genetic transformation and virulence. Pneumococcus expresses EndA during growth. However, it has been reported that EndA has no access to external DNA when pneumococcal cells are not competent for genetic transformation, and thus, unable to degrade extracellular DNA. Here, by using both biochemical and genetic methods, we demonstrate the existence of EndA-mediated nucleolytic activity independent of the competence state of pneumococcal cells. Pneumococcal mutants that are genetically deficient in competence development and genetic transformation have extracellular nuclease activity comparable to their parental wild type, including their ability to degrade neutrophil extracellular traps (NETs). The autolysis deficient DeltalytA mutant and its isogenic choline-treated parental wild-type strain D39 degrade extracellular DNA readily, suggesting that partial cell autolysis is not required for DNA degradation. We show that EndA molecules are secreted into the culture medium during the growth of pneumococcal cells, and contribute substantially to competence-independent nucleolytic activity. The competence-independent activity of EndA is responsible for the rapid degradation of DNA and NETs, and is required for the full virulence of Streptococcus pneumoniae during lung infection. PMID- 23936196 TI - Delta-9-tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study. AB - Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and (18)F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Delta(9)-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Delta(9)-THC was measured in 9 healthy cannabis users (average risk psychotic disorder), 8 patients with psychotic disorder (high risk psychotic disorder) and 7 un-related first-degree relatives (intermediate risk psychotic disorder). PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM), which accounts for time-dependent changes in (18)F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Delta(9)-THC administration, reflecting dopamine release. While Delta(9)-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Delta(9)-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Delta(9)-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis. PMID- 23936197 TI - Prevalence, risk factors and outcomes of velamentous and marginal cord insertions: a population-based study of 634,741 pregnancies. AB - OBJECTIVES: To determine the prevalence of, and risk factors for anomalous insertions of the umbilical cord, and the risk for adverse outcomes of these pregnancies. DESIGN: Population-based registry study. SETTING: Medical Birth Registry of Norway 1999-2009. POPULATION: All births (gestational age >16 weeks to <45 weeks) in Norway (623,478 singletons and 11,263 pairs of twins). METHODS: Descriptive statistics and odds ratios (ORs) for risk factors and adverse outcomes based on logistic regressions adjusted for confounders. MAIN OUTCOME MEASURES: Velamentous or marginal cord insertion. Abruption of the placenta, placenta praevia, pre-eclampsia, preterm birth, operative delivery, low Apgar score, transferral to neonatal intensive care unit (NICU), malformations, birthweight, and perinatal death. RESULTS: The prevalence of abnormal cord insertion was 7.8% (1.5% velamentous, 6.3% marginal) in singleton pregnancies and 16.9% (6% velamentous, 10.9% marginal) in twins. The two conditions shared risk factors; twin gestation and pregnancies conceived with the aid of assisted reproductive technology were the most important, while bleeding in pregnancy, advanced maternal age, maternal chronic disease, female foetus and previous pregnancy with anomalous cord insertion were other risk factors. Velamentous and marginal insertion was associated with an increased risk of adverse outcomes such as placenta praevia (OR = 3.7, (95% CI = 3.1-4.6)), and placental abruption (OR = 2.6, (95% CI = 2.1-3.2)). The risk of pre-eclampsia, preterm birth and delivery by acute caesarean was doubled, as was the risk of low Apgar score, transferral to NICU, low birthweight and malformations. For velamentous insertion the risk of perinatal death at term was tripled, OR = 3.3 (95% CI = 2.5-4.3). CONCLUSION: The prevalence of velamentous and marginal insertions of the umbilical cord was 7.8% in singletons and 16.9% in twin gestations, with marginal insertion being more common than velamentous. The conditions were associated with common risk factors and an increased risk of adverse perinatal outcomes; these risks were greater for velamentous than for marginal insertion. PMID- 23936198 TI - Functional divergence and convergent evolution in the plastid-targeted glyceraldehyde-3-phosphate dehydrogenases of diverse eukaryotic algae. AB - BACKGROUND: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme of the glycolytic pathway, reversibly catalyzing the sixth step of glycolysis and concurrently reducing the coenzyme NAD(+) to NADH. In photosynthetic organisms a GAPDH paralog (Gap2 in Cyanobacteria, GapA in most photosynthetic eukaryotes) functions in the Calvin cycle, performing the reverse of the glycolytic reaction and using the coenzyme NADPH preferentially. In a number of photosynthetic eukaryotes that acquired their plastid by the secondary endosymbiosis of a eukaryotic red alga (Alveolates, haptophytes, cryptomonads and stramenopiles) GapA has been apparently replaced with a paralog of the host's own cytosolic GAPDH (GapC1). Plastid GapC1 and GapA therefore represent two independent cases of functional divergence and adaptations to the Calvin cycle entailing a shift in subcellular targeting and a shift in binding preference from NAD(+) to NADPH. METHODS: We used the programs FunDi, GroupSim, and Difference Evolutionary-Trace to detect sites involved in the functional divergence of these two groups of GAPDH sequences and to identify potential cases of convergent evolution in the Calvin-cycle adapted GapA and GapC1 families. Sites identified as being functionally divergent by all or some of these programs were then investigated with respect to their possible roles in the structure and function of both glycolytic and plastid-targeted GAPDH isoforms. CONCLUSIONS: In this work we found substantial evidence for convergent evolution in GapA/B and GapC1. In many cases sites in GAPDHs of these groups converged on identical amino acid residues in specific positions of the protein known to play a role in the function and regulation of plastid-functioning enzymes relative to their cytosolic counterparts. In addition, we demonstrate that bioinformatic software like FunDi are important tools for the generation of meaningful biological hypotheses that can then be tested with direct experimental techniques. PMID- 23936201 TI - Spontaneous sleep-like brain state alternations and breathing characteristics in urethane anesthetized mice. AB - Brain state alternations resembling those of sleep spontaneously occur in rats under urethane anesthesia and they are closely linked with sleep-like respiratory changes. Although rats are a common model for both sleep and respiratory physiology, we sought to determine if similar brain state and respiratory changes occur in mice under urethane. We made local field potential recordings from the hippocampus and measured respiratory activity by means of EMG recordings in intercostal, genioglossus, and abdominal muscles. Similar to results in adult rats, urethane anesthetized mice displayed quasi-periodic spontaneous forebrain state alternations between deactivated patterns resembling slow wave sleep (SWS) and activated patterns resembling rapid eye movement (REM) sleep. These alternations were associated with an increase in breathing rate, respiratory variability, a depression of inspiratory related activity in genioglossus muscle and an increase in expiratory-related abdominal muscle activity when comparing deactivated (SWS-like) to activated (REM-like) states. These results demonstrate that urethane anesthesia consistently induces sleep-like brain state alternations and correlated changes in respiratory activity across different rodent species. They open up the powerful possibility of utilizing transgenic mouse technology for the advancement and translation of knowledge regarding sleep cycle alternations and their impact on respiration. PMID- 23936202 TI - Ergonomic status of laparoscopic urologic surgery: survey results from 241 urologic surgeons in china. AB - BACKGROUND: The prolonged and frequent use of laparoscopic equipment raises ergonomic risks that may cause physical distress for surgeons. We aimed to assess the prevalence of urologic surgeons' physical distress associated with ergonomic problems in the operating room (OR) and their awareness of the ergonomic guidelines in China. METHODS: A sample of 300 laparoscopic urologists in China was assessed using a questionnaire on demographic information, ergonomic issues in the OR, musculoskeletal symptoms, and awareness of the ergonomic guidelines for the OR. RESULTS: There were 241 survey respondents (86.7%) with valid questionnaires. Among the respondents, only 43.6% placed the operating table at pubic height during the actual operation. The majority of the respondents (63.5%) used only one monitor during the procedure. Only 29.9% placed the monitor below the eye level. More than half of the respondents (50.6%) preferred to use manual control instead of the foot pedal. Most of the respondents (95.0%) never used the body support. The respondents experienced discomfort in the following regions, in ascending order: leg (21.6%), hand (30.3%), wrist (32.8%), shoulder (33.6%), back (53.1%), and neck (58.1%). The respondents with over 250 total operations experienced less discomfort than those with less than 250 total operations. Most of the respondents (84.6%) were unaware of the ergonomic guidelines. However, almost all of the respondents (98.3%) regarded the ergonomic guidelines to be important in the OR. CONCLUSIONS: Most of the laparoscopic urologists were not aware of the ergonomic guidelines for the OR; hence, they have been suffering from varying degrees of physical discomfort caused by ergonomic issues. There is an urgent need for education regarding ergonomic guidelines in the OR for laparoscopic urologists in China. PMID- 23936200 TI - Characteristics and functional relevance of apolipoprotein-A1 and cholesterol binding in mammary gland tissues and epithelial cells. AB - Cholesterol in milk is derived from the circulating blood through a complex transport process involving the mammary alveolar epithelium. Details of the mechanisms involved in this transfer are unclear. Apolipoprotein-AI (apoA-I) is an acceptor of cellular cholesterol effluxed by the ATP-binding cassette (ABC) transporter A1 (ABCA1). We aimed to 1) determine the binding characteristics of (125)I-apoA-I and (3)H-cholesterol to enriched plasma membrane vesicles (EPM) isolated from lactating and non-lactating bovine mammary glands (MG), 2) optimize the components of an in vitro model describing cellular (3)H-cholesterol efflux in primary bovine mammary epithelial cells (MeBo), and 3) assess the vectorial cholesterol transport in MeBo using Transwell((r)) plates. The amounts of isolated EPM and the maximal binding capacity of (125)I-apoA-I to EPM differed depending on the MG's physiological state, while the kinetics of (3)H-cholesterol and (125)I-apoA-I binding were similar. (3)H-cholesterol incorporated maximally to EPM after 25+/-9 min. The time to achieve the half-maximum binding of (125)I apoA-I at equilibrium was 3.3+/-0.6 min. The dissociation constant (KD) of (125)I apoA-I ranged between 40-74 nmol/L. Cholesterol loading to EPM increased both cholesterol content and (125)I-apoA-I binding. The ABCA1 inhibitor Probucol displaced (125)I-apoA-I binding to EPM and reduced (3)H-cholesterol efflux in MeBo. Time-dependent (3)H-cholesterol uptake and efflux showed inverse patterns. The defined binding characteristics of cholesterol and apoA-I served to establish an efficient and significantly shorter cholesterol efflux protocol that had been used in MeBo. The application of this protocol in Transwell((r)) plates with the upper chamber mimicking the apical (milk-facing) and the bottom chamber corresponding to the basolateral (blood-facing) side of cells showed that the degree of (3)H-cholesterol efflux in MeBo differed significantly between the apical and basolateral aspects. Our findings support the importance of the apoA I/ABCA1 pathway in MG cholesterol transport and suggest its role in influencing milk composition and directing cholesterol back into the bloodstream. PMID- 23936199 TI - Phylogeographic analyses strongly suggest cryptic speciation in the giant spiny frog (Dicroglossidae: Paa spinosa) and interspecies hybridization in Paa. AB - Species identification is one of the most basic yet crucial issues in biology with potentially far-reaching implications for fields such as conservation, population ecology, and epidemiology. The widely distributed but threatened frog Paa spinosa has been speculated to represent a complex of multiple species. In this study, 254 individuals representing species of the genus Paa were investigated along the entire range of P. spinosa: 196 specimens of P. spinosa, 8 specimens of P. jiulongensis, 5 specimens of P. boulengeri, 20 specimens of P. exilispinosa, and 25 specimens of P. shini. Approximately 1333 bp of mtDNA sequence data (genes 12S rRNA and 16S rRNA) were used. Phylogenetic analyses were conducted using maximum parsimony, maximum likelihood and Bayesian inference. BEAST was used to estimate divergence dates of major clades. Results suggest that P. spinosa can be divided into three distinct major lineages. Each major lineage totally corresponds to geographical regions, revealing the presence of three candidate cryptic species. Isolation and differentiation among lineages are further supported by the great genetic distances between the lineages. The bifurcating phylogenetic pattern also suggests an east-west dispersal trend during historic cryptic speciation. Dating analysis estimates that P. spinosa from Western China split from the remaining P. spinosa populations in the Miocene and that P. spinosa from Eastern China diverged from Central China in the Pliocene. We also found that P. exilispinosa from Mainland China and Hong Kong might have a complex of multiple species. After identifying cryptic lineages, we then determine the discrepancy between the mtDNA and the morphotypes in several individuals. This discrepancy may have been caused by introgressive hybridization between P. spinosa and P. shini. PMID- 23936203 TI - Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells. AB - Multiple myeloma is a hematological cancer that is considered incurable despite advances in treatment strategy during the last decade. Therapies targeting single pathways are unlikely to succeed due to the heterogeneous nature of the malignancy. Proliferating cell nuclear antigen (PCNA) is a multifunctional protein essential for DNA replication and repair that is often overexpressed in cancer cells. Many proteins involved in the cellular stress response interact with PCNA through the five amino acid sequence AlkB homologue 2 PCNA-interacting motif (APIM). Thus inhibiting PCNA's protein interactions may be a good strategy to target multiple pathways simultaneously. We initially found that overexpression of peptides containing the APIM sequence increases the sensitivity of cancer cells to contemporary therapeutics. Here we have designed a cell penetrating APIM-containing peptide, ATX-101, that targets PCNA and show that it has anti-myeloma activity. We found that ATX-101 induced apoptosis in multiple myeloma cell lines and primary cancer cells, while bone marrow stromal cells and primary healthy lymphocytes were much less sensitive. ATX-101-induced apoptosis was caspase-dependent and cell cycle phase-independent. ATX-101 also increased multiple myeloma cells' sensitivity against melphalan, a DNA damaging agent commonly used for treatment of multiple myeloma. In a xenograft mouse model, ATX 101 was well tolerated and increased the anti-tumor activity of melphalan. Therefore, targeting PCNA by ATX-101 may be a novel strategy in multiple myeloma treatment. PMID- 23936204 TI - Action of shiga toxin type-2 and subtilase cytotoxin on human microvascular endothelial cells. AB - The hemolytic uremic syndrome (HUS) associated with diarrhea is a complication of Shiga toxin (Stx)-producing Escherichia coli (STEC) infection. In Argentina, HUS is endemic and responsible for acute and chronic renal failure in children younger than 5 years old. The human kidney is the most affected organ due to the presence of very Stx-sensitive cells, such as microvascular endothelial cells. Recently, Subtilase cytotoxin (SubAB) was proposed as a new toxin that may contribute to HUS pathogenesis, although its action on human glomerular endothelial cells (HGEC) has not been described yet. In this study, we compared the effects of SubAB with those caused by Stx2 on primary cultures of HGEC isolated from fragments of human pediatric renal cortex. HGEC were characterized as endothelial since they expressed von Willebrand factor (VWF) and platelet/endothelial cell adhesion molecule 1 (PECAM-1). HGEC also expressed the globotriaosylceramide (Gb3) receptor for Stx2. Both, Stx2 and SubAB induced swelling and detachment of HGEC and the consequent decrease in cell viability in a time-dependent manner. Preincubation of HGEC with C-9 -a competitive inhibitor of Gb3 synthesis-protected HGEC from Stx2 but not from SubAB cytotoxic effects. Stx2 increased apoptosis in a time-dependent manner while SubAB increased apoptosis at 4 and 6 h but decreased at 24 h. The apoptosis induced by SubAB relative to Stx2 was higher at 4 and 6 h, but lower at 24 h. Furthermore, necrosis caused by Stx2 was significantly higher than that induced by SubAB at all the time points evaluated. Our data provide evidence for the first time how SubAB could cooperate with the development of endothelial damage characteristic of HUS pathogenesis. PMID- 23936205 TI - A role for Innexin2 and Innexin3 proteins from Spodoptera litura in apoptosis. AB - Gap junctions formed by two hemichannels from two neighboring cells are cell-to cell communication channels; hemichannels are communication channels between intracellular and extracellular environments. Hemichannels are hexameric proteins formed by connexins, pannexins, innexins and vinnexins. Innexin-hemichannels (innexons) exist in the lepidopteran cell surface, but their component innexins and functions have not been reported. Recent studies by others have demonstrated that hemichannels, connexons and pannexons from vertebrates serve as regulators of apoptosis via inactivating the PI3K/Akt signaling pathway. Here, the apoptogenic properties of innexons are demonstrated using two innexin cDNAs, Spli inx2 and Spli-inx3, which were isolated from hemocytes of lepidopteran Spodoptera litura. Alignment analysis revealed that these two genes belong to a conserved innexin family, as they contain the insect signature YYQWV motif at the beginning of the second transmembrane domain. Immunofluorescence showed that two fusion proteins, Inx2-V5 and Inx3-V5, were localized predominantly in the cell membrane, cytoplasm and also nuclei. Ectopic expression in Sf9 cells and over-expression of Inx2 and Inx3 in Spli221 cells promoted apoptosis. In the Spli221 cells, apoptotic cells presented remarkable membrane blebbing. This study also showed that Sf9 and Spli221 cells undergo low level apoptosis under normal culture conditions, but not Hi5 cells. In Hi5 stable cell lines, biotinylation was used to isolate surface proteins and confirm Inx2 and Inx3 localization in the cell membrane and also further data showed that Hi5 cells may activate the PI3K signaling pathway via phosphorylating molecular Akt downstream. This result suggests that innexon-promoted apoptosis may be involving the PI3K/Akt signaling pathway. These findings will facilitate further examinations of the apoptotic regulation by the PI3K/Akt signaling pathway and comparative studies of innexons, connexons, pannexons, and vinnexons. PMID- 23936206 TI - Investigating the impact of storage conditions on microbial community composition in soil samples. AB - Recent advances in DNA sequencing technologies have allowed scientists to probe increasingly complex biological systems, including the diversity of bacteria in the environment. However, despite a multitude of recent studies incorporating these methods, many questions regarding how environmental samples should be collected and stored still persist. Here, we assess the impact of different soil storage conditions on microbial community composition using Illumina-based 16S rRNA V4 amplicon sequencing. Both storage time and temperature affected bacterial community composition and structure. Frozen samples maintained the highest alpha diversity and differed least in beta diversity, suggesting the utility of cold storage for maintaining consistent communities. Samples stored for intermediate times (three and seven days) had both the highest alpha diversity and the largest differences in overall beta diversity, showing the degree of community change after sample collection. These divergences notwithstanding, differences in neither storage time nor storage temperature substantially altered overall communities relative to more than 500 previously examined soil samples. These results systematically support previous studies and stress the importance of methodological consistency for accurate characterization and comparison of soil microbiological assemblages. PMID- 23936207 TI - Reduced heart rate variability in social anxiety disorder: associations with gender and symptom severity. AB - BACKGROUND: Polyvagal theory emphasizes that autonomic nervous system functioning plays a key role in social behavior and emotion. The theory predicts that psychiatric disorders of social dysfunction are associated with reduced heart rate variability, an index of autonomic control, as well as social inhibition and avoidance. The purpose of this study was to examine whether heart rate variability was reduced in treatment-seeking patients diagnosed with social anxiety disorder, a disorder characterized by social fear and avoidance. METHODS: Social anxiety patients (n = 53) were recruited prior to receiving psychological therapy. Healthy volunteers were recruited through the University of Sydney and the general community and were matched by gender and age (n = 53). Heart rate variability was assessed during a five-minute recording at rest, with participants completing a range of self-report clinical symptom measures. RESULTS: Compared to controls, participants with social anxiety exhibited significant reductions across a number of heart rate variability measures. Reductions in heart rate variability were observed in females with social anxiety, compared to female controls, and in patients taking psychotropic medication compared to non-medicated patients. Finally, within the clinical group, we observed significant associations between reduced heart rate variability and increased social interaction anxiety, psychological distress, and harmful alcohol use. CONCLUSIONS: The results of this study confirm that social anxiety disorder is associated with reduced heart rate variability. Resting state heart rate variability may therefore be considered a marker for social approach related motivation and capacity for social engagement. Additionally, heart rate variability may provide a useful biomarker to explain underlying difficulties with social approach, impaired stress regulation, and behavioral inhibition, especially in disorders associated with significant impairments in these domains. PMID- 23936208 TI - Expression of a2 vacuolar ATPase in spermatozoa is associated with semen quality and chemokine-cytokine profiles in infertile men. AB - BACKGROUND: A number of laboratory tests have been developed to determine properties of spermatozoa quality but few have been adopted into routine clinical use in place of the WHO semen analysis. We investigated whether Atp6v0a2 (a2 isoform of vacuolar ATPase) is associated with abnormal semen quality and changes in chemokine-cytokine profiles in infertile men. PATIENTS AND METHODS: Semen samples were collected from 35 healthy donors and 35 infertile men at the Andrology laboratory from August 2011 to June 2012. The levels of Atp6v0a2 mRNA and protein, and its localization in spermatozoa were determined. a2NTD (the N terminal portion of Atp6v0a2) and secreted chemokine-cytokine profiles in seminal fluid were measured. RESULTS: Atp6v0a2 protein (P<0.05) and mRNA (P<0.05) in spermatozoa from infertile men were significantly lower than those from fertile men. Fluorescent microscopy revealed that Atp6v0a2 is mainly expressed in the acrosomal region. Infertile men's seminal fluid had significantly lower G-CSF (P<0.01), GM-CSF (P<0.01), MCP-1 (P<0.05), MIP-1alpha (P<0.01) and TGF-beta1 (P<0.01) levels when compared to the seminal fluid from fertile men. Seminal fluid a2NTD levels were significantly correlated with G-CSF (P<0.01), GM-CSF (P<0.01), MCP-1 (P<0.05), MIP-1alpha (P<0.01) and TGF-beta1 (P<0.01) which are key molecules during the onset of pregnancy. CONCLUSION: These results suggested that a critical level of Atp6v0a2 is required for the fertile spermatozoa and its decreased level in spermatozoa could be used to predict male infertility. This study provides a possibility that Atp6v0a2 could be potentially used as a diagnostic marker for the evaluation of male infertility. PMID- 23936209 TI - Is midlife occupational physical activity related to disability in old age? The SNAC-Kungsholmen study. AB - OBJECTIVES: Leisure-time physical activity (PA) has been established to be related to more years lived without disability. However, less is known about the relationship between occupational PA and disability in old age. The aim of the study was 1) to investigate whether midlife occupational PA is related to late life disability, and 2) to test the hypothesis that the association differs according to the occupational categories of blue and white collar work. METHODS: The study population was derived from the Swedish National Study on Aging and Care, and consisted of a random sample of 1804 subjects aged 72 and above. The association of occupational PA during the longest held occupation with disability in old age was determined using logistic regression. RESULTS: There was no significant relationship between occupational PA and disability in personal or instrumental activities of daily living (ADL) after controlling for demographic and health-related factors. However, in stratified analyses moderate levels of occupational PA was associated with a lower odds ratio of dependency in personal ADL amongst white collar workers, compared to low level of occupational PA (OR = 0.34 95% C1 0.12-0.98). CONCLUSIONS: Moderate levels of midlife occupational PA were associated with a decreased risk of personal ADL disability in old age among white collar workers, but not among blue collar workers. Our results highlight the importance of encouraging white collar workers to engage in physical activity during or outside work hours. PMID- 23936210 TI - Determinants for simultaneous binding of copper and platinum to human chaperone Atox1: hitchhiking not hijacking. AB - Cisplatin (CisPt) is an anticancer agent that has been used for decades to treat a variety of cancers. CisPt treatment causes many side effects due to interactions with proteins that detoxify the drug before reaching the DNA. One key player in CisPt resistance is the cellular copper-transport system involving the uptake protein Ctr1, the cytoplasmic chaperone Atox1 and the secretory path ATP7A/B proteins. CisPt has been shown to bind to ATP7B, resulting in vesicle sequestering of the drug. In addition, we and others showed that the apo-form of Atox1 could interact with CisPt in vitro and in vivo. Since the function of Atox1 is to transport copper (Cu) ions, it is important to assess how CisPt binding depends on Cu-loading of Atox1. Surprisingly, we recently found that CisPt interacted with Cu-loaded Atox1 in vitro at a position near the Cu site such that unique spectroscopic features appeared. Here, we identify the binding site for CisPt in the Cu-loaded form of Atox1 using strategic variants and a combination of spectroscopic and chromatographic methods. We directly prove that both metals can bind simultaneously and that the unique spectroscopic signals originate from an Atox1 monomer species. Both Cys in the Cu-site (Cys12, Cys15) are needed to form the di-metal complex, but not Cys41. Removing Met10 in the conserved metal binding motif makes the loop more floppy and, despite metal binding, there are no metal-metal electronic transitions. In silico geometry minimizations provide an energetically favorable model of a tentative ternary Cu-Pt-Atox1 complex. Finally, we demonstrate that Atox1 can deliver CisPt to the fourth metal binding domain 4 of ATP7B (WD4), indicative of a possible drug detoxification mechanism. PMID- 23936211 TI - Pharmacological induction of transforming growth factor-beta1 in rat models enhances radiation injury in the intestine and the heart. AB - Radiation therapy in the treatment of cancer is dose limited by radiation injury in normal tissues such as the intestine and the heart. To identify the mechanistic involvement of transforming growth factor-beta 1 (TGF-beta1) in intestinal and cardiac radiation injury, we studied the influence of pharmacological induction of TGF-beta1 with xaliproden (SR 57746A) in rat models of radiation enteropathy and radiation-induced heart disease (RIHD). Because it was uncertain to what extent TGF-beta induction may enhance radiation injury in heart and intestine, animals were exposed to irradiation schedules that cause mild to moderate (acute) radiation injury. In the radiation enteropathy model, male Sprague-Dawley rats received local irradiation of a 4-cm loop of rat ileum with 7 once-daily fractions of 5.6 Gy, and intestinal injury was assessed at 2 weeks and 12 weeks after irradiation. In the RIHD model, male Sprague-Dawley rats received local heart irradiation with a single dose of 18 Gy and were followed for 6 months after irradiation. Rats were treated orally with xaliproden starting 3 days before irradiation until the end of the experiments. Treatment with xaliproden increased circulating TGF-beta1 levels by 300% and significantly induced expression of TGF-beta1 and TGF-beta1 target genes in the irradiated intestine and heart. Various radiation-induced structural changes in the intestine at 2 and 12 weeks were significantly enhanced with TGF-beta1 induction. Similarly, in the RIHD model induction of TGF-beta1 augmented radiation-induced changes in cardiac function and myocardial fibrosis. These results lend further support for the direct involvement of TGF-beta1 in biological mechanisms of radiation-induced adverse remodeling in the intestine and the heart. PMID- 23936212 TI - Human left ventral premotor cortex mediates matching of hand posture to object use. AB - Visuomotor transformations for grasping have been associated with a fronto parietal network in the monkey brain. The human homologue of the parietal monkey region (AIP) has been identified as the anterior part of the intraparietal sulcus (aIPS), whereas the putative human equivalent of the monkey frontal region (F5) is located in the ventral part of the premotor cortex (vPMC). Results from animal studies suggest that monkey F5 is involved in the selection of appropriate hand postures relative to the constraints of the task. In humans, the functional roles of aIPS and vPMC appear to be more complex and the relative contribution of each region to grasp selection remains uncertain. The present study aimed to identify modulation in brain areas sensitive to the difficulty level of tool object - hand posture matching. Seventeen healthy right handed participants underwent fMRI while observing pictures of familiar tool objects followed by pictures of hand postures. The task was to decide whether the hand posture matched the functional use of the previously shown object. Conditions were manipulated for level of difficulty. Compared to a picture matching control task, the tool object - hand posture matching conditions conjointly showed increased modulation in several left hemispheric regions of the superior and inferior parietal lobules (including aIPS), the middle occipital gyrus, and the inferior temporal gyrus. Comparison of hard versus easy conditions selectively modulated the left inferior frontal gyrus with peak activity located in its opercular part (Brodmann area (BA) 44). We suggest that in the human brain, vPMC/BA44 is involved in the matching of hand posture configurations in accordance with visual and functional demands. PMID- 23936213 TI - Alterations and abnormal mitosis of wheat chromosomes induced by wheat-rye monosomic addition lines. AB - BACKGROUND: Wheat-rye addition lines are an old topic. However, the alterations and abnormal mitotic behaviours of wheat chromosomes caused by wheat-rye monosomic addition lines are seldom reported. METHODOLOGY/PRINCIPAL FINDINGS: Octoploid triticale was derived from common wheat T. aestivum L. 'Mianyang11'*rye S. cereale L. 'Kustro' and some progeny were obtained by the controlled backcrossing of triticale with 'Mianyang11' followed by self-fertilization. Genomic in situ hybridization (GISH) using rye genomic DNA and fluorescence in situ hybridization (FISH) using repetitive sequences pAs1 and pSc119.2 as probes were used to analyze the mitotic chromosomes of these progeny. Strong pSc119.2 FISH signals could be observed at the telomeric regions of 3DS arms in 'Mianyang11'. However, the pSc119.2 FISH signals were disappeared from the selfed progeny of 4R monosomic addition line and the changed 3D chromosomes could be transmitted to next generation stably. In one of the selfed progeny of 7R monosomic addition line, one 2D chromosome was broken and three 4A chromosomes were observed. In the selfed progeny of 6R monosomic addition line, structural variation and abnormal mitotic behaviour of 3D chromosome were detected. Additionally, 1A and 4B chromosomes were eliminated from some of the progeny of 6R monosomic addition line. CONCLUSIONS/SIGNIFICANCE: These results indicated that single rye chromosome added to wheat might cause alterations and abnormal mitotic behaviours of wheat chromosomes and it is possible that the stress caused by single alien chromosome might be one of the factors that induced karyotype alteration of wheat. PMID- 23936214 TI - Defensive effect of lansoprazole in dementia of AD type in mice exposed to streptozotocin and cholesterol enriched diet. AB - The present study investigates the potential of lansoprazole (a proton pump inhibitor and agonist of liver x receptors) in experimental dementia of AD type. Streptozotocin [STZ, 3 mg/kg, injected intracerebroventricular (i.c.v), and high fat diet (HFD, administered for 90 days)] were used to induce dementia in separate groups of Swiss mice. Morris water maze (MWM) test was performed to assess learning and memory of the animals. A battery of biochemical and histopathological studies were also performed. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and HFD produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ/HFD treated mice exhibited a marked accentuation of AChE activity, TBARS and MPO levels along with a fall in GSH levels. Further, the stained micrographs of STZ/HFD treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. Lansoprazole treatment significantly attenuated STZ and HFD -induced memory deficits, biochemical and histopathological alterations. It also prevented HFD induced rise in the cholesterol level. Therefore, the findings demonstrate potential of lansoprazole in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory effects. Moreover, both cholesterol-dependent as well as cholesterol-independent effects of lansoprazole appear to play a role. In addition study indicates the role of liver x receptors in dementia. PMID- 23936215 TI - Ecosystem consequences of tree monodominance for nitrogen cycling in lowland tropical forest. AB - Understanding how plant functional traits shape nutrient limitation and cycling on land is a major challenge in ecology. This is especially true for lowland forest ecosystems of the tropics which can be taxonomically and functionally diverse and rich in bioavailable nitrogen (N). In many tropical regions, however, diverse forests occur side-by-side with monodominant forest (one species >60% of canopy); the long-term biogeochemical consequences of tree monodominance are unclear. Particularly uncertain is whether the monodominant plant-soil system modifies nutrient balance at the ecosystem level. Here, we use chemical and stable isotope techniques to examine N cycling in old-growth Mora excelsa and diverse watershed rainforests on the island of Trinidad. Across 26 small watershed forests and 4 years, we show that Mora monodominance reduces bioavailable nitrate in the plant-soil system to exceedingly low levels which, in turn, results in small hydrologic and gaseous N losses at the watershed-level relative to adjacent N-rich diverse forests. Bioavailable N in soils and streams remained low and remarkably stable through time in Mora forests; N levels in diverse forests, on the other hand, showed high sensitivity to seasonal and inter annual rainfall variation. Total mineral N losses from diverse forests exceeded inputs from atmospheric deposition, consistent with N saturation, while losses from Mora forests did not, suggesting N limitation. Our measures suggest that this difference cannot be explained by environmental factors but instead by low internal production and efficient retention of bioavailable N in the Mora plant soil system. These results demonstrate ecosystem-level consequences of a tree species on the N cycle opposite to cases where trees enhance ecosystem N supply via N2 fixation and suggest that, over time, Mora monodominance may generate progressive N draw-down in the plant-soil system. PMID- 23936216 TI - Mitogenomes from two uncommon haplogroups mark late glacial/postglacial expansions from the near east and neolithic dispersals within Europe. AB - The current human mitochondrial (mtDNA) phylogeny does not equally represent all human populations but is biased in favour of representatives originally from north and central Europe. This especially affects the phylogeny of some uncommon West Eurasian haplogroups, including I and W, whose southern European and Near Eastern components are very poorly represented, suggesting that extensive hidden phylogenetic substructure remains to be uncovered. This study expanded and re analysed the available datasets of I and W complete mtDNA genomes, reaching a comprehensive 419 mitogenomes, and searched for precise correlations between the ages and geographical distributions of their numerous newly identified subclades with events of human dispersal which contributed to the genetic formation of modern Europeans. Our results showed that haplogroups I (within N1a1b) and W originated in the Near East during the Last Glacial Maximum or pre-warming period (the period of gradual warming between the end of the LGM, ~19 ky ago, and the beginning of the first main warming phase, ~15 ky ago) and, like the much more common haplogroups J and T, may have been involved in Late Glacial expansions starting from the Near East. Thus our data contribute to a better definition of the Late and postglacial re-peopling of Europe, providing further evidence for the scenario that major population expansions started after the Last Glacial Maximum but before Neolithic times, but also evidencing traces of diffusion events in several I and W subclades dating to the European Neolithic and restricted to Europe. PMID- 23936217 TI - Aberrant expression and secretion of heat shock protein 90 in patients with bullous pemphigoid. AB - The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses and its inhibition has proven successful in different mouse models of autoimmune diseases, including epidermolysis bullosa acquisita. Here, we investigated expression levels and secretory responses of Hsp90 in patients with bullous pemphigoid (BP), the most common subepidermal autoimmune blistering skin disease. In comparison to healthy controls, the following observations were made: (i) Hsp90 was highly expressed in the skin of BP patients, whereas its serum levels were decreased and inversely associated with IgG autoantibody levels against the NC16A immunodominant region of the BP180 autoantigen, (ii) in contrast, neither aberrant levels of circulating Hsp90 nor any correlation of this protein with serum autoantibodies was found in a control cohort of autoimmune bullous disease patients with pemphigus vulgaris, (iii) Hsp90 was highly expressed in and restrictedly released from peripheral blood mononuclear cells of BP patients, and (iv) Hsp90 was potently induced in and restrictedly secreted from human keratinocyte (HaCaT) cells by BP serum and isolated anti-BP180 NC16A IgG autoantibodies, respectively. Our results reveal an upregulated Hsp90 expression at the site of inflammation and an autoantibody mediated dysregulation of the intracellular and extracellular distribution of this chaperone in BP patients. These findings suggest that Hsp90 may play a pathophysiological role and represent a novel potential treatment target in BP. PMID- 23936218 TI - Phylogenetic relationships and species delimitation in pinus section trifoliae inferrred from plastid DNA. AB - Recent diversification followed by secondary contact and hybridization may explain complex patterns of intra- and interspecific morphological and genetic variation in the North American hard pines (Pinus section Trifoliae), a group of approximately 49 tree species distributed in North and Central America and the Caribbean islands. We concatenated five plastid DNA markers for an average of 3.9 individuals per putative species and assessed the suitability of the five regions as DNA bar codes for species identification, species delimitation, and phylogenetic reconstruction. The ycf1 gene accounted for the greatest proportion of the alignment (46.9%), the greatest proportion of variable sites (74.9%), and the most unique sequences (75 haplotypes). Phylogenetic analysis recovered clades corresponding to subsections Australes, Contortae, and Ponderosae. Sequences for 23 of the 49 species were monophyletic and sequences for another 9 species were paraphyletic. Morphologically similar species within subsections usually grouped together, but there were exceptions consistent with incomplete lineage sorting or introgression. Bayesian relaxed molecular clock analyses indicated that all three subsections diversified relatively recently during the Miocene. The general mixed Yule-coalescent method gave a mixed model estimate of only 22 or 23 evolutionary entities for the plastid sequences, which corresponds to less than half the 49 species recognized based on morphological species assignments. Including more unique haplotypes per species may result in higher estimates, but low mutation rates, recent diversification, and large effective population sizes may limit the effectiveness of this method to detect evolutionary entities. PMID- 23936219 TI - Protein phosphatase 1beta limits ring canal constriction during Drosophila germline cyst formation. AB - Germline cyst formation is essential for the propagation of many organisms including humans and flies. The cytoplasm of germline cyst cells communicate with each other directly via large intercellular bridges called ring canals. Ring canals are often derived from arrested contractile rings during incomplete cytokinesis. However how ring canal formation, maintenance and growth are regulated remains unclear. To better understand this process, we carried out an unbiased genetic screen in Drosophila melanogaster germ cells and identified multiple alleles of flapwing (flw), a conserved serine/threonine-specific protein phosphatase. Flw had previously been reported to be unnecessary for early D. melanogaster oogenesis using a hypomorphic allele. We found that loss of Flw leads to over-constricted nascent ring canals and subsequently tiny mature ring canals, through which cytoplasmic transfer from nurse cells to the oocyte is impaired, resulting in small, non-functional eggs. Flw is expressed in germ cells undergoing incomplete cytokinesis, completely colocalized with the Drosophila myosin binding subunit of myosin phosphatase (DMYPT). This colocalization, together with genetic interaction studies, suggests that Flw functions together with DMYPT to negatively regulate myosin activity during ring canal formation. The identification of two subunits of the tripartite myosin phosphatase as the first two main players required for ring canal constriction indicates that tight regulation of myosin activity is essential for germline cyst formation and reproduction in D. melanogaster and probably other species as well. PMID- 23936220 TI - Role of reactive oxygen species in the radiation response of human hematopoietic stem/progenitor cells. AB - Hematopoietic stem/progenitor cells (HSPCs), which are present in small numbers in hematopoietic tissues, can differentiate into all hematopoietic lineages and self-renew to maintain their undifferentiated phenotype. HSPCs are extremely sensitive to oxidative stressors such as anti-cancer agents, radiation, and the extensive accumulation of reactive oxygen species (ROS). The quiescence and stemness of HSPCs are maintained by the regulation of mitochondrial biogenesis, ROS, and energy homeostasis in a special microenvironment called the stem cell niche. The present study evaluated the relationship between the production of intracellular ROS and mitochondrial function during the proliferation and differentiation of X-irradiated CD34(+) cells prepared from human placental/umbilical cord blood HSPCs. Highly purified CD34(+) HSPCs exposed to X rays were cultured in liquid and semi-solid medium supplemented with hematopoietic cytokines. X-irradiated CD34(+) HSPCs treated with hematopoietic cytokines, which promote their proliferation and differentiation, exhibited dramatically suppressed cell growth and clonogenic potential. The amount of intracellular ROS in X-irradiated CD34(+) HSPCs was significantly higher than that in non-irradiated cells during the culture period. However, neither the intracellular mitochondrial content nor the mitochondrial superoxide production was elevated in X-irradiated CD34(+) HSPCs compared with non-irradiated cells. Radiation-induced gamma-H2AX expression was observed immediately following exposure to 4 Gy of X-rays and gradually decreased during the culture period. This study reveals that X-irradiation can increase persistent intracellular ROS in human CD34(+) HSPCs, which may not result from mitochondrial ROS due to mitochondrial dysfunction, and indicates that substantial DNA double-strand breakage can critically reduce the stem cell function. PMID- 23936221 TI - Dexamethasone rapidly increases GABA release in the dorsal motor nucleus of the vagus via retrograde messenger-mediated enhancement of TRPV1 activity. AB - Glucocorticoids influence vagal parasympathetic output to the viscera via mechanisms that include modulation of neural circuitry in the dorsal vagal complex, a principal autonomic regulatory center. Glucocorticoids can modulate synaptic neurotransmitter release elsewhere in the brain by inducing release of retrograde signalling molecules. We tested the hypothesis that the glucocorticoid agonist dexamethasone (DEX) modulates GABA release in the rat dorsal motor nucleus of the vagus (DMV). Whole-cell patch-clamp recordings revealed that DEX (1-10 uM) rapidly (i.e. within three minutes) increased the frequency of tetrodotoxin-resistant, miniature IPSCs (mIPSCs) in 67% of DMV neurons recorded in acutely prepared slices. Glutamate-mediated mEPSCs were also enhanced by DEX (10 uM), and blockade of ionotropic glutamate receptors reduced the DEX effect on mIPSC frequency. Antagonists of type I or II corticosteroid receptors blocked the effect of DEX on mIPSCs. The effect was mimicked by application of the membrane impermeant BSA-conjugated DEX, and intracellular blockade of G protein function with GDP betaS in the recorded cell prevented the effect of DEX. The enhancement of GABA release was blocked by the TRPV1 antagonists, 5'-iodoresiniferatoxin or capsazepine, but was not altered by the cannabinoid type 1 receptor antagonist AM251. The DEX effect was prevented by blocking fatty acid amide hydrolysis or by inhibiting anandamide transport, implicating involvement of the endocannabinoid system in the response. These findings indicate that DEX induces an enhancement of GABA release in the DMV, which is mediated by activation of TRPV1 receptors on afferent terminals. The effect is likely induced by anandamide or other 'endovanilloid', suggesting activation of a local retrograde signal originating from DMV neurons to enhance synaptic inhibition locally in response to glucocorticoids. PMID- 23936222 TI - LPS unmasking of Shigella flexneri reveals preferential localisation of tagged outer membrane protease IcsP to septa and new poles. AB - The Shigella flexneri outer membrane (OM) protease IcsP (SopA) is a member of the enterobacterial Omptin family of proteases which cleaves the polarly localised OM protein IcsA that is essential for Shigella virulence. Unlike IcsA however, the specific localisation of IcsP on the cell surface is unknown. To determine the distribution of IcsP, a haemagglutinin (HA) epitope was inserted into the non essential IcsP OM loop 5 using Splicing by Overlap Extension (SOE) PCR, and IcsP(HA) was characterised. Quantum Dot (QD) immunofluorescence (IF) surface labelling of IcsP(HA) was then undertaken. Quantitative fluorescence analysis of S. flexneri 2a 2457T treated with and without tunicaymcin to deplete lipopolysaccharide (LPS) O antigen (Oag) showed that IcsP(HA) was asymmetrically distributed on the surface of septating and non-septating cells, and that this distribution was masked by LPS Oag in untreated cells. Double QD IF labelling of IcsP(HA) and IcsA showed that IcsP(HA) preferentially localised to the new pole of non-septating cells and to the septum of septating cells. The localisation of IcsP(HA) in a rough LPS S. flexneri 2457T strain (with no Oag) was also investigated and a similar distribution of IcsP(HA) was observed. Complementation of the rough LPS strain with rmlD resulted in restored LPS Oag chain expression and loss of IcsP(HA) detection, providing further support for LPS Oag masking of surface proteins. Our data presents for the first time the distribution for the Omptin OM protease IcsP, relative to IcsA, and the effect of LPS Oag masking on its detection. PMID- 23936223 TI - Identification of a novel bacterial outer membrane interleukin-1Beta-binding protein from Aggregatibacter actinomycetemcomitans. AB - Aggregatibacter actinomycetemcomitans is a gram-negative opportunistic oral pathogen. It is frequently associated with subgingival biofilms of both chronic and aggressive periodontitis, and the diseased sites of the periodontium exhibit increased levels of the proinflammatory mediator interleukin (IL)-1beta. Some bacterial species can alter their physiological properties as a result of sensing IL-1beta. We have recently shown that this cytokine localizes to the cytoplasm of A. actinomycetemcomitans in co-cultures with organotypic gingival mucosa. However, current knowledge about the mechanism underlying bacterial IL-1beta sensing is still limited. In this study, we characterized the interaction of A. actinomycetemcomitans total membrane protein with IL-1beta through electrophoretic mobility shift assays. The interacting protein, which we have designated bacterial interleukin receptor I (BilRI), was identified through mass spectrometry and was found to be Pasteurellaceae specific. Based on the results obtained using protein function prediction tools, this protein localizes to the outer membrane and contains a typical lipoprotein signal sequence. All six tested biofilm cultures of clinical A. actinomycetemcomitans strains expressed the protein according to phage display-derived antibody detection. Moreover, proteinase K treatment of whole A. actinomycetemcomitans cells eliminated BilRI forms that were outer membrane specific, as determined through immunoblotting. The protein was overexpressed in Escherichia coli in both the outer membrane associated form and a soluble cytoplasmic form. When assessed using flow cytometry, the BilRI-overexpressing E. coli cells were observed to bind 2.5 times more biotinylated-IL-1beta than the control cells, as detected with avidin-FITC. Overexpression of BilRI did not cause binding of a biotinylated negative control protein. In a microplate assay, soluble BilRI bound to IL-1beta, but this binding was not specific, as a control protein for IL-1beta also interacted with BilRI. Our findings suggest that A. actinomycetemcomitans expresses an IL-1beta-binding surface-exposed lipoprotein that may be part of the bacterial IL-1beta-sensing system. PMID- 23936224 TI - Conformational stability of fibrillar amyloid-beta oligomers via protofilament pair formation - a systematic computational study. AB - Amyloid-[Formula: see text] (A[Formula: see text]) oligomers play a crucial role in Alzheimer's disease due to their neurotoxic aggregation properties. Fibrillar A[Formula: see text] oligomerization can lead to protofilaments and protofilament pairs via oligomer elongation and oligomer association, respectively. Small fibrillar oligomers adopt the protofilament topology, whereas fibrils contain at least protofilament pairs. To date, the underlying growth mechanism from oligomers to the mature fibril still remains to be elucidated. Here, we performed all-atom molecular dynamics simulations in explicit solvent on single layer-like protofilaments and fibril-like protofilament pairs of different size ranging from the tetramer to the 48-mer. We found that the initial U-shaped topology per monomer is maintained over time in all oligomers. The observed deviations of protofilaments from the starting structure increase significantly with size due to the twisting of the in-register parallel [Formula: see text]-sheets. This twist causes long protofilaments to be unstable and leads to a breakage. Protofilament pairs, which are stabilized by a hydrophobic interface, exhibit more fibril-like properties such as the overall structure and the twist angle. Thus, they can act as stable conformational templates for further fibril growth. Key properties like the twist angle, shape complementarity, and energetics show a size-dependent behavior so that small oligomers favor the protofilament topology, whereas large oligomers favor the protofilament pair topology. The region for this conformational transition is at the size of approximately twelve A[Formula: see text] monomers. From that, we propose the following growth mechanism from A[Formula: see text] oligomers to fibrils: (1) elongation of short protofilaments; (2) breakage of large protofilaments; (3) formation of short protofilament pairs; and (4) elongation of protofilament pairs. PMID- 23936225 TI - Lentiviral vector mediated thymidine kinase expression in pluripotent stem cells enables removal of tumorigenic cells. AB - Embryonic stem cells (ES) and induced pluripotent stem (iPS) cells represent promising tools for cell-based therapies and regenerative medicine. Nevertheless, implantation of ES cell derived differentiated cells holds the risk of teratoma formation due to residual undifferentiated cells. In order to tackle this problem, we used pluripotent stem cells consisting of ES and iPS cells of mouse genetically modified by lentiviral vectors (LVs) carrying herpes simplex virus thymidine kinase (HSV-TK) under the control of different promoters of pluripotency genes. Cells expressing TK in turn are eliminated upon administration of the prodrug ganciclovir (GCV). Our aim was to study the conditions required for a safe mechanism to clear residual undifferentiated cells but using low MOIs of lentiviruses to reduce the risk of insertional mutagenesis. Our in vitro data demonstrated that TK expression in pluripotent stem cells upon treatment with GCV led to elimination of undifferentiated cells. However, introduction of hygromycin resistance in the LV transduced ES cells followed by pre-selection with hygromycin and GCV treatment was required to abolish undifferentiated cells. Most importantly, transplantation of pre-selected ES cells that had been transduced with low MOI LV in mice resulted in no teratoma development after GCV treatment in vivo. Taken together, our data show that pre selection of ES cells prior to in vivo application is necessary if vector integration events are minimized. The study presented here gives rise to safer use of pluripotent stem cells as promising cell sources in regenerative medicine in the future. PMID- 23936226 TI - Adaptor proteins intersectin 1 and 2 bind similar proline-rich ligands but are differentially recognized by SH2 domain-containing proteins. AB - BACKGROUND: Scaffolding proteins of the intersectin (ITSN) family, ITSN1 and ITSN2, are crucial for the initiation stage of clathrin-mediated endocytosis. These proteins are closely related but have implications in distinct pathologies. To determine how these proteins could be separated in certain cell pathways we performed a comparative study of ITSNs. METHODOLOGY/PRINCIPAL FINDINGS: We have shown that endogenous ITSN1 and ITSN2 colocalize and form a complex in cells. A structural comparison of five SH3 domains, which mediated most ITSNs protein protein interactions, demonstrated a similarity of their ligand-binding sites. We showed that the SH3 domains of ITSN2 bound well-established interactors of ITSN1 as well as newly identified ITSNs protein partners. A search for a novel interacting interface revealed multiple tyrosines that could be phosphorylated in ITSN2. Phosphorylation of ITSN2 isoforms but not ITSN1 short isoform was observed in various cell lines. EGF stimulation of HeLa cells enhanced tyrosine phosphorylation of ITSN2 isoforms and enabled their recognition by the SH2 domains of the Fyn, Fgr and Abl1 kinases, the regulatory subunit of PI3K, the adaptor proteins Grb2 and Crk, and phospholipase C gamma. The SH2 domains mentioned were unable to bind ITSN1 short isoform. CONCLUSIONS/SIGNIFICANCE: Our results indicate that during evolution of vertebrates ITSN2 acquired a novel protein-interaction interface that allows its specific recognition by the SH2 domains of signaling proteins. We propose that these data could be important to understand the functional diversity of paralogous ITSN proteins. PMID- 23936227 TI - The discrimination power of structural SuperIndices. AB - In this paper, we evaluate the discrimination power of structural superindices. Superindices for graphs represent measures composed of other structural indices. In particular, we compare the discrimination power of the superindices with those of individual graph descriptors. In addition, we perform a statistical analysis to generalize our findings to large graphs. PMID- 23936228 TI - SHBG is an important factor in stemness induction of cells by DHT in vitro and associated with poor clinical features of prostate carcinomas. AB - Androgen plays a vital role in prostate cancer development. However, it is not clear whether androgens influence stem-like properties of prostate cancer, a feature important for prostate cancer progression. In this study, we show that upon DHT treatment in vitro, prostate cancer cell lines LNCaP and PC-3 were revealed with higher clonogenic potential and higher expression levels of stemness related factors CD44, CD90, Oct3/4 and Nanog. Moreover, sex hormone binding globulin (SHBG) was also simultaneously upregulated in these cells. When the SHBG gene was blocked by SHBG siRNA knock-down, the induction of Oct3/4, Nanog, CD44 and CD90 by DHT was also correspondingly blocked in these cells. Immunohistochemical evaluation of clinical samples disclosed weakly positive, and areas negative for SHBG expression in the benign prostate tissues, while most of the prostate carcinomas were strongly positive for SHBG. In addition, higher levels of SHBG expression were significantly associated with higher Gleason score, more seminal vesicle invasions and lymph node metastases. Collectively, our results show a role of SHBG in upregulating stemness of prostate cancer cells upon DHT exposure in vitro, and SHBG expression in prostate cancer samples is significantly associated with poor clinicopathological features, indicating a role of SHBG in prostate cancer progression. PMID- 23936229 TI - CCR5 haplotypes influence HCV serostatus in Caucasian intravenous drug users. AB - BACKGROUND: Up to 90% HIV-1 positive intravenous drug users (IDUs) are co infected with HCV. Although best recognized for its function as a major co receptor for cell entry of HIV, CC chemokine receptor 5 (CCR5) has also been implicated in the pathogenesis of HCV infection. Here, we investigated whether CCR5 haplotypes influence HIV-1 and HCV seropositivity among 373 Caucasian IDUs from Estonia. METHODS: Of these IDUs, 56% and 44% were HIV and HCV seropositive, respectively, and 47% were coinfected. 500 blood donors seronegative for HIV and HCV were also evaluated. CCR5 haplotypes (HHA to HHG*2) were derived after genotyping nine CCR2-CCR5 polymorphisms. The association between CCR5 haplotypes with HIV and/or HCV seropositivity was determined using logistic regression analysis. Co-variates included in the models were length of intravenous drug use, HBV serostatus and copy number of CCL3L1, the gene encoding the most potent HIV suppressive chemokine and ligand for CCR5. RESULTS: Compared to IDUs seronegative for both HCV and HIV (HCV-/HIV-), IDUs who were HCV+/HIV- and HCV+/HIV+were 92% and 82%, respectively, less likely to possess the CCR5-HHG*1 haplotype, after controlling for co-variates (P(adjusted) = 1.89 * 10(-4) and 0.003, respectively). This association was mostly due to subjects bearing the CCR5 HHE and HHG*1 haplotype pairs. Approximately 25% and<10% of HCV-/HIV- IDUs and HCV /HIV- blood donors, respectively, possessed the HHE/HHG*1 genotype. CONCLUSIONS: Our findings suggest that HHG*1-bearing CCR5 genotypes influence HCV seropositivity in a group of Caucasian IDUs. PMID- 23936230 TI - Patterns of population differentiation and natural selection on the celiac disease background risk network. AB - Celiac disease is a common small intestinal inflammatory condition induced by wheat gluten and related proteins from rye and barley. Left untreated, the clinical presentation of CD can include failure to thrive, malnutrition, and distension in juveniles. The disease can additionally lead to vitamin deficiencies, anemia, and osteoporosis. Therefore, CD potentially negatively affected fitness in past populations utilizing wheat, barley, and rye. Previous analyses of CD risk variants have uncovered evidence for positive selection on some of these loci. These studies also suggest the possibility that risk for common autoimmune conditions such as CD may be the result of positive selection on immune related loci in the genome to fight infection. Under this evolutionary scenario, disease phenotypes may be a trade-off from positive selection on immunity. If this hypothesis is generally true, we can expect to find a signal of natural selection when we survey across the network of loci known to influence CD risk. This study examines the non-HLA autosomal network of gene loci associated with CD risk in Europe. We reject the null hypothesis of neutrality on this network of CD risk loci. Additionally, we can localize evidence of selection in time and space by adding information from the genome of the Tyrolean Iceman. While we can show significant differentiation between continental regions across the CD network, the pattern of evidence is not consistent with primarily recent (Holocene) selection across this network in Europe. Further localization of ancient selection on this network may illuminate the ecological pressures acting on the immune system during this critically interesting phase of our evolution. PMID- 23936231 TI - 9-Phenanthrol, a TRPM4 inhibitor, protects isolated rat hearts from ischemia reperfusion injury. AB - Despite efforts to elucidate its pathophysiology, ischemia-reperfusion injury lacks an effective preventative intervention. Because transient receptor potential cation channel subfamily M member 4 (TRPM4) is functionally expressed by many cell types in the cardiovascular system and is involved in the pathogenesis of various cardiovascular diseases, we decided to assess its suitability as a target of therapy. Thus, the aim of this study was to examine the possible cardioprotective effect of 9-phenanthrol, a specific inhibitor of TRPM4. Isolated Langendorff-perfused rat hearts were pretreated with Krebs Henseleit (K-H) solution (control), 9-phenanthrol, or 5-hydroxydecanoate (5-HD, a blocker of the ATP-sensitive potassium channel) and then subjected to global ischemia followed by reperfusion with the K-H solution. To evaluate the extent of heart damage, lactate dehydrogenase (LDH) activity in the effluent solution was measured, and the size of infarcted area of the heart was measured by 2,3,5 triphenyltetrazolium chloride staining. In controls, cardiac contractility decreased, and LDH activity and the infarcted area size increased. In contrast, in hearts pretreated with 9-phenanthrol, contractile function recovered dramatically, and the infarcted area size significantly decreased. The cardioprotective effects of 9-phenanthrol was not completely blocked by 5-HD. These findings show that 9-phenanthrol exerts a cardioprotective effect against ischemia in the isolated rat heart and suggest that its mechanism of action is largely independent of ATP-sensitive potassium channels. PMID- 23936232 TI - Upregulation of TrkB promotes epithelial-mesenchymal transition and anoikis resistance in endometrial carcinoma. AB - Mechanisms governing the metastasis of endometrial carcinoma (EC) are poorly defined. Recent data support a role for the cell surface receptor tyrosine kinase TrkB in the progression of several human tumors. Here we present evidence for a direct role of TrkB in human EC. Immunohistochemical analysis revealed that TrkB and its secreted ligand, brain-derived neurotrophic factor (BDNF), are more highly expressed in EC than in normal endometrium. High TrkB levels correlated with lymph node metastasis (p<0.05) and lymphovascular space involvement (p<0.05) in EC. Depletion of TrkB by stable shRNA-mediated knockdown decreased the migratory and invasive capacity of cancer cell lines in vitro and resulted in anoikis in suspended cells. Conversely, exogenous expression of TrkB increased cell migration and invasion and promoted anoikis resistance in suspension culture. Furthermore, over-expression of TrkB or stimulation by BDNF resulted in altered the expression of molecular mediators of the epithelial-to-mesenchymal transition (EMT). RNA interference (RNAi)-mediated depletion of the downstream regulator, Twist, blocked TrkB-induced EMT-like transformation. The use of in vivo models revealed decreased peritoneal dissemination in TrkB-depleted EC cells. Additionally, TrkB-depleted EC cells underwent mesenchymal-to-epithelial transition and anoikis in vivo. Our data support a novel function for TrkB in promoting EMT and resistance to anoikis. Thus, TrkB may constitute a potential therapeutic target in human EC. PMID- 23936233 TI - Metabolic adaption of ethanol-tolerant Clostridium thermocellum. AB - Clostridium thermocellum is a major candidate for bioethanol production via consolidated bioprocessing. However, the low ethanol tolerance of the organism dramatically impedes its usage in industry. To explore the mechanism of ethanol tolerance in this microorganism, systematic metabolomics was adopted to analyse the metabolic phenotypes of a C. thermocellum wild-type (WT) strain and an ethanol-tolerant strain cultivated without (ET0) or with (ET3) 3% (v/v) exogenous ethanol. Metabolomics analysis elucidated that the levels of numerous metabolites in different pathways were changed for the metabolic adaption of ethanol-tolerant C. thermocellum. The most interesting phenomenon was that cellodextrin was significantly more accumulated in the ethanol-tolerant strain compared with the WT strain, although cellobiose was completely consumed in both the ethanol tolerant and wild-type strains. These results suggest that the cellodextrin synthesis was active, which might be a potential mechanism for stress resistance. Moreover, the overflow of many intermediate metabolites, which indicates the metabolic imbalance, in the ET0 cultivation was more significant than in the WT and ET3 cultivations. This indicates that the metabolic balance of the ethanol tolerant strain was adapted better to the condition of ethanol stress. This study provides additional insight into the mechanism of ethanol tolerance and is valuable for further metabolic engineering aimed at higher bioethanol production. PMID- 23936234 TI - Silencing MED1 sensitizes breast cancer cells to pure anti-estrogen fulvestrant in vitro and in vivo. AB - Pure anti-estrogen fulvestrant has been shown to be a promising ER antagonist for locally advanced and metastatic breast cancer. Unfortunately, a significant proportion of patients developed resistance to this type of endocrine therapy but the molecular mechanisms governing cellular responsiveness to this agent remain poorly understood. Here, we've reported that knockdown of estrogen receptor coactivator MED1 sensitized fulvestrant resistance breast cancer cells to fulvestrant treatment. We found that MED1 knockdown further promoted cell cycle arrest induced by fulvestrant. Using an orthotopic xenograft mouse model, we found that knockdown of MED1 significantly reduced tumor growth in mice. Importantly, knockdown of MED1 further potentiated tumor growth inhibition by fulvestrant. Mechanistic studies indicated that combination of fulvestrant treatment and MED1 knockdown is able to cooperatively inhibit the expression of ER target genes. Chromatin immunoprecipitation experiments further supported a role for MED1 in regulating the recruitment of RNA polymerase II and transcriptional corepressor HDAC1 on endogenous ER target gene promoter in the presence of fulvestrant. These results demonstrate a role for MED1 in mediating resistance to the pure anti-estrogen fulvestrant both in vitro and in vivo. PMID- 23936235 TI - Assessments of total and viable Escherichia coli O157:H7 on field and laboratory grown lettuce. AB - Leafy green produce has been associated with numerous outbreaks of foodborne illness caused by strains of Escherichia coli O157:H7. While the amounts of culturable E. coli O157:H7 rapidly decline after introduction onto lettuce in the field, it remains to be determined whether the reduction in cell numbers is due to losses in cell viability, cell injury and a subsequent inability to be detected by standard laboratory culturing methods, or a lack of adherence and hence rapid removal of the organism from the plants during application. To assess which of these options is most relevant for E. coli O157:H7 on leafy green produce, we developed and applied a propidium monoazide (PMA) real-time PCR assay to quantify viable (with PMA) and total (without PMA) E. coli O157:H7 cells on growth chamber and field-grown lettuce. E. coli O157:H7, suspended in 0.1% peptone, was inoculated onto 4-week-old lettuce plants at a level of approximately 10(6) CFU/plant. In the growth chamber at low relative humidity (30%), culturable amounts of the nontoxigenic E. coli O157:H7 strain ATCC 700728 and the virulent strain EC4045 declined 100 to 1000-fold in 24 h. Fewer E. coli O157:H7 cells survived when applied onto plants in droplets with a pipette compared with a fine spray inoculation. Total cells for both strains were equivalent to inoculum levels for 7 days after application, and viable cell quantities determined by PMA real-time PCR were approximately 10(4) greater than found by colony enumeration. Within 2 h after application onto plants in the field, the number of culturable E. coli ATCC 700728 was reduced by up to 1000 fold, whereas PCR-based assessments showed that total cell amounts were equivalent to inoculum levels. These findings show that shortly after inoculation onto plants, the majority of E. coli O157:H7 cells either die or are no longer culturable. PMID- 23936236 TI - X-ray induced formation of gamma-H2AX foci after full-field digital mammography and digital breast-tomosynthesis. AB - PURPOSE: To determine in-vivo formation of x-ray induced gamma-H2AX foci in systemic blood lymphocytes of patients undergoing full-field digital mammography (FFDM) and to estimate foci after FFDM and digital breast-tomosynthesis (DBT) using a biological phantom model. MATERIALS AND METHODS: The study complies with the Declaration of Helsinki and was performed following approval by the ethic committee of the University of Erlangen-Nuremberg. Written informed consent was obtained from every patient. For in-vivo tests, systemic blood lymphocytes were obtained from 20 patients before and after FFDM. In order to compare in-vivo post exposure with pre-exposure foci levels, the Wilcoxon matched pairs test was used. For in-vitro experiments, isolated blood lymphocytes from healthy volunteers were irradiated at skin and glandular level of a porcine breast using FFDM and DBT. Cells were stained against the phosphorylated histone variant gamma-H2AX, and foci representing distinct DNA damages were quantified. RESULTS: Median in-vivo foci level/cell was 0.086 (range 0.067-0.116) before and 0.094 (0.076-0.126) after FFDM (p = 0.0004). In the in-vitro model, the median x-ray induced foci level/cell after FFDM was 0.120 (range 0.086-0.140) at skin level and 0.035 (range 0.030-0.050) at glandular level. After DBT, the median x-ray induced foci level/cell was 0.061 (range 0.040-0.081) at skin level and 0.015 (range 0.006 0.020) at glandular level. CONCLUSION: In patients, mammography induces a slight but significant increase of gamma-H2AX foci in systemic blood lymphocytes. The introduced biological phantom model is suitable for the estimation of x-ray induced DNA damages in breast tissue in different breast imaging techniques. PMID- 23936237 TI - Breast cancer survival in Germany: a population-based high resolution study from Saarland. AB - Population-based survival studies of breast cancer patients are commonly restricted to age- and stage-specific analyses. This study from Germany aimed at extending available population-based survival data on further prognostic cancer characteristics such as tumor grade, hormone receptor status and human epidermal growth factor receptor type 2 (HER2/neu) expression. Data from the population based Saarland Cancer Registry including female patients diagnosed with invasive breast cancer between 2000 and 2009 were included. Period analysis methodology and regression modelling were used to obtain estimates of 5-year relative survival and tumor related excess risks in 2005-2009. Overall age standardized 5 year relative survival was 83%. In addition to age and stage, tumor grade and hormone receptor status were independent predictors of 5-year relative survival. Detailed analyses by age, stage, morphology, tumor grade, hormone receptor status and HER2/neu expression consistently revealed lower survival of patients with high grade, hormone receptor negative or HER2/neu positive cancers and patients aged 70 years or older. This high resolution study extends available population based survival data of breast cancer patients. Particular efforts should be made to overcome the persisting large survival deficits, which were observed for elderly patients in all clinical subgroups. PMID- 23936238 TI - Downregulation of keratin 76 expression during oral carcinogenesis of human, hamster and mouse. AB - BACKGROUND: Keratins are structural marker proteins with tissue specific expression; however, recent reports indicate their involvement in cancer progression. Previous study from our lab revealed deregulation of many genes related to structural molecular integrity including KRT76. Here we evaluate the role of KRT76 downregulation in oral precancer and cancer development. METHODS: We evaluated KRT76 expression by qRT-PCR in normal and tumor tissues of the oral cavity. We also analyzed K76 expression by immunohistochemistry in normal, oral precancerous lesion (OPL), oral squamous cell carcinoma (OSCC) and in hamster model of oral carcinogenesis. Further, functional implication of KRT76 loss was confirmed using KRT76-knockout (KO) mice. RESULTS: We observed a strong association of reduced K76 expression with increased risk of OPL and OSCC development. The buccal epithelium of DMBA treated hamsters showed a similar trend. Oral cavity of KRT76-KO mice showed preneoplastic changes in the gingivobuccal epithelium while no pathological changes were observed in KRT76 negative tissues such as tongue. CONCLUSION: The present study demonstrates loss of KRT76 in oral carcinogenesis. The KRT76-KO mice data underlines the potential of KRT76 being an early event although this loss is not sufficient to drive the development of oral cancers. Thus, future studies to investigate the contributing role of KRT76 in light of other tumor driving events are warranted. PMID- 23936240 TI - TrOn: an anatomical ontology for the beetle Tribolium castaneum. AB - In a morphological ontology the expert's knowledge is represented in terms, which describe morphological structures and how these structures relate to each other. With the assistance of ontologies this expert knowledge is made processable by machines, through a formal and standardized representation of terms and their relations to each other. The red flour beetle Tribolium castaneum, a representative of the most species rich animal taxon on earth (the Coleoptera), is an emerging model organism for development, evolution, physiology, and pest control. In order to foster Tribolium research, we have initiated the Tribolium Ontology (TrOn), which describes the morphology of the red flour beetle. The content of this ontology comprises so far most external morphological structures as well as some internal ones. All modeled structures are consistently annotated for the developmental stages larva, pupa and adult. In TrOn all terms are grouped into three categories: Generic terms represent morphological structures, which are independent of a developmental stage. In contrast, downstream of such terms are concrete terms which stand for a dissectible structure of a beetle at a specific life stage. Finally, there are mixed terms describing structures that are only found at one developmental stage. These terms combine the characteristics of generic and concrete terms with features of both. These annotation principles take into account the changing morphology of the beetle during development and provide generic terms to be used in applications or for cross linking with other ontologies and data resources. We use the ontology for implementing an intuitive search function at the electronic iBeetle-Base, which stores morphological defects found in a genome wide RNA interference (RNAi) screen. The ontology is available for download at http://ibeetle-base.uni goettingen.de. PMID- 23936239 TI - The N-terminus of CD14 acts to bind apoptotic cells and confers rapid-tethering capabilities on non-myeloid cells. AB - Cell death and removal of cell corpses in a timely manner is a key event in both physiological and pathological situations including tissue homeostasis and the resolution of inflammation. Phagocytic clearance of cells dying by apoptosis is a complex sequential process comprising attraction, recognition, tethering, signalling and ultimately phagocytosis and degradation of cell corpses. A wide range of molecules acting as apoptotic cell-associated ligands, phagocyte associated receptors or soluble bridging molecules have been implicated within this process. The role of myeloid cell CD14 in mediating apoptotic cell interactions with macrophages has long been known though key molecules and residues involved have not been defined. Here we sought to further dissect the function of CD14 in apoptotic cell clearance. A novel panel of THP-1 cell-derived phagocytes was employed to demonstrate that CD14 mediates effective apoptotic cell interactions with macrophages in the absence of detectable TLR4 whilst binding and responsiveness to LPS requires TLR4. Using a targeted series of CD14 point mutants expressed in non-myeloid cells we reveal CD14 residue 11 as key in the binding of apoptotic cells whilst other residues are reported as key for LPS binding. Importantly we note that expression of CD14 in non-myeloid cells confers the ability to bind rapidly to apoptotic cells. Analysis of a panel of epithelial cells reveals that a number naturally express CD14 and that this is competent to mediate apoptotic cell clearance. Taken together these data suggest that CD14 relies on residue 11 for apoptotic cell tethering and it may be an important tethering molecule on so called 'non-professional' phagocytes thus contributing to apoptotic cell clearance in a non-myeloid setting. Furthermore these data establish CD14 as a rapid-acting tethering molecule, expressed in monocytes, which may thus confer responsiveness of circulating monocytes to apoptotic cell derived material. PMID- 23936241 TI - Plasticity response in the contralesional hemisphere after subtle neurotrauma: gene expression profiling after partial deafferentation of the hippocampus. AB - Neurotrauma or focal brain ischemia are known to trigger molecular and structural responses in the uninjured hemisphere. These responses may have implications for tissue repair processes as well as for the recovery of function. To determine whether the plasticity response in the uninjured hemisphere occurs even after a subtle trauma, we subjected mice to a partial unilateral deafferentation of the hippocampus induced by stereotactically performed entorhinal cortex lesion (ECL). The expression of selected genes was assessed by quantitative real-time PCR in the hippocampal tissue at the injured side and the contralesional side at day 4 and 14 after injury. We observed that expression of genes coding for synaptotagmin 1, ezrin, thrombospondin 4, and C1q proteins, that have all been implicated in the synapse formation, re-arrangement and plasticity, were upregulated both in the injured and the contralesional hippocampus, implying a plasticity response in the uninjured hemisphere. Several of the genes, the expression of which was altered in response to ECL, are known to be expressed in astrocytes. To test whether astrocyte activation plays a role in the observed plasticity response to ECL, we took advantage of mice deficient in two intermediate filament (nanofilament) proteins glial fibrillary acidic protein (GFAP) and vimentin (GFAP(-/-)Vim(-/-) ) and exhibiting attenuated astrocyte activation and reactive gliosis. The absence of GFAP and vimentin reduced the ECL induced upregulation of thrombospondin 4, indicating that this response to ECL depends on astrocyte activation and reactive gliosis. We conclude that even a very limited focal neurotrauma triggers a distinct response at the contralesional side, which at least to some extent depends on astrocyte activation. PMID- 23936242 TI - Quality control of RNA preservation and extraction from paraffin-embedded tissue: implications for RT-PCR and microarray analysis. AB - Analysis of RNA isolated from fixed and paraffin-embedded tissues is widely used in biomedical research and molecular pathological diagnostics. We have performed a comprehensive and systematic investigation of the impact of factors in the pre analytical workflow, such as different fixatives, fixation time, RNA extraction method and storage of tissues in paraffin blocks, on several downstream reactions including complementary DNA (cDNA) synthesis, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and microarray hybridization. We compared the effects of routine formalin fixation with the non-crosslinking, alcohol-based Tissue Tek Xpress Molecular Fixative (TTXMF, Sakura Finetek), and cryopreservation as gold standard for molecular analyses. Formalin fixation introduced major changes into microarray gene expression data and led to marked gene-to-gene variations in delta-ct values of qRT-PCR. We found that qRT-PCR efficiency and gene-to-gene variations were mainly attributed to differences in the efficiency of cDNA synthesis as the most sensitive step. These differences could not be reliably detected by quality assessment of total RNA isolated from formalin-fixed tissues by electrophoresis or spectrophotometry. Although RNA from TTXMF fixed samples was as fragmented as RNA from formalin fixed samples, much higher cDNA yield and lower ct-values were obtained in qRT-PCR underlining the negative impact of crosslinking by formalin. In order to better estimate the impact of pre-analytical procedures such as fixation on the reliability of downstream analysis, we applied a qRT-PCR-based assay using amplicons of different length and an assay measuring the efficiency of cDNA generation. Together these two assays allowed better quality assessment of RNA extracted from fixed and paraffin-embedded tissues and should be used to supplement quality scores derived from automated electrophoresis. A better standardization of the pre-analytical workflow, application of additional quality controls and detailed sample information would markedly improve the comparability and reliability of molecular studies based on formalin-fixed and paraffin-embedded tissue samples. PMID- 23936243 TI - Transcriptional profiling of mRNAs and microRNAs in human bone marrow precursor B cells identifies subset- and age-specific variations. AB - BACKGROUND: Molecular mechanisms explaining age-related changes in the bone marrow with reduced precursor B cell output are poorly understood. METHODS: We studied the transcriptome of five precursor B cell subsets in individual bone marrow samples from 4 healthy children and 4 adults employing GeneChip(r) Human Exon 1.0 ST Arrays (Affymetrix(r)) and TaqMan(r) Array MicroRNA Cards (Life TechnologiesTM). RESULTS: A total of 1796 mRNAs (11%) were at least once differentially expressed between the various precursor B cell subsets in either age group (FDR 0.1%, p<=1.13*10(-4)) with more marked cell stage specific differences than those related to age. In contrast, microRNA profiles of the various precursor B cell subsets showed less hierarchical clustering as compared to the corresponding mRNA profiles. However, 17 of the 667 microRNA assays (2.5%) were at least once differentially expressed between the subsets (FDR 10%, p<=0.004). From target analysis (Ingenuity(r) Systems), functional assignment between postulated interacting mRNAs and microRNAs showed especially association to cellular growth, proliferation and cell cycle regulation. One functional network connected up-regulation of the differentiation inhibitor ID2 mRNA to down regulation of the hematopoiesis- or cell cycle regulating miR-125b-5p, miR-181a 5p, miR-196a-5p, miR-24-3p and miR-320d in adult PreBII large cells. Noteworthy was also the stage-dependent expression of the growth promoting miR-17-92 cluster, showing a partly inverse trend with age, reaching statistical significance at the PreBII small stage (up 3.1-12.9 fold in children, p = 0.0084 0.0270). CONCLUSIONS: The global mRNA profile is characteristic for each precursor B cell developmental stage and largely similar in children and adults. The microRNA profile is much cell stage specific and not changing much with age. Importantly, however, specific age-dependent differences involving key networks like differentiation and cellular growth may indicate biological divergence and possibly also altered production potential with age. PMID- 23936244 TI - The complete genomic sequence of pepper yellow leaf curl virus (PYLCV) and its implications for our understanding of evolution dynamics in the genus polerovirus. AB - We determined the complete sequence and organization of the genome of a putative member of the genus Polerovirus tentatively named Pepper yellow leaf curl virus (PYLCV). PYLCV has a wider host range than Tobacco vein-distorting virus (TVDV) and has a close serological relationship with Cucurbit aphid-borne yellows virus (CABYV) (both poleroviruses). The extracted viral RNA was subjected to SOLiD next generation sequence analysis and used as a template for reverse transcription synthesis, which was followed by PCR amplification. The ssRNA genome of PYLCV includes 6,028 nucleotides encoding six open reading frames (ORFs), which is typical of the genus Polerovirus. Comparisons of the deduced amino acid sequences of the PYLCV ORFs 2-4 and ORF5, indicate that there are high levels of similarity between these sequences to ORFs 2-4 of TVDV (84-93%) and to ORF5 of CABYV (87%). Both PYLCV and Pepper vein yellowing virus (PeVYV) contain sequences that point to a common ancestral polerovirus. The recombination breakpoint which is located at CABYV ORF3, which encodes the viral coat protein (CP), may explain the CABYV like sequences found in the genomes of the pepper infecting viruses PYLCV and PeVYV. Two additional regions unique to PYLCV (PY1 and PY2) were identified between nucleotides 4,962 and 5,061 (ORF 5) and between positions 5,866 and 6,028 in the 3' NCR. Sequence analysis of the pepper-infecting PeVYV revealed three unique regions (Pe1-Pe3) with no similarity to other members of the genus Polerovirus. Genomic analyses of PYLCV and PeVYV suggest that the speciation of these viruses occurred through putative recombination event(s) between poleroviruses co-infecting a common host(s), resulting in the emergence of PYLCV, a novel pathogen with a wider host range. PMID- 23936245 TI - Epigenetic differentiation persists after male gametogenesis in natural populations of the perennial herb Helleborus foetidus (Ranunculaceae). AB - Despite the importance of assessing the stability of epigenetic variation in non model organisms living in real-world scenarios, no studies have been conducted on the transgenerational persistence of epigenetic structure in wild plant populations. This gap in knowledge is hindering progress in the interpretation of natural epigenetic variation. By applying the methylation-sensitive amplified fragment length polymorphism (MSAP) technique to paired plant-pollen (i.e., sporophyte-male gametophyte) DNA samples, and then comparing methylation patterns and epigenetic population differentiation in sporophytes and their descendant gametophytes, we investigated transgenerational constancy of epigenetic structure in three populations of the perennial herb Helleborus foetidus (Ranunculaceae). Single-locus and multilocus analyses revealed extensive epigenetic differentiation between sporophyte populations. Locus-by-locus comparisons of methylation status in individual sporophytes and descendant gametophytes showed that ~75% of epigenetic markers persisted unchanged through gametogenesis. In spite of some epigenetic reorganization taking place during gametogenesis, multilocus epigenetic differentiation between sporophyte populations was preserved in the subsequent gametophyte stage. In addition to illustrating the efficacy of applying the MSAP technique to paired plant-pollen DNA samples to investigate epigenetic gametic inheritance in wild plants, this paper suggests that epigenetic differentiation between adult plant populations of H. foetidus is likely to persist across generations. PMID- 23936246 TI - Intercropping competition between apple trees and crops in agroforestry systems on the Loess Plateau of China. AB - Agroforestry has been widely practiced in the Loess Plateau region of China because of its prominent effects in reducing soil and water losses, improving land-use efficiency and increasing economic returns. However, the agroforestry practices may lead to competition between crops and trees for underground soil moisture and nutrients, and the trees on the canopy layer may also lead to shortage of light for crops. In order to minimize interspecific competition and maximize the benefits of tree-based intercropping systems, we studied photosynthesis, growth and yield of soybean (Glycine max L. Merr.) and peanut (Arachis hypogaea L.) by measuring photosynthetically active radiation, net photosynthetic rate, soil moisture and soil nutrients in a plantation of apple (Malus pumila M.) at a spacing of 4 m * 5 m on the Loess Plateau of China. The results showed that for both intercropping systems in the study region, soil moisture was the primary factor affecting the crop yields followed by light. Deficiency of the soil nutrients also had a significant impact on crop yields. Compared with soybean, peanut was more suitable for intercropping with apple trees to obtain economic benefits in the region. We concluded that apple-soybean and apple-peanut intercropping systems can be practical and beneficial in the region. However, the distance between crops and tree rows should be adjusted to minimize interspecies competition. Agronomic measures such as regular canopy pruning, root barriers, additional irrigation and fertilization also should be applied in the intercropping systems. PMID- 23936247 TI - First fossil evidence for the advance of replacement teeth coupled with life history evolution along an anagenetic mammalian lineage. AB - In mammals that grow up more slowly and live longer, replacement teeth tend to appear earlier in sequence than in fast growing mammals. This trend, known as 'Schultz's Rule', is a useful tool for inferring life histories of fossil taxa. Deviations from this rule, however, suggest that in addition to the pace of life history, ecological factors may also drive dental ontogeny. Myotragus balearicus is an extinct insular caprine that has been proved to be an excellent test case to correlate morphological traits with life history. Here we show that Myotragus balearicus exhibits a slow signature of dental eruption sequence that is in agreement with the exceptionally slow life history of this species, thus conforming to 'Schultz's Rule'. However, our results also show an acceleration of the absolute pace of development of the permanent incisors in relation to that of the posterior teeth. The rodent-like incisors of Myotragus balearicus erupted early not only in relative but also in absolute terms (chronological age), suggesting that feeding characteristics also plays an important role in dental ontogeny. This is in agreement with ecological hypotheses based on primates. Our study documents a decoupling of the pace of development of teeth in mammals that is triggered by different selection pressures on dental ontogeny. Moreover, we show that Myotragus kopperi from the early Pleistocene (a direct ancestor of the late Pleistocene-Holocene M. balearicus) follows the pattern of first incisor replacement known in living bovids. Hence, the advance in the eruption sequence of the first incisors occurs along the Myotragus evolutionary lineage over a period of about 2.5 Myr. To our knowledge, this is the first fossil evidence of an advance of the emergence of the permanent first incisor along an anagenetic mammalian lineage. PMID- 23936248 TI - Instability of the middle cerebral artery blood flow in response to CO2. AB - BACKGROUND: The middle cerebral artery supplies long end-artery branches to perfuse the deep white matter and shorter peripheral branches to perfuse cortical and subcortical tissues. A generalized vasodilatory stimulus such as carbon dioxide not only results in an increase in flow to these various tissue beds but also redistribution among them. We employed a fast step increase in carbon dioxide to detect the dynamics of the cerebral blood flow response. METHODOLOGY/PRINCIPAL FINDINGS: The study was approved by the Research Ethics Board of the University Health Network at the University of Toronto. We used transcranial ultrasound to measure the time course of middle cerebral artery blood flow velocity in 28 healthy adults. Normoxic, isoxic step increases in arterial carbon dioxide tension of 10 mmHg from both hypocapnic and normocapnic baselines were produced using a new prospective targeting system that enabled a more rapid step change than has been previously achievable. In most of the 28 subjects the responses at both carbon dioxide ranges were characterised by more complex responses than a single exponential rise. Most responses were characterised by a fast initial response which then declined rapidly to a nadir, followed by a slower secondary response, with some showing oscillations before stabilising. CONCLUSIONS/SIGNIFICANCE: A rapid step increase in carbon dioxide tension is capable of inducing instability in the cerebral blood flow control system. These dynamic aspects of the cerebral blood flow responses to rapid changes in carbon dioxide must be taken into account when using transcranial blood flow velocity in a single artery segment to measure cerebrovascular reactivity. PMID- 23936249 TI - Transient decline in hippocampal theta activity during the acquisition process of the negative patterning task. AB - Hippocampal function is important in the acquisition of negative patterning but not of simple discrimination. This study examined rat hippocampal theta activity during the acquisition stages (early, middle, and late) of the negative patterning task (A+, B+, AB-). The results showed that hippocampal theta activity began to decline transiently (for 500 ms after non-reinforced stimulus presentation) during the late stage of learning in the negative patterning task. In addition, this transient decline in hippocampal theta activity in the late stage was lower in the negative patterning task than in the simple discrimination task. This transient decline during the late stage of task acquisition may be related to a learning process distinctive of the negative patterning task but not the simple discrimination task. We propose that the transient decline of hippocampal theta activity reflects inhibitory learning and/or response inhibition after the presentation of a compound stimulus specific to the negative patterning task. PMID- 23936250 TI - Dual-color fluorescence in situ hybridization reveals an association of chromosome 8q22 but not 8p21 imbalance with high grade invasive breast carcinoma. AB - We previously reported molecular karyotype analysis of invasive breast tumour core needle biopsies by comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) (Walker et al, Genes Chromosomes Cancer, 2008 May;47(5):405-17). That study identified frequently recurring gains and losses involving chromosome bands 8q22 and 8p21, respectively. Moreover, these data highlighted an association between 8q22 gain and typically aggressive grade 3 tumors. Here we validate and extend our previous investigations through FISH analysis of tumor touch imprints prepared from excised breast tumor specimens. Compared to post-surgical tumor excisions, core needle biopsies are known to be histologically less precise when predicting tumor grade. Therefore investigating these chromosomal aberrations in tumor samples that offer more reliable pathological assessment is likely to give a better overall indication of association. A series of 60 breast tumors were screened for genomic copy number changes at 8q22 and 8p21 by dual-color FISH. Results confirm previous findings that 8p loss (39%) and 8q gain (74%) occur frequently in invasive breast cancer. Both absolute quantification of 8q22 gain across the sample cohort, and a separate relative assessment by 8q22:8p21 copy number ratio, showed that the incidence of 8q22 gain significantly increased with grade (p = 0.004, absolute and p = 0.02, relative). In contrast, no association was found between 8p21 loss and tumor grade. These findings support the notion that 8q22 is a region of interest for invasive breast cancer pathogenesis, potentially harboring one or more genes that, when amplified, precipitate the molecular events that define high tumor grade. PMID- 23936251 TI - Physical predictors of cognitive performance in healthy older adults: a cross sectional analysis. AB - There is ample evidence that physical and cognitive performance are related, but the results of studies investigating this relationship show great variability. Both physical performance and cognitive performance are constructs consisting of several subdomains, but it is presently unknown if the relationship between physical and cognitive performance depends on subdomain of either construct and whether gender and age moderate this relationship. The aim of this study is to identify the strongest physical predictors of cognitive performance, to determine the specificity of these predictors for various cognitive subdomains, and to examine gender and age as potential moderators of the relationship between physical and cognitive performance in a sample of community-dwelling older adults. In total, 98 men and 122 women (average age 74.0+/-5.6 years) were subjected to a series of performance-based physical fitness and neuropsychological tests. Muscle strength, balance, functional reach, and walking ability (combined score of walking speed and endurance) were considered to predict cognitive performance across several domains (i.e. memory, verbal attention, visual attention, set-shifting, visuo-motor attention, inhibition and intelligence). Results showed that muscle strength was a significant predictor of cognitive performance for men and women. Walking ability and balance were significant predictors of cognitive performance for men, whereas only walking ability was significant for women. We did not find a moderating effect of age, nor did we find support for a differential effect of the physical predictors across different cognitive subdomains. In summary, our results showed a significant relationship between cognitive and physical performance, with a moderating effect of gender. PMID- 23936252 TI - Biventricular remodeling in murine models of right ventricular pressure overload. AB - Right ventricular (RV) failure is a major cause of mortality in acute or chronic lung disease and left heart failure. The objective of this study was to demonstrate a percutaneous approach to study biventricular hemodynamics in murine models of primary and secondary RV pressure overload (RVPO) and further explore biventricular expression of two key proteins that regulate cardiac remodeling: calcineurin and transforming growth factor beta 1 (TGFbeta1). METHODS: Adult, male mice underwent constriction of the pulmonary artery or thoracic aorta as models of primary and secondary RVPO, respectively. Conductance catheterization was performed followed by tissue analysis for changes in myocyte hypertrophy and fibrosis. RESULTS: Both primary and secondary RVPO decreased biventricular stroke work however RV instantaneous peak pressure (dP/dtmax) and end-systolic elastance (Ees) were preserved in both groups compared to controls. In contrast, left ventricular (LV) dP/dtmax and LV-Ees were unchanged by primary, but reduced in the secondary RVPO group. The ratio of RV:LV ventriculo-arterial coupling was increased in primary and reduced in secondary RVPO. Primary and secondary RVPO increased RV mass, while LV mass decreased in primary and increased in the secondary RVPO groups. RV fibrosis and hypertrophy were increased in both groups, while LV fibrosis and hypertrophy were increased in secondary RVPO only. RV calcineurin expression was increased in both groups, while LV expression increased in secondary RVPO only. Biventricular TGFbeta1 expression was increased in both groups. CONCLUSION: These data identify distinct effects of primary and secondary RVPO on biventricular structure, function, and expression of key remodeling pathways. PMID- 23936253 TI - Gene-by-temperature interactions and candidate plasticity genes for morphological traits in Drosophila melanogaster. AB - Understanding the genetic architecture of any quantitative trait requires identifying the genes involved in its expression in different environmental conditions. This goal can be achieved by mutagenesis screens in genetically tractable model organisms such as Drosophila melanogaster. Temperature during ontogenesis is an important environmental factor affecting development and phenotypic variation in holometabolous insects. In spite of the importance of phenotypic plasticity and genotype by environment interaction (GEI) for fitness related traits, its genetic basis has remained elusive. In this context, we analyzed five different adult morphological traits (face width, head width, thorax length, wing size and wing shape) in 42 co-isogenic single P-element insertional lines of Drosophila melanogaster raised at 17 degrees C and 25 degrees C. Our analyses showed that all lines differed from the control for at least one trait in males or females at either temperature. However, no line showed those differences for all traits in both sexes and temperatures simultaneously. In this sense, the most pleiotropic candidate genes were CG34460, Lsd-2 and Spn. Our analyses also revealed extensive genetic variation for all the characters mostly indicated by strong GEIs. Further, our results indicate that GEIs were predominantly explained by changes in ranking order in all cases suggesting that a moderate number of genes are involved in the expression of each character at both temperatures. Most lines displayed a plastic response for at least one trait in either sex. In this regard, P-element insertions affecting plasticity of a large number of traits were associated to the candidate genes Btk29A, CG43340, Drak and jim. Further studies will help to elucidate the relevance of these genes on the morphogenesis of different body structures in natural populations of D. melanogaster. PMID- 23936254 TI - Presentation of 493 consecutive girls with idiopathic central precocious puberty: a single-center study. AB - BACKGROUND: Despite the number of reported data concerning idiopathic central precocious puberty (CPP) in girls, major questions remain including its diagnosis, factors, and indications of gonadotropin releasing hormone (GnRH) analog treatment. METHODS: A retrospective, single-center study was carried out on 493 girls with CPP. RESULTS: Eleven girls (2.2%) were aged less than 3 years. Breast development was either isolated (Group 0, n = 99), or associated with one sign, pubic hair development, growth rate greater than 2 standard deviation score (SDS) or bone age (BA) >2 years above chronological age, (Group 1, n = 187), two signs (Group 2, n = 142) or three signs (Group 3, n = 65). The interval between onset of puberty and evaluation, body mass index (BMI) SDS, plasma luteinising hormone (LH) concentrations (basal and peak) and LH/ follicle-stimulating hormone (FSH) peak ratio after GnRH test, plasma estradiol and uterus length were significantly greater in Groups 2 and 3 than in Groups 0 and 1 respectively. 211 (42.8%) patients were obese and/or had excessive weight gain during the year before puberty. Obese girls more often had BA advance of >2 years (p = 0.0004) and pubic hair development (p = 0.003) than the others. BMI did not correlate with LH or with LH/FSH peak ratio. Girls with familial history of early puberty (41.4%) had greater frequencies of pubertal LH/FSH peak ratios (p = 0.02) than the others. During the 31 years of the study, there was no increase in the frequency of CPP or variation in its characteristics. CONCLUSION: Obesity is associated with a higher BA advance and higher frequency of pubic or axillary hair development but not with LH secretion, suggesting that obesity accelerates adrenarche but not the maturation of the hypothalamic-pituitary-ovarian axis. The LH/FSH peak ratio was more frequently pubertal in girls with a familial history of early puberty, suggesting that this maturation depends on genetic factors. PMID- 23936255 TI - Public hygiene campaign in denmark during the 2009 H1N1 pandemic had no effect on hospitalization rate of communicable diseases in children. AB - BACKGROUND: During the 2009 H1N1 pandemic the Danish National board of Health carried out massive public hygiene campaigns to limit spread of disease. We aimed to investigate whether this resulted in lower incidences of communicable diseases in the paediatric population. METHODS: The study compared annual hospitalization rates for childhood infections from 2005 to 2011. RESULTS: Admission rates for infections were higher during the year of the pandemic compared to the rest of the period. CONCLUSION: There were no indications of a preventive effect by the hygiene campaign on incidence of severe common childhood infections. PMID- 23936256 TI - Recombinant prion protein refolded with lipid and RNA has the biochemical hallmarks of a prion but lacks in vivo infectivity. AB - During prion infection, the normal, protease-sensitive conformation of prion protein (PrP(C)) is converted via seeded polymerization to an abnormal, infectious conformation with greatly increased protease-resistance (PrP(Sc)). In vitro, protein misfolding cyclic amplification (PMCA) uses PrP(Sc) in prion infected brain homogenates as an initiating seed to convert PrP(C) and trigger the self-propagation of PrP(Sc) over many cycles of amplification. While PMCA reactions produce high levels of protease-resistant PrP, the infectious titer is often lower than that of brain-derived PrP(Sc). More recently, PMCA techniques using bacterially derived recombinant PrP (rPrP) in the presence of lipid and RNA but in the absence of any starting PrP(Sc) seed have been used to generate infectious prions that cause disease in wild-type mice with relatively short incubation times. These data suggest that lipid and/or RNA act as cofactors to facilitate the de novo formation of high levels of prion infectivity. Using rPrP purified by two different techniques, we generated a self-propagating protease resistant rPrP molecule that, regardless of the amount of RNA and lipid used, had a molecular mass, protease resistance and insolubility similar to that of PrP(Sc). However, we were unable to detect prion infectivity in any of our reactions using either cell-culture or animal bioassays. These results demonstrate that the ability to self-propagate into a protease-resistant insoluble conformer is not unique to infectious PrP molecules. They suggest that the presence of RNA and lipid cofactors may facilitate the spontaneous refolding of PrP into an infectious form while also allowing the de novo formation of self propagating, but non-infectious, rPrP-res. PMID- 23936258 TI - 24-hour glycemic variations in drug-naive patients with type 2 diabetes: a continuous glucose monitoring (CGM)-based study. AB - OBJECTIVE: To investigate a 24-hour glycemic variation in drug-naive, type 2 diabetic patients by using CGM. METHODS: A total of 30 inpatients with type 2 diabetes were included in the study to analyze the 24-hour CGM data. RESULTS: The patients' median age was 58 years old (interquartile range: 42-66 years), and their median HbA1c value was 7.6 (6.7-8.8)%. The median time to postprandial peak glucose levels(Peak Time) for each meal was 70-85 minutes, with the range of postprandial glucose increases(Increase Range) for each meal being 83-109 mg/dL. There was a significant positive correlation between the HbA1c values and Increases Range, Peak Time observed after breakfast and dinner, respectively. When the patients were stratified by a median HbA1c value of 7.6% into 2 groups, Increases Range and Peak Time, after breakfast, were shown to be significantly higher in the high-HbA1c group (H) than in the low-HbA1c (L) group. When the subjects were divided into four groups according to HbA1c levels:1 (<7.0%, n = 8), 2 (7.0-7.9%, n = 8), 3 (8.0-8.9%, n = 8), and 4 (>=9%, n = 6), the average glucose level, pre-meal glucose level and postprandial peak glucose level increased steadily from group 1 to 4 in a stepwise manner. CONCLUSIONS: In drug naive, Japanese type 2 diabetic patients, the Peak Time and the Increase Range were maximal after dinner. It was shown that the greater the HbA1c values, the longer Peak time and the higher Increase Range after breakfast and dinner. The average glucose level, pre meal glucose level and postprandial peak glucose level increased steadily as HbA1c level increased. PMID- 23936257 TI - Glocal clinical registries: pacemaker registry design and implementation for global and local integration--methodology and case study. AB - BACKGROUND: The ability to apply standard and interoperable solutions for implementing and managing medical registries as well as aggregate, reproduce, and access data sets from legacy formats and platforms to advanced standard formats and operating systems are crucial for both clinical healthcare and biomedical research settings. PURPOSE: Our study describes a reproducible, highly scalable, standard framework for a device registry implementation addressing both local data quality components and global linking problems. METHODS AND RESULTS: We developed a device registry framework involving the following steps: (1) Data standards definition and representation of the research workflow, (2) Development of electronic case report forms using REDCap (Research Electronic Data Capture), (3) Data collection according to the clinical research workflow and, (4) Data augmentation by enriching the registry database with local electronic health records, governmental database and linked open data collections, (5) Data quality control and (6) Data dissemination through the registry Web site. Our registry adopted all applicable standardized data elements proposed by American College Cardiology / American Heart Association Clinical Data Standards, as well as variables derived from cardiac devices randomized trials and Clinical Data Interchange Standards Consortium. Local interoperability was performed between REDCap and data derived from Electronic Health Record system. The original data set was also augmented by incorporating the reimbursed values paid by the Brazilian government during a hospitalization for pacemaker implantation. By linking our registry to the open data collection repository Linked Clinical Trials (LinkedCT) we found 130 clinical trials which are potentially correlated with our pacemaker registry. CONCLUSION: This study demonstrates how standard and reproducible solutions can be applied in the implementation of medical registries to constitute a re-usable framework. Such approach has the potential to facilitate data integration between healthcare and research settings, also being a useful framework to be used in other biomedical registries. PMID- 23936259 TI - Antidiabetic and antioxidant effects and phytochemicals of mulberry fruit (Morus alba L.) polyphenol enhanced extract. AB - The antidiabetic and antioxidant activities of the ethyl acetate-soluble extract (MFE) of mulberry fruit (Morus alba L.) were investigated. In vitro, MFE showed potent alpha-glucosidase inhibitory activity and radical-scavenging activities against DPPH and superoxide anion radicals. In vivo, MFE could significantly decrease fasting blood glucose (FBG) and glycosylated serum protein (GSP), and increase antioxidant enzymatic activities (SOD, CAT, GSH-Px) in streptozotocin (STZ)-induced diabetic mice. Bioactivity-guided fractionation of the MFE led to the isolation of 25 phenolic compounds, and their structures were identified on the basis of MS and NMR data. All the 25 compounds were isolated from mulberry fruit for the first time. Also, the alpha-glucosidase inhibitory activity and antioxidant activity of the phenolics were evaluated. Potent alpha-glucosidase inhibitory and radical-scavenging activities of these phenolics suggested that they may be partially responsible for the antidiabetic and antioxidant activities of mulberry fruit. PMID- 23936260 TI - Virologic and immunologic response to cART by HIV-1 subtype in the CASCADE collaboration. AB - BACKGROUND: We aimed to compare rates of virologic response and CD4 changes after combination antiretroviral (cART) initiation in individuals infected with B and specific non-B HIV subtypes. METHODS: Using CASCADE data we analyzed HIV-RNA and CD4 counts for persons infected >=1996, >=15 years of age. We used survival and longitudinal modeling to estimate probabilities of virologic response (confirmed HIV-RNA <500 c/ml), and failure (HIV-RNA>500 c/ml at 6 months or >=1000 c/ml following response) and CD4 increase after cART initiation. RESULTS: 2003 (1706 B, 142 CRF02_AG, 55 A, 53 C, 47 CRF01_AE) seroconverters were included in analysis. There was no evidence of subtype effect overall for response or failure (p = 0.075 and 0.317, respectively) although there was a suggestion that those infected with subtypes CRF01_AE and A responded sooner than those with subtype B infection [HR (95% CI):1.37 (1.01-1.86) and 1.29 (0.96-1.72), respectively]. Rates of CD4 increase were similar in all subtypes except subtype A, which tended to have lower initial, but faster long-term, increases. CONCLUSIONS: Virologic and immunologic response to cART was similar across all studied subtypes but statistical power was limited by the rarity of some non-B subtypes. Current antiretroviral agents seem to have similar efficacy in subtype B and most widely encountered non-B infections in high-income countries. PMID- 23936262 TI - Spatio-temporal distribution of injured elephants in Masai Mara and the putative negative and positive roles of the local community. AB - BACKGROUND: Very few studies have ever focused on the elephants that are wounded or killed as local communities attempt to scare these animals away from their settlements and farms, or on the cases in which local people take revenge after elephants have killed or injured humans. On the other hand, local communities live in close proximity to elephants and hence can play a positive role in elephant conservation by informing the authorities of the presence of injured elephants. METHODOLOGY/PRINCIPAL FINDINGS: Between 2007 and 2011, 129 elephants were monitored in Masai Mara (Kenya), of which 54 had various types of active (intentionally caused) or passive (non-intentionally caused) injuries. Also studied were 75 random control samples of apparently unaffected animals. The observed active injuries were as expected biased by age, with adults suffering more harm; on the other hand, no such bias was observed in the case of passive injuries. Bias was also observed in elephant sex since more males than females were passively and actively injured. Cases of passive and active injuries in elephants were negatively related to the proximity to roads and farms; the distribution of injured elephants was not affected by the presence of either human settlements or water sources. Overall more elephants were actively injured during the dry season than the wet season as expected. Local communities play a positive role by informing KWS authorities of the presence of injured elephants and reported 43% of all cases of injured elephants. CONCLUSIONS: Our results suggest that the negative effect of local communities on elephants could be predicted by elephant proximity to farms and roads. In addition, local communities may be able to play a more positive role in elephant conservation given that they are key informants in the early detection of injured elephants. PMID- 23936261 TI - Stress-induced antinociception in fish reversed by naloxone. AB - Pain perception in non-mammalian vertebrates such as fish is a controversial issue. We demonstrate that, in the fish Leporinus macrocephalus, an imposed restraint can modulate the behavioral response to a noxious stimulus, specifically the subcutaneous injection of 3% formaldehyde. In the first experiment, formaldehyde was applied immediately after 3 or 5 min of the restraint. Inhibition of the increase in locomotor activity in response to formaldehyde was observed, which suggests a possible restraint-induced antinociception. In the second experiment, the noxious stimulus was applied 0, 5, 10 and 15 min after the restraint, and both 3 and 5 min of restraint promoted short-term antinociception of approximately 5 min. In experiments 3 and 4, an intraperitoneal injection of naloxone (30 mg.kg(-1)) was administered 30 min prior to the restraint. The 3- minute restraint-induced antinociception was blocked by pretreatment with naloxone, but the corresponding 5-minute response was not. One possible explanation for this result is that an opioid and a non preferential MU-opioid and/or non-opioid mechanism participate in this response modulation. Furthermore, we observed that both the 3- and 5- minutes restraint were severely stressful events for the organism, promoting marked increases in serum cortisol levels. These data indicate that the response to a noxious stimulus can be modulated by an environmental stressor in fish, as is the case in mammals. To our knowledge, this study is the first evidence for the existence of an endogenous antinociceptive system that is activated by an acute standardized stress in fish. Additionally, it characterizes the antinociceptive response induced by stress in terms of its time course and the opioid mediation, providing information for understanding the evolution of nociception modulation. PMID- 23936263 TI - The chloroplast min system functions differentially in two specific nongreen plastids in Arabidopsis thaliana. AB - The nongreen plastids, such as etioplasts, chromoplasts, etc., as well as chloroplasts, are all derived from proplastids in the meristem. To date, the Min system members in plants have been identified as regulators of FtsZ-ring placement, which are essential for the symmetrical division of chloroplasts. However, the regulation of FtsZ-ring placement in nongreen plastids is poorly understood. In this study, we investigated the division site placement of nongreen plastids by examining the etioplasts as representative in Arabidopsis Min system mutants. Surprisingly, the shape and number of etioplasts in cotyledons of arc3, arc11 and mcd1 mutants were similar to that observed in wild type plants, whereas arc12 and parc6 mutants exhibited enlarged etioplasts that were reduced in number. In order to examine nongreen plastids in true leaves, we silenced the ALB3 gene in these Min system mutant backgrounds to produce immature chloroplasts without the thylakoidal network using virus induced gene silencing (VIGS). Interestingly, consistent with our observations in etioplasts, enlarged and fewer nongreen plastids were only detected in leaves of parc6 (VIGS-ALB3) and arc12 (VIGS-ALB3) plants. Further, the FtsZ-ring assembled properly at the midpoint in nongreen plastids of arc3, arc11 and mcd1 (VIGS-ALB3) plants, but organized into multiple rings in parc6 (VIGS-ALB3) and presented fragmented filaments in arc12 (VIGS-ALB3) plants, suggesting that division site placement in nongreen plastids requires fewer components of the plant Min system. Taken together, these results suggest that division site placement in nongreen plastids is different from that in chloroplasts. PMID- 23936264 TI - Impact of latent infection treatment in indigenous populations. AB - The aims of the present study were to identify risk factors associated with latent tuberculosis (TB), examine the development of active disease among contacts, and assess the effectiveness of treating latent infection in indigenous Brazilians from January 2006 to December 2011. This was a retrospective study consisting of 1,371 tuberculosis contacts, 392 of whom underwent treatment for latent infection. Morbidity-from-TB data were obtained from the Information System for Disease Notification (SINAN) database, and the contacts' data were collected from the clinical records using forms employed by Special Department of Indigenous Health (SESAI) multidisciplinary teams, according to SESAI's instructions. The variables that were associated with latent infection among the contacts were age (odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.02 1.04) and close contact with a smear-positive index case (OR: 2.26, 95% CI: 1.59 3.22). The variables associated with the development of active TB among the contacts were a tuberculin skin test (TST) >=10 mm (relative risk [RR]: 1.12, 95% CI: 1.07-1.17), age (RR: 1.01, 95% CI: 1.00-1.03), and treatment of latent infection (RR: 0.03, 95% CI: 0.01-0.27). The estimated number of latent infection treatments needed to prevent one case of active TB among the contacts was 51 treatments (95% CI: 33-182). In contacts with TST >=10 mm, 10 (95% CI: 6-19) latent infection treatments were necessary to prevent one case of active TB. Age and close contact with a smear-positive index case were associated with latent TB. Screening with TST is a high priority among individuals contacting smear positive index cases. Age and TST are associated with the development of active TB among contacts, and treatment of latent infection is an effective measure to control TB in indigenous communities. PMID- 23936265 TI - NOTCH1 gain of function in germ cells causes failure of spermatogenesis in male mice. AB - NOTCH1 is a member of the NOTCH receptor family, a group of single-pass trans membrane receptors. NOTCH signaling is highly conserved in evolution and mediates communication between adjacent cells. NOTCH receptors have been implicated in cell fate determination, as well as maintenance and differentiation of stem cells. In the mammalian testis expression of NOTCH1 in somatic and germ cells has been demonstrated, however its role in spermatogenesis was not clear. To study the significance of NOTCH1 in germ cells, we applied a cre/loxP approach in mice to induce NOTCH1 gain- or loss-of function specifically in male germ cells. Using a Stra8-icre transgene we produced mice with conditional activation of the NOTCH1 intracellular domain (NICD) in germ cells. Spermatogenesis in these mutants was progressively affected with age, resulting in decreased testis weight and sperm count. Analysis of downstream target genes of NOTCH1 signaling showed an increased expression of Hes5, with a reduction of the spermatogonial differentiation marker, Neurog3 expression in the mutant testis. Apoptosis was significantly increased in mouse germ cells with the corresponding elevation of pro-apoptotic Trp53 and Trp63 genes' expression. We also showed that the conditional germ cell-specific ablation of Notch1 had no effect on spermatogenesis or male fertility. Our data suggest the importance of NOTCH signaling regulation in male germ cells for their survival and differentiation. PMID- 23936266 TI - Association of aldosterone synthase polymorphism (CYP11B2 -344T>C) and genetic ancestry with atrial fibrillation and serum aldosterone in African Americans with heart failure. AB - The objective of this study was to examine the extent to which aldosterone synthase genotype (CYP11B2) and genetic ancestry correlate with atrial fibrillation (AF) and serum aldosterone in African Americans with heart failure. Clinical data, echocardiographic measurements, and a genetic sample for determination of CYP11B2 -344T>C (rs1799998) genotype and genetic ancestry were collected from 194 self-reported African Americans with chronic, ambulatory heart failure. Genetic ancestry was determined using 105 autosomal ancestry informative markers. In a sub-set of patients (n = 126), serum was also collected for determination of circulating aldosterone. The CYP11B2 -344C allele frequency was 18% among the study population, and 19% of patients had AF. Multiple logistic regression revealed that the CYP11B2 -344CC genotype was a significant independent predictor of AF (OR 12.7, 95% CI 1.60-98.4, p = 0.0150, empirical p = 0.011) while holding multiple clinical factors, left atrial size, and percent European ancestry constant. Serum aldosterone was significantly higher among patients with AF (p = 0.036), whereas increased West African ancestry was inversely correlated with serum aldosterone (r = -0.19, p = 0.037). The CYP11B2 344CC genotype was also overrepresented among patients with extreme aldosterone elevation (>=90th percentile, p = 0.0145). In this cohort of African Americans with chronic ambulatory heart failure, the CYP11B2 -344T>C genotype was a significant independent predictor of AF while holding clinical, echocardiographic predictors, and genetic ancestry constant. In addition, increased West African ancestry was associated with decreased serum aldosterone levels, potentially providing an explanation for the lower risk for AF observed among African Americans. PMID- 23936267 TI - Immature dendritic cells generated from cryopreserved human monocytes show impaired ability to respond to LPS and to induce allogeneic lymphocyte proliferation. AB - Dendritic cells play a key role in the immune system, in the sensing of foreign antigens and triggering of an adaptive immune response. Cryopreservation of human monocytes was investigated to understand its effect on differentiation into immature monocyte-derived dendritic cells (imdDCs), the response to inflammatory stimuli and the ability to induce allogeneic lymphocyte proliferation. Cryopreserved (crp)-monocytes were able to differentiate into imdDCs, albeit to a lesser extent than freshly (frh)-obtained monocytes. Furthermore, crp-imdDCs had lower rates of maturation and cytokine/chemokine secretion in response to LPS than frh-imdDCs. Lower expression of Toll-like receptor 4 (at 24 and 48 h) and higher susceptibility to apoptosis in crp-imdDCs than in fresh cells would account for the impaired maturation and cytokine/chemokine secretion observed. A mixed leukocyte reaction showed that lymphocyte proliferation was lower with crp imdDCs than with frh-imdDCs. These findings suggested that the source of monocytes used to generate human imdDCs could influence the accuracy of results observed in studies of the immune response to pathogens, lymphocyte activation, vaccination and antigen sensing. It is not always possible to work with freshly isolated monocytes but the possible effects of freezing/thawing on the biology and responsiveness of imdDCs should be taken into account. PMID- 23936268 TI - Change in phylogenetic community structure during succession of traditionally managed tropical rainforest in southwest China. AB - Tropical rainforests in Southeast Asia are facing increasing and ever more intense human disturbance that often negatively affects biodiversity. The aim of this study was to determine how tree species phylogenetic diversity is affected by traditional forest management types and to understand the change in community phylogenetic structure during succession. Four types of forests with different management histories were selected for this purpose: old growth forests, understorey planted old growth forests, old secondary forests (~200-years after slash and burn), and young secondary forests (15-50-years after slash and burn). We found that tree phylogenetic community structure changed from clustering to over-dispersion from early to late successional forests and finally became random in old-growth forest. We also found that the phylogenetic structure of the tree overstorey and understorey responded differentially to change in environmental conditions during succession. In addition, we show that slash and burn agriculture (swidden cultivation) can increase landscape level plant community evolutionary information content. PMID- 23936269 TI - Frequency-risk and duration-risk relationships between aspirin use and gastric cancer: a systematic review and meta-analysis. AB - BACKGROUND: Although previous meta-analyses have suggested an association between aspirin use and risk of gastric cancer, current evidence is inconsistent. Additionally, it remains unclear whether there are frequency-risk and duration risk relationships and if a threshold of effect exists. METHODS: We identified studies by searching MEDLINE and PUBMED databases and reviewing relevant articles. We derived the summary risk estimates using fixed-effects or random effects model based on homogeneity analysis. The dose-response meta-analysis was performed by linear trend regression and restricted cubic spline regression. Potential heterogeneity was tested using the Q statistic and quantified with the I (2) statistic. Subgroup analyses and Galbraith plots were used to explore the potential sources of heterogeneity. Publication bias was evaluated with funnel plots and quantified by the Begg's and Egger's test. RESULTS: Fifteen studies were included in this meta-analysis. There was an overall 29% reduced risk of gastric cancer corresponding to aspirin use (RR = 0.71, 95% CI 0.60-0.82). We found there are nonlinear frequency-risk and linear duration-risk relations between aspirin use and gastric cancer. A monotonically decreasing relation was observed only for low-frequency (<=4.5 times/week) aspirin intake (10% decreased risk for once/week, 19% for twice/week and 29% for 4.5 times/week), and the frequency threshold of aspirin use is 4.5 times per week. Regarding those with duration of aspirin use, there was a tendency towards stronger risk reduction of gastric cancer for longer aspirin use (10% decreased risk for 4 years, 19% for 8 years and 28% for 12 years), and no duration threshold was observed. CONCLUSION: Our findings suggest that long-term (>=4 years) and low-frequency (1-4.5 times per week) aspirin use is associated with a statistically significant, dose dependent reduction in the risk of gastric cancer. PMID- 23936270 TI - A role for the protein tyrosine phosphatase CD45 in macrophage adhesion through the regulation of paxillin degradation. AB - CD45 is a protein tyrosine phosphatase expressed on all cells of hematopoietic origin that is known to regulate Src family kinases. In macrophages, the absence of CD45 has been linked to defects in adhesion, however the molecular mechanisms involved remain poorly defined. In this study, we show that bone marrow derived macrophages from CD45-deficient mice exhibit abnormal cell morphology and defective motility. These defects are accompanied by substantially decreased levels of the cytoskeletal-associated protein paxillin, without affecting the levels of other proteins. Degradation of paxillin in CD45-deficient macrophages is calpain-mediated, as treatment with a calpain inhibitor restores paxillin levels in these cells and enhances cell spreading. Inhibition of the tyrosine kinases proline-rich tyrosine kinase (Pyk2) and focal adhesion kinase (FAK), kinases that are capable of mediating tyrosine phosphorylation of paxillin, also restored paxillin levels, indicating a role for these kinases in the CD45 dependent regulation of paxillin. These data demonstrate that CD45 functions to regulate Pyk2/FAK activity, likely through the activity of Src family kinases, which in turn regulates the levels of paxillin to modulate macrophage adhesion and migration. PMID- 23936290 TI - Network effects of risk behavior change following prophylactic interventions. AB - We formulated a network-based model to understand how risk behavior change in conjunction with failure of prophylactic interventions can lead to unintended outcomes where "less (intervention) is more (effective)." Our model captures the distinction between one- and two-sided risk behavior change. In one-sided situations (e.g. influenza/H1N1) it is sufficient for either individual in an interaction to exhibit risk behavior change whereas in two-sided situations (e.g. AIDS/HIV) it is necessary for both individuals in the interaction to exhibit risk behavior change, for a potential transmission of the disease. A central discovery is that this phenomenon occurs at differing levels of intervention coverage depending upon the "sidedness" of the interaction. We find that for one-sided interactions, sufficiently high vaccination coverage is necessary for mitigating the effects of risk behavior; for two-sided interactions, it is essential to combine prophylactic treatments with programs aimed at reducing risky behavior. Furthermore, again dependent on the "sidedness," targeting highly connected nodes can be strictly worse than uniformly random interventions at the same level of coverage. PMID- 23936291 TI - Distribution of central corneal thickness and its association with ocular parameters in a large central European cohort: the Gutenberg health study. AB - MAIN OBJECTIVE: To evaluate the distribution of central corneal thickness (CCT) in a large German cohort and to analyse its relationship with intraocular pressure and further ocular factors. DESIGN: Population-based, prospective, cohort study. METHODS: The Gutenberg Health Study (GHS) cohort included 4,698 eligible enrollees of 5,000 subjects (age range 35-74 years) who participated in the survey from 2007 to 2008. All participants underwent an ophthalmological examination including slitlamp biomicroscopy, intraocular pressure measurement, central corneal thickness measurement, fundus examination, and were given a questionnaire regarding glaucoma history. Furthermore, all subjects underwent fundus photography and visual field testing using frequency doubling perimetry. RESULTS: Mean CCT was 557.3 +/- 34.3 um (male) and 551.6+/-35.2 um in female subjects (Mean CCT from right and left eyes). Younger male participants (35-44 years) presented slightly thicker CCT than those older. We noted a significant CCT difference of 4 um between right and left eyes, but a high correlation between eyes (Wilcoxon test for related samples: p<0.0001). Univariable linear regression stratified by gender showed that IOP was correlated with CCT (p<0.0001). A 10 um increase in CCT led to an increase in IOP between 0.35-0.38 mm Hg, depending on the eye and gender. Multivariable linear regression analysis revealed correlations between gender, spherical equivalent (right eyes), and CCT (p<.0001 and p=0.03, respectively). CONCLUSIONS: We observed positive correlations between CCT and IOP and gender. CCT was not correlated with age, contact lens wear, positive family history for glaucoma, lens status, or iris colour. PMID- 23936292 TI - Depth sensitivity and source-detector separations for near infrared spectroscopy based on the Colin27 brain template. AB - Understanding the spatial and depth sensitivity of non-invasive near-infrared spectroscopy (NIRS) measurements to brain tissue-i.e., near-infrared neuromonitoring (NIN) - is essential for designing experiments as well as interpreting research findings. However, a thorough characterization of such sensitivity in realistic head models has remained unavailable. In this study, we conducted 3,555 Monte Carlo (MC) simulations to densely cover the scalp of a well characterized, adult male template brain (Colin27). We sought to evaluate: (i) the spatial sensitivity profile of NIRS to brain tissue as a function of source detector separation, (ii) the NIRS sensitivity to brain tissue as a function of depth in this realistic and complex head model, and (iii) the effect of NIRS instrument sensitivity on detecting brain activation. We found that increasing the source-detector (SD) separation from 20 to 65 mm provides monotonic increases in sensitivity to brain tissue. For every 10 mm increase in SD separation (up to ~45 mm), sensitivity to gray matter increased an additional 4%. Our analyses also demonstrate that sensitivity in depth (S) decreases exponentially, with a "rule of-thumb" formula S=0.75*0.85(depth). Thus, while the depth sensitivity of NIRS is not strictly limited, NIN signals in adult humans are strongly biased towards the outermost 10-15 mm of intracranial space. These general results, along with the detailed quantitation of sensitivity estimates around the head, can provide detailed guidance for interpreting the likely sources of NIRS signals, as well as help NIRS investigators design and plan better NIRS experiments, head probes and instruments. PMID- 23936293 TI - HIV-1 tropism testing in subjects achieving undetectable HIV-1 RNA: diagnostic accuracy, viral evolution and compartmentalization. AB - BACKGROUND: Technically, HIV-1 tropism can be evaluated in plasma or peripheral blood mononuclear cells (PBMCs). However, only tropism testing of plasma HIV-1 has been validated as a tool to predict virological response to CCR5 antagonists in clinical trials. The preferable tropism testing strategy in subjects with undetectable HIV-1 viremia, in whom plasma tropism testing is not feasible, remains uncertain. METHODS & RESULTS: We designed a proof-of-concept study including 30 chronically HIV-1-infected individuals who achieved HIV-1 RNA <50 copies/mL during at least 2 years after first-line ART initiation. First, we determined the diagnostic accuracy of 454 and population sequencing of gp120 V3 loops in plasma and PBMCs, as well as of MT-2 assays before ART initiation. The Enhanced Sensitivity Trofile Assay (ESTA) was used as the technical reference standard. 454 sequencing of plasma viruses provided the highest agreement with ESTA. The accuracy of 454 sequencing decreased in PBMCs due to reduced specificity. Population sequencing in plasma and PBMCs was slightly less accurate than plasma 454 sequencing, being less sensitive but more specific. MT-2 assays had low sensitivity but 100% specificity. Then, we used optimized 454 sequence data to investigate viral evolution in PBMCs during viremia suppression and only found evolution of R5 viruses in one subject. No de novo CXCR4-using HIV-1 production was observed over time. Finally, Slatkin-Maddison tests suggested that plasma and cell-associated V3 forms were sometimes compartmentalized. CONCLUSIONS: The absence of tropism shifts during viremia suppression suggests that, when available, testing of stored plasma samples is generally safe and informative, provided that HIV-1 suppression is maintained. Tropism testing in PBMCs may not necessarily produce equivalent biological results to plasma, because the structure of viral populations and the diagnostic performance of tropism assays may sometimes vary between compartments. Thereby, proviral DNA tropism testing should be specifically validated in clinical trials before it can be applied to routine clinical decision-making. PMID- 23936294 TI - IL28B gene polymorphisms and US liver fatty changes in patients who spontaneously cleared hepatitis C virus infection. AB - BACKGROUND: Recent clinical studies have shown that the presence of CC genotype in the rs12979860 region of IL28B gene is associated with an increase in the probability of spontaneous clearance of hepatitis C virus (HCV). Moreover, IL28B polymorphism seems to influence the probability of developing liver steatosis in chronic HCV patients. AIMS: The aims of our clinical study were 1) to verify the distribution of IL28B genotypes (CC, CT or TT) among subjects with spontaneous clearance of HCV infection and 2) to examine the correlation between IL28B polymorphism and hepatic steatosis among these subjects. METHODS AND PATIENTS: We enrolled 41 subjects with spontaneous resolution of HCV infection (detectable serum anti-HCV but undetectable HCV-RNA) and 134 healthy controls from the same geographical area. The IL28B single-nucleotide polymorphism (SNP) rs12979860 was genotyped by using a PyrosequencingTM technique. The presence of steatosis was assessed by liver biopsy or ultrasound examination in the 41 study subjects. RESULTS: CC, CT and TT-genotypes of the SNP rs1979860 were found in 66%, 24% and 10% of the subjects who spontaneously cleared HCV and in 31%, 54% and 15% of controls, respectively (p = 0.0003). Among the study subjects, females with CC genotype were significantly more represented (p = 0.02). Hepatic steatosis did not correlate with IL28B genotype (p = 0,14) but only with a high body mass index (BMI) value (p = 0.03). CONCLUSIONS: Female subjects carrying IL28B CC-genotype are significantly more represented among Italian patients who spontaneously cleared HCV infection. In addition, among these subjects, the presence of liver steatosis does not correlate with IL28B genotype but is solely related to the occurrence of high BMI. Thus, the association between IL28B polymorphism and steatosis in chronic HCV patients requires the presence of active HCV replication to occur, while in subjects who have cleared the infection, the mechanism(s) inducing liver steatosis are independent from IL28B profile. PMID- 23936295 TI - Domestication process of the goat revealed by an analysis of the nearly complete mitochondrial protein-encoding genes. AB - Goats (Capra hircus) are one of the oldest domesticated species, and they are kept all over the world as an essential resource for meat, milk, and fiber. Although recent archeological and molecular biological studies suggested that they originated in West Asia, their domestication processes such as the timing of population expansion and the dynamics of their selection pressures are little known. With the aim of addressing these issues, the nearly complete mitochondrial protein-encoding genes were determined from East, Southeast, and South Asian populations. Our coalescent time estimations suggest that the timing of their major population expansions was in the Late Pleistocene and significantly predates the beginning of their domestication in the Neolithic era (~10,000 years ago). The omega (ratio of non-synonymous rate/synonymous substitution rate) for each lineage was also estimated. We found that the omega of the globally distributed haplogroup A which is inherited by more than 90% of goats examined, turned out to be extremely low, suggesting that they are under severe selection pressure probably due to their large population size. Conversely, the omega of the Asian-specific haplogroup B inherited by about 5% of goats was relatively high. Although recent molecular studies suggest that domestication of animals may tend to relax selective constraints, the opposite pattern observed in our goat mitochondrial genome data indicates the process of domestication is more complex than may be presently appreciated and cannot be explained only by a simple relaxation model. PMID- 23936296 TI - Placental growth factor expression is required for bone marrow endothelial cell support of primitive murine hematopoietic cells. AB - Two distinct microenvironmental niches that regulate hematopoietic stem/progenitor cell physiology in the adult bone marrow have been proposed; the endosteal and the vascular niche. While extensive studies have been performed relating to molecular interactions in the endosteal niche, the mechanisms that regulate hematopoietic stem/progenitor cell interaction with bone marrow endothelial cells are less well defined. Here we demonstrate that endothelial cells derived from the bone marrow supported hematopoietic stem/progenitor cells to a higher degree than other endothelial or stromal cell populations. This support was dependant upon placental growth factor expression, as genetic knockdown of mRNA levels reduced the ability of endothelial cells to support hematopoietic stem/progenitor cells in vitro. Furthermore, using an in vivo model of recovery from radiation induced myelosuppression, we demonstrate that bone marrow endothelial cells were able to augment the recovery of the hematopoietic stem/progenitor cells. However, this effect was diminished when the same cells with reduced placental growth factor expression were administered, possibly owing to a reduced homing of the cells to the bone marrow vasculature. Our data suggest that placental growth factor elaborated from bone marrow endothelial cells mediates the regulatory effects of the vascular niche on hematopoietic stem/progenitor cell physiology. PMID- 23936297 TI - Reliability of FEV1/FEV6 to diagnose airflow obstruction compared with FEV1/FVC: the PLATINO longitudinal study. AB - QUESTION: A 6-second spirometry test is easier than full exhalations. We compared the reliability of the ratio of the Forced expiratory volume in 1 second/Forced expiratory volume in 6 seconds (FEV1/FEV6) to the ratio of the FEV1/Forced vital capacity (FEV1/FVC) for the detection of airway obstruction. METHODS: The PLATINO population-based survey in individuals aged 40 years and over designed to estimate the prevalence of post-Bronchodilator airway obstruction repeated for the same study participants after 5-9 years in three Latin-American cities. RESULTS: Using the FEV1/FVC650 mm MAP) in South Africa that are colder and drier than most habitats in its native range. In a greenhouse experiment we tested whether its current distribution in South Africa can be explained by increased competitive ability and/or differentiation in drought tolerance relative to the native population. We compared aboveground biomass, biomass allocation, water use efficiency and relative yields of native and invasive C. odorata and the resident grass Panicum maximum in wet and dry conditions. Surprisingly, we found little differentiation between ranges. Invasive C. odorata showed no increased competitive ability or superior drought tolerance compared to native C. odorata. Moreover we found that P. maximum was a better competitor than either native or invasive C. odorata. These results imply that C. odorata is unlikely to expand its future range towards more extreme, drier, habitats beyond the limits of its current climatic niche and that the species' invasiveness most likely depends on superior light interception when temporarily released from competition by disturbance. Our study highlights the fact that species can successfully invade habitats that are at the extreme end of their ranges and thereby contributes towards a better understanding of range expansion during species invasions. PMID- 23936302 TI - Higher gravidity and parity are associated with increased prevalence of metabolic syndrome among rural Bangladeshi women. AB - BACKGROUND: Parity increases the risk for coronary heart disease; however, its association with metabolic syndrome among women in low-income countries is still unknown. OBJECTIVE: This study investigates the association between parity or gravidity and metabolic syndrome in rural Bangladeshi women. METHODS: A cross sectional study was conducted in 1,219 women aged 15-75 years from rural Bangladesh. Metabolic syndrome was defined according to the standard NCEP-ATP III criteria. Logistic regression was used to estimate the association between parity and gravidity and metabolic syndrome, with adjustment of potential confounding variables. RESULTS: Subjects with the highest gravidity (> = 4) had 1.66 times higher odds of having metabolic syndrome compared to those in the lowest gravidity (0-1) (P trend = 0.02). A similar association was found between parity and metabolic syndrome (P(trend) = 0.04), i.e., subjects in the highest parity (> = 4) had 1.65 times higher odds of having metabolic syndrome compared to those in the lowest parity (0-1). This positive association of parity and gravidity with metabolic syndrome was confined to pre-menopausal women (P(trend) <0.01). Among the components of metabolic syndrome only high blood pressure showed positive association with parity and gravidity (P(trend) = 0.01 and <0.001). Neither Parity nor gravidity was appreciably associated with other components of metabolic syndrome. CONCLUSIONS: Multi parity or gravidity may be a risk factor for metabolic syndrome. PMID- 23936303 TI - Surface acoustic waves enhance neutrophil killing of bacteria. AB - Biofilms are structured communities of bacteria that play a major role in the pathogenicity of bacteria and are the leading cause of antibiotic resistant bacterial infections on indwelling catheters and medical prosthetic devices. Failure to resolve these biofilm infections may necessitate the surgical removal of the prosthetic device which can be debilitating and costly. Recent studies have shown that application of surface acoustic waves to catheter surfaces can reduce the incidence of infections by a mechanism that has not yet been clarified. We report here the effects of surface acoustic waves (SAW) on the capacity of human neutrophils to eradicate S. epidermidis bacteria in a planktonic state and within biofilms. Utilizing a novel fibrin gel system that mimics a tissue-like environment, we show that SAW, at an intensity of 0.3 mW/cm(2), significantly enhances human neutrophil killing of S. epidermidis in a planktonic state and within biofilms by enhancing human neutrophil chemotaxis in response to chemoattractants. In addition, we show that the integrin CD18 plays a significant role in the killing enhancement observed in applying SAW. We propose from out data that this integrin may serve as mechanoreceptor for surface acoustic waves enhancing neutrophil chemotaxis and killing of bacteria. PMID- 23936304 TI - Procalcitonin guidance to reduce antibiotic treatment of lower respiratory tract infection in children and adolescents (ProPAED): a randomized controlled trial. AB - BACKGROUND: Antibiotics are overused in children and adolescents with lower respiratory tract infection (LRTI). Serum-procalcitonin (PCT) can be used to guide treatment when bacterial infection is suspected. Its role in pediatric LRTI is unclear. METHODS: Between 01/2009 and 02/2010 we randomized previously healthy patients 1 month to 18 years old presenting with LRTI to the emergency departments of two pediatric hospitals in Switzerland to receive antibiotics either according to a PCT guidance algorithm established for adult LRTI or standard care clinical guidelines. In intention-to-treat analyses, antibiotic prescribing rate, duration of antibiotic treatment, and number of days with impairment of daily activities within 14 days of randomization were compared between the two groups. RESULTS: In total 337 children, mean age 3.8 years (range 0.1-18), were included. Antibiotic prescribing rates were not significantly different in PCT guided patients compared to controls (OR 1.26; 95% CI 0.81, 1.95). Mean duration of antibiotic exposure was reduced from 6.3 to 4.5 days under PCT guidance (-1.8 days; 95% CI -3.1, -0.5; P = 0.039) for all LRTI and from 9.1 to 5.7 days for pneumonia (-3.4 days 95% CI -4.9, -1.7; P<0.001). There was no apparent difference in impairment of daily activities between PCT guided and control patients. CONCLUSION: PCT guidance reduced antibiotic exposure by reducing the duration of antibiotic treatment, while not affecting the antibiotic prescribing rate. The latter may be explained by the low baseline prescribing rate in Switzerland for pediatric LRTI and the choice of an inappropriately low PCT cut-off level for this population. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN17057980 http://www.controlled-trials.com/ISRCTN17057980. PMID- 23936305 TI - Systematic analysis and comparison of nucleotide-binding site disease resistance genes in a diploid cotton Gossypium raimondii. AB - Plant disease resistance genes are a key component of defending plants from a range of pathogens. The majority of these resistance genes belong to the super family that harbors a Nucleotide-binding site (NBS). A number of studies have focused on NBS-encoding genes in disease resistant breeding programs for diverse plants. However, little information has been reported with an emphasis on systematic analysis and comparison of NBS-encoding genes in cotton. To fill this gap of knowledge, in this study, we identified and investigated the NBS-encoding resistance genes in cotton using the whole genome sequence information of Gossypium raimondii. Totally, 355 NBS-encoding resistance genes were identified. Analyses of the conserved motifs and structural diversity showed that the most two distinct features for these genes are the high proportion of non-regular NBS genes and the high diversity of N-termini domains. Analyses of the physical locations and duplications of NBS-encoding genes showed that gene duplication of disease resistance genes could play an important role in cotton by leading to an increase in the functional diversity of the cotton NBS-encoding genes. Analyses of phylogenetic comparisons indicated that, in cotton, the NBS-encoding genes with TIR domain not only have their own evolution pattern different from those of genes without TIR domain, but also have their own species-specific pattern that differs from those of TIR genes in other plants. Analyses of the correlation between disease resistance QTL and NBS-encoding resistance genes showed that there could be more than half of the disease resistance QTL associated to the NBS encoding genes in cotton, which agrees with previous studies establishing that more than half of plant resistance genes are NBS-encoding genes. PMID- 23936306 TI - Oro-gustatory perception of dietary lipids and calcium signaling in taste bud cells are altered in nutritionally obesity-prone Psammomys obesus. AB - Since the increasing prevalence of obesity is one of the major health problems of the modern era, understanding the mechanisms of oro-gustatory detection of dietary fat is critical for the prevention and treatment of obesity. We have conducted the present study on Psammomys obesus, the rodent desert gerbil which is a unique polygenic natural animal model of obesity. Our results show that obese animals exhibit a strong preference for lipid solutions in a two-bottle test. Interestingly, the expression of CD36, a lipido-receptor, in taste buds cells (TBC), isolated from circumvallate papillae, was decreased at mRNA level, but remained unaltered at protein level, in obese animals. We further studied the effects of linoleic acid (LA), a long-chain fatty acid, on the increases in free intracellular calcium (Ca(2+)) concentrations, [Ca(2+)]i, in the TBC of P. obesus. LA induced increases in [Ca(2+)]i, largely via CD36, from intracellular pool, followed by the opening of store-operated Ca(2+) (SOC) channels in the TBC of these animals. The action of this fatty acid on the increases in [Ca(2+)]i was higher in obese animals than that in controls. However, the release of Ca(2+) from intracellular stores, studied also by employing thapsigargin, was lower in TBC of obese animals than control rodents. In this study, we show, for the first time, that increased lipid intake and altered Ca(2+) signaling in TBC are associated with obesity in Psammomys obesus. PMID- 23936307 TI - Clustered DNA lesions containing 5-formyluracil and AP site: repair via the BER system. AB - Lesions in the DNA arise under ionizing irradiation conditions or various chemical oxidants as a single damage or as part of a multiply damaged site within 1-2 helical turns (clustered lesion). Here, we explored the repair opportunity of the apurinic/apyrimidinic site (AP site) composed of the clustered lesion with 5 formyluracil (5-foU) by the base excision repair (BER) proteins. We found, that if the AP site is shifted relative to the 5-foU of the opposite strand, it could be repaired primarily via the short-patch BER pathway. In this case, the cleavage efficiency of the AP site-containing DNA strand catalyzed by human apurinic/apyrimidinic endonuclease 1 (hAPE1) decreased under AP site excursion to the 3'-side relative to the lesion in the other DNA strand. DNA synthesis catalyzed by DNA polymerase lambda was more accurate in comparison to the one catalyzed by DNA polymerase beta. If the AP site was located exactly opposite 5 foU it was expected to switch the repair to the long-patch BER pathway. In this situation, human processivity factor hPCNA stimulates the process. PMID- 23936308 TI - Error correcting mechanisms during antisaccades: contribution of online control during primary saccades and offline control via secondary saccades. AB - Errors in eye movements can be corrected during the ongoing saccade through in flight modifications (i.e., online control), or by programming a secondary eye movement (i.e., offline control). In a reflexive saccade task, the oculomotor system can use extraretinal information (i.e., efference copy) online to correct errors in the primary saccade, and offline retinal information to generate a secondary corrective saccade. The purpose of this study was to examine the error correction mechanisms in the antisaccade task. The roles of extraretinal and retinal feedback in maintaining eye movement accuracy were investigated by presenting visual feedback at the spatial goal of the antisaccade. We found that online control for antisaccade is not affected by the presence of visual feedback; that is whether visual feedback is present or not, the duration of the deceleration interval was extended and significantly correlated with reduced antisaccade endpoint error. We postulate that the extended duration of deceleration is a feature of online control during volitional saccades to improve their endpoint accuracy. We found that secondary saccades were generated more frequently in the antisaccade task compared to the reflexive saccade task. Furthermore, we found evidence for a greater contribution from extraretinal sources of feedback in programming the secondary "corrective" saccades in the antisaccade task. Nonetheless, secondary saccades were more corrective for the remaining antisaccade amplitude error in the presence of visual feedback of the target. Taken together, our results reveal a distinctive online error control strategy through an extension of the deceleration interval in the antisaccade task. Target feedback does not improve online control, rather it improves the accuracy of secondary saccades in the antisaccade task. PMID- 23936309 TI - Optimized position weight matrices in prediction of novel putative binding sites for transcription factors in the Drosophila melanogaster genome. AB - Position weight matrices (PWMs) have become a tool of choice for the identification of transcription factor binding sites in DNA sequences. DNA binding proteins often show degeneracy in their binding requirement and thus the overall binding specificity of many proteins is unknown and remains an active area of research. Although existing PWMs are more reliable predictors than consensus string matching, they generally result in a high number of false positive hits. Our previous study introduced a promising approach to PWM refinement in which known motifs are used to computationally mine putative binding sites directly from aligned promoter regions using composition of similar sites. In the present study, we extended this technique originally tested on single examples of transcription factors (TFs) and showed its capability to optimize PWM performance to predict new binding sites in the fruit fly genome. We propose refined PWMs in mono- and dinucleotide versions similarly computed for a large variety of transcription factors of Drosophila melanogaster. Along with the addition of many auxiliary sites the optimization includes variation of the PWM motif length, the binding sites location on the promoters and the PWM score threshold. To assess the predictive performance of the refined PWMs we compared them to conventional TRANSFAC and JASPAR sources. The results have been verified using performed tests and literature review. Overall, the refined PWMs containing putative sites derived from real promoter content processed using optimized parameters had better general accuracy than conventional PWMs. PMID- 23936310 TI - The new comorbidity index for predicting survival in elderly dialysis patients: a long-term population-based study. AB - BACKGROUND: The worldwide elderly (>= 65 years old) dialysis population has grown significantly. This population is expected to have more comorbid conditions and shorter life expectancies than the general elderly population. Predicting outcomes for this population is important for decision-making. Recently, a new comorbidity index (nCI) with good predictive value for patient outcomes was developed and validated in chronic dialysis patients regardless of age. Our study examined the nCI outcome predictability in elderly dialysis patients. METHODS AND FINDINGS: For this population-based cohort study, we used Taiwan's National Health Insurance Research Database of enrolled elderly patients, who began maintenance dialysis between January 1999 and December 2005. A total of 21,043 incident dialysis patients were divided into 4 groups by nCI score (intervals <= 3, 4-6, 7-9, >= 10) and followed nearly for 10 years. All-cause mortality and life expectancy were analyzed. During the follow-up period, 11272 (53.55%) patients died. Kaplan-Meier curves showed significant group difference in survival (log-rank: P<0.001). After stratification by age, life expectancy was found to be significantly longer in groups with lower nCI scores. CONCLUSION: The nCI, even without the age component, is a strong predictor of mortality in elderly dialysis patients. Because patients with lower nCI scores may predict better survival, more attention should paid to adequate dialysis rather than palliative care, especially in those without obvious functional impairments. PMID- 23936311 TI - Is the species flock concept operational? The Antarctic shelf case. AB - There has been a significant body of literature on species flock definition but not so much about practical means to appraise them. We here apply the five criteria of Eastman and McCune for detecting species flocks in four taxonomic components of the benthic fauna of the Antarctic shelf: teleost fishes, crinoids (feather stars), echinoids (sea urchins) and crustacean arthropods. Practical limitations led us to prioritize the three historical criteria (endemicity, monophyly, species richness) over the two ecological ones (ecological diversity and habitat dominance). We propose a new protocol which includes an iterative fine-tuning of the monophyly and endemicity criteria in order to discover unsuspected flocks. As a result nine " full " species flocks (fulfilling the five criteria) are briefly described. Eight other flocks fit the three historical criteria but need to be further investigated from the ecological point of view (here called "core flocks"). The approach also shows that some candidate taxonomic components are no species flocks at all. The present study contradicts the paradigm that marine species flocks are rare. The hypothesis according to which the Antarctic shelf acts as a species flocks generator is supported, and the approach indicates paths for further ecological studies and may serve as a starting point to investigate the processes leading to flock-like patterning of biodiversity. PMID- 23936312 TI - WT1 promotes cell proliferation in non-small cell lung cancer cell lines through up-regulating cyclin D1 and p-pRb in vitro and in vivo. AB - The Wilms' tumor suppressor gene (WT1) has been identified as an oncogene in many malignant diseases such as leukaemia, breast cancer, mesothelioma and lung cancer. However, the role of WT1 in non-small-cell lung cancer (NSCLC) carcinogenesis remains unclear. In this study, we compared WT1 mRNA levels in NSCLC tissues with paired corresponding adjacent tissues and identified significantly higher expression in NSCLC specimens. Cell proliferation of three NSCLC cell lines positively correlated with WT1 expression; moreover, these associations were identified in both cell lines and a xenograft mouse model. Furthermore, we demonstrated that up-regulation of Cyclin D1 and the phosphorylated retinoblastoma protein (p-pRb) was mechanistically related to WT1 accelerating cells to S-phase. In conclusion, our findings demonstrated that WT1 is an oncogene and promotes NSCLC cell proliferation by up-regulating Cyclin D1 and p-pRb expression. PMID- 23936313 TI - The effect of hydraulic loading rate and influent source on the binding capacity of phosphorus filters. AB - Sorption by active filter media can be a convenient option for phosphorus (P) removal and recovery from wastewater for on-site treatment systems. There is a need for a robust laboratory method for the investigation of filter materials to enable a reliable estimation of their longevity. The objectives of this study were to (1) investigate and (2) quantify the effect of hydraulic loading rate and influent source (secondary wastewater and synthetic phosphate solution) on P binding capacity determined in laboratory column tests and (3) to study how much time is needed for the P to react with the filter material (reaction time). To study the effects of these factors, a 2(2) factorial experiment with 11 filter columns was performed. The reaction time was studied in a batch experiment. Both factors significantly (alpha = 0.05) affected the P binding capacity negatively, but the interaction of the two factors was not significant. Increasing the loading rate from 100 to 1200 L m(-2) d(-1) decreased P binding capacity from 1.152 to 0.070 g kg(-1) for wastewater filters and from 1.382 to 0.300 g kg(-1) for phosphate solution filters. At a loading rate of 100 L m(-2) d(-1), the average P binding capacity of wastewater filters was 1.152 g kg(-1) as opposed to 1.382 g kg(-1) for phosphate solution filters. Therefore, influent source or hydraulic loading rate should be carefully controlled in the laboratory. When phosphate solution and wastewater were used, the reaction times for the filters to remove P were determined to be 5 and 15 minutes, respectively, suggesting that a short residence time is required. However, breakthrough in this study occurred unexpectedly quickly, implying that more time is needed for the P that has reacted to be physically retained in the filter. PMID- 23936314 TI - Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure. AB - These studies define a new mechanism-based approach to radiosensitize tumor cure by single dose radiotherapy (SDRT). Published evidence indicates that SDRT induces acute microvascular endothelial apoptosis initiated via acid sphingomyelinase (ASMase) translocation to the external plasma membrane. Ensuing microvascular damage regulates radiation lethality of tumor stem cell clonogens to effect tumor cure. Based on this biology, we engineered an ASMase-producing vector consisting of a modified pre-proendothelin-1 promoter, PPE1(3x), and a hypoxia-inducible dual-binding HIF-2alpha-Ets-1 enhancer element upstream of the asmase gene, inserted into a replication-deficient adenovirus yielding the vector Ad5H2E-PPE1(3x)-ASMase. This vector confers ASMase over-expression in cycling angiogenic endothelium in vitro and within tumors in vivo, with no detectable enhancement in endothelium of normal tissues that exhibit a minute fraction of cycling cells or in non-endothelial tumor or normal tissue cells. Intravenous pretreatment with Ad5H2E-PPE1(3x)-ASMase markedly increases SDRT cure of inherently radiosensitive MCA/129 fibrosarcomas, and converts radiation-incurable B16 melanomas into biopsy-proven tumor cures. In contrast, Ad5H2E-PPE1(3x)-ASMase treatment did not impact radiation damage to small intestinal crypts as non dividing small intestinal microvessels did not overexpress ASMase and were not radiosensitized. We posit that combination of genetic up-regulation of tumor microvascular ASMase and SDRT provides therapeutic options for currently radiation-incurable human tumors. PMID- 23936315 TI - Electroporation-based treatment planning for deep-seated tumors based on automatic liver segmentation of MRI images. AB - Electroporation is the phenomenon that occurs when a cell is exposed to a high electric field, which causes transient cell membrane permeabilization. A paramount electroporation-based application is electrochemotherapy, which is performed by delivering high-voltage electric pulses that enable the chemotherapeutic drug to more effectively destroy the tumor cells. Electrochemotherapy can be used for treating deep-seated metastases (e.g. in the liver, bone, brain, soft tissue) using variable-geometry long-needle electrodes. To treat deep-seated tumors, patient-specific treatment planning of the electroporation-based treatment is required. Treatment planning is based on generating a 3D model of the organ and target tissue subject to electroporation (i.e. tumor nodules). The generation of the 3D model is done by segmentation algorithms. We implemented and evaluated three automatic liver segmentation algorithms: region growing, adaptive threshold, and active contours (snakes). The algorithms were optimized using a seven-case dataset manually segmented by the radiologist as a training set, and finally validated using an additional four case dataset that was previously not included in the optimization dataset. The presented results demonstrate that patient's medical images that were not included in the training set can be successfully segmented using our three algorithms. Besides electroporation-based treatments, these algorithms can be used in applications where automatic liver segmentation is required. PMID- 23936316 TI - Evaluation of nutritional and antioxidant status of Lepidium latifolium Linn.: a novel phytofood from Ladakh. AB - Lepidium latifolium Linn. (perennial pepperweed) is one of the preferred phytofoods among cold arid region of Ladakh, India and its leaves contribute significantly to people's diet. This study was conducted to determine its nutritive value and antioxidant activity. Plant samples from three different locations were selected in the present study. Results showed that this plant is an excellent source of glucosinolates, notably sinigrin that is present in very high amount (~70-90%). Its value ranged from 149 to 199 ug per g fresh weight. Fatty acid composition analysis showed that its leaves were abundant in unsaturated fatty acids, specifically linolenic acid (18?3) whose percentage is about 50%. Higher glucose and crude protein along with higher nitrogen to sulfur ratio, supplements the nutritive value of this plant. Based on total phenol, flavanoids, free radical scavenging activity and DNA protective activity showed that this ecotype of perennial pepperweed contains high antioxidant properties. The percentage inhibition for O2(-) scavenging activity ranged from 41.3% to 83.9%. Higher content of phenols (26.89 to 50.51 mg gallic acid equivalents per g dry weight) and flavanoids (38.66 to 76.00 mg quercetin equivalents per g dry weight) in leaves could be responsible for the free radical scavenging activity of this plant. Depending upon the location of the plants, variations were observed in different activities. Based on the systematic evaluation in this study, preparations of Lepidium latifolium from Ladakh can be promoted as substitute to dietary requirements. PMID- 23936317 TI - Nuclear translocation of B-cell-specific transcription factor, BACH2, modulates ROS mediated cytotoxic responses in mantle cell lymphoma. AB - BACH2, a B-cell specific transcription factor, plays a critical role in oxidative stress-mediated apoptosis. Bortezomib (Velcade(TM)) is widely used to treat relapsed mantle cell lymphoma (MCL) patients despite varying clinical outcomes. As one of the potential mechanisms of action, bortezomib was reported to elicit endoplasmic reticulum (ER) stress which triggers reactive oxygen species (ROS). In the present study, we investigated the redox-sensitive intracellular mechanism that might play a critical role in bortezomib response in MCL cells. We demonstrated that in MCL cells that are sensitive to bortezomib treatments, BACH2 was translocated to the nucleus in response to bortezomib and induced apoptotic responses through the modulation of anti-oxidative and anti-apoptotic genes. On the other hand, in bortezomib resistant cells, BACH2 expression was confined in the cytoplasm and no suppression of antiapoptotic or antioxidative genes, Nrf2, Gss, CAT, HO-1 and MCL1, was detected. Importantly, levels of BACH2 were significantly higher in bortezomib sensitive MCL patient cells, indicating that BACH2 levels could be an indicator for clinical bortezomib responses. BACH2 translocation to the cytoplasm after phosphorylation was inhibited by PI3K inhibitors and combinatory regimens of bortezomib and PI3K inhibitors sensitized MCL cells to bortezomib. These data suggest that cellular distribution of BACH2 in response to ROS determines the threshold for the induction of apoptosis. Therapies that inhibit BACH2 phosphorylation could be the key for increasing bortezomib cytotoxic response in patients. PMID- 23936318 TI - Gene network analysis of candidate loci for human anorectal malformations. AB - Anorectal malformations (ARMs) are birth defects that require surgery and carry significant chronic morbidity. Our earlier genome-wide copy number variation (CNV) study had provided a wealth of candidate loci. To find out whether these candidate loci are related to important developmental pathways, we have performed an extensive literature search coupled with the currently available bioinformatics tools. This has allowed us to assign both genic and non-genic CNVs to interrelated pathways known to govern the development of the anorectal region. We have linked 11 candidate genes to the WNT signalling pathway and 17 genes to the cytoskeletal network. Interestingly, candidate genes with similar functions are disrupted by the same type of CNV. The gene network we discovered provides evidence that rare mutations in different interrelated genes may lead to similar phenotypes, accounting for genetic heterogeneity in ARMs. Classification of patients according to the affected pathway and lesion type should eventually improve the diagnosis and the identification of common genes/molecules as therapeutic targets. PMID- 23936319 TI - Expression of human Gaucher disease gene GBA generates neurodevelopmental defects and ER stress in Drosophila eye. AB - Gaucher disease (GD) is the most common of the lysosomal storage disorders and is caused by defects in the GBA gene encoding glucocerebrosidase (GlcCerase). The accumulation of its substrate, glucocylceramide (GlcCer) is considered the main cause of GD. We found here that the expression of human mutated GlcCerase gene (hGBA) that is associated with neuronopathy in GD patients causes neurodevelopmental defects in Drosophila eyes. The data indicate that endoplasmic reticulum (ER) stress was elevated in Drosophila eye carrying mutated hGBAs by using of the ER stress markers dXBP1 and dBiP. We also found that Ambroxol, a potential pharmacological chaperone for mutated hGBAs, can alleviate the neuronopathic phenotype through reducing ER stress. We demonstrate a novel mechanism of neurodevelopmental defects mediated by ER stress through expression of mutants of human GBA gene in the eye of Drosophila. PMID- 23936320 TI - Characterization of microRNA expression profiles and the discovery of novel microRNAs involved in cancer during human embryonic development. AB - MicroRNAs (miRNAs), approximately 22-nucleotide non-coding RNA molecules, regulate a variety of pivotal physiological or pathological processes, including embryonic development and tumorigenesis. To obtain comprehensive expression profiles of miRNAs in human embryos, we characterized miRNA expression in weeks 4 6 of human embryonic development using miRNA microarrays and identified 50 human embryo-specific miRNAs (HES-miRNAs). Furthermore, we selected three non-conserved or primate-specific miRNAs, hsa-miR-638, -720, and -1280, and examined their expression levels in various normal and tumor tissues. The results show that expression of most miRNAs is extremely low during early human embryonic development. In addition, the expression of some non-conserved or primate specific miRNAs is significantly different between tumor and the corresponding normal tissue samples, suggesting that the miRNAs are closely related to the pathological processes of various tumors. This study presents the first comprehensive overview of miRNA expression during human embryonic development and offers immediate evidence of the relationship between human early embryonic development and tumorigenesis. PMID- 23936321 TI - Impairment of neuronal glutamate uptake and modulation of the glutamate transporter GLT-1 induced by retinal ischemia. AB - Excitotoxicity has been implicated in the retinal neuronal loss in several ocular pathologies including glaucoma. Dysfunction of Excitatory Amino Acid Transporters is often a key component of the cascade leading to excitotoxic cell death. In the retina, glutamate transport is mainly operated by the glial glutamate transporter GLAST and the neuronal transporter GLT-1. In this study we evaluated the expression of GLAST and GLT-1 in a rat model of acute glaucoma based on the transient increase of intraocular pressure (IOP) and characterized by high glutamate levels during the reperfusion that follows the ischemic event associated with raised IOP. No changes were reported in GLAST expression while, at neuronal level, a reduction of glutamate uptake and of transporter reversal mediated glutamate release was observed in isolated retinal synaptosomes. This was accompanied by modulation of GLT-1 expression leading to the reduction of the canonical 65 kDa form and upregulation of a GLT-1-related 38 kDa protein. These results support a role for neuronal transporters in glutamate accumulation observed in the retina following an ischemic event and suggest the presence of a GLT-1 neuronal new alternative splice variant, induced in response to the detrimental stimulus. PMID- 23936322 TI - Anti-inflammatory effects of adult stem cells in sustained lung injury: a comparative study. AB - Lung diseases are a major cause of global morbidity and mortality that are treated with limited efficacy. Recently stem cell therapies have been shown to effectively treat animal models of lung disease. However, there are limitations to the translation of these cell therapies to clinical disease. Studies have shown that delayed treatment of animal models does not improve outcomes and that the models do not reflect the repeated injury that is present in most lung diseases. We tested the efficacy of amnion mesenchymal stem cells (AM-MSC), bone marrow MSC (BM-MSC) and human amniotic epithelial cells (hAEC) in C57BL/6 mice using a repeat dose bleomycin-induced model of lung injury that better reflects the repeat injury seen in lung diseases. The dual bleomycin dose led to significantly higher levels of inflammation and fibrosis in the mouse lung compared to a single bleomycin dose. Intravenously infused stem cells were present in the lung in similar numbers at days 7 and 21 post cell injection. In addition, stem cell injection resulted in a significant decrease in inflammatory cell infiltrate and a reduction in IL-1 (AM-MSC), IL-6 (AM-MSC, BM-MSC, hAEC) and TNF-alpha (AM-MSC). The only trophic factor tested that increased following stem cell injection was IL-1RA (AM-MSC). IL-1RA levels may be modulated by GM-CSF produced by AM-MSC. Furthermore, only AM-MSC reduced collagen deposition and increased MMP-9 activity in the lung although there was a reduction of the pro fibrogenic cytokine TGF-beta following BM-MSC, AM-MSC and hAEC treatment. Therefore, AM-MSC may be more effective in reducing injury following delayed injection in the setting of repeated lung injury. PMID- 23936323 TI - A strategy to model nonmonotonic dose-response curve and estimate IC50. AB - The half-maximal inhibitory concentration IC[Formula: see text] is an important pharmacodynamic index of drug effectiveness. To estimate this value, the dose response relationship needs to be established, which is generally achieved by fitting monotonic sigmoidal models. However, recent studies on Human Immunodeficiency Virus (HIV) mutants developing resistance to antiviral drugs show that the dose response curve may not be monotonic. Traditional models can fail for nonmonotonic data and ignore observations that may be of biologic significance. Therefore, we propose a nonparametric model to describe the dose response relationship and fit the curve using local polynomial regression. The nonparametric approach is shown to be promising especially for estimating the IC[Formula: see text] of some HIV inhibitory drugs, in which there is a dose dependent stimulation of response for mutant strains. This model strategy may be applicable to general pharmacologic, toxicologic, or other biomedical data that exhibits a nonmonotonic dose response relationship for which traditional parametric models fail. PMID- 23936324 TI - Fossil mice and rats show isotopic evidence of niche partitioning and change in dental ecomorphology related to dietary shift in Late Miocene of Pakistan. AB - Stable carbon isotope analysis in tooth enamel is a well-established approach to infer C3 and C4 dietary composition in fossil mammals. The bulk of past work has been conducted on large herbivorous mammals. One important finding is that their dietary habits of fossil large mammals track the late Miocene ecological shift from C3 forest and woodland to C4 savannah. However, few studies on carbon isotopes of fossil small mammals exist due to limitations imposed by the size of rodent teeth, and the isotopic ecological and dietary behaviors of small mammals to climate change remain unknown. Here we evaluate the impact of ecological change on small mammals by fine-scale comparisons of carbon isotope ratios (delta(13)C) with dental morphology of murine rodents, spanning 13.8 to ~2.0 Ma, across the C3 to C4 vegetation shift in the Miocene Siwalik sequence of Pakistan. We applied in-situ laser ablation GC-IRMS to lower first molars and measured two grazing indices on upper first molars. Murine rodents yield a distinct, but related, record of past ecological conditions from large herbivorous mammals, reflecting available foods in their much smaller home ranges. In general, larger murine species show more positive delta(13)C values and have higher grazing indices than smaller species inhabiting the same area at any given age. Two clades of murine rodents experienced different rates of morphological change. In the faster-evolving clade, the timing and trend of morphological innovations are closely tied to consumption of C4 diet during the vegetation shift. This study provides quantitative evidence of linkages among diet, niche partitioning, and dental morphology at a more detailed level than previously possible. PMID- 23936325 TI - The hymenopteran tree of life: evidence from protein-coding genes and objectively aligned ribosomal data. AB - Previous molecular analyses of higher hymenopteran relationships have largely been based on subjectively aligned ribosomal sequences (18S and 28S). Here, we reanalyze the 18S and 28S data (unaligned about 4.4 kb) using an objective and a semi-objective alignment approach, based on MAFFT and BAli-Phy, respectively. Furthermore, we present the first analyses of a substantial protein-coding data set (4.6 kb from one mitochondrial and four nuclear genes). Our results indicate that previous studies may have suffered from inflated support values due to subjective alignment of the ribosomal sequences, but apparently not from significant biases. The protein data provide independent confirmation of several earlier results, including the monophyly of non-xyelid hymenopterans, Pamphilioidea + Unicalcarida, Unicalcarida, Vespina, Apocrita, Proctotrupomorpha and core Proctotrupomorpha. The protein data confirm that Aculeata are nested within a paraphyletic Evaniomorpha, but cast doubt on the monophyly of Evanioidea. Combining the available morphological, ribosomal and protein-coding data, we examine the total-evidence signal as well as congruence and conflict among the three data sources. Despite an emerging consensus on many higher-level hymenopteran relationships, several problems remain unresolved or contentious, including rooting of the hymenopteran tree, relationships of the woodwasps, placement of Stephanoidea and Ceraphronoidea, and the sister group of Aculeata. PMID- 23936326 TI - Osteology of Huabeisaurus allocotus (Sauropoda: Titanosauriformes) from the Upper Cretaceous of China. AB - BACKGROUND: The Late Cretaceous titanosauriform sauropod Huabeisaurus allocotus Pang and Cheng is known from teeth and much of the postcranial skeleton. Its completeness makes it an important taxon for integrating and interpreting anatomical observations from more fragmentary Cretaceous East Asian sauropods and for understanding titanosauriform evolution in general. METHODOLOGY/PRINCIPAL FINDINGS: We present a detailed redescription of Huabeisaurus allocotus and a suite of anatomical comparisons with other titanosauriforms that demonstrate its validity via autapomorphies (e.g., division of some presacral vertebral laminae, reduced development of caudal ribs, the development of fossae relative to one another in caudal vertebral neural arches, high tibia-to-femur ratio). Huabeisaurus shares many features with other Cretaceous East Asian sauropods (e.g., pendant cervical ribs, anterior-middle caudal vertebrae with a nearly flat anterior centrum face and a concave posterior centrum face) that are absent in sauropods from other landmasses and strata, suggesting a close relationship among many of these forms within the clade Somphospondyli. CONCLUSIONS/SIGNIFICANCE: Restudy of Huabeisaurus provides further evidence for the existence of a clade of somphospondylans--Euhelopodidae--mainly found in the Cretaceous of East Asia. Euhelopodidae represents a fourth example of the evolution of narrow crowns within Sauropoda, along with diplodocoids, brachiosaurids, and advanced titanosaurs (lithostrotians). Despite being known from fewer species than Diplodocoidea, Brachiosauridae, or Lithostrotia, euhelopodids possessed a broader range of tooth shapes than any of these clades, suggesting that euhelopodids exemplified a comparably broad range of feeding strategies and perhaps diets. PMID- 23936327 TI - Relevance of distinct monocyte subsets to clinical course of ischemic stroke patients. AB - BACKGROUND AND PURPOSE: The most common strategy for treating patients with acute ischemic stroke is thrombolytic therapy, though only a few patients receive benefits because of the narrow time window. Inflammation occurring in the central nervous system (CNS) in association with ischemia is caused by immune cells including monocytes and involved in lesion expansion. If the specific roles of monocyte subsets in stroke can be revealed, they may become an effective target for new treatment strategies. METHODS: We performed immunological examinations of 36 consecutive ischemic stroke patients within 2 days of onset and compared the results with 24 age-matched patients with degenerative disorders. The stroke patients were repeatedly tested for the proportions of monocyte subsets in blood, and serum levels of pro- and anti-inflammatory cytokines immediately after admission, on days 3-7 and 12-16 after stroke onset, and on the day of discharge. In addition, immunological measurements were analyzed for relationships to stroke subtypes and complications, including progressive infarction (PI) and stroke associated infection (SAI). RESULTS: Monocyte count was significantly increased from 0-16 days after stroke as compared to the controls (p<0.05). CD14(high)CD16( ) classical and CD14(high)CD16(+) intermediate monocytes were significantly increased from 0-7 and 3-16 days after stroke, respectively (p<0.05), whereas CD14 (dim)CD16(high) non-classical monocytes were decreased from 0-7 days (p<0.05). Cardioembolic infarction was associated with a persistent increase in intermediate monocytes. Furthermore, intermediate monocytes were significantly increased in patients with PI (p<0.05), while non-classical monocytes were decreased in those with SAI (p<0.05). IL-17A levels were positively correlated with monocyte count (r=0.485, p=0.012) as well as the percentage of non-classical monocytes (r=0.423, p=0.028), and negatively with that of classical monocytes (r= 0.51, p=0.007) during days 12-16. CONCLUSIONS: Our findings suggest that CD14(high)CD16(+) intermediate monocytes have a role in CNS tissue damage during acute and subacute phases in ischemic stroke especially in relation to cardioembolism. PMID- 23936328 TI - Involvement of MAPK/NF-kappaB signaling in the activation of the cholinergic anti inflammatory pathway in experimental colitis by chronic vagus nerve stimulation. AB - BACKGROUND: Autonomic nervous system dysfunction is implicated in the etiopathogenesis of inflammatory bowel diseases (IBD). Therapies that increase cardiovagal activity, such as Mind-Body interventions, are currently confirmed to be effective in clinical trials in IBD. However, a poor understanding of pathophysiological mechanisms limits the popularization of therapies in clinical practice. The aim of the present study was to explore the mechanisms of these therapies against 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats using a chronic vagus nerve stimulation model in vivo, as well as the lipopolysaccharide (LPS)-induced inflammatory response in human epithelial colorectal adenocarcinoma cells (Caco-2) by acetylcholine in vitro. METHODS AND RESULTS: Colitis was induced in rats with rectal instillation of TNBS, and the effect of chronic VNS (0.25 mA, 20 Hz, 500 ms) on colonic inflammation was evaluated. Inflammatory responses were assessed by disease activity index (DAI), histological scores, myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS), TNF-alpha and IL-6 production. The expression of Mitogen activated protein kinases (MAPK) family members, IkappaB-alpha, and nuclear NF kappaB p65 were studied by immunoblotting. Heart rate variability (HRV) analysis was also applied to assess the sympathetic-vagal balance. DAI, histological scores, MPO activity, iNOS, TNF-alpha and IL-6 levels were significantly decreased by chronic VNS. Moreover, both VNS and acetylcholine reduced the phosphorylation of MAPKs and prevented the nuclear translocation of NF-kappaB p65. Methyllycaconitine (MLA) only reversed the inhibitory effect on p-ERK and intranuclear NF-kappaB p65 expression by ACh in vitro, no significant change was observed in the expression of p-p38 MAPK or p-JNK by MLA. CONCLUSION: Vagal activity modification contributes to the beneficial effects of the cholinergic anti-inflammatory pathway in IBD-related inflamed colonic mucosa based on the activation of MAPKs and nuclear translocation of NF-kappaB. Our work may provide key pathophysiological mechanistic evidence for novel therapeutic strategies that increase the cardiovagal activity in IBD patients. PMID- 23936329 TI - Optimization of substituted 6-salicyl-4-anilinoquinazoline derivatives as dual EGFR/HER2 tyrosine kinase inhibitors. AB - 4-Anilinoquinazolines as an important class of protein kinase inhibitor are widely investigated for epidermal growth factor receptor (EGFR) tyrosine kinase or epidermal growth factor receptor 2 (HER2) inhibition. A series of novel 6 salicyl-4-anilinoquinazoline derivatives 9-27 were prepared and evaluated for their EGFR/HER2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on three variant cancer cell lines (A431, MCF-7, and A549). The bioassay results showed most of the designed compounds exhibited moderate to potent in vitro inhibitory activity in the enzymatic and cellular assays, of which compound 21 revealed the most potent dual EGFR/HER2 inhibitory activity, with IC50 values of 0.12 uM and 0.096 uM, respectively, comparable to the control compounds Erlotinib and Lapatinib. Furthermore, the kinase selectivity profile of 21 was accessed and demonstrated its good selectivity over the majority of the close kinase targets. Docking simulation was performed to position compound 21 into the EGFR/HER2 active site to determine the probable binding pose. These new findings along with molecular docking observations could provide an important basis for further development of compound 21 as a potent EGFR/HER2 dual kinase inhibitor. PMID- 23936330 TI - RNA-Seq reveals dynamic changes of gene expression in key stages of intestine regeneration in the sea cucumber Apostichopus japonicus. [corrected]. AB - BACKGROUND: Sea cucumbers (Holothuroidea; Echinodermata) have the capacity to regenerate lost tissues and organs. Although the histological and cytological aspects of intestine regeneration have been extensively studied, little is known of the genetic mechanisms involved. There has, however, been a renewed effort to develop a database of Expressed Sequence Tags (ESTs) in Apostichopus japonicus, an economically-important species that occurs in China. This is important for studies on genetic breeding, molecular markers and special physiological phenomena. We have also constructed a library of ESTs obtained from the regenerative body wall and intestine of A. japonicus. The database has increased to ~30000 ESTs. RESULTS: We used RNA-Seq to determine gene expression profiles associated with intestinal regeneration in A. japonicus at 3, 7, 14 and 21 days post evisceration (dpe). This was compared to profiles obtained from a normally functioning intestine. Approximately 5 million (M) reads were sequenced in every library. Over 2400 up-regulated genes (>10%) and over 1000 down-regulated genes (~5%) were observed at 3 and 7dpe (log2Ratio >= 1, FDR <= 0.001). Specific "Go terms" revealed that the DEGs (Differentially Expressed Genes) performed an important function at every regeneration stage. Besides some expected pathways (for example, Ribosome and Spliceosome pathway term), the "Notch signaling pathway," the "ECM-receptor interaction" and the "Cytokine-cytokine receptor interaction" were significantly enriched. We also investigated the expression profiles of developmental genes, ECM-associated genes and Cytoskeletal genes. Twenty of the most important differentially expressed genes (DEGs) were verified by Real-time PCR, which resulted in a trend concordance of almost 100% between the two techniques. CONCLUSION: Our studies demonstrated dynamic changes in global gene expression during intestine regeneration and presented a series of candidate genes and enriched pathways that contribute to intestine regeneration in sea cucumbers. This provides a foundation for future studies on the genetics/molecular mechanisms associated with intestine regeneration. PMID- 23936331 TI - Assessment of urinary betaine as a marker of diabetes mellitus in cardiovascular patients. AB - Abnormal urinary excretion of betaine has been demonstrated in patients with diabetes or metabolic syndrome. We aimed to identify the main predictors of excretion in cardiovascular patients and to make initial assessment of its feasibility as a risk marker of future diabetes development. We used data from 2396 patients participating in the Western Norway B-vitamin Intervention Trial, who delivered urine and blood samples at baseline, and in the majority at two visits during follow-up of median 39 months. Betaine in urine and plasma were measured by liquid-chromatography-tandem mass spectrometry. The strongest determinants of urinary betaine excretion by multiple regression were diabetes mellitus, age and estimated glomerular filtration rate; all p<0.001. Patients with diabetes mellitus (n = 264) had a median excretion more than three times higher than those without. We found a distinct non-linear association between urinary betaine excretion and glycated hemoglobin, with a break-point at 6.5%, and glycated hemoglobin was the strongest determinant of betaine excretion in patients with diabetes mellitus. The discriminatory power for diabetes mellitus corresponded to an area under the curve by receiver-operating characteristics of 0.82, and betaine excretion had a coefficient of reliability of 0.73. We also found a significant, independent log-linear relation between baseline betaine excretion and the risk of developing new diabetes during follow-up. The good discriminatory power for diabetes, high test-retest stability and independent association with future risk of new diabetes should motivate further investigation on the role of betaine excretion in risk assessment and long-term follow-up of diabetes mellitus. PMID- 23936332 TI - Substrate-dependent assembly of the Tat translocase as observed in live Escherichia coli cells. AB - The twin-arginine translocation (Tat) pathway guides fully folded proteins across membranes of bacteria, archaea and plant chloroplasts. In Escherichia coli, Tat specific transport is executed in a still largely unknown manner by three functionally diverse membrane proteins, termed TatA, TatB, and TatC. In order to follow the intracellular distribution of the TatABC proteins in live E. coli cells, we have individually expressed fluorophore-tagged versions of each Tat protein in addition to a set of chromosomally encoded TatABC proteins. In this way, a Tat translocase could form from the native TatABC proteins and be visualized via the association of a fluorescent Tat variant. A functionally active TatA-green fluorescent protein fusion was found to re-locate from a uniform distribution in the membrane into a few clusters preferentially located at the cell poles. Clustering was absolutely dependent on the co-expression of functional Tat substrates, the proton-motive force, and the cognate TatBC subunits. Likewise, polar cluster formation of a functional TatB-mCherry fusion required TatA and TatC and that of a functional TatC-mCherry fusion a functional Tat substrate. Furthermore we directly demonstrate the co-localization of TatA and TatB in the same fluorescent clusters. Our collective results are consistent with distinct Tat translocation sites dynamically forming in vivo in response to newly synthesized Tat substrates. PMID- 23936333 TI - Endothelium dependent vasomotion and in vitro markers of endothelial repair in patients with severe sepsis: an observational study. AB - BACKGROUND: Outcome in sepsis is mainly defined by the degree of organ failure, for which endothelial dysfunction at the macro- and microvascular level is an important determinant. In this study we evaluated endothelial function in patients with severe sepsis using cellular endothelial markers and in vivo assessment of reactive hyperaemia. MATERIALS AND METHODS: Patients with severe sepsis (n = 30) and 15 age- and gender- matched healthy volunteers were included in this study. Using flow cytometry, CD34+/KDR+ endothelial progenitor cells (EPC), CD31+ T-cells, and CD31+/CD42b- endothelial microparticles (EMP) were enumerated. Migratory capacity of cultured circulating angiogenic cells (CAC) was assessed in vitro. Endothelial function was determined using peripheral arterial tonometry at the fingertip. RESULTS: In patients with severe sepsis, a lower number of EPC, CD31+ T-cells and a decreased migratory capacity of CAC coincided with a blunted reactive hyperaemia response compared to healthy subjects. The number of EMP, on the other hand, did not differ. The presence of organ failure at admission (SOFA score) was inversely related with the number of CD31+ T-cells. Furthermore, the number of EPC at admission was decreased in patients with progressive organ failure within the first week. CONCLUSION: In patients with severe sepsis, in vivo measured endothelial dysfunction coincides with lower numbers and reduced function of circulating cells implicated in endothelial repair. Our results suggest that cellular markers of endothelial repair might be valuable in the assessment and evolution of organ dysfunction. PMID- 23936334 TI - Serum TRPM1 autoantibodies from melanoma associated retinopathy patients enter retinal on-bipolar cells and attenuate the electroretinogram in mice. AB - Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome associated with cutaneous malignant melanoma and the presence of autoantibodies that label neurons in the inner retina. The visual symptoms and electroretinogram (ERG) phenotype characteristic of MAR resemble the congenital visual disease caused by mutations in TRPM1, a cation channel expressed by both melanocytes and retinal bipolar cells. Four serum samples from MAR patients were identified as TRPM1 immunoreactive by 1. Labeling of ON-bipolar cells in TRPM1+/+ but not TRPM1-/- mouse retina, 2. Labeling of TRPM1-transfected CHO cells; and 3. Attenuation of the ERG b-wave following intravitreal injection of TRPM1-positive MAR IgG into wild-type mouse eyes, and the appearance of the IgG in the retinal bipolar cells at the conclusion of the experiment. Furthermore, the epitope targeted by the MAR autoantibodies was localized within the amino-terminal cytoplasmic domain of TRPM1. Incubation of live retinal neurons with TRPM1-positive MAR serum resulted in the selective accumulation of IgG in ON-bipolar cells from TRPM1+/+ mice, but not TRPM1-/- mice, suggesting that the visual deficits in MAR are caused by the uptake of TRPM1 autoantibodies into ON-bipolar cells, where they bind to an intracellular epitope of the channel and reduce the ON-bipolar cell response to light. PMID- 23936335 TI - Cervical mucus properties stratify risk for preterm birth. AB - BACKGROUND: Ascending infection from the colonized vagina to the normally sterile intrauterine cavity is a well-documented cause of preterm birth. The primary physical barrier to microbial ascension is the cervical canal, which is filled with a dense and protective mucus plug. Despite its central role in separating the vaginal from the intrauterine tract, the barrier properties of cervical mucus have not been studied in preterm birth. METHODS AND FINDINGS: To study the protective function of the cervical mucus in preterm birth we performed a pilot case-control study to measure the viscoelasticity and permeability properties of mucus obtained from pregnant women at high-risk and low-risk for preterm birth. Using extensional and shear rheology we found that cervical mucus from women at high-risk for preterm birth was more extensible and forms significantly weaker gels compared to cervical mucus from women at low-risk of preterm birth. Moreover, permeability measurements using fluorescent microbeads show that high risk mucus was more permeable compared with low-risk mucus. CONCLUSIONS: Our findings suggest that critical biophysical barrier properties of cervical mucus in women at high-risk for preterm birth are compromised compared to women with healthy pregnancy. We hypothesize that impaired barrier properties of cervical mucus could contribute to increased rates of intrauterine infection seen in women with preterm birth. We furthermore suggest that a robust association of spinnbarkeit and preterm birth could be an effectively exploited biomarker for preterm birth prediction. PMID- 23936336 TI - Specific imaging of inflammation with the 18 kDa translocator protein ligand DPA 714 in animal models of epilepsy and stroke. AB - Inflammation is a pathophysiological hallmark of many diseases of the brain. Specific imaging of cells and molecules that contribute to cerebral inflammation is therefore highly desirable, both for research and in clinical application. The 18 kDa translocator protein (TSPO) has been established as a suitable target for the detection of activated microglia/macrophages. A number of novel TSPO ligands have been developed recently. Here, we evaluated the high affinity TSPO ligand DPA-714 as a marker of brain inflammation in two independent animal models. For the first time, the specificity of radiolabeled DPA-714 for activated microglia/macrophages was studied in a rat model of epilepsy (induced using Kainic acid) and in a mouse model of stroke (transient middle cerebral artery occlusion, tMCAO) using high-resolution autoradiography and immunohistochemistry. Additionally, cold-compound blocking experiments were performed and changes in blood-brain barrier (BBB) permeability were determined. Target-to-background ratios of 2 and 3 were achieved in lesioned vs. unaffected brain tissue in the epilepsy and tMCAO models, respectively. In both models, ligand uptake into the lesion corresponded well with the extent of Ox42- or Iba1-immunoreactive activated microglia/macrophages. In the epilepsy model, ligand uptake was almost completely blocked by pre-injection of DPA-714 and FEDAA1106, another high affinity TSPO ligand. Ligand uptake was independent of the degree of BBB opening and lesion size in the stroke model. We provide further strong evidence that DPA 714 is a specific ligand to image activated microglia/macrophages in experimental models of brain inflammation. PMID- 23936337 TI - Scaling up paediatric HIV care with an integrated, family-centred approach: an observational case study from Uganda. AB - Family-centred HIV care models have emerged as an approach to better target children and their caregivers for HIV testing and care, and further provide integrated health services for the family unit's range of care needs. While there is significant international interest in family-centred approaches, there is a dearth of research on operational experiences in implementation and scale-up. Our retrospective case study examined best practices and enabling factors during scale-up of family-centred care in ten health facilities and ten community clinics supported by a non-governmental organization, Mildmay, in Central Uganda. Methods included key informant interviews with programme management and families, and a desk review of hospital management information systems (HMIS) uptake data. In the 84 months following the scale-up of the family-centred approach in HIV care, Mildmay experienced a 50-fold increase of family units registered in HIV care, a 40-fold increase of children enrolled in HIV care, and nearly universal coverage of paediatric cotrimoxazole prophylaxis. The Mildmay experience emphasizes the importance of streamlining care to maximize paediatric capture. This includes integrated service provision, incentivizing care-seeking as a family, creating child-friendly service environments, and minimizing missed paediatric testing opportunities by institutionalizing early infant diagnosis and provider-initiated testing and counselling. Task-shifting towards nurse-led clinics with community outreach support enabled rapid scale-up, as did an active management structure that allowed for real-time review and corrective action. The Mildmay experience suggests that family-centred approaches are operationally feasible, produce strong coverage outcomes, and can be well-managed during rapid scale-up. PMID- 23936338 TI - The Goodwin model: behind the Hill function. AB - The Goodwin model is a 3-variable model demonstrating the emergence of oscillations in a delayed negative feedback-based system at the molecular level. This prototypical model and its variants have been commonly used to model circadian and other genetic oscillators in biology. The only source of non linearity in this model is a Hill function, characterizing the repression process. It was mathematically shown that to obtain limit-cycle oscillations, the Hill coefficient must be larger than 8, a value often considered unrealistic. It is indeed difficult to explain such a high coefficient with simple cooperative dynamics. We present here molecular models of the standard Goodwin model, based on single or multisite phosphorylation/dephosphorylation processes of a transcription factor, which have been previously shown to generate switch-like responses. We show that when the phosphorylation/dephosphorylation processes are fast enough, the limit-cycle obtained with a multisite phosphorylation-based mechanism is in very good quantitative agreement with the oscillations observed in the Goodwin model. Conditions in which the detailed mechanism is well approximated by the Goodwin model are given. A variant of the Goodwin model which displays sharp thresholds and relaxation oscillations is also explained by a double phosphorylation/dephosphorylation-based mechanism through a bistable behavior. These results not only provide rational support for the Goodwin model but also highlight the crucial role of the speed of post-translational processes, whose response curve are usually established at a steady state, in biochemical oscillators. PMID- 23936339 TI - New empirical equation for the atomic form factor function in the momentum transfer range, q=0-50 A(-1) for the elements in the range 1 <= Z <= 30. AB - The importance of Atomic Form Factors (f) is well-known to the scientific community. Tabulated values for f are mostly used in calculating cross-sections and Monte Carlo sampling for the coherent scattering of photons. The uses of these values are subjected to different approximations and interpolation techniques because the available data points for f in the literature for specified momentum-transfer-grids are very limited. In order to make it easier to accurately use the tabulated data, a mathematical expression for f functions would be a great achievement. Therefore, the current study was designed to suggest an empirical expression for the f functions. In the results, an empirical equation for Hubbell's tabulated data for f is created in the momentum transfer range, q=0-50 A(-1) for the elements in the range 1 <= Z <= 30. The number of applied parameters was seven. The fitting to f showed that the maximum deviation was within 3%, 4% and 5% for the element having, Z=1-11, Z=12-22 and Z=23-30, respectively, while the average deviations were within 0.3-2.25% for all elements (i.e., Z=1-30). The values generated by the analytical equation were used in the Monte Carlo code instead of Hubbell's tabulated values. The statistical noise in the Probability Distribution Functions of coherently scattered photons was efficiently removed. Furthermore, it also reduced the dependence on different interpolation techniques and approximations, and on the use of large tabulated data for f with the specified elements. PMID- 23936340 TI - Identification of benzimidazole diamides as selective inhibitors of the nucleotide-binding oligomerization domain 2 (NOD2) signaling pathway. AB - NOD2 is an intracellular pattern recognition receptor that assembles with receptor-interacting protein (RIP)-2 kinase in response to the presence of bacterial muramyl dipeptide (MDP) in the host cell cytoplasm, thereby inducing signals leading to the production of pro-inflammatory cytokines. The dysregulation of NOD2 signaling has been associated with various inflammatory disorders suggesting that small-molecule inhibitors of this signaling complex may have therapeutic utility. To identify inhibitors of the NOD2 signaling pathway, we utilized a cell-based screening approach and identified a benzimidazole diamide compound designated GSK669 that selectively inhibited an MDP-stimulated, NOD2-mediated IL-8 response without directly inhibiting RIP2 kinase activity. Moreover, GSK669 failed to inhibit cytokine production in response to the activation of Toll-like receptor (TLR)-2, tumor necrosis factor receptor (TNFR)-1 and closely related NOD1, all of which share common downstream components with the NOD2 signaling pathway. While the inhibitors blocked MDP-induced NOD2 responses, they failed to block signaling induced by NOD2 over-expression or single stranded RNA, suggesting specificity for the MDP-induced signaling complex and activator-dependent differences in NOD2 signaling. Investigation of structure activity relationship allowed the identification of more potent analogs that maintained NOD2 selectivity. The largest boost in activity was achieved by N methylation of the C2-ethyl amide group. These findings demonstrate that the NOD2 signaling pathway is amenable to modulation by small molecules that do not target RIP2 kinase activity. The compounds we identified should prove useful tools to investigate the importance of NOD2 in various inflammatory processes and may have potential clinical utility. PMID- 23936341 TI - DING proteins from phylogenetically different species share high degrees of sequence and structure homology and block transcription of HIV-1 LTR promoter. AB - Independent research groups reported that DING protein homologues isolated from bacterial, plant and human cells demonstrate the anti-HIV-1 activity. This might indicate that diverse organisms utilize a DING-mediated broad-range protective innate immunity response to pathogen invasion, and that this mechanism is effective also against HIV-1. We performed structural analyses and evaluated the anti-HIV-1 activity for four DING protein homologues isolated from different species. Our data show that bacterial PfluDING, plant p38SJ (pDING), human phosphate binding protein (HPBP) and human extracellular DING from CD4 T cells (X DING-CD4) share high degrees of structure and sequence homology. According to earlier reports on the anti-HIV-1 activity of pDING and X-DING-CD4, other members of this protein family from bacteria and humans were able to block transcription of HIV-1 and replication of virus in cell based assays. The efficacy studies for DING-mediated HIV-1 LTR and HIV-1 replication blocking activity showed that the LTR transcription inhibitory concentration 50 (IC50) values ranged from 0.052 0.449 ng/ml; and the HIV-1 replication IC50 values ranged from 0.075-0.311 ng/ml. Treatment of cells with DING protein alters the interaction between p65-NF-kappaB and HIV-1 LTR. Our data suggest that DING proteins may be part of an innate immunity defense against pathogen invasion; the conserved structure and activity makes them appealing candidates for development of a novel therapeutics targeting HIV-1 transcription. PMID- 23936342 TI - External beam radiotherapy for head and neck cancers is associated with increased variability in retinal vascular oxygenation. AB - BACKGROUND: Radiation retinopathy is a possible post-treatment complication of radiation therapy. The pathophysiologic mechanism is hypothesized to be microvascular in origin, but evidence is limited. In an effort to study retinal oxygenation in these patients, we herein evaluate the repeatability and variability of retinal oximetry measurements in subjects who had previously received radiation and make comparisons to a cohort of unirradiated subjects. METHODS: Using retinal oximetry, a non-invasive imaging modality, we performed in vivo measurements of arteriole (SaO2) and venule SO2 (SvO2) in subjects (n = 9, 18 retinas) who had received incidental radiation to their retinas (>= 45 Gy to one retina) and in healthy subjects (n = 20, 40 retinas). A total of 1367 SO2 observations on 593 vessels in 29 persons were analyzed to assess three sources of variance in vessel SO2: 1) variance in repeated measurements of the same vessel ("repeatability"), 2) variance in different vessels within the same subject ("within-subject variability"), and 3) variance between subjects ("between-subject variability"). RESULTS: Retinal oximetry measurements were highly repeatable in both irradiated patients and unirradiated subjects. The within-subject variability of SvO2 and SaO2 measurements constituted the highest component of variance in both groups and was significantly higher in venules vs. arterioles (relative effect size 1.8, p<0.001) and in irradiated subjects vs. unirradiated subjects (relative effect size 1.6, p<0.001). CONCLUSIONS: Retinal oximetry is a highly repeatable technology and can be reliably used to study vascular oxygenation in irradiated subjects. Different vessels within the same subject exhibit a high degree of variability, suggesting that pooled analyses of multiple vessels are most likely to be informative of regional retinal oxygenation. Finally, irradiated subjects exhibited significantly higher within subject variability in SO2 measurements, suggesting that radiation may cause regional alterations in retinal oxygen delivery and/or metabolism. PMID- 23936343 TI - The effect of soluble RAGE on inhibition of angiotensin II-mediated atherosclerosis in apolipoprotein E deficient mice. AB - BACKGROUND: The cross talk between RAGE and angiotensin II (AngII) activation may be important in the development of atherosclerosis. Soluble RAGE (sRAGE), a truncated soluble form of the receptor, acts as a decoy and prevents the inflammatory response mediated by RAGE activation. In this study, we sought to determine the effect of sRAGE in inhibiting AngII-induced atherosclerosis in apolipoprotein E knockout mice (Apo E KO). METHODS AND RESULTS: 9 week old Apo E KO mice were infused subcutaneously with AngII (1 ug/min/kg) and saline for 4 weeks using osmotic mini-pumps. The mice were divided into 4 groups 1. saline infusion and saline injection; 2. saline infusion and sRAGE injection; 3. AngII infusion and saline injection; 4. AngII infusion and sRAGE injection. Saline or 0.5 ug, 1 ug, to 2 ug/day/mouse of sRAGE were injected intraperitoneally daily for 28 days. We showed that atherosclerotic plaque areas in the AngII-infused Apo E KO mice and markers of inflammation such as RAGE, ICAM-1, VCAM-1, and MCP-1 were increased in aorta compared to that of the Apo E KO mice. However, the treatment of 0.5 ug, 1 ug, and 2 ug of sRAGE in AngII group resulted in the dose dependent decrease in atherosclerotic plaque area. We also demonstrated that sRAGE decreased RAGE expression level as well as inflammatory cytokines and cell adhesion molecules in AngII or HMGB1 treated-rat aorta vascular smooth muscle cells. CONCLUSION: The results demonstrated that partical blockade of RAGE activation by sRAGE prevent AngII -induced atherosclerosis. Therefore these results suggested that first, RAGE activation may be important in mediating AngII induced atherogenesis, and second, AngII activation is a major pathway in the development of atherosclerosis. Taken together, results from this study may provide the basis for future anti- atherosclerotic drug development mediated through RAGE activation. PMID- 23936344 TI - LT-IIb(T13I), a non-toxic type II heat-labile enterotoxin, augments the capacity of a ricin toxin subunit vaccine to evoke neutralizing antibodies and protective immunity. AB - Currently, there is a shortage of adjuvants that can be employed with protein subunit vaccines to enhance protection against biological threats. LT-IIb(T13I) is an engineered nontoxic derivative of LT-IIb, a member of the type II subfamily of heat labile enterotoxins expressed by Escherichia coli, that possesses potent mucosal adjuvant properties. In this study we evaluated the capacity of LT IIb(T13I) to augment the potency of RiVax, a recombinant ricin toxin A subunit vaccine, when co-administered to mice via the intradermal (i.d.) and intranasal (i.n.) routes. We report that co-administration of RiVax with LT-IIb(T13I) by the i.d. route enhanced the levels of RiVax-specific serum IgG antibodies (Ab) and elevated the ratio of ricin-neutralizing to non-neutralizing Ab, as compared to RiVax alone. Protection against a lethal ricin challenge was also augmented by LT IIb(T13I). While local inflammatory responses elicited by LT-IIb(T13I) were comparable to those elicited by aluminum salts (Imject(r)), LT-IIb(T13I) was more effective than aluminum salts at augmenting production of RiVax-specific serum IgG. Finally, i.n. administration of RiVax with LT-IIb(T13I) also increased levels of RiVax-specific serum and mucosal Ab and enhanced protection against ricin challenge. Collectively, these data highlight the potential of LT-IIb(T13I) as an effective next-generation i.d., or possibly i.n. adjuvant for enhancing the immunogenicity of subunit vaccines for biodefense. PMID- 23936345 TI - Malaria hotspots drive hypoendemic transmission in the Chittagong Hill Districts of Bangladesh. AB - BACKGROUND: Malaria is endemic in 13 of 64 districts of Bangladesh, representing a population at risk of about 27 million people. The highest rates of malaria in Bangladesh occur in the Chittagong Hill Districts, and Plasmodium falciparum (predominately chloroquine resistant) is the most prevalent species. METHODS: The objective of this research was to describe the epidemiology of symptomatic P. falciparum malaria in an area of Bangladesh following the introduction of a national malaria control program. We carried out surveillance for symptomatic malaria due to P. falciparum in two demographically defined unions of the Chittagong Hill Districts in Bangladesh, bordering western Myanmar, between October 2009 and May 2012. The association between sociodemographics and temporal and climate factors with symptomatic P. falciparum infection over two years of surveillance data was assessed. Risk factors for infection were determined using a multivariate regression model. RESULTS: 472 cases of symptomatic P. falciparum malaria cases were identified among 23,372 residents during the study period. Greater than 85% of cases occurred during the rainy season from May to October, and cases were highly clustered geographically within these two unions with more than 80% of infections occurring in areas that contain approximately one-third of the total population. Risk factors statistically associated with infection in a multivariate logistic regression model were living in the areas of high incidence, young age, and having an occupation including jhum cultivation and/or daily labor. Use of long lasting insecticide-treated bed nets was high (89.3%), but its use was not associated with decreased incidence of infection. CONCLUSION: Here we show that P. falciparum malaria continues to be hypoendemic in the Chittagong Hill Districts of Bangladesh, is highly seasonal, and is much more common in certain geographically limited hot spots and among certain occupations. PMID- 23936346 TI - Reliability measurement for mixed mode failures of 33/11 kilovolt electric power distribution stations. AB - The reliability of the electrical distribution system is a contemporary research field due to diverse applications of electricity in everyday life and diverse industries. However a few research papers exist in literature. This paper proposes a methodology for assessing the reliability of 33/11 Kilovolt high-power stations based on average time between failures. The objective of this paper is to find the optimal fit for the failure data via time between failures. We determine the parameter estimation for all components of the station. We also estimate the reliability value of each component and the reliability value of the system as a whole. The best fitting distribution for the time between failures is a three parameter Dagum distribution with a scale parameter [Formula: see text] and shape parameters [Formula: see text] and [Formula: see text]. Our analysis reveals that the reliability value decreased by 38.2% in each 30 days. We believe that the current paper is the first to address this issue and its analysis. Thus, the results obtained in this research reflect its originality. We also suggest the practicality of using these results for power systems for both the maintenance of power systems models and preventive maintenance models. PMID- 23936347 TI - Intradermal immunization with wall teichoic acid (WTA) elicits and augments an anti-WTA IgG response that protects mice from methicillin-resistant Staphylococcus aureus infection independent of mannose-binding lectin status. AB - The objectives of this study were to investigate the immune response to intradermal immunization with wall teichoic acid (WTA) and the effect of MBL deficiency in a murine model of infection with methicillin-resistant Staphylococcus aureus (MRSA). WTA is a bacterial cell wall component that is implicated in invasive infection. We tested susceptibility to MRSA infection in wild type (WT) and MBL deficient mice using two strains of MRSA: MW2, a community associated MRSA (CA-MRSA); and COL, a healthcare-associated MRSA (HA-MRSA). We also performed in vitro assays to investigate the effects of anti-WTA IgG containing murine serum on complement activation and bacterial growth in whole blood. We found that MBL knockout (KO) mice are relatively resistant to a specific MRSA strain, MW2 CA-MRSA, compared to WT mice, while both strains of mice had similar susceptibility to a different strain, COL HA-MRSA. Intradermal immunization with WTA elicited and augmented an anti-WTA IgG response in both WT and MBL KO mice. WTA immunization significantly reduced susceptibility to both MW2 CA-MRSA and COL HA-MRSA, independent of the presence of MBL. The protective mechanisms of anti-WTA IgG are mediated at least in part by complement activation and clearance of bacteria from blood. The significance of these findings is that 1) Intradermal immunization with WTA induces production of anti-WTA IgG; and 2) This anti-WTA IgG response protects from infection with both MW2 CA-MRSA and COL HA-MRSA even in the absence of MBL, the deficiency of which is common in humans. PMID- 23936349 TI - Directly writing resistor, inductor and capacitor to composite functional circuits: a super-simple way for alternative electronics. AB - BACKGROUND: The current strategies for making electronic devices are generally time, water, material and energy consuming. Here, the direct writing of composite functional circuits through comprehensive use of GaIn10-based liquid metal inks and matching material is proposed and investigated, which is a rather easy going and cost effective electronics fabrication way compared with the conventional approaches. METHODS: Owing to its excellent adhesion and electrical properties, the liquid metal ink was demonstrated as a generalist in directly making various basic electronic components such as planar resistor, inductor and capacitor or their combination and thus composing circuits with expected electrical functions. For a precise control of the geometric sizes of the writing, a mask with a designed pattern was employed and demonstrated. Mechanisms for justifying the chemical components of the inks and the magnitudes of the target electronic elements so as to compose various practical circuits were disclosed. RESULTS: Fundamental tests on the electrical components including capacitor and inductor directly written on paper with working time up to 48 h and elevated temperature demonstrated their good stability and potential widespread adaptability especially when used in some high frequency circuits. As the first proof-of concept experiment, a typical functional oscillating circuit including an integrated chip of 74HC04 with a supply voltage of 5 V, a capacitor of 10 nF and two resistors of 5 kOmega and 1 kOmega respectively was directly composed on paper through integrating specific electrical elements together, which presented an oscillation frequency of 8.8 kHz. CONCLUSIONS: The present method significantly extends the roles of the metal ink in recent works serving as only a single electrical conductor or interconnecting wires. It opens the way for directly writing out complex functional circuits or devices on different substrates. Such circuit composition strategy has generalized purpose and can be extended to more areas, even daily pervasive electronics. PMID- 23936348 TI - Expression of drug targets in patients treated with sorafenib, carboplatin and paclitaxel. AB - INTRODUCTION: Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). METHODS: Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-Rbeta, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. RESULTS: An association was found between high FGF-R1 and VEGF R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). CONCLUSIONS: In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen. PMID- 23936351 TI - Modelling the dynamics of an experimental host-pathogen microcosm within a hierarchical Bayesian framework. AB - The advantages of Bayesian statistical approaches, such as flexibility and the ability to acknowledge uncertainty in all parameters, have made them the prevailing method for analysing the spread of infectious diseases in human or animal populations. We introduce a Bayesian approach to experimental host pathogen systems that shares these attractive features. Since uncertainty in all parameters is acknowledged, existing information can be accounted for through prior distributions, rather than through fixing some parameter values. The non linear dynamics, multi-factorial design, multiple measurements of responses over time and sampling error that are typical features of experimental host-pathogen systems can also be naturally incorporated. We analyse the dynamics of the free living protozoan Paramecium caudatum and its specialist bacterial parasite Holospora undulata. Our analysis provides strong evidence for a saturable infection function, and we were able to reproduce the two waves of infection apparent in the data by separating the initial inoculum from the parasites released after the first cycle of infection. In addition, the parameter estimates from the hierarchical model can be combined to infer variations in the parasite's basic reproductive ratio across experimental groups, enabling us to make predictions about the effect of resources and host genotype on the ability of the parasite to spread. Even though the high level of variability between replicates limited the resolution of the results, this Bayesian framework has strong potential to be used more widely in experimental ecology. PMID- 23936350 TI - Isoniazid inhibits the heme-based reactivity of Mycobacterium tuberculosis truncated hemoglobin N. AB - Isoniazid represents a first-line anti-tuberculosis medication in prevention and treatment. This prodrug is activated by a mycobacterial catalase-peroxidase enzyme called KatG in Mycobacterium tuberculosis), thereby inhibiting the synthesis of mycolic acid, required for the mycobacterial cell wall. Moreover, isoniazid activation by KatG produces some radical species (e.g., nitrogen monoxide), that display anti-mycobacterial activity. Remarkably, the ability of mycobacteria to persist in vivo in the presence of reactive nitrogen and oxygen species implies the presence in these bacteria of (pseudo-)enzymatic detoxification systems, including truncated hemoglobins (trHbs). Here, we report that isoniazid binds reversibly to ferric and ferrous M. tuberculosis trHb type N (or group I; Mt-trHbN(III) and Mt-trHbN(II), respectively) with a simple bimolecular process, which perturbs the heme-based spectroscopic properties. Values of thermodynamic and kinetic parameters for isoniazid binding to Mt trHbN(III) and Mt-trHbN(II) are K= (1.1 +/- 0.1)* 10(-4) M, k on= (5.3 +/- 0.6)* 10(3) M(-1) s(-1) and k off= (4.6 +/- 0.5)* 10(-1) s(-1); and D= (1.2 +/- 0.2)* 10(-3) M, d on= (1.3 +/- 0.4)* 10(3) M(-1) s(-1), and d off=1.5 +/- 0.4 s(-1), respectively, at pH 7.0 and 20.0 degrees C. Accordingly, isoniazid inhibits competitively azide binding to Mt-trHbN(III) and Mt-trHbN(III)-catalyzed peroxynitrite isomerization. Moreover, isoniazid inhibits Mt-trHbN(II) oxygenation and carbonylation. Although the structure of the Mt-trHbN-isoniazid complex is not available, here we show by docking simulation that isoniazid binding to the heme-Fe atom indeed may take place. These data suggest a direct role of isoniazid to impair fundamental functions of mycobacteria, e.g. scavenging of reactive nitrogen and oxygen species, and metabolism. PMID- 23936353 TI - Emergence, development, and maturity of the gonad of two species of chitons "sea cockroach" (Mollusca: Polyplacophora) through the early life stages. AB - This study describes and recognises, using histological and microscopical examinations on a morphometrical basis, several gonad traits through the early life stages of Chiton articulatus and C. albolineatus. Gonadal ontogenesis, gonad development stages, sexual differentiation, onset of the first sexual maturity, and growth sequences or "early life stages" were determined. In addition, allometry between lengths and body weight pooled for both sexes per each chiton were calculated using equation Y = aX(b) . A total of 125 chitons (4<=TL<=40 mm, in total length "TL") were used. All allometric relations showed a strong positive correlation (r), close to 1, with b-values above three, indicating an isometric growth. Gonadal ontogenesis and gonad development stages were categorised into three periods ("Pw" without gonad, "Pe" gonad emergence, and "Pf" gonadal sac formed) and four stages ("S0" gametocytogenesis, "S1" gametogenesis, "S2" mature, and "S3" spawning), respectively. Compound digital images were attained for each process. Periods and stages are overlapped among them and between species, with the following overall confidence intervals in TL: Pw 6.13-14.32 mm, Pe 10.32-16.93 mm, Pf 12.99-25.01 mm, S0 16.08-24.34 mm (females) and 19.51-26.60 mm (males), S1 27.15-35.63 mm (females) and 23.45-32.27 mm (males), S2 24.48-40.24 mm (females) and 25.45-32.87 mm (males). Sexual differentiation (in S0) of both chitons occurs first as a female then as a male; although, males reach the onset of the first sexual maturity earlier than females, thus for C. articulatus males at 17 mm and females at 32 mm, and for C. albolineatus males at 23.5 mm and females at 28 mm, all in TL. Four early life stages (i.e., subjuvenile, juvenile, subadult, and adult) are described and proposed to distinguish growth sequences. Our results may be useful to diverse disciplines, from developmental biology to fisheries management. PMID- 23936352 TI - Concomitant loss of p120-catenin and beta-catenin membrane expression and oral carcinoma progression with E-cadherin reduction. AB - The binding of p120-catenin and beta-catenin to the cytoplasmic domain of E cadherin establishes epithelial cell-cell adhesion. Reduction and loss of catenin expression degrades E-cadherin-mediated carcinoma cell-cell adhesion and causes carcinomas to progress into aggressive states. Since both catenins are differentially regulated and play distinct roles when they dissociate from E cadherin, evaluation of their expression, subcellular localization and the correlation with E-cadherin expression are important subjects. However, the same analyses are not readily performed on squamous cell carcinomas in which E cadherin expression determines the disease progression. In the present study, we examined expression and subcellular localization of p120-catenin and beta-catenin in oral carcinomas (n = 67) and its implications in the carcinoma progression and E-cadherin expression using immunohitochemistry. At the invasive front, catenin membrane-positive carcinoma cells were decreased in the dedifferentiated (p120 catenin, P < 0.05; beta-catenin, P < 0.05) and invasive carcinomas (p120-catenin, P < 0.01; beta-catenin, P < 0.05) and with the E-cadherin staining (p120-catenin, P < 0.01; beta-catenin, P < 0.01). Carcinoma cells with beta-catenin cytoplasmic and/or nuclear staining were increased at the invasive front compared to the center of tumors (P < 0.01). Although the p120-catenin isoform shift from three to one associates with carcinoma progression, it was not observed after TGF-beta, EGF or TNF-alpha treatments. The total amount of p120-catenin expression was decreased upon co-treatment of TGF-beta with EGF or TNF-alpha. The above data indicate that catenin membrane staining is a primary determinant for E-cadherin mediated cell-cell adhesion and progression of oral carcinomas. Furthermore, it suggests that loss of p120-catenin expression and cytoplasmic localization of beta-catenin fine-tune the carcinoma progression. PMID- 23936354 TI - HIV-1 envelope glycoprotein variable loops are indispensable for envelope structural integrity and virus entry. AB - HIV-1 envelope (Env) glycoprotein is a trimer of heterodimer of gp120 and gp41, and derives from a trimeric glycoprotein precursor, gp160. Gp120 contains five conserved regions that are interspersed with 5 variable loop regions (V1-V5). Env variations in variable loop length and amino acid composition may associate with virus pathogenesis, virus sensitivity to neutralizing antibodies (nAbs) and disease progression. To investigate the role of each variable loop in Env function, we generated a panel of JRFL gp160 loop deletion mutants and examined the effects of each loop deletion on Env expression, Env cell surface display and Env-mediated virus entry into permissive cells. We found that deletion of V1 and V2 (DeltaV1V2), or loop D (DeltalpD) abolished virus entry, the same effect as deletion of V3 (DeltaV3), while deletion of V3 crown (DeltaV3C) significantly enhanced virus assembly and entry. We further found that deletion of V4 (DeltaV4) or V5 (DeltaV5), or replacement of V4 or V5 with flexible linkers of the same lengths knocked out the receptor and coreceptor binding sites in gp120, but significantly enhanced the exposure of the N-trimer structure and the membrane proximal external region (MPER) in gp41. Although deletion of V4 or V5 did not affect Env expression, they negatively affected Env cell surface display, leading to the failure in virus assembly and subsequent entry. Taken together, we found that Env variable loops were indispensable for Env structural integrity and virus entry. Our findings may have implications for development of HIV-1 vaccine immunogens and therapeutics. PMID- 23936355 TI - A rational diagnostic algorithm for the identification of ALK rearrangement in lung cancer: a comprehensive study of surgically treated Japanese patients. AB - BACKGROUND: EML4-ALK fusion gene is found in only a small subset (2-6%) of non small cell lung cancer. There is an urgent need to establish a rational diagnostic algorithm to identify this rare but important fusion in lung cancer. METHODS: We performed a comprehensive analysis of EGFR/KRAS mutation and ALK rearrangement in a total of 360 surgically resected lung cancers. ALK rearrangement was examined by 3 analyses: multiplex reverse transcription-PCR, fluorescent in situ hybridization (FISH), and immunohistochemistry (IHC) with the intercalated antibody-enhanced polymer method. A scoring system was used for IHC (iScore). A test set (202 patients with unselected lung cancer) was used for proposing a diagnostic algorithm. This diagnostic algorithm was validated in 158 patients with EGFR and KRAS mutation-negative adenocarcinoma. RESULTS: ALK rearrangement was identified in 2 patients (1.0%) from the test set and both adenocarcinomas were negative for EGFR and KRAS mutations. The results of FISH and RT-PCR were completely matched. The highest iScore 3 was found only in the 2 positive cases. A diagnostic algorithm was proposed: IHC screening for ALK rearrangement followed by confirmatory FISH. In the validation set, 8 cases (5.1%) had iScore 3 and were positive for FISH, while the other cases had iScore 0 and were negative for FISH. CONCLUSIONS: Screening for ALK rearrangement by IHC followed by confirmatory FISH is a rational diagnostic algorithm. If needed, patients may be selected for screening ALK rearrangement by their EGFR and KRAS mutation status. PMID- 23936356 TI - Exit, punishment and rewards in commons dilemmas: an experimental study. AB - Commons dilemmas are interaction situations where a common good is provided or exploited by a group of individuals so that optimal collective outcomes clash with private interests. Although in these situations, social norms and institutions exist that might help individuals to cooperate, little is known about the interaction effects between positive and negative incentives and exit options by individuals. We performed a modified public good game experiment to examine the effect of exit, rewards and punishment, as well as the interplay between exit and rewards and punishment. We found that punishment had a stronger effect than rewards on cooperation if considered by itself, whereas rewards had a stronger effect when combined with voluntary participation. This can be explained in terms of the 'framing effect', i.e., as the combination of exit and rewards might induce people to attach higher expected payoffs to cooperative strategies and expect better behaviour from others. PMID- 23936357 TI - MIDClass: microarray data classification by association rules and gene expression intervals. AB - We present a new classification method for expression profiling data, called MIDClass (Microarray Interval Discriminant CLASSifier), based on association rules. It classifies expressions profiles exploiting the idea that the transcript expression intervals better discriminate subtypes in the same class. A wide experimental analysis shows the effectiveness of MIDClass compared to the most prominent classification approaches. PMID- 23936358 TI - Production and characterization of novel recombinant adeno-associated virus replicative-form genomes: a eukaryotic source of DNA for gene transfer. AB - Conventional non-viral gene transfer uses bacterial plasmid DNA containing antibiotic resistance genes, cis-acting bacterial sequence elements, and prokaryotic methylation patterns that may adversely affect transgene expression and vector stability in vivo. Here, we describe novel replicative forms of a eukaryotic vector DNA that consist solely of an expression cassette flanked by adeno-associated virus (AAV) inverted terminal repeats. Extensive structural analyses revealed that this AAV-derived vector DNA consists of linear, duplex molecules with covalently closed ends (termed closed-ended, linear duplex, or "CELiD", DNA). CELiD vectors, produced in Sf9 insect cells, require AAV rep gene expression for amplification. Amounts of CELiD DNA produced from insect cell lines stably transfected with an ITR-flanked transgene exceeded 60 mg per 5 * 10(9) Sf9 cells, and 1-15 mg from a comparable number of parental Sf9 cells in which the transgene was introduced via recombinant baculovirus infection. In mice, systemically delivered CELiD DNA resulted in long-term, stable transgene expression in the liver. CELiD vectors represent a novel eukaryotic alternative to bacterial plasmid DNA. PMID- 23936359 TI - Rapid and sensitive detection of novel avian-origin influenza A (H7N9) virus by reverse transcription loop-mediated isothermal amplification combined with a lateral-flow device. AB - A severe disease in humans caused by a novel avian-origin influenza A (H7N9) virus emerged in China recently, which has caused at least 128 cases and 26 deaths. Rapid detection of the novel H7N9 virus is urgently needed to differentiate the disease from other infections, and to facilitate infection control as well as epidemiologic investigations. In this study, a reverse transcription loop-mediated isothermal amplification combined with a lateral flow device (RT-LAMP-LFD) assay to rapidly detect H7N9 virus was developed and evaluated. The RT-LAMP primers were designed to target the haemagglutinin (HA) and neuraminidase (NA) genes of H7N9 virus. Results of 10-fold dilution series assays showed that analysis of RT-LAMP products by the LFD method was as sensitive as real-time turbidity detection, and that the analytic sensitivities of the HA and NA RT-LAMP assays were both 10 copies of synthetic RNA. Furthermore, both the assays showed 100% clinical specificity for identification of H7N9 virus. The performance characteristics of the RT-LAMP-LFD assay were evaluated with 80 clinical specimens collected from suspected H7N9 patients. The NA RT-LAMP-LFD assay was more sensitive than real time RT-PCR assay. Compared with a combination of virus culture and real-time RT-PCR, the sensitivity, specificity, positive predictive value, and negative predictive value of the RT LAMP-LFD assay were all 100%. Overall, The RT-LAMP-LFD assay established in this study can be used as a reliable method for early diagnosis of the avian-origin influenza A (H7N9) virus infection. PMID- 23936360 TI - Tocilizumab induced acquired factor XIII deficiency in patients with rheumatoid arthritis. AB - Factor XIII is one of the twelve coagulation factors and also known as a fibrin stabilizing factor. In 2012, we encountered a male RA patient with hemorrhagic factor XIII deficiency who had been treated with tocilizumab for two years. There are few reports regarding the relationship between tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R)) and factor XIII. We measured the factor XIII activity levels in the plasma of 40 RA patients (10 patients treated without biologics, 30 patients treated with biologics (15 patients treated with necrosis factor inhibitors and 15 patients treated with tocilizumab)) and 19 healthy controls. Consequently, the tocilizumab group exhibited lower levels than the other three groups according to the Steel-Dwass test (P<0.01). Furthermore, we compared the plasma factor XIII activity levels and the plasma factor XIII concentrations in the RA patients treated with biologics. Pearson's correlation test was used to assess the relationship between the factor XIII activity levels and the plasma factor XIII concentrations (r=0.449, P=0.019). According to the multiple regression analysis, the treatment with tocilizumab is an independent risk factor for plasma factor XIII reduction in RA patients. In conclusion, RA patients treated with tocilizumab, an IL-6R blocker, are at risk of developing acquired factor XIII deficiency. The mechanisms underlying the reduced factor XIII activity observed in RA patients treated with tocilizumab may result from the quantitative reduction in the plasma. These data imply that IL-6 plays an important role in maintaining the factor XIII activity level. PMID- 23936361 TI - Functional interaction of SCAI with the SWI/SNF complex for transcription and tumor cell invasion. AB - We have recently characterized SCAI (Suppressor of Cancer Cell Invasion), a transcriptional modulator regulating cancer cell motility through suppression of MAL/SRF dependent gene transcription. We show here that SCAI is expressed in a wide range of normal human tissues and its expression is diminished in a large array of primary human breast cancer samples indicating that SCAI expression might be linked to the etiology of human cancer. To establish a functional link between SCAI and tumorigenesis we performed affinity columns to identify SCAI interacting proteins. Our data show that SCAI interacts with the tumor suppressing SWI/SNF chromatin remodeling complex to promote changes in gene expression and the invasive capacities of human tumor cells. Moreover our data implicate a functional hierarchy between SCAI and BRM, since SCAI function is abrogated in the absence of BRM expression. PMID- 23936362 TI - How lateral connections and spiking dynamics may separate multiple objects moving together. AB - Over successive stages, the ventral visual system of the primate brain develops neurons that respond selectively to particular objects or faces with translation, size and view invariance. The powerful neural representations found in Inferotemporal cortex form a remarkably rapid and robust basis for object recognition which belies the difficulties faced by the system when learning in natural visual environments. A central issue in understanding the process of biological object recognition is how these neurons learn to form separate representations of objects from complex visual scenes composed of multiple objects. We show how a one-layer competitive network comprised of 'spiking' neurons is able to learn separate transformation-invariant representations (exemplified by one-dimensional translations) of visual objects that are always seen together moving in lock-step, but separated in space. This is achieved by combining 'Mexican hat' functional lateral connectivity with cell firing-rate adaptation to temporally segment input representations of competing stimuli through anti-phase oscillations (perceptual cycles). These spiking dynamics are quickly and reliably generated, enabling selective modification of the feed forward connections to neurons in the next layer through Spike-Time-Dependent Plasticity (STDP), resulting in separate translation-invariant representations of each stimulus. Variations in key properties of the model are investigated with respect to the network's ability to develop appropriate input representations and subsequently output representations through STDP. Contrary to earlier rate-coded models of this learning process, this work shows how spiking neural networks may learn about more than one stimulus together without suffering from the 'superposition catastrophe'. We take these results to suggest that spiking dynamics are key to understanding biological visual object recognition. PMID- 23936363 TI - Sleep-effects on implicit and explicit memory in repeated visual search. AB - In repeated visual search tasks, facilitation of reaction times (RTs) due to repetition of the spatial arrangement of items occurs independently of RT facilitation due to improvements in general task performance. Whereas the latter represents typical procedural learning, the former is a kind of implicit memory that depends on the medial temporal lobe (MTL) memory system and is impaired in patients with amnesia. A third type of memory that develops during visual search is the observers' explicit knowledge of repeated displays. Here, we used a visual search task to investigate whether procedural memory, implicit contextual cueing, and explicit knowledge of repeated configurations, which all arise independently from the same set of stimuli, are influenced by sleep. Observers participated in two experimental sessions, separated by either a nap or a controlled rest period. In each of the two sessions, they performed a visual search task in combination with an explicit recognition task. We found that (1) across sessions, MTL independent procedural learning was more pronounced for the nap than rest group. This confirms earlier findings, albeit from different motor and perceptual tasks, showing that procedural memory can benefit from sleep. (2) Likewise, the sleep group compared with the rest group showed enhanced context-dependent configural learning in the second session. This is a novel finding, indicating that the MTL dependent, implicit memory underlying contextual cueing is also sleep-dependent. (3) By contrast, sleep and wake groups displayed equivalent improvements in explicit recognition memory in the second session. Overall, the current study shows that sleep affects MTL-dependent as well as MTL-independent memory, but it affects different, albeit simultaneously acquired, forms of MTL-dependent memory differentially. PMID- 23936364 TI - Screening for drug and alcohol use disorders and their association with HIV related sexual risk behaviors among men who have sex with men in Peru. AB - BACKGROUND: Peru's HIV epidemic is concentrated among men who have sex with men (MSM). The contribution of alcohol use disorders (AUDs) to known high-risk behaviors associated with HIV transmission in this context has not been well characterized. METHODS: Between June and October 2011, 5,148 sexually active MSM were recruited using convenience sampling in five cities to participate in a cross-sectional bio-behavioral survey. Five high-risk sexual criteria previously associated with incident HIV infection in this setting were selected a priori as the dependent outcomes. Screening for AUDs used the validated Alcohol Use Disorders Identification Test (AUDIT) and AUDS were stratified by severity. Unadjusted and adjusted odds ratios (AOR) were computed to establish the independent correlates of the five dependent outcomes. RESULTS: The majority (62.8%) of participants met screening criteria for having an AUD, which were independently correlated with each of the following high-risk sexual risk behaviors in the previous 6 months: 1) >5 sexual partners [AOR = 1.76; (1.54 2.02)]; 2) sex with an HIV-infected partner [AOR = 1.29; (1.03-1.62)]; 3) having a sexually transmitted infection [AOR = 1.38; (1.13-1.68)]; 4) being a sex worker [AOR = 1.61; (1.40-1.87)]; and 5) unprotected sex during last encounter [AOR = 1.22; (1.09-1.38)]. Recent drug use was also correlated with having >5 sexual partners [AOR = 1.42 (1.19-1.71)], sex work [AOR = 1.97 (1.63-2.39)] and unprotected sex during last encounter [AOR = 1.31 (1.11-1.54)]. For each dependent variable, the association with AUDs significantly increased with increasing AUD severity. CONCLUSIONS: AUDs are highly prevalent among MSM in Peru and are associated with increased HIV risk-taking behaviors that are associated with HIV transmission. Strategies that target problematic drinking such as medication-assisted therapy, behavioral counseling and structural interventions could potentially reduce risky behaviors and ultimately reduce HIV transmission among MSM in Peru. PMID- 23936365 TI - Pneumocystis jirovecii pneumonia in tropical and low and middle income countries: a systematic review and meta-regression. AB - OBJECTIVE: Pneumocystis jirovecii pneumonia (PCP), the commonest opportunistic infection in HIV-infected patients in the developed world, is less commonly described in tropical and low and middle income countries (LMIC). We sought to investigate predictors of PCP in these settings. DESIGN: Systematic review and meta-regression. METHODS: Meta-regression of predictors of PCP diagnosis (33 studies). Qualitative and quantitative assessment of recorded CD4 counts, receipt of prophylaxis and antiretrovirals, sensitivity and specificity of clinical signs and symptoms for PCP, co-infection with other pathogens, and case fatality (117 studies). RESULTS: The most significant predictor of PCP was per capita Gross Domestic Product, which showed strong linear association with odds of PCP diagnosis (p<0.0001). This was not explained by study design or diagnostic quality. Geographical area, population age, study setting and year of study also contributed to risk of PCP. Co-infection was common (444 episodes/1425 PCP cases), frequently with virulent organisms. The predictive value of symptoms, signs or simple tests in LMIC settings for diagnosis of PCP was poor. Case fatality was >30%; treatment was largely appropriate. Prophylaxis appeared to reduce the risk for development of PCP, however 24% of children with PCP were receiving prophylaxis. CD4 counts at presentation with PCP were usually <200*10(3/)ml. CONCLUSIONS: There is a positive relationship between GDP and risk of PCP diagnosis. Although failure to diagnose infection in poorer countries may contribute to this, we also hypothesise that poverty exposes at-risk patients to a wide range of infections and that the relatively non-pathogenic P. jirovecii is therefore under-represented. As LMIC develop economically they eliminate the conditions underlying transmission of virulent infection: P. jirovecii, ubiquitous in all settings, then becomes a greater relative threat. PMID- 23936367 TI - Manipulation of the porcine epidemic diarrhea virus genome using targeted RNA recombination. AB - Porcine epidemic diarrhea virus (PEDV) causes severe economic losses in the swine industry in China and other Asian countries. Infection usually leads to an acute, often lethal diarrhea in piglets. Despite the impact of the disease, no system is yet available to manipulate the viral genome which has severely hampered research on this virus until today. We have established a reverse genetics system for PEDV based on targeted RNA recombination that allows the modification of the 3'-end of the viral genome, which encodes the structural proteins and the ORF3 protein. Using this system, we deleted the ORF3 gene entirely from the viral genome and showed that the ORF3 protein is not essential for replication of the virus in vitro. In addition, we inserted heterologous genes (i.e. the GFP and Renilla luciferase genes) at two positions in the viral genome, either as an extra expression cassette or as a replacement for the ORF3 gene. We demonstrated the expression of both GFP and Renilla luciferase as well as the application of these viruses by establishing a convenient and rapid virus neutralization assay. The new PEDV reverse genetics system will enable functional studies of the structural proteins and the accessory ORF3 protein and will allow the rational design and development of next generation PEDV vaccines. PMID- 23936366 TI - Conditional knockout of tumor overexpressed gene in mouse neurons affects RNA granule assembly, granule translation, LTP and short term habituation. AB - In neurons, specific RNAs are assembled into granules, which are translated in dendrites, however the functional consequences of granule assembly are not known. Tumor overexpressed gene (TOG) is a granule-associated protein containing multiple binding sites for heterogeneous nuclear ribonucleoprotein (hnRNP) A2, another granule component that recognizes cis-acting sequences called hnRNP A2 response elements (A2REs) present in several granule RNAs. Translation in granules is sporadic, which is believed to reflect monosomal translation, with occasional bursts, which are believed to reflect polysomal translation. In this study, TOG expression was conditionally knocked out (TOG cKO) in mouse hippocampal neurons using cre/lox technology. In TOG cKO cultured neurons granule assembly and bursty translation of activity-regulated cytoskeletal associated (ARC) mRNA, an A2RE RNA, are disrupted. In TOG cKO brain slices synaptic sensitivity and long term potentiation (LTP) are reduced. TOG cKO mice exhibit hyperactivity, perseveration and impaired short term habituation. These results suggest that in hippocampal neurons TOG is required for granule assembly, granule translation and synaptic plasticity, and affects behavior. PMID- 23936368 TI - Identification and characterization of multiple TRIM proteins that inhibit hepatitis B virus transcription. AB - Tripartite motif (TRIM) proteins constitute a family of over 100 members that share conserved tripartite motifs and exhibit diverse biological functions. Several TRIM proteins have been shown to restrict viral infections and regulate host cellular innate immune responses. In order to identify TRIM proteins that modulate the infection of hepatitis B virus (HBV), we tested 38 human TRIMs for their effects on HBV gene expression, capsid assembly and DNA synthesis in human hepatoma cells (HepG2). The study revealed that ectopic expression of 8 TRIM proteins in HepG2 cells potently reduced the amounts of secreted HBV surface and e antigens as well as intracellular capsid and capsid DNA. Mechanistic analyses further demonstrated that the 8 TRIMs not only reduced the expression of HBV mRNAs, but also inhibited HBV enhancer I and enhancer II activities. Studies focused on TRIM41 revealed that a HBV DNA segment spanning nucleotide 1638 to nucleotide 1763 was essential for TRIM41-mediated inhibition of HBV enhancer II activity and the inhibitory effect depended on the E3 ubiquitin ligase activity of TRIM41 as well as the integrity of TRIM41 C-terminal domain. Moreover, knockdown of endogenous TRIM41 in a HepG2-derived stable cell line significantly increased the level of HBV preC/C RNA, leading to an increase in viral core protein, capsid and capsid DNA. Our studies have thus identified eight TRIM proteins that are able to inhibit HBV transcription and provided strong evidences suggesting the endogenous role of TRIM41 in regulating HBV transcription in human hepatoma cells. PMID- 23936369 TI - Prevalence and causes of ocular morbidity in Mbeere District, Kenya. Results of a population-based survey. AB - PURPOSE: Ocular morbidity (OM) describes any eye disease regardless of resultant visual loss. Ocular morbidity may affect large numbers of people in low income countries and could lead to many episodes of care. However there is limited evidence about the prevalence of ocular morbidity or resulting health-seeking behavior. This study in Mbeere District, Kenya, set out to explore both these issues. METHODS: A cross-sectional household survey was conducted in 2011. Trained teams moved from house to house examining and questioning residents on ocular morbidity and health-seeking behavior. Data were collected on standardized proformas and entered into a database for analysis. RESULTS: 3,691 people were examined (response rate 91.7%). 15.52% (95% CI 13.86-16.92) had at least one ocular morbidity in at least one eye. The leading cause was presbyopia which affected 25.11% (95% CI 22.05-28.45) of participants over 35 and increased with age. Other leading causes of OM were conditions that affected the lens (32.58%) and the conjunctiva (31.31%). No association was found between educational attainment or employment and OM. 9.63% (7.87-11.74) self-reported an ocular morbidity in the previous six months and 45.94% (95% CI 37.1-55.04) stated that they had sought treatment for the condition. CONCLUSION: A large number of people were affected by an ocular morbidity in this survey. Most of these people could potentially be managed in their own communities through primary care services (e.g. those with presbyopia). Further work is required to understand the best way of providing an effective, equitable service for ocular morbidity. PMID- 23936370 TI - Biomarker report from the phase II lamotrigine trial in secondary progressive MS neurofilament as a surrogate of disease progression. AB - OBJECTIVE: Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment. METHODS: SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12-24 and 0-24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored. RESULTS: Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12-24 months p=0.043, Nfh 0-24 months p=0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin. CONCLUSIONS: The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration. PMID- 23936371 TI - The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation. AB - The etiology of radiation-induced cardiovascular disease (CVD) after chronic exposure to low doses of ionizing radiation is only marginally understood. We have previously shown that a chronic low-dose rate exposure (4.1 mGy/h) causes human umbilical vein endothelial cells (HUVECs) to prematurely senesce. We now show that a dose rate of 2.4 mGy/h is also able to trigger premature senescence in HUVECs, primarily indicated by a loss of growth potential and the appearance of the senescence-associated markers beta-galactosidase (SA-beta-gal) and p21. In contrast, a lower dose rate of 1.4 mGy/h was not sufficient to inhibit cellular growth or increase SA-beta-gal-staining despite an increased expression of p21. We used reverse phase protein arrays and triplex Isotope Coded Protein Labeling with LC-ESI-MS/MS to study the proteomic changes associated with chronic radiation-induced senescence. Both technologies identified inactivation of the PI3K/Akt/mTOR pathway accompanying premature senescence. In addition, expression of proteins involved in cytoskeletal structure and EIF2 signaling was reduced. Age-related diseases such as CVD have been previously associated with increased endothelial cell senescence. We postulate that a similar endothelial aging may contribute to the increased rate of CVD seen in populations chronically exposed to low-dose-rate radiation. PMID- 23936372 TI - Influence of macrocyclic chelators on the targeting properties of (68)Ga-labeled synthetic affibody molecules: comparison with (111)In-labeled counterparts. AB - Affibody molecules are a class of small (7 kDa) non-immunoglobulin scaffold-based affinity proteins, which have demonstrated substantial potential as probes for radionuclide molecular imaging. The use of positron emission tomography (PET) would further increase the resolution and quantification accuracy of Affibody based imaging. The rapid in vivo kinetics of Affibody molecules permit the use of the generator-produced radionuclide (68)Ga (T1/2=67.6 min). Earlier studies have demonstrated that the chemical nature of chelators has a substantial influence on the biodistribution properties of Affibody molecules. To determine an optimal labeling approach, the macrocyclic chelators 1,4,7,10-tetraazacylododecane 1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA) and 1-(1,3-carboxypropyl)-1,4,7- triazacyclononane-4,7-diacetic acid (NODAGA) were conjugated to the N-terminus of the synthetic Affibody molecule ZHER2:S1 targeting HER2. Affibody molecules were labeled with (68)Ga, and their binding specificity and cellular processing were evaluated. The biodistribution of (68)Ga-DOTA-ZHER2:S1, (68)Ga-NOTA-ZHER2:S1 and (68)Ga-NODAGA-ZHER2:S1, as well as that of their (111)In-labeled counterparts, was evaluated in BALB/C nu/nu mice bearing HER2-expressing SKOV3 xenografts. The tumor uptake for (68)Ga-DOTA ZHER2:S1 (17.9 +/- 0.7%IA/g) was significantly higher than for both (68)Ga-NODAGA ZHER2:S1 (16.13 +/- 0.67%IA/g) and (68)Ga-NOTA-ZHER2:S1 (13 +/- 3%IA/g) at 2 h after injection. (68)Ga-NODAGA-ZHER2:S1 had the highest tumor-to-blood ratio (60 +/- 10) in comparison with both (68)Ga-DOTA-ZHER2:S1 (28 +/- 4) and (68)Ga-NOTA ZHER2:S1 (42 +/- 11). The tumor-to-liver ratio was also higher for (68)Ga-NODAGA ZHER2:S1 (7 +/- 2) than the DOTA and NOTA conjugates (5.5 +/- 0.6 vs.3.3 +/- 0.6). The influence of chelator on the biodistribution and targeting properties was less pronounced for (68)Ga than for (111)In. The results of this study demonstrate that macrocyclic chelators conjugated to the N-terminus have a substantial influence on the biodistribution of HER2-targeting Affibody molecules labeled with (68)Ga.This can be utilized to enhance the imaging contrast of PET imaging using Affibody molecules and improve the sensitivity of molecular imaging. The study demonstrated an appreciable difference of chelator influence for (68)Ga and (111)In. PMID- 23936373 TI - 20-HETE and EETs in diabetic nephropathy: a novel mechanistic pathway. AB - Diabetic nephropathy (DN), a major complication of diabetes, is characterized by hypertrophy, extracellular matrix accumulation, fibrosis and proteinuria leading to loss of renal function. Hypertrophy is a major factor inducing proximal tubular epithelial cells injury. However, the mechanisms leading to tubular injury is not well defined. In our study, we show that exposure of rats proximal tubular epithelial cells to high glucose (HG) resulted in increased extracellular matrix accumulation and hypertrophy. HG treatment increased ROS production and was associated with alteration in CYPs 4A and 2C11 expression concomitant with alteration in 20-HETE and EETs formation. HG-induced tubular injury were blocked by HET0016, an inhibitor of CYPs 4A. In contrast, inhibition of EETs promoted the effects of HG on cultured proximal tubular cells. Our results also show that alteration in CYPs 4A and 2C expression and 20HETE and EETs formation regulates the activation of the mTOR/p70S6Kinase pathway, known to play a major role in the development of DN. In conclusion, we show that hyperglycemia in diabetes has a significant effect on the expression of Arachidonic Acid (AA)-metabolizing CYPs, manifested by increased AA metabolism, and might thus alter kidney function through alteration of type and amount of AA metabolites. PMID- 23936374 TI - Sex role segregation and mixing among men who have sex with men: implications for biomedical HIV prevention interventions. AB - OBJECTIVE: Men who have sex with men (MSM) practice role segregation - insertive or receptive only sex positions instead of a versatile role - in several international settings where candidate biomedical HIV prevention interventions (e.g., circumcision, anal microbicide) will be tested. The effects of these position-specific interventions on HIV incidence are modeled. MATERIALS AND METHODS: We developed a deterministic compartmental model to predict HIV incidence among Indian MSM using data from 2003-2010. The model's sex mixing matrix was derived from network data of Indian MSM (n=4604). Our model captures changing distribution of sex roles over time. We modeled microbicide and circumcision efficacy on trials with heterosexuals. RESULTS: Increasing numbers of versatile MSM resulted in little change in HIV incidence over 20 years. Anal microbicides and circumcision would decrease the HIV prevalence at 10 years from 15.6% to 12.9% and 12.7% respectively. Anal microbicides would provide similar protection to circumcision at the population level despite lower modeled efficacy (54% and 60% risk reduction, respectively). Combination of the interventions were additive: in 5 years, the reduction in HIV prevalence of the combination (-3.2%) is almost the sum of their individual reductions in HIV prevalence (-1.8% and 1.7%). CONCLUSIONS: MSM sex role segregation and mixing, unlike changes in the sex role distribution, may be important for evaluating HIV prevention interventions in international settings. Synergies between some position-specific prevention interventions such as circumcision and anal microbicides warrant further study. PMID- 23936375 TI - SNP discovery in European anchovy (Engraulis encrasicolus, L) by high-throughput transcriptome and genome sequencing. AB - Increased throughput in sequencing technologies has facilitated the acquisition of detailed genomic information in non-model species. The focus of this research was to discover and validate SNPs derived from the European anchovy (Engraulis encrasicolus) transcriptome, a species with no available reference genome, using next generation sequencing technologies. A cDNA library was constructed from four tissues of ten fish individuals corresponding to three populations of E. encrasicolus, and Roche 454 GS FLX Titanium sequencing yielded 19,367 contigs. Additionally, the European anchovy genome was sequenced for the same ten individuals using an Illumina HiSeq2000. Using a computational pipeline for combining transcriptome and genome information, a total of 18,994 SNPs met the necessary minor allele frequency and depth filters. A series of further stringent filters were applied to identify those SNPs likely to succeed in genotyping assays, and for filtering of those in potential duplicated genome regions. A novel method for detecting potential intron-exon boundaries in areas of putative SNPs has also been applied in silico to improve genotyping success. In all, 2,317 filtered putative transcriptome SNPs suitable for genotyping primer design were identified. From those, a subset of 530 were selected, with the genotyping results showing the highest reported conversion and validation rates (91.3% and 83.2%, respectively) reported to date for a non-model species. This study represents a promising strategy to discover genotypable SNPs in the exome of non model organisms. The genomic resource generated for E. encrasicolus, both in terms of sequences and novel markers, will be informative for research into this species with applications including traceability studies, population genetic analyses and aquaculture. PMID- 23936376 TI - Using manifold learning for atlas selection in multi-atlas segmentation. AB - Multi-atlas segmentation has been widely used to segment various anatomical structures. The success of this technique partly relies on the selection of atlases that are best mapped to a new target image after registration. Recently, manifold learning has been proposed as a method for atlas selection. Each manifold learning technique seeks to optimize a unique objective function. Therefore, different techniques produce different embeddings even when applied to the same data set. Previous studies used a single technique in their method and gave no reason for the choice of the manifold learning technique employed nor the theoretical grounds for the choice of the manifold parameters. In this study, we compare side-by-side the results given by 3 manifold learning techniques (Isomap, Laplacian Eigenmaps and Locally Linear Embedding) on the same data set. We assess the ability of those 3 different techniques to select the best atlases to combine in the framework of multi-atlas segmentation. First, a leave-one-out experiment is used to optimize our method on a set of 110 manually segmented atlases of hippocampi and find the manifold learning technique and associated manifold parameters that give the best segmentation accuracy. Then, the optimal parameters are used to automatically segment 30 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). For our dataset, the selection of atlases with Locally Linear Embedding gives the best results. Our findings show that selection of atlases with manifold learning leads to segmentation accuracy close to or significantly higher than the state-of-the-art method and that accuracy can be increased by fine tuning the manifold learning process. PMID- 23936377 TI - Effects of acute exposure to moderate altitude on vascular function, metabolism and systemic inflammation. AB - BACKGROUND: Travel to mountain areas is popular. However, the effects of acute exposure to moderate altitude on the cardiovascular system and metabolism are largely unknown. OBJECTIVES: To investigate the effects of acute exposure to moderate altitude on vascular function, metabolism and systemic inflammation. METHODS: In 51 healthy male subjects with a mean (SD) age of 26.9 (9.3) years, oxygen saturation, blood pressure, heart rate, arterial stiffness, lipid profiles, low density lipoprotein (LDL) particle size, insulin resistance (HOMA index), highly-sensitive C-reactive protein and pro-inflammatory cytokines were measured at 490 m (Zurich) and during two days at 2590 m, (Davos Jakobshorn, Switzerland) in randomized order. The largest differences in outcomes between the two altitudes are reported. RESULTS: Mean (SD) oxygen saturation was significantly lower at 2590 m, 91.0 (2.0)%, compared to 490 m, 96.0 (1.0)%, p<0.001. Mean blood pressure (mean difference +4.8 mmHg, p<0.001) and heart rate (mean difference +3.3 bpm, p<0.001) were significantly higher at 2590 m, compared to 490 m, but this was not associated with increased arterial stiffness. At 2590 m, lipid profiles improved (median difference triglycerides -0.14 mmol/l, p=0.012, HDL +0.08 mmol/l, p<0.001, total cholesterol/HDL-ratio -0.25, p=0.001), LDL particle size increased (median difference +0.45 nm, p=0.048) and hsCRP decreased (median difference -0.18 mg/l, p=0.024) compared to 490 m. No significant change in pro-inflammatory cytokines or insulin resistance was observed upon ascent to 2590 m. CONCLUSIONS: Short-term stay at moderate altitude is associated with increased blood pressure and heart rate likely due to augmented sympathetic activity. Exposure to moderate altitude improves the lipid profile and systemic inflammation, but seems to have no significant effect on glucose metabolism. TRIAL REGISTRATION: ClinicalTrials.gov NCT01130948. PMID- 23936378 TI - Impaired prefronto-thalamic functional connectivity as a key feature of treatment resistant depression: a combined MEG, PET and rTMS study. AB - Prefrontal left-right functional imbalance and disrupted prefronto-thalamic circuitry are plausible mechanisms for treatment-resistant depression (TRD). Add on repetitive transcranial magnetic stimulation (rTMS), effective in treating antidepressant-refractory TRD, was administered to verify the core mechanisms underlying the refractoriness to antidepressants. Thirty TRD patients received a 2-week course of 10-Hz rTMS to the left dorsolateral prefrontal cortex (DLPFC). Depression scores were evaluated at baseline (W0), and the ends of weeks 1, 2, and 14 (W14). Responders were defined as those who showed an objective improvement in depression scores >=50% after rTMS. Left-right frontal alpha asymmetry (FAA) was measured by magnetoencephalography at each time point as a proxy for left-right functional imbalance. Prefronto-thalamic connections at W0 and W14 were assessed by studying couplings between prefrontal alpha waves and thalamic glucose metabolism (PWTMC, reflecting intact thalamo-prefrontal connectivity). A group of healthy control subjects received magnetoencephalography at W0 (N = 50) to study whether FAA could have a diagnostic value for TRD, or received both magnetoencephalography and positron emission-tomography at W0 (N = 10) to confirm the existence of PWTMC in the depression-free state. We found that FAA changes cannot differentiate between TRD and healthy subjects or between responders and non-responders. No PWTMC were found in the TRD group at W0, whereas restitution of the PWTMC was demonstrated only in the sustained responders at W14 and euthymic healthy controls. In conclusion, we affirmed impaired prefronto-thalamic functional connections, but not frontal functional imbalance, as a core deficit in TRD. PMID- 23936380 TI - The power of ground user in recommender systems. AB - Accuracy and diversity are two important aspects to evaluate the performance of recommender systems. Two diffusion-based methods were proposed respectively inspired by the mass diffusion (MD) and heat conduction (HC) processes on networks. It has been pointed out that MD has high recommendation accuracy yet low diversity, while HC succeeds in seeking out novel or niche items but with relatively low accuracy. The accuracy-diversity dilemma is a long-term challenge in recommender systems. To solve this problem, we introduced a background temperature by adding a ground user who connects to all the items in the user item bipartite network. Performing the HC algorithm on the network with ground user (GHC), it showed that the accuracy can be largely improved while keeping the diversity. Furthermore, we proposed a weighted form of the ground user (WGHC) by assigning some weights to the newly added links between the ground user and the items. By turning the weight as a free parameter, an optimal value subject to the highest accuracy is obtained. Experimental results on three benchmark data sets showed that the WGHC outperforms the state-of-the-art method MD for both accuracy and diversity. PMID- 23936379 TI - Isolation of a bacteriophage specific for a new capsular type of Klebsiella pneumoniae and characterization of its polysaccharide depolymerase. AB - BACKGROUND: Klebsiella pneumoniae is one of the major pathogens causing hospital acquired multidrug-resistant infections. The capsular polysaccharide (CPS) is an important virulence factor of K. pneumoniae. With 78 capsular types discovered thus far, an association between capsular type and the pathogenicity of K. pneumoniae has been observed. METHODOLOGY/PRINCIPAL FINDINGS: To investigate an initially non-typeable K. pneumoniae UTI isolate NTUH-K1790N, the cps gene region was sequenced. By NTUH-K1790N cps-PCR genotyping, serotyping and determination using a newly isolated capsular type-specific bacteriophage, we found that NTUH K1790N and three other isolates Ca0507, Ca0421 and C1975 possessed a new capsular type, which we named KN2. Analysis of a KN2 CPS(-) mutant confirmed the role of capsule as the target recognized by the antiserum and the phage. A newly described lytic phage specific for KN2 K. pneumoniae, named 0507-KN2-1, was isolated and characterized using transmission electron microscopy. Whole-genome sequencing of 0507-KN2-1 revealed a 159 991 bp double-stranded DNA genome with a G+C content of 46.7% and at least 154 open reading frames. Based on its morphological and genomic characteristics, 0507-KN2-1 was classified as a member of the Myoviridae phage family. Further analysis of this phage revealed a 3738-bp gene encoding a putative polysaccharide depolymerase. A recombinant form of this protein was produced and assayed to confirm its enzymatic activity and specificity to KN2 capsular polysaccharides. KN2 K. pneumoniae strains exhibited greater sensitivity to this depolymerase than these did to the cognate phage, as determined by spot analysis. CONCLUSIONS/SIGNIFICANCE: Here we report that a group of clinical strains possess a novel Klebsiella capsular type. We identified a KN2-specific phage and its polysaccharide depolymerase, which could be used for efficient capsular typing. The lytic phage and depolymerase also have potential as alternative therapeutic agents to antibiotics for treating K. pneumoniae infections, especially against antibiotic-resistant strains. PMID- 23936381 TI - High-throughput metabolic profiling of diverse green Coffea arabica beans identified tryptophan as a universal discrimination factor for immature beans. AB - The maturity of green coffee beans is the most influential determinant of the quality and flavor of the resultant coffee beverage. However, the chemical compounds that can be used to discriminate the maturity of the beans remain uncharacterized. We herein analyzed four distinct stages of maturity (immature, semi-mature, mature and overripe) of nine different varieties of green Coffea arabica beans hand-harvested from a single experimental field in Hawaii. After developing a high-throughput experimental system for sample preparation and liquid chromatography-mass spectrometry (LC-MS) measurement, we applied metabolic profiling, integrated with chemometric techniques, to explore the relationship between the metabolome and maturity of the sample in a non-biased way. For the multivariate statistical analyses, a partial least square (PLS) regression model was successfully created, which allowed us to accurately predict the maturity of the beans based on the metabolomic information. As a result, tryptophan was identified to be the best contributor to the regression model; the relative MS intensity of tryptophan was higher in immature beans than in those after the semi mature stages in all arabica varieties investigated, demonstrating a universal discrimination factor for diverse arabica beans. Therefore, typtophan, either alone or together with other metabolites, may be utilized for traders as an assessment standard when purchasing qualified trading green arabica bean products. Furthermore, our results suggest that the tryptophan metabolism may be tightly linked to the development of coffee cherries and/or beans. PMID- 23936382 TI - Molecular cloning and functional characterization of the dual oxidase (BmDuox) gene from the silkworm Bombyx mori. AB - Reactive oxygen species (ROS) from nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and their related dual oxidases are known to have significant roles in innate immunity and cell proliferation. In this study, the 5,545 bp cDNA of the silkworm Bombyx mori dual oxidase (BmDuox) gene containing a full-length open reading frame was cloned. It was shown to include an N-terminal signal peptide consisting of 28 amino acid residues, a 240 bp 5'-terminal untranslated region (5'-UTR), an 802 bp 3'-terminal region (3'-UTR), which contains nine ATTTA motifs, and a 4,503 bp open reading frame encoding a polypeptide of 1,500 amino acid residues. Structural analysis indicated that BmDuox contains a typical peroxidase domain at the N-terminus followed by a calcium-binding domain, a ferric-reducing domain, six transmembrane regions and binding domains for flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NAD). Transcriptional analysis revealed that BmDuox mRNA was expressed more highly in the head, testis and trachea compared to the midgut, hemocyte, Malpighian tube, ovary, fat bodies and silk glands. BmDuox mRNA was expressed during all the developmental stages of the silkworm. Subcellular localization revealed that BmDoux was present mainly in the periphery of the cells. Some cytoplasmic staining was detected, with rare signals in the nucleus. Expression of BmDuox was induced significantly in the larval midgut upon challenge by Escherichia coli and Bombyx mori nucleopolyhedrovirus (BmNPV). BmDuox-deleted larvae showed a marked increase in microbial proliferation in the midgut after ingestion of fluorescence labeled bacteria compared to the control. We conclude that reducing BmDuox expression greatly increased the bacterial load, suggesting BmDuox has an important role in inhibiting microbial proliferation and the maintenance of homeostasis in the silkworm midgut. PMID- 23936383 TI - Improved-throughput traction microscopy based on fluorescence micropattern for manual microscopy. AB - Traction force microscopy (TFM) is a quantitative technique for measuring cellular traction force, which is important in understanding cellular mechanotransduction processes. Traditional TFM has a significant limitation in that it has a low measurement throughput, commonly one per TFM dish, due to a lack of cell position information. To obtain enough cellular traction force data, an onerous workload is required including numerous TFM dish preparations and heavy cell-seeding activities, creating further difficulty in achieving identical experimental conditions among batches. In this paper, we present an improved throughput TFM method using the well-developed microcontact printing technique and chemical modifications of linking microbeads to the gel surface to address these limitations. Chemically linking the microbeads to the gel surface has no significant influence on cell proliferation, morphology, cytoskeleton, and adhesion. Multiple pairs of force loaded and null force fluorescence images can be easily acquired by means of manual microscope with the aid of a fluorescence micropattern made by microcontact printing. Furthermore, keeping the micropattern separate from cells by using gels effectively eliminates the potential negative effect of the micropattern on the cells. This novel design greatly improves the analysis throughput of traditional TFM from one to at least twenty cells per petri dish without losing unique advantages, including a high spatial resolution of traction measurements. This newly developed method will boost the investigation of cell-matrix mechanical interactions. PMID- 23936384 TI - Identification of a novel picornavirus in healthy piglets and seroepidemiological evidence of its presence in humans. AB - In this study, we describe a novel porcine parechovirus-like virus (tentatively named PLV-CHN) from healthy piglets in China using 454 high-throughput sequencing. The complete genome of the virus comprises 6832 bp, encoding a predicted polyprotein of 2132 amino acids that is most similar to Ljungan virus (32% identity). A similar virus that belongs to a novel Picornaviridae genus, named swine pasivirus 1 (SPaV-1), was reported during the preparation of this paper. Sequence analysis revealed that PLV-CHN and SPaV1 shared 82% nucleotide identity and 89% amino acid identity. Further genomic and phylogenetic analyses suggested that both SPaV1 and PLV-CHN shared similar genomic characteristics and belong to the same novel Picornaviridae genus. A total of 36 (20.0%) fecal samples from 180 healthy piglets were positive for PLV-CHN by RT-PCR, while no fecal samples from 100 healthy children and 100 children with diarrhea, and no cerebrospinal fluid samples from 196 children with suspected viral encephalitis, was positive for the virus. However, Western blot and enzyme-linked immunosorbent assays using recombinant PLV-CHN VP1 polypeptide as an antigen showed a high seroprevalence of 63.5% in the healthy population. When grouped by age, the antibody-positivity rates showed that the majority of children under 12 years of age have been infected by the virus. It was suggested that PLV-CHN, SPaV1, or an as-yet-uncharacterized virus can infect humans early in life. Thus, investigation of the role of this novel virus is vital. PMID- 23936385 TI - The efficacy of an immunoisolating membrane system for islet xenotransplantation in minipigs. AB - Developing a device that protects xenogeneic islets to allow treatment and potentially cure of diabetes in large mammals has been a major challenge in the past decade. Using xenogeneic islets for transplantation is required in light of donor shortage and the large number of diabetic patients that qualify for islet transplantation. Until now, however, host immunoreactivity against the xenogeneic graft has been a major drawback for the use of porcine islets. Our study demonstrates the applicability of a novel immunoprotective membrane that allows successful xenotransplantation of rat islets in diabetic minipigs without immunosuppressive therapy. Rat pancreatic islets were encapsulated in highly purified alginate and integrated into a plastic macrochamber covered by a poly membrane for subcutaneous transplantation. Diabetic Sinclair pigs were transplanted and followed for up to 90 days. We demonstrated a persistent graft function and restoration of normoglycemia without the need for immunosuppressive therapy. This concept could potentially offer an attractive strategy for a more widespread islet replacement therapy that would restore endogenous insulin secretion in diabetic patients without the need for immunosuppressive drugs and may even open up an avenue for safe utilization of xenogeneic islet donors. PMID- 23936386 TI - Why herd size matters - mitigating the effects of livestock crashes. AB - Analysing the effect of pastoral risk management strategies provides insights into a system of subsistence that have persevered in marginal areas for hundreds to thousands of years and may shed light into the future of around 200 million households in the face of climate change. This study investigated the efficiency of herd accumulation as a buffer strategy by analysing changes in livestock holdings during an environmental crisis in the Saami reindeer husbandry in Norway. We found a positive relationship between: (1) pre- and post-collapse herd size; and (2) pre-collapse herd size and the number of animals lost during the collapse, indicating that herd accumulation is an effective but costly strategy. Policies that fail to incorporate the risk-beneficial aspect of herd accumulation will have a limited effect and may indeed fail entirely. In the context of climate change, official policies that incorporate pastoral risk management strategies may be the only solution for ensuring their continued existence. PMID- 23936387 TI - A possible mechanism behind autoimmune disorders discovered by genome-wide linkage and association analysis in celiac disease. AB - Celiac disease is a common autoimmune disorder characterized by an intestinal inflammation triggered by gluten, a storage protein found in wheat, rye and barley. Similar to other autoimmune diseases such as type 1 diabetes, psoriasis and rheumatoid arthritis, celiac disease is the result of an immune response to self-antigens leading to tissue destruction and production of autoantibodies. Common diseases like celiac disease have a complex pattern of inheritance with inputs from both environmental as well as additive and non-additive genetic factors. In the past few years, Genome Wide Association Studies (GWAS) have been successful in finding genetic risk variants behind many common diseases and traits. To complement and add to the previous findings, we performed a GWAS including 206 trios from 97 nuclear Swedish and Norwegian families affected with celiac disease. By stratifying for HLA-DQ, we identified a new genome-wide significant risk locus covering the DUSP10 gene. To further investigate the associations from the GWAS we performed pathway analyses and two-locus interaction analyses. These analyses showed an over-representation of genes involved in type 2 diabetes and identified a set of candidate mechanisms and genes of which some were selected for mRNA expression analysis using small intestinal biopsies from 98 patients. Several genes were expressed differently in the small intestinal mucosa from patients with celiac autoimmunity compared to intestinal mucosa from control patients. From top-scoring regions we identified susceptibility genes in several categories: 1) polarity and epithelial cell functionality; 2) intestinal smooth muscle; 3) growth and energy homeostasis, including proline and glutamine metabolism; and finally 4) innate and adaptive immune system. These genes and pathways, including specific functions of DUSP10, together reveal a new potential biological mechanism that could influence the genesis of celiac disease, and possibly also other chronic disorders with an inflammatory component. PMID- 23936388 TI - Transcriptional events during the recovery from MRSA lung infection: a mouse pneumonia model. AB - Community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging threat to human health throughout the world. Rodent MRSA pneumonia models mainly focus on the early innate immune responses to MRSA lung infection. However, the molecular pattern and mechanisms of recovery from MRSA lung infection are largely unknown. In this study, a sublethal mouse MRSA pneumonia model was employed to investigate late events during the recovery from MRSA lung infection. We compared lung bacterial clearance, bronchoalveolar lavage fluid (BALF) characterization, lung histology, lung cell proliferation, lung vascular permeability and lung gene expression profiling between days 1 and 3 post MRSA lung infection. Compared to day 1 post infection, bacterial colony counts, BALF total cell number and BALF protein concentration significantly decreased at day 3 post infection. Lung cDNA microarray analysis identified 47 significantly up regulated and 35 down-regulated genes (p<0.01, 1.5 fold change [up and down]). The pattern of gene expression suggests that lung recovery is characterized by enhanced cell division, vascularization, wound healing and adjustment of host adaptive immune responses. Proliferation assay by PCNA staining further confirmed that at day 3 lungs have significantly higher cell proliferation than at day 1. Furthermore, at day 3 lungs displayed significantly lower levels of vascular permeability to albumin, compared to day 1. Collectively, this data helps us elucidate the molecular mechanisms of the recovery after MRSA lung infection. PMID- 23936389 TI - Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials. AB - OBJECTIVE: To compare the safety and efficacy of adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia. METHODS: POPULATION: adult patients presenting with antipsychotic-induced hyperprolactinemia diagnosed by prolactin level with or without prolactin-related symptoms. INTERVENTIONS: adjunctive aripiprazole vs. adjunctive placebo. OUTCOME MEASURES: adverse events and efficacy of treatment. STUDIES: randomized controlled trials. RESULTS: Five randomized controlled trials with a total of 639 patients (326 adjunctive aripiprazole, 313 adjunctive placebo) met the inclusion criteria. Adjunctive aripiprazole was associated with a 79.11% (125/158) prolactin level normalization rate. Meta-analysis of insomnia, headache, sedation, psychiatric disorder, extrapyramidal symptom, dry mouth, and fatigue showed no significant differences in the adjunctive aripiprazole treatment group compared with the placebo group (risk difference (Mantel-Haenszel, random or fixed) -0.05 to 0.04 (95% confidence interval -0.13 to 0.16); I(2) =0% to 68%, P=0.20 to 0.70). However, sedation, insomnia, and headache were more frequent when the adjunctive aripiprazole dose was higher than 15 mg/day. Meta-analysis of the prolactin level normalization indicated adjunctive aripiprazole was superior to placebo (risk difference (Mantel-Haenszel, random) 0.76 (95% confidence interval 0.67 to 0.85); I(2) =43%, P<0.00001). The subgroup analysis confirmed that the subjects who received adjunctive aripiprazole 5 mg/day showed a degree of prolactin normalization similar to that of all participants. No significant differences between groups in discontinuation and improvements of psychiatric symptoms. CONCLUSION: Adjunctive aripiprazole is both safe and effective as a reasonable choice treatment for patients with antipsychotic-induced hyperprolactinemia. The appropriate dose of adjunctive aripiprazole may be 5 mg/day. PMID- 23936390 TI - miRNA-29c suppresses lung cancer cell adhesion to extracellular matrix and metastasis by targeting integrin beta1 and matrix metalloproteinase2 (MMP2). AB - Our pilot study using miRNA arrays found that miRNA-29c (miR-29c) is differentially expressed in the paired low-metastatic lung cancer cell line 95C compared to the high-metastatic lung cancer cell line 95D. Bioinformatics analysis shows that integrin beta1 and matrix metalloproteinase 2 (MMP2) could be important target genes of miR-29c. Therefore, we hypothesized that miR-29c suppresses lung cancer cell adhesion to extracellular matrix (ECM) and metastasis by targeting integrin beta1 and MMP2. The gain-of-function studies that raised miR-29c expression in 95D cells by using its mimics showed reductions in cell proliferation, adhesion to ECM, invasion and migration. In contrasts, loss-of function studies that reduced miR-29c by using its inhibitor in 95C cells promoted proliferation, adhesion to ECM, invasion and migration. Furthermore, the dual-luciferase reporter assay demonstrated that miR-29c inhibited the expression of the luciferase gene containing the 3'-UTRs of integrin beta1 and MMP2 mRNA. Western blotting indicated that miR-29c downregulated the expression of integrin beta1 and MMP2 at the protein level. Gelatin zymography analysis further confirmed that miR-29c decreased MMP2 enzyme activity. Nude mice with xenograft models of lung cancer cells confirmed that miR-29c inhibited lung cancer metastasis in vivo, including bone and liver metastasis. Taken together, our results demonstrate that miR-29c serves as a tumor metastasis suppressor, which suppresses lung cancer cell adhesion to ECM and metastasis by directly inhibiting integrin beta1 and MMP2 expression and by further reducing MMP2 enzyme activity. The results show that miR-29c may be a novel therapeutic candidate target to slow lung cancer metastasis. PMID- 23936391 TI - Separate and joint associations of occupational and leisure-time sitting with cardio-metabolic risk factors in working adults: a cross-sectional study. AB - BACKGROUND: The workplace is a main setting for prolonged sitting for some occupational groups. Convincing evidence has recently accumulated on the detrimental cardio-metabolic health effects of leisure-time sitting. Yet, much less is known about occupational sitting, and the potential health risk attached compared to leisure-time sitting. OBJECTIVE: To explore the separate and joint associations of occupational and leisure-time sitting with cardio-metabolic risk factors in working adults. METHODS: All working adults (N = 2544) from the Health2006, a Danish population-based study, were included in this cross sectional study. Participants reported hours of sitting during work, during leisure-time along with socio-demographic and behavioral characteristics, including physical activity. Cardio-metabolic risk factors (waist circumference, body mass index, body fat percentage, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, insulin, hemoglobin A1c and plasma glucose) were measured. Associations were explored by linear regression for leisure-time, occupational, and overall sitting time. RESULTS: Statistically significant (p<.05) detrimental associations of leisure-time sitting were observed with all cardio-metabolic risk factors, except hemoglobin A1c and plasma glucose. Similarly, occupational sitting time was significantly detrimentally associated with HDL cholesterol, triglycerides, and insulin. For categories of sitting time, a joint adverse association of sitting much during both work-time and leisure time was observed. CONCLUSION: The associations of occupational sitting time with cardio-metabolic risk factors were fewer and weaker compared to leisure-time sitting. Yet, the joint associations of occupational and leisure-time sitting with cardio-metabolic risk factors were higher than the separate. Our findings amplify the need for further focus in this area prior to making assumptions about equivalent health risks across sedentary behaviors. To our knowledge, this is the first study to contrast the deleterious associations of prolonged occupational and leisure-time sitting, both separately and jointly. PMID- 23936392 TI - Heat stress reduces intestinal barrier integrity and favors intestinal glucose transport in growing pigs. AB - Excessive heat exposure reduces intestinal integrity and post-absorptive energetics that can inhibit wellbeing and be fatal. Therefore, our objectives were to examine how acute heat stress (HS) alters intestinal integrity and metabolism in growing pigs. Animals were exposed to either thermal neutral (TN, 21 degrees C; 35-50% humidity; n=8) or HS conditions (35 degrees C; 24-43% humidity; n=8) for 24 h. Compared to TN, rectal temperatures in HS pigs increased by 1.6 degrees C and respiration rates by 2-fold (P<0.05). As expected, HS decreased feed intake by 53% (P<0.05) and body weight (P<0.05) compared to TN pigs. Ileum heat shock protein 70 expression increased (P<0.05), while intestinal integrity was compromised in the HS pigs (ileum and colon TER decreased; P<0.05). Furthermore, HS increased serum endotoxin concentrations (P=0.05). Intestinal permeability was accompanied by an increase in protein expression of myosin light chain kinase (P<0.05) and casein kinase II-alpha (P=0.06). Protein expression of tight junction (TJ) proteins in the ileum revealed claudin 3 and occludin expression to be increased overall due to HS (P<0.05), while there were no differences in claudin 1 expression. Intestinal glucose transport and blood glucose were elevated due to HS (P<0.05). This was supported by increased ileum Na(+)/K(+) ATPase activity in HS pigs. SGLT-1 protein expression was unaltered; however, HS increased ileal GLUT-2 protein expression (P=0.06). Altogether, these data indicate that HS reduce intestinal integrity and increase intestinal stress and glucose transport. PMID- 23936393 TI - Contribution of FKBP5 genetic variation to gemcitabine treatment and survival in pancreatic adenocarcinoma. AB - PURPOSE: FKBP51, (FKBP5), is a negative regulator of Akt. Variability in FKBP5 expression level is a major factor contributing to variation in response to chemotherapeutic agents including gemcitabine, a first line treatment for pancreatic cancer. Genetic variation in FKBP5 could influence its function and, ultimately, treatment response of pancreatic cancer. EXPERIMENTAL DESIGN: We set out to comprehensively study the role of genetic variation in FKBP5 identified by Next Generation DNA resequencing on response to gemcitabine treatment of pancreatic cancer by utilizing both tumor and germline DNA samples from 43 pancreatic cancer patients, including 19 paired normal-tumor samples. Next, genotype-phenotype association studies were performed with overall survival as well as with FKBP5 gene expression in tumor using the same samples in which resequencing had been performed, followed by functional genomics studies. RESULTS: In-depth resequencing identified 404 FKBP5 single nucleotide polymorphisms (SNPs) in normal and tumor DNA. SNPs with the strongest associations with survival or FKBP5 expression were subjected to functional genomic study. Electromobility shift assay showed that the rs73748206 "A(T)" SNP altered DNA-protein binding patterns, consistent with significantly increased reporter gene activity, possibly through its increased binding to Glucocorticoid Receptor (GR). The effect of rs73748206 was confirmed on the basis of its association with FKBP5 expression by affecting the binding to GR in lymphoblastoid cell lines derived from the same patients for whom DNA was used for resequencing. CONCLUSION: This comprehensive FKBP5 resequencing study provides insights into the role of genetic variation in variation of gemcitabine response. PMID- 23936394 TI - Nation-wide, web-based, geographic information system for the integrated surveillance and control of dengue fever in Mexico. AB - Dengue fever incidence and its geographical distribution are increasing throughout the world. Quality and timely information is essential for its prevention and control. A web based, geographically enabled, dengue integral surveillance system (Dengue-GIS) was developed for the nation-wide collection, integration, analysis and reporting of geo-referenced epidemiologic, entomologic, and control interventions data. Consensus in the design and practical operation of the system was a key factor for its acceptance. Working with information systems already implemented as a starting point facilitated its acceptance by officials and operative personnel. Dengue-GIS provides the geographical detail needed to plan, asses and evaluate the impact of control activities. The system is beginning to be adopted as a knowledge base by vector control programs. It is used to generate evidence on impact and cost-effectiveness of control activities, promoting the use of information for decision making at all levels of the vector control program. Dengue-GIS has also been used as a hypothesis generator for the academic community. This GIS-based model system for dengue surveillance and the experience gathered during its development and implementation could be useful in other dengue endemic countries and extended to other infectious or chronic diseases. PMID- 23936395 TI - Absence of endochondral ossification and craniosynostosis in posterior frontal cranial sutures of Axin2(-/-) mice. AB - During the first month of life, the murine posterior-frontal suture (PF) of the cranial vault closes through endochondral ossification, while other sutures remain patent. These processes are tightly regulated by canonical Wnt signaling. Low levels of active canonical Wnt signaling enable endochondral ossification and therefore PF-suture closure, whereas constitutive activation of canonical Wnt causes PF-suture patency. We therefore sought to test this concept with a knockout mouse model. PF-sutures of Axin2(-/-) mice, which resemble a state of constantly activated canonical Wnt signaling, were investigated during the physiological time course of PF-suture closure and compared in detail with wild type littermates. Histological analysis revealed that the architecture in Axin2( /-) PF-sutures was significantly altered in comparison to wild type. The distance between the endocranial layers was dramatically increased and suture closure was significantly delayed. Moreover, physiological endochondral ossification did not occur, rather an ectopic cartilage appeared between the endocranial and ectocranial bone layers at P7 which eventually involutes at P13. Quantitative PCR analysis showed the lack of Col10alpha1 upregulation in Axin2(-/-) PF-suture. Immunohistochemistry and gene expression analysis also revealed high levels of type II collagen as compared to type I collagen and absence of Mmp-9 in the cartilage of Axin2(-/-) PF-suture. Moreover, TUNEL staining showed a high percentage of apoptotic chondrocytes in Axin2(-/-) PF-sutures at P9 and P11 as compared to wild type. These data indicated that Axin2(-/-) PF-sutures lack physiological endochondral ossification, contain ectopic cartilage and display delayed suture closure. PMID- 23936396 TI - The heterogeneity of early Parkinson's disease: a cluster analysis on newly diagnosed untreated patients. AB - BACKGROUND: The variability in the clinical phenotype of Parkinson's disease seems to suggest the existence of several subtypes of the disease. To test this hypothesis we performed a cluster analysis using data assessing both motor and non-motor symptoms in a large cohort of newly diagnosed untreated PD patients. METHODS: We collected data on demographic, motor, and the whole complex of non motor symptoms from 100 consecutive newly diagnosed untreated outpatients. Statistical cluster analysis allowed the identification of different subgroups, which have been subsequently explored. RESULTS: The data driven approach identified four distinct groups of patients, we have labeled: 1) Benign Pure Motor; 2) Benign mixed Motor-Non-Motor; 3) Non-Motor Dominant; and 4) Motor Dominant. CONCLUSION: Our results confirmed the existence of different subgroups of early PD patients. Cluster analysis revealed the presence of distinct subtypes of patients profiled according to the relevance of both motor and non-motor symptoms. Identification of such subtypes may have important implications for generating pathogenetic hypotheses and therapeutic strategies. PMID- 23936397 TI - Short term exercise induces PGC-1alpha, ameliorates inflammation and increases mitochondrial membrane proteins but fails to increase respiratory enzymes in aging diabetic hearts. AB - PGC-1alpha, a transcriptional coactivator, controls inflammation and mitochondrial gene expression in insulin-sensitive tissues following exercise intervention. However, attributing such effects to PGC-1alpha is counfounded by exercise-induced fluctuations in blood glucose, insulin or bodyweight in diabetic patients. The goal of this study was to investigate the role of PGC-1alpha on inflammation and mitochondrial protein expressions in aging db/db mice hearts, independent of changes in glycemic parameters. In 8-month-old db/db mice hearts with diabetes lasting over 22 weeks, short-term, moderate-intensity exercise upregulated PGC-1alpha without altering body weight or glycemic parameters. Nonetheless, such a regimen lowered both cardiac (macrophage infiltration, iNOS and TNFalpha) and systemic (circulating chemokines and cytokines) inflammation. Curiously, such an anti-inflammatory effect was also linked to attenuated expression of downstream transcription factors of PGC-1alpha such as NRF-1 and several respiratory genes. Such mismatch between PGC-1alpha and its downstream targets was associated with elevated mitochondrial membrane proteins like Tom70 but a concurrent reduction in oxidative phosphorylation protein expressions in exercised db/db hearts. As mitochondrial oxidative stress was predominant in these hearts, in support of our in vivo data, increasing concentrations of H2O2 dose-dependently increased PGC-1alpha expression while inhibiting expression of inflammatory genes and downstream transcription factors in H9c2 cardiomyocytes in vitro. We conclude that short-term exercise-induced oxidative stress may be key in attenuating cardiac inflammatory genes and impairing PGC-1alpha mediated gene transcription of downstream transcription factors in type 2 diabetic hearts at an advanced age. PMID- 23936398 TI - Discordance in CD4+T-cell levels and viral loads with co-occurrence of elevated peripheral TNF-alpha and IL-4 in newly diagnosed HIV-TB co-infected cases. AB - BACKGROUND: Cytokines are the hallmark of immune response to different pathogens and often dictate the disease outcome. HIV infection and tuberculosis (TB) are more destructive when confronted together than either alone. Clinical data related to the immune status of HIV-TB patients before the initiation of any drug therapy is not well documented. This study aimed to collect the baseline information pertaining to the immune status of HIV-TB co-infected patients and correlate the same with CD4+T cell levels and viral loads at the time of diagnosis prior to any drug therapy. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the cytokines, CD4+T cell levels and viral loads to determine the immune environment in HIV-TB co-infection. The study involved four categories namely, Healthy controls (n=57), TB infected (n=57), HIV infected (n=59) and HIV-TB co infected (n=57) patients. The multi-partite comparison and correlation between cytokines, CD4+T-cell levels and viral loads prior to drug therapy, showed an altered TH1 and TH2 response, as indicated by the cytokine profiles and skewed IFN-gamma/IL-10 ratio. Inadequate CD4+T cell counts in HIV-TB patients did not correlate with high viral loads and vice-versa. When compared to HIV category, 34% of HIV-TB patients had concurrent high plasma levels of IL-4 and TNF-alpha at the time of diagnosis. TB relapse was observed in 5 of these HIV-TB co-infected patients who also displayed high IFN-gamma/IL-10 ratio. CONCLUSION/SIGNIFICANCE: With these studies, we infer (i) CD4+T-cell levels as baseline criteria to report the disease progression in terms of viral load in HIV-TB co-infected patients can be misleading and (ii) co-occurrence of high TNF-alpha and IL-4 levels along with a high ratio of IFN-gamma/IL-10, prior to drug therapy, may increase the susceptibility of HIV-TB co-infected patients to hyper-inflammation and TB relapse. PMID- 23936399 TI - A systematic review of music therapy practice and outcomes with acute adult psychiatric in-patients. AB - BACKGROUND AND OBJECTIVES: There is an emerging evidence base for the use of music therapy in the treatment of severe mental illness. Whilst different models of music therapy have been developed in mental health care, none have specifically accounted for the features and context of acute in-patient settings. This review aimed to identify how music therapy is provided for acute adult psychiatric in-patients and what outcomes have been reported. REVIEW METHODS: A systematic review using medical, psychological and music therapy databases. Papers describing music therapy with acute adult psychiatric in-patients were included. Analysis utilised narrative synthesis. RESULTS: 98 papers were identified, of which 35 reported research findings. Open group work and active music making for nonverbal expression alongside verbal reflection was emphasised. Aims were engagement, communication and interpersonal relationships focusing upon immediate areas of need rather than longer term insight. The short stay, patient diversity and institutional structure influenced delivery and resulted in a focus on single sessions, high session frequency, more therapist direction, flexible use of musical activities, predictable musical structures, and clear realistic goals. Outcome studies suggested effectiveness in addressing a range of symptoms, but were limited by methodological shortcomings and small sample sizes. Studies with significant positive effects all used active musical participation with a degree of structure and were delivered in four or more sessions. CONCLUSIONS: No single clearly defined model exists for music therapy with adults in acute psychiatric in-patient settings, and described models are not conclusive. Greater frequency of therapy, active structured music making with verbal discussion, consistency of contact and boundaries, an emphasis on building a therapeutic relationship and building patient resources may be of particular importance. Further research is required to develop specific music therapy models for this patient group that can be tested in experimental studies. PMID- 23936400 TI - Plant species composition alters the sign and strength of an emergent multi predator effect by modifying predator foraging behaviour. AB - The prediction of pest-control functioning by multi-predator communities is hindered by the non-additive nature of species functioning. Such non-additivity, commonly termed an emergent multi-predator effect, is known to be affected by elements of the ecological context, such as the structure and composition of vegetation, in addition to the traits of the predators themselves. Here we report mesocosm experiments designed to test the influence of plant density and species composition (wheat monoculture or wheat and faba bean polyculture) on the emergence of multi-predator effects between Adalia bipunctata and Chrysoperla carnea, in their suppression of populations of the aphid Metopolophium dirhodum. The mesocosm experiments were followed by a series of behavioural observations designed to identify how interactions among predators are modified by plant species composition and whether these effects are consistent with the observed influence of plant species composition on aphid population suppression. Although plant density was shown to have no influence on the multi-predator effect on aphid population growth, plant composition had a marked effect. In wheat monoculture, Adalia and Chrysoperla mixed treatments caused greater suppression of M. dirhodum populations than expected. However this positive emergent effect was reversed to a negative multi-predator effect in wheat and faba bean polyculture. The behavioural observations revealed that although dominant individuals did not respond to the presence of faba bean plants, the behaviour of sub-dominants was affected markedly, consistent with their foraging for extra floral nectar produced by the faba bean. This interaction between plant composition and predator community composition on the foraging behaviour of sub dominants is thought to underlie the observed effect of plant composition on the multi-predator effect. Thus, the emergence of multi-predator effects is shown to be strongly influenced by plant species composition, mediated, in this case, by the provision of extra-floral nectar by one of the plant species. PMID- 23936401 TI - Assessing uncertainty in high-resolution spatial climate data across the US Northeast. AB - Local and regional-scale knowledge of climate change is needed to model ecosystem responses, assess vulnerabilities and devise effective adaptation strategies. High-resolution gridded historical climate (GHC) products address this need, but come with multiple sources of uncertainty that are typically not well understood by data users. To better understand this uncertainty in a region with a complex climatology, we conducted a ground-truthing analysis of two 4 km GHC temperature products (PRISM and NRCC) for the US Northeast using 51 Cooperative Network (COOP) weather stations utilized by both GHC products. We estimated GHC prediction error for monthly temperature means and trends (1980-2009) across the US Northeast and evaluated any landscape effects (e.g., elevation, distance from coast) on those prediction errors. Results indicated that station-based prediction errors for the two GHC products were similar in magnitude, but on average, the NRCC product predicted cooler than observed temperature means and trends, while PRISM was cooler for means and warmer for trends. We found no evidence for systematic sources of uncertainty across the US Northeast, although errors were largest at high elevations. Errors in the coarse-scale (4 km) digital elevation models used by each product were correlated with temperature prediction errors, more so for NRCC than PRISM. In summary, uncertainty in spatial climate data has many sources and we recommend that data users develop an understanding of uncertainty at the appropriate scales for their purposes. To this end, we demonstrate a simple method for utilizing weather stations to assess local GHC uncertainty and inform decisions among alternative GHC products. PMID- 23936402 TI - A handheld point-of-care genomic diagnostic system. AB - The rapid detection and identification of infectious disease pathogens is a critical need for healthcare in both developed and developing countries. As we gain more insight into the genomic basis of pathogen infectivity and drug resistance, point-of-care nucleic acid testing will likely become an important tool for global health. In this paper, we present an inexpensive, handheld, battery-powered instrument designed to enable pathogen genotyping in the developing world. Our Microfluidic Biomolecular Amplification Reader (uBAR) represents the convergence of molecular biology, microfluidics, optics, and electronics technology. The uBAR is capable of carrying out isothermal nucleic acid amplification assays with real-time fluorescence readout at a fraction of the cost of conventional benchtop thermocyclers. Additionally, the uBAR features cell phone data connectivity and GPS sample geotagging which can enable epidemiological surveying and remote healthcare delivery. The uBAR controls assay temperature through an integrated resistive heater and monitors real-time fluorescence signals from 60 individual reaction chambers using LEDs and phototransistors. Assays are carried out on PDMS disposable microfluidic cartridges which require no external power for sample loading. We characterize the fluorescence detection limits, heater uniformity, and battery life of the instrument. As a proof-of-principle, we demonstrate the detection of the HIV-1 integrase gene with the uBAR using the Loop-Mediated Isothermal Amplification (LAMP) assay. Although we focus on the detection of purified DNA here, LAMP has previously been demonstrated with a range of clinical samples, and our eventual goal is to develop a microfluidic device which includes on-chip sample preparation from raw samples. The uBAR is based entirely around open source hardware and software, and in the accompanying online supplement we present a full set of schematics, bill of materials, PCB layouts, CAD drawings, and source code for the uBAR instrument with the goal of spurring further innovation toward low-cost genetic diagnostics. PMID- 23936404 TI - Cell guidance on nanogratings: a computational model of the interplay between PC12 growth cones and nanostructures. AB - BACKGROUND: Recently, the effects of nanogratings have been investigated on PC12 with respect to cell polarity, neuronal differentiation, migration, maturation of focal adhesions and alignment of neurites. METHODOLOGY/PRINCIPAL FINDINGS: A synergistic procedure was used to study the mechanism of alignment of PC12 neurites with respect to the main direction of nanogratings. Finite Element simulations were used to qualitatively assess the distribution of stresses at the interface between non-spread growth cones and filopodia, and to study their dependence on filopodial length and orientation. After modelling all adhesions under non-spread growth cone and filopodial protrusions, the values of local stress maxima resulted from the length of filopodia. Since the stress was assumed to be the main triggering cause leading to the increase and stabilization of filopodia, the position of the local maxima was directly related to the orientation of neurites. An analytic closed form equation was then written to quantitatively assess the average ridge width needed to achieve a given neuritic alignment (R(2) = 0.96), and the alignment course, when the ridge depth varied (R(2) = 0.97). A computational framework was implemented within an improved free Java environment (CX3D) and in silico simulations were carried out to reproduce and predict biological experiments. No significant differences were found between biological experiments and in silico simulations (alignment, p = 0.3571; tortuosity, p = 0.2236) with a standard level of confidence (95%). CONCLUSIONS/SIGNIFICANCE: A mechanism involved in filopodial sensing of nanogratings is proposed and modelled through a synergistic use of FE models, theoretical equations and in silico simulations. This approach shows the importance of the neuritic terminal geometry, and the key role of the distribution of the adhesion constraints for the cell/substrate coupling process. Finally, the effects of the geometry of nanogratings were explicitly considered in cell/surface interactions thanks to the analytic framework presented in this work. PMID- 23936403 TI - Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease. AB - Parkinson's disease (PD) pathology is characterized by the formation of intra neuronal inclusions called Lewy bodies, which are comprised of alpha-synuclein (alpha-syn). Duplication, triplication or genetic mutations in alpha-syn (A53T, A30P and E46K) are linked to autosomal dominant PD; thus implicating its role in the pathogenesis of PD. In both PD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of protein aggregates (i.e., alpha-syn) and neurodegeneration. Characterization of the timing and nature of symptomatic dysfunction is important for understanding the impact of alpha-syn on disease progression. Furthermore, this knowledge is essential for identifying pathways and molecular targets for therapeutic intervention. To this end, we examined various functional and morphological endpoints in the transgenic mouse model expressing the human A53T alpha-syn variant directed by the mouse prion promoter at specific ages relating to disease progression (2, 6 and 12 months of age). Our findings indicate A53T mice develop fine, sensorimotor, and synaptic deficits before the onset of age-related gross motor and cognitive dysfunction. Results from open field and rotarod tests show A53T mice develop age-dependent changes in locomotor activity and reduced anxiety like behavior. Additionally, digigait analysis shows these mice develop an abnormal gait by 12 months of age. A53T mice also exhibit spatial memory deficits at 6 and 12 months, as demonstrated by Y-maze performance. In contrast to gross motor and cognitive changes, A53T mice display significant impairments in fine- and sensorimotor tasks such as grooming, nest building and acoustic startle as early as 1-2 months of age. These mice also show significant abnormalities in basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD). Combined, these data indicate the A53T model exhibits early- and late onset behavioral and synaptic impairments similar to PD patients and may provide useful endpoints for assessing novel therapeutic interventions for PD. PMID- 23936405 TI - Profiling the cross reactivity of ubiquitin with the Nedd8 activating enzyme by phage display. AB - The C-terminal peptides of ubiquitin (UB) and UB-like proteins (UBLs) play a key role in their recognition by the specific activating enzymes (E1s) to launch their transfer through the respective enzymatic cascades thus modifying cellular proteins. UB and Nedd8, a UBL regulating the activity of cullin-RING UB ligases, only differ by one residue at their C-termini; yet each has its specific E1 for the activation reaction. It has been reported recently that UAE can cross react with Nedd8 to enable its passage through the UB transfer cascade for protein neddylation. To elucidate differences in UB recognition by UAE and NAE, we carried out phage selection of a UB library with randomized C-terminal sequences based on the catalytic formation of UB~NAE thioester conjugates. Our results confirmed the previous finding that residue 72 of UB plays a "gate-keeping" role in E1 selectivity. We also found that diverse sequences flanking residue 72 at the UB C-terminus can be accommodated by NAE for activation. Furthermore heptameric peptides derived from the C-terminal sequences of UB variants selected for NAE activation can function as mimics of Nedd8 to form thioester conjugates with NAE and the downstream E2 enzyme Ubc12 in the Nedd8 transfer cascade. Once the peptides are charged onto the cascade enzymes, the full-length Nedd8 protein is effectively blocked from passing through the cascade for the critical modification of cullin. We have thus identified a new class of inhibitors of protein neddylation based on the profiles of the UB C-terminal sequences recognized by NAE. PMID- 23936406 TI - Inter- and intra-host viral diversity in a large seasonal DENV2 outbreak. AB - BACKGROUND: High genetic diversity at both inter- and intra-host level are hallmarks of RNA viruses due to the error-prone nature of their genome replication. Several groups have evaluated the extent of viral variability using different RNA virus deep sequencing methods. Although much of this effort has been dedicated to pathogens that cause chronic infections in humans, few studies investigated arthropod-borne, acute viral infections. METHODS AND PRINCIPAL FINDINGS: We deep sequenced the complete genome of ten DENV2 isolates from representative classical and severe cases sampled in a large outbreak in Brazil using two different approaches. Analysis of the consensus genomes confirmed the larger extent of the 2010 epidemic in comparison to a previous epidemic caused by the same viruses in another city two years before (genetic distance = 0.002 and 0.0008 respectively). Analysis of viral populations within the host revealed a high level of conservation. After excluding homopolymer regions of 454/Roche generated sequences, we found 10 to 44 variable sites per genome population at a frequency of >1%, resulting in very low intra-host genetic diversity. While up to 60% of all variable sites at intra-host level were non-synonymous changes, only 10% of inter-host variability resulted from non-synonymous mutations, indicative of purifying selection at the population level. CONCLUSIONS AND SIGNIFICANCE: Despite the error-prone nature of RNA-dependent RNA-polymerase, dengue viruses maintain low levels of intra-host variability. PMID- 23936407 TI - Educational intervention increased referrals to allopathic care by traditional healers in three high HIV-prevalence rural districts in Mozambique. AB - INTRODUCTION: Delayed uptake of clinical services impedes favorable clinical outcomes in Mozambique. Care is delayed among patients who initiate care with traditional healers; patients with conditions like human immunodeficiency virus (HIV) or tuberculosis are rarely referred to the health system in a timely fashion. METHODS: We conducted a pre-post educational intervention with traditional healers, assessing healer referral rates and HIV knowledge in three rural districts in Zambezia Province. RESULTS: The median monthly referral rate prior to the intervention was 0.25 patients (interquartile range [IQR]: 0-0.54) compared with a post-intervention rate of 0.34 patients (IQR: 0-0.71), a 35% increase (p=0.046). A median HIV knowledge score of 67% (IQR: 59-78) was noted 4 months pre-intervention and a median score of 81% (IQR: 74-89) was recorded 21/2 months post-intervention (p<0.001). One hundred and eleven healers referred 127 adults, 36 pregnant women, and 188 children to health facilities. Referred patients were most likely to be diagnosed with bronchopneumonia (20% adults; 13% children) and/or malaria (15% adults; 37% children). Of 315 non-pregnant persons referred, 3.5% were tested for HIV and 2.5% were tested for tuberculosis. DISCUSSION: We engaged traditional healers with some success; referral rates were low, but increased post-intervention. Once seen in the clinics, patients were rarely tested for HIV or tuberculosis, though symptoms suggested screening was indicated. We found increased referral rates through an inexpensive intervention with traditional healers, a viable, cost-effective method of directing patients to health facilities. However, quality improvement within the clinics is necessary before a substantial impact can be expected. PMID- 23936408 TI - Plasma level of adrenomedullin is influenced by a single nucleotide polymorphism in the adiponectin gene. AB - OBJECTIVE: Adrenomedullin (ADM) and adiponectin are both involved in inflammation and cardiovascular diseases. The plasma levels of these peptides are influenced by single nucleotide polymorphisms (SNPs) in the ADM and ADIPOQ genes respectively. There is some evidence that ADM may regulate adiponectin gene expression, but whether adiponectin can regulate ADM expression is unclear, and was therefore investigated. METHODS: Plasma ADM level was measured in 476 subjects in the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS2). We genotyped them for 2 ADIPOQ SNPs that are known to be associated with plasma adiponectin level. RESULTS: The minor allele frequencies of ADIPOQ SNPs rs182052 and rs12495941 were 40.6% and 42.2% respectively. Plasma ADM level was significantly associated with rs182052 after adjusting for age and sex (beta=0.104, P=0.023) but not with rs12495941 (beta=0.071, P=0.120). In multivariate analysis, plasma ADM level increased with the number of minor alleles of rs182052 (P=0.013). Compared to subjects with GG genotype, subjects with AA genotype had 17.7% higher plasma ADM level (95% CI: 3.6%-33.7%). Subgroup analysis revealed that the association was significant in diabetic patients (beta=0.344, P=0.001) but not in non-diabetic subjects. CONCLUSION: Plasma ADM level is related to SNP rs182052 in the ADIPOQ gene. Our findings provide new evidence of the interplay between these two important peptides in cardiovascular disease and diabetes. Knowing the genotype may help to refine the interpretation of these biomarkers. PMID- 23936409 TI - Structural integrity of the Greek key motif in betagamma-crystallins is vital for central eye lens transparency. AB - BACKGROUND: We highlight an unrecognized physiological role for the Greek key motif, an evolutionarily conserved super-secondary structural topology of the betagamma-crystallins. These proteins constitute the bulk of the human eye lens, packed at very high concentrations in a compact, globular, short-range order, generating transparency. Congenital cataract (affecting 400,000 newborns yearly worldwide), associated with 54 mutations in betagamma-crystallins, occurs in two major phenotypes nuclear cataract, which blocks the central visual axis, hampering the development of the growing eye and demanding earliest intervention, and the milder peripheral progressive cataract where surgery can wait. In order to understand this phenotypic dichotomy at the molecular level, we have studied the structural and aggregation features of representative mutations. METHODS: Wild type and several representative mutant proteins were cloned, expressed and purified and their secondary and tertiary structural details, as well as structural stability, were compared in solution, using spectroscopy. Their tendencies to aggregate in vitro and in cellulo were also compared. In addition, we analyzed their structural differences by molecular modeling in silico. RESULTS: Based on their properties, mutants are seen to fall into two classes. Mutants A36P, L45PL54P, R140X, and G165fs display lowered solubility and structural stability, expose several buried residues to the surface, aggregate in vitro and in cellulo, and disturb/distort the Greek key motif. And they are associated with nuclear cataract. In contrast, mutants P24T and R77S, associated with peripheral cataract, behave quite similar to the wild type molecule, and do not affect the Greek key topology. CONCLUSION: When a mutation distorts even one of the four Greek key motifs, the protein readily self-aggregates and precipitates, consistent with the phenotype of nuclear cataract, while mutations not affecting the motif display 'native state aggregation', leading to peripheral cataract, thus offering a protein structural rationale for the cataract phenotypic dichotomy "distort motif, lose central vision". PMID- 23936410 TI - Quantitative evaluation of contrast-enhanced ultrasonography in the diagnosis of chronic ischemic renal disease in a dog model. AB - OBJECTIVES: The aim of this feasibility study was to prospectively explore in a dog model of chronic ischemic renal disease (CIRD) the hypothesis that real-time contrast-enhanced ultrasonography (CEUS) can quantitatively evaluate the early perfusion changes of renal cortex. MATERIALS AND METHODS: In this animal care and use committee-approved study, the model of CIRD was carried out in healthy dogs (10.0~12.0 kg, n=5), by placing the Ameroid ring constrictors on the distal portion of right renal artery through operation. CEUS monitoring of right kidney perfusion was performed by intravenous bolus injection of 0.6 ml Sulfur hexafluoride filled microbubbles (SonoVue; Bracco S.P.A., Milan, Italy) every week after operation. The slope rate of ascending curve (A) and descending curve (alpha), area under curve (AUC), derived peak intensity (DPI), and time to peak (TTP) were measured in renal cortex using commercial quantification software (Q LAB version 6; Philips Medical Systems, Bothell,WA,USA). The sensitivity of CEUS was compared with blood serum urea nitrogen (BUN) and serum creatinine (SCr) level. RESULTS: With the progression of CIRD, dogs showed delayed enhancement and perfusion in renal CEUS curve. Earliest significant changes happened 4 weeks after operation on DPI and TTP which changed from 13.04 +/- 2.71 to 15.58 +/- 4.75 dB and 9.03 +/- 2.01 to 10.62 +/- 6.04 sec, respectively (P<.05). CONCLUSIONS: CEUS can display the perfusion changes of CIRD in the early period. PMID- 23936411 TI - Pancreaticoduodenectomy combined with vascular resection and reconstruction for patients with locally advanced pancreatic cancer: a multicenter, retrospective analysis. AB - OBJECTIVE: The aim of this study was to present the therapeutic outcome of patients with locally advanced pancreatic cancer treated with pancreatoduodenectomy combined with vascular resection and reconstruction in addition to highlighting the mortality/morbidity and main prognostic factors associated with this treatment. MATERIALS AND METHODS: We retrospectively analyzed the clinical and pathological data of a total of 566 pancreatic cancer patients who were treated with PD from five teaching hospitals during the period of December 2006-December 2011. This study included 119 (21.0%) patients treated with PD combined with vascular resection and reconstruction. We performed a detailed statistical analysis of various factors, including postoperative complications, operative mortality, survival rate, operative time, pathological type, and lymph node metastasis. RESULTS: The median survival time of the 119 cases that received PD combined with vascular resection was 13.3 months, and the 1-, 2-, and 3-year survival rates were 30.3%, 14.1%, and 8.1%, respectively. The postoperative complication incidence was 23.5%, and the mortality rate was 6.7%. For the combined vascular resection group, complications occurred in 28 cases (23.5%). For the group without vascular resection, complications occurred in 37 cases (8.2%). There was significant difference between the two groups (p = 0.001). The degree of tumor differentiation and the occurrence of complications after surgery were independent prognostic factors that determined the patients' long-term survival. CONCLUSIONS: Compared with PD without vascular resection, PD combined with vascular resection and reconstruction increased the incidence of postoperative complications. However, PD combined with vascular resection and reconstruction could achieve the complete removal of tumors without significantly increasing the mortality rate, and the median survival time was higher than that of patients who underwent palliative treatment. In addition, the two independent factors affecting the postoperative survival time were the degree of tumor differentiation and the presence or absence of postoperative complications. PMID- 23936412 TI - Role of CTLA4 in the proliferation and survival of chronic lymphocytic leukemia. AB - Earlier, we reported that CTLA4 expression is inversely correlated with CD38 expression in chronic lymphocytic leukemia (CLL) cells. However, the specific role of CTLA4 in CLL pathogenesis remains unknown. Therefore, to elucidate the possible role of CTLA4 in CLL pathogenesis, CTLA4 was down-regulated in primary CLL cells. We then evaluated proliferation/survival in these cells using MTT, (3)H-thymidine uptake and Annexin-V apoptosis assays. We also measured expression levels of downstream molecules involved in B-cell proliferation/survival signaling including STAT1, NFATC2, c-Fos, c-Myc, and Bcl-2 using microarray, PCR, western blotting analyses, and a stromal cell culture system. CLL cells with CTLA4 down-regulation demonstrated a significant increase in proliferation and survival along with an increased expression of STAT1, STAT1 phosphorylation, NFATC2, c-Fos phosphorylation, c-Myc, Ki-67 and Bcl-2 molecules. In addition, compared to controls, the CTLA4-downregulated CLL cells showed a decreased frequency of apoptosis, which also correlated with increased expression of Bcl-2. Interestingly, CLL cells from lymph node and CLL cells co-cultured on stroma expressed lower levels of CTLA4 and higher levels of c-Fos, c-Myc, and Bcl-2 compared to CLL control cells. These results indicate that microenvironment controlled-CTLA4 expression mediates proliferation/survival of CLL cells by regulating the expression/activation of STAT1, NFATC2, c-Fos, c-Myc, and/or Bcl 2. PMID- 23936413 TI - TACC3 is essential for EGF-mediated EMT in cervical cancer. AB - The third member of transforming acidic coiled-coil protein (TACC) family, TACC3, has been shown to be an important player in the regulation of centrosome/microtubule dynamics during mitosis and found to be deregulated in a variety of human malignancies. Our previous studies have suggested that TACC3 may be involved in cervical cancer progression and chemoresistance, and its overexpression can induce epithelial-mesenchymal transition (EMT) by activating the phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated protein kinases (ERKs) signal transduction pathways. However, the upstream mechanisms of TACC3-mediated EMT and its functional/clinical importance in human cervical cancer remain elusive. Epidermal growth factor (EGF) has been shown to be a potent inducer of EMT in cervical cancer and associated with tumor invasion and metastasis. In this study, we found that TACC3 is overexpressed in cervical cancer and can be induced upon EGF stimulation. The induction of TACC3 by EGF is dependent on the tyrosine kinase activity of the EGF receptor (EGFR). Intriguingly, depletion of TACC3 abolishes EGF-mediated EMT, suggesting that TACC3 is required for EGF/EGFR-driven EMT process. Moreover, Snail, a key player in EGF-mediated EMT, is found to be correlated with the expression of TACC3 in cervical cancer. Collectively, our study highlights a novel function for TACC3 in EGF-mediated EMT process and suggests that targeting of TACC3 may be an attractive strategy to treat cervical cancers driven by EGF/EGFR signaling pathways. PMID- 23936414 TI - Integrity of the Saccharomyces cerevisiae Rpn11 protein is critical for formation of proteasome storage granules (PSG) and survival in stationary phase. AB - Decline of proteasome activity has been reported in mammals, flies and yeasts during aging. In the yeast Saccharomyces cerevisiae, the reduction of proteolysis in stationary phase is correlated with disassembly of the 26S proteasomes into their 20S and 19S subcomplexes. However a recent report showed that upon entry into the stationary phase, proteasome subunits massively re-localize from the nucleus into mobile cytoplasmic structures called proteasome storage granules (PSGs). Whether proteasome subunits in PSG are assembled into active complexes remains an open question that we addressed in the present study. We showed that a particular mutant of the RPN11 gene (rpn11-m1), encoding a proteasome lid subunit already known to exhibit proteasome assembly/stability defect in vitro, is unable to form PSGs and displays a reduced viability in stationary phase. Full restoration of long-term survival and PSG formation in rpn11-m1 cells can be achieved by the expression in trans of the last 45 amino acids of the C-terminal domain of Rpn11, which was moreover found to co-localize with PSGs. In addition, another rpn11 mutant leading to seven amino acids change in the Rpn11 C-terminal domain, which exhibits assembled-26S proteasomes, is able to form PSGs but with a delay compared to the wild type situation. Altogether, our findings indicate that PSGs are formed of fully assembled 26S proteasomes and suggest a critical role for the Rpn11 protein in this process. PMID- 23936415 TI - First evidence of sternal wound biofilm following cardiac surgery. AB - Management of deep sternal wound infection (SWI), a serious complication after cardiac surgery with high morbidity and mortality incidence, requires invasive procedures such as, debridement with primary closure or myocutaneous flap reconstruction along with use of broad spectrum antibiotics. The purpose of this clinical series is to investigate the presence of biofilm in patients with deep SWI. A biofilm is a complex microbial community in which bacteria attach to a biological or non-biological surface and are embedded in a self-produced extracellular polymeric substance. Biofilm related infections represent a major clinical challenge due to their resistance to both host immune defenses and standard antimicrobial therapies. Candidates for this clinical series were patients scheduled for a debridement procedure of an infected sternal wound after a cardiac surgery. Six patients with SWI were recruited in the study. All cases had marked dehiscence of all layers of the wound down to the sternum with no signs of healing after receiving broad spectrum antibiotics post-surgery. After consenting patients, tissue and/or extracted stainless steel wires were collected during the debridement procedure. Debrided tissues examined by Gram stain showed large aggregations of Gram positive cocci. Immuno-fluorescent staining of the debrided tissues using a specific antibody against staphylococci demonstrated the presence of thick clumps of staphylococci colonizing the wound bed. Evaluation of tissue samples with scanning electron microscope (SEM) imaging showed three dimensional aggregates of these cocci attached to the wound surface. More interestingly, SEM imaging of the extracted wires showed attachment of cocci aggregations to the wire metal surface. These observations along with the clinical presentation of the patients provide the first evidence that supports the presence of biofilm in such cases. Clinical introduction of the biofilm infection concept in deep SWI may advance the current management strategies from standard antimicrobial therapy to anti-biofilm strategy. PMID- 23936416 TI - Different genetic associations of the IgE production among fetus, infancy and childhood. AB - Elevation of serum IgE levels has long been associated with allergic diseases. Many genes have been linked to IgE production, but few have been linked to the developmental aspects of genetic association with IgE production. To clarify developmental genetic association, we investigated what genes and gene-gene interactions affect IgE levels among fetus, infancy and childhood in Taiwan individuals. A birth cohort of 571 children with completion of IgE measurements from newborn to 1.5, 3, and 6 years of age was subject to genetic association analysis on the 384-customized SNPs of 159 allergy candidate genes. Fifty-three SNPs in 37 genes on innate and adaptive immunity, and stress and response were associated with IgE production. Polymorphisms of the IL13, and the HLA-DPA1 and HLA-DQA1 were, respectively, the most significantly associated with the IgE production at newborn and 6 years of age. Analyses of gene-gene interactions indentified that the combination of NPSR1, rs324981 TT with FGF1, rs2282797 CC had the highest risk (85.7%) of IgE elevation at 1.5 years of age (P=1.46 * 10( 4)). The combination of IL13, CYFIP2 and PDE2A was significantly associated with IgE elevation at 3 years of age (P=5.98 * 10(-7)), and the combination of CLEC2D, COLEC11 and CCL2 was significantly associated with IgE elevation at 6 years of age (P=6.65 * 10(-7)). Our study showed that the genetic association profiles of the IgE production among fetus, infancy and childhood are different. Genetic markers for early prediction and prevention of allergic sensitization may rely on age-based genetic association profiles. PMID- 23936417 TI - Learning theories reveal loss of pancreatic electrical connectivity in diabetes as an adaptive response. AB - Cells of almost all solid tissues are connected with gap junctions which permit the direct transfer of ions and small molecules, integral to regulating coordinated function in the tissue. The pancreatic islets of Langerhans are responsible for secreting the hormone insulin in response to glucose stimulation. Gap junctions are the only electrical contacts between the beta-cells in the tissue of these excitable islets. It is generally believed that they are responsible for synchrony of the membrane voltage oscillations among beta-cells, and thereby pulsatility of insulin secretion. Most attempts to understand connectivity in islets are often interpreted, bottom-up, in terms of measurements of gap junctional conductance. This does not, however, explain systematic changes, such as a diminished junctional conductance in type 2 diabetes. We attempt to address this deficit via the model presented here, which is a learning theory of gap junctional adaptation derived with analogy to neural systems. Here, gap junctions are modelled as bonds in a beta-cell network, that are altered according to homeostatic rules of plasticity. Our analysis reveals that it is nearly impossible to view gap junctions as homogeneous across a tissue. A modified view that accommodates heterogeneity of junction strengths in the islet can explain why, for example, a loss of gap junction conductance in diabetes is necessary for an increase in plasma insulin levels following hyperglycemia. PMID- 23936418 TI - Improved minimum squared error algorithm with applications to face recognition. AB - Minimum squared error based classification (MSEC) method establishes a unique classification model for all the test samples. However, this classification model may be not optimal for each test sample. This paper proposes an improved MSEC (IMSEC) method, which is tailored for each test sample. The proposed method first roughly identifies the possible classes of the test sample, and then establishes a minimum squared error (MSE) model based on the training samples from these possible classes of the test sample. We apply our method to face recognition. The experimental results on several datasets show that IMSEC outperforms MSEC and the other state-of-the-art methods in terms of accuracy. PMID- 23936419 TI - Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR. AB - OBJECTIVE: Genistein is a soy isoflavone that has antitumor activity both in vitro and in vivo. It has been shown that genistein inhibits many type of cancers including prostate cancer (PCa) by regulating several cell signaling pathways and microRNAs (miRNAs). Recent studies suggest that the long non-coding RNAs (lncRNAs) are also involved in many cellular processes. At present there are no reports about the relationship between gensitein, miRNAs and lncRNAs. In this study, we focused on miRNAs, lncRNA that are regulated by genistein and investigated their functional role in PCa. METHOD: Microarray (SurePrint G3 Human GE 8*60K) was used for expression profiling of genistein treated and control PCa cells (PC3 and DU145). Functional assay (cell proliferation, migration, invasion, apoptosis and cell cycle assays) were performed with the PCa cell lines, PC3 and DU145. Both in vitro and in vivo (nude mouse) models were used for growth assays. Luciferase reporter assays were used for binding of miR-34a to HOTAIR. RESULTS: LncRNA profiling showed that HOTAIR was highly regulated by genistein and its expression was higher in castration-resistant PCa cell lines than in normal prostate cells. Knockdown (siRNA) of HOTAIR decreased PCa cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. miR-34a was also up-regulated by genistein and may directly target HOTAIR in both PC3 and DU145 PCa cells. CONCLUSIONS: Our results indicated that genistein inhibited PCa cell growth through down-regulation of oncogenic HOTAIR that is also targeted by tumor suppressor miR-34a. These findings enhance understanding of how genistein regulates lncRNA HOTAIR and miR-34a in PCa. PMID- 23936420 TI - Identification and immunocytochemical characterization of Piccolino, a novel Piccolo splice variant selectively expressed at sensory ribbon synapses of the eye and ear. AB - Piccolo is one of the largest cytomatrix proteins present at active zones of chemical synapses, where it is suggested to play a role in recruiting and integrating molecules relevant for both synaptic vesicle exo- and endocytosis. Here we examined the retina of a Piccolo-mutant mouse with a targeted deletion of exon 14 in the Pclo gene. Piccolo deficiency resulted in its profound loss at conventional chemical amacrine cell synapses but retinal ribbon synapses were structurally and functionally unaffected. This led to the identification of a shorter, ribbon-specific Piccolo variant, Piccolino, present in retinal photoreceptor cells, bipolar cells, as well as in inner hair cells of the inner ear. By RT-PCR analysis and the generation of a Piccolino-specific antibody we show that non-splicing of intron 5/6 leads to premature translation termination and generation of the C-terminally truncated protein specifically expressed at active zones of ribbon synapse containing cell types. With in situ proximity ligation assays we provide evidence that this truncation leads to the absence of interaction sites for Bassoon, Munc13, and presumably also ELKS/CAST, RIM2, and the L-type Ca(2) (+) channel which exist in the full-length Piccolo at active zones of conventional chemical synapses. The putative lack of interactions with proteins of the active zone suggests a function of Piccolino at ribbon synapses of sensory neurons different from Piccolo's function at conventional chemical synapses. PMID- 23936421 TI - Affiliative behaviour and conflictual communication during brief family therapy of patients with anorexia nervosa. AB - OBJECTIVE: Although patients with anorexia nervosa (AN) present positive responses to family therapy, the key features of therapeutic changes still require identification. This study explores the role of conflictual communication and affiliative nonverbal behaviour in therapeutic change in brief strategic family therapy (BSFT) for AN patients. METHODS: Ten female AN patients and their parents were included in the sample and took part in a 6-month follow-up of BSFT. The durations of conflictual communication and of affiliative nonverbal behaviour estimated by eye contact were compared between the first and the last sessions of family-based treatment using nonparametric statistical tests. RESULTS: An increase of the Body Mass Index associated with an increase in the conflictual communication expressed during BSFT sessions were observed. Moreover, affiliative nonverbal behaviour expressed by the father and the patient decrease, after a BSFT follow-up, in conflictual situations only. By contrast, no significant difference was observed in affiliative nonverbal behaviour expressed by the mother. CONCLUSION: The present study demonstrates that the impact of the BSFT differs between members of a family: the AN patient and the father have established a new form of emotional functioning with a decrease in emotional involvement. The study of the combination between verbal and nonverbal communication can represent an important step in the understanding of the mechanisms of therapeutic change. PMID- 23936422 TI - Single cell analysis of human RAD18-dependent DNA post-replication repair by alkaline bromodeoxyuridine comet assay. AB - Damage to DNA can block replication progression resulting in gaps in the newly synthesized DNA. Cells utilize a number of post-replication repair (PRR) mechanisms such as the RAD18 controlled translesion synthesis or template switching to overcome the discontinuities formed opposite the DNA lesions and to complete DNA replication. Gaining more insights into the role of PRR genes promotes better understanding of DNA damage tolerance and of how their malfunction can lead to increased genome instability and cancer. However, a simple and efficient method to characterise gene specific PRR deficiencies at a single cell level has not been developed. Here we describe the so named BrdU comet PRR assay to test the contribution of human RAD18 to PRR at a single cell level, by which we kinetically characterized the consequences of the deletion of human RAD18 on the replication of UV-damaged DNA. Moreover, we demonstrate the capability of our method to evaluate PRR at a single cell level in unsynchronized cell population. PMID- 23936423 TI - Expression proteomics predicts loss of RXR-gamma during progression of epithelial ovarian cancer. AB - The process of cellular transformation involves cascades of molecular changes that are modulated through altered epigenetic, transcription, post-translational and protein regulatory networks. Thus, identification of transformation associated protein alterations can provide an insight into major regulatory pathways activated during disease progression. In the present protein expression profiling approach, we identified differential sets of proteins in a two dimensional gel electrophoresis screen of a serous ovarian adenocarcinoma progression model. Function-based categorization of the proteins exclusively associated with pre-transformed cells identified four cellular processes of which RXR-gamma is known to modulate cellular differentiation and apoptosis. We thus probed the functional relevance of RXR-gamma expression and signaling in these two pathways during tumor progression. RXR-gamma expression was observed to modulate cellular differentiation and apoptosis in steady-state pre-transformed cells. Interestingly, retinoid treatment was found to enhance RXR-gamma expression in transformed cells and sensitize them towards apoptosis in vitro, and also reduce growth of xenografts derived from transformed cells. Our findings emphasize that loss of RXR-gamma levels appears to provide mechanistic benefits to transformed cells towards the acquisition of resistance to apoptosis hallmark of cancer, while effective retinoid treatment may present a viable approach towards sensitization of tumor cells to apoptosis through induction of RXR-gamma expression. PMID- 23936424 TI - Clinical characteristics, etiology and antimicrobial susceptibility among overweight and obese individuals with diarrhea: observed at a large diarrheal disease hospital, Bangladesh. AB - BACKGROUND: The present study aimed to determine the clinical characteristics and etiology of overweight and obese (OO) individuals with diarrhea attending an urban Dhaka Hospital, International Centre for Diarrheal Disease Research (icddr,b), Bangladesh. METHODS: Total of 508 under-5 children, 96 individuals of 5-19 years and 1331 of >19 years were identified as OO from the Diarrheal Disease Surveillance System (DDSS) between 1993-2011. Two comparison groups such as well nourished and malnourished individuals from respective age stratums were selected. RESULTS: Isolation rate of rotavirus was higher among OO under-5 children compared to malnourished group (46% vs. 28%). Rotavirus infection among OO individuals aged 5-19 years (9% vs. 3%) (9% vs. 3%) and >19 years (6% vs. 4%) (6% vs. 3%) was higher compared to well-nourished and malnourished children. Conversely, Vibrio cholerae was lower among all OO age groups compared to well nourished and malnourished ones. Shigella (4% vs. 6%) (4% vs. 8%), and Campylobacter (3% vs. 5%) (3% vs. 5%) were lower only among OO in >19 years individuals compared to their counterparts of the same age stratum. Salmonella was similarly isolated in all age strata and nutritional groups. In multinomial logistic regression among under-5 children, significant association was observed only with use of antimicrobials at home [OR-1.97] and duration of hospital stay [OR-0.68]. For individuals aged 5-19 years, use of antimicrobials at home (OR 1.83), some or severe dehydration (OR-3.12), having received intravenous saline (OR-0.46) and rotavirus diarrhea (OR-2.96) were found to be associated with OO respectively. Moreover, significant associations were also found for duration of diarrhea before coming to hospital (>24 hours) (OR-1.24), Shigella (OR-0.46), and Campylobacter (OR-0.58) among >19 years OO individuals along with other associated co-variates in 5-19 years group (all p<0.05). CONCLUSION AND SIGNIFICANCE: Higher proportion of OO were infected with rotavirus and a greater proportion of them used antimicrobials before coming to the hospital. PMID- 23936425 TI - Life on magnets: stem cell networking on micro-magnet arrays. AB - Interactions between a micro-magnet array and living cells may guide the establishment of cell networks due to the cellular response to a magnetic field. To manipulate mesenchymal stem cells free of magnetic nanoparticles by a high magnetic field gradient, we used high quality micro-patterned NdFeB films around which the stray field's value and direction drastically change across the cell body. Such micro-magnet arrays coated with parylene produce high magnetic field gradients that affect the cells in two main ways: i) causing cell migration and adherence to a covered magnetic surface and ii) elongating the cells in the directions parallel to the edges of the micro-magnet. To explain these effects, three putative mechanisms that incorporate both physical and biological factors influencing the cells are suggested. It is shown that the static high magnetic field gradient generated by the micro-magnet arrays are capable of assisting cell migration to those areas with the strongest magnetic field gradient, thereby allowing the build up of tunable interconnected stem cell networks, which is an elegant route for tissue engineering and regenerative medicine. PMID- 23936426 TI - Campylobacter jejuni pdxA affects flagellum-mediated motility to alter host colonization. AB - Vitamin B6 (pyridoxal-5'-phosphate, PLP) is linked to a variety of biological functions in prokaryotes. Here, we report that the pdxA (putative 4-hydroxy-L threonine phosphate dehydrogenase) gene plays a pivotal role in the PLP-dependent regulation of flagellar motility, thereby altering host colonization in a leading foodborne pathogen, Campylobacter jejuni. A C. jejuni pdxA mutant failed to produce PLP and exhibited a coincident loss of flagellar motility. Mass spectrometric analyses showed a 3-fold reduction in the main flagellar glycan pseudaminic acid (Pse) associated with the disruption of pdxA. The pdxA mutant also exhibited reduced growth rates compared with the WT strain. Comparative metabolomic analyses revealed differences in respiratory/energy metabolism between WT C. jejuni and the pdxA mutant, providing a possible explanation for the differential growth fitness between the two strains. Consistent with the lack of flagellar motility, the pdxA mutant showed impaired motility-mediated responses (bacterial adhesion, ERK1/2 activation, and IL-8 production) in INT407 cells and reduced colonization of chickens compared with the WT strain. Overall, this study demonstrated that the pdxA gene affects the PLP-mediated flagellar motility function, mainly through alteration of Pse modification, and the disruption of this gene also alters the respiratory/energy metabolisms to potentially affect host colonization. Our data therefore present novel implications regarding the utility of PLP and its dependent enzymes as potent target(s) for the control of this pathogen in the poultry host. PMID- 23936427 TI - Impact on clinical and cost outcomes of a centralized approach to acute stroke care in London: a comparative effectiveness before and after model. AB - BACKGROUND: In July 2010 a new multiple hub-and-spoke model for acute stroke care was implemented across the whole of London, UK, with continuous specialist care during the first 72 hours provided at 8 hyper-acute stroke units (HASUs) compared to the previous model of 30 local hospitals receiving acute stroke patients. We investigated differences in clinical outcomes and costs between the new and old models. METHODS: We compared outcomes and costs 'before' (July 2007-July 2008) vs. 'after' (July 2010-June 2011) the introduction of the new model, adjusted for patient characteristics and national time trends in mortality and length of stay. We constructed 90-day and 10-year decision analytic models using data from population based stroke registers, audits and published sources. Mortality and length of stay were modelled using survival analysis. FINDINGS: In a pooled sample of 307 patients 'before' and 3156 patients 'after', survival improved in the 'after' period (age adjusted hazard ratio 0.54; 95% CI 0.41-0.72). The predicted survival rates at 90 days in the deterministic model adjusted for national trends were 87.2% 'before' % (95% CI 86.7%-87.7%) and 88.7% 'after' (95% CI 88.6%-88.8%); a relative reduction in deaths of 12% (95% CI 8%-16%). Based on a cohort of 6,438 stroke patients, the model produces a total cost saving of L5.2 million per year at 90 days (95% CI L4.9-L5.5 million; L811 per patient). CONCLUSION: A centralized model for acute stroke care across an entire metropolitan city appears to have reduced mortality for a reduced cost per patient, predominately as a result of reduced hospital length of stay. PMID- 23936428 TI - Increased risk of colon cancer in men in the pre-diabetes phase. AB - BACKGROUND: Historically, studies exploring the association between type 2 diabetes mellitus (DM) and cancer lack accurate definition of date of DM onset, limiting temporal analyses. We examined the temporal relationship between colon cancer risk and DM using an electronic algorithm and clinical, administrative, and laboratory data to pinpoint date of DM onset. METHODS: Subjects diagnosed with DM (N = 11,236) between January 1, 1995 and December 31, 2009 were identified and matched at a 5?1 ratio with 54 365 non-diabetic subjects by age, gender, smoking history, residence, and diagnosis reference date. Colon cancer incidence relative to the reference date was used to develop Cox regression models adjusted for matching variables, body mass index, insurance status, and comorbidities. Primary outcomes measures included hazard ratio (HR) and number needed to be exposed for one additional person to be harmed (NNEH). RESULTS: The adjusted HR for colon cancer in men before DM onset was 1.28 (95% CI 1.04-1.58, P = 0.0223) and the NNEH decreased with time, reaching 263 at DM onset. No such difference was observed in women. After DM onset, DM did not appear to alter colon cancer risk in either gender. CONCLUSIONS: Colon cancer risk is increased in diabetic men, but not women, before DM onset. DM did not alter colon cancer risk in men or women after clinical onset. In pre-diabetic men, colon cancer risk increased as time to DM onset decreased, suggesting that the effects of the pre diabetes phase on colon cancer risk in men are cumulative. PMID- 23936429 TI - Genome-wide expression of transcriptomes and their co-expression pattern in subtropical maize (Zea mays L.) under waterlogging stress. AB - Waterlogging causes extensive damage to maize crops in tropical and subtropical regions. The identification of tolerance genes and their interactions at the molecular level will be helpful to engineer tolerant genotypes. A whole-genome transcriptome assay revealed the specific role of genes in response to waterlogging stress in susceptible and tolerant genotypes. Genes involved in the synthesis of ethylene and auxin, cell wall metabolism, activation of G-proteins and formation of aerenchyma and adventitious roots, were upregulated in the tolerant genotype. Many transcription factors, particularly ERFs, MYB, HSPs, MAPK, and LOB-domain protein were involved in regulation of these traits. Genes responsible for scavenging of ROS generated under stress were expressed along with those involved in carbohydrate metabolism. The physical locations of 21 genes expressed in the tolerant genotype were found to correspond with the marker intervals of known QTLs responsible for development of adaptive traits. Among the candidate genes, most showed synteny with genes of sorghum and foxtail millet. Co expression analysis of 528 microarray samples including 16 samples from the present study generated seven functional modules each in the two genotypes, with differing characteristics. In the tolerant genotype, stress genes were co expressed along with peroxidase and fermentation pathway genes. PMID- 23936430 TI - Does clinical management improve outcomes following self-harm? Results from the multicentre study of self-harm in England. AB - BACKGROUND: Evidence to guide clinical management of self-harm is sparse, trials have recruited selected samples, and psychological treatments that are suggested in guidelines may not be available in routine practice. AIMS: To examine how the management that patients receive in hospital relates to subsequent outcome. METHODS: We identified episodes of self-harm presenting to three UK centres (Derby, Manchester, Oxford) over a 10 year period (2000 to 2009). We used established data collection systems to investigate the relationship between four aspects of management (psychosocial assessment, medical admission, psychiatric admission, referral for specialist mental health follow up) and repetition of self-harm within 12 months, adjusted for differences in baseline demographic and clinical characteristics. RESULTS: 35,938 individuals presented with self-harm during the study period. In two of the three centres, receiving a psychosocial assessment was associated with a 40% lower risk of repetition, Hazard Ratios (95% CIs): Centre A 0.99 (0.90-1.09); Centre B 0.59 (0.48-0.74); Centre C 0.59 (0.52 0.68). There was little indication that the apparent protective effects were mediated through referral and follow up arrangements. The association between psychosocial assessment and a reduced risk of repetition appeared to be least evident in those from the most deprived areas. CONCLUSION: These findings add to the growing body of evidence that thorough assessment is central to the management of self-harm, but further work is needed to elucidate the possible mechanisms and explore the effects in different clinical subgroups. PMID- 23936431 TI - Feeding blueberry diets to young rats dose-dependently inhibits bone resorption through suppression of RANKL in stromal cells. AB - Previous studies have demonstrated that weanling rats fed AIN-93G semi-purified diets supplemented with 10% whole blueberry (BB) powder for two weeks beginning on postnatal day 21 (PND21) significantly increased bone formation at PND35. However, the minimal level of dietary BB needed to produce these effects is, as yet, unknown. The current study examined the effects of three different levels of BB diet supplementation (1, 3, and 5%) for 35 days beginning on PND25 on bone quality, and osteoclastic bone resorption in female rats. Peripheral quantitative CT scan (pQCT) of tibia, demonstrated that bone mineral density (BMD) and content (BMC) were dose-dependently increased in BB-fed rats compared to controls (P<0.05). Significantly increased bone mass after feeding 5% BB extracts was also observed in a TEN (total enteral nutrition) rat model in which daily caloric and food intake was precisely controlled. Expression of RANKL (receptor activator of nuclear factor-kappaB ligand) a protein essential for osteoclast formation was dose-dependently decreased in the femur of BB animals. In addition, expression of PPARgamma (peroxisome proliferator-activated receptor gamma) which regulates bone marrow adipogenesis was suppressed in BB diet rats compared to non-BB diet controls. Finally, a set of in vitro cell cultures revealed that the inhibitory effect of BB diet rat serum on RANKL expression was more profound in mesenchymal stromal cells compared to its effect on mature osteoblasts, pre-adipocytes and osteocytes. These results suggest that inhibition of bone resorption may contribute to increased bone mass during early development after BB consumption. PMID- 23936432 TI - Inhibition of proliferation and induction of autophagy by atorvastatin in PC3 prostate cancer cells correlate with downregulation of Bcl2 and upregulation of miR-182 and p21. AB - The epidemiologic association between statin use and decreased risk of advanced prostate cancer suggests that statins may inhibit prostate cancer development and/or progression. Studies were performed to determine the effects of a model statin, atorvastatin (ATO), on the proliferation and differentiation of prostate cancer cells, and to identify possible mechanisms of ATO action. ATO inhibited the in vitro proliferation of both LNCaP and PC3 human prostate cancer cells in a dose- and time-dependent fashion. The greater inhibitory activity of ATO in PC3 cells was associated with induction of autophagy in that cell line, as demonstrated by increased expression of LC3-II. miR-182 was consistently upregulated by ATO in PC3 cells, but not in LNCaP cells. ATO upregulation of miR 182 in PC3 cells was p53-independent and was reversed by geranylgeraniol. Transfection of miR-182 inhibitors decreased expression of miR-182 by >98% and attenuated the antiproliferative activity of ATO. miR-182 expression in PC3 cells was also increased in response to stress induced by serum withdrawal, suggesting that miR-182 upregulation can occur due to nutritional stress. Bcl2 and p21 were identified to be potential target genes of miR-182 in PC3 cells. Bcl2 was downregulated and p21 was upregulated in PC3 cells exposed to ATO. These data suggest that miR-182 may be a stress-responsive miRNA that mediates ATO action in prostate cancer cells. PMID- 23936433 TI - Mutation rules and the evolution of sparseness and modularity in biological systems. AB - Biological systems exhibit two structural features on many levels of organization: sparseness, in which only a small fraction of possible interactions between components actually occur; and modularity--the near decomposability of the system into modules with distinct functionality. Recent work suggests that modularity can evolve in a variety of circumstances, including goals that vary in time such that they share the same subgoals (modularly varying goals), or when connections are costly. Here, we studied the origin of modularity and sparseness focusing on the nature of the mutation process, rather than on connection cost or variations in the goal. We use simulations of evolution with different mutation rules. We found that commonly used sum-rule mutations, in which interactions are mutated by adding random numbers, do not lead to modularity or sparseness except for in special situations. In contrast, product-rule mutations in which interactions are mutated by multiplying by random numbers--a better model for the effects of biological mutations--led to sparseness naturally. When the goals of evolution are modular, in the sense that specific groups of inputs affect specific groups of outputs, product-rule mutations also lead to modular structure; sum-rule mutations do not. Product-rule mutations generate sparseness and modularity because they tend to reduce interactions, and to keep small interaction terms small. PMID- 23936434 TI - Altered expression of 14-3-3zeta protein in spinal cords of rat fetuses with spina bifida aperta. AB - BACKGROUND: A large number of studies have confirmed that excessive apoptosis is one of the reasons for deficient neuronal function in neural tube defects (NTDs). A previous study from our laboratory used 2-D gel electrophoresis to demonstrate that 14-3-3zeta expression was low in the spinal cords of rat fetuses with spina bifida aperta at embryonic day (E) 17. As a member of the 14-3-3 protein family, 14-3-3zeta plays a crucial role in the determination of cell fate and anti apoptotic activity. However, neither the expression of 14-3-3zeta in defective spinal cords, nor the correlation between 14-3-3zeta and excessive apoptosis in NTDs has been fully confirmed. METHODOLOGY/PRINCIPAL FINDINGS: We used immunoblotting and quantitative real-time PCR (qRT-PCR) to quantify the expression of 14-3-3zeta and double immunofluorescence to visualize 14-3-3zeta and apoptosis. We found that, compared with controls, 14-3-3zeta was down regulated in spina bifida between E12 and E15. Excessive apoptotic cells and low expression of 14-3-3zeta were observed in the dorsal region of spinal cords with spina bifida during the same time period. To initially explore the molecular mechanisms of apoptosis in NTDs, we investigated the expression of microRNA-7 (miR-7), microRNA-375 (miR-375) and microRNA-451 (miR-451), which are known to down-regulate 14-3-3zeta in several different cell types. We also investigated the expression of p53, a molecule that is downstream of 14-3-3zeta and can be down-regulated by it. We discovered that, in contrast to the reduction of 14-3 3zeta expression, the expression of miR-451, miR-375 and p53 increased in spina bifida rat fetuses. CONCLUSIONS/SIGNIFICANCE: These data suggest that the reduced expression of 14-3-3zeta plays a role in the excessive apoptosis that occurs in spina bifida and may be partly regulated by the over-expression of miR-451 and miR-375, and the consequent up-regulation of p53 might further promote apoptosis in spina bifida. PMID- 23936435 TI - Photocoagulation of human retinal pigment epithelial cells in vitro: evaluation of necrosis, apoptosis, cell migration, cell proliferation and expression of tissue repairing and cytoprotective genes. AB - AIMS: Sight-threatening diabetic retinopathy has been treated with photocoagulation for decades but the mechanisms behind the beneficial clinical effects are poorly understood. One target of irradiation and a potential player in this process is the retinal pigment epithelium (RPE). Here we establish an in vitro model for photocoagulation of human RPE cells. METHODS: ARPE-19 cells were exposed to photocoagulation and studied at various time points up to 168h. Lesion morphology, necrosis and apoptosis were investigated by light microscopy; LIVE/DEAD staining and measurements of lactate dehydrogenase activity; and TUNEL- and ELISA-based quantification of DNA fragments, respectively. Cell migration and proliferation were explored using docetaxel and mitomycin C; temporal and spatial changes in proliferation were assessed by confocal immunofluorescence of proliferating cell nuclear antigen. Gene expression was measured by qPCR. RESULTS: Photocoagulation of ARPE-19 resulted in denaturation of proteins and reproducible lesion formation. A transient peak in necrosis, followed by a peak in apoptosis was observed in cells within the lesions at 6h and 24h, respectively after photocoagulation. Cell proliferation was depressed during the first hours after photocoagulation, back to control levels at 24h and augmented in the following days. These effects were not limited to cells in the lesions, but also evident in neighbouring cells. Changes in cell proliferation during lesion repair were preceded by changes in cell migration. Altered mRNA expression of genes previously implicated in the regulation of cell proliferation (FOS, IL-1beta, IL 8, HMGA2), migration and tissue repairing (TGFBR2, ADAMTS6, TIMP3, CTGF) was observed, as well as increased expression of the alarmin IL33 and the cytoprotective gene HSPA6. CONCLUSIONS: Using a laser system and experimental settings that comply with standards used in clinical practice, we have established a suitable model for in vitro photocoagulation of human RPE cells to isolate their contribution to the beneficial effects of laser treatment. PMID- 23936436 TI - Isolation and identification of myxobacteria from saline-alkaline soils in Xinjiang, China. AB - Fifty-eight terrestrial and salt-tolerant myxobacteria were isolated from the saline-alkaline soils collected from Xinjiang, China. Based on the morphologies and the 16S rRNA gene sequences, these isolates were assigned into 6 genera, Myxococcus, Cystobacter, Corallococcus, Sorangium, Nannocystis and Polyangium. All the strains grew better with 1% NaCl than without NaCl. Some Myxococcus strains were able to grow at 2% NaCl concentration, suggesting that these strains may be particular type of terrestrial myxobacteria. PMID- 23936437 TI - Autophagic impairment contributes to systemic inflammation-induced dopaminergic neuron loss in the midbrain. AB - BACKGROUND: Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD), inducing and accelerating dopaminergic (DA) neuron loss. Autophagy, a critical mechanism for clearing misfolded or aggregated proteins such as alpha-synuclein (alpha-SYN), may affect DA neuron survival in the midbrain. However, whether autophagy contributes to neuroinflammation-induced toxicity in DA neurons remains unknown. RESULTS: Intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) into young (3-month-old) and aged (16-month old) male C57BL/6J mice was observed to cause persistent neuroinflammation that was associated with a delayed and progressive loss of DA neurons and accumulation of alpha-SYN in the midbrain. The autophagic substrate-p62 (SQSTM1) persistently increased, whereas LC3-II and HDAC6 exhibited early increases followed by a decline. In vitro studies further demonstrated that TNF-alpha induced cell death in PC12 cells. Moreover, a sublethal dose of TNF-alpha (50 ng/ml) increased the expression of LC3-II, p62, and alpha-SYN, implying that TNF-alpha triggered autophagic impairment in cells. CONCLUSION: Neuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain. PMID- 23936438 TI - Exposure to advertisement calls of reproductive competitors activates vocal acoustic and catecholaminergic neurons in the plainfin midshipman fish, Porichthys notatus. AB - While the neural circuitry and physiology of the auditory system is well studied among vertebrates, far less is known about how the auditory system interacts with other neural substrates to mediate behavioral responses to social acoustic signals. One species that has been the subject of intensive neuroethological investigation with regard to the production and perception of social acoustic signals is the plainfin midshipman fish, Porichthys notatus, in part because acoustic communication is essential to their reproductive behavior. Nesting male midshipman vocally court females by producing a long duration advertisement call. Females localize males by their advertisement call, spawn and deposit all their eggs in their mate's nest. As multiple courting males establish nests in close proximity to one another, the perception of another male's call may modulate individual calling behavior in competition for females. We tested the hypothesis that nesting males exposed to advertisement calls of other males would show elevated neural activity in auditory and vocal-acoustic brain centers as well as differential activation of catecholaminergic neurons compared to males exposed only to ambient noise. Experimental brains were then double labeled by immunofluorescence (-ir) for tyrosine hydroxylase (TH), an enzyme necessary for catecholamine synthesis, and cFos, an immediate-early gene product used as a marker for neural activation. Males exposed to other advertisement calls showed a significantly greater percentage of TH-ir cells colocalized with cFos-ir in the noradrenergic locus coeruleus and the dopaminergic periventricular posterior tuberculum, as well as increased numbers of cFos-ir neurons in several levels of the auditory and vocal-acoustic pathway. Increased activation of catecholaminergic neurons may serve to coordinate appropriate behavioral responses to male competitors. Additionally, these results implicate a role for specific catecholaminergic neuronal groups in auditory-driven social behavior in fishes, consistent with a conserved function in social acoustic behavior across vertebrates. PMID- 23936439 TI - Does virulence assessment of Vibrio anguillarum using sea bass (Dicentrarchus labrax) larvae correspond with genotypic and phenotypic characterization? AB - BACKGROUND: Vibriosis is one of the most ubiquitous fish diseases caused by bacteria belonging to the genus Vibrio such as Vibrio (Listonella) anguillarum. Despite a lot of research efforts, the virulence factors and mechanism of V. anguillarum are still insufficiently known, in part because of the lack of standardized virulence assays. METHODOLOGY/PRINCIPAL FINDINGS: We investigated and compared the virulence of 15 V. anguillarum strains obtained from different hosts or non-host niches using a standardized gnotobiotic bioassay with European sea bass (Dicentrarchus labrax L.) larvae as model hosts. In addition, to assess potential relationships between virulence and genotypic and phenotypic characteristics, the strains were characterized by random amplified polymorphic DNA (RAPD) and repetitive extragenic palindromic PCR (rep-PCR) analyses, as well as by phenotypic analyses using Biolog's Phenotype MicroArrayTM technology and some virulence factor assays. CONCLUSIONS/SIGNIFICANCE: Virulence testing revealed ten virulent and five avirulent strains. While some relation could be established between serotype, genotype and phenotype, no relation was found between virulence and genotypic or phenotypic characteristics, illustrating the complexity of V. anguillarum virulence. Moreover, the standardized gnotobiotic system used in this study has proven its strength as a model to assess and compare the virulence of different V. anguillarum strains in vivo. In this way, the bioassay contributes to the study of mechanisms underlying virulence in V. anguillarum. PMID- 23936440 TI - Nephrology referral and outcomes in critically ill acute kidney injury patients. AB - BACKGROUND: Delayed nephrology consultation (NC) seems to be associated with worse prognosis in critically ill acute kidney injury (AKI) patients. DESIGN SETTING PARTICIPANTS & MEASUREMENTS: The aims of this study were to analyze factors related with timing of NC and its relation with AKI patients' outcome in intensive care units of a tertiary hospital. AKI was defined as an increase >=50% in baseline serum creatinine (SCr). Early NC and delayed NC were defined as NC performed before and two days after AKI diagnosis day. Multivariable logistic regression and propensity scores (PS) were used to adjust for confounding and selection biases. Hospital mortality and dialysis dependence on hospital discharge were the primary outcomes. RESULTS: A total of 366 AKI patients were analyzed and NCs were carried out in 53.6% of the patients. Hospital mortality was 67.8% and dialysis required in 31.4% patients (115/366). Delayed NCs (34%) occurred two days after AKI diagnosis day. This group presented higher mortality (OR: 4.04/CI: 1.60-10.17) and increased dialysis dependence (OR: 3.00/CI: 1.43 6.29) on hospital discharge. Four variables were retained in the PS model for delayed NC: diuresis (1000 ml/24 h--OR: 1.92/CI: 1.27-2.90), SCr (OR: 0.49/CI: 0.32-0.75), surgical AKI (OR: 3.67/CI: 1.65-8.15), and mechanical ventilation (OR: 2.82/CI: 1.06-7.44). After correction by PS, delayed NC was still associated with higher mortality (OR: 3.39/CI: 1.24-9.29) and increased dialysis dependence (OR: 3.25/CI: 1.41-7.51). Delayed NC was associated with increased mortality either in dialyzed patients (OR: 1.54/CI: 1.35-1.78) or non-dialyzed patients (OR: 2.89/CI: 1.00-8.35). CONCLUSION: Delayed NC was associated with higher mortality and increased dialysis dependence rates in critically ill AKI patients at hospital discharge. Further studies are necessary to ascertain whether this effect is due to delayed nephrology intervention or residual confounding factors. PMID- 23936441 TI - Characterization of leucocin B-KM432Bz from Leuconostoc pseudomesenteroides isolated from boza, and comparison of its efficiency to pediocin PA-1. AB - A bacteriocin-producing bacterium was isolated from boza and identified as Leuconostoc pseudomesenteroides KM432Bz. The antimicrobial peptide was purified and shown to be identical to other class IIa bacteriocins: leucocin A from Leuconostoc gelidum UAL-187 and Leuconostoc pseudomesenteroides QU15 and leucocin B from Leuconostoc carnosum Ta11a. The bacteriocin was named leucocin B-KM432Bz. Leucocin B-KM432Bz gene cluster encodes the bacteriocin precursor (lcnB), the immunity protein (lcnI) and the dedicated export machinery (lcnD and lcnE). A gene of unknown and non-essential function (lcnC), which is interrupted by an insertion sequence of the IS30 family, is localized between lcnB and lcnD. The activity of leucocin B-KM432Bz requires subunit C of the EII(t) Man mannose permease, which is the receptor for entry into target cells. The determination of the minimum inhibitory concentrations revealed the lowest values for leucocin B KM432Bz over Listeria strains, with 4 to 32 fold better efficiency than pediocin PA-1. PMID- 23936442 TI - Methicillin-resistant Staphylococcus aureus (MRSA) is increasing in Norway: a time series analysis of reported MRSA and methicillin-sensitive S. aureus cases, 1997-2010. AB - BACKGROUND: Accurate estimates of the incidence and prevalence of methicillin resistant Staphylococcus aureus (MRSA) infections are needed to inform public health policies. In Norway, where both MRSA infection and carriage are notifiable conditions, the reported incidence of MRSA is slowly increasing. However, the proportion of MRSA in relation to all S. aureus isolates is unknown, making it difficult to determine if the rising incidence is real or an artifact of an increasing number of tests performed. AIM: To characterize recent trends in MRSA infections and obtain a more complete understanding of the MRSA level in Norway. METHODS: All reported cases of MRSA and methicillin-sensitive S. aureus (MSSA) from Oslo County (1997-2010) and Health Region East (2008-2008), representing approximately 11% and 36% of the Norwegian population, respectively, were analyzed using a stochastic time series analysis to characterize trends. RESULTS: In Oslo County, the proportion of methicillin-resistant cases increased from 0.73% to 3.78% during the study period and was well modeled by an exponential growth with a doubling constant of 5.7 years (95% CI 4.5-7.4 years). In Health Region East, the proportion of MRSA cases increased from 0.4% to 2.1% from 2002 to 2008, with a best-fitting linear increase of 0.26% (95% CI 0.21-0.30%) per year. In both cases, the choice of a linear or exponential model for the time trend produced only marginally different model fits. We found no significant changes due to revised national MRSA guidelines published in June 2009. Significant variations in the increasing time trend were observed in the five hospitals within the region. The yearly reported incidence of MSSA was relatively stable in both study areas although we found seasonal patterns with peaks in August. CONCLUSION: The level of MRSA is increasing in Norway, and the proportion of methicillin resistance in all S. aureus isolates are higher than the reported proportion of MRSA in invasive infections. PMID- 23936443 TI - Decrease of fibulin-3 in hepatocellular carcinoma indicates poor prognosis. AB - Fibulin-3, originally identified in senescent and Werner syndrome fibroblasts, has been implicated in cell morphology, growth, adhesion and motility. Fibulin-3 exhibits both antitumor and oncogenic activities towards human cancers; however, the role of Fibulin-3 in hepatocellular carcinoma (HCC) remains elusive. In this study, we showed that both the mRNA and protein levels of Fibulin-3 were remarkably downregulated in HCC cell lines and fresh tissues. Immunohistochemical data revealed that Fibulin-3 was decreased in tumorous tissues in 67.1% (171/255) of cases compared to the corresponding adjacent nontumorous tissues. The results of statistical analysis indicated that low Fibulin-3 expression, defined by the receiver operating characteristic curve (ROC), was significantly associated with tumor differentiation (P=0.008), clinical stage (P=0.014) and serum AFP levels (P<0.01). Furthermore, Kaplan-Meier and multivariate analysis suggested that Fibulin-3 is an independent negative prognostic indicator for both overall (P<0.001) and recurrence-free (P=0.036) survival. In addition, an in vitro study demonstrated that knockdown of Fibulin-3 by siRNA markedly increased cell viability and promoted cell invasion in HCC cells. Collectively, our data suggest that Fibulin-3 exhibits antitumor effects towards HCC and serves as a biomarker of unfavorable prognosis for this deadly disease. PMID- 23936444 TI - High-resolution transcriptomic analyses of Sinorhizobium sp. NGR234 bacteroids in determinate nodules of Vigna unguiculata and indeterminate nodules of Leucaena leucocephala. AB - The rhizobium-legume symbiosis is a model system for studying mutualistic interactions between bacteria and eukaryotes. Sinorhizobium sp. NGR234 is distinguished by its ability to form either indeterminate nodules or determinate nodules with diverse legumes. Here, we presented a high-resolution RNA-seq transcriptomic analysis of NGR234 bacteroids in indeterminate nodules of Leucaena leucocephala and determinate nodules of Vigna unguiculata. In contrast to exponentially growing free-living bacteria, non-growing bacteroids from both legumes recruited several common cellular functions such as cbb3 oxidase, thiamine biosynthesis, nitrate reduction pathway (NO-producing), succinate metabolism, PHB (poly-3-hydroxybutyrate) biosynthesis and phosphate/phosphonate transporters. However, different transcription profiles between bacteroids from two legumes were also uncovered for genes involved in the biosynthesis of exopolysaccharides, lipopolysaccharides, T3SS (type three secretion system) and effector proteins, cytochrome bd ubiquinol oxidase, PQQ (pyrroloquinoline quinone), cytochrome c550, pseudoazurin, biotin, phasins and glycolate oxidase, and in the metabolism of glutamate and phenylalanine. Noteworthy were the distinct expression patterns of genes encoding phasins, which are thought to be involved in regulating the surface/volume ratio of PHB granules. These patterns are in good agreement with the observed granule size difference between bacteroids from L. leucocephala and V. unguiculata. PMID- 23936445 TI - Proprotein convertase subtilisin/kexin type 3 promotes adipose tissue-driven macrophage chemotaxis and is increased in obesity. AB - BACKGROUND: Matrix metalloproteinase (MMP)-dependent extracellular matrix (ECM) remodeling is a key feature in cardiometabolic syndrome-associated adipogenesis and atherosclerosis. Activation of membrane-tethered (MT) 1-MMP depends on furin (PCSK3). However, the regulation and function of the natural furin-inhibitor serpinB8 and thus furin/MT1-MMP-activity in obesity-related tissue inflammation/remodeling is unknown. Here we aimed to determine the role of serpinB8/furin in obesity-associated chronic inflammation. METHODS AND RESULTS: Monocyte -> macrophage transformation was characterized by decreases in serpinB8 and increases in furin/MT1-MMP. Rescue of serpinB8 by protein overexpression inhibited furin-dependent pro-MT1-MMP activation in macrophages, supporting its role as a furin-inhibitor. Obese white adipose tissue-facilitated macrophage migration was inhibited by furin- and MMP-inhibition, stressing the importance of the furin-MMP axis in fat tissue inflammation/remodeling. Monocytes from obese patients (body mass index (BMI) >30kg/m(2)) had higher furin, MT1-MMP, and resistin gene expression compared to normal weight individuals (BMI<25kg/m(2)) with significant correlations of BMI/furin and furin/MT1-MMP. In vitro, the adipocytokine resistin induced furin and MT1-MMP in mononuclear cells (MNCs), while MCP-1 had no effect. CONCLUSIONS: Acquisition of the inflammatory macrophage phenotype is characterized by an imbalance in serpinB8/furin, leading to MT1-MMP activation, thereby enhancing migration. Increases in MT1-MMP and furin are present in MNCs from obese patients. Dissecting the regulation of furin and its inhibitor serpinB8 should facilitate targeting inflammation/remodeling in cardiometabolic diseases. PMID- 23936446 TI - Maternal and perinatal outcomes of twin pregnancy in 23 low- and middle-income countries. AB - BACKGROUND: Twin pregnancies in low- and middle-income countries (LMICs) pose a high risk to mothers and newborns due to inherent biological risks and scarcity of health resources. We conducted a secondary analysis of the WHO Global Survey dataset to analyze maternal and perinatal outcomes in twin pregnancies and factors associated with perinatal morbidity and mortality in twins. METHODS: We examined maternal and neonatal characteristics in twin deliveries in 23 LMICs and conducted multi-level logistic regression to determine the association between twins and adverse maternal and perinatal outcomes. RESULTS: 279,425 mothers gave birth to 276,187 (98.8%) singletons and 6,476 (1.2%) twins. Odds of severe adverse maternal outcomes (death, blood transfusion, ICU admission or hysterectomy) (AOR 1.85, 95% CI 1.60-2.14) and perinatal mortality (AOR 2.46, 95% CI 1.40-4.35) in twin pregnancies were higher, however early neonatal death (AOR 2.50, 95% CI 0.95-6.62) and stillbirth (AOR 1.22, 95% CI 0.58-2.57) did not reach significance. Amongst twins alone, maternal age <18, poor education and antenatal care, nulliparity, vaginal bleeding, non-cephalic presentations, birth weight discordance >15%, born second, preterm birth and low birthweight were associated with perinatal mortality. Marriage and caesarean section were protective. CONCLUSIONS: Twin pregnancy is a significant risk factor for maternal and perinatal morbidity and mortality in low-resource settings; maternal risk and access to safe caesarean section may determine safest mode of delivery in LMICs. Improving obstetric care in twin pregnancies, particularly timely access to safe caesarean section, is required to reduce risk to mother and baby. PMID- 23936447 TI - De novo mutations in ataxin-2 gene and ALS risk. AB - Pathogenic CAG repeat expansion in the ataxin-2 gene (ATXN2) is the genetic cause of spinocerebellar ataxia type 2 (SCA2). Recently, it has been associated with Parkinsonism and increased genetic risk for amyotrophic lateral sclerosis (ALS). Here we report the association of de novo mutations in ATXN2 with autosomal dominant ALS. These findings support our previous conjectures based on population studies on the role of large normal ATXN2 alleles as the source for new mutations being involved in neurodegenerative pathologies associated with CAG expansions. The de novo mutations expanded from ALS/SCA2 non-risk alleles as proven by meta analysis method. The ALS risk was associated with SCA2 alleles as well as with intermediate CAG lengths in the ATXN2. Higher risk for ALS was associated with pathogenic CAG repeat as revealed by meta-analysis. PMID- 23936448 TI - Curcumin protects microglia and primary rat cortical neurons against HIV-1 gp120 mediated inflammation and apoptosis. AB - Curcumin is a molecule found in turmeric root that has anti-inflammatory, antioxidant, and anti-tumor properties and has been widely used as both an herbal drug and a food additive to treat or prevent neurodegenerative diseases. To explore whether curcumin is able to ameliorate HIV-1-associated neurotoxicity, we treated a murine microglial cell line (N9) and primary rat cortical neurons with curcumin in the presence or absence of neurotoxic HIV-1 gp120 (V3 loop) protein. We found that HIV-1 gp120 profoundly induced N9 cells to produce reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1). HIV-1 gp120 also induced apoptosis of primary rat cortical neurons. Curcumin exerted a powerful inhibitory effect against HIV-1 gp120-induced neuronal damage, reducing the production of ROS, TNF-alpha and MCP 1 by N9 cells and inhibiting apoptosis of primary rat cortical neurons. Curcumin may exert its biological activities through inhibition of the delayed rectification and transient outward potassium (K(+)) current, as curcumin effectively reduced HIV-1 gp120-mediated elevation of the delayed rectification and transient outward K(+) channel current in neurons. We conclude that HIV-1 gp120 increases ROS, TNF-alpha and MCP-1 production in microglia, and induces cortical neuron apoptosis by affecting the delayed rectification and transient outward K(+) channel current. Curcumin reduces production of ROS and inflammatory mediators in HIV-1-gp120-stimulated microglia, and protects cortical neurons against HIV-1-mediated apoptosis, most likely through inhibition of HIV-1 gp120 induced elevation of the delayed rectification and transient outward K(+) current. PMID- 23936449 TI - Effects of controlled-release fertiliser on nitrogen use efficiency in summer maize. AB - Nitrogen (N) is a nutrient element necessary for plant growth and development. However, excessive inputs of N will lead to inefficient use and large N losses to the environment, which can adversely affect air and water quality, biodiversity and human health. To examine the effects of controlled-release fertilisers (CRF) on yield, we measured ammonia volatilisation, N use efficiency (NUE) and photosynthetic rate after anthesis in summer maize hybrid cultivar Zhengdan958. Maize was grown using common compound fertiliser (CCF), the same amount of resin coated controlled release fertiliser (CRFIII), the same amount of sulphur-coated controlled release fertiliser (SCFIII) as CCF, 75% CRF (CRFII) and SCF (SCFII), 50% CRF (CRFI) and SCF (SCFI), and no fertiliser. We found that treatments CRFIII, SCFIII, CRFII and SCFII produced grain yields that were 13.15%, 14.15%, 9.69% and 10.04% higher than CCF. There were no significant differences in grain yield among CRFI, SCFI and CCF. We also found that the ammonia volatilisation rates of CRF were significantly lower than those of CCF. The CRF treatments reduced the emission of ammonia by 51.34% to 91.34% compared to CCF. In addition, after treatment with CRF, maize exhibited a higher net photosynthetic rate than CCF after anthesis. Agronomic NUE and apparent N recovery were higher in the CRF treatment than in the CCF treatment. The N uptake and physiological NUE of the four yield-enhanced CRF treatments were higher than those of CCF. These results suggest that the increase in NUE in the CRF treatments was generally attributable to the higher photosynthetic rate and lower ammonia volatilisation compared to CCF-treated maize. PMID- 23936450 TI - Revisiting the role of individual variability in population persistence and stability. AB - Populations often exhibit a pronounced degree of individual variability and this can be important when constructing ecological models. In this paper, we revisit the role of inter-individual variability in population persistence and stability under predation pressure. As a case study, we consider interactions between a structured population of zooplankton grazers and their predators. Unlike previous structured population models, which only consider variability of individuals according to the age or body size, we focus on physiological and behavioural structuring. We first experimentally demonstrate a high degree of variation of individual consumption rates in three dominant species of herbivorous copepods (Calanus finmarchicus, Calanus glacialis, Calanus euxinus) and show that this disparity implies a pronounced variation in the consumption capacities of individuals. Then we construct a parsimonious predator-prey model which takes into account the intra-population variability of prey individuals according to behavioural traits: effectively, each organism has a 'personality' of its own. Our modelling results show that structuring of prey according to their growth rate and vulnerability to predation can dampen predator-prey cycles and enhance persistence of a species, even if the resource stock for prey is unlimited. The main mechanism of efficient top-down regulation is shown to work by letting the prey population become dominated by less vulnerable individuals when predator densities are high, while the trait distribution recovers when the predator densities are low. PMID- 23936451 TI - An inhibitor of the deltaPKC interaction with the d subunit of F1Fo ATP synthase reduces cardiac troponin I release from ischemic rat hearts: utility of a novel ammonium sulfate precipitation technique. AB - We have previously reported protection against hypoxic injury by a cell permeable, mitochondrially-targeted deltaPKC-d subunit of F1Fo ATPase (dF1Fo) interaction inhibitor [NH2-YGRKKRRQRRRMLA TRALSLIGKRAISTSVCAGRKLALKTIDWVSFDYKDDDDK-COOH] in neonatal cardiac myo-cytes. In the present work we demonstrate the partitioning of this peptide to the inner membrane and matrix of mitochondria when it is perfused into isolated rat hearts. We also used ammonium sulfate ((NH4)2SO4) and chloroform/methanol precipitation of heart effluents to demonstrate reduced card-iac troponin I (cTnI) release from ischemic rat hearts perfused with this inhibitor. 50% (NH4)2SO4 saturation of perfusates collected from Langendorff rat heart preparations optimally precipitated cTnI, allowing its detection in Western blots. In hearts receiving 20 min of ischemia followed by 30, or 60 min of reperfusion, the Mean+/-S.E. (n=5) percentage of maximal cTnI release was 30 +/- 7 and 60 +/- 17, respectively, with additional cTnI release occurring after 150 min of reperfusion. Perfusion of hearts with the deltaPKC-dF1Fo interaction inhibitor, prior to 20 min of ischemia and 60-150 min of reperfusion, reduced cTnI release by 80%. Additionally, we found that when soybean trypsin inhibitor (SBTI), was added to rat heart effluents, it could also be precipitated using (NH4)2SO4 and detected in western blots. This provided a convenient method for normalizing protein recoveries between groups. Our results support the further development of the deltaPKC-dF1Fo inhibitor as a potential therapeutic for combating cardiac ischemic injury. In addition, we have developed an improved method for the detection of cTnI release from perfused rat hearts. PMID- 23936452 TI - D-cycloserine in prelimbic cortex reverses scopolamine-induced deficits in olfactory memory in rats. AB - A significant interaction between N-methyl-D-aspartate (NMDA) and muscarinic receptors has been suggested in the modulation of learning and memory processes. The present study further investigates this issue and explores whether d cycloserine (DCS), a partial agonist at the glycine binding site of the NMDA receptors that has been regarded as a cognitive enhancer, would reverse scopolamine (SCOP)-induced amnesia in two olfactory learning tasks when administered into the prelimbic cortex (PLC). Thus, in experiment 1, DCS (10 ug/site) was infused prior to acquisition of odor discrimination (ODT) and social transmission of food preference (STFP), which have been previously characterized as paradigms sensitive to PLC muscarinic blockade. Immediately after learning such tasks, SCOP was injected (20 ug/site) and the effects of both drugs (alone and combined) were tested in 24-h retention tests. To assess whether DCS effects may depend on the difficulty of the task, in the STFP the rats expressed their food preference either in a standard two-choice test (experiment 1) or a more challenging three-choice test (experiment 2). The results showed that bilateral intra-PLC infusions of SCOP markedly disrupted the ODT and STFP memory tests. Additionally, infusions of DCS alone into the PLC enhanced ODT but not STFP retention. However, the DCS treatment reversed SCOP-induced memory deficits in both tasks, and this effect seemed more apparent in ODT and 3-choice STFP. Such results support the interaction between the glutamatergic and the cholinergic systems in the PLC in such a way that positive modulation of the NMDA receptor/channel, through activation of the glycine binding site, may compensate dysfunction of muscarinic neurotransmission involved in stimulus-reward and relational learning tasks. PMID- 23936453 TI - Describing the relationship between cat bites and human depression using data from an electronic health record. AB - Data mining approaches have been increasingly applied to the electronic health record and have led to the discovery of numerous clinical associations. Recent data mining studies have suggested a potential association between cat bites and human depression. To explore this possible association in more detail we first used administrative diagnosis codes to identify patients with either depression or bites, drawn from a population of 1.3 million patients. We then conducted a manual chart review in the electronic health record of all patients with a code for a bite to accurately determine which were from cats or dogs. Overall there were 750 patients with cat bites, 1,108 with dog bites, and approximately 117,000 patients with depression. Depression was found in 41.3% of patients with cat bites and 28.7% of those with dog bites. Furthermore, 85.5% of those with both cat bites and depression were women, compared to 64.5% of those with dog bites and depression. The probability of a woman being diagnosed with depression at some point in her life if she presented to our health system with a cat bite was 47.0%, compared to 24.2% of men presenting with a similar bite. The high proportion of depression in patients who had cat bites, especially among women, suggests that screening for depression could be appropriate in patients who present to a clinical provider with a cat bite. Additionally, while no causative link is known to explain this association, there is growing evidence to suggest that the relationship between cats and human mental illness, such as depression, warrants further investigation. PMID- 23936454 TI - Microrheological characterization of collagen systems: from molecular solutions to fibrillar gels. AB - Collagen is the most abundant protein in the extracellular matrix (ECM), where its structural organization conveys mechanical information to cells. Using optical-tweezers-based microrheology, we investigated mechanical properties both of collagen molecules at a range of concentrations in acidic solution where fibrils cannot form and of gels of collagen fibrils formed at neutral pH, as well as the development of microscale mechanical heterogeneity during the self assembly process. The frequency scaling of the complex shear modulus even at frequencies of ~10 kHz was not able to resolve the flexibility of collagen molecules in acidic solution. In these solutions, molecular interactions cause significant transient elasticity, as we observed for 5 mg/ml solutions at frequencies above ~200 Hz. We found the viscoelasticity of solutions of collagen molecules to be spatially homogeneous, in sharp contrast to the heterogeneity of self-assembled fibrillar collagen systems, whose elasticity varied by more than an order of magnitude and in power-law behavior at different locations within the sample. By probing changes in the complex shear modulus over 100-minute timescales as collagen self-assembled into fibrils, we conclude that microscale heterogeneity appears during early phases of fibrillar growth and continues to develop further during this growth phase. Experiments in which growing fibrils dislodge microspheres from an optical trap suggest that fibril growth is a force generating process. These data contribute to understanding how heterogeneities develop during self-assembly, which in turn can help synthesis of new materials for cellular engineering. PMID- 23936455 TI - TP53 and let-7a micro-RNA regulate K-Ras activity in HCT116 colorectal cancer cells. AB - Recent reports have indicated that KRAS and TP53 mutations predict response to therapy in colorectal cancer. However, little is known about the relationship between these two common genetic alterations. Micro-RNAs (miRNAs), a class of noncoding RNA implicated in cellular processes, have been increasingly linked to KRAS and TP53. We hypothesized that lethal-7a (let-7a) miRNA regulates KRAS through TP53. To investigate the relationship between KRAS, TP53, and let-7a, we used HCT116 KRAS(mut) human colorectal cancer cells with four different genotypic modifications in TP53 (TP53(-/-), TP53(+/-), TP53(mut/+), and TP53(mut/-) ). Using these cells we observed that K-Ras activity was higher in cells with mutant or knocked out TP53 alleles, suggesting that wild-type TP53 may suppress K-Ras activity. Let-7a was present in HCT116 KRAS(mut) cells, though there was no correlation between let-7a level and TP53 genotype status. To explore how let-7a may regulate K-Ras in the different TP53 genotype cells we used let-7a inhibitor and demonstrated increased K-Ras activity across all TP53, thus corroborating prior reports that let-7a regulates K-Ras. To assess potential clinical implications of this regulatory network, we examined the influence of TP53 genotype and let-7a inhibition on colon cancer cell survival following chemoradiation therapy (CRT). We observed that cells with complete loss of wild type TP53 alleles ((-/-) or (-/mut)) were resistant to CRT following treatment with 5-fluorouracil and radiation. Further increase in K-Ras activity with let-7a inhibition did not impact survival in these cells. In contrast, cells with single or double wild-type TP53 alleles were moderately responsive to CRT and exhibited resistance when let-7a was inhibited. In summary, our results show a complex regulatory system involving TP53, KRAS, and let-7a. Our results may provide clues to understand and target these interactions in colorectal cancer. PMID- 23936456 TI - Small molecule ErbB inhibitors decrease proliferative signaling and promote apoptosis in philadelphia chromosome-positive acute lymphoblastic leukemia. AB - The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia (Ph(+)ALL) is a negative prognostic indicator. Tyrosine kinase inhibitors (TKI) that target BCR/ABL, such as imatinib, have improved treatment of Ph(+)ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50% of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 (ErbB2) is expressed in ~30% of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array (RPPA) with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56% of Ph(+)ALL as compared to just 4.8% of Ph(-)ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 (by 60% in Z119 and 39% in Z181 cells at 3 uM). Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner (by 91% in both cell lines at 3 uM). Canertinib treatment increased expression of the pro apoptotic protein Bim by as much as 144% in Z119 cells and 49% in Z181 cells, and further produced caspase-3 activation and consequent apoptotic cell death. Both canertinib and the FDA-approved ErbB1/2-directed TKI lapatinib abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs at clinically relevant doses. Our results suggest that ErbB signaling is an additional molecular target in Ph(+)ALL and encourage the development of clinical strategies combining ErbB and BCR/ABL kinase inhibitors for this subset of ALL patients. PMID- 23936457 TI - Pharmacometabolomic signature of ataxia SCA1 mouse model and lithium effects. AB - We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1) disease mouse model (Sca1(154Q/+)). To learn more about disease pathogenesis and molecular contributions to the neuroprotective effects of lithium, we investigated metabolomic profiles of cerebellar tissue and plasma from SCA1-model treated and untreated mice. Metabolomic analyses of wild-type and Sca1(154Q/+) mice, with and without lithium treatment, were performed using gas chromatography time-of-flight mass spectrometry and BinBase mass spectral annotations. We detected 416 metabolites, of which 130 were identified. We observed specific metabolic perturbations in Sca1(154Q/+) mice and major effects of lithium on metabolism, centrally and peripherally. Compared to wild-type, Sca1(154Q/+) cerebella metabolic profile revealed changes in glucose, lipids, and metabolites of the tricarboxylic acid cycle and purines. Fewer metabolic differences were noted in Sca1(154Q/+) mouse plasma versus wild-type. In both genotypes, the major lithium responses in cerebellum involved energy metabolism, purines, unsaturated free fatty acids, and aromatic and sulphur-containing amino acids. The largest metabolic difference with lithium was a 10-fold increase in ascorbate levels in wild-type cerebella (p<0.002), with lower threonate levels, a major ascorbate catabolite. In contrast, Sca1(154Q/+) mice that received lithium showed no elevated cerebellar ascorbate levels. Our data emphasize that lithium regulates a variety of metabolic pathways, including purine, oxidative stress and energy production pathways. The purine metabolite level, reduced in the Sca1(154Q/+) mice and restored upon lithium treatment, might relate to lithium neuroprotective properties. PMID- 23936458 TI - Distinct mechanisms for induction and tolerance regulate the immediate early genes encoding interleukin 1beta and tumor necrosis factor alpha. AB - Interleukin-1beta and Tumor Necrosis Factor alpha play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPbeta and NF-kappaB. Activation and DNA binding of these two pre expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. PMID- 23936459 TI - Functional identification of close proximity amino acid side chains within the transmembrane-spanning helixes of the P2X2 receptor. AB - The transition from the closed to open state greatly alters the intra- and inter subunit interactions of the P2X receptor (P2XR). The interactions that occur in the transmembrane domain of the P2X2R remain unclear. We used substituted cysteine mutagenesis disulfide mapping to identify pairs of residues that are in close proximity within the transmembrane domain of rP2X2R and compared our results to the predicted positions of these amino acids obtained from a rat P2X2R homology model of the available open and closed zebrafish P2X4R structures. Alternations in channel function were measured as a change in the ATP-gated current before and after exposure to dithiothreitol. Thirty-six pairs of double mutants of rP2X2R expressed in HEK293 cells produced normal functioning channels. Thirty-five pairs of these mutants did not exhibit a functionally detectable disulfide bond. The double mutant H33C/S345C formed redox-dependent cross-links in the absence of ATP. Dithiothreitol ruptured the disulfide bond of H33C/S345C and induced a 2 to 3-fold increase in current. The EC50 for H33C/S345C before dithiothreitol treatment was ~2-fold higher than that after dithiothreitol treatment. Dithiothreitol reduced the EC50 to wild-type levels. Furthermore, expression of trimeric concatamer receptors with Cys mutations at some but not all six positions showed that the more disulfide bond formation sites within the concatamer, the greater current potentiation after dithiothreitol incubation. Immunoblot analysis of H33C/S345C revealed one monomer band under nonreducing conditions strongly suggesting that disulfide bonds are formed within single subunits (intra-subunit) and not between two subunits (inter-subunit). Taken together, these data indicate that His33 and Ser345 are proximal to each other across an intra-subunit interface. The relative movement between the first transmembrane and the second transmembrane in the intra-subunit is likely important for transmitting the action of ATP binding to the opening of the channel. PMID- 23936460 TI - Understanding the links among neuromedin U gene, beta2-adrenoceptor gene and bone health: an observational study in European children. AB - Neuromedin U, encoded by the NMU gene, is a hypothalamic neuropeptide that regulates both energy metabolism and bone mass. The beta-2 adrenergic receptor, encoded by the ADRB2 gene, mediates several effects of catecholamine hormones and neurotransmitters in bone. We investigated whether NMU single nucleotide polymorphisms (SNPs) and haplotypes, as well as functional ADRB2 SNPs, are associated with bone stiffness in children from the IDEFICS cohort, also evaluating whether NMU and ADRB2 interact to affect this trait. A sample of 2,274 subjects (52.5% boys, age 6.2 +/- 1.8 years) from eight European countries, having data on calcaneus bone stiffness index (SI, mean of both feet) and genotyping (NMU gene: rs6827359, rs12500837, rs9999653; ADRB2 gene: rs1042713, rs1042714), was studied. After false discovery rate adjustment, SI was significantly associated with all NMU SNPs. rs6827359 CC homozygotes showed the strongest association (recessive model, Delta= -1.8, p=0.006). Among the five retrieved haplotypes with frequencies higher than 1% (range 2.0-43.9%), the CCT haplotype (frequency=39.7%) was associated with lower SI values (dominant model, Delta= -1.0, p=0.04) as compared to the most prevalent haplotype. A non significant decrease in SI was observed in in ADRB2 rs1042713 GG homozygotes, while subjects carrying SI-lowering genotypes at both SNPs (frequency = 8.4%) showed much lower SI than non-carriers (Delta= -3.9, p<0.0001; p for interaction=0.025). The association was more evident in preschool girls, in whom SI showed a curvilinear trend across ages. In subgroup analyses, rs9999653 CC NMU or both GG ADRB2 genotypes were associated with either lower serum calcium or beta-CrossLaps levels (p=0.01). This study in European children shows, for the first time in humans, a role for NMU gene through interaction with ADRB2 gene in bone strength regulation, more evident in preschool girls. PMID- 23936461 TI - Regulation of A1 by OX40 contributes to CD8(+) T cell survival and anti-tumor activity. AB - The TNFR family member OX40 (CD134) is critical for optimal clonal expansion and survival of T cells. However, the intracellular targets of OX40 in CD8 T cells are not fully understood. Here we show that A1, a Bcl-2 family protein, is regulated by OX40 in effector CD8 T cells. In contrast to wild-type T cells, OX40 deficient CD8 T cells failed to maintain A1 expression driven by antigen. Conversely, enforced OX40 stimulation promoted A1 expression. In both situations, the expression of A1 directly correlated with CD8 T cell survival. In addition, exogenous expression of A1 in OX40-deficient CD8 T cells reversed their survival defect in vitro and in vivo. Moreover, forced expression of A1 in CD8 T cells from OX40-deficient mice restored the ability of these T cells to suppress tumor growth in a murine model. These results indicate that OX40 signals regulate CD8 T cell survival at least in part through maintaining expression of the anti apoptotic molecule A1, and provide new insight into the mechanism by which OX40 may impact anti-tumor immunity. PMID- 23936462 TI - Perceptual distortions in pitch and time reveal active prediction and support for an auditory pitch-motion hypothesis. AB - A number of accounts of human auditory perception assume that listeners use prior stimulus context to generate predictions about future stimulation. Here, we tested an auditory pitch-motion hypothesis that was developed from this perspective. Listeners judged either the time change (i.e., duration) or pitch change of a comparison frequency glide relative to a standard (referent) glide. Under a constant-velocity assumption, listeners were hypothesized to use the pitch velocity (Deltaf/Deltat) of the standard glide to generate predictions about the pitch velocity of the comparison glide, leading to perceptual distortions along the to-be-judged dimension when the velocities of the two glides differed. These predictions were borne out in the pattern of relative points of subjective equality by a significant three-way interaction between the velocities of the two glides and task. In general, listeners' judgments along the task-relevant dimension (pitch or time) were affected by expectations generated by the constant-velocity standard, but in an opposite manner for the two stimulus dimensions. When the comparison glide velocity was faster than the standard, listeners overestimated time change, but underestimated pitch change, whereas when the comparison glide velocity was slower than the standard, listeners underestimated time change, but overestimated pitch change. Perceptual distortions were least evident when the velocities of the standard and comparison glides were matched. Fits of an imputed velocity model further revealed increasingly larger distortions at faster velocities. The present findings provide support for the auditory pitch-motion hypothesis and add to a larger body of work revealing a role for active prediction in human auditory perception. PMID- 23936463 TI - Nanosecond pulsed electric field suppresses development of eyes and germ cells through blocking synthesis of retinoic acid in Medaka (Oryzias latipes). AB - Application of nanosecond pulsed electric fields (nsPEFs) has attracted rising attention in various scientific fields including medical, pharmacological, and biological sciences, although its effects and molecular mechanisms leading to the effects remain poorly understood. Here, we show that a single, high-intensity (10 30 kV/cm), 60-ns PEF exposure affects gene expression and impairs development of eyes and germ cells in medaka (Oryzias latipes). Exposure of early blastula stage embryos to nsPEF down-regulated the expression of several transcription factors which are essential for eye development, causing abnormal eye formation. Moreover, the majority of the exposed genetic female embryos showed a fewer number of germ cells similar to that of the control (unexposed) genetic male at 9 days post-fertilization (dpf). However, all-trans retinoic acid (atRA) treatment following the exposure rescued proliferation of germ cells and resumption of normal eye development, suggesting that the phenotypes induced by nsPEF are caused by a decrease of retinoic acid levels. These results confirm that nsPEFs induce novel effects during embryogenesis in medaka. PMID- 23936465 TI - Peronosporomycetes (Oomycota) from a Middle Permian permineralised peat within the Bainmedart Coal Measures, Prince Charles Mountains, Antarctica. AB - The fossil record of Peronosporomycetes (water moulds) is rather sparse, though their distinctive ornamentation means they are probably better reported than some true fungal groups. Here we describe a rare Palaeozoic occurrence of this group from a Guadalupian (Middle Permian) silicified peat deposit in the Bainmedart Coal Measures, Prince Charles Mountains, Antarctica. Specimens are numerous and comprise two morphologically distinct kinds of ornamented oogonia, of which some are attached to hyphae by a septum. Combresomyces caespitosus sp. nov. consists of spherical oogonia bearing densely spaced, long, hollow, slender, conical papillae with multiple sharply pointed, strongly divergent, apical branches that commonly form a pseudoreticulate pattern under optical microscopy. The oogonia are attached to a parental hypha by a short truncated stalk with a single septum. Combresomyces rarus sp. nov. consists of spherical oogonia bearing widely spaced, hollow, broad, conical papillae that terminate in a single bifurcation producing a pair of acutely divergent sharply pointed branches. The oogonium bears a short truncate extension where it attaches to the parental hypha. We propose that similarities in oogonium shape, size, spine morphology and hyphal attachment between the Permian forms from the Prince Charles Mountains and other reported Peronosporomycetes from Devonian to Triassic strata at widely separated localities elsewhere in the world delimit an extinct but once cosmopolitan Palaeozoic to early Mesozoic branch of the peronosporomycete clade. We name this order Combresomycetales and note that it played an important role in late Palaeozoic and early Mesozoic peatland ecosystems worldwide. PMID- 23936464 TI - Cortical dynamics of semantic processing during sentence comprehension: evidence from event-related optical signals. AB - Using the event-related optical signal (EROS) technique, this study investigated the dynamics of semantic brain activation during sentence comprehension. Participants read sentences constituent-by-constituent and made a semantic judgment at the end of each sentence. The EROSs were recorded simultaneously with ERPs and time-locked to expected or unexpected sentence-final target words. The unexpected words evoked a larger N400 and a late positivity than the expected ones. Critically, the EROS results revealed activations first in the left posterior middle temporal gyrus (LpMTG) between 128 and 192 ms, then in the left anterior inferior frontal gyrus (LaIFG), the left middle frontal gyrus (LMFG), and the LpMTG in the N400 time window, and finally in the left posterior inferior frontal gyrus (LpIFG) between 832 and 864 ms. Also, expected words elicited greater activation than unexpected words in the left anterior temporal lobe (LATL) between 192 and 256 ms. These results suggest that the early lexical semantic retrieval reflected by the LpMTG activation is followed by two different semantic integration processes: a relatively rapid and transient integration in the LATL and a relatively slow but enduring integration in the LaIFG/LMFG and the LpMTG. The late activation in the LpIFG, however, may reflect cognitive control. PMID- 23936466 TI - The polymorphic AluYb8 insertion in the MUTYH gene is associated with reduced type 1 protein expression and reduced mitochondrial DNA content. AB - The human mutY homolog (MUTYH) participates in base excision repair (BER), which is critical for repairing oxidized DNA bases and maintaining DNA replication fidelity. The polymorphic AluYb8 insertion in the 15(th) intron of the MUTYH gene (AluYb8MUTYH) has been shown to associate with an aggregated 8-hydroxy-2' deoxyguanosine (8-OH-dG) lesion in genomic DNA and to serve as a risk factor for age-related diseases. In this work, we demonstrate that this variant is associated with a significant reduction of the type 1 MUTYH protein that localizes to mitochondria. Notably, this variant affects mitochondrial DNA (mtDNA) maintenance and functional mitochondrial mass in individuals homozygous for the AluYb8MUTYH variant. These findings provide evidence for an association between the AluYb8MUTYH variant and decreased mitochondrial homeostasis and, consequently, contribute to elucidating the roles of the AluYb8MUTYH variant in impairing the mitochondrial base excision repair (mtBER) system and increasing the risk of acquiring an age-related disease. PMID- 23936467 TI - Anti-tuberculosis drug resistance among new and previously treated sputum smear positive tuberculosis patients in Uganda: results of the first national survey. AB - BACKGROUND: Multidrug resistant and extensively drug resistant tuberculosis (TB) have become major threats to control of tuberculosis globally. The rates of anti TB drug resistance in Uganda are not known. We conducted a national drug resistance survey to investigate the levels and patterns of resistance to first and second line anti-TB drugs among new and previously treated sputum smear positive TB cases. METHODS: Sputum samples were collected from a nationally representative sample of new and previously treated sputum smear-positive TB patients registered at TB diagnostic centers during December 2009 to February 2011 using a weighted cluster sampling method. Culture and drug susceptibility testing was performed at the national TB reference laboratory. RESULTS: A total of 1537 patients (1397 new and 140 previously treated) were enrolled in the survey from 44 health facilities. HIV test result and complete drug susceptibility testing (DST) results were available for 1524 (96.8%) and 1325 (85.9%) patients, respectively. Of the 1209 isolates from new cases, resistance to any anti-TB drug was 10.3%, 5% were resistant to isoniazid, 1.9% to rifampicin, and 1.4% were multi drug resistant. Among the 116 isolates from previously treated cases, the prevalence of resistance was 25.9%, 23.3%, 12.1% and 12.1% respectively. Of the 1524 patients who had HIV testing 469 (30.7%) tested positive. There was no association between anti-TB drug resistance (including MDR) and HIV infection. CONCLUSION: The prevalence of anti-TB drug resistance among new patients in Uganda is low relative to WHO estimates. The higher levels of MDR-TB (12.1%) and resistance to any drug (25.3%) among previously treated patients raises concerns about the quality of directly observed therapy (DOT) and adherence to treatment. This calls for strengthening existing TB control measures, especially DOT, routine DST among the previously treated TB patients or periodic drug resistance surveys, to prevent and monitor development and transmission of drug resistant TB. PMID- 23936468 TI - A R2R3-MYB transcription factor from Epimedium sagittatum regulates the flavonoid biosynthetic pathway. AB - Herba epimedii (Epimedium), a traditional Chinese medicine, has been widely used as a kidney tonic and antirheumatic medicine for thousands of years. The bioactive components in herba epimedii are mainly prenylated flavonol glycosides, end-products of the flavonoid pathway. Epimedium species are also used as garden plants due to the colorful flowers and leaves. Many R2R3-MYB transcription factors (TFs) have been identified to regulate the flavonoid and anthocyanin biosynthetic pathways. However, little is known about the R2R3-MYB TFs involved in regulation of the flavonoid pathway in Epimedium. Here, we reported the isolation and functional characterization of the first R2R3-MYB TF (EsMYBA1) from Epimedium sagittatum (Sieb. Et Zucc.) Maxim. Conserved domains and phylogenetic analysis showed that EsMYBA1 belonged to the subgroup 6 clade (anthocyanin related MYB clade) of R2R3-MYB family, which includes Arabidopsis AtPAP1, apple MdMYB10 and legume MtLAP1. EsMYBA1 was preferentially expressed in leaves, especially in red leaves that contain higher content of anthocyanin. Alternative splicing of EsMYBA1 resulted in three transcripts and two of them encoded a MYB related protein. Yeast two-hybrid and transient luciferase expression assay showed that EsMYBA1 can interact with several bHLH regulators of the flavonoid pathway and activate the promoters of dihydroflavonol 4-reductase (DFR) and anthocyanidin synthase (ANS). In both transgenic tobacco and Arabidopsis, overexpression of EsMYBA1 induced strong anthocyanin accumulation in reproductive and/or vegetative tissues via up-regulation of the main flavonoid-related genes. Furthermore, transient expression of EsMYBA1 in E. sagittatum leaves by Agrobacterium infiltration also induced anthocyanin accumulation in the wounded area. This first functional characterization of R2R3-MYB TFs in Epimedium species will promote further studies of the flavonoid biosynthesis and regulation in medicinal plants. PMID- 23936469 TI - Lyn facilitates glioblastoma cell survival under conditions of nutrient deprivation by promoting autophagy. AB - Members of the Src family kinases (SFK) can modulate diverse cellular processes, including division, death and survival, but their role in autophagy has been minimally explored. Here, we investigated the roles of Lyn, a SFK, in promoting the survival of human glioblastoma tumor (GBM) cells in vitro and in vivo using lentiviral vector-mediated expression of constitutively-active Lyn (CA-Lyn) or dominant-negative Lyn (DN-Lyn). Expression of either CA-Lyn or DN-Lyn had no effect on the survival of U87 GBM cells grown under nutrient-rich conditions. In contrast, under nutrient-deprived conditions (absence of supplementation with L glutamine, which is essential for growth of GBM cells, and FBS) CA-Lyn expression enhanced survival and promoted autophagy as well as inhibiting cell death and promoting proliferation. Expression of DN-Lyn promoted cell death. In the nutrient-deprived GBM cells, CA-Lyn expression enhanced AMPK activity and reduced the levels of pS6 kinase whereas DN-Lyn enhanced the levels of pS6 kinase. Similar results were obtained in vitro using another cultured GBM cell line and primary glioma stem cells. On propagation of the transduced GBM cells in the brains of nude mice, the CA-Lyn xenografts formed larger tumors than control cells and autophagosomes were detectable in the tumor cells. The DN-Lyn xenografts formed smaller tumors and contained more apoptotic cells. Our findings suggest that on nutrient deprivation in vitro Lyn acts to enhance the survival of GBM cells by promoting autophagy and proliferation as well as inhibiting cell death, and Lyn promotes the same effects in vivo in xenograft tumors. As the levels of Lyn protein or its activity are elevated in several cancers these findings may be of broad relevance to cancer biology. PMID- 23936470 TI - Temporal population genetics of time travelling insects: a long term study in a seed-specialized wasp. AB - Many animal species experiencing spatial or interannual fluctuations of their environment are capable of prolonged diapause, a kind of dormancy that extends over more than one year. Such a prolonged diapause is commonly perceived as a temporal demographic refuge in stochastic environments, but empirical evidence is still lacking of its consequences on temporal population genetic structures. In this long-term study, we investigated how a particular pattern of prolonged diapause may influence the temporal population genetics of the invasive seed specialized wasp Megastigmus schimitscheki (Hymenoptera: Torymidae) in southeastern France. We characterized the diapause strategy of M. schimitscheki using records of emergence from diapause in 97 larval cohorts, and we conducted a temporal population genetic study on a natural invasive wasp population sampled during ten consecutive years (1999-2008) using polymorphic microsatellite markers. We found that M. schimitscheki can undergo a prolonged diapause of up to five years and displays two main adult emergence peaks after two and four years of diapause. Such a bimodal and atypical pattern did not disrupt temporal gene flow between cohorts produced in even and in odd years during the period of the study. Unexpectedly, we found that this wasp population consisted of two distinct genetic sub-populations that strongly diverged in their diapause strategies, with very few admixed individuals. One of the sub-populations displayed both short and prolonged diapause (2 and 4 years respectively) in equal proportions, whereas the other sub-population displayed mainly short diapause. This study provided empirical evidence that prolonged diapause phenotypes can substantially contribute to reproduction and impact temporal genetic structures. Prolonged diapause is likely to act as both demographic and genetic refuges for insect populations living in fluctuating environments. PMID- 23936471 TI - Measuring access to medicines: a survey of prices, availability and affordability in Shaanxi province of China. AB - OBJECTIVE: To measure the prices and availability of selected medicines in Shaanxi Province after the implementation of new healthcare reform in 2009. METHODS: Data on the prices and availability of 47 medicines were collected from 50 public and 36 private sector medicine outlets in six regions of Shaanxi Province, Western China using a standardized methodology developed by the World Health Organization and Health Action International from September to October 2010. Medicine prices were compared with international reference prices to obtain a median price ratio. Affordability was measured as the number of days' wages required for the lowest-paid unskilled government worker to purchase standard treatments for common conditions. FINDINGS: The mean availabilities of originator brands and lowest-priced generics were 8.9% and 26.5% in the public sector, and 18.1% and 43.6% in the private sector, respectively. The public sector procured generics and originator brands at median price ratios of 0.75 and 8.49, respectively, while patients paid 0.97 and 10.16. Final patient prices for lowest priced generics and originator brands in the private sector were about 1.53 and 8.36 times their international retail prices, respectively. Public sector vendors applied high markups of 30.4% to generics, and 19.6% to originator brands. In the private sector, originator brands cost 390.7% more, on average, than their generic equivalents. Generic medicines were priced 17.3% higher in the private sector than the public sector. The lowest-paid government worker would need 0.1 day's wages to purchase captopril for lowest-priced generics from private sector, while 6.6 days' wages for losartan. For originator brands, the costs rise to 1.2 days' wages for salbutamol inhaler and 15.6 days' wages for omeprazole. CONCLUSIONS: The prices, availability and affordability of medicines in China should be improved to ensure equitable access to basic medical treatments, especially for the poor. This requires multi-faceted interventions, as well as the review and refocusing of policies, regulations and educational interventions. PMID- 23936472 TI - Preclinical evaluation of 4-methylthiobutyl isothiocyanate on liver cancer and cancer stem cells with different p53 status. AB - Isothiocyanates from plants of the order Brassicales are considered promising cancer chemotherapeutic phytochemicals. However, their selective cytotoxicity on liver cancer has been barely researched. Therefore, in the present study, we systematically studied the chemotherapeutic potency of 4-methylthiobutyl isothiocyanate (MTBITC). Selective toxicity was investigated by comparing its effect on liver cancer cells and their chemoresistant subpopulations to normal primary hepatocytes and liver tissue slices. Additionally, in a first assessment, the in vivo tolerability of MTBITC was investigated in mice. Growth arrest at G2/M and apoptosis induction was evident in all in vitro cancer models treated with MTBITC, including populations with cancer initiating characteristics. This was found independent from TP53; however cell death was delayed in p53 compromised cells as compared to wt-p53 cells which was probably due to differential BH3 only gene regulation i. e. Noxa and its antagonist A1. In normal hepatocytes, no apoptosis or necrosis could be detected after repeated administration of up to 50 uM MTBITC. In mice, orally applied MTBITC was well tolerated over 18 days of treatment for up to 50 mg/kg/day, the highest dose tested. In conclusion, we could show here that the killing effect of MTBITC has a definite selectivity for cancer cells over normal liver cells and its cytotoxicity even applies for chemoresistant cancer initiating cells. Our study could serve for a better understanding of the chemotherapeutic properties of isothiocyanates on human liver-derived cancer cells. PMID- 23936473 TI - GPR88 reveals a discrete function of primary cilia as selective insulators of GPCR cross-talk. AB - A number of G protein-coupled receptors (GPCRs) localize to primary cilia but the functional significance of cilia to GPCR signaling remains incompletely understood. We investigated this question by focusing on the D1 dopamine receptor (D1R) and beta-2 adrenergic receptor (B2AR), closely related catecholamine receptors that signal by stimulating production of the diffusible second messenger cyclic AMP (cAMP) but differ in localization relative to cilia. D1Rs robustly concentrate on cilia of IMCD3 cells, as shown previously in other ciliated cell types, but disrupting cilia did not affect D1R surface expression or ability to mediate a concentration-dependent cAMP response. By developing a FRET-based biosensor suitable for resolving intra- from extra- ciliary cAMP changes, we found that the D1R-mediated cAMP response is not restricted to cilia and extends into the extra-ciliary cytoplasm. Conversely the B2AR, which we show here is effectively excluded from cilia, also generated a cAMP response in both ciliary and extra-ciliary compartments. We identified a distinct signaling effect of primary cilia through investigating GPR88, an orphan GPCR that is co-expressed with the D1R in brain, and which we show here is targeted to cilia similarly to the D1R. In ciliated cells, mutational activation of GPR88 strongly reduced the D1R-mediated cAMP response but did not affect the B2AR-mediated response. In marked contrast, in non-ciliated cells, GPR88 was distributed throughout the plasma membrane and inhibited the B2AR response. These results identify a discrete 'insulating' function of primary cilia in conferring selectivity on integrated catecholamine signaling through lateral segregation of receptors, and suggest a cellular activity of GPR88 that might underlie its effects on dopamine dependent behaviors. PMID- 23936475 TI - Isolation and characterization of the new mosaic filamentous phage VFJ Phi of Vibrio cholerae. AB - Filamentous phages have distinguished roles in conferring many pathogenicity and survival related features to Gram-negative bacteria including the medically important Vibrio cholerae, which carries factors such as cholera toxin on phages. A novel filamentous phage, designated VFJPhi, was isolated in this study from an ampicillin and kanamycin-resistant O139 serogroup V. cholerae strain ICDC-4470. The genome of VFJPhi is 8555 nucleotides long, including 12 predicted open reading frames (ORFs), which are organized in a modular structure. VFJPhi was found to be a mosaic of two groups of V. cholerae phages. A large part of the genome is highly similar to that of the fs2 phage, and the remaining 700 bp is homologous to VEJ and VCYPhi. This 700 bp region gave VFJPhi several characteristics that are not found in fs2 and other filamentous phages. In its native host ICDC-4470 and newly-infected strain N16961, VFJPhi was found to exist as a plasmid but did not integrate into the host chromosome. It showed a relatively wide host range but did not infect the classical biotype O1 V. cholerae strains. After infection, the host strains exhibited obvious inhibition of both growth and flagellum formation and had acquired a low level of ampicillin resistance and a high level of kanamycin resistance. The antibiotic resistances were not directly conferred to the hosts by phage-encoded genes and were not related to penicillinase. The discovery of VFJPhi updates our understanding of filamentous phages as well as the evolution and classification of V. cholerae filamentous phage, and the study provides new information on the interaction between phages and their host bacteria. PMID- 23936474 TI - Evidence for a critical role of catecholamines for cardiomyocyte lineage commitment in murine embryonic stem cells. AB - Catecholamine release is known to modulate cardiac output by increasing heart rate. Although much is known about catecholamine function and regulation in adults, little is known about the presence and role of catecholamines during heart development. The present study aimed therefore to evaluate the effects of different catecholamines on early heart development in an in vitro setting using embryonic stem (ES) cell-derived cardiomyocytes. Effects of catecholamine depletion induced by reserpine were examined in murine ES cells (line D3, alphaPIG44) during differentiation. Cardiac differentiation was assessed by immunocytochemistry, qRT-PCR, quantification of beating clusters, flow cytometry and pharmacological approaches. Proliferation was analyzed by EB cross-section measurements, while functionality of cardiomyocytes was studied by extracellular field potential (FP) measurements using microelectrode arrays (MEAs). To further differentiate between substance-specific effects of reserpine and catecholamine action via alpha- and beta-receptors we proved the involvement of adrenergic receptors by application of unspecific alpha- and beta-receptor antagonists. Reserpine treatment led to remarkable down-regulation of cardiac-specific genes, proteins and mesodermal marker genes. In more detail, the average ratio of ~40% spontaneously beating control clusters was significantly reduced by 100%, 91.1% and 20.0% on days 10, 12, and 14, respectively. Flow cytometry revealed a significant reduction (by 71.6%, n = 11) of eGFP positive CMs after reserpine treatment. By contrast, reserpine did not reduce EB growth while number of neuronal cells in reserpine-treated EBs was significantly increased. MEA measurements of reserpine-treated EBs showed lower FP frequencies and weak responsiveness to adrenergic and muscarinic stimulation. Interestingly we found that developmental inhibition after alpha- and beta-adrenergic blocker application mimicked developmental changes with reserpine. Using several methodological approaches our data suggest that reserpine inhibits cardiac differentiation. Thus catecholamines play a critical role during development. PMID- 23936476 TI - Inhibition of the differentiation of monocyte-derived dendritic cells by human gingival fibroblasts. AB - We investigated whether gingival fibroblasts (GFs) can modulate the differentiation and/or maturation of monocyte-derived dendritic cells (DCs) and analyzed soluble factors that may be involved in this immune modulation. Experiments were performed using human monocytes in co-culture with human GFs in Transwell(r) chambers or using monocyte cultures treated with conditioned media (CM) from GFs of four donors. The four CM and supernatants from cell culture were assayed by ELISA for cytokines involved in the differentiation of dendritic cells, such as IL-6, VEGF, TGFbeta1, IL-13 and IL-10. The maturation of monocyte derived DCs induced by LPS in presence of CM was also studied. Cell surface phenotype markers were analyzed by flow cytometry. In co-cultures, GFs inhibited the differentiation of monocyte-derived DCs and the strength of this blockade correlated with the GF/monocyte ratio. Conditioned media from GFs showed similar effects, suggesting the involvement of soluble factors produced by GFs. This inhibition was associated with a lower stimulatory activity in MLR of DCs generated with GFs or its CM. Neutralizing antibodies against IL-6 and VEGF significantly (P<0.05) inhibited the inhibitory effect of CM on the differentiation of monocytes-derived DCs and in a dose dependent manner. Our data suggest that IL-6 is the main factor responsible for the inhibition of DCs differentiation mediated by GFs but that VEGF is also involved and constitutes an additional mechanism. PMID- 23936477 TI - Variation in trans-3'-hydroxycotinine glucuronidation does not alter the nicotine metabolite ratio or nicotine intake. AB - BACKGROUND: CYP2A6 metabolizes nicotine to its primary metabolite cotinine and also mediates the metabolism of cotinine to trans-3'-hydroxycotinine (3HC). The ratio of 3HC to cotinine (the "nicotine metabolite ratio", NMR) is an in vivo marker for the rate of CYP2A6 mediated nicotine metabolism, and total nicotine clearance, and has been associated with differences in numerous smoking behaviors. The clearance of 3HC, which affects the NMR, occurs via renal excretion and metabolism by UGT2B17, and possibly UGT2B10, to 3HC-glucuronide. We investigated whether slower 3HC glucuronidation alters NMR, altering its ability to predict CYP2A6 activity and reducing its clinical utility. METHODS: Plasma NMR, three urinary NMRs, three urinary 3HC glucuronidation phenotypes and total nicotine equivalents were examined in 540 African American smokers. The UGT2B17 gene deletion and UGT2B10*2 were genotyped. RESULTS: The UGT2B17 gene deletion, but not UGT2B10*2 genotype, was associated with slower 3HC glucuronidation (indicated by three 3HC-glucuronidation phenotypes), indicating its role in this glucuronidation pathway. However, neither lower rates of 3HC glucuronidation, nor the presence of a UGT2B17 and UGT2B10 reduced function allele, altered plasma or urinary NMRs or levels of smoking. CONCLUSIONS: Variation in 3HC glucuronidation activity, including these caused by UGT2B17 gene deletions, did not significantly alter NMR and is therefore unlikely to affect the clinical utility of NMR in smoking behavior and cessation studies. This study demonstrates that NMR is not altered by differences in the rate of 3HC glucuronidation, providing further support that NMR is a reliable indicator of CYP2A6 mediated nicotine metabolism. PMID- 23936478 TI - Diagnostic performance of interferon-gamma releasing assay in HIV-infected patients in China. AB - BACKGROUND: Active tuberculosis infection represents a very common and significant threat to HIV-infected patients. But measures to accurately detect it are limited. OBJECTIVE: To compare and analyze the diagnostic efficacy of T SPOT.TB alone and in combination with TST in HIV-infected patients in China. METHOD: TST (tuberculin skin test) and T-SPOT.TB were performed on 131 HIV infected patients admitted in Beijing You'an Hospital and Beijing Ditan Hospital between Oct, 2010 and Jul, 2012, who were initially diagnosed as suspected ATB (active TB). The patients were further categorized into ATB and Not ATB based on clinical and cultural evidences. The performance of TST and T-SPOT.TB were analyzed and compared. RESULTS: The sensitivity and specificity of T-SPOT.TB were 41.3% and 94.6%, respectively, both higher than TST (12.9% and 91.8%). By combining T-SPOT.TB and TST, the sensitivity did not increase, but specificity was elevated to 100%. TST, T-SPOT.TB and their combinations all performed better in patients with extra-pulmonary diseases than with pulmonary disorders. False positive T-SPOT.TB results were found to be associated with history of prior TB. In addition, concomitant bacterial infections and low CD4 counts were associated with increased ATB risk. CONCLUSIONS: T-SPOT.TB is superior in screening ATB in HIV-infected patients in China over traditional TST. Additional TST would help to confirm a positive T-SPOT.TB result. Both tests work better for patients with extra-pulmonary conditions. PMID- 23936480 TI - Separating drought effects from roof artifacts on ecosystem processes in a grassland drought experiment. AB - 1: Given the predictions of increased drought probabilities under various climate change scenarios, there have been numerous experimental field studies simulating drought using transparent roofs in different ecosystems and regions. Such roofs may, however, have unknown side effects, called artifacts, on the measured variables potentially confounding the experimental results. A roofed control allows the quantification of potential artifacts, which is lacking in most experiments. 2: We conducted a drought experiment in experimental grasslands to study artifacts of transparent roofs and the resulting effects of artifacts on ecosystems relative to drought on three response variables (aboveground biomass, litter decomposition and plant metabolite profiles). We established three drought treatments, using (1) transparent roofs to exclude rainfall, (2) an unroofed control treatment receiving natural rainfall and (3) a roofed control, nested in the drought treatment but with rain water reapplied according to ambient conditions. 3: Roofs had a slight impact on air (+0.14 degrees C during night) and soil temperatures (-0.45 degrees C on warm days, +0.25 degrees C on cold nights), while photosynthetically active radiation was decreased significantly ( 16%). Aboveground plant community biomass was reduced in the drought treatment ( 41%), but there was no significant difference between the roofed and unroofed control, i.e., there were no measurable roof artifact effects. 4: Compared to the unroofed control, litter decomposition was decreased significantly both in the drought treatment (-26%) and in the roofed control treatment (-18%), suggesting artifact effects of the transparent roofs. Moreover, aboveground metabolite profiles in the model plant species Medicago x varia were different from the unroofed control in both the drought and roofed control treatments, and roof artifact effects were of comparable magnitude as drought effects. 5: Our results stress the need for roofed control treatments when using transparent roofs for studying drought effects, because roofs can cause significant side effects. PMID- 23936479 TI - Associations between two genetic variants in NKX2-5 and risk of congenital heart disease in Chinese population: a meta-analysis. AB - BACKGROUND: NKX2-5 is a transcriptional factor, which plays an important role in heart formation and development. Two genetic variants in the coding region of NKX2-5, 63A>G (rs2277923) and 606G>C (rs3729753), have been investigated in the risk of congenital heart disease (CHD), although with inconsistent results. Thus, a meta-analysis was performed to clarify the associations between the two variants and CHD risk in the Chinese population. METHODS AND RESULTS: Relevant studies were identified by searching PubMed, ISI Web of Science and CNKI databases and by reviewing the reference lists of retrieved articles. Then, the data from eligible studies were combined in an allelic model. A total of 7 and 4 studies were ultimately included for 63A>G and 606G>C, respectively. The results of overall meta-analyses showed that significant association was detected for 63A>G (OR = 1.26, 95% CI = 1.02-1.56, P(heterogeneity )= 0.009, I (2) = 65.1%), but not for 606G>C (OR = 1.22, 95% CI = 0.75-1.96, P(heterogeneity )= 0.412, I (2) = 0.0%). Regarding 63A>G variant, positive results were also obtained in the subgroups of atrial septal defect and large-sample-size study. Besides, the sensitivity analysis indicated that significant association was still detected after deletion of the individual studies with positive result and striking heterogeneity. CONCLUSION: Our results revealed that the 63A>G variant in NKX2-5, but not the 606G>C, may contribute to CHD risk for Chinese. PMID- 23936481 TI - Effect of byproducts of flue gas desulfurization on the soluble salts composition and chemical properties of sodic soils. AB - The byproducts of flue gas desulfurization (BFGD) are a useful external source of Ca(2+) for the reclamation of sodic soils because they are comparatively cheap, generally available and have high gypsum content. The ion solution composition of sodic soils also plays an important role in the reclamation process. The effect of BFGD on the soluble salts composition and chemical properties of sodic soils were studied in a soil column experiment. The experiment consisted of four treatments using two different sodic soils (sodic soil I and sodic soil II) and two BFGD rates. After the application of BFGD and leaching, the soil soluble salts were transformed from sodic salts containing Na2CO3 and NaHCO3 to neutral salts containing NaCl and Na2SO4. The sodium adsorption ratio (SAR), pH and electrical conductivity (EC) decreased at all soil depths, and more significantly in the top soil depth. At a depth of 0-40 cm in both sodic soil I and sodic soil II, the SAR, EC and pH were less than 13, 4 dS m(-1) and 8.5, respectively. The changes in the chemical properties of the sodic soils reflected the changes in the ion composition of soluble salts. Leaching played a key role in the reclamation process and the reclamation effect was positively associated with the amount of leaching. The soil salts did not accumulate in the top soil layer, but there was a slight increase in the middle and bottom soil depths. The results demonstrate that the reclamation of sodic soils using BFGD is promising. PMID- 23936482 TI - AAV-mediated administration of myostatin pro-peptide mutant in adult Ldlr null mice reduces diet-induced hepatosteatosis and arteriosclerosis. AB - Genetic disruption of myostatin or its related signaling is known to cause strong protection against diet-induced metabolic disorders. The translational value of these prior findings, however, is dependent on whether such metabolically favorable phenotype can be reproduced when myostatin blockade begins at an adult age. Here, we reported that AAV-mediated delivery of a myostatin pro-peptide D76A mutant in adult mice attenuates the development of hepatic steatosis and arteriosclerosis, two common diet-induced metabolic diseases. A single dose of AAV-D76A in adult Ldlr null mice resulted in sustained expression of myostatin pro-peptide in the liver. Compared to vehicle-treated mice, D76A-treated mice gained similar amount of lean and fat mass when fed a high fat diet. However, D76A-treated mice displayed significantly reduced aortic lesions and liver fat, in association with a reduction in hepatic expression of lipogenic genes and improvement in liver insulin sensitivity. This suggests that muscle and fat may not be the primary targets of treatment under our experimental condition. In support to this argument, we show that myostatin directly up-regulated lipogenic genes and increased fat accumulation in cultured liver cells. We also show that both myostatin and its receptor were abundantly expressed in mouse aorta. Cultured aortic endothelial cells responded to myostatin with a reduction in eNOS phosphorylation and an increase in ICAM-1 and VCAM-1 expression. CONCLUSIONS: AAV mediated expression of myostatin pro-peptide D76A mutant in adult Ldlr null mice sustained metabolic protection without remarkable impacts on body lean and fat mass. Further investigations are needed to determine whether direct impact of myostatin on liver and aortic endothelium may contribute to the related metabolic phenotypes. PMID- 23936483 TI - Canine adenovirus type 2 vector generation via I-Sce1-mediated intracellular genome release. AB - When canine adenovirus type 2 (CAdV-2, or also commonly referred to as CAV-2) vectors are injected into the brain parenchyma they preferentially transduce neurons, are capable of efficient axonal transport to afferent regions, and allow transgene expression for at last >1 yr. Yet, translating these data into a user friendly vector platform has been limited because CAV-2 vector generation is challenging. Generation of E1-deleted adenovirus vectors often requires transfection of linear DNA fragments of >30 kb containing the vector genome into an E1-transcomplementing cell line. In contrast to human adenovirus type 5 vector generation, CAV-2 vector generation is less efficient due, in part, to a reduced ability to initiate replication and poor transfectibility of canine cells with large, linear DNA fragments. To improve CAV-2 vector generation, we generated an E1-transcomplementing cell line expressing the estrogen receptor (ER) fused to I SceI, a yeast meganuclease, and plasmids containing the I-SceI recognition sites flanking the CAV-2 vector genome. Using transfection of supercoiled plasmid and intracellular genome release via 4-OH-tamoxifen-induced nuclear translocation of I-SceI, we improved CAV-2 vector titers 1,000 fold, and in turn increased the efficacy of CAV-2 vector generation. PMID- 23936484 TI - Characterization of synthetic Chikungunya viruses based on the consensus sequence of recent E1-226V isolates. AB - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that re-emerged in 2004 and has caused massive outbreaks in recent years. The lack of a licensed vaccine or treatment options emphasize the need to obtain more insight into the viral life cycle and CHIKV-host interactions. Infectious cDNA clones are important tools for such studies, and for mechanism of action studies on antiviral compounds. Existing CHIKV cDNA clones are based on a single genome from an individual clinical isolate, which is expected to have evolved specific characteristics in response to the host environment, and possibly also during subsequent cell culture passaging. To obtain a virus expected to have the general characteristics of the recent E1-226V CHIKV isolates, we have constructed a new CHIKV full-length cDNA clone, CHIKV LS3, based on the consensus sequence of their aligned genomes. Here we report the characterization of this synthetic virus and a green fluorescent protein-expressing variant (CHIKV LS3-GFP). Their characteristics were compared to those of natural strain ITA07-RA1, which was isolated during the 2007 outbreak in Italy. In cell culture the synthetic viruses displayed phenotypes comparable to the natural isolate, and in a mouse model they caused lethal infections that were indistinguishable from infections with a natural strain. Compared to ITA07-RA1 and clinical isolate NL10/152, the synthetic viruses displayed similar sensitivities to several antiviral compounds. 3-deaza-adenosine was identified as a new inhibitor of CHIKV replication. Cyclosporin A had no effect on CHIKV replication, suggesting that cyclophilins opposite to what was found for other +RNA viruses- do not play an essential role in CHIKV replication. The characterization of the consensus sequence-based synthetic viruses and their comparison to natural isolates demonstrated that CHIKV LS3 and LS3-GFP are suitable and representative tools to study CHIKV-host interactions, screen for antiviral compounds and unravel their mode of action. PMID- 23936485 TI - Modeling of cognitive impairment by disease duration in multiple sclerosis: a cross-sectional study. AB - BACKGROUND/AIMS: Large-scale population studies measuring rates and dynamics of cognitive decline in multiple sclerosis (MS) are lacking. In the current cross sectional study we evaluated the patterns of cognitive impairment in MS patients with disease duration of up to 30 years. METHODS: 1,500 patients with MS were assessed by a computerized cognitive battery measuring verbal and non-verbal memory, executive function, visual spatial perception, verbal function, attention, information processing speed and motor skills. Cognitive impairment was defined as below one standard deviation (SD) and severe cognitive impairment as below 2SD for age and education matched healthy population norms. RESULTS: Cognitive performance in our cohort was poorer than healthy population norms. The most frequently impaired domains were information processing speed and executive function. MS patients with secondary-progressive disease course performed poorly compared with clinically isolated syndrome, relapsing-remitting and primary progressive MS patients. By the fifth year from disease onset, 20.9% of patients performed below the 1SD cutoff for impairment, p=0.005, and 6.0% performed below the 2SD cutoff for severe cognitive impairment, p=0.002. By 10 years from onset 29.3% and 9.0% of patients performed below the 1SD and 2SD cutoffs, respectively, p=0.0001. Regression modeling suggested that cognitive impairment may precede MS onset by 1.2 years. CONCLUSIONS: The rates of cognitive impairment in this large sample of MS patients were lower than previously reported and severe cognitive impairment was evident only in a relatively small group of patients. Cognitive impairment differed significantly from expected normal distribution only at five years from onset, suggesting the existence of a therapeutic window during which patients may benefit from interventions to maintain cognitive health. PMID- 23936486 TI - Impaired Ca(2+) signaling in beta-cells lacking leptin receptors by Cre-loxP recombination. AB - Obesity is a major risk factor for diabetes and is typically associated with hyperleptinemia and a state of leptin resistance. The impact of chronically elevated leptin levels on the function of insulin-secreting beta-cells has not been elucidated. We previously generated mice lacking leptin signaling in beta cells by using the Cre-loxP strategy and showed that these animals develop increased body weight and adiposity, hyperinsulinemia, impaired glucose stimulated insulin secretion and insulin resistance. Here, we performed several in vitro studies and observed that beta-cells lacking leptin signaling in this model are capable of properly metabolizing glucose, but show impaired intracellular Ca(2+) oscillations and lack of synchrony within the islets in response to glucose, display reduced response to tolbutamide and exhibit morphological abnormalities including increased autophagy. Defects in intracellular Ca(2+) signaling were observed even in neonatal islets, ruling out the possible contribution of obesity to the beta-cell irregularities observed in adults. In parallel, we also detected a disrupted intracellular Ca(2+) pattern in response to glucose and tolbutamide in control islets from adult transgenic mice expressing Cre recombinase under the rat insulin promoter, despite these animals being glucose tolerant and secreting normal levels of insulin in response to glucose. This unexpected observation impeded us from discerning the consequences of impaired leptin signaling as opposed to long-term Cre expression in the function of insulin-secreting cells. These findings highlight the need to generate improved Cre-driver mouse models or new tools to induce Cre recombination in beta-cells. PMID- 23936487 TI - Geometric attributes of retaining glycosyltransferase enzymes favor an orthogonal mechanism. AB - Retaining glycosyltransferase enzymes retain the stereochemistry of the donor glycosidic linkage after transfer to an acceptor molecule. The mechanism these enzymes utilize to achieve retention of the anomeric stereochemistry has been a matter of much debate. Re-analysis of previously released structural data from retaining and inverting glycosyltransferases allows competing mechanistic proposals to be evaluated. The binding of metal-nucleotide-sugars between inverting and retaining enzymes is conformationally unique and requires the donor substrate to occupy two different orientations in the two types of glycosyltransferases. The available structures of retaining glycosyltransferases lack appropriately positioned enzymatic dipolar residues to initiate or stabilize the intermediates of a dissociative mechanism. Further, available structures show that the acceptor nucleophile and anomeric carbon of the donor sugar are in close proximity. Structural features support orthogonal (front-side) attack from a position lying <= 90 degrees from the C1-O phosphate bond for retaining enzymes. These structural conclusions are consistent with the geometric conclusions of recent kinetic and computational studies. PMID- 23936489 TI - Bronchiectasis-associated hospitalizations in Germany, 2005-2011: a population based study of disease burden and trends. AB - BACKGROUND: Representative population-based data on the epidemiology of bronchiectasis in Europe are limited. The aim of the present study was to investigate the current burden and the trends of bronchiectasis-associated hospitalizations and associated conditions in Germany in order to inform focused patient care and to facilitate the allocation of healthcare resources. METHODS: The nationwide diagnosis-related groups hospital statistics for the years 2005 2011 were used in order to identify hospitalizations with bronchiectasis as any hospital discharge diagnosis according to the International Classification of Diseases, 10th revision, code J47, (acquired) bronchiectasis. Poisson log-linear regression analysis was used to assess the significance of trends. In addition, the overall length of hospital stay (LOS) and the in-hospital mortality in comparison to the nationwide overall mortality due to bronchiectasis as the primary diagnosis was assessed. RESULTS: Overall, 61,838 records with bronchiectasis were extracted from more than 125 million hospitalizations. The average annual age-adjusted rate for bronchiectasis as any diagnosis was 9.4 hospitalizations per 100,000 population. Hospitalization rates increased significantly during the study period, with the highest rate of 39.4 hospitalizations per 100,000 population among men aged 75-84 years and the most pronounced average annual increases among females. Besides numerous bronchiectasis-associated conditions, chronic obstructive pulmonary disease (COPD) was most frequently found in up to 39.2% of hospitalizations with bronchiectasis as the primary diagnosis. The mean LOS was comparable to that for COPD. Overall, only 40% of bronchiectasis-associated deaths occurred inside the hospital. CONCLUSIONS: The present study provides evidence of a changing epidemiology and a steadily increasing prevalence of bronchiectasis-associated hospitalizations. Moreover, it confirms the diversity of bronchiectasis associated conditions and the possible association between bronchiectasis and COPD. As the major burden of disease may be managed out-of-hospital, prospective patient registries are needed to establish the exact prevalence of bronchiectasis according to the specific underlying condition. PMID- 23936488 TI - Gene expression profiling of histiocytic sarcomas in a canine model: the predisposed flatcoated retriever dog. AB - BACKGROUND: The determination of altered expression of genes in specific tumor types and their effect upon cellular processes may create insight in tumorigenesis and help to design better treatments. The Flatcoated retriever is a dog breed with an exceptionally high incidence of histiocytic sarcomas. The breed develops two distinct entities of histiocytic neoplasia, a soft tissue form and a visceral form. Gene expression studies of these tumors have value for comparable human diseases such as histiocytic/dendritic cell sarcoma for which knowledge is difficult to accrue due to their rare occurrence. In addition, such studies may help in the search for genetic aberrations underlying the genetic predisposition in this dog breed. METHODS: Microarray analysis and pathway analyses were performed on fresh-frozen tissues obtained from Flatcoated retrievers with localized, soft tissue histiocytic sarcomas (STHS) and disseminated, visceral histiocytic sarcomas (VHS) and on normal canine spleens from various breeds. Expression differences of nine genes were validated with quantitative real-time PCR (qPCR) analyses. RESULTS: QPCR analyses identified the significantly altered expression of nine genes; PPBP, SpiC, VCAM1, ENPEP, ITGAD (down-regulated), and GTSF1, Col3a1, CD90 and LUM (up-regulated) in the comparison of both the soft tissue and the visceral form with healthy spleen. DAVID pathway analyses revealed 24 pathways that were significantly involved in the development of HS in general, most of which were involved in the DNA repair and replication process. CONCLUSIONS: This study identified altered expression of nine genes not yet implicated in histiocytic sarcoma manifestations in the dog nor in comparable human histiocytic/dendritic sarcomas. Exploration of the downside effect of canine inbreeding strategies for the study of similar sarcomas in humans might also lead to the identification of genes related to these rare malignancies in the human. PMID- 23936490 TI - The first transmembrane domain of lipid phosphatase SAC1 promotes Golgi localization. AB - The lipid phosphatase Sac1 cycles between endoplasmic reticulum and cisternal Golgi compartments. In proliferating mammalian cells, a canonical dilysine motif at the C-terminus of Sac1 is required for coatomer complex-I (COP-I)-binding and continuous retrieval to the ER. Starvation triggers accumulation of Sac1 at the Golgi. The mechanism responsible for Golgi retention of Sac1 is unknown. Here we show that the first of the two transmembrane regions in human SAC1 (TM1) functions in Golgi localization. A minimal construct containing only TM1 and the adjacent flanking sequences is concentrated at the Golgi. Transplanting TM1 into transferrin receptor 2 (TfR2) induces Golgi accumulation of this normally plasma membrane and endosomal protein, indicating that TM1 is sufficient for Golgi localization. In addition, we determined that the N-terminal cytoplasmic domain of SAC1 also promotes Golgi localization, even when TM1 is mutated or absent. We conclude that the distribution of SAC1 within the Golgi is controlled via both passive membrane thickness-dependent partitioning of TM1 and a retention mechanism that requires the N-terminal cytoplasmic region. PMID- 23936491 TI - Risk map of cholera infection for vaccine deployment: the eastern Kolkata case. AB - BACKGROUND: Despite advancement of our knowledge, cholera remains a public health concern. During March-April 2010, a large cholera outbreak afflicted the eastern part of Kolkata, India. The quantification of importance of socio-environmental factors in the risk of cholera, and the calculation of the risk is fundamental for deploying vaccination strategies. Here we investigate socio-environmental characteristics between high and low risk areas as well as the potential impact of vaccination on the spatial occurrence of the disease. METHODS AND FINDINGS: The study area comprised three wards of Kolkata Municipal Corporation. A mass cholera vaccination campaign was conducted in mid-2006 as the part of a clinical trial. Cholera cases and data of the trial to identify high risk areas for cholera were analyzed. We used a generalized additive model (GAM) to detect risk areas, and to evaluate the importance of socio-environmental characteristics between high and low risk areas. During the one-year pre-vaccination and two-year post-vaccination periods, 95 and 183 cholera cases were detected in 111,882 and 121,827 study participants, respectively. The GAM model predicts that high risk areas in the west part of the study area where the outbreak largely occurred. High risk areas in both periods were characterized by poor people, use of unsafe water, and proximity to canals used as the main drainage for rain and waste water. Cholera vaccine uptake was significantly lower in the high risk areas compared to low risk areas. CONCLUSION: The study shows that even a parsimonious model like GAM predicts high risk areas where cholera outbreaks largely occurred. This is useful for indicating where interventions would be effective in controlling the disease risk. Data showed that vaccination decreased the risk of infection. Overall, the GAM-based risk map is useful for policymakers, especially those from countries where cholera remains to be endemic with periodic outbreaks. PMID- 23936493 TI - Maintenance of the cell morphology by MinC in Helicobacter pylori. AB - In the model organism Escherichia coli, Min proteins are involved in regulating the division of septa formation. The computational genome analysis of Helicobacter pylori, a gram-negative microaerophilic bacterium causing gastritis and peptic ulceration, also identified MinC, MinD, and MinE. However, MinC (HP1053) shares a low identity with those of other bacteria and its function in H. pylori remains unclear. In this study, we used morphological and genetic approaches to examine the molecular role of MinC. The results were shown that an H. pylori mutant lacking MinC forms filamentous cells, while the wild-type strain retains the shape of short rods. In addition, a minC mutant regains the short rods when complemented with an intact minCHp gene. The overexpression of MinCHp in E. coli did not affect the growth and cell morphology. Immunofluorescence microscopy revealed that MinCHp forms helix-form structures in H. pylori, whereas MinCHp localizes at cell poles and pole of new daughter cell in E. coli. In addition, co-immunoprecipitation showed MinC can interact with MinD but not with FtsZ during mid-exponential stage of H. pylori. Altogether, our results show that MinCHp plays a key role in maintaining proper cell morphology and its function differs from those of MinCEc. PMID- 23936492 TI - Optimized metabolomic approach to identify uremic solutes in plasma of stage 3-4 chronic kidney disease patients. AB - BACKGROUND: Chronic kidney disease (CKD) is characterized by the progressive accumulation of various potential toxic solutes. Furthermore, uremic plasma is a complex mixture hampering accurate determination of uremic toxin levels and the identification of novel uremic solutes. METHODS: In this study, we applied (1)H nuclear magnetic resonance (NMR) spectroscopy, following three distinct deproteinization strategies, to determine differences in the plasma metabolic status of stage 3-4 CKD patients and healthy controls. Moreover, the human renal proximal tubule cell line (ciPTEC) was used to study the influence of newly indentified uremic solutes on renal phenotype and functionality. RESULTS: Protein removal via ultrafiltration and acetonitrile precipitation are complementary techniques and both are required to obtain a clear metabolome profile. This new approach, revealed that a total of 14 metabolites were elevated in uremic plasma. In addition to confirming the retention of several previously identified uremic toxins, including p-cresyl sulphate, two novel uremic retentions solutes were detected, namely dimethyl sulphone (DMSO2) and 2-hydroxyisobutyric acid (2-HIBA). Our results show that these metabolites accumulate in non-dialysis CKD patients from 9+/-7 uM (control) to 51+/-29 uM and from 7 (0-9) uM (control) to 32+/-15 uM, respectively. Furthermore, exposure of ciPTEC to clinically relevant concentrations of both solutes resulted in an increased protein expression of the mesenchymal marker vimentin with more than 10% (p<0.05). Moreover, the loss of epithelial characteristics significantly correlated with a loss of glucuronidation activity (Pearson r = -0.63; p<0.05). In addition, both solutes did not affect cell viability nor mitochondrial activity. CONCLUSIONS: This study demonstrates the importance of sample preparation techniques in the identification of uremic retention solutes using (1)H-NMR spectroscopy, and provide insight into the negative impact of DMSO2 and 2-HIBA on ciPTEC, which could aid in understanding the progressive nature of renal disease. PMID- 23936494 TI - Effects of isometric scaling on vertical jumping performance. AB - Jump height, defined as vertical displacement in the airborne phase, depends on vertical takeoff velocity. For centuries, researchers have speculated on how jump height is affected by body size and many have adhered to what has come to be known as Borelli's law, which states that jump height does not depend on body size per se. The underlying assumption is that the amount of work produced per kg body mass during the push-off is independent of size. However, if a big body is isometrically downscaled to a small body, the latter requires higher joint angular velocities to achieve a given takeoff velocity and work production will be more impaired by the force-velocity relationship of muscle. In the present study, the effects of pure isometric scaling on vertical jumping performance were investigated using a biologically realistic model of the human musculoskeletal system. The input of the model, muscle stimulation over time, was optimized using jump height as criterion. It was found that when the human model was miniaturized to the size of a mouse lemur, with a mass of about one-thousandth that of a human, jump height dropped from 40 cm to only 6 cm, mainly because of the force velocity relationship. In reality, mouse lemurs achieve jump heights of about 33 cm. By implication, the unfavourable effects of the small body size of mouse lemurs on jumping performance must be counteracted by favourable effects of morphological and physiological adaptations. The same holds true for other small jumping animals. The simulations for the first time expose and explain the sheer magnitude of the isolated effects of isometric downscaling on jumping performance, to be counteracted by morphological and physiological adaptations. PMID- 23936495 TI - Extracellular vesicles secreted from cancer cell lines stimulate secretion of MMP 9, IL-6, TGF-beta1 and EMMPRIN. AB - Extracellular vesicles (EVs) are key contributors to cancer where they play an integral role in cell-cell communication and transfer pro-oncogenic molecules to recipient cells thereby conferring a cancerous phenotype. Here, we purified EVs using straightforward biochemical approaches from multiple cancer cell lines and subsequently characterized these EVs via multiple biochemical and biophysical methods. In addition, we used fluorescence microscopy to directly show internalization of EVs into the recipient cells within a few minutes upon addition of EVs to recipient cells. We confirmed that the transmembrane protein EMMPRIN, postulated to be a marker of EVs, was indeed secreted from all cell lines studied here. We evaluated the response to EV stimulation in several different types of recipient cells lines and measured the ability of these purified EVs to induce secretion of several factors highly upregulated in human cancers. Our data indicate that purified EVs preferentially stimulate secretion of several proteins implicated in driving cancer in monocytic cells but only harbor limited activity in epithelial cells. Specifically, we show that EVs are potent stimulators of MMP-9, IL-6, TGF-beta1 and induce the secretion of extracellular EMMPRIN, which all play a role in driving immune evasion, invasion and inflammation in the tumor microenvironment. Thus, by using a comprehensive approach that includes biochemical, biological, and spectroscopic methods, we have begun to elucidate the stimulatory roles. PMID- 23936496 TI - Anergic pulmonary tuberculosis is associated with contraction of the Vd2+T cell population, apoptosis and enhanced inhibitory cytokine production. AB - OBJECTIVE: To study the association of anergic pulmonary tuberculosis with Vdelta2(+) T cells and related cytokine levels. METHODS: 82 pulmonary tuberculosis patients were divided into two groups according to their purified protein derivative tuberculin skin test (TST) results: 39 with TST-negative anergic pulmonary tuberculosis and 43 with TST-positive pulmonary tuberculosis, while 40 healthy volunteers were used as control. Based on chest X-ray results, the tuberculosis lesions were scored according to their severity, with a score of <= 2.5 ranking as mild, 2.5-6 as moderate and >= 6 as severe. The Vdelta2(+) T cell percentage and their expression levels of the apoptosis-related membrane surface molecule FasL in peripheral blood and bronchoalveolar lavage fluids (BALF) were analyzed by flow cytometry, while IL-2, IL-4, IL-6 and IL-10 cytokine and gamma-interferon (gamma-IFN) concentrations in peripheral blood were determined by ELISA. RESULTS: Most of the patients with chest X-ray lesion scores higher than 6 belonged to the anergic tuberculosis group (P<0.05). Anergic pulmonary tuberculosis patients displayed reduced peripheral blood Vdelta2(+) T cell counts (P<0.05) and higher FasL expression in peripheral blood Vdelta2(+) T cells (P <0.05). The Vdelta2(+) T cell percentages in the BALF of all tuberculosis patients were lower than in their peripheral blood (P <0.05), and IL 4 and IL-10 concentrations in peripheral blood of anergic tuberculosis patients were higher than in TST-positive tuberculosis patients and healthy controls (P <0.05). CONCLUSION: Anergic pulmonary tuberculosis is accompanied by reduced Vdelta2(+) T cell percentage, and elevated Vdelta2(+) T cell FasL expression as well as enhanced IL-4 and IL-10 levels in peripheral blood. PMID- 23936497 TI - Baseline MELD score predicts hepatic decompensation during antiviral therapy in patients with chronic hepatitis C and advanced cirrhosis. AB - BACKGROUND AND AIMS: In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined. METHODS: In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18 +/- 2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240 weeks, +/- SD 136 weeks). RESULTS: Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 umol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p=0.015), mean platelets (102.64 vs. 138.95/nl, p=0.014) and mean leukocytes (4.02 vs. 5.68/nl, p=0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18-2.07; p=0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6-9, 10-13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001). CONCLUSIONS: Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis. PMID- 23936498 TI - Filter paper blood spot enzyme linked immunoassay for adiponectin and application in the evaluation of determinants of child insulin sensitivity. AB - BACKGROUND: Adiponectin is an adipocyte-derived hormone that acts as a marker of insulin sensitivity. Bloodspot sampling by fingerstick onto filter paper may increase the feasibility of large-scale studies of the determinants of insulin sensitivity. We first describe the validation of an enzyme-linked immunoassay (ELISA) for quantifying adiponectin from dried blood spots and then demonstrate its application in a large trial (PROBIT). METHODS: We quantified adiponectin from 3-mm diameter discs (~3 uL of blood) punched from dried blood spots obtained from: i) whole blood standards (validation); and ii) PROBIT trial samples (application) in which paediatricians collected blood spots from 13,879 children aged 11.5 years from 31 sites across Belarus. We examined the distribution of bloodspot adiponectin by demographic and anthropometric factors, fasting insulin and glucose. RESULTS: In the validation study, mean intra-assay coefficients of variation (n=162) were 15%, 13% and 10% for 'low' (6.78 ug/ml), 'medium' (18.18 ug/ml) and 'high' (33.13 ug/ml) internal quality control (IQC) samples, respectively; the respective inter-assay values (n=40) were 23%, 21% and 14%. The correlation coefficient between 50 paired whole bloodspot versus plasma samples, collected simultaneously, was 0.87 (95% CI: 0.78 to 0.93). Recovery of known quantities of adiponectin (between 4.5 to 36 ug/ml) was 100.3-133%. Bloodspot adiponectin was stable for at least 30 months at -80 degrees C. In PROBIT, we successfully quantified fasting adiponectin from dried blood spots in 13,329 of 13,879 (96%) children. Mean adiponectin (standard deviation) concentrations were 17.34 ug/ml (7.54) in boys and 18.41 ug/ml (7.92) in girls and were inversely associated with body mass index, fat mass, triceps and subscapular skin-fold thickness, waist circumference, height and fasting glucose. CONCLUSIONS: Bloodspot ELISA is suitable for measuring adiponectin in very small volumes of blood collected on filter paper and can be applied to large-scale studies. PMID- 23936499 TI - Ketamine does not produce relief of neuropathic pain in mice lacking the beta common receptor (CD131). AB - Neuropathic pain (NP) is a debilitating condition associated with traumatic, metabolic, autoimmune and neurological etiologies. Although the triggers for NP are diverse, there are common underlying pathways, including activation of immune cells in the spinal cord and up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Ketamine, a well-known NDMAR antagonist, reduces neuropathic pain in a sustained manner. Recent study has shown that the novel 11-amino acid peptide erythropoietin derivative ARA290 produces a similar, long-lasting relief of NP. Here, we show that both drugs also have similar effects on the expression of mRNA of the NMDAR, as well as that of microglia, astrocytes and chemokine (C-C motif) ligand 2, all-important contributors to the development of NP. Although the effects of ketamine and ARA 290 on NP and its molecular mediators suggest a common mechanism of action, ARA 290 has no affinity for the NMDAR and acts specifically via the innate repair receptor (IRR) involved in tissue protection. We speculated therefore, that the IRR might be critically involved in the action of ketamine on neuropathic pain. To evaluate this, we studied the effects of ketamine and ARA 290 on acute pain, side effects, and allodynia following a spared nerve injury model in mice lacking the beta-common receptor (betacR), a structural component of the IRR. Ketamine (50 mg/kg) and ARA 290 (30 ug/kg) produced divergent effects on acute pain: ketamine produced profound antinociception accompanied with psychomotor side effects, but ARA290 did not, in both normal and knock out mice. In contrast, while both drugs were antiallodynic in WT mice, they had no effect on NP in mice lacking the betacR. Together, these results show that an intact IRR is required for the effective treatment of NP with either ketamine or ARA 290, but is not involved in ketamine's analgesic and side effects. PMID- 23936500 TI - Dorsomorphin promotes survival and germline competence of zebrafish spermatogonial stem cells in culture. AB - Zebrafish spermatogonial cell cultures were established from Tg(piwil1:neo);Tg(piwil1:DsRed) transgenic fish using a zebrafish ovarian feeder cell line (OFC3) that was engineered to express zebrafish Lif, Fgf2 and Gdnf. Primary cultures, initiated from testes, were treated with G418 to eliminate the somatic cells and select for the piwil1:neo expressing spermatogonia. Addition of dorsomorphin, a Bmp type I receptor inhibitor, prolonged spermatogonial stem cell (SSC) survival in culture and enhanced germline transmission of the SSCs following transplantation into recipient larvae. In contrast, dorsomorphin inhibited the growth and survival of zebrafish female germline stem cells (FGSCs) in culture. In the presence of dorsomorphin, the spermatogonia continued to express the germ-cell markers dazl, dnd, nanos3, vasa and piwil1 and the spermatogonial markers plzf and sox17 for at least six weeks in culture. Transplantation experiments revealed that 6 week-old spermatogonial cell cultures maintained in the presence of dorsomorphin were able to successfully colonize the gonad in 18% of recipient larvae and produce functional gametes in the resulting adult chimeric fish. Germline transmission was not successful when the spermatogonia were cultured 6 weeks in the absence of dorsomorphin before transplantation. The results indicate that Bmp signaling is detrimental to SSCs but required for the survival of zebrafish FGSCs in culture. Manipulation of Bmp signaling could provide a strategy to optimize culture conditions of germline stem cells from other species. PMID- 23936501 TI - Trichothecin induces cell death in NF-kappaB constitutively activated human cancer cells via inhibition of IKKbeta phosphorylation. AB - Constitutive activation of the transcription factor nuclear factor-kappaB (NF kappaB) is involved in tumorigenesis and chemo-resistance. As the key regulator of NF-kappaB, IKKbeta is a major therapeutic target for various cancers. Trichothecin (TCN) is a metabolite isolated from an endophytic fungus of the herbal plant Maytenus hookeri Loes. In this study, we evaluated the anti-tumor activity of TCN and found that TCN markedly inhibits the growth of cancer cells with constitutively activated NF-kappaB. TCN induces G0/G1 cell cycle arrest and apoptosis in cancer cells, activating pro-apoptotic proteins, including caspase 3, -8 and PARP-1, and decreasing the expression of anti-apoptotic proteins Bcl-2, Bcl-xL, and survivin. Reporter activity assay and target genes expression analysis illustrated that TCN works as a potent inhibitor of the NF-kappaB signaling pathway. TCN inhibits the phosphorylation and degradation of IkappaBalpha and blocks the nuclear translocation of p65, and thus inhibits the expression of NF-kappaB target genes XIAP, cyclin D1, and Bcl-xL. Though TCN does not directly interfere with IKKbeta kinase, it suppresses the phosphorylation of IKKbeta. Overexpression of constitutively activated IKKbeta aborted TCN induced cancer cell apoptosis, whereas knockdown of endogenous IKKbeta with siRNA sensitized cancer cells toward apoptosis induced by TCN. Moreover, TCN showed a markedly weaker effect on normal cells. These findings suggest that TCN may be a potential therapeutic candidate for cancer treatment, targeting NF-kappaB signaling. PMID- 23936502 TI - Oncogenic mutations of p110alpha isoform of PI 3-kinase upregulate its protein kinase activity. AB - In addition to lipid kinase activity, the class-I PI 3-kinases also function as protein kinases targeting regulatory autophosphorylation sites and exogenous substrates. The latter include a recently identified regulatory phosphorylation of the GM-CSF/IL-3 betac receptor contributing to survival of acute myeloid leukaemia cells. Previous studies suggested differences in the protein kinase activity of the 4 isoforms of class-I PI 3-kinase so we compared the ability of all class-I PI 3-kinases and 2 common oncogenic mutants to autophosphorylate, and to phosphorylate an intracellular fragment of the GM-CSF/IL-3 betac receptor (betaic). We find p110alpha, p110beta and p110gamma all phosphorylate betaic but p110delta is much less effective. The two most common oncogenic mutants of p110alpha, H1047R and E545K have stronger protein kinase activity than wildtype p110alpha, both in terms of autophosphorylation and towards betaic. Importantly, the lipid kinase activity of the oncogenic mutants is still inhibited by autophosphorylation to a similar extent as wildtype p110alpha. Previous evidence indicates the protein kinase activity of p110alpha is Mn(2+) dependent, casting doubt over its role in vivo. However, we show that the oncogenic mutants of p110alpha plus p110beta and p110gamma all display significant activity in the presence of Mg(2+). Furthermore we demonstrate that some small molecule inhibitors of p110alpha lipid kinase activity (PIK-75 and A66) are equally effective against the protein kinase activity, but other inhibitors (e.g. wortmannin and TGX221) show different patterns of inhibition against the lipid and protein kinases activities. These findings have implications for the function of PI 3-kinase, especially in tumours carrying p110alpha mutations. PMID- 23936503 TI - A comparative analysis of feeding and trophic level ecology in stingrays (Rajiformes; Myliobatoidei) and electric rays (Rajiformes: Torpedinoidei). AB - Standardised diets and trophic level (T L) estimates were calculated for 75 ray species from the suborders Myliobatoidei (67 spp.) and Torpedinoidei (8 spp.). Decapod crustaceans (31.71 +/- 3.92%) and teleost fishes (16.45 +/- 3.43%) made the largest contribution to the standardised diet of the Myliobatoidei. Teleost fishes (37.40 +/- 16.09%) and polychaete worms (31.96 +/- 14.22%) were the most prominent prey categories in the standardised diet of the suborder Torpedinoidei. Cluster analysis identified nine major trophic guilds the largest of which were decapod crustaceans (24 species), teleost fishes (11 species) and molluscs (11 species). Trophic level estimates for rays ranged from 3.10 for Potamotrygon falkneri to 4.24 for Gymnura australis, Torpedo marmorata and T. nobiliana. Secondary consumers with a T L <4.00 represented 84% of the species examined, with the remaining 12 species (16%) classified as tertiary consumers (T L >= 4.00). Tertiary consumers included electric rays (Torpedo, 3 spp. and Hypnos, 1 sp.), butterfly rays (Gymnura, 4 spp.), stingrays (2 spp.) and Potamotrygonid stingrays (2 spp.). Feeding strategies were identified as the primary factor of influence with respect to Myliobatoidei and Torpedinoidei T L estimates with inter-family comparisons providing the greatest insight into Myliobatoidei and Torpedinoidei relationships. PMID- 23936504 TI - Decreased interhemispheric coordination in treatment-resistant depression: a resting-state fMRI study. AB - BACKGROUND: Previous studies have demonstrated that patients with treatment resistant depression (TRD) and treatment-sensitive depression (TSD) differed at neural level. However, it remains unclear if these two subtypes of depression differ in the interhemispheric coordination. This study was undertaken for two purposes: (1) to explore the differences in interhemispheric coordination between these two subtypes by using the voxel-mirrored homotopic connectivity (VMHC) method; and (2) to determine if the difference of interhemispheric coordination can be used as a biomarker(s) to differentiate TRD from both TSD and healthy subjects (HS). METHODS: Twenty-three patients with TRD, 22 with TSD, and 19 HS participated in the study. Data of these participants were analyzed with the VMHC and seed-based functional connectivity (FC) approaches. RESULTS: Compared to the TSD group, the TRD group showed significantly lower VMHC values in the calcarine cortex, fusiform gyrus, hippocampus, superior temporal gyrus, middle cingulum, and precentral gyrus. Lower VMHC values were also observed in the TRD group in the calcarine cortex relative to the HS group. However, the TSD group had no significant change in VMHC value in any brain region compared to the HS group. Receiver operating characteristic curves (ROC) analysis revealed that the VMHC values in the calcarine cortex had discriminatory function distinguishing patients with TRD from patients with TSD as well as those participants in the HS group. CONCLUSIONS: Lower VMHC values of patients with TRD relative to those with TSD and those in the HS group in the calcarine cortex appeared to be a unique feature for patients with TRD and it may be used as an imaging biomarker to separate patients with TRD from those with TSD or HS. PMID- 23936505 TI - Aging does not enhance experimental cigarette smoke-induced COPD in the mouse. AB - It has been proposed that the development of COPD is driven by premature aging/premature senescence of lung parenchyma cells. There are data suggesting that old mice develop a greater inflammatory and lower anti-oxidant response after cigarette smoke compared to young mice, but whether these differences actually translate into greater levels of disease is unknown. We exposed C57Bl/6 female mice to daily cigarette smoke for 6 months starting at age 3 months (Ayoung@) or age 12 months (Aold@), with air-exposed controls. There were no differences in measures of airspace size between the two control groups and cigarette smoke induced exactly the same amount of emphysema in young and old. The severity of smoke-induced small airway remodeling using various measures was identical in both groups. Smoke increased numbers of tissue macrophages and neutrophils and levels of 8-hydroxyguanosine, a marker of oxidant damage, but there were no differences between young and old. Gene expression studies using laser capture microdissected airways and parenchyma overall showed a trend to lower levels in older animals and a somewhat lesser response to cigarette smoke in both airways and parenchyma but the differences were usually not marked. Telomere length was greatest in young control mice and was decreased by both smoking and age. The senescence marker p21(Waf1) was equally upregulated by smoke in young and old, but p16(INK4a), another senescence marker, was not upregulated at all. We conclude, in this model, animal age does not affect the development of emphysema and small airway remodeling. PMID- 23936506 TI - Direct comparisons of 2D and 3D dental microwear proxies in extant herbivorous and carnivorous mammals. AB - The analysis of dental microwear is commonly used by paleontologists and anthropologists to clarify the diets of extinct species, including herbivorous and carnivorous mammals. Currently, there are numerous methods employed to quantify dental microwear, varying in the types of microscopes used, magnifications, and the characterization of wear in both two dimensions and three dimensions. Results from dental microwear studies utilizing different methods are not directly comparable and human quantification of wear features (e.g., pits and scratches) introduces interobserver error, with higher error being produced by less experienced individuals. Dental microwear texture analysis (DMTA), which analyzes microwear features in three dimensions, alleviates some of the problems surrounding two-dimensional microwear methods by reducing observer bias. Here, we assess the accuracy and comparability within and between 2D and 3D dental microwear analyses in herbivorous and carnivorous mammals at the same magnification. Specifically, we compare observer-generated 2D microwear data from photosimulations of the identical scanned areas of DMTA in extant African bovids and carnivorans using a scanning white light confocal microscope at 100x magnification. Using this magnification, dental microwear features quantified in 2D were able to separate grazing and frugivorous bovids using scratch frequency; however, DMTA variables were better able to discriminate between disparate dietary niches in both carnivorous and herbivorous mammals. Further, results demonstrate significant interobserver differences in 2D microwear data, with the microwear index remaining the least variable between experienced observers, consistent with prior research. Overall, our results highlight the importance of reducing observer error and analyzing dental microwear in three dimensions in order to consistently interpret diets accurately. PMID- 23936507 TI - A space oddity: geographic and specific modulation of migration in Eudyptes penguins. AB - Post-breeding migration in land-based marine animals is thought to offset seasonal deterioration in foraging or other important environmental conditions at the breeding site. However the inter-breeding distribution of such animals may reflect not only their optimal habitat, but more subtle influences on an individual's migration path, including such factors as the intrinsic influence of each locality's paleoenvironment, thereby influencing animals' wintering distribution. In this study we investigated the influence of the regional marine environment on the migration patterns of a poorly known, but important seabird group. We studied the inter-breeding migration patterns in three species of Eudyptes penguins (E. chrysolophus, E. filholi and E. moseleyi), the main marine prey consumers amongst the World's seabirds. Using ultra-miniaturized logging devices (light-based geolocators) and satellite tags, we tracked 87 migrating individuals originating from 4 sites in the southern Indian Ocean (Marion, Crozet, Kerguelen and Amsterdam Islands) and modelled their wintering habitat using the MADIFA niche modelling technique. For each site, sympatric species followed a similar compass bearing during migration with consistent species specific latitudinal shifts. Within each species, individuals breeding on different islands showed contrasting migration patterns but similar winter habitat preferences driven by sea-surface temperatures. Our results show that inter-breeding migration patterns in sibling penguin species depend primarily on the site of origin and secondly on the species. Such site-specific migration bearings, together with similar wintering habitat used by parapatrics, support the hypothesis that migration behaviour is affected by the intrinsic characteristics of each site. The paleo-oceanographic conditions (primarily, sea surface temperatures) when the populations first colonized each of these sites may have been an important determinant of subsequent migration patterns. Based on previous chronological schemes of taxonomic radiation and geographical expansion of the genus Eudyptes, we propose a simple scenario to depict the chronological onset of contrasting migration patterns within this penguin group. PMID- 23936508 TI - Functional properties of rare missense variants of human CDH13 found in adult attention deficit/hyperactivity disorder (ADHD) patients. AB - The CDH13 gene codes for T-cadherin, a GPI-anchored protein with cell adhesion properties that is highly expressed in the brain and cardiovascular system. Previous studies have suggested that CDH13 may be a promising candidate gene for Attention Deficit/Hyperactivity Disorder (ADHD). The aims of this study were to identify, functionally characterize, and estimate the frequency of coding CDH13 variants in adult ADHD patients and controls. We performed sequencing of the CDH13 gene in 169 Norwegian adult ADHD patients and 63 controls and genotyping of the identified variants in 641 patients and 668 controls. Native and green fluorescent protein tagged wild type and variant CDH13 proteins were expressed and studied in CHO and HEK293 cells, respectively. Sequencing identified seven rare missense CDH13 variants, one of which was novel. By genotyping, we found a cumulative frequency of these rare variants of 2.9% in controls and 3.2% in ADHD patients, implying that much larger samples are needed to obtain adequate power to study the genetic association between ADHD and rare CDH13 variants. Protein expression and localization studies in CHO cells and HEK293 cells showed that the wild type and mutant proteins were processed according to the canonical processing of GPI-anchored proteins. Although some of the mutations were predicted to severely affect protein secondary structure and stability, no significant differences were observed between the expression levels and distribution of the wild type and mutant proteins in either HEK293 or CHO cells. This is the first study where the frequency of coding CDH13 variants in patients and controls is reported and also where the functional properties of these variants are examined. Further investigations are needed to conclude whether CDH13 is involved in the pathogenesis of ADHD or other conditions. PMID- 23936510 TI - Evidence for a novel mechanism of the PAK1 interaction with the Rho-GTPases Cdc42 and Rac. AB - P21-activated kinase 1 (PAK1) is activated by binding to GTP-bound Rho GTPases Cdc42 and Rac via its CRIB domain. Here, we provide evidence that S79 in the CRIB domain of PAK1 is not directly involved in this binding but is crucial for PAK1 activation. S79A mutation reduces the binding affinity of PAK1 for the GTPases and inhibits autophosphorylation and kinase activity of PAK1. Thus, this mutation abrogates the ability of PAK1 to induce changes in cell morphology and motility and to promote malignant transformation of prostate epithelial cells. We also show that growth of the prostate cancer cell line PC3 is inhibited by the treatment of a PAK1-inhibiting peptide comprising 19 amino acids centered on S79, but not by the PAK1 peptide containing the S79A mutation, and that this growth inhibition is correlated with reduced autophosphorylation activity of PAK1. Together, these findings demonstrate a significant role of S79 in PAK1 activation and provide evidence for a novel mechanism of the CRIB-mediated interaction of PAK1 with Cdc42 and Rac. PMID- 23936511 TI - Incidence of spinal perineurial (Tarlov) cysts among East-European patients. AB - The spinal perineurial cyst (Tarlov) is a dilatation between the perineurium and endoneurium of spinal nerve roots, located at level of the spinal ganglion and filled with cerebrospinal fluid but without communication with the perineurial subarachnoid space. The aim of the study was to evaluate it incidence among East European patients. The retrospective data collected during various magnetic resonance spinal examinations and stored on the picture archiving and communication system was analyzed for an incidence of perineurial cysts. From among 842 patients that underwent examination, 75 cases perineurial cysts were revealed. In 22 cases single anomalies were found. In remaining 53 cases, multiple uni- or less frequently bilateral changes were noted. The most common position was the sacral canal, particularly the level of S2 and S3. Occasionally, cysts were also visible on the cervical, thoracic and lumbar level. Incidence of sacral perineurial cysts was significantly higher in females than in males. Similar data was found for single and multiple changes despite of their localization. Insignificant changes were seen for patient age and cyst size. Perineurial spinal cysts were the most frequently observed on the sacral level and such changes were more common in females. PMID- 23936512 TI - Deletion of thioredoxin reductase and effects of selenite and selenate toxicity in Caenorhabditis elegans. AB - Thioredoxin reductase-1 (TRXR-1) is the sole selenoprotein in C. elegans, and selenite is a substrate for thioredoxin reductase, so TRXR-1 may play a role in metabolism of selenium (Se) to toxic forms. To study the role of TRXR in Se toxicity, we cultured C. elegans with deletions of trxr-1, trxr-2, and both in axenic media with increasing concentrations of inorganic Se. Wild-type C. elegans cultured for 12 days in Se-deficient axenic media grow and reproduce equivalent to Se-supplemented media. Supplementation with 0-2 mM Se as selenite results in inverse, sigmoidal response curves with an LC50 of 0.20 mM Se, due to impaired growth rather than reproduction. Deletion of trxr-1, trxr-2 or both does not modulate growth or Se toxicity in C. elegans grown axenically, and (75)Se labeling showed that TRXR-1 arises from the trxr-1 gene and not from bacterial genes. Se response curves for selenide (LC50 0.23 mM Se) were identical to selenite, but selenate was 1/4(th) as toxic (LC50 0.95 mM Se) as selenite and not modulated by TRXR deletion. These nutritional and genetic studies in axenic media show that Se and TRXR are not essential for C. elegans, and that TRXR alone is not essential for metabolism of inorganic Se to toxic species. PMID- 23936513 TI - Mesenchymal-to-endothelial transition in Kaposi sarcoma: a histogenetic hypothesis based on a case series and literature review. AB - OBJECTIVES: Although several studies have been conducted regarding Kaposi sarcoma (KS), its histogenesis still remains to be elucidated. The aim of our study was to analyze the immunophenotype of Kaposi sarcoma and to present a hypothesis about the histogenesis of this tumor, based on a case series and a review of relevant literature. METHODS: In 15 cases of KSs diagnosed during 2000-2011, the clinicopathological features were correlated with the immunoexpression of c-Kit, SMA, CD34, CD31, vascular endothelial growth factor (VEGF), COX-2, c-KIT, smooth muscle antigen (SMA), and stem cell surface marker CD105. RESULTS: Both CD105 and c-KIT rate of the spindle-shaped tumor cell positivity increased in parallel to the pathological stage. All cases displayed CD105 and weak c-KIT positivity in the endothelial cells. SMA, VEGF, and COX-2 were focally expressed in all cases. CD34 marked both endothelium and spindle-shaped tumor cells. No c-KIT expression was noticed in KS of the internal organs. CONCLUSIONS: KS seems to be a variant of myofibroblastic tumors that originates from the viral modified pluripotent mesenchymal cells of the connective tissue transformed in spindle-shaped KS cells, followed by a mesenchymal-endothelial transition and a myofibroblastic like differentiation. This paper mailnly showed that KS cannot be considered a pure vascular tumor. PMID- 23936514 TI - Prophylactic antibiotics for endoscopy-associated peritonitis in peritoneal dialysis patients. AB - INTRODUCTION: Continuous ambulatory peritoneal dialysis (CAPD) peritonitis may develop after endoscopic procedures, and the benefit of prophylactic antibiotics is unclear. In the present study, we investigated whether prophylactic antibiotics reduce the incidence of peritonitis in these patients. PATIENTS AND METHODS: We retrospectively reviewed all endoscopic procedures, including esophagogastroduodenoscopy (EGD), colonoscopy, sigmoidoscopy, cystoscopy, hysteroscopy, and hysteroscopy-assisted intrauterine device (IUD) implantation/removal, performed in CAPD patients at Chang Gung Memorial Hospital, Taiwan, between February 2001 and February 2012. RESULTS: Four hundred and thirty three patients were enrolled, and 125 endoscopies were performed in 45 patients. Eight (6.4%) peritonitis episodes developed after the examination. Antibiotics were used in 26 procedures, and none of the patients had peritonitis (0% vs. 8.1% without antibiotic use; p=0.20). The peritonitis rate was significantly higher in the non-EGD group than in the EGD group (15.9% [7/44] vs. 1.2% [1/81]; p<0.005). Antibiotic use prior to non-EGD examinations significantly reduced the endoscopy associated peritonitis rate compared to that without antibiotic use (0% [0/16] vs. 25% [7/28]; p<0.05). Peritonitis only occurred if invasive procedures were performed, such as biopsy, polypectomy, or IUD implantation, (noninvasive procedures, 0% [0/20] vs. invasive procedures, 30.4% [7/23]; p<0.05). No peritonitis was noted if antibiotics were used prior to examination with invasive procedures (0% [0/10] vs. 53.8% [7/13] without antibiotic use; p<0.05). Although not statistically significant, antibiotics may play a role in preventing gynecologic procedure-related peritonitis (antibiotics, 0% [0/4] vs. no antibiotics, 55.6% [5/9]; p=0.10). CONCLUSION: Antibiotic prophylaxis significantly reduced endoscopy-associated PD peritonitis in the non-EGD group. Endoscopically assisted invasive procedures, such as biopsy, polypectomy, IUD implantation/removal, and dilatation and curettage (D&C), pose a high risk for peritonitis. Prophylactic antibiotics for peritonitis prevention may be required in colonoscopic procedures and gynecologic procedures. PMID- 23936515 TI - Endonuclease IV Is the major apurinic/apyrimidinic endonuclease in Mycobacterium tuberculosis and is important for protection against oxidative damage. AB - During the establishment of an infection, bacterial pathogens encounter oxidative stress resulting in the production of DNA lesions. Majority of these lesions are repaired by base excision repair (BER) pathway. Amongst these, abasic sites are the most frequent lesions in DNA. Class II apurinic/apyrimidinic (AP) endonucleases play a major role in BER of damaged DNA comprising of abasic sites. Mycobacterium tuberculosis, a deadly pathogen, resides in the human macrophages and is continually subjected to oxidative assaults. We have characterized for the first time two AP endonucleases namely Endonuclease IV (End) and Exonuclease III (XthA) that perform distinct functions in M.tuberculosis. We demonstrate that M.tuberculosis End is a typical AP endonuclease while XthA is predominantly a 3' >5' exonuclease. The AP endonuclease activity of End and XthA was stimulated by Mg(2+) and Ca(2+) and displayed a preferential recognition for abasic site paired opposite to a cytosine residue in DNA. Moreover, End exhibited metal ion independent 3'->5' exonuclease activity while in the case of XthA this activity was metal ion dependent. We demonstrate that End is not only a more efficient AP endonuclease than XthA but it also represents the major AP endonuclease activity in M.tuberculosis and plays a crucial role in defense against oxidative stress. PMID- 23936509 TI - Is clinical practice concordant with the changes in guidelines for antiretroviral therapy initiation during primary and chronic HIV-1 infection? The ANRS PRIMO and COPANA cohorts. AB - OBJECTIVE: Guidelines for initiating HIV treatment are regularly revised. We explored how physicians in France have applied these evolving guidelines for ART initiation over the last decade in two different situations: chronic (CHI) and primary HIV-1 infection (PHI), since specific recommendations for PHI are also provided in France. METHODS: Data came from the ANRS PRIMO (1267 patients enrolled during PHI in 1996-2010) and COPANA (800 subjects enrolled at HIV diagnosis in 2004-2008) cohorts. We defined as guidelines-inconsistent during PHI and CHI, patients meeting criteria for ART initiation and not treated in the following month and during the next 6 months, respectively. RESULTS: ART initiation during PHI dramatically decreased from 91% of patients in 1996-99 to 22% in 2007 and increased to 60% in 2010, following changes in recommendations. In 2007, however, after the CD4 count threshold was raised to 350 cells/mm(3) in 2006, only 55% of the patients with CD4<=350 were treated and 66% in 2008. During CHI, ART was more frequently initiated in patients who met the criteria at entry (96%) than during follow-up: 83% when recommendation to treat was 200 and 73% when it was 350 cells/mm(3). Independent risk factors for not being treated during CHI despite meeting the criteria were lower viral load, lower educational level, and poorer living conditions. CONCLUSION: HIV ART initiation guidelines are largely followed by practitioners in France. What can still be improved, however, is time to treat when CD4 cell counts reach the threshold to treat. Risk factors for lack of timely treatment highlight the need to understand better how patients' living conditions and physicians' perceptions influence the decision to initiate treatment. PMID- 23936516 TI - Crucial role of perilipin-3 (TIP47) in formation of lipid droplets and PGE2 production in HL-60-derived neutrophils. AB - Cytosolic lipid droplets (LDs), which are now recognized as multifunctional organelles, accumulate in leukocytes under various inflammatory conditions. However, little is known about the characteristic features of LDs in neutrophils. In this study, we show that perilipin-3 (PLIN3; formerly called TIP47) is involved in LD formation and the inflammatory response in HL-60-derived neutrophils. HL-60, a promyelocytic cell line, was differentiated into neutrophils via treatment with all-trans retinoic acid. After differentiation, cells were stimulated with Porphyromonas gingivalis lipopolysaccharide (P.g-LPS), a major pathogen in adult periodontitis. When HL-60-derived neutrophils were stimulated with P.g-LPS, LDs increased in both number and size. In the differentiated cells, PLIN3 was induced while PLIN1, PLIN2 and PLIN5 were not detected. PGE2 production and the PLIN3 protein level were increased by the P.g LPS treatment of the cells in a dose-dependent manner. When PLIN3 was down regulated with siRNA treatment, LDs essentially disappeared and the level of PGE2 secreted in the cell culture medium decreased by 65%. In addition, the suppression of PLIN3 repressed the PGE2 producing enzymes; i.e., microsomal PGE synthase-1, -2 and cyclooxygenase-2. These findings indicate that PLIN3 has a pivotal role in LD-biogenesis in HL-60-derived neutrophils, and that PLIN3 is associated with the synthesis and secretion of PGE2. PMID- 23936517 TI - Application of motif-based tools on evolutionary analysis of multipartite single stranded DNA viruses. AB - Multipartite viruses contain more than one distinctive genome component, and the origin of multipartite viruses has been suggested to evolve from a non-segmented wild-type virus. To explore whether recombination also plays a role in the evolution of the genomes of multipartite viruses, we developed a systematic approach that employs motif-finding tools to detect conserved motifs from divergent genomic regions and applies statistical approaches to select high confidence motifs. The information that this approach provides helps us understand the evolution of viruses. In this study, we compared our motif-based strategy with current alignment-based recombination-detecting methods and applied our methods to the analysis of multipartite single-stranded plant DNA viruses, including bipartite begomoviruses, Banana bunchy top virus (BBTV) (consisting of 6 genome components) and Faba bean necrotic yellows virus (FBNYV) (consisting of 8 genome components). Our analysis revealed that recombination occurred between genome components in some begomoviruses, BBTV and FBNYV. Our data also show that several unusual recombination events have contributed to the evolution of BBTV genome components. We believe that similar approaches can be applied to resolve the evolutionary history of other viruses. PMID- 23936518 TI - Flying between sky islands: the effect of naturally fragmented habitat on butterfly population structure. AB - High elevation montane areas are called "sky islands" when they occur as a series of high mountains separated by lowland valleys. Different climatic conditions at high elevations makes sky islands a specialized type of habitat, rendering them naturally fragmented compared to more continuous habitat at lower elevations. Species in sky islands face unsuitable climate in the intervening valleys when moving from one montane area to another. The high elevation shola-grassland mosaic in the Western Ghats of southern India form one such sky island complex. The fragmented patches make this area ideal to study the effect of the spatial orientation of suitable habitat patches on population genetic structure of species found in these areas. Past studies have suggested that sky islands tend to have genetically structured populations, possibly due to reduced gene flow between montane areas. To test this hypothesis, we adopted the comparative approach. Using Amplified Fragment Length Polymorphisms, we compared population genetic structures of two closely related, similar sized butterfly species: Heteropsis oculus, a high elevation shola-grassland specialist restricted to the southern Western Ghats, and Mycalesis patnia, found more continuously distributed in lower elevations. In all analyses, as per expectation the sky island specialist H. oculus exhibited a greater degree of population genetic structure than M. patnia, implying a difference in geneflow. This difference in geneflow in turn appears to be due to the natural fragmentation of the sky island complexes. Detailed analysis of a subset of H. oculus samples from one sky island complex (the Anamalais) showed a surprising genetic break. A possible reason for this break could be unsuitable conditions of higher temperature and lower rainfall in the intervening valley region. Thus, sky island species are not only restricted by lack of habitat continuity between montane areas, but also by the nature of the intervening habitat. PMID- 23936519 TI - Light driven CO2 fixation by using cyanobacterial photosystem I and NADPH dependent formate dehydrogenase. AB - The ultimate goal of this research is to construct a new direct CO2 fixation system using photosystems in living algae. Here, we report light-driven formate production from CO2 by using cyanobacterial photosystem I (PS I). Formate, a chemical hydrogen carrier and important industrial material, can be produced from CO2 by using the reducing power and the catalytic function of formate dehydrogenase (FDH). We created a bacterial FDH mutant that experimentally switched the cofactor specificity from NADH to NADPH, and combined it with an in vitro-reconstituted cyanobacterial light-driven NADPH production system consisting of PS I, ferredoxin (Fd), and ferredoxin-NADP(+)-reductase (FNR). Consequently, light-dependent formate production under a CO2 atmosphere was successfully achieved. In addition, we introduced the NADPH-dependent FDH mutant into heterocysts of the cyanobacterium Anabaena sp. PCC 7120 and demonstrated an increased formate concentration in the cells. These results provide a new possibility for photo-biological CO2 fixation. PMID- 23936520 TI - Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. AB - AIMS/HYPOTHESIS: Diabetes treatments were related with either an increased or reduced risk of cancer. There is ongoing debate about a potential protective action of metformin. To summarize evidence on the association between metformin and risk of cancer and cancer mortality in patients with diabetes. METHODS: DATA SOURCE: MEDLINE and EMBASE (January 1966-April 2012). We selected randomized studies comparing metformin and other hypoglycaemic agents and observational studies exploring the association between exposure to metformin and cancer. Outcomes were cancer mortality, all malignancies and site-specific cancers. RESULTS: Of 25307 citations identified, 12 randomized controlled trials (21,595 patients) and 41 observational studies (1,029,389 patients) met the inclusion criteria. In observational studies there was a significant association of exposure to metformin with the risk of cancer death [6 studies, 24,410 patients, OR:0.65, 95%CI: 0.53-0.80], all malignancies [18 studies, 561,836 patients, OR:0.73, 95%CI: 0.61-0.88], liver [8 studies, 312,742 patients, OR:0.34; 95%CI: 0.19-0.60] colorectal [12 studies, 871,365 patients, OR:0.83, 95%CI: 0.74-0.92], pancreas [9 studies, 847,248 patients, OR:0.56, 95%CI: 0.36-0.86], stomach [2 studies, 100701 patients, OR:0.83, 95%CI: 0.76-0.91], and esophagus cancer [2 studies, 100694 patients, OR:0.90, 95%CI: 0.83-0.98]. No significant difference of risk was observed in randomized trials. Metformin was not associated with the risk of: breast cancer, lung cancer, ovarian cancer, uterus cancer, prostate cancer, bladder cancer, kidney cancer, and melanoma. CONCLUSIONS/INTERPRETATION: Results suggest that Metformin might be associated with a significant reduction in the risk of cancer and cancer-related mortality. Randomized trials specifically designed to evaluate the efficacy of metformin as an anticancer agent are warranted. PMID- 23936521 TI - Low birthweight (LBW) and neonatal hyperbilirubinemia (NNH) in an Indian cohort: association of homocysteine, its metabolic pathway genes and micronutrients as risk factors. AB - BACKGROUND & AIMS: Indian subcontinent has the highest child mortality rates along with a very high frequency of low birthweight (LBW). Folate and vitamin B12 (Vit-B12) are necessary during foetal development and their deficiency prevalence in Indians is very high. The objective of the present paper is to assess whether foetal homocysteine (Hcy)/folate metabolic pathway genes, their cofactors and homocysteine level independently (or collectively) predispose children to Low birth weight. METHODS: Cord blood was collected for the study. Frequency of 5 SNPs in 4-Hcy-pathway genes, and levels of Hcy, Vit-B12 and folate were evaluated. RESULTS: Of the 421 newborns recruited for the study, 38% showed low birth weight (<2.5 kg) and 16% were preterm babies. 101 neonates developed neonatal hyperbilirubinemia (NNH). High prevalence of Vit-B12 (65%) and folate (27%) deficiency was observed in newborns along with hyperhomocystinemia (hypHcy 25%). Preterm delivery, micronutrient deficiency, hypHcy and MTHFR 677T SNP are associated as risk factor while G allele of TCN2 C776G is protective against LBW. MTHFR 677T allele and folate deficiency are also independent risk factors for NNH. CONCLUSION: We record the highest incidence of Vit-B12, folate deficiency and elevated Hcy levels, of all the studies so far reported on neonates. These together with MTHFR 677T are potential risk factors for LBW. Association of impaired folate/Hcy metabolism with NNH is reported for the first time and the possible way of interaction is discussed. It appears that proper nutritional management during pregnancy would reduce the risk of complex clinical outcomes. PMID- 23936522 TI - Bidirectional modulation of substantia nigra activity by motivational state. AB - A major output nucleus of the basal ganglia is the substantia nigra pars reticulata, which sends GABAergic projections to brainstem and thalamic nuclei. The GABAergic (GABA) neurons are reciprocally connected with nearby dopaminergic neurons, which project mainly to the basal ganglia, a set of subcortical nuclei critical for goal-directed behaviors. Here we examined the impact of motivational states on the activity of GABA neurons in the substantia nigra pars reticulata and the neighboring dopaminergic (DA) neurons in the pars compacta. Both types of neurons show short-latency bursts to a cue predicting a food reward. As mice became sated by repeated consumption of food pellets, one class of neurons reduced cue-elicited firing, whereas another class of neurons progressively increased firing. Extinction or pre-feeding just before the test session dramatically reduced the phasic responses and their motivational modulation. These results suggest that signals related to the current motivational state bidirectionally modulate behavior and the magnitude of phasic response of both DA and GABA neurons in the substantia nigra. PMID- 23936523 TI - Interleukin expression after injury and the effects of interleukin-1 receptor antagonist. AB - Ligament healing follows a series of complex coordinated events involving various cell types, cytokines, as well as other factors, producing a mechanically inferior tissue more scar-like than native tissue. Macrophages provide an ongoing source of cytokines to modulate inflammatory cell adhesion and migration as well as fibroblast proliferation. Studying interleukins inherent to ligament healing during peak macrophage activation and angiogenesis may elucidate inflammatory mediators involved in subsequent scar formation. Herein, we used a rat healing model assayed after surgical transection of their medial collateral ligaments (MCLs). On days 3 and 7 post-injury, ligaments were collected and used for microarray analysis. Of the 12 significantly modified interleukins, components of the interleukin-1 family were significantly up-regulated. We therefore examined the influence of interleukin-1 receptor antagonist (IL-1Ra) on MCL healing. Transected rat MCLs received PBS or IL-1Ra at the time of surgery. Inhibition of IL-1 activation decreased pro-inflammatory cytokines (IL-1alpha, IL-1beta, IL-12, IL-2, and IFN-gamma), myofibroblasts, and proliferating cells, as well as increased anti-inflammatory cytokines (IL-10), endothelial cells/blood vessel lumen, M2 macrophages, and granulation tissue size without compromising the mechanical properties. These results support the concept that IL-1Ra modulates MCL-localized granulation tissue components and cytokine production to create a transient environment that is less inflammatory. Overall, IL-1Ra may have therapeutic potential early in the healing cascade by stimulating the M2 macrophages and altering the granulation tissue components. However, the single dose of IL-1Ra used in this study was insufficient to maintain the more regenerative early response. Due to the transient influence on most of the healing components tested, IL-1Ra may have greater therapeutic potential with sustained delivery. PMID- 23936524 TI - Genome-wide linkage analysis of cardiovascular disease biomarkers in a large, multigenerational family. AB - Given the importance of cardiovascular disease (CVD) to public health and the demonstrated heritability of both disease status and its related risk factors, identifying the genetic variation underlying these susceptibilities is a critical step in understanding the pathogenesis of CVD and informing prevention and treatment strategies. Although one can look for genetic variation underlying susceptibility to CVD per se, it can be difficult to define the disease phenotype for such a qualitative analysis and CVD itself represents a convergence of diverse etiologic pathways. Alternatively, one can study the genetics of intermediate traits that are known risk factors for CVD, which can be measured quantitatively. Using the latter strategy, we have measured 21 cardiovascular related biomarkers in an extended multigenerational pedigree, the CARRIAGE family (Carolinas Region Interaction of Aging, Genes, and Environment). These biomarkers belong to inflammatory and immune, connective tissue, lipid, and hemostasis pathways. Of these, 18 met our quality control standards. Using the pedigree and biomarker data, we have estimated the broad sense heritability (H2) of each biomarker (ranging from 0.09-0.56). A genome-wide panel of 6,015 SNPs was used subsequently to map these biomarkers as quantitative traits. Four showed noteworthy evidence for linkage in multipoint analysis (LOD score >= 2.6): paraoxonase (chromosome 8p11, 21), the chemokine RANTES (22q13.33), matrix metalloproteinase 3 (MMP3, 17p13.3), and granulocyte colony stimulating factor (GCSF, 8q22.1). Identifying the causal variation underlying each linkage score will help to unravel the genetic architecture of these quantitative traits and, by extension, the genetic architecture of cardiovascular risk. PMID- 23936525 TI - Diversity and biotic homogenization of urban land-snail faunas in relation to habitat types and macroclimate in 32 central European cities. AB - The effects of non-native species invasions on community diversity and biotic homogenization have been described for various taxa in urban environments, but not for land snails. Here we relate the diversity of native and non-native land snail urban faunas to urban habitat types and macroclimate, and analyse homogenization effects of non-native species across cities and within the main urban habitat types. Land-snail species were recorded in seven 1-ha plots in 32 cities of ten countries of Central Europe and Benelux (224 plots in total). Each plot represented one urban habitat type characterized by different management and a specific disturbance regime. For each plot, we obtained January, July and mean annual temperature and annual precipitation. Snail species were classified into either native or non-native. The effects of habitat type and macroclimate on the number of native and non-native species were analysed using generalized estimating equations; the homogenization effect of non-native species based on the Jaccard similarity index and homogenization index. We recorded 67 native and 20 non-native species. Besides being more numerous, native species also had much higher beta diversity than non-natives. There were significant differences between the studied habitat types in the numbers of native and non-native species, both of which decreased from less to heavily urbanized habitats. Macroclimate was more important for the number of non-native than native species; however in both cases the effect of climate on diversity was overridden by the effect of urban habitat type. This is the first study on urban land snails documenting that non-native land-snail species significantly contribute to homogenization among whole cities, but both the homogenization and diversification effects occur when individual habitat types are compared among cities. This indicates that the spread of non-native snail species may cause biotic homogenization, but it depends on scale and habitat type. PMID- 23936526 TI - Involvement of Galectin-9/TIM-3 pathway in the systemic inflammatory response in early-onset preeclampsia. AB - BACKGROUND: Preeclampsia is a common obstetrical disease affecting 3-5% of pregnancies and representing one of the leading causes of both maternal and fetal mortality. Maternal symptoms occur as an excessive systemic inflammatory reaction in response to the placental factors released by the oxidatively stressed and functional impaired placenta. The T-cell immunoglobulin domain and mucin domain (TIM) family is a relatively newly described group of molecules with a conserved structure and important immunological functions. Identification of Galectin-9 as a ligand for TIM-3 has established the Galectin-9/TIM-3 pathway as an important regulator of Th1 immunity and tolerance induction. METHODS: The aim of our study was to investigate the expression and function of Galectin-9 and TIM-3 molecules by peripheral blood mononuclear cells and the possible role of Galectin-9/TIM-3 pathway in the immunoregulation of healthy pregnancy and early-onset preeclampsia. We determined TIM-3 and Gal-9 expression and cytotoxicicty of peripheral lymphocytes of early-onset preeclamptic women and healthy pregnant woman using flow cytometry. RESULTS: Investigating peripheral lymphocytes of women with early-onset preeclampsia, our results showed a decreased TIM-3 expression by T cells, cytotoxic T cells, NK cells and CD56(dim) NK cells compared to healthy pregnant women. Interestingly, we found a notably increased frequency of Galectin-9 positive cells in each investigated lymphocyte population in the case of early-onset preeclamptic patients. We further demonstrated increased cytotoxic activity by cytotoxic T and CD56(dim) NK cells in women with early-onset preeclampsia. Our findings showed that the strongest cellular cytotoxic response of lymphocytes occurred in the TIM-3 positive subpopulations of different lymphocytes subsets in early-onset preeclampsia. CONCLUSION: These data suggest that Gal-9/TIM-3 pathway could play an important role in the immune regulation during pregnancy and the altered Galectin-9 and TIM-3 expression could result an enhanced systemic inflammatory response including the activation of Th1 lymphocytes in preeclampsia. PMID- 23936528 TI - Upregulated expression of C-X-C chemokine receptor 4 is an independent prognostic predictor for patients with gastric cancer. AB - Aberrant chemokine (C-X-C motif) receptor CXCR4 expressions in malignant tissues have been reported, but its role in gastric cancer prognosis remains unknown. Our studies were designed to investigate the expression and prognostic significance of CXCR4 in patients with gastric cancer. CXCR4 expression was retrospectively analyzed by immunohistochemistry in 97 patients with gastric adenocarcinoma from China. Results were assessed for association with clinical features and overall survival by using Kaplan-Meier analysis. Prognostic values of CXCR4 expression and clinical outcomes were evaluated by Cox regression analysis. A molecular prognostic stratification scheme incorporating CXCR4 expression was determined by using receiver operating characteristic (ROC) analysis. The results show that CXCR4 predominantly localized in the cell membranes and cytoplasm. The protein level of CXCR4 was upregulation in gastric cancer tissues and upregulated expression of CXCR4 was only significantly associated with Lauren classification (P<0.001). Increased CXCR4 expression in gastric cancer tissues was positively correlated with poor overall survival of gastric cancer patients (P<0.001). Further multivariate Cox regression analysis suggested that intratumoral CXCR4 expression was an independent prognostic indicator for the disease. Applying the prognostic value of intratumoral CXCR4 density to TNM stage system showed a better prognostic value in patients with gastric cancer. In conclusion, intratumoral CXCR4 expression was recognized as an independent prognostic marker for the overall survival of patients with gastric cancer. On the basis of TNM stage, detection of CXCR4 expression will be helpful for predicting prognosis for patients with gastric cancer. PMID- 23936527 TI - Circadian rhythms of sense and antisense transcription in sugarcane, a highly polyploid crop. AB - Commercial sugarcane (Saccharum hybrid) is a highly polyploid and aneuploid grass that stores large amounts of sucrose in its stem. We have measured circadian rhythms of sense and antisense transcription in a commercial cultivar (RB855453) using a custom oligoarray with 14,521 probes that hybridize to sense transcripts (SS) and 7,380 probes that hybridize to antisense transcripts (AS).We estimated that 32% of SS probes and 22% AS probes were rhythmic. This is a higher proportion of rhythmic probes than the usually found in similar experiments in other plant species. Orthologs and inparalogs of Arabidopsis thaliana, sugarcane, rice, maize and sorghum were grouped in ortholog clusters. When ortholog clusters were used to compare probes among different datasets, sugarcane also showed a higher proportion of rhythmic elements than the other species. Thus, it is possible that a higher proportion of transcripts are regulated by the sugarcane circadian clock. Thirty-six percent of the identified AS/SS pairs had significant correlated time courses and 64% had uncorrelated expression patterns. The clustering of transcripts with similar function, the anticipation of daily environmental changes and the temporal compartmentation of metabolic processes were some properties identified in the circadian sugarcane transcriptome. During the day, there was a dominance of transcripts associated with photosynthesis and carbohydrate metabolism, including sucrose and starch synthesis. During the night, there was dominance of transcripts associated with genetic processing, such as histone regulation and RNA polymerase, ribosome and protein synthesis. Finally, the circadian clock also regulated hormone signalling pathways: a large proportion of auxin and ABA signalling components were regulated by the circadian clock in an unusual biphasic distribution. PMID- 23936529 TI - Rab41 is a novel regulator of Golgi apparatus organization that is needed for ER to-Golgi trafficking and cell growth. AB - BACKGROUND: The 60(+) members of the mammalian Rab protein family group into subfamilies postulated to share common functionality. The Rab VI subfamily contains 5 Rab proteins, Rab6a/a', Rab6b, Rab6c and Rab41. High-level knockdown of Rab6a/a' has little effect on the tightly organized Golgi ribbon in HeLa cells as seen by fluorescence microscopy. In striking contrast, we found Rab41 was strongly required for normal Golgi ribbon organization. METHODS/RESULTS: Treatment of HeLa cells with Rab41 siRNAs scattered the Golgi ribbon into clustered, punctate Golgi elements. Overexpression of GDP-locked Rab41, but not wild type or GTP-locked Rab41, produced a similar Golgi phenotype. By electron microscopy, Rab41 depletion produced short, isolated Golgi stacks. Golgi associated vesicles accumulated. At low expression levels, wild type and GTP locked Rab41 showed little concentration in the Golgi region, but puncta were observed and most were in ruffled regions at the cell periphery. There was 25% co localization of GTP-locked Rab41 with the ER marker, Sec61p. GDP-locked Rab41, as expected, displayed an entirely diffuse cytoplasmic distribution. Depletion of Rab41 or overexpression of GDP-locked Rab41 partially inhibited ER-to-Golgi transport of VSV-G protein. However, Rab41 knockdown had little, if any, effect on endosome-to-Golgi transport of SLTB. Additionally, after a 2-day delay, treatment with Rab41 siRNA inhibited cell growth, while overexpression of GDP locked Rab41, but not wild type or GTP-locked Rab41, produced a rapid, progressive cell loss. In double knockdown experiments with Rab6, the Golgi ribbon was fragmented, a result consistent with Rab41 and Rab6 acting in parallel. CONCLUSION: We provide the first evidence for distinctive Rab41 effects on Golgi organization, ER-to-Golgi trafficking and cell growth. When combined with the evidence that Rab6a/a' and Rab6b have diverse roles in Golgi function, while Rab6c regulates mitotic function, our data indicate that Rab VI subfamily members, although related by homology and structure, share limited functional conservation. PMID- 23936530 TI - Laulimalide induces dose-dependent modulation of microtubule behaviour in the C. elegans embryo. AB - Laulimalide is a microtubule-binding drug that was originally isolated from marine sponges. High concentrations of laulimalide stabilize microtubules and inhibit cell division similarly to paclitaxel; however, there are important differences with respect to the nature of the specific cellular defects between these two drugs and their binding sites on the microtubule. In this study, we used Caenorhabditis elegans embryos to investigate the acute effects of laulimalide on microtubules in vivo, with a direct comparison to paclitaxel. We observed surprising dose-dependent effects for laulimalide, whereby microtubules were stabilized at concentrations above 100 nM, but destabilized at concentrations between 50 and 100 nM. Despite this behaviour at low concentrations, laulimalide acted synergistically with paclitaxel to stabilize microtubules when both drugs were used at sub-effective concentrations, consistent with observations of synergistic interactions between these two drugs in other systems. Our results indicate that laulimalide induces a concentration dependent, biphasic change in microtubule polymer dynamics in the C. elegans embryo. PMID- 23936531 TI - SnoN facilitates axonal regeneration after spinal cord injury. AB - Adult CNS neurons exhibit a reduced capacity for growth compared to developing neurons, due in part to downregulation of growth-associated genes as development is completed. We tested the hypothesis that SnoN, an embryonically regulated transcription factor that specifies growth of the axonal compartment, can enhance growth in injured adult neurons. In vitro, SnoN overexpression in dissociated adult DRG neuronal cultures significantly enhanced neurite outgrowth. Moreover, TGF-beta1, a negative regulator of SnoN, inhibited neurite outgrowth, and SnoN over-expression overcame this inhibition. We then examined whether SnoN influenced axonal regeneration in vivo: indeed, expression of a mutant form of SnoN resistant to degradation significantly enhanced axonal regeneration following cervical spinal cord injury, despite peri-lesional upregulation of TGF beta1. Thus, a developmental mechanism that specifies extension of the axonal compartment also promotes axonal regeneration after adult CNS injury. PMID- 23936532 TI - Prognostic value of survivin in patients with gastric cancer: a systematic review with meta-analysis. AB - OBJECTIVE: The prognostic significance of survivin for the survival of patients with gastric cancer remains controversial. Thus, the objective of this study was to conduct a systematic review of the literature evaluating survivin expression in gastric cancer as a prognostic indicator. METHODS: Relevant literature was searched using PubMed, EMBASE, and Chinese biomedicine databases. A meta-analysis of the association between survivin expression and overall survival in patients with gastric cancer was performed. Studies were pooled and summary hazard ratios (HRs) were calculated. Subgroup analyses were also conducted. RESULTS: Final analysis of 1365 patients from 16 eligible studies was performed. Combined HR suggested that survivin expression had an unfavorable impact on survival of gastric cancer patients (HR=1.39, 95% CI: 1.16-1.68). The unfavorable impact also appeared significant when stratified according to the studies categorized by patients' ethnicity, detection methods, type of sample, and HR estimate. The combined HR in the English literature showed an inverse effect on survival (HR=1.40, 95% CI: 1.13-1.75), while HR in the non-English literature did not (HR=1.38, 95% CI: 0.93-2.05). When stratified according to the location of survivin expression, combined HR showed that expression in cytoplasm was significantly associated with poor prognosis of gastric cancer patients (HR=1.46, 95% CI: 1.12-1.90). While expression in nucleus was not significantly associated with poor prognosis (HR=1.29, 95% CI: 0.72-2.31), the heterogeneity was highly significant (chi-squared=11.5, I(2)=74%, p=0.009). CONCLUSIONS: This study showed that survivin expression was associated with a poor prognosis in patients with gastric cancer. Cytoplasmic expression of survivin may be regarded as a prognostic factor for gastric cancer patients. In contrast, survivin expression in nucleus did not have a significant impact on patients' overall survival. PMID- 23936533 TI - STAT3 activation promotes oncolytic HSV1 replication in glioma cells. AB - Recent studies report that STAT3 signaling is a master regulator of mesenchymal transformation of gliomas and that STAT3 modulated genes are highly expressed in the mesenchymal transcriptome of gliomas. A currently studied experimental treatment for gliomas consists of intratumoral injection of oncolytic viruses (OV), such as oncolytic herpes simplex virus type 1 (oHSV). We have described one particular oHSV (rQNestin34.5) that exhibits potent anti-glioma activity in animal models. Here, we hypothesized that alterations in STAT3 signaling in glioma cells may affect the replicative ability of rQNestin34.5. In fact, human U251 glioma cells engineered to either over-express STAT3 or with genetic down regulation of STAT3 supported oHSV replication to a significantly higher or lesser degree, respectively, when compared to controls. Administration of pharmacologic agents that increase STAT3 phosphorylation/activation (Valproic Acid) or increase STAT3 levels (Interleukin 6) also significantly enhanced oHSV replication. Instead, administration of inhibitors of STAT3 phosphorylation/activation (LLL12) significantly reduced oHSV replication. STAT3 led to a reduction in interferon signaling in oHSV infected cells and inhibition of interferon signaling abolished the effect of STAT3 on oHSV replication. These data thus indicate that STAT3 signaling in malignant gliomas enhances oHSV replication, likely by inhibiting the interferon response in infected glioma cells, thus suggesting avenues for possible potentiation of oncolytic virotherapy. PMID- 23936534 TI - Why movement is captured by music, but less by speech: role of temporal regularity. AB - Music has a pervasive tendency to rhythmically engage our body. In contrast, synchronization with speech is rare. Music's superiority over speech in driving movement probably results from isochrony of musical beats, as opposed to irregular speech stresses. Moreover, the presence of regular patterns of embedded periodicities (i.e., meter) may be critical in making music particularly conducive to movement. We investigated these possibilities by asking participants to synchronize with isochronous auditory stimuli (target), while music and speech distractors were presented at one of various phase relationships with respect to the target. In Exp. 1, familiar musical excerpts and fragments of children poetry were used as distractors. The stimuli were manipulated in terms of beat/stress isochrony and average pitch to achieve maximum comparability. In Exp. 2, the distractors were well-known songs performed with lyrics, on a reiterated syllable, and spoken lyrics, all having the same meter. Music perturbed synchronization with the target stimuli more than speech fragments. However, music superiority over speech disappeared when distractors shared isochrony and the same meter. Music's peculiar and regular temporal structure is likely to be the main factor fostering tight coupling between sound and movement. PMID- 23936536 TI - Visualized computational predictions of transcriptional effects by intronic endogenous retroviruses. AB - When endogenous retroviruses (ERVs) or other transposable elements (TEs) insert into an intron, the consequence on gene transcription can range from negligible to a complete ablation of normal transcripts. With the advance of sequencing technology, more and more insertionally polymorphic or private TE insertions are being identified in humans and mice, of which some could have a significant impact on host gene expression. Nevertheless, an efficient and low cost approach to prioritize their potential effect on gene transcription has been lacking. By building a computational model based on artificial neural networks (ANN), we demonstrate the feasibility of using machine-learning approaches to predict the likelihood that intronic ERV insertions will have major effects on gene transcription, focusing on the two ERV families, namely Intracisternal A-type Particle (IAP) and Early Transposon (ETn)/MusD elements, which are responsible for the majority of ERV-induced mutations in mice. We trained the ANN model using properties associated with these ERVs known to cause germ-line mutations (positive cases) and properties associated with likely neutral ERVs of the same families (negative cases), and derived a set of prediction plots that can visualize the likelihood of affecting gene transcription by ERV insertions. Our results show a highly reliable prediction power of our model, and offer a potential approach to computationally screen for other types of TE insertions that may affect gene transcription or even cause disease. PMID- 23936535 TI - Slx8 removes Pli1-dependent protein-SUMO conjugates including SUMOylated topoisomerase I to promote genome stability. AB - The SUMO-dependent ubiquitin ligase Slx8 plays key roles in promoting genome stability, including the processing of trapped Topoisomerase I (Top1) cleavage complexes and removal of toxic SUMO conjugates. We show that it is the latter function that constitutes Slx8's primary role in fission yeast. The SUMO conjugates in question are formed by the SUMO ligase Pli1, which is necessary for limiting spontaneous homologous recombination when Top1 is present. Surprisingly there is no requirement for Pli1 to limit recombination in the vicinity of a replication fork blocked at the programmed barrier RTS1. Notably, once committed to Pli1-mediated SUMOylation Slx8 becomes essential for genotoxin resistance, limiting both spontaneous and RTS1 induced recombination, and promoting normal chromosome segregation. We show that Slx8 removes Pli1-dependent Top1-SUMO conjugates and in doing so helps to constrain recombination at RTS1. Overall our data highlight how SUMOylation and SUMO-dependent ubiquitylation by the Pli1-Slx8 axis contribute in different ways to maintain genome stability. PMID- 23936537 TI - A method for 3D immunostaining and optical imaging of the mouse brain demonstrated in neural progenitor cells. AB - It is important to understand changes in cell distribution that occur as a part of disease progression. This is typically achieved using standard sectioning and immunostaining, however, many structures and cell distribution patterns are not readily appreciated in two-dimensions, including the distribution of neural stem and progenitor cells in the mouse forebrain. Three-dimensional immunostaining in the mouse brain has been hampered by poor penetration. For this reason, we have developed a method that allows for entire hemispheres of the mouse brain to be stained using commercially available antibodies. Brains stained for glial fibrillary acidic protein, doublecortin and nestin were imaged in three dimensions using optical projection tomography and serial two-photon tomography. This staining method is simple, using a combination of heat, time and specimen preparation procedures readily available, so that it can be easily implemented without the need for specialized equipment, making it accessible to most laboratories. PMID- 23936538 TI - Characterization of the molecular interplay between Moraxella catarrhalis and human respiratory tract epithelial cells. AB - Moraxella catarrhalis is a mucosal pathogen that causes childhood otitis media and exacerbations of chronic obstructive pulmonary disease in adults. During the course of infection, M. catarrhalis needs to adhere to epithelial cells of different host niches such as the nasopharynx and lungs, and consequently, efficient adhesion to epithelial cells is considered an important virulence trait of M. catarrhalis. By using Tn-seq, a genome-wide negative selection screenings technology, we identified 15 genes potentially required for adherence of M. catarrhalis BBH18 to pharyngeal epithelial Detroit 562 and lung epithelial A549 cells. Validation with directed deletion mutants confirmed the importance of aroA (3-phosphoshikimate 1-carboxyvinyl-transferase), ecnAB (entericidin EcnAB), lgt1 (glucosyltransferase), and MCR_1483 (outer membrane lipoprotein) for cellular adherence, with DeltaMCR_1483 being most severely attenuated in adherence to both cell lines. Expression profiling of M. catarrhalis BBH18 during adherence to Detroit 562 cells showed increased expression of 34 genes in cell-attached versus planktonic bacteria, among which ABC transporters for molybdate and sulfate, while reduced expression of 16 genes was observed. Notably, neither the newly identified genes affecting adhesion nor known adhesion genes were differentially expressed during adhesion, but appeared to be constitutively expressed at a high level. Profiling of the transcriptional response of Detroit 562 cells upon adherence of M. catarrhalis BBH18 showed induction of a panel of pro-inflammatory genes as well as genes involved in the prevention of damage of the epithelial barrier. In conclusion, this study provides new insight into the molecular interplay between M. catarrhalis and host epithelial cells during the process of adherence. PMID- 23936539 TI - Mutation of the LXCXE binding cleft of pRb facilitates transformation by ras in vitro but does not promote tumorigenesis in vivo. AB - BACKGROUND: The Retinoblastoma protein (pRB) is a key tumor suppressor that is functionally inactivated in most cancers. pRB regulates the cell division cycle and cell cycle exit through protein-protein interactions mediated by its multiple binding interfaces. The LXCXE binding cleft region of pRB mediates interactions with cellular proteins that have chromatin regulatory functions. Chromatin regulation mediated by pRB is required for a stress responsive cell cycle arrest, including oncogene induced senescence. The in vivo role of chromatin regulation by pRB during senescence, and its relevance to cancer is not clear. METHODOLOGY/PRINCIPAL FINDINGS: Using gene-targeted mice, uniquely defective for pRB mediated chromatin regulation, we investigated its role during transformation and tumor progression in response to activation of oncogenic ras. We report that the pRB(?L) mutation confers susceptibility to escape from HrasV12 induced senescence and allows transformation in vitro, although these cells possess high levels of DNA damage. Intriguingly, LSL-Kras, Rb1 (?L/?L) mice show delayed lung tumor formation compared to controls. This is likely due to the increased apoptosis seen in the early hyperplastic lesions shortly following ras activation that inhibits tumor progression. Furthermore, DMBA treatment to induce sporadic ras mutations in other tissues also failed to reveal greater susceptibility to cancer in Rb1 (?L/?L) mice. CONCLUSIONS/SIGNIFICANCE: Our data suggests that chromatin regulation by pRB can function to limit proliferation, but its loss fails to contribute to cancer susceptibility in ras driven tumor models because of elevated levels of DNA damage and apoptosis. PMID- 23936540 TI - Erg channel is critical in controlling cell volume during cell cycle in embryonic stem cells. AB - The cell cycle progression in mouse embryonic stem cells (mESCs) is controlled by ion fluxes that alter cell volume [1]. This suggests that ion fluxes might control dynamic changes in morphology over the cell cycle, such as rounding up of the cell at mitosis. However, specific channels regulating such dynamic changes and the possible interactions with actomyosin complex have not been clearly identified. Following RNAseq transcriptome analysis of cell cycle sorted mESCs, we found that expression of the K(+) ion channel Erg1 peaked in G1 cell cycle phase, which was confirmed by immunostaining. Inhibition of Erg channel activity caused loss of G1 phase cells via non-apoptotic cell death. Cells first lost the ability of membrane blebbing, a typical feature of cultured embryonic stem cells. Continued Erg inhibition further increased cell volume and the cell eventually ruptured. In addition, atomic force measurements on live cells revealed a decreased cortical stiffness after treatment, suggesting alterations in actomyosin organization. When the intracellular osmotic pressure was experimentally decreased by hypertonic solution or block of K(+) ion import via the Na, K-ATPase, cell viability was restored and cells acquired normal volume and blebbing activity. Our results suggest that Erg channels have a critical function in K(+) ion homeostasis of mESCs over the cell cycle, and that cell death following Erg inhibition is a consequence of the inability to regulate cell volume. PMID- 23936541 TI - Levels of murine, but not human, CXCL13 are greatly elevated in NOD-SCID mice bearing the AIDS-associated Burkitt lymphoma cell line, 2F7. AB - Currently, few rodent models of AIDS-associated non-Hodgkin's lymphoma (AIDS-NHL) exist. In these studies, a novel mouse/human xenograft model of AIDS-associated Burkitt lymphoma (AIDS-BL) was created by injecting cells of the human AIDS-BL cell line, 2F7, intraperitoneally into NOD-SCID mice. Mice developed tumors in the peritoneal cavity, with metastases to the spleen, thymus, and mesenteric lymph nodes. Expression of the chemokine receptor, CXCR5, was greatly elevated in vivo on BL tumor cells in this model, as shown by flow cytometry. CXCL13 is the ligand for CXCR5, and serum and ascites levels of murine, but not human, CXCL13 showed a striking elevation in tumor-bearing mice, with levels as high as 200,000 pg/ml in ascites, as measured by ELISA. As shown by immunohistochemistry, murine CXCL13 was associated with macrophage-like tumor-infiltrating cells that appeared to be histiocytes. Blocking CXCR5 on 2F7 cells with neutralizing antibodies prior to injection into the mice substantially delayed tumor formation. The marked elevations in tumor cell CXCR5 expression and in murine CXCL13 levels seen in the model may potentially identify an important link between tumor-interacting histiocytes and tumor cells in AIDS-BL. These results also identify CXCL13 as a potential biomarker for this disease, which is consistent with previous studies showing that serum levels of CXCL13 were elevated in human subjects who developed AIDS-lymphoma. This mouse model may be useful for future studies on the interactions of the innate immune system and AIDS-BL tumor cells, as well as for the assessment of potential tumor biomarkers for this disease. PMID- 23936542 TI - Elevated levels of procoagulant plasma microvesicles in dialysis patients. AB - Cardiovascular (CV) death remains the largest cause of mortality in dialysis patients, unexplained by traditional risk factors. Endothelial microvesicles (EMVs) are elevated in patients with traditional CV risk factors and acute coronary syndromes while platelet MVs (PMVs) are associated with atherosclerotic disease states. This study compared relative concentrations of circulating MVs from endothelial cells and platelets in two groups of dialysis patients and matched controls and investigated their relative thromboembolic risk. MVs were isolated from the blood of 20 haemodialysis (HD), 17 peritoneal dialysis (PD) patients and 20 matched controls. Relative concentrations of EMVs (CD144(+ ve)) and PMVs (CD42b(+ ve)) were measured by Western blotting and total MV concentrations were measured using nanoparticle-tracking analysis. The ability to support thrombin generation was measured by reconstituting the MVs in normal plasma, using the Continuous Automated Thrombogram assay triggered with 1uM tissue factor. The total concentration of MVs as well as the measured sub-types was higher in both patient groups compared to controls (p<0.05). MVs from HD and PD patients were able to generate more thrombin than the controls, with higher peak thrombin, and endogenous thrombin potential levels (p<0.02). However there were no differences in either the relative quantity or activity of MVs between the two patient groups (p>0.3). Dialysis patients have higher levels of circulating procoagulant MVs than healthy controls. This may represent a novel and potentially modifiable mediator or predictor of occlusive cardiovascular events in these patients. PMID- 23936543 TI - Self-sustained motor activity triggered by interlimb reflexes in chronic spinal cord injury, evidence of functional ascending propriospinal pathways. AB - The loss or reduction of supraspinal inputs after spinal cord injury provides a unique opportunity to examine the plasticity of neural pathways within the spinal cord. In a series of nine experiments on a patient, quadriplegic due to spinal cord injury, we investigated interlimb reflexes and self-sustained activity in completely paralyzed and paretic muscles due to a disinhibited propriospinal pathway. Electrical stimuli were delivered over the left common peroneal nerve at the fibular head as single stimuli or in trains at 2-100 Hz lasting 1 s. Single stimuli produced a robust interlimb reflex twitch in the contralateral thumb at a mean latency 69 ms, but no activity in other muscles. With stimulus trains the thumb twitch occurred at variable subharmonics of the stimulus rate, and strong self-sustained activity developed in the contralateral wrist extensors, outlasting both the stimuli and the thumb reflex by up to 20 s. Similar behavior was recorded in the ipsilateral wrist extensors and quadriceps femoris of both legs, but not in the contralateral thenar or peroneal muscles. The patient could not terminate the self-sustained activity voluntarily, but it was abolished on the left by attempted contractions of the paralyzed thumb muscles of the right hand. These responses depend on the functional integrity of an ascending propriospinal pathway, and highlight the plasticity of spinal circuitry following spinal cord injury. They emphasize the potential for pathways below the level of injury to generate movement, and the role of self-sustained reflex activity in the sequelae of spinal cord injury. PMID- 23936544 TI - Induction of TGF-beta1 synthesis by macrophages in response to apoptotic cells requires activation of the scavenger receptor CD36. AB - BACKGROUND/OBJECTIVE: Phosphatidylserine (PS) exposed on apoptotic cells has been shown to stimulate production of transforming growth factor-beta (TGF-beta) and promote anti-inflammatory responses. However, the PS receptor(s) responsible for this induction has not been clearly determined. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, using RAWTbetaRII cells in which a truncated dominant negative TGF-beta receptor II was stably transfected in order to avoid auto feedback induction of TGF-beta, we show that TGF-beta1 synthesis is initiated via activation of the scavenger receptor, CD36. The response requires exposure of PS on the apoptotic cell surface and was absent in macrophages lacking CD36. Direct activation of CD36 with an anti-CD36 antibody initiated TGF-beta1 production, and signaling pathways involving both Lyn kinase and ERK1/2 were shown to participate in CD36-driven TGF-beta1 expression. CONCLUSION/SIGNIFICANCE: Since CD36 has been previously implicated in activation of secreted latent TGF-beta, the present study indicates its role in the multiple steps to generation of this important biological mediator. PMID- 23936546 TI - Persistent racial disparities in survival among u.s. Adults with hepatocellular carcinoma after liver transplantation: the paradox of all-cause and cause specific mortality. PMID- 23936545 TI - Akonni TruTip((r)) and Qiagen((r)) methods for extraction of fetal circulating DNA--evaluation by real-time and digital PCR. AB - Due to the low percentage of fetal DNA present in maternal plasma (< 10%) during early gestation, efficient extraction processes are required for successful downstream detection applications in non-invasive prenatal diagnostic testing. In this study, two extraction methods using similar chemistries but different workflows were compared for isolation efficiency and percent fetal DNA recovery. The Akonni Biosystems TruTip technology uses a binding matrix embedded in a pipette tip; the Circulating Nucleic Acids Kit from Qiagen employs a spin column approach. The TruTip method adds an extra step to decrease the recovery of DNA fragments larger than 600 bp from the sample to yield an overall higher percentage of smaller molecular weight DNA, effectively enriching for fetal DNA. In this evaluation, three separate extraction comparison studies were performed- a dilution series of fragmented DNA in plasma, a set of clinical maternal samples, and a blood collection tube time point study of maternal samples. Both extraction methods were found to efficiently extract small fragment DNA from large volumes of plasma. In the amended samples, the TruTip extraction method was ~15% less efficient with overall DNA recovery, but yielded an 87% increase in % fetal DNA relative to the Qiagen method. The average percent increase of fetal DNA of TruTip extracted samples compared to the Qiagen method was 55% for all sets of blinded clinical samples. A study comparing extraction efficiencies from whole blood samples incubated up to 48 hours prior to processing into plasma resulted in more consistent % fetal DNA recoveries using TruTip. The extracted products were tested on two detection platforms, quantitative real-time PCR and droplet digital PCR, and yielded similar results for both extraction methods. PMID- 23936547 TI - Characteristics and outcomes of adenosquamous carcinoma of the pancreas. AB - BACKGROUND: Adenosquamous carcinoma of the pancreas (ASCAP) is a rare histologic type of pancreatic carcinoma that constitutes 1% to 4% of all pancreatic exocrine malignancies. It has a clinical presentation similar to that of adenocarcinoma of the pancreas (ACP), but may have a worse overall prognosis, with most patients surviving for less than 2 years. METHODS: This was an institutional, retrospective, cohort analysis of 237 patients who underwent resection of pancreatic cancer with curative intent. RESULTS: Of the 237 cases examined, we identified 7 (2.9%) with histologically confirmed ASCAP. Demographics, comorbidities, risk factors, presenting symptoms, survival data, tumor characteristics, and types of treatment for each patient were included in the analysis. Risk factors for development of ASCAP were not conclusive. Although human papilloma virus (HPV) has been implicated in other squamous cell cancers, in our cohort, its involvement in ASCAP was 0%. Presurgical fine-needle aspiration failed to identify the invasive squamous cell component in all cases. In this cohort analysis, overall survival ranged from 3 to 25 months, with 2 patients surviving more than 20 months after surgical resection. With a median follow-up of 2.9 years, our data demonstrate a trend to worse median overall survival for ASCAP than for ACP (8.2 vs. 20.4 months; P = .23), with a limited number of long-term survivors. CONCLUSIONS: Although recommended, adjuvant treatment was inconsistently provided for patients in this ASCAP cohort. Published data show variability in overall survival, but our findings support that surgical resection is one of the few options for control of this rare, poorly understood pancreatic malignancy. Further research is necessary to define risk factors and adjuvant and neoadjuvant treatments, to help improve patient outcomes. PMID- 23936548 TI - Above-Label Doses of Octreotide-LAR in Patients With Metastatic Small Intestinal Carcinoid Tumors. AB - BACKGROUND: Octreotide LAR is indicated for treatment of malignant carcinoid syndrome and has been studied at doses of 10 to 30 mg intramuscularly every 4 weeks. In clinical practice, higher doses are often prescribed for patients who experience refractory carcinoid syndrome (flushing and/or diarrhea) or tumor growth while on the maximum label-recommended dose. METHODS: We performed a retrospective, longitudinal review of octreotide LAR administration at a tertiary institution to determine the frequency of above-label dosing and outcomes. RESULTS: Three hundred thirty-eight patients were considered evaluable, among whom 100 (30%) underwent at least 1 increase in dose or frequency of octreotide LAR above the standard label dose. The most common maximum doses were 40 mg every 4 weeks (n = 37 patients), 60 mg every 4 weeks (n = 34), and 30 mg every 3 weeks (n = 18). The indications for dose increase were worsening carcinoid syndrome (n = 60), radiographic progression (n = 33), and rising urine 5-HIAA (n = 6). Of the patients whose doses were increased for refractory carcinoid syndrome, 62% (n = 34) experienced improvement in diarrhea, and 56% (n = 28) experienced improvement in flushing. CONCLUSIONS: In conclusion, octreotide LAR is commonly prescribed in doses or schedules above the recommended dose and frequency. Patients with refractory carcinoid syndrome appear to experience a clinical benefit from this change. Prospective data may be used to further evaluate this strategy. PMID- 23936549 TI - A 40-year-old woman with locally advanced rectal cancer and a solitary liver metastasis. PMID- 23936550 TI - An extremely rare case of pancreatic cancer presenting with leptomeningeal carcinomatosis and synchronous intraparenchymal brain metastasis. PMID- 23936553 TI - Upcoming articles. PMID- 23936551 TI - Optimal chemotherapy dosing in a bilateral lower extremities amputee with metastatic pancreatic adenocarcinoma. PMID- 23936557 TI - NTDs in the heart of darkness: the Democratic Republic of Congo's unknown burden of neglected tropical diseases. PMID- 23936558 TI - Efficacy and safety of anthelmintics tested against Taenia solium cysticercosis in pigs. AB - Porcine cysticercosis, an infection caused by Taenia solium metacestodes, is continuously being reported in low-income countries of Latin America, Asia, and sub-Saharan Africa. The disease was declared eradicable by the International Task Force for Diseases Eradication (ITFDE) in 1993, and it is listed among the 17 WHO Neglected Tropical Diseases and Neglected Zoonoses that are potentially eradicable. In view of that, WHO has proposed a step-wise approach to its elimination, including chemotherapy of infected pigs. Different drugs have been tested on porcine cysticercosis with varying efficacies. These include flubendazole, fenbendazole, albendazole, albendazole sulphoxide, oxfendazole, praziquantel, and nitazoxanide. This review summarises available information on the efficacies and adverse effects shown by these drugs in pigs. Oxfendazole has shown to be effective for the control of porcine cysticercosis; however, it needs to be integrated with other control approaches. There is a need for standardised guidelines for evaluating the efficacy of anthelmintics against porcine cysticercosis, and more efficacy studies are needed since the conclusions so far are based on a limited number of studies using few infected pigs. PMID- 23936559 TI - A very high infection intensity of Schistosoma mansoni in a Ugandan Lake Victoria Fishing Community is required for association with highly prevalent organ related morbidity. AB - BACKGROUND: In schistosomiasis control programmes using mass chemotherapy, epidemiological and morbidity aspects of the disease need to be studied so as to monitor the impact of treatment, and make recommendations accordingly. These aspects were examined in the community of Musoli village along Lake Victoria in Mayuge district, highly endemic for Schistosoma mansoni infection. METHODOLOGY AND PRINCIPAL FINDINGS: A cross sectional descriptive study was undertaken in a randomly selected sample of 217 females and 229 males, with a mean age of 26 years (SD +/- 16, range 7-76 years). The prevalence of S. mansoni was 88.6% (95% CI: 85.6-91.5). The geometric mean intensity (GMI) of S. mansoni was 236.2 (95% CI: 198.5-460.9) eggs per gram (epg) faeces. Males had significantly higher GMI (370.2 epg) than females (132.6 epg) and age was also significantly associated with intensity of infection. Levels of water contact activities significantly influenced intensity of infection and the highest intensity of infection was found among people involved in fishing. However, organomegaly was not significantly associated with S. mansoni except for very heavy infection (>2000 epg). Liver image patterns C and D indicative of fibrosis were found in only 2.2% and 0.2%, respectively. S. mansoni intensity of infection was associated with portal vein dilation and abnormal spleen length. Anaemia was observed in 36.4% of the participants but it was not associated with S. mansoni infection intensity. Considering growth in children as one of the morbidity indicators of schistosomiasis, intensity of S. mansoni was significantly associated with stunting. CONCLUSION: Although organ-related morbidity, with the exception of periportal fibrosis, and S. mansoni infections were highly prevalent, the two were only associated for individuals with very high infection intensities. These results contrast starkly with reports from Ugandan Lake Albert fishing communities in which periportal fibrosis is more prevalent. PMID- 23936561 TI - Linking environmental drivers to infectious diseases: the European environment and epidemiology network. PMID- 23936560 TI - TLR9 activation dampens the early inflammatory response to Paracoccidioides brasiliensis, impacting host survival. AB - BACKGROUND: Paracoccidioides brasiliensis causes paracoccidioidomycosis, one of the most prevalent systemic mycosis in Latin America. Thus, understanding the characteristics of the protective immune response to P. brasiliensis is of interest, as it may reveal targets for disease control. The initiation of the immune response relies on the activation of pattern recognition receptors, among which are TLRs. Both TLR2 and TLR4 have been implicated in the recognition of P. brasiliensis and regulation of the immune response. However, the role of TLR9 during the infection by this fungus remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: We used in vitro and in vivo models of infection by P. brasiliensis, comparing wild type and TLR9 deficient ((-/-)) mice, to assess the contribution of TLR9 on cytokine induction, phagocytosis and outcome of infection. We show that TLR9 recognizes either the yeast form or DNA from P. brasiliensis by stimulating the expression/production of pro-inflammatory cytokines by bone marrow derived macrophages, also increasing their phagocytic ability. We further show that TLR9 plays a protective role early after intravenous infection with P. brasiliensis, as infected TLR9(-/-) mice died at higher rate during the first 48 hours post infection than wild type mice. Moreover, TLR9(-/-) mice presented tissue damage and increased expression of several cytokines, such as TNF-alpha and IL-6. The increased pattern of cytokine expression was also observed during intraperitoneal infection of TLR9(-/-) mice, with enhanced recruitment of neutrophils. The phenotype of TLR9(-/-) hosts observed during the early stages of P. brasiliensis infection was reverted upon a transient, 48 hours post-infection, neutrophil depletion. CONCLUSIONS/SIGNIFICANCE: Our results suggest that TLR9 activation plays an early protective role against P. brasiliensis, by avoiding a deregulated type of inflammatory response associated to neutrophils that may lead to tissue damage. Thus modulation of TLR9 may be of interest to potentiate the host response against this pathogen. PMID- 23936562 TI - Immune response to snake envenoming and treatment with antivenom; complement activation, cytokine production and mast cell degranulation. AB - BACKGROUND: Snake bite is one of the most neglected public health issues in poor rural communities worldwide. In addition to the clinical effects of envenoming, treatment with antivenom frequently causes serious adverse reactions, including hypersensitivity reactions (including anaphylaxis) and pyrogenic reactions. We aimed to investigate the immune responses to Sri Lankan snake envenoming (predominantly by Russell's viper) and antivenom treatment. METHODOLOGY/PRINCIPAL FINDINGS: Plasma concentrations of Interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNFalpha), soluble TNF receptor I (sTNFRI), anaphylatoxins (C3a, C4a, C5a; markers of complement activation), mast cell tryptase (MCT), and histamine were measured in 120 Sri Lankan snakebite victims, both before and after treatment with antivenom. Immune mediator concentrations were correlated with envenoming features and the severity of antivenom-induced reactions including anaphylaxis. Envenoming was associated with complement activation and increased cytokine concentrations prior to antivenom administration, which correlated with non-specific systemic symptoms of envenoming but not with coagulopathy or neurotoxicity. Typical hypersensitivity reactions to antivenom occurred in 77/120 patients (64%), satisfying criteria for a diagnosis of anaphylaxis in 57/120 (48%). Pyrogenic reactions were observed in 32/120 patients (27%). All patients had further elevations in cytokine concentrations, but not complement activation, after the administration of antivenom, whether a reaction was noted to occur or not. Patients with anaphylaxis had significantly elevated concentrations of MCT and histamine. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that Sri Lankan snake envenoming is characterized by significant complement activation and release of inflammatory mediators. Antivenom treatment further enhances the release of inflammatory mediators in all patients, with anaphylactic reactions characterised by high levels of mast cell degranulation but not further complement activation. Anaphylaxis is probably triggered by non allergen-specific activation of mast cells and may be related to the quality of available antivenom preparations, as well as a priming effect from the immune response to the venom itself. PMID- 23936564 TI - Immunological profile of HTLV-1-infected patients associated with infectious or autoimmune dermatological disorders. AB - In the present study, the frequency, the activation and the cytokine and chemokine profile of HTLV-1 carriers with or without dermatological lesions were thoroughly described and compared. The results indicated that HTLV-1-infected patients with dermatological lesions have distinct frequency and activation status when compared to asymptomatic carriers. Alterations in the CD4(+)HLA DR(+), CD8(+) T cell, macrophage-like and NKT subsets as well as in the serum chemokines CCL5, CXCL8, CXCL9 and CXCL10 were observed in the HTLV-1-infected group with skin lesions. Additionally, HTLV-1 carriers with dermatological skin lesions showed more frequently high proviral load as compared to asymptomatic carriers. The elevated proviral load in HTLV-1 patients with infectious skin lesions correlated significantly with TNF-alpha/IL-10 ratio, while the same significant correlation was found for the IL-12/IL-10 ratio and the high proviral load in HTLV-1-infected patients with autoimmune skin lesions. All in all, these results suggest a distinct and unique immunological profile in the peripheral blood of HTLV-1-infected patients with skin disorders, and the different nature of skin lesion observed in these patients may be an outcome of a distinct unbalance of the systemic inflammatory response upon HTLV-1 infection. PMID- 23936563 TI - Spatially explicit modeling of schistosomiasis risk in eastern China based on a synthesis of epidemiological, environmental and intermediate host genetic data. AB - Schistosomiasis japonica is a major parasitic disease threatening millions of people in China. Though overall prevalence was greatly reduced during the second half of the past century, continued persistence in some areas and cases of re emergence in others remain major concerns. As many regions in China are approaching disease elimination, obtaining quantitative data on Schistosoma japonicum parasites is increasingly difficult. This study examines the distribution of schistosomiasis in eastern China, taking advantage of the fact that the single intermediate host serves as a major transmission bottleneck. Epidemiological, population-genetic and high-resolution ecological data are combined to construct a predictive model capable of estimating the probability that schistosomiasis occurs in a target area ("spatially explicit schistosomiasis risk"). Results show that intermediate host genetic parameters are correlated with the distribution of endemic disease areas, and that five explanatory variables--altitude, minimum temperature, annual precipitation, genetic distance, and haplotype diversity-discriminate between endemic and non-endemic zones. Model predictions are correlated with human infection rates observed at the county level. Visualization of the model indicates that the highest risks of disease occur in the Dongting and Poyang lake regions, as expected, as well as in some floodplain areas of the Yangtze River. High risk areas are interconnected, suggesting the complex hydrological interplay of Dongting and Poyang lakes with the Yangtze River may be important for maintaining schistosomiasis in eastern China. Results demonstrate the value of genetic parameters for risk modeling, and particularly for reducing model prediction error. The findings have important consequences both for understanding the determinants of the current distribution of S. japonicum infections, and for designing future schistosomiasis surveillance and control strategies. The results also highlight how genetic information on taxa that constitute bottlenecks to disease transmission can be of value for risk modeling. PMID- 23936565 TI - Dengue and other common causes of acute febrile illness in Asia: an active surveillance study in children. AB - BACKGROUND: Common causes of acute febrile illness in tropical countries have similar symptoms, which often mimic those of dengue. Accurate clinical diagnosis can be difficult without laboratory confirmation and disease burden is generally under-reported. Accurate, population-based, laboratory-confirmed incidence data on dengue and other causes of acute fever in dengue-endemic Asian countries are needed. METHODS AND PRINCIPAL FINDINGS: This prospective, multicenter, active fever surveillance, cohort study was conducted in selected centers in Indonesia, Malaysia, Philippines, Thailand and Vietnam to determine the incidence density of acute febrile episodes (>= 38 degrees C for >= 2 days) in 1,500 healthy children aged 2-14 years, followed for a mean 237 days. Causes of fever were assessed by testing acute and convalescent sera from febrile participants for dengue, chikungunya, hepatitis A, influenza A, leptospirosis, rickettsia, and Salmonella Typhi. Overall, 289 participants had acute fever, an incidence density of 33.6 per 100 person-years (95% CI: 30.0; 37.8); 57% were IgM-positive for at least one of these diseases. The most common causes of fever by IgM ELISA were chikungunya (in 35.0% of in febrile participants) and S. Typhi (in 29.4%). The overall incidence density of dengue per 100 person-years was 3.4 by nonstructural protein 1 (NS1) antigen positivity (95% CI: 2.4; 4.8) and 7.3 (95% CI: 5.7; 9.2) by serology. Dengue was diagnosed in 11.4% (95% CI: 8.0; 15.7) and 23.9% (95% CI: 19.1; 29.2) of febrile participants by NS1 positivity and serology, respectively. Of the febrile episodes not clinically diagnosed as dengue, 5.3% were dengue positive by NS1 antigen testing and 16.0% were dengue-positive by serology. CONCLUSIONS: During the study period, the most common identified causes of pediatric acute febrile illness among the seven tested for were chikungunya, S. Typhi and dengue. Not all dengue cases were clinically diagnosed; laboratory confirmation is essential to refine disease burden estimates. PMID- 23936566 TI - Polyethyleneimine mediated DNA transfection in schistosome parasites and regulation of the WNT signaling pathway by a dominant-negative SmMef2. AB - Schistosomiasis is a serious global problem and the second most devastating parasitic disease following malaria. Parasitic worms of the genus Schistosoma are the causative agents of schistosomiasis and infect more than 240 million people worldwide. The paucity of molecular tools to manipulate schistosome gene expression has made an understanding of genetic pathways in these parasites difficult, increasing the challenge of identifying new potential drugs for treatment. Here, we describe the use of a formulation of polyethyleneimine (PEI) as an alternative to electroporation for the efficacious transfection of genetic material into schistosome parasites. We show efficient expression of genes from a heterologous CMV promoter and from the schistosome Sm23 promoter. Using the schistosome myocyte enhancer factor 2 (SmMef2), a transcriptional activator critical for myogenesis and other developmental pathways, we describe the development of a dominant-negative form of the schistosome Mef2. Using this mutant, we provide evidence that SmMef2 may regulate genes in the WNT pathway. We also show that SmMef2 regulates its own expression levels. These data demonstrate the use of PEI to facilitate effective transfection of nucleic acids into schistosomes, aiding in the study of schistosome gene expression and regulation, and development of genetic tools for the characterization of molecular pathways in these parasites. PMID- 23936568 TI - The schistosome oesophageal gland: initiator of blood processing. AB - BACKGROUND: Although the ultrastructure of the schistosome esophageal gland was described >35 years ago, its role in the processing of ingested blood has never been established. The current study was prompted by our identification of MEG-4.1 expression in the gland and the observation of erythrocyte uncoating in the posterior esophagus. METHODOLOGY/PRINCIPAL FINDINGS: The salient feature of the posterior esophagus, characterized by confocal and electron microscopy, is the enormous increase in membrane surface area provided by the plate-like extensions and basal invaginations of the lining syncytium, with unique crystalloid vesicles releasing their contents between the plates. The feeding process was shown by video microscopy to be divided into two phases, blood first accumulating in the anterior lumen before passing as a bolus to the posterior. There it streamed around a plug of material revealed by confocal microscopy as tethered leucocytes. These were present in far larger numbers than predicted from the volume of the lumen, and in varying states of damage and destruction. Intact erythrocytes were detected in the anterior esophagus but not observed thereafter, implying that their lysis occurred rapidly as they enter the posterior. Two further genes, MEGs 4.2 and 14, were shown to be expressed exclusively in the esophageal gland. Bioinformatics predicted that MEGs 4.1 and 4.2 possessed a common hydrophobic region with a shared motif, while antibodies to SjMEG-4.1 showed it was bound to leucocytes in the esophageal lumen. It was also predicted that MEGs 4.1 and 14 were heavily O-glycosylated and this was confirmed for the former by 2D electrophoresis and Western blotting. CONCLUSIONS/SIGNIFICANCE: The esophageal gland and its products play a central role in the processing of ingested blood. The binding of host antibodies in the esophageal lumen shows that some constituents are antibody targets and could provide a new source of vaccine candidates. PMID- 23936567 TI - Whole-organ isolation approach as a basis for tissue-specific analyses in Schistosoma mansoni. AB - BACKGROUND: Schistosomiasis is one of the most important parasitic diseases worldwide, second only to malaria. Schistosomes exhibit an exceptional reproductive biology since the sexual maturation of the female, which includes the differentiation of the reproductive organs, is controlled by pairing. Pathogenicity originates from eggs, which cause severe inflammation in their hosts. Elucidation of processes contributing to female maturation is not only of interest to basic science but also considering novel concepts combating schistosomiasis. METHODOLOGY/PRINCIPAL FINDINGS: To get direct access to the reproductive organs, we established a novel protocol using a combined detergent/protease-treatment removing the tegument and the musculature of adult Schistosoma mansoni. All steps were monitored by scanning electron microscopy (SEM) and bright-field microscopy (BF). We focused on the gonads of adult schistosomes and demonstrated that isolated and purified testes and ovaries can be used for morphological and structural studies as well as sources for RNA and protein of sufficient amounts for subsequent analyses such as RT-PCR and immunoblotting. To this end, first exemplary evidence was obtained for tissue specific transcription within the gonads (axonemal dynein intermediate chain gene SmAxDynIC; aquaporin gene SmAQP) as well as for post-transcriptional regulation (SmAQP). CONCLUSIONS/SIGNIFICANCE: The presented method provides a new way of getting access to tissue-specific material of S. mansoni. With regard to many still unanswered questions of schistosome biology, such as elucidating the molecular processes involved in schistosome reproduction, this protocol provides opportunities for, e.g., sub-transcriptomics and sub-proteomics at the organ level. This will promote the characterisation of gene-expression profiles, or more specifically to complete knowledge of signalling pathways contributing to differentiation processes, so discovering involved molecules that may represent potential targets for novel intervention strategies. Furthermore, gonads and other tissues are a basis for cell isolation, opening new perspectives for establishing cell lines, one of the tools desperately needed in the post-genomic era. PMID- 23936569 TI - CD4+ Th17 cells discriminate clinical types and constitute a third subset of non Th1, Non Th2 T cells in human leprosy. AB - BACKGROUND: Patients with localized tuberculoid and generalized lepromatous leprosy show respectively Th1 and Th2 cytokine profile. Additionally, other patients in both types of leprosy also show a non discriminating Th0 cytokine profile with both interferon-gamma and IL-4. The present study investigated the role of Th17 cells which appear to be a distinct subtype of Th subtypes in 19 tuberculoid and 18 lepromatous leprosy patients. Five healthy subjects with long term exposure to infection and 4 skin biopsies from healthy subjects undergoing cosmetic surgery were used as controls. METHODOLOGY/PRINCIPLE FINDINGS: An array of Th17 related primers for cytokines, chemokines and transcription factors was used in real time reverse transcribed PCR to evaluate gene expression, ELISA for cytokine secretion in the supernatants of antigen stimulated PBMC cultures and flow cytometry for establishing the phenotype of the IL-17, IL-21 producing cells. CONCLUSIONS/SIGNIFICANCE: IL-17 isoforms showed significantly higher expression and release in supernatants of antigen stimulated PBMC cultures and dermal lesions of healthy contacts and tuberculoid leprosy as compared to lepromatous leprosy (p<0.003). This was further confirmed by Th17 associated transcription factor RORC, cytokines IL-21, IL-22, and IL-23, chemokines MMP13, CCL20, CCL22. Of interest was the association of IL-23R and not IL-6R with IL 17(+) cells. The Th17 cells were CD4(+) CCR6(+) confirming their effector cell lineage. Polarized Th1 cytokines were seen in 3/7 tuberculoid and Th2 cytokines in 5/10 lepromatous leprosy patients. Of importance was the higher association of Th17 pathway factors with the non-polarized Th0 types as compared to the polarized Th1 and Th2 (p<0.01). Our study draws attention to a third type of effector Th cell that may play a role in leprosy. PMID- 23936570 TI - Dried-blood spots: a cost-effective field method for the detection of Chikungunya virus circulation in remote areas. AB - BACKGROUND: In 2005, there were outbreaks of febrile polyarthritis due to Chikungunya virus (CHIKV) in the Comoros Islands. CHIKV then spread to other islands in the Indian Ocean: La Reunion, Mauritius, Seychelles and Madagascar. These outbreaks revealed the lack of surveillance and preparedness of Madagascar and other countries. Thus, it was decided in 2007 to establish a syndrome-based surveillance network to monitor dengue-like illness. OBJECTIVE: This study aims to evaluate the use of capillary blood samples blotted on filter papers for molecular diagnosis of CHIKV infection. Venous blood samples can be difficult to obtain and the shipment of serum in appropriate temperature conditions is too costly for most developing countries. METHODOLOGY AND PRINCIPAL FINDINGS: Venous blood and dried-blood blotted on filter paper (DBFP) were collected during the last CHIKV outbreak in Madagascar (2010) and as part of our routine surveillance of dengue-like illness. All samples were tested by real-time RT-PCR and results with serum and DBFP samples were compared for each patient. The sensitivity and specificity of tests performed with DBFP, relative to those with venous samples (defined as 100%) were 93.1% (95% CI:[84.7-97.7]) and 94.4% (95% CI:[88.3-97.7]), respectively. The Kappa coefficient 0.87 (95% CI:[0.80-0.94]) was excellent. CONCLUSION: This study shows that DBFP specimens can be used as a cost-effective alternative sampling method for the surveillance and monitoring of CHIKV circulation and emergence in developing countries, and probably also for other arboviruses. The loss of sensitivity is insignificant and involved a very small number of patients, all with low viral loads. Whether viruses can be isolated from dried blood spots remains to be determined. PMID- 23936571 TI - Validation of a remote sensing model to identify Simulium damnosum s.l. breeding sites in Sub-Saharan Africa. AB - BACKGROUND: Recently, most onchocerciasis control programs have begun to focus on elimination. Developing an effective elimination strategy relies upon accurately mapping the extent of endemic foci. In areas of Africa that suffer from a lack of infrastructure and/or political instability, developing such accurate maps has been difficult. Onchocerciasis foci are localized near breeding sites for the black fly vectors of the infection. The goal of this study was to conduct ground validation studies to evaluate the sensitivity and specificity of a remote sensing model developed to predict S. damnosum s.l. breeding sites. METHODOLOGY/PRINCIPAL FINDINGS: Remote sensing images from Togo were analyzed to identify areas containing signature characteristics of S. damnosum s.l. breeding habitat. All 30 sites with the spectral signature were found to contain S. damnosum larvae, while 0/52 other sites judged as likely to contain larvae were found to contain larvae. The model was then used to predict breeding sites in Northern Uganda. This area is hyper-endemic for onchocerciasis, but political instability had precluded mass distribution of ivermectin until 2009. Ground validation revealed that 23/25 sites with the signature contained S. damnosum larvae, while 8/10 sites examined lacking the signature were larvae free. Sites predicted to have larvae contained significantly more larvae than those that lacked the signature. CONCLUSIONS/SIGNIFICANCE: This study suggests that a signature extracted from remote sensing images may be used to predict the location of S. damnosum s.l. breeding sites with a high degree of accuracy. This method should be of assistance in predicting communities at risk for onchocerciasis in areas of Africa where ground-based epidemiological surveys are difficult to implement. PMID- 23936572 TI - Chikungunya virus infection results in higher and persistent viral replication in aged rhesus macaques due to defects in anti-viral immunity. AB - Chikungunya virus (CHIKV) is a re-emerging mosquito-borne Alphavirus that causes a clinical disease involving fever, myalgia, nausea and rash. The distinguishing feature of CHIKV infection is the severe debilitating poly-arthralgia that may persist for several months after viral clearance. Since its re-emergence in 2004, CHIKV has spread from the Indian Ocean region to new locations including metropolitan Europe, Japan, and even the United States. The risk of importing CHIKV to new areas of the world is increasing due to high levels of viremia in infected individuals as well as the recent adaptation of the virus to the mosquito species Aedes albopictus. CHIKV re-emergence is also associated with new clinical complications including severe morbidity and, for the first time, mortality. In this study, we characterized disease progression and host immune responses in adult and aged Rhesus macaques infected with either the recent CHIKV outbreak strain La Reunion (LR) or the West African strain 37997. Our results indicate that following intravenous infection and regardless of the virus used, Rhesus macaques become viremic between days 1-5 post infection. While adult animals are able to control viral infection, aged animals show persistent virus in the spleen. Virus-specific T cell responses in the aged animals were reduced compared to adult animals and the B cell responses were also delayed and reduced in aged animals. Interestingly, regardless of age, T cell and antibody responses were more robust in animals infected with LR compared to 37997 CHIKV strain. Taken together these data suggest that the reduced immune responses in the aged animals promotes long-term virus persistence in CHIKV-LR infected Rhesus monkeys. PMID- 23936573 TI - Association between ocular bacterial carriage and follicular trachoma following mass azithromycin distribution in The Gambia. AB - BACKGROUND: Trachoma, caused by ocular Chlamydia trachomatis infection, is the leading infectious cause of blindness, but its prevalence is now falling in many countries. As the prevalence falls, an increasing proportion of individuals with clinical signs of follicular trachoma (TF) is not infected with C. trachomatis. A recent study in Tanzania suggested that other bacteria may play a role in the persistence of these clinical signs. METHODOLOGY/PRINCIPAL FINDINGS: We examined associations between clinical signs of TF and ocular colonization with four pathogens commonly found in the nasopharnyx, three years after the initiation of mass azithromycin distribution. Children aged 0 to 5 years were randomly selected from 16 Gambian communities. Both eyes of each child were examined and graded for trachoma according to the World Health Organization (WHO) simplified system. Two swabs were taken from the right eye: one swab was processed for polymerase chain reaction (PCR) using the Amplicor test for detection of C. trachomatis DNA and the second swab was processed by routine bacteriology to assay for the presence of viable Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Moraxella catarrhalis. Prevalence of TF was 6.2% (96/1538) while prevalence of ocular C. trachomatis infection was 1.0% (16/1538). After adjustment, increased odds of TF were observed in the presence of C. trachomatis (OR = 10.4, 95%CI 1.32-81.2, p = 0.03), S. pneumoniae (OR = 2.14, 95%CI 1.03-4.44, p = 0.04) and H. influenzae (OR = 4.72, 95% CI 1.53-14.5, p = 0.01). CONCLUSIONS/SIGNIFICANCE: Clinical signs of TF can persist in communities even when ocular C. trachomatis infection has been controlled through mass azithromycin distribution. In these settings, TF may be associated with ocular colonization with bacteria commonly carried in the nasopharnyx. This may affect the interpretation of impact surveys and the determinations of thresholds for discontinuing mass drug administration. PMID- 23936574 TI - TNF-alpha and CD8+ T cells mediate the beneficial effects of nitric oxide synthase-2 deficiency in pulmonary paracoccidioidomycosis. AB - BACKGROUND: Nitric oxide (NO), a key antimicrobial molecule, was previously shown to exert a dual role in paracoccidioidomycosis, an endemic fungal infection in Latin America. In the intravenous and peritoneal models of infection, NO production was associated with efficient fungal clearance but also with non organized granulomatous lesions. Because paracoccidioidomycosis is a pulmonary infection, we aimed to characterize the role of NO in a pulmonary model of infection. METHODOLOGY/PRINCIPAL FINDINGS: C57Bl/6 wild type (WT) and iNOS(-/-) mice were i.t. infected with 1*10(6) Paracoccidioides brasiliensis yeasts and studied at several post-infection periods. Unexpectedly, at week 2 of infection, iNOS(-/-) mice showed decreased pulmonary fungal burdens associated with an M2 like macrophage profile, which expressed high levels of TGF-beta impaired ability of ingesting fungal cells. This early decreased fungal loads were concomitant with increased DTH reactions, enhanced TNF-alpha synthesis and intense migration of activated macrophages, CD4(+) and CD8(+) T cells into the lungs. By week 10, iNOS(-/-) mice showed increased fungal burdens circumscribed, however, by compact granulomas containing elevated numbers of activated CD4(+) T cells. Importantly, the enhanced immunological reactivity of iNOS(-/-) mice resulted in decreased mortality rates. In both mouse strains, depletion of TNF-alpha led to non organized lesions and excessive influx of inflammatory cells into the lungs, but only the iNOS(-/-) mice showed increased mortality rates. In addition, depletion of CD8(+) cells abolished the increased migration of inflammatory cells and decreased the number of TNF-alpha and IFN-gamma CD4(+) and CD8(+) T cells into the lungs of iNOS(-/-) mice. CONCLUSIONS/SIGNIFICANCE: Our study demonstrated that NO plays a deleterious role in pulmonary paracoccidioidomycosis due to its suppressive action on TNF-alpha production, T cell immunity and organization of lesions resulting in precocious mortality of mice. It was also revealed that uncontrolled fungal growth can be overcome by an efficient immune response. PMID- 23936575 TI - Identification of immunogenic Salmonella enterica serotype Typhi antigens expressed in chronic biliary carriers of S. Typhi in Kathmandu, Nepal. AB - BACKGROUND: Salmonella enterica serotype Typhi can colonize and persist in the biliary tract of infected individuals, resulting in a state of asymptomatic chronic carriage. Chronic carriers may act as persistent reservoirs of infection within a community and may introduce infection to susceptible individuals and new communities. Little is known about the interaction between the host and pathogen in the biliary tract of chronic carriers, and there is currently no reliable diagnostic assay to identify asymptomatic S. Typhi carriage. METHODOLOGY/PRINCIPAL FINDINGS: To study host-pathogen interactions in the biliary tract during S. Typhi carriage, we applied an immunoscreening technique called in vivo-induced antigen technology (IVIAT), to identify potential biomarkers unique to carriers. IVIAT identifies humorally immunogenic bacterial antigens expressed uniquely in the in vivo environment, and we hypothesized that S. Typhi surviving in the biliary tract of humans may express a distinct antigenic profile. Thirteen S. Typhi antigens that were immunoreactive in carriers, but not in healthy individuals from a typhoid endemic area, were identified. The identified antigens included a number of putative membrane proteins, lipoproteins, and hemolysin-related proteins. YncE (STY1479), an uncharacterized protein with an ATP-binding motif, gave prominent responses in our screen. The response to YncE in patients whose biliary tract contained S. Typhi was compared to responses in patients whose biliary tract did not contain S. Typhi, patients with acute typhoid fever, and healthy controls residing in a typhoid endemic area. Seven of 10 (70%) chronic carriers, 0 of 8 bile culture negative controls (0%), 0 of 8 healthy Bangladeshis (0%), and 1 of 8 (12.5%) Bangladeshis with acute typhoid fever had detectable anti-YncE IgG in blood. IgA responses were also present. CONCLUSIONS/SIGNIFICANCE: Further evaluation of YncE and other antigens identified by IVIAT could lead to the development of improved diagnostic assays to identify asymptomatic S. Typhi carriers. PMID- 23936576 TI - Antibody prevalence and factors associated with exposure to Orientia tsutsugamushi in different aboriginal subgroups in West Malaysia. AB - BACKGROUND: Limited data is available on the current status of scrub typhus infection in the aboriginal population in Malaysia. This study was aimed to provide recent data on the degree of exposure of 280 individuals from seven aboriginal subgroups to Orientia tsutsugamushi (causative agent of scrub typhus) in West Malaysia. The environment, socioeconomic and behavioural risk factors associated with the disease were also investigated. METHODS/FINDINGS: The antibody prevalence to O. tsutsugamushi ranged from 0 to 36.4% in seven subgroups, with high prevalence rates noted in subgroups involved in agricultural activity and the lowest prevalence rates noted in subgroups whose main occupations were associated to fishing. Univariate analysis indicated populations with age above 18 years (OR = 1.15, 95% CI = 1.02-1.30, P = 0.015), working (OR = 1.99, 95% CI = 1.01-3.92, P = 0.044), working at agriculture area (OR = 1.18, 95% CI = 0.98-1.42, P = 0.031), receiving household income less than US$ 166.7 (RM500) per month (OR = 2.43, 95% CI = 1.16-5.11, P = 0.016) and having close contact with animal pets (OR = 4.06, 95% CI = 1.20-13.76, P = 0.016) are significantly associated with exposure to O. tsutsugamushi. Multivariate analysis confirms that participants who are above 18 years old, receiving household income less than US$ 166.7 (RM500) per month and having close contact with animal pets are 3.6 times (95% CI = 1.81-7.03, P<0.001), 1.3 times (95% CI = 1.14-1.64, P = 0.002) and 1.2 times (95% CI = 1.05-1.06, P = 0.006) more likely to have exposure to O. tsutsugamushi, respectively. CONCLUSION: The present study indicates that scrub typhus is still an important disease in the aboriginal population in Malaysia. Awareness about the disease and education on the preventive measures are important in reducing the risk of acquiring scrub typhus in the population studied. PMID- 23936577 TI - Mini-FLOTAC, an innovative direct diagnostic technique for intestinal parasitic infections: experience from the field. AB - BACKGROUND: Soil-transmitted helminths and intestinal protozoa infection are widespread in developing countries, yet an accurate diagnosis is rarely performed. The aim of this study was to evaluate the recently developed mini FLOTAC method and to compare with currently more widely used techniques for the diagnosis of intestinal parasitic infections in different settings. METHODOLOGY/PRINCIPAL FINDINGS: The study was carried out in Dharamsala, Himachal Pradesh, India, and in Bukumbi, Tanzania. A total of 180 pupils from two primary schools had their stool analyzed (n = 80 in Dharamsala and n = 100 in Bukumbi) for intestinal parasitic infections with three diagnostic methods: direct fecal smear, formol-ether concentration method (FECM) and mini-FLOTAC. Overall, 72% of the pupils were positive for any intestinal parasitic infection, 24% carried dual infections and 11% three infections or more. The most frequently encountered intestinal parasites were Entamoeba coli, Entamoeba histolytica/dispar, Giardia intestinalis, hookworm, (and Schistosoma mansoni, in Tanzania). Statistically significant differences were found in the detection of parasitic infections among the three methods: mini-FLOTAC was the most sensitive method for helminth infections (90% mini-FLOTAC, 60% FECM, and 30% direct fecal smear), whereas FECM was most sensitive for intestinal protozoa infections (88% FECM, 70% direct fecal smear, and 68% mini-FLOTAC). CONCLUSION/SIGNIFICANCE: We present the first experiences with the mini-FLOTAC for the diagnosis of intestinal helminths and protozoa. Our results suggest that it is a valid, sensitive and potentially low cost alternative technique that could be used in resource-limited settings- particularly for helminth diagnosis. PMID- 23936578 TI - Potential cost-effectiveness of schistosomiasis treatment for reducing HIV transmission in Africa--the case of Zimbabwean women. AB - BACKGROUND: Epidemiological data from Zimbabwe suggests that genital infection with Schistosoma haematobium may increase the risk of HIV infection in young women. Therefore, the treatment of Schistosoma haematobium with praziquantel could be a potential strategy for reducing HIV infection. Here we assess the potential cost-effectiveness of praziquantel as a novel intervention strategy against HIV infection. METHODS: We developed a mathematical model of female genital schistosomiasis (FGS) and HIV infections in Zimbabwe that we fitted to cross-sectional data of FGS and HIV prevalence of 1999. We validated our epidemic projections using antenatal clinic data on HIV prevalence. We simulated annual praziquantel administration to school-age children. We then used these model predictions to perform a cost-effectiveness analysis of annual administration of praziquantel as a potential measure to reduce the burden of HIV in sub-Saharan Africa. FINDINGS: We showed that for a variation of efficacy between 30-70% of mass praziquantel administration for reducing the enhanced risk of HIV transmission per sexual act due to FGS, annual administration of praziquantel to school-age children in Zimbabwe could result in net savings of US$16-101 million compared with no mass treatment of schistosomiasis over a ten-year period. For a variation in efficacy between 30-70% of mass praziquantel administration for reducing the acquisition of FGS, annual administration of praziquantel to school age children could result in net savings of US$36-92 million over a ten-year period. CONCLUSIONS: In addition to reducing schistosomiasis burden, mass praziquantel administration may be a highly cost-effective way of reducing HIV infections in sub-Saharan Africa. Program costs per case of HIV averted are similar to, and under some conditions much better than, other interventions that are currently implemented in Africa to reduce HIV transmission. As a cost-saving strategy, mass praziquantel administration should be prioritized over other less cost-effective public health interventions. PMID- 23936579 TI - Aedes (Stegomyia) albopictus (Skuse): a potential vector of Zika virus in Singapore. AB - BACKGROUND: Zika virus (ZIKV) is a little known arbovirus until it caused a major outbreak in the Pacific Island of Yap in 2007. Although the virus has a wide geographic distribution, most of the known vectors are sylvatic Aedes mosquitoes from Africa where the virus was first isolated. Presently, Ae. aegypti is the only known vector to transmit the virus outside the African continent, though Ae. albopictus has long been a suspected vector. Currently, Ae. albopictus has been shown capable of transmitting more than 20 arboviruses and its notoriety as an important vector came to light during the recent chikungunya pandemic. The vulnerability of Singapore to emerging infectious arboviruses has stimulated our interest to determine the competence of local Ae. albopictus to transmit ZIKV. METHODOLOGY/PRINCIPAL FINDINGS: To determine the competence of Ae. albopictus to ZIKV, we orally infected local mosquito strains to a Ugandan strain virus. Fully engorged mosquitoes were maintained in an environmental chamber set at 29 degrees C and 80-85%RH. Twelve mosquitoes were then sampled daily from day one to seven and on day 10 and 14 post infection (pi). Zika virus titre in the midgut and salivary glands of each mosquito were determined using tissue culture infectious dose50 assay, while transmissibility of the virus was determined by detecting viral antigen in the mosquito saliva by qRT-PCR. High dissemination and transmission rate of ZIKV were observed. By day 7-pi, all mosquitoes have disseminated infection and 73% of these mosquitoes have ZIKV in their saliva. By day 10-pi, all mosquitoes were potentially infectious. CONCLUSIONS/SIGNIFICANCE: The study highlighted the potential of Ae. albopictus to transmit ZIKV and the possibility that the virus could be established locally. Nonetheless, the threat of ZIKV can be mitigated by existing dengue and chikungunya control program being implemented in Singapore. PMID- 23936582 TI - Nonfixed Retirement Age for University Professors: Modeling Its Effects on New Faculty Hires. AB - We model the set of tenure-track faculty members at a university as a queue, where "customers" in queue are faculty members in active careers. Arrivals to the queue are usually young, untenured assistant professors, and departures from the queue are primarily those who do not pass a promotion or tenure hurdle and those who retire. There are other less-often-used ways to enter and leave the queue. Our focus is on system effects of the elimination of mandatory retirement age. In particular, we are concerned with estimating the number of assistant professor slots that annually are no longer available because of the elimination of mandatory retirement. We start with steady-state assumptions that require use of Little's Law of Queueing, and we progress to a transient model using system dynamics. We apply these simple models using available data from our home university, the Massachusetts Institute of Technology. PMID- 23936581 TI - Epidemiology of and impact of insecticide spraying on Chagas disease in communities in the Bolivian Chaco. AB - BACKGROUND: Chagas disease control campaigns relying upon residual insecticide spraying have been successful in many Southern American countries. However, in some areas, rapid reinfestation and recrudescence of transmission have occurred. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a cross-sectional survey in the Bolivian Chaco to evaluate prevalence of and risk factors for T. cruzi infection 11 years after two rounds of blanket insecticide application. We used a cubic B spline model to estimate change in force of infection over time based on age specific seroprevalence data. Overall T. cruzi seroprevalence was 51.7%. The prevalence was 19.8% among children 2-15, 72.7% among those 15-30 and 97.1% among participants older than 30 years. Based on the model, the estimated annual force of infection was 4.3% over the two years before the first blanket spray in 2000 and fell to 0.4% for 2001-2002. The estimated annual force of infection for 2004 2005, the 2 year period following the second blanket spray, was 4.6%. However, the 95% bootstrap confidence intervals overlap for all of these estimates. In a multivariable model, only sleeping in a structure with cracks in the walls (aOR = 2.35; 95% CI = 1.15-4.78), age and village of residence were associated with infection. CONCLUSIONS/SIGNIFICANCE: As in other areas in the Chaco, we found an extremely high prevalence of Chagas disease. Despite evidence that blanket insecticide application in 2000 may have decreased the force of infection, active transmission is ongoing. Continued spraying vigilance, infestation surveillance, and systematic household improvements are necessary to disrupt and sustain interruption of infection transmission. PMID- 23936580 TI - Health access livelihood framework reveals potential barriers in the control of schistosomiasis in the Dongting Lake area of Hunan Province, China. AB - BACKGROUND: Access to health care is a major requirement in improving health and fostering socioeconomic development. In the People's Republic of China (P.R. China), considerable changes have occurred in the social, economic, and health systems with a shift from a centrally planned to a socialist market economy. This brought about great benefits and new challenges, particularly for vertical disease control programs, including schistosomiasis. We explored systemic barriers in access to equitable and effective control of schistosomiasis. METHODOLOGY: Between August 2002 and February 2003, 66 interviews with staff from anti-schistosomiasis control stations and six focus group discussions with health personnel were conducted in the Dongting Lake area, Hunan Province. Additionally, 79 patients with advanced schistosomiasis japonica were interviewed. The health access livelihood framework was utilized to examine availability, accessibility, affordability, adequacy, and acceptability of schistosomiasis-related health care. PRINCIPAL FINDINGS: We found sufficient availability of infrastructure and human resources at most control stations. Many patients with advanced schistosomiasis resided in non-endemic or moderately endemic areas, however, with poor accessibility to disease-specific knowledge and specialized health services. Moreover, none of the patients interviewed had any form of health insurance, resulting in high out-of-pocket expenditure or unaffordable care. Reports on the adequacy and acceptability of care were mixed. CONCLUSIONS/SIGNIFICANCE: There is a need to strengthen health awareness and schistosomiasis surveillance in post transmission control settings, as well as to reduce diagnostic and treatment costs. Further studies are needed to gain a multi-layered, in-depth understanding of remaining barriers, so that the ultimate goal of schistosomiasis elimination in P.R. China can be reached. PMID- 23936583 TI - Efficacy of peginterferon alpha-2a and predictors of response in HBeAg-negative, genotype D-naive patients. AB - BACKGROUND: Peginterferon (PEG-IFN) alpha-2a has been shown to induce a sustained virologic response (SVR) in 20-30% of "hepatitis B e antigen (HBeAg)"-negative patients. AIM: To determine the safety and efficacy of PEG-IFN alpha-2a in HBeAg negative, genotype D-naive patients and to analyze the predictors of response. METHODS: This prospective, multicenter, open-label, nonrandomized trial was conducted at four hospitals. A total of 35 consecutive HBeAg-negative naive genotype D patients received PEG-IFN alpha-2a for 48 weeks. RESULTS: Based on a cutoff of hepatitis B virus (HBV) DNA <400 copies ml(-1), an early virologic response (EVR) at week 12, end of treatment virologic response (ETVR) at week 48, and SVR at week 72 were achieved by 3 (9%), 9 (26%), and 8 patients (23%), respectively. The EVR rate improved to 43%, ETVR to 49%, and SVR to 57%, when a HBV DNA cutoff level of <20,000 copies ml(-1) was used. Pretreatment HBsAg level was not a predictor for SVR on univariate analysis, but correlated with decline in HBV DNA levels at weeks 48 and 72. On multivariate logistic regression analysis, low body weight, high alanine aminotransferase (ALT), low HBV DNA, and low triglyceride levels were identified as baseline predictors of SVR. CONCLUSION: HBeAg-negative genotype D-naive patients treated with PEG-IFN alpha 2a achieved SVR in 23 (HBV <400 copies ml(-1)) and 57% (HBV <20,000 copies ml( 1)) of patients, a better response than previously reported that might be related to the absence of drug resistance in these naive patients. Pretreatment predictors of SVR were low body weight, high ALT, low HBV DNA, and low triglycerides. PMID- 23936584 TI - Non-rigid registration and KLT filter to improve SNR and CNR in GRE-EPI myocardial perfusion imaging. AB - The purpose of the study was to evaluate the effect of motion compensation by non rigid registration combined with the Karhunen-Loeve Transform (KLT) filter on the signal to noise (SNR) and contrast-to-noise ratio (CNR) of hybrid gradient-echo echoplanar (GRE-EPI) first-pass myocardial perfusion imaging. Twenty one consecutive first-pass adenosine stress perfusion MR data sets interpreted positive for ischemia or infarction were processed by non-rigid Registration followed by KLT filtering. SNR and CNR were measured in abnormal and normal myocardium in unfiltered and KLT filtered images following non-rigid registration to compensate for respiratory and other motions. Image artifacts introduced by filtering in registered and nonregistered images were evaluated by two observers. There was a statistically significant increase in both SNR and CNR between normal and abnormal myocardium with KLT filtering (mean SNR increased by 62.18% +/- 21.05% and mean CNR increased by 58.84% +/- 18.06%; p = 0.01). Motion correction prior to KLT filtering reduced significantly the occurrence of filter induced artifacts (KLT only-artifacts in 42 out of 55 image series vs. registered plus KLT-artifacts in 3 out of 55 image series). In conclusion the combination of non- rigid registration and KLT filtering was shown to increase the SNR and CNR of GRE EPI perfusion images. Subjective evaluation of image artifacts revealed that prior motion compensation significantly reduced the artifacts introduced by the KLT filtering process. PMID- 23936585 TI - High-throughput asparaginase activity assay in serum of children with leukemia. AB - Asparaginase is an antineoplastic agent used in combination therapy for acute lymphoblastic leukemia (ALL). The asparaginase activity measured in serum reflects the effectiveness of the drug. However, the wide inter-individual variability in the pharmacokinetics of asparaginase suggests that the serum activity should be closely monitored in patients during therapy. In order to identify patients with low asparaginase exposure during treatment, a fast, sensitive, and high-throughput assay is required for measuring asparaginase activity in patient sera. In this study, asparaginase activity was determined by monitoring the enzymatically-coupled oxidation of reduced nicotinamide adenine dinucleotide (NADH) to NAD(+) in a 96-well format. The rate of disappearance of NADH (DeltamOD/minute) was directly proportional to the activity of asparaginase, and the linear range of the assay was established from 0.025 to 2.2 IU/mL (R(2) = 0.998) with a reportable range that was extended to 4.0 IU/mL by dilution with serum albumin. Inter-assay precision was established (low control CV% = 8.8, high control CV% = 9.0), as was intra-assay precision (low control CV% = 3.3, high control CV% = 2.7). The method is high-throughput and provides a broader linear range of detection compared to previously described assays. The speed, ease, and accuracy of the assay make it suitable for assessing serum asparaginase activity after standard doses of native E. coli, Erwinia, and PEGylated E. coli asparaginase given to children during the treatment of leukemia. PMID- 23936586 TI - Surgical treatment of large substernal thyroid goiter: analysis of 12 patients. AB - This study was carried out to evaluate the clinical presentation, surgical treatment, complications, and risk of malignancy for large substernal goiter. From March 2010 to December 2012, 12 patients with large substernal thyroid goiter who underwent surgery in our Department were enrolled in the study. Their medical records were retrospectively analyzed. Collar-shaped incision was adequate for resection of the lesions in 10 (83%) patients, while two (17%) patients required combined cervical-thoracic incision. In addition, one case was subjected to postoperative tracheotomy. Transient hypocalcaemia occurred in one case. The incidence of transient hoarseness, tracheomalacia and hypothyroidism was 8.3%. There was no perioperative bleeding, thyroid storm as well as other serious complications. All patients were clinically cured. Therefore, cervical collar incision is nearly always adequate for most cases of larger substernal goiter, and sternotomy can be avoided. Furthermore, the application of intraoperative ultrasonic knife can effectively reduce intraoperative and postoperative complications. Aggressive perioperative management is crucial for the successful removal of large substernal goiter. PMID- 23936587 TI - Expression of apolipoprotein D and androgen receptor in axillary osmidrosis and its molecular mechanism. AB - OBJECTIVE: To investigate the expression of apolipoprotein D (ApoD) and androgen receptor (AR), two proteins related to E-3M2H secretion, in the apocrine sweat gland of patients with axillary osmidrosis (AO) and healthy subjects, and to explore the cause of abnormal ApoD expression in these patients. METHODS: Samples were collected from healthy controls (n=4) and AO patients (n=10). Immunohistochemistry, real-time PCR and western blot assay were performed to measure the mRNA and protein expression of ApoD and AR. In vitro sweat gland cells were treated with androgen to explore the AR signals in regulation of ApoD expression and the role of JNK1 signaling pathway in the ApoD expression. RESULTS: There was significant difference in the expression of ApoD and AR between AO patients and healthy controls. The ApoD expression in AO patients was 2-fold higher than that in healthy controls and the AR expression in AO patients was also markedly increased when compared with healthy controls. Moreover, the activation of JNK1 increased in AO patients. Androgen can increase the ApoD expression in healthy subjects accompanied bu JNK1 activation. Inhibition of JNK1 activation may reduce the ApoD expression in AO patients and the androgen induced ApopD expression. CONCLUSION: The increase ApoD expression is closely related to the AR signaling pathway. JNK1 activation is a major cause of increased ApoD expression in AO patients and the androgen induced ApopD expression. To inhibit the JNK1 activation may suppress the endogenous ApoD expression in AO patients and the androgen induced ApopD expression. PMID- 23936588 TI - Lymphoplasmacyte-rich meningioma: our experience with 19 cases and a systematic literature review. AB - OBJECTIVE: To investigate the clinicopathological characteristics, prognosis, pathology, and differential diagnosis of LPM by analyzing our experience and reviewed relevant literature. We also postulated the necessity of postoperative adjuvant therapy. METHODS: 19 patients with LPM underwent surgical treatment from 2007 through 2010 in our department. The clinical charts of the patients, including surgical, histological, and follow-up records, as well as imaging studies, were analyzed retrospectively. Other 43 cases searched from the literature were also included, so that 62 LPM cases were summarized and reviewed together. RESULTS: The summarized 62 patients comprised 30 males and 31 females aged 9 years to 79 years (40.7+/-18.3 years). The most common locations were convexity, skull base, para-sagittal and cervical canal. Multiple or diffuse lesions were found in 8 cases. There were 13 patients had peripheral blood abnormalities (21%). One-third of the cases had moderate to severe peritumoral brain edema. Thirty-eight patients had total resection, 12 patients not specified while 12 received subtotal resection or only biopsy. MIB-1 was available in 24 cases and a third of them were higher than 3%. Follow-up more than 3 year was only completed in 19/62 cases. Seven cases suffered recurrence and two of them died after 2 years of operation. CONCLUSION: LPM is a very rare benign variant of intracranial meningioma. Both lesions and hematological abnormalities have a predilection for younger individuals. Preoperative diagnosis of this subtype of meningioma is still difficult. Surgical resection is the primary treatment option, and supportive care for those not totally removed is very important, because the recurrence rate for this subtype is rather low. However, the massive infiltration of lymphocytes and plasma cells in LPMs are still controversial and the long-term follow-ups are needed. Radiotherapy is not recommended, and hormonal or immune-inhibitor therapy might be helpful. PMID- 23936590 TI - Decellularized porcine pulmonary arteries cross-linked by carbodiimide. AB - The physical properties of the tissues are weakened after decellularization, and the exposed collagen fibers are prone to thrombogenesis. Several studies have proven that the use of carbodiimide (EDC) as a cross-linking agent can improve the properties of decellularized xenogeneic scaffold materials. We adopted EDC for the treatment of porcine pulmonary arteries in an effort to improve the physical properties of these arteries following decellularization. Twenty porcine pulmonary arteries were randomly divided into 3 groups. The control group (group A) consisted of fresh porcine pulmonary arteries with no further processing; group B was treated with trypsin and the detergent Triton X-100 to remove cells; and group C was cross-linked with EDC after trypsin and Triton X-100 treatment, as in group B. The pulmonary arteries were assessed based on water content, thickness, tensile strength, and thermal shrinkage temperature, to evaluate the physical properties of all of the samples. The scaffolds were then subcutaneously embedded in rabbits. These constructs were removed after 4 weeks and checked. The cells and matrix components of the arterial walls were removed and the fibrous scaffolds were retained. In group B, the moisture content of the pulmonary arterial walls was increased; and the thickness of the walls and the tensile strength of the pulmonary arteries were decreased in comparison with group A. In subcutaneous embedding of the group B samples in rabbits, after 4 weeks, fibroblasts had grown into the scaffolds and regenerated the tissue. The water content was decreased in the pulmonary arterial walls, there was an increase in the tensile strength and the thermal shrinkage temperature in group C compared with group B. The EDC-based cross-linking procedure can enhance the tensile strength of decellularized pulmonary arteries and decrease scaffold rejection and degradation and promote tissue regeneration in vivo. PMID- 23936589 TI - Effects of ischemic preconditioning and iloprost on myocardial ischemia reperfusion damage in rats. AB - This study investigates the effects of cardiac ischemic preconditioning and iloprost on reperfusion damage in rats with myocardial ischemia/reperfusion. 38 male Wistar Albino rats used in this study were divided into 5 groups. The control group (Group 1) (n=6), ischemia/reperfusion (IR) group (Group 2) (n=8), cardiac ischemic preconditioning (CIP) group (Group 3) (n=8), iloprost (ILO) group (Group 4) (n=8), and cardiac ischemic preconditioning + iloprost (CIP+ILO) group (Group 5) (n=8). Pre-ischemia, 15 minutes post-ischemia, 45 minutes post reperfusion, mean blood pressure (MBP), and heart rates (HR) were recorded. The rate-pressure product (RPP) was calculated. Post-reperfusion plasma creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin (cTn) vlaues, and infarct size/area at risk (IS/AAR) were calculated from myocardial tissue samples. Arrhythmia and ST segment elevations were evaluated during the ischemia and reperfusion stages. Although the MBP, HR, RPP values, biochemical parameters of CK-MB and LDH levels, IS/AAR rates, ST segment elevation values were found to be similar in CIP and CIP+ILO groups and the IR and ILO groups (p>0.05), CIP containing group values had a positively meaningful difference (p<0.05) compared with the IR and ILO group. While mild-moderate findings of damage were observed in Group 3 and Group 5, severely findings of damage were releaved in Group 2 and Group 4. The arrhythmia score of the ILO group was meaningfully lower (F: 41.4, p<0.001) than the IR group. We can conclude that the effects of myocardial reperfusion damage can be reduced by cardiac ischemic preconditioning, intravenous iloprost reduced the incidence of ventricular arrhythmia associated with reperfusion, and its use with CIP caused no additional changes. PMID- 23936591 TI - Skeletal muscle mitochondrial depletion and dysfunction in chronic kidney disease. AB - Advanced chronic kidney disease (CKD) is associated with impaired exercise capacity, skeletal muscle dysfunction, and oxidative stress. Mitochondria are the primary source for energy production and generation of reactive oxygen species (ROS). Mitochondrial state 3 respiration, mitochondrial complex I enzyme activity, and tissue porin/actin ratio were determined in the gastrocnemius muscle of male SD rats 14 weeks after 5/6 nephrectomy (CKD) or sham-operation (control). The CKD group exhibited azotemia, hypertension, significant reduction (-39%) of state 3 mitochondrial respiration, and a significant increase in the mitochondrial complex I enzyme activity. The latter is the first step in oxidative phosphorylation, a process linked to production of ROS. These abnormalities were associated with a significant reduction in muscle porin/beta actin ratio denoting substantial reduction of mitochondrial mass in skeletal muscle of animals with CKD. CKD results in impaired mitochondrial respiration, reduced muscle mitochondrial mass, depressed energy production and increased ROS generation in the skeletal muscle. These events can simultaneously contribute to the reduction of exercise capacity and oxidative stress in CKD. PMID- 23936592 TI - Neuronal apoptosis in morphine addiction and its molecular mechanism. AB - OBJECTIVE: This study aimed to investigate neuronal apoptosis and expression of apoptosis related proteins (Fas, Caspase-3 and Bcl-2) in the brain of rates with morphine addiction. METHODS: A total of 48 adult male Sprague-Dawley rats weighing 190-210 g were randomly divided into 3 groups (n=16 per group): morphine addiction group, morphine abstinence group and control group. Rats in the addiction group and the abstinence group were intraperitoneally treated with morphine for 13 days to induce morphine addiction. In abstinence group, rats were then intraperitoneally treated with naloxone at 5 mg/kg to induce abstinence for 30 min. Rats in the control group were injected with normal saline. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was employed to detect apoptotic cells. Immunohistochemistry and Western blot assay were performed to determine the expressions of Fas, Bcl-2 and Caspase-3 in the hippocampus. RESULTS: When compared with the control group, the proportion of apoptotic neurons increased significantly in the addiction group and the abstinence group (P<0.01), accompanied by significantly increased expressions of Fas and Caspase-3 (P<0.01) and markedly decreased Bcl-2 expression (P<0.01) in the hippocampuse. However, no significant differences were observed between the addiction and the abstinence group (P>0.05). CONCLUSION: Long term use of morphine can induce neuronal apoptosis in the brain by increasing the expressions of pro-apoptotic Fas and Caspase-3 and decreasing the anti-apoptotic Bcl-2 expression, which might be one of mechanisms underlying the opiate-induced neuronal damage. PMID- 23936593 TI - Effect of caspase-9 inhibition on endoplasmic reticulum stress induced cortical neuronal injury in rats. AB - Our study investigated the apoptotic mechanism of rat cortical neurons following hypoxia/reperfusion induced endoplasmic reticulum stress (ERS) in vitro and to explore the effect of caspase-9 inhibition on ERS induced apoptosis. Cortical neurons were collected from neonatal rats and cultured in vitro. Immunohistochemistry and immunofluorescence staining for neuron-specific enolase (NSE) were performed to determine the purity of neurons. AnnexinV/PI staining followed by flow cytometry was employed to detect apoptosis rate. Fluorescein isothiocyanate (FITC) staining was done to measure the expression of caspase-3 and -9. Western blot assay was carried out to measure the protein expression of caspase-12, glucose-regulated protein (GRP) 78 and Cytochrome C. The cortical neurons from neonatal rats could be purified and cultured in vitro. In the in vitro hypoxia/reperfusion of cortical neurons (hypoxia for 6 h and reperfusion for 24 h and 48 h), the protein expression of GRP78, caspase-3, 9 and 12 was markedly increased (P < 0.01). Following pre-treatment with caspase-9 inhibitor, the number of apoptotic cells was significantly reduced following hypoxia for 6 and reperfusion for 24 h or 48 h (P < 0.05). Moreover, the expression of caspse-3 and 12 and GRP78 was also significantly reduced in the presence of caspase-9 inhibitor treatment (P < 0.05), but the release of Cytochrome C remained unchanged (P > 0.05). These results demonstrated that ERS is involved in the neuronal apoptosis following in vitro hypoxia/reperfusion, and caspase-9 inhibition can depress the ERS induced apoptosis of neurons. PMID- 23936594 TI - Influence of CYP3A4 genotypes in the outcome of serous ovarian cancer patients treated with first-line chemotherapy: implication of a CYP3A4 activity profile. AB - CYP3A4 is a key enzyme involved in the metabolism of numerous compounds, such as paclitaxel, and its activity shows an extensive inter-individual variation which can influence treatment response. The study's purpose was to investigate the potential predictive role of a CYP3A4 profile (CYP3A4*1B, rs2740574 and CYP3A4*22, rs35599367) in serous ovarian cancer patients treated with first-line chemotherapy (paclitaxel and cisplatin or carboplatin), after cytoreductive surgery. CYP3A4*1B and CYP3A4*22 genotypes were determined by Nested PCR-RFLP and Taqman(r) Allelic Discrimination, respectively. We observed that the mean survival rates were statistically different according the patients CYP3A4 genotypes. The group of patients carrying the CYP3A4*1B G allele present a decreased mean survival rate when compared with AA genotype patients (103.93 and 134.44 months, respectively, p = 0.010). This result is consistent after multivariate Cox regression analysis (HR, 2.15; 95% CI, 1.03-4.52; p = 0.043). The combination of CYP3A4*1B and CYP3A4*22 polymorphisms result in the definition of a CYP3A4 activity profile: the group of patients with a higher CYP3A4 activity profile had significantly diminished survival when compared with patients with a lower CYP3A4 activity profile (101.06 and 134.44 months, respectively, p = 0.012). Multivariate Cox regression analysis revealed a diminished overall survival time for patients with CYP3A4 high activity profile (HR, 2.29; 95% CI, 1.05-5.02; p = 0.038). The definition of a CYP3A4 activity profile resulted in the increase of prediction ability, using Harrels's concordance indexes (C-index from 0.617 to 0.626). To conclude, our results demonstrate an association between CYP3A4*1B and a diminished overall survival of patients with serous ovarian cancer. The definition of a CYP3A4 activity profile proved to be benefic and the CYP3A4 high activity profile was associated with a lower overall survival. We consider that the definition of a CYP3A4 activity profile might be useful as molecular marker for predicting the clinical outcome of serous ovarian cancer patients. PMID- 23936595 TI - Diagnostic performances of high resolution trans-thoracic lung ultrasonography in pulmonary alveoli-interstitial involvement of rheumatoid lung disease. AB - INTRODUCTION: Alveolointerstitial involvement is a common manifestation in patients with connective tissue disorders. The aim of our study is to investigate the utility of modified TTUS scoring system compared with HRCT findings of pulmonary involvement in rheumatoid lung disease. MATERIAL AND METHODS: Thirty one consecutive patients with a suspected diagnosis of rheumatoid lung involvement were examined with high resolution transthoracic ultrasonography for detecting of ultrasonographic comet tail signe as a ultrasonographic marker of lung involvement in alveolointerstitial involvement in rheumatoid lung disease and the results of them were compared with High resolution computed tomography as gold standard method for diagnosis of lung involvement in this patients. RESULTS: In comparison with HRCT as gold standard method, the sensitivity, specificity, positive and negative predictive value of TTUS was 73.58%, 88.23%, 95.12% and 51.72% respectively. CONCLUSION: Modified TTUS can be a useful imaging modality in the evaluation of even early stages of pulmonary involvement in rheumatoid lung disease. PMID- 23936596 TI - Matrix metalloproteinase 10 gene polymorphism and atherothrombotic cerebral infarction risk in a Han Chinese population. AB - BACKGROUND: Matrix metalloproteinase 10 (MMP10) plays an important role in ischemic stroke and has a close relationship with some stroke risk factors. The aim of this study was to investigate the relationship between two single nucleotide polymorphisms (SNP) in the exon regions of the MMP10 gene and atherothrombotic cerebral infarction risk. METHODS: Five hundred and thirty-seven hospital-based patients who had suffered first atherothrombotic cerebral infarction and 580 unrelated healthy controls were enrolled. Demographic and clinical features of the subjects were recorded, and two polymorphisms, rs17435959 (G>C), rs17293607 (C>T) were chosen to be genotyped by real-time polymerase chain reaction-restriction TaqMan probes using the ABI 7300 TaqMan platform. RESULTS: There were several clinical parameters, such as blood pressure, fasting blood glucose, total cholesterol, homocysteine, as well as carotid plaque and smoking, but not average age and sex ratios that showed significant differences between patients and control subjects. For rs17435959, there was no significant difference between the ischemic stroke group and the healthy control group in genotype frequency (OR=1.295, P=0.187, 95% CI (0.882 1.899)) or allele frequency (OR=1.267, P=0.202, 95% CI (0.881-1.823)). Moreover, in smoking, none smoking, having carotid plaque, no carotid plaque, male or female subtypes, there was significant difference between patients and control subjects in genotype frequencies or allele frequencies. The minor allele frequency of rs17293607 was 0.92%, prohibiting further study of this allele. CONCLUSIONS: These findings suggest that the rs17435959 SNP may not associated with atherothrombotic cerebral infarction risk. We also found that rs17293607 is not polymorphic in our study population. PMID- 23936597 TI - Sedoanalgesia in pediatric daily surgery. AB - PURPOSE: The present report was focused on clinical advantages of sedoanalgesia in the pediatric outpatient surgical cases. METHOD: Sedoanalgesia has been used to sedate patients for a variety of pediatric procedures in our department between 2007 and 2010. This is a retrospective review of 2720 pediatric patients given ketamine for sedation with midazolam premedication. Ketamine was given intravenously (1-2 mg/kg) together with atropine (0.02 mg/kg) and midazolam (0.1 mg/kg) + a local infiltration anesthetic 2 mg/kg 0.5% bupivacaine hydrochloride. RESULT: Median age of the patients included in the study was 5.76 +/- 2.12 (0-16 years). The main indications for ketamine include circumcision (69%), inguinal pathologies (inguinal hernia (17%), orchidopexy (2.68%), hydrocele (3.38%), hypospadias (1.94%), urethral fistula repair (0.33%), urethral dilatation (0.25%), and other conditions. All of our patients were discharged home well. In this regard, we have the largest group of patients ever given ketamine. CONCLUSION: Sedoanalgesia might be used as a quite effective method for daily surgical procedures in children. PMID- 23936598 TI - The incidence and characteristics of uterine bleeding during postoperative GnRH agonist treatment combined with estrogen-progestogen add-back therapy in endometriosis patients of reproductive age. AB - To evaluate the incidence and characteristics of uterine bleeding during postoperative gonadotropin-releasing hormone agonist (GnRHa) treatment combined with the lowest effective dose of estrogen-progestogen add-back therapy in Chinese women of reproductive age with endometriosis. Seventy Chinese women aged 18 to 50 years with stage III or IV endometriosis and treated with postoperative GnRHa after conservative surgery for endometriosis were eligible for this study. Patients were randomly divided into two equal groups, G and A. Group G (n = 35) received three 28-day cycles of postoperative GnRHa treatment by subcutaneous injection (goserelin, 3.6 mg). Group A (n = 35) received the same GnRHa treatment in addition to daily estradiol valerate (0.5 mg) and dydrogesterone (5 mg) add back therapy. Serum E2 and FSH levels were assessed at the end of each treatment cycle, as well as incidence and patterns of uterine bleeding. After the last GnRHa treatment cycle, endometrial thickness was evaluated by ultrasonography and the recovery of menstruation was recorded. Uterine bleeding incidence was above 90% in both groups during the first treatment cycle (group G: 90.6%; group A: 93.8%), but decreased markedly in the second treatment cycle (group G: 15.6%; group A: 21.9%), and continued to decline until the end of the third treatment cycle (group G: 6.3%; group A: 12.5%). For each cycle, the incidence of uterine bleeding in group A was slightly but not statistically higher. Irregular spotting was the most common uterine bleeding pattern observed in each of the three treatment cycle. The addition of estrogen and progestogen therapy to a postoperative GnRHa regimen does not lead to an increase in the duration or amount of treatment-induced uterine bleeding. PMID- 23936599 TI - Music therapy as an early intervention to prevent chronification of tinnitus. AB - In the present study a music therapeutic intervention according to the 'Heidelberg Model' was evaluated as a complementary treatment option for patients with acute tinnitus whom medical treatment only brought minimal or no improvement. The central question was if music therapy in an early phase of tinnitus was able to reduce tinnitus symptoms and to prevent them from becoming chronical. 23 patients with acute tinnitus (6-12 weeks) were included in this study and took part in our manualized short term music therapeutic treatment which lasted ten consecutive 50-minutes sessions of individualized therapy. Tinnitus severity and individual tinnitus related distress were assessed by the Tinnitus Beeintrachtigungs-Fragebogen (i.e. Tinnitus Impairment Questionnaire, TBF-12) at baseline, start of treatment, and end of treatment. Score changes in TBF-12 from start to end of the treatment showed significant improvements in tinnitus impairment. This indicates that this music therapy approach applied in an initial stage of tinnitus can make an important contribution towards preventing tinnitus from becoming a chronic condition. PMID- 23936600 TI - Anticoagulation management of patients with long-term warfarin therapy after valve replacement during the perioperative period of pacemaker implantation. AB - BACKGROUND: To explore an optimal management of perioperative anticoagulation for patients with long-term warfarin therapy after valve replacement during the perioperative of pacemaker implantation. METHODS: We retrospectively reviewed consecutive patients undergoing pacemaker implantation who received long-term warfarin therapy after valve replacements at our hospital. They were divided into 3 groups: discontinued group, bridging group and continued group. We analyzed the relationship between different anticoagulation methods during the peri-procedure period and hemorrhage and embolism events. RESULTS: 132 patients were enrolled. There was no significant difference concerning the mean age, sex, concomitant diseases, atrial fibrillation and whether performed pacemaker replacement among 3 groups. The incidence of hematomas was irrespective of the perioperative anticoagulation strategy used (P = 0.125). A strategy involving bridging anticoagulation with therapeutic-dose heparin was associated with an incidence of wound errhysis (P = 0.008). There was no thromboembolism event in these three groups. CONCLUSION: The results showed that there was no significant difference in hematoma rate among continued group, discontinued group, and bridging group, but there was much more wound errhysis in the bridging group. Also, the study shows that if warfarin is continued, it will not increase the risk of bleeding when the International Normalized Ratio (INR) is around 1.7 during the procedure. PMID- 23936601 TI - Prior esophagogastroduodenoscopy does not affect the cecal intubation time at bidirectional endoscopies. AB - Bidirectional endoscopy (BE) is often used to assess patients for the reason of anemia or to screen asymptomatic population for malignancy. Limited clinical data favors to perform first the upper gastrointestinal system endoscopy, but its effect to the duration of colonoscopy is yet to be determined. The aim of this retrospective study is to evaluate the effect of upper gastrointestinal system endoscopy on the time to achieve cecal intubation during colonoscopy in patients undergoing BE. Patients of four endoscopists at similar experience levels were retrospectively identified and categorized into the upper gastrointestinal system endoscopy before colonoscopy group (group 1) or the colonoscopy only group (group 2). The demographics, clinical data and the time to achieve cecal intubation for each patient were analyzed. The mean time to achieve cecal intubation in the first group that included 319 cases was 8.4 +/- 0.93 minutes and the mean time in the second group that included 1672 cases was 8.56 +/- 1.16 minutes. There was no statistically significant difference between the groups. There was also no significant difference between the Group 1 and Group 2 when compared according to which of the four endoscopists performed the procedures. Performing the upper gastrointestinal system endoscopy prior to colonoscopy did not affect the time to achieve cecal intubation. Considering that performing the upper gastrointestinal system endoscopy prior to the colonoscopy is more advantageous in terms of patient comfort and analgesic requirement, beginning to BE with it seems more favorable. PMID- 23936602 TI - An easy technique for removal of knotted catheter in the bladder: percutaneous suprapubic cystoscopic intervention. AB - Uncontaminated urine samples are indispensable to precisely diagnose urinary tract infections in new-borns or infants. Among many clinical interventions for urine collection are described, the most common noninvasive practice is using sterile bags, associated with significant contamination of samples. In children, however, invasive methods i.e. catheterization, are generally needed for reliable urine specimens. Almost always all the inserted catheters are easily drawn back, nevertheless, might not work as expected, and lead to considerable problems that cannot be overcome. Herein, a case of a female newborn treated with a successful percutaneous suprapubic cystoscopic procedure for extracting knotted urinary catheter in the bladder is presented. The least invasive and easiest technic is suggested to be used when catheter is knotted in the bladder, as elaborately stated. PMID- 23936603 TI - Brachial plexus compression: a rare sequelae of malignant papillary thyroid carcinoma. AB - Invasive papillary thyroid carcinoma (PTC) can rarely invade adjacent vital structures. There has been one report on secondary brachial plexopathy associated with locally invasive PTC. Here we report a patient with a large locally invasive PTC associated with secondary neoplastic brachial plexopathy. The case exhibits an extremely rare occurrence that has substantial impact on surgical planning and management. PMID- 23936604 TI - The contribution of melanocytes to pathological scar formation during wound healing. AB - Both hypertrophic scars and keloid scars are caused by abnormal wound healing, the key feature of which is excess collagen fiber secretion by fibroblasts. Many different factors could affect the process of hypertrophic scar and keloid formation, but most have not been identified to date. We assume that, during wound healing, melanocytes from the stratum basale contact or interact with fibroblasts from the dermal layers after the basal membrane is damaged, which in turn facilitates fibroblast proliferation and the secretion and deposition of collagen. This plays a significant role in the generation of hypertrophic scars and keloids. PMID- 23936605 TI - A Neurologist's Guide to Acute Migraine Therapy in the Emergency Room. AB - Migraine is a common reason for visits to the emergency room. Attacks that lead patients to come to the emergency room are often more severe, refractory to home rescue medication, and have been going on for longer. All of these features make these attacks more challenging to treat. The purpose of this article is to review available evidence pertinent to the treatment of acute migraine in adults in the emergency department setting in order to provide neurologists with a rational approach to management. Drug classes and agents reviewed include opioids, dopamine receptor antagonists, triptans, nonsteroidal anti-inflammatory drugs, corticosteroids, and sodium valproate. PMID- 23936606 TI - Genomic structure and variation of nuclear factor (erythroid-derived 2)-like 2. AB - High-density mapping of mammalian genomes has enabled a wide range of genetic investigations including the mapping of polygenic traits, determination of quantitative trait loci, and phylogenetic comparison. Genome sequencing analysis of inbred mouse strains has identified high-density single nucleotide polymorphisms (SNPs) for investigation of complex traits, which has become a useful tool for biomedical research of human disease to alleviate ethical and practical problems of experimentation in humans. Nuclear factor (erythroid derived 2)-like 2 (NRF2) encodes a key host defense transcription factor. This review describes genetic characteristics of human NRF2 and its homologs in other vertebrate species. NRF2 is evolutionally conserved and shares sequence homology among species. Compilation of publically available SNPs and other genetic mutations shows that human NRF2 is highly polymorphic with a mutagenic frequency of 1 per every 72 bp. Functional at-risk alleles and haplotypes have been demonstrated in various human disorders. In addition, other pathogenic alterations including somatic mutations and misregulated epigenetic processes in NRF2 have led to oncogenic cell survival. Comprehensive information from the current review addresses association of NRF2 variation and disease phenotypes and supports the new insights into therapeutic strategies. PMID- 23936607 TI - Effect of Tai Chi versus walking on oxidative stress in Mexican older adults. AB - It has recently been reported that the practice of Tai Chi reduces oxidative stress (OxS), but it is not clear whether walking or Tai Chi produces a greater antioxidant effect. The aim of the present study was to evaluate the effect of the practice of Tai Chi and walking on markers for OxS. We carried out a quasi experimental study with 106 older adults between 60 and 74 years of age who were clinically healthy and divided into the following groups: (i) control group (n = 23), (ii) walking group (n = 43), and (iii) Tai Chi group (n = 31). We measured the levels of lipoperoxides (LPO), antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), and total antioxidant status (TAS) pre- and post-intervention in all subjects. The data were subjected to a covariant analysis. We found lower levels of LPO in the Tai Chi group compared with the walking group (Tai Chi, 0.261 +/- 0.02; walking, 0.331 +/- 0.02; control, 0.304 +/- 0.023 umol/L; P = 0.05). Likewise, we observed significantly higher SOD activity and lower OxS-score in the Tai Chi group (P < 0.05). Our findings suggest that the practice of Tai Chi produces a more effective antioxidant effect than walking. PMID- 23936608 TI - Age-related hearing loss in Mn-SOD heterozygous knockout mice. AB - Age-related hearing loss (AHL) reduces the quality of life for many elderly individuals. Manganese superoxide dismutase (Mn-SOD), one of the antioxidant enzymes acting within the mitochondria, plays a crucial role in scavenging reactive oxygen species (ROS). To determine whether reduction in Mn-SOD accelerates AHL, we evaluated auditory function in Mn-SOD heterozygous knockout (HET) mice and their littermate wild-type (WT) C57BL/6 mice by means of auditory brainstem response (ABR). Mean ABR thresholds were significantly increased at 16 months when compared to those at 4 months in both WT and HET mice, but they did not significantly differ between them at either age. The extent of hair cell loss, spiral ganglion cell density, and thickness of the stria vascularis also did not differ between WT and HET mice at either age. At 16 months, immunoreactivity of 8-hydroxydeoxyguanosine was significantly greater in the SGC and SV in HET mice compared to WT mice, but that of 4-hydroxynonenal did not differ between them. These findings suggest that, although decrease of Mn-SOD by half may increase oxidative stress in the cochlea to some extent, it may not be sufficient to accelerate age-related cochlear damage under physiological aging process. PMID- 23936609 TI - Neurodegeneration in Friedreich's ataxia: from defective frataxin to oxidative stress. AB - Friedreich's ataxia is the most common inherited autosomal recessive ataxia and is characterized by progressive degeneration of the peripheral and central nervous systems and cardiomyopathy. This disease is caused by the silencing of the FXN gene and reduced levels of the encoded protein, frataxin. Frataxin is a mitochondrial protein that functions primarily in iron-sulfur cluster synthesis. This small protein with an alpha / beta sandwich fold undergoes complex processing and imports into the mitochondria, generating isoforms with distinct N terminal lengths which may underlie different functionalities, also in respect to oligomerization. Missense mutations in the FXN coding region, which compromise protein folding, stability, and function, are found in 4% of FRDA heterozygous patients and are useful to understand how loss of functional frataxin impacts on FRDA physiopathology. In cells, frataxin deficiency leads to pleiotropic phenotypes, including deregulation of iron homeostasis and increased oxidative stress. Increasing amount of data suggest that oxidative stress contributes to neurodegeneration in Friedreich's ataxia. PMID- 23936610 TI - Resveratrol prevents dendritic cell maturation in response to advanced glycation end products. AB - Advanced glycation end products (AGEs), generated through nonenzymatic glycosylation of proteins, lipids, and nucleic acids, accumulate in the body by age thus being considered as biomarkers of senescence. Senescence is characterized by a breakdown of immunological self-tolerance, resulting in increased reactivity to self-antigens. Previous findings suggest that AGE and its receptor RAGE may be involved in the pathogenesis of autoimmune reactions through dendritic cell (DC) activation. The aim of this study was to investigate whether resveratrol, a polyphenolic antioxidant compound with tolerogenic effects on DCs, was able to counteract the mechanisms triggered by AGE/RAGE interaction on DCs. By immunochemical and cytofluorimetric assays, we demonstrated that in vitro pretreatment of human monocyte-derived DCs with resveratrol prevents DC activation in response to glucose-treated albumin (AGE-albumin). We found that resveratrol exerts an inhibitory effect on DC surface maturation marker and RAGE up-regulation in response to AGE-albumin. It also inhibited proinflammatory cytokine expression, allostimulatory ability upregulation, mitogen-activated protein (MAP) kinases, and NF-kappaB activation in AGE-albumin-stimulated DCs. We suggest that resveratrol, by dismantling AGE/RAGE signaling on DCs may prevent or reduce increased reactivity to self-molecules in aging. PMID- 23936611 TI - Grape polyphenols increase the activity of HDL enzymes in old and obese rats. AB - HDL particles are protein-rich particles that act as a vehicle for reverse cholesterol transport from tissues to the liver. The purpose of this study was to investigate age-dependent changes in the functional activity of HDL and the effect of high-energy diet on this index, as well as to correct it under the influence of grape polyphenols from "Enoant" obtained from Vitis vinifera grapes. We observed the age-dependent composition changes in HDL particle. It was shown that total lipids and triacylglycerol (TG) levels were higher in 24-month-old animals. In obese rats, HDL total lipids and TG levels were higher in 24-month old than in the 3-month-old and 12-month-old groups but did not differ from 24 month-old group. The plasma HDL paraoxonase (PON) and lecithin:cholesterol acyltransferase (LCAT) activity levels were decreased in old-aged rats, and cholesteryl ester transfer protein (CETP) activity was higher in old rats. Keeping 12-month-old animals on high-fructose diet completely leveled the age differences in the data that have been measured between 12-month-old and 24-month old rats. After "Enoant" administration, an increase of HDL PON and LCAT activity levels and a reduction of CETP activity were found in 24-month-old and obese rats. PMID- 23936612 TI - Maintenance of mitochondrial morphology by autophagy and its role in high glucose effects on chronological lifespan of Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae, mitochondrial morphology changes when cells are shifted between nonfermentative and fermentative carbon sources. Here, we show that cells of S. cerevisiae grown in different glucose concentrations display different mitochondrial morphologies. The morphology of mitochondria in the cells growing in 0.5% glucose was similar to that of mitochondria in respiring cells. However, the mitochondria of cells growing in higher glucose concentrations (2% and 4%) became fragmented after growth in these media, due to the production of acetic acid; however, the fragmentation was not due to intracellular acidification. From a screen of mutants involved in sensing and utilizing nutrients, cells lacking TOR1 had reduced mitochondrial fragmentation, and autophagy was found to be essential for this reduction. Mitochondrial fragmentation in cells grown in high glucose was reversible by transferring them into conditioned medium from a culture grown on 0.5% glucose. Similarly, the chronological lifespan of cells grown in high glucose medium was reduced, and this phenotype could be reversed when cells were transferred to low glucose conditioned medium. These data indicate that chronological lifespan seems correlated with mitochondrial morphology of yeast cells and that both phenotypes can be influenced by factors from conditioned medium of cultures grown in low glucose medium. PMID- 23936613 TI - The benefits of humanized yeast models to study Parkinson's disease. AB - Over the past decade, the baker's yeast Saccharomyces cerevisiae has proven to be a useful model system to investigate fundamental questions concerning the pathogenic role of human proteins in neurodegenerative diseases such as Parkinson's disease (PD). These so-called humanized yeast models for PD initially focused on alpha -synuclein, which plays a key role in the etiology of PD. Upon expression of this human protein in the baker's yeast Saccharomyces cerevisiae, the events leading to aggregation and the molecular mechanisms that result in cellular toxicity are faithfully reproduced. More recently, a similar model to study the presumed pathobiology of the alpha -synuclein interaction partner synphilin-1 has been established. In this review we will discuss recent advances using these humanized yeast models, pointing to new roles for cell wall integrity signaling, Ca(2+) homeostasis, mitophagy, and the cytoskeleton. PMID- 23936614 TI - Xenobiotic sensor- and metabolism-related gene variants in environmental sensitivity-related illnesses: a survey on the Italian population. AB - In the environmental sensitivity-related illnesses (SRIs), multiple chemical sensitivity (MCS), chronic fatigue syndrome (FCS), and fibromyalgia (FM), the search for genetic polymorphisms of phase I/II xenobiotic-metabolizing enzymes as suitable diagnostic biomarkers produced so far inconclusive results, due to patient heterogeneity, geographic/ethnic differences in genetic backgrounds, and different methodological approaches. Here, we compared the frequency of gene polymorphisms of selected cytochrome P450 (CYP) metabolizing enzymes and, for the first time, the frequency of the xenobiotic sensor Aryl hydrocarbon receptor (AHR) in the three cohorts of 156 diagnosed MCS, 94 suspected MCS, and 80 FM/FCS patients versus 113 healthy controls. We found significantly higher frequency of polymorphisms CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2D6*4 and CYP2D6*41 in patients compared with controls. This confirms that these genetic variants represent a genetic risk factor for SRI. Moreover, the compound heterozygosity for CYP2C9*2 and *3 variants was useful to discriminate between either MCS or FM/CFS versus SMCS, while the PM *41/*41 genotype discriminated between MCS and either SMCS or FM/CFS. The compound heterozygosity for CYP2C9 *1/*3 and CYP2D6 *1/*4 differentiated MCS and SMCS cases from FM/CFS ones. Interestingly, despite the distribution of the AHR Arg554Lys variant did not result significantly different between SRI cases and controls, it resulted useful for the discrimination between MCS and SMCS cases when considered within haplotypes in combination with CYP2C19 *1/*2 and CYP2D6 *1/*4. Results allowed us to propose the genotyping for these specific CYP variants, together with the AHR Arg554Lys variant, as reliable, cost effective genetic parameters to be included in the still undefined biomarkers' panel for laboratory diagnosis of the main types of environmental-borne SRI. PMID- 23936615 TI - Phosphorylation of tau protein as the link between oxidative stress, mitochondrial dysfunction, and connectivity failure: implications for Alzheimer's disease. AB - Alzheimer's disease (AD) is defined by the concurrence of abnormal aggregates composed of phosphorylated tau protein and of abnormal cellular changes including neurite degeneration, loss of neurons, and loss of cognitive functions. While a number of mechanisms have been implicated in this complex disease, oxidative stress remains one of the earliest and strongest events related to disease progression. However, the mechanism that links oxidative stress and cognitive decline remains elusive. Here, we propose that phosphorylated tau protein could be playing the role of potential connector and, therefore, that a combined therapy involving antioxidants and check points for synaptic plasticity during early stages of the disease could become a viable therapeutic option for AD treatment. PMID- 23936616 TI - Management of acute promyelocytic leukemia in the elderly. AB - Unlike other forms of AML, APL is less frequently diagnosed in the elderly and has a relatively favourable outcome. Elderly patients with APL seem at least as responsive to therapy as do younger patients, but rates of response and survival are lower in this age setting owing to a higher incidence of early deaths and deaths in remission when conventional treatment with ATRA and chemotherapy is used. Elderly APL patients are more likely to present with low-risk features compared with younger patients, and this may explain the relative low risk of relapse reported in several clinical studies. Alternative approaches, such as arsenic trioxide and gentuzumab ozogamicin have been tested with success in this setting and could replace in the near future frontline conventional chemotherapy and ATRA. PMID- 23936618 TI - Von Willebrand Factor Abnormalities Studied in the Mouse Model: What We Learned about VWF Functions. AB - Up until recently, von Willebrand Factor (VWF) structure-function relationships have only been studied through in vitro approaches. A powerful technique known as hydrodynamic gene transfer, which allows transient expression of a transgene by mouse hepatocytes, has led to an important shift in VWF research. Indeed this approach has now enabled us to transiently express a number of VWF mutants in VWF deficient mice in order to test the relative importance of specific residues in different aspects of VWF biology and functions in an in vivo setting. As a result, mice reproducing various types of von Willebrand disease have been generated, models that will be useful to test new therapies. This approach also allowed a more precise identification of the importance of VWF interaction with subendothelial collagens and with platelets receptors in hemostasis and thrombosis. The recent advances gathered from these studies as well as the pros and cons of the technique will be reviewed here. PMID- 23936619 TI - Complete remission obtained with azacitidine in a patient with concomitant therapy related myeloid neoplasm and pulmonary mucormycosis. AB - Mucormycosis is the third cause of invasive mycosis after candidiasis and aspergillosis in AML patients, representing a poor prognostic factor associated with a high rate of fatal outcome. We report a case of a patient with AML and a concomitant pulmonary mucormycosis at diagnosis, who obtained a complete remission both of her AML and of the fungal infection. The incidence of the infection at the onset of leukemia is extremely unusual, and, to our knowledge, the sporadic cases reported in the literature are included in heterogeneous series retrospectively examined. In our case, Liposomal Amphotericin B as single agent appeared incapable of controlling the infection, so anti-infective therapy was intensified with posaconazole and simultaneously antileukemic treatment with 5-azacitidine was started, with the understanding that the only antifungal treatment would not have been able to keep the infection under control for a long time if not associated with a reversal of neutropenia related to the disease. We observed a progressive improvement of the general conditions, a healing of pneumonia and a complete remission of the leukemic disease, suggesting that a careful utilization of the new compounds available today, in terms of both antifungal and antileukemic treatment, may offer a curative chance a patient who would have otherwise been considered unfit for a potentially curative therapeutic strategy. PMID- 23936620 TI - Diagnosis of congenital cytomegalovirus infection in high risk neonates. AB - OBJECTIVES: This study aimed to compare polymerase chain reaction (PCR) and IgM detection using enzyme linked immune-sorbent assay (ELISA) in diagnosis of congenital cytomegalovirus (CMV) infection. METHODS: This study was conducted from May 2009 to December 2010. Urine and blood samples were collected from 94 neonates with suspected congenital CMV infection. Serum and part of urine samples were stored at -20 degrees C freezer, until the serologic and PCR tests were achieved. A 94 fresh urine samples were processed for cell culture. Nineteen (20.2%) out of 94 urine samples were proven positive for CMV infection by viral culture. For comparing PCR and IgM ELISA we used tissue culture technique as a reference, the 19 positive samples on culture (CMV group) and 20 negative samples (control group) were included in the comparison. Some characteristics of CMV and control groups were compared including sex, age, birth weight, gestational age < 37 and small for gestational age. Clinical and laboratory abnormalities were also compared in both groups. RESULTS: This study showed that the sensitivity and specificity of PCR in relation to viral culture were 100% and 100% respectively, there was excellent agreement between both tests (Kappa coefficient was 1 and P=0.000). On the other hand, the sensitivity of IgM CMV ELISA in relation to viral culture was 63.2% and the specificity was 85%. There was good agreement between both tests (Kappa coefficient was 0.48 and P=0.002). By comparing CMV and control groups, there were high statistically significant differences between both groups as regard the birth weight, gestational age < 37 and small for gestational age items (P= 0.00, 0.03 and 0.01 respectively). There were statistically insignificant differences as regarding the clinical and laboratory abnormalities detected for neonates of both groups. In this study jaundice (63%) and hepato-splenomegaly (42%) were the most common clinical signs in both groups. CONCLUSIONS: PCR is more sensitive and specific technique for detection of congenital CMV infection than CMV IgM ELISA. Being more cost effective, less cumbersome and less time consuming in relation to viral culture, PCR may be used in detection of congenital CMV infection. PMID- 23936621 TI - Therapeutic Options for Patients who are not Eligible for Intensive Chemotherapy. AB - Although "less intense" therapies are finding more use in AML, the principal problem in AML remains lack of efficacy rather than toxicity. Hence less intense therapies are of little use if they are not more effective as well as less toxic than standard therapies. Assignment of patients to less intense therapies should be based on other factors in addition to age. Azacitidine and decitabine, the most commonly used less intense therapies in AML very probably produce better OS than best "supportive care" or "low-dose" ara-C. However improvement is relatively small when compared to expected life expectancy in the absence of disease. Accordingly, while azacitidine or decitabine should be considered the standards against which newer therapies are compared, continued investigation of potentially more effective therapies needs to continue. Better means for evaluating the large number of these therapies (and their combinations) are also needed. PMID- 23936617 TI - On the versatility of von Willebrand factor. AB - Von Willebrand factor (VWF) is a large multimeric protein, the function of which has been demonstrated to be pivotal to the haemostatic system. Indeed, quantitative and/or qualitative abnormalities of VWF are associated with the bleeding disorder Von Willebrand disease (VWD). Moreover, increased plasma concentrations of VWF have been linked to an increased risk for thrombotic complications. In the previous decades, many studies have contributed to our understanding of how VWF is connected to the haemostatic system, particularly with regard to structure-function relationships. Interactive sites for important ligands of VWF (such as factor VIII, collagen, glycoprotein Ibalpha, integrin alphaIIbbeta3 and protease ADAMTS13) have been identified, and mutagenesis studies have confirmed the physiological relevance of the interactions between VWF and these ligands. However, we have also become aware that VWF has a more versatile character than previously thought, given its potential role in various non-hemostatic processes, like intimal thickening, tumor cell apoptosis and inflammatory processes. In the presence review, a summary of our knowledge on VWF structure-function relationships is provided in the context of the "classical" haemostatic task of VWF and in perspective of pathological processes beyond haemostasis. PMID- 23936622 TI - The Role of Bleeding History and Clinical Markers for the Correct Diagnosis of VWD. AB - Quantification of the bleeding severity by use of bleeding assessment tools (BAT) and bleeding score (BS) has been consistently shown to improve the clinical diagnosis of von Willebrand disease (VWD) while helping researchers establish phenotype/genotype correlations. Subjects with a BS equal or higher than 3 may be consider having a bleeding tendency, and should be referred for a laboratory investigation, particularly for VWD. In the diagnosis of type 1 VWD, the use of the BS has been shown to be highly specific (>95%) with reported sensitivities ranging from 40 to 100%. The BS is related to all available measurements of von Willebrand factor activity, including the PFA-100 closure time. Therefore, in clinical practice the use of BAT should always be the first step to standardize the assessment of patients with suspected VWD. The use of the recent ISTH consensus BAT is suggested to harmonize the collection of bleeding symptoms in patients with a suspected or confirmed hemostatic disorder, particularly VWD. The ISTH BAT is also coupled with a Web-based repository of bleeding symptoms, therefore providing an integrated framework for collaboration in the field of clinical evaluation of VWD and mild bleeding disorders. PMID- 23936623 TI - Changes of von Willebrand Factor during Pregnancy in Women with and without von Willebrand Disease. AB - Delivery in von Willebrand disease (VWD) represents a significant hemostatic challenge because of the variable pattern of changes observed during pregnancy of von Willebrand factor (VWF) and factor VIII (FVIII), the protein carried by VWF. Since a wide heterogeneity of phenotypes and of the underlying pathophysiological mechanisms is associated with this disorder, a prompt and careful evaluation of pregnant women with VWD is requested in order to plan the most appropriate treatment at time of parturition. VWF and FVIII increase significantly during pregnancy in normal women, already within the first trimester, reaching levels by far >100 U/dL by the time of parturition. Women with VWD, levels at baseline of VWF and FVIII >30 U/dL have us a high likelihood to achieve normal levels at the end of pregnancy; thus specific anti-hemorrhagic prophylaxis is seldom required. Women with basal level <20 U/dL usually have a poor increase since most of these women carry mutations associated with increased VWF clearance or are compound heterozygous for different VWF mutations; that prevent the achievement of satisfactory hemostatic levels. While women with mutations associated with increased clearance show a full, albeit transitory correction of their hemostatic deficiency after desmopressin administration, compound heterozygous need replacement therapy because they do not respond well to this agent. Patients with abnormal VWF:RCo/VWF:Ag ratio at baseline (e.g. <0.6), typically associated with type 2 VWD, maintain the abnormality throughout pregnancy and VWF:RCo usually does not attain safe levels >=50 U/dL. These women require replacement therapy with VWF-FVIII concentrates. Delayed post-partum bleeding may occur when replacement therapy is not continued for some days. Tranexamic acid may be useful at discharge to avoid excessive lochia. PMID- 23936624 TI - A texaphyrin-oxaliplatin conjugate that overcomes both pharmacologic and molecular mechanisms of cisplatin resistance in cancer cells. AB - A texaphyrin-oxaliplatin conjugate, oxaliTEX, was designed to test the concept that a platinum analog can overcome defects in drug accumulation and p53 dependent DNA damage response in a tumor model expressing multifactorial mechanisms of cisplatin resistance. Cytotoxic studies resulted in a resistance factor of only 1.2, which essentially indicated complete reversal of resistance in 2780CP cells expressing a factor of 22 with cisplatin. Unlike cisplatin, oxaliTEX accumulated and formed DNA adducts, stabilized and activated p53 at similar levels in both sensitive and resistant cells, and induced apoptosis in both models. The ability and importance of a designer drug, such as oxaliTEX, to overcome cisplatin resistance by targeting two dominant resistance mechanisms is discussed. PMID- 23936626 TI - Progress and challenges in the computational prediction of gene function using networks. AB - In this opinion piece, we attempt to unify recent arguments we have made that serious confounds affect the use of network data to predict and characterize gene function. The development of computational approaches to determine gene function is a major strand of computational genomics research. However, progress beyond using BLAST to transfer annotations has been surprisingly slow. We have previously argued that a large part of the reported success in using "guilt by association" in network data is due to the tendency of methods to simply assign new functions to already well-annotated genes. While such predictions will tend to be correct, they are generic; it is true, but not very helpful, that a gene with many functions is more likely to have any function. We have also presented evidence that much of the remaining performance in cross-validation cannot be usefully generalized to new predictions, making progressive improvement in analysis difficult to engineer. Here we summarize our findings about how these problems will affect network analysis, discuss some ongoing responses within the field to these issues, and consolidate some recommendations and speculation, which we hope will modestly increase the reliability and specificity of gene function prediction. PMID- 23936625 TI - Diffusion-weighted MRI as a biomarker for treatment response in glioma. AB - Diffusion-weighted imaging (DWI) is a powerful MRI method, which probes abnormalities of tissue structure by detecting microscopic changes in water mobility at a cellular level beyond what is available with other imaging techniques. Accordingly, DWI has the potential to identify pathology before gross anatomic changes are evident on standard anatomical brain images. These features of tissue characterization and earlier detection are what make DWI particularly appealing for the evaluation of gliomas and the newer therapies where standard anatomical imaging is proving insufficient. This article focuses on the basic principles and applications of DWI, and its derived parameter, the apparent diffusion coefficient, for the purposes of diagnosis and evaluation of glioma, especially in the context of monitoring response to therapy. PMID- 23936627 TI - Fungal granulomatous interstitial nephritis presenting as acute kidney injury diagnosed by renal histology including PCR assay. AB - We describe two cases of fungal granulomatous interstitial nephritis (GIN) presenting as acute kidney injury (AKI). Increased serum creatinine was detected in Patient 1 after chemotherapy for pharyngeal cancer and in Patient 2 after steroid pulse therapy for bronchial asthma. Renal histology of both patients revealed GIN. Polymerase chain reaction (PCR)-based detection of fungal DNA sequences from kidney tissue demonstrated Trichosporon laibachii and Candida albicans, respectively. When AKI occurs in an immunocompromised host, differential diagnosis of fungal interstitial nephritis should be considered. Furthermore, PCR-based detection of fungal DNA sequences from renal specimens can be useful for rapid diagnosis. PMID- 23936629 TI - Caught in the act. AB - The crystal structure of a HECT E3 enzyme has been captured as it transfers ubiquitin to a target protein, revealing the dramatic changes in shape that enable it to modify particular residues in its targets. PMID- 23936628 TI - Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3. AB - Ubiquitination by HECT E3 enzymes regulates myriad processes, including tumor suppression, transcription, protein trafficking, and degradation. HECT E3s use a two-step mechanism to ligate ubiquitin to target proteins. The first step is guided by interactions between the catalytic HECT domain and the E2~ubiquitin intermediate, which promote formation of a transient, thioester-bonded HECT~ubiquitin intermediate. Here we report that the second step of ligation is mediated by a distinct catalytic architecture established by both the HECT E3 and its covalently linked ubiquitin. The structure of a chemically trapped proxy for an E3~ubiquitin-substrate intermediate reveals three-way interactions between ubiquitin and the bilobal HECT domain orienting the E3~ubiquitin thioester bond for ligation, and restricting the location of the substrate-binding domain to prioritize target lysines for ubiquitination. The data allow visualization of an E2-to-E3-to-substrate ubiquitin transfer cascade, and show how HECT-specific ubiquitin interactions driving multiple reactions are repurposed by a major E3 conformational change to promote ligation. DOI:http://dx.doi.org/10.7554/eLife.00828.001. PMID- 23936630 TI - A Simple Nanoscale Interface Directs Alignment of a Confluent Cell Layer on Oxide and Polymer Surfaces. AB - Templating of cell spreading and proliferation is described that yields confluent layers of cells aligned across an entire two-dimensional surface. The template is a reactive, two-component interface that is synthesized in three steps in nanometer thick, micron-scaled patterns on silicon and on several biomaterial polymers. In this method, a volatile zirconium alkoxide complex is first deposited at reduced pressure onto a surface pattern that is prepared by photolithography; the substrate is then heated to thermolyze the organic ligands to form surface-bound zirconium oxide patterns. The thickness of this oxide layer ranges from 10 to 70 nanometers, which is controlled by alkoxide complex deposition time. The oxide layer is treated with 1,4-butanediphosphonic acid to give a monolayer pattern whose composition and spatial conformity to the photolithographic mask are determined spectroscopically. NIH 3T3 fibroblasts and human bone marrow-derived mesenchymal stem cells attach and spread in alignment with the pattern without constraint by physical means or by arrays of cytophilic and cytophobic molecules. Cell alignment with the pattern is maintained as cells grow to form a confluent monolayer across the entire substrate surface. PMID- 23936631 TI - New Hosts of Simplicimonas similis and Trichomitus batrachorum Identified by 18S Ribosomal RNA Gene Sequences. AB - Trichomonads are obligate anaerobes generally found in the digestive and genitourinary tract of domestic animals. In this study, four trichomonad isolates were obtained from carabao, dog, and pig hosts using rectal swab. Genomic DNA was extracted using Chelex method and the 18S rRNA gene was successfully amplified through novel sets of primers and undergone DNA sequencing. Aligned isolate sequences together with retrieved 18S rRNA gene sequences of known trichomonads were utilized to generate phylogenetic trees using maximum likelihood and neighbor-joining analyses. Two isolates from carabao were identified as Simplicimonas similis while each isolate from dog and pig was identified as Pentatrichomonas hominis and Trichomitus batrachorum, respectively. This is the first report of S. similis in carabao and the identification of T. batrachorum in pig using 18S rRNA gene sequence analysis. The generated phylogenetic tree yielded three distinct groups mostly with relatively moderate to high bootstrap support and in agreement with the most recent classification. Pathogenic potential of the trichomonads in these hosts still needs further investigation. PMID- 23936632 TI - Noncompliance with Ocular Hypertensive Treatment in Patients with Primary Open Angle Glaucoma among the Arab Population in Israel: A Cross-Sectional Descriptive Study. AB - Objective. To evaluate the noncompliance treatment rates among primary open angle glaucoma (POAG) Arab patients in Israel and to verify the associated factors for noncompliance. Patients and Methods. A cross-sectional study took place using a questionnaire. Patients were initially interviewed and requested to answer a questionnaire. The questionnaire was developed based on a pilot test. Items included information about age, gender, number of prescribed drugs, and multiple reasons for noncompliance with drug therapy. Setting. Ophthalmologic HMO clinics, located in 3 Arab cities in the center of Israel. Participants. 400 Arab participants (197 men, 203 women) undergoing routine clinical care were recruited. Results. General rate of noncompliance, for both genders, was found to be 50%. Factors associated with nonadherence included inadequate knowledge (32%), underestimation of the disease severity (25.5%), and denial 15.5%. Compliance rates were unaffected by gender or number of prescribed drugs. Compliance was significantly higher in younger patients (age < 50) and in older patients (age > 80), 63% and 77%, respectively, (P < 0.05). Conclusion(s). Noncompliance was found to be common among an Arab population in Israel, particularly between the ages of 50 and 80. Educational programs, improving patient-physician relationship, and personalizing treatment could provide means for improved adherence. PMID- 23936633 TI - An Acidic Thermostable Recombinant Aspergillus nidulans Endoglucanase Is Active towards Distinct Agriculture Residues. AB - Aspergillus nidulans is poorly exploited as a source of enzymes for lignocellulosic residues degradation for biotechnological purposes. This work describes the A. nidulans Endoglucanase A heterologous expression in Pichia pastoris, the purification and biochemical characterization of the recombinant enzyme. Active recombinant endoglucanase A (rEG A) was efficiently secreted as a 35 kDa protein which was purified through a two-step chromatography procedure. The highest enzyme activity was detected at 50 degrees C/pH 4. rEG A retained 100% of activity when incubated at 45 and 55 degrees C for 72 h. Purified rEG A kinetic parameters towards CMC were determined as K m = 27.5 +/- 4.33 mg/mL, V max = 1.185 +/- 0.11 mmol/min, and 55.8 IU (international units)/mg specific activity. Recombinant P. pastoris supernatant presented hydrolytic activity towards lignocellulosic residues such as banana stalk, sugarcane bagasse, soybean residues, and corn straw. These data indicate that rEG A is suitable for plant biomass conversion into products of commercial importance, such as second generation fuel ethanol. PMID- 23936635 TI - Determinants of fast food consumption among Iranian high school students based on planned behavior theory. AB - OBJECTIVE: This study was conducted to identify some factors (beliefs and norms) which are related to fast food consumption among high school students in Isfahan, Iran. We used the framework of the theory planned behavior (TPB) to predict this behavior. SUBJECTS & METHODS: Cross-sectional data were available from high school students (n = 521) who were recruited by cluster randomized sampling. All of the students completed a questionnaire assessing variables of standard TPB model including attitude, subjective norms, perceived behavior control (PBC), and the additional variables past behavior, actual behavior control (ABC). RESULTS: The TPB variables explained 25.7% of the variance in intentions with positive attitude as the strongest (beta = 0.31, P < 0.001) and subjective norms as the weakest (beta = 0.29, P < 0.001) determinant. Concurrently, intentions accounted for 6% of the variance for fast food consumption. Past behavior and ABC accounted for an additional amount of 20.4% of the variance in fast food consumption. CONCLUSION: Overall, the present study suggests that the TPB model is useful in predicting related beliefs and norms to the fast food consumption among adolescents. Subjective norms in TPB model and past behavior in TPB model with additional variables (past behavior and actual behavior control) were the most powerful predictors of fast food consumption. Therefore, TPB model may be a useful framework for planning intervention programs to reduce fast food consumption by students. PMID- 23936634 TI - p38 MAPK Signaling in Pemphigus: Implications for Skin Autoimmunity. AB - p38 mitogen activated protein kinase (p38 MAPK) signaling plays a major role in the modulation of immune-mediated inflammatory responses and therefore has been linked with several autoimmune diseases. The extent of the involvement of p38 MAPK in the pathogenesis of autoimmune blistering diseases has started to emerge, but whether it pays a critical role is a matter of debate. The activity of p38 MAPK has been studied in great detail during the loss of keratinocyte cell-cell adhesions and the development of pemphigus vulgaris (PV) and pemphigus foliaceus (PF). These diseases are characterised by autoantibodies targeting desmogleins (Dsg). Whether autoantibody-antigen interactions can trigger signaling pathways (such as p38 MAPK) that are tightly linked to the secretion of inflammatory mediators which may perpetuate inflammation and tissue damage in pemphigus remains unclear. Yet, the ability of p38 MAPK inhibitors to block activation of the proapoptotic proteinase caspase-3 suggests that the induction of apoptosis may be a consequence of p38 MAPK activation during acantholysis in PV. This review discusses the current evidence for the role of p38 MAPK in the pathogenesis of pemphigus. We will also present data relating to the targeting of these cascades as a means of therapeutic intervention. PMID- 23936636 TI - Reliability of questionnaires to assess the healthy eating and activity environment of a child's home and school. AB - Childhood overweight and obesity are a growing concern globally, and environments, including the home and school, can contribute to this epidemic. This paper assesses the reliability of two questionnaires (parent and teacher) used in the evaluation of a community-based childhood obesity prevention intervention, the eat well be active (ewba) Community Programs. Parents and teachers were recruited from two primary schools and they completed the same questionnaire twice in 2008 and 2009. Data from both questionnaires were classified into outcomes relevant to healthy eating and activity, and target outcomes, based on the goals of the ewba Community Programs, were identified. Fourteen and 12 outcomes were developed from the parent and teacher questionnaires, respectively. Sixty parents and 28 teachers participated in the reliability study. Intraclass correlation coefficients for outcomes ranged from 0.37 to 0.92 (parent) (P < 0.05) and from 0.42 to 0.86 (teacher) (P < 0.05). Internal consistency, measured by Cronbach's alpha, of teacher scores ranged from 0.11 to 0.91 and 0.13 to 0.78 for scores from the parent questionnaire. The parent and teacher questionnaires are moderately reliable tools for simultaneously assessing child intakes, environments, attitudes, and knowledge associated with healthy eating and physical activity in the home and school and may be useful for evaluation of similar programs. PMID- 23936637 TI - Pomegranate polyphenols lower lipid peroxidation in adults with type 2 diabetes but have no effects in healthy volunteers: a pilot study. AB - Aims. To examine the antioxidant and anti-inflammatory effects of pomegranate polyphenols in obese patients with type 2 diabetes (T2DM) (n = 8) and in healthy nondiabetic controls (n = 9). Methods. Participants received 2 capsules of pomegranate polyphenols (POMx, 1 capsule = 753 mg polyphenols) daily for 4 weeks. Blood draws and anthropometrics were performed at baseline and at 4 weeks of the study. Results. Pomegranate polyphenols in healthy controls and in T2DM patients did not significantly affect body weight and blood pressure, glucose and lipids. Among clinical safety profiles, serum electrolytes, renal function tests, and hematological profiles were not significantly affected by POMx supplementation. However, aspartate aminotransferase (AST) showed a significant increase in healthy controls, while alanine aminotransferase (ALT) was significantly decreased in T2DM patients at 4 weeks (P < 0.05), though values remained within the normal ranges. Among the biomarkers of lipid oxidation and inflammation, oxidized LDL and serum C-reactive protein (CRP) did not differ at 4 weeks in either group, while pomegranate polyphenols significantly decreased malondialdehyde (MDA) and hydroxynonenal (HNE) only in the diabetic group versus baseline (P < 0.05). Conclusions. POMx reduces lipid peroxidation in patients with T2DM, but with no effects in healthy controls, and specifically modulates liver enzymes in diabetic and nondiabetic subjects. Larger clinical trials are merited. PMID- 23936638 TI - Quality assessment of the genetic test for familial hypercholesterolemia in the Netherlands. AB - Introduction. Familial hypercholesterolemia (FH) is an inherited disorder associated with a severely increased risk of cardiovascular disease. Although DNA test results in FH are associated with important medical and ethical consequences, data on accuracy of genetic tests is scarce. Methods. Therefore, we performed a prospective study to assess the overall accuracy of the DNA test used in the genetic cascade screening program for FH in The Netherlands. Individuals aged 18 years and older tested for one of the 5 most prevalent FH mutations, were included consecutively. DNA samples were analyzed by the reference and a counter expertise laboratory following a standardized procedure. Results. 1003 cases were included. In the end, 317 (32%) carried an FH mutation, whereas in 686 (69%) samples no mutation was found. The overall accuracy of the reference laboratory was 99.8%, with two false positive results identified by the counter-expertise laboratory. Conclusion. The currently used mutation analysis is associated with a very low error rate. Therefore, we do not recommend routine use of duplicate testing. PMID- 23936639 TI - Validation of computerized automatic calculation of the sequential organ failure assessment score. AB - Purpose. To validate the use of a computer program for the automatic calculation of the sequential organ failure assessment (SOFA) score, as compared to the gold standard of manual chart review. Materials and Methods. Adult admissions (age > 18 years) to the medical ICU with a length of stay greater than 24 hours were studied in the setting of an academic tertiary referral center. A retrospective cross-sectional analysis was performed using a derivation cohort to compare automatic calculation of the SOFA score to the gold standard of manual chart review. After critical appraisal of sources of disagreement, another analysis was performed using an independent validation cohort. Then, a prospective observational analysis was performed using an implementation of this computer program in AWARE Dashboard, which is an existing real-time patient EMR system for use in the ICU. Results. Good agreement between the manual and automatic SOFA calculations was observed for both the derivation (N=94) and validation (N=268) cohorts: 0.02 +/- 2.33 and 0.29 +/- 1.75 points, respectively. These results were validated in AWARE (N=60). Conclusion. This EMR-based automatic tool accurately calculates SOFA scores and can facilitate ICU decisions without the need for manual data collection. This tool can also be employed in a real-time electronic environment. PMID- 23936640 TI - Trends of postpartum depression in iran: a systematic review and meta-analysis. AB - Background. Postpartum depression (PPD) is a serious mental health disorder affecting 13% of women in developed communities. The present study reviews available epidemiological publications on PPD-related aspects in Iranian women to help policy makers and health workers to design preventative strategies and further researches. Materials and Methods. A systematic review was constructed based on the computerized literature valid database. The 95% confidence intervals were calculated by random effects models. Metaregression was introduced to explore and explain heterogeneity between studies. Data manipulation and statistical analyses were performed using Stata 11. Results. Overall, 41 studies met the inclusion criteria. The pooled prevalence of PPD in Iran was 25.3% (95% CI: 22.7%-27.9%). Amongst subgroups of unwanted delivery, illiterate, housewives, and having history of depression the prevalence was 43.4% (35.6-51.1), 31.6% (18.1-45.0), 30.7% (25.2-36.3), and 45.2% (35.4-53.1), respectively. Conclusions. Interventions that would specifically target women with a prior history of depression, illiterates, housewives, or women with unwanted pregnancies could be helpful to decrease the prevalence of postpartum depression in Iran. PMID- 23936641 TI - Ketogenic diet in epileptic encephalopathies. AB - The ketogenic diet is a medically supervised high-fat, low-carbohydrate diet that has been found useful in patients with refractory epilepsy. It has been shown to be effective in treating multiple seizure types and epilepsy syndromes. In this paper, we review the use of the ketogenic diet in epileptic encephalopathies such as Ohtahara syndrome, West syndrome, Dravet syndrome, epilepsy with myoclonic atonic seizures, and Lennox-Gastaut syndrome. PMID- 23936642 TI - Genetic heterogeneity of breast cancer metastasis may be related to miR-21 regulation of TIMP-3 in translation. AB - PURPOSE: MicroRNAs are noncoding RNA molecules that posttranscriptionally regulated expression of target gene and implicate the progress of cancer proliferation, differentiation, and apoptosis. The aim of this study is to determine whether microRNA-21 (miR-21), a specific microRNA implicated in multiple aspects of carcinogenesis, promoted breast cancer metastasis by regulating the tissue inhibitor of metalloproteinase 3 (TIMP-3) gene. METHODS: miR-21 of serum and tissue from 40 patients (30 patients with breast cancer) were detected by real-time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR). TIMP-3 of tissue from the patient was tested by real-time RT qPCR. Protein expression of TIMP-3 was evaluated by western blotting. Correlation analysis was performed between miR-21 and TIMP-3. RESULTS: Of the 40 samples from tissue and serum analyzed, the miR-21 expression was significantly higher in high invasion metastasis group (HIMG) that in low invasion metastasis group (LIMG); the latter was higher than that in normal group (NG). Additionally, the TIMP-3 expression was significantly lower in HIMG than in LIMG; the latter was lower than that in NG. There was significantly inverse correlation between miR-21 and TIMP-3 extracted from tissue. CONCLUSION: Our data suggest that miR-21 could promote metastasis in breast cancer via the regulation of TIMP3 translation, and there was consistency between miR-21 of serum and miR-21 in tissue. PMID- 23936643 TI - Epigenetics in critical illness: a new frontier. AB - Epigenetics is the study of alterations in the function of genes that do not involve changes in the DNA sequence. Within the critical care literature, it is a relatively new and exciting avenue of research in describing pathology, clinical course, and developing targeted therapies to improve outcomes. In this paper, we highlight current research relative to critical care that is focused within the major epigenetic mechanisms of DNA methylation, histone modification, microRNA regulation, and composite epigenetic scoring. Within this emerging body of research it is quite clear that the novel therapies of the future will require clinicians to understand and navigate an even more complex and multivariate relationship between genetic, epigenetic, and biochemical mechanisms in conjunction with clinical presentation and course in order to significantly improve outcomes within the acute and critically ill population. PMID- 23936644 TI - The Supraorbital Keyhole Craniotomy through an Eyebrow Incision: Its Origins and Evolution. AB - In the modern era of neurosurgery, the use of the operative microscope, rigid rod lens endoscope, and neuronavigation has helped to overcome some of the previous limitations of surgery due to poor lighting and anatomic localization available to the surgeon. Over the last thirty years, the supraorbital craniotomy and subfrontal approach through an eyebrow incision have been developed and refined to play a legitimate role in the armamentarium of the modern skull base neurosurgeon. With careful patient selection, the supraorbital "keyhole" approach offers a less invasive but still efficacious approach to a number of lesions along the subfrontal corridor. Well over 1000 cases have been reported in the literature utilizing this approach establishing its safety and efficacy. This paper discusses the nuances of this approach, including the benefits and limitations of its use described through our technique, review of the literature, and case illustration. PMID- 23936645 TI - Robotically Assisted Hysterectomy versus Vaginal Hysterectomy for Benign Disease: A Prospective Study. AB - Objectives. A prospective study was carried out to compare vaginal hysterectomy (VH) and robotically assisted hysterectomy (RH) for benign gynecological disease. Materials and Methods. All patients who underwent hysterectomy from March 2010 to March 2012 for a benign disease were included. Patients' demographics per and post surgery results were collected from medical files. A questionnaire was also conducted 2 months after surgery. Results. Sixty patients were included in the RH group and thirty four in the VH one. Operative time was significantly longer in the RH group (132.1 +/- 5.7 versus 75.3 +/- 6.7 min; P < 0.0001). Blood loss and length of hospital stay were significantly reduced: 47 +/- 7 versus 125 +/- 20 ml; P < 0.01, and 2.4 +/- 0.1 versus 3.3 +/- 0.2 days; P < 0.0001, respectively. Less pain was reported at D1 and D2 by RH patients, and levels of analgesia were lower compared to those observed in the VH group. No differences were found regarding the rate of conversion to laparotomy, intra- or postoperative complications. Conclusion. Robotically assisted hysterectomy appears to reduce blood loss, postoperative pain, and length of hospital stay, but it is associated with longer operative time and higher cost. Specific indications for RH remain to be defined. PMID- 23936646 TI - Assessing Improvement in Quality of Life and Patient Satisfaction following Body Contouring Surgery in Patients with Massive Weight Loss: A Critical Review of Outcome Measures Employed. AB - Body contouring following massive weight loss is a rapidly expanding field in plastic surgery. However, healthcare payers are reluctant to fund such procedures, viewing them as purely cosmetic. This has resulted in a flurry of studies assessing quality of life (QoL) and patient satisfaction following body contouring surgery in this cohort of patients to establish an evidence base to support the idea that body contouring is as much (or even more) a functional procedure as it is cosmetic. However, the methods employed in these studies are seldom ideal, and hence the conclusions are unreliable. The gold standard to assess QoL and patient satisfaction is to use patient specific psychometrically validated patient reported outcome (PRO) measures. Developing such measures consists of a three-step process which includes a review of the current literature, qualitative patient interviews to determine what patients consider the most important, and expert opinion. This study aims to appraise the currently available literature on assessment of QoL and patient satisfaction in body contouring surgery patients. This will hopefully provide an understanding of methodological weaknesses in current studies and inform future investigators of the design of ideal instruments for assessing QoL and patient satisfaction in body contouring patients. PMID- 23936647 TI - The Influence of Hypoxia and pH on Bioluminescence Imaging of Luciferase Transfected Tumor Cells and Xenografts. AB - Bioluminescence imaging (BLI) is a relatively new noninvasive technology used for quantitative assessment of tumor growth and therapeutic effect in living animal models. BLI involves the generation of light by luciferase-expressing cells following administration of the substrate luciferin in the presence of oxygen and ATP. In the present study, the effects of hypoxia, hypoperfusion, and pH on BLI signal (BLS) intensity were evaluated in vitro using cultured cells and in vivo using a xenograft model in nude mice. The intensity of the BLS was significantly reduced in the presence of acute and chronic hypoxia. Changes in cell density, viability, and pH also affected BLS. Although BLI is a convenient non-invasive tool for tumor assessment, these factors should be considered when interpreting BLS intensity, especially in solid tumors that could be hypoxic due to rapid growth, inadequate blood supply, and/or treatment. PMID- 23936648 TI - Evaluation of Nonradiative Clinical Imaging Techniques for the Longitudinal Assessment of Tumour Growth in Murine CT26 Colon Carcinoma. AB - Background and Objectives. To determine the most appropriate technique for tumour followup in experimental therapeutics, we compared ultrasound (US) and magnetic resonance imaging (MRI) to characterize ectopic and orthotopic colon carcinoma models. Methods. CT26 tumours were implanted subcutaneously (s.c.) in Balb/c mice for the ectopic model or into the caecum for the orthotopic model. Tumours were evaluated by histology, spectrofluorescence, MRI, and US. Results. Histology of CT26 tumour showed homogeneously dispersed cancer cells and blood vessels. The visualization of the vascular network using labelled albumin showed that CT26 tumours were highly vascularized and disorganized. MRI allowed high-resolution and accurate 3D tumour measurements and provided additional anatomical and functional information. Noninvasive US imaging allowed good delineation of tumours despite an hypoechogenic signal. Monitoring of tumour growth with US could be accomplished as early as 5 days after implantation with a shorter acquisition time (<5 min) compared to MRI. Conclusion. MRI and US afforded excellent noninvasive imaging techniques to accurately follow tumour growth of ectopic and orthotopic CT26 tumours. These two techniques can be appropriately used for tumour treatment followup, with a preference for US imaging, due to its short acquisition time and simplicity of use. PMID- 23936650 TI - Mild cognitive impairment in Parkinson's disease: a review of current concepts. AB - Mild Cognitive Impairment in Parkinson's Disease (PD-MCI) is common and may be associated with accelerated progression to dementia. Considering the importance of this emerging entity, new diagnostic criteria have recently been proposed. Early recognition and accurate classification of PD-MCI could offer opportunities for novel therapeutic interventions. This review discusses current definitions for PD-MCI, the screening tools used, the pattern of cognitive deficits observed, and the predictors of cognitive decline and transition to Parkinson's Disease Dementia. Emerging biomarkers, which may aid diagnosis, are also explored and the role of novel treatment options is considered. PMID- 23936651 TI - Geriatric chest imaging: when and how to image the elderly lung, age-related changes, and common pathologies. AB - Even in a global perspective, societies are getting older. We think that diagnostic lung imaging of older patients requires special knowledge. Imaging strategies have to be adjusted to the needs of frail patients, for example, immobility, impossibility for long breath holds, renal insufficiency, or poor peripheral venous access. Beside conventional radiography, modern multislice computed tomography is the method of choice in lung imaging. It is especially important to separate the process of ageing from the disease itself. Pathologies with a special relevance for the elderly patient are discussed in detail: pneumonia, aspiration pneumonia, congestive heart failure, chronic obstructive pulmonary disease, the problem of overlapping heart failure and chronic obstructive pulmonary disease, pulmonary drug toxicity, incidental pulmonary embolism pulmonary nodules, and thoracic trauma. PMID- 23936652 TI - Can we trust the internet to measure psychotic symptoms? AB - Online studies are increasingly utilized in applied research. However, lack of external diagnostic verification in many of these investigations is seen as a threat to the reliability of the data. The present study examined the robustness of internet studies on psychosis against simulation. We compared the psychometric properties of the Community Assessment of Psychic Experiences scale (CAPE), a self-report instrument measuring psychotic symptoms, across three independent samples: (1) participants with a confirmed diagnosis of schizophrenia, (2) participants with self-reported schizophrenia who were recruited over the internet, and (3) clinical experts on schizophrenia as well as students who were asked to simulate a person with schizophrenia when completing the CAPE. The CAPE was complemented by a newly developed 4-item psychosis lie scale. Results demonstrate that experts asked to simulate schizophrenia symptoms could be distinguished from real patients: simulators overreported positive symptoms and showed elevated scores on the psychosis lie scale. The present study suggests that simulated answers in online studies on psychosis can be distinguished from authentic responses. Researchers conducting clinical online studies are advised to adopt a number of methodological precautions and to compare the psychometric properties of online studies to established clinical indices to assert the validity of their results. PMID- 23936649 TI - Pathophysiologic mechanisms of cardiovascular disease in obstructive sleep apnea syndrome. AB - Obstructive sleep apnea syndrome (OSAS) is a highly prevalent sleep disorder, characterized by repeated disruptions of breathing during sleep. This disease has many potential consequences including excessive daytime sleepiness, neurocognitive deterioration, endocrinologic and metabolic effects, and decreased quality of life. Patients with OSAS experience repetitive episodes of hypoxia and reoxygenation during transient cessation of breathing that provoke systemic effects. Furthermore, there may be increased levels of biomarkers linked to endocrine-metabolic and cardiovascular alterations. Epidemiological studies have identified OSAS as an independent comorbid factor in cardiovascular and cerebrovascular diseases, and physiopathological links may exist with onset and progression of heart failure. In addition, OSAS is associated with other disorders and comorbidities which worsen cardiovascular consequences, such as obesity, diabetes, and metabolic syndrome. Metabolic syndrome is an emerging public health problem that represents a constellation of cardiovascular risk factors. Both OSAS and metabolic syndrome may exert negative synergistic effects on the cardiovascular system through multiple mechanisms (e.g., hypoxemia, sleep disruption, activation of the sympathetic nervous system, and inflammatory activation). It has been found that CPAP therapy for OSAS provides an objective improvement in symptoms and cardiac function, decreases cardiovascular risk, improves insulin sensitivity, and normalises biomarkers. OSAS contributes to the pathogenesis of cardiovascular disease independently and by interaction with comorbidities. The present review focuses on indirect and direct evidence regarding mechanisms implicated in cardiovascular disease among OSAS patients. PMID- 23936653 TI - Transperitoneal calcium balance in anuric continuous ambulatory peritoneal dialysis and automated peritoneal dialysis patients. AB - Backgrounds. Calcium (Ca) and bone metabolism in continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) patients show a remarkable difference depending on dialysis modalities. The levels of serum Ca and phosphate (P) in HD patients fluctuate contributing to the intermittent and rapid removal of plasma solute unlike in CAPD. Characteristics of plasma solute transport in automated peritoneal dialysis (APD) patients are resembled with that in HD. The purpose of the present study was to examine the difference of transperitoneal Ca removal between APD and CAPD anuric patients. Subjects and Methods. Twenty-three APD anuric patients were enrolled in this study. Biochemical parameters responsible for transperitoneal Ca removal in 24-hour and 4-hour peritoneal effluents were analyzed on CAPD and APD. Results. Transperitoneal Ca removal on APD was smaller compared with that on CAPD. The Ca removal was related to the ultrafiltration during short-time dwell. Decrease of the Ca removal during NPD induced by short time dialysate dwell caused negative or small Ca removal in APD patients. The levels of intact PTH were increased at the end of PET. Conclusion. It appears that short-time dwell and frequent dialysate exchanging might suppress the transperitoneal Ca removal in anuric APD patients. PMID- 23936654 TI - Body mass index, gestational weight gain, and obstetric complications in Moroccan population. AB - OBJECTIVES: To evaluate the impact of the body mass index (BMI) before pregnancy and the weight gain during pregnancy, on the occurrence of maternal and neonatal morbidity in the Moroccan population, as well as to analyze the quality of the weight gain depending on the BMI. METHODS: A study was carried out over a period of one year from October 1, 2010 to October 1, 2011, using data collected from a descriptive-transversal study. We recruited nondiabetic women without several HTAs, delivering singletons from 37 completed weeks up to 42 weeks gestation. RESULTS: Total of 1408 were analyzed. The risks of moderate hypertension, macrosomia, dystocia, and resort to cesarean section were higher among overweight or obese women, as well as among women whose weight gain was >16 kg. The differences were significant <0.05. CONCLUSION: This study demonstrates that overweight women before pregnancy and weight gain during pregnancy are associated with higher risks of maternal and neonatal complications. These data provide ideas on prevention opportunities. PMID- 23936655 TI - Lipid-based nanoparticles in cancer diagnosis and therapy. AB - Today, researchers are constantly developing new nanomaterials, nanodevices, and nanoparticles to meet unmet needs in the delivery of therapeutic agents and imaging agents for cancer therapy and diagnosis, respectively. Of particular interest here are lipid-based nanoparticles (LNPs) that are genuine particles (approximately 100 nm in dimension) assembled from varieties of lipid and other chemical components that act collectively to overcome biological barriers (biobarriers), in order for LNPs to preferentially accumulate in or around disease-target cells for the functional delivery of therapeutic agents for treatment or of imaging agents for diagnosis. The capabilities of these LNPs will clearly vary depending on functional requirements, but the nanoscale allows for an impressive level of diversity in capabilities to enable corresponding LNPs to address an equally diverse range of functional requirements. Accordingly, LNPs should be considered appropriate vehicles to provide an integrated, personalized approach to cancer diagnosis and therapy in future cancer disease management. PMID- 23936657 TI - Evaluation of central venous catheter associated blood stream infections: a microbiological observational study. AB - There are substantial morbidity and mortality associated with vascular catheter use among crictically ill patients. The attributable mortality is 10% to 25% which is associated with bacteremia among those who are hospitalized. This study was undertaken to identify catheter related blood stream infections, to isolate pathogenic microorganisms present in intravascular catheter related local infections, exit site infections, and to determine the predisposing factors for the development of such infections and antibiotic sensitivity pattern of the isolated organisms in tertiary care hospital. PMID- 23936656 TI - Polymeric micelles, a promising drug delivery system to enhance bioavailability of poorly water-soluble drugs. AB - Oral administration is the most commonly used and readily accepted form of drug delivery; however, it is find that many drugs are difficult to attain enough bioavailability when administered via this route. Polymeric micelles (PMs) can overcome some limitations of the oral delivery acting as carriers able to enhance drug absorption, by providing (1) protection of the loaded drug from the harsh environment of the GI tract, (2) release of the drug in a controlled manner at target sites, (3) prolongation of the residence time in the gut by mucoadhesion, and (4) inhibition of efflux pumps to improve the drug accumulation. To explain the mechanisms for enhancement of oral bioavailability, we discussed the special stability of PMs, the controlled release properties of pH-sensitive PMs, the prolongation of residence time with mucoadhesive PMs, and the P-gp inhibitors commonly used in PMs, respectively. The primary purpose of this paper is to illustrate the potential of PMs for delivery of poorly water-soluble drugs with bioavailability being well maintained. PMID- 23936659 TI - Hepatocellular Carcinoma More Than 3 cm in Diameter: A Systematic Review of Transcatheter Arterial Chemoembolization Plus Percutaneous Ethanol Injection versus Transcatheter Arterial Chemoembolization Alone. AB - Objective. To identify the efficiency and safety of transcatheter arterial chemoembolization (TACE) combined with percutaneous ethanol (PEI) for patients with hepatocellular carcinoma (HCC) more than 3 cm in diameter in comparison with those of transcatheter arterial chemoembolization monotherapy. Methods. All databases were searched up to February 22, 2013. The literature retrieval was conducted through Pubmed, Web of Science, and Cochrane Library. We also searched Chinese databases, including Chinese National Knowledge Infrastructure (CNKI), Chinese Biology Medicine (CBM), Wanfang database, and VIP Database for Chinese Technical Periodicals without language limitations. Results. Based on the criteria, we found 12 RCTs including 825 patients. Our results showed that TACE combined with PEI therapy compared with TACE monotherapy improved overall survival and tumor response. Conclusion. The combination of TACE and PEI compared with TACE monotherapy improved overall survival rates and tumor response of patients with large HCC. Besides, larger and more methodologically rigorous clinical trials are needed to confirm this outcome. PMID- 23936658 TI - The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias. AB - The development of the genetic studies on acute myeloid leukemias (AMLs) has led to the identification of some recurrent genetic abnormalities. Their discovery was of fundamental importance not only for a better understanding of the molecular pathogenesis of AMLs, but also for the identification of new therapeutic targets. In this context, it is essential to identify AML-associated "driver" mutations, which have a causative role in leukemogenesis. Evidences accumulated during the last years indicate that activating internal tandem duplication mutations in FLT3 (FLT3-ITD), detected in about 20% of AMLs, represents driver mutations and valid therapeutic targets in AMLs. Furthermore, the screening of FLT3-ITD mutations has also considerably helped to improve the identification of more accurate prognostic criteria and of the therapeutic selection of patients. PMID- 23936660 TI - The incidence of colorectal cancer is decreasing in the older age cohorts in the zaanstreek region in the Netherlands: an age-cohort effect. AB - Introduction. Colorectal cancer (CRC) has a high incidence. Removal of adenomas, the precursor lesion, could be helpful in the prevention of cancer. Aim. To investigate the yearly incidence of CRC in consecutive years. Patients and Methods. All patients diagnosed with CRC in the years 1990 till 2010 were studied. Date of diagnosis, age at time of diagnosis, gender, and localisation of the tumour were assessed. Results. A total of 1575 incident CRC were diagnosed, 865 men (55%) and 710 women (45%). CRC occurred more often in men. In the course of the years, the occurrence of CRC increased. After exclusion of rectal cancer, the percentage of proximal cancer in the colon shows a trend towards increase in the consecutive years. In the twenty consecutive years, the population of the Zaanstreek region increased from 130.000 to 145.330. There was a significant increase of CRC in the age cohort 51-70 in the period of twenty years, while a significant decreasing incidence of cancer was seen in patients above 71 years. Conclusion. The decreasing incidence of colorectal cancer in the age cohorts above 71 years possibly reflects indirect evidence of an age-cohort effect due to removal of adenomas in these age cohorts earlier in life. PMID- 23936661 TI - Frequency and Outcome of Graft versus Host Disease after Stem Cell Transplantation: A Six-Year Experience from a Tertiary Care Center in Pakistan. AB - Objective. The objective of this study was to evaluate the frequency and outcome of graft versus host disease after stem cell transplantation for various haematological disorders in Pakistan. Materials and Methods. Pretransplant workup of the patient and donor was performed. Mobilization was done with G-CSF 300 MU g twice daily for five day. Standard GvHD prophylaxis was done with methotrexate 15 mg/m(2) on day +1 followed by 10 mg/m(2) on days +3 and +6 and cyclosporine. Grading was done according to the Glucksberg classification. Results. A total of 153 transplants were done from April 2004 to December 2011. Out of these were allogeneic transplants. There were females and males. The overall frequency of any degree of graft versus host disease was 34%. Acute GvHD was present in patients while had chronic GvHD. Grade II GvHD was present in patients while grade III and IV GvHD was seen in patients each. Acute myeloid leukemia and chronic myeloid leukemia were most commonly associated with GvHD. The mortality in acute and chronic GvHD was 8.8% and 12% respectively. Conclusion. The frequency of graft versus host disease in this study was 34% which is lower compared to international literature. The decreased incidence can be attributed to reduced diversity of histocompatibility antigens in our population. PMID- 23936662 TI - Applicability of the rapid biophysical profile in antepartum fetal well-being assessment in high-risk pregnancies from a university hospital in sao paulo, Brazil: preliminary results. AB - Objective. To evaluate the clinical applicability of the rapid biophysical profile (rBPP), comparing results of the rBPP to umbilical cord pH values and Apgar scores. Methods. A cross-sectional study was conducted with 37 pregnant women from our high-risk service. All of them gave birth at our institution. rBPP was conducted up to 24 h prior to delivery and pH values were obtained from the umbilical vein immediately after birth. The mean and standard deviations for maternal age, gestational age at birth, pH values, and Apgar score in the 1st and 5th minutes after birth were calculated. An unpaired Student's t-test was applied to evaluate the correlation between these variables and rBPP scores of 2 and 4. Results. rBPP score of 2 was observed in 8 patients (21.6%) and score 4 was observed in 29 cases (78.4%). No patients received score zero. The difference between the Apgar scores of the rBPP score 2 and 4 was statistically significant (P < 0.01) while the same was not true with the umbilical cord pH (P = 0.08), even though the values tended to be lower in the rBPP 2 group. Conclusion. The rBPP is a fast and practical method of assessment of antepartum fetal well-being. Further studies, with a larger number of patients, are necessary to evaluate the applicability of the method. PMID- 23936663 TI - Retrospective study of seven cases with acute Fatty liver of pregnancy. AB - Objectives. Our aim is to explore the clinical outcome of patients with acute fatty liver of pregnancy (AFLP), and evaluate the effect of early diagnosis and treatment. Methods. Seven patients who were diagnosed with AFLP were retrospectively analyzed from February 2005 to January 2013. The clinical records of the patients with AFLP were reviewed for clinical features, laboratory examinations, and maternal and perinatal prognosis. Routine laboratory evaluation revealed hyperbilirubinemia, moderately elevated liver transaminase, but negative serum hepatitis virus in each patient. For additional evidence, 126 cases of AFLP were reviewed retrospectively from original articles researched in A Medline based English and Chinese Knowledge Infrastructure between the same periods. Results. The initial symptoms of all the 7 cases with AFLP were gastrointestinal symptoms; anorexia, nausea, vomiting, and progressive jaundice. Complications revealed with renal insufficiency in all 7 patients. Hepatic failure, MODS, hypoglycemia and DIC were seen in 4 patients (57.1%). Hemorrhagic shock, ARDS, and hepatic encephalopathy were seen in 3 patients (42.8%). There was only one case of maternal death (14.2%), three cases of perinatal death (30%) and one postnatal death (10%). Conclusion. AFLP occurs in late pregnancy is a rare clinical syndrome occurs at about 36 weeks of gestation. Early diagnosis and prompt termination of pregnancy is the key of management with multidisciplinary collaboration, comprehensive treatment and effective prevention are helpful to improve prognosis of the cases with AFLP and perinatal death. PMID- 23936664 TI - Four Hour Temporal Relation of 5-HTP and L-DOPA Induces Inhibitory Responses in Recrudescing Gonad of Indian Palm Squirrel (Funambulus pennantii). AB - Daily injections of L-dihydroxyphenylalanine (L-DOPA, dopamine precursor) given 4 h after 5-hydroxytryptophan (5-HTP, serotonin precursor) induced inhibitory responses in recrudescing gonad (in the first week of December) of Indian palm squirrel, a seasonally breeding subtropical animal. Other temporal relations (L DOPA given at 0, 8, 12, 16, and 20 h after 5-HTP administration) did not show any effect on the recrudescing gonad. This inhibitory effect of 4 h was evident under short day length (6 : 18) group but was masked by the increasing day length of nature (NDL, late December onwards) and increased photoperiod of long day group (16 : 8). It is apparent that seasonal testicular recrudescence of Indian palm squirrel during short day length by 4 h relation of 5-HTP and L-DOPA is not a pharmacological effect but actually is an alteration of seasonality in this annually breeding mammal. It seems that endogenous mechanism controlling seasonal testicular recrudescence of Indian palm squirrel is reset by timed daily injections of these neurotransmitter drugs. It is suggested that in spite of different environmental factors (photoperiod, humidity, etc.) used by different species to time their annual reproduction, basic mechanism of seasonality appears to be the same, that is, the temporal synergism of neurotransmitter activity. PMID- 23936666 TI - Paradoxically Low Levels of Total and HMW Adiponectin in Relation to Metabolic Parameters in a Tongan Population. AB - Aim. Adiponectin has demonstrated anti-inflammatory and insulin sensitising properties, and low circulating levels may be an important risk factor for diabetes. We examined levels of adiponectin and its insulin-sensitising HMW isoform and their relationship with metabolic parameters in Tongans, a population prone to type II diabetes. Methods. Adiponectin and its HMW isoform were quantitated by Elisa in specimens from a randomly recruited, multistage cluster population survey of Tongans and from a group of Caucasians. Anthropometric, clinical, and biochemical data were collected on each subject. Results. Both male and female Tongans had lower levels of total and HMW adiponectin than their Caucasian counterparts. Levels of total and HMW adiponectin were higher in females than males in each group. Adiponectin levels were inversely related to BMI, weight, and HOMA in Tongan males and females, as well as to dyslipidemia in both sexes. Conclusion. Tongans had lower levels of both total and HMW adiponectin than Caucasians population, even after matching Tongans to their Caucasian counterparts based on BMI, age, and sex. These findings may reflect differences in body composition between the populations not adequately assessed by BMI, lifestyle factors, or a genetic variant likely in a genetically homogenous population. PMID- 23936667 TI - Selected Health Status Measures of Children from US Immigrant Families. AB - Using the 2007 National Survey of Children's Health (N = 91,532), we studied the relationship between the joint effects of immigrant family type (foreign-born children, US-born children/one foreign-born parent, US-born children/both foreign born parents, and US-born children/US-born parents) and race/ethnicity on various health measures (parent-reported physical and dental health, obesity/overweight, breast-feeding, school absence, injury, and chronic condition). We used weighted logistic regression to examine the independent effects of the 12-level joint variable on various health status measures while controlling for confounding factors. Overall, nearly one-third of families with both foreign-born parents were poor, and one-quarter of the parents in these households did not complete high school. Compared with non-Hispanic White US-born children, multivariable analyses indicate that all Hispanic children have higher odds of obesity, poor physical and dental health, with Hispanic foreign-born children 7 times as likely to report poor/fair physical health. Most children of immigrant parents were more likely to have been breast-fed and less likely to miss school more than 11 days. Child age and household poverty status were independently associated with most of the health status measures. Combined race/ethnicity and immigrant family type categories have heterogeneous associations with each health outcome measure examined. Culturally competent interventions and policies should be developed to serve these expanding communities. PMID- 23936668 TI - In Vivo and In Vitro Antidiabetic Activity of Terminalia paniculata Bark: An Evaluation of Possible Phytoconstituents and Mechanisms for Blood Glucose Control in Diabetes. AB - The present study was aimed to investigate in vivo, in vitro antidiabetic activity of aqueous extract of Terminalia paniculata bark (AETPB) and characterize its possible phytoconstituents responsible for the actions. Type 2 diabetes was induced in rats by streptozotocin-nicotinamide (65 mg/kg-110 mg/kg; i.p.) administration. Oral treatment of AETPB using rat oral needle at 100 and 200 mg/kg doses significantly (P < 0.001) decreased blood glucose and glycosylated haemoglobin levels in diabetic rats than diabetic control rats. AETPB-treated diabetic rats body weight, total protein, insulin, and haemoglobin levels were increased significantly (P < 0.001) than diabetic control rats. A significant (P < 0.001) reduction of total cholesterol and triglycerides and increase in high-density lipoprotein levels were observed in type 2 diabetic rats after AETPB administration. Presence of biomarkers gallic acid, ellagic acid, catechin, and epicatechin in AETPB was confirmed in HPLC analysis. AETPB and gallic acid showed significant (P < 0.001) enhancement of glucose uptake action in presence of insulin in muscle cells than vehicle control. Also AETPB inhibited pancreatic alpha -amylase and alpha -glucosidase enzymes. In conclusion, the above actions might be responsible for the antidiabetic activity of AETPB due to presence of gallic acid and other biomarkers. PMID- 23936665 TI - Estrogen signaling and the aging brain: context-dependent considerations for postmenopausal hormone therapy. AB - Recent clinical studies have spurred rigorous debate about the benefits of hormone therapy (HT) for postmenopausal women. Controversy first emerged based on a sharp increase in the risk of cardiovascular disease in participants of the Women's Health Initiative (WHI) studies, suggesting that decades of empirical research in animal models was not necessarily applicable to humans. However, a reexamination of the data from the WHI studies suggests that the timing of HT might be a critical factor and that advanced age and/or length of estrogen deprivation might alter the body's ability to respond to estrogens. Dichotomous estrogenic effects are mediated primarily by the actions of two high-affinity estrogen receptors alpha and beta (ER alpha & ER beta ). The expression of the ERs can be overlapping or distinct, dependent upon brain region, sex, age, and exposure to hormone, and, during the time of menopause, there may be changes in receptor expression profiles, post-translational modifications, and protein:protein interactions that could lead to a completely different environment for E2 to exert its effects. In this review, factors affecting estrogen-signaling processes will be discussed with particular attention paid to the expression and transcriptional actions of ER beta in brain regions that regulate cognition and affect. PMID- 23936669 TI - Role of monoaminergic system in the etiology of olive oil induced antidepressant and anxiolytic effects in rats. AB - Olive oil is the major component of the Mediterranean diet and has rich history of nutritional and medicinal uses. In the present study, the antidepressant and anxiolytic effects and their neurochemical basis following repeated administration of extravirgin olive oil were monitored. Male albino Wistar rats were used during study. Animals of test group were given olive oil orally at the dose of 0.25 mL/kg daily for 4 weeks. Control rats received equal volume of water. Elevated-plus maze (EPM) test and forced swim test (FST) were performed for the assessment of anxiety and depression like symptoms. An increase in time spent in open arm in EPM and increased struggling time in FST following long-term administration of olive oil indicate that olive oil has anxiolytic and antidepressant properties. Neurochemical results showed that repeated administration of olive oil decreased the levels of brain 5-HT (5 hydroxytryptamine), 5-HIAA (5-hydroxyindoleacetic acid), and levels of DA (dopamine); however, levels of DA metabolite HVA (homovalinic acid) were increased. Hence, present findings suggest that olive oil has neuroprotective effects. It reduces behavioral deficits via altering 5-HT and DA metabolism. So it could be used as a therapeutic substance for the treatment of depression and anxiety. PMID- 23936670 TI - Organochlorine pesticide levels and risk of Parkinson's disease in north Indian population. AB - The cause of Parkinson's disease (PD) remains elusive, but environmental chemical exposures have been postulated to be involved in the etiology of PD. We examined the association between the persistent organochlorine pesticides (OCPs) and PD in the North Indian population. This case control study included 70 PD and 75 control subjects in the age group of 50 to 85 years. Blood samples were collected and high-purity grade hexane and acetone (2 : 1 ratio) were used for extraction of organochlorine residues. OCPs (hexachlorocyclohexane (HCH), aldrin, dieldrin, endosulfan, pp'-Dichlorodiphenyldichloroethylene (pp'-DDE), op'-DDE, pp'- Dichlorodiphenyltrichloroethane (pp'-DDT), op'-DDT, pp' dichlorodiphenyldichloroethane (pp'-DDD) and op'-DDD) were quantitatively estimated by using gas chromatography. The most frequently detected OCP was dieldrin, which was present in 9.3% of control and 61.4% of PD. The strongest predictor was beta-hexachlorocyclohexane (beta-HCH), which reported an odds ratio of 2.566, indicating that for every additional one unit of beta-HCH, patients had 2.566 times more chances of presence of PD. This study indicates that increased level of beta-HCH and dieldrin may be associated with the risk of PD. PMID- 23936671 TI - The role of phenytoin in the treatment of localization related epilepsy: an international internet-based survey of neurologists and epileptologists. AB - Phenytoin (PHT) has been the most widely used medication to treat both partial and generalized seizures. However, over the past twenty years, a variety of new compounds have been released with comparable efficacy, fewer adverse effects, and more predictable pharmacokinetic properties. We surveyed neurologists and epileptologists to determine current practice patterns relating to the use of PHT using an online survey instrument. A total of 200 responses were obtained though response rates for each survey question varied. Of the respondents, 78.1% were epilepsy specialists; 60% were adult practitioners; and the remainder saw either, only children or both adults and children. For new onset partial seizures only 10 respondents said PHT would be their first or second choice, while 45% reported that they would not consider PHT. This study shows that in the era of newer medications, the role of PHT has been placed in the category of a reserve medication in intractable epilepsy. PMID- 23936672 TI - Assessment of Risk Factor for Cardiovascular Disease Using Heart Rate Variability in Postmenopausal Women: A Comparative Study between Urban and Rural Indian Women. AB - Cardiovascular diseases are important causes of morbidity and mortality in postmenopausal women. A major determinant of cardiovascular health is the status of autonomic nervous system and assessment of Heart Rate Variability (HRV). Heart Rate Variability is a noninvasive and sensitive technique to evaluate cardiovascular autonomic control. Reduced HRV is an independent risk factor for the development of heart disease. This study evaluated the risk factors for cardiovascular diseases using HRV, between urban and rural Indian postmenopausal women ranging in age from 40 to 75 years. Findings of the analysis of HRV have showed that the total power which reflects overall modulation of cardiac autonomic activity (759 +/- 100 versus 444 +/- 65), the absolute power of high frequency which is surrogate of cardiovagal activity (247 +/- 41 versus 163 +/- 45), and low frequency that reflects cardiac sympathetic activity (205 +/- 26 versus 127 +/- 18) were significantly higher in urban women than that of their rural counterparts. Further, among the anthropometric measures, waist circumference was significantly correlated with indices of HRV. The study concludes that rural Indian women are associated with an additional risk beyond that of ageing and postmenopausal status when compared to the urban women. The higher central obesity could be the contributing factor for developing higher risk for cardiovascular disease among the rural women. PMID- 23936673 TI - Difference in Risk Factors for Breast Cancer by ER Status in an Indigenous African Population. AB - Introduction. Breast cancer is the commonest cancer among women globally. In Uganda, it is on the rise, projected at a 4.5% annual ASR increase (age standardized incidence rate). The reasons for this steep increase are not fully established. In the recent past, gene profiling in tumor tissues suggests that breast cancers are divided into subtypes dependent on the presence or absence of oestrogen receptor, progesterone, and human epidermal growth factor receptor 2 (HER 2). These subtypes do have distinctive clinical outcomes and perhaps risk factors from past studies. There is paucity of data on hormonal receptor status and the traditionally known risk factors in sub-Saharan Africa. The purpose of this study therefore was to establish the differences between ER status and the traditionally known risk factors for breast cancer in Uganda. Methods. An observational analytical hospital, based study, carried out at Makerere University, College of Health Sciences. Formalin fixed and paraffin imbedded sections were prepared for haemotoxylin and eosin (H&E) stains and immunohistochemistry (IHC). Ethical approval was obtained. Results. A total of 113 women were recruited. Mean age was 45 years (SD14). There were no significant differences in selected risk factors (setting, age, contraceptive use, parity, breast feeding, or menarche) by ER status although ER negative tumors had significantly higher grade tumors (by a factor of two) compared to ER positive tumors. Conclusion. There were no significant differences among risk factors by ER status contrary to what several other studies suggest. The manifestation of breast cancer in Africa warrants further extensive inquiry. PMID- 23936674 TI - Clinical stages in patients with primary and subsequent cancers based on the czech cancer registry 1976-2005. AB - Of 1,486,984 new cancers registered in the Czech Cancer Registry in 1976-2005, 290,312 (19.5%) were multiple malignant neoplasms (MMNs), of which there were 65,292 primary and 89,796 subsequent cases in men and 59,970 primary and 75,254 subsequent cases in women. The duplicities were higher in women, and the triplicities and others (3-6 MMNs) were higher in men. The most frequent diagnoses were the primary cancers of skin, gastrointestinal and urinary tract, male genital organs, respiratory tract in men, and cancers of skin, breast, female genital organs, and gastrointestinal tract in women. The analysis of the early and advanced clinical stages shows that the number of subsequent advanced stages increased after primary advanced stages. Their time-age-space distributions visualized maps of MMNs in 14 Czech regions. These results support the improvement of algorithms of dispensary care for the early detection of the subsequent neoplasms. PMID- 23936675 TI - Fine-needle aspiration cytology can play a role in neoadjuvant chemotherapy in operable breast cancer. AB - Despite the fact that CNB has been progressively replaced by FNAC in the investigation of nonpalpable lesions or microcalcifications without a clinical or radiological mass lesion, FNAC has yet a role in palpable lesions provided it is associated with the triple diagnosis and experienced cytologist. In these conditions, FNAC is a safe, effective, economical, and accurate technique for breast cancer evaluation. Numerous literature reviews and meta-analyses illustrated the advantages and disadvantages of both methods CNB and FNAC. The difference does not seem significant when noninformative and unsatisfactory FNAC was excluded. Recently, cytological methods using liquid-based cytology (LBC) technology improve immunocytological and molecular tests with the same efficiency as classical immunohistochemistry. The indications of FNAC were, for palpable lesions, relative contraindication of CNB (elderly or frailty), staging of multiple nodules in conjunction or not with CNB, staging of lymph node status, newly appearing lesion in patient under neoadjuvant treatment, decreasing of anxiety with a rapid diagnosis, evaluation of biomarkers and new biomarkers, and chronological evaluation of biomarker following the neoadjuvant therapy response. PMID- 23936676 TI - Gastrostomy tube use after transoral robotic surgery for oropharyngeal cancer. AB - Objective. To evaluate factors that influence gastrostomy tube (g-tube) use after transoral robotic surgery (TORS) for oropharyngeal (OP) cancer. Study Design/Methods. Retrospective review of TORS patients with OP cancer. G-tube presence was recorded before and after surgery at followup. Kaplan-Meier and Cox hazards model evaluated effects of early (T1 and T2) and advanced (T3, T4) disease, adjuvant therapy, and free flap reconstruction on g-tube use. Results. Sixteen patients had tonsillar cancer and 13 tongue base cancer. Of 22 patients who underwent TORS as primary therapy, 17 had T1 T2 stage and five T3 T4 stage. Seven underwent salvage therapy (four T1 T2 and three T3 T4). Nine underwent robotic-assisted inset free flap reconstruction. Seventeen received adjuvant therapy. Four groups were compared: primary early disease (PED) T1 and T2 tumors, primary early disease with adjunctive therapy (PEDAT), primary advanced disease (PAD) T3 and T4 tumors, and salvage therapy. Within the first year of treatment, 0% PED, 44% PEDAT, 40% PAD, and 57% salvage patients required a g-tube. Fourteen patients had a temporary nasoenteric tube (48.3%) postoperatively, and 10 required a g-tube (34.5%) within the first year. Four of 22 (18.2%) with TORS as primary treatment were g-tube dependent at one year and had received adjuvant therapy. Conclusion. PED can be managed without a g-tube after TORS. Similar feeding tube rates were found for PEDAT and PAD patients. Salvage patients have a high rate of g-tube need after TORS. PMID- 23936677 TI - Changes in the cochlear vasculature and vascular endothelial growth factor and its receptors in the aging c57 mouse cochlea. AB - Introduction. Previous work has shown a strong association between alterations in cochlear vasculature, aging, and the development of presbycusis. The important role of vascular endothelial growth factor (VEGF) and its receptors Flt-1 and Flk 1 in angiogenesis suggests a potential role for involvement in this process. The aim of this study was to characterize vascular structure and VEGF and its' receptors in young and old C57 Mice. Methods. Young (4 weeks, n = 14) and aged (32-36 weeks, n = 14) C57BL/6 mice were used. Hearing was evaluated using auditory brainstem response. Cochleas were characterized with qRT-PCR, immunohistochemistry, and gross histological quantification. Results. Old C57 mice demonstrated significantly decreased strial area, blood vessel number, luminal size, and luminal area normalized to strial area (vascularity). qRT-PCR showed a significant upregulation of Flt-1, a VEGF receptor, in older animals. No differences were found in VEGF-A or Flk-1. Immunohistochemistry did not show any differences in staining intensity or area with age or cochlear turn location. Conclusion. The marked deafness of aged C57 mice could be in part meditated by loss of vascular development and alterations in VEGF signaling. PMID- 23936678 TI - Gene expression patterns underlying the reinstatement of plasticity in the adult visual system. AB - The nervous system is highly sensitive to experience during early postnatal life, but this phase of heightened plasticity decreases with age. Recent studies have demonstrated that developmental-like plasticity can be reactivated in the visual cortex of adult animals through environmental or pharmacological manipulations. These findings provide a unique opportunity to study the cellular and molecular mechanisms of adult plasticity. Here we used the monocular deprivation paradigm to investigate large-scale gene expression patterns underlying the reinstatement of plasticity produced by fluoxetine in the adult rat visual cortex. We found changes, confirmed with RT-PCRs, in gene expression in different biological themes, such as chromatin structure remodelling, transcription factors, molecules involved in synaptic plasticity, extracellular matrix, and excitatory and inhibitory neurotransmission. Our findings reveal a key role for several molecules such as the metalloproteases Mmp2 and Mmp9 or the glycoprotein Reelin and open up new insights into the mechanisms underlying the reopening of the critical periods in the adult brain. PMID- 23936680 TI - Suitability of Biomorphic Silicon Carbide Ceramics as Drug Delivery Systems against Bacterial Biofilms. AB - The present work is aimed at getting a new insight into biomorphic silicon carbides (bioSiCs) as bone replacement materials. BioSiCs from a variety of precursors were produced, characterized, and loaded with a broad-spectrum antibiotic. The capacity of loaded bioSiCs for preventing and/or treating preformed S. aureus biofilms has been studied. The differences in precursor characteristics are maintained after the ceramic production process. All bioSiCs allow the loading process by capillarity, giving loaded materials with drug release profiles dependent on their microstructure. The amount of antibiotic released in liquid medium during the first six hours depends on bioSiC porosity, but it could exceed the minimum inhibitory concentration of Staphylococcus aureus, for all the materials studied, thus preventing the proliferation of bacteria. Differences in the external surface and the number and size of open external pores of bioSiCs contribute towards the variations in the effect against bacteria when experiments are carried out using solid media. The internal structure and surface properties of all the systems seem to facilitate the therapeutic activity of the antibiotic on the preformed biofilms, reducing the number of viable bacteria present in the biofilm compared to controls. PMID- 23936679 TI - System consolidation of spatial memories in mice: effects of enriched environment. AB - Environmental enrichment (EE) is known to enhance learning and memory. Declarative memories are thought to undergo a first rapid and local consolidation process, followed by a prolonged process of system consolidation, which consist in a time-dependent gradual reorganization of brain regions supporting remote memory storage and crucial for the formation of enduring memories. At present, it is not known whether EE can affect the process of declarative memory system consolidation. We characterized the time course of hippocampal and cortical activation following recall of progressively more remote spatial memories. Wild type mice either exposed to EE for 40 days or left in standard environment were subjected to spatial learning in the Morris water maze and to the probe test 1, 10, 20, 30, and 50 days after learning. Following the probe test, regional expression of the inducible immediate early gene c-Fos was mapped by immunohistochemistry, as an indicator of neuronal activity. We found that activation of the medial prefrontal cortex (mPFC), suggested to have a privileged role in processing remote spatial memories, was evident at shorter time intervals after learning in EE mice; in addition, EE induced the progressive activation of a distributed cortical network not activated in non-EE mice. This suggests that EE not only accelerates the process of mPFC recruitment but also recruits additional cortical areas into the network supporting remote spatial memories. PMID- 23936681 TI - Microemulsion: new insights into the ocular drug delivery. AB - Delivery of drugs into eyes using conventional drug delivery systems, such as solutions, is a considerable challenge to the treatment of ocular diseases. Drug loss from the ocular surface by lachrymal fluid secretion, lachrymal fluid-eye barriers, and blood-ocular barriers are main obstacles. A number of ophthalmic drug delivery carriers have been made to improve the bioavailability and to prolong the residence time of drugs applied topically onto the eye. The potential use of microemulsions as an ocular drug delivery carrier offers several favorable pharmaceutical and biopharmaceutical properties such as their excellent thermodynamic stability, phase transition to liquid-crystal state, very low surface tension, and small droplet size, which may result in improved ocular drug retention, extended duration of action, high ocular absorption, and permeation of loaded drugs. Further, both lipophilic and hydrophilic characteristics are present in microemulsions, so that the loaded drugs can diffuse passively as well get significantly partitioned in the variable lipophilic-hydrophilic corneal barrier. This review will provide an insight into previous studies on microemulsions for ocular delivery of drugs using various nonionic surfactants, cosurfactants, and associated irritation potential on the ocular surface. The reported in vivo experiments have shown a delayed effect of drug incorporated in microemulsion and an increase in the corneal permeation of the drug. PMID- 23936682 TI - Myoclonus following a Peripheral Nerve Block. AB - Myoclonus is an extremely rare perioperative complication following neuraxial anesthesia. It has also been reported to occur due to peripheral nerve lesions. We report a case of self-limiting myoclonus following a routine peripheral nerve block in an otherwise healthy patient. PMID- 23936683 TI - Intraoperative alcohol withdrawal syndrome: a coincidence or precipitation? AB - As the prevalence of alcohol dependence is approximately half in surgical patients with an alcohol use disorder, anesthetist often encounters such patients in the perioperative settings. Alcohol withdrawal syndrome (AWS) is one of the most feared complications of alcohol dependence and can be fatal if not managed actively. A 61-year-old man, alcoholic with 50 h of abstinence before surgery, received spinal anesthesia for surgery for femoral neck fracture. To facilitate positioning for spinal anesthesia, fascia iliaca compartmental block with 0.25% bupivacaine (30 mL) was administered 30 min prior to spinal block. Later, in the intraoperative period the patient developed AWS; however, the features were similar to that of local anesthetic toxicity. The case was successfully managed with intravenous midazolam, esmolol, and propofol infusion. Due to similarity of clinical features of AWS and mild local anesthetic toxicity, an anesthetist should be in a position to differentiate the condition promptly and manage it aggressively. PMID- 23936684 TI - The Correlation between Chronic Periodontitis and Oral Cancer. AB - Infections are increasingly considered as potential trigger for carcinogenesis apart from risk factors like alcohol and tobacco. The discussion about human papilloma virus (HPV) in oral squamous cell carcinoma (OSCC) points at a general role of infection for the development of oral carcinomas. Furthermore, first studies describe a correlation between chronic periodontitis and OSCC, thus, characterizing chronic inflammation as being a possible trigger for OSCC. In front of this background, we present four well-documented clinical cases. All patients showed a significant anatomical relation between OSCC and clinical signs of chronic periodontitis. The interindividual differences of the clinical findings lead to different theoretical concepts: two with coincidental appearance of OSCC and chronic periodontitis and two with possible de novo development of OSCC triggered by chronic inflammation. We conclude that the activation of different inflammatory cascades by chronic periodontitis negatively affects mucosa and bone. Furthermore, the inflammatory response has the potential to activate carcinogenesis. Apart from a mere coincidental occurrence, two out of four patients give first clinical hints for a model wherein chronic periodontitis represents a potential risk factor for the development of OSCC. PMID- 23936685 TI - A direct investment method of closed two-piece hollow bulb obturator. AB - Maxillary defects occur due to surgical treatment of benign and malignant tumors, congenital malformation, and trauma. Prosthetic rehabilitation in such patients is influenced by the size and location of the defect. The most common of all intraoral defects are seen in the maxilla, in the form of an opening into the maxillary sinus and nasopharynx. These defects create disabilities in speech, deglutition, and mastication. The prosthesis which closes such an opening and recreates the functional separation of the oral cavity and sinus and nasal cavities is referred to as an obturator. Numerous techniques of hollow bulb fabrication have been mentioned in the literature from time to time. But there are only a few methods for bulb fabrication in two-piece obturator. This technique describes a direct investment method of waxed-up closed hollow bulb two piece obturator. PMID- 23936686 TI - Solitary angiokeratoma of oral mucosa: a rare presentation. AB - Solitary angiokeratoma of oral mucosa is rare entity. The term Angiokeratoma is used to refer to several lesions, whose common denominator is the presence of dilated blood vessels in association with epidermal hyperplasia. Mucosal involvement, including oral cavity is occasionally found either as a component of the systemic variety, cutaneous involvement or isolated oral involvement. Clinically, the lesion is irregular, whitish to dark brown in color, with female predominance. The etiological factors include injury, trauma, or chronic irritation to the wall of a papillary dermis. Histologically, it is characterized by hyperkeratosis, acanthosis, and dilated vascular spaces with or without organizing thrombi in papillary dermis. The vascular spaces are partly or completely enclosed by elongated ret-ridges. Along with this reporting a case of solitary angiokeratoma affecting tongue in a 38-year-old male patient, along with the literature review is presented. PMID- 23936687 TI - Coverage of gingival fenestration using modified pouch and tunnel technique: a novel approach. AB - Gingival fenestration defects are a rare phenomenon. Gingival fenestration means the exposure of the tooth due to loss of the overlying bone and gingiva. Though treatment of mucosal fenestration occurring in association with chronic periapical inflammation has been reported previously, the occurrence and treatment of gingival fenestration have not been documented in great detail. This report describes the occurrence of a gingival fenestration that developed secondarily to a gutka chewing habit. Treatment of the fenestration along with coverage of an adjacent recession defect in a single-step procedure using a pouch and tunnel technique is described. PMID- 23936688 TI - Rapidly growing thyroid mass in an immunocompromised young male adult. AB - We describe a 20-year-old man diagnosed with a myelodysplastic syndrome (MDS), admitted to our hospital due to pancytopenia and fever of undetermined origin after myelosuppression with chemotherapy. Disseminated aspergillosis (DIA) was suspected when he developed skin and lung involvement. A rapidly growing mass was detected on the left neck area, during hospitalization. A thyroid ultrasound reported a 3.7 * 2.5 * 2.9 cm oval heterogeneous structure, suggestive of an abscess versus a hematoma. Fine needle aspiration of the thyroid revealed invasion of aspergillosis. Fungal thyroiditis is a rare occurrence. Thyroid fungal infection is difficult to diagnose; for this reason it is rarely diagnosed antemortem. To our knowledge, this is the 10th case reported in the literature in an adult where the diagnosis of fungal invasion to the thyroid was able to be corroborated antemortem by fine needle aspiration biopsy. PMID- 23936689 TI - Contrast enhanced ultrasound of a gallbladder lesion in a patient with a history of renal cell and rectal cancer. AB - The gallbladder is an uncommon site of metastatic cancer. Although ultrasound can be regarded as a first line investigation for the detection of gallbladder lesions, differentiation between benign and malignant tumors usually requires resection. Real-time contrast enhanced ultrasound (CEUS) is a well-established technique for the classification of liver, pancreatic, and renal diseases (Weskott, 2008). The application of CEUS in the diagnosis of gallbladder tumors has rarely been described. We report the application of contrast enhanced ultrasound for the characterization of a gallbladder lesion in a 63-year-old patient with a history of renal cell and rectal cancer. PMID- 23936690 TI - Isolated p.H62L Mutation in the CYP21A2 Gene in a Simple Virilizing 21 Hydroxylase Deficient Patient. AB - Congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for 90% 95% of cases. This autosomal recessive disorder has a broad spectrum of clinical forms, ranging from severe or classical, which includes the salt-wasting and simple virilizing forms, to the mild late onset or nonclassical form. Most of the disease-causing mutations described are likely to be the consequence of nonhomologous recombination or gene conversion events between the active CYP21A2 gene and its homologous CYP21A1P pseudogene. Nevertheless, an increasing number of naturally occurring mutations have been found. The change p.H62L is one of the most frequent rare mutations of the CYP21A2 gene. It was suggested that the p.H62L represents a mild mutation that may be responsible for a more severe enzymatic impairment when presented with another mild mutation on the same allele. In this report, a 20-year-old woman carrying an isolated p.H62L mutation in compound heterozygosity with c.283-13A/C>G mutation is described. Although a mildly nonclassical phenotype was expected, clinical signs and hormonal profile of the patient are consistent with a more severe simple virilizing form of 21 hydroxylase deficiency. The study of genotype-phenotype correlation in additional patients would help in defining the role of p.H62L in disease manifestation. PMID- 23936691 TI - Bilateral radial ulnar synostosis and vertebral anomalies in a child with a de novo 16p13.3 interstitial deletion. AB - We describe an 8-year-old boy with developmental delay, clinical bilateral radial ulnar synostosis, Klippel-Feil anomaly, and other vertebral deformities who was found to have a de novo deletion of 114.5kb at 16p13.3. The deletion contains five genes and three miRNAs. The genes are E4F1, DNASE1L2, ECI1, RNPS1, and ABCA3; miRNAs are MIR3677, MIR940, and MIR4717. The specific deletion has never been previously reported. We describe the phenotype of the boy and review the genes in the deleted region. None of the regulatory elements have any known linkage to skeletal formation and/or maintenance. We believe this deletion is causative given that it was de novo and that this patient cannot be easily explained as having any other specific recognizable pattern of human malformation. PMID- 23936692 TI - Novel t(5;19) Translocation in a Patient with PDGFRB Associated Chronic Leukemia: Implications for Treatment Strategy. AB - Myeloproliferative disorders are variable disorders, based on the genetic abnormality present and the cell line progenitors that are affected. In this case, we discuss a novel gene translocation in the subset of PDGFRB mutations, first seen with prominent hyperbasophilia. This case demonstrates the possibility for lower therapeutic doses of imatinib mesylate than previously reported, in order to control leukocyte counts and reverse the genetic mutation. PMID- 23936693 TI - Fatal strongyloides hyperinfection complicating a gram-negative sepsis after allogeneic stem cell transplantation: a case report and review of the literature. AB - Strongyloides stercoralis is an intestinal nematode that causes strongyloidiasis, which affects 30 to 100 million people worldwide. Risk factors for hyperinfection and disseminated disease include immunosuppressive drug therapy, human T lymphotropic virus-1 (HTLV-1) infection, solid organ and bone marrow transplantation, hematologic malignant diseases, hypogammaglobulinemia, and severe malnutrition and associated conditions. The diagnosis can be difficult because a single stool examination fails to detect larvae in up to 70% of the cases, and the symptoms are nonspecific. Although eosinophilia is a common finding in patients with chronic Strongyloides infection, it is an unreliable predictor of hyperinfection. Furthermore, the lack of eosinophilia while receiving immunosuppressive therapy cannot reliably exclude the underlying chronic Strongyloides infection. We report here a fatal Strongyloides hyperinfection in a patient receiving allogeneic stem cell transplantation; risk factors and outcome in this clinical setting are discussed. PMID- 23936694 TI - Early Death in Two Patients with Acute Promyelocytic Leukemia Presenting the bcr3 Isoform, FLT3-ITD Mutation, and Elevated WT1 Level. AB - Despite major advances in the treatment of acute promyelocytic leukemia (APL), the problem of early death (ED) remains unsolved. Alongside the currently known clinical and hematological risk factors, prognostic significance has been attributed to internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD), hypogranular variant morphology, and the bcr-3 isoform of PML-RAR alpha . We describe premature death of two patients with the hypogranular variant of APL who presented remarkably high expression levels of Wilms' tumor gene (WT1). Our results point to WT1 as an important prognostic factor of ED that needs to be promptly evaluated in all newly diagnosed cases of APL. PMID- 23936695 TI - Fatal Disseminated Kaposi's Sarcoma due to Immune Reconstitution Inflammatory Syndrome following HAART Initiation. AB - This is a case report of disseminated Kaposi's sarcoma in the context of immune reconstitution inflammatory syndrome in an HIV-infected patient on HAART regimen for 2 months. The patient rapidly progressed to death in 5 days after worsening pulmonary infiltrates and multiple organ failure. PMID- 23936696 TI - A rare neurological complication of ranolazine. AB - Myoclonus is not a known side effect of ranolazine. We report a case of myoclonus in a 72-year-old female who underwent cardiac catheterization for angina and was started on ranolazine after the procedure. Two days after ranolazine therapy on 1000 mg per day in divided doses, myoclonus developed, which severely impaired her normal activity. Her symptoms resolved 2 days after discontinuation of ranolazine. Ranolazine was resumed after discharge from hospital with recurrent myoclonus after two days of therapy. The causal relationship between ranolazine and myoclonus was suggested by cessation of myoclonus after ranolazine was discontinued. PMID- 23936697 TI - Anti-glycine receptor antibody mediated progressive encephalomyelitis with rigidity and myoclonus associated with breast cancer. AB - We describe a 66-year-old woman who presented with a dramatic course of PERM. Anti-glycine receptor antibodies were found. She stabilized after plasma-exchange and partly recovered. Eighteen months later, a diagnosis of smouldering breast cancer with bone marrow metastasis was made. There are indications that this tumor was already present at first presentation. An overview of PERM and anti glycine receptor antibodies is given. PMID- 23936698 TI - Arabin cerclage pessary as a treatment of an acute urinary retention in a pregnant woman with uterine prolapse. AB - A 35-year-old gravida 7, para 1, and abortus 5 female with hypogastric pain and inability to void urine after 14 + 3 weeks of amenorrhea was examined in the emergency department. One year before, a uterine prolapse had been diagnosed in another hospital. Examination showed a uterine prolapse grade 2 with palpable bladder. The patient was unable to void urine. After a manual reduction of the uterine prolapse, the patient underwent an emergency catheterization for bladder drainage. A Hodge pessary (size 70) was placed, which led to spontaneous micturitions. Due to the persistence of the symptoms the following day, Hodge pessary was replaced by an Arabin cerclage pessary. Although the pessary could be removed from the beginning of the second trimester, due to the uterine prolapse as a predisposing factor in the patient and the uncomplicated progression of pregnancy, it was decided to maintain it in our patient. Therefore, Arabin cerclage pessary allowed a successful pregnancy outcome and was not associated with threatened preterm delivery or vaginal infection. PMID- 23936699 TI - Large bowel obstruction in a young woman simulating a malignant neoplasm: a case report of actinomyces infection. AB - Pelvic and intra-abdominal Actinomycosis can be difficult to diagnose preoperatively and it may also mimic many other diseases, including malignancies. We present a patient with pelvic Actinomycosis probably caused by a long-standing intrauterine device (IUD). We emphasize the challenges in diagnostic process and stress that though a rare disease, intra-abdominal Actinomycosis should be suspected in cases with intra-abdominal mass of uncertain etiology. The early recognition may spare the patient from extensive surgical operation. PMID- 23936700 TI - PET/MRI Imaging in High-Risk Sarcoma: First Findings and Solving Clinical Problems. AB - Simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) is a new whole-body hybrid PET/MR imaging technique that combines metabolic and cross-sectional diagnostic imaging. Since the use of MRI in imaging of soft tissue sarcoma is extremely beneficial, investigation of the combined PET/MRI is of great interest. In this paper, we present three cases and first data. Combined PET/MRI technique can support the process of clinical decision-making and give answers to some meaningful questions when treating patients with STS. Therefore, the combined modality of simultaneous PET/MRI offers new pieces to the puzzle of sarcoma treatment. PMID- 23936701 TI - Enterococcus faecalis Endogenous Endophthalmitis from Valvular Endocarditis. AB - We report a case of a 74-year-old female, with a mitral heart valve, who presented with pain and blurred vision in the right eye for 2 days. Her visual acuity was light perception (LP) in the right eye and 20/40 in the left eye. Slit lamp examination showed corneal edema and hypopyon, and a view of the right fundus was impossible. Echography showed vitreous condensation. One day after presentation, the patient developed acute lung edema requiring hospitalization, so she was not submitted to vitreous tap and intravitreal treatment. The cardiac and systemic evaluations revealed a mitral endocarditis secondary to Enterococcus faecalis. The patient improved systemically with treatment with gentamicin, vancomycin, and linezolid. Her visual acuity remained as no LP, and her intraocular pressure (IOP) has been controlled with brimonidine bid despite developing a total cataract with 360 degrees posterior synechia. A cardiac source for endogenous endophthalmitis should be considered in the presence of a prosthetic cardiac valve. The treatment and followup must be made in cooperation with a cardiologist specialist, but the ophthalmologist can play a key role in the diagnosis. PMID- 23936702 TI - Biopsy with the new essen biopsy forceps. AB - Purpose. To present initial experience with a novel biopsy method, the Essen biopsy forceps. Therefore, two patients with diagnostic suspicion of uveal melanoma underwent biopsy for histopathological confirmation. Case Presentation. Two patients presented with painless unilateral vision reduction. Ultrasound revealed the diagnostic suspicion of uveal melanoma. Therefore, biopsy with the Essen biopsy forceps using a sutureless 23-gauge three-port vitrectomy system was performed. The specimens were then submitted to a pathologist and processed. Histopathology of the obtained specimen confirmed the diagnostic suspicion of choroid melanoma in both patients. Conclusion. Essen biopsy forceps is a very practicable alternative method to the FNAB, allowing a combined histopathological and immunohistochemical examination for achieving high diagnostic accuracy at minimal risk. PMID- 23936703 TI - Isolated Bulbar Conjunctival Kaposi's Sarcoma as a Primary Presentation of AIDS: A Case Report. AB - Kaposi's sarcoma (KS) is a malignant vascular tumor, caused by the human herpesvirus 8. It is one of the commonest tumors in human immunodeficiency virus (HIV) patients and not uncommonly the first manifestation of acquired immunodeficiency syndrome (AIDS). Case. We present a case of an isolated bulbar conjunctival KS on a 43-year-old HIV positive male, with no other lesions. Excision and cryotherapy were performed, and the patient remains free of lesions to date. Conclusion. Isolated bulbar conjunctival KP is an unusual site for its initial presentation and must be kept in mind in HIV positive patients. PMID- 23936704 TI - Secondary Knee Osteoarthritis due to Neurofibromatosis Type 1 Treated with above the Knee Amputation: A Case Report. AB - Background. Neurofibromatosis Type 1 (NF-1) has a variety of associated orthopaedic manifestations that have been previously reported. We report a case of severe, grade 4 knee osteoarthritis (OA) with recurrent subluxation and joint laxity due to multiple extra-articular neurofibromas ultimately treated with Above the Knee Amputation (AKA). Case Description. A 39-year-old man presented with multiple neurofibromas and lymphedema leading to degenerative changes of the knee. Conservative treatment failed due to the severity of the knee degeneration and patient discomfort. Likewise, arthroplasty was not possible due to poor bone quality and joint instability. Therefore, AKA was selected to relieve symptoms and provide functional improvement. six months after the procedure the patient has increased functional capacity for ambulation and activities of daily living, as well as significant decrease in pain and discomfort. Clinical Relevance. Extra articular neurofibromas causing severe secondary OA in relatively young patients can be functionally improved with AKA and prosthetic device use. PMID- 23936705 TI - Subchondral bone regenerative effect of two different biomaterials in the same patient. AB - This case report aims at highlighting the different effects on subchondral bone regeneration of two different biomaterials in the same patient, in addition to bone marrow derived cell transplantation (BMDCT) in ankle. A 15-year-old boy underwent a first BMDCT on a hyaluronate membrane to treat a deep osteochondral lesion (8 mm). The procedure failed: subchondral bone was still present at MRI. Two years after the first operation, the same procedure was performed on a collagen membrane with DBM filling the defect. After one year, AOFAS score was 100 points, and MRI showed a complete filling of the defect. The T2 mapping MRI after one year showed chondral tissue with values in the range of hyaline cartilage. In this case, DBM and the collagen membrane were demonstrated to be good biomaterials to restore subchondral bone: this is a critical step towards the regeneration of a healthy hyaline cartilage. PMID- 23936706 TI - Inflammatory myofibroblastic tumor of the nasal septum. AB - We report an extremely rare case of inflammatory myofibroblastic tumor of the posterior edge of the nasal septum. An 11-year-old boy presented with frequent epistaxis and nasal obstruction persisting for one year. Based on the clinical presentation and imaging studies, juvenile angiofibroma was suspected, but angiography suggested the possibility of another type of tumor. Transnasal endoscopic surgery found that the tumor protruded into the nasopharynx from the posterior end of the nasal septum. Histological examination identified spindle cells with immunoreaction for vimentin, smooth muscle actin, and anaplastic lymphoma kinase (ALK), but not for desmin and cytokeratin. This is a report of inflammatory myofibroblastic tumor mimicking juvenile angiofibroma. This case suggests that angiography is helpful in the differential diagnosis of epipharyngeal tumor in adolescence. PMID- 23936707 TI - Sinonasal melioidosis in a returned traveller presenting with nasal cellulitis and sinusitis. AB - We illustrate a case involving a 51-year-old man who presented to a tertiary hospital with sepsis secondary to an abscess of the nasal vestibule and pustular eruptions of the nasal mucosa. Associated cellulitis extended across the face to the eye, and mucosal thickening of the sinuses was seen on computed tomography. The patient underwent incision and drainage and endoscopic sinus surgery. Blood cultures and swabs were positive for a gram-negative bacillus, Burkholderia pseudomallei. He had multiple risk factors including travel to an endemic area. The patient received extended antibiotic therapy in keeping with published national guidelines. Melioidosis is caused by Burkholderia pseudomallei, found in the soil in Northern Australia and Asia. It is transmitted via cutaneous or inhaled routes, leading to pneumonia, skin or soft tissue abscesses, and genitourinary infections. Risk factors include diabetes, chronic lung disease, and alcohol abuse. It can exist as a latent, active, or reactivated infection. A high mortality rate has been identified in patients with sepsis. Melioidosis is endemic in tropical Northern Australia and northeastern Thailand where it is the most common cause of severe community-acquired sepsis. There is one other report of melioidosis in the literature involving orbital cellulitis and sinusitis. PMID- 23936708 TI - Fungus ball in concha bullosa: a rare case with anosmia. AB - Concha bullosa is the pneumatization of the concha and is one of the most common variations of the sinonasal anatomy. The histopathological changes caused by the infections which arise from the impaired aeration of conchal cavity are frequently found. Fungus ball of the nasal cavity is an extremely rare, fungal infection with only three cases reported previously. In this paper, we present the fourth fungus ball case which developed within a concha bullosa and presented with anosmia. PMID- 23936709 TI - Intrathyroidal parathyroid carcinoma: report of an unusual case and review of the literature. AB - Intrathyroidal parathyroid carcinoma is an exceedingly rare cause of primary hyperparathyroidism. A 51-year-old African American female presented with goiter, hyperparathyroidism, and symptomatic hypercalcemia. Sestamibi scan revealed diffuse activity within an enlarged thyroid gland with uptake in the right thyroid lobe suggestive of hyperfunctioning parathyroid tissue. The patient underwent thyroidectomy and parathyroidectomy. At exploration, a 2.0 cm nodule in the usual location of the right inferior parathyroid was sent for intraoperative frozen consultation, which revealed only ectopic thyroid tissue. No parathyroid glands were identified grossly on the external aspect of the thyroid. Interestingly, postoperative parathyroid hormone levels normalized after removal of the thyroid gland. Examination of the thyroidectomy specimen revealed a 1.4 cm parathyroid nodule located within the parenchyma of the right superior thyroid, with capsular and vascular invasion and local infiltration into surrounding thyroid tissue. We present only the eighth reported case of intrathyroidal parathyroid carcinoma and review the literature. PMID- 23936710 TI - Pulmonary and Meningeal Cryptococcosis after Corticosteroid Therapy for Autoimmune Hepatitis: Coexistence of Cryptococci within Pulmonary Cancer Nodule. AB - A case of autoimmune hepatitis complicated with pulmonary and meningeal cryptococcosis during long-term treatment with corticosteroid is reported. An 84 year-old woman who received long-term corticosteroid therapy (40 mg/day prednisolone for two years) for autoimmune hepatitis developed a headache, slight fever, and anorexia and was diagnosed with cryptococcal meningitis two months prior to hospital admission. Due to deterioration of her condition, the patient was transferred to our university hospital. After admission, a pulmonary nodule 1 cm in diameter was noticed in the patient's right lower lobe. Cryptococcal meningitis was diagnosed as positive for cryptococcal antigen from both serum and cerebrospinal fluid (CSF) as well as the growth of Cryptococcus neoformans (C. neoformans) in fungal culture. A combination therapy of amphotericin B and flucytosine was started, and the corticosteroid therapy was gradually reduced and finally discontinued. In addition to continuous cryptococcal infection, complications of Pseudomonas aeruginosa and methicillin-resistance Staphylococcus aureus infection caused death after a 2-month hospitalization. Autopsy disclosed encapsulated yeast in the lungs and subarachnoid space characteristic of Cryptococcus. The pulmonary nodule was found to be squamous cell carcinoma coexisting with C. neoformans within and around the cancer cell nests. PMID- 23936711 TI - A neonate with subcutaneous fat necrosis after passive cooling: does polycythemia have an effect? AB - Subcutaneous fat necrosis (SCFN) is an inflammatory disorder of adipose tissue. The main risk factors for the development of SCFN are perinatal asphyxia and hypothermia. Presented here is a case of a newborn who developed SCFN in association with polycythemia and hypocalcemia following treatment by passive cooling. Neonates who undergo passive or whole body cooling therapy should be closely monitored for any signs of SCFN. PMID- 23936712 TI - Novel finding of coronary ectasia in a case of acute rheumatic Fever. AB - A 10-year-old boy presented to his pediatrician with acute fever, rash, and polyarthritis. Laboratory studies revealed elevated inflammatory markers and positive throat culture. Echocardiogram demonstrated panvalvular insufficiency consistent with acute rheumatic fever (ARF) and coronary artery ectasia. This latter finding, typically associated with Kawasaki disease, has not been previously reported in ARF. PMID- 23936713 TI - Uncommon presentation of a benign nasopharyngeal mass in an adolescent: comprehensive review of pediatric nasopharyngeal masses. AB - Nasopharyngeal masses in the pediatric population are quite rare, and the majority of these are benign. In adolescent boys, there should be a high index of suspicion for juvenile nasopharyngeal angiofibromas. When malignant, the most common lesions encountered are rhabdomyosarcomas, carcinomas, and lymphomas. We report a single case from a tertiary care institution of an adolescent male with an unusual presentation of a benign nasopharyngeal mass and provide a comprehensive review of pediatric nasopharyngeal masses. Whenever possible, radiographic imaging should be obtained, in addition to biopsy, to assist in the diagnosis of pediatric nasopharyngeal masses. PMID- 23936714 TI - Lamotrigine augmentation of serotonin reuptake inhibitors in severe and long-term treatment-resistant obsessive-compulsive disorder. AB - The treatment recommendations in obsessive-compulsive disorder (OCD) after lack of response to selective serotonin reuptake inhibitors (SSRIs) include augmentation with other drugs, particularly clomipramine, a more potent serotonin reuptake inhibitor (SRI), or antipsychotics. We present two cases of response to lamotrigine augmentation in treatment-refractory OCD; each received multiple SRI trials over a >10-year period. The first patient had eleven years of treatment with multiple combinations including clomipramine and SSRIs. She had a >50% decrease of Y-BOCS (from 29 to 14) by augmenting paroxetine (60 mg/day) with lamotrigine (100 mg/day). The second patient had 22 years of treatment with multiple combinations, including combinations of SSRIs with clomipramine and risperidone. She had an almost 50% decrease of Y-BOCS (from 30 to 16) and disappearance of tics by augmenting clomipramine (225 mg/d) with lamotrigine (200 mg/day). These two patients were characterized by lack of response to multiple treatments, making a placebo response to lamotrigine augmentation unlikely. Prospective randomized trials in treatment-resistant OCD patients who do not respond to combinations of SSRIs with clomipramine and/or antipsychotics are needed, including augmentation with lamotrigine. Until these trials are available, our cases suggest that clinicians may consider lamotrigine augmentation in such treatment-resistant OCD patients. PMID- 23936715 TI - Auditory hallucinations in a deaf patient: a case report. AB - This case report describes the progression of symptoms in a young deaf female. Her initial psychotic symptoms occur at the age of 16, but she did not come into contact with a psychiatric treatment facility before the age of 27, where she felt symptoms were distressing. The case report describes the difficulties in evaluating psychotic symptoms in a deaf patient, as well as the use of specialized scales in combination with the standard psychiatric evaluation. The current evidence, concerning the prevalence of psychotic symptoms, as well as the influence of deafness on the understanding of psychosis, is described. PMID- 23936716 TI - A New Case of DRESS Syndrome Induced by Sulfasalazine and Triggered by Amoxicillin. AB - Drug Rash Eosinophilia Systemic Symptoms (DRESS) syndrome is a systemic hypersensitivity reaction characterized by exfoliative dermatitis and maculopapular rash, lymphadenopathy, fever, eosinophilia, leukocytosis, and involvement of internal organs as liver, lung, heart, and kidney; the disorder starts within 2-6 weeks after taking a drug with an incidence that ranges from 1/1000 to 1/10000 exposures. Fatal cases are reported. The exact pathogenesis of DRESS syndrome is not completely understood, while it is reported that amoxicillin could trigger it in patients who are taking allopurinol, sulfasalazine, NSAIDs, carbamazepine, strontium ranelate, lisinopril, lansoprazole, and minocycline. Amoxicillin could act directly, inducing the reactivation of a viral infection (HHV 6 and EBV) with symptoms similar to DRESS syndrome or by reducing the patients' ability to detoxify the body from substances chronically taken. We describe a case of a patient admitted to our hospital for a DRESS syndrome flared after amoxicilline intake during treatment with sulfasalazine; this combination can activate severe reactions often with an insidious onset that can mimic an infectious disease. PMID- 23936717 TI - Behcet's Disease and Intracardiac Thrombosis: A Report of Three Cases. AB - We present three patients with Behcet's disease associated with intracardiac thrombus and pulmonary vascular involvement. One of these patients had also Budd Chiari syndrome. All patients were treated with corticosteroid plus monthly intravenous cyclophosphamide as first line treatment and with no recurrences. Immunosuppressive therapy was successful in the treatment of intracardiac thrombus and also in the regression of pulmonary vascular thromboses in these patients. Intracardiac thrombus in Behcet's disease is rarely seen. Behcet's disease should be remembered in the differential diagnosis of the patients with intracardiac mass, especially in patients from the Mediterranean and Middle East populations. PMID- 23936718 TI - Diabetic mastopathy: an uncommon complication of diabetes mellitus. AB - Introduction. Whilst most consequences of diabetes mellitus are well recognized, breast-related complications remain obscure. The term diabetic mastopathy (DMP) attempts to describe the breast-related consequences of diabetes. Methods. We report the clinicopathologic findings in a patient with DMP and review the literature on this uncommon entity. Results. A 33-year-old woman with type 1 diabetes had excision biopsy of a 2 cm breast lump. Histopathologic evaluation revealed classic features of DMP: parenchymal fibrosis; keloid-like hyalinization of interlobular stroma; adipose tissue entrapment; lobular compression; dense chronic inflammatory cell infiltration; and lymphoid follicle formation. Conclusion. Clinicians should be aware of DMP as a differential for breast disease in women with uncontrolled diabetes. PMID- 23936719 TI - Chronic constipation in the elderly: an unusual presentation of colonic dysmotility in an elderly patient. AB - Introduction. Chronic constipation is common in the elderly, and often no underlying pathology is found. Primary colonic dysmotility has been described in children but is rare in the elderly. Case report. We present an 82-year-old female with long standing constipation presenting acutely with large bowel obstruction. Laparotomy and Hartman's procedure was performed, and a grossly distended sigmoid colon was resected. Histology revealed a primary myopathic process. Conclusion. Primary colonic myopathy should be considered in elderly patients presenting with large bowel obstruction and a long preceding history of constipation, particularly when previous endoscopic examinations were normal. PMID- 23936720 TI - Acute abdominal pain secondary to chilaiditi syndrome. AB - Chilaiditi syndrome is a rare condition occurring in 0.025% to 0.28% of the population. In these patients, the colon is displaced and caught between the liver and the right hemidiaphragm. Patients' symptoms can range from asymptomatic to acute intermittent bowel obstruction. Diagnosis is best achieved with CT imaging. Identification of Chilaiditi syndrome is clinically significant as it can lead to many significant complications such as volvulus, perforation, and bowel obstruction. If the patient is symptomatic, treatment is usually conservative. Surgery is rarely indicated with indications including ischemia and failure of resolution with conservative management. PMID- 23936721 TI - Renal cell carcinoma of the kidney with synchronous ipsilateral transitional cell carcinoma of the renal pelvis. AB - A 73-year-old man was admitted to our clinic with flank pain and gross macroscopic hematuria. Radiologic examination revealed a solid mass in the left kidney and additionally another mass in the ureteropelvic junction of the same kidney with severe hydronephrosis. Left nephroureterectomy with bladder cuff removel was performed, and histopathological evolution showed a Fuhrman grade 3 clear cell type RCC with low-grade TCC of the pelvis. PMID- 23936722 TI - Primary plasmacytoma of the kidney. AB - Primary renal plasmacytomas are an extremely rare clinical condition. Their management is particularly challenging due to the paucity of evidence, with only just over a dozen previously reported cases. We report a case of a primary extramedullary plasmacytoma of the kidney and performed a review of the literature. The case is presented as a learning point that it is imperative to keep plasmacytic tumours in mind and to include them in the differential diagnosis of anaplastic tumours, even in unusual locations, such as the kidney. PMID- 23936723 TI - Emphysematous cystitis occurred in the case treated with steroid for autoimmune hepatitis. AB - Emphysematous cystitis is a rare clinically entity, more commonly seen in diabetic, immunocompromised patients, which was characterized by air within the bladder wall and lumen. A 83-year-old woman was introduced to our department with fever elevation and abnormal findings of computed tomography (CT). She took orally prednisolone for autoimmune hepatitis. Pelvic CT revealed diffuse air throughout the bladder wall. Urinalysis showed combined hematuria and pyuria. Escherichia coli was detected in blood culture. Abnormal findings of complete blood count and laboratory examination included an elevated WBC count (12,200/MUL), C-reactive protein (11.7 mg/dL), and creatinine (1.07 mg/dL). Cystoscopy confirmed diffuse submucosal emphysema throughout. On the basis of diagnosis with emphysematous cystitis, she was treated with antibiotics based on the results of blood culture and indwelling Foley catheter. After treatment, the improvement of inflammatory findings and submucosal emphysema on cystoscopy and CT were achieved. PMID- 23936724 TI - Extra-anatomical bypass: a surgical option for recurrent aortic coarctation. AB - Background. Balloon aortoplasty with or without stenting is a less invasive alternative to open surgery for the management of recurrent isthmic coarctation. However, in patients with previous small size tube graft, an open surgical correction is mandatory and, in most cases, an anatomical aortic reconstruction is carried out. Methods. We present the case of a 48-year-old woman with recurrent aortic coarctation and systemic hypertension with systolic value around 190-200 mmHg and preoperative systolic pressure gradient 70 mmHg, submitted to an extra-anatomical bypass. Through a median sternotomy, an extra-anatomical bypass from ascending to descending aorta was performed. Results. No intra- or postoperative complications were observed. The postoperative pressure gradient was 10 mmHg and the systolic pressure ranged from 130 to 140 mmHg. Conclusion. The extra-anatomical bypass can be considered an effective and safe alternative to the anatomical aortic reconstruction in the cases with recurrent aortic coarctation unfit for endovascular treatment. PMID- 23936725 TI - Successful therapy of ventricular rupture by percutaneous intrapericardial instillation of fibrin glue: a case report. AB - Rupture of the ventricular myocardium is an often lethal complication after myocardial infarction. Due to the dramatic hemodynamics and the short time frame between ventricular rupture and surgical closure of the defect, additional therapeutic strategies are needed. Here we report the successful therapy of ventricular rupture by percutaneous intrapericardial instillation of fibrin glue in a 72-year-old male patient with postinfarct angina secondary to anterior myocardial infarction. PMID- 23936726 TI - Endovascular treatment of infrarenal abdominal aortic aneurysm with short and angulated neck in high-risk patient. AB - Endovascular treatment of abdominal aortic aneurysms (AAA) is an established alternative to open repair. However lifelong surveillance is still required to monitor endograft function and signal the need for secondary interventions (Hobo and Buth 2006). Aortic morphology, especially related to the proximal neck, often complicates the procedure or increases the risk for late device-related complications (Hobo et al. 2007 and Chisci et al. 2009). The definition of a short and angulated neck is based on length (<15 mm), and angulation (>60 degrees ) (Hobo et al. 2007 and Chisci et al. 2009). A challenging neck also offers difficulties during open repairs (OR), necessitating extensive dissection with juxta- or suprarenal aortic cross-clamping. Patients with extensive aneurysmal disease typically have more comorbidities and may not tolerate extensive surgical trauma (Sarac et al. 2002). It is, therefore, unclear whether aneurysms with a challenging proximal neck should be offered EVAR or OR (Cox et al. 2006, Choke et al. 2006, Robbins et al. 2005, Sternbergh III et al. 2002, Dillavou et al. 2003, and Greenberg et al. 2003). In our case the insertion of a thoracic endograft followed by the placement of a bifurcated aortic endograft for the treatment of a very short and severely angulated neck proved to be feasible offering acceptable duration of aneurysm exclusion. This adds up to our armamentarium in the treatment of high-risk patients, and it should be considered in emergency cases when the fenestrated and branched endografts are not available. PMID- 23936727 TI - Biodegradation of polyethoxylated nonylphenols. AB - Polyethoxylated nonylphenols, with different ethoxylation degrees (NPEO x ), are incorporated into many commercial and industrial products such as detergents, domestic disinfectants, emulsifiers, cosmetics, and pesticides. However, the toxic effects exerted by their degradation products, which are persistent in natural environments, have been demonstrated in several animal and invertebrate aquatic species. Therefore, it seems appropriate to look for indigenous bacteria capable of degrading native NPEO x and its derivatives. In this paper, the isolation of five bacterial strains, capable of using NPEO 15 , as unique carbon source, is described. The most efficient NPEO 15 degrader bacterial strains were identified as Pseudomonas fluorescens (strain Yas2) and Klebsiella pneumoniae (strain Yas1). Maximal growth rates were reached at pH 8, 27 degrees C in a 5% NPEO 15 medium. The NPEO 15 degradation extension, followed by viscometry assays, reached 65% after 54.5 h and 134 h incubation times, while the COD values decreased by 95% and 85% after 24 h for the Yas1 and Yas2 systems, respectively. The BOD was reduced by 99% and 99.9% levels in 24 h and 48 h incubations. The viscosity data indicated that the NPEO 15 biodegradation by Yas2 follows first order kinetics. Kinetic rate constant (k) and half life time (tau) for this biotransformation were estimated to be 0.0072 h(-1) and 96.3 h, respectively. PMID- 23936728 TI - Degradation of [Dha(7)]MC-LR by a Microcystin Degrading Bacterium Isolated from Lake Rotoiti, New Zealand. AB - For the first time a microcystin-degrading bacterium (NV-3 isolate) has been isolated and characterized from a NZ lake. Cyanobacterial blooms in New Zealand (NZ) waters contain microcystin (MC) hepatotoxins at concentrations which are a risk to animal and human health. Degradation of MCs by naturally occurring bacteria is an attractive bioremediation option for removing MCs from drinking and recreational water sources. The NV-3 isolate was identified by 16S rRNA sequence analysis and found to have 100% nucleotide sequence homology with the Sphingomonas MC-degrading bacterial strain MD-1 from Japan. The NV-3 isolate (concentration of 1.0 * 10(8) CFU/mL) at 30 degrees C degraded a mixture of [Dha(7)]MC-LR and MC-LR (concentration 25 MU g/mL) at a maximum rate of 8.33 MU g/mL/day. The intermediate by-products of [Dha(7)]MC-LR degradation were detected and similar to MC-LR degradation by-products. The presence of three genes (mlrA, mlrB, and mlrC), that encode three enzymes involved in the degradation of MC-LR, were identified in the NV-3 isolate. This study confirmed that degradation of [Dha(7)]MC-LR by the Sphingomonas isolate NV-3 occurred by a similar mechanism previously described for MC-LR by Sphingomonas strain MJ-PV (ACM-3962). This has important implications for potential bioremediation of toxic blooms containing a variety of MCs in NZ waters. PMID- 23936729 TI - Which Aspects of Postural Control Differentiate between Patients with Parkinson's Disease with and without Freezing of Gait? AB - This exploratory study aimed to identify which aspects of postural control are able to distinguish between subgroups of patients with Parkinson's disease (PD) and controls. Balance was tested using static and dynamic posturography. Freezers (n = 9), nonfreezers (n = 10), and controls (n = 10) stood on a movable force platform and performed 3 randomly assigned tests: (1) sensory organization test (SOT) to evaluate the effective use of sensory information, (2) motor control test (MCT) to assess automatic postural reactions in response to platform perturbations, and (3) rhythmic weight shift test (RWS) to evaluate the ability to voluntarily move the center of gravity (COG) mediolaterally and anterior posteriorly (AP). The respective outcome measures were equilibrium and postural strategy scores, response strength and amplitude of weight shift. Patients were in the "on" phase of the medication cycle. In general, freezers performed similarly on SOT and MCT compared to nonfreezers. Freezers showed an intact postural strategy during sensory manipulations and an appropriate response to external perturbations. However, during voluntary weight shifting, freezers showed poorer directional control compared to nonfreezers and controls. This suggests that freezers have adequate automatic postural control and sensory integration abilities in quiet stance, but show specific directional control deficits when weight shifting is voluntary. PMID- 23936730 TI - Advances in our understanding of "resistance" to antiplatelet agents for prevention of ischemic stroke. AB - We review the role of aspirin and clopidogrel for prevention of ischemic stroke and explore the concept of antiplatelet therapy resistance both from a laboratory and clinical perspective and genetic polymorphisms that might influence platelet reactivity with clopidogrel administration. Debates have raged over the years about the application of platelet function tests in clinical practice. We conclude that platelet function testing is not indicated in routine clinical practice. This recommendation is supported by clinical guideline statements, a lack of a global platelet function measure, and limitations of current platelet function test methods as applied in practice. We discuss a recently hypothesized hierarchy of patient characteristics in relation to which patients are most likely to benefit from platelet function studies based on acuity (i.e., risk) of cardiovascular disease. A focus of antiplatelet therapy administration should include emphasis on compliance/adherence and in the example of aspirin, use of well-absorbed forms of aspirin and avoidance of drugs that may interact with aspirin to inhibit its mechanism of action (e.g., certain nonsteroidal anti inflammatory drugs). PMID- 23936731 TI - Survey for highly pathogenic avian influenza from poultry in two northeastern States, Nigeria. AB - Highly pathogenic avian influenza (HPAI) is a major global zoonosis. It has a complex ecological distribution with almost unpredictable epidemiological features thus placing it topmost in the World Organization for Animal Health list A poultry diseases. Structured questionnaire survey of poultry farmer's knowledge, attitudes, and practices (KAP) in two Nigerian states revealed the presence of risk farming practices that may enable avian influenza high chance of introduction/reintroduction. There existed significant statistical association between farmer's educational levels and AI awareness and zoonotic awareness (P < 0.005). Poultry rearing of multiage and species (81%), multiple sources of stock (62%), inadequate dead-bird disposal (71%), and access to live bird markets (LBMs) (62%) constituted major biosecurity threats in these poultry farming communities. Haemagglutination inhibition (HI) test detected antibodies against H5 avian influenza (AI) in 8 of the 400 sera samples; rapid antigen detection test kit (RADTK) was negative for all the 400 cloaca and trachea swabs. These results and other poultry diseases similar to AI observed in this study could invariably affect avian influenza early detection, reporting, and control. We recommend strong policy initiatives towards poultry farmers' attitudinal change and increasing efforts on awareness of the implications of future HPAI outbreaks in Nigeria. PMID- 23936732 TI - Water-Soluble N-Acetyl-L-cysteine-Capped CdTe Quantum Dots Application for Hg(II) Detection. AB - A simple, rapid, and specific method for Hg(II) detection has been proposed based on the fluorescence change of N-acetyl-L-cysteine-capped CdTe quantum dots (QDs). The presence of Hg(II) ions could quench the fluorescence of QDs at 565 nm and meanwhile produce new peak in 700-860 nm wavelength range. The linear response range is 20-430 nM with the detection limit at 8.0 nM Hg(II). It was found that the position of the new peak was irrelevant to the size of QDs. Furthermore, the mechanism of the quenching of QDs fluorescence by Hg(II) and the appearance of new peak in near-infrared area were also discussed and deduced through ultraviolet absorption spectrum, fluorescence spectrum, and X-ray photoelectron spectrum. PMID- 23936733 TI - The effectiveness of a geriatric hip fracture clinical pathway in reducing hospital and rehabilitation length of stay and improving short-term mortality rates. AB - BACKGROUND: A geriatric hip fracture clinical pathway, led by an orthopedic surgeon, was developed in 2007. This clinical pathway team is multidisciplinary and consists of surgeons, physicians, anesthetists, nurses, physiotherapists, occupational therapists, medical social workers, dieticians as well as voluntary support groups. METHODS: From early 2007 onward, all patients older than 65 years with acute isolated hip fractures were included. During the whole inpatient treatment, all relevant data were captured prospectively. The data in 2006, before the implementation of the clinical pathway, were collected retrospectively through computer record system. A study of the length of stay in acute and rehabilitation hospital and also the short-term mortality rate was carried out to compare the difference before and after the implementation of the pathway. RESULTS: From 2007 onward, more than 1300 hip fractures were treated. After the implementation of the pathway, the preoperative length of stay was markedly shortened by 4 days, from an average of 6.1 days in 2006 to 1.5 days in 2011 (P < .05). The postoperative length of stay and the overall acute hospital length of stay also improved significantly. The length of stay in rehabilitation hospital was also significantly shorter in the 4-year period. Although the number of hip fractures increased annually with increased age and number of comorbidities each year, the inpatient mortality rate showed a gradual decrease from 2.7% in 2006 to 1.25% in 2010. The 30 days mortality rate also showed a decrease from 3.65% in 2006 to 2.75% in 2010. CONCLUSION: Geriatric hip fracture clinical pathway is an excellent approach to the geriatric hip fracture service. The most significant improvement is the dramatic shortening of the length of hospital stay. Our success in the past 5 years has proven its value and sustainability. PMID- 23936734 TI - Comanagement of geriatric patients with hip fractures: a retrospective, controlled, cohort study. AB - The objective of this 3-year retrospective, controlled, cohort study is to characterize an interdisciplinary method of managing geriatric patients with hip fracture. All patients aged 65 years or older admitted to a single academic level I trauma center during a 3-year period with an isolated hip fracture were included as participants for this study. Thirty-one geriatric patients with hip fracture were treated with historical methods of care (cohort 1). The comparison group of 115 similar patients was treated under a newly developed, institutional comanagement hip fracture protocol (cohort 2). There were no differences in age, sex distribution, or comorbidity distribution between the 2 cohorts. Patients requiring intensive care unit (ICU) admission decreased significantly from 48% in cohort 1 to 23% in cohort 2 (P = .0091). Length of ICU stay for patients requiring ICU admission also decreased significantly, from a mean of 8.1 days in cohort 1 to 1.8 days in cohort 2 (P = .024). Total hospital stay decreased significantly, from a mean of 9.9 days in cohort 1 to 7.1 days in cohort 2 (P = .021). Although no decrease in in-hospital mortality rates was noted from cohort 1 to cohort 2, a trend toward decreased 1-year mortality rates was seen after implementation of the hip fracture protocol. Hospital charges decreased significantly, from US$52 323 per patient in cohort 1 to US$38 586 in cohort 2 (P = .0183). Implementation of a comanagement protocol for care of geriatric patients with hip fracture, consisting of admission to a geriatric primary care service, standardized perioperative assessment regimens, expeditious surgical treatment, and continued primary geriatric care postoperatively, resulted in reductions in lengths of stay, ICU admissions, and hospital costs per patient. On an annualized basis, this represented a savings of over US$700 000 for our institution. PMID- 23936735 TI - Clinical outcomes of distal femoral fractures in the geriatric population using locking plates with a minimally invasive approach. AB - BACKGROUND: Fractures of the distal femur comprise 4% to 6% of all femoral fractures. Elderly patients are predisposed to low-energy fractures due to osteoporosis. Treatment of these fractures in the elderly group remains a challenge. Our hypothesis is that locking plates inserted with minimally invasive plate osteosynthesis (MIPO) techniques will produce better results compared to those inserted by open technique. The objective of this study is to evaluate the clinical outcomes of MIPO technique using locking plates in the elderly patients. MATERIALS AND METHODS: A total of 24 elderly patients (mean age 73 years) with distal femur fractures treated using the MIPO technique (2007-2010) were reviewed retrospectively. Parameters analyzed included classification of fracture, time to fracture union, knee range of motion, functional knee score (Knee Society Score Functional) at 6 months, and other significant complications. One patient was lost to follow-up. RESULTS: In all, 88% of the fractures were extraarticular. The mean time to union was 13.48 (range: 8-28) weeks. Mean range of motion achieved at 6 months and beyond was 100 degrees ranging from 0 to 30 (extension) to 90 to 140 (flexion). Functional knee scores at 6 months from fixation were satisfactory (mean score 88.8). There were no cases of implant failure, nonunion, and infection. In all, 6 (25%) patients developed deep vein thrombosis (DVT) in the early postoperative period, all of which were below the level of the knee joint. CONCLUSION: Locking plates inserted using MIPO techniques in elderly patients with distal femur fractures appear to be promising based on clinical outcome measurements. However, there was a high incidence of DVT noted. PMID- 23936736 TI - Outcomes After Fixation of Proximal Humerus (OTA Type 11) Fractures in the Elderly Patients Using Modern Techniques. AB - PURPOSE: To investigate the effects of age on the clinical, functional, and radiographic outcomes of patients with proximal humerus fractures treated operatively with locking plates. METHODS: Between February 2003 and July 2012, all patients who sustained a proximal humerus fracture who presented to our institution were enrolled into a database. Patients were followed up at 1, 6, 12, 26, and 52 weeks postoperatively with physical examination and radiographs. Validated functional outcomes scores were collected at 6 and 12 months. Complications were recorded as they occurred. Statistical analysis was conducted to assess for functional, physical, or radiographic differences between patients age younger than 65 and patients age 65 or older. RESULTS: Of the 147 consecutive patients treated operatively for a proximal humerus fracture, 115 (78%) patients with an average follow-up of 16 months met the inclusion criteria for this study. The young cohort (patients < 65) included 70 patients with an average age of 53, whereas the elderly cohort (patients >= 65) included 45 patients with an average age of 73. The older cohort had significantly more women (P = .04), but there was no statistical difference in fracture type between the age groups. There were no differences in the radiographic measures of screw penetration, humeral head height, and neck-shaft angle between the age groups. There were no differences in physical examination scores between the age groups. There were no significant differences in functional outcomes or complication rates between the age groups. CONCLUSION: Treating proximal humerus fractures operatively with locked plates can overcome the challenges of poor bone quality that often occur with increasing age. Age should not play a significant role in the decision-making process for treating proximal humerus fractures that would otherwise be indicated for surgical fixation. PMID- 23936737 TI - Case discussion: hip fracture in a patient on hospice with dementia and anemia. AB - This case presents a discussion of a frail 98-year-old woman in hospice care, with a history of dementia, previous hip fracture, and anemia, who is admitted with a left intertrochanteric fracture. Care is coordinated and expedited by an interdisciplinary team to optimize her outcome, in the context of her goals of care. PMID- 23936738 TI - Identification of coding sequences from a freshly prepared Trypanosoma brucei brucei expression library by polymerase chain reaction. AB - Animal African trypanosomiasis (AAT) also known as Nagana is a devastating disease among domestic animals in large parts of Sub-Saharan Africa causing loses in milk and meat production as well as traction power. However, there is currently no commercial vaccine against AAT. The parasites have also developed resistance to some of the drugs in use. Moreover, the use of affordable computer aided wet bench methods in the search for vaccine and/or new drug targets against this disease have not yet been fully explored in developing countries. This study, therefore, explored the use of PCR to screen a freshly prepared bloodstream form Trypanosoma brucei brucei (T. b. brucei) expression library for coding sequences followed by bioinformatics analyses specifying the functions and importance of these proteins to parasite survival. Eleven protein coding sequences were identified from twenty nine purified clones. The putative retro transposon hot spot protein 4 (RHSP 4) was the only protein with a fully annotated DNA sequence. All the others were hypothetical or had partial or unqualified annotations. RHSP 4 and pyruvate dehydrogenase E1 component, alpha sub-unit (PDE1alpha) are involved in aerobic respiration whereas succinyl-Co A-3 ketoacid-coenzyme A transferase mitochondrial precursor (SKTMP) is predicted to be involved in ketone body catabolism. Cystathionine beta-synthase (CBS) and alpha-1,3-mannosyltransferase (alphaMT) have been predicted in cysteine biosynthesis and vesicular transport respectively. The functions of the hypothetical proteins encountered have neither been experimentally determined nor predicted. We hypothesize that both CBS and PDE1alpha are good drug targets. Overall, about 300 plates are required to PCR screen the entire Trypanosoma brucei genome in approximately eight months. This method is therefore, applicable and affordable in the search for new drug targets under conditions of limited resources among developing countries. PMID- 23936739 TI - TMEFF2 modulates the AKT and ERK signaling pathways. AB - The transmembrane protein with epidermal growth factor (EGF) and two follistatin (FS) motifs 2 (TMEFF2) has a limited tissue distribution with strong expression only in brain and prostate. While TMEFF2 is overexpressed in prostate cancer indicating an oncogenic role, several studies indicate a tumor suppressor role for this protein. This dual mode of action is, at least in part, the result of metalloproteinase-dependent shedding that generates a soluble TMEFF2 ectodomain with a growth promoting function. While recent studies have shed some light on the biology of different forms of TMEFF2, little is known about the molecular mechanisms that influence its oncogenic/tumor suppressive function. In several non-prostate cell lines, it has been shown that a recombinant form of the TMEFF2 ectodomain can interact with platelet derived growth factor (PDGF)-AA to suppress PDGF receptor signaling and can promote ErbB4 and ERK1/2 phosphorylation. However, the role of the full length TMEFF2 in these pathways has not been examined. Using prostate cell lines, here we examine the role of TMEFF2 in ERK and Akt activation, two pathways implicated in prostate cancer progression and that have been shown to cross talk in several cancers. Our results show that different forms of TMEFF2 distinctly affect Akt and ERK activation and this may contribute to a different cellular response of either proliferation or tumor suppression. PMID- 23936740 TI - Evidence of a novel allergenic protein Narcin in the bulbs of Narcissus tazetta. AB - Several plant-derived allergens have been identified which result in the formation of immunoglobulin E antibodies. Primarily, these allergens belong to the protein families including seed storage proteins, structural proteins and pathogenesis-related proteins. Several allergens are also reported from flower bulbs which cause contact dermatitis. Such symptoms are highly common with the bulb growers handling different species of Narcissus. Narcissus toxicity is also reported if the bulbs are consumed accidentally. The present study aimed to characterize the protein from the bulbs of Narcissus tazetta responsible for its allergenic response. A 13 kDa novel allergenic protein, Narcin was isolated from the bulbs of Narcissus tazetta. The protein was extracted using ammonium sulfate fractionation. The protein was further purified by anion exchange chromatography followed by gel filtration chromatography. The N-terminal sequence of the first 15 amino-acid residues was determined using Edman degradation. The allergenicity of the protein was measured by cytokine production using flow cytometry in peripheral blood mononuclear cells. Further estimation of total IgE was performed by ELISA method. This novel protein was found to induce pro-inflammatory cytokines and thus induce allergy by elevating total IgE level. The novel protein, Narcin isolated from Narcissus tazetta was found to exhibit allergenic properties. PMID- 23936741 TI - Identification of a FXIIIA variant in human neuroblastoma cell lines. AB - FXIII is a transglutaminase consisting of two catalytic (FXIIIA) and two non catalytic subunits (FXIIIB) in plasma, where this enzyme is responsible for stabilizing fibrin clots. Although possible functions of intracellular FXIIIA have been proposed, these remain to be established. We show that a 40 kDa protein species of FXIIIA is present in the human neuroblastoma cell lines SH-SY5Y and LAN5. These data reveal the presence of a new uncharacterised variant of FXIIIA, possibly due to an alternative splicing, in nervous cells. PMID- 23936742 TI - Validated Liquid Culture Monitoring System for Lifespan Extension of Caenorhabditis elegans through Genetic and Dietary Manipulations. AB - Nutritional and genetic factors influence aging and life expectancy. The reduction of food intake without malnutrition, referred to caloric restriction (CR), has been shown to increase lifespan in a wide variety of species. The nematode Caenorhabditis elegans (C. elegans) is one of the principle models with which to study the biology of aging and search for anti-aging compounds. In this study, we validated and optimized a high-throughput liquid culture system to monitor C. elegans lifespan with minimized mechanical stress. We used alive and ultraviolet (UV)-killed Escherichia coli (E. coli) OP50 at 10(8) or 10(9) colony forming units (cfu)/ml to feed Bristol N2 wild-type (WT) and mutant worms of a well-characterized insulin/insulin-like growth factor signaling (ILS) pathway: the insulin receptor homolog daf-2 (e1370), phosphatidylinositol 3-kinase age-1 (hx546), and transcriptional factor FOXO homolog daf-16 (mu86 and mgDf50). Compared with alive E. coli at 10(9) cfu/ml, supplementations of alive E. coli at 10(8) cfu/ml or UV-killed E. coli at 10(9) cfu/ml dramatically prolonged lifespan in WT and age-1 mutants, and to a lesser extent, in daf-2 and daf-16 mutants, suggesting that signaling pathways in CR and ILS do not overlap fully. Feeding 10(8) cfu/ml UV-killed E. coli, which led to maximally saturated longevity in WT and daf-2 mutant, can prolonged lifespan in age-1, but not daf-16, mutants. This approach will be useful for investigating the biology of aging, physiological responses and gene functions under CR conditions and also for screening pharmacologic compounds to extend lifespan or affect other biologic processes. PMID- 23936744 TI - Older Subjects without Radiographic Knee Osteoarthritis: Weight, Height, and Body Mass Index. AB - Osteoarthritis, the most common form of arthritis, conservatively affects 27 million American adults. While nearly all joints can be affected, knee osteoarthritis is of particular interest as it has the potential to severely limit mobility. Despite its ubiquity, not everyone is affected. Few studies on the characteristics of these persons exist. This descriptive paper examined older subjects without radiographic knee osteoarthritis (RKOA) at age 78, describing their height, weight and body mass index (BMI). Oldest subjects without RKOA at age 78 (n=143) were selected from the parent Clearwater Osteoarthritis Study, conducted from 1988-2009. Recalled weight and height for ages 25 and 45, as well as current weight and height were collected via questionnaire. Current measurements were also taken. BMI was derived. Absence of RKOA was determined using Kellgren-Lawrence criteria. DEMOGRAPHICS: mostly female (72%), all Caucasian, better educated than the average US citizen, and more subjects lived with others. At all three life-stages, weights and BMI were lower, while heights were comparable to US 2000 figures. BMI was in the "normal" category at age 25 and in the "overweight" category at age 78. Weight was under reported and height was over reported, but by less than the general population. Both the increase in weight and decrease in height with age were statistically significant. Absence of RKOA appears to be related to lower weights, average heights, and lower BMI, relative to population norms at all three life-stages. These findings also suggest that the relationship may be more complicated. Higher BMI is ubiquitously recognized as a risk factor for RKOA, yet the average BMI of the subjects without RKOA was in the "overweight" category at age 78. A possible explanation may be an "inflated" BMI based on decrease in height, not just increase in weight. PMID- 23936743 TI - Functional Analysis and Molecular Docking studies of Medicinal Compounds for AChE and BChE in Alzheimer's Disease and Type 2 Diabetes Mellitus. AB - Acetylcholinesterase and Butyrylcholinesterase share unravelling link with components of metabolic syndromes that's characterised by low levels of HDL cholesterol, obesity, high fast aldohexose levels, hyper-trigliceridaemia and high blood pressure, by regulation of cholinergic transmission and therefore the enzyme activity within a living system. The phosphomotifs associated with amino acid and tyrosine binding motifs in AChE and BChE were known to be common. Phylogenetic tree was constructed to these proteins usinf UPGMA and Maximum Likelihood methods in MEGA software has shown interaction of AChE and BChE with ageing diseases like Alzheimer's disease and Diabetes. AChE has shown closely related to BChE, retinol dehydrogenase and beta-polypeptide. The present studies is also accomplished that AChE, BChE, COLQ, HAND1, APP, NLGN2 and NGF proteins has interactions with diseases such as Alzheimer's and D2M using Pathwaylinker and STRING. Medicinal compounds like Ortho-7, Dibucaine and HI-6 are predicted as good targets for modeled AChE and BChE proteins based on docking studies. Hence perceptive studies of cholinesterase structure and the biological mechanisms of inhibition are necessary for effective drug development. PMID- 23936745 TI - Alzheimer's disease and immunotherapy. AB - Alzheimer's disease (AD) is a growing health care epidemic. It is the most common cause of dementia and its incidence is rising. Age, which influences the oxidative and inflammatory states of the brain, is the most important risk factor. Currently there is no disease modifying treatments available for this irreversible, progressive debilitating disease. Immunotherapy represents an emerging, potentially disease modifying strategy aimed at reducing the pathological lesions of AD and facilitating cognitive improvement. Many clinical trials are currently underway. This literature review highlights current knowledge regarding the physiology of aging and how it relates to the pathogenesis of AD. In addition, immunotherapy is discussed in the context of its mechanism, current studies and future goals. PMID- 23936747 TI - Tobacco-free Take Action!: Increasing Policy Adherence on a College Campus. AB - INTRODUCTION: One in five college students report tobacco use, thus universities are making strides to reduce tobacco use by adopting smoke- or tobacco-free policies. PURPOSE: Describe an innovative ambassador program to increase adherence with a tobacco-free campus policy. METHODS: The Tobacco-Free Take Action! (TFTA!) Ambassador program was created to form an environment of compliance. Hot spots were targeted by Ambassadors, who were trained to use scripted messages. Ambassadors completed an online documentation form to assess the number of violators observed and approached. The Tobacco-Free Compliance Assessment Tool (TF-CAT) was used to collect pre- and post-cigarette butt data at each hot spot. RESULTS: During the 4-week intervention period, Ambassadors approached 332 violators (529 observed), of which 68% responded positively and complied with the policy. The number of cigarette butts declined by 25%. DISCUSSION: Adherence with campus tobacco-free policies remains a challenge. Lessons learned from this innovative approach will benefit those currently implementing and planning tobacco-free campus policies. PMID- 23936746 TI - Aging, neurogenesis, and caloric restriction in different model organisms. AB - Brain aging is a multifactorial process that is occurring across multiple cognitive domains. A significant complaint that occurs in the elderly is a decrement in learning and memory ability. Both rodents and zebrafish exhibit a similar problem with memory during aging. The neurobiological changes that underlie this cognitive decline are complex and undoubtedly influenced by many factors. Alterations in the birth of new neurons and neuron turnover may contribute to age-related cognitive problems. Caloric restriction is the only non genetic intervention that reliably increases life span and healthspan across multiple organisms although the molecular mechanisms are not well-understood. Recently the zebrafish has become a popular model organism for understanding the neurobiological consequences but to date very little work has been performed. Similarly, few studies have examined the effects of dietary restriction in zebrafish. Here we review the literature related to memory decline, neurogenesis, and caloric restriction across model organisms and suggest that zebrafish has the potential to be an important animal model for understanding the complex interactions between age, neurobiological changes in the brain, and dietary regimens or their mimetics as interventions. PMID- 23936748 TI - Differentiation of Human Adipose-derived Stem Cells along the Keratocyte Lineage In vitro. AB - PURPOSE: To evaluate differentiation of human adipose-derived stem cells (hASCs) to the keratocyte lineage by co-culture with primary keratocytes in vitro. MATERIALS AND METHODS: A co-culture system using transwell inserts to grow hASCs on bottom and keratocytes on top in keratocyte differentiating medium (KDM) was developed. hASCs that were cultured in complete culture medium (CCM) and KDM were used as control. After 16 days, hASCs were examined for morphologic changes and proliferation by cell count. qRT-PCR and flow cytometry were used to detect the expression of aldehyde dehydrogenase 3 family, member A1 (ALDH3A1) and keratocan. RESULTS: hASCs became more dendritic and elongated in co-culture system relative to CCM and KDM. The doubling time of the cells was longer as differentiation progressed. qRT-PCR showed a definite trend towards increased expression of both ALDH3A1 and keratocan in co-culture system despite statistically non-significant p-values. Flow cytometry showed significantly increased protein levels of ALDH3A1 and keratocan in co-culture system relative to CCM group (p < 0.001) and even relative to KDM group (p < 0.001 for ALDH3A1 and p < 0.01 for keratocan). CONCLUSION: The co-culture method is a promising approach to induce differentiation of stem cell populations prior to in vivo applications. This study reveals an important potential for bioengineering of corneal tissue using autologous multi-potential stem cells. PMID- 23936749 TI - Effects of different warm-up programs on golf performance in elite male golfers. AB - BACKGROUND: The physical demands required of the body to execute a shot in golf are enormous. Current evidence suggests that warm-up involving static stretching is detrimental to immediate performance in golf as opposed to active dynamic stretching. However the effect of resistance exercises during warm-up before golf on immediate performance is unknown. Therefore, the purpose of this study was to assess the effects of three different warm-up programs on immediate golf performance. METHODS: Fifteen elite male golfers completed three different warm up programs over three sessions on non-consecutive days. After each warm-up program each participant hit ten maximal drives with the ball flight and swing analyzed with Flightscope(r) to record maximum club head speed (MCHS), maximal driving distance (MDD), driving accuracy (DA), smash factor (SF) and consistent ball strike (CBS). RESULTS: Repeated measures ANOVA tests showed statistically significant difference within 3 of the 5 factors of performance (MDD, CBS and SF). Subsequently, a paired t-test then showed statistically significant (p<0.05) improvements occurred in each of these three factors in the group performing a combined active dynamic and functional resistance (FR) warm-up as opposed to either the active dynamic (AD) warm-up or the combined AD with weights warm-up (WT). There were no statistically significant differences observed between the AD warm-up and the WT warm-up for any of the five performance factors and no statistical significant difference between any of the warm-ups for maximum clubhead speed (MCHS) and driving accuracy (DA). CONCLUSION: Performing a combined AD and FR warm up with Theraband(r) leads to significant increase in immediate performance of certain factors of the golf drive compared to performing an AD warm-up by itself or a combined AD with WT warm-up. No significant difference was observed between the three warm-up groups when looking at immediate effect on driving accuracy or maximum club head speed. The addition of functional resistance activities to active dynamic stretching has immediate benefits to elite male golfers in relation to some factors of their performance. LEVEL OF EVIDENCE: This study is a Quantitative Experimental design using repeated measures and multiple crossovers. It cannot be classified using the descriptive level of evidence. PMID- 23936750 TI - Brief Strategic Family Therapy: An Intervention to Reduce Adolescent Risk Behavior. AB - This article reviews the brief strategic family therapy (BSFT; J. Szapocznik, M. A. Scopetta, & O. E. King, 1978, The effect and degree of treatment comprehensiveness with a Latino drug abusing population. In D. E. Smith, S. M. Anderson, M. Burton, N. Gotlieb, W. Harvey, & T. Chung, Eds, A multicultural view of drug abuse, pp. 563-573, Cambridge, MA: G. K. Hall & J. Szapocznik, M. A. Scopetta, & O. E. King, 1978, Theory and practice in matching treatment to the special characteristics and problems of Cuban immigrants, Journal of Community Psychology, 6, 112-122.) approach to treating adolescent drug abuse and related problem behaviors. The treatment intervention is reviewed, including specialized features such as engagement of difficult families. Empirical evidence supporting the BSFT approach is presented. We then illustrate ways in which clinicians can use the model with troubled families whose adolescents may be at risk for drug use and HIV. Finally, future directions for BSFT research are described. PMID- 23936753 TI - Balancing the Budget through Social Exploitation: Why Hard Times Are Even Harder for Some. AB - In all societies needs and wants regularly exceed resources. Thus societies are always in deficit; demand always exceeds supply and "balancing the budget" is a constant social problem. To make matters somewhat worse, research suggests that need- and want-fulfillment tends to further stimulate the cycle of wantseeking rather than satiating desire. Societies use various resource-allocation mechanisms, including price, to cope with gaps between wants and resources. Social exploitation is a second mechanism, securing labor from population segments that can be coerced or convinced to perform necessary work for free or at below-market compensation. Using practical examples, this article develops a theoretical framework for understanding social exploitation. It then offers case examples of how different segments of the population emerge as exploited groups in the United States, due to changes in social policies. These exploitative processes have been exacerbated and accelerated by the economic downturn that began in 2007. PMID- 23936755 TI - Cerium oxide nanoparticles accelerate the decay of peroxynitrite (ONOO(-)). AB - Cerium oxide nanoparticles (CeO2 NPs) have been shown to possess a substantial oxygen storage capacity via the interchangeable surface reduction and oxidation of cerium atoms, cycling between the Ce(4+) and Ce(3+) redox states. It has been well established in many studies that depending on their reactivity and surface chemistry, CeO2 NPs can effectively convert both reactive oxygen species (superoxide, O2 (*-), and hydrogen peroxide) into more inert species and scavenge reactive nitrogen species (RNS)(nitric oxide, *NO), both in vitro and in vivo. Since much of damage attributed to *NO and O2 (*-) is actually the result of oxidation or nitration by peroxynitrite or its breakdown products and due to the multiple species that these nanoparticles target in vivo, it was logical to test their interaction with the highly reactive molecule peroxynitrite (ONOO(-)). Here, we report that CeO2 NPs significantly accelerated the decay of ONOO(-) by three independent methods. Additionally, our data suggest the ability of CeO2 NPs to interact with ONOO(-) is independent of the Ce(3+)/Ce(4+) ratio on the surface of the CeO2 NPs. The accelerated decay was not observed when reactions were carried out in an inert gas (argon), suggesting strongly that the decay of peroxynitrite is being accelerated due to a reaction of CeNPs with the carbonate radical anion. These results suggest that one of the protective effects of CeO2 NPs during RNS is likely due to reduction in peroxynitrite or its reactive breakdown products. PMID- 23936754 TI - Dual-function theranostic nanoparticles for drug delivery and medical imaging contrast: perspectives and challenges for use in lung diseases. AB - Theranostic nanoparticles with both therapeutic and imaging abilities have the promise to revolutionize diagnosis, therapy, and prognosis. Early and accurate detection along with swift treatment are the most important steps in the successful treatment of any disease. Over the last decade, a variety of nanotechnology-based platforms have been created in the hope of improving the treatment and diagnosis of a wide variety of diseases. However, significant hurdles still remain before theranostic nanoparticles can bring clinical solutions to the fight against chronic respiratory diseases. Some fundamental issues such as long-term toxicity, a precise understanding of the accumulation, degradation and clearance of these particles, and the correlation between basic physicochemical properties of these nanoparticles and their in vivo behavior have to be fully understood before they can be used clinically. To date, very little theranostic nanoparticle research has focused on the treatment and diagnosis of chronic respiratory illnesses. Nanomedicine approaches incorporating these theranostic nanoparticles could potentially be translated into clinical advances to improve diagnosis and treatment of these chronic respiratory diseases and enhance quality of life for the patients. PMID- 23936756 TI - Exercise training and implantable cardioverter-defibrillator shocks in patients with heart failure: results from HF-ACTION (Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing). AB - OBJECTIVES: The purpose of this study was to determine whether exercise training is associated with an increased risk of implantable cardioverter-defibrillator (ICD) therapy in patients with heart failure (HF). BACKGROUND: Few data are available regarding the safety of exercise training in patients with ICDs and HF. METHODS: HF-ACTION (Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing) randomized 2,331 outpatients with HF and an ejection fraction (EF) <=35% to exercise training or usual care. Cox proportional hazards modeling was used to examine the relationship between exercise training and ICD shocks. RESULTS: We identified 1,053 patients (45%) with an ICD at baseline who were randomized to exercise training (n = 546) or usual care (n = 507). Median age was 61 years old, and median EF was 24%. Over a median of 2.2 years of follow up, 20% (n = 108) of the exercise patients had a shock versus 22% (n = 113) of the control patients. A history of sustained ventricular tachycardia/fibrillation (hazard ratio [HR]: 1.93 [95% confidence interval (CI): 1.47 to 2.54]), previous atrial fibrillation/flutter (HR: 1.63 [95% CI: 1.22 to 2.18]), exercise-induced dysrhythmia (HR: 1.67 [95% CI: 1.23 to 2.26]), lower diastolic blood pressure (HR for 5-mm Hg decrease <60: 1.35 [95% CI: 1.12 to 1.61]), and nonwhite race (HR: 1.50 [95% CI: 1.13 to 2.00]) were associated with an increased risk of ICD shocks. Exercise training was not associated with the occurrence of ICD shocks (HR: 0.90 [95% CI: 0.69 to 1.18], p = 0.45). The presence of an ICD was not associated with the primary efficacy composite endpoint of death or hospitalization (HR: 0.99 [95% CI: 0.86 to 1.14], p = 0.90). CONCLUSIONS: We found no evidence of increased ICD shocks in patients with HF and reduced left ventricular function who underwent exercise training. Exercise therapy should not be prohibited in ICD recipients with HF. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437) PMID- 23936757 TI - An Assay for the Rate of Removal of Extracellular Hydrogen Peroxide by Cells. AB - Cells have a wide range of capacities to remove extracellular hydrogen peroxide. At higher concentrations of extracellular H2O2 (micromolar) the rate of removal can be approximated by a rate equation that is first-order in the concentration of H2O2 and cell density. Here we present a method to determine the observed rate constant for the removal of extracellular H2O2 on a per cell basis. In the cells examined, when exposed to 20 MUM H2O2, these rate constants (kcell) range from 0.46 * 10-12 s-1 cell-1 L for Mia PaCa-2 cells (human pancreatic carcinoma) to 10.4 * 10-12 s-1 cell-1 L for U937 cells (human histiocytic lymphoma). For the relatively small red blood cell kcell = 2.9 * 10-12 s-1 cell-1 L. These rate constants, kcell, can be used to compare the capacity of cells to remove higher levels of extracellular H2O2, as often presented in cell culture experiments. They also provide a means to estimate the rate of removal of extracellular H2O2, rate = - kcell [H2O2] (cells L-1), and the half-life of a bolus of H2O2. This information is essential to optimize experimental design and interpret data from experiments that expose cells to extracellular H2O2. PMID- 23936759 TI - Behavior of advanced gastrointestinal stromal tumor in a patient with von Recklinghausen disease: Case report. AB - Gastrointestinal stromal tumors (GISTs) represent a malignant gastrointestinal tumor of neurofibromatosis type 1 (NF1) Von Recklinghausen disease. In the current case, we report a 27-year-old woman with NF1, who presented with a lower abdominal mass, symptomatic anaemia, and significant weight loss. We employed multiple approaches to assess the tumor behavior, including computed tomography (CT) scan, surgical tumor resection, histological and immunohistochemical analysis and gene sequencing. Additionally, the patient was given Imatinib mesylate (Gleevec) as adjuvant therapy. CT scan delineated a large thick wall cavity lesion connecting to the small bowel segment. Resection of the tumor yielded a mass of 17 cm * 13 cm with achievement of safety margins. The diagnosis was GIST, confirmed by immunohistochemical expression of CD117, CD34, and Bcl-2. Sequencing revealed no mutations in either KIT or platelet-derived growth factor receptor-alpha, genes which are mutated in over 85% of sporadic GIST cases. Further, there was no evidence of recurrence, metastasis or metachronous GIST for over three years in our patient. From our analyses, we believe selective genotyping is advisable for high risk patients to predict potential tumor behavior. PMID- 23936760 TI - Angioimmunoblastic T-cell lymphoma-associated pure red cell aplasia with abdominal pain. AB - Angioimmunoblastic T-cell lymphoma (AITL) is a unique type of peripheral T-cell lymphoma with a constellation of clinical symptoms and signs, including weight loss, fever, chills, anemia, skin rash, hepatosplenomegaly, lymphadenopathy, thrombocytopenia and polyclonal hypergammaglobulinemia. The histological features of AITL are also distinctive. Pure red cell aplasia is a bone marrow failure characterized by progressive normocytic anemia and reticulocytopenia without leucopenia or thrombocytopenia. However, AITL with abdominal pain and pure red cell aplasia has rarely been reported. Here, we report a rare case of AITL associated pure red cell aplasia with abdominal pain. The diagnosis was verified by a biopsy of the enlarged abdominal lymph nodes with immunohistochemical staining. PMID- 23936758 TI - Role of E3 ubiquitin ligases in lung cancer. AB - E3 ubiquitin ligases are a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome. Therefore, E3 ubiquitin ligases play an essential role in a variety of biological processes including cell cycle regulation, proliferation and apoptosis. E3 ubiquitin ligases are often found overexpressed in human cancers, including lung cancer, and their deregulation has been shown to contribute to cancer development. However, the lack of specific inhibitors in clinical trials is a major issue in targeting E3 ubiquitin ligases with currently only one E3 ubiquitin ligase inhibitor being tested in the clinical setting. In this review, we focus on E3 ubiquitin ligases that have been found deregulated in lung cancer. Furthermore, we discuss the processes in which they are involved and evaluate them as potential anti-cancer targets. By better understanding the mechanisms by which E3 ubiquitin ligases regulate biological processes and their exact role in carcinogenesis, we can improve the development of specific E3 ubiquitin ligase inhibitors and pave the way for novel treatment strategies for cancer patients. PMID- 23936761 TI - Antifungal cyclic peptides from the marine sponge Microscleroderma herdmani. AB - Screening natural product extracts from the National Cancer Institute Open Repository for antifungal discovery afforded hits for bioassay-guided fractionation. Using LC-MS analysis to generate chemical structure information on potentially active compounds, two new cyclic hexapeptides, microsclerodermins J (1) and K (2), were isolated from the deep-water sponge Microscleroderma herdmani, along with microsclerodermins A (3) and B (4), previously isolated from an unidentified Microscleroderma species. The structures of the new compounds were elucidated by spectroscopic analysis and chemical methods. In vitro antifungal testing showed that the four compounds possessed strong activities against the opportunistic fungal pathogens Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, and Aspergillus fumigatus. PMID- 23936762 TI - Nanocarrier-mediated targeting of tumor and tumor vascular cells improves uptake and penetration of drugs into neuroblastoma. AB - Neuroblastoma (NB) is the most common extracranial solid tumor in children, accounting for about 8% of childhood cancers. Despite aggressive treatment, patients suffering from high-risk NB have very poor 5-year overall survival rate, due to relapsed and/or treatment-resistant tumors. A further increase in therapeutic dose intensity is not feasible, because it will lead to prohibitive short-term and long-term toxicities. New approaches with targeted therapies may improve efficacy and decrease toxicity. The use of drug delivery systems allows site specific delivery of higher payload of active agents associated with lower systemic toxicity compared to the use of conventional ("free") drugs. The possibility of imparting selectivity to the carriers to the cancer foci through the use of a targeting moiety (e.g., a peptide or an antibody) further enhances drug efficacy and safety. We have recently developed two strategies for increasing local concentration of anti-cancer agents, such as CpG-containing oligonucleotides, small interfering RNAs, and chemotherapeutics in NB. For doing that, we have used the monoclonal antibody anti-disialoganglioside (GD2), able to specifically recognize the NB tumor and the peptides containing NGR and CPRECES motifs, that selectively bind to the aminopeptidase N-expressing endothelial and the aminopeptidase A-expressing perivascular tumor cells, respectively. The review will focus on the use of tumor- and tumor vasculature-targeted nanocarriers to improve tumor targeting, uptake, and penetration of drugs in preclinical models of human NB. PMID- 23936763 TI - Targeting genomic alterations in squamous cell lung cancer. AB - Squamous cell lung cancer causes approximately 400,000 deaths worldwide per year. Identification of specific molecular alterations, such as activating mutations in the epidermal growth factor receptor kinase and echinoderm microtubule-associated protein-like 4/anaplastic lymphoma kinase fusions have led to significant therapeutic gains in patients with adenocarcinoma. However, meaningful therapeutic gains based on the molecular pathobiology of squamous cell lung cancer have not yet been realized. A comprehensive genomic characterization of 178 cases of squamous cell lung cancer has recently been reported. Squamous cell lung cancer appears to be characterized by a broader and more complex group of genomic alterations than adenocarcinoma. In this review, potentially targetable genes or pathways in squamous cell lung cancer are emphasized in relation to available therapeutic agents in development or active clinical trials. This organization of data will provide a framework for development for clinical investigation. Squamous cell lung cancer appears to be characterized by not only driver mutations in candidate genes but also gene copy number alterations resulting in tumor proliferation and survival. Better understanding of these genetic alterations and their use as therapeutic targets will require broad collaboration between industry, government, the cooperative groups, and academic institutions with the ultimate goal of rapid translation of scientific advancement to patient benefit. PMID- 23936764 TI - PML: Not all about Tumor Suppression. PMID- 23936765 TI - A Rising Cancer Prevention Target of RSK2 in Human Skin Cancer. AB - RSK2 is a p90 ribosomal S6 kinase family (p90(RSK)) member regulating cell proliferation and transformation induced by tumor promoters such as epithelial growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate. This family of p90(RSK) has classified as a serine/threonine kinase that respond to many growth factors, peptide hormones, neurotransmitters, and environmental stresses such as ultraviolet (UV) light. Our recent study demonstrates that RSK2 plays a key role in human skin cancer development. Activation of RSK2 by EGF and UV through extracellular-activated protein kinases signaling pathway induces cell cycle progression, cell proliferation, and anchorage-independent cell transformation. Moreover, knockdown of RSK2 by si-RNA or sh-RNA abrogates cell proliferation and cell transformation of non-malignant human skin keratinocyte, and colony growth of malignant melanoma (MM) cells in soft agar. Importantly, activated and total RSK2 protein levels are highly detected in human skin cancer tissues including squamous cell carcinoma, basal-cell carcinoma, and MM. Kaempferol and eriodictyol are natural substances to inhibit kinase activity of the RSK2 N-terminal kinase domain, which is a critical kinase domain to transduce their activation signals to the substrates by phosphorylation. In this review, we discuss the role of RSK2 in skin cancer, particularly in activation of signaling pathways and potent natural substances to target RSK2 as chemopreventive and therapeutic agents. PMID- 23936766 TI - Serum Retinol and Carotenoids in Association with Biomarkers of Insulin Resistance among Premenopausal Women. AB - OBJECTIVE: The aim of this study was to investigate how serum retinol and carotenoids (beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, lycopene) are associated with biomarkers of insulin resistance. RESEARCH METHODS AND PROCEDURES: The BioCycle Study (2005-2007) is a prospective cohort of 259 healthy premenopausal women. Fasting serum samples were collected at up to sixteen clinic visits, from which retinol, carotenoids, insulin, glucose, and sex hormone binding globulin (SHBG) were measured. Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). Linear mixed models were used to determine associations adjusting for age, race, body mass index (BMI), education, smoking, physical activity, triglycerides, and energy intake. RESULTS: Retinol was positively associated with HOMA-IR (beta = 0.19 (95% CI: 0.07, 0.32)) units per ug/mL increase in retinol; the relationship was driven by insulin (beta = 0.20 (95% CI: 0.08, 0.31)). Retinol was inversely associated with SHBG (beta = 0.22 (95% CI: -0.28, -0.16)). Although no significant associations were found between serum carotenoids and HOMA-IR, beta-carotene was positively associated with SHBG and beta-cryptoxanthin inversely with fasting plasma glucose. CONCLUSION: Results indicate a possible role for serum retinol in the pathogenesis of type 2 diabetes. However, they do not support a strong association between individual or total serum carotenoids and insulin resistance. PMID- 23936767 TI - A Complex Network of MicroRNAs Expressed in Brain and Genes Associated with Amyotrophic Lateral Sclerosis. AB - Amyotrophic Lateral Sclerosis (ALS) is a rare neurological disease affecting mainly motor neurons and often leads to paralysis and death in extreme cases. For exploring the role of microRNAs in genes regulation in ALS disease, miRanda was employed for prediction of target sites of miRNAs expressed in various parts of brain and CNS on 35 genes associated with ALS. Similar search was conducted using TargetScan and PicTar for prediction of target sites in 3' UTR only. 1456 target sites were predicted using miRanda and more target sites were found in 5' UTR and CDS region as compared to 3' UTR. 11 target sites were predicted to be common by all the algorithms and, thus, these represent the most significant sites. Target site hotspots were identified and were recognized as hotspots for multiple miRNAs action, thus, acting as favoured sites of action for the repression of gene expression. The complex interplay of genes and miRNAs brought about by multiplicity and cooperativity was explored. This investigation will aid in elucidating the mechanism of action of miRNAs for the considered genes. The intrinsic network of miRNAs expressed in nervous system and genes associated with ALS may provide rapid and effective outcome for therapeutic applications and diagnosis. PMID- 23936769 TI - Detection of gender differences in incomplete revascularization after coronary artery bypass surgery varies with classification technique. AB - BACKGROUND: Incomplete revascularization negatively affects survival after coronary artery bypass surgery (CABG). Since gender and classification technique might impact outcome and reporting, we investigated their effect on revascularization patterns and mortality. METHODS: A cohort of bypass patients (N = 1545, 23% women) was enrolled prospectively. The degree of revascularization was determined as mathematical difference between affected vessels upon diagnosis and number of grafts or the surgeon's rating on the case file. RESULTS: Although men displayed more triple-vessel disease, they obtained complete revascularization more frequently than women (85% versus 77%, P < 0.001). The two calculation methods identified analogous percentages of incompletely revascularized patients, yet there was only a 50% overlap between the two groups. Mathematically, more women, older patients, and patients with NYHA class III/IV appeared incompletely revascularized, while the surgeons identified more patients undergoing technically challenging procedures. Regardless of the definition, incompleteness was a significant risk factor for mortality in both genders (mathematical calculation: HR 2.62, 95% CI 1.76-3.89, P < 0.001; surgeon: HR 2.04, 95% CI 1.35-3.89, P = 0.001). CONCLUSIONS: Given the differences in identification patterns, we advise that the mathematical calculation be performed after-procedure in all patients regardless of the surgeons' rating to uncover additional subjects at increased risk. PMID- 23936770 TI - The glycosylation of AGP and its associations with the binding to methadone. AB - Methadone remains the most common form of pharmacological therapy for opioid dependence; however, there is a lack of explanation for the reports of its relatively low success rate in achieving complete abstinence. One hypothesis is that in vivo binding of methadone to the plasma glycoprotein alpha-1-acid glycoprotein (AGP), to a degree dependent on the molecular structure, may render the drug inactive. This study sought to determine whether alterations present in the glycosylation pattern of AGP in patients undergoing various stages of methadone therapy (titration < two weeks, harm reduction < one year, long-term > one and a half years) could affect the affinity of the glycoprotein to bind methadone. The composition of AGP glycosylation was determined using high pH anion exchange chromatography (HPAEC) and intrinsic fluorescence analysed to determine the extent of binding to methadone. The monosaccharides galactose and N acetyl-glucosamine were elevated in all methadone treatment groups indicating alterations in AGP glycosylation. AGP from all patients receiving methadone therapy exhibited a greater degree of binding than the normal population. This suggests that analysing the glycosylation of AGP in patients receiving methadone may aid in determining whether the therapy is likely to be effective. PMID- 23936768 TI - Prostate stem cells in the development of benign prostate hyperplasia and prostate cancer: emerging role and concepts. AB - Benign Prostate hyperplasia (BPH) and prostate cancer (PCa) are the most common prostatic disorders affecting elderly men. Multiple factors including hormonal imbalance, disruption of cell proliferation, apoptosis, chronic inflammation, and aging are thought to be responsible for the pathophysiology of these diseases. Both BPH and PCa are considered to be arisen from aberrant proliferation of prostate stem cells. Recent studies on BPH and PCa have provided significant evidence for the origin of these diseases from stem cells that share characteristics with normal prostate stem cells. Aberrant changes in prostate stem cell regulatory factors may contribute to the development of BPH or PCa. Understanding these regulatory factors may provide insight into the mechanisms that convert quiescent adult prostate cells into proliferating compartments and lead to BPH or carcinoma. Ultimately, the knowledge of the unique prostate stem or stem-like cells in the pathogenesis and development of hyperplasia will facilitate the development of new therapeutic targets for BPH and PCa. In this review, we address recent progress towards understanding the putative role and complexities of stem cells in the development of BPH and PCa. PMID- 23936771 TI - In vitro release kinetics of antituberculosis drugs from nanoparticles assessed using a modified dissolution apparatus. AB - The aim of this study was to assess the in vitro release kinetics of antituberculosis drug-loaded nanoparticles (NPs) using a "modified" cylindrical apparatus fitted with a regenerated cellulose membrane attached to a standard dissolution apparatus (modifiedcylinder method). The model drugs that were used were rifampicin (RIF) and moxifloxacin hydrochloride (MX). Gelatin and polybutyl cyanoacrylate (PBCA) NPs were evaluated as the nanocarriers, respectively. The dissolution and release kinetics of the drugs from loaded NPs were studied in different media using the modified cylinder method and dialysis bag technique was used as the control technique. The results showed that use of the modified cylinder method resulted in different release profiles associated with unique release mechanisms for the nanocarrier systems investigated. The modified cylinder method also permitted discrimination between forced and normal in vitro release of the model drugs from gelatin NPs in the presence or absence of enzymatic degradation. The use of dialysis bag technique resulted in an inability to differentiate between the mechanisms of drug release from the NPs in these cases. This approach offers an effective tool to investigate in vitro release of RIF and MX from NPs, which further indicate that this technique can be used for performance testing of nanosized carrier systems. PMID- 23936772 TI - The association of the immune response genes to human papillomavirus-related cervical disease in a Brazilian population. AB - The genetic variability of the host contributes to the risk of human papillomavirus (HPV)-related cervical disease. Immune response genes to HPV must be investigated to define patients with the highest risk of developing malignant disease. The aim of this study was to investigate the association of polymorphic immune response genes, namely KIR, HLA class I and II, and single-nucleotide polymorphisms (SNPs) of cytokines with HPV-related cervical disease. We selected 79 non-related, admixed Brazilian women from the state of Parana, southern region of Brazil, who were infected with high carcinogenic risk HPV and present cervical intraepithelial neoplasia grade 3 (CIN3), and 150 HPV-negative women from the same region matched for ethnicity. KIR genes were genotyped using an in-house PCR SSP. HLA alleles were typed using a reverse sequence-specific oligonucleotide technique. SNPs of TNF -308G>A, IL6 -174G>C, IFNG +874T>A, TGFB1 +869T>C +915G>C, and IL10 -592C>A -819C>T -1082G>A were evaluated using PCR-SSP. The KIR genes were not associated with HPV, although some pairs of i(inhibitory)KIR-ligands occurred more frequently in patients, supporting a role for NK in detrimental chronic inflammatory and carcinogenesis. Some HLA haplotypes were associated with HPV. The associations of INFG and IL10 SNPs potentially reflect impaired or invalid responses in advanced lesions. PMID- 23936773 TI - The exposure of breast cancer cells to fulvestrant and tamoxifen modulates cell migration differently. AB - There is no doubt that there are increased benefits of hormonal therapy to breast cancer patients; however, current evidence suggests that estrogen receptor (ER) blockage using antiestrogens is associated with a small induction of invasiveness in vitro. The mechanism by which epithelial tumor cells escape from the primary tumor and colonize to a distant site is not entirely understood. This study investigates the effect of two selective antagonists of the ER, Fulvestrant (Fulv) and Tamoxifen (Tam), on the invasive ability of breast cancer cells. We found that 17 beta -estradiol (E2) demonstrated a protective role regarding cell migration and invasion. Fulv did not alter this effect while Tam stimulated active cell migration according to an increase in Snail and a decrease in E cadherin protein expression. Furthermore, both tested agents increased expression of matrix metalloproteinases (MMPs) and enhanced invasive potential of breast cancer cells. These changes were in line with focal adhesion kinase (FAK) rearrangement. Our data indicate that the anti-estrogens counteracted the protective role of E2 concerning migration and invasion since their effect was not limited to antiproliferative events. Although Fulv caused a less aggressive result compared to Tam, the benefits of hormonal therapy concerning invasion and metastasis yet remain to be investigated. PMID- 23936774 TI - LRP-1: a checkpoint for the extracellular matrix proteolysis. AB - Low-density lipoprotein receptor-related protein-(LRP-1) is a large endocytic receptor that binds more than 35 ligands and exhibits signaling properties. Proteinases capable of degrading extracellular matrix (ECM), called matrix proteinases in this paper, are mainly serine proteinases: the activators of plasminogen into plasmin, tissue-type (tPA) and urokinase-type (uPA) plasminogen activators, and the members of the matrix metalloproteinase (MMP) family. LRP-1 is responsible for clearing matrix proteinases, complexed or not with inhibitors. This paper attempts to summarize some aspects on the cellular and molecular bases of endocytic and signaling functions of LRP-1 that modulate extra- and pericellular levels of matrix proteinases. PMID- 23936775 TI - 1-aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as VEGFR-2 tyrosine kinase inhibitors: synthesis, biological evaluation, and molecular modelling studies. AB - The vascular endothelial growth factor receptor-2 (VEGFR-2) is a tyrosine kinase receptor involved in the growth and differentiation of endothelial cells that are implicated in tumor-associated angiogenesis. In this study, novel 1-aryl-3-[4 (thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas were synthesized and evaluated for the VEGFR-2 tyrosine kinase inhibition. Three of these compounds showed good VEGFR-2 inhibition presenting low IC50 values (150-199 nM) in enzymatic assays, showing also a significant proliferation inhibition of VEGF-stimulated human umbilical vein endothelial cells (HUVECs) at low concentrations (0.5-1 uM), using the Bromodeoxyuridine (BrdU) assay, not affecting cell viability. The determination of the total and phosphorylated (active) VEGFR-2 was performed by western blot, and it was possible to conclude that the compounds significantly inhibit the phosphorylation of the receptor at 1 uM pointing to their antiproliferative mechanism of action in HUVECs. The molecular rationale for inhibiting the tyrosine kinase domain of VEGFR-2 was also performed and discussed using molecular docking studies. PMID- 23936776 TI - Production and characterization of keratinolytic protease from new wool-degrading Bacillus species isolated from Egyptian ecosystem. AB - Novel keratin-degrading bacteria were isolated from sand soil samples collected from Minia Governorate, Egypt. In this study, the isolates were identified as Bacillus amyloliquefaciens MA20 and Bacillus subtilis MA21 based on morphological and biochemical characteristics as well as 16S rRNA gene sequencing. B. amyloliquefaciens MA20 and B. subtilis MA21 produced alkaline keratinolytic serine protease when cultivated in mineral medium containing 1% of wool straight off sheep as sole carbon and nitrogen source. The two strains were observed to degrade wool completely to powder at pH 7 and 37 degrees C within 5 days. Under these conditions the maximum activity of proteases produced by B. amyloliquefaciens MA20 and B. subtilis MA21 was 922 and 814 U/ml, respectively. The proteases exhibited optimum temperature and pH at 60 degrees C and 9, respectively. However, the keratinolytic proteases were stable in broad range of temperature and pH values towards casein Hammerstein. Furthermore the protease inhibitor studies indicated that the produced proteases belong to serine protease because of their sensitivity to PMSF while they were inhibited partially in presence of EDTA. The two proteases are stable in most of the used organic solvents and enhanced by metals suggesting their potential use in biotechnological applications such as wool industry. PMID- 23936777 TI - Modulation of neurological deficits and expression of glutamate receptors during experimental autoimmune encephalomyelitis after treatment with selected antagonists of glutamate receptors. AB - The aim of our investigation was to characterize the role of group I mGluRs and NMDA receptors in pathomechanisms of experimental autoimmune encephalomyelitis (EAE), the rodent model of MS. We tested the effects of LY 367385 (S-2-methyl-4 carboxyphenylglycine, a competitive antagonist of mGluR1), MPEP (2-methyl-6 (phenylethynyl)-pyridine, an antagonist of mGluR5), and the uncompetitive NMDA receptor antagonists amantadine and memantine on modulation of neurological deficits observed in rats with EAE. The neurological symptoms of EAE started at 10-11 days post-injection (d.p.i.) and peaked after 12-13 d.p.i. The protein levels of mGluRs and NMDA did not increase in early phases of EAE (4 d.p.i.), but starting from 8 d.p.i. to 25 d.p.i., we observed a significant elevation of mGluR1 and mGluR5 protein expression by about 20% and NMDA protein expression by about 10% over the control at 25 d.p.i. The changes in protein levels were accompanied by changes in mRNA expression of group I mGluRs and NMDARs. During the late disease phase (20-25 d.p.i.), the mRNA expression levels reached 300% of control values. In contrast, treatment with individual receptor antagonists resulted in a reduction of mRNA levels relative to untreated animals. PMID- 23936778 TI - Montreal Cognitive Assessment is superior to Standardized Mini-Mental Status Exam in detecting mild cognitive impairment in the middle-aged and elderly patients with type 2 diabetes mellitus. AB - AIM: This study compares the usefulness of Montreal Cognitive Assessment (MoCA) to Standardized Mini-Mental Status Exam (SMMSE) for diagnosing mild cognitive impairment (MCI) in Type 2 diabetes mellitus (DM) population. METHODS: This prospective pilot study enrolled 30 community dwelling adults with Type 2 DM aged 50 years and above. Subjects were assessed using both the SMMSE and MoCA for MCI. In all subjects, depression and dementia were ruled out using the DSM IV criteria, and a functional assessment was done. MCI was diagnosed using the standard test, the European consortium criteria. Sensitivity and specificity analysis, positive and negative predictive values, likelihood ratios and Kappa statistic were calculated. RESULTS: In comparison to consortium criteria, the sensitivity and specificity of MoCA were 67% and 93% in identifying individuals with MCI, and SMMSE were 13% and 93%, respectively. The positive and negative predictive values for MoCA were 84% and 56%, and for SMMSE were 66% and 51%, respectively. Kappa statistics showed moderate agreement between MoCA and consortium criteria (kappa = 0.4) and a low agreement between SMMSE and consortium criteria (kappa = 0.07). CONCLUSION: In this pilot study, MoCA appears to be a better screening tool than SMMSE for MCI in the diabetic population. PMID- 23936779 TI - Characterization and complete sequence of lactonase enzyme from Bacillus weihenstephanensis isolate P65 with potential activity against acyl homoserine lactone signal molecules. AB - Acyl homoserine lactones (AHLs) are the most common class of quorum sensing signal molecules (autoinducers) that have been reported to be essential for virulence of many relevant pathogenic bacteria such as Pseudomonas aeruginosa. New approach for controlling infections of such bacteria is through quorum quenching. In this study, the acyl homoserine lactone inhibitory activity of the crude enzyme from a Bacillus weihenstephanensis-isolate P65 was characterized. The crude enzyme was found to have relatively high thermal stability and was stable in pH range 6 to 9. The crude enzyme extract was found to have lactonase activity of 36.3 U/mg total protein. Maximum enzyme activity was achieved within a range of 28-50 degrees C and pH 6-9. None of the metals used enhanced the activity neither did EDTA inhibit it. However, a concentration of 10 mM Fe(+2) reduced the activity to 73.8%. Catalytic activity and kinetic constants were determined using hexanoyl homoserine lactone as a substrate. Studying enzyme substrate specificity using synthetic standard signals displayed broad spectrum of activity. The enzyme was found to be constitutive. Isolation and complete nucleotide sequence of the respective lactonase gene were done and submitted to the Genbank database under accession code KC823046. PMID- 23936780 TI - Absorption of hazardous pollutants by a medicinal fern Blechnum orientale L. AB - A Chinese medicinal fern Blechnum orientale (Linn) was separately collected from polluted and unpolluted sites to determine whether it could accumulate hazardous pollutants or not. Metal concentrations (Cu, Zn, Mn, Pb, Cd, Cr, As, and Hg) both in the fronds and roots and polycyclic aromatic hydrocarbons (PAHs) in the fronds of this fern were quantified. At both sites, roots of B. orientale had significantly higher heavy metals than the fronds. Concentrations of Pb, As, Hg, Cd, and Cu in the fronds at the polluted site were more than 2, 6, 7, 14, 5, and 13 times of those at the unpolluted site. Translocation factor and bioaccumulation factor implied that B. orientale did not have a good ability to transport heavy metals from the roots to the fronds. Total PAHs in the fronds at the polluted site were significantly higher than those at the unpolluted site, indicating the physiological PAHs absorption by B. orientale growing at polluted sites. Uptake of pollutants via stomata might be the main reason causing the significant accumulation of hazardous pollutants in the fronds of B. orientale. Large-scale systematical survey and intensive monitoring on pollutants in this medicinal fern should be necessarily strengthened. PMID- 23936782 TI - Effect of NaCl on heat resistance, antibiotic susceptibility, and Caco-2 cell invasion of Salmonella. AB - This study evaluated the effects of NaCl on heat resistance, antibiotic susceptibility, and Caco-2 cell invasion of Salmonella. Salmonella typhimurium NCCP10812 and Salmonella enteritidis NCCP12243 were exposed to 0, 2, and 4% NaCl and to sequential increase of NaCl concentrations from 0 to 4% NaCl for 24 h at 35 degrees C. The strains were then investigated for heat resistance (60 degrees C), antibiotic susceptibility to eight antibiotics, and Caco-2 cell invasion efficiency. S. typhimurium NCCP10812 showed increased thermal resistance (P < 0.05) after exposure to single NaCl concentrations. A sequential increase of NaCl concentration decreased (P < 0.05) the antibiotic sensitivities of S. typhimurium NCCP10812 to chloramphenicol, gentamicin, and oxytetracycline. NaCl exposure also increased (P < 0.05) Caco-2 cell invasion efficiency of S. enteritidis NCCP12243. These results indicate that NaCl in food may cause increased thermal resistance, cell invasion efficiency, and antibiotic resistance of Salmonella. PMID- 23936781 TI - Interleukin-33 drives activation of alveolar macrophages and airway inflammation in a mouse model of acute exacerbation of chronic asthma. AB - We investigated the role of interleukin-33 (IL-33) in airway inflammation in an experimental model of an acute exacerbation of chronic asthma, which reproduces many of the features of the human disease. Systemically sensitized female BALB/c mice were challenged with a low mass concentration of aerosolized ovalbumin for 4 weeks to induce chronic asthmatic inflammation and then received a single moderate-level challenge to trigger acute airway inflammation simulating an asthmatic exacerbation. The inflammatory response and expression of cytokines and activation markers by alveolar macrophages (AM) were assessed, as was the effect of pretreatment with a neutralizing antibody to IL-33. Compared to chronically challenged mice, AM from an acute exacerbation exhibited significantly enhanced expression of markers of alternative activation, together with enhanced expression of proinflammatory cytokines and of cell surface proteins associated with antigen presentation. In parallel, there was markedly increased expression of both mRNA and immunoreactivity for IL-33 in the airways. Neutralization of IL 33 significantly decreased both airway inflammation and the expression of proinflammatory cytokines by AM. Collectively, these data indicate that in this model of an acute exacerbation of chronic asthma, IL-33 drives activation of AM and has an important role in the pathogenesis of airway inflammation. PMID- 23936783 TI - Barriers to acceptance of provider-initiated testing and counseling among men who have sex with men in Shenyang, China: a cross-sectional study. AB - A high prevalence of HIV infection is present among men who have sex with men (MSM) in China, but many people living with HIV or AIDS (PLWHs) are unaware of their HIV infection status. Provider-initiated HIV testing and counseling (PITC) is a streamlined model that can significantly enhance HIV detection and detect infections earlier. However, PITC has not yet been widely applied, and no studies have been conducted on MSM's attitudes towards PITC in China. In this study, a total of 438 MSM were recruited in Shenyang city. A multivariate logistic regression model showed that certain conditions made MSM more accepting of PITC: those who had attended VCT (voluntary counseling and testing) more than three times (odds ratio [OR]: 2.95, 95% CI: 1.36-6.37), those who considered PITC beneficial for family and friends (OR: 1.91, 95% CI: 1.25-2.92), those who obtained HIV/AIDS knowledge from brochures (OR: 2.52, 95% CI: 1.64-3.87), those who obtained HIV/AIDS knowledge from the Internet (OR: 1.66, 95% CI: 1.07-2.58), and those who were highly aware of their own risk of being infected with HIV (OR: 2.84, 95% CI: 1.37-5.91). To improve acceptance of PITC among MSM in China, stronger efforts are needed to lower the psychosocial barriers to receiving PITC, to promote HIV/AIDS awareness, and to encourage the extension of HIV testing. PMID- 23936784 TI - The role of magnetic nanoparticles in the localization and treatment of breast cancer. AB - The role of magnetic nanoparticles (MNPs) in medical applications is rapidly developing. Advances in nanotechnology are bringing us closer to the development of dual and multifunctional nanoparticles that are challenging the traditional distinction between diagnostic and treatment agents. The current use of MNPs in breast cancer falls into four main groups: (1) imaging of primary and metastatic disease, (2) sentinel lymph node biopsy (SLNB), (3) drug delivery systems, and (4) magnetic hyperthermia. The current evidence for the use of MNPs in these fields is mounting, and potential cutting-edge clinical applications, particularly with relevance to the fields of breast oncological surgery, are emerging. PMID- 23936785 TI - Serotype distribution of Salmonella isolates from turkey ground meat and meat parts. AB - The aim of the study was to find out the serotype distribution of 169 Salmonella colonies recovered from 112 Salmonella positive ground turkey (115 colonies) and 52 turkey meat parts (54 colonies). Out of 15 Salmonella serotypes: S. Corvallis, S. Kentucky, S. Bredeney, S. Virchow, S. Saintpaul and S. Agona were identified as the predominant serovars at the rates of 27%, 13%, 12%, 12%, 11%, and 10%, respectively. Other serotypes were below 6% of the total isolates. All S. Kentucky and S. Virchow and most of the S. Corvallis (39/46) and S. Heidelberg (9/9) serotypes were recovered from ground turkey. The results indicate that turkey ground meat and meat parts were contaminated with quite distinct Salmonella serotypes. This is the first study reporting Salmonella serotype distribution in turkey meat and S. Corvallis as predominant serotype in poultry meat in Turkey. PMID- 23936786 TI - Analysis of activated platelet-derived growth factor beta receptor and Ras-MAP kinase pathway in equine sarcoid fibroblasts. AB - Equine sarcoids are skin tumours of fibroblastic origin affecting equids worldwide. Bovine papillomavirus type-1 (BPV-1) and, less commonly, type-2 are recognized as etiological factors of sarcoids. The transforming activity of BPV is related to the functions of its major oncoprotein E5 which binds to the platelet-derived growth factor beta receptor (PDGFbetaR) causing its phosphorylation and activation. In this study, we demonstrate, by coimmunoprecipitation and immunoblotting, that in equine sarcoid derived cell lines PDGFbetaR is phosphorylated and binds downstream molecules related to Ras mitogen-activated protein kinase-ERK pathway thus resulting in Ras activation. Imatinib mesylate is a tyrosine kinase receptors inhibitor which selectively inhibits the activation of PDGFbetaR in the treatment of several human and animal cancers. Here we show that imatinib inhibits receptor phosphorylation, and cell viability assays demonstrate that this drug decreases sarcoid fibroblasts viability in a dose-dependent manner. This study contributes to a better understanding of the molecular mechanisms involved in the pathology of sarcoids and paves the way to a new therapeutic approach for the treatment of this common equine skin neoplasm. PMID- 23936787 TI - Biosynthesis, antimicrobial and cytotoxic effect of silver nanoparticles using a novel Nocardiopsis sp. MBRC-1. AB - The biosynthesis of nanoparticles has been proposed as a cost effective environmental friendly alternative to chemical and physical methods. Microbial synthesis of nanoparticles is under exploration due to wide biomedical applications, research interest in nanotechnology and microbial biotechnology. In the present study, an ecofriendly process for the synthesis of nanoparticles using a novel Nocardiopsis sp. MBRC-1 has been attempted. We used culture supernatant of Nocardiopsis sp. MBRC-1 for the simple and cost effective green synthesis of silver nanoparticles. The reduction of silver ions occurred when silver nitrate solution was treated with the Nocardiopsis sp. MBRC-1 culture supernatant at room temperature. The nanoparticles were characterized by UV visible, TEM, FE-SEM, EDX, FTIR, and XRD spectroscopy. The nanoparticles exhibited an absorption peak around 420 nm, a characteristic surface plasmon resonance band of silver nanoparticles. They were spherical in shape with an average particle size of 45 +/- 0.15 nm. The EDX analysis showed the presence of elemental silver signal in the synthesized nanoparticles. The FTIR analysis revealed that the protein component in the form of enzyme nitrate reductase produced by the isolate in the culture supernatant may be responsible for reduction and as capping agents. The XRD spectrum showed the characteristic Bragg peaks of 1 2 3, 2 0 4, 0 4 3, 1 4 4, and 3 1 1 facets of the face centered cubic silver nanoparticles and confirms that these nanoparticles are crystalline in nature. The prepared silver nanoparticles exhibited strong antimicrobial activity against bacteria and fungi. Cytotoxicity of biosynthesized AgNPs against in vitro human cervical cancer cell line (HeLa) showed a dose-response activity. IC50 value was found to be 200 MUg/mL of AgNPs against HeLa cancer cells. Further studies are needed to elucidate the toxicity and the mechanism involved with antimicrobial and anticancer activity of the synthesized AgNPs as nanomedicine. PMID- 23936788 TI - miR156- and miR171-binding sites in the protein-coding sequences of several plant genes. AB - We identified the interaction sites of several miRNAs with the mRNAs from paralogs and orthologs of the SPL and HAM genes in A. thaliana. miRNAs from the miR156 and miR157 families in A. thaliana are shown to have binding sites within the mRNAs of SPL genes. The ath-miR156a-j binding sites located in the mRNAs of the SPL paralogs contain the sequence GUGCUCUCUCUCUUCUGUCA. This sequence encodes the ALSLLS motif. miR157a-d bind to mRNAs of the SPL family at the same site. We suggest merging the miR156 and miR157 families into one family. Several SPL genes in eight plants contain conserved miR156 binding sites. GUGCUCUCUCUCUUCUGUCA polynucleotide is homologous in its binding sites. The ALSLLS hexapeptide is also conserved in the SPL proteins from these plants. Binding sites for ath-miR171a-c and ath-miR170 in HAM1, HAM2, and HAM3 paralog mRNAs are located in the CDSs. The conserved miRNA binding sequence GAUAUUGGCGCGGCUCAAUCA encodes the ILARLN hexapeptide. Nucleotides within the HAM1, HAM2, and HAM3 miRNA binding sites are conserved in the mRNAs of 37 orthologs from 13 plants. The miR171- and miR170 binding sites within the ortholog mRNAs were conserved and encode the ILARLN motif. We suggest that the ath-miR170 and ath-miR171a-c families should be in one family. PMID- 23936789 TI - The exploding spark: workplace violence in an infectious disease hospital--a longitudinal study. AB - OBJECTIVES: Workplace violence (WV) is an important occupational hazard for healthcare workers (HCWs). METHODS: A longitudinal study was carried out on HCWs from an infectious disease hospital. Work-related stress, anxiety, and depression were measured at baseline in 2003, and they were reassessed in 2005, along with the assaults that occurred in the previous year. RESULTS: One-year prevalences of 6.2% and 13.9% were reported for physical and verbal aggressions, respectively. Perpetrators were mainly patients. The professional groups most frequently attacked were physicians, followed by nurses. Workers with job strain at baseline had a significant risk of being subject to aggression (OR 7.7; CI 95%, 3.3-17.9) in the following year. The relationship between job strain and subsequent WV remained significant even after correction for anxiety, depression, and other confounders. Conversely, experiencing WV was associated with a high risk of job strain and effort-reward imbalance in the following year. The final levels of anxiety and depression were predicted using regression models that included physical aggression among predictive variables. CONCLUSIONS: WV is the spark that sets off a problematic work situation. Effective prevention of WV can only be achieved within the framework of an overall improvement in the quality of work. PMID- 23936790 TI - Association of Toll-like receptor 4 polymorphisms with diabetic foot ulcers and application of artificial neural network in DFU risk assessment in type 2 diabetes patients. AB - The Toll-Like receptor 4 (TLR4) plays an important role in immunity, tissue repair, and regeneration. The objective of the present work was to evaluate the association of TLR4 single nucleotide polymorphisms (SNPs) rs4986790, rs4986791, rs11536858 (merged into rs10759931), rs1927911, and rs1927914 with increased diabetic foot ulcer (DFU) risk in patients with type 2 diabetes mellitus (T2DM). PCR-RFLP was used for genotyping TLR4 SNPs in 125 T2DM patients with DFU and 130 controls. The haplotypes and linkage disequilibrium between the SNPs were determined using Haploview software. Multivariate linear regression (MLR) and artificial neural network (ANN) modeling was done to observe their predictability for the risk of DFU in T2DM patients. Risk genotypes of all SNPs except rs1927914 were significantly associated with DFU. Haplotype ACATC (P value = 9.3E - 5) showed strong association with DFU risk. Two haplotypes ATATC (P value = 0.0119) and ATGTT (P value = 0.0087) were found to be protective against DFU. In conclusion TLR4 SNPs and their haplotypes may increase the risk of impairment of wound healing in T2DM patients. ANN model (83%) is found to be better than the MLR model (76%) and can be used as a tool for the DFU risk assessment in T2DM patients. PMID- 23936791 TI - Acetylcholinesterase as a biomarker in environmental and occupational medicine: new insights and future perspectives. AB - Acetylcholinesterase (AChE) is a key enzyme in the nervous system. It terminates nerve impulses by catalysing the hydrolysis of neurotransmitter acetylcholine. As a specific molecular target of organophosphate and carbamate pesticides, acetylcholinesterase activity and its inhibition has been early recognized to be a human biological marker of pesticide poisoning. Measurement of AChE inhibition has been increasingly used in the last two decades as a biomarker of effect on nervous system following exposure to organophosphate and carbamate pesticides in occupational and environmental medicine. The success of this biomarker arises from the fact that it meets a number of characteristics necessary for the successful application of a biological response as biomarker in human biomonitoring: the response is easy to measure, it shows a dose-dependent behavior to pollutant exposure, it is sensitive, and it exhibits a link to health adverse effects. The aim of this work is to review and discuss the recent findings about acetylcholinesterase, including its sensitivity to other pollutants and the expression of different splice variants. These insights open new perspective for the future use of this biomarker in environmental and occupational human health monitoring. PMID- 23936792 TI - Enhanced EGFP fluorescence emission in presence of PEG aqueous solutions and PIB1000-PEG6000-PIB1000 copolymer vesicles. AB - An EGFP construct interacting with the PIB1000-PEG6000-PIB1000 vesicles surface reported a ~2-fold fluorescence emission enhancement. Because of the constructs nature with the amphiphilic peptide inserted into the PIB core, EGFP is expected to experience a "pure" PEG environment. To unravel this phenomenon PEG/water solutions at different molecular weights and concentrations were used. Already at ~1:10 protein/PEG molar ratio the increase in fluorescence emission is observed reaching a plateau correlating with the PEG molecular weight. Parallel experiments in presence of glycerol aqueous solutions did show a slight fluorescence enhancement however starting at much higher concentrations. Molecular dynamics simulations of EGFP in neat water, glycerol, and PEG aqueous solutions were performed showing that PEG molecules tend to "wrap" the protein creating a microenvironment where the local PEG concentration is higher compared to its bulk concentration. Because the fluorescent emission can be perturbed by the refractive index surrounding the protein, the clustering of PEG molecules induces an enhanced fluorescence emission already at extremely low concentrations. These findings can be important when related to the use of EGFP as reported in molecular biology experiments. PMID- 23936793 TI - A mouse model of interstitial pneumonitis induced by murine cytomegalovirus infection after allogeneic skin transplantation. AB - We investigated the effect of murine cytomegalovirus (MCMV) on interstitial pneumonia in transplant recipients in an experimental skin allograft model. Skin transplantation between C57BL/6J and BALB/c mice was performed in the presence or absence of cyclosporin A treatment. Flow cytometry showed that the number of CD4(+) and CD8(+) cells and the level of IFN- gamma decreased significantly in the groups treated with cyclosporin A. We either mock-infected or infected the mice with MCMV by intranasal administration and monitored pathophysiological behavior and body weight. The infected mice were sacrificed at different days postinfection for histology, immunohistochemistry, and molecular biological evaluations. Interstitial pneumonitis was observed in positive control groups as well as in experimental group that received cyclosporin A, a skin transplant, and infected with the highest dose of virus (10(5) PFU). Transmission electronic microscopy demonstrated the presence of herpes virus particles. MCMV DNA and glycoprotein B were demonstrated in the epithelial cells of the lung tissue in those animals by in situ hybridization and immunohistochemistry, respectively. Our data demonstrated the establishment of a mouse model of interstitial pneumonitis via MCMV infection after allogeneic skin transplantation. PMID- 23936794 TI - Relationship between circulating BAFF serum levels with proliferating markers in patients with multiple myeloma. AB - In multiple myeloma, there are many factors influencing the growth of the malignant clone in direct and indirect manners. BAFF is a growth factor for myeloma cells. The aim of the study was to measure its circulating levels in 54 pretreatment patients, along with serum levels of other proliferation markers, such as interleukins-6, -10, and -15, CRP, and beta-2 microglobulin, as well as bone marrow plasma cell infiltration and expression of Ki-67 PI, in various stages of the disease and after effective treatment in 28 of them. Serum levels of the previously mentioned factors were measured by ELISA, whereas bone marrow plasma cell infiltration and Ki-67 expression were estimated immunohistochemically. All measured parameters were higher in pretreated myeloma patients compared to healthy population and were also increasing with the progression of the disease. They all also decreased after effective therapy. Furthermore, all pretreatment values correlated to each other. BAFF seems to be an important growth factor for myeloma plasma cells. Measuring its serum levels, along with the previously mentioned cytokines, may provide important information regarding the degree of myeloma cells' proliferation. Therefore, they all could be used as markers of proliferation and disease activity. PMID- 23936795 TI - Comparative evaluation of infected and noninfected Amblyomma triste ticks with Rickettsia parkeri, the agent of an emerging rickettsiosis in the New World. AB - The distribution of Rickettsia parkeri in South America has been associated with Amblyomma triste ticks. The present study evaluated under laboratory conditions two colonies of A. triste: one started from engorged females that were naturally infected by R. parkeri (designated as infected group); the other started from noninfected females (designated as control group). Both colonies were reared in parallel for five consecutive generations. Tick-naive domestic rabbits were used for feeding of each tick stage and generation. R. parkeri was preserved by transstadial maintenance and transovarial transmission in A. triste ticks for five consecutive generations, because all tested larvae, nymphs, and adults from the infected group were shown by PCR to contain rickettsial DNA. All rabbits infested by larvae, nymphs, and adults from the infected group seroconverted, indicating that these tick stages were all vector competent for R. parkeri. Expressive differences in mortality rates were observed between engorged nymphs from the infected and control groups, as indicated by 65.9% and 92.4% molting success, respectively. Our results indicate that A. triste can act as a natural reservoir for R. parkeri. However, due to deleterious effect caused by R. parkeri on engorged nymphs, amplifier vertebrate hosts might be necessary for natural long-term maintenance of R. parkeri in A. triste. PMID- 23936796 TI - Polyisoprenylated methylated protein methyl esterase is both sensitive to curcumin and overexpressed in colorectal cancer: implications for chemoprevention and treatment. AB - Inhibition of PMPMEase, a key enzyme in the polyisoprenylation pathway, induces cancer cell death. In this study, purified PMPMEase was inhibited by the chemopreventive agent, curcumin, with a K(i) of 0.3 MUM (IC50 = 12.4 MUM). Preincubation of PMPMEase with 1 mM curcumin followed by gel-filtration chromatography resulted in recovery of the enzyme activity, indicative of reversible inhibition. Kinetics analysis with N-para-nitrobenzoyl-S-trans,trans farnesylcysteine methyl ester substrate yielded K M values of 23.6 +/- 2.7 and 85.3 +/- 15.3 MUM in the absence or presence of 20 MUM curcumin, respectively. Treatment of colorectal cancer (Caco2) cells with curcumin resulted in concentration-dependent cell death with an EC50 of 22.0 MUg/mL. PMPMEase activity in the curcumin-treated cell lysate followed a similar concentration-dependent profile with IC50 of 22.6 MUg/mL. In colorectal cancer tissue microarray studies, PMPMEase immunoreactivity was significantly higher in 88.6% of cases compared to normal colon tissues (P < 0.0001). The mean scores +/- SEM were 91.7 +/- 11.4 (normal), 75.0 +/- 14.4 (normal adjacent), 294.8 +/- 7.8 (adenocarcinoma), and 310.0 +/- 22.6 (mucinous adenocarcinoma), respectively. PMPMEase overexpression in colorectal cancer and cancer cell death stemming from its inhibition is an indication of its possible role in cancer progression and a target for chemopreventive agents. PMID- 23936797 TI - Quantitative PCR as an alternative in the diagnosis of long-QT syndrome. AB - Congenital long-QT syndrome is a genetic disorder associated with abnormalities in the function and/or structure of cardiac ion channels. Up to the present, 13 types of the disease have been described (LQTS1-13) which result from the fact that 13 genes of which mutations can have an influence on the occurrence of the disease have been identified. Characteristic symptoms of the disease include the changes in the ECG (QT interval prolonged above 450 ms), "torsade de pointes," fainting, and even sudden cardiac death. The present study has been focused on two types of the disease, namely, LQTS1 and LQTS2. The examination of two appropriate genes expression (KCNQ1; KCNH2) at the transcription level by QRT-PCR in a group of LQTS patients and a healthy control group showed different transcriptional activities of KCNH2 gene in LQTS2 patients compared to the control individuals. KCNQ1 gene expression study did not reveal such differences between both groups. The results indicate that QRT-PCR may serve as a complimentary method to the identification of molecular alterations in genetic determinants of LQTS2 only, but it cannot be used as a sole diagnostic criterion. PMID- 23936798 TI - Downregulation of ADAM10 expression inhibits metastasis and invasiveness of human hepatocellular carcinoma HepG2 cells. AB - OBJECTIVE: This study aims to investigate the effects of ADAM10 expression on metastasis and invasiveness of human hepatocellular carcinoma HepG2 cells. METHODS: The HepG2 cells were transfected with medium only, the empty vector, the control siRNA, or siRNA against ADAM10, respectively. Cell migration assay and Transwell invasiveness assay were performed to detect the effects of ADAM10 knockdown on migration and invasiveness of HepG2 cells. Western blotting and real time RT PCR were performed to investigate the effects of knock-down of ADAM10 on protein and mRNA levels of E-cadherin gene. RESULTS: Cell migration and invasiveness of HepG2 cells transfected with ADAM10 siRNA were significantly decreased, when compared with the cells transfected with the control siRNA, suggesting that the downregulation of ADAM10 expression inhibits cell migration and invasiveness. The Western blotting results suggest that the down-regulation of ADAM10 expression increases E-cadherin protein levels. The real-time RT-PCR results indicated that the mRNA level of E-cadherin is not detectably affected by the knock-down of ADAM10 gene. CONCLUSIONS: Expression of ADAM10 may be related to cell migration and invasiveness of human hepatocellular carcinoma HepG2 cells via a mechanism related to E-cadherin. PMID- 23936800 TI - Side-by-side comparison of the biological characteristics of human umbilical cord and adipose tissue-derived mesenchymal stem cells. AB - Both human adipose tissue-derived mesenchymal stem cells (ASCs) and umbilical cord-derived mesenchymal stem cells (UC-MSCs) have been explored as attractive mesenchymal stem cells (MSCs) sources, but very few parallel comparative studies of these two cell types have been made. We designed a side-by-side comparative study by isolating MSCs from the adipose tissue and umbilical cords from mothers delivering full-term babies and thus compared the various biological aspects of ASCs and UC-MSCs derived from the same individual, in one study. Both types of cells expressed cell surface markers characteristic of MSCs. ASCs and UC-MSCs both could be efficiently induced into adipocytes, osteoblasts, and neuronal phenotypes. While there were no significant differences in their osteogenic differentiation, the adipogenesis of ASCs was more prominent and efficient than UC-MSCs. In the meanwhile, ASCs responded better to neuronal induction methods, exhibiting the higher differentiation rate in a relatively shorter time. In addition, UC-MSCs exhibited a more prominent secretion profile of cytokines than ASCs. These results indicate that although ASCs and UC-MSCs share considerable similarities in their immunological phenotype and pluripotentiality, certain biological differences do exist, which might have different implications for future cell-based therapy. PMID- 23936801 TI - Near-infrared spectroscopy of the urinary bladder during voiding in men with lower urinary tract symptoms: a preliminary study. AB - OBJECTIVES: To determine the difference in response of NIRS of the bladder during voiding between men with and without BOO.LUTS. METHODS: A prospective, case series, study included 36 men with LUTS. Patients completed the IPSS questionnaire; prostate volumes were measured sonographically. Patients underwent pressure flow study (PFS) with simultaneous NIRS of the bladder. Amplitudes of HHb, O2Hb, and Hbsum were calculated at Qmax, relative to baseline. Patients were urodynamically classified as obstructed and unobstructed. Recursive partition analysis (RPA) was performed to reclassify patients using NIRS amplitudes, followed by combined data of NIRS amplitudes, prostate volume, IPSS, and Qmax to determine the best predictor(s) of BOO. RESULTS: PFS classified 28 patients as obstructed and 8 as unobstructed. The median HHb amplitude was significantly higher in obstructed group. RPA of NIRS amplitudes correctly reclassified 89% of patients [AUC: 0.91]. RPA of the combined IPSS, prostate volume, PVR, and Qmax correctly reclassified 72% of patients [AUC: 0.84]. When NIRS amplitudes were added to this combination, RPA revealed a significantly (P < 0.01) higher rate of correct reclassification in 89% of patients with 89.3% sensitivity and 88% specificity for obstruction [AUC: 0.96]. CONCLUSION: NIRS data can be of diagnostic value for BOO in men with LUTS. PMID- 23936799 TI - Molecular basis of cardioprotective effect of antioxidant vitamins in myocardial infarction. AB - Acute myocardial infarction (AMI) is the leading cause of mortality worldwide. Major advances in the treatment of acute coronary syndromes and myocardial infarction, using cardiologic interventions, such as thrombolysis or percutaneous coronary angioplasty (PCA) have improved the clinical outcome of patients. Nevertheless, as a consequence of these procedures, the ischemic zone is reperfused, giving rise to a lethal reperfusion event accompanied by increased production of reactive oxygen species (oxidative stress). These reactive species attack biomolecules such as lipids, DNA, and proteins enhancing the previously established tissue damage, as well as triggering cell death pathways. Studies on animal models of AMI suggest that lethal reperfusion accounts for up to 50% of the final size of a myocardial infarct, a part of the damage likely to be prevented. Although a number of strategies have been aimed at to ameliorate lethal reperfusion injury, up to date the beneficial effects in clinical settings have been disappointing. The use of antioxidant vitamins could be a suitable strategy with this purpose. In this review, we propose a systematic approach to the molecular basis of the cardioprotective effect of antioxidant vitamins in myocardial ischemia-reperfusion injury that could offer a novel therapeutic opportunity against this oxidative tissue damage. PMID- 23936802 TI - What is the incidence of intracranial bleeding in patients with mild traumatic brain injury? A retrospective study in 3088 Canadian CT head rule patients. AB - OBJECTIVE: Only limited data exists in terms of the incidence of intracranial bleeding (ICB) in patients with mild traumatic brain injury (MTBI). METHODS: We retrospectively identified 3088 patients (mean age 41 range (7-99) years) presenting with isolated MTBI and GCS 14-15 at our Emergency Department who had undergone cranial CT (CCT) between 2002 and 2011. Indication for CCT was according to the "Canadian CT head rules." Patients with ICB were either submitted for neurosurgical treatment or kept under surveillance for at least 24 hours. Pearson's correlation coefficient was used to correlate the incidence of ICB with age, gender, or intake of coumarins, platelet aggregation inhibitors, or heparins. RESULTS: 149 patients (4.8%) had ICB on CCT. No patient with ICB died or deteriorated neurologically. The incidence of ICB increased with age and intake of anticoagulants without clinically relevant correlation (R = 0.11; P < 0.001; R = -0.06; P < 0.001). CONCLUSION: Our data show an incidence of 4.8% for ICB after MTBI. However, neurological deterioration after MTBI seems to be rare, and the need for neurosurgical intervention is only required in selected cases. The general need for CCT in patients after MTBI is therefore questionable, and clinical surveillance may be sufficient when CCT is not available. PMID- 23936803 TI - Synthesis and biological evaluation of O-[3-18F-fluoropropyl]-alpha-methyl tyrosine in mesothelioma-bearing rodents. AB - Radiolabeled tyrosine analogs enter cancer cells via upregulated amino acid transporter system and have been shown to be superior to (18)F-fluoro-2-deoxy-D glucose ((18)F-FDG) in differential diagnosis in cancers. In this study, we synthesized O-[3-(19)F-fluoropropyl]-alpha-methyl tyrosine ((19)F-FPAMT) and used manual and automated methods to synthesize O-[3-(18)F-fluoropropyl]-alpha-methyl tyrosine ((18)F-FPAMT) in three steps: nucleophilic substitution, deprotection of butoxycarbonyl, and deesterification. Manual and automated synthesis methods produced (18)F-FPAMT with a radiochemical purity >96%. The decay-corrected yield of (18)F-FPAMT by manual synthesis was 34% at end-of-synthesis (88 min). The decay-corrected yield of (18)F-FPAMT by automated synthesis was 15% at end-of synthesis (110 min). (18)F-FDG and (18)F-FPAMT were used for in vitro and in vivo studies to evaluate the feasibility of (18)F-FPAMT for imaging rat mesothelioma (IL-45). In vitro studies comparing (18)F-FPAMT with (18)F-FDG revealed that (18)F-FDG had higher uptake than that of (18)F-FPAMT, and the uptake ratio of (18)F-FPAMT reached the plateau after being incubated for 60 min. Biodistribution studies revealed that the accumulation of (18)F-FPAMT in the heart, lungs, thyroid, spleen, and brain was significantly lower than that of (18)F-FDG. There was poor bone uptake in (18)F-FPAMT for up to 3 hrs suggesting its in vivo stability. The imaging studies showed good visualization of tumors with (18)F FPAMT. Together, these results suggest that (18)F-FPAMT can be successfully synthesized and has great potential in mesothelioma imaging. PMID- 23936804 TI - Use of Metarhizium anisopliae chitinase genes for genotyping and virulence characterization. AB - Virulence is the primary factor used for selection of entomopathogenic fungi (EPF) for development as biopesticides. To understand the genetic mechanisms underlying differences in virulence of fungal isolates on various arthropod pests, we compared the chitinase genes, chi2 and chi4, of 8 isolates of Metarhizium anisopliae. The clustering of the isolates showed various groups depending on their virulence. However, the analysis of their chitinase DNA sequences chi2 and chi4 did not reveal major divergences. Although their protein translates have been implicated in fungal virulence, the predicted protein structure of chi2 was identical for all isolates. Despite the critical role of chitin digestion in fungal infection, we conclude that chi2 and chi4 genes cannot serve as molecular markers to characterize observed variations in virulence among M. anisopliae isolates as previously suggested. Nevertheless, processes controlling the efficient upregulation of chitinase expression might be responsible for different virulence characteristics. Further studies using comparative "in vitro" chitin digestion techniques would be more appropriate to compare the quality and the quantity of chitinase production between fungal isolates. PMID- 23936806 TI - Three-dimensional supermacroporous carrageenan-gelatin cryogel matrix for tissue engineering applications. AB - A tissue-engineered polymeric scaffold should provide suitable macroporous structure similar to that of extracellular matrix which can induce cellular activities and guide tissue regeneration. Cryogelation is a technique in which appropriate monomers or polymeric precursors frozen at sub-zero temperature leads to the formation of supermacroporous cryogel matrices. In this study carrageenan gelatin (natural polymers) cryogels were synthesized by using glutaraldehyde and 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride and N hydroxysuccinimide (EDC-NHS) as crosslinking agent at optimum concentrations. Matrices showed large and interconnected pores which were in the range of 60-100 MUm diameter. Unconfined compression analysis showed elasticity and physical integrity of all cryogels, as these matrices regained their original length after 90% compressing from the original size. Moreover Young's modulus was found to be in the range of 4-11 kPa for the dry cryogel sections. These cryogels also exhibited good in vitro degradation capacity at 37 degrees C within 4 weeks of incubation. Supermacroporous carrageenan-gelatin cryogels showed efficient cell adherence and proliferation of Cos-7 cells which was examined by SEM. PI nuclear stain was used to observe cell-matrix interaction. Cytotoxicity of the scaffolds was checked by MTT assay which showed that cryogels are biocompatible and act as a potential material for tissue engineering and regenerative medicine. PMID- 23936805 TI - Licochalcone A-induced human bladder cancer T24 cells apoptosis triggered by mitochondria dysfunction and endoplasmic reticulum stress. AB - Licochalcone A (LCA), a licorice chalconoid, is considered to be a bioactive agent with chemopreventive potential. This study investigated the mechanisms involved in LCA-induced apoptosis in human bladder cancer T24 cells. LCA significantly inhibited cells proliferation, increased reactive oxygen species (ROS) levels, and caused T24 cells apoptosis. Moreover, LCA induced mitochondrial dysfunction, caspase-3 activation, and poly-ADP-ribose polymerase (PARP) cleavage, which displayed features of mitochondria-dependent apoptotic signals. Besides, exposure of T24 cells to LCA triggered endoplasmic reticulum (ER) stress; as indicated by the enhancement in 78 kDa glucose-regulated protein (GRP 78), growth arrest and DNA damage-inducible gene 153/C/EBP homology protein (GADD153/CHOP) expression, ER stress-dependent apoptosis is caused by the activation of ER-specific caspase-12. All the findings from our study suggest that LCA initiates mitochondrial ROS generation and induces oxidative stress that consequently causes T24 cell apoptosis via the mitochondria-dependent and the ER stress-triggered signaling pathways. PMID- 23936807 TI - Effect of intermittent low-frequency electrical stimulation on the rat gastrocnemius muscle. AB - Low-frequency neuromuscular electrical stimulation (NMES) has been used as an endurance exercise model. This study aimed to test whether low-frequency NMES increases the phosphorylation of anabolic signaling molecules and induces skeletal muscle hypertrophy, as seen with high-frequency NMES. Using Sprague Dawley rats, 1 bout of exercise (with dissection done immediately (Post0) and 3 h (Post3) after exercise) and another 6 sessions of training were performed. All experimental groups consisted of high- and low-frequency stimulation (HFS: 100 Hz; LFS: 10 Hz). Periodic acid-Schiff (PAS) staining was conducted to investigate type II fiber activation, and western blot analysis (WB) was conducted to examine whether NMES leads to anabolic intracellular signaling. At first, we examined the acute effect of exercise. PAS staining revealed that glycogen depletion occurred in both type I and type II fibers. WB results demonstrated that p70S6K phosphorylation was significantly increased by HFS, but there was no significant difference with LFS. In contrast, ERK 1/2 phosphorylation was increased by LFS at Post0. In the 6-session training, the wet weight and myofibrillar protein were significantly increased by both HFS and LFS. In conclusion, LFS has a similar anabolic effect for skeletal muscle hypertrophy as HFS, but the mediating signaling pathway might differ. PMID- 23936808 TI - Investigating mechanisms of alkalinization for reducing primary breast tumor invasion. AB - The extracellular pH (pHe) of many solid tumors is acidic as a result of glycolytic metabolism and poor perfusion. Acidity promotes invasion and enhances metastatic potential. Tumor acidity can be buffered by systemic administration of an alkaline agent such as sodium bicarbonate. Tumor-bearing mice maintained on sodium bicarbonate drinking water exhibit fewer metastases and survive longer than untreated controls. We predict this effect is due to inhibition of tumor invasion. Reducing tumor invasion should result in fewer circulating tumor cells (CTCs). We report that bicarbonate-treated MDA-MB-231 tumor-bearing mice exhibited significantly lower numbers of CTCs than untreated mice (P < 0.01). Tumor pHe buffering may reduce optimal conditions for enzymes involved in tumor invasion such as cathepsins and matrix metalloproteases (MMPs). To address this, we tested the effect of transient alkalinization on cathepsin and MMP activity using enzyme activatable fluorescence agents in mice bearing MDA-MB-231 mammary xenografts. Transient alkalinization significantly reduced the fluorescent signal of protease-specific activatable agents in vivo (P <= 0.003). Alkalinization, however, did not affect expression of carbonic anhydrase IX (CAIX). The findings suggest a possible mechanism in a live model system for breast cancer where systemic alkalinization slows the rate of invasion. PMID- 23936809 TI - Cardiovascular disease and hip fracture among older inpatients in Beijing, China. AB - OBJECTIVES: To examine the associations between cardiovascular disease (CVD) and hip fracture and to determine if these associations are attributable to hypertensive disease. METHODS: Data were obtained from 2006-2010 hospitalization summary reports of 31 tertiary hospitals in Beijing, China. This study included 864,408 inpatients aged >=55 years. Occurrence rate of hip fracture was based on the first-listed ICD-10 codes (S72.0, S72.1, and S72.2) and of CVD as comorbidities were based on the second- to the eighth-listed ICD-10 codes (I00 I99). RESULTS: The occurrence rate of hip fracture is 53% higher among older inpatients with a diagnosis of CVD than those without (RR = 1.53, 95% CI 1.47 1.60). Those with hip fracture were more likely to have hypertensive or cerebrovascular disease, with the risk ranging from 1.34 to 1.70. Compared with those without hip fracture, the occurrence rate of overall CVDs increased by 80%, 83%, and 16% among hip fracture patients aged 55-64, 65-79, and >=80 years. In addition, hypertensive disease did not modify the association between cerebrovascular disease and hip fracture. CONCLUSION: CVD was positively associated with hip fracture, and the associations observed in this sample of Chinese inpatients were similar to those reported from cohort studies conducted in the European populations. PMID- 23936810 TI - New bioactive fungal molecules with high antioxidant and antimicrobial capacity isolated from Cerrena unicolor idiophasic cultures. AB - Three bioactive fractions, extracellular laccase (ex-LAC), crude endopolysaccharides (c-EPL), and a low molecular subfraction of secondary metabolites (ex-LMS), were isolated from the idiophasic cultures of the white rot fungus Cerrena unicolor. For the first time, we determined the antioxidant properties of these samples by chemiluminometric measurement (a) and assessment of the scavenging effect on ABTS (b) and the DPPH reduction rate (c). The highest reducing capability was found for the ex-LMS fraction: 39-90% for (a), 20-90% for (b), and 10-59% for (c) at the concentration of 6.25-800 ug/mL. The scavenging abilities of the C. unicolor c-EPL were between 36 and 70% for (a), 2 and 60% for (b), and 28 and 32% for (c) at the concentration of 6.25-800 ug/mL. A very high prooxidative potential was observed for the ex-LAC probes. The preliminary toxicity tests were done using the Microtox system and revealed the following percentage of the toxic effect against Vibrio fischeri: 85.37% for c-EPL, 50.67% for ex-LAC, and 99.8% for ex-LMS, respectively. The ex-LAC sample showed the antibacterial activity against Escherichia coli, c-EPL against Staphylococcus aureus, and ex-LMS against both bacterial strains, respectively, but the stronger inhibitory effect was exerted on S. aureus. PMID- 23936811 TI - Affinity labeling of membrane receptors using tissue-penetrating radiations. AB - Photoaffinity labeling, a useful in vivo biochemical tool, is limited when applied in vivo because of the poor tissue penetration by ultraviolet (UV) photons. This study investigates affinity labeling using tissue-penetrating radiation to overcome the tissue attenuation and irreversibly label membrane receptor proteins. Using X-ray (115 kVp) at low doses (<50 cGy or Rad), specific and irreversible binding was found on striatal dopamine transporters with 3 photoaffinity ligands for dopamine transporters, to different extents. Upon X-ray exposure (115 kVp), RTI-38 and RTI-78 ligands showed irreversible and specific binding to the dopamine transporter similar to those seen with UV exposure under other conditions. Similarly, gamma rays at higher energy (662 keV) also affect irreversible binding of photoreactive ligands to peripheral benzodiazepine receptors (by PK14105) and to the dopamine (D2) membrane receptors (by azidoclebopride), respectively. This study reports that X-ray and gamma rays induced affinity labeling of membrane receptors in a manner similar to UV with photoreactive ligands of the dopamine transporter, D2 dopamine receptor (D2R), and peripheral benzodiazepine receptor (PBDZR). It may provide specific noninvasive irreversible block or stimulation of a receptor using tissue penetrating radiation targeting selected anatomic sites. PMID- 23936813 TI - Laboratory genetic testing in clinical practice. PMID- 23936812 TI - Novel 4-arm poly(ethylene glycol)-block-poly(anhydride-esters) amphiphilic copolymer micelles loading curcumin: preparation, characterization, and in vitro evaluation. AB - A novel 4-arm poly(ethylene glycol)-block-poly(anhydride-esters) amphiphilic copolymer (4-arm PEG-b-PAE) was synthesized by esterization of 4-arm poly(ethylene glycol) and poly(anhydride-esters) which was obtained by melt polycondensation of alpha -, omega -acetic anhydride terminated poly(L-lactic acid). The obtained 4-arm PEG-b-PAE was characterized by (1)H-NMR and gel permeation chromatography. The critical micelle concentration of 4-arm PEG-b-PAE was 2.38 MUg/mL. The curcumin-loaded 4-arm PEG-b-PAE micelles were prepared by a solid dispersion method and the drug loading content and encapsulation efficiency of the micelles were 7.0% and 85.2%, respectively. The curcumin-loaded micelles were spherical with a hydrodynamic diameter of 151.9 nm. Curcumin was encapsulated within 4-arm PEG-b-PAE micelles amorphously and released from the micelles, faster in pH 5.0 than pH 7.4, presenting one biphasic drug release pattern with rapid release at the initial stage and slow release later. The hemolysis rate of the curcumin-loaded 4-arm PEG-b-PAE micelles was 3.18%, which was below 5%. The IC50 value of the curcumin-loaded micelles against Hela cells was 10.21 MUg/mL, lower than the one of free curcumin (25.90 MUg/mL). The cellular uptake of the curcumin-loaded micelles in Hela cell increased in a time dependent manner. The curcumin-loaded micelles could induce G2/M phase cell cycle arrest and apoptosis of Hela cells. PMID- 23936814 TI - Cytotoxicity of biologically synthesized silver nanoparticles in MDA-MB-231 human breast cancer cells. AB - Silver nanoparticles (AgNPs) have been used as an antimicrobial and disinfectant agents. However, there is limited information about antitumor potential. Therefore, this study focused on determining cytotoxic effects of AgNPs on MDA-MB 231 breast cancer cells and its mechanism of cell death. Herein, we developed a green method for synthesis of AgNPs using culture supernatant of Bacillus funiculus, and synthesized AgNPs were characterized by various analytical techniques such as UV-visible spectrophotometer, particle size analyzer, and transmission electron microscopy (TEM). The toxicity was evaluated using cell viability, metabolic activity, and oxidative stress. MDA-MB-231 breast cancer cells were treated with various concentrations of AgNPs (5 to 25 MUg/mL) for 24 h. We found that AgNPs inhibited the growth in a dose-dependent manner using MTT assay. AgNPs showed dose-dependent cytotoxicity against MDA-MB-231 cells through activation of the lactate dehydrogenase (LDH), caspase-3, reactive oxygen species (ROS) generation, eventually leading to induction of apoptosis which was further confirmed through resulting nuclear fragmentation. The present results showed that AgNPs might be a potential alternative agent for human breast cancer therapy. PMID- 23936815 TI - Prevalence of overweight and obesity in urban elementary school children in northeastern Romania: its relationship with socioeconomic status and associated dietary and lifestyle factors. AB - The purpose of this paper is to estimate the prevalence of obesity and to identify its potential determinants to optimize the methods of prevention to combat further increases in childhood overweight. The study was carried out on 3444 school children of 6-10 years of age attending 30 schools in northeast Romania. Schools were classified by geographical location and socioeconomic status (SES). Overweight and obesity status were determined using IOTF BMI cut off points. Prevalence of overweight (including obesity) was found to be 24.6% among boys and 22.6% among girls, whereas the prevalence of obesity was 7.8% in boys and 6.3% in girls. High SES (OR: 1.46; 95% CI: 1.10-1.93) and eating French fries and chips (OR: 1.81; 95% CI: 1.24-2.67) were associated with increased risk of overweight. In high- and medium-SES children, overweight was positively associated with the consumption of French fries and chips (2.93, 95% CI: 1.54 5.60 and 1.82, 95% CI: 1.04-3.21). In low-SES children, overweight was associated with low fruit consumption (0.21, 95% CI: 0.05-1.00) and sedentary behavior (3.37, 95% CI: 1.13-10.05). Therefore, the social and environmental determinants should be considered when constructing and implementing preventive measures regarding overweight and obesity. PMID- 23936816 TI - Hydroquinone: environmental pollution, toxicity, and microbial answers. AB - Hydroquinone is a major benzene metabolite, which is a well-known haematotoxic and carcinogenic agent associated with malignancy in occupational environments. Human exposure to hydroquinone can occur by dietary, occupational, and environmental sources. In the environment, hydroquinone showed increased toxicity for aquatic organisms, being less harmful for bacteria and fungi. Recent pieces of evidence showed that hydroquinone is able to enhance carcinogenic risk by generating DNA damage and also to compromise the general immune responses which may contribute to the impaired triggering of the host immune reaction. Hydroquinone bioremediation from natural and contaminated sources can be achieved by the use of a diverse group of microorganisms, ranging from bacteria to fungi, which harbor very complex enzymatic systems able to metabolize hydroquinone either under aerobic or anaerobic conditions. Due to the recent research development on hydroquinone, this review underscores not only the mechanisms of hydroquinone biotransformation and the role of microorganisms and their enzymes in this process, but also its toxicity. PMID- 23936817 TI - Leptin modulates norepinephrine-mediated melatonin synthesis in cultured rat pineal gland. AB - Pineal melatonin synthesis can be modulated by many peptides, including insulin. Because melatonin appears to alter leptin synthesis, in this work we aimed to investigate whether leptin would have a role on norepinephrine- (NE-)mediated melatonin synthesis in cultured rat pineal glands. According to our data, cultured rat pineal glands express leptin receptor isoform b (Ob-Rb). Pineal expression of Ob-Rb mRNA was also observed in vivo. Administration of leptin (1 nM) associated with NE ( 1 uM) reduced melatonin content as well as arylalkylamine-N-acetyl transferase (AANAT) activity and expression in cultured pineal glands. Leptin treatment per se induced the expression of STAT3 in cultured pineal glands, but STAT3 does not participate in the leptin modulation of NE-mediated pineal melatonin synthesis. In addition, the expression of inducible cAMP early repressor (ICER) was further induced by leptin challenge when associated with NE. In conclusion, leptin inhibition of pineal melatonin synthesis appears to be mediated by a reduction in AANAT activity and expression as well as by increased expression of Icer mRNA. Peptidergic signaling within the pineal gland appears to be one of the most important signals which modulates melatonin synthesis; leptin, as a member of this system, is not an exception. PMID- 23936818 TI - Transcriptomic profiling of the four adenosine receptors in human leukocytes of heart failure patients. AB - In this study the transcriptomic profiling of adenosine receptors (ARs) in human leukocytes of heart failure (HF) patients as a function of clinical severity, assessing the possible changes with respect to healthy subjects (C), was evaluated. Total RNA was extracted from leukocytes of C (n = 8) and of HF patients (NYHA I-II n = 9; NYHA III-IV n = 14) with a PAXgene Blood RNA Kit. An increase as a function of clinical severity was observed in each AR (A1R: C = 0.02 +/- 0.009, NYHA I-II = 0.21 +/- 0.09, NYHA III-IV = 3.6 +/- 1.3, P = 0.03 C versus NYHA III-IV, P = 0.02 NYHA I-II versus NYHA III-IV; A2aR: C = 0.2 +/- 0.05, NYHA I-II = 0.19 +/- 0.04, NYHA III-IV = 1.32 +/- 0.33, P = 0.005 C versus NYHA III-IV, P = 0.003 NYHA I-II versus NYHA III-IV; A2bR: C = 1.78 +/- 0.36, NYHA I-II = 1.35 +/- 0.29, NYHA III-IV = 4.07 +/- 1.21, P = 0.03: NYHA I-II versus NYHA III-IV; A3R: C = 0.76 +/- 0.21, NYHA I-II = 0.94 +/- 0.19, NYHA III IV = 3.14 +/- 0.77, P = 0.01 C versus NYHA III-IV and NYHA I-II versus NYHA III IV, resp.). The mRNA expression of the ectonucleoside triphosphate diphosphohydrolase (CD39) and the ecto-5'-nucleotidase (CD73) were also evaluated. They resulted up-regulated. These findings show that components of adenosine metabolism and signalling are altered to promote adenosine production and signalling in HF patients. Thus, HF may benefit from adenosine-based drug therapy after confirmation by clinical trials. PMID- 23936819 TI - Ctla-4 expression and polymorphisms in lung tissue of patients with diagnosed non small-cell lung cancer. AB - Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a potent immunoregulatory molecule that downregulates T-cell activation and thus influences the antitumor immune response. CTLA-4 polymorphisms are associated with various cancers, and CTLA-4 mRNA/protein increased expression is found in several tumor types. However, most of the studies are based on peripheral blood mononuclear cells, and much less is known about the relationship between CTLA-4 expression, especially gene expression, and its polymorphic variants in cancer tissue. In our study we assessed the distribution of CTLA-4 two polymorphisms (+49A/G and -318C/T), using TaqMan probes (rs231775 and rs5742909, resp.), and CTLA-4 gene expression in real time PCR assay in non-small-cell lung cancer (NSCLC) tissue samples. The increased CTLA-4 expression was observed in the majority of NSCLC patients, and it was significantly correlated with TT genotype (-318C/T) and with tumor size (T2 versus T3 + T4). The presence of G allele and GG genotype in cancer tissue (+49A/G) was significantly associated with the increased NSCLC risk. Additionally, we compared genotype distributions in the corresponding tumor and blood samples and found statistically significant differences. The shift from one genotype in the blood to another in the tumor may confirm the complexity of gene functionality in cancer tissue. PMID- 23936820 TI - Evaluation of kinesiophobia and its correlations with pain and fatigue in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type. AB - Ehlers-Danlos syndrome hypermobility type a. k. a. joint hypermobility syndrome (JHS/EDS-HT) is a hereditary musculoskeletal disorder associating generalized joint hypermobility with chronic pain. Anecdotal reports suggest a prominent role for kinesiophobia in disease manifestations, but no study has systematically addressed this point. OBJECTIVE: To investigate the impact of kinesiophobia and its relationship with pain, fatigue, and quality of life in JHS/EDS-HT. DESIGN: Cross-sectional study. SUBJECTS/PATIENTS: 42 patients (40 female and 2 male) with JHS/EDS-HT diagnosis following standardized diagnostic criteria were selected. METHODS: Disease features were analyzed by means of specific questionnaires and scales evaluating kinesiophobia, pain, fatigue, and quality of life. The relationships among variables were investigated using the Spearman bivariate analysis. RESULTS: Kinesiophobia resulted predominantly in the patients' sample. The values of kinesiophobia did not correlate with intensity of pain, quality of life, and (or) the single component of fatigue. A strong correlation was discovered between kinesiophobia and general severity of fatigue. CONCLUSIONS: In JHS/EDS-HT, the onset of pain-avoiding strategies is related to the presence of pain but not to its intensity. The clear-cut correlation between kinesiophobia and severity of fatigue suggests a direct link between musculoskeletal pain and fatigue. In JHS/EDS-HT, the underlying mechanism is likely to be facilitated by primary disease characteristics, including hypotonia. PMID- 23936821 TI - Cirrhosis and rapid virological response to peginterferon plus ribavirin determine treatment outcome in HCV-1 IL28B rs12979860 CC patients. AB - BACKGROUND: The rs12979860 CC genotype of the interleukin 28B (IL28B) polymorphism is associated with high rates of sustained virological response (SVR) to peginterferon (PegIFN) and ribavirin (Rbv) in hepatitis C virus genotype 1 (HCV-1) patients. The impact of baseline predictors of treatment outcome and their interplay with viral kinetics in HCV-1 CC patients has not been fully evaluated. AIM: To identify baseline and on-therapy predictors of treatment failure in HCV-1 IL28B CC patients. METHODS: Treatment-naive HCV-1 patients, compliant to PegIFN and Rbv who did not discontinue treatment for nonvirological reasons, were analyzed. RESULTS: 109 HCV-1 IL28B CC were studied. Sixty were males, 39 with BMI >25, 69 with >600,000 IU/mL HCV RNA, 15 with HCV1a, and 30 with cirrhosis. Overall, 75 (69%) achieved an SVR; cirrhosis was the only baseline predictor of treatment failure (OR: 2.58, 95% CI: 1.07-6.21) as SVR rates were 53% in cirrhotics versus 75% in noncirrhotics (P = 0.03). HCV RNA undetectability (<50 IU/mL) at week 4 (RVR) was achieved by 58 patients (53%). The SVR rates were independent of RVR in noncirrhotics, 76% (34/45) RVR (+) and 74% (25/34) RVR (-) (P = 0.9). In cirrhotic patients, SVR rates were significantly higher in RVR (+) compared to RVR (-) (10/13 (77%) versus 6/17 (35%) P = 0.03). CONCLUSIONS: In HCV-1 IL28B CC patients, cirrhosis is the only clinical baseline predictor of PegIFN and Rbv treatment failure. However, in IL28B CC cirrhotics, the achievement of RVR identifies those patients who still have high rates of SVR to Peg-IFN/Rbv therapy. PMID- 23936823 TI - Application of a low-level laser therapy and the purified protein from natural latex (Hevea brasiliensis) in the controlled crush injury of the sciatic nerve of rats: a morphological, quantitative, and ultrastructural study. AB - This study analyzed the effects of a low-level laser therapy (LLLT, 15 J/cm(2), 780 nm wavelength) and the natural latex protein (P1, 0.1%) in sciatic nerve after crush injury (15 Kgf, axonotmesis) in rats. Sixty rats (male, 250 g) were allocated into the 6 groups (n = 10): CG-control group; EG-nerve exposed; IG injured nerve without treatment; LG-crushed nerve treated with LLLT; PG-injured nerve treated with P1; and LPG-injured nerve treated with LLLT and P1. After 4 or 8 weeks, the nerve samples were processed for morphological, histological quantification and ultrastructural analysis. After 4 weeks, the myelin density and morphological characteristics improved in groups LG, PG, and LPG compared to IG. After 8 weeks, PG, and LPG were similar to CG and the capillary density was higher in the LG, PG, and LPG. In the ultrastructural analysis the PG and LPG had characteristics that were similar to the CG. The application of LLLT and/or P1 improved the recovery from the nerve crush injury, and in the long term, the P1 protein was the better treatment used, since only the application of LLLT has not reached the same results, and these treatments applied together did not potentiate the recovery. PMID- 23936822 TI - Assessing competence of broccoli consumption on inflammatory and antioxidant pathways in restraint-induced models: estimation in rat hippocampus and prefrontal cortex. AB - A growing body of evidence advocated the protective and therapeutic potential of natural compounds and phytochemicals used in diets against pathological conditions. Herein, the outcome of dietary whole broccoli consumption prior to restraint stress has been investigated in the hippocampus and prefrontal cortex of male rats, two important regions involved in the processing of responses to stressful events. Interestingly, a region-specific effect was detected regarding some of antioxidant defense system factors: nuclear factor erythroid-derived 2 related factor 2 (Nrf-2) antioxidant pathway, mitochondrial prosurvival proteins involved in mitochondrial biogenesis, and apoptotic cell death proteins. Dietary broccoli supplementation modulated the restraint-induced changes towards a consistent overall protection in the hippocampus. In the prefrontal cortex, however, despite activation of most of the protective factors, presumably as an attempt to save the system against the stress insult, some detrimental outcomes such as induced malate dehydrogenase (MDA) level and cleaved form of caspase-3 were detectable. Such diversity may be attributed in one hand to the different basic levels and/or availability of defensive mechanisms within the two studied cerebral regions, and on the other hand to the probable dose-dependent and hormetic effects of whole broccoli. More experiments are essential to demonstrate these assumptions. PMID- 23936824 TI - A replication study from Chinese supports association between lupus-risk allele in TNFSF4 and renal disorder. AB - A recent phenotypic association study of genetic susceptibility loci in SLE suggested that TNFSF4 gene might be useful to predict renal disorder in lupus patients. To replicate the association, two single-nucleotide polymorphisms (SNPs: rs2205960 and rs10489265) were genotyped in 814 SLE patients. Correlations between genotypes and TNFSF4 expression were determined. The stainings of TNFSF4 in renal biopsy specimens were checked by immunohistochemistry. The SNPs of TNFSF4 were associated with renal involvement in lupus patients from the Chinese population (P values for rs2205960 and rs10489265 were 0.014 and 0.005 in additive model, resp.). An association between risk genotypes and low C3 levels was also observed (P = 0.034). Functional prediction suggested that rs2205960 had a regulatory feature. The risk alleles seemingly correlated with lower TNFSF4 expression. Strong TNFSF4 expression was detected in lymph nodes and "apparently normal" paratumor renal biopsy but not in renal biopsies from lupus nephritis. In genome-wide expression data, TNFSF4 was also observed to be downregulated in LN in both glomeruli and tubulointerstitium from kidney biopsies. However, the associations were marginally significant. Our data firstly replicated the association of TNFSF4 with renal disorder in SLE patients in the Chinese population, which supported that TNFSF4 may act as a marker of lupus nephritis. The detailed mechanisms of its role in pathogenesis will still be further needed. PMID- 23936825 TI - Enhanced transdermal delivery of diclofenac sodium via conventional liposomes, ethosomes, and transfersomes. AB - The aim of this study was to improve the transdermal permeation of Diclofenac sodium, a poorly water-soluble drug, employing conventional liposomes, ethosomes, and transfersomes. The prepared formulations had been characterized for the loaded drug amount and vesicle size. The prepared vesicular systems were incorporated into 1% Carbopol 914 gel, and a survey of in vitro drug release and drug retention into rat skin has been done on them using a modified Franz diffusion cell. The cumulative amount of drug permeated after 24 h, flux, and permeability coefficient were assessed. Stability studies were performed for three months. The size of vesicles ranged from 145 to 202 nm, and the encapsulation efficiency of the Diclofenac sodium was obtained between 42.61% and 51.72%. The transfersomes and ethosomes provided a significantly higher amount of cumulative permeation, steady state flux, permeability coefficient, and residual drug into skin compared to the conventional liposomes, conventional gel, or hydroethanolic solution. The in vitro release data of all vesicular systems were well fit into Higuchi model (RSD > 0.99). Stability tests indicated that the vesicular formulations were stable over three months. Results revealed that both ethosome and transfersome formulations can act as drug reservoir in skin and extend the pharmacologic effects of Diclofenac sodium. PMID- 23936826 TI - Role of corneal epithelium in riboflavin/ultraviolet-A mediated corneal cross linking treatment in rabbit eyes. AB - PURPOSE: To evaluate the role of corneal epithelium in riboflavin/ultraviolet-A (UVA) mediated corneal collagen cross-linking treatment. METHODS: Fifty New Zealand rabbits were divided into 5 groups: UVA treatment with or without corneal epithelium, UVA+riboflavin treatment with or without corneal epithelium, and control without any treatment. All rabbits were sacrificed after irradiation and subsequently 4 mm * 10 mm corneal strips were harvested for biomechanical evaluation. RESULTS: UVA irradiation alone did not enhance the maximal stress and Young's modulus of corneal specimens with (3.15 +/- 0.56 mpa, 1.00 +/- 0.09 mpa) or without (3.53 +/- 0.85 mpa, 0.94 +/- 0.21 mpa) the corneal epithelium, compared to specimens in the control group (4.30 +/- 0.68 mpa, 1.03 +/- 0.24 mpa). However, UVA irradiation combined with riboflavin significantly increased the maximal stress and Young's modulus of corneal specimens with (5.27 +/- 1.09 mpa, 1.23 +/- 0.23 mpa, P < 0.05) or without (7.16 +/- 1.88 mpa, 1.42 +/- 0.16 mpa, P < 0.05) corneal epithelium when compared to the control group. The maximal stress and Young's modulus of cornea in UVA+riboflavin and "epithelium-off" group were 35.9% and 15.4% higher compared to the UVA+riboflavin and "epithelium-on" group, respectively (P < 0.05). CONCLUSIONS: Our study shows that UVA+riboflavin treatment significantly affects the biomechanical properties of the cornea with and without epithelial removal. However, corneas without epithelium seem to benefit more compared to corneas with the epithelium. PMID- 23936827 TI - Molecular dynamics studies on the conformational transitions of adenylate kinase: a computational evidence for the conformational selection mechanism. AB - Escherichia coli adenylate kinase (ADK) is a monomeric phosphotransferase enzyme that catalyzes reversible transfer of phosphoryl group from ATP to AMP with a large-scale domain motion. The detailed mechanism for this conformational transition remains unknown. In the current study, we performed long time-scale molecular dynamics simulations on both open and closed states of ADK. Based on the structural analyses of the simulation trajectories, we detected over 20 times conformational transitions between the open and closed states of ADK and identified two novel conformations as intermediate states in the catalytic processes. With these findings, we proposed a possible mechanism for the large scale domain motion of Escherichia coli ADK and its catalytic process: (1) the substrate free ADK adopted an open conformation; (2) ATP bound with LID domain closure; (3) AMP bound with NMP domain closure; (4) phosphoryl transfer occurred with ATP, and AMP converted into two ADPs, and no conformational transition was detected in the enzyme; (5) LID domain opened with one ADP released; (6) another ADP released with NMP domain open. As both open and closed states sampled a wide range of conformation transitions, our simulation strongly supported the conformational selection mechanism for Escherichia coli ADK. PMID- 23936828 TI - Haplogroup T is an obesity risk factor: mitochondrial DNA haplotyping in a morbid obese population from southern Italy. AB - Mitochondrial DNA (mtDNA) haplogroups have been associated with the expression of mitochondrial-related diseases and with metabolic alterations, but their role has not yet been investigated in morbid obese Caucasian subjects. Therefore, we investigated the association between mitochondrial haplogroups and morbid obesity in patients from southern Italy. The mtDNA D-loop of morbid obese patients (n = 500; BMI > 40 kg/m(2)) and controls (n = 216; BMI < 25 kg/m(2)) was sequenced to determine the mtDNA haplogroups. The T and J haplogroup frequencies were higher and lower, respectively, in obese subjects than in controls. Women bearing haplogroup T or J had twice or half the risk of obesity. Binomial logistic regression analysis showed that haplogroup T and systolic blood pressure are risk factors for a high degree of morbid obesity, namely, BMI > 45 kg/m(2) and in fact together account for 8% of the BMI. In conclusion, our finding that haplogroup T increases the risk of obesity by about two-fold, suggests that, besides nuclear genome variations and environmental factors, the T haplogroup plays a role in morbid obesity in our study population from southern Italy. PMID- 23936829 TI - Joint involvement in primary Sjogren's syndrome: an ultrasound "target area approach to arthritis". AB - OBJECTIVE: To characterize the ultrasound (US) pattern of joint involvement in primary Sjogren's syndrome (pSS). METHODS: Seventeen patients with pSS, 18 with secondary Sjogren's syndrome (sSS), and 17 healthy controls underwent US examinations of various articular regions. Synovitis (synovial hypertrophy/joint effusion), power Doppler (PD) signals, and erosions were assessed. RESULTS: In patients with pSS, synovitis was found in the metacarpophalangeal joints (MCP, 76%), wrists (76%), and knees (76%), while the proximal interphalangeal joints, elbows, and ankles were mostly unscathed. Intra-articular PD signals were occasionally detected in wrists (12%), elbows (6%), and knees (6%). Erosions were evident in the wrists of three (18%) patients with pSS, one of these also having anti-cyclic citrullinated peptide (anti-CCP) antibodies. While US synovitis does not discriminate between sSS and pSS, demonstration of bone erosions in the 2nd MCP joints showed 28.8% sensitivity and 100% specificity for diagnosing sSS; in comparison, these figures were 72.2 and 94.1% for circulating anti-CCP antibodies. CONCLUSIONS: In pSS, the pattern of joint involvement by US is polyarticular, bilateral, and symmetrical. Synovitis is the US sign most commonly found in patients with pSS, especially in MCP joints, wrists, and knees, and bone erosions also may occur. PMID- 23936830 TI - Particulate matter and nanoparticles toxicology. PMID- 23936831 TI - Molecular characterization of BK and JC viruses circulating among potential kidney donors in Kuwait. AB - BK and JC polyomaviruses can be associated with nephropathy following renal transplantation. The aim of this study was to determine the prevalence, load, and genotypes of BK and JC viruses circulated in potential kidney donors in Kuwait. The detection of polyomavirus DNA was carried out in serum and urine samples of 165 potential kidney donors. Seventy (42%) individuals were tested positive for polyomavirus DNA, of whom 20 (12%) had detectable polyomavirus DNA in their serum samples, 40 (24%) in their urine samples, and 10 (6%) in both serum and urine samples. In the group of polyomavirus-positive patients, JC DNA could be detected in 78% of urine samples and 11% of serum samples, whereas BK DNA could be detected in 7% of urine samples and 3% of serum samples. The median polyomaviral load was low. The detected BK sequences in Kuwaiti adults formed new clusters sharing common ancestor with subgroups Ib1 and IVc, which are prevalent in Asia and Europe. Additionally, around half of the detected JCV sequences in Kuwaiti adults formed new clusters within the African subtype 3. Our results suggest high rate of polyomavirus shedding among healthy adults in Kuwait that can jeopardize their suitability for kidney donation. PMID- 23936832 TI - Long-term impact of immunosuppressants at therapeutic doses on male reproductive system in unilateral nephrectomized rats: a comparative study. AB - Cyclosporine, tacrolimus, and sirolimus are commonly used in renal transplant recipients to prevent rejection. However, information for comparative effects of these agents on the male productive system is extremely limited and controversial. In a physiologically and clinically relevant rat model of unilateral nephrectomy, we demonstrated that long-term oral administration of both cyclosporine and sirolimus at doses equivalent to the therapeutic levels used for postrenal transplant patients significantly affects testicular development and the hypothalamic-pituitary-gonadal axis accompanied by profound histological changes of testicular structures on both light and electron microscopic examinations. Spermatogenesis was also severely impaired as indicated by low total sperm counts along with reduction of sperm motility and increase in sperm abnormality after treatment with these agents, which may lead to male infertility. On the other hand, treatment with therapeutic dose of tacrolimus only induced mild reduction of sperm count without histological evidence of testicular injury. The current study clearly demonstrates that commonly used immunosuppressants have various impacts on male reproductive system even at therapeutic levels. Our data provide useful information for the assessment of male infertility in renal transplant recipients who wish to father children. Clinical trials to address these issues should be urged. PMID- 23936834 TI - Efficacy of Iranian traditional medicine in the treatment of epilepsy. AB - Epilepsy is a brain disorder which affects about 50 million people worldwide. Ineffectiveness of the drugs in some cases and the serious side effects and chronic toxicity of the antiepileptic drugs lead to use of herbal medicine as a form of complementary and alternative medicine. In this review modern evidences for the efficacy of antiepileptic medicinal plants in Traditional Iranian Medicine (TIM) will be discussed. For this purpose electronic databases including PubMed, Scopus, Sciencedirect, and Google Scholar were searched for each of the antiepileptic plants during 1970-February 2013.Anticonvulsant effect of some of the medicinal plants mentioned in TIM like Anacyclus pyrethrum, Pimpinella anisum, Nigella sativa, and Ferula gummosa was studied with different models of seizure. Also for some of these plants like Nigella sativa or Piper longum the active constituent responsible for antiepileptic effect was isolated and studied. For some of the herbal medicine used in TIM such as Pistacia lentiscus gum (Mastaki), Bryonia alba (Fashra), Ferula persica (Sakbinaj), Ecballium elaterium (Ghesa-al Hemar), and Alpinia officinarum (Kholanjan) there is no or not enough studies to confirm their effectiveness in epilepsy. It is suggested that an evaluation of the effects of these plants on different epileptic models should be performed. PMID- 23936835 TI - The diagnostic accuracy of radionuclide arthrography for prosthetic loosening in hip and knee arthroplasty. AB - PURPOSE OF STUDY: Diagnosis of prosthetic loosening in hip and knee arthroplasty remains a challenge. Although there are a number of diagnostic tools, no single test or combination is 100% sensitive or specific. There has been a recent interest in the use of radionuclide arthrography (RNA) for detection of prosthetic loosening. METHODS: A retrospective review of 45 consecutive RNA scans from 2005 to 2010 was conducted. RNA findings were compared with intraoperative findings at revision and/or serial radiographic examinations to confirm loosening. A component was considered loose if sequential radiographs demonstrated macromotion, gross subsidence, or progressive radiolucency. RESULTS: There were 26 females and 17 males, with mean age at RNA of 71 years (range of 53 89 years) and mean time from index surgery, 6.4 years (range of 0.5-23 years). There were 23 total knee replacements (TKR) (19 primary and 4 revision) and 20 total hip replacements (THR) (11 primary and 9 revision). 15 patients underwent revision surgery following RNA. Strict inclusion criteria allowed 27 patients for further analysis. Sixteen RNA scans were suggestive of loosening, of which 14 were confirmed loose. Eleven scans were suggestive of a stable prosthesis, of which 10 were confirmed well fixed. RNA had a sensitivity of 93%, specificity of 83%, positive predictive value of 88%, and negative predictive value of 91%. CONCLUSION: Radionuclide arthrography should be considered a useful adjunct in the diagnosis of prosthetic loosening in the challenging patient. PMID- 23936836 TI - Embryotoxic and teratogenic effects of nickel in Swiss albino mice during organogenetic period. AB - The present study evaluates potential hazardous of nickel (Ni(+2) as NiCl2 .6H2O) to Swiss albino mice fetus. Ni was administered orally on body weight base from days 6 to 13 of gestation period. Based on LD50, Ni doses (46.125, 92.25, and 184.5) mg Ni/kg b.wt. were used. On day 18 of gestation, uteri of the sacrificed dams were examined. A dose-dependent decrease (P < 0.01) in the body weight of the pregnant females and fetuses during the gestation period was observed. Number of implant sites and placental weight at all the three dose levels was lower compared with their respective control groups. Average number of live fetuses/dams reduced significantly (P < 0.01) at 184.5 mg Ni/kg b.wt. with concomitant increase in the percentage of postimplantation death and percentage of resorbed, macerated, and dead fetuses, respectively. Exposure increased the fetal malformations, namely, hydrocephaly, open eyelids, microphthalmia, exophthalmia, club foot, umbilical hernia, and skeletal anomalies. Reduced ossification of nasal, frontal, parietal, intraparietal, and supraoccipital bones, absence/gap between the ribs, reduced/fused sternebrae, vertebral centra, and caudal vertebrae, reduced pelvic elements, absence of carpals, metacarpals, tarsals, metatarsals, and phalanges were distinct. This indicates vulnerability of the mice fetus to nickel during prenatal exposure. PMID- 23936833 TI - Understanding the dengue viruses and progress towards their control. AB - Traditionally, the four dengue virus serotypes have been associated with fever, rash, and the more severe forms, haemorrhagic fever and shock syndrome. As our knowledge as well as understanding of these viruses increases, we now recognise not only that they are causing increasing numbers of human infections but also that they may cause neurological and other clinical complications, with sequelae or fatal consequences. In this review we attempt to highlight some of these features in the context of dengue virus pathogenesis. We also examine some of the efforts currently underway to control this "scourge" of the tropical and subtropical world. PMID- 23936837 TI - Role of digoxin-like immunoreactive substance in the pathogenesis of transient tachypnea of newborn. AB - BACKGROUND: Transient tachypnea of newborn (TTN) is usually observed in term or near-term infants. It constitutes an important part of the respiratory distress cases observed in the neonatal intensive care unit (NICU). AIM: This paper examines the effects of digoxin-like immunoreactive substance (DLIS) on fluid and ion balance, hemodynamic and echocardiographic parameters of neonates with TTN. METHODS: Plasma DLIS, Na(+), K(+), urea, creatinine, serum and urine osmolarity, urine FeNa(+), 24-hour urine output, echocardiographic investigation and mean blood pressure, and clinical parameters of disease severity were recorded in TTN group and compared with control on the 1st and 7th days of their lives. RESULTS: Plasma DLIS levels were statistically higher in TTN group (0.66 +/- 0.37 ng/mL) compared to control group (0.24 +/- 0.20 ng/mL) both on the 1st day (P < 0.01) and the 7th day (P < 0.05). For TTN group, significant correlation was found between plasma DLIS levels and maximum respiratory rate, duration of tachypnea, and length of hospitalization on the 1st day. Plasma DLIS levels were correlated negatively with serum osmolarity levels. Plasma DLIS levels were positively correlated with urine output, urinary FeNa(+) levels, cardiac output, left ventricles end diastolic diameters, and right ventricles end diastolic diameters. CONCLUSIONS: Increased DLIS levels were correlated with disease severity in cases with TTN. This increase may be a primary or secondary event in the disease progress. It may help reduce the fluid overload due to already disturbed cardiac functions in patients by increasing urine output and natriuresis; however it may also contribute to disease pathogenesis, by inhibiting alveolar Na(+)-K(+)-ATPase which further decreases fetal alveolar fluid resorption. PMID- 23936838 TI - The role of PTPN22 C1858T gene polymorphism in diabetes mellitus type 1: first evaluation in Greek children and adolescents. AB - Type 1 diabetes mellitus (T1DM) is an autoimmune multifactorial disease. Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes lymphoid-specific tyrosine phosphatase (Lyp), an inhibitor of T cell activation. PTPN22 C1858T polymorphism was associated with T1DM in populations of Caucasian origin. The aim of this study was the investigation for the first time of the association of PTPN22 C1858T polymorphism with T1DM in Greek population. We studied 130 children and adolescents with T1DM and 135 healthy individuals of Greek origin. The polymorphism was genotyped using polymerase chain reaction with restriction fragment length polymorphism. C1858T and T1858T genotypes as well as 1858T allele were found more frequently in patients (10.8% and 5.8%, resp.) than in healthy individuals (5.9% and 3.0%, resp.) but at non statistically significant level. There was no statistically significant association found with gender, age at diagnosis, severity of onset, history of Hashimoto thyroiditis or family history of T1DM. Increased frequency of 1858T allele in patients than in controls, implying a probable association, agrees with results of similar studies on other populations. The inability to find a statistically significant difference is probably due to the decreased frequency of minor allele in Greek population, indicating the need for a larger sample. PMID- 23936839 TI - Biological activities of phosphocitrate: a potential meniscal protective agent. AB - Phosphocitrate (PC) inhibited meniscal calcification and the development of calcium crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the mechanisms remain elusive. This study sought to examine the biological activities of PC in the absence of calcium crystals and test the hypothesis that PC is potentially a meniscal protective agent. We found that PC downregulated the expression of many genes classified in cell proliferation, ossification, prostaglandin metabolic process, and wound healing, including bloom syndrome RecQ helicase-like, cell division cycle 7 homolog, cell division cycle 25 homolog C, ankylosis progressive homolog, prostaglandin-endoperoxide synthases 1/cyclooxygenase-1, and plasminogen activator urokinase receptor. In contrast, PC stimulated the expression of many genes classified in fibroblast growth factor receptor signaling pathway, collagen fibril organization, and extracellular structure organization, including fibroblast growth factor 7, collagen type I, alpha 1, and collagen type XI, alpha 1. Consistent with its effect on the expression of genes classified in cell proliferation, collagen fibril organization, and ossification, PC inhibited the proliferation of OA meniscal cells and meniscal cell-mediated calcification while stimulating the production of collagens. These findings indicate that PC is potentially a meniscal protective agent and a disease-modifying drug for arthritis associated with severe meniscal degeneration. PMID- 23936840 TI - The role of insula-associated brain network in touch. AB - The insula is believed to be associated with touch-evoked effects. In this work, functional MRI was applied to investigate the network model of insula function when 20 normal subjects received tactile stimulation over segregated areas. Data analysis was performed with SPM8 and Conn toolbox. Activations in the contralateral posterior insula were consistently revealed for all stimulation areas, with the overlap located in area Ig2. The area Ig2 was then used as the seed to estimate the insula-associated network. The right insula, left superior parietal lobule, left superior temporal gyrus, and left inferior parietal cortex showed significant functional connectivity with the seed region for all stimulation conditions. Connectivity maps of most stimulation conditions were mainly distributed in the bilateral insula, inferior parietal cortex, and secondary somatosensory cortex. Post hoc ROI-to-ROI analysis and graph theoretical analysis showed that there were higher correlations between the left insula and the right insula, left inferior parietal cortex and right OP1 for all networks and that the global efficiency was more sensitive than the local efficiency to detect differences between notes in a network. These results suggest that the posterior insula serves as a hub to functionally connect other regions in the detected network and may integrate information from these regions. PMID- 23936841 TI - Diffusion-weighted magnetic resonance application in response prediction before, during, and after neoadjuvant radiochemotherapy in primary rectal cancer carcinoma. AB - INTRODUCTION: Our interest was to monitor treatment response using ADC value to predict response of rectal tumour to preoperative radiochemotherapy. MATERIALS AND METHODS: Twenty-two patients were treated with long course of radiochemotherapy, followed by surgery. Patients were examined by diffusion weighted imaging MRI at three-time points (prior, during, and after radiochemotherapy) and were classified as responders and nonresponders. RESULTS: A statistical significant correlation was found between preradiochemotherapy ADC values and during treatment ADC values, in responders (F = 21.50, P value <0.05). An increase in ADC value during treatment was predictive of at least a partial response. DISCUSSION: Response of tumour to neoadjuvant therapy cannot be easily evaluated, and such capability might be of great importance in clinical practice, because the number of irradiated and operated patients may be superior to the number of who will really benefit from this multimodal treatment. A reliable prediction of the final clinical TN stage would allow radiotherapist to adapt multidisciplinary approach to a less invasive management, sparing surgical procedure in responder patients or even allowing an early surgery in nonresponders, which would significantly reduce radiochemotherapy related toxicity. Conclusion. Early evaluation of response during neoadjuvant radiochemotherapy treatment shows great promise to predict tumour response. PMID- 23936842 TI - High-yield soluble expression and simple purification of the antimicrobial peptide OG2 using the intein system in Escherichia coli. AB - OG2 is a modified antimicrobial peptide, that is, derived from the frog peptide Palustrin-OG1. It has high antimicrobial activity and low cytotoxicity, and it is therefore promising as a therapeutic agent. Both prokaryotic (Escherichia coli) and eukaryotic (Pichia pastoris) production host systems were used to produce OG2 in our previous study; however, it was difficult to achieve high expression yields and efficient purification. In this study, we achieved high-yield OG2 expression using the intein fusion system. The optimized OG2 gene was cloned into the pTWIN1 vector to generate pTWIN-OG2-intein2 (C-terminal fusion vector) and pTWIN-intein1-OG2 (N-terminal fusion vector). Nearly 70% of the expressed OG2 intein2 was soluble after the IPTG concentration and induction temperature were decreased, whereas only 42% of the expressed of intein1-OG2 was soluble. Up to 75 mg of OG2-intein2 was obtained from a 1l culture, and 85% of the protein was cleaved by 100 mM DTT. Intein1-OG2 was less amenable to cleavage due to the inhibition of cleavage by the N-terminal amino acid of OG2. The purified OG2 exhibited strong antimicrobial activity against E. coli K88. The intein system is the best currently available system for the cost-effective production of OG2. PMID- 23936843 TI - Differential influence of components resulting from atmospheric-pressure plasma on integrin expression of human HaCaT keratinocytes. AB - Adequate chronic wound healing is a major problem in medicine. A new solution might be non-thermal atmospheric-pressure plasma effectively inactivating microorganisms and influencing cells in wound healing. Plasma components as, for example, radicals can affect cells differently. HaCaT keratinocytes were treated with Dielectric Barrier Discharge plasma (DBD/air, DBD/argon), ozone or hydrogen peroxide to find the components responsible for changes in integrin expression, intracellular ROS formation or apoptosis induction. Dependent on plasma treatment time reduction of recovered cells was observed with no increase of apoptotic cells, but breakdown of mitochondrial membrane potential. DBD/air plasma increased integrins and intracellular ROS. DBD/argon caused minor changes. About 100 ppm ozone did not influence integrins. Hydrogen peroxide caused similar effects compared to DBD/air plasma. In conclusion, effects depended on working gas and exposure time to plasma. Short treatment cycles did neither change integrins nor induce apoptosis or ROS. Longer treatments changed integrins as important for influencing wound healing. Plasma effects on integrins are rather attributed to induction of other ROS than to generation of ozone. Changes of integrins by plasma may provide new solutions of improving wound healing, however, conditions are needed which allow initiating the relevant influence on integrins without being cytotoxic to cells. PMID- 23936844 TI - Increased expression of CCN2 in the red flashing light-induced myopia in guinea pigs. AB - Visual environment plays an important role in the occurrence of myopia. We previously showed that the different flashing lights could result in distinct effects on the ocular growth and development of myopia. CCN2 has been reported to regulate various cellular functions and biological processes. However, whether CCN2 signaling was involved in the red flashing light-induced myopia still remains unknown. In the present study, we investigated the effects of the red flashing lights exposure on the refraction and axial length of the eyes in vivo and then evaluated their effects on the expression of CCN2 and TGF- beta in sclera tissues. Our data showed that the eyes exposed to the red flashing light became more myopic with a significant increase of the axial length and decrease of the refraction. Both CCN2 and TGF- beta , as well as p38 MAPK and PI3K, were highly expressed in the sclera tissues exposed to the red flashing light. Both CCN2 and TGF- beta were found to have the same gene expression profile in vivo. In conclusion, our findings found that CCN2 signaling pathway plays an important role in the red flashing light-induced myopia in vivo. Moreover, our study establishes a useful animal model for experimental myopia research. PMID- 23936845 TI - Chromosome instability and oxidative stress markers in patients with ataxia telangiectasia and their parents. AB - Ataxia telangiectasia (AT) is a rare neurodegenerative disorder, inherited in an autosomal recessive manner. Total blood samples were collected from 20 patients with AT, 13 parents of patients, and 17 healthy volunteers. This study aimed at evaluating the frequency of chromosomal breaks in spontaneous cultures, induced by bleomycin and ionizing radiation, and further evaluated the rates of oxidative stress in AT patients and in their parents, compared to a control group. Three cell cultures were performed to each individual: the first culture did not receive induction to chromosomal instability, the second was exposed to bleomycin, and the last culture was exposed to ionizing radiation. To evaluate the rates of oxidative stress, the markers superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid (TBARS) were utilized. Significant differences were observed between the three kinds of culture treatments (spontaneous, bleomycin, and radiation induced) and the breaks and chromosomal aberrations in the different groups. The oxidative stress showed no significant differences between the markers. This study showed that techniques of chromosomal instability after the induction of ionizing radiation and bleomycin are efficient in the identification of syndrome patients, with the ionizing radiation being the most effective. PMID- 23936846 TI - The presence of asthma, the use of inhaled steroids, and parental education level affect school performance in children. AB - OBJECTIVE: Childhood asthma is a frequent cause of absenteeism that affects school performance. We aimed to investigate the impact of asthma on absenteeism and school performance level of elementary and high school students. METHODS: Data about sociodemographics, absenteeism, and academic achievement were obtained from 1539 students attending 98 schools in Greece. School performance was assessed for the last two years of school attendance using parents' and teachers' reports and grade point average promotion. RESULTS: The mean of the days of absence of students with asthma was higher compared to the healthy students (6.2 +/- 11.7 versus 0.3 +/- 3.1, resp., P < 0.001). Students with reduced healthcare use presented less absenteeism than those with increased healthcare use for asthma (4.3 +/- 8.6 versus 12.4 +/- 17.0 days, resp., P < 0.001). Asthma and healthcare use for asthma accounted for an overall estimated variability in absence days of 13.8% and 9%, respectively. Absenteeism was associated with poor school performance for the last two years of school (P = 0.002) and with lower grade point promotion in elementary school students (P = 0.001) but not in high school students (P = 0.316). Higher level of parental education was associated with better school performance (P < 0.001). Asthma was associated with a decreased possibility for excellent performance (OR = 0.64, P = 0.049, 95%CI = 0.41-1.00) in elementary students. Students with asthma using inhalers were four times more likely to perform excellently in elementary school (OR = 4.3, P = 0.028, 95%CI = 1.17-15.95) than their asthmatic peers with alternative asthma treatments. Conclusions. Asthma and increased healthcare use enhance school absenteeism. Inhaled steroid use and the higher parental education level were the most important predicting factors for good school performance in elementary school asthmatic children. PMID- 23936847 TI - Supplementation with natural forms of vitamin E augments antigen-specific TH1 type immune response to tetanus toxoid. AB - This study compared the ability of three forms of vitamin E [tocotrienol-rich fraction (TRF), alpha-tocopherol (alpha-T), and delta-tocotrienol (delta-T3)] to enhance immune response to tetanus toxoid (TT) immunisation in a mouse model. Twenty BALB/c mice were divided into four groups of five mice each. The mice were fed with the different forms of vitamin E (1 mg) or vehicle daily for two weeks before they were given the TT vaccine [4 Lf] intramuscularly (i.m.). Booster vaccinations were given on days 28 and 42. Serum was collected (days 0, 28, and 56) to quantify anti-TT levels. At autopsy, splenocytes harvested were cultured with TT or mitogens. The production of anti-TT antibodies was augmented (P < 0.05) in mice that were fed with delta-T3 or TRF compared to controls. The production of IFN-gamma and IL-4 by splenocytes from the vitamin E treated mice was significantly (P < 0.05) higher than that from controls. The IFN-gamma production was the highest in animals supplemented with delta-T3 followed by TRF and finally alpha-T. Production of TNF-alpha was suppressed in the vitamin E treated group compared to vehicle-supplemented controls. Supplementation with delta-T3 or TRF can enhance immune response to TT immunisation and production of cytokines that promote cell-mediated (TH1) immune response. PMID- 23936848 TI - Integrative analysis of methylome and transcriptome reveals the importance of unmethylated CpGs in non-CpG island gene activation. AB - BACKGROUND: Promoter methylation is associated with gene repression; however, little is known about its mechanism. It was proposed that the repression of methylated genes is achieved through the recruitment of methyl binding proteins (MBPs) that participate in closing the chromatin. An alternative mechanism suggests that methylation interferes with the binding of either site specific activators or more general activators that bind to the CpG dinucleotide. However, the relative contribution of these two mechanisms to gene repression is not known. RESULTS: Bioinformatics analyses of genome-wide transcriptome and methylome data support the latter hypothesis by demonstrating a strong association between transcription and the number of unmethylated CpGs at the promoter of genes lacking CpG islands. CONCLUSIONS: Our results suggest that methylation represses gene expression mainly by preventing the binding of CpG binding activators. PMID- 23936849 TI - Evaluating compliance with institutional preoperative testing guidelines for minimal-risk patients undergoing elective surgery. AB - BACKGROUND: Few investigations preoperatively are important for low-risk patients. This study was designed to determine the level of compliance with preoperative investigation guidelines for ASA I patients undergoing elective surgery. Secondary objectives included the following: to identify common inappropriate investigations, to evaluate the impact of abnormal testing on patient management, to determine factors affecting noncompliant tests, and to estimate unnecessary expenditure. METHODS: This retrospective study was conducted on adult patients over a one-year period. The institute's guidelines recommend tests according to the patients' age groups: a complete blood count (CBC) for those patients aged 18-45; CBC, chest radiograph (CXR) and electrocardiography (ECG) for those aged 46-60; and CBC, CXR, ECG, electrolytes, blood glucose, blood urea nitrogen (BUN), and creatinine (Cr) for patients aged 61-65. RESULTS: The medical records of 1,496 patients were reviewed. Compliant testing was found in only 12.1% (95% CI, 10.5-13.9). BUN and Cr testings were the most frequently overprescribed tests. Overinvestigations tended to be performed on major surgery and younger patients. Overall, overinvestigation incurred an estimated cost of US 200,000 dollars during the study period. CONCLUSIONS: The need to utilize the institution's preoperative guidelines should be emphasized in order to decrease unnecessary testing and the consequential financial burden. PMID- 23936850 TI - Expression of melatonin synthesizing enzymes in Helicobacter pylori infected gastric mucosa. AB - Helicobacter pylori colonization of gastric mucosa causes pain of unknown etiology in about 15-20% of infected subjects. The aim of the present work was to determine the level of expression of enzymes involved in the synthesis of melatonin in gastric mucosa of asymptomatic and symptomatic H. pylori infected patients. To diagnose H. pylori infection, histological analysis and the urea breath test (UBT C13) were performed. The levels of mRNA expression of arylalkylamine-N-acetyltransferase (AA-NAT) and acetylserotonin methyltransferase (ASMT) were estimated in gastric mucosa with RT-PCR. The level of AA-NAT expression and AMST was decreased in H. pylori infected patients and was increased after H. pylori eradication. We conclude that decreased expression of melatonin synthesizing enzymes, AA-NAT and ASMT, in patients with symptomatic H. pylori infection returns to normal level after H. pylori eradication. PMID- 23936851 TI - Button battery foreign bodies in children: hazards, management, and recommendations. AB - OBJECTIVE: The demand and usage of button batteries have risen. They are frequently inadvertently placed by children in their ears or noses and occasionally are swallowed and lodged along the upper aerodigestive tract. The purpose of this work is to study the different presentations of button battery foreign bodies and present our experience in the diagnosis and management of this hazardous problem in children. PATIENTS AND METHODS: This study included 13 patients. The diagnostic protocol was comprised of a thorough history, head and neck physical examination, and appropriate radiographic evaluation. The button batteries were emergently extracted under general anesthesia. RESULTS: The average follow-up period was 4.3 months. Five patients had a nasal button battery. Four patients had an esophageal button battery. Three patients had a button battery in the stomach. One patient had a button battery impacted in the left external ear canal. Apart from a nasal septal perforation and a tympanic membrane perforation, no major complications were detected. CONCLUSION: Early detection is the key in the management of button battery foreign bodies. They have a distinctive appearance on radiography, and its prompt removal is mandatory, especially for batteries lodged in the esophagus. Physicians must recognize the hazardous potential and serious implications of such an accident. There is a need for more public education about this serious problem. PMID- 23936853 TI - The variable origin of the recurrent artery of Heubner: an anatomical and morphometric study. AB - The recurrent artery of Heubner (RAH) is the largest vessel of the medial lenticulostriate arteries. It supplies many deep structures, mainly the corpus striatum, the globus pallidus, and the anterior crus of the internal capsule. The aim of the present paper was studying the morphological variations of the RAH and its diameter in relation to different areas of origin. The series contained the records from 183 formalin-fixed adult human brains. The calibrated digital images of the studied brains were evaluated and measured by Image J, which can calculate the number of pixels and convert them to metric measures. The RAH arose most often from the postcommunicating part of the anterior cerebral artery (47.81%). It originated from the precommunicating part of the anterior cerebral artery in 3.55% and at the level of the anterior communicating artery in 43.4% of cases. The RAH was missing in 5.19% and doubled in 6.28% of cases. The mean outer diameter of the RAH was 0.6 mm. The maximal measured diameter was 1.34 mm, and the minimal diameter was 0.19 mm. The awareness of the various anatomical and morphometric variations of the RAH is essential in planning the neurosurgical procedures to avoid unexpected neurological complications. PMID- 23936852 TI - Hyperpolarization-activated current, If, in mathematical models of rabbit sinoatrial node pacemaker cells. AB - A typical feature of sinoatrial (SA) node pacemaker cells is the presence of an ionic current that activates upon hyperpolarization. The role of this hyperpolarization-activated current, If, which is also known as the "funny current" or "pacemaker current," in the spontaneous pacemaker activity of SA nodal cells remains a matter of intense debate. Whereas some conclude that If plays a fundamental role in the generation of pacemaker activity and its rate control, others conclude that the role of If is limited to a modest contribution to rate control. The ongoing debate is often accompanied with arguments from computer simulations, either to support one's personal view or to invalidate that of the antagonist. In the present paper, we review the various mathematical descriptions of If that have been used in computer simulations and compare their strikingly different characteristics with our experimental data. We identify caveats and propose a novel model for If based on our experimental data. PMID- 23936855 TI - Effect of experimental infection with Haemonchus contortus on parasitological and local cellular responses in resistant and susceptible young Creole goats. AB - This study was carried out to evaluate the relationships of cellular changes in the abomasal mucosa and parasitological parameters, by comparing resistant and susceptible young Creole goats (kids) after experimental infection with Haemonchus contortus. The kids were infected over 2 periods (challenges 1 and 2) of 7 and 6 weeks, respectively. Fecal egg count (FEC), blood eosinophilia, packed cell volume (PCV), and body weight were weekly monitored. At the end of both challenges a subgroup of kids was slaughtered for nematode burden measurements and analysis of inflammatory cell infiltration in the abomasal mucosa. The average daily gain was higher in resistant kids after both challenges. Blood eosinophilia and FEC were higher in susceptible kids after both challenges. The number of immature worms and the means of female length were lower after challenge 2 whatever the genetic status. No differences were observed in the eosinophil and mononuclear cell infiltration between challenges 1 and 2 and resistant and susceptible kids. Globule leukocyte infiltration was found higher after the challenge 1 in resistant kids. This effect of the genetic status on globule leukocytes counts but not on the other inflammatory cell highlights the need for further study on the functional activity of these cell populations. PMID- 23936854 TI - The adaptive nature of the bone-periodontal ligament-cementum complex in a ligature-induced periodontitis rat model. AB - The novel aspect of this study involves illustrating significant adaptation of a functionally loaded bone-PDL-cementum complex in a ligature-induced periodontitis rat model. Following 4, 8, and 15 days of ligation, proinflammatory cytokines (TNF- alpha and RANKL), a mineral resorption indicator (TRAP), and a cell migration and adhesion molecule for tissue regeneration (fibronectin) within the complex were localized and correlated with changes in PDL-space (functional space). At 4 days of ligation, the functional space of the distal complex was widened compared to controls and was positively correlated with an increased expression of TNF- alpha. At 8 and 15 days, the number of RANKL(+) cells decreased near the mesial alveolar bone crest (ABC) but increased at the distal ABC. TRAP(+) cells on both sides of the complex significantly increased at 8 days. A gradual change in fibronectin expression from the distal PDL-secondary cementum interfaces through precementum layers was observed when compared to increased and abrupt changes at the mesial PDL-cementum and PDL-bone interfaces in ligated and control groups. Based on our results, we hypothesize that compromised strain fields can be created in a diseased periodontium, which in response to prolonged function can significantly alter the original bone and apical cementum formations. PMID- 23936856 TI - Persistent primitive olfactory artery in Serbian population. AB - The continuation of the cranial branch of the primitive internal carotid artery is called the primitive olfactory artery (POlA). It takes this name according to the fact that it is mainly concerned with supplying the developing nasal region. We reported two new cases of the persistent POlA (PPOlA) in Serbian population after retrospective analysis of digital images of 200 fetal and 269 adult cases. This PPOlA originated from the precommunicating part (A1) of the right anterior cerebral artery, coursed along the olfactory tract, and turned on the medial cerebral hemisphere in both male adults. Some vascular variations (fenestration of the A1 and the median artery of the corpus callosum) were associated with this persistent vessel. According to the fact that we did not find aneurysm in our previous and two recent cases, we are of the opinion that PPOlA is usually asymptomatic in Serbian population. PMID- 23936857 TI - Mechanical strength and biocompatibility of ultrafine-grained commercial purity titanium. AB - The effect of grain refinement of commercial purity titanium by equal channel angular pressing (ECAP) on its mechanical performance and bone tissue regeneration is reported. In vivo studies conducted on New Zealand white rabbits did not show an enhancement of biocompatibility of ECAP-modified titanium found earlier by in vitro testing. However, the observed combination of outstanding mechanical properties achieved by ECAP without a loss of biocompatibility suggests that this is a very promising processing route to bioimplant manufacturing. The study thus supports the expectation that commercial purity titanium modified by ECAP can be seen as an excellent candidate material for bone implants suitable for replacing conventional titanium alloy implants. PMID- 23936858 TI - Mechanostimulation protocols for cardiac tissue engineering. AB - Owing to the inability of self-replacement by a damaged myocardium, alternative strategies to heart transplantation have been explored within the last decades and cardiac tissue engineering/regenerative medicine is among the present challenges in biomedical research. Hopefully, several studies witness the constant extension of the toolbox available to engineer a fully functional, contractile, and robust cardiac tissue using different combinations of cells, template bioscaffolds, and biophysical stimuli obtained by the use of specific bioreactors. Mechanical forces influence the growth and shape of every tissue in our body generating changes in intracellular biochemistry and gene expression. That is why bioreactors play a central role in the task of regenerating a complex tissue such as the myocardium. In the last fifteen years a large number of dynamic culture devices have been developed and many results have been collected. The aim of this brief review is to resume in a single streamlined paper the state of the art in this field. PMID- 23936859 TI - Clinical application neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 as indicators of inflammation persistence and acute kidney injury in children with urinary tract infection. AB - BACKGROUND: The aim of this study was to examine the novel renal biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) to assist pediatricians in the assessment of longer duration of inflammation and acute kidney injury (AKI) development during urinary tract infection (UTI). METHODS: The patients enrolled in the study comprised 50 children (mean age was 6 months) with UTI. NGAL in serum and urine (sNGAL and uNGAL, resp.) and KIM-1 in urine were measured by enzyme-linked immunosorbent assays. RESULTS: uNGAL levels in subjects with longer duration of inflammation were higher (115.37 ng/mL) than uNGAL levels in subjects with shorter duration of inflammation (67.87 ng/mL, P = 0.022). Difference in sNGAL and KIM-1 levels was not significant (P = 0.155 and P = 0.198, resp.). Significant difference was seen in KIM-1 excretion among groups with and without AKI (P = 0.038). KIM-1 was not able to discriminate between subjects with and without AKI (area under the curves (AUC) = 0.620, P = 0.175). CONCLUSIONS: uNGAL cannot be used for screening of the duration of inflammation during UTI. Accuracy of KIM-1 in screening of AKI development in children with UTI is low. We suggest larger studies to check the negative predictive value of KIM-1 for the development of AKI. PMID- 23936860 TI - Sexual function in women with stress urinary incontinence treated with the SPARC sling system. AB - AIM: To evaluate the impact of SPARC on female sexual function. METHODS: 151 women with a mean age of 60 +/- 11.90 and SUI had a complete urodynamic investigation and underwent SPARC operation. 98 women completed the validated female sexual function index questionnaire (FSFI) at baseline and 94 women at follow-up. A minimum follow-up of 12 months was required for study inclusion. RESULTS: 52/98 women were sexually active at baseline. Postoperatively only 33 patients were sexually active. The FSFI score of all 33 pre- and postoperative sexually active women increased from 25.3 +/- 5.7 at baseline to 27.4 +/- 4.8 at follow-up (P = 0.1). Scores of women with reduced sexual function at baseline increased significantly in the domains desire, arousal, and lubrication as well as orgasm and satisfaction and total FSFI-score (P = 0.002) postoperatively. CONCLUSIONS: Our results suggest that the SPARC-sling procedure for SUI did not negatively interfere with female sexual function. PMID- 23936862 TI - Identification of potential or preclinical cognitive impairment and the implications of sophisticated screening with biomarkers and cognitive testing: does it really matter? AB - The last decade has seen an enormous growth in the interest in the recognition of and intervention in those diagnosed and living with the whole range of cognitive impairment and frank dementia. In the western world, the recognition of the impact on patients, families, health care systems, and societies that dementia poses has led to great efforts to help define the indicators for current and future dementia with the intention to treat those already afflicted even with the primarily symptomatic medications that exist and to recognize those at future risk with the hope of providing counselling to forestall its future development. The idea of "early diagnosis" appears at first glance to be attractive for the purposes of future planning and research studies, but it is not clear what the benefits and risks might be if screening processes define people at risk when beneficial interventions might not yet be determined. The ethical as well as financial implications must be explored and defined before implementation of such screening becomes a normal standard of practice. PMID- 23936861 TI - Nonsmall cell lung cancer therapy: insight into multitargeted small-molecule growth factor receptor inhibitors. AB - To date, lung cancer is the leading cause of cancer-related death worldwide, among which nonsmall cell lung cancer (NSCLC) comprises about 85%. Taking into account the side effects of surgery, radiation, platinum-based doublet chemotherapy, and the growth self-sufficiency characteristic of cancer cells, drugs have been discovered toward growth factor receptor (GFR) to treat NSCLC. As expected, these drugs provide a greater benefit. To increase the efficacy of such growth factor receptor tyrosine kinase inhibitors (RTKIs), coinhibition of GFR signaling pathways and combination of inhibitors along with radiation or chemotherapy have drew intense insight. Although clinical trials about single agent RTKIs or their combination strategies suggest their increase potency against cancer, they are not beyond adverse effects, and sometimes the effects are more deadly than chemotherapy. Nevertheless the hope for RTKIs may be proved true by further researches and digging deep into cancer therapeutics. PMID- 23936863 TI - Evaluation of an adsorbent based on agricultural waste (corn cobs) for removal of tyrosine and phenylalanine from aqueous solutions. AB - Adsorption of phenolic amino acids, such as phenylalanine and tyrosine, is quite relevant for the production of protein hydrolysates used as dietary formulations for patients suffering from congenital disorders of amino acid metabolism, such as phenylketonuria. In this study, an adsorbent prepared from corn cobs was evaluated for the removal of tyrosine (Tyr) from both a single component solution and a binary aqueous solution with phenylalanine (Phe). The adsorption behavior of tyrosine was similar to that of phenylalanine in single component solutions, however, with a much lower adsorption capacity (14 mg g(-1) for Tyr compared to 109 mg g(-1) for Phe). Tyr adsorption kinetics was satisfactorily described by a pseudosecond-order model as it was for Phe. In adsorption equilibrium studies for binary mixtures, the presence of Tyr in Phe solutions favored Phe faster adsorption whereas the opposite behavior was observed for the presence of Phe in Tyr solutions. Such results indicate that, in binary systems, Phe will be adsorbed preferably to Tyr, and this is a welcome feature when employing the prepared adsorbent for the removal of Phe from protein hydrolysates to be used in dietary formulations for phenylketonuria treatment. PMID- 23936865 TI - Vitamin D deficiency is not associated with changes in retinal geometric parameters in young people with type 1 diabetes. AB - Changes in retinal geometric parameters predict risk and progression of diabetic retinopathy (DR). We have shown that vitamin D deficiency (VDD) is associated with DR. We hypothesized that VDD mediates changes in retinal geometric parameters. Retinal vascular geometric parameters were assessed using a semiautomated computer program in photographs from young people with type 1 diabetes (T1D) (n = 481) and summarized as central retinal arteriolar and venular equivalents (CRAE, CRVE), fractal dimension, length-diameter ratio, branching angle and curvature tortuosity. Parameters were compared between those with and without DR and VDD (25-hydroxyvitamin D concentration <= 50 nmol/L). Retinal vascular geometric parameters were also compared across quartiles of vitamin D levels. Median CRVE was higher in patients with DR compared with those without (median (IQR) CRVE 247.3 MU m (31.3) versus 238.8 MU m (23.5), P = 0.01). Fractal dimension was marginally greater in patients without VDD (1.49 (0.06) versus 1.47 (0.07) P = 0.03). There was no difference in CRAE, CRVE, length diameter ratio, branching angle, and curvature tortuosity between those with and without VDD and across quartiles of 25OHD. In conclusion, DR is associated with higher CRVE in young people with T1D; however, VDD is not associated with changes in retinal vascular geometric measures, suggesting an earlier role in the time course of DR pathogenesis. PMID- 23936864 TI - Role of HLA, KIR, MICA, and cytokines genes in leprosy. AB - Many genes including HLA, KIR, and MICA genes, as well as polymorphisms in cytokines have been investigated for their role in infectious disease. HLA alleles may influence not only susceptibility or resistance to leprosy, but also the course of the disease. Some combinations of HLA and KIR may result in negative as well as positive interactions between NK cells and infected host cells with M. leprae, resulting in activation or inhibition of NK cells and, consequently, in death of bacillus. In addition, studies have demonstrated the influence of MICA genes in the pathogenesis of leprosy. Specifically, they may play a role in the interaction between NK cells and infected cells. Finally, pro- and anti-inflammatory cytokines have been influencing the clinical course of leprosy. Data from a wide variety of sources support the existence of genetic factors influencing the leprosy pathogenesis. These sources include twin studies, segregation analyses, family-based linkage and association studies, candidate gene association studies, and, most recently, genome-wide association studies (GWAS). The purpose of this brief review was to highlight the importance of some immune response genes and their correlation with the clinical forms of leprosy, as well as their implications for disease resistance and susceptibility. PMID- 23936867 TI - The effects of glucose fluctuation on the severity of coronary artery disease in type 2 diabetes mellitus. AB - OBJECTIVES: To explore the difference of glucose fluctuations between the normal subjects and diabetes mellitus (DM) patients and explore their impact on the development of CAD in type 2 DM patients. METHODS: The subjects were divided into 3 groups: normal control (group A, n = 40), type 2 DM patients without cardiovascular complications (group B, n = 56), and type 2 DM patients with cardiovascular complications (group C, n = 92). The SYNTAX scores were collected in group C. CGMS for 72 h was applied on all the subjects. The indexes such as MBG and the LAGE were calculated. Glycemic excursions were compared between groups A, B, and C, respectively. RESULTS: The tested indexes had significant differences among the three groups. SYNTAX scores are related to systolic blood pressure, CRP, MAGE, and HbA1c and are significantly correlated at 6:00-8:00 and 11:00-13:00 time points in group C. CONCLUSIONS: Compared with normal subjects, T2DM patients have greater blood glucose fluctuations; T2DM patients with CAD have larger glucose fluctuations than T2DM patients without CAD. Blood glucose fluctuations are positively correlated with carotid artery intima-media thickness in T2DM patients and have a significant influence on the development of coronary artery. PMID- 23936866 TI - Both ERK/MAPK and TGF-Beta/Smad signaling pathways play a role in the kidney fibrosis of diabetic mice accelerated by blood glucose fluctuation. AB - BACKGROUND: The notion that diabetic nephropathy is the leading cause of renal fibrosis prompted us to investigate the effects of blood glucose fluctuation (BGF) under high glucose condition on kidney in the mice. METHODS: The diabetic and BGF animal models were established in this study. Immunohistochemistry, Western blot, and RT-PCR analysis were applied to detect the expression of type I collagen, matrix metalloproteinase-1 (MMP1), metalloproteinase inhibitor 1 (TIMP1), transforming growth factor beta 1 (TGF- beta 1), phosphorylated-ERK, p38, smad2/3, and Akt. RESULTS: BGF treatment increased type I collagen synthesis by two times compared with the control. The expression of MMP1 was reduced markedly while TIMP1 synthesis was enhanced after BGF treatment. ERK phosphorylation exhibits a significant increase in the mice treated with BGF. Furthermore, BGF can markedly upregulate TGF- beta 1 expression. The p-smad2 showed 2-fold increases compared with the only diabetic mice. However, p-AKT levels were unchanged after BGF treatment. CONCLUSIONS: These data demonstrate that BGF can accelerate the trend of kidney fibrosis in diabetic mice by increasing collagen production and inhibiting collagen degradation. Both ERK/MAPK and TGF- beta /smad signaling pathways seem to play a role in the development of kidney fibrosis accelerated by blood glucose fluctuation. PMID- 23936868 TI - Low Molecular Weight Antagonists of Plasminogen Activator Inhibitor-1: Therapeutic Potential in Cardiovascular Disease. AB - Plasminogen activator inhibitor-1 (PAI-1; SERPINE1) is the major physiologic regulator of the plasmin-based pericellular proteolytic cascade, a modulator of vascular smooth muscle cell (VSMC) migration and a causative factor in cardiovascular disease and restenosis, particularly in the context of increased vessel transforming growth factor- beta1 (TGF-beta1) levels. PAI-1 limits conversion of plasminogen to plasmin (and, thereby, fibrin degradation) by inhibiting its protease targets urokinase and tissue-type plasminogen activators (uPA, tPA). PAI-1 also has signaling functions and binds to the low density lipoprotein receptor-related protein 1 (LRP1) to regulate LRP1-dependent cell motility that, in turn, contributes to neointima formation. PAI-1/uPA/uPA receptor/LRPI/integrin complexes are endocytosed with subsequent uPAR/LRP1/integrin redistribution to the leading edge, initiating an "adhesion detachment-readhesion" cycle to promote cell migration. PAI-1 also interacts with LRP1 in a uPA/uPAR-independent manner triggering Jak/Stat1 pathway activation to stimulate cell motility. PAI-1 itself is a substrate for extracellular proteases and exists in a "cleaved" form which, while unable to interact with uPA and tPA, retains LRP1-binding and migratory activity. These findings suggest that there are multiple mechanisms through which inhibition of PAI-1 may promote cardiovascular health. Several studies have focused on the design, synthesis and preclinical assessment of PAI-1 antagonists including monoclonal antibodies, peptides and low molecular weight (LMW) antagonists. This review discusses the translational impact of LMW PAI-1 antagonists on cardiovascular disease addressing PAI-1-initiated signaling, PAI-1 structure, the design and characteristics of PAI-1-targeting drugs, results of in vitro and in vivo studies, and their clinical implications. PMID- 23936869 TI - Ethnic-Specific WRN Mutations in South Asian Werner Syndrome Patients: Potential Founder Effect in Patients with Indian or Pakistani Ancestry. AB - Werner syndrome is a rare autosomal recessive disorder characterized by multiple features consistent with accelerated aging. It is caused by mutations in the WRN gene, which encodes a RecQ type helicase. To date, more than 70 disease-causing mutations have been reported. While founder mutations and a corresponding relatively high incidence of WS have been reported in Japan and Sardinia, such mutations have not been previously described among patients of South Asian descent. Here we report two novel WRN mutations in three pedigrees. A homozygous c.561A>G mutation in exon 6 was identified both in a pedigree from Kerala, India and in a British patient of Pakistani ancestry. Although c.561A>G does not alter the corresponding amino acid (p.K187K), it creates a cryptic splice site resulting in a 98bp deletion at the mRNA level (r.557-654del98) followed by a frameshift (p.K187fs). These two cases shared the same haplotype across the WRN gene, and were distinct from another Indian Werner patient with a homozygous stop codon mutation, c.2855 C>A (p.S952*) in exon 24. As the Indian population increases and the awareness of Werner syndrome grows, we anticipate that more cases will be identified with these founder mutations among South Asian Werner syndrome patients. PMID- 23936871 TI - Human Stem Cell Derivatives Retain More Open Epigenomic Landscape When Derived from Pluripotent Cells than from Tissues. AB - The growing number of identified stem cell derivatives and escalating concerns for safety and efficacy of these cells towards clinical applications have made it increasingly crucial to be able to assess the relative risk-benefit ratio of a given stem cell from a given source for a particular disease. Discerning the intrinsic plasticity and regenerative potential of human stem cell populations might reside in chromatin modifications that shape the respective epigenomes of their derivation routes. Previously, we have generated engraftable human neuronal progenitors direct from pluripotent human embryonic stem cells (hESCs) by small molecule induction (hESC-I hNuPs). Unlike the prototypical neuroepithelial-like nestin-positive human neural stem cells (hNSCs), these in vitro neuroectoderm derived Nurr1-positive hESC-I hNuPs are a more neuronal lineage-specific and plastic hESC derivative. In this study, the global chromatin landscape changes in pluripotent hESCs and their neuronal lineage-specific derivative hESC-I hNuPs were profiled using genome-wide mapping and compared to CNS tissue-derived hNSCs. This study found that the broad potential of pluripotent hESCs is defined by an epigenome constituted of open conformation of chromatin mediated by a pattern of Oct-4 global distribution that corresponds closely with those of acetylated nucleosomes genome-wide. The epigenomic transition from pluripotency to restriction in lineage choices is characterized by genome-wide increases in histone H3K9 methylation that mediates global chromatin-silencing and somatic identity. Tissue-resident CNS-derived hNSCs have acquired a substantial number of additional histone H3K9 methylation, therefore, more silenced chromatin. These data suggest that the intrinsic plasticity and regenerative potential of human stem cell derivatives can be differentiated by their epigenomic landscape features, and that human stem cell derivatives retain more open epigenomic landscape, therefore, more developmental potential for scale-up regeneration, when derived from the hESCs in vitro than from the CNS tissue in vivo. PMID- 23936872 TI - The burden of celiac disease in Canada: more work needed to lighten the load. PMID- 23936870 TI - 11beta-Hydroxysteroid Dehydrogenase Type II is a Potential Target for Prevention of Colorectal Tumorigenesis. AB - Colorectal cancer (CRC) is a leading cause of cancer death, yet primary prevention remains the best approach to reducing overall morbidity and mortality. There is a clear molecular link between cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) production and CRC progression. Although selective COX-2 inhibitors as well as non-steroidal anti-inflammatory drugs (NSAIDs) reduce the number and sizes of colonic adenomas, increased cardiovascular risks of selective COX-2 inhibitors and increased gastrointestinal side-effects of NSAIDs limit their use in chemoprevention of CRC. Glucocorticoids induce apoptosis and are endogenous, potent COX-2 inhibitors. Glucocorticoids have been used for the treatment of hematologic malignancies, but not for solid tumors due to adverse side-effects such as immunosuppression and osteoporosis. In tissues, glucocorticoid actions are down-regulated by t y p e 2 1 1 beta-hydroxysteroid dehydrogenase (11betaHSD2), and inhibition of 11betaHSD2 activity will elevate intracellular active glucocorticoid to levels that effectively suppress COX-2 expression. Both COX-2 and 11betaHSD2 increase in Apc+/min mouse intestinal adenomas and human colonic adenomas and either pharmacologic or genetic 11betaHSD2 inhibition leads to decreases in COX-2-mediated PGE2 production in tumors and prevents adenoma formation, tumor growth, and metastasis. 11betaHSD2 inhibition may represent a novel approach for CRC chemoprevention by increasing tumor cell intracellular glucocorticoid activity, which in turn inhibits tumor growth by suppressing the COX-2-derived PGE2 pathway, as well as other pathways, without potential side-effects relating to chronic application of COX-2 inhibitors, NSAIDs and glucocorticoids. PMID- 23936874 TI - Predictors of early rebleeding after endoscopic therapy in patients with nonvariceal upper gastrointestinal bleeding secondary to high-risk lesions. AB - BACKGROUND: In an era of increasingly shortened admissions, data regarding predictors of early rebleeding among patients with nonvariceal upper gastrointestinal bleeding (NVUGIB) exhibiting high-risk stigmata (HRS) having undergone endoscopic hemostasis are lacking. OBJECTIVES: To determine predictors of early rebleeding, defined as rebleeding before completion of recommended 72 h intravenous proton pump inhibitor infusion postendoscopic hemostasis. METHODS: Data from a national registry of patients with upper gastrointestinal bleeding (the REASON registry) were accessed. Univariable and multivariable analyses were sequentially performed to identify significant independent predictors among a comprehensive list of clinical and laboratory characteristics. RESULTS: Overall, 393 patients underwent endoscopic hemostasis for NVUGIB with HRS. Forty patients rebled <=72 h thereafter (32.5% female, mean [+/- SD] age 70.2 +/- 11.8 years, 2.88 +/- 2.11 comorbidities), while 21 rebled later (38.1% female, mean 70.5 +/- 14.1 years of age, 2.62 +/- 2.06 comorbidities). Hematemesis or bright red blood per nasogastric tube aspirate was identified as the sole independent significant predictor of early rebleeding versus later among both NVUGIB and, more specifically, patients with peptic ulcer bleeding (OR 7.94 [95% CI 1.80 to 35.01]; P<0.01, and OR 8.41 [95% CI 1.54 to 46.10]; P=0.014, respectively). CONCLUSIONS: When attempting to determine the optimal duration of pharmacotherapy and timing of discharge for patients following endoscopic hemostasis for NVUGIB with HRS, it is noteworthy that individuals who present with hematemesis or bright red blood per nasogastric tube aspirate are at particularly high risk for rebleeding within the first 72 h. PMID- 23936873 TI - Clinical features and symptom recovery on a gluten-free diet in Canadian adults with celiac disease. AB - BACKGROUND: Celiac disease can present with mild or nongastrointestinal symptoms, and may escape timely recognition. The treatment of celiac disease involves a gluten-free diet, which is complex and challenging. OBJECTIVE: To evaluate clinical features and symptom recovery on a gluten-free diet in a Canadian adult celiac population. METHODS: All adult members (n=10,693) of the two national celiac support organizations, the Canadian Celiac Association and Fondation quebecoise de la maladie coeliaque, were surveyed using a questionnaire. RESULTS: A total of 5912 individuals (>=18 years of age) with biopsy-confirmed celiac disease and/or dermatitis herpetiformis completed the survey. The female to male ratio was 3:1, and mean (+/- SD) age at diagnosis was 45.2 +/- 16.4 years. Mean time to diagnosis after onset of symptoms was 12.0 +/- 14.4 years. Abdominal pain and bloating (84.9%), extreme weakness/tiredness (74.2%), diarrhea (71.7%) and anemia (67.8%) were the most commonly reported symptoms at the time of diagnosis. Many respondents continued to experience symptoms after being on a gluten-free diet for >5 years. Sex differences were reported in clinical features before diagnosis, recovery after being on gluten-free diet and perceived quality of life, with women experiencing more difficulties than men. CONCLUSIONS: Delays in diagnosis of celiac disease in Canada remain unacceptably long despite wider availability of serological screening tests. Many patients report continuing symptoms despite adhering to a gluten-free diet for >5 years, with women experiencing more symptoms and a lower recovery rate than men. Awareness of celiac disease needs improvement, and follow-up with a physician and a dietitian is essential for all patients with celiac disease. PMID- 23936875 TI - Transnasal endoscopic evaluation of swallowing: a bedside technique to evaluate ability to swallow pureed diets in elderly patients with dysphagia. AB - BACKGROUND: Endoscopic evaluation of swallowing (EES) is not commonly used by gastroenterologists to evaluate swallowing in patients with dysphagia. OBJECTIVE: To use transnasal endoscopy to identify factors predicting successful or failed swallowing of pureed foods in elderly patients with dysphagia. METHODS: EES of pureed foods was performed by a gastroenterologist using a small-calibre transnasal endoscope. Factors related to successful versus unsuccessful swallowing of pureed foods were analyzed with regard to age, comorbid diseases, swallowing activity, saliva pooling, vallecular residues, pharyngeal residues and airway penetration/aspiration. Unsuccessful swallowing was defined in patients who could not eat pureed foods at bedside during hospitalization. Logistic regression analysis was used to identify independent predictors of swallowing of pureed foods. RESULTS: During a six-year period, 458 consecutive patients (mean age 80 years [range 39 to 97 years]) were considered for the study, including 285 (62%) men. Saliva pooling, vallecular residues, pharyngeal residues and penetration/aspiration were found in 240 (52%), 73 (16%), 226 (49%) and 232 patients (51%), respectively. Overall, 247 patients (54%) failed to swallow pureed foods. Multivariate logistic regression analysis demonstrated that the presence of pharyngeal residues (OR 6.0) and saliva pooling (OR 4.6) occurred significantly more frequently in patients who failed to swallow pureed foods. CONCLUSIONS: Pharyngeal residues and saliva pooling predicted impaired swallowing of pureed foods. Transnasal EES performed by a gastroenterologist provided a unique bedside method of assessing the ability to swallow pureed foods in elderly patients with dysphagia. PMID- 23936876 TI - Patient and parent satisfaction with a dietitian- and nurse- led celiac disease clinic for children at the Stollery Children's Hospital, Edmonton, Alberta. AB - OBJECTIVE: To assess patient and parent satisfaction with a primarily nurse- and dietitian-led celiac disease clinic in a tertiary pediatric centre. METHODS: An online survey was sent to families and patients attending the Stollery Children's Hospital's Multidisciplinary Pediatric Celiac Clinic (Edmonton, Alberta) since 2007. The survey focused on clinic attendance, satisfaction with clinic structure, processes, and education and preference for alternatives to the current process. Respondents were asked to rank satisfaction or preference on a five-point Likert scale, with 1 being lowest and 5 being highest. RESULTS: Most satisfaction related to follow-up with serology (4.6) and with a dietitian (4.3). The most preferred changes included either meeting the entire multidisciplinary team after the biopsy (4.7), or meeting with only the dietitian and nurse after the biopsy (4.4). The preferred education resources were the Internet (4.3) and the dietitian (4.2). The mean overall satisfaction score of the Multidisciplinary Pediatric Celiac Clinic was 4.0. CONCLUSIONS: Results of the present survey suggested that patients and families value a multidisciplinary follow-up clinic for children with celiac disease. In particular, feedback based on repeat blood work and regular contact with a dietitian were highly valued. The present survey, outlining the most valued aspects of the clinic, may be useful for service delivery in other regions. In addition, it provides information on how to better support pediatric patients with celiac disease. PMID- 23936877 TI - Diagnostic value of stool DNA testing for multiple markers of colorectal cancer and advanced adenoma: a meta-analysis. AB - BACKGROUND AND OBJECTIVES: The diagnostic value of stool DNA (sDNA) testing for colorectal neoplasms remains controversial. To compensate for the lack of large scale unbiased population studies, a meta-analysis was performed to evaluate the diagnostic value of sDNA testing for multiple markers of colorectal cancer (CRC) and advanced adenoma. METHODS: The PubMed, Science Direct, Biosis Review, Cochrane Library and Embase databases were systematically searched in January 2012 without time restriction. Meta-analysis was performed using a random-effects model using sensitivity, specificity, diagnostic OR (DOR), summary ROC curves, area under the curve (AUC), and 95% CIs as effect measures. Heterogeneity was measured using the chi(2) test and Q statistic; subgroup analysis was also conducted. RESULTS: A total of 20 studies comprising 5876 individuals were eligible. There was no heterogeneity for CRC, but adenoma and advanced adenoma harboured considerable heterogeneity influenced by risk classification and various detection markers. Stratification analysis according to risk classification showed that multiple markers had a high DOR for the high-risk subgroups of both CRC (sensitivity 0.759 [95% CI 0.711 to 0.804]; specificity 0.883 [95% CI 0.846 to 0.913]; AUC 0.906) and advanced adenoma (sensitivity 0.683 [95% CI 0.584 to 0.771]; specificity 0.918 [95% CI 0.866 to 0.954]; AUC 0.946) but not for the average-risk subgroups of either. In the methylation subgroup, sDNA testing had significantly higher DOR for CRC (sensitivity 0.753 [95% CI 0.685 to 0.812]; specificity 0.913 [95% CI 0.860 to 0.950]; AUC 0.918) and advanced adenoma (sensitivity 0.623 [95% CI 0.527 to 0.712]; specificity 0.926 [95% CI 0.882 to 0.958]; AUC 0.910) compared with the mutation subgroup. There was no significant heterogeneity among studies for subgroup analysis. CONCLUSION: sDNA testing for multiple markers had strong diagnostic significance for CRC and advanced adenoma in high-risk subjects. Methylation makers had more diagnostic value than mutation markers. PMID- 23936878 TI - Magnetic resonance imaging of the perineum in pediatric patients with inflammatory bowel disease. AB - Magnetic resonance imaging (MRI) has profoundly changed and improved the investigation of abdominal and pelvic inflammatory bowel disease (IBD) in pediatrics. Using an imaging modality without ionizing radiation is of particular advantage because the pediatric IBD population is young and often requires repeat evaluation. MRI of the pelvis has become the imaging gold standard for detecting and monitoring perianal disease while bowel-directed imaging techniques (eg, enterography, enteroclysis and colonography) can accurately evaluate bowel inflammation in IBD. With recent technological innovations leading to faster and higher resolution, the role of MRI in IBD will likely continue to expand. The present article focuses on MRI of the perineum in pediatric IBD. PMID- 23936879 TI - Understanding disparity on the Canadian prairies: a step toward improving tuberculosis outcomes. PMID- 23936880 TI - Dyspnea, massive effusion and lytic rib lesion as initial presentation of multiple myeloma in a young man. AB - Multiple myeloma, a disorder commonly encountered in elderly patients, represents a malignant proliferation of plasma cells that primarily affects bone marrow. Pleural effusion as the presenting manifestation of the disease is uncommon. The authors report a case of multiple myeloma with unusual features presenting at a relatively young age with massive spontaneous hemothorax and multiple thoracic masses completely obscuring rib shadow on plain chest imaging. The patient demonstrated a good response to melphalan chemotherapy without recurrence of effusion or the need for additional chemical or surgical pleural interventions. PMID- 23936881 TI - Optimal oxygen titration in patients with chronic obstructive pulmonary disease: a role for automated oxygen delivery? AB - Oxygen therapy can be life-saving for patients with chronic obstructive pulmonary disease (COPD) and is the backbone of any acute COPD treatment strategy. Although largely considered to be a benign drug, many publications have highlighted the need to accurately adjust oxygen delivery to avoid both hypoxemia and the problem of hyperoxia-induced hypercapnia. Recent clinical data have shown that the deleterious effects of excess oxygen treatment can not only alter carbon dioxide levels (which has been known for more than 60 years) but can also lead to an increase in mortality. Nevertheless, despite the extensive literature, the risks associated with hyperoxia are often overlooked and published clinical recommendations are largely ignored. This failure in knowledge translation has become increasingly important not only because of the desire to reduce medical error, but in a society with limited health care resources, the economic burden of COPD is such that it cannot afford to make preventable medical mistakes. Recently, novel devices have been developed to automatically adjust oxygen flow rates to maintain stable oxygen saturations. These closed-loop oxygen delivery systems have the potential to reduce medical error, improve morbidity and mortality, and reduce health care costs. Preliminary data in this field are promising and will require a significant amount of research in the coming years to determine the precise indications for these systems. The importance of appropriate oxygen dosing and the current literature regarding novel oxygen delivery systems are reviewed. PMID- 23936882 TI - An introduction to the knowledge translation special issue of the Canadian respiratory journal. PMID- 23936883 TI - Introducing the Canadian Thoracic Society framework for guideline dissemination and implementation, with concurrent evaluation. AB - The Canadian Thoracic Society (CTS) is leveraging its strengths in guideline production to enable respiratory guideline implementation in Canada. The authors describe the new CTS Framework for Guideline Dissemination and Implementation, with Concurrent Evaluation, which has three spheres of action: guideline production, implementation infrastructure and knowledge translation (KT) methodological support. The Canadian Institutes of Health Research 'Knowledge-to Action' process was adopted as the model of choice for conceptualizing KT interventions. Within the framework, new evidence for formatting guideline recommendations to enhance the intrinsic implementability of future guidelines were applied. Clinical assemblies will consider implementability early in the guideline production cycle when selecting clinical questions, and new practice guidelines will include a section dedicated to KT. The framework describes the development of a web-based repository and communication forum to inventory existing KT resources and to facilitate collaboration and communication among implementation stakeholders through an online discussion board. A national forum for presentation and peer-review of proposed KT projects is described. The framework outlines expert methodological support for KT planning, development and evaluation including a practical guide for implementers and a novel 'Clinical Assembly-KT Action Team', and in-kind logistical support and assistance in securing peer-reviewed funding. PMID- 23936884 TI - Major care gaps in asthma, sleep and chronic obstructive pulmonary disease: a road map for knowledge translation. AB - Large gaps between best evidence-based care and actual clinical practice exist in respiratory medicine, and carry a significant health burden. The authors reviewed two key care gaps in each of asthma, chronic obstructive pulmonary disease and obstructive sleep apnea. Using the 'Knowledge-to-Action Framework', the nature of each gap, its magnitude, the barriers that cause and perpetuate it, and past and future strategies that might address the problem were considered. In asthma: disease control is ascertained inadequately, leading to a prevalence of poor asthma control of approximately 50%; and asthma action plans, a key component of asthma management, are provided by only 22% of physicians. In obstructive sleep apnea: disease is under-recognized, with sleep histories ascertained in only 10% of patients; and Canadian polysomnography wait times remain longer than recommended, leading to unnecessary morbidity and societal cost. In chronic obstructive pulmonary disease: a large proportion of patients seen in primary care remain undiagnosed, mainly due to underuse of spirometry; and <10% of patients are referred for pulmonary rehabilitation, despite strong evidence demonstrating its cost effectiveness. Given the prevalence of these chronic conditions and the size and nature of these gaps, the latter exact an important toll on patients, the health care system and society. In turn, complex barriers at the patient, provider and health care system levels contribute to each gap. There have been few previous attempts to bridge these gaps. Innovative and multifaceted implementation approaches are needed and have the potential to make a large impact on Canadian respiratory health. PMID- 23936885 TI - Knowledge brokering: an innovative model for supporting evidence-informed practice in respiratory care. AB - The process of adopting research findings in the clinical setting is challenging, regardless of the area of practice. One strategy to facilitate this process is the use of knowledge brokering. Knowledge brokers (KBs) are individuals who work to bridge the gap between researchers and knowledge users. In the health care setting, KBs work closely with clinicians to facilitate enhanced uptake of research findings into clinical practice. They also work with researchers to ensure research findings are translatable and meaningful to clinical practice. The present article discusses a KB's role in a respiratory care setting. Working closely with both researchers and clinicians, the KB has led teams in the process of conceptualizing, developing, testing, disseminating and evaluating several projects related to respiratory care, including projects related to mobility in critical care settings and acute exacerbations of chronic obstructive pulmonary disease; inspiratory muscle training; and the use of incentive spirometry in postsurgical populations. The KB role has provided an important communication link between researcher and knowledge user that has facilitated evidence-informed practice to improve patient care. PMID- 23936887 TI - Safe and effective prescription of exercise in acute exacerbations of chronic obstructive pulmonary disease: rationale and methods for an integrated knowledge translation study. AB - BACKGROUND: Patients hospitalized with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) engage in low levels of activity, putting them at risk for relapse and future readmissions. There is little direction for health care providers regarding the parameters for safe exercise during an AECOPD that is effective for increasing activity tolerance before discharge from hospital, especially for patients with associated comorbid conditions. OBJECTIVE: To report the rationale for and methods of a study to develop evidence-informed care recommendations that guide health care providers in the assessment, prescription, monitoring and progression of exercise for patients hospitalized with AECOPD. METHODS: The present study was a multicomponent knowledge translation project incorporating evidence from systematic reviews of exercise involving populations with chronic obstructive pulmonary disease and/or common comorbidities. A Delphi process was then used to obtain expert opinion from clinicians, academics and patients to identify the parameters of safe and effective exercise for patients with AECOPD. RESULTS: Clinical decision-making tool(s) for patients and practitioners supported by a detailed knowledge dissemination, implementation and evaluation framework. CONCLUSION: The present study addressed an important knowledge gap: the lack of availability of parameters to guide safe and effective exercise prescription for hospitalized patients with AECOPD, with or without comorbid conditions. In the absence of such parameters, health care professionals may adopt an 'activity as tolerated' approach, which may not improve physical activity levels in their patients. The present study synthesizes the best available evidence and expert opinion, and will generate decision-making tools for use by patients and their health care providers. PMID- 23936886 TI - Asthma and chronic obstructive pulmonary disease guideline implementation: lessons learned on recruitment of primary care physicians to a knowledge translation study. AB - BACKGROUND: Implementation of current clinical practice guidelines in asthma and chronic obstructive pulmonary disease (COPD) is suboptimal. New implementation strategies should be developed and evaluated. METHODS: The authors report the rationale and planned methods of a project that sought to use a multifaceted knowledge translation intervention consisting of interactive education, mentorship through quality circles and practice-based tools in primary care to address key asthma and COPD care gaps. The present study was aborted due to inadequate primary care physician recruitment. Accordingly, the authors provide a critical review of their recruitment strategies and discuss alternative approaches and examples based on previous literature. DISCUSSION: These practical lessons and discussion seek to inform researchers involved in designing and recruiting for future knowledge translation studies addressing chronic disease management in primary care. PMID- 23936888 TI - Facilitators and solutions for practicing optimal guided asthma self-management: the physician perspective. AB - OBJECTIVE: To identify key solutions that facilitate the prescription of long term asthma controller and provision of written self-management plans by physicians. METHODS: One hour individualized semistructured interviews were conducted with physicians. Interviews were transcribed verbatim and analyzed independently by two trained qualitative researchers. A taxonomy of facilitators (contemplated solutions) and experienced solutions was achieved by consensus within the research team. RESULTS: Forty-two physicians (family physicians, pediatricians, emergency physicians, pulmonologists and allergists) were interviewed. The 867 facilitators and solutions, grouped in 10 categories, addressed three physician needs: support physicians in delivering optimal care (guideline dissemination, workplace culture, physician training and experience, physician attitudes toward optimal practice, tools and resources supporting physicians' decision making); assist patients with following recommendations (patient characteristics, experiences and attitudes; physician behaviour; and tools and resources supporting patient self-management); and offer efficient services (reorganization of care; interprofessional patient management). Suggestions pertaining to the latter two categories were most frequently cited to optimize asthma management and use of self-management plans (e.g., access to self management plans; education by allied health care professionals). The most cited suggestions to support prescribing long-term controller pertained to physician behaviour (e.g., involvement in patient education, personalization of prescriptions, feedback to patients of the benefits of long-term controller). The distribution of facilitators and solutions varied across specialties. CONCLUSIONS: Physicians proposed multiple facilitators and solutions to support optimal practice, leading to the development of a novel taxonomy. Key suggestions varied across physician specialties and behaviours sought, emphasizing the need to carefully select the most promising knowledge translation interventions. PMID- 23936889 TI - Asthma education program for First Nations children: an exemplar of the knowledge to-action framework. AB - BACKGROUND: The prevalence of asthma in Aboriginal children is 6% to 14%. Gaps in knowledge regarding asthma and its management exist in First Nations (FN) communities, and culturally relevant education and resources are required. Studies have recommended that the children's asthma education program, the 'Roaring Adventures of Puff', be modified through partnership with FN communities to be culturally appropriate. OBJECTIVE: To adapt this knowledge tool and design an effective implementation process for FN knowledge users (children with asthma and care providers), guided by the Canadian Institutes of Health Research knowledge translation framework. METHODS: The problem was identified, knowledge was identified/reviewed/selected (literature review); knowledge was adapted to the local context (FN working and advisory groups); barriers to knowledge use were assessed (by knowledge users); and interventions were selected, tailored and implemented (modified curricula and the creation of a new activity book and web based resources, and regional coordinators, asthma educator mentors and community teams were recruited). RESULTS: Major outcomes were the adapted tools and blueprints for tailoring implementation. Additional outcomes were preliminary observations and outputs from the iterative processes, including information about local context and barriers. Specific additions were roles for community members supported by asthma educators (applying FN teaching models and addressing health care demands); relevant triggers (addressing knowledge gaps); and FN images and stories, themes of circle, sacred teachings, nature and family/elders (culture and addressing low reading levels). CONCLUSION: The framework model provides a logical, valuable tool for adapting a knowledge tool and implementation process to new knowledge users. Future research should measure uptake, effect on health outcomes of FN asthma sufferers and sustainability. PMID- 23936890 TI - Development and pilot testing of a mobile health solution for asthma self management: asthma action plan smartphone application pilot study. AB - BACKGROUND: Collaborative self-management is a core recommendation of national asthma guidelines; the written action plan is the knowledge tool that supports this objective. Mobile health technologies have the potential to enhance the effectiveness of the action plan as a knowledge translation tool. OBJECTIVE: To design, develop and pilot a mobile health system to support asthma self management. METHODS: The present study was a prospective, single-centre, nonrandomized, pilot preintervention-postintervention analysis. System design and development were guided by an expert steering committee. The network included an agnostic web browser-based asthma action plan smartphone application (SPA). Subjects securely transmitted symptoms and peak flow data daily, and received automated control assessment, treatment advice and environmental alerts. RESULTS: Twenty-two adult subjects (mean age 47 years, 82% women) completed the study. Biophysical data were received on 84% of subject days (subject day = 1 subject * 1 day). Subjects viewed their action plan current zone of control on 54% and current air quality on 61% of subject days, 86% followed self-management advice and 50% acted to reduce exposure risks. A large majority affirmed ease of use, clarity and timeliness, and 95% desired SPA use after the study. At baseline, 91% had at least one symptom criterion for uncontrolled asthma and 64% had >=2, compared with 45% (P=0.006) and 27% (P=0.022) at study close. Mean Asthma Quality of Life Questionnaire score improved from 4.3 to 4.8 (P=0.047). CONCLUSIONS: A dynamic, real-time, interactive, mobile health system with an integrated asthma action plan SPA can support knowledge translation at the patient and provider levels. PMID- 23936892 TI - Psychiatric morbidity in pain conditions: results from the Singapore Mental Health Study. AB - BACKGROUND: Chronic pain is a common problem among the general population and has been found to be associated with psychiatric disorders in studies based on both clinical samples and epidemiological surveys. OBJECTIVES: To establish the prevalence, correlates and comorbidities of chronic pain disorders among the adult population of Singapore. METHODS: The data used in the present analysis were derived from the Singapore Mental Health Study, a cross-sectional epidemiological survey of a representative sample of the adult resident population of Singapore. Diagnoses of psychiatric disorders were established using the Composite International Diagnostic Interview version 3.0. A modified version of the Composite International Diagnostic Interview 3.0 checklist of chronic medical disorders was used, in which the chronic medical disorders were reclassified into eight types of physical disorders. Chronic pain disorders included arthritis or rheumatism, back problems including disk or spine problems, and migraine headaches. RESULTS: The lifetime prevalence estimates for arthritis, back pain and migraine in the Singapore general population were 6.0% (n=282), 7.0% (n=436) and 5.6% (n=446), respectively. After adjusting for sociodemographic factors, comorbid pain disorders and the presence of other chronic physical conditions, migraine remained significantly associated with major depressive disorder (adjusted OR=2.4), generalized anxiety disorder (adjusted OR=3.0) and alcohol use disorders (adjusted OR=2.1), while back pain was significantly associated with major depressive disorder (adjusted OR=2.0). CONCLUSIONS: The significant association between pain and psychiatric disorders emphasizes the need to screen individuals with chronic pain conditions for psychiatric disorders, particularly depression. There is a need to develop integrated pharmacological and psychological treatments for both conditions. PMID- 23936893 TI - Toy-mediated distraction: clarifying the role of agent of distraction and preneedle distress in toddlers. AB - BACKGROUND: Distraction has recently gained attention as a technique that may help reduce acute pain in infants and toddlers; however, results remain equivocal. It appears that these mixed results stem from a variety of methodological differences with regard to how distraction is implemented. OBJECTIVES: To offer more definitive conclusions regarding the efficacy and mechanisms of distraction for pain management during infancy. Specifically, the goal was to examine whether the agent of distraction (i.e., the specific person conducting the distraction) and preneedle distress behaviours impact the efficacy of distraction when toddlers were held by parents. METHODS: A total of 99 toddlers were randomly assigned to one of three conditions (typical care, research assistant-directed distraction or parent-directed distraction). Toddler distress behaviours were assessed pre- and postneedle. Toddlers were further grouped according to distress behaviours preneedle (low/no distress versus high distress). Parental soothing behaviours were also assessed as a manipulation check. RESULTS: Toddler postneedle pain did not significantly differ among groups. However, toddlers who were distressed preneedle displayed significantly more pain postneedle, regardless of the treatment group. There were no significant interactions between treatment group and preneedle distress behaviours. CONCLUSIONS: These results suggest that, when being held by a parent, distraction using a toy does not result in lower pain scores in the context of immunization, regardless of who offers the distraction. Furthermore, these findings raise the notion that if clinicians ensured toddlers were regulated before attempting an immunization, postneedle pain may be significantly reduced. PMID- 23936894 TI - Locus of control patterns in headaches and chronic pain. AB - BACKGROUND: Locus of control (LOC) is related to the impact of headaches and chronic pain; however, literature evidence regarding LOC is not always consistent. Several authors consider this to be due, in part, to the separate interpretation of LOC factors, during which the interaction among them is ignored. In 1982, Wallston and Wallston proposed eight possible LOC health patterns depending on whether the individual scored high or low in each of three dimensions. OBJECTIVE: To identify these LOC patterns in patients with headaches and chronic pain, and to validate them in terms of their association with a selection of the main pain indicators. METHODS: A total of 228 individuals were recruited at three public centres in Seville, Spain. Participants completed a semistructured clinical interview and several questionnaires assessing psychological variables related to pain. The main statistical analyses used were two-step cluster analysis and ANCOVA. RESULTS: The six-cluster solution was optimal. The patterns observed coincided with: the believer in control; the yea sayer; the pure chance; the pure internal; the pure professional; and the nay sayer clusters. The double external or type VI clusters were not observed. Clusters could be classified from the best to the worst adjustment to chronic pain. CONCLUSIONS: These results support the empirical validity of the theoretical model of LOC patterns proposed in 1982 by Wallston and Wallston among a chronic pain population. The analysis of patterns provides more accurate information regarding the adjustment to pain compared with analysis of the LOC factors separately. PMID- 23936896 TI - Specific site binding of metal ions on the intramolecular charge transfer fluorophore in micelles. AB - The binding interactions of Cu(2+), an essential trace metal ion, and Cd(2+), a deleterious metal ion, with 2-(4'-N,N-dimethylaminophenyl)oxazolo[4,5-b]pyridine (DMAPOP) were studied in acetonitrile and sodium dodecyl sulphate (SDS). The studies show that the surfactant can formulate the metal ions to bind at a specific binding site. In acetonitrile, the Cu(2+) binds at the dimethylamino nitrogen and pyridine nitrogen to form two different types of complexes with DMAPOP. On the other hand, Cd(2+) coordinates through the dimethylamino nitrogen and oxazole nitrogen to form two different types of complexes with DMAPOP in acetonitrile. But SDS effectively controls the binding site and both metal ions bind at the same ring nitrogen in SDS. The binding affinities of both metal ions with DMAPOP vary with the concentration of SDS. PMID- 23936895 TI - Assessing the subjective and physiological effects of intranasally administered crushed extended-release morphine formulations with and without a sequestered naltrexone core in recreational opioid users. AB - OBJECTIVE: To evaluate the pharmacodynamic (PD) effects of morphine sulfate and naltrexone hydrochloride extended-release (MSN) capsules compared with controlled release morphine sulfate (MS) and placebo when crushed and administered intranasally. METHODS: The present study was a randomized, double-blinded, placebo-controlled, single-dose (30 mg), three-way crossover study in healthy, nondependent recreational opioid users. PD measures included assessment of subjective drug effects using visual analogue scales (VAS) ranging from 0 to 100 and assessments of pupil diameter. Blood samples were collected for pharmacokinetic analyses. RESULTS: Both MS and MSN showed significantly higher PD values compared with placebo. MSN showed significantly lower scores for drug liking and high VAS scores on both mean peak effect (Emax) (69.6 and 55.2, respectively) and in area under the effect curve over 2 h (86.3 and 66.7, respectively) following dosing compared with MS (Emax 87.6 and 86.6, respectively; area under the curve over 2 h 120.6 and 132.9, respectively; P<0.001). MSN showed significantly lower Emax for all other positive subjective effects (good drug effects, overall drug liking, and take drug again VAS scores) compared with MS (P<0.001). Peak minimum pupil diameter was significantly larger for MSN than MS (P=0.002). Mean peak plasma concentration (Cmax) and median time to Cmax for morphine following administration of MSN and MS were similar (27.3 ng/mL and 0.57 h versus 27.7 ng/mL and 0.6 h, respectively). Naltrexone mean Cmax was 1497 pg/mL after MSN and median time to Cmax was 0.55 h. CONCLUSIONS: When crushed and administered intranasally, MSN was associated with significantly lower ratings of drug liking and other positive subjective effects compared with MS. PMID- 23936897 TI - Enhanced pi-frustration in carbo-benzenic chromophores. AB - The synthesis, structure, and absorption spectra of highly pi-frustrated carbo benzenes with indolic enamine substituents more or less directly conjugated to the C18 macro-aromatic core are described, and their peculiar reactivity is analyzed. PMID- 23936898 TI - CO2 switchable dual responsive polymers as draw solutes for forward osmosis desalination. AB - Low molecular weight dual responsive polymers, after purging with CO2, become polyelectrolytes with high osmolality, which can be used as draw solutes for seawater desalination. These polymers precipitate above their Lower Critical Solution Temperature (LCST) after removal of CO2 via purging with inert gas for ease of recovery and reuse. PMID- 23936899 TI - A luminescent and dichroic hexagermane. AB - The hexagermane Pr(i)3Ge(GePh2)4GePr(i)3 has been synthesized and is not only the first such linear oligogermane to be structurally characterized but also is the first such compound to exhibit fluorescence and dichroic properties when observed under different orientations of plane polarized visible light. PMID- 23936900 TI - Atomic selectivity in dissociative electron attachment to dihalobenzenes. AB - We investigated electron attachment to three dihalobenzene molecules, bromochlorobenzene (BCB), bromoiodobenzene (BIB) and chloroiodobenzene (CIB), by molecular beam photoelectron spectroscopy. The most prominent product of electron attachment in the anion mass spectra was the atomic fragment of the less electronegative halogen of the two, i.e., Br(-) for BCB and I(-) for BIB and CIB. Photoelectron spectroscopy and ab initio calculations suggested that the approaching electron prefers to attack the less electronegative atom, a seemingly counterintuitive finding but consistent with the mass spectrometric result. For the iodine-containing species BIB and CIB, the photoelectron spectrum consists of bands from both the molecular anion and atomic I(-), the latter of which is produced by photodissociation of the former. Molecular orbital analysis revealed that a large degree of orbital energy reordering takes place upon electron attachment. These phenomena were shown to be readily explained by simple molecular orbital theory and the electronegativity of the halogen atoms. PMID- 23936901 TI - Electron transfer in proteins: theory, applications and future perspectives. AB - The study of electron transfer (ET) by means of computational techniques has experienced a great development in the last few decades. In particular, understanding the atomic details of its mechanism in complex biological systems is currently possible with a large range of different in silico modelling tools. We review here some theories and representative major contributions to this development. We also underline some of our group's main inputs, focusing on long range and protein-protein electron transfer, and analyse future perspectives. At the end of the article, we emphasize the importance of the basic electron transfer knowledge in the frame of medical and bioengineering applications: mitochondrial therapeutic targets, bioengineering for clean energy, and biosensors. PMID- 23936902 TI - Theoretical modeling of optical properties of Ag8 and Ag14 silver clusters embedded in an LTA sodalite zeolite cavity. AB - Optical properties of silver Ag(n) nanoclusters are demonstrated to be dependent on their size, structure and charge state. It is found that when being contained in the sodalite cavity of LTA zeolite the tetradecanuclear hexacation silver cluster Ag14(6+) is stable. Its lower-lying states and optical spectrum are theoretically determined using the quantum chemical TD-DFT method. Its ground state possesses an outer-shell electron configuration of A1g(2)T2g(6) mimicking the s(2)p(6) valence of noble gas atoms. These frontier orbitals are constructed from 5s,5p(Ag)-AOs with contributions from framework oxygen atoms. Light absorption of Ag14(6+) embedded in the sodalite cage which is characterized by strong peaks centered at 331 and 476 nm (transitions 5s,p(Ag) -> 5s,p(Ag)) leads to much longer wavelength emission. The sodalite cage, as a container, stabilizes the central Ag14(6+) cluster by electrostatic attraction. The absorption spectrum of the isovalent neutral Ag8 cluster embedded inside the same sodalite cavity is also simulated using TD-DFT and CASPT2 methods. This absorption spectrum which is similar to that of the Ag14(6+) cluster has two absorption bands in the near UV and visible regions. PMID- 23936903 TI - Oxygen reduction reaction on stepped platinum surfaces in alkaline media. AB - The oxygen reduction reaction (ORR) in 0.1 M NaOH on platinum single crystal electrodes has been studied using hanging meniscus rotating disk electrode configuration. Basal planes and stepped surfaces with (111) and (100) terraces have been employed. The results indicate that the Pt(111) electrode has the highest electrocatalytic activity among all the studied surfaces. The addition of steps on this electrode surface significantly diminishes the reactivity of the surface towards the ORR. In fact, the reactivity of the steps on the surfaces with wide terraces can be considered negligible with respect to that measured for the terrace. On the other hand, Pt(100) and Pt(110) electrodes have much lower activity than the Pt(111) electrode. These results have been compared with those obtained in acid media to understand the effect of the pH and the adsorbed OH on the mechanism. It is proposed that the surface covered by adsorbed OH is active for the reduction of the oxygen molecules. PMID- 23936904 TI - Molecular dynamics simulation of a DOPA/ST monolayer on the Au(111) surface. AB - In order to study the influence of molecular structure on the formation of a monolayer, two molecules have been considered, namely N-stearoyldopamine (DOPA) and 4-stearyl-catechol (ST). The difference between these two molecules is the amide group in DOPA. By investigating these monolayers at different surface areas per molecule, the molecular configurations of a DOPA/ST monolayer on the Au(111) surface were obtained. We conclude that for both kinds of molecules, the pi interaction between the catechol group and the Au(111) surface is important. Compared to experimental results, the catechol groups are found either parallel or perpendicular to the Au(111) surface in MD simulation. The difference between DOPA and ST systems is that when there are fewer molecules on the Au(111) surface, in the DOPA system, the amount of catechol groups perpendicular with their hydroxyls orienting towards the surface is less than that of the ST system. Further analysis of catechol groups and amide groups indicates that various kinds of hydrogen bonds formed in the DOPA system have a profound influence on the structure and regularity of the monolayer. PMID- 23936905 TI - Conversion reactions for sodium-ion batteries. AB - Research on sodium-ion batteries has recently been rediscovered and is currently mainly focused on finding suitable electrode materials that enable cell reactions of high energy densities combined with low cost. Naturally, an assessment of potential electrode materials requires a rational comparison with the analogue reaction in lithium-ion batteries. In this paper, we systematically discuss the broad range of different conversion reactions for sodium-ion batteries based on their basic thermodynamic properties and compare them with their lithium analogues. Capacities, voltages, energy densities and volume expansions are summarized to sketch out the scope for future studies in this research field. We show that for a given conversion electrode material, replacing lithium by sodium leads to a constant shift in cell potential DeltaE degrees (Li-Na) depending on the material class. For chlorides DeltaE degrees (Li-Na) equals nearly zero. The theoretical energy densities of conversion reactions of sodium with fluorides or chlorides as positive electrode materials typically reach values between 700 W h kg(-1) and 1000 W h kg(-1). Next to the thermodynamic assessment, results on several conversion reactions between copper compounds (CuS, CuO, CuCl, CuCl2) and sodium are being discussed. Reactions with CuS and CuO were chosen because these compounds are frequently studied for conversion reactions with lithium. Chlorides are interesting because of DeltaE degrees (Li-Na)~ 0 V. As a result of chloride solubility in the electrolyte, the conversion process proceeds at defined potentials under rather small kinetic limitations. PMID- 23936906 TI - When a proton attacks cellobiose in the gas phase: ab initio molecular dynamics simulations. AB - Investigations of reaction pathways between a proton and cellobiose (CB), a glucose disaccharide of importance, were carried out in cis and trans CB using Ab Initio Molecular Dynamics (AIMD) simulations starting from optimized configurations where the proton is initially placed near groups with affinity for it. Near and above 300 K, protonated CB (H(+)CB) undergoes several transient reactions including charge transfer to the sugar backbone, water formation and dehydration, ring breaking and glycosidic bond breaking events as well as mutarotation and ring puckering events, all on a 10 ps timescale. cis H(+)CB is energetically favoured over trans H(+)CB in vacuo, with an energy gap larger than for the neutral CB. PMID- 23936907 TI - Using crystallographic shear to reduce lattice thermal conductivity: high temperature thermoelectric characterization of the spark plasma sintered Magneli phases WO2.90 and WO2.722. AB - Engineering of nanoscale structures is a requisite for controlling the electrical and thermal transport in solids, in particular for thermoelectric applications that require a conflicting combination of low thermal conductivity and low electrical resistivity. We report the thermoelectric properties of spark plasma sintered Magneli phases WO2.90 and WO2.722. The crystallographic shear planes, which are a typical feature of the crystal structures of Magneli-type metal oxides, lead to a remarkably low thermal conductivity for WO2.90. The figures of merit (ZT = 0.13 at 1100 K for WO2.90 and 0.07 at 1100 K for WO2.722) are relatively high for tungsten-oxygen compounds and metal oxides in general. The electrical resistivity of WO2.722 shows a metallic behaviour with temperature, while WO2.90 has the characteristics of a heavily doped semiconductor. The low thermopower of 80 MUV K(-1) at 1100 K for WO2.90 is attributed to its high charge carrier concentration. The enhanced thermoelectric performance for WO2.90 compared to WO2.722 originates from its much lower thermal conductivity, due to the presence of crystallographic shear and dislocations in the crystal structure. Our study is a proof of principle for the development of efficient and low-cost thermoelectric materials based on the use of intrinsically nanostructured materials rather than artificially structured layered systems to reduce lattice thermal conductivity. PMID- 23936908 TI - Double vision. PMID- 23936909 TI - Uncertain times. PMID- 23936910 TI - Shades of grey. PMID- 23936911 TI - Adsorption in columns packed with porous adsorbent particles having partially fractal structures. AB - A mathematical model is constructed and solved that could describe the dynamic behavior of the adsorption of a solute of interest in single and stratified columns packed with partially fractal porous adsorbent particles. The results show that a stratified column bed whose length is the same as that of a single column bed, provides larger breakthrough times and a higher dynamic utilization of the adsorptive capacity of the particles than those obtained from the single column bed, and the superior performance of the stratified bed becomes especially more important when the superficial velocity of the flowing fluid stream in the column is increased to accommodate increases in the system throughput. This occurs because the stratified column bed provides larger average external and intraparticle mass transfer and adsorption rates per unit length of packed column. It is also shown that increases in the total number of recursions of the fractal and the ratio of the radii between larger and smaller microspheres that make up the partially fractal particles, increase the intraparticle mass transfer and adsorption rates and lead to larger breakthrough times and dynamic utilization of the adsorptive capacity of the particles. The results of this work indicate that highly efficient adsorption separations could be realized through the use of a stratified column comprised from a practically reasonable number of sections packed with partially fractal porous adsorbent particles having reasonably large (i) total number of recursions of the fractal and (ii) ratio of the radii between larger and smaller microspheres from which the partially fractal particles are made from. It is important to mention here that the physical concepts and modeling approaches presented in this work could be, after a few modifications of the model, applied in studying the dynamic behavior of chemical catalysis and biocatalysis in reactor beds packed with partially fractal porous catalyst particles. PMID- 23936912 TI - Separation and purification of flavonoid from Taxus remainder extracts free of taxoids using polystyrene and polyamide resin. AB - An efficient separation process of flavonoid from Taxus wallichiana var. mairei remainder extracts free of taxoids was developed in this study. AB-8 macroporous resin and polyamide resin offered the fine adsorption capacity, and its adsorption rate at 30 degrees C fitted well to the Langmuir and Freundich isotherms. Resin dynamic adsorption and desorption experiments were conducted to optimize the separation process of total flavonoids from T. wallichiana var. mairei remainder extracts free of taxoids. The optimum parameters for adsorption by AB-8 resin were as follows: (1) the concentration of flavonoids in a sample solution of 5.61 mg/mL with a processing volume of 2 bed volume (BV) (60 mL); (2) for desorption, ethanol-water (80:20, v/v), with 6 BV as an eluent at a flow rate of 2 BV/h. After a one-run treatment with AB-8 resin, the content of flavonoids was increased 5.10-fold from 4.05 to 20.65%. The optimum parameters for adsorption by polyamide resin were as follows: processing volume of 2 BV (30 mL); for desorption, ethanol-water (70:30, v/v), with 8 BV as an eluent at a flow rate of 2 BV/h. After one-run treatment with polyamide resin, the content of total flavonoids increased from 20.65 to 65.21%. The method will provide a potential approach for large-scale separation and purification of flavonoid for its wide pharmaceutical use. PMID- 23936913 TI - Global detection and identification of components from Yunnan Baiyao based on liquid chromatography hybrid ion trap time-of-flight mass spectrometry. AB - Yunnan Baiyao is a widely used herbal prescription in traditional medicine for the treatment of bleeding and hematological diseases, while its chemical profile remains elusive. In this work, a novel methodology combining polarity-directed extraction technique with a diagnostic ion filtering strategy based on LC hybrid ion trap TOF-MS analysis was developed for global, efficient, and rapid characterization of components in Yunnan Baiyao. Di-ethyl ether, n-butanol, and ethanol/water (70:30, v/v) covering low-to-high polarity ranges were chosen as the extraction solvent, respectively. The results clearly showed that, compared with conventional single extraction solvent, collaboratively using extraction solvents with different polarities can effectively increase the number of detected peaks and enrich the product ions information in multistage mass spectra analysis. By further matching diagnostic ions and fragmental pathways, a total of 34 components were successfully identified. Our work clearly demonstrates that integrating polarity-directed extraction and diagnostic ion filtering techniques is a powerful and reliable strategy for global detection and identification of complex chemicalome from herbal prescriptions, and may open new avenues for chemical analysis in other complex mixtures. PMID- 23936914 TI - Simultaneous determination of 11 related impurities in propofol by gas chromatography/tandem mass spectrometry coupled with pulsed splitless injection technique. AB - A variety of related impurities, including starting materials, process impurities, and degradation products, can be detected in propofol. In this article, a sensitive and selective GC-MS/MS method using pulsed splitless injection technique for the determination of 11 main related impurities in propofol in one chromatogram is investigated. This method is extensively validated for its linearity, recovery, precision, LOD, and LOQ, and is able to detect trace-level related impurities (LOD = 0.2-5.6 MUg/g) in propofol bulk drug. Stressed tests proposed that oxidative degradation, photolytic degradation, and heat are the main causes for the formation of degradation products in propofol. PMID- 23936915 TI - Determination of phthalate esters in bottled water using dispersive liquid-liquid microextraction coupled with GC-MS. AB - Dispersive liquid-liquid microextraction method was developed for the determination of the amount of phthalate esters in bottled drinking water samples and dispersive liquid-liquid microextraction samples were analyzed by GC-MS. Various experimental conditions influencing the extraction were optimized. Under the optimized conditions, very good linearity was observed for all analytes in a range between 0.05 and 150 MUg/L with coefficient of determination (R2) between 0.995 and 0.999. The LODs based on S/N = 3 were 0.005-0.22 MUg/L. The reproducibility of dispersive liquid-liquid microextraction was evaluated. The RSDs were 1.3-5.2% (n = 3). The concentrations of phthalates were determined in bottled samples available in half shell. To understand the leaching profile of these phthalates from bottled water, bottles were exposed to direct sunlight during summer (temperature from 34-57 degrees C) and sampled at different intervals. Result showed that the proposed dispersive liquid-liquid microextraction is suitable for rapid determination of phthalates in bottled water and di-n-butyl, butyl benzyl, and bis-2-ethylhexyl phthalate compounds leaching from bottles up to 36 h. Thereafter, degradation of phthalates was observed. PMID- 23936916 TI - Critical appraisal. Dental erosion. PMID- 23936918 TI - A 29 year old woman with acute mental status changes. AB - Moyamoya disease is a rare cerebrovascular disease that causes occlusion of the supraclinoid internal carotid arteries and its branches within the Circle of Willis. While rare in the United States and Europe, moyamoya disease is much more common in eastern Asian populations. We present a 29 year-old Caucasian woman who initially presented with severe mental status changes and ataxia. MRI and MRA imaging, as well as pathologic examination at autopsy, revealed occlusion of the middle cerebral and anterior cerebral arteries bilaterally with associated infarctions. This case underscores the importance considering this diagnosis as an etiologic possibility during the workup of multiple infarcts, even in non Asian populations. PMID- 23936917 TI - 29 Year-old man with new onset seizures. AB - Imaging of a 29-year-old man with seizures showed a frontal lobe mass with curvilinear narrow calcifications, cystic components and multiple flow-voids. An AVM was considered. A DSA confirmed the hypervascular nature of the lesion. It was resected and microscopic examination showed an anaplastic oligodendroglioma remarkable for a diffuse and hypertrophic vasculature with areas of frank vascular proliferation. The marked vascularity seen on the MRI, the gyriform calcifications and the cystic degeneration are all features which can be encountered in an AVM. This case illustrates that highly vascular malignant gliomas can simulate vascular lesions by radiology and may require an angiogram for diagnosis. PMID- 23936919 TI - A 68-year old man with a cerebellopontine angle tumor. AB - We report on a 68-year-old male with a cerebellopontine angle tumor manifesting at the 8th cranial nerve and presenting histopathological features of a rhabdomyoma. A literature review revealed four reports of intracranial nerve rhabdomyoma, all of adult type and including one manifestation at the vestibular nerve. We present the first case of a fetal type extracardiac rhabdomyoma manifesting at a cranial nerve. Although rare, rhabdomyomas must be considered in the differential diagnosis of vestibular schwannomas. PMID- 23936920 TI - Forensic familial searching: scientific and social implications. PMID- 23936921 TI - [Not Available]. PMID- 23936922 TI - [Not Available]. PMID- 23936923 TI - [Not Available]. PMID- 23936924 TI - Response to letter regarding article,"cardiovascular events as a function of serum bilirubin levels in a large,statin-treated cohort". PMID- 23936925 TI - Health policy in the daily newspapers. PMID- 23936926 TI - Bullied and leaving. PMID- 23936928 TI - Mandate safety against needlestick injuries. PMID- 23936927 TI - Re-assess clinical training. PMID- 23936929 TI - Humanitarian policy for immigrant women. PMID- 23936930 TI - Employing legal workers. PMID- 23936931 TI - By whose standard? PMID- 23936932 TI - Telehealth tackles elderly health care. PMID- 23936933 TI - Nurses urged to raise awareness of pap tests. PMID- 23936934 TI - Breaking down the barriers to therapy. PMID- 23936935 TI - Topical nitrates in painful diabetic neuropathy. PMID- 23936936 TI - Work related hypertension. PMID- 23936937 TI - Patient confidentiality. PMID- 23936938 TI - Reply: To PMID 23550254. PMID- 23936939 TI - Maps and arterial roads. AB - It can all look good on the map. The pathway seems clear. You have a system- what can go wrong on the way from here to there? It is only when looking closely - or when trying to work out why you are in the wrong place - that the complexity becomes apparent, and the weaknesses inherent in the system obvious. The road that you planned to take is blocked by an accident, the side street which you then find as a way out is clogged by parked cars, and then everyone decides to use the bus lane to keep more lanes of traffic moving. PMID- 23936940 TI - CT and MRI in tuberculosis. PMID- 23936942 TI - Chronic, non-bacterial prostatitis. PMID- 23936941 TI - Reply: To PMID 23550245. PMID- 23936943 TI - Reply: To PMID 23550248. PMID- 23936944 TI - [A 71 year-old man with progressive dysarthria]. PMID- 23936945 TI - Epidemiology of atrial fibrillation in Turkey: preliminary results in the multicenter AFTER study. PMID- 23936946 TI - Epidemiology of atrial fibrillation in Turkey: preliminary results in the multicenter AFTER study. Author reply. PMID- 23936947 TI - The economics of cancer. PMID- 23936948 TI - Profile of childhood cancers: a multicentric study. AB - The incidence of cancer has been increasing steadily in the developing world including India. Childhood cancers are a special entity with different genetic, environmental factors playing a role in their aetiology. The profiles of cancer incidence reflect the racial, cultural and geographical diversity within populations. This article shows the profile of childhood cancer across three medical college hospitals in the state of West Bengal in India and the data were collected from the period between 2008 and 2011. The results showed leukaemia was the most common cancer affecting children followed by lymphoma and retinoblastoma.The profile of childhood cancers showed wide variation among the age groups. Frequency of retinoblastoma, renal tumours, neuroblastoma and hepatic tumours were higher in children less than five years whereas lymphoma, leukaemia, bone tumours and central nervous system tumours were found more in children above five years. As many of common childhood malignancies are curable there is need to have a dedicated paediatric cancer registry for assessing the magnitude of problem in our country as paediatric cancers show wide variation across centres. PMID- 23936949 TI - Prevalence of known prognostic factors in female breast carcinoma including oestrogen receptor, progesterone receptor and Her-2/neu status--a study in a tertiary care centre. AB - Breast cancer is second most common cancer in Indian women. It is often curable by various treatment modalities when detected in early stage. Prognosis and selection of therapy in breast cancer depends upon various factors including clinical parameters, histopathological subtype and molecular characteristics of primary tumour. The aim of this study was to determine the prevalence of different prognostics factors including immunohistochemical marker ie, oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (Her 2/neu) status in female breast carcinoma in a tertiary care centre. In this study 80 females patients who were found to have carcinoma of breast by fine needle aspiration cytology (FNAC) and consequently confirmed by histopathology were followed up for one year. Immunohistochemical staining for molecular markers like oestrogen receptor (ER), progesterone receptor (PR) and Her-2/neu were done in selected 48 cases. Various clinical parameters, cytopathological and hispathological findings as well as immunohistochemical studies were correlated to know the prevalence of these important prognostic factors. It was found that majority of patients were under 50 years of age group with high parity status. Significant patients had breast lump > 4 cm in size. Infiltrating duct carcinoma not otherwise specified (NOS) was the most common histological type showing predominantly microscopic grade II as per Nottingham's Modification of Bloom Richardson grading system. Immunohistochemistry showed 75% ER positivity, 66.66% PR positivity and 25% Her-2/neu positivity. PMID- 23936950 TI - Knowledge, attitude and practice of smoking in subjects of lung cancer. AB - Lung cancer is the most common cancer in the world since 1988, both in terms of incidence and mortality among both men and women. Approximately half of the cases of lung cancer now occur in developing countries compared to 1980. Tobacco smoking is by far the predominant risk factor for lung cancer. A knowledge, attitude and practice of smoking among 132 cases of lung cancer in this study was undertaken. Amongst 113 ever smokers, out of 132 cases, 91.18% of males and 36.36% of female subjects continued smoking despite knowing the harmful effects of tobacco, displayed over the cigarette or bidi packets. In these group squamous cell carcinoma was the most common type followed by adenocarcinoma. Among the never smokers adenocarcinoma was the commonest type, females accounting for 75% of the cases, though a good number was observed among male ever smokers, signifying the changing histological types of lung cancer today. PMID- 23936951 TI - The effects in correction of anaemia in chronic kidney disease with erythropoietin therapy--preference to cardiovascular, neurologic and general well being of patients from a tertiary care centre. AB - Anaemia, the major sequelae of chronic renal disease (CRD) needs to be investigated because it acts as an independent risk factor for worsening of cardiovascular survival, cognitive impairment and poor quality of life. In this prospective tertiary care hospital-based study we have followed up 100 randomly assigned CRD patients who were not on dialysis for at least 6 months. Left ventricular mass index (LVMI), ejection fraction (EF), mini-mental status examination (MMSE) and general well-being of these patients were assessed quantitatively on admission and at 3rd and 6th months of follow-up after receiving recombinant human erythropoietin (rHuEPO) and aggressive intravenous iron therapy for anaemia correction. The median study duration was 6 years. Statistical analysis also showed the positive impact of anaemia correction which, even when partial, caused significant improvement in cardiovascular function as evidenced by increase in EF (p = 0.004) and decrease in LVMI (p = 0.016) along with substantial enhancement of general well-being (p < 0.001). Cognition did not show significant change within a short spell of 6 months. This study thus emphasises on earliest detection and correction of anaemia in CRD population to enhance both short-term and long-term survival as a whole. PMID- 23936952 TI - Laparoscopic versus open splenectomy in the treatment of idiopathic thrombocytopenic purpura: an Indian experience. AB - Laparoscopic splenectomy (LS) is emerging as the treatment of choice over open splenectomy (OS) in cases of idiopathic (immune) thrombocytopenic purpura (ITP) that is either steroid resistant or steroid unresponsive.The aim of the present study is to compare therapeutic response and outcome of patients with ITP undergoing LS with a similar group undergoing OS.The study was performed on 63 patients with ITP attending Medical College and Hospital, Kolkata, a tertiary level referral centre in Eastern India during 2005-2009.Twenty-seven patients with ITP underwent LS and the rest underwent OS. Twenty-eight patients were steroid resistant whereas the rest were diagnosed to be refractory to steroids. Parameters assessed were demographic characteristics of patients, peri-operative data, complications and haematological outcome.The patients were followed up for a mean period of 40 months. RESULTS: Demographic characteristics of the patients in LS and OS group were comparable. Patients undergoing LS were found to require a longer operative time but had lower intra-operative blood loss, less postoperative pain, decreased incidence of complications, reduced hospital stay and comparable haematological response as compared to that for patients undergoing OS. LS for ITP is a safe technique associated with lower morbidity and faster convalescence and similar haematological response when compared to OS. PMID- 23936953 TI - Ovarian cancer. PMID- 23936954 TI - Results of diagnostic dilemma between lung cancer and sputum negative pulmonary tuberculosis: a retrospective study. AB - Diagnostic dilemma owing to radiological similarities between smear negative pulmonary tuberculosis and bronchogenic lung cancer pose a critical problem of late detection of the later with all its impact on the life of the victims.The aim of the study was to assess the magnitude and consequence of diagnostic dilemma between lung cancer and smear negative pulmonary tuberculosis. The retrospective observational study was conducted in the radiotherapy department of RG Kar Medical College and Hospital, Kolkata, West Bengal involving the lung cancer patients reported from February, 2009 to March, 2011. Out of the 76 lung cancer patients, 39.47% had exposure to anti tuberculosis treatment (ATT) before the actual diagnosis of lung cancer. Significantly higher proportion of rural patients was put on the ATT compared to their urban counterpart. Duration of symptoms before arrival was found significantly more among those who got ATT. Presence of any history of tuberculosis within the family was found to have significant association with the exposure to ATT before diagnosis as lung cancer. So in conclusion the treating physician must think twice before stamping a case as smear negative tuberculosis based on the radiological findings. High index of suspicion should also be maintained during treatment and follow-up of both smear positive and smear negative pulmonary tuberculosis as because the lung cancer may be preceded by or coexist with pulmonary tuberculosis. PMID- 23936955 TI - Profile of colorectal cancer in Eastern India. AB - Although colorectal cancer is a major cause of concern in the western population, recent studies are showing the incidence and mortality of colorectal cancer to be rapidly rising in Asia. The present study is an insight into the epidemiological profile of colorectal cancer of a representative Eastern Indian population. Over a period of three years, all histologically proved patients with colorectal cancer were assessed for age, sex, body mass index, dietary habits, socioeconomic status and stage of disease. Of a total of 168 patients male to female ratio was 1.7:1.The mean age of presentation was 47.01 years. Although colorectal cancer has been known as a disease of sedentary obese men, 41.66% of the patients were from a low socioeconomic rural set-up and 40.47% were involved in heavy physical labour with only 15% of being obese; 62% patients were harbouring a locally advanced disease at the time of presentation. The epidemiological pattern of colorectal cancer in India is different from that of the west as regards to earlier age of presentation, prevalence in low socio economic class with low fat diet and scanty meat intake. PMID- 23936956 TI - Clinical spectrum of dengue fever in a tertiary care centre with particular reference to atypical presentation in the 2012 outbreak in Kolkata. AB - During the summer of 2012, dengue fever epidemic has emerged in Kolkata and spread throughout West Bengal. During the epidemic period, wide spectrum of atypical presentations of dengue fever has been observed. Here, in this study, the spectrum of dengue fever was analysed in 300 patients who were found to have dengue serology positive (NS1, IgM, IgG). The study was done in the department of medicine, RG Kar Medical College, Kolkata. The patients were classified according to age, gender, duration of symptoms on admission, associated comorbidities and coinfections, complications that developed after admission, the final outcome and duration till death after symptoms developed. The dengue fever cases started to appear from April but it attained its peak during August-September this year. All ages were affected but the brunt was borne maximally by those between 15 and 40 years. Females were more affected than males. It may be concluded from the study that 30% had no complications while 70% cases developed complications, 4% cases had underlying comorbidities and coinfections, 68% developed thrombocytopenia and other haemorrhagic features, 55% serositis, 25% acalculous cholecystitis, 20% myocarditis, 15% pancreatitis, 5% had central nervous system involvement, 0.66% rhabdomyolysis and myositis, 0.33% secondary vasculitis and death occurred in 3% cases. More number of patients were having multiple and atypical complications requiring hospitalisation. Mortality was more common in patients with associated comorbidities and coinfection. Awareness, early treatment with aggressive fluid replacement therapy with close monitoring, supportive management andpatient education showed promising results. PMID- 23936957 TI - A clinical study of ischaemic strokes with micro-albuminuria for risk stratification, short-term predictive value and outcome. AB - Stroke results more than 4.3 million deaths worldwide per annum and 85% of all strokes are ischaemic in nature. Besides numerous modifiable and non-modifiable known risk factors, microalbuminuria is thought to be an important marker of global endothelial dysfunction and associated with cardiovascular disease including stroke. Fifty ischaemic stroke cases and 50 (age, sex matched) control subjects were subjected to study to compare and evaluate risk stratification of micro-albuminuria, its predictive value and outcome on day 1 and day 7 among admitted ischaemic stroke cases.The result was found that micro-albuminuria was present in 66% of ischaemic stroke cases compared to only 8% of control group (p < 0.001). Most validated National Institute of Health Stroke Scale (NIHSS) score was used for evaluation and calculation of predictive value and outcome of micro albuminuria positive patient where higher value indicates poor prognosis, and the result was mean NIHSS score 29.12 versus 18.88 between two groups of strokes ie, with and without micro-albuminuria. Out of 50 ischaemic stroke patients 33 (66%) had micro-albuminuria. Among 11 patients who died, 10 (90.9%) had micro albuminuria and NIHSS score was 33.64 and 25.0 on day 1 and day 7. Among 39 patients who were discharged, 23 patients (58.97%) were MA positive and NIHSS score was much less than death group ie, 23.38 and 16.38 on day 1 and day 7 respectively. So this study reveals micro-albuminuria itself results higher risk for ischaemic stroke compared to control group and it shows good predictive value for early assessment of clinical severity and subsequent fatal outcome. This is also simple, cost effective and affordable. PMID- 23936958 TI - A study on blood culture positivity and C-reactive protein variability in neonatal septicaemia at neonatal intensive care unit of a tertiary care hospital. AB - Neonatal septicaemia is an important cause of neonatal morbidity and mortality. Blood culture is the gold standard for diagnosis of neonatal septicaemia. Several laboratory investigations are available to detect neonatal sepsis, one important is 'sepsis screen' which includes C-reactive protein (CRP), micro -ESR, total WBC count including immature to mature (VT) ratio and absolute neutrophil count. Blood culture was done among 210 samples from neonatal intensive care unit (NICU), RG Kar Medical College with suspected septicaemia along with CRP estimation. Among all the parameters, clinical correlation of CRP is significant; 65.2% of patients has blood culture positive. CRP positivity varied in different organisms. CRP is a non-specific acute phase reactant and rises significantly after 12 hours onwards. It can be used as an important parameter in infant at risk of septicaemia (significant > 6 mg/dl) and early institution of antimicrobials therapy. It has got prognostic value. PMID- 23936959 TI - Change of patellar height with age and sex. AB - Patellar height is one of the important parameter in patellar stability. Growth spurt or excessive physical strain can lead to high-riding patella or patella alta. But this is not yet proved. This study was mainly targeted at eliciting the influence of age on Insall-Salvati index, one of the important index to measure patellar height. As the present study is meant for measuring the patellar height separately in male and female, it is also to find out the effect of gender on patellar height if any. The study was been conducted in North Bengal Medical College and Hospital among 93 subjects covering both adult and adolescent age groups. Patellar height of respective subjects was measured radiologically using Insall-Salvati Index; results were extrapolated for statistical analysis. It revealed that value of Insall-Salvati index was higher in adult compared to adolescent group but the difference was not statistically significant. Statistical tests shows no significant difference in Insall-Salvati index according to sex. While screening the athletes patella alta must be kept in mind as this can be associated with patellofemoral pain syndrome, chondromalacia patellae, knees with apophysitis of tibial tubercle (Osgood-Schiatter disease). Not only that, significant cause of recurrent patellar dislocation can be associated with patella alta PMID- 23936960 TI - Giant neurilemmoma of the vagus nerve: a case report and review of literature. AB - Cervical vagal neurilemmomas are rare, usually asymptomatic, slow-growing tumours and defined as a benign, encapsulated neoplasm that arises in the nerve fibre. Magnetic resonant imaging (MRI) plays a central role in diagnosing vagal nerve neoplasm and in fact, provides important pre-operative information useful in planning optimal surgical treatment. A rare case of giant neurilemmoma is presented with a large swelling in the right side of the neck associated with breathlessness and paroxysmal cough. X-ray chest revealed large homogenous opacity in apical area of the right lung extending into the lower neck. MRI revealed a large 6 x 8 x 13 cm soft tissue, well defined mass with lobulated contours on the right side of the neck. The mass was pushing sternomastoid muscle anteriorly and carotid artery was pushed anteromedially. The mass was abutting the brachial plexus and compressing internal jugular vein. The mass was extending into the mediastinum up to the level of carina. The mass was also pushing the vessels in superior mediastinum towards left and was compressing the veins. Tumour was extending posterior to trachea and pushing trachea anteriorly and towards left and also compressing it. There was also erosion of adjacent anterior aspect of the right upper ribs. Subclavian artery was also encased by the mass. Multiple enlarged lymph nodes were seen in right cervical area. A provisional diagnosis of malignant schwannoma of right vagus nerve was made. Cytology from the fine needle aspirate of the right lower Cervical region of the swelling revealed features of neurilemmoma. Complete surgical resection is the treatment of choice with excellent prognosis, as the tumour was benign, and recurrence is nearly unknown, so it is possible and indeed recommended to preserve nerve integrity with careful dissection. PMID- 23936961 TI - Adenoma malignum of the uterine cervix--an enigma. AB - Adenoma malignum is a rare variant of cervical adenocarcinoma which presents a great diagnostic and therapeutic challenge to an oncologist. A 31-year-old woman presented with a mass filling up whole of the vagina which showed no evidence of malignancy by scraping cytology or punch biopsy. But histological examination of the resected mass turned up to be adenoma malignum of the cervix. The patient was subsequently treated by Wertheim's hysterectomy and radiotherapy. PMID- 23936962 TI - A rare anomaly in twin pregnancy--acardiac twin. AB - Twin reversed arterial perfusion syndrome is the extreme manifestation of twin to twin transfusion syndrome. The pathogenesis is thought to be reversed arterial transfusion. Acardiac foetus grossly features severe reduction anomalies particularly of the upper body. Although the acardiac twin is nonviable, it can cause severe obstetric, foetal and maternal complications. Here, one such case of acardiac twin in reported. PMID- 23936963 TI - Anaesthetic management of a patient with motor neuron disease posted for microlaryngeal surgery. AB - Motor neuron disease (MND) typically affects upper and lower motor neurons without any sensory involvement. Regional anaesthesia is preferred in motor neuron disease patients to avoid aspiration and possibility of prolonged postoperative ventilation following general anaesthesia. As microlaryngeal surgery in a motor neuron disease patient needed airway protection, it was decided to perform the surgery under general anaesthesia with awake intubation following airway block and avoiding muscle relaxant agents completely to minimise unnecessary complications. The patient was allowed spontaneous breathing while maintaining anaesthesia and stable haemodynamic condition with combination of anaesthetic and analgesic agents accordingly throughout the operation. PMID- 23936964 TI - Health plans lag providers on molecular profiling. PMID- 23936965 TI - Health coverage lessons from the Greek meltdown. PMID- 23936966 TI - Analyst: pharmacists have nothing to complain about. PMID- 23936967 TI - Aetna joins with providers in private-label health plans. PMID- 23936968 TI - A conversation with Peter Kongstvedt, MD: provider & manufacturer pricing need reform too. PMID- 23936969 TI - Too much health care can be hazardous to your health. PMID- 23936970 TI - 'You talking to me?' Docs and feedback. PMID- 23936971 TI - Do the numbers add up for oral oncology quantity-limit programs? PMID- 23936972 TI - Engaging busy physicians key to improving outcomes. PMID- 23936974 TI - Horizon rolls out exchange for mid-sized companies. PMID- 23936973 TI - Molecular monitoring of response in patients with chronic myeloid leukemia. AB - PURPOSE: To discuss the importance of regular, consistent use of molecular testing to monitor treatment response and minimal residual disease in patients with chronic myeloid leukemia (CML), as recommended in established practice guidelines. DESIGN: This review outlines the efficacy of BCR-ABL1 tyrosine kinase inhibitors (TKIs) in eliciting significant treatment responses in patients with CML; describes the positive effect of achieving molecular responses on long-term outcomes; discusses the importance of regular, consistent molecular monitoring in CML; and highlights issues critical to the implementation of molecular monitoring in routine practice. METHODS: Published literature pertaining to molecular monitoring of the response to BCR-ABL1 TKI therapy for CML was searched and reviewed. RESULTS: BCR-ABL1 TKI therapy for CML can reduce the disease burden to a level detectable only by molecular methods. Although practice guidelines recognize the importance of molecular monitoring of disease PMID- 23936975 TI - Do comparable efficacy & convenient dosing justify Procysbi's extremely high price? PMID- 23936976 TI - Association of MTHFR C677T polymorphism with bone mineral density of osteoporosis in postmenopausal Thai women. AB - BACKGROUND: Osteoporosis and osteopenia is rising with the increase in numbers of postmenopausal women. Methylenetetrahydrofolate reductase (MTHFR), a homocysteine catabolizing enzyme, is involved in the regulation of bone mineral density (BMD). The association between MTHFR C677T polymorphism with osteoporosis in postmenopausal Thai women is hitherto unclear. OBJECTIVE: To investigate the association between MTHFR C677T and BMD in postmenopausal Thai women. MATERIAL AND METHOD: The study subjects consisted of 346 postmenopausal Thai women volunteers. Standard dual-energy X-ray absorptiometry (DXA) was used for measurement of BMD T-score. Restriction fragment length polymorphism (RFLP) analysis was used for measurement of MTHFR C677T polymorphism. RESULTS: In the evaluation of 346 postmenopausal Thai women heterozygous (CT) genotype had a risk of osteopenia than normal control (odds ratio (OR) = 5.66, p < 0.001). BMD T scores at each bone position revealed that heterozygous (CT) genotype had increased risk of osteopenic bones than normal controls at lumbar spines 1, 2, and 4 (OR = 2.48, p < 0.001, OR = 1.98, p = 0.008 and OR = 1.83, p = 0.016 respectively), ward's triangle (OR = 2.08, p = 0.008), and head of radius (OR = 2.95, p = 0.008). CONCLUSION: These results indicate the possibility of using MTHFR C677T polymorphism to identify postmenopausal Thai women at high risk of osteopenia. PMID- 23936977 TI - Cumulative recurrence rates of endometriosis-associated pain after long-term intramuscular depot medroxyprogesterone acetate therapy. AB - OBJECTIVE: To determine the cumulative recurrence rates of endometriosis associated pain after long-term intramuscular depot medroxyprogesterone acetate (DMPA) therapy. MATERIAL AND METHOD: Sixty-one patients with symptomatic endometriosis, who had been treated with DMPA for 15 months and were satisfied with the treatment, were included in the present study. Telephone questionnaires were used to collect information including pain recurrence. Medical records were reviewed to obtain more information. Estimates of cumulative recurrence rates of pain were calculated using the Kaplan-Meier technique and estimates of risk were computed using the Cox proportional hazards models. RESULTS: The cumulative recurrence rates of pain after DMPA treatment were 18%, 28%, 41%, 46%, and 50% at months 12, 24, 36, 48, and 60, respectively. Age > 30 years (hazard ratio = 4.40 [95% CI, 1.45-13.37]; p = 0.009), moderate to severe stages of endometriosis (3.02 [1.30-7.03]; p = 0.010), and severe pain prior to treatment (7.80 [1.02 59.61]; p = 0.048) were found to be independent risk factors for the recurrence of pain. CONCLUSION: Half of the patients had recurrent pain five years after DMPA treatment ended. PMID- 23936978 TI - Prevalence of urinary incontinence during the late third trimester and three months postpartum period in King Chulalongkorn Memorial Hospital. AB - OBJECTIVE: To assess prevalence of Urinary Incontinence (UI) during the late third trimester and three months postpartum period in King Chulalongkorn Memorial Hospital. MATERIAL AND METHOD: The present study population comprised > or = 36 weeks singleton pregnant women attending the ANC at King Chulalongkorn Memorial Hospital between 2009 and 2010. Questionnaire was developed from International Continence Society Questionnaire, which consisted of two parts, (1) socioeconomic demographic, characteristics related to UI, and (2) obstetric characteristic, UI experienced after delivery. Validity and reliability of the questionnaire were tested (Cronbach's alpha = 0.8). Chi-square, t-test, Pearson correlation McNemar test, and Binary logistic regression were used for comparison. RESULTS: The majority of the participants (93.8%) were aged between 20 and 39 years old. The prevalence of UI during late pregnancy and three months postpartum were 53.8% and 7.8%, respectively. This difference reached statistical significance (p < 0.001). There were 53.5% of stress UI, 20% of urge incontinence, and 7.8% of mixed type UI during late third trimester, whereas only stress UI was found in three months postpartum period. The only risk factor for late antenatal and early postpartum UI was high pre-pregnancy BMI (OR 2.3; 95% CI 1.38-3.85, p < 0.001 and OR 3.3; 95% CI 1.8-6.0, p < 0.001, respectively). CONCLUSION: The prevalence of UI was quite high during the late third trimester (53.8%) and decreased significantly three months postpartum (7.8%). Pre-pregnancy BMI is the only risk factor for developing UI in late antenatal and early postpartum period. This may help obstetricians for prediction and prevention of UI during pregnancy and postpartum in high-risk group. PMID- 23936979 TI - Comparison of long-term outcome of patients with Wilson's disease presenting with acute liver failure versus acute-on-chronic liver failure. AB - OBJECTIVE: Wilson's disease (WD) is an inherited disorder of copper metabolism, leading to hepatic and neuropsychiatric manifestations. The long-term outcome of patients with Wilson's disease presenting with acute liver failure (ALF) versus those with acute-on-chronic liver failure (ACLF) has not been well documented. The authors' aimed to compare the clinical presentations and long-term outcome after standard treatments between patients with ALF versus those with ACLF. MATERIAL AND METHOD: The authors performed a retrospective review of 39 patients with Wilson's disease, at the King Chulalongkorn Memorial Hospital between January 2003 and December 2011. Primary outcome of the present study was liver complications or deaths from any cause. ACLF was defined as an acute hepatic insult in patients with previously diagnosed or undiagnosed chronic liver disease, whereas ALF was defined as an occurrence in the absence of any preexisting liver disease. RESULTS: Twenty-two of 39 patients (56.4%) presented predominantly with hepatic symptoms with the mean duration of follow-up of 7.7 +/ 8.5 years. Ten of them (45%) presented with ALF, whereas 12 patients (55%) presented with ACLF. Patients with ALF showed a significantly earlier age of onset of presenting symptoms than those with ACLF (15.4 +/- 4.5 vs. 28.1 +/- 13.0 years; p < 0.05). The mean baseline of 24-hour urinary copper in patients with ALF was higher than those found in ACLF (1,645 +/- 1,406 vs. 441 +/- 434 mg/day; p < 0.05, respectively). Fourteen patients (63.6%) improved with supportive care and chelating agents. No significant difference of clinical improvement was found between patients presented with ALF and ACLF (80% vs. 50%; p = 0.19). By using the survival analysis, the mean duration time to liver complications or all cause of death in patients with ALF was significantly longer than those with ACLF (16.2 +/- 2.3 years vs. 8.5 +/- 3.2 years; p = 0.012) as well as higher cumulative percent of free a period from liver complication or death during a 9-year period (80% vs. 21%, p = 0.012). CONCLUSION: Patients with Wilson's disease presenting with acute-on-chronic liver failure manifested symptoms later and had more liver complications than patients with acute liver failure, as well as a lower cumulative free period from liver complication or death. PMID- 23936980 TI - Predictors of in-hospital mortality in acute decompensated heart failure (Thai ADHERE). AB - BACKGROUND: Heart failure had emerged as a major public health problem and became the leading cause of hospitalization. The Acute Decompensated Heart Failure National Registry (ADHERE) of US patients hospitalized with a primary diagnosis of acute decompensated heart Failure (ADHF) had been reported worldwide for the risk stratification and predicting In-hospital mortality. OBJECTIVE: Identify clinical risk factors or treatment procedures that could predict In-hospital mortality in Thai patients with ADHF. MATERIAL AND METHOD: Thai ADHERE is a multicenter, observational, prospective study. The data were collected via web based electronic data capture and analyzed. Two thousand forty one hospitalization episodes involving 1,671 patients in the 18 participating hospitals between March 2006 and September 2007 were analyzed. All clinical factors associated with In-hospital mortality identified by univariated analysis were further analyzed by Logistic regression model. RESULTS: One hundred thirteen patients died during the hospitalization period with overall mortality rate of 5.5%. Systolic blood pressure < 90 mmHg, creatinine > 2.0 mg/dL, history of stroke/TIA, and NYHA class IV were independent risk factors for In-hospital mortality with adjusted OR (95% CI) = 3.45 (1.77-6.79), 1.99 (1.30-3.05), 1.85 (1.11-3.08) and 1.69 (1.08-2.64) respectively. Hypertensive cause of CHF, prior use of lipid lowering drug, and hemoglobin level were associated with lower risk, adjusted OR (95% CI) = 0.35 (0.15-0.81), 0.51 (0.34-0.78) and 0.90 (0.82-0.98) respectively. CONCLUSION: The clinical predictors for In-hospital mortality of Thai ADHERE that associated with worse outcome were systolic blood pressure < 90 mmHg, creatinine > 2.0 mg/dL, history of stroke/TIA, and NYHA class IV. Hypertensive cause of CHF, prior use of lipid lowering drug, and hemoglobin were associated favorable outcome. PMID- 23936981 TI - Rapid recovery time of hemoglobin level in female regular blood donors with ferrous fumarate and high dose of ascorbic acid supplement. AB - BACKGROUND: Iron deficiency anemia has occurred more frequently in female than male regular blood donors. Iron supplement is necessary for maintaining the hemoglobin level. A combination with ascorbic acid increases the absorption of iron. OBJECTIVE: Compare the effect of ferrous fumarate 200 mg/day and the combination of ferrous fumarate 200 mg/day with ascorbic acid 100 mg/day and 500 mg/day on hemoglobin level and red blood cell indices in female regular blood donors. MATERIAL AND METHOD: Female regular blood donor volunteers were randomly divided into three equal groups to supplement with each regimen for one month. Hemoglobin (Hb), MCV, MCH, and MCHC before and after blood donation at 0.5, 1, 2, and 3 months, were compared. RESULTS: Ninety-six volunteers were included and equally divided into three groups of 32 volunteers each. There were no significant differences between age, BMI, ABO blood group, Rh, Hb, MC, MCH, and MCHC before blood donation between each group (p > 0.05). The duration of recovery times of Hb to before blood donation levels in group I, II, and III being 2, 3, and 1 month, respectively were statistically significant difference (p < 0.001). The duration of recovery times of MCV, MCH, and MCHC to before blood donation levels in both group II and III were similar (0.5 months in every value), which was more rapid than in group I (> 3, 3, and 1 month, respectively) with statistically significant difference (p < 0.001). All three groups tolerated well. No participant withdrew from the present study because of side effects. CONCLUSION: The present study shows that a combination of ferrous fumarate 200 mg and ascorbic acid 500 mg per day accelerates timing of hemoglobin and red blood cell indices in recovery to the level of before blood donation in female regular blood donors. PMID- 23936982 TI - Accuracy of transcutaneous bilirubin measurement in term newborns. AB - OBJECTIVE: 1) To evaluate the accuracy of transcutaneous bilirubin (TcB) compared with serum bilirubin (TsB) in full-term infants, 2) To compare the accuracy of TcB reading from two, three, and four measurements and, 3) To compare the accuracy of TcB measured at the forehead and sternum. MATERIAL AND METHOD: Full term infants who were diagnosed neonatal jaundice and underwent blood tests for TsB were eligible for enrollment. Infants who were born at gestational age less than 37 weeks, unstable, previously received phototherapy, or exchange transfusion were excluded. TcB was measured at forehead and sternum two, three, and four times at each site. TcB measurements were done within 30 minutes before or after blood sampling for TsB. RESULTS: The authors obtained 294 paired TcB-TsB from 257 full-term infants. TsB ranged from 1.60 to 21.18 mg/dL (mean 11.03, SD 2.73). The correlation coefficients between TcB at forehead and TsB were significant for two, three, and four measurements (r = 0.812, 0.800, and 0.800 respectively). TcB measured at sternum also had significant correlation with TsB (r = 0.829, 0.844, and 0.823 for two, three, and four measurements). TcB tended to underestimate TsB. Measurements at the sternum seemed to have better correlation with TsB than at the forehead. CONCLUSION: TcB has good correlation coefficient to TsB. Two measurements have enough accuracy to estimate TsB level and measurement at the sternum gives better correlation with TsB than at forehead. PMID- 23936983 TI - Apparent diffusion coefficients in evaluation of pediatric brain tumors. AB - BACKGROUND: MRI, which has high sensitivity in brain tumor detection, cannot reliably determine tumor grading or histology. Diffusion-weighted imaging and apparent diffusion coefficients (ADCs) provide information of tumor cellularity that can correlate with grading. OBJECTIVE: To investigate ADCs in differentiation low-grade from high-grade pediatric brain tumors. MATERIAL AND METHOD: Preoperative MRI, DWI, and ADC images of pediatric patients with pathologically proven brain tumors were retrospectively reviewed at a university hospital in two-year periods and classified into low-grade and high-grade categories. Regions of interest were placed manually at the center and periphery of the solid tumor regions, then ADC values were calculated at "b" values = 0, 1000 sec/mm2. RESULTS: The ADC values were calculated in 15 patients, which included 12 males and three females with an age range from three to 14 years. Seven and eight were with low- and high-grade tumors respectively. The ADC values of low-grade tumors were markedly higher than those of high-grade tumors with statistically significant differences by all methods of measurements at the central peripheral, and average areas on Man-Whitney U test, with p-values of 0.037, 0.009, and 0.021, respectively. CONCLUSION: MRI with ADCs for preoperative pediatric tumor evaluation may be useful for predicting tendency of tumor grading and surgical planning. PMID- 23936984 TI - Incidence of recurrent wheezing in under 5-year-old human bocavirus infection during one year follow-up. AB - BACKGROUND: Human bocavirus (HBoV) is a newly identified virus that can cause acute wheezing in young children. The present study aimed to evaluate the incidence and factors associated with recurrent wheezing during 1 year after HBoV lower respiratory tract infection (LRI). MATERIAL AND METHOD: Children younger than 5 years old who were admitted to King Chulalongkorn Memorial Hospital between February 1, 2006 and September 30, 2008 due to LRI were recruited. Their nasopharyngeal aspirates were evaluated for respiratory virus by polymerase chain reaction (PCR) assays. Those who had positive PCR for HBoV and had no underlying diseases were studied. Their clinical presentations were evaluated and their clinical data about recurrent wheezing as well as pulmonary function tests were followed-up for 1 year. RESULTS: Fifteen patients with HBoV-LRI were regularly followed-up. Seven patients (47%) had co-infection with other respiratory viruses. Generalized wheezing was the most common lung sign detected in 73% of cases (11 cases) and 36% (4 cases) of them responded well to bronchodilators. During one year follow-up, serial pulmonary function tests were normal in all cases and most patients were doing well. However 27% of HBoV infected patients (4 cases) developed recurrent wheezing associated with respiratory tract infections. Two of them had to be re-hospitalized. Compared to patients without recurrent wheezing, eosinophil count tended to be higher in those with recurrent wheezing and isolated HBoV infected patients tended to develop recurrent wheezing more than those with co-infection. CONCLUSION: Acute wheezing is a common presenting lung sign in HBo V-LRI. Although the pulmonary function tests of all patients were normal, more than a quarter of patients suffered from recurrent wheezing during one-year follow-up. PMID- 23936985 TI - Lower prevalence of atopic dermatitis in breast-fed infants whose allergic mothers restrict dairy products. AB - OBJECTIVE: To study the prevalence of atopic dermatitis in exclusively breast-fed infants of allergic mothers who were placed either on liberal diets or on dairy product-restricted diets. MATERIAL AND METHOD: Infants aged 0 to 4 months old, who were exclusively breast-fed and whose mothers had a history of allergic disease, were the subjects of the present study. The mothers were randomized into two groups; mothers in a control group were on liberal diets, while mothers in an intervened group were on dairy product-restricted diets. Infants of both groups were examined for atopic dermatitis at seven days, one month, and four months of age. RESULTS: There were 32 and 30 infants in the control and intervened groups, respectively. Eight infants in the control group and two infants in the intervened group developed atopic dermatitis by the age of four months. The prevalence of atopic dermatitis in the intervened group was significantly lower than that in the control group (6.67% vs. 25%, p < 0.05). CONCLUSION: Dairy product restriction in allergic mothers results in decreasing prevalence of atopic dermatitis in 4-month-old infants who were exclusively breast-fed. PMID- 23936986 TI - Cardiac trauma: has survival improved? A university hospital experience in Bangkok, Thailand. AB - BACKGROUND: Cardiac trauma, if not recognized and properly treated, will lead to a fatal outcome. For the past 16 years, the authors' policy for diagnosing and treating cardiac trauma has not changed but the survival rate in our institute has improved when compared between the two cohorts. OBJECTIVE: Study the factors for survival in patients with cardiac trauma. MATERIAL AND METHOD: Data was collected from chart review between September 1994 and April 2010. Patients presenting in extremis with suspected cardiac trauma will receive emergency room thoracotomy. Patients with equivocal Focused Assessment with Sonography for Trauma will receive formal transthoracic echocardiography. If still in doubt, the authors' policy will proceed with intra operative subxiphoid window and a set up for median sternotomy. RESULTS: Throughout the study period, 44 patients had cardiac trauma and the overall mortality rate was 13.6%. Four patients had blunt injury resulting in one ventricular septal defect and three ruptured right atrium. Right ventricle was injured the most 44%, right atrium 23%, left ventricle 20%, left atrium 2%, one patient had superior vena cava injury, and another patient had inferior vena cava injury. In this cohort, 30% underwent emergency room thoracotomy. Associated injuries were presented in 38% of cases. CONCLUSION: High index of suspicion and prompt management for cardiac trauma should be considered in patients presenting with injuries to the chest, which has been the authors' policy for the past 16 years. The mortality rate had dropped from 26% to 4% but is not statistically significant. PMID- 23936987 TI - Comparison of fixed bearing and mobile bearing total knee arthroplasty using identical femoral component. AB - BACKGROUND: The theoretical advantages of Mobile bearing (MB) prosthesis does not appear to be documented in terms of functional outcomes compared to Fixed bearing (FB) designs. Rarely that two identically designed knee prostheses were compared in the literature. OBJECTIVE: Compare clinical and functional results of MB and FB prostheses using identical femoral components at intermediate term follow-up. MATERIAL AND METHOD: Total knee arthroplasties (TKA) performed between January 2004 and December 2006 at Nopparat Rajatanee hospital were retrospectively reviewed. The American Knee Society scoring system and functional score were used for outcome measurement. RESULTS: There were 102 and 103 patients in FB and MB group respectively. At the average follow-up of 75 months for FB and 73 months for MB group, the knee scores and functional scores of both groups had obviously improved from the preoperative period. However no statistically significant differences were noted between the two groups. One patient in the MB group developed infected loosening 5.1 years after the operation and had two stages revision successfully done. CONCLUSION: MB prosthesis has no clinical advantage over FB at intermediate term follow-up despite using identical femoral component. PMID- 23936988 TI - Health-related quality of life in Thai patients with obstructive sleep disordered breathing. AB - OBJECTIVE: To assess the health-related quality of life (HRQOL) of Thai patients with obstructive sleep disordered breathing (OSDB) and their responses to continuous positive airway pressure (CPAP) treatment. MATERIAL AND METHOD: Thirty eight healthy volunteers, 35 primary snorers (PS), and 108 patients with obstructive sleep apnea (OSA) diagnosed with polysomnography (PSG) were asked to fill questionnaires including Thai version of Short Form-36 (SF-36), and Epworth sleepiness scale (ESS). Thirty-two subjects with OSA who had been using CPAP adequately were asked to complete SF-36 twice, before and three months after treatment initiation. RESULTS: The role-physical and general health dimensions of SF-36 in OSA patients and PS were significantly lower than healthy volunteers (p < 0.05). Other dimensions were not significantly different among groups of subjects. Nonetheless, the scores in all dimensions of SF-36 in OSA patients were lower than those of general population of Thailand, except for mental health. There were only weak but significant correlations between physical function, role physical, general health, vitality, and role-emotional dimensions and ESS scores (r = 0.17-0.29). Most of PSG parameters, particularly apnea-hypopnea index, did not correlate with SF-36 scores except for a weak correlation between mean oxygen saturation and role-physical, mental health, and vitality dimensions. However there was a significant improvement in all dimensions of SF-36 after three months of adequate CPAP therapy (p < 0.01). CONCLUSION: Thai patients with OSDB had poorer HRQOL compared to healthy subjects and general population at least in some dimensions, and an effective CPAP use can improve them. However there was almost no relationship between HRQOL and PSG findings. PMID- 23936989 TI - Evaluation of standard liver volume in adult Thai population using CT volumetric measurement. AB - OBJECTIVE: 1) to assess the various existing formulas and the simple, diameter base equation for calculation of standard liver volume (SLV) in a Thai population, using CT volumetric measurement (CTV) as gold standard. 2) to develop a new formula for calculation of SLV in a Thai population. MATERIAL AND METHOD: Liver volume of 117 patients who underwent abdominal MDCT for various indications was measured, using CTV. Correlation between CTV and calculated liver volume, acquired from the simple, diameter-base equation and six previously reported formulas, were analyzed. The new formula correlating body weight (BW) or body surface area (BSA) to the measured liver volume from CTV were established using regression analysis. RESULTS: All existing formulas offer fair to moderate agreement with the measured liver volume from CTV with intra-class correlation (ICC) ranging from 0.280 to 0.576. BW was found to correlate with the measured liver volume from CTV more closely than BSA, then the new formula based on BW was constructed; 21.127 x BW (kg). However our new formula still has only moderate agreement with measured liver volume from CTV (ICC = 0.598). Liver volume calculated from simple, diameter-base equation offer very strong agreement with the measured liver volume from CTV (ICC = 0.829). CONCLUSION: All formulas based on BW and BSA offer only fair to moderate agreement with measured liver volume CTV, which can lead to high degree error in liver volume estimation. The present study supports that liver volume can be more accurately estimated on CT scan using simple, diameter-based equation. This simple, reproducible method can be used as a good alternative for liver volume calculation. It is particularly useful in case where there is no Digital Imaging and Communications in Medicine (DICOM) data or dedicated 3D software with volumetric measurement application available. PMID- 23936990 TI - Ultrasound predictors of thyroid cancer. AB - OBJECTIVE: To identify ultrasound (US) features associated with cancer in thyroid nodules. MATERIAL AND METHOD: During a two and a half-year period, medical charts, US images, and pathological findings in 629 consecutive patients with thyroid nodules who underwent US examination as well as fine needle aspiration biopsy (FNAB) or surgical excision or both were retrospectively reviewed. Clinical and US findings associated with thyroid cancer were identified using statistical models. RESULTS: Unequivocal cytological or pathological findings were available for 578 patients. Forty-eight patients (8%) had thyroid cancer. Independent clinical and US features associated with thyroid cancer included younger age, symptoms other than palpable mass, solid nodules, fewer number of nodules, presence of calcifications, and enlarged cervical lymph nodes. The combination of all these features was most specific for the diagnosis of thyroid cancer. The absence of all these features could rule out all thyroid cancers. CONCLUSION: The risk of the thyroid cancer in patients with thyroid nodules could be estimated by using relevant clinical and US features. PMID- 23936991 TI - Cognitive enhancement effects of Bacopa monnieri (Brahmi) on novel object recognition and NMDA receptor immunodensity in the prefrontal cortex and hippocampus of sub-chronic phencyclidine rat model of schizophrenia. AB - BACKGROUND: Cognitive impairment is a common characteristic in schizophrenia that cannot be attenuated by antipsychotics. Brahmi, popularly known as a cognitive enhancer might be a new frontier of cognitive deficit treatment in schizophrenia. OBJECTIVE: To study effects of Brahmi on attenuation at cognitive deficit and cerebral glutamate/N-methyl-D-aspartate (NMDA) receptor density in sub-chronic phencyclidine (PCP) rat model of schizophrenia. MATERIAL AND METHOD: Rats were administered PCP or vehicle. Half of the PCP-group was treated with Brahmi. Discrimination ratio (DR) representing cognitive ability was obtained from novel object recognition task. NMDA immunodensity was measured in prefrontal cortex, striatum, cornu ammonis fields 1 to 3 of hippocampus (CA1-3), and dentate gyrus (DG) using immunohistochemistry. RESULTS: DR in PCP-group was significantly decreased compared with control. This occurred alongside NMDA up-regulation in prefrontal cortex and CA1-3, but not in striatum and DG. PCP with Brahmi showed a significant increase in DR score compared with PCP alone. This occurred alongside significant decrease in NMDA immunodensity in prefrontal cortex and CA1-3. No significant difference in cerebral NMDA immunodensity was observed between PCP with Brahmi and control. CONCLUSION: Cognitive deficit observed in PCP administered rats was mediated by NMDA up-regulation in prefrontal cortex and CA1 3. Interestingly, Brahmi could recover this cognitive deficit by decreasing NMDA density in these brain areas to normal. PMID- 23936992 TI - Polyhydramnios, an unusual complication in pregnancy with hyperreactio luteinalis: a case report. AB - Reports of hyperreactio luteinalis in a spontaneously conceived pregnancy are uncommon. Hyperreactio luteinalis complicated by polyhydramnios without an identifiable cause has never been reported. The authors report a case of a 25 year-old, gravida 4, para 2-0-1-2, 16-week pregnant woman who presented with bilateral ovarian enlargement. The beta-human chorionic gonadotropin hormone was at a normal level. An exploratory laparotomy with biopsy was performed at 17 weeks of gestation. Polyhydramnios without an identifiable cause was detected at 30 weeks of gestation. A full-term healthy baby was delivered. Intrapartum and postpartum were unremarkable and both ovaries spontaneously regressed. PMID- 23936993 TI - Tuberculosis of middle ear and mastoid. AB - OBJECTIVE: Review clinical manifestations, investigation, and treatment of tuberculosis of the middle ear. MATERIAL AND METHOD: A retrospective review of six cases diagnosed as tuberculosis of the middle ear at a tertiary referral center was included in the present study. The outcome measures were history, clinical manifestations, investigation, and treatment were reviewed in the medical records. RESULTS: The authors retrospectively reviewed data of our patients diagnosed as tuberculosis of the middle ear. It has been found that the most common manifestation is chronic otorrhea. Investigations are variable such as histopathology, tissue culture, or polymerase chain reaction for identification of tuberculosis. Treatment is mainly medication, however, surgery is considered for histopathology in selected cases. CONCLUSION: Tuberculosis of the middle ear is a rare disease that requires high index of suspicion for diagnosis due to the variety of clinical manifestations. Identification of tuberculosis is a key for diagnosis and treatment. PMID- 23936994 TI - Primary prevention of dementia: focus on modifiable risk factors. AB - BACKGROUND: Dementia will inevitably increase in the aging world. Moreover there is no cure for dementia. Therefore, primary prevention is very important. There are several factors possibly and/or certainly influencing dementia risk including non-modifiable and modifiable risk factors. There are evidences that the risk of developing dementia may be reduced by modifiable risk factors. LIFESTYLE FACTORS: The strategies are to encourage regular physical and mental exercise in midlife and in late-life. Those include cognitive activity and higher education, mentally demanding occupations or participation in mentally challenging leisure activities, being more socially active, a diet that is low in saturated fat, a diet with lots of fruits and vegetables, smoking cessation, and prevention of head injury, with loss of consciousness. Chronic disease factors: The strategies are to prevent high blood pressure, especially at midlife, diabetes, high serum cholesterol, especially at midlife, and depression or high depressive symptoms. CONCLUSION: It is important to develop a systematic public-health strategy and research specific to primary prevention of dementia in Thailand with the evidence based medicine. PMID- 23936995 TI - School nurses--supporting education, advancing student health. PMID- 23936996 TI - Reducing the risks of delegation: use of procedure skills checklists for unlicensed assistive personnel in schools, Part 1. AB - School nurses are challenged by federal civil rights laws and the standards of school nursing practice to care for a burgeoning population of students with special health care needs. Due to the realities of current school nurse-to student ratios, school nurses are frequently responsible for directing unlicensed assistive personnel (UAPs) to support the health and safety needs of students, where State Nurse Practice Acts, state legislation, and local policy mandates allow. The delegation of health care tasks to UAPs poses many professional, ethical, and legal dilemmas for school nurses. One strategy to reduce the risks of delegation is through the use of procedure skills checklists, as highlighted by the experience of one large urban school district. Part 1 of this two-part article will explore the scope of the problem and the principles of delegation, including legal and ethical considerations. PMID- 23936997 TI - NASN endowment fund: the future is now! PMID- 23936998 TI - Innovative solutions for mandated vision screenings. PMID- 23936999 TI - Science translated into practice: implementing practice change based on the best evidence. PMID- 23937000 TI - Emergency preparedness: school nurses leading the way. AB - Nurses are trained to think in terms of the nursing process, which encompasses the five steps of assessment, diagnosis, outcomes/planning, implementation, and evaluation. Cities and towns have developed emergency plans based on the "all hazards" approach. School district plans are also formulated based on the all hazards approach of hazard mitigation, preparedness, response, and recovery, which mirrors the nursing process. Individual school efforts focus on thesefourprinciples to facilitate development of a comprehensive plan for each school. Utilizing the principles of education, collaboration, resource utilization, leadership, and advocacy throughout the evolution of an updated and functional plan allows for an inclusive and adaptable plan. Like the nursing process, these steps are not separate and distinct, but a continuous process. PMID- 23937001 TI - Moving forward a focus on NASN priorities: 2013 annual highlights report. AB - For the 3rd consecutive year the July issue of NASN School Nurse has published this NASN Annual Highlights Report. This 2013 report emphasizes current NASN priorities, discussing the updated strategic plan and providing insight into the accomplishments and strengths of our organization. Carolyn Duff the newly installed NASN president, and Donna Mazyck, NASN executive director collaborated to provide information of significance to NASN membership and stakeholders through the use of an interview format. As always, we encourage members to connect with NASN through a variety of formats outlined in the member center on our website (www.nasn.org). PMID- 23937002 TI - Education, licensure, and certification of school nurses: position statement. AB - It is the position of the National Association of School Nurses (NASN) that every school-age child deserves a school nurse who has a baccalaureate degree in nursing from an accredited college or university and is licensed as a registered nurse through the state board of nursing. These requirements constitute minimal preparation needed to practice at the entry level of school nursing (American Nurses Association [ANA] & NASN, 2011). Additionally, NASN supports state school nurse certification, where required, and promotes national certification of school nurses through the National Board for Certification of School Nurses. PMID- 23937003 TI - Legalization of marijuana: NASN consensus statement. PMID- 23937004 TI - [Cochlear implantation in patients with auditory neuropathy assisted by intra operative EABR and the therapeutic effect evaluation]. AB - OBJECTIVE: To evaluate the pathological position of auditory neuropathy and investigate the hearing and speech rehabilitation results of cochlear implantation in patients with auditory neuropathy. METHOD: In our hospital, among the patients received cochlear implantation, 8 cases with auditory neuropathy were selected, and 8 cases of non-auditory neuropathy patients with profound deafness were selected as matched control group with the background close to the study group. The preoperative hearing data of these two groups were retrospectively analyzed. During operation, the homemade stimulation electrodes were inserted to test the electric evoked auditory brainstem response(EABR) for assessing the auditory pathway; EABR and neural response telemetry(NRT) were tested after implantation, and T, C value were acquired 1 month later. CAP, SIR and speech recognition rate were used to assess hearing and speech rehabilitation effect 12 months after booting. RESULT: Intra-operative EABR wave can be derived in 8 cases of auditory neuropathy, but the wave pattern exhibited variations compared with normal wave. It needed increased stimulation or adjusted parameters, with variable V latency. After cochlear implantation, the waveforms of NRT and EABR were similar between the two groups, and the post-operative V waveform was close to the intra-operative EABR. 8 pairs of patients can present listening response after booting. There was no statistically significant difference in T, C value, CAP (6.50 +/- 0.94 and 6.90 +/- 0.77) and speech recognition rate (85.00% +/- 11.66% and 89.50% +/- 9.02%) between the auditory neuropathy group and the control group 1 year after booting. CONCLUSION: Pre operative EABR can be used as an effective tool to assess the auditory pathway of auditory neuropathy patients, improving the pre-operative examination and helping with selecting the suitable cochlear implant patient. Cochlear implantation can help patients with auditory neuropathy to improve hearing and speech. PMID- 23937005 TI - [The impact of malleus processing in ossicular chain reconstruction on the therapeutic effect in patients with tympanosclerosis]. AB - OBJECTIVE: To investigate the effect of different malleus treatments on the postoperative efficacy in the tympanosclerosis patients receiving ossicular chain reconstruction. METHOD: Fifty-nine patients (62 ears) with tympanosclerosis were treated by ossicular chain reconstruction. All the patients were divided into three groups, including malleus removal group (A, 24 ears), retaining only the malleus handle group (B, 18 ears) and the intact malleus group (C, 20 ears). All the patients were followed up 3 months pre-operation, 3 months and 1 year post operation by audiometric measurement (the average hearing threshold at 0.5, 1.0, 2.0 kHz HI). Tympanic membrane was examined by ear endoscope. RESULT: The pre operation mean air bone gap (ABG) in these groups were 40.07 +/- 77.56 dB, 37.31 +/- 76.45 dB, and 36.75 +/- 76.72 dB, among which the difference had no statistical significance (P > 0.05). At 3 months after operation, the ABG in all cases was improved at 0.5, 1 and 2 kHz. The difference of ABG improvement among these three groups had no statistical significance (P > 0.05). One year after surgery, the ABG of the three groups were decreased by 17.92 +/- 9.28 dB, 16.76 +/- 5.19 dB and 10.58 +/- 7.38 dB respectively. The hearing improvement in group C is less than the other two groups (P = 0.03, P = 0.016). The difference of hearing improvement between group A and group B had no statistical significance(P > 0.05). Group A and group B each have one case of tympanic membrane perforation and artificial ossicle falling off. CONCLUSION: The operating processes of malleus in ossicular chain reconstruction of patients with tympanosclerosis were introduced. In terms of short-term efficacy, the three groups showed no significant difference. However, the long-term efficacy of the patients in the group A and group B were better compared with the group C. PMID- 23937006 TI - [To analyse the impact of tinnitus loudness and hearing loss on the life of tinnitus patient]. AB - OBJECTIVE: To analyse the impact of tinnitus loudness, tinnitus frequency, hearing loss, tinnitus subjective loudness on the life of tinnitus patient. METHOD: To inspect the 154 tinnitus patients with pure tone audiometry, tinnitus matching, tinnitus classification questionnaire and THI scale. This study applies THI scale to evaluate the impact of tinnitus on the life of tinnitus patient. Using statistical methods to analyse the relationship between tinnitus loudness, tinnitus frequency, hearing loss, tinnitus subjective loudness and the impact of tinnitus on the life of tinnitus patient. RESULT: (1) Tinnitus frequency is closed with the frequency of hearing loss. (2) There is no significant correlation between tinnitus loudness and the impact of tinnitus on the life of tinnitus patient. (3) There is no distinction between hearing loss and the THI scores. (4) The patient gets more scores in subgroup of THI with the increase of tinnitus subjective loudness classification. CONCLUSION: The impact of tinnitus loudness, hearing loss on the life of tinnitus patient is not very clearly, while the impact of tinnitus subjective loudness classification on the life of tinnitus patient is significant. In clinical, we can not evaluate the effect of the tinnitus treatment relying on tinnitus loudness and hearing loss simply.The finding provides us individual treatment to tinnitus patients. PMID- 23937007 TI - [Evaluating the effects of hearing aids combined with psychological counseling on tinnitus in patients with deafness]. AB - OBJECTIVE: To evaluate the effects of hearing aids combined with psychological counseling on subjective tinnitus. METHOD: One hundred and fifty four tinnitus patients with deafness were randomly divided into two groups: 84 cases in study group, receiving hearing aids combined with psychological counseling therapy; 70 cases in control group, receiving counseling therapy only. Two groups were assessed at 3, 6 and 12 months after the beginning of the therapy. In study group, 6 cases were bilaterally aided and 78 cases were unilaterally aided. The 78 cases are divided into three subgroups: Group A (moderate hearing loss), Group B (moderate to severe hearing loss), and Group C(severe hearing loss) according to the severity of hearing loss. RESULT: At 3, 6 and 12 months after the beginning of the therapy ,the effective rates in study group are 26.19%, 63.10% and 72.62% respectively and the effective rates in control group are 8.57%, 18.57% and 25.71% respectively. There are statistically significant differences between the effective rates of the two groups after 3,6 and 12 months since the therapy started (P < 0.01). The tinnitus improvement of Group A is the most, and that of Group C is the least. The effective rate of Group A is higher than groups B and C with statistically significant differences (P < 0.0167). The effective rate of Group B is higher than Group C while with no statistically significant difference(P > 0.05). CONCLUSION: Hearing aids can not only improve hearing but also help with the treatment of tinnitus. Hearing aids combined with psychological counseling treatment is an ideal method for dealing with tinnitus in patients with deafness. PMID- 23937008 TI - [Study on gender difference of tinnitus in medical staff]. AB - OBJECTIVE: To investigate whether there is gender difference in the incidence and severity of tinnitus in medical staff (including doctors, nurses, and technicians). METHOD: A total of 354 people (all are medial stuff from hospitals in Guangzhou) were invited to be involved in the investigation and granted a self reported questionnaire of tinnitus (designed by the authors; based on the scoring method of severity of tinnitus (Liu et al.). Statistical analysis on the data was performed using SPSS Statistics 17.0. RESULT: (1) The incidence of tinnitus of the sample was 43.22%, with that in female higher than in male (P < 0.05), and that in nurses higher than in doctors or technicians (P < 0.01). (2) The effect of working position factor on the incidence of prolonged tinnitus was significant (P < 0.01). However, no statistically significant gender difference was detected in the incidence of prolonged tinnitus. (3) There was no statistically significant difference of tinnitus severity scores between different genders or among different positions (P > 0.05). (4) There was statistically significant difference among the four sub-items of the questionnaire (P < 0.01), with the mean score of "occurred environment" higher than "the impact on sleeping", "the impact on everyday life", and "the impact on emotion". CONCLUSION: (1) The effort reward imbalance might be the key factor of the gender difference in the incidence of tinnitus. (2) For patients of tinnitus, improving the knowledge about their symptoms as well as levels of psychological resilience would be helpful to relieve the mental impairment of tinnitus. PMID- 23937009 TI - [Clinical characteristics and surgical management of extensive cholesteatoma of external auditory canal]. AB - OBJECTIVE: To classify the external auditory canal cholesteatoma(EACC) by high resolution temporal bone CT scans and the clinical findings of the patients, and to discuss the clinical and imaging characteristics and the surgical management of the extensive EACC. METHOD: A retrospective study was carried out among 56 patients (58 ears) with EACC and their clinical data were carefully analyzed. We classified EACC as the extensive type and the localized type. The operation strategy depended on the extent of lesion. All cases were followed up for 1 to 6 years after surgery. RESULT: There were 31 patients with localized EACC, 2 with no bone erosion and 29 (31 ears) with bone erosion within external auditory canal, and 25 patients with extensive EACC, 16 with bone erosion of intra temporal bone and 9 with bone erosion of extra temporal bone. Among all the 25 patients with the extensive type, the most common symptoms were otorrhea, otalgia and hearing loss, with 25, 23, 22 cases, respectively. The tympanic membrane (TM) was intact in 23 patients and perforated in two. The mastoid air cells in 23 patients were involved by the lesion, as well as tympanic antrum in eight, tympanic cavity in two, sigmoid sinus bony wall in five, mastoid segment of facial canal in four, and temporomandibular joint in two patients. Twenty patients underwent modified radical mastoidectomy, only one underwent reconstruction of ossicular chain, and four underwent canaloplasty. The average time of ear dry after surgery was 29 days. The postoperative hearing was improved by an average of 15 dB. No recurrence except for one patient was found during the follow-up period. CONCLUSION: It was of important clinical significance to classify EACC as the extensive type and the localized type. The extensive EACC was misdiagnosed easily because of the complicated clinical manifestations. The classification was helpful for the diagnosis and the selection of surgery strategy of EACC. PMID- 23937010 TI - [Study on the preventive effect of the gelomyrtol forte from secretory otitis media in patients with nasopharyngeal carcinoma after radiotherapy]. AB - OBJECTIVE: To observed the prevention efficacy of secretory otitis media after radiation therapy by the Myrtol Standardized Enteric Coated Soft Capsules. METHOD: Sixty patients with nasopharyngeal carcinoma who Diagnosis without secretory otitis media before radiation therapy were divided into experimental group and control group, 30 cases in each group. After the start of radiation therapy ,the experimental group patients oral the Myrtol Standardized Enteric Coated Soft Capsules, each 0.3 g, 3 times a day, 7 days a course of treatment, oral the medication three months, the patients in the control group received no treatment. 3 months and 6 months after the end of radiation therapy, whether there is a difference comparison of experimental group and the control group in symptoms, signs, pure tone audiometry and tympanogram change. RESULT: Seventeen patients (18 ears) (56.67%, 17/30) in the control group were suffering from secretory otitis media, 7 patients (7 ears) (23.33%, 7/30) in the experimental group were suffering from secretory otitis media. The difference between the two groups was statistically significant (P < 0.01). 17 patients (17 ears) in the control group and 7 patients (7 ears) in the experimental group were suffering from tinnitus. 20 patients(20 ears) in the control group and 9 patients (10 ears) in the experimental group have ear choking feeling. The difference between the two groups was statistically significant (P < 0.01). The air conduction hearing threshold of the experimental group before radiation therapy is (7.5 +/- 2.0) dB HL and the air conduction hearing threshold of the control group patients is (8.3 +/- 4.0) dB HL. The difference between the two groups was not statistically significant (P > 0.05). 3 months after radiation therapy,the gas conductive hearing threshold of the experimental group is (25.6 +/- 3.0) dB HL, but the data in the control group is (40.7 +/- 5.0) dB HL. The difference between the two groups was statistically significant (P < 0.01). CONCLUSION: Patients with nasopharyngeal carcinoma oral the the Myrtol Standardized Enteric Coated Soft Capsules before radiation therapy can effectively reduce the incidence of secretory otitis media after radiotherapy, it can prevent the occurrence of secretory otitis media. PMID- 23937011 TI - [Protection of vagus nerve during the cervical vagal schwannoma resection and functional rehabilitation]. AB - OBJECTIVE: To explore the clinical anatomy of vagal schwannoma and the methods to preserve the continuity of vagus nerve during tumor resection and postoperative functional rehabilitation methods of the nerve. METHOD: To review 15 cases of vagal schwannoma from 2002.07 to 2011.08 treated in the Department of Otolaryngology, West China Hospital. The operative modality was to strip the tumor while keeping the Schwann membrane almost intact so that to protect the nerve fibers as much as possible. postoperative treatment included glucocorticoids, neurotrophic medication, as well as voice and swallowing rehabilitation. RESULT: Among 15 cases of schwannoma patients, 3 cases (3/15) experienced hoarseness of voice with the ipsilateral vocal cord located at the median position 2 years after operation. 2 cases(2/15) experienced no obvious hoarseness of voice with vocal cords slight vibration when pronouncing and reached normal vocal cord movement 3 months after operation, 10 cases were healed without vocal cord complications, 7 cases (7/15) experienced choking during drinking and the symptom was gradually eliminated 1 3 months thereafter. CONCLUSION: To carefully discern and preserve the vagal fibers during the operation of vagal schwannoma could eliminate postoperative hoarseness and choking. Protection of superior laryngeal nerve should be also brought to the forefront because it could affect the quality of swallowing and speaking. PMID- 23937012 TI - [The effect of dexmedetomidine on post-operative blood pressure after controlled hypotension in endoscopic sinus surgery]. AB - OBJECTIVE: To observe the variance of blood pressure (BP) after controlled hypotension in endoscopic sinus surgery with dexmedetomidine. METHOD: Sixty patients undergoing elective endoscopic sinus surgery were randomly assigned to receive dexmedetomidine (Group D) or physiological saline (Group S). For the two groups, after the same induction of anesthesia procedure, Group D were injected with dexmedetomidine with 0.8 microg/kg of priming dose in 10 min and 0.5 microg/(kg x h) of maintenance dose i. v. drip for 30 min. The Group S were injected with physiological saline in the dose the same as Group D. The measurement of the mean aortic pressure(MAP), heart rate (HR) and the colouration of the Nasal packing material and exudation were taken at the end of the surgery (T1), at the time of extubation (T2), 10 min after extubation (T3), 30 min after extubation (T4), 2 h after extubation (T5), and 4 h after extubation (T6). RESULT: The MAP and HR of Group S at the points T2-T6 were significantly higher compared with those at the point T1 (P < 0.05). The MAP and HR of Group D at each time point did not change significantly (P > 0.05). The MAP and HR of Group S at each time point were higher compared with Group D (P < 0.05). The number of cases with postoperative nasal exudate in Group S was significantly more than in Group D (27:18) (P < 0.05). CONCLUSION: The perioperative dexmedetomidine medication can significantly reduce fluctuations in BP in endoscopic sinus surgery, so that to stable hemodynamics and reduce nasal bleeding. PMID- 23937013 TI - [Speech and pitch perception with the new fine structure speech coding strategy]. AB - OBJECTIVE: To assess the performance of the new fine structure processing strategy(FS4) compared to the previous generation coding strategy HDCIS. METHOD: Twelve post-lingual hearing-impaired cochlear implant users were included. FS4 and HDCIS were compared in music pitch perception and speech perception test. RESULT: Acute comparison between FS4 and HDCIS showed that FS4 performed as well as HDCIS in speech perception tests, and outperformed HDCIS in music pitch perception. CONCLUSION: Results indicate that FS4 performs better than HDCIS in music perception. Differences between the two strategies were not significant for speech test. PMID- 23937014 TI - [Clinical analysis of 32 cases of Ramsay Hunt syndrome]. AB - OBJECTIVE: To observe the clinical features and the treatment effect of 32 cases of Ramsay Hunt syndrome and explore the relationship between different clinical manifestations and the prognosis. METHOD: Using the integrated therapy including the medication and physiotherapy of ultrashort wave, the relationship between clinical manifestations and recovery time was analyzed. RESULT: Twenty two cases were cured, 10 cases showed improvement of the symptoms, and no patients complained ineffectiveness. The effective rate was 100%. The shortest recovery time was 13 days, and the longest recovery time was 1 year and 7 months. CONCLUSION: The key to cure Ramsay Hunt syndrome is comprehensive treatment in time. The different clinical manifestations have something to do with the prognosis. PMID- 23937015 TI - [The effect of hyalinized chorda tympani nerve canal in protection of mastoid segment of facial nerve in middle ear surgery]. AB - OBJECTIVE: To investigate the effect of hyalinized chorda tympani nerve canal in mastoid segment to landmark facial nerve in middle ear surgery by means of observing the location relationship between hyalinized chorda tympani nerve canal and facial nerve. METHOD: 118 cases of cholesteatoma otitis media in our hospital undergoing tympanoplasty from 2008 to 2011 were retrospectively analyzed. In all the cases, the position of horizontal semicircular and fossa incus as well as the hyalinized chorda tympani nerve canal were used for landmark the height of facial ridge and vertical segment of facial nerve. RESULT: The chorda tympani nerve of 99 patients were higher than the vertical segment of the facial nerve which were not exposed, and the vertical segment of the facial nerve in 9 patients, which were exposed, were 1-2 mm lower and 2-3 mm ahead or backward than the chorda tympani nerve. The horizontal semicircular and fossa incus were broken in 9 patients, of whom the vertical segments of the facial nerve were 1-2 mm lower and 2-3 mm ahead or backward than the chorda tympani nerve. The chorda tympani nerve of 1 patient were lower than the exposed vertical segment of facial nerve. CONCLUSION: The hyalinized chorda tympani nerve canal in mastoid segment can landmark the positon of facial ridge, and it would be the complement to the traditional method of landmarking vertical segment of facial nerve, especially for those whose horizontal semicircular canal and fossa incus had been broken. PMID- 23937016 TI - [Clinical application of tympanostomy tube placement to prevent secretory otitis media in patients with nasopharyngeal carcinoma after radiotherapy]. PMID- 23937017 TI - [Cochlear implantation: analysis of 35 cases]. PMID- 23937018 TI - [To observe the curative effect of paracentesis and plaster mold compression fixation for the treatment of pseudocyst of auricle]. PMID- 23937019 TI - [One case report of Kimura disease combined with secretory otitis media]. AB - The patient is a 75 years old man complaining of ear plug and hearing loss for about three days. Physical examination shows liquid in two tympanic cavities. Chronic congestion occurs to nasal mucosa. Bilateral inferior turbinates are a little bigger than normal. Both inferior meatus are unblocked and pharyngeal recess is smooth. This patient is fat. Bilateral eye lids are swollen. A tumour could be touched in bilateral parotids with good movement and no tenderness. Its size is as big as an egg. Several lymph nodes could be touched under the jaw. The blood test is normal and IgG, IgA, IgM, ANA, anti-ENA, C3, C4, CRP and ESR is normal but RF is high. The function of liver and kidney is normal. B-mode ultrasonography result shows bilateral parotids are diffusely swollen and several swollen lymph nodes in cervix. Pathology examination of lower mandibular lymph node and parotid shows follicular lymphaticus hyperplasia with several plasmacytes and eosinophil granulocytes. The diagnosis accords with Kimura disease. PMID- 23937020 TI - [One case of pulsatile tinnitus and literatures review]. AB - To investigate the etiology.diagnosis and treatment of pulsatile tinnitus. One case with pulsatile tinnitus in our hospital admitted in May 2012 was reported and the relevant literatures were reviewed. The chief complaint when visited was pulsatile tinnitus. This case was treated by surgery. Pulsatile tinnitus was completely subsided without recurrence. Pulsatile tinnitus is an uncommon otologic symptom, which often presents a diagnostic and treatment dilemma to the otolaryngologist. The majority of patients with pulsatile tinnitus have a treatable cause. Failure to establish correct diagnosis may have disastrous consequences, because a potentially life threatening and underlying disorder may be present. PMID- 23937021 TI - [Viral infection and ear diseases]. AB - The association of viral infection to ear disease has triggered a great deal of interests. In the present paper, we provide a critical review of the viral hypothesis of ear diseases. Detection of viral antigen and antibody or RNA and DNA in the patients serum, endolymphatic fluid or surgical pathology specimens reveals that virus may have relevance to certain kinds of ear diseases, such as Meniere's disease, idiopathic sudden sensorineural hearing loss, otosclerosis. Bell's palsy and otitis media. The most appealing is the herpesvirus, which can cause latent infection in the neurons, and its reactivation may be the mechanism of recurrent attacks of ear diseases. Currently, antiviral drug treatment plus supportive therapy are the most effective managements dealing with viral infection. Although antiviral vaccine will become a promising preventive strategy in the future. PMID- 23937022 TI - [Recognition of reconstruction of cruciate ligament with remnant preservation]. PMID- 23937023 TI - [Case-control studies on double bundle posterior cruciate ligament reconstruction with remnant fiber preservation]. AB - OBJECTIVE: To study the clinical efficacy of double bundle posterior cruciate ligament (PCL) reconstruction with remnant preservation. METHODS: From January 2007 to November 2011, 50 patients with PCL rupture met the inclusion criteria were divided into two groups: remnant preservation group (RP group) and remnant resection group (RR group). There were 19 males and 7 females in the RP group, ranging in age from 18 to 55 years, with a mean of (32.250 +/- 11.085) years old. The duration from injury to operation ranged from 2 to 66 months, with an average of (17.481 +/- 3.568) months. Among the RR group, 17 patients were male and 7 patients were female, ranging in age from 20 to 54 years old, with an average of (31.458 +/- 9.569) years. The duration from injury to operation ranged from 3 to 72 months, with a mean of (19.354 +/- 3.950) months. The patients in both groups suffered from instability of knee joint, got a positive result of posterior drawer test. In the RP group, the intercondylar notch remnant fiber, scar tissue and synovial were preserved in operation, only the free ligament in the intercondylar notch was resected. In the RR group, the remnant fiber, scar tissue and synovial tissue of adhesive parts were resected. In both groups, autologous semitendinosus and gracilis tendon double-bundle PCL reconstruction were carried out, the tibia was fixed with an absorbable interference screw with post-tie fixation, and the femur side was compositely fixed with absorbable interference screws and suspending fixation. Each patient received both subjective assessment (IKDC subjective evaluation, Lysholm scoring and Cincinnati rating) and objective clinical assessment (IKDC objective evaluation and Kneelax 3 tibia backward measurement) before operation and two years after operation. RESULTS: IKDC subjective evaluation: 92.167 +/- 4.177 in the RP group,which was higher than 87.542 +/- 5.687 in the RR group (P = 0.010). Lysholm scores: 90.917 +/- 4.413 in the RP group, which was higher than 87.083 +/- 5.149 in the RR group (P = 0.027). Cincinnati knee scores: 92.125 +/- 4.003 in the RP group, which was higher than 87.791 +/- 6.665 in the RR group (P = 0.027). IKDC objective evaluation:no significant statistical differences between RP group and RR group. Kneelax 3 assessment : tibia backward test with Kneelax 3 under 132 N showed no significant statistical difference between RP group and RR group, which were (3.958 +/- 0.693) mm and (4.029 +/- 0.846) mm respectively (P = 0.795). CONCLUSION: The study shows a significant advantage of remnant fiber preservation than remnant fiber resection in double-bundle PCL construction in terms of subjective knee function recovery after operation. There is no significant difference in postoperative knee stability. PMID- 23937024 TI - [Case-control studies on clinical effects of non- and remnant preservation for reconstruction of posterior cruciate ligament]. AB - OBJECTIVE: To evaluate the methods and therapeutic effects of the posterior cruciate ligament (PCL) reconstruction with remnant preservation and no preservation. METHODS: From January 2006 to January 2011,45 patients received arthroscopic PCL reconstruction by using hamstring tendon autograft fixed with bioabsorbable interference screw. Twenty-five patients were treated with PCL reconstruction with remnant no preservation, including 19 males and 6 females. During the operation, remnant PCL was not preserved, double-screws and whole-bone tunnel technique was used to fix the tibial side. Twenty patients were treated with PCL reconstruction with remnant preservation, including 15 males and 5 females. Although the fixation technique was similar to the remnant no preservation group, the remnant was preserved. All the patients were followed up with a mean period of 18 months. Each patient was evaluated using the following variables: posterior laxity on KT-2000, Lysholm knee score, International Knee Documentation Committee (IKDC) knee score and grade. RESULTS: At the latest follow-up, the results of mean side-to-side differences in posterior tibial translation, Lysholm knee score and IKDC score were (4.2 +/- 2.1) mm, 84.3 +/- 10.5 and 64.5 +/- 8.8 in the remnant no preservation group separately, and (3.9 +/- 1.8) mm, 86.5+/- 8.9 and 68.6 +/- 7.9 in the remnant preservation group separately. There were no statistical differences of above results between the two groups. However, IKDC objective grade differed significantly between the two groups and the result in remnant preservation group was better than that of remnant no preservation group. CONCLUSION: Remnant preservation in PCL reconstruction can provide better activity-related outcomes than remnant no preservation. PMID- 23937025 TI - [Arthroscopic anterior cruciate ligament reconstruction with remnant preserving technique]. AB - OBJECTIVE: To evaluate the clinical outcome of arthroscopic reconstruction of anterior cruciate ligament (ACL) with remnant preserving technique. METHODS: From May 2008 to October 2010,68 patients with ACL deficiency (33 males and 35 females, with an average age of 25.8 years, ranged from 17 to 43 years) were treated with arthroscopy. The average duration of the disease was (4.5 +/- 1.1) months. The pivot shift test showed positive results in 55 cases, Lachman test showed positive results in 68 cases, and the ADT (anterior drawer test) showed positive results in 68 cases. The anterior transition of the tibia measured by KT2000 instrument was (7.2 +/- 2.3) mm (5 to 9 mm) more than that of the opposite knee. The average Lysholm score was 55.7 +/- 5.4 (45 to 67). The average Tegner activity scores was 3.1 +/- 0.6 (2 to 4). The tibial tunnels and femoral tunnels were drilled in the middle of the footprint of the ACL, and the graft was wrapped by the remnant. Grafts were fixed with cross pin at the femoral side and with biodegradable interference screw at the tibial side. Postoperative symptoms and signs were observed in the follow-up duration. The anterior transition of the tibia was measured by KT2000, the Lysholm and Tegner scores were used to evaluate knee functions. RESULTS: All the patients were followed up, and the duration ranged from 24 to 42 months, with a mean of (31.5 +/- 2.4) months. At the latest follow-up, there was no patients had positive result by civot shift test, while the Lachman test showed results of negative or positive of grade I, and the ADT test showed results of negative or positive of grade I or II. The anterior transition of the tibia measured by KT2000 instrument decreased to (1.9 +/- 0.7) mm (0 to 3 mm) more than that of the opposite knee (t = 21.15, P = 0.000 1). The postoperative Lysholm score 86.0 +/- 5.1(81 to 97) and Tegner score 7.8 +/- 0.3 (6 to 9) all increased compared with preoperative 55.7 +/- 5.4 and 3.1 +/- 0.6 (t = 18.55, P = 0.001 0; t = 9.11, P = 0.000 5). According to Lysholm score, excellent results were obtained in 55 cases, good in 10, poor in 3 and no bad results. CONCLUSION: The ACL remnant provide vascular and nerve supply for the graft, promoting union and remodeling of grafts. PMID- 23937026 TI - [Arthroscopic reconstruction of anterior cruciate ligament with preservation of the remnant bundle]. AB - OBJECTIVE: To evaluate clinical effects of arthroscopic anterior cruciate ligament (ACL) reconstruction with preservation of the remnant bundle. METHODS: From January 2002 to December 2009, 57 patients with ACL partial rupture were treated with preservation of the remnant bundle. There were 39 males and 18 females, with an average age of 28.5 years old (ranged, 16 to 49 years old). Thirty-three patients had injuries in the left knees,and 24 patients had injuries in the right knees. Forty patients had injuries caused by sports, 7 patients had injuries caused by traffic accidents and 10 patients had injuries caused by daily sprain. The anterior drawer test showed positive results in 23 patients, weakly positive results in 6 cases; Lachman test showed positive results in 19 patients, and weakly positive in 4 patients. Both anterior drawer test and Lachman test showed positive results in 5 patients; and valgus stress test (medial) showed positive results in 24 patients. The mean value of Rolimeter measurement was 8.7 mm, (ranged, 7.5 to 11.5 mm). The mean International Knee Documentation Committee (IKDC) score was 70.0 +/- 7.5 and the Lysholm score was 68.0 +/- 6.3. The duration from injury to surgery was 1 week to 12 months,with an average of 3.1 months. RESULTS: There were 32 patients treated with anteromedial bundle reconstruction and 25 patients treated with poterolateral bundle reconstruction. Fifty-seven patients were followed up, and the mean follow-up time was 22.5 months (ranged, 13 to 37 months). The anterior drawer test and Lachman test were all negative at 1 month post-operation. At the end of the follow-up, the range of motion of all the knees was 120 to 130 degree. There were 54 patients with negative results of anterior drawer test and Lachman test, 1 with weakly positive result of anterior drawer test and 2 with weakly positive results of Lachman test. The measurements of Rolimeter showed excellent stability of the knee. The mean IKDC score was 92.0 +/- 4.9 and the mean Lysholm score was 91.0 +/- 3.7, which all improved compared to preoperative scores. CONCLUSION: Arthroscopic reconstruction of anterior cruciate ligament with preservation of the remnant bundle has satisfactory effects on the knee stability, which could increase the angiogenesis and collagen of the ACL and improve the proprioception of the knee. PMID- 23937027 TI - [Clinical applications of sternoclavicular hook plate for the treatment of sternoclavicular joint dislocation]. AB - OBJECTIVE: To observe the clinical therapeutic effects of sternoclavicular hook plate for the treatment of sternoclavicular joint dislocation. METHODS: From June 2010 to June 2012, 7 patients with sternoclavicular joint dislocation were treated with sternoclavicular hook plate fixation. Among the 7 patients, 5 patients were male and 2 patients were female, and the average age was 42.3 years, ranging from 38 to 54 years. The course of the disease ranged from 1 to 4 weeks. All the patients had trauma history. The clinical manifestations included: obvious swelling and pain of sternoclavicular joint, restricted shoulder joint activity. The sternoclavicular joint dislocation was proved by preoperative X-ray and CT. The postoperative curative effect was evaluated according to Rockwood scoring method. RESULTS: According to Rockwood scoring method, the excellent results obtained in 6 cases, good in 1. There were no complications such as internal fixation loosening or broken, second dislocation, pain in the sternoclavicular joint, and deformity. The function of shoulder joint was good, and the limb activity was free and no pain appeared. CONCLUSION: The sternoclavicular hook plate for the treatment of sternoclavicular joint dislocation has follow advantages: simple procedure, stable fixation, definite therapeutic effects. PMID- 23937028 TI - [Intrafix fixation and remnants preservation in single-tunnel double-bundle reconstruction of anterior cruciate ligament with anatomical placement of hamstring tendons]. AB - OBJECTIVE: To study the feasibility and short-term effects of Intrafix fixation and remnants preservation in single -tunnel double-bundle reconstruction of anterior cruciate ligament (ACL) with anatomical placement of hamstring tendons. METHODS: From August 2011 to November 2011, 25 patients with ACL injuries were treated with arthroscopic reconstruction of ACL using hamstring tendon. There were 19 males and 6 females, with a mean age of (26.26 +/- 9.53) years (ranged, 16 to 50 years). Fifteen patients had injuries in left knees, and 10 patients had injuries in right knees. The duration of the disease ranged from 1 to 60 d, with a mean of 9.6 d. All patients with acute injuries had swelling and pain on the knee, and anterior drawer test showed positive results in 14 cases, Lachman test showed positive results in 17 cases. Among patients with old injuries, 5 patients had knee joint pain, 5 patients had unstability of knee joint, 5 patients had positive results of anterior drawer test, and 5 patients had positive results of Lachman test. The diagnosis of ACL injury was determined by the anterior drawer test and Lachman test. There were 20 patients with acute injuries and 5 patients with old injuries. MRI was performed in all patients to confirm the diagnosis of ACL injuries and provide additional information on meniscal and other ligament injuries. Preservation of the remnants was through patellar tendon portal using meniscus suture guide. The femoral tunnel was placed at lateral femoral condyle at 2:00 or 10:00 position through the anteromedial (AM) portal with the knee flexed to 120 degree using an offset guide (DePuy Mitek). The tibia tunnel was placed at the center of the ACL remnant through the AM portal using a tibia guide set 45 degree. The AM and PL bundles were rotated by rotating the positioning tool to achieve the desired positions of the bundles and were fixed by femoral Intrafix and tibia Bio-Intrafix fixation. The anterior drawer test, Lachman test and Lysholm scores were observed to determinate the function of the knee and the activity of the patients. RESULTS: All the patients were followed up, and the duration ranged from 12 to 18 months. The Lysholm scores improved from preoperative 34.08 +/- 7.60 (25 to 49 scores) to 94.52 +/- 2.86 (89 to 98 scores) at the follow-up time (t = 21.29, P < 0.01). No postoperative complications such as synovitis, ligament rupture and movement restriction occurred. CONCLUSION: Intrafix fixation and remnants preservation in single-tunnel double-bundle reconstruction of ACL with anatomical placement of hamstring tendons is simple, effective, useful, reproducible, and gives a satisfactory short-term results. PMID- 23937029 TI - [Anterior cruciate ligament reconstruction with tendon graft enveloped by preserved remnants]. AB - OBJECTIVE: To explore the curative effect of anterior cruciate ligament (ACL) reconstruction with tendon graft enveloped by preserved remnants. METHODS: From June 2009 to June 2011,76 patients with ACL injury were treated, and the ACL was reconstructed with tendon graft enveloped by preserved remnants. There were 59 males and 17 females, aged 15 to 46 years with an average of 29 years. The causes of injuries included sports in 32 cases, training in 20 cases, traffic accidents in 16 cases, and other reasons in 8 cases. The average disease duration was 3 weeks (2 to 5 weeks). The results of Lachman test was positive in 72 cases and anterior drawer test were positive in 76 cases. The preoperative IKDC score was 45.9 +/- 3.6. The preoperative Lysholm knee score was 54.3 +/- 4.5. RESULTS: All incisions got an one stage healing, and no early complications occurred. Sixty nine cases were followed up, and the duration ranged from 17 to 31 months (mean, 23 months). The result of Lachman test was negative at the latest follow-up. At the latest follow-up, the degree of IKDC was A in 36 cases, B in 30 cases, C in 3 cases, no one in degree D. The postoperative IKDC score was 91.5 +/- 3.4, showing significant difference compared with preoperative score. The postoperative Lysholm score was 92.4 +/- 3.8, showing a significant difference compared with preoperative score. CONCLUSION: The clinical effect of anterior cruciate ligament (ACL) reconstruction with tendon graft enveloped by preserved remnants is satisfactory. PMID- 23937030 TI - [Arthroscopic treatment of painful heel syndrome with radio-frequency]. AB - OBJECTIVE: To evaluate therapy effect of radiofrequency in the treatment of painful heel syndrome under arthroscopy. METHODS: From January 2006 to December 2011, 13 patients with painful heel syndrome being admitted into our hospital were studied. There were 5 males and 8 femals, ranging in age from 35 to 68 years. All these surgeries were performed under local anesthesia. After constructing a man-made lacouna in the subcutaneous tissue above plantar fascia, a medial and a lateral portal were established on both sides of plantar fascia and at the anterior edge of calcaneal tuberosity. Hyperplasia and torn fiber tissue of plantar fascia, and plantar calcaneal bursa were removed with radiofrequency probe under arthroscopy. Then penetration of the plantar fascia was carried out in a reticulation-shaped pattern with a special radiofrequency probe TOPAZ. Each patient was assessed with VAS pain evaluation criteria and AOFAS ankle-hindfoot score system (AOFAS-AH) before and after operation. All the patients were followed up, and the duration ranged from 6 to 12 months. RESULTS: All the 13 patients got excellent recovery with their heel pain relieved significantly. VAS score was 8.71 +/- 1.64 before operation, 6.27 +/- 2.53 at the 1st month after operation, and 2.30 +/- 2.69 at the 6th month after operation. AOFAS-AH score was 56.43 +/- 3.72 preoperation, 68.15 +/- 7.38 at 1st month post operation, and 84.51 +/- 2.93 at 6th month after operation. There were no perioperative and postoperative complications related to the procedure, such as blood vessel and nerve injury, and infection. CONCLUSION: Plantar fasciitis and plantar calcaneal bursitis are main factors of painful heel syndrome. Due to advantages of being easy to operate, having definite effect and no use to do spur removal or plantar fasciotomy. Endoscopy assisted plantar calcaneal bursa removal and plantar fascia penetration by radiofrequency technique can be a satisfactory treatment method for painful heel syndrome. PMID- 23937031 TI - [Chronic osteomyelitis easily misdiagnosed by giant cell tumors of bone: a case report]. PMID- 23937032 TI - [Case-control studies on therapeutic effects of arthroscopic reconstruction of anterior cruciate ligament with preservation of remnant through outside-in and transtibial tunel]. AB - OBJECTIVE: To compare the properties and clinical outcomes of arthroscopic reconstruction of anterior cruciate ligament (ACL) with preservation of remnant through outside-in and transtibial tunel. METHODS: From June 2005 to January 2012, 145 patients were treated with arthroscopic reconstruction of ACL with preservation of remnant. Among the patients, 88 patients were treated with outside-in techniques (outside-in group), including 55 males and 33 females, ranging in age from 18 to 52 years, with a mean of (29.22 +/- 7.31) years; 57 patients were treated with transtibial technique (transtibial group), including 35 males and 22 females, ranging in age from 18 to 51 years, with a mean of (29.28 +/- 8.07) years. The Lysholm, VAS and IKDC scores were compared between two groups before operation, after operation and at the latest follow-up time. RESULTS: The average operation time was (76.94 +/- 10.83) min in the outside-in group, and (70.35 +/- 10.11) min in the transbibial group, there was a significant difference between two groups. There was no significant difference of hydrops articuli scores at the early stage between the two groups (P = 0.065). At follow-up from 18 to 60 months, there were great improvements in the knee stabilities in each group compared with the preoperative data respectively. The Lysholm score improved from 54.75 +/- 10.58 preoperatively to 95.80 +/- 5.16 at the follow-up in the outside-in group; and improved from 52.51 +/- 11.38 preoperatively to 94.86 +/- 5.50 at follow-up in the transtibial group. Additionally, IKDC grades also improved in both groups. However, no significant differences were seen in stabilities shown by pivot shift test, Lachman test and anterior drawer test. And there also no significant differences of Lysholm scores and IKDC grades between two groups after operation. CONCLUSION: The outside-in technique has advantages to create an anatomical femoral tunnel easily with minimal intra-articular interference, and disadvantages of complicated manipulation. The transtibial technique is easy to operate and gain time. Using either of responding technique according to the actual situation, satisfactory outcome could be archived. PMID- 23937033 TI - [Extracorporeal shock wave combined with functional training for the treatment of frozen shoulder]. PMID- 23937034 TI - [Case-control studies on therapeutic effects of combined methods of minimally invasive percutaneous proximal humerus locked osteosynthesis plate with injectable bone for the treatment of proximal humerus fractures in elderly patients]. AB - OBJECTIVE: To evaluate the clinical effects of combined methods of minimally invasive percutaneous proximal humeral internal locking system (PHILOS) and injectable bone for the treatment of proximal humerus fractures in elderly patients. METHODS: From January 2006 to January 2012, 80 patients with proximal humerus fractures were randomly divided into two groups (n = 40). The patients in the research group were treated with minimally invasive PHILOS fixation combined with injectable bone, including 20 males and 20 females, with an average age of (68.4 +/- 11.9) years; according to AO classification, 2 cases of type A1, 3 cases of type A2, 6 cases of type B1, 7 cases of type B2, 9 cases of type B3, 6 cases of type C1, 7 cases of type C2. The patients in the control group were treated with PHILOS fixation, including 18 males and 22 females, with an average age of (65.4 +/- 10.7) years; according to AO classification, 3 cases of type A1, 4 cases of type A2, 5 cases of type B1, 8 cases of type B2, 10 cases of type B3, 5 cases of type C, and 5 cases of type C2. The BMD, satisfactory rate, postoperative complications,bone healing time, Constant-Murley score in the two groups were reviewed and compared. RESULTS: In the research group, no patients had necrosis of femoral head, 1 patient had shoulder varus, 1 patient had internal fixation loosening, 36 patients were satisfactory with the treatment results, BMD was (1.013 +/- 0.109) g/cm2, bone healing time averaged (12.00 +/- 3.79) weeks, and the Constant-Murley score was 97.2 +/- 4.6. In the control group, 3 patients had necrosis of femoral head, 5 patients had shoulder varus, 6 patients had internal fixation loosening, 32 patients were satisfactory with the treatment results, BMD was (0.812 +/- 0.089) g/cm2, bone healing time averaged (20.00 +/- 8.67) weeks,and the Constant-Murley score was 78.5 +/- 3.2. The results of BMD, satisfactory rate, postoperative complications, bone healing time, and Constant-Murley score in the research group were better than those of control group (P < 0.05). CONCLUSION: PHILOS combined with injectable bone for the treatment of proximal humerus fractures in elderly patients has advantages of minimal wound, stable fixation, and earlier rehabilitation. PMID- 23937035 TI - [Emergency operation for the treatment of intertrochanteric fractures in elderly patients]. AB - OBJECTIVE: To evaluate the emergency therapeutic effects of intertrochanteric fractures in elderly patients. METHODS: A retrospective study was designed. From March 2006 to March 2012, 254 patients with intertrochanteric fractures treated in Mianyang Central Hospital were reviewed. The patients with old fractures, pathological fractures, multiple trauma and severe medical comorbidities of admission were excluded. So 127 patients with intertrochanteric fractures over 70 years old were included in the study, including 38 males and 89 females, and the patients were divided into 2 groups: 56 patients underwent emergency operation within 24 h after injury (emergency operation group), 71 patients underwent an operation more than 24 h after injury (not emergency operation group). The following data were collected retrospectively for all patients: (1) in hospitalcomplications, including electrolyte disturbance, hidden blood loss, delirium, deep vein thrombosis, upper gastrointestinal hemorrhage, pulmonary infection, urinary tract infection, cardiovascular and cerebrovascular disease, bedsore. (2) prognosis, ineluding in-hospital mortality, mortality in the 1st year, length of hospital stay, fracture healing times, hip score. Comparisons between the two groups were made using SPSS13.0. The quantitative data and categorical data were analyzed by t test and chi2 test, respectively. RESULTS: The main medical complications in emergency operation group were hidden blood loss, delirium, pulmonary infection, electrolyte disturbances, urinary tract infections, and in not emergency operation group followed respectively by hidden blood loss, lung infection, electrolyte disturbances, delirium, and pulmonary infection. In-hospital mortality was zero, and 1 in the 1st year in emergency operation group; while in not emergency operation group were 4 and 7 respectively. An average length of hospital stay with (9 +/- 3) d in emergency operation group was lower than (17 +/- 8) d in not emergency operation group. Fracture healing time was (12 +/- 2) weeks in both groups. The significant variables with P < 0.05 between the two groups were electrolyte disorders, delirium, deep venous thrombosis, pulmonary infection, urinary tract infection, bedsore, in-hospital mortality, mortality in the 1st year, and length of hospital stay. The differences of hidden blood loss, upper gastrointestinal hemorrhage, cardiovascular and cerebrovascular disease, fracture healing times, hip score between the two groups had no significant differences (P > 0.05). CONCLUSION: The emergency surgery (within 24 h after injury) reduces length of hospital stay, and may also reduce complications and mortality. PMID- 23937036 TI - [Treatment of posterior shoulder dislocation with different manual reductions]. PMID- 23937037 TI - [Inhibitory effect of recombinant receptor activator of nuclear factor kappaB protein on bone loss in ovariectomized mice]. AB - OBJECTIVE: To compare inhibitory effects of recombinant receptor activator of nuclear factor kappaB protein with bisphosphonate treatment (ALN) on osteoclasts activity and bone loss in ovariectomized mice. METHODS: Twenty-four female KM mice were ovariectomized bilaterally and treated with recombinant receptor activator of nuclear factor kappaB protein, alendronate, or PBS. Twelve weeks later, body weight, biochemical markers of bone metabolism, Micro CT scan and bone morphology were examined. RESULTS: After 12 weeks administration, the Micro CT scan and bone morphology values of each group were as follow. The control group: BMD (92.600 +/- 14.319) mg/cc, Tb.Th (0.094 +/- 0.011) mm, Tb.Sp (0.455 +/ 0.124) mm, BVF 0.192 +/- 0.023, SMI 1.388 +/- 0.328; the recombinant receptor activator of nuclear factor kappaB protein group: BMD (133.050 +/- 13.022) mg/cc, Tb.Th (0.098 +/- 0.009) mm, Tb.Sp (0.365 +/- 0.105) mm,BVF (0.291 +/- 0.025)%, SMI 0.661 +/- 0.384; the ALN group: BMD(128.013 +/- 16.040) mg/cc, Tb.Th (0.097 +/- 0.011) mm, Tb.Sp (0.376 +/- 0.104) mm, BVF 0.281 +/- 0.024, SMI 0.753 +/- 0.307. In the ovariectomized mice experiments, both recombinant receptor activator of nuclear factor kappaB protein and ALN significantly inhibited ovariectomy-induced bone loss. Compared to the control group (PBS), the recombinant receptor activator of nuclear factor kappaB protein group showed increased distal femur BMD and decreased trabecular spacing (Tb.Sp), whereas the control group had significantly decreased distal femur BMD, significantly decreased Tb.Th, and increased Tb.Sp. There was a significant difference in bone volume fraction among the groups. The TRAP-positive osteoclasts in distal femur bone slices were nearly complete inhibited for Recombinant receptor activator of nuclear factor kappaB protein group and alendronate group. CONCLUSION: In vivo, recombinant receptor activator of nuclear factor kappaB protein effectively inhibits the activity of osteoclasts and the resulting bone loss, which has a similar effect as alendronate. PMID- 23937038 TI - [Effect of osthole on proliferation of neonatal rat osteoblast and the relative mechanism research]. AB - OBJECTIVE: To investigate the effects of osthole on proliferation of neonatal rat osteoblast and the mechanism. METHODS: Ten 24 hours old SD rats were executed by dislocating. The cranium of rats were removed and cut into blocks of 1 mm x 1 mm size. After digested by trypsin for 15 min, the cranium were digested by type I collagenase for one hour two times. The mixed cells were cultured in thermostat incubator with 5% CO2 under the condition of 37 degrees C. To identify the cells, ALP staining and alizarin red staining were performed after cultured 48 h and 28 d. The osteoblasts were randomly divided into five groups. Cells were treated with osthole at concentrations of 100, 50, 25, 12.5, 0 micromol/L. CCK-8 method was used to evaluate the proliferation after 24 h,48 h and 72 h. The expression of PCNA and beta-catenin protein were detected through the method of Western Blot after one week. RESULTS: The cells had irregular shapes and showed typical features of osteoblast. The results of ALP staining and alizarin red staining were both positive. CCK-8 detection showed that the osthole with final concentration of 100 micromol/L inhibited the proliferation of osteoblast after 24 h, while the osthole with final concentrations of 50 micromol/L and 25 micromol/L displayed the inhibition effect after 48 h. The osthole of 12.5 micromol/L had no obvious influence on the proliferation of osteoblast. The result of Western Blot showed that osthole reduced the expression of PCNA and beta-catenin protein in a dose-dependent manner. CONCLUSION: The osthole with final concentrations of 100, 50, 25 micromol/L inhibited the proliferation of osteoblast (P < 0.05). The osthole with final concentrations of 12.5 micromol/L had no obvious influence on the proliferation of osteoblast (P > 0.05). These findings demonstrate that osthole may inhibit the proliferation of osteoblast by regulating the Wnt/beta-catenin signaling in osteoblast. PMID- 23937039 TI - [In vivo experimental study on MAO-ZK60 magnesium alloy bio-safety and degradation]. AB - OBJECTIVE: To investigate the tissue toxicity and degradation of ZK60 magnesium alloy with micro-arc oxidation coatings (MAO-ZK60), in order to discuss the possibility of its potential application for orthopedic implantation. METHODS: Eighteen Sprague-Dawley rats were randomized equally to three groups of A, B, C. MAO-ZK60 sticks were implanted in the femoral condyles of rats in group A (experimental group). Sticks of ZK60 magnesium alloy without any surface treatment (ZK60) were implanted in the femoral condyles of rats in group B (control group). The poly L-lactic acid (PLLA) sticks were implanted in the femoral condyles of rats in group C (control group). The changes of blood bio chemical indexes of different groups were observed and compared. All the rats were sacrificed at 12 weeks and histological observation of liver and kidney were carried out to evaluate the hepatic and renal toxicity. Micro-CT was used to evaluate the degradation of the implants and to observe the bone-implant interface. GEHC MicroView software was operated to calculate the volume variation of magnesium alloy. RESULTS: There was no apparent biochemical index change with time in each group, and there was no significant change among each group. No significant pathology change of liver and kidney was detected among three groups. By using a micro-CT, a gap was found on the bone-implant interface at 4 weeks after implantation in group A, which decreased gradually at 8 weeks after implantation and continued to decrease at 12 weeks after implantation. A good combination between bone and implant formed at 12 weeks after implantation. Group A has less change of volume with time than group B (P < 0.05). CONCLUSION: ZK60 magnesium alloy with micro-arc oxidation coatings is safe in vivo. It has higher corrosion resistance than ZK60 magnesium alloy without any surface treatment. PMID- 23937040 TI - [Balloon kyphoplasty for the treatment of osteoporotic Kummell's disease]. AB - OBJECTIVE: To explore the clinical efficacy of the percutaneous kyphoplasty for the treatment of osteoporotic Kummell's disease. METHODS: From May 2010 to February 2012, 8 patients with osteoporotic Kummell's disease were treated with percutaneous balloon kyphoplasty. There were 2 males and 6 females, with a mean age of 73.4 years. All the patients suffered from lower back pain for 4.7 months, which affected seriously the patient's quality of life. The anterior vertebral height and Cobb angel was measured on standing lateral radiograph at pre- and post-operatively (2 days after operation) and during the final follow-up. Visual analog scale (VAS), Japanese Orthopedic Association (JOA) and Oswestry disability index (ODI) were used to evaluate pain and function. RESULTS: Incision of all patients healed normally without infection. The level of back pain decreased remarkably after surgery. The mean time of ambulation was 4.3 days (ranged, 1 to 10 days). Cement leakage occurred in 1 case with no symptom. The anterior vertebral height and Cobb angel of the fractured vertebra recovered respectively from preoperative (30.4 +/- 7.4)% and (31.3 +/- 9.9) degree to (70.3 +/- 3.3)% and (9.1 +/- 3.0) degree at the 2nd day after operation. VAS and JOA scores, ODI improved from preoperative 8.7 +/- 1.2, 12.3 +/- 1.7 and (93.3 +/- 4.6)% to 3.1 +/- 1.1, 24.9 +/- 1.6 and (32.2 +/- 5.4)% respectively at the 2nd day after operation. All the patients were followed up, and the duration ranged from 3 to 24 months, with a mean of 4.7 months. At the latest follow-up, the anterior vertebral height and Cobb angel of the fractured vertebra were (69.9 +/- 3.2)% and (10.9 +/- 2.4) degree; the VAS and JOA scores and ODI were 2.2 +/- 1.0, 26.4 +/- 1.4 and (29.2 +/- 4.5)% respectively, which had no obvious difference compared to those results at the 2nd day after operation. CONCLUSION: Balloon kyphoplasty is safe and effective treatment for osteoporotic Kummell's disease. PMID- 23937041 TI - [Treatment of comminuted distal tibial fractures with the less invasive stabilization system (LISS)]. AB - OBJECTIVE: To evaluate clinical effects of minimal invasive stabilization system (LISS) for the treatment of comminuted distal tibial fractures. METHODS: From February 2006 to February 2010, 48 patients with comminuted distal tibial fractures were treated with LISS. There were 30 males and 18 females, ranging in age from 18 to 78 years. According to AO classification, there were 13 cases of A3, 19 cases of B1, 10 cases of C1 and 6 cases of C2. All the patients were treated with indirect reduction, small incision and followed up at the 1st, 3rd and 6 months, 1 year after operation. RESULTS: All the patients were followed up, and the duration ranged from 6 to 15 months (averaged, 12.5 months). Active and passive exercises started at the first day after surgery without casting. The average time of full weight loading were 12.3 weeks (ranged, 11 to 16 weeks). No complications, such as nonunion, breakage of plate and screw or deep infection, occurred in all patients. The mean operation time was 50 minutes (ranged, 45 to 60 min) and the average length of incision was 6 cm (ranged, 5 to 7 cm). According to Helfer criterion for clinical result, excellent results were obtained in 37 patients, good in 7, and fair in 4. CONCLUSION: Since LISS combined with indirect reduction and minimal invasion provides solid fixation, promotes bone heeling and permits early functional rehabilitation, which is well suited for the treatment of severe distal tibial fractures. PMID- 23937042 TI - [Research on minimally invasive release treatment of stenosing tenosynovitis of flexor digitorum]. AB - The minimally invasive release treatment of TCM Small Needle-Knife for the stenosing tenosynovitis of flexor digtorum-"trigger finger" has a more satisfied efficacy. In recent years, many clinicians use self-made small sharp scalpels, iris knives, small sickles, push shear knives, and other improved alternatives to instead of the traditional small needle-knives. Changing the original small needle-knife vertical stabbed cutting method, take a mini-incision, along the traveling direction of flexor tendon make a vertical hook cut, pick cut, straight push cut and any other cuts, completely cut the stenosis of the tendon sheath pulley, to achieve the release therapeutic purposes. The experience of most scholars is: Detailed and thorough understanding refers to the anatomical level of the flexor tendon and surrounding tissue, the structural relationship; Strictly adhere to the indications of minimally invasive release therapy; Proficiency in a dedicated minimally invasive release needle-knives, scalpels, and standardized methods of operation; Accurate positioning before surgery, in surgery traveling direction along flexor tendon, continuous incision to release the middle along the tendon. It can achieve the same or even higher incision release efficacy than the traditional treatment, at the same time also avoids common adverse complications. PMID- 23937043 TI - [Research advances in anterior cruciate ligament reconstructions with remnant preservation]. AB - More ACL tissue were preserved in ACL reconstruction with remnant-preserving than in classic ACL reconstruction. Some studies showed the results in promoting biological healing after undergoing these two procedures, while other studies did not find the clear advantages in clinical outcomes comparing with the classical ACL reconstruction. There were still some controversies in clinical significances for these complicated ACL reconstructions with remnant-preserving. The article summarized recent original studies about ACL reconstruction with remnant preserving, as well as reviewed the biological characteristics, classification, procedure and clinical outcomes for these two techniques. PMID- 23937044 TI - [Biological role of fetuin A and its potential importance for prediction of cardiovascular risk in patients with type 2 diabetes mellitus]. AB - The authors' data and those from literature concerning biological role of fetuin A glycoprotein have been generalized in the article. A direct correlation has been established between fetuin A and some adipokines involved in the formation of insulin resistance and atherogenesis (progranulin, omentin-1), and osteoprotegerin (the novel cardiovascular risk factor) as well as an increase of circulating levels of fetuin A in patients with type 2 diabetes mellitus with high cardiovascular risk metabolic pattern but without manifestations of macrovascular complications. This substantiates the involvement of fetuin A in the complex of biomarkers of subclinical atherosclerosis. PMID- 23937045 TI - [Effect of glyphosate on the energy exchange in carp organs]. AB - The use of glyphosate as a herbicide in agriculture can lead to the presence of its residues and metabolites (aminomethylphosphonic acid) in food for human consumption and pose a threat to health. The effect of these herbicides on the fish organism at the biochemical level has been insufficiently studied. We studied changes in the content of adenine nucleotides, enzyme activity, quantitative indexes of energy metabolism substrates in carp under the action of glyphosate. It has been found that proteins are the major energy substrate under the influence of glyphosate in the liver, brain, white muscle of carp yearlings. Glyphosphate decreases energy metabolism in the brain of carp and increases it in the white muscles. The growth of activity of catabolic enzymes in the liver under the influence of glyphosate can be attributed to the adaptive remodelling of metabolic pathways for homeostasis and enantiostasis in response to herbicides. PMID- 23937046 TI - [Purification and properties of a catalytically active fragment of soluble nucleoside triphosphatase from bovine kidney]. AB - A catalytic fragment of soluble NTPase has been isolated from bovine kidneys.The 236-fold purification was carried out to obtain the preparation with a specific activity of 37.7 U/mg of protein. The purification scheme included the enzyme extraction followed by four column chromatography steps. The catalytic fragment was activated with divalent metal ions, had a pH optimum of 7.0, and possessed specificity for ITP, GTP, UTP and XTP. The apparent K(m) for Mg-ITP, Mg-GTP and Mg-UTP complexes were calculated from Hanes plots to be 1.70 mM, 0.93 mM and 0.48 mM, respectively. As estimated by gel filtration and SDS-PAAGE, the catalytic fragment has Mw 54.7 kDa being composed of two identical polypeptide chains. Our results suppose soluble NTPase from bovine kidney to consist of regulatory and catalytic structural units. PMID- 23937047 TI - [The effect of ATP-dependent K(+)-channel opener on the functional state and the opening of cyclosporine-sensitive pore in rat liver mitochondria]. AB - The effect of mitochondrial ATP-dependent K(+)-channel (K+(ATP)-channel) opener diazoxide (DZ) on the oxygen consumption, functional state and the opening of cyclosporine-sensitive pore in the rat liver mitochondria has been studied. It has been established that K+(ATP)-channel activation results in the increase of the oxygen consumption rate (V4(s)) and the uncoupling due to the acceleration of K(+)-cycling, the decrease in state 3 respiration rate (V3) and the respiratory control ratio (RCR). Under K+(ATP)-channel activation an inhibition of oxidative phosphorylation takes place which reduces the rate of ATP synthesis and hydrolysis as well as ATP production and consequently results in the seeming increase of P/O ratio. It has been shown that the increase in ATP-dependent K(+) uptake accompanied by the opening of mitochondrial permeability transition pore (MPTP) leads to dramatic uncoupling of the respiratory chain due to simultaneous activation of K(+)- and Ca(2+)-cycling supported by MPTP and Ca(2+)-uniporter as well as K(+)-channels and K+/H(+)-exchange. K+(ATP)-channel activation leads to the partial inhibition of MPTP, but insufficient for the restoration of mitochondrial functions. Elimination of Ca(2+)-cycling after MPTP opening is necessary to return mitochondrial functions back to the control level which shows that MPTP could serve as the mechanism of reversible modulation of bioenergetic effects of K+(ATP)-channel activation. PMID- 23937048 TI - [Functions of metallothioneins and a system of antioxidant defense under the effect of Co- and Zn-containing nanocomposites on crucian carp (Carassius auratus gibelio)]. AB - The effect of metal-nanocomposites (Me-NC) of cobalt and zinc (Co- and Zn-NC, correspondingly) synthecized on the basis of vinylpyrrolidone (PS) on the metal accumulative proteins with antioxidant potential metallothioneins (MT) in crucian carp (Carassius auratus gibelio) was studied. Fish was subjected to the effect of Co-NC, Zn-NC, Co2+, Zn2+ or polymer carrier (PC) in the concentrations correspondent to 50 microg x Co/l or 100 microg x Zn/l during 14 days. It was shown that the MTs response is highly specific for the nature of metal, both in ion and Me-NC form: the effect of Co and Co-NC provoked the elevation of total MT concentration (MT-SH) and activation of antioxidant defence, whereas Zn and Zn-NC induced the decrease of the concentration of MT-SH and the inhibition of antioxidant defense. All the exposures provoked the decrease of the concentration of immunoreactive chelating MT form (MTi) and reduced glutathione, activation of anaerobiosys and Mn-superoxide dismutase, and also decrease of the concentration of proteins and lipids oxidative injury products. It was accompanied by the increase of the content of erythrocytes with nuclear abnormalities but did not cause the decrease of choline esterase activity. According to the rate of MT-SH and MTi concentrations, antioxidant potential of MTs is determined by its apoform. Our data indicate that partial biodegradation of Me-NC occurs in the organism of crucian carp. PMID- 23937049 TI - [Reactive oxygen forms and Ca ions as possible intermediaries under the induction of heat resistance of plant cells by jasmonic acid]. AB - The participation of reactive oxygen species (ROS) and calcium ions in realization of influence of exogenous jasmonic acid (JA) on the heat resistance of wheat coleoptiles has been investigated. Influence of 1 microM JA caused the transitional intensifying of generation of superoxide anion-radical (O2*-) and hydrogen peroxide in coleoptiles with the maximum within 15-30 minutes after the treatment beginning. Within the first hour after the beginning of coleoptiles treatment with JA the increase of superoxide dismutase (SOD) activity was noted. Later on (within 5-24 hours after the treatment beginning) there was the lowering of ROS generation by coleoptiles of experimental variant, and the SOD activity approached the control value. Intensifying of generation of superoxide radical induced by JA was suppressed by the antioxidant ionol and was partially levelled by imidazole (inhibitor of NADPH-oxidase), EGTA (chelator of extracellular calcium) and lanthanum chloride (calcium channels blocker). Pretreatment of coleoptiles with the ionol, imidazole, EGTA and LaC3l3 also partially removed the effect of increase of their resistance to the damaging heating caused by exogenous JA. It is supposed that the ROS generated with participation NADPH oxidase, which activity depends on the receipt of calcium ions from extracellular space in the cytosol, are involved in realization of physiological effects of JA. PMID- 23937050 TI - [Adjuvant properties of polymer based on acrylic acid]. AB - Adjuvant properties of the polymer containing acrylic acid, glycidyl methacrylate, triethylene glycol methacrylate and butyl acrylate have been established. Antibodies to ovalbumin and bovine serum albumin in the blood of mice were revealed using dot blot analysis and immunoenzyme analysis when applying the investigated polymer as a carrier of these protein antigens. Adjuvant properties of the polymer were compared to aluminum hydroxide, which is a component of many traditional vaccines. Experimental polymer was a stronger adjuvant because it led to an increase of specific antibodies against ovalbumin and bovine serum albumin. PMID- 23937051 TI - [Effect of dihydropyrrol and maleimide derivatives on the state of the liver and colon in normal rats and those with colorectal carcinogenesis induced by dimethylhydrazine]. AB - No liver and colon alterations in rats, caused by cytostatic compounds 5-amino-4 (1,3-benzothyazol-2-yl)-1-(3-methoxyphenyl)-1,2-dihydro-3H-pyrrol-3-one (D1) and 1-(4-Cl-benzyl)-3-Cl-4-(CF3-phenylamino)-1H-pyrrol-2,5-dione (MI-1) when administered over a long time were found, as evidenced by the histopathological data and the data of activity of transaminases, alkaline phosphatase and lactate dehydrogenase in the blood serum. D1 and MI-1 in vivo decrease the total area of DMH-induced colon tumors in rats by 46-60%. Furthermore, D1 and MI-1 partially protect the liver and colon mucosa from toxic effects caused by 1,2 dimethylhydrazine (DMH) reducing DNA oxidative modifications, as evidenced by urine 8-hydroxydeoxyguanosine level. The effects of both compounds are similar, but MI-1 is less toxic for the liver and colon of intact animals possessing more pronounced antitumor activity and protective properties in the setting of chemically induced carcinogenesis. PMID- 23937052 TI - [Influence of ademol on NO metabolism indices in rats with modeling myocardial infarction]. AB - It was established in experiments on the rats in the acute period of modeling pituitrin-isadrin myocardial infarction the formation of nitrogen monoxide decreases along with its accelerated transformation into peroxynitrite. It was evidenced by more than double inhibition of NO synthase activity in the myocardium and by decreasing the amount of nitrates on the background of the increasing level of peroxynitrites' marker--nitrotyrosine by 246.6% at an average. Experimental therapy of rats by ademol which is a derivate of adamantan (1-adamantiloxy-3-morpholino-2 propanol hydrochloride) better than by corvitin normalizes the processes of synthesis of nitric oxide. At the same time ademol probably exceeded the reference drug in ability to increase NO synthase activity and amount of nitrate, and promoted a decrease of the level of nitrotyrosine in the myocardium on the average by 36.3; 50.6 and 12.7%, respectively. Corrective influence of ademol on indicators of metabolism in NO system under the conditions of acute cardiac ischemia indicates to promicing development of domestic cardioprotector on its base. PMID- 23937053 TI - Facile method for site-specific gene integration in Lysobacter enzymogenes for yield improvement of the anti-MRSA antibiotics WAP-8294A and the antifungal antibiotic HSAF. AB - Lysobacter is a genus of Gram-negative gliding bacteria that are emerged as novel biocontrol agents and new sources of bioactive natural products. The bacteria are naturally resistant to many antibiotics commonly used in transformant selection, which has hampered the genetic manipulations. Here, we described a facile method for quick-and-easy identification of the target transformants from a large population of the wild type and nontarget transformants. The method is based on a distinct yellow-to-black color change as a visual selection marker for site specific integration of the gene of interest. Through transposon random mutagenesis, we identified a black-colored strain from the yellow-colored L. enzymogenes . The black strain was resulted from a disruption of hmgA, a gene required for tyrosine/phenylalanine metabolism. The disruption of hmgA led to accumulation of dark brown pigments. As proof of principle, we constructed a series of expression vectors for a regulator gene found within the WAP-8294A biosynthetic gene cluster. The yield of WAP-8294A in the black strains increased by 2 fold compared to the wild type. Interestingly, the yield of another antibiotic (HSAF) increased up to 7 fold in the black strains. WAP-8294A is a family of potent anti-MRSA antibiotics and is currently in clinical studies, and HSAF is an antifungal compound with distinct structural features and a novel mode of action. This work represents the first successful metabolic engineering in Lysobacter. The development of this facile method opens a way toward manipulating antibiotic production in the largely unexplored sources. PMID- 23937054 TI - Cd2+ as a Ca2+ surrogate in protein-membrane interactions: isostructural but not isofunctional. AB - Due to its favorable spectroscopic properties, Cd(2+) is frequently used as a probe of Ca(2+) sites in proteins. We investigate the ability of Cd(2+) to act as a structural and functional surrogate of Ca(2+) in protein-membrane interactions. C2 domain from protein kinase Calpha (C2alpha) was chosen as a paradigm for the Ca(2+)-dependent phosphatidylserine-binding peripheral membrane domains. We identified the Cd(2+)-binding sites of C2alpha using NMR spectroscopy, determined the 1.6 A crystal structure of Cd(2+)-bound C2alpha, and characterized metal-ion dependent interactions between C2alpha and phospholipid membranes using fluorescence spectroscopy and ultracentrifugation experiments. We show that Cd(2+) forms a tight complex with the membrane-binding loops of C2alpha but is unable to support its membrane-binding function. This is in sharp contrast with Pb(2+), which is almost as effective as Ca(2+) in driving the C2alpha-membrane association process. Our results provide the first direct evidence for the specific role of divalent metal ions in mediating protein-membrane interactions, have important implications for metal substitution studies in proteins, and illustrate the potential diversity of functional responses caused by toxic metal ions. PMID- 23937055 TI - Kinetics of xylem loading, membrane potential maintenance, and sensitivity of K(+) -permeable channels to reactive oxygen species: physiological traits that differentiate salinity tolerance between pea and barley. AB - Salt sensitive (pea) and salt tolerant (barley) species were used to understand the physiological basis of differential salinity tolerance in crops. Pea plants were much more efficient in restoring otherwise depolarized membrane potential thereby effectively decreasing K(+) efflux through depolarization-activated outward rectifying potassium channels. At the same time, pea root apex was 10 fold more sensitive to physiologically relevant H2 O2 concentration and accumulated larger amounts of H2 O2 under saline conditions. This resulted in a rapid loss of cell viability in the pea root apex. Barley plants rapidly loaded Na(+) into the xylem; this increase was only transient, and xylem and leaf Na(+) concentration remained at a steady level for weeks. On the contrary, pea plants restricted xylem Na(+) loading during the first few days of treatment but failed to prevent shoot Na(+) elevation in the long term. It is concluded that superior salinity tolerance of barley plants compared with pea is conferred by at least three different mechanisms: (1) efficient control of xylem Na(+) loading; (2) efficient control of H2 O2 accumulation and reduced sensitivity of non-selective cation channels to H2 O2 in the root apex; and (3) higher energy saving efficiency, with less ATP spent to maintain membrane potential under saline conditions. PMID- 23937056 TI - A systematic review of activities of daily living measures for children and adolescents with cerebral palsy. AB - AIM: This study aimed to systematically review the psychometric properties and clinical utility of measures of activities of daily living (ADL) for children with cerebral palsy (CP) aged 5 to 18 years. METHOD: Five electronic databases were searched to identify available ADL measures with published psychometric data for school-aged children with CP. Measures were included if at least 60% of the items addressed ADL in the full assessment or in an independent domain. A modified CanChild Outcome Rating Form was used to report the validity, reliability, responsiveness, and clinical utility of the measures. RESULTS: Twenty-six measures were identified and eight met inclusion criteria. The Pediatric Evaluation of Disability Inventory (PEDI) had the strongest psychometric properties but was limited by its age range. The Assessment of Motor and Process Skills (AMPS) was the most comprehensive evaluation of underlying motor and cognitive abilities yet further psychometric testing is required for children with CP. INTERPRETATION: The PEDI should be used to measure ADL capability in elementary school aged children. The AMPS is the best measure to evaluate ADL performance or capacity and is suitable for all ages. Future research should examine the reliability of the AMPS to determine its stability in children and adolescents with CP. PMID- 23937057 TI - Conjugate addition reactions of N-carbamoyl-4-pyridones and 2,3-dihydropyridones with Grignard reagents in the absence of Cu(I) salts. AB - N-Boc- and N-ethoxycarbonyl-4-pyridones and the resulting 2,3-dihydropyridones undergo 1,4-addition reactions with Grignard reagents in the presence of chlorotrimethylsilane (TMSCl) or BF3.Et2O in excellent yields. Copper catalysis is not required, and mechanistic considerations suggest that the reaction is proceeding by a conjugate addition pathway rather than by a pathway involving 1,2 addition to an intermediate pyridinium ion. TMSCl-mediated conjugate addition of Grignard reagents to 2-substituted-2,3-dihydropyridones gives the trans-2,6 disubstitued piperidinones stereoselectively, while cuprate reagents give either the trans or cis diastereomers or mixtures. PMID- 23937058 TI - An examination of the baropathic nature of axial myopia. AB - An examination of how intraocular pressure distending forces on the posterior sclera are an important mechanism in the development and progression of axial myopia has been made. Papers were selected from the results of PubMed (143) and Science Direct (1,398) searches using the key word combinations of 'axial myopia' and 'intraocular pressure'. The main points include that the sclera is exposed to distending forces at all levels of physiological and pathological intraocular pressure. Reversible axial elongation is a common physiological response to elevated intraocular pressure in healthy eyes but more so in myopic eyes. Key variables, which appear to determine pathological (non-reversible) axial elongation include the thickness, rigidity and viscoelasticity of the posterior sclera and the associated increased susceptibility of it to distending forces. Intraocular pressure appears likely to have a greater role when it is above normal. Intraocular pressure elevations, which are not detected by clinical or experimental tonometry, may be significant contributors to axial elongation. Axial elongation can be pathological in myopic or myopically predisposed eyes, when elongation is not reversible. Axial elongation has also been associated with retinal defocus in both animals and humans, when thinning due to loss of scleral collagen and/or ground substance, which is driven by the retina, appears likely to be associated with increased scleral susceptibility to intraocular pressure. As myopia progresses, signs of retinal and choroidal stretching are an increasingly apparent consequence of the balloon-like expansion of the posterior sclera in response to intraocular pressure. Avoidance or moderation of activities which are known to elevate intraocular pressure may improve the prognosis for patients with genetic and/or environmental predisposition to myopic progression and may be an important consideration, even when other myopic control measures are being used. PMID- 23937059 TI - Diphenyl viologen on an HOPG electrode surface: less sharp redox wave than dibenzyl viologen. AB - Redox behavior of diphenyl viologen (dPhV) on a basal plane of a highly oriented pyrolytic graphite (HOPG) electrode was described using the results of voltammetric and electroreflectance measurements. Its characteristics were compared to those of dibenzyl viologen (dBV), which undergoes the first-order faradaic phase transition. Unlike dBV, dPhV-dication (dPhV(2+)) was found to take a strongly adsorbed state on an HOPG surface. This is due to much stronger pi-pi interaction between phenyl rings of dPhV(2+) and HOPG surface than between benzyl groups of dBV(2+) and the surface. The participation of this strongly adsorbed dPhV(2+) in the redox process can be avoided by (1) a shorter than ~3 min time period elapsing from touching a freshly cleaved HOPG surface to dPhV solution until the start of potential scan, (2) complete equilibration at the electrode potentials at which superficial dPhV molecules are fully reduced, or (3) multiple cyclic potential scanning to repeat oxidation-reduction of adsorbed species. Even in such conditions, although voltammograms of thin-layer electrochemistry for the surface-confined dPhV(*+)/dPhV(2+) couple are obtained with peak widths being as narrow as those of dBV, it is not the first-order phase transition. The participation of strongly adsorbed dPhV(2+) molecules results in another new voltammetric feature with a broader peak. The film formed by strongly adsorbed dPhV(2+) was hydrophilic, whereas dBV(2+) does not form such a film but only a gas-like layer. Measurements using X-ray photoelectron spectroscopy confirmed that the film consists of dPhV(2+) with coexistent water. These results reveal a typical case that delicate interaction balance among V(2+), V(*+), and electrode surface determines whether the two-dimensional first-order transition takes place or not. PMID- 23937060 TI - "It's not all doom and gloom": perceptions of medical students talking to hospice patients. AB - BACKGROUND: End-of-life care has become a priority in medical education internationally. A previous study of hospice patients and staff regarding medical students teaching in a hospice showed positive responses from patients and hospice staff. However concern was expressed by some staff regarding medical students' welfare, contributing to gatekeeping by professionals. Studies have shown that medical students feel underprepared to care for the dying by the time they qualify. OBJECTIVE: The study's objective was to explore in more detail the views and experience of medical students who had spoken with patients during their hospice placement. DESIGN: This was a qualitative study. SETTING/SUBJECTS: The study was carried out with 14 Hull York Medical School (HYMS) students who had responded in an electronic survey that they had spoken with patients during their hospice placement. MEASUREMENT: Semistructured interviews provided the study's data. RESULTS: Although students expressed some anxieties prior to their hospice visit about meeting patients who were near the end of life, they felt that the overall experience, and the time spent with patients in particular, provided valuable learning about palliative care and preparation for caring for dying patients. CONCLUSIONS: We would encourage staff to not be overprotective but to support students to take every opportunity to meet with patients in a hospice. PMID- 23937061 TI - Hospice staff perspectives on Dignity Therapy. AB - BACKGROUND: Dignity Therapy is a brief psychotherapy performed with patients at the end of life. Previous research has examined the effects of Dignity Therapy with patients and family, but none has examined hospice staff perceptions of the treatment. OBJECTIVE: The study objective was to investigate hospice staff perspectives regarding the impact and value of Dignity Therapy when provided as a clinical service. METHODS: Eighteen hospice staff members who referred patients for Dignity Therapy were asked to rate the value of the treatment. The staff also completed qualitative interviews to gather more detailed information about their most common reasons for referral; their perspectives regarding the therapy's impact on patients; and their beliefs about the costs, benefits, and barriers to treatment. The staff interview responses were qualitatively analyzed to measure the most common emergent themes. RESULTS: Hospice staff members rated Dignity Therapy as worthwhile, and somewhat able to reduce patients' pain and suffering. The vast majority (92%) of hospice staff members believed the treatment would help patients' families in the future, and 100% reported a desire to recommend the treatment to others. Qualitative analyses revealed that staff commonly viewed Dignity Therapy as a positive, affirming experience for patients and felt the emotional or time requirements of the treatment were justified. As a result of offering the service, the staff noted an increased connection with patients and related increases in job satisfaction. CONCLUSIONS: Hospice staff believe Dignity Therapy is a worthwhile service that offers a positive, quality-enhancing experience for patients at the end of life. The addition of this clinical service may further enhance staff members' job satisfaction and connection with patients. These findings provide useful information for clinicians or organizational leaders who consider offering Dignity Therapy in their setting. PMID- 23937063 TI - An evaluation of interactive web-based curricula for teaching code status discussions. AB - BACKGROUND: Teaching resuscitation discussions to medical students and residents is time intensive and should be taught by teachers with competence in this area of clinical practice. There are plenty of data that these discussions are often inadequate, and that communication skills training, while time and faculty intensive, improves these conversations. The role of online instruction in teaching communication skills, such as resuscitation discussions, is not established. OBJECTIVE: The study objective was to evaluate the effectiveness of an interactive online curriculum in teaching code status discussions to third year medical students at one medical school. DESIGN: In this study we block randomized third-year medical students to one of two web-based curricula versus a similar written curriculum and used standardized patient scores on a communication exercise to measure differences in performance. We used student surveys to measure student satisfaction with the curricula. SETTING/SUBJECTS: Of 121 students participating in the study between April 2007 and March 2008, 88 were randomized to one of two website formats and 33 to the written curriculum. MEASUREMENTS: We compared average scores on content and communication checklists between groups. RESULTS: There were no differences between the three groups in the primary outcome of student performance. We could not analyze data on satisfaction with or completion rates for the three curricula due to poor response rates to the student surveys. CONCLUSIONS: This block randomized study of web-based curricula versus a written curriculum did not show differences in student performance in code status discussions. The optimal use of online communication training remains unclear and requires further investigation. PMID- 23937062 TI - The utility of reflective writing after a palliative care experience: can we assess medical students' professionalism? AB - BACKGROUND: Medical education leaders have called for a curriculum that proactively teaches knowledge, skills, and attitudes required for professional practice and have identified professionalism as a competency domain for medical students. Exposure to palliative care (PC), an often deeply moving clinical experience, is an optimal trigger for rich student reflection, and students' reflective writings can be explored for professional attitudes. OBJECTIVE: Our aim was to evaluate the merit of using student reflective writing about a PC clinical experience to teach and assess professionalism. METHODS: After a PC patient visit, students wrote a brief reflective essay. We explored qualitatively if/how evidence of students' professionalism was reflected in their writing. Five essays were randomly chosen to develop a preliminary thematic structure, which then guided analysis of 30 additional, randomly chosen essays. Analysts coded transcripts independently, then collaboratively, developed thematic categories, and selected illustrative quotes for each theme and subtheme. RESULTS: Essays revealed content reflecting more rich information about students' progress toward achieving two professionalism competencies (demonstrating awareness of one's own perspectives and biases; demonstrating caring, compassion, empathy, and respect) than two others (displaying self-awareness of performance; recognizing and taking actions to correct deficiencies in one's own behavior, knowledge, and skill). CONCLUSIONS: Professional attitudes were evident in all essays. The essays had limited use for formal summative assessment of professionalism competencies. However, given the increasing presence of PC clinical experiences at medical schools nationwide, we believe this assessment strategy for professionalism has merit and deserves further investigation. PMID- 23937064 TI - Using medical words with family caregivers. AB - BACKGROUND: Although there is poor communication about pain management between informal caregivers and hospice providers, little research has examined these interactions. OBJECTIVE: This study explored communication between informal caregivers and hospice team members by investigating the use of medical words in care planning discussions. DESIGN: Transcripts of clinical communication between caregivers and hospice team members were reviewed for use of medical words, word placement (statement or question), whether or not the word was explained, and the caregiver's response to the word. SETTING/SUBJECTS: As part of an ongoing randomized clinical trial in the midwestern United States, informal hospice caregivers participated in recorded hospice care planning discussions. MEASURES: A selection of videorecorded interactions from an ongoing study was analyzed. RESULTS: Hospice team members used six times as many medical words compared to caregivers. The majority of medical words used by caregivers and team members were drug names. Medical words were predominantly used as statements rather than questions that sought clarification. Three-fourths of medical words used by team members were not explained to caregivers. Caregivers provided little response to medical word use, indicating a lack of understanding. CONCLUSIONS: The propensity to use medical words during clinical communication with family caregivers is cautioned. In order to recognize the caregiver as a contributing team member, clinicians should limit the use of medical words, provide lay explanation alongside medical terminology, and use questions to check for understanding. More research is needed to determine assessment tools to capture the caregiver's level of understanding of medication and pain management protocol. PMID- 23937065 TI - Haploinsufficiency of endogenous parathyroid hormone-related peptide impairs bone fracture healing. AB - Previous studies have demonstrated that endogenous parathyroid hormone-related peptide (PTHrP) plays a central role in the physiological regulation of bone formation. However, it is unclear whether endogenous PTHrP plays an important function in enhancing bone fracture healing. To determine whether endogenous PTHrP haploinsufficiency impaired bone fracture healing, closed mid-diaphyseal femur fractures were created in 8-week-old wild-type and Pthrp(+/-) mice. Callus tissue properties were analysed 1, 2 and 4 weeks after fracture by radiography, histology, histochemistry, immunohistochemistry and molecular biology. The size of the calluses was reduced 2 weeks after fracture, and the fracture repairs were poor 4 weeks after fractures, in Pthrp(+/-) compared with wild-type mice. Cartilaginous callus areas were reduced 1 week after fracture, but were increased 2 weeks after fracture in Pthrp(+/-) mice. There was a reduction in the number of ostoblasts, alkaline phosphatase (ALP)-positive areas, Type I collagen immunopositive areas, mRNA levels of ALP, Runt-related transcription factor 2 (Runx2) and Type I collagen, Runx2 and insulin-like growth factor-1 protein levels, the number of osteoclasts and the surface in callus tissues in Pthrp(+/-) compared with wild-type mice. These results demonstrate that endogenous PTHrP haploinsufficiency impairs the fracture repair process by reducing cartilaginous and bony callus formation, with downregulation of osteoblastic gene and protein expression and a reduction in endochondral bone formation, osteoblastic bone formation and osteoclastic bone resorption. Together, the results indicate that endogenous PTHrP plays an important role in fracture healing. PMID- 23937066 TI - Tanshinone IIA exhibits anticonvulsant activity in zebrafish and mouse seizure models. AB - Danshen or Chinese red sage (Salvia miltiorrhiza, Bunge) is used by traditional Chinese medicine (TCM) practitioners to treat neurological, cardiovascular, and cerebrovascular disorders and is included in some TCM formulations to control epileptic seizures. In this study, acetonic crude extracts of danshen inhibited pentylenetetrazol (PTZ)-induced seizure activity in zebrafish larvae. Subsequent zebrafish bioassay-guided fractionation of the extract resulted in the isolation of four major tanshinones, which suppressed PTZ-induced activity to varying degrees. One of the active tanshinones, tanshinone IIA, also reduced c-fos expression in the brains of PTZ-exposed zebrafish larvae. In rodent seizure models, tanshinone IIA showed anticonvulsive activity in the mouse 6-Hz psychomotor seizure test in a biphasic manner and modified seizure thresholds in a complex manner for the mouse i.v. PTZ seizure assay. Interestingly, tanshinone IIA is used as a prescription drug in China to address cerebral ischemia in patients. Here, we provide the first in vivo evidence demonstrating that tanshinone IIA has anticonvulsant properties as well. PMID- 23937067 TI - The metabolic effect of resistant starch and yoghurt on the renal and faecal nitrogen and ammonia excretion in humans as measured by lactose-[(15)N2]ureide. AB - Resistant starch (RS) and Lactobacillus acidophilus yoghurt (LC1) were supplemented simultaneously in healthy adults to evaluate the effect on the urinary and faecal nitrogen and ammonia excretion by means of lactose [(15)N2]ureide ((15)N-LU) degradation. Nineteen subjects received a regular daily diet either without or with supplementation of an RS-LC1-mixture composed of fibre of potatoes (RS type 1), wrinkle pea starch (RS type 2), and LC1 over a 20 day period in randomised order. Thereafter, (15)N-LU was administered together with breakfast. Urine and faeces were collected over a period of 48 and 72 h, respectively. The (15)N abundances were measured by isotope ratio mass spectrometry. The intake of the pre- and probiotic mixture composed of RS of type 1, type 2 and of LC1 significantly lowered the colonic generation and the renal excretion of toxic (15)NH3 and functioned as an ammonia shift from urinary to faecal (15)N excretion when using (15)N-LU as a xenobiotic marker. PMID- 23937068 TI - Ultraviolet photodissociation dynamics of the o-pyridyl radical. AB - Ultraviolet (UV) photodissociation dynamics of jet-cooled o-pyridyl radical (o C5H4N) was studied in the photolysis region 224-246 nm using the high-n Rydberg atom time-of-flight (HRTOF) technique. The o-pyridyl radicals were produced from 193 nm photolysis of 2-chloropyridine and 2-bromopyridine precursors. The H-atom photofragment yield (PFY) spectrum contains a broad peak in this wavelength region and reveals the UV absorption feature of o-pyridyl for the first time. The translational energy distributions of the H-atom loss product channel, P(ET)'s, peak at ~7 kcal/mol, and the fraction of average translational energy in the total excess energy, , is nearly constant at ~0.18 in the region 224-242 nm. The P(ET) distribution indicates the production of the lowest energy dissociation products, H + cyanovinylacetylene. The H-atom product angular distribution is isotropic. The dissociation mechanism is consistent with unimolecular dissociation of the hot o-pyridyl radical to H + cyanovinylacetylene after internal conversion from the electronically excited state. PMID- 23937069 TI - Cellular uptake on N- and C-termini conjugated FITC of Rath cell penetrating peptides and its consequences for gene-expression profiling in U-937 human macrophages and HeLa cervical cancer cells. AB - Rath peptide has been introduced as a delivery vector that transports various membrane-impermeable cargoes in a non-covalent fashion. In this paper, we present a study on Rath peptide conjugated with fluorescein-5-isothiocynate (FITC) differing in its N- and C-termini. We conducted cellular toxicity and uptake experiments in U-937 and HeLa cells to analyze biocompatibility profiles and translocation efficiencies of Rath peptide with FITC serving as both a cargo and a fluorescent marker. We found that the conjugation of FITC on Rath peptide at N terminus (FITC-Rath) led to more rapid cellular uptake in U-937 cells and significantly higher cellular uptake in HeLa cells than that which occurred at C terminus. From DNA microarray analysis, FITC-Rath induced gene expression changes in both U-937 and HeLa cells. Five overlapping regulated genes were identified, and this overlap indicated that FITC-Rath displayed some degree of generality regarding gene responses in the two cell lines used. A real-time quantitative reverse transcriptase-polymerase chain reaction was used to confirm which regulated genes were affected by FITC-Rath. Cell communication, signal transduction, cell surface receptor signaling pathway, signal transducer activity and cellular process, were identified as overlapping biological themes. These data provide useful information on molecular mechanisms for using Rath-based delivery systems. PMID- 23937071 TI - A hospital nursing research enhancement model. AB - Evidence-based practice is fundamental to nursing, yet there are many reports in the literature of the difficulty associated with incorporating research activity that leads to evidence-based practice into daily practice. This study used a hospital-based research enhancement model (HREM) to plan, develop, and implement a research outreach ward-based seminar (ROWS) program and evaluate its effectiveness as a means for nurses to increase their knowledge and capacity in research and evidence-based practice. A survey was used to collect both quantitative and qualitative data for evaluation of the program. A total of 78 evaluations were returned after ROWS attendance. Three main themes from the survey were explored. These include accessibility of research, appreciation and application of research, and training in research. The results suggested that nurses are interested in participating in research activities, including projects, best practice forums, journal clubs, and seminars. The HREM can address some common barriers to an evidence-based practice culture and the application of evidence-based practice within nursing. PMID- 23937070 TI - Transcriptome deep-sequencing and clustering of expressed isoforms from Favia corals. AB - BACKGROUND: Genomic and transcriptomic sequence data are essential tools for tackling ecological problems. Using an approach that combines next-generation sequencing, de novo transcriptome assembly, gene annotation and synthetic gene construction, we identify and cluster the protein families from Favia corals from the northern Red Sea. RESULTS: We obtained 80 million 75 bp paired-end cDNA reads from two Favia adult samples collected at 65 m (Fav1, Fav2) on the Illumina GA platform, and generated two de novo assemblies using ABySS and CAP3. After removing redundancy and filtering out low quality reads, our transcriptome datasets contained 58,268 (Fav1) and 62,469 (Fav2) contigs longer than 100 bp, with N50 values of 1,665 bp and 1,439 bp, respectively. Using the proteome of the sea anemone Nematostella vectensis as a reference, we were able to annotate almost 20% of each dataset using reciprocal homology searches. Homologous clustering of these annotated transcripts allowed us to divide them into 7,186 (Fav1) and 6,862 (Fav2) homologous transcript clusters (E-value <= 2e(-30)). Functional annotation categories were assigned to homologous clusters using the functional annotation of Nematostella vectensis. General annotation of the assembled transcripts was improved 1-3% using the Acropora digitifera proteome. In addition, we screened these transcript isoform clusters for fluorescent proteins (FPs) homologs and identified seven potential FP homologs in Fav1, and four in Fav2. These transcripts were validated as bona fide FP transcripts via robust fluorescence heterologous expression. Annotation of the assembled contigs revealed that 1.34% and 1.61% (in Fav1 and Fav2, respectively) of the total assembled contigs likely originated from the corals' algal symbiont, Symbiodinium spp. CONCLUSIONS: Here we present a study to identify the homologous transcript isoform clusters from the transcriptome of Favia corals using a far-related reference proteome. Furthermore, the symbiont-derived transcripts were isolated from the datasets and their contribution quantified. This is the first annotated transcriptome of the genus Favia, a major increase in genomics resources available in this important family of corals. PMID- 23937072 TI - Increased apoptosis and suburothelial inflammation in patients with ketamine related cystitis: a comparison with non-ulcerative interstitial cystitis and controls. AB - OBJECTIVE: To investigate the suburothelial inflammation and urothelial dysfunction that occurs with ketamine-related cystitis (KC) and interstitial cystitis/bladder pain syndrome (IC/BPS). PATIENTS AND METHODS: Bladder tissues from 16 patients with KC, 17 patients with IC/BPS and 10 control subjects were analysed. Immunofluorescence staining of the junction protein E-cadherin was carried out, and tryptase levels and a TUNEL assay were used to assess mast-cell activation and urothelial apoptosis, respectively. The fluorescence intensity of E-cadherin was measured using the ImageJ method. The percentages of activated mast cells and apoptotic cells were calculated as positive cells per unit area (4 MUm(2) ). RESULTS: The mean (sd) ages of the patients in the KC, IC/BPS and control groups were 25.0 (3.8), 41.3 (13.7) and 50.5 (9.6) years, respectively (P < 0.05). The mean (sd) distributions of E-cadherin in KC (10.1 [11.2]) and IC/BPS (25.1 [16.3]) tissues were significantly lower than in the control tissues (42.4 [16.7]; both P < 0.05). The mean (sd) number of activated mast cells, measured by tryptase signals in the KC (6.5 [3.7]) and IC/BPS (4.6 [3.0]) tissues, were significantly higher than in the control tissues (1.3 [1.12]; both P < 0.05). TUNEL staining showed a significantly higher mean (sd) number of apoptotic cells in KC (4.4 [2.5]) and IC/BPS (2.4 [1.7]) tissues than in control tissues (0.1 [0.3]; both P < 0.05). Tissues from the KC bladders had significantly lower expression of E-cadherin (P = 0.024) and significantly higher numbers of apoptotic cells (P = 0.02) compared with the IC/BPS bladder tissues. Greater numbers of apoptotic cells and lower expression levels of E-cadherin significantly correlated with maximum bladder capacity in the overall patient samples (P < 0.05). CONCLUSIONS: KC and IC/BPS tissues both showed defective junction protein, increased suburothelial inflammation and increased urothelial cell apoptosis. Decreased expression of E-cadherin and increased apoptosis were more severe in KC than in IC/BPS bladder tissues and these findings were associated with the clinical symptoms of KC and IC/BPS. PMID- 23937073 TI - Ultrasonographic measurement of amniochorionic membrane in asymptomatic pregnant women is not a useful tool for preterm birth prediction. AB - AIM: The objective of this study was to determine the accuracy of ultrasonographic measurement of amniochorionic membrane thickness (AMT) in the prediction of preterm birth among an asymptomatic pregnant population. METHODS: One hundred and ninety consecutive singleton pregnant women presenting for prenatal care between May 2010 and August 2011 were recruited for the study. AMT of the patients was measured once between 18 and 22 weeks of gestation and then again between 28 and 32 weeks of gestation with transabdominal ultrasound. The results of measurements were recorded and compared with the perinatal outcome related to prematurity. RESULTS: Thirteen of the 190 births were preterm. The mean AMT of the pregnant women who delivered at term were 0.79 +/- 0.23 mm in the second trimester and 0.88 +/- 0.27 mm in the third trimester. The mean AMT of pregnant women who delivered preterm were 0.77 +/- 0.27 mm in the second trimester and 0.91 +/- 0.20 mm in the third trimester. There were no statistically significant differences between the second and third trimester AMT of the preterm delivery group and term delivery group (P = 0.542 and P = 0.448, respectively). CONCLUSION: In this study, ultrasonographic measurement of fetal membranes was not found to be a useful marker for prediction of preterm birth. The findings of our study may help in understanding ultrasonographic changes in fetal membranes in normal pregnancies. PMID- 23937074 TI - The evaluation of patient self-completion concordance forms used in community pharmacy: a comparison of two European countries. AB - OBJECTIVES: To evaluate the use of patient self-completion concordance forms in Dutch and Bulgarian pharmacies. Second, to show any differences in pharmacy practice and patient behaviour in two European countries: the Netherlands and Bulgaria. METHODS: A random sample of 500 pharmacies were approached per country. Patients at the start of a chronic treatment were invited to participate. At the first dispensing patients received a self-completion concordance form (SCCF). Patients were asked to fill in the SCCF at home and bring it to the appointment for their consultation at the second dispensing. After the consultations patients and pharmacists were asked to fill in a questionnaire. KEY FINDINGS: Twenty-four Dutch pharmacies (99 patients) and 41 Bulgarian pharmacies (241 patients) sent back study results. A higher proportion of Bulgarian patients answered questions on the SCCF compared to Dutch patients. Patients from both countries are satisfied with the SCCF, consultation and newly started medicine. CONCLUSIONS: Although differences between pharmacies from the Netherlands and Bulgaria exist, the SCCF can be used at the start of chronic treatment. More research in other European countries will be necessary to further develop the use of the SCCF in community pharmacies. Eventually this could be used to develop indicators to measure patient involvement in pharmaceutical care. PMID- 23937075 TI - Expression of programmed death-1 (CD279) in primary cutaneous B-cell lymphomas with correlation to lymphoma entities and biological behaviour. AB - BACKGROUND: Programmed death-1 (PD-1/CD279) is a cell-surface protein expressed in activated T cells and a subset of T lymphocytes including follicular helper T cells (TFH ). The interaction between PD-1 and its ligands plays a role in immune response and evasion of malignancies. In nodal follicular lymphoma, the number of intratumoral PD-1-positive lymphocytes is associated with overall survival. OBJECTIVES: To investigate 28 cases of primary cutaneous B-cell lymphoma, including the subtypes PCFCL (n = 10), PCMZL (n = 10) and DLBCL-LT (n = 8) for the number and density of PD-1-positive cells. METHODS: Immunohistochemical staining and a computerized morphometric analysis for evaluation were applied. The results were correlated with the clinical outcome. To distinguish between activated T cells and TFH we performed PD-1/bcl-6 double staining and compared these results with CXCL-13 staining. Double staining for PD-1 and PAX-5 was used to investigate whether tumour cells were positive for PD-1. RESULTS: The PD-1 positive cells represented tumour-infiltrating T cells (TILs). Only a minor subset was represented by TFH . Patients with DLBCL-LT had a significantly lower number of PD-1-positive TILs than those with PCMZL (P = 0.012) and PCFCL (P = 0.002) or both (P = 0.001). The difference between PCMZL and PCFCL did not reach significance (P = 0.074). The tumour cells were negative for PD-1. CONCLUSIONS: A higher number of PD-1-expressing cells was found in indolent PCMZL and PCFCL than in high-malignant DLBCL-LT. The PD-1-positive cells represented not only TFH , but also other activated T cells as a part of the tumour microenvironment. The tumour cells in all investigated types of PCBCL did not show aberrant PD-1 expression. PMID- 23937076 TI - Copper-catalyzed C-N cross-coupling of sulfondiimines with boronic acids. AB - The copper-catalyzed C-N cross-coupling of sulfondiimines with boronic acids has been developed. The reaction proceeds at room temperature in good to excellent yields and provides access to a variety of N,N'-disubstituted sulfondiimines, including N-(hetero)aryl sulfondiimines and the first reported N-alkenylated sulfondiimine. PMID- 23937077 TI - Oral contraceptive use and risk of vulvodynia: a population-based longitudinal study. AB - OBJECTIVE: To assess whether the risk of vulvodynia is associated with previous use of oral contraceptives (OCs). DESIGN: Longitudinal population-based study. SETTING: Four counties in south-east Michigan, USA. POPULATION: A population based sample of women, aged 18 years and older, enrolled using random-digit dialling. METHODS: Enrolled women completed surveys that included information on demographic characteristics, health status, current symptoms, past and present OC use, and a validated screen for vulvodynia. The temporal relationship between OC use and subsequent symptoms of vulvodynia was assessed using Cox regression, with OC exposure modelled as a time-varying covariate. MAIN OUTCOME MEASURE: Vulvodynia, as determined by validated screen. RESULTS: Women aged <50 years who provided data on OC use, completed all questions required for the vulvodynia screen, and had first sexual intercourse prior to the onset of vulvodynia symptoms were eligible (n = 906). Of these, 71.2% (n = 645) had used OCs. The vulvodynia screen was positive in 8.2% (n = 74) for current vulvodynia and in 20.8% (n = 188) for past vulvodynia. Although crude cross-tabulation suggested that women with current or past vulvodynia were less likely to have been exposed to OCs prior to the onset of pain (60.7%), compared with those without this disorder (69.3%), the Cox regression analysis identified no association between vulvodynia and previous OC use (HR 1.08, 95% CI 0.81-1.43, P = 0.60). This null finding persisted after controlling for ethnicity, marital status, educational level, duration of use, and age at first OC use. CONCLUSION: For women aged <50 years of age, OC use did not increase the risk of subsequent vulvodynia. PMID- 23937078 TI - The decay of stem cell nourishment at the niche. AB - One of the main features of human aging is the loss of adult stem cell homeostasis. Organs that are very dependent on adult stem cells show increased susceptibility to aging, particularly organs that present a vascular stem cell niche. Reduced regenerative capacity in tissues correlates with reduced stem cell function, which parallels a loss of microvascular density (rarefraction) and plasticity. Moreover, the age-related loss of microvascular plasticity and rarefaction has significance beyond metabolic support for tissues because stem cell niches are regulated co-ordinately with the vascular cells. In addition, microvascular rarefaction is related to increased inflammatory signals that may negatively regulate the stem cell population. Thus, the processes of microvascular rarefaction, adult stem cell dysfunction, and inflammation underlie the cycle of physiological decline that we call aging. Observations from new mouse models and humans are discussed here to support the vascular aging theory. We develop a novel theory to explain the complexity of aging in mammals and perhaps in other organisms. The connection between vascular endothelial tissue and organismal aging provides a potential evolutionary conserved mechanism that is an ideal target for the development of therapies to prevent or delay age related processes in humans. PMID- 23937080 TI - Pre-clinical pharmacokinetics and acute toxicological evaluation of a monastrol derivative anticancer candidate LaSOM 65 in rats. AB - 1. The present work investigated the pharmacokinetic and tissue distribution as well as acute toxicity of a new chemical entity (NCE), the anticancer candidate LaSOM 65 in Wistar rats. 2. LaSOM 65 pharmacokinetics was investigated after intravenous (i.v., 1 mg/kg) and oral (p.o., 10 and 30 mg/kg) dosing. Tissue distribution was assessed after i.v. bolus dose. Acute toxicity was evaluated after i.v. (1, 2.5 and 5 mg/kg) and p.o. (50, 100 and 150 mg/kg) administration. 3. Short half-life (1.75 +/- 0.71 h), a clearance of 0.85 +/- 0.18 L/h/kg and a volume of distribution of 1.76 +/- 0.24 L/kg were observed after i.v. dosing. The compound showed good bioavailability and linear pharmacokinetics after oral doses. The NCE distributes consistently in lung and fatty tissues, with penetration ratios of 2.7 and 1.4, respectively. The other tissues investigated presented smaller penetration ratios. Adverse clinical symptoms were observed only after i.v. administration, and regressed 3 h after dosing. Compared with controls, no statistical differences were found for serum analysis, body weight and relative organ weight, indicating no acute toxicological effects. 4. Overall, LaSOM 65 showed good pharmacokinetic characteristics and no signs of acute toxicity, indicating that it is a promising anticancer candidate. PMID- 23937079 TI - Mucosal and systemic T cell response in mice intragastrically infected with Neospora caninum tachyzoites. AB - The murine model has been widely used to study the host immune response to Neospora caninum. However, in most studies, the intraperitoneal route was preferentially used to establish infection. Here, C57BL/6 mice were infected with N. caninum tachyzoites by the intragastric route, as it more closely resembles the natural route of infection through the gastrointestinal tract. The elicited T cell mediated immune response was evaluated in the intestinal epithelium and mesenteric lymph nodes (MLN). Early upon the parasitic challenge, IL-12 production by conventional and plasmacytoid dendritic cells was increased in MLN. Accordingly, increased proportions and numbers of TCRalphabeta+CD8+IFN-gamma+ lymphocytes were detected, not only in the intestinal epithelium and MLN, but also in the spleen of the infected mice. In this organ, IFN-gamma-producing TCRalphabeta+CD4+ T cells were also found to increase in the infected mice, however later than CD8+ T cells. Interestingly, splenic and MLN CD4+CD25+ T cells sorted from infected mice presented a suppressive activity on in vitro T cell proliferation and cytokine production above that of control counterparts. These results altogether indicate that, by producing IFN-gamma, TCRalphabeta+CD8+ cells contribute for local and systemic host protection in the earliest days upon infection established through the gastrointestinal tract. Nevertheless, they also provide substantial evidence for a parasite-driven reinforcement of T regulatory cell function which may contribute for parasite persistence in the host and might represent an additional barrier to overcome towards effective vaccination. PMID- 23937081 TI - Results from the multisite implementation of STAR-VA: a multicomponent psychosocial intervention for managing challenging dementia-related behaviors of veterans. AB - Dementia is often associated with challenging behaviors that can significantly impact the quality of life of individuals with dementia and pose great difficulty for long-term care staff. Antipsychotic medications, historically the mainstay approach for managing such behaviors, have increasingly been associated with limited efficacy and increased death risk with older dementia patients. In an effort to promote and realize the promise of nonpharmacological management of challenging dementia-related behaviors, the U.S. Department of Veterans Affairs (VA) health care system has developed and implemented STAR-VA, an interdisciplinary behavioral intervention for managing challenging dementia related behaviors of veterans, in 17 VA nursing homes, as part of a pilot implementation initiative. Sixty-four veterans with challenging behaviors associated with dementia participated in the STAR-VA intervention coordinated by Mental Health Providers completing specialized training. Challenging behaviors clustered into 6 behavior types: resistance to care, agitation, violence/aggression, vocalization, wandering, and other. Results indicate that STAR-VA led to significant reductions in the frequency and severity of challenging dementia-related behaviors, with overall effect sizes of approximately 1. In addition, the intervention led to significant reductions in depression and anxiety. Overall, the results support the feasibility and effectiveness of STAR-VA for managing challenging dementia-related behaviors in veterans in real-world, nursing home settings. PMID- 23937082 TI - A meta-analysis of the relationship between job burnout and secondary traumatic stress among workers with indirect exposure to trauma. AB - The study provides a systematic review of the empirical evidence for associations between job burnout and secondary traumatic stress (STS) among professionals working with trauma survivors, indirectly exposed to traumatic material. Differences in the conceptualization and measurement of job burnout and STS were assumed to moderate these associations. A systematic review of literature yielded 41 original studies, analyzing data from a total of 8,256 workers. Meta-analysis indicated that associations between job burnout and STS were strong (weighted r = .69). Studies applying measures developed within the compassion fatigue framework (one of the conceptualizations of job burnout and STS) showed significantly stronger relationships between job burnout and STS, indicating a substantial overlap between measures (weighted r = .74; 55% of shared variance). Research applying other frameworks and measures of job burnout (i.e., stressing the role of emotional exhaustion) and STS (i.e., focusing on symptoms resembling posttraumatic stress disorder or a cognitive shift specific for vicarious trauma) showed weaker, although still substantial associations (weighted r = .58; 34% of shared variance). Significantly stronger associations between job burnout and STS were found for: (a) studies conducted in the United States compared to other countries; (b) studies using English-language versions of the questionnaires compared to other-language versions, and (c) research in predominantly female samples. The results suggest that, due to high correlations between job burnout and STS, there is a substantial likelihood that a professional exposed to secondary trauma would report similar levels of job burnout and STS, particularly if job burnout and STS were measured within the framework of compassion fatigue. PMID- 23937084 TI - The "PE coach" smartphone application: an innovative approach to improving implementation, fidelity, and homework adherence during prolonged exposure. AB - Prolonged exposure (PE) is an empirically supported treatment that is being disseminated broadly to providers in the Department of Veterans Affairs and Department of Defense. Innovative methods are needed to support the implementation, dissemination, and patient and provider adherence to PE. The PE Coach is a smartphone application (app) designed to mitigate barriers to PE implementation. PE Coach is installed on the patient's phone and includes a range of capabilities for use during the PE session and after each session to support the treatment. Functions include the ability to audio record treatment sessions onto the patient's device, to construct the in vivo hierarchy on the device, to record completed homework exercises, to review homework adherence, and to track symptom severity over time. The app also allows sessions and homework to be scheduled directly in the app, populating the device calendar with patient reminder notifications. In the final session, a visual display of symptom improvement and habituation to items on the in vivo hierarchy is presented. These capabilities may significantly improve convenience, provider implementation and adherence, and patient compliance with treatment. Future research is needed to test whether PE Coach is useful and effective. PMID- 23937085 TI - Integrating care coordination home telehealth and home based primary care in rural Oklahoma: a pilot study. AB - The purpose of this program was to evaluate the benefits of integrating VA Care Coordination Home Telehealth and Telemental health within HBPC. A case study design was used to determine quality assurance and quality improvement of incorporating additional home telehealth equipment within Home Based Primary Care (HBPC). Veterans with complex medical conditions and their caregivers living in rural Oklahoma were enrolled. Veterans received the same care other HBPC patients received with the addition of home telehealth equipment. Members from the interdisciplinary treatment team were certified to use the telehealth equipment. Veterans and their caregivers were trained on use of the equipment in their homes. Standard HBPC program measures were used to assess the program success. Assessments from all disciplines on the HBPC team were at baseline, 3, and 6 months, and participants provided satisfaction and interview data to assess the benefits of integrating technology into standard care delivery within an HBPC program. Six veterans were enrolled (mean age = 72 yrs) with a range of physical health conditions including: chronic obstructive pulmonary disease, cerebrovascular accident, spinal cord injury, diabetes, hypertension, and syncope. Primary mental health conditions included depression, dementia, anxiety, and PTSD. Scores on the Mini-Mental State Examination ranged from 18 to 30. Over a 6-month period, case studies indicated improvements in strength, social functioning, decreased caregiver burden, and compliance with treatment plan. This integration of CCHT and HBPC served previously underserved rural veterans having complex medical conditions and appears both feasible and clinically beneficial to veterans and their caregivers. PMID- 23937086 TI - Glucagon-like peptide-1 protects human islets against cytokine-mediated beta-cell dysfunction and death: a proteomic study of the pathways involved. AB - Glucagon-like peptide-1 (GLP-1) has been shown to protect pancreatic beta-cells against cytokine-induced dysfunction and destruction. The mechanisms through which GLP-1 exerts its effects are complex and still poorly understood. The aim of this study was to analyze the protein expression profiles of human islets of Langerhans treated with cytokines (IL-1beta and IFN-gamma) in the presence or absence of GLP-1 by 2D difference gel electrophoresis and subsequent protein interaction network analysis to understand the molecular pathways involved in GLP 1-mediated beta-cell protection. Co-incubation of cytokine-treated human islets with GLP-1 resulted in a marked protection of beta-cells against cytokine-induced apoptosis and significantly attenuated cytokine-mediated inhibition of glucose stimulated insulin secretion. The cytoprotective effects of GLP-1 coincided with substantial alterations in the protein expression profile of cytokine-treated human islets, illustrating a counteracting effect on proteins from different functional classes such as actin cytoskeleton, chaperones, metabolic proteins, and islet regenerating proteins. In summary, GLP-1 alters in an integrated manner protein networks in cytokine-exposed human islets while protecting them against cytokine-mediated cell death and dysfunction. These data illustrate the beneficial effects of GLP-1 on human islets under immune attack, leading to a better understanding of the underlying mechanisms involved, a prerequisite for improving therapies for diabetic patients. PMID- 23937087 TI - Fully automated algorithm for wound surface area assessment. AB - Worldwide, clinicians, dentists, nurses, researchers, and other health professionals need to monitor the wound healing progress and to quantify the rate of wound closure. The aim of this study is to demonstrate, step by step, a fully automated numerical method to estimate the size of the wound and the percentage damaged relative to the body surface area (BSA) in images, without the requirement for human intervention. We included the formula for BSA in rats in the algorithm. The methodology was validated in experimental wounds and human ulcers and was compared with the analysis of an experienced pathologist, with good agreement. Therefore, this algorithm is suitable for experimental wounds and burns and human ulcers, as they have a high contrast with adjacent normal skin. PMID- 23937088 TI - Is testosterone replacement therapy in males with hypogonadism cost-effective? An analysis in Sweden. AB - INTRODUCTION: Testosterone replacement therapy (TRT) has been recommended for the treatment of primary and secondary hypogonadism. However, long-term implications of TRT have not been investigated extensively. AIM: The aim of this analysis was to evaluate health outcomes and costs associated with life-long TRT in patients suffering from Klinefelter syndrome and late-onset hypogonadism (LOH). METHODS: A Markov model was developed to assess cost-effectiveness of testosterone undecanoate (TU) depot injection treatment compared with no treatment. Health outcomes and associated costs were modeled in monthly cycles per patient individually along a lifetime horizon. Modeled health outcomes included development of type 2 diabetes, depression, cardiovascular and cerebrovascular complications, and fractures. Analysis was performed for the Swedish health-care setting from health-care payer's and societal perspective. One-way sensitivity analyses evaluated the robustness of results. MAIN OUTCOME MEASURES: The main outcome measures were quality-adjusted life-years (QALYs) and total cost in TU depot injection treatment and no treatment cohorts. In addition, outcomes were also expressed as incremental cost per QALY gained for TU depot injection therapy compared with no treatment (incremental cost-effectiveness ratio [ICER]). RESULTS: TU depot injection compared to no-treatment yielded a gain of 1.67 QALYs at an incremental cost of 28,176 EUR (37,192 USD) in the Klinefelter population. The ICER was 16,884 EUR (22,287 USD) per QALY gained. Outcomes in LOH population estimated benefits of TRT at 19,719 EUR (26,029 USD) per QALY gained. Results showed to be considerably robust when tested in sensitivity analyses. Variation of relative risk to develop type 2 diabetes had the highest impact on long-term outcomes in both patient groups. CONCLUSION: This analysis suggests that lifelong TU depot injection therapy of patients with hypogonadism is a cost-effective treatment in Sweden. Hence, it can support clinicians in decision making when considering appropriate treatment strategies for patients with testosterone deficiency. PMID- 23937089 TI - Text message reminders to improve outpatient therapy attendance among adolescents: a pilot study. AB - High rates of missed appointments and attrition are common barriers to treatment for adolescents attending outpatient mental health treatment. Such figures indicate a need for innovative strategies to engage youth in treatment. The current quasi-experimental pilot study examined the feasibility, acceptability, and preliminary efficacy of text message (TM) appointment reminders to improve attendance in a sample of 48 adolescents attending outpatient therapy. The sample was approximately 46% Latino and 40% African American with an equal number of males and females. Adolescents receiving TM reminders demonstrated significantly higher rates of attendance (65%) than a historical control group (49%) (p < .05). Participants in the TM group received reminders for the majority (88%) of their scheduled sessions with only 4% of reminders not received due to phone-related problems. Additionally, TM reminders received high patient satisfaction ratings. Findings from the present study suggest that TM reminders may be a cost-effective and developmentally appropriate strategy for engaging adolescents in treatment. PMID- 23937090 TI - Development of an in-home telehealth program for outpatient veterans with substance use disorders. AB - A variety of obstacles (e.g., lack of transportation, less availability of treatment in rural districts) contribute to underutilization of treatment among patients with substance use disorders, warranting the need to develop innovative strategies for enhancing access to treatment for these patients. The telehealth in-home-messaging-device is a small message-delivering and monitoring device connected via landline phone to a secure server that provides assessment and disease self-management education to patients in their homes. We describe the development of a Substance Use Disorder telehealth management program (SUD program) for use on this device and a feasibility pilot of the program with six outpatient veterans with substance use disorders referred by their primary medical care providers. These patients indicated that the SUD program was acceptable, easy to use, and helpful toward addressing their substance use problems. Home telehealth technology may be an innovative and feasible approach for providing substance abuse evidence-based treatment either as an adjunct to specialty treatment for substance use disorders or as a stand-alone intervention within primary care for a larger number of patients who may otherwise not access traditional treatment services. PMID- 23937091 TI - Self-help stress management training through mobile phones: an experience with oncology nurses. AB - Although all professions are susceptible to work-related stress, the nursing profession has been identified as particularly stressful; indeed, oncology nursing is often described as being among the most stressful specialty areas. The current study tested the short-term effects of an innovative self-help stress management training for oncology nurses supported by mobile tools. The sample included 30 female oncology nurses with permanent status employed in six oncology hospitals in Milan, Italy. The stress inoculation training (SIT) methodology served as the basis of the training, with the innovative challenge being the use of mobile phones to support the stress management experience. To test the efficacy of the protocol, the study used a between-subjects design, comparing the experimental condition (SIT through mobile phones) with a control group (neutral video through mobile phones). The findings indicated psychological improvement of the experimental group in terms of anxiety state, anxiety trait reduction, and coping skills acquisition. This paper discusses implications for the implementation of this protocol in several contexts. PMID- 23937092 TI - The therapeutic value of adolescents' blogging about social-emotional difficulties. AB - Research shows that writing a personal diary is a valuable therapeutic means for relieving emotional distress and promoting well-being, and that diary writing during adolescence helps in coping with developmental challenges. Current technologies and cultural trends make it possible and normative to publish personal diaries on the Internet through blogs--interactive, online forms of the traditional personal diary. We examined the therapeutic value of blogging for adolescents who experience social-emotional difficulties. The field experiment included randomly assigned adolescents, preassessed as having social-emotional difficulties, to 6 groups (26-28 participants in each): Four groups were assigned to blogging (writing about their difficulties or free writing; either open or closed to responses), a group assigned to writing a diary on personal computers, and a no-treatment control group. Participants in the 5 writing groups were instructed to post messages at least twice a week over 10 weeks. Outcome measures included scales of social-emotional difficulties and self-esteem, a social activities checklist, and textual analyses of participants' posts. Measurement took place at pre- and postintervention and at follow-up 2 months later. Results showed that participants maintaining a blog significantly improved on all measures. Participants writing about their difficulties in blogs open to responses gained the most. These results were consistent in the follow-up evaluation. PMID- 23937093 TI - A macrocyclic dimeric diterpene with a C2 symmetry axis. AB - An unprecedented macrocyclic dimeric diterpene containing a C2 symmetry axis was isolated from Acacia schaffneri . This compound, named schaffnerine, was characterized as (5S,7S,8R,9R,10S,17S,5'S,7'S,8'R,9'R,10'S,17'S) 7,8:7,17':16,17:17,7':7',8':16',17'-hexaepoxy-7,8-seco-7',8'-seco-dicassa-13,13' diene (1) from its spectroscopic data. Comparison of its experimental vibrational circular dichroism spectrum with that calculated using density functional theory, at the B3LYP/DGDZVP level, assigned its preferred conformation and absolute configuration. The latter was confirmed by evaluation of the Flack and Hooft parameters obtained after single-crystal X-ray diffraction analysis. PMID- 23937094 TI - Mannan-conjugated adenovirus enhanced gene therapy effects on murine hepatocellular carcinoma cells in vitro and in vivo. AB - The incidence of advanced hepatocellular carcinoma (HCC) is increasing worldwide, and its prognosis is extremely poor. For some patients for whom surgical treatments are not appropriate, one can only rely on chemotherapy. In the conventional chemotherapy, side effects usually occurred in most cases due to high toxicity levels. Moreover, the development of drug resistance toward chemotherapeutic agents often prevents the successful long-term use of chemotherapy for HCC. Gene therapy represents the exciting biotechnological advance that may revolutionize the conventional fashion of cancer treatment. Overexpression of phosphatase and tensin homologue (PTEN) in cancer cells carrying deletion/mutant type of it can induce the apoptosis of cancer cells and inhibit cell proliferation. In this work, in order to make full use of the high transfectivity of adenovirus, we managed to conjugate the polysaccharide mannan (polymannose) to the surface of the adenovirus chemically under appropriate oxidizing conditions to prepare the mannan-modified adenovirus (Man-Ad5-PTEN). The cytotoxicity and anticancer activity of Man-Ad5-PTEN were assessed in vitro. Reporter gene expression of LacZ transferred by Man-Ad5-LacZ was verified on mannose receptor-deficient NIH/3T3 cells versus mannose receptor-efficient macrophages. Hepatocellular carcinoma cell lines transduced by mannan-modified adenovirus were assayed for cell cycle, apoptosis, invasion, and migration. Further, we detected the antitumor effect on intraperitoneal H22 tumor-bearing mice treated by Man-Ad5-PTEN alone or combined with chemotherapeutic agent of doxorubicin. The results demonstrated that cell growth suppression was not observed in Chang normal hepatocyte cells and the cell killing by Man-Ad5-PTEN is tumor selective. Further, the results showed that the strategy of mannan conjugation could enhance adenovirus-mediated PTEN gene therapy effects on murine hepatocellular carcinoma cells in vitro and in vivo. PMID- 23937095 TI - Directional phytoscreening: contaminant gradients in trees for plume delineation. AB - Tree sampling methods have been used in phytoscreening applications to delineate contaminated soil and groundwater, augmenting traditional investigative methods that are time-consuming, resource-intensive, invasive, and costly. In the past decade, contaminant concentrations in tree tissues have been shown to reflect the extent and intensity of subsurface contamination. This paper investigates a new phytoscreening tool: directional tree coring, a concept originating from field data that indicated azimuthal concentrations in tree trunks reflected the concentration gradients in the groundwater around the tree. To experimentally test this hypothesis, large diameter trees were subjected to subsurface contaminant concentration gradients in a greenhouse study. These trees were then analyzed for azimuthal concentration gradients in aboveground tree tissues, revealing contaminant centroids located on the side of the tree nearest the most contaminated groundwater. Tree coring at three field sites revealed sufficiently steep contaminant gradients in trees reflected nearby groundwater contaminant gradients. In practice, trees possessing steep contaminant gradients are indicators of steep subsurface contaminant gradients, providing compass-like information about the contaminant gradient, pointing investigators toward higher concentration regions of the plume. PMID- 23937096 TI - Impact of nanoscale surface heterogeneity on precursor film growth and macroscopic spreading of [Rmim][NTf2] ionic liquids on mica. AB - The connection between the interfacial properties of ionic liquids and their wetting behavior has been studied very little to date and not at all on heterogeneous surfaces. Therefore, we have investigated the static and dynamic wetting for a family of ionic liquids, 1-alkyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide, [Rmim][NTf2], on mica, where R represents an ethyl, butyl, or hexyl alkyl chain on the imidazolium ring. Spreading is impacted greatly by a precursor film that forms on both homogeneous and heterogeneous mica surfaces. Macroscopically, the initial viscous spreading of the ionic liquid droplet on bare mica occurs within seconds but is then followed by a very slow relaxation that can be closely correlated with the typical time-scales of the precursor film growth. The contact angle for [emim][NTf2] and [bmim][NTf2] relaxes from about 40 degrees to 23 degrees over 30 and 90 min, respectively. For [hmim][NTf2], the process takes approximately 24 h and approaches complete wetting. The thickness of the precursor films for [emim][NTf2], [bmim][NTf2], and [hmim][NTf2] were 0.53, 0.65, and 1.0 nm, respectively, according to atomic force microscopy (AFM). These values are consistent with a monolayer of ionic liquid cations on mica, rather than ion pairs. A monolayer of octadecylphosphonic acid (OPA) on mica prevents both the formation of a precursor film and the relaxation of the contact angle. However, only a partial surface coverage of ~60% OPA is required to have the same effect. Quenching of precursor film formation (and associated contact angle relaxation) is due to an increasingly connected network of OPA regions that closes the nanoscale paths of bare mica on which the precursor film can develop via surface diffusion. PMID- 23937097 TI - Protein-like tertiary folding behavior from heterogeneous backbones. AB - Because proteins play vital roles in life, much effort has been invested in their mimicry by synthetic agents. One approach is to design unnatural backbone oligomers ("foldamers") that fold like natural peptides. Despite success in secondary structure mimicry by such species, protein-like tertiary folds remain elusive. A fundamental challenge underlying this task is the design of a sequence of side chains that will specify a complex tertiary folding pattern on an unnatural backbone. We report here a sequence-based approach to convert a natural protein with a compact tertiary fold to an analogue with a backbone composed of ~20% unnatural building blocks but folding behavior similar to that of the parent protein. PMID- 23937099 TI - Extracytoplasmic proteases determining the cleavage and release of secreted proteins, lipoproteins, and membrane proteins in Bacillus subtilis. AB - Gram-positive bacteria are known to export many proteins to the cell wall and growth medium, and accordingly, many studies have addressed the respective protein export mechanisms. In contrast, very little is known about the subsequent fate of these proteins. The present studies were therefore aimed at determining the fate of native exported proteins in the model organism Bacillus subtilis. Specifically, we employed a gel electrophoresis-based liquid chromatography-mass spectrometry approach to distinguish the roles of the membrane-associated quality control proteases HtrA and HtrB from those of eight other proteases that are present in the cell wall and/or growth medium of B. subtilis. Notably, HtrA and HtrB were previously shown to counteract potentially detrimental "protein export stresses" upon overproduction of membrane or secreted proteins. Our results show that many secreted proteins, lipoproteins, and membrane proteins of B. subtilis are potential substrates of extracytoplasmic proteases. Moreover, potentially important roles of HtrA and HtrB in the folding of native secreted proteins into a protease-resistant conformation, the liberation of lipoproteins from the membrane-cell wall interface, and the degradation of membrane proteins are uncovered. Altogether, our observations show that HtrA and HtrB are crucial for maintaining the integrity of the B. subtilis cell even under nonstress conditions. PMID- 23937098 TI - Increased catecholamine secretion from single adrenal chromaffin cells in DOCA salt hypertension is associated with potassium channel dysfunction. AB - The mechanism of catecholamine release from single adrenal chromaffin cells isolated from normotensive and DOCA-salt hypertensive rats was investigated. These cells were used as a model for sympathetic nerves to better understand how exocytotic release of catecholamines is altered in this model of hypertension. Catecholamine secretion was evoked by local application of acetylcholine (1 mM) or high K+ (70 mM), and continuous amperometry was used to monitor catecholamine secretion as an oxidative current. The total number of catecholamine molecules secreted from a vesicle, the total number of vesicles fusing and secreting, and the duration of secretion in response to a stimulus were all significantly greater for chromaffin cells from hypertensive rats as compared to normotensive controls. The greater catecholamine secretion from DOCA-salt cells results, at least in part, from functionally impaired large conductance, Ca2+-activated (BK) and ATP-sensitive K+ channels. This work reveals that there is altered vesicular release of catecholamines from these cells (and possibly from perivascular sympathetic nerves) and this may contribute to increased vasomotor tone in DOCA salt hypertension. PMID- 23937100 TI - Geriatric resources in acute care hospitals and trauma centers: a scarce commodity. AB - The number of older adults admitted to acute care hospitals with traumatic injury is rising. The purpose of this study was to examine the location of five prominent geriatric resource programs in U.S. acute care hospitals and trauma centers (N = 4,865). As of 2010, 5.8% of all U.S. hospitals had at least one of these programs. Only 8.8% of trauma centers were served by at least one program; the majorities were in level I trauma centers. Slow adoption of geriatric resource programs in hospitals may be due to lack of champions who will advocate for these programs, lack of evidence of their impact on outcomes, or lack of a business plan to support adoption. Future studies should focus on the benefits of geriatric resource programs from patients' perspectives, as well as from business case and outcomes perspectives. PMID- 23937101 TI - Is it time for a public health nursing approach to aging? AB - Following the enactment of Medicare in 1965, access to health care for older adults in the United States improved. At the same time, nurse researchers and policy leaders developed individual and family-centered care interventions and programs that led to improvements in quality of health and life. In the next 20 to 30 years, U.S. and global projections of an expanding aging cohort with potential increases in health care needs, coupled with continued nursing shortage projections, present challenges and opportunities to enhance gerontological nursing's approach to aging care. Invigorating a public health nursing focus on the needs of a population of older adults could enhance nursing's ability to create policy and programs of care that promote quality of life for older adults and their families. Nurses using public health approaches can lead and support social policies regarding the physical environment and daily life circumstances that contribute to health equity. Heightened attention to competencies in community/public health nursing education and promotion of public health nursing careers will be important policy considerations as we face the looming increase in a population of older adults throughout the world. PMID- 23937102 TI - Differences in assisted living staff perceptions, experiences, and attitudes. AB - Research within residential care/assisted living (RC/AL) settings has shown that the attitudes of personal care (PC) staff toward their organization and its residents and families can affect the quality of resident care. This article describes the perceptions, experiences, and attitudes of PC staff and their supervisors, and considers these data in the context of non-hierarchical staffing patterns-a philosophically expected, yet unproven tenet of RC/AL. Using data collected from 18 RC/AL communities, these analyses compared the characteristics, perceptions, experiences, and attitudes of PC staff (N = 250) and supervisors (N = 30). Compared to supervisors, PC staff reported greater burden, frustration, depersonalization, hassles, and feeling significantly more controlling of, and less in partnership with, families (p < 0.05). Because the PC staff experience is crucial for resident outcomes, more work is needed to create an environment where PC staff are less burdened and have better attitudes toward work and families. PMID- 23937103 TI - The effects of baseline estimation on the reliability, validity, and precision of CBM-R growth estimates. AB - This study examined the effect of baseline estimation on the quality of trend estimates derived from Curriculum Based Measurement of Oral Reading (CBM-R) progress monitoring data. The authors used a linear mixed effects regression (LMER) model to simulate progress monitoring data for schedules ranging from 6-20 weeks for datasets with high and low levels of residual variance (poor and good quality datasets respectively). Three observations per day for the first three days of data collection were generated for baseline estimation. As few as one and as many as nine observations were used to calculate baseline. The number of weeks of progress monitoring and the quality of the dataset were highly influential on the reliability, validity, and precision of simulated growth estimates. Results supported the use of using the median of three observations collected on the first day to estimate baseline, particularly when the first observation of that day systematically underestimated student performance. Collecting a large number of observations to estimate baseline does not appear to improve the quality of CBM-R growth estimates. PMID- 23937104 TI - Daily stressors in school-age children: a multilevel approach. AB - This study uses hierarchical or multilevel modeling to identify variables that contribute to daily stressors in a population of schoolchildren. Four hierarchical levels with several predictive variables were considered: student (age, sex, social adaptation of the student, number of life events and chronic stressors experienced, and educational level of the father and mother), class (number of students per class), school (type of school), and province (number of inhabitants per province). Participants were 6,078 students from primary years 3 6 in the region of Andalusia (Spain). After conducting a multilevel regression analysis, the final fitted model was a random intercept and random slope model (at the school level) for the variable age, with the fixed factors being the variables social adaptation, life events and chronic stressors, and the educational level of the father and mother. This model yielded a specific profile of daily stressors in childhood: children with the highest levels of daily stressors are younger, present aggressive or inhibited behavior, have experienced more life events and chronic stressors, and have parents who did not complete their primary education. The results provide relevant information for the design of psychoeducational interventions in relation to children's daily stressors. PMID- 23937105 TI - CD30 expression in acute lymphoblastic leukemia as assessed by flow cytometry analysis. AB - We assessed CD30 expression in patients with acute lymphoblastic leukemia (ALL) of either T-cell or B-cell lineage to examine the potential benefit of anti-CD30 targeted therapy in this group of patients. Bone marrow specimens of 34 patients with T- and 44 with B-ALL were assessed for CD30 expression by multicolor flow cytometry immunophenotyping analysis. Of these 78 patients, 75 (96%) were adults; and 63 (81%) had refractory/relapsed disease. Using an arbitrary 20% cut-off, 13/34 (38%) cases of T-ALL and 6/44 (13%) cases of B-ALL were considered to express CD30. In five patients with T-ALL with sequential bone marrow tested, increased CD30 expression was observed during the course of high-dose chemotherapy (p = 0.025). Philadelphia chromosome/BCR-ABL1 fusion was positive in 14/44 cases of B-ALL and 2/32 cases of T-ALL, which showed no significant correlation with CD30 expression. In summary, we detected CD30 expression in approximately one-third of patients with T-ALL, and less frequently in B-ALL (p = 0.017). In T-ALL, CD30 expression is up-regulated during high-dose chemotherapy. These data indicate that anti-CD30-targeted therapy may be a potential option for patients with T-ALL with refractory/relapsed disease. PMID- 23937106 TI - A short, protecting group-free total synthesis of bruceollines D, E, and J. AB - A short, protecting group-free total synthesis of bruceollines D, E, and J has been achieved. The enantioselective reduction of bruceolline E with beta chlorodiisopinocampheylborane delivers both the natural and unnatural enantiomers of bruceolline J in excellent yields and enantioselectivities. Reduction with baker's yeast and sucrose was shown to provide the unnatural enantiomer of bruceolline J in 98% ee. PMID- 23937107 TI - Strategies for delivering local anesthetics to the skin: focus on liposomes, solid lipid nanoparticles, hydrogels and patches. AB - INTRODUCTION: Dermal and transdermal drug delivery systems offer the possibility to control the release of the drug for an extended period of time. In particular, skin-delivery of local anesthetics (LA) is one of the most important strategies to increase the local drug concentration and to reduce systemic adverse reactions. AREAS COVERED: During the development phase of new formulations for skin-delivery of LA one should consider a set of desirable features such providing suitable adhesion, easy application/removal and also to be biocompatible, biodegradable and non-toxic. This review emphasizes the main strategies for skin-delivery of LA considering those features in relation to the composition of the delivery systems described. The topics highlight the relationships between physico-chemical studies and pharmaceutical applications for liposomes and solid lipid nanoparticles as well as the formulation and clinical applications for hydrogels and patches. EXPERT OPINION: The development of LA skin-delivery systems using hydrogels and different permeation enhancers, liposomes or lipid nanoparticles (as isolated carrier systems or as their dispersion in a gel-base) and patches have been explored as alternatives to commercial formulations, modifying the release rate of LA, increasing bioadhesive properties and reducing toxicity, resulting in an improved therapeutic efficacy. This review should provide to the reader a special emphasis on four delivery systems, comprising the group of liposomes and lipid nanoparticles, hydrogels and patches technologies looking forward their application for skin anesthesia. PMID- 23937108 TI - Male circumcision and HIV: a controversy study on facts and values. AB - We present a controversy study on the association between male circumcision (MC) and HIV. Our general goal is to shed light on the issue, unravelling and comparing different conceptions of scientific evidence and their respective world views. We seek to reconstruct, based on an analysis of the literature on the topic, key moments in the history of the controversy about the association between MC and HIV prevention, analysing more closely three recent randomised studies, given their relevance to the argumentative strategy employed by those who defend circumcision as a prevention method. Following this, we present a synthesis of the main arguments against the three referred studies. In conclusion, it seems that reasonable arguments for a more cautious approach are not being adequately considered. PMID- 23937109 TI - Interleukin-27 rs153109 polymorphism and the risk for immune thrombocytopenia. AB - The aim of the present study was to investigate the association of single nucleotide polymorphisms (SNP) of the interleukin-27 (IL-27) genes with the risk for immune thrombocytopenia (ITP). In this case-control study, the genotyping of IL-27 rs153109 polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In ITP patients, the frequencies of GG, GA and AA genotypes, and G and A alleles were 9.7%, 58.5%, 31.8%, 38.9% and 61.1%, respectively. There was no significant difference in genotype and alleles distribution between the ITP patient and the healthy controls (p = 0.68 and 0.80, respectively). Similar results were found between the two groups when stratified by the age and disease course including non-chronic adult, chronic adult, non chronic childhood, and chronic childhood. In conclusion, the IL-27 polymorphism may not be involved in susceptibility to ITP in a Chinese population. PMID- 23937110 TI - Stable isotope composition of the meteoric precipitation in Croatia. AB - The precipitation is the input into the water system. Its stable isotope composition has to be known for the proper use and management of water resources. Croatia is not well represented in the Global Network of Isotopes in Precipitation (GNIP) database, and the geomorphology of the country causes specific local conditions. Therefore, at the Stable Isotope Laboratory (SILab), Rijeka, we monitor the stable isotope composition (delta(18)O, delta(2)H) of precipitation. Since delta(18)O and delta(2)H are well correlated, we concentrate the discussion on the delta(18)O distribution. Together with GNIP, our database contains 40 stations in Croatia and in the neighbouring countries. Their different latitudes, longitudes and altitudes give information of great detail, including the influence of the topographic structure on the precipitation in the south-eastern part of Europe, as well as the complex interplay of the different climate conditions in the area. Within a few hundred kilometres, the stable isotope values display a significant change from the maritime character in the south (mean delta(18)O around-6 to-80/00) to the continental behaviour in the north (mean delta(18)O around-8 to-110/00). Depending on the location, the mean delta(18)O values vary with altitude at a rate of approximately-0.20/00/100 m and 0.40/00/100 m, respectively. Also the deuterium excess has been found to depend on location and altitude. The data are being used to construct a delta(18)O map for the entire area. PMID- 23937111 TI - Succession of hydrocarbon-degrading bacteria in the aftermath of the deepwater horizon oil spill in the gulf of Mexico. AB - The Deepwater Horizon oil spill produced large subsurface plumes of dispersed oil and gas in the Gulf of Mexico that stimulated growth of psychrophilic, hydrocarbon degrading bacteria. We tracked succession of plume bacteria before, during and after the 83-day spill to determine the microbial response and biodegradation potential throughout the incident. Dominant bacteria shifted substantially over time and were dependent on relative quantities of different hydrocarbon fractions. Unmitigated flow from the wellhead early in the spill resulted in the highest proportions of n-alkanes and cycloalkanes at depth and corresponded with dominance by Oceanospirillaceae and Pseudomonas. Once partial capture of oil and gas began 43 days into the spill, petroleum hydrocarbons decreased, the fraction of aromatic hydrocarbons increased, and Colwellia, Cycloclasticus, and Pseudoalteromonas increased in dominance. Enrichment of Methylomonas coincided with positive shifts in the delta(13)C values of methane in the plume and indicated significant methane oxidation occurred earlier than previously reported. Anomalous oxygen depressions persisted at plume depths for over six weeks after well shut-in and were likely caused by common marine heterotrophs associated with degradation of high-molecular-weight organic matter, including Methylophaga. Multiple hydrocarbon-degrading bacteria operated simultaneously throughout the spill, but their relative importance was controlled by changes in hydrocarbon supply. PMID- 23937112 TI - Autotransfecting short interfering RNA through facile covalent polymer escorts. AB - Short interfering ribonucleic acids (siRNAs) are important agents for RNA interference (RNAi) that have proven useful in gene function studies and therapeutic applications. However, the efficacy of exogenous siRNAs for gene knockdown remains hampered by their susceptibility to cellular nucleases and impermeability to cell membranes. We report here new covalent polymer-escort siRNA constructs that address both of these constraints simultaneously. By simple postsynthetic click conjugation of polymers to the passenger strand of an siRNA duplex followed by annealing with the complementary guide strand, we obtained siRNA in which one strand includes terminal polymer escorts. The polymer escorts both confer protection against nucleases and facilitate cellular internalization of the siRNA. These autotransfecting polymer-escort siRNAs are viable in RNAi and effective in knocking down reporter and endogenous genes. PMID- 23937113 TI - Population-based studies of brain imaging patterns in cerebral palsy. AB - AIM: The aim of this study was to review the distribution of neuroimaging findings from a contemporary population cohort of individuals with cerebral palsy (CP) and to facilitate standardization of imaging classification. METHOD: Publications from 1995 to 2012 reporting imaging findings in population cohorts were selected through a literature search, and review of the titles, abstracts, and content of studies. Relevant data were extracted, including unpublished data from Victoria, Australia. The proportions for each imaging pattern were tabulated, and heterogeneity was assessed for all individuals with CP, and for subgroups based on gestational age, CP subtype, and Gross Motor Function Classification System level. RESULTS: Studies from three geographic regions met the inclusion criteria for individuals with CP, and two additional studies reported on specific CP subtypes. Brain abnormalities were observed in 86% of scans, but were observed least often in children with ataxia (24-57%). White matter injury was the most common imaging pattern (19-45%), although the proportions showed high heterogeneity. Additional patterns were grey matter injury (21%), focal vascular insults (10%), malformations (11%), and miscellaneous findings (4-22%). INTERPRETATION: This review suggests areas where further dialogue will facilitate progress towards standardization of neuroimaging classification. Standardization will enable future collaborations aimed at exploring the relationships among magnetic resonance imaging patterns, risk factors, and clinical outcomes, and, ultimately, lead to better understanding of causal pathways and opportunities for prevention. PMID- 23937114 TI - Importance of the national petroleum reserve-alaska for aquatic birds. AB - We used data from aerial surveys (1992-2010) of >100,000 km(2) and ground surveys (1998-2004) of >150 km(2) to estimate the density and abundance of birds on the North Slope of Alaska (U.S.A.). In the ground surveys, we used double sampling to estimate detection ratios. We used the aerial survey data to compare densities of birds and Arctic fox (Vulpes lagopus), the major nest predator of birds, on the North Slope, in Prudhoe Bay, and in nearby areas. We partitioned the Prudhoe Bay oil field into 2 * 2 km plots and determined the relation between density of aquatic birds and density of roads, buildings, and other infrastructure in these plots. Abundance and density (birds per square kilometer) of 3 groups of aquatic birds-waterfowl, loons, and grebes; shorebirds; and gulls, terns, and jaegers were highest in the National Petroleum Reserve-Alaska (NPRA) and lowest in the Arctic National Wildlife Refuge. Six other major wetlands occur in the Arctic regions of Canada and Russia, but the largest population of aquatic birds was in the NPRA. Aquatic birds were concentrated in the northern part of the NPRA. For example, an area that covered 18% of the NPRA included 53% of its aquatic birds. The aerial surveys showed that bird density was not lower and fox density was not higher in Prudhoe Bay than in surrounding areas. Density of infrastructure did not significantly affect bird density for any group of species. Our results establish that the NPRA is one of the most important areas for aquatic birds in the Arctic. Our results and those of others also indicate that oil production, as practiced in Prudhoe Bay, does not necessarily lead to substantial declines in bird density or productivity in or near the developed areas. Prioridades para la Conservacion de Aves en el Norte de Alaska. PMID- 23937115 TI - Treatment decision-making for post-partum hemorrhage using dynamic contrast enhanced computed tomography. AB - AIM: Post-partum hemorrhage (PPH) is the leading cause of maternal mortality. Identification of the precise bleeding site is generally important to control hemorrhage, but such an approach has not been fully established in the context of PPH. We postulated that visualization of bleeding sites could aid treatment decisions in the management of PPH. METHODS: We conducted a prospective review of 26 patients who underwent dynamic computed tomography (CT) for PPH. RESULTS: A total of 17 cases presented with uterine bleeding, eight with vaginal hematomas, and one with hemoperitoneum. Overall, dynamic CT identified contrast media extravasation in the arterial phase in 12 of 26 (46.2%) cases: the upper (n = 4) and the lower uterine segment including the cervix (n = 2), subfascial space (n = 1) and vagina (n = 5). Identification of precise arterial bleeding sites using CT provided informative guidance about where to place balloons for intractable uterine bleeding, and how to manage hemoperitoneum and vaginal hematomas. In addition, dynamic CT revealed the existence of a subtype of uterine atony, which is characterized by focal active arterial bleeding in the upper uterine segment. Furthermore, negative contrast extravasation extracted cases of PPH that were well controlled without the need for surgical or radiological intervention. No patient required emergency hysterectomy to control PPH. CONCLUSION: Dynamic CT has potential clinical utility in treatment decision-making for PPH. PMID- 23937116 TI - Lactobacillus plantarum MYL26 induces endotoxin tolerance phenotype in Caco-2 cells. AB - BACKGROUND: Crohn's disease and ulcerative colitis are the major types of chronic inflammatory bowel disease occurring in the colon and small intestine. A growing body of research has proposed that probiotics are able to attenuate the inflammatory symptoms of these diseases in vitro and in vivo. However, the mechanism of probiotic actions remains unclear. RESULTS: Our results suggested Lactobacillus plantarum MYL26 inhibited inflammation in Caco-2 cells through regulation of gene expressions of TOLLIP, SOCS1, SOCS3, and IkappaBalpha, rather than SHIP-1 and IRAK-3. CONCLUSIONS: We proposed that live/ heat-killed Lactobacillus plantarum MYL26 and bacterial cell wall extract treatments impaired TLR4-NFkappab signal transduction through Tollip, SOCS-1 and SOCS-3 activation, thus inducing LPS tolerance. Our findings suggest that either heat-killed probiotics or probiotic cell wall extracts are able to attenuate inflammation through pathways similar to that of live bacteria. PMID- 23937117 TI - Narrowband ultraviolet B phototherapy in children with moderate-to-severe eczema: a comparative cohort study. AB - BACKGROUND: There is only retrospective evidence for the efficacy of narrowband ultraviolet B (NB-UVB) in children with eczema. OBJECTIVES: To measure the difference in means for objective scores [Six Area Six Sign Atopic Dermatitis score (SASSAD), percentage surface area] and quality-of-life scores, between patients treated with NB-UVB and unexposed cohorts at the end of treatment, and 3 and 6 months post-treatment. METHODS: Twenty-nine children aged 3-16 years for whom NB-UVB was indicated, were scored prospectively using SASSAD and percentage surface area involvement at baseline, at 12 weeks (end of treatment) and 3 and 6 months post-NB-UVB. Their scores were compared with those of unexposed children (n = 26) for whom NB-UVB phototherapy was indicated and offered, but who chose not to undertake treatment. RESULTS: There was a 61% reduction in mean SASSAD score in the NB-UVB cohort compared with an increase of 6% in the unexposed cohort. Mean SASSAD score for the NB-UVB cohort at the end of treatment was 11.6 vs. 24.8 for the unexposed; difference in means -13.2 [95% confidence interval (CI) -18.7 to -7.7, P < 0.0001]. Mean surface area involvement at the end of treatment was 11% for the NB-UVB cohort vs. 36% for the unexposed cohort; difference in means -25% (95% CI -34% to -16%, P < 0.0001). Subjective and quality-of-life scores showed significant difference between cohorts at the end of treatment (P < 0.05). Objective scores remained significantly lower than in the unexposed cohort 3 and 6 months after treatment. CONCLUSION: NB-UVB is clinically effective and improves quality of life in children with moderate-to severe eczema. The effect is maintained for 6 months after treatment. PMID- 23937118 TI - GST-omega genes interact with environmental tobacco smoke on adult level of lung function. AB - BACKGROUND: Lung growth in utero and lung function loss during adulthood can be affected by exposure to environmental tobacco smoke (ETS). The underlying mechanisms have not been fully elucidated. Both ETS exposure and single nucleotide polymorphisms (SNPs) in Glutathione S-Transferase (GST) Omega genes have been associated with the level of lung function. This study aimed to assess if GSTO SNPs interact with ETS exposure in utero and during adulthood on the level of lung function during adulthood. METHODS: We used cross-sectional data of 8,128 genotyped participants from the LifeLines cohort study. Linear regression models (adjusted for age, sex, height, weight, current smoking, ex-smoking and packyears smoked) were used to analyze the associations between in utero, daily and workplace ETS exposure, GSTO SNPs, the interaction between ETS and GSTOs, and level of lung function (FEV(1), FEV(1)/FVC). Since the interactions between ETS and GSTOs may be modified by active tobacco smoking we additionally assessed associations in never and ever smokers separately. A second sample of 5,308 genotyped LifeLines participants was used to verify our initial findings. RESULTS: Daily and workplace ETS exposure was associated with significantly lower FEV(1)levels. GSTO SNPs (recessive model) interacted with in utero ETS and were associated with higher levels of FEV(1), whereas the interactions with daily and workplace ETS exposure were associated with lower levels of FEV(1), effects being more pronounced in never smokers. The interaction of GSTO2 SNP rs156697 with in utero ETS associated with a higher level of FEV(1) was significantly replicated in the second sample. Overall, the directions of the interactions of in utero and workplace ETS exposure with the SNPs found in the second (verification) sample were in line with the first sample. CONCLUSIONS: GSTO genotypes interact with in utero and adulthood ETS exposure on adult lung function level, but in opposite directions. PMID- 23937119 TI - Multiple-digit periungual Bowen's disease: a novel treatment approach with radiotherapy. AB - Multiple periungual Bowen disease [BD; also known as squamous cell carcinoma (SCC) in situ] is rare. The pathogenesis of the disease is linked to human papilloma virus, and in some instances to chronic immunosuppression. The usual management of periungual BD is by local excision, Mohs micrographic surgery or distal phalanx amputation. Our patient was offered radiotherapy in the hope of maximizing residual function and minimizing morbidity from treatment. A good response was seen at 2 months post-radiotherapy, but this was followed by relapses at 4 and 6 months post-radiotherapy. Persistent anonychia resulted in improved access to the involved skin, making topical therapy possible. Radiotherapy can be a valuable management approach for periungual SCC/BD in locations where amputation could result in substantial disability. PMID- 23937120 TI - Important information regarding reporting of adverse drug reactions: a qualitative study. AB - OBJECTIVE: To give an overview of the views of different types of reporters (patients and healthcare professionals (HCPs)) and assessors of adverse drug reactions (ADRs) on what they consider important information regarding an ADR report. METHODS: A semi-structured interview was conducted among reporters and assessors of ADRs in the Netherlands. All interviews were audiotaped and transcribed verbatim. Content analysis was used on the data. All transcripts were coded individually by two researchers. A list was drafted of all elements of information mentioned during the interviews. KEY FINDINGS: In total 16 interviews were conducted. Elements of information that were explicitly brought up during the interviews were the impact of the ADR on the patient's daily life and information regarding causality. Furthermore, the correctness of reported information was found important by assessors of ADRs. Generally, patient reporting was seen as a very positive development for pharmacovigilance. CONCLUSION: Patients reported that the severity of ADRs and their impact on daily life were important subjects. In the interviews with HCPs, either reporters or assessors, the focus was mainly on causality. The correctness of the given information is considered by ADR assessors to be very important. Regarding patient reporting the overall view was positive. Because HCPs and patients have different views regarding ADR reporting, in daily practice it is important to receive reports from both groups to assess the true nature of the ADR. PMID- 23937121 TI - Investigating the influence of morphology in the dynamical behavior of semicrystalline Triton X-100: insights in the detection/nondetection of the alpha'-process. AB - The paper investigates the influence of the crystalline structure in the dynamical behavior of semicrystalline Triton X-100 allowing enlightening the reason for the detection/nondetection of the alpha'-process. The work was preceded by the study of the full amorphous material for which dielectric relaxation spectroscopy (DRS) identified multiple relaxations: the alpha-process associated with the dynamical glass transition and two secondary relaxations (beta- and gamma- processes). To evaluate how crystallinity affects the detected relaxation processes, different crystallizations were induced under high and low undercooling conditions. While the secondary relaxations are unaffected by crystallization, the mobility of the cooperative bulk alpha-process is sensitive to the distinct morphologies. The distinct semicrystalline states were structurally characterized by X-ray diffraction and polarized optical microscopy (POM). Differential scanning calorimetry (DSC) was used as a complementary tool. Depending on the extension of undercooling, large and well-defined shperulites or grainy-like structure emerge, respectively, for low and high undercooling degrees, as monitored by POM. In the two crystalline structures, X-ray diffraction patterns detected the amorphous halo meaning that both are semicrystalline. However, no differences between the amorphous regions are indentified by this technique; the distinction was done by means of dielectric measurements probing different mobilities in each of those regions. When the large spherulites evolve, the bulk-like alpha-process never goes to extinction and slightly shifts to low frequencies increasing the associated glass transition by 2-3 K, as confirmed by DSC; the slight change is an indication that the dimensions of the persisting amorphous regions become comparable to the length scale inherent to the cooperative motion that determines the glass transition in the full amorphous material. For the grainy-like structure, the alpha-process becomes extinct and an alpha'-process evolves as revealed by isochronal plots of dielectric measurements, with the features of a glass transition as confirmed by temperature modulated differential scanning calorimetry; both techniques indicate a 10-12 K displacement of the associated hindered glass transition toward higher temperatures relative to the amorphous glass transition. It is concluded that the detection of the alpha'-process in Triton X-100 is greatly determined by the high degree of constraining of the amorphous regions imposed by the grainy crystalline structure disabling the occurrence of a bulk-like alpha-process. Triton X-100 can be taken as a model for understanding low molecular weight materials crystallization, allowing correlating the observed dynamical behavior with the achieved crystalline morphology. PMID- 23937122 TI - Effect of intracavernous administration of angiopoietin-4 on erectile function in the streptozotocin-induced diabetic mouse. AB - INTRODUCTION: Erectile dysfunction (ED) is a highly prevalent complication of diabetes, and the severity of endothelial dysfunction is one of the most important factors in reduced responsiveness to oral phosphodiesterase type 5 inhibitors. AIM: To study the effects of human angiopoietin-4 (Ang-4) protein on erectile function in diabetic mice. METHODS: Diabetes was induced by intraperitoneal injection of streptozotocin into 8-week-old C57BL/6J male mice. At 8 weeks after the induction of diabetes, the animals were divided into four groups: control nondiabetic mice and diabetic mice receiving two successive intracavernous injections of phosphate buffered saline (days -3 and 0), a single intracavernous injection of Ang-4 protein (day 0), or two successive intracavernous injections of Ang-4 protein (days -3 and 0). MAIN OUTCOME MEASURES: One week after treatment, we measured erectile function by electrical stimulation of the cavernous nerve. The penis was harvested and stained with hydroethidine or antibodies to Ang-4, platelet/endothelial cell adhesion molecule 1, and phosphorylated endothelial nitric oxide synthase (eNOS). We also determined the differential expression of Ang-4 in cavernous tissue in the control and diabetic mice. The effect of Ang-4 protein on the phosphorylation of Tie-2, Akt, and eNOS was determined in human umbilical vein endothelial cells (HUVECs) by Western blot. RESULTS: The cavernous expression of Ang-4 was downregulated in diabetic mice; Ang-4 was mainly expressed in endothelial cells. Local delivery of Ang-4 protein significantly increased cavernous endothelial content, induced eNOS phosphorylation, and decreased the generation of superoxide anion and apoptosis in diabetic mice. Ang-4 protein strongly increased the phosphorylation of Tie-2, Akt, and eNOS in HUVECs. Repeated intracavernous injections of Ang-4 induced significant restoration of erectile function in diabetic mice (87% of control values), whereas a single intracavernous injection of Ang-4 protein elicited modest improvement. CONCLUSIONS: Cavernous endothelial regeneration by use of Ang-4 protein may have potential for the treatment of vascular disease-induced ED, such as diabetic ED. PMID- 23937123 TI - Deciphering the metabolic pathways influencing heat and cold responses during post-harvest physiology of peach fruit. AB - Peaches are highly perishable and deteriorate quickly at ambient temperature. Cold storage is commonly used to prevent fruit decay; however, it affects fruit quality causing physiological disorders collectively termed 'chilling injury' (CI). To prevent or ameliorate CI, heat treatment is often applied prior to cold storage. In the present work, metabolic profiling was performed to determine the metabolic dynamics associated with the induction of acquired CI tolerance in response to heat shock. 'Dixiland' peach fruits exposed to 39 degrees C, cold stored, or after a combined treatment of heat and cold, were compared with fruits ripening at 20 degrees C. Dramatic changes in the levels of compatible solutes such as galactinol and raffinose were observed, while amino acid precursors of the phenylpropanoid pathway were also modified due to the stress treatments, as was the polyamine putrescine. The observed responses towards temperature stress in peaches are composed of both common and specific response mechanisms to heat and cold, but also of more general adaptive responses that confer strategic advantages in adverse conditions such as biotic stresses. The identification of such key metabolites, which prime the fruit to cope with different stress situations, will likely greatly accelerate the design and the improvement of plant breeding programs. PMID- 23937124 TI - Kidney transplantation from living related donors aged more than 60 years: a single center experience. AB - OBJECTIVES: To evaluate whether the outcomes of renal grafts from living related donors more than 60 years old are acceptable, in terms of renal function and patient/graft survival. MATERIAL AND METHODS: Twenty-one patients who received kidneys from donors older than 60 years constituted the study group (Group 1). The control group (Group 2) consisted of 110 patients who received renal transplants from ideal donors, aged 18 to 45 years. The recipients were analyzed for posttransplantation serum creatinine, the number of acute rejection episodes and delayed graft function, and patient/graft survival. RESULTS: The mean age of donors was 62.6 +/- 2.2 years in Group 1 and 32.8 +/- 7.0 years in Group 2. Recipient serum creatinine was higher on postoperative day 1, year 1, year 5 in Group 1 than that in Group 2 (536.8 +/- 203.3 vs. 409.8 +/- 213.8, 142.4 +/- 38.2 vs. 100.3 +/- 22.9, 152.6 +/- 42.7 vs. 107.1 +/- 22.1, respectively; all p < 0.05). Acute rejection was seen in 4 cases in Group 1 (19.0%) and in 15 cases in Group 2 (13.6%; p = 0.759). Delayed graft function was seen in two cases in Group 1 (9.5%) and in four cases in Group 2 (3.6%; p = 0.540). One-, 3- and 5-year patient survival was 100%, 100% and 100% for Group 1, and 97%, 97% and 97% for Group 2. Corresponding death-censored graft survival was 100%, 100% and 100% for Group 1, and 98%, 98% and 96% for Group 2. No significant difference was observed in terms of patient/graft survival. CONCLUSIONS: Although compromising renal function, donor age did not affect patient and graft survival in the 5-year follow-up in our study. Age alone seems not to be an exclusion criterion to living kidney donation. PMID- 23937125 TI - An in vitro wound healing model for evaluation of dermal substitutes. AB - Reepithelialization of skin wounds is essential to restore barrier function and prevent infection. This process requires coordination of keratinocyte proliferation, migration, and differentiation, which may be impeded by various extrinsic and host-dependent factors. Deep, full-thickness wounds, e.g., burns, are often grafted with dermal matrices before transplantation of split-skin grafts. These dermal matrices need to be integrated in the host skin and serve as a substrate for neoepidermis formation. Systematic preclinical analysis of keratinocyte migration on established and experimental matrices has been hampered by the lack of suitable in vitro model systems. Here, we developed an in vitro full-thickness wound healing model in tissue-engineered human skin that allowed analysis of the reepithelialization process across different grafted dermal substitutes. We observed strong differences between porous and nonporous matrices, the latter being superior for reepithelialization. This finding was corroborated in rodent wound healing models. The model was optimized using lentivirus-transduced keratinocytes expressing enhanced green fluorescent protein and by the addition of human blood, which accelerated keratinocyte migration underneath the clot. Our model shows great potential for preclinical evaluation of tissue-engineered dermal substitutes in a medium-throughput format, thereby obviating the use of large numbers of experimental animals. PMID- 23937126 TI - What is going on with my samples? A general approach to parallelism assessment and data interpretation for biomarker ligand-binding assays. PMID- 23937128 TI - Interview with Irving W Wainer. AB - Irving W Wainer, Senior Investigator in the Intramural Research Program at the National Institute on Aging/NIH received his PhD degree in chemistry from Cornell University and did postdoctoral doctoral studies in molecular biology (University of Oregon) and clinical pharmacology (Thomas Jefferson Medical School). He worked for the US FDA and held positions at St Jude's Children's Research Hospital, at McGill University as Professor in the Department of Oncology, and as a Professor of Pharmacology at Georgetown University. Wainer has published over 350 scientific papers, 10 books, 25 book chapters and holds 11 patents. His awards include: 'A.J.P. Martin Medal' presented by the Chromatographic Society; Doctor HonorisCausa awarded by the Medical University of Gdansk (Gdansk, Poland, 2006), Doctor HonorisCausa awarded by the Department of Medicine, University of Liege (Liege, Belgium, 2012), and the 2013 Eastern Analytical Symposium Award for Outstanding Contributions to the Fields of Analytical Chemistry. Wainer's research includes the development of new therapeutic agents for the treatment of congestive heart failure, cancer, pain and depression, many of which are in the later stages of drug development. His laboratory has also continued the development of cellular membrane affinity chromatography technology, and recent work includes the development of columns containing immobilized forms of the breast cancer resistance protein found in cellular and nuclear membranes and mitochondrial membrane columns. Wainer's laboratory has also continued its study of the effect of disease progression and aging on drug metabolism in critically ill and terminal patients. Interview was conducted by Lisa Parks, Assistant Commissioning Editor of Bioanalysis. PMID- 23937129 TI - Ask the experts: automation: part I. AB - Bioanalysis invited a selection of leading researchers to express their views on automation in the bioanalytical laboratory. The topics discussed include the challenges that the modern bioanalyst faces when integrating automation into existing drug-development processes, the impact of automation and how they envision the modern bioanalytical laboratory changing in the near future. Their enlightening responses provide a valuable insight into the impact of automation and the future of the constantly evolving bioanalytical laboratory. PMID- 23937130 TI - Conference Report: Pittcon 2013: microfluidics, electrochemistry, and much much more. AB - The Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy, also known as Pittcon, is the world's largest annual conference and exposition based on measurement science and instrumentation. Each year, more than 18,000 worldwide participants, coming mostly from academia, industry and government agencies, attend Pittcon to exchange information on the latest analytical techniques, the most advanced instrumentation and the current job market. In 2013, the 64th Pittcon Conference was held at the Pennsylvania Conference Center in Philadephia, PA, USA. Herein, we highlight just a few of the many presentations that describe creative and transformative research efforts aimed at obtaining bioanalytical measurements that enhance knowledge of living systems and improve human health. PMID- 23937131 TI - New bioanalytical technologies and concepts: worth the fuss? PMID- 23937132 TI - New bioanalytical technologies and concepts: worth the effort? PMID- 23937133 TI - Measurement of in vivo therapeutic mAb concentrations: comparison of conventional serum/plasma collection and analysis to dried blood spot sampling. AB - BACKGROUND: Development of an alternative sampling method that uses small amounts of whole blood, such as dried blood spots (DBS), would be an advance in the quantitative assay field. Previously, we assessed the ability to quantitate therapeutic monoclonal antibodies present in DBS compared with a typical serum sample-based method, and concluded that measurements in DBS were reproducible and yielded methods that met requirements for precision, accuracy and sensitivity. The goal herein was to assess the measurement of therapeutic antibodies in DBS compared with serum and plasma in vivo. RESULTS: Comparison of DBS versus serum in Sprague-Dawley rats and DBS versus plasma in cynomolgus monkeys for measurement of antibody concentrations revealed a two- to three-fold difference in exposure between the samples. CONCLUSION: Overall, there was good correlation between DBS versus serum and DBS versus plasma, but there was a discrepancy in DBS exposures, presumably attributable to hematocrit and recovery effects. PMID- 23937134 TI - Characterization and validation of an isotope-dilution LC-MS/MS method for quantification of total desmosine and isodesmosine in plasma and serum. AB - BACKGROUND: Desmosine/isodesmosine (DES/IDS) is a promising biomarker for estimating activity of elastin degradation. RESULTS/METHODOLOGY: A stable isotope dilution LC-MS/MS method for measuring serum/plasma DES/IDS was developed and validated. The reportable range of this assay was 0.1-160 ng/ml. Serum/plasma DES/IDS level was stable at room temperature or 4 degrees C for 20 h, and for three freeze-thaw cycles. Interferences from endogenous compounds and ion suppression/enhancing effect were also evaluated. Our results suggest the absolute necessity of using an IS in the measurement. We found that serum/plasma DES/IDS levels from patients with chronic obstructive pulmonary disease and cystic fibrosis were significantly higher compared with healthy smokers. CONCLUSION: These results demonstrate that the LC-MS/MS method provides sensitive, reproducible and accurate quantification of total serum/plasma DES/IDS. PMID- 23937135 TI - ADME of monoclonal antibody biotherapeutics: knowledge gaps and emerging tools. AB - Absorption, distribution, metabolism and excretion (ADME) data are pivotal for small-molecule drug development, with well-developed in vitro and in vivo correlation tools and guidances from regulatory agencies. In the past two decades, monoclonal antibody (mAb) biotherapeutics have been successfully approved, including derived novel conjugates of active molecules (toxins or bioactive peptides) for specific target delivery or half-life extension. However, ADME information of mAb therapeutics lags behind that of small molecules due to the complex nature of the molecules and lack of appropriate tools to study drug exposure, biotransformation, and target engagement in the vascular and tissue spaces. In this perspective, the current knowledge gaps on ADME of mAb-related therapeutics are reviewed with potential solutions from emerging analytical technologies. PMID- 23937136 TI - About sound science, stable isotope dilution, blasphemy and heresy. AB - The molar ratio between an analyte and its equal labeled with stable isotope(s), used as a bioanalytical IS, is here suggested as an essential (and currently not commonly applied) validation parameter. This parameter, when calculated and measured, gives the possibility for the bioanalyst to compare calibration graphs and QC samples over time independently of added amount of IS. Additionally, when QC samples and calibration samples do not agree it is obvious to identify where the discrepancies are. Whether calibration samples are needed when this parameter is extensively and carefully validated and understood, is also discussed. PMID- 23937137 TI - Hemato-critical issues in quantitative analysis of dried blood spots: challenges and solutions. AB - Dried blood spot (DBS) sampling for quantitative determination of drugs in blood has entered the bioanalytical arena at a fast pace during the last decade, primarily owing to progress in analytical instrumentation. Despite the many advantages associated with this new sampling strategy, several issues remain, of which the hematocrit issue is undoubtedly the most widely discussed challenge, since strongly deviating hematocrit values may significantly impact DBS-based quantitation. In this review, an overview is given of the different aspects of the 'hematocrit problem' in quantitative DBS analysis. The different strategies that try to cope with this problem are discussed, along with their potential and limitations. Implementation of some of these strategies in practice may help to overcome this important hurdle in DBS assays, further allowing DBS to become an established part of routine quantitative bioanalysis. PMID- 23937138 TI - Hemoglobin variant analysis of whole blood and dried blood spots by MS. AB - MS allows for the unequivocal diagnosis of hemoglobin variants, or hemoglobinopathies. Hemoglobinopathies are the most common inherited disorder and there is a need for rapid detection of clinically significant variants, such as sickle hemoglobin, which is responsible for sickle cell disease. In this review, we describe the development of MS approaches for the determination of hemoglobin variants from both whole blood samples and dried blood spots. MS approaches that are suitable for population screening are discussed, as are recent advances in direct surface analysis of dried blood spots. PMID- 23937139 TI - Application of population pharmacokinetics for preclinical safety and efficacy studies. AB - From the beginning of the 1980s, population PK has been primarily used in clinical development and only in the last decade has it been convincingly applied in a preclinical setting. Sparse sampling and covariate analyses are key features of preclinical popPK, useful for toxicology and efficacy studies in animals to assemble data obtained from different studies; for describing individual PK and PD; for building mechanistic models; and for performing interspecies scaling-up of disposition and efficacy. Application in disease models, mainly in behavioral and neurological models, allows the quantitative description of PK and PD without frequent blood sampling and recurrent physiological measurements, which are the critical and compromising perturbations of experimental systems. A preclinical population approach to PK and PD, by its versatility and possibility of simulating 'what if' scenarios, offers a unique and potent tool in the development of new drugs, in particular biologics. PMID- 23937141 TI - Laparoscopic and robot-assisted continent urinary diversions (Mitrofanoff and Yang-Monti conduits) in a consecutive series of 15 adult patients: the Saint Augustin technique. AB - OBJECTIVE: To present a series of 15 laparoscopic and robot-assisted Mitrofanoff and Yang-Monti vesicostomies in an adult population, and to assess the feasibility and safety of these minimally invasive approaches. PATIENTS AND METHODS: Between 2009 and 2012, 15 patients underwent laparoscopic (n = 11) or robot-assisted (n = 4) construction of vesicostomy by a single surgeon (D.R.): Mitrofanoff appendicovesicostomy (n = 11) or double Yang-Monti ileal conduit (n = 4). Fourteen patients underwent concomitant augmentation enterocystoplasty. Indications for surgery included neurogenic bladder (n = 11) and urethral dysfunction (n = 4). The patients were evaluated postoperatively using cystography. Quality of life (QoL) was evaluated using an internally developed questionnaire. RESULTS: All surgeries were successfully completed with no conversions. Operating time was always <5 h. The mean estimated blood loss was 150 mL and the mean follow-up was 22 months. Early postoperative complications included deep retrovesical abscess (n = 2) and upper urinary tract infections (n = 4), and one patient had peri-operative cardiac failure. Late postoperative complications included stomal stenosis (n = 2), persistent low-pressure bladder incontinence (n = 1) and recurrent infections (n = 1). Surgical excision of the conduit was necessary in one patient. Postoperatively, patients showed complete bladder emptying and no leak on follow-up cystography. According to our QoL questionnaire, 13/15 patients did not regret the surgery. CONCLUSIONS: While a longer follow-up is needed to assess the durability of our results, this series shows that the laparoscopic and robot-assisted approaches for the construction of continent urinary diversions are feasible and safe in an adult population. PMID- 23937142 TI - Safety and efficacy of single-port colectomy for sigmoid colon cancer: a phase II clinical trial. AB - BACKGROUND: Recently, single-port surgery for colon cancer has been increasingly attempted. However, prospective studies investigating the efficacy of single-port colectomy for colon cancer are lacking. The aim of this study is to determine whether single-port colectomy for sigmoid colon cancer is a safe and effective surgical option. SUBJECTS AND METHODS: Forty-eight patients were enrolled for this prospective single-arm Phase II trial. All patients underwent single-port laparoscopic-assisted sigmoidectomy through the umbilicus. The primary outcome was the number of retrieved lymph nodes. Secondary measures included the conversion rate, postoperative morbidities, mortalities, and short-term clinical outcomes. RESULTS: The mean number of retrieved lymph nodes was 21.1 (95% confidence interval, 18.1-23.99). The conversion rate was 14.6% (open conversion, 4.2%), and the overall proportion of morbidity was 31.2%. The majority of complications involved wound problems (18.8%); the mortality rate was 0%. The median postoperative hospital stay was 8 days (range, 7-12 days), and the median time from surgery until the first episode of flatus was 3 days (range, 1-5 days). CONCLUSIONS: Single-port colectomy for sigmoid colon cancer is safe and oncologically feasible in selected patients. Considering the relatively high conversion rates, improvement of the instruments for single-port colectomy is needed. PMID- 23937143 TI - Laparoscopic transperitoneal repair of pediatric diaphragm eventration using an endostapler device. AB - BACKGROUND: Minimally invasive repairs of pediatric diaphragm eventration have been well described via a thoracoscopic approach, oftentimes requiring single lung ventilation and tube thoracostomy, with the disadvantage of not being able to clearly visualize what lies beneath the diaphragm. We describe a novel pediatric diaphragm eventration repair using a laparoscopic transperitoneal approach and an endostapler device. We also describe our initial experience with this technique. PATIENTS AND METHODS: Four pediatric diaphragmatic eventration patients underwent laparoscopic transperitoneal repair using an endostapler device. Repairs were performed in both male and female patients with right-sided eventrations. We approach the repair in a transperitoneal fashion using inverting sutures at the apex of the diaphragm to create tension toward the pelvis. Subsequently, an endostapler is used to remove the redundant portion of diaphragm, leaving a repaired, taut diaphragm. RESULTS: The median age at operation was 10.5 months. The median operative time was 70 minutes. There was no mortality, surgical complications, or recurrence at a median follow-up of 17 months. CONCLUSIONS: This laparoscopic approach allows for clear visualization of the intraabdominal organs and, at least in our early experience, a very simple, straightforward operation. Additionally, with the use of the endostapler, the redundant, often weakened diaphragm is removed, leaving the native, healthy diaphragm behind, resulting in a reliable and reproducible repair. This repair should be considered as a feasible alternative approach to the more traditional open and thoracoscopic repairs. PMID- 23937144 TI - High-intensity exercise promotes postexercise hypotension greater than moderate intensity in elderly hypertensive individuals. AB - OBJECTIVE: To evaluate the effects of high-intensity resistance exercise on postexercise hypotension (PEH) and forearm vascular resistance (FVR) in the hypertensive elderly. METHODOLOGY: The study was conducted with ten hypertensive elderly individuals (65 +/- 3 years, 28.7 +/- 3 kg m(-2)). They were subjected to three experimental sessions: control session (SC), exercise 50% (S50%) and 80% (S80%) of 1RM. For each session, subjects were evaluated pre-and postintervention. In the preintervention, the blood pressure (BP) and FVR were measured after 10 min of rest. Thereafter, they were taken to the gym to perform the exercise sessions or remained at rest in each of the equipment during the same time. Both S50% and S80% were composed of a set of ten repetitions of ten exercises, with an interval of 90 s between exercises. Subsequently, the FVR and BP measurements were again performed at 10, 30, 50, 70 and 90 min of recovery (postintervention). RESULTS: The PEH was greater in S80% compared with S50%, with the lower value of BP being found at 90 min of recovery for the two sessions (systolic BP: 115 +/- 3,0 mmHg versus 124 +/- 5 mmHg; diastolic BP: 75 +/- 5 mmHg versus 86 +/- 3 mmHg and mean BP: 87 +/- 3 mmHg versus 95 +/- 4 mmHg, respectively). Concomitantly, the FVR also decreased significantly in both sessions, this reduction being more evident in S80% (P<0.05). CONCLUSION: High intensity resistance exercise was effective in promoting PEH, this phenomenon being accompanied by a reduction in FVR within the first minute of recovery in the hypertensive elderly. PMID- 23937145 TI - Six-membered spirocycle triggered probe for visualizing Hg2+ in living cells and bacteria-EPS-mineral aggregates. AB - A novel rhodamine based probe with a unique six-membered spirocycle was rationally designed for detection of Hg(2+) with greatly improved selectivity, sensitivity, and photostability. The probe has been shown to be suitable for Hg(2+) imaging in living cells and mapping Hg(2+) distribution in living cell-EPS mineral aggregates under anoxic conditions. PMID- 23937146 TI - Potential impacts of CO2 leakage on groundwater chemistry from laboratory batch experiments and field push-pull tests. AB - Storage of CO2 in deep saline reservoirs has been proposed to mitigate anthropogenically forced climate change. If injected CO2 unexpectedly migrates upward in shallow groundwater resources, potable groundwater may be negatively affected. This study examines the effects of an increase in pCO2 (partial pressure of CO2) on groundwater chemistry in a siliclastic-dominated aquifer by comparing a laboratory batch experiment and a field single-well push-pull test on the same aquifer sediment and groundwater. Although the aquifer mineralogy is predominately siliclastic, carbonate dissolution is the primary geochemical reaction. In the batch experiment, Ca concentrations increase until calcite saturation is reached at ~500 h. The concentrations of the elements Ca, Mg, Sr, Ba, Mn, and U are controlled by carbonate dissolution. Silicate dissolution controls Si and K concentrations and is ~2 orders of magnitude slower than carbonate dissolution. Changing pH conditions through the experiment initially mobilize Mo, V, Zn, Se, and Cd; sorption reactions later remove these elements from solution and concentrations drop to pre-experiment levels. The EPA's primary and secondary MCL's are not exceeded except for Mn, which exceeded the EPA's secondary standard of 0.05 mg/L. Push-pull results also identify carbonate and silicate dissolution reactions ~2 orders of magnitude slower than batch experiments. PMID- 23937147 TI - Gold nanoparticle delivery-enhanced proteasome inhibitor effect in adenocarcinoma cells. AB - BACKGROUND: Proteasome inhibition is a current therapeutic strategy used in the treatment of multiple myeloma. Drugs controlling proteasome activity are ideally suited for unidirectional manipulation of cellular pathways such as apoptosis. The first proteasome inhibitor approved in clinics was bortezomib. This drug is currently used in combination with other anticancer agents. OBJECTIVES: In this study, the enhancement of bortezomib activity was evaluated using gold nanoparticles coated with poly(ethylene glycol). The uptake mechanism of the gold nanoparticles in pancreatic cell lines, S2-013 and hTERT-HPNE, was assessed by laser scanning confocal microscopy (LSCM). RESULTS: Pancreatic cancer cells internalized the nanoparticles together with the drug in few minutes through the formation of endocytic vesicles. This rapid uptake leads to an increase in the concentration and diffusion of bortezomib in the cytoplasm yielding an increased toxicity on the cells when compared to the drug alone. CONCLUSION: Gold nanoparticles can be used as effective delivery systems to increasing the permeation and retention of drugs in cancer cells. PMID- 23937148 TI - Carbon-sulfur bond formation catalyzed by [Pd(IPr*(OMe))(cin)Cl] (cin = cinnamyl). AB - The newly prepared complex [Pd(IPr*(OMe))(cin)(Cl)] provides high catalytic activity for carbon-sulfur cross-coupling reactions. Nonactivated and deactivated aryl halides were successfully coupled with a large variety of aryl- and alkylthiols using this well-defined palladium N-heterocyclic carbene (NHC) complex. PMID- 23937149 TI - Illness representations as mediators of the relationship between dispositional optimism and depression in patients with chronic tinnitus: a cross-sectional study. AB - OBJECTIVE: Both dispositional optimism and illness representations are related to psychological health in chronic patients. In a group of chronic tinnitus sufferers, the interplay between these two variables was examined. Specifically, it was tested to what extent the relationship between dispositional optimism and depression is mediated by more positive illness representations. METHOD: The study had a cross-sectional design. One hundred and eighteen patients diagnosed with chronic tinnitus completed questionnaires assessing optimism (Life Orientation Test-Revised [LOT-R]), illness representations (Illness Perceptions Questionnaire-Revised [IPQ-R]) and depression (Hospital Anxiety and Depression Scale [HADS]). RESULTS: Correlation analysis showed that optimism was associated with more positive illness representations and lower levels of depression. Simple mediation analyses revealed that the relationship between optimism and depression was partially mediated by the illness representation dimensions consequences, treatment control, coherence, emotional representations and internal causes. A multiple mediation analysis indicated that the total mediation effect of illness representations is particularly due to the dimension consequences. CONCLUSION: Optimism influences depression in tinnitus patients both directly and indirectly. The indirect effect indicates that optimism is associated with more positive tinnitus-specific illness representations which, in turn, are related to less depression. These findings contribute to a better understanding of the interplay between generalised expectancies, illness-specific perceptions and psychological adjustment to medical conditions. PMID- 23937150 TI - Designing and refining Ni(II)diimine catalysts toward the controlled synthesis of electron-deficient conjugated polymers. AB - Electron-deficient pi-conjugated polymers are important for organic electronics, yet the ability to polymerize electron-deficient monomers in a controlled manner is challenging. Here we show that Ni(II)diimine catalysts are well suited for the controlled polymerization of electron-deficient heterocycles. The relative stability of the calculated catalyst-monomer (or catalyst-chain end) complex directly influences the polymerization. When the complex is predicted to be most stable (139.2 kJ/mol), these catalysts display rapid reaction kinetics, leading to relatively low polydispersities (~1.5), chain lengths that are controlled by monomer:catalyst ratio, controlled monomer consumption up to 60% conversion, linear chain length growth up to 40% conversion, and 'living' chain ends that can be readily extended by adding more monomer. These are desirable features that highlight the importance of catalyst design for the synthesis of new conjugated polymers. PMID- 23937151 TI - Using the Assisting Hand Assessment and the Mini-AHA for clinical evaluation and further research and development. PMID- 23937152 TI - Get out of here, quick! Problems with transparent labels on glass doors. AB - We studied the case of transparent word labels (e.g., "push") placed on glass doors, when viewed from the other side as mirror-reversed script, hence requiring an action opposite to word meaning. As compared with a regular view, labels seen "from the other side" in the glass door situation caused strong delays of actions and a tripling of error rates. This problem is unrelated to mirror reading but is at least partially due to the need to act opposite to word meaning. The glass door effect was not related to practice and age and showed no adaptation effect after incompatible trials. Distribution analyses showed an increased correct reaction time (RT) effect for slower responses, whereas accuracy effects were specific for fast responses. In the literature, problems with such mixed mappings have often been interpreted in the sense of competing action tendencies. Experiments 1 to 4, however, demonstrated that this might merely be a task difficulty effect due to the necessity for a mental transformation in case of mirror-reversed labels. Moreover, our results strongly advocate against using transparent labels because they may pose a considerable risk. PMID- 23937153 TI - Serum or breast milk immunoglobulins mask the self-reactivity of human natural IgG antibodies. AB - B cells producing IgG antibodies specific to a variety of self- or foreign antigens are a normal constituent of the immune system of all healthy individuals. These naturally occurring IgG antibodies are found in the serum, external secretions, and pooled human immunoglobulin preparations. They bind with low affinity to antigens, which can also be targets for pathologic autoantibodies. An enhancement of naturally occurring IgG autoantibody activity was observed after treatment of human IgG molecules with protein-destabilizing agents. We have investigated the interactions of human immunoglobulins that were obtained from serum or from breast milk of healthy individuals or IVIg with human liver antigens. Proteins from an individual serum or milk were isolated by two methods, one of which included exposure to low pH and the other did not. Purified serum, mucosal IgM, IgA, and the fraction containing immunoglobulin G F(ab')2 fragments each inhibited the binding of a single donor or pooled IgG to human liver antigens. Our study presents findings regarding the role of the breast milk or serum antibodies in blocking the self-reactivity of IgG antibodies. It supports the suggestion that not IVIg only, but also the pooled human IgM and IgA might possess a potent beneficial immunomodulatory activity in autoimmune patients. PMID- 23937154 TI - Information needs of people with asthma. AB - OBJECTIVES: To describe the information needs of a group of Australians with asthma and the extent to which their needs had been met. METHODS: A self administered survey was completed by people with asthma either presenting at community pharmacies or registered with a medical research institute database. The survey questions were developed based on a review of the literature, and included questions regarding participants' information needs about their asthma, their sources of asthma information and the extent to which these information needs had been met. The responses concerning information needs were analysed thematically. Responses concerning sources of asthma information and the extent to which needs were met were analysed using descriptive and correlational statistics. KEY FINDINGS: Seventy-one people completed the survey. Key information needs that were identified included medications, management of asthma, asthma triggers, cure, aetiology of asthma and latest research. A third of participants reported having only 'very little', 'a little' or 'some' of their information needs met. The most common source of information was from a doctor (94% respondents), followed by a pharmacist or pharmacy assistant (56%). CONCLUSION: Insights into the information needs of people with asthma have been provided. In light of the level of unmet information needs of people with asthma, and the types of information sought, pharmacists are in an ideal position to close the information gap and promote optimal asthma self-management practices. PMID- 23937155 TI - Myofibroblast expression in airways and alveoli is affected by smoking and COPD. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by structural changes in alveoli and airways. Our aim was to analyse the numbers of alpha-smooth muscle actin (alpha-SMA) positive cells, as a marker of myofibroblasts, in different lung compartments in non-smokers and smokers with normal lung function or COPD. METHODS: alpha-SMA, tenascin-C (Tn-C) and EDA fibronectin in alveolar level and airways were assayed by immunohistochemistry and quantified by image analysis. Immunohistochemical findings were correlated with clinical data. alpha-SMA protein was also analysed by Western blotting from fibroblastic cells cultured from peripheral lung of non-smokers, smokers without COPD and smokers with COPD. RESULTS: In many cases, the endings of the detached alveolar walls were widened, the structures of which were named as widened alveolar tips. Widened alveolar tips contained alpha-SMA positive cells, which were obviously myofibroblasts. There were less alveolar tips containing positive cells for alpha-SMA in alveoli and alpha-SMA positive cells in bronchioles in smokers and in COPD compared to non-smokers. The quantity of alpha-SMA positive cells was increased in bronchi in COPD. Tn-C was elevated in bronchi in COPD and smokers' lung. The alpha-SMA protein level was 1.43-fold higher in stromal cells cultured from non-smokers than in those of smokers. CONCLUSIONS: Myofibroblasts are localized variably in normal and diseased lung. This indicates that they have roles in both regeneration of lung and pathogenesis of COPD. The widened alveolar tips, these newly characterized histological structures, seemed to be the source of myofibroblasts at the alveolar level. PMID- 23937157 TI - Lead-free piezoelectrics based on potassium-sodium niobate with giant d(33). AB - High-performance lead-free piezoelectrics (d33 > 400 pC/N) based on 0.96(K0.5Na0.5)0.95Li0.05Nb1-xSbxO3-0.04BaZrO3 with the rhombohedral-tetragonal (R-T) phase boundary have been designed and prepared. The R-T phase boundary lies the composition range of 0.04 <= x <= 0.07, and the dielectric and piezoelectric properties of the ceramics with the compositions near the phase boundary are significantly enhanced. In addition, the ceramic with x = 0.07 has a giant d33 of ~425 pC/N, which is comparable to that (~416 pC/N) of textured KNN-based ceramics (Saito, Y.; Takao, H.; Tani, T.; Nonoyama, T.; Takatori, K.; Homma, T.; Nagaya, T.; Nakamura, M. Nature 2004, 432, 84). The underlying physical mechanisms for enhanced piezoelectric properties are addressed. We believe that the material system is the most promising lead-free piezoelectric candidates for the practical applications. PMID- 23937156 TI - Autophagy-mediated turnover of dynamin-related protein 1. AB - BACKGROUND: Drp1 is the primary protein responsible for mitochondrial fission. Perturbations of mitochondrial morphology and increased fission are seen in neurodegeneration. While Drp1 degradation induced by Parkin overexpression can be prevented by proteasome inhibition, there are numerous links between proteasomal and autophagic processes in mitochondrial protein degradation. Here we investigated the role of autophagy in Drp1 regulation. RESULTS: We demonstrate that autophagy plays a major role in the control of Drp1 levels. In HEK-293T cells, inhibitors of autophagy increase total Drp1 and levels of Drp1 in the mitochondrial cellular fraction. Similarly by silencing ATG7, which is required for initiation of autophagy, there is an increased level of Drp1. Because of the role of increased Drp1 in neurodegeneration, we then examined the ability to modulate Drp1 levels in neurons by inducing autophagy. We are able to decrease Drp1 levels in a time- and dose-dependent manner with the potent neuronal autophagy inducer 10-NCP, as well as structurally related compounds. Further, 10 NCP was able increase average mitochondrial size and length verifying a functional result of Drp1 depletion in these neurons. CONCLUSIONS: These pharmacological and genetic approaches indicate that autophagy targets Drp1 for lysosomal degradation. Additionally these data suggest a mechanism, through Drp1 downregulation, which may partly explain the ability of autophagy to have a neuroprotective effect. PMID- 23937158 TI - Melanoma in situ affecting the penis of a naturist. PMID- 23937159 TI - Successful therapy of refractory Hailey-Hailey disease with oral alitretinoin. PMID- 23937160 TI - Development and in vitro evaluation of diclofenac sodium loaded mucoadhesive microsphere with natural gum for sustained delivery. AB - The objective of this study was to develop and evaluate mucoadhesive microsphere of diclofenac sodium with natural gums for sustained delivery. Guar gum and tragacanth were used along with sodium alginate as mucoadhesive polymers. Microspheres were formulated using orifice-ionic gelation method. Particle size, surface morphology, swelling study and drug entrapment efficiency of the prepared microspheres were determined. In vitro evaluation was carried out comprising of mucoadhesion and drug release study. The prepared microspheres were discrete and free flowing. Sodium alginate and natural gum, at a ratio of 1:0.25, showed good mucoadhesive property and they had high drug entrapment efficiencies. They also exhibited the best rate retarding effect among all the formulations. Drug entrapment efficiency of all the microspheres ranged from 80.42% to 91.67%. An inverse relationship was found between extent of crosslinking and drug release rate. Release rate was slow and extended in case of the formulations of 1:0.25 ratio (F1 and F3), releasing 68.36% and 70.56% drug respectively after 8 hours. Tragacanth-containing microspheres of F1 showed superiority over other formulations, with best mucoadhesive and rate retarding profile. The correlation value (r(2)) indicated that the drug release of all the formulations followed Higuchi's model. Overall, the results indicated that mucoadhesive microspheres containing natural gum can be promising in terms of prolonged delivery with good mucoadhesive action, targeting the absorption site to thrive oral drug delivery. PMID- 23937161 TI - Novel interpenetrating polymer matrix network microparticles for intestinal drug delivery. AB - This paper deals with the synthesis and characterization of Ghatti gum (GG) and chitosan (CS) IPN MP prepared by emulsion-cross-linking method. Glutaraldehyde (GA) was used as a cross-linker. IPN microparticles were used to deliver (DS) Diclofenac sodium (Model anti inflammatory drug) to the intestine. IPN MP were characterized by Scanning electron microscopy (SEM), differential scanning calorimetric (DSC), Fourier Transform Infrared Spectroscopy (FTIR) and evaluated for in vitro dissolution rate. FTIR studies assessed the formation of IPN structure. The surface morphology was studied by SEM. Particle sizes ranged between 294 to 366 MUm. After encapsulation into IPN microparticles DSC studies were performed to recognize the crystalline nature of drug. DS percentage encapsulation efficiency (%EE) ranged from 84.09 to 96.81%. Equilibrium swelling was performed in buffer solution (pH 7.4). In-vitro release studies indicated the dependence of drug release rates on both the amount of chitosan and GG used in grounding of microparticles. The release was extended up to 12 hrs and release rates were fitted into an empirical equation to work out the diffusion parameter which indicates a Non-Fickian release. Continuous dissolution-absorption studies were carried out using everted rat intestine for optimized formulation (F9). PMID- 23937162 TI - Prodrug/Enzyme based acceleration of absorption of hydrophobic drugs: an in vitro study. AB - Poor water solubility of APIs is a key challenge in drug discovery and development as it results in low drug bioavailability upon local or systemic administration. The prodrug approach is commonly utilized to enhance solubility of hydrophobic drugs. However, for accelerated drug absorption, supersaturated solutions need to be employed. In this work, a novel prodrug/enzyme based system was developed wherein prodrug and enzyme are coadministered at the point of absorption (e.g., nasal cavity) to form in situ supersaturated drug solutions for enhanced bioavailability. A combination of fosphenytoin/alkaline phosphatase was used as a model system. Prodrug conversion kinetics were evaluated with various prodrug/enzyme ratios at pH 7.4 and 32 degrees C. Phenytoin permeation rates were determined at various degrees of supersaturation (S = 0.8-6.1), across confluent Madin Darby canine kidney II-wild type monolayers (a nasal epithelium model), with prodrug and enzyme spiked into the apical chamber. Membrane intactness was confirmed by measuring transepithelial electrical resistance and inulin permeability. Fosphenytoin and phenytoin concentrations were analyzed using HPLC. Results indicated that a supersaturated solution could be formed using such prodrug/enzyme systems. Drug absorption increased proportionately with increasing degrees of supersaturation; this flux was 1.5-6 fold greater than that for the saturated phenytoin solution. The experimental data fitted reasonably well to a two compartment pharmacokinetic (PK) model with first order conversion of prodrug to drug. This prodrug/enzyme system markedly enhances drug transport across the model membrane. Applied in vivo, this strategy could be used to facilitate drug absorption through mucosal membranes when absorption is limited by solubility. PMID- 23937163 TI - Limit of miscibility and nanophase separation in associated mixtures. AB - We present a detailed analysis of the mixing process in an associating system, the water-tert-butanol (2-methyl-2-propanol) mixture. Using molecular dynamics simulations, together with neutron, X-ray diffraction experiments, and pulsed gradient spin-echo NMR, we study the local structure and dynamic properties over the full concentration range, and thereby provide quantitative data that reveal relationships between local structure and macroscopic behavior. For an alcohol rich mixture, diffraction patterns from both neutron and X-ray experiments exhibit a peak at low wavelength vector (q ~ 0.7 A(-1)) characteristic of supermolecular structures. On increasing the water content, this "prepeak" progressively flattens and shifts to low wave vector . We identify hydrogen bonds in the system as the driving force for the specific organization that appears in mixtures, and provide an analysis of the variation of the cluster size distribution with composition. We find that the sizes of local hydrogen-bonded clusters observed in alcohol-rich mixtures become larger as the mole fraction, x(w), of water is increased; a nanophase separation is seen for x(w) in the range 0.6-0.7. This corresponds to several changes in some macroscopic properties of the liquid mixture. Thus, we propose a microscopic description of the effect of water addition in alcohol, which is in agreement with both neutron diffraction pattern and mobility of water and alcohol species. In summary we present a full and comprehensive description of miscibility at its limit in an associated system. PMID- 23937164 TI - Rechargeable Mg-ion batteries based on WSe2 nanowire cathodes. AB - The increasing interest in future energy storage technologies has generated the urgent need for alternative rechargeable magnesium ion batteries due to their innate merits in terms of raw abundance, theoretical capacity, and operational safety. Herein, we report an alternative pathway to a new energy storage regime: toward advanced rechargeable magnesium-ion batteries based on WSe2 nanowire assembled film cathodes. The as-grown electrodes delivered efficient Mg(2+) intercalation/insertion activity, excellent cycling life, enhanced specific capacity, and excellent rate capability. We also evaluated the influence of Mg intercalation behavior on Mg-ion batteries based on WSe2 film cathodes via the first-principles DFT computations. The results reveal the feasibility of using advanced magnesium-ion batteries based on WSe2 film as energy storage components in next-generation optoelectronic systems. PMID- 23937165 TI - Case of maternal and fetal deaths due to severe congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) during pregnancy. AB - Upshaw-Schulman syndrome (USS) involves a congenital deficiency of von Willebrand factor-cleaving metalloprotease (ADAMTS13) activity due to gene mutations. Female patients develop overt thrombotic thrombocytopenic purpura (TTP) caused by a decline of ADAMTS13 activity in pregnancy. A 23-year-old nulliparous Japanese woman died due to severe, rapid progression of TTP with intrauterine fetal death at 20 weeks of gestation after its onset, even though she underwent intensive treatment which included plasma exchange. She had a history of idiopathic thrombocytopenic purpura at the age of 3 years. The patient's ADAMTS13 activity was of very low level. It should be borne in mind that there is the possibility of rapidly progressive fulminant USS during pregnancy. PMID- 23937166 TI - Ten kidney paired donation transplantation on World Kidney Day 2013: raising awareness and time to take action to increase donor pool. AB - BACKGROUND: Kidney paired donation (KPD) is feasible for any center that performs living related donor renal transplantation (LRDRTx). Lack of awareness, counseling and participation are important hurdles in KPD patients with incompatible donors. MATERIALS AND METHODS: This is an institutional review board approved study of 10 ESRD patients who consented to participate in the KPD transplantation at our center. All the surgeries were carried out on the same day at the same center on the occasion of World Kidney Day (WKD) (14 March 2013). All recipients had anatomic, functional and immunological similar donors. RESULTS: KPD were performed to avoid blood group incompatibility (n = 8) or to avoid a positive crossmatch (n = 2). None of the patients experienced delayed graft function and surgical complications. At 3 month follow-up, median serum creatinine was 1 (range 0.6 to 1.25) mg/dL and two patients developed allograft biopsy-proven acute rejection and responded to antirejection therapy. Due to impact of our awareness activity, 20 more KPD patients are medically fit for transplantation and waiting for permission from the authorization committee before transplantation. CONCLUSION: This is a report of 10 simultaneous KPD transplantations in a single day in a single centre on WKD raising awareness of KPD. KPD is viable, legal and rapidly growing modality for facilitating LRDRTx for patients who are incompatible with their healthy, willing LRD. PMID- 23937167 TI - Pilot echographic study of the differences in clitoral involvement following clitoral or vaginal sexual stimulation. AB - INTRODUCTION: Women describe at least two types of orgasms: clitoral and vaginal. However, the differences, if any, are a matter of controversy. In order to clarify the functional anatomy of this sexual pleasure, most frequently achieved through clitoral stimulation, we used sonography with the aim of visualizing the movements of the clitorourethrovaginal (CUV) complex both during external, direct stimulation of the clitoris and during vaginal stimulation. METHOD: The ultrasounds were performed in three healthy volunteers with the General Electric(r) Voluson(r) sonography system (General Electric Healthcare, Velizy, France), using a 12-MHz flat probe and a vaginal probe. We used functional sonography of the stimulated clitoris either during manual self-stimulation of the external clitoris or during vaginal penetration with a wet tampon. MAIN OUTCOME MEASURES: Functional and anatomic description, based on bidimensional ultrasounds, of the clitoris and CUV complex, as well as color Doppler signal indicating speed of venous blood flow, during arousal obtained by external or internal stimulation. RESULTS: The sagittal scans obtained during external stimulation and vaginal penetration demonstrated that the root of the clitoris is not involved with external clitoral stimulation. In contrast, during vaginal stimulation, because of the movements and displacements, the whole CUV complex and the clitoral roots in particular are involved, showing functional differences depending on the type of stimulation. The color signal indicating flow speed in the veins mirrored the anatomical changes. CONCLUSIONS: Despite a common assumption that there is only one type of female orgasm, we may infer, on the basis of our findings, that the different reported perceptions from these two types of stimulation can be explained by the different parts of the clitoris (external and internal) and CUV complex that are involved. PMID- 23937168 TI - Concise synthesis of the multiply oxygenated ABC-ring system of the dihydro-beta agarofurans. AB - The multiply oxygenated ABC-ring system of the dihydro-beta-agarofurans was synthesized by employing two highly stereoselective reactions. The quinidine catalyzed Diels-Alder reaction between a chiral dienophile and 3-hydroxy-4-methyl 2-pyrone simultaneously installed the C2-stereogenic center and two contiguous tetrasubstituted carbon centers (C5 and C10) of the A-ring. After 12 additional transformations, the aldol reaction of the resulting spiral AC-ring cyclized the B-ring with stereoselective introduction of the C7- and C8-centers. PMID- 23937169 TI - Contemporary sediment-transport processes in submarine canyons. AB - Submarine canyons are morphological incisions into continental margins that act as major conduits of sediment from shallow- to deep-sea regions. However, the exact mechanisms involved in sediment transfer within submarine canyons are still a subject of investigation. Several studies have provided direct information about contemporary sedimentary processes in submarine canyons that suggests different modes of transport and various triggering mechanisms. Storm-induced turbidity currents and enhanced off-shelf advection, hyperpycnal flows and failures of recently deposited fluvial sediments, dense shelf-water cascading, canyon-flank failures, and trawling-induced resuspension largely dominate present day sediment transfer through canyons. Additionally, internal waves periodically resuspend ephemeral deposits within canyons and contribute to dispersing particles or retaining and accumulating them in specific regions. These transport processes commonly deposit sediments in the upper- and middle-canyon reaches for decades or centuries before being completely or partially flushed farther down canyon by large sediment failures. PMID- 23937170 TI - Kannurin, a novel lipopeptide from Bacillus cereus strain AK1: isolation, structural evaluation and antifungal activities. AB - AIM: This study was performed to isolate and characterize novel antifungal lipopeptide from Bacillus cereus. METHODS AND RESULTS: Elucidation of its chemical structure was carried out by electrospray ionization mass spectra (ESI MS) and Fourier transform infrared spectroscopy (FT-IR). The compound is a cyclic heptapeptide and composed of amino acids, Leu-Asp-Val-Leu-Leu-Leu-Leu. The in vitro activity of Kannurin against various pathogenic yeasts was assessed by CLSI M27-A and moulds by M38-A. It demonstrated broad-spectrum, fungicidal activity against clinically relevant yeasts and moulds. Kannurin exhibited low haemolytic activity and remained active over a wide pH and temperature range. In addition, Kannurin did not bind with melanin particles and was as active in inhibiting biofilms. CONCLUSIONS: An antifungal surfactin-like lipopeptide produced by Bacillus cereus strain AK1 was purified and chemically characterized. We propose to name this lipopeptide compound 'Kannurin'. To our knowledge, this is the first report of Bacillus cereus producing surfactin-like lipopeptide antibiotic with stronger antifungal activity. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results provide a valuable contribution towards a better understanding of the lipopeptide of Bacillus cereus. Moreover, it raises the possibility of using as an alternative antibiotic in clinical medicine. PMID- 23937171 TI - Can neuroimaging help identify effective strategies for constraint therapy in congenital hemiparesis? PMID- 23937172 TI - Fundamentals of randomized clinical trials in wound care: reporting standards. AB - In wound care research, available high-level evidence according to the evidence pyramid is rare, and is threatened by a poor study design and reporting. Without comprehensive and transparent reporting, readers will not be able to assess the strengths and limitations of the research performed. Randomized clinical trials (RCTs) are universally acknowledged as the study design of choice for comparing treatment effects. To give high-level evidence the appreciation it deserves in wound care, we propose a step-by-step reporting standard for comprehensive and transparent reporting of RCTs in wound care. Critical reporting issues (e.g., wound care terminology, blinding, predefined outcome measures, and a priori sample size calculation) and wound-specific barriers (e.g., large diversity of etiologies and comorbidities of patients with wounds) that may prevent uniform implementation of reporting standards in wound care research are addressed in this article. The proposed reporting standards can be used as guidance for authors who write their RCT, as well as for peer reviewers of journals. Endorsement and application of these reporting standards may help achieve a higher standard of evidence and allow meta-analysis of reported wound care data. The ultimate goal is to help wound care professionals make better decisions for their patients in clinical practice. PMID- 23937173 TI - Curcuminoid metabolism and its contribution to the pharmacological effects. AB - Curcuminoids are safe natural yellow pigments used as food coloring agents and traditional drugs with a variety of biological functions such as antitumor, anti inflammatory and antioxidant activities. Poor oral bioavailability and the low plasma concentration of curcuminoids limited their clinical use, and one of the major reasons is their rapid metabolism in vivo. The predominant metabolic pathways are reduction and conjugation, and some drug metabolizing enzymes such as alcohol dehydrogenase, UDP-glucuronosyltransferases (UGTs) or sulfotransferases (SULTs) involved in the metabolic reactions. Besides the major metabolic pathways, dehydroxylation, cyclization and methylation can also occur in vivo. In addition, more than thirty metabolites of curcuminoids have been identified in biological matrices including the plasma, urine and bile from rats or humans by LC-MS/MS analysis and other methods. Some metabolites such as tetrahydro-curcuminoids have been reported to be active, which may explain how and why curcuminoids with poor oral bioavailability display their effectiveness in vivo. The present review mainly summarizes curcuminoid metabolism and its contribution to the pharmacological effects. PMID- 23937174 TI - Capillary electrophoresis-mass spectrometry in metabolomics: the potential for driving drug discovery and development. AB - Metabolomics represents the global profiling of metabolites in a given biological system. It has been used to facilitate pharmaceutical discovery and development for over a decade. Advances in instrumentation have positioned capillary electrophoresis-mass spectrometry (CE-MS) as an important platform for both targeted and non-targeted metabolomics. In this mini-review covering the last five years, we focus on the latest development of CE-MS based metabolomics in (a) identification and validation of novel valuable therapeutic targets, (b) evaluation of drug efficacy, and (c) monitoring of drug unanticipated adverse effects. Some of the current issues and future directions of CE-MS metabolomics are also discussed in the end. PMID- 23937175 TI - Biological insight, high-throughput datasets and the nature of neuro-degenerative disorders. AB - Life sciences are experiencing a historical shift towards a quantitative, data rich regime. This transition has been associated with the advent of bio informatics: mathematicians, physicists, computer scientists and statisticians are now commonplace in the field, working on the analysis of ever larger data sets. An open question regarding what should drive scientific progress in this new era remains: will biological insight become increasingly irrelevant in a world of hypothesis-free, unbiased data analysis? This piece offers a different perspective, pin-pointing that biological thought is more-than-ever relevant in a data-rich setting. Some of the novel highthroughput information being acquired in the field of neuro-degenerative disorders is highlighted here. As but one example of how theory and experiment can interact in this new reality, our efforts in developing an idiopathic neuro-degenerative disease hematopoietic stemcell ageing theory are described. PMID- 23937176 TI - Reversing one's fortune by pushing away bad luck. AB - Across cultures, people try to "undo" bad luck with superstitious rituals such as knocking on wood, spitting, or throwing salt. We suggest that these rituals reduce the perceived likelihood of anticipated negative outcomes because they involve avoidant actions that exert force away from one's representation of self, which simulates the experience of pushing away bad luck. Five experiments test this hypothesis by having participants tempt fate and then engage in avoidant actions that are either superstitious (Experiment 1, knocking on wood) or nonsuperstitious (Experiments 2-5, throwing a ball). We find that participants who knock down (away from themselves) or throw a ball think that a jinxed negative outcome is less likely than participants who knock up (toward themselves) or hold a ball. Experiments 3 and 4 provide evidence that after tempting fate, engaging in an avoidant action leads to less clear mental representations for the jinxed event, which, in turn, leads to lower perceived likelihoods. Finally, we demonstrate that engaging in an avoidant action-rather than creating physical distance-is critical for reversing the perceived effect of the jinx. Although superstitions are often culturally defined, the underlying psychological processes that give rise to them may be shared across cultures. PMID- 23937177 TI - Hippocampal and neocortical oscillatory contributions to visuospatial binding and comparison. AB - Over 50 years of research has revealed a critical role for the hippocampus in the formation of long-term declarative memories. More recent evidence has specified the functions of the hippocampus as the binding and comparison of memory representations that may be used under shorter, as well as longer, delays (Olsen, Moses, Riggs, & Ryan, 2012). Hippocampal neural oscillations (e.g., theta rhythm) have been studied extensively in animals; however, the oscillations that underlie binding, comparison, and their relationship to memory performance remain to be fully explored in humans. Here magnetoencephalography was used to examine theta oscillations within the hippocampus and cortex to address this critical gap in the literature. The task consisted of (a) an encoding phase in which participants had to integrate the relative spatial positions among 3 sequentially presented objects, (b) a delay phase, and (c) a test phase in which all study objects were presented simultaneously in novel locations, and participants had to indicate whether the relative positions had changed. Theta power in the hippocampus and medial prefrontal cortex (PFC) increased across encoding and delay periods during which binding and maintenance processes dominate, while comparison of spatial relations at test was associated with greater theta power in right lateral PFC and intraparietal sulcus for manipulated versus intact trials. Critically, relational memory was positively related to hippocampal theta power increases across the encoding period. These findings provide novel evidence for the role of hippocampal theta in the incremental formation and retention of relations across space and time. PMID- 23937178 TI - Hippocampal contributions to language: evidence of referential processing deficits in amnesia. AB - A growing body of work suggests the hippocampus contributes to a variety of cognitive domains beyond its traditional role in memory. We propose that the hippocampus, in its capacity for relational binding, representational flexibility, and online maintenance and integration of multimodal relational representations, is a key contributor to language processing. Here we test the hypothesis that the online interpretation of pronouns is hippocampus-dependent. We combined eye tracking with neuropsychological methods, where participants (4 patients with bilateral hippocampal damage and severe declarative memory impairment, 4 patients with ventromedial prefrontal cortex [vmPFC] damage, and healthy comparison participants) viewed a scene while listening to short dialogues introducing 2 characters; for example, Melissa is playing violin for Debbie/Danny as the sun is shining overhead. She is wearing a blue/purple dress. Consistent with previous work, analysis of eye gaze showed that younger and older healthy comparison participants and the vmPFC patients rapidly identified the intended referent of the pronoun when gender uniquely identified the referent, and when it did not, they showed a preference to interpret the pronoun as referring to the first-mentioned character. By contrast, hippocampal patients, while exhibiting a similar gender effect, exhibited significant disruptions in their ability to use information about which character had been mentioned first to interpret the pronoun. This finding suggests that the hippocampus plays a role in maintaining and integrating information even over a very short discourse history. These observed disruptions in referential processing demonstrate how promiscuously the hallmark processing features of the hippocampus are used in service of a variety of cognitive domains including language. PMID- 23937179 TI - Childhood amnesia in the making: different distributions of autobiographical memories in children and adults. AB - Within the memory literature, a robust finding is of childhood amnesia: a relative paucity among adults for autobiographical or personal memories from the first 3 to 4 years of life, and from the first 7 years, a smaller number of memories than would be expected based on normal forgetting. Childhood amnesia is observed in spite of strong evidence that during the period eventually obscured by the amnesia, children construct and preserve autobiographical memories. Why early memories seemingly are lost to recollection is an unanswered question. In the present research, we examined the issue by using the cue word technique to chart the distributions of autobiographical memories in samples of children ages 7 to 11 years and samples of young and middle-aged adults. Among adults, the distributions were best fit by the power function, whereas among children, the exponential function provided a better fit to the distributions of memories. The findings suggest that a major source of childhood amnesia is a constant rate of forgetting in childhood, seemingly resulting from failed consolidation, the outcome of which is a smaller pool of memories available for later retrieval. PMID- 23937180 TI - I want to help you, but I am not sure why: gaze-cuing induces altruistic giving. AB - Detecting subtle indicators of trustworthiness is highly adaptive for moving effectively amongst social partners. One powerful signal is gaze direction, which individuals can use to inform (or deceive) by looking toward (or away from) important objects or events in the environment. Here, across 5 experiments, we investigate whether implicit learning about gaze cues can influence subsequent economic transactions; we also examine some of the underlying mechanisms. In the 1st experiment, we demonstrate that people invest more money with individuals whose gaze information has previously been helpful, possibly reflecting enhanced trust appraisals. However, in 2 further experiments, we show that other mechanisms driving this behavior include obligations to fairness or (painful) altruism, since people also make more generous offers and allocations of money to individuals with reliable gaze cues in adapted 1-shot ultimatum games and 1-shot dictator games. In 2 final experiments, we show that the introduction of perceptual noise while following gaze can disrupt these effects, but only when the social partners are unfamiliar. Nonconscious detection of reliable gaze cues can prompt altruism toward others, probably reflecting the interplay of systems that encode identity and control gaze-evoked attention, integrating the reinforcement value of gaze cues. PMID- 23937181 TI - Large capacity temporary visual memory. AB - Visual working memory (WM) capacity is thought to be limited to 3 or 4 items. However, many cognitive activities seem to require larger temporary memory stores. Here, we provide evidence for a temporary memory store with much larger capacity than past WM capacity estimates. Further, based on previous WM research, we show that a single factor--proactive interference--is sufficient to bring capacity estimates down to the range of previous WM capacity estimates. Participants saw a rapid serial visual presentation of 5-21 pictures of familiar objects or words presented at rates of 4/s or 8/s, respectively, and thus too fast for strategies such as rehearsal. Recognition memory was tested with a single probe item. When new items were used on all trials, no fixed memory capacities were observed, with estimates of up to 9.1 retained pictures for 21 item lists, and up to 30.0 retained pictures for 100-item lists, and no clear upper bound to how many items could be retained. Further, memory items were not stored in a temporally stable form of memory but decayed almost completely after a few minutes. In contrast, when, as in most WM experiments, a small set of items was reused across all trials, thus creating proactive interference among items, capacity remained in the range reported in previous WM experiments. These results show that humans have a large-capacity temporary memory store in the absence of proactive interference, and raise the question of whether temporary memory in everyday cognitive processing is severely limited, as in WM experiments, or has the much larger capacity found in the present experiments. PMID- 23937182 TI - Parahippocampal cortex activation during context reinstatement predicts item recollection. AB - Episodic memory is the binding of an event with information about the context in which that event (or item) was experienced. The context of an event may include its spatial and temporal location as well as goal-directed, conscious thoughts evoked during the event. We call this latter type of information cognitive context. The binding of items and context (BIC) theory of medial temporal lobe function proposes that the parahippocampal cortex (PHc) plays a key role in processing cognitive context. Therefore, we predicted that activity in the PHc during reactivation of a previously experienced cognitive context would be correlated with item recollection, even when the associated item and its episodic binding had not yet been retrieved. Using a novel paradigm, we measured brain activation with functional magnetic resonance imaging in response to covert reinstatement of a cognitive context, prior to presenting an item memory probe. Contexts were studied with multiple items to ensure that spontaneous item retrieval would not occur prior to the test probe. At test, contexts were reinstated for 8 s before the test probe was presented. We manipulated whether the reinstated context matched the encoding context of the test probe that followed. For such matching contexts, we found that increased PHc activation prior to the test probe predicted recollection following the test probe. If a context unrelated to the eventual test item probe was reinstated, there was no such association between PHc activation during context reinstatement and eventual memory judgments. These findings suggest that PHc activation is correlated with cognitive context retrieval. PMID- 23937183 TI - Recognition memory impairments caused by false recognition of novel objects. AB - A fundamental assumption underlying most current theories of amnesia is that memory impairments arise because previously studied information either is lost rapidly or is made inaccessible (i.e., the old information appears to be new). Recent studies in rodents have challenged this view, suggesting instead that under conditions of high interference, recognition memory impairments following medial temporal lobe damage arise because novel information appears as though it has been previously seen. Here, we developed a new object recognition memory paradigm that distinguished whether object recognition memory impairments were driven by previously viewed objects being treated as if they were novel or by novel objects falsely recognized as though they were previously seen. In this indirect, eyetracking-based passive viewing task, older adults at risk for mild cognitive impairment showed false recognition to high-interference novel items (with a significant degree of feature overlap with previously studied items) but normal novelty responses to low-interference novel items (with a lower degree of feature overlap). The indirect nature of the task minimized the effects of response bias and other memory-based decision processes, suggesting that these factors cannot solely account for false recognition. These findings support the counterintuitive notion that recognition memory impairments in this memory impaired population are not characterized by forgetting but rather are driven by the failure to differentiate perceptually similar objects, leading to the false recognition of novel objects as having been seen before. PMID- 23937184 TI - The performance heuristic: a misguided reliance on past success when predicting prospects for improvement. AB - In estimating whether they are likely to improve on a performance task, people lean on a performance heuristic. That is, people rely on their previous performance success as a positive cue when estimating their prospects for performance improvement. Participants whose initial performance was better- either at a darts game (Study 1) or an anagram task (Study 2)-bet more money (Study 1) or estimated a higher subjective likelihood (Study 2) that their subsequent performance would show a specified amount of improvement. Reliance on the heuristic was unwise, for initial performance did not positively predict (and, in fact, negatively predicted) performance improvement. Study 2 suggests that the performance heuristic emerges because forecasters engage in attribute substitution, naturally focusing on their demonstrated performance instead of whether they have already maxed out their potential for improvement on the task. Self-assessments of their initial performance mediated the performance heuristic, but focusing participants on how much performance potential lay before them disrupted it (Study 2). Study 3 showed that the performance heuristic is a general-purpose heuristic that is used not merely to predict one's own prospects for improvement, but the prospects for other improvement (e.g., mutual funds' rate of return) as well. PMID- 23937186 TI - Breaking the cycle of mistrust: wise interventions to provide critical feedback across the racial divide. AB - Three double-blind randomized field experiments examined the effects of a strategy to restore trust on minority adolescents' responses to critical feedback. In Studies 1 and 2, 7th-grade students received critical feedback from their teacher that, in the treatment condition, was designed to assuage mistrust by emphasizing the teacher's high standards and belief that the student was capable of meeting those standards--a strategy known as wise feedback. Wise feedback increased students' likelihood of submitting a revision of an essay (Study 1) and improved the quality of their final drafts (Study 2). Effects were generally stronger among African American students than among White students, and particularly strong among African Americans who felt more mistrusting of school. Indeed, among this latter group of students, the 2-year decline in trust evident in the control condition was, in the wise feedback condition, halted. Study 3, undertaken in a low-income public high school, used attributional retraining to teach students to attribute critical feedback in school to their teachers' high standards and belief in their potential. It raised African Americans' grades, reducing the achievement gap. Discussion centers on the roles of trust and recursive social processes in adolescent development. PMID- 23937185 TI - Medial temporal lobe contributions to short-term memory for faces. AB - The role of the medial temporal lobes (MTL) in short-term memory (STM) remains a matter of debate. Whereas imaging studies commonly show hippocampal activation during short-delay memory tasks, evidence from amnesic patients with MTL lesions is mixed. It has been argued that apparent STM impairments in amnesia may reflect long-term memory (LTM) contributions to performance. We challenge this conclusion by demonstrating that MTL amnesic patients show impaired delayed matching-to sample (DMS) for faces in a task that meets both a traditional delay-based and a recently proposed distractor-based criterion for classification as an STM task. In Experiment 1, we demonstrate that our face DMS task meets the proposed distractor-based criterion for STM classification, in that extensive processing of delay-period distractor stimuli disrupts performance of healthy individuals. In Experiment 2, MTL amnesic patients with lesions extending into anterior subhippocampal cortex, but not patients with lesions limited to the hippocampus, show impaired performance on this task without distraction at delays as short as 8 s, within temporal range of delay-based STM classification, in the context of intact perceptual matching performance. Experiment 3 provides support for the hypothesis that STM for faces relies on configural processing by showing that the extent to which healthy participants' performance is disrupted by interference depends on the configural demands of the distractor task. Together, these findings are consistent with the notion that the amnesic impairment in STM for faces reflects a deficit in configural processing associated with subhippocampal cortices and provide novel evidence that the MTL supports cognition beyond the LTM domain. PMID- 23937187 TI - Rapid hydraulic recovery in Eucalyptus pauciflora after drought: linkages between stem hydraulics and leaf gas exchange. AB - In woody plants, photosynthetic capacity is closely linked to rates at which the plant hydraulic system can supply water to the leaf surface. Drought-induced embolism can cause sharp declines in xylem hydraulic conductivity that coincide with stomatal closure and reduced photosynthesis. Recovery of photosynthetic capacity after drought is dependent on restored xylem function, although few data exist to elucidate this coordination. We examined the dynamics of leaf gas exchange and xylem function in Eucalyptus pauciflora seedlings exposed to a cycle of severe water stress and recovery after re-watering. Stomatal closure and leaf turgor loss occurred at water potentials that delayed the extensive spread of embolism through the stem xylem. Stem hydraulic conductance recovered to control levels within 6 h after re-watering despite a severe drought treatment, suggesting an active mechanism embolism repair. However, stomatal conductance did not recover after 10 d of re-watering, effecting tighter control of transpiration post drought. The dynamics of recovery suggest that a combination of hydraulic and non-hydraulic factors influenced stomatal behaviour post drought. PMID- 23937188 TI - Problem-based learning: an exploration of student opinions on its educational role in one UK pharmacy undergraduate curriculum. AB - OBJECTIVE: Problem-based learning (PBL) was introduced into the first 3 years of the undergraduate degree course at the University of East Anglia (UEA) to both enhance the student learning experience and to enable it to meet external course accreditation criteria. Evidence to support both of these assertions is required. The objective was to determine student opinions on the value of PBL and the PBL learning process at one UK school of pharmacy. METHOD: Utilising the professional accreditation criteria for UK schools of pharmacy a questionnaire was devised and piloted before being given to all UEA undergraduate pharmacy students for self completion. The most appropriate method of dissemination was determined from a student-led focus group. KEY FINDINGS: A total of 201/329 (61.1%) students responded. The majority of students agreed that PBL improved their team working (83.1%), oral communication (89.1%) and problem-solving skills (61.7%). Additionally PBL improved students' ability to identify and address ethical dilemmas (74.5%) as well as enhancing their ability to manage their own learning (67.6%). Male students and those with a stated preference for team working were found to prefer PBL. CONCLUSION: Students generally believe that PBL develops a number of key skills and consequently inclusion of PBL alongside traditional teaching methods enables the school to meet a number of degree accreditation criteria. Male students, those who enjoyed team working and working with their current group were more positive about PBL. Further work is required to improve the experience for all students. PMID- 23937189 TI - Assembly and fiber formation of a gemini-type hexathienocoronene amphiphile for electrical conduction. AB - We report the synthesis, characterization, and self-assembly of a new gemini-type amphiphilic hexathienocoronene (HTCGemini), which owes its amphiphilicity to two hydrophobic dodecyl chains on one side of the HTC core and two hydrophilic triethylene glycol (TEG) chains on the other. Bearing a "softer" aromatic HTC core than the conventional hexa-peri-hexabenzocoronenes (HBC), and being more planar than contorted-hexabenzocoronenes (c-HBC), HTCGemini is demonstrated to yield various well-ordered assemblies in solution, at the liquid-solid interface, and in solid state by the use of different processing techniques. Regular fibers, helices, and tubes can be formed simply by processing from different solvents. At the liquid-solid interface, as visualized by scanning tunneling microscopy (STM), pairs of molecules adsorb very close to each other and arrange in the p2 plane group, driven by packing constraints and weak van der Waals interactions between adjacent molecules. HTCGemini also exhibits phase forming behavior in the bulk upon thermal treatment, resulting in a crystalline, herringbone-like columnar structure. Owning to an electron enriched aromatic core with respect to other reported coronenes, HTCGemini easily forms a stable radical cation, both in solution and in the bulk, upon oxidative doping with nitrosonium tetrafluoroborate (NOBF4). Furthermore, light irradiation of the blend film of HTCGemini and phenyl-C61-butyric acid methyl ester (PCBM) generates a prominent photocurrent which can be switched repeatedly with a large on/off ratio (6.0 * 10(4)). The self-assembled structures obtained from HTCGemini at different length scales have potential applications in optoelectronic devices, solar cells, and redox sensors. PMID- 23937190 TI - Safety evaluation of trabectedin in treatment of soft-tissue sarcomas. AB - INTRODUCTION: Trabectedin gained the approval by the European Medicines Agency (EMA) in 2007 for the treatment of patients affected by soft-tissue sarcomas (STS). Its safety and activity profiles have been assessed in many clinical trials as well as in standard clinical practice for > 10 years. AREAS COVERED: This article extensively reviews the most common and specific adverse events associated with trabectedin. Moreover, we compare these toxicity data with other drugs active in STS such as doxorubicin and ifosfamide. Also, we provide a comprehensive view of the special mechanism of action of this drug and its clinical applications. Additionally, we discuss the current role of trabectedin in the treatment of STS and give a future perspective with the review of ongoing clinical trials and potential new indications. EXPERT OPINION: Trabectedin is, in general, a well-tolerated drug with a favorable toxicity profile. The majority of its side effects are mild and easily manageable. Specific adverse events such as liver toxicity and rhabdomyolysis do not usually have a significant clinical impact. Overall, trabectedin is a safe and active treatment option in STS. PMID- 23937191 TI - Expression of SV2 isoforms during rodent brain development. AB - BACKGROUND: SV2A, SV2B and SV2C are synaptic vesicle proteins that are structurally related to members of the major facilitator superfamily (MFS). The function and transported substrate of the SV2 proteins is not clearly defined although they are linked to neurotransmitters release in a presynaptic calcium concentration-dependent manner. SV2A and SV2B exhibit broad expression in the central nervous system while SV2C appears to be more restricted in defined areas such as striatum. SV2A knockout mice start to display generalized seizures at a late developmental stage, around post-natal day 7 (P7), and die around P15. More recently, SV2A was demonstrated to be the molecular target of levetiracetam, an approved anti-epileptic drug (AED). The purpose of this work was to precisely analyze and quantify the SV2A, SV2B and SV2C expression during brain development to understand the contribution of these proteins in brain development and their impact on epileptic seizures. RESULTS: First, we systematically analyzed by immunohistofluorescence, the SV2A, SV2B and SV2C expression during mouse brain development, from embryonic day 12 (E12) to P30. This semi-quantitative approach suggests a modulation of SV2A and SV2B expression in hippocampus around P7. This is the reason why we used various quantitative approaches (laser microdissection of whole hippocampus followed by qRT-PCR and western blot analysis) indicating that SV2A and SV2B expression increased between P5 and P7 and remained stable between P7 and P10. Moreover, the increase of SV2A expression in the hippocampus at P7 was mainly observed in the CA1 region while SV2B expression in this region remains stable. CONCLUSIONS: The observed alterations of SV2A expression in hippocampus are consistent with the appearance of seizures in SV2A-/- animals at early postnatal age and the hypothesis that SV2A absence favors epileptic seizures around P7. PMID- 23937192 TI - Characterization of the mechanisms controlling the permeability changes of fractured cements flowed through by CO2-rich brine. AB - Experiments were conducted to assess the potential impact of fractured well cement degradation on leakage rate. Permeability was monitored while CO2-enriched reservoir-equilibrated brine was flowed at constant rate through a single fracture in a class G cement core under conditions mimicking geologic sequestration environments (temperature 60 degrees C, pressure 10 MPa). The results demonstrate that, at least for the conditions used in the experiment, an initial leakage in a 42 MUm aperture fracture (permeability = 1.5 * 10(-10) m(2)) can be self-mitigated due to the decrease of the fracture hydraulic aperture after about 15 h. This decrease results from the development of continuous highly hydrated amorphous Si-rich alteration products at the edge of the fracture and the dense carbonation of the bulk cement that mitigate the penetration of the alteration front. PMID- 23937193 TI - Enantioselective synthesis of quaternary 3-aminooxindoles via organocatalytic asymmetric Michael addition of 3-monosubstituted 3-aminooxindoles to nitroolefins. AB - An enantioselective synthesis of quaternary 3-aminooxindoles with 3 monosubstituted 3-aminooxindoles as nucleophiles is first presented. A Michael addition reaction of 3-monosubstituted 3-aminooxindoles to nitroolefins has been developed with a bifunctional thiourea-tertiary amine as a catalyst to afford a range of 3,3-disubstituted oxindoles bearing adjacent quaternary-tertiary centers in good results (up to 98% yield, >99:1 dr, and 92% ee). We also demonstrate the potential synthetic utility of this methodology by a transformation of the product into a spirocyclic oxindole compound. PMID- 23937194 TI - 4273pi: bioinformatics education on low cost ARM hardware. AB - BACKGROUND: Teaching bioinformatics at universities is complicated by typical computer classroom settings. As well as running software locally and online, students should gain experience of systems administration. For a future career in biology or bioinformatics, the installation of software is a useful skill. We propose that this may be taught by running the course on GNU/Linux running on inexpensive Raspberry Pi computer hardware, for which students may be granted full administrator access. RESULTS: We release 4273pi, an operating system image for Raspberry Pi based on Raspbian Linux. This includes minor customisations for classroom use and includes our Open Access bioinformatics course, 4273pi Bioinformatics for Biologists. This is based on the final-year undergraduate module BL4273, run on Raspberry Pi computers at the University of St Andrews, Semester 1, academic year 2012-2013. CONCLUSIONS: 4273pi is a means to teach bioinformatics, including systems administration tasks, to undergraduates at low cost. PMID- 23937195 TI - Sociodemographic and clinical differences between suicide ideators and attempters: a study of mood disordered patients 50 years and older. AB - Our study sought to characterize mood disordered suicide ideators and attempters 50 years and older admitted to a psychiatric ward either for a recent suicide attempt or for ongoing suicidal ideation. We enrolled 50 patients with suicide ideation consecutively admitted to an inpatient department and 50 patients admitted for a suicide attempt made in the last 48 hours. Suicide attempters more frequently had low social support and an age of onset of mood disorder of 46 years and older, and less frequently had a history of suicidal behaviors in the family members and pharmacological treatment, despite the fact that the groups did not differ with regard to antidepressants prescribed. The groups were not distinguishable based on several variables assumed to be risk factors for suicide behavior, such as proximal life events and stressors or alcohol use disorders. In both samples, comorbidity with organic diseases, the presence of stressful life events in the past 12 months, and a diagnosis of major depression were frequently reported. In conclusion, the presence of low social support and the absence of a pharmacotherapy may increase suicidal behaviors in patients at risk. PMID- 23937196 TI - The opioid neuropeptides in uterine fibroid pseudocapsules: a putative association with cervical integrity in human reproduction. AB - The myoma pseudocapsule (MP) is a fibro-vascular network rich of neurotransmitters, as a neurovascular bundle, surrounding fibroid and separating myoma from myometrium. We investigated the distribution of the opioid neuropeptides, as enkephalin (ENK) and oxytocin (OXT), in the nerve fibers within MP and their possible influence in human reproduction in 57 women. An histological and immunofluorescent staining of OXT and ENK was performed on nerve fibers of MP samples from the fundus, corpus and isthmian-cervical regions, with a successive morphometric quantification of OXT and ENK. None of the nerve fibers in the uterine fundus and corpus MPs contained ENK and the nerve fibers in the isthmian-cervical region demonstrated an ENK value of up to 94 +/- 0.7 CU. A comparatively lower number of OXT-positive nerve fibers were found in the fundal MP (6.3 +/- 0.8 CU). OXT-positive nerve fibers with OXT were marginally increased in corporal MP (15.0 +/- 1.4 CU) and were substantially higher in the isthmian cervical region MP (72.1 +/- 5.1 CU) (p < 0.01). The distribution of OXY neurofibers showed a slight into the uterine corpus, while are highly present into the cervico-isthmic area, with influence on reproductive system and sexual disorders manifesting after surgical procedures on the cervix. PMID- 23937197 TI - Radix Angelica Sinensis that contains the component Z-ligustilide promotes adult neurogenesis to mediate recovery from cognitive impairment. AB - Radix Angelica Sinensis (RAS) has beneficial effects in patients suffering from cognitive impairment associated with chronic cerebral hypoperfusion. It has previously been demonstrated that RAS prevents the neurotoxic effects of beta amyloid (Abeta) in vitro, protects from injuries due to oxidative stress, inflammation and apoptosis and ameliorates scopolamine-induced amnesia in rats. Here, we studied the effects of RAS on cognitive improvement and neurogenic enhancement and examined the possible underlying mechanisms in a rat model with permanent bilateral common carotid artery occlusion, which serves as a model of chronic cerebral hypoperfusion-related neurodegenerative diseases. RAS enhances adult neurogenesis in the hippocampus following chronic cerebral hypoperfusion and improves the cognitive decline associated with hypoperfusion. Long-term ablation of adult hippocampal neurogenesis through cranial irradiation abolishes the protective effects of RAS on cognition. Furthermore, administration of RAS restores the decrease of brain-derived neurotrophic factor (BDNF) expression, the phosphorylation of cAMP-responsive element binding protein (CREB) and the glutamic acid decarboxylase 65 (GAD65) staining intensity in rats with chronic cerebral hypoperfusion. The present study supports the hypothesis that adult neurogenesis is required for RAS to facilitate recovery from the cognitive impairment induced by chronic cerebral hypoperfusion, while neurogenic enhancement secondary to RAS treatment may be due to increased BDNF and phosphorylated cAMP-responsive element binding protein (p-CREB) levels and increased gamma-aminobutyric acid (GABA) expression. Based on the possible mechanisms suggested by the present study, this well-known traditional medicine may represent a candidate therapeutic agent for the treatment of dementia associated with vascular injury. PMID- 23937198 TI - Vehicles for lipophilic drugs: implications for experimental design, neuroprotection, and drug discovery. AB - The delivery of some classes of drugs is challenging. Solubility, absorption, distribution, and duration of action may all be altered by combination with vehicle molecules. It has already been discovered that polyethylene glycol - which is used as a stabiliser in peptide drug formulations - has biological activity in its own right, including potential neuroprotective properties. In this article we review the evidence for confounding activity for four distinct compounds that have been used as solvents and/or carrier molecules for the delivery of lipophilic drugs under investigation for potential neuroprotective properties. We discuss the evidence that cyclodextrins, ethanol, dimethyl sulphoxide, and a castor oil derivative - CremophorTM EL - have all been found to have mild to moderate neuroprotective effects. We argue that this has probably reduced the statistical power and increased the Type II error rates of neuroprotection experiments that have employed these vehicles, and suggest experimental design considerations to help correct the problem. However, we also note that the properties of these compounds may represent an opportunity for drug development, particularly for the newer compounds that have been subject to only limited experimental investigation. PMID- 23937199 TI - Transient blood brain barrier disruption induced by oleic acid is mediated by nitric oxide. AB - The blood brain barrier (BBB) maintains cerebral microenvironmental homeostasis. Transient disruption of the BBB after brain fat embolism in clinical cases and animal models has been reported but the precise mechanism underlying this occurrence is unclear. In the present study, we investigated BBB alterations in rats treated oleic acid (OA) delivered intra-arterially. Following OA treatment, transient brain edema, extravasation of Evans blue and Fluorescein isothiocyanate (FITC)-labeled dextran, and loss of laminin in the affected brain area were observed. Activation of matrix metalloproteinase (MMP)-2, -3, and -13 was found in the cerebral vessels 2 h after OA administration. Expression of intercellular adhesion molecule (ICAM)-1 in the vessels and neutrophil infiltration into the brain tissue was also observed. Inducible nitric oxide synthase (iNOS) was expressed in the neutrophils and nitrotyrosine was produced mainly in the vessels. Inhibitor of iNOS activity suppressed the loss of laminin, leakage of FITC-labeled dextran and Evans blue, and activation of MMP-2 and -13. Protein level of aquaporin (AQ)-4 was increased after OA administration but was not affected by treatment with iNOS inhibitor. In conclusion, we suggest that nitric oxide (NO) contributes to OA-induced MMP activation, BBB disruption and the development of transient brain edema. PMID- 23937200 TI - Prolactin and blood-brain barrier permeability. AB - The blood-brain barrier (BBB) consists in part of a highly specialized set of cells which separates the brain from the vascular system. The BBB controls the entry and exit of substances from the brain tissue through tight junctions (TJs) between endothelial cells. It is known that the hormone prolactin (PRL) is able to regulate endothelial-dependent processes, like the balance between proliferation and apoptosis and the mammary epithelial permeability. However, the effects of PRL and the role it plays in the BBB permeability are still not well understood. A primary culture of bovine brain microvessel endothelial cells was used as in vitro model of BBB. Cells were treated with PRL (0.1, 1, 10 and 100 nM) for 24 hours. PRL significantly increased cellular proliferation at 10 and 100 nM, but did not modify basal apoptosis. These effects were dependent on the production of the mitogenic factor nitric oxide (NO). PRL significantly decreased the permeability and promoted an increase in trans-endothelial electrical resistance in a NO-independent way. PRL also increased the expression of the TJs proteins claudin-5 and occludin. The short form of the PRL receptor was detected in these cells but its expression was not modified by PRL. Together, these results suggest that PRL has the ability to increase cellular proliferation associated with a decrease on BBB permeability by increasing the expression of TJs proteins. PMID- 23937201 TI - Platelet-derived secreted amyloid-precursor protein-beta as a marker for diagnosing Alzheimer's disease. AB - A marker of Alzheimer's disease (AD) with a high sensitivity and specificity would facilitate a diagnosis at early stages. Blood platelets may be of particular interest in search of biomarkers, because they express amyloid precursor protein (APP), and display a dysfunctional processing in AD. The aim of the present study is to establish and validate an assay for secreted amyloid precursor protein (sAPP)-alpha and -beta in platelets of AD and mild cognitively impaired (MCI) subjects, compared to healthy young and old controls. Freshly isolated platelet extracts (25 ug) were incubated with or without recombinant BACE1 (beta-site APP-Cleaving Enzyme; beta-secretase, 8U) at 37 degrees C and low pH and the levels of sAPP-alpha and sAPP-b were measured by specific ELISAs. Our data show that sAPP-alpha levels were not different between AD, MCI and control subjects. However, sAPP-beta levels in MCI and AD were significantly elevated relative to controls. When recombinant BACE1 was added, no changes were seen in sAPP-alpha levels, but the processed sAPP-beta levels were again markedly increased. The sAPP-beta processing was specific and selective after 2.5 hours at 37 degrees C, and was possibly mediated by exogenous BACE1, because it was blocked by a BACE1 inhibitor and BACE1 enzyme levels were enhanced in AD patients. Our data reveal that quantitive analysis of platelet sAPP-beta assay by ELISA may be a novel diagnostic biomarker for MCI and AD. PMID- 23937202 TI - Assessing the dual activity of a chalcone-phthalocyanine conjugate: design, synthesis, and antivascular and photodynamic properties. AB - Photodynamic therapy (PDT) and vascular-disrupting agents (VDA) each have their advantages in the treatment of solid tumors, but also present drawbacks. In PDT, hypoxia at the center of the tumor limits conversion of molecular oxygen into singlet oxygen, while VDAs are deficient at affecting the rim of the tumor. A phthalocyanine-chalcone conjugate combining the VDA properties of chalcones with the PDT properties of phthalocyanines was designed to address these deficiencies. Its vascular targeting, photophysical, photochemical, photodynamic activities are reported herein. PMID- 23937203 TI - Simultaneous dual scope endotherapy of esophago-airway fistulas and obstructions. AB - Management of esophago-airway fistulas (EAF) and obstructions often involves therapy with esophageal and/or airway stents. We present a unique approach for the management of EAF and obstructions with simultaneous upper endoscopy and bronchoscopy (two scopes inserted simultaneously through the mouth). The aim is to assess the efficacy and safety of a simultaneous dual scope approach for management of EAF and obstructions. The endoscopy database at the University of Florida was reviewed from October 2007 to April 2012 to identify adult patients who had undergone simultaneous upper endoscopy and bronchoscopy for EAF and obstructions. Medical records were reviewed for demographics, indication, pathology, imaging, simultaneous endoscopic and bronchoscopic findings/maneuvers, outcomes, and adverse events. Outcomes assessed included: (i) technical success, (ii) fistula occlusion, (iii) dysphagia score, and (iv) adverse events. Thirteen patients with EAF and/or obstruction underwent simultaneous dual scope endoscopy. Dual scope procedures were technically successful in 12/13 (92%) patients. Dysphagia score improved from three to one in both patients with dysphagia without EAF. Fistula occlusion was observed in 7/10 patients (70%) with EAF. With this technique, stents were placed accurately without airway compression, migrated esophageal stents extracted from the tracheal lumen without trauma, and tracheal stents not displaced during esophageal manipulations. EAF not otherwise apparent were identified in two patients. Adverse events occurred in 2/13 (15%) patients, and 5/13 (38%) patients died from advanced cancer during follow up (mean 4.1 months, range 1-8 months). Simultaneous dual scope (two scopes inserted through the mouth at the same time) therapy of EAF and obstructions is feasible, effective, and safe, and may develop to be the preferred approach for the management of complex esophago-airway diseases. PMID- 23937204 TI - The interpretation of long-term trials of biologic treatments for psoriasis: trial designs and the choices of statistical analyses affect ability to compare outcomes across trials. AB - Psoriasis is a chronic disease requiring long-term therapy, which makes finding treatments with favourable long-term safety and efficacy profiles crucial. The goal of this review is to provide the background needed to evaluate properly long term studies of biologic treatments for psoriasis. Firstly, important elements of design and analysis strategies are described. Secondly, data from published trials of biologic therapies for psoriasis are reviewed in light of the design and analysis choices implemented in the studies. Published reports of clinical trials of biologic treatments (adalimumab, alefacept, etanercept, infliximab or ustekinumab) that lasted 33 weeks or longer and included efficacy results and statistical analysis were reviewed. Study designs and statistical analyses were evaluated and summarized, emphasizing patient follow-up methods and handling of missing data. Various trial designs and data handling methods are used in long term studies of biologic psoriasis treatments. Responder analyses in long-term trials can be conducted in responder enrichment, re-treated nonresponder or intent-to-treat trials. Missing data can be handled in four ways, including, from most to least conservative, nonresponder imputation, last-observation-carried forward, as-observed analysis and anytime analysis. Long-term clinical trials have shown that adalimumab, alefacept, etanercept, infliximab and ustekinumab are efficacious for psoriasis treatment; however, without common standards for these trials, direct comparisons of these agents are difficult. Understanding differences in trial design and data handling is essential to make informed treatment decisions. PMID- 23937205 TI - Employment outcomes for adults with cerebral palsy: an issue that needs to be addressed. PMID- 23937206 TI - Prospective evaluation of urinary incontinence, voiding symptoms and quality of life after open and robot-assisted radical prostatectomy. AB - OBJECTIVE: To compare functional outcomes, i.e. urinary incontinence (UI), voiding symptoms and quality of life, after open (ORP) and robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: Between September 2009 and July 2011, 180 consecutive patients underwent radical prostatectomy; of these, 116 underwent ORP and 64 underwent RARP. We prospectively assessed the functional outcomes of each group during the first year of follow-up. We measured UI on the 3 days before surgery (24-h pad test) and daily after surgery until total continence, defined as 3 consecutive days of 0 g urine leak, was achieved. Additionally, all patients were assessed before surgery and at 1, 3, 6 and 12 months after surgery using the International Prostate Symptom Score (IPSS) and the King's Health Questionnaire (KHQ). All patients received pelvic floor muscle training until continence was achieved. Kaplan-Meier analyses and Cox regression with correction for covariates were used to compare time to continence. A Mann-Whitney U-test was used to assess IPSS and KHQ. RESULTS: Patients in the RARP group had a significantly lower D'Amico risk group allocation and underwent more nerve sparing surgery. Other characteristics were similar. Patients in the RARP group regained continence sooner than those in the ORP group (P = 0.007). In the RARP group, the median time to continence (16 vs 46 days, P = 0.026) was significantly shorter and the median amount of first day UI (44 vs 186 g, P < 0.01) was significantly smaller than in the ORP group. After correction for all covariates, the difference remained significant (P = 0.036, hazard ratio [HR] 1.522 (1.027 2.255). In addition, younger men, men with positive surgical margins and men without preoperative incontinence achieved continence sooner. A comparison of time to continence between groups with a sufficient number of patients (intermediate risk and/or bilateral nerve-sparing) still showed a faster return of continence after RARP, but the effect decreased in size and was nonsignificant (HR>1.2, P > 0.05). Only six patients (two in the RARP and four in the ORP group) still had UI after 1 year. Patients in the RARP group had significantly better IPSS scores at 1 (P = 0.013) and 3 (P = 0.038) months, and scored better in almost all KHQ aspects. CONCLUSION: In this prospective trial, patients treated with RARP tended to regain urinary continence sooner than patients treated with ORP, but in subgroup analyses statistical significance disappeared and effect size decreased dramatically, indicating that the results must be interpreted with caution. PMID- 23937208 TI - Effect of the shell-forming polymer ratio on the encapsulation of tea tree oil by complex coacervation as a natural biocide. AB - The aim of this study was to develop footwear materials with antimicrobial properties using microencapsulated Tea Tree oil (TTO) as a natural biocide. For that purpose, gelatine-carboxymethylcellulose based microcapsules containing TTO were synthesised by a complex coacervation process. Furthermore, the influence of the gelatine (G)/sodium carboxymethylmethyl cellulose (CMC) ratio (G/C) on the microcapsule properties, as well as in the microencapsulation oil efficiency, was evaluated. The microcapsules were characterised by different experimental techniques and applied to footwear materials (leather and textile) to evaluate their performance. The microcapsule durability under different conditions, such as rubbing and ironing, was analysed in order to simulate shoe manufacturing and shoe wearing. The properties of the microcapsules obtained by complex coacervation, using gelatine and sodium carboxymethylcellulose as shell-forming polymers, are determined by the ratio between those two polymers (G/C). The results obtained showed a notable effect of G/C ratio on the formation of the coacervate during the synthesis process and also on the encapsulation efficiency of the antimicrobial oil, with the optimal value for the G/C ratio being around 10. PMID- 23937207 TI - iTRAQ-based proteomics reveals novel biomarkers of osteoarthritis. AB - OBJECTIVE: We performed comprehensive proteomic analyses of articular cartilage by using the isobaric tags for relative and absolute quantitation (iTRAQ) method, and searched for candidate biomarkers for osteoarthritis (OA). METHODS: Articular cartilage was collected from patients with OA or femoral neck fracture for the control group. Molecular variations were detected by the iTRAQ method, and quantitative analyses were performed by western blot. RESULTS: Using the iTRAQ method, we identified 76 proteins with different expression levels in OA patients and the control group. Among these proteins, we selected LECT2 (leukocyte cell derived chemotaxin-2), BAALC (brain and acute leukemia, cytoplasmic), and PRDX6 (peroxiredoxin-6), which had not been reported as biomarkers for OA. CONCLUSIONS: Use of these proteins in combination with conventional OA biomarkers may better reflect the grade and prognosis of OA. PMID- 23937209 TI - Cold-set whey protein microgels containing immobilised lipid phases to modulate matrix digestion and release of a water-soluble bioactive. AB - This study investigated the in-vitro digestibility of cold-set whey protein (WP) microgels prepared by two gelation methods (external and internal) containing lipids (0%, 10% or 20% w/w). The incorporation of lipids into these matrices achieved higher entrapment of the bioactive vitamin riboflavin, as well as significant reductions in rates of both the digestion of the protein matrix, and the subsequent diffusion of the water-soluble bioactive. A biexponential model accounted for the contribution of digestion- and diffusion-driven mechanisms in describing the release of riboflavin into enzyme containing simulated gastrointestinal fluids. In particular, for external gelation microgels, as the lipid load within the matrices increased, the contribution of a faster diffusion driven release was almost completely negated by a slower digestion-assisted release. Lipid loads provided a composite matrix capable of alternating from a burst to a sustained release of bioactive. PMID- 23937210 TI - N-lauroyl chitosan surface-modified PLGA nanoparticles as carrier for adriamycin to overcome cancer drug resistance. AB - N-lauroyl chitosan (NLCS) conjugates with different degrees of substitution (DS) of lauroyl group were synthesized and used to prepare surface modified poly(lactic-co-glycolic) acid (NLCS-PLGA) nanoparticles via hydrophobic interaction and ionic bond force. NLCS-PLGA nanoparticles had spherical shape with shell-core structure and exhibited the smallest size and narrowest size distribution when DS of lauroyl group of NLCS was 8.5%. Adriamycin (ADR), as a model antitumor drug, was loaded into NLCS-PLGA nanoaprticles and its initial burst release from PLGA nanoparticles was significantly reduced. MTT assay showed that NLCS-2-PLGA nanoaprticles evidently enhanced cytotoxicity of ADR against drug-resistant breast cancer MCF-7/ADR cells, both compared to free ADR and ADR loaded PLGA nanoparticles. Moreover, cell-live images showed that the cellular uptake and nuclear location of ADR in MCF-7/ADR cells were significantly enhanced by loading of NLCS-2-PLGA nanoparticles. In conclusion, this novel carrier of anticancer drugs has the potential to overcome drug resistance in cancer cells. PMID- 23937211 TI - Breastfeeding and the prevention of breast cancer: a retrospective review of clinical histories. AB - AIMS AND OBJECTIVES: To evaluate at what age parous and nonparous women were diagnosed with breast cancer. Factors taken into account for parous women were whether they had breastfed their children, and if so, the length of the lactation period. Other factors considered for both groups were obesity, family histories of cancer, smoking habits and alcohol consumption. BACKGROUND: Breast cancer is the most common form of cancer in younger women in Western countries. Its growing incidence as well as the increasingly early age of diagnosis led us to carefully analyse its possible causes and the preventive measures to be taken. This is a particularly important goal in epidemiological research. DESIGN: A retrospective study of the clinical histories of patients diagnosed with breast cancer at the San Cecilio University Hospital in Granada (Spain). METHODS: In this study, we analysed 504 medical records of female patients, 19-91 years of age, who had been diagnosed and treated for breast cancer from 2004-2009 at the San Cecilio University Hospital in Granada (Spain). Relevant data (age of diagnosis, period of lactation, family history of cancer, obesity, alcohol consumption and smoking habits) were collected from the clinical histories of each patient and analysed. A conditional inference tree was used to relate the age of diagnosis to smoking habits and the length of the lactation period. RESULTS: The conditional inference tree identified significant differences between the age of the patients at breast cancer diagnosis, smoking habits (p < 0.001) and lactation period if the subjects had breastfed their children for more than six months (p = 0.006), regardless of whether they had a family history of cancer. CONCLUSIONS: Our study concluded that breastfeeding for over six months not only provides children with numerous health benefits, but also protects mothers from breast cancer when the mothers are nonsmokers. RELEVANCE TO CLINICAL PRACTICE: Nurses play a crucial role in encouraging new mothers to breastfeed their children, and this helps to prevent breast cancer. PMID- 23937212 TI - Mycobacteria in Finnish cooling tower waters. AB - Evaporative cooling towers are water systems used in, e.g., industry and telecommunication to remove excess heat by evaporation of water. Temperatures of cooling waters are usually optimal for mesophilic microbial growth and cooling towers may liberate massive amounts of bacterial aerosols. Outbreaks of legionellosis associated with cooling towers have been known since the 1980's, but occurrences of other potentially pathogenic bacteria in cooling waters are mostly unknown. We examined the occurrence of mycobacteria, which are common bacteria in different water systems and may cause pulmonary and other soft tissue infections, in cooling waters containing different numbers of legionellae. Mycobacteria were isolated from all twelve cooling systems and from 92% of the 24 samples studied. Their numbers in the positive samples varied from 10 to 7.3 * 10(4) cfu/L. The isolated species included M. chelonae/abscessus, M. fortuitum, M. mucogenicum, M. peregrinum, M. intracellulare, M. lentiflavum, M. avium/nebraskense/scrofulaceum and many non-pathogenic species. The numbers of mycobacteria correlated negatively with the numbers of legionellae and the concentration of copper. The results show that cooling towers are suitable environments for potentially pathogenic mycobacteria. Further transmission of mycobacteria from the towers to the environment needs examination. PMID- 23937213 TI - Shear strengthens fibrin: the knob-hole interactions display 'catch-slip' kinetics. PMID- 23937214 TI - Visual salience can co-exist with dilution during visual selection. AB - The perceptual load theory contends that the locus of visual selection is dependent on the availability of perceptual resources, and findings have shown significant distractor interference under conditions of low perceptual load, but not under conditions of high perceptual load. Recently, other researchers have suggested that this pattern of distractor interference may actually be due to changes in the quality of the distractor's representation (known as the dilution account) and/or changes in its relative salience (known as the salience account). The present study attempted to advance theoretical understanding of visual selection by comparing the effects of high versus low visual salience while holding the effects of perceptual load and dilution constant. The results of two experiments showed that the relative salience of the distractor influenced the magnitude of distractor interference under these conditions. These results suggest that the effects of visual salience can coexist with the effects of dilution (and load). PMID- 23937215 TI - Relevance-based selectivity: the case of implicit learning. AB - Learning the structure of the environment (e.g., what usually follows what) enables animals to behave in an effective manner and prepare for future events. Unintentional learning is capable of efficiently producing such knowledge as has been demonstrated with the Artificial Grammar Learning paradigm (AGL), among others. It has been argued that selective attention is a necessary and sufficient condition for visual implicit learning. Experiment 1 shows that spatial attention is not sufficient for implicit learning. Learning does not occur if the stimuli instantiating the structure are task irrelevant. In a second experiment, we demonstrate that this holds even with abundance of available attentional resources. Together, these results challenge the current view of the relations between attention, resources, and implicit learning. PMID- 23937216 TI - How do the regions of the visual field contribute to object search in real-world scenes? Evidence from eye movements. AB - An important factor constraining visual search performance is the inhomogeneity of the visual system. Engaging participants in a scene search task, the present study explored how the different regions of the visual field contribute to search. Gaze-contingent Blindspots and Spotlights were implemented to determine the absolute and relative importance of the different visual regions for object in-scene search. Three Blindspot/Spotlight radii (1.6 degrees , 2.9 degrees , and 4.1 degrees ) were used to differentiate between foveal, parafoveal, and peripheral vision. When searching the scene with artificially impaired foveal or central vision (Blindspots), search performance was surprisingly unimpaired. Foveal vision was not necessary to attain normal search performance. When high resolution scene information was withheld in both foveal and parafoveal vision (4.1 degrees Blindspot), target localization was unimpaired but it took longer to verify the identity of the target. Artificially impairing extrafoveal scene analysis (Spotlights) affected attentional selection and visual processing; shrinking the Spotlight of high resolution led to longer search times, shorter saccades, and more and longer fixations. The 4.1 degrees radius was identified as the crossover point of equal search times in Blindspot and Spotlight conditions. However, a gaze-data based decomposition of search times into behaviorally defined epochs revealed differences in particular subprocesses of search. PMID- 23937217 TI - Calibration is action specific but perturbation of perceptual units is not. AB - G. P. Bingham and C. C. Pagano (1998, The necessity of a perception/action approach to definite distance perception: Monocular distance perception to guide reaching. Journal of Experimental Psychology: Human Perception and Performance, 24, 145-168) argued that metric space perception should be investigated using relevant action measures because calibration is an intrinsic component of perception/action that yields accurate targeted actions. They described calibration as a mapping from embodied units of perception to embodied units of action. This mapping theory yields a number of predictions. We tested two of them. The first prediction is that calibration should be action specific because what is calibrated is a mapping from perceptual units to a unit of action. Thus, calibration does not generalize to other actions. This prediction is consistent with the "action-specific approach" to calibration (D. R. Proffitt, 2008, An action specific approach to spatial perception. In R. L. Klatzky, B. MacWhinney, & M. Behrmann (Eds.), Embodiment, ego-space and action (pp. 179-202). New York, NY: Psychology Press.). The second prediction is that a change in perceptual units should generalize to all relevant actions that are guided using that perceptual information. The same perceptual units can be mapped to different actions. Change in the unit affects all relevant actions. This prediction is consistent with the "general purpose perception approach" (J. M. Loomis & J. W. Philbeck, 2008, Measuring spatial perception with spatial updating and action. In R. L. Klatzky, B. MacWhinney, & M. Behrmann (Eds.), Embodiment, ego-space and action (pp. 1-43). New York, NY: Psychology Press). In Experiment 1, two targeted actions, throwing and extended reaching were tested to determine if they were comparable in precision and in response to distorted calibration. They were. Comparing these actions, the first prediction was tested in Experiment 2 and confirmed. The second prediction was tested in Experiment 3 and confirmed. The action-specific and general purpose perception approaches each fail to predict the alternative results predicted by the other. Both sets of results were predicted by the mapping among embodied units theory of calibration. PMID- 23937218 TI - On the costs of lag-1 sparing. AB - The attentional blink (AB) is a dual-target, rapid serial visual presentation (RSVP) deficit thought to represent a failure of perceptual awareness that reflects the dynamics of temporal attention. However, second target (T2) report is typically unimpaired when the targets appear within 150 ms of one another (i.e., lag-1 sparing). In addition, this sparing can be extended if more targets appear sequentially. It is thought that sequential targets are processed in the same attentional window. Here, we investigated the fate of targets processed in these windows and, specifically, the consequence for subsequent targets when an item at lag-1 is reported versus missed. The results demonstrated that target encoding in attentional windows has an all-or-none influence on subsequent item report: When comparing two- and three-target (T1 and T2 not separated by distractors) RSVP streams, there was no difference in AB magnitude for the final target when either T2 or T1 was missed in the three-target condition, but both of these conditions had significantly smaller blinks than those observed when T1 and T2 were accurately reported. A comparison of our results to a computational model of temporal attention demonstrates how structural limitations on the rate of encoding affect perception, even during sparing. PMID- 23937219 TI - Case of streptococcal toxic shock syndrome caused by rapidly progressive group A hemolytic streptococcal infection during postoperative chemotherapy for cervical cancer. AB - Streptococcal toxic shock syndrome (STSS) is a severe infectious disease caused by group A hemolytic streptococcus (Streptococcus pyogenes). This condition is a serious disease that involves rapidly progressive septic shock. We experienced a case of STSS caused by primary peritonitis during treatment with paclitaxel and cisplatin (TP therapy) as postoperative chemotherapy for cervical cancer. STSS mostly develops after extremity pain, but initial influenza-like symptoms of fever, chill, myalgia and gastrointestinal symptoms may also occur. TP therapy is used to treat many cancers, including gynecological cancer, but may cause adverse reactions of neuropathy and nephrotoxicity and sometimes fever, arthralgia, myalgia, abdominal pain and general malaise. The case reported here indicates that development of STSS can be delayed after chemotherapy and that primary STSS symptoms may be overlooked because they may be viewed as adverse reactions to chemotherapy. To our knowledge, this is the first report of a case of STSS during chemotherapy. PMID- 23937220 TI - Immune responses of chickens inoculated with recombinant Lactobacillus expressing the haemagglutinin of the avian influenza virus. AB - AIMS: To develop a safe, effective and convenient vaccine for the prevention of highly pathogenic avian influenza (HPAI), we have successfully constructed a recombinant lactobacillus (LDL17-pH) that expresses the foreign HPAI protein, haemagglutinin 1 (HA1 ). METHODS AND RESULTS: The mucosal and systemic immune responses that are triggered by LDL17-pH following the oral administration to 10 day-old chickens were evaluated. The results showed that LDL17-pH could significantly increase the specific anti-HA1 IgA antibody level in the mucosa and the anti-HA1 IgG level in sera. Tissues were isolated from trachea and Peyer's patches(PPs)and caecal tonsils of chickens, and gene expression was analysed via real-time quantitative PCR. CONCLUSIONS: The results showed that LDL17-pH could significantly induce the specific anti-HA1 IgA antibody level in the trachea and intestine and the specific anti-HA1 IgG antibody level in the serum (P < 0.05). Additionally, LDL17-pH was in the capacity to induce the expression of cytokines IFN-gamma, TLR-2 and AvBD-9 in the PPs and caecal tonsils. Most importantly, the chickens that were immunized with LDL17-pH were protected against lethal challenge of the H5N1 virus to some extent. SIGNIFICANCE AND IMPACT OF THE STUDY: Therefore, LDL17-pH could be a promising oral vaccine candidate against HPAI. PMID- 23937221 TI - Development of an efficient regeneration and transformation method for the new potential oilseed crop Lepidium campestre. AB - BACKGROUND: Lepidium campestre is an undomesticated oilseed species with a great potential to become a new crop for both food and industrial feedstocks production. Genetic modification is needed for further improving the oil quantity and quality of Lepidium. Studies on in vitro shoot regeneration of Lepidium are very limited and there is no transformation protocol available. RESULTS: We have investigated the effects of different factors, especially the type, concentration and combination of plant growth regulators (PGRs) on in vitro shoot regeneration of Lepidium. The results showed that the 2,4-D treatment was crucial to shoot regeneration from different explants. The duration of 2,4-D exposure between 2-4 days did not show significant difference in shoot regeneration, while the effect of 2,4-D concentration varied greatly depending on the type of explants and cytokinins used, for example, the low concentration of 2,4-D combined with TDZ significantly increased the regeneration frequency of hypocotyls. Cotyledon and hypocotyl explants responded differently to cytokinin, for example, TDZ was more effective than zeatin in promoting shoot regeneration from hypocotyls, but did not affect the regeneration of cotyledons which was more affected by high concentration of zeatin. The results also showed that NAA was not effective for shoot regeneration. Germination in light increased the regeneration frequency compared to that in dark. After optimization of the different conditions, an efficient regeneration protocol was developed with the regeneration efficiency of 92.7%. Using this protocol, the transformation frequency of 6% in average was achieved. The presence of transgenes in the transgenic lines was confirmed by GUS staining, PCR and Southern blot analyses. CONCLUSION: Through systematic investigation of important factors affecting in vitro shoot regeneration, we have developed an efficient regeneration and transformation protocol for the genetic modification of Lepidium campestre. The method may also be applied to the related species. PMID- 23937222 TI - Expression patterns of key iron and oxygen metabolism genes during magnetosome formation in Magnetospirillum gryphiswaldense MSR-1. AB - To evaluate the expression patterns of genes involved in iron and oxygen metabolism during magnetosome formation, the profiles of 13 key genes in Magnetospirillum gryphiswaldense MSR-1 cells cultured under high-iron vs. low iron conditions were examined. Cell growth rates did not differ between the two conditions. Only the high-iron cells produced magnetosomes. Transmission electron microscopy observations revealed that magnetosome formation began at 6 h and crystal maturation occurred from 10 to 18 h. Real-time polymerase chain reaction analysis showed that expression of these genes increased during cell growth and magnetosome synthesis, particularly for ferric reductase gene (fer6) and ferrous transport system-related genes feoAB1, feoAB2, sodB, and katG. The low-iron cells showed increased expression of feoAB1 and feoB2 from 12 to 18 h but no clear expression changes for the other genes. Expression patterns of the genes were divided by hierarchical clustering into four clusters for the high-iron cells and three clusters for the low-iron cells. Each cluster included both iron and oxygen metabolism genes showing similar expression patterns. The findings indicate the coordination and co-dependence of iron and oxygen metabolism gene activity to achieve a balance during the biomineralization process. Future transcriptome analysis will help elucidate the mechanism of biomineralization in MSR-1 magnetosome formation. PMID- 23937223 TI - 8-Functionalization of alkyl-substituted-3,8-dimethyl BODIPYs by Knoevenagel condensation. AB - New 8-alkenylBODIPYs have been synthesized by Knoevenagel condensation between a series of alkyl-substituted-3,8-dimethylBODIPYs and aromatic or aliphatic aldehydes. This is in clear contrast with literature precedents, which indicate that this reaction occurs exclusively on the methyl group at C-3. The change in hybridization of the carbon at the 8-position (from sp(3) to sp(2)) determines the fluorescence emission of the BODIPY, while the presence of electron-donating or -withdrawing groups leads to intramolecular charge transfer processes. PMID- 23937224 TI - Metformin in lung cancer: rationale for a combination therapy. AB - INTRODUCTION: Metformin is a widely used antidiabetic drug, which also displays significant growth inhibitory and proapoptotic effects in several cancer models, including lung cancer, alone or in combination with chemotherapeutic drugs. AREAS COVERED: The role of metformin as a chemopreventive drug in lung cancer is still an object of debate as epidemiological studies have shown contrasting results. More preclinical data support its role as an adjuvant drug in the treatment of lung cancer, in combination with chemotherapy or targeted molecular drugs, although the complete mechanism of action of metformin is still unclear, and potentially may exert unexpected effects with contradictory clinical implications. EXPERT OPINION: Future perspective studies are required in nonsmall cell lung cancer (NSCLC) patients to better investigate the effect of metformin action on the RAS/RAF/MAPK pathway and the best context in which to use metformin in combination with molecularly targeted agents. PMID- 23937226 TI - Controls on water use for thermoelectric generation: case study Texas, US. AB - Large-scale U.S. dependence on thermoelectric (steam electric) generation requiring water for cooling underscores the need to understand controls on this water use. The study objective was to quantify water consumption and withdrawal for thermoelectric generation, identifying controls, using Texas as a case study. Water consumption for thermoelectricity in Texas in 2010 totaled ~0.43 million acre feet (maf; 0.53 km(3)), accounting for ~4% of total state water consumption. High water withdrawals (26.2 maf, 32.3 km(3)) mostly reflect circulation between ponds and power plants, with only two-thirds of this water required for cooling. Controls on water consumption include (1) generator technology/thermal efficiency and (2) cooling system, resulting in statewide consumption intensity for natural gas combined cycle generators with mostly cooling towers (0.19 gal/kWh) being 63% lower than that of traditional coal, nuclear, or natural gas steam turbine generators with mostly cooling ponds (0.52 gal/kWh). The primary control on water withdrawals is cooling system, with ~2 orders of magnitude lower withdrawals for cooling towers relative to once-through ponds statewide. Increases in natural gas combined cycle plants with cooling towers in response to high production of low cost natural gas has greatly reduced water demand for thermoelectric cooling since 2000. PMID- 23937225 TI - Real-time nanoscale proteomic analysis of the novel multi-kinase pathway inhibitor rigosertib to measure the response to treatment of cancer. AB - INTRODUCTION: Rigosertib (ON01910.Na), is a targeted therapeutic that inhibits multiple kinases, including PI3K and PIk-1. Rigosertib has been found to induce the proliferative arrest and apoptosis of myeloblasts but not of other normal hematopoietic cells. Rigosertib has significant clinical activity as a therapy for patients with high-risk myelodysplastic syndrome who are otherwise refractory to DNA methyltransferase inhibitors. Moreover, rigosertib has potential clinical activity in a multitude of solid tumors. AREAS COVERED: The objective of this review is to evaluate the mechanism of activity, efficacy and dosing of rigosertib. Furthermore, the challenge in the clinical development of rigosertib, to identify the specific patients that are most likely to benefit from this therapeutic agent, is discussed. A PubMed search was performed using the following key words: rigosertib and ON01910.Na. EXPERT OPINION: We describe the application of a novel nanoscale proteomic assay, the nanoimmunoassay, a tractable approach for measuring the activity and predicting the efficacy of rigosertib, in real-time, using limited human clinical specimens. Our strategy suggests a possible paradigm where proteomic analysis during the pre-clinical and clinical development of a therapy can be used to uncover biomarkers for the analysis and prediction of efficacy in human patients. PMID- 23937227 TI - Ectomycorrhizas with Paxillus involutus enhance cadmium uptake and tolerance in Populus * canescens. AB - Ectomycorrhizas (EMs), which are symbiotic organs formed between tree roots and certain fungi, can mediate cadmium (Cd) tolerance of host plants, but the underlying physiological and molecular mechanisms are not fully understood. To investigate EMs mediated Cd tolerance in woody plants, Populus * canescens was inoculated with Paxillus involutus (strain MAJ) to establish mycorrhizal roots. Mycorrhizal poplars and non-mycorrhizal controls were exposed to 0 or 50 MUM CdSO4 . EMs displayed higher net Cd(2+) influx than non-mycorrhizal roots. Net Cd(2+) influx was coupled with net H(+) efflux and inactivation of plasma membrane (PM) H(+) -ATPases reduced Cd(2+) uptake of EMs less than of non mycorrhizal roots. Consistent with higher Cd(2+) uptake in EMs, in most cases, transcript levels of genes involved in Cd(2+) uptake, transport and detoxification processes were increased in EMs compared to non-mycorrhizal roots. Higher CO2 assimilation, improved nutrient and carbohydrate status, and alleviated oxidative stress were found in mycorrhizal compared to non-mycorrhizal poplars despite higher Cd(2+) accumulation. These results indicate that mycorrhizas increase Cd(2+) uptake, probably by an enlarged root volume and overexpression of genes involved in Cd(2+) uptake and transport, and concurrently enhance Po. * canescens Cd tolerance by increased detoxification, improved nutrient and carbohydrate status and defence preparedness. PMID- 23937228 TI - Successful medical treatment of glans ischemia after voluntary buprenorphine injection. AB - INTRODUCTION: The diverted use of synthetic opioid buprenorphine by drug addicts can be responsible for serious ischemic and infectious complications, particularly in the case of intravenous injection. AIM: We present a case of serious glans ischemia after buprenorphine injection directly into the deep dorsal vein of the penis. Analysis using new medical imaging techniques and treatments is detailed below. METHODS: A 26-year-old male drug addict presented with glans pain 4 days after self-injection of buprenorphine into the deep dorsal vein of the penis. The patient was apyretic and presented a urethral discharge. His glans was blue without discoloration on digital pressure. Additionally, his biologic and serologic tests were normal while bacteriology showed the presence of Enterobacter cloacae urethritis. RESULTS: After 48 hours of intravenous antibiotic treatment without improvement, a specific medical treatment using enoxaparin and ilomedin was initiated, with the assumption that there was an ischemic complication. Laser speckle contrast imaging allowed confirmation of the presence of distal penis ischemia and provided an accurate mapping of the ischemic zone. A 28-day treatment combining antibiotics, subcutaneous heparin at curative dose, antiplatelet drug, ilomedin, and hyperbaric oxygen therapy resulted in clinical improvement of the lesions with no functional complications. CONCLUSIONS: To date, no consensus exists on the proper diagnostic and treatment approach to severe glans ischemia due to buprenorphine injection into the deep dorsal vein of the penis. The results of laser speckle contrast imaging were of real interest during the process of diagnosis. In addition, the combination of ilomedin with hyperbaric oxygen therapy and anticoagulant and antiplatelet drugs appeared to be an effective therapy. PMID- 23937229 TI - RCircos: an R package for Circos 2D track plots. AB - BACKGROUND: Circos is a Perl language based software package for visualizing similarities and differences of genome structure and positional relationships between genomic intervals. Running Circos requires extra data processing procedures to prepare plot data files and configure files from datasets, which limits its capability of integrating directly with other software tools such as R. Recently published R Bioconductor package ggbio provides a function to display genomic data in circular layout based on multiple other packages, which increases its complexity of usage and decreased the flexibility in integrating with other R pipelines. RESULTS: We implemented an R package, RCircos, using only R packages that come with R base installation. The package supports Circos 2D data track plots such as scatter, line, histogram, heatmap, tile, connectors, links, and text labels. Each plot is implemented with a specific function and input data for all functions are data frames which can be objects read from text files or generated with other R pipelines. CONCLUSION: RCircos package provides a simple and flexible way to make Circos 2D track plots with R and could be easily integrated into other R data processing and graphic manipulation pipelines for presenting large-scale multi-sample genomic research data. It can also serve as a base tool to generate complex Circos images. PMID- 23937230 TI - Chiral bis(imidazolinyl)phenyl NCN pincer rhodium(III) catalysts for enantioselective allylation of aldehydes and carbonyl-ene reaction of trifluoropyruvates. AB - Chiral NCN pincer rhodium(III) complexes with bis(imidazolinyl)phenyl ligands were found to be effective catalysts for the allylation of a variety of electronically and structurally diverse aldehydes with allyltributyltin, giving the corresponding optically active homoallylic alcohols in high yields with enantioselectivities of up to 97% ee. These complexes were also applied in the carbonyl-ene reaction of ethyl or methyl trifluoropyruvate with various 2 arylpropenes. With the aid of silver trifluoromethanesulfonate, the pincer rhodium(III) catalysts could catalyze the reaction to provide the corresponding chiral alpha-hydroxy-alpha-trifluoromethyl esters in good yields with high stereoselectivities (up to 95% ee). PMID- 23937231 TI - Molecular recognition of tachykinin receptor selective agonists: insights from structural studies. AB - This Review deals essentially with the elucidation of structural features of Tachykinin family of neuropeptides, which are known to interact through three distinct GPCR subtypes, namely NK1 (Neurokinin 1), NK2 (Neurokinin 2) and NK3 (Neurokinin 3) receptors. In mammals, Tachykinins have been shown to elicit a wide array of activities such as powerful vasodilatation, hypertensive action and stimulation of extravascular smooth muscle and are known to be involved in a variety of clinical conditions including chronic pain, Parkinson's disease, Alzheimer's disease, depression, rheumatoid arthritis, irritable bowel syndrome and asthma. This broad spectrum of action of Tachykinins is attributed to the lack of selectivity of tachykinins to their receptors. All tachykinins interact with all the three-receptor subtypes with SP preferring NK1, NKA preferring NK2 and NKB preferring NK3. This lack of specificity can be accounted for by the conformational flexibility of these short, linear peptides. Hence, identification of structural features of the agonists important for receptor binding and biological activity is of great significance in unraveling the molecular mechanisms involved in tachykinin receptor activation and also in rational design of novel therapeutic agents. Understanding structure of the ligand-receptor complex and analysis of topography of the binding pocket of the tachykinin receptor is also crucial in rational design of drugs. PMID- 23937232 TI - Pyrazole derivatives as antitumor, anti-inflammatory and antibacterial agents. AB - Within the past years, many researches on the synthesis, structure-activity relationships (SAR), antitumor, antiinflammatory and anti-bacterial activities of the pyrazole derivatives have been reported. Several pyrazole derivatives possess important pharmacological activities and they have been proved useful materials in drug research. Pyrazole derivatives play an important role in antitumor agents because of their good inhibitory activity against BRAF(V600E), EGFR, telomerase, ROS Receptor Tyrosine Kinase and Aurora-A kinase. In addition, pyrazole derivatives also show good antiinflammatory and anti-bacterial activities. In this review, the bioactivities of the pyrazole derivatives mentioned above will be summarized in detail. We sincerely hope that increasing knowledge of the SAR and cellular processes underlying the bioactivity of pyrazole derivatives will be beneficial to the rational design of new generation of small molecule drugs. PMID- 23937234 TI - Egocentric coding of space for incidentally learned attention: effects of scene context and task instructions. AB - Visuospatial attention prioritizes regions of space for perceptual processing. Knowing how attended locations are represented is critical for understanding the architecture of attention. We examined the spatial reference frame of incidentally learned attention and asked how it is influenced by explicit, top down knowledge. Participants performed a visual search task in which a target was more likely to appear in one, "rich," quadrant of the screen than in the others. The spatial relationship between the display and the viewer's perspective changed partway through the experiment. Because incidentally learned attention is persistent, the spatial bias that developed during training was present following the change in viewer perspective. Despite the presence of multiple environmental landmarks including a background scene, participants prioritized rich regions relative to their perspective, rather than relative to the environment. Remarkably, the egocentric attentional bias was unaffected by explicit knowledge of where the target was likely to appear. Although participants used this knowledge to prioritize the region of space they were told was likely to contain a target, a strong egocentric bias to a region that was unlikely to contain a target persisted. These data indicate that incidental attention differs fundamentally from attention driven by explicit knowledge. We propose that attention takes 2 forms. One is declarative, based on maps that explicitly prioritize some regions of space over others. The other is procedural, influenced by implicit knowledge that modulates how attention is moved through space. PMID- 23937233 TI - Examination of frontal and parietal tectocortical attention pathways in spina bifida meningomyelocele using probabilistic diffusion tractography. AB - Abnormalities of the midbrain tectum are common but variable malformations in spina bifida meningomyelocele (SBM) and have been linked to neuropsychological deficits in attention orienting. The degree to which variations in tectum structure influence white matter (WM) connectivity to cortical regions is unknown. To assess the relationship of tectal structure and connectivity to frontal and parietal cortical regions, probabilistic diffusion tractography was performed on 106 individuals (80 SBM, 26 typically developing [TD]) to isolate anterior versus posterior tectocortical WM pathways. Results showed that those with SBM exhibited significantly reduced tectal volume, along with decreased fractional anisotropy (FA) in posterior but not anterior tectocortical WM pathways when compared with TD individuals. The group with SBM also showed greater within-subject discrepancies between frontal and parietal WM integrity compared with the TD group. Of those with SBM, qualitative classification of tectal beaking based on radiological review was associated with increased axial diffusivity across both anterior and posterior tectocortical pathways, relative to individuals with SBM and a normal appearing tectum. These results support previous volumetric findings of greater impairment to posterior versus anterior brain regions in SBM, and quantifiably relate tectal volume, tectocortical WM integrity, and tectal malformations in this population. PMID- 23937235 TI - The influence of contextual diversity on eye movements in reading. AB - Recent research has shown contextual diversity (i.e., the number of passages in which a given word appears) to be a reliable predictor of word processing difficulty. It has also been demonstrated that word-frequency has little or no effect on word recognition speed when accounting for contextual diversity in isolated word processing tasks. An eye-movement experiment was conducted wherein the effects of word-frequency and contextual diversity were directly contrasted in a normal sentence reading scenario. Subjects read sentences with embedded target words that varied in word-frequency and contextual diversity. All 1st-pass and later reading times were significantly longer for words with lower contextual diversity compared to words with higher contextual diversity when controlling for word-frequency and other important lexical properties. Furthermore, there was no difference in reading times for higher frequency and lower frequency words when controlling for contextual diversity. The results confirm prior findings regarding contextual diversity and word-frequency effects and demonstrate that contextual diversity is a more accurate predictor of word processing speed than word-frequency within a normal reading task. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23937236 TI - The role of reminding in the effects of spaced repetitions on cued recall: sufficient but not necessary. AB - Three experiments examined the role of study-phase retrieval (reminding) in the effects of spaced repetitions on cued recall. Remindings were brought under task control to evaluate their effects. Participants studied 2 lists of word pairs containing 3 item types: single items that appeared once in List 2, within-list repetitions that appeared twice in List 2, and between-list repetitions that appeared once in List 1 and once in List 2. Our primary interest was in performance on between-list repetitions. Detection of between-list repetitions was encouraged in an n-back condition by instructing participants to indicate when a presented item was a repetition of any preceding item, including items presented in List 1. In contrast, detection of between-list repetitions was discouraged in a within-list back condition by instructing participants only to indicate repetitions occurring in List 2. Cued recall of between-list repetitions was enhanced when instructions encouraged detection of List 1 presentations. These results accord with those from prior experiments showing a role of study phase retrieval in effects of spacing repetitions. Past experiments have relied on conditionalized data to draw conclusions, producing the possibility that performance benefits merely reflected effects of item selection. By bringing effects under task control, we avoided that problem. Our results provide evidence that reminding resulting from retrieval of earlier presentations plays a role in the effects of spaced repetitions on cued recall. However, our results also reveal that such retrievals are not necessary to produce an effect of spacing repetitions. PMID- 23937237 TI - Hyper-binding across time: age differences in the effect of temporal proximity on paired-associate learning. AB - Older adults show hyper- (or excessive) binding effects for simultaneously and sequentially presented distraction. Here, we addressed the potential role of hyper-binding in paired-associate learning. Older and younger adults learned a list of word pairs and then received an associative recognition task in which rearranged pairs were formed from items that had originally occurred either close together or far apart in the study list. Across 3 experiments, older adults made more false alarms to near re-pairings than to far re-pairings. Younger adults, on the other hand, showed no difference in false alarms to the 2 types of rearranged pairs. These findings may be tied to the greater tendency of older adults to maintain access to recently attended information, inadvertently forming broader associations across time, than is the case for younger adults. PMID- 23937239 TI - Neurodevelopmental outcome, psychological adjustment, and quality of life in adolescents with congenital heart disease. AB - AIM: The aim of this study was to examine neurodevelopment, psychological adjustment, and health-related quality of life (HRQoL) in adolescents after bypass surgery for congenital heart disease (CHD) during early childhood. METHOD: Fifty-nine adolescents (34 females, 25 males) with CHD were examined at a median age of 13 years 8 months (range 11 y 5 mo-16 y 11 mo). Outcome was assessed with the Wechsler Intelligence Scale for Children, (fourth edition); the Beery Test of Visual-Motor Integration; the Rey-Osterrieth Complex Figure Test; the Zurich Neuromotor Assessment; the Strengths and Difficulties Questionnaire; and the KIDSCREEN questionnaires. Results were compared with those of 40 age- and sex matched healthy comparison individuals. RESULTS: Outcome with regard to full scale IQ, perceptual reasoning, and the working memory scale was poorer in patients with CHD than in the comparison group (all p <= 0.001). Visual perception, visuomotor integration (p <= 0.001), and executive functions (Rey figure copy: p=0.05) were also affected. Patients with CHD also had lower scores on all motor domains (p < 0.02) except static balance. Psychological adjustment was affected only in the 'peer relationship' domain (p=0.05). Quality of life was similar to that of typically developing peers. INTERPRETATION: Adolescents with CHD may manifest persistent cognitive and motor impairments, while psychological adjustment and self-reported HRQoL are mostly typical. Thus, long-term neurodevelopmental evaluations are necessary to provide early educational and therapeutic support. PMID- 23937238 TI - Potential link between biotic defense activation and recalcitrance to induction of somatic embryogenesis in shoot primordia from adult trees of white spruce (Picea glauca). AB - BACKGROUND: Among the many commercial opportunities afforded by somatic embryogenesis (SE), it is the ability to clonally propagate individual plants with rare or elite traits that has some of the most significant implications. This is particularly true for many long-lived species, such as conifers, but whose long generation times pose substantive challenges, including increased recalcitrance for SE as plants age. Identification of a clonal line of somatic embryo-derived trees whose shoot primordia have remained responsive to SE induction for over a decade, provided a unique opportunity to examine the molecular aspects underpinning SE within shoot tissues of adult white spruce trees. RESULTS: Microarray analysis was used to conduct transcriptome-wide expression profiling of shoot explants taken from this responsive genotype following one week of SE induction, which when compared with that of a nonresponsive genotype, led to the identification of four of the most differentially expressed genes within each genotype. Using absolute qPCR to expand the analysis to three weeks of induction revealed that differential expression of all eight candidate genes was maintained to the end of the induction treatment, albeit to differing degrees. Most striking was that both the magnitude and duration of candidate gene expression within the nonresponsive genotype was indicative of an intense physiological response. Examining their putative identities further revealed that all four encoded for proteins with similarity to angiosperm proteins known to play prominent roles in biotic defense, and that their high-level induction over an extended period is consistent with activation of a biotic defense response. In contrast, the more temperate response within the responsive genotype, including induction of a conifer-specific dehydrin, is more consistent with elicitation of an adaptive stress response. CONCLUSIONS: While additional evidence is required to definitively establish an association between SE responsiveness and a specific physiological response, these results suggest that biotic defense activation may be antagonistic, likely related to the massive transcriptional and metabolic reprogramming that it elicits. A major issue for future work will be to determine how and if suppressing biotic defense activation could be used to promote a physiological state more conducive to SE induction. PMID- 23937240 TI - Synthesis and stability of oxetane analogs of thalidomide and lenalidomide. AB - Oxetanes are used in drug discovery to enable physicochemical and metabolic property enhancement for the structures to which they are grafted. An imide C?O to oxetane swap on thalidomide and lenalidomide templates provides analogs with similar physicochemical and in vitro properties of the parent drugs, with an important exception: oxetane analog 2 displays a clear differentiation with respect to human plasma stability. The prospect of limiting in vivo stability/metabolism, blocking in vivo racemization, and potentially altering teratogenicity is appealing. PMID- 23937241 TI - Vascular endothelial growth factor (VEGF) expression and microvascular density in salivary gland tumours. AB - This study investigates whether salivary tumours with different morphology and evolution also differ in terms of neovascularization and VEGF expression and the prognostic value of the results. Surgical specimens from 45 patients - 8 pleomorphic adenomas (PA), 7 Warthin tumours (WT), 5 basal cell adenomas (BA), 6 carcinomas ex-pleomorphic adenoma (CEPA), 6 mucoepidermoid carcinomas (MEC), 5 acinic cell carcinomas (AC), 4 adenoid cystic carcinomas (ACC) and 4 adenocarcinomas not otherwise specified (ADK NOS) - were immunostained. In malignant salivary tumours, the following mean microvascular density (MVD) values were recorded (+/- SD = Standard Deviation): 27.61 (SD +/- 2.27) in cases with CEPA, 27.08 (DS +/- 7.81) in AC and 32.93 (SD +/- 7.76) in ADK NOS, with lower values for MEC 24.31(SD +/- 2.88) and for ACC 22.13 (SD +/- 5.44). For benign tumours, an MVD of 35.71 (SD +/- 2.09) was recorded in WT and lower average values in PA (MVD = 14.84; SD +/- 4.86) and in BA (MVD = 23.96; SD +/- 9.13). MVD did not correlate with the investigated clinicopathological parameters. The VEGF expression is significantly more important (p = 0.001) in malignant salivary tumours as compared with benign ones. The VEGF expression and the microvascularization in salivary gland tumours are important elements to be considered when formulating a diagnosis and assessing case evolutions in patients with such tumours. PMID- 23937242 TI - Role of gamma-glutamyltranspeptidase in the pathogenesis of Helicobacter pylori infection. AB - gamma-Glutamyltranspeptidase and asparaginase have been shown to play important roles in Helicobacter pylori colonization and cell death induced by H. pylori infection. In this study, the association of gamma-glutamyltranspeptidase and asparaginase was elucidated by comparing activities of both deamidases in H. pylori strains from patients with chronic gastritis, gastric and duodenal ulcers, and gastric cancer. gamma-Glutamyltranspeptidase activities in H. pylori strains from patients with gastric cancer were significantly higher than in those from patients with chronic gastritis or gastric ulcers. There was a wide range of asparaginase activities in H. pylori strains from patients with gastric cancer and these were not significantly than those from patients with other diseases. To identify the contributions of gamma-glutamyltranspeptidase and asparaginase to gastric cell inflammation, human gastric epithelial cells (AGS line) were infected with H. pylori wild-type and knockout strains and inflammatory responses evaluated by induction of interleukin-8 (IL-8). IL-8 response was significantly decreased by knockout of the gamma-glutamyltranspeptidase-encoding gene but not by knockout of the asparaginase-encoding gene. Additionally, IL-8 induction by infection with the H. pylori wild-type strain was significantly decreased by adding glutamine during infection. These findings indicate that IL-8 induction caused by gamma-glutamyltranspeptidase activity in H. pylori is mainly attributable to depletion of glutamine. These data suggest that gamma glutamyltranspeptidase plays a significant role in the chronic inflammation caused by H. pylori infection. PMID- 23937243 TI - Multidimensional network structures and versatile magnetic properties of intermolecular compounds of a radical-anion ligand, [1,2,5]thiadiazolo[3,4 f][1,10]phenanthroline 1,1-dioxide. AB - The crystal structures and magnetic properties of seven kinds of [1,2,5]thiadiazolo[3,4-f][1,10]phenanthroline 1,1-dioxide (tdapO2) radical-anion salts, namely, K.tdapO2, K.tdapO2.0.5MeCN, K.(tdapO2)2, Rb.(tdapO2)2, Cs7.(tdapO2)6.ClO4, (NH4)2.tdapO2.I, and Hppda.tdapO2.MeCN, were investigated. Single-crystal X-ray analyses of these radical-anion salts revealed formation of pi-stacking columns and the presence of intercolumnar coordination bonding or hydrogen bonding. The intermolecular magnetic coupling constants in these salts range from strong antiferromagnetic (J/kB = -310 K) to ferromagnetic (J/kB = 24 K). Ab initio calculations performed on the nearest-neighbor radical pairs in the pi-stacking columns suggested that the magnetic interactions are strongly governed by the overlap between the two anionic radical species and well explain the observed ferromagnetic and antiferromagnetic interactions. In addition, calculations of a hypothetical oxygen-less tdap analogue suggested that the presence of oxygen in tdapO2 significantly reduces the hopping integral and enhances the probability of ferromagnetic interaction. PMID- 23937244 TI - Efficacy of a general practitioner training campaign for early detection of melanoma in France. AB - BACKGROUND: To date, no strategy for improving early diagnosis of melanoma has been evaluated on a population basis in France. OBJECTIVE: To evaluate the efficacy of a general practitioner (GP) awareness and training campaign in a pilot French geographical region (Champagne-Ardenne), including 1.34 million inhabitants, 1241 GPs, 56 dermatologists and a population-based melanoma registry. METHODS: All GPs received repeated awareness postal mailings in 2008 and 398 (32.1%) attended training sessions organized by 27 dermatologists. The pre- (2005-7) and post-campaign (2009-11) periods were compared for the following: primary endpoint - the world-standardized incidence of very thick melanomas (VTM) (Breslow thickness >= 3 mm); secondary endpoints--the mean Breslow thickness; the proportions of VTM and of thin (< 1 mm) melanomas among invasive cases; and the ratio of in situ/all melanoma cases. Similar measures were performed in the control area of Doubs/Belfort territory (655,000 ha), where no similar campaign was carried out. RESULTS: The incidence of VTM decreased from 1.07 to 0.71 per 100 000 habitants per year (P = 0.01), the mean Breslow thickness from 1.95 to 1.68 mm (P = 0.06) and the proportion of VTM from 19.2% to 12.8% (P = 0.01). The proportion of thin and in situ melanomas increased from 50.9% to 57.4% (P = 0.05) and from 20.1% to 28.2% (P = 0.001), respectively. No significant variation was observed in Doubs/Belfort territory. CONCLUSION: These results strongly support the efficacy of such a campaign targeting GPs and provide a rationale for a larger public health campaign in France, including training of GPs by dermatologists and encouraging patients to ask their GP for a systematic skin examination. PMID- 23937245 TI - Direct measurement of band edge discontinuity in individual core-shell nanowires by photocurrent spectroscopy. AB - Group III-V coaxial core-shell semiconducting nanowire heterostructures possess unique advantages over their planar counterparts in logic, photovoltaic, and light-emitting devices. Dimensional confinement of electronic carriers and interface complexity in nanowires are known to produce local electronic potential landscapes along the radial direction that deviate from those along the normal to planar heterojunction interfaces. However, understanding of selected electronic and optoelectronic carrier transport properties and device characteristics remains lacking without a direct measurement of band alignment in individual nanowires. Here, we report on, in the GaAs/AlxGa1-xAs and GaAs/AlAs core-shell nanowire systems, how photocurrent and photoluminescence spectroscopies can be used together to construct a band diagram of an individual heterostructure nanowire with high spectral resolution, enabling quantification of conduction band offsets. PMID- 23937246 TI - Genome-wide screening for components of small interfering RNA (siRNA) and micro RNA (miRNA) pathways in the brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae). AB - The brown planthopper (BPH), Nilaparvata lugens, is a major rice pest in Asia, and accumulated evidence indicates that this species is susceptible to RNA interference (RNAi); however, the mechanism underlying RNAi and parental RNAi has not yet been determined. We comprehensively investigated the repertoire of core genes involved in small interfering RNA (siRNA) and micro-RNA (miRNA) pathways in the BPH by comparing its newly assembled transcriptome and genome with those of Drosophila melanogaster, Tribolium castaneum and Caenorhabditis elegans. Our analysis showed that the BPH possesses one drosha and two Dicer (dcr) genes, three dsRNA-binding motif protein genes, two Argonaute (ago) genes, two Eri-1 like genes (eri-1), and a Sid-1-like gene (sid-1). Additionally, we report for first time that parental RNAi might occur in this species, and siRNA pathway and Sid-1 were required for high efficiency of systemic RNAi triggered by exogenous dsRNA. Furthermore, our results also demonstrated that the miRNA pathway was involved in BPH metamorphosis as depletion of the ago1 or dcr1 gene severely impaired ecdysis. The BPH might be a good model system to study the molecular mechanism of systemic RNAi in hemimetabolous insects, and RNAi has potential to be developed to control this pest in agricultural settings. PMID- 23937247 TI - The selectivity and potency of the new PDE5 inhibitor TPN729MA. AB - INTRODUCTION: TPN729MA is a newly developed phosphodiesterase type 5 inhibitor (PDE5i) for the treatment of erectile dysfunction, which offers potential for greater selectivity and longer duration of action than PDE5i in current clinical use. AIM: We investigated the in vitro inhibitory potency and selectivity of TPN729MA on PDE isozymes, and its efficacy in animal models. METHODS: The inhibition of 11 human recombinant PDEs by TPN729MA, sildenafil, and tadalafil were determined using radioimmunoassay. The effect of TPN729MA and sildenafil on intracavernous pressure (ICP), blood pressure (BP), and ICP/BP ratio were determined in a rat model of erection induced by electric stimulation and in a dog model of erection induced by sodium nitroprusside injection. MAIN OUTCOME MEASURES: The main outcome measures were IC50 of TPN729MA, sildenafil, and tadalafil for PDE1-PDE11; maximum ICP; BP and ICP/BP ratio. RESULTS: The IC50 of TPN729MA, sildenafil, and tadalafil for PDE5 was 2.28, 5.22, and 2.35 nM, respectively. TPN729MA showed 248, 366, 20, and 2671-fold selectivity against PDE1, PDE4, PDE6, and PDE11, respectively. TPN729MA showed excellent selectivity against PDE2, 3, 7, 8, 9, and 10 (>10,000-fold). In the rat model of erection, TPN729MA (5.0 and 2.5 mg/kg), but not sildenafil, significantly increased the maximum ICP compared with vehicle. Significantly increased ICP/BP was observed in the TPN729MA (5.0 mg/kg) group at all time points, in the TPN729MA (2.5 mg/kg) group at 75, 90, 105, and 120 minutes time points, and in sildenafil group at 75 and 90 minutes time points compared with vehicle. In the dog model of erection, TPN729MA and sildenafil significantly increased ICP and ICP/BP but showed no significant effect on BP compared with vehicle. CONCLUSIONS: TPN729MA is a potent PDE5i with a balanced selectivity profile. TPN729MA shows excellent in vitro and in vivo potency, and a longer effect on erectile function than sildenafil in animal model. PMID- 23937248 TI - Differences in collagen ultrastructure of human first trimester decidua basalis and parietalis: implications for trophoblastic invasion of the placental bed. AB - AIM: The human embryo-maternal interface in the first trimester of pregnancy is an area of extensive tissue remodeling. Because collagen is the most abundant constituent of the extracellular matrix of the placental bed, successful invasion must involve its rapid turnover. We compared the nature and distribution of collagen fibrils in decidua basalis and parietalis. METHODS: We used a direct vision hysteroscopic technique to obtain biopsies of the decidua basalis and parietalis from 11 women undergoing pregnancy termination in the first trimester. The biopsies were subjected to light, transmission and scanning electron microscopy, and immunohistochemical studies using mouse monoclonal antibodies against cytokeratin 7 and collagen types I, III and V. RESULTS: Collagen fibrils in the stroma of decidua basalis were significantly thicker when compared to those in decidua parietalis (56.48 +/- 1.37 nm vs 45.64 +/- 0.85 nm; P < 0.0001 [mean +/- standard error]) between 9 and 12 weeks gestation, but this difference in thickness was not observed at gestations below 9 weeks. In basalis, the fibrils appeared disrupted at most places surrounding the decidual/trophoblast cells while a uniform regular arrangement was preserved throughout most of parietalis. CONCLUSION: There are differences in the ultrastructure of collagen fibrils between basalis and parietalis, with thicker and disrupted fibrils within abundant amorphous tissue in basalis, and thinner uniform fibrils in parietalis. These differences may reflect an adaptive response by decidua or a direct consequence of the invading trophoblast cells. PMID- 23937249 TI - Group sparse canonical correlation analysis for genomic data integration. AB - BACKGROUND: The emergence of high-throughput genomic datasets from different sources and platforms (e.g., gene expression, single nucleotide polymorphisms (SNP), and copy number variation (CNV)) has greatly enhanced our understandings of the interplay of these genomic factors as well as their influences on the complex diseases. It is challenging to explore the relationship between these different types of genomic data sets. In this paper, we focus on a multivariate statistical method, canonical correlation analysis (CCA) method for this problem. Conventional CCA method does not work effectively if the number of data samples is significantly less than that of biomarkers, which is a typical case for genomic data (e.g., SNPs). Sparse CCA (sCCA) methods were introduced to overcome such difficulty, mostly using penalizations with l-1 norm (CCA-l1) or the combination of l-1and l-2 norm (CCA-elastic net). However, they overlook the structural or group effect within genomic data in the analysis, which often exist and are important (e.g., SNPs spanning a gene interact and work together as a group). RESULTS: We propose a new group sparse CCA method (CCA-sparse group) along with an effective numerical algorithm to study the mutual relationship between two different types of genomic data (i.e., SNP and gene expression). We then extend the model to a more general formulation that can include the existing sCCA models. We apply the model to feature/variable selection from two data sets and compare our group sparse CCA method with existing sCCA methods on both simulation and two real datasets (human gliomas data and NCI60 data). We use a graphical representation of the samples with a pair of canonical variates to demonstrate the discriminating characteristic of the selected features. Pathway analysis is further performed for biological interpretation of those features. CONCLUSIONS: The CCA-sparse group method incorporates group effects of features into the correlation analysis while performs individual feature selection simultaneously. It outperforms the two sCCA methods (CCA-l1 and CCA-group) by identifying the correlated features with more true positives while controlling total discordance at a lower level on the simulated data, even if the group effect does not exist or there are irrelevant features grouped with true correlated features. Compared with our proposed CCA-group sparse models, CCA-l1 tends to select less true correlated features while CCA-group inclines to select more redundant features. PMID- 23937250 TI - Biotechnological potential of microbial alpha-galactosidases. AB - The enzyme alpha-galactosidase (alpha-D-galactoside galactohydrolase; EC 3.2.1.22) catalyzes the hydrolysis of alpha-1,6-linked galactose residues in oligosaccharides and polymeric galactomannan. The alpha-galactosidases are of particular interest in view of their many potential biotechnological and medical applications. These enzymes have found wide use in various industries such as food and feed, sugar and paper and pulp for the removal of raffinose and stachyose. They are also important medically for blood group conversion and in the treatment of Fabry disease. Most of the research on alpha-galactosidases has focused on their isolation from various microbial sources. In the last decade, cloning of novel alpha-galactosidase genes and their heterologous expression has gained momentum. The present review focuses on the production of alpha galactosidases from bacteria, fungi and yeast, and discusses their properties. Recent progress on cloning and heterologous expression in various hosts is summarized with special emphasis on their application in various fields. PMID- 23937251 TI - Metallic nanoparticles: microbial synthesis and unique properties for biotechnological applications, bioavailability and biotransformation. AB - The impact of nanotechnology in all areas of science and technology is evident. The expanding availability of a variety of nanostructures with properties in the nanometer size range has sparked widespread interest in their use in biotechnological systems, including the field of environmental remediation. Nanomaterials can be used as catalysts, adsorbents, membranes, water disinfectants and additives to increase catalytic activity and capability due to their high specific surface areas and nanosize effects. Thus, nanomaterials appear promising for new effective environmental technologies. Definitely, nanotechnology applications for site remediation and wastewater treatment are currently in research and development stages, and new innovations are underway. The synthesis of metallic nanoparticles has been intensively developed not only due to its fundamental scientific interest but also for many technological applications. The use of microorganisms in the synthesis of nanoparticles is a relatively new eco-friendly and promising area of research with considerable potential for expansion. On the other hand, chemical synthesis occurs generally under extreme conditions (e.g. pH, temperature) and also chemicals used may have associated environmental and human health impacts. This review is an overview of current research worldwide on the use of microorganisms during the biosynthesis of metallic nanoparticles and their unique properties that make them good candidates for many applications, including in biotechnology. PMID- 23937252 TI - A current assessment on the production of bacterial keratinases. AB - Keratinolytic proteases are microbial enzymes that hydrolyze keratins, recalcitrant proteins found in the epidermis and epidermal appendages of vertebrates. Keratin-rich materials are abundantly generated as wastes from agroindustrial activities, particularly the meat and poultry industries. Therefore, these enzymes are postulated for several applications, including the bioconversion of keratin-rich materials, utilization as animal feed supplements, action as de-hairing agents in tannery, prion degradation, among others. Consequently, production of keratinases in sufficient amounts is necessary to meet industrial and commercial demands. This manuscript presents an overview regarding the sources of keratinases, emphasizing general aspects and mechanisms, such as substrate induction and catabolite repression, controlling keratinase synthesis by Bacillus species. The current research status and main approaches employed to obtain keratinases are discussed in a biotechnological perspective, highlighting the role of keratin-rich wastes as growth substrates, the use of mathematical models to optimize keratinase yield and also investigations on the heterologous expression of keratinases. PMID- 23937253 TI - Trends and outcomes in the use of surgery and radiation for the treatment of locally advanced esophageal cancer: a propensity score adjusted analysis of the surveillance, epidemiology, and end results registry from 1998 to 2008. AB - We examined outcomes and trends in surgery and radiation use for patients with locally advanced esophageal cancer, for whom optimal treatment isn't clear. Trends in surgery and radiation for patients with T1-T3N1M0 squamous cell or adenocarcinoma of the mid or distal esophagus in the Surveillance, Epidemiology, and End Results database from 1998 to 2008 were analyzed using generalized linear models including year as predictor; Surveillance, Epidemiology, and End Results doesn't record chemotherapy data. Local treatment was unimodal if patients had only surgery or radiation and bimodal if they had both. Five-year cancer-specific survival (CSS) and overall survival (OS) were analyzed using propensity-score adjusted Cox proportional-hazard models. Overall 5-year survival for the 3295 patients identified (mean age 65.1 years, standard deviation 11.0) was 18.9% (95% confidence interval: 17.3-20.7). Local treatment was bimodal for 1274 (38.7%) and unimodal for 2021 (61.3%) patients; 1325 (40.2%) had radiation alone and 696 (21.1%) underwent only surgery. The use of bimodal therapy (32.8-42.5%, P = 0.01) and radiation alone (29.3-44.5%, P < 0.001) increased significantly from 1998 to 2008. Bimodal therapy predicted improved CSS (hazard ratios [HR]: 0.68, P < 0.001) and OS (HR: 0.58, P < 0.001) compared with unimodal therapy. For the first 7 months (before survival curve crossing), CSS after radiation therapy alone was similar to surgery alone (HR: 0.86, P = 0.12) while OS was worse for surgery only (HR: 0.70, P = 0.001). However, worse CSS (HR: 1.43, P < 0.001) and OS (HR: 1.46, P < 0.001) after that initial timeframe were found for radiation therapy only. The use of radiation to treat locally advanced mid and distal esophageal cancers increased from 1998 to 2008. Survival was best when both surgery and radiation were used. PMID- 23937255 TI - Histology core-specific evaluation of the European Society of Urogenital Radiology (ESUR) standardised scoring system of multiparametric magnetic resonance imaging (mpMRI) of the prostate. AB - OBJECTIVES: To evaluate the Prostate Imaging Reporting and Data System (PIRADS) in multiparametric magnetic resonance imaging (mpMRI) based on single cores and single-core histology. To calculate positive (PPV) and negative predictive values (NPV) of different modalities of mpMRI. PATIENTS AND METHODS: We performed MRI targeted transrectal ultrasound-guided perineal prostate biopsies on 50 patients (mean age 66 years, mean PSA level of 9.9 ng/mL) with suspicion of prostate cancer. The biopsy trajectories of every core taken were documented in three dimensions (3D) in a 3D-prostate model. Every core was evaluated separately for prostate cancer and the performed biopsy trajectories were projected on mpMRI images. PIRADS scores of 1177 cores were then assessed by a histology 'blinded' uro-radiologist in T2-weighted (T2W), dynamic contrast-enhanced (DCE), diffusion weighted imaging (DWI) and magnetic resonance spectroscopy (MRS). RESULTS: The PIRADS score was significantly higher in cores positive for cancer than in negative cores. There was a significant correlation between the PIRADS score and histopathology for every modality. Receiver operating characteristic (ROC) analysis showed excellent specificity for T2W (90% peripheral zone/97% transition zone) and DWI (98%/97%) images regardless of the prostate region observed. These numbers decreased for DCE (80%/93%) and MRS (76%/83%). All modalities had NPVs of 99%, if a PIRADS score threshold of 2 (for T2W, DCE, and MRS) or 3 (for DWI) was used. However, PPVs were low. CONCLUSIONS: Our results show that PIRADS scoring is feasible for clinical routine and allows standardised reporting. PIRADS can be used as a decision-support system for targeting of suspicious lesions. mpMRI has a high NPV for prostate cancer and, thus, might be a valuable tool in the initial diagnostic evaluation. PMID- 23937256 TI - A constrained tricyclic nucleic acid analogue of alpha-L-LNA: investigating the effects of dual conformational restriction on duplex thermal stability. AB - A constrained tricyclic analogue of alpha-L-LNA (2), which contains dual modes of conformational restriction about the ribose sugar moiety, has been synthesized and characterized by X-ray crystallography. Thermal denaturation experiments of oligonucleotide sequences containing this tricyclic alpha-L-LNA analogue (alpha-L TriNA 2, 5) indicate that this modification is moderately stabilizing when paired with complementary DNA and RNA, but less stabilizing than both alpha-L-LNA (2) and alpha-L-TriNA 1 (4). PMID- 23937257 TI - Early diagnosis of adenylosuccinate lyase deficiency using a high-throughput screening method and a trial of oral S-adenosyl-l-methionine as a treatment method. AB - AIM: The aim of this study was to develop a high-throughput urine screening technique for adenylosuccinate lyase (ADSL) deficiency and to evaluate S-adenosyl l-methionine (SAMe) as a potential treatment for this disorder. METHOD: Testing for succinyladenosine (S-Ado), a marker of ADSL deficiency, was incorporated into a screening panel for urine biomarkers for inborn errors of metabolism using electrospray tandem mass spectrometry. Liquid chromatography-mass spectrometry and high-performance liquid chromatography were used to confirm and monitor the response of metabolites to oral SAMe treatment. RESULTS: Increased levels of S Ado were detected in a 3-month-old male infant with hypotonia and seizures. ADSL gene sequencing revealed a previously described c.-49T>C mutation and a novel c.889_891dupAAT mutation, which was likely to disrupt enzyme function. After 9 months of SAMe treatment, there was no clear response evidenced in urine metabolite levels or clinical parameters. INTERPRETATION: These results demonstrate proof of the principle for the high-throughput urine screening technique, allowing earlier diagnosis of patients with ADSL deficiency. However, early treatment with SAMe does not appear to be effective in ADSL deficiency. It is suggested that although SAMe treatment may ameliorate purine nucleotide deficiency, it cannot correct metabolic syndromes in which a toxic nucleotide is present, in this case presumed to be succinylaminoimidazole carboxamide ribotide. PMID- 23937258 TI - Risk factors for dental caries in small rural and regional Australian communities. AB - INTRODUCTION: Dental decay (caries) can cause pain, infection and tooth loss, negatively affecting eating, speaking and general health. People living in rural and regional Australian communities have more caries, more severe caries and more untreated caries than those in the city. The unique environmental conditions and population groups in these communities may contribute to the higher caries burden. In particular, some towns lack community water fluoridation, and some have a high proportion of Aboriginal people, who have significantly worse oral health than their non-Aboriginal counterparts. Because of these and other unique circumstances, mainstream research on caries risk factors may not apply in these settings. This study aimed to gather contemporary oral health data from small rural or regional Australian communities, and investigate caries risk factors in these communities. METHODS: A cross-sectional survey consisting of a standardized dental examination and questionnaire was used to measure the oral health of 434 children (32% Aboriginal) aged 3-12 years in three small rural or regional areas. Oral health was determined as the deciduous and permanent decayed, missing and filled teeth (dmft/DMFT), and the proportion of children without caries. Risk factors were investigated by logistic regression. RESULTS: The dmft/DMFT for children in this study was 1.5 for 5-6 year olds and 1.0 for 11-12 year olds (index groups reported). Independent predictors of having caries (Yes/No) were age group, holding a concession card (OR=2.45, 95%CI=1.58-3.80) and tooth brushing less than twice per day (OR=2.11, 95% CI=1.34-3.34). Aboriginal status also became a significant variable under sensitivity analyses (OR 1.9, CI 1.12 3.24) when the tooth-brushing variable was removed. Gender, water fluoridation and parental education were not significant predictors of caries in these communities. CONCLUSIONS: The rural/remote children in this study had worse oral health than either state or national average in both the 5-6 year old and 11-12 year age group. Socioeconomic status, tooth-brushing and Aboriginal status were significantly associated with caries in these communities. To close the substantial gap in oral health outcomes between rural and metropolitan residents, approaches that target rural areas, Aboriginal people and those from low socioeconomic backgrounds are needed. PMID- 23937260 TI - Cellular immune dysfunction in immune thrombocytopenia (ITP). AB - Over the past decades, a wealth of information has been reported about the pathogenic features of immune thrombocytopenia (ITP). To this day, however, it is unclear whether the immune abnormalities associated with ITP play causative roles in the disease or are secondary epiphenomena brought on by the inflammatory processes that are associated with the disorder. Like the majority of all autoimmune diseases, ITP is an organ-specific disease and abnormalities in immune cell types, such as antigen-presenting cells (APC), T cells and B cells have been shown to play some sort of role in the initiation and/or perpetuation of the disease. This review will discuss recent advances in understanding three immune cells important in ITP pathophysiology: APC, T cells and B cells, and will review how they interact with each other to initiate and perpetuate ITP, particularly the chronic form of the disorder. It will also focus on new data related to the genetics of the disorder and discuss relevant animal models of ITP. PMID- 23937259 TI - Identification of protein phosphatase 1 as a regulator of the LRRK2 phosphorylation cycle. AB - A cluster of phosphorylation sites in LRRK2 (leucine-rich repeat kinase 2), including Ser910, Ser935, Ser955 and Ser973, is important for PD (Parkinson's disease) pathogenesis as several PD-linked LRRK2 mutants are dephosphorylated at these sites. LRRK2 is also dephosphorylated in cells after pharmacological inhibition of its kinase activity, which is currently proposed as a strategy for disease-modifying PD therapy. Despite this importance of LRRK2 dephosphorylation in mutant LRRK2 pathological mechanism(s) and in LRRK2's response to inhibition, the mechanism by which this occurs is unknown. Therefore we aimed to identify the phosphatase for LRRK2. Using a panel of recombinant phosphatases, we found that PP1 (protein phosphatase 1) efficiently dephosphorylates LRRK2 in vitro. PP1 activity on LRRK2 dephosphorylation was confirmed in cells using PP1 inhibition to reverse LRRK2 dephosphorylation induced by the potent LRRK2 kinase inhibitor LRRK2-IN1 as well as in R1441G mutant LRRK2. We also found that PP1 and LRRK2 can form a complex in cells. Furthermore, we observed that PP1 inhibition modulates LRRK2's cellular phenotype by reducing skein-like LRRK2-positive structures associated with dephosphorylation. In conclusion, the present study reveals PP1 as the physiological LRRK2 phosphatase, responsible for LRRK2 dephosphorylation observed in PD mutant LRRK2 and after LRRK2 kinase inhibition. PMID- 23937261 TI - Diagnostic value and cost-benefit analysis of 24 hours ambulatory blood pressure monitoring in primary care in Portugal. AB - BACKGROUND: Hypertensive patients (HTs) are usually attended in primary care (PC). We aimed to assess the diagnostic accuracy and cost-benefit ratio of 24 hour ambulatory blood pressure monitoring (ABPM) in all newly diagnosed hypertensive patients (HTs) attended in PC. METHODS: In a cross-sectional study ABPM was recorded in all 336 never treated HTs (Office BP >=140 and/or >= 90 mm Hg) that were admitted during 16 months. Since benefits from drug treatment in white-coat hypertension (WCH) remain unproven, a cost benefit estimation of a general use of ABPM (vs absence of ABPM) in HTs was calculated comparing the cost of usual medical assistance of HTs only diagnosed in office with that based both on refraining from drug treatment all subjects identified as WCH and on the reduction by half of the frequency of biochemical exams and doctor visits. RESULTS: Women were 56%, age 51 +/- 14 years and BMI 27 +/- 4 Kg/m2. Out of these, 206 were considered as true HTs, daytime ABPM >= 135 and/or >=85 mm Hg and 130 (38,7%) were identified as having white coat hypertension (WCH), daytime ABPM <135/85 mm Hg. Versus HTs, WCH group showed higher percentage of women (68% vs 51%) and lower values of an index composed by the association of cardiovascular risk factors. We estimated that with ABPM total medical expenses can be reduced by 23% (157.500 euros) with a strategy based on ABPM for 1000 patients followed for 2 years. CONCLUSIONS: In PC, the widespread use of ABPM in newly diagnosed HTs increases diagnostic accuracy of hypertension, improves cardiovascular risk stratification, reduces health expenses showing a highly favourable benefit-cost ratio vs a strategy without ABPM. PMID- 23937262 TI - Microbiota in experimental periodontitis and peri-implantitis in dogs. AB - AIM: To analyze the microbial profile around teeth and implants following ligature removal in experimental periodontitis and peri-implantitis in dogs. MATERIAL AND METHODS: Four implants with similar geometry and with two different surface characteristics (implant A: turned/implant B: TiUnite; NobelBiocare AB) were placed pairwise in the right side of the mandible 3 months after tooth extraction in five dogs. Experimental periodontitis and peri-implantitis were initiated 3 months later by ligature placement around implants and mandibular premolars and plaque formation. The ligatures were removed after 10 weeks. Microbial samples were obtained using paper points immediately after ligature removal, at 10 and 25 weeks after ligature removal. The microbiological analysis was performed by "checkerboard" DNA-DNA hybridization, including a panel of 16 bacterial species. RESULTS: The amount of bone loss that occurred during the period following ligature removal was significantly larger at implants with a modified surface than at implants with a turned surface and at teeth. The microbiological analysis revealed that the total bacterial load increased during the period following ligature removal and established an anaerobic Gram-negative microflora. CONCLUSION: It is suggested that the large variation in regard to the microbial profiles makes interpretation of a correlation between disease progression and microbial profiles difficult. PMID- 23937263 TI - The effect of insertional suspensory branch desmitis on racing performance in juvenile Thoroughbred racehorses. AB - REASONS FOR PERFORMING THE STUDY: Limited information exists regarding the prognosis for juvenile racehorses sustaining injury to the suspensory ligament branch insertion (JISBI). OBJECTIVES: To investigate the effect of JISBI on racing performance; and to assess whether the severity of JISBI is prognostically important. STUDY DESIGN: Retrospective cohort study. METHODS: Records were reviewed for 896 juvenile Thoroughbreds in training, to identify horses with JISBI limited to one branch (cases). The ability of cases to start a race was compared to their cohorts. Race records of maternal siblings were compared to cases. RESULTS: The prevalence of JISBI for this population was 9.5%. Cohorts were 3.2 times more likely to start as a 2-year-old and 3.6 times more likely to start as a 3-year-old compared to horses with JISBI. Of 58 cases that were compared to maternal siblings, the total earnings per start (EPS), 2- and 3-year old EPS were all reduced (P<0.01). Cases raced a mean of 3.8 times compared to 7.4 races for controls over the study period and were 113.2 days older by the time of first start (P<0.01). 'Speed figures' and EPS were, however, similar between cases that had raced and controls. Cases with a moderate-severe lesion (>= Grade 2) were at significantly greater risk of reinjury than mild cases (P<0.05). CONCLUSIONS: JISBI causes decreased racing ability as a 2-year-old. Mild cases perform similarly to controls by their 3-year-old season, but more severe cases demonstrate reduced ability as a 3-year-old, with an increased likelihood of reinjury. Although the wastage was higher in case horses with JISBI, individual cases that make it to a race have similar earnings per start as their controls. PMID- 23937264 TI - Synthesis and biophysical properties of constrained D-altritol nucleic acids (cANA). AB - The first synthesis of constrained altritol nucleic acids (cANA) containing antisense oligonucleotides (ASOs) was carried out to ascertain how conformationally restricting the D-altritol backbone-containing ASO (Me-ANA) would affect their ability to form duplexes with RNA. It was found that the thermal stability was reduced (cANA/RNA -1.1 degrees C/modification) compared to DNA/RNA, suggesting the constrained system results in a small destabilizing perturbation in the duplex structure. PMID- 23937266 TI - Pathological characteristics of patients who develop hepatocellular carcinoma with negative results of both serous hepatitis B surface antigen and hepatitis C virus antibody. AB - AIM: We tried to characterize the pathological features of patients who developed hepatocellular carcinoma (HCC) with the negative results of both serous hepatitis B surface antigen and hepatitis C virus antibody (non-B, non-C). METHODS: In a multicenter study in Kyushu, Japan, we studied the histopathological characteristics of non-cancerous liver tissues in 129 patients (103 men and 26 women) with non-B, non-C HCC. The histological liver damage was evaluated for fibrosis (stage) and inflammation (grade) according to the Ludwig classification of chronic hepatitis. In addition, we examined the hepatitis B virus (HBV) genome in serum samples and liver tissues of 20 patients with non-B, non-C HCC. RESULTS: Positivity of serum hepatitis B core (HBc) antibody, alcohol abuse, diabetes and non-alcoholic steatohepatitis were present in 61 (47%), 76 (59%), 57 (44%) and eight (6%) patients, respectively. The degree of fibrosis was mild (stage 1.6 +/- 1.2). The stage of patients with neither serum HBc antibody nor alcohol abuse was significantly lower than the stage of patients with HBc antibody and no alcohol abuse (P < 0.05). HBV genome was detected in 15 cancerous tissues (75%) and 16 non-cancerous liver tissues (80%) in 20 patients with non-B, non-C HCC. Only three of the 20 patients were positive for serum HBc antibody. CONCLUSION: Non-B, non-C patients appear to develop HCC at a low stage of fibrosis. Occult hepatitis B virus infection is the major risk factor for HCC of non-B, non-C patients in Kyushu, Japan. PMID- 23937265 TI - Noninvasive imaging of hypoxia-inducible factor-1alpha gene therapy for myocardial ischemia. AB - Hypoxia-inducible factor-1 alpha (HIF-1alpha) gene therapy holds great promise for the treatment of myocardial ischemia. Both preclinical and clinical evaluations of this therapy are underway and can benefit from a vector strategy that allows noninvasive assessment of HIF-1alpha expression as an objective measure of gene delivery. We have developed a novel bidirectional plasmid vector (pcTnT-HIF-1alpha-VP2-TSTA-fluc), which employs the cardiac troponin T (cTnT) promoter in conjunction with a two-step transcriptional amplification (TSTA) system to drive the linked expression of a recombinant HIF-1alpha gene (HIF 1alpha-VP2) and the firefly luciferase gene (fluc). The firefly luciferase (FLuc) activity serves as a surrogate for HIF-1alpha-VP2 expression, and can be noninvasively assessed in mice using bioluminescence imaging after vector delivery. Transfection of cultured HL-1 cardiomyocytes with pcTnT-HIF-1alpha-VP2 TSTA-fluc led to a strong correlation between FLuc and HIF-1alpha-dependent vascular endothelial growth factor expression (r(2)=0.88). Intramyocardial delivery of pcTnT-HIF-1alpha-VP2-TSTA-fluc into infarcted mouse myocardium led to persistent HIF-1alpha-VP2 expression for 4 weeks, even though it improved neither CD31+ microvessel density nor echocardiographically determined left ventricular systolic function. These results lend support to recent findings of suboptimal efficacy associated with plasmid-mediated HIF-1alpha therapy. The imaging techniques developed herein should be useful for further optimizing HIF-1alpha VP2 therapy in preclinical models of myocardial ischemia. PMID- 23937267 TI - Uterine preservation surgery for placental polyp. AB - AIM: To examine clinical and surgical performances of cases with placental polyps in which uterine preservation surgery was conducted. METHODS: During the period September 2002 to April 2009, we examined eight cases (hysteroscopic resection, six cases; laparotomy, one case; dilatation and curettage, one case) diagnosed with placental polyp that had been treated with polyp extraction surgery. Imaging evaluation was done using magnetic resonance imaging and 2-D ultrasound. RESULTS: Three of the eight cases (37.5%) had been first-time pregnancies. Most of our cases experienced minimal surgical manipulation after medical abortion. Among them, six cases (75%) were mid-term medical abortions, one case (12.5%) received no treatment after spontaneous abortion, and one case (12.5%) had postsurgical abortion (dilatation and curettage). All cases showed variable amount of blood flow in the internal mass and myometrium by color Doppler ultrasound. Magnetic resonance imaging angiography showed contrast effects in the intrauterine cavity and myometrium in selected cases. The average duration from diagnosis to surgery was 32 days (range, 11-105). Color Doppler revealed a reduction in blood flow in five cases during the waiting period until surgery with an average blood loss of 10 g (range, 0-20) during surgery. CONCLUSION: Use of color Doppler ultrasound may be useful in diagnosing placental polyp. Although hysteroscopic resection of placental polyp is effective in patients hoping for uterine preservation, delaying timing of surgery may reduce blood loss during operative procedure. PMID- 23937269 TI - Synthesis, structure, and magnetic properties of bithiophene- and terthiophene linked manganese metal-organic frameworks. AB - A series of metal-organic frameworks (MOFs) containing manganese centers and oligothiophene dicarboxylate linkers have been synthesized: [Mn(3PhT2DC)(DMF)0.45(H2O)2.55.1.55DMF]n (1), [Mn6(3HT2DC)6(DMF)3(H2O)5.xDMF.yH2O]n (2), [Mn(T3DC)(H2O)2]n (3), [Mn(T3DC)(H2O)1.5]n (4), and [Mn(Ph2T3DC)(DMF)2]n (5) (H23PhT2DC = 3,3'-diphenyl 2,2-bithiophene-5,5'-dicarboxylic acid; H23HT2DC= 3,3'-dihexyl-2,2'-bithiophene 5,5'-dicarboxylic acid; H2T3DC = 2,2':5',2"-terthiophene-5,5"-dicarboxylic acid; H2Ph2T3DC = 3',4'-diphenyl-2,2':5',2"-terthiophene-5,5"-dicarboxylic acid, DMF = N,N-dimethylformamide). Compound 1 exists as a 2D sheet, 2-4 are 3D frameworks, and 5 is a 1D chain. Compounds 3 and 4 are isomers, and 3-5 are the first examples of crystallographically characterized terthiophene coordination polymers. In the case of 1, 2, and 5, the extended structure is sensitive to beta substitution of the oligothiophene linkers. Compounds 1-3 and 5 show antiferromagnetic behavior with typical values of g and J, and 3 exhibits a spin canting transition at 40 K. PMID- 23937268 TI - A simple methodology to assess endolysosomal protease activity involved in antigen processing in human primary cells. AB - BACKGROUND: Endolysosomes play a key role in maintaining the homeostasis of the cell. They are made of a complex set of proteins that degrade lipids, proteins and sugars. Studies involving endolysosome contribution to cellular functions such as MHC class I and II epitope production have used recombinant endolysosomal proteins, knockout mice that lack one of the enzymes or purified organelles from human tissue. Each of these approaches has some caveats in analyzing endolysosomal enzyme functions. RESULTS: In this study, we have developed a simple methodology to assess endolysosomal protease activity. By varying the pH in crude lysate from human peripheral blood mononuclear cells (PBMCs), we documented increased endolysosomal cathepsin activity in acidic conditions. Using this new method, we showed that the degradation of HIV peptides in low pH extracts analyzed by mass spectrometry followed similar kinetics and degradation patterns as those performed with purified endolysosomes. CONCLUSION: By using crude lysate in the place of purified organelles this method will be a quick and useful tool to assess endolysosomal protease activities in primary cells of limited availability. This quick method will especially be useful to screen peptide susceptibility to degradation in endolysosomal compartments for antigen processing studies, following which detailed analysis using purified organelles may be used to study specific peptides. PMID- 23937270 TI - Traumatic brain injury in rats induces lung injury and systemic immune suppression. AB - Traumatic brain injury (TBI) is frequently complicated by acute lung injury, which is predictive for poor outcome. However, it is unclear whether lung injury develops independently or as a result of mechanical ventilation after TBI. Further, TBI is strongly associated with the development of pneumonia, suggesting a specific vulnerability for the development of nosocomial infections in the lung after TBI. In this study, we evaluated whether indeed pulmonary injury and immune suppression develop spontaneously in an animal model of mild TBI (mTBI). TBI was induced in male PVG rats by closed-head trauma using a weight-drop device. Subsequently, we evaluated the effects of this on the lungs as well as on the excitability of the systemic immune system. Finally, we performed an experiment in which TBI was followed by induction of pneumonitis and evaluated whether TBI affects the severity of subsequent pneumonitis induced by intratracheal instillation of heat-killed Staphylococcus aureus. mTBI resulted in significant lung injury, as evidenced by pulmonary edema, protein leakage to the alveolar compartment, and increased concentrations of interleukin-1 and -6 in broncho alveolar lavage fluid (all p<0.05 vs. sham-treated animals). Further, after TBI, the release of tumor necrosis factor alpha was decreased when whole blood was stimulated ex vivo (p<0.05 TBI vs. sham), indicating systemic immune suppression. When TBI was followed by pneumonitis, the severity of subsequent pneumonitis was not different in rats previously subjected to TBI or sham treatment (p>0.05), suggesting that systemic immune suppression is not translated toward the pulmonary compartment in this specific model. We here show that during mild experimental TBI, acute pulmonary injury, as well as a decrease in the excitability of the systemic immune system, can be observed. PMID- 23937271 TI - Comparison between on-demand dosing of dapoxetine alone and dapoxetine plus mirodenafil in patients with lifelong premature ejaculation: prospective, randomized, double-blind, placebo-controlled, multicenter study. AB - INTRODUCTION: There is partial evidence to support the use of phophodiesterase-5 inhibitor (PDE5-I) for the treatment of premature ejaculation (PE). AIM: We compared on-demand dosing of dapoxetine alone and combined with mirodenafil in subjects with lifelong PE and without erectile dysfunction (ED). METHODS: Our prospective, randomized, double-blind, placebo-controlled, multicenter trial enrolled 118 subjects with lifelong PE without ED. PE was diagnosed using Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision. Patients were divided into two groups: dapoxetine 30 mg plus placebo (group A, n=56) and dapoxetine 30 mg plus mirodenafil 50 mg (group B, n=62). MAIN OUTCOME MEASURES: During 12 weeks, intravaginal ejaculatory latency time (IELT) and the time from foreplay to beginning intercourse (FTIT) with a stopwatch, and Premature Ejaculation Profile (PEP) were measured. Overall sexual act time (OSAT; sum of FTIT and IELT) was calculated. Any treatment-emergent adverse events (TEAEs) were also recorded. RESULTS: Over 12 weeks, IELT, OSAT, and PEP index score significantly improved in group B compared with group A (increased geometric mean IELT in group A and B=3.6 and 6.1 minutes, P=0.026; increased geometric mean OSAT in group A and B=5.5 and 9.9 minutes, P=0.012; increased median PEP index score in group A and B=1.0 and 1.3, P=0.046). However, there was no significant difference between two groups with respect to improvement of FTIT (P=0.147). TEAEs did not differ between groups (all P>0.05), and there was no serious adverse event in any subjects. CONCLUSIONS: Low dose of dapoxetine combined with mirodenafil showed better results in terms of IELT, OSAT, and PEP index score, and similar TEAEs, compared with that of dapoxetine only. Our results support the suggestion that the PDE5-Is have a potential role in the treatment of PE without ED. PMID- 23937272 TI - Hierarchical NiCo2O4@NiCo2O4 core/shell nanoflake arrays as high-performance supercapacitor materials. AB - Hierarchical NiCo2O4@NiCo2O4 core/shell nanoflake arrays on nickel foam for high performance supercapacitors are fabricated by a two-step solution-based method which involves in hydrothermal process and chemical bath deposition. Compared with the bare NiCo2O4 nanoflake arrays, the core/shell electrode displays better pseudocapacitive behaviors in 2 M KOH, which exhibits high areal specific capacitances of 1.55 F cm(-2) at 2 mA cm(-2) and 1.16 F cm(-2) at 40 mA cm(-2) before activation as well as excellent cycling stability. The specific capacitance can achieve a maximum of 2.20 F cm(-2) at a current density of 5 mA cm(-2), which can still retain 2.17 F cm(-2) (98.6% retention) after 4000 cycles. The enhanced pseudocapacitive performances are mainly attributed to its unique core/shell structure, which provides fast ion and electron transfer, a large number of active sites, and good strain accommodation. PMID- 23937273 TI - Echocardiographically measured epicardial fat predicts restenosis after coronary stenting. AB - OBJECTIVE: Epicardial adipose tissue (EAT), deposited around subepicardial coronary vessels, may contribute directly to perivascular inflammation and smooth muscle cell proliferation. This study assessed the relationship between EAT and in-stent restenosis. METHODS: Four hundred and seven patients had received successful coronary intervention. EAT thickness was measured by echocardiography. Angiographic follow-up was obtained between 6 months and 2 years. Restenosis was defined as target lesion revascularization (TLR). EAT thickness of patients was compared by TLR controlling for additional well-known predictors of restenosis. The TLR-free survival analysis according to EAT thickness was estimated using the Kaplan-Meier method and the differences between groups were assessed by the log rank test. RESULTS: Median EAT thickness was significantly increased in patients undergoing TLR compared with those without restenosis (3.7 vs. 3.0 mm, p = 0.001). EAT thickness was one of the independent factors associated with restenosis (Odds ratio = 1.19, 95% confidence interval = 1.01-1.33, p = 0.007). The TLR-free survival of patients with thick EAT was significantly worse than patients with thin EAT (log-rank p = 0.001). CONCLUSIONS: EAT thickness is related with restenosis and may provide additional information for future restenosis. PMID- 23937274 TI - Dynamics of Polycomb chromatin domains under conditions of increased molecular crowding. AB - BACKGROUND INFORMATION: A Polycomb (PcG) body is an orphan nuclear subcompartment characterised by accumulations of Polycomb repressive complex 1 (PRC1) proteins. However, seemingly contradictory reports have appeared that describe the PcG bodies either as protein-based bodies in the interchromatin compartment or chromatin domains. In this respect, molecular crowding is an important factor for the assembly and stability of nuclear subcompartments. In order to settle this contradiction, crowding experiments, that represent a convenient model distinguishing between interchromatin and chromatin compartments, were carried out. RESULTS: In sucrose-hypertonically induced crowding, we observed in U-2 OS cells that PcG bodies disappeared, but persisted as nuclear domains characterised by accumulations of DNA. This phenomenon was also observed in cells hypertonically treated with sorbitol and NaCl. Importantly, the observed changes were quickly reversible after re-incubation of cells in normal medium. We found that the PcG foci disappearance and the dissociation of PRC1 proteins (BMI1 and RING1a proteins) from chromatin were associated with their hyper-phosphorylation. In addition, under hyper- and hypotonic conditions, the behaviour of the PcG bodies differed from that of the typical nucleoplasmic body. CONCLUSION: PRC1 proteins accumulations do not represent a genuine nuclear subcompartment. The PcG body is a chromosomal domain, rather than a nucleoplasmic body. PMID- 23937275 TI - Ab initio study of molecular interactions in cellulose Ialpha. AB - Biomass recalcitrance, the resistance of cellulosic biomass to degradation, is due in part to the stability of the hydrogen bond network and stacking forces between the polysaccharide chains in cellulose microfibers. The fragment molecular orbital (FMO) method at the correlated Moller-Plesset second order perturbation level of theory was used on a model of the crystalline cellulose Ialpha core with a total of 144 glucose units. These computations show that the intersheet chain interactions are stronger than the intrasheet chain interactions for the crystalline structure, while they are more similar to each other for a relaxed structure. An FMO chain pair interaction energy decomposition analysis for both the crystal and relaxed structures reveals an intricate interplay between electrostatic, dispersion, charge transfer, and exchange repulsion effects. The role of the primary alcohol groups in stabilizing the interchain hydrogen bond network in the inner sheet of the crystal and relaxed structures of cellulose Ialpha, where edge effects are absent, was analyzed. The maximum attractive intrasheet interaction is observed for the GT-TG residue pair with one intrasheet hydrogen bond, suggesting that the relative orientation of the residues is as important as the hydrogen bond network in strengthening the interaction between the residues. PMID- 23937276 TI - Chronic cough management: dealing with a sensation of irritation in the throat. AB - Among the various types of laryngeal paraesthesia suffered by chronic cough patients, we often encounter 'a sensation of irritation in the throat (SIT)'. Our study indicated that capsaicin cough threshold was significantly (P < 0.05) lower in the SIT-positive group (13.9 MUmol/L) than in the SIT-negative group (49.6 MUmol/L). The establishment of treatment strategies for SIT would be advantageous for treating chronic cough patients suffering from this laryngeal sensation. PMID- 23937277 TI - Ki67 is an independent predictor of oncological outcomes in patients with localized clear-cell renal cell carcinoma. AB - OBJECTIVE: To validate the impact of Ki67 expression on oncological outcomes of patients treated for clinically localized clear-cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: Immunohistochemistry for Ki67 was performed on tissue microarray constructs of patients treated with radical or partial nephrectomy for clinically localized (M0) ccRCC and Ki67 expression >10% was considered abnormal. Clinical and pathological data elements were entered into an institutional review board-approved database. The Kaplan-Meier method and Cox regression models were used to analyse disease-free survival (DFS) and cancer specific survival (CSS) probabilities. RESULTS: Of 401 patients, 59.6% were males. The median (range) age was 58 (17-85) years, follow-up was 22 (0-150) months and time to death was 27 (0-150) months. A total of 20.2% of patients had advanced stage (pT3-T4) and 31% had advanced grade (3-4) disease. Abnormal expression of Ki67 was seen in 6.5% of our cohort and was associated with adverse pathological features (P < 0.05). Patients with high expression of Ki67 were found to have 5-year DFS and CSS rates of 67 and 84%, respectively, vs 87 and 95%, respectively, in those with normal expression (P < 0.001 and P < 0.05, respectively). In multivariable analyses, adjusting for stage and grade, abnormal Ki67 expression was an independent predictor of DFS (hazard ratio [HR] 3.77, P = 0.011, 95% confidence interval [CI] 1.35-10.52), but not of CSS (HR 3.51 P = 0.137, 95% CI 0.671-18.35). CONCLUSIONS: Our findings support the role of Ki67 as a powerful independent predictor of inferior oncological outcomes in patients with ccRCC. Further prospective studies are needed to determine the clinical applicability of these findings. PMID- 23937278 TI - Combined oral contraceptives affect liver mitochondrial activity. AB - OBJECTIVES: To examine liver mitochondrial function in women using combined oral contraceptives (COCs) containing ethinylestradiol. METHODS: A breath test after oral administration of 1 mg/kg (13)C-alpha-ketoisocaproic acid ((13)C-KICA) and 20 mg/kg L-leucine was performed twice: (i) in 15 women on day 14, 15, 16, 17 or 18 of COC intake, and between day 1 and 5 of the withdrawal bleeding; and (ii) in 15 regularly menstruating females not taking hormonal contraceptives: during the luteal phase, between the 18th and the 22nd day of the cycle, and again between day 1 and 5 of the menstruation. RESULTS: In women on COCs the maximum (13)C elimination in breath air (Dmax) was higher (26.8 +/- 1.6%/h) than during withdrawal bleeding (23.5 +/- 1.2%/h; p = 0.012). The time to reach the Dmax was similar on the two study days: 33.3 +/- 2.4 min during the phase of pill intake vs. 37.0 +/- 2.5 min during the pill-free interval. The one-hour cumulative breath (13)C elimination was greater after two weeks of COC intake than during the withdrawal bleeding: 17.49 +/- 1.03% vs. 15.32 +/- 0.85% (p = 0.024). In the control group no menstrual cycle phase-dependent fluctuations in the results of the (13)C-KICA breath test were observed. CONCLUSION: The metabolism of (13)C alpha-ketoisocaproic acid augments during the intake of COCs containing ethinylestradiol, reflecting enhanced liver mitochondrial metabolic activity. PMID- 23937280 TI - Synthesis of cis- and trans-alpha-l-[4.3.0]bicyclo-DNA monomers for antisense technology: methods for the diastereoselective formation of bicyclic nucleosides. AB - Two alpha-L-ribo-configured bicyclic nucleic acid modifications, represented by analogues 12 and 13, which are epimeric at C3' and C5' have been synthesized using a carbohydrate-based approach to build the bicyclic core structure. An intramolecular L-proline-mediated aldol reaction was employed to generate the cis configured ring junction of analogue 12 and represents a rare application of this venerable organocatalytic reaction to a carbohydrate system. In the case of analogue 13, where a trans-ring junction was desired, an intermolecular diastereoselective Grignard reaction followed by ring-closing metathesis was used. In order to set the desired stereochemistry at the C5' positions of both nucleoside targets, a study of diastereoselective Lewis acid mediated allylation reactions on a common bicyclic aldehyde precursor was carried out. Analogue 12 was incorporated in oligonucleotide sequences, and thermal denaturation experiments indicate that it is destabilizing when paired with complementary DNA and RNA. However, this construct shows a significant improvement in nuclease stability relative to a DNA oligonucleotide. PMID- 23937279 TI - Adsorbed fibrinogen enhances production of bone- and angiogenic-related factors by monocytes/macrophages. AB - Macrophages are phagocytic cells with great importance in guiding multiple stages of inflammation and tissue repair. By producing a large number of biologically active molecules, they can affect the behavior of other cells and events, such as the foreign body response and angiogenesis. Since protein adsorption to biomaterials is crucial for the inflammatory process, we addressed the ability of the pro-inflammatory molecule fibrinogen (Fg) to modulate macrophage behavior toward tissue repair/regeneration. For this purpose, we used chitosan (Ch) as a substrate for Fg adsorption. Freshly isolated human monocytes were seeded on Ch substrates alone or previously adsorbed with Fg, and allowed to differentiate into macrophages for 10 days. Cell adhesion and morphology, formation of foreign body giant cells (FBGC), and secretion of a total of 80 cytokines and growth factors were evaluated. Both substrates showed similar numbers of adherent macrophages along differentiation as compared with RGD-coated surfaces, which were used as positive controls. Fg did not potentiate FBGC formation. In addition, actin cytoskeleton staining revealed the presence of punctuate F-actin with more elongated and interconnecting cells on Ch substrates. Antibody array screening and quantification of inflammation- and wound-healing-related factors indicated an overall reduction in Ch-based substrates versus RGD-coated surfaces. At late times, most inflammatory agents were down-regulated in the presence of Fg, in contrast to growth factor production, which was stimulated by Fg. Importantly, on Ch+Fg substrates, fully differentiated macrophages produced significant amounts of macrophage inflammatory protein-1delta (MIP-1delta), platelet-derived growth factor-BB, bone morphogenetic protein (BMP)-5, and BMP-7 compared with Ch alone. In addition, other important factors involved in bone homeostasis and wound healing, such as growth hormone, transforming growth factor beta3, and insulin-like growth factor-binding proteins, as well as several angiogenic mediators, including endocrine gland-derived vascular endothelial factor, fibroblast growth factor-7, and placental growth factor, were significantly promoted by Fg. This work provides a new perspective on the inflammatory response in the context of bone repair/regeneration mediated by a pro-inflammatory protein (Fg) adsorbed onto a biomaterial (Ch) that does not otherwise exhibit osteogenic properties. PMID- 23937281 TI - Abstracts of the 50th Annual Meeting of the Spanish League against Epilepsy (LECE). PMID- 23937282 TI - Equivalency of tricyclic antidepressants in open-label neuropathic pain study. AB - OBJECTIVES: To compare adverse effects, tolerability and efficacy of the tricyclic antidepressants (TCAs) amitriptyline and nortriptyline in management of neuropathic pain due to peripheral neuropathy (PN). MATERIALS & METHODS: We performed a prospective open-label flexible-dosing comparison of monotherapy or adjuvant therapy using amitriptyline or nortriptyline in PN-associated neuropathic pain. Primary outcomes were quantitative adverse effects and discontinuation rates. Secondary outcomes assessed changes in pain severity, quality of life, disability, sleep efficacy, mood and anxiety, and global improvement. Assessments occurred at 3 and 6 months after initiation. Our hypothesis was that nortriptyline would have better tolerance than amitriptyline. RESULTS: A total of 228 PN patients were enrolled approximately equally for monotherapy and adjuvant therapy. Adverse effects and discontinuation rates were similar between amitriptyline and nortriptyline interventions. Weight gain was more common with amitriptyline, while nortriptyline use was associated with greater prevalence of dry mouth. Secondary outcome measures were similar in both groups, demonstrating improvement from baseline. CONCLUSIONS: Amitriptyline and nortriptyline are equivalent for overall adverse effects and discontinuation rates. Either TCA should be equally considered for use in neuropathic pain due to PN. When used as monotherapy or as part of adjuvant therapy, either TCA can be expected to provide approximately 23-26% visual analog scale pain reduction if tolerated. Discontinuations due to inefficacy or adverse effects can be anticipated in 26-37% of patients initiated on either TCA for PN-associated neuropathic pain. PMID- 23937284 TI - Body image, body dissatisfaction and weight status in children from Emilia Romagna (Italy): comparison between immigrant and native-born. AB - BACKGROUND: Cross-sectional study among immigrant and native children from Emilia Romagna (Italy). AIM: The purpose of the present study was to examine the relative contribution of weight status, ethnicity and sex on body dissatisfaction in a sample of children from Emilia-Romagna (Italy). SUBJECTS AND METHODS: Primary school children (226 immigrants and 1206 Italians) aged 6-11 years were measured: immigrant children were divided into Asians, Africans, Latin Americans and East Europeans. Height and weight were measured and Body Mass Index (BMI) was calculated. Body image perception was assessed using Body Silhouette Charts. A body dissatisfaction score (BDS) was derived by subtracting the "ideal self" from the "self" score. RESULTS: Weight status disorders were higher in immigrants than in native-born males; Italian females had higher prevalence of underweight and overweight and lower prevalence of obesity than immigrants peers. BDS rose with the increase of weight status categories. CONCLUSIONS: Awareness of body image size and increasing body dissatisfaction with higher weight status is established in childhood, regardless of ethnicity and gender. PMID- 23937285 TI - What do child daycare center teachers know about atopic dermatitis? AB - Atopic dermatitis (AD) is the most common childhood inflammatory skin disorder. The purpose of this study was to elucidate the knowledge level of daycare center teachers about AD and related factors. Study subjects were 297 teachers (287 female, 10 male) from 20 randomly selected daycare centers in Istanbul. The knowledge level of teachers was assessed using a questionnaire with 21 questions about AD. The teachers were asked nine additional questions about demographic and other characteristics of the child care centers and about themselves. The mean age of the teachers was 26.4 +/- 8.1 years (range 20-53 yrs). The mean score for the 21 questions was 71.4 +/- 12.1 (68%) from a maximum of 105 points. The response rate of teachers rate for each question ranged from 54% to 90%. The completely true response rate for each question ranged from 3.0% to 66.7%. The knowledge level of the teachers was related to the number of children in the daycare center, but not to sex, age, education level, family history of atopy, teacher's monthly salary, location, or whether the daycare center was public or private. Although teachers in daycare centers have some knowledge about AD, widespread educational programs for teachers about AD may help to improve the understanding of the disease and the quality of life of affected children in daycare centers. PMID- 23937286 TI - Clinical use of new oral anticoagulant drugs: dabigatran and rivaroxaban. AB - Orally active small molecules that selectively and specifically inhibit coagulation serine proteases have been developed for clinical use. For some patients these oral direct inhibitors (ODIs) offer substantial benefits over oral vitamin K antagonists (VKA). However, for the majority of patients with good anticoagulant control with VKAs the advantages of the ODIs are primarily convenience and few drug interactions. The drugs are prescribed at fixed dose without the need for monitoring or dose adjustment in the majority of patients and the rapid onset of anticoagulation and short half-life make initiation and interruption of anticoagulation considerably easier than with VKAs. As yet, specific antidotes to ODIs are not available for clinical use but these are in development as rapid reversal agents. As with all anticoagulants produced so far, there is a correlation between intensity of anticoagulation and bleeding. Consequently, the need to consider the balance of benefit and risk in each individual patient is no less important than with VKA therapy. Dabigatran and rivaroxaban have been chosen for this review as examples of a thrombin inhibitor and an inhibitor of factor Xa respectively. The clinical application of these drugs is the focus of the review. PMID- 23937287 TI - A systematic review on marginal bone loss around short dental implants (<10 mm) for implant-supported fixed prostheses. AB - PURPOSE: This systematic review aimed to evaluate the effect of implant length on peri-implant marginal bone loss (MBL) and its associated influencing factors. MATERIAL AND METHODS: An electronic search of the PubMed and MEDLINE databases for relevant studies published in English from November 2006 to July 2012 was performed by one examiner (AM). Selected studies were randomized clinical trials, human experimental clinical trials or prospective studies (e.g., cohort as well as case series) with a clear aim of investigating marginal bone loss of short dental implants (<10 mm) supporting fixed prostheses. A random-effect meta regression model was used to determine the relationship between the effect size mean MBL and the covariate "implant length." Additionally, a subgroup analysis, by means of a random-effect one-way ANOVA model, comparing mean MBL values at different levels of each factor ("type of connection" and "type of prostheses") was also performed. RESULTS: The meta-regression of mean MBL on the moderator "implant length" was found to be insignificant (P = 0.633). Therefore, it could not be concluded that implant length had an effect on peri-implant MBL. In addition, standardized differences in mean MBL on the subgroups short (<10 mm) and standard (>= 10 mm) implants, as determined by the meta-analysis (random effect model), were found to be statistically insignificant (P = 0.222). CONCLUSIONS: Within limitations of the present systematic review, it could be concluded that short dental implants (<10 mm) had similar peri-implant MBL as standard implants (>= 10 mm) for implant-supported fixed prostheses. PMID- 23937288 TI - Emulating the logic of monoterpenoid alkaloid biogenesis to access a skeletally diverse chemical library. AB - We have developed a synthetic strategy that mimics the diversity-generating power of monoterpenoid indole alkaloid biosynthesis. Our general approach goes beyond diversification of a single natural product-like substructure and enables production of a highly diverse collection of small molecules. The reaction sequence begins with rapid and highly modular assembly of the tetracyclic indoloquinolizidine core, which can be chemoselectively processed into several additional skeletally diverse structural frameworks. The general utility of this approach was demonstrated by parallel synthesis of two representative chemical libraries containing 847 compounds with favorable physicochemical properties to enable its subsequent broad pharmacological evaluation. PMID- 23937289 TI - Cervical perforation by the strings of a levonorgestrel releasing-intrauterine system: a case report. AB - A very rare case of perforation of the uterine cervix by the strings of a levonorgestrel releasing-intrauterine system (LNG-IUS) in a 47-year-old woman is presented. The method to retrieve the strings back into the cervical canal, leaving the LNG-IUS in situ, is described. We suggest that the threads of an intrauterine contraceptive occasionally may penetrate tissue like setons do, when used for treatment of fistulae. PMID- 23937290 TI - Do the symptoms of bipolar disorder really show seasonal variation? PMID- 23937292 TI - Vulvar pseudoepitheliomatous hyperplasia associated with herpes simplex virus type II mimicking cancer in an immunocompromised patient. AB - We report an exaggerated dermatological inflammatory condition in an immunocompromised patient. The patient was a 51-year-old woman who had HIV infection and a history of cervical cancer. Three years after highly active antiretroviral therapy with an improved immune status, and 2 years after remission of cervical cancer, she developed verrucous perineal masses. Provisional diagnosis was recurrent cervical cancer or primary vulvar cancer. Pathological features revealed pseudoepitheliomatous hyperplasia associated with herpes viral infection. After minimal response to systemic oral antiviral drugs and topical imiquimod, she had clinical resolution with the addition of systemic oral corticosteroid. PMID- 23937291 TI - Tropisetron attenuates amyloid-beta-induced inflammatory and apoptotic responses in rats. AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder featured by deposition of beta-amyloid (Abeta) plaques in the hippocampus and associated cortices and progressive cognitive decline. Tropisetron, a selective 5-HT3 receptor antagonist, is conventionally used to counteract chemotherapy-induced emesis. Recent investigations describe antiphlogistic properties for tropisetron. It has been shown that tropisetron protects against rat embolic stroke. We investigated protective properties of tropisetron in a beta-amyloid (Abeta) rat model of AD and possible involvement of 5-HT3 receptors. MATERIAL AND METHODS: Abeta (1-42) was injected into the hippocampus of male rats. Animals were treated intracerebroventricularly with tropisetron, mCPBG (selective 5-HT3 receptor agonist) or mCPBG plus tropisetron on days 1, 3, 5 and 7. Seven days following Abeta administration, inflammatory markers (TNF-alpha, COX-2, iNOS and NF kappaB), apoptotic markers (caspase 3 cytochrome c release) and calcineurin phosphatase activity were assessed in hippocampus. RESULTS: Seven days following Abeta inoculation, control animals displayed dramatic increase in TNF-alpha, COX 2, iNOS, NF-kappaB, active caspase 3, cytochrome c release and calcineurin phosphatase activity in the hippocampus. Tropisetron significantly diminished the elevated levels of these markers and reversed the cognitive deficit. Interestingly, tropisetron was also found to be a potent inhibitor of calcineurin phosphatase activity. The selective 5-HT3 receptor agonist mCPBG, when co administered with tropisetron, completely reversed the procognitive and anti apoptotic properties of tropisetron while it could only partially counteract the anti-inflammatory effects. mCPBG alone significantly aggravated Abeta-induced injury. CONCLUSION: Our findings indicate that tropisetron protects against Abeta induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and independent pathways. PMID- 23937293 TI - PTC bitter taste genetic polymorphism, food choices, physical growth in body height and body fat related traits among adolescent girls from Kangra Valley, Himachal Pradesh (India). AB - BACKGROUND: Bitter sensitivity among individuals and ethnic groups is partly due to polymorphic bitter taste receptor genes (TAS2Rs). PTC/PROP bitter taste responsiveness at locus TAS2R38 is a well-established index of individual variation in oral sensation that has been linked with predicting food liking and consumption. Previous studies suggest that the relationship between PTC/PROP and anthropometric traits remains controversial. OBJECTIVES: To explore the role of TAS2R38 locus in taste choices, adolescent growth trend for body height, weight and fat patterning among girls and to evaluate their growth status. MATERIALS AND METHODS: Cross-sectional data on 210 girls ranging in age from 11-18 years were collected from Palampur in the Kangra valley of Himachal Pradesh. RESULTS: The proportion of PTC non-tasters was 19.52%. PTC tasters and non-tasters had some differences in their food choices and preferences. More sensitive PTC tasters had a low preference for raw cruciferous vegetables and bitter tasting foods (like bitter gourd) and beverages, while they had higher preference for sweet-tasting foods (p < 0.05). PTC tasters overtook their PTC non-taster counterparts from age 14 through 16 years in having higher mean average skinfold, percentage body fat, fat mass index and fat-free mass index. PTC non-tasters had higher mean stature than tasters through all age groups. PTC tasters had slightly higher mean body weight than tasters at age 11, but in later years the advantage was lost; the total gain among non-tasters through adolescence was higher (78.20%) than tasters (66.92%). PTC thresholds significantly and negatively correlated with body height. CONCLUSIONS: TAS2R38 locus seems to have a role in food tastes, choices and preferences. Perceived bitterness of PTC/PROP thresholds were significantly and negatively correlated with body height and fat-free mass. These results, thus, tentatively suggest that the PTC non-taster gene may help in better absorption of calcium than its counter taster allele. Studies on differences in calcium metabolism between PTC tasters and non-tasters are needed to confirm these indications across cultures. PMID- 23937295 TI - Olfactory dysfunction in sporadic Parkinson's Disease and LRRK2 carriers. AB - OBJECTIVE: The aim of the study was to examine the sense of smell in LRRK2 mutation carriers and in patients with sporadic PD (sPD). MATERIALS AND METHODS: A total of 343 individuals were included: 275 sPD of whom 90 were de novo patients with sPD, 17 LRRK2 PD, 36 healthy LRRK2 mutation carriers, and 15 healthy family members without mutation. All subjects underwent neurologic examination and olfactory sense testing with B-SIT (a 12-item test). Linear regression analysis was applied to build different models with B-SIT as dependent variable. RESULTS: Sporadic PD had significantly lower scores in olfaction compared with LRRK2 PD (P < 0.001). B-SIT scores were lowest in medicated sPD, and higher scores were found in de novo patients. LRRK2 PD had similar sense of smell to healthy LRRK2 mutation carriers and to healthy family members without mutation when adjusting for age. CONCLUSION: Hyposmia was pronounced already at time of diagnosis in the sPD cases but was not present in healthy LRRK2 mutation carriers and less pronounced in LRRK2 PD compared with sporadic cases. Smell testing may be a preclinical marker in sporadic PD but does not seem applicable in LRRK2 cases. PMID- 23937294 TI - The role of Zic transcription factors in regulating hindbrain retinoic acid signaling. AB - BACKGROUND: The reiterated architecture of cranial motor neurons aligns with the segmented structure of the embryonic vertebrate hindbrain. Anterior-posterior identity of cranial motor neurons depends, in part, on retinoic acid signaling levels. The early vertebrate embryo maintains a balance between retinoic acid synthetic and degradative zones on the basis of reciprocal expression domains of the retinoic acid synthesis gene aldhehyde dehydrogenase 1a2 (aldh1a2) posteriorly and the oxidative gene cytochrome p450 type 26a1 (cyp26a1) in the forebrain, midbrain, and anterior hindbrain. RESULTS: This manuscript investigates the role of zinc finger of the cerebellum (zic) transcription factors in regulating levels of retinoic acid and differentiation of cranial motor neurons. Depletion of zebrafish Zic2a and Zic2b results in a strong downregulation of aldh1a2 expression and a concomitant reduction in activity of a retinoid-dependent transgene. The vagal motor neuron phenotype caused by loss of Zic2a/2b mimics a depletion of Aldh1a2 and is rescued by exogenously supplied retinoic acid. CONCLUSION: Zic transcription factors function in patterning hindbrain motor neurons through their regulation of embryonic retinoic acid signaling. PMID- 23937296 TI - Degradation of organic/organic interfaces in organic light-emitting devices due to polaron-exciton interactions. AB - We study the stability of common hole transport material/electron transport material (HTM/ETM) interfaces present in typical organic light-emitting devices (OLEDs) under various stress scenarios. We determined that these interfaces degrade rapidly, because of an interaction between HTM positive polarons and HTM singlet excitons. The phenomenon results in a deterioration in conduction across the interface, and contributes to the commonly observed increase in OLED driving voltage with electrical driving time. This interfacial degradation can be slowed if the exciton lifetime becomes shorter. The findings uncover a new degradation mechanism that is interfacial in nature, which affects organic/organic interfaces in OLEDs and contributes to their limited electroluminescence stability, and shed light on approaches for reducing it. Although this study has focused on OLEDs, we can expect the same degradation mechanism to affect organic/organic interfaces in other organic optoelectronic devices where both excitons and polarons are present in high concentrations, such as in organic solar cells or photodetectors. PMID- 23937297 TI - Discourse-based intervention for modifying supervisory communication as leverage for safety climate and performance improvement: a randomized field study. AB - The article presents a randomized field study designed to improve safety climate and resultant safety performance by modifying daily messages in supervisor-member communications. Supervisors in the experimental group received 2 individualized feedback sessions regarding the extent to which they integrated safety and productivity-related issues in daily verbal exchanges with their members; those in the control group received no feedback. Feedback data originated from 7-9 workers for each supervisor, reporting about received supervisory messages during the most recent verbal exchange. Questionnaire data collected 8 weeks before and after the 12-week intervention phase revealed significant changes for safety climate, safety behavior, subjective workload, teamwork, and (independently measured) safety audit scores for the experimental group. Data for the control group (except for safety behavior) remained unchanged. These results are explained by corresponding changes (or lack thereof in the control group) in perceived discourse messages during the 6-week period between the 1st and 2nd feedback sessions. Theoretical and practical implications for climate improvement and organizational discourse research are discussed. PMID- 23937298 TI - Do candidate reactions relate to job performance or affect criterion-related validity? A multistudy investigation of relations among reactions, selection test scores, and job performance. AB - Considerable evidence suggests that how candidates react to selection procedures can affect their test performance and their attitudes toward the hiring organization (e.g., recommending the firm to others). However, very few studies of candidate reactions have examined one of the outcomes organizations care most about: job performance. We attempt to address this gap by developing and testing a conceptual framework that delineates whether and how candidate reactions might influence job performance. We accomplish this objective using data from 4 studies (total N = 6,480), 6 selection procedures (personality tests, job knowledge tests, cognitive ability tests, work samples, situational judgment tests, and a selection inventory), 5 key candidate reactions (anxiety, motivation, belief in tests, self-efficacy, and procedural justice), 2 contexts (industry and education), 3 continents (North America, South America, and Europe), 2 study designs (predictive and concurrent), and 4 occupational areas (medical, sales, customer service, and technological). Consistent with previous research, candidate reactions were related to test scores, and test scores were related to job performance. Further, there was some evidence that reactions affected performance indirectly through their influence on test scores. Finally, in no cases did candidate reactions affect the prediction of job performance by increasing or decreasing the criterion-related validity of test scores. Implications of these findings and avenues for future research are discussed. PMID- 23937299 TI - Political skill: explaining the effects of nonnative accent on managerial hiring and entrepreneurial investment decisions. AB - We propose and test a new theory explaining glass-ceiling bias against nonnative speakers as driven by perceptions that nonnative speakers have weak political skill. Although nonnative accent is a complex signal, its effects on assessments of the speakers' political skill are something that speakers can actively mitigate; this makes it an important bias to understand. In Study 1, White and Asian nonnative speakers using the same scripted responses as native speakers were found to be significantly less likely to be recommended for a middle management position, and this bias was fully mediated by assessments of their political skill. The alternative explanations of race, communication skill, and collaborative skill were nonsignificant. In Study 2, entrepreneurial start-up pitches from national high-technology, new-venture funding competitions were shown to experienced executive MBA students. Nonnative speakers were found to have a significantly lower likelihood of receiving new-venture funding, and this was fully mediated by the coders' assessments of their political skill. The entrepreneurs' race, communication skill, and collaborative skill had no effect. We discuss the value of empirically testing various posited reasons for glass ceiling biases, how the importance and ambiguity of political skill for executive success serve as an ostensibly meritocratic cover for nonnative speaker bias, and other theoretical and practical implications of this work. PMID- 23937300 TI - Expectation-maximization of the potential of mean force and diffusion coefficient in Langevin dynamics from single molecule FRET data photon by photon. AB - The dynamics of a protein along a well-defined coordinate can be formally projected onto the form of an overdamped Lagevin equation. Here, we present a comprehensive statistical-learning framework for simultaneously quantifying the deterministic force (the potential of mean force, PMF) and the stochastic force (characterized by the diffusion coefficient, D) from single-molecule Forster-type resonance energy transfer (smFRET) experiments. The likelihood functional of the Langevin parameters, PMF and D, is expressed by a path integral of the latent smFRET distance that follows Langevin dynamics and realized by the donor and the acceptor photon emissions. The solution is made possible by an eigen decomposition of the time-symmetrized form of the corresponding Fokker-Planck equation coupled with photon statistics. To extract the Langevin parameters from photon arrival time data, we advance the expectation-maximization algorithm in statistical learning, originally developed for and mostly used in discrete-state systems, to a general form in the continuous space that allows for a variational calculus on the continuous PMF function. We also introduce the regularization of the solution space in this Bayesian inference based on a maximum trajectory entropy principle. We use a highly nontrivial example with realistically simulated smFRET data to illustrate the application of this new method. PMID- 23937301 TI - A simple modification for a longer and larger internal thoracic artery as a composite Y-graft. AB - OBJECTIVES: Coronary artery bypass grafting (CABG) using bilateral internal thoracic artery (BITA) has been proven to improve survival. Many surgeons use the composite Y-graft which is made of left ITA (LITA) and right ITA (RITA) grafts. The LITA is typically anastomosed to left anterior descending artery (LAD). However, we have used RITA for LAD instead of LITA and reviewed the patency of ITA grafts and their clinical outcomes. METHODS: We analyzed 48 patients who underwent CABG using a BITA composite Y-graft from 2002 to 2012. In 30, LITA was anastomosed to LAD (Group L). The other 18 had RITA to LAD anastomosis (Group R). RESULTS: The mean age of Group R was higher than that of Group L (p = 0.009). Postoperative angiography was performed in 35 patients (73%). Two patients in Group L and none of the patients in Group R had an ITA graft failure. The incidence of ITA graft failure and new adverse cardiovascular events were not different between the two groups. CONCLUSION: The clinical outcome of RITA to LAD anastomosis is comparable with anastomosis of LITA to LAD in CABG using BITA composite Y-grafts. This technique may be useful when longer and larger ITA grafts are needed. PMID- 23937302 TI - "Rescue" ablation of electrical storm in arrhythmogenic right ventricular cardiomyopathy in pregnancy. AB - BACKGROUND: Radiofrequency ablation (RFCA) became a treatment of choice in patients with recurrent ventricular tachycardia, ventricular fibrillation, and appropriate interventions of implanted cardioverter-defibrillator (ICD), however, electrical storm (ES) ablation in a pregnant woman has not yet been reported. CASE PRESENTATION: We describe a case of a successful rescue ablation of recurrent ES in a 26-year-old Caucasian woman during her first pregnancy (23rd week). The arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) was diagnosed 3 years earlier and several drugs as well as 2 ablations failed to control recurrences of ventricular tachycardia. RFCA was performed on the day of the third electric storm. The use of electroanatomic mapping allowed very low X ray exposure, and after applications in the right ventricular outflow tract, arrhythmia disappeared. Three months after ablation, a healthy girl was delivered without any complications. During twelve-month follow-up there was no recurrence of ventricular tachycardia or ICD interventions. CONCLUSIONS: This case documents the first successful RFCA during ES due to recurrent unstable ventricular arrhythmias in a patient with ARVD/C in pregnancy. Current guidelines recommend metoprolol, sotalol and intravenous amiodarone for prevention of recurrent ventricular tachycardia in pregnancy, however, RFCA should be considered as a therapeutic option in selected cases. The use of 3D navigating system and near zero X-ray approach is associated with minimal radiation exposure for mother and fetus as well as low risk of procedural complication. PMID- 23937303 TI - Resection of glioma in an fMRI-defined "split" Broca's area. AB - Gross total resection of gliomas can be limited by the involvement of tumor in eloquent areas. Moreover, lesions can impart cortical reorganization and make the precise determination of hemispheric dominance and localization of language function even more difficult. Preoperative mapping with functional magnetic resonance imaging (fMRI), intraoperative imaging modalities, and intraoperative direct cortical stimulation enable surgeons to map the functional topography of the brain in relation to the tumor and perform a safe maximal resection. In this report, we present a patient with left frontal glioma of complex morphology, wherein the tumor was enveloped by Broca's area on fMRI. Intraoperative mapping and intraoperative magnetic resonance imaging (iMRI) allowed gross total resection of the tumor with preservation of language function and illustrate the utility of multiple contemporary modalities in the surgical management of low grade gliomas located in eloquent cortices. PMID- 23937304 TI - Thyroid hormone-induced hypertrophy in mesenchymal stem cell chondrogenesis is mediated by bone morphogenetic protein-4. AB - Chondrogenic differentiating mesenchymal stem cells (MSCs) express markers of hypertrophic growth plate chondrocytes. As hypertrophic cartilage undergoes ossification, this is a concern for the application of MSCs in articular cartilage tissue engineering. To identify mechanisms that elicit this phenomenon, we used an in vitro hypertrophy model of chondrifying MSCs for differential gene expression analysis and functional experiments with the focus on bone morphogenetic protein (BMP) signaling. Hypertrophy was induced in chondrogenic MSC pellet cultures by transforming growth factor beta (TGFbeta) and dexamethasone withdrawal and addition of triiodothyronine. Differential gene expression analysis of BMPs and their receptors was performed. Based on these results, the in vitro hypertrophy model was used to investigate the effect of recombinant BMP4 and the BMP inhibitor Noggin. The enhancement of hypertrophy could be shown clearly by an increased cell size, alkaline phosphatase activity, and collagen type X deposition. Upon induction of hypertrophy, BMP4 and the BMP receptor 1B were upregulated. Addition of BMP4 further enhanced hypertrophy in the absence, but not in the presence of TGFbeta and dexamethasone. Thyroid hormone induced hypertrophy by upregulation of BMP4 and this induced enhancement of hypertrophy could be blocked by the BMP antagonist Noggin. BMP signaling is an important modulator of the late differentiation stages in MSC chondrogenesis and the thyroid hormone induces this pathway. As cartilage tissue engineering constructs will be exposed to this factor in vivo, this study provides important insight into the biology of MSC-based cartilage. Furthermore, the possibility to engineer hypertrophic cartilage may be helpful for critical bone defect repair. PMID- 23937305 TI - Validation of association of genetic variants at 10q with prostate-specific antigen (PSA) levels in men at high risk for prostate cancer. AB - OBJECTIVE: To validate six previously identified markers among men at increased risk of prostate cancer (African-American men and those with a family history of prostate cancer) enrolled in the Prostate Cancer Risk Assessment Program (PRAP), a prostate cancer screening study. PATIENTS AND METHODS: Eligibility criteria for PRAP include age 35-69 years with a family history of prostate cancer, African American ethnicity regardless of family history, and known BRCA gene mutations. The genome-wide association study markers assessed included rs2736098 (5p15.33), rs10993994 (10q11), rs10788160 (10q26), rs11067228 (12q24), rs4430796 (17q12) and rs17632542 (19q13.33). Genotyping methods included either the Taqman((r)) single nucleotide polymorphism (SNP) genotyping assay (Applied Biosystems, Foster City, CA, USA) or pyrosequencing. Linear regression models were used to evaluate the association between individual markers and log-transformed baseline PSA levels, while adjusting for potential confounders. RESULTS: A total of 707 participants (37% Caucasian, 63% African-American) with clinical and genotype data were included in the analysis. Rs10788160 (10q26) was strongly associated with PSA levels among Caucasian participants in the high-risk group (P < 0.01), with a 33.2% increase in PSA level with each A-allele carried. Furthermore, rs10993994 (10q11) was found to be associated with PSA level (P = 0.03) in Caucasian men in the high-risk group, with a 15% increase in PSA level with each T-allele carried. A PSA adjustment model based on allele carrier status at rs10788160 and rs10993994 was proposed, specific to high-risk Caucasian men. CONCLUSIONS: Genetic variation at 10q may be particularly important in personalizing the interpretation of PSA level for Caucasian men in the high-risk group. Such information may have clinical relevance in shared decision-making and individualized prostate cancer screening strategies for Caucasian men in the high risk group, although further study is warranted. PMID- 23937306 TI - A randomized controlled clinical trial to evaluate a new xenograft for alveolar socket preservation. AB - OBJECTIVE: The aim of this clinical trial was to compare the effect of Bio Oss((r)) and a new bovine xenograft (Osseus((r)) ) in alveolar sockets after a 24 week healing period. MATERIALS AND METHODS: A total of 20 adult volunteers ages 30-60 were subjected to single tooth extraction. A tooth extraction was performed at the baseline. All sites were randomly allocated to two test groups (TG1: grafted using a new bovine xenograft, Osseus((r)) , and TG2: grafted using commercially available bovine xenograft-Bio-Oss((r)) ). Six months later, a sample of the grafted area was obtained and implants were inserted in the same site. Histological sections were examined focusing on the presence of fibrous connective tissue (CT), and newly formed bone in direct contact with the graft. The HE-stained sections were subjected to histomorphometrical evaluation using Image Pro-Plus((r)) software (Release 7.0). The definitive crown was placed 3 months later. RESULTS: Upon completion of the study, no patients were removed from the study and all inserted implants (10 in each group) were eventually integrated. After 6 months, in the TG1, the mean value of new bone formation was 33.7 (+/- 7.1), for CT was 32.3 (+/- 8.9) and for the remaining biomaterial was 10.7 (+/- 16.2). In the TG2, the mean value of new bone formation was 19.3 (+/- 22.6), of the CT was 49.9 (+/- 14.1) and of the remaining biomaterial was 22.6 (+/- 7.9). CONCLUSIONS: No statistically significant difference was observed between TG1 and TG2 after 6 months (P > 0.05), and both biomaterials afforded a more favorable implant position. PMID- 23937307 TI - Structural coupling of extrinsic proteins with the oxygen-evolving center in red algal photosystem II as revealed by light-induced FTIR difference spectroscopy. AB - Effects of binding of extrinsic proteins (PsbO, PsbQ', PsbV, and PsbU) on the structure of the oxygen-evolving center (OEC) in photosystem II core complexes from a red alga, Cyanidium caldarium, were studied using Fourier transform infrared (FTIR) spectroscopy. S2-minus-S1 FTIR difference spectra showed that the protein conformations of the OEC, revealed by the changes in amide I and II bands, were significantly altered upon depletion of all the extrinsic proteins, but mostly recovered when PsbV was rebound with the support of other extrinsic proteins. The recovery of protein conformations correlated well with O2 evolution activity. This PsbV function of retaining a proper OEC conformation in red algae resembles that of PsbP in higher plants reported previously. PMID- 23937308 TI - X-ray absorption spectroscopy proves the trigonal-planar sulfur-only coordination of copper(I) with high-affinity tripodal pseudopeptides. AB - A series of tripodal ligands L derived from nitrilotriacetic acid (NTA) and extended by three converging metal-binding cysteine chains were previously found to bind selectively copper(I) both in vitro and in vivo. The ligands L(1) (ester) and L(2) (amide) were demonstrated to form copper(I) species with very high affinities, close to that reported for the metal-sequestering metallothioneins (MTs; log K(Cu-MT) ~ 19). Here, an in-depth study by Cu K-edge X-ray absorption spectroscopy (XAS) was performed to completely characterize the copper(I) coordination sphere in the complexes, previously evidenced by other physicochemical analyses. The X-ray absorption near-edge structure (XANES) spectra shed light on the equilibrium between a mononuclear complex and a cluster for both L(1) (ester) and L(2) (amide). The exclusive symmetric CuS3 geometry adopted in the mononuclear complexes (Cu-S ~ 2.23 A) was clearly demonstrated by extended X-ray absorption fine structure (EXAFS) analyses. The EXAFS analyses also proved that the clusters are organized on a symmetric CuS3 core (Cu-S ~ 2.26 A) and interact with three nearby copper atoms (Cu---Cu ~ 2.7 A), consistent with the Cu6S9-type clusters previously characterized by pulsed gradient spin echo NMR spectroscopy. XAS data obtained for other architectures based on the NTA template (L(3) acid, L(4) without a functionalized carbonyl group, etc.) demonstrated the formation of polymetallic species only, which evidence the necessity of the proximal ester or amide group to stabilize the CuS3 mononuclear species. Finally, XAS was demonstrated to be a powerful method to quantify the equilibrium between the two copper(I) environments evidenced with L(1) and L(2) at different copper concentrations and to determine the equilibrium constants between these two complexes. PMID- 23937309 TI - Does male circumcision affect sexual function, sensitivity, or satisfaction?--a systematic review. AB - INTRODUCTION: Circumcision of males is commonly carried out worldwide for reasons of health, medical need, esthetics, tradition, or religion. Whether circumcision impairs or improves male sexual function or pleasure is controversial. AIMS: The study aims to conduct a systematic review of the scientific literature. METHODS: A systematic review of published articles retrieved using keyword searches of the PubMed, EMBASE, and Cochrane databases was performed. MAIN OUTCOME MEASURES: The main outcome measure is the assessment of findings in publications reporting original data relevant to the search terms and rating of quality of each study based on established criteria. RESULTS: Searches identified 2,675 publications describing the effects of male circumcision on aspects of male sexual function, sensitivity, sensation, or satisfaction. Of these, 36 met our inclusion criteria of containing original data. Those studies reported a total of 40,473 men, including 19,542 uncircumcised and 20,931 circumcised. Rated by the Scottish Intercollegiate Guidelines Network grading system, 2 were 1++ (high quality randomized controlled trials) and 34 were case-control or cohort studies (11 high quality: 2++; 10 well-conducted: 2+; 13 low quality: 2-). The 1++, 2++, and 2+ studies uniformly found that circumcision had no overall adverse effect on penile sensitivity, sexual arousal, sexual sensation, erectile function, premature ejaculation, ejaculatory latency, orgasm difficulties, sexual satisfaction, pleasure, or pain during penetration. Support for these conclusions was provided by a meta-analysis. Impairment in one or more parameters was reported in 10 of the 13 studies rated as 2-. These lower-quality studies contained flaws in study design (11), selection of cases and/or controls (5), statistical analysis (4), and/or data interpretation (6); five had multiple problems. CONCLUSION: The highest-quality studies suggest that medical male circumcision has no adverse effect on sexual function, sensitivity, sexual sensation, or satisfaction. PMID- 23937310 TI - Clofarabine in combination with pegylated asparaginase in the frontline treatment of childhood acute lymphoblastic leukaemia: a feasibility report from the CoALL 08-09 trial. AB - Clofarabine was the latest new drug to be approved, in 2004, for relapsed or refractory acute lymphoblastic leukaemia (ALL). To investigate its value in the frontline treatment of ALL we applied clofarabine 5 * 40 mg/m(2) in combination with pegylated asparaginase (PEG-ASP) 1 * 2500 iu/m(2) in high risk ALL patients as a novel post-induction element in the German Co-operative Study Group for treatment of ALL (CoALL) trial 08-09. Newly diagnosed ALL patients, defined by a significant minimal residual disease (MRD) load at the end of induction (B progenitor ALL at day 29 >= 10(-4) and T-ALL at day 43 >= 10(-3) ) were eligible for this phase II trial. All other patients received the standard treatment consisting of high-dose cytarabine (HIDAC) 4 * 3 g/m2 in combination with Peg-ASP 2500 iu/m2. Forty-two patients (39 B-progenitor; 3 T-ALL) fulfilled the criteria, were stratified and received the clofarabine/PEG-ASP treatment resulting in 24/39 (61%) MRD-negative B-progenitor patients compared to 18/39 (46%) after HIDAC/PEG ASP in CoALL 07-03. Overall, the toxicity profile of clofarabine/PEG-ASP was similar to HIDAC/PEG-ASP without unexpected severe side effects. Clofarabine combined with PEG-ASP is safe and effective in the frontline treatment of ALL. A prospective, randomized trial is warranted to evaluate the antileukaemic efficacy of clofarabine versus HIDAC combined with PEG-ASP. PMID- 23937311 TI - The severity of individual obstruction events is related to increased mortality rate in severe obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is linked to an increased mortality rate. However, the severity of individual obstruction events is rarely considered quantitatively in clinical practice. We hypothesized that OSA with especially severe obstruction events would predispose a patient to greater health risks than OSA with a similar apnea-hypopnea index (AHI), but lower severity of individual events. This hypothesis was tested in a follow-up (198.2 +/- 24.7 months) of a population of 1068 men referred for ambulatory polygraphic recording due to suspected OSA. The recordings were analysed according to the guidelines of the American Academy of Sleep Medicine. Furthermore, a novel obstruction severity parameter was determined; this was defined as the product of duration of the individual obstruction event and area of the related desaturation event. Patients treated with continuous positive airway pressure (CPAP) were omitted. We identified 125 deceased patients from our original population and for 113 of these a matching alive patient with similar AHI, age, body mass index (BMI), smoking habits and follow-up time could be found. The deceased patients with severe OSA (based on conventional AHI) showed higher obstruction severity values than their AHI matched alive controls. Based on the multivariate logistic regression analysis, obstruction severity was the only parameter which was related statistically significantly to mortality in the severe OSA category. Furthermore, 59% of all deceased patients and 83% of those who had severe OSA displayed higher obstruction severity than the AHI-matched alive counterparts. To conclude, the obstruction severity parameter provided valuable prognostic information supplementing AHI. The obstruction severity parameter might improve recognition of the patients with the highest risk. PMID- 23937312 TI - Theoretical investigation of the reaction mechanism of ClONO2 + HCl -> HNO3 + Cl2 on (H2O)n (n = 0-3) cluster. AB - Hydrated chlorine nitrate and hydrogen chloride ClONO2.HCl.(H2O)n (n = 0-3) clusters were investigated by using the MP2/aug-cc-pVTZ level of theory to clarify the reaction mechanism of Cl2 production. Isomeric stable structures found in n = 2 and 3 clusters have equivalent binding energies and the reaction barrier drastically decreases to be 2.1 kcal/mol at n = 3. The plausible reaction pathways were proposed according to calculated structures and energies, where the zero-point-energy corrections are important to determine the energy profiles of reactions especially for the n = 3 cluster. The kinetic analysis using the transition state theory suggested that the reaction rate constant from the original reactants to the product of n = 3 is 1.8 * 10(5) times larger than that of n = 2 cluster. Even though the small amount of the molar concentration of HCl(H2O)3 is obtained, the overall reaction rate of the trihydrate reaction is still 35 times faster than that of the dihydrate. PMID- 23937313 TI - Antidepressant tolerability in anxious and depressed youth at high risk for bipolar disorder: a prospective naturalistic treatment study. AB - OBJECTIVE: Depressive and anxiety disorders are common in youth who are at risk for bipolar disorder (i.e., youth who have at least one parent with bipolar disorder) and antidepressants are commonly prescribed as treatment. However, there are few data regarding the safety and tolerability of antidepressants in this population. Therefore, we sought to prospectively examine the effects of these medications in children and adolescents who are diagnosed with depressive or anxiety disorders and have a parent with bipolar I disorder. METHODS: Youth aged 9-20 years, with at least one parent with bipolar I disorder [high risk (HR)], were recruited (n = 118) and assessed using semi-structured diagnostic interviews. Participants were prospectively evaluated using a modified version of the Longitudinal Interval Follow-up Evaluation to assess changes in affective and anxiety symptoms and were treated naturalistically. RESULTS: Over the course of 43-227 weeks (mean duration of follow-up: 106 +/- 55 weeks), 21% (n = 25) of youth had antidepressant exposure and, of these, 57% (n = 12) had an adverse reaction (e.g., irritability, aggression, impulsivity, or hyperactivity) that led to antidepressant discontinuation. Those patients who experienced an adverse reaction were significantly younger than those who did not (p = 0.02) and discontinuation of antidepressant therapy secondary to an adverse event occurred at an average of 16.7 +/- 17.4 weeks (median: 11 weeks, range: 2-57 weeks). Cox proportional hazard analyses yielded a hazard ratio of 0.725 (p = 0.03), suggesting that there is a 27% decrease in the likelihood of an antidepressant related adverse event leading to discontinuation with each one-year increase in age. CONCLUSIONS: Antidepressant medications may be poorly tolerated in youth with a familial risk for developing mania. Controlled studies further assessing treatments for depression and anxiety in HR youth are urgently needed. PMID- 23937314 TI - Emerging drugs for eosinophilic esophagitis. AB - INTRODUCTION: Eosinophilic esophagitis (EoE) has emerged over the past two decades as an important esophageal disorder with significant associated morbidity. The prevalence of EoE now approximates that of commonly recognized gastrointestinal diseases including inflammatory bowel disease. In adults, EoE is now a leading cause of dysphagia and food impaction. Medications, food elimination diets and esophageal dilation are currently utilized for the treatment of EoE. While these approaches are often effective, no pharmaceutical agents have yet been approved by the Food and Drug Administration (FDA). The current medical therapies for EoE primarily consist of topical corticosteroids that have been adopted from formulations designed for pulmonary delivery in patients with asthma and have not been optimized for esophageal delivery. AREAS COVERED: This article focuses on therapeutics being developed for EoE. Several trials have evaluated improved steroid vehicles designed for topical delivery to the esophagus. Novel biologic compounds, including anti-interleukin-5 and anti interleukin-13, are being evaluated as targeted treatment options in EoE patients. Inhibitors of mast cell-derived prostaglandin D2 (PGD2) are also being studied, based on the concept that mast cells play an important role in EoE pathogenesis. Additional therapies, including immunomodulators, leukotriene antagonists, allergy immunotherapy and angiotensin II receptor blockers, are also examined in this article. EXPERT OPINION: No FDA-approved prescription medications are currently available for EoE patients. Although a number of novel agents are being developed and tested, Phase III clinical trials are scarce. Since EoE is a newly described disease, physicians have an incomplete understanding of the disease's pathogenesis, natural history and disease manifestations. This has led to significant difficulties in determining the most appropriate endpoints of therapy. Clinical trials are hampered by the lack of an accepted, standardized disease activity measure or biomarker by which therapeutic efficacy is assessed. Effective and approved pharmaceutical therapies are eagerly awaited by both physicians and patients for this increasingly recognized and clinically important disease. PMID- 23937315 TI - Parallelization of MODFLOW using a GPU library. AB - A new method based on a graphics processing unit (GPU) library is proposed in the paper to parallelize MODFLOW. Two programs, GetAb_CG and CG_GPU, have been developed to reorganize the equations in MODFLOW and solve them with the GPU library. Experimental tests using the NVIDIA Tesla C1060 show that a 1.6- to 10.6 fold speedup can be achieved for models with more than 10(5) cells. The efficiency can be further improved by using up-to-date GPU devices. PMID- 23937316 TI - Reading comprehension and its underlying components in second-language learners: A meta-analysis of studies comparing first- and second-language learners. AB - We report a systematic meta-analytic review of studies comparing reading comprehension and its underlying components (language comprehension, decoding, and phonological awareness) in first- and second-language learners. The review included 82 studies, and 576 effect sizes were calculated for reading comprehension and underlying components. Key findings were that, compared to first-language learners, second-language learners display a medium-sized deficit in reading comprehension (pooled effect size d = -0.62), a large deficit in language comprehension (pooled effect size d = -1.12), but only small differences in phonological awareness (pooled effect size d = -0.08) and decoding (pooled effect size d = -0.12). A moderator analysis showed that characteristics related to the type of reading comprehension test reliably explained the variation in the differences in reading comprehension between first- and second-language learners. For language comprehension, studies of samples from low socioeconomic backgrounds and samples where only the first language was used at home generated the largest group differences in favor of first-language learners. Test characteristics and study origin reliably contributed to the variations between the studies of language comprehension. For decoding, Canadian studies showed group differences in favor of second-language learners, whereas the opposite was the case for U.S. studies. Regarding implications, unless specific decoding problems are detected, interventions that aim to ameliorate reading comprehension problems among second language learners should focus on language comprehension skills. PMID- 23937317 TI - Relative dose intensity in early stage breast cancer chemotherapy: A retrospective analysis of incidence, risk factors and outcomes at a south-west Sydney cancer clinic. AB - AIM: In early stage breast cancer chemotherapy relative dose intensity (RDI) of <85% leads to poorer outcomes. This study assesses what proportion of such patients at a south-west Sydney cancer clinic received optimal RDI and the reasons and risk factors contributing to RDI reduction, as well as comparing survival outcomes. METHODS: A retrospective analysis of 308 patients treated with adjuvant chemotherapy for early stage breast cancer at the Macarthur Cancer Centre was undertaken, with an overall RDI calculated for each patient. The study analysed reasons for reductions in RDI as well as predictive factors for reduced RDI and overall and disease-free survival. RESULTS: Mean RDI was 92%. Of the participants, 17% had an RDI less than 85%, 55% received 100% RDI. Hematological toxicity, infection and patient choice were the most common reasons for RDI reduction. Body surface area capping (BSA) was the most common cause of initial dose reduction. Obesity, increasing body mass index and age >=65 years were risk factors for RDI reduction. Disease-free and overall survival were reduced with RDI < 50%; overall survival decreased when RDI < 65%. CONCLUSION: Most patients attained the RDI benchmark; however dose intensity reducing events occurred frequently. Despite contrary recommendations in the literature, BSA capping and dose reduction due to patient choice were common. Implementation of focused patient and physician education strategies may improve these results, as could measures directed as supporting those at risk (i.e. elderly or obese). PMID- 23937318 TI - OnabotulinumtoxinA significantly attenuates bladder afferent nerve firing and inhibits ATP release from the urothelium. AB - OBJECTIVE: To investigate the direct effect of onabotulinumtoxinA (OnaBotA) on bladder afferent nerve activity and release of ATP and acetylcholine (ACh) from the urothelium. MATERIALS AND METHODS: Bladder afferent nerve activity was recorded using an in vitro mouse preparation enabling simultaneous recordings of afferent nerve firing and intravesical pressure during bladder distension. Intraluminal and extraluminal ATP, ACh, and nitric oxide (NO) release were measured using the luciferin-luciferase and Amplex((r)) Red assays (Molecular Probes, Carlsbad, CA, USA), and fluorometric assay kit, respectively. OnaBotA (2U), was applied intraluminally, during bladder distension, and its effect was monitored for 2 h after application. Whole-nerve activity was analysed to classify the single afferent units responding to physiological (low-threshold [LT] afferent <15 mmHg) and supra-physiological (high-threshold [HT] afferent >15 mmHg) distension pressures. RESULTS: Bladder distension evoked reproducible pressure-dependent increases in afferent nerve firing. After exposure to OnaBotA, both LT and HT afferent units were significantly attenuated. OnaBotA also significantly inhibited ATP release from the urothelium and increased NO release. CONCLUSION: These data indicate that OnaBotA attenuates the bladder afferent nerves involved in micturition and bladder sensation, suggesting that OnaBotA may exert its clinical effects on urinary urgency and the other symptoms of overactive bladder syndrome through its marked effect on afferent nerves. PMID- 23937320 TI - Compassion into action. PMID- 23937319 TI - Effect of estradiol valerate on endometrium thickness during clomiphene citrate stimulated ovulation. AB - AIM: The aim of this study was to examine the effects of estradiol valerate (EV) on the thickness of clomiphene citrate (CC)-stimulated endometrium. MATERIAL AND METHODS: Thirty-four normal ovulatory women were randomized double-blindly into two groups to receive CC 100 mg/day on day 2-6 of the treatment cycle, and either vitamin B (placebo) or EV 6 mg/day on day 10-14 of the cycle. The endometrial thickness, endometrial pattern, numbers of mature follicles, and maximal diameters of preovulatory follicles were evaluated by transvaginal sonographic examination. RESULTS: Thirty women completed both treatment cycles. Two other participants dropped out during the treatment due to side-effects (headache). The average endometrial thickness of the group treated with CC + placebo became slightly thinner when compared to the thickness at the baseline (9.04 vs 9.52 mm; P = 0.24). The CC + placebo and the CC + EV resulted in similar endometrial pattern, ovulation day, numbers of mature follicles, and sizes of the leading follicles before ovulation. However, an addition of EV into the CC cycle significantly increased the average endometrial thickness (10.7 mm vs 9.04 mm; P < 0.001). CONCLUSIONS: We concluded that the addition of 6 mg/day EV following the CC treatment can prevent the endometrial thinning without perturbing folliculogenesis and ovulation. PMID- 23937321 TI - Radiofrequency ablation for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality worldwide. Unfortunately, only 20% of HCC patients are amenable to curative therapy (liver transplantation or surgical resection). Locoregional therapies such as radiofrequency ablation (RFA), percutaneous ethanol injection, microwave coagulation therapy, and transcatheter arterial chemoembolisation play a key role in the management of HCC. The choice of the treatment modality depends on the size of the tumour, tumour location, anatomic considerations and the number of tumours present and liver function. RFA therapy for HCC can be performed safely using a percutaneous, laparoscopic, or an open approach, even in patients with poor functional reserve. Since the introduction of RFA, several randomised controlled trials and non-randomised studies comparing RFA and other therapies for HCC have been conducted. In addition, in the last decade there have been technical advances in RFA therapy for HCC, resulting in significant improvement in the prognosis of HCC patients treated with this modality. In this review, we primarily focus on percutaneous RFA therapy for HCC and refer to current knowledge and future perspectives for this therapy. We also discuss new emerging ablation techniques. PMID- 23937322 TI - Implanted cardiac devices are reliably detected by commercially available metal detectors. AB - OBJECTIVE: Explosions of Cardiovascular Implantable Electronic Devices (CIEDs) (pacemakers, defibrillators, and loop recorders) are a well-recognized problem during cremation, due to lithium-iodine batteries. In addition, burial of the deceased with a CIED can present a potential risk for environmental contamination. Therefore, detection of CIEDs in the deceased would be of value. This study evaluated a commercially available metal detector for detecting CIEDs. DESIGN: Observational study including pacemaker patients (n = 70) and a control group without pacemaker (n = 95). The investigational device was a hand-held metal detector for detecting metal or electricity wiring. RESULTS: The metal detector detected the pacemaker in all pacemaker patients and thus exhibited a sensitivity of 100%. The specificity of the metal detector was 86%, and the negative predictive value was 100%. Thirteen individuals without pacemakers were falsely identified as having an implanted device due to implanted prosthetic material or elements of clothing. CONCLUSION: A simple hand-held metal detector may detect CIEDs with a high sensitivity. It may be of value in detecting CIEDs in deceased persons before burial or cremation. Any signal detected by the metal detector should prompt further investigation of the body and patient files. PMID- 23937323 TI - Aqueous-phase linker-assisted attachment of cysteinate(2-)-capped cdse quantum dots to TiO2 for quantum dot-sensitized solar cells. AB - We have synthesized water-dispersible cysteinate(2-)-capped CdSe nanocrystals and attached them to TiO2 using one-step linker-assisted assembly. Room-temperature syntheses yielded CdSe magic-sized clusters (MSCs) exhibiting a narrow and intense first excitonic absorption band centered at 422 nm. Syntheses at 80 degrees C yielded regular CdSe quantum dots (RQDs) with broader and red-shifted first excitonic absorption bands. Cysteinate(2-)-capped CdSe MSCs and RQDs adsorbed to bare nanocrystalline TiO2 films from aqueous dispersions. CdSe functionalized TiO2 films were incorporated into working electrodes of quantum dot-sensitized solar cells (QDSSCs). Short-circuit photocurrent action spectra of QDSSCs corresponded closely to absorptance spectra of CdSe-functionalized TiO2 films. Power-conversion efficiencies were (0.43+/-0.04)% for MSC-functionalized TiO2 and (0.83+/-0.11)% for RQD-functionalized TiO2. Absorbed photon-to-current efficiencies under white-light illumination were approximately 0.3 for both MSC- and RQD-based QDSSCs, despite the significant differences in the electronic properties of MSCs and RQDs. Cysteinate(2-) is an attractive capping group and ligand, as it engenders water-dispersibility of CdSe nanocrystals with a range of photophysical properties, enables facile all-aqueous linker-assisted attachment of nanocrystals to TiO2, and promotes efficient interfacial charge transfer. PMID- 23937324 TI - Using yeast to uncover the regulation of protein kinase Cdelta by ceramide. AB - The regulation of protein kinase C (PKC) isoforms by ceramide is still controversial. In this work, the yeast Saccharomyces cerevisiae was used as a model to elucidate the effect of ceramide on the activity of mammalian PKC isoforms. For that, isc1Delta cells, with a deletion in the pathway for ceramide production by hydrolysis of complex sphingolipids, individually expressing mammalian PKCalpha, delta and zeta were used. Contrary to PKCalpha and zeta, expression of PKCdelta in isc1Delta cells exhibited a similar phenotype to that observed with wild-type yeast cells expressing PKCdelta treated with a PKC activator, as phorbol 12-myristate 13-acetate (PMA), specifically a growth inhibition associated with a G2/M cell cycle arrest. Interestingly, in isc1Delta yeast cells expressing PKCdelta this phenotype was completely abrogated in the presence of exogenous ceramide. Moreover, using a yeast-based assay previously developed for the screening of PKC inhibitors, it was also shown that, like the known PKC inhibitor NPC 15437, ceramide reduced the PMA-induced growth inhibition, supporting an inhibitory effect of ceramide on PKCdelta. Altogether, these results may indicate that ceramide distinctly interfere with the activity of PKCalpha, delta and zeta. Most importantly, they showed that ceramide is an inhibitor of PKCdelta. PMID- 23937325 TI - Perceived facilitators and barriers in diabetes care: a qualitative study among health care professionals in the Netherlands. AB - BACKGROUND: The need to understand barriers to the implementation of health care innovations in daily practice has been widely documented, but perceived facilitators and barriers in diabetes care by Dutch health care professionals remain unknown. The aim of this study was to investigate these factors among health care professionals (HCPs) using a qualitative research design. METHODS: Data were collected from 18 semi-structured interviews with HCPs from all professions relevant to diabetes care. The interviews were recorded and transcribed verbatim and the data were analyzed using NVivo 8.0. RESULTS: Major facilitators were the more prominent role of the practice nurses and diabetes nurses in diabetes care, benchmarking, the Care Standard (CS) of the Netherlands Diabetes federation and multidisciplinary collaboration, although collaboration with certain professional groups (i.e. dieticians, physical therapists and pharmacists), as well as the collaboration between primary and secondary care, could still be improved. The bundled payment system for the funding of diabetes care and the role of the health insurers were perceived as major barriers within the health care system. Other important barriers were reported to be the lack of motivation among patients and the lack of awareness of lifestyle programs and prevention initiatives for diabetes patients among professionals. CONCLUSIONS: Organizational changes in diabetes care, as a result of the increased attention given to management continuity of care, have led to an increased need for multidisciplinary collaboration within and between health care sectors (e.g. public health, primary care and secondary care). To date, daily routines for shared care are still sub-optimal and improvements in facilities, such as registration systems, should be implemented to further optimize communication and exchange of information. PMID- 23937326 TI - Role of trichoscopy in children's scalp and hair disorders. AB - Hair and scalp disorders in children may originate from the hair itself, scalp skin, or infectious causes and be congenital or acquired. The most common sign is alopecia, frequently brought on by tinea capitis, patchy alopecia areata, or trichotillomania. Sometimes less frequent and clinically more elusive conditions such as initial androgenetic alopecia, congenital triangular alopecia, or alopecia areata incognita may be responsible for hair loss. The noninvasive technique known as trichoscopy is being used more frequently, aiding in the prompt differential diagnosis and follow-up of many of these diseases, oftentimes providing further examination before a treatment decision is made. This review of trichoscopy of the main scalp and hair disorders afflicting children and adolescents discusses the most important dermoscopic criteria and the usefulness of this technique. PMID- 23937327 TI - Tracking the evolution of sex chromosome systems in Melanoplinae grasshoppers through chromosomal mapping of repetitive DNA sequences. AB - BACKGROUND: The accumulation of repetitive DNA during sex chromosome differentiation is a common feature of many eukaryotes and becomes more evident after recombination has been restricted or abolished. The accumulated repetitive sequences include multigene families, microsatellites, satellite DNAs and mobile elements, all of which are important for the structural remodeling of heterochromatin. In grasshoppers, derived sex chromosome systems, such as neo XY?/XX? and neo-X1X2Y?/X1X1X2X2?, are frequently observed in the Melanoplinae subfamily. However, no studies concerning the evolution of sex chromosomes in Melanoplinae have addressed the role of the repetitive DNA sequences. To further investigate the evolution of sex chromosomes in grasshoppers, we used classical cytogenetic and FISH analyses to examine the repetitive DNA sequences in six phylogenetically related Melanoplinae species with X0?/XX?, neo-XY?/XX? and neo X1X2Y?/X1X1X2X2? sex chromosome systems. RESULTS: Our data indicate a non spreading of heterochromatic blocks and pool of repetitive DNAs (C0t-1 DNA) in the sex chromosomes; however, the spreading of multigene families among the neo sex chromosomes of Eurotettix and Dichromatos was remarkable, particularly for 5S rDNA. In autosomes, FISH mapping of multigene families revealed distinct patterns of chromosomal organization at the intra- and intergenomic levels. CONCLUSIONS: These results suggest a common origin and subsequent differential accumulation of repetitive DNAs in the sex chromosomes of Dichromatos and an independent origin of the sex chromosomes of the neo-XY and neo-X1X2Y systems. Our data indicate a possible role for repetitive DNAs in the diversification of sex chromosome systems in grasshoppers. PMID- 23937328 TI - Metal complexes (M = Zn, Sn, and Pb) of 2-phosphinobenzenethiolates: insights into ligand folding and hemilability. AB - The divalent metal complexes M(II){(SC6H4-2-PR2)-kappa(2)S,P}2 (3-7, and 9-11) (M = Zn, Sn, or Pb; R = (i)Pr, (t)Bu, or Ph), the Sn(IV) complexes Sn{(SC6H4-2-PR2) kappa(2)-S,P}Ph2Cl (12 and 13) (R = (i)Pr and (t)Bu), and the ionic Sn(IV) complexes [Sn{(SC6H4-2-PR2)-kappa(2)-S,P}Ph2][BPh4] (14 and 15) (R = (i)Pr and (t)Bu) have been prepared and characterized by multinuclear NMR spectroscopy and single crystal X-ray diffraction when suitable crystals were afforded. The Sn(II) and Pb(II) complexes with R = Ph, (i)Pr, or (t)Bu (5, 6, 9, and 10) demonstrated ligand "folding" hinging on the P,S vector-a behavior driven by the repulsions of the metal/phosphorus and metal/sulfur lone pairs and increased M-S sigma bonding strength. This phenomenon was examined by density functional theory (DFT) calculations for the compounds in both folded and unfolded states. The Sn(IV) compound 13 (R = (t)Bu) crystallized with the phosphine in an axial position of the pseudotrigonal bipyramidal complex and also exhibited hemilability in the Sn P dative bond, while compound 12 (R = (i)Pr), interestingly, crystallized with phosphine in an equatorial position and did not show hemilability. Finally, the crystal structure of 15 (R = (t)Bu) revealed the presence of an uncommon, 4 coordinate, stable Sn(IV) cation. PMID- 23937329 TI - Intermittent fasting during Ramadan: does it affect sleep? AB - Islamic intermittent fasting is distinct from regular voluntary or experimental fasting. We hypothesised that if a regimen of a fixed sleep-wake schedule and a fixed caloric intake is followed during intermittent fasting, the effects of fasting on sleep architecture and daytime sleepiness will be minimal. Therefore, we designed this study to objectively assess the effects of Islamic intermittent fasting on sleep architecture and daytime sleepiness. Eight healthy volunteers reported to the Sleep Disorders Centre on five occasions for polysomnography and multiple sleep latency tests: (1) during adaptation; (2) 3 weeks before Ramadan, after having performed Islamic fasting for 1 week (baseline fasting); (3) 1 week before Ramadan (non-fasting baseline); (4) 2 weeks into Ramadan (Ramadan); and (5) 2 weeks after Ramadan (non-fasting; Recovery). Daytime sleepiness was assessed using the Epworth Sleepiness Scale and the multiple sleep latency test. The participants had a mean age of 26.6 +/- 4.9 years, a body mass index of 23.7 +/- 3.5 kg m(-2) and an Epworth Sleepiness Scale score of 7.3 +/- 2.7. There was no change in weight or the Epworth Sleepiness Scale in the four study periods. The rapid eye movement sleep percentage was significantly lower during fasting. There was no difference in sleep latency, non-rapid eye movement sleep percentage, arousal index and sleep efficiency. The multiple sleep latency test analysis revealed no difference in the sleep latency between the 'non-fasting baseline', 'baseline fasting', 'Ramadan' and 'Recovery' time points. Under conditions of a fixed sleep-wake schedule and a fixed caloric intake, Islamic intermittent fasting results in decreased rapid eye movement sleep with no impact on other sleep stages, the arousal index or daytime sleepiness. PMID- 23937330 TI - Intravenous lacosamide or phenytoin for treatment of refractory status epilepticus. AB - OBJECTIVES: To compare intravenous phenytoin (PHT) and intravenous lacosamide (LCM) for treatment of status epilepticus after failure of the first and second drug. METHODS: We retrospectively identified patients from a large community hospital in northern Germany who had been diagnosed with SE between August 2008 and December 2010. Patients who had failed to respond to the first two drugs were selected for this analysis. RESULTS: Forty-six patients (23 female, median age 68 years) were identified. LCM was used as third drug in 21 patients (median bolus 400 mg) and PHT in 15 patients (median bolus 1500 mg). Pretreatment was similar regarding substance groups (benzodiazepine as first line, levetiracetam as second line drug) and bolus doses. Status epilepticus was terminated in six patients (40%) of the PHT group and in seven patients (33%) of the LCM group. Four patients (27%) of the PHT group and no patient of the LCM group suffered from a relevant, treatment-related side effect during administration of the third drug. CONCLUSION: Lacosamide and PHT showed similar success rates for treatment of SE when used after failure of benzodiazepines and levetiracetam. However, PHT was associated with relevant side effects that were not seen with LCM. PMID- 23937331 TI - L-asparaginase with methotrexate and dexamethasone is an effective treatment combination in blastic plasmacytoid dendritic cell neoplasm. PMID- 23937333 TI - Effects of pH and charge state on peptide assembly: the YVIFL model system. AB - Peptide oligomerization is necessary but not sufficient for amyloid fibril formation. Here, we use a combination of experiments and simulations to understand how pH influences the aggregation properties of a small hydrophobic peptide, YVIFL, which is a mutant form of [Leu-5]-Enkephalin. Transmission electron microscopy and atomic force microscopy measurements reveal that this peptide forms small aggregates under acidic conditions (pH = 2), but that extensive fibrillization only occurs under basic conditions (pH = 9 and 11). Ion mobility mass spectrometry identifies key oligomers in the oligomerization process, which are further characterized at an atomistic level by molecular dynamics simulations. These simulations suggest that terminal charges play a critical role in determining aggregation propensity and aggregate morphology. They also reveal the presence of steric zipper oligomers under basic conditions, a possible precursor to fibril formation. Our experiments suggest that multiple aggregation pathways can lead to YVIFL fibrils, and that cooperative and multibody interactions are key mechanistic elements in the early stages of aggregation. PMID- 23937332 TI - Applications of small molecule probes in dissecting mechanisms of bacterial virulence and host responses. AB - Elucidating the molecular and biochemical details of bacterial infections can be challenging because of the many complex interactions that exist between a pathogen and its host. Consequently, many tools have been developed to aid the study of bacterial pathogenesis. Small molecules are a valuable complement to traditional genetic techniques because they can be used to rapidly perturb genetically intractable systems and to monitor post-translationally regulated processes. Activity-based probes are a subset of small molecules that covalently label an enzyme of interest based on its catalytic mechanism. These tools allow monitoring of enzyme activation within the context of a native biological system and can be used to dissect the biochemical details of enzyme function. This review describes the development and application of activity-based probes for examining aspects of bacterial infection on both sides of the host-pathogen interface. PMID- 23937334 TI - Clinical usefulness of double-guidewire technique for difficult biliary cannulation in endoscopic retrograde cholangiopancreatography. AB - BACKGROUND AND AIM: Although biliary cannulation with pancreatic guidewire placement (P-GW) is useful for difficult cases in endoscopic retrograde cholangiopancreatography (ERCP), the clinical significance of wire-guided cannulation with P-GW (double-guidewire technique: DGT) has not been clarified. The aim of the present study was to evaluate the usefulness of DGT for difficult biliary cannulation after unsuccessful biliary cannulation using a cannula/sphincterotome under guidance of injected contrast with P-GW (single guidewire technique: SGT). METHODS: One-hundred and forty-six patients with difficult biliary cannulation who underwent SGT were included in this retrospective study. DGT was carried out if SGT was unsuccessful. Pancreatic duct (PD) stenting was attempted to prevent post-ERCP pancreatitis (PEP) in all patients. The success rate of cannulation and the risk factors for PEP were investigated. RESULTS: Biliary cannulation with SGT was achieved in 70%. DGT was carried out in 25 patients with unsuccessful SGT, biliary cannulation being successful in 72%. Of the 13 patients who underwent precut sphincterotomy, biliary cannulation was achieved in 46%. The incidence of PEP in patients who had undergone SGT, DGT, and precut sphincterotomy was 8% (12: mild, 8; moderate, 3; severe, 1), 4% (mild, 1), and 0%, respectively. PD stenting was successfully carried out in 86%. Multivariate analysis revealed unsuccessful PD stenting to be the only risk factor for PEP (OR 8.3, 95% CI 2.3-30). CONCLUSIONS: DGT may replace SGT or become the salvage procedure in cases of unsuccessful SGT as a result of its high success rate with an acceptable incidence of PEP. Failed pancreatic duct stenting in these techniques was frequently associated with PEP. PMID- 23937335 TI - Solvent-assisted self-assembly of fullerene into single-crystal ultrathin microribbons as highly sensitive UV-visible photodetectors. AB - The size, shape, and crystallinity of organic nanostructures play an important role in their physical properties and are mainly determined by the self assembling kinetics of molecular components often involving the solvent conditions. Here, we reported a kinetically controlled self-assembly of C60 assisted by the solvent carbon bisulfide (CS2) into single-crystal ultrathin microribbons of 2C60.3CS2, upon mixing the poor solvent isopropyl alcohol with a C60/CS2 stock solution. Surface energy calculations reveal that these microribbons represent a kinetically favored high-energy state as compared with the thermodynamically stable shape of prismatic rods. High-resolution transmission electron microscopy observations clarify that association of CS2 at the nucleation stage helps to guide and rigidify the formation of pi-pi stacking 1D chains of C60 through the surrounding CS2 cage-like structures, which further act as glue, boosting lateral assembly of as-formed 1D chains into untrathin 2D microribbon single crystals. Precise control over the thickness, width, and length of 2C60.3CS2 microribbons was achieved by manipulation of the growth kinetics through adjusting the solvent conditions. Upon heating to 120 degrees C, sublimation of CS2 components results in fcc C60 microribbons. We found that both microribbons of solvated monoclinic 2C60.3CS2 and pure fcc C60 exhibit highly sensitive photoconductivity properties with a spectral response range covering UV to visible. The highest on/off ratio of two-terminal photodetectors based on single ribbons reaches around 250, while the responsitivity is about 75.3 A W(-1) in the UV region and 90.4 A W(-1) in the visible region. PMID- 23937336 TI - The effect of network biology on drug toxicology. AB - INTRODUCTION: The high failure rate of drug candidates due to toxicity, during clinical trials, is a critical issue in drug discovery. Network biology has become a promising approach, in this regard, using the increasingly large amount of biological and chemical data available and combining it with bioinformatics. With this approach, the assessment of chemical safety can be done across multiple scales of complexity from molecular to cellular and system levels in human health. Network biology can be used at several levels of complexity. AREAS COVERED: This review describes the strengths and limitations of network biology. The authors specifically assess this approach across different biological scales when it is applied to toxicity. EXPERT OPINION: There has been much progress made with the amount of data that is generated by various omics technologies. With this large amount of useful data, network biology has the opportunity to contribute to a better understanding of a drug's safety profile. The authors believe that considering a drug action and protein's function in a global physiological environment may benefit our understanding of the impact some chemicals have on human health and toxicity. The next step for network biology will be to better integrate differential and quantitative data. PMID- 23937337 TI - Physiological aspects of raffinose family oligosaccharides in plants: protection against abiotic stress. AB - Abiotic stresses resulting from water deficit, high salinity or periods of drought adversely affect plant growth and development and represent major selective forces during plant evolution. The raffinose family oligosaccharides (RFOs) are synthesised from sucrose by the subsequent addition of activated galactinol moieties donated by galactinol. RFOs are characterised as compatible solutes involved in stress tolerance defence mechanisms, although evidence also suggests that they act as antioxidants, are part of carbon partitioning strategies and may serve as signals in response to stress. The key enzyme and regulatory point in RFO biosynthesis is galactinol synthase (GolS), and an increase of GolS in expression and activity is often associated with abiotic stress. It has also been shown that different GolS isoforms are expressed in response to different types of abiotic stress, suggesting that the timing and accumulation of RFOs are controlled for each abiotic stress. However, the accumulation of RFOs in response to stress is not universal and other functional roles have been suggested for RFOs, such as being part of a carbon storage mechanism. Transgenic Arabidopsis plants with increased galactinol and raffinose concentrations had better ROS scavenging capacity, while many sugars have been shown in vitro to have antioxidant activity, suggesting that RFOs may also act as antioxidants. The RFO pathway also interacts with other carbohydrate pathways, such as that of O-methyl inositol (OMI), which shows that the functional relevance of RFOs must not be seen in isolation to overall carbon re-allocation during stress responses. PMID- 23937338 TI - Novel and simple alternative to create nanofibrillar matrices of interest for tissue engineering. AB - Synthetic analogs to natural extracellular matrix (ECM) at the nanometer level are of great potential for regenerative medicine. This study introduces a novel and simple method to produce polymer nanofibers and evaluates the properties of the resulting structures, as well as their suitability to support cells and their potential interest for bone and vascular applications. The devised approach diffracts a polymer solution by means of a spraying apparatus and of an airstream as sole driving force. The resulting nanofibers were produced in an effective fashion and a factorial design allowed isolating the processing parameters that control nanofiber size and distribution. The nanofibrillar matrices revealed to be of very high porosity and were effectively colonized by human bone marrow mesenchymal cells, while allowing ECM production and osteoblastic differentiation. In vivo, the matrices provided support for new bone formation and provided a good patency as small diameter vessel grafts. PMID- 23937339 TI - Brain metastasis in sarcoma: Does metastasectomy or aggressive multi-disciplinary treatment improve survival outcomes. AB - AIM: Brain metastasis is rare in sarcoma. Prognostic factors, optimal management strategies and therapeutic outcomes of such patients are not well studied. We aimed to evaluate the incidence, clinical characteristics and treatment outcomes of parenchymal brain metastasis in sarcoma patients. METHODS: This is a single center retrospective analysis. Overall survival (OS) was calculated from the time of diagnosis of brain metastasis to time of death. RESULTS: Sixteen patients (2.1%) with complete electronic medical records treated at our institution from 2002 to 2010 were identified. Median age was 52 years; 88% had additional sites of metastases. Eight different subtypes of soft tissue and bone sarcoma were identified. Eighty-one percent of the patients developed metachronous brain metastasis at a median of 14 months after initial sarcoma diagnosis. Thirty-eight percent of patients had solitary brain metastasis and 44% underwent aggressive therapy for brain metastasis, defined as either surgical resection or multimodality treatment. The remaining 56% received conservative treatment (either whole brain radiation alone, chemotherapy alone or best supportive care). Median OS for the entire cohort was 3.5 months (95% CI 1.1-6.3 months). A trend toward improved OS was observed with an aggressive treatment approach, 3.7 months versus 1.2 months (P = 0.077) and the usage of chemotherapy (P = 0.071). CONCLUSION: Brain metastasis in sarcoma is rare, usually coexists with significant systemic disease and is associated with a grave prognosis. Use of chemotherapy and an aggressive treatment approach in well-selected patients may be associated with improved survival. Prospective studies are needed to confirm these findings. PMID- 23937340 TI - In-situ sonication for enhanced recovery of aquifer microbial communities. AB - Sampling methods for characterization of microbial communities in aquifers should target both suspended and attached microorganisms (biofilms). We investigated the effectiveness and reproducibility of low-frequency (200 Hz) sonication pulses on improving extraction efficiency and quality of microorganisms from a petroleum contaminated aquifer in Studen (Switzerland). Sonication pulses at different power levels (0.65, 0.9, and 1.1 kW) were applied to three different groundwater monitoring wells. Groundwater samples extracted after each pulse were compared with background groundwater samples for cell and adenosine tri-phosphate concentration. Turbidity values were obtained to assess the release of sediment fines and associated microorganisms. The bacterial community in extracted groundwater samples was analyzed by terminal-restriction-fragment-length polymorphism and compared with communities obtained from background groundwater samples and from sediment cores. Sonication enhanced the extraction efficiency up to 13-fold, with most of the biomass being associated with the sediment fines extracted with groundwater. Consecutive pulses at constant power were decreasingly effective, while pulses with higher power yielded the best results both in terms of extraction efficiency and quality. Our results indicate that low frequency sonication may be a viable and cost-effective tool to improve the extraction of microorganisms from aquifers, taking advantage of existing groundwater monitoring wells. PMID- 23937342 TI - Size-controlled polyelectrolyte complexes: direct measurement of the balance of forces involved in the triggered collapse of layer-by-layer assembled nanocapsules. AB - Polyelectrolyte multilayers composed of poly(allylamine hydrochloride) and poly(styrene sulfonate) were assembled on 13 nm gold nanoparticles and characterized by Transmission Electron Microscopy and Atomic Force Microscopy. The direct measurement of the interactions at the molecular level using a Surface Force Apparatus revealed that the colloidal stability of such coated particles in aqueous media is brought about concomitantly by electrostatic and steric repulsive interactions. The cyanide induced dissolution of the gold cores yields either hollow nanocapsules or collapsed nanospheres, two species which are very difficult to distinguish. In contrast to the established micron sized hollow capsules, the dissolution of the nanosized gold cores may induce a substantial swelling of the polyelectrolyte complex into the central void as induced by the temporary local increase of the ionic strength. At least three layer pairs are required to maintain the structural integrity of the polyelectrolyte shells to yield hollow nanospheres. At about three layer pairs, thin nanocapsules are mechanically compressible and may collapse on themselves following mechanical stimulation to form even smaller spherical polyelectrolyte complex particles that retain the small polydispersity of the gold cores. Thus, the templating of polyelectrolyte shells around, e.g., gold nanoparticles followed by the dissolution of the respective cores constitutes a new method for the synthesis of extremely small polyelectrolyte complex particles with very low polydispersity. PMID- 23937341 TI - Mucosa of human detrusor impairs contraction and beta-adrenoceptor-mediated relaxation. AB - OBJECTIVES: To elucidate the impact of the mucosa on detrusor muscle function by investigating force of contraction under various stimulatory conditions and during subsequent relaxation using catecholamines. PATIENTS AND METHODS: Detrusor tissue was obtained from patients who had undergone cystectomy for bladder cancer and strips of intact or mucosa-denuded muscle were set up for force measurement. Preparations were precontracted with KCl, carbachol or electric-field stimulation (EFS). Precontracted strips were relaxed using increasing concentrations of catecholamines in the absence and presence of the subtype-selective beta adrenoceptor (AR) blockers CGP 20712A (beta1-ARs), ICI 118,551 (beta2-ARs), and L 748,337 (beta3-ARs). RESULTS: Force development in response to KCl (40 mM), carbachol (1 MUM) or EFS was larger in the absence of mucosa than in intact muscle strips. The force of contraction of mucosa-denuded strips with detached urothelium incubated in the same chamber was as low as in intact strips. Noradrenaline relaxed precontracted detrusor strips to a significantly larger extent and at lower concentrations in denuded than in intact strips. CGP 20712A did not affect noradrenaline-induced relaxation of denuded and intact strips, and ICI 118,551 did not influence noradrenaline-induced relaxation in denuded strips, but abolished the difference between denuded and intact strips. The antagonism of the relaxant effects of noradrenaline by L-748,337 was slightly smaller in intact than denuded strips. CONCLUSIONS: The mucosa of human detrusor strips impairs force development when stimulated with KCl, carbachol or EFS. The mucosa also blunts the relaxing effects of catecholamines. The latter effect does not involve the activation of beta1-ARs but only of beta2-ARs, whereas beta3-ARs mediate the relaxation of human detrusor. PMID- 23937343 TI - Photo-induced dipoles: a new method to convert photons into photovoltage in quantum dot sensitized solar cells. AB - A high photovoltage is an essential ingredient for the construction of a high efficiency quantum dot sensitized solar cell (QDSSC). In this paper we present a novel configuration of QDSSC which incorporates the photoinduced dipole (PID) phenomenon for improved open circuit voltage (Voc). This configuration, unlike previously studied ones with molecular dipoles, is based on a dipole moment which is created only under illumination and is a result of exciton dissociation. The generation of photodipoles was achieved by the creation of long-lived trapped holes inside a core of type-II ZnSe/CdS colloidal core/shell QDs, which are placed on top of the standard CdS QD sensitizer layer. Upon photoexcitation, the created photodipole negatively shifts the TiO2 energy bands, resulting in a photovoltage that is higher by ~100 mV compared to the standard cell, without type-II QDs. The extra photovoltage gained diminishes the excessive overpotential losses caused by the energetic difference between the CdS sensitizer layer and the TiO2, without harming the charge injection processes. Moreover, we show that the extent of the additional photovoltage is controlled by the illumination intensity. This work provides new understanding regarding the operation mechanisms of photoelectrochemical cells, while presenting a new strategy for constructing a high-voltage QDSSCs. In addition, the PID effect has the potential to be implemented in other promising photovoltaic technologies. PMID- 23937344 TI - Evaluation of the false recent classification rates of multiassay algorithms in estimating HIV type 1 subtype C incidence. AB - Laboratory cross-sectional assays are useful for the estimation of HIV incidence, but are known to misclassify individuals with long-standing infection as recently infected. The false recent rate (FRR) varies widely across geographic areas; therefore, accurate estimates of HIV incidence require a locally defined FRR. We determined FRR for Botswana, where HIV-1 subtype C infection is predominant, using the BED capture enzyme immunoassay (BED), a Bio-Rad Avidity Index (BAI) assay (a modification of the Bio-Rad HIV1/2+O EIA), and two multiassay algorithms (MAA) that included clinical data. To estimate FRR, stored blood samples from 512 antiretroviral (ARV)-naive HIV-1 subtype C-infected individuals from a prospective cohort in Botswana were tested at 18-24 months postenrollment. The following FRR mean (95% CI) values were obtained: BED 6.05% (4.15-8.48), BAI 5.57% (3.70-8.0), BED-BAI 2.25% (1.13-4.0), and a combination of BED-BAI with CD4 (>200) and viral load (>400) threshold 1.43% (0.58-2.93). The interassay agreement between BED and BAI was 92.8% (95% CI, 90.1-94.5) for recent/long-term classification. Misclassification was associated with viral suppression for BED [adjusted OR (aOR) 10.31; p=0.008], BAI [aOR 9.72; p=0.019], and MAA1 [aOR 16.6; p=0.006]. Employing MAA can reduce FRR to <2%. A local FRR can improve cross sectional HIV incidence estimates. PMID- 23937345 TI - D-cycloserine augmentation of cognitive behavioral group therapy of social anxiety disorder: prognostic and prescriptive variables. AB - OBJECTIVE: The aim of the current study was to identify individual characteristics that (a) predict symptom improvement with group cognitive behavioral therapy (CBT) for social anxiety disorder (SAD; i.e., prognostic variables) or (b) moderate the effects of d-cycloserine (DCS) versus placebo augmentation of CBT for SAD (i.e., prescriptive variables). METHOD: Adults with SAD (N = 169) provided Liebowitz Social Anxiety Scale scores in a trial evaluating DCS augmentation of group CBT. Rate of symptom improvement during therapy and posttreatment symptom severity were evaluated using multilevel modeling. As predictors of these 2 parameters, we selected the range of variables assessed at baseline (demographic characteristics, clinical characteristics, personality traits). Using step-wise analyses, we first identified prognostic and prescriptive variables within each of these domains and then entered these significant predictors simultaneously in 1 final model. RESULTS: African American ethnicity and cohabitation status were associated with greater overall rates of improvement during therapy and lower posttreatment severity. Higher initial severity was associated with a greater improvement during therapy but also higher posttreatment severity (the greater improvement was not enough to overcome the initial higher severity). DCS augmentation was evident only among individuals low in conscientiousness and high in agreeableness. CONCLUSIONS: African American ethnicity, cohabitation status, and initial severity are prognostic of favorable CBT outcomes in SAD. DCS augmentation appears particularly useful for patients low in conscientiousness and high in agreeableness. These findings can guide clinicians in making decisions about treatment strategies and can help direct research on the mechanisms of these treatments. PMID- 23937346 TI - RCT of web-based personalized normative feedback for college drinking prevention: are typical student norms good enough? AB - OBJECTIVES: Personalized normative feedback (PNF) interventions are generally effective at correcting normative misperceptions and reducing risky alcohol consumption among college students. However, research has yet to establish what level of reference group specificity is most efficacious in delivering PNF. This study compared the efficacy of a web-based PNF intervention using 8 increasingly specific reference groups against a Web-BASICS intervention and a repeated assessment control in reducing risky drinking and associated consequences. METHOD: Participants were 1,663 heavy-drinking Caucasian and Asian undergraduates at 2 universities. The referent for web-based PNF was either the typical same campus student or a same-campus student at 1 (either gender, race, or Greek affiliation), or a combination of 2 (e.g., gender and race), or all 3 levels of specificity (i.e., gender, race, and Greek affiliation). Hypotheses were tested using quasi-Poisson generalized linear models fit by generalized estimating equations. RESULTS: The PNF intervention participants showed modest reductions in all 4 outcomes (average total drinks, peak drinking, drinking days, and drinking consequences) compared with control participants. No significant differences in drinking outcomes were found between the PNF group as a whole and the Web-BASICS group. Among the 8 PNF conditions, participants receiving typical student PNF demonstrated greater reductions in all 4 outcomes compared with those receiving PNF for more specific reference groups. Perceived drinking norms and discrepancies between individual behavior and actual norms mediated the efficacy of the intervention. CONCLUSIONS: Findings suggest a web-based PNF intervention using the typical student referent offers a parsimonious approach to reducing problematic alcohol use outcomes among college students. PMID- 23937347 TI - An independent randomized clinical trial of multisystemic therapy with non-court referred adolescents with serious conduct problems. AB - OBJECTIVE: Adolescent conduct problems exact serious social as well as personal costs, and effective treatments are essential. One of the most widely disseminated and effective programs for the treatment of serious conduct problems in adolescents is Multisystemic Therapy (MST). However, most evaluations of MST have involved the developers of MST. The purpose of the present study was to conduct an independent evaluation of MST, with non-court-referred adolescents with conduct problems. METHOD: Participants were 164 adolescents ages 11-18 years who were recruited from self-contained behavior intervention classrooms in public schools. Adolescents and their families were randomly assigned to receive MST or services as usual. Outcome measures assessed conduct problems, school functioning, and court records of criminal behavior. Participants were followed for 18 months after baseline using parent, adolescent, and teacher reports; arrest data were collected for 2.5 years postbaseline. RESULTS: Two of 4 primary outcome measures focused on externalizing problems showed significant treatment effects favoring MST. Several secondary and intervention targets pertaining to family functioning and parent psychopathology showed positive effects of MST, and no negative effects were identified. CONCLUSIONS: Results provide some further support for the effectiveness of MST, although smaller effect sizes than previous studies also suggest the complexity of successful dissemination, particularly to non-court-referred populations. PMID- 23937348 TI - Rare case of massive congenital bilateral chylothorax in a hydropic fetus with true mosaicism 47,XXX/46,XX. AB - Fetal congenital chylothorax is a rare condition that occurs sporadically or can be associated with abnormal karyotype or structural chromosomal anomalies. We report a unique case of fetal congenital bilateral chylothorax associated with mosaicism 47,XXX/46,XX. A female fetus affected by massive bilateral hydrothorax and ascites was diagnosed at 34(+1) weeks of gestation. Previous ultrasonographic exams were completely normal. Immune causes of hydrops were excluded. Elective cesarean section was performed soon after bilateral thoracocentesis. The analysis of drained pleural fluid revealed its lymphatic nature. The fetal karyotyping, performed on chorionic villi at the 11th week, had shown mosaicism 47,XXX/46,XX, later confirmed in the newborn's blood. We hypothesized that chylothorax may be part of the phenotypic spectrum of 47 XXX karyotype and we suggest an ultrasound follow-up of the fetus at closer intervals than the routine timing for this condition, even if it is not usually characterized by severe phenotypic features. PMID- 23937351 TI - PPARgamma silencing enhances osteogenic differentiation of human adipose-derived mesenchymal stem cells. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is the master regulator of adipogenesis, and has been indicated as a potential therapeutic target to promote osteoblast differentiation. However, recent studies suggest that suppression of PPARgamma inhibits adipogenesis, but does not promote osteogenic differentiation in human bone marrow-derived mesenchymal stem cells (hBMSCs). It was reasoned that the osteogenic effect of PPARgamma suppression may be masked by the strong osteogenesis-inducing condition commonly used, resulting in a high degree of matrix mineralization in both control and experimental groups. This study investigates the role of PPARgamma in the lineage commitment of human adipose-derived mesenchymal stem cells (hADSCs) by interfering with the function of PPARgamma mRNA through small interfering RNAs (siRNAs) specific for PPARgamma2. By applying an osteogenic induction condition less potent than that used conventionally, we found that PPARgamma silencing led to retardation of adipogenesis and stimulated a higher level of matrix mineralization. The mRNA level of PPARgamma decreased to 47% of control 2 days after treatment with 50 nmol/l PPARgamma2 siRNA, while its protein expression was 60% of mock control. In the meantime, osteogenic marker genes, including bone morphogenic protein 2 (BMP2), runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and osteocalcin (OC), were up-regulated under PPARgamma silencing. Our results suggest that transient suppression of PPARgamma promotes the onset of osteogenesis, and may be considered a new strategy to stimulate bone formation in bone tissue engineering using hADSCs. PMID- 23937352 TI - Bonding preference of carbon, nitrogen, and oxygen in niobium-based rock-salt structures. AB - Carbon, nitrogen, and oxygen are essential components in solid-state materials. However, understanding their preference on the bonding to metals has not been straightforward. Here, niobium carbide, nitride, and oxide with simple rock-salt based structures were analyzed by first-principles calculations and synchrotron X ray diffraction. We found that an increase in the atomic number from carbon to oxygen formed fewer and shorter bonds to metals with better hybridization of atomic orbitals. This can provide a simple guiding principle for understanding the bonding and designing carbides, nitrides, oxides, and mixed-anion compounds. PMID- 23937350 TI - Beyond the niche: tissue-level coordination of stem cell dynamics. AB - Adult animals rely on populations of stem cells to ensure organ function throughout their lifetime. Stem cells are governed by signals from stem cell niches, and much is known about how single niches promote stemness and direct stem cell behavior. However, most organs contain a multitude of stem cell-niche units, which are often distributed across the entire expanse of the tissue. Beyond the biology of individual stem cell-niche interactions, the next challenge is to uncover the tissue-level processes that orchestrate spatial control of stem based renewal, repair, and remodeling throughout a whole organ. Here we examine what is known about higher order mechanisms for interniche coordination in epithelial organs, whose simple geometry offers a promising entry point for understanding the regulation of niche number, distribution, and activity. We also consider the potential existence of stem cell territories and how tissue architecture may influence niche coordination. PMID- 23937353 TI - Pathophysiology of gastro-esophageal reflux disease: a role for mucosa integrity? AB - BACKGROUND: Gastro-esophageal reflux disease (GERD) is very prevalent and has a high burden on health security system costs. Nevertheless, pathophysiology is complex and not well-understood. Several mechanisms have been proposed: decreased salivation, impaired esophageal clearance, decreased lower esophageal sphincter pressure resting tone, presence of hiatal hernia, increased number of transient lower esophageal sphincter relaxations (TLESRs), increased acid, and pepsin secretion, pyloric incompetence provoking duodeno-gastro-esophageal reflux of bile acids and trypsin. Independent of the relevance of each mechanism, the ultimate phenomenon is that mucosal epithelium is exposed for a longer time to agents as acid and pepsin or is in contact to luminal agents not commonly present in gastric refluxate as trypsin or bile acids. This leads to a visible damage of the epithelium (erosive esophagitis -EE) or impairing mucosal integrity without any sign of macroscopic alteration as occurs in non-erosive reflux disease (NERD). Luminal factors are not the only responsible for such impairment; more recent data indicate that endogenous factors may also play a role. PURPOSE: This review will update the most recent findings on the putative pathophysiological mechanisms and specially will focus on the role of esophageal mucosal integrity in GERD. Methodologies used for the evaluation of mucosal integrity, its relevance in EE and NERD, its involvement in symptoms perception and the effect of luminal and endogenous factors will be discussed. PMID- 23937355 TI - The Fukushima nuclear accident and the pale grass blue butterfly: evaluating biological effects of long-term low-dose exposures. AB - BACKGROUND: On August 9th 2012, we published an original research article in Scientific Reports, concluding that artificial radionuclides released from the Fukushima Dai-ichi Nuclear Power Plant exerted genetically and physiologically adverse effects on the pale grass blue butterfly Zizeeria maha in the Fukushima area. Immediately following publication, many questions and comments were generated from all over the world. Here, we have clarified points made in the original paper and answered questions posed by the readers. RESULTS: The following points were clarified. (1) There are many advantages to using the pale grass blue butterfly as an indicator species. (2) The forewings of the individuals collected in Fukushima were significantly smaller than in the northern and southern localities. (3) We observed growth retardation in the butterflies from the Fukushima area. (4) The aberrant colour patterns in the butterflies obtained in the Fukushima area were different from the colour patterns induced by temperature and sibling crosses but similar to those induced by external and internal exposures to the artificial radionuclides and by a chemical mutagen, suggesting that genetic mutations caused the aberrations. (5) This species of butterfly has been plentiful in Fukushima area for at least half a century. We here present specimens collected from Fukushima Prefecture before the accident. (6) Mutation accumulation was detected by the increase in the abnormality rates from May 2011 to September 2011. (7) The abnormal traits were heritable. (8) Our sampling localities were not affected by the tsunami. (9) We used a high enough number of samples to obtain statistically significant results. (10) The standard rearing method was followed, producing normal adults in the control groups. (11) The exposure experiments successfully reproduced the results of the field work. This species of butterfly is vulnerable to long-term low-dose internal and external exposures; however, insect cells are known to be resistant to short-term high-dose irradiation. This discrepancy is reconcilable based on the differences in the experimental conditions. CONCLUSIONS: We are just beginning to understand the biological effects of long-term low-dose exposures in animals. Further research is necessary to accurately assess the possible biological effects of the accident. PMID- 23937356 TI - Registry of gastric cancer treatment evaluation (REGATE): I baseline disease characteristics. AB - AIMS: A better understanding of treatment patterns and outcomes in different countries should improve the management of patients with gastric cancer globally. The REgistry of GAstric Cancer Treatment Evaluation (REGATE) study was established to evaluate variations in gastric cancer disease characteristics and treatment patterns in different parts of the world. METHODS: REGATE was a prospective international registry enrolling patients with newly diagnosed gastric cancer at any stage of the disease. RESULTS: A total of 10 299 patients (65% male; mean age 59 years) were recruited in 22 countries between 2004 and 2008. Tumor location at a proximal site was more common in Europe, Latin America and North Africa (approximately 20%) than in Asia-Pacific, where antral location predominated. Signet-ring cell histology predominated except in Europe, where adenocarcinoma was most prevalent. Stage I cancers were more frequent in Asia Pacific (39%) versus other regions (6-18%), whereas stage IV cancers were more frequent outside Asia-Pacific. Surgery was planned for most patients, although in general fewer patients actually received surgery than originally planned. Adjuvant therapy and palliative care were generally used more frequently than originally planned. Overall, 15% of patients received no treatment (Asia-Pacific 8%; Indian subcontinent 25%). CONCLUSIONS: These results provide a comprehensive database representative of gastric cancer disease characteristics and treatment patterns across the world. PMID- 23937357 TI - Maternal care, mother-offspring aggregation and age-dependent coadaptation in the European earwig. AB - Benefits and costs of parental care are expected to change with offspring development and lead to age-dependent coadaptation expressed as phenotypic (behavioural) matches between offspring age and parental reproductive stage. Parents and offspring interact repeatedly over time for the provision of parental care. Their behaviours should be accordingly adjusted to each other dynamically and adaptively, and the phenotypic match between offspring age and parental stage should stabilize the repeated behavioural interactions. In the European earwig (Forficula auricularia), maternal care is beneficial for offspring survival, but not vital, allowing us to investigate the extent to which the stability of mother offspring aggregation is shaped by age-dependent coadaptation. In this study, we experimentally cross-fostered nymphs of different age classes (younger or older) between females in early or late reproductive stage to disrupt age-dependent coadaptation, thereby generating female-nymph dyads that were phenotypically matched or mismatched. The results revealed a higher stability in aggregation during the first larval instar when care is most intense, a steeper decline in aggregation tendency over developmental time and a reduced developmental rate in matched compared with mismatched families. Furthermore, nymph survival was positively correlated with female-nymph aggregation stability during the early stages when maternal care is most prevalent. These results support the hypothesis that age-related phenotypically plastic coadaptation affects family dynamics and offspring developmental rate. PMID- 23937354 TI - The pre-synaptic motor nerve terminal as a site for antibody-mediated neurotoxicity in autoimmune neuropathies and synaptopathies. AB - The pre-synaptic motor nerve terminal is a highly complex and dynamic compartment within the lower motor neuron responsible for converting electrical signals into secreted chemicals. This self-renewing process of synaptic transmission is accomplished by the calcium-triggered fusion of neurotransmitter-containing vesicles with the plasma membrane and the subsequent retrieval and recycling of vesicle components. Besides this conventional physiological role, the highly active process of vesicle fusion and re-uptake into endosomal sorting pathways acts as a conduit for entry of a range of substances into the intracellular compartment of the motor nerve terminal. Whilst this entry portal sub-serves many vital physiological processes, such as those mediated by neurotrophin trafficking, there is also the potential for substantial pathological consequences resulting from uptake of noxious agents, including autoantibodies, viruses and toxins. These may act locally to induce disease within the nerve terminal, or traffic beyond to the motor neuron cell body and central nervous system to exert their pathological effects. This review focuses on the recent evidence that the ganglioside-rich pre-synaptic membrane acts as a binding site for potentially neurotoxic serum autoantibodies that are present in human autoimmune motor neuropathies. Autoantibodies that bind surface antigens induce membrane lytic effects, whereas their uptake attenuates local injury and transfers any potential pathological consequences to the intracellular compartment. Herein the thesis is explored that a balance exists between local injury at the exofacial leaflet of the pre-synaptic membrane and antibody uptake, which dictates the overall level and site of motor nerve injury in this group of disorders. PMID- 23937358 TI - Tunable superlattice in graphene to control the number of Dirac points. AB - Superlattice in graphene generates extra Dirac points in the band structure and their number depends on the superlattice potential strength. Here, we have created a lateral superlattice in a graphene device with a tunable barrier height using a combination of two gates. In this Letter, we demonstrate the use of lateral superlattice to modify the band structure of graphene leading to the emergence of new Dirac cones. This controlled modification of the band structure persists up to 100 K. PMID- 23937349 TI - Integrative mechanisms of oriented neuronal migration in the developing brain. AB - The emergence of functional neuronal connectivity in the developing cerebral cortex depends on neuronal migration. This process enables appropriate positioning of neurons and the emergence of neuronal identity so that the correct patterns of functional synaptic connectivity between the right types and numbers of neurons can emerge. Delineating the complexities of neuronal migration is critical to our understanding of normal cerebral cortical formation and neurodevelopmental disorders resulting from neuronal migration defects. For the most part, the integrated cell biological basis of the complex behavior of oriented neuronal migration within the developing mammalian cerebral cortex remains an enigma. This review aims to analyze the integrative mechanisms that enable neurons to sense environmental guidance cues and translate them into oriented patterns of migration toward defined areas of the cerebral cortex. We discuss how signals emanating from different domains of neurons get integrated to control distinct aspects of migratory behavior and how different types of cortical neurons coordinate their migratory activities within the developing cerebral cortex to produce functionally critical laminar organization. PMID- 23937359 TI - Polyarteritis nodosa in childhood: recognition of early dermatologic signs may prevent morbidity. AB - Systemic polyarteritis nodosa (PAN) is a vasculitis that affects small to medium size arteries. Onset in childhood is rare and can cause significant morbidity. Often, cutaneous manifestations can provide early clues toward diagnosis. This article describes a case of childhood systemic PAN that presented with fever, a necrotic skin lesion, and oral ulceration. Intestinal perforation complicated this case. Prompt recognition of childhood PAN is important to prevent serious complications. PMID- 23937360 TI - Computed tomography in acute abdominal pain: an overused investigation? AB - BACKGROUND: The use of computed tomography (CT) for the evaluation of patients presenting to the emergency department (ED) with acute abdominal pain has increased. We set out to investigate its effectiveness. METHODS: A prospective study conducted at a tertiary referral centre between August and September 2012, utilizing a questionnaire completed by the ordering doctors. Patients with acute abdominal pain who underwent an abdominal CT scan were included in the study, excluding those with a history of recent abdominal trauma or abdominal, pelvic, groin or scrotal surgery. RESULTS: Of the 260 patients undergoing an abdominal CT scan for the investigation of acute abdominal pain, 60 had questionnaires completed. Fifty-seven per cent of abdominal CT scans were ordered by an ED registrar or consultant. Sixty-five per cent of patients were not discussed with the surgical team prior to ED staff ordering the CT scan. 'To confirm clinical suspicion' and 'to rule out sinister aetiology' were the most important reasons for ordering an abdominal CT. In 54% of cases, there was a change in primary diagnosis post CT scan and in 50% of patients, a change in disposition. Diagnostic confidence in the primary diagnosis did not change significantly post CT scan. There was no significant difference between which group ordered a CT scan and the probability that the scan showed nil acute pathology. DISCUSSION: Abdominal CT scans frequently changed the clinical diagnosis and patient disposition. Twenty-three per cent of patients had no identifiable cause on CT scan for their acute abdominal pain. PMID- 23937368 TI - Social intervention for adolescents with autism and significant intellectual disability: initial efficacy of reciprocal imitation training. AB - Individuals with autism have difficulty with social skills across the lifespan. Few social interventions have been examined for older individuals with autism who also have significant intellectual disabilities (ID). Previous research suggests that reciprocal imitation training (RIT) improves imitation and social engagement in young children with autism. This study used a multiple-baseline design to examine whether RIT could improve social behaviors in four adolescents with autism and significant ID. All adolescents improved their spontaneous imitation and two improved their joint engagement. In addition, two adolescents decreased their rate of self-stimulatory behaviors over the course of treatment. Overall, these results suggest that RIT may be effective at improving social interaction and decreasing self-stimulatory behavior in adolescents with autism and significant ID. PMID- 23937369 TI - Social behavior and characteristics of autism spectrum disorder in Angelman, Cornelia de Lange, and Cri du Chat syndromes. AB - We evaluated autism spectrum disorder (ASD) characteristics and social behavior in Angelman (AS; n = 19; mean age = 10.35 years), Cornelia de Lange (CdLS; n = 15; mean age = 12.40 years), and Cri du Chat (CdCS, also known as 5 p syndrome; n = 19; mean age = 8.80 years) syndromes. The proportion of individuals meeting the ASD cutoff on the Social Communication Questionnaire was significantly higher in the AS and CdLS groups than in the CdCS group (p < .01). The groups demonstrated divergent social behavior profiles during social conditions in which adult availability, adult familiarity, and social demand were manipulated. Social enjoyment was significantly heightened in AS, whereas social approaches were heightened in individuals with CdCS. Social motivation, social communication, and enjoyment were significantly lower in CdLS. The findings highlight the importance of detailed observation when evaluating ASD and social behavior in genetic syndromes. PMID- 23937370 TI - Developmental and behavioral pediatricians' attitudes toward screening for fragile X. AB - Developmental and behavioral pediatricians (DBP) diagnose and care for children with fragile X syndrome. Their attitudes toward FMR1 newborn screening (NBS) and FMR1 carrier testing in childhood could highlight potential pitfalls with FMR1 NBS. We conducted a cross-sectional survey with an adjusted response rate of 61%. Among DBP, 74% supported universal FMR1 NBS, preferring to identify both full mutations and premutations. DBP also support FMR1 testing of asymptomatic siblings. Although DBP support testing for premutations at various points in the lifespan, DBP are not familiar with the array of fragile X-associated disorders (FXAD). Targeted educational interventions are needed to ensure that all health care providers have the knowledge and competence to consent and to counsel families on FXAD. PMID- 23937371 TI - Long-term impact of parental well-being on adult outcomes and dementia status in individuals with Down syndrome. AB - Parental characteristics were significant predictors of health, functional abilities, and behavior problems in adults with Down syndrome (n = 75) over a 22-year time span, controlling for initial levels and earlier changes in these outcomes. Lower levels of behavior problems were predicted by improvements in maternal depressive symptoms. Higher levels of functional abilities were predicted by prior measures of and improvements in maternal depressive symptoms. Better health was predicted by prior measures of maternal depressive symptoms, paternal positive psychological well-being, relationship quality between fathers and their adult children, and improvements in maternal positive psychological well-being. Dementia status was also predicted by parental characteristics. The study suggests the importance of the family context for healthy aging in adults with Down syndrome. PMID- 23937372 TI - Influences on maternal responsivity in mothers of children with fragile X syndrome. AB - This study investigated the influence of maternal and child variables on the maternal responsivity of 55 mothers with young children with fragile X syndrome. Data included video observations of mother-child interactions in four different contexts, standardized assessments with the children, and standardized questionnaires for the mothers. The video observations were coded for child communication acts; maternal responsivity was coded at two levels: a more general measure and a behavior-by-behavior measure. Results indicated that child developmental level and language ability strongly influenced behavior-by-behavior responsivity, while maternal IQ was the strongest predictor of both general and behavior-by-behavior responsivity, after controlling for child developmental level. PMID- 23937373 TI - Accuracy of self-reported cervical and breast cancer screening by women with intellectual disability. AB - This study examines the accuracy of self-report of cervical and breast cancer screening by women with intellectual disability (n = 155). Data from face-to face interviews and medical records were analyzed. Total agreement, sensitivity, specificity, positive predictive value and negative predictive value were calculated. Total agreement between self-report and medical record on receipt of both procedures was 75% for Pap test and 87% for mammography. Self-reported Pap tests and mammography showed >90% sensitivity, but specificity was low for both procedures (41% for Pap test, 30% for mammogram), indicating overreporting of receipt of Pap tests and mammography similar to women without disabilities. Clinicians and researchers are cautioned to corroborate self-reported data with other sources for patients and research participants with intellectual disability. PMID- 23937376 TI - Result of endoureterotomy in the management of primary obstructive megaureter in the first year of life: preliminary report. AB - PURPOSE: The present study aimed to investigate the efficacy of endoureterotomy in patients who were less than 1-year-old with primary obstructive megaureter (POMU). PATIENTS AND METHODS: Three of 10 patients with POMU aged between 2 and 12 months for whom conservative management was not applicable had recurrent urinary tract infection (UTI) and urosepsis, while the rest had decreased renal function. After obtaining the clinical history and performing physical examinations and imaging studies (ultrasonography, voiding cystourethrography (VCUG), radionuclide renal scan), the patients underwent endoureterotomy using a neonatal ureteroscope (4.5F) and Bugbee electrode with pure cutting current at the 6 o'clock position. A Double-J stent was inserted and removed 1 week later. This was followed by serial physical examination, renal function test, urine analysis, urine culture, and imaging studies in the 1st month and every 3 months after Double-J stent removal. RESULTS: Hydroureteronephrosis was significantly decreased in nine patients. Postoperative VCUG revealed no sign of iatrogenic vesicoureteral reflux. In addition, a follow-up renal scan showed remarkable improvement in the renal function in the patients who had decreased renal function, except for one patient in whom uncontrolled urosepsis developed in the follow-up; the patient underwent cutaneous ureterostomy. No UTI was detected in the group who presented with recurrent UTI and urosepsis. CONCLUSION: According to the results of our study, endoureterotomy may be an alternative in management of POMU. Of course, further studies with longer follow-up periods are needed to confirm the applicability of this method in patients younger than 1 year. PMID- 23937377 TI - Lower urinary tract functions in a series of Charcot-Marie-Tooth neuropathy patients. AB - OBJECTIVES: To evaluate lower urinary tract (LUT), bowel, and sexual dysfunctions in a series of patients with Charcot-Marie-Tooth disease (CMT). MATERIALS AND METHODS: A cohort of 58 patients and 54 healthy controls filled out the International Prostate Symptoms Score (IPSS) and the International Consultation on Incontinence Modular (ICIQ) Questionnaires to assess their symptoms and their impact on the patient's quality of life. RESULTS: On the IPSS questionnaire, CMT patients reported a significantly higher score compared with the healthy controls in 7 of 8 questions. The ICIQ-male LUT symptoms questionnaire revealed a significantly higher score in 7 of 26 questions. In the ICIQ-female LUT questionnaire, a significantly higher score was observed in 13 of 24 questions. When assessing the bowel function in CMT patients using the ICIQ-bowel questionnaire, a significantly higher score in 30 of 40 questions was noted. No differences in sexual function were found in either group. CONCLUSIONS: The occurrence of the LUT symptoms and bowel dysfunctions in CMT patients was significantly higher when compared with an age-matched control group. The symptoms were more frequent in female patients. The findings suggest that autonomic dysfunction should be evaluated and included in the diagnostic approach and care of CMT patients. PMID- 23937378 TI - One-step synthesis of robust amine- and vinyl-capped magnetic iron oxide nanoparticles for polymer grafting, dye adsorption, and catalysis. AB - Magnetic iron oxide nanoparticles (MIONs) bearing amine and vinyl groups are fabricated straightforwardly using vinyl-based tertiary amine molecules as both alkaline source and ligands based on the coprecipitation of iron ions in aqueous solution. The as-prepared MIONs present amphiphilic performance that can be well dispersed both in aqueous solution and common organic solvents (e.g., ethanol, dichloromethane and tetrahydrofuran). Transmission electron microscopy (TEM), X ray diffraction (XRD), and vibrating sample magnetometer (VSM) measurements reveal that the MIONs are superparamagnetic Fe3O4 nanoparticles with a mean diameter below 10 nm. The presence of ligands on the surface of MIONs was confirmed by thermogravimetric analysis (TGA), Fourier transform infrared (FTIR), and X-ray photoelectron spectroscopy (XPS) characterizations. Benefiting from the surface vinyl groups, the MIONs are able to graft polyvinyl-based polymers by in situ polymerization of the corresponding vinyl monomers as confirmed by grafting poly(methyl methacrylate) (PMMA) in this paper. On the basis of their surface amine groups, the MIONs show high adsorption capacity (ca. 0.42 mmol/g) for congo red dye and excellent performance for in situ growth of Pt nanocatalyst. Moreover, the MIONs possess high stability and can be reused several times without obvious decrease of their adsorption capacity and catalytic efficiency. Considering the facile fabrication process and versatile performance of the obtained MIONs, this work may open up new opportunities for the large-scale applications of MIONs. PMID- 23937379 TI - Peptides identified in soybean protein increase plasma cholesterol in mice on hypercholesterolemic diets. AB - The in vitro micellar cholesterol displacement assay has been used to identify peptides that may potentially reduce cholesterol in vivo. Two of these peptides, LPYPR and WGAPSL, derived from soybean protein (SP) that have been reported to displace cholesterol from micelles were tested by feeding them as a part of a hypercholesterolemic diet to mice for 3 weeks. Except reduction of very low density lipoprotein cholesterol (VLDL-C) and triglyceride contents, the peptide containing diets increased plasma cholesterol content with the increasing dose of the peptides. Mice fed diets supplemented with the peptides also had lower fecal bile acid excretion. Negative correlations between fecal bile acid excretion and plasma total cholesterol content (r = -0.876, P = 0.062) and non-HDL-C content (r = -0.831, P = 0.084) were observed. The mRNA levels of the genes for cholesterol and bile acid metabolism, CYP51, LDLR, CYP7A1, and LPL, were up-regulated in mice fed diets supplemented with peptides except the group fed the low dose of WGAPSL. The results suggested that higher plasma total cholesterol content possibly due to lower fecal steroid excretion as well as lower VLDL-C and triglyceride contents might due to the up-regulated expression levels of the genes CYP51, LDLR, and LPL. PMID- 23937380 TI - Mastering developmental transitions in immigrant adolescents: the longitudinal interplay of family functioning, developmental and acculturative tasks. AB - Immigrant youth differ in their adaptation, which is judged on the basis of how well they deal with developmental and acculturative tasks. While immigrant adolescents are faced with the realities of 2 different cultures, they also have to master age-salient tasks, such as self-efficacy and identity development. To get a better insight into the interplay of developmental and acculturative tasks and their relationship with family functioning, we used 3-wave longitudinal data over a 2-year period from 13-year-old immigrant students (N = 609) in Athens, Greece. Cross-lagged models revealed that family functioning and acculturation were resources for the mastery of developmental tasks. Involvement in the host culture prospectively predicted self-efficacy beliefs, and involvement in the ethnic culture prospectively predicted ethnic identity. These effects increased over time. Family functioning prospectively predicted self-efficacy and ethnic identity. These effects decreased over time. The findings suggest that a well functioning family, for early adolescents, and being involved in the host culture and in ethnic cultures, for middle adolescents, are particularly important resources to master the tasks of their developmental period. Our findings underscore the importance of developmentally sensitive approaches and the need to account for acculturative challenges in order to understand individual differences in immigrant youth adaptation. PMID- 23937381 TI - Is the prediction of adolescent outcomes from early child care moderated by later maternal sensitivity? Results from the nichd study of early child care and youth development. AB - Longitudinal data are used to examine whether effects of early child care are amplified and/or attenuated by later parenting. Analyses tested these interactions using parenting as both a categorical and continuous variable to balance power and flexibility in testing moderation. The most consistent finding was that maternal sensitivity during adolescence accentuated the association between child care quality and adolescent academic-cognitive skills at age 15 years when maternal sensitivity during adolescence was high. This interaction was obtained in analyses with maternal sensitivity as both a categorical and continuous variable. Relations between early child care hours and adolescent behavioral outcomes also were moderated by maternal sensitivity, with longer child care hours predicting more impulsivity and externalizing at age 15 when maternal sensitivity during middle childhood, scored as a categorical variable, was low to moderate and when maternal sensitivity during adolescence, scored as a continuous variable, was lower. These findings suggest that some child care effects are moderated by subsequent parenting and that this moderation may take both linear and nonlinear forms. PMID- 23937382 TI - Rethinking private speech in preschoolers: the effects of social presence. AB - Private speech utterances (PS) from 24 preschool children and 24 adults were obtained under (noninteracting) listener present and listener absent conditions using 2 tasks with an identical structure. Children produced significantly more PS in the listener present condition. Similar results were obtained with adults, albeit with a reduced incidence of private speech. The children's PS was further subdivided into 4 main categories: task irrelevant, task relevant general, task relevant focused, and incoherent mutterings. The last 2 of these categories accounted for 75% of PS in the absent condition, offering a more conservative coding of speech that could be regarded truly "private," i.e., only for "self." This subset of utterances, however, was still significantly more prevalent in the listener present condition. The results are interpreted as showing a social motive in talking out loud during problem solving and are considered in terms of a reappraisal of what is implied by the term "private speech." PMID- 23937383 TI - Young children help others to achieve their social goals. AB - From early in development, humans have strong prosocial tendencies. Much research has documented young children's propensity to help others achieve their unfulfilled goals toward physical objects. Yet many of our most common and important goals are social--directed toward other people. Here we demonstrate that children are also inclined, and able, to help others achieve their social goals. Three-year-old children observed an experimenter trying unsuccessfully to get the attention of another individual and then helped by directing the 2nd individual's attention back to the experimenter. A control condition ensured that children's responses were not motivated by a general desire to inform the 2nd individual about interesting events. A 2nd experiment showed that children distinguish between fulfilled and frustrated versions of this social goal and help appropriately on the basis of this distinction. Young children are therefore willing to intervene in a 3rd-party interaction to help it along. This result expands the range of situations in which young children are known to spontaneously help others into the social domain, thereby underscoring the pervasiveness of their prosocial motivations and identifying a critical area for further research. PMID- 23937384 TI - A walker used as a lifting device. AB - PURPOSE: To develop assistive technology that would help an older person to arise from a kneeling position to a standing one. METHODS: Developing a prototype, based on an inclusive design and then testing the prototype to verify the approach. The prototype was subsequently tested by a panel of 20 elderly users. These tests were observed and filmed. Participants' experiences of being lifted with the elevation seat were registered with the VIDAR ergonomic assessment system. RESULT: None of the 20 participants used a walker at that time. In response to a question of whether, assuming they might have to use a walker in the future, they thought that a walker with an elevating seat would be helpful, 18 said that it would. Two of the participants did not believe that they would ever have to use a walker. CONCLUSION: A simple assistive technology such as a walker equipped with an elevating seat would in many of these cases simplify matters and reduce the distress of people who fall often. In addition, such a device can allow people who fall often to live in their homes longer. For caregivers dealing frequently with people who fall, this assistive device can contribute to decreasing occupational injuries. IMPLICATIONS FOR REHABILITATION: Development of a lifting device that can help people raise themselves up entirely on their own, or with minimal assistance, would be a revolutionary step for the individual. Lifting devices in use today requires much more extensive assistance from home helpers or others and due to the risk of injuries it is a great value for the helpers that easy to use devices develops. A walker equipped with an elevating seat could even provide a potential for people to stay in their homes longer. PMID- 23937385 TI - Experiences of using an Environmental Control System (ECS) for persons with high cervical spinal cord injury: the interplay between hassle and engagement. AB - PURPOSE: Environmental Control Systems (ECS) have many benefits; however studies of personal experience of ECS use are scarce. This qualitative study explored the insiders' experience of using an ECS. METHOD: An ECS starter-pack was compiled and trialled for an eight-week period with six persons with high spinal cord injuries (SCI) living in Ireland. Semi-structured interviews were subsequently completed with each person and analysed using Interpretative Phenomenological Analysis (IPA). FINDINGS: Two major themes emerged: "Taking back a little of what has been lost", and "Getting used to ECS" which is the focus of the current paper. This theme captured a dynamic interplay between the experience of "hassle" and "engagement" for new users of ECS. "Hassle" resulted from technological frustrations and the challenge of breaking familiar habits, while "Engagement" resulted from feeling good, having fun and being surprised. CONCLUSIONS: The complex interweaving of hassle and engagement experienced by new ECS users reflects the clinical experience of rehabilitation providers. The importance of overcoming initial hassle needs to be understood by clinicians and users in order to maximise the potential benefit of ECS. Non-use must be considered one reasonable outcome if based on realistic ECS trials. PMID- 23937386 TI - Adenoviral expression of TDP-43 and FUS genes and shRNAs for protein degradation pathways in rodent motoneurons in vitro and in vivo. AB - Formation of cytoplasmic aggregates in neuronal and glial cells is one of the pathological hallmarks of amyotrophic lateral sclerosis (ALS). Mutations in two genes encoding transactivation response (TAR) DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS), both of which are main constituents of cytoplasmic aggregates, have been identified in patients with familial and sporadic ALS. Impairment of protein degradation machineries has also been recognized to participate in motoneuron degeneration in ALS. In the present study, we produced recombinant adenovirus vectors encoding wild type and mutant TDP-43 and FUS, and those encoding short hairpin RNAs (shRNAs) for proteasome (PSMC1), autophagy (ATG5), and endosome (VPS24) systems to investigate whether the coupled gene transductions in motoneurons by these adenoviruses elicit ALS pathology. Cultured neurons, astrocytes and oligodendrocytes differentiated from adult rat neural stem cells and motoneurons derived from mouse embryonic stem cells were successfully infected with these adenoviruses showing cytoplasmic aggregate formation. When these adenoviruses were injected into the facial nerves of adult rats, exogenous TDP-43 and FUS proteins were strongly expressed in facial motoneurons by a retrograde axonal transport of the adenoviruses. Co-infections of adenovirus encoding shRNA for PSMC1, ATG5 or VPS24 with TDP-43 or FUS adenovirus enhanced cytoplasmic aggregate formation in facial motoneurons, suggesting that impairment of protein degradation pathways accelerates formation of TDP-43 and FUS-positive aggregates in ALS. PMID- 23937387 TI - Efficacy and safety of oral tapentadol extended release in Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain. AB - OBJECTIVE: This phase 3 study evaluated the efficacy and safety of tapentadol extended release (ER) compared with oxycodone controlled release (CR) for the management of moderate to severe, chronic malignant tumor-related cancer pain. RESEARCH DESIGN AND METHODS: This randomized, double-blind, active-controlled study included Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain. Patients were randomized (1:1) to receive oral tapentadol ER (25-200 mg bid) or oral oxycodone HCl CR (5-40 mg bid) for 4 weeks of double-blind treatment. ClinicalTrials.gov identifier: NCT01165281. MAIN OUTCOME MEASURES: This study was designed to evaluate the non-inferiority of the efficacy provided by tapentadol ER versus oxycodone CR, based on the mean change in average pain intensity (11 point numerical rating scale) from baseline to the last 3 days of study drug administration. Treatment-emergent adverse events (TEAEs) were recorded throughout the study. RESULTS: Of the 374 patients who were screened, 343 were randomized and 236 completed treatment. The least-squares mean difference in the change in pain intensity from baseline to the last 3 days of study treatment between tapentadol ER and oxycodone CR was -0.06 (95% confidence interval [CI], -0.506 to 0.383). The upper limit of the 95% CI was <1 (the predefined threshold value for non-inferiority), indicating that tapentadol ER provided analgesic efficacy that was non-inferior to that of oxycodone CR. The percentage of patients reporting at least one TEAE was similar in the tapentadol ER (87.5% [147/168]) and oxycodone CR (90.1% [155/172]) treatment groups, but the incidence of gastrointestinal TEAEs was lower in the tapentadol ER group (55.4% [93/168]) than in the oxycodone CR group (67.4% [116/172]). CONCLUSIONS: Tapentadol ER (25-200 mg bid) provides analgesic efficacy that is non-inferior to that provided by oxycodone HCl CR (5-40 mg bid) for the management of moderate to severe, chronic malignant tumor-related pain, and is well tolerated overall, with a better gastrointestinal tolerability profile than oxycodone CR. PMID- 23937388 TI - Methylxanthines inhibit late-onset circulatory collapse in preterm infants. AB - BACKGROUND: Several drugs, when used chronically in very preterm infants, are considered to be associated with the development of late-onset circulatory collapse (LCC), which can lead to neurodevelopmental impairment. Despite its clinical importance, conclusive risk factors for LCC have yet to be identified. The aim of the present study was to investigate the relationship between LCC and diuretics, methylxanthines, levothyroxine, and sodium chloride. METHODS: Infants born at <28 weeks gestational age were enrolled and divided into two groups: the LCC group and the non-LCC group. Use of diuretics, methylxanthines, or levothyroxine, and the sodium intake in each infant were recorded. We then determined if these represented primary risk factors associated with the development of LCC, using multivariate analysis to exclude confounding factors. RESULTS: Thirty-seven preterm infants were eligible for this study. LCC developed in 10 infants; 27 infants did not develop the disease. Only methylxanthine was significantly associated with a decrease in the incidence of LCC (odds ratio, 0.04; P < 0.05). We also observed a significant positive correlation between sodium intake and the period from diuretic treatment to LCC onset. CONCLUSIONS: Methylxanthine use was significantly associated with LCC onset. Diuretics may have the ability to provoke LCC through sodium wasting, resulting in a negative balance of the electrolyte. The incidence of LCC could be lowered by paying particular attention to infants' sodium balance, and by aggressive methylxanthine treatment. PMID- 23937389 TI - Cutaneous and systemic plasmocytosis. AB - Cutaneous and systemic plasmacytosis is a rare disorder observed mainly in Japanese that features an infiltration of mature plasma cells in various organ systems. In addition to the skin, lymph nodes and bone marrow are regularly affected. Laboratory tests show a polyclonal hypergammaglobulinemia. The cutaneous morphology is characterized by red to dark brown macules, papules and plaques a few centimeters in diameter, usually distributed symmetrically on the face, neck and back. Etiology and pathogenesis are not known. It is speculated that a reactive dysfunction of plasma cells may be triggered by various stimuli, such as interleukin 6. Treatment of cutaneous and systemic plasmacytosis is difficult. A standardized treatment concept does not yet exist. Topical corticosteroids and calcineurin inhibitors are mainly used. PMID- 23937390 TI - Importance of HOX genes in normal prostate gland formation, prostate cancer development and its early detection. AB - The aims of this paper were to review the published literature on the role of HOX genes in the development of the normal prostate gland and in prostate cancer and to discuss the potential role of the HOX family member, Engrailed-2 (EN2), as a diagnostic test of PCa. Hox genes were first described in the fruit fly Drosphila melanogaster, where they specify the body plan and control the formation of body segments. They belong to a family of homeodomain-containing transcription factors that determine cell and tissue identity during normal embryonic development. They have been shown to be re-expressed by several different types of cancers. Studies have shown that different Hox genes are responsible for the development of the separate lobes of the prostate gland, the seminal vesicles and the epididymis. All HOX13 paralogues are expressed in the adult human prostate, suggesting the possibility of similarities between the function and expression of HOX genes within urological structures at similar anterior-posterior positions. The oncogenic and tumour suppressor signalling pathways associated with PCa converge on the HOX gene network, which ultimately controls gene expression, affecting tumour formation and metastatic progression. The Engrailed genes (EN1 and EN2) from the HOX gene family show a very high degree of functional conservation during embryonic development. Urinary EN2 is being investigated as a potential diagnostic marker of early PCa. It is secreted into the urine by PCa cells but not by normal prostatic tissue. A recent study has shown an association between urinary EN2 levels and cancer volume in radical prostatectomy specimens. The ability to predict tumour volume could inform the treatment decision-making process for patients with localized PCa choosing between active surveillance and radical treatment options. PMID- 23937392 TI - Semi-parametric proportional hazards models with crossed random effects for psychometric response times. AB - The semi-parametric proportional hazards model with crossed random effects has two important characteristics: it avoids explicit specification of the response time distribution by using semi-parametric models, and it captures heterogeneity that is due to subjects and items. The proposed model has a proportionality parameter for the speed of each test taker, for the time intensity of each item, and for subject or item characteristics of interest. It is shown how all these parameters can be estimated by Markov chain Monte Carlo methods (Gibbs sampling). The performance of the estimation procedure is assessed with simulations and the model is further illustrated with the analysis of response times from a visual recognition task. PMID- 23937391 TI - The epidemic of thyroid cancer in the United States: the role of endocrinologists and ultrasounds. AB - BACKGROUND: The incidence of thyroid cancer has increased at an alarming rate in both men and women in the United States. The etiology of this epidemic is unclear. We tested the hypothesis that a significant component of this epidemic is due to increased detection of occult disease. We examined whether the density of endocrinologists and general surgeons as well as employment of cervical ultrasonography were factors associated with this epidemic. METHODS: Thyroid cancer incidence rates by states were obtained from the United States Cancer Statistics 1999-2009 reported by the National Program of Cancer Registries. The densities of endocrinologists and general surgeons and the employment of cervical ultrasonography were calculated on a statewide basis and correlated with the incidence of thyroid cancer. RESULTS: Age-standardized incidence rates of thyroid cancer have increased in every state in the United States. Significant regional variations were noted, with the highest incidence rates in the northeast and the lowest in the south. The incidence rates were significantly correlated with the density of endocrinologists (r = 0.58, p<0.0001 for males; r = 0.44, p = 0.0031 for females) and the employment of cervical ultrasonography (r = 0.40, p = 0.0091 for males; r = 0.36, p = 0.0197 for females). Both the density of endocrinologists and general surgeons and employment of cervical ultrasonography could explain 57% of the variability in state-level incidence for males and 49% for females. CONCLUSIONS: These data offer evidence to suggest that the epidemic of thyroid cancer is due to increased detection of a reservoir of previously occult disease. The increased detection of thyroid cancer results in therapeutic interventions including surgery and radioactive thyroid treatment that may be of limited benefit. PMID- 23937393 TI - Co-infection of an animal with more than one genotype can occur in anthrax. AB - During the routine fingerprinting of outbreak strains of Bacillus anthracis of European and African origin by means of a 31-marker multi-locus variable number of tandem repeats analysis (MLVA), four cultures, two from the Etosha National Park (ENP), Namibia, and two from an outbreak in the Pyrenees in 1997, were found to harbour different genotypes (GTs). To investigate this further, isolates from 10 samples of blood-soaked soil from beneath anthrax carcasses and 18 clinical swabs taken from carcasses in the ENP were examined by a 31-marker MLVA. While only a single GT was found in any one of the 10 soil samples, four of the 18 swabs (22%) yielded different GTs. Two GTs were isolated from each of a zebra and a springbok and three GTs from each of a second zebra and an elephant. These animals had died in a region of the ENP where deaths caused by anthrax regularly occur every year. The results confirm the indications noted previously that co infection with more than one GT is probably not especially uncommon. The results show that, for the purpose of analysing genotypes involved in an outbreak, it is important to examine more than a single colony from a clinical sample. SIGNIFICANCE AND IMPACT OF THE STUDY: Multi-locus variable number of tandem repeats analysis (MLVA)-based fingerprinting techniques have been used in many studies worldwide to characterize the occurrence of different genotypes of Bacillus anthracis in outbreaks of wildlife or livestock and to draw conclusions about the source, the possible routes of spread and the temporal and spatial distribution of outbreak strains. Simultaneous isolation of different genotypes from the same host revealed in our study by MLVA highlights the importance of examining more than a single colony from a clinical sample. This conclusion is not specific for MLVA but holds true for every high-resolution method, including full-genome sequencing. PMID- 23937394 TI - Prechemistry nucleotide selection checkpoints in the reaction pathway of DNA polymerase I and roles of glu710 and tyr766. AB - The accuracy of high-fidelity DNA polymerases such as DNA polymerase I (Klenow fragment) is governed by conformational changes early in the reaction pathway that serve as fidelity checkpoints, identifying inappropriate template-nucleotide pairings. The fingers-closing transition (detected by a fluorescence resonance energy transfer-based assay) is the unique outcome of binding a correct incoming nucleotide, both complementary to the templating base and with a deoxyribose (rather than ribose) sugar structure. Complexes with mispaired dNTPs or complementary rNTPs are arrested at an earlier stage, corresponding to a partially closed fingers conformation, in which weak binding of DNA and nucleotide promote dissociation and resampling of the substrate pool. A 2 aminopurine fluorescence probe on the DNA template provides further information about the steps preceding fingers closing. A characteristic 2-aminopurine signal is observed on binding a complementary nucleotide, regardless of whether the sugar is deoxyribose or ribose. However, mispaired dNTPs show entirely different behavior. Thus, a fidelity checkpoint ahead of fingers closing is responsible for distinguishing complementary from noncomplementary nucleotides and routing them toward different outcomes. The E710A mutator polymerase has a defect in the early fidelity checkpoint such that some complementary dNTPs are treated as if they were mispaired. In the Y766A mutant, the early checkpoint functions normally, but some correctly paired dNTPs do not efficiently undergo fingers closing. Thus, both mutator alleles cause a blurring of the distinction between correct and incorrect base pairs and result in a larger fraction of errors passing through the prechemistry fidelity checkpoints. PMID- 23937395 TI - NMR and Raman spectroscopy monitoring of proton/deuteron exchange in aqueous solutions of ionic liquids forming hydrogen bond: a role of anions, self aggregation, and mesophase formation. AB - The H/D exchange process in the imidazolium-based room temperature ionic liquids (RTILs) 1-decyl-3-methyl-imidazolium bromide- and chloride ([C10mim][Br] and [C10mim][Cl]) in D2O solutions of various concentrations was studied applying (1)H, (13)C NMR, and Raman spectroscopy. The time dependencies of integral intensities in NMR spectra indicate that the H/D exchange in [C10mim][Br] at very high dilution (10(-4) mole fraction of RTIL) runs only slightly faster than in [C10mim][Cl]. The kinetics of this process drastically changes above critical aggregation concentration (CAC). The time required to reach the apparent reaction saturation regime in the solutions of 0.01 mole fraction of RTIL was less 10 h for [C10mim][Br], whereas no such features were seen for [C10mim][Cl] even tens of days after the sample was prepared. The H/D exchange was not observed in the liquid crystalline gel mesophase. The role of anions, self-aggregation (micellization), and mesophase formation has been discussed. Crucial influence of Br(-) and Cl(-) anions on the H/D exchange rates above CAC could be related to the short-range ordering and molecular microdynamics, in particular that of water molecules. The concept of the conformational changes coupled with the H/D exchange in imidazolium-based ionic liquids with longer hydrocarbon chains can be rejected in the light of (13)C NMR experiment. The revealed changes in (13)C NMR spectra are caused by the secondary ((13)C) isotope effects not being the signal shifts due to the conformational trans-gauche transition. PMID- 23937396 TI - Developing an indigenous surgical workforce for Australasia. AB - BACKGROUND: Progress has been made in Australia and New Zealand to increase the numbers of indigenous students (Aboriginal, Torres Strait Islander and Maori) entering primary medical qualification courses. In New Zealand, up to 20 Maori are graduating annually, with similar numbers possible in Australia, creating a potential opportunity to develop an indigenous surgical workforce. METHODS: A literature review identified factors utilized by medical schools to attract indigenous students into medical careers and the interventions necessary to ensure successful graduation. A further search identified those factors important in encouraging indigenous medical graduates to enter specialist training programmes and achieve faculty appointments. RESULTS: All medical schools have utilized elements of a 'pipeline approach' encompassing contact with students at secondary school level to encourage aspirational goals and assist with suitable subject selection. Bridging courses can ensure students leaving school have appropriate skill sets before entering medical degree courses. Extensive practical help is available during primary medical qualification study. The elements necessary for primary medical qualification success - dedicated and focused study, developing appropriate skill sets, mentoring, support, and an institutional and collegial commitment to success - are also the elements required for postgraduate achievement. CONCLUSION: The Royal Australasian College of Surgeons (RACS) is primarily involved in training rather than service provision. The increasing numbers of indigenous medical graduates in both Australia and New Zealand represent an opportunity for the College to contribute to improving indigenous health status by implementing specific measures to increase numbers of indigenous surgeons. PMID- 23937397 TI - Unravelling the blood supply to the zebrafish pharyngeal jaws and teeth. AB - We describe the vascular supply to the pharyngeal jaws and teeth in zebrafish, from larval stages to juveniles, using serial high quality semithin sections and 3D reconstructions. We have identified that the arterial blood supply to the last pair of branchial arches, which carries the teeth, issues from the hypobranchial artery. Surprisingly, the arteries supplying the pharyngeal jaws show an asymmetric branching pattern that is modified over ontogeny. Moreover, the blood vessel pattern that serves each jaw can best be described as a sinusoidal cavity encircling the bases of both the functional and replacement teeth. Capillaries branching from this sinusoidal cavity enter the pulp and constitute the intrinsic blood supply to the attached teeth. The role of these blood vessels during tooth development (whether instructive or nutritive) remains to be determined and requires further study. However, we have provided a firm morphological basis that will aid in the interpretation of experiments addressing this question. PMID- 23937398 TI - "Psychiatry is not a science like others" - a focus group study on psychotropic prescribing in primary care. AB - BACKGROUND: Psychotropic drug prescribing is problematic and knowledge of factors affecting the initiation and maintenance of such prescribing is incomplete. Such knowledge could provide a basis for the design of interventions to change prescribing patterns for psychotropics. The aim of this study was to explore the views of general practitioners (GPs), GP interns, and heads of primary care units on factors affecting the prescribing of psychotropic drugs in primary care. METHODS: We performed four focus group discussions in Gothenburg, Sweden, with a total of 21 participants (GPs, GP interns, and heads of primary care units). The focus group discussions were transcribed verbatim and analyzed using manifest content analysis. RESULTS: Three different themes emerged from the focus group discussions. The first theme Seeking care for symptoms, reflects the participants' understanding of why patients approach primary care and comprised categories such as knowledge, attitudes, and society and the media. The second theme, Lacking a framework, resources, and treatment alternatives, which reflects the conditions for the physician-patient interaction, comprised categories such as economy and resources, technology, and organizational aspects. The third theme, Restricting or maintaining prescriptions, with the subthemes Individual factors and External influences, reflects the physicians' internal decision making and comprised categories such as emotions, knowledge, and pharmaceutical industry. CONCLUSION: The results of the present study indicate that a variety of factors may affect the prescribing of psychotropic medications in primary care. Many factors were related to characteristics of the patient, the physician or their interaction, rather than the patients' medical needs per se. The results may be useful for interventions to improve psychotropic prescribing in primary care. PMID- 23937399 TI - Patterned defect structures predicted for graphene are observed on single-layer silica films. AB - Topological defects in two-dimensional materials such as graphene are considered as a tool for tailoring their physical properties. Here, we studied defect structures on a single-layer silica (silicatene) supported on Ru(0001) using a low energy electron diffraction, scanning tunneling microscopy, infrared reflection-absorption spectroscopy, and photoelectron spectroscopy. The results revealed easy formation of periodic defect structures, which were previously predicted for graphene on a theoretical ground, yet experimentally unrealized. The structural similarities between single-layer materials (graphene, silicene, silicatene) open a new playground for deeper understanding and tailoring structural, electronic, and chemical properties of the truly two-dimensional systems. PMID- 23937400 TI - Loose anagen hair syndrome in black-haired Indian children. AB - Loose anagen hair syndrome (LAHS) is an uncommonly reported autosomal dominant hair disorder with incomplete penetrance that primarily affects children but is occasionally seen in adults. LAHS is characterized by the ability to easily and painlessly extract unsheathed anagen hairs from the scalp with gentle traction. The hair is sparse and does not grow long. Usually the hairs are not fragile and do not have areas of breakage. Initially it was considered a rare, sporadic condition found predominantly in young white girls with blonde hair. Because autosomal dominant inheritance has been reported, it was suspected that the condition might be equally common in boys but was probably underdiagnosed. PMID- 23937401 TI - The role of resin cement on bond strength of glass-fiber posts luted into root canals: a systematic review and meta-analysis of in vitro studies. AB - Because there are several ways to cement glass-fiber posts (GFPs) into root canals, there is no consensus on the best strategy to achieve high bond strengths. A systematic review was conducted to determine if there is difference in bond strength to dentin between regular and self-adhesive resin cements and to verify the influence of several variables on the retention of GFPs. This report followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. In vitro studies that investigated the bond strength of GFPs luted with self-adhesive and regular resin cements were selected. Searches were carried out in the PubMed and Scopus databases. No publication year or language limit was used, and the last search was done in October 2012. A global comparison was performed between self-adhesive and regular resin cements. Two subgroup analyses were performed: 1) Self-adhesive * Regular resin cement + Etch-and-rinse adhesive and 2) Self-adhesive * Regular resin cement + Self-etch adhesive. The analyses were carried out using fixed-effect and random-effects models. The results showed heterogeneity in all comparisons, and higher bond strength to dentin was identified for self-adhesive cements. Although the articles included in this meta analysis showed high heterogeneity and high risk of bias, the in vitro literature seems to suggest that use of self-adhesive resin cement could improve the retention of GFPs into root canals. PMID- 23937402 TI - In vitro evaluation of benzalkonium chloride in the preservation of adhesive interfaces. AB - Inhibition of endogenous dentin matrix metalloproteinases (MMPs) by benzalkonium chloride (BAC) decreases collagen solubilization and may help improve resin dentin bond stability. OBJECTIVE: This study evaluated the resin-dentin bond stability of experimental adhesive blends containing BAC and the stability of dentin matrices by assessing the mass loss and collagen solubilization from dentin beams pretreated with BAC. MATERIALS AND METHODS: Twenty-five healthy molars were used for the bond strength evaluation of a two-step etch-and-rinse adhesive (Adper Single Bond Plus, SB) modified with BAC or not. The following groups were tested: 1) SB with no inhibitor (control); 2) topical 2.0% chlorhexidine + SB; 3) 1.0% BAC etchant + SB; 4) 0.5% BAC-SB; and 5) 1.0% BAC-SB. Microtensile bond strength (MUTBS) and failure mode distribution under standard error of the mean were evaluated after 24 hours and six months of storage in artificial saliva (AS). A two-way analysis of variance and Tukey test with a significance level of p<0.05 was used for data analysis. In addition, 30 completely demineralized dentin beams from human molars were either dipped in deionized water (DW, control) or dipped in 0.5% and 1.0% BAC for 60 seconds, and then incubated in AS. Collagen solubilization was assessed by evaluating the dry mass loss and quantifying the amount of hydroxyproline (HYP) released from hydrolyzed specimens after four weeks of incubation. RESULTS: The control group demonstrated lower MUTBS than some of the experimental groups containing BAC at 24 hours and six months (p<0.05). When BAC was incorporated into the adhesive blend in concentrations of 0.5% and 1.0%, no reduction in dentin bond strength was observed after six months (p<0.05). Less mass loss and HYP release was seen for dentin matrices pretreated with BAC relative to the control pretreated with DW (p<0.05). CONCLUSION: This in vitro study demonstrates that BAC contributes to the preservation of resin-dentin bonds by reducing collagen degradation. PMID- 23937403 TI - Evaluation of dental restorations: a comparative study between clinical and digital photographic assessments. AB - The aim of this study was to compare the efficacy of a direct clinical evaluation method with an indirect digital photographic method in assessing the quality of dental restorations. Seven parameters (color, occlusal marginal adaptation, anatomy form, roughness, occlusal marginal stain, luster, and secondary caries) were assessed in 89 Class I and Class II restorations from 36 adults using the modified US Public Health Service/Ryge criteria. Standardized photographs of the same restorations were digitally processed by Adobe Photoshop software, separated into the following four groups and assessed by two calibrated examiners: Group A: The original photograph displayed at 100%, without modifications (IMG100); Group B: Formed by images enlarged at 150% (IMG150); Group C: Formed by digital photographs displayed at 100% (mIMG100), with digital modifications (levels adjustment, shadow and highlight correction, color balance, unsharp Mask); and Group D: Formed by enlarged photographs displayed at 150% with modifications (mIMG150), with the same adjustments made to Group C. Photographs were assessed on a calibrated screen (Macbook) by two calibrated clinicians, and the results were statistically analyzed using Wilcoxon tests (SSPS 11.5) at 95% CI. RESULTS: The photographic method produced higher reliability levels than the direct clinical method in all parameters. The evaluation of digital images is more consistent with clinical assessment when restorations present some moderate defect (Bravo) and less consistent when restorations are clinically classified as either satisfactory (Alpha) or in cases of severe defects (Charlie). CONCLUSION: The digital photographic method is a useful tool for assessing the quality of dental restorations, providing information that goes unnoticed with the visual tactile clinical examination method. Additionally, when analyzing restorations using the Ryge modified criteria, the digital photographic method reveals a significant increase of defects compared to those clinically observed with the naked eye. Photography by itself, without the need for enlargement or correction, provides more information than clinical examination and can lead to unnecessary overtreatment. PMID- 23937404 TI - Direct spectrometry: a new alternative for measuring the fluorescence of composite resins and dental tissues. AB - The aim of this study was to evaluate the fluorescence intensity of different composite resins and compare those values with the fluorescence intensity of dental tissues. Different composite resins were used to make 10 discs (2 mm in depth and 4 mm in diameter) of each brand, divided into groups: 1) Z (Filtek Z350, 3M ESPE), 2) ES (Esthet-X, Dentsply), 3) A (Amelogen Plus, Ultradent), 4) DVS (Durafill-VS, Heraeus Kulzer) with 2 mm composite resin for enamel (A2), 5) OES ([Esthet-X] opaque-OA [1 mm] + enamel-A2 [1 mm]); 6) ODVSI ([Charisma Opal/Durafill-VSI], opaque-OM (1 mm) + translucent [1mm]), and 7) DVSI ([Durafill VSI] translucent [2 mm]). Dental tissue specimens were obtained from human anterior teeth cut in a mesiodistal direction to obtain enamel, dentin, and enamel/dentin samples (2 mm). The fluorescence intensity of specimens was directly measured using an optic fiber associated with a spectrometer (Ocean Optics USB 4000) and recorded in graphic form (Origin 8.0 program). Data were submitted to statistical analysis using Dunnet, Tukey, and Kruskall-Wallis tests. Light absorption of the composite resins was obtained in a spectral range from 250 to 450 nm, and that of dental tissues was between 250 and 300 nm. All composite resins were excited at 398 nm and exhibited maximum emissions of around 485 nm. Fluorescence intensity values for all of the resins showed statistically significant differences (measured in arbitrary units [AUs]), with the exception of groups Z and DVS. Group DVSI had the highest fluorescence intensity values (13539 AU), followed by ODVS (10440 AU), DVS (10146 AU), ES (3946 AU), OES (3841 AU), A (3540 AU), and Z (1146 AU). The fluorescence intensity values for the composite resins differed statistically from those of dental tissues (E=1380 AU; D=6262 AU; E/D=3251 AU). The opacity interfered with fluorescence intensity, and group Z demonstrated fluorescence intensity values closest to that of tooth enamel. It is concluded that the fluorescence intensity values were significantly different among the composite resins and compared with dental tissues. The direct spectrofluorimetric method represents a tool for evaluating the fluorescence of composite resins. PMID- 23937405 TI - Clinical performance of one-step self-etch adhesives applied actively in cervical lesions: 24-month clinical trial. AB - OBJECTIVES: To evaluate the clinical performance of two one-step self-etch adhesives in noncarious cervical lesions (NCCL) under active or passive application mode. METHODS: Thirty-one patients with four NCCL were enrolled in this study. One hundred and twenty-four restorations were placed according to one of the following conditions: 1) Adper Prompt L-Pop (AP), active application (APA); 2) AP, passive application (APP); 3) Xeno III (XE), active application (XEA), or 4) XE, passive application (XEP). The restorations were evaluated by the FDI World Dental Federation criteria at baseline and after six, 12, and 24 months of clinical service. The effects of adhesive, mode of application, and recall period were assessed via mixed generalized linear model (alpha=0.05). RESULTS: The adhesive AP and the passive application mode showed significantly higher marginal staining than did XE and active application, respectively (p<0.05). With regard to the retention rates, the active application mode yielded higher retention rates at the 24-month recall compared to the passive application, regardless of the material. The individual retention rates (95% confidence interval) of both adhesives in the active application mode were the same, 96.8% (83.8-99.4%), while in the passive application rates were 87.1% (71.2 94.9%) and 80.7% (63.7-90.8%) for XE and AP, respectively. CONCLUSIONS: The active application improved the retention rates of both adhesives after 24 months and minimized the marginal staining at enamel margins. PMID- 23937406 TI - Influence of an intermediary base on the microleakage of simulated class II composite resin restorations. AB - The aim of this in vitro study was to qualitatively and quantitatively evaluate the microleakage of Class II cavities restored with a methacrylate-based composite (Filtek Z250, 3M ESPE) or silorane-based composite (Filtek LS, 3M ESPE), varying the application of an intermediary base, using a low-viscosity composite resin (Filtek Z350 Flow, 3M ESPE) or resin-modified glass ionomer cement (RMGIC) (Vitrebond, 3M ESPE) and no intermediary base (control groups). Sixty cavities were prepared on the proximal surfaces of bovine teeth and were randomly divided according to the experimental groups (n=10). Following the restorative procedures and thermocycling, the samples were immersed in methylene blue for two hours. The qualitative evaluation was made using a stereomicroscope, whereby two observers analyzed the infiltration level of the dye within the tooth/filling. Microleakage scores among the groups were compared using the Kruskal-Wallis test followed by the Mann-Whitney test (p<=0.05). The samples were then ground and the powder was prepared for quantitative analysis in an absorbance spectrophotometer. The results were statistically analyzed by analysis of variance and the Tukey test (p<=0.05). Results from the quantitative analysis showed that LS presented higher values of microleakage than did Z250. There was a significant difference between both composites concerning the intermediary materials, with the lowest values obtained using RMGIC as an intermediary base. Results from the qualitative analysis showed that there were no statistically significant differences between composites; however, there were significant differences for both composites concerning the intermediary materials, with the lowest values obtained using RMGIC as an intermediary. It is possible to conclude that using RMGIC as an intermediary base provided lower microleakage, indicating better sealing of the tooth-restoration interface. PMID- 23937407 TI - Polyelectrolyte interlayer for ultra-sensitive organic transistor humidity sensors. AB - We demonstrate low-voltage, flexible, transparent pentacene humidity sensors with ultrahigh sensitivity, good reliability, and fast response/recovery behavior. The excellent performances of these devices are derived from an inserted polyelectrolyte (poly[2-(methacryloyloxy)ethyltrimethylammonium chloride-co-3 (trimethoxysilyl)propyl methacrylate] (poly(METAC-co-TSPM)) interlayer, which releases free Cl- ions in the electrolyte dielectric layer under humid conditions and boosts the electrical current in the transistor channel. This has led to extreme device sensitivity, such that electrical signal variations exceeding 7 orders of magnitude have been achieved in response to a 15% change in the relative humidity level. The new sensors exhibit a fast responsivity and a stable performance toward changes in humidity levels. Furthermore, the humidity sensors, mounted on flexible substrates, provided low voltage (<5 V) operation while preserving the unique ultrasensitivity and fast responsivity of these devices. We believe that the strategy of utilizing the enhanced ion motion in an inserted polyelectrolyte layer of an OFET structure can potentially improve sensor technologies beyond humidity-responsive systems. PMID- 23937408 TI - Gum chewing promotes bowel motility after a radical retropubic prostatectomy. AB - AIM: To investigate the efficacy of gum chewing in aiding the recovery of bowel motility after a radical retropubic prostatectomy METHODS: Thirty-seven patients who underwent retropubic radical prostatectomy from January 2010 to February 2012 for localized prostate cancer were enrolled. They were divided, in an alternate pattern, into the gum-chewing group and the control group. Patient demographics and operative outcomes were compared. The time to first postoperative passage of flatus and bowel movement, the duration of hospital stay and the side effects were recorded. RESULTS: The patients' demographics and operative outcomes showed no differences between the control (n = 19) and gum-chewing (n = 18) groups. The time to flatus was significantly shorter in the gum-chewing group than in the control group (27.1 vs 39.8 h), and the time-to-first bowel movement was faster in gum-chewing patients (46.1 vs 60.7 h). Surgical hospital stay was shorter in gum-chewing group than in the control group (5.1 vs 6.4 days). CONCLUSIONS: Gum chewing has a positive effect on the recovery of bowel motility and reduction of surgical hospital stay after a radical prostatectomy. Although retropubic radical prostatectomy does not involve bowel manipulation, gum chewing is an effective and side-effect-free method for the resolution of ileus after surgery. PMID- 23937409 TI - Homochiral zinc(II) coordination compounds based on in-situ-generated chiral amino acid-tetrazole ligands: circular dichroism, excitation light-induced tunable photoluminescence, and energetic performance. AB - We employed two pairs of new in-situ-generated chiral amino acid-tetrazole ligands in constructing homochiral Zn(II) coordination compounds: [Zn(tzet)]n (1a for (S)-tzet and 1b for (R)-tzet, H2tzet = N-[2-(1H-tetrazol-5 yl)ethyl]tryptophan) and [Zn(tzep)(H2O)2].H2O (2a for (S)-tzep and 2b for (R) tzep, H2tzep = N-[2-(1H-tetrazol-5-yl)ethyl]proline), which were hydrothermally synthesized and structurally characterized by single-crystal X-ray diffraction. Structural analysis reveals that 1 features a 2D homochiral framework generated by both tetrazolate and carboxylate bridges in tzet(2-) ligands. The isolated structure of 2 is stabilized by extensive hydrogen bonds, which leads to formation of a supramolecular 2D architecture. The absolute configuration induced at the nitrogen atoms of 1 and 2 is strictly related to the neighboring chiral carbon atoms by hydrogen-bond interactions. To further investigate their chirality, the combined experimental and theoretical analyses of circular dichroism spectra reveal the absolute configurations and nature of the Cotton effects. Solid-state excitation and emission spectra for 1 and 2 at room temperature were investigated with relevant density of states calculation, and tunable photoluminescence emission of 1 under different excitation wavelengths was discussed. As nitrogen-rich tetrazolate compounds, 1 and 2 possess higher enthalpies of combustion and may serve as a new family of promising energetic materials. PMID- 23937410 TI - SNP-revealed genetic diversity in wild emmer wheat correlates with ecological factors. AB - BACKGROUND: Patterns of genetic diversity between and within natural plant populations and their driving forces are of great interest in evolutionary biology. However, few studies have been performed on the genetic structure and population divergence in wild emmer wheat using a large number of EST-related single nucleotide polymorphism (SNP) markers. RESULTS: In the present study, twenty-five natural wild emmer wheat populations representing a wide range of ecological conditions in Israel and Turkey were used. Genetic diversity and genetic structure were investigated using over 1,000 SNP markers. A moderate level of genetic diversity was detected due to the biallelic property of SNP markers. Clustering based on Bayesian model showed that grouping pattern is related to the geographical distribution of the wild emmer wheat. However, genetic differentiation between populations was not necessarily dependent on the geographical distances. A total of 33 outlier loci under positive selection were identified using a FST-outlier method. Significant correlations between loci and ecogeographical factors were observed. CONCLUSIONS: Natural selection appears to play a major role in generating adaptive structures in wild emmer wheat. SNP markers are appropriate for detecting selectively-channeled adaptive genetic diversity in natural populations of wild emmer wheat. This adaptive genetic diversity is significantly associated with ecological factors. PMID- 23937411 TI - Intestinal recruiting and activation profiles in peripheral blood mononuclear cells in response to pathogen-associated molecular patterns stimulation in patients with IBS. AB - BACKGROUND: Immune activation, increased Toll-like Receptors (TLR) expression, and gut epithelial diffusion of bacterial molecules have been reported in irritable bowel syndrome (IBS). Thus, we sought to relate these factors by analyzing gut homing (integrin alpha4beta7), intestinal recruiting (CCR5) and activation (CD28) phenotypes, and the cytokines and chemokines concentration in peripheral blood T-lymphocytes stimulated with TLR-ligands. METHODS: Twenty-one IBS-Rome II (1 PI-IBS) patients and 19 controls were studied. Isolated peripheral blood mononuclear cells were cultured with and without Escherichia coli lipopolysaccharide (LPS), Staphylococcus aureus peptidoglycan (PGN), and unmethylated cytosine-phosphate-guanine motifs (CpG). Phenotypes were investigated by flow cytometry and supernatant cytokines and chemokines were also measured. KEY RESULTS: After LPS, CCR5 expression in CD4+ alpha4beta7+ cells remained unchanged in IBS, but decreased in controls (p = 0.002), to lower levels than in IBS (Mean fluorescence intensity [MFI]: 1590 +/- 126.9 vs 2417 +/- 88.4, p < 0.001). There were less CD8(+) alpha4beta7+ CCR5+ cells (85.7 +/- 1.5 vs 90.8 +/- 0.9%, p = 0.006) after LPS and CD3+ alpha4beta7+ CCR5+ (40.0 +/- 1.7 vs 51.2 +/- 4.3%, p = 0.006) after PGN in controls. Also, after LPS, CD28 decreased in CD4+ alpha4beta7+ CCR5+ in IBS (MFI: 2337 +/- 47.2 vs 1779 +/- 179.2, p < 0.001), but not in controls. Cytokines and chemokines were similar, except for lower IL8/CXCL8 in the unstimulated condition in IBS (4.18, 95% CI: 3.94-4.42 vs 3.77, 3.59-3.95; p = 0.006). CONCLUSIONS & INFERENCES: Pathogen-associated molecular patterns stimulation of peripheral blood T cells expressing gut homing marker in IBS compared with controls resulted in an unsuccessful down-regulation of the co expression of intestinal recruiting/residence phenotype and a state of activation. These findings support an interaction between an innate immune predisposition and microbial triggers, which may unleash or exacerbate IBS. PMID- 23937412 TI - Exploring patterns of variation in clutch size-density reaction norms in a wild passerine bird. AB - Negative density dependence of clutch size is a ubiquitous characteristic of avian populations and is partly due to within-individual phenotypic plasticity. Yet, very little is known about the extent to which individuals differ in their degree of phenotypic plasticity, whether such variation has a genetic basis and whether level of plasticity can thus evolve in response to selection. Using 18 years of data of a Dutch great tit population (Parus major), we show that females reduced clutch size with increasing population density (slopes of the reaction norms), differed strongly in their average clutch size (elevations of the reaction norms) at the population-mean density and that the latter variation was partly heritable. In contrast, we could not detect individual variation in phenotypic plasticity ('I * E'). Level of plasticity is thus not likely to evolve in response to selection in this population. Observed clutch sizes deviated more from the estimated individual reaction norms in certain years and densities, implying that the within-individual between-year variance (so-called residual variance) of clutch size was heterogeneous with respect to these factors. Given the observational nature of this study, experimental manipulation of density is now warranted to confirm the causality of the observed density effects. Our analyses demonstrate that failure to acknowledge this heterogeneity would have inflated the estimate of 'I * E' and led to misinterpretation of the data. This paper thereby emphasizes the fact that heterogeneity in residuals can provide biologically insightful information about the ecological processes underlying the data. PMID- 23937413 TI - Effect of a cysteinyl leukotriene receptor antagonist on experimental emphysema and asthma combined with emphysema. AB - The incidence of overlapping bronchial asthma and chronic obstructive pulmonary disease has increased in recent years. Cysteinyl leukotrienes (CysLTs) play an important role in asthma, and the type 1 CysLT receptor (CysLT1R) is expressed by many inflammatory cells. We evaluated the effect of montelukast, a CysLT1R antagonist, on mouse models of asthma, porcine pancreatic elastase (PPE)-induced emphysema, and asthma combined with emphysema. Mice were sensitized with ovalbumin (OVA) on Days 0 and 14 and subsequently challenged with OVA on Days 28, 29, and 30. Pulmonary emphysema was induced by intratracheal instillation of PPE on Day 25. Mice were treated subcutaneously with montelukast or vehicle from Day 25 to Day 31. Airway hyperresponsiveness (AHR), static compliance; the number of inflammatory cells, the levels of cytokines, chemokines, LTs, and perforin in the bronchoalveolar lavage fluid, and the quantitative morphometry of lung sections were analyzed on Day 32. Treatment with montelukast significantly attenuated the AHR and eosinophilic airway inflammation in OVA-sensitized and OVA-challenged mice. Administration of montelukast significantly reduced the AHR, static compliance, and neutrophilic airway inflammation, while attenuating emphysematous lung changes, in PPE-treated mice. In PPE-treated mice subjected to allergen sensitization and challenges, montelukast significantly suppressed the AHR, static compliance, and eosinophilic and neutrophilic airway inflammation in addition to the development of experimentally induced emphysema in the lungs. Our data suggest that CysLT1R antagonists may be effective in ameliorating the consequences of PPE-induced lung damage and the changes that follow allergen sensitization and challenges. PMID- 23937414 TI - Young women's perceptions of fertility-related information and fertility distress before surgery for ovarian cysts. AB - OBJECTIVE: To investigate young women's reproductive desire and perceptions of fertility-related information when scheduled for ovarian cyst surgery with a possible impact on fertility. DESIGN: Cross-sectional study. SETTING: University Hospital. POPULATION: Women of reproductive age (n = 106, mean age 32.3 years, range 18-44 years) with a diagnosis of ovarian cyst and scheduled ovarian cyst surgery between March 2011 and September 2012 were included. METHODS: The women answered a questionnaire after the presurgery consultation with the gynecologist. The questionnaire included study-specific measures of reproductive desire, perception of fertility-related information received, worry about future fertility and sociodemographic characteristics. MAIN OUTCOME MEASURE: Reproductive desire and recalled information on the impact of surgery on fertility. RESULTS: A high proportion of the women (72%) reported a desire for having children in the future and more than half of them (58%) recalled receiving information about the impact of surgery on fertility. In a multivariable logistic regression model adjusted for parity, education and age, a desire to have children increased the likelihood of recalling having received fertility-related information (odds ratio 3.2, 95% CI 1.1-9.2). CONCLUSIONS: Almost half of women with reproductive desire had ovarian surgery without recalling a discussion of fertility issues. Development of written information or interactive information might improve women's perception of fertility-related information. PMID- 23937417 TI - Simulation of bronchial mucociliary clearance of insoluble particles by computational fluid and particle dynamics methods. AB - For a correct assessment of health consequences of inhaled aerosols as a function of dose, whether for environmental, occupational or therapeutic agents, knowledge of their deposition distribution in the respiratory tract and subsequent clearance is important. The objective of this study is to model particle clearance at bronchial airway bifurcation level and to analyze the combined effect of deposition and clearance. For this purpose, a numerical model has been implemented. Air and mucus flow fields were computed in a model bronchial airway bifurcation. Inhaled particles with 1 and 10 um aerodynamic diameters were tracked to determine deposition and clearance patterns. Simulation results revealed the existence of a slow clearance zone around the peak of the airway bifurcation causing delayed clearance of the particles depositing or entering here. Particles clearing up from the deeper airways and crossing the studied bifurcation do not accumulate in this zone, because of their tendency to avoid it. The average residence time of these particles was around 20 min independently of particle size (whether it is 1 or 10 um). However, as a result of the superposition of deposition and clearance mechanisms, the final spatial distribution of particles deposited primarily in the target bifurcation is size dependent, because deposition is size specific. Although deposition density of particles deposited in the slow clearance area is one-two orders of magnitude higher than the average deposition density, these values are reduced by clearance by the factors of 4-7, depending on the particle size and the surface area of the selected slow clearance zone. In conclusion, although particle deposition is inhomogeneous, clearance can significantly decrease the degree of spatial non uniformity of the particles. Therefore, for a correct assessment of doses at local levels, it is important to consider both deposition and clearance. Although future research may overwrite some of the model assumptions on the nature of mucus, the authors think that most of the current predictions will hold. PMID- 23937416 TI - Thrombin promotes airway remodeling via protease-activated receptor-1 and transforming growth factor-beta1 in ovalbumin-allergic rats. AB - BACKGROUND: Protease-activated receptor-1 (PAR-1) is widely distributed in platelets and involved in coagulation cascade activated by thrombin. In this study, we intend to explore the role of PAR-1 in the process of thrombin-inducing transforming growth factor-beta1 (TGF-beta1) to promote airway remodeling in ovalbumin (OVA)-allergic rats. MATERIALS AND METHODS: A rat model of chronic asthma was set up by systemic sensitization and repeated challenge to OVA. The doses of thrombin, recombinant hirudin, PAR-1 inhibitor ER-112780-06 varied for different groups. We evaluated the bronchoalveolar lavage fluid (BALF) concentration of thrombin in these groups. The protein and gene expression of PAR 1 was assessed and the expression of TGF-beta1 was also detected. RESULTS: The PAR-1 mRNA level and the protein level were higher in the airway of asthmatic rats than those of normal rats, and were significantly increased by thrombin treatment but decreased by thrombin-inhibitor treatment. Airway remodeling was strengthened by thrombin but weakened by thrombin inhibitor and PAR-1 antagonist. Expression of TGF-beta1 protein in asthmatic rats was significantly increased by thrombin treatment and decreased by thrombin-inhibitor treatment and PAR-1 antagonist treatment. CONCLUSION: The expression of PAR-1 is regulated by thrombin that induces the expression of TGF-beta1 to promote airway remodeling via PAR-1 in OVA-allergic rats. PMID- 23937418 TI - Synthesis and biological evaluation of benzofuroxan derivatives as fungicides against phytopathogenic fungi. AB - Forty-four benzofuroxan derivatives were designed and prepared as antifungal agents. Their structures were characterized by (1)H NMR, (13)C NMR, and HRMS. Their antifungal activities were tested in vitro with four important phytopathogenic fungi, namely, Rhizoctonia solani , Sclerotinia sclerotiorum , Fusarium graminearum and Phytophthora capsici , using the mycelium growth inhibition method. Compound A5 displayed the maximum antifungal activity against F. graminearum (IC50 = 1.1 MUg/mL, which is about 2-fold higher than that of the well-known positive control carbendazim (IC50 = 0.5 MUg/mL). A14 exhibited high antifungal effect against both S. sclerotiorum and F. graminearum Sehw., with IC50 values of 2.52 and 3.42 MUg/mL, respectively. Among 14 benzofuroxan derivatives with substitutions at the R(2) and R(3) positions of the phenyl ring (B series), 7 compounds displayed strong growth inhibition against R. solani (IC50 <= 3.0 MUg/mL). Analysis of the structure-activity relationship data of these compounds revealed that (1) introduction of an electron-donating amino group to the R(2) position of the phenyl ring favors antifungal activity against R. solani and (2) the presence of a nitro group at the R(4) position and substituent variation at the R(1) position of the phenyl ring can result in good antifungal candidates against F. graminearum Sehw. Overall, the benzofuroxan was discovered as a novel scaffold for the development of fungicides. Significantly, A14 was demonstrated to successfully suppress disease development in S. sclerotiorum infected cole in vivo. PMID- 23937419 TI - Economic hardship and Mexican-origin adolescents' adjustment: examining adolescents' perceptions of hardship and parent-adolescent relationship quality. AB - Studies examining economic hardship consistently have linked family economic hardship to adolescent adjustment via parent and family functioning, but limited attention has been given to adolescents' perceptions of these processes. To address this, the authors investigated the intervening effects of adolescents' perceptions of economic hardship and of parent-adolescent warmth and conflict on the associations between parental economic hardship and adolescent adjustment (i.e., depressive symptoms, risky behaviors, and school performance) in a sample of 246 Mexican-origin families. Findings revealed that both mothers' and fathers' reports of economic hardship were positively related to adolescents' reports of economic hardship, which in turn, were negatively related to parent-adolescent warmth and positively related to parent-adolescent conflict with both mothers and fathers. Adolescents' perceptions of economic hardship were indirectly related to (a) depressive symptoms through warmth with mothers and conflict with mothers and fathers, (b) involvement in risky behaviors through conflict with mothers and fathers, and (c) GPA through conflict with fathers. Our findings highlight the importance of adolescents' perceptions of family economic hardship and relationships with mothers and fathers in predicting adolescent adjustment. PMID- 23937415 TI - Clinical investigation of receptor and non-receptor tyrosine kinase inhibitors for the treatment of epithelial ovarian cancer. AB - INTRODUCTION: Epithelial ovarian cancer (EOC) is the second most common gynecologic malignancy and the leading cause of death from gynecologic cancer in the USA. EOC is an exquisitely chemo-sensitive disease with response rates of over 75% in the upfront setting. Despite this, due to high rates of recurrence and development of chemo-resistance, the overall survival of EOC remains about 25%. Thus, there is a great need for new therapeutic approaches to render more durable responses. Based on preclinical and early phase clinical studies, key targeted pathways include targets that drive angiogenesis and chemo-resistance. Receptor tyrosine kinases and non-receptor tyrosine kinases play important roles in these processes and several small molecule tyrosine kinase inhibitors (TKIs) are in clinical development. AREAS COVERED: This review summarizes clinical rationale, mechanisms of action and clinical data for the TKIs under evaluation in the Phase III setting for EOC. EXPERT OPINION: Despite reasonable preclinical activity, small molecule TKIs are unlikely to improve patient survival as single agent therapies in an unselected EOC population. Incorporation of tissue evaluation during ongoing clinical trials is required to identify molecularly defined groups that respond to single agents and direct rational combination strategies based on mechanisms of resistance to improve outcomes in EOC. PMID- 23937420 TI - Mothers' parenting and child sex differences in behavior problems among African American preschoolers. AB - Sex differences in rates of behavior problems, including internalizing and externalizing problems, begin to emerge during early childhood. These sex differences may occur because mothers parent their sons and daughters differently, or because the impact of parenting on behavior problems is different for boys and girls. In this study, we examined whether associations between observations of mothers' positive and negative parenting and children's externalizing and internalizing behaviors vary as a function of child sex. The sample consisted of 137 African American low-income families with one sibling approximately 2 years old and the closest-aged older sibling who was approximately 4 years old. Results from fixed-effects within-family models indicate clear sex differences regardless of child age. Mothers were observed to use less positive parenting with sons than with daughters. Higher levels of observed negative parenting were linked to more externalizing behaviors for boys, whereas lower levels of positive parenting were linked to more externalizing behaviors for girls. No child sex differences emerged regarding associations between observed positive and negative parenting and internalizing behaviors. PMID- 23937421 TI - The efficacy and safety of bazedoxifene in postmenopausal women by baseline kidney function status. AB - INTRODUCTION: Two global, double-blind, placebo- and active-controlled, phase-3 studies (2-year prevention (n = 1583) and 3-year treatment (n = 7492)) have shown that bazedoxifene (BZA) is safe and effective for prevention and treatment of postmenopausal osteoporosis. OBJECTIVE: To evaluate the efficacy/safety of BZA according to baseline kidney function. METHODS: Data for the BZA 20- and 40-mg and placebo groups from both studies were integrated for assessment of bone turnover markers (BTMs), bone mineral density (BMD), and fracture incidence (treatment study only). Safety was assessed using integrated data for the BZA, placebo, and raloxifene 60-mg groups from both studies. Baseline glomerular filtration rate (GFR) was estimated by the Modification of Diet in Renal Disease Study equation; among subjects with baseline GFR, renal function categories were defined by GFR (ml/min per 1.73 m(2)): normal (GFR >= 90; n = 1982), mild impairment (60 <= GFR < 90; n = 6032), or moderate/severe impairment (GFR < 60; n = 723). RESULTS: Demographics were similar across treatment groups and within GFR subgroups. Across GFR subgroups, BZA 20 and 40 mg reduced BTM levels and improved lumbar spine and total hip BMD versus placebo. At month 24, there were significant treatment-by-GFR (p = 0.003) and treatment-by-serum creatinine (p = 0.034) interactions for the increase in lumbar spine BMD versus placebo. Fracture incidence was lower with BZA than placebo across all GFR categories, with no treatment-by-GFR interaction. There were no significant differences among treatment groups in incidences of overall, serious, or renal-related adverse events across GFR subgroups. CONCLUSIONS: Mild to moderate kidney impairment did not affect the efficacy and safety of BZA in postmenopausal women. PMID- 23937423 TI - Frequency and long-term outcomes of post-transplant hypophosphatemia after kidney transplantation. PMID- 23937422 TI - Growth and bone mineralization in small-for-gestational-age preterm infants. AB - BACKGROUND: Preterm infants are at risk for metabolic bone disease and suboptimal growth. This study examined the hypothesis that, apart from prematurity, intrauterine growth status (expressed as gestational age-specific birthweight standard deviation score) influences bone mineralization and body composition in early infancy. METHODS: In this retrospective study, the groups consisted of preterm small-for-gestational-age (SGA) infants (n = 18; SGA group) and preterm appropriate-for-gestational-age (AGA) infants (n = 24; AGA group). Postnatal bone mineralization was measured at term-adjusted age (postmenstrual age, 37-42 weeks). Bone mineral content (BMC) and body composition were determined on dual energy X-ray absorptiometry of the whole body. RESULTS: BMC and lean mass were significantly lower in the SGA group than in the AGA group at term-adjusted age (37-42 weeks postmenstrual age). Stepwise regression analysis identified weight at examination as the most significant factor, accounting for 51% of the variance in BMC. CONCLUSION: Bodyweight at term-adjusted age, rather than intrauterine growth, may affect postnatal bone mineralization in preterm low-birthweight infants. Therefore, promoting an increase in body size might increase postnatal bone mineralization in preterm SGA infants. PMID- 23937424 TI - Trends in renal function after radical nephrectomy: a multicentre analysis. AB - OBJECTIVE: To evaluate serial changes in renal function by investigating various clinical factors after radical nephrectomy (RN). PATIENTS AND METHODS: The study population consisted of 2068 consecutive patients who were treated at multiple institutions by RN for renal cortical tumour without metastasis between 1999 and 2011. We measured the serial change in estimated glomerular filtration rate (eGFR) and clinical factors during a 60-month follow-up period. The changes in eGFR over time were analysed according to baseline eGFR (eGFR >=60 and 15-59 mL/min/1.73m(2) ) using a linear mixed model. The independent prognostic value of various clinical factors on the increase in eGFR was ascertained by multivariate mixed regression model. RESULTS: Overall, there was a subsequent restoration of renal function over the 60 months. The slope for the relationship between the eGFR and the time since RN was 0.082 (95% confidence interval [CI] 0.039-0.104; P < 0.001) and 0.053 (95% CI 0.006-0.100; P = 0.038) in each baseline group, indicating that each month after RN was associated with an increase in eGFR of 0.082 and 0.053 mL/min/1.73m(2) , respectively. When we analysed renal function based on various factors, postoperative eGFR of patients with diabetes mellitus, old age (>=70 years) or a preoperative eGFR of <30 mL/min/1.73 m(2) , was decreased or maintained at a certain level without any improvement in renal function. Preoperative predictors of an increase in eGFR after RN were young age, no DM, no hypertension, a preoperative eGFR of >=30 mL/min/1.73m(2) and time after surgery (>=36 months). CONCLUSIONS: Renal function recovered continuously during the 60-month follow-up period after RN. However, the trends in functional recovery change were different according to various clinical factors and such information should be discussed with patients when being counselled about their treatment for renal cell carcinoma (RCC). PMID- 23937425 TI - Efficient colonization and harpins mediated enhancement in growth and biocontrol of wilt disease in tomato by Bacillus subtilis. AB - Both Bacillus subtilis and harpins stimulate plant growth and defence against various plant pathogens. In this study, B. subtilis 168 and two derivatives, surfactin producer OKB105 and combined surfactin and HpaGX ooc producer OKBHF, were applied to tomato plants to investigate the mechanisms underlying this effect. To evaluate colonization ability, strains were labelled with green fluorescent protein (GFP). Although biofilm distribution of the three strains was similar on root surfaces, Colonization populations of the two surfactin producers were approximately 2- to 3-fold higher than that of strain 168, and this was accompanied by significantly increased tomato growth. These results suggest that efficient colonization, possibly facilitated by surfactin production, enhanced the efficiency of plant growth promotion by B. subtilis. All three B. subtilis treatments caused plants to have less severe disease symptoms after inoculation with Ralstonia solanacearum, with plants treated with OKBHF being the most resistant, suggesting that hpaGX ooc improves biocontrol efficiency of B. subtilis. Analysis of defence-related genes showed a synergistic effect of HpaGX ooc on B. subtilis enhancement of the expression of the pathogenesis-related genes PR1b1 and PR-P2. In contrast, expression of the defence-related genes PINI and PINII was suppressed. SIGNIFICANCE AND IMPACT OF THE STUDY: Bacillus subtilis and harpins are biological control agents with respective advantages. In this study, combinations of the both were applied to tomato in the form of hpaGX ooc expressing B. subtilis, showed much better effects on resistance to wilt disease, and equivalent effects on plant growth promotion compared with the progenitor strain have a great potential in agricultural use. PMID- 23937427 TI - Analysis of neoadjuvant therapies in breast cancer with respect to pathological complete response, disease-free survival and overall survival: 15 years follow-up data from Kuwait. AB - AIMS: Optimizing neoadjuvant chemotherapy regimens is essential for achieving maximal pathological complete response (pCR) in patients with breast cancer. pCR is usually considered as a surrogate marker for survival. The aim of this study was to analyze pCR with respect to various neoadjuvant regimens and its effect on survival. METHODS: This retrospective analysis included 377 patients with stages II and III breast cancer treated between 1998 and 2009 with neoadjuvant chemotherapy. Neoadjuvant regimens were analyzed with respect to pCR, disease free survival (DFS) and overall survival (OS). RESULTS: The median age of our population was 50 years with the majority being premenopausal and locally advanced. The overall pCR rate was 13.7% with higher rates seen in patients receiving combination of anthracyclines and taxanes (14.2%). The practice of sandwiching surgery and chemotherapy was inferior to true neoadjuvant chemotherapy of eight cycles. Addition of trastuzumab to Her2 positive patients resulted in higher pCR rates (P = 0.006). Achievement of pCR with neoadjuvant chemotherapy resulted in significantly higher DFS and OS. CONCLUSION: pCR is associated with better survival in breast cancer patients receiving neoadjuvant chemotherapy. Initial anthracycline-based chemotherapy followed by non-cross resistant taxane-based chemotherapy along with the addition of trastuzumab in Her2 positive patients might be the optimal neoadjuvant regimen in breast cancer patients. PMID- 23937426 TI - Drugs or diet?--Developing novel therapeutic strategies targeting the free fatty acid family of GPCRs. AB - Free fatty acids (FFAs) are metabolic intermediates that may be obtained through the diet, synthesized endogenously, or produced via fermentation of carbohydrates by gut microbiota. In addition to serving as an important source of energy, FFAs are known to produce a variety of both beneficial and detrimental effects on metabolic and inflammatory processes. While historically, FFAs were believed to produce these effects only through intracellular targets such as peroxisome proliferator-activated receptors, it has now become clear that FFAs are also agonists for several GPCRs, including a family of four receptors now termed FFA1 4. Increasing evidence suggests that FFA1-4 mediate many of the beneficial properties of FFAs and not surprisingly, this has generated significant interest in the potential of these receptors as therapeutic targets for the treatment of a variety of metabolic and inflammatory disorders. In addition to the traditional strategy of developing small-molecule therapeutics targeting these receptors, there has also been some consideration given to alternate therapeutic approaches, specifically by manipulating endogenous FFA concentrations through alteration of either dietary intake, or production by gut microbiota. In this review, the current state of knowledge for FFA1-4 will be discussed, together with their potential as therapeutic targets in the treatment of metabolic and inflammatory disorders. In particular, the evidence in support of small molecule versus dietary and microbiota-based therapeutic approaches will be considered to provide insight into the development of novel multifaceted strategies targeting the FFA receptors for the treatment of metabolic and inflammatory disorders. PMID- 23937429 TI - Perception and pain thresholds for cutaneous heat and cold, and rectal distension: associations and disassociations. AB - BACKGROUND: Hypersensitivity to somatic or visceral pain has been reported in numerous clinical conditions such as fibromyalgia or the irritable bowel syndrome, and general hypersensitivity has been proposed to be the underlying mechanism. However, cross-modal relationships especially between somatic and visceral pain have rarely been investigated even in healthy volunteers. Furthermore, psychological influences on pain have rarely been characterized across modalities. METHODS: Sixty-one healthy participants underwent testing of perception and pain thresholds for cutaneous thermode heat and cold, as well as for rectal balloon distension. Psychological testing for anxiety, depression, and pain experience (including catastrophizing and coping) as well as cardiac interoception was performed. Measurement quality and the correlations between the different modalities were examined. KEY RESULTS: Significant correlations existed between the perception thresholds for cold/heat (tauB = -0.28, p = 0.002) and cold/distension (tauB = -0.21, p = 0.03) and for the pain thresholds for cold/heat (r = -0.61, p < 0.001) and heat/distension (r = 0.33, p = 0.01). No association was found between pain thresholds and anxiety, depression, psychological experience with and processing of pain, or cardiac interoception. Retest reliabilities for pain measurements were satisfying after short intertrial intervals (all intraclass correlation coefficients >0.8), but less so after longer intervals. The individuals contributing to the respective correlations differ between measurements. CONCLUSIONS & INFERENCES: Moderate associations were found for pain thresholds across modalities. The strength of the associations and their stability over time warrants further investigation and might serve to increase the understanding of conditions affecting multiple pain modalities. PMID- 23937428 TI - Transforming growth factor-beta(1) represses bone morphogenetic protein-mediated Smad signaling in pulmonary artery smooth muscle cells via Smad3. AB - Previous studies of pulmonary arterial hypertension (PAH) have implicated excessive transforming growth factor (TGF)-beta1 signaling and reduced bone morphogenetic protein (BMP) signaling in the disease pathogenesis. Reduced BMP signaling in pulmonary artery smooth muscle cells (PASMCs) from patients with heritable PAH is a consequence of germline mutations in the BMP type II receptor (BMPR-II). We sought to establish whether the TGF-beta1 and BMP4 pathways interact in PASMCs, and if this is altered in cells with BMPR-II mutations. Control PASMCs or from patients with PAH harboring BMPR-II mutations were treated with BMP4, TGF-beta1, or cotreated with both ligands. Signaling was assessed by examination of Smad phosphorylation, luciferase reporters, and the transcription of BMP4 or TGF-beta1-responsive genes. TGF-beta1 attenuated BMP4-mediated inhibitors of differentiation 1/2 induction and abolished the response in BMPR-II mutant PASMCs, whereas BMP4 did not alter TGF-beta1-mediated transcription. Activin-like kinase 5 inhibition blocked this effect, whereas cycloheximide or pharmacological inhibitors of TGF-beta-activated kinase 1, extracellular signal regulated kinase 1/2, or p38 mitogen-activated protein kinase were ineffective. BMP4 and TGF-beta1 cotreatment did not alter the activation or nuclear translocation of their respective Smad signaling proteins. Small interfering RNA for Smad3, but not Smad2, Smad6, or Smad7, reversed the inhibition by TGF-beta1. In addition, TGF-beta-activated kinase 1 inhibition blocked Smad3 phosphorylation, implying that C-terminal Smad3 phosphorylation is not required for the inhibition of BMP4 signaling by TGF-beta1. TGF-beta1 reduces BMP4 signaling in PASMCs, a response that is exacerbated on the background of reduced BMP responsiveness due to BMPR-II mutations. These data provide a rationale for therapeutic inhibition of TGF-beta1 signaling in PAH. PMID- 23937430 TI - Signal-to-noise ratio enhancement of silicon nanowires biosensor with rolling circle amplification. AB - Herein, we describe a novel approach for rapid, label-free and specific DNA detection by applying rolling circle amplification (RCA) based on silicon nanowire field-effect transistor (SiNW-FET) for the first time. Highly responsive SiNWs were fabricated with a complementary metal oxide semiconductor (CMOS) compatible anisotropic self-stop etching technique which eliminated the need for hybrid method. The probe DNA was immobilized on the surface of SiNW, followed by sandwich hybridization with the perfectly matched target DNA and RCA primer that acted as a primer to hybridize the RCA template. The RCA reaction created a long single-stranded DNA (ssDNA) product and thus enhanced the electronic responses of SiNW significantly. The signal-to-noise ratio (SNR) as a figure-of-merit was analyzed to estimate the signal enhancement and possible detection limit. The nanosensor showed highly sensitive concentration-dependent conductance change in response to specific target DNA sequences. Because of the binding of an abundance of repeated sequences of RCA products, the SNR of >20 for 1 fM DNA detection was achieved, implying a detection floor of 50 aM. This RCA-based SiNW biosensor also discriminated perfectly matched target DNA from one-base mismatched DNA with high selectivity due to the substantially reduced nonspecific binding onto the SiNW surface through RCA. The combination of SiNW FET sensor with RCA will increase diagnostic capacity and the ability of laboratories to detect unexpected viruses, making it a potential tool for early diagnosis of gene-related diseases. PMID- 23937431 TI - Liquid-vapor interfacial properties of aqueous solutions of guanidinium and methyl guanidinium chloride: influence of molecular orientation on interface fluctuations. AB - The guanidinium cation (C(NH2)3(+)) is a highly stable cation in aqueous solution due to its efficient solvation by water molecules and resonance stabilization of the charge. Its salts increase the solubility of nonpolar molecules ("salting in") and decrease the ordering of water. It is one of the strongest denaturants used in biophysical studies of protein folding. We investigate the behavior of guanidinium and its derivative, methyl guanidinium (an amino acid analogue) at the air-water surface, using atomistic molecular dynamics (MD) simulations and calculation of potentials of mean force. Methyl guanidinium cation is less excluded from the air-water surface than guanidinium cation, but both cations show orientational dependence of surface affinity. Parallel orientations of the guanidinium ring (relative to the Gibbs dividing surface) show pronounced free energy minima in the interfacial region, while ring orientations perpendicular to the GDS exhibit no discernible surface stability. Calculations of surface fluctuations demonstrate that, near the air-water surface, the parallel-oriented cations generate significantly greater interfacial fluctuations compared to other orientations, which induces more long-ranged perturbations and solvent density redistribution. Our results suggest a strong correlation with induced interfacial fluctuations and ion surface stability. These results have implications for interpreting molecular-level, mechanistic action of this osmolyte's interaction with hydrophobic interfaces as they impact protein denaturation (solubilization). PMID- 23937432 TI - Effects of mind-body therapies on symptom clusters during the menopausal transition. AB - AIMS: Although most women experience symptom clusters during the menopausal transition and early postmenopause, investigators reporting clinical trial effects for hot flushes often omit co-occurring symptoms. Our aim was to review controlled clinical trials of mind-body therapies for hot flushes and at least one other co-occurring symptom from these groups: sleep, cognitive function, mood, and pain. METHODS: An experienced reference librarian performed an extensive search of PubMed/Medline, CINAHL Plus, PsycInfo, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, EMBASE, AMED, and Alt-Health Watch for randomized controlled trials reported in English between 2004 and July 2011. Of 1193 abstracts identified, 58 trials examining effectiveness of therapies for hot flushes and at least one additional co-occurring symptom of interest were identified. RESULTS: Eight trials (ten publications) examined relaxation, yoga, or exercise. Physical activity/exercise trials (six) yielded mixed results; only one significantly reduced hot flushes and mood symptoms. Of two relaxation therapy trials, only mindfulness-based stress reduction training reduced sleep and mood symptoms and had within-group treatment effects on hot flushes. Yoga (one trial) significantly reduced hot flushes and improved cognitive symptoms more than exercise, and also had within-group effects on sleep and pain symptoms. CONCLUSIONS: Studies of mind body therapies for hot flushes increasingly measure multiple symptom outcomes, but few report treatment effects in ways that allow clinicians to consider symptom clusters when prescribing therapies. Future studies need to measure and report results for individual symptoms or group like symptoms together into subscales rather than use subscales with mixed dimensions. Trials with larger numbers of participants are essential to allow evaluation of these therapies on multiple co-occurring symptoms. PMID- 23937433 TI - Overweight increases risk of first trimester hypothyroxinaemia in iodine deficient pregnant women. AB - Hypothyroxinaemia early in pregnancy may impair fetal brain development. Increased body weight has been associated with low thyroxine concentrations in non-pregnant women. In pregnant women, morbid maternal obesity is a risk factor for thyroid dysfunction. But whether lesser degrees of overweight that are much more common could be a risk factor for hypothyroxinaemia in pregnancy is unclear. The objective of this study was to investigate if overweight increases risk for thyroid dysfunction, and specifically hypothyroxinaemia, in iodine-deficient pregnant women. We performed a cross-sectional study at first hospital visit among healthy Thai pregnant women. We measured weight and height, urinary iodine concentration (UIC), serum thyroid hormones and thyroglobulin. Pre-pregnancy weight and relevant dietary factors were determined by questionnaire, and body mass index (BMI) was used to classify weight status. Among 514 women (mean gestational age, 11 weeks) with a median UIC of 111 MUg dL(-1) , indicating mild iodine deficiency, 12% had low free thyroxine (fT4) concentrations: 3% had overt hypothyroidism; 7% had subclinical hypothyroidism; and 8% had isolated hypothyroxinaemia. Based on pre-pregnancy BMI, 26% of women were overweight or obese. In a multiple regression model, BMI was a negative predictor of fT4 (beta = -0.20, P < 0.001). Compared to normal weight women, the prevalence ratio (95% CI) of a low fT4 in overweight women was 3.64 (2.08-6.37) (P < 0.01). Iodine deficient pregnant Thai women who are overweight have a 3.6-fold higher risk of hypothyroxinaemia in the first trimester compared to normal weight women. Targeted screening should consider overweight a potential risk factor for thyroid dysfunction in pregnant women in iodine-deficient areas. PMID- 23937434 TI - Characteristics of collaborative care in increasing access to mental health service in the Asian community. AB - This study examined the use of thematic analysis to determine how characteristics of collaborative care facilitate accessibility to mental health services among the Asian community in the United States. This investigation explored characteristics of collaborative care in patient treatment, barriers that prevent the Asian community from utilizing care, and how collaborative settings can facilitate mental health care access in the Asian community. Mental health providers with relevant experiences in collaborative care were recruited through snowball sampling to participate in a telephone interview with the researchers. The results suggested a collectivistic culture, valuing authority, acculturation, language, and stigma as themes of Asian patients as well as key providers (mental and medical health providers), colocation, the physician's leading role, the provider's language, and collaboration among providers as themes for collaborative care. The study suggests that collaborative care's foundational characteristics can promote easier access to mental health care for the Asian community. PMID- 23937435 TI - Shifting processes model: a conceptual model for sustainable weight management. AB - Weight-loss maintenance is widely accepted to be a difficult and often elusive process. The transtheoretical model (TTM) provides a useful description of five stages of change. Applied to weight management, weight loss occurs during the action stage and weight-loss maintenance occurs during the maintenance stage. Despite its broad utility, the TTM does not adequately explain the complexity involved with a shift from action to maintenance. Based on Engel's (G. L. Engel, 1977, The need for a new medical model: A challenge for biomedicine, Science, Vol. 196, pp. 129-136) biopsychosocial model and family systems theory, a shifting processes model is proposed to describe the potential differences and shift that occurs between weight loss and weight-loss maintenance processes within relational contexts. PMID- 23937436 TI - Glioblastoma: from molecular pathology to targeted treatment. AB - Glioblastoma (GBM) is one of the most lethal human cancers. Genomic analyses are defining the molecular architecture of GBM, uncovering relevant subsets of patients whose disease may require different treatments. Many pharmacological targets have been revealed, promising to transform patient care through targeted therapies. However, for most patients, clinical responses to targeted inhibitors are either not apparent or not durable. In this review, we address the challenge of developing more effective, molecularly guided approaches for the treatment of GBM patients. We summarize the current state of knowledge regarding molecular classifiers and examine their benefit for stratifying patients for treatment. We survey the molecular landscape of the disease, discussing the challenges raised by acquired drug resistance. Furthermore, we analyze the biochemical features of GBM, suggesting a next generation of drug targets, and we examine the contribution of tumor heterogeneity and its implications. We conclude with an analysis of the experimental approaches and their potential benefit to patients. PMID- 23937437 TI - Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. AB - Hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis, which is disrupted in disorders affecting the circulatory system and in cancer. The role of HIFs in these diseases has been elucidated by clinical studies and by analyses of mouse models. HIFs play a protective role in the pathophysiology of myocardial ischemia due to coronary artery disease, limb ischemia due to peripheral arterial disease, pressure-overload heart failure, wound healing, and chronic rejection of organ transplants. In contrast, HIFs contribute to the pathogenesis of pulmonary arterial hypertension, systemic hypertension associated with sleep apnea, ocular neovascularization, hereditary erythrocytosis, and cancer. PMID- 23937438 TI - Origin and pathogenesis of pelvic (ovarian, tubal, and primary peritoneal) serous carcinoma. AB - A new paradigm for the pathogenesis of female pelvic cancer helps explain persistent problems in describing the development and diverse morphology of these neoplasms. This paradigm incorporates recent advances in the molecular pathogenesis of epithelial ovarian cancer (EOC) with new insights into the origin of these tumors. Correlated clinicopathologic and molecular genetic studies gave rise to a dualistic model that divides the various histologic types of EOCs into two broad categories designated type I and type II. Because serous carcinomas are the most common EOC and account for the vast majority of deaths, they form the subject of this review. Recent studies indicate that the precursor of ovarian high-grade serous carcinoma appears to develop from an occult intraepithelial carcinoma in the fimbria of the fallopian tube and involves the ovary secondarily. Another possible mechanism is implantation of normal fimbrial epithelium on the denuded ovarian surface at the site of rupture when ovulation occurs, causing the development of cortical inclusion cysts. The dualistic model serves as a framework for the study of ovarian cancer and can help investigators organize this complex group of neoplasms. It also facilitates the development of novel approaches to prevention, screening, and treatment of this devastating disease. PMID- 23937440 TI - Weak evidence for anticipatory parental effects in plants and animals. AB - The evolution of adaptive phenotypic plasticity relies on the presence of cues that enable organisms to adjust their phenotype to match local conditions. Although mostly studied with respect to nonsocial cues, it is also possible that parents transmit information about the environment to their offspring. Such 'anticipatory parental effects' or 'adaptive transgenerational plasticity' can have important consequences for the dynamics and adaptive potential of populations in heterogeneous environments. Yet, it remains unknown how widespread this form of plasticity is. Using a meta-analysis of experimental studies with a fully factorial design, we show that there is only weak evidence for higher offspring performance when parental and offspring environments are matched compared with when they are mismatched. Estimates of heterogeneity among studies suggest that effects, when they occur, are subtle. Study features, environmental context, life stage and trait categories all failed to explain significant amounts of variation in effect sizes. We discuss theoretical and methodological reasons for the limited evidence for anticipatory parental effects and suggest ways to improve our understanding of the prevalence of this form of plasticity in nature. PMID- 23937441 TI - Effect of the glycemic index of pre-exercise snack bars on substrate utilization during subsequent exercise. AB - PURPOSE: To investigate the effect of the glycemic index (GI) of pre-exercise snack bars on substrate utilization during subsequent moderate intensity exercise. METHODS: Fourteen male participants (Age: 27 +/- 5 yr; BMI: 22.5 +/- 2.7 kg m(-2); [Formula: see text]: 48.7 +/- 6.1 mL kg(-1 )min(-1)) completed two trials in a randomized and counterbalanced crossover design. Two iso-caloric snack bars with different GI values (20, LGI versus 68, HGI) were provided to the participants. Ninety minutes later, all participants completed 45 minutes of ergometer cycling at 65% [Formula: see text]. Substrate utilization was measured using indirect calorimetry. RESULTS: During exercise, higher fat oxidation and lower carbohydrate (CHO) oxidation were observed in the LGI trial (LGI versus HGI: CHO, 87.3 +/- 20.1 versus 99.2 +/- 19.0 g, p < 0.05; Fat, 15.0 +/- 5.8 versus 9.7 +/- 7.0 g, p < 0.05). CONCLUSION: Compared with an iso-caloric HGI snack bar, pre-exercise LGI snack bar consumption may facilitate a shift of substrate utilization from CHO to fat during subsequent moderate intensity exercise. PMID- 23937442 TI - Birth, death and horizontal transfer of the fumonisin biosynthetic gene cluster during the evolutionary diversification of Fusarium. AB - Fumonisins are a family of carcinogenic secondary metabolites produced by members of the Fusarium fujikuroi species complex (FFSC) and rare strains of Fusarium oxysporum. In Fusarium, fumonisin biosynthetic genes (FUM) are clustered, and the cluster is uniform in gene organization. Here, sequence analyses indicated that the cluster exists in five different genomic contexts, defining five cluster types. In FUM gene genealogies, evolutionary relationships between fusaria with different cluster types were largely incongruent with species relationships inferred from primary-metabolism (PM) gene genealogies, and FUM cluster types are not trans-specific. In addition, synonymous site divergence analyses indicated that three FUM cluster types predate diversification of FFSC. The data are not consistent with balancing selection or interspecific hybridization, but they are consistent with two competing hypotheses: (i) multiple horizontal transfers of the cluster from unknown donors to FFSC recipients and (ii) cluster duplication and loss (birth and death). Furthermore, low levels of FUM gene divergence in F. bulbicola, an FFSC species, and F. oxysporum provide evidence for horizontal transfer of the cluster from the former, or a closely related species, to the latter. Thus, uniform gene organization within the FUM cluster belies a complex evolutionary history that has not always paralleled the evolution of Fusarium. PMID- 23937443 TI - Pharmacological treatment for keloids. AB - INTRODUCTION: Keloids are fibroproliferative disorders that are characterized by histological accumulation of collagens and fibroblasts, refractory clinical symptoms such as itching, topical invasiveness, and frequent postsurgical recurrence. At present, to treat or prevent keloids, new drugs are currently being designed and the pharmaceutical indications of known drugs are being expanded. AREAS COVERED: The current pharmacological interventions for keloids are mainly described on the basis of the various hypotheses on keloid etiology and the keloid ingredients that are targeted. These interventions include angiotension-converting enzyme inhibitors and calcium-channel blockers (based on hypertension hypothesis), selective estrogen receptor modulator (based on endocrinological hypothesis), vitamins and essential fatty acids (based on immunonutritional hypothesis), and transglutaminase inhibitor (based on metabolic hypothesis). Drugs that directly target the reduction or destruction of the major extracellular matrix or cellular constituents of keloids are also included. Besides, drugs that indirectly modulate the biochemical microenvironment are described. These include growth factors, immunomodulators, and anti-inflammation and anti-allergy drugs. EXPERT OPINION: Due to the unclear etiology of keloids and the lack of animal models, efficient, reliable, and specific pharmaceutical interventions for keloids continue to be lacking. The reliability of current data and clinical observations must be strengthened by large-scale, randomized, controlled clinical trials. PMID- 23937439 TI - The influence of innate and adaptive immune responses on atherosclerosis. AB - Both the chronic development of atherosclerotic lesions and the acute changes in lesion phenotype that lead to clinical cardiovascular events are significantly influenced by the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall. The rapid pace of discovery of mechanisms of immunologic recognition, effector functions, and regulation has significantly influenced the study of atherosclerosis, and our new knowledge is beginning to affect how we treat this ubiquitous disease. In this review, we discuss recent advances in our understanding of how innate and adaptive immunity contribute to atherosclerosis, as well as therapeutic opportunities that arise from this knowledge. PMID- 23937444 TI - Nonremoval of an abnormally invasive placenta at cesarean section with postoperative uterine artery embolization. AB - OBJECTIVE: To evaluate the outcome of three different modes of management of abnormally invasive placenta over a 6-year period. DESIGN: Retrospective cohort study. SETTING: Tertiary hospital in Hong Kong. POPULATION: In 39 757 deliveries, 25 cases of abnormally invasive placenta were identified at cesarean section. METHODS: Identification of cases by hospital database and review of medical records. MAIN OUTCOME MEASURES: Blood loss, blood transfusion requirement, operative time, duration of hospital stay, secondary postpartum hemorrhage and endometritis. RESULTS: Six women were managed by leaving the placenta in situ and by postoperative uterine artery embolization. Ten women were managed by an extirpative approach and nine women with direct cesarean hysterectomy. The success rate of nonremoval of the placenta with uterine artery embolization was 4/6 (67%). The intraoperative blood loss, blood transfusion requirements and operation times were lowest in the group with nonremoval of the placenta, although a higher secondary complication rate and a longer hospital stay followed. CONCLUSION: Nonremoval of an abnormally invasive placenta at cesarean section and prophylactic postoperative uterine artery embolization are an alternative to elective cesarean hysterectomy. PMID- 23937446 TI - Inhibitory activities of some vitamins on the formation of cholesterol oxidation products in beef patties. AB - The capacities of 15 vitamins to inhibit the formation of 7alpha hydroxycholesterol, 7beta-hydroxycholesterol, and 7-ketocholesterol were examined in beef patties. Their inhibitory activities were tested at a concentration of 0.4 mmol in 30 g of beef. Among them, L-ascorbic acid, retinoic acid, and alpha (+/-)-tocopherol were found to exert a potent inhibitory effect (30-50%) on 7 ketocholesterol formation and (~20%) on 7alpha-hydroxycholesterol and 7beta hydroxycholesterol formations. Pyridoxamine inhibited 7-ketocholesterol formation by 60% with a statistically significant difference (p < 0.05) from that achieved in the control setup. To further elucidate the possible inhibitory mechanism of pyridoxamine against cholesterol oxidation, a chemical model with pyridoxamine added in the cholesterol oxidation system (heated at 140 degrees C for 240 min in dimethyl sulfoxide) was employed. It was demonstrated that pyridoxamine could directly react with 7-ketocholesterol via the addition reaction. The reaction involved a nucleophilic attack of the free amine group of pyridoxamine on 7 ketocholesterol (an alpha,beta-unsaturated carbonyl compound). This type of reaction was also found to occur in beef patties by chromatographic and spectral analyses. PMID- 23937447 TI - Synergistic effect of dual interfacial modifications with room-temperature-grown epitaxial ZnO and adsorbed indoline dye for ZnO nanorod array/P3HT hybrid solar cell. AB - ZnO nanorod (NR)/poly(3-hexylthiophene) (P3HT) hybrid solar cells with interfacial modifications are investigated in this work. The ZnO NR arrays are modified with room-temperature (RT)-grown epitaxial ZnO shells or/and D149 dye molecules prior to the P3HT infiltration. A synergistic effect of the dual modifications on the efficiency of the ZnO NR/P3HT solar cell is observed. The open-circuit voltage and fill factor are considerable improved through the RT grown ZnO and D149 modifications in sequence on the ZnO NR array, which brings about a 2-fold enhancement of the efficiency of the ZnO NR/P3HT solar cell. We suggested that the more suitable surface of RT-grown ZnO for D149 adsorption, the chemical compatibility of D149 and P3HT, and the elevated conduction band edge of the RT-grown ZnO/D149-modified ZnO NR array construct the superior interfacial morphology and energetics in the RT-grown ZnO/D149-modified ZnO NR/P3HT hybrid solar cell, resulting in the synergistic effect on the cell efficiency. An efficiency of 1.16% is obtained in the RT-grown ZnO/D149-modified ZnO NR/P3HT solar cell. PMID- 23937445 TI - Angiotensin II type 1a receptor signalling directly contributes to the increased arrhythmogenicity in cardiac hypertrophy. AB - BACKGROUND AND PURPOSE: Angiotensin II has been implicated in the development of various cardiovascular ailments, including cardiac hypertrophy and heart failure. The fact that inhibiting its signalling reduced the incidences of both sudden cardiac death and heart failure in several large-scale clinical trials suggests that angiotensin II is involved in increased cardiac arrhythmogenicity during the development of heart failure. However, because angiotensin II also promotes structural remodelling, including cardiomyocyte hypertrophy and cardiac fibrosis, it has been difficult to assess its direct contribution to cardiac arrhythmogenicity independently of the structural effects. EXPERIMENTAL APPROACH: We induced cardiac hypertrophy in wild-type (WT) and angiotensin II type 1a receptor knockout (AT1aR-KO) mice by transverse aortic constriction (TAC). The susceptibility to ventricular tachycardia (VT) assessed in an in vivo electrophysiological study was compared in the two genotypes. The effect of acute pharmacological blockade of AT1R on the incidences of arrhythmias was also assessed. KEY RESULTS: As described previously, WT and AT1aR-KO mice with TAC developed cardiac hypertrophy to the same degree, but the incidence of VT was much lower in the latter. Moreover, although TAC induced an increase in tyrosine phosphorylation of connexin 43, a critical component of gap junctional channels, and a reduction in ventricular levels of connexin 43 protein in both genotypes, the effect was significantly ameliorated in AT1aR-KO mice. Acute pharmacological blockade of AT1R also reduced the incidence of arrhythmias. CONCLUSIONS AND IMPLICATIONS: Our findings demonstrate that AT1aR-mediated signalling makes a direct contribution to the increase in arrhythmogenicity in hypertrophied hearts independently of structural remodelling. PMID- 23937448 TI - Modulation of intracellular ATP determines adenosine release and functional outcome in response to metabolic stress in rat hippocampal slices and cerebellar granule cells. AB - Cerebral ischaemia rapidly depletes cellular ATP. Whilst this deprives brain tissue of a valuable energy source, the concomitant production of adenosine mitigates the damaging effects of energy failure by suppressing neuronal activity. However, the production of adenosine and other metabolites, and their loss across the blood-brain barrier, deprives the brain of substrates for the purine salvage pathway, the primary means by which the brain makes ATP. Because of this, cerebral ATP levels remain depressed after brain injury. To test whether manipulating cellular ATP levels in brain tissue could affect functional neuronal outcomes in response to oxygen/glucose deprivation (OGD), we examined the effects of creatine and d-ribose and adenine (RibAde). In hippocampal slices creatine delayed ATP breakdown, reduced adenosine release, retarded both the depression of synaptic transmission and the anoxic depolarization caused by OGD, and improved the recovery of transmission. In contrast, RibAde increased cellular ATP, caused increased OGD-induced adenosine release and accelerated the depression of synaptic transmission, but did not improve functional recovery. However, RibAde improved the viability of cerebellar granule cells when administered after OGD. Our data indicate that RibAde may be effective in promoting recovery of brain tissue after injury, potentially via enhancement of salvage-mediated ATP production. PMID- 23937449 TI - Off-label and unlicensed drug use among neonatal intensive care units in Southern Italy. AB - BACKGROUND: Many drugs used for neonates are unlicensed or off-label. An increased risk of medication errors and unexpected adverse drug reactions is associated with their use. This risk is even higher in preterm newborns, because of their physiological immaturity and the exposure to many different medicines. The objective of this study was to evaluate the use of unlicensed or off-label drugs in eight tertiary-level neonatal intensive care units (NICU) from two different southern Italian regions. METHODS: All drugs prescribed to newborns admitted to each NICU, during 1 month of observation, were recorded and classified as licensed, unlicensed or off-label, according, respectively, first, to their license status and, then, their indications, dose, treatment route, and duration of treatment specified in each specific marketing authorization. RESULTS: A total of 126 newborns were treated with at least one drug during the observation period. A total of 483 prescriptions referred to 87 different drugs, classified as licensed, unlicensed or off-label. Each newborn was exposed to three (median) different drugs; 88.6% were licensed and 11.4% unlicensed (range, according to different NICU, 1.9-26.7%). Among licensed drugs, 37.4% were used as off-label (range, 27.3-53.4%). CONCLUSIONS: The use of unlicensed or off-label drugs use is common practice in NICU, with wide variation in local policies and newborn characteristics. Well-designed and -conducted pharmaceutical studies in newborns are needed to increase the number of licensed drugs, thereby reducing any risk for patients due to over- or under-treatment, and also legal issues for clinicians. PMID- 23937450 TI - Psoriasis first presenting around an enteral feeding tube in three pediatric patients: an important consideration for timely diagnosis and management. AB - Pediatric dermatologists may care for patients with percutaneous enteral feeding tubes. Although ostomy complications such as allergic contact and irritant dermatitis are common, psoriasis may be misdiagnosed. We report three novel cases of childhood psoriasis first presenting around an enteral feeding tube site. Localized psoriasis is an important clinical consideration in children with ostomy site eruptions to ensure timely diagnosis and effective management. PMID- 23937451 TI - Proton disorder in ice Ih and inhomogeneous broadening in two-dimensional infrared spectroscopy. AB - It is well-known that in ice Ih the oxygen atoms form a regular hexagonal lattice while the positions of the hydrogen atoms are disordered, called proton disorder in the literature. Various OH (OD) stretch vibrational spectroscopies (e.g., IR, Raman, two-dimensional IR (2DIR), and hole burning) have been used to probe this proton disorder in the past several decades. However, the presence and the magnitude of the inhomogeneous broadening due to this proton disorder in the vibrational spectroscopy is still controversial. In this work, we calculate 2DIR spectroscopy for HOD in D2O ice Ih at 80 K with a mixed quantum/classical approach, and make comparison to a recent 2DIR experiment on the same system. Fair agreement is achieved between theory and experiment, although the calculated 2DIR line shape shows inhomogeneous broadening that was not observed in the experiment. However, the theory reproduces the linear IR for the same system fairly well, and the inhomogeneous broadening from the calculation is consistent with the extrapolation of the experimental IR line-widths in the literature. The effect of this proton disorder on the 2DIR line shape is explored in detail. We also calculate the vibrational three-pulse photon echo peak shift signal, which shows signatures of both low-frequency dynamics and inhomogeneous broadening. PMID- 23937452 TI - Genotype is an important determinant factor of host susceptibility to periodontitis in the Collaborative Cross and inbred mouse populations. AB - BACKGROUND: Periodontal infection (Periodontitis) is a chronic inflammatory disease, which results in the breakdown of the supporting tissues of the teeth. Previous epidemiological studies have suggested that resistance to chronic periodontitis is controlled to some extent by genetic factors of the host. The aim of this study was to determine the phenotypic response of inbred and Collaborative Cross (CC) mouse populations to periodontal bacterial challenge, using an experimental periodontitis model. In this model, mice are co-infected with Porphyromonas gingivalis and Fusobacterium nucleatum, bacterial strains associated with human periodontal disease. Six weeks following the infection, the maxillary jaws were harvested and analyzed for alveolar bone loss relative to uninfected controls, using computerized microtomography (microCT). Initially, four commercial inbred mouse strains were examined to calibrate the procedure and test for gender effects. Subsequently, we applied the same protocol to 23 lines (at inbreeding generations 10-18) from the newly developed mouse genetic reference population, the Collaborative Cross (CC) to determine heritability and genetic variation of control bone volume prior to infection (CBV, naive bone volume around the teeth of uninfected mice), and residual bone volume (RBV, bone volume after infection) and loss of bone volume (LBV, the difference between CBV and RBV) following infection. RESULTS: BALB/CJ mice were highly susceptible (P<0.05) whereas DBA/2J, C57BL/6J and A/J mice were resistant. Six lines of the tested CC population were susceptible, whereas the remaining lines were resistant to alveolar bone loss. Gender effects on bone volume were tested across the four inbred and 23 CC lines, and found not to be significant. Based on ANOVA analyses, broad-sense heritabilities were statistically significant and equal to 0.4 for CBV and 0.2 for LBV. CONCLUSIONS: The moderate heritability values indicate that the variation in host susceptibility to the disease is controlled to an appreciable extent by genetic factors. These results strongly support the possibility of using the Collaborative Cross, as well as developing dedicated F2 (resistant x susceptible inbred strains) resource populations, for future dissection of genetic factors in periodontitis. PMID- 23937453 TI - Application of C-11-acetate positron-emission tomography (PET) imaging in prostate cancer: systematic review and meta-analysis of the literature. AB - To review the literature on the application of (11) C-acetate positron-emission tomography (PET) imaging in prostate cancer. We systematically reviewed the available literature and presented the results in meta-analysis format. PubMed, SCOPUS, ISI web of knowledge, Science Direct, Springer, and Google Scholar were searched with 'Acetate AND PET AND Prostate' as keywords. All studies that evaluated accuracy of (11) C-acetate imaging in primary or recurrent prostate cancer were included, if enough data could be extracted for calculation of sensitivity and/or specificity. In all, 23 studies were included in the study. For evaluation of primary tumour, pooled sensitivity was 75.1 (69.8-79.8)% and specificity was 75.8 (72.4-78.9)%. For detection of recurrence, sensitivity was 64 (59-69)% and specificity was 93 (83-98)%. Sensitivity for recurrence detection was higher in post-surgical vs post-radiotherapy patients and in patients with PSA at relapse of >1 ng/mL. Studies using PET/computed tomography vs PET also showed higher sensitivity for detection of recurrence. Imaging with (11) C acetate PET can be useful in patients with prostate cancer. This is especially true for evaluation of patients at PSA relapse, although the sensitivity is overall low. For primary tumour evaluation (localisation of tumour in the prostate and differentiation of malignant from benign lesions), (11) C-acetate is of limited value due to low sensitivity and specificity. Due to the poor quality of the included studies, the results should be interpreted with caution and further high-quality studies are needed. PMID- 23937455 TI - Molecular imprinted magnetic nanoparticles for controlled delivery of mitomycin C. AB - Controlled drug delivery system is a technique which has considerable recent potential in the fields of pharmacy and medicine. Mitomycin C is commonly used drug in the treatment of superficial bladder and breast cancers. In the present study, mitomycin C-imprinted magnetic poly(hydroxyethyl methacrylate)-based nanoparticles (MIMNs) were prepared using surfactant free emulsion polymerization for controlled delivery of mitomycin C. The MIMNs were characterized by fourier transform infrared spectroscopy, scanning electron microscopy, atomic force microscopy, electron spin resonance, and elemental analysis. The average particle diameter of MIMNs was about 200 nm. PMID- 23937454 TI - High expression level and nuclear localization of Sam68 are associated with progression and poor prognosis in colorectal cancer. AB - BACKGROUND: Src-associated in mitosis (Sam68; 68 kDa) has been implicated in the oncogenesis and progression of several human cancers. The aim of this study was to investigate the clinicopathologic significance of Sam68 expression and its subcellular localization in colorectal cancer (CRC). METHODS: Sam68 expression was examined in CRC cell lines, nine matched CRC tissues and adjacent noncancerous tissues using reverse transcription (RT)-PCR, quantitative RT-PCR and Western blotting. Sam68 protein expression and localization were determined in 224 paraffin-embedded archived CRC samples using immunohistochemistry. Statistical analyses were applied to evaluate the clinicopathologic significance. RESULTS: Sam68 was upregulated in CRC cell lines and CRC, as compared with normal tissues; high Sam68 expression was detected in 120/224 (53.6%) of the CRC tissues. High Sam68 expression correlated significantly with poor differentiation (P = 0.033), advanced T stage (P < 0.001), N stage (P = 0.023) and distant metastasis (P = 0.033). Sam68 nuclear localization correlated significantly with poor differentiation (P = 0.002) and T stage (P =0.021). Patients with high Sam68 expression or Sam68 nuclear localization had poorer overall survival than patients with low Sam68 expression or Sam68 cytoplasmic localization. Patients with high Sam68 expression had a higher risk of recurrence than those with low Sam68 expression. CONCLUSIONS: Overexpression of Sam68 correlated highly with cancer progression and poor differentiation in CRC. High Sam68 expression and Sam68 nuclear localization were associated with poorer overall survival. PMID- 23937456 TI - Laterally emitted surface second harmonic generation in a single ZnTe nanowire. AB - We report a direct observation on the laterally emitted surface second harmonic generation (SHG) in a single ZnTe nanowire. The highly directional surface SHG radiates vertically to the nanowire growth-axis with a high conversion efficiency of 5 * 10(-6) and a low divergence angle of 4 degrees . Polarization state, emission intensity, and direction of the surface SHG are found to be dependent on the polarization of the pumping laser, which is further confirmed by numerical simulations. The laterally emitted surface SHG with a high efficiency and low divergence angle has great potential for short-wavelength nanolasers, nonlinear microscopic imaging, and polarization-dependent photonic integrating. PMID- 23937457 TI - Commentary: coeliac disease and atherosclerosis--hand in hand? PMID- 23937458 TI - Commentary: coeliac disease and atherosclerosis--hand in hand? Authors' reply. PMID- 23937459 TI - Commentary: is Faecalibacterium prausnitzii a potential treatment for maintaining remission in ulcerative colitis? PMID- 23937460 TI - Commentary: antibodies reacting with the infliximab Fab portion--something new? Authors' reply. PMID- 23937461 TI - Commentary: antibodies reacting with the infliximab Fab portion--something new? PMID- 23937462 TI - Commentary: absolute and relative contraindications to pegylated-interferon or ribavirin in the US general patient population with chronic hepatitis C. PMID- 23937463 TI - Commentary: absolute and relative contraindications to pegylated-interferon or ribavirin in the US general patient population with chronic hepatitis C--authors' reply. PMID- 23937464 TI - Commentary: predicting complicated Crohn's disease and surgery--phenotypes, genetics, serology and psychological characteristics of a population-based cohort. PMID- 23937465 TI - Commentary: predicting complicated Crohn's disease and surgery--phenotypes, genetics, serology and psychological characteristics of a population-based cohort -authors' reply. PMID- 23937466 TI - Commentary: durability of SVR in chronic hepatitis C patients treated with peginterferon-a2a/ribavirin in combination with a direct-acting anti-viral. PMID- 23937467 TI - Commentary: durability of SVR in chronic hepatitis C patients treated with peginterferon-a2a/ribavirin in combination with a direct-acting anti-viral- authors' reply. PMID- 23937468 TI - Letter: atherosclerosis and coeliac disease--another feature of the changing paradigm? PMID- 23937469 TI - Letter: the role of sub-clinical inflammation and TRPV1 in the development of IBS like symptoms in ulcerative colitis in remission. PMID- 23937470 TI - Letter: atherosclerosis and coeliac disease--another feature of the changing paradigm? Authors' reply. PMID- 23937471 TI - Letter: antibiotic dose adjustment in patients with advanced liver disease. PMID- 23937472 TI - Letter: antibiotic dose adjustment in patients with advanced liver disease- authors' reply. PMID- 23937473 TI - The Reading the Mind in the Eyes test: validation of a French version and exploration of cultural variations in a multi-ethnic city. AB - INTRODUCTION: The first aim of our study was to validate the French version of the Reading the Mind in the Eyes test, a theory of mind test. The second aim was to test whether cultural differences modulate performance on this test. METHODS: A total of 109 participants completed the original English version and 97 participants completed the French version. Another group of 30 participants completed the French version twice, one week apart. RESULTS: We report a similar overall distribution of scores in both versions and no differences in the mean scores between them. However, 2 items in the French version did not collect a majority of responses, which differed from the results of the English version. Test-retest showed good stability of the French version. As expected, participants who do not speak French or English at home, and those born in Asia, performed worse than North American participants, and those who speak English or French at home. CONCLUSIONS: We report a French version with acceptable validity and good stability. The cultural differences observed support the idea that Asian culture does not use theory of mind to explain people's behaviours as much as North American people do. PMID- 23937474 TI - Impairment of thymocyte function via induction of apoptosis by areca nut extract. AB - Areca quid (AQ) chewing is a popular oral habit, especially in Southeast Asia cultures, in which children may be engaged in the addictive habit early in their lives. Extracts of areca nuts, the main component of AQ, have been shown to affect the functionality of T-cells. However, the potential influence of ANE on the development of T-cells is unknown. This study, therefore, investigated the impact of areca nut extracts (ANE) on thymocytes and the potential mechanisms of action. Mice administered intraperitoneally with ANE at 1, 5, or 25 mg/kg daily for 5 days showed significant dose-dependent reductions in thymocyte viability. A marked decrease in the total number of thymocytes and the proportion of thymic CD4(+)CD8(+) cells was observed in the 25 mg ANE/kg-treated mice, whereas the proportion of CD4 and CD8 single positive and CD4(-)CD8(-) cells was significantly increased. Further examination on the functionality of thymocytes showed that ANE suppress IL-2 production both ex vivo and in vitro. These results suggest that ANE may attenuate the development and functionality of thymic T cells. ANE also directly induced apoptosis in thymic T-cells through activation of casapase-3 and apoptosis inducing factor (AIF). Collectively, the data suggested that the thymus is a sensitive target to ANE. Early exposure to ANE may interfere with the development and functionality of thymic T-cells. PMID- 23937476 TI - Effect of surface sensory and motor electrical stimulation on chronic poststroke oropharyngeal dysfunction. AB - BACKGROUND: Chronic poststroke oropharyngeal dysfunction (OD) is a common condition, leading to severe complications, including death. Treatments for chronic poststroke OD are scarce. The aim of our study was to assess and compare the efficacy and safety of treatment with surface electrical stimulation (e-stim) at sensory and motor intensities in patients with chronic poststroke OD. METHODS: Twenty chronic poststroke patients with OD were randomly assigned to (i) sensory e-stim (treatment intensity: 75% of motor threshold) or (ii) motor e-stim (treatment intensity: motor threshold). Patients were treated during 10 days, 1 h/day. Videofluoroscopy was performed at the beginning and end of the study to assess signs of impaired efficacy and safety of swallow and timing of swallow response. KEY RESULTS: Patients presented advanced age (74.95 +/- 2.18), 75% were men. The mean days poststroke was 336.26 +/- 89.6. After sensory stimulation, the number of unsafe swallows was reduced by 66.7% (p < 0.001), the laryngeal vestibule closure time by 22.94% (p = 0.027) and maximal vertical hyoid extension time by 18.6% (p = 0.036). After motor stimulation, the number of unsafe swallows was reduced by 62.5% (p = 0.002), the laryngeal vestibule closure time by 38.26% (p = 0.009) and maximal vertical hyoid extension time by 24.8% (p = 0.008). Moreover, the motor stimulus reduced the pharyngeal residue by 66.7% (p = 0.002), the upper esophageal sphincter opening time by 39.39% (p = 0.009), and increased bolus propulsion force by 211.1% (p = 0.008). No serious adverse events were detected during the treatment. CONCLUSIONS & INFERENCES: Surface e-stim is a safe and effective treatment for chronic poststroke dysphagic patients. PMID- 23937475 TI - The power of integrating kinetic isotope effects into the formalism of the Michaelis-Menten equation. AB - The final arbiter of enzyme mechanism is the ability to establish and test a kinetic mechanism. Isotope effects play a major role in expanding the scope and insight derived from the Michaelis-Menten equation. The integration of isotope effects into the formalism of the Michaelis-Menten equation began in the 1970s and has continued until the present. This review discusses a family of eukaryotic copper proteins, including dopamine beta-monooxygenase, tyramine beta monooxygenase and peptidylglycine alpha-amidating enzyme, which are responsible for the synthesis of neuroactive compounds, norepinephrine, octopamine and C terminally carboxamidated peptides, respectively. The review highlights the results of studies showing how combining kinetic isotope effects with initial rate parameters permits the evaluation of: (a) the order of substrate binding to multisubstrate enzymes; (b) the magnitude of individual rate constants in complex, multistep reactions; (c) the identification of chemical intermediates; and (d) the role of nonclassical (tunnelling) behaviour in C-H activation. PMID- 23937477 TI - Local climate determines intra- and interspecific variation in sexual size dimorphism in mountain grasshopper communities. AB - The climate is often evoked to explain broad-scale clines of body size, yet its involvement in the processes that generate size inequality in the two sexes (sexual size dimorphism) remains elusive. Here, we analyse climatic clines of sexual size dimorphism along a wide elevation gradient (i) among grasshopper species in a phylogenetically controlled scenario and (ii) within species differing in distribution and cold tolerance, to highlight patterns generated at different time scales, mainly evolutionary (among species or higher taxa) and ontogenetic or microevolutionary (within species). At the interspecific level, grasshoppers were slightly smaller and less dimorphic at high elevations. These clines were associated with gradients of precipitation and sun exposure, which are likely indicators of other factors that directly exert selective pressures, such as resource availability and conditions for effective thermoregulation. Within species, we found a positive effect of temperature and a negative effect of elevation on body size, especially on condition-dependent measures of body size (total body length rather than hind femur length) and in species inhabiting the highest elevations. In spite of a certain degree of species-specific variation, females tended to adjust their body size more often than males, suggesting that body size in females can evolve faster among species and can be more plastic or dependent on nutritional conditions within species living in adverse climates. Natural selection on female body size may therefore prevail over sexual selection on male body size in alpine environments, and abiotic factors may trigger consistent phenotypic patterns across taxonomic scales. PMID- 23937478 TI - Auditory-visual localization in hemianopia. AB - OBJECTIVE: Beyond visual field defects, patients with hemianopia have been suggested to perceive horizontal visual space in a distorted manner. However, the pattern of these distortions remained debatable. The aim of this study was to estimate the geometry of the visual representation of space in hemianopia using an auditory marker. METHOD: Patients with pure left or right hemianopia (without neglect) were tested in tasks requiring them to bring a visual stimulus into spatial alignment with a target sound (Experiment 1) or vice versa (Experiment 2). RESULTS: In Experiment 1, patients adjusted the location of a light such that it was displaced toward the anopic side with reference to the physical sound position. In Experiment 2, patients adjusted the location of a sound such that it was displaced opposite to the anopic side with reference to the actual position of the visual target. Both experiments consistently indicated that hemianopic patients perceived a sound and a light to be in spatial alignment when the physical position of the light deviated by several degrees from the sound toward the side of the anopic hemifield, that is, to the contralesional side. CONCLUSIONS: Given that auditory localization in patients with hemianopia has been previously shown to be only slightly biased toward the anopic side, the observed distortion of visual space with reference to auditory space can be explained by assuming that visual positions were, in absolute terms, perceived as shifted toward the intact side. As a result, HA patients may perceive visual space as compressed on their ipsilesional (intact), in comparison with their contralesional (anopic) side. PMID- 23937479 TI - Spatial processing in adults with attention deficit hyperactivity disorder. AB - BACKGROUND: "Global processing bias" is an automatic tendency to process the global picture prior to the local details. The right hemisphere is known to be more dominant in global processing, and some researchers have demonstrated its important role in alertness. Converging evidence implies some dysfunction in right hemisphere activation in people suffering from attention deficit hyperactivity disorder (ADHD). Global processing is yet to be understood in ADHD. OBJECTIVE: We examined whether adults with ADHD show deficient global processing and whether this could be alleviated by the presence of an alerting signal. METHOD: Adult participants (20 ADHD, 20 typically developing controls) responded to a global-local Navon task in which they were asked to respond to the large stimulus or the small component stimuli, and to a Navon-like task with an alerting cue. Reaction time and accuracy were measured. RESULTS: Unlike controls, adults with ADHD did not have global precedence; irrelevant global stimuli (when asked to respond to the local level) and irrelevant local stimuli (when asked to respond to the global level) produced similar interference in ADHD participants. Appearance of an alerting cue increased global processing bias (i.e., increased interference from global stimuli in the local block and reduced interference from local stimuli in the global block) for both groups, such that global processing in ADHD participants was comparable to that of controls. CONCLUSION: ADHD participants showed lack of a global processing bias. Most important, global processing bias was reinstated by an alerting cue. Implications for the definition of ADHD, which currently emphasizes failure to pay close attention to details, will be discussed. Moreover, the current results have important implications for social functioning of people suffering from ADHD. PMID- 23937480 TI - Separate components of emotional go/no-go performance relate to autism versus attention symptoms in children with autism. AB - OBJECTIVE: The present investigation examined whether higher functioning children with autism would demonstrate impaired response inhibition performance in an emotional go/no-go task, and whether severity of attention-deficit/hyperactivity disorder (ADHD) or autism symptoms correlated with performance. METHOD: Forty four children (21 meeting criteria for autism; 23 typically developing controls [TDCs]) completed an emotional go/no-go task in which an emotional facial expression (angry, fearful, happy, or sad) was the go stimulus and a neutral facial expression was the no-go stimulus, and vice versa. RESULTS: The autism group was faster than the TDC group on all emotional go trials. Moreover, the children in the autism group who had the fastest reaction times on emotional go trials were rated as having the greatest number of symptoms (Autism Diagnostic Observation Schedule Social + Communication score), even after accounting for the association with ADHD symptoms. The autism group also made more impulsive responses (i.e., lower d', more false alarms) than the TDC group on all trials. As d' decreased or false alarms increased, so did ADHD symptoms. Hyperactivity/impulsivity symptoms were significantly correlated with false alarms, but inattention symptoms were not. There was not a significant relationship between no-go false alarms and autism symptoms; even after partialing out associations with autism symptoms, the significant correlation between ADHD symptoms and no-go false alarms remained. CONCLUSION: The present findings support a comorbidity model that argues for shared and independent risk factors, because ADHD and autism symptoms related to independent aspects of emotional go/no-go performance. PMID- 23937482 TI - Neural correlates of quantity processing of numeral classifiers. AB - OBJECTIVE: Classifiers play an important role in describing the quantity information of objects. Few studies have been conducted to investigate the brain organization for quantity processing of classifiers. In the current study, we investigated whether activation of numeral classifiers was specific to the bilateral inferior parietal areas, which are believed to process numerical magnitude. METHOD: Using functional MRI, we explored the neural correlates of numeral classifiers, as compared with those of numbers, dot arrays, and nonquantity words (i.e., tool nouns). RESULTS: Our results showed that numeral classifiers and tool nouns elicited greater activation in the left inferior frontal lobule and left middle temporal gyrus than did numbers and dot arrays, but numbers and dot arrays had greater activation in the middle frontal gyrus, precuneus, and the superior and inferior parietal lobule in the right hemisphere. No differences were found between numeral classifiers and tool nouns. CONCLUSION: The results suggest that quantity processing of numeral classifiers is independent of that of numbers and dot arrays, supporting the notation-dependent hypothesis of quantity processing. PMID- 23937481 TI - Brain white matter tract integrity and cognitive abilities in community-dwelling older people: the Lothian Birth Cohort, 1936. AB - OBJECTIVE: The present study investigates associations between brain white matter tract integrity and cognitive abilities in community-dwelling older people (N = 655). We explored two potential confounds of white matter tract-cognition associations in later life: (a) whether the associations between tracts and specific cognitive abilities are accounted for by general cognitive ability (g); and (b) how the presence of atrophy and white matter lesions affect these associations. METHOD: Tract integrity was determined using quantitative diffusion magnetic resonance imaging tractography (tract-averaged fractional anisotropy [FA]). Using confirmatory factor analysis, we compared first-order and bifactor models to investigate whether specific tract-ability associations were accounted for by g. RESULTS: Significant associations were found between g and FA in bilateral anterior thalamic radiations (r range: .16-.18, p < .01), uncinate (r range: .19-.26, p < .001), arcuate fasciculi (r range: .11-.12, p < .05), and the splenium of corpus callosum (r = .14, p < .01). After controlling for g within the bifactor model, some significant specific cognitive domain associations remained. Results also suggest that the primary effects of controlling for whole brain integrity were on g associations, not specific abilities. CONCLUSION: Results suggest that g accounts for most of, but not all, the tract-cognition associations in the current data. When controlling for age-related overall brain structural changes, only minor attenuations of the tract-cognition associations were found, and these were primarily with g. In totality, the results highlight the importance of controlling for g when investigating associations between specific cognitive abilities and neuropsychology variables. PMID- 23937484 TI - Medical and lifestyle interventions, not procedures, should be the primary focus in stroke prevention. PMID- 23937483 TI - Motor demands impact speed of information processing in autism spectrum disorders. AB - The apparent contradiction between preserved or even enhanced perceptual processing speed on inspection time tasks in autism spectrum disorders (ASD) and impaired performance on complex processing speed tasks that require motor output (e.g., Wechsler Processing Speed Index) has not yet been systematically investigated. This study investigates whether adding motor output demands to an inspection time task impairs ASD performance compared to that of typically developing control (TDC) children. The performance of children with ASD (n = 28; mean Full Scale IQ (FSIQ) = 115) and TDC (n = 25; mean FSIQ = 122) children was compared on processing speed tasks with increasing motor demand. Correlations were run between ASD task performance and Autism Diagnostic Observation Schedule (ADOS) Communication scores. Performance by the ASD and TDC groups on a simple perceptual processing speed task with minimal motor demand was equivalent, though it diverged (ASD worse than TDC) on 2 tasks with the same stimuli but increased motor output demands. ASD performance on the moderate but not the high speeded motor output demand task was negatively correlated with ADOS communication symptoms. These data address the apparent contradiction between preserved inspection time in the context of slowed "processing speed" in ASD. They show that processing speed is preserved when motor demands are minimized, but that increased motor output demands interfere with the ability to act on perceptual processing of simple stimuli. Reducing motor demands (e.g., through the use of computers) may increase the capacity of people with ASD to demonstrate good perceptual processing in a variety of educational, vocational, and social settings. PMID- 23937485 TI - From brain to heart: a (not so) long way to go. PMID- 23937486 TI - Malnutrition in children with food allergies in the UK. AB - BACKGROUND: The mainstay of dietary management of food allergies remains the elimination diet. However, the removal of major food groups may predispose children to an inadequate nutrient intake. We therefore set out to establish growth status in food allergic children receiving dietetic input in the UK. METHODS: Dietitians were approached via the Food Allergy and Intolerance Specialist Group from the British Dietetic Association and asked to submit anthropometrical data for children with food allergies. Data collected related to the systems involved and number of foods excluded. Malnutrition was defined according to World Health Organization standards. RESULTS: Data from 13 different centres yielded 97 patients (51 male and 46 female) of which 66 excluded <=2 foods and 31 excluded >=3 foods. Data indicated that 8.5% had a weight for age <= -2 Z-score and, conversely, 8.5% were >=2 Z-score. For height for age, 11.1% were <= -2 Z-score and, for weight for height, 3.7% were <= -2 Z-score and 7.5% >=2 Z score. Type of allergy, system involved and specific food elimination did not impact on the level of malnutrition. However, the elimination of >=3 foods significantly impacted on weight for age (P = 0.044). CONCLUSIONS: The present study demonstrates that children with food allergies are more underweight than the general UK population, which appears to be linked to the number of foods excluded. However, the impact of the disease process itself should not be disregarded. Additionally, obesity can also occur in this population despite dietary elimination. PMID- 23937488 TI - Admitting day. PMID- 23937489 TI - "I want to tea": an entering medical student's perspective on geriatrics. PMID- 23937487 TI - Real-time characterization of cannabinoid receptor 1 (CB1 ) allosteric modulators reveals novel mechanism of action. AB - BACKGROUND AND PURPOSE: The cannabinoid receptor type 1 (CB1 ) has an allosteric binding site. The drugs ORG27569 {5-chloro-3-ethyl-N-[2-[4-(1 piperidinyl)phenyl]ethyl]-1H-indole-2-carboxamide} and PSNCBAM-1 {1-(4 chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea} have been extensively characterized with regard to their effects on signalling of the orthosteric ligand CP55,940 {(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl] trans-4-(3-hydroxypropyl)cyclohexanol}, and studies have suggested that these allosteric modulators increase binding affinity but act as non-competitive antagonists in functional assays. To gain a deeper understanding of allosteric modulation of CB1 , we examined real-time signalling and trafficking responses of the receptor in the presence of allosteric modulators. EXPERIMENTAL APPROACH: Studies of CB1 signalling were carried out in HEK 293 and AtT20 cells expressing haemagglutinin-tagged human and rat CB1 . We measured real-time accumulation of cAMP, activation and desensitization of potassium channel-mediated cellular hyperpolarization and CB1 internalization. KEY RESULTS: ORG27569 and PSNCBAM-1 produce a complex, concentration and time-dependent modulation of agonist mediated regulation of cAMP levels, as well as an increased rate of desensitization of CB1 -mediated cellular hyperpolarization and a decrease in agonist-induced receptor internalization. CONCLUSIONS AND IMPLICATIONS: Contrary to previous studies characterizing allosteric modulators at CB1, this study suggests that the mechanism of action is not non-competitive antagonism of signalling, but rather that enhanced binding results in an increased rate of receptor desensitization and reduced internalization, which results in time dependent modulation of cAMP signalling. The observed effect of the allosteric modulators is therefore dependent on the time frame over which the signalling response occurs. This finding may have important consequences for the potential therapeutic application of these compounds. PMID- 23937490 TI - Losing spouses. PMID- 23937491 TI - Caregiver support groups. PMID- 23937492 TI - Length of time required to achieve a stable baseline blood pressure in the diagnosis of orthostatic hypotension. PMID- 23937493 TI - Recovery from possible late-onset Alzheimer's dementia? Evidence from a longitudinal community-based age-cohort study. PMID- 23937494 TI - Effects of a combined aquatic-nonaquatic training program on static and dynamic balance in elderly men. PMID- 23937495 TI - Two-year anemia incidence and causes in older individuals with near-abnormal baseline hemoglobin levels: the Sao Paulo Ageing and Health study. PMID- 23937496 TI - Barriers to and facilitators of participation of older adults in a placebo controlled randomized clinical trial. PMID- 23937497 TI - Is once-weekly resistance training enough to prevent sarcopenia? PMID- 23937498 TI - Low-intensity whole-body vibration training to reduce fall risk in active, elderly residents of a retirement village. PMID- 23937499 TI - Intervention to prevent falls in elderly adults living in a residential home. PMID- 23937500 TI - Trends in hospitalization associated with Alzheimer's disease in the United States. PMID- 23937501 TI - Inadequate knowledge of pneumococcal vaccine of nursing home healthcare workers affects the pneumococcal vaccination uptake of older adults in nursing homes. PMID- 23937502 TI - Is nursing home residence an independent risk factor of mortality in Chinese older adults? PMID- 23937503 TI - Abdominal wall hematoma and hemoperitoneum in an individual with concomitant use of warfarin and moxifloxacin. PMID- 23937504 TI - Rectal perforation after colonoscopic polypectomy presented as subcutaneous emphysema, pneumomediastinum and pneumoretroperitoneum successfully treated conservatively in an elderly adult. PMID- 23937505 TI - Sigmoid volvulus showing a "whirl sign" in coronal and sagittal views of computed tomography. PMID- 23937506 TI - Mattress crackles and diaphragm crackles: misleading physical signs with easy correctives. PMID- 23937507 TI - A biological basis for the sex bias of antipsychotic drugs adverse events. PMID- 23937509 TI - Metabolic alterations associated with schizophrenia: a critical evaluation of proton magnetic resonance spectroscopy studies. AB - By reviewing the existing (1) H-magnetic resonance spectroscopy literature in schizophrenia, the relationship of different sample characteristics and applied methodologies with metabolite alterations is explored. Furthermore, we emphasize common pitfalls and discrepancies in the methodological framework of the reviewed studies that introduce unwanted variation in findings and complicate the comparison of studies. A total of 92 studies were reviewed. Articles were retrieved by searching the Pubmed database. Care was taken to note down reliability and validity measures of each included study. Despite many methodological differences and shortcomings, progressive NAA reductions could be seen in several brain regions implicated in the pathogenesis of schizophrenia. In terms of treatment effects, cross-sectional evidence implicates a normalizing role for atypical antipsychotic medication; however, longitudinal studies remain inconclusive on this issue. Choline, creatine, and myo-inositol levels remain largely unchanged and a time-dependent role of glutamate finds confirmation in several spectroscopy studies. Other findings are less consistent and need further replication. Most studies lack power and methodological precision. Future studies should aim for standardization and for more distinguished study populations to gain more valid and reliable findings. PMID- 23937510 TI - The impact of telemedicine intensivist support and a pediatric hospitalist program on a community hospital. AB - BACKGROUND: Because of centralization of care, pediatric patients often require transfer for subspecialty care. We evaluated the impact of telemedicine critical care consultation and a pediatric hospitalist program on enabling patients to remain at a community hospital. PATIENTS AND METHODS: This is a retrospective chart review of pediatric patients at a community hospital receiving critical care consultation from a tertiary children's hospital from January 2006 to October 2009. Patient cohorts differed by modality of intensivist consultation (telephone versus telemedicine) and modality of inpatient ward care at the community hospital (primary care physician versus hospitalist). Patients were compared for differences in transfer rate and rate of diversion from the pediatric intensive care unit to the tertiary ward. RESULTS: One hundred fifty three charts were analyzed: 41 from prior to hospitalist and telemedicine implementation (Cohort 1), 56 from post-implementation of telemedicine but pre hospitalist program (Cohort 2), and 56 after implementation of both the telemedicine and hospitalist programs (Cohort 3). Baseline data did not differ among cohorts. Transfer rates after intensivist consultation were lower after implementation of telemedicine consultation (100%, 85.7%, and 87.5% in Cohorts 1 3, respectively; p=0.04). The proportion of transferred patients who were diverted to the tertiary ward decreased over time (19.5%, 14.5%, and 6.1% in Cohorts 1-3, respectively; p=0.003). CONCLUSIONS: Telemedicine consultation between pediatric intensivists and community hospital physicians combined with a pediatric hospitalist program at the community hospital has the potential to improve triage of pediatric patients and reduce the need to transfer patients. PMID- 23937511 TI - Improved performance of CuInS2 quantum dot-sensitized solar cells based on a multilayered architecture. AB - This article describes a CuInS2 quantum dot (QD)-sensitized solar cell (QDSSC) with a multilayered architecture and a cascaded energy-gap structure fabricated using a successive ionic-layer adsorption and reaction process. We initially used different metal chalcogenides as interfacial buffer layers to improve unmatched band alignments between the TiO2 and CuInS2 QD sensitizers. In this design, the photovoltaic performance, in terms of the short-circuit current density (JSC), open-circuit voltage (VOC), fill factor (FF), and power conversion efficiency (PCE), was significantly improved. Both JSC and VOC were improved in CuInS2-based QDSSCs in the presence of interfacial buffer layers because of proper band alignment across the heterointerface and the negative band edge movement of TiO2. The PCE of CuInS2-based QDSSCs containing In2Se3 interfacial buffer layers was 1.35%, with JSC=5.83 mA/cm2, VOC=595 mV, and FF=39.0%. We also examined the use of alternative CdS and CdSe hybrid-sensitized layers, which were sequentially deposited onto the In2Se3/CuInS2 configuration for creating favorable cascaded energy-gap structures. Both JSC (11.3 mA cm(-2)) and FF (47.3%) for the CuInS2/CdSe hybrid-sensitized cells were higher than those for CuInS2-based cells (JSC=5.83 mA cm(-2) and FF=39.0%). In addition, the hybrid-sensitized cells had PCEs that were 1.3 times those of cells containing identically pretreated In2Se3 interfacial buffer layers. Additionally, we determined that ZnSe served as a good passivation layer on the surface of CuInS2/CdSe hybrid-sensitized QDs, prevented current leakage from the QDs to electrolytes, and lowered interfacial charge recombination. Under simulated illumination (AM 1.5, 100 mW cm(-2)), multilayered QDSSCs with distinct architectures delivered a maximum external quantum efficiency of 80% at 500 nm and a maximum PCE of 4.55%, approximately 9 times that of QDSSCs fabricated with pristine CuInS2. PMID- 23937512 TI - Diagnostic markers of serious bacterial infections in febrile infants younger than 90 days old. AB - BACKGROUND: The aim of this study was to assess correlations between demographic, clinical and laboratory characteristics and the risk of serious bacterial infection (SBI) in febrile <90-day-old infants. METHODS: Medical records of all infants younger than 90 days old hospitalized at Dana-Dwek Children's Hospital (2006-2008) for evaluation of fever were retrospectively reviewed. Data on clinical, laboratory and demographic characteristics were retrieved and evaluated. RESULTS: Forty-eight of the 401 study infants (12%) had SBI: most of them had urinary tract infection (43 infants; 90% of all SBI), three infants had bacteremia, one had bacterial pneumonia and one had bacterial meningitis. Significant independent clinical predictors for the diagnosis of SBI included duration of fever, absence of rhinitis and the absence of lung and skin manifestations. Significant independent laboratory predictors were absolute neutrophil count (ANC), platelets, blood urea nitrogen and C-reactive protein (CRP) level. On receiver operating characteristic curve analysis, the CRP area under the curve (0.819) was significantly superior to ANC and leukocyte count. CONCLUSION: Of the clinical and laboratory variables selected for evaluation, qualitative CRP was the strongest independent predictor for diagnosing SBI and a significantly better diagnostic marker than clinical characteristics, ANC and white blood cell count. PMID- 23937513 TI - A cohort study of digoxin exposure and mortality in men with prostate cancer. AB - OBJECTIVE: To examine the association between digoxin exposure and mortality in men with prostate cancer using linked Irish National Cancer Registry and pharmacy claims data. PATIENTS AND METHODS: Prostate cancer cases were identified from the database and digoxin exposure at prostate cancer diagnosis was identified from prescription claims. Digoxin users were matched to non-users using a propensity score to identify men with similar cardiovascular comorbidity. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the association between digoxin exposure and all-cause and prostate cancer-specific mortality (PCSM). Analyses were repeated in the propensity score-matched cohort. Effect modification of treatment with radiation or androgen-deprivation therapy by digoxin exposure was also assessed. RESULTS: In all, 5732 men with a prostate cancer diagnosis (2001-2006) were identified (digoxin exposed, 391). The median follow-up was 4.3 years. Digoxin exposure was associated with a small non significant increase in PCSM in the full cohort (HR 1.13, 95% CI 0.91, 1.42) and the propensity. score-matched cohort (HR 1.17, 95% CI 0.88, 1.57). Adjusted HRs for all-cause mortality were increased for digoxin exposed men (HR 1.24, 95% CI 1.07, 1.43). Interactions with treatments received were not significant. CONCLUSIONS: These results suggest digoxin exposure is not associated with reduced PCSM. Further investigation of other cardiac glycosides that have shown anti-cancer potential may be warranted. PMID- 23937514 TI - Predictors of mother and child DNA yields in buccal cell samples collected in pediatric cancer epidemiologic studies: a report from the Children's Oncology group. AB - BACKGROUND: Collection of high-quality DNA is essential for molecular epidemiology studies. Methods have been evaluated for optimal DNA collection in studies of adults; however, DNA collection in young children poses additional challenges. Here, we have evaluated predictors of DNA quantity in buccal cells collected for population-based studies of infant leukemia (N = 489 mothers and 392 children) and hepatoblastoma (HB; N = 446 mothers and 412 children) conducted through the Children's Oncology Group. DNA samples were collected by mail using mouthwash (for mothers and some children) and buccal brush (for children) collection kits and quantified using quantitative real-time PCR. Multivariable linear regression models were used to identify predictors of DNA yield. RESULTS: Median DNA yield was higher for mothers in both studies compared with their children (14 MUg vs. <1 MUg). Significant predictors of DNA yield in children included case-control status (beta = -0.69, 50% reduction, P = 0.01 for case vs. control children), brush collection type, and season of sample collection. Demographic factors were not strong predictors of DNA yield in mothers or children in this analysis. CONCLUSIONS: The association with seasonality suggests that conditions during transport may influence DNA yield. The low yields observed in most children in these studies highlight the importance of developing alternative methods for DNA collection in younger age groups. PMID- 23937515 TI - Photochemical and optical properties of water-soluble xanthophyll antioxidants: aggregation vs complexation. AB - Xanthophyll carotenoids can self-assemble in aqueous solution to form J- and H type aggregates. This feature significantly changes the photophysical and optical properties of these carotenoids, and has an impact on solar energy conversion and light induced oxidative damage. In this study we have applied EPR and optical absorption spectroscopy to investigate how complexation can affect the aggregation ability of the xanthophyll carotenoids zeaxanthin, lutein, and astaxanthin, their photostability, and antioxidant activity. It was shown that complexation with the polysaccharide arabinogalactan (AG) polymer matrix and the triterpene glycoside glycyrrhizin (GA) dimer reduced the aggregation rate but did not inhibit aggregation completely. Moreover, these complexants form inclusion complexes with both monomer and H-aggregates of carotenoids. H-aggregates of carotenoids exhibit higher photostability in aqueous solutions as compared with monomers, but much lower antioxidant activity. It was found that complexation increases the photostability of both monomers and the aggregates of xanthophyll carotenoids. Also their ability to trap hydroperoxyl radicals increases in the presence of GA as the GA forms a donutlike dimer in which the hydrophobic polyene chain of the xanthophylls and their H-aggregates lies protected within the donut hole, permitting the hydrophilic ends to be exposed to the surroundings. PMID- 23937516 TI - In vivo diagnosis of gastric signet-ring cell carcinoma by confocal laser endomicroscopy. PMID- 23937517 TI - Effect of cyclical forces on the periodontal ligament and alveolar bone remodeling during orthodontic tooth movement. AB - OBJECTIVE: To investigate the effect of externally applied cyclical (vibratory) forces on the rate of tooth movement, the structural integrity of the periodontal ligament, and alveolar bone remodeling. METHODS: Twenty-six female Sprague-Dawley rats (7 weeks old) were divided into four groups: CTRL (unloaded), VBO (molars receiving a vibratory stimulus only), TMO (molars receiving an orthodontic spring only), and TMO+VB (molars receiving an orthodontic spring and the additional vibratory stimulus). In TMO and TMO+VB groups, the rat first molars were moved mesially for 2 weeks using Nickel-Titanium coil spring delivering 25 g of force. In VBO and TMO+VB groups, cyclical forces at 0.4 N and 30 Hz were applied occlusally twice a week for 10 minutes. Microfocus X-ray computed tomography analysis and tooth movement measurements were performed on the dissected rat maxillae. Tartrate-resistant acid phosphatase staining and collagen fiber assessment were performed on histological sections. RESULTS: Cyclical forces significantly inhibited the amount of tooth movement. Histological analysis showed marked disorganization of the collagen fibril structure of the periodontal ligament during tooth movement. Tooth movement caused a significant increase in osteoclast parameters on the compression side of alveolar bone and a significant decrease in bone volume fraction in the molar region compared to controls. CONCLUSIONS: Tooth movement was significantly inhibited by application of cyclical forces. PMID- 23937518 TI - Pattern of emergency department visits by elderly patients: study from a tertiary care hospital, Karachi. AB - BACKGROUND: Worldwide the proportion of elderly people in the population is increasing. Currently in Pakistan 7.3 million people (5.6% of total population) are more than 60 years old. This age shift has emerged as an important health issue and is associated with an increased utilization of emergency services by the elderly. We carried out this study to assess the pattern of elderly patients (>60 years) who visit emergency departments in comparison to young adults (18-60 years). METHODS: Data was collected retrospectively of patients aged 18 years or more who visited the Emergency Department (ED) of Aga Khan University Hospital, Karachi (AKUH) during September, 2009 to September, 2011. The data collection sheet included patient's demographic information, triage category, reason for visit, clinical presentation, ED length of stay, day and time of presentation and their disposition. Data was entered and analyzed using SPSS version 19.0. Descriptive statistics were used to describe patient's demographics. Chi-square (chi2) test was used as a test of significance to compare differences between groups for categorical data and t-test for continuous data. Multiple logistic regression analysis was done to find out the association between the patient characteristics and outcomes (admission and expiry). RESULTS: Almost 24% (n = 13014) of all adults (n = 54588) presenting to the ED were over the age of 60 years. More than 57% of elderly patients belonged to the high priority triage category compared to 35% in younger patients. Most of the elderly patients ( 27%) presented with nonspecific complaints followed by shortness of breath (13%) and fever (9%). The median length of stay (LOS) in the ED for elderly was 379 minutes (252 min in under-60 yrs patients) and they were more likely to get admitted to in-patient departments compared to younger patients (OR 1.7 95% CI 1.6-1.8). A high proportion of those admitted (20%) required intensive or special care. Mortality in elderly patients was 2.3% as compared to 0.7% in young adults. This was accompanied by a higher mortality risk in the elderly with an odds ratio of 2.3 (CI 2-2.5). CONCLUSION: Elderly ED users differ significantly from younger adults in terms of criticality on presentation, ED LOS and final disposition. PMID- 23937519 TI - Carotid intima-media thickness assessment in refinement of the Framingham Risk Score: can it predict ST-elevation myocardial infarction? A pilot study. AB - Patients who suffer a first ST-elevation myocardial infarction (STEMI) typically have fewer identifiable risk factors than those who suffer other types of acute coronary syndromes. As such, risk assessment tools such as the Framingham Risk Score (FRS) often fail to classify these patients as high risk. In this study, we tested the ability of assessment of carotid intima-media thickness (CIMT) to enhance the ability to identify patients who are at risk for STEMI, using a CIMT derived "vascular age" in place of chronologic age in the calculation of FRS. We applied a CIMT-based vascular age to the assessment of FRS in a cohort of patients who presented with a first STEMI. Using CIMT-derived vascular age in place of chronologic age increased both the mean FRS and predicted 10 year cardiovascular event rate of the cohort. More importantly, the use of a CIMT derived vascular age in the calculation of FRS significantly improved the ability to identify patients with STEMI as high risk and candidates for statin therapy based on ATPIII criteria (19.2% vs. 57.7%, P = 0.010). The use of CIMT to derive a vascular age may improve the ability of FRS to identify patients at risk for STEMI. PMID- 23937521 TI - Preparation of well-defined ibuprofen prodrug micelles by RAFT polymerization. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat acute pain, fever, and inflammation and are being explored in a new indication in cancer. Side effects associated with long-term use of NSAIDs such as gastrointestinal damage and elevated risk of stroke, however, can limit their use and exploration in new indications. Here we report a facile method to prepare well-defined amphiphilic diblock copolymer NSAID prodrugs by direct reversible addition-fragmentation transfer (RAFT) polymerization of the acrylamide derivative of ibuprofen (IBU), a widely used NSAID. The synthesis and self assembling behavior of amphiphilic diblock copolymers (PEG-PIBU) having a hydrophilic poly(ethylene glycol) block and a hydrophobic IBU-bearing prodrug block were investigated. Release profiles of IBU from the micelles by hydrolysis were evaluated. Furthermore, the antiproliferative action of the IBU-containing micelles in human cervical carcinoma (HeLa) and murine melanoma (B16-F10) cells was assessed. PMID- 23937522 TI - Chemically functionalized single-walled carbon nanotube films modulate the morpho functional and proliferative characteristics of astrocytes. AB - We used single-walled carbon nanotube (CNT) films to modulate the morpho functional and proliferative characteristics of astrocytes. When plated on the CNT films of various thicknesses, astrocytes grow bigger and rounder in shape with a decrease in the immunoreactivity of glial fibrillary acidic protein along with an increase in their proliferation, changes associated with the dedifferentiation of astrocytes in culture. Thus, CNT films, as a coating material for electrodes used in brain machine interface, could reduce astrogliosis around the site of implantation. PMID- 23937520 TI - RON12, a novel Plasmodium-specific rhoptry neck protein important for parasite proliferation. AB - Apicomplexan parasites invade host cells by a conserved mechanism: parasite proteins are secreted from apical organelles, anchored in the host cell plasma membrane, and then interact with integral membrane proteins on the zoite surface to form the moving junction (MJ). The junction moves from the anterior to the posterior of the parasite resulting in parasite internalization into the host cell within a parasitophorous vacuole (PV). Conserved as well as coccidia-unique rhoptry neck proteins (RONs) have been described, some of which associate with the MJ. Here we report a novel RON, which we call RON12. RON12 is found only in Plasmodium and is highly conserved across the genus. RON12 lacks a membrane anchor and is a major soluble component of the nascent PV. The bulk of RON12 secretion happens late during invasion (after parasite internalization) allowing accumulation in the fully formed PV with a small proportion of RON12 also apparent occasionally in structures resembling the MJ. RON12, unlike most other RONs is not essential, but deletion of the gene does affect parasite proliferation. The data suggest that although the overall mechanism of invasion by Apicomplexan parasites is conserved, additional components depending on the parasite-host cell combination are required. PMID- 23937523 TI - Bacterial motility confers fitness advantage in the presence of phages. AB - Dispersal provides the opportunity to escape harm and colonize new patches, enabling populations to expand and persist. However, the benefits of dispersal associated with escaping harm will be dependent on the structure of the environment and the likelihood of escape. Here, we empirically investigate how the spatial distribution of a parasite influences the evolution of host dispersal. Bacteriophages are a strong and common threat for bacteria in natural environments and offer a good system with which to explore parasite-mediated selection on host dispersal. We used two transposon mutants of the opportunistic bacteria, Pseudomonas aeruginosa, which varied in their motility (a disperser and a nondisperser), and the lytic bacteriophage FKZ. The phage was distributed either in the central point of colony inoculation only, thus offering an escape route for the dispersing bacteria; or, present throughout the agar, where benefits of dispersal might be lost. Surprisingly, we found dispersal to be equally advantageous under both phage conditions relative to when phages were absent. A general explanation is that dispersal decreased the spatial structuring of host population, reducing opportunities for parasite transmission, but other more idiosyncratic mechanisms may also have contributed. This study highlights the crucial role the parasites can play on the evolution of dispersal and, more specifically, that bacteriophages, which are ubiquitous, are likely to select for bacterial motility. PMID- 23937524 TI - Status epilepticus following inhalational exposure to bifenthrin, a Type II pyrethroid. PMID- 23937525 TI - Contribution of serum ethanol concentration to the osmol gap: a prospective volunteer study. PMID- 23937526 TI - Tender Nesting Polypore (Hapalopilus rutilans) poisoning: report of two cases. AB - INTRODUCTION: Only four cases of Hapalopilus rutilans poisoning have been previously published. We report two new cases. CASE REPORTS: A father and his 13 year-old daughter picked mushrooms identified as Fistulina hepatica specimens and ate an unknown quantity (Hour 0). At Hour 12 post-ingestion, both subjects complained of abdominal pain, then nausea, vomiting, anorexia, asthenia, diplopia, and blurred vision. The father also had visual hallucinations. On Day 2 post-ingestion, clinical examination showed multidirectional nystagmus. The father also had balance disorders and both subjects emitted purple urine. Laboratory tests showed elevated serum creatinine and blood urea levels, proteinuria and leukocyturia in both subjects, and mild elevation of hepatic enzymes in the father. Urine color returned to normal on Day 2 and Day 7 post ingestion in the girl and her father, respectively. Complete clinical and biochemical recovery was obtained within one week in both cases. DISCUSSION: Signs and symptoms are similar to those previously reported after H. rutilans ingestion. This mushroom can be easily confused with F. hepatica. Purple discoloration of the urine after ingestion of a polyporic mushroom is highly suggestive of H. rutilans poisoning. Polyporic acid is probably the active toxin. PMID- 23937527 TI - Pre-hospital management and outcome of acute poisonings by ambulances in Yekaterinburg, Russia. AB - INTRODUCTION: Large, prospective pre-hospital studies of acute poisonings are scarce. We present the epidemiology of the pre-hospital poisonings, the treatment given, the complications of the poisoning itself and the treatment, predictors for hospitalization, and the safety of the present approach in a large industrial Russian city. METHODS: Data were collected from March 2009 to March 2010. All adult (>= 16 years) acute poisonings in the city of Yekaterinburg, Russia were included. The prospective cohort inclusion of data included age, gender, simple clinical features (including consciousness, respiratory status, circulatory status, convulsions, etc.), main toxic agent, reason why poisoning was suspected, treatment given, and outcome. Multivariate logistic regression analysis was used to identify the factors associated with hospitalization of the patients. RESULTS: In total, 1795/2536 patients (71%) were brought to hospitals, 736/2536 (29%) were discharged by the ambulance, and 5/2536 (0.2%) died on scene. The most frequent main agents were opioids (25%), ethanol (9%), benzodiazepines (8%), corrosive substances (7%), carbon monoxide (5%), and neuroleptics (5%). Pre-hospital treatment was given to 73% of patients; 3% were intubated, and antidotes were given in 27% (naloxone 24%, atropine 2%, and flumazenil 0.2%). Gastric lavage was performed in 34%, but only 20% within the first hour after ingestion; 49% had a Glasgow Coma Scale (GCS)< 15, but only 6% of them were intubated in the ambulance. Activated charcoal was given to two patients, both with a GCS = 15. A suicidal behavior was the strongest predictor for hospitalization. CONCLUSION: This study reveals current practice differing from the common treatment practice in most places, especially concerning the use of gastric lavage. Whether the current practice led to an increased morbidity and mortality is uncertain, but it justifies the need for thorough evaluation of clinical practice. These findings highlight the importance of studies like the present to improve diagnostics, triage, and treatment in acute poisonings. PMID- 23937528 TI - Non-celiac gluten sensitivity: clinical relevance and recommendations for future research. AB - BACKGROUND: There has been increasing interest in the entity of Non-Celiac Gluten Sensitivity (NCGS) in recent years; however, it still remains a controversial topic and its pathogenesis is not well understood. Celiac Disease, in contrast, is a well-studied condition that has become increasingly recognized as a prevalent condition arising from a heightened immunological response to gluten. Wheat allergy is an IgE-mediated condition capable of causing a variety of gastrointestinal symptoms. However, the number of patients who have neither celiac disease nor wheat allergy, but appear to derive benefit from a gluten-free diet, is also increasing substantially. The use of the term NCGS as a way of describing this condition has become increasingly prevalent in recent years. PURPOSE: In this review, we will focus on gastrointestinal manifestations of NCGS and discuss the evidence for the condition and its putative pathogenesis. We will discuss areas of controversy and areas for potential future research. PMID- 23937529 TI - Texturing formulations for uranium skin decontamination. AB - CONTEXT: Since no specific treatment exists in case of cutaneous contamination by radionuclides such as uranium, a nanoemulsion comprising calixarene molecules, known for their good chelation properties, was previously designed. However, this fluid topical form may be not suitable for optimal application on the skin or wounds. OBJECTIVE: To develop a texturing pharmaceutical form for the treatment of wounded skins contaminated by uranium. MATERIALS AND METHODS: The formulations consisted in oil-in-water (O/W) nanoemulsions, loaded with calixarene molecules. The external phase of the initial liquid nanoemulsion was modified with a combination of thermosensitive gelifying polymers: Poloxamer and HydroxyPropylMethylcellulose (HPMC) or methylcellulose (MC). These new formulations were characterized then tested by ex vivo experiments on Franz cells to prevent uranyl ions diffusion through excoriated pig ear skin explants. RESULTS: Despite strong changes in rheological properties, the physico-chemical characteristics of the new nanoemulsions, such as the size and the zeta potential as well as macroscopic aspect were preserved. In addition, on wounded skin, diffusion of uranyl ions, measured by ICP-MS, was limited to less than 5% for both HPMC and MC nanoemulsions. CONCLUSIONS: These results demonstrated that a hybrid formulation of nanoemulsion in hydrogel is efficient to treat uranium skin contamination. PMID- 23937530 TI - Dose-dependent inhibitory effects of proton pump inhibitors on human osteoclastic and osteoblastic cell activity. AB - Proton pump inhibitors (PPIs), a class of molecules that are used to decrease gastric acid production, might have adverse effects on bone metabolism. The aim of this study was to characterize the concentration-dependent and time-dependent effects of three PPIs (omeprazole, esomeprazole, and lansoprazole) on human osteoclast precursor cells isolated from peripheral blood, and on human mesenchymal stem cells (osteoblast precursors). Cell cultures were characterized for total protein content, apoptosis, and several osteoclastic/osteoblastic features, and also for the involvement of some intracellular signaling pathways. PPIs caused a dose-dependent decrease in cellular density, which correlated with an increase in the apoptosis rate, effects that became statistically significant at concentrations >= 10(-5) m. They also inhibited phenotype-related gene expression and functional parameters. For both cell types, cellular function, i.e. osteoclastic resorption and the formation of mineralized deposits by osteoblastic cells, was more affected than proliferation-related parameters. The three PPIs showed similar qualitative and quantitative effects, but displayed some differences in the underlying intracellular signaling pathways. These results suggest that PPIs might have a direct deleterious effect on bone cells, with the possibility of decreased bone turnover. PMID- 23937531 TI - Fibrinogen monolayer characterization by colloid deposition. AB - Colloid particle deposition was applied to characterize bovine and human fibrinogen (Fb) monolayers on mica produced by controlled adsorption under diffusion transport at pH 3.5. The surface concentration of Fb was determined by AFM enumeration of single molecules adsorbed over the substrate surface. The electrokinetic properties of Fb monolayers for various ionic strength were studied using the in situ streaming potential measurements. It was shown that Fb adsorbs irreversibly on mica for a broad range of ionic strength of 4 * 10(-4) to 0.15 M, NaCl. The overcharging of initially negative mica surface occurred for fibrinogen surface concentrations higher than 1400 MUm(-2). The orientation of fibrinogen molecules in the monolayers was evaluated by the colloid deposition method involving negatively charged polystyrene latex microspheres, 820 nm in diameter. An anomalous deposition of negative latex particles on substrates exhibiting a negative zeta potential was observed, which contradicts the mean field DLVO predictions. Measurable deposition was observed even at low ionic strength where the minimum approach distance of latex particles to the interface exceeds 70 nm (for 6 * 10(-4) M NaCl). This confirms that, at this pH, fibrinogen molecules adsorb end-on on mica assuming extended conformations with the positive charge located mostly in the end part of the alphaA chains. This agrees with previous experimental and theoretical results discussed in the literature (Santore, M. M.; Wertz Ch. F. Protein spreading kinetics at liquid-solid interfaces via an adsorption probe method. Langmuir 2005, 21, 10172-10178 (experimental); Adamczyk, Z.; Barbasz, J.; Ciesla, M.; Mechanisms of fibrinogen adsorption at solid substrates. Langmuir, 2011, 25, 6868-6878 (theoretical)). This unusual latex deposition on Fb monolayers was quantitatively interpreted in terms of the model developed in ref 55 (Jin, X.; Wang, N. H. L.; Tarjus, G.; Talbot, J. Irreversible adsorption on nonuniform surfaces: the random site model. J. Phys. Chem. 1993, 97, 4256-4258). It was concluded that the colloid deposition method is an efficient tool for revealing protein adsorption mechanisms at solid/electrolyte interfaces. PMID- 23937533 TI - Personality Assessment Inventory scores as predictors of misconduct among sex offenders civilly committed as sexually violent predators. AB - We examined the usefulness of scores on the Personality Assessment Inventory (PAI; Morey, 1991) in predicting treatment program violations among 76 sexual offenders civilly committed as sexually violent predators. Scores on the Borderline Features scale (area under the curve [AUC] = .69, p = .005) and Negative Relationships subscale (BOR-N: AUC = .71, p < .001) were the strongest predictors of misconduct, outperforming scores on scales designed to predict poor treatment amenability and antisocial behavior. Incremental validity analyses indicated that BOR scores made a significant contribution to the prediction of misconduct after controlling for scores on measures of overall self-reported distress (e.g., Mean Clinical Elevation, Negative Impression), which were also predictive of program violations. Overall, our findings point to the potential utility of integrating components of treatment for borderline personality disorder into sex offender treatment. PMID- 23937532 TI - The dopamine patchwork of the rat nucleus accumbens core. AB - The dopamine (DA) terminal field in the rat dorsal striatum is organized as a patchwork of domains that show distinct DA kinetics. The rate and short-term plasticity of evoked DA release, the rate of DA clearance and the actions of several dopaminergic drugs are all domain-dependent. The patchwork arises in part from local variations in the basal extracellular concentration of DA, which establishes an autoinhibitory tone in slow but not fast domains. The present study addressed the hypothesis that a domain patchwork might also exist in the nucleus accumbens core (NAcc), a DA terminal field that is deeply involved in reward processing and the mechanisms underlying substance abuse. DA recordings in the NAcc by fast-scan voltammetry during electrical stimulation of the medial forebrain bundle confirmed that the NAcc contains a patchwork of fast and slow domains showing significantly different rates of evoked DA release and DA clearance. Moreover, the NAcc domains are substantially different from those in the dorsal striatum. There were no signs in the NAcc of short-term plasticity of DA release during multiple consecutive stimuli, and no signs of a domain dependent autoinhibitory tone. Thus, the NAcc domains are distinct from each other and from the domains of the dorsal striatum. PMID- 23937534 TI - How well is psychometric g indexed by global composites? Evidence from three popular intelligence tests. AB - Global composites (e.g., IQs) calculated in intelligence tests are interpreted as indexes of the general factor of intelligence, or psychometric g. It is therefore important to understand the proportion of variance in those global composites that is explained by g. In this study, we calculated this value, referred to as hierarchical omega, using large-scale, nationally representative norming sample data from 3 popular individually administered tests of intelligence for children and adolescents. We also calculated the proportion of variance explained in the global composites by g and the group factors, referred to as omega total, or composite reliability, for comparison purposes. Within each battery, g was measured equally well. Using total sample data, we found that 82%-83% of the total test score variance was explained by g. The group factors were also measured in the global composites, with both g and group factors explaining 89% 91% of the total test score variance for the total samples. Global composites are primarily indexes of g, but the group factors, as a whole, also explain a meaningful amount of variance. PMID- 23937535 TI - Examining tenets of personal growth initiative using the personal growth initiative scale-II. AB - One promising antecedent of optimal functioning is personal growth initiative (PGI), which is the active and intentional desire to grow as a person. PGI theory and its measure, the Personal Growth Initiative Scale, have consistently shown positive relations with optimal functioning and growth. Recently, the PGI theory and its measure have been revised to account for theoretical advances. Consequently, testing of the revised theory and measure is needed to assess their capacity to predict psychological functioning and growth. The current study examined 2 tenets of PGI theory in a sample of college students. Results indicated that 3 of the 4 factors of PGI were positively related to psychological well-being and negatively related to aspects of psychological distress. In addition, the same 3 factors were related to growth in a salient domain (vocational identity development) and explained variance beyond that accounted for by more stable personality traits. PMID- 23937536 TI - Young children's self-reported emotional, behavioral, and peer problems: the Berkeley Puppet Interview. AB - Adult observers are typically the only informants on emotional and behavioral problems in young children. Although additional information can be provided by child self-report, few validated, structured instruments are available to obtain self-report from young children. The Berkeley Puppet Interview (BPI) has been developed to obtain structured self-reports on multiple domains of mental health and social well-being. This study was the 1st to evaluate the psychometric properties of the BPI in a large sample. We studied 8 a priori scales of the interview in a Dutch community sample of 6,375 children ages 5-7 years. Using confirmatory factor analysis, we demonstrated adequate fit (Tucker-Lewis index = .90; comparative fit index = .90; root-mean-square error of approximation = .03) of a multidimensional model with 50 items loading on 8 latent factors (Depression, Separation Anxiety, Overanxious, Oppositional Defiant, Overt Hostility, Conduct Problems, Bullied by Peers, and Peer Acceptance/Rejection). This model was invariant across gender. Children reported anxiety-related problems more frequently than depressive problems, behavioral problems, or difficulties in peer relations. Reliability analyses showed that 3 broadband scales designated as Internalizing, Externalizing, and Peer Relations were homogeneous constructs (alphas = .68-.79). Higher scores on most BPI scales were associated with lower maternal education, lower family income, and non-Western ethnicity. Boys reported more behavioral and peer relation problems, whereas girls reported more emotional problems. The findings indicate that young children from socioeconomically and demographically diverse backgrounds are capable of providing valid, multidimensional information on their emotional, behavioral, and peer relation problems using the BPI. Young children's self-report is a promising addition to existing assessment tools. PMID- 23937537 TI - A comparison of three self-report measures of intolerance of uncertainty: an examination of structure and incremental explanatory power in a community sample. AB - Intolerance of uncertainty (IU) has been broadly defined as a dispositional fear of the unknown and appears to span across emotional disorders. Despite the fact that IU has received increased attention from clinical researchers, little systematic research has been completed to compare existing self-report measures of this construct. To help fill this gap in the extant literature, the structure and incremental explanatory power of 3 self-report measures of IU were examined in the present research using a large community sample of adults in the United States (N = 624). Results from confirmatory factor analyses supported the distinctiveness of the items of the 3 measures. Nonetheless, a higher order factor accounted for the latent correlations among the 3 measures, indicating that each measure assesses the same construct. Results from structural regression models indicated that each measure of IU tended to evidence incremental explanatory power beyond one another in the concurrent prediction of variance in scores of symptom measures. These results support the notion that all 3 of the targeted measures assess IU, although each measure appears to assess a distinct aspect of this construct. PMID- 23937538 TI - Changes in the relative abundance and movement of insect pollinators during the flowering cycle of Brassica rapa crops: implications for gene flow. AB - The potential movement of transgenes from genetically modified crops to non genetically modified crops via insect-mediated pollen dispersal has been highlighted as one of the areas of greatest concern in regards to genetically modified crops. Pollen movement depends sensitively on spatial and temporal variation in the movement of insect pollinators between crop fields. This study tested the degree of variation in the diversity and relative abundance of flower visiting insects entering versus leaving pak choi, Brassica rapa var. chinensis L. (Brassicales: Brassicaceae), crops throughout different stages of the flowering cycle. The relative abundance of flower-visiting insects varied significantly with Brassica crop phenology. Greater numbers of flower-visiting insects were captured inside rather than outside the crop fields, with the highest capture rates of flower-visitors coinciding with the peak of flowering in both spring-flowering and summer-flowering crops. Moreover, the ratio of flower visiting insects entering versus leaving crop fields also varied considerably with changing crop phenology. Despite high variation in relative capture rates, the data strongly indicate non-random patterns of variation in insect movement in relation to crop phenology, with early-season aggregation of flower-visiting insects entering and remaining in the crop, and then mass emigration of flower visiting insects leaving the crop late in the flowering season. Although pollen movement late in the flowering cycle might contribute relatively little to total seed set (and hence crop production), the findings here suggest that extensive late-season pollinator redistribution in the landscape could contribute disproportionately to long-distance gene movement between crops. PMID- 23937540 TI - Rates of lumbosacral transforaminal injections interpreted as intravascular: fluoroscopy alone or with digital subtraction. AB - We investigated the rate of injections interpreted as intravascular during imaging of lumbosacral transforaminal epidural injections, using fluoroscopy alone or with digital subtraction. We evaluated 732 injections performed on 348 patients: 8.1% (59/732) and 10.5% (77/732) of injections were interpreted as intravascular during fluoroscopy and digital subtraction, respectively, p = 0.13. The odds ratio (95% CI) for interpreting injections as intravascular increased for both fluoroscopy and digital subtraction fluoroscopy, with: each year of age, 1.04 (1.01-1.07) and 1.03 (1.00-1.06), p = 0.011 and 0.024, respectively; sacral compared with lumbar injections, 10 (5-19) and 8 (5-15), p < 0.001 for both. The odds ratio for intravascular injection increased with three other variables during digital subtraction fluoroscopy: spinal stenosis, 5.1 (1.5-17.1), p = 0.009; failed back surgery syndrome, 4.3 (1.2-15.8), p = 0.025; compression fracture, 8.0 (1.6-39.4), p = 0.011. PMID- 23937541 TI - Transformation of TiOF2 cube to a hollow nanobox assembly from anatase TiO2 nanosheets with exposed {001} facets via solvothermal strategy. AB - Hierarchical nanostructures have attracted increasing interest due to their exceptional properties and widespread potential applications. In this paper, anatase TiO2 hollow nanoboxes (TiO2-HNBs) are formed by assembly of nanosheets with exposed {001} facets by solvothermal treatment of TiOF2 cubes in alcohols (tert-butanol and ethanol) at 180 degrees C. It was found that phase transformation of TiOF2 to anatase TiO2 begins at corners and edges of TiOF2 cubes due to in situ hydrolysis of TiOF2, where water was produced by dehydration of alcohol molecules. With extension the reaction time, TiO2-HNB assemblies from nanosheets with exposed high-energy {001} facets were formed due to the steady inside-outside dissolution-recrystallization process. However, the resulting hierarchical TiO2-HNBs are unstable, which can decompose to discrete high-energy TiO2 nanosheets if the reaction time is further extended. The hierarchical TiO2 HNBs show higher photocatalytic activity than discrete high-energy TiO2 nanosheets and P25 TiO2 due to the unique structures of TiO2-HNBs. PMID- 23937542 TI - Evaluation of non-surgical causes of cardiac tamponade in children at a cardiac surgery center. AB - BACKGROUND: The aim of this study was to examine the causes of cardiac tamponade in children undergoing percutaneous pericardiocentesis. METHOD: Patients who presented with other complaints but were diagnosed with cardiac tamponade based on clinical and echocardiographic findings between January 2010 and January 2013 were retrospectively investigated. Electrocardiography, telecardiography and transthoracic echocardiography were performed. Pericardiocentesis was performed percutaneously under continuous blood pressure and rhythm monitoring with echocardiography and fluoroscopy. Pericardial fluid was analyzed on hemography and biochemistry. RESULTS: Fourteen patients (six boys, eight girls; median age, 7 years) underwent pericardiocentesis for cardiac tamponade. At presentation, 78% had dyspnea, 56% chest pain, and 49% fever. All had cardiomegaly, and their cardiothoracic index was 0.56-0.72. Also, all patients had sinus tachycardia; 78%, low QRS voltage; 70%, ST-T changes; and 50% QRS alternans. On echocardiography the widest diameter of pericardial effusion was between 12 mm and 36 mm depth around the heart. The pericardial fluid was purulent in one, serohemorrhagic in seven, serofibrinous in two, and serous in four cases. Pericardiocentesis was unsuccessful in two patients, who underwent open surgical drainage, with no complications. Based on pericardial fluid characteristics and additional tests, cardiac tamponade was caused by an infection in five patients, hypothyroidism in two, familial Mediterranean fever in two, malignancy in one, acute rheumatic fever in one, collagen tissue disease (systemic lupus erythematosus) in one, catheter placement-associated damage in one, and idiopathic pulmonary arterial hypertension in one patient. CONCLUSION: Pericardial effusion and cardiac tamponade in children have varied causes, and early treatment is life saving. PMID- 23937543 TI - Alliance, reactions to treatment, and counter-transference in the process of recovery from suicidal phenomena in long-term dynamic psychotherapy. AB - OBJECTIVE: We studied therapeutic processes associated with improvement in suicidality in a naturalistic study of long-term dynamic psychotherapy. METHODS: In a naturalistic study of long-term dynamic psychotherapy (n = 53), 31 patients reported suicidal ideation, eight of whom also reported prior suicide attempts, while 22 were non-suicidal. Suicide ideation and attempts and components of therapy alliance were followed at 6 month intervals. RESULTS: Suicidal patients had more psychiatric diagnoses, were treated longer and reported more negative reactions to treatment than non-suicidal patients. Alliance moderated (a) the relationship between negative reaction to treatment and improvement in suicidal ideation and (b) the relationship between quality of patient-therapist interaction and improvement. CONCLUSIONS: Suicidal patients manifest hostility and negative reactions to treatment, indicating negative transference. Avoiding therapist errors emanating from negative countertransference improves the therapeutic interaction, which is followed by faster rate of improvement in suicidality. PMID- 23937544 TI - Discovery and design of tricyclic scaffolds as protein kinase CK2 (CK2) inhibitors through a combination of shape-based virtual screening and structure based molecular modification. AB - Protein kinase CK2 (CK2), a ubiquitous serine/threonine protein kinase for hundreds of endogenous substrates, serves as an attractive anticancer target. One of its most potent inhibitors, CX-4945, has entered a phase I clinical trial. Herein we present an integrated workflow combining shape-based virtual screening for the identification of novel CK2 inhibitors. A shape-based model derived from CX-4945 was built, and the subsequent virtual screening led to the identification of several novel scaffolds with high shape similarity to that of CX-4945. Among them two tricyclic scaffolds named [1,2,4]triazolo[4,3-c]quinazolin and [1,2,4]triazolo[4,3-a]quinoxalin attracted us the most. Combining strictly chemical similarity analysis, a second-round shape-based screening was performed based on the two tricyclic scaffolds, leading to 28 derivatives. These compounds not only targeted CK2 with potent and dose-dependent activities but also showed acceptable antiproliferative effects against a series of cancer cell lines. Our workflow supplies a high efficient strategy in the identification of novel CK2 inhibitors. Compounds reported here can serve as ideal leads for further modifications. PMID- 23937545 TI - Evaluation of the taxonomic status of populations assigned to Phyllomedusa hypochondrialis (Anura, Hylidae, Phyllomedusinae) based on molecular, chromosomal, and morphological approach. AB - BACKGROUND: The taxonomic and phylogenetic relationships of the genus Phyllomedusa have been amply discussed. The marked morphological similarities among some species hamper the reliable identification of specimens and may often lead to their incorrect taxonomic classification on the sole basis of morphological traits. Phenotypic variation was observed among populations assigned to either P. azurea or P. hypochondrialis. In order to evaluate whether the variation observed in populations assigned to P. hypochondrialis is related to that in genotypes, a cytogenetic analysis was combined with phylogenetic inferences based on mitochondrial and nuclear sequences. RESULTS: The inter- and intra-population variation in the external morphology observed among the specimens analyzed in the present study do not reflect the phylogenetic relationships among populations. A monophyletic clade was recovered, grouping all the specimens identified as P. hypochondrialis and specimens assigned P. azurea from Minas Gerais state. This clade is characterized by conserved chromosomal morphology and a common C-banding pattern. Extensive variation in the nucleolar organizing region (NOR) was observed among populations, with four distinct NOR positions being recognized in the karyotypes. Intra-population polymorphism of the additional rDNA clusters observed in specimens from Barreiras, Bahia state, also highlights the marked genomic instability of the rDNA in the genome of this group. Based on the topology obtained in the phylogenetic analyses, the re evaluation of the taxonomic status of the specimens from the southernmost population known in Brazil is recommended. CONCLUSIONS: The results of this study support the need for a thorough revision of the phenotypic features used to discriminate P. azurea and P. hypochondrialis. The phylogenetic data presented here also contribute to an extension of the geographic range of P. hypochondrialis, which is known to occur in the Amazon basin and neighboring areas of the Cerrado savanna, where it may be sympatric with P. azurea, within contact zones. The misidentification of specimens may have led to inconsistencies in the original definition of the geographic range of P. azurea. The variability observed in the NOR of P. hypochondrialis reinforces the conclusion that these sites represent hotspots of rearrangement. Intraspecific variation in the location of these sites is the result of constant rearrangements that are not detected by classical cytogenetic methods or are traits of an ancestral, polymorphic karyotype, which would not be phylogenetically informative for this group. PMID- 23937539 TI - Small-interfering RNAs (siRNAs) as a promising tool for ocular therapy. AB - RNA interference (RNAi) can be used to inhibit the expression of specific genes in vitro and in vivo, thereby providing an extremely useful tool for investigating gene function. Progress in the understanding of RNAi-based mechanisms has opened up new perspectives in therapeutics for the treatment of several diseases including ocular disorders. The eye is currently considered a good target for RNAi therapy mainly because it is a confined compartment and, therefore, enables local delivery of small-interfering RNAs (siRNAs) by topical instillation or direct injection. However, delivery strategies that protect the siRNAs from degradation and are suitable for long-term treatment would be help to improve the efficacy of RNAi-based therapies for ocular pathologies. siRNAs targeting critical molecules involved in the pathogenesis of glaucoma, retinitis pigmentosa and neovascular eye diseases (age-related macular degeneration, diabetic retinopathy and corneal neovascularization) have been tested in experimental animal models, and clinical trials have been conducted with some of them. This review provides an update on the progress of RNAi in ocular therapeutics, discussing the advantages and drawbacks of RNAi-based therapeutics compared to previous treatments. PMID- 23937546 TI - Size effect on nucleation rate for homogeneous crystallization of nanoscale water film. AB - The nucleation rate from classical nucleation theory is independent of sample size. In the past decades, several experimental and theoretical studies argued that the homogeneous nucleation rate of ice in supercooled droplets increases when the drop size is decreased. In this paper, we investigate the nucleation of ice in nanoscale water films using molecular dynamics simulations. We found that the nucleation rate of ice actually decreases when the film thickness decreases in the nanoscale regime. A theoretical model is presented to interpret the mechanism of nucleation rate decrease, which agrees well with the simulation results. The model divides films into the near-surface and the middle regions that are characterized by relatively low and high nucleation rates, respectively. The middle region dominates the nucleation process of films, whereas its effect is continuously weakened when increasing volume fraction of the near-surface region by decreasing the film size, leading to a decrease of the total nucleation rate. The structural and thermodynamic analyses indicate that the high stress induced by the surface layering slows down the diffusion and increases the nucleation barrier in the near-surface region, which is responsible for the low nucleation rate and eventually the decrease of the total nucleation rate. PMID- 23937547 TI - Hereditary-like urothelial carcinomas of the upper urinary tract benefit more from adjuvant cisplatin-based chemotherapy after radical nephroureterectomy than do sporadic tumours. AB - OBJECTIVE: To evaluate the impact of 'hereditary-like' status in upper tract urothelial carcinoma (UTUC) on the survival of patients who have undergone radical nephroureterectomy (RNU) and adjuvant chemotherapy. PATIENTS AND METHODS: A multicentre retrospective study was performed on all patients with high-risk UTUC who underwent RNU and adjuvant cisplatin-based chemotherapy. Using a patient risk identification tool, we distinguished tumours suspected to be hereditary from sporadic tumours and compared survival rates. RESULTS: A total of 112 patients with a median age of 67 years were included. Hereditary-like tumour status was detected in 35 patients (31.3%), while 77 patients (68.7%) had sporadic tumours. The median age was significantly younger in the hereditary-like tumour group (56.0 vs 69.8 years, P < 0.001). Overall survival (OS) after chemotherapy was significantly better in the group with hereditary-like tumours than in the group with sporadic tumours (5-year OS: 48.2 vs 32%; P = 0.008). The cancer-specific survival (CSS) rate was significantly better in the group with 'hereditary-like' tumours than in the group with sporadic tumours (5-year CSS: 58 vs 35%; P = 0.006). Although there was a trend in favour of the hereditary-like tumours, we observed no significant difference regarding progression-free survival (PFS) between the two groups (5-year PFS: 71 vs 52%; P = 0.07). CONCLUSION: Adjuvant chemotherapy after RNU improves survival outcomes in patients with hereditary-like UTUC compared with those with sporadic tumours. PMID- 23937548 TI - EFV/FTC/TDF-associated hepatotoxicity: a case report and review. AB - The fixed-dose combination efavirenz, emtricitabine, and tenofovir (EFV/FTC/TDF) is a first-line agent for the treatment of HIV. We report the case of a 40-year old female with a history of HIV acquired through heterosexual contact who initiated EFV/FTC/TDF. Hepatitis B and C serologies were negative, CD4 cell count was 253 cells per cubic millimeter (15.8%), and HIV viral load was 67,373 copies per milliliter. Eight months later she developed transaminitis and severe right upper quadrant pain. Neither illicit drug abuse nor hepatotoxic medication such as acetaminophen was reported. After evaluation including negative acute viral hepatitis studies, EFV/FTC/TDF was discontinued; both her transaminitis and pain resolved. Hepatotoxicity is most often associated with efavirenz. Rarely, fulminant hepatic failure occurs. Efavirenz-related hepatotoxicity is thought to result from a cellular self-digestion process known as autophagy. This is the first report to our knowledge of EFV/FTC/TDF-related hepatotoxicity. PMID- 23937549 TI - Initiation of antiretroviral therapy in youth with HIV: a U.S.-based provider survey. AB - In 2009, the Department of Health and Human Services (DHHS) recommended initiating antiretroviral therapy (ART) for youth with HIV at higher CD4 counts (<=500 cells/mm3) than previously recommended (<=350 cells/mm3). Barriers experienced by providers regarding ART initiation in this population have not been assessed. From 12/2011-01/2012, we asked providers from the American Academy of HIV Medicine (AAHIVM) [corrected] listserv who prescribed ART to youth (ages 13-25 years) with behaviorally-acquired HIV to complete a web-based survey. We presented a clinical vignette to explore potential barriers for initiating ART. Overall, 274/290 (94%) respondents completed the survey. Most felt confident that evidence supported initiating ART at higher CD4 counts (94%), and that benefits outweighed the risks of long-term toxicity (98%) or developing resistance (88%). Most (96%) initiated ART in the patient vignette (age 19 years, CD4 count ~400). Patient characteristics (e.g., unstable housing or drug use) were perceived as large barriers to ART initiation. Low response rate (13%) was a limitation. Respondents were knowledgeable about relevant DHHS guidelines, believed sufficient evidence supported ART initiation at higher CD4 counts, and would provide treatment to those with CD4 counts <=500cells/mm3. Understanding and overcoming barriers to initiation of ART perceived by providers is important to ensure implementation of ART treatment guidelines. PMID- 23937550 TI - A Case of LV "Pseudo" Pseudodyskinesis. PMID- 23937551 TI - Evaluation of the automated hematology analyzer ADVIA(r) 120 for cerebrospinal fluid analysis and usage of unique hemolysis reagent. AB - INTRODUCTION: In this study, we evaluated the performance of the ADVIA 120 hematology system for cerebrospinal fluid (CSF) assay. METHODS: Cell counts and leukocyte differentials in CSF were examined with the ADVIA 120 hematology system, while simultaneously confirming an effective hemolysis agent for automated CSF cell counts. RESULTS: The detection limits of both white blood cell (WBC) counts and red blood cell (RBC) counts on the measurement of CSF cell counts by the ADVIA 120 hematology system were superior at 2 cells/MUL (10(-6) L). The WBC count was linear up to 9.850 cells/MUL, and the RBC count was linear up to approximately 20 000 cells/MUL. The intrarun reproducibility indicated good precision. The leukocyte differential of CSF cells, performed by the ADVIA120 hematology system, showed good correlation with the microscopic procedure. The VersaLyse hemolysis solution efficiently lysed the samples without interfering with cell counts and leukocyte differential, even in a sample that included approximately 50 000/MUL RBC. CONCLUSION: These data show the ADVIA 120 hematology system correctly measured the WBC count and leukocyte differential in CSF. The VersaLyse hemolysis solution is considered to be optimal for hemolysis treatment of CSF when measuring cell counts and differentials by the ADVIA 120 hematology system. PMID- 23937552 TI - A historical comparison of single incision and conventional multiport laparoscopic right hemicolectomy. AB - AIM: Single incision laparoscopic surgery (SILS) is specially suited for surgery of the right colon. This study presents the results of a historical controlled trial comparing single incision and multiport laparoscopic surgery (MLS) for right hemicolectomy. METHOD: A review of outcome data from 149 patients who underwent laparoscopic right hemicolectomy was performed from the Concord Hospital laparoscopic colorectal database. RESULTS: Between July 2006 and December 2011, 149 consecutive laparoscopic right hemicolectomies were performed. The first 74 were performed by MLS and from February 2009 all cases were performed by SILS (n = 75).The median ages in the MLS and SILS groups were 74 and 68 years. The median body mass index was 27 kg/m(2) in both groups. Patients were hospitalized for a median of 8 days in the MLS group compared with 5 days in the SILS group. The median length of the extraction wound was 50 mm in the MLS group compared with 43 mm in the SILS group. The indications for surgery were similar in both groups, being 67% and 68%. One patient in each group required conversion to open laparotomy, and no patient in the SILS group required conversion to a conventional multiport technique. Postoperative morbidity was similar in both groups. CONCLUSION: SILS offers a safe minimally invasive approach to right colon resection. In our series SILS patients had a shorter extraction wound size and shorter length of stay in hospital. PMID- 23937553 TI - Prediction of methicillin-resistant Staphylococcus aureus in patients with non nosocomial pneumonia. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is recognized as an important cause of not only hospital acquired pneumonia, but also non nosocomial pneumonia. However, the risk factors for non-nosocomial MRSA pneumonia are not clearly defined. Our objective was to identify risk factors at admission that were associated with non-nosocomial MRSA pneumonia. METHODS: We evaluated 943 patients admitted to a university-affiliated hospital with culture-positive bacterial pneumonia developed outside the hospital from January 2008 to December 2011. We compared the clinical characteristics between MRSA and non-MRSA pneumonia, and identified risk factors associated with MRSA pneumonia. RESULTS: Of 943 patients, MRSA was identified in 78 (8.2%). Higher mortality was observed in MRSA than in non-MRSA patients (33.3% vs. 21.5%; P = 0.017). In a logistic regression analysis, MRSA pneumonia was observed more frequently in patients with a previous history of MRSA infection (OR = 6.05; P < 0.001), a PSI score >=120 (OR = 2.40; P = 0.015), intravenous antibiotic treatment within 30 days of pneumonia (OR = 2.23; P = 0.018). By contrast, non-MRSA pneumonia was observed more often in patients with a single infiltrate on chest radiography (OR = 0.55; P = 0.029). CONCLUSIONS: Anti-MRSA antibiotics could be considered in hospitalized non-nosocomial patients with several risk factors identified herein. The presence or absence of these factors would provide useful guidance in selecting initial empirical antibiotics. PMID- 23937554 TI - Chirality-dependent vapor-phase epitaxial growth and termination of single-wall carbon nanotubes. AB - Structurally uniform and chirality-pure single-wall carbon nanotubes are highly desired for both fundamental study and many of their technological applications, such as electronics, optoelectronics, and biomedical imaging. Considerable efforts have been invested in the synthesis of nanotubes with defined chiralities by tuning the growth recipes but the approach has only limited success. Recently, we have shown that chirality-pure short nanotubes can be used as seeds for vapor phase epitaxial cloning growth, opening up a new route toward chirality controlled carbon nanotube synthesis. Nevertheless, the yield of vapor-phase epitaxial growth is rather limited at the present stage, due in large part to the lack of mechanistic understanding of the process. Here we report chirality dependent growth kinetics and termination mechanism for the vapor-phase epitaxial growth of seven single-chirality nanotubes of (9, 1), (6, 5), (8, 3), (7, 6), (10, 2), (6, 6), and (7, 7), covering near zigzag, medium chiral angle, and near armchair semiconductors, as well as armchair metallic nanotubes. Our results reveal that the growth rates of nanotubes increase with their chiral angles while the active lifetimes of the growth hold opposite trend. Consequently, the chirality distribution of a nanotube ensemble is jointly determined by both growth rates and lifetimes. These results correlate nanotube structures and properties with their growth behaviors and deepen our understanding of chirality controlled growth of nanotubes. PMID- 23937555 TI - Droplet-based microfluidic platform for high-throughput, multi-parameter screening of photosensitizer activity. AB - We present a fully integrated droplet-based microfluidic platform for the high throughput assessment of photodynamic therapy photosensitizer (PDT) efficacy on Escherichia coli. The described platform is able to controllably encapsulate cells and photosensitizer within pL-volume droplets, incubate the droplets over the course of several days, add predetermined concentrations of viability assay agents, expose droplets to varying doses of electromagnetic radiation, and detect both live and dead cells online to score cell viability. The viability of cells after encapsulation and incubation is assessed in a direct fashion, and the viability scoring method is compared to model live/dead systems for calibration. Final results are validated against conventional colony forming unit assays. In addition, we show that the platform can be used to perform concurrent measurements of light and dark toxicity of the PDT agents and that the platform allows simultaneous measurement of experimental parameters that include dark toxicity, photosensitizer concentration, light dose, and oxygenation levels for the development and testing of PDT agents. PMID- 23937556 TI - Analysis of G-block distributions and their impact on gel properties of in vitro epimerized mannuronan. AB - This paper reports a study of the distribution and function of homopolymeric guluronic acid blocks (G-blocks) in enzymatically modified alginate. High molecular weight mannuronan was incubated with one native (AlgE6) and two engineered G-block generating mannuronan C-5 epimerases (AlgE64 and EM1). These samples were found to contain G-blocks with a DP ranging from 20 to approximately 50, lacking the extremely long G-blocks (DP > 100) found in algal alginates. Calcium gels from epimerized materials were highly compressible and exhibited higher syneresis and rupture strength but lower Youngs modulus than gels made from algal polymers of similar G-content. Addition of extremely long G-blocks to the epimerized alginate resulted in decreased syneresis and rupture strength and an increased Young's modulus that can be explained by reinforcement of the cross linking zones at the cost of length and/or numbers of elastic segments. The presence and impact of these extremely long G-blocks found in natural alginates suggest that alginate gels can be viewed as a nanocomposite material. PMID- 23937557 TI - Role of partition coefficients in determining the percutaneous penetration of salicylic acid and formaldehyde under varying occlusion durations. AB - CONTEXT: Occlusion is widely utilized to enhance the percutaneous penetration of applied drugs in clinical practice; however, occlusion does not increase the penetration of all chemicals. OBJECTIVE: This study determines: (1) whether occlusion enhances the percutaneous penetration of the lipophilic salicylic acid or the hydrophilic formaldehyde when compared to non-occlusion, (2) evaluate whether occlusion duration affects the penetration of compounds and (3) establish to what extent occlusive films in clinical practice interact with topically applied chemicals and possibly hinder penetration. MATERIALS AND METHODS: Separately, single doses of [14C]-formaldehyde and [14C]-salicylic acid were applied onto human skin overlying diffusion cells under non-occlusion as well as various occlusive time periods (1, 4 and 8 h). The percent dose penetrating into each compartment as well the percent dose adhering to the plastic wrap were determined. RESULTS: The radioactivity recovery as percent of applied dose of [14C]-salicylic acid was significantly higher under occlusion versus non occlusion in the epidermis, dermis and receptor fluid after 24 h (p < 0.05). For [14C]-formaldehyde, no significant statistical differences were observed between occlusion versus non-occlusion. The plastic wrap often used to enhance the penetration of topically applied drugs does not itself substantially adhere to the tested chemicals. CONCLUSION: Occlusion duration, previously undocumented for in vitro studies, impacted the percutaneous penetration of the lipophilic salicylic acid more so than the hydrophilic formaldehyde. A strong correlation between occlusion-enhanced penetration and partition coefficients was observed, but we do not wish to overgeneralize these results until more compounds of varying physical--chemical properties are studied. PMID- 23937558 TI - The importance of social dimension and maturation stage for the probabilistic maturation reaction norm in Poecilia reticulata. AB - Maturation is an important event in an organism's life history, with important implications on dynamics of both wild and captive populations. The probabilistic maturation reaction norm (PMRN) has emerged as an important method to describe variation in maturation in wild fish. Because most PMRNs are based on age and size only, it is important to understand limitations of these variables in explaining maturation. We experimentally assessed (i) the sensitivity of age- and size-based PMRNs to unaccounted sources of plasticity, (ii) the role of social environment on maturation and (iii) the significance of estimating PMRNs early and late in the maturation process (initiation and completion of maturation, respectively). We reared male guppies (Poecilia reticulata) under laboratory conditions, subjected to two food levels and three different social cues. We found that growth and social environment affected the maturation in a way that could not be accounted for by their effect on age and size. PMRNs estimated for the initiation stage were less plastic (growth differences and social cues influenced the PMRN shape only little) than those for completion. The initiation of maturation is probably closer to the maturation 'decision' and allows determining factors influencing maturation decision most accurately. PMID- 23937559 TI - Novel lectin-modified poly(ethylene-co-vinyl acetate) mucoadhesive nanoparticles of carvedilol: preparation and in vitro optimization using a two-level factorial design. AB - Carvedilol used in cardiovascular diseases has systemic bioavailability of 25 35%. The objective of this study was production of lectin-modified poly(ethylene co-vinyl acetate) (PEVA) as mucoadhesive nanoparticles to enhance low oral bioavailability of carvedilol. Nanoparticles were prepared by the emulsification solvent evaporation method using a two-level factorial design. The studied variables included the vinyl acetate content of the polymer, drug and polymer content. Surface modification of PEVA nanoparticles with lectin was carried out by the adsorption method and coupling efficiency was determined using the Bradford assay. Mucoadhesion of nanoparticles was studied on mucin. The particle size, polydispersity index, zeta potential, drug loading and drug release from nanoparticles were studied. The morphology of nanoparticles and crystalline status of the entrapped drug were studied by SEM, DSC and XRD tests, respectively. Results showed the most effective factor on particle size and zeta potential was the interaction of polymer and drug content while, drug loading efficiency and mucoadhesion were more affected by the interaction of polymer type and drug content. Drug concentration was the most effective variable on the drug release rate. The drug was in amorphous state in nanoparticles. The optimum nanoparticles obtained by 45 mg of copolymer contained 12% vinyl acetate/4.3 ml of organic phase and drug concentration of 37.5 wt% of polymer. PMID- 23937560 TI - Survival analysis of Y-90 radiosynovectomy in the treatment of haemophilic synovitis of the knee: a 10-year retrospective review. AB - Despite recent advances including new therapeutic options and availability of primary prophylaxis in haemophiliacs, haemophilic synovitis is still the major clinical problem in significant patient population worldwide. We retrospectively reviewed our 10-year experience with Y-90 radiosynovectomy to determine the outcome in the knee joints of patients with haemophilic synovitis. Between 2002 and 2012, 82 knee joints of 67 patients with haemophilic synovitis were treated with Y-90 radiosynovectomy. The mean age was 16.8 +/- 7.8 years (range: 5-39 years). The mean follow-up period was 39.6 +/- 25.6 months (range: 12-95 months). Failure of therapy represented re-bleeding after a radiosynovectomy was used as an end point in patient time to progression (TTP) analysis. The median TTP was calculated as 72.0 +/- 3.6 months (95% CI 64.8-79.1 months) in Kaplan-Meier analysis. The 1, 3 and 5-year survival rates were 89%, 73% and 63% respectively. Longer TTP (hazard ratio for progression, 2.5; P = 0.00) was evident in patients who have greater reduction in bleeding frequency within 6 months after radiosynovectomy. We did not find a relationship between the TTP and the following variables: age, type and severity of haemophilia, the presence or absence of inhibitor, the radiological score, range of motion status of joints and the pretreatment bleeding frequency. We concluded that Y-90 radiosynovectomy in knee joint represents an important resource for the treatment of haemophilic synovitis, markedly reducing joint bleeding and long-term durability, irrespective of the radiographic stage and inhibitor status. PMID- 23937561 TI - Role of N-terminal extension of Bacillus stearothermophilus RNase H2 and C terminal extension of Thermotoga maritima RNase H2. AB - Bacillus stearothermophilus RNase H2 (BstRNH2) and Thermotoga maritima RNase H2 (TmaRNH2) have N-terminal and C-terminal extensions, respectively, as compared with Aquifex aeolicus RNase H2 (AaeRNH2). To analyze the role of these extensions, BstRNH2 and TmaRNH2 without these extensions were constructed, and their biochemical properties were compared with those of their intact partners and AaeRNH2. The far-UV CD spectra of all proteins were similar, suggesting that the protein structure is not significantly altered by removal of these extensions. However, both the junction ribonuclease and RNase H activities of BstRNH2 and TmaRNH2, as well as their substrate-binding affinities, were considerably decreased by removal of these extensions. The stability of BstRNH2 and TmaRNH2 was also decreased by removal of these extensions. The activity, substrate binding affinity and stability of TmaRNH2 without the C-terminal 46 residues were partly restored by the attachment of the N-terminal extension of BstRNH2. These results suggest that the N-terminal extension of BstRNH2 functions as a substrate-binding domain and stabilizes the RNase H domain. Because the C terminal extension of TmaRNH2 assumes a helix hairpin structure and does not make direct contact with the substrate, this extension is probably required to make the conformation of the substrate-binding site functional. AaeRNH2 showed comparable junction ribonuclease activity to those of BstRNH2 and TmaRNH2, and was more stable than these proteins, indicating that bacterial RNases H2 do not always require an N-terminal or C-terminal extension to increase activity, substrate-binding affinity, and/or stability. PMID- 23937562 TI - Manifestation of polar reaction pathways of 2,3-dichloro-5,6-dicyano-p benzoquinone. AB - Reactions of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) with silyl enol ethers, silyl ketene acetals, allylsilanes, enamino esters, and diazomethanes have been studied in CH3CN and CH2Cl2 solutions. The second-order rate constants for C attack at DDQ (log k(C)) correlate linearly with the nucleophile-specific parameters N and s(N) and are 2-5 orders of magnitude larger than expected for SET processes, which strongly supports the polar mechanism for C-C bond formation. The second-order rate constants for O attack agree well with the calculated rate constants for rate-determining single electron transfer (SET). As a radical clock experiment ruled out outer sphere electron transfer, an inner sphere electron transfer mechanism is suggested for O attack. PMID- 23937563 TI - Vibrational cross-angles in condensed molecules: a structural tool. AB - The fluctuations of three-dimensional molecular conformations of a molecule in different environments play critical roles in many important chemical and biological processes. X-ray diffraction (XRD) techniques and nuclear magnetic resonance (NMR) methods are routinely applied to monitor the molecular conformations in condensed phases. However, some special requirements of the methods have prevented them from exploring many molecular phenomena at the current stage. Here, we introduce another method to resolve molecular conformations based on an ultrafast MIR/T-Hz multiple-dimensional vibrational spectroscopic technique. The model molecule (4'-methyl-2'-nitroacetanilide, MNA) is prepared in two of its crystalline forms and liquid samples. Two polarized ultrafast infrared pulses are then used to determine the cross-angles of vibrational transition moment directions by exciting one vibrational band and detecting the induced response on another vibrational band of the molecule. The vibrational cross-angles are then converted into molecular conformations with the aid of calculations. The molecular conformations determined by the method are supported by X-ray diffraction and molecular dynamics simulation results. The experimental results suggest that thermodynamic interactions with solvent molecules are not altering the molecular conformations of MNA in the solutions to control their ultimate conformations in the crystals. PMID- 23937564 TI - Protective effects of peroxiredoxin 6 overexpression on amyloid beta-induced apoptosis in PC12 cells. AB - Oxidative stress triggered by amyloid beta (Abeta) accumulation contributes substantially to the pathogenesis of Alzheimer's disease (AD). In the present study, we examined the involvement of the antioxidant activity of peroxiredoxin 6 (Prdx 6) in protecting against Abeta25-35-induced neurotoxicity in rat PC12 cells. Treatment of PC12 cells with Abeta25-35 resulted in a dose- and time dependent cytotoxicity that was associated with increased accumulation of intracellular reactive oxygen species (ROS) and mitochondria-mediated apoptotic cell death, including activation of Caspase 3 and 9, inactivation of poly ADP ribosyl polymerse (PARP), and dysregulation of Bcl-2 and Bax. This apoptotic signaling machinery was markedly attenuated in PC12 cells that overexpress wild type Prdx 6, but not in cells that overexpress the C47S catalytic mutant of Prdx 6. This indicates that the peroxidase activity of Prdx 6 protects PC12 cells from Abeta25-35-induced neurotoxicity. The neuroprotective role of the antioxidant Prdx 6 suggests its therapeutic and/or prophylactic potential to slow the progression of AD and limit the extent of neuronal cell death caused by AD. PMID- 23937565 TI - Consumption of home-made spirits is one of the main source of exposure to higher alcohols and there may be a link to immunotoxicity. PMID- 23937568 TI - Mixed methyl- and propyl-thiolate monolayers on a Au(111) surface. AB - Mixed methyl- and propyl-thiolate self-assembled monolayers (SAMs) are prepared on a Au(111) surface by exposing the gold substrate to methyl-propyl-disulfide vapor at room temperature. Scanning tunneling microscopy imaging of such SAMs reveals a (3 * 4) phase consisting of CH3-S-Au-S-CH3, CH3-S-Au-S-(CH2)2CH3, and CH3-(CH2)2-S-Au-S-(CH2)2CH3. Partial desorption of methyl-thiolate occurs when samples are thermally annealed to 373 K, leading to the formation of a striped phase consisting of primarily CH3-(CH2)2-S-Au-S-(CH2)2CH3. PMID- 23937566 TI - Inhibitory effects of marine-derived DNA-binding anti-tumour tetrahydroisoquinolines on the Fanconi anaemia pathway. AB - BACKGROUND AND PURPOSE: We have previously shown that cells with a defective Fanconi anaemia (FA) pathway are hypersensitive to trabectedin, a DNA-binding anti-cancer tetrahydroisoquinoline (DBAT) whose adducts functionally mimic a DNA inter-strand cross link (ICL). Here we expand these observations to new DBATs and investigate whether our findings in primary untransformed cells can be reproduced in human cancer cells. EXPERIMENTAL APPROACH: Initially, the sensitivity of transformed and untransformed cells, deficient or not in one component of the FA pathway, to mitomycin C (MMC) and three DBATs, trabectedin, Zalypsis and PM01183, was assessed. Then, the functional interaction of these drugs with the FA pathway was comparatively investigated. KEY RESULTS: While untransformed FA-deficient haematopoietic cells were hypersensitive to both MMC and DBATs, the response of FA-deficient squamous cell carcinoma (SCC) cells to DBATs was similar to that of their respective FA-competent counterparts, even though these FA-deficient SCC cells were hypersensitive to MMC. Furthermore, while MMC always activated the FA pathway, the DBATs inhibited the FA pathway in the cancer cell lines tested and this enhanced their response to MMC. CONCLUSIONS AND IMPLICATIONS: Our data show that although DBATs functionally interact with DNA as do agents that generate classical ICL, these drugs should be considered as FA pathway inhibitors rather than activators. Moreover, this effect was most significant in a variety of cancer cells. These inhibitory effects of DBATs on the FA pathway could be exploited clinically with the aim of 'fanconizing' cancer cells in order to make them more sensitive to other anti-tumour drugs. PMID- 23937567 TI - Quantitative variation in plasma angiotensin-I converting enzyme activity shows allelic heterogeneity in the ABO blood group locus. AB - Angiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ~36% lower) and Type B alleles (in whom plasma ACE activity was ~36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects. PMID- 23937569 TI - Selectivity data: assessment, predictions, concordance, and implications. AB - Could high-quality in silico predictions in drug discovery eventually replace part or most of experimental testing? To evaluate the agreement of selectivity data from different experimental or predictive sources, we introduce the new metric concordance minimum significant ratio (cMSR). Empowered by cMSR, we find the overall level of agreement between predicted and experimental data to be comparable to that found between experimental results from different sources. However, for molecules that are either highly selective or potent, the concordance between different experimental sources is significantly higher than the concordance between experimental and predicted values. We also show that computational models built from one data set are less predictive for other data sources and highlight the importance of bias correction for assessing selectivity data. Finally, we show that small-molecule target space relationships derived from different data sources and predictive models share overall similarity but can significantly differ in details. PMID- 23937570 TI - Measuring the orientation of taurine in the active site of the non-heme Fe(II)/alpha-ketoglutarate-dependent taurine hydroxylase (TauD) using electron spin echo envelope modulation (ESEEM) spectroscopy. AB - The position and orientation of taurine near the non-heme Fe(II) center of the alpha-ketoglutarate (alpha-KG)-dependent taurine hydroxylase (TauD) was measured using Electron Spin Echo Envelope Modulation (ESEEM) spectroscopy. TauD solutions containing Fe(II), alpha-KG, and natural abundance taurine or specifically deuterated taurine were prepared anaerobically and treated with nitric oxide (NO) to make an S = 3/2 {FeNO}(7) complex that is suitable for robust analysis with EPR spectroscopy. Using ratios of ESEEM spectra collected for TauD samples having natural abundance taurine or deuterated taurine, (1)H and (14)N modulations were filtered out of the spectra and interactions with specific deuterons on taurine could be studied separately. The Hamiltonian parameters used to calculate the amplitudes and line shapes of frequency spectra containing isolated deuterium ESEEM were obtained with global optimization algorithms. Additional statistical analysis was performed to validate the interpretation of the optimized parameters. The strongest (2)H hyperfine coupling was to a deuteron on the C1 position of taurine and was characterized by an effective dipolar distance of 3.90 +/- 0.25 A from the {FeNO}(7) paramagnetic center. The principal axes of this C1-(2)H hyperfine coupling and nuclear quadrupole interaction tensors were found to make angles of 26 +/- 5 and 52 +/- 17 degrees , respectively, with the principal axis of the {FeNO}(7) zero-field splitting tensor. These results are discussed within the context of the orientation of substrate taurine prior to the initiation of hydrogen abstraction. PMID- 23937571 TI - Nucleotide-binding oligomerization domain containing-like receptor family, caspase recruitment domain (CARD) containing 4 (NLRC4) regulates intrapulmonary replication of aerosolized Legionella pneumophila. AB - BACKGROUND: Legionella pneumophila (Lp) flagellin activates signaling pathways in murine macrophages that control Lp replication. Nucleotide-binding oligomerization domain (NOD) containing-like receptor (NLR) family, caspase recruitment domain (CARD) containing 4 (NLRC4) and Toll-like Receptor (TLR5) both recognize Lp flagellin in vitro, but whether these two receptors play redundant or separate functional roles in vivo is unknown. METHODS: The immune response of Nlrc4-/-, Nlrc4-/-/Tlr5-/-, and wild type C57Bl/6 mice was analyzed after in vivo infection with aerosolized Lp. RESULTS: Lp clearance from the lungs was delayed in Nlrc4-/- mice over seven days in comparison to wild type controls. Nlrc4-/ /Tlr5-/- mice had no additional defect. In contrast to TLR5, NLRC4 did not regulate recruitment of neutrophils to the lung. Although there were no differences among the mouse strains in the lung transcriptome at 4 hours, Nlrc4-/ and Nlrc4-/-Tlr5-/- mice had increased lung inflammation at 72 hours in comparison to WT. Nlrc4-/-/Tlr5-/- mice also had altered cytokine production at both 4 and 24 hours post infection when compared to wild-type (WT) and Nlrc4-/- mice. Lp replication in murine alveolar macrophages was NLRC4-dependent and TLR5 independent. CONCLUSION: These studies reveal that NLRC4 and TLR5 mediate different roles in the inflammatory response to Lp flagellin in an aerosolized infection model and NLRC4 regulates replication in both lungs and alveolar macrophages. PMID- 23937573 TI - Abstracts of the 53rd Annual Meeting of the Society for Psychophysiological Research. Florence, Italy. October 2-6, 2013. PMID- 23937572 TI - 'Indeterminate for malignancy' (Tir3/Thy3 in the Italian and British systems for classification) thyroid fine needle aspiration (FNA) cytology reporting: morphological criteria and clinical impact. AB - BACKGROUND: The British system (Thy1-5), the Bethesda system for reporting thyroid cytopathology (BSRTC) and the Italian Society of Anatomic Pathology and Cytology (SIAPEC) classification represent the most important international classifications for thyroid cytopathology. Irrespective of the system used, the 'indeterminate' categories are still debated among cytopathologists, particularly with regard to diagnostic criteria, clinical impact of subclassification and role of molecular techniques. AIM: We aimed to find answers to the following questions: Are there shared criteria in cytological preparations that allow the division of indeterminate follicular lesions into subcategories? What is the true clinical impact of this possible subclassification? METHODS: Among 1150 consecutive thyroid fine needle aspiration (FNA) specimens, 80 patients had nodules with a final cytological report of Tir3 (SIAPEC)/Thy3. These 80 cases were re-evaluated and subclassified according to morphological criteria into three groups: pure follicular proliferations, Hurthle cell follicular lesions and atypical proliferations. RESULTS: Sixteen (20%) cases were categorized as pure follicular proliferations, 40 (50%) as Hurthle cell follicular lesions and 24 (30%) as atypical proliferations. Surgery was performed in 57 cases (71%). Cyto histological correlation showed that follicular adenoma was the most frequent final diagnosis in the cases treated by surgery (24/57, 42%). The overall malignancy rate in the Tir3 category was 28% (16/57). Atypical proliferations were more often malignant than either of the follicular groups (53% versus 19%, P = 0.019). CONCLUSIONS: A five-tiered classification, subdividing the 'indeterminate for malignancy' class into 'follicular proliferations' and 'atypical lesions' could be adopted. As a result of their higher risk of malignancy, surgical management of the atypical lesions would be justified. In future, the introduction of a genetic panel might contribute to their stratification, to the determination of a more accurate risk of malignancy of the atypical lesions and to the verification of follicular proliferations that are benign. PMID- 23937574 TI - Use of rectus sheath catheters for pain relief in patients undergoing major pelvic urological surgery. AB - OBJECTIVE: To report on the safety and efficacy of rectus sheath blocks, 'topped up' using bilateral rectus sheath catheters (RSCs), in patients undergoing major open urological surgery. METHODS: The RSCs were inserted under ultrasound guidance into 200 patients between April 2008 and August 2011, of whom 106 patients underwent radical retropubic prostatectomy (RRP) and 94 underwent open radical cystectomy (ORC). A retrospective case-note review was undertaken. Outcomes included technical success and complication rates of the insertion and use of RSC, visual analogue pain scores, additional analgesia requirements and length of hospital stay (LOS). RESULTS: All RSCs were successfully placed without complication and used for a mean of 3.6 days for ORC and 2.1 days for RRP. Early removal occurred in 6.49% of patients. Low overall pain scores were reported in both groups. Patients were more likely to require a patient-controlled analgesia system in the ORC group but the overall need for additional analgesia was low in both groups, reducing significantly after the initial 24 h. In combination with an enhanced recovery programme, LOS reduced from 17.0 to 10.8 days in the ORC group and from 6.2 to 2.8 days in the RRP group. CONCLUSION: The use of RSCs appears to offer an effective and safe method of peri-operative analgesia in patients undergoing major open urological pelvic surgery. PMID- 23937575 TI - Whence lepidic?: the history of a Canadian neologism. AB - The term lepidic is used prominently in the recently published multidisciplinary classification of adenocarcinoma. The lack of use in common (nonmedical) English has led to some confusion over the proper definition of this term. This historical perspective traces the history of the term lepidic from its origins at McGill University in Montreal, Canada, through its uses in English pathologic descriptions, to its current state in pulmonary pathology. PMID- 23937576 TI - Capturing the population structure of microparasites: using ITS-sequence data and a pooled DNA approach. AB - The internal transcribed spacer (ITS) region of nuclear ribosomal DNA is a common marker not only for the molecular identification of different taxa and strains, but also for the analysis of population structure of wild microparasite communities. Importantly, the multicopy nature of this region allows the amplification of low-quantity samples of the target DNA, a common problem in studies on unicellular, unculturable microparasites. We analysed ITS sequences from the protozoan parasite Caullerya mesnili (class Ichthyosporea) infecting waterflea (Daphnia) hosts, across several host population samples. We showed that analysing representative ITS-types [as identified by statistical parsimony network analysis (SPN)] is a suitable method to address relevant polymorphism. The spatial patterns were consistent regardless of whether parasite DNA was extracted from individual hosts or pooled host samples. Remarkably, the efficiency in detecting different sequence types was even higher after sample pooling. As shown by simulations, an easily manageable number of sequences from pooled DNA samples are sufficient to resolve the spatial population structure in this system. In summary, the ITS region analysed from pooled DNA samples can provide valuable insights into the spatial and temporal dynamics of microparasites. Moreover, the application of SPN analysis is a good alternative to the well-established neighbour-joining method (NJ) for the identification of representative ITS-types. SPN can even outperform NJ by joining most of the singleton sequences to representative sequence clusters. PMID- 23937577 TI - DifferInt: compositional differentiation among populations at three levels of genetic integration. AB - In many fields of study, it is important to know how different populations are genetically. Commonly used measures such as FST and its derivatives based on gene identity probabilities do not reliably reflect difference, as they can be maximal when almost all populations are identical and very small when populations are completely distinct. Compositional differentiation, in contrast, is maximal only for completely distinct populations. Moreover, underlying forces of fragmentation that act on single- and multilocus genotypes may be missed if only the allelic level is viewed. For these reasons, descriptive measures of compositional differentiation based on untransformed distributions of genetic types at different levels of genetic integration (alleles, single- and multilocus genotypes) were derived. Here, two measures of complementary differentiation and two new measures of dispersive differentiation are described. One of each considers genic differences between individuals, ensuring their consistency across integration levels. An increase from one level to the next indicates differences among the populations in their forms of gene association. The computer program DifferInt calculates these measures for one or more codominantly expressed gene loci at the gene-pool, single-locus and multilocus levels. Effects of gene pools and gene association on differentiation are compared by permutation analysis. Snail diagrams depict the contribution of each population to differentiation. Results are demonstrated using a numerical example. The applicability of the measures calculated by this program in conservation, phylogeography, mating system analysis and adaptation studies is discussed. PMID- 23937578 TI - Permanent genetic resources added to molecular ecology resources database 1 April 2013-31 May 2013. AB - This article documents the addition of 234 microsatellite marker loci to the Molecular Ecology Resources Database. Loci were developed for the following species: Acipenser sinensis, Aleochara bilineata, Aleochara bipustulata, Barbus meridionalis, Colossoma macropomum, Delia radicum, Drosophila nigrosparsa, Fontainea picrosperma, Helianthemum cinereum, Liomys pictus, Megabalanus azoricus, Pelteobagrus vachelli, Pleuragramma antarcticum, Podarcis hispanica type 1A, Sardinella brasiliensis and Sclerotinia homoeocarpa. These loci were cross-tested on the following species: Acipenser dabryanus, Barbus balcanicus, Barbus barbus, Barbus cyclolepis, Drosophila hydei, Drosophila melanogaster, Drosophila obscura, Drosophila subobscura, Fontainea australis, Fontainea fugax, Fontainea oraria, Fontainea rostrata, Fontainea venosa, Podarcis bocagei, Podarcis carbonelli, Podarcis liolepis, Podarcis muralis and Podarcis vaucheri. PMID- 23937579 TI - Incidence and index of severity of hemolytic uremic syndrome in a 26 year period in Fukushima Prefecture, Japan. AB - BACKGROUND: There have been a number of reports on large outbreaks of hemolytic uremic syndrome (HUS), but there have been no long-term studies of sporadic HUS in Japan. This study therefore investigated the epidemiology and prognosis of HUS in Fukushima Prefecture over a 26 year period. METHODS: The medical records of 26 patients with HUS between 1987 and 2012 were collected. These children were divided into two groups: those with HUS following an episode of gastroenteritis, often with bloody diarrhea (D + HUS; n = 24) and those with HUS not associated with prodromal diarrhea (D-HUS; n = 2). The D + HUS group was further subdivided into group A (11 patients requiring dialysis) and group B (13 patients not requiring dialysis). The epidemiological and clinical data, as well as prognosis, were retrospectively investigated for each group. RESULTS: Approximately 90% of HUS patients belonged to the D + HUS group. In this group, the mean number of patients per year from 1987 to 1999, and from 2000 to 2012 was 0.92 +/- 0.95, and 1.08 +/- 0.86, respectively. On admission, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), blood urea nitrogen (BUN), serum creatinine and serum fibrinogen degradation product (FDP) levels in group A were all higher than in group B. Serum albumin level and estimated glomerular filtration rate (eGFR) in group A were lower than in group B. At 6 months after the onset of HUS in the D + HUS group, renal function was normal. CONCLUSIONS: The frequency of HUS was constant from 1987 to 2012 in Fukushima. and serum LDH, ALT, BUN, creatinine, and FDP levels as well as eGFR might be risk factors for dialysis in D + HUS children. PMID- 23937580 TI - Effect of diclofenac on ocular levels of ciprofloxacin and lomefloxacin in rabbits with endophthalmitis. AB - The purpose of this study was to analyze ciprofloxacin and lomefloxacin penetration into the anterior eye tissues after topical instillation in healthy rabbits and with experimental Staphylococcus aureus endophthalmitis. Additionally, effect of diclofenac sodium eye drops on the distribution of both fluoroquinolones in the inflamed eye tissues was investigated. An intense protocol with frequent antibiotic administration was chosen. Samples from aqueous humor were obtained 2 and 6 h after the start of the treatment. Samples from cornea and iris were obtained at the end of the experiment, after euthanasia of the animals. Drug concentrations were measured by HPLC method. The median levels of ciprofloxacin and lomefloxacin in aqueous humor of healthy animals, 2 and 6 h after drug administration were 6.39-9.65 and 5.30-6.81 ug/ml, respectively. Ciprofloxacin levels were neither changed from the inflammation nor after instillation of diclofenac. In contrary, lomefloxacin concentrations in aqueous humour of inflamed eye were significantly increased 12.15-15.08 ug/ml, especially after diclofenac administration (17.12-27.76 ug/ml). Levels of both fluoroquinolones in cornea (13.08 ug/g for ciprofloxacin and 12.25 ug/g for lomefloxacin) and in iris (0.84 ug/g for ciprofloxacin and 1.34 ug/g for lomefloxacin) were higher than MIC and MBC values against S. aureus ATCC 25923. Although higher lomefloxacin concentrations were observed in the aqueous humor after instillation of diclofenac, the levels of both fluoroquinolones in iris and in cornea were not significantly changed. Topical administration of lomefloxacin and diclofenac in combination improved penetration of the antibacterial agent in the aqueous humor which can be of clinical importance. PMID- 23937581 TI - Effect of binder liquid type on spherical crystallization. AB - AIM: Spherical crystallization is a process of formation of agglomerates of crystals held together by binder liquid. This research focused on understanding the effect of type of solvents used as binder liquid on the agglomeration of crystals. METHOD: Carbamazepine and ethanol/water were used respectively as a model drug and crystallization system. Eight solvents as binder liquid including chloroform, dichloromethane, isopropyl acetate, ethyl acetate, n-hexane, dimethyl aniline, benzene and toluene were examined to better understand the relationship between the physical properties of the binder liquid and its ability to bring about the formation of the agglomerates. Moreover, the agglomerates obtained from effective solvents as binder liquid were evaluated in term of size, apparent particle density and compressive strength. RESULTS: In this study the clear trend was observed experimentally in the agglomerate formation as a function of physical properties of the binder liquid such as miscibility with crystallization system. Furthermore, the properties of obtained agglomerates such as size, apparent particle density and compressive strength were directly related to physical properties of effective binder liquids. CONCLUSION: RESULTS of this study offer a useful starting point for a conceptual framework to guide the selection of solvent systems for spherical crystallization. PMID- 23937582 TI - Recent advances in gel technologies for topical and transdermal drug delivery. AB - Transdermal drug delivery systems are a constant source of interest because of the benefits that they afford in overcoming many drawbacks associated with other modes of drug delivery (i.e. oral, intravenous). Because of the impermeable nature of the skin, designing a suitable drug delivery vehicle that penetrates the skin barrier is challenging. Gels are semisolid formulations, which have an external solvent phase, may be hydrophobic or hydrophilic in nature, and are immobilized within the spaces of a three-dimensional network structure. Gels have a broad range of applications in food, cosmetics, biotechnology, pharmatechnology, etc. Typically, gels can be distinguished according to the nature of the liquid phase, for example, organogels (oleogels) contain an organic solvent, and hydrogels contain water. Recent studies have reported other types of gels for dermal drug application, such as proniosomal gels, emulgels, bigels and aerogels. This review aims to introduce the latest trends in transdermal drug delivery via traditional hydrogels and organogels and to provide insight into the latest gel types (proniosomal gels, emulgels, bigels and aerogels) as well as recent technologies for topical and transdermal drug delivery. PMID- 23937583 TI - The angiogenic effect of ONO-1301, a novel long-acting prostacyclin agonist loaded in PLGA microspheres prepared using different molecular weights of PLGA, in a murine sponge model. AB - The purpose of this study was to evaluate the angiogenic effect of topical application of three types of ONO-1301-loaded poly (lactide-co-glycolide) microspheres (ONO-1301 PLGA MS). ONO-1301 PLGA MS were prepared with PLGA 5010, 5020 and 5050 (with molecular weights of 10 K, 20 K and 50 K, respectively), using the solvent evaporation method. The lactide:glycolide ratio was fixed at 50:50; only the molecular weight was varied. The microspheres had an average diameter of almost 25 um, and a loading efficiency of at least 70%. The sustained release effect and its dependence on the molecular weight of the polymer used was confirmed in an in vitro drug-release test and by measuring subcutaneous plasma levels after administration of the three types of ONO-1301 PLGA MS to rats for 28 days. In the murine sponge model, the three types of ONO-1301 PLGA MS were administered to mice in a subcutaneously placed sponge and hemoglobin and hepatocyte growth factor (HGF) levels in the sponge were measured at predefined intervals up to 28 days. The hemoglobin and HGF levels obtained were significantly higher than those obtained after daily administration of ONO-1301 powder. Additional in vivo fluorescence imaging showed that PLGA MS remained in the sponge for 28 days. In conclusion, the three types of ONO-1301 PLGA MS prepared with PLGA three different molecular weight suppress the burst release, stimulate angiogenesis on topical application in a murine sponge model. This formulation may therefore be capable of improving the clinical picture in some types of vascular disease. PMID- 23937584 TI - Potential technique for tiny crystalline detection in lycopene-loaded SLN and NLC development. AB - CONTEXT: The advantage of solid nanocarriers like solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC) is related to some degree of crystalline characteristics of the lipid. However, the detection of tiny content of crystalline structure in such nanoparticles is difficult. OBJECTIVE: The aim of this study was to explore a potential method for detection of low degree of crystalline characteristics of lycopene-loaded SLN and NLC. METHODS: Crystalline characteristics investigation was done by polarized light microscope (PLM), differential scanning calorimeter (DSC), X-ray diffractometer (XRD) and transmission electron microscope (TEM). RESULTS AND DISCUSSION: It was found that high crystalline characteristics as anisotropic molecular organization crystal of pure orange wax and lycopene could be investigated by PLM, DSC and WAXS. Low crystallinity of lycopene-loaded SLN and NLC could not be detected by those techniques. Electron diffraction mode of TEM showed potential detection of tiny crystalline characteristics of such systems. The diffraction pattern of lycopene loaded SLN and NLC exhibited obvious zero order laue zone indicating an isotropic fine grained polycrystalline of the nanoparticles. CONCLUSION: It could be concluded that TEM is a promising method for detection of low-level crystallinity of solid nanocarriers. PMID- 23937585 TI - Solanum torvum responses to the root-knot nematode Meloidogyne incognita. AB - BACKGROUND: Solanum torvum Sw is worldwide employed as rootstock for eggplant cultivation because of its vigour and resistance/tolerance to the most serious soil-borne diseases as bacterial, fungal wilts and root-knot nematodes. The little information on Solanum torvum (hereafter Torvum) resistance mechanisms, is mostly attributable to the lack of genomic tools (e.g. dedicated microarray) as well as to the paucity of database information limiting high-throughput expression studies in Torvum. RESULTS: As a first step towards transcriptome profiling of Torvum inoculated with the nematode M. incognita, we built a Torvum 3' transcript catalogue. One-quarter of a 454 full run resulted in 205,591 quality-filtered reads. De novo assembly yielded 24,922 contigs and 11,875 singletons. Similarity searches of the S. torvum transcript tags catalogue produced 12,344 annotations. A 30,0000 features custom combimatrix chip was then designed and microarray hybridizations were conducted for both control and 14 dpi (day post inoculation) with Meloidogyne incognita-infected roots samples resulting in 390 differentially expressed genes (DEG). We also tested the chip with samples from the phylogenetically-related nematode-susceptible eggplant species Solanum melongena. An in-silico validation strategy was developed based on assessment of sequence similarity among Torvum probes and eggplant expressed sequences available in public repositories. GO term enrichment analyses with the 390 Torvum DEG revealed enhancement of several processes as chitin catabolism and sesquiterpenoids biosynthesis, while no GO term enrichment was found with eggplant DEG.The genes identified from S. torvum catalogue, bearing high similarity to known nematode resistance genes, were further investigated in view of their potential role in the nematode resistance mechanism. CONCLUSIONS: By combining 454 pyrosequencing and microarray technology we were able to conduct a cost-effective global transcriptome profiling in a non-model species. In addition, the development of an in silico validation strategy allowed to further extend the use of the custom chip to a related species and to assess by comparison the expression of selected genes without major concerns of artifacts. The expression profiling of S. torvum responses to nematode infection points to sesquiterpenoids and chitinases as major effectors of nematode resistance. The availability of the long sequence tags in S. torvum catalogue will allow precise identification of active nematocide/nematostatic compounds and associated enzymes posing the basis for exploitation of these resistance mechanisms in other species. PMID- 23937586 TI - Implications of enzyme deficiencies on mitochondrial energy metabolism and reactive oxygen species formation of neurons involved in rotenone-induced Parkinson's disease: a model-based analysis. AB - Steadily growing experimental evidence suggests that mitochondrial dysfunction plays a key role in the age-dependent impairment of nerve cells underlying several neurodegenerative diseases. In particular, the citric acid cycle enzyme complex alpha-ketoglutarate dehydrogenase (KGDHC) and respiratory chain complex I of the respiratory chain often show reduced activities in the dopaminergic neurons involved in Parkinson's disease, both giving rise to an impaired mitochondrial energy metabolism as demonstrated in a number of in vitro studies with cell lines as well as isolated mitochondria. To understand the metabolic regulation underlying these experimental findings we used a detailed kinetic model of mitochondrial energy metabolism. First, we investigated the effect of complex I inhibition on energy production and formation of reactive oxygen species (ROS). Next, we applied the model to a situation where both KGDHC and complex I exhibit reduced activities. These calculations reveal synergistic effects with respect to the energy metabolism but antagonistic effects with respect to ROS formation: the drop in the ATP production capacity is more pronounced than at inhibition of either enzyme complex alone. Interestingly, however, the reduction state of the ROS-generating sites of the impaired complex I becomes significantly lowered if additionally the activity of the KGDHC is reduced. We discuss the pathophysiological consequences of these intriguing findings. PMID- 23937587 TI - The diagnosis and treatment of a mycotic coronary artery aneurysm: a case report. AB - Aneurysms of the coronary arteries are rare and are usually associated with atherosclerosis in adults. Mycotic coronary artery aneurysms are exceedingly uncommon and are typically associated with systemic bacteremia, endocarditis, or septic emboli. Literature and data describing the management of mycotic coronary artery aneurysms are limited. This case describes the successful diagnosis of a large right coronary artery aneurysm by transesophageal echocardiogram as well as the successful management of the aneurysm. PMID- 23937588 TI - Electrical spin injection and detection in Mn5Ge3/Ge/Mn5Ge3 nanowire transistors. AB - In this Letter, we report the electrical spin injection and detection in Ge nanowire transistors with single-crystalline ferromagnetic Mn5Ge3 as source/drain contacts formed by thermal reactions. Degenerate indium dopants were successfully incorporated into as-grown Ge nanowires as p-type doping to alleviate the conductivity mismatch between Ge and Mn5Ge3. The magnetoresistance (MR) of the Mn5Ge3/Ge/Mn5Ge3 nanowire transistor was found to be largely affected by the applied bias. Specifically, negative and hysteretic MR curves were observed under a large current bias in the temperature range from T = 2 K up to T = 50 K, which clearly indicated the electrical spin injection from ferromagnetic Mn5Ge3 contacts into Ge nanowires. In addition to the bias effect, the MR amplitude was found to exponentially decay with the Ge nanowire channel length; this fact was explained by the dominated Elliot-Yafet spin-relaxation mechanism. The fitting of MR further revealed a spin diffusion length of lsf = 480 +/- 13 nm and a spin lifetime exceeding 244 ps at T = 10 K in p-type Ge nanowires, and they showed a weak temperature dependence between 2 and 50 K. Ge nanowires showed a significant enhancement in the measured spin diffusion length and spin lifetime compared with those reported for bulk p-type Ge. Our study of the spin transport in the Mn5Ge3/Ge/Mn5Ge3 nanowire transistor points to a possible realization of spin based transistors; it may also open up new opportunities to create novel Ge nanowire-based spintronic devices. Furthermore, the simple fabrication process promises a compatible integration into standard Si technology in the future. PMID- 23937590 TI - Adoption of polymeric micelles to enhance the oral bioavailability of dexibuprofen: formulation, in-vitro evaluation and in-vivo pharmacokinetic study in healthy human volunteers. AB - This work aimed to incorporate Dexibuprofen (DXI), the pharmacologically active and more potent form of ibuprofen, into polymeric micelles based tablets with enhanced oral bioavailability. Thin film hydration technique was employed to prepare DXI polymeric micelles using Pluronic(r) F127 and/or P123 solutions in different ratios (ranging from 1:1 up to 1:10). Prepared micelles were characterized regarding particle size, drug loading and entrapment efficiency. Selected formulae were lyophilized in presence of cryoprotectants and subjected to solid-state characterization as well as scanning and transmission electron microscopy. Subsequently, tablets were prepared and evaluated in-vitro regarding physical properties and drug release. An in-vivo pharmacokinetic study was performed in six healthy human volunteers in comparison to the commercially available tablet of DXI. Solid-state characterization proved that DXI was homogenously dispersed in Pluronic micelles' matrices. Formula TF5 tablets comprising lyophilized micelles (F5; DXI: Pluronic F127 in 1:1 ratio and 0.25% mannitol) showed higher Cmax and earlier tmax values than those of the commercial formula, where the relative bioavailability was calculated to be 160.15%. The experimental evidence in this research leads to the conclusion that polymeric micelles present enabling properties for oral delivery of drugs with low solubility. PMID- 23937591 TI - Editorial board changes at OPO. PMID- 23937592 TI - Integrated sample preparation methodology for proteomics: analysis of native proteins. AB - An innovative sample preparation strategy is reported for protein identification in complex mixtures based on integration of affinity chromatographic selection and accelerated trypsin digestion using a continuous flow immobilized enzyme reactor (cf-IMER). Affinity selected glycoproteins were released to a cf-IMER column which converted native proteins to peptides in 5 min at elevated temperature. Digestion with the cf-IMER was compared to the traditional 16 h solution-based trypsin digestion of reduced and alkylated proteins. With immobilized antibody selection of Lewis x (Le(x)) glycan bearing glycoproteins from plasma, 66 proteins were identified in total with the two methods while approximately 1/3 of the total proteins and peptides were only observed with the cf-IMER. This suggests that proteomics based on protein identification by reduction and alkylation with solution-based trypsin digestion alone may not be identifying large numbers of proteins or peptides present at detectable levels in samples. Furthermore, except for proteins containing a high content of disulfide bonds, the majority of proteins did not require reduction and alkylation steps for their identification. The validity of the proposed proteolysis was evaluated in several ways by analyses of a model protein and yeast lysates where the reproducibility of quantification was essentially the same with both cf-IMER and solution-based proteolysis. PMID- 23937589 TI - Redox signaling mediated by the gut microbiota. AB - The microbiota that occupies the mammalian intestine can modulate a range of physiological functions, including control over immune responses, epithelial barrier function, and cellular proliferation. While commensal prokaryotic organisms are well known to stimulate inflammatory signaling networks, less is known about control over homeostatic pathways. Recent work has shown that gut epithelia contacted by enteric commensal bacteria rapidly generate reactive oxygen species (ROS). While the induced production of ROS in professional phagocytes via stimulation of formyl peptide receptors (FPRs) and activation of NADPH oxidase 2 (Nox2) is a well-studied process, ROS are also similarly elicited in other cell types, including intestinal epithelia, in response to microbial signals via FPRs and the epithelial NADPH oxidase 1 (Nox1). ROS generated by Nox enzymes have been shown to function as critical second messengers in multiple signal transduction pathways via the rapid and transient oxidative inactivation of a distinct class of sensor proteins bearing oxidant-sensitive thiol groups. These redox-sensitive proteins include tyrosine phosphatases that serve as regulators of MAP kinase pathways, focal adhesion kinase, as well as components involved in NF-kappaB activation. As microbe-elicited ROS has been shown to stimulate cellular proliferation and motility, and to modulate innate immune signaling, we hypothesize that many of the established effects of the normal microbiota on intestinal physiology may be at least partially mediated by this ROS-dependent mechanism. PMID- 23937593 TI - 8-year-old boy with progressive headache. PMID- 23937594 TI - A 59-year-old woman with a retroauricular tumor. PMID- 23937595 TI - A genome-wide search for type 2 diabetes susceptibility genes in an extended Arab family. AB - Twenty percent of people aged 20 to 79 have type 2 diabetes (T2D) in the United Arab Emirates (UAE). Genome-wide association studies (GWAS) to identify genes for T2D have not been reported for Arab countries. We performed a discovery GWAS in an extended UAE family (N=178; 66 diabetic; 112 healthy) genotyped on the Illumina Human 660 Quad Beadchip, with independent replication of top hits in 116 cases and 199 controls. Power to achieve genome-wide significance (commonly P=5*10(-8)) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12-p13 (KCTD8: rs4407541, P=9.70*10(-6); GABRB1: rs10517178/rs1372491, P=4.19*10(-6)) and 14q13 (PRKD1: rs10144903, 3.92*10(-6)), supported by analysis using a linear mixed model approximation in GenABEL (4p12-p13 GABRG1/GABRA2: rs7662743, Padj-agesex=2.06*10( 5); KCTD8: rs4407541, Padj-agesex=1.42*10(-4); GABRB1: rs10517178/rs1372491, Padj agesex=0.027; 14q13 PRKD1: rs10144903, Padj-agesex=6.95*10(-5)). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (Padj agesex=0.030) and rs2055942 (Padj-agesex=0.022) at COX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: Padj-agesex=0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: Padj-agesex-combined=3*10(-4)) and at KCTD8 (rs4695718: Padj-agesex combined=2*10(-4)). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; Padj-agesex=0.031; Padj-agesex-combined=2*10(-4)). These genes may provide important functional leads in understanding disease pathogenesis in this population. PMID- 23937596 TI - Orienting attention within visual short-term memory: development and mechanisms. AB - How does developing attentional control operate within visual short-term memory (VSTM)? Seven-year-olds, 11-year-olds, and adults (total n = 205) were asked to report whether probe items were part of preceding visual arrays. In Experiment 1, central or peripheral cues oriented attention to the location of to-be-probed items either prior to encoding or during maintenance. Cues improved memory regardless of their position, but younger children benefited less from cues presented during maintenance, and these benefits related to VSTM span over and above basic memory in uncued trials. In Experiment 2, cues of low validity eliminated benefits, suggesting that even the youngest children use cues voluntarily, rather than automatically. These findings elucidate the close coupling between developing visuospatial attentional control and VSTM. PMID- 23937597 TI - Marijuana's dose-dependent effects in daily marijuana smokers. AB - Active marijuana produces significant subjective, psychomotor, and physiological effects relative to inactive marijuana, yet demonstrating that these effects are dose-dependent has proven difficult. This within-subject, double-blind study was designed to develop a smoking procedure to obtain a marijuana dose-response function. In four outpatient laboratory sessions, daily marijuana smokers (N = 17 males, 1 female) smoked six 5-s puffs from 3 marijuana cigarettes (2 puffs/cigarette). The number of puffs from active (>=5.5% Delta9 tetrahydrocannabinol/THC) and inactive (0.0% THC) marijuana varied according to condition (0, 2, 4, or 6 active puffs); active puffs were always smoked before inactive puffs. Subjective, physiological, and performance effects were assessed prior to and at set time points after marijuana administration. Active marijuana dose-dependently increased heart rate and decreased marijuana craving, despite evidence (carbon monoxide expiration, weight of marijuana cigarettes post smoking) that participants inhaled less of each active marijuana cigarette than inactive cigarettes. Subjective ratings of marijuana "strength," "high," "liking," "good effect," and "take again" were increased by active marijuana compared with inactive marijuana, but these effects were not dose-dependent. Active marijuana also produced modest, non-dose-dependent deficits in attention, psychomotor function, and recall relative to the inactive condition. In summary, although changes in inhalation patterns as a function of marijuana strength likely minimized the difference between dose conditions, dose-dependent differences in marijuana's cardiovascular effects and ratings of craving were observed, whereas subjective ratings of marijuana effects did not significantly vary as a function of dose. PMID- 23937599 TI - A retrospective study of oral prednisolone treatment in canine chronic hepatitis. AB - BACKGROUND: Only one study reports prednisone to prolong survival in dogs with chronic hepatitis irrespective of the causative agent. The aim of this retrospective study was to investigate the effects of prednisolone treatment on survival, clinicopathological variables, and histological grade and stage of idiopathic chronic hepatitis in 36 dogs. ANIMALS AND METHODS: Medical records were reviewed of 36 prednisolone-treated dogs (median age: 8.6 years; range: 2.0 14.6 years) with chronic hepatitis not associated with primary copper accumulation. Clinicopathological results were analyzed pair-wise for 20 dogs, before and after oral prednisolone administration (1 mg/kg BW/day). Dogs were treated for at least 6 weeks, and for an additional 6 weeks if hepatitis was still present at rebiopsy. Follow-up data pertaining to clinical outcome and survival time (Kaplan-Meier estimate procedure) were analyzed. RESULTS: At the follow-up, 11 dogs were in complete remission, 8 dogs had recurrent clinical signs, and 17 dogs had residual disease. Despite treatment, 20 dogs died of hepatitis-related causes. Dogs without cirrhosis survived significantly longer than dogs with cirrhosis. Prednisolone treatment normalized coagulopathies associated with chronic idiopathic hepatitis within one week in all 10 dogs that had coagulopathies at initial diagnosis. CONCLUSIONS: Our findings suggest that prednisolone has, in part, beneficial effects on hepatic inflammation and that it may, at least in some cases, limit the progression of fibrosis, which emphasizes the importance of early diagnosis and treatment. We did not see any benefit of prednisolone treatment for dogs with cirrhosis. We could document a highly favorable effect of prednisolone treatment on the coagulopathy associated with canine chronic idiopathic hepatitis. PMID- 23937598 TI - A human alcohol self-administration paradigm to model individual differences in impaired control over alcohol use. AB - We developed an alcohol self-administration paradigm to model individual differences in impaired control. The paradigm includes moderate drinking guidelines meant to model limits on alcohol consumption, which are typically exceeded by people with impaired control. Possible payment reductions provided a disincentive for excessive drinking. Alcohol use above the guideline, despite possible pay reductions, was considered to be indicative of impaired control. Heavy-drinking 21- to 25-year-olds (n = 39) were randomized to an experimental condition including the elements of the impaired control paradigm or to a free drinking condition without these elements. Alcohol self-administration was compared between these two conditions to establish the internal validity of the experimental paradigm. In both conditions, participants self-administered beer and nonalcoholic beverages for 3 hours in a bar setting with 1-3 other participants. Experimental condition participants self-administered significantly fewer beers and drank to lower blood-alcohol concentrations (BACs) on average than those in the free-drinking condition. Experimental condition participants were more likely than free-drinking condition participants to intersperse nonalcoholic beverages with beer and to drink at a slower pace. Although experimental condition participants drank more moderately than those in the free drinking condition overall, their range of drinking was considerable (BAC range = .024-.097), with several participants drinking excessively. A lower initial subjective response to alcohol and earlier age of alcohol use onset were associated with greater alcohol self-administration in the experimental condition. Given the variability in response, the impaired control laboratory paradigm may have utility for preliminary tests of novel interventions in future studies and for identifying individual differences in problem-drinking risk. PMID- 23937601 TI - Institutional Review Board approval and innovation in urology: current practice and safety issues. AB - OBJECTIVE: To retrospectively review recent publications describing novel procedures/techniques, and describe the Institutional Review Board (IRB)/ethics approval process and potential ethical dilemmas in their reporting. MATERIALS AND METHODS: We searched PubMed for papers about innovative or novel procedures/techniques between 2011 and August 2012. A query of titles/abstracts in the Journal of Urology, Journal of Endourology, European Urology, BJU International, and Urology identified relevant papers. These results were reviewed for human studies that described an innovative technique, procedure, approach, initial series, and/or used new technology. RESULTS: In all, 91 papers met criteria for inclusion; 25 from the Journal of Endourology, 14 from the Journal of Urology, nine from European Urology, 15 from the BJU International and 28 from Urology. IRB/ethics approval was given for an experimental procedure or database in 24% and 22%, respectively. IRB/ethics approval was not mentioned in 52.7% of studies. CONCLUSIONS: Published IRB/ethics approvals for innovative techniques are heterogeneous including database, retrospective, and prospective approvals. Given the concept that innovations are likely not in the legal or ethical standard of care, strong consideration should be given to obtaining IRB/ethics approval before the actual procedure, instead of approval to merely report database outcomes. PMID- 23937602 TI - Mixed mycobacterial infection in an adult koi carp Cyprinus carpio L. PMID- 23937604 TI - Use of Rome II versus Rome III criteria for diagnosis of functional constipation in young children. AB - BACKGROUND: There has been no study to evaluate the use of the Rome III criteria for diagnosis of constipation in the unselected young pediatric population. The aim of this study was to evaluate and compare the use of the Rome II and Rome III criteria for diagnosis of constipation in a group of unselected young Thai children. METHODS: This cross-sectional study was conducted in 3010 healthy children aged 4 months-5 years who attended a well-baby clinic. Data concerning bowel habits and behavioral components of defecation of the children were obtained by interviewing the parents. Presence of a large fecal mass in the rectum of children with possible constipation was evaluated by abdominal palpation. RESULTS: Seventy-one children (2.4%) were found to have constipation, based on at least one of the two sets of criteria, at the time of interview. The prevalence of constipation as defined according to the Rome II and Rome III criteria for functional constipation (FC) was 1.9% and 1.6%, respectively. The majority of constipated children (47.9%) met the diagnostic criteria of both the Rome II and Rome III for FC, followed by the Rome II criteria for FC alone (32.4%) and the Rome III criteria for FC alone (18.3%). Twenty-one children (0.7%) whose parents reported defecation difficulties did not fulfill any diagnostic criteria for constipation. CONCLUSIONS: The prevalence of FC in young Thai children is low. For unselected young children, the Rome II criteria for FC are still appropriate for diagnosis of FC. PMID- 23937603 TI - Incidence and risk factors of herpes zoster among hiv-positive patients in the german competence network for HIV/AIDS (KompNet): a cohort study analysis. AB - BACKGROUND: HIV infection is a risk factor for the development of Herpes zoster (HZ) and its complications. Prior to antiretroviral therapy (ART), HZ incidence in HIV-infected individuals ranged from 2.9-5.1/100 person-years. There is limited evidence for the impact of ART on HZ occurrence among HIV-infected adults. We analysed the incidence of, and risk factors for, HZ in a large cohort of German HIV-positive patients. METHODS: The study population was taken from the German KompNet cohort, a nationwide multicenter HIV cohort study. The study population was defined by age (>= 18 years), year of first positive HIV diagnosis, CD4 values +/- 6 months from HIV diagnosis (t0), and month of HZ diagnosis. Incidences were estimated using a Poisson distribution, and uni- and multivariate Cox proportional Hazard ratio (HR) regression models were fitted to identify risk factors for developing an initial HZ episode. Independent variables were sex, age at HIV diagnosis, route of HIV transmission, ART status, CD4 count before HZ episode, immunosuppressive medication, and mode of data documentation (retrospective or prospective). RESULTS: HZ incidence in the overall study population was 1.2/100 person-years. In a subset of patients for that we were able to examine risk factors the following was observed: We examined 3,757 individuals whose mean age at t0 was 38 years. Of those individuals, 96% were diagnosed with HIV in 1996 or later, with a mean observation time of 5.8 years. HZ episodes (n = 362) were recorded in 326 patients (8.7%), resulting in annual HZ incidences of 1.7/100 person-years overall, and 1.6/100 person-years for initial HZ cases. The main risk factors associated with an initial HZ episode were: not partaking in ART compared with an ART regimen containing a non nucleoside reverse-transcriptase inhibitor (HR 0.530, p < 0.001) or a protease inhibitor (HR 0.624, p = 0.004); and lower CD4 count by 100 cells/MUl (HR 0.918, p=0.001). CONCLUSIONS: HZ incidence was 4-11-fold higher than in non HIV-infected individuals, but in our study HZ incidences were lower than in previous studies relating to HIV-positive patients. We showed that ART is an important protective factor for HZ episodes. PMID- 23937605 TI - Malakoplakia diagnosed by fine needle aspiration (FNA) and liquid-based cytology (LBC) presenting as a pararenal mass in a transplant kidney. PMID- 23937606 TI - How to increase quality of care during coercive admission? A review of literature. AB - BACKGROUND: Involuntary admission is still raising in numbers and as a procedure a widely discussed subject from ethical point of view. A common dilemma is the tension between individual freedom and the need to protect the patient. Patients who are coerced during the admission process often report negative feelings or trauma. Finding out quality issues remains a challenge for providing good care during coercive admission. AIM: This study aims to explore themes from patients' and professionals' perspectives within scientific literature on involuntary admission. METHODS: A literature review of English articles using Academic Search Elite, Cinahl, Medline, PubMed and Social Science Journals for the period 1995 2012 was conducted. Additional studies were identified using the National Centre for Biotechnology Information (NCBI). Search terms included involuntary, hospitalisation, ethical, admission, nursing home, coercion and factor. Finally, twenty-two articles were included and analysed out of 1216. RESULTS AND CONCLUSION: Articles were divided between those describing themes from patients' perspective and articles describing themes from professionals' perspective. Findings show that most experiences of patients can be traced back to one core experience: not being listened to or listened to. When patients experience being listened to genuinely, they feel more respected as a human being. The challenge for the professional carer seems to explicitly pay attention and stay in touch with the patients' emotional struggles while making the necessarily decision to admit the patient to prevent harm. Quality of care during coercive admission improves when professionals are able to do justice to both inside and outside perspectives simultaneously. PMID- 23937607 TI - Conformational study of an axially chiral Salen ligand in solution using two photon circular dichroism and the fragment-recombination approach. AB - Herein we report on the conformational study of a chiral Salen ligand, AFX-155, in THF solution using two-photon absorption (TPA) and, even more importantly, two photon circular dichroism (TPCD). The fragment-recombination approach (FRA), employed to perform computations on half-AXF-155 (AXF-169') and the center (C-AXF 155), allowed us to overcome the current computational limitations found in calculations of the TPCD spectra of large molecules. The comparative experimental theoretical analysis of AXF-155 showed that its TPA is mainly determined by AXF 169' and validated, through TPCD, the presence of the two dominant Trans_R Intra(NHB)//Trans_R-Extra(HB) and Trans_R-Intra(NHB)//Trans_R-Extra(NHB) structure in THF with a DeltaDelta propeller chirality on the diphenylamine moieties at the end of each AXF-169'. The application of FRA for the analysis of the TPCD spectra of large chiral molecules has been proven to be effective. PMID- 23937608 TI - EGFR mutations in US Hispanic versus non-Hispanic white patients with lung adenocarcinoma. AB - CONTEXT: Lung cancer is the leading cause of cancer deaths worldwide. First generation tyrosine kinase inhibitors improve progression-free survival in lung cancers with epidermal growth factor receptor (EGFR) mutations. EGFR mutations occur predominantly in exons 19 and 21 in lung adenocarcinomas of Asians (~30%), whites (~15%), and African Americans (~19%). However, minimal information exists on the prevalence or type of genetic changes that occur in lung cancers in US Hispanic patients. We investigated the EGFR mutation frequency in primary lung adenocarcinomas in US Hispanics compared with non-Hispanic whites. OBJECTIVE: To evaluate EGFR mutations in lung adenocarcinomas from US Hispanic patients compared with those from non-Hispanic white patients. DESIGN: DNA samples were extracted from paraffin-embedded tissue of consecutive lung adenocarcinomas from 83 patients. Samples were collected from 40 Hispanics and 43 non-Hispanic whites. Mutations in EGFR were analyzed using a custom assay. Results.-Fourteen of 83 patients (16.9%) had EGFR mutations in their tumor DNA, including 6 of 40 Hispanics (15.0%) and 8 of 43 non-Hispanic whites (18.6%). No association with age, sex, or tumor stage was identified. Smoking history could not be obtained for most of the 83 patients, although 8 of the 11 patients with EGFR mutations for whom smoking history was obtained were nonsmokers. Most of the tumors with EGFR mutations (12 of 14; 85.7%) were acinar with lepidic or papillary subtypes. EGFR mutations occurred in exon 19 (42.8%), exon 18 (28.6%), exon 20 (28.6%), and exon 21 (14.3%). Two cases had 2 mutations identified in different exons. CONCLUSION: The frequency of EGFR mutations is similar in US Hispanics compared with non-Hispanic whites. PMID- 23937609 TI - A call to standardize preanalytic data elements for biospecimens. AB - CONTEXT: Biospecimens must have appropriate clinical annotation (data) to ensure optimal quality for both patient care and research. Clinical preanalytic variables are the focus of this study. OBJECTIVE: To define the essential preanalytic variables (data fields) that should be attached to every collected biospecimen and to provide a complete list of such variables, along with their relative importance, which can vary, depending on downstream use, institutional needs, and information technology capabilities. DESIGN: The College of American Pathologists Diagnostic Intelligence and Health Information Technology Committee sponsored a Biorepository Working Group to develop a ranked list of the preanalytic variables for annotating biospecimens. Members of the working group were experts in anatomic, clinical, and molecular pathology; biobanking; medical informatics; and accreditation. Several members had experience with federal government programs, such as the National Cancer Institute's Biospecimens and Biorepository Branch and the National Cancer Institute's Community Cancer Center Program. Potential preanalytic variables were identified and ranked along with available supporting evidence, definitions, and potential negative effects if the variable was not attached to the biospecimen. Additional national and international stakeholders reviewed the draft manuscript. RESULTS: The ranked listing of 170 preanalytic variables produced can be used as a guide for site specific implementation into patient care and/or research biorepository processes. Conclusions.-In our collective experience, it is often difficult to choose which of the many preanalytic variables to attach to any specific set of biospecimens used for patient care and/or research. The provided ranked list should aid in the selection of preanalytic variables for a given biospecimen collection. PMID- 23937610 TI - Sequential nucleophilic substitutions permit orthogonal click functionalization of multicomponent PEG brushes. AB - Multicomponent poly(ethylene glycol) (PEG) brushes (i.e., >= 2 adjacent PEG brushes) can be used to engineer culture substrates with microscale, nonfouling regions decorated with covalently immobilized ligands that mediate biospecific interactions. However, synthesizing such brushes with orthogonal immobilization chemistries to permit differential biofunctionalization is nontrivial and often requires synthesis of PEG-co-polymers. To simplify synthesis and enhance the versatility of such substrates, we developed a protocol for generating orthogonal click-functionalized multicomponent PEG brushes using sequential nucleophilic substitutions by sodium azide, ethanolamine, and propargylamine. The novel application of propargylamine-mediated substitution functionalizes PEG brushes with acetylene groups, and for the first time, ethanolamine-mediated substitution is shown to be sufficient for passivating the "living" polymer chain ends between brush synthesis steps. Thus, our multicomponent PEG brushes present dual orthogonal chemistries (i.e., azido and acetylene groups) for ligand immobilization via versatile copper-free click reactions, which are useful for in situ surface modifications during cell culture. PMID- 23937611 TI - Preserving precision of inkjet-printed features with solvents of different volatilities. AB - For printed micropatterns on plastic substrates, the decreasing volume because of solvent evaporation frequently leads to contact line receding and changes the original printed pattern. To prevent printing quality deterioration caused by contact line motions, an ink formulation method was developed. A nearly non volatile solvent [polyethylene glycol (PEG)] with a low receding angle on polyethylene terephthalate (PET) sheets was added in water to hold the contact line. To understand the dewetting phenomena of inks, the geometrical evolution of circular liquid films under evaporation was recorded and analyzed. The results showed that the contact line receded as water evaporated for inks with low PEG concentrations but remained pinned at a moderate PEG concentration (~10 wt %). A simple model was proposed to explain the dewetting phenomena and can successfully predict the critical PEG concentration, beyond which the contact lines will be unconditionally pinned. The optimized water/PEG solvent can then be used to prepare dye- or particle-based inks, which preserved accurate features after solvent evaporation. PMID- 23937613 TI - Electrosynthesis of imidazolium carboxylates. AB - Synthesis of imidazolium carboxylate compounds was efficiently achieved by electrochemical reduction of imidazolium precursors under very mild conditions. PMID- 23937614 TI - Desmopressin (DDAVP) in the management of patients with congenital bleeding disorders. AB - Bleeding disorders, including haemophilia, von Willebrand disease, and platelet function abnormalities pose a substantial, ongoing management challenge. Patients with these disorders not only require treatment during bleeding events but also need effective management strategies to prepare for events ranging from minor dental procedures to major surgery and childbirth. Moreover, women with bleeding disorders often require ongoing treatment to prevent menorrhagia during childbearing years. Desmopressin (DDAVP), a synthetic derivative of the antidiuretic hormone l-arginine vasopressin, has become a well-established tool for the management of patients with bleeding disorders in a variety of clinical settings. However, despite the widespread use of DDAVP, the available clinical evidence on its efficacy and safety in these settings is limited, and there has not been a recent comprehensive review of its role in the clinical management of patients with bleeding disorders. As such, this article provides a review of the mechanism of action and pharmacokinetic properties of DDAVP, followed by a concise summary of the available evidence for its use in the treatment and prevention of bleeding. PMID- 23937612 TI - Viewing serine/threonine protein phosphatases through the eyes of drug designers. AB - Protein phosphatases, as the counterpart to protein kinases, are essential for homeostatic balance of cell signaling. Small chemical compounds that modulate the specific activity of phosphatases can be powerful tools to elucidate the biological functions of these enzymes. More importantly, many phosphatases are central players in the development of pathological pathways where inactivation can reverse or delay the onset of human diseases. Therefore, potent inhibitors for such phosphatases can be of great therapeutic benefit. In contrast to the seemingly identical enzymatic mechanism and structural characterization of eukaryotic protein kinases, protein phosphatases evolved from diverse ancestors, resulting in different domain architectures, reaction mechanisms and active site properties. In this review, we discuss for each family of serine/threonine protein phosphatases their involvement in biological processes and corresponding strategies for small chemical intervention. Recent advances in modern drug discovery technologies have markedly facilitated the identification of selective inhibitors for some members of the phosphatase family. Furthermore, the rapid growth in knowledge about structure-activity relationships related to possible new drug targets has aided the discovery of natural product inhibitors for the phosphatase family. This review summarizes the current state of investigation of the small molecules that regulate the function of serine/threonine phosphatases, the challenges presented and also strategies to overcome these obstacles. PMID- 23937615 TI - Comparison of physical activity sensors and heart rate monitoring for real-time activity detection in type 1 diabetes and control subjects. AB - BACKGROUND: Currently, patients with type 1 diabetes decide on the amount of insulin to administer based on several factors, including current plasma glucose value, expected meal input, and physical activity (PA). One future therapeutic modality for patients with type 1 diabetes is the artificial endocrine pancreas (AEP). Incorporation of PA could enhance the efficacy of AEP significantly. We compared the main technologies used for PA quantitation. SUBJECTS AND METHODS: Data were collected during inpatient studies involving healthy control subjects and type 1 diabetes. We report PA quantified from accelerometers (acceleration units [AU]) and heart rate (HR) monitors during a standardized activity protocol performed after a dinner meal at 7 p.m. from nine control subjects (four were males, 37.4+/-12.7 years old, body mass index of 24.8+/-3.8 kg/m(2), and fasting plasma glucose of 4.71+/-0.63 mmol/L) and eight with type 1 diabetes (six were males, 45.2+/-13.4 years old, body mass index of 25.1+/-2.9 kg/m(2), and fasting plasma glucose of 8.44+/-2.31 mmol/L). RESULTS: The patient-to-patient variability was considerably less when examining AU compared with HR monitors. Furthermore, the exercise bouts and rest periods were more evident from the data streams when AUs were used to quantify activity. Unlike the AU, the HR measurements provided little insight for active and rest stages, and HR data required patient-specific standardizations to discern any meaningful pattern in the data. CONCLUSIONS: Our results indicated that AU provides a reliable signal in response to PA, including low-intensity activity. Correlation of this signal with continuous glucose monitoring data would be the next step before exploring inclusion as input for AEP control. PMID- 23937616 TI - Margins, ischaemia and complications rate after laparoscopic partial nephrectomy: impact of learning curve and tumour anatomical characteristics. AB - OBJECTIVES: To present our laparoscopic partial nephrectomy (LPN) results according to the margin, ischaemia and complications (MIC) system recently proposed for the standardized reporting of partial nephrectomy (PN) outcomes. To assess the role of learning curve and tumour anatomical characteristics on the outcomes by using MIC system. PATIENTS AND METHODS: Data were obtained from our prospectively maintained LPN database, including only patients who underwent LPN performed with vascular clamping. According to the MIC system definition, the goal of LPN was reached (i.e. MIC was achieved) when surgical margins were negative, warm ischaemia time (WIT) was <20 min and no major complications occurred. Patients were stratified by quartiles of distribution, named LPN eras 1 4, and MIC rates in different LPN eras were compared, evaluating the impact of learning curve and tumour anatomical characteristics (as assessed by Preoperative Aspects and Dimensions Used for an Anatomical [PADUA] score on the outcomes. RESULTS: The study population consisted of 206 patients. The overall MIC rate was 63.1%: it progressively increased along the learning curve, reaching 84.9% in LPN era 4 (P < 0.001). PADUA-score risk group categories were inversely correlated with MIC score (P = 0.001). When simultaneously considering the effects of both LPN eras and PADUA-score risk group categories, a trend towards a higher MIC rate was found in the latest series, regardless of tumour anatomical characteristics. When MIC score components were separately analysed, WIT decreased significantly from LPN era 1 to LPN era 4 (P < 0.001) and from PADUA-score risk group categories 3 to 1 (P = 0.001) A trend towards a decrease in the complication rate along the learning curve was observed (P = 0.251), while LPN era and PADUA score together significantly influenced the complications rate (P < 0.001). The positive surgical margin rate was very low (2.9% overall) and stable throughout the case study. CONCLUSION: The MIC rate increased with surgeon's experience and decreased when complex lesions were treated. The MIC system was found to be an easy, useful and reproducible tool to report LPN data series. PMID- 23937617 TI - Application of a drainage film reduces fibroblast ingrowth into large-pored polyurethane foam during negative-pressure wound therapy in an in vitro model. AB - Negative-pressure wound therapy (NPWT) is an advantageous treatment option in wound management to promote healing and reduce the risk of complications. NPWT is mainly carried out using open-cell polyurethane (PU) foams that stimulate granulation tissue formation. However, growth of wound bed tissue into foam material, leading to disruption of newly formed tissue upon dressing removal, has been observed. Consequently, it would be of clinical interest to preserve the positive effects of open-cell PU foams while avoiding cellular ingrowth. The study presented analyzed effects of NPWT using large-pored PU foam, fine-pored PU foam, and the combination of large-pored foam with drainage film on human dermal fibroblasts grown in a collagen matrix. The results showed no difference between the dressings in stimulating cellular migration during NPWT. However, when NPWT was applied using a large-pored PU foam, the fibroblasts continued to migrate into the dressing. This led to significant breaches in the cell layers upon removal of the samples after vacuum treatment. In contrast, cell migration stopped at the collagen matrix edge when fine-pored PU foam was used, as well as with the combination of PU foam and drainage film. In conclusion, placing a drainage film between collagen matrix and the large-pored PU foam dressing reduced the ingrowth of cells into the foam significantly. Moreover, positive effects on cellular migration were not affected, and the effect of the foam on tissue surface roughness in vitro was also reduced. PMID- 23937618 TI - Real time three-dimensional transesophageal echocardiography: a novel approach for the assessment of prosthetic heart valves. AB - OBJECTIVES: To explore our initial experience with real time three-dimensional transesophageal echocardiography (RT3DTEE) for the assessment of prosthetic valves (PV). METHODS: The study included 40 patients (mean age 35 +/- 8.5 years, 68% male) who underwent PV implant. Fifty PV (34 bioprosthetic and 16 mechanical) were evaluated using two-dimensional (2D)TEE and RT3DTEE to rule out PV dysfunction. RESULTS: In all patients, RT3DTEE allowed good and simultaneous visualization of PV leaflets. Ten patients had normal functioning PV (5 in mitral, 3 in aortic, and 2 in tricuspid positions). Infective endocarditis was evident in 13 patients (20 PV) by repeated 2DTEE. RT3DTEE confirmed the 2DTEE diagnosis of endocarditis in same patients. Clear delineation of vegetations (size, site, and number) was obtained from RT3DTEE full volume while the vegetation attachment, consistency, mobility and its relation to valve structure were obtained using zoom 3D. Paraaortic abscesses size, site, extension, wall thickness of the abscess could be identified by RT3DTEE in 7 PV. Through cropping of the full-volume 3D images, the orifice of communication between the abscess cavity and aorta could be visualized well in en face view. Color full-volume allowed the detection of paravalvular regurgitation (size, location, direction, and extent) in 8 patients. In the 18 PV who underwent redo surgery, the intra operative findings confirmed the RT3DTEE description of PV lesions. CONCLUSION: Real time 3DTEE improved the anatomical and functional assessment of PV with better understanding of the underlying causes of PV dysfunction; hence, it could improve the management planning for such patients. PMID- 23937619 TI - Can exploiting natural genetic variation in leaf photosynthesis contribute to increasing rice productivity? A simulation analysis. AB - Rice productivity can be limited by available photosynthetic assimilates from leaves. However, the lack of significant correlation between crop yield and leaf photosynthetic rate (A) is noted frequently. Engineering for improved leaf photosynthesis has been argued to yield little increase in crop productivity because of complicated constraints and feedback mechanisms when moving up from leaf to crop level. Here we examined the extent to which natural genetic variation in A can contribute to increasing rice productivity. Using the mechanistic model GECROS, we analysed the impact of genetic variation in A on crop biomass production, based on the quantitative trait loci for various photosynthetic components within a rice introgression line population. We showed that genetic variation in A of 25% can be scaled up equally to crop level, resulting in an increase in biomass of 22-29% across different locations and years. This was probably because the genetic variation in A resulted not only from Rubisco (ribulose 1,5-bisphosphate carboxylase/oxygenase)-limited photosynthesis but also from electron transport-limited photosynthesis; as a result, photosynthetic rates could be improved for both light-saturated and light limited leaves in the canopy. Rice productivity could be significantly improved by mining the natural variation in existing germ-plasm, especially the variation in parameters determining light-limited photosynthesis. PMID- 23937620 TI - Impaired renal function impacts negatively on vascular stiffness in patients with coronary artery disease. AB - BACKGROUND: Chronic kidney disease (CKD) and coronary artery disease (CAD) are independently associated with increased vascular stiffness. We examined whether renal function contributes to vascular stiffness independently of CAD status. METHODS: We studied 160 patients with CAD and 169 subjects without CAD. The 4 variable MDRD formula was used to estimate glomerular filtration rate (eGFR); impaired renal function was defined as eGFR <60 mL/min. Carotid-femoral pulse wave velocity (PWV) was measured with the SphygmoCor(r) device. Circulating biomarkers were assessed in plasma using xMAP(r) multiplexing technology. RESULTS: Patients with CAD and impaired renal function had greater PWV compared to those with CAD and normal renal function (10.2 [9.1;11.2] vs 7.3 [6.9;7.7] m/s; P < 0.001). In all patients, PWV was a function of eGFR (beta = -0.293; P < 0.001) even after adjustment for age, sex, systolic blood pressure, body mass index and presence or absence of CAD. Patients with CAD and impaired renal function had higher levels of adhesion and inflammatory molecules including E selectin and osteopontin (all P < 0.05) compared to those with CAD alone, but had similar levels of markers of oxidative stress. CONCLUSIONS: Renal function is a determinant of vascular stiffness even in patients with severe atherosclerotic disease. This was paralleled by differences in markers of cell adhesion and inflammation. Increased vascular stiffness may therefore be linked to inflammatory remodeling of the vasculature in people with impaired renal function, irrespective of concomitant atherosclerotic disease. PMID- 23937621 TI - Nrf2 is required to maintain the self-renewal of glioma stem cells. AB - BACKGROUND: Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioma stem cells (GSCs). Self-renewal is a complex biological process necessary for maintaining the glioma stem cells. Nuclear factor rythroid 2-related factor 2(Nrf2) plays a significant role in protecting cells from endogenous and exogenous stresses. Nrf2 is a key nuclear transcription factor that regulates antioxidant response element (ARE)-containing genes. Previous studies have demonstrated the significant role of Nrf2 in the proliferation of glioblastoma, and in their resistance to radioactive therapies. We examined the effect of knocking down Nrf2 in GSCs. METHODS: Nrf2 expression was down-regulated by shRNA transinfected with lentivirus. Expression levels of Nestin, Nrf2, BMI-1, Sox2 and Cyclin E were assessed by western blotting, quantitative polymerase chain reaction (qPCR) and immunohistochemistry analysis. The capacity for self-renewal in vitro was assessed by genesis of colonies. The capacity for self-renewal in vivo was analyzed by tumor genesis of xenografts in nude mice. RESULTS: Knockdown of Nrf2 inhibited the proliferation of GSCs, and significantly reduced the expression of BMI-1, Sox2 and CyclinE. Knocking down of Nrf2 changed the cell cycle distribution of GSCs by causing an uncharacteristic increase in the proportion of cells in the G2 phase and a decrease in the proportion of cells in the S phase of the cell cycle. CONCLUSIONS: Nrf2 is required to maintain the self-renewal of GSCs, and its down-regulation can attenuate the self-renewal of GSCs significantly. PMID- 23937622 TI - Childhood-onset psoriasis: association with future cardiovascular and metabolic comorbidities. AB - BACKGROUND: Psoriasis is associated with higher prevalences of cardiovascular and metabolic comorbidities in adults but the relationship of age at onset and those prevalences is unknown. OBJECTIVE: To evaluate whether the childhood onset of psoriasis (COP) is correlated with the frequency of cardiovascular and metabolic comorbidities in adulthood. METHODS: This noninterventional, cross-sectional, multicentre study of adults with psoriasis was conducted in 29 dermatology centres in France. Data on sex, age at onset of psoriasis and its clinical characteristics, and cardiovascular risk factors, including weight, body mass index, waist circumference, dyslipidaemia, diabetes, hypertension, smoking, and personal/familial major adverse cardiovascular events (MACE) were systematically recorded. RESULTS: Two thousand two hundred and one patients with psoriasis (male: 56%; mean age: 49 years; 25% with COP) were included consecutively in the study. Univariate analysis showed that COP was associated with lower frequencies of obesity, high waist circumference, diabetes, dyslipidaemia, hypertension, familial cardiovascular disease, MACE and metabolic syndrome, but more frequent active smoking. Multivariate analysis retained age as being associated with frequency of cardiovascular and metabolic comorbidities, and sex with smoking, but not age at the onset of psoriasis. Psoriasis severity was associated with higher frequencies of obesity and psoriatic arthritis. CONCLUSION: Our results showed that COP does not seem to be an additional risk factor for higher frequencies of cardiovascular and metabolic comorbidities during adulthood. PMID- 23937623 TI - MHC genotyping of non-model organisms using next-generation sequencing: a new methodology to deal with artefacts and allelic dropout. AB - BACKGROUND: The Major Histocompatibility Complex (MHC) is the most important genetic marker to study patterns of adaptive genetic variation determining pathogen resistance and associated life history decisions. It is used in many different research fields ranging from human medical, molecular evolutionary to functional biodiversity studies. Correct assessment of the individual allelic diversity pattern and the underlying structural sequence variation is the basic requirement to address the functional importance of MHC variability. Next generation sequencing (NGS) technologies are likely to replace traditional genotyping methods to a great extent in the near future but first empirical studies strongly indicate the need for a rigorous quality control pipeline. Strict approaches for data validation and allele calling to distinguish true alleles from artefacts are required. RESULTS: We developed the analytical methodology and validated a data processing procedure which can be applied to any organism. It allows the separation of true alleles from artefacts and the evaluation of genotyping reliability, which in addition to artefacts considers for the first time the possibility of allelic dropout due to unbalanced amplification efficiencies across alleles. Finally, we developed a method to assess the confidence level per genotype a-posteriori, which helps to decide which alleles and individuals should be included in any further downstream analyses. The latter method could also be used for optimizing experiment designs in the future. CONCLUSIONS: Combining our workflow with the study of amplification efficiency offers the chance for researchers to evaluate enormous amounts of NGS-generated data in great detail, improving confidence over the downstream analyses and subsequent applications. PMID- 23937624 TI - In-gel beta-elimination and aqueous-organic partition for improved O- and sulfoglycomics. AB - Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) is a widely used technique for protein separation, and in-gel tryptic digestion of resolved protein bands has enhanced the resolution of protoeomic analysis. To augment this technology and expand its usefulness for glycoproteomics, we have developed and improved methods to release and recover O-linked glycans from proteins resolved in SDS-PAGE gels for subsequent analysis by mass spectrometry (MS). Gel pieces containing target proteins are washed to remove contaminants. O-linked glycans are released through reductive beta-elimination by hydrating gel pieces in base and adding reductant. Following straightforward sample cleanup, this simple treatment of glycoprotein gel pieces produces material suitable for MS analysis. We have applied this method to the analysis of mucin-type glycoproteins that are expected to carry high densities of sialylated and sulfated O-linked glycans. However, the strongly acidic nature of the sulfate moiety suppresses MS signal intensities, hampering detection and quantitative analysis. To enhance detection, we present an improved method for sulfoglycomics. A mixture of sulflo-, sialo-, and neutral glycans were permethylated and partitioned into a water dichloromethane (DCM) solvent mixture. Sulfated glycans were selectively recovered from the aqueous phase, while neutral and sialylated glycans remained in the DCM phase. When applied to the analysis of human mucin salivary glycans, this partition method generated material of sufficient quality to identify more than 60 glycan structures by NSI-MS (LTQ-Orbitrap) in positive and negative ion modes. Also, nearly 100% of the sulfated O-linked glycans were recovered in the aqueous phase, demonstrating the feasibility of in-depth sulfoglycomic analysis using SDS-PAGE resolved proteins. PMID- 23937625 TI - Telomeres and endocrine dysfunction of the adrenal and GH/IGF-1 axes. AB - Telomeres, located at the end of linear chromosomes, are essential to maintain genomic stability. Telomere biology has recently emerged as an important player in the fields of ageing and disease. To maintain telomere length (TL) and reduce its degradation after mitosis, the telomerase enzyme complex is produced. Genetic, epigenetic, hormonal and environmental factors can regulate telomerase function. These include stress hormones such as cortisol and growth factors. The hypothalamic-pituitary-adrenal (HPA) axis has been evaluated in psychiatric diseases where hypercortisolism and oxidative stress are often present. Some researches have linked TL shortening to increases in stress-related cortisol, but others have not. The effects of cortisol on the telomere system are complex and may depend on the intensity and duration of exposure. On the other hand, low levels of IGF-1 are associated with inflammation and ageing-related diseases (ischaemic heart disease, congestive heart failure). Both IGF-1 and TL diminish with age and are positively and strongly correlated with each other. It is not clear whether this positive correlation reflects a single association or a cause effect relationship. Further research will ideally investigate longitudinal changes in telomeres and both these hormonal axes. To our knowledge, TL dysfunction has not been described in either endogenous hypercortisolism (Cushing's syndrome) or acromegaly where excessive amounts of GH and consequently IGF-1 are produced. This review focuses on the possible relationships between telomere dysfunction and the hypothalamic-pituitary-adrenal (HPA) axis and GH-IGF 1 system. PMID- 23937627 TI - Experimental and theoretical study of the reactions between MO2- (M = Fe, Co, Ni, Cu, and Zn) cluster anions and hydrogen sulfide. AB - Transition metal oxide cluster anions M(m)(18)O(n)(-) (M = Fe, Co, Ni, Cu, and Zn) were prepared by laser ablation and reacted with H2S in a fast flow reactor under thermal collision conditions. A time-of-flight mass spectrometer was used to detect the cluster distributions before and after the interactions with H2S. The experiments reveal a suite of oxygen/sulfur (O/S) exchange and oxygen/sulfydryl (O/SH) exchange reactions. The O/S exchange reaction to release water was evidenced for all of the MO2(-) cluster anions: MO2(-) + H2S -> MOS(-) + H2O, whereas the O/SH exchange reaction to derive MOSH(-) and OH species was only observed for reactions of NiO2(-), CuO2(-), and ZnO2(-). Density functional theory calculations were performed for reaction mechanisms of MO2(-) + H2S (M = Fe, Co, Ni, Cu, and Zn). The computational results are generally in good agreement with the experimental results. This gas-phase study provides an insight into the metal dependent reactivity in the removal of H2S over metal oxides. PMID- 23937626 TI - Paraneoplastic neurological syndromes. AB - Paraneoplastic neurological syndromes are immune-mediated erroneous attacks on the central or peripheral nervous systems, or both, directed originally against the tumour itself. They have been known for more than 40 years, but recently the discovery of new subgroups of paraneoplastic encephalitis syndromes with a remarkably good response to immune therapy has ignited new clinical and scientific interest. Knowledge of these subgroups and their associated autoantibodies is important in therapeutic decision-making. However, the abundance of new autoantibodies and syndromes can be confusing. This review paper summarizes current knowledge and new developments in the field of paraneoplastic neurological syndromes, their classification, pathophysiology and treatment. PMID- 23937628 TI - Outcome in patients with exclusive carcinoma in situ (CIS) after radical cystectomy. AB - OBJECTIVE: To evaluate oncological outcomes of patients with carcinoma in situ (CIS) exclusively at radical cystectomy (RC) and no previous history of >=T1 disease. PATIENTS AND METHODS: Patients undergoing RC with curative intent for CIS between 1971 and 2008 at the University of Southern California were included if they met all the following criteria: (i) pathological CIS-only disease at RC, (ii) preoperative clinical stage cCIS and/or cCIS + cTa, and (iii) no previous history of lamina propria invasion (>=pT1). Kaplan-Meier plots were used to estimate the probabilities of recurrence-free survival (RFS) and overall survival (OS). RESULTS: Of the 1964 consented patients 52 met the inclusion criteria with a median (range) follow-up of 8.5 (0.008-34) years. A median (range) of 36 (10 95) lymph nodes were identified per patient but no metastases found. Estimated 5- and 10-year RFS rates were 94% and 90%, respectively and estimated 5- and 10-year OS rates were 85% and 66%, respectively. Different mechanisms of recurrence were found in four (8%) patients after a median (range) interval of 2.4 (0.6-7.1) years. While two patients had metachronous recurrence within the urinary tract, the first of the other two had early systemic recurrence and the second late local recurrence. CONCLUSIONS: We noticed excellent outcomes after RC for CIS only disease. However, patients may have synchronous and/or develop metachronous tumours, as well as local and/or distant/systemic recurrence that can be cured but may also lead to fatal outcomes. PMID- 23937629 TI - Biogenesis of yeast Mia40 - uncoupling folding from import and atypical recognition features. AB - The discovery of the mitochondrial intermembrane space assembly (MIA) pathway was followed by studies that focused mainly on the typical small substrates of this disulfide relay system and the interactions between its two central partners: the oxidoreductase Mia40 and the FAD-protein Erv1. Recent studies have revealed that more complex proteins utilize this pathway, including Mia40 itself. In the present study, we dissect the Mia40 biogenesis in distinct stages, supporting a kinetically coordinated sequence of events, starting with (a) import and insertion through the Tim23 translocon, followed by (b) folding of the core of imported Mia40 assisted by the endogenous Mia40 and (c) final interaction with Erv1. The interaction with endogenous Mia40 and the subsequent interaction with Erv1 represent kinetically distinguishable steps that rely on completely different determinants. Interaction with Mia40 proceeds very early (within 30 s) and is characterized by no Cys-specificity, an increased tolerance to mutations of the hydrophobic substrate-binding cleft and no apparent dependence on glutathione as a proofreading mechanism. All of these features illustrate a very atypical behaviour for the Mia40 precursor compared to other substrates of the MIA pathway. By contrast, interaction with Erv1 occurs after 5 min of import and relies on a more stringent specificity. PMID- 23937630 TI - Integration of ultrasound findings with Alvarado score in children with suspected appendicitis. AB - BACKGROUND: The aim of this study was to investigate the integration of ultrasound (US) findings with Alvarado score in diagnosing or excluding acute appendicitis. METHODS: Data were analyzed in 122 pediatric patients with suspected appendicitis who had undergone US. The US findings were classified into four groups, and the patients were classified into three groups according to Alvarado score. US results and Alvarado score were compared. RESULTS: Alvarado score was a good predictor of appendicitis for scores >=7. CONCLUSION: In the case of non-visualization of the appendix without a high Alvarado score, appendicitis can be safely ruled out. PMID- 23937631 TI - Antiviral spirooliganones A and B with unprecedented skeletons from the roots of Illicium oligandrum. AB - Two novel spirooliganones A (1) and (2), a pair of spiro carbon epimers, with a rare dioxaspiro skeleton were isolated from the roots of Illicium oligandrum. The structures were fully determined by spectroscopic analysis and chemical methods, especially modified Mosher's method, and X-ray diffraction analysis. Spirooliganone B was found to exhibit more potent activities against coxsackie virus B3 and influenza virus A (H3N2) (IC50 3.70-5.05 MUM) than spirooliganone A. The biosynthetic pathway involving a hetero-Diels-Alder reaction of the epimers was proposed. PMID- 23937632 TI - Long-range surface-induced water structures and the effect of 1-butanol studied by 1H nuclear magnetic resonance. AB - Thin films of water between glass plates were investigated in this study with regard to water structure and dynamics in the temperature range of 278-313 K. We further investigated how addition of 1-butanol (0.05 and 0.5 M) affects the range and properties of the surface-induced water structures. From the observation of two (1)H nuclear magnetic resonance (NMR) water resonances and two relaxation components, it was found that the interfacial water exists in a two-state mixture in dynamic equilibrium, with the respective structures interpreted as being high density water (HDW) and low-density water (LDW). In the absence of 1-butanol, the LDW state is more pronounced, with a further shift in equilibrium toward the LDW state with an increase in temperature. However, in water film samples containing 1-butanol, the HDW state dominates at low temperatures while the LDW state becomes more visible at higher temperatures. Furthermore, the addition of 1 butanol significantly increased the extent of the surface-induced water structures. NMR relaxation shows that the dynamics of water in the HDW state is significantly affected by the presence of 1-butanol and further indicates that the distribution of values for the enthalpy of activation associated with translational motion of water molecules in the HDW state is narrower in the 0.05 M 1-butanol sample than in the 0.5 M 1-butanol sample. PMID- 23937633 TI - Predictors of health care professionals' attitudes towards involvement in safety relevant behaviours. AB - BACKGROUND: Patients can make valuable contributions towards promoting the safety of their health care. Health care professionals (HCPs) could play an important role in encouraging patient involvement in safety-relevant behaviours. However, to date factors that determine HCPs' attitudes towards patient participation in this area remain largely unexplored. OBJECTIVE: To investigate predictors of HCPs' attitudes towards patient involvement in safety-relevant behaviours. DESIGN: A 22-item cross-sectional fractional factorial survey that assessed HCPs' attitudes towards patient involvement in relation to two error scenarios relating to hand hygiene and medication safety. SETTING: Four hospitals in London PARTICIPANTS: Two hundred sixteen HCPs (116 doctors; 100 nurses) aged between 21 and 60 years (mean: 32): 129 female. OUTCOME MEASURES: Approval of patient's behaviour, HCP response to the patient, anticipated effects on the patient-HCP relationship, support for being asked as a HCP, affective rating response to the vignettes. RESULTS: HCPs elicited more favourable attitudes towards patients intervening about a medication error than about hand sanitation. Across vignettes and error scenarios, the strongest predictors of attitudes were how the patient intervened and how the HCP responded to the patient's behaviour. With regard to HCP characteristics, doctors viewed patients intervening less favourably than nurses. CONCLUSIONS: HCPs perceive patients intervening about a potential error less favourably if the patient's behaviour is confrontational in nature or if the HCP responds to the patient intervening in a discouraging manner. In particular, if a HCP responds negatively to the patient (irrespective of whether an error actually occurred), this is perceived as having negative effects on the HCP patient relationship. PMID- 23937634 TI - Stabilizing impact of N-glycosylation on the WW domain depends strongly on the Asn-GlcNAc linkage. AB - N-glycans play important roles in many cellular processes and can increase protein conformational stability in specific structural contexts. Glycosylation (with a single GlcNAc) of the reverse turn sequence Phe-Yyy-Asn-Xxx-Thr at Asn stabilizes the Pin 1 WW domain by -0.85 +/- 0.12 kcal mol(-1). Alternative methods exist for attaching carbohydrates to proteins; some occur naturally (e.g., the O-linkage), whereas others use chemoselective ligation reactions to mimic the natural N- or O-linkages. Here, we assess the energetic consequences of replacing the Asn linkage in the glycosylated WW domain with a Gln linkage, with two natural O-linkages, with two unnatural triazole linkages, and with an unnatural alpha-mercaptoacetamide linkage. Of these alternatives, only glycosylation of the triazole linkages stabilizes WW, and by a smaller amount than N-glycosylation, highlighting the need for caution when using triazole- or alpha-mercaptoacetamide-linked carbohydrates to mimic native N-glycans, especially where the impact of glycosylation on protein conformational stability is important. PMID- 23937635 TI - Acceleration of cutaneous wound healing by brassinosteroids. AB - Brassinosteroids are plant growth hormones involved in cell growth, division, and differentiation. Their effects in animals are largely unknown, although recent studies showed that the anabolic properties of brassinosteroids are possibly mediated through the phosphoinositide 3-kinase/protein kinase B signaling pathway. Here, we examined biological activity of homobrassinolide (HB) and its synthetic analogues in in vitro proliferation and migration assays in murine fibroblast and primary keratinocyte cell culture. HB stimulated fibroblast proliferation and migration and weakly induced keratinocyte proliferation in vitro. The effects of topical HB administration on progression of wound closure were further tested in the mouse model of cutaneous wound healing. C57BL/6J mice were given a full-thickness dermal wound, and the rate of wound closure was assessed daily for 10 days, with adenosine receptor agonist CGS-21680 as a positive control. Topical application of brassinosteroid significantly reduced wound size and accelerated wound healing in treated animals. mRNA levels of transforming growth factor beta and intercellular adhesion molecule 1 were significantly lower, while tumor necrosis factor alpha was nearly suppressed in the wounds from treated mice. Our data suggest that topical application of brassinosteroids accelerates wound healing by positively modulating inflammatory and reepithelialization phases of the wound repair process, in part by enhancing Akt signaling in the skin at the edges of the wound and enhancing migration of fibroblasts in the wounded area. Targeting this signaling pathway with brassinosteroids may represent a promising approach to the therapy of delayed wound healing. PMID- 23937636 TI - Radical prostatectomy vs radiotherapy vs observation among older patients with clinically localized prostate cancer: a comparative effectiveness evaluation. AB - OBJECTIVE: To compare efficacy between radical prostatectomy (RP), radiotherapy and observation with respect to overall survival (OS) in patients with clinically localized prostate cancer (PCa). METHODS: Using data (1988-2005) from the Surveillance, Epidemiology, and End Results-Medicare linked database, 67 087 men with localized PCa were identified. The prevalence of the initial treatment strategy was quantified according to patients' life expectancy ([LE] <10 vs >=10 years) at initial diagnosis and according to tumour stage. To reduce the unmeasured bias associated with treatment, we performed an instrumental variable analysis. Stratified (by stage and LE) Cox regression and competing-risks regression analyses were generated for the prediction of OS and cancer-specific mortality, respectively. RESULTS: Among patients with <10 years of LE, most were treated with radiotherapy (49%) or observation (47%). Among patients with >=10 years of LE, most received radiotherapy (49%), followed by RP (26%). In men with <10 years of LE, RP and radiotherapy were not different with respect to OS (hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.45-1.48, P = 0.499). Conversely, in men with >=10 years of LE, RP was associated with an improved OS compared with observation (HR: 0.59, 95% CI: 0.49-0.71, P < 0.001) and radiotherapy (HR: 0.66, 95% CI: 0.56-0.79, P < 0.001). Similar results were recorded in competing-risks regression analyses. CONCLUSION: In patients with an estimated LE >=10 years at initial diagnosis, RP was associated with improved survival compared with radiotherapy and observation, regardless of disease stage. PMID- 23937637 TI - Chronic granulomatous disease-haematopoietic stem cell transplantation versus conventional treatment. AB - AIM: Chronic granulomatous disease (CGD) is a rare X-linked or autosomal recessive primary immune deficiency characterized by recurrent, life-threatening bacterial and fungal infections. Mortality rates are high with conventional treatment. However, haematopoietic stem cell transplantation (HSCT) offers cure. Here, we compare the outcome of HSCT in 14 Swedish patients with CGD to that in 27 patients with CGD who were given conventional treatment. METHODS: Forty-one patients in Sweden were diagnosed with CGD between 1990 and 2012. From 1997 to 2012, 14 patients with CGD, aged 1-35 years, underwent HSCT and received grafts either from an HLA-matched sibling donor or a matched unrelated donor. RESULTS: Thirteen of the 14 transplanted patients are alive and well. Mean age at transplantation was 10.4 years, and the mean survival time was 7.7 years. In contrast, seven of 13 Swedish men or boys with X-linked CGD who were treated conventionally died from complications of CGD at a mean age of 19 years, while the remaining patients suffered life-threatening infections. CONCLUSION: The outcome of the patients who underwent HSCT supports HSCT as being the preferable treatment for severe CGD. Our results advocate early HSCT for all patients with X linked CGD, using grafts from either a matched sibling donor or a matched unrelated donor. PMID- 23937638 TI - Demyelination initiated by oligodendrocyte apoptosis through enhancing endoplasmic reticulum-mitochondria interactions and Id2 expression after compressed spinal cord injury in rats. AB - BACKGROUND: Demyelination is one of the most important pathological factors of spinal cord injury. Oligodendrocyte apoptosis is involved in triggering demyelination. However, fewer reports on pathological changes and mechanism of demyelination have been presented from compressed spinal cord injury (CSCI). The relative effect of oligodendrocyte apoptosis on CSCI-induced demyelination and the mechanism of apoptosis remain unclear. AIMS: In this study, a custom-designed model of CSCI was used to determine whether or not demyelination and oligodendrocyte apoptosis occur after CSCI. The pathological changes in axonal myelinated fibers were investigated by osmic acid staining and transmission electron microscopy. Myelin basic protein (MBP), which is used in myelin formation in the central nervous system, was detected by immunofluorescence and Western blot assays. Oligodendrocyte apoptosis was revealed by in situ terminal deoxytransferase-mediated dUTP nick-end labeling. To analyze the mechanism of oligodendrocyte apoptosis, we detected caspase-12 [a representative of endoplasmic reticulum (ER) stress], cytochrome c (an apoptotic factor and hallmark of mitochondria), and inhibitor of DNA binding 2 (Id2, an oligodendrocyte lineage gene) by immunofluorescence and Western blot assays. RESULTS: The custom-designed model of CSCI was successfully established. The rats were spastic, paralyzed, and incontinent. The Basso, Beattie, and Bresnahan (BBB) locomotor rating scale scores were decreased as time passed. The compressed spinal cord slices were ischemic. Myelin sheaths became swollen and degenerative; these sheaths were broken down as time passed after CSCI. MBP expression was downregulated after CSCI and consistent with the degree of demyelination. Oligodendrocyte apoptosis occurred at 1 day after CSCI and increased as caspase 12 expression was enhanced and cytochrome c was released. Id2 was distributed widely in the white matter. Id2 expression increased with time after CSCI. CONCLUSION: Demyelination occurred after CSCI and might be partly caused by oligodendrocyte apoptosis, which was positively correlated with ER-mitochondria interactions and enhanced Id2 expression after CSCI in rats. PMID- 23937639 TI - NtProRP1, a novel proline-rich protein, is an osmotic stress-responsive factor and specifically functions in pollen tube growth and early embryogenesis in Nicotiana tabacum. AB - Proline-rich proteins (PRPs) are known to play important roles in sexual plant reproduction. Most of the known proteins in the family were found in styles or pollen and modulate pollen tube growth. Here, we identified a novel member of the gene family, NtProRP1, which is preferentially expressed in tobacco pollen grains, pollen tubes and zygotes. NtProRP1 could be secreted into the extracellular space including the cell wall, and the predicted N-terminal signal peptide is crucial for its secretion. In NtProRP1-RNAi plants, pollen germination and pollen tube growth were significantly slower and showed zigzag or swell morphology in vitro. Early embryogenesis also exhibited aberrant development, indicative of its critical role in both pollen tube growth and early embryogenesis. Further investigation revealed that NtProRP1 plays a crucial role in osmotic stress response during pollen tube growth and is likely regulated by Tsi, a stress-responsive gene, suggesting that the regulatory mechanism is also involved in the stress response during sexual plant reproduction. These data provide evidence that NtProRP1 functions as a downstream factor of Tsi1 in the stress response and converges the stress signal into the modulation of pollen tube growth and early embryogenesis. PMID- 23937640 TI - The future of closed loop. PMID- 23937641 TI - Knowledge, attitude, and practices of individuals to prevent and manage metabolic syndrome in an Indian setting. AB - BACKGROUND: Patients' knowledge, attitudes, and behavior play a large role in preventing and managing the risk factors making up metabolic syndrome (MetS). MetS is associated with increased morbidity and mortality per the World Health Organization criteria. The objective of the study was to examine the current health literacy levels, risk perceptions about MetS, and associated management challenges in diverse Indian settings. SUBJECTS AND METHODS: This cross-sectional study was performed during the period of April-May 2012 by enrolling 125 individuals at risk of MetS from urban, rural, and slum settings in India. A convenience sample was recruited from primary care clinics. In-depth interviews were conducted using ground theory and framework analysis. Individuals 30 years old and above with confirmed diagnosis of obesity, type 2 diabetes mellitus, hypertension, or hypercholesterolemia and willing to participate in the in-depth interviews were included in the study. Individuals involved in other research studies were excluded. RESULTS: Difficulty in understanding healthcare information was commonly reported, especially in rural and slum settings. Only 10% of the individuals perceived lifestyle behaviors as a risk factor of acquiring MetS. Significant disparities were seen among urban, rural, and slum individuals about using diet and exercise as means to manage their MetS. Individuals in slum and rural settings were rarely advised about diet and exercise approaches to manage MetS. Access to appropriate information and direction from the healthcare professionals is lacking. CONCLUSIONS: Different perceptions about MetS and its varied management approaches exist across the three settings. An urgent need exists to develop interactive health education programs that can enhance self-management approaches to meet the growing burden of MetS by providing access to right information applicable to individuals living in diverse Indian settings. PMID- 23937642 TI - Comparison of therapy augmentation and deviation rates from the recommended once daily dosing regimen between LDX and commonly prescribed long-acting stimulants for the treatment of ADHD in youth and adults. AB - OBJECTIVE: To compare therapy augmentation and deviation rates from the recommended once-daily dosing regimen in Attention Deficit Hyperactivity Disorder (ADHD) patients initiated on lisdexamfetamine (LDX) vs other once-daily Food and Drug Administration (FDA) approved stimulants. METHODS: ADHD patients initiated on a long-acting ADHD stimulant medication (index medication) in/after 2007 were selected from a large U.S. administrative claims database. Patients were required to be persistent for >=90 days and continuously enrolled in their healthcare plan for >=12 months following treatment initiation date. Based on age and previous treatment status, patients were classified into treatment-naive children and adolescents (6-17 years old), previously treated children and adolescents, treatment-naive adults (>=18 years old), and previously treated adults. Furthermore, patients were classified into four mutually exclusive treatment groups, based on index medication: lisdexamfetamine (LDX), osmotic release methylphenidate hydrochloride long-acting (OROS MPH), other methylphenidate/dexmethylphenidate long-acting (MPH LA), and amphetamine/dextroamphetamine long-acting (AMPH LA). The average daily consumption was measured as the quantity of index medication supplied in the 12 month study period divided by the total number of days of supply. Therapy augmentation was defined as the use of another ADHD medication concomitantly with the index medication for >=28 consecutive days. Therapy augmentation and deviation rates from the recommended once-daily dosing regimen were compared between treatment groups using multivariate logistic regression models. RESULTS: Compared to the other treatment groups, LDX patients were less likely to augment with another ADHD medication (range odds ratios [OR]; 1.28-3.30) and to deviate from the recommended once-daily dosing regimen (range OR; 1.73-4.55), except for previously treated adult patients, where therapy augmentation differences were not statistically significant when compared to OROS MPH and MPH LA patients. LIMITATION: This study did not control for ADHD severity. CONCLUSION: Overall, compared to LDX-treated patients, patients initiated on other ADHD medications were equally or more likely to have a therapy augmentation and more likely to deviate from the recommended once-daily dosing regimen. PMID- 23937643 TI - Diminishing self-disclosure to maintain security in partners' care. AB - Six studies demonstrate that perceivers' desire to bond with targets motivates perceivers to misconstrue their own self-disclosure in ways that maintain perceivers' security in targets' care and commitment. Perceivers who strongly valued relationships with targets reported high levels of global self-disclosure, consistent with many findings suggesting salutary effects of disclosure. However, these same perceivers reported low self-disclosure of needs and desires in hypothetical (Study 1) and actual (Study 2) situations characterized by targets' unresponsive behavior. Similarly, in daily report (Study 3) and behavioral observation (Study 4) studies, perceivers who valued relationships with targets perceived high levels of self-disclosure when targets were responsive, but they perceived low self-disclosure when targets were unresponsive, and these perceptions seemed partly illusory. In turn, these perceptions of low self disclosure in situations characterized by partners' unresponsive behavior predicted decreased perceptions of diagnosticity of targets' behavior (Studies 1 3) and buffered the negative affective and interpersonal effects of unresponsive behavior (Study 4). Experimental manipulations (Studies 5 and 6) demonstrated the motivational nature of perceived self-disclosure. Collectively, the results suggest that a desire to bond with targets motivates perceivers to downplay the diagnosticity of targets' unresponsive behavior through diminishing their self disclosure, in turn preserving perceivers' trust in targets' care and commitment. PMID- 23937644 TI - Negotiating power: agenda ordering and the willingness to negotiate in asymmetric intergroup conflicts. AB - In this research, we investigated how group power influences the way members of groups in asymmetrical conflict approach intergroup negotiations. Drawing on theories of negotiations and of intergroup power, we predicted that group power would interact with features of the proposed negotiating agenda to influence willingness to come to the table. Based on the negotiation literature, we focused on 2 types of sequential negotiation agendas: 1 beginning with the discussion of consequential issues before less consequential issues (consequential first) and 1 leaving the discussion of consequential issues until after less consequential issues are discussed (consequential later). Because they are motivated to advance changes to their disadvantaged status quo, we expected low-power group members to favor consequential first over consequential later invitations to negotiate. High power group members, motivated to protect their advantage, were expected to show the reverse preference. Converging evidence from 5 experiments involving real world and experimental groups supported these predictions. Across studies, participants received an invitation to negotiate from the other group involving either a consequential first or consequential later agenda. Low-power group members preferred consequential first invitations because these implied less stalling of change to the status quo, and high-power group members preferred consequential later invitations because these invitations seemed to pose less threat to their position. Theoretical and practical implications for negotiations research and conflict resolution are discussed. PMID- 23937645 TI - Tasks performed by migrant live-in care workers during hospitalization of their older care recipients. AB - The goals of the study were to examine: (a) the tasks that migrant live-in care workers are expected to perform and actually perform during the hospitalization of their care recipients, and (b) the factors that explain the level of involvement by care workers in caring for hospitalized care recipients. A sample of 535 dyads of family caregivers and care workers of hospitalized care recipients in two general hospitals in Israel was interviewed. Results showed a high level of congruence between the care workers' and family caregivers' perceptions of the roles that the paid carers should perform. Paid carers' involvement in care provision varied by hospital and type of ward and was best explained by the hospital characteristics and congruence in the care workers' perceived roles. The extensive needs of hospitalized functionally disabled older adults necessitate explicit policies and guidelines regarding private care provided in hospital wards. PMID- 23937646 TI - Paper-based microfluidic electrochemical immunodevice integrated with nanobioprobes onto graphene film for ultrasensitive multiplexed detection of cancer biomarkers. AB - To the best of our knowledge, this was the first report on the integration of a signal amplification strategy into a microfluidic paper-based electrochemical immunodevice for the multiplexed measurement of cancer biomarkers. Signal amplification was achieved through the use of graphene to modify the immunodevice surface to accelerate the electron transfer and the use of silica nanoparticles as a tracing tag to label the signal antibodies. Accurate, rapid, simple, and inexpensive point-of-care electrochemical immunoassays were demonstrated using a photoresist-patterned microfluidic paper-based analytical device (MUPAD). Using the horseradish peroxidase (HRP)-O-phenylenediamine-H2O2 electrochemical detection system, the potential clinical applicability of this immunodevice was demonstrated through its ability to identify four candidate cancer biomarkers in serum samples from cancer patients. The novel signal-amplified strategy proposed in this report greatly enhanced the sensitivity of the detection of cancer biomarkers. In addition, the electrochemical immunodevice exhibited good stability, reproducibility, and accuracy and thus had potential applications in clinical diagnostics. PMID- 23937647 TI - Stepwise helicity inversions by multisequential metal exchange. AB - Development of artificial helical molecules that can undergo responsive helicity inversion has been a challenging research target in functional molecular chemistry. However, most reported helicity inversions are based on a single-mode transition, i.e., the conversion between right- and left-handed states. We report here the first molecular system that allows stepwise multisequential helicity inversion utilizing metal exchange of helical complexes derived from a hexaoxime ligand, H6L(1). The ligand H6L(1) underwent a four-step conversion (H6L(1) -> L(1)Zn3 -> L(1)Zn5 -> L(1)Zn3Ba -> L(1)Zn3La) upon sequential metal addition (Zn(2+), Ba(2+), then La(3+)). Associated with the conversion, three-step helicity inversion took place (L(1)Zn3, right-handed -> L(1)Zn5, left-handed -> L(1)Zn3Ba, right-handed -> L(1)Zn3La, left-handed). This is the first example of stepwise multimode helicity inversion of a discrete molecule, which could be useful as a platform for construction of dynamic regulation systems with multiple asymmetric functions. PMID- 23937648 TI - Reticular erythematous mucinosis: a review of patients' characteristics, associated conditions, therapy and outcome in 25 cases. AB - BACKGROUND: Reticular erythematous mucinosis (REM) is an uncommon disease, the nosology and specific characteristics of which are controversial because most reports deal with single cases or small series. OBJECTIVES: To describe the characteristics of patients with REM regarding demographics, clinical and pathological features, comorbidities, treatment and course. METHODS: A retrospective and prospective study was conducted on 25 patients diagnosed with REM in the setting of university-affiliated dermatology departments and dermatopathology centres. RESULTS: Of the 25 patients with REM, 16 were women (sex ratio 2 : 1) and the mean age was 46 years. The roles of sun exposure and oral contraceptives were ambiguous. Associated diseases included hypertension (n = 4), malignancies (n = 3), autoimmune diseases (n = 3) and Borrelia infection (n = 1). Immunological studies (including serology and direct immunofluorescence) were noncontributory. The response to antimalarial treatment was good in > 80% of cases. Worsening or recurrence of the lesion after treatment discontinuation, or in the course of the disease, occurred in 31% of patients. CONCLUSIONS: We present the largest REM case series to date. The reticular pattern with involvement of the midline of the chest and back, the predilection for middle aged women, the controversial relationship with photosensitivity and the possible association with other conditions such as malignancies and thyroid dysfunctions are the main characteristics that makes REM a recognizable disease. PMID- 23937649 TI - (68) Ga- DOTA(0) -Tyr(3) octreotide (DOTATOC) positron emission tomography (PET)/CT in five cases of ectopic adrenocorticotropin-secreting tumours. PMID- 23937651 TI - Levosimendan limits reperfusion injury in a rat middle cerebral artery occlusion (MCAO) model. AB - BACKGROUND: Neuroprotective strategies in ischemic stroke are an important challenge in clinical and experimental research as an adjunct to reperfusion therapy that may reduce neurologic injury and improve outcome. The neuroprotective properties of levosimendan in traumatic brain injury in vitro, transient global brain ischemia and focal spinal cord ischemia suggest the potential for similar effects in transient brain ischemia. METHODS: Transient brain ischemia was induced for 60 min by intraluminal occlusion of the middle cerebral artery in 40 male Wistar rats under general anesthesia with s-ketamine and xylazine and with continuous monitoring of their blood pressure and cerebral perfusion. Five minutes before inducing reperfusion, a levosimendan bolus (24 MUg kg -1) was administered over a 20 minute period. Infarct size, brain swelling, neurological function and the expression of inflammatory markers were quantified 24 hours after reperfusion. RESULTS: Although levosimendan limited the infarct size and brain swelling by 40% and 53%, respectively, no effect on neurological outcome or mortality could be demonstrated. Upregulation of tumor necrosis factor alpha and intercellular adhesion molecule 1 was significantly impeded. Cerebral blood flow during reperfusion was significantly reduced as a consequence of sustained autoregulation. CONCLUSIONS: Levosimendan demonstrated significant neuroprotective properties in a rat model of transient brain ischemia by reducing reperfusion injury. PMID- 23937652 TI - Rekindling the lost hair-forming world. PMID- 23937650 TI - Genome-wide analyses of Epstein-Barr virus reveal conserved RNA structures and a novel stable intronic sequence RNA. AB - BACKGROUND: Epstein-Barr virus (EBV) is a human herpesvirus implicated in cancer and autoimmune disorders. Little is known concerning the roles of RNA structure in this important human pathogen. This study provides the first comprehensive genome-wide survey of RNA and RNA structure in EBV. RESULTS: Novel EBV RNAs and RNA structures were identified by computational modeling and RNA-Seq analyses of EBV. Scans of the genomic sequences of four EBV strains (EBV-1, EBV-2, GD1, and GD2) and of the closely related Macacine herpesvirus 4 using the RNAz program discovered 265 regions with high probability of forming conserved RNA structures. Secondary structure models are proposed for these regions based on a combination of free energy minimization and comparative sequence analysis. The analysis of RNA-Seq data uncovered the first observation of a stable intronic sequence RNA (sisRNA) in EBV. The abundance of this sisRNA rivals that of the well-known and highly expressed EBV-encoded non-coding RNAs (EBERs). CONCLUSION: This work identifies regions of the EBV genome likely to generate functional RNAs and RNA structures, provides structural models for these regions, and discusses potential functions suggested by the modeled structures. Enhanced understanding of the EBV transcriptome will guide future experimental analyses of the discovered RNAs and RNA structures. PMID- 23937653 TI - Mitochondrial respiratory chain dysfunction modulates metalloproteases -1, -3 and -13 in human normal chondrocytes in culture. AB - BACKGROUND: Mitochondrion has an important role in the osteoarthritis (OA) pathology. We have previously demonstrated that the alteration of the mitochondrial respiratory chain (MRC) contributes to the inflammatory response of the chondrocyte. However its implication in the process of cartilage destruction is not well understood yet. In this study we have investigated the relationship between the MRC dysfunction and the regulation of metalloproteases (MMPs) in human normal chondrocytes in culture. METHODS: Human normal chondrocytes were isolated from human knees obtained form autopsies of donors without previous history of rheumatic disease. Rotenone, 3-Nitropropionic acid (NPA), Antimycin A (AA), Sodium azide and Oligomycin were used to inhibit the activity of the mitochondrial complexes I, II, III, IV and V respectively. The mRNA expression of MMPs -1, -3 and -13 was studied by real time PCR. The intracellular presence of MMP proteins was evaluated by western blot. The liberation of these proteins to the extracellular media was evaluated by ELISA. The presence of proteoglycans in tissue was performed with tolouidin blue and safranin/fast green. Immunohistochemistry was used for evaluating MMPs on tissue. RESULTS: Firstly, cells were treated with the inhibitors of the MRC for 24 hours and mRNA expression was evaluated. An up regulation of MMP-1 and -3 mRNA levels was observed after the treatment with Oligomycin 5 and 100 MUg/ml (inhibitor of the complex V) for 24 hours. MMP-13 mRNA expression was reduced after the incubation with AA 20 and 60 MUg/ml (inhibitor of complex III) and Oligomycin. Results were validated at protein level observing an increase in the intracellular levels of MMP-1 and -3 after Oligomycin 25 MUg/ml stimulation [(15.20+/-8.46 and 4.59+/ 1.83 vs. basal=1, respectively (n=4; *P<0.05)]. However, AA and Oligomycin reduced the intracellular levels of the MMP-13 protein (0.70+/-0.16 and 0.3+/ 0.24, respectively vs. basal=1). In order to know whether the MRC dysfunction had an effect on the liberation of MMPs, their levels were evaluated in the supernatants. After 36 hours of stimulation, values were: MMP-1=18.06+/-10.35 with Oligomycin 25 MUg/ml vs. basal=1, and MMP-3=8.49+/-4.32 with Oligomycin 5 MUg/ml vs. basal=1 (n=5; *P<0.05). MMP-13 levels in the supernatants were reduced after AA 60 MUg/ml treatment (0.50+/-0.13 vs. basal=1) and Oligomycin 25 MUg/ml (0.41+/-0.14 vs. basal=1); (n=5; *P<0.05). The treatment of explants with Oligomycin, showed an increase in the positivity of MMP-1 and -3. Explants stimulated with AA or Oligomycin revealed a decrease in MMP-13 expression. Proteoglycan staining demonstrated a reduction of proteoglycan levels in the tissues treated with Oligomycin. CONCLUSIONS: These results reveal that MRC dysfunction modulates the MMPs expression in human normal chondrocytes demonstrating its role in the regulation of the cartilage destruction. PMID- 23937654 TI - Perinatal factors in patent ductus arteriosus in very low-birthweight infants. AB - BACKGROUND: The relationship between hemoglobin and patent ductus arteriosus (PDA) has not been discussed before. The aim of this study was to assess the influence of hemoglobin and perinatal factors on PDA in very low-birthweight (VLBW) infants. METHODS: Using data from the Premature Baby Foundation of Taiwan (PBFA), the characteristics, perinatal factors, and hemoglobin of VLBW infants with and without PDA and treatment were compared. RESULTS: Between January 2008 and December 2010, 89 VLBW infants were admitted to hospital. The overall survival rate was 87.6%. Twelve infants were excluded. Compared to those without PDA, the 34 infants with PDA received oral indomethacin or surgery, had smaller mean gestational age (GA; 27.93 +/- 1.818 weeks, P = 0.000003), lower mean birthweight (BW; 1031 +/- 259 g, P = 0.0001), significantly lower Apgar score at 5 min, more severe respiratory distress syndrome (RDS; grade 3 or 4), greater use of surfactants, and lower mean hemoglobin (P = 0.018) after birth than those without PDA. Compared to those with indomethacin, the seven infants with surgery had lower mean GA (26.43 +/- 1.718 weeks, P = 0.011), significantly lower Apgar scores at 1 min, but higher platelet count (P = 0.002) after birth, and more red blood cell transfusions (P = 0.039). CONCLUSIONS: Smaller GA, lower BW, lower Apgar score at 5 min, more severe RDS, greater use of surfactants, and lower hemoglobin after birth place VLBW infants at greater risk of PDA. Proper prenatal care, and prevention of premature labor and delivery may be the most important preventative factors. The appropriate hemoglobin level for PDA closure requires further investigation. PMID- 23937655 TI - Adverse effects following lidocaine treatment are limited with current dosing regimens. PMID- 23937656 TI - Temperature-programmed electrospray-differential mobility analysis for characterization of ligated nanoparticles in complex media. AB - An electrospray-differential mobility analyzer (ES-DMA) was operated with an aerosol flow-mode, temperature-programmed approach to enhance its ability to characterize the particle size distributions (PSDs) of nanoscale particles (NPs) in the presence of adsorbed and free ligands. Titanium dioxide NPs (TiO2-NPs) stabilized by citric acid (CA) or bovine serum albumin (BSA) were utilized as representative systems. Transmission electron microscopy (TEM) and inductively coupled plasma mass spectrometry were used to provide visual information and elemental-based PSDs, respectively. Results show that the interference resulting from electrospray-dried nonvolatile salt residual nanoscale particles (S-NPs) could be effectively reduced using the thermal treatment process: PSDs were accurately measured at temperatures above 200 degrees C for CA-stabilized TiO2 NPs and above 400 degrees C for BSA-stabilized TiO2-NPs. Moreover, TEM confirmed the volumetric shrinkage of S-NPs due to thermal treatment and also showed that the primary structure of TiO2-NPs was relatively stable over the temperature range studied (i.e., below 700 degrees C). Conversely, the shape factor for TiO2 NPs decreased after treatment above 500 degrees C, possibly due to a change in the secondary (aggregate) structure. S-NPs from BSA-stabilized TiO2-NPs exhibited higher global activation energies toward induced volumetric shrinkage than those of CA-stabilized TiO2-NPs, suggesting that activation energy is dependent on ligand size. This prototype study demonstrates the efficacy of using ES-DMA coupled with thermal treatment for characterizing the physical state of NPs, even in a complex medium (e.g., containing plasma proteins) and in the presence of particle agglomerates induced by interaction with binding ligands. PMID- 23937657 TI - Randomized placebo-controlled human pilot study of cold atmospheric argon plasma on skin graft donor sites. AB - Cold atmospheric plasma has already been shown to decrease the bacterial load in chronic wounds. However, until now it is not yet known if plasma treatment can also improve wound healing. We aimed to assess the impact of cold atmospheric argon plasma on the process of donor site healing. Forty patients with skin graft donor sites on the upper leg were enrolled in our study. The wound sites were divided into two equally sized areas that were randomly assigned to receive either plasma treatment or placebo (argon gas) for 2 minutes. Donor site healing was evaluated independently by two blinded dermatologists, who compared the wound areas with regard to reepithelialization, blood crusts, fibrin layers, and wound surroundings. From the second treatment day onwards, donor site wound areas treated with plasma (n = 34) showed significantly improved healing compared with placebo-treated areas (day 1, p = 0.25; day 2, p = 0.011; day 3, p < 0.001; day 4, p < 0.001; day 5, p = 0.004; day 6, p = 0.008; day 7, p = 0.031). Positive effects were observed in terms of improved reepithelialization and fewer fibrin layers and blood crusts, whereas wound surroundings were always normal, independent of the type of treatment. Wound infection did not occur in any of the patients, and no relevant side effects were observed. Both types of treatment were well tolerated. The mechanisms contributing to these clinically observed effects should be further investigated. PMID- 23937659 TI - Direct catalytic asymmetric reductive amination of simple aromatic ketones. AB - A green method for chiral amine synthesis, the direct catalytic asymmetric reductive amination, was developed. Phenylhydrazide is an ideal nitrogen source for reductive amination. Molecular sieves play dual roles in this reaction. They help to remove H2O to form imine, as well as promote an imine reduction. f Binaphane minimizes the inhibition effect from amines and helps the coordination of sterically demanding imines to the iridium center, thus leading to a smooth reaction. PMID- 23937658 TI - Affinity purification strategies for proteomic analysis of transcription factor complexes. AB - Affinity purification (AP) coupled to mass spectrometry (MS) has been successful in elucidating protein molecular networks of mammalian cells. These approaches have dramatically increased the knowledge of the interconnectivity present among proteins and highlighted biological functions within different protein complexes. Despite significant technical improvements reached in the past years, it is still challenging to identify the interaction networks and the subsequent associated functions of nuclear proteins such as transcription factors (TFs). A straightforward and robust methodology is therefore required to obtain unbiased and reproducible interaction data. Here we present a new approach for TF AP-MS, exemplified with the CCAAT/enhancer binding protein alpha (C/EBPalpha). Utilizing the advantages of a double tag and three different MS strategies, we conducted a total of six independent AP-MS strategies to analyze the protein-protein interactions of C/EBPalpha. The resultant data were combined to produce a cohesive C/EBPalpha interactome. Our study describes a new methodology that robustly identifies specific molecular complexes associated with transcription factors. Moreover, it emphasizes the existence of TFs as protein complexes essential for cellular biological functions and not as single, static entities. PMID- 23937660 TI - Prognostic value of preoperative multiparametric magnetic resonance imaging (MRI) for predicting biochemical recurrence after radical prostatectomy. AB - OBJECTIVE: To evaluate the suitability of preoperative multiparametric magnetic resonance imaging (MRI) positivity as a predictor of biochemical recurrence after radical prostatectomy (RP). PATIENTS AND METHODS: We reviewed the clinical records of patients who underwent either standard RP or laparoscopic RP between January 2005 and December 2009 at our institution. Patients who received radiotherapy or androgen deprivation therapy before surgery were excluded. A total of 314 patients met the study inclusion criteria. Cox proportional hazard regression models were used for analyses. In accordance with the criteria in the established guidelines, a radiologist scored the probability of the presence of prostate cancer using a five-point scale of diagnostic confidence level. The highest confidence level of any pulse sequence was considered as the evaluation result. RESULTS: MRI positivity was significantly associated with a high clinical stage (cT >= 2; P = 0.039), a high positive biopsy core rate (>=0.2; P < 0.001), a high biopsy Gleason score ([GS] >=8; P < 0.001) and a high pathological GS (>=8; P = 0.005). Univariate analysis and multivariate analysis showed that MRI positivity was a prognostic indicator in the analysis that included only preoperative variables and also in the analysis including preoperative and pathological variables. CONCLUSION: Multiparametric MRI positivity can independently predict biochemical recurrence after RP. PMID- 23937661 TI - A 22-nt artificial microRNA mediates widespread RNA silencing in Arabidopsis. AB - It is known that 22-nucleotide (nt) microRNAs (miRNAs) derived from asymmetric duplexes trigger phased small-interfering RNA (phasiRNA) production from complementary targets. Here we investigate the efficacy of 22-nt artificial miRNA (amiRNA)-mediated RNA silencing relative to conventional hairpin RNA (hpRNA) and 21-nt amiRNA-mediated RNA silencing. CHALCONE SYNTHASE (CHS) was selected as a target in Arabidopsis thaliana due to the obvious and non-lethal loss of anthocyanin accumulation upon widespread RNA silencing. Over-expression of CHS in the pap1-D background facilitated visual detection of both local and systemic RNA silencing. RNA silencing was initiated in leaf tissues from hpRNA and amiRNA plant expression vectors under the control of an Arabidopsis RuBisCo small subunit 1A promoter (SSU). In this system, hpRNA expression triggered CHS silencing in most leaf tissues but not in roots or seed coats. Similarly, 21-nt amiRNA expression from symmetric miRNA/miRNA* duplexes triggered CHS silencing in all leaf tissues but not in roots or seed coats. However, 22-nt amiRNA expression from an asymmetric duplex triggered CHS silencing in all tissues, including roots and seed coats, in the majority of plant lines. This widespread CHS silencing required RNA-DEPENDENT RNA POLYMERASE6-mediated accumulation of phasiRNAs from the endogenous CHS transcript. These results demonstrate the efficacy of asymmetric 22-nt amiRNA-directed RNA silencing and associated phasiRNA production and activity, in mediating widespread RNA silencing of an endogenous target gene. Asymmetric 22-nt amiRNA-directed RNA silencing requires little modification of existing amiRNA technology and is expected to be effective in suppressing other genes and/or members of gene families. PMID- 23937662 TI - Impaired skin microcirculation in paediatric patients with type 1 diabetes mellitus. AB - AIMS/HYPOTHESIS: We used Laser Doppler Fluximetry (LDF) to define "normal" endothelial function in a large cohort of healthy children and adolescents and to evaluate skin microcirculation in paediatric patients with type 1 diabetes mellitus. METHODS: LDF was performed in 102 healthy children (12.8 +/- 3.3 years of age; 48 male) and 68 patients (12.9 +/- 3.3 years of age; 33 male). Duration of disease was 5.0 +/- 3.97 years. Each participant sequentially underwent three stimulation protocols (localized thermal hyperaemia with localized warming to maximum 40 degrees C, iontophoretic delivery of pilocarpine hydrochloride (PCH) and sodium nitroprusside (SNP)). The maximum relative increase in skin blood flow and the total relative response, i.e. the area under the curve (AUC) to each stimulus (AUCheat, AUCPCH, AUCSNP) was determined. In addition, the area of a right-angled triangle summarizing the time to and the amplitude of the first peak, which represents the axon reflex mediated neurogenic vasodilation (ARR) was calculated. RESULTS: In healthy controls, AUCheat, AUCPCH, AUCSNP, and ARR turned out to be independent of sex, age, and anthropometric values. Per parameter the 10th percentile generated from data of healthy controls was used as the lower threshold to define normal endothelial function. Diabetic patients showed significantly reduced vasodilatative response to either physical or pharmacological stimulation with SNP, whereas the response to PCH was comparable in both cohorts. In patients compared to controls i) a significantly higher frequency of impaired vasodilatation in response to heat and SNP was noted and ii) vascular response was classified as pathological in more than one of the parameters with significantly higher frequency. CONCLUSIONS/INTERPRETATION: Skin microvascular endothelial dysfunction is already present in about 25% of paediatric type 1 diabetic patients suffering from type 1 diabetes for at least one year. Future studies are needed to assess the predictive value of endothelial dysfunction in the development of long-term (cardio)vascular comorbidity in these patients. PMID- 23937663 TI - Influenza infection results in local expansion of memory CD8(+) T cells with antigen non-specific phenotype and function. AB - Primary viral infections induce activation of CD8(+) T cells responsible for effective resistance. We sought to characterize the nature of the CD8(+) T cell expansion observed after primary viral infection with influenza. Infection of naive mice with different strains of influenza resulted in the rapid expansion of memory CD8(+) T cells exhibiting a unique bystander phenotype with significant up regulation of natural killer group 2D (NKG2D), but not CD25, on the CD44(high) CD8(+) T cells, suggesting an antigen non-specific phenotype. We further confirmed the non-specificity of this phenotype on ovalbumin-specific (OT-I) CD8(+) T cells, which are not specific to influenza. These non-specific CD8(+) T cells also displayed increased lytic capabilities and were observed primarily in the lung. Thus, influenza infection was shown to induce a rapid, antigen non specific memory T cell expansion which is restricted to the specific site of inflammation. In contrast, CD8(+) T cells of a similar phenotype could be observed in other organs following administration of systemic agonistic anti-CD40 and interleukin-2 immunotherapy, demonstrating that bystander expansion in multiple sites is possible depending on whether the nature of activation is either acute or systemic. Finally, intranasal blockade of NKG2D resulted in a significant increase in viral replication early during the course of infection, suggesting that NKG2D is a critical mediator of anti-influenza responses prior to the initiation of adaptive immunity. These results characterize further the local bystander expansion of tissue-resident, memory CD8(+) T cells which, due to their early induction, may play an important NKG2D-mediated, antigen non-specific role during the early stages of viral infection. PMID- 23937664 TI - Mena/VASP and alphaII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy. AB - BACKGROUND: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks. RESULTS: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct alphaII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and beta-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, beta actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired. CONCLUSIONS: Together, our data suggest that Mena, VASP, and alphaII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted beta-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities. PMID- 23937665 TI - Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity. AB - Pyrrolizidine alkaloid-containing plants are the most common poisonous plants affecting livestock, wildlife, and humans. The U.S. National Toxicology Program (NTP) classified riddelliine, a tumorigenic pyrrolizidine alkaloid, as "reasonably anticipated to be a human carcinogen" in the NTP 12th Report on Carcinogens in 2011. We previously determined that four DNA adducts were formed in rats dosed with riddelliine. The structures of the four DNA adducts were elucidated as (i) a pair of epimers of 7-hydroxy-9-(deoxyguanosin-N(2) yl)dehydrosupinidine adducts (termed as DHP-dG-3 and DHP-dG-4) as the predominant adducts; and (ii) a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N(6) yl)dehydrosupinidine adducts (termed as DHP-dA-3 and DHP-dA-4 adducts). In this study, we selected a nontumorigenic pyrrolizidine alkaloid, platyphylliine, a pyrrolizidine alkaloid N-oxide, riddelliine N-oxide, and nine tumorigenic pyrrolizidine alkaloids (riddelliine, retrorsine, monocrotaline, lycopsamine, retronecine, lasiocarpine, heliotrine, clivorine, and senkirkine) for study in animals. Seven of the nine tumorigenic pyrrolizidine alkaloids, with the exception of lycopsamine and retronecine, are liver carcinogens. At 8-10 weeks of age, female F344 rats were orally gavaged for 3 consecutive days with 4.5 and 24 MUmol/kg body weight test article in 0.5 mL of 10% DMSO in water. Twenty-four hours after the last dose, the rats were sacrificed, livers were removed, and liver DNA was isolated for DNA adduct analysis. DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts were formed in the liver of rats treated with the individual seven hepatocarcinogenic pyrrolizidine alkaloids and riddelliine N-oxide. These DNA adducts were not formed in the liver of rats administered retronecine, the nontumorigenic pyrrolizidine alkaloid, platyphylliine, or vehicle control. These results indicate that this set of DNA adducts, DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, is a common biological biomarker of pyrrolizidine alkaloid-induced liver tumor formation. To date, this is the first finding that a set of exogenous DNA adducts are commonly formed from a series of tumorigenic xenobiotics. PMID- 23937666 TI - A preliminary study on the relationship between central auditory processing and childhood primary headaches in the intercritical phase. AB - BACKGROUND: Recently, an increasing number of articles have appeared on central auditory processing disorders, but in the literature there is only one study that evaluated the possible correlation between migraine in the critical phase and central auditory processing. The aim of our study was to assess the correlation between auditory processing information and childhood primary headaches in the intercritical phase. METHODS: This is an observational study. We enrolled 54 patients, 30 with primary headache (migraine and tension headache) and 24 normal controls, matched for sex and age. The mean age at first observation was 9 years 10 months; the duration of observational follow-up was 2 years. Both groups had normal audiological and neurological profiles, normal peripheral hearing acuity and normal cognitive and behavioral skills. We excluded patients who had undergone pharmacological prophylactic treatment for headaches in the 6 months preceding the study and subjects with a frequency of headache lower than one every two months. After enrolment, both groups were analyzed with a computerized test battery for Speech Perception Tests in silence and in noise background to assess speech perception disabilities. In addition, with a test battery of Speech Perception Tests, we compared patients with migraines and tension-type headaches. The non-parametric chi2 test, the Mann-Whitney U-test and the Wilcoxon signed ranks test were used for statistical analysis. P-values <0.05 were considered significant and STATA 10 software was used for statistical analyses. RESULTS: Our results showed that patients with primary headache (migraine and tension-type headache), had a deficit of auditory processing in noisy background compared to control cases, but we found no significant differences when we compared patients with migraine and tension-type headache. CONCLUSIONS: This is a work in progress and further studies are needed to assess the relationship between the impairment of auditory processing and primary headache, not only to improve the diagnostic approach to primary headache, but also to improve therapeutic intervention. PMID- 23937667 TI - Alternative replication factor C protein, Elg1, maintains chromosome stability by regulating PCNA levels on chromatin. AB - Proliferating cell nuclear antigen (PCNA) is loaded on chromatin upon initiation of the S phase and acts as a platform for a large number of proteins involved in chromosome duplication at the replication fork. As duplication is completed, PCNA dissociates from chromatin, and thus, chromatin-bound PCNA levels are regulated during the cell cycle. Although the mechanism of PCNA loading has been extensively investigated, the unloading mechanism has remained unclear. Here, we show that Elg1, an alternative replication factor C protein, is required for the regulation of chromatin-bound PCNA levels. When Elg1 was depleted by small interfering RNA, chromatin-bound PCNA levels were extremely increased during the S phase. The number of PCNA foci, regions in the nucleus normally representing DNA replication sites, was increased and PCNA remained on chromatin after DNA replication. Various chromatin-associated protein levels on chromatin were affected, and chromatin loop size was increased. During mitosis, cells with aberrant chromosomes and lagging chromosomes were frequently detected. Our findings suggest that Elg1 has an important role in maintaining chromosome integrity by regulating PCNA levels on chromatin, thereby acting as a PCNA unloading factor. PMID- 23937668 TI - Radiotherapy of abdomen with precise renal assessment with SPECT/CT imaging (RAPRASI): design and methodology of a prospective trial to improve the understanding of kidney radiation dose response. AB - BACKGROUND: The kidneys are a principal dose-limiting organ in radiotherapy for upper abdominal cancers. The current understanding of kidney radiation dose response is rudimentary. More precise dose-volume response models that allow direct correlation of delivered radiation dose with spatio-temporal changes in kidney function may improve radiotherapy treatment planning for upper-abdominal tumours. METHODS/DESIGN: The Radiotherapy of Abdomen with Precise Renal Assessment with SPECT/CT Imaging (RAPRASI) is an observational clinical research study with participating sites at Sir Charles Gairdner Hospital (SCGH) in Perth, Australia and the Peter MacCallum Cancer Centre (PMCC) in Melbourne, Australia. Eligible patients are those with upper gastrointestinal cancer, without metastatic disease, undergoing conformal radiotherapy that will involve incidental radiation to one or both kidneys. For each patient, total kidney function is being assessed before commencement of radiotherapy treatment and then at 4, 12, 26, 52 and 78 weeks after the first radiotherapy fraction, using two procedures: a Glomerular Filtration Rate (GFR) measurement using the 51Cr ethylenediamine tetra-acetic acid (EDTA) clearance; and a regional kidney perfusion measurement assessing renal uptake of 99mTc-dimercaptosuccinic acid (DMSA), imaged with a Single Photon Emission Computed Tomography / Computed Tomography (SPECT/CT) system. The CT component of the SPECT/CT provides the anatomical reference of the kidney's position. The data is intended to reveal changes in regional kidney function over the study period after the radiotherapy. These SPECT/CT scans, co-registered with the radiotherapy treatment plan, will provide spatial correlation between the radiation dose and regional renal function as assessed by SPECT/CT. From this correlation, renal response patterns will likely be identified with the purpose of developing a predictive model. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000322235. PMID- 23937669 TI - Tadalafil once daily in the treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) in men without erectile dysfunction. AB - OBJECTIVES: To assess the safety and efficacy of tadalafil once daily on lower urinary tract symptoms suggestive of clinical benign prostatic hyperplasia (BPH LUTS) in men without erectile dysfunction (ED). To compare these with effects in men with ED. PATIENTS AND METHODS: After a 4-week washout period and 4-week placebo run-in period, 1089 men without ED (n = 338) and with ED (n = 751) were randomly assigned to placebo or tadalafil 5 mg once daily for 12 weeks in three global clinical studies with similar designs. In the pooled dataset, post hoc analyses of covariance assessed the impact and severity of BPH-LUTS using the International Prostate Symptom Score (IPSS) and the BPH Impact Index (BII) and IPSS quality-of-life (IPSS-QoL) subscores. Safety was assessed using treatment emergent adverse events. The treatment-by-ED-status interaction was used to assess efficacy differences between the with/without ED subgroups. RESULTS: Men without ED were similar in BPH-LUTS severity/previous therapy to men with ED. Tadalafil significantly reduced BPH-LUTS from baseline when compared with placebo in men without ED (IPSS -5.4 vs -3.3, P < 0.01; IPSS voiding subscore -3.5 vs 2.0, P < 0.01; IPSS storage subscore -1.9 vs -1.3, P < 0.05). Tadalafil also significantly improved quality of life from baseline when compared with placebo in men without ED (IPSS-QoL -1.0 vs -0.7, BII -1.4 vs -1.0; both P < 0.05). Between-ED-subgroup interactions were not significant (all P > 0.68). Tadalafil was safe and well tolerated. CONCLUSION: Tadalafil 5 mg once daily improved BPH LUTS in men without ED by a magnitude similar to that observed in men with ED. The adverse event profile in men without ED was consistent with that observed in men with ED. PMID- 23937670 TI - Efficient NQO1 substrates are potent and selective anticancer agents. AB - A major goal of personalized medicine in oncology is the identification of drugs with predictable efficacy based on a specific trait of the cancer cell, as has been demonstrated with gleevec (presence of Bcr-Abl protein), herceptin (Her2 overexpression), and iressa (presence of a specific EGFR mutation). This is a challenging task, as it requires identifying a cellular component that is altered in cancer, but not normal cells, and discovering a compound that specifically interacts with it. The enzyme NQO1 is a potential target for personalized medicine, as it is overexpressed in many solid tumors. In normal cells NQO1 is inducibly expressed, and its major role is to detoxify quinones via bioreduction; however, certain quinones become more toxic after reduction by NQO1, and these compounds have potential as selective anticancer agents. Several quinones of this type have been reported, including mitomycin C, RH1, EO9, streptonigrin, beta lapachone, and deoxynyboquinone (DNQ). However, no unified picture has emerged from these studies, and the key question regarding the relationship between NQO1 processing and anticancer activity remains unanswered. Here, we directly compare these quinones as substrates for NQO1 in vitro, and for their ability to kill cancer cells in culture in an NQO1-dependent manner. We show that DNQ is a superior NQO1 substrate, and we use computationally guided design to create DNQ analogues that have a spectrum of activities with NQO1. Assessment of these compounds definitively establishes a strong relationship between in vitro NQO1 processing and induction of cancer cell death and suggests these compounds are outstanding candidates for selective anticancer therapy. PMID- 23937671 TI - An analysis of the molecular evolution of hepatitis B viral genotypes A/B/D using a Bayesian evolutionary method. AB - BACKGROUND: Hepatitis B virus (HBV) infection is a major global health problem. The infectious virion contains an inner "core particle", which is made of 180 or 240 copies of core protein, alternatively known as hepatitis B core antigen, or HBcAg which encloses the viral genome. METHOD: In this study, we characterized HBV genotypes and used Bayesian analyses to estimate date of emergence of the most recent common ancestor (TMRCA) of three HBV genotypes, A, B, and D. RESULTS: We estimated that the rate of evolution of HBV core protein gene to be 1.127 (0.925-1.329, 95% HPD) substitutions per site per year. The TMRCA of HBV for genotypes A, B, D were 118 (54-194, 95% HPD) year, 184 (78-323, 95% HPD) year and 133 (65-230, 95% HPD) year, respectively. Demographic histories of the HBcAg gene showed that the relative genetic diversity had a sharp increase within the first 10 years of its emergence. CONCLUSION: Using a bayesian evolutionary method to predict the outbreak trends of HBV through evolutionary trees of HBV, and provide theoretical foundations for clinical prevention and treatment of HBV. PMID- 23937672 TI - Exploiting the higher specificity of silver amalgamation: selective detection of mercury(II) by forming Ag/Hg amalgam. AB - Heavy metal ion pollution poses severe risks in human health and the environment. Driven by the need to detect trace amounts of mercury, this article demonstrates, for the first time, that silver/mercury amalgamation, combining with DNA protected silver nanoparticles (AgNPs), can be used for rapid, easy and reliable screening of Hg(2+) ions with high sensitivity and selectivity over competing analytes. In our proposed approach, Hg(2+) detection is achieved by reducing the mercury species to elemental mercury, silver atoms were chosen as the mercury atoms' acceptors by forming Ag/Hg amalgam. To signal fluorescently this silver amalgamation event, a FAM-labeled ssDNA was employed as the signal reporter. AgNPs were grown on the DNA strand that resulted in greatly quenching the FAM fluorescence. Formation of Ag/Hg amalgam suppresses AgNPs growth on the DNA, leading to fluorescence signal increase relative to the fluorescence without Hg(2+) ions, as well as marked by fluorescence quenching. This FAM fluorescence enhancement can be used for detection of Hg(2+) at the a few nanomolar level. Moreover, due to excellent specificity of silver amalgamation with mercury, the sensing system is highly selective for Hg(2+) and does not respond to other metal ions with up to millimolar concentration levels. This sensor is successfully applied to determination of Hg(2+) in tap water, spring water and river water samples. The results shown herein have important implications in the development of new fluorescent sensors for the fast, easy, and selective detection and quantification of Hg(2+) in environmental and biological samples. PMID- 23937673 TI - Adding home health care to the discussion on health information technology policy. AB - The potential for health information technology to improve the efficiency and effectiveness of health care has resulted in several U.S. policy initiatives aimed at integrating health information technology into health care systems. However, home health care agencies have been excluded from incentive programs established through policies, raising concerns on the extent to which health information technology may be used to improve the quality of care for older adults with chronic illness and disabilities. This analysis examines the potential issues stemming from this exclusion and explores potential opportunities of integrating home health care into larger initiatives aimed at establishing health information technology systems for meaningful use. PMID- 23937674 TI - Lessons learned from gene expression profiling of cutaneous T-cell lymphoma. AB - Gene expression studies of cutaneous T-cell lymphoma (CTCL) span a decade, yet the pathogenesis is poorly understood and diagnosis remains a challenge. This review examines the varied approaches to gene expression analysis of CTCL, with emphasis on cell populations, control selection and expression data collection. Despite discordant results, several dysregulated genes have been identified across multiple studies, including PLS3, KIR3DL2, TWIST1 and STAT4. Here, we provide an overview of the most consistently expressed genes across different studies and bring them together through common pathways biologically relevant to CTCL. Four pathways - evasion of activation-induced cell death, T helper 2 lymphocyte differentiation, transforming growth factor-beta receptor expression, and tumour necrosis factor receptor ligands - appear to encompass the most frequently affected genes, hypothetically providing insight into the disease pathogenesis. PMID- 23937675 TI - Oral antigen exposure in extreme early life in lambs influences the magnitude of the immune response which can be generated in later life. AB - BACKGROUND: Previous investigations in newborn lambs determined that adenovirus mediated expression of antigen to a localized region of the gut induced antigen specific mucosal and systemic immunity. These experiments were limited in that the localized region of the gut to which antigen was introduced was sterile and the influence of colostrum on the antigen was not assessed but they do suggest that mucosal vaccines may be an effective vaccination strategy to protect neonatal lambs. We propose that persistent oral antigen exposure introduced in extreme early life can induce immunity in lambs, despite the presence of commensal bacteria and colostrum. RESULTS: To test this hypothesis, conventionally raised newborn lambs (n = 4 per group) were gavaged with ovalbumin (OVA) starting the day after birth for either a single day (2.27 g), every day for 3 days (0.23 g/day), or every day for 3 days then every second day until nine days of age (0.023 g/day). Lambs gavaged with OVA for 3 to 9 days developed significant serum anti-OVA IgG titres (p < 0.05), but not IgA titres, relative to control lambs (n = 4) after 3 and 4 weeks. At 4 weeks of age, lambs were immunized with OVA in Incomplete Freund's Adjuvant via intraperitoneal (i.p.) injection then lambs were euthanized at 7 weeks. Serum anti-OVA IgG titres were further augmented after i.p. immunization indicating immunity persisted and tolerance was not induced. Serum IgA titres remained low regardless of treatment. It is known that i.p. priming of sheep with antigen in Freund's complete adjuvant leads to an enhanced number of IgA and IgG antibody containing cells in the respiratory mucosa (Immunology 53(2):375-384, 1984). Lambs gavaged with a single bolus of 2.27 g OVA prior to i.p. immunization showed very low titres of anti-OVA IgA in the lung lavage. These data suggest that a single, high dose exposure to OVA can promote tolerance which impacts response to systemic vaccination in later life. Lambs gavaged with 0.023 g OVA for 9 days (Group C) generated significant anti-OVA IgA titres in lung (p < 0.001) compared to negative control lambs but no additive effect was observed compared to parenteral control lambs. When splenocytes were re-stimulated with OVA ex vivo, all groups failed to show increased lymphocyte proliferation or interferon (IFN)-gamma production relative to the parenteral control group. CONCLUSIONS: In agreement with our hypothesis, persistent low dose antigen exposure primes humoral antibody production in serum in conventionally raised newborn lambs. In contrast, a single high dose bolus of antigen triggered oral tolerance which negatively impacted the quality and magnitude of the immune response to i.p. immunization in later life. These tangential responses are important as they indicate that the dose and/or repeated oral exposure to antigen, such as that which may be found in the neonate's environment, may promote immunity or alternatively it may negatively impact responses to parenteral vaccination. PMID- 23937676 TI - miRNA and miRNA target genes in copy number variations occurring in individuals with intellectual disability. AB - BACKGROUND: MicroRNAs (miRNAs) are a family of short, non-coding RNAs modulating expression of human protein coding genes (miRNA target genes). Their dysfunction is associated with many human diseases, including neurodevelopmental disorders. It has been recently shown that genomic copy number variations (CNVs) can cause aberrant expression of integral miRNAs and their target genes, and contribute to intellectual disability (ID). RESULTS: To better understand the CNV-miRNA relationship in ID, we investigated the prevalence and function of miRNAs and miRNA target genes in five groups of CNVs. Three groups of CNVs were from 213 probands with ID (24 de novo CNVs, 46 familial and 216 common CNVs), one group of CNVs was from a cohort of 32 cognitively normal subjects (67 CNVs) and one group of CNVs represented 40 ID related syndromic regions listed in DECIPHER (30 CNVs) which served as positive controls for CNVs causing or predisposing to ID. Our results show that 1). The number of miRNAs is significantly higher in de novo or DECIPHER CNVs than in familial or common CNV subgroups (P < 0.01). 2). miRNAs with brain related functions are more prevalent in de novo CNV groups compared to common CNV groups. 3). More miRNA target genes are found in de novo, familial and DECIPHER CNVs than in the common CNV subgroup (P < 0.05). 4). The MAPK signaling cascade is found to be enriched among the miRNA target genes from de novo and DECIPHER CNV subgroups. CONCLUSIONS: Our findings reveal an increase in miRNA and miRNA target gene content in de novo versus common CNVs in subjects with ID. Their expression profile and participation in pathways support a possible role of miRNA copy number change in cognition and/or CNV-mediated developmental delay. Systematic analysis of expression/function of miRNAs in addition to coding genes integral to CNVs could uncover new causes of ID. PMID- 23937677 TI - Atypical teratoid/rhabdoid tumour in an adult with disseminated mediastinal germ cell tumour. PMID- 23937678 TI - Folic acid supplementation, dietary folate intake during pregnancy and risk for spontaneous preterm delivery: a prospective observational cohort study. AB - BACKGROUND: Health authorities in numerous countries recommend periconceptional folic acid to pregnant women to prevent neural tube defects. The objective of this study was to examine the association of folic acid supplementation during different periods of pregnancy and of dietary folate intake with the risk of spontaneous preterm delivery (PTD). METHODS: The Norwegian Mother and Child Cohort Study is a population-based prospective cohort study. A total of 65,668 women with singleton pregnancies resulting in live births in 1999-2009 were included. Folic acid supplementation was self-reported from 26 weeks before pregnancy until week 24 during pregnancy. At gestational week 22, the women completed a food frequency questionnaire, which allowed the calculation of their average total folate intake from foods and supplements for the first 4-5 months of pregnancy. Spontaneous PTD was defined as the spontaneous onset of delivery between weeks 22+0 and 36+6 (n = 1,628). RESULTS: The median total folate intake was 266 MUg/d (interquartile range IQR 154-543) in the overall population and 540 MUg/d (IQR 369-651) in the supplement users. Eighty-three percent reported any folic acid supplementation from <8 weeks before to 24 weeks after conception while 42% initiated folic acid supplementation before their pregnancy. Cox regression analysis showed that the amount of folate intake from the diet (hazard ratio HR 1.16; confidence interval CI 0.65-2.08) and from the folic acid supplements (HR 1.04; CI 0.95-1.13) was not significantly associated with the risk of PTD. The initiation of folic acid supplementation more than 8 weeks before conception was associated with an increased risk for PTD (HR 1.19; CI 1.05 1.34) compared to no folic acid supplementation pre-conception. There was no significant association with PTD when supplementation was initiated within 8 weeks pre-conception (HR 1.01; CI 0.88-1.16). All analyses were adjusted for maternal characteristics and socioeconomic, health and dietary variables. CONCLUSIONS: Our findings do not support a protective effect of dietary folate intake or folic acid supplementation on spontaneous PTD. Pre-conceptional folic acid supplementation starting more than 8 weeks before conception was associated with an increased risk of PTD. These results require further investigation before discussing an expansion of folic acid supplementation guidelines. PMID- 23937679 TI - Safety and efficacy of epelsiban in the treatment of men with premature ejaculation: a randomized, double-blind, placebo-controlled, fixed-dose study. AB - AIM: To assess the efficacy and safety of the selective oxytocin receptor antagonist epelsiban in the treatment of premature ejaculation (PE). METHODS: Double-blind, randomized, parallel-group, placebo-controlled, stopwatch monitored, phase 2, multicenter study (GSK557296; NCT01021553) conducted in men (N=77) 18-55 years of age, with PE defined as per International Society for Sexual Medicine consensus definition. Patients provided informed consent prior to a 4-week un-medicated run-in to determine baseline intravaginal ejaculatory latency times (IELT) recorded in an electronic diary. Patients needed to make a minimum of four intercourse attempts and have a mean IELT<65 seconds to be considered for randomization. Men with moderate-to-severe erectile dysfunction were excluded from the study. Eligible patients were randomized to placebo, epelsiban 50 mg, or 150 mg, taken 1 hour before sexual activity. Active treatment IELT times were recorded in an electronic diary, along with subjective measures of intercourse satisfaction, over an 8-week treatment period. The Modified Index of Premature Ejaculation and International Index of Erectile Function were completed at study visits. MAIN OUTCOME MEASURES: Stopwatch timed IELT recordings and a modified version of the patient-reported outcome questionnaire the IPE were used in this study to determine the effect of epelsiban when taken orally prior to intercourse in subjects diagnosed with PE. RESULTS: The baseline (mean) IELT for patients pretreatment was (0.52, 0.63, and 0.59 minutes) for placebo, epelsiban 50 mg and 150 mg, respectively. On-treatment, average geometric least squares means of the median IELT values (mean) were slightly higher in the 50 mg and 150 mg groups (0.72 and 0.69 minutes), respectively, vs. the placebo group (0.62 minutes). Headache was the most common adverse event, and rates were similar across all groups. CONCLUSIONS: Epelsiban 50 mg and 150 mg were well tolerated, but did not result in a clinically or statistically significant change in IELT in men with PE, compared with placebo. PMID- 23937680 TI - Association of problem behavior with sleep problems and gastroesophageal reflux symptoms. AB - BACKGROUND: There are few large-scale epidemiologic studies examining the associations between sleep problems, gastroesophageal reflux disease (GERD) symptoms, lifestyle and food habits and problem behaviors (PB) in adolescents. The aim of this study was to evaluate the associations among these factors in Japanese adolescents. METHODS: A cross-sectional survey of 1840 junior high school students was carried out using questionnaires. The subjects were classified into PB or normal behavior (NB) groups using the Pediatric Symptom Checklist (PSC). The scores of the sleep-related factors, sleep bruxism, lifestyle and food habits, and GERD symptoms were compared. Logistic regression analysis was used to determine the factors related to PB. RESULTS: Mean subject age was 13.3 +/- 1.8 years. The PB group had significantly longer sleep latency and higher GERD symptom score (P < 0.001). Furthermore, the PB group was significantly more likely to experience absence of the mother at dinner time, skip breakfast, and have <30 min of conversation among family at dinner time. The PB group had significantly higher frequencies of sleep bruxism, difficulty falling asleep within 30 min, nightmares, feeling of low sleep quality, daytime somnolence, and daytime lack of motivation. Feelings of low sleep quality had the strongest association with PB, with an adjusted odds ratio of 12.88 (95% confidence interval: 8.99-18.46). CONCLUSIONS: PB in adolescents are associated with sleep problems, including sleep bruxism, as well as lifestyle and food habits and GERD symptoms. PMID- 23937682 TI - Adipose tissue-derived stem cells (ADSCs) transplantation promotes regeneration of expanded skin using a tissue expansion model. AB - Transplantation of adipose tissue-derived stem cells (ADSCs) is a promising method that has been used in regenerative medicine because it has shown the capacity to accelerate wound healing. However, roles of ADSCs transplantation in expanded-skin regeneration have remained unknown. To clarify the roles, a tissue expansion model was used in this study. The study comprised three groups of 13 rats in each group: the ADSCs group, the fibroblast (FB) group, and the control group. The skin regeneration in the ADSCs group was enhanced, as evidenced by increased cell proliferation and a higher hydroxyproline content and degree of neovascularization, all with p < 0.05, when compared with both the FB group and the control group. Consistent with enhanced cell proliferation and neovascularization, the regenerated skin in the ADSCs group was much thicker, which further reduced the retraction ratio of the expanded skin. Four weeks after operation, 5'-bromo-2'-deoxyuridine-labeled ADSCs appeared in subcutaneous tissue, vascular vessels, and hair follicles. The up-regulation of protein expression, such as epidermal growth factor and vascular endothelial growth factor, primarily emerged in the ADSC group, with the up-regulated basic fibroblast growth factor appearing in the FB group. Collectively, these results suggest that the transplantation of ADSCs could enhance the regeneration of expanded skin by participating in skin structures and up-regulating the secretion of epidermal growth factor and vascular endothelial growth factor. PMID- 23937683 TI - Covering surface nanobubbles with a NaCl nanoblanket. AB - By letting a NaCl aqueous solution of low (0.01 M) concentration evaporate on a highly oriented pyrolytic graphite (HOPG) surface, it is possible to form a thin film of salt. However, pre-existing surface nanobubbles prevent the homogeneous coverage of the surface with the salt, keeping the footprint areas on the substrate pristine. Comparing the surface nanobubbles in the salt solution with their associated footprint after drying, provides information on the shrinkage of nanobubbles during the hours-long process of drying the liquid film. At a slightly higher NaCl concentration and thus salt layer thickness, the nanobubbles are covered with a thin blanket of salt. Once the liquid film has evaporated until a water film remains that is smaller than the height of the nanobubbles, the blanket of salt cracks and unfolds into a flower-like pattern of salt flakes that is located at the rim of the nanobubble footprint. The formation of a blanket of salt covering the nanobubbles is likely to considerably or even completely block the gas out-flux from the nanobubble, partially stabilizing the nanobubbles against dissolution. PMID- 23937684 TI - Hospital- and community-associated methicillin-resistant Staphylococcus aureus: a 6-year surveillance study of invasive infections in Chinese children. AB - AIM: To investigate and compare the characteristics of invasive hospital associated (HA) and community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) infections in Chinese children. METHODS: Clinical data on 59 paediatric patients with invasive MRSA isolated from the normally sterile sites between 2006 and 2011 were obtained from the clinical MRSA surveillance database of Beijing Children's Hospital. The molecular characteristics of the invasive MRSA strains were then analysed. RESULTS: Invasive MRSA infections rose from 0.89 per 10 000 admissions in 2006 to 3.75 in 2011, with a notable increase in invasive CA-MRSA infections from 0 to 2.43 over the same period. The median age of the CA patients (n = 29) was 0.33 years, compared with 1.17 years for the HA patients (n = 30). Multisite infection, severe pneumonia and empyema were found in 55.2%, 73.1% and 61.5% of CA children and in 30%, 32% and 24% of HA patients, respectively. ST59-MRSA-IVa accounted for 40.7% of all isolates and the Panton-Valentine leukocidin (PVL) gene carriage rate was significantly higher in patients with necrotizing pneumonia and osteoarthritis than in those with other diseases. CONCLUSION: The incidence of paediatric invasive MRSA infection, particularly CA-MRSA infection, increased in Chinese children between 2006 and 2011. The invasive infections caused by CA-MRSA occurred more frequently in younger children with more severe pneumonia or empyema. PMID- 23937685 TI - Treatment burden in stage I seminoma: a comparison of surveillance and adjuvant radiation therapy. AB - OBJECTIVE: To examine the management and outcomes of patients with stage I seminoma and to relate these to overall treatment burden. PATIENTS AND METHODS: A total of 764 patients with stage I seminoma underwent surveillance or adjuvant radiation therapy (RT) at a single institution. First relapse on surveillance was managed with RT alone, or with combination chemotherapy (ChT) for more extensive recurrence. Second relapse was managed with ChT. Relapse after adjuvant RT was treated with ChT. The treatment burden was measured, according to the specific treatment undertaken after orchiectomy, by defining treatment episodes as follows: surgery - one episode; one course of RT - one episode; one course of ChT - one episode. RESULTS: In all, 484 patients underwent surveillance and 280 received adjuvant RT. The 5- and 10-year overall survival rates were 98.6 and 97.7% for surveillance, and 97.2 and 91.4% for adjuvant RT. A total of 72 (15%) patients in the surveillance group relapsed; treatment for relapse was RT (n = 56), ChT (n = 15) and surgery (n = 1). Second relapse occurred in six patients; these patients were treated with ChT. Of the patients in the adjuvant RT group, 14 (5%) relapsed: salvage treatment was 10 - ChT (n = 10) surgery (n = 1) and further RT (n = 3). The overall treatment burden represented by number of treatment episodes per patient was 0.16 in the surveillance group and 1.05 in the adjuvant RT group. CONCLUSIONS: Surveillance reduces the overall treatment burden in patients with stage I seminoma and is the preferred management option. The selective use of RT at first relapse for patients on surveillance leads to a similar requirement for subsequent ChT to that for patients on adjuvant RT. PMID- 23937686 TI - Flow Heck reactions using extremely low loadings of phosphine-free palladium acetate. AB - High-yielding Heck reactions are demonstrated using 0.05 mol % Pd(OAc)2 without phosphine ligands. These reactions are run in a mesoscale flow reactor which allows precise control of reaction times and temperatures. Profiling yield and selectivity versus Pd loading shows 500 ppm to be optimal for aryl iodides; higher loadings favor side reactions caused by Pd(II) species. Aryl halides are examined via concise Design of Experiment to expand the scope and optimize conditions. PMID- 23937687 TI - Differential proteomic analysis of the secretome of Irpex lacteus and other white rot fungi during wheat straw pretreatment. AB - BACKGROUND: Identifying new high-performance enzymes or enzyme complexes to enhance biomass degradation is the key for the development of cost-effective processes for ethanol production. Irpex lacteus is an efficient microorganism for wheat straw pretreatment, yielding easily hydrolysable products with high sugar content. Thus, this fungus was selected to investigate the enzymatic system involved in lignocellulose decay, and its secretome was compared to those from Phanerochaete chrysosporium and Pleurotus ostreatus which produced different degradation patterns when growing on wheat straw. Extracellular enzymes were analyzed through 2D-PAGE, nanoLC/MS-MS, and homology searches against public databases. RESULTS: In wheat straw, I. lacteus secreted proteases, dye decolorizing and manganese-oxidizing peroxidases, and H2O2 producing-enzymes but also a battery of cellulases and xylanases, excluding those implicated in cellulose and hemicellulose degradation to their monosaccharides, making these sugars poorly available for fungal consumption. In contrast, a significant increase of beta-glucosidase production was observed when I. lacteus grew in liquid cultures. P. chrysosporium secreted more enzymes implicated in the total hydrolysis of the polysaccharides and P. ostreatus produced, in proportion, more oxidoreductases. CONCLUSION: The protein pattern secreted during I. lacteus growth in wheat straw plus the differences observed among the different secretomes, justify the fitness of I. lacteus for biopretreatment processes in 2G ethanol production. Furthermore, all these data give insight into the biological degradation of lignocellulose and suggest new enzyme mixtures interesting for its efficient hydrolysis. PMID- 23937689 TI - The selective role of premotor cortex in speech perception: a contribution to phoneme judgements but not speech comprehension. AB - Several accounts of speech perception propose that the areas involved in producing language are also involved in perceiving it. In line with this view, neuroimaging studies show activation of premotor cortex (PMC) during phoneme judgment tasks; however, there is debate about whether speech perception necessarily involves motor processes, across all task contexts, or whether the contribution of PMC is restricted to tasks requiring explicit phoneme awareness. Some aspects of speech processing, such as mapping sounds onto meaning, may proceed without the involvement of motor speech areas if PMC specifically contributes to the manipulation and categorical perception of phonemes. We applied TMS to three sites-PMC, posterior superior temporal gyrus, and occipital pole-and for the first time within the TMS literature, directly contrasted two speech perception tasks that required explicit phoneme decisions and mapping of speech sounds onto semantic categories, respectively. TMS to PMC disrupted explicit phonological judgments but not access to meaning for the same speech stimuli. TMS to two further sites confirmed that this pattern was site specific and did not reflect a generic difference in the susceptibility of our experimental tasks to TMS: stimulation of pSTG, a site involved in auditory processing, disrupted performance in both language tasks, whereas stimulation of occipital pole had no effect on performance in either task. These findings demonstrate that, although PMC is important for explicit phonological judgments, crucially, PMC is not necessary for mapping speech onto meanings. PMID- 23937688 TI - Effects of acute dopamine precusor depletion on immediate reward selection bias and working memory depend on catechol-O-methyltransferase genotype. AB - Little agreement exists as to acute dopamine (DA) manipulation effects on intertemporal choice in humans. We previously found that catechol-O methyltransferase (COMT) Val158Met genotype predicts individual differences in immediate reward selection bias among adults. Moreover, we and others have shown that the relationship between COMT genotype and immediate reward bias is inverted in adolescents. No previous pharmacology studies testing DA manipulation effects on intertemporal choice have accounted for COMT genotype, and many have included participants in the adolescent age range (18-21 years) as adults. Moreover, many studies have included female participants without strict cycle phase control, although recent evidence demonstrates that cyclic estradiol elevations interact with COMT genotype to affect DA-dependent cognition. These factors may have interacted with DA manipulations in past studies, potentially occluding detection of effects. Therefore, we predicted that, among healthy male adults (ages 22-40 years), frontal DA tone, as indexed by COMT genotype, would interact with acute changes in DA signaling to affect intertemporal choice. In a double-blind, placebo-controlled design, we decreased central DA via administration of an amino acid beverage deficient in the DA precursors, phenylalanine and tyrosine, and tested effects on immediate reward bias in a delay-discounting (DD) task and working memory (WM) in an n-back task. We found no main effect of beverage on DD or WM performance but did find significant beverage*genotype effects. These results suggest that the effect of DA manipulations on DD depends on individual differences in frontal DA tone, which may have impeded some past efforts to characterize DA's role in immediate reward bias in humans. PMID- 23937690 TI - Resting-state modulation of alpha rhythms by interference with angular gyrus activity. AB - The default mode network is active during restful wakefulness and suppressed during goal-driven behavior. We hypothesize that inhibitory interference with spontaneous ongoing, that is, not task-driven, activity in the angular gyrus (AG), one of the core regions of the default mode network, will enhance the dominant idling EEG alpha rhythms observed in the resting state. Fifteen right handed healthy adult volunteers underwent to this study. Compared with sham stimulation, magnetic stimulation (1 Hz for 1 min) over both left and right AG, but not over FEF or intraparietal sulcus, core regions of the dorsal attention network, enhanced the dominant alpha power density (8-10 Hz) in occipitoparietal cortex. Furthermore, right AG-rTMS enhanced intrahemispheric alpha coherence (8 10 Hz). These results suggest that AG plays a causal role in the modulation of dominant low-frequency alpha rhythms in the resting-state condition. PMID- 23937691 TI - Beyond the tripartite cognition-emotion-interoception model of the human insular cortex. AB - Functional MRI studies report insular activations across a wide range of tasks involving affective, sensory, and motor processing, but also during tasks of high level perception, attention, and control. Although insular cortical activations are often reported in the literature, the diverse functional roles of this region are still not well understood. We used a meta-analytic approach to analyze the coactivation profiles of insular subdivisions-dorsal anterior, ventral anterior, and posterior insula-across fMRI studies in terms of multiple task domains including emotion, memory, attention, and reasoning. We found extensive coactivation of each insular subdivision, with substantial overlap between coactivation partners for each subdivision. Functional fingerprint analyses revealed that all subdivisions cooperated with a functionally diverse set of regions. Graph-theoretical analyses revealed that the dorsal anterior insula was a highly "central" structure in the coactivation network. Furthermore, analysis of the studies that activate the insular cortex itself showed that the right dorsal anterior insula was a particularly "diverse" structure in that it was likely to be active across multiple task domains. These results highlight the nuanced functional profiles of insular subdivisions and are consistent with recent work suggesting that the dorsal anterior insula can be considered a critical functional hub in the human brain. PMID- 23937692 TI - Dorsal and ventral attention systems underlie social and symbolic cueing. AB - Eye gaze is a powerful cue for orienting attention in space. Studies examining whether gaze and symbolic cues recruit the same neural mechanisms have found mixed results. We tested whether there is a specialized attentional mechanism for social cues. We separately measured BOLD activity during orienting and reorienting attention following predictive gaze and symbolic cues. Results showed that gaze and symbolic cues exerted their influence through the same neural networks but also produced some differential modulations. Dorsal frontoparietal regions in left intraparietal sulcus (IPS) and bilateral MT(+)/lateral occipital cortex only showed orienting effects for symbolic cues, whereas right posterior IPS showed larger validity effects following gaze cues. Both exceptions may reflect the greater automaticity of gaze cues: Symbolic orienting may require more effort, while disengaging attention during reorienting may be more difficult following gaze cues. Face-selective regions, identified with a face localizer, showed selective activations for gaze cues reflecting sensory processing but no attentional modulations. Therefore, no evidence was found linking face-selective regions to a hypothetical, specialized mechanism for orienting attention to gaze cues. However, a functional connectivity analysis showed greater connectivity between face-selective regions and right posterior IPS, posterior STS, and inferior frontal gyrus during gaze cueing, consistent with proposals that face selective regions may send gaze signals to parts of the dorsal and ventral frontoparietal attention networks. Finally, although the default-mode network is thought to be involved in social cognition, this role does not extend to gaze orienting as these regions were more deactivated following gaze cues and showed less functional connectivity with face-selective regions during gaze cues. PMID- 23937693 TI - Diagnosis, classification and grading of canine mammary tumours as a model to study human breast cancer: an Clinico-Cytohistopathological study with environmental factors influencing public health and medicine. AB - BACKGROUND: The human "Elston and Ellis grading method" was utilized in dogs with mammary tumor to examine its relation to prognosis in this species, based on a 2 year follow-up period. Although cytopathology is widely used for early diagnosis of human neoplasms, it is not commonly performed in veterinary medicine. Our objectives in this study were to identify cytopathology criteria of malignancy for canine mammary tumors and the frequency of different types of mammary lesions and their relationship with histologic grade was investigated. Another aim of this study was to differentiate the simple and adenocarcinoma tumors from the complex or mixed tumor described by Elston and Ellis grading method. METHODS: The study was performed in 15 pure or mixed-breed female dogs submitted to surgical resections of mammary tumours. The mammary tumours were excised by simple mastectomy or regional mastectomy, with or without the superficial inguinal lymph nodes. Female dogs were mainly terriers (9 dogs) or mixed (3 dogs), the 3 other animals were a German shepherd, Dachshund and Pekingese. Before surgical excision of the tumour, FNAC was performed using a 0.6 mm diameter needle attached to a 10 ml syringe held in a standard metal syringe holder. The cytological sample was smeared onto a glass slide and either air-dried for May-Grunwald-stain, or ethanol-fixed for Papanicolaou stain and masses were surgically removed, the tumours were grossly examined and tissue samples were fixed in 10%-buffered formalin and embedded in paraffin. Sections 4 MUm thick were obtained from each sample and H&E stained. RESULTS: We obtained a correct cytohistological correlation in 14/15 cases (93.3%) when all cytopathological examinations were considered. Of the 15 cases examined, 2(13.3%) had well-differentiated (grade I), 6(40%) had moderately differentiated (grade II) and 7(46.7%) had poorly differentiated (grade III) tumours. Classification of all canine mammary gland lesions revealed 13(86.7%) malignant and 2(13.3%) benign tumors. The histological examination showed that the most common tumor types of mammary glands in bitches were: complex carcinoma, adenocarcinoma, malignant mixed tumour, benign mixed tumour, simple carcinoma- (5/15; 33.3%), (3/15; 20%), (3/15; 20%) and (2/15;13.3%), respectively. Simple carcinoma and cystic hyperplasia were less common - (1/15; 6.7%), and (1/15; 6.7%), respectively. Moreover, the most often tumors occur in inguinal mammary (60%) and abdominal (27%) glands. CONCLUSIONS: Our results demonstrate that, because of the similarity of the cytohistopathological findings in the human and canine mammary gland tumours, it is possible to use the same cytopathological criteria applied in human pathology for the diagnosis of canine mammary gland tumours. Furthemoer, routine use of this human grading method would help the clinician to make a more accurate prognosis in the interests of post-surgical management in dogs with mammary carcinomas. Furthermore, this research will allow a more discriminating classification of mammary tumors and probably has a bearing on cytohistopathology, epidemiology, pathogenesis and prognosis. The most often tumors occur in inguinal mammary (60%) and abdominal (27%) glands. This interesting regional difference may be due to a) the duration of the growth before the diagnosis; b) the age of the dogs; and c) high prevelance of unspayed animals. Moreover, the most common type of tumor was complex carcinoma - 33.3% (5 cases). PMID- 23937694 TI - Resistance gene enrichment sequencing (RenSeq) enables reannotation of the NB-LRR gene family from sequenced plant genomes and rapid mapping of resistance loci in segregating populations. AB - RenSeq is a NB-LRR (nucleotide binding-site leucine-rich repeat) gene-targeted, Resistance gene enrichment and sequencing method that enables discovery and annotation of pathogen resistance gene family members in plant genome sequences. We successfully applied RenSeq to the sequenced potato Solanum tuberosum clone DM, and increased the number of identified NB-LRRs from 438 to 755. The majority of these identified R gene loci reside in poorly or previously unannotated regions of the genome. Sequence and positional details on the 12 chromosomes have been established for 704 NB-LRRs and can be accessed through a genome browser that we provide. We compared these NB-LRR genes and the corresponding oligonucleotide baits with the highest sequence similarity and demonstrated that ~80% sequence identity is sufficient for enrichment. Analysis of the sequenced tomato S. lycopersicum 'Heinz 1706' extended the NB-LRR complement to 394 loci. We further describe a methodology that applies RenSeq to rapidly identify molecular markers that co-segregate with a pathogen resistance trait of interest. In two independent segregating populations involving the wild Solanum species S. berthaultii (Rpi-ber2) and S. ruiz-ceballosii (Rpi-rzc1), we were able to apply RenSeq successfully to identify markers that co-segregate with resistance towards the late blight pathogen Phytophthora infestans. These SNP identification workflows were designed as easy-to-adapt Galaxy pipelines. PMID- 23937697 TI - Tropical medicine & international health. PMID- 23937695 TI - Regulation of the SNARE-interacting protein Munc18c tyrosine phosphorylation in adipocytes by protein-tyrosine phosphatase 1B. AB - BACKGROUND: Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of insulin signaling and adiposity and is a drug target for the treatment of obesity and diabetes. The molecular mechanisms underlying PTP1B metabolic actions require additional investigation. RESULTS: Herein, we identify Munc18c as a novel PTP1B substrate in adipocytes and in vivo. We demonstrate nutritional regulation of Munc18c in adipose tissue revealing decreased expression upon high fat feeding. In addition, PTP1B deficiency leads to elevated Munc18c tyrosine phosphorylation and dissociation from syntaxin4. At the molecular level, we identify Munc18c Tyr218/219 and Tyr521 as key residues that mediate Munc18c interaction with PTP1B. Further, we uncover an essential role of Munc18c total tyrosine phosphorylation in general, and Tyr218/219 and Tyr521 in particular, in regulating its interactions and glucose uptake in adipocytes. CONCLUSION: In conclusion, our findings identify PTP1B as the first known tyrosine phosphatase for Munc18c and a regulator of its phosphorylation and function in adipocytes. PMID- 23937696 TI - Multiple sclerosis presenting initially with a worsening of migraine symptoms. AB - Multiple sclerosis (MS) is a chronic autoimmune disease that targets myelinated axons in the central nervous system. Headache has been reported as a subtle symptom of the onset of MS, with a variable frequency of 1.6-28.5%; however, it remains unclear whether headache is a true symptom of MS onset. Here, we report the case of a female patient who had a history of migraine without aura and experienced worsening of migraine-headache symptoms as the initial manifestation of MS. Three similar cases were reported previously; however, unlike this case, those cases had no history of migraine without aura. In our case, we excluded factors that could trigger migraine attacks, such as changes in weather, drugs, alcohol, caffeine withdrawal, stress, fatigue, lack of sleep, hormonal therapy, diet, and hunger. The patient had one episode of MS attack with the simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions, including hyperintense lesions in the bilateral periventricular white matter, body of the corpus callosum, and periaqueductal grey matter, as observed on the T2-weighted images obtained at the first brain magnetic resonance imaging. In addition, after the injection of gadolinium contrast, ring enhancement over these lesions was noted in T1-weighted images, which was suggestive of active demyelination. MS was diagnosed according to the McDonald criteria (2010 revision). We conclude that MS with periaqueductal grey matter involvement may present with worsening migraine. It is important to be cautious if any secondary causes exist, especially when the patient has a history of migraine without aura. MS should be one of the differential diagnoses in young women showing a change in headache pattern or poor clinical drug response to migraine treatment accompanied by episodes of focal neurological deficit. Failure to recognize MS may lead to inappropriate treatment and worse prognosis; early diagnosis in patients with MS is essential to improve their clinical outcomes and quality of life. PMID- 23937698 TI - Climate change, child health and the role of the paediatric profession in under resourced settings. PMID- 23937699 TI - Cryptococcal antigen prevalence in HIV-infected Tanzanians: a cross-sectional study and evaluation of a point-of-care lateral flow assay. AB - OBJECTIVES: Cryptococcal antigen (CRAG) screening at antiretroviral therapy (ART) initiation and pre-emptive antifungal treatment for those testing positive could prevent many cases of cryptococcal meningitis (CM). To investigate whether CRAG screening would be feasible in Tanzania, we conducted a cross-sectional study measuring CRAG prevalence in ART clinic patients and comparing the novel lateral flow assay (LFA) with the cryptococcal latex agglutination (LA) test. METHODS: Consecutive HIV-infected outpatients with CD4 counts <200 cells/uL, who were ART naive or had been on ART for <6 months, were screened for CRAG using the LA and LFA kits. For further assay validation, HIV-infected inpatients with suspected cryptococcal disease were also tested using the LA and LFA kits. RESULTS: Cryptococcal antigen was detected in seven of 218 ART clinic attendees (3%). Six patients (5%) with CD4 cell counts <=100 cells/uL (n = 124) were CRAG-positive. Agreement between the LA and LFA test in the 218 outpatients was 100%. Another 101 inpatients were tested for CRAG, of whom 56 (55%) were CRAG-positive on both the LA and LFA tests. One patient was positive using the LFA test but negative on the LA test. The overall agreement between the two assays was 99.7%, kappa coefficient 0.99 (standard error 0.06, P < 0.001). CONCLUSIONS: Five percentage of ART clinic patients with CD4 cell counts <=100 cells/uL in northern Tanzania had asymptomatic cryptococcal antigenaemia, suggesting that CRAG screening would be worthwhile in the Tanzanian ART programme. The LFA is a reliable, cheap and practical alternative to LA for detection of CRAG. PMID- 23937700 TI - Practical dosing of praziquantel for schistosomiasis in preschool-aged children. AB - OBJECTIVE: Schistosomiasis is known to occur in preschool-aged children, but achieving accurate dosing of praziquantel in its current form is challenging. While waiting for a paediatric formulation, there is a need to develop a means for using the available products to treat this age group. Current 600-mg tablets are differently scored to give units of 150 mg (a quarter of a tablet) or 300 mg (half a tablet). METHODS: We examined several dosing schemes to dose accurately (40-60 mg/kg) children aged 3-72 months (weight range 4-25 kg, based on available weight-for-age growth references from sub-Saharan Africa and Brazil, n = 106,230). RESULTS: Adequate dosing can be achieved with formulations that can be split into four 150 mg quarters for children weighing 5 kg or more, and with tablets than can be split into two 300 mg halves for children weighing 10 kg or more. Giving 1/2 tablet for 5-7 kg; 3/4 tablet for 8-10 kg; 1 tablet for 11-15 kg; 1 1/2 tablet for 16-21 kg; and two tablets for 22-25 kg will have 100% of subjects correctly dosed within the target 40-60 mg/kg range. CONCLUSIONS: Formulations that can be divided into four parts (to give 150 mg increments) are preferred for children weighing less than 11 kg; the same dosing can be applied with 600 mf praziquantel formulations that can be divided into four quarters or two halves from 11 kg body weight. PMID- 23937701 TI - Detectable urogenital schistosome DNA and cervical abnormalities 6 months after single-dose praziquantel in women with Schistosoma haematobium infection. AB - We explored response to single-dose praziquantel therapy in a cohort of 33 women with Schistosoma haematobium infection in rural Mwanza, Tanzania. Women with S. haematobium infection confirmed both by eggs in urine and by polymerase chain reaction (PCR) received single-dose praziquantel and treatment of concomitant sexually transmitted infections. Macroscopic cervical abnormalities were also quantified. After 6 months, microscopically detectable egg excretion was eliminated, but 8 of 33 women (24%) were persistently positive for S. haematobium by PCR, and 11 (33%) had cervical abnormalities potentially attributable to schistosomiasis. This suggests that praziquantel treatment more frequently than every 6 months may be necessary for complete elimination of the parasite and prevention of genital tissue pathology. This aggressive therapy may in turn play a key role decreasing HIV susceptibility in millions of people living in regions in which S. haematobium is endemic. PMID- 23937702 TI - Socio-economic determinants of HIV testing and counselling: a comparative study in four African countries. AB - OBJECTIVES: Research indicates that individuals tested for HIV have higher socio economic status than those not tested, but less is known about how socio-economic status is associated with modes of testing. We compared individuals tested through provider-initiated testing and counselling (PITC), those tested through voluntary counselling and testing (VCT) and those never tested. METHODS: Cross sectional surveys were conducted at health facilities in Burkina Faso, Kenya, Malawi and Uganda, as part of the Multi-country African Testing and Counselling for HIV (MATCH) study. A total of 3659 clients were asked about testing status, type of facility of most recent test and socio-economic status. Two outcome measures were analysed: ever tested for HIV and mode of testing. We compared VCT at stand-alone facilities and PITC, which includes integrated facilities where testing is provided with medical care, and prevention of mother-to-child transmission (PMTCT) facilities. The determinants of ever testing and of using a particular mode of testing were analysed using modified Poisson regression and multinomial logistic analyses. RESULTS: Higher socio-economic status was associated with the likelihood of testing at VCT rather than other facilities or not testing. There were no significant differences in socio-economic characteristics between those tested through PITC (integrated and PMTCT facilities) and those not tested. CONCLUSIONS: Provider-initiated modes of testing make testing accessible to individuals from lower socio-economic groups to a greater extent than traditional VCT. Expanding testing through PMTCT reduces socio-economic obstacles, especially for women. Continued efforts are needed to encourage testing and counselling among men and the less affluent. PMID- 23937703 TI - Estimation of content of anti-TB drugs supplied at centres of the Revised National TB Control Programme in Tamil Nadu, India. AB - OBJECTIVE: To determine the content of certain antituberculosis (TB) drugs supplied at TB treatment centres of the Revised National TB Control Programme (RNTCP) in the state of Tamil Nadu, India. METHODS: Eight districts across the state were selected, and the following drugs were collected from five settings (District TB centre, TB unit, designated microscopy centres, DOT providers) in each district: rifampicin (150 and 450 mg), isoniazid (300 mg), pyrazinamide (500 and 750 mg), ethambutol (400 and 600 mg), ethionamide (250 mg), levofloxacin (500 mg) and cycloserine (250 mg). A maximum of 10 tablets/capsules were collected from each setting. The drugs were coded prior to analysis. All drugs were assayed by validated spectrophotometric methods. The acceptable limits for drug content were taken as 90-110% of the stated content. RESULTS: More than 90% of tablets of rifampicin 450 mg, isoniazid 300 mg, pyrazinamide 500 and 750 mg, ethambutol 400 and 600 mg and ethionamide 250 mg were within acceptable limits. Eighty per cent of rifampicin 150 mg, 21% of cycloserine 250 mg and 87% of levofloxacin 500 mg were within acceptable limits. The mean cycloserine content was below the acceptable limit in all districts, the mean drug content being 200 mg (range: 108 245 mg). CONCLUSION: This systematic study showed that the stated drug content of cycloserine was not reached in all districts. Deterioration of cycloserine could be minimised by storing the drug in refrigerators. The geographical location of the districts had no influence on the drug content. PMID- 23937704 TI - Progression of leprosy disability after discharge: is multidrug therapy enough? AB - OBJECTIVE: To evaluate the risk factors related to worsening of physical disabilities after treatment discharge among patients with leprosy administered 12 consecutive monthly doses of multidrug therapy (MDT/WHO). METHODS: Cohort study was carried out at the Leprosy Laboratory in Rio de Janeiro, Brazil. We evaluated patients with multibacillary leprosy treated (MDT/WHO) between 1997 and 2007. The Cox proportional hazards model was used to estimate the relationship between the onset of physical disabilities after release from treatment and epidemiological and clinical characteristics. RESULTS: The total observation time period for the 368 patients was 1 570 person-years (PY), averaging 4.3 years per patient. The overall incidence rate of worsening of disability was 6.5/100 PY. Among those who began treatment with no disability, the incidence rate of physical disability was 4.5/100 PY. Among those who started treatment with Grade 1 or 2 disabilities, the incidence rate of deterioration was 10.5/100 PY. The survival analysis evidenced that when disability grade was 1, the risk was 1.61 (95% CI: 1.02-2.56), when disability was 2, the risk was 2.37 (95% CI 1.35-4.16), and when the number of skin lesions was 15 or more, an HR = 1.97 (95% CI: 1.07 3.63). Patients with neuritis showed a 65% increased risk of worsening of disability (HR = 1.65 [95% CI: 1.08-2.52]). CONCLUSION: Impairment at diagnosis was the main risk factor for neurological worsening after treatment/MDT. Early diagnosis and prompt treatment of reactional episodes remain the main means of preventing physical disabilities. PMID- 23937705 TI - The power of data: using routinely collected data to improve public health programmes and patient outcomes in low- and middle-income countries. PMID- 23937706 TI - Capillary HPLC-accurate mass MS/MS quantitation of N7-(2,3,4-trihydroxybut-1-yl) guanine adducts of 1,3-butadiene in human leukocyte DNA. AB - 1,3-Butadiene (BD) is a high volume industrial chemical commonly used in polymer and rubber production. It is also present in cigarette smoke, automobile exhaust, and urban air, leading to widespread exposure of human populations. Upon entering the body, BD is metabolized to electrophilic epoxides, 3,4-epoxy-1-butene (EB), diepoxybutane (DEB), and 3,4-epoxy-1,2-diol (EBD), which can alkylate DNA nucleobases. The most abundant BD epoxide, EBD, modifies the N7-guanine positions in DNA to form N7-(2, 3, 4-trihydroxybut-1-yl) guanine (N7-THBG) adducts, which can be useful as biomarkers of BD exposure and metabolic activation to DNA reactive epoxides. In the present work, a capillary HPLC-high resolution ESI+ MS/MS (HPLC-ESI+-HRMS/MS) methodology was developed for accurate, sensitive, and reproducible quantification of N7-THBG in cell culture and in human white blood cells. In our approach, DNA is subjected to neutral thermal hydrolysis to release N7-guanine adducts from the DNA backbone, followed by ultrafiltration, solid phase extraction, and isotope dilution HPLC-ESI+-HRMS/MS analysis on an Orbitrap Velos mass spectrometer. Following method validation, N7-THBG was quantified in human fibrosarcoma (HT1080) cells treated with micromolar concentrations of DEB and in DNA isolated from blood of smokers, nonsmokers, individuals participating in a smoking cessation program, and occupationally exposed workers. N7-THBG concentrations increased linearly from 31.4 +/- 4.84 to 966.55 +/- 128.05 adducts per 109 nucleotides in HT1080 cells treated with 1-100 MUM DEB. N7-THBG amounts in leukocyte DNA of nonsmokers, smokers, and occupationally exposed workers were 7.08 +/- 5.29, 8.20 +/- 5.12, and 9.72 +/- 3.80 adducts per 109 nucleotides, respectively, suggesting the presence of an endogenous or environmental source for this adduct. The availability of sensitive HPLC-ESI+-HRMS/MS methodology for BD-induced DNA adducts in humans will enable future population studies of interindividual and ethnic differences in BD bioactivation to DNA-reactive epoxides. PMID- 23937707 TI - Effectivity of pazopanib treatment in orthotopic models of human testicular germ cell tumors. AB - BACKGROUND: Cisplatin (CDDP) resistance in testicular germ cell tumors (GCTs) is still a clinical challenge, and one associated with poor prognosis. The purpose of this work was to test pazopanib, an anti-tumoral and anti-angiogenic multikinase inhibitor, and its combination with lapatinib (an anti-ErbB inhibitor) in mouse orthotopic models of human testicular GCTs. METHODS: We used two different models of human testicular GCTs orthotopically grown in nude mice; a CDDP-sensitive choriocarcinoma (TGT38) and a new orthotopic model generated from a metastatic GCT refractory to first-line CDDP chemotherapy (TGT44). Nude mice implanted with these orthotopic tumors were treated with the inhibitors and the effect on tumoral growth and angiogenesis was evaluated. RESULTS: TGT44 refractory tumor had an immunohistochemical profile similar to the original metastasis, with characteristics of yolk sac tumor. TGT44 did not respond when treated with cisplatin. In contrast, pazopanib had an anti-angiogenic effect and anti-tumor efficacy in this model. Pazopanib in combination with lapatinib in TGT38, an orthotopic model of choriocarcinoma had an additive effect blocking tumor growth. CONCLUSIONS: We present pazopanib as a possible agent for the alternative treatment of CDDP-sensitive and CDDP-refractory GCT patients, alone or in combination with anti-ErbB therapies. PMID- 23937708 TI - Nightly vs on-demand sildenafil for penile rehabilitation after minimally invasive nerve-sparing radical prostatectomy: results of a randomized double blind trial with placebo. AB - OBJECTIVES: To clarify the role of phosphodiesterase type 5 (PDE5) inhibitors in post-prostatectomy penile rehabilitation (PPPR). To compare nightly and on-demand use of PDE5 inhibitors after nerve-sparing minimally invasive radical prostatectomy (RP). PATIENTS AND METHODS: We conducted a single-institution, double-blind, randomized controlled trial of nightly vs on-demand 50-mg sildenafil citrate after nerve-sparing minimally invasive RP. A total of 100 preoperatively potent men, aged <65 years, with scores on the Erectile Function domain of the International Index of Erectile Function (IIEF-EF) >=26, underwent nerve-sparing surgery. The patients were randomized to either nightly sildenafil and on-demand placebo (nightly sildenafil group), or on-demand sildenafil and nightly placebo (on-demand sildenafil group; maximum on-demand dose six tablets/month) for 12 months. Patients then underwent a 1-month washout period. Validated measures of erectile function (IIEF-EF score and the Expanded Prostate Cancer Index Composite [EPIC]) were compared between treatment groups over the entire 13-month time course, using multivariable mixed linear regression models. RESULTS: The treatment groups were well matched preoperatively (mean age 54.3 vs 54.6 years, baseline IIEF-EF score 29.4 vs 29.3, for the nightly vs the on-demand sildenafil groups, respectively). No significant differences were found in erectile function between treatments (nightly vs on-demand sildenafil) at any single timepoint after RP, after adjusting for potential confounding factors. When evaluated over all timepoints simultaneously, no significant effects of treatment group (nightly vs on-demand sildenafil) were found on recovery of potency, as assessed by absolute IIEF-EF scores (P = 0.765), on percentage of men returning to an IIEF-EF score >21 (P = 0.830), or on IIEF-EF score recovery to a percentage of baseline value (P = 0.778). When evaluated over all timepoints simultaneously, no significant effects of treatment group were found on secondary endpoints such as assessment of potency (including EPIC item 59 response 'erections firm enough for intercourse'), attempted intercourse frequency or confidence. CONCLUSIONS: Erectile recovery up to 1 year after RP does not differ between previously potent men who use sildenafil nightly compared to on-demand. This trial does not support chronic nightly sildenafil as being any better than on-demand sildenafil for use in penile rehabilitation after nerve-sparing minimally invasive RP. PMID- 23937709 TI - The Vertebrate Trait Ontology: a controlled vocabulary for the annotation of trait data across species. AB - BACKGROUND: The use of ontologies to standardize biological data and facilitate comparisons among datasets has steadily grown as the complexity and amount of available data have increased. Despite the numerous ontologies available, one area currently lacking a robust ontology is the description of vertebrate traits. A trait is defined as any measurable or observable characteristic pertaining to an organism or any of its substructures. While there are several ontologies to describe entities and processes in phenotypes, diseases, and clinical measurements, one has not been developed for vertebrate traits; the Vertebrate Trait Ontology (VT) was created to fill this void. DESCRIPTION: Significant inconsistencies in trait nomenclature exist in the literature, and additional difficulties arise when trait data are compared across species. The VT is a unified trait vocabulary created to aid in the transfer of data within and between species and to facilitate investigation of the genetic basis of traits. Trait information provides a valuable link between the measurements that are used to assess the trait, the phenotypes related to the traits, and the diseases associated with one or more phenotypes. Because multiple clinical and morphological measurements are often used to assess a single trait, and a single measurement can be used to assess multiple physiological processes, providing investigators with standardized annotations for trait data will allow them to investigate connections among these data types. CONCLUSIONS: The annotation of genomic data with ontology terms provides unique opportunities for data mining and analysis. Links between data in disparate databases can be identified and explored, a strategy that is particularly useful for cross-species comparisons or in situations involving inconsistent terminology. The VT provides a common basis for the description of traits in multiple vertebrate species. It is being used in the Rat Genome Database and Animal QTL Database for annotation of QTL data for rat, cattle, chicken, swine, sheep, and rainbow trout, and in the Mouse Phenome Database to annotate strain characterization data. In these databases, data are also cross-referenced to applicable terms from other ontologies, providing additional avenues for data mining and analysis. The ontology is available at http://bioportal.bioontology.org/ontologies/50138. PMID- 23937711 TI - Parents' experiences with physical and occupational therapy for their young child with cerebral palsy: a mixed studies review. AB - Understanding the experiences of parents with their child's intervention might help meet the needs of parents and, subsequently get them engaged in their child's intervention. As parents' early beliefs regarding their child's intervention has consequences for treatment participation, it is important to understand these parental perspectives. The aim of this mixed studies review was to give an overview of the experiences and related factors of parents of young children (0-5 years of age) with cerebral palsy in relation to the physical and/or occupational therapy of their child in a rehabilitation setting. The literature was searched systematically for qualitative and quantitative studies published between January 1990 and July 2011. Inclusion criteria were (1) the study population consisted of parents of children with cerebral palsy, with at least 25% of children under the age of five; (2) children had received physical and/or occupational therapy in a rehabilitation setting; and (3) the experiences of the parents with their child's therapy were addressed. Data were synthesized with the framework synthesis method resulting in a conceptual framework describing the factors that are related to the parents' experiences with their child's interventions. A total of 13 studies (eight qualitative and five quantitative) were included and evaluated. Parents expressed various aspects in context, process and outcomes when asked about their experiences with their child's intervention. They had different needs over time and needed time to build a collaborative relationship with their child's therapists. The proposed framework acknowledges the various aspects in context, process and outcomes that parents reported when asked about their experiences. Knowing this, the importance of the broader context of the child in a family should be acknowledged; realizing the impact that the demands of daily life, supports and resources provided to parents, attitudes in the community and culture have on parental experiences. PMID- 23937710 TI - Anxiety symptoms in older home health care recipients: prevalence and associates. AB - This study examined the prevalence and associates of anxiety symptoms in older home health care recipients (N = 249) who completed structured interviews assessing sociodemographic, cognitive, medical and disability, and psychosocial variables--including anxiety (assessed by the Clinical Anxiety Scale). Mild or moderate anxiety was reported by 3.6% of the sample. No anxiety symptoms whatsoever were reported by 63.9%, while the remaining endorsed at least one symptom. Binary logistic regression analysis revealed that the odds of having any anxiety were elevated among participants who had had a recent fall, OR = 2.81, 95% CI [1.46, 5.43]; and those with major depression, OR = 4.78, 95% CI [1.46, 15.68]. These findings point to the importance of conducting studies to clarify whether the mild severity of anxiety found in this sample is best accounted for by protective factors inherent to the home health care setting or assessment factors that diminish the reporting of anxiety symptoms. PMID- 23937712 TI - Expression and characterization of highly antigenic domains of chicken anemia virus viral VP2 and VP3 subunit proteins in a recombinant E. coli for sero diagnostic applications. AB - BACKGROUND: Chicken anemia virus (CAV) is an important viral pathogen that causes anemia and severe immunodeficiency syndrome in chickens worldwide. Generally, CAV infection occurs via vertical transmission in young chicks that are less than two weeks old, which are very susceptible to the disease. Therefore, epidemiological investigations of CAV infection and/or the evaluation of the immunization status of chickens is necessary for disease control. Up to the present, systematically assessing viral protein antigenicity and/or determining the immunorelevant domain(s) of viral proteins during serological testing for CAV infection has never been performed. The expression, production and antigenic characterization of CAV viral proteins such as VP1, VP2 and VP3, and their use in the development of diagnostic kit would be useful for CAV infection prevention. RESULTS: Three CAV viral proteins VP1, VP2 and VP3 was separately cloned and expressed in recombinant E. coli. The purified recombinant CAV VP1, VP2 and VP3 proteins were then used as antigens in order to evaluate their reactivity against chicken sera using indirect ELISA. The results indicated that VP2 and VP3 show good immunoreactivity with CAV-positive chicken sera, whereas VP1 was found to show less immunoreactivity than VP2 and VP3. To carry out the further antigenic characterization of the immunorelevant domains of the VP2 and VP3 proteins, five recombinant VP2 subunit proteins (VP2-435N, VP2-396N, VP2-345N, VP2-171C and VP2 318C) and three recombinant VP3 subunit proteins (VP3-123N, VP3-246M, VP3-366C), spanning the defined regions of VP2 and VP3 were separately produced by an E. coli expression system. These peptides were then used as antigens in indirect ELISAs against chicken sera. The results of these ELISAs using truncated recombinant VP2 and VP3 subunit proteins as coating antigen showed that VP2-345N, VP2-396N and VP3-246M gave good immunoreactivity with CAV-positive chicken sera compared to the other subunit proteins. Moreover, the VP2-396N and VP2-345 based ELISAs had better sensitivity (97.5%) and excellent specificity (100%) during serodiagnosis testing using a mean plus three standard deviations cut-off. The VP3-246M based ELISA showed a sensitivity of 85% and a specificity of 100% at the same cut-off value. CONCLUSIONS: This is the first report to systematically assess the antigenic characteristics of CAV viral proteins for sero-diagnosis purposes. Purified recombinant VP2-396N and VP2-345N subunit proteins, which span defined regions of VP2, were demonstrated to have good antigenicity and higher sensitivities than VP3-246M and were able to recognize CAV-positive chicken serum using an ELISA assay. The defined antigenicity potential of these chimeric subunit proteins produced by expression in E. coli seem to have potential and could be useful in the future for the development of the CAV diagnostic tests based on a subunit protein ELISA system. PMID- 23937713 TI - Isolation of midgut escape mutants of two American genotype dengue 2 viruses from Aedes aegypti. AB - BACKGROUND: Several studies have shown that American genotype dengue 2 viruses (DENV2) have reduced viral fitness in the mosquito vector, Aedes aegypti, compared to other DENV2 genotypes. Diminished replication efficiency or inability to efficiently traverse membrane barriers encompassing organs such as the midgut or salivary glands are considered major factors negatively impacting viral fitness in the mosquito. RESULTS: We analyzed the vector competence of Ae. aegypti for two American DENV2 strains, QR94 and PR159 originating from Mexico and Puerto-Rico, respectively. Both strains infected mosquito midguts following acquisition of infectious bloodmeals. However, DENV2-QR94 and DENV2-PR159 poorly disseminated from the midgut at 7 or 14 days post-bloodmeal (pbm). We detected one virus isolate, EM33, among 31 DENV2-QR94 infected mosquitoes, and one isolate, EM41, among 121 DENV2-PR159 infected mosquitoes, generating high virus titers in mosquito carcasses at 7 days pbm. In oral challenge experiments, EM33 and EM41 showed midgut dissemination rates of 40-50%. Replication efficiency of EM41 in secondary mosquito tissue was similar to that of a dissemination competent control strain, whereas the replication efficiency of EM33 was significantly lower than that of the control virus. The genome sequence of DENV2 QR94 encoded seven unique amino acids (aa), which were not found in 100 of the most closely related DENV2 strains. EM33 had one additional aa change, E202K, in the E protein. DENV2-PR159 encoded four unique aa residues, one of them E202K, whereas EM41 had two additional aa substitutions, Q77E in the E protein and E93D in NS3. CONCLUSIONS: Our results indicate that the midgut of Ae. aegypti acts as a selective sieve for DENV2 in which genetically distinct, dissemination competent virus variants are rapidly selected from the viral quasispecies to be transmitted to vertebrates. PMID- 23937715 TI - Cardiac conduction system abnormalities in ankylosing spondylitis: a cross sectional study. AB - BACKGROUND: Cardiac conduction disturbances are common in spondyloarthropathies such as ankylosing spondylitis (AS). Whether their occurrence can be linked to signs and symptoms of rheumatic disease activity is an unsettled issue addressed in this study. METHODS: In this cross-sectional study patients with AS according to modified New York criteria but without psoriasis, inflammatory bowel disease, dementia, pregnancy, other severe diseases such as malignancy and difficulties in answering questionnaires were invited; and 210 participated (120 men), mean age 49 years (SD 13; range: 16-77). Questionnaires, physical examination, ECG, and laboratory tests were performed at the same visit. RESULTS: Cardiac conduction disturbances were common and diagnosed in 10-33%, depending on if conservative or less conservative predefined criteria were applied. They consisted mostly of 1st degree atrio-ventricular block and prolonged QRS duration, but one patient had a pacemaker and 7 more had complete bundle branch blocks. Conduction abnormalities were associated mainly with age, male gender and body weight, and not with laboratory measures of inflammation or with Bath Ankylosing Spondylitis Disease Activity Index. Neither were they associated with the presence of HLA B27, which was found in 87% of all patients; the subtype B270502 dominated in all patients. CONCLUSIONS: Cardiac conduction abnormalities are common in AS, but not associated with markers of disease activity or specific B27 subtypes. Even relatively mild conduction system abnormalities might, however, indirectly affect morbidity and mortality. PMID- 23937714 TI - Genome-wide profiling identifies a subset of methamphetamine (METH)-induced genes associated with METH-induced increased H4K5Ac binding in the rat striatum. AB - BACKGROUND: METH is an illicit drug of abuse that influences gene expression in the rat striatum. Histone modifications regulate gene transcription. METHODS: We therefore used microarray analysis and genome-scale approaches to examine potential relationships between the effects of METH on gene expression and on DNA binding of histone H4 acetylated at lysine 4 (H4K5Ac) in the rat dorsal striatum of METH-naive and METH-pretreated rats. RESULTS: Acute and chronic METH administration caused differential changes in striatal gene expression. METH also increased H4K5Ac binding around the transcriptional start sites (TSSs) of genes in the rat striatum. In order to relate gene expression to histone acetylation, we binned genes of similar expression into groups of 100 genes and proceeded to relate gene expression to H4K5Ac binding. We found a positive correlation between gene expression and H4K5Ac binding in the striatum of control rats. Similar correlations were observed in METH-treated rats. Genes that showed acute METH induced increased expression in saline-pretreated rats also showed METH-induced increased H4K5Ac binding. The acute METH injection caused similar increases in H4K5Ac binding in METH-pretreated rats, without affecting gene expression to the same degree. Finally, genes that showed METH-induced decreased expression exhibited either decreases or no changes in H4K5Ac binding. CONCLUSION: Acute METH injections caused increased gene expression of genes that showed increased H4K5Ac binding near their transcription start sites. PMID- 23937716 TI - Multiple pregnancy, short cervix, part-time worker, steroid use, low educational level and male fetus are risk factors for preterm birth in Japan: a multicenter, prospective study. AB - AIM: To examine the relationship between preterm birth and socioeconomic factors, past history, cervical length, cervical interleukin-8, bacterial vaginosis, underlying diseases, use of medication, employment status, sex of the fetus and multiple pregnancy. METHODS: In a multicenter, prospective, observational study, 1810 Japanese women registering their future delivery were enrolled at 8+0 to 12+6 weeks of gestation. Data on cervical length and delivery were obtained from 1365 pregnant women. Multivariate logistic regression analysis was performed. RESULTS: Short cervical length, steroid use, multiple pregnancy and male fetus were risk factors for preterm birth before 34 weeks of gestation. Multiple pregnancy, low educational level, short cervical length and part-timer were risk factors for preterm birth before 37 weeks of gestation. CONCLUSION: Multiple pregnancy and cervical shortening at 20-24 weeks of gestation was a stronger risk factor for preterm birth. Any pregnant woman being part-time employee or low educational level, having a male fetus and requiring steroid treatment should be watched for the development of preterm birth. PMID- 23937718 TI - Sterically stabilized colloids with tunable repulsions. AB - When studying tunable electrostatic repulsions in aqueous suspensions of charged colloids, irreversible colloid aggregation or gelation may occur at high salt concentrations. For many commonly used synthetic colloids, such as polystyrene and silica particles, the reason for coagulation is the presence of unbalanced, strongly attractive, and short-ranged van der Waals (VDW) forces. Here, we present an aqueous polystyrene model colloid that is sterically stabilized against VDW attractions. We show that the synthesis procedure, based on a neutral initiator couple and a nonionic surfactant, introduces surface charges that can be further increased by the addition of charged comonomer methacrylic acid. Thus, the interactions between the polystyrene spheres can be conveniently tuned from hard-sphere-like to charge-stabilized with long-ranged electrostatic repulsions described by a Yukawa-type pair potential. The particle size, grafting density, core-shell structure, and surface charge are characterized by light and neutron scattering. Using X-ray and neutron scattering in combination with an accurate analytic integral equation scheme for the colloidal static structure factor, we deduce effective particle charges for colloid volume fractions >=0.1 and salt concentrations in the range of 1.5 to 50 mM. PMID- 23937717 TI - Enhanced interaction between natural killer cells and lung cancer cells: involvement in gefitinib-mediated immunoregulation. AB - BACKGROUND: Natural killer (NK) cells can kill tumor cells in a non-MHC restricted manner. However, cancer cells frequently escape from the attack of NK cells by multiple ways. In this study, we investigated the effect of gefitinib on the interaction between NK cells and lung cancer cells. METHODS: 51Cr release assay, CD107a assay, and IFN-gamma secretion assay were performed to detect the sensitivity of lung cancer cell lines A549 and H1975 to NK cells cytotoxicity in the presence of gefitinib. Human NK cells were co-cultured with A549 and H1975 cell lines in the presence of gefitinib. NKG2D ligands, ULBP1, ULBP2, MICA, and MHC-I on tumor cells, and NKG2D, NKp44 and NKp46 on NK cells were evaluated with flow cytometry. 51Cr release assay was performed when NKG2D antibody were added into the co-culture system. Expressions of stat3 and LC3 I/II on tumor cells were determined with western blot after co-cultured with NK cells. After treated with gefitinib, mannose-6-phosphate receptor (MPR) on H1975 cells was evaluated by flow cytometry. 51Cr release assay were performed when MPR antagonist were used. RESULTS: Gefitinib increased cytotoxicity of NK cells to human lung cancer H1975 cells with EGFR L858R + T790M mutations, while not in A549 cells with wild type EGFR. Gefitinib could block the immune escape by up-regulating the expression of NKG2D ligands ULBP1, ULBP2 or MICA on tumor cells and NKG2D on NK cells in the co culture system. Gefitinib and NK cells up-regulated MHC-I expression in A549 while not in H1975 cells. NKG2D antibody blocked the enhanced NK cytotoxicity by gefitinib. The combination of NK cells and gefitinib could significantly down regulate stat3 expression. Furthermore, NK cells-mediated tumor cell autophagy was observed in A549 cells while not in H1975 cells. Notably, gefitinib increased autophagy and MPR expression in H1975 cells, which improved the sensitivity to NK cell-based immunotherapy. CONCLUSIONS: Gefitinib greatly enhanced NK cell cytotoxicity to lung cancer cells with EGFR L858R + T790M resistance mutation. Combination of EGFR tyrokinase inhibitors and NK cells adoptive immunotherapy may represent a potentially effective strategy for patients with non-small cell lung cancer. PMID- 23937719 TI - Two types of exercise-induced neuroplasticity in congenital hemiparesis: a transcranial magnetic stimulation, functional MRI, and magnetoencephalography study. AB - AIM: Early unilateral brain lesions can lead to a persistence of ipsilateral corticospinal projections from the contralesional hemisphere, which can enable the contralesional hemisphere to exert motor control over the paretic hand. In contrast to the primary motor representation (M1), the primary somatosensory representation (S1) of the paretic hand always remains in the lesioned hemisphere. Here, we report on differences in exercise-induced neuroplasticity between individuals with such ipsilateral motor projections (ipsi) and individuals with early unilateral lesions but 'healthy' contralateral motor projections (contra). METHOD: Sixteen children and young adults with congenital hemiparesis participated in the study (contralateral [Contra] group: n=7, four females, three males; age range 10-30y, median age 16y; ipsilateral [Ipsi] group: n=9, four females, five males; age range 11-31y, median age 12y; Manual Ability Classification System levels I to II in all individuals in both groups). The participants underwent a 12-day intervention of constraint-induced movement therapy (CIMT), consisting of individual training (2h/d) and group training (8h/d). Before and after CIMT, hand function was tested using the Wolf Motor Function Test (WMFT) and diverging neuroplastic effects were observed by transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Statistical analysis of TMS data was performed using the non-parametric Wilcoxon signed-rank test for pair-wise comparison; for fMRI standard statistical parametric and non-parametric mapping (SPM5, SnPM3) procedures (first level/second level) were carried out. Statistical analyses of MEG data involved analyses of variance (ANOVA) and t-tests. RESULTS: While MEG demonstrated a significant increase in S1 activation in both groups (p=0.012), TMS showed a decrease in M1 excitability in the Ipsi group (p=0.036), but an increase in M1 excitability in the Contra group (p=0.043). Similarly, fMRI showed a decrease in M1 activation in the Ipsi group, but an increase in activation in the M1-S1 region in the Contra group (for both groups p<0.001 [SnPM3] within the search volume). INTERPRETATION: Different patterns of sensorimotor (re)organization in individuals with early unilateral lesions show, on a cortical level, different patterns of exercise-induced neuroplasticity. The findings help to improve the understanding of the general principles of sensorimotor learning and will help to develop more specific therapies for different pathologies in congenital hemiparesis. PMID- 23937720 TI - Contemporary treatment of sexual dysfunction: reexamining the biopsychosocial model. AB - INTRODUCTION: The introduction of phosphodiesterase type 5 inhibitors has revolutionized the armamentarium of clinicians in the field of sexual medicine. However, pharmacotherapy as a stand-alone treatment option has been criticized, particularly by psychosocial therapists, as incomplete. Specifically, it is widely argued that drug treatment alone often does not meet the standards of biopsychosocial (BPS) therapy. AIM: A literature review was performed to explore the role of the biopsychosocial paradigm in the treatment of sexual dysfunction and outline some of the key challenges and possible shortcomings in the current application of biopsychosocial treatment. MAIN OUTCOME MEASURE: Published treatment outcomes of integrative biopsychosocial clinical practice, including medical outcomes, psychological and relational factors, treatment of comorbid conditions, cost of treatment, and treatment efficacy, were investigated. METHODS: Using Medline, PubMed, and EMBASE databases, a literature search for articles published from January 1, 1980, to March 1, 2013, was performed, examining current approaches to the biopsychosocial model of sexual dysfunction and sexual medicine. Data were reviewed and combined, allowing characterization of current treatment approaches and recommendations for clinical practice and future research. RESULTS: The biopsychosocial model of treatment appears to have an intuitively obvious meaning (i.e., treatment of all three facets of the patient's biological-psychological-social condition). However, research suggests that clear treatment algorithms are still in development. By virtue of the ongoing development of biopsychosocial methods in sexual medicine, new models and research initiatives may be warranted. The evidence identified allows for characterization of some of the current clinical, professional, financial, and systemic challenges to biopsychosocial treatment, with the aim of helping identify possible directions for future research. CONCLUSION: Implementation of biopsychosocial treatment, though mandated by process-of-care guidelines, may be limited in the field of sexual health owing to resource limitations, limitations in physician training curricula, and structural obstacles preventing interdisciplinary collaboration. Nonetheless, a number of current treatment developments are biopsychosocially integrative, and a number of established models are biopsychosocially informed. These models and concrete strategies may provide a way forward for developing further initiatives to advance BPS treatment. PMID- 23937721 TI - Comparison of placental growth factor and fetal flow Doppler ultrasonography to identify fetal adverse outcomes in women with hypertensive disorders of pregnancy: an observational study. AB - BACKGROUND: Hypertensive disorders of pregnancy and intrauterine growth restriction (IUGR) are leading causes of maternal and perinatal morbidity and mortality. Failure to detect intrauterine growth restriction in women at high risk has been highlighted as a significant avoidable cause of serious fetal outcome. In this observational study we compare fetal flow using Doppler ultrasonography with a new test for placental growth factor (PlGF) to predict fetal adverse events. METHODS: Eighty-nine women with hypertensive disorders of pregnancy (24 with chronic hypertension, 17 with gestational hypertension, 12 with HELLP syndrome, 19 with preeclampsia and 17 with superimposed preeclampsia) were enrolled. A single maternal blood sample to measure free PlGF (Alere Triage) taken before 35 weeks of pregnancy was compared to the last Doppler ultrasound measurement of fetal flow before delivery. PlGF was classified as normal (PlGF>=100 pg/ml), low (120.05). However, a significantly higher implantation rate was observed in the morphology assessment plus aCGH screening group compared to the morphology assessment alone group (65.0% vs. 33.3%, respectively; p = 0.038). There was no miscarriage observed in Group A while a 16.7% miscarriage rate was recorded in Group B (0% vs. 16.7%, respectively; p >0.05). CONCLUSIONS: While aCGH screening has been recently applied to select euploid blastocysts for fresh transfer in young, low risk IVF patients, this is the first prospective study on the impact of aCGH specifically on blastocyst survival and implantation outcomes in the subsequent FET cycles of IVF patients with good prognosis. The present study demonstrates that aCGH screening of blastocysts prior to cryopreservation significantly improves implantation rates and may reduce the risk of miscarriage in subsequent FET cycles. Further randomized clinical studies with a larger sample size are needed to validate these preliminary findings. PMID- 23937724 TI - A semantic-based method for extracting concept definitions from scientific publications: evaluation in the autism phenotype domain. AB - BACKGROUND: A variety of informatics approaches have been developed that use information retrieval, NLP and text-mining techniques to identify biomedical concepts and relations within scientific publications or their sentences. These approaches have not typically addressed the challenge of extracting more complex knowledge such as biomedical definitions. In our efforts to facilitate knowledge acquisition of rule-based definitions of autism phenotypes, we have developed a novel semantic-based text-mining approach that can automatically identify such definitions within text. RESULTS: Using an existing knowledge base of 156 autism phenotype definitions and an annotated corpus of 26 source articles containing such definitions, we evaluated and compared the average rank of correctly identified rule definition or corresponding rule template using both our semantic based approach and a standard term-based approach. We examined three separate scenarios: (1) the snippet of text contained a definition already in the knowledge base; (2) the snippet contained an alternative definition for a concept in the knowledge base; and (3) the snippet contained a definition not in the knowledge base. Our semantic-based approach had a higher average rank than the term-based approach for each of the three scenarios (scenario 1: 3.8 vs. 5.0; scenario 2: 2.8 vs. 4.9; and scenario 3: 4.5 vs. 6.2), with each comparison significant at the p-value of 0.05 using the Wilcoxon signed-rank test. CONCLUSIONS: Our work shows that leveraging existing domain knowledge in the information extraction of biomedical definitions significantly improves the correct identification of such knowledge within sentences. Our method can thus help researchers rapidly acquire knowledge about biomedical definitions that are specified and evolving within an ever-growing corpus of scientific publications. PMID- 23937725 TI - HRG-beta1-driven ErbB3 signaling induces epithelial-mesenchymal transition in breast cancer cells. AB - BACKGROUND: Heregulin (HRG; also known as neuregulin) is a ligand for ErbB3. One of its isotypes, HRG-beta1, binds to ErbB3 and forms heterodimers with other ErbB family members, thereby enhancing the proliferation and tumorigenesis of breast cancer cells. HRG stimulation may contribute to the progression of epithelial mesenchymal transition (EMT) and tumor metastasis in breast cancer. Majority of studies regarding EMT has been concentrated on TGF-beta signaling. Therefore, we investigated whether the HRG-beta1 and ErbB3 activate Smad2 signaling during process of EMT in breast cancer cells. METHODS: The SK-BR-3 and MCF7 breast cancer cell lines were used. The expressions of phospho-Smad2 and EMT markers were observed by western blotting and immunofluorescence assays after treatment with HRG-beta1. The cell motility and invasiveness were determined by wound healing and matrigel invasion assays. Smad2 and ErbB3 small interfering RNA (siRNA) transfections were performed to assess the involvement of ErbB3 and Smad2 in HRG-beta1-induced EMT. RESULTS: HRG-beta1 induced EMT through activation of Smad2. The expression of E-cadherin was decreased after HRG-beta1 treatment, while the expressions of Snail, vimentin, and fibronectin were increased. The HRG beta1-induced expressions of Snail, vimentin, and fibronectin, and nuclear colocalization of phospho-Smad2 and Snail were inhibited by pretreatment with a PI3k inhibitor, LY294002, or two phospho-Smad2 inhibitors, PD169316 or SB203580 and cancer cell migration by HRG-beta1 was inhibited. Knockdown of Smad2 by siRNA transfection suppressed the expressions of Snail and fibronectin in response to HRG-beta1 stimulation and knockdown of ErbB3 suppressed the expressions of phospho-Smad2, Snail, and fibronectin induced by HRG-beta1, whereas E-cadherin was increased compared with control siRNA-transfected cells. Knockdown of ErbB3 and Smad2 also decreased SK-BR-3 and MCF7 cell invasion. CONCLUSIONS: Our data suggest that HRG-beta1 and ErbB3 induce EMT, cancer cell migration and invasion through the PI3k/Akt-phospho-Smad2-Snail signaling pathway in SK-BR-3 and MCF7 breast cancer cells. PMID- 23937726 TI - Alternative sigma factor RpoN and its modulation protein YhbH are indispensable for Erwinia amylovora virulence. AB - In Erwinia amylovora, ECF (extracytoplasmic functions) alternative sigma factor HrpL regulates the transcription of hrp (hypersensitive response and pathogenicity)-type III secretion system (T3SS) genes by binding to a consensus sequence known as the hrp box in hrp gene promoters. In turn, the expression of hrpL has been proposed to be positively controlled by alternative sigma factor 54 (sigma(54)) (RpoN) and HrpS, a member of the sigma(54) enhancer-binding proteins (EBPs). However, the function of RpoN has not been characterized genetically in E. amylovora. In this study, we investigated the role of RpoN, a nitrogen limitation sigma factor, and its modulation protein YhbH, a novel ribosome associated protein, in E. amylovora virulence. Our results showed that mutations in hrpS, hrpL, rpoN and yhbH, but not yfiA and rmf3, resulted in a nonpathogenic phenotype on immature pear fruits and apple shoots. Consistently, the expression of T3SS genes, including hrpL, dspE, hrpN and hrpA, was barely detected in hrpS, hrpL, rpoN and yhbH mutants. These mutants were also not capable of eliciting a hypersensitive response (HR) on tobacco; however, the overexpression of hrpL using an inducible promoter rescued the HR-eliciting abilities of these mutants. These results suggest that a sigma factor cascade exists in the regulatory networks of E. amylovora and regulates important virulence factors. On the basis of this study and previously reported data, a model is proposed for the regulation of T3SS in E. amylovora. PMID- 23937727 TI - Use of a colorimetric (DELI) test for the evaluation of chemoresistance of Plasmodium falciparum and Plasmodium vivax to commonly used anti-plasmodial drugs in the Brazilian Amazon. AB - BACKGROUND: The emergence and spread of Plasmodium falciparum and Plasmodium vivax resistance to available anti-malarial drugs represents a major drawback in the control of malaria and its associated morbidity and mortality. The aim of this study was to evaluate the chemoresistance profile of P. falciparum and P. vivax to commonly used anti-plasmodial drugs in a malaria-endemic area in the Brazilian Amazon. METHODS: The study was carried out in Manaus (Amazonas state), in the Brazilian Amazon. A total of 88 P. falciparum and 178 P. vivax isolates was collected from 2004 to 2007. The sensitivity of P. falciparum isolates was determined to chloroquine, quinine, mefloquine and artesunate and the sensitivity of P. vivax isolates was determined to chloroquine and mefloquine, by using the colorimetric DELI test. RESULTS: As expected, a high prevalence of P. falciparum isolates resistant to chloroquine (78.1%) was observed. The prevalence of isolates with profile of resistance or decreased sensitivity for quinine, mefloquine and artesunate was 12.7, 21.2 and 11.7%, respectively. In the case of P. vivax, the prevalence of isolates with profile of resistance for chloroquine and mefloquine was 9.8 and 28%, respectively. No differences in the frequencies of isolates with profile of resistance or geometric mean IC50s were seen when comparing the data obtained in 2004, 2005, 2006 and 2007, for all tested anti malarials. CONCLUSIONS: The great majority of P. falciparum isolates in the Brazilian malaria-endemic area remain resistant to chloroquine, and the decreased sensitivity to quinine, mefloquine and artesunate observed in 10-20% of the isolates must be taken with concern, especially for artesunate. Plasmodium vivax isolates also showed a significant proportion of isolates with decreased sensitivity to chloroquine (first-line drug) and mainly to mefloquine. The data presented here also confirm the usefulness of the DELI test to generate results able to impact on public health policies. PMID- 23937728 TI - Female genital mutilation in Iraqi Kurdistan: description and associated factors. AB - The high prevalence of female genital mutilation has been a concern in Iraqi Kurdistan. This study was undertaken to estimate its prevalence and describe factors associated with its occurrence. A cross-sectional survey was undertaken from March to April 2011 of females aged up to 20 years using interviews and clinical examination. The survey included 1,508 participants with mean age of 13.5 years (SD 5.6). Overall female genital mutilation prevalence was 23%, and the mean age at which it had been performed was 4.6 years (SD 2.4). Type I (partial or total removal of the clitoris) comprised 76% of those who had had female genital mutilation; in 79% of cases the decision to perform it was made by the mother; and in 54% of cases it was performed by traditional birth attendants/midwives. Women aged 16 years and over were more likely to have had female genital mutilation compared to children aged below 6 years (OR 11.9, p < .001). Children of uneducated mothers were eight times as likely to have had genital mutilation compared to children of mothers with over nine years of education (OR 8.0, p < .001). Among women aged 17 years and younger, 34% of those who were married had been circumcised versus 17% of those who were not married (p < .001). Participants residing in the northeast of Kurdistan region were more likely to have been circumcised. The study results show that female genital mutilation is a frequent practice in Iraqi Kurdistan. Attention and intervention is needed to address this aspect of the well-being of girls and women. PMID- 23937730 TI - Homelessness among female veterans: a systematic review of the literature. AB - The authors conducted a systematic, critical review of the literature to assess and summarize existing research on homelessness among female veterans. They searched seven electronic databases (ERIC, Proquest Dissertations and Theses, PsycINFO, PubMed, Social Services Abstracts, Social Science Citation Index, and Sociological Abstracts), websites of several government and research organizations, and reference lists of prior studies. They abstracted data on study design, funding source, and topic from studies meeting inclusion criteria and classified each study into one of the following categories: epidemiology, health and other services utilization, and interventions. The authors included both experimental and observational studies of interventions in the review and performed a narrative synthesis for each of the 26 studies identified. No studies were experimental, 20 were observational, and the remainder were either qualitative or descriptive. Of the 26 identified studies, 14 were epidemiologic, 7 focused on the health and additional service utilization, and 5 were intervention studies. Findings provided important baseline epidemiologic information about homelessness among female veterans and indicated that female veterans were at an increased risk of homelessness relative to their male veteran and female non-veteran counterparts. Additional research is needed to develop and implement effective, evidence-based programs to prevent and end homelessness among women veterans. PMID- 23937729 TI - Patterns and determinants of breast and cervical cancer non-screening among Appalachian women. AB - Breast and cervical cancer account for nearly one-third of new cancer cases and one-sixth of cancer deaths. Cancer, the second leading cause of all deaths in the United States, will claim the lives of nearly 800,000 women this year, which is particularly unfortunate because effective modes of early detection could significantly reduce mortality from breast and cervical cancer. Researchers examined patterns of non-screening among Appalachian women. In-person interviews were conducted with 222 Appalachian women who fell outside of screening recommendations for timing of Pap tests and mammograms. These women, from six Appalachian counties, were participating in a group-randomized, multi-component trial aimed at increasing adherence to cancer screening recommendations. Results indicated that participants who were rarely or never screened for breast cancer were also likely to be rarely or never screened for cervical cancer. In addition, four key barriers were identified as independently and significantly associated with being rarely or never screened for both cervical and breast cancer. An improved understanding of cancer screening patterns plus the barriers underlying lack of screening may move researchers closer to developing effective interventions that facilitate women's use of screening. PMID- 23937731 TI - Does pilates-based exercise improve postural alignment in adult women? AB - A randomized, controlled trial was conducted to determine the effect of Pilates based exercise on postural alignment. Seventy-four adult women (mean age +/- SD, 34.9 +/- 16.4 years) were randomized to a Pilates-based mat class (n = 40) or a control group (n = 34). Pilates-based exercise participants were taught the Initial Mat of Body Control Pilates for 6 months, twice a week, for 60 minutes per session; the control group received no exercise intervention. Repeated measurements were performed at baseline, 3 months, and 6 months of the frontal alignment of the thoracolumbar spine, shoulder, and pelvis, and sagittal alignment of the head and pelvis. No differences were found in either group, over time, on frontal alignment of the thoracolumbar spine and pelvis. The experimental group showed significant improvements in frontal alignment of the shoulder and sagittal alignment of the head and pelvis at 6 months. The Pilates based exercise enhanced some parameters of the postural alignment of women, as measured by frontal alignment of the shoulder and sagittal alignment of the head and pelvis. The significant improvement in sagittal alignment of the head may imply that 6 months of Pilates-based exercise enhances sagittal alignment of the cervical or thoracic spine. PMID- 23937732 TI - Contributions of a group-based exercise program for coping with fibromyalgia: a qualitative study giving voice to female patients. AB - Numerous quantitative studies have illustrated the potential usefulness of exercise programs for women with fibromyalgia. However, a deeper understanding of the physical and especially psychosocial benefits of exercise therapy from the subjective perspective of this population is still needed. This study was conducted with 25 women who had fibromyalgia and were participating in a nine month, group-based exercise program. The aim was to provide an in-depth description and analysis of the perceived physical and psychosocial benefits of participation. Qualitative data were collected through observation, interviews, and focus groups. The exercise program not only alleviated the physical symptoms of fibromyalgia, but social interactions within the group helped to counteract the isolation, frustration, and depression often associated with this chronic condition. The data from this study may contribute to a deeper understanding of the benefits of exercise for women with fibromyalgia and might be useful for the improvement of future exercise programs for this population. PMID- 23937733 TI - Barriers and facilitators to HPV vaccination: perspectives from Malawian women. AB - The aim of this research was to elucidate potential barriers and facilitators to human papillomavirus (HPV) vaccination in Malawi, a sub-Saharan country. In Malawi, approximately 31 out of every 100,000 women develop cervical cancer annually, and 80% of those affected die from this malignancy. HPV vaccination may provide a feasible strategy for cervical cancer prevention in Malawi. However, important questions and concerns regarding cervical cancer and HPV vaccination acceptance among individuals and their communities must be considered prior to vaccine delivery. Qualitative interviews were conducted with 30 Malawian mothers aged 18-49 years from Chiradzulu District. Women's knowledge and beliefs about HPV, cervical cancer, and vaccination, and their social-ecological contexts were explored in-depth. Thematic analyses revealed that despite women's limited knowledge, cervical cancer was perceived to be a serious disease. Participants believed that as women, they were responsible for their children's health. Women unanimously reported that they would vaccinate their children against HPV, especially if a health professional recommended it. Malawi's health care infrastructure could present challenges to HPV vaccine programs; however, participants did not typically report this to be a barrier to vaccination. These data shed light on factors that may influence HPV vaccination acceptance and uptake in Malawi. PMID- 23937734 TI - Radiologic case study. PMID- 23937735 TI - Legislative option for the Independent Payment Advisory Board. PMID- 23937736 TI - Delamination of tantalum porous coating from a TKA due to regional dissemination of debris. AB - Metallic debris from metal-on-metal bearings is a recognized mode of failure that may lead to implant loosening and periprosthetic soft tissue reactions. The sequelae of metallosis have been most commonly reported with respect to total hip arthroplasty. The authors report a rare case of metallosis following a hybrid metal-on-polyethylene total knee arthroplasty that used a porous tantalum tibial knee component. A total knee arthroplasty patient who presented with knee pain but normal radiographs was found to have delamination of her tibial component that resulted in marked periprosthetic soft tissue metallosis. PMID- 23937737 TI - Novel reconstruction technique using a frozen tumor-bearing vertebra from a total en bloc sponydylectomy for spinal tumors. AB - This article describes a novel reconstruction technique using frozen tumor bearing vertebrae in total en bloc spondylectomy for spinal tumors. Instead of harvesting autograft from the ilium or fibula, the resected lamina and vertebral body from the total en bloc spondylectomy are frozen in liquid nitrogen and used as grafted bone for spinal reconstruction. A retrospective review of 56 patients was undertaken. As a result of this review, it was determined that this technique has the benefits of no pain at the bone harvest site, shortened operative time, decreased blood loss, and an additional antitumor immune response. PMID- 23937738 TI - Musculoskeletal cancers in adolescents. PMID- 23937739 TI - Internal fixation in a combat theater hospital. AB - Limited data are available on the use of internal fixation in combat zone hospitals. The authors performed a retrospective review of 713 surgical cases during 2 Operation Enduring Freedom deployments to a Level III theater hospital in 2007 and 2009 to 2010. The epidemiology and short- to intermediate-term outcomes of patients treated with internal fixation devices were studied. The authors found that, with judicious use, internal fixation under a damage control protocol in a combat theater hospital can be performed with acceptable complication rates. PMID- 23937740 TI - Acute lower-leg compartment syndrome. AB - Acute compartment syndrome remains a challenging problem for orthopedic surgeons because its diagnosis is not always straightforward and it has a high risk of associated limb morbidity if left undiagnosed or untreated. Failure to diagnose and treat acute compartment syndrome is one of the most common causes of successful medical liability claims. The authors review the current literature concerning the diagnosis of acute compartment syndrome and discuss new non invasive technologies that may allow for earlier and more accurate diagnosis of impending acute compartment syndrome. PMID- 23937741 TI - Massive rotator cuff tear. PMID- 23937743 TI - Computer-assisted navigation in orthopedic surgery. AB - Computer-assisted navigation has a role in some orthopedic procedures. It allows the surgeons to obtain real-time feedback and offers the potential to decrease intra-operative errors and optimize the surgical result. Computer-assisted navigation systems can be active or passive. Active navigation systems can either perform surgical tasks or prohibit the surgeon from moving past a predefined zone. Passive navigation systems provide intraoperative information, which is displayed on a monitor, but the surgeon is free to make any decisions he or she deems necessary. This article reviews the available types of computer-assisted navigation, summarizes the clinical applications and reviews the results of related series using navigation, and informs surgeons of the disadvantages and pitfalls of computer-assisted navigation in orthopedic surgery. PMID- 23937744 TI - Bench testing of a knee joint arthrometer. AB - The KT1000 and KT2000 knee joint arthrometers (MEDmetric Corp, San Diego, California) have been shown to overestimate the measurement of knee joint sagittal laxity. The purpose of this study was to investigate the accuracy of the KT arthrometers as measures of anterior and posterior linear displacement. The anterior and posterior linear displacements of 3 KT arthrometers (2 KT1000 arthrometers and 1 KT2000 arthrometer) were compared with the simultaneous displacement measured by a precision linear Vernier Dial Test Indicator (Davenport Ltd, London, United Kingdom). The displacement calculated using the analog output of the KT2000 was also compared with the values on the KT2000 displacement dial. Compared with the Vernier Dial Test Indicator, the KT arthrometers overestimated anterior linear displacement by between 22% and 24%. True anterior displacement for all 3 arthrometers, as recorded by the Vernier Dial Test Indicator, was found by multiplying the KT value by 0.79. When compared with the Vernier Dial Test Indicator, the KT arthrometers underestimated posterior linear displacement by between 18% and 19%. True posterior displacement, as recorded by the Vernier Dial Test Indicator, was found by multiplying the KT1000 value by 1.17 and the KT2000 value by 1.16. The internal apparatus of the KT2000 and KT1000 knee joint arthrometers overestimates anterior displacement and underestimates posterior displacement with a predictable relative systematic error. Future validation studies should use these correction equations to assess the accuracy of the KT arthrometers. Sagittal plane knee laxity measured with the KT devices requires systematic correction for optimal accuracy. PMID- 23937745 TI - Cross-sectional analysis of trends in meniscectomy and meniscus repair. AB - Knee arthroscopy to address meniscus tears is among the most common orthopedic procedures performed, and technical advances in the treatment of meniscus tears have affected the treatment options available to orthopedic surgeons. The purpose of this study was to perform a large cross-sectional analysis of orthopedic patients to investigate trends in arthroscopic meniscectomy and meniscus repair in the United States. Patients who underwent arthroscopic meniscectomy (Current Procedural Terminology codes 29881 and 29880) and arthroscopic meniscus repair (Current Procedural Terminology codes 29882 and 29883) were identified using the PearlDiver Patient Record Database, which is a national database of insurance records. The authors identified 187,607 arthroscopic medial or lateral meniscectomies and repairs performed between 2004 and 2009. Ninety-six percent of patients underwent meniscectomy and 4% underwent repair. No change occurred in the incidence of medial or lateral meniscectomy. The incidence of medial meniscus repair decreased from 5.3 cases per 10,000 patients in 2004 to 3.8 in 2009 (P<.001), although no significant change occurred in the incidence of lateral meniscus repair. Medial meniscectomy was most commonly performed in patients aged 50 to 59 years, whereas lateral meniscectomy demonstrated a bimodal age distribution. Conversely, meniscus repairs were most frequently performed in patients aged 10 to 19 years. Sex differences were more pronounced with meniscus repair (63% male vs 37% female) compared with meniscectomy (53% male vs 47% female). A high frequency of meniscus debridement can be expected in arthroscopic knee surgery. Despite advances in meniscus repair techniques and devices, no increase occurred in the performance of meniscus repair compared with meniscectomy. PMID- 23937746 TI - Value of forceps biopsy and kyphoplasty in Kummell's disease. AB - The diagnosis of Kummell's disease mainly depends on clinical and radiologic findings. However, these are not the gold standards for diagnosing this disease; bone biopsy is required. The authors performed modified bone biopsy and cement filling techniques during kyphoplasty and investigated the feasibility and efficacy of kyphoplasty for the treatment of Kummell's disease. This study included 28 patients (9 men and 19 women; average age, 71.9 years) with Kummell's disease. All patients underwent the modified biopsy procedure and kyphoplasty with the modified cement-filling technique. Treatment efficacy was evaluated using visual analog scale pain scores, Oswestry Disability Index scores, vertebral height, and Cobb angles pre- and postoperatively and at final follow up. All patients tolerated the procedure well and had immediate back pain relief after kyphoplasty. Biopsy examination revealed necrotic bone in 24 patients and sparse cancellous bone in 2; it was unsuccessful in 2 patients. No severe complication occurred in any patient. Two patients had cement leakage but no clinical symptoms. All efficacy measures were significantly better at the postoperative assessments than the preoperative assessments (P<.05) but were similar at the postoperative and final follow-up assessments. Kyphoplasty is a relatively effective and safe method for treating Kummell's disease when modified techniques are performed to prevent cement leakage, and forceps biopsy can be used in the differential diagnosis of this condition. PMID- 23937747 TI - Uniextrapedicular kyphoplasty for the treatment of thoracic osteoporotic vertebral fractures. AB - Osteoporotic vertebral compression fractures are common and cause pain and disability. Most osteoporotic vertebral compression fractures occur in the lower thoracic and thoracolumbar spine. Percutaneous balloon kyphoplasty through a transpedicular approach is a classic procedure performed to treat osteoporotic vertebral compression fractures. However, due to the slender morphology of the pedicles, small pedicle size, and the angular severity of thoracic kyphosis, performing kyphoplasty in middle and high thoracic levels is technically challenging. The purpose of this retrospective study was to evaluate the clinical outcomes of single-balloon kyphoplasty for the treatment of thoracic osteoporotic vertebral compression fractures via an extrapedicular approach. Between July 2004 and May 2008, thirty-eight patients with thoracic osteoporotic vertebral compression fractures underwent percutaneous kyphoplasty via a unilateral extrapedicular approach. Average patient age was 60.3 years. Symptomatic levels ranged from T4 to T12. All affected vertebrae were identified via physical examination, magnetic resonance imaging, and radiographs. Pain relief, vertebral height restoration, and kyphosis correction were compared pre- and postoperatively using the visual analog scale and radiographs. The operation was successful in all patients. Average injected bone cement volume was 3.2+/-1.4 mL. Mean follow-up was 9.5 months. Visual analog scale pain score improved in 36 of 38 patients postoperatively. Mean visual analog scale pain score was 8.92+/-0.682 preoperatively and 2.40+/-0.31 postoperatively and remained at 2.80+/-0.34 until last follow-up. Mean middle body height correction ratio was 50.9%+/-34.6%. No lateral wedging was found in the coronal alignment of the treated vertebrae. Three (7.9%) patients sustained cement extravasation with no adverse events. Kyphoplasty through a unilateral extrapedicular approach can achieve convergent and proper cement filling in the affected vertebrae to effectively restore stiffness, relieve pain, and correct kyphosis in fractured vertebrae. PMID- 23937748 TI - Minimally invasive plating osteosynthesis for mid-distal third humeral shaft fractures. AB - Mid-distal third humeral shaft fractures can be effectively treated with minimally invasive plating osteosynthesis and intramedullary nailing (IMN). However, these 2 treatments have not been adequately compared. Forty-seven patients (47 fractures) with mid-distal third humeral shaft fractures were randomly allocated to undergo either minimally invasive plating osteosynthesis (n=24) or IMN (n=23). The 2 groups were similar in terms of fracture patterns, fracture location, age, and associated injuries. Intraoperative measurements included blood loss and operative time. Clinical outcome measurements included fracture healing, radial nerve recovery, and elbow and shoulder discomfort. Radiographic measurements included fracture alignment, time to healing, delayed union, and nonunion. Functional outcome was satisfactory in both groups. Mean American Shoulder and Elbow Surgeons score and Mayo score were both better for the minimally invasive plating osteosynthesis group than for the IMN group (98.2 vs 97.6, respectively, and 93.5 vs 94.1, respectively; P<.001). Operative time was shorter and less intraoperative blood loss occurred in the minimally invasive plating osteosynthesis group than in the IMN group. Average time to union was similar in both groups. Primary union was achieved in 23 of 24 patients in the minimally invasive plating osteosynthesis group and in 22 of 23 in the IMN group. Minimally invasive plating osteosynthesis may have outcomes comparable with IMN for the management of mid-distal third humeral shaft fractures. Minimally invasive plating osteosynthesis is more suitable for complex fractures, especially for radial protection and motion recovery of adjacent joints, compared with IMN for simple fractures. PMID- 23937749 TI - Knotless single-row rotator cuff repair: a comparative biomechanical study of 2 knotless suture anchors. AB - The purpose of this study was to compare the gap formation during cyclic loading, maximum repair strength, and failure mode of single-row full-thickness supraspinatus repairs performed using 2 knotless suture anchors with differing internal suture-retention mechanisms in a human cadaver model. Nine matched pairs of cadaver shoulders were used. Full-thickness tears were induced by detaching the supraspinatus tendon from the greater tuberosity. Single-row repairs were performed with either type I (Opus Magnum PI; ArthroCare, Austin, Texas) or type II (ReelX STT; Stryker, Mahwah, New Jersey) knotless suture anchors. The repaired tendon was cycled from 10 to 90 N for 500 cycles, followed by load to failure. Gap formation was measured at 5, 100, 200, 300, 400, and 500 cycles with a video digitizing system. Anchor type or location (anterior or posterior) had no effect on gap formation during cyclic loading regardless of position (anterior, P=.385; posterior, P=.389). Maximum load to failure was significantly greater (P=.018) for repairs performed with type II anchors (288+/-62 N) compared with type I anchors (179+/-39 N). Primary failure modes were anchor pullout and tendon tearing for type II anchors and suture slippage through the anchor for type I anchors. The internal ratcheting suture-retention mechanism of type II anchors may have helped this anchor outperform the suture-cinching mechanism of type I anchors by supporting significantly higher loads before failure and minimizing suture slippage, potentially leading to stronger repairs clinically. PMID- 23937750 TI - Quality of information on the Internet about carpal tunnel syndrome: an update. AB - The use of the Internet for health-related information has increased significantly. In 2000, the current authors examined the source and content of orthopedic information on the Internet. At that time, Internet information regarding carpal tunnel syndrome was found to be of limited quality and poor informational value. The purposes of the current study were to reevaluate the type and quality of information on the Internet regarding carpal tunnel syndrome and to determine whether the quality of information available has improved compared with 1 decade ago. The phrase carpal tunnel syndrome was entered into the 5 most commonly used Internet search engines. The top 50 nonsponsored and the top 5 sponsored universal resource locators identified by each search engine were collected. Each unique Web site was evaluated for authorship and content, and an informational score ranging from 0 to 100 points was assigned. Approximately one third of nonsponsored Web sites were commercial sites or selling commercial products. Seventy-six percent of sponsored sites were selling a product for the treatment of carpal tunnel syndrome. Thirty-eight percent of nonsponsored sites provided unconventional information, and 48% of sponsored sites provided misleading information. Just more than half of nonsponsored sites were authored by a physician or academic institution. The informational mean score was 53.8 points for nonsponsored sites and 14.5 points for sponsored sites. The informational quality on the Internet on carpal tunnel syndrome has improved over the past decade. Despite this progress, significant room exists for improvement in the quality and completeness of the information available. PMID- 23937751 TI - Rate of clinically significant posttraumatic arthritis after small finger intra articular carpometacarpal fractures. AB - Although small finger intra-articular carpometacarpal joint fractures are relatively common hand injuries, few studies in the orthopedic literature report their clinical outcomes. The goal of this study was to analyze the rate of symptomatic posttraumatic arthritis following small finger intra-articular carpometacarpal joint fractures. The authors performed a chart review of 82 consecutive patients with a small finger intra-articular carpometacarpal fractures treated at their institution over a 5-year period. Operative indications included irreducible small finger intra-articular carpometacarpal fractures and recurrent small finger carpometacarpal joint instability after attempted reduction. Group 1 included 66 patients with small finger intra articular carpometacarpal fractures who were treated with cast immobilization alone for 6 weeks, whereas group 2 included 16 patients treated surgically followed by 6 weeks of cast immobilization. Clinical outcome parameters included posttreatment serial radiographs, a visual scale based on subjective pain scores (0-10) as part of a routine clinic intake form, and the need for subsequent small finger carpometacarpal arthrodesis. All patients included in the study had a minimum 12-month follow-up. In group 1, 6 (9.1%) of 66 patients developed symptomatic posttraumatic arthritis and required a subsequent small finger carpometacarpal arthrodesis. In group 2, none of the patients developed symptomatic posttraumatic arthritis or required arthrodesis. This study reports a relatively higher rate of small finger carpometacarpal arthrodesis after closed treatment alone for intra-articular small finger carpometacarpal fractures compared with open treatment, suggesting that anatomic alignment is important in this injury pattern. PMID- 23937752 TI - Biomechanical evaluation of anatomical double-bundle coracoclavicular ligament reconstruction secured with knot fixation versus screw fixation. AB - Methods to reconstruct the coracoclavicular ligaments anatomically have been described. No clear advantage of 1 technique has been elucidated. The authors' hypothesis was that the biomechanical properties of a modified knot fixation technique would be similar to the anatomical double-bundle technique. Sixteen matched cadaveric shoulders were used for this study, and 1 additional shoulder was used in the knot fixation group only. Shoulders were randomly assigned to the anatomical double-bundle coracoclavicular ligament reconstruction technique (n=8) or a knot fixation technique (n=9). The intact coracoclavicular ligaments were tested to failure with superior displacement at a rate of 2 mm/s. Reconstruction was performed using a semitendinosus tendon allograft, and load to failure was repeated for each construct. Ultimate failure load, stiffness, and failure mode were compared using a paired t test (P<.05). No significant difference existed in load to failure between native and reconstructed ligaments or between reconstruction techniques. Stiffness decreased significantly after reconstruction in the double-bundle group (from 32.5 to 22.5 N/mm; P=.035) and in the modified knot fixation group (from 35.5 to 21.9 N/mm; P=.043). No significant difference existed in stiffness between the 2 reconstruction groups. A significant difference (P=.003) existed between failure modes between the 2 reconstruction techniques. Although less stiff than the native ligament, either technique used to reconstruct the coracoclavicular ligament can be performed to yield a load to failure similar to the intact ligament. The majority of failures in the double bundle group were by means of the graft slipping at the screw-tendon interface at 1 of the clavicular drill holes. The modified knot fixation technique failed the majority of the time by graft elongation. PMID- 23937753 TI - Outcomes of functional weight-bearing rehabilitation of Achilles tendon ruptures. AB - The introduction of functional rehabilitation for patients with Achilles tendon rupture has dramatically changed treatment programs for this condition. The authors introduced a functional weight-bearing protocol for patients with an acute Achilles tendon rupture treated operatively and nonoperatively in 2002. They hypothesized that no significant differences would exist in the rerupture rates and functional outcomes between the groups. Between 2002 and 2008, the authors collected data on 80 consecutive patients treated with a weight-bearing functional orthosis for complete Achilles tendon rupture. Following evidence based counseling, 51 patients chose nonoperative treatment and 29 chose operative treatment. Outcome measures included rerupture rates, other complications, and functional scoring. The nonoperative group was a decade older (median age, 47 years [range, 27-80 years]) than the operative group (median age, 37 years [range, 24-55 years]). Rerupture was noted in 2 (4%) patients in the nonoperative treatment group and 1 (3%) patient in the operative group. Two (7%) patients in the operative group developed superficial wound infections and reported no nerve injuries. Median Achilles Tendon Total Rupture Score was 82 points in the nonoperative group and 94 in the operative group. Median Victorian Institute of Sports Assessment-Achilles tendinopathy questionnaire scores were 60 and 91 for the nonoperative and operative groups, respectively. Both groups had low rerupture rates. Functional scores, using the newly validated Achilles Tendon Total Rupture Score, were lower in the nonoperative group. PMID- 23937754 TI - 3.0-Tesla MRI and arthroscopy for assessment of knee articular cartilage lesions. AB - The purpose of this study was to evaluate the ability of 3.0-Tesla magnetic resonance imaging (MRI) to accurately assess knee articular cartilage lesions. Sixteen patients who had knee 3.0-T MRI and underwent knee arthroscopy for partial meniscectomy were included. Three fellowship-trained sports medicine orthopedic surgeons reviewed all images. Articular lesions on MRI were graded from I to IV and compared with arthroscopic grading using the Outerbridge and the International Cartilage Repair Society (ICRS) classifications. The articular surface was divided into 6 regions. Based on MRI findings, of the 288 articular surface evaluations, 113 (39%) surface evaluations were classified as disease positive (grade 2 to 4). Kappa interrater reliability scores for MRI evaluation, Outerbridge classification, and ICRS classification were 0.13, 0.54, and 0.41, respectively. Using the Outerbridge classification as a reference standard, the sensitivity, specificity, and accuracy were 57%, 71%, and 63%, respectively. Using the ICRS classification, sensitivity, specificity, and accuracy were 59%, 71%, and 69%, respectively. When isolating the articular grading to the senior author on MRI evaluation vs Outerbridge classification, the sensitivity, specificity, and accuracy were 54%, 92%, and 75%, respectively. Based on the current findings, 3.0-T MRI is as an invaluable noninvasive tool with good diagnostic value for assessing articular cartilage lesions of the knee, although it may not be as sensitive and accurate as previously reported. PMID- 23937755 TI - Operative treatment of acetabular fractures in the Medicare population. AB - The purpose of this study was to determine the incidence of and evaluate the risk for complications and mortality following open treatment of acetabular fractures in the Medicare population. Patients treated with open reduction and internal fixation (ORIF) for acetabular fractures were identified using current procedural terminology codes in a 5% national sample of Medicare records. Complications within 90 days and within 1 year were evaluated based on the presence of ICD-9-CM diagnosis codes and Current Procedural Terminology reoperation codes. A total of 1286 fractures were treated closed and 359 were treated with ORIF. Multivariate Cox regression was performed to compare complication rates and risk factors. The incidence of acetabular fractures in the Medicare population has increased by 29% since 1998. Complications in the ORIF group included cardiac complications, deep venous thrombosis, infection, pulmonary embolism, refixation, and conversion to total hip arthroplasty. Risk factors for complications with ORIF included advanced age and comorbidities. Mortality in the ORIF group was 14.4% at 1 year. The incidence of reoperation with conversion to total hip arthroplasty or revision fixation following ORIF is 10% and 15%, respectively. Further investigation is required to improve outcomes and decrease complications in this group of patients, especially cardiac, deep vein thrombosis, and infection. PMID- 23937756 TI - Minimally invasive unilateral pedicle screw fixation and lumbar interbody fusion for the treatment of lumbar degenerative disease. AB - Minimally invasive unilateral pedicle screw fixation for the treatment of degenerative lumbar diseases has won the support of many surgeons. However, few data are available regarding clinical research on unilateral pedicle screw fixation associated with minimally invasive techniques for the treatment of lumbar spinal diseases. The purpose of this study was to evaluate clinical outcomes in a selected series of patients with lumbar degenerative diseases treated with minimally invasive unilateral vs classic bilateral pedicle screw fixation and lumbar interbody fusion. Patients in the unilateral group (n=43) underwent minimally invasive unilateral pedicle screw fixation with the Quadrant system (Medtronic, Memphis, Tennessee). The bilateral group (n=42) underwent bilateral instrumentation via the classic approach. Visual analog scale pain scores, Oswestry Disability Index scores, fusion rate, operative time, blood loss, and complications were analyzed. Mean operative time was 75 minutes in the unilateral group and 95 minutes in the bilateral group. Mean blood loss was 220 mL in the unilateral group and 450 mL in the bilateral group. Mean postoperative visual analog scale pain score was 3.10+/-0.16 in the unilateral group and 3.30+/ 1.10 in the bilateral group. Mean postoperative Oswestry Disability Index score was 15.67+/-2.3 in the unilateral group and 14.93+/-2.6 in the bilateral group. Successful fusion was achieved in 92.34% of patients in the unilateral group and 93.56% of patients in the bilateral group. Minimally invasive unilateral pedicle screw fixation is an effective and reliable option for the surgical treatment of lumbar degenerative disease. It causes less blood loss, requires less operative time, and has a fusion rate comparable with that of conventional bilateral fixation. PMID- 23937757 TI - Mechanical axis of the lower extremity determined by a new digital photographic method. AB - Assessment of the mechanical axis is routine during the examination of patients with lower extremity pain. Long-leg radiographic examination is the gold standard for exact measurement, but it is associated with a significant radiation dose. An alternative method to examine the mechanical axis has been warranted. This article validates a newly developed computerized photograph method to calculate the mechanical axis using a digital photograph. The location of the center of the femoral head was calculated using ink marks on both superior iliac spines. Twenty five patients (10 women and 15 men) had both legs examined using the photographic method and long-leg radiography examination. The digital photograph method was found to be highly reliable. The interobserver absolute mean difference was 0.99 degrees +/-0.85 degrees , and the intraobserver absolute mean difference (day-to day variation) was 1.04 degrees +/-0.81 degrees . The mechanical axis determined by the 2 methods was highly correlated (R=0.943). The long-leg radiography method was within an average of +/-1.88 degrees of the photographic method, with a 95% probability. The photographic method appears to be an effective alternative to conventional long-leg radiography. The photographic method seems convenient in the routine examination of patients with leg pain and children with suspected axial deformity and for follow-up after treatment for malalignment. Calculation coefficients for children and a possible racial difference remain to be studied. PMID- 23937758 TI - One-stage posterior surgical treatment for lumbosacral tuberculosis with major vertebral body loss and kyphosis. AB - The treatment goals of tuberculous spondylitis are to eradicate infection and to prevent or treat instability, deformity, and neurologic deficit. The purpose of this study was to evaluate the clinical outcomes following chemotherapy with 1 stage posterior debridement, correction, and instrumentation and fusion for the treatment of lumbosacral tuberculosis with major vertebral body loss and kyphosis. Fourteen patients with lumbosacral tuberculosis with major vertebral body loss and kyphosis underwent 1-stage posterior surgery. Clinical assessments included low back ache, Oswestry Disability Index, Scoliosis Research Society-22 scores, neurologic deficit, erythrocyte sedimentation rate, and C-reactive protein level. Radiographic parameters included kyphosis angle, anteroposterior translation, local scoliosis, lumbar lordosis, pelvic parameters, sagittal offset, and fusion. Thorough debridement was performed. Patients were followed for an average of 39.3 months. Constitutional symptoms, low back ache, and functional outcome improved in all patients postoperatively. At final follow-up, Frankel Grade improved by 0 to 2 grades, mean kyphosis angle improvement was 44.3 degrees , and satisfactory spinopelvic and sagittal balance were achieved. Spinal posterolateral fusion was obtained in all patients and no fixation loosening was found at 2-year follow-up. Differences existed between the pre- and postoperative radiographic parameters (P<.05). Correction loss at last follow-up was not statistically significant (P>.05). No surgical complications or infection recurrence occurred. Tuberculosis can be cured and effective correction of kyphosis can be achieved for lumbosacral tuberculosis with major vertebral body loss and kyphosis by performing 1-stage posterior surgery and chemotherapy. PMID- 23937759 TI - Venous arterialization for the treatment of large-area foot skin retrograde avulsion. AB - Between 2009 and 2011, three patients with large-area foot skin retrograde avulsion (more than 1% of the body surface area) underwent venous arterialization. Anastomosis of the artery in the wound surface with the vein in the skin flap and an appropriate number of venous end-to-end anastomoses were performed. The skin flaps survived in all 3 patients. Six months postoperatively, the flap elasticity and appearance were close to that of normal skin, and foot function was better without scar contracture. When venous arterialization is used to treat foot avulsion, the following points should be noted. Surgical indications include no fresh bleeding from the wound edge of the avulsed skin after debridement, more complete avulsed skin, and superficial veins that do not completely separate from the avulsed skin. Venous arterialization is not suitable to avulsion with fresh bleeding, avulsed skin in small fragments, and avulsion with a subcutaneous venous network embolism. During debridement, the subcutaneous venous network should be protected to avoid exposing the vein stems outside the fat layer. If the avulsion is less than 1% of the body surface area, arterial venous anastomosis can provide adequate blood supply. Venous-venous anastomosis is performed as much as possible to enhance venous return and decrease microcirculatory pressure, which is conducive to the establishment of effective blood circulation. PMID- 23937760 TI - Electrothermal ring burn from a car battery. AB - Despite prevention efforts, burn injuries among auto mechanics are described in the literature. Electrothermal ring burns from car batteries occur by short circuiting through the ring when it touches the open terminal or metal housing. This article describes a 34-year-old male auto mechanic who was holding a wrench when his gold ring touched the positive terminal of a 12-volt car battery and the wrench touched both his ring and the negative terminal. He felt instant pain and had a deep partial-thickness circumferential burn at the base of his ring finger. No other soft tissues were injured. He was initially managed conservatively, but after minimal healing at 3 weeks, he underwent a full-thickness skin graft. The graft incorporated well and healed by 4 weeks postoperatively. He had full range of motion. The cause of ring burns has been controversial, but based on reports similar to the current patient's mechanism, they are most likely electrothermal burns. Gold, a metal with high thermal conductivity, can heat up to its melting point in a matter of seconds. Many treatments have been described, including local wound care to split- and full-thickness skin grafts. Because most burns are preventable, staff should be warned and trained about the potential risks of contact burns. All jewelry should be removed, and the live battery terminal should be covered while working in the vicinity of the battery. PMID- 23937761 TI - Clavicle fracture with intrathoracic displacement. AB - Clavicle fractures are common, and most are isolated injuries. Injury to the nearby subclavian vessels and brachial plexus have classically been described as potential complications of clavicle fractures. However, in the setting of a substantially displaced clavicle fracture, concomitant thoracic trauma is relatively frequent. Injury to the thorax can be difficult to identify on physical examination, and advanced imaging modalities may be required for diagnosis. The evaluation, workup, and management of a patient with intrathoracic displacement of a clavicle fracture are described. Despite the significant fracture displacement and associated pneumothorax, the injury severity was not clinically obvious. Imaging, including a screening chest radiograph and subsequent axial computed tomography, played an important role in diagnosis and management. The patient underwent successful open reduction and plate fixation. A thoracostomy tube was not required at any point during the hospitalization. The patient recovered uneventfully and returned to full work duty by 3 months postoperatively. Including the current report, only 3 cases of intrathoracic displacement of the clavicle have been published in the English literature. All involved fractures of the middle third of the clavicle. The severity of displacement was not obvious in any patient, and diagnosis was dependent on additional imaging. Given the frequency of associated chest trauma and limitations of physical examination, chest radiography should be considered in the evaluation of patients with substantially displaced clavicle fractures. PMID- 23937762 TI - Subdeltoid lipoma arborescens combined with rotator cuff tears. AB - Lipoma arborescens, a rare benign intra-articular lesion, is characterized by lipomatous proliferation of the synovium in which the subsynovial tissue is replaced by mature adipocytes. Subdeltoid bursa is a rare location for lipoma arborescens, and only a few cases have been reported in the literature. This article reports 2 cases of subdeltoid lipoma arborescens combined with rotator cuff tears, and the possible relationships between subdeltoid lipoma arborescens and rotator cuff tears are discussed. The intra-articular villous proliferations on fat-suppressed T2-weighted magnetic resonance imaging appeared as yellowish white lipomatous villous proliferations on arthroscopy, and finger-like lipomatous proliferation of the synovium, where the subsynovial connective tissue is replaced by mature adipocytes, on histology. Although further evidence would be necessary, the bony proliferations, in addition to bone-to-bone abrasion and inflammatory processes, may contribute to the relationship between subdeltoid lipoma arborescens and rotator cuff tears. Because this is a rare disease in a rare location, no established treatment guidelines are available for lipoma arborescens in subdeltoid bursa. For the current patients, arthroscopic excision of the lipoma arborescens and concomitant rotator cuff repair were prescribed after more than 6 months of conservative management. All patients had symptom relief and were satisfied with their results. Paying special attention to the radiologic and arthroscopic characteristics of the lipoma arborescens will help physicians and surgeons to achieve a more accurate diagnosis and effective treatment strategy, especially in patients with concomitant rotator cuff tears. PMID- 23937763 TI - Local application of free antibiotic powder in the treatment of osteomyelitis in a rat model. AB - To date, several strategies have been developed to provide local antibiotic therapy in the treatment of osteomyelitis, such as antibiotic-loaded bone cement, antibiotic-impregnated collagen sponges, polymethylmethacrylate beads, antibiotic loaded bone graft, antibiotic-loaded synthetic bone substitutes, and antibiotic coated implants. The optimum carrier for local antibiotic therapy has not been identified. Tibial osteomyelitis using methicillin-sensitive Staphylococcus aureus was created in a rat model. Rats were assigned to 3 treatment groups: group A, systemic antibiotics only; group B, systemic antibiotics plus surgical debridement; and group C, systemic antibiotics, surgical debridement, and application of cefazolin. Infection was assessed using gross tissue analysis, radiographs, quantitative bacteriology, and histopathology. One-half of the rat tibias were randomly chosen for histological evaluation and the other half were used for microbiological analysis. Radiographs were reviewed and graded by 4 blinded board-certified radiologists. Histology slides were reviewed and graded by a blinded board-certified pathologist. Gross tissue analysis of treatment groups B and C demonstrated a statistically significant improvement in soft tissue infection clearance compared with group A (P<.05). No difference was found between treatment groups B and C. No significant difference existed in gross tissue, radiographic, microbiologic, or histopathologic analyses among the 3 groups for osteomyelitis. The results of this study demonstrated that the local application of free antibiotic powder is as effective as local debridement alone in treating soft tissue infection associated with tibial osteomyelitis in a rat model. PMID- 23937764 TI - Ilizarov external fixator for stump salvage in infected nonunions. AB - Infected nonunions are potentially difficult complications to treat in the context of complex tibial fractures. Often, such complications necessitate amputation to prevent further sequelae, such as fulminant sepsis and complete loss of the limb. As such, the eradication of infection, the decision regarding when to amputate, and the length of the residual stump are important factors to optimize patient outcome. The authors present a unique scenario whereby an Ilizarov external fixation device was used to treat an infected tibial nonunion while simultaneously salvaging stump length to enable fitting for a below-knee prostheses. The use of the Ilizarov device can prevent abrupt dissemination of infection, stabilize the fracture, and bridge nonunion gaps. This is augmented by the unique ability of the construct to be periodically readjusted and realigned where needed to permit osteogenesis and proper alignment. The result in this case was complete eradication of infection, with the use of continuous antibiotics as a pharmacological adjunct, union of the tibial fragments, and a below-knee amputation with adequate stump length and prosthetic fit. The success of this treatment strategy was predicated on the above factors, with an emphasis on amputation level and its effect on function. The Ilizarov external fixator is a device that has been widely used to treat limb-length discrepancies, correct deformities, and induce osseous growth in bony nonunion. The authors present the Ilizarov device as a viable option for the treatment of infected tibial nonunions and stump length salvage. PMID- 23937765 TI - AO X-shaped midfoot locking plate to treat displaced isolated greater tuberosity fractures. AB - Although various implants exist for 3- and 4-part fractures, few implants are appropriate for isolated greater tuberosity fractures. This retrospective study evaluated the efficacy of AO X-shaped midfoot locking plates for greater tuberosity fractures. Between May 2008 and September 2009, nineteen patients with displaced greater tuberosity fractures were treated with open reduction and internal fixation using AO X-shaped midfoot locking plates. Postoperatively, radiographs, functional results, and complications were evaluated. All patients were followed up for a mean 33.2 months (range, 24-42 months). Mean healing time was 9.4 weeks (range, 8-14 weeks). Mean Constant score was 90.6+/-4.0 points (range, 77-95 points). Excellent results were obtained in 16 cases, good in 2 cases, moderate in 1 case, and poor in 0 cases. The excellent-good rate was 94.7%. No recurrence of dislocation occurred in the 11 cases with shoulder dislocation. All fractures healed without the complications of wound infection, skin numbness, subacromial impingement syndrome, nonunion, secondary displacement, and implant loosening. The described technique is an effective, simple, and inexpensive method with a short learning curve. PMID- 23937766 TI - Improving practice in community-based settings: a randomized trial of supervision - study protocol. AB - BACKGROUND: Evidence-based treatments for child mental health problems are not consistently available in public mental health settings. Expanding availability requires workforce training. However, research has demonstrated that training alone is not sufficient for changing provider behavior, suggesting that ongoing intervention-specific supervision or consultation is required. Supervision is notably under-investigated, particularly as provided in public mental health. The degree to which supervision in this setting includes 'gold standard' supervision elements from efficacy trials (e.g., session review, model fidelity, outcome monitoring, skill-building) is unknown. The current federally-funded investigation leverages the Washington State Trauma-focused Cognitive Behavioral Therapy Initiative to describe usual supervision practices and test the impact of systematic implementation of gold standard supervision strategies on treatment fidelity and clinical outcomes. METHODS/DESIGN: The study has two phases. We will conduct an initial descriptive study (Phase I) of supervision practices within public mental health in Washington State followed by a randomized controlled trial of gold standard supervision strategies (Phase II), with randomization at the clinician level (i.e., supervisors provide both conditions). Study participants will be 35 supervisors and 130 clinicians in community mental health centers. We will enroll one child per clinician in Phase I (N = 130) and three children per clinician in Phase II (N = 390). We use a multi-level mixed within- and between-subjects longitudinal design. Audio recordings of supervision and therapy sessions will be collected and coded throughout both phases. Child outcome data will be collected at the beginning of treatment and at three and six months into treatment. DISCUSSION: This study will provide insight into how supervisors can optimally support clinicians delivering evidence-based treatments. Phase I will provide descriptive information, currently unavailable in the literature, about commonly used supervision strategies in community mental health. The Phase II randomized controlled trial of gold standard supervision strategies is, to our knowledge, the first experimental study of gold standard supervision strategies in community mental health and will yield needed information about how to leverage supervision to improve clinician fidelity and client outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01800266. PMID- 23937767 TI - Bullying in schools: the power of bullies and the plight of victims. AB - Bullying is a pervasive problem affecting school-age children. Reviewing the latest findings on bullying perpetration and victimization, we highlight the social dominance function of bullying, the inflated self-views of bullies, and the effects of their behaviors on victims. Illuminating the plight of the victim, we review evidence on the cyclical processes between the risk factors and consequences of victimization and the mechanisms that can account for elevated emotional distress and health problems. Placing bullying in context, we consider the unique features of electronic communication that give rise to cyberbullying and the specific characteristics of schools that affect the rates and consequences of victimization. We then offer a critique of the main intervention approaches designed to reduce school bullying and its harmful effects. Finally, we discuss future directions that underscore the need to consider victimization a social stigma, conduct longitudinal research on protective factors, identify school context factors that shape the experience of victimization, and take a more nuanced approach to school-based interventions. PMID- 23937768 TI - The relation between body mass index and musculoskeletal symptoms in the working population. AB - BACKGROUND: The primary aim of this study was to investigate the association between BMI and musculoskeletal symptoms in interaction with physical workload. In addition, it was aimed to obtain insight into whether overweight and obesity are associated with an increase in occurrence of symptoms and/or decrease in recovery from symptoms. METHODS: Based on a large working population sample (n = 44,793), using the data from The Netherlands Working Conditions Survey (NWCS), logistic regression analyses were carried out to investigate the association between BMI and musculoskeletal symptoms, with adjustment for potential confounders. Longitudinal data from the Netherlands Working Conditions Cohort Study (NWCCS) of 7,909 respondents was used for the second research aim (i.e., to investigate the transition in musculoskeletal symptoms). RESULTS: For high BMI an increased 12-month prevalence of musculoskeletal symptoms was found (overweight: OR 1.13, 95% CI: 1.08-1.19 and obesity: OR 1.28, 95% CI: 1.19-1.39). The association was modified by physical workload, with a stronger association for employees with low physical workload than for those with high physical workload. Obesity was related to developing musculoskeletal symptoms (OR 1.37, 95% CI: 1.05 1.79) and inversely related to recovery from symptoms (OR 0.76, 95% CI: 0.59 0.97). CONCLUSION: BMI was associated with musculoskeletal symptoms, in particular symptoms of the lower extremity. Furthermore, the association differed for employees with high or low physical workload. Compared to employees with normal weight, obese employees had higher risk for developing symptoms as well as less recovery from symptoms. This study supports the role of biomechanical factors for the relationship between BMI and symptoms in the lower extremity. PMID- 23937769 TI - Japanese encephalitis virus infects porcine kidney epithelial PK15 cells via clathrin- and cholesterol-dependent endocytosis. AB - BACKGROUND: Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes acute viral encephalitis in humans. Pigs are important amplifiers of JEV. The entry mechanism of JEV into porcine cells remains largely unknown. In this study, we present a study of the internalization mechanism of JEV in porcine kidney epithelial PK15 cells. RESULTS: We demonstrated that the disruption of the lipid raft by cholesterol depletion with methyl-beta-cyclodextrin (MbetaCD) reduced JEV infection. We also found that the knockdown of clathrin by small interfering RNA (siRNA) significantly reduced JEV-infected cells and JEV E glycoprotein levels, suggesting that JEV utilizes clathrin-dependent endocytosis. In contrast, the knockdown of caveolin-1, a principal component of caveolae, had only a small (although statistically significant) effect on JEV infection, however, JEV entry was not affected by genistein. These results suggested that JEV entry was independent of caveolae. CONCLUSIONS: Taken together, our results demonstrate that JEV enters porcine kidney epithelial PK15 cells through cholesterol- and clathrin-mediated endocytosis. PMID- 23937770 TI - Comparison of peri-operative outcomes of robot-assisted vs laparoscopic partial nephrectomy: a meta-analysis. AB - OBJECTIVE: To conduct a meta-analysis of the literature on the peri-operative outcomes of both robot-assisted partial nephrectomy (RAPN) and laparoscopic partial nephrectomy (LPN). MATERIALS AND METHODS: An electronic database search of MEDLINE, EMBASE, Google Scholar and the Cochrane Library was performed for publications up to 8 January 2013. All studies comparing RAPN with LPN were included. The outcome measures were demographic and peri-operative results, including operating time, warm ischaemia time, blood loss, length of hospital stay, conversion rates, positive surgical margins and complications. A meta analysis of the results was conducted. RESULTS: A total of 766 patients were included, 425 patients in the RAPN group and 341 patients in the LPN group. There was no significant difference between the two groups in any of the demographic variables (age: P = 0.89; sex: P = 0.31; malignant pathology: P = 0.54; tumour size: P = 0.99; tumour laterality: P = 0.06). There was no difference between the two groups regarding operating times (P = 0.75), estimated blood loss (P = 0.75), conversion rates (P = 0.52), positive surgical margins (P = 0.61), complications (P = 0.27) or length of hospital stay (P = 0.27), but the RAPN group had significantly shorter warm ischaemia times than the LPN group (P = 0.01; weighted mean difference: -3.65; 95% confidence interval, -6.46 to -0.83). CONCLUSION: This meta-analysis shows that RAPN provides equivalent peri-operative outcomes to those of LPN, with the added advantage of a significantly shorter warm ischaemia time. PMID- 23937771 TI - Annual Papanicolaou screening for 5 years among human papillomavirus-negative women. AB - BACKGROUND: Primary human papilloma virus (HPV) screening is more effective than cytology in reducing the risk of cervical cancer, but screening intervals should be extended in HPV-negative women. However, some Markov models predicted that long intervals are associated with an excess risk of cervical cancer. The aim of this analysis was to estimate the real-life risks and benefits of annual Papanicolaou (Pap) screening in HPV-negative women with normal cytology. METHODS: Women with negative Hybrid Capture 2 (HC2) results and normal cytology at the time of inclusion in the Hannover HPV screening trial underwent annual Pap smears for 5 years. A subgroup was randomly selected for retesting with cytology, HC2, and colposcopy 60-68 months after recruitment. RESULTS: Of 4236 women included, 3406 had at least one Pap smear, but only 1185 attended all five annual screening visits. The proportion of women with at least one abnormal smear was 14.4% in 60 months. The probability of abnormal smears increased continuously over time. No case of >= CIN2+ was observed during 5 years. Of 605 women selected for subgroup analysis, 292 agreed to be retested (48.3%). The rate of high-risk HPV at 60-68 months was 3.0% (9/296). CONCLUSIONS: The long-term risk of high-grade neoplasia after an initial negative HC2 test and normal cytology result was low, while the rate of false-positive abnormal Pap smears was significant and increased constantly over time. Pap smear screening of HPV-negative women more frequently than every 5 years could be potentially harmful and seems to be of little clinical value. PMID- 23937773 TI - The central role of biological data mining in connecting diverse disciplines. PMID- 23937772 TI - Treatment of malignant pleural mesothelioma by fibroblast activation protein specific re-directed T cells. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is an incurable malignant disease, which results from chronic exposition to asbestos in at least 70% of the cases. Fibroblast activation protein (FAP) is predominantly expressed on the surface of reactive tumor-associated fibroblasts as well as on particular cancer types. Because of its expression on the cell surface, FAP is an attractive target for adoptive T cell therapy. T cells can be re-directed by retroviral transfer of chimeric antigen receptors (CAR) against tumor-associated antigens (TAA) and therefore represent a therapeutic strategy of adoptive immunotherapy. METHODS: To evaluate FAP expression immunohistochemistry was performed in tumor tissue from MPM patients. CD8+ human T cells were retrovirally transduced with an anti-FAP F19-?CD28/CD3zeta-CAR. T cell function was evaluated in vitro by cytokine release and cytotoxicity assays. In vivo function was tested with an intraperitoneal xenograft tumor model in immunodeficient mice. RESULTS: FAP was found to be expressed in all subtypes of MPM. Additionally, FAP expression was evaluated in healthy adult tissue samples and was only detected in specific areas in the pancreas, the placenta and very weakly for cervix and uterus. Expression of the anti-FAP-F19-?CD28/CD3zeta-CAR in CD8+ T cells resulted in antigen-specific IFNgamma release. Additionally, FAP-specific re-directed T cells lysed FAP positive mesothelioma cells and inflammatory fibroblasts in an antigen-specific manner in vitro. Furthermore, FAP-specific re-directed T cells inhibited the growth of FAP positive human tumor cells in the peritoneal cavity of mice and significantly prolonged survival of mice. CONCLUSION: FAP re-directed CD8+ T cells showed antigen-specific functionality in vitro and in vivo. Furthermore, FAP expression was verified in all MPM histotypes. Therefore, our data support performing a phase I clinical trial in which MPM patients are treated with adoptively transferred FAP-specific re-directed T cells. PMID- 23937775 TI - Clinical cures, ethical questions. PMID- 23937774 TI - The epidemiology of life-threatening complications associated with reproductive process in public hospitals in Argentina. AB - OBJECTIVE: To analyse life-threatening obstetric complications that occurred in public hospitals in Argentina. DESIGN: Multicentre collaborative cross-sectional study. SETTING: Twenty-five hospitals included in the Perinatal Network of Buenos Aires Metropolitan Area. POPULATION: Women giving birth in participating hospitals during a 1-year period. METHODS: All cases of severe maternal morbidity (SMM) and maternal mortality (MM) during pregnancy (including miscarriage and induced abortion), labour and puerperium were included. Data were collected prospectively. MAIN OUTCOME MEASURES: Identification criteria, main causes and incidence of SMM; case-fatality rates, morbidity-mortality index and effective intervention's use rate. RESULTS: A total of 552 women with life-threatening conditions were identified: 518 with SMM, 34 with MM. Identification criteria for SMM were case-management (48.9%), organ dysfunction (15.2%) and mixed criteria (35.9%). Incidence of SMM was 0.8% (95% confidence interval [95% CI] 0.73-0.87%) and hospital maternal death ratio was 52.3 per 100 000 live births (95% CI 35.5 69.1). Main causes of MM were abortion complications and puerperal sepsis; main causes of SMM were postpartum haemorrhage and hypertension. Overall case-fatality rate was 6.2% (95% CI 4.4-8.6): the highest due to sepsis (14.8%) and abortion complications (13.3%). Morbidity-mortality index was 15:1 (95% CI 7.5-30.8). Use rate of known effective interventions to prevent or treat main causes of MM and SMM was 52.3% (95% CI 46.9-57.7). CONCLUSIONS: This study describes the importance of life-threatening obstetric complications that took place in public hospitals with comprehensive obstetric care and the low utilisation of known effective interventions that may decrease rates of SMM and MM. It also provides arguments that justify the need to develop a surveillance system for SMM. PMID- 23937776 TI - Minors' right to know and therapeutic privilege. PMID- 23937777 TI - Allocation of drugs in short supply. PMID- 23937778 TI - End-of-life decisions and off-label drug use. PMID- 23937779 TI - 2012 winning essay. Joey knows best? Balancing conflicts and defending a child's best interest in difficult clinical decisions. PMID- 23937780 TI - 2012 runner-up essay. Pediatric assent in clinical research: a patient-centered perspective using motivational interviewing. PMID- 23937781 TI - 2012 runner-up essay. Keeping Joey at the center of the conversation: ethical considerations in a challenging pediatric case. PMID- 23937782 TI - The medical student and care at the end of life. PMID- 23937783 TI - Why clinical oncologists should talk about the price of cancer drugs. PMID- 23937784 TI - The promise and pitfalls of genomics-driven cancer medicine. PMID- 23937785 TI - The terminally ill, access to investigational drugs, and FDA rules. PMID- 23937786 TI - Overcoming inequalities: the Affordable Care Act and cancer treatment. PMID- 23937787 TI - What cancer survivorship means. PMID- 23937788 TI - Images in cigarette warning labels: how should they warn? PMID- 23937789 TI - Defining quality, disseminating evidence, and enforcing guidelines for cancer treatment. PMID- 23937790 TI - Automatic lumen segmentation in IVOCT images using binary morphological reconstruction. AB - BACKGROUND: Atherosclerosis causes millions of deaths, annually yielding billions in expenses round the world. Intravascular Optical Coherence Tomography (IVOCT) is a medical imaging modality, which displays high resolution images of coronary cross-section. Nonetheless, quantitative information can only be obtained with segmentation; consequently, more adequate diagnostics, therapies and interventions can be provided. Since it is a relatively new modality, many different segmentation methods, available in the literature for other modalities, could be successfully applied to IVOCT images, improving accuracies and uses. METHOD: An automatic lumen segmentation approach, based on Wavelet Transform and Mathematical Morphology, is presented. The methodology is divided into three main parts. First, the preprocessing stage attenuates and enhances undesirable and important information, respectively. Second, in the feature extraction block, wavelet is associated with an adapted version of Otsu threshold; hence, tissue information is discriminated and binarized. Finally, binary morphological reconstruction improves the binary information and constructs the binary lumen object. RESULTS: The evaluation was carried out by segmenting 290 challenging images from human and pig coronaries, and rabbit iliac arteries; the outcomes were compared with the gold standards made by experts. The resultant accuracy was obtained: True Positive (%) = 99.29 +/- 2.96, False Positive (%) = 3.69 +/- 2.88, False Negative (%) = 0.71 +/- 2.96, Max False Positive Distance (mm) = 0.1 +/- 0.07, Max False Negative Distance (mm) = 0.06 +/- 0.1. CONCLUSIONS: In conclusion, by segmenting a number of IVOCT images with various features, the proposed technique showed to be robust and more accurate than published studies; in addition, the method is completely automatic, providing a new tool for IVOCT segmentation. PMID- 23937791 TI - The different biological effects of single, fractionated and continuous low dose rate irradiation on CL187 colorectal cancer cells. AB - PURPOSE: To determine the biological effectiveness of single, fractionated and continuous low dose rate irradiation on the human colorectal cancer cell line CL187 in vitro and explore the cellular mechanisms. MATERIALS AND METHODS: The CL187 cells were exposed to radiation of 6 MV X-ray at a high dose rate of 4Gy/min and 125I seed at a low dose rate of 2.77 cGy/h. Three groups were employed: single dose radiation group (SDR), fractionated dose radiation group (FDR) by 2Gy/f and continuous low dose rate radiation group (CLDR). Four radiation doses 2, 4, 6 and 8Gy were chosen and cells without irradiation as the control. The responses of CL187 cells to distinct modes of radiation were evaluated by the colony-forming assay, cell cycle progression as well as apoptosis analysis. In addition, we detected the expression patterns of DNA-PKcs, Ku70 and Ku80 by Western blotting. RESULTS: The relative biological effect for 125I seeds compared with 6 MV X-ray was 1.42. 48 hrs after 4Gy irradiation, the difference between proportions of cells at G2/M phase of SDR and CLDR groups were statistically significant (p = 0.026), so as the FDR and CLDR groups (p = 0.005). 48 hrs after 4Gy irradiation, the early apoptotic rate of CLDR group was remarkably higher than SDR and FDR groups (CLDR vs. SDR, p = 0.001; CLDR vs. FDR, p = 0.02), whereas the late apoptotic rate of CLDR group increased significantly compared with SDR and FDR group (CLDR vs. SDR, p = 0.004; CLDR vs. FDR, p = 0.007). Moreover, DNA-PKcs and Ku70 expression levels in CLDR-treated cells decreased compared with SDR and FDR groups. CONCLUSIONS: Compared with the X-ray high dose rate irradiation, 125I seeds CLDR showed more effective induction of cell apoptosis and G2/M cell cycle arrest. Furthermore, 125I seeds CLDR could impair the DNA repair capability by down-regulating DNA-PKcs and Ku70 expression. PMID- 23937792 TI - Individual differences in cognitive reappraisal usage modulate the time course of brain activation during symptom provocation in specific phobia. AB - BACKGROUND: Extinction learning is proposed to be one key mechanism of action underlying exposure-based cognitive-behavioral therapy (CBT) in specific phobia. Beyond that, cognitive reappraisal, one important strategy to regulate negative emotions, is a crucial component of CBT interventions, but has been disregarded in previous studies investigating neural change processes in specific phobia. The aim of this study was to investigate the association of individual differences in habitual/dispositional cognitive reappraisal usage and the time course of brain activation during phobic stimulation in specific phobia. METHODS: Dental phobic patients and healthy control subjects participated in a functional magnetic resonance imaging (fMRI) study whilst being confronted with phobic, disgust, fear and neutral pictures. Individual differences in cognitive reappraisal usage were assessed via a self-report questionnaire and correlated with activation decreases over the course of time. RESULTS: Phobic individuals with higher dispositional cognitive reappraisal scores showed a more pronounced activation decline in the right dorsomedial prefrontal cortex (dmPFC) which might be associated with a diminution of explicit cognitive emotion regulation over the course of time. Less decrease of activation in the right ventromedial prefrontal cortex (vmPFC) and the lateral orbitofrontal cortex (lOFC) over time in subjects with higher cognitive reappraisal scores might be related to a stronger automatic regulation of emotions or even emotional relearning. Additionally, phobic subjects compared with healthy controls showed a stronger habituation of the left dmPFC over the course of symptom provocation. CONCLUSIONS: The results of this study show for the first time that individual differences in cognitive reappraisal usage are associated with the time course of brain activation during symptom provocation in specific phobia. Additionally, the present study gives first indications for the importance of considering individual differences in cognitive reappraisal usage in the treatment of specific phobia. PMID- 23937793 TI - Growth receptor binding protein 10 inhibits glucose-stimulated insulin release from pancreatic beta-cells associated with suppression of the insulin/insulin like growth factor-1 signalling pathway. AB - Growth receptor binding protein 10 (Grb10) is an adaptor protein that interacts with the insulin receptor and insulin-like growth factor (IGF)-1 receptor. Overexpression of Grb10 in muscle cells and adipocytes inhibits insulin signalling, and transgenic mice overexpressing Grb10 exhibit impaired glucose tolerance. However, the roles of Grb10 in beta-cells remain unknown. The aim of the present study was to explore the effect of Grb10 on beta-cell function. The effects of Grb10 on glucose-stimulated insulin secretion (GSIS) and the insulin/IGF-1 signalling pathway were investigated in rat islets and/or dispersed islet cells with Grb10 overexpresion by adenovirus transfection. Protein expression was detected by western blot analysis. We found that Grb10 was expressed in both human and rat pancreas. Expression of Grb10 was increased in islets isolated from rats fed a high-fat plus high-sugar diet compared with islets isolated from rats fed normal chow diet, as well as in INS 832/13 cells exposed to high levels of glucose (20 mmol/L), palmitate (1 mmol/L) and interleukin-1beta (50 U/mL). Overexpression of Grb10 in INS 832/13 cells or rat islets impaired GSIS compared with the respective control (all P < 0.05). Moreover, inhibition of GSIS by Grb10 overexpression was associated with a decrease in insulin- and IGF-1-induced Akt and extracellular signal-regulated kinase 1/2 phosphorylation. The results of the present study demonstrate that Grb10 is an important negative regulator of insulin/IGF-1 signalling in pancreatic beta-cells and a potential target to improve beta-cell function. PMID- 23937794 TI - Expression of TRAIL-splice variants in gastric carcinomas: identification of TRAIL-gamma as a prognostic marker. AB - BACKGROUND: TNF-related apoptosis inducing ligand (TRAIL) belongs to the TNF superfamily that induces apoptotic cell death in a wide range of neoplastic cells in vivo as well as in vitro. We identified two alternative TRAIL-splice variants, i.e. TRAIL-beta and TRAIL-gamma that are characterized by the loss of their proapoptotic properties. Herein, we investigated the expression and the prognostic values of the TRAIL-splice variants in gastric carcinomas. METHODS: Real time PCR for amplification of the TRAIL-splice variants was performed in tumour tissue specimens and corresponding normal tissues of 41 consecutive patients with gastric carcinoma. Differences on mRNA-expression levels of the TRAIL-isoforms were compared to histo-pathological variables and correlated with survival data. RESULTS: All three TRAIL-splice variants could be detected in both non-malignant and malignant tissues, irrespective of their histological staging, grading or tumour types. However, TRAIL-beta exhibited a higher expression in normal gastric tissue. The proapoptotic TRAIL-alpha expression was increased in gastric carcinomas when compared to TRAIL-beta and TRAIL-gamma. In addition, overexpression of TRAIL-gamma was associated with a significant higher survival rate. CONCLUSIONS: This is the first study that investigated the expression of TRAIL-splice variants in gastric carcinoma tissue samples. Thus, we provide first data that indicate a prognostic value for TRAIL-gamma overexpression in this tumour entity. PMID- 23937795 TI - Competence-based curriculum development for general practice in Germany: a stepwise peer-based approach instead of reinventing the wheel. AB - BACKGROUND: Improving postgraduate medical training is one important step to attract more medical students into general practice. Keeping pace with international developments moving to competence-based curricula for general practice training, the aim of this project was to develop and implement such a curriculum in Germany. METHODS: A five-step, peer-based method was used for the curriculum development process including panel testing and a "test version" of the curriculum for the pilot implementation phase. The CanMEDS framework served as a basis for a new German competence-based curriculum in general practice training. Four curricula from European countries and Canada were reviewed and, following required cultural adaptions, key strengths from these were integrated. For the CanMEDS "medical expertise" element of the curriculum, the WONCA ICPC-2 classification of patient's "reason for encounters" was also integrated. RESULTS: Altogether, 37 participants were involved in the development process representing 12 different federal states in Germany, and including an expert advisor from Denmark. An official "test version" of the curriculum consisting of three parts: medical expertise, additional competencies and medical procedures was established. A system of self-assessment for trainees was integrated into the curriculum using a traffic light scale. Since March 2012, the curriculum has been made freely available online as a "test version". In 2014, an evaluation is planned using feedback from users of the test model as a further stage of the implementation process. CONCLUSIONS: The first German competence-based curriculum for general practice training has been developed using a pragmatic peer controlled approach and implementation is being trialed with a "test version" of the curriculum. This model project and its peer-based methodology may support competence-based curriculum development for other medical specialties both inside and outside Germany. PMID- 23937796 TI - A retrospective review of patient-reported outcomes on the impact on quality of life in patients undergoing total abdominal hysterectomy and bilateral salpingo oophorectomy for endometriosis. AB - OBJECTIVE: The Endometriosis Health Profile-30 (EHP-30), an endometriosis specific health-related quality of life (HRQoL) questionnaire, forms part of our service evaluation of all women undergoing total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometriosis in our reproductive medicine unit. We used the EHP-30 to investigate patient-reported outcomes in all patients undergoing this procedure. STUDY DESIGN: Retrospective review of 16 women with endometriosis undergoing total abdominal hysterectomy and bilateral salpingo oophorectomy for debilitating symptoms after other modalities of treatment had failed. Patients completed EHP-30 questionnaires before the operation and again three months after surgery. RESULTS: Total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometriosis results in a significant improvement in HRQoL. The impact was greatest in the core domains--control and powerlessness, emotional wellbeing and social support. There was a 100% response rate for the core domains whereas in the modular domains, missing response rates ranged from 12.5% to 62.5%, with the percentage of missing data being greatest in the concern on infertility and relationship with children domains. Pain was significantly positively correlated with control and powerlessness, emotional wellbeing, work life and relationship with children. After multiple regression analyses, only control and powerlessness and emotional wellbeing were found to be predictive of pain. Additionally, changes in pain before and after total abdominal hysterectomy and bilateral salpingo-oophorectomy were significantly positively correlated with the changes in the core domains--control and powerlessness, emotional wellbeing and self image. After multiple regression analyses, change in pain was found to be predictive of DeltaControl and powerlessness in our study subjects. CONCLUSION: Total abdominal hysterectomy and bilateral salpingo-oophorectomy significantly improves HRQoL in patients debilitated by symptoms attributable to endometriosis and in whom other modalities of treatment have failed. PMID- 23937797 TI - Muscle force production with low and medium frequency burst modulated biphasic pulsed currents. AB - OBJECTIVE: Russian current, a medium frequency burst modulated alternating current (BMAC), is widely used for NMES, but has not been shown to elicit forces near voluntary maximum. In contrast, low frequency BMAC has been shown to produce greater force production than Russian and most recently, medium frequency burst modulated biphasic pulsed current (BMBPC) elicited greater force than Russian. Whether low frequency BMBPC yields greater force than medium frequency BMBPC is unknown. This study examined elicited forces using BMBPC with low and medium frequency carrier currents. DESIGN: A cross-over design where percent maximal isometric knee extensor forces (%MVIF) elicited using BMBPC with low or medium kilohertz carrier frequencies were compared in 23 subjects. Perceived discomfort was also assessed. Data were compared using paired samples t-tests. RESULTS: 98.4% of the MVIF was elicited with the low frequency BMBPC which was significantly greater (p < 0.001) than the 40.4% yielded by the medium frequency current. Cohen's d effect size of 2.146 indicated a "huge effect". Perceived discomfort of the low frequency current was 5.7/10 and was significantly greater (p < 0.001) than the medium frequency current (3.6/10). CONCLUSION: BMBPC with low frequency carrier current elicits forces approximating maximal volitional force. These findings offer new evidence with strong clinical implications when using NMES. PMID- 23937798 TI - Abnormal interhemispheric connectivity in male psychopathic offenders. AB - BACKGROUND: Psychopathic offenders inevitably violate interpersonal norms and frequently resort to aggressive and criminal behaviour. The affective and cognitive deficits underlying these behaviours have been linked to abnormalities in functional interhemispheric connectivity. However, direct neurophysiological evidence for dysfunctional connectivity in psychopathic offenders is lacking. METHODS: We used transcranial magnetic stimulation combined with electroencephalography to examine interhemispheric connectivity in the dorsolateral and motor cortex in a sample of psychopathic offenders and healthy controls. We also measured intracortical inhibition and facilitation over the left and right motor cortex to investigate the effects of local cortical processes on interhemispheric connectivity. RESULTS: We enrolled 17 psychopathic offenders and 14 controls in our study. Global abnormalities in right to left functional connectivity were observed in psychopathic offenders compared with controls. Furthermore, in contrast to controls, psychopathic offenders showed increased intracortical inhibition in the right, but not the left, hemisphere. LIMITATIONS: The relatively small sample size limited the sensitivity to show that the abnormalities in interhemispheric connectivity were specifically related to the dorsolateral prefrontal cortex in psychopathic offenders. CONCLUSION: To our knowledge, this study provides the first neurophysiological evidence for abnormal interhemispheric connectivity in psychopathic offenders and may further our understanding of the disruptive antisocial behaviour of these offenders. PMID- 23937801 TI - The distribution and diversity of benthic macroinvertebrate fauna in Pondicherry mangroves, India. AB - BACKGROUND: Species distribution, abundance and diversity of mangrove benthic macroinvertebrate fauna and the relationships to environmental conditions are important parts of understanding the structure and function of mangrove ecosystems. In this study seasonal variation in the distribution of macrobenthos and related environmental parameters were explored at four mangrove stations along the Pondicherry coast of India, from September 2008 to July 2010. Multivariate statistical analyses, including cluster analysis, principal component analysis and non-multidimensional scales plot were employed to help define trophic status, water quality and benthic characteristic at the four monitoring stations. RESULTS: Among the 528 samples collected over 168 ha of mangrove forest 76 species of benthic macroinvertebrate fauna were identified. Macrofauna were mainly composed of deposit feeders, dominated numerically by molluscs and crustaceans. Statistical analyses yielded the following descriptors of benthic macroinvertebrate fauna species distribution: densities between 140 1113 ind. m-2, dominance 0.17-0.50, diversity 1.80-2.83 bits ind-1, richness 0.47 0.74 and evenness 0.45-0.72, equitability 0.38-0.77, berger parker 0.31-0.77 and fisher alpha 2.46-5.70. Increases of species diversity and abundance were recorded during the post monsoon season at station 1 and the lowest diversity was recorded at station 2 during the monsoon season. The pollution indicator organisms Cassidula nucleus, Melampus ceylonicus, Sphaerassiminea minuta were found only at the two most polluted regions, i.e. stations 3 and 4. Benthic macroinvertebrate fauna abundances were inversely related to salinity at the four stations, Based on Bray-Curtis similarity through hierarchical clustering implemented in PAST, it was possible to define three distinct benthic assemblages at the stations. CONCLUSIONS: From a different multivariate statistical analysis of the different environmental parameters regarding species diversity and abundance of benthic macroinvertebrate fauna, it was found that benthic communities are highly affected by all the environmental parameters governing the distribution and diversity variation of the macrofaunal community in Pondicherry mangroves. Salinity, dissolved oxygen levels, organic matter content, sulphide concentration were the most significant parameters. PMID- 23937800 TI - Rectal endoscopy findings following stereotactic body radiation therapy for clinically localized prostate cancer. AB - BACKGROUND: Treating prostate cancer with SBRT could potentially minimize radiation proctitis by reducing high-dose rectal irradiation. In addition, it offers the potential radiobiologic benefits of hypofractionation. This study reports the endoscopic changes and the associated clinical rectal toxicity in these patients. METHODS: We reviewed the records of patients treated from 2008 2011 for localized prostate cancer who had rectal endoscopy following SBRT. SBRT was delivered either as primary treatment in 5 fractions of 7-7.25 Gy, or as an initial boost in 3 fractions of 6.5 Gy followed by conventionally fractionated radiotherapy to 45-50.4 Gy. Endoscopic changes were graded using the Vienna Rectoscopy Score (VRS). Rectal toxicity was graded via CTCAEv.4. Rectal quality of life (QOL) was assessed via the bowel domain of the EPIC-26 questionnaire. RESULTS: Fifty-one patients with a median 23 months follow-up were analyzed. Thirty-five patients completed SBRT monotherapy and 16 patients received SBRT as a boost to conventionally fractionated IMRT. The median interval from SBRT to rectal endoscopy was 13 months. Endoscopy revealed VRS Grade 1-2 telangiectasias for 10 patients and VRS Grade 1-2 mucosal edema for 12 patients. No rectal ulcerations, strictures or necrosis were observed. Grade 1-2 late rectal bleeding occurred in 10 patients. There were no CTCAEv.4 Grade >=3 toxicities. Mean EPIC bowel scores decreased from a baseline value of 96.9 to 82.3 at 1-month, but subsequently increased to 91.0 at 24 months. CONCLUSIONS: In this cohort that is skewed towards patients with rectal complaints, the rate and severity of endoscopic changes following SBRT is low. Rectal toxicity and QOL were comparable to patients treated with other radiation modalities. Prospective trials examining the endoscopic outcomes following SBRT for prostate cancer are needed for confirmation of the findings of this study. TRIAL REGISTRATION: The Georgetown Institutional Review Board has approved this retrospective study (IRB 2009-510). PMID- 23937802 TI - Acute lower respiratory infections on lung sequelae in Cambodia, a neglected disease in highly tuberculosis-endemic country. AB - BACKGROUND: Little is known about post-infectious pulmonary sequelae in countries like Cambodia where tuberculosis is hyper-endemic and childhood pulmonary infections are highly frequent. We describe the characteristics of hospitalized Cambodian patients presenting with community-acquired acute lower respiratory infections (ALRI) on post-infectious pulmonary sequelae (ALRIPS). METHODS: Between 2007 and 2010, inpatients >=15 years with ALRI were prospectively recruited. Clinical, biological, radiological and microbiological data were collected. Chest radiographs were re-interpreted by experts to compare patients with ALRIPS, on previously healthy lungs (ALRIHL) and active pulmonary tuberculosis (TB). Patients without chest radiograph abnormality or with abnormality suggestive as other chronic respiratory diseases were excluded from this analysis. RESULTS: Among the 2351 inpatients with community-acquired ALRI, 1800 were eligible: 426 (18%) ALRIPS, 878 (37%) ALRIHL and 496 (21%) TB. ALRIPS patients had less frequent fever than other ALRI (p < 0.001) and more productive cough than ALRIHL (p < 0.001). Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa accounted for 83% of ALRIPS group positive cultures. H. influenzae and P. aeruginosa were significantly associated with ALRIPS compared with ALRIHL. Treatment was appropriate in 58% of ALRIPS patients. Finally, 79% of ALRIPS were not recognized by local clinicians. In-hospital mortality was low (1%) but probably underestimated in the ALRIPS group. CONCLUSION: ALRIPS remains often misdiagnosed as TB with inappropriate treatment in low-income countries. Better-targeted training programs would help reduce the morbidity burden and financial costs. PMID- 23937803 TI - Development of skin hypopigmentation in a patient with metastatic papillary carcinoma thyroid treated with Sorafenib. AB - BACKGROUND: Sorafenib can be considered as the effective option of treatment in patients with metastatic radioiodine refractory differentiated thyroid cancers. The cutaneous manifestations of Sorafenib include rash, desquamation, hand foot skin reactions, pruritus, alopecia and erythema. We report the first case of hypopigmentation related to sorafenib therapy. CASE PRESENTATION: We report the case of a middle aged gentleman with metastatic papillary carcinoma of thyroid diagnosed in 2005. He was managed with total thyroidectomy, radioactive iodine and TSH suppressive therapy. Despite receiving radioactive iodine 530 mci cumulative dose, patient had persistant disease with lung metastasis. Therefore a TKI, sorafenib, was started. He developed hypopigmentation of the skin more prominent on face six weeks after starting sorafenib treatment.He also developed diarrhea, desquamation of hands and feet, hair loss over scalp, eye brows and moustache. Sorafenib treatment was discontinued. His diarrhea stopped in one week and after four weeks his skin became normalized whereas he regained his hairs in six weeks. CONCLUSION: To our knowledge, hypopigmentation in our patient appears to be the first reported of its kind in the literature to date. Sorafenib is used in Renal cell carcinoma, Hepatcellular carcinoma and radioactive iodine refractory thyroid carcinoma therefore it is very important to be aware of hypopigmentation as a potential side effect for both physicians and patients. PMID- 23937804 TI - Hybrid ZnO NR/graphene structures as advanced optoelectronic devices with high transmittance. AB - A hybrid structure (HS) made of one-dimensional ZnO nanorods (NRs) and a two dimensional synthesized graphene sheet was successfully constructed in this study. The uniform ZnO NRs were obtained by hydrothermal method and grown on a graphene surface that had been transferred to a polyethylene terephthalate substrate. The HS exhibited high transmittance (approximately 75%) over the visible wavelength range, even after cyclic bending with a small radius of curvature. Raman spectroscopy and Hall measurement were carried out to verify the chemical composition and electrical properties of the structure. Stable electrical conductance of the ZnO NR/graphene HS was achieved, and increase in carrier mobility decreased the resistance of the ZnO-with-graphene sheet in comparison with bare ZnO NRs. PMID- 23937805 TI - Measurements of radon concentration levels in thermal waters in the region of Konya, Turkey. AB - (222)Rn (radon) is one of the most important sources of natural radiation to which people are exposed. It is an alpha-emitting noble gas and it can be found in various concentrations in soil, air and in different kinds of water. In this study, we present the results of radon concentration measurements in thermal waters taken from the sources in the region of Konya located in the central part of Turkey. The radon activity concentrations in 10 thermal water samples were measured by using the AlphaGUARD PQ 2000PRO radon gas analyser in spring and summer of the year 2012. We found that radon activity concentrations range from 0.60+/-0.11 to 70.34+/-3.55 kBq m(-3) and from 0.67+/-0.03 to 36.53+/-4.68 kBq m( 3) in spring and summer, respectively. We also calculated effective doses per treatment in the spas for the spring and summer seasons. It was found that the minimum and maximum effective doses per treatment are in the range of 0.09-10.13 nSv in spring and in the range of 0.1-5.26 nSv in summer. PMID- 23937806 TI - Group A streptococcal necrotizing fasciitis in the emergency department. AB - BACKGROUND: Group A Streptococcal (GAS) necrotizing fasciitis is a critical emergency. Patients with necrotizing fasciitis principally present to emergency departments (EDs), but most studies are focused on hospitalized patients. OBJECTIVE: An ED patient-based retrospective study was conducted to investigate the clinical characteristics, associated factors, and outcomes of GAS necrotizing fasciitis in the ED. METHODS: Patients visiting the ED from January 2005 through December 2011 with the diagnosis of GAS necrotizing fasciitis were enrolled. All patients with the diagnosis of noninvasive skin and soft-tissue infections caused by GAS were included as the control group. RESULTS: During the study period, 75 patients with GAS necrotizing fasciitis were identified. Males accounted for 84% of patients. The most prevalent underlying disease was diabetes mellitus (45.3%). Bullae were recognized in 37.3% of patients. One third of cases were complicated by bacteremia. Polymicrobial infections were found in 30.7% of patients. Overall mortality rate for GAS necrotizing fasciitis was 16%. Patients aged >60 years with diabetes mellitus, liver cirrhosis, and gout were considerably more likely to have GAS necrotizing fasciitis than noninvasive infections. Patients presenting with bacteremia, shock, duration of symptoms/signs <5 days, low white blood cell count, low platelet count, and prolonged prothrombin time were associated with increased mortality. Surgery is a significantly negative factor for mortality of patients with GAS necrotizing fasciitis (odds ratio = 0.16; 95% confidence interval 0.002-0.16; p < 0.001). CONCLUSIONS: A better understanding of the associated factors and initiation of adequate treatments will allow for improved survival after GAS necrotizing fasciitis. PMID- 23937807 TI - Satisfaction and emergency department revisits in patients with possible acute coronary syndrome. AB - BACKGROUND: Patients with possible acute coronary syndrome (ACS) are typically instructed to return to the emergency department (ED) if their condition worsens. Little is known about the relationship between patient satisfaction in the ED and subsequent return visits. OBJECTIVE: Our aim was to determine the association between satisfaction with ED care and subsequent ED return visits. METHODS: One thousand and five consecutive ED patients with symptoms of possible ACS who participated in a prospective guideline implementation trial at two university hospitals completed a telephone survey at 30-day follow-up. Satisfaction with care at the initial ED visit was measured using items from the Press Ganey satisfaction questionnaire. Logistic regression was used to determine the association between individual satisfaction items and the occurrence of any ED revisits, and the association between satisfaction items and return visits to the same ED. RESULTS: Patients who reported superior ratings of person-centered care ("staff cared about you as a person") were significantly less likely to return to any ED during 30-day follow-up: 59 vs. 71%, adjusted odds ratio = 0.57 (95% confidence interval 0.37-0.87). Among those with ED revisits, superior ratings of personal care and perceived waiting time for emergency physician evaluation were significantly associated with return to the same ED. CONCLUSIONS: Although diagnostic workup and risk stratification are the primary focus in evaluating patients with possible ACS, greater attention to the patient's experience of care may have the positive impact of reducing ED return visits and increasing the likelihood that patients will return to the same ED for re-evaluation. PMID- 23937808 TI - Focused cardiac ultrasound diagnosis of thoracic aortic aneurysm: two cases. AB - BACKGROUND: Thoracic aortic aneurysms (TAAs) are less prevalent than abdominal aortic aneurysms. Symptomatic TAAs need to be identified quickly by the emergency physician (EP) since mortality rates increase dramatically once complications such as rupture or dissection occur. Compared with validated EP-performed ultrasound of the abdominal aorta, EP-performed focused cardiac ultrasound that includes evaluation of the thoracic aorta is relatively unreported. OBJECTIVE: Two cases illustrate EP-performed focused cardiac ultrasound and evaluation of the thoracic aorta for aneurysmal dilation. CASE REPORTS: (1) A 60-year-old man presented to the emergency department (ED) after a blunt traumatic injury to his back while at work. During the focused cardiac ultrasound examination, the aortic outflow tract distal to the aortic valve appeared enlarged and the aortic root measured 5.49 cm. (2) An 82-year-old man with hypertension presented to the ED with 1 month of chest pain radiating to the back. The focused cardiac ultrasound examination demonstrated enlargement of the descending thoracic aorta at 4.82 cm. CONCLUSION: EPs performing focused cardiac ultrasound can visualize regions of the thoracic aorta that may reveal an aneurysm, particularly in the parasternal long axis view. PMID- 23937809 TI - Oxygen saturation can predict pediatric pneumonia in a resource-limited setting. AB - BACKGROUND: The World Health Organization (WHO) recommends using age-specific respiratory rates for diagnosing pneumonia in children. Past studies have evaluated the WHO criteria with mixed results. OBJECTIVE: We examined the accuracy of clinical and laboratory factors for diagnosing pediatric pneumonia in resource-limited settings. METHODS: We conducted a retrospective chart review of children under 5 years of age presenting with respiratory complaints to three rural hospitals in Rwanda who had received a chest radiograph. Data were collected on the presence or absence of 31 historical, clinical, and laboratory signs. Chest radiographs were interpreted by pediatric radiologists as the gold standard for diagnosing pneumonia. Overall correlation and test characteristics were calculated for each categorical variable as compared to the gold standard. For continuous variables, we created receiver operating characteristic (ROC) curves to determine their accuracy for predicting pneumonia. RESULTS: Between May 2011 and April 2012, data were collected from 147 charts of children with respiratory complaints. Approximately 58% of our sample had radiologist-diagnosed pneumonia. Of the categorical variables, a negative blood smear for malaria (chi(2) = 6.21, p = 0.013) and the absence of history of asthma (chi(2) = 4.48, p = 0.034) were statistically associated with pneumonia. Of the continuous variables, only oxygen saturation had a statistically significant area under the ROC curve (AUC) of 0.675 (95% confidence interval [CI] 0.581-0.769 and p = 0.001). Respiratory rate had an AUC of 0.528 (95% CI 0.428-0.627 and p = 0.588). CONCLUSION: Oxygen saturation was the best clinical predictor for pediatric pneumonia and should be further studied in a prospective sample of children with respiratory symptoms in a resource-limited setting. PMID- 23937810 TI - Lifelong learning and self-assessment is relevant to emergency physicians. AB - BACKGROUND: The Lifelong Learning and Self-assessment (LLSA) component of the American Board of Emergency Medicine (ABEM) Maintenance of Certification (MOC) program is a self-assessment exercise for physicians. Beginning in 2011, an optional continuing medical education (CME) activity was added. OBJECTIVES: As a part of a CME activity option for the LLSA, a survey was used to determine the relevancy of the LLSA readings and the degree to which medical knowledge garnered by the LLSA activity would modify clinical care. METHODS: Survey results from the 2011 LLSA CME activity were reviewed. This survey was composed of seven items, including questions about the relevancy of the readings and the impact on the physician's clinical practice. The questions used a 5-point Likert scale and data underwent descriptive analyses. RESULTS: There were 2841 physicians who took the LLSA test during the study period, of whom 1354 (47.7%) opted to participate in the 2011 LLSA CME activity. All participants completed surveys. The LLSA readings were reported to be relevant to the overall clinical practice of Emergency Medicine (69.6% strongly relevant, 28.1% some relevance, and 2.3% little or no relevance), and provided information that would likely help them change their clinical practices (high likelihood 38.8%, some likelihood 53.0%, little or no change 8.2%). CONCLUSIONS: The LLSA component of the ABEM MOC program is relevant to the clinical practice of Emergency Medicine. Through this program, physicians gain new knowledge about the practice of Emergency Medicine, some of which is reported to change physicians' clinical practices. PMID- 23937811 TI - The flatness index of inferior vena cava is useful in predicting hypovolemic shock in severe multiple-injury patients. AB - BACKGROUND: Computed tomography (CT) signs of hypovolemic shock have been reported previously. Whether these signs can be used to clinically predict hypovolemic shock remains unclear. OBJECTIVE: To investigate the predictive value of CT signs for hypovolemic shock in severe multiple-injury patients. METHODS: The clinical and multi-slice spiral CT (MSCT) data from 63 severe multiple-injury patients admitted to our trauma center from January 2008 to December 2011 were reviewed. The caliber of the inferior vena cava (IVC) and abdominal aorta, and mean CT value of the abdominal organs in both the early and the delayed phases were measured. The patients were divided into two groups, a shock group (n = 34) and a stable group (n = 29), based on the occurrence of hypovolemic shock within 24 h after the CT scan. Receiver operating characteristic curve (ROC) analysis was performed to assess the predictive accuracy of these signs for hypovolemic shock. RESULTS: The shock group, compared to the stable group, had a higher Injury Severity Score (30 +/- 8 vs. 22 +/- 6, respectively, p < 0.001), shock index (1.17 +/- 0.37 vs. 0.96 +/- 0.33, respectively, p = 0.019), and lactate level (3.27 +/- 0.69 mmol/L vs. 2.56 +/- 0.89 mmol/L, respectively, p = 0.001). Among all the CT signs, the flatness index of IVC had the largest area under the curve (0.833) in ROC analysis, with sensitivity of 73.5% and specificity of 86.2%, higher than traditional indices and other CT signs. The optimal diagnostic cutoff value for the flatness index of IVC was 3.02. CONCLUSION: MSCT can provide useful information for predicting hyovolemic shock in severe multiple-injury patients. An IVC flatness index > 3.02 suggests the presence of hypovolemic shock in severe multiple-injury patients. PMID- 23937812 TI - Fatal infant myocardial infarction caused by ball-IN-valve mechanism from a dysplastic aortic valve. AB - BACKGROUND: Acute myocardial infarction (AMI) can occur in infants. Early identification of AMI can allow for specific therapies aimed at improving patient outcomes. OBJECTIVE: This article describes a case of an infant with AMI caused by a previously unreported mechanism and reviews diagnostic and therapeutic strategies for dealing with this rare disease. CASE REPORT: We present a case of a 5-week-old infant with a fatal AMI due to a pedunculated nodule from a dysplastic aortic valve leaflet creating a ball-in-valve mechanism and occluding the left main coronary artery. CONCLUSION: AMI is an important diagnostic consideration in any infant presenting with signs of unexplained cardiogenic shock. Practitioners who care for children should be aware of diagnostic and therapeutic strategies for AMI in infants. PMID- 23937813 TI - Atrial fibrillation with rapid ventricular response resulting from low-voltage electrical injury. AB - BACKGROUND: Cardiac dysrhythmias after electrical injury have been reported previously, however, atrial fibrillation after low-voltage electrical injury is extremely rare. We present a case of atrial fibrillation with rapid ventricular response resulting from a low-voltage electrical injury. CASE REPORT: A 24-year old active duty Navy sailor presented to the emergency department after an electrical shock from a 440-V furnace. He experienced severe pain in both hands and a racing sensation in his chest. He denied other symptoms. An electrocardiogram was performed demonstrating atrial fibrillation with a rapid ventricular response (132 beats/min). After analgesia and sedation, synchronized cardioversion (100 J) was performed with complete resolution of cardiac symptoms and restoration of normal sinus rhythm (75 beats/min). Cutaneous wounds were bandaged and the patient was discharged with cardiology follow-up. At follow-up, the patient reported no symptoms and an echocardiogram revealed no structural abnormalities. CONCLUSIONS: Atrial fibrillation in the setting of electrical injury is rarely reported in the published medical literature. In patients without history suggestive of cardiac structural abnormalities, synchronized cardioversion is a potential option for restoration of normal sinus rhythm and resolution of symptoms after electrical injury-induced atrial fibrillation with rapid ventricular response. PMID- 23937814 TI - Reconstruction of elasticity: a stochastic model-based approach in ultrasound elastography. AB - BACKGROUND: The convectional strain-based algorithm has been widely utilized in clinical practice. It can only provide the information of relative information of tissue stiffness. However, the exact information of tissue stiffness should be valuable for clinical diagnosis and treatment. METHODS: In this study we propose a reconstruction strategy to recover the mechanical properties of the tissue. After the discrepancies between the biomechanical model and data are modeled as the process noise, and the biomechanical model constraint is transformed into a state space representation the reconstruction of elasticity can be accomplished through one filtering identification process, which is to recursively estimate the material properties and kinematic functions from ultrasound data according to the minimum mean square error (MMSE) criteria. In the implementation of this model-based algorithm, the linear isotropic elasticity is adopted as the biomechanical constraint. The estimation of kinematic functions (i.e., the full displacement and velocity field), and the distribution of Young's modulus are computed simultaneously through an extended Kalman filter (EKF). RESULTS: In the following experiments the accuracy and robustness of this filtering framework is first evaluated on synthetic data in controlled conditions, and the performance of this framework is then evaluated in the real data collected from elastography phantom and patients using the ultrasound system. Quantitative analysis verifies that strain fields estimated by our filtering strategy are more closer to the ground truth. The distribution of Young's modulus is also well estimated. Further, the effects of measurement noise and process noise have been investigated as well. CONCLUSIONS: The advantage of this model-based algorithm over the conventional strain-based algorithm is its potential of providing the distribution of elasticity under a proper biomechanical model constraint. We address the model-data discrepancy and measurement noise by introducing process noise and measurement noise in our framework, and then the absolute values of Young's modulus are estimated through the EFK in the MMSE sense. However, the initial conditions, and the mesh strategy will affect the performance, i.e., the convergence rate, and computational cost, etc. PMID- 23937815 TI - [Type 2 diabetes mellitus: new treatments]. AB - The benefits and problems associated with traditional hypoglycemic drugs, such as failure of beta cells, hypoglycemia and weight gain, that lead to a worsening of diabetes, are reviewed. New hypoglycemic drugs with incretin effect (glucagon like peptide-1 agonists and dipeptidyl peptidase 4 inhibitors), achieve, in a glucose dependent manner, an glycosylated hemoglobin reduction without hypoglycemia or increase in body weight. Recently, another group of oral hypoglycemic drugs, sodium-glucose cotransporter type 2 inhibitors, have demonstrated efficacy in diabetes control by inhibiting renal glucose reabsorption. However, long-term effects and cardiovascular prevention remain to be demonstrated. We have more and better drugs nowadays. Hypoglycemic treatment should be customized (glycosylated hemoglobin levels, risk-benefit, risk of hypoglycemia, weight changes, cardiovascular risk), with a combination of drugs being necessary in most cases. However, we do not have yet an ideal hypoglycemic drug. Moreover we must remember that an early and intensive treatment of dyslipidemia and hypertension is essential for the prevention of cardiovascular disease in patients with type 2 diabetes. PMID- 23937816 TI - [Resting heart rate and cardiovascular disease]. AB - Heart rate reflects autonomic nervous system activity. Numerous studies have demonstrated that an increased heart rate at rest is associated with cardiovascular morbidity and mortality as an independent risk factor. It has been shown a link between cardiac autonomic balance and inflammation. Thus, an elevated heart rate produces a micro-inflammatory response and is involved in the pathogenesis of endothelial dysfunction. In turn, decrease in heart rate produces benefits in congestive heart failure, myocardial infarction, atrial fibrillation, obesity, hyperinsulinemia, insulin resistance, and atherosclerosis. Alteration of other heart rate-related parameters, such as their variability and recovery after exercise, is associated with risk of cardiovascular events. Drugs reducing the heart rate (beta-blockers, calcium antagonists and inhibitors of If channels) have the potential to reduce cardiovascular events. Although not recommended in healthy subjects, interventions for reducing heart rate constitute a reasonable therapeutic goal in certain pathologies. PMID- 23937817 TI - [Atrial myxoma]. PMID- 23937818 TI - [Lung transplantation in sporadic lymphangioleiomyomatosis: study of 7 cases]. AB - BACKGROUND AND OBJECTIVE: Sporadic lymphangioleiomyomatosis (S-LAM) is a rare disease that affects only women. It is characterized by an abnormal proliferation of immature smooth muscle cells (LAM cells) that grow in an aberrant manner in the airway, parenchymal lung lymph and blood vessels, determining the onset of pulmonary cystic lesions. The disease has no treatment, progressing to respiratory failure, and lung transplantation (LT) may be a treatment option at this stage. Our goal was to study 7 patients undergoing LT for S-LAM. MATERIAL AND METHOD: We studied a series of clinical and demographic characteristics, diagnostic modality and post-transplant outcomes. We performed a descriptive analysis of the series. The Kaplan-Meier method was used to estimate survival. RESULTS: The mean age of onset of symptoms was 35 years, the diagnosis of 37 years and that of LT 38 years. The most common symptom was dyspnea. Four patients had a history of pneumothorax and pleural effusion. The mean forced expiratory volume in one second was 32.7% and the diffusing capacity for carbon monoxide was 29%. All patients were subjected to LT and survival was 100, 85.7 and 57.1% at one, 3 and 5 years, respectively. Three died of bronchiolitis obliterans and 2 necropsies did not show evidence of disease recurrence. CONCLUSIONS: LT is a therapeutic option in patients with S-LAM with an advanced respiratory functional impairment. PMID- 23937819 TI - [Current issues of adult-onset Still's disease]. PMID- 23937820 TI - [Chest pain of 48 hours of evolution in a 41 years-old man]. PMID- 23937821 TI - [Idiopathic granulomatous lobular mastitis: A case report]. PMID- 23937822 TI - Polyarthropathy in type 2 diabetes patients treated with DPP4 inhibitors. AB - Dipeptidyl peptidase-4 inhibitors (DPP-4Is) inhibit the inactivation of incretin hormones while also affecting the immune system, since CD26/DPP-4 is involved in immune regulation. The current study shows that the use of DPP-4Is as therapy for type 2 diabetes patients may induce joint symptoms with decrease in plasma SDF 1alpha level. PMID- 23937823 TI - Appendicitis in adults with incidental midgut malrotation: CT findings. AB - AIM: To report the computed tomography (CT) findings of acute and complicated appendicitis in adults with incidental midgut malrotation. MATERIALS AND METHODS: The medical records and CT studies of eight patients with appendicitis and incidental midgut malrotation who presented to two medical centres between 1998 and 2009 were reviewed. RESULTS: All patients presented with 1-5 days of acute abdominal pain, which was diffuse in two, left-sided in two, lower abdominal in two, and in the right lower quadrant in two patients. The inflamed appendix was right-sided in three, left-sided in three, and in the midline in two patients. Three cases were complicated by a peri-appendicular abscess, and one patient also had a small bowel obstruction. All patients had a complete non-rotation with right-sided duodenum and jejunum, and left-sided colon. All eight patients had an abnormal superior mesenteric artery-superior mesenteric vein (SMA/SMV) relationship and a dysplastic uncinate process of the pancreas. Urgent surgery was performed in six patients and the remaining two were treated conservatively. CONCLUSION: Altered anatomy in malrotation affects the typical clinical and CT findings of acute appendicitis, therefore delaying diagnosis. When CT shows focal inflammation anywhere within the abdomen, along with an abnormal SMA/SMV relationship, the position of the caecum should be ascertained and acute appendicitis ruled out. PMID- 23937824 TI - CT of the neonatal head. AB - Computed tomography (CT) is used less often than other techniques on neonatal units. However, in the acute setting, CT can be invaluable in diagnosing or excluding potentially life-threatening conditions and guiding initial management in neonates. Common indications for scanning include trauma, suspected non accidental injury, infection, or an acute hypoxic or metabolic event. The aim of this review is to provide an overview of the normal neonatal head at CT and compare this to the common pathological abnormalities. Several key features of each condition will be highlighted. It is important to note that some pathological conditions can have overlapping features at CT and, therefore, the clinical history and additional investigations are also of key importance in determining the diagnosis. PMID- 23937825 TI - Imaging appearances for recurrent nasopharyngeal carcinoma and post-salvage nasopharyngectomy. AB - Nasopharyngeal carcinoma (NPC) is a head and neck neoplasm that occurs in endemic numbers among people of southern Chinese descent. External beam radiation to the nasopharyngeal bed and primary draining lymph node echelons is the mainstay of treatment with concurrent cisplatin-based chemotherapy for more advanced disease. Detection of residual and/or recurrent NPC has important clinical implications, as salvage protocols are available. The review aims to increase awareness of the imaging features of NPC recurrences at local and distant sites using computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET). Important changes in imaging seen in patients after nasopharyngectomy are also discussed. PMID- 23937826 TI - Fibrous tumours of the ovary: aetiologies and MRI features. AB - The ovaries can be affected by a vast variety of tumours, which may be benign or malignant, solid or cystic. Although ultrasonography is often the first examination performed in the evaluation of gynaecological conditions, magnetic resonance imaging is nowadays the most accurate imaging technique in the characterization of ovarian masses. Once the ovarian origin of a pelvic mass has been determined, the detection of any fibrous component within the lesion significantly reduces the spectrum of aetiologies that should be considered. Fibrotic tissue usually displays marked low-signal intensity on T2-weighted sequences at MRI, and enhancement is mostly moderate after intravenous administration of gadolinium chelates. This review aims to provide the main diagnoses to consider at MRI whenever an ovarian tumour, both purely solid or solid and cystic, contains a fibrous component, even if minimally abundant. The corresponding key imaging features are provided. PMID- 23937827 TI - Radiological approach to a child with hip pain. AB - Hip pain in a child can be a diagnostic challenge partly because of barriers to communication in the paediatric age group. Pain or limp may result from infective, inflammatory, traumatic, neoplastic, or developmental causes. A meticulous history and detailed clinical examination guide the radiological investigation in the appropriate direction. The age of the child further helps to narrow the differential as certain diseases are more common in certain age groups. In most patients plain radiograph and/or ultrasound is adequate. Ultrasound has the added advantage of being real time and can be used to guide aspiration. Magnetic resonance imaging (MRI) and bone scintigraphy can be used for problem solving, looking for multifocal disease, and staging. Computed tomography (CT) has a limited role to play because of the risks associated with ionizing radiation. In this review we discuss the approach to imaging a child who presents with pain in the hip or with a limp. The various common and rare, but important, diseases are illustrated with examples from our clinical practice. PMID- 23937828 TI - Prevalence of cerebral aneurysms in patients treated for left cardiac myxoma: a prospective study. AB - AIM: To estimate the prevalence of cerebral aneurysms in patients previously treated for left cardiac myxoma (LCM). MATERIALS AND METHODS: This prospective institutional review board-approved study included patients treated for LCM. All patients treated at our institution (IRCCS Policlinico San Donato, Italy) were telephoned and those enrolled underwent unenhanced brain magnetic resonance imaging (MRI) using sagittal T1-weighted turbo spin-echo (TSE); axial T2-weighted TSE; axial fluid-attenuated inversion-recovery; axial echo-planar diffusion weighted; and three-dimensional time-of-flight angiographic sequences. RESULTS: Seventy-six patients were telephoned, and data regarding their clinical history since tumor resection were obtained for 49 patients (64%). Four of the 49 (8%) patients were deceased, one due to a cerebral hemorrhage from a ruptured cerebral aneurysm 8 years after tumor resection. One patient had a pacemaker preventing MRI. Of the remaining 44 patients, 31 refused MRI and 13 were enrolled (10 females; mean age 64 years). Three of the 13 (23%; two females; 59-78 years) were diagnosed with a cerebral aneurysm, from 2 mm to 4-5 mm in diameter, involving the right middle cerebral artery (n = 2) or the right internal carotid artery (n = 1). Including the deceased patient, the resulting prevalence was 4/14 (29%). CONCLUSION: From this preliminary study, one-third of patients treated for LCM may present with a cerebral aneurysm. Longitudinal large studies are needed to further clarify this matter. PMID- 23937829 TI - A systematic review of surgical techniques used in the treatment of female urethral stricture. AB - CONTEXT: Female urethral stricture (FUS) is a rare and challenging clinical entity. Several new surgical techniques have been described for the treatment of FUS, although with the limited number of reports, there is no consensus on best management. OBJECTIVE: We evaluated the evidence for surgical interventions reported for treating FUS. EVIDENCE ACQUISITION: We performed a systematic review of the PubMed and Scopus databases, classifying the results by surgical technique and type of graft in the case of graft augmentation urethroplasty. EVIDENCE SYNTHESIS: A total of 221 patients have been reported on with outcome measures after intervention for FUS. The mean age of women was 51.8 yr of age (range: 22 91). All studies were retrospective case series. There was no consistent definition of FUS nor unified diagnostic criteria. Most studies used a combination of diagnostic tests. Where aetiology was defined, idiopathic and iatrogenic stricture were the two most common causes. Ninety-eight patients underwent prior intervention for FUS, mostly urethral dilatation or urethrotomy. Success was defined as the lack of need for further intervention. Urethral dilatation, assessed in 107 patients, had a mean success rate of 47% at a mean follow-up of 43 mo. Fifty-eight patients had vaginal or labial flap augmentation, with a mean success rate of 91% at 32.1 mo of mean follow-up. Vaginal or labial graft augmentation had a mean success rate of 80% in 25 patients at a mean follow up of 22 mo. Oral mucosal augmentation, performed in 32 patients, had a mean success rate of 94% at 15 mo of mean follow-up. No instances of de novo stress incontinence were reported. CONCLUSION: The techniques of urethroplasty all have a higher mean success rate (80-94%) than urethral dilatation (<50%), although with shorter mean follow-up. Urethroplasty in experienced hands appears to be a feasible option in women who have failed urethral dilatation, although there is a lack of high-level evidence to recommend one technique over another. PMID- 23937830 TI - [Relationship between the clustering of risk factors and the prevalence of hypertension in the community residents living in Shanghai]. AB - OBJECTIVE: To study the association between the clustering manifestation of factors as overweight and central obesity, family heredity, immoderate alcohol drinking, tobacco smoking, hyperlipidemia, hyperglycemia and the prevalence of hypertension. METHODS: Data was from a program related to the comprehensive prevention and control strategies on cardiac-cerebral vascular disease carried out in the communities of Shanghai, to describe the relationship between the clustering of risk factors and hypertension. This program included 15 158 people with complete data at the age of 35 - 74, from 2008 - 2011. Both single factor and multi-factor analysis were used and longitudinal study was performed to further explore the causal relationship. RESULTS: The overall prevalence of hypertension at the baseline survey was 41.9%. The associated ORs (age-adjusted) of hypertension parallelly increased with the number of risk factors under clustering. The associated OR of the males with 1, 2, 3, 4 as well as 5 and above risk factors were 3.157 [95% confidence interval (CI): 2.152 - 4.630], 6.428 (95%CI: 4.435 - 9.319), 11.797 (95%CI: 8.135 - 17.105), 19.723 (95%CI: 13.414 - 29.000), 33.051 (95%CI: 21.449 - 50.930) respectively. In females with 1, 2, 3 as well as 4 risk factors, the associated ORs were 2.917 (95%CI: 2.374 - 3.585), 6.499 (95%CI: 5.307 - 7.959), 15.717 (95%CI: 12.609 - 19.591) and 31.719 (95%CI: 21.744 - 46.270), respectively. For longitudinal study, the 2-year incidence of hypertension in males and females were 1.9% and 1.6%, respectively. Compared to those people without risk factors, the incidence was higher in the people with a larger number of clustering. When the clustering number reaching 2 or 3 in females, the relative risk (RR) were 2.111 (95%CI: 1.024 - 4.350) and 3.000 (95%CI: 1.287 - 6.995) respectively, with statistically significant difference. CONCLUSION: The risk of hypertension parallelly increased with the clustering number of relevant risk factors. Comprehensive prevention and control on related risk factors was required. PMID- 23937831 TI - [Prevalence and risk factors of pre-hypertension among adults of Zhejiang province]. AB - OBJECTIVE: To access the prevalence rates of pre-hypertensive patients at different stages and its associated risk factors among adults of Zhejiang province. METHODS: Study subjects were selected among local residents aged >= 18 years from 15 counties by multi stage stratified cluster random sampling method, from July to November, 2010. Each participant was required to complete questionnaire, physical examination and testing for overnight fasting blood specimen. RESULTS: 17 437 residents were surveyed including 8169 males and 9268 females. The overall prevalence of prehypertension was 34.39%. The prevalence of pre-hypertension appeared to be higher in males (38.57%) than in females (30.70%) (chi(2) = 119.36, P < 0.0001). The prevalence of pre-hypertension decreased with the increase of age in males who were above 25 year olds (chi(2) = 76.94, P < 0.0001) and in females who were above 45 year olds (chi(2) = 114.66, P < 0.0001). The prevalence of pre-hypertension appeared to be higher in the rural (35.60%) than in the urban (32.39%) areas (chi(2) = 18.69, P < 0.0001). Data from multivariable logistic regression showed that factors as being male, aged older than 35 years of age, with waist circumference as >= 85 cm for men and >= 80 cm for women, body mass index >= 25.0 kg/m(2) and triglyceride >= 1.7 mmol/L were risk factors of pre-hypertension while having had higher education was a protective factor. CONCLUSION: Pre-hypertension was prevalent among adults residents in Zhejiang province. Factors as overweight, obesity, dyslipidemia appeared to be major risk factors for pre-hypertension. PMID- 23937832 TI - [Seasonal variation of blood pressure and related factors in Chinese adults: a survey of over 50 000 people in Suzhou, China]. AB - OBJECTIVE: Seasonal variation in blood pressure had been observed in several studies on Western populations, but uncertainty remains about the strength of the relationship in other populations and the extent to which it was modified by other factors. METHODS: This study was based on cross-sectional data from the China Kadoorie Biobank study with 53 260 men and women from the Suzhou area involved. Linear regression model was used to analyze the association of blood pressure with outdoor temperature-overall and in various subgroups. RESULTS: Blood pressure varied with the seasons, ascending in winter and descending in summer. The difference in systolic blood pressure (SBP) between summer and winter was 8.8 mm Hg in men and 7.0 mm Hg in women. SBP was inversely correlated with outdoor temperature, especially above 10 degrees C, with every 10 degrees C colder temperature causing 6.1 mm Hg increase of SBP. The seasonal variation in SBP was more obviously seen in older people and in those with lower body mass index. CONCLUSION: Blood pressure was strongly and inversely associated with outdoor temperature in the population in Suzhou area. Seasonal variation of blood pressure should be considered when the hypertension screening programs, clinical management and data management on hypertensive patients. PMID- 23937833 TI - [Study on the association of oral contraceptives, angiotensinogen gene polymorphisms and the risk of stroke in women]. AB - OBJECTIVE: To evaluate the associations of oral contraceptives (OC) exposure, angiotensinogen (AGT) gene polymorphism and joint effects on the risk of stroke in Chinese women. METHODS: On the basis of a prospective female cohort of contraceptive use, the first-ever-developed (FED) stroke cases, as well as, two sets of age-(+/- 3 years) and region-matched controls (including neighborhoods and hospitalized patients) were recruited. Between 1 July 2000 and 30 June 2009, a total of 453 FED stroke cases and 919 controls were recruited. Genotyping for polymorphisms of AGT gene was detected by Taqman method. RESULTS: (1) The risk of stroke gradually increased with the cumulative time of OC use in women (P < 0.0001). Compared with the non-users, the risk of hemorrhagic stroke slightly increased among those with OC use (OR = 1.83, 95%CI: 1.25 - 2.66). (2) Women with AG/GG genotypes of A-6G locus or CA/AA genotypes of C11535A locus indicated that there was a slightly reduced risk of stroke (OR = 0.78, 95%CI: 0.61 - 0.99; OR = 0.73, 95%CI: 0.56 - 0.95). (3) Women with AA genotypes of A-20C locus and AG/GG genotypes of A-6G, when incorporated with CA/AA genotypes of C11535A locus with OC, it could increase the risk of hemorrhagic stroke (OR = 1.99, 95%CI: 1.34 - 2.97; OR = 1.84, 95%CI: 1.15 - 2.94; OR = 1.73, 95%CI: 1.06 - 2.85). CONCLUSION: The AGT gene polymorphisms showed that they did have an impact on the risk of stroke. And the joint effect between women using OC and AGT gene polymorphisms could slightly increase the risk of stroke. PMID- 23937834 TI - [Effects related to gene-gene interactions of peroxisome proliferator-activated receptor on essential hypertension]. AB - OBJECTIVE: To explore the impact of the gene-gene interaction among the single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptor alpha/delta/gamma on essential hypertension (EH). METHODS: Participants were recruited based on the previous work of the PMMJS (Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu Province) cohort study in Jiangsu province of China. A total number of 820 subjects were randomly selected from the cohort and received gene polymorphism detection covered ten SNPs:PPARalpha/delta/gamma (PPARalpha: rs135539, rs1800206 and rs4253778; PPARdelta: rs2016520 and rs9794; PPARgamma: rs10865710, rs1805192, rs4684847, rs709158 and rs3856806). Generalized Multifactor Dimensionality Reduction (GMDR) model was used to evaluate the association between gene-gene interaction among the ten SNPs and EH. RESULTS: After adjusting factors as gender, age, BMI, FPG, TG, HDL-C, high fat diet, low fiber diet and physical activity, results from the GMDR analysis showed that the best qualitative trait models were 7/9-dimensional model (EH: cross-validation consistency were 9/10 and 10/10, prediction accuracy were 0.5862 and 0.5885), 5/9-dimensional model (SBP:cross-validation consistency were 10/10 and 8/10, prediction accuracy were 0.6055 and 0.6011), and 8/9 dimensional model (DBP: cross-validation consistency both were 10/10, prediction accuracy were 0.5926 and 0.5972), while the best quantitative trait models were 4/5-dimensional model (SBP: cross-validation consistency were 10/10 and 8/10, prediction accuracy were 0.6111 and 0.6072), and 5-dimensional model (DBP: cross validation consistency were 9/10, prediction accuracy were 0.5753). CONCLUSION: Interactions among ten SNPs of PPARs seemed to have existed and with significant impact on the levels of blood pressure. PMID- 23937835 TI - [The impact of ambient particulate matter (PM10) on the population mortality for cerebrovascular diseases-a case-crossover study]. AB - OBJECTIVE: To analyze the association between the concentration of ambient inhalable particulate matter (PM10) and population mortality for cerebrovascular diseases and to explore the impact of PM10 on cerebrovascular diseases. METHODS: Data including meteorological factors, air pollutants (NO2, SO2 and PM10) and cerebrovascular disease mortality in one district of Beijing from 2004 to 2008 were collected and both symmetric bidirectional case-crossover design and conditional logistic regression model were used to analyze the associations among them. RESULTS: After adjusting the influence of meteorological factors as daily average temperature and relative humidity, the single pollutant model showed that there was no significant lag effect. In the multi-pollutant model, the effect of the every 105.43 ug/m(3) increase of ambient PM10 had a larger impact on the daily death of the cerebrovascular diseases with statistically significant difference (P < 0.05). The effect of ambient PM10 pollution on daily death of cerebrovascular diseases was significant for females, 65 year-olds and in winter season. CONCLUSION: Our data showed that elevated levels of ambient PM10 was positively associated with the increase of cerebrovascular disease mortality. The elevated levels of ambient PM10 could lead to the increase of the daily mortality on cerebrovascular diseases for females, elderly who were 65 or older and in winter seasons. PMID- 23937836 TI - [Epidemiological characteristics of metabolic syndrome among Kazakh children aged from 6 to 13 in Xinjiang, China]. AB - OBJECTIVE: This study was designed to evaluate the epidemiology and clinical characteristics on metabolic syndrome (MetS) among overweight and obese children aged from 6 to 13 years old in Kazakh ethnic populations. METHODS: Based on the data including body mass index (BMI), waist circumference (WC) and blood pressure measured from the 'Kazakh ethnic child Health examination study in Yili', 5360 Kazakh children aged 6 - 13 were screened for overweight and obesity in Xinjiang, using the Chinese BMI cutoffs for schoolchildren (7 - 18 years) and WHO growth reference for school-aged children and adolescents (6 year). Simultaneously a group of children with normal BMI were selected as the control group. Fasting plasma glucose (FPG), insulin (FINS), serum high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) were examined. HOMA-IR index was calculated to estimate the individual insulin resistance. Children under study were older than or equal to 10 years and met the criteria according to the definition of metabolic syndrome, prophylaxis and treatment on Chinese children and adolescents, proposed by the Society of Pediatrics in China or NCEP-ATPIII definition as MetS. Risk factors related to cardiovascular diseases were analyzed according to the criteria by the Society of Pediatrics among those aged from 6 to 10 years old children. Connection between waist-to-height ratio (WHtR) and biochemical indexes was explored. RESULTS: Prevalence rates of MetS according to the criteria from Society of Pediatrics in China were: 0%, 9.57%, 19.64% in the normal weight, overweight and obese children, respectively. The rates diagnosed by NCEP-ATPIII definition were 0.64%, 2.61%, 16.07% respectively. The detective rates of individual MetS component among obese children were: 78.95% for abdominal obesity, 29.82% for elevated BPs, 26.32% for high TG, 22.81% for low HDL-C, 0.88% for FPG. High TG (31.15%), abdominal obesity (23.77%) and low HDL-C (22.95%) appeared as the leading three abnormal indices among the overweight children. With increased BMI, the clustering of MetS components were also remarkably increasing. The detective rates of cardiovascular-related risk factors among overweight or obesity children from 6 to 10 years old were:abdominal obesity or obesity, low HDL-C, high TG, impaired FPG, elevated BPs. Differences were seen between overweight or obesity children and normal weight children on the detective rates of high TG, low HDL-C, abdominal obesity or obesity. WHtR was related with FINS, HOMA-IR index and LDL-C. CONCLUSION: MetS seemed epidemic among obese Hazakh children. Abdominal obesity, elevated BPs and high TG were the leading three abnormal factors among obese children. Compare to NCEP-ATPIII, abnormal biochemical indices on overweight Kazakh children seemed to be more sensitive, proposed by the Society of Pediatrics in China. PMID- 23937837 TI - [Pre-conceptive factors on the birth ponderal index]. AB - OBJECTIVE: To analyze the pre-conceptive factors on birth ponderal index (PI). METHODS: Fourteen towns were selected randomly from the 37 towns of Liuyang county, Hunan province, through cluster sampling in a prospective cohort study. Information was collected on all the women registered at the Maternity and Child Care Departments, and were planning to give birth in the coming year plus willing to receive a blood test and then followed-up until delivery. Single factor analysis would involve chi-square test and correlation analysis, while the multiple-factor analysis would adopt binary logistic regression method. RESULTS: A total of 1368 women were recruited in the cohort and 611 of them had a delivery of one child. Means of birth weight, birth length, and birth PI were (3.26 +/- 0.43) kg, (50 +/- 0.46) cm and 26.08 +/- 3.43, respectively. Data from the multiple stepwise regression analysis showed that income (OR = 6.920, 95%CI: 1.089 - 43.974) and cortisone levels (OR = 5.121, 95%CI: 0.886 - 29.611) were related to low PI, while LDL-C (OR = 3.736, 95%CI: 0.848 - 16.461), waistline (OR = 6.846, 95%CI: 1.441 - 32.532), education (OR = 0.169, 95%CI: 0.029 - 0.995), and insulin (OR = 0.141, 95%CI: 0.016 - 1.277) were related to high PI. CONCLUSION: Birth PI was associated with income, waistline, education, insulin, cortisone, and LDL-C. Before conception, women should go through necessary tests and keep a good physical condition to reduce their neonates of having abnormal PI. PMID- 23937838 TI - [Ethnic differences on nutritional status of children under 3 years old in poor counties of the western China]. AB - OBJECTIVE: To explore the ethnic differences on nutritional status of children under three years old, in the western areas of China and to identify the affecting factors. METHODS: 14 072 children under the age of three years and their mothers were recruited, using the proportion population sampling method in 45 counties in the western areas of China. Height and weight were used as the measurement on nutrition of children. RESULTS: Height and weight of children with Han, Uyghur, Tibetan and Zhuang ethnicities were all lower than the WHO standards and with differences on height and weight among them. There were also ethnic differences on the status of malnutrition. Prevalence rates of stunting were 14.7%, 20.3%, 26.9% and 26.5% for Han, Uyghur, Tibetan and Zhuang ethnicities, respectively. Prevalence rates of underweight were 6.1%, 10.7%, 6.8% and 15.5% among the Han, Uyghur, Tibetan and Zhuang ethnicities, respectively. The prevalence rates of wasting were 4.2%, 5.3%, 2.9%, 8.9%, and of under nutrition were 19.2%, 25.5%, 30.3% and 36.5% for the Han, the Uyghur, the Tibetan and the Zhuang ethnicities, respectively. When factors as family size, years of schooling of parents, family numbers, sex, age (months), mother's height and weight, ways of feeding and sources of family income etc. were adjusted, children with Uyghur, Tibetan, Zhuang and other ethnicities were still presented more malnutrition than the children with Han ethnicity. CONCLUSION: There were differences on malnutrition status of children under the age of three years among the studies on different ethnicities. Undernutrition was less than nutritional status, seen in children of the Han nationality than other minority ethnicities. Ethnicity seemed to be related to differences in the nutritional status of children in western China while children of the Han nationality would be better than other minorities on nutritional status if they were in same living conditional. PMID- 23937839 TI - [Changes in knowledge and behavior related to tobacco consumption among urban population before and after the enforcement of the Smoke Control Ordinance in Public Places of Hangzhou in 2010]. AB - OBJECTIVE: To examine the changes in tobacco related knowledge, smoking habit and the amount if environmental tobacco smoke (ETS) among urban population before and after the enforcement of the Smoke Control Ordinance in Public Places of Hangzhou in March 2010. METHODS: Two independent cross-sectional surveys were conducted on random samples from adults aged 18 - 64 years in three districts of Hangzhou city between two petiods: October 2008 to August 2009 and June 2011 to February 2012. RESULTS: A total of 2016 adults at the initial stage and 2016 adults during the follow-up program completed the survey. Nine out of the ten indices related to the knowledge on tobacco presented an improvement during the follow-up process. All the participants (22.4% vs. 17.7%, P < 0.001) and men (44.2% vs. 37.3%, P = 0.004) showed statistically significant declines in the prevalence of smoking, when compared with women (1.7% vs. 1.2%, P = 0.379). The proportions of individuals who had noticed anyone smoking in the previous 30 days demonstrated statistically significant declines in nine types of places: school (5.6% vs. 2.7%, P < 0.001), health centre (11.4% vs. 3.7%, P < 0.001), public transportation (19.2% vs. 12.2%, P < 0.001), government building (11.3% vs. 5.6%, P < 0.001), restaurant (67.0% vs. 61.3%, P = 0.002), workplace (49.7% vs. 38.3%, P < 0.001), private office building (23.6% vs. 19.9%, P = 0.023), home (41.0% vs. 35.5%, P = 0.003), friend's home (33.9% vs. 29.5%, P = 0.017). CONCLUSION: Positive changes were noticed among urban population with respect to tobacco related knowledge, prevalence of smoking, and the environmental tobacco smoke (ETS) after the enforcement of the Smoke Control Ordinance in Public Places of Hangzhou. PMID- 23937840 TI - [The adolescent physical exercise behavior-psychological measurement scale on the Chinese version and its reliability and validity study]. AB - OBJECTIVE: To develop a suitable physical exercise behavior-psychological scale for the Chinese adolescents and to evaluate its validity and reliability. METHODS: A total of 3600 junior students were recruited and tested through multistage sampling method. Reliability was assessed, using Cronbach's alpha and split-half reliability; while exploratory factor analysis and confirmatory factor analysis were used to test its validity, with entries-dimension correlation coefficient (IIC), correlation coefficient between the scores and the dimension, the dimension of correlation coefficient test content validity. RESULTS: The internal consistency reliabilities for total scale score (Cronbach's alpha = 0.888), Cronbach's alpha of four domains were 0.880, 0.706, 0.552 and 0.839, respectively. The four-domain split-efficacy reliabilities were ranged between 0.559 and 0.876. Data from the exploratory factor analysis revealed the following dimensions: the entries were all inclusive; the cumulative contribution rate was more than 40%. RESULTS: from the confirmatory factor analysis showed that the absolute fit measures of GFI = 0.972, AGFI = 0.958, RMSEA = 0.032 (90%CI: 0.030 - 0.034) could satisfy the condition while the model fit was better. The results of IIC showed: in the four dimensions, and the contained entries between Spearman correlation coefficient range were 0.396 - 0.700, 0.470 - 0.709, 0.696 - 0.771 and 0.665 - 0.813, while other dimensions from weak to moderate relationships, the r value range was from 0.386 to 0.935. With the change of the phase changing process, decision balance, self-efficacy scores were differently prompting the health-related intervention periodically and pertinently. CONCLUSION: The reliability and validity of the 'Adolescent physical exercise behavior psychological scales (Chinese version) ' were good, and could be used to measure the adolescent's physical training behavior-psychological conditions. PMID- 23937841 TI - [Epidemiological and etiological characteristics of hand-foot-mouth disease in Ningbo, Zhejiang province, 2008-2011]. AB - OBJECTIVE: To analyze the epidemiological characteristics of hand foot and mouth disease (HFMD) in Ningbo. METHODS: A descriptive analysis was conducted through the surveillance data of HFMD in Ningbo, Zhejiang province, from 2008 to 2011. Genes on EV71 and Cox A16 were amplified with RT-PCT from the stool samples of HFMD patients. Sequences were analyzed by bioinformatics software. RESULTS: 37 524 cases of HFMD were reported from 2008 to 2011, including 196 severe cases and 12 deaths. The reported incidence was 145.26 per 100 000 and the case fatality was 0.03%. Cases in children aged 5 or younger accounted for 95.89%, and the scattered cases accounted for 64.10%. Xiangshan and Ninghai counties had the highest incidence rates in Ningbo. The peak of incidence was from April to July. The number of male patients was obviously higher than females. 2394 cases of HFMD were laboratory confirmed and EV71 with the predominant epidemic strain. Data from phylogenetic analysis revealed that EV71 isolated from HFMD patients in Ningbo belonged to C4a evolution branch of C4 sub-genotype, with several transmission chains. Cox A16 belonged to B1 evolution branch. 53.48% of the healthy children in Ningbo showed EV71 antibody positive. The geometric mean of the antibody titer (GMT) was 11.23 (8.33 - 14.98) in healthy children. Cox A16 antibody was detected at 63.18% of the healthy children in Ningbo. GMT in healthy children was 12.61 (6.70 - 16.52). CONCLUSION: HFMD was highly endemic in Ningbo, with children under 5 years old were at high-risk. The major etiologic agent was EV71 which belonged to C4a in the C4 sub-genotypes. Cox A16 belonged to the B1 evolution branch, which were in line with the predominant virus circulating in the mainland of China. PMID- 23937842 TI - [Molecular evolution of two lineages related to influenza B virus based on HA1 gene]. AB - OBJECTIVE: To study the evolutionary characteristics and rules of two lineages on influenza B virus. METHODS: A total of 126 HA1 sequences of strains isolated during 1940 to 2012 were downloaded from the GenBank. Time of the most recent common ancestor (TMRCA) and divergence of the two lineages were calculated based on the data from phylogenetic analysis of HA1 gene, using Bayesian Markov Chain Monte Carlo (Bayesian-MCMC) and molecular clock method. RESULTS: The average amino acid variant ratios were ranged from 5.4% to 10.2% within the strains of influenza B virus isolated during 1978 to 2010. Compared with the Victoria-like strains, all Yamagata-like strains showed an amino acid deletion at 163(th) site, while some of them showing a deletion at position 166. HA1 gene of influenza B virus seemed not have been affected by positive selection except a few sites. The evolutionary average rate on HA1 gene was 2.138*10(-3) substitutions/site/year (95% HPD: 1.833*10(-3) - 2.437*10(-3) substitutions/site/year). The estimated dates for TMRCA of the two lineages of influenza B virus could be dated back to 1971 (95% HPD: 1969 - 1972), while the divergence times of the two lineages were 1973 (95% HPD: 1971 - 1974) and 1977 (95% HPD: 1975 - 1978) respectively. CONCLUSION: Significant differences were found on HA1 gene between earlier and recent identified strains of Victoria and Yamagata lineage. Differences between the two lineages increased and showing the potential of dividing themselves into different subtypes in the future. More attention should be paid to these trends and the related epidemiological significance. PMID- 23937843 TI - [A nitrite poisoning event associated with intentional chemical releases]. AB - OBJECTIVE: To compare the field epidemiological investigation and the criminal investigation on a nitrite poisoning event caused by deliberate contamination. METHODS: Cases were searched according to the definition of the disease. Information on the histories of onset and diet of all the cases and normal population on site, were investigated face to face. Information as ingredients, processing and sales of foods was also gathered. Samples were collected and nitrite detection were performed. Relevant materials were searched, cases were interviewed and data related to criminal results were collected. RESULTS: Poisoned persons were staff of a big company in Longgang district of Shenzhen. The overall attack rate was 56.25% (63/112), with suspected and confirmed rates as 41.96% and 14.28%, respectively. The fatality rate was 3.17% (2/63). Clinical manifestation and effect of treatment were in accordance with the characteristics of an episode related to acute nitrite food poisoning in terms of factors as the time of onset, involving different age, sex and jobs of the patients. A total of 191 samples, including vomits from patients and seven batches of food and environment samples, were collected, with a positive detected rate of nitrite as 18.84%. Information gathered from the field environment, food distribution and processing supported the assumption that this was an incident of nitrite poisoning event with intention. RESULTS: from the criminal investigation showed that the suspect stemmed from the market management rivalry, bought nitrite, dissolved and spread on food stalls F9 and F10. CONCLUSION: This event of intentional nitrite release resulting in food contamination which further leading to food poisoning, was completely proved by the joint efforts of the teams and expertise from the field epidemiology survey and the criminal investigation. PMID- 23937844 TI - [Origin, phylogeny, and spread of Mycobacterium tuberculosis Beijing lineage in the five provinces of northern China]. AB - OBJECTIVE: Using methodology of molecular genetics to explore the origin, phylogen, and gene flow of Mycobacterium tuberculosis (MTB) Beijing lineage in the five provinces from northern China, including Heilongjiang, Jilin, Liaoning, Neimenggu and Ningxia. METHODS: 234 MTB Beijing lineage strains were genotyped by 24 Variable Number Tandem Repeat (VNTR), and the h (the allelic diversity) value of each VNTR locus was calculated. On individual level of phylogeny, it was constructed Neighbor-Joining (N-J) tree and minimum spanning tree (MST). Phylogenetic tree was built at the population level, and the most recent common ancestor (TMRCA) was estimated through Bayesian model. Molecular variance (AMOVA) was used to understand the gene flow among strains discovered from the five provinces. RESULTS: Allelic diversities of the 24 VNTR loci were low (h: 0.000 - 0.744). 234 strains of MTB Beijing lineage were dispersed in individual branch of the N-J tree, with 62.0% (145) of them grouped to the same "colonial complexes" in MST. At the population level, the evolution relationship of 234 strains appeared the closest to Beijing lineage, which was from MIRU-VNTRplus database, and the bootstrap was 100. The TMRCA was 5308 (95%CI: 4263 - 6470) years. Differences of pairwise Fst values acquired by AMOVA between Jilin and Heilongjiang, Liaoning, Neimenggu and Ningxia, were not statistically significant (P > 0.05). CONCLUSION: The genetic similarity of Beijing lineage MTB from the five provinces of northern China was high. The phylogeny branches had no characteristic dispersal in each province. It was speculated that these strains showed an evolution from a clone of MTB Beijing lineage (about 5000 years ago). The gene flow was taking place between neighboring zones. PMID- 23937845 TI - [A primary investigation on the isoniazid-induced alterations in efflux gene expression among the isoniazid resistant Mycobacterium tuberculosis clinical isolates]. AB - OBJECTIVE: To detect the changes on the expression of putative drug efflux genes caused by isoniazid-inducement in single resistance to the isoniazid Mycobacterium tuberculosis (M. tuberculosis) clinical isolates, for exploring the putative efflux genes which causing M. tuberculosis isoniazid resistance as well as the mechanism related to high expression of the putative efflux genes. METHODS: We selected 35 M. tuberculosis clinical isolates which were only resistant to isoniazid as well as 10 sensitive M. tuberculosis clinical isolates and using H37Rv as control. Each strain was cultured in 7H9 liquid medium without isoniazid and with subinhibitory isoniazid concentration (1/4 MIC) induction. After RNA extraction and reverse transcription, real-time PCR was conducted to assess the expression changes of 27 putative drug efflux pump genes with formula 2(-DeltaDeltaCT) to calculate the expression of each putative drug efflux pump genes. RESULTS: Of the 27 putative genes, 13 of them were expressed at high level. High expression of Rv1258c gene had the maximum number of 6 strains, followed by high expression of Rv0849 and Rv2265 which both had 5 strains. Fourteen strains (40.00%) out of the 35 strains had high expression pump genes. Six strains (17.14%) had only one highly expressed putative efflux pump gene. Eight strains (22.86%) had two or more highly expressed putative efflux pump genes, including two, four, five, seven genes that highly expressed in 4, 2, 1, 1 strains respectively. For the 27 putative genes, ten sensitive strains and H37Rv did not show highly expressed genes. CONCLUSION: Rv1258c, Rv2265, Rv0849, etc. genes might be the putative efflux pumps genes of M. tuberculosis resistant to isoniazid. Isoniazid might serve as the inducer of M. tuberculosis part putative efflux pump genes, inducing activation and causing high expression of these putative efflux pump genes. PMID- 23937846 TI - [A case-control study regarding tea consumption and risk of hip fractures in middle-aged and elderly Chinese]. AB - OBJECTIVE: To assess the impact of tea consumption on the risk of osteoporotic hip fractures. METHODS: Between January 2008 and June 2012, 581 (148 males, 433 females) incident cases of hip fractures were enrolled from four hospitals in Guangdong province, with 581 sex- and age-matched (+/- 3 years) controls from either hospitals or communities. Face-to-face interviews were conducted to collect data pertaining to tea drinking and various covariates. RESULTS RESULTS: from univariate conditional logistic analyses showed that an inverse association was observed in tea drinking and hip fracture risk. Longer time, greater frequency and dosage of tea consumption were dose-dependently associated with lower risk of hip fractures (P-trend < 0.05). Compared to non-drinkers, the odd ratios related to regular tea drinkers, subgroups with different length, frequency, dosage, type of tea consumption were ranged between 0.54 and 0.74 (all P < 0.05). After adjustment for factors as age, daily energy intake, BMI, education levels, passive smoking, calcium supplement and physical activity, the dose-dependent associations among above said factors still remained significant. However, the strength of the association lowered slightly. The beneficial effect of tea was significant only in men but not in women. Similar effects were found in subjects with different education levels. CONCLUSION: Regular tea drinking habit might decrease the risk of osteoporotic hip fractures in the elderly males. PMID- 23937847 TI - [Risk factors related to infantile spastic cerebral palsy among 145 cases]. AB - OBJECTIVE: To study the risk factors related to spastic type of cerebral palsy through a screening program. METHODS: With a 1:2 matched case-control study design, 145 cases were selected from the Cerebral Palsy Treatment and Management Center in Heilongjiang Province from Dec., 2007 through May 2009. Another 290 cases of children as control group were chosen from the First Affiliated Hospital of Jiamusi University, in the same period. Controls were excluded the central nervous system diseases, matching with cases at the age differences no more than 3 months, with same sex and ethnicity. Questionnaire survey was used to access relevant information, while logistic regression analysis was used to screen the risk factors. RESULTS: Data from Single factor logistic regression analysis notified 39 items as statistically significant factors. Through multivariate logistic regression analysis, 11 factors in all the cerebral palsy cases, and incidence of cerebral palsy risk factors related to low or high birth weight were discovered as follows: mother with college degree, newborns with high muscle tone, skin color as purple, taking antipyretic analgesics drugs during pregnancy, experience significant events during pregnancy, situation of environment pollution around the house, having intracranial hemorrhage and birth asphyxia, fetal distress during pregnancy or neonatal stage etc. CONCLUSION: Pre/Neonatal factors were closely related to cerebral palsy, suggesting that health care knowledge be popularized and related management be strengthened, to reduce the cerebral palsy incidence in the newborns. PMID- 23937848 TI - [Analyses on the relative factors regarding diabetic nephropathy]. AB - OBJECTIVE: To analyze the related factors regarding diabetic nephropathy (DN). METHODS: A total number of 756 diabetic patients from 2009 to 2011 were analyzed retrospectively. Three groups were formed according to the urinary albumin excretion rates (UAER). Patients with UAER < 20 ug/min was grouped to group A, with UAER from 20 to 200 ug/min as group B, and the others with UAER >= 200 ug/min was grouped to group C. General characteristics and laboratory parameters were then compared and related factors of DN analyzed. RESULTS: The constituent ratio of nephropathy was 30.2% (228/756). Patient's age, duration of disease, both diastolic and systolic blood pressure of group A were significantly higher than the non-DN group (A) (P < 0.05). Patient's age, disease duration, both diastolic and systolic blood pressure of group C were (64.08 +/- 11.71) years, (14.67 +/- 7.34) years, (87.43 +/- 14.36) mm Hg, (152.45 +/- 18.48) mm Hg, respectively, with statistically significant difference (P < 0.05) between group C and group B. FPG, TG, TC, HDL-C, UA, HbA1c, FINS, FCP of group B were (9.27 +/- 3.06) mmol/L, (1.98 +/- 0.37) mmol/L, (5.01 +/- 1.08) mmol/L, (1.05 +/- 0.35) mmol/L, (312.78 +/- 39.83) mmol/L, (9.33 +/- 1.47)%, (11.45 +/- 7.83) uU/ml, (509.73 +/- 132.78) pmol/L respectively, with significant difference (P < 0.05) between group B and group A. FPG, TG, HDL-C, UA, FINS, FCP of group C were (9.29 +/- 3.12) mmol/L, (2.02 +/- 0.36) mmol/L, (1.04 +/- 0.27) mmol/L, (389.72 +/- 46.32) mmol/L, (11.09 +/- 8.29) uU/ml, (575.77 +/- 143.29) pmol/L respectively, with significant difference (P < 0.05) between group C and group A. UA, FINS, FCP were found with significant differences (P < 0.05) between group C and group B. Data from multivariate logistic regression showed that DNs were related with disease duration, BMI, systolic blood pressure, HbAlc, FPG, UA. CONCLUSION: DN was closely related to the duration, age, blood sugar, blood lipids, blood pressure, uric acid levels of the disease. PMID- 23937849 TI - [Different combination of drugs regarding the damage on organs targeting salt sensitivity or non-salt-sensitive hypertension]. AB - OBJECTIVE: To study the damage on organs from salt sensitivity hypertension or non-salt-sensitive hypertension and the selection of drug combination. METHODS: 120 hypertensive patients including 60 cases salt-sensitive (SS) and 60 non-salt sensitive (NSS) groups were selected in our hospital and their salt load tested. These two groups were randomly divided into two groups, each group with 30 patients, one was given felodipine and perindopril and the others were given indapamide sustained release tablets and perindopril to facilitate the 12-week treatment. Before and after the treatment, patients were tested for physiological indicators, such as sitting blood pressure, 24-hour ambulatory blood pressure, insulin resistance index, comparing changes of various sub-index etc. RESULTS: Significantly different were seen in indices as fasting blood glucose and serum creatinine (P < 0.01), fasting insulin, left ventricular mass index, urinary albumin, body mass index, insulin resistance indices, while between the SS group and the NSS group (P < 0.05). In the SS group, when patients with various sub indicators were using perindopril combined with indapamide treatment, the related detected indicators tended to be normal and with statistically significant differences (P < 0.05). In the NSS group, those related indexes also tended to be more normal when using felodipine combined with perindopril. However, there were statistically significant differences between the two groups (P < 0.05). CONCLUSION: On SS hypertensive patients with target organ damages, perindopril and indapamide seemed to be more effective in NSS patients, indicating that the use of perindopril and felodipine combination, seemed to be more suitable. PMID- 23937850 TI - [Cost-effectiveness analysis on the once-in-a-lifetime cervical cancer screening program for women living in rural and urban areas of China]. AB - OBJECTIVE: To estimate the cost-effectiveness of once-in-a-lifetime cervical cancer screening program and to predict the optimal modality for its operation on women living in rural and urban areas of China, based on Markov modeling and simulation. METHODS: Three modalities including visual inspection with acetic acid plus Lugol's iodine (VIA/VILI), conventional Pap Smear (Pap Smear), and simple HPV DNA testing (careHPV) were hypothesized for the rural cohort, whereas other five modalities including Pap Smear, liquid-based cytology (LBC), simple HPV DNA testing (careHPV), Hybrid Capture 2 HPV DNA testing (HC2), and LBC plus HC2 (LBC + HC2) were tested for the urban cohort. A Markov model was constructed based on the factors as natural history, screening, diagnosis and treatment on cervical cancer using data related to the epidemics and the costs from rural and urban areas of the country. Long-term effectiveness and cost-effectiveness were predicted through simulation of the model. RESULTS: Compared to the non-screening scenario, the amount of life years saved were 277.97 - 2727.53 and 134.02 - 1446.84 years per 100 000 women, respectively, for different cohorts in rural and urban areas. The cost-effectiveness ratios were 1520.99 - 2453.74 and 3847.35 - 44 570.35 RMB per life year saved, respectively, for different cohorts in rural and urban areas. The incremental cost-effective ratio for careHPV starting from 40 years old (careHPV@40) and careHPV from 30 years old (careHPV@30) dominated other strategies for the rural cohort, while careHPV@40, careHPV@30, HC2 from 30 years old (HC2@30), and LBC + HC2 from 30 years old (LBC + HC2@30) were dominant for the urban cohort. CONCLUSION: All eight once-in-a-lifetime cervical cancer screening modalities were cost-effective based on our model. In particular, careHPV screening starting from 40 years old seemed to be the most cost-effective one for women living in both rural and urban areas. PMID- 23937851 TI - [Prediction of influenza-like illness in Shanghai based on the generalized additive method]. AB - The aim of the current research topic was to test the generalized additive method (GAM), using data from the analysis and prediction on influenza-like illness (ILI) in Shanghai. Through collecting the meteorological data as well as the ILI from 2006 to 2010, we established several nonlinear regression candidate models based on the GAM. These models considered factors as: the nonlinear dependence on the meteorological data, i.e. weekly average temperature and weekly average (maximum) temperature differences and the ILI. The AIC (Akaike information criterion) involved two simplified models which were implemented for further analysis and prediction. Finally, numerical examples showed that the proposed models could shed light on the connection between the meteorological data and the ILI. GAM could be used to fit the frequencies of ILI and meteorological factors in Shanghai. The proposed models were able to accurately analyze the onset of ILI, implying that GAM might be suitable for the prediction and analysis of those meteorological correlative diseases. PMID- 23937852 TI - [Recent advances in the epidemiological research on recurrent tuberculosis]. PMID- 23937854 TI - Impact of methadone maintenance on health utility, health care utilization and expenditure in drug users with HIV/AIDS. AB - BACKGROUND: This study assessed the impact of methadone maintenance treatment (MMT) on health utility, health care service utilization, and out-of-pocket (OOP) health expenditure in drug users with HIV/AIDS in Vietnam. METHODS: Using the 2012 Vietnam HIV Service Users Survey data, a post-evaluation was designed to compare 121 MMT patients with 347 non-MMT patients who were matched using propensity scores of MMT covariates. Health utility was measured using the EuroQOL - five dimensions - five levels (EQ-5D-5L) and a visual analogue scale (EQ-VAS). RESULTS: The mean EQ-5D-5L single index and EQ-VAS score of MMT patients were 0.68 (95% CI=0.64-0.73) and 71.5% (95% CI=68.2-74.9). Compared with the control group, the adjusted differences in health utility were 0.08 and 4.43% (p=0.07), equivalent to 12.1% and 6.5% increases during MMT. There was a 45.9% decrease in the frequency of health care service utilization that was attributable to MMT. Although, antiretroviral treatment and MMT services were free-of-charge, MMT and non-MMT patients still paid their OOP for health care for averagely US$ 16.3/month and US$ 28.9/month. The adjusted difference between the two groups was US$ 19.3/month ($ 231.6/year) that equivalents to a reduction of 66.7% in OOP health expenditure related to MMT. CONCLUSION: MMT was associated with a clinically important difference in health utility, large reductions in health care service utilization and OOP health expenditure in HIV-positive drug users. Scaling up MMT in large drug-using population could help improve the outcomes of HIV/AIDS interventions and reduce economic vulnerability of affected households. PMID- 23937853 TI - Using in vivo probabilistic tractography to reveal two segregated dorsal 'language-cognitive' pathways in the human brain. AB - Primate studies have recently identified the dorsal stream as constituting multiple dissociable pathways associated with a range of specialized cognitive functions. To elucidate the nature and number of dorsal pathways in the human brain, the current study utilized in vivo probabilistic tractography to map the structural connectivity associated with subdivisions of the left supramarginal gyrus (SMG). The left SMG is a prominent region within the dorsal stream, which has recently been parcellated into five structurally-distinct regions which possess a dorsal-ventral (and rostral-caudal) organisation, postulated to reflect areas of functional specialisation. The connectivity patterns reveal a dissociation of the arcuate fasciculus into at least two segregated pathways connecting frontal-parietal-temporal regions. Specifically, the connectivity of the inferior SMG, implicated as an acoustic-motor speech interface, is carried by an inner/ventro-dorsal arc of fibres, whilst the pathways of the posterior superior SMG, implicated in object use and cognitive control, forms a parallel outer/dorso-dorsal crescent. PMID- 23937855 TI - High-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in locally advanced non-small-cell lung cancer: a feasibility study. AB - BACKGROUND: Increasing the radiotherapy dose can result in improved local control for non-small-cell lung cancer (NSCLC) and can thereby improve survival. Accelerated hypofractionated radiotherapy can expose tumors to a high dose of radiation in a short period of time, but the optimal treatment regimen remains unclear. The purpose of this study was to evaluate the feasibility of utilizing high-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine (NVB) and carboplatin (CBP) chemotherapy for the treatment of local advanced NSCLC. METHODS: Untreated patients with unresectable stage IIIA/IIIB NSCLC or patients with a recurrence of NSCLC received accelerated hypofractionated three-dimensional conformal radiotherapy. The total dose was greater than or equal to 60 Gy. The accelerated hypofractionated radiotherapy was conducted once daily at 3 Gy/fraction with 5 fractions per week, and the radiotherapy was completed in 5 weeks. In addition to radiotherapy, the patients also received at least 1 cycle of a concurrent two drug chemotherapy regimen of NVB and CBP. RESULTS: A total of 26 patients (19 previously untreated cases and 7 cases of recurrent disease) received 60Gy-75Gy radiotherapy with concurrent chemotherapy. All of the patients underwent evaluations for toxicity and preliminary therapeutic efficacy. There were no treatment-related deaths within the entire patient group. The major acute adverse reactions were radiation esophagitis (88.5%) and radiation pneumonitis (42.3%). The percentages of grade III acute radiation esophagitis and grade III radiation pneumonitis were 15.4% and 7.7%, respectively. Hematological toxicities were common and did not significantly affect the implementation of chemoradiotherapy after supportive treatment. Two patients received high dose of 75 Gy had grade III late esophageal toxicity, and none had grade IV and above. Grade III and above late lung toxicity did not occur. CONCLUSION: High-dose accelerated hypofractionated three-dimensional conformal radiotherapy with a dose of 60 Gy or greater with concurrent NVB and CBP chemotherapy might be feasible. However esophagus toxicity needs special attention. A phase I trial is recommended to obtain the maximum tolerated radiation dose of accelerated hypofractionated radiotherapy with concurrent chemotherapy. PMID- 23937856 TI - Cases of typhoid fever in Copenhagen region: a retrospective study of presentation and relapse. AB - BACKGROUND: Typhoid fever is a systemic illness which in high-income countries mainly affects travellers. The incidence is particularly high on the Indian subcontinent. Travellers who visit friends and relatives (VFR) have been shown to have a different risk profile than others. We wished to identify main characteristics for travellers infected with S. Typhi considering both clinical and laboratory findings in order to provide for faster and better diagnostics in the future. The outcome of treatment, especially concerning relapse, was evaluated as well. METHODS: Retrospectively collected data from 19 adult cases of typhoid fever over a 5-year period at the Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre Denmark. RESULTS: The patients were young adults, presenting with symptoms within a month after travelling. 84% were returned from travelling in the Indian subcontinent. 17 out of 19 patients were VFR-travellers. The main symptoms were fever (100%), gastrointestinal symptoms (84%), headache (58%) and dry cough (26%). Laboratory findings showed elevated C reactive protein (CRP) and lactate dehydrogenase (LDH) in all cases and elevated alanine transaminase (ALAT) in 47% of cases. In primary cases 4 isolates were fully susceptible to ciprofloxacin, the remaining were intermediate susceptible. Relapse occurred in 37% of the cases and only in cases where the patient was infected by a strain with intermediate susceptibility. CONCLUSIONS: Better pre travel counselling should be given to VFR-travellers. The main symptoms and laboratory findings confirm previous findings. The relapse rate was unexpected high and could be correlated to ciprofloxacin-resistance. PMID- 23937857 TI - Idiopathic pulmonary fibrosis: the need for early diagnosis. AB - Idiopathic pulmonary fibrosis (IPF), a chronic fibrosing lung disease of a progressive nature and unknown etiology, has the largest epidemiological impact and the worst prognosis among the idiopathic interstitial pneumonias (IIP). Despite the progress in pathogenetic knowledge, many aspects are still dubious, in particular the biomolecular mechanisms activated in the early stages of the disease. Early diagnosis is desirable not only to better define aspects of the natural history of the disease, but also to customize treatment protocols. An early diagnosis of IPF should necessarily be based on the ability to highlight a number of features drawn not only from a careful composition of specific anamnestic data with clinical, functional and radiological parameters, but also from biological markers that, in a proper context, can provide guidance and confirm a clinical-anamnestic suspicion. The identification of specific biomarkers for IPF is a modern and attractive look for the potential clinical implications in terms of diagnosis, prediction of disease progression and prognosis. Biomolecular investigations on IPF were performed selectively on tissue samples, bronchoalveolar lavage (BAL), or blood: nowadays the "multi-omic" approach may allow studying individual constitutional profiles resorting to a series of biomolecular disciplines, the so-called "omics", which focuses on responses of the entire genomic complex, in line with the current trend to quantitatively analyze the interactions of all components of a biological system. Such refined investigations are an essential base for research now, but they might become a routine in the near future, allowing a more precise classification of patients suffering from a disease of unclear taxonomy. PMID- 23937858 TI - Efficacy and safety of pharmacological interventions in second- or later-line treatment of patients with advanced soft tissue sarcoma: a systematic review. AB - BACKGROUND: Current guidelines recommend anthracycline-based chemotherapy primarily with doxorubicin either as monotherapy or in combination with ifosfamide as the first-line treatment for most advanced STS subtypes. Therapeutic options after failure of doxorubicin and/or ifosfamide are limited. This study aimed to comprehensively review available data on the activity and safety of interventions in second- or later-line treatment of advanced STS. METHODS: Electronic literature databases (Embase(r), MEDLINE(r), MEDLINE(r) In Process, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews) were searched from 1980 to 01 March 2012 to identify randomised controlled trials (RCTs) and non-randomised studies (both prospective and retrospective) evaluating pharmacological interventions in patients with advanced STS pre-treated with anthracycline- and/or ifosfamide-based therapy. RESULTS: The review identified six RCTs (one phase III and five phase II trials) and 94 non-randomised studies. Based on the primary trial endpoints, RCTs demonstrated favourable efficacy for pazopanib over placebo (PFS: 4.6 months vs. 1.6 months), gemcitabine plus dacarbazine over dacarbazine monotherapy (3-month PFS rate: 54.2% vs. 35.2%), and trabectedin 3-weekly schedule over weekly schedule (TTP: 3.7 months vs. 2.3 months. The non-randomised studies demonstrated heterogeneity in efficacy and safety results. CONCLUSIONS: Across the RCTs, pazopanib over placebo, gemcitabine-dacarbazine over dacarbazine, and trabectedin 3-weekly over weekly regimen clearly demonstrated a PFS advantage in the second- and later-line treatment of advanced STS. With only one phase III trial in this setting, there is a clear need for additional comparative trials to better understand the risk: benefit ratios of available agents and combinations. PMID- 23937859 TI - Proteomic analysis of kidneys from selenoprotein M transgenic rats in response to increased bioability of selenium. AB - BACKGROUND: To characterize changes in global protein expression in kidneys of transgenic rats overexpressing human selenoprotein M (SelM) in response to increased bioabivility of selenium (Sel), total proteins extracted from kidneys of 10-week-old CMV/hSelM Tg and wild-type rats were separated by 2-dimensional gel electrophoresis and measured for changes in expression. RESULTS: Ten and three proteins showing high antioxidant enzymatic activity were up- and down regulated, respectively, in SelM-overexpressing CMV/hSelM Tg rats compared to controls based on an arbitrary 2-fold difference. Up-regulated proteins included LAP3, BAIAP2L1, CRP2, CD73 antigen, PDGF D, KIAA143 homolog, PRPPS-AP2, ZFP313, HSP-60, and N-WASP, whereas down-regulated proteins included ALKDH3, rMCP-3, and STC-1. After Sel treatment, five of the up-regulated proteins were significantly increased in expression in wild-type rats, whereas there were no changes in CMV/hSelM Tg rats. Only two of the down-regulated proteins showed reduced expression in wild-type and Tg rats after Sel treatment. CONCLUSIONS: These results show the primary novel biological evidences that new functional protein groups and individual proteins in kidneys of Tg rats relate to Sel biology including the response to Sel treatment and SelM expression. PMID- 23937861 TI - Development of non-lethal sampling of carbon and nitrogen stable isotope ratios in salmonids: effects of lipid and inorganic components of fins. AB - The preferred tissue for analyses of fish stable isotope ratios for most researchers is muscle, the sampling of which typically requires the specimen to be sacrificed. The use of non-destructive methods in fish isotopic research has been increasing recently, but as yet is not a standard procedure. Previous studies have reported varying levels of success regarding the utility of non lethally obtained stable isotope materials, e.g. fins, but none have accounted for the potential compounding effects of inorganic components of fin rays or lipids. Comparisons of carbon (delta(13)C) and nitrogen (delta(15)N) stable isotope ratios of muscle with adipose and caudal fin of two salmonids, Atlantic salmon (Salmo salar L.) and brown trout (Salmo trutta L.), revealed that caudal fin can be used as a non-destructive surrogate for muscle in stable isotope analysis, but that adipose fin, where available, is a better proxy. The use of a published model to inexpensively counteract the confounding effect of lipids, which are depleted in (13)C, greatly improved the relationship between fish muscle and fins. However, efforts to account for the inorganic components of fin rays were counterproductive and required twice the biomass of fins clipped from each fish. As this experiment was conducted on wild fish, controlled laboratory studies are required to confirm these field observations. PMID- 23937860 TI - Asbestos and erionite prime and activate the NLRP3 inflammasome that stimulates autocrine cytokine release in human mesothelial cells. AB - BACKGROUND: Pleural fibrosis and malignant mesotheliomas (MM) occur after exposures to pathogenic fibers, yet the mechanisms initiating these diseases are unclear. RESULTS: We document priming and activation of the NLRP3 inflammasome in human mesothelial cells by asbestos and erionite that is causally related to release of IL-1beta, IL-6, IL-8, and Vascular Endothelial Growth Factor (VEGF). Transcription and release of these proteins are inhibited in vitro using Anakinra, an IL-1 receptor antagonist that reduces these cytokines in a human peritoneal MM mouse xenograft model. CONCLUSIONS: These novel data show that asbestos-induced priming and activation of the NLRP3 inflammasome triggers an autocrine feedback loop modulated via the IL-1 receptor in mesothelial cell type targeted in pleural infection, fibrosis, and carcinogenesis. PMID- 23937862 TI - Short and long-term career plans of final year dental students in the United Arab Emirates. AB - BACKGROUND: New dental schools have been established to train dentists in many parts of the world. This study examines the future dental workforce from the first dental school in the United Arab Emirates [UAE]; the aim of this study was to explore the short and long-term career aspirations of the final year dental students in the UAE in relation to their demography. METHOD: Final year dental students of the Ajman University's College of Dentistry (n=87) were invited to participate in a self-completion questionnaire survey. Descriptive analysis, chi square tests, and binary logistic regression analysis were carried out on career aspirations using SPSS v20. RESULTS: Eighty-two percent of students (n=71) responded, the majority of whom were female (65%; n=46). Ethnicity was reported as: 'other Arab' (61%; n=43), 'Emirati' (17%, n=12), and 'Other' (21%, n=15). In the short-term, 41% (n=29) expressed a desire to work in government training centres, with Emirati students significantly more likely to do so (p=0.002). 'Financial stability' (80%; n=57) and 'gaining professional experience' (76%; n=54) emerged as the most important influences on their short-term career plans. The vast majority of students wished to specialise in dentistry (92%; n=65) in the longer term; logistic regression analysis revealed that the odds of specialising in the most popular specialties of Orthodontics and Oral and Maxillofacial Surgery were less for the 'Other' ethnic group when compared with 'Emirati' students (0.26; 95% CI 0.068-0.989; p=0.04). Almost three-quarters of the students overall (72%; n=51) intended to work full-time. 'High income/financial security' (97%; n=69), 'standard of living' (97%; n=69), 'work/life balance' (94%; n=67), and 'professional fulfilment' (87%; n=62) were reported by the students as the most influential items affecting their long-term professional career choices. CONCLUSION: The findings suggest that students aspire to make a long-term contribution to the profession and there is a high level of interest in specialisation with a desire to achieve financial stability and quality of life. PMID- 23937863 TI - Retinoblastoma in Turkey: results from a tertiary care center in Ankara. AB - PURPOSE: To evaluate the presentation patterns and results of management of retinoblastoma at a tertiary care center in Ankara, Turkey, with special emphasis on globe conservation rate in unilateral and bilateral intraocular retinoblastoma. METHODS: Patients were grouped according to the International Classification of Retinoblastoma. For intraocular retinoblastoma, group E and some group D eyes underwent primary enucleation. Secondary enucleation was performed after failure of chemoreduction, focal treatments, external beam radiotherapy (EBRT), and intra-arterial chemotherapy used in various combinations. For extraocular retinoblastoma cases, treatment consisted of enucleation/exenteration or orbital biopsy, high-dose chemotherapy, and EBRT to the orbit and metastatic sites. RESULTS: During the study period from October 1998 to May 2010, 165 of 192 (85.9%) patients had intraocular disease and 27 (14.1%) patients had extraocular disease. In total, primary or secondary enucleation was performed in 70 of 94 eyes with unilateral retinoblastoma (74.5%) and in 34 of 142 eyes with bilateral retinoblastoma (23.9%). The overall globe conservation rate was 69.6%. Only one patient in the intraocular retinoblastoma group died of metastatic retinoblastoma to the central nervous system. Twenty of 27 patients (74.1%) with extraocular retinoblastoma were found to have metastasis to the central nervous system, bone, bone marrow, and/or lymph nodes. At a mean follow-up of 28.0 months (median: 12 months; range: 1 to 120 months), survival was 33.3% despite intensive treatment. CONCLUSIONS: The overall risk of enucleation was 75% in eyes with unilateral retinoblastoma and 24% in eyes with bilateral retinoblastoma. Extraocular retinoblastoma carries a 75% risk of systemic metastasis and 67% risk of death. PMID- 23937864 TI - Surgical results of consecutive exotropia. AB - PURPOSE: To determine the success rates of different surgical procedures and the risk factors of surgical failure among patients with consecutive exotropia. METHODS: Forty patients with exotropia were observed at least 6 weeks after their esotropia surgery. Surgical planning was based on the medial rectus muscle function. Lateral rectus weakening in patients with normal medial rectus function, medial rectus strengthening for patients with limited medial rectus function (-1 to -3), and combined procedure occurred when the correction of each type of surgery was less than the amount of deviation. Postoperatively, patients were divided into success (8 prism diopters [PD] or less) or failure (8 PD or greater) groups. The follow-up period was at least 3 months. RESULTS: The mean preoperative exotropia was 29 +/- 13 PD, which was reduced to 7 +/- 7 PD postoperatively (P < .001). Successful results were achieved in 31 patients (77.5%), 17 (81%) in lateral rectus weakening, 10 (83%) in medial rectus strengthening, and 4 (57%) in the combined procedure group. More preoperative exodeviation was observed in the failure group compared to the success group (P = .015).The mean dose response was 2.27 +/- 0.92 PD/mm in the lateral rectus weakening, 4.25 +/- 2.27 PD/mm in the medial rectus strengthening, and 2.31 +/- 0.66 PD/mm in the combined procedure groups. CONCLUSION: If the choice of surgical planning is based on medial rectus function and the amount of exodeviation, satisfactory alignment would be achieved in the majority of patients with consecutive exotropia. The preoperative amount of exodeviation was the only risk factor of surgical failure in the study. PMID- 23937865 TI - Investigating the role of capacitive coupling between the operating table and the return electrode of an electrosurgery unit in the modification of the current density distribution within the patients' body. AB - BACKGROUND: Electrosurgery units are widely employed in modern surgery. Advances in technology have enhanced the safety of these devices, nevertheless, accidental burns are still regularly reported. This study focuses on possible causes of sacral burns as complication of the use of electrosurgery. Burns are caused by local densifications of the current, but the actual pathway of current within patient's body is unknown. Numerical electromagnetic analysis can help in understanding the issue. METHODS: To this aim, an accurate heterogeneous model of human body (including seventy-seven different tissues), electrosurgery electrodes, operating table and mattress was build to resemble a typical surgery condition. The patient lays supine on the mattress with the active electrode placed onto the thorax and the return electrode on his back. Common operating frequencies of electrosurgery units were considered. Finite Difference Time Domain electromagnetic analysis was carried out to compute the spatial distribution of current density within the patient's body. A differential analysis by changing the electrical properties of the operating table from a conductor to an insulator was also performed. RESULTS: Results revealed that distributed capacitive coupling between patient body and the conductive operating table offers an alternative path to the electrosurgery current. The patient's anatomy, the positioning and the different electromagnetic properties of tissues promote a densification of the current at the head and sacral region. In particular, high values of current density were located behind the sacral bone and beneath the skin. This did not occur in the case of non-conductive operating table. CONCLUSION: Results of the simulation highlight the role played from capacitive couplings between the return electrode and the conductive operating table. The concentration of current density may result in an undesired rise in temperature, originating burns in body region far from the electrodes. This outcome is concordant with the type of surgery-related sacral burns reported in literature. Such burns cannot be immediately detected after surgery, but appear later and can be confused with bedsores. In addition, the dosimetric analysis suggests that reducing the capacity coupling between the return electrode and the operating table can decrease or avoid this problem. PMID- 23937866 TI - Nonenhancing epidural abscess and discitis in an immunocompromised patient: a case report. PMID- 23937867 TI - Composite polymerization stress as a function of specimen configuration assessed by crack analysis and finite element analysis. AB - OBJECTIVES: To test the null hypothesis that polymerization-induced stress was not influenced by cavity dimensions and geometries. METHODS: Four experimental groups, with different C-factors and specimen volumes were defined using bottom less glass disks (height: 1 or 2mm) with a central hole 3 or 6mm in diameter, and 3mm wall thickness. Another four groups were created by bonding a glass plate to the bottom of the disks. Additionally, disks with 2-mm height, 3mm in cavity diameter, and 4.5-mm thick walls were prepared. Vickers indents (9.8N, 20s) were made at the top surface at 600MUm from the cavity margin. The lengths of the indentation diagonal and the corner cracks parallel to the cavity margin were measured. Ten minutes after restoration (Majesty Esthetic, Kuraray), cracks were re-measured. Stresses at the indent site were calculated based on glass fracture toughness and increase in crack length. Data were subjected to ANOVA/Tukey or Kruskal-Wallis/Mann-Whitney tests (alpha: 5%, n=8). Finite element analysis (FEA) was used to estimate stress at the interface and the effective structural rigidity of the substrate. RESULTS: Overall, for experimental and FEA results, cavities developed higher stress than bottom-less disks. Increasing wall thickness did not affect stress. When similar geometries and C-factors were compared, higher volumes developed higher stress and had greater incidence of margin cracking. CLINICAL SIGNIFICANCE: C-factor is a suitable predictor for polymerization stress in low compliance environments, particularly due to its simplicity. However, the influence of cavity size cannot be disregarded especially for the development of marginal cracking. The interaction between size, geometry and stiffness is likely to become more complex according to the complexity of the cavity shape. PMID- 23937868 TI - Exploring payment schemes used to promote integrated chronic care in Europe. AB - The rising burden of chronic conditions has led several European countries to reform healthcare payment schemes. This paper aimed to explore the adoption and success of payment schemes that promote integration of chronic care in European countries. A literature review was used to identify European countries that employed pay-for-coordination (PFC), pay-for-performance (PFP), and bundled payment schemes. Existing evidence from the literature was supplemented with fifteen interviews with chronic care experts in these countries to obtain detailed information regarding the payment schemes, facilitators and barriers to their implementation, and their perceived success. Austria, France, England, the Netherlands, and Germany have implemented payment schemes that were specifically designed to promote the integration of chronic care. Prominent factors facilitating implementation included stakeholder cooperation, adequate financial incentives for stakeholders, and flexible task allocation among different care provider disciplines. Common barriers to implementation included misaligned incentives across stakeholders and gaming. The implemented payment schemes targeted different stakeholders (e.g. individual caregivers, multidisciplinary organizations of caregivers, regions, insurers) in different countries depending on the structure and financing of each health care system. All payment reforms appeared to have changed the structure of chronic care delivery. PFC, as it was implemented in Austria, France and Germany, was perceived to be the most successful in increasing collaboration within and across healthcare sectors, whereas PFP, as it was implemented in England and France, was perceived most successful in improving other indicators of the quality of the care process. Interviewees stated that the impact of the payment reforms on healthcare expenditures remained questionable. The success of a payment scheme depends on the details of the specific implementation in a particular country, but a combination of the schemes may overcome the barriers of each individual scheme. PMID- 23937869 TI - Targeted strategies in the prevention and management of atypical HUS recurrence after kidney transplantation. AB - Atypical hemolytic and uremic syndrome (aHUS) is associated with a high rate of recurrence and poor outcomes after kidney transplantation. Fortunately, recent advances in the understanding of the pathogenesis of aHUS have permitted an individualized risk assessment of post-transplant recurrence. Acquired or inherited dysregulation of the alternative complement pathway, thought to be the driving force of the disease, is identified in most aHUS patients. Notably, depending on the mutations involved, the risk of recurrence greatly varies, highlighting the importance of undertaking etiological investigations prior to kidney transplantation. In those with moderate to high risk of recurrence, the use of a prophylactic therapy, consisting in either plasmapheresis or eculizumab therapies, represents a major stride forward in the prevention of aHUS recurrence after kidney transplantation. In those who experience aHUS recurrence, a growing number of observations suggest that eculizumab therapy outperforms curative plasma therapy. The optimal duration of both prophylactic and curative therapies remains an important, yet unaddressed, issue. In this respect, the kidney transplant recipients, continuously exposed to endothelial-insulting factors, referred here as to triggers, might have a sustained high risk of recurrence. A global therapeutic approach should thus attempt to reduce exposure to these triggers. PMID- 23937870 TI - [Screening for colonic and rectal cancer--it's coming!]. PMID- 23937871 TI - [Few complications, but only little effect on cancer related death by screening colonoscopy]. AB - In 2014, screening for colorectal cancer is scheduled to be introduced in Denmark using immunochemical test for blood in faeces (iFOBT). Positive tests are followed by colonoscopy. This review evaluates the risk of perforation, haemorrhage and death associated with screening colonoscopy based on selected recent publications. The risk of perforation and haemorrhage was reported to be 0.01% and 0.02% respectively. No deaths were reported. The studies vary in design and demographic characteristics why the findings are relevant regarding the planned national screening programme. PMID- 23937872 TI - [Treatment of chronic constipation in children]. AB - Chronic functional constipation is a common disorder in childhood. The treatment most often consists of the modalities education, disimpaction and maintenance. In a recent Cochrane review of maintenance treatment polyethylene glycol (PEG) seems to be superior to placebo and to other laxatives including lactulose. This conclusion is in line with practice at most paediatric departments in Denmark. Still, larger randomized controlled studies with the curing of constipation as the primary end point are needed. PMID- 23937873 TI - [Childhood asthma: Danish guidelines for diagnosis and treatment]. AB - These clinical guidelines were developed by the Danish Pediatric Asthma Center in collaboration with the Danish Paediatric Society. Key messages in the guidelines are: 1) Inhaled steroids are the most effective preventive medication and are first choice in children with persistent symptoms. 2) There is rarely indication for more than low to moderate doses of inhaled steroids as preventive medication. 3) There is insufficient evidence for preventive medication in pre-school children with intermittent asthma; a trial of leukotriene-receptor-antagonists or inhaled steroids could be done. PMID- 23937874 TI - [It is impossible to get information on the components of drugs that are derived from animals]. AB - For religious reasons, Muslims, Hindus and Sikhs can refuse treatment with a drug of animal origin. However, the origin is not always explicit and it is impossible to obtain the relevant information in a clinical situation. The aim of this study was to clarify whether it is possible to obtain information about animal products in medicines and thereby determine if it is possible for physicians to obtain informed consent from patients. PMID- 23937875 TI - [Salmonella is a rare cause of meningitis in infants]. AB - In developed countries, invasive disease caused by non typhoidal Salmonella spp. is rare. Here we present a Danish case of Salmonella enterica serovar Enteritidis (S. Enteritidis) meningitis in an infant who had no underlying diseases. The child had had no known expositions, and the source of the infection was never identified. The chance of finding uncommon microorganisms as cause of invasive infections such as meningitis and the choice of initial empiric antimicrobial treatments is discussed. PMID- 23937876 TI - [Duodenal biopsy is the most important examination when diagnosing Whipple's disease]. AB - Whipple's disease is a rare disease caused by the bacteria Tropheryma whipplei. It can present with different disease patterns including arthritis, gastrointestinal symptoms with abdominal pain and diarrhoea, malnutrition, anaemia and neurological symptoms. We present a case of a 71-year-old man who underwent a six-month long, thorough investigation before reaching the right diagnosis. After sufficient treatment the symptoms remitted. Physicians should be vigilant of this differential diagnosis in medical patients who have uncharacteristic symptoms consistent with Whipple's disease. PMID- 23937877 TI - [Severe thrombocytopenia after diagnosis of deep venous thrombosis]. AB - A patient presented with erysipelas and developed deep venous thrombosis (DVT) and later idiopatic thrombocytopenic purpura (ITP). In the literature we find no reports of ITP following DVT. It is well known that patients can develop HIT after DVT or DVT after ITP, both caused by the medicine used for treatment. Patients have developed ITP after heparin-induced thrombocytopenia (HIT). Cases are also described in which heparin antibodies are found, but in which the final diagnosis was ITP. The diagnosis of the patient in our case story could be ITP based on DVT, but with no history of HIT. Alternatively, he could have developed two complications to an infection. PMID- 23937878 TI - [Osteosarcoma in the patella in a patient with Rothmund-Thomson syndrome]. AB - Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive genodermatosis. We describe a 31-year-old male known with RTS who had a rare presentation of osteosarcoma in the patella. He initially fractured the patella, and had surgery. On suspicion infection he was treated with antibiotics several times. His condition did not improve, and a biopsy was made consequently. Pathology showed osteosarcoma. The patella was removed, but later the patient had a femur amputation. This case emphasises that patients with rare genetic defects associated with high risk of cancer must be treated by specialists. PMID- 23937879 TI - [Cutaneous leishmaniasis]. PMID- 23937880 TI - The role of chest ultrasonography in the management of respiratory diseases: document I. AB - Chest ultrasonography can be a useful diagnostic tool for respiratory physicians. It can be used to complete and widen the general objective examination also in emergency situations, at the patient's bedside. The aim of this document is to promote better knowledge and more widespread use of thoracic ultrasound among respiratory physicians in Italy. This document I is focused on basic knowledge of chest ultrasonography technique, physical basis, aims and characteristics, fields of application. Document I shows how chest ultrasonography can be useful to detect and monitor pleural diseases, pleural effusions and pneumothorax and how it can assess diaphragmatic kinetics and pathologies. PMID- 23937881 TI - Rare cytogenetic abnormalities in acute myeloid leukemia transformed from Fanconi anemia - a case report. AB - BACKGROUND: Fanconi's anemia (FA) is an inherited bone marrow failure syndrome that carries a higher risk of transformation to acute myeloid leukemia (AML) when compared with general population. AML is the initial presentation in approximately one third of patients. CASE PRESENTATION: A 17 year old male presented to the emergency room with history of high grade fever since two weeks. Examination revealed pallor, short stature and thumb polydactyly. There was no visceromegaly or lymphadenopathy. Complete blood count showed haemoglobin 3.4 gm/dl, MCV 100 fl and MCH 36 pg, white blood cell count 55.9 * 10 E9/L and platelet count 8 * 10E9/L. Peripheral blood smear revealed 26% blast cells. Bone marrow was hypercellular exhibiting infiltration with 21% blast cells. Auer rods were seen in few blast cells. These findings were consistent with acute myelomonocytic leukemia. These blasts cells expressed CD33, CD13, HLA-DR, CD117, CD34 antigens and cytoplasmic myeloperoxidase on immunophenotyping. Bone marrow cytogenetics revealed 46, XY, t (8:21) (q22; q22) [11] / 46, XY, add (2) (q37), t (8; 21) [4] / 46, XY [5]. Molecular studies showed positivity of FLT 3 D835 variant and negativity of NPM 1 and FLT3 ITD (internal tandem domain) mutation. Peripheral blood analysis for chromosomal breakage exhibited tri-radial and complex figures. He received induction chemotherapy with cytarabine and daunorubicin (3 + 7). Day 14 marrow revealed clearance of blast cells. CONCLUSION: The recognition of specific cytogenetic abnormalities present in FA known to predispose to AML is crucial for early haematopoietic stem cell transplant (HSCT) before transformation to leukemia. PMID- 23937882 TI - Fondaparinux: an effective bridging strategy in heparin-induced thrombocytopenia and mechanical circulatory support. PMID- 23937883 TI - Aortic valve opening and thrombotic events with continuous-flow left ventricular assist devices. PMID- 23937884 TI - Tissue Doppler imaging for rejection surveillance in pediatric heart transplant recipients. AB - BACKGROUND: Most transplant centers perform serial cardiac biopsies for rejection surveillance in pediatric heart transplant (HT) recipients. We sought to assess tissue Doppler imaging (TDI) findings during biopsy specimen-proven rejection in pediatric HT recipients and to develop TDI criteria for absence of rejection with high predictive accuracy. METHODS: We included the 122 HT recipients in follow-up at our center (median age at HT, 8.7 years). We identified all echocardiograms with adequate TDI data performed within 24 hours of a cardiac biopsy during 2005 to 2011. Rejection was defined as Grade >= 2R cellular rejection or antibody mediated rejection. Paired comparisons of TDI velocities were made using patients' baseline velocities as the control. RESULTS: Overall, 647 specimen pairs were identified where there was no rejection at baseline. In 24 of these, the second biopsy specimen demonstrated rejection. Using receiver operating characteristic curve analysis of percentage change from baseline, we identified < 15% decline in left ventricular (LV) S' velocity and < 5% decline in LV A' velocity to individually predict non-rejection with > 99% accuracy. When joint criteria were used, the predictive accuracy was 100%, and no rejection event was misclassified. More than 75% of TDI pairs met these criteria for non-rejection. CONCLUSIONS: Biopsy specimen-proven rejection is associated with a significant decline in biventricular TDI velocities from baseline in pediatric HT recipients. By using well-defined TDI criteria to predict non-rejection, a substantial proportion of planned biopsies may be deferred or avoided at minimal risk to pediatric HT recipients. PMID- 23937885 TI - Continuous-flow left ventricular assist device exchange: clinical outcomes. AB - BACKGROUND: A percentage of patients with a left ventricular assist device (LVAD) require device exchange. Although this is an important clinical entity, there are only a handful of relevant studies on this topic in the literature. METHODS: From 2004 to 2012, 30 device exchanges (HeartMate II to HeartMate II) were performed. Since June 2011, we have employed the subcostal approach for device exchange if indicated. Sixteen patients underwent device exchange through a subcostal approach (S group), whereas 14 patients had devices exchanged through a full sternotomy (F group). Pre- and post-operative data were retrospectively reviewed. RESULTS: There was no difference in baseline patient characteristics between the two groups. Overall, mean duration between primary surgery and device exchange was 425 +/- 407 days. Surgical indications included device thrombus/hemolysis (N = 19), device malfunction (N = 9) and infection (N = 2). Cardiopulmonary bypass time was significantly shorter in the S group (S: 40 +/- 23 minutes, F: 105 +/- 84 minutes; p < 0.05), and post-operative bleeding within 24 hours after surgery was less in the S group (S: 362 +/- 367 ml, F: 1,286 +/- 971 ml; p < 0.05). Length of ICU stay was significantly shorter in the S group (S: 4.6 +/- 1.8 days, F: 8.2 +/- 4.9 days; p < 0.05). There was no difference in post-operative complications, except for prolonged intubation (F: N = 6 [43%], S: N = 1 [6.3%]; p < 0.05). There were 3 deaths in the F group and 0 in the S group, with no statistical difference (p = 0.09). Also, there was no significant difference in other outcomes, including transplantation, device explantation and ongoing LVAD support. CONCLUSIONS: A subcostal approach may be preferred for HeartMate II device exchange if indicated. PMID- 23937886 TI - Postoperative radiotherapy for completely resected Masaoka stage III thymoma: a retrospective study of 65 cases from a single institution. AB - BACKGROUND: The role of adjuvant radiotherapy (RT) for patients with stage III thymoma after complete resection is not definite. Some authors have advocated postoperative RT after complete tumor resection, but some others suggested observation. In this study, we retrospectively evaluated the effect of postoperative RT on survival as well as tumor control in patients with Masaoka stage III thymoma. METHODS: Between June 1982 and December 2010, 65 patients who underwent complete resection of stage III thymoma entered the study. Fifty-three patients had adjuvant RT after surgery (S + R) and 12 had surgery only (S alone). Of patients who had adjuvant RT, 28 had three-dimensional conformal RT (3D CRT)/intensity modulated RT (IMRT) and 25 had conventional RT. A median prescribed dose of 56 Gy (range, 28-60 Gy) was given. RESULTS: The median follow up time was 50 months (range, 5-360 months). Five- and 10-year overall survival (OS) rates were 91.7% and 71.6%, respectively, for S + R and 81.5% and 65.2% for S alone (P = 0.5), respectively. In the subgroup analysis, patients with 3D CRT/IMRT showed a trend of improved 5-year OS rate compared with conventional RT (100% vs. 86.9%, P =0.12). Compared with S alone, the 5-year OS rate was significantly improved (100% vs. 81.5%, P = 0.049). Relapses occurred in 15 patients (23.1%). There was a trend of lower crude local recurrence rates for S + R (3.8%) compared with S alone (16.7%) (P = 0.09), whereas the crude regional recurrence rates were similar (P = 0.9). No clear dose-response relationship was found according to prescribed doses. CONCLUSIONS: Adjuvant 3D-CRT/IMRT showed potential advantages in improving survival and reducing relapse in patients with stage III thymoma after complete resection, whereas adjuvant RT did not significantly improve survival or reduce recurrence for the cohort as a whole. Doses of <= 50 Gy may be effective and could be prescribed for adjuvant RT. To confirm the role of adjuvant 3D-CRT/IMRT in patients who undergo a complete resection of thymoma, a multicenter randomized study should be performed. PMID- 23937888 TI - Retraction: Severe contact dermatitis due to camomile: a common complementary remedy with potential sensitization risks. PMID- 23937887 TI - 5-HT2CR blockade in the amygdala conveys analgesic efficacy to SSRIs in a rat model of arthritis pain. AB - BACKGROUND: Pain, including arthritic pain, has a negative affective component and is often associated with anxiety and depression. However, selective serotonin reuptake inhibitor antidepressants (SSRIs) show limited effectiveness in pain. The amygdala plays a key role in the emotional-affective component of pain, pain modulation and affective disorders. Neuroplasticity in the basolateral and central amygdala (BLA and CeA, respectively) correlate positively with pain behaviors. Evidence suggests that serotonin receptor subtype 5-HT2CR in the amygdala contributes critically to anxiogenic behavior and anxiety disorders. In this study, we tested the hypothesis that 5-HT2CR in the amygdala accounts for the limited effectiveness of SSRIs in reducing pain behaviors and that 5-HT2CR blockade in the amygdala renders SSRIs effective. RESULTS: Nocifensive reflexes, vocalizations and anxiety-like behavior were measured in adult male Sprague Dawley rats. Behavioral experiments were done in sham controls and in rats with arthritis induced by kaolin/carrageenan injections into one knee joint. Rats received a systemic (i.p.) administration of an SSRI (fluvoxamine, 30 mg/kg) or vehicle (sterile saline) and stereotaxic application of a selective 5-HT2CR antagonist (SB242084, 10 MUM) or vehicle (ACSF) into BLA or CeA by microdialysis. Compared to shams, arthritic rats showed decreased hindlimb withdrawal thresholds (increased reflexes), increased duration of audible and ultrasonic vocalizations, and decreased open-arm choices in the elevated plus maze test suggesting anxiety like behavior. Fluvoxamine (i.p.) or SB242084 (intra-BLA) alone had no significant effect, but their combination inhibited the pain-related increase of vocalizations and anxiety-like behavior without affecting spinal reflexes. SB242084 applied into the CeA in combination with systemic fluvoxamine had no effect on vocalizations and spinal reflexes. CONCLUSIONS: The data suggest that 5 HT2CR in the amygdala, especially in the BLA, limits the effectiveness of SSRIs to inhibit pain-related emotional-affective behaviors. PMID- 23937889 TI - Cross-sectional study of the association of body composition and physical fitness with bone status in children and adolescents from 11 to 16 years old. AB - BACKGROUND: The aim of the study was to verify the association between body composition and physical fitness with bone status in children and adolescents. METHODS: A cross-sectional study was conducted with 300 healthy students (148 boys, 152 girls). Weight, height, fat and fat-free mass, and percentage of body fat (%BF) were evaluated, as were physical fitness (abdominal exercise, flexibility, and horizontal jump tests) and maximum oxygen consumption. Bone parameters (amplitude-dependent speed of sound; AD-SoS) and the Ultrasound Bone Profile Index (UBPI) were evaluated using DBM Sonic BP ultrasonography. RESULTS: In the study group, girls had higher bone parameter values than boys. A univariate analysis assessed in a stepwise multiple regression model was conducted. It showed that for boys, the %BF and height were significant independent variables for AD-SoS and UBPI, but the horizontal jump test only for AD-SoS (adjusted r2 = 0.274; p < 0.001), and pubertal maturation only for UBPI (adjusted r2 = 0.295; p < 0.001). For girls, age and %BF were identified as significant independent variables for AD-SoS and UBPI (adjusted r2 = 0.093; p < 0.001) but height only for AD-SoS (adjusted r2 = 0.408; p < 0.001). CONCLUSIONS: Variables related to growth (age, height, and pubertal maturation) are independent positive predictors for the bone parameters in both boys and girls. %BF is an independent negative predictor. For boys, the horizontal jump test was an independent positive predictor for AD-SoS, indicating that physical fitness related to the neuromotor system can influence the amount of bone present. PMID- 23937890 TI - The hemozoin conundrum: is malaria pigment immune-activating, inhibiting, or simply a bystander? AB - In malaria, hemozoin (Hz) is released during erythrocyte rupture, and subsequent phagocytosis appears to cause important immune-modulatory effects. Hz obtained from Plasmodium falciparum cultures or synthesized from heme is used to study this modulation in vitro. Immune-activating and suppressive effects have been reported, and these discrepant results are often attributed to the different types of Hz that were used. However, it remains unclear which type of Hz accurately reproduces what happens in vivo. Importantly, Hz remains in the body for long periods and appears to be actively redistributed. Thus, phagocytosis of Hz in the body is not static but probably happens more than once, and the characteristics of Hz may change over time, eventually causing different immune modulatory effects. PMID- 23937891 TI - Modelling the landscape of palliative care for people with dementia: a European mixed methods study. AB - BACKGROUND: Palliative care for people with dementia is often sub-optimal. This is partly because of the challenging nature of dementia itself, and partly because of system failings that are particularly salient in primary care and community services. There is a need to systematize palliative care for people with dementia, to clarify where changes in practice could be made.To develop a model of palliative care for people with dementia that captures commonalities and differences across Europe, a technology development approach was adopted, using mixed methods including 1) critical synthesis of the research literature and policy documents, 2) interviews with national experts in policy, service organisation, service delivery, patient and carer interests, and research in palliative care, and 3) nominal groups of researchers tasked with synthesising data and modelling palliative care. DISCUSSION: A generic model of palliative care, into which quality indicators can be embedded. The proposed model includes features deemed important for the systematisation of palliative care for people with dementia. These are: the division of labour amongst practitioners of different disciplines; the structure and function of care planning; the management of rising risk and increasing complexity; boundaries between disease modifying treatment and palliative care and between palliative and end-of-life care; and the process of bereavement. SUMMARY: The co-design approach to developing a generic model of palliative care for people with dementia has placed the person needing palliative care within a landscape of services and professional disciplines. This model will be explored further in the intervention phase of the IMPACT project. PMID- 23937892 TI - Confinement during field studies may jeopardize antioxidant and physiological responses of Nile tilapia to contaminants. AB - This work evaluates the effects of caging, a known confinement stress, in Nile tilapia (Oreochromis niloticus) during an environmental study in Cubatao river, southern Brazil. Caging animals for 7 days, regardless of being at the reference or at a contaminated site, resulted in lower levels of antioxidant-related defenses (glutathione, glutathione S-transferase, glucose-6-phosphate dehydrogenase) in liver and physiological parameters (blood glucose and lactate) as compared with free-swimming animals. Higher hepatic glutathione reductase activity and elevated Hb content could be associated to contaminant exposure. In conclusion, the confinement stress in caged Nile tilapia biochemical and physiological disturbances, acting as a confounding factor in field studies. PMID- 23937893 TI - Residency, site fidelity and habitat use of Atlantic cod (Gadus morhua) at an offshore wind farm using acoustic telemetry. AB - Because offshore wind energy development is fast growing in Europe it is important to investigate the changes in the marine environment and how these may influence local biodiversity and ecosystem functioning. One of the species affected by these ecosystem changes is Atlantic cod (Gadus morhua), a heavily exploited, commercially important fish species. In this research we investigated the residency, site fidelity and habitat use of Atlantic cod on a temporal scale at windmill artificial reefs in the Belgian part of the North Sea. Acoustic telemetry was used and the Vemco VR2W position system was deployed to quantify the movement behaviour. In total, 22 Atlantic cod were tagged and monitored for up to one year. Many fish were present near the artificial reefs during summer and autumn, and demonstrated strong residency and high individual detection rates. When present within the study area, Atlantic cod also showed distinct habitat selectivity. We identified aggregation near the artificial hard substrates of the wind turbines. In addition, a clear seasonal pattern in presence was observed. The high number of fish present in summer and autumn alternated with a period of very low densities during the winter period. PMID- 23937894 TI - Equity in health care utilization in Chile. AB - One of the most extensive Chilean health care reforms occurred in July 2005, when the Regime of Explicit Health Guarantees (AUGE) became effective. This reform guarantees coverage for a specific set of health conditions. Thus, the purpose of this study is to provide timely evidence for policy makers to understand the current distribution and equity of health care utilization in Chile.The authors analyzed secondary data from the National Socioeconomic Survey (CASEN) for the years 1992-2009 and the 2006 Satisfaction and Out-of-Pocket Payment Survey to assess equity in health care utilization using two different approaches. First, we used a two-part model to estimate factors associated with the utilization of health care. Second, we decomposed income-related inequalities in medical care use into contributions of need and non-need factors and estimated a horizontal inequity index.Findings of this empirical study include evidence of inequities in the Chilean health care system that are beneficial to the better-off. We also identified some key factors, including education and health care payment, which affect the utilization of health care services. Results of this study could help researchers and policy makers identify targets for improving equity in health care utilization and strengthening availability of health care services accordingly. PMID- 23937895 TI - [Anhedonia in depression]. AB - Anhedonia, or markedly diminished interest or pleasure, is a hallmark symptom of major depression, schizophrenia, and other neuropsychiatric disorders. The term "anhedonia" was introduced by the French psychologist Ribot in 1896 to describe the counterpart to analgesia in his patients, for which "it was impossible to find the least pleasure". Over the last decades, the clinical definition of anhedonia has remained relatively unchanged, but recently, behavioral neurosciences have significantly changed our knowledge of reward-related processes. Now, the construct of anhedonia reflects deficits in hedonic capacity, and is closely linked to the processes of reward valuation, decision-making, anticipation, and motivation. The neural circuits underlying these reward-related mechanisms include essentially the ventral striatum and prefrontal cortical regions. Here, we review the clinical concepts, neural bases and psychopharmacological data related to the deficits of hedonia in depression. Understanding anhedonia will facilitate diagnosis and treatment management. PMID- 23937898 TI - Mercury in contaminated sites: identification, characterisation, impacts, and remediation. PMID- 23937897 TI - The role of chest ultrasonography in the management of respiratory diseases: document II. AB - Chest ultrasonography can be a useful diagnostic tool for respiratory physicians. It can be used to complete and widen the general objective examination also in emergency situations, at the patient's bedside. The aim of this document is to promote better knowledge and more widespread use of thoracic ultrasound among respiratory physicians in Italy.This document II is focused on advanced approaches to chest ultrasonography especially in diagnosing sonographic interstitial syndrome with physical hypotheses about the genesis of vertical artifacts, differential diagnosis of cardiogenic pulmonary edema and non cardiogenic pulmonary edema, raising diagnostic suspicion of pulmonary embolism, ultrasound characterization of lung consolidations and the use of ultrasonography to guide procedural interventions in pulmonology.Finally, document II focuses on chest ultrasonography as useful diagnostic tool in neonatal and pediatric care. PMID- 23937899 TI - Assessment of mercury erosion by surface water in Wanshan mercury mining area. AB - Soil erosion is a main cause of land degradation, and in its accelerated form is also one of the most serious ecological environmental problems. Moreover, there are few studies on migration of mercury (Hg) induced by soil erosion in seriously Hg-polluted districts. This paper selected Wanshan Hg mining area, SW China as the study area. Revised universal soil loss equation (RUSLE) and Geographic information system (GIS) methods were applied to calculate soil and Hg erosion and to classify soil erosion intensity. Our results show that the soil erosion rate can reach up to 600,884tkm(-2)yr(-1). Surfaces associated with very slight and extremely severe erosion include 76.6% of the entire land in Wanshan. Furthermore, the cumulative erosion rates in the area impacted by extremely severe erosion make up 90.5% of the total. On an annual basis, Hg surface erosion load was predicted to be 505kgyr(-1) and the corresponding mean migration flux of Hg was estimated to be 3.02kgkm(-2)yr(-1). The erosion loads of Hg resulting from farmland and meadow soil were 175 and 319kgyr(-1) respectively, which were enhanced compared to other landscape types due to the fact that they are generally located in the steep zones associated with significant reclamation. Contributing to establish a mass balance of Hg in Wanshan Hg mining area, this study supplies a dependable scientific basis for controlling soil and water erosion in the local ecosystems. Land use change is the most effective way for reducing Hg erosion load in Wanshan mining area. PMID- 23937900 TI - Immunofluorescence labeling of cell surface antigens in Dictyostelium. AB - BACKGROUND: Immunolocalization of cellular antigens typically requires fixation and permeabilization of cells, prior to incubation with antibodies. FINDINGS: Assessing a test protein abundantly present at the cell surface of Dictyostelium cells, we show that in fixed cells, permeabilization extracts almost completely this cell surface antigen. The extent of this artifact is variable depending on the procedure used for labeling and permeabilization, as well as on the antigen considered. CONCLUSIONS: An optimized protocol for labeling both surface and intracellular antigens without significant loss of labeling is proposed. PMID- 23937901 TI - Intramembrane proteolysis by rhomboids: catalytic mechanisms and regulatory principles. AB - Rhomboids are intramembrane serine proteases that cleave membrane proteins within the bilayer, and which control a wide variety of biological processes. Recent structures of Escherichia coli rhomboids in complex with mechanism-based inhibitors provide insight into their catalytic mechanism. The inhibitor structures also reveal potential substrate-binding sites within the enzyme and provide a template for modeling substrate binding at the active site. The regulation of rhomboid activity exploits the different membrane compartments in cells to segregate enzyme and substrate. Catalytically inactive rhomboid-like proteins called iRhoms provide another form of regulation, by interacting with rhomboid substrates and preventing their cleavage. Extramembranous domains of rhomboids may play an as yet unexplored role in substrate recognition and regulation. PMID- 23937902 TI - The structural basis of specific protease-inhibitor interactions at the plant pathogen interface. AB - Antagonistic host-pathogen interactions offer intriguing insights into coevolutionary processes at the molecular level. Studies on secreted immune proteases from the model plant tomato and their interactions with different unrelated pathogen-derived inhibitors revealed that the inhibitors exhibit a remarkable selectivity towards different host proteases, and that the host proteases accumulate variant residues at the interaction surfaces that interfere with inhibitor binding. Here, we summarize and discuss the recent findings and use structural models to identify the molecular features underpinning protease selectivity. The observed basic principles translate to other examples of secreted immune hydrolases and their putative inhibitors. PMID- 23937903 TI - Hereditary angioedema with C1 inhibitor deficiency: delay in diagnosis in Europe. AB - BACKGROUND: Hereditary angioedema (HAE) is a rare, debilitating, and potentially life-threatening disease characterized by recurrent edema attacks. Important advances in HAE treatment have been made, including the development of new therapies for treating or preventing attacks. Nevertheless, the disease is still frequently misdiagnosed and inappropriately treated, potentially exposing patients with laryngeal attacks to the risk of asphyxiation. METHODS: The Icatibant Outcome Survey (IOS) is an international, observational study that documents the clinical outcome of HAE patients eligible for treatment with icatibant. Patient ages at first symptoms and at diagnosis were recorded at enrolment, and the delay between first symptoms and diagnosis was calculated. RESULTS: The median [range] diagnostic delay in HAE type I and II patients across eight countries was 8.5 years [0-62.0]. The median delay in diagnosis was longer for HAE type II versus type I (21 versus 8 years, respectively), although this did not quite reach statistical significance. CONCLUSIONS: Although it can be difficult to differentiate HAE symptoms from those of more common angioedema sub types (e.g. idiopathic or acquired angioedema), our results show that HAE type I and II patients have an unacceptable delay in diagnosis, even those with a family history of the disease. Raising physician awareness of this disabling and potentially fatal disease may lead to a more accurate diagnosis and timely treatment. PMID- 23937904 TI - Objective assessment of drowsiness and reaction time during intermittent Ramadan fasting in young men: a case-crossover study. AB - BACKGROUND: Ramadan fasting and its attendant lifestyle changes induce changes in the circadian rhythm and in associated physiological and metabolic functions. Previous studies that have assessed psychomotor performance during Ramadan fasting have reported conflicting results. Therefore, we designed this study to objectively assess the effects of intermittent fasting during and outside Ramadan (to control for lifestyle changes) on drowsiness, blink total duration and mean reaction time (MRT) test while controlling for potential confounders. METHODS: Eight healthy volunteers with a mean age of 25.3 +/- 2.9 years and a mean body mass index (BMI) of 23.4 +/- 3.2 kg/m2 reported to the sleep laboratory on four occasions for polysomnography (PSG) and drowsiness and psychomotor assessments as follows: 1) adaptation; 2) 4 weeks before Ramadan while performing the Islamic fasting for 1 week (baseline fasting) (BLF); 3) 1 week before Ramadan (non fasting baseline) (BL); and 4) during the second week of Ramadan while fasting (Ramadan). OPTALERTTM was used to objectively assess daytime drowsiness using the Johns Drowsiness Scale (JDS), and blink total duration and a visual reaction time test were used to assess MRT. RESULTS: Rapid eye movement (REM) sleep percentage was significantly lower at BLF (17.7 +/- 8.1%) and at Ramadan (18.6 +/- 10.7%) compared with BL (25.6 +/- 4.8%) (p < 0.05). There were no significant differences between JDS scores and blink total duration during the two test periods in BL, BLF and Ramadan. There were no significant changes in MRT during BL, BLF and Ramadan. CONCLUSIONS: Under controlled conditions of fixed light/dark exposure, caloric intake, sleep/wake schedule and sleep quality, the Islamic intermittent fasting has no impact on drowsiness and vigilance as measured by the JDS, total blink duration and MRT. PMID- 23937905 TI - Polyacetylenes from the leaves of Vernonia scorpioides (Asteraceae) and their antiproliferative and antiherpetic activities. AB - Polyacetylenes constitute an underexplored and unstable class of compounds that are found mainly in the Apiaceae, Araliaceae and Asteraceae families. Vernonia scorpioides (Lam.) Pers., Asteraceae is a lianous neotropical herb that usually grows in soils that have been deforested and are of poor quality. It is used in folk medicine for the treatment of several skin conditions. This study addresses the characterisation of eight polyacetylenes isolated from the leaves of V. scorpioides. Their structures were established on the basis of 1D and 2D NMR spectroscopy and MS analysis. Ab initio calculations including solvent effects were employed to aid the elucidation of the absolute configurations of the compounds. The in vitro antiproliferative and anti-herpetic activities of the polyacetylenes were determined. The isolated compounds presented no inhibitory effect against a human cell line of non-small cell lung cancer, but presented a mild non-selective in vitro antiviral activity, although their corresponding glycosides were inactive. PMID- 23937907 TI - The stability of osseous metastases of the spine in lung cancer--a retrospective analysis of 338 cases. AB - BACKGROUND: The objective of this retrospective analysis is to systematically assess osseous lesions on the basis of a validated scoring system in terms of stability and fractures prior to and following radiotherapy in 338 lung cancer patients with bone metastases in the vertebral column. METHODS: The stability of 338 patients with 981 osteolytic metastases in the thoracic and lumbar spine was evaluated retrospectively on the basis of the Taneichi-Score between January 2000 and January 2012. RESULTS: 64% (215 patients) were classified stable prior to radiotherapy. Of the stable osseous metastases, none were rated unstable in the further course (p < 0.001, McNemar test). Of the 123 patients in whom the metastases were classified unstable prior to radiotherapy, 21 patients (17%) were classified stable after three months, and 30 patients (24%) stable after six months. A pathological fracture was diagnosed in 62 patients (18%) prior to radiotherapy. Regarding cases of osteolytic metastases of the vertebral bodies in which no fractures could be detected prior to the start of therapy, fractures occurred in 2% of all patients (n = 7) within six months following radiotherapy. CONCLUSIONS: Our analysis demonstrated that pathological fractures following radiotherapy occur in the very minority of vertebral lesions for patients with a favorable outcome. The use of a systematic radiological scoring system to classify osteolytic metastases of the vertebral column has shown to be feasible in daily routine. Prospective clinical trials are warranted in order to analyse, to what extent patients with osseous metastases can be mobilized by physiotherapy for strengthening the paravertebral muscles before radiotherapy effects can be measured by means of radiological recalcification. PMID- 23937906 TI - USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy. AB - Reversible protein ubiquitination is emerging as a key process for maintaining cell homeostasis, and the enzymes that participate in this process, in particular E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly being regarded as candidates for drug discovery. Human DUBs are a group of approximately 100 proteins, whose cellular functions and regulatory mechanisms remain, with some exceptions, poorly characterized. One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays an important role in the cellular response to DNA damage. USP1 levels, localization and activity are modulated through several mechanisms, including protein-protein interactions, autocleavage/degradation and phosphorylation, ensuring that USP1 function is carried out in a properly regulated spatio-temporal manner. Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy. This view has gained recent support with the finding that USP1 inhibition may contribute to revert cisplatin resistance in an in vitro model of non-small cell lung cancer (NSCLC). Here, we describe the current knowledge on the cellular functions and regulatory mechanisms of USP1. We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data. Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells. PMID- 23937908 TI - The co-expression of functional gastric proteins in dynamic gastric diseases and its clinical significance. AB - BACKGROUND: Pepsinogen C (PGC) and mucin1 (MUC1) are important physiologically functional gastric proteins; Mucin2 (MUC2) is an "ectopic" functional protein in intestinal metaplasia of gastric mucosa. We analyzed the co-expression of the above-mentioned three proteins in dynamic gastric diseases {superficial gastritis (SG)-atrophic gastritis (AG)--gastric cancer (GC)} as well as different histological types of gastric cancer in order to find molecular phenotypes of gastric cancer and precancerous disease and further explore the potential co function of PGC, MUC1 and MUC2 in the occurrence and development of gastric cancer. METHODS: The SG-AG-GC sequence was 57-57-70 cases in this case-control study, respectively. Different histological types of GC were 28 cases of highly and moderately differentiated aden ocarcinoma (HMDA),30 of poorly differentiated adenocarcinoma (PDA) and 12 of mucinous adenocarcinoma (MA) or signet ring cell carcinoma (SRCC). PGC, MUC1 and MUC2 expression in situ were detected in all 184 cases using immunohistochemistry. RESULTS: Both PGC and MUC1 had a significantly decreased expression in GC than in SG and AG (P < 0.0001 and P < 0.01, respectively); While MUC2 had a significant increased expression in AG than in SG and GC (P < 0.0001). Seven phenotypes of PGC, MUC1 and MUC2 co-expression were found in which PGC+/MUC1+/MUC2- phenotype took 94.7%(54/57) in SG group; PGC+/MUC1+/MUC2+ and PGC-/MUC1+/MUC2+ phenotype took 43.9% (25/57) and 52.6% (30/57) in AG; the phenotypes in GC group appeared variable; extraordinarily, PGC /MUC1-/MUC2+ phenotype took 100% (6/6) in MA or SRCC group and had a statistical significance compared with others (P < 0.05). CONCLUSIONS: Phenotypes of PGC, MUC1 and MUC2 co-expression in dynamic gastric diseases are variable. In SG group it always showed PGC+/MUC1+/MUC2- phenotype and AG group showed two phenotypes (PGC+/MUC1+/MUC2+ and PGC-/MUC1+/MUC2+); the phenotypes in GC group appeared variable but the phenotype of PGC-/MUC1-/MUC2+ may be a predictive biomarker for diagnosing MA or SRCC, or distinguishing histological MA or SRCC from tubular adenocarcinoma accompanied by mucinous secretion or signet ring cell scattered distribution. PMID- 23937909 TI - High adiposity is associated cross-sectionally with low self-concept and body size dissatisfaction among indigenous Cree schoolchildren in Canada. AB - BACKGROUND: Obesity and mental health problems are prevalent among indigenous children in Canada and the United States. In this cross-sectional study the associations between adiposity and body size satisfaction, body image and self concept were examined in indigenous children in grades four to six living in Cree communities in the Province of Quebec (Canada). METHODS: Weight status and body mass index (BMI) z-scores were derived from children's measured height and weight using the World Health Organization growth reference. Multivariate regression models that included child's age and sex were used to assess the association between (a) weight status and physical appearance satisfaction using pictorial and verbal body rating measures in 202 of 263 children, and (b) BMI z-score and self-concept measured using the Piers-Harris Children's Self-Concept Scale in a subset of 78 children. RESULTS: Children (10.67 +/- 0.98 years) were predominantly overweight (28.2%) or obese (45.0%). Many (40.0%) children had low global self-concept indicating that they had serious doubts about their self worth and lacked confidence. About one-third (34.7%) of children did not like the way they looked and 46.3% scored low on the physical appearance and attributes domain of self-concept indicating poor self-esteem in relation to their body image and physical strength, feeling unattractive, or being bothered by specific aspects of their physical appearance. Compared to normal weight children, overweight and obese children were more likely to desire being smaller (OR=4.3 and 19.8, respectively), say their body size was too big (OR=7.7 and 30.6, respectively) and not liking the way they looked (OR=2.4 and 7.8, respectively). Higher BMI z-score was associated with lower scores for global self-concept (beta=-1.3), intellectual and school status (beta=-1.5) and physical appearance and attributes (beta=-1.3) indicating negative self-evaluations in these areas. Despite comparable weight status to boys, girls were more likely to have lower scores for global self-concept (beta=-3.8), physical appearance and attributes (beta=-4.2), desiring to be smaller (OR=4.3) and not liking the way they looked (OR=2.3). CONCLUSIONS: The psychosocial correlates of obesity are important considerations for indigenous children, particularly girls, given that poor self concept and body size dissatisfaction negatively impact mental and emotional qualities of life. PMID- 23937910 TI - Prior experience of interprofessional learning enhances undergraduate nursing and healthcare students' professional identity and attitudes to teamwork. AB - BACKGROUND: How willing are today's medical, nursing and other healthcare students to undertake some of their studies as shared learning? There is a lack of evidence of students' views by discipline despite this being a priority task for higher education sectors. This study explored the views of nursing, midwifery, nursing-emergency health (paramedic), medical, physiotherapy and nutrition-dietetics students. METHODS: Senior undergraduate students from six disciplines at one university completed the Readiness for Interprofessional Learning Scale prior to participating in interprofessional clinical learning modules. RESULTS: For 741 students, the highest ranked response was agreement about a need for teamwork (mean 4.42 of 5 points). Nursing students held significantly more positive attitudes towards Teamwork/Collaboration, and were more positive about Professional Identity than medical students (p < .001). Midwifery and nursing-emergency-health students rejected uncertainty about Roles/Responsibilities compared with medical students (p < .001). One-third of all students who had prior experience of interprofessional learning held more positive attitudes in each of four attitude domains (p < .05). CONCLUSION: Overall, students' attitudes towards interprofessional learning were positive and all student groups were willing to engage in learning interprofessionally. Early introduction of IPL is recommended. Further studies should explore the trajectory of students' attitudes throughout the university degree. PMID- 23937911 TI - High-throughput generation of spheroids using magnetic nanoparticles for three dimensional cell culture. AB - Various attempts have been made to develop three-dimensional (3-D) cell culture methods because 3-D cells mimic the structures and functional properties of real tissue compared with those of monolayer cultures. Here, we report on a highly simple and efficient 3-D spheroid generation method based on a magnetic pin-array system to concentrate magnetic nanoparticle-incorporated cells in a focal direction. This system was comprised only of external magnets and magnetically induced iron pins to generate a concentrated magnetic field for attracting cells in a focused direction. 3-D spheroid generation was achieved simply by adding magnetic nanoparticle-incorporated cells into a well and covering the plate with a magnetic lid. Cell clustering occurred rapidly within 5 min and created more compact cells with time through the focused magnetic force. This system ensured not only reproducible and size-controlled generation of spheroids but also versatile types of spheroids such as random mixed, core-shell, and fused spheroids, providing a very useful tool for various biological applications. PMID- 23937912 TI - Poly(N-isopropylacrylamide-co-acrylic acid) nanogels for tracing and delivering genes to human mesenchymal stem cells. AB - Drugs, proteins, and cells can be macro- and micro-encapsulated by unique materials that respond to specific stimuli. The phases and hydrophobic interactions of these materials are reversibly altered by environmental stimuli such as pH and temperature. These changes can lead to self-assembly of the materials, which enables controlled drug release and safe gene delivery into cells and tissues. The fate of stem cells delivered by such methods is of great interest. The formation of transgenic tissues requires genes to be delivered safely into stem cells. A cell tracing vehicle and a gene delivery carrier were simultaneously introduced into human mesenchymal stem cells (hMSCs). A thermo sensitive hydrogel, poly(N-isopropylacrylamide-co-acrylic acid) (p(NiPAAm-co AAc)), was created to generate self-assembled nanoparticles with nanogel characteristics. Hydrophobic interactions mediated the binding of the carboxyl group on the outside of p(NiPAAm-co-AAc) with the amine group of iron oxide. Nanogels carrying iron oxide and a fluorescent dye were complexed with specific genes. These nanogels could be internalized by hMSCs, and the transplantation of these cells into mice was monitored by in vivo imaging. Self-assembled p(NiPAAm co-dAAc) nanogels complexed with green fluorescent protein were highly expressed in hMSCs and are a potential material for gene delivery. PMID- 23937913 TI - Targeting colorectal cancer cells with single-walled carbon nanotubes conjugated to anticancer agent SN-38 and EGFR antibody. AB - In this study, single-walled carbon nanotubes (SWNTs) conjugated with antibody C225 were used to achieve targeted therapy against EGFR over-expressed colorectal cancer cells. In addition, the control release of the chemotherapeutic drug, 7 Ethyl-10-hydroxy-camptothecin (SN38), was studied. We used three different colorectal cancer cell lines, HCT116, HT29, and SW620, listed in the order of decreasing expression levels of EGFR. Our results showed that SWNT could use C225 to specifically bind to EGFR-expressed cells. The cellular uptakes of SWNT of EGFR over-expressed cells (HCT116 and HT29) were much higher than that of the negative control (SW620). We, next, demonstrated that receptor-mediated endocytosis was the primary cell entry route for SWNT. As a consequence, abundant amount of SN38 was released and EGFR over-expressed cells were killed. The drug control release process was studied by utilizing human carboxylesterase enzyme (hCE) that would break the bond linking SN38 and SWNT-carrier in cytoplasm. The intracellular SN38 release observed by confocal microscopy showed that SN38 actually dissociated from the SWNT-carrier first. SN38's entry to nucleus was then followed while the SWNT-carrier still remained in the cytoplasm. Overall, all these data suggested that SWNT could be a good carrier for targeting controlled release therapy. PMID- 23937914 TI - Comparison and characterization of multiple biomaterial conduits for peripheral nerve repair. AB - Four biomaterial tubes, poly(lactic-co-glycolic acid) (PLGA), poly(caprolactone fumarate) (PCLF), a neutral oligo[(polyethylene glycol) fumarate] (OPF) hydrogel or a positively charged oligo[(polyethylene glycol) fumarate] (OPF(+)) hydrogel with a PCLF sleeve, have previously been shown to have benefits for nerve repair. However, no direct comparison to identify the optimal material have been made. Herein, these nerve tubes were implanted in a rat sciatic nerve model and nerve regeneration was quantified and compared by using accepted nerve assessment techniques. Using standard statistical methods, no significant differences of individual parameters were apparent between groups despite PCLF showing a tendency to perform better than the others. Using a mean-variance based ranking system of multiple independent parameters, statistical differences became apparent. It was clear that the PLCF tube supported significantly improved nerve regeneration and recovery compared to the other three biomaterial conduits. The ability to simultaneously compare a number of regenerative parameters and elucidate the best material from the combination of these individual parameters is of importance to the nerve regeneration area and has implications for the tissue engineering field. By using this method of comparison, a number of biomaterial constructs may be compared under similar conditions and the optimal construct elucidated using the minimal number of animals and materials. PMID- 23937915 TI - 3D graphene oxide-encapsulated gold nanoparticles to detect neural stem cell differentiation. AB - Monitoring of stem cell differentiation and pluripotency is an important step for the practical use of stem cells in the field of regenerative medicine. Hence, a new non-destructive detection tool capable of in situ monitoring of stem cell differentiation is highly needed. In this study, we report a 3D graphene oxide encapsulated gold nanoparticle that is very effective for the detection of the differentiation potential of neural stem cells (NSCs) based on surface-enhanced Raman spectroscopy (SERS). A new material, 3D GO-encapsulated gold nanoparticle, is developed to induce the double enhancement effect of graphene oxide and gold nanoparticle on SERS signals which is only effective for undifferentiated NSCs. The Raman peaks achieved from undifferentiated NSCs on the graphene oxide (GO) encapsulated gold nanoparticles were 3.5 times higher than peaks obtained from normal metal structures and were clearly distinguishable from those of differentiated cells. The number of CC bonds and the Raman intensity at 1656 cm( 1) was found to show a positive correlation, which matches the differentiation state of the NSCs. Moreover, the substrate composed of 3D GO-encapsulated gold nanoparticles was also effective at distinguishing the differentiation state of single NSC by using electrochemical and electrical techniques. Hence, the proposed technique can be used as a powerful non-destructive in situ monitoring tool for the identification of the differentiation potential of various kinds of stem cells (mesenchymal, hematopoietic, and neural stem cells). PMID- 23937916 TI - Persistent unilateral facial pain in lung cancer patients with mediastinal nodal involvement. AB - Persistent idiopathic facial pain associated with mediastinal involvement in non small cell lung cancer (NSCLC) may occur at presentation or at relapse. It is often under-recognised, leading to prolonged symptoms, distress and sometimes inappropriate interventions. We present three case histories and a review of the published literature to highlight this important symptom. PMID- 23937917 TI - Memory loss during lenalidomide treatment: a report on two cases. AB - BACKGROUND: There are many reports of cognitive dysfunction in patients receiving chemotherapy or targeted therapies. Many antineoplastic agents may be involved in the condition also known as "chemo brain" or "chemo fog". CASE PRESENTATION: Two male patients (aged 41 and 70) with multiple myeloma developed severe, rapidly progressing cognitive impairment (mostly involving episodic memory) and loss of independence in activities of daily living during lenalidomide-based treatment. On withdrawal of the drug, one patient recovered normal cognitive function and independence in activities of daily living, whereas mild cognitive impairment persisted in the other patient. The Naranjo Adverse Drug Reaction Probability Scale score was 6 out of 13 for the first patient and 5 out of 13 for the second, suggesting a probable causal relationship between the adverse event and lenalidomide administration. CONCLUSION: Lenalidomide may induce particular cognitive disorders (notably episodic memory impairments) in some patients. The drug's putative neurotoxicity is probably promoted by specific risk factors (such as previous chemotherapy, prior mild cognitive impairment, age and the presence of cerebrovascular lesions). PMID- 23937918 TI - Voxel-level comparison of arterial spin-labeled perfusion magnetic resonance imaging in adolescents with internet gaming addiction. AB - BACKGROUND: Although recent studies have clearly demonstrated functional and structural abnormalities in adolescents with internet gaming addiction (IGA), less is known about how IGA affects perfusion in the human brain. We used pseudocontinuous arterial spin-labeling (ASL) perfusion functional magnetic resonance imaging (fMRI) to measure the effects of IGA on resting brain functions by comparing resting cerebral blood flow in adolescents with IGA and normal subjects. METHODS: Fifteen adolescents with IGA and 18 matched normal adolescents underwent structural and perfusion fMRI in the resting state. Direct subtraction, voxel-wise general linear modeling was performed to compare resting cerebral blood flow (CBF) between the 2 groups. Correlations were calculated between the mean CBF value in all clusters that survived AlphaSim correction and the Chen Internet Addiction Scale (CIAS) scores, Barratt Impulsiveness Scale-11 (BIS-11) scores, or hours of Internet use per week (hours) in the 15 subjects with IGA. RESULTS: Compared with control subjects, adolescents with IGA showed significantly higher global CBF in the left inferior temporal lobe/fusiform gyrus, left parahippocampal gyrus/amygdala, right medial frontal lobe/anterior cingulate cortex, left insula, right insula, right middle temporal gyrus, right precentral gyrus, left supplementary motor area, left cingulate gyrus, and right inferior parietal lobe. Lower CBF was found in the left middle temporal gyrus, left middle occipital gyrus, and right cingulate gyrus. There were no significant correlations between mean CBF values in all clusters that survived AlphaSim correction and CIAS or BIS-11 scores or hours of Internet use per week. CONCLUSIONS: In this study, we used ASL perfusion fMRI and noninvasively quantified resting CBF to demonstrate that IGA alters the CBF distribution in the adolescent brain. The results support the hypothesis that IGA is a behavioral addiction that may share similar neurobiological abnormalities with other addictive disorders. PMID- 23937919 TI - Precocious pseudopuberty due to an autonomous ovarian follicular cyst: case report with a review of literatures. AB - BACKGROUND: Small follicular cysts are commonly found in the ovaries of prepubertal girls, and in most cases, they are of no clinical importance. These cysts are usually self-limiting and resolve spontaneously. However, occasionally, these cysts may enlarge and continue to produce estrogen, resulting in signs of sexual precocity. Here, we report a case of precocious pseudopuberty associated with an autonomous ovarian follicular cyst. CASE PRESENTATION: A 5.9-year-old girl initially presented to a local clinic with vaginal bleeding and a large unilateral ovarian cyst. At 6 months after the initial acute episode, the patient visited our hospital as the ovarian cyst had persisted and increased in size. Endocrinological examination showed elevated estrogen levels and suppressed gonadotropin levels on GnRH stimulation test. Also, no skin pigmentation or bone anomaly was noted. Based on these observations, laparoscopic cystectomy was performed, and histologic analysis confirmed the diagnosis of a follicular cyst. After the laparoscopic cystectomy, the patient's hormone levels returned to normal and no ovarian cyst was detected by ultrasound. CONCLUSIONS: As autonomous ovarian cysts are usually self-limiting disorder, no treatment is necessary. Therefore, surgical management should be deferred as long as possible to avoid the risk of repeat surgery, as pseudoprecocious puberty due to autonomous ovarian cysts can resolve spontaneoulsy and frequently recurs. Precocious pseudopuberty with an ovarian cyst may be due to granulosa cell tumor or may be one symptom of the McCune-Albright Syndrome (MAS). A careful longer-term follow up of patients with autonomous ovarian cysts and/or molecular studies may be necessary in such cases. PMID- 23937920 TI - Infection following simultaneous bilateral total knee arthroplasty. AB - Between 2000 and 2009, demographics, clinical characteristics, and infection details were compared among patients undergoing simultaneous BTKA (SBTKA), staged or UTKA. 2825 (16%) patients underwent SB, 1151 (6%) staged, and 13,983 (78%) UTKA. The overall infection rate following SBTKA (0.57%) was lower compared to staged (1.39%) or UTKA (1.1%) (P=0.01). The in-hospital infection rate was lower for the SB group (0.28% vs. 0.96% vs. 0.69%, respectively, P=0.01). The rate of late infections was comparable between the groups (0.32% vs. 0.43% vs. 0.43%, respectively, P=0.72). The rate of superficial infection was lower in the simultaneous cohort (0.28% vs. 1.04% vs. 0.87%; P=0.003). The overall rate of deep infection and reoperation for infection was similar among the groups. Among patients with late infection, age, gender, comorbidity score, time to infection, and most common organism isolated were not significantly different between the groups. Among infected patients after SB or staged TKA, 3 SB patients (18.75%), and 3 staged (20%) had bilateral involvement (P=1.0). Staged patients had more 2nd side infections, while simultaneous patients had more 1st side infections (P=0.02). Regression analysis showed that UTKA patients were 2.5 times more likely to develop in-hospital infection compared to SBTKA, while staged patients were almost 3.4 times more likely. Each additional hospital day increased the risk of late infection by 11.3%. SBTKA demonstrates an advantage over staged and maintains the safety profile of unilateral approaches with respect to infectious complications. PMID- 23937921 TI - Mortality after septic versus aseptic revision total hip arthroplasty: a matched cohort study. AB - Mortality rates after revision total hip arthroplasty (THA) for periprosthetic sepsis were investigated in 93 patients and compared to 93 patients, matched for age, gender, year of surgery, who underwent revision for aseptic failures. The mortality rate was 33% (31/93) in the septic group and 22% (20/93) in the aseptic group at 5 and 6 year follow-up, respectively (P=0.10). Patients in the septic group died on average 6 years earlier (74 versus 80 yrs; P<0.05) than those in the aseptic group. Charlson Comorbidity Index (CCI) was an independent predictor of mortality among the both groups (P<0.05), while age (P<0.01) was a predictor of mortality only in the aseptic group. While revision THA for sepsis alone did not predict increased mortality, a 33% mortality rate at five years in patients with an average age of 66 years and earlier death by 6 years compared to aseptic revisions is alarming. PMID- 23937922 TI - Correlation between stress shielding and clinical outcomes after total hip arthroplasty with extensively porous coated stems. AB - Relations between stress shielding and the clinical outcomes of total hip arthroplasty(THA) remain topics of debate. This study was performed on 51 patients that underwent unilateral primary THA with an extensively porous coated stem. Contralateral normal femurs were used as controls. Dual energy x-ray absorptiometry data was used to quantify bone mineral density(BMD) on proximal femurs. Clinical outcomes were estimated by using Harris hip scores (HHSs). BMD in operated sides were lower than in control sides. HHS and pain scores were not related to BMD changes. An extensively porous coated stem can be used for THA and that concerns regarding the effects of stress shielding of the proximal femur are unwarranted. PMID- 23937923 TI - Dexamethasone reduces length of hospitalization and improves postoperative pain and nausea after total joint arthroplasty: a prospective, randomized controlled trial. AB - Controlling postoperative pain and nausea after total joint arthroplasty remains an important challenge. We conducted a prospective, randomized controlled trial with 120 patients to determine if the addition of perioperative dexamethasone to a multimodal regimen improves antiemetic and analgesic control, enhances mobility, and shortens hospital length of stay after total hip and knee arthroplasty. Patients administered 10mg of intravenous dexamethasone intraoperatively consumed less daily rescue anti-emetic and analgesic medication, reported superior VAS nausea and pain scores, ambulated further distances, and had a significantly shorter length of stay compared to the control group (P<0.05). A second, 24-hour postoperative dose of 10mg intravenous dexamethasone provided significant additional pain and nausea control and further reduced length of stay (P<0.05). No adverse events were detected with the administration of the intraoperative and/or postoperative dexamethasone. PMID- 23937924 TI - Surgeon delivered psoas compartment block in total hip arthroplasty. AB - Total hip arthroplasty is associated with significant postoperative pain. A psoas compartment block is superior to other regional techniques in analgesia post THA. However, traditional methods of delivery are associated with serious complications. We present a technique of a surgeon delivered lumbar plexus block through injection at the portion of the iliopsoas seen intraoperatively. We randomised fifty-three consecutive patients into two groups. The group that received the block had an increased period prior to requesting supplementary analgesia and lower overall pain scores. There were no adverse effects. We have demonstrated the analgesic efficacy of Psoas Compartment Block performed during surgical access for total hip arthroplasty. This technique should be considered in the analgesic regimen for total hip arthroplasty. PMID- 23937925 TI - Peak knee flexion angles during stair descent in TKA patients. AB - Reduced peak knee flexion during stair descent (PKSD) is demonstrated in subjects with total knee arthroplasty (TKA), but the underlying factors are not well studied. 3D gait patterns during stair descent, peak passive knee flexion (PPKF), quadriceps strength, pain, proprioception, demographics, and anthropometrics were assessed in 23 unilateral TKA-subjects ~19 months post-operatively, and in 23 controls. PKSD, PPKF and quadriceps strength were reduced in the TKA-side, but also in the contralateral side. A multiple regression analysis identified PPKF as the only predictor (57%) to explain the relationship with PKSD. PPKF was, however sufficient for normal PKSD. Deficits in quadriceps strength in TKA-group suggest that strength is also contributing to smaller PKSD. Increased hip adduction at PKSD may indicate both compensatory strategy and reduced hip strength. PMID- 23937927 TI - Characteristics of small to medium-sized rotator cuff tears with and without disruption of the anterior supraspinatus tendon. AB - BACKGROUND: The purpose of this study was to examine the baseline function and results of arthroscopic cuff repair in shoulders with small and medium-sized full thickness cuff tears with complete supraspinatus disruption compared with those with an intact anterior supraspinatus tendon. METHODS: The study evaluated 112 subjects with small and medium-sized cuff tears. Subjects were grouped according to anterior supraspinatus integrity (83 shoulders intact, group 1; and 29 shoulders with anterior supraspinatus tendon disruption, group 2). Functional assessments included visual analogue scale for pain, American Shoulder and Elbow Surgeons (ASES) score, Simple Shoulder Test score, and Constant score. Repair integrity was assessed by ultrasound examination. RESULTS: Group 2 shoulders had greater mean tear width, length, and area (P < .0001) and greater supraspinatus muscle degenerative changes (P < .0001) compared with shoulders with an intact anterior supraspinatus tendon. There were no differences in demographics or baseline function (ASES score: 45 group 1 vs 46 group 2, P = .79; Constant score: 56 group 1 vs 52 group 2, P = .29) before surgery. There were no differences in any functional parameter (ASES score: 92 group 1 vs 93 group 2, P = .71; Constant score: 84 group 1 vs 85 group 2, P = .84) after surgery. There was no difference in tendon healing rates (93% group 1 vs 86% group 2; P = .26). CONCLUSIONS: In the setting of painful small and medium-sized rotator cuff tears, disruption of the anterior supraspinatus tendon was associated with greater tear size and more advanced supraspinatus muscle degeneration. However, anterior supraspinatus tendon integrity had no influence on the clinical presentation or the functional and structural results of cuff repair surgery. PMID- 23937928 TI - Shoulder arthroplasty for osteoarthritis secondary to glenoid dysplasia: an update. AB - BACKGROUND: Glenoid component fixation is an issue in shoulder arthroplasty for glenoid dysplasia with osteoarthritis because of the small amount of bone available. In 2002, we described 6 patients (7 shoulders) undergoing shoulder arthroplasty for this condition. This report expands that experience to further understand the role of anatomic shoulder arthroplasty (both hemiarthroplasty and total shoulder arthroplasty), to outline results, and to identify complications and reoperations-all to better understand whether other treatment options need to be developed and explored. Our hypothesis is that treatment of this problem with anatomic arthroplasty is not ideal. METHODS: Between 1980 and 2008, 20 patients (22 shoulders) underwent anatomic shoulder arthroplasty for treatment of osteoarthritis secondary to glenoid dysplasia. There were 8 hemiarthroplasties and 14 total shoulder arthroplasties. Average follow-up was 6 years (range, 0.4 to 23.1 years). RESULTS: Pain was relieved in 4 of 8 shoulders undergoing hemiarthroplasty and in 10 of 14 shoulders undergoing total arthroplasty. Mean active elevation improved from 96 degrees to 125 degrees , and external rotation improved from 19 degrees to 42 degrees . Motion improvements were similar for hemiarthroplasty and total shoulder arthroplasty. Four shoulders having hemiarthroplasty underwent revision surgery because of painful glenoid arthrosis. Two shoulders with total arthroplasty underwent revision for infection, and 3 underwent revision for glenoid component issues. CONCLUSION: Favorable results can be obtained with the use of anatomic implants in the treatment of glenoid dysplasia. However, continuing subluxation, glenoid arthrosis, and glenoid component problems necessitating revision surgery are frequent. Alternative treatment methods should be considered. PMID- 23937926 TI - Pronounced cancer resistance in a subterranean rodent, the blind mole-rat, Spalax: in vivo and in vitro evidence. AB - BACKGROUND: Subterranean blind mole rats (Spalax) are hypoxia tolerant (down to 3% O2), long lived (>20 years) rodents showing no clear signs of aging or aging related disorders. In 50 years of Spalax research, spontaneous tumors have never been recorded among thousands of individuals. Here we addressed the questions of (1) whether Spalax is resistant to chemically-induced tumorigenesis, and (2) whether normal fibroblasts isolated from Spalax possess tumor-suppressive activity. RESULTS: Treating animals with 3-Methylcholantrene (3MCA) and 7,12 Dimethylbenz(a) anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA), two potent carcinogens, confirmed Spalax high resistance to chemically induced cancers. While all mice and rats developed the expected tumors following treatment with both carcinogens, among Spalax no tumors were observed after DMBA/TPA treatment, while 3MCA induced benign fibroblastic proliferation in 2 Spalax individuals out of12, and only a single animal from the advanced age group developed malignancy 18 months post-treatment. The remaining animals are still healthy 30 months post-treatment. In vitro experiments showed an extraordinary ability of normal Spalax cultured fibroblasts to restrict malignant behavior in a broad spectrum of human-derived and in newly isolated Spalax 3MCA-induced cancer cell lines. Growth of cancer cells was inhibited by either direct interaction with Spalax fibroblasts or with soluble factors released into culture media and soft agar. This was accompanied by decreased cancer cell viability, reduced colony formation in soft agar, disturbed cell cycle progression, chromatin condensation and mitochondrial fragmentation. Cells from another cancer resistant subterranean mammal, the naked mole rat, were also tested for direct effect on cancer cells and, similar to Spalax, demonstrated anti-cancer activity. No effect on cancer cells was observed using fibroblasts from mouse, rat or Acomys. Spalax fibroblast conditioned media had no effect on proliferation of noncancerous cells. CONCLUSIONS: This report provides pioneering evidence that Spalax is not only resistant to spontaneous cancer but also to experimentally induced cancer, and shows the unique ability of Spalax normal fibroblasts to inhibit growth and kill cancer cells, but not normal cells, either through direct fibroblast-cancer cell interaction or via soluble factors. Obviously, along with adaptation to hypoxia, Spalax has evolved efficient anti-cancer mechanisms yet to be elucidated. Exploring the molecular mechanisms allowing Spalax to survive in extreme environments and to escape cancer as well as to kill homologous and heterologous cancer cells may hold the key for understanding the molecular nature of host resistance to cancer and identify new anti-cancer strategies for treating humans. PMID- 23937929 TI - Limb function after excision of a deltoid muscle sarcoma. AB - BACKGROUND: Limb function after excision of deltoid muscle sarcomas has not been thoroughly investigated, although a large defect of soft tissue often causes some degree of dysfunction after wide excision. We formulated a hypothesis that the limb functional results depend on the volume of the excised deltoid muscle and examined the clinical outcomes in patients with a sarcoma in the deltoid muscle treated by surgical resection. METHODS: The clinical outcomes of 8 patients with a malignant soft tissue tumor in the deltoid muscle were retrospectively reviewed. The following items were evaluated: type of excision of the deltoid muscle, including total excision, subtotal excision, and partial excision; surgical margins; reconstruction procedure used; postoperative complications; local recurrence; metastasis; survival; and functional results (determined by the Musculoskeletal Tumor Society scoring system). RESULTS: After surgical resection, reconstruction in 6 of 8 patients was performed by pedicled latissimus dorsi musculocutaneous or muscle flap or pedicled trapezius musculocutaneous flap. Two patients did not undergo reconstruction because skin closure was possible. The partial excision group had a Musculoskeletal Tumor Society score of 100.0%, and the subtotal excision case and the total excision group had scores of 76.6% and 82.2%, respectively. None of the patients has demonstrated any evidence of local recurrence. CONCLUSION: We conclude that the functional results may depend on the volume of the excised deltoid muscle. Latissimus dorsi and trapezius musculocutaneous flaps were found to be useful for covering a defect of the deltoid muscle, although these flaps did not contribute to function of the shoulder. PMID- 23937930 TI - Acute lateral dislocated clavicular fractures: arthroscopic stabilization with TightRope. AB - HYPOTHESIS: Type IIA, IIB, and V lateral clavicular fractures (Craig modification of the Neer classification) are characterized by a constant displacement and are associated with a high rate of nonunion. The aim of this study is to verify whether the reduction and arthroscopic stabilization of these clavicular fractures with coracoclavicular cerclage provide stable fixation to allow for bone healing. To date, the treatment of these fractures is still controversial in young active patients in whom functional requirements are to be met. METHODS: Fourteen male patients, with type IIA, IIB, and V lateral clavicular fractures (2 type IIA, 10 type IIB, and 2 type V) had been treated arthroscopically with a TightRope (Arthrex, Naples, FL, USA) and had a radiologic/clinical follow-up of at least 2 years. RESULTS: All fractures were confirmed to have healed without limitations in range of motion or loss of reduction. The acromioclavicular joint and the coracoclavicular interspace were restored to the level of the healthy site in all but 1 patient, in whom a reduction was observed because of hypercorrection of the fracture. The mean Constant score was 95, and all patients had a Simple Shoulder Test score of 12 points. Healing was delayed up to 20 days in 1 patient because of a skin infection, and the coracoid bone tunnel was too marginal in another patient, in whom the coracoid button broke the lateral side of the tunnel during fixation. CONCLUSIONS: The arthroscopic procedure with the TightRope allows for fracture healing with no loss of reduction in the acromioclavicular joint and full return to everyday activities. PMID- 23937931 TI - Is forensic science the last bastion of resistance against statistics? PMID- 23937932 TI - Difficulties of sex determination from forensic bone degraded DNA: A comparison of three methods. AB - Sex determination is of paramount importance in forensic anthropology. Numerous anthropological methods have been described, including visual assessments and various measurements of bones. Nevertheless, whatever the method used, the percentage of correct classification of a single bone usually varies between 80% and 95%, due to significant intra- and inter-population variations, and sometimes variations coming from secular trends. DNA is increasingly used in a forensic context. But forensic DNA extraction from bone raises several issues, because the samples are very often badly altered and/or in very small quantity. Nuclear DNA is difficult to get from degraded samples, according to low copy number, at least in comparison with mitochondrial DNA. In a forensic context (as in a paeleoanthropological context) DNA sex determination is usually complicated by the weak amount of DNA, the degraded nature of nucleic acids, the presence of enzymatic inhibitors in DNA extracts, the possible faint amplification of Y band and the risk of contamination during either excavation or manipulation of samples. The aim of this work was to compare three methods of DNA sex determination from bones: procedure #1 using a single PCR amplification, procedure #2 using a double PCR amplification, and procedure #3 adding bleaching for decontamination of the bone, instead of simply rubbing the bone. These processes were applied to samples of bones (49 samples coming from 39 individuals) that were in various states of post mortem alteration. The main results are the following. (i) No DNA could be extracted from three skulls (parietal bones, mastoid process), the compact bone of one rib, and the diaphysis of one femur; (ii) there was a contamination in three skulls; and (iii) the Y band did not appear in two male cases, with one of the three procedures (male tibia, procedure #2) and with procedures #2 and #3 (male femur). This study emphasises the main issue while working with altered bones: the impossibility to extract DNA in some cases, and, worth of all, the contamination of the sample or the faint amplification of Y band which leads to a wrong sex answer. Multiple and significant precautions have to be taken to avoid such difficulties. PMID- 23937933 TI - RNA cell typing and DNA profiling of mixed samples: can cell types and donors be associated? AB - Forensic samples regularly involve mixtures, which are readily recognised in forensic analyses. Combined DNA and mRNA profiling is an upcoming forensic practice to examine donors and cell types from the exact same sample. From DNA profiles individual genotypes may be deconvoluted, but to date no studies have established whether the cell types identified in corresponding RNA profiles can be associated with individual donors. Although RNA expression levels hold many variables from which an association may not be expected, proof of concept is important to forensic experts who may be cross examined about this possible correlation in court settings. Clearly, the gender-specificity of certain body fluids (semen, vaginal mucosa, menstrual secretion) can be instructive. However, when donors of the same gender or gender-neutral cell types are involved, alternatives are needed. Here we analyse basic two-component mixtures (two cell types provided by different donors) composed of six different cell types, and assess whether the heights of DNA and RNA peaks may guide association of donor and cell type. Divergent results were obtained; for some mixtures RNA peak heights followed the DNA results, but for others the major DNA component did not present higher RNA peaks. Also, variation in mixture ratios was observed for RNA profiling replicates and when different donor couples gave the same two body fluids. As sample degradation may affect the two nucleic acids and/or distinct cell types differently (and thus influence donor and cell type association), mixtures were subjected to elevated temperature or UV-light. Variation in DNA and RNA stability was observed both between and within cell types and depended on the method inducing degradation. Taken together, we discourage to associate cell types and donors from peak heights when performing RNA and DNA profiling. PMID- 23937934 TI - The age estimation of blood stains up to 30 days old using visible wavelength hyperspectral image analysis and linear discriminant analysis. AB - A novel application of visible wavelength hyperspectral image analysis has been applied to determine the age of blood stains up to 30 days old. Reflectance spectra from selected locations within the hyperspectral image, obtained from a portable instrument, were subjected to spectral pre-processing. This was followed by the application of a linear discriminant classification model, making estimations possible with an average error of +/-0.27days for the first 7 days and an overall average error of +/-1.17days up to 30 days. This is also the first reported study of the determination of the age of fresh blood stains (less than one day old) with an error of +/-0.09h. The studies have been made under controlled conditions and represent, at this stage, proof of concept results but also are the most accurate age estimation results for measurements between 0 and 30 days reported to date. The results are consistent with well-established kinetic processes suggesting that the pre-processing stages described are revealing spectroscopic changes which are reliably following the time dependent oxidation of HbO2. The potential for parameterisation of environmental factors to make the method generally applicable at crime scenes is discussed, along with the developments required to further improve classification and to make the instrument genuinely portable. PMID- 23937935 TI - Elemental profiling using ICPMS of methylamphetamine hydrochloride prepared from proprietary medication using the Moscow and hypophosphorous synthesis. AB - Illicit drugs manufactured from clandestine laboratories are often impure due to poor laboratory conditions, variations in synthesis and impure starting materials extracted either from common household products or pharmaceutical grade chemicals. Inductively coupled plasma mass spectrometry (ICPMS) can be utilised as a multi-element analytical tool to elicit the inorganic impurities which may be present in such samples, however the interpretation of the resultant data can be problematic and complex. This is particularly true when dealing with seized samples of unknown provenance. In this work, we have presented and interpreted inorganic profiles as a means to explore within and between batch variations in known provenance samples produced via two different popular synthetic routes. Samples were prepared from essential chemicals recovered from household materials and pharmaceutical medication available in the UK and extracted using different solvents. The presence or absence of elements in the final synthesised products could be linked to the synthesis route, salting out method and potentially the solvent used in the precursor extraction process. PMID- 23937936 TI - Identification of two cannabimimetic compounds WIN48098 and AM679 in illegal products. AB - Two synthetic cannabinoids have been identified, during a survey, as new adulterants; they might have been intended to be used as ingredients for smart drugs. The characterization of these compounds has been made by gas chromatography-mass spectrometry (GC-MS), Orbitrap high resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR), leading to the identification of WIN48098, a compound disclosed as a new adulterant in herbal and powder products, and AM679, identified in Italy for the first time. Taking into account the high number of synthetic cannabinoids seized during the last year in Italy, how quickly they appear on the illegal market and the rapidity required for analytical results, a method was developed for the simultaneous quantitation of several synthetic cannabinoids, using gas chromatography-flame ionization detection (GC-FID). PMID- 23937937 TI - Selective and sensitive detection of chromium(VI) in waters using electrospray ionization mass spectrometry. AB - From 2000 through 2011, there were 14 criminal cases of violations of the Clean Water Act involving the discharge of chromium, a toxic heavy metal, into drinking and surface water sources. As chromium(VI), a potential carcinogen present in the environment, represents a significant safety concern, it is currently the subject of an EPA health risk assessment. Therefore, sensitive and selective detection of this species is highly desired. This study reports the analysis of chromium(VI) in water samples by electrospray ionization mass spectrometry (ESI-MS) following its reduction and complexation with ammonium pyrrolidinedithiocarbamate (APDC). The reduction and subsequent complexation produce a characteristic [Cr(III)O]-PDC complex which can be detected as a protonated ion of m/z 507 in the positive ion mode. The detection is selective to chromium(VI) under acidic pH, even in the presence of chromium(III) and other metal ions, providing high specificity. Different water samples were examined, including deionized, tap, and river waters, and sensitive detection was achieved. In the case of deionized water, quantification over the concentration range of 3.7 to 148ppb gave an excellent correlation coefficient of 0.9904 using the enhanced MS mode scan. Using the single-reaction monitoring (SRM) mode (monitoring the characteristic fragmentation of m/z 507 to m/z 360), the limit of detection (LOD) was found to be 0.25ppb. The LOD of chromium(VI) for both tap and river water samples was determined to be 2.0ppb. A preconcentration strategy using simple vacuum evaporation of the aqueous sample was shown to further improve the ESI signal by 15 fold. This method, with high sensitivity and selectivity, should provide a timely solution for the real-world analysis of toxic chromium(VI). PMID- 23937938 TI - Determination of efficacy of fingermark enhancement reagents; the use of propyl chloroformate for the derivatization of fingerprint amino acids extracted from paper. AB - The analysis of the constituents of fingerprints has been described numerous times, mainly with the purpose of determining the aging effect on fingerprints or showing the differences between donors or groups of donors. In this paper we describe the use of derivatized amino acids to determine the efficacy of the visualization reagents 1,8-diazafluoren-9-one (DFO) and ninhydrin. At present certain conditions are used for the application of these reagents, as determined by trial-and-error investigations, to the effect on fingerprints. The recovery of amino acids from a porous surface can be used as a measure for the efficacy of a visualization agent. In this paper we describe a method for the determination of the amount of amino acid left after reaction with well known fingerprint visualization reagents. This will allow a more scientific approach to method development for fingermark enhancement techniques. Furthermore, investigations on the influence of the concentration of fingermark amino acids, the order of application of and exposure time to reagents and the influence of age of the amino acids were carried out. These studies have resulted in a broader understanding of the mechanism involved in visualization of fingermarks using DFO and ninhydrin. PMID- 23937939 TI - Visualisation of fingermarks and grab impressions on dark fabrics using silver vacuum metal deposition. AB - Vacuum metal deposition (VMD) involves the thermal evaporation of metal (silver) in a vacuum, resulting in a uniform layer being deposited on the specimen being treated. This paper examines the use of silver on dark fabrics, thus offering a simpler operation and more obvious colouration to that of the traditional use of gold and zinc metals which must be evaporated separately. The aim of this study was to investigate the effect of fabric type, donor, mark age and method of fingermark deposition on the quality of marks visualised using silver VMD. This was achieved by collecting fingermark deposits from fifteen donors, of both sexes and various ages, by a grab or a press method. Four different fabrics: satin, polyester, polycotton and cotton were studied over a 10day timeline of 1, 2, 3, 4, 5, 6, 7, 14, 21 and 28+ days. It was found that satin and polyester gave the most positive results, with polyester often producing excellent ridge detail. Cotton and polycotton were less successful with no ridge detail being observed. The donors also had an observable effect on the results obtained probably due to variations in secretions produced or pressures applied during specimen collection. The age of the mark or the method of mark deposition had little influence on the results obtained. Silver VMD is a viable process for visualising marks on certain dark fabrics and has the advantage over gold/zinc VMD in that the marks visualised are light in colour which contrasts well against the dark background. PMID- 23937941 TI - An investigation into the enhancement of fingermarks in blood on fruit and vegetables. AB - A number of studies have reported the successful enhancement of latent fingermarks on fruit and vegetables. A study was set up to identify the most effective technique for the enhancement of fingermarks in blood on various fruit and vegetables. The enhancement techniques targeted different components in blood and consisted of protein stains (e.g. acid black 1), peroxidase reagents (e.g. leuco crystal violet) and amino acid stains (e.g. ninhydrin). Different variables such as the ageing periods of the marks and a diminishing series were employed to assess the suitability and sensitivity of the enhancement techniques. Overall, the use of different protein stains appeared to be the most effective techniques for the enhancement of fingermarks in blood on fruit and vegetables. In addition, the aubergine and cucumber skins appeared to be the most responsive surface to the different chemical techniques during enhancement. On the contrary, little or no enhancement was achieved for fingermarks in blood on the nectarine fruit. PMID- 23937940 TI - An investigation into the enhancement of fingermarks in blood on paper with genipin and lawsone. AB - The abilities of two natural products, genipin and lawsone, to enhance blood contaminated fingermarks on papers of various porosities and colour were investigated and compared to the routinely used amino acid reagents, ninhydrin and 1,8-diazafluoren-9-one (DFO). Fingermarks in blood were deposited as a split depletion series on various paper types and colours for ageing periods of 6 weeks, 4 weeks, 2 weeks and 1 week before enhancement. The developed marks were observed under different lighting conditions, recorded and graded by way of attributing quantitative data to each series. Results indicated that while genipin showed some potential as a reagent for the enhancement of latent fingermarks, it displayed no suitability for the enhancement of fingermarks in blood on paper. Lawsone also failed to successfully enhance either type of fingermark. Upon comparison of the results with those of ninhydrin and DFO it was found that ninhydrin displayed the highest success rate of development of these marks. PMID- 23937942 TI - Solving underwater crimes: development of latent prints made on submerged objects. AB - Underwater crime scenes always present a challenge for forensic researchers, as the destructive effect of water considerably complicates the chances of recovering material of evidential value. The aim of this study is to tackle the problem of developing marks that have been left on submerged objects. Fingermark deposition was randomly made on two surfaces - glass and plastic whilst the material was submerged under tap water and then left for one to fifteen days before drying and development. For their later development, various reagents - Black Powder, Silver Metallic Powder, Fluorescent Powder, Sudan Black (powder and solution) and Small Particle Reagent - were used and the effectiveness of each of them on this particular type of evidence was then evaluated. The results show the possibility of obtaining good quality developed marks, even under such adverse circumstances. Further and wider research should, therefore, be undertaken in which other variables are introduced such as different substrates, other types of liquids, and environmental or time factors. PMID- 23937943 TI - Application of Raman spectroscopy in forensic investigation of questioned documents involving stamp inks. AB - Stamp pad inks from different manufacturers across India have been analyzed to investigate the feasibility of Raman scattering as a tool for forensic analysis of questioned documents involving stamp inks. Nine different stamping inks were analyzed by both Raman spectroscopic and HPTLC methods. The results demonstrate the effectiveness of these methods in classifying the investigated stamping inks based on their spectral pattern and HPTLC chromatogram. Raman scattering tool was able to determine the sequence of heterogeneous intersection strokes involving a blue stamp pad ink and other writing instruments, such as ballpoint pen ink (red and black), pencil and laser printer toner. However, this method was unable to resolve the exact sequencing for the intersection strokes involving investigated stamp ink and blue ballpoint ink or gel pen ink (all colors). PMID- 23937944 TI - The identification of individuals by observational gait analysis using closed circuit television footage. AB - This study investigated the ability of individuals with experience in gait analysis to identify people by observing features of gait recorded by closed circuit television cameras (CCTV). Seven experienced analysts each viewed five samples of footage. Each sample showed a "target walker" and five "suspect walkers." The task of the experienced analysts was to determine which, if any, of the "suspect walkers" was the "target walker." All of the participant "walkers" wore identical loose fitting clothing to mask anatomical and body contour features, and balaclavas to obscure facial features. The overall results showed that the experienced analysts made a correct decision in 124 of 175 cases (71%), significantly better than would have been expected to have occurred by chance (p<0.05). A significant variation in correct decisions (p<0.05) was shown to occur between the various angles from which the footage was recorded, footage recorded in the saggital plane showing the highest number of correct decisions. Significantly more correct decisions (p<0.05) were also shown to occur when the footage of the "target walker" and that of the "suspect walker" were taken from the same angle. The results suggest that individuals with experience in gait analysis perform well in the comparative identification of suspects from CCTV footage, and therefore do have a role to play as expert witnesses in this field. PMID- 23937945 TI - A contribution to the discussion on the safety of air weapons. AB - Firearms legislation in the UK stems from the Firearms Act 1968 with its definition of a firearm as a lethal barrelled weapon of any description. The Act allows certain exceptions to be held without licence, most notably air weapons although these are limited by The Firearms (Dangerous Air Weapons) Rules 1969 and related regulations to below 12ft lb (16.3J) for air rifles and below 6ft lb (8.1J) for air pistols. Despite this there are occasional fatalities, typically 1 or 2 each year in the UK, from legally owned air weapons. In the USA there are over 20,000 visits each year to emergency departments due to injuries from air weapons and paintball guns. Despite this, limited research appears to have been carried out into the safety of air weapons and the present study tries to address this. Fresh samples of animal tissue were obtained from an abattoir or butcher and were embedded in ballistic gelatin. Pig heart, lung, liver and shoulder were used. By firing pellets into gelatin alone and into the combination of the gelatin and animal tissue it was possible to compare gelatin as a model for these tissues. The depth of penetration was similar but the residual track appeared to remain more open in the animal tissue. Pellets penetrated completely through the organ, with total penetration of gelatin and organ being typically around 10 15cm. Samples of pig, cow and chicken skin were placed in contact with the gelatin or embedded in the gelatin to simulate the effect of skin on penetration into a body. Chicken skin had no effect, pig skin stopped the pellet and cow skin was perforated by the pellet. If cow skin was embedded in the gelatin there was little effect on the total amount of penetration, but cow skin on the front surface of the gelatin reduced penetration by about 30%. Computed tomography was used to examine the pellet track and to calculate the volume of damage produced. However, due to the similar densities of gelatin and organ a technique had to be developed to differentiate phases. A barium salt paste was applied to outer surfaces and iodine solution or barium nitrate solution containing red food colouring was injected into the pellet track to enhance the contrast of the track. The track through the gelatin tended to enclose itself whereas the track through the organ remained more open, presumably due to the inhomogeneity of the fibrous nature of the tissue. Pellets were also fired at construction materials (wood, plasterboard and brick) and computed tomography used to determine the volume of damage created. Pellets perforated single layers of wood and plasterboard and would embed in a second layer. However, if the two layers were in contact the pellet did not penetrate the first layer. An air rifle pellet could therefore perforate house construction materials, although the resultant kinetic energy would be low and further damage would be limited. Some of the possible physical parameters are discussed that might help predict the degree of damage caused, but from this study it is not possible to define a limit which could be proposed as safe. PMID- 23937946 TI - Systematical method for polyacrylamide and residual acrylamide detection in cosmetic surgery products and example application. AB - INTRODUCTION: In this paper, the authors presented a case of acrylamide poisoning in a middle-aged woman who had underwent unsuccessful cosmetic surgery six years earlier. The victim was told that the product that had been injected into her face was Restylane(r), which mainly contained sodium hyaluronate and was the first and only Food and Drug Administration (FDA)-approved dermal filler for lip enhancement in the USA for more than 20 years. Widespread facial infections occurred several years post-injection; finally, the victim had to undergo removal surgery. Acrylamide poisoning was strongly suspected based on the victim's clinical manifestation. The product that had been injected into the victim's face was probably polyacrylamide hydrogel-based product, which had been prohibited by the State Food and Drug Administration (SFDA) in China in 2006. To confirm this suspicion, a systematical method was established to differentiate varieties of cosmetic surgery products and identify residential acrylamide. METHODS: The removed objects, original products and a certified reference sample of Restylane(r) were collected for examination. A direct microscopic examination was applied as a rapid screening method. Fourier transform infrared (FTIR) microspectroscopy analysis was subsequently performed to distinguish the main components from each sample. Automated solid phase extraction, ultra high performance liquid chromatography (SPE UHPLC) analysis was ultimately utilised and optimised to detect the residual acrylamide. Chromatographic separation was achieved on an ACQUITY UHPLC HSS T3 column. The mobile phase consisted of 0.01% aqueous formic acid solution and acetonitrile. The tunable UV (TUV) detection wavelength was at 202nm. RESULTS: The microscopic examination indicated that different samples had different morphological characteristics, depending on their main components. The FTIR spectrum showed that different polymers could be distinguished according to the CO stretching vibration (1655cm(-1)), NH bending vibration (1540cm(-1)) and CO stretching vibration (1078 and 1045cm(-1)). The UHPLC results demonstrated that the calibration curve was linear in the range of 0.5-20.0MUg/mL, with a correlation coefficient of 0.999. The average recoveries of the method were 99-107% with an RSD of 1.6-6.3%. The detection limit was 0.1MUg/mL (S/N=3). The analytical time was 6min per sample. Acrylamide was detected in the allegedly Restylane(r) injection. CONCLUSIONS: This systematical method provides a rapid, accurate and sensitive determination of polyacrylamide and residual acrylamide. The microscopic and FTIR spectroscopic examinations help to verify the existence of polyacrylamide quickly and easily. The optimised SPE UHPLC-TUV method offers a simpler and more sensitive approach to confirm the amount of acrylamide, comparing to the methods in the literature. PMID- 23937947 TI - Development of a methodology for the standardisation and improvement of 'Smartphone' photography of patterned bruises and other cutaneous injuries. AB - Human bite-mark analyses can play a prominent role in forensic case investigations, including those involving sexual assault. High-quality photographs routinely secure a link between a bite-mark and an individual's dentition. Access to around the clock forensic photography, however, is often limited, resulting in delay and/or missed opportunities to record valuable evidence. The emergence of Smartphone high-quality photographic technology now provides a previously unimagined opportunity to gather timely forensic photographic evidence. Problems can arise, however, due to the relatively poor quality of the photographs, as a result of many of those taking photographs having received little or no forensic photography training. This study compares unassisted photography with assisted photography, by a specifically developed camera application (App), to provide a standardised method for taking forensic photographs. An App, written in Java, was hosted on the Google Android Operating System, on a Samsung Galaxy SII Smartphone. Twenty-four volunteers participated in a study to photograph a pseudo bite-mark using three methods, (1) unassisted (as a control), (2) assisted by an ABFO No.2 right-angled photographic reference scale and (3) assisted by the App. The App, method (3), was shown to consistently outperform methods (1) and (2), demonstrating greater standardisation and precision (p<0.001). Analysis of the data showed the extent to which acquiring an accurate photograph depends on the image being orthogonal to the camera. It appears likely that the relatively inaccurate photographs acquired by methods (1) and (2), were as a result of deviation from the plane, orthogonal to the bite mark. Therefore, the App was successful in ensuring that the camera was both orthogonal and at an appropriate distance, relative to the bite-mark. Thus, the App enhanced the abilities of non-experts to acquire more accurate photographs and created the potential to significantly improve the quality of forensic photographs. PMID- 23937948 TI - Corrosion behaviour of four handguns in aqueous environments: corrosion product characterization and effects on estimating the time since deposition. AB - When a firearm has been disposed of in a body of water and becomes corroded, its appearance is altered and determining a time-since-immersion may be of import to the investigation. Therefore, in this study, the corrosion and mass loss of four handgun slides over a period of 180days were examined. Solid-state characterization of the metals and their corrosion products via SEM/EDX and powder X-ray Diffraction (pXRD) was performed. The pXRDs were analyzed against the NIST Powder Diffraction Database to determine the crystalline phases. Filings from the SS416 standard, Llama and Ruger handgun slide predominantly consisted of iron alloys. After 180-days in solution, pXRD indicated that the adherent corrosion products consisted of 1) gamma-FeOOH and 2) iron oxide (Fe3O4 or Fe2O3). Additionally, pXRD analysis indicated that the adherent corrosion products of the SS416 standard also consisted of CrO3. Metal filings from the Raven and Jennings handgun slides were a mixture of iron-nickel-zinc and EDX and pXRD analyses of the corrosion products, when submersed in deionized water, indicated that the products consisted of: 1) gamma-FeOOH, 2) iron oxide (Fe3O4 or Fe2O3), and 3) ZnFe2O4 or ZnO; where the Jennings adherent rust contained ZnFe2O4 and the Raven adherent rust contained ZnO. Further, pXRD of the corrosion products from these alloys, when submersed in 25 PSU (Practical Salinity Unit) solution, indicated that the products consisted of: 1) ZnO, 2) Zn(OH)2, 3) alpha Ni(OH)2, and 4) NaCl. The data thus indicated that both metal composition and the presence of chloride ions had significant impacts on rates and products of corrosion and suggest that the presence of Cl(-) changes not only the rate of corrosion, but also the corroding species itself. While mechanisms and rates of the chloride driven corrosion processes offer explanations as to the different oxides and hydroxides observed between immersion conditions, they do not offer an explanation for the differences observed between handguns. Therefore, utilizing a general approach where surface area coverage of corrosion products is the sole consideration is not sufficient to determine time-since-immersion. Attempts to determine a time-since-immersion would require a priori knowledge of the mechanism of corrosion for a given metal mixture within a specified environment. The results described herein give indications as to the possible corrosion mechanism driving the process in high and low Cl(-) environments and show the necessity of including the metal composition, rust composition and ion concentration in any models that attempt to elucidate the time-since-immersion of handguns for forensic applications. PMID- 23937949 TI - Consideration of the probative value of single donor 15-plex STR profiles in UK populations and its presentation in UK courts II. PMID- 23937950 TI - A feeling of flow: exploring junior scientists' experiences with dictation of scientific articles. AB - BACKGROUND: Science involves publishing results, but many scientists do not master this. We introduced dictation as a method of producing a manuscript draft, participating in writing teams and attending a writing retreat to junior scientists in our department. This study aimed to explore the scientists' experiences with this process. METHODS: Four focus group interviews were conducted and comprised all participating scientists (n = 14). Each transcript was transcribed verbatim and coded independently by two interviewers. The coding structure was discussed until consensus and from this the emergent themes were identified. RESULTS: Participants were 7 PhD students, 5 scholarship students and 2 clinical research nurses. Three main themes were identified: 'Preparing and then letting go' indicated that dictating worked best when properly prepared. 'The big dictation machine' described benefits of writing teams when junior scientists got feedback on both content and structure of their papers. 'Barriers to and drivers for participation' described flow-like states that participants experienced during the dictation. CONCLUSIONS: Motivation and a high level of preparation were pivotal to be able to dictate a full article in one day. The descriptions of flow-like states seemed analogous to the theoretical model of flow which is interesting, as flow is usually deemed a state reserved to skilled experts. Our findings suggest that other academic groups might benefit from using the concept including dictation of manuscripts to encourage participants' confidence in their writing skills. PMID- 23937951 TI - Critical role of leukotriene B4 receptor signaling in mouse 3T3-L1 preadipocyte differentiation. AB - BACKGROUND: Various inflammatory mediators related to obesity might be closely related to insulin resistance. Leukotrienes (LTs) are involved in inflammatory reactions. However, there are few reports regarding the role of LTs in adipocyte differentiation. Therefore, we investigated the role of leukotriene B4 (LTB4) leukotriene receptor (BLT) signaling in mouse 3T3-L1 fibroblastic preadipocyte differentiation to mature adipocytes. METHODS: Mouse 3T3-L1 preadipocytes were treated with lipoxygenase (LOX) inhibitors, BLT antagonist, and small interfering RNA (siRNA) for BLT1 and BLT2 to block the LTB4-BLT signaling pathway, then the adipocyte differentiation such as lipid accumulation and the increase in triglyceride was evaluated. RESULTS: Blockade of BLT signaling by treatment with a LOX inhibitor or a BLT antagonist suppressed preadipocyte differentiation into mature adipocytes. In addition, knockdown of BLT1 and BLT2 by siRNAs dramatically inhibited differentiation. These results indicate the LTB4-BLT signaling pathway may positively regulate preadipocyte differentiation and be a rate-limiting system to control adipocyte differentiation. CONCLUSIONS: The LTB4-BLT signaling pathway provides a potent regulatory signal that accelerates the differentiation of mouse 3T3-L1 preadipocytes. Further investigations are necessary to confirm the exact role of LTB4 and BLTs signaling pathways in preadipocyte differentiation. PMID- 23937952 TI - Traumatic appendicitis: a case report and literature review. AB - Appendicitis and trauma may exist together, which causes an interesting debate whether trauma has led to appendicitis. We report a case of appendicitis after an abdominal trauma. Our patient developed acute appendicitis following a stab wound in the right iliac fossa. Surgical exploration confirmed the traumatic origin of appendicitis, appendectomy was performed and our patient made an excellent recovery. In non operative management of abdominal trauma, physical examinations and radiological explorations should be repeated in order to diagnose traumatic appendicitis. PMID- 23937953 TI - A novel method of teaching surgical techniques to residents--computerized enhanced visual learning (CEVL) with simulation to certify mastery of training: a model using newborn clamp circumcision. AB - OBJECTIVE: To assess the learning process of combining a web-based video of a simulated surgical procedure with a step-by-step checklist of the same procedure in achieving competency of the simulated technique, in this case a newborn clamp circumcision. Fundamental to this particular learning process is immediate mentor step-by-step feedback which specifically follows the procedure's step-by-step checklist. MATERIALS AND METHODS: Pediatric residents naive to newborn circumcision were enrolled (n = 7). A circumcision simulator, instruments, and web access to the learning module were provided. Residents trained independently and then performed two simulations with the mentor. The first simulation was completed with formative scored feedback. The learner then performed a second scored simulation. RESULTS: All learners showed improvement between the first and second simulation (mean 85.3-97.4). All residents achieved competency (96/100 or greater) by the second simulation. On post-procedure surveys, learners demonstrated increased comfort and reduced apprehension in performing the procedure. CONCLUSION: Combining a web-accessible video of a procedure, a checklist, and a simulator followed by a single mentor session with immediate formative feedback which follows the steps of the checklist is a useful method to teach the simulation technique of circumcision. We plan to study if this paradigm is transferable to clinical circumcision. PMID- 23937954 TI - Screening for developmental delay among children attending a rural community welfare clinic in Ghana. AB - BACKGROUND: Periodic screening for developmental delays (DD) could avert the incidence of disability among children. However, such routine programme is yet to take off in rural welfare clinics in Ghana. METHOD: Mothers of under-5 children who were attending rural child welfare clinic participated in this study. The socio-demographic data of the mothers and their children were recorded. The children were screened to assess their gross motor skills, fine motor skills, communication skills, problem solving/cognition and social/personal interaction using Ages and Stages Questionnaire. Score below the threshold points on a developmental domain defines DD for a child. Data analysis involved percentages and frequency while Chi-square was performed to determine the associations between the selected socio-demographic risk factors and DD. Alpha value was set at p < 0.05. RESULTS: Three hundren and thirty (330) children were screened and majority 60(18%), were found within the age range 3 months 1 day to 5 months 0 day. 251(76%) had normal weight (2.5 kg-3.5) while 26(7.6%) were underweight (<2.5 kg). Generally, 147(44.6%) of the children had DD in the different domains of the questionnaires. 41(12.4%) had DD in social/personal interaction while 19(5.8%) were delayed in the communication domain. Birth weight and duration of gestation were significantly associated with communication domain while the level of education of the mothers and duration of gestation were significantly associated with gross motor domain. CONCLUSION: An appreciable proportion of the children were found to experience developmental delays and the most prevalent occurence was in personal/social interaction. Birth weight, gestational age and maternal educational level provide insight into a link with communication and gross motor skills. PMID- 23937955 TI - Sedation in French intensive care units: a survey of clinical practice. AB - BACKGROUND: Sedation is used frequently for patients in intensive care units who require mechanical ventilation, but oversedation is one of the main side effects. Different strategies have been proposed to prevent oversedation. The extent to which these strategies have been adopted by intensivists is unknown. METHODS: We developed a six-section questionnaire that covered the drugs used, modalities of drug administration, use of sedation scales and procedural pain scales, use of written local procedures, and targeted objectives of consciousness. In November 2011, the questionnaire was sent to 1,078 intensivists identified from the French ICU Society (SRLF) database. RESULTS: The questionnaire was returned by 195 intensivists (response rate 18.1%), representing 135 of the 282 ICUs (47.8%) listed in the French ICU society (SRLF) database. The analysis showed that midazolam and sufentanil are the most frequently used hypnotics and opioids, respectively, administered in continuous intravenous (IV) infusions. IV boluses of hypnotics without subsequent continuous IV infusion are used occasionally (in <25% of patients) by 65% of intensivists. Anxiolytic benzodiazepines (e.g., clorazepam, alprazolam), hydroxyzine, and typical neuroleptics, via either an enteral or IV route, are used occasionally by two thirds of respondents. The existence of a written, local sedation management procedure in the ICU is reported by 55% of respondents, 54% of whom declare that they use it routinely. Written local sedation procedures mainly rely on titration of continuous IV hypnotics (90% of the sedation procedures); less frequently, sedation procedures describe alternative approaches to prevent oversedation, including daily interruption of continuous IV hypnotic infusion, hypnotic boluses with no subsequent continuous IV infusion, or the use of nonhypnotic drugs. Among the responding intensivists, 98% consider eye opening, either spontaneously or after light physical stimulation, a reasonable target consciousness level in patients with no severe respiratory failure or intracranial hypertension. CONCLUSIONS: Despite a low individual response rate, the respondents to our survey represent almost half of the ICUs in the French SRLF database. The presence of a written local sedation procedure, a cornerstone of preventing oversedation, is reported by only half of respondents; when present, it is used in for a limited number of patients. Sedation procedures mainly rely on titration of continuous IV hypnotics, but other strategies to limit oversedation also are included in sedation procedures. French intensivists no longer consider severely altered consciousness a sedation objective for most patients. PMID- 23937956 TI - Parabolic replicator dynamics and the principle of minimum Tsallis information gain. AB - BACKGROUND: Non-linear, parabolic (sub-exponential) and hyperbolic (super exponential) models of prebiological evolution of molecular replicators have been proposed and extensively studied. The parabolic models appear to be the most realistic approximations of real-life replicator systems due primarily to product inhibition. Unlike the more traditional exponential models, the distribution of individual frequencies in an evolving parabolic population is not described by the Maximum Entropy (MaxEnt) Principle in its traditional form, whereby the distribution with the maximum Shannon entropy is chosen among all the distributions that are possible under the given constraints. We sought to identify a more general form of the MaxEnt principle that would be applicable to parabolic growth. RESULTS: We consider a model of a population that reproduces according to the parabolic growth law and show that the frequencies of individuals in the population minimize the Tsallis relative entropy (non-additive information gain) at each time moment. Next, we consider a model of a parabolically growing population that maintains a constant total size and provide an "implicit" solution for this system. We show that in this case, the frequencies of the individuals in the population also minimize the Tsallis information gain at each moment of the 'internal time" of the population. CONCLUSIONS: The results of this analysis show that the general MaxEnt principle is the underlying law for the evolution of a broad class of replicator systems including not only exponential but also parabolic and hyperbolic systems. The choice of the appropriate entropy (information) function depends on the growth dynamics of a particular class of systems. The Tsallis entropy is non-additive for independent subsystems, i.e. the information on the subsystems is insufficient to describe the system as a whole. In the context of prebiotic evolution, this "non-reductionist" nature of parabolic replicator systems might reflect the importance of group selection and competition between ensembles of cooperating replicators. PMID- 23937957 TI - Comparison of bag-valve-mask hand-sealing techniques in a simulated model. AB - STUDY OBJECTIVE: Bag-valve-mask ventilation remains an essential component of airway management. Rescuers continue to use both traditional 1- or 2-handed mask face sealing techniques, as well as a newer modified 2-handed technique. We compare the efficacy of 1-handed, 2-handed, and modified 2-handed bag-valve-mask technique. METHODS: In this prospective, crossover study, health care providers performed 1-handed, 2-handed, and modified 2-handed bag-valve-mask ventilation on a standardized ventilation model. Subjects performed each technique for 5 minutes, with 3 minutes' rest between techniques. The primary outcome was expired tidal volume, defined as percentage of total possible expired tidal volume during a 5-minute bout. A specialized inline monitor measured expired tidal volume. We compared 2-handed versus modified 2-handed and 2-handed versus 1-handed techniques. RESULTS: We enrolled 52 subjects: 28 (54%) men, 32 (62%) with greater than or equal to 5 actual emergency bag-valve-mask situations. Median expired tidal volume percentage for 1-handed technique was 31% (95% confidence interval [CI] 17% to 51%); for 2-handed technique, 85% (95% CI 78% to 91%); and for modified 2-handed technique, 85% (95% CI 82% to 90%). Both 2-handed (median difference 47%; 95% CI 34% to 62%) and modified 2-handed technique (median difference 56%; 95% CI 29% to 65%) resulted in significantly higher median expired tidal volume percentages compared with 1-handed technique. The median expired tidal volume percentages between 2-handed and modified 2-handed techniques did not significantly differ from each other (median difference 0; 95% CI -2% to 2%). CONCLUSION: In a simulated model, both 2-handed mask-face sealing techniques resulted in higher ventilatory tidal volumes than 1-handed technique. Tidal volumes from 2-handed and modified 2-handed techniques did not differ. Rescuers should perform bag-valve-mask ventilation with 2-handed techniques. PMID- 23937958 TI - Association of placental perfusion, as assessed by magnetic resonance imaging and uterine artery Doppler ultrasound, and its relationship to pregnancy outcome. AB - PURPOSE: To investigate (a) if placental perfusion in the second trimester of pregnancy, measured by two non-invasive magnetic resonance imaging (MRI) techniques, is related to impedance to flow in the uterine arteries, as assessed by Doppler ultrasound; and (b) if these measures are associated with future gestational outcome. METHODS: In 37 singleton pregnancies at 24-29 weeks' gestation, uterine artery pulsatility index (PI) was measured by Doppler ultrasound and placental perfusion was measured by Arterial Spin Labelling (flow sensitive alternating inversion recovery (FAIR)) and intravoxel incoherent motion (IVIM) echo-planar imaging at 1.5 T in basal, central and placental regions of interest. The values were compared between those delivering small for gestational age (SGA) and appropriate for gestational age (AGA) neonates. RESULTS: In 23 pregnancies that resulted in delivery of SGA neonates, compared to the 14 with AGA neonates, the median basal FAIR measure was significantly lower (923.0 vs. 2359.0 arbitrary units; p = 0.003) as were IVIM measures of perfusing fraction (f) in basal, central and whole-placental regions (37.8 vs. 40.7%; p = 0.046; 24.3 vs. 35.1%; p = 0.014 and 27.9% vs. 36.2%; p = 0.001, respectively). In the SGA group, the median uterine artery PI was increased (1.96 vs. 1.03; p = 0.001). There were significant associations between uterine artery PI and placental perfusion assessed by both FAIR and IVIM. CONCLUSION: Pregnancies that result in SGA neonates exhibited reduced placental perfusion as assessed by MRI during the second trimester. This measurement was found to be strongly associated with impedance to flow in the uterine arteries. We suggest that FAIR or IVIM MRI examinations may be used to directly and non-invasively determine placental perfusion, and that the measured values are strong indicators of future gestational outcome. PMID- 23937959 TI - Conservative management of morbidly adherant placenta - a case report and review of literature. AB - Placenta accreta is a condition when the placenta is abnormally adherent to the uterus. This can result in complications like severe haemorrhage, injuries to pelvic organs, possible need for Caesarian hysterectomy. There is always high risk of maternal morbidity and mortality. Over the last decade there has been gradual shift towards conservative management of placenta accreta involving uterine and placental conservation, with the main aim to reduce pelvic injury and to achieve haemostasis with the aid of intervention radiology by means of Uterine Artery embolisation and use of medical chemotherapeutic agents like Methotrexate. This strategy has previously been shown to reduce morbidity and mortality in carefully selected cases of Placenta accreta. We have successfully managed a case of Placenta percreta conservatively using Uterine Artery embolisation followed by Injection methotrexate. PMID- 23937960 TI - In vivo transmission blocking activities of artesunate on the avian malaria parasite Plasmodium gallinaceum. AB - Infection and transmission of the avian malaria parasite Plasmodium gallinaceum in domestic chickens is associated with high economic burden and presents a major challenge to poultry industry in South East Asia. Development of drugs targeting both asexual blood stage parasites and sexual stages of the avian malarias will be beneficial for malaria treatment and eradication. However, current drugs recommended for treatment of the avian malaria parasites target specifically the asexual blood stage parasites, but have little or no impact to the gametocytes, the major target for development of transmission-blocking strategies. In the present work, we established a simple procedure to evaluate gametocytocidal and transmission blocking activities in a P. gallinaceum-avian model. The assays involved administration of seven consecutive daily doses of test compounds into P. gallinaceum-infected chickens with 10% parasitaemia and 1% gametocytaemia. Our studies indicated that intramuscular injection with seven daily low doses (the minimum effective dose of 10mg/kg) of artesunate blocked the gametocyte production and transmission to the mosquito vector Aedes aegypti. This assay can be further applicable for testing new compounds against P. gallinaceum and for other parasitic protozoa infecting birds. PMID- 23937961 TI - Left ventricular systolic function in HER2/neu negative breast cancer patients treated with anthracycline chemotherapy: a comparative analysis of left ventricular ejection fraction and myocardial strain imaging over 12 months. AB - AIM: Anthracycline agents are undermined by their cardiotoxicity. As life expectancy following treatment is greatly improved, techniques that ensure early detection and timely management of cardiotoxicity are essential. The aim of the present study was to evaluate left ventricular (LV) systolic function with LV ejection fraction (LVEF) and two-dimensional myocardial strain up to 12 months after anthracycline chemotherapy, specifically in HER2/neu negative breast cancer patients. METHODS: Seventy-eight consecutive anthracycline naive breast cancer patients were studied before and immediately after anthracycline chemotherapy. Fifty HER2/neu negative patients were studied over 12 months with serial echocardiograms at four time points. All patients were treated with standard regimens containing anthracyclines. RESULTS: Global systolic strain was significantly reduced immediately after, and 6 months after anthracyclines (-19.0 +/- 2.3% to -17.5 +/- 2.3% (P<0.001) and -18.2 +/- 2.2% (P=0.01) respectively). A non-uniform reduction in strain was observed each time with relative sparing of the LV apex. LVEF remained largely unchanged at both time points. Global strain normalised by 12 months in the majority of patients. Persistently reduced strain was observed in 16% (n=8); these patients had a greater reduction in strain at 6 months (<= -17.2%), and had received higher cumulative anthracycline doses. CONCLUSION: Myocardial strain imaging is more sensitive than LVEF for the early detection and intermediate term monitoring of LV systolic function following anthracycline chemotherapy in HER2/neu negative breast cancer patients, and may aid in the development of improved monitoring protocols. PMID- 23937962 TI - Plasma procalcitonin is associated with all-cause and cancer mortality in apparently healthy men: a prospective population-based study. AB - BACKGROUND: The inflammatory mediator procalcitonin (PCT) has previously been associated with prognosis in myocardial infarction, cancer and sepsis patients. The importance of PCT in the general population is currently unknown. Our aim was to assess the relationship between plasma PCT and the risk of all-cause and cause specific mortality in apparently healthy individuals with no previous history of cardiovascular disease or cancer. METHODS: We performed a prospective, population based study on 3,322 individuals recruited from the Malmo Diet and Cancer cohort, with a median follow-up time of 16.2 years. Plasma PCT, high-sensitivity C reactive protein (hsCRP), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides and cystatin C were measured at baseline and a thorough risk factor assessment was performed for all subjects. The primary end-points of the study were all-cause mortality, cancer mortality and cardiovascular mortality. RESULTS: Men had higher PCT levels compared to women. In Cox proportional hazard models adjusted for age, sex, hypertension, diabetes, plasma lipids, renal function, body mass index and smoking, baseline PCT was associated with all-cause mortality and cancer mortality in men. The hazard ratio (HR) for men with PCT levels within the highest compared with the lowest quartile was 1.52 (95% confidence interval (CI) 1.07 to 2.16; P = 0.024) for all-cause mortality and 2.37 (95% CI 1.36 to 4.14; P = 0.006) for cancer mortality. Additionally, men with increased plasma PCT were found to be at a higher risk to develop colon cancer (HR per 1 SD increase = 1.49 (95% CI 1.13 to 1.95); P = 0.005). In multivariate Cox regression analyses with mutual adjustments for PCT and hsCRP, PCT was independently associated with cancer death (HR per 1 SD increase = 1.28 (95% CI 1.10 to 1.49); P = 0.001) and hsCRP with cardiovascular death (HR per 1 SD increase = 1.42 (95% CI 1.11 to 1.83); P = 0.006) in men. We found no significant correlations between baseline PCT or hsCRP and incident cancer or cardiovascular death in women. CONCLUSIONS: We disclose for the first time important independent associations between PCT and the risk for all-cause and cancer mortality in apparently healthy men. Our findings warrant further investigation into the mechanisms underlying the relationship between PCT and cancer. PMID- 23937963 TI - The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. AB - PURPOSE: Antiepileptic drugs may affect the endocrine system. We investigated the effects of valproic acid and topiramate on the levels of insulin, c-peptide and adipocytokines in pre-pubertal patients with idiopathic partial and generalized epilepsy. METHODS: Forty-one children with epilepsy were included. The patients were divided into two groups (valproic acid; n = 21, topiramate; n = 20). The weight, height, body mass index and homeostasis model assessment of insulin resistance (HOMA-IR) were recorded and insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin and resistin levels were determined at 0, 6 and 12 months of therapy. RESULTS: In the valproate group, weight and height increased significantly. Seven of 21 patients were overweight at the end of one year. Leptin was higher in the overweight subgroup. Although insulin and HOMA-IR increased (p < 0.05), none of the patients showed hyperinsulinism or IR. Resistin had decreased at the 6th and 12th months (p < 0.05). In the topiramate group, some statistically nonsignificant changes were demonstrated. CONCLUSION: The mechanisms behind valproate and topiramate-related weight control are still unclear, especially in children. Valproate and topiramate affect the weight, BMI, and insulin, leptin and adipocytokine levels in prepubertal children. We suggest that further studies including more patients with a long follow-up period are necessary to draw a firm conclusion regarding an association between the treatment with these drugs and the levels of leptin, insulin and adipocytokines. PMID- 23937964 TI - Role of hypoxia inducible factor-1 in keratinocyte inflammatory response and neutrophil recruitment. AB - BACKGROUND: Hypoxia inducible factor-1 (HIF-1) is a major regulator of the cellular adaption to low oxygen stress and the innate immune function of myeloid cells. Treatment with the novel HIF-1 stabilizing drug AKB-4924 has been shown to enhance the bactericidal activity of keratinocytes as well as phagocytic cells. In this study, we sought to investigate the effect of pharmacological boosting of HIF-1 with AKB-4924 in keratinocytes and their contribution to the innate immune response. FINDINGS: Treatment with the novel HIF-1 stabilizing drug AKB-4924 can increase keratinocyte production of pro-inflammatory cytokines in vitro and enhance neutrophil recruitment in vivo. CONCLUSIONS: HIF plays an important role in cytokine production by keratinocytes and in neutrophil recruitment to the skin. The HIF-boosting drug AKB-4924 has the potential to enhance the immune response even in the complex environment of bacterial skin infections. PMID- 23937965 TI - Privacy and information security risks in a technology platform for home-based chronic disease rehabilitation and education. AB - BACKGROUND: Privacy and information security are important for all healthcare services, including home-based services. We have designed and implemented a prototype technology platform for providing home-based healthcare services. It supports a personal electronic health diary and enables secure and reliable communication and interaction with peers and healthcare personnel. The platform runs on a small computer with a dedicated remote control. It is connected to the patient's TV and to a broadband Internet. The platform has been tested with home based rehabilitation and education programs for chronic obstructive pulmonary disease and diabetes. As part of our work, a risk assessment of privacy and security aspects has been performed, to reveal actual risks and to ensure adequate information security in this technical platform. METHODS: Risk assessment was performed in an iterative manner during the development process. Thus, security solutions have been incorporated into the design from an early stage instead of being included as an add-on to a nearly completed system. We have adapted existing risk management methods to our own environment, thus creating our own method. Our method conforms to ISO's standard for information security risk management. RESULTS: A total of approximately 50 threats and possible unwanted incidents were identified and analysed. Among the threats to the four information security aspects: confidentiality, integrity, availability, and quality; confidentiality threats were identified as most serious, with one threat given an unacceptable level of High risk. This is because health-related personal information is regarded as sensitive. Availability threats were analysed as low risk, as the aim of the home programmes is to provide education and rehabilitation services; not for use in acute situations or for continuous health monitoring. CONCLUSIONS: Most of the identified threats are applicable for healthcare services intended for patients or citizens in their own homes. Confidentiality risks in home are different from in a more controlled environment such as a hospital; and electronic equipment located in private homes and communicating via Internet, is more exposed to unauthorised access. By implementing the proposed measures, it has been possible to design a home-based service which ensures the necessary level of information security and privacy. PMID- 23937966 TI - Multiple tuberculous nodules with metachronous changes: a case report. AB - BACKGROUND: Spontaneous regression of lesions occurs in non-infectious benign diseases, such as sarcoidosis, as well as in infectious diseases, such as tuberculosis. Lung cancer and malignant lymphoma, on the other hand, rarely follow a similar course. We report a rare case of lung tuberculosis that presented with multiple nodules with metachronous changes in size. CASE PRESENTATION: We describe the case of a 50-year-old immunocompetent Japanese man with pulmonary tuberculosis in the form of multifocal nodules. He came to our hospital because of a chest X-ray abnormality. During the course of observation, some nodules reduced while others enlarged in size. Two years after the first visit, fever and pleural effusion appeared. The sputum examination turned out to be positive for tuberculosis. A course of anti-tubercular agents resolved the pleural effusion and multifocal nodules. CONCLUSION: Differences in the manner of granuloma formation suggest that the local immune response can be different even in the same lung field. PMID- 23937967 TI - Mortality after in-hospital cardiopulmonary resuscitation: multicenter analysis in Korea. AB - PURPOSE: The purpose of this study is to evaluate factors associated with the mortality of patients admitted to intensive care units (ICUs) after in-hospital cardiopulmonary resuscitation (CPR) and the impact of a hospital rapid response system (RRS) on patient mortality in Korea. MATERIALS AND METHODS: A prospective multicenter cohort study was done in 22 ICUs of 15 centers from July 1, 2010, to January 31, 2011. We only enrolled patients admitted to ICUs after in-hospital CPR and divided eligible patients into 2 groups-survivors and nonsurvivors. RESULTS: Among 4617 patients, 150 patients were admitted post-CPR, 76 died, and 74 survived. At 24 hours, the Sequential Organ Failure Assessment score, Simplified Acute Physiology Score II, and the best Glasgow Coma Scale were significantly lower in the nonsurvivors than in the survivors. In multivariate analysis, the Simplified Acute Physiology Score II and presence of lower respiratory infection were both independently associated with mortality. At the first hour after admission, lowest serum potassium and highest heart rate were associated with mortality. At 24 hours after admission, lowest mean arterial pressure, HCO3 level, and venous oxygen saturation level; highest heart rate; and use of vasoactive drugs were associated with mortality. The mortality of patients in hospitals with an RRS was not significantly different from that of hospitals without an RRS. CONCLUSION: Various physiologic and laboratory parameters were associated with the mortality of post-CPR ICU admitted patients, and the presence of an RRS did not reduce mortality of these patients in our study. PMID- 23937968 TI - Red blood cell transfusion is associated with decreased in-hospital muscle strength among critically ill patients requiring mechanical ventilation. AB - PURPOSE: Red blood cell (RBC) transfusion is linked to poor functional recovery after surgery and trauma. To investigate one potential mechanism, we examined the association between RBC transfusion and muscle strength in a cohort of critically ill patients. METHODS: We performed a secondary analysis of 124 critically ill, mechanically ventilated patients enrolled in 2 prospective cohort studies where muscle strength testing was performed at a median of 12 days after mechanical ventilation onset. We examined the association between RBC transfusion and dynamometry handgrip strength using multivariable linear regression, adjusting for study site, age, sex, Acute Physiology and Chronic Health Evaluation, Sequential Organ Failure Assessment score, days from hospital admission to examination, and steroid use. Secondary outcomes included systematic manual muscle strength and intensive care unit-acquired paresis. RESULTS: Among 124 subjects, 73 (59%) received RBC transfusion in the 30 days before examination. In adjusted analyses, RBC transfusion was significantly associated with weaker handgrip (adjusted mean difference, -9.9 kg; 95% confidence interval, -16.6 to 3.2; P < .01) and proximal manual muscle strength (adjusted mean difference in Medical Research Council score, -0.5; 95% confidence interval, -0.7 to -0.2; P < .01) but not intensive care unit-acquired paresis. CONCLUSIONS: Red blood cell transfusion was associated with decreased muscle strength in this cohort of critically ill patients after adjusting for illness severity and organ dysfunction. Further studies are needed to validate these results and probe mechanisms. PMID- 23937969 TI - A population based study of hospitalised seriously injured in a region of Northern Italy. AB - BACKGROUND: Injury is a public health problem in terms of mortality, morbidity and disability. The implementation of a regionalised trauma system has been proved to significantly reduce the social impact of severe trauma on population. A population-based registry may be useful to obtain reliable epidemiologic data. AIM: To perform an exhaustive analysis of severe trauma patients hospitalised in Lombardia, a region of northern Italy. MATERIALS AND METHODS: The regional Hospital Discharge Registry (HDR) was used to retrieve data of all patients who suffered from serious injuries from 2008 to 2010. ICD9-CM codes of discharge diagnoses were analysed and patients coded from 800.0 to 939.9 or from 950.0 to 959.9 have been retrieved. Femur fractures in elderly and patients with length of hospital stay less than 2 days were excluded. Patients have been considered seriously injured if discharged dead or any of followings: admission or transit in ICU, need of mechanical ventilation, tracheotomy, invasive hemodynamic monitoring. Average reimbursement based on DRG has been evaluated. STATISTICS: Student's t test, ANOVA for continuous data, chi-square test for categorical data were used, and a p value less than 0.05 was considered significant. RESULTS: The severely injured patients hospitalised in Lombardia in three years were 11704, 391 per million per year. Overall mortality was 24.17% and increased with age. Males aging from 18 to 64 years had more occupational injuries, trauma on the road and violence by others. Females were more susceptible to domestic injuries and self inflicted violence, mostly in older ages. Acute mortality was higher after traffic accidents, while late mortality was increased in domestic trauma. Pediatric cases were unusual. A significant increase (+10.18%) in domestic trauma, with a concomitant decrease (-17.76%) in road-related accidents was observed in the three years study period. Reimbursement paid to hospitals for seriously injured was insufficient with regard to estimated costs of care. CONCLUSION: Serious injury requiring hospitalisation in Lombardia is still an healthcare problem, with a trend toward a decrease of traffic accidents, increase in domestic trauma and involvement of older people. These results may help to plan a new regionalised Trauma System. PMID- 23937970 TI - Comparison of thermodilution measured extravascular lung water with chest radiographic assessment of pulmonary oedema in patients with acute lung injury. AB - BACKGROUND: Acute lung injury and the acute respiratory distress syndrome (ALI/ARDS) are characterized by pulmonary oedema, measured as extravascular lung water (EVLW). The chest radiograph (CXR) can potentially estimate the quantity of lung oedema while the transpulmonary thermodilution method measures the amount of EVLW. This study was designed to determine whether EVLW as estimated by a CXR score predicts EVLW measured by the thermodilution method and whether changes in EVLW by either approach predict mortality in ALI/ARDS. METHODS: Clinical data were collected within 48 hours of ALI/ARDS diagnosis and daily up to 14 days on 59 patients with ALI/ARDS. Two clinicians scored each CXR for the degree of pulmonary oedema, using a validated method. EVLW indexed to body weight was measured using the single indicator transpulmonary thermodilution technique. RESULTS: The CXR score had a modest, positive correlation with the EVLWI measurements (r = 0.35, p < 0.001). There was a 1.6 ml/kg increase in EVLWI per 10-point increase in the CXR score (p < 0.001, 95% confidence interval 0.92 2.35). The sensitivity of a high CXR score for predicting a high EVLWI was 93%; similarly the negative predictive value was high at 94%; the specificity (51%) and positive predictive value (50%) were lower. The CXR scores did not predict mortality but the EVLW thermodilution did predict mortality. CONCLUSION: EVLW measured by CXR was modestly correlated with thermodilution measured EVLW. Unlike CXR findings, transpulmonary thermodilution EVLWI measurements over time predicted mortality in patients with ALI/ARDS. PMID- 23937971 TI - Exogenous prenatal corticosterone exposure mimics the effects of prenatal stress on adult brain stress response systems and fear extinction behavior. AB - Exposure to early-life stress is a risk factor for the development of cognitive and emotional disorders later in life. We previously demonstrated that prenatal stress (PNS) in rats results in long-term, stable changes in central stress response systems and impairs the ability to extinguish conditioned fear responding, a component of post-traumatic stress disorder (PTSD). Maternal corticosterone (CORT), released during prenatal stress, is a possible mediator of these effects. The purpose of the present study was to investigate whether fetal exposure to CORT at levels induced by PNS is sufficient to alter the development of adult stress neurobiology and fear extinction behavior. Pregnant dams were subject to either PNS (60 min immobilization/day from ED 14-21) or a daily injection of CORT (10mg/kg), which approximated both fetal and maternal plasma CORT levels elicited during PNS. Control dams were given injections of oil vehicle. Male offspring were allowed to grow to adulthood undisturbed, at which point they were sacrificed and the medial prefrontal cortex (mPFC), hippocampus, hypothalamus, and a section of the rostral pons containing the locus coeruleus (LC) were dissected. PNS and prenatal CORT treatment decreased glucocorticoid receptor protein levels in the mPFC, hippocampus, and hypothalamus when compared to control offspring. Both treatments also decreased tyrosine hydroxylase levels in the LC. Finally, the effect of prenatal CORT exposure on fear extinction behavior was examined following chronic stress. Prenatal CORT impaired both acquisition and recall of cue-conditioned fear extinction. This effect was additive to the impairment induced by previous chronic stress. Thus, these data suggest that fetal exposure to high levels of maternal CORT is responsible for many of the lasting neurobiological consequences of PNS as they relate to the processes underlying extinction of learned fear. The data further suggest that adverse prenatal environments constitute a risk factor for PTSD-like symptomatology, especially when combined with chronic stressors later in life. PMID- 23937972 TI - Consent, including advanced consent, of older adults to research in care homes: a qualitative study of stakeholders' views in South Wales. AB - BACKGROUND: Care home residents, especially those lacking capacity to provide consent for themselves, are frequently excluded from research, thus limiting generalisability of study findings. We set out to explore stakeholders' views about the ethical and practical challenges associated with recruiting care home residents into research studies. METHODS: Qualitative individual interviews with care home residents (n = 14), their relatives (n = 14), and general practitioners (GPs) (n = 10), and focus groups (n = 2) with care home staff. Interviews focused on the issues of older adults consenting to research in care homes, including advanced consent, in general and through reference to a particular study on the use of probiotics to prevent Antibiotic Associated Diarrhoea. Data were analysed using a thematic approach incorporating themes that had been identified in advance, and themes derived from the data. Researchers discussed evidence for themes, and reached consensus on the final themes. RESULTS: Respondents were generally accepting of low risk observational studies and slightly less accepting of low risk randomised trials of medicinal products. Although respondents identified some practical barriers to informed consent, consenting arrangements were considered workable. Residents and relatives varied in the amount of detail they wanted included in information sheets and consent discussions, but were generally satisfied that an advanced consent model was acceptable and appropriate. Opinions differed about what should happen should residents lose capacity during a research study. CONCLUSIONS: Research staff should be mindful of research guidance and ensure that they have obtained an appropriate level of informed consent without overwhelming the participant with unnecessary detail. For research involving medicinal products, research staff should also be more explicit when recruiting that consent is still valid should an older person lose capacity during a trial provided the individual did not previously state a wish to be withdrawn if they lose capacity, and provided they do not indicate objection or resistance after loss of capacity. PMID- 23937973 TI - Pneumolabyrinth after intratympanic steroid injection in patient with prosthesis of the stapes: a case report. AB - The aim of this study is to present a patient who developed a pneumolabyrinth following intratympanic steroid injection performed one year after stapes surgery. The patient started a medical treatment but since no improvement of his symptoms occurred, 10 days after the intratympanic injection a surgical treatment was proposed. An exploratory tympanotomy showed a displacement of the stapes prosthesis from the platinotomy, a dislocation of the incus long process, a fracture of the footplate and a depression into the vestibule. The fragment of the broken footplate was removed, a new prosthesis was located. Nausea, vertigo and nystagmus resolved immediately following surgery with a hearing threshold unchanged. In the present case report, the pathogenesis of pneumolabyrinth may be connected to an IT steroid injection proposed to the patient for the onset of sudden sensorineural hearing loss. To our knowledge, no case of a pneumolabyrinth provoked by intratympanic steroid injection has been previously described. PMID- 23937974 TI - Can zinc depletion play a role in LEV-induced hair loss? Considerations from a case study. PMID- 23937975 TI - Stepped-care to prevent depression and anxiety in visually impaired older adults- design of a randomised controlled trial. AB - BACKGROUND: Subthreshold depression and anxiety are common in the growing population of visually impaired older adults and increase the risk of full-blown depressive or anxiety disorders. Adequate treatment may prevent the development of depression or anxiety in this high risk group. METHOD/DESIGN: A stepped-care programme was developed based on other effective interventions and focus groups with professionals and patient representatives of three low vision rehabilitation organisations in The Netherlands and Belgium. The final programme consists of four steps: 1) watchful waiting, 2) guided self-help, 3) problem solving treatment, 4) referral to general practitioner. The (cost-)effectiveness of this programme is evaluated in a randomised controlled trial. Patients (N = 230) are randomly assigned to either a treatment group (stepped-care) or a control group (usual care). The primary outcome is the incidence of depressive and anxiety disorders, measured with the Mini International Neuropsychiatric Interview (MINI). DISCUSSION: Preventive interventions for depression and anxiety have received little attention in the field of low vision. A stepped-care programme that focuses on both depression and anxiety has never been investigated in visually impaired older adults before. If the intervention is shown to be effective, this study will result in an evidence based treatment programme to prevent depression or anxiety in patients from low vision rehabilitation organisations. The pragmatic design of the study greatly enhances the generalisability of the results. However, a possible limitation is the difficulty to investigate the contribution of each individual step. TRIAL REGISTRATION: Identifier: NTR3296. PMID- 23937976 TI - A rare missense variant abrogates the signaling activity of tetherin/BST-2 without affecting its effect on virus release. AB - BACKGROUND: Tetherin (or BST-2) is an antiviral host restriction factor that suppresses the release of HIV-1 and other enveloped viruses by tethering them to the cell surface. Recently, it has been demonstrated that tetherin also acts as an innate sensor of HIV-1 assembly that induces NF-kappaB-dependent proinflammatory responses. Furthermore, it has been reported that polymorphisms in the promoter and 3' untranslated region of the bst2 gene may affect the clinical outcome of HIV-1 infection. However, non-synonymous polymorphisms in the bst2 open reading frame have not yet been described or functionally characterized. RESULTS: Mining of the Exome Variant Server database identified seven very rare naturally occurring missense variants of tetherin (Y8H, R19H, N49S, D103N, E117A, D129E and V146L) in human populations. Functional analyses showed that none of these sequence variants significantly affects the ability of tetherin to inhibit HIV-1 virion release or its sensitivity to antagonism by HIV 1 Vpu or SIVtan Env, although Y8H alters a potential YxY endocytic motif proposed to play a role in virion uptake. Thus, these variants do most likely not represent an evolutionary advantage in directly controlling HIV-1 replication or spread. Interestingly, however, the R19H variant selectively abrogated the signaling activity of tetherin. CONCLUSIONS: Restriction of HIV-1 virion release and immune sensing are two separable functions of human tetherin and the latter activity is severely impaired by a single amino acid variant (R19H) in the cytoplasmic part of tetherin. PMID- 23937977 TI - Computational studies of novel carbonyl-containing diazabicyclic ligands interacting with alpha4beta2 nicotinic acetylcholine receptor (nAChR) reveal alternative binding modes. AB - We have carried out computational studies on interactions of diazabicyclic amide analogs with alpha4beta2 nAChR using homology modeling, docking and pharmacophore elucidation techniques. We have found alternative ligand binding modes in most cases. All these diverse poses exhibit the quintessential hydrogen-bonding interaction between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the highly conserved Trp-149. This hydrogen bond was always found to be shorter than the one contracted by the ligand carbonyl group and a second hydrogen-bond made by the cationic center with Tyr-93 of the principal face of the protein. In most of the poses observed, cation-pi interactions involved three aromatic residues located in the principal face of the protein: Trp-149, Tyr-190 and Tyr-197. The latter amino acid residue appears to often donate a hydrogen bond to the ligand carbonyl oxygen atom. We also describe two rings of alternative receptor-based hydrogen-bond donor features equidistantly separated from the carbonyl oxygen of the highly conserved Trp-149 approximately by 5 and 8A, respectively. These findings could be exploited to design diverse and selective novel chemical libraries for the treatment of diseases and conditions where the alpha4beta2 nAChR is disrupted, such as Alzheimer disease, Parkinson's disease and l-dopa-induced dyskinesia (LID). PMID- 23937978 TI - A synthetic approach to novel carvotacetone and antheminone analogues with anti tumour activity. AB - A synthetic approach to analogues of the terpenoid natural product antheminone A is described which employs (-)-quinic acid as starting material. A key conjugate addition step proved to be unpredictable regarding its stereochemical outcome however the route allowed access to two diastereoisomeric series of compounds. The results of biological assay of the toxicity of the target compounds towards non-small-cell lung cancer cell line A549 are reported. PMID- 23937979 TI - Discovery of N-(2,3,5-triazoyl)mycophenolic amide and mycophenolic epoxyketone as novel inhibitors of human IMPDH. AB - Syntheses of ten derivatives of mycophenolic acid (MPA) at C-6' position, and structure-activity relationship study among these derivatives, MPA and mycophenolic hydroxamic acid (MPHA) led to discovery of N-(2,3,5 triazolyl)mycophenolic amide 4, (7'S) mycophenolic epoxyketone 9 and (7'R) mycophenolic epoxyketone 10 having potent inhibitory activity against human inosine-5'-monophosphate dehydrogenase (IMPDH) type I and II as well as antiproliferative activity on human leukemia K562 cells. Compounds 4, 9, and 10 showed induction activity of erythroid differentiation in K562 cells. Inhibitory effects of 4 and 10 against IMPDH were attenuated by supplemental guanosine in K562 cells. In contrast, attenuation effect by supplemental guanosine was not significant in the case of 9. Compound 9 weakly inhibited the enzyme activity of HDAC in the nuclear lysate of K562 cells at 10 MUM. These observations suggest that the primary target of 4, 9, and 10 is IMPDH, whereas compound 9 partially inhibits a certain type of HDAC. PMID- 23937980 TI - Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility. AB - Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants. PMID- 23937981 TI - Syntheses and antitumor activities of N'1,N'3-dialkyl-N'1,N'3-di (alkylcarbonothioyl) malonohydrazide: the discovery of elesclomol. AB - A series of N'(1),N'(3)-dialkyl-N'(1),N'(3)-di(alkylcarbonothioyl) malonohydrazides have been designed and synthesized as anticancer agents by targeting oxidative stress and Hsp70 induction. Structure-activity relationship (SAR) studies lead to the discovery of STA-4783 (elesclomol), a novel small molecule that has been evaluated in a number of clinical trials as an anticancer agent in combination with Taxol. PMID- 23937982 TI - Design, synthesis and biological evaluation of azithromycin glycosyl derivatives as potential antibacterial agents. AB - A series of 11,12-cyclic carbonate azithromycin-4"-O-carbamoyl glycosyl derivatives were designed, synthesized, and evaluated as antibacterial agents to search for target compounds with excellent activity. The results of preliminary antibacterial tests against eight strains in vitro revealed that all of the title compounds exhibited improved activities with broad spectrum compared with the parent compound. The glycosylated side chains may be the pharmacophores responsible for the improved activity. PMID- 23937983 TI - Evaluation of 99mTc-probestin for imaging APN expressing tumors by SPECT. AB - Aminopeptidase N (APN) is known to play important roles in tumor angiogenesis, tumor cell invasion, and metastasis. Thus, APN is an attractive biomarker for imaging tumor angiogenesis. Here we report results obtained from biodistribution and single photon emission computed tomography (SPECT) imaging studies of a technetium-99m labeled probestin (a potent APN inhibitor) conjugate containing a tripeptide, Asp-DAP-Cys (DAP=2,3-diaminopropionic acid), chelator and a 8-amino 3,6-dioxaoctanoic acid (PEG2) linker conducted in nude mice xenografted with HT 1080 human fibrosarcoma tumors (APN-positive tumors). These results collectively demonstrate that (99m)Tc-probestin uptake by tumors and other APN expressing tissues in vivo is specific and validate the use of probestin as a vector for targeting APN in vivo. PMID- 23937984 TI - Pregnancies in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitor. AB - We presented our experience in chronic myeloid leukemia (CML) patients who conceived children and/or became pregnant while receiving tyrosine kinase inhibitor (TKI). Among 7 male patients, 7 pregnancies resulted in the birth of 7 healthy babies. Among 18 female patients, 8 ended in elective abortion; 3 had spontaneous abortion, and 7 carried to term, resulting in the birth of 8 healthy babies. All children have normal growth and development. All patients remain in TKI therapy and in good response. It is suggested that female patients are advised to practice adequate contraception. No special precautions apply for male patients receiving TKI. PMID- 23937985 TI - Absolute monocyte count trichotomizes chronic lymphocytic leukemia into high risk patients with immune dysregulation, disease progression and poor survival. AB - Peripheral absolute monocyte count (AMC) has been reported to correlate with clinical outcome in different types of cancers. This association may relate to alteration in circulating monocytic subpopulations and tumor infiltrating macrophages. In this study we evaluated the clinical significance of peripheral AMC in 80 treatment naive patients with CLL. Measurement of AMC was based on direct morphological enumeration, due to our findings that complete blood count data may yield incorrect monocytes enumeration values in CLL. The median AMC in patients with CLL was within normal limits, however the AMC range exceeded the values of healthy individuals. The AMC trichotomized patients into 3 distinct sub groups with different characteristics and outcomes. High AMC patients were younger and had higher absolute lymphocytes count, while patients with low AMC had prominent immune dysregulation (lower serum IgA levels, susceptibility to infections and a tendency for positive direct anti-globulin test). The low and high AMC patients had a shorter time to treatment compared to the intermediates AMC subgroups, whereas low AMC was associated with increased mortality caused by infectious complications. In conclusion, AMC quantification during the disease course classifies CLL patients into subgroups with unique clinical features and outcomes. PMID- 23937986 TI - Can pesticide exposure cause childhood leukemia? PMID- 23937987 TI - A comparative study of deferasirox and deferiprone in the treatment of iron overload in patients with myelodysplastic syndromes. AB - One hundred thirteen patients with myelodysplastic syndromes (MDS) with <10% of bone marrow blasts received either deferiprone in a daily dose of 40-90 mg/kg (48 patients) or deferasirox in a daily dose of 10-40 mg/kg (65 patients). Median duration of treatment was 10,9 months for deferiprone and 13,7 months for deferasirox. A substantial reduction of iron stores evaluated as a decrease in serum ferritin of more than 50% of pretreatment level was achieved in 18 patients in deferasirox group (27.7%) but not in any patient treated with deferiprone, The incidence of adverse effects (mostly gastrointestinal symptoms) was similar after administration of both the drugs. The symptoms of deferasirox toxicity were mild and mostly transient and no drug related myelosuppresive effect was observed in contrast to deferiprone where agranulocytosis occurred in 4% of patients and the treatment had to be discontinued due to side effects in 20% of patients. The results confirmed the usefulness of deferasirox as an effective and safe iron chelator in MDS patients and indication of deferiprone as an alternative treatment only in patients with mild or moderate iron overload clearly not indicated for deferasirox. PMID- 23937989 TI - Demographics and outcomes of critically ill patients transferred from other hospitals to a tertiary care academic referral center in Saudi Arabia. AB - BACKGROUND: The objective of this study was to examine the outcomes of critically ill patients who were transferred from other hospitals to a tertiary care center in Saudi Arabia as a quality improvement project. METHODS: This was a retrospective study of adult patients admitted to the medical-surgical intensive care unit (ICU) of a tertiary care hospital. Patients were divided according to the source of referral into three groups: transfers from other hospitals, and direct admissions from emergency department (ED) and from hospital wards. Standardized mortality ratio (SMR) was calculated. Multivariate analysis was performed to determine the independent predictors of mortality. RESULTS: Of the 7,654 patients admitted to the ICU, 611 patients (8%) were transferred from other hospitals, 2,703 (35.3%) were direct admissions from ED and 4,340 (56.7%) from hospital wards. Hospital mortality for patients transferred from other hospitals was not significantly different from those who were directly admitted from ED (35% vs. 33.1%, p = 0.37) but was lower than those who were directly admitted from hospital wards (35% vs. 51.2%, p < 0.0001). SMRs did not differ significantly across the three groups. CONCLUSIONS: Critically ill patients who were transferred from other hospitals constituted 8% of all ICU admissions. Mortality of these patients was similar to patients with direct admission from the ED and lower than that of patients with direct admission from hospital wards. However, risk-adjusted mortality was not different from the other two groups. PMID- 23937988 TI - The Diabetes Self-Management Questionnaire (DSMQ): development and evaluation of an instrument to assess diabetes self-care activities associated with glycaemic control. AB - BACKGROUND: Though several questionnaires on self-care and regimen adherence have been introduced, the evaluations do not always report consistent and substantial correlations with measures of glycaemic control. Small ability to explain variance in HbA1c constitutes a significant limitation of an instrument's use for scientific purposes as well as clinical practice. In order to assess self-care activities which can predict glycaemic control, the Diabetes Self-Management Questionnaire (DSMQ) was designed. METHODS: A 16 item questionnaire to assess self-care activities associated with glycaemic control was developed, based on theoretical considerations and a process of empirical improvements. Four subscales, 'Glucose Management' (GM), 'Dietary Control' (DC), 'Physical Activity' (PA), and 'Health-Care Use' (HU), as well as a 'Sum Scale' (SS) as a global measure of self-care were derived. To evaluate its psychometric quality, 261 patients with type 1 or 2 diabetes were assessed with the DSMQ and an established analogous scale, the Summary of Diabetes Self-Care Activities Measure (SDSCA). The DSMQ's item and scale characteristics as well as factorial and convergent validity were analysed, and its convergence with HbA1c was compared to the SDSCA. RESULTS: The items showed appropriate characteristics (mean item-total correlation: 0.46 +/- 0.12; mean correlation with HbA1c: -0.23 +/- 0.09). Overall internal consistency (Cronbach's alpha) was good (0.84), consistencies of the subscales were acceptable (GM: 0.77; DC: 0.77; PA: 0.76; HU: 0.60). Principal component analysis indicated a four factor structure and confirmed the designed scale structure. Confirmatory factor analysis indicated appropriate fit of the four factor model. The DSMQ scales showed significant convergent correlations with their parallel SDSCA scales (GM: 0.57; DC: 0.52; PA: 0.58; HU: n/a; SS: 0.57) and HbA1c (GM: -0.39; DC: -0.30; PA: -0.15; HU: -0.22; SS: -0.40). All correlations with HbA1c were significantly stronger than those obtained with the SDSCA. CONCLUSIONS: This study provides preliminary evidence that the DSMQ is a reliable and valid instrument and enables an efficient assessment of self-care behaviours associated with glycaemic control. The questionnaire should be valuable for scientific analyses as well as clinical use in both type 1 and type 2 diabetes patients. PMID- 23937990 TI - Changes in the expression of Heat Shock Proteins in ovaries from bovines with cystic ovarian disease induced by ACTH. AB - Cystic ovarian disease (COD), which is considered one of the most important causes of reproductive failure in dairy cattle, induces intraovarian changes in the expression of numerous genes. The purpose of this study was to analyze the changes in the expression of Heat Shock Proteins (HSPs) in ovaries from bovines with cystic ovarian disease induced by ACTH. Immunoreactivity for Heat Shock Proteins (HSPs) in ovaries of cows with induced COD showed differential expression patterns in growing follicles from the control group. The immunopositive area for Hsp27 and Hsp60 in granulosa cells showed significant differences between tertiary follicles from normal cycling animals and those from animals with induced COD. The cysts showed increased Hsp27 immunostaining in theca cells in relation to tertiary follicles from normal cycling cows. Hsp70 immunostaining was more intense in cystic follicles than in other follicular categories from animals with induced COD, in both granulosa and theca cells. In granulosa cells, tertiary follicles from the control group showed higher levels of Hsp90 than cysts. These results demonstrate that there are differences in HSP protein expression when COD is induced. In fact, HSP expression would be part of the functional response to the changes in hormones and neurotransmitters induced by stress, indicating that HSPs can control hormonal functions and vice versa. PMID- 23937991 TI - A comparison of two morphine doses on the quality of recovery from general anaesthesia in horses. AB - Previous studies indicated that perioperative morphine improves recovery quality after general anaesthesia in horses. This clinical trial investigated whether this effect was dose-dependant. Twenty-six horses anaesthetised for surgery were block-randomised to receive one of two intraoperative morphine treatments: Treatment M1 consisted of a constant rate infusion (CRI) of morphine at 0.1mg/kg/h, begun after a loading dose (LD) of 0.15 mg/kg. Treatment M2 was a CRI of 0.2mg/kg/h preceded by an LD of 0.3mg/kg. During recovery, times at the first attempt and at achieving sternal recumbency and standing, and the total recovery duration were not different between groups. Total recovery quality score was not significantly different between groups. Scores for the "sternal phase" were higher (of poorer quality) for M2 but scores in both groups were low. Morphine doses of M2, which are greater than those described previously, do not appear to alter or improve the quality or duration of recovery in horses after surgical anaesthesia. PMID- 23937992 TI - Recombinant flagellin and its cross-talk with lipopolysaccharide--effect on pooled chicken peripheral blood mononuclear cells. AB - Toll-like receptors (TLRs) are one of the types of pattern recognition receptors (PRRs) that recognize conserved pathogen molecules. TLRs link innate and adaptive arms of immune system and are implicated in the development of defense against invading pathogens. Lipopolysaccharide (LPS) and flagellin are recognized by TLR4 and TLR5, respectively. In this study, the effect of flagellin and lipopolysaccharide alone and in combination on chicken peripheral blood mononuclear cells (PBMCs) was investigated. The FliC gene of Salmonella typhimurium was expressed in a prokaryotic expression system and the recombinant flagellin was used to stimulate the chicken PBMCs. A combination of recombinant flagellin and LPS synergistically upregulated nitric oxide production, IL-12 and IL-6 expression but antagonistically down regulated IL-4 expression in comparison to recombinant flagellin alone. The results indicate that these agonists synergistically interact and enhance macrophage function and promote Th1 immune response in chicken PBMCs. PMID- 23937993 TI - Longitudinal strain and strain rate by two-dimensional speckle tracking in non sedated healthy cats. AB - Two dimensional speckle tracking (2D-ST) is a relatively new tool that has been used in veterinary medicine to quantify myocardial function. However, there is little information about the use of this tool in healthy cats. Thus, the aim of this study was to evaluate left ventricular longitudinal strain and strain rate in non-sedated healthy cats, as well as longitudinal velocity and displacement, by means of 2D-ST echocardiography. Thirty non-sedated healthy cats were examined and 2D images were obtained for 2D-ST analyzes. The global mean strain and strain rate was -15.65 +/- 5.46% and -1.80 +/- 0.59 s(-1), respectively. Velocity and displacement were 1.41 +/- 0.87 cm/s and 1.27 +/- 0.80 mm, respectively. Thus, 2D ST demonstrated to be feasible for measuring left ventricular longitudinal strain, strain rate, velocity and displacement in cats and preliminary reference values for non-sedated healthy cats can be established from the results of this study. PMID- 23937995 TI - Ethical considerations in an era of mass drug administration. AB - In a Plenary debate at the 51st Spring meeting of the British Society of Parasitology, Bristol, UK, April 8-11, 2013, the bioethicist James Wilson used the value of a life in the present and future to question the effectiveness of current health strategies. PMID- 23937994 TI - Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile. AB - BACKGROUND: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression. METHODS: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3). RESULTS: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies. CONCLUSIONS: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer. PMID- 23937998 TI - Obstructive sleep apnoea, gout and cardiovascular risk: a worth studying association. PMID- 23937996 TI - Perioperative ketorolac in high risk breast cancer patients. Rationale, feasibility and methodology of a prospective randomized placebo-controlled trial. AB - Ketorolac, a NSAID routinely used during surgery proposed to have anticancer effects, is a promising way to improve postoperative oncological outcome. This effect may be particularly prominent in patients with elevated preoperative inflammatory scores, like the neutrophil:lymphocyte ratio. In this paper, we describe the rationale, the preliminary analyses in our patients, the feasibility and the methodology of a prospective randomized trial called "Ketorolac in Breast Cancer trial" (KBCt) (NCT01806259). PMID- 23937997 TI - Is there a hierarchy of survival reflexes? AB - A hierarchy of survival reflexes for prioritising assessment and treatment in patients with pain of insidious onset is hypothesised. The hierarchy asserts that some systems are more vital than others and that the central nervous system (CNS) prioritises systems based on their significance to survival. The hypothesis suggests that dysfunction in more important systems will cause compensation in less important systems. This paper presents studies examining these effects for each system, arguing that each section of the hierarchy may have effects on other systems within the hierarchy. This concept is untested empirically, highly speculative and substantial research is required to validate the suggested hierarchical prioritisation by the CNS. Nonetheless, the hierarchy does provide a theoretical framework to use to exclude contributing systems in patients with pain of insidious onset. PMID- 23937999 TI - PACE--the first placebo controlled trial of paracetamol for acute low back pain: statistical analysis plan. AB - BACKGROUND: Paracetamol (acetaminophen) is recommended in most clinical practice guidelines as the first choice of treatment for low back pain, however there is limited evidence to support this recommendation. The PACE trial is the first placebo controlled trial of paracetamol for acute low back pain. This article describes the statistical analysis plan. RESULTS: PACE is a randomized double dummy placebo controlled trial that investigates and compares the effect of paracetamol taken in two regimens for the treatment of low back pain. The protocol has been published. The analysis plan was completed blind to study group and finalized prior to initiation of analyses. All data collected as part of the trial were reviewed, without stratification by group, and classified by baseline characteristics, process of care and trial outcomes. Trial outcomes were classified as primary and secondary outcomes. Appropriate descriptive statistics and statistical testing of between-group differences, where relevant, have been planned and described. CONCLUSIONS: A standard analysis plan was developed for the results of the PACE study. This plan comprehensively describes the data captured and pre-determined statistical tests of relevant outcome measures. The plan demonstrates transparent and verifiable use of the data collected. This a priori plan will be followed to ensure rigorous standards of data analysis are strictly adhered to. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry ACTRN12609000966291. PMID- 23938000 TI - Preoperative chlorhexidine baths/showers: for or against? PMID- 23938001 TI - Surgical site infection after cesarean section: implementing 3 changes to improve the quality of patient care. AB - BACKGROUND: Surgical site infection (SSI) is an important complication of cesarean section (CS) delivery and a key quality indicator of patient care. METHODS: A baseline assessment was undertaken to determine SSI rates, and subsequently a quality improvement program was introduced, followed by repeat surveillance. Data were collected during in-hospital stays and for up to 30 days after CS during both periods. Interventions in the quality improvement program included the use of nonabsorbable sutures for skin closure, use of clippers instead of razors, and use of 2% ChloraPrep for skin disinfection before incision. RESULTS: A total of 710 patients were surveyed before the interventions, and 824 patients were surveyed after the interventions. Of these, 114 (16%) had an SSI before the interventions, and 40 (4.9%) had an SSI after the interventions (P < .001; odds ratio, 0.27), with 90% and 83%, respectively, detected after hospital discharge. In multivariate analysis, obesity (P = .002) and the use of absorbable suture materials for skin closure (P = .008) were significantly associated with a higher SSI rate before the interventions; however, only obesity was associated with a higher SSI rate after the quality program. CONCLUSION: Surveillance of SSI rates after CS followed by 3 interventions contributed to a significant reduction in SSI rate and improved patient care. PMID- 23938002 TI - Incidence of intraoperative hypotension during isoflurane-fentanyl and propofol fentanyl anaesthesia in dogs. AB - Most anaesthetic and analgesic drugs affect the cardiovascular system and can cause intraoperative hypotension (IOH). This study aimed to compare the incidence of IOH in anaesthetised dogs when isoflurane-fentanyl was used, compared to propofol-fentanyl. Intraoperative hypotension was defined as an episode of mean blood pressure below 60 mmHg for more than 5 min during anaesthesia. The incidence of IOH was 65.3% for isoflurane-fentanyl and 27.6% for propofol fentanyl. The adjusted odds ratio for IOH when propofol-fentanyl was compared to isoflurane-fentanyl was 0.2 (95% CI 0.11-0.38). These results suggest that propofol-fentanyl is associated with a lower risk of IOH than isoflurane-fentanyl anaesthesia. PMID- 23938003 TI - Veterinarian awareness of farmer goals and attitudes to herd health management in The Netherlands. AB - In providing advice on herd health, veterinarians need to be aware of farmers' goals and priorities. To determine the level of awareness, 29 veterinarians from 15 practices completed questionnaires during visits to dairy farms within the scope of veterinary herd health management (VHHM) programmes. The farmers (n=30) were asked to complete a questionnaire and their discussions with the veterinarian were recorded using a voice recorder. Herd performance goals were set by the farmer and veterinarian in 24% of cases. Veterinarians who did not set goals indicated that they and the farmer 'intuitively knew' what each wanted to achieve, and that the setting of performance goals was considered 'too formal'. Veterinarians often could not identify a farmer's main goal, and typically found milk production and nutrition significantly more important (P<0.01, and P<0.02, respectively), and fertility significantly less important (P<0.01) than the farmers. During on-farm conversations, veterinarians did not actively seek to identify farmers' goals or problems, suggest a co-operative strategy or summarise any advice given. The findings of this survey suggest that veterinarians need to focus more on goal setting, since awareness of goals and priorities is important for both communication and compliance with advice given. The needs of farmers with respect to herd health should also be more actively sought by veterinarians as the findings indicate that most farmers do not readily volunteer such information. PMID- 23938004 TI - An update on the pathogenesis of syringomyelia secondary to Chiari-like malformations in dogs. AB - Syringomyelia (SM) is a spinal cord disease that can cause neuropathic pain in dogs. The pathogenesis of SM secondary to Chiari-like malformation (CM) has been the focus of intense research in recent years. The gulf in our understanding of CM/SM in dogs relative to the analogous human condition has progressively narrowed. CM is primarily a disease of abnormal geometric morphometry affecting the caudal cranial fossa and the brain parenchyma contained within it. This review describes how advanced imaging techniques have revealed a series of morphometric abnormalities associated with CM/SM. The series is presented in a logical order to help describe the pathogenesis of CM and the subsequent formation of syringes, with particular reference to the concepts of craniospinal compliance and cerebrospinal fluid pulse pressure timing. PMID- 23938005 TI - Comparative investigation of diagnosis media for induction machine mechanical unbalance fault. AB - For an induction machine, we suggest a theoretical development of the mechanical unbalance effect on the analytical expressions of radial vibration and stator current. Related spectra are described and characteristic defect frequencies are determined. Moreover, the stray flux expressions are developed for both axial and radial sensor coil positions and a substitute diagnosis technique is proposed. In addition, the load torque effect on the detection efficiency of these diagnosis media is discussed and a comparative investigation is performed. The decisive factor of comparison is the fault sensitivity. Experimental results show that spectral analysis of the axial stray flux can be an alternative solution to cover effectiveness limitation of the traditional stator current technique and to substitute the classical vibration practice. PMID- 23938006 TI - Promoting mental health: the work of the International Council of Nurses. PMID- 23938009 TI - Drugs to treat overweight and obesity. PMID- 23938012 TI - Retrievable stent thrombectomy in the treatment of acute ischemic stroke: analysis of a revolutionizing treatment technique. AB - Acute ischemic stroke resulting from intracranial vessel occlusion is associated with high morbidity and mortality. The mainstays of therapy are fibrinolytics and mechanical thrombectomy in properly selected patients. A new Food and Drug Administration-approved technology to perform thrombectomy, retrievable stenting, may provide superior revascularization rates and improved patient outcomes. We analyzed the cumulative human experience reported for the Trevo Pro Retrieval System (Stryker, Kalamazoo, MI, USA) and the Solitaire FR Revascularization Device (ev3, Irvine, CA, USA) as the definitive treatment for acute ischemic stroke. A literature search was undertaken to identify studies using the retrievable stents published up to September 2012. Nineteen studies identified a total of 576 patients treated with either the Trevo (n=221) or Solitaire (n=355) devices. Pooled data analysis identified median baseline National Institutes of Health Stroke Scale scores of 18.5 +/- 0.289 (standard error of the mean) and 17.9 +/- 0.610, and time to recanalization of 53.9 +/- 23.6 minutes and 59.0 +/- 8.0 minutes for the Trevo and Solitaire groups, respectively. Recanalization was variably defined by individual studies, most commonly achieving at least a thrombolysis in cerebral infarction score of 2a-3 or a thrombolysis in myocardial infarction score of 2-3. Revascularization (83%, 82%), mortality (31%, 14%), hemorrhage (8%, 6%), device complications (5%, 6%), and good patient outcomes (51%, 47%) were found with the Trevo and Solitaire devices, respectively. Preliminary analysis reveals excellent clinical outcomes for retrievable stent technology. This may be attributable to both high rates of revascularization with a relatively short time to perfusion restoration. PMID- 23938013 TI - Complete recovery following intra-arterial tenecteplase administration in a woman with acute ischemic stroke. AB - A 23-year-old woman, who underwent a percutaneous transluminal mitral commissurotomy for a tight mitral stenosis, developed an acute ischemic stroke involving the proximal right middle cerebral artery territory. She had a dense left hemiplegia with a National Institutes of Health Stroke Scale score of 12. She was emergently treated within 1 hour with intra-arterial tenecteplase and made a dramatic recovery. Intra-arterial tenecteplase is an attractive option for treating acute ischemic stroke with proximal or major vessel occlusion. PMID- 23938014 TI - Fibroblast growth factor 20 polymorphism in sporadic Parkinson's disease in Northern Han Chinese. AB - Fibroblast growth factor (FGF) 20 is a neurotrophic factor that exerts strong neurotrophic properties in the brain and could significantly enhance the survival of rat midbrain dopaminergic neurons. The genetic association of the FGF20 gene with Parkinson's disease (PD) remains controversial. We used the polymerase chain reaction-restriction length polymorphism assay to assess the association of two single nucleotide polymorphisms, rs12720208 and rs1721100, within the FGF20 gene in 178 PD patients and 190 healthy controls from a Northern Han Chinese population. The results showed no significant differences in the presence of rs1721100 or rs12720208 in the FGF20 gene between PD patients and controls. This indicates the FGF20 gene might not play a major role in the genetic predisposition to PD in this population. PMID- 23938015 TI - Effects of antiepileptic drugs on reproductive endocrine function, sexual function and sperm parameters in Chinese Han men with epilepsy. AB - The effects of the antiepileptic drugs sodium valproate (VPA) and levetiracetam (LEV) on reproductive endocrine function, sexual function, and spermatozoa were explored, together with their possible etiological mechanisms, in Chinese Han men with epilepsy. Following VPA treatment (n=32), luteinizing hormone and follicle stimulating hormone levels were significantly lower than in controls (n=30). The bioactive testosterone/luteinizing hormone ratio and the prolactin level were significantly elevated in the VPA treatment group. There were no significant differences in these hormones between the LEV treatment (n=20) and control groups. The rates of sperm morphologic abnormality (head, body, and tail) were significantly higher in the VPA treatment group than the control group but did not differ significantly between the LEV treatment and control groups. The sperm motility rate was significantly lower in the VPA treatment group (grade A sperm motility rate <25%, grade A+B sperm motility rate <50%) than in controls, as well as in the LEV treatment group (grade A sperm motility rate <25%). Patients in the VPA and LEV treatment groups had lower scores on questions 1, 2 and 3 of a simplified International Index of Erectile Function Scale than controls, but no significant difference on questions 4 or 5. The total International Index of Erectile Function Scale scores were significantly lower in the VPA and LEV treatment groups. We conclude that treatment with VPA adversely affects reproductive endocrine function, sperm parameters and sexual function to varying degrees in Chinese men with epilepsy. PMID- 23938016 TI - Status and costs of primary prevention for ischemic stroke in China. AB - Despite the benefits in reducing the risk of stroke, primary prevention is not well translated into practice. We sought to evaluate patient compliance with guidelines and the cost of primary stroke prevention in southwest China. We consecutively enrolled 305 patients with headaches and/or dizziness who were at high risk of stroke from our hospital. We retrospectively obtained their information, including the extent of their knowledge of stroke risk factors, adherence to guidelines, medications taken, and costs of primary prevention for stroke within the past year. Only 45.9% of patients had any knowledge of primary prevention, and only 17.0% had completely followed guidelines. Moreover, 79.0% of the patients were using medications, but only 39.3% took their medication as recommended. In patients who took medication, 89.6% were prescribed by physicians. The annual costs of primary prevention were estimated to be US$517.8 per capita, which included direct medical costs (US$435.4), direct non-medical costs (US$18.1), and indirect costs (US$64.3). Costs in the hypertension group were less than those reported by a similar international study. Although our population sample may not be representative of the population at high risk of stroke in China, it is appropriate for the evaluation of our primary prevention system. Primary prevention for stroke in southwest China is very challenging, with few medical resource investments. There is a current urgency to improve patient knowledge of primary prevention, which would bridge the gaps between guidelines and practice and increase medical resource investments. PMID- 23938018 TI - The prevalence of child maltreatment in the Netherlands across a 5-year period. AB - The prevalence of child maltreatment in the Netherlands was in 2005 first systematically examined in the Netherlands' Prevalence study on Maltreatment of children and youth (NPM-2005), using sentinel reports and substantiated CPS cases, and in the Pupils on Abuse study (PoA-2005), using high school students' self-report. In this second National Prevalence study on Maltreatment (NPM-2010), we used the same three methods to examine the prevalence of child maltreatment in 2010, enabling a cross-time comparison of the prevalence of child maltreatment in the Netherlands. First, 1,127 professionals from various occupational branches (sentinels) reported each child for whom they suspected child maltreatment during a period of three months. Second, we included 22,661 substantiated cases reported in 2010 to the Dutch Child Protective Services. Third, 1,920 high school students aged 12-17 years filled out a questionnaire on their experiences of maltreatment in 2010. The overall prevalence of child maltreatment in the Netherlands in 2010 was 33.8 per 1,000 children based on the combined sentinel and CPS reports and 99.4 per 1,000 adolescents based on self-report. Major risk factors for child maltreatment were parental low education, immigrant status, unemployment, and single parenthood. We found a large increase in CPS-reports, whereas prevalence rates based on sentinel and self-report did not change between 2005 and 2010. Based on these findings a likely conclusion is that the actual number of maltreated children has not increased from 2005 to 2010, but that professionals have become more aware of child maltreatment, and more likely to report cases to CPS. PMID- 23938019 TI - Understanding the decline in unwanted online sexual solicitations for U.S. youth 2000-2010: findings from three Youth Internet Safety Surveys. AB - To explore the decline in online sexual solicitations between 2000 and 2010 by examining the characteristics of solicitations to better inform prevention efforts. Data are from the Youth Internet Safety Surveys (YISS); three cross sectional, nationally representative telephone surveys of 3561 youth Internet users in the United States, ages 10 through 17 (1501 in YISS-1; 1500 in YISS-2; 1560 in YISS-3). Unwanted online sexual solicitation was defined as requests to engage in sexual activities or sexual talk or give personal sexual information that were unwanted or, whether wanted or not, made by an adult. The decline in unwanted sexual solicitations from 19% in 2000 to 13% in 2005 to 9% in 2010 was driven by a reduction in youth who were being asked to talk about sex or for personal sexual information online. Pre-teens (ages 10-12) accounted for the majority of this decline. Multiple solicitations over the course of a year also decreased. More solicitations occurred at the hands of people youth knew in person prior to the incident - mainly friends and acquaintances, and less so at the hands of people youth met online. By 2010 most solicitations were occurring through social networking sites. Victims were disclosing solicitation incidents at greater rates in 2010 - mostly to friends. In spite of continuing anxiety about the impact of the Internet on the safety of youth, encouraging trends suggest experiences, behavior and education are moving in the direction of greater online safety and improved experiences for youth. PMID- 23938020 TI - Signet-ring cell carcinoma of the breast: a case report. AB - Signet-ring cell carcinoma (SRCC) can arise from virtually all organs. However, primary SRCC of the breast is very rare. Until 2003, SRCC was placed under 'mucin producing carcinomas' and separated from other carcinomas by the World Health Organization (WHO). To date, only a few cases have been reported. A case of a 46 year-old woman with primary SRCC of the breast is presented in this report. The patient underwent a right modified radical mastectomy with axillary lymph node dissection. Characteristic features and differential diagnosis of this tumor are discussed in the light of pertinent literature. PMID- 23938021 TI - Electron microscopy of human peripheral nerves of clinical relevance to the practice of nerve blocks. A structural and ultrastructural review based on original experimental and laboratory data. AB - AIM: The goal is to describe the ultrastructure of normal human peripheral nerves, and to highlight key aspects that are relevant to the practice of peripheral nerve block anaesthesia. METHOD: Using samples of sciatic nerve obtained from patients, and dural sac, nerve root cuff and brachial plexus dissected from fresh human cadavers, an analysis of the structure of peripheral nerve axons and distribution of fascicles and topographic composition of the layers that cover the nerve is presented. Myelinated and unmyelinated axons, fascicles, epineurium, perineurium and endoneurium obtained from patients and fresh cadavers were studied by light microscopy using immunohistochemical techniques, and transmission and scanning electron microscopy. Structure of perineurium and intrafascicular capillaries, and its implications in blood-nerve barrier were revised. RESULTS: Each of the anatomical elements is analyzed individually with regard to its relevance to clinical practice to regional anaesthesia. CONCLUSIONS: Routine practice of regional anaesthetic techniques and ultrasound identification of nerve structures has led to conceptions, which repercussions may be relevant in future applications of these techniques. In this regard, the ultrastructural and histological perspective accomplished through findings of this study aims at enlightening arising questions within the field of regional anaesthesia. PMID- 23938022 TI - Incorporating the effects of humidity in a mechanistic model of Anopheles gambiae mosquito population dynamics in the Sahel region of Africa. AB - BACKGROUND: Low levels of relative humidity are known to decrease the lifespan of mosquitoes. However, most current models of malaria transmission do not account for the effects of relative humidity on mosquito survival. In the Sahel, where relative humidity drops to levels <20% for several months of the year, we expect relative humidity to play a significant role in shaping the seasonal profile of mosquito populations. Here, we present a new formulation for Anopheles gambiae sensu lato (s.l.) mosquito survival as a function of temperature and relative humidity and investigate the effect of humidity on simulated mosquito populations. METHODS: Using existing observations on relationships between temperature, relative humidity and mosquito longevity, we developed a new equation for mosquito survival as a function of temperature and relative humidity. We collected simultaneous field observations on temperature, wind, relative humidity, and anopheline mosquito populations for two villages from the Sahel region of Africa, which are presented in this paper. We apply this equation to the environmental data and conduct numerical simulations of mosquito populations using the Hydrology, Entomology and Malaria Transmission Simulator (HYDREMATS). RESULTS: Relative humidity drops to levels that are uncomfortable for mosquitoes at the end of the rainy season. In one village, Banizoumbou, water pools dried up and interrupted mosquito breeding shortly after the end of the rainy season. In this case, relative humidity had little effect on the mosquito population. However, in the other village, Zindarou, the relatively shallow water table led to water pools that persisted several months beyond the end of the rainy season. In this case, the decrease in mosquito survival due to relative humidity improved the model's ability to reproduce the seasonal pattern of observed mosquito abundance. CONCLUSIONS: We proposed a new equation to describe Anopheles gambiae s.l. mosquito survival as a function of temperature and relative humidity. We demonstrated that relative humidity can play a significant role in mosquito population and malaria transmission dynamics. Future modeling work should account for these effects of relative humidity. PMID- 23938023 TI - Antimicrobial action and anti-corrosion effect against sulfate reducing bacteria by lemongrass (Cymbopogon citratus) essential oil and its major component, the citral. AB - The anti-corrosion effect and the antimicrobial activity of lemongrass essential oil (LEO) against the planktonic and sessile growth of a sulfate reducing bacterium (SRB) were evaluated. Minimum inhibitory concentration (MIC) of LEO and its major component, the citral, was 0.17 mg ml-1. In addition, both LEO and citral showed an immediate killing effect against SRB in liquid medium, suggesting that citral is responsible for the antimicrobial activity of LEO against SRB. Transmission electron microscopy revealed that the MIC of LEO caused discernible cell membrane alterations and formed electron-dense inclusions. Neither biofilm formation nor corrosion was observed on carbon steel coupons after LEO treatment. LEO was effective for the control of the planktonic and sessile SRB growth and for the protection of carbon steel coupons against biocorrosion. The application of LEO as a potential biocide for SRB growth control in petroleum reservoirs and, consequently, for souring prevention, and/or as a coating protection against biocorrosion is of great interest for the petroleum industries. PMID- 23938024 TI - Regulation of host gene expression by HIV-1 TAR microRNAs. AB - BACKGROUND: The transactivating response (TAR) element of human immunodeficiency virus type 1 (HIV-1) is the source of two functional microRNAs (miRNAs), miR-TAR 5p and miR-TAR-3p. The objective of this study was to characterize the post transcriptional regulation of host messenger RNAs (mRNAs) relevant to HIV-1 pathogenesis by HIV-1 TAR miRNAs. RESULTS: We demonstrated that TAR miRNAs derived from HIV-1 can incorporate into host effector Argonaute protein complexes, which is required if these miRNAs are to regulate host mRNA expression. Bioinformatic predictions and reporter gene activity assays identified regulatory elements complementary and responsive to miR-TAR-5p and miR TAR-3p in the 3' untranslated region (UTR) of several candidate genes involved in apoptosis and cell survival. These include Caspase 8, Aiolos, Ikaros and Nucleophosmin (NPM)/B23. Analyses of Jurkat cells that stably expressed HIV-1 TAR or contained a full-length latent HIV provirus suggested that HIV-1 TAR miRNAs could regulate the expression of genes in T cells that affect the balance between apoptosis and cell survival. CONCLUSIONS: HIV-1 TAR miRNAs may contribute to the replication cycle and pathogenesis of HIV-1, by regulating host genes involved in the intricate balance between apoptosis and infected cell, to induce conditions that promote HIV-1 propagation and survival. PMID- 23938025 TI - Application of clinical pathway using electronic medical record system in pediatric patients with supracondylar fracture of the humerus: a before and after comparative study. AB - BACKGROUND: This study was performed to investigate the usefulness of clinical pathway (CP) using an electronic medical record (EMR) in pediatric patients undergoing closed pinning for supracondylar fracture of the humerus, by analyzing the length of hospital stay, hospital cost and satisfaction of the medical teams. METHODS: This before and after comparative study included consecutive children who underwent closed pinning for supracondylar fracture of the humerus since 2009. The pre-CP group consists of 90 patients with the mean age of 5.7 years, and the post-CP group consists of 32 patients with the mean age of 6.2 years. Multidisciplinary work-team developed CP using an EMR system in March 2011. The length of hospital stay was the primary outcome variable, and hospital cost and medical team's satisfaction score were secondary outcome variables. The non inferiority test was used to demonstrate the efficiency of the pathway. RESULTS: The length of hospital stay decreased from 2.9 +/- 0.7 days to 2.4 +/- 0.7 days by 15.0%, after the implementation of CP, and the lower bound of the 95% CI of the difference (0.14 day) was within the non-inferiority margin of -0.3 days. The hospital cost decreased from 1162.2 +/- 236.7 US$ to 1139.8 +/- 291.1 US$ by 1.9% and the lower bound of the 95% CI of the difference was -81.3 US$, which did not exceed the non-inferiority margin of -116.2 US$. Therefore, the post-CP group was not inferior compared with the pre-CP group in term of the length of hospital stay and total hospital cost. There was significant increase in the satisfaction score for doctors after implementation of CP (p < 0.001), but, no change in the satisfaction score for nursing staffs (p = 0.793). CONCLUSIONS: The development and implementation of CP, using an EMR, in pediatric patients undergoing closed pinning for supracondylar fracture of the humerus enhances the treatment efficiency by streamlining the treatment process with no increases of the length of the hospital stay and total hospital costs. PMID- 23938026 TI - Development of a quantitative food frequency questionnaire for Brazilian patients with type 2 diabetes. AB - BACKGROUND: To investigate the association between dietary components and development of chronic diabetic complications, the dietary evaluation should include a long period, months or years. The present manuscript aims to develop a quantitative food frequency questionnaire (FFQ) and a portfolio with food photos to assess the usual intake pattern of Brazilian patients with type 2 diabetes to be used in future studies. METHODS: Dietary data using 3-day weighed diet records (WDR) from 188 outpatients with type 2 diabetes were used to construct the list of usually consumed foods. Foods were initially clustered into eight groups: "cereals, tubers, roots, and derivatives"; "vegetables and legumes"; "fruits"; "beans"; "meat and eggs"; "milk and dairy products"; "oils and fats", and "sugars and sweets". The frequency of food intake and the relative contribution of each food item to the total energy and nutrient intakes were calculated. Portion sizes were determined according to the 25th, 50th, 75th, and 95th percentiles of intake for each food item. RESULTS: A total of 62 food items were selected based on the 3-day WDR and another 27 foods or how they are prepared and nine beverages were included after the expert examination. Also, a portfolio with food photos of each included food item and portion sizes was made to assist the patients in identifying the consumed portion. CONCLUSIONS: We developed a practical quantitative FFQ and portfolio with photos of 98 food items covering those most commonly consumed in the past 12 months, to assess the usual diet pattern of patients with type 2 diabetes in Southern Brazil. PMID- 23938027 TI - Autophagy is involved in oligodendroglial precursor-mediated clearance of amyloid peptide. AB - BACKGROUND: Accumulation of beta-amyloid peptides is an important hallmark of Alzheimer's disease (AD). Tremendous efforts have been directed to elucidate the mechanisms of beta-amyloid peptides degradation and develop strategies to remove beta-amyloid accumulation. In this study, we demonstrated that a subpopulation of oligodendroglial precursor cells, also called NG2 cells, were a new cell type that can clear beta-amyloid peptides in the AD transgene mice and in NG2 cell line. RESULTS: NG2 cells were recruited and clustered around the amyloid plaque in the APPswe/PS1dE9 mice, which is Alzheimer's disease mouse model. In vitro, NG2 cell line and primary NG2 cells engulfed beta-amyloid peptides through the mechanisms of endocytosis in a time dependent manner. Endocytosis is divided into pinocytosis and phagocytosis. Abeta(42) internalization by NG2 cells was mediated by actin-dependent macropinocytosis. The presence of beta-amyloid peptides stimulated the autophagic pathway in NG2 cells. Once inside the cells, the beta amyloid peptides in NG2 cells were transported to lysosomes and degraded by autophagy. CONCLUSIONS: Our findings suggest that NG2 cells are a new cell type that can clear beta-amyloid peptides through endocytosis and autophagy. PMID- 23938028 TI - Dexamethasone reduces emesis after major gastrointestinal surgery (DREAMS). AB - BACKGROUND: Postoperative nausea and vomiting is one of the most common complications affecting patients after surgery and causes significant morbidity and increased length of hospital stay. It is accepted that patients undergoing surgery on the bowel are at a higher risk. In the current era of minimally invasive colorectal surgery combined with enhanced recovery, reducing the incidence and severity of postoperative nausea and vomiting is particularly important. Dexamethasone is widely, but not universally used. It is known to improve appetite and gastric emptying, thus reduce vomiting. However, this benefit is not established in patients undergoing bowel surgery, and dexamethasone has possible side effects such as increased risk of wound infection and anastomotic leak that could adversely affect recovery. DESIGN: DREAMS is a phase III, double-blind, multicenter, randomized controlled trial with the primary objective of determining if preoperative dexamethasone reduces postoperative nausea and vomiting in patients undergoing elective gastrointestinal resections. DREAMS aims to randomize 1,350 patients over 2.5 years.Patients undergoing laparoscopic or open colorectal resections for malignant or benign pathology are randomized between 8 mg intravenous dexamethasone and control (no dexamethasone). All patients are given one additional antiemetic at the time of induction, prior to randomization. Both the patient and their surgeon are blinded as to the treatment arm.Secondary objectives of the DREAMS trial are to determine whether there are other measurable benefits during recovery from surgery with the use of dexamethasone, including quicker return to oral diet and reduced length of stay. Health-related quality of life, fatigue and risks of infections will be investigated. TRIAL REGISTRATION: ISRCTN21973627. PMID- 23938029 TI - A reverse glyoxylate shunt to build a non-native route from C4 to C2 in Escherichia coli. AB - Most central metabolic pathways such as glycolysis, fatty acid synthesis, and the TCA cycle have complementary pathways that run in the reverse direction to allow flexible storage and utilization of resources. However, the glyoxylate shunt, which allows for the synthesis of four-carbon TCA cycle intermediates from acetyl CoA, has not been found to be reversible to date. As a result, glucose can only be converted to acetyl-CoA via the decarboxylation of the three-carbon molecule pyruvate in heterotrophs. A reverse glyoxylate shunt (rGS) could be extended into a pathway that converts C4 carboxylates into two molecules of acetyl-CoA without loss of CO2. Here, as a proof of concept, we engineered in Escherichia coli such a pathway to convert malate and succinate to oxaloacetate and two molecules of acetyl-CoA. We introduced ATP-coupled heterologous enzymes at the thermodynamically unfavorable steps to drive the pathway in the desired direction. This synthetic pathway in essence reverses the glyoxylate shunt at the expense of ATP. When integrated with central metabolism, this pathway has the potential to increase the carbon yield of acetate and biofuels from many carbon sources in heterotrophic microorganisms, and could be the basis of novel carbon fixation cycles. PMID- 23938030 TI - A rare complication of a retained wire during endovascular abdominal aortic aneurysm repair. AB - We present a case of a high-risk 76-year-old man who was electively admitted for repair of a large infrarenal abdominal aortic aneurysm. After placement of the main body of the bifurcated graft, the contralateral guidewire became entrapped at the level of suprarenal fixation. Multiple endovascular maneuvers were attempted to remove this wire from the femoral approach, but all were unsuccessful. The wire was then transected at the level of the common femoral artery and anchored to the arterial wall with 1 small monofilament suture. A short bare stent was also used to secure this wire to the inner wall of the external iliac artery. However, the proximal end of the wire that extended freely up to the mid-descending aorta was left undisturbed. On postoperative day 2, an attempt at snaring the proximal end of the wire via a brachial approach also failed to displace the trapped wire. At 1-year of follow-up, the patient has been asymptomatic with no obvious sequelae, such as thromboembolism or aortic dissection, and there is no evidence of damage to the aorta or graft on computed tomographic imaging. To our knowledge, this complication has not been previously reported. PMID- 23938031 TI - Hypoxia-induced senescence contributes to the regulation of microenvironment in melanomas. AB - Senescence, an irreversible state of cell cycle arrest, maintains metabolic activity. Although being a barrier against tumor development, senescence could also promote tumor progression by influencing the microenvironment. Necrosis is a common feature of various malignant tumors, which also has two opposing effects: pro-tumor by chronic inflammation and anti-tumor by effective cell clearance. However, the role of senescence in melanoma and whether it is associated with necrosis remain unclear. By detecting senescence-associated beta-galactosidase activity and pimonidazole (hypoxia probe), we found that senescent cells (SA-beta gal positive) are mainly located around the necrotic/hypoxic areas of melanoma from C57BL/6J mice. Moreover, treatment of hypoxia induced irreversibly cellular senescence in vitro. In addition, the senescent cells may facilitate microenvironment modulation and promote the invasion of melanoma cells by secreting matrix metalloproteinase-2(MMP-2). Moreover, Kaplan-Meier analysis showed that the presence of necrosis in melanomas had an inverse correlation with patient survival and may serve as an independent prognostic marker. Therefore, hypoxic stress imposed on melanomas may lead to cellular senescence surrounding necrotic areas, and the adverse effects of necrosis in tumor may be attributed to the adjacent senescent cells with senescence-associated secretion phenotype (SASP), including secretion of MMP-2. PMID- 23938032 TI - Merkel cell carcinoma of the ethmoid sinus. PMID- 23938033 TI - [Development of a tool for recording involvement/engagement in activities in the systematic observation of elderly persons with cognitive impairment]. AB - INTRODUCTION: As the level of cognitive impairment in people with dementia increases, it seems that the interventions aimed at this group do not obtain the expected results. Thus, it is clear that there is a need to develop specific assessment tools. One of the important aspects in people with dementia is the engagement, involvement in task and activities. Engagement is considered a quality of life and quality of care indicator. The aim of the study is to develop an Engagement recording tool for mapping people with dementia, and to obtain reliability measures. METHOD: The present paper aims to present the current development of engagement behaviours. The pilot study had a sample of 19 people distributed into two groups, which were observed in order to obtain inter-rater reliability measurements using the percentage of inter-rater agreement. RESULTS: An observational mapping instrument was developed that achieved a high inter rater reliability. CONCLUSION: The Engagement recording tool makes it possible to gather promising results on the effects of the interventions for people with severe dementia. On the other hand, these results point to the possibilities of more specific tools to assess the different interventions which aim is to improve quality of life and quality of care in people with dementia. PMID- 23938034 TI - A radical sense of direction: signalling and mechanism in cryptochrome magnetoreception. AB - The remarkable phenomenon of magnetoreception in migratory birds and other organisms has fascinated biologists for decades. Much evidence has accumulated to suggest that birds sense the magnetic field of the Earth using photochemical transformations in cryptochrome flavoproteins. In the last 5 years this highly interdisciplinary field has seen advances in structural biology, biophysics, spin chemistry, and genetic studies in model organisms. We review these developments and consider how this chemical signal can be integrated into the cellular response. PMID- 23938035 TI - Adult centronuclear myopathies: A hospital-based study. AB - INTRODUCTION: Centronuclear myopathies (CNM) are rare inherited disorders characterized by nuclei placed in rows in the central part of the muscle fibres. Three CNM-causing genes have been identified, with MTM1 mutations provoking X linked myotubular myopathy, DNM2 mutations provoking autosomal dominant (AD) CNM, and BIN1 mutations provoking autosomal recessive (AR) CNM. METHODS: In this retrospective monocentric study, we describe 14 adult patients (age>18 years) diagnosed with CNM in our hospital in the 2000-2012 interval. Twelve patients originated from four families, and two patients presented with sporadic CNM. All patients underwent standardized clinical examinations, biological tests, electrophysiological studies, muscle biopsy, and molecular testing. RESULTS: Seven patients developed CNM before age 15, and seven after age 25. All patients presented with distal upper and lower limbs weakness, and normal CK levels. Disease severity remained mild, with all patients being able to walk without assistance even after decades-long disease duration. Cognitive impairment was found in seven cases, axonal polyneuropathy in six cases and ophthalmoparesis and ptosis in five cases. DNM2 gene mutations were found in eight patients, whereas BIN1 and MTM1 mutations were not observed. Overall, no molecular diagnosis was available for six patients. CONCLUSION: Adult CNM is a slowly progressive distal myopathy with normal CK levels sometimes associated with cognitive impairment, axonal polyneuropathy, and ophthalmoparesis and ptosis. DNM2 mutations were found in eight patients, including AD and sporadic cases, and represent the major cause of CNM in this adult cohort. In contrast, no MTM1 and BIN1 mutations were observed in our series, leaving six patients with no molecular diagnosis. As these six patients presented with AD (3 cases), AR (2 cases), and sporadic (1 case) CNM, it is likely that several CNM-causing genes remain to be discovered. PMID- 23938036 TI - Optimized dose regimen for whole-body FDG-PET imaging. AB - BACKGROUND: The European Association of Nuclear Medicine procedure guidelines for whole-body fluorodeoxyglucose positron-emission tomography (FDG-PET) scanning prescribe a dose proportional to the patient's body mass. However, clinical practice shows degraded image quality in obese patients indicating that using an FDG dose proportional to body mass does not overcome size-related degradation of the image quality. The aim of this study was to optimize the administered FDG dose as a function of the patient's body mass or a different patient-dependent parameter, providing whole-body FDG-PET images of a more constant quality. METHODS: Using a linear relation between administered dose and body mass, FDG-PET imaging was performed on two PET/computed tomography scanners (Biograph TruePoint and Biograph mCT, Siemens). Image quality was assessed by the signal-to-noise ratio (SNR) in the liver in 102 patients with a body mass of 46 to 130 kg. Moreover, the best correlating patient-dependent parameter was derived, and an optimized FDG dose regimen was determined. This optimized dose regimen was validated on the Biograph TruePoint system in 42 new patients. Furthermore, this relation was verified by a simulation study, in which patients with different body masses were simulated with cylindrical phantoms. RESULTS: As expected, both PET systems showed a significant decrease in SNR with increasing patient's body mass when using a linear dosage. When image quality was fitted to the patient dependent parameters, the fit with the patient's body mass had the highest R2. The optimized dose regimen was found to be Anew= c/t * m2, where m is the body mass, t is the acquisition time per bed position and c is a constant (depending on scanner type). Using this relation, SNR no longer varied with the patient's body mass. This quadratic relation between dose and body mass was confirmed by the simulation study. CONCLUSION: A quadratic relation between FDG dose and the patient's body mass is recommended. Both simulations and clinical observations confirm that image quality remains constant across patients when this quadratic dose regimen is used. PMID- 23938037 TI - 'It is like a tomato stall where someone can pick what he likes': structure and practices of female sex work in Kampala, Uganda. AB - BACKGROUND: Effective interventions among female sex workers require a thorough knowledge of the context of local sex industries. We explore the organisation of female sex work in a low socio-economic setting in Kampala, Uganda. METHODS: We conducted a qualitative study with 101 participants selected from an epidemiological cohort of 1027 women at high risk of HIV in Kampala. Repeat in depth life history and work practice interviews were conducted from March 2010 to June 2011. Context specific factors of female sex workers' day-to-day lives were captured. Reported themes were identified and categorised inductively. RESULTS: Of the 101 women, 58 were active self-identified sex workers operating in different locations within the area of study and nine had quit sex work. This paper focuses on these 67 women who gave information about their involvement in sex work. The majority had not gone beyond primary level of education and all had at least one child. Thirty one voluntarily disclosed that they were HIV-positive. Common sex work locations were streets/roadsides, bars and night clubs. Typically sex occurred in lodges near bars/night clubs, dark alleyways or car parking lots. Overall, women experienced sex work-related challenges at their work locations but these were more apparent in outdoor settings. These settings exposed women to violence, visibility to police, a stigmatising public as well as competition for clients, while bars provided some protection from these challenges. Older sex workers tended to prefer bars while the younger ones were mostly based on the streets. Alcohol consumption was a feature in all locations and women said it gave them courage and helped them to withstand the night chill. Condom use was determined by clients' willingness, a woman's level of sobriety or price offered. CONCLUSIONS: Sex work operates across a variety of locations in the study area in Kampala, with each presenting different strategies and challenges for those operating there. Risky practices are present in all locations although they are higher on the streets compared to other locations. Location specific interventions are required to address the complex challenges in sex work environments. PMID- 23938038 TI - Genetic variations in the beta-tubulin gene and the internal transcribed spacer 2 region of Trichuris species from man and baboons. AB - BACKGROUND: The whipworm Trichuris trichiura has been estimated to infect 604 - 795 million people worldwide. The current control strategy against trichuriasis using the benzimidazoles (BZs) albendazole (400 mg) or mebendazole (500 mg) as single-dose treatment is not satisfactory. The occurrence of single nucleotide polymorphisms (SNPs) in codons 167, 198 or 200 of the beta-tubulin gene has been reported to convey BZ-resistance in intestinal nematodes of veterinary importance. It was hypothesised that the low susceptibility of T. trichiura to BZ could be due to a natural occurrence of such SNPs. The aim of this study was to investigate whether these SNPs were present in the beta-tubulin gene of Trichuris spp. from humans and baboons. As a secondary objective, the degree of identity between T. trichiura from humans and Trichuris spp. from baboons was evaluated based on the beta-tubulin gene and the internal transcribed spacer 2 region (ITS2). METHODS: Nucleotide sequences of the beta-tubulin gene were generated by PCR using degenerate primers, specific primers and DNA from worms and eggs of T. trichiura and worms of Trichuris spp. from baboons. The ITS2 region was amplified using adult Trichuris spp. from baboons. PCR products were sequenced and analysed. The beta-tubulin fragments were studied for SNPs in codons 167, 198 or 200 and the ITS2 amplicons were compared with GenBank records of T. trichiura. RESULTS: No SNPs in codons 167, 198 or 200 were identified in any of the analysed Trichuris spp. from humans and baboons. Based on the ITS2 region, the similarity between Trichuris spp. from baboons and GenBank records of T. trichiura was found to be 98 - 99%. CONCLUSIONS: Single nucleotide polymorphisms in codon 167, 198 and 200, known to confer BZ-resistance in other nematodes, were absent in the studied material. This study does not provide data that could explain previous reports of poor BZ treatment efficacy in terms of polymorphism in these codons of beta-tubulin. Based on a fragment of the beta-tubulin gene and the ITS2 region sequenced, it was found that T. trichiura from humans and Trichuris spp. isolated from baboons are closely related and may be the same species. PMID- 23938039 TI - Quantitative analysis of the time-course of viral DNA forms during the HIV-1 life cycle. AB - BACKGROUND: HIV-1 DNA is found both integrated in the host chromosome and unintegrated in various forms: linear (DNAL) or circular (1-LTRc, 2-LTRc or products of auto-integration). Here, based on pre-established strategies, we extended and characterized in terms of sensitivity two methodologies for quantifying 1-LTRc and DNAL, respectively, the latter being able to discriminate between unprocessed or 3'-processed DNA. RESULTS: Quantifying different types of viral DNA genome individually provides new information about the dynamics of all viral DNA forms and their interplay. For DNAL, we found that the 3'-processing reaction was efficient during the early stage of the replication cycle. Moreover, strand-transfer inhibitors (Dolutegravir, Elvitegravir, Raltegravir) affected 3' processing differently. The comparisons of 2-LTRc accumulation mediated by either strand-transfer inhibitors or catalytic mutation of integrase indicate that 3' processing efficiency did not influence the total 2-LTRc accumulation although the nature of the LTR-LTR junction was qualitatively affected. Finally, a significant proportion of 1-LTRc was generated concomitantly with reverse transcription, although most of the 1-LTRc were produced in the nucleus. CONCLUSIONS: We describe the fate of viral DNA forms during HIV-1 infection. Our study reveals the interplay between various forms of the viral DNA genome, the distribution of which can be affected by mutations and by inhibitors of HIV-1 viral proteins. In the latter case, the quantification of 3'-processed DNA in infected cells can be informative about the mechanisms of future integrase inhibitors directly in the cell context. PMID- 23938040 TI - An investigation of the effect of nurses' technology readiness on the acceptance of mobile electronic medical record systems. AB - BACKGROUND: Adopting mobile electronic medical record (MEMR) systems is expected to be one of the superior approaches for improving nurses' bedside and point of care services. However, nurses may use the functions for far fewer tasks than the MEMR supports. This may depend on their technological personality associated to MEMR acceptance. The purpose of this study is to investigate nurses' personality traits in regard to technology readiness toward MEMR acceptance. METHODS: The study used a self-administered questionnaire to collect 665 valid responses from a large hospital in Taiwan. Structural Equation modeling was utilized to analyze the collected data. RESULTS: Of the four personality traits of the technology readiness, the results posit that nurses are optimistic, innovative, secure but uncomfortable about technology. Furthermore, these four personality traits were all proven to have a significant impact on the perceived ease of use of MEMR while the perceived usefulness of MEMR was significantly influenced by the optimism trait only. The results also confirmed the relationships between the perceived components of ease of use, usefulness, and behavioral intention in the Technology Acceptance Model toward MEMR usage. CONCLUSIONS: Continuous educational programs can be provided for nurses to enhance their information technology literacy, minimizing their stress and discomfort about information technology. Further, hospital should recruit, either internally or externally, more optimistic nurses as champions of MEMR by leveraging the instrument proposed in this study. Besides, nurses' requirements must be fully understood during the development of MEMR to ensure that MEMR can meet the real needs of nurses. The friendliness of user interfaces of MEMR and the compatibility of nurses' work practices as these will also greatly enhance nurses' willingness to use MEMR. Finally, the effects of technology personality should not be ignored, indicating that hospitals should also include more employees' characteristics beyond socio demographic profiles in their personnel databases. PMID- 23938041 TI - The effects of exogenous putrescine on sex-specific responses of Populus cathayana to copper stress. AB - We used the dioecious tree, Populus cathayana, as a model species to study plants' physiological and biochemical responses to copper (Cu) stress, exogenous putrescine (Put) treatment and their interaction. Although males accumulated higher Cu concentrations in leaves than did females under Cu stress, they did not suffer more damage than females, as reflected by changes in gas exchange, pigment contents, membrane lipid peroxidation (thiobarbituric acid reactive substances, TBARS) and protein oxidation (carbonyl). Higher Cu tolerance of males was correlated with a higher H2O2 scavenging ability and proline responses, and a better maintenance of non-protein thiols (NP-SHs) and spermine (Spm) contents. We also discovered that mitigation effects of exogenous Put on Cu stress occurred, as visible as a recovery of the total chlorophyll content, and lower TBARS and carbonyl under interaction treatment when compared to Cu stress alone. Exogenous Put decreased the Cu concentration in leaves of both sexes, but to different degrees. Such effects of exogenous Put suggested that Put may play important roles in the stabilization of membrane integrity and protein structures, and it may modulate the uptake and transportation of Cu. Our results indicated that (1) males are more tolerant to Cu stress than females; (2) Put could mitigate Cu toxicity in P. cathayana, but to a different degree in males and females; (3) males are better candidates than females for Cu extraction and phytoremediation. PMID- 23938042 TI - Effect of cadmium on the physiological parameters and the subcellular cadmium localization in the potato (Solanum tuberosum L.). AB - The pollution of agricultural soils with cadmium (Cd) has become a serious problem worldwide. The potato (Solanum tuberosum L.) was used to investigate how different concentrations of Cd (1, 5, and 25mgkg(-1)) affected the physiological parameters and the subcellular distribution of Cd in the potato. The analyses were conducted using scanning electron microscopy coupled with energy dispersive X-ray (SEM-EDX). The results suggest that the leaf is the organ with the highest accumulation of Cd. The malondialdehyde (MDA) content increased and the chlorophyll content decreased in response to high level of Cd. The SEM-EDX microanalysis revealed that Cd was primarily deposited in the spongy and palisade tissues of the leaf. Furthermore, Cd was also detected in the cortex and the adjacent phloem and was observed inside the intercellular space, the interior surface of the plasma membrane, and on the surface of the elliptical starch granules in the tubers of the potato. Although low concentrations of Cd migrated from the root to the tuber, the accumulation of Cd in the tuber exceeded the standard for food security. Therefore, the planting of potato plants in farmland containing Cd should be seriously evaluated because Cd-containing potatoes might present high health risk to humans. PMID- 23938043 TI - Rectal lymph node metastasis in recurrent ovarian carcinoma: essential role of 18F-FDG PET/CT in treatment planning. AB - Although uncommon, ovarian cancer cells may spread to the rectal lymph nodes. However, few reports have described how to detect and treat such metastases. We report a case of a 59-year-old woman with mesorectal and pararectal lymph node metastases in recurrent ovarian carcinoma, detected conclusively using 18F fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), and treated by low anterior resection with total mesorectal excision aiming for macroscopic complete resection. The treatment goals for the patient were gradually changed from curative to palliative chemotherapy; she survived for 45 months without rectal obstruction after secondary debulking surgery, and was followed up until autopsy. Thus, 18F-FDG PET/CT may be valuable for detecting rectal lymph node metastasis and can play an essential role in planning treatment for recurrent ovarian carcinoma. PMID- 23938044 TI - Liver involvement in adults with measles. AB - We retrospectively collected the characteristics of 80 consecutive adult patients with biologically confirmed measles during a recent epidemic in France. We report on the frequency and severity of liver involvement in adult patients with measles. In our experience, measles in adults was not severe and hepatitis was not correlated with severe cases or bacterial infection. Therefore, hepatitis should be regarded as a usual symptom rather than a complication of measles infection in adults. PMID- 23938045 TI - Oncogenic human papillomavirus-associated nasopharyngeal carcinoma: an observational study of correlation with ethnicity, histological subtype and outcome in a UK population. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) accounts for 0.6% of all cancers worldwide with the highest prevalence in South East Asia, Southern China and Northern Africa but the disease is uncommon in Europe with an annual incidence in this region of less than 1 per 100 000. Although the Epstein-Barr virus (EBV) is a well known causative agent in NPC, recent reports have implicated oncogenic Human Papillomavirus (HPV) in a subgroup of these tumours. The recent striking rise of oropharyngeal carcinoma has been attributed to HPV, but little is known about the prevalence and clinical significance of the virus in NPC. The aim of this study was to determine the prevalence of oncogenic HPV in NPC from tissue archives of two head and neck cancer centres in the UK. METHODS: Samples were available for 67 patients with clinically validated NPC. The detection of high risk HPV was carried out by screening all cases for p16 using immunohistochemistry and HPV DNA by polymerase chain reaction (PCR) using GP5+/6+ primers. All cases with p16 over-expression or positive for HPV by PCR were then examined by high-risk HPV DNA in-situ hybridisation and genotype analysis by PCR. RESULTS: Eleven cases (11/67, 16.4%) showed concurrent over-expression of p16 and evidence of high-risk HPV DNA by in-situ hybridisation; the majority were HPV16 positive. Of these 11 cases, nine occurred in Whites and two in Blacks. Histologically, there were two keratinising squamous cell carcinoma and nine non keratinising carcinomas (eight differentiated and one undifferentiated). None of the HPV-positive cases showed any co-infection with EBV. There was no statistically significant difference in overall survival outcome between patients with HPV-positive and HPV-negative NPC. CONCLUSION: The results of this study show that oncogenic HPV is associated with a subgroup of NPCs and is more likely to occur in Whites. However, unlike oropharyngeal carcinoma there was no significant difference in overall survival between patients with HPV-positive and HPV-negative NPC. PMID- 23938047 TI - [Functional dyspepsia and the satiety test: its usefulness in clinical practice]. AB - INTRODUCTION: According to the Rome III Criteria, functional dyspepsia (FD) is classified as postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). On the other hand, the satiety test (ST) has been used to evaluate gastric accommodation and emptying, distinguishing healthy individuals from those with dyspepsia. AIMS: To determine whether the ST can distinguish dyspeptic individuals from healthy ones and to evaluate its usefulness in differentiating the two FD subtypes. METHODS: Adults with FD were consecutively enrolled in a cross-sectional study within the time frame of August 2011 and October 2012. Healthy subjects participated as controls. The ST consisted of the intake of a nutritional supplement (Fortisip(r), Nutricia Bago(r)) at a constant speed; satiety was graded at 5-minute intervals (1 to 5 points). Intake was suspended when the maximum score was reported. The total ingested volume and caloric intake was recorded and the Mann-Whitney U test was used in the statistical analysis. RESULTS: The study included 39 dyspeptic patients and 20 control individuals. The patients were predominantly women (84.6 vs. 25%; p < 0.0001) and they were similar in age (39.59 +/- 13.53 vs. 34.70 +/- 9.85 years) and BMI (24.32 +/- 3.52 vs. 25.82 +/- 3.34 kg/m2) with respect to the controls. The FD subtype percentages were PDS: 61%, EPS: 31%, and Mixed syndrome: 8%. There was a lower ingested volume and caloric intake on the part of the dyspeptic patients (185 vs. 300 ml and 277 vs. 520 Kcal, respectively. Both: P<.001). No differences in the ST were observed between the two pure dyspepsia subtypes. CONCLUSIONS: There was a difference in the ST between healthy individuals and those with dyspepsia, but the ingested volume and caloric intake in the two FD subtypes were similar. PMID- 23938046 TI - The effectiveness of aerobic training, cognitive behavioural therapy, and energy conservation management in treating MS-related fatigue: the design of the TREFAMS ACE programme. AB - BACKGROUND: TREFAMS is an acronym for TReating FAtigue in Multiple Sclerosis, while ACE refers to the rehabilitation treatment methods under study, that is, Aerobic training, Cognitive behavioural therapy, and Energy conservation management. The TREFAMS-ACE research programme consists of four studies and has two main objectives: (1) to assess the effectiveness of three different rehabilitation treatment strategies in reducing fatigue and improving societal participation in patients with MS; and (2) to study the neurobiological mechanisms of action that underlie treatment effects and MS-related fatigue in general. METHODS/DESIGN: Ambulatory patients (n = 270) suffering from MS-related fatigue will be recruited to three single-blinded randomised clinical trials (RCTs). In each RCT, 90 patients will be randomly allocated to the trial-specific intervention or to a low-intensity intervention that is the same for all RCTs. This low-intensity intervention consists of three individual consultations with a specialised MS-nurse. The trial-specific interventions are Aerobic Training, Cognitive Behavioural Therapy, and Energy Conservation Management. These interventions consist of 12 individual therapist-supervised sessions with additional intervention-specific home exercises. The therapy period lasts 16 weeks. All RCTs have the same design and the same primary outcome measures: fatigue - measured with the Checklist Individual Strength, and participation - measured with the Impact on Participation and Autonomy questionnaire. Outcomes will be assessed 1 week prior to, and at 0, 8, 16, 26 and 52 weeks after randomisation. The assessors will be blinded to allocation. Pro- and anti inflammatory cytokines in serum, salivary cortisol, physical fitness, physical activity, coping, self-efficacy, illness cognitions and other determinants will be longitudinally measured in order to study the neurobiological mechanisms of action. DISCUSSION: The TREFAMS-ACE programme is unique in its aim to assess the effectiveness of three rehabilitation treatments. The programme will provide important insights regarding the most effective treatment for MS-related fatigue and the mechanisms that underlie treatment response. A major strength of the programme is that the design involves three almost identical RCTs, enabling a close comparison of the treatment strategies and a strong overall meta-analysis. The results will also support clinical practice guidelines for the treatment of MS-related fatigue. TRIAL REGISTRATIONS: Current Controlled Trials ISRCTN69520623, ISRCTN58583714, and ISRCTN82353628. PMID- 23938048 TI - Harmonizing WHO's International Classification of Diseases (ICD) and International Classification of Functioning, Disability and Health (ICF): importance and methods to link disease and functioning. AB - BACKGROUND: To understand the full burden of a health condition, we need the information on the disease and the information on how that disease impacts the functioning of an individual. The ongoing revision of the International Classification of Diseases (ICD) provides an opportunity to integrate functioning information through the International Classification of Functioning, Disability and Health (ICF). DISCUSSION: Part of the ICD revision process includes adding information from the ICF by way of "functioning properties" to capture the impact of the disease on functioning. The ICD content model was developed to provide the structure of information required for each ICD-11 disease entity and one component of this content model is functioning properties. The activities and participation domains from ICF are to be included as the value set for functioning properties in the ICD revision process. SUMMARY: The joint use of ICD and ICF could create an integrated health information system that would benefit the implementation of a standard language-based electronic health record to better capture and understand disease and functioning in healthcare. PMID- 23938049 TI - Dietary polyphenols as potential nutraceuticals in management of diabetes: a review. AB - In recent years, there is growing evidence that plant-foods polyphenols, due to their biological properties, may be unique nutraceuticals and supplementary treatments for various aspects of type 2 diabetes mellitus. In this article we have reviewed the potential efficacies of polyphenols, including phenolic acids, flavonoids, stilbenes, lignans and polymeric lignans, on metabolic disorders and complications induced by diabetes. Based on several in vitro, animal models and some human studies, dietary plant polyphenols and polyphenol-rich products modulate carbohydrate and lipid metabolism, attenuate hyperglycemia, dyslipidemia and insulin resistance, improve adipose tissue metabolism, and alleviate oxidative stress and stress-sensitive signaling pathways and inflammatory processes. Polyphenolic compounds can also prevent the development of long-term diabetes complications including cardiovascular disease, neuropathy, nephropathy and retinopathy. Further investigations as human clinical studies are needed to obtain the optimum dose and duration of supplementation with polyphenolic compounds in diabetic patients. PMID- 23938050 TI - What do hands know about hills? Interpreting Taylor-Covill and Eves (2013) in context. AB - Hills appear much steeper than they are. Although near surface slant is also exaggerated, near surfaces appear much shallower than equivalently slanted hills. Taylor-Covill and Eves (2013) propose a new type of palm orientation measuring device that provides outputs that accurately reflect the physical slants of stairs and hills from 19 to 30 degrees and also seems to accurately reflect the slants of near surfaces (25-30 degrees ). They question the validity of the observations of Durgin, Hajnal, Li, Tonge & Stigliani (2010), who observed that palm boards grossly underestimated near surfaces. Here I review our recent work on the visual and haptic perception of near surface orientation in order to place Taylor-Covill and Eves' arguments in context. I note in particular that free hand measures of real surfaces in near space show excellent calibration, but free hand measures show gross exaggeration for hills. This leads to the question of the grounds for preferring a mechanical device to a freely wielded hand. In addition I report an investigative replication of the crucial observations that led to our concerns about the value of palm boards as measures of perception and note the specific methodological details that we have accounted for in our procedures. Finally, I propose some testable hypotheses regarding how better-than-expected haptic matches to hills may arise. PMID- 23938051 TI - [Alterations in the protein content and dysfunction of high-density lipoproteins from hyperhomocysteinemic mice]. AB - AIM: The aim of this study was to evaluate the proteic changes in high-density lipoproteins (HDL) induced by methionine-induced hyperhomocysteinemia in mice and its relationship with two of their main antiatherogenic properties. METHODS AND RESULTS: The oral administration of methionine resulted in an elevation (~8 times) in the plasma concentration of homocysteine. Hyperhomocysteinemia was inversely correlated with the plasma concentration of HDL cholesterol and its main protein component of HDL, apolipoprotein (apo) A-I, respectively. The cholesterol efflux in vivo from macrophages to HDL was decreased in hyperhomocysteinemic mice compared with the control mice. However, the reverse cholesterol transport from macrophages to feces remained unchanged. On the other hand, the ability of HDL from hyperhomocysteinemic mice to prevent the oxidative modification of low-density lipoproteins (LDL) was found decreased and associated with a concomitant reduction in the plasma activity of paraoxonase-1 (PON1) and the plasma concentration of apoA-I, and with a relative reduction in the apoA-IV content (~1.5 times) in the hyperhomocysteinemic HDL, respectively. CONCLUSION: The decrease in the ability of HDL from hyperhomocysteinemic mice to prevent LDL from oxidation was associated with a decrease in the apoA-I, PON1 and apoA-IV. PMID- 23938052 TI - Synthesis, enzyme kinetics and computational evaluation of N-(beta-D glucopyranosyl) oxadiazolecarboxamides as glycogen phosphorylase inhibitors. AB - All possible isomers of N-beta-D-glucopyranosyl aryl-substituted oxadiazolecarboxamides were synthesised. O-Peracetylated N-cyanocarbonyl-beta-D glucopyranosylamine was transformed into the corresponding N-glucosyl tetrazole-5 carboxamide, which upon acylation gave N-glucosyl 5-aryl-1,3,4-oxadiazole-2 carboxamides. The nitrile group of the N-cyanocarbonyl derivative was converted to amidoxime which was ring closed by acylation to N-glucosyl 5-aryl-1,2,4 oxadiazole-3-carboxamides. A one-pot reaction of protected beta-D glucopyranosylamine with oxalyl chloride and then with arenecarboxamidoximes furnished N-glucosyl 3-aryl-1,2,4-oxadiazole-5-carboxamides. Removal of the O acetyl protecting groups by the Zemplen method produced test compounds which were evaluated as inhibitors of glycogen phosphorylase. Best inhibitors of these series were N-(beta-D-glucopyranosyl) 5-(naphth-1-yl)-1,2,4-oxadiazol-3 carboxamide (Ki = 30 MUM), N-(beta-D-glucopyranosyl) 5-(naphth-2-yl)-1,3,4 oxadiazol-2-carboxamide (Ki =33 MUM), and N-(beta-D-glucopyranosyl) 3-phenyl 1,2,4-oxadiazol-5-carboxamide (Ki = 104 MUM). ADMET property predictions revealed these compounds to have promising oral drug-like properties without any toxicity. PMID- 23938053 TI - Synthesis and biological evaluation of novel benzyl-substituted (S)-phenylalanine derivatives as potent dipeptidyl peptidase 4 inhibitors. AB - A series of novel benzyl-substituted (S)-phenylalanine derivatives were synthesized and evaluated for their dipeptidyl peptidase 4 (DPP-4) inhibitory activity and selectivity. It was found that most synthesized target compounds were potent DPP-4 inhibitors with IC50 values in 3.79-25.52 nM, which were significantly superior to that of the marketed drug sitagliptin. Furthermore, the 4-fluorobenzyl substituted phenylalanine derivative 6g not only displayed the potent DPP-4 inhibition with an IC50 value of 3.79 nM, but also showed better selectivity against DPP-4 over other related enzymes including DPP-7, DPP-8, and DPP-9. In an oral glucose tolerance test (OGTT) in normal Sprague Dawley rats, compound 6g reduced blood glucose excursion in a dose-dependent manner. PMID- 23938055 TI - Subject-specific modeling of the scapula bone tissue adaptation. AB - Adaptation of the scapula bone tissue to mechanical loading is simulated in the current study using a subject-specific three-dimensional finite element model of an intact cadaveric scapula. The loads experienced by the scapula during different types of movements are determined using a subject-specific large-scale musculoskeletal model of the shoulder joint. The obtained density distributions are compared with the CT-measured density distribution of the same scapula. Furthermore, it is assumed that the CT-measured density distribution can be estimated as a weighted linear combination of the density distributions calculated for different loads experienced during daily life. An optimization algorithm is used to determine the weighting factors of fourteen different loads such that the difference between the weighted linear combination of the calculated density distributions and the CT-measured density is minimal. It is shown that the weighted linear combination of the calculated densities matches the CT-measured density distribution better than every one of the density distributions calculated for individual movements. The weighting factors of nine out of fourteen loads were estimated to be zero or very close to zero. The five loads that had larger weighting factors were associated with either one of the following categories: (1) small-load small-angle abduction or flexion movements that occur frequently during our daily lives or (2) large-load large-angle abduction or flexion movements that occur infrequently during our daily lives. PMID- 23938056 TI - Phenomenological models of the dynamics of muscle during isotonic shortening. AB - We investigated the effectiveness of simple, Hill-type, phenomenological models of the force-length-velocity relationship for simulating measured length trajectories during muscle shortening, and, if so, what forms of the model are most useful. Using isotonic shortening data from mouse soleus and toad depressor mandibulae muscles, we showed that Hill-type models can indeed simulate the shortening trajectories with sufficiently good accuracy. However, we found that the standard form of the Hill-type muscle model, called the force-scaling model, is not a satisfactory choice. Instead, the results support the use of less frequently used models, the f-max scaling model and force-scaling with parallel spring, to simulate the shortening dynamics of muscle. PMID- 23938054 TI - Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice. AB - BACKGROUND: In autosomal recessive early-onset Parkinsonism (PARK2), the pathogenetic process from the loss of function of a ubiquitin ligase parkin to the death of dopamine neurons remains unclear. A dominant hypothesis attributes the neurotoxicity to accumulated substrates that are exempt from parkin-mediated degradation. Parkin substrates include two septins; SEPT4/CDCrel-2 which coaggregates with alpha-synuclein as Lewy bodies in Parkinson's disease, and its closest homolog SEPT5/CDCrel-1/PNUTL1 whose overload with viral vector can rapidly eliminate dopamine neurons in rats. However, chronic effects of pan neural overload of septins have never been examined in mammals. To address this, we established a line of transgenic mice that express the largest gene product SEPT4(54kDa) via the prion promoter in the entire brain. RESULTS: Histological examination and biochemical quantification of SEPT4-associated proteins including alpha-synuclein and the dopamine transporter in the nigrostriatal dopamine neurons found no significant difference between Sept4(Tg/+) and wild-type littermates. Thus, the hypothetical pathogenicity by the chronic overload of SEPT4 alone, if any, is insufficient to trigger neurodegenerative process in the mouse brain. Intriguingly, however, a systematic battery of behavioral tests revealed unexpected abnormalities in Sept4(Tg/+) mice that include consistent attenuation of voluntary activities in distinct behavioral paradigms and altered social behaviors. CONCLUSIONS: Together, these data indicate that septin dysregulations commonly found in postmortem human brains with Parkinson's disease, schizophrenia and bipolar disorders may be responsible for a subset of behavioral abnormalities in the patients. PMID- 23938057 TI - Collagen abundance in mechanically stimulated osteoblast cultures using near infrared microscopy. AB - Collagen abundance in osteoblast cell cultures was determined using near infrared microscopy with chemical imaging (NIR-CI) with and without mechanical stimulation of the the cells. MC3T3-E1 mouse osteoblast cells seeded on a polycarbonate substrate were mechanically stimulated using static loads of 13.5 N, 27 N and 40 N applied to the substrates during 2, 4, 6 and 8 days of incubation. Results show that the cells increased their collagen production with 13.5 N and 27 N loads when compared to the control sample with a 27 N load resulting in a noteworthy increase (109%) in collagen production. The 40 N load on the other hand, resulted in an initial decrease in the collagen expression in the extracellular matrix, possibly as a result of cell death or inhibition of the protein secretion process followed by an increase in collagen after cell recovery and proliferation. Qualitative confirmation of these results was performed using confocal microscopy. PMID- 23938058 TI - Pure cultures and characterization of yak Sertoli cells. AB - The culture of primary Sertoli cells has become an important resource in the study of their function. However, their use is limited because of contamination of isolated cells with other testicular cells, mainly germ cells. The aim was to establish technique to obtain pure yak Sertoli cells as well as to study the growth kinetics and biological characteristics of Sertoli cells in vitro. Two step enzyme digestion was used to separate and culture yak Sertoli cells. Cultured using starvation method and the hypotonic treatment were also invented to get pure yak Sertoli cells. Furthermore, the purification of Yak Sertoli cells were identified according to their characteristics, such as bipolar corpuscular around the nucleus and expression of Fasl, in addition to their morphology. The average viability of the Sertoli cells was 97% before freezing and 94.5% after thawing, indicating that cryopreservation in liquid nitrogen had little influence on the viability of Sertoli cells. The growth tendency of yak Sertoli cells was similar to an S-shaped growth curve. Purified yak Sertoli cells frequently exhibited bipolar corpuscula in nucleus after Feulgen staining, and did have a positive reaction of Fasl by the immunocytochemical identification. After recovery chromosomal analysis of Sertoli cells had a normal chromosomal number of 60, comprising 29 pairs of autosomes and one pair of sex chromosomes. Assays for bacteria, fungi and mycoplasmas were negative. In conclusion, yak Sertoli cells have been successfully purified and cultured in vitro, and maintain stable biological characteristics after thawing. Therefore, it will not only preserve the genetic resources of yaks at the cellular level, but also provide valuable materials for transgenic research and feeder layer and nuclear donor cells in yak somatic cell cloning technology. PMID- 23938059 TI - Influence of patient characteristics on perceived risks and willingness to take a proposed anti-rheumatic drug. AB - BACKGROUND: The causes of the underutilization of disease modifying anti rheumatic drugs (DMARDS) for rheumatoid arthritis (RA) are not fully known, but may in part, relate to individual patient factors including risk perception. Our objective was to identify the determinants of risk perception (RP) in RA patients and predictors of their willingness to take a proposed DMARD (DMARD willingness). METHODS: A cross-sectional mail survey of RA patients in a community rheumatology practice. Patients were presented a hypothetical decision scenario where they were asked to consider switching DMARDs. They evaluated how risky the proposed medication was and how likely they would be to take it. RESULTS: The completed sample included 1009 RA patients. The overall survey response rate was 71%. PATIENT CHARACTERISTICS: age 61.6 years (range 18-93), 75% female, minority 6.5%, low or marginal health literacy 8.8%, depression 15.0%, duration RA 13.1 years (range 0.5 - 68). Regression models demonstrated that health literacy, independent of low educational achievement or other demographic (including race), was a common predictor of both RP and DMARD willingness. There was partial mediation of the effects of HL on DMARD willingness through RP. Depression and happiness had no significant effect on RP or DMARD willingness. RP was influenced by negative RA disease and treatment experience, while DMARD willingness was affected mainly by perceived disease control. CONCLUSIONS: Risk aversion may be the result of potentially recognizable and correctable cognitive defect. Heightened clinician awareness, formal screening for low health literacy or cognitive impairment in high-risk populations, may identify patients could benefit from additional decision support. PMID- 23938060 TI - Seropositivity for CMV and IL-6 levels are associated with grip strength and muscle size in the elderly. AB - BACKGROUND: Sarcopenia is an important cause of morbidity and mortality in older adults, with immunosenescence and inflammation being possible underlying mechanisms. We investigated the relationship between latent cytomegalovirus (CMV) infection, Interleukin 6 (IL-6) levels, muscle size and strength in a group of healthy older community-dwelling people. METHODS: Participants were healthy volunteers from the Lothian Birth Cohort 1936 study. Participants had IL-6 level and CMV antibody titre measured at age 70 years and grip strength and a volumetric T1-weighted MRI brain scan (allowing measurement of neck muscle cross sectional area (CSA)) at age 73. Markers of childhood deprivation were adjusted for in the analysis due to correlations between childhood deprivation and latent CMV infection. RESULTS: 866 participants were studied; 448 men (mean age 72.48 years, sd 0.70) and 418 women (mean age 72.51 years, sd 0.72). In men, CMV seropositivity was associated with smaller neck muscle CSA (p = 0.03, partial eta squared = 0.01), even after adjustment for IL-6 levels. Neck muscle CSA was not associated with CMV seropositivity in women, or CMV antibody titre or IL-6 level in either sex. Grip strength associated negatively with IL-6 level (right grip strength p<0.00001, partial eta squared 0.032 and left grip strength p<0.00001, partial eta squared 0.027) with or without adjustment for CMV serostatus or antibody titre. CMV status and antibody titre were not significantly associated with grip strength in either hand. CONCLUSION: These findings support the hypothesis that there is a relationship between markers of immunosenescence (i.e. CMV serostatus and IL6 level) and low muscle mass and strength and longitudinal studies in older cohorts are now required to investigate these relationships further. PMID- 23938061 TI - Ropinirole in patients with restless legs syndrome and baseline IRLS total scores >= 24: efficacy and tolerability in a 26-week, double-blind, parallel-group, placebo-controlled study followed by a 40-week open-label extension. AB - BACKGROUND: As with studies of other dopamine agonists, previously reported studies of ropinirole in restless legs syndrome (RLS) recruited patients with baseline International Restless Legs Scale (IRLS) total scores >= 15. The reported pooled analyses of clinical trials data suggest benefits of ropinirole in patients with IRLS total scores >= 24, but the effects of ropinirole have not been prospectively evaluated in this patient population. OBJECTIVE: The goal of this study was to evaluate the efficacy and tolerability of ropinirole in patients with RLS and baseline IRLS total scores >= 24. This study was conducted in part to fulfill a postlicensing commitment between the maker of ropinirole and the European Union's Committee for Medicinal Products for Human Use. METHODS: The protocol for this study comprised a randomized, double-blind, placebo-controlled, parallel-group, 26-week phase during which adults with baseline IRLS total scores >= 24 received a ropinirole dose from 0.25 to 4 mg (n = 197) or placebo (n = 207) followed by a 40-week, open-label phase during which all patients (n = 269) received ropinirole. The primary efficacy end point was the change from baseline in the IRLS total score at week 12. Tolerability measures included the incidence of adverse events, augmentation, and early morning rebound. Due to the possibility of a treatment-by-center group interaction (P = 0.04) in the IRLS analysis, further efficacy exploratory analyses were performed to assess the impact of the interaction on the overall assessment of efficacy. RESULTS: Demographic characteristics were comparable between groups (mean [SD] age: placebo, 56.1 [11.38] years; ropinirole, 56.5 [11.92] years; 63% female in both groups). All of the patients in the ropinirole group were white; 99% of the placebo group was white. Ropinirole was significantly better than placebo for change from baseline in the IRLS total score during both short- and long-term treatment, with mean treatment differences of -2.1 (P = 0.039) and -2.5 (P = 0.023) for weeks 12 and 26, respectively. A statistically significant treatment by center group interaction was observed (P = 0.040) for the change from baseline in IRLS total score, indicating variation of treatment effects among center groups; however, all center groups showed an improvement from baseline at both week 12 and week 26 for the ropinirole immediate-release group and the placebo group. The incidences of augmentation and early morning rebound were <= 4% for ropinirole. The adverse event profile of ropinirole was consistent with that reported in previous clinical trials. CONCLUSIONS: In this subset of patients with RLS and a baseline IRLS total score >= 24, ropinirole was effective and well tolerated compared with placebo. The incidence of augmentation and early morning rebound in this study was low. PMID- 23938062 TI - Monitoring of transient cavitation induced by ultrasound and intense pulsed light in presence of gold nanoparticles. AB - One of the most important challenges in medical treatment is invention of a minimally invasive approach in order to induce lethal damages to cancer cells. Application of high intensity focused ultrasound can be beneficial to achieve this goal via the cavitation process. Existence of the particles and vapor in a liquid decreases the ultrasonic intensity threshold required for cavitation onset. In this study, synergism of intense pulsed light (IPL) and gold nanoparticles (GNPs) has been investigated as a means of providing nucleation sites for acoustic cavitation. Several approaches have been reported with the aim of cavitation monitoring. We conducted the experiments on the basis of sonochemiluminescence (SCL) and chemical dosimetric methods. The acoustic cavitation activity was investigated by determining the integrated SCL signal acquired over polyacrylamide gel phantoms containing luminol in the presence and absence of GNPs in the wavelength range of 400-500 nm using a spectrometer equipped with cooled charged coupled devices (CCD) during irradiation by different intensities of 1 MHz ultrasound and IPL pulses. In order to confirm these results, the terephthalic acid chemical dosimeter was utilized as well. The SCL signal recorded in the gel phantoms containing GNPs at different intensities of ultrasound in the presence of intense pulsed light was higher than the gel phantoms without GNPs. These results have been confirmed by the obtained data from the chemical dosimetry method. Acoustic cavitation in the presence of GNPs and intense pulsed light has been suggested as a new approach designed for decreasing threshold intensity of acoustic cavitation and improving targeted therapeutic effects. PMID- 23938063 TI - The pathologic response of resected synovial sarcomas to hyperthermic isolated limb perfusion with melphalan and TNF-alpha: a comparison with the whole group of resected soft tissue sarcomas. AB - BACKGROUND: Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan (TM-HILP) has been successfully used to treat limb soft tissue sarcomas (STSs) with high response rates. The data on the effectiveness of HILP TM for the treatment of STSs are mainly based on various STS types. The aim of this study was to investigate the responses of synovial sarcomas (SS) to TM-HILP. METHODS: A total of 125 TM-HILP-treated tumors (STS all), including 14 SSs, were included in the study. The tumors were subdivided into proximal and distal limb localizations. Tumor typing (using the WHO classification), resection status (using the UICC classification), and response to therapy were assessed using light microscopy. The SSs were tested for the SYT-SSX translocation using RT-PCR. The following tests were applied: a chi-squared test, a t test, and the Mann Whitney U test. RESULTS: The SSs were localized distally more often than were the STS cohort (STS(-SS)) (85.7% vs. 32.4%) and were smaller (5.8 cm vs. 10.7 cm). There were no differences in the responder/nonresponder ratios or the mean percentages of pathological regression between the SS and STS(-SS) cohorts (74.0% vs. 76.0%). A general localization-dependent difference in the tumor responses to TM-HILP could not be detected in the STS all cohort (distal, 72.0% vs. proximal, 78.0%); however, a UICC R0 status was more often observed in proximal tumors (distal, 50.0% vs. proximal, 71.4%). There was no association between the SYT-SSX type and SS responses to TM-HILP. CONCLUSIONS: Because of the high response rates, TM-HILP is recommended for the treatment of SSs. The distal limb localization of TM-HILP-treated STSs was generally (STS all cohort) associated with fewer R0 resections. PMID- 23938064 TI - Persistent organic pollutants in meat, liver, tallow and bone marrow from semi domesticated reindeer (Rangifer tarandus tarandus L.) in Northern Norway. AB - BACKGROUND: The aim of this project was to study 14 polychlorinated biphenyls (PCBs), 5 dichlorodiphenyl trichloroethans (DDTs), 12 organochlorine pesticides (OCPs) and 6 polybrominated diphenylethers (PBDEs) in meat, liver, tallow and bone marrow from semi-domesticated reindeer. METHODS: Meat, liver, tallow, and bone marrow samples (n= 30) were collected from semi-domesticated reindeer in Northern Norway. Determination of the persistent organic pollutants (POPs) concentrations was done by using gas chromatography-mass spectrometry (GC-MS). Dependent sample t-test and Pearson's correlation test were used in statistical analysis. RESULTS: Concentrations of the persistent organic pollutants in the samples from semi-domesticated reindeer were generally low and slightly above the limit of detection (LOD). For PCBs and OCPs, >= 50% of the samples had concentrations above LOD. For the DDTs and PBDEs, the proportion of samples with concentrations above LOD varied between 3.7 and 45.5% depending on the sample type. Concentrations of PCB 99, 105, 138/163, 153 and 187 differed significantly between meat and liver, whereas concentrations of PCB 183 were significantly different between tallow and bone marrow. Furthermore, concentrations of hexachlorobenzene (HCB) were significantly different between meat and liver. Significant correlations were revealed in concentrations of 5 PCB congeners between the studied tissue types. CONCLUSION: Concentrations of the POPs revealed in this study were generally low. PMID- 23938065 TI - Concurrent malignant melanoma and cutaneous involvement by classical Hodgkin lymphoma (CHL) in a 63 year-old man. AB - Classical Hodgkin lymphoma (CHL) is a lymphoproliferative disorder that has a bimodal age distribution, affecting young and elderly individuals, and is curable in more than 90% of patients. Here we report the coexistence of cutaneous CHL and malignant melanoma as the presentation of papules and a plaque, in an individual with remote history of systemic CHL. One of the biopsies showed a mononuclear cell infiltrate with Reed-Sternberg (RS) like cells that were positive for CD30 and CD15, but negative for CD45. A second concurrent biopsy showed an atypical melanocytic proliferation with significant pagetoid spreading and diffuse Melan-A staining. Based on morphology alone, it is almost impossible to distinguish CHL from other primary cutaneous lymphoproliferative disorders, such as CD30+ lymphoproliferative disorder (lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma), or even tumor stage mycosis fungoides when the epidermotropism is minimal. Additionally, bizarre melanocytic cells can also appear similar to RS cells. Our case illustrates the first case report of malignant melanoma and CHL in a patient presenting simultaneously. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8979757349937225. PMID- 23938066 TI - Early assessment for Alzheimer's disease and dementia: comparison of two metamemory diagnostic tests. AB - Alzheimer's disease (AD) is a growing problem in the United States. Because of the inability of the Mini-Mental State Examination to detect AD in the early stages, other avenues of assessment must be explored. Two subjective assessment tests have been proposed to help evaluate progression from nonclinical to clinical AD: the Feeling-of-Knowing and Judgment-of-Learning tests. Currently, no conclusive evidence exists as to which test is better suited to assess for progression toward AD. These tests, however, have been reliable when used to assess metamemory. A decrease in metamemory can be an indicator of nonclinical AD. This article provides practice implications for mental health nurses in administering either test and calculating scores over time. The hope is that by using these two assessment tests, patients with AD may be diagnosed earlier and subsequently lead longer, better quality lives. PMID- 23938067 TI - Self-management of unpleasant auditory hallucinations: a tested practice model. AB - Individuals who experience auditory hallucinations (AH) frequently report hearing unpleasant voices saying disturbing things to them, making derogatory remarks about them, or commanding them to do something, including harming themselves or someone else. The Self-Management of Unpleasant Auditory Hallucinations Practice Model was developed to help psychiatric-mental health nurses in both inpatient and outpatient settings implement evidence-based nursing care for voice hearers who are distressed by unpleasant voices. The model's utility extends to nursing education, administration, and research. The model is comprised of three parts: (a) Assessment of Voice Hearer's Experience, (b) Nursing Interventions, and (c) Voice Hearer's Expected Positive Outcomes. These three parts of the model describe nursing assessments conducted with an interview guide and two self report tools, nursing interventions that teach strategies to manage unpleasant AH in a 10-session course or individually, and evaluation of voice hearer outcomes with two self-report tools. PMID- 23938068 TI - College students with body art: well-being or high-risk behavior? AB - Body art is mainstream, with wearers readily admitting to being risk takers. Yet, are high-risk behaviors (e.g., cigarette, alcohol, and illegal drug use, sexual activity) and emotional distress (e.g., depression, suicide, eating disorders, abuse/forced sexual activity) present in all individuals with body art? Of the 595 college students who were queried, 127 (21%) had tattoos and 195 (33%) had lifetime piercings, with 17 (3%) having intimate (nipple, genital, or both) piercings; they also reported their self-views regarding religion, self-esteem, and Need for Uniqueness. Three consistent self-identity outcomes for their body art were: it helped me (a) express myself, (b) feel unique, and (c) be myself. When quantifying their body art amounts, well-being similar to that of individuals with no body art was present in those with one tattoo and less than four piercings. Individuals with four or more tattoos, seven or more piercings, and/or intimate piercings described higher risk behaviors and emotional distress. Education, monitoring, and non-profiling should continue as body art is only "skin deep." PMID- 23938069 TI - A "glucose eater" drug as a therapeutic agent in psychiatry. AB - Metformin, currently approved for the treatment of type 2 diabetes, is an interesting drug that has various cellular and molecular mechanisms. These mechanisms have justified other off-label clinical and investigational uses for diabetes prevention in high-risk patients, for polycystic ovary syndrome, non diabetic obesity, non-alcoholic fatty liver disease, and for prevention or treatment of cancer. A large number of controlled and uncontrolled studies have generally found metformin to be effective, well tolerated, and safe for preventing or treating antipsychotic-related weight gain and for improving metabolic abnormalities in psychiatric patient populations. Metformin has the potential effect of inducing hippocampal neurogenesis, and additional studies of this drug are warranted in patients with mood or cognitive disorders. PMID- 23938070 TI - Progestin effects on cell proliferation pathways in the postmenopausal mammary gland. AB - INTRODUCTION: Menopausal hormone therapies vary widely in their effects on breast cancer risk, and the mechanisms underlying these differences are unclear. The primary goals of this study were to characterize the mammary gland transcriptional profile of estrogen + progestin therapy in comparison with estrogen-alone or tibolone and investigate pathways of cell proliferation in a postmenopausal primate model. METHODS: Ovariectomized female cynomolgus macaque monkeys were randomized into the following groups: placebo (Con), oral conjugated equine estrogens (CEE), CEE with medroxyprogesterone acetate (MPA) (CEE + MPA), and tibolone given at a low or high dose (Lo or Hi Tib). All study treatment doses represented human clinical dose equivalents and were administered in the diet over a period of 2 years. RESULTS: Treatment with CEE + MPA had the greatest effect on global mRNA profiles and markers of mammary gland proliferation compared to CEE or tibolone treatment. Changes in the transcriptional patterns resulting from the addition of MPA to CEE were related to increased growth factors and decreased estrogen receptor (ER) signaling. Specific genes induced by CEE + MPA treatment included key members of prolactin receptor (PRLR)/signal transducer and activator of transcription 5 (STAT5), epidermal growth factor receptor (EGFR), and receptor activator of nuclear factor kappa B (RANK)/receptor activator of nuclear factor kappa B ligand (RANKL) pathways that were highly associated with breast tissue proliferation. In contrast, tibolone did not affect breast tissue proliferation but did elicit a mixed pattern of ER agonist activity. CONCLUSION: Our findings indicate that estrogen + progestin therapy results in a distinct molecular profile compared to estrogen-alone or tibolone therapy, including upregulation of key growth factor targets associated with mammary carcinogenesis in mouse models. These changes may contribute to the promotional effects of estrogen + progestin therapy on breast cancer risk. PMID- 23938071 TI - Illness, medical expenditure and household consumption: observations from Taiwan. AB - BACKGROUND: Illness conditions lead to medical expenditure. Even with various types of medical insurance, there can still be considerable out-of-pocket costs. Medical expenditure can affect other categories of household consumptions. The goal of this study is to provide an updated empirical description of the distributions of illness conditions and medical expenditure and their associations with other categories of household consumptions. METHODS: A phone call survey was conducted in June and July of 2012. The study was approved by ethics review committees at Xiamen University and FuJen Catholic University. Data was collected using a Computer-Assisted Telephone Survey System (CATSS). "Household" was the unit for data collection and analysis. Univariate and multivariate analyses were conducted, examining the distributions of illness conditions and the associations of illness and medical expenditure with other household consumptions. RESULTS: The presence of chronic disease and inpatient treatment was not significantly associated with household characteristics. The level of per capita medical expenditure was significantly associated with household size, income, and household head occupation. The presence of chronic disease was significantly associated with levels of education, insurance and durable goods consumption. After adjusting for confounders, the associations with education and durable goods consumption remained significant. The presence of inpatient treatment was not associated with consumption levels. In the univariate analysis, medical expenditure was significantly associated with all other consumption categories. After adjusting for confounding effects, the associations between medical expenditure and the actual amount of entertainment expenses and percentages of basic consumption, savings, and insurance (as of total consumption) remained significant. CONCLUSION: This study provided an updated description of the distributions of illness conditions and medical expenditure in Taiwan. The findings were mostly positive in that illness and medical expenditure were not observed to be significantly associated with other consumption categories. This observation differed from those made in some other Asian countries and could be explained by the higher economic status and universal basic health insurance coverage of Taiwan. PMID- 23938072 TI - Omalizumab in the treatment of chronic urticaria. AB - Omalizumab is a monoclonal anti-immunoglobulin E antibody currently only approved for use in severe, refractory asthma. In recent years, many authors have reported satisfactory results with omalizumab in patients with difficult-to-treat chronic urticaria. As a result, clinical trials were undertaken to broaden the indication of omalizumab to include chronic urticaria, and the drug was recently cited as a third-line treatment after selective antihistamines at high doses in a consensus document on the treatment of chronic urticaria. In this article our aim is to provide a comprehensive update on the use of omalizumab in the treatment of chronic urticaria. The structure of this biologic agent and its possible mechanisms of actions in this setting will be presented. Treatment strategies and the different dosage regimens used in the series of cases published to date will also be reviewed. Finally, we will discuss the adverse effects that may arise with treatment and the recommended strategies for minimizing the most feared effect, anaphylaxis. Based on the experience of many researchers, omalizumab is emerging as a novel treatment for certain types of spontaneous refractory chronic urticaria and has shown promising results in this setting. The drug has a good safety profile and the main limitation is its high cost. PMID- 23938073 TI - Clinical management of paradoxical psoriasiform reactions during TNF- alpha therapy. AB - There have been reports of paradoxical induction or worsening of psoriasis during treatment with tumor necrosis factor (TNF) alpha agents (infliximab, etanercept, adalimumab, and certolizumab). It has been hypothesized that an imbalance between TNF-alpha and interferon alpha might have a role in the etiology and pathogenesis of these reactions. Paradoxical psoriasiform reactions can be divided clinically into de novo psoriasis and exacerbation of preexisting psoriasis. The first, which is more common and more extensively described in the literature, occurs in patients without a history of psoriasis who are receiving TNF-alpha therapy for another inflammatory disorder. The second can occur with or without changes in the morphology of the lesions. In this article, we review the literature on the clinical and histologic features of paradoxical psoriasiform reactions, analyze their clinical course and treatment, and propose a clinical management model for use in routine practice. PMID- 23938075 TI - [An erythematous lesion of the thigh]. PMID- 23938074 TI - The importance of age composition of 12-step meetings as a moderating factor in the relation between young adults' 12-step participation and abstinence. AB - BACKGROUND: Participation in 12-step mutual help organizations (MHO) is a common continuing care recommendation for adults; however, little is known about the effects of MHO participation among young adults (i.e., ages 18-25 years) for whom the typically older age composition at meetings may serve as a barrier to engagement and benefits. This study examined whether the age composition of 12 step meetings moderated the recovery benefits derived from attending MHOs. METHOD: Young adults (n=302; 18-24 years; 26% female; 94% White) enrolled in a naturalistic study of residential treatment effectiveness were assessed at intake, and 3, 6, and 12 months later on 12-step attendance, age composition of attended 12-step groups, and treatment outcome (Percent Days Abstinent [PDA]). Hierarchical linear models (HLM) tested the moderating effect of age composition on PDA concurrently and in lagged models controlling for confounds. RESULTS: A significant three-way interaction between attendance, age composition, and time was detected in the concurrent (p=0.002), but not lagged, model (b=0.38, p=0.46). Specifically, a similar age composition was helpful early post-treatment among low 12-step attendees, but became detrimental over time. CONCLUSIONS: Treatment and other referral agencies might enhance the likelihood of successful remission and recovery among young adults by locating and initially linking such individuals to age appropriate groups. Once engaged, however, it may be prudent to encourage gradual integration into the broader mixed-age range of 12-step meetings, wherein it is possible that older members may provide the depth and length of sober experience needed to carry young adults forward into long-term recovery. PMID- 23938076 TI - [Immunological screening and follow-up of celiac disease: experience of the University Hospital of Marseille]. AB - PURPOSE: Anti-tissue transglutaminase antibodies (ATTG) have helped to distinguish atypical and silent clinical forms of celiac disease (CD). Immunological diagnosis or follow-up of the disease is now based in France in first line upon IgA ATTG serum evaluation. In the University Hospital of Marseille, the serological diagnosis of CD had consisted during several years in simultaneous determination of both IgA anti-endomysial antibodies (AEA) and IgA ATTG. In literature, few studies focused on the concordance between the two tests and a very few epidemiological data about CD in France are available. METHODS: Five thousand nine hundred and eighty-one patients for whom both AEA and ATTG testing were available were retrospectively included. Characteristics of this cohort were detailed. We numbered and analyzed especially bioclinical charts from patients with AAE/AATG discordance. RESULTS: Among our patients, all ages and all medical subspecialties were represented. Eighty-five new cases of CD were identified. Among the 6516 serum evaluations performed, only 31 tests were discordant. CONCLUSIONS: Our data give information about CD epidemiology in France. They support the contention that ATTG have to be evaluated in first line for CD diagnosis. PMID- 23938077 TI - Presence of a radioactive gas in archaeological excavations, determination and mitigation. AB - During recent archaeological discovery and excavation of a tunnel build approximately 2000 years ago by the Teotihuacans under the feathered serpent temple, in Mexico, abnormal radon concentrations up to 700 Bq m(-3) were measured at several excavation stages. The tunnel is at 15m below the earth surface with a vertical rectangular entrance of 4*4 m(2), a semi cylindrical shape of 3m in diameter, with a probable length of 100 m. This study supports the assumption that at the opening of the tunnel radon concentration was around 5500 Bq m(-3); however, although natural convection in the tunnel atmosphere naturally pups radon out, it build up to a maximum concentration of 2000 Bq m(-3). This paper presents the identification of the radon problem in this archaeological site, dose determination, and the mitigation actions that reduced the radon concentration down to 40 Bq m(-3) that ensure a negligible radon risk for archaeologist. PMID- 23938078 TI - Exploratory survey of image quality on CR digital mammography imaging systems in Mexico. AB - The purpose of this study was to assess the current status of image quality and dose in computed radiographic digital mammography (CRDM) systems. Studies included CRDM systems of various models and manufacturers which dose and image quality comparisons were performed. Due to the recent rise in the use of digital radiographic systems in Mexico, CRDM systems are rapidly replacing conventional film-screen systems without any regard to quality control or image quality standards. Study was conducted in 65 mammography facilities which use CRDM systems in the Mexico City and surrounding States. The systems were tested as used clinically. This means that the dose and beam qualities were selected using the automatic beam selection and photo-timed features. All systems surveyed generate laser film hardcopies for the radiologist to read on a scope or mammographic high luminance light box. It was found that 51 of CRDM systems presented a variety of image artefacts and non-uniformities arising from inadequate acquisition and processing, as well as from the laser printer itself. Undisciplined alteration of image processing settings by the technologist was found to be a serious prevalent problem in 42 facilities. Only four of them showed an image QC program which is periodically monitored by a medical physicist. The Average Glandular Dose (AGD) in the surveyed systems was estimated to have a mean value of 2.4 mGy. To improve image quality in mammography and make more efficient screening mammographic in early detection of breast cancer is required new legislation. PMID- 23938079 TI - Preparation methods of thermoluminescent materials for dosimetric applications: an overview. AB - Many different natural minerals and synthetic inorganic compounds present the phenomenon of thermoluminescence (TL); however, only a part of them satisfy the requirements to be used as TL dosimeters. The mechanism of excitation energy transformation into the output of light is one of the most important points in the TL materials designing. Both the threshold detection dose and accuracy of measurements depend on the efficiency of energy transformation. The role of diverse mechanisms of energy transfer and energy losses is very different depending on the nature of the TL material and its composition including intrinsic defects and those induced by impurities. The structure of these defects can be controlled to a high extent by the preparation method. That is why the most important fact is to find the interrelations among the preparation methods, the structural defects and the TL properties of the material. The aim of this paper is to give a selected review on the preparation methods of the most popular and commercially available phosphors as well as those less used or "homemade" for special studies. PMID- 23938081 TI - Development of a fast analytical method for the individual determination of pyrethrins residues in fruits and vegetables by liquid chromatography-tandem mass spectrometry. AB - Pyrethrins are natural insecticides derived from chrysanthemum flowers containing a mixture of six components: pyrethrin I, cinerin I, jasmolin I, pyrethrin II, cinerin II, and jasmolin II. In this work, a rapid and sensitive LC-(ESI)-MS/MS method has been developed for the individual quantification and confirmation of pyrethrin residues in fruit and vegetable samples by monitoring two specific transitions for each pyrethrin component under Selected Reaction Monitoring (SRM) mode. Samples were extracted with acetone/water or acetone, depending on the sample type, and raw extracts were directly injected in the LC-MS/MS system. Method validation was carried out evaluating linearity, accuracy, precision, specificity, limit of quantification (LOQ) and limit of detection (LOD) in eight types of fruit and vegetable samples at 0.05mg/kg and 0.5mg/kg (referred to the sum of all pyrethrins). The method based on acetone/water (70:30) extraction led to satisfactory recoveries (70-110%) and good precision (below 14%) for all pyrethrin components in lettuce, pepper, strawberry and potato. The method based on acetone extraction allowed satisfactory recoveries for lettuce, cucumber, tomato and rice samples with recoveries between 71 and 107% and RSDs below 15%. For pistachio samples, satisfactory results were obtained only for some analytes and extracts were also injected using APCI interface, but the lower sensitivity achieved allowed only the validation at 0.5mg/kg. The analytical methodology developed was applied to the analysis of fruit and vegetable samples. PMID- 23938080 TI - Epigenetic changes: a common theme in acute myelogenous leukemogenesis. AB - Acute myeloid leukemia (AML) is a rather common disease, characterized by the presence of a clonal population of hematopoietic progenitor cells with impaired differentiation. Although traditionally AML has been considered the result of genetic alterations, more recently experimental evidence have demonstrated that epigenetic modifications are important in development and maintenance of leukemia cells. In this review we summarize current scientific knowledge of epigenetic alterations involved in leukemogenesis. We also highlight the developing of new technological strategies that are based on epigenetic processes and have been registered as Patents of Inventions in the United Nations dependent World Intellectual Property Office (WIPO) and the main Patent offices worldwide. PMID- 23938082 TI - Comprehensive and sensitive quantification of long-chain and very long-chain polyunsaturated fatty acids in small samples of human and mouse retina. AB - Fatty acids (FAs), including long-chain and very long-chain polyunsaturated fatty acids (LC-PUFAs, C12-22; VLC-PUFAs, C24-38), play an important role in retinal function and health. Deficiencies in LC-PUFAs and VLC-PUFAs, as well as mutations in the enzyme responsible for elongation of very long-chain fatty acids (ELOVL4), have been associated with macular dystrophies and degenerations. Published analytical methods, including high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) and gas chromatography-MS (GC-MS), can quantify VLC PUFAs but require at least an entire human retina which limits the ability to understand physiologically relevant variations in lipids that can occur at a regional level within the retina. Until now, quantification of VLC-PUFAs in just the human macula, the cone-rich region of the central retina responsible for high acuity vision, has not been feasible due to its small size (4-5mm in diameter). In this study, we have developed a sensitive GC-MS method using newer generation enhanced GC-MS detector sensitivity which for the first time quantifies not only 14 VLC-PUFAs and 26 LC-FAs but also n-3/n-6 ratios of PUFAs in 4mm punches of human retina or a single pair of mouse retinas. Our results showed that saturated LC-FAs are higher in the human peripheral retina than in the macula, while unsaturated LC-FAs are higher in the macula than in the peripheral retina. On the other hand, the VLC-PUFAs are higher in the peripheral retina compared to macula. There is no difference in n-3/n-6 ratios of PUFAs observed between human macula and peripheral retina, while mouse retina has almost ten times more VLC-PUFAs than human macula and peripheral retina (2.27% versus 0.25% and 0.32%, respectively) and much higher n-3/n-6 ratios compared to human retina (9:1 versus ~0.9:1). This high sensitivity analytical technique provides a valuable new tool for studies on the role of FAs in the pathological processes of macular degenerations and dystrophies. PMID- 23938083 TI - A qualitative study of cardiac rehabilitation patients' perspectives on taking medicines: implications for the 'medicines-resistance' model of medicine-taking. AB - BACKGROUND: The appropriate use of medicines continues to be an important area of inter-disciplinary research activity both in the UK and beyond. Key qualitative work in this area in the last decade has included the 'medicines resistance' model of medicine-taking, which was based on a meta-ethnography of 37 qualitative studies. This model proposed that patients approach medicine-taking as 'passive accepters', 'active accepters', 'active modifiers' or 'complete rejecters', of which the latter two categories were considered to show 'resistance' to medicines. However, critical assessment of the model appears to be currently lacking, particularly in terms of its use in clinical practice. This paper seeks to contribute to the literature in this area by critically examining the practical application of the model in light of the findings from a qualitative, follow-up study of cardiac rehabilitation patients' perspectives and experiences of using medicines. METHODS: Following ethical approval, in-depth, audiotaped, qualitative interviews were conducted with fifteen patients who had completed a UK hospital-based cardiac rehabilitation programme. Participants were aged 42-65, white British and from a variety of socioeconomic backgrounds. Interview topics included perspectives on coronary heart disease, medicine-taking and lifestyle changes. Follow-up interviews with ten patients approximately nine months later explored whether their perspectives had changed. RESULTS: The findings suggest that the active/passive and accepter/modifier distinctions may not allow for clear determination of which profile a patient fits into at any given point, and that definitions such as 'accepter' and 'resistance' may be insufficiently discerning to categorise patients' use of medicines in practice. These problems appear to arise when the issue of patients' accounts about medicines adherence are considered, since patients may have concerns or disquiet about medicines whether or not they are adherent and the model does not consider disquiet in isolation from adherence. CONCLUSIONS: Practical application of the 'medicines resistance' model of medicine-taking may be problematic in this patient group. Dissociation of disquiet about medicines from medicines adherence may allow for a focus on helping patients to resolve their disquiet, if possible, without this necessarily having to be viewed in terms of its potential effect on adherence. PMID- 23938084 TI - Hidden diversity in Senegalese bats and associated findings in the systematics of the family Vespertilionidae. AB - INTRODUCTION: The Vespertilionidae is the largest family of bats, characterized by high occurrence of morphologically convergent groups, which impedes the study of their evolutionary history. The situation is even more complicated in the tropics, where certain regions remain under-sampled. RESULTS: Two hundred and thirteen vespertilionid bats from Senegal (West Africa) were studied with the use of non-differentially stained karyotypes and multi-locus sequence data analysed with maximum likelihood and Bayesian methods. These bats were identified as 10 different taxa, five of which were distinctive from their nominate species (Pipistrellus hesperidus, Nycticeinops schlieffenii, Scotoecus hirundo, Neoromicia nana and N. somalica), based on both karyotypes and molecular data. These five cryptic taxa are unrelated, suggesting that these West African populations have long been isolated from other African regions. Additionally, we phylogenetically analysed 166 vespertilionid taxa from localities worldwide using GenBank data (some 80% of the genera of the family) and 14 representatives of closely related groups, together with our Senegalese specimens. The systematic position of several taxa differed from previous studies and the tribes Pipistrellini and Vespertilionini were redefined. The African Pipistrellus rueppellii was basal to the Pipistrellus/Nyctalus clade and the Oriental species Glischropus tylopus was basal to the East Asian pipistrelles within the tribe Pipistrellini. The African genus Neoromicia was confirmed to be diphyletic. Based on GenBank data, Eptesicus was polyphyletic, with the Asian E. nasutus and E. dimissus both supported as phylogenetically distinct from the Eptesicus clade. The subfamily Scotophilinae was confirmed as one of the basal branches of Vespertilionidae. CONCLUSIONS: New taxa and new systematic arrangements show that there is still much to resolve in the vespertilionids and that West Africa is a biogeographic hotspot with more diversity to be discovered. PMID- 23938085 TI - Automated detection of gait initiation and termination using wearable sensors. AB - This paper presents algorithms for detection of gait initiation and termination using wearable inertial measurement units and pressure-sensitive insoles. Body joint angles, joint angular velocities, ground reaction force and center of plantar pressure of each foot are obtained from these sensors and input into supervised machine learning algorithms. The proposed initiation detection method recognizes two events: gait onset (an anticipatory movement preceding foot lifting) and toe-off. The termination detection algorithm segments gait into steps, measures the signals over a buffer at the beginning of each step, and determines whether this measurement belongs to the final step. The approach is validated with 10 subjects at two gait speeds, using within-subject and subject independent cross-validation. Results show that gait initiation can be detected timely and accurately, with few errors in the case of within-subject cross validation and overall good performance in subject-independent cross-validation. Gait termination can be predicted in over 80% of trials well before the subject comes to a complete stop. Results also show that the two sensor types are equivalent in predicting gait initiation while inertial measurement units are generally superior in predicting gait termination. Potential use of the algorithms is foreseen primarily with assistive devices such as prostheses and exoskeletons. PMID- 23938086 TI - Three-dimensional reconstruction of the lower limb from biplanar calibrated radiographs. AB - Three-dimensional (3D) reconstruction of lower limbs is essential for surgical planning and clinical outcome evaluation. 3D reconstruction from biplanar calibrated radiographs may be an alternative to irradiation issues of CT-scan. A previous study proposed a two-step reconstruction method based on parametric models and statistical inferences leading to a fast Initial Solution (IS) followed by manual adjustments. This study aims to improve the IS using a new 3D database, a novel parametric model of the tibia and a different regression approach. The IS was evaluated in terms of shape accuracy on 9 lower limbs and reproducibility of clinical measurements on 22 lower limbs. Reconstruction time was also evaluated. Comparison to the previous method showed an improvement of the IS in terms of shape accuracy (1.3 vs. 1.6 and 2 mm respectively for both femur and tibia) and reproducibility of clinical measurements (i.e. 3.1 degrees vs. 8.3 degrees for neck-shaft-angle; 4.2 degrees and 5 degrees vs. 5 degrees and 6 degrees for tibial and femoral torsion respectively). The proposed approach constitutes a considerable step towards an automatic 3D reconstruction of lower limb. PMID- 23938087 TI - CellSegm - a MATLAB toolbox for high-throughput 3D cell segmentation. AB - : The application of fluorescence microscopy in cell biology often generates a huge amount of imaging data. Automated whole cell segmentation of such data enables the detection and analysis of individual cells, where a manual delineation is often time consuming, or practically not feasible. Furthermore, compared to manual analysis, automation normally has a higher degree of reproducibility. CellSegm, the software presented in this work, is a Matlab based command line software toolbox providing an automated whole cell segmentation of images showing surface stained cells, acquired by fluorescence microscopy. It has options for both fully automated and semi-automated cell segmentation. Major algorithmic steps are: (i) smoothing, (ii) Hessian-based ridge enhancement, (iii) marker-controlled watershed segmentation, and (iv) feature-based classfication of cell candidates. Using a wide selection of image recordings and code snippets, we demonstrate that CellSegm has the ability to detect various types of surface stained cells in 3D. After detection and outlining of individual cells, the cell candidates can be subject to software based analysis, specified and programmed by the end-user, or they can be analyzed by other software tools. A segmentation of tissue samples with appropriate characteristics is also shown to be resolvable in CellSegm. The command-line interface of CellSegm facilitates scripting of the separate tools, all implemented in Matlab, offering a high degree of flexibility and tailored workflows for the end-user. The modularity and scripting capabilities of CellSegm enable automated workflows and quantitative analysis of microscopic data, suited for high-throughput image based screening. PMID- 23938088 TI - Case report: Locoregional (perineum and inguinal) recurrence after treatment of rectal cancer by low anterior resection. AB - This report presents a case of perineal and inguinal recurrence and metastasis after treatment of rectal cancer by low anterior resection. A 57-year-old Chinese woman was diagnosed with rectal cancer in September 2008. The tumor and metastasis were recurrent many times in the perineum and inguinal regions from first diagnosis to October 2011. Twelve surgeries were performed and several nodules were removed. Adjuvant radiation therapy and chemotherapy were also carried out. Pathological analysis indicated that most nodules were adenocarcinoma. The interesting finding was that this case did not seem to belong to any traditional rectal cancer metastasis pathway. This case is representative and worthy of further study to explore whether there is another rectal cancer metastasis pathway. PMID- 23938090 TI - Adenomatoid odontogenic tumor associated with odontoma: a case report and critical review of the literature. AB - We describe a case of adenomatoid odontogenic tumor (AOT) associated with odontoma occurring in the posterior mandible of a 32-year-old man. Although calcifications are commonly found in the AOT, the presence of rudimentary dental structures is a very rare phenomenon. Cases with similar aspects have been described as ameloblastic dentinoma, ameloblastic odontoma, adenoameloblastic odontoma and AOT associated with odontoma. After a careful analysis of the literature we describe the clinical aspects of this tumor. Further case reports and surveys of odontogenic tumors are necessary to define whether AOT associated with odontoma is a variant of AOT or a distinct clinicopathologic condition. PMID- 23938089 TI - Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells. AB - INTRODUCTION: Signal transducers and activators of transcription 3 (STAT3) signaling is constitutively activated in various cancers including breast cancer and has emerged as a novel potential anti-cancer target. STAT3 has been demonstrated to be a target of sorafenib, and a protein tyrosine phosphatase Src homology 2-domain containing tyrosine phosphatase 1 (SHP-1) has been demonstrated to downregulate p-STAT3 via its phosphatase activity. Here, we tested the efficacy of two sorafenib analogues, SC-1 and SC-43, in breast cancer cells and examined the drug mechanism. METHODS: Breast cancer cell lines were used for in vitro studies. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was examined by flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. In vivo efficacy of sorafenib, SC-1 and SC-43 was tested in xenografted nude mice. RESULTS: SC-1 and SC-43 induced more potent apoptosis than sorafenib, in association with downregulation of p-STAT3 and its downstream proteins cyclin D1 and survivin in a dose-dependent manner in breast cancer cell lines (HCC-1937, MDA-MB-468, MDA-MB-231, MDA-MB-453, SK-BR3, MCF-7). Overexpression of STAT3 in MDA-MB-468 cells protected the cells from apoptosis induced by sorafenib, SC-1 and SC-43. Moreover, SC-1 and SC-43 upregulated SHP-1 activity to a greater extent than sorafenib as measured by in vitro phosphatase assays. Knockdown of SHP-1 by siRNA reduced apoptosis induced by SC-1 and SC-43. Importantly, SC-1 and SC-43 showed more efficacious antitumor activity and p STAT3 downregulation than sorafenib in MDA-MB-468 xenograft tumors. CONCLUSIONS: Novel sorafenib analogues SC-1 and SC-43 induce apoptosis through SHP-1 dependent STAT3 inactivation and demonstrate greater potency than sorafenib in human breast cancer cells. PMID- 23938091 TI - Learning in action: developing safety improvement capabilities through action learning. AB - Patient safety is one of the greatest challenges facing health care today and nurses are well placed to find opportunities for enhancing care and making it safer. Nurse education has an important role to play in ensuring future professions have capabilities and confidence to meet this challenge however this requires new pedagogies in nurse education. This paper reports on an initiative to develop the safety improvement and leadership capabilities of final year nursing students using Action Learning to support students to undertake a safety improvement project in the clinical setting. A qualitative, interpretive research approach was used to explore students' experiences of participation in Action Learning. 52 nursing students from a UK University participated in the study. Student accounts of their experiences were generated through focus group and individual interviews and data were subject to thematic analysis. Findings are discussed in relation to three categories including "creating an enabling environment", "learning through action and reflection" and "the emergence of safety improvement and leadership practices." The study findings provide valuable insights into how AL processes can engender personal leadership capabilities and support students to make a valuable contribution to safer care practices, both as students and as future health care professionals. PMID- 23938092 TI - Development and validation of a new tool measuring nurses self-reported professional competence--the nurse professional competence (NPC) Scale. AB - OBJECTIVES: To develop and validate a new tool intended for measuring self reported professional competence among both nurse students prior to graduation and among practicing nurses. The new tool is based on formal competence requirements from the Swedish Board of Health and Welfare, which in turn are based on WHO guidelines. DESIGN: A methodological study including construction of a new scale and evaluation of its psychometric properties. PARTICIPANTS AND SETTINGS: 1086 newly graduated nurse students from 11 universities/university colleges. RESULTS: The analyses resulted in a scale named the NPC (Nurse Professional Competence) Scale, consisting of 88 items and covering eight factors: "Nursing care", "Value-based nursing care", "Medical/technical care", "Teaching/learning and support", "Documentation and information technology", "Legislation in nursing and safety planning", "Leadership in and development of nursing care" and "Education and supervision of staff/students". All factors achieved Cronbach's alpha values greater than 0.70. A second-order exploratory analysis resulted in two main themes: "Patient-related nursing" and "Nursing care organisation and development". In addition, evidence of known-group validity for the NPC Scale was obtained. CONCLUSIONS: The NPC Scale, which is based on national and international professional competence requirements for nurses, was comprehensively tested and showed satisfactory psychometrical properties. It can e.g. be used to evaluate the outcomes of nursing education programmes, to assess nurses' professional competences in relation to the needs in healthcare organisations, and to tailor introduction programmes for newly employed nurses. PMID- 23938093 TI - Clinical reasoning in nursing, a think-aloud study using virtual patients - a base for an innovative assessment. AB - In health-care education, it is important to assess the competencies that are essential for the professional role. To develop clinical reasoning skills is crucial for nursing practice and therefore an important learning outcome in nursing education programmes. Virtual patients (VPs) are interactive computer simulations of real-life clinical scenarios and have been suggested for use not only for learning, but also for assessment of clinical reasoning. The aim of this study was to investigate how experienced paediatric nurses reason regarding complex VP cases and how they make clinical decisions. The study was also aimed to give information about possible issues that should be assessed in clinical reasoning exams for post-graduate students in diploma specialist paediatric nursing education. The information from this study is believed to be of high value when developing scoring and grading models for a VP-based examination for the specialist diploma in paediatric nursing education. Using the think-aloud method, data were collected from 30 RNs working in Swedish paediatric departments, and child or school health-care centres. Content analysis was used to analyse the data. The results indicate that experienced nurses try to consolidate their hypotheses by seeing a pattern and judging the value of signs, symptoms, physical examinations, laboratory tests and radiology. They show high specific competence but earlier experience of similar cases was also of importance for the decision making. The nurses thought it was an innovative assessment focusing on clinical reasoning and clinical decision making. They thought it was an enjoyable way to be assessed and that all three main issues could be assessed using VPs. In conclusion, VPs seem to be a possible model for assessing the clinical reasoning process and clinical decision making, but how to score and grade such exams needs further research. PMID- 23938094 TI - Medication errors in pediatric nursing: assessment of nurses' knowledge and analysis of the consequences of errors. AB - AIM: The purposes of this study were (i) to evaluate pediatric nurses' knowledge of pharmacology, and (ii) to analyze known pediatric administration errors. BACKGROUND: Medication errors occur frequently and ubiquitously, but medication errors involving pediatric patients attract special attention for their high incidence and injury rates. METHODS: A cross-sectional study was conducted. A questionnaire with 20 true-false questions regarding pharmacology was used to evaluate nurses' knowledge, and the known pediatric administration errors were reported by nurses. FINDINGS: The overall correct answer rate on the knowledge of pharmacology was 72.9% (n=262). Insufficient knowledge (61.5%) was the leading obstacle nurses encountered when administering medications. Of 141 pediatric medication errors, more than 60% (61.0%) of which were wrong doses, 9.2% of the children involved suffered serious consequences. CONCLUSIONS: Evidence-based results demonstrate that pediatric nurses have insufficient knowledge of pharmacology. Such strategies as providing continuing education and double checking dosages are suggested. PMID- 23938095 TI - Microdistortions in Bowman's layer following femtosecond laser small incision lenticule extraction observed by Fourier-Domain OCT. AB - PURPOSE: To study microdistortions in Bowman's layer after femtosecond laser small incision lenticule extraction (SMILE) using Fourier-domain optical coherence tomography (OCT) and to investigate possible sources and potential visual impacts. METHODS: A nonrandomized controlled prospective study enrolled 52 eyes of 29 consecutive patients undergoing SMILE, with spherical equivalent of 6.33 +/- 1.88 diopters and 4.2 mm superior incision. The microdistortions in Bowman's layer were counted at 1 day, 1 week, and 1 month postoperatively and at long-term follow-up. Another 38 eyes of 20 patients undergoing femtosecond laser assisted LASIK (FS-LASIK) were examined at 1 day and long-term postoperatively as the control group. RESULTS: Microdistortions in Bowman's layer were observed by OCT, with no clinically significant corneal striae under slit-lamp microscopy, in 46 eyes (88.5%) on day 1 after SMILE and in 16 eyes (42.1%) after FS-LASIK, with more in SMILE eyes than in FS-LASIK eyes. The amount decreased at 1 week and then remained stable. There were more microdistortions in the center area than in the periphery in both groups. Microdistortions were more in the inferior than the superior quadrant on the first day after SMILE but there was no difference at long-term follow-up. Microdistortions after SMILE were associated with the refractive lenticule thickness and surgery order but had no significant impact on long-term visual outcomes or wavefront aberrations. CONCLUSIONS: Microdistortions in Bowman's layer after SMILE were associated with the refractive lenticule thickness and surgery order. The microdistortions remained stable after 1 week and had no impact on long-term visual performance. PMID- 23938096 TI - A hard place: calcified neck mass. PMID- 23938098 TI - ICU survivors' utilisation of diaries post discharge: a qualitative descriptive study. AB - BACKGROUND: A growing body of evidence has confirmed that intensive care unit survivors encounter myriad of physical and psychological complications during their recovery. The incidence of psychological morbidity in intensive care survivors is increasingly being recognised. The causes of psychological morbidity are multi-factorial but may be associated with a complete lack of, or delusional recall of events in intensive care. Intensive care unit diaries are an initiative designed to enable survivors to help restore factual memories and differentiate those from delusional. PURPOSE: To explore survivors' and family members' perceptions and utilisation of diaries following discharge from hospital. METHOD: A single centre qualitative descriptive study was undertaken in a general intensive care unit in Western Australia. Participants were surveyed 3, 6 and 12 months following discharge from hospital. Eighteen participants completed one or more surveys. FINDINGS: Many of the participants who completed the surveys read their diaries but few made entries in them following discharge. Reading the diaries evoked mixed emotions for these participants; however they still viewed the diaries as a positive initiative in their recovery. Diaries enabled survivors to fill the memory gaps, make sense of their experience and reinforced the human connection when they were immersed in a technological environment. CONCLUSION: Use of patient diaries was received positively by the participants in this study. Diaries are a simple, cost effective initiative which enabled survivors to piece together the time they had lost, concreted their experience in reality and enabled them to retain a connection with their loved ones whilst immersed in a technological environment. PMID- 23938097 TI - Stores Healthy Options Project in Remote Indigenous Communities (SHOP@RIC): a protocol of a randomised trial promoting healthy food and beverage purchases through price discounts and in-store nutrition education. AB - BACKGROUND: Indigenous Australians suffer a disproportionate burden of preventable chronic disease compared to their non-Indigenous counterparts--much of it diet-related. Increasing fruit and vegetable intakes and reducing sugar sweetened soft-drink consumption can reduce the risk of preventable chronic disease. There is evidence from some general population studies that subsidising healthier foods can modify dietary behaviour. There is little such evidence relating specifically to socio-economically disadvantaged populations, even though dietary behaviour in such populations is arguably more likely to be susceptible to such interventions.This study aims to assess the impact and cost effectiveness of a price discount intervention with or without an in-store nutrition education intervention on purchases of fruit, vegetables, water and diet soft-drinks among remote Indigenous communities. METHODS/DESIGN: We will utilise a randomised multiple baseline (stepped wedge) design involving 20 communities in remote Indigenous Australia. The study will be conducted in partnership with two store associations and twenty Indigenous store boards. Communities will be randomised to either i) a 20% price discount on fruit, vegetables, water and diet soft-drinks; or ii) a combined price discount and in store nutrition education strategy. These interventions will be initiated, at one of five possible time-points, spaced two-months apart. Weekly point-of-sale data will be collected from each community store before, during, and for six months after the six-month intervention period to measure impact on purchasing of discounted food and drinks. Data on physical, social and economic factors influencing weekly store sales will be collected in order to identify important covariates. Intervention fidelity and mediators of behaviour change will also be assessed. DISCUSSION: This study will provide original evidence on the effectiveness and cost-effectiveness of price discounts with or without an in store nutrition education intervention on food and drink purchasing among a socio economically disadvantaged population in a real-life setting. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12613000694718. PMID- 23938099 TI - Smoker with Raynaud phenomenon and painful nodules on the legs. PMID- 23938100 TI - Spot the differences between 2 pigmented papules. PMID- 23938101 TI - A "virtually minimal" visuo-haptic training of attention in severe traumatic brain injury. AB - BACKGROUND: Although common during the early stages of recovery from severe traumatic brain injury (TBI), attention deficits have been scarcely investigated. Encouraging evidence suggests beneficial effects of attention training in more chronic and higher functioning patients. Interactive technology may provide new opportunities for rehabilitation in inpatients who are earlier in their recovery. METHODS: We designed a "virtually minimal" approach using robot-rendered haptics in a virtual environment to train severely injured inpatients in the early stages of recovery to sustain attention to a visuo-motor task. 21 inpatients with severe TBI completed repetitive reaching toward targets that were both seen and felt. Patients were tested over two consecutive days, experiencing 3 conditions (no haptic feedback, a break-through force, and haptic nudge) in 12 successive, 4 minute blocks. RESULTS: The interactive visuo-haptic environments were well tolerated and engaging. Patients typically remained attentive to the task. However, patients exhibited attention loss both before (prolonged initiation) and during (pauses during motion) a movement. Compared to no haptic feedback, patients benefited from haptic nudge cues but not break-through forces. As training progressed, patients increased the number of targets acquired and spontaneously improved from one day to the next. CONCLUSIONS: Interactive visuo haptic environments could be beneficial for attention training for severe TBI patients in the early stages of recovery and warrants further and more prolonged clinical testing. PMID- 23938102 TI - Starch biosynthesis in cassava: a genome-based pathway reconstruction and its exploitation in data integration. AB - BACKGROUND: Cassava is a well-known starchy root crop utilized for food, feed and biofuel production. However, the comprehension underlying the process of starch production in cassava is not yet available. RESULTS: In this work, we exploited the recently released genome information and utilized the post-genomic approaches to reconstruct the metabolic pathway of starch biosynthesis in cassava using multiple plant templates. The quality of pathway reconstruction was assured by the employed parsimonious reconstruction framework and the collective validation steps. Our reconstructed pathway is presented in the form of an informative map, which describes all important information of the pathway, and an interactive map, which facilitates the integration of omics data into the metabolic pathway. Additionally, to demonstrate the advantage of the reconstructed pathways beyond just the schematic presentation, the pathway could be used for incorporating the gene expression data obtained from various developmental stages of cassava roots. Our results exhibited the distinct activities of the starch biosynthesis pathway in different stages of root development at the transcriptional level whereby the activity of the pathway is higher toward the development of mature storage roots. CONCLUSIONS: To expand its applications, the interactive map of the reconstructed starch biosynthesis pathway is available for download at the SBI group's website (http://sbi.pdti.kmutt.ac.th/?page_id=33). This work is considered a big step in the quantitative modeling pipeline aiming to investigate the dynamic regulation of starch biosynthesis in cassava roots. PMID- 23938103 TI - "They just scraped off the calluses": a mixed methods exploration of foot care access and provision for people with rheumatoid arthritis in south-western Sydney, Australia. AB - BACKGROUND: There is little indication that foot health services in Australia are meeting modern day recommendations for Rheumatoid Arthritis (RA) patients. The overall objective of this study was to explore the current state of foot health services for patients with RA with an emphasis on identifying barriers to the receipt of appropriate foot care in South-West Sydney, New South Wales, Australia. METHODS: A mixed (quantitative and qualitative) approach was adopted. Indications for appropriate access to foot care were determined by comparing the foot health, disease and socio-demographic characteristics of patients with unmet foot care demands, foot care users and patients with no demands for foot care. Perceptions of provision of, and access to, foot care were explored by conducting telephone-based interviews using an interpretative phenomenology approach with thematic analysis. RESULTS: Twenty-nine participants took part in the cross sectional quantitative research study design, and 12 participants took part in the interpretative phenomenological approach (qualitative study). Foot care access appeared to be driven predominantly by the presence of rearfoot deformity, which was significantly worse amongst participants in the foot care user group (p = 0.02). Five main themes emerged from the qualitative data: 1) impact of disease related foot symptoms, 2) footwear difficulties, 3) medical/rheumatology encounters, 4) foot and podiatry care access and experiences, and 5) financial hardship. CONCLUSIONS: Foot care provision does not appear to be driven by appropriate foot health characteristics such as foot pain or foot-related disability. There may be significant shortfalls in footwear and foot care access and provision in Greater Western Sydney. Several barriers to adequate foot care access and provision were identified and further efforts are required to improve access to and the quality of foot care for people who have RA. Integration of podiatry services within rheumatology centres could resolve unmet needs of people with RA by permitting rapid access to expert-led multidisciplinary foot care for people with RA. PMID- 23938104 TI - The Shock Index revisited - a fast guide to transfusion requirement? A retrospective analysis on 21,853 patients derived from the TraumaRegister DGU. AB - INTRODUCTION: Isolated vital signs (for example, heart rate or systolic blood pressure) have been shown unreliable in the assessment of hypovolemic shock. In contrast, the Shock Index (SI), defined by the ratio of heart rate to systolic blood pressure, has been advocated to better risk-stratify patients for increased transfusion requirements and early mortality. Recently, our group has developed a novel and clinical reliable classification of hypovolemic shock based upon four classes of worsening base deficit (BD). The objective of this study was to correlate this classification to corresponding strata of SI for the rapid assessment of trauma patients in the absence of laboratory parameters. METHODS: Between 2002 and 2011, data for 21,853 adult trauma patients were retrieved from the TraumaRegister DGU database and divided into four strata of worsening SI at emergency department arrival (group I, SI <0.6; group II, SI >=0.6 to <1.0; group III, SI >=1.0 to <1.4; and group IV, SI >=1.4) and were assessed for demographics, injury characteristics, transfusion requirements, fluid resuscitation and outcomes. The four strata of worsening SI were compared with our recently suggested BD-based classification of hypovolemic shock. RESULTS: Worsening of SI was associated with increasing injury severity scores from 19.3 (+/- 12) in group I to 37.3 (+/- 16.8) in group IV, while mortality increased from 10.9% to 39.8%. Increments in SI paralleled increasing fluid resuscitation, vasopressor use and decreasing hemoglobin, platelet counts and Quick's values. The number of blood units transfused increased from 1.0 (+/- 4.8) in group I to 21.4 (+/- 26.2) in group IV patients. Of patients, 31% in group III and 57% in group IV required >=10 blood units until ICU admission. The four strata of SI discriminated transfusion requirements and massive transfusion rates equally with our recently introduced BD-based classification of hypovolemic shock. CONCLUSION: SI upon emergency department arrival may be considered a clinical indicator of hypovolemic shock in respect to transfusion requirements, hemostatic resuscitation and mortality. The four SI groups have been shown to equal our recently suggested BD-based classification. In daily clinical practice, SI may be used to assess the presence of hypovolemic shock if point-of-care testing technology is not available. PMID- 23938105 TI - Into the abyss: diabetes process of care indicators and outcomes of defaulters from a Canadian tertiary care multidisciplinary diabetes clinic. AB - BACKGROUND: Continuity of care is essential for good quality diabetes management. We recently found that 46% of patients defaulted from care (had no contact with the clinic for 18 months after a follow-up appointment was ordered) in a Canadian multidisciplinary tertiary care diabetes clinic. The primary aim was to compare characteristics, diabetes processes of care, and outcomes from referral to within 1 year after leaving clinic or to the end of the follow-up period among those patients who defaulted, were discharged or were retained in the clinic. METHODS: Retrospective cohort study of 193 patients referred to the Foustanellas Endocrine and Diabetes Center (FEDC) for type 2 diabetes from January 1, 2005 to June 30, 2005. The FEDC is the primary academic referral centre for the Ottawa Region and provides multidisciplinary diabetes management. Defaulters (mean age 58.5 +/- 12.5 year, 60% M) were compared to patients who were retained in the clinic (mean age 61.4 +/- 10.47 years, 49% M) and those who were formally discharged (mean age 61.5 +/- 13.2 years, 53.3% M). The chart audit population was then individually linked on an individual patient basis for laboratory testing, physician visits billed through OHIP, hospitalizations and emergency room visits using Ontario health card numbers to health administrative data from the Ministry of Health and Long-Term Care at the Institute for Clinical and Evaluative Sciences (ICES). RESULTS: Retained and defaulted patients had significantly longer duration of diabetes, more microvascular complications, were more likely to be on insulin and less likely to have a HbA1c < 7.0% than patients discharged from clinic. A significantly lower proportion of patients who defaulted from tertiary care received recommended monitoring for their diabetes (HbA1c measurements, lipid measurements, and periodic eye examinations), despite no difference in median number of visits to a primary care provider (PCP). Emergency room visits were numerically higher in the defaulters group. CONCLUSIONS: Patients defaulting from a tertiary care diabetes hospital do not receive the recommended monitoring for their diabetes management despite attending PCP appointments. Efforts should be made to minimize defaulting in this group of individuals. PMID- 23938106 TI - Electrocardiogram as a screening tool in the general population: a strategic review. AB - Sudden cardiac death (SCD) is a major public health concern, accounting for 400,000 deaths in the US each year. Clinical and autopsy studies have consistently demonstrated a predominant, common pathophysiology in Western populations, showing that the most common electrophysiological mechanism of SCD is ventricular fibrillation, and the most common pathologic substrate is coronary heart disease (CHD). In about half of SCD cases, death is the first clinical manifestation of CHD. Yet risk factors of SCD early in the natural history of conditions predisposing SCD have not been fully identified, and SCD risk stratification strategy in the general population has not been developed. ECG is an easily available, non-expensive and non-invasive tool, which carries valuable information on electrophysiological properties of the heart. However, traditional analysis of ECG includes very limited assessment of the arrhythmogenic substrate. In this review rationale for development of ECG SCD risk score for screening in the general population is discussed. PMID- 23938107 TI - Pre-hospital diagnosis and transfer of patients with acute myocardial infarction- a decade long experience from one of Europe's largest STEMI networks. AB - Early reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) is essential. Although primary percutaneous coronary intervention (pPCI) is the preferred revascularization technique, it often involves longer primary transportation or secondary inter-hospital transfers and thus longer system related delays. The current ESC Guidelines state that PCI should be performed within 120 minutes from first medical contact, and door-to-balloon time should be <60 minutes in order to reduce long term mortality. STEMI networks should be established with regionalization of pPCI treatment to address the challenges regarding pre-hospital treatment, triage and transport of STEMI patients and collaborations between hospitals and Emergency Medical Services (EMS). We report on a regional decade long experience from one of Europe's largest STEMI networks located in Eastern Denmark, which serves a catchment area of 2.5 million inhabitants by processing ~4000 prehospital ECGs annually transmitted from 4 EMS systems to a single pPCI center treating 1100 patients per year. This organization has led to a significant improvement of the standard of therapy for acute myocardial infarction (MI) patients leading to historically low 30-day mortality for STEMI patients (<6%). About 70-80% of all STEMI patients are being triaged from the field and rerouted to the regional pPCI center. Significant delays are still found among patients who present to local hospitals and for those who are first admitted to a local emergency room and thus subject to inter hospital transfer. In the directly transferred group, approximately 80% of patients can be treated within the current guideline time window of 120 minutes when triaged within a 185 km (~115 miles) radius. Since 2010, a Helicopter Emergency Medical Service has been implemented for air rescue. Air transfer was associated with a 20-30 minute decrease from first medical contact to pPCI, at distances down to 90 km from the pPCI center and with a trend toward better survival among air transported patients. The pPCI center also serves a small island in the Baltic Sea, where STEMI patients are rescued via air force helicopters. Based on data from more than 100 patients transferred over the past decade, we have found a similar in-hospital and long term mortality rate compared to the main island inhabitants. In conclusion, with the optimal collaboration within a STEMI network including local hospitals, university clinics, EMS and military helicopters using the same telemedicine system and field triage of STEMI patients, most patients can be treated within the time limits suggested by the current guidelines. These organizational changes are likely to contribute to the improved mortality rate for STEMI patients. PMID- 23938108 TI - Relationship of QT interval variability to heart rate and RR interval variability. AB - The study investigated whether the beat-to-beat QT interval variability relationship to the mean heart rate and the RR interval variability depended on the cardiovascular autonomic status changed by postural positioning. Repeated long-term 12-lead Holter recordings were obtained from 352 healthy subjects (mean age 32.7 +/- 9.1 years, 176 females) while they underwent postural provocative tests involving supine, unsupported sitting and unsupported standing positions. Each recording was processed as a sequence of overlapping 10-second segments. In each segment, the mean RR interval, the coefficients of variance of the RR intervals (RRCV) and the QT intervals (QTCV) were obtained. In each subject, these characteristics, corresponding to different postural positions, were firstly averaged and secondly used to obtain within-subject correlation coefficients between the different characteristics at different postural positions. While the within-subject means of RRCV generally decreased when changing the position from supine to sitting and to standing (4.53 +/- 1.95%, 4.12 +/- 1.51% and 3.26 +/- 1.56% in females and 3.99 +/- 1.44%, 4.00 +/- 1.24% and 3.53 +/- 1.32% in males respectively), the means of QTCV systematically increased during these position changes (0.96 +/- 0.40%, 1.30 +/- 0.56% and 1.88 +/- 1.46% in females and 0.85 +/- 0.30%, 1.13 +/- 0.41% and 1.41 +/- 0.59% in males, respectively). The intra-subject relationship between QTCV, RRCV and mean RR intervals was highly dependent on postural positions. The study concludes that no universally applicable normalization of the QT interval variability for the heart rate and/or the RR interval variability should be assumed. In future studies of the QT variability, it seems preferable to report on the absolute values of QT variability, RR variability and mean heart rate separately. PMID- 23938109 TI - Indigenous knowledge of zootherapeutic use among the Biate tribe of Dima Hasao District, Assam, Northeastern India. AB - BACKGROUND: The present study addresses the use of zootherapy in the traditional healthcare system of the Biate tribe of Dima Hasao district, Assam, India. It sought to identify the different species used for zootherapeutic use with the detailed methods of usages to create awareness and contribute to the conservation and sustainable utilization of the resources. METHOD: 15 Biate villages within the district of Dima Hasao were surveyed through semi-structured questionnaires and informal interviews. Detailed information on the uses of each animal was recorded. Species were identified using standard literature. Fidelity level (FL) was calculated to demonstrate the percentage of respondents claiming the use of a certain animal for the same major purposes. RESULT: The study documents 34 species for the treatment of about 34 different ailments. The largest number of species reported was mammals with17 species. Maximum number of species has been reported for the treatment of diabetes and its high fidelity levels warrants in depth studies to establish its pharmacological activity. The usages documented herein are unique to the Biate tribe. Very often, these animals are hunted and sold openly at the local markets in the lure of quick money. A 300 gm live Gekko gecko may fetch a sum of 2,50,000 Indian Rupees (INR), and smoked meat of Hoolock hoolock cost approximately 250-300 INR per kg. Animals are also hunted for its hide. The unrestricted hunting of species like Capricornis sumatraensis has almost wiped out the population within the district. Some species are also reared as pets while some are used for display as a sign of expertise in hunting. The present study has documented the usage of at least 15 animals listed in the IUCN Red List. CONCLUSION: The study illustrates the in-depth knowledge of the Biate tribe on zootherapy. Systematic investigation to identify the active ingredient may lead to the development of new drugs, which would prompt protection of these valuable resources. PMID- 23938110 TI - Meeting summary: Ethical aspects of whole exome and whole genome sequencing studies (WES/WGS) in rare diseases, Tel Aviv, Israel, January 2013. AB - A recent E-Rare workshop reviewed the ethical aspects of whole exome and whole genome-sequencing studies (WES and WGS, respectively) in rare diseases. Leveraging new genomic technologies, which output vast amounts of known and novel genetic variants, researchers are learning more about the genetic basis and mechanisms involved in rare diseases. In some cases, these findings are translated into diagnostic tools for the benefit of rare disease patients. Among the disclosed data, which can assist in treatment management, incidental findings await, bringing with them ethical concerns for the clinicians, researchers and patients. PMID- 23938111 TI - Sparse group penalized integrative analysis of multiple cancer prognosis datasets. AB - In cancer research, high-throughput profiling studies have been extensively conducted, searching for markers associated with prognosis. Owing to the 'large d, small n' characteristic, results generated from the analysis of a single dataset can be unsatisfactory. Recent studies have shown that integrative analysis, which simultaneously analyses multiple datasets, can be more effective than single-dataset analysis and classic meta-analysis. In most of existing integrative analysis, the homogeneity model has been assumed, which postulates that different datasets share the same set of markers. Several approaches have been designed to reinforce this assumption. In practice, different datasets may differ in terms of patient selection criteria, profiling techniques, and many other aspects. Such differences may make the homogeneity model too restricted. In this study, we assume the heterogeneity model, under which different datasets are allowed to have different sets of markers. With multiple cancer prognosis datasets, we adopt the accelerated failure time model to describe survival. This model may have the lowest computational cost among popular semiparametric survival models. For marker selection, we adopt a sparse group minimax concave penalty approach. This approach has an intuitive formulation and can be computed using an effective group coordinate descent algorithm. Simulation study shows that it outperforms the existing approaches under both the homogeneity and heterogeneity models. Data analysis further demonstrates the merit of heterogeneity model and proposed approach. PMID- 23938112 TI - A meta-analysis study of gene expression datasets in mouse liver under PPARalpha knockout. AB - Gene expression profiling of peroxisome-proliferator-activated receptor alpha (PPARalpha) has been used in several studies, but there were no consistent results on gene expression patterns involved in PPARalpha activation in genome wide due to different sample sizes or platforms. Here, we employed two published microarray datasets both PPARalpha dependent in mouse liver and applied meta analysis on them to increase the power of the identification of differentially expressed genes and significantly enriched pathways. As a result, we have improved the concordance in identifying many biological mechanisms involved in PPARalpha activation. We suggest that our analysis not only leads to more identified genes by combining datasets from different resources together, but also provides some novel hepatic tissue-specific marker genes related to PPARalpha according to our re-analysis. PMID- 23938113 TI - The causal meaning of Fisher's average effect. AB - In order to formulate the Fundamental Theorem of Natural Selection, Fisher defined the average excess and average effect of a gene substitution. Finding these notions to be somewhat opaque, some authors have recommended reformulating Fisher's ideas in terms of covariance and regression, which are classical concepts of statistics. We argue that Fisher intended his two averages to express a distinction between correlation and causation. On this view, the average effect is a specific weighted average of the actual phenotypic changes that result from physically changing the allelic states of homologous genes. We show that the statistical and causal conceptions of the average effect, perceived as inconsistent by Falconer, can be reconciled if certain relationships between the genotype frequencies and non-additive residuals are conserved. There are certain theory-internal considerations favouring Fisher's original formulation in terms of causality; for example, the frequency-weighted mean of the average effects equaling zero at each locus becomes a derivable consequence rather than an arbitrary constraint. More broadly, Fisher's distinction between correlation and causation is of critical importance to gene-trait mapping studies and the foundations of evolutionary biology. PMID- 23938114 TI - Enteral versus parenteral nutritional support in allogeneic haematopoietic stem cell transplantation. AB - BACKGROUND: Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) is associated with frequent and severe malnutrition, which may contribute to transplant-related morbidity. While both enteral nutrition (EN) via a nasogastric tube and parenteral nutrition (PN) are effective, it remains unclear what is the optimal method of nutritional support. AIMS: We propose to compare the impact of EN versus PN on early outcome after allo-HSCT. METHODS: We evaluated the effect of initial nutritional support with EN versus PN on early outcome in 56 patients who required nutritional support after first allo-HSCT for haematological malignancies in our centre. Patients were offered EN but could decline and chose to be treated by PN. RESULTS: Twenty patients received myeloablative conditioning and 36 received reduced-intensity conditioning. Twenty-eight patients received EN and 28 received PN. Compared with PN, EN was associated with a lower median duration of fever (2 versus 5 days; p < 0.01), a reduced need for empirical antifungal therapy (7 versus 17 patients; p < 0.01), a lower rate of central venous catheter replacement (9 versus 3 patients; p = 0.051) and a lower rate of transfer to intensive care (2 versus 8 patients; p = 0.036). The early death rate (<100 days) was the same in both groups (14%). CONCLUSIONS: Compared with PN, EN was associated with a lower risk of infection in allo-HSCT, without an increase in the incidence of graft-versus-host disease. PMID- 23938115 TI - Management of distal choroidal artery aneurysms in patients with moyamoya disease: report of three cases and review of the literature. AB - Prevention of rebleeding plays an important role in the treatment of hemorrhagic moyamoya disease, because rebleeding results in high mortality and morbidity. We discuss possible treatment for patients with moyamoya disease accompanied with distal choroidal artery aneurysms and review the literature to summarize clinical treatment and mechanisms. The cases of three male patients who suffered from intraventricular hemorrhage are presented. Computed tomography (CT) and digital subtractive angiography (DSA) revealed that bleeding was believed to be caused by ruptured aneurysms originating from distal choroidal artery aneurysms. Two patients successfully underwent superficial temporal artery (STA)-middle cerebral artery (MCA) bypass combined with encephalo-duro-myo-synangiosis (EDMS) and the obliteration of the aneurysm. The follow-up DSA or CT scan demonstrated that the aneurysms completely disappeared with the patency of the reconstructed artery. Neither of the patients experienced rebleeding during the follow-up period (up to 34 months). Given conservative treatment, the third patient experienced recurrent hemorrhages 4 months after the first ictus. This study describes treatment for moyamoya disease accompanied with distal choroidal artery aneurysms. Our experience suggests that cerebral revascularization combined with obliteration of the complicated distal aneurysm in the same session is a possible treatment. PMID- 23938116 TI - Whole genomic analyses of equine group A rotaviruses from Japan: evidence for bovine-to-equine interspecies transmission and reassortment events. AB - Equine group A rotaviruses (RVA) are a major cause of severe diarrhea in foals. The whole genomes of only six common and three unusual equine RVA strains have been analyzed so far. To date, there are no reports on whole genomic analyses of equine RVAs from Asian countries. We report here the whole genomic analyses of three common (strains RVA/Horse-tc/JPN/BI/1981/G3P[12], RVA/Horse-tc/JPN/HH 22/1989/G3P[12] and RVA/Horse-tc/JPN/CH-3/1987/G14P[12]) and an unusual (RVA/Horse-tc/JPN/OH-4/1982/G6P[5]) equine RVA strains isolated from diarrheic foals in Japan. Strains BI, HH-22 and CH-3 shared a largely conserved genotype constellation (G3/G14-P[12]-I2/I6-R2-C2-M3-A10-N2-T3-E2-H7) with each other and with those of common equine RVAs from other continents. Phylogenetically, most of the genes of BI, HH-22 and CH-3 were closely related to those of other common equine RVAs. On the other hand, the NSP2 genes of BI and CH-3 formed a distinct lineage, and were distantly related to the other, major equine RVA cluster within the NSP2-N2 genotype. The NSP4 gene of HH-22 appeared to originate from possible reassortment events involving common equine RVAs and co-circulating bovine or bovine-like equine RVAs, revealing the presence of a bovine RVA-like NSP4 gene on a typical equine RVA genetic backbone. All the 11 gene segments of the unusual equine RVA strain OH-4 were found to be more closely related to those of bovine and bovine-like human RVAs than to those of other RVAs, providing the first conclusive evidence for artiodactyl(likely bovine)-to-equine interspecies transmission events. Taken together, these observations provided important insights into the genetic diversity of equine RVAs. PMID- 23938117 TI - Evaluation of emergency department performance - a systematic review on recommended performance and quality-in-care measures. AB - BACKGROUND: Evaluation of emergency department (ED) performance remains a difficult task due to the lack of consensus on performance measures that reflects high quality, efficiency, and sustainability. AIM: To describe, map, and critically evaluate which performance measures that the published literature regard as being most relevant in assessing overall ED performance. METHODS: Following the PRISMA guidelines, a systematic literature review of review articles reporting accentuated ED performance measures was conducted in the databases of PubMed, Cochrane Library, and Web of Science. Study eligibility criteria includes: 1) the main purpose was to discuss, analyse, or promote performance measures best reflecting ED performance, 2) the article was a review article, and 3) the article reported macro-level performance measures, thus reflecting an overall departmental performance level. RESULTS: A number of articles addresses this study's objective (n = 14 of 46 unique hits). Time intervals and patient-related measures were dominant in the identified performance measures in review articles from US, UK, Sweden and Canada. Length of stay (LOS), time between patient arrival to initial clinical assessment, and time between patient arrivals to admission were highlighted by the majority of articles. Concurrently, "patients left without being seen" (LWBS), unplanned re attendance within a maximum of 72 hours, mortality/morbidity, and number of unintended incidents were the most highlighted performance measures that related directly to the patient. Performance measures related to employees were only stated in two of the 14 included articles. CONCLUSIONS: A total of 55 ED performance measures were identified. ED time intervals were the most recommended performance measures followed by patient centeredness and safety performance measures. ED employee related performance measures were rarely mentioned in the investigated literature. The study's results allow for advancement towards improved performance measurement and standardised assessment across EDs. PMID- 23938118 TI - Anaerobic digestion of seven different sewage sludges: a biodegradability and modelling study. AB - Seven mixed sewage sludges from different wastewater treatment plants, which have an anaerobic digester in operation, were evaluated in order to clarify the literature uncertainty with regard to the sewage sludge characterisation and biodegradability. Moreover, a methodology is provided to determine the Anaerobic Digestion Model No. 1 parameters, coefficients and initial state variables as well as a discussion about the accuracy of the first order solubilisation constant, which was obtained through biomethane potential test. The results of the biomethane potential tests showed ultimate methane potentials from 188 to 214 mL CH4 g(-1) CODfed, COD removals between 58 and 65% and two homogeneous groups for the first order solubilisation constant: (i) the lowest rate group from 0.23 to 0.35 day(-1) and (ii) the highest rate group from 0.27 to 0.43 day(-1). However, no statistically significant relationship between the ultimate methane potential or the disintegration constant and the sewage sludge characterisation was found. Next, a methodology based on the sludge characterisation before and after the biomethane potential test was developed to calculate the biodegradable fraction, the composite concentration and stoichiometric coefficients and the soluble COD of the sewage sludge; required parameters for the implementation of the Anaerobic Digestion Model No. 1. The comparison of the experimental and the simulation results proved the consistency of the developed methodology. Nevertheless, an underestimation of the first order solubilisation constant was detected when the experimental results were simulated with the solubilisation constant obtained from the linear regression experimental data fitting. The latter phenomenon could be related to the accumulation of intermediary compounds during the biomethane potential assay. PMID- 23938119 TI - In-situ caustic generation from sewage: the impact of caustic strength and sewage composition. AB - Periodic caustic dosage is a commonly used method by the water industry to elevate pH levels and deactivate sewer biofilms responsible for hydrogen sulfide generation. Caustic (NaOH) can be generated in-situ from sewage using a divided electrochemical cell, which avoids the need for transport, handling and storage of concentrated caustic solutions. In this study, we investigated the impact of caustic strength in the cathode compartment and the impact of sodium concentration in sewage on the Coulombic efficiency (CE) for caustic generation. The CE was found to be independent of the caustic strength produced in the range of up to ~3 wt%. Results showed that a caustic solution of ~3 wt% could be produced directly from sewage at a CE of up to 75 +/- 0.5%. The sodium concentration in sewage had a significant impact on the CE for caustic generation as well as on the energy requirements of the system, with a higher sodium concentration leading to a higher CE and lower energy consumption. The proton, calcium, magnesium and ammonium concentrations in sewage affected the CE for caustic generation, especially at low sodium concentrations. Economical assessment based on the experimental results indicated that sulfide control in sewers using electrochemically-generated caustic from sewage is an economically attractive strategy. PMID- 23938120 TI - Myopia and age-related cataract: a systematic review and meta-analysis. AB - PURPOSE: To examine if myopia is a risk factor for age-related cataract. DESIGN: Systematic review and meta-analysis. METHODS: A systematic review of the literature was performed using PubMed and Embase from their inception to March 2013 for population-based studies with data on myopia and age-related cataract, including nuclear, cortical, and posterior subcapsular (PSC) cataract. Separate meta-analyses for case-control/cross-sectional studies and cohort studies were conducted using random-effects models, with results reported as adjusted odds ratios (ORs) and relative risks (RRs), respectively. RESULTS: A total of 38 007 subjects aged 30-97 years from 12 population-based studies were included in the meta-analysis. Meta-analysis of the 7 cross-sectional studies and 1 case-control study confirmed that myopia was associated with increasingly prevalent nuclear (pooled OR 2.81, 95% CI 1.94-4.06) and PSC cataract (pooled OR 1.93, 95% CI 1.49 2.49) but not with cortical cataract (pooled OR 1.08, 95% CI 0.90-1.30). Meta analysis from 3 or 4 cohort studies showed nonsignificant associations of myopia with incident nuclear (pooled RR 1.25, 95% CI 0.71-2.21), cortical (pooled RR 1.21, 95% CI 0.67-2.19), and PSC cataract (pooled RR 1.26, 95% CI 0.92-1.74). CONCLUSIONS: The associations of myopia with prevalent nuclear and PSC cataract are confirmed in meta-analysis of 8 study findings. The association of myopia with incidence of age-related cataract could not be confirmed in meta-analysis of 4 study findings. PMID- 23938122 TI - Long-term stability of vascular endothelial growth factor suppression time under ranibizumab treatment in age-related macular degeneration. AB - PURPOSE: To determine intra-individual long-term stability of vascular endothelial growth factor (VEGF) suppression time in eyes with neovascular age related macular degeneration (AMD) treated with ranibizumab. DESIGN: Nonrandomized, prospective clinical study. METHODS: Eighty-three eyes of 83 patients with neovascular AMD undergoing intravitreal ranibizumab injections were included in the study. A total of 859 aqueous humor specimens were taken before each intravitreal ranibizumab injection. Vascular endothelial growth factor A was measured by multiplex bead analysis. RESULTS: Ranibizumab resulted in complete VEGF suppression within a mean period of 36.4 days (standard deviation +/-6.7 days; range, 26-69 days). Intra-individual suppression time was stable within a period of up to 3 years. Among 859 VEGF measurements, only 5 (0.58%) deviated from this pattern. Nonsuppressed VEGF levels did not differ significantly between baseline and recurrence (68.0 pg/mL vs 69.3 pg/mL) and did not correlate with choroidal neovascularization size and lesion type. CONCLUSIONS: Both the long term stability and the broad range of individual suppression times after ranibizumab injections would allow and justify adjustment of continuous injections individually in order to achieve permanent VEGF suppression in patients. PMID- 23938123 TI - Canaliculops: clinicopathologic features and treatment with marsupialization. AB - PURPOSE: To report the features of the rare and under-recognized condition of canaliculops (or canaliculocele) of the eyelid, which is a dilation of the canaliculus, and to evaluate treatment with marsupialization. DESIGN: Retrospective interventional case series. METHODS: The records of 2 patients with canaliculops from the Massachusetts Eye and Ear Infirmary were reviewed. Data collected included clinical history, surgical technique, histopathologic analysis, and comparative immunohistochemical analysis of a range of cytokeratins in normal conjunctival epithelium, normal canalicular epithelium, and canaliculops epithelium. RESULTS: Two women, 53 and 66 years of age, experienced chronic, noninflammatory, painless medial eyelid and eyelid margin fluctuant swelling after earlier trauma or eyelid surgery. The external mass was accompanied by a whitish opalescent or bluish discoloration of a palpebral surface bulge. Biopsy revealed multilaminar (up to 12 cells thick), nonkeratinizing, tightly packed small squamous epithelial cells that surmounted a highly regimented basal layer with a picket fence arrangement. No goblet cells or subepithelial inflammation were present. Immunohistochemistry revealed only superficial CK7 immunostaining and positive patchy suprabasilar CK17 staining in the canaliculops epithelium, contrasting with their full-thickness positivity and negativity, respectively, in normal conjunctival epithelium. Marsupialization achieved resolution of the condition in each patient. CONCLUSIONS: An improved awareness of the normal canalicular epithelial structure and its immunohistochemical features can definitively separate canaliculops from conjunctival cysts. Previous treatment of canaliculops has involved complete excisions. Canaliculops may, however, be effectively treated with less invasive marsupialization while obtaining an adequate biopsy specimen for histopathologic diagnosis. PMID- 23938124 TI - Postoperative optical coherence tomographic appearance and relation to visual acuity after vitrectomy for myopic foveoschisis. AB - PURPOSE: To investigate the appearance of postoperative spectral-domain optical coherence tomography (SD-OCT) and the relationship of the findings to visual acuity in myopic foveoschisis. DESIGN: Retrospective observational case series. METHODS: We studied 17 eyes (17 women; mean age, 66.4 years) with myopic foveoschisis. SD-OCT was performed preoperatively and 1, 3, 6, and 12 months after vitrectomy. The average central foveal thickness and choroidal thickness and the integrity of the foveal photoreceptor inner segment/outer segment junction as well as the external limiting membrane were correlated with the postoperative best-corrected visual acuity (BCVA). RESULTS: The mean refractive error was -11.9 diopters, axial length 29.7 mm, choroidal thickness 29.9 MUm, and logarithm of the maximum angle of resolution (logMAR) visual acuity 0.52 at baseline. The mean preoperative central foveal thickness was 470.8 MUm, which was not associated with age, refractive error, symptom duration, or BCVA. The mean postoperative retinal thicknesses at 1, 3, 6, and 12 months were 310.4, 251.8, 218.2, and 218.7 MUm, respectively (P < 0.01 at all time points). The final BCVA improved significantly (P < 0.001). The preoperative BCVA (P < 0.0001) difference in central foveal thickness between 3 and 12 months postoperatively (P < 0.05), the final integrity of the inner segment/outer segment junction (P < 0.05), and the ELM (P < 0.05) were significantly associated with the final BCVA. The preoperative choroidal thickness was negatively associated with axial length (P < 0.05) but not with postoperative central foveal thickness or BCVA. CONCLUSIONS: The final BCVA in myopic foveoschisis is associated with the retinal thickness changes postoperatively and recovery of the photoreceptor cells as seen in OCT images. PMID- 23938121 TI - Associations of candidate genes to age-related macular degeneration among racial/ethnic groups in the multi-ethnic study of atherosclerosis. AB - PURPOSE: To describe the relationships of selected candidate genes to the prevalence of early age-related macular degeneration (AMD) in a cohort of whites, blacks, Hispanics, and Chinese Americans. DESIGN: Cross-sectional study. METHODS: setting: Multicenter study. study population: A total of 2456 persons aged 45-84 years with genotype information and fundus photographs. procedures: Twelve of 2862 single nucleotide polymorphisms (SNPs) from 11 of 233 candidate genes for cardiovascular disease were selected for analysis based on screening with marginal unadjusted P value <.001 within 1 or more racial/ethnic groups. Logistic regression models tested for association in case-control samples. main outcome measure: Prevalence of early AMD. RESULTS: Early AMD was present in 4.0% of the cohort and varied from 2.4% in blacks to 6.0% in whites. The odds ratio increased from 2.3 for 1 to 10.0 for 4 risk alleles in a joint effect analysis of Age Related Maculopathy Susceptibility 2 rs10490924 and Complement Factor H Y402H (P for trend = 4.2*10(-7)). Frequencies of each SNP varied among the racial/ethnic groups. Adjusting for age and other factors, few statistically significant associations of the 12 SNPs with AMD were consistent across all groups. In a multivariate model, most candidate genes did not attenuate the comparatively higher odds of AMD in whites. The higher frequency of risk alleles for several SNPs in Chinese Americans may partially explain their AMD frequency's approaching that of whites. CONCLUSIONS: The relationships of 11 candidate genes to early AMD varied among 4 racial/ethnic groups, and partially explained the observed variations in early AMD prevalence among them. PMID- 23938125 TI - Correlation between corneal and scleral pneumatonometry: an alternative method for intraocular pressure measurement. AB - PURPOSE: To evaluate scleral pneumatonometry as an alternative method for measuring intraocular pressure (IOP). DESIGN: Prospective cross-sectional study. METHODS: Adult subjects with healthy eyes were recruited from the Comprehensive Eye Service at the University of Illinois Eye and Ear Infirmary from August 2008 through February 2009. Study measurements included corneal pneumatonometry (IOPk), scleral pneumatonometry (IOPs), axial length (AL), spherical equivalent (SE), and central corneal thickness (CCT). Main outcome measures were scleral IOP and corneal IOP. RESULTS: Analysis included a monocular data set from single eyes of 97 subjects (age: 18-82 years). IOPs was consistently higher than IOPk, and correlated positively with IOPk (r = 0.57, P < .0001), age (r = 0.51, P < .0001), and SE (r = 0.32, P = .0002). The difference between scleral and corneal IOP (IOPs - IOPk) correlated positively with IOPs (r = 0.89, P < .0001), age (r = 0.57, P < .0001), and SE (r = 0.34, P < 0.0001). Bland-Altman analysis for agreement between scleral and corneal pneumatonometry measurements showed a mean difference of 8.08 mm Hg, with the 95% limit of agreement between -3.47 and 19.64 mm Hg. Regression analysis yielded the following equation: IOPk = 11.9 + 0.32(IOPs) - 0.05(Age). CONCLUSIONS: Scleral pneumatonometry correlates positively with corneal pneumatonometry and is more accurate at lower values and in younger patients. When adjusted for age, scleral pneumatonometry may be an adequate alternative in situations where corneal measurements are impractical. PMID- 23938126 TI - Anterior segment optical coherence tomography of long-term phakic angle-supported intraocular lenses. AB - PURPOSE: To evaluate the long-term age-related anterior chamber changes by anterior segment optical coherence tomography (OCT) and the impact of such changes on the stability and behavior of angle-supported phakic intraocular lenses (IOLs). DESIGN: A retrospective consecutive observational cohort study. METHODS: A total of 23 eyes with high myopia implanted with an angle-supported phakic IOL between 1990 and 1996 at Vissum Corporacion Oftalmologica de Alicante were included in the study. Patients were evaluated using OCT. Anterior chamber depth, anterior chamber width, crystalline lens rise, and the distance between phakic IOL and endothelium were measured. RESULTS: Fifteen years after implantation, anterior chamber depth was 2.9 +/- 0.3 mm, crystalline lens rise 748.18 +/- 393.13 MUm, and phakic IOL-endothelium distance 2.1 +/- 0.30 mm. The predictive model showed that 30 years after implantation, endothelial cell count was less than 600 cells/mm(2) in patients with a preoperative spherical equivalent of -25 diopters (D). Twenty years after implantation, the safety zone of 1.5 mm between endothelium and the lens will not be respected in patients with a preoperative spherical equivalent of -20 D. CONCLUSIONS: The findings of this study could have an important influence on the decision about the indication to implant angle-supported phakic IOLs in young patients with a long postoperative life expectancy, as age-related changes in the anatomy of the anterior segment may create a long-term hazard for the implanted eye. PMID- 23938127 TI - Prevalence and characteristics of age-related macular degeneration in the Japanese population: the Nagahama study. AB - PURPOSE: To estimate the age- and sex-specific prevalence of early age-related macular degeneration (AMD; drusen and retinal pigment abnormalities) and late AMD (exudative AMD and geographic atrophy) in the Japanese population. DESIGN: Community-based, cross-sectional study. METHODS: The study was held in Nagahama, Japan, and included 6065 Japanese individuals (aged >=50 years) recruited in 2008 2010. We graded fundus photographs of both eyes for the AMD phenotype based on drusen size, the presence of retinal pigment abnormalities, and late AMD. The associations between smoking and AMD phenotypes were also evaluated. RESULTS: We assessed 5595 subjects (women, 65%) with a gradable macular condition. Early and late AMD prevalence increased from 16.1% and 0.27% at 50-59 years to 31.2% and 0.98%, respectively, at 70-74 years and was predominant in male subjects in each age group. Smoking was associated with both early and late AMD stages and retinal pigment abnormalities (P < .0001), but not with drusen (P = .305). The prevalence of retinal pigment abnormalities was significantly higher in men (P < .0001), which was associated with high rates of cigarette smoking. We found no sex difference for the prevalence of large drusen (P = .264). CONCLUSIONS: The prevalence of early AMD among adult Japanese persons was similar to the rates in white populations. The prevalence of late AMD in Japanese people aged <70 years was similar to that observed in white populations, whereas that in Japanese people aged >=70 years was relatively lower. PMID- 23938128 TI - Losing independence--the lived experience of being long-term sick-listed. AB - BACKGROUND: Sickness absence is a multifaceted problem. Much is known about risk factors for being long-term sick-listed, but there is still little known about the various aftermaths and experiences of it. The aim of this qualitative study was to describe, analyze and understand long-term sickness-absent people's experiences of being sick-listed. METHODS: The design was descriptive and had a phenomenological approach. Sixteen long-term sickness-absent individuals were purposively sampled from three municipalities in Sweden in 2011, and data were collected through semi-structured, individual interviews. The interview questions addressed how the participants experienced being sick-listed and how the sick listing affected their lives. Transcribed interviews were analysed using Giorgi's phenomenological method. RESULTS: The interviews revealed that the participants' experiences of being sick-listed was that they lost their independence in the process of stepping out of working society, attending the mandatory steps in the rehabilitation chain and having numerous encounters with professionals. The participants described that their life-worlds were radically changed when they became sick-listed. Their experiences of their changing life-worlds were mostly highly negative, but there were also a few positive experiences. The most conspicuous findings were the fact that stopping working brought with it so many changes, the participants' feelings of powerlessness in the process, and their experiences of offensive treatment by and/or encounters with professionals. CONCLUSIONS: Sick-listed persons experienced the process of being on long-term sickness absent as very negative. The negative experiences are linked to consequences of stopping to work, consequences of social insurance rules and to negative encounters with professionals handling the sickness absence. The positive experiences of being sick-listed were few in the present study. There is a need to further examine the extent of these negative experiences are and how they affect sick-listed people's recovery and return to work. Long-term sickness absence; sick leave; experiences; interviews; phenomenology; Sweden. PMID- 23938129 TI - Cultural humility: essential foundation for clinical researchers. AB - Cultural humility is a process of self-reflection and discovery in order to build honest and trustworthy relationships. It offers promise for researchers to understand and eliminate health disparities, a continual and disturbing problem necessitating attention and action on many levels. This paper presents a discussion of the process of cultural humility and its important role in research to better understand the perspectives and context of the researcher and the research participant. We discern cultural humility from similar concepts, specifically cultural competence and reflexivity. We will also explore ways to cultivate cultural humility in the context of human subjects research. Mindfulness is one approach that can be helpful in enhancing awareness of self and others in this process. With a foundation in cultural humility, nurse researchers and other investigators can implement meaningful and ethical projects to better address health disparities. PMID- 23938130 TI - Improving access to care in low and middle-income countries: institutional factors related to enrollment and patient outcome in a cancer drug access program. AB - BACKGROUND: Limited access to drugs is a crucial barrier to reducing the growing impact of cancer in low- and middle-income countries. Approaches based on drug donations or adaptive pricing strategies yield promising but varying results across countries or programs, The Glivec International Patient Assistance Program (GIPAP) is a program designed to provide imatinib free of charge to patients with chronic myeloid leukemia (CML) or gastrointestinal stromal tumors (GIST). The objective of this work was to identify institutional factors associated with enrollment and patient survival in GIPAP. METHODS: We analyzed follow-up data from 4,946 patients participating in 47 institutions within 44 countries between 2003 and 2010. Active status in the program was considered as a proxy for survival. RESULTS: Presence of >=1 hematologist or oncologist at the institution was associated with increased patient enrollment. After adjusting for individual factors such as age (>55 years: Hazard Ratio [HR] = 1.42 [1.16; 1.73]; p = 0.001) and initial stage of disease (accelerated or blast crisis at diagnosis: HR = 4.16 [1.87; 9.25]; p < 10-4), increased survival was found in institutions with research capabilities (HR = 0.55 [0.35; 0.86]; p = 0.01) and those with enrollment of >5 patients/year into GIPAP (HR = 0.48 [0.35; 0.67]; p < 10-4), while a non-significant trend for decreased survival was found for treatment at a public institution (HR = 1.32 [0.95; 1.84]; p = 0.10). The negative impact of an accelerated form of CML was attenuated by the presence of >=1 hematologist or oncologist at the institution (interaction term HR = 0.43 [0.18; 0.99]; p = 0.05). CONCLUSIONS: Application of these findings to the support and selection of institutions participating in GIPAP may help to optimize care and outcomes for CML and GIST patients in the developing world. These results may also be applicable to the treatment of patients with other forms of cancer, due to the overlap of infrastructure and staff resources used to treat a variety of cancer indications. A multi-sector approach is required to address these barriers. PMID- 23938131 TI - Simultaneous model discrimination and parameter estimation in dynamic models of cellular systems. AB - BACKGROUND: Model development is a key task in systems biology, which typically starts from an initial model candidate and, involving an iterative cycle of hypotheses-driven model modifications, leads to new experimentation and subsequent model identification steps. The final product of this cycle is a satisfactory refined model of the biological phenomena under study. During such iterative model development, researchers frequently propose a set of model candidates from which the best alternative must be selected. Here we consider this problem of model selection and formulate it as a simultaneous model selection and parameter identification problem. More precisely, we consider a general mixed-integer nonlinear programming (MINLP) formulation for model selection and identification, with emphasis on dynamic models consisting of sets of either ODEs (ordinary differential equations) or DAEs (differential algebraic equations). RESULTS: We solved the MINLP formulation for model selection and identification using an algorithm based on Scatter Search (SS). We illustrate the capabilities and efficiency of the proposed strategy with a case study considering the KdpD/KdpE system regulating potassium homeostasis in Escherichia coli. The proposed approach resulted in a final model that presents a better fit to the in silico generated experimental data. CONCLUSIONS: The presented MINLP based optimization approach for nested-model selection and identification is a powerful methodology for model development in systems biology. This strategy can be used to perform model selection and parameter estimation in one single step, thus greatly reducing the number of experiments and computations of traditional modeling approaches. PMID- 23938133 TI - Measuring depressive symptoms using the Patient Health Questionnaire-9 in Hong Kong Chinese subjects with type 2 diabetes. AB - BACKGROUND: Depression is common in type 2 diabetes although the prevalence in Chinese patients remains unclear. We validated the Patient Health Questionnaire(PHQ-9), a popular depression screening tool, in Chinese with type 2 diabetes, and documented the prevalence, demographic,and clinical characteristics associated with depression. METHODS: A consecutive cohort of 586 Hong Kong Chinese outpatients completed the PHQ-9 during comprehensive diabetes complication assessment. Within 2-4 weeks, 40 patients were retested via telephone survey. Ninety-nine randomly selected patients were interviewed by psychiatrists using the Mini International Neuropsychiatric Interview as a golden standard. Receiver operating characteristic curve was used to assess performance of the PHQ-9. RESULTS: The internal consistency of the PHQ-9 was 0.86 and test retest reliability was 0.70. The 3 somatic items explained 53.6% of the PHQ-9 score. The optimal cutoff value was 7 with 82.6% sensitivity and 73.7% specificity, giving a depression prevalence of 18.3% (n=107). Of these, 18.7% had been previously diagnosed with depression. Depression was more prevalent in women than men. After controlling for confounders, patients with depression had higher HbA1c (7.80 +/- 1.86% versus 7.43 +/- 1.29%, [61.7 +/- 20.4 versus 57.8 +/- 14.1 mmol/mol], P<0.05), reduced likelihood of achieving HbA1c target of <7.0% (33.6% versus 41.8%, P<0.05), and were more likely to have self-reported hypoglycemia in the previous 3 months (18.7% versus 6.7%, P<0.01). LIMITATION: A small sample was used in the criterion validation and the cross-sectional design precludes causal inference. CONCLUSIONS: PHQ-9 is a validated tool for screening for depression, which is common and frequently undiagnosed in Chinese type 2 diabetic patients and is associated with suboptimal glycemic control, hypoglycemia, and somatization. PMID- 23938132 TI - Metabolic actions of Rho-kinase in periphery and brain. AB - Obesity has increased at an alarming rate in recent years and is now a worldwide public health problem. Elucidating the mechanisms behind the metabolic dysfunctions associated with obesity is of high priority. The metabolic function of Rho-kinase (Rho-associated coiled-coil-containing kinase; ROCK) has been the subject of a great deal of investigation in metabolic-related diseases. It appears that inhibition of ROCK activity is beneficial for the treatment of a wide range of cardiovascular-related diseases. However, recent studies with genetic models of ROCK demonstrate that ROCK plays a positive role in insulin and leptin signaling. Here we discuss the newly identified functions of ROCK in regulating glucose and energy metabolism, with particular emphasis on metabolic actions of insulin and leptin. PMID- 23938134 TI - Thalamic volume and related visual recognition are associated with freezing of gait in non-demented patients with Parkinson's disease. AB - BACKGROUND: The pathophysiology of freezing of gait (FOG) in non-demented Parkinson's disease (PD) patients remains poorly understood. Recent studies have suggested that neurochemical alterations in the cholinergic systems play a role in the development of FOG. Here, we evaluated the association between subcortical cholinergic structures and FOG in patients with non-demented PD. METHODS: We recruited 46 non-demented patients with PD, categorized into PD with (n = 16) and without FOG (n = 30) groups. We performed neuropsychological test, region-of interest-based volumetric analysis of the substantia innominata (SI) and automatic analysis of subcortical brain structures using a computerized segmentation procedure. RESULTS: The comprehensive neuropsychological assessment showed that PD patients with FOG had lower cognitive performance in the frontal executive and visual-related functions compared with those without freezing of gait. The normalized SI volume did not differ significantly between the two groups (1.65 +/- 0.18 vs. 1.68 +/- 0.31). The automatic analysis of subcortical structures revealed that the thalamic volumes were significantly reduced in PD patients with FOG compared with those without FOG after adjusting for age, sex, disease duration, the Unified PD Rating Scale scores and total intracranial volume (left: 6.71 vs. 7.16 cm3, p = 0.029, right: 6.47 vs. 6.91 cm3, p = 0.026). Multiple linear regression analysis revealed that thalamic volume showed significant positive correlations with visual recognition memory (left: beta = 0.441, p = 0.037, right: beta = 0.498, p = 0.04). CONCLUSIONS: These data suggest that thalamic volume and related visual recognition, rather than the cortical cholinergic system arising from the SI, may be a major contributor to the development of freezing of gait in non-demented patients with PD. PMID- 23938135 TI - Survival in esophageal high-grade dysplasia/adenocarcinoma post endoscopic resection. AB - BACKGROUND: Endoscopic resection followed by ablative therapy is frequently used to treat esophageal high-grade dysplasia or early esophageal adenocarcinoma. AIMS: To study outcomes in patients with high-grade dysplasia compared to those with esophageal adenocarcinoma after endoscopic resection. METHODS: Retrospective, observational, descriptive, single-centre study from a prospective database. We extracted data from 116 endoscopic resections. Survival was plotted using Kaplan-Meier curves multivariable Cox-proportional hazard assess for possible predictors of survival post-endoscopic resection was performed. RESULTS: 116 patients (64 esophageal adenocarcinoma, 52 high-grade dysplasia) underwent endoscopic resection from May 2003 to June 2010. Mean age was 71 +/- 11 years for high-grade dysplasia and 72 +/- 10 years for esophageal adenocarcinoma. Median follow-up was 17 months. Eighty-five patients had negative margins on endoscopic resection. Five-year survivals for high-grade dysplasia and esophageal adenocarcinoma were 86% (range 68-100%) and 78% (59-96%), respectively. Survival was not significantly different between groups (p=0.20). Overall mortality rate was 10.6% (9/85). At multivariable Cox regression increased Barrett's oesophagus length was associated with worse survival (HR 1.18 [1.06-1.33], p=0.0039). Survival was not affected by the pathology before resection: HR 2.4 [95%CI, 0.70 8.4], p=0.16. CONCLUSIONS: Survival in patients with high-grade dysplasia of the oesophagus is similar to those with esophageal adenocarcinoma. Longer Barrett's oesophagus segments are associated with decreased survival. PMID- 23938136 TI - The effect of vibrotactile feedback on postural sway during locomotor activities. AB - BACKGROUND: Although significant progress has been achieved in developing sensory augmentation methods to improve standing balance, attempts to extend this research to locomotion have been quite limited in scope. The goal of this study was to characterize the effects of two real-time feedback displays on locomotor performance during four gait-based tasks ranging in difficulty. METHODS: Seven subjects with vestibular deficits used a trunk-based vibrotactile feedback system that provided real-time feedback regarding their medial-lateral (M/L) trunk tilt when they exceeded a subject-specific predefined tilt threshold during slow and self-paced walking, walking along a narrow walkway, and walking on a foam surface. Two feedback display configurations were evaluated: the continuous display provided real-time continuous feedback of trunk tilt, and the gated display provided feedback for 200 ms during the period immediately following heel strike. The root-mean-square (RMS) trunk tilt and percentage of time below the tilt thresholds were calculated for all locomotor tasks. RESULTS: Use of continuous feedback resulted in significant decreases in M/L trunk tilt and increases in percentage times below the tilt thresholds during narrow and foam trials. The gated display produced generally smaller changes. CONCLUSIONS: This preliminary study demonstrated that use of continuous vibrotactile feedback during challenging locomotor tasks allowed subjects with vestibular deficits to significantly decrease M/L RMS trunk tilt. Analysis of the results also showed that continuous feedback was superior. PMID- 23938137 TI - Osteosarcoma metastasis causing ileo-ileal intussusception. AB - Osteosarcoma metastasis causing intussusception is a very rare entity, with a pejorative prognosis. Based on a case, we performed a literature review in order to better assess this situation. We conclude that, in patients with a history of osteosarcoma lung metastasis, echographic and/or computed tomography scan evidence of a small bowel obstruction with intussusception should lead to an open surgical procedure if the laparoscopic approach does not allow to accurately explore and resect the lesion, in order to prevent misdiagnosis and to avoid further delay in the management. PMID- 23938138 TI - Antiarrhythmia drugs for cardiac arrest: a systemic review and meta-analysis. AB - INTRODUCTION: Antiarrhythmia agents have been used in the treatment of cardiac arrest, and we aimed to review the relevant clinical controlled trials to assess the effects of antiarrhythmics during cardiopulmonary resuscitation. METHODS: We searched databases including Cochrane Central Register of Controlled Trials; MEDLINE, and EMBASE. Clinical controlled trials that addressed the effects of antiarrhythmics (including amiodarone, lidocaine, magnesium, and other new potassium-channel blockers) on the outcomes of cardiac arrest were included. Data were collected independently by two authors. The risk ratio of each outcome was collected, and meta-analysis was used for data synthesis if appropriate. Heterogeneity was assessed with the chi2 test and the I2 test. RESULTS: Ten randomized controlled trials and seven observational trials were identified. Amiodarone (relative risk (RR), 0.82; 95% confidence interval (CI), 0.54 to 1.24), lidocaine (RR, 2.26; 95% CI, 0.93 to 5.52), magnesium (RR, 0.82; 95% CI, 0.54 to 1.24) and nifekalant were not shown to improve the survival to hospital discharge compared with placebo, but amiodarone, lidocaine, and nifekalant were shown to be beneficial to initial resuscitation, assessed by the rate of return of spontaneous circulation and survival to hospital admission, with amiodarone being superior to lidocaine (RR, 1.28; 95% CI, 0.57 to 2.86) and nifekalant (RR, 0.50; 95% CI, 0.19 to 1.31). Bretylium and sotalol were not shown to be beneficial. CONCLUSIONS: Our review suggests that when administered during resuscitation, antiarrhythmia agents might not improve the survival to hospital discharge, but they might be beneficial to initial resuscitation. This is consistent with the AHA 2010 guidelines for resuscitation and cardiovascular emergency, but more studies with good methodologic quality and large numbers of patients are still needed to make further assessment. PMID- 23938139 TI - Frequency and imaging findings of variations in human aortic arch anatomy based on multidetector computed tomography data. AB - The purpose of this study was to describe the frequency of the variations in the branching pattern of the aortic arch (AA) according to multidetector computed tomography (MDCT) imaging findings. MDCT images of 1136 consecutive patients who had undergone imaging of the chest were retrospectively examined. Eleven different branching patterns were observed. A left-sided AA with three major branches was seen in 74.4% of the patients. Bovine-type AA (21.1%) and independent origin of the left vertebral artery (3.7%) were the next two most common patterns. PMID- 23938140 TI - Sonographic findings of an ovarian serous surface papillary borderline tumor. AB - Sonographic findings of a serous surface papillary borderline tumor of the ovary have rarely been reported in the English literature. Here, we describe a case of serous surface papillary borderline tumor, which was depicted on gray-scale and Doppler ultrasonography as smoothly lobulated and polypoid heterogeneous echoic bilateral adnexal masses encased or surrounded by what was presumed to be normal appearing ovarian follicles with increased vascular flow. PMID- 23938141 TI - PET and PET-CT imaging findings of peritoneal and omental involvement in patients with lymphoma. AB - A retrospective institutional-review-board-approved study was performed evaluating positron emission tomography (PET)-computed tomography (CT) imaging findings of peritoneal and omental involvement of lymphoma. Twelve patients were identified with a wide spectrum of imaging findings on PET-CT including but not limited to peritoneal thickening, ascites, and serosal involvement. Lymphoma is among the rare causes of malignant peritoneal or omental involvement. The most common manifestations of peritoneal lymphomatosis are peritoneal 2-[fluorine 18] fluoro-2-deoxy-D-glucose uptake with corresponding peritoneal thickening and nonobstructive serosal masses on CT. PMID- 23938142 TI - Multidetector computed tomography findings of the sternoclavicular joint in patients with rheumatoid arthritis. AB - We evaluated the multidetector computed tomography (MDCT) findings of the sternoclavicular joint in patients with rheumatoid arthritis (RA) and compare them with general population. Chest MDCT scans of RA patients were reviewed. The control group was formed from age and sex-matched individuals. The most common CT findings were cortical irregularity, joint space narrowing, and osteophytes in study group. There were no statistically significant differences in the MDCT findings between the two groups except that osteophytes were observed more often in the control group. It is difficult to distinguish between the involvement of RA and age-related degenerative changes at the sternoclavicular joint. PMID- 23938143 TI - Demonstrating compliance with protection objectives for non-human biota within post-closure safety cases for radioactive waste repositories. AB - Over recent years, a number of approaches have been developed that enable the calculation of dose rates to animals and plants following the release of radioactivity to the environment. These approaches can be used to assess the potential impacts of activities that may release radioactivity to the environment, such as the operation of waste repositories. A number of national and international studies have identified screening criteria to indicate those assessment results below which further consideration is not generally required. However no internationally agreed criteria are currently available and consistency in criteria between countries has not been achieved. Furthermore, since screening criteria are not intended to be applied as limits, it is clear that they cannot always form a sufficient basis for assessing the adequacy of protection afforded. Typically, exceeding a screening value leads to a regulatory requirement to undertake a further, more detailed assessment. It does not, per se, imply that there is inadequate protection of the organism types at the specific site under assessment. Therefore, there is a need to develop a more structured approach to dealing with situations in which current screening criteria are exceeded. As a contribution to the developing international discussions, and as an interim measure for application where assessments are required currently, a two-tier, three zone framework is proposed here, relevant to the long term assessment of potential impacts from the deep disposal of radioactive wastes. The purpose of the proposed framework is to promote a proportionate and risk-based approach to the level of effort required in undertaking and interpreting an assessment. PMID- 23938144 TI - Bioefficacy of acyclic monoterpenes and their saturated derivatives against the West Nile vector Culex pipiens. AB - Twenty acyclic monoterpenes with different functional groups (acetoxy, hydroxyl, carbonyl and carboxyl) bearing a variable number of carbon double bonds were assayed as repellent and larvicidal agents against the West Nile vector Culex pipiens. Seven of them were derivatives that were synthesized through either hydrogenation or oxidation procedures. All repellent compounds were tested at the dose of 1mgcm(-2) and only neral and geranial were also tested at a 4-fold lower dose (0.25mgcm(-2)). Repellency results revealed that geranial, neral, nerol, citronellol, geranyl acetate and three more derivatives dihydrolinalool (3), dihydrocitronellol (5) and dihydrocitronellyl acetate (6) resulted in no landings. Based on the LC50 values the derivative dihydrocitronellyl acetate (6) was the most active of all, resulting in an LC50 value of 17.9mgL(-1). Linalyl acetate, citronellyl acetate, neryl acetate, geranyl acetate, dihydrocitronellol (5), dihydrocitronellal (7), citronellol, dihydrolinalyl acetate (2), citronellic acid and tetrahydrolinalyl acetate (1) were also toxic with LC50 values ranging from 23 to 45mgL(-1). Factors modulating toxicity have been identified, thus providing information on structural requirements for the selected acyclic monoterpenes. The acetoxy group enhanced toxicity, without being significantly affected by the unsaturation degree. Within esters, reduction of the vinyl group appears to decrease potency. Presence of a hydroxyl or carbonyl group resulted in increased activity but only in correlation to saturation degree. Branched alcohols proved ineffective compared to the corresponding linear isomers. Finally, as it concerns acids, data do not allow generalizations or correlations to be made. PMID- 23938145 TI - Equipment to prevent, diagnose, and treat hypothermia: a survey of Norwegian pre hospital services. AB - INTRODUCTION: Hypothermia is associated with increased morbidity and mortality in trauma patients and poses a challenge in pre-hospital treatment. The aim of this study was to identify equipment to prevent, diagnose, and treat hypothermia in Norwegian pre-hospital services. METHOD: In the period of April-August 2011, we conducted a survey of 42 respondents representing a total of 543 pre-hospital units, which included all the national ground ambulance services, the fixed wing and helicopter air ambulance service, and the national search and rescue service. The survey explored available insulation materials, active warming devices, and the presence of protocols describing wrapping methods, temperature monitoring, and the use of warm i.v. fluids. RESULTS: Throughout the services, hospital duvets, cotton blankets and plastic "bubble-wrap" were the most common insulation materials. Active warming devices were to a small degree available in vehicle ambulances (14%) and the fixed wing ambulance service (44%) but were more common in the helicopter services (58-70%). Suitable thermometers for diagnosing hypothermia were lacking in the vehicle ambulance services (12%). Protocols describing how to insulate patients were present for 73% of vehicle ambulances and 70% of Search and Rescue helicopters. The minority of Helicopter Emergency Medical Services (42%) and Fixed Wing (22%) units was reported to have such protocols. CONCLUSION: The most common equipment types to treat and prevent hypothermia in Norwegian pre-hospital services are duvets, plastic "bubble wrap", and cotton blankets. Active external heating devices and suitable thermometers are not available in most vehicle ambulance units. PMID- 23938146 TI - Hereditary lissencephaly and cerebellar hypoplasia in Churra lambs. AB - BACKGROUND: Lissencephaly is a rare developmental brain disorder in veterinary and human medicine associated with defects in neuronal migration leading to a characteristic marked reduction or absence of the convolutional pattern of the cerebral hemispheres. In many human cases the disease has a genetic basis. In sheep, brain malformations, mainly cerebellar hypoplasia and forms of hydrocephalus, are frequently due to in utero viral infections. Although breed related malformations of the brain have been described in sheep, breed-related lissencephaly has not been previously recorded in a peer reviewed publication. RESULTS: Here we report neuropathological findings in 42 newborn lambs from a pure Churra breed flock, with clinical signs of weakness, inability to walk, difficulty in sucking and muscular rigidity observed immediately after birth. All the lambs showed near-total agyria with only a rudimentary formation of few sulci and gyri, and a severe cerebellar hypoplasia. On coronal section, the cerebral grey matter was markedly thicker than that of age-matched unaffected lambs and the ventricular system was moderately dilated. Histologically, the normal layers of the cerebral cortex were disorganized and, using an immunohistochemical technique against neurofilaments, three layers were identified instead of the six present in normal brains. The hippocampus was also markedly disorganised and the number and size of lobules were reduced in the cerebellum. Heterotopic neurons were present in different areas of the white matter. The remainder of the brain structures appeared normal. The pathological features reported are consistent with the type LCH-b (lissencephaly with cerebellar hypoplasia group b) defined in human medicine. No involvement of pestivirus or bluetongue virus was detected by immunohistochemistry. An analysis of pedigree data was consistent with a monogenic autosomal recessive pattern inheritance. CONCLUSIONS: The study describes the clinical and pathological findings of lissencephaly with cerebellar hypoplasia in Churra lambs for which an autosomal recessive inheritance was the most likely cause. Histopathological features observed in the cerebral cortex and hippocampus are consistent with a possible failure in neuronal migration during brain development. This report suggests that lissencephaly should be considered in the differential diagnosis of congenital neurological disease in newborn lambs showing weakness, inability to walk and difficulty sucking. PMID- 23938147 TI - Prostatitis and male infertility. AB - The prostate gland plays an important role in male reproduction. Inflammation of the prostate gland (prostatitis) is a common health problem affecting many young and middle aged men. Prostatitis is considered a correctable cause of male infertility, but the pathophysiology and appropriate treatment options of prostatitis in male infertility remain unclear. This literature review will focus on current data regarding prostatitis and its impact on male infertility. PMID- 23938148 TI - Risk factors of suicidal ideation and attempt in women with drug user spouses. AB - BACKGROUND: Despite ample evidence of the presence of mental and psychological disorders observed in the family members of drug users, few studies have attempted to focus on suicidal behavior in women whose spouses are drug users. METHODS: This cross-sectional study focused on 131 women who had a drug user spouse. They had all been married for >2 years, with no mental or psychological disorders and no history of drug use prior to marriage. Drug use history after marriage, the extent and nature of physical and non-physical wife abuse, and any history of suicidal ideation and attempt in the past year were collected, in addition to data about anxiety and depression. RESULTS: Our study showed that women who identified with a history of suicidal ideation and attempt were younger, had a shorter marital duration, had a more extensive history of drug use, were more likely to be abused by their spouse, and had higher anxiety and depression scores than their counterparts. Suicidal ideation predictors included a personal history of drug use [odds ratio (OR) = 9.217, 95% confidence interval (CI) = 1.727-49.180, p = 0.009] and anxiety and depression (OR = 1.080, 95% CI = 1.022-1.141, p = 0.004), whereas suicidal attempt predictors included a personal history of drug use (OR = 7.236, 95% CI = 1.671-31.326, p = 0.010), exposure to physical abuse by spouse (OR = 4.005, 95% CI = 1.393-11.523, p = 0.008), and anxiety and depression (OR = 1.092, 95% CI = 1.015-1.175, p = 0.018). CONCLUSION: The findings of this study showed that a personal history of drug use, an elevated anxiety score, and depression and exposure to physical abuse by their spouse may act as predictors of suicidal ideation or attempt in women with a drug user spouse. These findings may serve to benefit and support healthcare systems, associated with ongoing efforts to develop preventive programs for suicidal behavior in this population. PMID- 23938149 TI - The prognostic value of circumferential resection margin in esophageal squamous cell carcinoma after concurrent chemoradiation therapy and surgery. AB - BACKGROUND: Despite the significant advances in surgical techniques and multimodality treatments for esophageal cancer, the overall survival remains unsatisfactory. During the past years, efforts were made to determine the prognostic factors that would help in identifying patients suitable for surgery or guiding adjuvant therapy. Positive circumferential resection margins (CRMs) in esophageal cancer have been previously linked with poor prognosis, but their impact on survival remains controversial in patients treated by a multimodality protocol. The aim of our study was to examine the significance of tumor involvement of CRM in patients with esophageal squamous cell carcinoma after concurrent chemoradiation therapy followed by esophagectomy. METHODS: Between 2000 and 2010, 94 esophageal squamous cell carcinoma patients who received preoperative concurrent chemoradiation therapy followed by surgery were enrolled in our study. We focused on the CRM, which was defined microscopically as clear (negative) or involved (positive). Univariate and multivariate survival analyses were performed with overall survival as the endpoint. RESULTS: Our cohort was predominantly male (94.7%) with a median age of 57 years. All of them received concurrent chemoradiation therapy followed by esophagectomy. Overall, 17 patients (18.1%) had positive CRM. Kaplan-Meier survival analysis demonstrated that the 5 year overall survival of patients with clear and involved CRM is 60.1% and 11.8%, respectively (log rank p < 0.001). Multivariate analysis with the Cox proportional hazard model demonstrated that CRM involvement is a significant prognostic factor for overall survival (p < 0.001). CONCLUSION: In patients with esophageal squamous cell carcinoma who underwent trimodality treatment, CRM involvement is a significant risk factor predicting survival. Additional effort is required to achieve a clear CRM in esophageal cancer treatment. PMID- 23938150 TI - Barriers and enablers to the provision and receipt of preoperative pelvic floor muscle training for men having radical prostatectomy: a qualitative study. AB - BACKGROUND: Strong evidence exists to support preoperative pelvic floor muscle training (PFMT) to reduce the severity and duration of urinary incontinence after radical prostatectomy. Receipt of preoperative PFMT amongst men having radical prostatectomy in Western Sydney, however, is suboptimal. This study was undertaken to investigate barriers and enablers to provision/receipt of preoperative PFMT from the perspectives of potential referrers to and providers of PFMT, and of men having radical prostatectomy. METHODS: A qualitative research design was used. Semi-structured, one-to-one interviews were conducted with participants from three groups: (i) current and potential referrers to PFMT, including urological cancer surgeons, urological cancer nurses and general practitioners (n = 11); (ii) current and potential providers of PFMT across public and private sector hospital and outpatient settings, including physiotherapists and continence nurses (n = 14); and (iii) men having had radical prostatectomy at a specific public and co-located private hospital in Western Sydney (n = 13). Interview schedules were developed using Michie's theoretical domains for investigating the implementation of evidence-based practice, and allowed participants to identify potential and actual barriers and enablers to preoperative PFMT. Transcribed interview data were analysed using a framework approach, and key themes were identified. RESULTS: Participant groups concurred that a recommendation for PFMT from the urological cancer surgeon, accompanied with a referral to a specific provider, was a key enabler of preoperative PFMT. Perceived barriers varied between participant groups and across public and private healthcare settings. Perceptions of financial cost of private sector PFMT, limited knowledge amongst referrers of public sector providers of PFMT, and limited awareness amongst patients of the benefits of PFMT were all posited to contribute to suboptimal PFMT provision and receipt. CONCLUSIONS: This study has provided valuable data on barriers and enablers to preoperative PFMT, with implications for the planning of a behaviour change intervention to improve provision and receipt of preoperative PFMT in Western Sydney. PMID- 23938151 TI - WITHDRAWN: Age-dependent muscle dystrophy related changes of craniofacial morphology in mdx mice. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23938152 TI - Transdifferentiation of pancreatic cells by loss of contact-mediated signaling. AB - BACKGROUND: Replacement of dysfunctional beta-cells in the islets of Langerhans by transdifferentiation of pancreatic acinar cells has been proposed as a regenerative therapy for diabetes. Adult acinar cells spontaneously revert to a multipotent state upon tissue dissociation in vitro and can be stimulated to redifferentiate into beta-cells. Despite accumulating evidence that contact mediated signals are involved, the mechanisms regulating acinar-to-islet cell transdifferentiation remain poorly understood. RESULTS: In this study, we propose that the crosstalk between two contact-mediated signaling mechanisms, lateral inhibition and lateral stabilization, controls cell fate stability and transdifferentiation of pancreatic cells. Analysis of a mathematical model combining gene regulation with contact-mediated signaling reveals the multistability of acinar and islet cell fates. Inhibition of one or both modes of signaling results in transdifferentiation from the acinar to the islet cell fate, either by dedifferentiation to a multipotent state or by direct lineage switching. CONCLUSIONS: This study provides a theoretical framework to understand the role of contact-mediated signaling in pancreatic cell fate control that may help to improve acinar-to-islet cell transdifferentiation strategies for beta cell neogenesis. PMID- 23938153 TI - Differences of radiological artefacts in cochlear implantation in temporal bone and complete head. AB - OBJECTIVES: Accurate radiological evaluation of cochlear implants is essential for improvement of devices and techniques and also for assessing the position of the electrodes within the cochlea. Radiological study of implants has focused on isolated temporal bones. Previous studies showed relevant sizes of artefacts (dimensions of the radiological image compared with the actual dimensions of the electrode) in visualization of cochlear implants in computed tomography and cone beam computed tomography (CBCT). In this study, we aimed to obtain CBCT images of cochlear electrodes in isolated temporal bones and in whole heads and to assess the differences in image quality between the two. METHODS: Cochlear electrodes were implanted in three complete human heads. Radiological examinations were performed using a single CBCT scanner with varying x-ray tube currents, voltages, and rotation angles. The temporal bones were then removed and the same radiological examinations were repeated, with and without the receiver coils. Artefacts from a basal electrode (electrode 9) and an apical electrode (electrode 2) were calculated. These were compared with each other by measuring the diameter of the image of the electrode (electrode inclusive of imaging artefacts) and with the real electrode diameters from the manufacturer's data. Additionally, the radiological diameters (inclusive of artefact) of the electrodes were compared to the cross-sectional diameters of the basal and apical coils of the cochlea at the locations of these two electrodes. RESULTS: In comparison to the real electrode diameters, radiological artefact proportions of 51-58% for electrode 9 and 56-61% for electrode 2 were calculated. The differences between whole head images (group 1) and temporal bone images with and without the receiver coil (groups 2 and 3) were highly significant for each protocol (P < 0.001). DISCUSSION AND CONCLUSION: These results indicate that it is not possible reliably to determine the exact intracochlear positions of electrodes using CBCT. Imaging of isolated temporal bones produced significantly greater artefacts than imaging of the whole head. Evaluations of image quality based only on results for isolated temporal bones are not transferable to clinical situations, and should be assessed critically. PMID- 23938154 TI - Development and evaluation of a structured programme for promoting physical activity among seniors with intellectual disabilities: a study protocol for a cluster randomized trial. AB - BACKGROUND: Older people with intellectual disabilities have very low physical activity levels. Well designed, theory-driven and evidence-based health promotion programmes for the target population are lacking. This paper describes the design of a cluster-randomised trial for a systematically developed health promotion programme aimed at improving physical activity and increasing fitness among seniors with intellectual disabilities. METHODS AND DESIGN: The Intervention Mapping protocol was used for programme development. After defining the programme's objectives, the following behavioural techniques were selected to achieve them: Tailoring, Education, Modelling, Mirroring, Feedback, Reinforcement and Grading. With professionals and managers of provider services for people with intellectual disabilities, we translated these strategies into a structured day activity programme, that consisted of a physical activity and an education programme. The programme will be executed in five day-activity centres in groups of eight to ten seniors during eight months, whereas seniors in five other centres receive care as usual. The physical activity level, as measured in number of steps a day, will be used as primary outcome measurement. Secondary outcome measurements include motor fitness, cardio respiratory fitness, morphological and metabolic fitness, ADL, functional deterioration and depressive symptoms. Differences in the primary and secondary outcome measures between participants and controls will be analysed using generalized estimation equations, correcting for day-activity center as cluster. DISCUSSION: This paper provides insight into the development and content of a theory-driven intervention aimed at behavioural change in a population with a low intellectual level. Its evaluation design is described. The programme's applicability to other populations is discussed. PMID- 23938155 TI - Inflammation triggers high mobility group box 1 (HMGB1) secretion in adipose tissue, a potential link to obesity. AB - BACKGROUND: Low grade inflammation is one of the major metabolic disorders in case of obesity due to variable secretion of adipose derived cytokines called adipokines. Recently the nuclear protein HMGB1 was identified as an inflammatory alarmin in obesity associated diseases. However HMGB1 role in adipose tissue inflammation is not yet studied. OBJECTIVES: The aim of this study was to prove the expression of HMGB1 in human adipose tissue and to assess the levels of expression between normo-weight and obese individuals. Furthermore we determined which type of cells within adipose tissue is involved in HMGB1 production under inflammatory signal. METHODS: Western-blot was performed on protein lysates from human normo-weight and obese adipose tissue to study the differential HMGB1 expression. Human normo-weight adipose tissue, adipose-derived stromal cells (ASCs) and adipocytes were cultured and stimulated with LPS to induce inflammation. HMGB1, IL-6 and MCP-1 secretion and gene expression were quantified by ELISA and Q-PCR respectively, as well as cell death by LDH assay. HMGB1 translocation during inflammation was tracked down by immunofluorescence in ASCs. RESULTS: HMGB1 was expressed 2-fold more in adipose tissue from obese compared to normo-weight individuals. LPS led to an up-regulation in HMGB1 secretion and gene expression in ASCs, while no change was noticed in adipocytes. Moreover, this HMGB1 release was not attributable to any cell death. In LPS-stimulated ASCs, HMGB1 translocation from nucleus to cytoplasm was detectable at 12h and the nuclear HMGB1 was completely drained out after 24h of treatment. CONCLUSION: The expression level studies between adipose tissue from normo-weight and obese individuals together with in vitro results strongly suggest that adipose tissue secretes HMGB1 in response to inflammatory signals which characterized obesity. PMID- 23938156 TI - Chronic muscle stimulation improves muscle function and reverts the abnormal surface EMG pattern in myotonic dystrophy: a pilot study. AB - BACKGROUND: To date, in Myotonic Dystrophy type 1 (DM1) the rehabilitative interventions have always been aimed at muscle strengthening, increasing of fatigue resistance and improving of aerobic metabolism efficiency whereas the electrical membrane fault has always been addressed pharmacologically. Neuromuscular electrical stimulation (NMES) is a useful therapeutic tool in sport medicine and in the rehabilitation of many clinical conditions characterized by motor impairment such as stroke, cerebral palsy and spinal cord injury. METHODS: Five DM1 patients and one patient with Congenital Myotonia (CM) performed a home electrical stimulation of the tibialis anterior muscle lasting 15 days with a frequency of two daily sessions of 60 minutes each. Muscle strength was assessed according to the MRC scale (Medical Research Council) and functional tests (10 Meter Walking Test, 6 Minutes Walking Test and Timed Up and Go Test) were performed. We analyzed the average rectified value of sEMG signal amplitude (ARV) to characterize the sarcolemmal excitability. RESULTS: After the treatment an increase of muscle strength in those DM1 patients with a mild strength deficit was observed. In all subjects an improvement of 10MWT was recorded. Five patients improved their performance in the 6MWT. In TUG test 4 out of 6 patients showed a slight reduction in execution time. All patients reported a subjective improvement when walking. A complete recovery of the normal increasing ARV curve was observed in 4 out of 5 DM1 patients; the CM patient didn't show modification of the ARV pattern. CONCLUSIONS: NMES determined a clear-cut improvement of both the muscular weakness and the sarcolemmal excitability alteration in our small group of DM1 patients. Therefore this rehabilitative approach, if confirmed by further extensive studies, could be considered early in the management of muscular impairment in these patients. An attractive hypothesis to explain our encouraging result could be represented by a functional inhibition of SK3 channels expressed in muscle of DM1 subjects. PMID- 23938157 TI - Neurofibrosarcoma of the gallbladder: a case report. AB - Sarcoma of the gallbladder is a rare entity. This report presents an extremely rare clinical case of a neurofibrosarcoma of the gallbladder. On examination, a mass was felt in the right hypochondrium. An ultrasound of the abdomen showed a mass in the gallbladder. Computed tomography (CT) scan of the abdomen showed a grossly distended gallbladder with soft tissue mass in the gallbladder. The mass was diagnosed as carcinoma of the gallbladder and an extended cholecystectomy was performed. Histopathological examination revealed spindle-cell proliferation and the possibility of a malignant tumor of mesenchymal origin. PMID- 23938158 TI - Impact of nursing care services on self-efficacy perceptions and healthy lifestyle behaviors of nursing home residents. AB - The purpose of this study was to evaluate the impact of tailored individualized nursing care services on the self-efficacy perceptions and healthy lifestyle behaviors of older adults living in a nursing home in Turkey. This outcomes evaluation research used a quasi-experimental study design in which outcomes evaluations were repeated within time intervals in a single group. The study sample included 30 older adults. Nursing diagnoses and interventions were identified using the Omaha System. The impact of implemented nursing care services was evaluated using the Self-Efficacy Scale and Healthy Life-Style Behaviours Scale II. A total of 3,024 nursing interventions were performed, and self-efficacy perceptions and healthy lifestyle behaviors of older nursing home residents were significantly increased in a positive manner (p < 0.05). The results suggest that nurses should assess self-efficacy perceptions and healthy lifestyle behaviors of older adults and that nursing care services directed at health promotion of older adults should be maintained. PMID- 23938159 TI - Testing a theory-based mobility monitoring protocol using in-home sensors: a feasibility study. AB - Mobility is a key factor in the performance of many everyday tasks required for independent living as a person ages. The purpose of this mixed-methods study was to test a theory-based mobility monitoring protocol by comparing sensor-based measures to self-report measures of mobility and assess the acceptability of in home sensors with older adults. Standardized instruments to measure physical, psychosocial, and cognitive parameters were administered to 8 community-dwelling older adults at baseline, 3-month, and 6-month visits. Semi-structured interviews to characterize acceptability of the technology were conducted at the 3-month and 6-month visits. Technical issues prevented comparison of sensor-based measures with self-report measures. In-home sensor technology for monitoring mobility is acceptable to older adults. Implementing our theory-based mobility monitoring protocol in a field study in the homes of older adults is a feasible undertaking but requires more robust technology for sensor-based measure validation. PMID- 23938160 TI - Validation of the professional issues scales with Portuguese nurses. AB - The Professional Issues (PI) scales were designed to measure potential barriers that nurses perceive as obstacles to providing quality care to hospitalized older adults. This study involved validation of the PI scales among 1,068 Portuguese nurses and evaluated the influence of hospital and nurse characteristics on the perception of PI related to nursing care. A six-factor solution was obtained (i.e., staff/family/patient disagreement, perceived legal vulnerability, burden of upsetting behaviors, staff disagreement, perceived upsetting behaviors, use of geriatric services), with Cronbach's alpha coefficients ranging from 0.857 to 0.716. These factors were significantly associated with the following variables: sex, hospital type, hospital location, unit type, perceived institutional support for geriatric-specific education, perceived staff knowledge, and the burden of caring for older adults. The PI scales are reliable and valid for assessing the geriatric-related PI of nurses working in Portuguese hospitals and are useful for developing, planning, and implementing geriatric programs. PMID- 23938161 TI - Allelotyping analysis suggesting a consecutive progression from intratubular germ cell neoplasia to seminoma and then to embryonal carcinoma of the adult testis. AB - Among adult testicular germ cell tumors, the pathogenesis of embryonal carcinoma remains a matter of debate. Some studies suggest a single consecutive progression from intratubular germ cell neoplasia, unclassified (IGCNU), to seminoma and then to embryonal carcinoma; others suggest that seminoma and embryonal carcinoma derive independently from IGCNU. This allelotyping study aimed to clarify the genetic relationship between embryonal carcinoma components and coexisting seminoma and/or IGCNU components. From a cohort of 18 patients with embryonal carcinoma, 11 coexisting seminoma components and 14 coexisting IGCNUs were identified. DNA isolated from each laser-microdissected tissue was subjected to polymerase chain reaction and loss of heterozygosity (LOH) analysis, using 20 polymorphic markers located on 12 chromosome arms (3q, 5q, 6p, 9p, 10q, 11p, 12p, 12q, 13q, 17p, 17q, and 18q). The concordance rate for allelic patterns was 82% between IGCNU and the coexisting seminoma components, 71% between IGCNU and the coexisting embryonal carcinoma components, and 80% between seminoma components and the coexisting embryonal carcinoma components. Estimation of probability indicated that these events were very unlikely to have occurred by chance. The total frequency of LOH increased progressively from IGCNU to seminoma and then to embryonal carcinoma, with statistically significant differences. In 7 cases with 3 histologic components, 28 chromosomal loci that showed LOH in the seminoma and embryonal carcinoma components were identified, and 15 (54%) retained heterozygosity in the coexisting IGCNUs. These findings suggest that a consecutive progression from IGCNU to seminoma, and ultimately, to embryonal carcinoma mainly occurred in the testicular germ cell tumor cases. PMID- 23938163 TI - Editorial for Midwifery special issue on MDGs: Midwives and the Millennium Development Goals. PMID- 23938162 TI - Histopathologic assessment of the entire endometrium in asymptomatic women. AB - Knowledge on the nature of the endometrium in women without symptoms of endometrial disease is poor. Therefore, the aim of this prospective study was to describe the endometrium of a cohort of asymptomatic women. The entire endometrium of premenopausal and postmenopausal women was embedded for histologic examination. All included patients underwent a hysterectomy on indication of uterovaginal prolapse, from July 2011 to October 2012, in 3 hospitals in the South of the Netherlands. Exclusion criteria were symptoms of postmenopausal vaginal blood loss or premenopausal disordered vaginal bleeding. As a result, 68 women were included in the study, 48 women were postmenopausal and 20 were premenopausal. In the endometrium of 10 women, simple hyperplasia was found (15%); 1, complex hyperplasia (2%); 2, simple atypical hyperplasia (3%); 2, complex atypical hyperplasia (3%); and 2, a small focus of intramucosal endometrioid endometrial carcinoma (3%). In general, the endometrium was heterogeneous, and most lesions were not present in the entire endometrium. In conclusion, after examining the entire endometrium, a remarkable high prevalence of endometrial pathology was found in asymptomatic women. The clinical meaning of these lesions is not yet clear, but endometrial pathology may frequently exist without symptoms. PMID- 23938164 TI - Final year students' learning experiences of the Bachelor of Midwifery course. AB - AIM: the aim of the study was to explore the concerns of 3rd year Bachelor of Midwifery students. BACKGROUND: earlier research indicates that midwifery students experience a number of conflicting learning demands and expectations, during their student years. These difficulties can lead to anxiety and a lack of confidence, which have implications for student integration and socialisation into the profession. METHODS: a qualitative method was used, underpinned by Smith and Osborn's (2008) approach to interpretative phenomenological analysis IPA. In depth interviews were conducted among 10 senior midwifery students as they looked back over their three year course. Data were analysed using steps proposed by Smith and Osborn (2008). KEY FINDINGS: more than two-thirds of participants were over 35 years, and had two or more children. More than half were living with a spouse/partner and the majority worked 16 hours or less per week. Themes emerging from the data included (1) linking theory to practice; (2) a focus on clinical skills; (3) learning expectations and experiences; and (4) the role of midwifery lecturers/educators. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: midwifery students experience a number of challenges associated with their pre-registration midwifery education, including difficulty understanding the relevance of some study units to midwifery practice. A strong focus on practical skills may inhibit the development of cognitive skills such as critical evaluation and reflection. PMID- 23938165 TI - Yemeni women's perceptions of own authority during childbirth: what does it have to do with achieving the Millennium Development Goals? AB - BACKGROUND: women's underutilisation of professional care during childbirth in many low-income countries is a serious concern in terms of achievement of maternal Millennium Development Goal 5. OBJECTIVE: to explore women's perceived own authority within the modern and traditional spheres of childbirth in a high maternal mortality setting on the Arab peninsula. Yemen is a signatory to the Millennium Development Goals and one of 10 countries chosen for the United Nations Millennium Project. In Yemen, home birth has remained the norm for several decades in spite of high maternal mortality and morbidity rates. DESIGN: a multistage (stratified-purposive-random) sampling process was used. Two hundred and twenty women with childbirth experience in urban/rural Yemen were selected at random for interview. Answers to the question 'Did you feel that you were the authority during childbirth?' were analysed using qualitative content analysis. SETTING: the governorates of Aden, Lahej, Hadramout, Taiz and Hodeidah. FINDINGS: three main themes emerged from the analysis: (i) 'Being at the centre', including two categories 'being able to follow through on own wants' and its opposite 'to be under the authority of others'; (ii) 'A sense of belonging' with the categories 'belonging and support among women in the community' and 'the denial of support, the experience of separation' and (iii) 'Husband's role in childbirth' including one category 'opportunity to show authority over the husband'. Authority was experienced primarily among women within the traditional childbirth sector although a general complaint among women delivered by trained medical staff was the loss of own authority. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: these findings show that women's authority during childbirth is decreasing in the context of Safe Motherhood and the expansion of modern delivery care. This is likely to be an important reason why women underutilise professional care. Acquisition of knowledge from the traditional childbirth sector regarding how women exercise authority to facilitate childbirth would constitute an asset to skilled delivery and Safe Motherhood. The findings from Yemen are likely to be relevant for other low-income countries with similar persistent high home delivery rates, low status of women, and high maternal mortality and morbidity rates. PMID- 23938166 TI - Quantitative and qualitative symptomatic differences in individuals at Ultra-High Risk for psychosis and healthy controls. AB - Patients at Ultra-High Risk (UHR) for developing a first psychosis vary widely in their symptom presentation and illness course. An important aim in UHR research concerns the characterization of the clinical heterogeneity in this population. We aimed to identify qualitatively and quantitatively different clinical symptom profiles at baseline and at 2-year follow-up in a group of UHR subjects and healthy controls. We employed a Latent Class Factor Analysis (LCFA) to the 19 items of the Structured Interview for Prodromal Syndromes (SIPS) ratings at baseline and at 2-year follow-up in a sample of 147 UHR subjects and 141 controls from the Dutch Prediction of Psychosis Study (DUPS) in the Netherlands. Additionally, a stepwise logistic regression analysis was performed with transition to psychosis as a dependent variable and baseline latent variable scores as predictors. Variation in symptomatology at baseline was explained by both quantitative and qualitative differences; at 2-year follow-up qualitative differences between individuals were no longer observed. Quantitative differences showed moderate stability over time (range=0.109-0.42). Within the UHR sample, transition to psychosis was significantly associated with quantitative differences in baseline SIPS scores. The results of our study suggest a 'quasi' continuous extended psychosis phenotype, a finding that merits replication in other samples. PMID- 23938167 TI - Authors' response to commentary on suicidal ideas and immediate suicide risk. PMID- 23938168 TI - Optimizing Bi2O3 and TiO2 to achieve the maximum non-linear electrical property of ZnO low voltage varistor. AB - BACKGROUND: In fabrication of ZnO-based low voltage varistor, Bi2O3 and TiO2 have been used as former and grain growth enhancer factors respectively. Therefore, the molar ratio of the factors is quit important in the fabrication. In this paper, modeling and optimization of Bi2O3 and TiO2 was carried out by response surface methodology to achieve maximized electrical properties. The fabrication was planned by central composite design using two variables and one response. To obtain actual responses, the design was performed in laboratory by the conventional methods of ceramics fabrication. The actual responses were fitted into a valid second order algebraic polynomial equation. Then the quadratic model was suggested by response surface methodology. The model was validated by analysis of variance which provided several evidences such as high F-value (153.6), very low P-value (<0.0001), adjusted R-squared (0.985) and predicted R squared (0.947). Moreover, the lack of fit was not significant which means the model was significant. RESULTS: The model tracked the optimum of the additives in the design by using three dimension surface plots. In the optimum condition, the molars ratio of Bi2O3 and TiO2 were obtained in a surface area around 1.25 point that maximized the nonlinear coefficient around 20 point. Moreover, the model predicted the optimum amount of the additives in desirable condition. In this case, the condition included minimum standard error (0.35) and maximum nonlinearity (20.03), while molar ratio of Bi2O3 (1.24 mol%) and TiO2 (1.27 mol%) was in range. The condition as a solution was tested by further experiments for confirmation. As the experimental results showed, the obtained value of the non linearity, 21.6, was quite close to the predicted model. CONCLUSION: Response surface methodology has been successful for modeling and optimizing the additives such as Bi2O3 and TiO2 of ZnO-based low voltage varistor to achieve maximized non linearity properties. PMID- 23938169 TI - In vitro prion protein conversion suggests risk of bighorn sheep (Ovis canadensis) to transmissible spongiform encephalopathies. AB - BACKGROUND: Transmissible spongiform encephalopathies (TSEs) affect both domestic sheep (scrapie) and captive and free-ranging cervids (chronic wasting disease; CWD). The geographical range of bighorn sheep (Ovis canadensis; BHS) overlaps with states or provinces that have contained scrapie-positive sheep or goats and areas with present epizootics of CWD in cervids. No TSEs have been documented in BHS, but the susceptibility of this species to TSEs remains unknown. RESULTS: We acquired a library of BHS tissues and found no evidence of preexisting TSEs in these animals. The prion protein gene (Prnp) in all BHS in our library was identical to scrapie-susceptible domestic sheep (A136R154Q171 genotype). Using an in vitro prion protein conversion assay, which has been previously used to assess TSE species barriers and, in our study appears to recollect known species barriers in mice, we assessed the potential transmissibility of TSEs to BHS. As expected based upon Prnp genotype, we observed BHS prion protein conversion by classical scrapie agent and evidence for a species barrier between transmissible mink encephalopathy (TME) and BHS. Interestingly, our data suggest that the species barrier of BHS to white-tailed deer or wapiti CWD agents is likely low. We also used protein misfolding cyclic amplification to confirm that CWD, but not TME, can template prion protein misfolding in A136R154Q171 genotype sheep. CONCLUSIONS: Our results indicate the in vitro conversion assay used in our study does mimic the species barrier of mice to the TSE agents that we tested. Based on Prnp genotype and results from conversion assays, BHS are likely to be susceptible to infection by classical scrapie. Despite mismatches in amino acids thought to modulate prion protein conversion, our data indicate that A136R154Q171 genotype sheep prion protein is misfolded by CWD agent, suggesting that these animals could be susceptible to CWD. Further investigation of TSE transmissibility to BHS, including animal studies, is warranted. The lack of reported TSEs in BHS may be attributable to other host factors or a lack of TSE surveillance in this species. PMID- 23938170 TI - Alcohol consumption and electrocardiographic left ventricular hypertrophy and mediation by elevated blood pressure in older Chinese men: the Guangzhou Biobank Cohort Study. AB - BACKGROUND: Chinese people have a markedly lower alcohol consumption than people in the West. Whether alcohol consumption at such levels is associated with left ventricular hypertrophy, and the role of blood pressure (BP) in this relationship is unclear. We investigated the association between alcohol consumption and electrocardiographic left ventricular hypertrophy (ECG-LVH) and the mediating role of BP in Chinese men aged >=50 years. METHODS AND RESULTS: A case-control analysis was conducted on baseline cross-sectional data from the community-based Guangzhou Biobank Cohort Study (2003-2008), using standard 12-lead resting electrocardiograms. By comparing 191 new ECG-LVH cases with 4311 controls, excessive drinking (>210 g/week) showed excess risks for ECG-LVH (odds ratio [OR] = 1.90, 95% confidence interval [CI] = 1.12-3.24), after adjusting for education, income, occupation, physical activity, smoking, body mass index, fasting glucose, triglyceride, total cholesterol, high-density lipoprotein cholesterol, BP, and antihypertensive medication. Mediation analysis showed a significant mediating effect of BP on the association between excessive drinking and ECG-LVH: systolic (31%) and diastolic (16%). After multivariate adjustment, no significant association was found between occasional drinking (=once/week to <=210 g/week: OR = 0.88, 95% CI = 0.53-1.47) with increased/decreased risk of ECG-LVH. CONCLUSIONS: Alcohol consumption at >210 g/week in Chinese men is an independent risk factor for ECG LVH. Low power prevented us from examining whether drinking at = 20 on the Positive and Negative Syndrome Scale (PANSS), were randomized into either the modafinil (n=12) or placebo (n=12) group. The modafinil group received flexible does of modafinil 50-200mg/day. Primary measurements were the Simpson Angus Scale (SAS) for extrapyramidal side effects (EPS), the Epworth Sleepiness Scale (ESS), the PANSS and a neuropsychological (NP) test battery. Data were collected on Days 0, 14, 28, 42 and 56 for rating scales, and on Days 0, 28 and 56 for NP tests. RESULTS: Mixed model analyses showed a significant group-x-time interaction for total SAS scores (P<0.006), with scores decreasing in the modafinil group but remaining the same in the placebo group. There were no significant group-x-time interactions for scores of ESS (total), PANSS (total, positive and negative), and NP tests (composite and domains) (all P's>0.5). No significant adverse events were observed. CONCLUSION: The data suggest that modafinil was a safe adjunctive treatment which improved parkinsonian symptoms and signs in patients with schizophrenia or schizoaffective disorder. Further studies in larger samples and with longer study time are needed to test/confirm the beneficial effects of modafinil on motor function. PMID- 23938175 TI - The relative contribution of neurocognition and social cognition to 6-month vocational outcomes following Individual Placement and Support in first-episode psychosis. AB - AIMS: To examine whether baseline neurocognition and social cognition predict vocational outcomes over 6 months in patients with first-episode psychosis (FEP) enrolled in a randomised controlled trial of Individual Placement and Support (IPS) versus treatment as usual (TAU). METHODS: 135 FEP participants (IPS n=69; TAU n=66) completed a comprehensive neurocognitive and social cognitive battery. Principal axis factor analysis using PROMAX rotation was used to determine the underlying cognitive structure of the battery. Setwise (hierarchical) logistic and multivariate linear regressions were used to examine predictors of: (a) enrolment in education and employment; and (b) hours of employment over 6 months. Neurocognition and social cognition factors were entered into the models after accounting for premorbid IQ, baseline functioning and treatment group. RESULTS: Six cognitive factors were extracted: (i) social cognition; (ii) information processing speed; (iii) verbal learning and memory; (iv) attention and working memory; (v) visual organisation and memory; and (vi) verbal comprehension. Enrolment in education over 6 months was predicted by enrolment in education at baseline (p=.002) and poorer visual organisation and memory (p=.024). Employment over 6 months was predicted by employment at baseline (p=.041) and receiving IPS (p=.020). Better visual organisation and memory predicted total hours of paid work over 6 months (p<.001). CONCLUSIONS: Visual organisation and memory predicted the enrolment in education and duration of employment, after accounting for premorbid IQ, baseline functioning and treatment. Social cognition did not contribute to the prediction of vocational outcomes. Neurocognitive interventions may enhance employment duration in FEP. PMID- 23938176 TI - Pharmacological approaches to treating negative symptoms: a review of clinical trials. AB - Clinical trials of pharmacological agents targeting negative symptoms in schizophrenia are reviewed. The focus is on trials that occurred in patients who were stable on an antipsychotic medication at entry to the trial. A small number of trials compared antipsychotics as monotherapy for negative symptoms. Although the data supporting amisulpride for negative symptoms is promising the trials have limitations and it is plausible that the advantages of amisulpride over placebo may result from effects on secondary negative symptoms. Among available agents, antidepressant medications may have effects in negative symptoms. Other promising agents include minocycline, glutamatergic agents, and alpha-7 nicotinic agents. More than 15 active trials are currently underway to evaluate new treatments for negative symptoms. PMID- 23938174 TI - DNA-methylation gene network dysregulation in peripheral blood lymphocytes of schizophrenia patients. AB - The epigenetic dysregulation of the brain genome associated with the clinical manifestations of schizophrenia (SZ) includes altered DNA promoter methylation of several candidate genes. We and others have reported that two enzymes that belong to the DNA-methylation/demethylation network pathways-DNMT1 (DNA methyltransferase) and ten-eleven translocator-1(TET1) methylcytosine deoxygenase are abnormally increased in corticolimbic structures of SZ postmortem brain. The objective of this study was to investigate whether the expression of these components of the DNA-methylation-demethylation pathways known to be altered in the brain of SZ patients are also altered in peripheral blood lymphocytes (PBL). The data show that increases in DNMT1 and TET1 and in glucocorticoid receptor (GCortR) and brain derived neurotrophic factor (BDNF) mRNAs in PBL of SZ patients are comparable to those reported in the brain of SZ patients. The finding that the expressions of DNMT1 and TET1 are increased and SZ candidate genes such as BDNF and GCortR are altered in the same direction in both the brain and PBL together with recent studies showing highly correlated patterns of DNA methylation across the brain and blood, support the hypothesis that a common epigenetic dysregulation may be operative in the brain and peripheral tissues of SZ patients. PMID- 23938177 TI - Testing the estrogen hypothesis of schizophrenia: associations between cumulative estrogen exposure and cerebral structural measures. AB - BACKGROUND: Bone mineral density (BMD), as an indicator of cumulative estrogen exposure, may be reduced in female patients with psychotic disorder (van der Leeuw et al., 2013), possibly reflecting reduced cerebral exposure to estrogen and alterations in neuroprotective effects. To the degree that BMD is a marker of cumulative (endogenous) estrogen exposure, we hypothesized that BMD would be positively associated with cerebral gray and white matter indices. METHODS: Dual X-ray absorptiometry (DEXA) and magnetic resonance (MRI) scans were acquired in fourteen female patients diagnosed with a psychotic disorder. BMD was expressed in total BMD (g/cm(2)), Z- and T-scores. Cerebral cortical thickness (CT) (as indicator of gray matter status) and fractional anisotropy (FA) (as indicator of white matter integrity) were measured and served as the dependent variables in multilevel random regression models. BMD measures were the independent variables. RESULTS: Femoral BMD measures were positively associated with CT at trend significance (total BMD: B=0.266, 95% CI: -0.019-0.552, p=0.067; Z-score: B=0.034, 95% CI: 0.001-0.067, p=0.046; T-score: B=0.034, 95% CI: 0.000-0.068, p=0.052). There were no significant associations between femoral BMD measures and FA. CONCLUSIONS: The data suggest that in women with psychotic disorder, alterations in the neuroprotective effect of estrogen (as measured by BMD) impact cortical gray matter, but not white matter integrity. These findings merit further investigation and, if replicated, would lend support to the estrogen hypothesis of schizophrenia. PMID- 23938179 TI - Cytogenetic and single nucleotide polymorphism array findings in soft tissue tumors in infants. AB - Soft tissue tumors in children under one year of age (infants) are rare. The etiology is usually unknown, with external factors or congenital birth defects and hereditary syndromes being recognized in only a small proportion of the cases. We ascertained the cytogenetic findings in 16 infants from whom tumor tissue had been obtained during a 25-year period. In eight of them, single nucleotide polymorphism (SNP) array analyses could also be performed. No constitutional chromosome aberrations were detected, and assessment of clinical files did not reveal any congenital or later anatomical defects. Three tumors- one infantile fibrosarcoma, one embryonal rhabdomyosarcoma, and one angiomatoid fibrous histiocytoma (AFH)--had abnormal karyotypes. As the AFH had an exchange between chromosome arms 12p and 15q, additional fluorescence in situ hybridization and reverse transcription-polymerase chain reaction analyses were performed, unexpectedly revealing an ETV6/NTRK3 fusion. Three of the eight tumors, including the AFH with an abnormal karyotype, analyzed by SNP array showed aberrations (loss of heterozygosity or imbalances). The present series suggests that the addition of array-based technologies is valuable for detecting underlying pathogenetic mechanisms. PMID- 23938178 TI - Different effects of progesterone and estradiol on chimeric and wild type aldosterone synthase in vitro. AB - BACKGROUND: Familial hyperaldosteronism type I (FH-I) is caused by the unequal recombination between the 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, resulting in the generation of a CYP11B1/B2 chimeric gene and abnormal adrenal aldosterone production. Affected patients usually show severe hypertension and an elevated frequency of stroke at a young age. Aldosterone levels rise during pregnancy, yet in pregnant women with FH-1, their hypertensive condition either remains unchanged or may even improve. The purpose of this study was to investigate in vitro whether female sex steroids modulate the activity of chimeric (ASCE) or wild type (ASWT) aldosterone synthase enzymes. METHODS: We designed an in vitro assay using HEK-293 cell line transiently transfected with vectors containing the full ASCE or ASWT cDNAs. Progesterone or estradiol effects on AS enzyme activities were evaluated in transfected cells incubated with deoxycorticosterone (DOC) alone or DOC plus increasing doses of these steroids. RESULTS: In our in vitro model, both enzymes showed similar apparent kinetic parameters (Km = 1.191 microM and Vmax = 27.08 microM/24 h for ASCE and Km = 1.163 microM and Vmax = 36.98 microM/24 h for ASWT; p = ns, Mann-Whitney test). Progesterone inhibited aldosterone production by ASCE- and ASWT-transfected cells, while estradiol demonstrated no effect. Progesterone acted as a competitive inhibitor for both enzymes. Molecular modelling studies and binding affinity estimations indicate that progesterone might bind to the substrate site in both ASCE and ASWT, supporting the idea that this steroid could regulate these enzymatic activities and contribute to the decay of aldosterone synthase activity in chimeric gene-positive patients. CONCLUSIONS: Our results show an inhibitory action of progesterone in the aldosterone synthesis by chimeric or wild type aldosterone synthase enzymes. This is a novel regulatory mechanism of progesterone action, which could be involved in protecting pregnant women with FH 1 against hypertension. In vitro, both enzymes showed comparable kinetic parameters, but ASWT was more strongly inhibited than ASCE. This study implicates a new role for progesterone in the regulation of aldosterone levels that could contribute, along with other factors, to the maintenance of an adequate aldosterone-progesterone balance in pregnancy. PMID- 23938180 TI - New insights into the ear region anatomy and cranial blood supply of advanced stem Strepsirhini: evidence from three primate petrosals from the Eocene of Chambi, Tunisia. AB - We report the discovery of three isolated primate petrosal fragments from the fossiliferous locality of Chambi (Tunisia), a primate-bearing locality dating from the late early to the early middle Eocene. These fossils display a suite of anatomical characteristics otherwise found only in strepsirhines, and as such might be attributed either to Djebelemur or/and cf. Algeripithecus, the two diminutive stem strepsirhine primates recorded from this locality. Although damaged, the petrosals provide substantial information regarding the ear anatomy of these advanced stem strepsirhines (or pre-tooth-combed primates), notably the patterns of the pathway of the arterial blood supply. Using MUCT-scanning techniques and digital segmentation of the structures, we show that the transpromontorial and stapedial branches of the internal carotid artery (ICA) were present (presence of bony tubes), but seemingly too small to supply enough blood to the cranium alone. This suggests that the ICA was not the main cranial blood supply in stem strepsirhines, but that the pharyngeal or vertebral artery primitively ensured a great part of this role instead, an arterial pattern that is reminiscent of modern cheirogaleid, lepilemurid lemuriforms and lorisiforms. This could explain parallel loss of the ICA functionality among these families. Specific measurements made on the cochlea indicate that the small strepsirhine primate(s) from Chambi was (were) highly sensitive to high frequencies and poorly sensitive to low frequencies. Finally, variance from orthogonality of the plane of the semicircular canals (SCs) calculated on one petrosal (CBI-1-569) suggests that Djebelemur or cf. Algeripithecus likely moved (at least its head) in a way similar to that of modern mouse lemurs. PMID- 23938181 TI - The effect of post-stroke lower-limb spasticity on the control of standing balance: Inter-limb spatial and temporal synchronisation of centres of pressure. AB - BACKGROUND: Challenges in stability control are common post-stroke. Although lower-limb spasticity is a common sensorimotor consequence post-stroke, its potential to further complicate stability control among stroke-survivors remains largely unknown. Advancing such understanding can help inform strategies to reduce fall risk and increase independence among these individuals. The purpose of this study was to characterise the extent of limb-specific dyscontrol among individuals with spasticity. METHODS: A retrospective analysis of 131 patients assessed for spasticity was performed. Patients selected for inclusion were categorised into two groups, with (n=19) or without (n=63) unilateral lower-limb spasticity. Two force platforms were used to determine the individual-limb and net centres of pressure in both anteroposterior and mediolateral directions during 30s of quiet standing. Limb-specific dyscontrol was assessed by calculating weight-bearing symmetry ratios, cross-correlation coefficients at zero phase-shift (temporal synchrony) and ratios of individual-limb root-mean square displacements (spatial symmetry). Total body postural control was assessed by examining the root-mean-square of the net centre of pressure displacement. FINDINGS: The group with spasticity bore less weight on the affected limb and exhibited reduced temporal synchrony of centre of pressure displacements. There were no differences in inter-limb root-mean-square centre of pressure ratios or in the root-mean-square of the net centre of pressure displacement. INTERPRETATION: Individuals with lower-limb spasticity may have additional challenges with stability control, specifically linked to the ability to modify the location of the centre of pressure beneath the affected limb, in a time sensitive manner so as to contribute beneficially to the control of whole body stability. PMID- 23938182 TI - Sagittal plane joint loading is related to knee flexion in osteoarthritic gait. AB - BACKGROUND: High mechanical loading has been consistently linked with medial tibiofemoral osteoarthritis, and is considered to play a central role in the pathogenesis of the disease. Evidence from healthy adults indicates that knee flexion kinematics may influence knee load. The purpose of this study therefore, was to investigate the association between knee flexion kinematics and indicators of joint loading during walking (peak moments and vertical ground reaction force), in individuals with medial tibiofemoral osteoarthritis. METHODS: In this cross-sectional study, 89 participants with painful medial tibiofemoral osteoarthritis completed three-dimensional walking gait analysis to measure stance phase ground reaction forces, knee joint moments, and knee flexion kinematics. FINDINGS: In stepwise regression, greater knee flexion excursion was associated with higher peak vertical ground reaction force, accounting for 10% of its variance (B=0.62 [95% CI 0.34, 0.89], P<0.001). Greater peak knee flexion was associated with a higher flexion moment, accounting for 44% of its variance (B=0.12 [95% CI 0.09, 0.15], P<0.001). No association was found between the knee adduction moment and knee flexion kinematics during walking. INTERPRETATION: Our data suggest that greater knee flexion is associated with higher joint loads in the sagittal plane (i.e. a higher peak knee flexion moment). However, knee flexion kinematics were not associated with the knee adduction moment - a proxy measure of medial compartment knee load. Thus, high knee flexion should be considered an undesirable gait characteristic with respect to knee load in individuals with medial tibiofemoral osteoarthritis. PMID- 23938183 TI - Pharmacokinetics and thrombolytic effects of the recombinant tissue-type plasminogen activator in horses. AB - BACKGROUND: To test the efficacy of the recombinant tissue-type plasminogen activator (rt-PA) alteplase in horses, the thrombolytic effect was tested in in vitro generated equine thrombi. The extent of lysis was determined by measuring the decrease in thrombi weight over a period of 4 hours. In vivo pharmacokinetics of alteplase were determined in 6 healthy horses. A single dose (1 mg/kg) was applied via intravenous infusion over a period of 30 minutes Coagulation-related variables, blood count and clinical parameters were taken before the treatment and until 48 h after treatment. In addition, plasma rt-PA concentration was measured until 300 min after commencing the infusion. RESULTS: In vitro, a dose dependent decrease of thrombus weight ranging from a 56 (+/- 6.5) % decrease for 0.5 MUg/ml to 92 (+/- 2.1) % decrease for 5 MUg/ml rt-PA was noted. The D-dimer concentration in the lysis medium correspondingly increased from 0.10 up to 10.8 mg/l. In vivo, none of the horses showed an adverse reaction to the alteplase infusion. In some horses blood parameters were slightly altered. The 1 mg/kg dose yielded the following pharmacokinetic parameters: Cmax = 1.25 +/- 0.27 MUg/ml; CL = 21.46 +/- 5.67 ml/min/kg; dominant half life (t1/2alpha) = 6.81 +/- 1.48 minutes; median elimination half life (t1/2beta) = 171 min (range: 85-1061); AUC = 50.33 +/- 17.62 MUg . min /ml. CONCLUSION: These findings indicate that a single dose of 1 mg/kg alteplase results in rt-PA plasma concentrations comparable to those in humans and might be sufficient for a thrombolytic therapy in horses. Further studies must be performed to determine the alteplase effectiveness in horses with jugular vein thrombosis. PMID- 23938184 TI - Viral taxonomy needs a spring clean; its exploration era is over. AB - The International Committee on Taxonomy of Viruses has recently changed its approved definition of a viral species, and also discontinued work on its database of virus descriptions. These events indicate that the exploration era of viral taxonomy has ended; over the past century the principles of viral taxonomy have been established, the tools for phylogenetic inference invented, and the ultimate discriminatory data required for taxonomy, namely gene sequences, are now readily available. Further changes would make viral taxonomy more informative. First, the status of a 'taxonomic species' with an italicized name should only be given to viruses that are specifically linked with a single 'type genomic sequence' like those in the NCBI Reference Sequence Database. Secondly all approved taxa should be predominately monophyletic, and uninformative higher taxa disendorsed. These are 'quality assurance' measures and would improve the value of viral nomenclature to its users. The ICTV should also promote the use of a public database, such as Wikipedia, to replace the ICTV database as a store of the primary metadata of individual viruses, and should publish abstracts of the ICTV Reports in that database, so that they are 'Open Access'. PMID- 23938185 TI - Validity of summing painful joint sites to assess joint-pain comorbidity in hip or knee osteoarthritis. AB - BACKGROUND: Previous studies in patients with hip and knee osteoarthritis (OA) have advocated the relevance of assessing the number of painful joint sites, other than the primary affected joint, in both research and clinical practice. However, it is unclear whether joint-pain comorbidities can simply be summed up. METHODS: A total of 401 patients with hip or knee OA completed questionnaires on demographic variables and joint-pain comorbidities. Rasch analysis was performed to evaluate whether a sum score of joint-pain comorbidities can be calculated. RESULTS: Self-reported joint-pain comorbidities showed a good fit to the Rasch model and were not biased by gender, age, disease duration, BMI, or patient group. As a group, joint-pain comorbidities covered a reasonable range of severity levels, although the sum score had rather low reliability levels suggesting it cannot discriminate well among patients. CONCLUSIONS: Joint-pain comorbidities, in other than the primary affected joints, can be summed into a joint pain comorbidity score. Nevertheless, its use is discouraged for individual decision making purposes since its lacks discriminative power in patients with minimal or extreme joint pain. PMID- 23938186 TI - Decisions about dialysis initiation in the elderly. PMID- 23938188 TI - Association between dietary intake of n-3 polyunsaturated fatty acids and severity of skin photoaging in a middle-aged Caucasian population. AB - BACKGROUND: Intake of long-chain n-3 polyunsaturated fatty acid (PUFAs) supplementation has been reported to be associated with reduced UVB-erythemal sensitivity, but their relationship to photoaging has not been studied to date. OBJECTIVE: To investigate associations between daily n-3 PUFA intake and the severity of skin photoaging. METHODS: A cross-sectional study was conducted on 2919 subjects aged 45-60 years from the SU.VI.MAX cohort. At baseline, trained investigators graded the severity of facial skin photoaging using a validated 6 grade scale during a clinical examination. Intake of alpha-linolenic (ALA), eicosapentaenoic (EPA), docosapentaenoic (DPA), and docosahexaenoic acids (DHA) were evaluated by dietary source using ten 24-h dietary record questionnaires during the first 2.5 years of the follow-up period. RESULTS: After adjustment for possible confounders, severe photoaging was found to be inversely associated with higher intake of ALA in men and with higher intake of EPA in women. When considering the different food sources of ALA for men, an inverse association appeared between severe photoaging and ALA from vegetable oils, as well as with ALA from fruit and vegetables, whereas no association was observed for ALA from dairy products. In women, ALA from vegetable oils also tended to be inversely linked to photoaging. CONCLUSIONS: These findings suggest a possible benefit effect of n-3 PUFAs on skin aging. Nonetheless, further epidemiological studies are necessary to confirm our results and to gain additional insights into underlying mechanisms. PMID- 23938189 TI - Metastatic brachial plexopathy from breast cancer detected by 18F-FDG PET/MRI. PMID- 23938190 TI - Discordance between MRI and bone scan findings in a child with acute complicated osteomyelitis: scintigraphic features that contribute to the early diagnosis. AB - Early diagnosis and prompt treatment of acute osteomyelitis are of paramount importance in children because they can prevent irreversible bone damage. Magnetic resonance imaging (MRI) with its superior spatial resolution and lack of ionizing radiation is routinely preferred over bone scan for this purpose. Increased blood flow, hyperemia and focally increased tracer uptake shown by "three phase" bone scan are the typical scintigraphic findings of acute osteomyelitis. In addition, diffuse uptake along the shaft of long bones and focal "cold" lesions are two special features that may be highly suggestive of infective periostitis, soft tissue sepsis and subperiosteal abscess formation, due to the loose attachment of periosteum to bone during childhood. We present a case of complicated osteomyelitis in a child with inconclusive MRI correctly diagnosed on the basis of these special scintigraphic findings resulting in treatment change from double i.v. Vancomycin--Ceftriaxone scheme to surgical intervention. PMID- 23938191 TI - [Variables that influence the indication of a second myocardial perfusion gated SPECT after a normal stress-rest gated SPECT]. AB - OBJECTIVE: The objective of this study was to investigate predictor variables at the moment of normal stress-rest myocardial perfusion gated SPECT for indication of a second gated SPECT. MATERIAL AND METHODS: A prospective, single center cohort study was conducted. We evaluated 2326 consecutive patients (age 63.6 +/- 13 years, 57.3% females) without perfusion defects and with normal left ventricular ejection fraction on a myocardial perfusion gated SPECT. Clinical and stress test variables were studied to predict indication of a second gated SPECT and presence of reversible perfusion defects in the second gated SPECT. RESULTS: During a mean follow-up of 3.6 +/- 2 years a second gated SPECT was performed in 286 patients (12.3%). Independent predictor variables of a second gated SPECT were presence of three or more cardiovascular risk factors (chi(2): 5.510; HR: 1.4; p=0.019), previous acute myocardial infarction (chi(2): 3.867; HR: 1.4; p=0.049), previous coronary revascularization (chi(2): 41.081; HR: 2.5; p<0.001), and a positive stress test (chi(2): 8.713; HR: 1.5; p=0.003). Observation of perfusion defects in the 280 patients in whom a second stress-rest gated SPECT was performed was more likely in male patients (chi(2): 4.322; HR: 1.9; p=0.038) who had a first pure pharmacological gated-SPECT (chi(2): 7.182; HR: 2.6; p=0.007). CONCLUSIONS: In patients with a first normal myocardial perfusion gated SPECT, various clinical factors and variables derived from the stress test affect the indication of a second gated SPECT and the presence of ischemia in the latter. PMID- 23938192 TI - Evaluation of physicochemical and antioxidant properties of sourwood and other Malaysian honeys: a comparison with manuka honey. AB - BACKGROUND: The aim of the present study was to evaluate the physical, biochemical and antioxidant properties of four Malaysian monofloral types of honey (gelam, longan, rubber tree and sourwood honeys) compared to manuka honey. Several physical parameters of honey, such as pH, moisture content, electrical conductivity (EC), total dissolved solids (TDS), color intensity, total sugar and sucrose content, were measured. A number of biochemical and antioxidant tests were performed to determine the antioxidant properties of the honey samples. Hydroxymethylfurfural (HMF) levels were determined using high performance liquid chromatography. RESULTS: The mean pH, moisture content, EC and TDS of Malaysian honey were 3.90 +/- 0.12, 17.01 +/- 3.07%, 0.59 +/- 0.17 mS/cm and 294.87 +/- 81.96 ppm, respectively. The mean color and HMF level was 102.07 +/- 41.77 mm Pfund and 49.51 +/- 0.12 mg/kg, respectively. Sourwood honey contained the highest contents of phenolics (580.03 +/- 0.38 mggalic acid/kg) and flavonoids (156.82 +/- 0.47 mgcatechin/kg) with high DPPH radical scavenging activity (59.26 +/- 3.77%) as well as ferric reducing power [648.25 +/- 0.90 MUM Fe (II)/100 g]. Sourwood honey also exhibited the highest color intensity. Several strong positive correlations were observed amongst the different antioxidant parameters and the various antioxidant tests. CONCLUSION: This is the first time that the antioxidant potential of both sourwood and rubber tree honeys have been reported. Our results indicated that Malaysian honey (specifically sourwood honey and longan honey) is a good source of antioxidants compared to Manuka honey. PMID- 23938194 TI - Rupture of the ulnar collateral ligament of the thumb - a review. AB - Skier's thumb is a partial or complete rupture of the ulnar collateral ligament of the metacarpophalangeal joint of the thumb. It is an often-encountered injury and can lead to chronic pain and instability when diagnosed incorrectly. Knowledge of the anatomy and accurate physical examination are essential in the evaluation of a patient with skier's thumb. This article provides a review of the relevant anatomy, the correct method of physical examination and the options for additional imaging and treatment with attention to possible pitfalls. PMID- 23938193 TI - The neurogenic response of cardiac resident nestin(+) cells was associated with GAP43 upregulation and abrogated in a setting of type I diabetes. AB - BACKGROUND: Cardiac nestin(+) cells exhibit properties of a neural progenitor/stem cell population characterized by the de novo synthesis of neurofilament-M in response to ischemic injury and 6-hydroxydopamine administration. The induction of growth associated protein 43 (GAP43) was identified as an early event of neurogenesis. The present study tested the hypothesis that the de novo synthesis of neurofilament-M by nestin(+) cells was preceded by the transient upregulation of GAP43 during the acute phase of reparative fibrosis in the infarcted male rat heart. Secondly, a seminal feature of diabetes is impaired wound healing secondary to an inadequate neurogenic response. In this regard, an additional series of experiments tested the hypothesis that the neurogenic response of cardiac nestin(+) cells was attenuated in a setting of type I diabetes. METHODS: The neurogenic response of cardiac nestin(+) cells was examined during the early phase of reparative fibrosis following permanent ligation of the left anterior descending coronary artery in the adult male rat heart. The experimental model of type I diabetes was created following a single injection of streptozotocin in adult male rats. The impact of a type I diabetic environment on the neurogenic response of cardiac nestin(+) cells was examined during myocardial infarction and following the administration of 6-hydroxydopamine. RESULTS: During the early phase of scar formation/healing, the density of GAP43/nestin(+) fibres innervating the peri-infarct/infarct region was significantly increased, whereas neurofilament-M/nestin(+) fibres were absent. With ongoing scar formation/healing, a temporal decrease of GAP43/nestin(+) fibre density and a concomitant increase in the density of innervating neurofilament-M/nestin(+) fibres were observed. The neurogenic response of cardiac nestin(+) cells during scar formation/healing was inhibited following the superimposition of type I diabetes. The de novo synthesis of neurofilament-M by nestin(+) cells after 6-hydroxydopamine administration was likewise attenuated in the heart of type I diabetic rats whereas the density of GAP43/nestin(+) fibres remained elevated. CONCLUSION: The transient upregulation of GAP43 apparently represents a transition event during the acquisition of a neuronal-like phenotype and a type I diabetic environment attenuated the neurogenic response of cardiac nestin(+) cells to ischemia and 6-hydroxydopamine. PMID- 23938195 TI - Autologous microtia reconstruction combined with ancillary procedures: a comprehensive reconstructive approach. AB - INTRODUCTION: Autologous microtia reconstruction is generally performed in two stages. The second stage presents a unique opportunity to carry out other complementary procedures. The present study describes our approach to microtia reconstruction, wherein the second stage of reconstruction is combined with final refinements to the ear construct and/or additional procedures to enhance facial contour and symmetry. METHODS: Retrospective analysis of patients who underwent two-stage microtia reconstruction by a single surgeon (NWB) was conducted in order to ascertain those that had ancillary procedures at the time of the second stage. Patient and operative details were collected. RESULTS: Thirty-four patients (male, 15, median age and age range at second stage, 11 and 10-18 years, respectively) who had complementary procedures executed during the second stage of auricular reconstruction were identified. Collectively, these included centralizing genioplasty (n = 1), fat transfer (n = 22), ear piercing (n = 7), and contralateral prominauris correction (n = 7). Six patients had correction for unilateral isolated microtia and in the remaining 28 patients, auricular reconstruction for microtia associated with a named syndrome. All patients reported a high rate of satisfaction with the result achieved and the majority (85%) reported no perceived need for additional surgical refinements to the ear or procedure(s) to achieve further facial symmetry. No peri- or post-operative complications were noted. CONCLUSION: Combining the final stage of autologous microtia reconstruction with other ancillary procedures affords a superior aesthetic outcome and decreased patient morbidity. PMID- 23938196 TI - Gastroesophageal reflux as a predictor of complications after adenotonsillectomy in young children. AB - OBJECTIVE: To examine characteristics of young children with gastroesophageal reflux (GER) who experienced complications within the first 24h after adenotonsillectomy. STUDY DESIGN: Subset analysis of a larger retrospective cohort. METHODS: A retrospective chart review was performed at a tertiary care children's hospital. Consecutive records of children 3 years old and younger undergoing adenotonsillectomy (AT) over a 5-year period were reviewed. Children with a clinical history of GER were selected for the study. RESULTS: 993 children were included in the initial analysis, and GER was found to be a significant independent variable predictive of early complications. 81 children with a history of GER were included in this study and 8 (9.9%) were found to have experienced complications within the first 24h. Six of the complications were airway-related; two required re-intubation within the first 24h. All 8 children with complications had symptoms of sleep-disordered breathing and two had documented severe obstructive sleep apnea (AHI 18.6 and 27.2). Seven children had other risk factors for complications after AT. Eighteen (22%) children had a prolonged length of stay (range 2-7 days); additional risk factors were present in these patients as well. CONCLUSIONS: Knowledge of risk factors for complications following adenotonsillectomy is critical for identifying at-risk patients that may warrant closer post-operative observation. GER has been previously identified as a risk factor for complications in young children. Upon closer analysis, young children with GER who have other known risk factors may be at a further increased risk for airway complications and prolonged hospitalization. Parents of these children can be counseled on the post-operative risks and the possibility of a longer hospitalization. PMID- 23938197 TI - 1st minimum consensus meeting on standardization in biodegradable metals: at the 4th Biometal Conference, Maratea, Italy, August 28-September 1, 2012. PMID- 23938198 TI - Ca(2+) released from calcium alginate gels can promote inflammatory responses in vitro and in vivo. AB - In general, alginate hydrogels are considered to be biologically inert and are commonly used for biomedical purposes that require minimum inflammation. However, Ca(2+), which is commonly used to crosslink alginate, is a critical second messenger in immune cell signaling, and little has been done to understand its effect on immune cell fate when delivered as a component of alginate gels. We found that dendritic cells (DCs) encapsulated in Ca(2+)-crosslinked alginate (calcium alginate) secreted at least fivefold more of the inflammatory cytokine IL-1beta when compared to DCs encapsulated in agarose and collagen gels, as well as DCs plated on tissue-culture polystyrene (TCPS). Plating cells on TCPS with the alginate polymer could not reproduce these results, whereas culturing DCs on TCPS with increasing concentrations of Ca(2+) increased IL-1beta, MHC class II and CD86 expression in a dose-dependent manner. In agreement with these findings, calcium alginate gels induced greater maturation of encapsulated DCs compared to barium alginate gels. When injected subcutaneously in mice, calcium alginate gels significantly upregulated IL-1beta secretion from surrounding tissue relative to barium alginate gels, and similarly, the inflammatory effects of LPS were enhanced when it was delivered from calcium alginate gels rather than barium alginate gels. These results confirm that the Ca(2+) used to crosslink alginate gels can be immunostimulatory and suggest that it is important to take into account Ca(2+)'s bioactive effects on all exposed cells (both immune and non immune) when using calcium alginate gels for biomedical purposes. This work may strongly impact the way people use alginate gels in the future as well as provide insights into past work utilizing alginate gels. PMID- 23938200 TI - In vivo inhibition of hypertrophic scars by implantable ginsenoside-Rg3-loaded electrospun fibrous membranes. AB - Clinically, hypertrophic scarring (HS) is a major concern for patients and has been a challenge for surgeons, as there is a lack of treatments that can intervene early in the formation of HS. This study reports on a Chinese drug, 20(R)-ginsenoside Rg3 (GS-Rg3), which can inhibit in vivo the early formation of HS and later HS hyperplasia by inducing the apoptosis of fibroblasts, inhibiting inflammation and down-regulating VEGF expression. Implantable biodegradable GS Rg3-loaded poly(l-lactide) (PLA) fibrous membranes were successfully fabricated using co-electrospinning technology to control drug release and improve drug utilization. The in vivo releasing time of GS-Rg3 lasts for 3 months, and the drug concentration released in rabbits can be controlled by varying the drug content of the electrospun fibers. Histological observations of HE staining indicate that GS-Rg3/PLA significantly inhibits the HS formation, with obvious improvements in terms of dermis layer thickness, epidermis layer thickness and fibroblast proliferation. The results of immunohistochemistry staining and Masson's trichrome staining demonstrate that GS-Rg3/PLA electrospun fibrous membranes significantly inhibit HS formation, with decreased expression of collagen fibers and microvessels. VEGF protein levels are much lower in the group treated with GS-Rg3/PLA eletrospun membranes compared with other groups. These results demonstrate that GS-Rg3 is a novel drug, capable of inhibiting the early formation of HS and later HS hyperplasia. GS-Rg3/PLA electrospun membrane is a very promising new treatment for early and long-term treatment of HS. PMID- 23938199 TI - Tropoelastin: a versatile, bioactive assembly module. AB - Elastin provides structural integrity, biological cues and persistent elasticity to a range of important tissues, including the vasculature and lungs. Its critical importance to normal physiology makes it a desirable component of biomaterials that seek to repair or replace these tissues. The recent availability of large quantities of the highly purified elastin monomer, tropoelastin, has allowed for a thorough characterization of the mechanical and biological mechanisms underpinning the benefits of mature elastin. While tropoelastin is a flexible molecule, a combination of optical and structural analyses has defined key regions of the molecule that directly contribute to the elastomeric properties and control the cell interactions of the protein. Insights into the structure and behavior of tropoelastin have translated into increasingly sophisticated elastin-like biomaterials, evolving from classically manufactured hydrogels and fibers to new forms, stabilized in the absence of incorporated cross-linkers. Tropoelastin is also compatible with synthetic and natural co polymers, expanding the applications of its potential use beyond traditional elastin-rich tissues and facilitating finer control of biomaterial properties and the design of next-generation tailored bioactive materials. PMID- 23938201 TI - A duplex, SYBR Green I-based RT-qPCR assay for the simultaneous detection of Apple chlorotic leaf spot virus and Cherry green ring mottle virus in peach. AB - BACKGROUND: Co-infections of Apple chlorotic leaf spot virus (ACLSV) and Cherry green ring mottle virus (CGRMV) in peach is common in China and have resulted in significant yield reductions. A reliable, sensitive and quantitive method is needed to detect and distinguish between ACLSV and CGRMV in peach. FINDINGS: We developed a sensitive and specific SYBR Green-I based RT-qPCR for the quantification of ACLSV and CGRMV in different peach tissues, and a duplex RT qPCR system to detect ACLSV and CGRMV simultaneously. The RT-qPCR method was optimized using standard samples transcribed by the T7 Large Scale RNA Production System in vitro. The peach genes, RNA Polymerase subunit II (RPII) and Ubiquitin 10 (UBQ10), which were used as the internal controls for the quantification assay also showed good expression stability in this system. Single RT-qPCR assays showed that CGRMV in peach accumulates to a higher level than ACLSV. The detection limits of the duplex RT-qPCR assay were 102 and 104 copies for ACLSV and CGRMV, respectively. The sensitivity of the duplex RT-qPCR was as high as RT qPCR and higher than RT-PCR. CONCLUSIONS: The SYBR Green-I RT-qPCR assay provided a sensitive, specific and reliable method for the detection and quantification of ACLSV and CGRMV in different peach tissues. The duplex RT-qPCR system provided a sensitive and specific method to detect and differentiate between ACLSV and CGRMV in a single sample. This RT-qPCR assay could be a useful tool for the routine diagnosis of these two viruses and for disease epidemiology studies in peach orchards. PMID- 23938202 TI - The local dinucleotide preference of APOBEC3G can be altered from 5'-CC to 5'-TC by a single amino acid substitution. AB - APOBEC3A and APOBEC3G are DNA cytosine deaminases with biological functions in foreign DNA and retrovirus restriction, respectively. APOBEC3A has an intrinsic preference for cytosine preceded by thymine (5'-TC) in single-stranded DNA substrates, whereas APOBEC3G prefers the target cytosine to be preceded by another cytosine (5'-CC). To determine the amino acids responsible for these strong dinucleotide preferences, we analyzed a series of chimeras in which putative DNA binding loop regions of APOBEC3G were replaced with the corresponding regions from APOBEC3A. Loop 3 replacement enhanced APOBEC3G catalytic activity but did not alter its intrinsic 5'-CC dinucleotide substrate preference. Loop 7 replacement caused APOBEC3G to become APOBEC3A-like and strongly prefer 5'-TC substrates. Simultaneous loop 3/7 replacement resulted in a hyperactive APOBEC3G variant that also preferred 5'-TC dinucleotides. Single amino acid exchanges revealed D317 as a critical determinant of dinucleotide substrate specificity. Multi-copy explicitly solvated all-atom molecular dynamics simulations suggested a model in which D317 acts as a helix-capping residue by constraining the mobility of loop 7, forming a novel binding pocket that favorably accommodates cytosine. All catalytically active APOBEC3G variants, regardless of dinucleotide preference, retained human immunodeficiency virus type 1 restriction activity. These data support a model in which the loop 7 region governs the selection of local dinucleotide substrates for deamination but is unlikely to be part of the higher level targeting mechanisms that direct these enzymes to biological substrates such as human immunodeficiency virus type 1 cDNA. PMID- 23938203 TI - Structural basis for the interaction of human beta-defensin 6 and its putative chemokine receptor CCR2 and breast cancer microvesicles. AB - Human beta-defensins (hBDs) are believed to function as alarm molecules that stimulate the adaptive immune system when a threat is present. In addition to its antimicrobial activity, defensins present other activities such as chemoattraction of a range of different cell types to the sites of inflammation. We have solved the structure of the hBD6 by NMR spectroscopy that contains a conserved beta-defensin domain followed by an extended C-terminus. We use NMR to monitor the interaction of hBD6 with microvesicles shed by breast cancer cell lines and with peptides derived from the extracellular domain of CC chemokine receptor 2 (Nt-CCR2) possessing or not possessing sulfation on Tyr26 and Tyr28. The NMR-derived model of the hBD6/CCR2 complex reveals a contiguous binding surface on hBD6, which comprises amino acid residues of the alpha-helix and beta2 beta3 loop. The microvesicle binding surface partially overlaps with the chemokine receptor interface. NMR spin relaxation suggests that free hBD6 and the hBD6/CCR2 complex exhibit microsecond-to-millisecond conformational dynamics encompassing the CCR2 binding site, which might facilitate selection of the molecular configuration optimal for binding. These data offer new insights into the structure-function relation of the hBD6-CCR2 interaction, which is a promising target for the design of novel anticancer agents. PMID- 23938204 TI - Teaching old NCATs new tricks: using non-canonical amino acid tagging to study neuronal plasticity. AB - The non-canonical amino acid labeling techniques BONCAT (bioorthogonal non canonical amino acid tagging) and FUNCAT (fluorescent non-canonical amino acid tagging) enable the specific identification and visualization of newly synthesized proteins. Recently, these techniques have been applied to neuronal systems to elucidate protein synthesis dynamics during plasticity, identify stimulation-induced proteomes and subproteomes and to investigate local protein synthesis in specific subcellular compartments. The next generation of tools and applications, reviewed here, includes the development of new tags, the quantitative identification of newly synthesized proteins, the application of NCAT to whole animals, and the ability to genetically restrict NCAT labeling. These techniques will enable not only improved detection but also allow new scientific questions to be tackled. PMID- 23938205 TI - Ability of ellagic acid to alleviate osmotic stress on chickpea seedlings. AB - Seed germination and growth of seedlings are critical phases of plant life that are adversely affected by various environmental cues. Water availability is one of the main factors that limit the productivity of many crops. This study was conducted to assess the changes in the sensitivity of chickpea seedlings to osmotic stress by prior treatment of chickpea seeds with a low concentration (50 ppm) of ellagic acid. Ellagic acid was isolated and purified from Padina boryana Thivy by chromatographic techniques. After ellagic acid treatment, seeds were germinated for 10 days under different osmotic potentials (0, -0.2, -0.4, -0.6 and -0.8 MPa) of polyethylene glycol (PEG) solutions. Ellagic acid treatment accelerated the germination and seedling growth of chickpea under osmotic stress conditions. Consistent with the accelerated growth, ellagic acid-treated seedlings also showed a significant increase in the total antioxidant capacity (FRAP) as well as an increase in the compatible solutes (proline and glycine betaine) content. Additionally, treated seedlings revealed lower lipid peroxidation levels (MDA), electrolyte leakage (EL) and H2O2. Flavonoid and reduced glutathione (GSH) content, and the activity of antioxidant enzymes [catalase (CAT), peroxidase (POX), superoxide dismutase (SOD), glutathione reductase (GR)] and enzymes of the shikimic acid pathway [phenylalanine ammonia lyase (PAL) and chalcone synthase (CHS)] all showed a remarkable increase with ellagic acid pretreatment compared to untreated seedlings especially under mild osmotic stress values (-0.2 and -0.4 MPa). These results suggested that treatment with ellagic acid could confer an increased tolerance of chickpea seedlings to osmotic stress, through reducing levels of H2O2 and increasing antioxidant capacity. PMID- 23938206 TI - Proteomic and metabolomic analysis reveal gender-specific responses of mussel Mytilus galloprovincialis to 2,2',4,4'-tetrabromodiphenyl ether (BDE 47). AB - Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame-retardants (BFRs) that are widely used in industrial products and have posed potential risk on the coastal environment of the Laizhou Bay in China. They are of great concern due to their toxicities, such as hepatotoxicity, carcinogenecity, neurotoxicity, immunotoxicity and endocrine disrupting effects in animals. In this work, we focused on the gender-specific responses of BDE 47 in mussel Mytilus galloprovincialis using a combined proteomic and metabolomic approach. Metabolic responses indicated that BDE 47 mainly caused disturbance in energy metabolism in male mussel gills. For female mussel samples, disruption in both osmotic regulation and energy metabolism was found in terms of differential metabolic profiles. Proteomic responses revealed that BDE 47 induced cell apoptosis and reduced reactive oxygen species (ROS) production in both male and female mussels, disturbance in protein homeostasis in male mussels as well as disturbance in female mussel proteolysis based on the differential proteomic biomarkers. Overall, these results confirmed the gender-specific responses in mussels to BDE 47 exposures. This work demonstrated that an integrated metabolomic and proteomic approach could provide an important insight into the toxicological effects of environmental pollutant to organisms. PMID- 23938207 TI - Single-crystal X-ray diffraction analysis of designer drugs: hydrochlorides of metaphedrone and pentedrone. AB - This article, written as a result of cooperation between a police forensic laboratory and an academic institution, outlines the possibility of applying single-crystal X-ray diffraction analysis as an effective method of identifying designer drugs in forensic analysis. This technique allows crystalline samples to be determined with full assurance about their identity, even in the case of new substances for which no reference standards yet exist. Here, single-crystal X-ray diffraction measurements of single-crystal specimens obtained from two samples were performed. Solution and refinement of the structures demonstrated that the target compounds were metaphedrone and pentedrone hydrochlorides - synthetic cathinone derivatives used as recreational stimulants. In addition to the identification of the title compounds, this paper gives a first report on their crystal structures. Once the CIF-files containing the crystal structure data of the title compounds have been deposited in the Cambridge Structural Database - the world repository of small molecule crystal structures - it will be possible to identify single crystals of the title compounds quickly on the basis of simple parameters (lattice parameters a, b, c, alpha, beta, gamma and unit cell volume). This description of the relationship between the geometrical parameters of moieties and the analysis of intermolecular interactions occurring in crystals of the title compounds extends knowledge about the synthetic derivatives of cathinone and may play a role in future studies, leading to a better understanding of their characteristic properties. PMID- 23938208 TI - Stimulus-dependent activations and attention-related modulations in the auditory cortex: a meta-analysis of fMRI studies. AB - We meta-analyzed 115 functional magnetic resonance imaging (fMRI) studies reporting auditory-cortex (AC) coordinates for activations related to active and passive processing of pitch and spatial location of non-speech sounds, as well as to the active and passive speech and voice processing. We aimed at revealing any systematic differences between AC surface locations of these activations by statistically analyzing the activation loci using the open-source Matlab toolbox VAMCA (Visualization and Meta-analysis on Cortical Anatomy). AC activations associated with pitch processing (e.g., active or passive listening to tones with a varying vs. fixed pitch) had median loci in the middle superior temporal gyrus (STG), lateral to Heschl's gyrus. However, median loci of activations due to the processing of infrequent pitch changes in a tone stream were centered in the STG or planum temporale (PT), significantly posterior to the median loci for other types of pitch processing. Median loci of attention-related modulations due to focused attention to pitch (e.g., attending selectively to low or high tones delivered in concurrent sequences) were, in turn, centered in the STG or superior temporal sulcus (STS), posterior to median loci for passive pitch processing. Activations due to spatial processing were centered in the posterior STG or PT, significantly posterior to pitch processing loci (processing of infrequent pitch changes excluded). In the right-hemisphere AC, the median locus of spatial attention-related modulations was in the STS, significantly inferior to the median locus for passive spatial processing. Activations associated with speech processing and those associated with voice processing had indistinguishable median loci at the border of mid-STG and mid-STS. Median loci of attention related modulations due to attention to speech were in the same mid-STG/STS region. Thus, while attention to the pitch or location of non-speech sounds seems to recruit AC areas less involved in passive pitch or location processing, focused attention to speech predominantly enhances activations in regions that already respond to human vocalizations during passive listening. This suggests that distinct attention mechanisms might be engaged by attention to speech and attention to more elemental auditory features such as tone pitch or location. This article is part of a Special Issue entitled Human Auditory Neuroimaging. PMID- 23938209 TI - Pitch coding and pitch processing in the human brain. AB - Neuroimaging studies have provided important information regarding how and where pitch is coded and processed in the human brain. Recordings of the frequency following response (FFR), an electrophysiological measure of neural temporal coding in the brainstem, have shown that the precision of temporal pitch information is dependent on linguistic and musical experience, and can even be modified by short-term training. However, the FFR does not seem to represent the output of a pitch extraction process, and this raises questions regarding how the peripheral neural signal is processed to produce a unified sensation. Since stimuli with a wide variety of spectral and binaural characteristics can produce the same pitch, it has been suggested that there is a place in the ascending auditory pathway at which the representations converge. There is evidence from many different human neuroimaging studies that certain areas of auditory cortex are specifically sensitive to pitch, although the location is still a matter of debate. Taken together, the results suggest that the initial temporal pitch code in the auditory periphery is converted to a code based on neural firing rate in the brainstem. In the upper brainstem or auditory cortex, the information from the individual harmonics of complex tones is combined to form a general representation of pitch. This article is part of a Special Issue entitled Human Auditory Neuroimaging. PMID- 23938210 TI - Objectively measured muscle fatigue in Crohn's disease: correlation with self reported fatigue and associated factors for clinical application. AB - BACKGROUND & AIMS: The association of fatigue with decreased physical performance and underlying mechanisms are poorly understood in Crohn's disease (CD). We aimed to measure and compare self-reported fatigue with skeletal muscle fatigue in CD subjects and healthy controls, and to identify associated factors that may be amenable to change. METHODS: Demographic and clinical data were collected and fatigue assessed using the Fatigue Impact Scale (FIS) in 27 consecutive CD patients and 22 matched healthy controls. Circulating cytokines and growth factors were measured. The rate of quadriceps muscle fatigue was assessed using an isokinetic dynamometer as the decrement of force with 30 contractions performed over a 5-minute period. RESULTS: Compared with healthy controls, CD patients reported greater levels of fatigue (mean global FIS score 45.3 vs 10.5, physical dimension score 12.3 vs 2.7 respectively; each p<0.01) and muscle fatigue (-5.2 vs -1.3 Nm min(-1); p<0.05). The two indices were correlated (r = 0.52 in CD; p<0.01). Patients with CD had lower mean serum IGF-1 levels (16.1 vs 25.4 pmol/L, p<0.01) and higher oxidative stress (TBARS assay 4.3 vs 3.9 MUM, p<0.05). On multivariate analysis, low serum vitamin D, IGF-1 and magnesium, and higher IL-6 levels were associated with increased muscle fatigue (all p <= 0.05). CONCLUSION: Subjects with CD had more muscle fatigue than matched healthy controls and this correlated well with self-reported fatigue. Of circulating factors that were independently associated with increased muscle fatigue, vitamin D, magnesium and IGF-1 could be targeted in future studies to reduce fatigue and improve physical performance. PMID- 23938211 TI - Point-counterpoint: Are we overtreating patients with mild ulcerative colitis? PMID- 23938212 TI - Unusual presentation of alveolar echinococcosis as prostatic and paraprostatic cysts in a dog. AB - BACKGROUND: Alveolar echinococcosis (AE) is caused by the larval stage (metacestode) of Echinococcus multilocularis. The domestic dog can act as a definitive host and harbor adult cestodes in its small intestine or become an aberrant intermediate host carrying larval stages that may cause severe lesions in the liver, lungs and other organs with clinical signs similar to AE in humans. CASE PRESENTATION: A case of canine AE, affecting the liver and prostate with development of multilocular hydatid paraprostatic cysts and possible lung involvement is described in an 8-year-old neutered male Labrador retriever dog.The dog presented with progressive weight loss, acute constipation, stranguria and a suspected soft tissue mass in the sublumbar region. Further evaluation included computed tomography of the thorax and abdomen, which revealed cystic changes in the prostate, a paraprostatic cyst, as well as lesions in the liver and lungs. Cytological examination of fine-needle aspirates of the liver, prostate and paraprostatic cyst revealed parasitic hyaline membranes typical of an Echinococcus infection and the presence of E. multilocularis-DNA was confirmed by PCR. The dog was treated with albendazole and debulking surgery was considered in case there was a good response to antiparasitic treatment. Constipation and stranguria resolved completely. Six months after the definitive diagnosis, the dog was euthanized due to treatment-resistant ascites and acute anorexia and lethargy. CONCLUSIONS: To the authors' knowledge, this is the first publication of an E. multilocularis infection in a dog causing prostatic and paraprostatic cysts. Although rare, E. multilocularis infection should be considered as an extended differential diagnosis in dogs presenting with prostatic and paraprostatic disease, especially in areas where E. multilocularis is endemic. PMID- 23938213 TI - Germline deletions in the EPCAM gene as a cause of Lynch syndrome - literature review. AB - Lynch syndrome (clinically referred to as HNPCC - Hereditary Non-Polyposis Colorectal Cancer) is a frequent, autosomal, dominantly-inherited cancer predisposition syndrome caused by various germline alterations that affect DNA mismatch repair genes, mainly MLH1 and MSH2. Patients inheriting this predisposition are susceptible to colorectal, endometrial and other extracolonic tumors. It has recently been shown that germline deletions of the last few exons of the EPCAM gene are involved in the etiology of Lynch syndrome. Such constitutional mutations lead to subsequent epigenetic silencing of a neighbouring gene, here, MSH2, causing Lynch syndrome. Thus, deletions of the last few exons of EPCAM constitute a distinct class of mutations associated with HNPCC. Worldwide, several investigators have reported families with EPCAM 3'end deletions. The risk of colorectal cancer in carriers of EPCAM deletions is comparable to situations when patients are MSH2 mutation carriers, and is associated with high expression levels of EPCAM in colorectal cancer stem cells. A lower risk of endometrial cancer was also reported. Until now the standard diagnostic tests for Lynch syndrome have contained analyses such as immunohistochemistry and tests for microsatellite instability of mismatch repair genes. The identification of EPCAM deletions or larger EPCAM-MSH2 deletions should be included in routine mutation screening, as this has implications for cancer predisposition. PMID- 23938215 TI - Impact of anatomical subtype and medical comorbidities on hospitalizations in adults with single ventricle congenital heart disease. AB - BACKGROUND: Most patients with single ventricle congenital heart disease (SV) are now expected to survive to adulthood. Medical comorbidities are common in SV. METHODS: We used data from 43 pediatric hospitals in the 2004 to 2011 Pediatric Health Information System database to identify patients >=18 years of age admitted with International Classification of Diseases-9th Revision codes for a diagnosis of either hypoplastic left heart syndrome (HLHS), tricuspid atresia (TA) or common ventricle (CV). Primary (PD) and secondary diagnoses (SD), length of stay (LOS) and hospital charges were determined. Multilevel models were used to evaluate differences in demographics, diagnoses, and admission outcomes among the three subgroups (HLHS, TA, and CV). Interactions of charges with PD and admission year were examined using ANOVA. RESULTS: There were 801 SV patients with 1330 admissions during the study period. Mean age was 24.8+/-6.2 years (55% male) and mean LOS was 6.8+/-11.3 days. Total hospital charges were $135 million with mean charge per admission of $101,131+/-205,808. The mean charge per day was $15,407+/-16,437. Hospital charges correlated with PD group (p<0.001). Admission rate remained stable (~180/year) from 2006 to 2011. LOS decreased (p=0.0308) and hospital charges per day increased across the study period (p<0.001). PD was non cardiac in 28% of admissions. Liver-related conditions were more common in patients with HLHS (p<0.001). CONCLUSIONS: Hospitalization costs in adults with SV are significant and are impacted by comorbid medical conditions. Hospitalization rates for adults with SV are not increasing. Gastroenterologic comorbidities including protein-losing enteropathy (PLE) are common in HLHS. PMID- 23938216 TI - Differential activation of myocardial ER stress response: a possible role in hypoxic tolerance. AB - BACKGROUND: Low oxygen availability in the high altitude milieu causes adverse physiological and pathological consequences to the cardiopulmonary system. A key role is played by proteins in maintaining optimal cardiac function under stress. Differential response to hypoxia may be linked to the susceptibility of proteins to free radical induced modifications. The present study was designed to understand the significance of protein oxidation and ER stress in the myocardial response to hostile environments. METHODS: Sprague-Dawley rats were exposed to simulated hypoxia equivalent to 223 mmHg pressure, screened on the basis of time taken for onset of a characteristic hyperventilatory response and categorized as susceptible (<10 min), normal (10-25 min) or tolerant (>25 min). Protein modifications and activity of cellular proteolytic enzymes were assayed in myocardial tissue extracts to identify alterations in protein homeostasis. To evaluate the ER stress response, expression of various ER marker chaperones was investigated. RESULTS: Susceptible animals displayed a distinct increase in protein oxidation and intracellular thiol content. They showed higher expression of ER stress hallmarks, GRP78, PDI and ERO1alpha, and exhibited a greater activation of the proteasome and calpain proteolytic systems, associated with elevated oxidized proteins. While a marked upregulation in the prosurvival signaling cascade PI3K/Akt/mTOR was observed in tolerant animals, the expression of pro-apoptotic caspase-3 and CHOP remained unaltered. CONCLUSION: Thus, higher susceptibility to hypoxia is linked to a disruption in the proteostasis and activation of the ER stress response. Enhanced tolerance to hostile environments may be contributed by better maintenance of protein folding homeostasis. PMID- 23938217 TI - A meta-analysis of using a stent-based strategy for chronic total coronary occlusions recanalization: effects of length of follow-up on clinical outcomes. PMID- 23938214 TI - Environmental assessment and exposure reduction of cockroaches: a practice parameter. AB - This parameter was developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "Environmental assessment and remediation: a practice parameter." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single person, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC). PMID- 23938218 TI - Left ventricular fibrosis in adults after coarctation repair, does it play a role? PMID- 23938219 TI - Low vitamin D levels in adults with longer time to fall asleep: US NHANES, 2005 2006. PMID- 23938220 TI - Rheumatoid arthritis and risk of acute myocardial infarction--a nationwide retrospective cohort study. AB - OBJECTIVES: Rheumatoid arthritis (RA) imposes substantial social costs, including an increased risk of work-related disability and accelerated cardiovascular diseases. The aim of the study is to determine the risk of acute myocardial infarction (AMI) associated with RA in a nationwide retrospective cohort study. METHODS: Using the catastrophic illness registry of the Taiwan National Health Insurance Research Database (NHIRD), we identified patients with RA from 1998 to 2010. We also randomly selected non-RA controls frequency-matched by age, sex, and index year from the general population free of RA. The risk of AMI was analyzed using Cox proportional hazards regression models including sex, age, and comorbidities. RESULTS: From a total of 23.74 million people in the cohort, 29,260 RA patients and 117,040 controls were followed for 193,987 and 792,254 person-years, respectively. The incidence density rate increased in all groups of RA patients than those of the controls. RA patients had a 1.33-fold higher overall incidence of AMI than controls, with an adjusted hazard ration of 1.38. Although the overall adjusted hazard ratio of AMI increased with age, the age specific RA patients to controls incidence rate ratio was higher for younger RA patients. Subjects with comorbidities of hypertension, diabetes hyperlipidemia, CVA, COPD, or ESRD had increased risk of AMI. Subjects with ESRD had the highest hazard of AMI. CONCLUSION: This nationwide retrospective cohort study indicates that AMI risk increased by 38% in RA patients compared to the general population. Comorbidities increase the AMI risk independently. PMID- 23938221 TI - Alice's evidence: reply to "Statins: a sine qua non of the management of patients with abdominal aortic aneurysms". PMID- 23938222 TI - Mechanical characterization of nanoporous materials by use of atomic force acoustic microscopy methods. AB - We have used the atomic force acoustic microscopy (AFAM) method to determine the indentation modulus of nanoporous thin-film materials with ultralow values of dielectric permittivity (dielectric constant k < 2.4). The AFAM method is based on the contact mode of atomic force microscopy (AFM) and as such is able to characterize materials with high spatial resolution. The tested material was porous organosilicate glass with nominal porosity ranging from 27% to 40%. The values obtained for the indentation modulus varied from 4 to 7 GPa depending on the pore concentration. The values obtained for the indentation modulus by use of the AFAM method were in very good agreement with those determined by nanoindentation. In addition, a part of the AFAM results obtained for the sample with the highest porosity content showed dependence of the effective indentation modulus on the applied load. Preliminary data analysis suggests that the stress rate is the critical factor in triggering this particular mechanical response of the porous material. PMID- 23938223 TI - Central granular cell odontogenic tumor of the mandible. PMID- 23938224 TI - Proteomic analysis of B-cell receptor signaling in chronic lymphocytic leukaemia reveals a possible role for kininogen. AB - CLL is an incurable disease with variable prognosis. The hyper reactivity of the B-cell receptor (BCR) to unknown antigen ligation plays a pivotal role in CLL cell survival. We aimed to investigate the BCR signalling pathway using proteomics to identify novel proteins which may have clinical relevance in this disease. Three CLL samples were selected based upon BCR responsiveness, demonstrated by upregulation of phospho-ERK following in vitro stimulation. The differential expression of proteins, upon artificial stimulation of the BCR, was examined in these samples using two-dimensional gel electrophoresis in combination with mass spectrometry. Proteins of interest were subsequently examined using immunoblotting. Proteomic analysis revealed that kininogen, a critical protein of kinin-kallikrein system, was upregulated in all 3 clinical samples upon BCR stimulation. There are 2 forms of kininogen: HMWK and LMWK. The upregulation of LMWK upon BCR stimulation was confirmed by immunoblotting in all 3 of these samples. In a pilot series of 52 unselected CLL samples, 71% demonstrated basal LMWK expression. There was a trend towards shorter median survival in LMWK positive cases (147months versus 253months for LMWK negative cases; p=0.125). Kininogen may be a novel therapeutic target in CLL and the possible association with prognosis warrants further investigation. BIOLOGICAL SIGNIFICANCE: We have identified the upregulation of LMWK upon BCR stimulation of CLL samples. There is no previous published research to suggest a link between kininogen and normal B-cells or CLL cells. In 52 unselected CLL samples, 71% demonstrated basal LMWK expression. There was a trend towards shorter median survival in LMWK positive cases. The absence of LMWK protein expression on normal B-cells suggests that this could be a biomarker for CLL and further research should be undertaken. PMID- 23938225 TI - James Parkinson: the man behind the shaking palsy. AB - James Parkinson occupies a unique position in the history of Parkinson's disease. As the man responsible for originally identifying and describing the disease that he called the Shaking Palsy, his name is familiar to anybody with a connection with the disease - patients, carers, clinicians and members of the general public alike. This review summarises the life and career of one of the most recognizable names in neurology. PMID- 23938226 TI - Levodopa-induced-dyskinesias clinical features, incidence, risk factors, management and impact on quality of life. AB - Levodopa-induced dyskinesias (LID) belong to the most common dose-limiting adverse effects of levodopa therapy. "Peak-dose" LID occur with the maximum effect of medication, 'diphasic dyskinesias' have a "beginning- and end-of-dose" pattern, and the, "off-period dyskinesia" occur during off-periods, most frequently in the early mornings and are typically dystonic in nature. The majority of patients will have developed dyskinesias after 10 years of treatment, and about 40-50% after 5 years. Occurrence of LID appears to be related to dose and duration of treatment with levodopa and severity and duration of disease. In addition, patients with younger age of onset have been reported to have an earlier onset and higher rate of LID. The important aetiological role of non physiological pulsatile stimulation of dopaminergic receptors is increasingly recognized and more continuous dopaminergic stimulation with the longer acting dopamine agonists has been shown to reduce and delay the onset of dyskinesias. LID may not have a significant effect on quality of life in patients with early disease or in very advanced disease stages. when often other problems arise, but in other patients they may be severely disabling. Treatment strategies to overcome LID include adjustment of timing, type and amount of dopaminergic medication, treatment with amantadine and, in treatment resistant cases, stereotactic surgery involving deep brain stimulation or lesioning procedures. A number of other pharmacological options are also being explored. Several methods for the assessment of LID are available to attempt accurate assessment of efficacy, although all of these have limitations, and further evidence on their utility if needed. PMID- 23938227 TI - Prevalence and clinical course of olfactory hallucinations in idiopathic Parkinson's disease. AB - BACKGROUND: Olfactory hallucinations are known to occur in idiopathic Parkinson's disease (IPD) but are much less well-described than visual hallucinations. OBJECTIVE: To report the prevalence, clinical features, response to treatment and prognosis of olfactory hallucinations in IPD. METHODS: 205 consecutively reviewed IPD patients and 205 non-IPD control patients attending the local hospital were surveyed for the presence of olfactory hallucinations by specific questioning; the IPD patients were followed up for at least three years. RESULTS: Of 188 patients who had a clinical course remaining consistent with IPD, four were initially found to have olfactory hallucinations, yielding a prevalence of 2.1% (95% confidence interval 0.4-5.4%). Two further patients developed such hallucinations later during the study. Olfactory hallucinations were not always accompanied by other hallucination modalities. The patients had a long duration of disease treated with dopaminergic medication, loss of sense of smell typical for IPD, no dementia or features suggestive of non-idiopathic PD after three years follow-up, a lack of insight into their hallucinations with consequent failure to report them spontaneously, and a good and lasting response to modest doses of atypical antipsychotics. CONCLUSIONS: This study confirms the significant prevalence of olfactory hallucinations, describes their clinical features and indicates that they may occur in isolation and not predict other psychotic or dementing features. The nuisance that such hallucinations cause, their ease of treatment and their failure to be volunteered as a symptom means that specific questioning for their presence should be included in routine assessment of patients with IPD. PMID- 23938228 TI - The relationship between the grooved pegboard test and clinical motor symptom evaluation across the spectrum of Parkinson's disease severity. AB - BACKGROUND: The Unified Parkinson's Disease Rating Scale (UPDRS) is the gold standard for assessing Parkinsonian symptoms, yet objective outcome measures are needed to complement the UPDRS in research and clinical practice. OBJECTIVE: This study aimed to investigate the relationship between performance on the Grooved Pegboard Test (GP) and clinical assessment of Parkinson's motor symptoms with the UPDRS. METHODS: A large sample of individuals with Parkinson's disease (n = 191) were assessed with the GP and UPDRS motor section. The GP was separated into a place (more representative of visuospatial accuracy) and remove phase (general representation of motor speed and bradykinesia). Both tests were completed at peak anti-parkinsonian medication levels, and UPDRS subscores were calculated to represent upper-limb control, rigidity, bradykinesia, and tremor. A subsequent correlation analysis was completed. RESULTS: The strongest relationships were between the GP place phase (both limbs) and total UPDRS motor score (affected: r = 0.604, less-affected: r = 0.587), upper-limb control (affected: r = 0.367, less affected: r = 0.426), rigidity (affected: r = 0.479, less-affected: r = 0.457) and body bradykinesia (affected: r = 0.375, less-affected: r = 0.438). The GP remove phase had weak positive relationships with total UPDRS scores (affected: r = 0.31, less-affected r = 0.31) and body bradykinesia (r = 0.31). CONCLUSIONS: Clinical assessment of upper-limb control, rigidity and bradykinesia are well represented by the GP place phase. Interestingly, it appeared that GP performance of the more affected limb may be more representative of motor severity in the early stages of disease, while more research is needed to understand the utility of the GP in the advanced stages of disease. PMID- 23938230 TI - Exploring hypersexual behavior in men with Parkinson's disease: is it compulsive sexual behavior? AB - BACKGROUND: A range of impulse control disorders has been described in Parkinson's disease, including compulsive sexual behavior. Excessive sexual demands of parkinsonian men can lead to considerable tension within the couple. Thorough sexual interviews reveal that these cases may reflect various types of sexual dysfunctions that present as hypersexuality. OBJECTIVE: This study aims to analyze cases of presumed and true compulsive male sexual behavior, and to propose a practical tool for clinicians, assisting them with the diagnosis and management of compulsive sexual behavior and other sexual dysfunctions in parkinsonian patients. METHODS: We describe four male patients with Parkinson's disease from the movement disorders clinic, which were referred to the sex therapist as suspected hypersexuality. RESULTS: The sexual assessment revealed that only one of the cases involved true hypersexuality due to compulsive sexual behavior. The other three presented with erectile dysfunction, difficulties reaching orgasm (delayed ejaculation), and a gap in desire within the couple. CONCLUSIONS: Complaints about hypersexual behavior in patients with Parkinson's disease must be carefully evaluated, involving a multidisciplinary team. A comprehensive diagnostic and therapeutic algorithm is suggested. PMID- 23938231 TI - Treating orthostatic hypotension in patients with Parkinson's disease and atypical Parkinsonism improves function. AB - BACKGROUND: Patients with idiopathic Parkinson's disease (PD) or atypical Parkinsonism (AP) often present with orthostatic hypotension (OH) as a result of the dysautonomia associated with the disease or as a side effect of the dopaminergic medications used to treat it. Our recent study suggested that OH negatively impacts gross motor, balance, and cognitive functions in patients with PD. OBJECTIVE: To determine if correcting the orthostatic hypotension (OH) of patients with PD or AP improves their gross motor, balance, and cognitive functions. METHODS: Forty patients with PD or AP were assessed before and after correcting their OH using a staged approach with a goal of SBP >80 when standing and SBP <180 when laying. Step 1 of treatment included reducing antihypertensive medications, as possible, maintaining hydration with 1500cc/day, decreasing dietary salt, wearing high compression stockings, and keeping the head of bed elevated at 30 degrees when supine. If SBP <80 with standing after step 1, then treatment was started with fludrocortisone and/or midodrine. RESULTS: Patients' OH was managed as part of a rehabilitation program. Tests such as the Motor and Cognitive Functional Independence Measures, Berg Balance Scale, Two Minute Walking test, and the Finger Tapping test showed significant improvements (p < 0.05) in their gross motor, walking, balance and cognitive function with our OH management plan. No significant differences between admission and discharge were found in the Timed Up and Go test. CONCLUSION: Our data suggest that monitoring and correcting the OH of patients with PD or AP improves their gross motor, balance, and cognitive function. PMID- 23938232 TI - Cardiovascular responses during a submaximal exercise test in patients with Parkinson's disease. AB - BACKGROUND: Patients with Parkinson's disease (PD) are physically less active than controls, and autonomic dysfunction may contribute to this sedentary lifestyle. Specifically, an altered cardiovascular response to physical effort may restrict physical activities. OBJECTIVE: To assess the cardiovascular responses to a submaximal exercise test in PD patients and controls, 546 sedentary PD patients and 29 sedentary healthy controls performed the Astrand Rhyming submaximal cycle exercise test. METHODS: Average heart rate was used to estimate maximal oxygen consumption (VO2max). Variables that may affect submaximal activity in PD patients, including disease severity, fatigue, and level of physical activity in daily life, were recorded. RESULTS: Fewer PD patients (46%) completed the submaximal exercise test successfully than the controls (86%). The estimated VO2max of patients with a successful test was 34% lower than the controls (p < 0.001). Multivariate regression analyses revealed that higher body weight, lower systolic blood pressure, lower resting heart rate, and lower maximal workload were associated with an increased risk of an inadequate heart rate increase during submaximal exercise (R2 = 27%). PD patients with a successful submaximal exercise test had lower estimated VO2max values than controls. CONCLUSIONS: Importantly, half of the PD patients had an inadequate heart rate increase during submaximal exercise, which was likely caused by cardiac sympathetic denervation leading to autonomic dysfunction. PD patients should therefore be screened to identify their limitations in exercise performance. Caution should be applied when prescribing beta blockers, as they might limit physical activities further. PMID- 23938229 TI - Pilot study assessing the feasibility of applying bilateral subthalamic nucleus deep brain stimulation in very early stage Parkinson's disease: study design and rationale. AB - BACKGROUND: Deep brain stimulation provides significant symptomatic benefit for people with advanced Parkinson's disease whose symptoms are no longer adequately controlled with medication. Preliminary evidence suggests that subthalamic nucleus stimulation may also be efficacious in early Parkinson's disease, and results of animal studies suggest that it may spare dopaminergic neurons in the substantia nigra. OBJECTIVE: We report the methodology and design of a novel Phase I clinical trial testing the safety and tolerability of deep brain stimulation in early Parkinson's disease and discuss previous failed attempts at neuroprotection. METHODS: We recently conducted a prospective, randomized, parallel-group, single-blind pilot clinical trial of deep brain stimulation in early Parkinson's disease. Subjects were randomized to receive either optimal drug therapy or deep brain stimulation plus optimal drug therapy. Follow-up visits occurred every six months for a period of two years and included week-long therapy washouts. RESULTS: Thirty subjects with Hoehn & Yahr Stage II idiopathic Parkinson's disease were enrolled over a period of 32 months. Twenty-nine subjects completed all follow-up visits; one patient in the optimal drug therapy group withdrew from the study after baseline. Baseline characteristics for all thirty patients were not significantly different. CONCLUSIONS: This study demonstrates that it is possible to recruit and retain subjects in a clinical trial testing deep brain stimulation in early Parkinson's disease. The results of this trial will be used to support the design of a Phase III, multicenter trial investigating the efficacy of deep brain stimulation in early Parkinson's disease. PMID- 23938233 TI - Simultaneous use of different communication mechanisms leads to spatial sorting and unexpected collective behaviours in animal groups. AB - Communication among individuals forms the basis of social interactions in every animal population. In general, communication is influenced by the physiological and psychological constraints of each individual, and in large aggregations this means differences in the reception and emission of communication signals. However, studies on the formation and movement of animal aggregations usually assume that all individuals communicate with neighbours in the same manner. Here, we take a new approach on animal aggregations and use a nonlocal mathematical model to investigate theoretically the simultaneous use of two communication mechanisms by different members of a population. We show that the use of multiple communication mechanisms can lead to behaviours that are not necessarily predicted by the behaviour of subpopulations that use only one communication mechanism. In particular, we show that while the use of one communication mechanism by the entire population leads to deterministic movement, the use of multiple communication mechanisms can lead in some cases to chaotic movement. Finally, we show that the use of multiple communication mechanisms leads to the sorting of individuals inside aggregations: individuals that are aware of the location and the movement direction of all their neighbours usually position themselves at the centre of the groups, while individuals that are aware of the location and the movement direction of only some neighbours position themselves at the edges of the groups. PMID- 23938234 TI - Allee threshold and stochasticity in biological invasions: colonization time at low propagule pressure. AB - We consider the problem of estimating the time needed for species colonization. The analysis is based upon the known population dynamic models by Dennis with minor modification to the Allee effect description, which allows us to obtain an analytical expression for the colonization time. For the stochastic counterpart of the models in diffusion approximation, we (1) propose the description of immigration stochasticity, (2) provide the estimates of time required for the population to overcome strong demographic Allee effect, and (3) consider the numerical results for mean colonization time and its uncertainty. Strong Allee effect strictly disallows populations at small immigration rates to colonize new habitats, unless the stochasticity in immigration, environment, or demography is present, or incorporated into the model. Immigration stochasticity, complementing with environmental and demographic stochasticity, enables the populations to overcome the Allee threshold even at low values of propagule pressure. PMID- 23938235 TI - Pattern of heat shock factor and heat shock protein expression in lymphocytes of bipolar patients: increased HSP70-glucocorticoid receptor heterocomplex. AB - Bipolar disorder (BD), a stress-related disease, is characterized by altered glucocorticoid receptor (GR) signalling. Stress response includes activation of heat shock factor (HSF) and subsequent heat shock protein (HSP) synthesis which regulate GR folding and function. The objective of this study was to investigate the possible role of HSFs, HSPs and their interaction with GR in BD. We applied immunoprecipitation, SDS-PAGE/Western blot analysis and electrophoretic mobility shift assay (EMSA) in lymphocytes (whole cell or nuclear extracts) from BD patients and healthy subjects and determined the HSPs (HSP90 and HSP70), the heterocomplexes HSP90-GR and HSP70-GR, the HSFs (HSF1 and HSF4) as well as the HSF-DNA binding. The HSP70-GR heterocomplex was elevated (p < 0.05) in BD patients vs healthy subjects, and nuclear HSP70 was reduced (p <= 0.01) in bipolar manic patients. Protein levels of HSF1, HSF4, HSP90, HSP90-GR heterocomplex, and HSF-DNA binding remained unaltered in BD patients vs healthy subjects. The corresponding effect sizes (ES) indicated a large ES for HSP70-GR, HSP70, HSF-DNA binding and HSF4, and a medium ES for HSP90, HSF1 and HSP90-GR between healthy subjects and bipolar patients. Significant correlations among HSFs, HSPs, GR and HSP70-GR heterocomplex were observed in healthy subjects, which were abrogated in bipolar patients. The higher interaction between GR and HSP70 and the disturbances in the relations among heat shock response parameters and GR as observed in our BD patients may provide novel insights into the contribution of these factors in BD aetiopathogenesis. PMID- 23938236 TI - Gender and age groups interactions in the quantification of bone marrow fat content in lumbar spine using 3T MR spectroscopy: a multivariate analysis of covariance (Mancova). AB - INTRODUCTION: There is an age-related conversion of red to yellow bone marrow in the axial skeleton, with a gender-related difference less well established. Our purpose was to clarify the variability of bone marrow fat fraction (FF) in the lumbar spine due to the interaction of gender and age groups. METHODS: 44 healthy volunteers (20 males, 30-65 years old and 24 females, 30-69 years old) underwent 3T magnetic resonance spectroscopy (MRS) and conventional MRI examination of the lumbar spine; single-voxel spectrum was acquired for each vertebral body (VB). After controlling body mass index (BMI), a two-way between-groups multivariate analysis of covariance (MANCOVA) assessed the gender and age group differences in FF quantification for each lumbar VB. RESULTS: There was a significant interaction between gender and age group, p=.017, with a large effect size (partial eta(2)=.330). However the interaction explained only 33% of the observed variance. Main effects were not statistically significant. BMI was non significantly related to FF quantification. CONCLUSIONS: Young males showed a high FF content, which declined in the 4th decade, then increased the next 3 decades to reach a FF content just below the initial FF means. Females' FF were low in the 3rd decade, depicted an accelerated increase in the 4th decade, then a gradual increase the next 3 decades to reach a FF content similar to males' values. Our findings suggest that quantification of bone marrow FF using MRS might be used as a surrogate biomarker of bone marrow activity in clinical settings. PMID- 23938238 TI - Elasticity and healing: a moment of renewal. AB - The simultaneous celebration of the donation by Dr. Judith Dupont of the Ferenczi Archive to the London Freud Museum and of the launch of two new books on Ferenczi in the Karnac History of Psychoanalysis Series provides an occasion for reflection on the trauma inflicted on the psychoanalytic world by the Freud Ferenczi rift and on the hope for renewal symbolized by Dr. Dupont's gift. Tribute is paid to Judith Dupont and to Andre Haynal for their contributions to preserving Ferenczi's legacy. It is argued that Freud bears responsibility for pathologizing those with whom he had intellectual disagreements, but that Ferenczi's concept of elasticity points the way to a reconciliation of Freud and Ferenczi that renders it no longer necessary to "rescue psychoanalysis from Freud." PMID- 23938237 TI - An international review of the main cost-effectiveness drivers of virtual colonography versus conventional colonoscopy for colorectal cancer screening: is the tide changing due to adherence? AB - OBJECTIVES: The majority of recent cost-effectiveness reviews concluded that computerised tomographic colonography (CTC) is not a cost-effective colorectal cancer (CRC) screening strategy yet. The objective of this review is to examine cost-effectiveness of CTC versus optical colonoscopy (COL) for CRC screening and identify the main drivers influencing cost-effectiveness due to the emergence of new research. METHODS: A systematic review was conducted for cost-effectiveness studies comparing CTC and COL as a screening tool and providing outcomes in life years saved, published between January 2006 and November 2012. RESULTS: Nine studies were included in the review. There was considerable heterogeneity in modelling complexity and methodology. Different model assumptions and inputs had large effects on resulting cost-effectiveness of CTC and COL. CTC was found to be dominant or cost-effective in three studies, assuming the most favourable scenario. COL was found to be not cost effective in one study. CONCLUSIONS: CTC has the potential to be a cost-effective CRC screening strategy when compared to COL. The most important assumptions that influenced the cost-effectiveness of CTC and COL were related to CTC threshold-based reporting of polyps, CTC cost, CTC sensitivity for large polyps, natural history of adenoma transition to cancer, AAA parameters and importantly, adherence. There is a strong need for a differential consideration of patient adherence and compliance to CTC and COL. Recent research shows that laxative-free CTC screening has the potential to become a good alternative screening method for CRC as it can improve patient uptake of screening. PMID- 23938239 TI - Georg Groddeck's maternal turn: its evolution and influence on early psychoanalysts. AB - The paper examines the biographical, cultural and clinical influences on the "maternal turn" of Georg Groddeck, a German physician and correspondent of Sigmund Freud. It demonstrates Groddeck's influence on Sandor Ferenczi, Frieda Fromm-Reichmann and Karen Horney, each of whom influenced generations of psychoanalysts. The authors explore the resonance of Groddeck's work with several concepts of contemporary psychoanalysis and raise the question as to whether the roots of these psychoanalytic concepts were seeded by Groddeck's "maternal turn", passed on by the above psychoanalysts through intergenerational psychoanalytic training and further elaborated by later investigators who were not necessarily familiar with the work of Groddeck. PMID- 23938240 TI - The beginnings of psychoanalytic supervision: the crucial role of Max Eitingon. AB - Psychoanalytic supervision is moving well into its 2nd century of theory, practice, and (to a limited extent) research. In this paper, I take a look at the pioneering first efforts to define psychoanalytic supervision and its importance to the psychoanalytic education process. Max Eitingon, the "almost forgotten man" of psychoanalysis, looms large in any such consideration. His writings or organizational reports were seemingly the first psychoanalytic published material to address the following supervision issues: rationale, screening, notes, responsibility, supervisee learning/personality issues, and the extent and length of supervision itself. Although Eitingon never wrote formally on supervision, his pioneering work in the area has continued to echo across the decades and can still be seen reflected in contemporary supervision practice. I also recognize the role of Karen Horney-one of the founders of the Berlin Institute and Poliklinik, friend of Eitingon, and active, vital participant in Eitingon's efforts-in contributing to and shaping the beginnings of psychoanalytic education. PMID- 23938241 TI - Forms of concern: toward an intersubjective perspective. AB - The growing interest in the issue of concern, which appeared relatively late in psychoanalytical literature, resulted in several distinctions. Winnicott distinguished between concern as an expression of guilt and concern as a manifestation of joy, Brenman Pick distinguished between real concern and spurious concern, and Bowlby distinguished between sensitive and compulsive caregiving. The basic concepts of Buber's dialogical philosophy and intersubjective approaches in psychoanalysis have created fertile ground for the study of concern, and enabled us to conceptualize these distinctions in a way that has heretofore been lacking in psychoanalytical thought. PMID- 23938242 TI - Desiring (with) bion: an experience in reading. AB - This article considers my experience of reading Wilfred R. Bion's book Learning from experience (1962) and how transference operates in and around his work. I argue that Bion's work cannot simply be read but must be felt. I highlight the importance of Learning from experience for psychoanalytic practitioners becoming more self-reflexive about our theoretical and clinical practices, but also to bring attention to the process through which many of us come to Bion's insights "first hand" if you like, which is through his writings, in our position as readers. PMID- 23938248 TI - Characterization of the transcriptional activity of the basic helix-loop-helix (bHLH) transcription factor Atoh8. AB - The atonal-related Neurogenin/NeuroD family of basic helix-loop-helix (bHLH) transcription factors comprises potent inducers of neuronal and endocrine differentiation programs in the nervous and digestive system. Atonal homolog 8 (Atoh8) displays high similarity in the bHLH domain with NeuroD proteins. Yet, available evidences indicate that Atoh8 has distinctive features including a ubiquitous expression pattern in embryonic tissues and the ability to inhibit differentiation. To gain insights into Atoh8 function, we aimed at identifying Atoh8 targets and investigated the effects of Atoh8 on global gene expression patterns in pancreatic mPAC cells, a model of bHLH-dependent endocrine differentiation. Our data reveal that Atoh8 is a weak transcriptional activator and does not exhibit proendocrine activity. Conversely, it blocks the induction of a reduced group of gene targets of the atonal-related proendocrine factor Neurogenin3. We show that Atoh8 lacks a transactivation domain and possesses intrinsic repressor activity that depends on a conserved Proline-rich domain. Atoh8 binds the ubiquitous E protein E47 and its ability to repress transcription may partly result from its ability to inhibit E47/E47 and Neurogenin3/E47 dimer activities. These results reveal distinctive transcriptional properties of Atoh8 within the atonal-related bHLH family that may be associated with the acquisition of new biological functions. PMID- 23938249 TI - Intragenic DNA methylation in transcriptional regulation, normal differentiation and cancer. AB - Ever since the discovery of DNA methylation at cytosine residues, the role of this so called fifth base has been extensively studied and debated. Until recently, the majority of DNA methylation studies focused on the analysis of CpG islands associated to promoter regions. However, with the upcoming possibilities to study DNA methylation in a genome-wide context, this epigenetic mark can now be studied in an unbiased manner. As a result, recent studies have shown that not only promoters but also intragenic and intergenic regions are widely modulated during physiological processes and disease. In particular, it is becoming increasingly clear that DNA methylation in the gene body is not just a passive witness of gene transcription but it seems to be actively involved in multiple gene regulation processes. In this review we discuss the potential role of intragenic DNA methylation in alternative promoter usage, regulation of short and long non-coding RNAs, alternative RNA processing, as well as enhancer activity. Furthermore, we summarize how the intragenic DNA methylome is modified both during normal cell differentiation and neoplastic transformation. PMID- 23938250 TI - Comparison of electromyographic signals from monopolar current and potential amplifiers derived from a penniform muscle, the gastrocnemius medialis. AB - Electromyograms (EMGs) are measured by bipolar surface electrodes that quantify potential differences. Bipolar potentials over penniform muscles may be associated with errors. Our assumption was that muscle activity can be quantified more reliably and with a higher spatial resolution using current measurements. The purpose of this work is: (a) to introduce the concept of current measurements to detect muscle activity, (b) to show the coherences observed over a segment of a typical penniform muscle, the gastrocnemius medialis where one would expect a synchronicity of the activation, and (c) to show the amount of mixing that is caused by the finite inter electrode resistance. A current amplifier was developed. EMGs were recorded at 40% of maximum voluntary contraction during isometric contractions of the gastrocnemius medialis. EMGs of twelve persons were recorded with an array of four peripheral and one central electrode. Monopolar EMGs were recorded for "all-potential", "center at current" and "all-current" conditions. Coherence revealed the similarity of signals recorded from neighboring electrodes. Coherence was high for the "all-potential", significant for the "current at center" condition and disappeared in the "all-current" condition. It was concluded that EMG array recordings strongly depends on the measurement configuration. The proposed current amplifier significantly improves spatial resolution of EMG array recordings because the inter-electrode cross talk is reduced. PMID- 23938251 TI - Bluetongue surveillance system in Belgium: a stochastic evaluation of its risk based approach effectiveness. AB - BACKGROUND: The aim of this study was to assess the sensitivity of the four major bluetongue surveillance components implemented in Belgium in 2007 for farmed animals and prescribed by the European Union regulation; winter serological screening, sentinel system, passive clinical surveillance, export testing. Scenario tree methodology was used to evaluate the relative sensitivity of detection and targeted approach of each component in terms of early detection and freedom of infection substantiation. Field data collected from the previous year's outbreaks in Belgium were used to determine the risk groups to be considered. RESULTS: The best sensitivities at herd level, taking into account the diagnostic test sensitivity, design prevalence and the number of animals tested within a herd were obtained with the winter screening and sentinel component. The sensitivities at risk group level, taking into account the obtained herd sensitivity, effective probabilities of infection and number of herds tested were high in all components, except for the export component. Component sensitivities ranged between 0.77 and 1 for all components except for the export component with a mean value of 0.22 (0.17-0.26). In terms of early detection, the probability of detection was best using the passive clinical component or the sentinel component. Sensitivity analysis showed that the passive clinical component sensitivity was mostly affected by the diagnostic process and the number of herds sampled. The sentinel and export components sensitivity were mainly affected by the relative risk estimates whereas the winter screening component was mainly affected by the assumptions about the design prevalence. CONCLUSIONS: This study revealed interesting features regarding the sensitivity of detection and early detection of infection in the different surveillance components and their risk based approach as requested by the international standards. PMID- 23938252 TI - Phytoestrogens mediated anti-inflammatory effect through suppression of IRF-1 and pSTAT1 expressions in lipopolysaccharide-activated microglia. AB - Microglial activation has been implicated in various neurological disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and HIV encephalopathy. Phytoestrogens have been shown to be neuroprotective in neurotoxicity models; however, their effect on microglia has not been well established. In the current study, we report that the soy phytoestrogens, genistein, daidzein, and coumestrol, decreased nitric oxide (NO) production induced by lipopolysaccharide (LPS) in the rat microglial cell line (HAPI). The levels of inducible NO synthase (iNOS) mRNA and protein expression were also reduced. Transcription factors known to govern iNOS expression including interferon regulatory factor-1 (IRF-1) and phosphorylated STAT1 were down regulated. These observations explain, at least in part, the inhibitory effect of phytoestrogens on NO production. The levels of monocyte chemoattractant protein-1 and interleukin-6 mRNA, proinflammatory chemokine and cytokine associated with various neurological disorders, were also reduced following LPS stimulation when HAPI cells were pretreated with phytoestrogens. Hence, genistein, daidzein, and coumestrol could serve as anti-inflammatory agents and may have beneficial effects in the treatment of neurodegenerative diseases. PMID- 23938253 TI - 11beta-Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis. AB - 11beta-Hydroxysteroid dehydrogenase 1 (11beta-HSD1) plays an important role in inflammation. However, the role of 11beta-HSD1 in rheumatoid arthritis (RA) remains unknown. The purpose of this study was to evaluate the therapeutic effects of a selective 11beta-HSD1 inhibitor BVT-2733 in collagen-induced arthritis (CIA) and its underlying mechanisms. CIA mice were treated with BVT 2733 (100 mg/kg, orally) or vehicle twice daily for 2 weeks. Arthritis score and joint histology were investigated. The levels of pro-inflammatory cytokines as well as anti-type II collagen antibody (anti-CII) were detected by ELISA. Western blot analysis was used to assess the activation of NF-kappaB and NLRP1 inflammasome in joint tissues and in human RA synovial cells. BVT-2733 treatment attenuated the arthritis severity and anti-CII level in CIA mice. BVT-2733 also decreased the levels of serum TNF-alpha, IL-1beta, IL-6 and IL-17. BVT-2733 treatment also significantly reduced synovial inflammation and joint destruction. NF-kappaB activation and NLRP1 inflammasome assembly were also inhibited in arthritic joints and human RA synovial cells. In conclusion, BVT-2733 exhibits an anti-inflammatory effect on CIA. This protective effect is, at least partly, mediated by inhibition of the NF-kappaB and NLRP1 inflammasome signaling pathways. 11beta-HSD1 inhibition may represent a potential therapeutic target for RA patients. PMID- 23938254 TI - Nobiletin and tangeretin ameliorate scratching behavior in mice by inhibiting the action of histamine and the activation of NF-kappaB, AP-1 and p38. AB - Nobiletin and tangeretin are polymethoxy flavonoids that are abundantly present in the pericarp of Citrus unshiu (family Rutaceae) and the fruit of Citrus depressa (family Rutaceae). They exhibit various biological activities, including anti-inflammatory and anti-asthmatic effects. To evaluate the anti-allergic effects of nobiletin and tangeretin, we measured their inhibitory effects in histamine- or compound 48/80-induced scratching behavioral mice. Nobiletin and tangeretin potently inhibited scratching behavior, as well as histamine-induced vascular permeability. Furthermore, they inhibited the expression of the allergic cytokines, IL-4 and TNF-alpha as well as the activation of their transcription factors NF-kappaB, AP-1 and p38 in histamine-stimulated skin tissues. They also inhibited the expression of IL-4 and TNF-alpha and the activation of NF-kappaB and c-jun in PMA-stimulated RBL-2H3 cells. Furthermore, nobiletin and tangeretin inhibited protein kinase C (PKC) activity and the IgE-induced degranulation of RBL-2H3 cells. These agents showed potent anti-histamine effect through the Magnus test when guinea pig ileum was used. Based on these results, nobiletin and tangeretin may ameliorate scratching behavioral reactions by inhibiting the action of histamine as well as the activation of the transcription factors NF kappaB and AP-1 via PKC. PMID- 23938256 TI - Sustained response to deep brain stimulation in LRRK2 parkinsonism with the Y1699C mutation. AB - Although effective deep brain stimulation of the subthalamic nucleus (STN-DBS) is reported in G2019S leucine-rich repeat kinase 2 (LRRK2) parkinsonism, response to surgery in other LRRK2 mutations has not been previously reported. We present an affected individual from the Lincolnshire pedigree (Y1699C), on whom bilateral STN-DBS was performed to control severe motor fluctuations and dyskinesias. He showed a marked improvement in Unified Parkinson's Disease Rating Scale (UPDRS) Part III scores in the "on" and "off" states, sustained for more than three years. Bilateral STN-DBS in LRRK2-parkinsonism with the Y1699C mutation can be as effective as in sporadic PD. PMID- 23938257 TI - Factors affecting pain in Parkinson's disease. AB - BACKGROUND: Despite being an important non-motor symptom of PD, pain remains largely understudied in PD patients. Experiencing symptoms of pain is highly disruptive of general functioning, as it may hinder both physical prowess and psychological well-being. Although pain is prevalent in the otherwise healthy geriatric population, its increased presence in PD, and the difficulty it poses when combined with other hallmark motor symptoms necessitates further investigation. An improved understanding of factors that aggravate pain, and methods that alleviate discomfort may provide significant insight on the basis of pain in PD. Such information may ultimately allow healthcare professionals to achieve the goal of improved PD patient management. OBJECTIVE: To study the associations between various factors and pain in a Parkinson's disease (PD) patient population. METHODS: This study investigated 121 PD patients, of which 80 reported to have pain in at least one area of the body. Exclusion criteria included patients suffering from external causes of pain, such as trauma and patients with cognitive impairment whose accounts may not have been reliable. Further inquiry determined the etiology of pain, as well as aggravating and alleviating factors. The efficacies of pharmacological or non-pharmacological therapies were assessed through additional questioning. Individuals were also asked whether their pain was unintentionally affected by other measures, such as prescribed PD medications. RESULTS: Multiple linear regression analysis with a Wald test value of 4.070 (p = 0.044) demonstrated a statistically significant relationship between the administration of analgesics in patients with high reported pain and their pain relief. However, patients who experienced moderate pain did not exhibit any statistically significant levels of pain relief with the use of analgesics (Wald = 2.097, p = 0.148). Similarly, non-pharmacological therapies, PD medicine, and comorbidities showed no statistically significant correlations with pain relief. CONCLUSIONS: Physicians should be aware of the physiological and psychological factors that form major components of pain relief, and that patient education and support are critical to successful treatment programs. PMID- 23938258 TI - Impact of ethnicity on non-motor symptoms of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative illness characterized by various non-motor symptoms that may contribute to disability, impaired quality of life and shortened life expectancy. The aim of present study was to determine the relative prevalence of common non-motor symptoms in various ethnic groups. A retrospective chart analysis was performed on Parkinson's disease patients where a total of 314 PD patients from six ethnic categories were examined for the occurrence of anxiety, visual hallucinations, nocturia, drooling and dementia. Our results show that anxiety in PD patients was correlated with their ethnicity classification. Interesting trends were observed with respect to nocturia and dementia symptoms and no significant differences were found between ethnic groups for visual hallucinations and drooling. Our study shows that non-motor symptoms of Parkinson's disease are prevalent across all ethnic groups, and except anxiety there may not be any impact of ethnicity on dementia, nocturia, drooling, and visual hallucinations. PMID- 23938259 TI - The neuroprotective effect of fisetin in the MPTP model of Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is characterized by excessive deposition of neuritic plaques known as Lewy bodies of which alpha-synuclein is the major contributor to neuronal death. Both oxidative stress and cytokines signaling have been proposed to play an important role in alpha-synuclein-induced neuronal death in MPTP and PD-related neuronal cell death. Fisetin, a natural polyphenol, possesses antioxidant, anti-inflammatory, and anti-apoptotic properties. However, the molecular neuroprotective mechanisms of fisetin against MPTP-induced cytotoxicity are still unknown. OBJECTIVE: The present study investigated the inhibitory effect of fisetin on MPTP/MPP+-induced neurotoxicity in PC12 cells. METHODS: Cells were pretreated with varying concentrations of fisetin prior exposure to MPTP/MPP+. Cell viability and apoptosis were investigated using MTT assay and DNA fragmentation. The expression and release of transcription factor, pro-inflammatory cytokines, and apoptotic mediators were assessed using western blot analysis and ELISA. RESULTS: Results showed that a pre-treatment with fisetin before exposure to MPTP/MPP+ significantly decreased MPTP/MPP+-induced cytotoxicity and cell death probably by decreasing alpha-synuclein expression. Mechanisms study showed that fisetin has the potential to inhibit several apoptotic and inflammatory pathways, which play important roles in the initiation and progression of PD. CONCLUSIONS: Altogether, these observations indicate that fisetin is capable of attenuating alpha-synuclein levels and promoting neuroprotective effects, meanwhile also present some insights into the potential signaling pathways that are involved. Thus, these findings support the role of natural polyphenols in preventive and/or complementary therapies for neurodegenerative diseases. PMID- 23938261 TI - Unilateral 6-OHDA lesions induce lateralised deficits in a 'skinner box' operant choice reaction time task in rats. AB - BACKGROUND: Parkinson's disease (PD) is most commonly modelled in rats via injection of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Assessment of lateralised choice reaction time is usually conducted in the 9 hole box, a highly specialized apparatus that is not widely available in many behavioural laboratories. The retractable lever Skinner box on the other hand is more readily available and may have the additional advantage of faster training of animals. OBJECTIVE: The present study assesses the performance of lesioned rats on a lateralised choice reaction time task that allows for quantitative assessment of the behavioural profile of models of neurodegenerative diseases in the retractable lever Skinner box. METHODS: Here we compared the post lesion performance of pretrained female Lister hooded rats that received unilateral 6-OHDA lesions to the medial forebrain bundle and untreated controls on the choice reaction time task conducted in the Skinner box. RESULTS: Lesioned animals displayed impairments in contralateral accuracy, a reduced number of usable trials, as well as a slowing down of contralateral reaction and bilateral movement time latencies. CONCLUSIONS: The findings presented allow greater comparison between laboratories, and may be useful for the investigation of treatment strategies and remedies on this model of PD. PMID- 23938255 TI - Loss of functional alpha-synuclein: a toxic event in Parkinson's disease? AB - The discovery that alpha-synuclein (alpha-syn) is the primary component of the neuropathological hallmarks of Parkinson's disease (PD) and the identification of alpha-syn mutations in numerous inherited forms of PD has positioned alpha-syn at the top of the list of important factors in the pathogenesis of PD. Based on the pathological accumulation of alpha-syn in the brains of patients, the field is currently focused on therapeutic strategies that aim to reduce or eliminate alpha syn. However, recent evidence suggests alpha-syn is a critical protein in neuron (i.e. dopamine neurons) survival and that maintaining a certain level of biologically functional alpha-syn is an important consideration in targeting alpha-syn for therapies. Despite the widespread interest in alpha-syn, the normal biological functions remain elusive, but a large body of work is focused on addressing this issue. In this review, we will discuss the current evidence related to alpha-syn function, alpha-syn folding and aggregation, and alpha-syn's role in disease. Finally, we will propose a relatively novel hypothesis on the pathogenesis of PD that hinges upon the premises that functional alpha-syn is critical to cell survival and that a reduction in biologically functional alpha syn, whether through aggregation or reduced expression, may lead to the neurodegeneration in PD. PMID- 23938260 TI - LINE-1 DNA methylation, smoking and risk of Parkinson's disease. AB - BACKGROUND: Long interspersed nucleotide element-1 (LINE-1) retrotransposons are located throughout the human genome. Those retaining an intact 5' promoter can copy and insert themselves into the DNA of neural progenitor cells that express tyrosine hydroxylase, which may influence differentiation and survival of these cells. LINE-1 promoter methylation is associated with decreased LINE-1 propagation. OBJECTIVE: To investigate whether LINE-1 promoter methylation is associated with Parkinson's disease (PD). METHODS: We compared LINE-1 methylation profiles in blood mononuclear cells between 292 newly diagnosed PD cases and 401 unrelated, neurologically normal controls, all non-Hispanic Caucasians in western Washington state. RESULTS: Overall, PD was not associated with percent methylation of the LINE-1 promoter. However, the predictable inverse association between PD and ever smoking tobacco was strongest for men and women with the lowest LINE-1 promoter methylation, and less apparent as LINE-1 methylation increased. Underlying this possible interaction, ever regularly smoking tobacco was associated with decreased LINE-1 methylation in controls (age- and sex adjusted linear regression beta = -0.24, 95% confidence interval [CI] -0.43, 0.04), but not in cases (beta = 0.06, 95% CI -0.17, 0.28, interaction p = 0.06). CONCLUSION: PD cases may have innate differences in their ability to respond to tobacco smoke. PMID- 23938262 TI - Plasma-based circulating MicroRNA biomarkers for Parkinson's disease. AB - BACKGROUND: The current "gold-standard" for Parkinson's disease (PD) diagnosis is based primarily on subjective clinical rating scales related with motor features. Molecular biomarkers that are objective and quantifiable remain attractive as clinical tools to detect PD prior to its motor onsets. OBJECTIVE: Here, we aimed to identify, develop, and validate plasma-based circulating microRNA (miRNAs) as biomarkers for PD. METHODS: Global miRNA expressions were acquired from a discovery set of 32 PD/32 controls using microarrays. k-Top Scoring Pairs (k-TSP) algorithm and significance analysis of microarrays (SAM) were applied to obtain comprehensive panels of PD-predictive biomarkers. TaqMan miRNA-specific real-time PCR assays were performed to validate the microarray data and to evaluate the biomarker performance using a new replication set of 42 PD/30 controls. Data was analyzed in a paired PD-control fashion. The validation set was composed of 30 PD, 5 progressive supranuclear palsy, and 4 multiple system atrophy samples from a new clinical site. RESULTS: We identified 9 pairs of PD-predictive classifiers using k-TSP analysis and 13 most differentially-expressed miRNAs by SAM. A combination of both data sets produced a panel of PD-predictive biomarkers: k TSP1 (miR-1826/miR-450b-3p), miR-626, and miR-505, and achieved the highest predictive power of 91% sensitivity, 100% specificity, 100% positive predicted value, and 88% negative predicted value in the replication set. However, low predictive values were shown in the validation set. CONCLUSIONS: This proof-of concept study demonstrates the feasibility of using plasma-based circulating miRNAs as biomarkers for neurodegenerative disorders such as PD and shows the challenges of molecular biomarker research using samples from multiple clinical sites. PMID- 23938263 TI - A model of GDNF gene therapy in mice with 6-Hydroxydopamine lesions: time course of Neurorestorative effects and ERK1/2 activation. AB - BACKGROUND: Glial cell line-derived neurotrophic factor (GDNF) is the most promising neurotrophin for restorative treatments in Parkinson's disease, but its biological effects are not completely understood. OBJECTIVE: To define a model of GDNF gene therapy in the mouse, we studied the long-term effects of lentiviral GDNF delivery in mice with striatal 6-hydroxydopamine (6-OHDA) lesions. METHODS: Lentiviral vectors coding for GDNF or green fluorescent protein (GFP) were injected unilaterally in the striatum two weeks prior to the 6-OHDA lesion. Mice were monitored on tests of spontaneous activity and amphetamine-induced rotation at 1, 4, 10 and 35 weeks post-lesion. Brains were processed immunohistochemically for tyrosine hydroxylase (TH) and markers of extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation at the same time points. RESULTS: Lentiviral GDNF significantly inhibited both spontaneous and amphetamine-induced rotation. Compared to the control vector, lentiviral GDNF resulted in a partial protection of TH-positive cells in the substantia nigra, and in a nearly total restoration of striatal TH immunostaining by 35 weeks. A progressive sprouting of TH-positive neurites occurred in both the globus pallidus and the substantia nigra, reaching a 4-5 fold increase above controls by 35 weeks. This effect was paralleled by a long-term supranormal activation of ERK1/2 and its downstream target, phospho Ser31 TH. CONCLUSIONS: Lentiviral GDNF delivery produced robust long-term signaling responses and neurorestoration. This experimental model of GDNF gene therapy will be particularly suitable to study the molecular mechanisms of dopaminergic fiber sprouting, a long-term response to GDNF delivery that also occurs in Parkinson's disease patients. PMID- 23938265 TI - Protein interaction networks as starting points to identify novel antimicrobial drug targets. AB - Novel classes of antimicrobials are needed to address the challenge of multidrug resistant bacteria. Current bacterial drug targets mainly consist of specific proteins or subsets of proteins without regard for either how these targets are integrated in cellular networks or how they may interact with host proteins. However, proteins rarely act in isolation, and the majority of biological processes are dependent on interactions with other proteins. Consequently, protein-protein interaction (PPI) networks offer a realm of unexplored potential for next-generation drug targets. In this review, we argue that the architecture of bacterial or host-pathogen protein interactomes can provide invaluable insights for the identification of novel antibacterial drug targets. PMID- 23938266 TI - Immunofluorescence evidence of melanotrophs in the pituitary of four odontocete species. An immunohistochemical study and a critical review of the literature. AB - Cetaceans share peculiar features of their pituitary glands, with a complete separation of pars distalis and pars nervosa by a dural septum and the absence of an intermediate lobe and cleft. In most mammals the pars intermedia is the main source of circulating alpha-melanocyte stimulating hormone (alpha-MSH), derived from a large precursor called proopiomelanocortin (POMC), which also generates adrenocorticotropic hormone (ACTH) in the adenohypophysis. The lack of an intermediate lobe in cetaceans led us to investigate whether their glands are able to produce alpha-MSH, and if this hormone is secreted by a distinct population of melanotrophs or by corticotrophs in the pars distalis. Immunofluorescence evidences seem to support the first assumption, with ACTH immunoreactive (-ir) elements rarely overlapping with alpha-MSH-ir ones. The discovery of a population of true melanotrophs in the hypophysis of some odontocetes underscores the need for further research on the melanocortin system of cetaceans. PMID- 23938267 TI - The identification and restitution of human remains from an Ache girl named "Damiana": an interdisciplinary approach. AB - In June 2010, the postcranial skeleton of an adolescent girl was returned by the Natural History Museum of La Plata, Argentina, to the Ache community in Paraguay. In March 2011 the missing skull was identified in the anatomical collection of Charite in Berlin. We initiated a historical and anthropological investigation to confirm the identity of the human remains and to reconstruct the fate of the individual in question in its historical context. Anthropological publications from Argentina had indicated that the girl named "Damiana" was abducted by colonising settlers in Southern Paraguay in 1897 at the age of 3-4 years, later taken to La Plata in Argentina where she grew up as a "maidservant", and died in 1907 of "galloping consumption". In accordance with these reports, the present palaeopathological investigation confirms tuberculous meningitis as a likely cause of death. It also demonstrates some markers of "stress", the nature of which, however, is difficult to determine. Surviving letters and publications by Berlin anatomist Hans Virchow reveal that the girl's preserved head was sent from La Plata to Berlin in January 1908 for comparative investigations in the context of the racial theories of the time. We were convinced that the justified wishes of the Ache community to bury these remains alongside those restituted in 2010 outweighed any future scientific interest in these remains. In April 2012, the skull and two related specimens were returned from the Charite to the Ache community, mediated by the Paraguayan ambassador in Berlin. PMID- 23938270 TI - Study of simultaneous reduction and nitrogen doping of graphene oxide Langmuir Blodgett monolayer sheets by ammonia plasma treatment. AB - Graphene oxide (GO) monolayer sheets, transferred onto Si by the Langmuir Blodgett technique, were subjected to ammonia plasma treatment at room temperature with the objective of simultaneous reduction and doping. Scanning electron microscopy and atomic force microscopy studies show that plasma treatment at a relatively low power (~10 W) for up to 15 min does not affect the morphological stability and monolayer character of GO sheets. X-ray photoelectron spectroscopy has been used to study de-oxygenation of GO monolayers and the incorporation of nitrogen in graphitic-N, pyrrolic-N and pyridinic-N forms due to the plasma treatment. The corresponding changes in the valence band electronic structure, density of states at the Fermi level and work function have been investigated by ultraviolet photoelectron spectroscopy. These studies, supported by Raman spectroscopy and electrical conductivity measurements, have shown that a short duration plasma treatment of up to 5 min results in an increase of sp2-C content along with a substantial incorporation of the graphitic-N form, leading to the formation of n-type reduced GO. Prolonged plasma treatment for longer durations results in a decrease of electrical conductivity, which is accompanied by a substantial decrease of sp2-C and an increase in defects and disorder, primarily attributed to the increase in pyridinic-N content. PMID- 23938269 TI - Structurally flexible triethanolamine-core poly(amidoamine) dendrimers as effective nanovectors to deliver RNAi-based therapeutics. AB - RNAi-based nucleic acid molecules have attracted considerable attention as compelling therapeutics providing safe and competent delivery systems are available. Dendrimers are emerging as appealing nanocarriers for nucleic acid delivery thanks to their unique well-defined architecture and the resulting cooperativity and multivalency confined within a nanostructure. The present review offers a brief overview of the structurally flexible triethanolamine-core poly(amidoamine) (PAMAM) dendrimers developed in our group as nanovectors for the delivery of RNAi therapeutics. Their excellent activity for delivering different RNAi therapeutics in various disease models in vitro and in vivo will be highlighted here. PMID- 23938271 TI - Serum amyloid A activation of human coronary artery endothelial cells exhibits a neutrophil promoting molecular profile. AB - BACKGROUND: Serum amyloid A (SAA) has been shown to be an active participant in atherosclerosis and cardiovascular diseases. SAA-stimulated human coronary artery endothelial cells (HCAEC) were reported to release pro-inflammatory cytokines, chemokines and adhesion molecules; however it remains unclear which putative SAA receptors are present in these cells and how they act. We investigated the effects of inflammatory stimuli on the expression of SAA receptors, signaling pathways and molecular profiles in HCAEC. METHODOLOGY/PRINCIPLE FINDINGS: HCAEC were cultured in vitro and stimulated with SAA (1000nM) or IL-1beta (1000pg/ml). Expression of mRNA was determined by qPCR, and expression and quantification of proteins were assessed by dot array blots and ELISA, respectively. Protein phosphorylation was determined by dot blot arrays and Western blots. We report that all potential SAA receptors tested (FPR2/ALX, RAGE, TANIS, TLR2, TLR4 and CLA-1/hSR-B1) are expressed in HCAEC. Importantly, IL-1beta or SAA significantly increased solely the expression of the innate immune receptor TLR2. SAA upregulated the phosphorylation of ERK1/2, NF-kappaB (p65, p105) and JNK, as well as expression/release of IL-6, IL-8, G-CSF, GM-CSF, ICAM-1 and VCAM-1, all potent molecules involved in neutrophil-related activities. A TLR2-dependent positive feedback mechanism of SAA expression was found. CONCLUSION/SIGNIFICANCE: SAA stimulated responses in HCAEC target neutrophil rather than monocyte/macrophage activation. PMID- 23938272 TI - Aligned human microvessels formed in 3D fibrin gel by constraint of gel contraction. AB - This study aimed to form microvessels in fibrin gels, which is of interest both for studying the fundamental cell-matrix interactions as well as for tissue engineering purposes, and to align the microvessels, which would provide natural inlet and outlet sides for perfusion. The data reported here demonstrate the formation of highly interconnected microvessels in fibrin gel under defined medium conditions and the ability to align them using two methods, both of which involved anchoring the gel at both ends to constrain the cell-induced compaction. The first method used only defined medium and resulted in moderate alignment. The second method used defined and serum-containing media sequentially to achieve high levels of microvessel alignment. PMID- 23938273 TI - Hospital readmission rates: signal of failure or success? AB - Hospital readmission rates are increasingly used as signals of hospital performance and a basis for hospital reimbursement. However, their interpretation may be complicated by differential patient survival rates. If patient characteristics are not perfectly observable and hospitals differ in their mortality rates, then hospitals with low mortality rates are likely to have a larger share of un-observably sicker patients at risk of a readmission. Their performance on readmissions will then be underestimated. We examine hospitals' performance relaxing the assumption of independence between mortality and readmissions implicitly adopted in many empirical applications. We use data from the Hospital Episode Statistics on emergency admissions for fractured hip in 290,000 patients aged 65 and over from 2003 to 2008 in England. We find evidence of sample selection bias that affects inference from traditional models. We use a bivariate sample selection model to allow for the selection process and the dichotomous nature of the outcome variables. PMID- 23938274 TI - The ontogeny of lexical networks: toddlers encode the relationships among referents when learning novel words. AB - Although the semantic relationships among words have long been acknowledged as a crucial component of adult lexical knowledge, the ontogeny of lexical networks remains largely unstudied. To determine whether learners encode relationships among novel words, we trained 2-year-olds on four novel words that referred to four novel objects, which were grouped into two visually similar pairs. Participants then listened to repetitions of word pairs (in the absence of visual referents) that referred to objects that were either similar or dissimilar to each other. Toddlers listened significantly longer to word pairs referring to similar objects, which suggests that their representations of the novel words included knowledge about the similarity of the referents. A second experiment confirmed that toddlers can learn all four distinct words from the training regime, which suggests that the results from Experiment 1 reflected the successful encoding of referents. Together, these results show that toddlers encode the similarities among referents from their earliest exposures to new words. PMID- 23938275 TI - The illusion of saving face: how people symbolically cope with embarrassment. AB - People who feel embarrassed are often motivated to avoid social contact--that is, to hide their face. At the same time, they may be motivated to restore the positive image that has been tarnished by the embarrassing event (or, in other words, to restore the face lost in the event). Individuals can symbolically employ these coping strategies by choosing commercial products that literally either hide their face (e.g., sunglasses) or repair it (e.g., restorative cosmetics). However, the two coping strategies have different consequences. Although symbolically repairing one's face eliminates aversive feelings of embarrassment and restores one's willingness to engage in social activities, symbolically hiding one's face has little impact. PMID- 23938276 TI - Two items remembered as precisely as one: how integral features can improve visual working memory. AB - In the ongoing debate about the efficacy of visual working memory for more than three items, a consensus has emerged that memory precision declines as memory load increases from one to three. Many studies have reported that memory precision seems to be worse for two items than for one. We argue that memory for two items appears less precise than that for one only because two items present observers with a correspondence challenge that does not arise when only one item is stored--the need to relate observations to their corresponding memory representations. In three experiments, we prevented correspondence errors in two item trials by varying sample items along task-irrelevant but integral (as opposed to separable) dimensions. (Initial experiments with a classic sorting paradigm identified integral feature relationships.) In three memory experiments, our manipulation produced equally precise representations of two items and of one item. PMID- 23938277 TI - Coloured Letters and Numbers (CLaN): a reliable factor-analysis based synaesthesia questionnaire. AB - Synaesthesia is a heterogeneous phenomenon, even when considering one particular sub-type. The purpose of this study was to design a reliable and valid questionnaire for grapheme-colour synaesthesia that captures this heterogeneity. By the means of a large sample of 628 synaesthetes and a factor analysis, we created the Coloured Letters and Numbers (CLaN) questionnaire with 16 items loading on 4 different factors (i.e., localisation, automaticity/attention, deliberate use, and longitudinal changes). These factors were externally validated with tests which are widely used in the field of synaesthesia research. The questionnaire showed good test-retest reliability and construct validity (i.e., internally and externally). Our findings are discussed in the light of current theories and new ideas in synaesthesia research. More generally, the questionnaire is a useful tool which can be widely used in synaesthesia research to reveal the influence of individual differences on various performance measures and will be useful in generating new hypotheses. PMID- 23938280 TI - Sleeve gastrectomy: an ideal choice for T2DM. PMID- 23938282 TI - Sleeve gastrectomy: the ideal option for metabolic surgery? PMID- 23938283 TI - Surgery: T2DM remission after RYGB-a 'gutsy' move. PMID- 23938285 TI - Description of Ambrosiozyma oregonensis sp. nov., and reassignment of Candida species of the Ambrosiozyma clade to Ambrosiozyma kashinagacola f.a., comb. nov., Ambrosiozyma llanquihuensis f.a., comb. nov., Ambrosiozyma maleeae f.a., comb. nov., Ambrosiozyma pseudovanderkliftii f.a., comb. nov., and Ambrosiozyma vanderkliftii f.a., comb. nov. AB - Ambrosiozyma oregonensis sp. nov. is described from two strains, one isolated from a mountain stream in Oregon, USA (NRRL Y-6106(T) = CBS 5560(T)), and a second (NRRL YB-4169) from an unknown substrate from Marion, Illinois, USA. The species forms four hat-shaped ascospores in each deliquescent ascus and appears to be homothallic. Abundant true hyphae are produced with some having apparent dolipore-like septa. Analyses of nuclear gene sequences for the D1/D2 domains of large-subunit rRNA, small-subunit rRNA, translation elongation factor-1alpha, and subunits B1 and B2 of RNA polymerase II show the proposed novel species to be distinct from other species of the Ambrosiozyma clade. Because of their placement in the Ambrosiozyma clade, Candida kashinagacola, Candida llanquihuensis, Candida maleeae, Candida pseudovanderkliftii and Candida vanderkliftii are reassigned to the genus Ambrosiozyma as new combinations, and the description of the genus Ambrosiozyma is emended to reflect the resulting changes in phenotypic characters. PMID- 23938284 TI - Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches. AB - Osteoporosis is a skeletal disorder characterized by bone loss, which results in architectural deterioration of the skeleton, compromised bone strength and an increased risk of fragility fractures. Most current therapies for osteoporosis stabilize the skeleton by inhibiting bone resorption (antiresorptive agents), but the development of anabolic therapies that can increase bone formation and bone mass is of great interest. Wnt signalling induces differentiation of bone-forming cells (osteoblasts) and suppresses the development of bone-resorbing cells (osteoclasts). The Wnt pathway is controlled by antagonists that interact either directly with Wnt proteins or with Wnt co-receptors. The importance of Wnt signalling in bone formation is indicated by skeletal disorders such as sclerosteosis and van Buchem syndrome, which are caused by mutations in the gene encoding the Wnt antagonist sclerostin (SOST). Experiments in mice have shown that downregulation or neutralization of Wnt antagonists enhances bone formation. Phase II clinical trials show that 1-year treatment with antisclerostin antibodies increases bone formation, decreases bone resorption and leads to a substantial increase in BMD. Consequently, Wnt signalling can be targeted by the neutralization of its extracellular antagonists to obtain a skeletal anabolic response. PMID- 23938286 TI - Atherosclerosis susceptibility Loci identified in an extremely atherosclerosis resistant mouse strain. AB - BACKGROUND: C3H/HeJ (C3H) mice are extremely resistant to atherosclerosis, especially males. To understand the underlying genetic basis, we performed quantitative trait locus (QTL) analysis on a male F2 (the second generation from an intercross between 2 inbred strains) cohort derived from an intercross between C3H and C57BL/6 (B6) apolipoprotein E-deficient (Apoe(-/-)) mice. METHODS AND RESULTS: Two hundred forty-six male F2 mice were started on a Western diet at 8 weeks of age and kept on the diet for 5 weeks. Atherosclerotic lesions in the aortic root and fasting plasma lipid levels were measured. One hundred thirty four microsatellite markers across the entire genome were genotyped. Four significant QTLs on chromosomes (Chr) 2, 4, 9, and 15 and 4 suggestive loci on Chr1, Chr4, and Chr7 were identified for atherosclerotic lesions. Unexpectedly, the C3H allele was associated with increased lesion formation for 2 of the 4 significant QTLs. Six loci for high-density lipoprotein (HDL), 6 for non-HDL cholesterol, and 3 for triglycerides were also identified. The QTL for atherosclerosis on Chr9 replicated Ath29, originally mapped in a female F2 cohort derived from B6 and C3H Apoe(-/-) mice. This locus coincided with a QTL for HDL, and there was a moderate, but statistically significant, correlation between atherosclerotic lesion sizes and plasma HDL cholesterol levels in F2 mice. CONCLUSIONS: These data indicate that most atherosclerosis susceptibility loci are distinct from those for plasma lipids except for the Chr9 locus, which exerts effect through interactions with HDL. PMID- 23938287 TI - Arginase II: atherogenesis beyond enzyme activity. PMID- 23938288 TI - Is plasma pentadecanoic acid a reasonable biomarker of dairy consumption? PMID- 23938289 TI - Prognostic factors in patients with advanced cancer: a comparison of clinicopathological factors and the development of an inflammation-based prognostic system. AB - PURPOSE: In advanced cancer, oncological treatment is influenced by performance status (PS); however, this has limitations. Biomarkers of systemic inflammation may have prognostic value in advanced cancer. The study compares key factors in prognosis (performance status, patient-reported outcomes; PRO) with an inflammation-based score (Glasgow Prognostic Score, mGPS). A new method of prognosis in advanced cancer (combining performance status and mGPS) is tested and then validated. EXPERIMENTAL DESIGN: Two international biobanks of patients with advanced cancer were analyzed. Key prognostic factors [performance status, PROs (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C-30), and mGPS (using C-reactive protein and albumin concentrations)] were examined. The relationship between these and survival was examined using Kaplan-Meier and Cox regression methods, in a test sample before independent validation. RESULTS: Data were available on 1,825 patients (test) and 631 patients (validation). Median survival ranged from 3.2 months (test) to 7.03 months (validation). On multivariate analysis, performance status (HR 1.62-2.77) and mGPS (HR 1.51-2.27) were independently associated with, and were the strongest predictors of survival (P < 0.01). Survival at 3 months varied from 82% (mGPS 0) to 39% (mGPS 2) and from 75% (performance status 0-1) to 14% (performance status 4). When used together, survival ranged from 88% (mGPS 0, PS 0-1) to 10% (mGPS 2, performance status 4), P < 0.001. CONCLUSION: A systemic inflammation-based score, mGPS, and performance status predict survival in advanced cancer. The mGPS is similar to performance status in terms of prognostic power. Used together, performance status and mGPS act synergistically improving prognostic accuracy. This new method may be of considerable value in the management of patients with advanced cancer. PMID- 23938290 TI - HLA and killer immunoglobulin-like receptor genes as outcome predictors of hepatitis C virus-related hepatocellular carcinoma. AB - PURPOSE: We evaluated the impact of the killer immunoglobulin-like receptors (KIR) of natural killer (NK) cells and of their HLA ligands over the clinical outcome of hepatitis C virus (HCV)-related hepatocellular carcinoma after curative treatment by either surgical resection or radiofrequency thermal ablation (RTA). EXPERIMENTAL DESIGN: Sixty-one consecutive patients with HCV related hepatocellular carcinoma underwent KIR genotyping and HLA typing. A phenotypic/functional characterization of NK cells was carried out in patients with different KIR/KIR-ligand genotype. RESULTS: Activating KIR2DS5 was associated with significantly longer time to recurrence (TTR) and overall survival (OS; P < 0.03 each). Homozygous HLA-C1 (P < 0.02) and HLA-Bw4I80 (P < 0.05) were expressed by patients with significantly better OS, whereas HLA-C2 (P < 0.02) and HLA-Bw4T80 (P < 0.01) were associated with a worse OS. Multivariate analysis identified as parameters independently related to TTR the type of treatment (surgical resection vs. RTA; P < 0.03) and HLA-C1 (P < 0.03), whereas only KIR2DS5 was an independent predictor of longer OS (P < 0.05). Compound KIR2DL2-C1 and KIR3DS1-Bw4T80 genotypes were associated with better TTR (P < 0.03) and worse OS (P = 0.02), respectively. A prevalent cytotoxic (CD56(dim)) NK phenotype was detected in patients with both longer TTR and OS. Cytotoxic capacity measured by upregulation of CD107a was significantly higher in subjects with HLA-C1 alone or combined with KIR2DL2/KIR2DL3. CONCLUSIONS: These results support a central role of NK cells in the immune response against hepatocellular carcinoma, providing a strong rationale for therapeutic strategies enhancing NK response and for individualized posttreatment monitoring schemes. PMID- 23938291 TI - Identification of transcriptional subgroups in EGFR-mutated and EGFR/KRAS wild type lung adenocarcinoma reveals gene signatures associated with patient outcome. AB - PURPOSE: In lung adenocarcinoma, EGFR and KRAS mutations dominate the mutational spectrum and have clear therapeutic implications. We sought to determine whether transcriptional subgroups of clinical relevance exist within EGFR-mutated, KRAS mutated, or EGFR and KRAS wild-type (EGFRwt/KRASwt) adenocarcinomas. EXPERIMENTAL DESIGN: Gene expression profiles from 1,186 adenocarcinomas, including 215 EGFR mutated, 84 KRAS-mutated, and 219 EGFRwt/KRASwt tumors, were assembled and divided into four discovery (n = 522) and four validation cohorts (n = 664). Subgroups within the mutation groups were identified by unsupervised consensus clustering, significance analysis of microarrays (SAM) analysis, and centroid classification across discovery cohorts. Genomic alterations in identified mutation subgroups were assessed by integration of genomic profiles for 158 cases with concurrent data. Multicohort expression subgroup predictors were built for each mutation group using the discovery cohorts, and validated in the four validation cohorts. RESULTS: Consensus clustering within the mutation groups identified reproducible transcriptional subgroups in EGFR-mutated and EGFRwt/KRASwt tumors, but not in KRAS-mutated tumors. Subgroups displayed differences in genomic alterations, clinicopathologic characteristics, and overall survival. Multicohort gene signatures derived from the mutation subgroups added independent prognostic information in their respective mutation group, for adenocarcinoma in general and stage I tumors specifically, irrespective of mutation status, when applied to the validation cohorts. Consistent with their worse clinical outcome, high-risk subgroups showed higher expression of proliferation-related genes, higher frequency of copy number alterations/amplifications, and association with a poorly differentiated tumor phenotype. CONCLUSIONS: We identified transcriptional subgroups in EGFR-mutated and EGFRwt/KRASwt adenocarcinomas with significant differences in clinicopathologic characteristics and patient outcome, not limited to a mutation specific setting. PMID- 23938292 TI - Computerized tomography-based radiotherapy improves heterotopic ossification outcomes. AB - PURPOSE: To report the impact of computerized tomography (CT) based radiotherapy (RT) on heterotopic ossification (HO) outcomes. METHODS: This is a single institution, retrospective study of 532 patients who were treated for traumatic acetabular fractures (TAF). All patients underwent open-reduction internal fixation (ORIF) of the TAF followed by RT for HO prophylaxis. Postoperative RT was delivered within 72h, in a single fraction of 7Gy. The patients were divided into 2 groups based on RT planning: CT (A) vs. clinical setup (B). RESULTS: At a median follow up of 8years the incidence of HO was 21.6%. Multivariate regression analysis revealed that group (A) vs. (B) had HO incidence of 6.6% vs. 24.6% (p<0.001), respectively. Furthermore, HO Brooker grade >=3 was observed in 2.2% vs. 10.8% (p=0.007) in group (A) vs. (B), respectively. Thus, the odds of developing HO and Brooker grades >=3 were 4.7 and 4.5 times higher, respectively, in patients who underwent clinical setup. CONCLUSION: Our data suggest that using CT based RT allowed more accurate delineation of the tissues and better clinical outcomes. Although CT-based RT is associated with additional cost the efficacy of CT-based RT reduces the risk of HO, thereby decreasing the need for additional surgical interventions. PMID- 23938293 TI - Spiking the MERS-coronavirus receptor. AB - A novel coronavirus, the Middle East respiratory syndrome coronavirus, recently emerged through zoonotic transmission, causing a severe lower respiratory tract infection in humans. In two recent papers, one published in Cell Research, the crystal structure of the viral receptor-binding domain in complex with the host CD26/dipeptidyl peptidase 4 receptor has now been characterized. PMID- 23938294 TI - MeCP2: making sense of missense in Rett syndrome. AB - Fine scale genomic regulation is critical for maintaining genomic integrity and is often disrupted in neurodevelopmental disorders. An intriguing new study reveals the intricate biochemical complexity of de novo post-translational modifications of MeCP2, including activity-dependent protein-protein interactions that 'bridge' the nuclear receptor co-repressor (NCoR) complex to chromatin and lead to alterations in gene expression that characterize Rett syndrome. PMID- 23938295 TI - Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. AB - Although the function of DNA methylation in gene promoter regions is well established in transcriptional repression, the function of the evolutionarily conserved widespread distribution of DNA methylation in gene body regions remains incompletely understood. Here, we show that DNA methylation is enriched in included alternatively spliced exons (ASEs), and that inhibition of DNA methylation results in aberrant splicing of ASEs. The methyl-CpG-binding protein MeCP2 is enriched in included ASEs, particularly those that are also highly methylated, and inhibition of DNA methylation disrupts specific targeting of MeCP2 to exons. Interestingly, ablation of MeCP2 results in increased histone acetylation and aberrant ASE-skipping events. We further show that inhibition of histone deacetylase (HDAC) activity leads to exon skipping that shows a highly significant degree of overlap with that caused by MeCP2 knockdown. Together, our data indicate that intragenic DNA methylation operates in exon definition to modulate alternative RNA splicing and can enhance exon recognition via recruitment of the multifunctional protein MeCP2, which thereby maintains local histone hypoacetylation through the subsequent recruitment of HDACs. PMID- 23938296 TI - Pdx-1 activates islet alpha- and beta-cell proliferation via a mechanism regulated by transient receptor potential cation channels 3 and 6 and extracellular signal-regulated kinases 1 and 2. AB - The homeodomain transcription factor Pdx-1 has important roles in pancreatic development and beta-cell function and survival. In the present study, we demonstrate that adenovirus-mediated overexpression of Pdx-1 in rat or human islets also stimulates cell replication. Moreover, cooverexpression of Pdx-1 with another homeodomain transcription factor, Nkx6.1, has an additive effect on proliferation compared to either factor alone, implying discrete activating mechanisms. Consistent with this, Nkx6.1 stimulates mainly beta-cell proliferation, whereas Pdx-1 stimulates both alpha- and beta-cell proliferation. Furthermore, cyclins D1/D2 are upregulated by Pdx-1 but not by Nkx6.1, and inhibition of cdk4 blocks Pdx-1-stimulated but not Nkx6.1-stimulated islet cell proliferation. Genes regulated by Pdx-1 but not Nkx6.1 were identified by microarray analysis. Two members of the transient receptor potential cation (TRPC) channel family, TRPC3 and TRPC6, are upregulated by Pdx-1 overexpression, and small interfering RNA (siRNA)-mediated knockdown of TRPC3/6 or TRPC6 alone inhibits Pdx-1-induced but not Nkx6.1-induced islet cell proliferation. Pdx-1 also stimulates extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, an effect partially blocked by knockdown of TRPC3/6, and blockade of ERK1/2 activation with a MEK1/2 inhibitor partially impairs Pdx-1 stimulated proliferation. These studies define a pathway by which overexpression of Pdx-1 activates islet cell proliferation that is distinct from and additive to a pathway activated by Nkx6.1. PMID- 23938297 TI - Analysis of mice lacking the heparin-binding splice isoform of platelet-derived growth factor A. AB - Platelet-derived growth factor A-chain (PDGF-A) exists in two evolutionarily conserved isoforms, PDGF-Along and PDGF-Ashort, generated by alternative RNA splicing. They differ by the presence (in PDGF-Along) or absence (in PDGF-Ashort) of a carboxy-terminal heparin/heparan sulfate proteoglycan-binding motif. In mice, similar motifs present in other members of the PDGF and vascular endothelial growth factor (VEGF) families have been functionally analyzed in vivo, but the specific physiological importance of PDGF-Along has not been explored previously. Here, we analyzed the absolute and relative expression of the two PDGF-A splice isoforms during early postnatal organ development in the mouse and report on the generation of a Pdgfa allele (Pdgfa(Deltaex6)) incapable of producing PDGF-Along due to a deletion of the exon 6 splice acceptor site. In situations of limiting PDGF-A signaling through PDGF receptor alpha (PDGFRalpha), or in mice lacking PDGF-C, homozygous carriers of Pdgfa(Deltaex6) showed abnormal development of the lung, intestine, and vertebral column, pinpointing developmental processes where PDGF-Along may play a physiological role. PMID- 23938299 TI - Stress-free with Rpd3: a unique chromatin complex mediates the response to oxidative stress. PMID- 23938300 TI - Protein-bound uremic toxins...new targets to prevent insulin resistance and dysmetabolism in patients with chronic kidney disease. AB - The retention of p-cresyl sulfate (PCS), the prototype of protein-bound uremic toxins that is produced by the gut microbiota and normally excreted by the kidney, may contribute to the development of insulin resistance in patients with chronic kidney disease. In a recent study, we demonstrated in mice, as in cultured muscle cells, that PCS interferes with intracellular insulin signaling pathways and triggers insulin resistance. The treatment of CKD mice with a prebiotic that reduces the intestinal production and decreases blood levels of PCS prevented insulin resistance and lipid abnormalities, suggesting new opportunities to prevent metabolic disturbances in patients with CKD. This study highlights the uremic toxins as new actors in metabolic alterations associated with CKD and allows for the consideration of new therapeutic approaches (e.g., prebiotics, probiotics, adsorbents) to better prevent them. PMID- 23938298 TI - Activation of a novel ubiquitin-independent proteasome pathway when RNA polymerase II encounters a protein roadblock. AB - Topoisomerase IIbeta (Top2beta)-DNA cleavage complexes are known to arrest elongating RNA polymerase II (RNAPII), triggering a proteasomal degradation of the RNAPII large subunit (RNAPII LS) and Top2beta itself as a prelude to DNA repair. Here, we demonstrate that the degradation of Top2beta occurs through a novel ubiquitin-independent mechanism that requires only 19S AAA ATPases and 20S proteasome. Our results suggest that 19S AAA ATPases play a dual role in sensing the Top2beta cleavage complex and coordinating its degradation by 20S proteasome when RNAPII is persistently stalled by the Top2beta protein roadblock. Clarification of this transcription-associated proteasome pathway could shed light on a general role of 19S AAA ATPases in processing tight protein-DNA complexes during transcription elongation. PMID- 23938301 TI - Hydrophobic amino acids as a new class of kinetic inhibitors for gas hydrate formation. AB - As the foundation of energy industry moves towards gas, flow assurance technology preventing pipelines from hydrate blockages becomes increasingly significant. However, the principle of hydrate inhibition is still poorly understood. Here, we examined natural hydrophobic amino acids as novel kinetic hydrate inhibitors (KHIs), and investigated hydrate inhibition phenomena by using them as a model system. Amino acids with lower hydrophobicity were found to be better KHIs to delay nucleation and retard growth, working by disrupting the water hydrogen bond network, while those with higher hydrophobicity strengthened the local water structure. It was found that perturbation of the water structure around KHIs plays a critical role in hydrate inhibition. This suggestion of a new class of KHIs will aid development of KHIs with enhanced biodegradability, and the present findings will accelerate the improved control of hydrate formation for natural gas exploitation and the utilization of hydrates as next-generation gas capture media. PMID- 23938302 TI - Unilateral absence of pulmonary artery: pathophysiology, symptoms, diagnosis and current treatment. AB - Unilateral absence of pulmonary artery (UAPA) is a rare malformation that can present as an isolated lesion or may be associated with other congenital heart defects. UAPA is often associated with other congenital cardiovascular anomalies, such as tetralogy of Fallot, atrial septal defect, coarctation of aorta, right aortic arch, truncus arteriosus and pulmonary atresia. Diagnosis of UAPA is very difficult and is based on taking a complete medical history, physical examination and imaging examinations. Clinical symptoms include exercise intolerance, haemoptysis and recurrent respiratory infections. Adult patients with UAPA are often asymptomatic. There is no consensus regarding the treatment for UAPA. The therapeutic approach should be based on symptoms of the patient, pulmonary artery anatomy and associated aortopulmonary collaterals. Treatment options for these patients include partial or total pneumonectomy, closure of selected collateral arteries not solely responsible for pulmonary blood flow or a primary versus staged pulmonary artery anastomosis. This review summarizes pathophysiology, symptomatology and current diagnosis and treatment of this disease. PMID- 23938304 TI - Human herpesvirus-6 DNAemia is a sign of impending primary CMV infection in CMV sero-discordant renal transplantations. AB - BACKGROUND: Human herpesvirus-6 (HHV-6) frequently reactivates in immunocompromized individuals. Most commonly HHV-6 DNA is detected without organ localized disease. This HHV-6 DNAemia usually occurs in patients who also have CMV reactivations. The question if reactivation of one virus causes reactivation of the other, or whether both viruses reactivate independently, cannot be answered in populations with high seroprevalence for both viruses. Our study is the first in which 35 patients have been included who were CMV seronegative prior to transplantation. OBJECTIVE: We investigated the occurrence of HHV-6 reactivations in relation to the CMV-serostatus of renal transplantation donor and recipient. STUDY DESIGN: 9 consecutive patients receiving a renal transplantation were included. All available stored whole blood samples were tested for HHV-6 DNA by quantitative PCR. Details including CMV serostatus of donor and recipient were recorded. RESULTS: CMV-seropositive recipients have a 68% chance of developing HHV-6 DNAemia if the kidney came from a CMV-seropositive donor, compared to 26% if the kidney came from a CMV-seronegative donor. CMV seronegative recipients, who are bound to undergo primary CMV infections following transplantation with a renal graft from a CMV-seropositive donor, have 88% chance of developing HHV-6 DNAemia. If they receive a graft from a CMV seronegative donor the chance of developing HHV-6 DNAemia is 22%. CONCLUSION: Receiving a renal transplant from a CMV-seropositive donor increases the chance of developing HHV-6 DNAemia. HHV-6 DNAemia is a sign of impending primary CMV infections following sero-discordant renal transplantations. PMID- 23938303 TI - Pleurodynia caused by an echovirus 1 brought back from the tropics. AB - A 31 year-old woman presented with acute pain on the left side of the thorax and abdomen, radiating to the back together with fever, after she had returned from traveling in Southeast Asia. Except for pleural friction rub auscultated on the left hemithorax, no physical abnormalities were detected. We diagnosed a classical course of Bornholm disease, caused by an echovirus type 1. While described as a classical pathogen causing Bornholm disease, this genotype has not been reported frequently in Surveillance data in the Western World. PMID- 23938305 TI - Escherichia albertii, a newly emerging enteric pathogen with poorly defined properties. AB - Escherichia albertii is a newly emerging enteric pathogen that has been associated with sporadic infections among humans and birds. Selected coliform isolates were screened for allelic variation in 2 housekeeping genes (lysP and mdh) specific for E. albertii. The 48 strains that were identified as E. albertii were tested for 15 virulence markers and biochemical and serogical properties. All E. albertii strains were non-motile, fermented D-glucose (with gas), D mannitol, and D-mannose, but failed to ferment lactose and other sugars. Variable positive reactions were noted for other tests. Most strains were rough or failed to agglutinate with Shigella boydii 13 antisera and E. coli antisera with few exceptions. All strains were positive for the eaeA gene, and variable numbers were positive for the cdtB, phoE, ehxA, and stx2f genes. Results illustrate the variability extent within this lineage and highlight the importance of accurately distinguishing it within the genus Escherichia and including information within commercial databases to improve their identification. PMID- 23938307 TI - mTOR inhibition alleviates L-DOPA-induced dyskinesia in parkinsonian rats. AB - The development of dyskinesia upon chronic L-DOPA treatment is a major complication for the management of the motor symptoms in Parkinson's disease (PD) patients. Efforts are made to understand the underlying mechanisms and identify targets for the pharmacological alleviation of dyskinesia without affecting the therapeutic effect of L-DOPA. Previous studies have shown that the mTOR pathway is hyperactive in dyskinesia as a consequence of D1 receptor hypersensitivity. We investigated the effect of the FDA-approved mTOR inhibitor Temsirolimus (CCI 779), currently used in the clinic, on the development of LID and on the severity of already established LID in hemi-parkinsonian rats. Systemic delivery of CCI 779 prevented the development of LID and significantly alleviated the severity of dyskinesia in L-DOPA-primed animals. This was associated with a reduced activation of the mTOR pathway in striatal medium spiny neurons. Drugs with mTOR inhibiting activity that are actively developed in cancer research may be of interest for the management of LID in PD patients. PMID- 23938308 TI - Found in transcription: accurate Parkinson's disease classification in peripheral blood. AB - BACKGROUND: A blood-based test for the early detection of Parkinson's disease (PD) would be an important diagnostic tool and useful for patient selection when developing novel drugs or treatments for the disease. OBJECTIVE: Here, we aimed to identify potential biomarkers associated with PD. METHODS: We applied gene expression profiling to the study of peripheral blood from 75 healthy control subjects and 79 PD patients at different stages of the disease. Healthy control subjects were matched for age and gender with PD subjects, and the diagnosis of patients was based on clinical evaluation by specialists in movement disorders. RNA was extracted from the blood samples and the gene expressions were measured using the Illumina HumanHT-12 v4.0 Expression BeadChip. RESULTS: Our results support previous studies that gene expression in blood may be instrumental in the search for molecular biomarkers for PD. Single cross-validation results show that PD can be correctly classified from healthy controls with an agreement of 88% to clinical diagnosis. De novo PD patients are classified with a sensitivity of 87%, which is close to what was achieved for the patients having a confirmed PD diagnosis with disease duration <5 and >5 years (93% and 88%). A double cross validation procedure showed that using a selected set of around 650 informative genes, similar results are achieved. Functional analysis of the selected genes showed genes significantly associated to mitochondrial dysfunction, protein ubiquitination, gene expression and cell death. CONCLUSIONS: PD affects gene expression in blood, suggesting the potential for the development of a blood based gene expression test. PMID- 23938309 TI - Inhaled apomorphine in patients with 'on-off' fluctuations: a randomized, double blind, placebo-controlled, clinic and home based, parallel-group study. AB - BACKGROUND: In later stages of Parkinson's disease, treatment of 'off' periods with subcutaneous apomorphine is helpful but requires injection; inhaled apomorphine would be potentially more convenient. OBJECTIVES: To identify optimal efficacy, safety and tolerability for inhaled apomorphine in reversing Parkinson's disease 'off' periods. METHODS: A randomized, double-blind, 2:1 active:placebo, parallel-group, ascending dose titration study was conducted at 16 centres in 3 countries. Inhaled apomorphine was administered under observation, at escalating fine particle doses of 1.5, 2.5, 3.5 and 4.5 mg. This was followed by at-home patient self-treatment for 2 to 4 weeks, assessed from 'on-off' diaries. RESULTS: In 55 patients, mean age 65.6 years (range 47-79), mean disease duration 12 years (range 5-22), the mean improvement in the unified PD rating scale part 3 (UPDRS 3) was significantly greater for apomorphine (mean dose 2.3 mg) at 19.5 (standard deviation 13.6) than for placebo at 9.9 (9.6), least squares mean difference 8.4 (95% confidence interval 1.2 to 15.5, p = 0.023). During at-home testing, mean 'off' time per day was reduced by 139.8 minutes (standard deviation 149.6) for apomorphine versus 68.0 (108.6) minutes for placebo, least squares mean difference not significant at 100.5 minutes (95% confidence interval -12.0 to 212.9, p = 0.078). The onset of action was faster for apomorphine (mean 8.1 SD 6.2 minutes) than placebo (mean 13.1 SD 6.6 minutes) (p < 0.0001). Reversal of 'off' episodes was significantly more likely for episodes treated with apomorphine than those treated with placebo: apomorphine 64.6% SD 32.3 of episodes versus placebo 11.1% SD 15.3 (p < 0.0001). During at home treatment, 36% of apomorphine and 20% of placebo patients experienced adverse events. CONCLUSIONS: Inhaled apomorphine in the dose range 1.5 to 4.5 mg, significantly improved UPDRS 3 scores in the clinic, and aborted a greater proportion of 'off' periods at-home, compared to placebo. However, daily 'off' time was not significantly reduced by the use of inhaled apomorphine. PMID- 23938310 TI - Personality affects aspects of health-related quality of life in Parkinson's disease via psychological coping strategies. AB - BACKGROUND: Personality traits influence health-related quality of life (HRQoL) in Parkinson's disease (PD). Further, an individual's personality traits can influence the strategies they use to cope with a particular stressful situation. However, in PD, the interplay between personality traits, choice of coping strategy, and their subsequent effect on HRQoL remains unclear. OBJECTIVE: The objective of this study was to examine whether personality (neuroticism and extraversion) indirectly affects HRQoL through the use of specific psychological coping strategies. METHODS: One hundred and forty-six patients with PD completed questionnaires on personality (Big Five Aspects Scale; BFAS), coping (Ways of Coping Questionnaire; WCQ), and mood-specific (Depression, Anxiety and Stress Scale; DASS-21) and disease-specific HRQoL (Parkinson's Disease Questionnaire; PDQ-39). RESULTS: After controlling for gender, age at diagnosis, and age at testing, the emotion-focused coping strategy of escape-avoidance was significantly correlated with neuroticism and certain aspects of HRQoL (cognitive impairment and social support). This suggests that neurotic personality traits may negatively impact on some aspects of HRQoL due to an increased use of escape avoidance coping strategies. By contrast, planned problem-solving and escape avoidance coping strategies were both significantly linked to extraversion and interpersonal and mood-related domains of HRQoL. This suggests that extraversion may positively impact on some aspects of HRQoL due to patients adopting greater planned, problem-solving coping strategies, and using fewer escape-avoidance coping mechanisms. CONCLUSIONS: Psychological interventions aimed at targeting maladaptive coping strategies, such as the use of escape-avoidance coping, may be effective in minimising the negative impact of neuroticism on HRQoL in PD. PMID- 23938306 TI - Parkinson's disease--the debate on the clinical phenomenology, aetiology, pathology and pathogenesis. AB - The definition of Parkinson's disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article--widening the definition of PD/LBD/synucleinopathies and the heterogeneity that exists within PD itself from a clinical, pathological and genetic perspective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include--Parkinson's syndrome, Parkinson's syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA). PMID- 23938311 TI - Improving detection of psychiatric disturbances in Parkinson's disease: the role of informants. AB - BACKGROUND: Under-recognition of psychiatric disturbances in patients with Parkinson's disease (PD) contributes to greater overall morbidity. Little is known about the value of collateral psychiatric history, obtained using standardized assessments with informants, for increasing recognition of PD related psychiatric illness. OBJECTIVE: To examine the extent to which informants provide critical information that enabled psychiatrists to establish psychiatric diagnoses in patients with PD. METHODS: Individuals with PD (n = 223) and an informant were interviewed separately regarding the PD patient's psychiatric history and current status. A six-psychiatrist panel rated the extent to which informant data was required to establish the final consensus best-estimate current psychiatric diagnoses. Informants rated as "Crucial" or "Significantly Informative" comprised a "Critical Informant" (CI) subgroup; remaining informants were classified as the "Non-Critical Informant" (NCI) subgroup. RESULTS: Of the informants, 71 (31.4%) were "critical" for determining a psychiatric diagnosis. Without a CI, 81.3% of those with impulse control disorders and 43.8% of those with anxiety disorders would not have been diagnosed. Male PD patients and those with less severe motor deficits were also more likely to require a CI. CONCLUSIONS: Informants aid in the identification of psychiatric diagnoses, especially impulse control and anxiety disorders. This has implications for clinical practice and conduction of clinical trials. PMID- 23938312 TI - Guided self-help for the management of worry in Parkinson's disease: a pilot study. AB - BACKGROUND: Anxiety disorder and anxiety symptomatology are common in Parkinson's disease (PD), with up to 25% patients experiencing significant worry. There is no systematic evidence base for the management of anxiety or anxiety related symptoms such as worry in PD. OBJECTIVES: To investigate whether cognitive therapy, delivered as bibliotherapy, is an effective intervention for worry in PD. METHODS: 54 participants were randomly allocated to a guided reading group and a control group. The guided reading group were given a CBT based self-help resource called What? Me Worry!?! to work through over eight weeks, with telephone support at two week intervals. Controls were given information about worry only, and one phone call. Measures of worry, intolerance of uncertainty, metacognitions and health status were taken at baseline and after 3 months. RESULTS: Analysable data were obtained for 15 controls and 17 from the guided reading group. Worry and intolerance of uncertainty were significantly reduced in the guided reading group. However, no significant differences were found for the follow up measures between the groups. CONCLUSIONS: Bibliotherapy has the potential to be useful and cost effective as a management strategy for the treatment of worry in people with PD. PMID- 23938314 TI - Saffron pre-treatment offers neuroprotection to Nigral and retinal dopaminergic cells of MPTP-Treated mice. AB - BACKGROUND: There is growing evidence that the spice saffron, which contains powerful anti-oxidants, offers protection against neurodegenerative disorders, including age-related macular degeneration and Alzheimer's disease. OBJECTIVE: We examined whether saffron pre-treatment protects dopaminergic cells of the substantia nigra pars compacta (SNc) and retina in an acute MPTP (1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease. METHODS: BALB/c mice received MPTP or saline injections over a 30 hour period, followed by six days survival. For five days prior to injections, the drinking water of the saffron groups was supplemented with saffron (0.01% w/v), while non-saffron groups received normal tap water. After the survival period was complete, brains were processed for tyrosine hydroxylase (TH) immunochemistry and the number of TH+ cells was analysed using the optical fractionator method. RESULTS: In both the SNc and retina, non-conditioned MPTP-injected mice had a reduced number of TH+ cells (30-35%) compared to the saline-injected controls. Saffron pre conditioning mitigated the reduction, with pre-conditioned MPTP-injected mice having SNc and retinal TH+ cell numbers close to control levels, significantly (25-35%) higher than in non-conditioned MPTP-injected mice. CONCLUSIONS: Our results indicated that saffron pre-treatment of mice saved many dopaminergic cells of the SNc and retina from parkinsonian (MPTP) insult. PMID- 23938313 TI - Mapping cortical atrophy in Parkinson's disease patients with dementia. AB - BACKGROUND: Cognitive impairment is very common in patients with Parkinson's disease (PD). Brain changes accompanying cognitive decline in PD are still not fully established. METHODS: We applied cortical pattern matching and cortical thickness analyses to the three-dimensional T1-weighted brain MRI scans of 14 age matched cognitively normal elderly (NC), 12 cognitively normal PD (PDC), and 11 PD dementia (PDD) subjects. We used linear regression models to investigate the effect of diagnosis on cortical thickness. All maps were adjusted for multiple comparisons using permutation testing with a threshold p < 0.01. RESULTS: PDD showed significantly thinner bilateral sensorimotor, perisylvian, lateral parietal, as well as right posterior cingulate, parieto-occipital, inferior temporal and lateral frontal cortices relative to NC (left p(corrected) = 0.06, right p(corrected) = 0.009). PDD showed significantly thinner bilateral sensorimotor, right frontal and right parietal-occipital cortices relative to PDC (right p(corrected) = 0.05). The absolute difference in cortical thickness between PDD and the other diagnostic groups ranged from 3% to 19%. CONCLUSION: Our data shows that cognitive decline in PD is associated with cortical atrophy. PDD subjects have the most widespread gray matter atrophy suggesting more cortical involvement as PD patients progress to dementia. PMID- 23938315 TI - The neuronal protective effects of local brain cooling at the craniectomy site after lateral fluid percussion injury in a rat model. AB - BACKGROUND: The aim of the present study is to investigate whether local brain cooling at the craniectomy site causes attenuation of traumatic brain injury (TBI) induced by fluid percussion injury (FPI). METHODS: Anesthetized male Sprague-Dawley rats were divided into two major treatment groups. Immediately after the onset of fluid percussion TBI, a craniectomy window of 6 * 8 mm was made at the right parietal, and a cold water bag (0 degrees C-1 degrees C or 5 degrees C-6 degrees C) was applied locally for 30 min. Additional groups of rats were used as craniectomy and craniectomy + FPI controls. Physiological parameters, such as brain and colonic temperature, mean arterial pressure, and heart rate, were monitored during FPI. Functional motor outcomes were evaluated using the inclined plane test (maximal grasp angle). Cellular infarction volume was calculated using triphenyltetrazolium chloride staining. Apoptosis and neuronal marker-positive cells in the cortex were measured by immunofluorescence staining. All functional and morphologic parameters were assessed 72 h after injury. RESULTS: Compared with the craniectomy + FPI control groups, the groups treated with 5 degrees C-6 degrees C local cold water therapy showed significant attenuation of the FPI-induced motor deficits, weight loss, and cerebral infarction but no effect on colonic temperature. The FPI-induced apoptosis and neuronal loss were also significantly reduced by local cooling. CONCLUSIONS: Our results suggest that local cooling with 5 degrees C-6 degrees C cold water therapy may ameliorate TBI in rats by reducing infarction volume, neuronal cell loss, and apoptosis, resulting in improved functional outcome. We propose that the use of local cooling at the craniectomy site after FPI might have clinical benefits in the future. PMID- 23938316 TI - Abundant sequence divergence in the native Japanese cattle Mishima-Ushi (Bos taurus) detected using whole-genome sequencing. AB - The native Japanese cattle Mishima-Ushi, a designated national natural treasure, are bred on a remote island, which has resulted in the conservation of their genealogy. We examined the genetic characteristics of 8 Mishima-Ushi individuals by using single nucleotide polymorphisms (SNPs), insertions, and deletions obtained by whole-genome sequencing. Mapping analysis with various criteria showed that predicted heterozygous SNPs were more prevalent than predicted homozygous SNPs in the exonic region, especially non-synonymous SNPs. From the identified 6.54 million polymorphisms, we found 400 non-synonymous SNPs in 313 genes specific to each of the 8 Mishima-Ushi individuals. Additionally, 3,170,833 polymorphisms were found between the 8 Mishima-Ushi individuals. Phylogenetic analysis confirmed that the Mishima-Ushi population diverged from another strain of Japanese cattle. This study provides a framework for further genetic studies of Mishima-Ushi and research on the function of SNP-containing genes as well as understanding the genetic relationship between the domestic and native Japanese cattle breeds. PMID- 23938317 TI - Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems. AB - It is increasingly appreciated that altered neuroimmune mechanisms might play a role in the development of schizophrenia and related psychotic illnesses. On the basis of human epidemiological findings, a number of translational rodent models have been established to explore the consequences of prenatal immune activation on brain and behavioral development. The currently existing models are based on maternal gestational exposure to human influenza virus, the viral mimic polyriboinosinic-polyribocytidilic acid [Poly(I:C)], the bacterial endotoxin lipopolysaccharide, the locally acting inflammatory agent turpentine, or selected inflammatory cytokines. These models are pivotal for establishing causal relationships and for identifying cellular and molecular mechanisms that affect normal brain development in the event of early-life immune exposures. An important aspect of developmental immune activation models is that they allow a multi-faceted, longitudinal monitoring of the disease process as it unfolds during the course of neurodevelopment from prenatal to adult stages of life. An important recent refinement of these models is the incorporation of multiple etiologically relevant risk factors by combining prenatal immune challenges with specific genetic manipulations or additional environmental adversities. Converging findings from such recent experimental attempts suggest that prenatal infection can act as a "neurodevelopmental disease primer" that is likely relevant for a number of chronic mental illnesses. Hence, the adverse effects induced by prenatal infection might reflect an early entry into the neuropsychiatric route, but the specificity of subsequent disease or symptoms is likely to be strongly influenced by the genetic and environmental context in which the prenatal infectious process occurs. PMID- 23938318 TI - Deep brain stimulation induces striatal dopamine release in obsessive-compulsive disorder. AB - BACKGROUND: Obsessive-compulsive disorder is a chronic psychiatric disorder related to dysfunctional dopaminergic neurotransmission. Deep brain stimulation (DBS) targeted at the nucleus accumbens (NAc) has recently become an effective treatment for therapy-refractory obsessive-compulsive disorder, but its effect on dopaminergic transmission is unknown. METHODS: We measured the effects of NAc DBS in 15 patients on the dopamine D2/3 receptor availability in the striatum with [(123)I]iodobenzamide ([(123)I]IBZM) single photon emission computed tomography. We correlated changes in [(123)I]IBZM binding potential (BP) with plasma levels of homovanillic acid (HVA) and clinical symptoms. RESULTS: Acute (1-hour) and chronic (1-year) DBS decreased striatal [(123)I]IBZM BP compared with the nonstimulated condition in the putamen. BP decreases were observed after 1 hour of stimulation, and chronic stimulation was related to concurrent HVA plasma elevations, implying DBS-induced dopamine release. BP decreases in the area directly surrounding the electrodes were significantly correlated with changes in clinical symptoms (45% symptom decrease). CONCLUSIONS: NAc DBS induced striatal dopamine release, which was associated with increased HVA plasma levels and improved clinical symptoms, suggesting that DBS may compensate for a defective dopaminergic system. PMID- 23938319 TI - Distinct electrophysiological indices of maintenance in auditory and visual short term memory. AB - We compared the electrophysiological correlates for the maintenance of non musical tones sequences in auditory short-term memory (ASTM) to those for the short-term maintenance of sequences of coloured disks held in visual short-term memory (VSTM). The visual stimuli yielded a sustained posterior contralateral negativity (SPCN), suggesting that the maintenance of sequences of coloured stimuli engaged structures similar to those involved in the maintenance of simultaneous visual displays. On the other hand, maintenance of acoustic sequences produced a sustained negativity at fronto-central sites. This component is named the Sustained Anterior Negativity (SAN). The amplitude of the SAN increased with increasing load in ASTM and predicted individual differences in the performance. There was no SAN in a control condition with the same auditory stimuli but no memory task, nor one associated with visual memory. These results suggest that the SAN is an index of brain activity related to the maintenance of representations in ASTM that is distinct from the maintenance of representations in VSTM. PMID- 23938320 TI - The functional neuroanatomy of multitasking: combining dual tasking with a short term memory task. AB - Insight into the neural architecture of multitasking is crucial when investigating the pathophysiology of multitasking deficits in clinical populations. Presently, little is known about how the brain combines dual-tasking with a concurrent short-term memory task, despite the relevance of this mental operation in daily life and the frequency of complaints related to this process, in disease. In this study we aimed to examine how the brain responds when a memory task is added to dual-tasking. Thirty-three right-handed healthy volunteers (20 females, mean age 39.9 +/- 5.8) were examined with functional brain imaging (fMRI). The paradigm consisted of two cross-modal single tasks (a visual and auditory temporal same-different task with short delay), a dual-task combining both single tasks simultaneously and a multi-task condition, combining the dual-task with an additional short-term memory task (temporal same-different visual task with long delay). Dual-tasking compared to both individual visual and auditory single tasks activated a predominantly right-sided fronto-parietal network and the cerebellum. When adding the additional short-term memory task, a larger and more bilateral frontoparietal network was recruited. We found enhanced activity during multitasking in components of the network that were already involved in dual-tasking, suggesting increased working memory demands, as well as recruitment of multitask-specific components including areas that are likely to be involved in online holding of visual stimuli in short-term memory such as occipito-temporal cortex. These results confirm concurrent neural processing of a visual short-term memory task during dual-tasking and provide evidence for an effective fMRI multitasking paradigm. PMID- 23938321 TI - Cerebral mechanisms for different second language writing systems. AB - In this fMRI study, we examined the cerebral processing associated with second language (L2) reading in different writing systems in late L2 learners. To examine the impacts of cross-linguistic differences between the first language (L1) and L2 on learning to read in L2, we employed a bidirectional approach and compared brain activation during single word processing in two groups of late L2 readers: (1) L2 readers of English whose L1 was Japanese (Japanese-L1/English-L2) and (2) L2 readers of Japanese (of syllabic Kana only) whose L1 was English (English-L1/Japanese-L2). During English reading, the L2 readers of English (Japanese-L1/English-L2) exhibited stronger activation in the left superior parietal lobule/supramarginal gyrus, relative to the L1 readers of English (English-L1/Japanese-L2). This is a region considered to be involved in phonological processing. The increased activation in the Japanese-L1/English-L2 group likely reflects the increased cognitive load associated with L2 English reading, possibly because L1 readers of Kana, which has an extremely regular orthography, may need to adjust to the greater phonological demands of the irregular L2 English orthography. In contrast, during Kana reading, the L2 readers of Japanese Kana (English-L1/Japanese-L2) exhibited stronger activation in the lingual gyrus in both the left and right hemispheres compared to the L1 readers of Kana (Japaese-L1/English-L2). This additional activation is likely to reflect the lower level of visual familiarity to the L2 symbols in the English L1/Japanese-L2 group; Kana symbols are uniquely used only in Japan, whereas Roman alphabetic symbols are seen nearly everywhere. These findings, bolstered by significant relationships between the activation of the identified regions and cognitive competence, suggest that the cerebral mechanisms for L2 reading in late learners depends both on which language is their L1 and which language is to be learnt as their L2. Educational implications of these results are discussed. PMID- 23938322 TI - Controlled modification of mono- and bilayer graphene in O2, H2 and CF4 plasmas. AB - In this work, covalent modification of mono- and bilayer graphene is achieved using tetrafluoromethane (CF4), oxygen and hydrogen RF plasma. Controlled modification of graphene is usually difficult to achieve, in particular with oxygen plasma, which is rather aggressive and usually leads to etching of graphene. Here we use x-ray photoelectron spectroscopy and Raman spectroscopy to show that mild plasma conditions and fine tuning of the number of functional groups can be obtained in all plasmas by varying parameters such as exposure time and sample position inside the chamber. We found that even for the usual harsh oxygen treatment the defect density could be lowered, down to one defect for 3.5 * 104 carbon atoms. Furthermore, we show that CF4 plasma leads to functionalization without etching and that graphene becomes an insulator at saturation coverage. In addition, the reactivity of mono- and bilayer graphene was studied revealing faster modification of monolayer in oxygen and CF4 plasma, in agreement with previous works. In contrast, similar modification rates were observed for both mono- and bilayer during hydrogenation. We attribute this discrepancy to the presence of more energetic species in the hydrogen plasma such as positive ions that could play a role in the functionalization process. PMID- 23938325 TI - Preventive Cardiovascular Nurses Association. PMID- 23938324 TI - Cytokine and chemokine profiles in lung tissues from fatal cases of 2009 pandemic influenza A (H1N1): role of the host immune response in pathogenesis. AB - Pathological studies on fatal cases caused by 2009 pandemic influenza H1N1 virus (2009 pH1N1) reported extensive diffuse alveolar damage and virus infection predominantly in the lung parenchyma. However, the host immune response after severe 2009 pH1N1 infection is poorly understood. Herein, we investigated viral load, the immune response, and apoptosis in lung tissues from 50 fatal cases with 2009 pH1N1 virus infection. The results suggested that 7 of the 27 cytokines/chemokines showed remarkably high expression, including IL-1 receptor antagonist protein, IL-6, tumor necrosis factor-alpha, IL-8, monocyte chemoattractant protein-1, macrophage inflammatory protein 1-beta, and interferon inducible protein-10 in lung tissues of 2009 pH1N1 fatal cases. Viral load, which showed the highest level on day 7 of illness onset and persisted until day 17 of illness, was positively correlated with mRNA levels of IL-1 receptor antagonist protein, monocyte chemoattractant protein-1, macrophage inflammatory protein 1 beta, interferon-inducible protein-10, and regulated on activation normal T-cell expressed and secreted. Apoptosis was evident in lung tissues stained by the TUNEL assay. Decreased Fas and elevated FasL mRNA levels were present in lung tissues, and cleaved caspase-3 was frequently seen in pneumocytes, submucosal glands, and lymphoid tissues. The pathogenesis of the 2009 pH1N1 virus infection is associated with viral replication and production of proinflammatory mediators. FasL and caspase-3 are involved in the pathway of 2009 pH1N1 virus-induced apoptosis in lung tissues, and the disequilibrium between the Fas and FasL level in lung tissues could contribute to delayed clearance of the virus and subsequent pathological damages. PMID- 23938323 TI - Cooperation between Dmp1 loss and cyclin D1 overexpression in breast cancer. AB - Cyclin D1 is a component of the core cell-cycle machinery and is frequently overexpressed in breast cancer. It physically interacts with the tumor suppressor Dmp1 that attenuates the oncogenic signals from Ras and HER2 by inducing Arf/p53 dependent cell-cycle arrest. Currently, the biological significance of Dmp1 cyclin D1 interplay in breast cancer has not been determined. Here, we show that cyclin D1 bound to Dmp1 to activate both Arf and Ink4a promoters and, consequently, induced apoptosis or G2/M cell-cycle delay in normal cells to protect them from neoplastic transformation. The cyclin D1-induced Ink4a/Arf gene expression was dependent on Dmp1 because the induction was not detected in Dmp1 deficient or DMP1-depleted cells. Arf/Ink4a expression was increased in pre malignant mammary glands from Dmp1(+/+);MMTV-cyclin D1 and Dmp1(+/+);MMTV-D1T286A mice but significantly down-regulated in those from Dmp1-deficient mice. Selective Dmp1 deletion was found in 21% of the MMTV-D1 and D1T286A mammary carcinomas, and the Dmp1 heterozygous status significantly accelerated mouse mammary tumorigenesis with reduced apoptosis and increased metastasis. Overall, our study reveals a pivotal role of combined Dmp1 loss and cyclin D1 overexpression in breast cancer. PMID- 23938326 TI - The Green Heart Initiative: using air quality information to reduce adverse health effects in patients with heart and vascular disease. PMID- 23938327 TI - Summaries of nursing care-related systematic reviews from the Cochrane Library: adenosine-diphosphate receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus. PMID- 23938329 TI - Body, heal thyself. An interview with Kenneth Chien, Professor of Cardiovascular Research at the Department of Cell & Molecular Biology, and the Department of Medicine at Karolinska Institutet in Sweden. Interview by Holger Breithaupt. PMID- 23938328 TI - Differential characteristics in polypathological inpatients in internal medicine departments and acute geriatric units: the PLUPAR study. AB - AIM: To determine whether there are any differences between polypathological patients attended in Internal Medicine departments and acute Geriatric units. METHODS: A cross-sectional multicenter study was performed. Polypathological patients admitted to an internal medicine or geriatrics department and attended by investigators consecutively between March 1 and June 30, 2011 were included. Data of age, sex, living in a nursing residence or at home, diagnostic category, use of chronic medication, Charlson, Barthel and Lawton-Brody indexes, Pfeiffer questionnaire, delirium during last admission, need of a caregiver, and having a caregiver were gathered. The need of a caregiver was defined when the Barthel index was<60 or Pfeiffer questionnaire >= 3 errors. RESULTS: 471 polypathological patients, 337 from internal medicine and 144 from geriatrics units were included. Geriatrics inpatients were older and more frequently female. Cardiac (62.1% vs 49.6%; p=.01), digestive (8.3% vs 3.0%; p=.04) and oncohematological diseases (30.2% vs 18.8%; p=.01) were more frequent in patients of internal medicine units and neurological (66.2% vs 40.2%; p<.001) and locomotive ones (39.1% vs 20.4%; p<.001) in geriatrics inpatients. Charlson index was higher for internal medicine inpatients [4.0(2.1) vs 3.5(2.1); p=.04). Patients attended in geriatrics scored higher in Pfeiffer questionnaire [5.5(3.7) vs 3.8(3.3); p<.001], and lower in Barthel [38.8(32.5) vs 61.2(34.3); p=.001] and Lawton-Brody indexes [0.9(1.6) vs 3.0(2.9); p<.001], and more frequently needed a caregiver (87.8% vs 53.6%; p<.001) and had it. CONCLUSIONS: There are differences in disease profile and functional and cognitive situation between polypathological patients of internal medicine and geriatrics departments. PMID- 23938330 TI - A late spring in Europe and the adaptability of plants. Epigenetic regulation seems to play a major role in plants' ability to adapt to and remember unusual climate patterns. PMID- 23938331 TI - Our sense of self. Phenomenology is a philosophical discipline that gives a detailed description of selfhood; it can contribute to understanding psychiatric diseases such as schizophrenia and its neurological causes. PMID- 23938332 TI - The responsibility of the scientist. What can history teach us about how scientists should handle research that has the potential to create harm? PMID- 23938333 TI - Consequences of ethanol exposure on cued and contextual fear conditioning and extinction differ depending on timing of exposure during adolescence or adulthood. AB - Some evidence suggests that adolescents are more sensitive than adults to ethanol induced cognitive deficits and that these effects may be long-lasting. The purpose of Exp 1 was to determine if early-mid adolescent [postnatal day (P) 28 48] intermittent ethanol exposure would affect later learning and memory in a Pavlovian fear conditioning paradigm differently than comparable exposures in adulthood (P70-90). In Exp 2 animals were exposed to ethanol during mid-late adolescence (P35-55) to assess whether age of initiation within the adolescent period would influence learning and memory differentially. Male Sprague-Dawley rats were given 4 g/kg i.g. ethanol (25%) or water every 48 h for a total of 11 exposures. After a 22 day non-ethanol period, animals were fear conditioned to a context (relatively hippocampal-dependent task) or tone (amygdala-dependent task), followed by retention tests and extinction (mPFC-dependent) of this conditioning. Despite similar acquisition, a deficit in context fear retention was evident in animals exposed to ethanol in early adolescence, an effect not observed after a comparable ethanol exposure in mid-late adolescence or adulthood. In contrast, animals that were exposed to ethanol in mid-late adolescence or adulthood showed enhanced resistance to context extinction. Together these findings suggest that repeated ethanol imparts long-lasting consequences on learning and memory, with outcomes that differ depending on age of exposure. These results may reflect differential influence of ethanol on the brain as it changes throughout ontogeny and may have implications for alcohol use not only throughout the developmental period of adolescence, but also in adulthood. PMID- 23938334 TI - Macular findings in healthy full-term Hispanic newborns observed by hand-held spectral-domain optical coherence tomography. AB - BACKGROUND AND OBJECTIVE: To enhance understanding of ethnically diverse normal newborn retinal morphology, the authors report spectral-domain optical coherence tomography (SD-OCT) macular findings in healthy Hispanic newborns. PATIENTS AND METHODS: In this IRB-approved prospective, observational case series, 20 full term Hispanic newborns had dilated retinal examinations and imaging by hand-held SD-OCT without sedation at the Duke Birthing Center. RESULTS: Of 20 newborns imaged (35% male; median gestational age: 39 weeks; range: 36 to 40 weeks), two (10%) had bilateral subfoveal fluid, including one case of bilateral double subretinal fluid pockets. Three eyes of two infants (10%) had retinal macular cystoid structures (one enlarged at 1.5 months, with resolution by 3 months). These SD-OCT findings were not visible by indirect ophthalmoscopy. CONCLUSION: Some Hispanic newborns have subretinal fluid or macular cystoid structures on SD OCT. This study expands our understanding of findings seen by SD-OCT in healthy full-term newborns of various races. PMID- 23938335 TI - S100B protein in children with carbon monoxide poisoning. PMID- 23938336 TI - Thermally induced shape modification of free-standing nanostructures for advanced functionalities. AB - Shape manipulation of nanowires is highly desirable in the construction of nanostructures, in producing free-standing interconnect bridges and as a building block of more complex functional structures. By introducing asymmetry in growth parameters, which may result in compositional or microstructural non-uniformity in the nanowires, thermal annealing can be used to induce shape modification of free-standing nanowires. We demonstrate that such manipulation is readily achieved using vertically grown Pt-Ga-C composite nanowires fabricated by focused ion-beam induced chemical vapor deposition. Even and controllable bending of the nanowires has been observed after a rapid thermal annealing in a N2 atmosphere. The mechanisms of the shape modification have been examined. This approach has been used to form electrical contacts to freestanding nano-objects as well as nano-'cages' for the purpose of securing ZnO tubs. These results suggest that thermally induced bending of nanowires may have potential applications in constructing three-dimensional nanodevices or complex structures for the immobilization of particles and large molecules. PMID- 23938337 TI - Video illustration in scientific journals and its interest in physical and rehabilitation medicine. PMID- 23938338 TI - Fate of abstracts presented at the 2008 congress of the French Physical and Rehabilitation Medicine Society. AB - Publication of abstracts presented at a scientific meeting is a measure of the latter's scientific quality. OBJECTIVES: To evaluate the publication rate for abstracts presented at the 2008 congress of the French Physical and Rehabilitation Medicine Society (SOFMER) and to identify (i) factors that were predictive of publication and (ii) the main reasons for non-publication. METHODS: We searched the PubMed database for publications related to SOFMER 2008 abstracts. We then screened the abstracts' characteristics for features that were predictive of publication. Authors of abstracts that had not been published were contacted (by e-mail) in order to establish the reason(s) for non-publication. RESULTS: Of the 231 abstracts presented at SOFMER 2008, 49 (21.2%) had been published. Original studies submitted by French university teams were more likely to be published. Most of the unpublished abstracts had never been submitted to scientific journals. A heavy workload (limiting the time available for drafting a publication) and unwillingness to submit incomplete or preliminary studies were the main barriers to submission for publication. CONCLUSION: SOFMER 2008s abstract publication rate was lower than those of other national or international medical congresses. University status and the performance of original research were predictive of publication. PMID- 23938339 TI - Effects of visual information regarding allocentric processing in haptic parallelity matching. AB - Research has revealed that haptic perception of parallelity deviates from physical reality. Large and systematic deviations have been found in haptic parallelity matching most likely due to the influence of the hand-centered egocentric reference frame. Providing information that increases the influence of allocentric processing has been shown to improve performance on haptic matching. In this study allocentric processing was stimulated by providing informative vision in haptic matching tasks that were performed using hand- and arm-centered reference frames. Twenty blindfolded participants (ten men, ten women) explored the orientation of a reference bar with the non-dominant hand and subsequently matched (task HP) or mirrored (task HM) its orientation on a test bar with the dominant hand. Visual information was provided by means of informative vision with participants having full view of the test bar, while the reference bar was blocked from their view (task VHP). To decrease the egocentric bias of the hands, participants also performed a visual haptic parallelity drawing task (task VHPD) using an arm-centered reference frame, by drawing the orientation of the reference bar. In all tasks, the distance between and orientation of the bars were manipulated. A significant effect of task was found; performance improved from task HP, to VHP to VHPD, and HM. Significant effects of distance were found in the first three tasks, whereas orientation and gender effects were only significant in tasks HP and VHP. The results showed that stimulating allocentric processing by means of informative vision and reducing the egocentric bias by using an arm-centered reference frame led to most accurate performance on parallelity matching. PMID- 23938340 TI - Successful treatment of cerebral venous thrombosis associated with ulcerative colitis. AB - Thromboembolic complications, such as deep venous thrombosis and pulmonary embolism, are well described in patients with inflammatory bowel disease, but cerebral venous thrombosis (CVT) is a rare but potentially devastating complication. The authors describe the case of a 36-year-old Japanese man presenting with CVT associated with ulcerative colitis (UC) that was successfully treated with a combination of continuous anticoagulant and pulse steroid therapy. Our observations suggest that aggressive therapy for inducing acute UC remission is vitally important for CVT associated with UC. PMID- 23938342 TI - A systematic review of impulse control disorders in Parkinson's disease. AB - Throughout the past decade it has been recognized that dopaminergic medication administered to remedy motor symptoms in Parkinson's disease is associated with an enhanced risk for impulse control disorders and related compulsive behaviors such as hobbyism, punding, and the dopamine dysregulation syndrome. These complications are relatively frequent, affecting 6-15.5% of patients, and they most often appear, or worsen, after initiation of dopaminergic therapy or dosage increase. Recently, impulse control disorders have also been associated with subthalamic nucleus deep brain stimulation. Here we present a systematic overview of literature published between 2000 and January 2013 reporting impulse control disorders in Parkinson's disease. We consider prevalence rates and discuss the functional neuroanatomy, the impact of dopamine-serotonin interactions, and the cognitive symptomatology associated with impulse control disorders in Parkinson's disease. Finally, perspectives for future research and management of impulse control disorders in Parkinson's disease are discussed. PMID- 23938344 TI - Measurement of LRRK2 and Ser910/935 phosphorylated LRRK2 in peripheral blood mononuclear cells from idiopathic Parkinson's disease patients. AB - A significant number of autosomal dominantly inherited Parkinson's disease (PD) cases are due to mutations in the leucine-rich repeat kinase 2 (LRRK2) gene. In cells, these pathogenic mutations have a number of differing effects on LRRK2 enzymatic activity and protein stability. In particular, five of the six described pathogenic LRRK2 mutations ablate the constitutive phosphorylation of LRRK2 on Ser910 and Ser935, two residues required for binding of LRRK2 to 14-3-3 proteins. This suggests a potential pathogenic role for these residues. However, LRRK2 kinase inhibitors, which have shown early promise as neuroprotective agents, also ablate the phosphorylation of Ser910 and Ser935. Additionally, LRRK2 is phosphorylated on Ser910 and Ser935 following activation of the inflammatory toll-like receptor pathway and inflammatory cytokines are often increased in PD patients. Whether LRRK2 protein or phosphorylation is altered in idiopathic PD is unknown. We therefore measured LRRK2 protein and its phosporylation in peripheral blood mononuclear cells (PBMCs) from 33 idiopathic Parkinson's disease patients and 27 age-matched controls. We found no significant difference in total LRRK2 protein levels in PBMCs from PD patients compared to controls. Furthermore, total LRRK2 protein expression was not effected by age, disease duration, disease severity or levodopa medication. The amount of phosphorylation on LRRK2 at both Ser910 and Ser935 correlated highly with total LRRK2 levels and was also unchanged in PD patients. Therefore, changes in LRRK2 Ser910/Ser935 phosphorylation in PBMCs are unlikely to contribute to idiopathic Parkinson's disease or be of utility as a disease biomarker. However, the invariance of Ser910 and Ser935 phosphorylation in PD PBMC's suggests that these residues could be used as pharmacodynamic biomarkers for the effectiveness of LRRK2 kinase inhibitors in patients. PMID- 23938341 TI - LRRK2: cause, risk, and mechanism. AB - In 2004 it was first shown that mutations in LRRK2 can cause Parkinson's disease. This initial discovery was quickly followed by the observation that a single particular mutation is a relatively common cause of Parkinson's disease across varied populations. Further genetic investigation has revealed a variety of genetic ties to Parkinson's disease across this gene. These include common alleles with quite broad effects on risk, likely through both alterations at the protein sequence level, and in the context of expression. A great deal of functional characterization of LRRK2 and disease-causing mutations in this protein has occurred over the last 9 years, and considerable progress has been made. Particular attention has been paid to the kinase activity of LRRK2 as a therapeutic target, and while it is no means certain that this is viable target it is likely that this hypothesis will be tested in clinical trials sooner rather than later. We believe that the future goals for LRRK2 research are, while challenging, relatively clear and that the next 10 years of research promises to be perhaps more exciting than the last. PMID- 23938343 TI - Dopamine agonists rather than deep brain stimulation cause reflection impulsivity in Parkinson's disease. AB - BACKGROUND: Dopamine agonist therapy is the main risk factor for impulse control disorders in Parkinson's disease (PD). However, it is unclear whether bilateral deep brain stimulation of the subthalamic nucleus also causes impairment in decision making. OBJECTIVES: To assess the role of dopamine agonist therapy and deep brain stimulation on reflection impulsivity in non-demented patients with PD. METHODS: We recruited 61 PD patients, 20 treated with L-dopa in combination with a dopamine agonist, 14 taking L-dopa monotherapy, a further 16 PD patients with bilateral subthalamic nucleus deep brain stimulation treated with L-dopa in combination with a dopamine agonist, and 11 PD patients with bilateral subthalamic nucleus deep brain stimulation taking L-dopa but not a dopamine agonist. Results were compared with 18 healthy controls. Patients who had evidence of impulsive compulsive behaviour were excluded. Reflection impulsivity was assessed with the beads task, which is a validated information sampling task. RESULTS: All patients treated with a dopamine agonist gathered significantly less information and made more irrational decisions than all other groups regardless of whether they had surgical treatment. CONCLUSIONS: Our results imply that dopamine agonist therapy but not deep brain stimulation leads to "reflection impulsivity" in PD. PMID- 23938345 TI - Postural/Gait and cognitive function as predictors of driving performance in Parkinson's disease. AB - BACKGROUND: The primary influence of motor symptoms on driving performance remains unclear due to the inconsistent use of various motor rating scales used in prior studies. OBJECTIVE: This study aimed to determine which of three measures utilized in PD, the Unified Parkinson's Disease Rating Scale (UPDRS) motor section; the Modified Hoehn and Yahr; and the Rapid Paced Walk Test would best predict pass/fail outcomes on a road test in a sample of PD drivers. METHODS: All participants (N = 55; 79% men) completed a road test. Receiver Operating Characteristics were then contrasted for all subjects based on assessments from all three disease severity indices. MMSE scores were then modelled with significant disease severity measures (if any) to determine if the predictive accuracy could be improved. RESULTS: The Rapid Paced Walk Test and the Modified Hoehn & Yahr both predicted pass/fail outcomes on the road test (Area under the curve of 0.73 and 0.82, respectively). UPDRS motor scores, however, did not predict safe driving. When optimal cut-off points on the Modified Hoehn & Yahr (>= 2.5) and Rapid Paced Walk Test (>6.22 seconds) were modelled with MMSE scores indicative of mild cognitive impairment (<27), the model accurately classified 92% and 100% as failing the road test, respectively. CONCLUSION: Although the Rapid Paced Walk Test had a slight advantage in differentiating between pass/fail outcomes compared to the Modified Hoehn & Yahr, both tests alone cannot be used in isolation to predict driving safety. Predictive accuracy can be improved using both select cut-off points on the Modified Hoehn & Yahr and Rapid Paced Walk test with MMSE scores in PD drivers. Though these findings are useful, an on-road test is still the gold standard, and screening should always be followed by formal testing. PMID- 23938346 TI - The alpha7 nAChR agonist PNU-282987 reduces inflammation and MPTP-induced nigral dopaminergic cell loss in mice. AB - BACKGROUND: Parkinson's disease (PD) is associated with neurodegeneration of dopaminergic neurons and an accompanying neuroinflammatory process in the substantia nigra (SN). The cholinergic anti-inflammatory signalling pathway allows the autonomic nervous system to modulate immunologic stimuli and inflammatory processes. A major component of this pathway is the alpha7 nicotinic acetylcholine receptor (alpha7 nACh receptor), which is expressed on immune cells such as microglia. OBJECTIVE: To determine the role of this cholinergic anti inflammatory signalling pathway, we investigated the effects of the selective alpha7 nACh agonist PNU-282987 and of the non-competitive nACh antagonist mecamylamine on microglia-induced neuroinflammation and toxin-induced degeneration of dopaminergic neurons in a mouse model of PD. METHODS: PNU-282987, mecamylamine or placebo administration was started one day before MPTP intoxication and repeated daily until sacrifice after MPTP intoxication. C57Bl/6 mice were injected intraperitoneally four times at 2 h intervals with either 20 mg/kg MPTP-HCl or a corresponding volume of saline. Two or seven days after the end of the MPTP intoxication, the animals were killed and their brains were processed for further analysis. RESULTS: Treatment with PNU-282987 resulted in an attenuation of neuroinflammation in the MPTP-lesioned SN. Furthermore, PNU-282987 attenuated MPTP-induced dopaminergic cell loss in the SN and reduced striatal dopamine depletion. Unexpectedly, mecamylamine lowered neuroinflammation as well, though it did not show a neuroprotective potential at the nigral level. CONCLUSIONS: Our results demonstrate the therapeutic potential of the selective alpha7 nicotinic acetylcholine agonist PNU-282987 in attenuating neuroinflammation and toxin-induced loss of dopaminergic neurons in the acute MPTP mouse model of PD. PMID- 23938348 TI - Prevalence of Parkinson disease among the Navajo: a preliminary examination. AB - BACKGROUND: The prevalence of Parkinson disease (PD) varies by geographic location and ethnicity, but has never been studied among the Navajo. METHODS: Period prevalence was calculated using the number of people diagnosed with PD in the Shiprock Service Unit Indian Health Service database during 1995-1999, 2000 2004, and 2005-2009 as the numerator, and the number seen for any reason as the denominator. Age-standardized rates were calculated using the 2000 US population. RESULTS: During 2005-2009, 126 people were seen with PD (crude prevalence = 203.7/100,000 population). The age-adjusted rate was 335.9 (95% C. I. 277.8 394.0) overall, 438.5 (95% C.I. 336.5-540.5) in men and 259.7 (95% C.I. 192.8 326.7; p = 0.004) in women. The adjusted rate increased with age: 788.8 (95% C.I. 652.0-925.7) for age 40 and above to 1964.9 (95% C.I. 1613.7-2316.1) for age 60 and above. Adjusted rates were 246.6 (95% C.I. 187.2-306.0) in 1995-1999 and 284.7 (95% C.I. 227.0-342.4) in 2000-2004. CONCLUSION: Parkinson disease appears common among the Navajo. Estimates increased with age and time, and were higher in men. In-person interviews are needed to confirm these estimates, and to determine incidence, quality of care, and risk factors for PD among the Navajo. PMID- 23938347 TI - Movement activation and inhibition in Parkinson's disease: a functional imaging study. AB - BACKGROUND: Parkinson's disease (PD), traditionally considered a movement disorder, has been shown to affect executive function such as the ability to adapt behavior in response to new environmental situations. OBJECTIVE: to identify the impact of PD on neural substrates subserving two specific components of normal movement which we refer to as activation (initiating an un-cued response) and inhibition (suppressing a cued response). METHODS: We used fMRI to measure pre-movement processes associated with activating an un-cued response and inhibiting a cued response plan in 13 PD (ON anti-parkinsonian medications) and 13 control subjects. Subjects were shown a visual arrow cue followed by a matched or mismatched response target that instructed them to respond with a right, left, or bilateral button press. In mismatched trials, an un-cued (new) response was initiated, or the previously cued response was suppressed. RESULTS: We were able to isolate pre-movement responses in dorsolateral prefrontal cortex, specifically in the right hemisphere. During the activation of an un-cued movement, PD subjects showed decreased activity in the putamen and increased cortical activity in bilateral DLPFC, SMA, subcentral gyrus and inferior frontal operculum. During inhibition of a previously cued movement, the PD group showed increased activation in SMA, S1/M1, premotor and superior parietal areas. CONCLUSION: Right DLPFC plays a role in pre-movement processes, and DLPFC activity is abnormal in PD. Decreased specificity of responses was observed in multiple ROI's. The basal ganglia are involved in circuits that coordinate activation and inhibition involved in action selection as well as execution. PMID- 23938349 TI - Comparison of handheld video camera and GAITRite(r) measurement of gait impairment in people with early stage Parkinson's disease: a pilot study. AB - In this pilot study, we investigated the validity and reliability of low-cost handheld video camera recordings for measuring gait in people with early stage Parkinson's disease (PD). Five participants with PD, Hoehn & Yahr stage I-II, mean age 66.2 years and five healthy age-matched controls were recruited. Participants walked across a GAITRite(r) electronic walkway at self-selected pace while video was simultaneously recorded. Data from both systems were analyzed and compared. Step time variability, measured from handheld video recordings, revealed significant (p <= 0.05) differences between the gait of early stage PD and controls. Concurrent validity between video analyses and GAITRite were good (ICC(2,1) >= 0.86) for mean step time and mean dual support duration. However, the inter-assessor reliability for the video analysis was poor for step time variability (ICC(2,1) = 0.18). More reliable measurement of step time variability may require a system to measure extended periods of walking. Further research involving longer walks and more participants with higher stages of PD is required to investigate if step time variability can be measured with acceptable reliability using video recordings. If this could be demonstrated, this simple technology could be adapted to run on a tablet or smart phone, providing low cost gait assessments without the need for specialized equipment and expensive infrastructure. PMID- 23938350 TI - Pacific Northwest Udall Center of excellence clinical consortium: study design and baseline cohort characteristics. AB - BACKGROUND: The substantial proportion of individuals with Parkinson's disease (PD) who have or are expected to develop concomitant cognitive impairment emphasizes the need for large, well-characterized participant cohorts to serve as a basis for research into the causes, manifestations, and potential treatments of cognitive decline in those with PD. OBJECTIVE: To establish a multi-site clinical core that cognitively and clinically characterizes patients with PD by obtaining quality longitudinal clinical, neuropsychological, and validated biomarker data. METHODS: Six hundred nineteen participants with idiopathic PD (68.0 +/- 9.1 years, 7.1 +/- 6.2 years since diagnosis, 70% males) were enrolled in the Pacific Northwest Udall Center (PANUC), one of the Morris K. Udall Centers of Excellence for Parkinson's Research, Clinical Consortium and underwent comprehensive clinical and neuropsychological assessment. Participants were diagnosed with no cognitive impairment (PD-NCI), mild cognitive impairment (PD-MCI), or dementia (PDD) at a diagnostic consensus conference. RESULTS: A substantial proportion of the overall sample was diagnosed with cognitive impairment at baseline: 22% with PDD and 59% with PD-MCI. A higher rate of cognitive impairment was observed in men than women (87% vs. 68%, p < 0.0001), despite a higher level of education. Most patients older than 50 years at the time of diagnosis and with disease duration greater than 10 years were cognitively impaired or demented. CONCLUSIONS: The PANUC Clinical Consortium is a clinically and cognitively well characterized cohort of patients with PD. Baseline cohort characteristics demonstrate a high rate of cognitive impairment in the sample, as well as potential sex differences with regard to cognitive diagnosis. The PANUC Clinical Consortium, with its access to biomarker, genetic, and autopsy data, provides an excellent foundation for detailed research related to cognitive impairment in PD. PMID- 23938351 TI - Neuronal expression of familial Parkinson's disease A53T alpha-synuclein causes early motor impairment, reduced anxiety and potential sleep disturbances in mice. AB - BACKGROUND: Mutations in the human alpha-synuclein gene lead to early-onset Parkinson's disease (PD); however, phenotypes of alpha-synuclein mutant mice vary depending upon the promoter driving transgene expression. OBJECTIVE: The goal of this study was to characterize behavior and neurochemical alterations in mice expressing mutant (A53T) human alpha-synuclein, controlled by a neuron-specific Thy-1 promoter. Our data provide important additional phenotypic and biochemical characterization of a previously generated model of PD. METHODS: A53T (SNCA) and wild type (WT) littermate mice were evaluated for motor function (rotarod and stride length) and anxiety (elevated plus maze and open field) every 2 weeks. At 24 weeks mice were evaluated in a Comprehensive Lab Animal Monitoring System (CLAMS). A separate cohort of mice were euthanized at 12, 24 and 36 weeks for immunoblot analysis of alpha-synuclein, dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the striatum, and hypothalamic serotonin and metabolites were measured. RESULTS: SNCA mice display significant motor deficits at 14-18 weeks of age compared to WT mice, which progress over time. CLAMS analysis revealed an increase in activity during the dark phase and a reduction in overall estimated sleep time for SNCA mice compared to WT consistent with clinical reports of sleep abnormalities in PD. A transient change in the levels of DAT appeared at 12 weeks in the striatum and serotonin levels were also altered in the hypothalamus at this time point. CONCLUSIONS: This PD model displays consistent and clinically relevant motor and sleep phenotypes. Anxiety phenotypes are consistent with other alpha-synuclein based PD models yet incongruous with typical clinical symptoms. Early increases in serotonin levels potentially explain reductions in anxiety behaviors and sleep. PMID- 23938352 TI - Re: Childhood adversity and cell-mediated immunity in young adulthood. PMID- 23938353 TI - Myasthenia gravis: new therapeutic approaches based on pathophysiology. AB - Over the past 40 years Dr. Robert Lisak has made important contributions to our understanding of the pathophysiology and therapy of myasthenia gravis. This review will touch upon some of his work as it discusses current therapies and the potential for new treatments based on the evolving knowledge of the underlying basis of the disease. The recognition of different immune mechanisms that can cause the phenotype that we acknowledge as myasthenia gravis coincides with the introduction of monoclonal antibodies and other new therapies that can target specific aspects of the disease. This has raised our hopes for treatments that will have less side effects and be more effective. In some cases these hopes have been realized. In other instances, the situation remains a "work in progress". Dr. Lisak's work and teachings remain cogent to our modern approach to this classic immunologic disease. PMID- 23938354 TI - Idiopathic normal-pressure hydrocephalus, cortical thinning, and the cerebrospinal fluid tap test. AB - When considering the underlying pathophysiological mechanisms involved in idiopathic normal pressure hydrocephalus (iNPH), white matter is often the main locus of investigation. However, when an axon in the brain is damaged, degeneration of the neuron can occur proximally (dying back) and Alzheimer's disease (AD), associated with cortical thinning, is a common pathologic comorbidity with iNPH. We investigated differences in cortical thickness between CSF tap test (CSFTT) responders and non-responders in iNPH patients and compared patterns of cortical thickness in iNPH patients with that of AD patients. Thirty two iNPH patients (16 CSFTT responders and 16 CSFTT non-responders) and 16 AD patients were imaged with MRI, including 3-dimensional volumetric images for cortical thickness analysis across the entire brain. Among the iNPH patients, CSFTT non-responders, when compared to responders, had statistically significant cortical thinning in the left superior frontal gyrus at the level of a false discovery rate (FDR) p<0.05, and tended to show widespread cortical thinning in most areas of the brain. Relative to the CSFTT responders, AD patients showed statistically significant cortical thinning in superior and medial frontal gyrus, left precentral gyrus, postcentral gyrus, paracentral lobule, precuneus, and superior parietal lobule after FDR correction (p<0.05). However, comparing patterns of cortical thinning between AD patients and CSFTT non-responders revealed no statistically significant differences. Differences in cortical thickness correlated with CSFTT response for iNPH patients may indicate a possibility for considering patterns of cortical thinning in patients with ventriculomegaly as potential brain imaging markers for the prediction of CSFTT responders. And, our findings suggest that comorbid AD pathology might be related to the cortical thinning patterns found in CSFTT non-responders. Larger studies, using normal controls and combinations of other biomarkers associated with AD, would be necessary to evaluate these hypotheses. PMID- 23938355 TI - Young unlicensed drivers and fatal road traffic crashes in the USA in the past decade. A neglected public health issue. AB - It is unknown whether road traffic crashes (RTCs) involving young unlicensed drivers follow the downward trend of those involving licensed drivers. Our national register-based study from 2000 to 2011 indicates that the downward trend for young unlicensed drivers (<25 years) is significantly less pronounced. These drivers account for 10.7% to 11.5% of the fatal RTCs involving young drivers during that time period; this percentage is consistently higher in the Western and Southern states and has increased in recent years in the Midwest. PMID- 23938357 TI - Improving medical device alarm safety in hospitals. PMID- 23938356 TI - A molecularly-imprinted electrochemical sensor based on a graphene-Prussian blue composite-modified glassy carbon electrode for the detection of butylated hydroxyanisole in foodstuffs. AB - In this study, we developed a novel molecularly-imprinted electrochemical sensor based on a glassy carbon electrode (GCE) decorated by graphene-Prussian blue (GR PB) composites for the selective and sensitive determination of butylated hydroxyanisole (BHA). The molecularly-imprinted polymers (MIPs) were synthesized by BHA and pyrrole as the template molecule and functional monomer, respectively. Also, the MIPs were assembled on the surface of the GR-PB/GCE by electropolymerization. The sensor was characterized by cyclic voltammetry (CV), scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS) and chronoamperometry. It was confirmed that the synergistic effects of GR and PB could improve the electrochemical response and the sensitivity of the sensor. The linear range of the sensor was from 9 * 10(-8) mol L(-1) to 7 * 10(-5) mol L(-1), with a limit of detection (LOD) of 7.63 * 10(-8) mol L(-1) (S/N = 3). The proposed sensor displayed high selectivity, excellent stability and good reproducibility for the determination of BHA. It was successfully applied to the determination of BHA in real samples. PMID- 23938358 TI - Improving care transitions from hospital to home: standardized orders for home health nursing with remote telemonitoring. AB - A task force at a multihospital health care system partnered with home health agencies to improve gaps during the discharge transition process. A standardized order template for home health nursing and remote telemonitoring was developed to decrease discrepancies in communication between hospital health care providers and home health nurses caring for patients with heart failure. Pilot results showed significantly improved communication with no readmissions, using the order template. PMID- 23938359 TI - A multifunctional proton-conducting and sensing pillar-layer framework based on [24-MC-6] heterometallic crown clusters. AB - 3D pillar-layer framework with [24-MC-6] heterometallic crown clusters exhibits proton conductivity and selective sensing of acetone as well as Cu(2+) ions. PMID- 23938360 TI - Endoscopic submucosal dissection with a novel traction method using a steerable grasper: a feasibility study in a porcine model. AB - INTRODUCTION: Endoscopic submucosal dissection (ESD) is a technically challenging procedure in which complications and operative times depend on the operator's expertise as well as on the location and size of the lesion. Good visualization of the submucosal dissection plane is essential to perform a safe and effective ESD. OBJECTIVES: To evaluate the feasibility, efficacy, and safety of a novel traction method using an over-the-scope steerable grasper to improve the exposure of the dissection plane during gastric ESD. RESULTS: A total of 24 ESDs were performed without any complications in various locations of porcine stomachs, including antrum, gastric body, and cardia. En bloc complete resections were achieved in all cases. The mean specimen size was 44.92 +/- 8.30 mm, mean total procedure time was 29.17 +/- 11.27 minutes, and mean dissection time was 15.08 +/ 7.21 minutes. The optimal dissection plane could be obtained by controlling the grasper in all cases. CONCLUSIONS: Technical feasibility, efficacy, and safety of the over-the-scope steerable grasper technique were demonstrated in order to provide dynamic and controlled traction during ESD at different locations of porcine stomachs. PMID- 23938361 TI - Fine tuning of graphene-metal adhesion by surface alloying. AB - We show that bimetallic surface alloying provides a viable route for governing the interaction between graphene and metal through the selective choice of the elemental composition of the surface alloy. This concept is illustrated by an experimental and theoretical characterization of the properties of graphene on a model PtRu surface alloy on Ru(0001), with a concentration of Pt atoms in the first layer between 0 and 50%. The progressive increase of the Pt content determines the gradual detachment of graphene from the substrate, which results from the modification of the carbon orbital hybridization promoted by Pt. Alloying is also found to affect the morphology of graphene, which is strongly corrugated on bare Ru, but becomes flat at a Pt coverage of 50%. The method here proposed can be readily extended to several supports, thus opening the way to the conformal growth of graphene on metals and to a full tunability of the graphene substrate interaction. PMID- 23938362 TI - Towards reference dosimetry for the MR-linac: magnetic field correction of the ionization chamber reading. AB - In the UMC Utrecht a prototype MR-linac has been installed. The system consists of a 6 MV Elekta (Crawley, UK) linear accelerator and a 1.5 T Philips (Best, The Netherlands) Achieva MRI system. This paper investigates the feasibility to correct the ionization chamber reading for the magnetic field within the dosimetry calibration method described by Almond et al (1999 Med. Phys. 26 1847 70). Firstly, the feasibility of using an ionization chamber in an MR-linac was assessed by investigating possible influences of the magnetic field on NE2571 Farmer-type ionization chamber characteristics: linearity, repeatability, orientation in the magnetic field; and AAPM TG51 correction factor for voltage polarity and ion recombination. We found that these AAPM correction factors for the NE2571 chamber were not influenced by the magnetic field. Secondly, the influence of the permanent 1.5 T magnetic field on the NE2571 chamber reading was quantified. The reading is influenced by the magnetic field; therefore, a correction factor has been added. For the standardized setup used in this paper, the NE2571 chamber reading increases by 4.9% (+/- 0.2%) due to the transverse 1.5 T magnetic field. Dosimetry measurements in an MR-linac are feasible, if a setup specific magnetic field correction factor (P1.5 T) for the charge reading is introduced. For the setup investigated in this paper, the P1.5 T has a value of 0.953. PMID- 23938363 TI - Omics technologies and the study of human ageing. AB - Normal ageing is associated with diverse physiological changes in all organ systems but the rate and extent of these changes vary markedly among individuals. One aspect of ageing research focuses on the molecular profiling of the changes that occur with increasing age in humans. Such profiling has implications for disease prevention and treatment. New high-throughput 'omics' technologies (such as genomics, metabolomics, metagenomics and transcriptomics) are enabling detailed studies of these molecular changes and are thus revealing information about the biological pathways that change with age. PMID- 23938364 TI - Development: Replication factors make the transition. PMID- 23938369 TI - Gene expression: a cycle route to transcriptional noise. PMID- 23938370 TI - REPO4 (RE = La, Nd, Eu) affinity nanorods modified on a MALDI plate for rapid capture of target peptides from complex biosamples. AB - A novel affinity MALDI target plate modified with rare-earth phosphate nanorods for rapid, direct and selective capture of phosphopeptides from complex biosamples. PMID- 23938371 TI - [Cardiovascular evaluation in children and its relation to altitude]. PMID- 23938372 TI - Introduction of staging laparoscopy in the management of advanced epithelial ovarian, tubal and peritoneal cancer: impact on prognosis in a single institution experience. AB - OBJECTIVE: To evaluate the prognostic impact of routinely use of staging laparoscopy (S-LPS) in patients with primary advanced epithelial ovarian cancer (AEOC). METHODS: All women were submitted to S-LPS before receiving primary debulking surgery (PDS) or neoadjuvant treatment (NACT). The surgical and survival outcome were evaluated by univariate and multivariate analysis. RESULTS: Among 300 consecutive patients submitted to S-LPS no complications related to the surgical procedure were registered. The laparoscopic evaluation showed that almost half of the patients (46.3%) had a high tumor load. One-hundred forty eight (49.3%) women were considered suitable for PDS and the remaining 152 (50.7%) were submitted to NACT. The percentages of complete (residual tumor, RT=0) and optimal (RT<1cm) cytoreduction of PDS and interval debulking surgery (IDS) were 62.1% and 57.5%, 22.5% and 27.7%, respectively, p=0.07. The post operative complications of NACT/IDS group were lower than PDS group (p=0.01). The median progression free survival in women with RT=0 at PDS was 25 months (95% CI, 15.1-34.8), which was statistically significant longer than in all other patients, irrespective of the type of treatment they received (p=0.0001). At multivariate analysis, residual disease (p=0.011) and performance status (p=0.016) maintained an independent association with the PFS. CONCLUSIONS: Including S-LPS in a tertiary referral center for the management AEOC does not appear to have a negative impact in terms of survival and it may be helpful to individualize the treatment avoiding unnecessary laparotomies and surgical complications. PMID- 23938373 TI - Pushing the bar in treatment of cervical cancer: what can comprehensive cancer centers do on their own? PMID- 23938374 TI - Clinical and toxicity predictors of response and progression to temsirolimus in women with recurrent or metastatic endometrial cancer. AB - OBJECTIVE: Temsirolimus (TEM) has recently shown activity (NCIC CTG phase II trial) in endometrial cancer (EC). Despite EC having a high rate of PTEN mutation, in this trial activity was independent of PTEN and other molecular markers. We explored whether treatment related toxicity occurring in cycle one was predictive of outcomes. METHODS: Patients were those enrolled on two sequential phase II studies of the NCIC CTG that evaluated single agent TEM in women with recurrent or metastatic chemotherapy naive or treated EC. An exploratory landmark analysis examined the relationship between early treatment related toxicities as well as prior chemotherapy and efficacy outcomes (response, progression, and tumor size shrinkage) in univariate and multivariate analyses. The relationship between molecular markers and outcomes was also reexamined in patients. RESULTS: Mucositis, diarrhea, decreased absolute neutrophil count, as well as elevated glucose, or cholesterol were not independent predictors of response or progression. Highest fasting triglyceride predicted for a 3.5% tumor shrinkage from baseline. Women previously treated with chemotherapy were at 7.37 times greater risk of progression and experienced 20.9% increased tumor growth compared to chemotherapy naive women. Molecular markers were not predictors of response or progression. CONCLUSIONS: Except for elevation in fasting triglyceride being associated with minimal tumor shrinkage, no other relationship between efficacy and TEM induced adverse events was found. mTOR inhibition activity in EC seems greatest in chemo-naive patients. Future studies of mTOR inhibitors in EC should focus on women without prior chemotherapy while continuing to explore molecular mechanisms of benefit. PMID- 23938375 TI - MMR deficiency is common in high-grade endometrioid carcinomas and is associated with an unfavorable outcome. AB - OBJECTIVE: To assess the prevalence of MMR deficiency (dMMR) in contemporary reclassified high-grade endometrial carcinomas and correlate dMMR with molecular alterations and patient outcome. METHODS: In this study we evaluated the expression of MLH1, MSH2, PMS2 and MSH6 assessed by two different methods in a series of 102 high-grade endometrial carcinomas. The series was comprised of 64 high-grade endometrioid carcinomas (HGEC), 27 serous (ESC), and 11 clear cell (CCC) carcinomas. Absence of expression in any of the proteins was considered dMMR. dMMR was correlated with clinicopathological parameters using a Chi-square test. Univariate and multivariate survival analysis was performed using Kaplan Meier and Cox regression analyses. RESULTS: The overall prevalence of dMMR was 28% (29/102) and was seen in 29/64 (45%) HGEC but not detected in any of the ESC and CCC. Within HGEC, dMMR was associated with loss of ARID1A (p=0.0099), loss of PTEN (p=0.044) and wild-type TP53 (p=0.024) expression. dMMR was associated with increased risk for disease specific death by univariate analysis (p=0.013) among stage III/IV HGEC but not in multivariate analysis (p=0.12). CONCLUSIONS: Among high-grade endometrial carcinomas, dMMR is restricted to HGEC and could be used as an adjunct diagnostic tool to refute a diagnosis of ESC. The association with dMMR in HGEC with ARID1A/PTEN alterations, TP53 wild type expression pattern and unfavorable outcome suggests that different oncogenetic pathways within HGEC are present. PMID- 23938376 TI - Potent inhibitors precise to S1' loop of MMP-13, a crucial target for osteoarthritis. AB - Matrix metalloproteinase-13 (MMP-13) is the primary MMP involved in cartilage degradation through its particular ability to cleave type-II collagen. This protein is expressed by chondrocytes and synovial cells in human osteoarthritis and rheumatoid arthritis; hence, it is an attractive target for the treatment of arthritic diseases. Currently available inhibitors lack specificity for metalloproteinase because of a common Zn binding site in MMPs; thus, there is a need to identify selective MMP-13 inhibitors for osteoarthritis therapy. Because selectivity is the major concern, both ligand-based and protein-based pharmacophore methodologies were used to identity potent and selective MMP-13 inhibitors. Different hypotheses were validated, and the best hypothesis was used to screen Zinc (natural and chemical) databases to seek novel scaffolds as MMP-13 inhibitors. The identified hits were validated using different strategies, such as Glide Standard precision, extra precision, E-model energies and receiver operating curve (ROC). In addition, potent inhibitors were selected based on two criteria: a similar binding mode as that of the active site PB3 crystal ligand and crucial amino acid interactions that are catalytically important for the function of MMP-13. The candidate potent inhibitors ZINC 02535232, ZINC 08399795, ZINC 12419118 and ZINC 00624580 nearly reproduced the H-bond interactions formed in the crystal structure of 1XUC with reasonable RMSD values exhibiting a novel interaction pattern that was not previously observed in MMP-13 inhibitors. The identified potent hits with diverse chemical scaffolds may be useful in designing new MMP-13 inhibitors. PMID- 23938377 TI - What history tells us XXXII. The long and tortuous history of epigenetic marks. PMID- 23938378 TI - Male- and female-specific variants of doublesex gene products have different roles to play towards regulation of Sex combs reduced expression and sex comb morphogenesis in Drosophila. AB - Sexually dimorphic characters have two-fold complexities in pattern formation as they have to get input from both somatic sex determination as well as the positional determining regulators. Sex comb development in Drosophila requires functions of the somatic sex-determining gene doublesex and the homeotic gene Sex combs reduced. Attempts have not been made to decipher the role of dsx in imparting sexually dimorphic expression of SCR and the differential function of sex-specific variants of dsx products in sex comb development. Our results in this study indicate that male-like pattern of SCR expression is independent of dsx function, and dsx F must be responsible for bringing about dimorphism in SCR expression, whereas dsx M function is required with Scr for the morphogenesis of sex comb. PMID- 23938379 TI - Effect of zinc and calcium ions on the rat kidney membrane-bound form of dipeptidyl peptidase IV. AB - Dipeptidyl peptidase IV (DPP-IV) is an ectopeptidase with many roles, and a target of therapies for different pathologies. Zinc and calcium produce mixed inhibition of porcine DPP-IV activity. To investigate whether these results may be generalized to mammalian DPP-IV orthologues, we purified the intact membrane bound form from rat kidney. Rat DPP-IV hydrolysed Gly-Pro-p-nitroanilide with an average Vmax of 0.86 +/- 0.01 meu mol min-1mL-1 and KM of 76 +/- 6 meu M. The enzyme was inhibited by the DPP-IV family inhibitor L-threo-Ile-thiazolidide (Ki=64.0 +/- 0.53 nM), competitively inhibited by bacitracin (Ki=0.16 +/- 0.01 mM) and bestatin (Ki=0.23 +/- 0.02 mM), and irreversibly inhibited by TLCK (IC50 value of 1.20 +/- 0.11 mM). The enzyme was also inhibited by divalent ions like Zn2+ and Ca2+, for which a mixed inhibition mechanism was observed (Ki values of the competitive component: 0.15 +/- 0.01 mM and 50.0 +/- 1.05 mM, respectively). According to bioinformatic tools, Ca2+ ions preferentially bound to the beta propeller domain of the rat and human enzymes, while Zn2+ ions to the alpha-beta hydrolase domain; the binding sites were essentially the same that were previously reported for the porcine DPP-IV. These data suggest that the cationic susceptibility of mammalian DPP-IV orthologues involves conserved mechanisms. PMID- 23938380 TI - Fluorescent tag is not a reliable marker for small RNA transfection in the presence of serum. AB - Chemically synthetic siRNA and miRNA have become powerful tools to study gene function in the past decade. Fluorescent dyes covalently attached to the 5' or 3' ends of synthetic small RNAs are widely used for fluorescently imaging and detection of these RNAs. However, the reliability of fluorescent tags as small RNA markers in different conditions has not attracted enough attention. We used Cy3-labelled small RNAs to explore the reliability of fluorescent tags as small RNA markers in cell cultures involving serum. A strong Cy3-fluorescence signal was observed in the cytoplasm of the cells transfected with Cy3-miR24 in the culture medium containing fetal bovine serum (FBS), but qRT-PCR results showed that little miR24 were detected in these cells. Further study demonstrated that small RNAs were degraded in the presence of FBS, suggesting that it was Cy3-RNA fragments, rather than the original Cy3-miR24, diffused into cells. These phenomena disappeared when FBS was replaced by boiled-FBS, further supporting that the Cy3-fluorescence we observed in cells in the presence of FBS could not represent the presence of intact small RNAs. These findings addressed that fluorescent tags are not reliable for small RNA transfection in the presence of serum in culture. PMID- 23938381 TI - Down-regulation of human cytomegalovirus UL138, a novel latency-associated determinant, by hcmv-miR-UL36. AB - MicroRNAs (miRNAs) are small RNAs, 19-23 nucleotides in length, which regulate a variety of cellular processes. Human cytomegalovirus (HCMV) encodes only one intronic miRNA: human cytomegalovirus microRNA UL36 (hcmv-miR-UL36). In this study, we found that over-expression of hcmv-miR-UL36 resulted in a more than threefold increase in HCMV DNA synthesis at 24 h post infection. Fifteen putative targets of hcmv-miR-UL36 were identified using hybrid PCR, one being the HCMV UL138 gene that has previously been identified as a novel latency-associated determinant of HCMV infection. Down-regulation of UL138 expression by hcmv-miR UL36 was validated using luciferase reporter assays and Western blot analysis in HEK293 cells. In the presence of hcmv-miR-UL36, we observed a 74.6 percent decrease in luciferase activity and a 46.2 percent decrease in HCMV UL138 protein expression. Our results indicate that hcmv-miR-UL36 may be a viral miRNA contributing to HCMV replication. PMID- 23938382 TI - ParA encoded on chromosome II of Deinococcus radiodurans binds to nucleoid and inhibits cell division in Escherichia coli. AB - Bacterial genome segregation and cell division has been studied mostly in bacteria harbouring single circular chromosome and low-copy plasmids. Deinococcus radiodurans, a radiation-resistant bacterium, harbours multipartite genome system. Chromosome I encodes majority of the functions required for normal growth while other replicons encode mostly the proteins involved in secondary functions. Here, we report the characterization of putative P-loop ATPase (ParA2) encoded on chromosome II of D. radiodurans. Recombinant ParA2 was found to be a DNA-binding ATPase. E. coli cells expressing ParA2 showed cell division inhibition and mislocalization of FtsZ-YFP and those expressing ParA2-CFP showed multiple CFP foci formation on the nucleoid. Although, in trans expression of ParA2 failed to complement SlmA loss per se, it could induce unequal cell division in slmAminCDE double mutant. These results suggested that ParA2 is a nucleoid-binding protein, which could inhibits cell division in E. coli by affecting the correct localization of FtsZ and thereby cytokinesis. Helping slmAminCDE mutant to produce minicells, a phenotype associated with mutations in the 'Min' proteins, further indicated the possibility of ParA2 regulating cell division by bringing nucleoid compaction at the vicinity of septum growth. PMID- 23938383 TI - A low-pH medium in vitro or the environment within a macrophage decreases the transcriptional levels of fimA, fimZ and lrp in Salmonella enterica serovar Typhimurium. AB - Many Salmonella Typhimurium isolates produce type 1 fimbriae and exhibit fimbrial phase variation in vitro. Static broth culture favours the production of fimbriae, while solid agar medium inhibits the generation of these appendages. Little information is available regarding whether S. Typhimurium continues to produce type 1 fimbriae during in vivo growth. We used a type 1 fimbrial phase variable strain S. Typhimurium LB5010 and its derivatives to infect RAW 264.7 macrophages. Following entry into macrophages, S. Typhimurium LB5010 gradually decreased the transcript levels of fimbrial subunit gene fimA, positive regulatory gene fimZ, and global regulatory gene lrp. A similar decrease in transcript levels was detected by RT-PCRwhen the pH of static brothmediumwas shifted frompH 7 to amore acidic pH 4. A fimA-deleted strain continued to multiply within macrophages as did the parental strain. An lrp deletion strain was unimpaired for in vitro growth at pH 7 or pH 4, while a strain harboring an lrp-containing plasmid exhibited impaired in vitro growth at pH 4. We propose that acidic medium, which resembles one aspect of the intracellular environment in a macrophage, inhibits type 1 fimbrial production by down-regulation of the expression of lrp, fimZ and fimA. PMID- 23938384 TI - A functional connection of Dictyostelium paracaspase with the contractile vacuole and a possible partner of the vacuolar proton ATPase. AB - Dictyostelium discoideum possesses only one caspase family member, paracaspase (pcp). Two separate mutant cell lines were first analysed: one cell line was an over-expressed GFP-tagged Pcp (GFP-Pcp), while the other cell line was a pcp-null (pcp-). Microscopic analysis of cells expressing GFP-Pcp revealed that Pcp was associated with the contractile vacuole membrane consisting of bladder-like vacuoles. This association was disrupted when cells were exposed to osmotic stress conditions. Compared with wild-type cells, the GFP-Pcp-over-expressing cells were susceptible to osmotic stress and were seen to be very rounded in hypo osmotic conditions and contained more abnormally swollen contractile vacuole. Cells with pcp- were also rounded but had few, if any, contractile vacuoles. These observations suggest that Pcp is essential for Dictyostelium osmotic regulation via its functioning in the contractile vacuole system. Subjecting these cells to selected contractile vacuole inhibitor provided additional support for these findings. Furthermore, yeast two-hybrid system identified vacuolar proton ATPase (VatM) as the protein interacting with Pcp. Taken together, this work gives evidence for an eukaryotic paracaspase to be associated with both localization in and regulation of the contractile vacuolar system, an organelle critical for maintaining the normal morphology of the cell. PMID- 23938385 TI - MiR-200a enhances the migrations of A549 and SK-MES-1 cells by regulating the expression of TSPAN1. AB - MicroRNA-200a (miR-200a) has been reported to regulate tumour progression in several tumours; however, little is known about its role in non-small cell lung cancer cells (NSCLCs). Here, we found that miR-200a was up-regulated in A549 and SK-MES-1 cells compared with normal lung cells HELF. By a series of gain-of function and loss-offunction studies, over-expression of miR-200a was indicated to enhance cells migration, and its knock-down inhibited migration of cells in NSCLC cell lines. Furthermore, miR-200a was identified to induce TSPAN1 expression which was related to migration. TSPAN1 was proved to induce migration, and so up-regulation of TSPAN1 by miR-200a may explain why over-expressing miR 200a promotes NSCLC cells migration. PMID- 23938386 TI - NOD1 and NOD2 receptors in mrigal (Cirrhinus mrigala): inductive expression and downstream signalling in ligand stimulation and bacterial infections. AB - Nucleotide binding and oligomerization domain (NOD)1 and NOD2 are important cytoplasmic pattern recognition receptors (PRRs) and key members of the NOD-like receptor (NLR) family. They sense a wide range of bacteria or their products and play a key role in inducing innate immunity. This report describes the role of NOD1 and NOD2 receptors signalling in innate immunity in the Indian major carp, mrigal (Cirrhinus mrigala). Tissue-specific expression analysis of NOD1 and NOD2 genes by quantitative real-time PCR (qRT-PCR) revealed their wide distribution in various organs/tissues. In the untreated fish, the highest expression of NOD1 and NOD2 was detected in liver and blood, respectively. Stimulation with NOD1- and NOD2-specific ligands, i.e. iE-DAP and MDP, activated NOD1 and NOD2 receptor signalling in vivo and in vitro resulting in significant (p less than 0.05) induction of downstream signalling molecule RICK, and the effector molecules IL-1 beta, IL-8 and IFN- gamma in the treated group as compared to their controls. In response to both Gram-positive and Gram-negative bacterial infections, NOD1 and NOD2 receptors signalling were activated and IL-1 beta, IL-8 and IFN- gamma were induced. These findings highlight the important role of NOD receptors in eliciting innate immune response during the pathogenic invasion to the fish. PMID- 23938387 TI - Rhodnius prolixus and Rhodnius robustus-like (Hemiptera, Reduviidae) wing asymmetry under controlled conditions of population density and feeding frequency. AB - Habitat change in Rhodnius spp may represent an environmental challenge for the development of the species, particularly when feeding frequency and population density vary in nature. To estimate the effect of these variables in stability on development, the degree of directional asymmetry (DA) and fluctuating asymmetry (FA) in the wing size and shape of R. prolixus and R. robustus-like were measured under laboratory controlled conditions. DA and FA in wing size and shape were significant in both species, but their variation patterns showed both inter specific and sexual dimorphic differences in FA of wing size and shape induced by nutrition stress. These results suggest different abilities of the genotypes and sexes of two sylvatic and domestic genotypes of Rhodnius to buffer these stress conditions. However, both species showed non-significant differences in the levels of FA between treatments that simulated sylvan vs domestic conditions, indicating that the developmental noise did not explain the variation in wing size and shape found in previous studies. Thus, this result confirm that the variation in wing size and shape in response to treatments constitute a plastic response of these genotypes to population density and feeding frequency. PMID- 23938388 TI - Repeated oral administration of capsaicin increases anxiety-like behaviours with prolonged stress-response in rats. AB - This study was conducted to examine the psycho-emotional effects of repeated oral exposure to capsaicin, the principal active component of chili peppers. Each rat received 1 mL of 0.02 percent capsaicin into its oral cavity daily, and was subjected to behavioural tests following 10 daily administrations of capsaicin. Stereotypy counts and rostral grooming were significantly increased, and caudal grooming decreased, in capsaicin-treated rats during the ambulatory activity test. In elevated plus maze test, not only the time spent in open arms but also the percent arm entry into open arms was reduced in capsaicin-treated rats compared with control rats. In forced swim test, although swimming duration was decreased, struggling increased in the capsaicin group, immobility duration did not differ between the groups. Repeated oral capsaicin did not affect the basal levels of plasma corticosterone; however, the stress-induced elevation of plasma corticosterone was prolonged in capsaicin treated rats. Oral capsaicin exposure significantly increased c-Fos expression not only in the nucleus tractus of solitarius but also in the paraventricular nucleus. Results suggest that repeated oral exposure to capsaicin increases anxiety-like behaviours in rats, and dysfunction of the hypothalamic-pituitary-adrenal axis may play a role in its pathophysiology. PMID- 23938389 TI - Production of marker-free and RSV-resistant transgenic rice using a twin T-DNA system and RNAi. AB - A twin T-DNA system is a convenient strategy for creating selectable marker-free transgenic plants. The standard transformation plasmid, pCAMBIA 1300, was modified into a binary vector consisting of two separate T-DNAs, one of which contained the hygromycin phosphotransferase (hpt) marker gene. Using this binary vector, we constructed two vectors that expressed inverted-repeat (IR) structures targeting the rice stripe virus (RSV) coat protein (CP) gene and the special disease protein (SP) gene. Transgenic rice lines were obtained via Agrobacterium mediated transformation. Seven independent clones harbouring both the hpt marker gene and the target genes (RSV CP or SP) were obtained in the primary transformants of pDTRSVCP and pDTRSVSP, respectively. The segregation frequencies of the target gene and the marker gene in the T1 plants were 8.72 percent for pDTRSVCP and 12.33 percent for pDTRSVSP. Two of the pDTRSVCP lines and three pDTRSVSP lines harbouring the homozygous target gene, but not the hpt gene, were strongly resistant to RSV. A molecular analysis of the resistant transgenic plants confirmed the stable integration and expression of the target genes. The resistant transgenic plants displayed lower levels of the transgene transcripts and specific small interfering RNAs, suggesting that RNAi induced the viral resistance. PMID- 23938390 TI - Down-regulation of OsSAG12-1 results in enhanced senescence and pathogen-induced cell death in transgenic rice plants. AB - Senescence is a highly regulated process accompanied by changes in gene expression. While the mRNA levels of most genes decline, the mRNA levels of specific genes (senescence associated genes, SAGs) increase during senescence. Arabidopsis SAG12 (AtSAG12) gene codes for papain-like cysteine protease. The promoter of AtSAG12 is SA-responsive and reported to be useful to delay senescence by expressing cytokinin biosynthesis gene isopentenyltransferase specifically during senescence in several plants including Arabidopsis, lettuce and rice. The physiological role of AtSAG12 is not known; the homozygous atsag12 mutant neither fails to develop senescenceassociated vacuoles nor shows any morphological phenotype. Through BLAST search using AtSAG12 amino acid sequences as query, we identified a few putative homologues from rice genome (OsSAGs; Oryza sativa SAGs). OsSAG12-1 is the closest homologue of AtSAG12 with 64% similar amino acid composition. Expression of OsSAG12-1 is induced during senescence and pathogen-induced cell death. To evaluate the possible role of OsSAG12-1 we generated RNAi transgenic lines in Japonica rice cultivar TP309. The transgenic lines developed early senescence at varying levels and showed enhanced cell death when inoculated with bacterial pathogen Xanthomonas oryzae pv.oryzae. Our results suggest that OsSAG12-1 is a negative regulator of cell death in rice. PMID- 23938391 TI - Functional analyses of a flavonol synthase-like gene from Camellia nitidissima reveal its roles in flavonoid metabolism during floral pigmentation. AB - The flavonoids metabolic pathway plays central roles in floral coloration, in which anthocyanins and flavonols are derived from common precursors, dihydroflavonols. Flavonol synthase (FLS) catalyses dihydroflavonols into flavonols, which presents a key branch of anthocyanins biosynthesis. The yellow flower of Camellia nitidissima Chi. is a unique feature within the genus Camellia, which makes it a precious resource for breeding yellow camellia varieties. In this work, we characterized the secondary metabolites of pigments during floral development of C. nitidissima and revealed that accumulation of flavonols correlates with floral coloration. We first isolated CnFLS1 and showed that it is a FLS of C. nitidissima by gene family analysis. Second, expression analysis during floral development and different floral organs indicated that the expression level of CnFLS1 was regulated by developmental cues, which was in agreement with the accumulating pattern of flavonols. Furthermore, over expression of CnFLS1 in Nicotiana tabacum altered floral colour into white or light yellow, and metabolic analysis showed significant increasing of flavonols and reducing of anthocyanins in transgenic plants. Our work suggested CnFLS1 plays critical roles in yellow colour pigmentation and is potentially a key point of genetic engineering toward colour modification in Camellia. PMID- 23938392 TI - Role of sound stimulation in reprogramming brain connectivity. AB - Sensory stimulation has a critical role to play in the development of an individual. Environmental factors tend to modify the inputs received by the sensory pathway. The developing brain is most vulnerable to these alterations and interacts with the environment to modify its neural circuitry. In addition to other sensory stimuli, auditory stimulation can also act as external stimuli to provide enrichment during the perinatal period. There is evidence that suggests that enriched environment in the form of auditory stimulation can play a substantial role in modulating plasticity during the prenatal period. This review focuses on the emerging role of prenatal auditory stimulation in the development of higher brain functions such as learning and memory in birds and mammals. The molecular mechanisms of various changes in the hippocampus following sound stimulation to effect neurogenesis, learning and memory are described. Sound stimulation can also modify neural connectivity in the early postnatal life to enhance higher cognitive function or even repair the secondary damages in various neurological and psychiatric disorders. Thus, it becomes imperative to examine in detail the possible ameliorating effects of prenatal sound stimulation in existing animal models of various psychiatric disorders, such as autism. PMID- 23938394 TI - Stem cell function and maintenance - ends that matter: role of telomeres and telomerase. AB - Stem cell research holds a promise to treat and prevent age-related degenerative changes in humans. Literature is replete with studies showing that stem cell function declines with aging, especially in highly proliferative tissues/ organs. Among others, telomerase and telomere damage is one of the intrinsic physical instigators that drive agerelated degenerative changes. In this review we provide brief overview of telomerase-deficient aging affects in diverse stem cells populations. Furthermore, potential disease phenotypes associated with telomerase dysregulation in a specific stem cell population is also discussed in this review. Additionally, the role of telomerase in stem cell driven cancer is also briefly touched upon. PMID- 23938395 TI - The aging of the 2000 and 2011 Hallmarks of Cancer reviews: a critique. AB - Two review articles published in 2000 and 2011 by Hanahan and Weinberg have dominated the discourse about carcinogenesis among researchers in the recent past. The basic tenets of their arguments favour considering cancer as a cell based, genetic disease whereby DNA mutations cause uncontrolled cell proliferation. Their explanation of cancer phenotypes is based on the premises adopted by the somatic mutation theory (SMT) and its cell-centered variants. From their perspective, eight broad features have been identified as so-called 'Hallmarks of Cancer'. Here, we criticize the value of these features based on the numerous intrinsic inconsistencies in the data and in the rationale behind SMT. An alternative interpretation of the same data plus data mostly ignored by Hanahan and Weinberg is proposed, based instead on evolutionarily relevant premises. From such a perspective, cancer is viewed as a tissue-based disease. This alternative, called the tissue organization field theory, incorporates the premise that proliferation and motility are the default state of all cells, and that carcinogenesis is due to alterations on the reciprocal interactions among cells and between cells and their extracellular matrix. In this view, cancer is development gone awry. PMID- 23938396 TI - Biomphalaria alexandrina in Egypt: past, present and future. AB - The African species of Biomphalaria appeared as a result of the relatively recent west-to-east trans-Atlantic dispersal of the Biomphalaria glabrata-like taxon. In Egypt, Biomphalaria alexandrina is the intermediate host for Schistosoma mansoni. Biomphalaria alexandrina originated in the area between Alexandria and Rosetta and has historically been confined to the Nile Delta. Schistosoma mansoni reached Egypt via infected slaves and baboons from the Land of Punt through migrations that occurred as early as the Vth Dynasty. The suggestion of the presence of Schistosoma mansoni infection in Lower Egypt during Pharaonic times is discussed despite the fact that that there is no evidence of such infection in Egyptian mummies. It is only recently that Biomphalaria alexandrina colonized the Egyptian Nile from the Delta to Lake Nasser. This change was likely due to the construction of huge water projects, the development of new water resources essential for land reclamation projects and the movement of refugees from the Suez Canal zone to the Delta and vice versa. The situation with respect to Biomphalaria in Egypt has become complicated in recent years by the detection of Biomphalaria glabrata and a hybrid between both species; however, follow-up studies have demonstrated the disappearance of such species within Egypt. The National Schistosoma Control Program has made great strides with respect to the eradication of schistosoma; however, there has unfortunately been a reemergence of Schistosoma mansoni resistant to praziquantel. There are numerous factors that may influence the prevalence of snails in Egypt, including the construction of water projects, the increase in reclaimed areas, global climate change and pollution. Thus, continued field studies in addition to the cooperation of several scientists are needed to obtain an accurate representation of the status of this species. In addition, the determination of the genome sequence for Biomphalaria alexandrina and the use of modern technology will allow for the study of the host-parasite relationship at a molecular level. PMID- 23938397 TI - Metabolic acidosis and topiramate. Use of Winters' formula. PMID- 23938398 TI - CASE 1-2014 Left Ventricular Assist Device Insertion and the Mitral Valve. PMID- 23938393 TI - mRNA quality control pathways in Saccharomyces cerevisiae. AB - Efficient production of translation-competent mRNAs involves processing and modification events both in the nucleus and cytoplasm which require a number of complex machineries at both co-transcriptional and posttranscriptional levels. Mutations in the genomic sequence sometimes result in the formation of mutant nonfunctional defective messages. In addition, the enormous amounts of complexities involved in the biogenesis of mRNPs in the nucleus very often leads to the formation of aberrant and faulty messages along with their functional counterpart. Subsequent translation of these mutant and defective populations of messenger RNAs could possibly result in the unfaithful transmission of genetic information and thus is considered a threat to the survival of the cell. To prevent this possibility, mRNA quality control systems have evolved both in the nucleus and cytoplasm in eukaryotes to scrutinize various stages of mRNP biogenesis and translation. In this review, we will focus on the physiological role of some of these mRNA quality control systems in the simplest model eukaryote Saccharomyces cerevisiae. PMID- 23938399 TI - Genotype assessment as a tool for improved risk prediction in cardiac surgery. PMID- 23938400 TI - Network meta-analyses: the "white whale" for cardiovascular specialists. PMID- 23938403 TI - Direct splitting of pure water into hydrogen and oxygen using rutile titania powder as a photocatalyst. AB - Direct splitting of pure water into hydrogen and oxygen was demonstrated using the rutile TiO2 powder under band gap irradiation. The successful water splitting results at least in part from the intrinsic properties of the rutile surface that is less sensitive to photoreduction of O2, a reverse reaction in water splitting. PMID- 23938404 TI - Improvement in the measurement of focal length using spot patterns and spherical aberration. AB - Using an optical setup that includes a square array of 3*3 holes, we used nine meridional rays to measure the effective focal length of a lens. We observed the selected meridional rays as a spot pattern on a diffuse screen. First, we generated a regular square spot pattern (reference pattern) without a lens to test, and then we generated two spot patterns in two different axial positions when the lens being tested refracts the rays. By selecting two sets of four rays of each spot pattern, we were able to measure the difference of the longitudinal (primary) spherical aberration in two positions. With this difference we were able to improve the calculation of the effective focal length. To determine the method's precision, we first simulated the relative error in the effective focal length considering the error in the measurement of the ray heights. Then we determined the experimental relative error by means of the standard deviation of the focal lengths obtained for each spot (in the image of reference and for the images at the two different locations) for both sets of four spots. The experimental results agree very well with the simulation. The error analysis allows us to establish under what conditions it is possible to obtain relative errors of less than 1% in the effective focal length. PMID- 23938405 TI - Broadband and wide-angle antireflection realized by multireflection effect in a micro-?-shape array. AB - Antireflective surfaces are often realized by minimizing the refractive index contrast between the air and substrate using subwavelength microstructures. In this paper, we introduce another kind of geometry-induced antireflective surface using multireflection to suppress reflection to a very low extent. This surface is composed of micro-?-shape array with the wedge size much larger than the wavelength of the incident light. Simulation and experimental results show that the micro-?-shape array can effectively suppress the reflection within wide incident angles and large wavelength ranges. The enhanced light adsorption caused by the greatly increased light path length within the micro-?-shape array is responsible for the antireflection phenomena. Such antireflective surface may find various applications, in solar cells, for example. PMID- 23938402 TI - The concentration of glutathione in human erythrocytes is a heritable trait. AB - Glutathione (GSH) is a ubiquitous, redox-active, small molecule that is critical to cellular and organism health. In red blood cells (RBCs), the influence of the environment (e.g., diet and lifestyle) on GSH levels has been demonstrated in numerous studies. However, it remains unknown if levels of GSH are determined principally by environmental factors or if there is a genetic component, i.e., heritability. To investigate this we conducted a twin study. Twin studies are performed by comparing the similarity in phenotypes between mono- and dizygotic twin pairs. We determined the heritability of GSH, as well as its oxidation product glutathione disulfide (GSSG), the sum of GSH equivalents (tGSH), and the status of the GSSG/2GSH couple (marker of oxidation status, Ehc) in RBCs. In our study population we found that the estimated heritability for the intracellular concentration of GSH in RBCs was 57 %; for GSSG it was 51 %, tGSH 63 %, and Ehc 70 %. We conclude that a major portion of the phenotype of these traits is controlled genetically. We anticipate that these heritabilities will also be reflected in other cell types. The discovery that genetics plays a major role in the innate levels of redox-active species in RBCs is paradigm shifting and opens new avenues of research in the field of redox biology. Inherited RBC antioxidant levels may be important disease modifiers. By identifying the relative contributions of genes and the environment to antioxidant variation between individuals, new therapeutic strategies can be developed. Understanding the genetic determinants of these inherited traits may allow personalized approaches to relevant therapies. PMID- 23938406 TI - Three-dimensional modeling of light rays on the surface of a slanted lenticular array for autostereoscopic displays. AB - In this paper, we developed an optical model describing the behavior of light at the surface of a slanted lenticular array for autostereoscopic displays in three dimensions and simulated the optical characteristics of autostereoscopic displays using the Monte Carlo method under actual design conditions. The behavior of light is analyzed by light rays for selected inclination and azimuthal angles; numerical aberrations and conditions of total internal reflection for the lenticular array were found. The intensity and the three-dimensional crosstalk distributions calculated from our model coincide very well with those from conventional design software, and our model shows highly enhanced calculation speed that is 67 times faster than that of the conventional software. From the results, we think that the optical model is very useful for predicting the optical characteristics of autostereoscopic displays with enhanced calculation speed. PMID- 23938401 TI - Implications of autophagy for vascular smooth muscle cell function and plasticity. AB - Vascular smooth muscle cells (VSMCs) are fundamental in regulating blood pressure and distributing oxygen and nutrients to peripheral tissues. They also possess remarkable plasticity, with the capacity to switch to synthetic, macrophage-like, or osteochondrogenic phenotypes when cued by external stimuli. In arterial diseases such as atherosclerosis and restenosis, this plasticity seems to be critical and, depending on the disease context, can be deleterious or beneficial. Therefore, understanding the mechanisms regulating VSMC phenotype and survival is essential for developing new therapies for vascular disease as well as understanding how secondary complications due to surgical interventions develop. In this regard, the cellular process of autophagy is increasingly being recognized as a major player in vascular biology and a critical determinant of VSMC phenotype and survival. Although autophagy was identified in lesional VSMCs in the 1960s, our understanding of the implications of autophagy in arterial diseases and the stimuli promoting its activation in VSMCs is only now being elucidated. In this review, we highlight the evidence for autophagy occurring in VSMCs in vivo, elaborate on the stimuli and processes regulating autophagy, and discuss the current understanding of the role of autophagy in vascular disease. PMID- 23938407 TI - Determination of ablation threshold of copper alloy with orthogonal dual-pulse laser-ablation laser-induced breakdown spectroscopy. AB - Orthogonal dual-pulse laser-ablation laser-induced breakdown spectroscopy was first used to determine the laser-ablation threshold of samples. In this technique, the first laser pulse was used to ablate samples and the second time delayed laser pulse was used to break down the ablated samples. Orthogonal geometric arrangement was adopted in this technique to ensure both high spatial resolution and high detection sensitivity. By monitoring the intensities of the atomic emission of the plasma under different pulse energies of the ablation laser and using an extrapolation method, the minimum pulse energy needed for the ablation of copper alloy under the tightly focused condition with a nanosecond 532 nm ablation laser was determined to be 1.9+/-0.1 MUJ. After experimentally determining the beam spot size on the focal plan, the fluence threshold of the studied sample was determined to be 0.64+/-0.06 J/cm2. This technique is able to realize direct and sensitive determination of a laser-ablation threshold of solid samples, and it is possible to find some important applications in different fields. PMID- 23938408 TI - Photoluminescence properties of Tm3+/Tb3+/Eu3+ tri-doped phosphate glass and glass ceramics for white-light-emitting diodes. AB - Tm(3+)/Tb(3+)/Eu(3+) tri-doped phosphate glasses are synthesized to explore new white-light-emitting materials. Under 365 nm excitation, the CIE coordinates (x=0.339, y=0.341) of the Eu0.07 glass sample are close to the standard equal energy white-light illumination (x=0.333, y=0.333). The quantum efficiency is very high (~72.27%). The energy transition from Tb(3+) to Eu(3+) is reasonably interpreted based on the analysis of the luminescence lifetimes. To enhance the white-light emission, Tm(3+)/Tb(3+)/Eu(3+) tri-doped phosphate glass ceramics are prepared. PMID- 23938409 TI - Stabilization of pupils in a zoom lens with two independent movements. AB - A procedure for thin lens structural design of a new class of pupil stabilized zoom systems is presented. This is facilitated by an implementation of evolutionary programming that searches a multivariate hyperspace formed by design variables, namely, powers of individual components and intercomponent separations. Two coupled components in the lens system act as the variator for the zoom system, and another component in the system acts as the compensator. A fixed axial location of the image plane is achieved by moving the coupled variator and the compensator nonlinearly, while the entrance and the exit pupils are allowed small shifts in their axial locations over the zooming range. The latter relaxation opens up the possibility for effective two-conjugate zoom systems with only two independent component movements. Illustrative examples for thin lens structures of two-conjugate zoom systems are presented. PMID- 23938410 TI - Analytical approach of laser beam propagation in the hollow polygonal light pipe. AB - An analytical method of researching the light distribution properties on the output end of a hollow n-sided polygonal light pipe and a light source with a Gaussian distribution is developed. The mirror transformation matrices and a special algorithm of removing void virtual images are created to acquire the location and direction vector of each effective virtual image on the entrance plane. The analytical method is demonstrated by Monte Carlo ray tracing. At the same time, four typical cases are discussed. The analytical results indicate that the uniformity of light distribution varies with the structural and optical parameters of the hollow n-sided polygonal light pipe and light source with a Gaussian distribution. The analytical approach will be useful to design and choose the hollow n-sided polygonal light pipe, especially for high-power laser beam homogenization techniques. PMID- 23938411 TI - Sun glint estimation in marine satellite images: a comparison of results from calculation and radiative transfer modeling. AB - The intensity and location of Sun glint in two Medium Resolution Imaging Spectrometer (MERIS) images was modeled using a radiative transfer model that includes elevation features as well as the slope of the sea surface. The results are compared to estimates made using glint flagging and correction approaches used within standard atmospheric correction processing code. The model estimate gives a glint pattern with a similar width but lower peak level than any current method, or than that estimated by a radiative transfer model with surfaces that include slope but not height. The MERIS third reprocessing recently adopted a new slope statistics model for Sun glint correction; the results show that this model is an outlier with respect to both the elevation model and other slope statistics models and we recommend that its adoption should be reviewed. PMID- 23938412 TI - Reflective terahertz imaging with the TEM01 mode laser beam. AB - Reflective terahertz imaging with a first-order Hermite-Gaussian laser beam was experimentally investigated. High spatial resolution targets prepared by direct laser microprocessing were used to evaluate the performance. The reflection imaging system at 2.524 THz frequency demonstrated up to diffraction limited resolution using the single focusing mirror with the numerical aperture not smaller than 0.6. The TEM(01) mode laser beam was also applied for practical samples such as silicon solar cell terahertz (THz) imaging. It is shown that usage of appropriate optics enables us to obtain high-quality THz images with the multimode laser beam. PMID- 23938413 TI - Optical identity authentication scheme based on elliptic curve digital signature algorithm and phase retrieval algorithm. AB - An optical identity authentication scheme based on the elliptic curve digital signature algorithm (ECDSA) and phase retrieval algorithm (PRA) is proposed. In this scheme, a user's certification image and the quick response code of the user identity's keyed-hash message authentication code (HMAC) with added noise, serving as the amplitude and phase restriction, respectively, are digitally encoded into two phase keys using a PRA in the Fresnel domain. During the authentication process, when the two phase keys are presented to the system and illuminated by a plane wave of correct wavelength, an output image is generated in the output plane. By identifying whether there is a match between the amplitude of the output image and all the certification images pre-stored in the database, the system can thus accomplish a first-level verification. After the confirmation of first-level verification, the ECDSA signature is decoded from the phase part of the output image and verified to allege whether the user's identity is legal or not. Moreover, the introduction of HMAC makes it almost impossible to forge the signature and hence the phase keys thanks to the HMAC's irreversible property. Theoretical analysis and numerical simulations both validate the feasibility of our proposed scheme. PMID- 23938414 TI - Embedding a nondiffracting defect site in helical lattice wave-field by optical phase engineering. AB - We present a technique to optically induce a defect site in helical lattice wave field where the combined wave-field continues to maintain its nondiffracting (ND) nature. This is done by coherently superposing a helical lattice wave-field and a Bessel beam by method of phase engineering. The results are confirmed by numerical simulations and experimentally as well by generating the ND defect beam by displaying the numerically calculated phase pattern on a phase-only spatial light modulator. This technique is wavelength independent, completely scalable, and can easily be used to generate or transfer these structures in any photosensitive medium. PMID- 23938415 TI - Compact and low-latency instantaneous frequency measurement using 38 cm bismuth oxide fiber and fiber Bragg gratings. AB - We demonstrated a compact and low-latency photonic approach for broadband RF signal frequency measurement. The photonic approach does not require high-speed electronics for gigahertz RF signal measurement. Frequency-to-intensity mapping is achieved based on a two-tap finite-impulse-response filter architecture, where the time delay between signals is provided by fiber Bragg grating array. With four-wave mixing (FWM) as an optical broadband mixer, sinusoid frequency response is transferred to a DC output, where FWM is achieved in a 38 cm bismuth-oxide fiber. Thus, the resultant signal does not consist of any high-frequency component and no high-speed oscilloscope is needed for the measurement. PMID- 23938416 TI - Image quality improvement in optical coherence tomography using Lucy-Richardson deconvolution algorithm. AB - Optical coherence tomography (OCT) has the potential for skin tissue characterization due to its high axial and transverse resolution and its acceptable depth penetration. In practice, OCT cannot reach the theoretical resolutions due to imperfections of some of the components used. One way to improve the quality of the images is to estimate the point spread function (PSF) of the OCT system and deconvolve it from the output images. In this paper, we investigate the use of solid phantoms to estimate the PSF of the imaging system. We then utilize iterative Lucy-Richardson deconvolution algorithm to improve the quality of the images. The performance of the proposed algorithm is demonstrated on OCT images acquired from a variety of samples, such as epoxy-resin phantoms, fingertip skin and basaloid larynx and eyelid tissues. PMID- 23938417 TI - Attenuation performance of reflection-mode AlGaN photocathode under different preparation methods. AB - To research the attenuation performance of the AlGaN photocathode, three samples with the same structures grown by metalorganic chemical vapor deposition were activated with three different activation methods, which are called Cs-only, Cs O, and Cs-O-Cs activation, respectively. The spectral responses and attenuated photocurrents of the three AlGaN photocathodes were measured. The results show that the Cs-O activated AlGaN photocathode exhibits the lowest attenuation speed in the first few hours, and the attenuation speed of the Cs-only activated one is fastest. After attenuating for 90 min, the attenuation photocurrent curve of the Cs-O-Cs activated sample is coincident with that of the Cs-O activated one. The main factor affecting the photocurrent attenuation is related to Cs atoms desorbed from the photocathode surface. PMID- 23938418 TI - High-dynamic angle measurement based on laser displacement sensors. AB - It is currently difficult to achieve good real-time dynamic angle measurements with high accuracy and large ranges. In this paper, a photoelectric measurement method for dynamic angles based on three laser displacement sensors (LDSs) is proposed. Offline, a dynamic angle vision measurement model is established, and the system is calibrated by using a planar target moved by a 2D moving platform. In the course of measurement, three laser beams emitted from three LDSs are projected onto a rotating plane, and three noncollinear points are acquired synchronously; then the rotation angle is calculated in real time. Simulations verify the feasibility of the method theoretically. Experimental results demonstrate that the method achieves measurement accuracies of 0.008 degrees and 0.046 degrees under quasi-static condition of 80 degrees /s and highly dynamic condition of 1000 degrees /s within the measurement range of about +/-40 degrees , respectively. PMID- 23938419 TI - Modified stitching algorithm for annular subaperture stitching interferometry for aspheric surfaces. AB - In this paper, a modified stitching algorithm for annular subaperture stitching interferometry (ASSI) for aspheric surfaces is proposed. The mathematical model of adjustment error is deduced based on the wavefront aberration theory and rigid body movement; meanwhile, its basic principle and theory are introduced. The modified stitching algorithm is established based on the mathematical model and the simultaneous least-squares method, which keeps the error from transmitting and accumulating. So the adjustment error can be compensated efficiently. In addition, the standard deviation (SD) in the overlapped regions is used as the figure of merit to determine the stitching accuracy. Finally, simulations and experiments are given to verify the validity and rationality of the proposed algorithm. The results show that the introduced method is quite efficient. PMID- 23938420 TI - Terahertz surface plasmon sensor for distinguishing gasolines. AB - Gasolines of two different octane numbers are experimentally distinguished using a thin metal sheet perforated with a periodic hole array terahertz surface plasmon (SP) sensor. This sensor is proved to be very sensitive to the change in permittivities of analytes. The differences between the gasolines 93# and 97# in composition lead to various refractive indices, permittivities, and absorption coefficients, thus varying their interactions with surface waves on the sensor, which enables a distinction of 6 GHz between the two octane numbers in the transmission peaks. The freestanding SP sensor is effective and reliable and can be simply employed in analyte distinction, which has potential applications in the petroleum industry. PMID- 23938421 TI - All-optical switching in Sagnac loop mirror containing an ytterbium-doped fiber and fiber Bragg grating. AB - A configuration of all-optical switching based on a Signac loop mirror that incorporates an ytterbium-doped fiber and uniform fiber Bragg grating (FBG) is proposed in this paper. It is found that the transmission spectrum of this structure is the narrow splitting of the reflection spectrum of the FBG. The shift of this ultranarrow transmission spectrum is very sensitive to the intensity of the pump power. Thus, the threshold switching power can be greatly reduced by shifting such narrow transmission spectrum. Compared with the single FBG, the threshold switching power of this configuration is reduced by 4 orders of magnitude. In addition, the results indicate that this optical switching has a high extinction ratio of 20 dB and a ultrafast response time of 3 ns. The operation regime and switching performance under the cross-phase modulation cases are also investigated. PMID- 23938422 TI - Diffraction of a plane wave by an infinitely long circular cylinder or a sphere: solution from Mie theory. AB - Diffraction of an infinitely long circular cylinder normally illuminated by a plane wave is discussed from the classical Mie theory. A rigorous expression of the diffracted light is obtained, which is simply characterized by a factor (theta/2)/sin(theta/2) and the sinc function sin(alphatheta)/(alphatheta). Numerical calculation shows an apparent difference between our results and those from scalar wave diffraction theory, especially in large diffraction angles. The factor (theta/2)/sin(theta/2) is introduced into the diffracted light by a sphere, which leads to an alternative approximation of the diffracted light. PMID- 23938423 TI - Stabilized fiber-optic Mach-Zehnder interferometer for carrier-frequency rejection. AB - We have demonstrated stabilization of a fiber-optic Mach-Zehnder interferometer, with a centimeter-scale path difference, to the transmission minimum for the carrier wave of a frequency-modulated laser beam. A time-averaged extinction of 32 dB, limited by the bandwidth of the feedback, was maintained over several hours. The interferometer was used to remove the carrier wave from a 780 nm laser beam that had been phase modulated at 2.7 GHz. PMID- 23938424 TI - Enhanced sensitivity in dark-field microscopy by optimizing the illumination angle. AB - Dark-field microscopy is a well-known technique used to exclude the bright background of unscattered photons from a measurement. We show that by choosing an appropriate illumination angle, the background of unwanted scattered light can also be suppressed. The collected flux of scattered photons is calculated in the Mie scattering regime for various particle sizes and objectives over a range of illumination angles. In the case that the dark-field measurement is limited by background scattering, we find that the sensitivity can be improved by lowering the objective numerical aperture. The collected photon flux is calculated for an exemplary dark-field microscopy experiment in which lipid granules were studied within yeast cells. Our model suggests that the signal-to-noise ratio was over three-orders-of-magnitude higher than it would have been with an equivalent bright-field setup. PMID- 23938425 TI - Aberration correction of zoom lenses using evolutionary programming. AB - A systematic approach for the aberration correction of zoom systems is presented. It is assumed that the powers and movements of the components of the zoom systems are known. Each component is considered as a system of thin lenses in contact. An evolutionary algorithm is developed to explore the multivariate hyperspace of design variables formed by spherical aberration, central coma, and longitudinal chromatic aberration of each component for infinite conjugate. The primary aberrations for each component at any zoom position are deduced from three central aberration coefficients of the component for infinite conjugate using conjugate shift formulas. Overall system aberrations of the zoom systems are determined by using stop shift formulas. In most of the zoom lens systems it is important to achieve stability in the primary aberrations of the system over the zoom range. This is facilitated by proper formulation of the merit function for the optimization process. Investigations have been carried out on four-component zoom lenses, and an ab initio structure of a four-component zoom lens is presented. PMID- 23938426 TI - Low-loss hybrid plasmonic modes guided by metal-coated dielectric wedges for subwavelength light confinement. AB - The optical characteristics of a metal-coated dielectric wedge structure are investigated at a wavelength of 1550 nm. The effects of the metal/gap layers' thicknesses, as well as the dimension of the dielectric wedge on the guided modes' properties, are systematically analyzed. It is revealed that the characteristics of the fundamental quasi-TE and quasi-TM plasmonic modes supported by the configuration demonstrate similar trends against the variation of the metal layer thickness while exhibiting quite different behaviors with the change of the wedge size. By choosing appropriate physical dimensions, both modes could simultaneously achieve low modal loss and subwavelength field confinement, along with reasonable mode power inside the low-index gap region. Investigations on the directional coupling between adjacent identical waveguides indicate that ultralow crosstalk can be enabled by the quasi-TE mode, with the coupling length more than two orders of magnitude larger than that achieved by the plasmonic mode in conventional hybrid counterparts. The presented metal-coated dielectric wedge structures can be employed as important building blocks for a number of integrated nanophotonic components, and could also enable numerous applications at the subwavelength scale. PMID- 23938427 TI - Improvements in electric-field sensor sensitivity by exploiting a tangential field condition. AB - This paper presents improvements to slab-coupled optical fiber sensors for electric-field sensing. The sensors are comprised of a potassium titanyl phosphate (KTP) crystal mounted on a D-fiber. The improvements are based on changing the crystal orientation, which enhances sensitivity due to a combined increase in the effective electro-optic coefficient and electric-field penetration into the KTP crystal. The paper provides a detailed comparison of the improved sensor, which uses x-cut KTP to the previous sensor design using z-cut KTP. The measurements show an 8.6* improvement in the sensitivity. PMID- 23938428 TI - Optimization and tolerance analysis of a polarimeter with ferroelectric liquid crystals. AB - We present the design of Stokes and Mueller polarimeters based on ferroelectric liquid crystal (FLC) panels. The instrument is complete and takes time-sequential measurements. A FLC device is modeled as a uniaxial birefringent waveplate with two stable optical axis orientations switchable by a squared electrical signal. The optical parameters of the LC device (retardance and the two stable orientations of the fast axis) are calibrated. Then the orientations of the optical elements of the setup are optimized in order to minimize the propagation of the noise. We also provide a tolerance study to achieve 2% accuracy for the Stokes vector and Mueller matrix metrology. These analyses are conducted as a function of the incident state of polarization and of the Mueller matrix to be measured, respectively. The optimized system is implemented and calibrated in the laboratory. We evaluate its repeatability over 24 h of operation, and the dependence with the temperature is discussed. In addition, we include a study related to the speed of taking the measurements. Finally, we provide some experimental measurements of different Stokes vectors and Mueller matrices, validating the proposed prototypes. PMID- 23938429 TI - Method of excess fractions with application to absolute distance metrology: analytical solution. AB - Multiwavelength interferometry provides a solution to a number of applications in metrology for the measurement of optical path differences longer than the source wavelength. To this day, the method of excess fractions (EF) has proved to provide very long, unambiguous measurement ranges with the highest reliability for a given set of wavelengths and level of phase noise. This is achieved because EF combines the individual phase values in an equivalent least-square problem and evaluates the correspondence for all possible solutions. However, this procedure can be slow for a number of applications. In this paper, an analytical solution for EF is presented that allows the direct calculation of the unknown integer fringe order. It is shown that this solution is consistent with the other phase unwrapping approaches as beat wavelength or Chinese remainder theorem-based solutions, but moreover, it can be understood as a unified representation and solution of the fringe order problem. PMID- 23938430 TI - Spatial properties of coaxial superposition of two coherent Gaussian beams. AB - In this paper, we explore theoretically and experimentally the laser beam shaping ability resulting from the coaxial superposition of two coherent Gaussian beams (GBs). This technique is classified under interferometric laser beam shaping techniques contrasting with the usual ones based on diffraction. The experimental setup does not involve the use of some two-wave interferometer but uses a spatial light modulator for the generation of the necessary interference term. This allows one to avoid the thermal drift occurring in interferometers and gives a total flexibility of the key parameter setting the beam transformation. In particular, we demonstrate the reshaping of a GB into a bottle beam or top-hat beam in the focal plane of a focusing lens. PMID- 23938431 TI - Carrier-suppressed modulation and self-mixing demodulation for vibration measurement. AB - We present a double-sideband suppressed-carrier (DSB-SC) technique achieved by an optical balanced detection approach for measuring small vibrations. The baseband signal is recovered by demodulating the DSB-SC signal with a self-mixing approach without local oscillator, which is usually required in coherent detection. The achievement of carrier suppression and vibration measurement is experimentally demonstrated, and the result closely agrees with the theoretical predictions. PMID- 23938432 TI - Modeling and validation of polishing tool influence functions for manufacturing segments for an extremely large telescope. AB - We present a simulation technique to predict tool influence functions (TIFs) based on the Precessions polishing process, which is driven by addressing mass fabrication of the European Extremely Large Telescope mirror segments. Precessions polishing requires accurate and predictable TIFs to optimize the multiple process parameters, particularly when sequential polishing runs are performed by different polishing tools. In this paper, the static and dynamic TIFs are simulated based on the Preston equation. The velocity distribution is calculated according to the geometry of the precession motion. The pressure distribution at the polishing spot is calculated by means of finite element analysis (FEA). The FEA result is validated by direct force measurement with a simulation error of 4.3%. The simulation results of TIFs are verified by an experiment that shows the residual errors are less than 5% for both static and dynamic TIFs. PMID- 23938433 TI - Thin-film thickness-modulated designs for optical minus filter. AB - We proposed an analytical method to design optical minus filters by the thickness modulation of discrete, homogeneous thin-film layers of a two-material multilayer coating. The main stack provides the narrow, second-order rejection band, and the correct thickness-modulation apodization and match layers can effectively suppress the sidelobes of the passband. Using this approach, we can design minus filters with layer thicknesses close to half-wave of the rejection wavelength, making this method well suited for accurate monitoring during the deposition. PMID- 23938434 TI - Analysis and simulation of a fiber bundle method for creating a partially spatially coherent beam. AB - A fiber bundle arrangement containing a distribution of fiber lengths has been proposed in the literature to produce a partially spatially coherent beam. Light input to the bundle with limited temporal coherence is translated into limited spatial coherence. Expressions are developed for the bundle pupil autocorrelation function and far-field irradiance pattern. A numerical simulation approach is implemented and results are compared with a speckle-free result. The fiber bundle approach tends to create an irradiance pattern whose average shape matches the pattern produced by a single fiber. A "smoothed" far-field pattern is obtained if the fiber length difference is much greater than the source temporal coherence length. PMID- 23938435 TI - High efficiency coupling of light from a ridge to a photonic crystal waveguide. AB - We present theoretical and experimental demonstration of two designs to achieve group velocity insensitive coupling of light from a ridge waveguide to a photonic crystal waveguide. We demonstrate an average improvement of 62% in coupling to low group velocity modes and an average coupling enhancement of 11.5% at large group velocities. PMID- 23938436 TI - Nucleonic-resolution optical mass sensor based on a graphene nanoribbon quantum dot. AB - The high frequency and ultrasmall mass of graphene make it an ideal material for ultrasensitive mass sensing. In this article, based on the all-optical technique, we propose a scheme of an optical mass sensor to weigh the mass of a single atom or molecule via a doubly clamped Z-shaped graphene nanoribbon (GNR). We use the detection of shifts in the resonance frequency of the Z-shaped GNR to determine the mass of an external particle landing on the GNR. The highly sensitive mass sensor proposed here can weigh particles down to the yoctogram and may eventually be enable to realize the mass measurement of nucleons. PMID- 23938437 TI - Generation of programmable 3D optical vortex structures through devil's vortex lens arrays. AB - Different spatial distributions of optical vortices have been generated and characterized by implementing arrays of devil's vortex lenses in a reconfigurable spatial light modulator. A simple design procedure assigns the preferred position and topological charge value to each vortex in the structure, tuning the desired angular momentum. Distributions with charges and momenta of the opposite sign have been experimentally demonstrated. The angular velocity exhibited by the phase distribution around the focal plane has been visualized, showing an excellent agreement with the simulations. The practical limits of the method, with interest for applications involving particle transfer and manipulation, have been evaluated. PMID- 23938438 TI - Two-component cavity based on a regular photonic crystal nanobeam. AB - The authors propose and numerically examine a two-component design for an optical nanocavity. Such a nanocavity consists, first, of a photonic crystal (PC) nanobeam, in which the PC unit cell is not changed. Second, the cavity contains a fragment of some supplementary material of the size of several or several tens of PC unit cells. When the two components are combined, a defect forms in which the resonant mode can be excited. The advantages of the proposed cavity model are reported, particularly the possibility of implementing electrically pumped light sources and amplifiers and the simplification of development of nanocavities with nonlinear properties. The fabrication tolerances of the proposed nanocavity were investigated. It has been found that existing structural layer alignment technologies can be used for fabricating the suggested cavity. PMID- 23938439 TI - Feedback phase correction of Bessel beams in confocal line light-sheet microscopy: a simulation study. AB - Confocal line detection has been shown to improve contrast in light-sheet-based microscopy especially when illuminating the sample by Bessel beams. Besides their self-reconstructing capability, the stability in propagation direction of Bessel beams allows to block the unwanted emission light from the Bessel beam's ring system. However, due to phase aberrations induced especially at the border of the specimen, Bessel beams may not propagate along lines parallel to the slit detector. Here we present a concept of how to correct the phase of each incident Bessel beam such that the efficiency of confocal line detection is improved by up to 200%-300%. The applicability of the method is verified by the results obtained from numerical simulations based on the beam propagation method. PMID- 23938440 TI - Design of plastic diffractive-refractive compact zoom lenses for visible-near-IR spectrum. AB - The requirements for selecting the initial scheme for a compact plastic zoom lens are formulated. The main stages of the initial scheme of the transformation, incorporating the diffractive lens and replacement of the lenses' glasses by optical plastics, are presented. The efficiency of the suggested techniques of the optical layout process are demonstrated by using the example of the design and analysis of a zoom lens intended for use in security cameras for day or night vision. PMID- 23938441 TI - Asymmetric design of photonic crystal surface-emitting lasers with low-threshold characteristics. AB - We present AlGaAs-InGaAs multiquantum wells photonic crystal surface-emitting lasers by using the transfer matrix method and coupled wave method to achieve a low-threshold operation. The extremely low-threshold gain is achieved by adopting an asymmetric cladding layer design to enhance both of the vertical optical confinement factors for the quantum wells and photonic crystal (PC). By modifying the composition of the AlGaAs layer to raise the refractive index in the p-type cladding, optical field distribution will obviously be shifted to the p side. Hence, it results in a significant coupling enhancement between the optical mode profile and the PC layer. The optimized value of the vertically optical confinement factor of the PC layer is 13.94%, and the corresponding threshold gain can be as low as 19.45 cm(-1). PMID- 23938442 TI - Analysis and characterization of Er-Yb codoped-depressed inner cladding fiber. AB - A 125 MUm-diameter erbium-ytterbium-codoped single-mode fiber is reported. The utilization of depressed inner cladding guarantees the improvement of trade-off between the effective area and bending sensitivity compared to step-index profiles. Changes of cutoff wavelength, effective area, and macrobend loss under the influence of various structural parameters, and the balancing selection of core radius and subsidence layer width are investigated systematically. For the laboratory-made depressed inner cladding fiber, a macrobend loss of 0.06 dB/loop for a bending radius as tight as 10 mm was achieved, while maintaining an effective area of 164.22 MUm2 with intact single-mode properties at 1550 nm. The maximum small signal gain was achieved at 40.9 dB, and the gain fluctuation was less than 1 dB at the C-band. The fiber is suitable for high-power, small, portable, and handy optical fiber devices. PMID- 23938443 TI - Accurate position measurement of a high-density beam spot array in digital maskless lithography. AB - Since patterns in digital maskless lithography are formed by accumulating the exposure energy of a high-density beam spot array, the accurate position measurement of the spot array is essential for the precise operation of the system. We propose a measurement technique for detecting the position of a high density, subpixel size beam spot array with a charge-coupled device (CCD). In order to determine the position of each beam spot with a small number of CCD pixels, we assign 3*3 pixels of the CCD for each spot and scan the CCD to determine the signal of a center pixel. We numerically analyze the measurement uncertainty in the pixel position for various scanning conditions. We set up an experimental system for proof of concept and to detect the position of a 10*10 beam spot array with an uncertainty less than 100 nm. Additionally, the measurement uncertainty quantitatively matches the numerical analysis results. PMID- 23938444 TI - The higher the better? Interval training intensity in coronary heart disease. AB - OBJECTIVES: Peak oxygen uptake (VO2 peak) increases more after high intensity interval training compared to isocaloric moderate exercise in patients with coronary heart disease (CHD). We assessed the impact of exercise intensity during high intensity intervals on the increase in VO2 peak. DESIGN/METHODS: We included 112 patients with coronary heart disease who had participated in randomized trials of interval training consisting of four times four minutes intervals at 85 95% of heart rate maximum (HRmax) for 12 weeks. Exercise intensity was calculated for each patient using HR during the two last minutes of each interval, expressed as percentage of HRmax. We used a univariate general linear model with VO2 peak increase as the dependent variable and percentage of HRmax, age, number of exercise sessions, and baseline VO2 peak as covariates. Exercise intensity was also divided into three categories; <88%, 88-92%, and >92% of HRmax, and these categories were used as a fixed factor in the model. RESULTS: VO2 peak increased by 3.9 (SD 3.1) mL kg(-1)min(-1), equal to 11.9% after 23.4 exercise sessions. Percentage of HRmax had a significant effect on increase in VO2 peak, both as a continuous (p=0.019) and categorical variable (p=0.020). The estimated marginal means and 95% confidence intervals of the increase in VO2 peak for the three intensity categories were 3.1 (2.0, 4.2), 3.6 (2.8, 4.4), and 5.2 (4.1, 6.3) for the <88%, the 88-92%, and the >92% category, respectively. CONCLUSIONS: Even within the high intensity training zone, exercise intensity was an important determinant for improving VO2 peak in patients with coronary heart disease. PMID- 23938445 TI - A novel solid-state electrochemiluminescence sensor for the determination of hydrogen peroxide based on an Au nanocluster-silica nanoparticle nanocomposite. AB - A gold nanocluster@bovine serum albumin-silica nanoparticle composite has been synthesized and used for the solid-state electrochemiluminescence (ECL) sensing of hydrogen peroxide. The ECL characteristics have also been studied. PMID- 23938446 TI - Impact of carbonaceous materials in soil on the transport of soil-bound PAHs during rainfall-runoff events. AB - Polycyclic Aromatic Hydrocarbons (PAHs) transported from contaminated soils by surface runoff pose significant risk for aquatic ecosystems. Based on a rainfall runoff simulation experiment, this study investigated the impact of carbonaceous materials (CMs) in soil, identified by organic petrology analysis, on the transport of soil-bound PAHs under rainfall conditions. The hypothesis that composition of soil organic matter significantly impacts the enrichment and transport of PAHs was proved. CMs in soil, varying significantly in content, mobility and adsorption capacity, act differently on the transport of PAHs. Anthropogenic CMs like black carbon (BC) largely control the transport, as PAHs may be preferentially attached to them. Eventually, this study led to a rethink of the traditional enrichment theory. An important implication is that CMs in soil have to be explicitly considered to appropriately model the nonpoint source pollution of PAHs (possibly other hydrophobic chemicals as well) and assess its environmental risk. PMID- 23938447 TI - Photosynthetic response of early and late leaves of white birch (Betula platyphylla var. japonica) grown under free-air ozone exposure. AB - Betula platyphylla var. japonica (white birch) has heterophyllous leaves (i.e., early and late leaves) and is a typical pioneer tree species in northern Japan. Seedlings of white birch were exposed to ozone during two growing seasons, and measurements were carried out in the second year. Early leaves did not show an ozone-induced reduction in photosynthesis because of lower stomatal conductance resulting in higher avoidance capacity for ozone-induced stress. Also, an ozone related increase in leaf nitrogen content may partly contribute to maintain the photosynthetic capacity in early leaves under elevated ozone in autumn. On the other hand, late leaves showed an ozone-induced decline of photosynthesis and early defoliation of leaves occurred. Also, smaller leaf size and higher stomatal density in late leaves were observed under elevated ozone. Differences in stress resistance to ozone may be related to differing functional roles of early and late leaves for birch species. PMID- 23938448 TI - Complexation with dissolved organic matter and mobility control of heavy metals in the rhizosphere of hyperaccumulator Sedum alfredii. AB - The complexation of Zn, Cd and Pb with dissolved organic matter (DOM) in the rhizosphere of hyperaccumulating ecotype (HE) and a non-hyperaccumulating ecotype (NHE) of Sedum alfredii was measured using resin equilibration method. After the growth of HE S. alfredii, the rhizosphere soil pH was reduced by 0.27-0.33 units, due to enhanced DOM derived from root exudation. For both ecotypes of S. alfredii, the fraction of free metal as a percentage of soluble metal varied from 22.1 to 42.5% for Zn(2+), from 8.1 to 15.5% for Cd(2+), and from 4.5 to 10.4% for Pb(2+). Resin equilibration experiment results indicated that HE-DOM had greater ability to form complexes with Zn, Cd and Pb than NHE-DOM, Visual MINTEQ model gave excellent predictions of the complexation of Zn and Cd by DOM (R(2) > 0.97). DOM in the rhizosphere of HE S. alfredii could significantly increase metal mobility through the formation of soluble DOM-metal complexes. PMID- 23938449 TI - Mercury concentrations in human placenta, umbilical cord, cord blood and amniotic fluid and their relations with body parameters of newborns. AB - Studies were conducted on samples taken from giving birth women (n = 40) living in Poland, representing three age groups: 19-25, 26-30 and 31-38 years old. Mercury concentrations were measured with CV-AAS in placenta, umbilical cord, cord blood and amniotic fluid. The placentas weight did not exceed the 750 g value and was heavier than 310 g. Mean values of Hg concentrations in blood, placenta and umbilical cord were similar (c.a. 9 MUg/g). High levels of mercury were noted in cord blood which in 75% of all observations exceeded (up to 17 MUg/L) the safe dose set by US EPA (5.8 MUg/L). No statistically significant differences in medium level of Hg in all the studied tissues among age groups of women were observed. Positive correlations between Hg concentrations in placenta and umbilical cord and cord blood were revealed as well as some negative ones between mercury concentrations and pregnancy parameters. PMID- 23938450 TI - Comparison of earthworm responses to petroleum hydrocarbon exposure in aged field contaminated soil using traditional ecotoxicity endpoints and 1H NMR-based metabolomics. AB - (1)H NMR metabolomics and conventional ecotoxicity endpoints were used to examine the response of earthworms exposed to petroleum hydrocarbons (PHCs) in soil samples collected from a site that was contaminated with crude oil from a pipeline failure in the mid-1990s. The conventional ecotoxicity tests showed that the soils were not acutely toxic to earthworms (average survival >= 90%), but some soil samples impaired reproduction endpoints by >50% compared to the field control soil. Additionally, metabolomics revealed significant relationships between earthworm metabolic profiles (collected after 2 or 14 days of exposure) and soil properties including soil PHC concentration. Further comparisons by partial least squares regression revealed a significant relationship between the earthworm metabolomic data (collected after only 2 or 14 days) and the reproduction endpoints (measured after 63 days). Therefore, metabolomic responses measured after short exposure periods may be predictive of chronic, ecologically relevant toxicity endpoints for earthworms exposed to soil contaminants. PMID- 23938451 TI - Liver disease: Quest to find new mouse models for liver diseases. PMID- 23938453 TI - IBD: Activity of IBD during pregnancy. AB - Women worry that their IBD will flare during pregnancy. A prospective multicentre study from Europe has now demonstrated that although women with Crohn's disease do not have an increased risk of relapse during pregnancy, women with ulcerative colitis are at increased risk of relapse, both during pregnancy and postpartum. PMID- 23938452 TI - Chemopreventive strategies in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer. The incidence and mortality of HCC are increasing in most Western countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Chemopreventive strategies aimed at decreasing the risk or delaying the onset of HCC are needed. Universal immunization against HBV and antiviral therapy against HBV and HCV in patients with established disease has consistently been associated with reduced HCC risk, especially in patients who achieve sustained virologic response. However, the cost-effectiveness of antiviral therapy for primary HCC prevention is not known. Several commonly prescribed medications seem promising as chemopreventive agents against HCC, including statins, antidiabetic medications and aspirin. Dietary agents such as coffee, vitamin E and fish oil as well as phytochemicals might also be associated with reduced risk of HCC. Though randomized controlled trials are ideally needed to firmly establish efficacy, such chemoprevention trials are logistically and ethically challenging. Well designed, prospective, population-based cohort studies might provide the best evidence for chemopreventive efficacy of these agents. PMID- 23938455 TI - Multiplex picodroplet digital PCR to detect KRAS mutations in circulating DNA from the plasma of colorectal cancer patients. AB - BACKGROUND: Multiplex digital PCR (dPCR) enables noninvasive and sensitive detection of circulating tumor DNA with performance unachievable by current molecular-detection approaches. Furthermore, picodroplet dPCR facilitates simultaneous screening for multiple mutations from the same sample. METHODS: We investigated the utility of multiplex dPCR to screen for the 7 most common mutations in codons 12 and 13 of the KRAS (Kirsten rat sarcoma viral oncogene homolog) oncogene from plasma samples of patients with metastatic colorectal cancer. Fifty plasma samples were tested from patients for whom the primary tumor biopsy tissue DNA had been characterized by quantitative PCR. RESULTS: Tumor characterization revealed that 19 patient tumors had KRAS mutations. Multiplex dPCR analysis of the plasma DNA prepared from these samples identified 14 samples that matched the mutation identified in the tumor, 1 sample contained a different KRAS mutation, and 4 samples had no detectable mutation. Among the tumor samples that were wild type for KRAS, 2 KRAS mutations were identified in the corresponding plasma samples. Duplex dPCR (i.e., wild-type and single-mutation assay) was also used to analyze plasma samples from patients with KRAS-mutated tumors and 5 samples expected to contain the BRAF (v-raf murine sarcoma viral oncogene homolog B) V600E mutation. The results for the duplex analysis matched those for the multiplex analysis for KRAS-mutated samples and, owing to its higher sensitivity, enabled detection of 2 additional samples with low levels of KRAS-mutated DNA. All 5 samples with BRAF mutations were detected. CONCLUSIONS: This work demonstrates the clinical utility of multiplex dPCR to screen for multiple mutations simultaneously with a sensitivity sufficient to detect mutations in circulating DNA obtained by noninvasive blood collection. PMID- 23938456 TI - Current methods for fluorescence-based universal sequence-dependent detection of nucleic acids in homogenous assays and clinical applications. AB - BACKGROUND: Specific and sensitive nucleic acid (NA) testing in research and clinical diagnostics is usually performed by use of labeled oligonucleotide probes. However, the use of target-specific fluorogenic probes increases the cost of analysis. Therefore, universal sequence-dependent (USD) NA detection methods have been developed to facilitate cost-effective target detection using standardized reagents. CONTENT: We provide a comprehensive review of the current methods for fluorescence-based USD NA detection. Initially, we focus on the emergence of these methods as a means to overcome the shortcomings of common NA detection methods, such as hydrolysis probes and molecular beacons. Thereafter, we provide a critical evaluation of the individual detection methods. These methods include (a) target amplification with bipartite primers introducing a universal detection tag to the amplicon (UniPrimer PCR, universal fluorescence energy transfer probe PCR, attached universal duplex probe PCR, and universal strand displacement amplification) or combined with bipartite probes comprising a universal detection region (mediator probe PCR, universal strand displacement amplification, universal quenching probe PCR) and (b) amplification-independent assays employing either a universal variant of the invader assay or universal NA hybridization sensors. We discuss differences between the methods and review clinical applications. SUMMARY: The current methods for USD NA testing are cost effective and flexible and have concordant analytical performance in comparison with common probe-based techniques. They can detect any target sequence by the simple use of a label-free, low-cost primer or probe combined with a universal fluorogenic reporter. The methods differ in the number of target specificities, capability of multiplexing, and incubation requirements (isothermal/thermocycling). Extensive clinical applications comprise detection of single-nucleotide polymorphisms, study of gene expression, in situ PCR, and quantification of pathogen load. PMID- 23938458 TI - Novel 3D ultrasound image-based biomarkers based on a feature selection from a 2D standardized vessel wall thickness map: a tool for sensitive assessment of therapies for carotid atherosclerosis. AB - With the advent of new therapies and management strategies for carotid atherosclerosis, there is a parallel need for measurement tools or biomarkers to evaluate the efficacy of these new strategies. 3D ultrasound has been shown to provide reproducible measurements of plaque area/volume and vessel wall volume. However, since carotid atherosclerosis is a focal disease that predominantly occurs at bifurcations, biomarkers based on local plaque change may be more sensitive than global volumetric measurements in demonstrating efficacy of new therapies. The ultimate goal of this paper is to develop a biomarker that is based on the local distribution of vessel-wall-plus-plaque thickness change (VWT Change) that has occurred during the course of a clinical study. To allow comparison between different treatment groups, the VWT-Change distribution of each subject must first be mapped to a standardized domain. In this study, we developed a technique to map the 3D VWT-Change distribution to a 2D standardized template. We then applied a feature selection technique to identify regions on the 2D standardized map on which subjects in different treatment groups exhibit greater difference in VWT-Change. The proposed algorithm was applied to analyse the VWT-Change of 20 subjects in a placebo-controlled study of the effect of atorvastatin (Lipitor). The average VWT-Change for each subject was computed (i) over all points in the 2D map and (ii) over feature points only. For the average computed over all points, 97 subjects per group would be required to detect an effect size of 25% that of atorvastatin in a six-month study. The sample size is reduced to 25 subjects if the average were computed over feature points only. The introduction of this sensitive quantification technique for carotid atherosclerosis progression/regression would allow many proof-of-principle studies to be performed before a more costly and longer study involving a larger population is held to confirm the treatment efficacy. PMID- 23938457 TI - Oral fluid cannabinoids in chronic cannabis smokers during oral delta9 tetrahydrocannabinol therapy and smoked cannabis challenge. AB - BACKGROUND: Oral Delta(9)-tetrahydrocannabinol (THC) is effective for attenuating cannabis withdrawal and may benefit treatment of cannabis use disorders. Oral fluid (OF) cannabinoid testing, increasing in forensic and workplace settings, could be valuable for monitoring during cannabis treatment. METHODS: Eleven cannabis smokers resided on a closed research unit for 51 days and received daily 0, 30, 60, and 120 mg of oral THC in divided doses for 5 days. There was a 5-puff smoked cannabis challenge on the fifth day. Each medication session was separated by 9 days of ad libitum cannabis smoking. OF was collected the evening before and throughout oral THC sessions and analyzed by 2-dimensional GC-MS for THC, cannabidiol (CBD), cannabinol (CBN), 11-hydroxy-THC (11-OH-THC), and 11-nor-9 carboxy-THC (THCCOOH). RESULTS: During all oral THC administrations, THC OF concentrations decreased to <= 78.2, 33.2, and 1.4 MUg/L by 24, 48, and 72 h, respectively. CBN also decreased over time, with concentrations 10-fold lower than THC, with none detected beyond 69 h. CBD and 11-OH-THC were rarely detected, only within 19 and 1.6 h after smoking, respectively. THCCOOH OF concentrations were dose dependent and increased over time during 120-mg THC dosing. After cannabis smoking, THC, CBN, and THCCOOH concentrations showed a significant dose effect and decreased significantly over time. CONCLUSIONS: Oral THC dosing significantly affected OF THCCOOH but minimally contributed to THC OF concentrations; prior ad libitum smoking was the primary source of THC, CBD, and CBN. Higher cannabinoid concentrations following active oral THC administrations vs placebo suggest a compensatory effect of THC tolerance on smoking topography. PMID- 23938459 TI - A convenient synthesis of quinolizinium salts through Rh(III) or Ru(II)-catalyzed C-H bond activation of 2-alkenylpyridines. AB - An efficient synthesis of quinolizinium salts from 2-vinylpyridines and alkynes via Rh(III) or Ru(II)-catalyzed C-H activation and annulation reaction is described. A possible mechanism involving pyridine assisted vinylic ortho-C-H activation, alkyne insertion and reductive elimination is proposed. PMID- 23938461 TI - A bio-mimetic approach to DNA photoprotection. PMID- 23938460 TI - Complement factor H: a biomarker for progression of cutaneous squamous cell carcinoma. AB - The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing globally. We have studied the expression of complement system components in cSCC. Expression profiling of cSCC cell lines (n=8) and normal human epidermal keratinocytes (n=5) with Affymetrix and quantitative real-time PCR (qPCR) revealed upregulation of complement factor H (CFH) and factor H-like protein-1 (FHL-1) in cSCC cell lines. The expression of CFH and FHL-1 mRNAs was also significantly higher in cSCC tumors (n=6) than in normal skin (n=11). Analysis of CFH and FHL-1 expression in vivo in invasive cSCCs (n=65), in situ cSCCs (n=38), and premalignant lesions (actinic keratoses, n=37) by immunohistochemistry showed that they were specifically expressed by tumor cells in cSCCs and the staining intensity was stronger in cSCCs than in in situ cSCCs and actinic keratoses. The expression of CFH by cSCC cells was upregulated by IFN-gamma and the basal CFH and FHL-1 expression was dependent on extracellular signal-regulated kinase (ERK)1/2 and p38 signaling. Knockdown of CFH and FHL-1 expression inhibited proliferation and migration of cSCC cells and inhibited basal ERK1/2 activation. These results provide evidence for a role of CFH and FHL-1 in cSCC progression and identify them as progression markers and potential therapeutic targets in SCCs of skin. PMID- 23938462 TI - IL-18 regulates melanoma VLA-4 integrin activation through a Hierarchized sequence of inflammatory factors. AB - Very late antigen-4 (VLA-4) is frequently overexpressed on melanoma cells contributing to inflammation-dependent metastasis. Melanoma cell adhesion to endothelium via VLA-4-vascular cell adhesion molecule-1 (VCAM-1) interaction was used to study VLA-4 activation during melanoma cell response to inflammation. Cooperation among major inflammatory mediators was analyzed in melanoma cells exposed to single inflammatory factors in the presence of inhibitors for other assayed mediators. A stepwise cascade of hierarchized molecules heterogeneously made and used during melanoma response to IL-18, induced hydrogen peroxide (H2O2), in turn activating VLA-4 and melanoma cell adhesion to endothelium. The cascade involved prostaglandin E2 (PGE2) production from melanoma induced by IL 18-dependent tumor necrosis factor-alpha (TNFalpha); next, PGE2-induced IL-1beta via vascular endothelial growth factor (VEGF) secretion, which in turn induced VLA-4 activation via cyclooxygenase 2-dependent H2O2. This sequence operated in IL-18R/VLA-4/VEGF-expressing murine (B16) and human (A375 and 883) melanomas, but not in those without this phenotype. Separation of active VLA-4-expressing B16 melanoma cells through immobilized VCAM-1 verified their higher IL 18R/TNFR1/VEGFR2 expression and metastatic growth than inactive VLA-4-expressing cells. However, cooperation among melanoma cell sub-populations with heterogeneous cytokine receptor levels may occur through VLA-4-stimulating factors, leading to intratumoral amplification of metastatic potential. Therefore, expression of the VLA-4-stimulating factor sequence may help to predict melanoma prometastatic risk, and offers therapeutic targets for metastatic melanoma deactivation through VLA-4 activation blockade. PMID- 23938463 TI - A somatic mutation of the KEAP1 gene in malignant melanoma is involved in aberrant NRF2 activation and an increase in intrinsic drug resistance. PMID- 23938464 TI - Patterns and predictors of changes in active commuting over 12 months. AB - OBJECTIVE: To assess the predictors of uptake and maintenance of walking and cycling, and of switching to the car as the usual mode of travel, for commuting. METHODS: 655 commuters in Cambridge, UK reported all commuting trips using a seven-day recall instrument in 2009 and 2010. Individual and household characteristics, psychological measures relating to car use and environmental conditions on the route to work were self-reported in 2009. Objective environmental characteristics were assessed using Geographical Information Systems. Associations between uptake and maintenance of commuting behaviours and potential predictors were modelled using multivariable logistic regression. RESULTS: Mean within-participant changes in commuting were relatively small (walking: +3.0 min/week, s.d.=66.7; cycling: -5.3 min/week, s.d.=74.7). Self reported and objectively-assessed convenience of public transport predicted uptake of walking and cycling respectively, while convenient cycle routes predicted uptake of cycling and a pleasant route predicted maintenance of walking. A lack of free workplace parking predicted uptake of walking and alternatives to the car. Less favourable attitudes towards car use predicted continued use of alternatives to the car. CONCLUSIONS: Improving the convenience of walking, cycling and public transport and limiting the availability of workplace car parking may promote uptake and maintenance of active commuting. PMID- 23938465 TI - Health impact assessment of increasing public transport and cycling use in Barcelona: a morbidity and burden of disease approach. AB - OBJECTIVE: Quantify the health impacts on morbidity of reduced car trips and increased public transport and cycling trips. METHODS: A health impact assessment study of morbidity outcomes related to replacing car trips in Barcelona metropolitan (3,231,458 inhabitants). Through 8 different transport scenarios, the number of cases of disease or injuries related to physical activity, particulate matter air pollution <2.5 MUm (PM2.5) and traffic incidents in travelers was estimated. We also estimate PM2.5 exposure and cases of disease in the general population. RESULTS: A 40% reduction in long-duration car trips substituted by public transport and cycling trips resulted in annual reductions of 127 cases of diabetes, 44 of cardiovascular diseases, 30 of dementia, 16 minor injuries, 0.14 major injuries, 11 of breast cancer and 3 of colon-cancer, amounting to a total reduction of 302 Disability Adjusted Life Years per year in travelers. The reduction in PM2.5 exposure in the general population resulted in annual reductions of 7 cases of low birth weight, 6 of preterm birth, 1 of cardiovascular disease and 1 of lower respiratory tract infection. CONCLUSIONS: Transport policies to reduce car trips could produce important health benefits in terms of reduced morbidity, particularly for those who take up active transportation. PMID- 23938466 TI - A low-cost banding device for oesophageal varices using Foley catheters. AB - Our institution has devised a low cost method of banding oesophageal varices by loading cut Foley catheters on to a banding apparatus. PMID- 23938471 TI - Does boat traffic cause displacement of fish in estuaries? AB - Estuaries are increasingly under threat from a variety of human impacts. Recreational and commercial boat traffic in urban areas may represent a significant disturbance to fish populations and have particularly adverse effects in spatially restricted systems such as estuaries. We examined the effects of passing boats on the abundance of different sized fish within the main navigation channel of an estuary using high resolution sonar (DIDSON). Both the smallest (100-300 mm) and largest (>501 mm) size classes had no change in their abundance following the passage of boats. However, a decrease in abundance of mid-sized fish (301-500 mm) occurred following the passage of boats. This displacement may be attributed to a number of factors including noise, bubbles and the rapidly approaching object of the boat itself. In highly urbanised estuarine systems, regular displacement by boat traffic has the potential to have major negative population level effects on fish assemblages. PMID- 23938467 TI - Linking spermatid ribonucleic acid (RNA) binding protein and retrogene diversity to reproductive success. AB - Spermiogenesis is a postmeiotic process that drives development of round spermatids into fully elongated spermatozoa. Spermatid elongation is largely controlled post-transcriptionally after global silencing of mRNA synthesis from the haploid genome. Here, rats that differentially express EGFP from a lentiviral transgene during early and late steps of spermiogenesis were used to flow sort fractions of round and elongating spermatids. Mass-spectral analysis of 2D gel protein spots enriched >3-fold in each fraction revealed a heterogeneous RNA binding proteome (hnRNPA2/b1, hnRNPA3, hnRPDL, hnRNPK, hnRNPL, hnRNPM, PABPC1, PABPC4, PCBP1, PCBP3, PTBP2, PSIP1, RGSL1, RUVBL2, SARNP2, TDRD6, TDRD7) abundantly expressed in round spermatids prior to their elongation. Notably, each protein within this ontology cluster regulates alternative splicing, sub-cellular transport, degradation and/or translational repression of mRNAs. In contrast, elongating spermatid fractions were enriched with glycolytic enzymes, redox enzymes and protein synthesis factors. Retrogene-encoded proteins were over represented among the most abundant elongating spermatid factors identified. Consistent with these biochemical activities, plus corresponding histological profiles, the identified RNA processing factors are predicted to collectively drive post-transcriptional expression of an alternative exome that fuels finishing steps of sperm maturation and fitness. PMID- 23938472 TI - Surface enhanced Raman scattering based sensitive detection of histone demethylase activity using a formaldehyde-selective reactive probe. AB - A novel surface enhanced Raman scattering (SERS) based assay using a formaldehyde selective reactive probe for sensitive detection of activity of histone demethylases (HDMs) by direct observation of by-product formaldehyde was reported. PMID- 23938468 TI - A proteomic perspective of inbuilt viral protein regulation: pUL46 tegument protein is targeted for degradation by ICP0 during herpes simplex virus type 1 infection. AB - Much like the host cells they infect, viruses must also regulate their life cycles. Herpes simples virus type 1 (HSV-1), a prominent human pathogen, uses a promoter-rich genome in conjunction with multiple viral trans-activating factors. Following entry into host cells, the virion-associated outer tegument proteins pUL46 and pUL47 act to increase expression of viral immediate-early (alpha) genes, thereby helping initiate the infection life cycle. Because pUL46 has gone largely unstudied, we employed a hybrid mass spectrometry-based approach to determine how pUL46 exerts its functions during early stages of infection. For a spatio-temporal characterization of pUL46, time-lapse microscopy was performed in live cells to define its dynamic localization from 2 to 24 h postinfection. Next, pUL46-containing protein complexes were immunoaffinity purified during infection of human fibroblasts and analyzed by mass spectrometry to investigate virus-virus and virus-host interactions, as well as post-translational modifications. We demonstrated that pUL46 is heavily phosphorylated in at least 23 sites. One phosphorylation site matched the consensus 14-3-3 phospho-binding motif, consistent with our identification of 14-3-3 proteins and host and viral kinases as specific pUL46 interactions. Moreover, we determined that pUL46 specifically interacts with the viral E3 ubiquitin ligase ICP0. We demonstrated that pUL46 is partially degraded in a proteasome-mediated manner during infection, and that the catalytic activity of ICP0 is responsible for this degradation. This is the first evidence of a viral protein being targeted for degradation by another viral protein during HSV-1 infection. Together, these data indicate that pUL46 levels are tightly controlled and important for the temporal regulation of viral gene expression throughout the virus life cycle. The concept of a structural virion protein, pUL46, performing nonstructural roles is likely to reflect a theme common to many viruses, and a better understanding of these functions will be important for developing therapeutics. PMID- 23938473 TI - Optimized graded index two-mode optical fiber with low DMD, large A(eff) and low bending loss. AB - An optimized two-mode optical fiber (TMF) with the graded index (GI) profile is designed and fabricated. We clarify an appropriate region of GI-TMF satisfying DMD = 0 ps/km, the large effective area A(eff), and the low bending loss for LP(11) at 1550 nm. According to our fiber design, GI-TMF is successfully fabricated to have the large effective area A(eff) of 150 MUm(2) for LP(01) mode, and low DMD below 36 ps/km including zero in the C-band. We expect that our design GI-TMF is suitable for MDM and can reduce MIMO-DSP complexity. PMID- 23938470 TI - Estimation of effective imaging dose for kilovoltage intratreatment monitoring of the prostate position during cancer radiotherapy. AB - Kilovoltage intratreatment monitoring (KIM) is a novel real-time localization modality where the tumor position is continuously measured during intensity modulated radiation therapy (IMRT) or intensity modulated arc therapy (IMAT) by a kilovoltage (kV) x-ray imager. Adding kV imaging during therapy adds radiation dose. The additional effective dose is quantified for prostate radiotherapy and compared to dose from other localization modalities. The software PCXMC 2.0 was used to calculate the effective dose delivered to a phantom as a function of imager angle and field size for a Varian On-Board Imager. The average angular effective dose was calculated for a field size of 6 cm * 6 cm. The average angular effective dose was used in calculations for different treatment scenarios. Treatment scenarios considered were treatment type and fractionation. For all treatment scenarios, (i.e. conventionally fractionated and stereotactic body radiotherapy (SBRT), IMRT and IMAT), the total KIM dose at 1 Hz ranged from 2-10 mSv. This imaging dose is less than the Navotek radioactive implant dose (64 mSv) and a standard SBRT cone beam computed tomography pretreatment scan dose (22 mSv) over an entire treatment regime. KIM delivers an acceptably low effective dose for daily use as a real-time image-guidance method for prostate radiotherapy. PMID- 23938469 TI - Regulation of stress-inducible phosphoprotein 1 nuclear retention by protein inhibitor of activated STAT PIAS1. AB - Stress-inducible phosphoprotein 1 (STI1), a cochaperone for Hsp90, has been shown to regulate multiple pathways in astrocytes, but its contributions to cellular stress responses are not fully understood. We show that in response to irradiation-mediated DNA damage stress STI1 accumulates in the nucleus of astrocytes. Also, STI1 haploinsufficiency decreases astrocyte survival after irradiation. Using yeast two-hybrid screenings we identified several nuclear proteins as STI1 interactors. Overexpression of one of these interactors, PIAS1, seems to be specifically involved in STI1 nuclear retention and in directing STI1 and Hsp90 to specific sub-nuclear regions. PIAS1 and STI1 co-immunoprecipitate and PIAS1 can function as an E3 SUMO ligase for STI. Using mass spectrometry we identified five SUMOylation sites in STI1. A STI1 mutant lacking these five sites is not SUMOylated, but still accumulates in the nucleus in response to increased expression of PIAS1, suggesting the possibility that a direct interaction with PIAS1 could be responsible for STI1 nuclear retention. To test this possibility, we mapped the interaction sites between PIAS1 and STI1 using yeast-two hybrid assays and surface plasmon resonance and found that a large domain in the N terminal region of STI1 interacts with high affinity with amino acids 450-480 of PIAS1. Knockdown of PIAS1 in astrocytes impairs the accumulation of nuclear STI1 in response to irradiation. Moreover, a PIAS1 mutant lacking the STI1 binding site is unable to increase STI1 nuclear retention. Interestingly, in human glioblastoma multiforme PIAS1 expression is increased and we found a significant correlation between increased PIAS1 expression and STI1 nuclear localization. These experiments provide evidence that direct interaction between STI1 and PIAS1 is involved in the accumulation of nuclear STI1. This retention mechanism could facilitate nuclear chaperone activity. PMID- 23938474 TI - Light Sheet Tomography (LST) for in situ imaging of plant roots. AB - The production of crops capable of efficient nutrient use is essential for addressing the problem of global food security. The ability of a plant's root system to interact with the soil micro-environment determines how effectively it can extract water and nutrients. In order to assess this ability and develop the fast and cost effective phenotyping techniques which are needed to establish efficient root systems, in situ imaging in soil is required. To date this has not been possible due to the high density of scatterers and absorbers in soil or because other growth substrates do not sufficiently model the heterogeneity of a soil's microenvironment. We present here a new form of light sheet imaging with novel transparent soil containing refractive index matched particles. This imaging method does not rely on fluorescence, but relies solely on scattering from root material. We term this form of imaging Light Sheet Tomography (LST). We have tested LST on a range of materials and plant roots in transparent soil and gel. Due to the low density of root structures, i.e. relatively large spaces between adjacent roots, long-term monitoring of lettuce root development in situ with subsequent quantitative analysis was achieved. PMID- 23938475 TI - Electric field detection of phase-locked near-infrared pulses using photoconductive antenna. AB - We have demonstrated that a photoconductive antenna gated with 5-fs ultrashort laser pulses can detect electric field transients of near-infrared pulses at least up to 180 THz. Measured sensitivity spectrum of the antenna shows a good agreement with a simple calculation, demonstrating the promising capability of the antenna to near infrared spectroscopy. Using this setup, near-infrared time domain spectroscopy and characterization of phase controlled near-infrared pulses are demonstrated. Observed absorption spectrum of a polystyrene film and complex refractive index dispersion of a fused silica plate both agree well with those obtained by the conventional methods. PMID- 23938476 TI - Generation of high fidelity 62-fs, 7-nJ pulses at 1035 nm from a net normal dispersion Yb-fiber laser with anomalous dispersion higher-order-mode fiber. AB - Fiber oscillators operating in the normal dispersion regime allow generating high energy output pulses. The best stability of such oscillators is observed when the intracavity dispersion is close to zero. Intracavity dispersion compensation in such oscillators can be achieved using a higher-order mode fiber, which substantially reduces the higher order dispersion compared to all-normal dispersion oscillators or oscillators using intracavity gratings for dispersion compensation. Using this approach, we are able to obtain relatively high energy pulses, with high fidelity. Our modeling based on an analytic approach for oscillators operating in the normal dispersion regime predicts that at intermediate pulse energies an almost flat chirp can be obtained at the oscillator output enabling good pulse compression with a grating compressor close to Fourier limited duration. Here, we present a mode-locked ytterbium-doped fiber oscillator with a higher-order mode fiber operating in the net normal-dispersion regime, delivering 7.2 nJ pulses that can be dechirped down to 62 fs using a simple grating compressor. PMID- 23938477 TI - Investigation of the role of the lateral photo-Dember effect in the generation of terahertz radiation using a metallic mask on a semiconductor. AB - Pulses of coherent terahertz radiation can be efficiently generated by a lateral diffusion current after ultrafast generation of photo-carriers near a metal interface on the surface of a semiconductor, this is known as the lateral photo Dember effect. We investigate how the emission depends on the pump spot position, size, power and how it is affected by the application of an applied external bias. We study the role of the metallic mask and how it suppresses emission from the carriers diffusing under it due to a reduction of available radiation states both theoretically and experimentally. PMID- 23938478 TI - Arrays of recycled power TM polarized nano-antennas. AB - In recent years, plasmonic nano-antennas have been used in a wide range of applications in sensing, particle detection, imaging and Surface Enhanced Raman Scattering (SERS) detection. Also, arrays of nano-antennas have been recently developed to produce more directional radiation beams or to operate over a wide range of wavelengths. In this article, it is shown that small arrays of nano antennas can be created by recycling the power that flows through their antenna gaps. PMID- 23938479 TI - Mapping of phase singularities with spiral phase contrast microscopy. AB - In spiral phase contrast (SPC) microscopy the edge-enhancement is typically independent of the helicity of the phase vortex filter. Here we show that for layered specimens containing screw-dislocations, as are e.g. present in mica or some crystallized organic substances, the intensity distribution in the filtered image acquires a dependence on the rotational direction of the filter. This allows one to map the distribution of phase singularities in the topography of the sample, by taking the intensity difference between two images recorded with opposite handedness. For the demonstration of this feature in a microscopy set up, we encode the vortex filter as a binary off-axis hologram displayed on a spatial light modulator (SLM) placed in a Fourier plane. Using a binary grating, the diffraction efficiencies for the plus and minus first diffraction orders are equal, giving rise to two image waves which travel in different directions and are Fourier filtered with opposite helicity. The corresponding two images can be recorded simultaneously in two separate regions of the camera chip. This enables mapping of dislocations in the sample in a single camera exposure, as was demonstrated for various transparent samples. PMID- 23938480 TI - Tm-Ho co-doped all-fiber brand-range self-sweeping laser around 1.9 MUm. AB - We present a brand-range self-sweeping Tm-Ho co-doped fiber laser experimentally. The laser's center wavelength sweeps periodically around 1.9 MUm with self sweeping range of 4 nm ~17 nm, and the sweep rate can be changed in the range of 0.4 nm/s ~1.5 nm/s. The sweep range increases and the sweep rate declines when the pump power rises. PMID- 23938481 TI - Experimental setup for investigating silicon solid phase crystallization at high temperatures. AB - An experimental setup is presented to measure and interpret the solid phase crystallization of amorphous silicon thin films on glass at very high temperatures of about 800 degrees C. Molybdenum-SiO(2)-silicon film stacks were irradiated by a diode laser with a well-shaped top hat profile. From the relevant thermal and optical parameters of the system the temperature evolution can be calculated accurately. A time evolution of the laser power was applied which leads to a temperature constant in time in the center of the sample. Such a process will allow the observation and interpretation of solid phase crystallization in terms of nucleation and growth in further work. PMID- 23938482 TI - Spectral and lasing investigations of Yb:YSGG crystal. AB - We report on a systematic study of the absorption and emission spectral properties of (Yb(0.1)Y(0.9))(3)(Sc(1.5)Ga(0.5))Ga(3)O(12) (Yb:YSGG) crystals. The broad fluorescence spectral lines indicate great potential of Yb:YSGG for tunable and ultrafast laser applications. Efficient continuous-wave (cw) laser oscillation was also demonstrated at room temperature (RT), generating an output power of 6.11 W with an optical-to-optical efficiency of 64.2%, and a slope efficiency of 80.1% with respect to absorbed pump power. The laser emission spectrum shifts to shorter wavelengths as the transmission of the output coupler varies from 3% to 20%, a result that can be explained based on the effective gain cross-sections of Yb:YSGG. PMID- 23938483 TI - Integrated temperature sensor based on an enhanced pyroelectric photonic crystal. AB - In this paper, temperature variations are detected thanks to an enhanced nano optical pyroelectric sensor. Sensing is obtained with the pyroelectric effect of lithium niobate (LN) in which, a suitable air-membrane photonic crystal cavity has been fabricated. The wavelength position of the cavity mode is tuned 11.5 nm for a temperature variation of only 32 degrees C. These results agree quite well with 3D-FDTD simulations that predict tunability of 12.5 nm for 32 degrees C. This photonic crystal temperature sensor shows a sensitivity of 0.359 nm/ degrees C for an active length of only ~5.2 MUm. PMID- 23938484 TI - Quantitative allocation of Bragg scattering effects in highly efficient OLEDs fabricated on periodically corrugated substrates. AB - Bragg scattering effects in bottom-emitting organic light-emitting diodes (OLEDs) grown on corrugated aluminum-doped zinc oxide electrodes are analyzed. Periodic corrugation is introduced by structuring the oxide electrode via UV laser ablation, a process that enables flexible adjustment of the period and height of corrugation. We demonstrate that fabrication of stable and electrically efficient OLEDs on these rough substrates is feasible. Sharp spectral features are superimposed onto the broad emission spectra of the OLEDs, providing clear evidence for Bragg scattering of light from guided modes into the air cone. Theoretical analysis based on an emissive dipole model and conservation of momentum considerations allows a quantitative description of scattering and the associated dispersion relations. PMID- 23938485 TI - Ultra-compact low loss polarization insensitive silicon waveguide splitter. AB - We observe that the cascaded typical Y junctions will introduce unwanted periodic fringes over the spectrum in practical systems when they link with multimode waveguides. To solve the problem, we design and experimentally demonstrate a wavelength insensitive multimode interferometer (MMI) based 3-dB splitter which has all the merits of Y-splitters such as polarization insensitivity and ultra compactness. The splitter has a footprint of 1.5 * 1.8 um(2), nearly one order smaller than the previously reported MMI splitters. The measured excess losses for TE and TM modes at telecom wavelength are as low as -0.11 dB and -0.18 dB respectively. PMID- 23938486 TI - Experimental validation of LIFT for estimation of low-order modes in low-flux wavefront sensing. AB - Laser Tomographic and Multi-Conjugate Adaptive Optics systems rely on natural guide stars to sense low order aberrations (tip/tilt and focus). LIFT is a novel focal plane wavefront sensor (WFS), performing a maximum likelihood phase retrieval on a single image, with better sensitivity than a 2 * 2 Hartmann-Shack WFS. Its performance for the estimation of tip/tilt and focus is similar to a pyramid WFS without modulation, but with a simpler set-up. We present here the LIFT concept and associated data processing, as well as experimental results. We validate the estimation of tip/tilt and focus, with monochromatic and large bandwidth light, and verify the low noise sensitivity predicted by theory. PMID- 23938487 TI - Spectral binning for mitigation of polarization mode dispersion artifacts in catheter-based optical frequency domain imaging. AB - Polarization mode dispersion (PMD) has been recognized as a significant barrier to sensitive and reproducible birefringence measurements with fiber-based, polarization-sensitive optical coherence tomography systems. Here, we present a signal processing strategy that reconstructs the local retardation robustly in the presence of system PMD. The algorithm uses a spectral binning approach to limit the detrimental impact of system PMD and benefits from the final averaging of the PMD-corrected retardation vectors of the spectral bins. The algorithm was validated with numerical simulations and experimental measurements of a rubber phantom. When applied to the imaging of human cadaveric coronary arteries, the algorithm was found to yield a substantial improvement in the reconstructed birefringence maps. PMID- 23938488 TI - Directional emission of dielectric disks with a finite scatterer in the THz regime. AB - In the Terahertz (THz) domain, we investigate both numerically and experimentally the directional emission of whispering gallery mode resonators that are perturbed by a small scatterer in the vicinity of the resonators rim. We determine quality factor degradation, the modal structure and the emission direction for various geometries. We find that scatterers do allow for directional emission without destroying the resonator's quality factor. This finding allows for new geometries and outcoupling scenarios for active whispering gallery mode structures such as quantum cascade lasers and passive resonators such as evanescent sensors. The experimental results agree well with finite difference time domain simulations. PMID- 23938489 TI - An optically tunable wideband optoelectronic oscillator based on a bandpass microwave photonic filter. AB - An optoelectronic oscillator (OEO) with wideband frequency tunability and stable output based on a bandpass microwave photonic filter (MPF) has been proposed and experimentally demonstrated. Realized by cascading a finite impulse response (FIR) filter and an infinite impulse response (IIR) filter together, the tunable bandpass MPF successfully replaces the narrowband electrical bandpass filter in a conventional single-loop OEO and serves as the oscillating frequency selector. The FIR filter is based on a tunable multi-wavelength laser and dispersion compensation fiber (DCF) while the IIR filter is simply based on an optical loop. Utilizing a long length of DCF as the dispersion medium for the FIR filter also provides a long delay line for the OEO feedback cavity and as a result, optical tuning over a wide frequency range can be achieved without sacrificing the quality of the generated signal. By tuning the wavelength spacing of the multi wavelength laser, the oscillation frequency can be tuned from 6.88 GHz to 12.79 GHz with an average step-size of 0.128 GHz. The maximum frequency drift of the generated 10 GHz signal is observed to be 1.923 kHz over 1 hour and its phase noise reaches the -112 dBc/Hz limit of our measuring equipment at 10 kHz offset frequency. PMID- 23938490 TI - Bipolar optical pulse coding for performance enhancement in BOTDA sensors. AB - A pump signal based on bipolar pulse coding and single-sideband suppressed carried (SSB-SC) modulation is proposed for Brillouin optical time-domain analysis (BOTDA) sensors. Making a sequential use of the Brillouin gain and loss spectra, the technique is experimentally validated using bipolar complementary correlation Golay codes along a 100 km-long fiber and 2 m spatial resolution, fully resolving a 2 m hot-spot at the end of the sensing fiber with no distortion introduced by the decoding algorithm. Experimental results, in good agreement with the theory, indicate that bipolar Golay codes provide a higher signal-to noise ratio enhancement and stronger robustness to pump depletion in comparison to optimum unipolar pulse codes known for BOTDA sensing. PMID- 23938491 TI - Short-range optical air data measurements for aircraft control using rotational Raman backscatter. AB - A first laboratory prototype of a novel concept for a short-range optical air data system for aircraft control and safety was built. The measurement methodology was introduced in [Appl. Opt. 51, 148 (2012)] and is based on techniques known from lidar detecting elastic and Raman backscatter from air. A wide range of flight-critical parameters, such as air temperature, molecular number density and pressure can be measured as well as data on atmospheric particles and humidity can be collected. In this paper, the experimental measurement performance achieved with the first laboratory prototype using 532 nm laser radiation of a pulse energy of 118 mJ is presented. Systematic measurement errors and statistical measurement uncertainties are quantified separately. The typical systematic temperature, density and pressure measurement errors obtained from the mean of 1000 averaged signal pulses are small amounting to < 0.22 K, < 0.36% and < 0.31%, respectively, for measurements at air pressures varying from 200 hPa to 950 hPa but constant air temperature of 298.95 K. The systematic measurement errors at air temperatures varying from 238 K to 308 K but constant air pressure of 946 hPa are even smaller and < 0.05 K, < 0.07% and < 0.06%, respectively. A focus is put on the system performance at different virtual flight altitudes as a function of the laser pulse energy. The virtual flight altitudes are precisely generated with a custom-made atmospheric simulation chamber system. In this context, minimum laser pulse energies and pulse numbers are experimentally determined, which are required using the measurement system, in order to meet measurement error demands for temperature and pressure specified in aviation standards. The aviation error margins limit the allowable temperature errors to 1.5 K for all measurement altitudes and the pressure errors to 0.1% for 0 m and 0.5% for 13000 m. With regard to 100-pulse-averaged temperature measurements, the pulse energy using 532 nm laser radiation has to be larger than 11 mJ (35 mJ), regarding 1-sigma (3-sigma) uncertainties at all measurement altitudes. For 100-pulse-averaged pressure measurements, the laser pulse energy has to be larger than 95 mJ (355 mJ), respectively. Based on these experimental results, the laser pulse energy requirements are extrapolated to the ultraviolet wavelength region as well, resulting in significantly lower pulse energy demand of 1.5 - 3 mJ (4-10 mJ) and 12-27 mJ (45-110 mJ) for 1-sigma (3-sigma) 100-pulse averaged temperature and pressure measurements, respectively. PMID- 23938492 TI - Growth and optical properties of nonlinear LuAl3(BO3)4 crystals. AB - The optical properties of pure LuAl(3)(BO(3))(4) (abbreviated as LuAB) crystals were investigated for the first time. Large UV-transparent LuAl(3)(BO(3))(4) crystals were grown by a high-temperature top-seeding method with Li(2)WO(4)O(7) B(2)O(3) as the flux. The refractive indices of LuAl(3)(BO(3))(4) at several wavelengths covering ultraviolet-visible and near-infrared regions were measured by the auto-collimation method. The parameters of Sellmeier's dispersion equation were determined from the experimental data. The phase-matching curve of second harmonic generation was measured. The nonlinear optical coefficient d(11) of LuAB crystal was determined to be 1.10 pm/V by a phase-matching method. The UV cut-off wavelength of the LuAl(3)(BO(3))(4) crystal was shorter than 190 nm. PMID- 23938493 TI - Second harmonic generation in a low-loss orientation-patterned GaAs waveguide. AB - The technology of low-loss orientation-patterned gallium arsenide (OP-GaAs) waveguided crystals was developed and realized by reduction of diffraction scattering on the waveguide pattern. The propagation losses in the OP-GaAs waveguide were estimated to be as low as 2.1 dB/cm, thus demonstrating the efficient second harmonic generation at 1621 nm under an external pumping. PMID- 23938494 TI - Probing timescales during back side ablation of Molybdenum thin films with optical and electrical measurement techniques. AB - In this study we present a new measurement technique to investigate the timescales of back side ablation of conductive films, using Molybdenum as an application example from photovoltaics. With ultrashort laser pulses at fluences below 0.6 J/cm(2), we ablate the Mo film in the shape of a fully intact Mo 'disc' from a transparent substrate. By monitoring the time-dependent current flow across a specifically developed test structure, we determine the time required for the lift-off of the disc. This value decreases with increasing laser fluence down to a minimum of 21 +/- 2 ns. Furthermore, we record trajectories of the discs using a shadowgraphic setup. Ablated discs escape with a maximum velocity of 150 +/- 5 m/s whereas droplets of Mo forming at the center of the disc can reach velocities up to 710 +/- 11 m/s. PMID- 23938495 TI - Multipolar effects on the dipolar polarizability of magneto-electric antennas. AB - We show the important role played by the multipolar coupling between the illuminating field and magneto-electric scatterers even in the small particle limit (lambda/10). A general multipolar method is presented which, for the case of planar non centrosymmetric particles, generates a simple expression for the polarizability tensor that directly links the dipolar moment to the incident field. The relevancy of this approach is demonstrated by comparing thoroughly the dipolar moments predicted by the method with full numerical calculations. PMID- 23938496 TI - Design and analysis of perfect terahertz metamaterial absorber by a novel dynamic circuit model. AB - Metamaterial terahertz absorbers composed of a frequency selective layer followed by a spacer and a metallic backplane have recently attracted great attention as a device to detect terahertz radiation. In this work, we present a quasistatic dynamic circuit model that can decently describe operational principle of metamaterial terahertz absorbers based on interference theory of reflected waves. The model comprises two series LC resonance components, one for resonance in frequency selective surface (FSS) and another for resonance inside the spacer. Absorption frequency is dominantly determined by the LC of FSS while the spacer LC changes slightly the magnitude and frequency of absorption. This model fits perfectly for both simulated and experimental data. By using this model, we study our designed absorber and we analyze the effect of changing in spacer thickness and metal conductivity on absorption spectrum. PMID- 23938497 TI - Narrow-band generation in random distributed feedback fiber laser. AB - Narrow-band emission of spectral width down to ~0.05 nm line-width is achieved in the random distributed feedback fiber laser employing narrow-band fiber Bragg grating or fiber Fabry-Perot interferometer filters. The observed line-width is ~10 times less than line-width of other demonstrated up to date random distributed feedback fiber lasers. The random DFB laser with Fabry-Perot interferometer filter provides simultaneously multi-wavelength and narrow-band (within each line) generation with possibility of further wavelength tuning. PMID- 23938498 TI - Picosecond opto-acoustic interferometry and polarimetry in high-index GaAs. AB - By means of a metal opto-acoustic transducer we generate quasi-longitudinal and quasi-transverse picosecond strain pulses in a (311)-GaAs substrate and monitor their propagation by picosecond acoustic interferometry. By probing at the sample side opposite to the transducer the signals related to the compressive and shear strain pulses can be separated in time. In addition to conventional monitoring of the reflected probe light intensity we monitor also the polarization rotation of the optical probe beam. This polarimetric technique results in improved sensitivity of detection and provides comprehensive information about the elasto optical anisotropy. The experimental observations are in a good agreement with a theoretical analysis. PMID- 23938499 TI - Controllable broadband nonlinear optical response of graphene dispersions by tuning vacuum pressure. AB - Nonlinear scattering, originating from laser induced solvent micro-bubbles and/or micro-plasmas, is regarded as the principal mechanism for nonlinear optical (NLO) response of graphene dispersions at ns timescale. In this work, we report the significant enhancement of NLO response of graphene dispersions by decreasing the atmospheric pressure, which has strong influence on the formation and growth of micro-bubbles and/or micro-plasmas. A modified open-aperture Z-scan apparatus in combination with a vacuum system was used to study the effect of vacuum pressure on the NLO property of graphene dispersions prepared by liquid-phase exfoliation technique. We show that the atmospheric pressure can be utilized to control and tune the nonlinear responses of the graphene dispersions for ns laser pulses at both 532 nm and 1064 nm. The lower the vacuum pressure was, the larger the NLO response was. In contrast, the NLO property of fullerene was found to be independent of the pressure change, due to its nature of nonlinear absorption. This work affords a simple method to distinguish the nonlinear scattering and absorption mechanisms for NLO nanomaterials. PMID- 23938500 TI - Parameter space for the collective laser coupling in the laser fusion driver based on the concept of fiber amplification network. AB - Collective laser coupling of the fiber array in the inertial confinement fusion (ICF) laser driver based on the concept of fiber amplification network (FAN) is researched. The feasible parameter space is given for laser coupling of the fundamental, second and third harmonic waves by neglecting the influence of the frequency conversion on the beam quality under the assumption of beam quality factor conservation. Third harmonic laser coupling is preferred due to its lower output energy requirement from a single fiber amplifier. For coplanar fiber array, the energy requirement is around 0.4 J with an effective mode field diameter of around 500 MUm while maintaining the fundamental mode operation which is more than one order of magnitude higher than what can be achieved with state of-the-art technology. Novel waveguide structure needs to be developed to enlarge the fundamental mode size while mitigating the catastrophic self-focusing effect. PMID- 23938501 TI - Resonant coupling from a new angle: coherent control through geometry. AB - We demonstrate that interference of absorption pathways can be used to control resonant coupling of light to guided modes in a manner analogous to quantum coherent control or electronically induced transparency. We illustrate the control of resonant coupling that interference affords using a plasmonic test system where tuning the phase of a grating is sufficient to vary the transfer of energy into the surface plasmon polariton by a factor of over 10(6). We show that such a structure could function as a one-way coupler, and present a simple explanation for the underlying physics. PMID- 23938502 TI - Spatial dispersion and nonlocal effective permittivity for periodic layered metamaterials. AB - The feature of spatial dispersion in periodic layered metamaterials is theoretically investigated. An effective medium model is proposed to derive the nonlocal effective permittivity tensor, which exhibits drastic variations in the wave vector domain. Strong spatial dispersion is found in the frequency range where surface plasmon polaritons are excited. In particular, the nonlocal effect gives rise to additional waves that are identified as the bonding or antibonding modes with symmetric or antisymmetric surface charge alignments. Spatial dispersion is also manifest on the parabolic-like dispersion, a non-standard type of dispersion in the medium. The associated negative refraction and backward wave occur even when the effective permittivity components are all positive, which is considered a property not available in the local medium. PMID- 23938503 TI - Simultaneous DPSK demodulation and chirp management using delay interferometer in symmetric 40-Gb/s capability TWDM-PON system. AB - We propose a symmetric 40-Gb/s aggregate rate time and wavelength division multiplexed passive optical network (TWDM-PON) system with the capability of simultaneous downstream differential phase shift keying (DPSK) signal demodulation and upstream signal chirp management based on delay interferometer (DI). With the bi-pass characteristic of DI, we experimentally demonstrate the bidirectional transmission of signals at 10-Gb/s per wavelength, and achieve negligible power penalties after 50-km single mode fiber (SMF). For the uplink transmission with DI, a ~11-dB optical power budget improvement at a bit error ratio of 1e-3 is obtained and the extinction ratio (ER) of signal is also improved from 3.4 dB to 13.75 dB. Owing to this high ER, the upstream burst-mode transmitting is successfully presented in term of time-division multiplexing. Moreover, in our experiment, a ~38-dB power budget is obtained to support 256 users with 50-km SMF transmission. PMID- 23938504 TI - Proposal of a wavelength filter with a cut corner based on Equilateral-Triangle Resonator. AB - We propose an equilateral triangle resonator filter with an output waveguide and analyzed by the finite-difference time-domain technique. The filter can realize directional output with a high Q mode by means of the mode-field coupled into the output waveguide, which results a reduction in the scattering loss at the vertices. In addition, to the deformed equilateral triangle resonator filter, an optimum parameter with a cut corner of 0.23 MUm, which is equal to that of the input waveguide and can be an optimal cut, is found to help increase in finesse, Q factors, extinction ratio and the output intensity on resonance of the drop port normalized with the through port . PMID- 23938505 TI - A multi-modal stereo microscope based on a spatial light modulator. AB - Spatial Light Modulators (SLMs) can emulate the classic microscopy techniques, including differential interference (DIC) contrast and (spiral) phase contrast. Their programmability entails the benefit of flexibility or the option to multiplex images, for single-shot quantitative imaging or for simultaneous multi plane imaging (depth-of-field multiplexing). We report the development of a microscope sharing many of the previously demonstrated capabilities, within a holographic implementation of a stereo microscope. Furthermore, we use the SLM to combine stereo microscopy with a refocusing filter and with a darkfield filter. The instrument is built around a custom inverted microscope and equipped with an SLM which gives various imaging modes laterally displaced on the same camera chip. In addition, there is a wide angle camera for visualisation of a larger region of the sample. PMID- 23938506 TI - In-line rainbow trapping based on plasmonic gratings in optical microfibers. AB - In-line rainbow trapping is demonstrated in an optical microfiber with a plasmonic grating. The dispersions of x- and y-polarized surface plasmon polariton (SPP) modes are analyzed in detail by the 3D finite element method (FEM). In this system, the incident light is coupled from an optical microfiber into a graded grating. The plasmonic structure shows strong localization as the dispersion curve approaches cut-off frequency. Gradually increasing the depth or width of the grating elements ensures that the cut-off frequency of the SPP mode varies with the position along the microfiber. Near-infrared light at different frequencies can be trapped in different spatial positions. The in-line rainbow trapping is important for potential applications including optical storage, slow light, optical switch and enhanced light-matter interactions in fiber integrated devices and highly integrated optical circuits. PMID- 23938507 TI - Mass-producible and efficient optical antennas with CMOS-fabricated nanometer scale gap. AB - Optical antennas have been widely used for sensitive photodetection, efficient light emission, high resolution imaging, and biochemical sensing because of their ability to capture and focus light energy beyond the diffraction limit. However, widespread application of optical antennas has been limited due to lack of appropriate methods for uniform and large area fabrication of antennas as well as difficulty in achieving an efficient design with small mode volume (gap spacing < 10nm). Here, we present a novel optical antenna design, arch-dipole antenna, with optimal radiation efficiency and small mode volume, 5 nm gap spacing, fabricated by CMOS-compatible deep-UV spacer lithography. We demonstrate strong surface enhanced Raman spectroscopy (SERS) signal with an enhancement factor exceeding 108 from the arch-dipole antenna array, which is two orders of magnitude stronger than that from the standard dipole antenna array fabricated by e-beam lithography. Since the antenna gap spacing, the critical dimension of the antenna, can be defined by deep-UV lithography, efficient optical antenna arrays with nanometer-scale gap can be mass-produced using current CMOS technology. PMID- 23938509 TI - Improvement of UV electroluminescence of n-ZnO/p-GaN heterojunction LED by ZnS interlayer. AB - n-ZnO/p-GaN heterojunction light emitting diodes with different interfacial layers were fabricated by pulsed laser deposition. The electroluminescence (EL) spectra of the n-ZnO/p-GaN diodes display a broad blue-violet emission centered at 430 nm, whereas the n-ZnO/ZnS/p-GaN and n-ZnO/AlN/p-GaN devices exhibit ultraviolet (UV) emission. Compared with the AlN interlayer, which is blocking both electron and hole at hetero-interface, the utilization of ZnS as intermediate layer can lower the barrier height for holes and keep an effective blocking for electron. Thus, an improved UV EL intensity and a low turn-on voltage (~5V) were obtained. The results were studied by peak-deconvolution with Gaussian functions and were discussed using the band diagram of heterojunctions. PMID- 23938508 TI - Slope efficiency and spurious-free dynamic range of silicon Mach-Zehnder modulator upon carrier depletion and injection effects. AB - We investigate the performances of a silicon PN-junction Mach-Zehnder modulator for analog application. The slope efficiency and spurious-free dynamic range (SFDR) of such a modulator upon carrier depletion and carrier injection effects are characterized and compared. Input RF frequency-dependence measurements show that the depletion-type modulator is usually with ~20 dB ? Hz(2/3) higher SFDR comparing to the injection-type modulator, yet with an order-of-magnitude lower slope efficiency. For the depletion-type and injection-type modulators, the measured maximum SFDRs are respectively ~95 dB ? Hz(2/3) and 75 dB?Hz(2/3), with maximum slope efficiency of 0.3 V(-1) and 8 V(-1<). We numerically model the SFDR by using the experimentally extracted effective refractive index change, which shows good agreement with the measurements. PMID- 23938510 TI - Improving signal detection in emission optical projection tomography via single source multi-exposure image fusion. AB - We demonstrate a technique to improve structural data obtained from Optical Projection Tomography (OPT) using Image Fusion (IF) and contrast normalization. This enables the visualization of molecular expression patterns in biological specimens with highly variable contrast values. In the approach, termed IF-OPT, different exposures are fused by assigning weighted contrasts to each. When applied to projection images from mouse organs and digital phantoms our results demonstrate the capability of IF-OPT to reveal high and low signal intensity details in challenging specimens. We further provide measurements to highlight the benefits of the new algorithm in comparison to other similar methods. PMID- 23938512 TI - High spectral efficient W-band OFDM-RoF system with direct-detection by two cascaded single-drive MZMs. AB - W-band wireless transmission has attracted a lot of interest due to its wider available bandwidth (i.e. 75-110 GHz). In this article, we propose a direct detection orthogonal frequency division multiplexing radio over fiber (OFDM-RoF) system via two cascaded single-drive MZMs at center frequency of 103 GHz. We discuss maximum bandwidth of different modulation formats under forward error correction (FEC) threshold (3.8 x 10(-3)). Up to 40-Gbps 16-QAM OFDM signals is achieved over 25-km fiber and 2-m wireless transmission. To overcome the penalty from uneven frequency response, bit-loading algorithm is applied to discuss data rate and spectral efficiency with signal bandwidth from 5 to 10 GHz. With 10-GHz bandwidth, 46.4-Gb/s data rate and 4.64-bit/s/Hz spectral efficiency was achieved. To achieve 40-Gbps data rate, the required bandwidth of OFDM signal with bit-loading is 2 GHz less than that without bit-loading. PMID- 23938511 TI - Studies on transmitted beam modulation effect from laser induced damage on fused silica optics. AB - UV laser induced damage (LID) on exit surface of fused silica could cause modulation effect to transmitted beam and further influence downstream propagation properties. This paper presents our experimental and analytical studies on this topic. In experiment, a series of measurement instruments are applied, including beam profiler, interferometer, microscope, and optical coherent tomography (OCT). Creating and characterizing of LID on fused silica sample have been implemented. Morphological features are studied based on their particular modulation effects on transmitted beam. In theoretical investigation, analytical modeling and numerical simulation are performed. Modulation effects from amplitude, phase, and size factors are analyzed respectively. Furthermore, we have novelly designed a simplified polygon model to simulate actual damage site with multiform modulation features, and the simulation results demonstrate that the modeling is usable and representative. PMID- 23938513 TI - Tunable broadband light coupler based on two parallel all-fiber acousto-optic tunable filters. AB - Based on the evanescent-field coupling between the cladding modes of two adjacent and parallel all-fiber acousto-optic tunable filters, tunable broadband light coupling with relatively uniform insertion loss of trapping spectrum was achieved. In the experiments, a wide spectral tuning range from 1490 nm to 1610 nm, covering the whole C- and L-band and parts of S-bands, was demonstrated with a wavelength tunability slope of -0.72 nm/kHz. The insertion loss of the trapping spectrum was uniform (around -5.0 dB, which can be improved with a longer evanescent-field coupling length) within the whole tuning spectral range. Such a light coupling structure would be useful in tunable broadband light coupler and broadband optical fiber add/drop multiplexer for applications in coarse wavelength division multiplexing systems. PMID- 23938514 TI - Combining near-field scanning optical microscopy with spectral interferometry for local characterization of the optical electric field in photonic structures. AB - We show how a combination of near-field scanning optical microscopy with crossed beam spectral interferometry allows a local measurement of the spectral phase and amplitude of light propagating in photonic structures. The method only requires measurement at the single point of interest and at a reference point, to correct for the relative phase of the interferometer branches, to retrieve the dispersion properties of the sample. Furthermore, since the measurement is performed in the spectral domain, the spectral phase and amplitude could be retrieved from a single camera frame, here in 70 ms for a signal power of less than 100 pW limited by the dynamic range of the 8-bit camera. The method is substantially faster than most previous time-resolved NSOM methods that are based on time-domain interferometry, which also reduced problems with drift. We demonstrate how the method can be used to measure the refractive index and group velocity in a waveguide structure. PMID- 23938515 TI - Real-time observation of ultrafast internal conversion in ethylbenzene by femtosecond time-resolved photoelectron imaging. AB - The ultrafast dynamics of the second singlet electronically excited state (S2) in ethylbenzene has been studied by femtosecond time-resolved photoelectron imaging. The time evolution of the photoelectron signal can be well described by a biexponential decay: a rapid relaxation pathway with a time constant of 60 ( +/- 9) fs and a longer-lived channel on a timescale of 2.58 ( +/ 0.22) ps. The rapid relaxation is ascribed to the ultrafast internal conversion from the S2 state to the vibrationally hot S1 state. This internal conversion process has been observed in real time. The slow photoelectron signal reflects the depopulation of secondarily populated high vibronic S1 state. PMID- 23938516 TI - Miniature spectrometer and beam splitter for an optical coherence tomography on a silicon chip. AB - Optical coherence tomography (OCT) has enabled clinical applications that revolutionized in vivo medical diagnostics. Nevertheless, its current limitations owing to cost, size, complexity, and the need for accurate alignment must be overcome by radically novel approaches. Exploiting integrated optics, we assemble the central components of a spectral-domain OCT system on a silicon chip. The spectrometer comprises an arrayed-waveguide grating with 136-nm free spectral range and 0.21-nm wavelength resolution. The beam splitter is realized by a non uniform adiabatic coupler with its 3-dB splitting ratio being nearly constant over 150 nm. With this device whose overall volume is 0.36 cm(3) we demonstrate high-quality in vivo imaging in human skin with 1.4-mm penetration depth, 7.5-um axial resolution, and a signal-to-noise ratio of 74 dB. Considering the reasonable performance of this early OCT on-a-chip system and the anticipated improvements in this technology, a completely different range of devices and new fields of applications may become feasible. PMID- 23938517 TI - Fabrication of high-aspect-ratio grooves in silicon using femtosecond laser irradiation and oxygen-dependent acid etching. AB - We demonstrated a new method to fabricate micron-sized grooves with high aspect ratios in silicon wafers by combining femtosecond laser irradiation and oxygen dependent acid etching. Femtosecond laser was employed to induce structure changes and incorporate oxygen into silicon, and then materials in oxygen containing regions were etched by hydrofluoric acid (HF) solution to form grooves. The etching could be attributed to the reaction between HF and silicon oxides formed by femtosecond laser irradiation. The dependences of the aspect ratios of grooves on the laser fluence and the scanning velocity were also investigated. PMID- 23938518 TI - Experimental circular quantum secret sharing over telecom fiber network. AB - We present a robust single photon circular quantum secret sharing (QSS) scheme with phase encoding over 50 km single mode fiber network using a circular QSS protocol. Our scheme can automatically provide a perfect compensation of birefringence and remain stable for a long time. A high visibility of 99.3% is obtained. Furthermore, our scheme realizes a polarization insensitive phase modulators. The visibility of this system can be maintained perpetually without any adjustment to the system every time we test the system. PMID- 23938519 TI - Broadband terahertz conductivity and optical transmission of indium-tin-oxide (ITO) nanomaterials. AB - Indium-tin-oxide (ITO) nanorods (NRs) and nanowhiskers (NWhs) were fabricated by an electron-beam glancing-angle deposition (GLAD) system. These nanomaterials are of interests as transparent conducting electrodes in various devices. Two terahertz (THz) time-domain spectrometers (TDS) with combined spectral coverage from 0.15 to 9.00 THz were used. These allow accurate determination of the optical and electrical properties of such ITO nanomaterials in the frequency range from 0.20 to 4.00 THz. Together with Fourier transform infrared spectroscopic (FTIR) measurements, we found that the THz and far-infrared transmittance of these nanomaterials can be as high as 70% up to 15 THz, as opposed to about 9% for sputtered ITO thin films. The complex conductivities of ITO NRs, NWhs as well films are well fitted by the Drude-Smith model. Taking into account that the volume filling factors of both type of nanomaterials are nearly same, mobilities, and DC conductivities of ITO NWhs are higher than those of NRs due to less severe carrier localization effects in the former. On the other hand, mobilities of sputtered ITO thin films are poorer than ITO nanomaterials because of larger concentration of dopant ions in films, which causes stronger carrier scattering. We note further that consideration of the extreme values of Re{sigma} and Im{sigma} as well the inflection points, which are functions of the carrier scattering time (tau) and the expectation value of cosine of the scattering angle (gamma), provide additional criteria for accessing the accuracy of the extraction of electrical parameters of non-Drude-like materials using THz-TDS. Our studies so far indicate ITO NWhs with heights of ~1000 nm show outstanding transmittance and good electrical characteristics for applications such as transparent conducting electrodes of THz Devices. PMID- 23938520 TI - FWM-based wavelength conversion of 40 Gbaud PSK signals in a silicon germanium waveguide. AB - We demonstrate four wave mixing (FWM) based wavelength conversion of 40 Gbaud differential phase shift keyed (DPSK) and quadrature phase shift keyed (QPSK) signals in a 2.5 cm long silicon germanium waveguide. For a 290 mW pump power, bit error ratio (BER) measurements show approximately a 2-dB power penalty in both cases of DPSK (measured at a BER of 10(-9)) and QPSK (at a BER of 10(-3)) signals that we examined. PMID- 23938521 TI - Optical properties of silicon germanium waveguides at telecommunication wavelengths. AB - We present a systematic experimental study of the linear and nonlinear optical properties of silicon-germanium (SiGe) waveguides, conducted on samples of varying cross-sectional dimensions and Ge concentrations. The evolution of the various optical properties for waveguide widths in the range 0.3 to 2 um and Ge concentrations varying between 10 and 30% is considered. Finally, we comment on the comparative performance of the waveguides, when they are considered for nonlinear applications at telecommunications wavelengths. PMID- 23938522 TI - Whiteness metric for light sources of arbitrary color temperatures: proposal and application to light-emitting-diodes. AB - We study the quantification of whiteness perception under illumination from various light sources. We discuss an existing metric for sources with high correlated color temperature (CCT), CIE whiteness, and propose a procedure to adapt it to sources of any CCT. We illustrate our approach by comparing the ability of different warm-white sources to render whiteness. We show that a careful engineering of the spectrum -facilitated by the flexibility of light emitting diode sources - is essential to render whiteness. PMID- 23938523 TI - Improved sinusoidal gating with balanced InGaAs/InP Single Photon Avalanche Diodes. AB - We report balanced InGaAs/InP single photon avalanche diodes (SPADs) operated in sinusoidal gating mode with a tunable phase shifter to reduce common mode noise. This technique enables detection of small avalanche pulses, which results in reduced afterpulsing. For laser repletion rate of 20 MHz at 240 K, the dark count rate for photon detection efficiency of 10% is 8.9 kHz. PMID- 23938524 TI - Coherently wavelength injection-locking a 600-MUm long cavity colorless laser diode for 16-QAM OFDM at 12 Gbit/s over 25-km SMF. AB - The coherent injection-locking and directly modulation of a long-cavity colorless laser diode with 1% end-facet reflectance and weak-resonant longitudinal modes is employed as an universal optical transmitter to demonstrated for optical 16-QAM OFDM transmission at 12 Gbit/s over 25 km in a DWDM-PON system. The optimized bias current of 30 mA (~1.5Ith) with corresponding extinction ratio (ER) of 6 dB and the external injection power of -9 dBm is (are) required for such a wavelength-locked universal transmitter to carry the 16-QAM and 122-subcarrier formatted OFDM and data-stream. By increasing external injection-locking from -9 dBm to 0 dBm, the peak-to-peak chirp of the OFDM data stream reduces from 7.7 to 5.4 GHz. The side mode suppression ratio (SMSR) of up to 50 dB is achieved with wider detuning range between -0.5 nm to 2.0 nm under an injection power of 0 dBm. By modulating such a colorless laser diode with an OFDM data stream of 122 subcarriers at a central carrier frequency of 1.5625 GHz and a total bandwidth of 3 GHz, the transmission data rate of up to 12 Gbit/s in standard single-mode fiber over 25 km is demonstrated to achieve an error vector magnitude (EVM) of 5.435%. Such a universal colorless DWDM-PON transmitter can deliver the optical OFDM data-stream at 12 Gbit/s QAM-OFDM data after 25-km transmission with a receiving power sensitivity of -7 dBm at BER of 3.6 * 10(-7) when pre-amplifying the OFDM data by 5 dB. PMID- 23938525 TI - Flexible real-time natural 2D color and 3D shape measurement. AB - The majority of existing real-time 3D shape measurement systems only generate non nature texture (i.e., having illumination other than ambient lights) that induces shadow related issues. This paper presents a method that can simultaneously capture natural 2D color texture and 3D shape in real time. Specifically, we use an infrared fringe projection system to acquire 3D shapes, and a secondary color camera to simultaneously capture 2D color images of the object. Finally, we develop a flexible and simple calibration technique to determine the mapping between the 2D color image and the 3D geometry. Experimental results demonstrate the success of the proposed technique. PMID- 23938526 TI - Investigation of interface states in single-negative metamaterial layered structures based on the phase properties. AB - The physical mechanism of the interface states in layered structures consisting of single-negative metamaterials is investigated using a simple resonant cavity model. We found that the interface states and their corresponding tunneling transmission modes appeared when the resonant condition is satisfied. Such resonant condition depends on the phase changes inside the resonant cavity. Based on these results, we proposed an efficient method to precisely predict the frequencies of the tunneling interface states inside the single-negative metamaterial layers. Our method is effective for interface states corresponding to perfect or imperfect tunneling transmission. Composite right/left-handed transmission lines were used to realize the pair and sandwich metamaterial layered structures in the microwave region. Electromagnetic tunneling interface states were observed in the measurements, which agreed well with the theory. Our study offers a way for effectively designing metamaterial devices with novel electromagnetic tunneling properties. PMID- 23938527 TI - General properties of the surface charge pattern of one-dimensional metallic gratings. AB - Under light illumination, metallic gratings present unexpected and fascinating phenomena, which are due to the complex charge patterns generated on the grating surfaces. The moving electrons are due to the launching of surface plasmon polaritons (SPPs), but only in part. We derive analytical expressions quantifying the plasmonic character of the surface charge patterns, i.e. the contribution of SPPs to its formation. The expressions have a general significance, in the sense that they may be applied to a variety of geometries and spectral ranges, irrespective of whether the grating absorbs, transmits, reflects, or how strongly it resonates. PMID- 23938528 TI - Using graphene nano-particle embedded in photonic crystal fiber for evanescent wave mode-locking of fiber laser. AB - A photonic crystal fiber (PCF) with high-quality graphene nano-particles uniformly dispersed in the hole cladding are demonstrated to passively mode-lock the erbium-doped fiber laser (EDFL) by evanescent-wave interaction. The few-layer graphene nano-particles are obtained by a stabilized electrochemical exfoliation at a threshold bias. These slowly and softly exfoliated graphene nano-particle exhibits an intense 2D band and an almost disappeared D band in the Raman scattering spectrum. The saturable phenomena of the extinction coefficient beta in the cladding provides a loss modulation for the intracavity photon intensity by the evanescent-wave interaction. The evanescent-wave mode-locking scheme effectively enlarges the interaction length of saturable absorption with graphene nano-particle to provide an increasing transmittance DeltaT of 5% and modulation depth of 13%. By comparing the core-wave and evanescent-wave mode-locking under the same linear transmittance, the transmittance of the graphene nano-particles on the end-face of SMF only enlarges from 0.54 to 0.578 with DeltaT = 3.8% and the modulation depth of 10.8%. The evanescent wave interaction is found to be better than the traditional approach which confines the graphene nano-particles at the interface of two SMF patchcords. When enlarging the intra-cavity gain by simultaneously increasing the pumping current of 980-nm and 1480-nm pumping laser diodes (LDs) to 900 mA, the passively mode-locked EDFL shortens its pulsewidth to 650 fs and broadens its spectral linewidth to 3.92 nm. An extremely low carrier amplitude jitter (CAJ) of 1.2-1.6% is observed to confirm the stable EDFL pulse train with the cladding graphene nano-particle based evanescent-wave mode locking. PMID- 23938529 TI - 409-Tb/s + 409-Tb/s crosstalk suppressed bidirectional MCF transmission over 450 km using propagation-direction interleaving. AB - We demonstrate bidirectional transmission over 450 km of newly-developed dual ring structured 12-core fiber with large effective area and low crosstalk. Inter core crosstalk is suppressed by employing propagation-direction interleaving, and 409-Tb/s capacities are achieved for both directions. PMID- 23938530 TI - Enhanced terahertz emission by coherent optical absorption in ultrathin semiconductor films on metals. AB - We report on the surprisingly strong, broadband emission of coherent terahertz pulses from ultrathin layers of semiconductors such as amorphous silicon, germanium and polycrystalline cuprous oxide deposited on gold, upon illumination with femtosecond laser pulses. The strength of the emission is surprising because the materials are considered to be bad (amorphous silicon and polycrystalline cuprous oxide) or fair (amorphous germanium) terahertz emitters at best. We show that the strength of the emission is partly explained by cavity-enhanced optical absorption. This forces most of the light to be absorbed in the depletion region of the semiconductor/metal interface where terahertz generation occurs. For an excitation wavelength of 800 nm, the strongest terahertz emission is found for a 25 nm thick layer of amorphous germanium, a 40 nm thick layer of amorphous silicon and a 420 nm thick layer of cuprous oxide, all on gold. The emission from cuprous oxide is similar in strength to that obtained with optical rectification from a 300 MUm thick gallium phosphide crystal. As an application of our findings we demonstrate how such thin films can be used to turn standard optical components, such as paraboloidal mirrors, into self-focusing terahertz emitters. PMID- 23938531 TI - Fabrication of spherical mitigation pit on KH2PO4 crystal by micro-milling and modeling of its induced light intensification. AB - Micro-machining is the most promising method for KH(2)PO(4) crystal to mitigate the surface damage growth in high power laser system. In this work, spherical mitigation pit is fabricated by micro-milling with an efficient machining procedure. The light intensification caused by rear surface features before and after mitigation is numerically modeled based on the finite-difference time domain method. The results indicate that the occurrence of total internal reflections should be responsible for the largest light intensification inside the crystal. For spherical pits after mitigation, the light intensification can be greatly alleviated by preventing the occurrence of total internal reflections. The light intensification caused by spherical mitigation pit is strongly dependent on the width-depth ratio and it is suggested that the width-depth ratio of spherical mitigation pit must be devised to be larger than 5.0 to achieve the minimal light intensification for the mitigation of surface damage growth. Laser damage tests for KH(2)PO(4) crystal validate that the laser damage resistance of initially damaged surface can be retrieved to near the level of ideal surface by replacing initial damage site with predesigned mitigation pit. PMID- 23938532 TI - Linear optical pulse compression based on temporal zone plates. AB - We propose and demonstrate time-domain equivalents of spatial zone plates, namely temporal zone plates, as alternatives to conventional time lenses. Both temporal intensity zone plates, based on intensity-only temporal modulation, and temporal phase zone plates, based on phase-only temporal modulation, are introduced and studied. Temporal zone plates do not exhibit the limiting tradeoff between temporal aperture and frequency bandwidth (temporal resolution) of conventional linear time lenses. As a result, these zone plates can be ideally designed to offer a time-bandwidth product (TBP) as large as desired, practically limited by the achievable temporal modulation bandwidth (limiting the temporal resolution) and the amount of dispersion needed in the target processing systems (limiting the temporal aperture). We numerically and experimentally demonstrate linear optical pulse compression by using temporal zone plates based on linear electro optic temporal modulation followed by fiber-optics dispersion. In the pulse compression experiment based on temporal phase zone plates, we achieve a resolution of ~25.5 ps over a temporal aperture of ~5.77 ns, representing an experimental TBP larger than 226 using a phase-modulation amplitude of only ~0.8pi rad. We also numerically study the potential of these devices to achieve temporal imaging of optical waveforms and present a comparative analysis on the performance of different temporal intensity and phase zone plates. PMID- 23938533 TI - Extraction of anisotropic parameters of turbid media using hybrid model comprising differential- and decomposition-based Mueller matrices. AB - A hybrid model comprising the differential Mueller matrix formalism and the Mueller matrix decomposition method is proposed for extracting the linear birefringence (LB), linear dichroism (LD), circular birefringence (CB), circular dichroism (CD), and depolarization properties (Dep) of turbid optical samples. In contrast to the differential-based Mueller matrix method, the proposed hybrid model provides full-range measurements of all the anisotropic properties of the optical sample. Furthermore, compared to the decomposition-based Mueller matrix method, the proposed model is insensitive to the multiplication order of the constituent basis matrices. The validity of the proposed method is confirmed by extracting the anisotropic properties of a compound chitosan-glucose-microsphere sample with LB/CB/Dep properties and two ferrofluidic samples with CB/CD/Dep and LB/LD/Dep properties, respectively. It is shown that the proposed hybrid model not only yields full-range measurements of all the anisotropic parameters, but is also more accurate and more stable than the decomposition method. Moreover, compared to the decomposition method, the proposed model more accurately reflects the dependency of the phase retardation angle and linear dichroism angle on the direction of the external magnetic field for ferrofluidic samples. Overall, the results presented in this study confirm that the proposed model has significant potential for extracting the optical parameters of real-world samples characterized by either single or multiple anisotropic properties. PMID- 23938534 TI - Size-controlled InGaN/GaN nanorod array fabrication and optical characterization. AB - We demonstrate a cost-effective top-down approach for fabricating InGaN/GaN nanorod arrays using a wet treatment process in a KOH solution. The average diameter of the as-etched nanorods was effectively reduced from 420 nm to 180 nm. The spatial strain distribution was then investigated by measuring the high resolution cathodoluminescence directly on top of the nanorods. The smaller nanorods showed a higher internal quantum efficiency and lower potential fluctuation, which can subsequently be exploited for high-efficiency photonic devices. PMID- 23938535 TI - Highly contrasted Bessel fringe minima visualization for time-averaged vibration profilometry using Hilbert transform two-frame processing. AB - Time-averaged fringe patterns in vibration testing of MEMS (microelectromechanical systems) are unaffected by carrier displacements. They are additive superimposition type moires. These features and Hilbert transform vulnerability to additive trend are utilized for visualization of centers of dark Bessel fringes. Two frames with shifted carrier are subtracted for background and noise correction. Two normalized images of this pattern are calculated with slightly different bias levels and subtracted. The method does not require precise phase shifting between two frames, cosinusoidal carrier and linear recording. It enables detecting light power variations and phase shifting nonuniformities. Synthetic and experimental results corroborate the robustness of the method. PMID- 23938536 TI - High Q SiC microresonators. AB - We demonstrate photonic devices based on standard 3C SiC epitaxially grown on silicon. We achieve high optical confinement by taking advantage of the high stiffness of SiC and undercutting the underlying silicon substrate. We demonstrate a 20 MUm radius suspended microring resonator with Q=14,100 fabricated on commercially available SiC-on-silicon substrates. PMID- 23938537 TI - Low-voltage quantum well microring-enhanced Mach-Zehnder modulator. AB - Modulation characteristics of a novel InGaAs/InAlAs multiple quantum well (MQW) microring-enhanced Mach-Zehnder modulator (MRE-MZM) is investigated in detail and its low-voltage operation with high extinction ratio is demonstrated. The MZM has a single microring resonator in one arm and is driven by the change in electrorefractive index induced by the quantum-confined Stark effect in the MQW core layer. As the MQW, a multiple five-layer asymmetric coupled quantum well (FACQW) is used to obtain a large electrorefractive index change. The driving voltage of the proposed MZM is significantly reduced owing to the enhanced phase shift in the microring resonator. High-mesa waveguide structures are grown by solid-source molecular beam epitaxy and fabricated by inductively coupled plasma etching. A directional coupler with an asymmetric branching ratio is used as an input coupler to prevent the degradation of the extinction ratio of the MZM. The extinction ratio of the fabricated MRE-MZM is approximately 27 dB. The product of the half-wave voltage and phase shifter length, V(pi) . L, is 1.7 Vmm in static modulation. This value is one-quarter that of a conventional MZM with the same waveguide structure. PMID- 23938538 TI - Stroboscopic white-light interferometry of vibrating microstructures. AB - We describe a LED-based stroboscopic white-light interferometer and a data analysis method that allow mapping out-of-plane surface vibration fields in electrically excited microstructures with sub-nm amplitude resolution for vibration frequencies ranging up to tens of MHz. The data analysis, which is performed entirely in the frequency domain, makes use of the high resolution available in the measured interferometric phase data. For demonstration, we image the surface vibration fields in a square-plate silicon MEMS resonator for three vibration modes ranging in frequency between 3 and 14 MHz. The minimum detectable vibration amplitude in this case was less than 100 pm. PMID- 23938539 TI - Kerr parametric oscillations and frequency comb generation from dispersion compensated silica micro-bubble resonators. AB - Silica micro-bubble resonators (MBRs) with cavity quality factor as high as Q = 5 * 10(7) are fabricated. The total dispersion of MBRs is analyzed. The thin-wall structure opens a new anomalous dispersion window and thus supports the dispersion compensation for hyper-parametric frequency conversion processes. Experimentally, Kerr parametric oscillation is observed in a 136 MUm diameter MBR, frequency comb generation is also realized. Meanwhile the same nonlinear process is not allowed in solid silica spheres with size smaller than 150 MUm. PMID- 23938540 TI - Attosecond pulse characterization. AB - In this work we propose a novel procedure for the characterization of attosecond pulses. The method relies on the conversion of the attosecond pulse into electron wave-packets through photoionization of atoms in the presence of a weak IR field. It allows for the unique determination of the spectral phase making up the pulses by accurately taking into account the atomic physics of the photoionization process. The phases are evaluated by optimizing the fit of a perturbation theory calculation to the experimental result. The method has been called iPROOF (improved Phase Retrieval by Omega Oscillation Filtering) as it bears a similarity to the PROOF technique [Chini et al. Opt. Express 18, 13006 (2010)]. The procedure has been demonstrated for the characterization of an attosecond pulse train composed of odd and even harmonics. We observe a large phase shift between consecutive odd and even harmonics. The resulting attosecond pulse train has a complex structure not resembling a single attosecond pulse once per IR period, which is the case for zero phase. Finally, the retrieval procedure can be applied to the characterization of single attosecond pulses as well. PMID- 23938541 TI - Multiwavelength narrow linewidth erbium-doped fiber laser based on FP-LDs. AB - In this paper, we propose and demonstrate a technique to realize multiwavelength operation in erbium-doped fiber lasers (EDFLs) by inserting two Fabry Perot laser diodes (FP-LDs) in the laser cavity respectively in cascaded and parallel way. The FP-LDs not only act as wavelength selection elements, but also offer optical gain or loss for the operation wavelengths in the laser cavity. The gains or losses for the oscillation wavelengths obtained from FP-LDs differ with adjustment of the driving current of the FP-LDs. Thus, the utilization of the FP LDs in the laser cavity can introduce wavelength dependent gain or loss which can effectively suppress the competition caused by the homogeneous gain broadening of the erbium-doped fiber (EDF). As a result, 16-wavelength and 20-wavelength operation with a wavelength-spacing of 1.25 nm has been achieved respectively in the cascaded and parallel FP-LDs based EDFL schemes. The measured power fluctuation of each wavelength is smaller than 0.4dB for both EDFLs. Furthermore, the injection locking of the FP-LDs ensures a narrow linewidth of the EDFL output and the linewidth is estimated to be narrower than 100 MHz for the cascaded scheme based EDFL. PMID- 23938542 TI - Confocal microphotoluminescence mapping of coupled and detuned states in photonic molecules. AB - We study the coupling of cavities defined by the local modulation of the waveguide width using confocal photoluminescence microscopy. We are able to spatially map the profile of the antisymmetric (antibonding) and symmetric (bonding) modes of a pair of strongly coupled cavities (photonic molecule) and follow the coupled cavity system from the strong coupling to the weak coupling regime in the presence of structural disorder. The effect of disorder on this photonic molecule is also investigated numerically with a finite-difference time domain method and a semi-analytical approach, which enables us to quantify the light localization observed in either cavity as a function of detuning. PMID- 23938543 TI - Silicon avalanche photodiode operation and lifetime analysis for small satellites. AB - Silicon avalanche photodiodes (APDs) are sensitive to operating temperature fluctuations and are also susceptible to radiation flux expected in satellite based quantum experiments. We introduce a low power voltage adjusting mechanism to overcome the effects of in-orbit temperature fluctuations. We also present data on the performance of Si APDs after irradiation (gamma-ray and proton beam). Combined with an analysis of expected orbital irradiation, we propose that a Si APD in a 400 km equatorial orbit may operate beyond the lifetime of the satellite. PMID- 23938545 TI - Infrared diffractive filtering for extreme ultraviolet multilayer Bragg reflectors. AB - We report on the development of a hybrid mirror realized by integrating an EUV reflecting multilayer coating with a lamellar grating substrate. This hybrid mirror acts as an efficient Bragg reflector for extreme ultraviolet (EUV) radiation at a given wavelength while simultaneously providing spectral-selective suppression of the specular reflectance for unwanted longer-wavelength radiation due to the grating phase-shift resonance. The test structures, designed to suppress infrared (IR) radiation, were fabricated by masked deposition of a Si grating substrate followed by coating of the grating with a Mo/Si multilayer. To give the proof of principle, we developed such a hybrid mirror for the specific case of reflecting 13.5 nm radiation while suppressing 10 MUm light, resulting in 61% reflectance at the wavelength of 13.5 nm together with the 70 * suppression rate of the specular reflection at the wavelength of 10 MUm, but the considered filtering principle can be used for a variety of applications that are based on utilization of broadband radiation sources. PMID- 23938544 TI - Integrated interferometric approach to solve microring resonance splitting in biosensor applications. AB - Silicon-on-insulator microring resonators have proven to be an excellent platform for label-free nanophotonic biosensors. The high index contrast of silicon-on insulator allows for fabrication of micrometer-size sensors. However, it also limits the quality of the resonances by introducing an intrinsic mode-splitting. Backscattering of optical power at small waveguide variations lifts the degeneracy of the normal resonator modes. This severely deteriorates the quality of the output signal, which is of utmost importance to determine the performance of the microrings as a biosensor. We suggest an integrated interferometric approach to give access to the unsplit, high-quality normal modes of the microring resonator and experimentally show an improvement of the quality factor by a factor of 3. PMID- 23938546 TI - Electromagnetic dipole coupling mechanism in layered terahertz metamaterials. AB - Interplay between adjacent dipoles is an experimental priori for designing artificially-engineered structure because the dipole coupling is one critical factor for determining the electromagnetic response in metamaterials. Although numerous investigations have been performed to study the coupling effect of the split-ring resonator (SRR), the interlayer dipole coupling of its complementary SRR, called C-SRR, has been largely unexplored. Here, we present experimental and theoretical investigations on the electromagnetic coupling effect in the two stacks of layered C-SRR structures. By adjusting the relative lateral distance between the two-dimensionally stacked meta-structures, we observe that the confined magnetic dipole plays an important role in determining the resonance frequency and the bandwidth broadening of the C-SRR, exhibiting an exactly opposite behavior to the SRR structure. Our investigation provides experimental basis for developing frequency tunable three-dimensional metamaterial devices. PMID- 23938547 TI - Dual-polarization multi-band OFDM versus single-carrier DP-QPSK for 100 Gb/s long haul WDM transmission over legacy infrastructure. AB - The transmission performance of coherent dual-polarization multi-band OFDM (DP-MB OFDM) and QPSK (DP-QPSK) are experimentally compared for 100 Gb/s long-haul transport over legacy infrastructure combining G.652 fiber and 10 Gb/s WDM system. It is shown that DP-MB-OFDM and DP-QPSK have nearly the same performance at 100 Gb/s after transmission over a 10 * 100-km fiber line. Furthermore, the origin of performance degradations and limitations of the DP-MB-OFDM is explored numerically, as well as the impact of transmission distance and sub-band spacing. PMID- 23938548 TI - Metamaterial filters at optical-infrared frequencies. AB - We propose two distinctive designs of metamaterials demonstrating filtering functions in the visible and near infrared region. Since the emissivity is related to the absorption of a material, these filters would then offer a high emissivity in the visible and near infrared, and a low one beyond those wavelengths. Usually, such a system find their applications in the thermo photovoltaics field as it can find as well a particular interest in optoelectronics, especially for optical detection. Numerical analysis has been performed on common metamaterial designs: a perforated metallic plate and a metallic cross grating. Through all these structures, we have demonstrated the various physical phenomena contributing to a reduction in the reflectivity in the optical and near infrared region. By showing realistic geometric parameters, the structures were not only designed to demonstrate an optical filtering function but were also meant to be feasible on large surfaces by lithographic methods such as micro contact printing or nano-imprint lithography. PMID- 23938549 TI - Propagation of partially coherent light through a light pipe. AB - In laser projection applications, laser light modules are often combined with rotating diffusers in order to reduce the appearance of speckle on the projection screen. The rotation of a diffuser in a laser beam generates a beam of partially coherent light. Propagation of this light through the different optical components constituting the laser projector is thus essential when investigating the appearance of speckle. In this paper, a computationally efficient simulation model is presented to propagate partially coherent light through a homogenizing rectangular light pipe. The light pipe alters the coherence properties of the light and different consequences are discussed. The outcomes of the simulation model are experimentally verified using a reversing wavefront Michelson interferometer. PMID- 23938550 TI - Improving working lifetime and efficiency of phosphor doped organic light emitting diodes. AB - Long working lifetime and high efficient phosphorescent organic light-emitting diode (PHOLED) in which mixed host composed of wide-band-gap based 4, 7-diphenyl 1, 10-phenanthroline (Bphen) and (4,4'-bis(carbazol-9-yl)-biphenyl) (CBP) was demonstrated. The PHOLED with structure of ITO/MoO(3)/CBP:MoO(3) (15 v%, 30 nm)/CBP(10 nm)/([50v%:50v% CBP:Bphen]: 6v% Ir(ppy)(3))(30 nm)/Bphen (40 nm)/LiF (1 nm)/Al offers a peak power efficiency of 41.6 lm/W (a peak current efficiency of 39.8 cd/A)) at a low driving voltage of 3 V which increases by 55% and 27% compared to that of corresponding single-host (SH) and double emitting layer (DML) devices, respectively. Especially very long work lifetime (3530 hs) at an initial luminance of 500 cd/m(2) of the mixed hosted device is exhibited, rising by about 4.1 and 2.46 times relative to that of corresponding SH and DML devices. High efficiency and longer working lifetime was attributed to the absence of heterojunction and balanced charge carrier transport characteristics in the mixed host based OLED structure. The more detail mechanism was also presented. PMID- 23938551 TI - Three-dimensional laser micro-sculpturing of silicone: towards bio-compatible scaffolds. AB - Possibility to form three-dimensional (3D) micro-structures in silicone elastomer (polydimethylsiloxane; PDMS) doped with different photo-initiators was systematically investigated using direct laser writing with femtosecond laser pulses at different exposure conditions. Accuracy of the 3D structuring with resolution of ~5 MUm and a fabrication throughput of ~720 MUm(3)/s, which is exceeding the previously reported values by ~ 300(*), was achieved. Practical recording velocities of ~ 1 mm/s were used in PDMS with isopropyl-9H-thioxanthen 9-one (ISO) and thioxanthen-9-one (THIO) photo-initiators which both have absorption at around 360 nm wavelength. The 3D laser fabrication in PDMS without any photo-initiator resulting in a fully bio-compatible material has been achieved for the first time. Rates of multi-photon absorption and avalanche for the structuring of silicone are revealed: the two-photon absorption is seeding the avalanche of a radical generation for subsequent cross-linking. Direct writing enables a maskless manufacturing of molds for soft-lithography and 3D components for microfluidics as well as scaffolds for grafts in biomedical applications. PMID- 23938552 TI - High precision wavelength estimation method for integrated optics. AB - A novel and simple approach to optical wavelength measurement is presented in this paper. The working principle is demonstrated using a tunable waveguide micro ring resonator and single photodiode. The initial calibration is done with a set of known wavelengths and resonator tunings. The combined spectral sensitivity function of the resonator and photodiode at each tuning voltage was modeled by a neural network. For determining the unknown wavelengths, the resonator was tuned with a set of heating voltages and the corresponding photodiode signals were collected. The unknown wavelength was estimated, based on the collected photodiode signals, the calibrated neural networks, and an optimization algorithm. The wavelength estimate method provides a high spectral precision of about 8 pm (5 . 10(-6) at 1550 nm) in the wavelength range between 1549 nm to 1553 nm. A higher precision of 5 pm (3 . 10(-6)) is achieved in the range between 1550.3 nm to 1550.8 nm, which is a factor of five improved compared to a simple lookup of data. The importance of our approach is that it strongly simplifies the optical system and enables optical integration. The approach is also of general importance, because it may be applicable to all wavelength monitoring devices which show an adjustable wavelength response. PMID- 23938553 TI - Low-loss light transmission in a rectangular-shaped hybrid metal trench at 1550 nm. AB - A hybrid plasmonic waveguide consisting of a high-index dielectric core embedded inside a rectangular-shaped metallic trench is proposed and its guiding properties are investigated at the wavelength of 1550 nm. Numerical simulations based on the finite element method have demonstrated that the introduced dielectric core could greatly reduce the modal loss of the metal trench while maintaining strong confinement of light. The effects of dielectric core size, material of the cladding and the dielectric core on the modal properties have been systematically investigated. The proposed hybrid plasmonic structure can be realized employing fabrication techniques of the traditional metal trench waveguides and could be leveraged as important elements for highly-integrated photonic circuits. PMID- 23938554 TI - LiF, an underestimated supercontinuum source in femtosecond transient absorption spectroscopy. AB - We present supercontinua generated in LiF and CaF(2) revealing that LiF is advantageous especially in the near UV region since it pushes the cut-off wavelength about 17 nm towards lower wavelengths and the occurrence of color centers, which has been considered as a drawback up to now, is not a limitation for its applicability in femtosecond transient absorption spectroscopy. Even though the color centers occur within a short time of illumination, they do not influence the supercontinuum generation significantly and they can furthermore, if desired, be eliminated from the substrate simply by heating. Thus LiF is a promising substrate for broad band measurements in the UV/vis range. PMID- 23938555 TI - Active unidirectional propagation of surface plasmons at subwavelength slits. AB - Highly efficient, active and compact, unidirectional surface plasmon (SP) propagator composed of double subwavelength slits; filled with organic electro optic (EO) material is proposed and investigated. By selecting appropriate structure parameters, obtained by solving phase relations between slits, the relative phase of SP generated at the slit exit aperture can be tailored. Simulation results show under normal illumination and external voltage of 8.7 V, SP launching efficiency of 55% and unidirectional SP extinction ratio about 47dB at wavelength of 632.8 nm is achieved. The power consumption of the structure is on the order of 9 fJ/bit which meet the power consumption limitation for optical devices. Moreover, the structure is very compact with effective total length of 1.2 um and thickness of 0.6 um. PMID- 23938556 TI - Estimation of angle-dependent mode coupling and attenuation in step-index plastic optical fibers from impulse responses. AB - We report on a method for estimation of angle-dependent mode coupling and attenuation in step-index plastic optical fibers (SI-POFs) from the shapes of impulse responses at two different fiber lengths. While alternating the fiber lengths, deviations between simulated and reference impulse responses are minimized by optimizing both mode coupling and attenuation parameters using pattern-search routines. Applying a matrix-based finite-difference approach to Gloge's time-dependent power flow equation fast computation of simulated impulse responses is enabled. We demonstrate that mode-dependent coupling and attenuation parameters converge to values that reconstruct fiber characteristics reported by other authors. We show that our results can be used for prediction of impulse responses, yielding determination of frequency responses, fiber bandwidths and coupling lengths. We conclude that our method enables characterization of SI-POFs from fiber impulse response measurements. PMID- 23938557 TI - Nanoscale dielectric-graphene-dielectric tunable infrared waveguide with ultrahigh refractive indices. AB - We propose in this paper a dielectric-graphene-dielectric tunable infrared waveguide based on multilayer metamaterials with ultrahigh refractive indices. The waveguide modes with different orders are systematically analyzed with numerical simulations based on both multilayer structures and effective medium approach. The waveguide shows hyperbolic dispersion properties from mid-infrared to far-infrared wavelength, which means the modes with ultrahigh mode indices could be supported in the waveguide. Furthermore, the optical properties of the waveguide modes could be tuned by the biased voltages on graphene layers. The waveguide may have various promising applications in the quantum cascade lasers and bio-sensing. PMID- 23938558 TI - Integrated polarization rotator/converter by stimulated Raman adiabatic passage. AB - We proposed a polarization rotator inspired by stimulated Raman adiabatic passage model from quantum optics, which is composed of a signal waveguide and an ancillary waveguide. The two orthogonal modes in signal waveguide and the oblique mode in ancillary waveguide form a Lambda-type three-level system. By controlling the width of signal waveguide and the gap between two waveguides, adiabatic conversion between two orthogonal modes can be realized in the signal waveguide. With such adiabatic passage, polarization conversion is completed within 150 MUm length, with the efficiencies over 99% for both conversions between horizontal polarization and vertical polarization. In addition, such a polarization rotator is quite robust against fabrication error, allowing a wide range of tolerances for the rotator geometric parameters. Our work is not only significative to photonic simulations of coherent quantum phenomena with engineered photonic waveguides, but also enlightens the practical applications of these phenomena in optical device designs. PMID- 23938559 TI - Optical fingerprint recognition based on local minutiae structure coding. AB - A parallel volume holographic optical fingerprint recognition system robust to fingerprint translation, rotation and nonlinear distortion is proposed. The optical fingerprint recognition measures the similarity by using the optical filters of multiplexed holograms recorded in the holographic media. A fingerprint is encoded into multiple template data pages based on the local minutiae structure coding method after it is adapted for the optical data channel. An improved filter recording time schedule and a post-filtering calibration technology are combined to suppress the calculating error from the large variations in data page filling ratio. Experimental results tested on FVC2002 DB1 and a forensic database comprising 270,216 fingerprints demonstrate the robustness and feasibility of the system. PMID- 23938560 TI - Control of the properties of micro-structured waveguides in lithium niobate crystal. AB - We study numerically depressed-index cladding, buried, micro-structured optical waveguides that can be formed in a lithium niobate crystal by femtosecond laser writing. We demonstrate to which extent the waveguiding properties can be controlled by the waveguide geometry at the relatively moderate induced refractive index contrasts that are typical of the direct femtosecond inscription. PMID- 23938561 TI - Compact and phase-error-robust multilayered AWG-based wavelength selective switch driven by a single LCOS. AB - A novel liquid crystal on silicon (LCOS)-based wavelength selective switch (WSS) is proposed, fabricated, and demonstrated. It employs a multilayered arrayed waveguide grating (AWG) as a wavelength multiplex/demultiplexer. The LCOS deflects spectrally decomposed beams channel by channel and switches them to desired waveguide layers of the multilayered AWG. In order to obtain the multilayered AWG with high yield, phase errors of the AWG is externally compensated for by an additional phase modulation with the LCOS. This additional phase modulation is applied to the equivalent image of the facet of the AWG, which is projected by a relay lens. In our previously-reported WSS configuration, somewhat large footprint and increased cost were the drawbacks, since two LCOSs were required: one LCOS was driven for the inter-port switching operation, and the other was for the phase-error compensation. In the newly proposed configuration, on the other hand, both switching and compensation operations are performed using a single LCOS. This reduction of the component count is realized by introducing the folded configuration with a reflector. The volume of the WSS optics is 80 * 100 * 60 mm3, which is approximately 40% smaller than the previous configuration. The polarization-dependent loss and inter-channel crosstalk are less than 1.5 dB and -21.0 dB, respectively. An error-free transmission of 40-Gbit/s NRZ-OOK signal through the WSS is successfully demonstrated. PMID- 23938562 TI - Near- and far-field spectroscopic imaging investigation of resonant square-loop infrared metasurfaces. AB - Optical metamaterials have unique properties which result from geometric confinement of the optical conductivity. We developed a series of infrared metasurfaces based on an array of metallic square loop antennas. The far-field absorption spectrum can be designed with resonances across the infrared by scaling the geometric dimensions. We measure the amplitude and phase of the resonant mode as standing wave patterns within the square loops using scattering scanning near-field optical microscopy (s-SNOM). Further, using a broad-band synchrotron-based FTIR microscope and s-SNOM at the Advanced Light Source, we are able to correlate far-field spectra to near-field modes of the metasurface as the resonance is tuned between samples. The results highlight the importance of multi modal imaging for the design and characterization of optical metamaterials. PMID- 23938563 TI - Portable, miniaturized, fibre delivered, multimodal CARS exoscope. AB - We demonstrate for the first time, a portable multimodal coherent anti-Stokes Raman scattering microscope (exoscope) for minimally invasive in-vivo imaging of tissues. This device is based around a micro-electromechanical system scanning mirror and miniaturized optics with light delivery accomplished by a photonic crystal fibre. A single Ti:sapphire femtosecond pulsed laser is used as the light source to produce CARS, two photon excitation fluorescence and second harmonic generation images. The high resolution and distortion-free images obtained from various resolution and bio-samples, particularly in backward direction (epi) successfully demonstrate proof of concept, and pave the path towards future non or minimally-invasive in vivo imaging. PMID- 23938564 TI - Plasmon resonances and strong electric field enhancements in side-by-side tangent nanospheroid homodimers. AB - The plasmon resonance and electric field enhancement in a side-by-side tangent nanospheroid homodimer (TNSHD) have been investigated theoretically by using DDA and FDTD methods, respectively. The simulation results indicate that this side-by side TNSHD has its novel optical properties. We find that the plasmon resonance with a distinct Fano lineshape can be achieved and the electric field intensity can be enhanced strongly. The tunability of the Fano resonance could provide important applications in biosensing. The obtained electric field enhancement might open a promising pathway for surface-enhanced Raman scattering (SERS) and light trapping in solar cells. PMID- 23938565 TI - BOTDA measurements tolerant to non-local effects by using a phase-modulated probe wave and RF demodulation. AB - We demonstrate a Brillouin optical time domain analysis sensor based on a phase modulated probe wave and RF demodulation that provides measurements tolerant to frequency-dependent variations of the pump pulse power induced by non-local effects. The tolerance to non-local effects is based on the special characteristics of the detection process, which provides an RF phase-shift signal that is largely independent of the Brillouin gain magnitude. Proof-of-concept experiments performed over a 20-km-long fiber demonstrate that the measured RF phase-shift spectrum remains unaltered for large frequency-dependent deformations of the pump pulse power. Therefore, it allows the use of a higher optical power of the probe wave, which leads to an enhancement of the detected signal to noise ratio. This can be used to extend the sensing distance, to improve the accuracy of the Brillouin frequency shift measurements, and to reduce the measurement time. PMID- 23938566 TI - Probing terahertz metamaterials with subwavelength optical fibers. AB - Transmission through a subwavelength terahertz fiber, which is positioned in parallel to a frequency selective surface, is studied using several finite element tools. Both the band diagram technique and the port-based scattering matrix technique are used to explain the nature of various resonances in the fiber transmission spectrum. First, we observe that spectral positions of most of the transmission peaks in the port-based simulation can be related to the positions of Van Hove singularities in the band diagram of a corresponding infinite periodic system. Moreover, spectral shape of most of the features in the fiber transmission spectrum can be explained by superposition of several Fano type resonances. We also show that center frequencies and bandwidths of these resonances and, as a consequence, spectral shape of the resulting transmission features can be tuned by varying the fiber-metamaterial separation. PMID- 23938567 TI - Fabrication tolerances of SOI based directional couplers and ring resonators. AB - In this work the effect of deviations of the waveguide shape introduced by manufacturing tolerances on the performance of lateral directional couplers and ring resonators based on SOI-rib-waveguides are investigated by using Full Wave 3D Finite Element Method. Beside dimensional deviations like waveguide width and slab thickness for the first time the influence of waveguide sidewall angle and wet chemical cleaning procedures on the device performance are carefully analyzed. Efficient measures against systematic process tolerances are proposed and possible actions to improve device stability and reproducibility are discussed. PMID- 23938568 TI - Plasmonic photoconductive detectors for enhanced terahertz detection sensitivity. AB - A photoconductive terahertz detector based on plasmonic contact electrodes is presented. The use of plasmonic electrodes mitigates the inherent tradeoff between high quantum efficiency and ultrafast operation of the employed photoconductor, enabling significantly higher detection sensitivities compared to conventional photoconductive terahertz detectors. Prototypes of comparable photoconductive detectors with and without plasmonic contact electrode gratings were fabricated and characterized in a time-domain terahertz spectroscopy setup under the same operation conditions. The experimental results show that the plasmonic photoconductive detector offers more than 30 times higher terahertz detection sensitivities compared to the comparable conventional photoconductive detector without plasmonic contact electrodes over 0.1-1.5 THz frequency band. PMID- 23938569 TI - Phase-shifting interferometry based on the lateral displacement of the light source. AB - A simple and inexpensive optical setup to phase-shifting interferometry is proposed. This optical setup is based on the Twyman-Green Interferometer where the phase shift is induced by the lateral displacement of the point laser source. A theoretical explanation of the induced phase by this alternative method is given. The experimental results are consistent with the theoretical expectations. Both, the phase shift and the wrapped phase are recovered by a generalized phase shifting algorithm from two or more interferograms with arbitrary and unknown phase shift. The experimental and theoretical results show the feasibility of this unused phase-shifting technique. PMID- 23938570 TI - Phase extraction from interferograms with unknown tilt phase shifts based on a regularized optical flow method. AB - A novel method is presented to extract phase distribution from phase-shifted interferograms with unknown tilt phase shifts. The proposed method can estimate the tilt phase shift between two temporal phase-shifted interferograms with high accuracy, by extending the regularized optical flow method with the spatial image processing and frequency estimation technology. With all the estimated tilt phase shifts, the phase component encoded in the interferograms can be extracted by the least-squares method. Both simulation and experimental results have fully proved the feasibility of the proposed method. Particularly, a flat-based diffractive optical element with quasi-continuous surface is tested by the proposed method with introduction of considerably large tilt phase shift amounts (i.e., the highest estimated tilt phase shift amount between two consecutive frame reaches 6.18lambda). The phase extraction result is in good agreement with that of Zygo's MetroPro software under steady-state testing conditions, and the residual difference between them is discussed. In comparison with the previous methods, the proposed method not only has relatively little restrictions on the amounts or orientations of the tilt phase shifts, but also works well with interferograms including open and closed fringes in any combination. PMID- 23938571 TI - Evanescent wave coupling in terahertz waveguide arrays. AB - We study energy transfer among an array of identical finite-width parallel-plate waveguides in close proximity, via evanescent wave coupling of broadband terahertz waves. We observe stronger coupling with larger plate separations and longer propagation paths. This work establishes a platform to investigate new opportunities for THz components and devices based on evanescent wave coupling. PMID- 23938573 TI - Generation of tunable three-dimensional polarization in 4Pi focusing system. AB - We show that, by uniformly modulating the amplitude or polarization of one half of the input beam, a tunable three-dimensional (3D) polarization field near the focus of a 4Pi focusing system can be generated. If the input field is radially polarized and modulated by an amplitude-phase modulator, the longitudinal component of the focused field will partially convert to the transversal one according to the modulation factor and a 3D linear polarization state is created. If the input field is circularly polarized in one half and elliptically polarized in another half, the focal field will have elliptical polarization with the normal to the polarization ellipse being 3D controllable, corresponding to a 3D controllable spin angular momentum. PMID- 23938574 TI - Enhancement of multi-pulse laser induced damage threshold on Cu mirror under vacuum condition. AB - Multi-pulse laser induced damage threshold (LIDT) for metallic mirrors are important issue for laser diagnostics in future fusion devices. In this paper, the mechanism of multi-pulse LIDT and the influence of the slip formation and oxidization in atmosphere were investigated experimentally with a Nd:YAG pulse laser whose pulse width and wavelength are ~ 5 ns and 1064 nm, respectively. From detailed surface analysis of laser irradiated part by transmission electron microscopy (TEM), it was found that the miniaturization of crystal size and slip formation were observed on damaged area. Oxidization feature was also revealed from the TEM analysis. It was shown that the multi-pulse LIDT could be increased under vacuum condition compared with that in air atmosphere. PMID- 23938572 TI - Two-photon imaging of multiple fluorescent proteins by phase-shaping and linear unmixing with a single broadband laser. AB - Imaging multiple fluorescent proteins (FPs) by two-photon microscopy has numerous applications for studying biological processes in thick and live samples. Here we demonstrate a setup utilizing a single broadband laser and a phase-only pulse shaper to achieve imaging of three FPs (mAmetrine, TagRFPt, and mKate2) in live mammalian cells. Phase-shaping to achieve selective excitation of the FPs in combination with post-imaging linear unmixing enables clean separation of the fluorescence signal of each FP. This setup also benefits from low overall cost and simple optical alignment, enabling easy adaptation in a regular biomedical research laboratory. PMID- 23938575 TI - Controlling mode instabilities by dynamic mode excitation with an acousto-optic deflector. AB - We demonstrate an approach to actively stabilize the beam profile of a fiber amplifier above the mode instability threshold. Both the beam quality and the pointing stability are significantly increased at power levels of up to three times the mode instabilities threshold. The physical working principle is discussed at the light of the recently published theoretical explanations of mode instabilities. PMID- 23938576 TI - Focusing polychromatic light through strongly scattering media. AB - We demonstrate feedback-optimized focusing of spatially coherent polychromatic light after transmission through strongly scattering media, and describe the relationship between optimized focus intensity and initial far-field speckle contrast. Optimization is performed using a MEMS spatial light modulator with camera-based or spectrometer-based feedback. We observe that the spectral bandwidth of the optimized focus depends on characteristics of the feedback signal. We interpret this dependence as a modification in the number of independent frequency components, or spectral correlations, transmitted by the sample, and introduce a simple model for polychromatic focus enhancement that is corroborated by experiment with calibrated samples. PMID- 23938577 TI - Ge/Si heterojunction photodiodes fabricated by low temperature wafer bonding. AB - We report on the photoresponse of an asymmetrically doped p(-)-Ge/n(+)-Si heterojunction photodiode fabricated by wafer bonding. Responsivities in excess of 1 A/W at 1.55 MUm are measured with a 5.4 MUm thick Ge layer under surface normal illumination. Capacitance-voltage measurements show that the interfacial band structure is dependent on both temperature and light level, moving from depletion of holes at -50 degrees C to accumulation at 20 degrees C. Interface traps filled by photo-generated and thermally-generated carriers are shown to play a crucial role. Their filling alters the potential barrier height at the interface leading to increased flow of dark current and the above unity responsivity. PMID- 23938578 TI - On-chip optical phase locking of single growth monolithically integrated Slotted Fabry Perot lasers. AB - This work investigates the optical phase locking performance of Slotted Fabry Perot (SFP) lasers and develops an integrated variable phase locked system on chip for the first time to our knowledge using these lasers. Stable phase locking is demonstrated between two SFP lasers coupled on chip via a variable gain waveguide section. The two lasers are biased differently, one just above the threshold current of the device with the other at three times this value. The coupling between the lasers can be controlled using the variable gain section which can act as a variable optical attenuator or amplifier depending on bias. Using this, the width of the stable phase locking region on chip is shown to be variable. PMID- 23938579 TI - Controlling the optical properties of composite multilayered photonic structures: effect of superposition. AB - Tunability of the optical response of multilayered photonic structures has been compared with sequential (SQ) and superposition (SP) addition of refractive index profile functions. The optical response of the composite multilayered structure, formed after the SP addition of the two Bragg type refractive index profile functions has been studied as a function of percentage overlap and relative shift between the profiles. Apart from the substantial advantage in terms of the reduced physical thickness of the SP composite structures (over the SQ addition), at certain optimum values of relative shift, photonic structures with better quality factor resonant modes or a broader PBG could be designed. Similar analysis has been extended for rugate filters as well. The experimental verification of the optical response, was carried out through multilayered dielectric porous silicon structures fabricated by electrochemical anodization. PMID- 23938580 TI - X-ray phase contrast imaging and noise evaluation using a single phase grating interferometer. AB - In this paper we present some quantitative measurements of X-ray phase contrast images and noise evaluation obtained with a recent grating based X-ray phase contrast interferometer. This device is built using a single phase grating and a large broadband X-ray source. It was calibrated using a reference sample and finally used to perform measurements of a biological fossil: a mosquito trapped in amber. As phase images, noise was evaluated from the measured interferograms. PMID- 23938581 TI - In-line flat-top comb filter based on a cascaded all-solid photonic bandgap fiber intermodal interferometer. AB - In this paper, an in-line comb filter with flat-top spectral response is proposed and constructed based on a cascaded all-solid photonic bandgap fiber modal interferometer. It consists of two short pieces of all-solid photonic bandgap fiber and two standard single-mode fibers as lead fibers with core-offset splices between them. The theoretical and experimental results demonstrated that by employing a cut and resplice process on the central position of all-solid photonic bandgap fiber, the interference spectra are well tailored and flat-top spectral profiles could be realized by the controllable offset amount of the resplice. The channel position also could be tuned by applying longitudinal torsion with up to 4 nm tuning range. Such a flat-top fiber comb filter is easy to-fabricate and with a designable passband width and flat-top profile. PMID- 23938582 TI - Efficient Ho:LuLiF4 laser diode-pumped at 1.15 MUm. AB - We report the first laser operation based on Ho(3+)-doped LuLiF(4) single crystal, which is directly pumped with 1.15-MUm laser diode (LD). Based on the numerical model, it is found that the "two-for-one" effect induced by the cross relaxation plays an important role for the laser efficiency. The maximum continuous wave (CW) output power of 1.4 W is produced with a beam propagation factor of M(2) ~2 at the lasing wavelength of 2.066 MUm. The slope efficiency of 29% with respect to absorbed power is obtained. PMID- 23938583 TI - Time-spatial drift of decelerating electromagnetic pulses. AB - A time dependent electromagnetic pulse generated by a current running laterally to the direction of the pulse propagation is considered in paraxial approximation. It is shown that the pulse envelope moves in the time-spatial coordinates on the surface of a parabolic cylinder for the Airy pulse and a hyperbolic cylinder for the Gaussian. These pulses propagate in time with deceleration along the dominant propagation direction and drift uniformly in the lateral direction. The Airy pulse stops at infinity while the asymptotic velocity of the Gaussian is nonzero. PMID- 23938584 TI - Study of EDFA and Raman system transmission reach with 256 Gb/s PM-16QAM signals over three optical fibers with 100 km spans. AB - We compare the transmission performance of three different optical fibers in separate 256 Gb/s PM-16QAM systems amplified with erbium doped fiber amplifiers (EDFAs) and distributed Raman amplification. The span length in each system is 100 km. The fibers studied include standard single-mode fiber, single-mode fiber with ultra-low loss, and ultra-low loss fiber with large effective area. We find that the single-mode fiber with ultra-low loss and the large effective area fiber with ultra-low loss afford reach advantages of up to about 31% and 80%, respectively, over standard fiber measured at distances with 3 dB margin over the forward error correction (FEC) threshold. The Raman amplified systems provide about 50% reach length enhancement over the EDFA systems for all three fibers in the experimental set-up. For the best performing fiber with large effective area and ultra-low loss, the absolute reach lengths with 3 dB margin are greater than 1140 km and 1700 km for the for EDFA and Raman systems, respectively. PMID- 23938585 TI - Efficient group delay averaging in graded-index plastic optical fiber with microscopic heterogeneous core. AB - Intrinsic mode coupling in a graded-index plastic optical fiber (GI POF) is investigated using the developed coupled power theory for a GI POF with a microscopic heterogeneous core. The results showed that the intrinsic material properties can induce random power transitions between all the guided modes, whereas the structural deformation of microbending results in nearest-neighbor coupling. It was numerically demonstrated that efficient group-delay averaging due to intrinsic mode coupling brings the pronounced bandwidth enhancement in fibers with much shorter length than the case of glass multimode fibers. PMID- 23938586 TI - Magnetic field sensor based on fiber Bragg grating with a spiral microgroove ablated by femtosecond laser. AB - A novel magnetic field sensor based on Terfenol-D coated fiber Bragg grating with spiral microstructure was proposed and demonstrated. Through a specially-designed holder, the spiral microstructure was ablated into the fiber Bragg grating (FBG) cladding by femtosecond laser. Due to the spiral microstructure, the sensitivity of FBG coated with magnetostrictive film was enhanced greatly. When the spiral pitch is 50 MUm and microgroove depth is 13.5 MUm, the sensitivity of the magnetic field sensor is roughly 5 times higher than that of non-microstructured standard FBG. The response to magnetic field is reversible, and could be applicable for magnetic field detection. PMID- 23938587 TI - Controllable double tunneling induced transparency and solitons formation in a quantum dot molecule. AB - We consider the coupling effect between interdot tunneling coupling and external optical control field to study the linear optical property and the formation of temporal optical solitons in a quantum dot molecules system, analytically. The results show that the double tunneling induced transparency (TIT) windows are appeared in the absorption curve of probe field because of the formation of dynamic Stark splitting and quantum destructive interference effect from the two upper levels. Interestingly, the width of the TIT window becomes wider with the increasing intensity of the optical control field. We also find that the Kerr nonlinear effect of the probe field can be modulated effectively through coherent control both the control field and the interdot tunneling coupling in this system. Meanwhile, we demonstrate that the formation of dark or bright solitons can be practical regulated by varying the intensity of the optical control field. PMID- 23938588 TI - Circular hybrid plasmonic waveguide with ultra-long propagation distance. AB - We propose a novel plasmonic waveguide structure, which is referred to as a circular hybrid plasmonic waveguide (HPW) and consists of a metal wire covered with low- and high-index dielectric layers. The circular HPW exhibits two distinctly different modes, namely, the strongly localized mode and the extremely low-loss mode. Our numerical calculation demonstrates that the strongly localized mode exhibits 10-4 order scale in normalized mode area and can be performed even in tens of nanometer sizes of waveguide geometry. In the extremely low-loss mode, the HPW exhibits ultra-long propagation distance of more than 103MUm that can be achieved by forming the dipole-like hybrid mode and properly adjusting the radius of the metal wire. It is also shown that, even with this long-range propagation, the mode area of the dipole-like hybrid mode can be maintained at subwavelength scale. The simultaneous achievement of a small mode area and ultra-long propagation distance contributes to the ultra-high propagation distance to mode size ratio of the waveguide. The HPW results are very helpful for plasmonic device applications in the fields of low-threshold nanolasers, ultrafast modulators, and optical switches. PMID- 23938589 TI - High slope efficiency and high refractive index change in direct-written Yb-doped waveguide lasers with depressed claddings. AB - We report the first Yb:ZBLAN and Yb:IOG10 waveguide lasers fabricated by the fs laser direct-writing technique. Pulses from a Titanium-Sapphire laser oscillator with 5.1 MHz repetition rate were utilized to generate negative refractive index modifications in both glasses. Multiple modifications were aligned in a depressed cladding geometry to create a waveguide. For Yb:ZBLAN we demonstrate high laser slope efficiency of 84% with a maximum output power of 170 mW. By using Yb:IOG10 a laser performance of 25% slope efficiency and 72 mW output power was achieved and we measured a remarkably high refractive index change exceeding Deltan = 2.3 * 10(-2). PMID- 23938590 TI - Characterization of task-free and task-performance brain states via functional connectome patterns. AB - Both resting state fMRI (R-fMRI) and task-based fMRI (T-fMRI) have been widely used to study the functional activities of the human brain during task-free and task-performance periods, respectively. However, due to the difficulty in strictly controlling the participating subject's mental status and their cognitive behaviors during R-fMRI/T-fMRI scans, it has been challenging to ascertain whether or not an R-fMRI/T-fMRI scan truly reflects the participant's functional brain states during task-free/task-performance periods. This paper presents a novel computational approach to characterizing and differentiating the brain's functional status into task-free or task-performance states, by which the functional brain activities can be effectively understood and differentiated. Briefly, the brain's functional state is represented by a whole-brain quasi stable connectome pattern (WQCP) of R-fMRI or T-fMRI data based on 358 consistent cortical landmarks across individuals, and then an effective sparse representation method was applied to learn the atomic connectome patterns (ACPs) of both task-free and task-performance states. Experimental results demonstrated that the learned ACPs for R-fMRI and T-fMRI datasets are substantially different, as expected. A certain portion of ACPs from R-fMRI and T-fMRI data were overlapped, suggesting some subjects with overlapping ACPs were not in the expected task-free/task-performance brain states. Besides, potential outliers in the T-fMRI dataset were further investigated via functional activation detections in different groups, and our results revealed unexpected task-performances of some subjects. This work offers novel insights into the functional architectures of the brain. PMID- 23938591 TI - Novel WWP2 ubiquitin ligase isoforms as potential prognostic markers and molecular targets in cancer. AB - The WWP2 E3 ubiquitin ligase has previously been shown to regulate TGFbeta/Smad signalling activity linked to epithelial-mesenchymal transition (EMT). Whilst inhibitory I-Smad7 was found to be the preferred substrate for full-length WWP2 FL and a WWP2-C isoform, WWP2-FL also formed a stable complex with an N-terminal WWP2 isoform (WWP2-N) in the absence of TGFbeta, and rapidly stimulated activating Smad2/3 turnover. Here, using stable knockdown experiments we show that specific depletion of individual WWP2 isoforms impacts differentially on Smad protein levels, and in WWP2-N knockdown cells we unexpectedly find spontaneous expression of the EMT marker vimentin. Re-introduction of WWP2-N into WWP2-N knockout cells also repressed TGFbeta-induced vimentin expression. In support of the unique role for WWP2-N in regulating TGFbeta/Smad functional activity, we then show that a novel V717M-WWP2 mutant in the MZ7-mel melanoma cell line forms a stable complex with the WWP2-N isoform and promotes EMT by stabilizing Smad3 protein levels. Finally, we report the first analysis of WWP2 expression in cancer cDNA panel arrays using WWP2 isoform-specific probes and identify unique patterns of WWP2 isoform abundance associated with early/advanced disease stages. WWP2-N is significantly downregulated in stage IIIC melanoma and up-regulated in stage II/III prostate cancer, and we also find isolated examples of WWP2-FL and WWP2-C overexpression in early-stage breast cancer. Together, these data suggest that individual WWP2 isoforms, and particularly WWP2-N, could play central roles in tumourigenesis linked to aberrant TGFbeta-dependent signalling function, and also have potential as both prognostic markers and molecular therapeutic targets. PMID- 23938592 TI - Functional and connectivity changes during working memory in Huntington's disease: 18 month longitudinal data from the IMAGE-HD study. AB - BACKGROUND: This study aimed to characterize, for the first time, 18 month longitudinal changes in both functional activation and functional connectivity during working memory in premanifest Huntington's disease (pre-HD) and symptomatic HD (symp-HD). METHODS: Functional magnetic resonance imaging (fMRI) was used to investigate longitudinal changes in neuronal activity during working memory performance via an N-BACK task (0-BACK and 1-BACK) in 27 pre-HD, 17 symp HD, and 23 control participants. Whole-brain analysis of activation and region-of interest analysis of functional connectivity was applied to longitudinal fMRI data collected at baseline and 18 months follow-up. RESULTS: Compared with controls, the pre-HD group showed significantly increased activation longitudinally during 1-BACK versus 0-BACK in the lateral and medial prefrontal, anterior cingulate, primary motor, and temporal areas cortically, and caudate and putamen subcortically. Pre-HD far from onset, compared with controls, showed further longitudinal increases in the right and left dorsolateral prefrontal cortex (DLPFC). Longitudinal increased activation in anterior cingulate and medial primary motor areas were associated with disease burden in the pre-HD group. Moreover, in pre-HD increased activation over time in primary motor and putamen regions were associated with average response time during 1-BACK performance. During 1-BACK, functional connectivity between the right DLPFC and posterior parietal, anterior cingulate, and caudate was significantly reduced over 18months only in the pre-HD group. CONCLUSIONS: Longitudinal reductions in connectivity over 18 months may represent an early signature of cortico-cortical and cortico-striatal functional disconnectivity in pre-HD, whereas the concomitant increased cortical and subcortical activation may reflect a compensatory response to the demands for cognitive resources required during task performance. Our findings demonstrate that functional imaging modalities have the potential to serve as sensitive methods for the assessment of cortical and subcortical responses to future treatment measures. PMID- 23938593 TI - Polycystic kidney disease: Cyst growth and cilia in ADPKD. PMID- 23938594 TI - Nephrotic syndrome: Rituximab in childhood steroid-dependent nephrotic syndrome. PMID- 23938595 TI - Transplantation: Risk of graft loss in adolescent kidney allograft recipients. PMID- 23938597 TI - Dialysis: A step towards optimal dialysate bicarbonate concentration. PMID- 23938596 TI - Stromal cells in tissue homeostasis: balancing regeneration and fibrosis. AB - The ageing population and the increasing prevalence of noncommunicable diseases such as diabetes and hypertension have led to an increased prevalence of chronic kidney disease. The generation of de novo kidney tissue from embryonic tissue and stem cells using tissue engineering approaches is being explored as an alternative to renal replacement therapy for treating the disease. It is, however, becoming clear that resident cells can not only induce fibrotic repair, but can also restore damaged kidney tissue. Mobilizing this innate capacity of the kidney to regenerate is of particular interest in the prevention of irreversible kidney failure. A novel concept is that the interaction of interstitial stromal cells with the local immune system may regulate tissue homeostasis and the balance between tissue repair and fibrosis. Mesenchymal stromal cells (MSCs), in particular, may enhance the intrinsic reparative capabilities of the kidney. This Perspectives article considers the innate regenerative potential of the kidney in the context of ongoing studies of MSC therapy. PMID- 23938599 TI - A simulation-based approach for improving utilization of thrombolysis in acute brain infarction. AB - BACKGROUND: Treatment with tissue plasminogen activator (tPA) is the most effective treatment in acute brain infarction. However, estimated worldwide treatment rates are <10%, with many barriers hampering broad implementation. Organization and resource-intense randomized controlled trials cannot address all potential barriers simultaneously. Simulation, however, may provide an efficient research means for testing interventions aimed at resolving barriers along the care pathway. RESEARCH DESIGN: A simulation-based approach reflecting the setup of a regional Dutch acute stroke pathway was used. First, barriers along the overall pathway were identified. Next, solutions to barriers were configured, and subsequently tested using simulation. RESULTS: Barriers along the stroke pathway and possible solutions were identified from the literature and expert consultation. The simulation model closely reproduced actually observed tPA treatment rate and overall process time (21.8% and 129 min for model outcomes vs. 22.1% and 127 min, P=0.89 and 0.64, respectively). Two barriers were overcome: (1) time spent by ambulance personnel on scene by a scoop-and-run protocol (1.4% increase in tPA rate, 7 min decrease in overall process time), and (2) time to laboratory results by introducing a point-of-care diagnostic device (3.2% increase in tPA rate, 20 min decrease in overall process time). CONCLUSIONS: A simulation-based approach is well suited to efficiently assess solutions to barriers along the overall stroke pathway. Substantial improvements in treatment rates and efficacy of thrombolysis may be achieved by implementing a scoop-and run protocol and point-of-care device. PMID- 23938598 TI - Validity of Race, Ethnicity, and National Origin in Population-based Cancer Registries and Rapid Case Ascertainment Enhanced With a Spanish Surname List. AB - BACKGROUND: Accurate information regarding race, ethnicity, and national origins is critical for identifying disparities in the cancer burden. OBJECTIVES: To examine the use of a Spanish surname list to improve the quality of race-related information obtained from rapid case ascertainment (RCA) and to estimate the accuracy of race-related information obtained from cancer registry records collected by routine reporting. SUBJECTS: Self-reported survey responses of 3954 participants from California enrolled in the Cancer Care Outcomes Research and Surveillance Consortium. MEASURES: Sensitivity, specificity, positive predictive value, and percent agreement. We used logistic regression to identify predictors of underreporting and overreporting of a race/ethnicity. RESULTS: Use of the Spanish surname list increased the sensitivity of RCA for Latino ethnicity from 37% to 83%. Sensitivity for cancer registry records collected by routine reporting was >=95% for whites, blacks, and Asians, and specificity was high for all groups (86%-100%). However, patterns of misclassification by race/ethnicity were found that could lead to biased cancer statistics for specific race/ethnicities. Discordance between self-reported and registry-reported race/ethnicity was more likely for women, Latinos, and Asians. CONCLUSIONS: Methods to improve race and ethnicity data, such as using Spanish surnames in RCA and instituting data collection guidelines for hospitals, are needed to ensure minorities are accurately represented in clinical and epidemiological research. PMID- 23938601 TI - Photocatalytic hydrogen production from a noble metal free system based on a water soluble porphyrin derivative and a cobaloxime catalyst. AB - A combination of noble-metal free components, a water soluble porphyrin photosensitizer zinc meso-tetrakis(1-methylpyridinium-4-yl)porphyrin chloride [ZnTMPyP(4+)]Cl4 (1) with cobaloxime complex [Co(III)(dmgH)2(py)Cl] (2) as a catalyst, creates an efficient system for photochemical hydrogen production acting under visible light with 280 TONs. This is the first example of a water soluble porphyrin acting as a photosensitizer for cobaloxime catalysed H2 production. PMID- 23938600 TI - Collaborative chronic care models for mental health conditions: cumulative meta analysis and metaregression to guide future research and implementation. AB - OBJECTIVE: Prior meta-analysis indicates that collaborative chronic care models (CCMs) improve mental and physical health outcomes for individuals with mental disorders. This study aimed to investigate the stability of evidence over time and identify patient and intervention factors associated with CCM effects to facilitate implementation and sustainability of CCMs in clinical practice. METHODS: We reviewed 53 CCM trials that analyzed depression, mental quality of life (QOL), or physical QOL outcomes. Cumulative meta-analysis and metaregression were supplemented by descriptive investigations across and within trials. RESULTS: Most trials targeted depression in the primary care setting, and cumulative meta-analysis indicated that effect sizes favoring CCM quickly achieved significance for depression outcomes, and more recently achieved significance for mental and physical QOL. Four of 6 CCM elements (patient self management support, clinical information systems, system redesign, and provider decision support) were common among reviewed trials, whereas 2 elements (health care organization support and linkages to community resources) were rare. No single CCM element was statistically associated with the success of the model. Similarly, metaregression did not identify specific factors associated with CCM effectiveness. Nonetheless, results within individual trials suggest that increased illness severity predicts CCM outcomes. CONCLUSIONS: Significant CCM trials have been derived primarily from 4 original CCM elements. Nonetheless, implementing and sustaining this established model will require health care organization support. Although CCMs have typically been tested as population based interventions, evidence supports stepped care application to more severely ill individuals. Future priorities include developing implementation strategies to support adoption and sustainability of the model in clinical settings while maximizing fit of this multicomponent framework to local contextual factors. PMID- 23938602 TI - The pathological significance of Notch1 in oral squamous cell carcinoma. AB - Notch signaling has been reported to be involved in several types of malignant tumors; however, the role and activation mechanism of Notch signaling in oral squamous cell carcinoma (OSCC) remains poorly characterized. The purpose of this study was to elucidate the pathological significance of Notch signaling and its activation mechanism in the development and progression of OSCC. In this study, we showed that the expression of Notch1 and intracellular Notch domain (NICD) are upregulated in OSCCs. In addition, Notch1 and NICD were found to be characteristically localized at the invasive tumor front. TNF-alpha, a major inflammatory cytokine, significantly activated Notch signaling in vitro. In a clinicopathological analysis, Notch1 expression correlated with both the T-stage and the clinical stage. Furthermore, loss of Notch1 expression correlated with the inhibition of cell proliferation and TNF-alpha-dependent invasiveness in an OSCC cell line. In addition, gamma-secretase inhibitor (GSI) prevented cell proliferation and TNF-alpha-dependent invasion of OSCC cells in vitro. These results indicate that altered expression of Notch1 is associated with increased cancer progression and that Notch1 regulates the steps involved in cell metastasis in OSCC. Moreover, inactivating Notch signaling with GSI could therefore be a useful approach for treating patients with OSCC. PMID- 23938603 TI - Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin. AB - Vascular tumors are endothelial cell neoplasms whose cellular and molecular mechanisms, leading to tumor formation, are poorly understood, and current therapies have limited efficacy with significant side effects. We have investigated mechanistic (mammalian) target of rapamycin (mTOR) signaling in benign and malignant vascular tumors, and the effects of mTOR kinase inhibitor as a potential therapy for these lesions. Human vascular tumors (infantile hemangioma and angiosarcoma) were analyzed by immunohistochemical stains and western blot for the phosphorylation of p70 S6-kinase (S6K) and S6 ribosomal protein (S6), which are activated downstream of mTOR complex-1 (mTORC1). To assess the function of S6K, tumor cells with genetic knockdown of S6K were analyzed for cell proliferation and migration. The effects of topical rapamycin, an mTOR inhibitor, on mTORC1 and mTOR complex-2 (mTORC2) activities, as well as on tumor growth and migration, were determined. Vascular tumors showed increased activation of S6K and S6. Genetic knockdown of S6K resulted in reduced tumor cell proliferation and migration. Rapamycin fully inhibited mTORC1 and partially inhibited mTORC2 activities, including the phosphorylation of Akt (serine 473) and PKCalpha, in vascular tumor cells. Rapamycin significantly reduced vascular tumor growth in vitro and in vivo. As a potential localized therapy for cutaneous vascular tumors, topically applied rapamycin effectively reduced tumor growth with limited systemic drug absorption. These findings reveal the importance of mTOR signaling pathways in benign and malignant vascular tumors. The mTOR pathway is an important therapeutic target in vascular tumors, and topical mTOR inhibitors may provide an alternative and well-tolerated therapy for the treatment of cutaneous vascular lesions. PMID- 23938604 TI - Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells. AB - Lung cancers harboring epidermal growth factor receptor (EGFR) mutations depend on constitutive activation of the kinase for survival. Although most EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs) and shrink in response to treatment, acquired resistance to TKI therapy is common. We demonstrate here that two EGFR-mutated lung adenocarcinoma cell lines, HCC827 and HCC4006, contain a subpopulation of cells that have undergone epithelial-to mesenchymal transition and survive independent of activated EGFR. These EGFR independent cancer cells, herein termed gefitinib-resistant (GR) cells, demonstrate higher levels of basal autophagy than their parental cells and thrive under hypoxic, reduced-serum conditions in vitro; this somewhat simulates the hypoxic environment common to cancerous tissues. We show that depletion of the essential autophagy gene, ATG5, by small interfering RNA (siRNA) or chloroquine, an autophagy inhibitor, markedly reduces GR cell viability under hypoxic conditions. Moreover, we show a significant elevation in caspase activity in GR cells following knockdown of ATG5. These results suggest that GR cells can evade apoptosis and survive in hostile, hypoxic environments with constant autophagic flux. We also show the presence of autophagosomes in some cancer cells from patient samples, even in untreated EGFR-mutant lung cancer tissue samples. Together, our results indicate that autophagy inhibitors alone or in combination with EGFR TKIs may be an effective approach for the treatment of EGFR-mutant lung cancers, where basal autophagy of some cancer cells is upregulated. PMID- 23938605 TI - Antiviral functions of CD8(+) cytotoxic T cells in teleost fish. AB - Cytotoxic T-cells (CTLs) play a pivotal role in eliminating viruses in mammalian adaptive immune system. Many recent studies on T-cell immunity of fish have suggested that teleost CTLs are also important for antiviral immunity. Cellular functional studies using clonal ginbuan crucian carp and rainbow trout have provided in vivo and in vitro evidence that in many respects, virus-specific CTLs of fish have functions similar to those of mammalian CTLs. In addition, mRNA expression profiles of CTL-related molecules, such as CD8, TCR and MHC class I, have shown that in a wide range of fish species, CTLs are involved in antiviral adaptive immunity. These findings are a basis to formulate possible vaccination strategies to trigger effective antiviral CTL responses in teleost fish. This review describes recent advances in our understanding of antiviral CTL functions in teleost fish and discusses vaccination strategies for efficiently inducing CTL activities. PMID- 23938606 TI - Upconverting and NIR emitting rare earth based nanostructures for NIR-bioimaging. AB - In recent years, significant progress was achieved in the field of nanomedicine and bioimaging, but the development of new biomarkers for reliable detection of diseases at an early stage, molecular imaging, targeting and therapy remains crucial. The disadvantages of commonly used organic dyes include photobleaching, autofluorescence, phototoxicity and scattering when UV (ultraviolet) or visible light is used for excitation. The limited penetration depth of the excitation light and the visible emission into and from the biological tissue is a further drawback with regard to in vivo bioimaging. Lanthanide containing inorganic nanostructures emitting in the near-infrared (NIR) range under NIR excitation may overcome those problems. Due to the outstanding optical and magnetic properties of lanthanide ions (Ln(3+)), nanoscopic host materials doped with Ln(3+), e.g. Y2O3:Er(3+),Yb(3+), are promising candidates for NIR-NIR bioimaging. Ln(3+)-doped gadolinium-based inorganic nanostructures, such as Gd2O3:Er(3+),Yb(3+), have a high potential as opto-magnetic markers allowing the combination of time-resolved optical imaging and magnetic resonance imaging (MRI) of high spatial resolution. Recent progress in our research on over-1000 nm NIR fluorescent nanoprobes for in vivo NIR-NIR bioimaging will be discussed in this review. PMID- 23938607 TI - Addition of lithium carbenoids to isocyanates: a direct access to synthetically useful N-substituted 2-haloacetamides. AB - The addition of lithium carbenoids to isocyanates provides a versatile access to N-substituted 2-haloacetamides: the reaction tolerates the presence of variously functionalized substituents on the nitrogen atom, including sterically demanding ones and reactive halogens. No erosion of the enantiopurity was observed in the case of optically active isocyanates. One of the substrates prepared has been employed in Charette's type chemoselective addition of a Grignard reagent to access an alpha-chloroketone. PMID- 23938608 TI - The risk of uterine malignancy is linearly associated with body mass index in a cohort of US women. AB - OBJECTIVE: We sought to quantify the relationship of uterine malignancy with body mass index (BMI). STUDY DESIGN: The University HealthSystem Consortium database was queried to identify all women undergoing total hysterectomy with a recorded BMI in the overweight and obese categories. Least squares regression was applied to evaluate the association between increasing BMI and the proportion of women with a diagnosis of uterine malignancy. Multivariate binary logistic regression was performed to adjust for other known risk factors including age, race, and other comorbidities. RESULTS: There were 6905 women who met inclusion criteria; 1891 (27.4%) of these had uterine malignancy. There is a linear relationship (y = 0.015x - 0.23, R(2) = 0.92) of the probability of uterine malignancy vs BMI. After adjusting for other risk factors, we found that each 1-U increase in BMI was significantly, independently associated with an 11% increase in the proportion of patients diagnosed with uterine malignancy (odds ratio, 1.11; 95% confidence interval, 1.09-1.13; P < .001). CONCLUSION: In a population of women undergoing hysterectomy, we observed a linear increase in the frequency of uterine cancer associated with increasing BMI. This finding suggests that even relatively modest weight gain may significantly raise cancer risk. In the United States, the mean BMI for women is 26.5 kg/m(2) and it is estimated that more than half of US women have a BMI within the study's range. Our results could, therefore, be relevant to a majority of the population. The findings could increase popular acceptance of weight management as a key component of general health maintenance and, possibly, as an additional approach to cancer risk reduction. PMID- 23938609 TI - Diversities and similarities in pH dependency among bacterial NhaB-like Na+/H+ antiporters. AB - NhaB-like antiporters were the second described class of Na(+)/H(+) antiporters, identified in bacteria more than 20 years ago. While nhaB-like gene sequences have been found in a number of bacterial genomes, only a few of the NhaB-like antiporters have been functionally characterized to date. Although earlier studies have identified a few pH-sensitive and -insensitive NhaB-like antiporters, the mechanisms that determine their pH responses still remain elusive. In this study, we sought to investigate the diversities and similarities among bacterial NhaB-like antiporters, with particular emphasis on their pH responsiveness. Our phylogenetic analysis of NhaB-like antiporters, combined with pH profile analyses of activities for representative members of several phylogenetic groups, demonstrated that NhaB-like antiporters could be classified into three distinct types according to the degree of their pH dependencies. Interestingly, pH-insensitive NhaB-like antiporters were only found in a limited proportion of enterobacterial species, which constitute a subcluster that appears to have diverged relatively recently among enterobacterial NhaB-like antiporters. Furthermore, kinetic property analyses of NhaB-like antiporters at different pH values revealed that the degree of pH sensitivity of antiport activities was strongly correlated with the magnitude of pH-dependent change in apparent Km values, suggesting that the dramatic pH sensitivities observed for several NhaB like antiporters might be mainly due to the significant increases of apparent Km at lower pH. These results strongly suggested the possibility that the loss of pH sensitivity of NhaB-like antiporters had occurred relatively recently, probably via accumulation of the mutations that impair pH-dependent change of Km in the course of molecular evolution. PMID- 23938610 TI - Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. AB - IMPORTANCE: One in 88 children in the United States is diagnosed as having autism spectrum disorder. Significant interest centers on understanding the environmental factors that may contribute to autism risk. OBJECTIVE: To examine whether induced (stimulating uterine contractions prior to the onset of spontaneous labor) and/or augmented (increasing the strength, duration, or frequency of uterine contractions with spontaneous onset of labor) births are associated with increased odds of autism. DESIGN, SETTING, AND PARTICIPANTS: We performed an epidemiological analysis using multivariable logistic regression modeling involving the North Carolina Detailed Birth Record and Education Research databases. The study featured 625,042 live births linked with school records, including more than 5500 children with a documented exceptionality designation for autism. EXPOSURES: Induced or augmented births. MAIN OUTCOMES AND MEASURES: Autism as assessed by exceptionality designations in child educational records. RESULTS: Compared with children born to mothers who received neither labor induction nor augmentation, children born to mothers who were induced and augmented, induced only, or augmented only experienced increased odds of autism after controlling for potential confounders related to socioeconomic status, maternal health, pregnancy-related events and conditions, and birth year. The observed associations between labor induction/augmentation were particularly pronounced in male children. CONCLUSIONS AND RELEVANCE: Our work suggests that induction/augmentation during childbirth is associated with increased odds of autism diagnosis in childhood. While these results are interesting, further investigation is needed to differentiate among potential explanations of the association including underlying pregnancy conditions requiring the eventual need to induce/augment, the events of labor and delivery associated with induction/augmentation, and the specific treatments and dosing used to induce/augment labor (e.g., exogenous oxytocin and prostaglandins). PMID- 23938611 TI - Phenotypic characterization of transgenic Japanese medaka (Oryzias latipes) that express a red fluorescent protein in hepatocytes. AB - Transgenic organisms that express fluorescent proteins are used frequently for in vivo visualization of proteins and cells. The phenotype of a transgenic medaka (Oryzias latipes) strain that expresses a red fluorescent protein (RFP) in hepatocytes was characterized using light and fluorescence microscopy, immunohistochemistry, and transmission electron microscopy (TEM). Expression of RFP was first detected by confocal fluorescence microscopy in the location of the liver bud of live medaka embryos at 60 hr postfertilization (developmental stage 27). Subsequently, RFP signal was observed exclusively in hepatocytes throughout life using fluorescence microscopy in live fish and immunohistochemistry in formalin-fixed, paraffin-embedded liver sections. As the fish aged, prominent intracytoplasmic eosinophilic inclusions immunoreactive for RFP were observed by light microscopy and were correlated with membrane-bound electron dense inclusions on TEM. These results define the onset and location of RFP expression in the Tg(zf.L-fabp:DsRed) medaka and characterize a histologic phenotype that results from RFP expression in hepatocytes. PMID- 23938612 TI - Inhomogeneous phase-visibility modulating interferometry by space on-off non quadrature amplitude modulation. AB - A new method in interferometry based on on-off non-quadrature amplitude modulation for object phase retrieval is presented. Although the technique introduces inhomogeneous visibility and phase variations in the interferogram, it is shown that the phase retrieval of a given object is still possible. This method is implemented by using three beams and two Mach-Zehnder interferometers in series. One of the arms of the system is used as a probe beam and the other two are used as reference beams, yielding from their sum the conventional reference beam of a two-beam interferometer. We demonstrate that, if there is a phase difference within the range of (0,pi) between these two beams, the effect of modulation in both amplitude and phase is generated for the case of on-off non quadrature amplitude modulation. An analytical discussion is provided to sustain this method. Numerical and experimental results are also shown. PMID- 23938613 TI - Broadband subwavelength focusing of light using a passive sink. AB - Optical absorption is usually considered deleterious, something to avoid if at all possible. We propose a broadband nanoabsorber that completely eliminates the diffracting wave, resulting in a subwavelength enhancement of the field. Broadband operation is made possible by engineering the dispersion of the complex dielectric function. The local enhancement can be significantly improved compared to the standard plane wave illumination of a metallic nanoparticle. Our numerical simulation shows that an optical pulse as short as 6 fs can be focused to a 11 nm region. Not only the local field, but also its gradient are greatly enhanced, pointing to applications in ultrafast nonlinear spectroscopy, sensing and communication with deep-subwavelength resolution. PMID- 23938614 TI - Fluorescence enhancement with deep-ultraviolet surface plasmon excitation. AB - We report the experimental demonstration of fluorescence enhancement in fluorescent thin film using surface plasmon excitation in deep-ultraviolet (deep UV) region. Surface plasmon resonance in deep-UV is excited on aluminum thin film in the Kretschmann-Raether geometry. Considering the oxidation thickness of aluminum, the experimentally measured incident angle dependence of reflectance show good agreement with Fresnel theory. Surface plasmon resonance was excited at the incident angle of 49 degrees for 266 nm p-polarized excitation light on the film of 18 nm-thick aluminum with 6.5 nm-thick alumina. Fluorescence of CdS quantum dots coated on this aluminum film was enhanced to 18-fold in intensity by the surface plasmon excitation. PMID- 23938615 TI - Mobile device camera design with Q-type polynomials to achieve higher production yield. AB - The camera lenses that are built into the current generation of mobile devices are extremely stressed by the excessively tight packaging requirements, particularly the length. As a result, the aspheric departures and slopes on the lens surfaces, when designed with conventional power series based aspheres, are well beyond those encountered in most optical systems. When the as-manufactured performance is considered, the excessive aspheric slopes result in unusually high sensitivity to tilt and decenter and even despace resulting in unusually low manufacturing yield. Q(bfs) polynomials, a new formulation for nonspherical optical surfaces introduced by Forbes, not only build on orthogonal polynomials, but their unique normalization provides direct access to the RMS slope of the aspheric departure during optimization. Using surface shapes with this description in optimization results in equivalent performance with reduced alignment sensitivity and higher yield. As an additional approach to increasing yield, mechanically imposed external pivot points, introduced by Bottema, can be used as a design technique to further reduce alignment sensitivity and increase yield. In this paper, the Q-type polynomials and external pivot points were applied to a mobile device camera lens designed using an active RMS slope constraint that was then compared to a design developed using conventional power series surface descriptions. Results show that slope constrained Q-type polynomial description together with external pivot points lead directly to solutions with significantly higher manufacturing yield. PMID- 23938616 TI - Non-contact detection of oxygen saturation based on visible light imaging device using ambient light. AB - A method that remotely measures blood oxygen saturation through two cameras under regular lighting is proposed and experimentally demonstrated. Two narrow-band filters with their visible wavelength of 660nm and 520nm are mounted to two cameras respectively, which are then used to capture two photoplethysmographic (PPG) from the subject simultaneously. The data gathered from this system, including both blood oxygen saturation and heart rate, is compared to the output of a traditional figure blood volume pulse (BVP) senor that was employed on the subject at the same time. Result of the comparison showed that the data from the new, non-contact system is consistent and comparable with the BVP senor. Compared to other camera-based measuring method, which requires additional close-up lighting, this new method is achievable under regular lighting condition, therefore more stable and easier to implement. This is the first demonstration of an accurate video-based method for non-contact oxygen saturation measurements by using ambient light with their respective visible wavelength of 660nm and 520nm which is free from interference of the light in other bands. PMID- 23938617 TI - Physical insights into inverse-scattering profiles and symmetric dispersionless FBG designs. AB - We revisit representative and widely used inverse-scattering fiber Bragg grating designs and shed physical insight into their characteristics. We first demonstrate numerically and experimentally that dispersionless square filters are actually dispersion compensated devices and we physically identify the spatially separated main (dispersive) reflector and dispersion compensator sections. We also look into the features of pure 2nd-order dispersion and 3rd-order dispersion compensator designs and discuss their physical importance. Finally, we use the gained physical insight to design strong symmetric gratings with dispersionless response from both sides. Using this knowledge we design and fabricate strong (>30dB) bidirectional dispersionless filters. PMID- 23938618 TI - Composite structure of SiO2@AgNPs@p-SiNWs for enhanced broadband optical antireflection. AB - The composite structure of SiO(2)@AgNPs@p-SiNWs based on silicon nanowires (SiNWs) produced by metal-assisted chemical etching (MaCE) method has been designed to realize the significant reflection suppression over a broad wavelength range (300 - 2500 nm). Especially, the reflectivity of the structure even below 0.3% at a wide range of 620 - 1950 nm can be achieved. It also has been demonstrated that SiO(2) capers play a dominant role in the significant reflection suppression of the composite structure. PMID- 23938619 TI - Reflection resonance switching in metamaterial twisted nematics cell. AB - Electric switching of reflection resonances at near-IR spectral range is experimentally demonstrated in a reflective metamaterial twisted nematic liquid crystal cell. Reflective metamaterial composed of nano-sized double-split ring resonator aperture is fabricated by a focused ion beam milling. Two-fold rotational symmetry of double-split ring resonators allows for two orthogonal polarization-dependent reflection resonances in the reflective metamaterial. With an external voltage of 10V across 12MUm cell gap, a full switching is achieved between two reflection resonances. Dynamic measurements show the time constants of switch-on and switch-off are in the order of 100ms and 10ms, respectively. PMID- 23938620 TI - Effects of driving laser jitter on the attosecond streaking measurement. AB - Driving laser jitter is one of the main factors affecting the attosecond streaking measurement. The effect of carrier-envelope phase (CEP) jitter and the pulse energy jitter on the attosecond pulse characterization is studied in this paper. We have theoretically calculated and experimentally confirmed that CEP jitter could result in a symmetry trace in the streaking spectrogram, while the intensity jitter could result in a slight shift and broadening of the trace. Both of them can lead to an underestimate of the retrieved attosecond pulse duration. PMID- 23938621 TI - 1.76Tb/s Nyquist PDM 16QAM signal transmission over 714km SSMF with the modified SCFDE technique. AB - Nyquist pulse shaping is a promising technique for high-speed optical fiber transmission. We experimentally demonstrate the generation and transmission of a 1.76Tb/s, polarization-division-multiplexing (PDM) 16 quadrature amplitude modulation (QAM) Nyquist pulse shaping super-channel over 714km standard single mode fiber (SSMF) with Erbium-doped fiber amplifier (EDFA) only amplification. The superchannel consists of 40 subcarriers tightly spaced at 6.25GHz with a spectral efficiency of 7.06b/s/Hz. The experiment is successfully enabled with the modified single carrier frequency domain estimation and equalization (SCFDE) scheme by performing training sequence based channel estimation in frequency domain and subsequent channel equalization in time domain. After 714km transmission, the bit-error-rate (BER) of all subcarriers are lower than the forward error correction limit of 3.8 * 10(-3). PMID- 23938622 TI - Propagation of cosine-Gaussian-correlated Schell-model beams in atmospheric turbulence. AB - A stochastic beam generated by a recently introduced source of Schell type with cosine-Gaussian spectral degree of coherence is shown to possess interesting novel features on propagation in isotropic and homogeneous atmospheric turbulence with general non-Kolmogorov power spectrum. It is shown that while at small distances from the source the beam's intensity exhibits annular profile with adjustable area of the dark region, the center disappears at sufficiently large distances and the beam's intensity tends to Gaussian form. Hence the 3D bottle beam is produced by the cumulative effect of the random source and the atmosphere. The distances at which the on-axis beam intensity has local minima and maxima are shown to have analytic dependence on the source and the atmospheric parameters. And the influence of the fractal constant of the atmospheric power spectrum and refractive-index structure constant on beam characteristics is analyzed in depth. The novel double-cycle qualitative change in the degree of coherence is shown to occur on atmospheric propagation which was not previously known for any other beams. PMID- 23938623 TI - Dual and anti-dual modes in dielectric spheres. AB - We present how the angular momentum of light can play an important role to induce a dual or anti-dual behaviour on a dielectric particle. Although the material the particle is made of is not dual, i.e. a dielectric does not interact with an electrical field in the same way as it does with a magnetic one, a spherical particle can behave as a dual system when the correct excitation beam is chosen. We study the conditions under which this dual or anti-dual behaviour can be induced. PMID- 23938624 TI - TE-mode coplanar imaging using weakly anisotropic metasurface. AB - We analyze and experimentally realize coplanar imaging of transverse-electric (TE) modes surface waves using weakly anisotropic metasurface consisting of non periodic subwavelength U-shaped metallic structures. Such metallic structures with the exciting coplanar dipole are integrated on the top surface of a thin dielectric board. A circuit model is utilized to analyze the characteristics of the surface waves supported by the metasurface. By varying the geometrical parameters of the U-shaped metallic structures, the phases of surface waves are modulated, from which a planar lens is presented for the TE-mode coplanar imaging. The analyses and measurements show that anisotropies of the U-shaped metallic structures have little influence on the imaging properties of the planar lens. The measurement results have good agreements to numerical simulations. PMID- 23938625 TI - Mimicking the nonlinear dynamics of optical fibers with waveguide arrays: towards a spatiotemporal supercontinuum generation. AB - We numerically demonstrate the formation of the spatiotemporal version of the so called diffractive resonant radiation generated in waveguide arrays with Kerr nonlinearity when a long pulse is launched into the system. The phase matching condition for the diffractive resonant radiation that we have found earlier for CW beams also works well in the spatiotemporal case. By introducing a linear potential, one can introduce a continuous shift of the central wavenumber of a linear pulse, whereas in the nonlinear case one can demonstrate that the soliton self-wavenumber shift can be compensated by the emission of diffractive resonant radiation, in a very similar fashion as it is done in optical fibers. This work paves the way for designing unique optical devices that generate spectrally broad supercontinua with a controllable directionality by taking advantage of the combined physics of optical fibers and waveguide arrays. PMID- 23938626 TI - Full-wave approach for x-ray phase imaging. AB - We present a rigorous forward model for phase imaging of a 3-D object illuminated by a cone-shaped x-ray beam. Our model is based on a full-wave approach valid under the first Rytov approximation, and thus can be used with large and thick objects, e.g., luggage and human patients. We unify light-matter interaction and free-space propagation into an integrated wave optics framework. Therefore, our model can accurately calculate x-ray phase images formed with sources of arbitrary shape, and it can be effectively incorporated into x-ray phase tomography as a forward model. Within the best of our knowledge, this is the first non-paraxial, full-wave model for X-ray phase imaging. PMID- 23938627 TI - Holographic plasmonic lenses for surface plasmons with complex wavefront profile. AB - We present a direct-method solution toward the general problem of plasmonic wavefront manipulation and shaping to realize pre-designated functionalities based on the surface-wave holography (SWH) method. We demonstrate theoretically and experimentally the design and fabrication of holographic plasmonic lenses over surface plasmons with complex wavefront profiles. We show that visible light at 632.8 nm transmitting through a high-aspect-ratio slit or a micro-rectangle hole in a silver film can be focused to a preset three-dimensional point spot in free space via appropriately manipulating the interaction of excited surface plasmons with the nanoscale groove pattern of the holographic lens. The experiment results of scanning near-field optical microscopy for measuring the three-dimensional optical field distribution agree well both with designs and with numerical simulations, and this strongly supports the effectiveness and efficiency of the SWH method in the design of plasmonic devices that can fulfill manipulation and transformation of complicated-profile surface plasmons. PMID- 23938629 TI - Dipole plasmon resonance induced large third-order optical nonlinearity of Au triangular nanoprism in infrared region. AB - Au triangular nanoprisms with strong dipole plasmon absorption peak at 1240 nm were prepared by wet chemical methods. Both numerical calculations and experiments were carried out to investigate the optical properties of the samples. Finite difference time domain (FDTD) and Local Density of States (LDOS) calculations demonstrate that strong electric field enhancement and large LDOS can be obtained at tip areas of the Au triangular nanoprisms. Z scan techniques were used to characterize the nonlinear absorption, nonlinear refraction, as well as one- and two-photon figures of merit (W and T, respectively) of the sample. The results show that maximum nonlinear refractive index can be obtained around the resonance absorption wavelength of 1240 nm, detuning the wavelength from the absorption peak will lead to the decrease of the nonlinear refractive index n(2), while the nonlinear absorption coefficient beta doesn't change much with the wavelength. This large wavelength dependence of n(2) and small change of beta enable the sample to satisfy the all-optical switching demand of W> 1 and T< 1 easily in a large wavelength range of 1200-1300 nm. These significant nonlinear properties of the sample imply that Au triangular nanoprism is a good candidate for future optical switches in infrared optical communication wavelength region. PMID- 23938630 TI - Orientation-dependant inclinometer based on intermodal coupling of two-LP-modes in a polarization-maintaining photonic crystal fiber. AB - A reflective optic-fiber orientation-dependant inclinometer, in which a short piece of polarization-maintaining photonic crystal fiber (PM-PCF) is spliced with a lead-in single mode fiber (SMF) without any offset, is proposed and experimentally demonstrated. The hollow holes within the PM-PCF are partly collapsed due to the directional arc-heating splicing and couple two linearly polarized (LP) modes into the downstream PM-PCF. Then two LP-modes are reflected at the end face of PM-PCF and recoupled back into the lead-in SMF again via the collapsed splicing cross section. A well-defined interference pattern is obtained as the result of polarized modes interference. Both orientation and sensitivity of bending is determined unambiguously with this compact PM-PCF configuration. PMID- 23938631 TI - Displaying a high-resolution digital hologram on a low-resolution spatial light modulator with the same resolution obtained from the hologram. AB - In this paper, a fast method for displaying a digital, real and off-axis Fresnel hologram on a lower resolution device is reported. Preserving the original resolution of the hologram upon display is one of the important attributes of the proposed method. Our method can be divided into 3 stages. First, a digital hologram representing a given three dimensional (3D) object is down-sampled based on a fix, jitter down-sampling lattice. Second, the down-sampled hologram is interpolated, through pixel duplication, into a low resolution hologram that can be displayed with a low-resolution spatial light modulator (SLM). Third, the SLM is overlaid with a grating which is generated based on the same jitter down sampling lattice that samples the hologram. The integration of the grating and the low-resolution hologram results in, to a good approximation, the resolution of the original hologram. As such, our proposed method enables digital holograms to be displayed with lower resolution SLMs, paving the way for the development of low-cost holographic video display. PMID- 23938632 TI - Effect of pump depletion on second harmonic generation in multiple quasi-phase matching gratings. AB - Second harmonic generation (SHG) from the aperiodic optical superlattice (AOS) in considering the pump depletion is investigated. It is found the domain configuration designed in undepleted pump approximation (UPA) can also be used to achieve multiple wavelength SHGs with high enough conversion efficiency for an exact solution. The applicable scope of UPA was estimated by a relative tolerance based on the related SHG conversion efficiency calculated in UPA and an exact solution. Results reveal that the relative tolerance is solely determined by the conversion efficiency, and unrelated to the sample configuration, pump intensity, incidental wavelength and nonlinear media. A model to evaluate an exact solution is proposed, and it is suggested that the SHG conversion efficiency can be easily assessed by the developed model. These results can be used to provide direct guidance for practical application, and can also make the estimation of practical samples more convenient. PMID- 23938633 TI - Fabrication imperfection analysis and statistics generation using precision and reliability optimization method. AB - This paper applies a recently proposed dominant point detection method - precision and reliability optimization (PRO) - for representing shapes in the microscopy images of fabricated structures. This method uses both the local and the global nature of fit for dominant point detection. A smaller value of its control parameter better represents the local curvature properties of the shape while a larger value better indicates the global curvature properties. The applicability of this method to a wide range of microscopy images is demonstrated using four microscopy examples of brightness enhancement films, electromagnetic and photonic band gap materials, and aspherical mirror alignments. It is shown that PRO can clearly highlight several image effects and imperfections which may not be easily identifiable by human eye or may be difficult to analyze and assess. Further, for large scale arrays, it can be used to generate useful fabrication accuracy statistics and detect features with low fidelity or more imperfections. PMID- 23938634 TI - Parametric seeding of a microresonator optical frequency comb. AB - We have investigated parametric seeding of a microresonator frequency comb (microcomb) by way of a pump laser with two electro-optic-modulation sidebands. We show that the pump-sideband spacing is precisely replicated throughout the microcomb's optical spectrum, and we demonstrate a record absolute line-spacing stability for microcombs of 1.6 * 10(-13) at 1 s. The spectrum of a microcomb is complex, and often non-equidistant subcombs are observed. Our results demonstrate that parametric seeding can not only control the subcombs, but can lead to the generation of a strictly equidistant microcomb spectrum. PMID- 23938635 TI - Inherent optical properties of the coccolithophore: Emiliania huxleyi. AB - A realistic nonspherical model for Emiliania huxleyi (EHUX) is built, based on electron micrographs of coccolithophore cells. The Inherent Optical Properties (IOP) of the EHUX are then calculated numerically by using the discrete dipole approximation. The coccolithophore model includes a near-spherical core with the refractive index of 1.04 + m(i)j, and a carbonate shell formed by smaller coccoliths with refractive index of 1.2 + m(i)j, where m(i) = 0 or 0.01 and j(2) = -1. The reported IOP are the Mueller scattering matrix, backscattering probability, and depolarization ratio. Our calculation shows that the Mueller matrices of coccolithophores show different angular dependence from those of coccoliths. PMID- 23938636 TI - Super-resolving single nitrogen vacancy centers within single nanodiamonds using a localization microscope. AB - In this paper, we show super-resolving single nitrogen vacancy (NV) centers with a sub-20 nanometer resolution in a wide-field localization microscope based on the discovery of photoluminescence blinking in high-pressure high-temperature nanodiamonds (NDs). The photon statistics reveals that NDs containing not only single but also multiple NV centers show photoluminescence blinking. The combination of an atomic force microscope and an optical localization microscope built on the blinking feature enables the optically resolved two NV centers within single NDs for the first time. Our method establishes new avenues for studying nanoscale photon dynamics associated with single NV centers within NDs together with ND-based ultra-sensitive bioimaging devices. PMID- 23938637 TI - Observation of a cascaded process in intracavity terahertz optical parametric oscillators based on lithium niobate. AB - Cascaded difference frequency generation has been observed in intracavity optical parametric oscillators based on bulk lithium niobate and producing nanosecond pulses of terahertz radiation. Two idler waves are generated, namely: the primary idler wave associated with the parametric down conversion process itself; and a secondary idler wave, due to difference frequency generation. Experimental investigations of the frequency, temporal evolution, propagation direction, intensity, phase matching and oscillation threshold of the generated down converted waves are reported. The overall generation efficiency for the terahertz radiation is enhanced, thereby overcoming the Manley-Rowe limit. Advantages of the present approach over schemes based on periodically poled lithium niobate are identified. PMID- 23938638 TI - Noise performance of phase-insensitive frequency multicasting in parametric mixer with finite dispersion. AB - Noise performance of dual-pump, multi-sideband parametric mixer operated in phase insensitive mode is investigated theoretically and experimentally. It is shown that, in case when a large number of multicasting idlers are generated, the noise performance is strictly dictated by the dispersion characteristics of the mixer. We find that the sideband noise performance is significantly degraded in anomalous dispersion region permitting nonlinear noise amplification. In contrast, in normal dispersion region, the noise performance converges to the level of four-sideband parametric process, rather than deteriorates with increased sideband creation. Low noise generation mandates precise dispersion induced phase mismatch among pump and sideband waves in order to control the noise coupling. We measure the noise performance improvement for a many-sideband, multi-stage mixer by incorporating new design technique. PMID- 23938640 TI - Scalable photonic quantum computing assisted by quantum-dot spin in double-sided optical microcavity. AB - We investigate the possibility of achieving scalable photonic quantum computing by the giant optical circular birefringence induced by a quantum-dot spin in a double-sided optical microcavity as a result of cavity quantum electrodynamics. We construct a deterministic controlled-not gate on two photonic qubits by two single-photon input-output processes and the readout on an electron-medium spin confined in an optical resonant microcavity. This idea could be applied to multi qubit gates on photonic qubits and we give the quantum circuit for a three-photon Toffoli gate. High fidelities and high efficiencies could be achieved when the side leakage to the cavity loss rate is low. It is worth pointing out that our devices work in both the strong and the weak coupling regimes. PMID- 23938641 TI - Vertical light-emitting diodes with surface gratings and rough surfaces for effective light extraction. AB - For enhancing the light extraction of a light-emitting diode, surface grating fabrication based on a simple method of combining photoelectrochemical (PEC) etching with phase mask interferometry has been demonstrated. To understand the optimum grating period in forming a surface grating on a vertical light-emitting diode (VLED), we construct a Llyod's interferometer within PEC electrolyte (KOH) to fabricate surface gratings of various periods on VLEDs for comparing their light extraction efficiencies. Also, to compare the effectiveness of light extraction enhancement between surface grating and rough surface, VLEDs with the rough surfaces fabricated with two different KOH wet etching methods are fabricated. The comparisons of VLED characterizations show that among those grating VLEDs, the light extraction is more effective in a VLED of a smaller grating period. Also, compared with VLEDs of rough surfaces, the grating VLEDs of short grating periods (<2 MUm) have the higher light extraction efficiencies, even though the root-mean-square roughness of the rough surface is significantly larger than the grating groove depth. PMID- 23938642 TI - Anomalous laser-induced group velocity dispersion in fused silica. AB - We present 20fs(2) accuracy laser-induced group velocity dispersion (LI-GVD) measurements, resulting from propagation of a femtosecond laser pulse in 1mm of fused silica, as a function of peak intensity. For a 5.5 * 10(11) W/cm(2) peak intensity, LI-GVD values are found to vary from -3 to + 15 times the material GVD. Normal induced dispersion can be explained by the Kerr effect, but anomalous LI-GVD, found when the input pulses have negative pre-chirp, cannot. These findings have significant implications regarding self-compression and the design of femtosecond lasers. PMID- 23938643 TI - Theoretical modeling and experiments on a DBR waveguide laser fabricated by the femtosecond laser direct-write technique. AB - We present a model for a Yb-doped distributed Bragg reflector (DBR) waveguide laser fabricated in phosphate glass using the femtosecond laser direct-write technique. The model gives emphasis to transverse integrals to investigate the energy distribution in a homogenously doped glass, which is an important feature of femtosecond laser inscribed waveguide lasers (WGLs). The model was validated with experiments comparing a DBR WGL and a fiber laser, and then used to study the influence of distributed rare earth dopants on the performance of such lasers. Approximately 15% of the pump power was absorbed by the doped "cladding" in the femtosecond laser inscribed Yb doped WGL case with the length of 9.8 mm. Finally, we used the model to determine the parameters that optimize the laser output such as the waveguide length, output coupler reflectivity and refractive index contrast. PMID- 23938644 TI - Quantitative lateral and axial flow imaging with optical coherence microscopy and tomography. AB - Optical coherence tomography (OCT) and optical coherence microscopy (OCM) allow the acquisition of quantitative three-dimensional axial flow by estimating the Doppler shift caused by moving scatterers. Measuring the velocity of red blood cells is currently the principal application of these methods. In many biological tissues, blood flow is often perpendicular to the optical axis, creating the need for a quantitative measurement of lateral flow. Previous work has shown that lateral flow can be measured from the Doppler bandwidth, albeit only for simplified optical systems. In this work, we present a generalized model to analyze the influence of relevant OCT/OCM system parameters such as light source spectrum, numerical aperture and beam geometry on the Doppler spectrum. Our analysis results in a general framework relating the mean and variance of the Doppler frequency to the axial and lateral flow velocity components. Based on this model, we present an optimized acquisition protocol and algorithm to reconstruct quantitative measurements of lateral and axial flow from the Doppler spectrum for any given OCT/OCM system. To validate this approach, Doppler spectrum analysis is employed to quantitatively measure flow in a capillary with both extended focus OCM and OCT. PMID- 23938645 TI - Virtual image display as a backlight for 3D. AB - We describe a device which has the potential to be used both as a virtual image display and as a backlight. The pupil of the emitted light fills the device approximately to its periphery and the collimated emission can be scanned both horizontally and vertically in the manner needed to illuminate an eye in any position. The aim is to reduce the power needed to illuminate a liquid crystal panel but also to enable a smooth transition from 3D to a virtual image as the user nears the screen. PMID- 23938646 TI - Subluminal and superluminal terahertz radiation in metamaterials with electromagnetically induced transparency. AB - We propose a scheme to design a new type of optical metamaterial that can mimic the functionality of four-state atomic systems of N-type energy-level configuration with electromagnetically induced transparency (EIT). We show that in such metamaterial a transition from a single EIT to a double EIT of terahertz radiation may be easily achieved by actively tuning the intensity of the infrared pump field or passively tuning the geometrical parameters of resonator structures. In addition, the group velocity of the terahertz radiation can be varied from subluminal to superluminal by changing the pump field intensity. The scheme suggested here may be used to construct chip-scale slow and fast light devices and to realize rapidly responded switching of terahertz radiation at room temperature. PMID- 23938647 TI - Continuous-wave Nd:YVO4 self-Raman lasers operating at 1109nm, 1158nm and 1231nm. AB - Several continuous-wave Nd:YVO(4) self-Raman lasers based on the primary and secondary Raman transitions of YVO(4) (893cm(-1) and 379cm(-1) respectively) are reported in this paper. Laser outputs were obtained at a wavelength of 1109nm, 1158nm and 1231nm with maximum output powers of 1.0W, 700mW and 540mW respectively. The respective absorbed pump power to Raman output power conversion efficiencies were measured at 8.4%, 5.4%, and 5.4%. PMID- 23938648 TI - Fano resonance formula for lossy two-port systems. AB - We provide a modified Fano resonance formula applicable to dissipative two-port resonance systems. Based on a generic coupled-resonator model, the formula embodies loss-related correction terms and fundamental resonance parameters that can be determined by an analytic method or experimentally as opposed to finding phenomenological parameters by fitting to numerical results. The theory applies physically meaningful resonance parameters including resonance frequency, total decay rates, and partial radiation probabilities. For example, it shows that the classic Fano shape parameter q is given directly in terms of the phase difference between the resonant and non-resonant transmission pathways. Our new resonance formula quantitatively expresses the resonance spectra pertaining to modal nanophotonic and surface-plasmonic thin-film structures as verified by comparing with exact numerical models. PMID- 23938649 TI - Kovacs effect enhanced broadband large field of view electro-optic modulators in nanodisordered KTN crystals. AB - The unique physical effect-Kovacs effect is explored to enhance the performance of EO modulators by employing the non-thermal equilibrium state nanodisordered KTN crystals created by super-cooling process, which can have a significant 3.5 fold increase in quadratic electro-optic coefficient. This enables to reduce the switching half wave voltage (almost by half) so that a broadband (~GHz range) and large field of view (+/-30 deg) electro-optic modulator can be realized with much lowered driving power, which can be very useful for a variety of applications: laser Q-switches, laser pulse shaping, high speed optical shutters and modulating retro reflectors. PMID- 23938650 TI - Femtosecond parabolic pulse shaping in normally dispersive optical fibers. AB - Formation of parabolic pulses at femtosecond time scale by means of passive nonlinear reshaping in normally dispersive optical fibers is analyzed. Two approaches are examined and compared: the parabolic waveform formation in transient propagation regime and parabolic waveform formation in the steady-state propagation regime. It is found that both approaches could produce parabolic pulses as short as few hundred femtoseconds applying commercially available fibers, specially designed all-normal dispersion photonic crystal fiber and modern femtosecond lasers for pumping. The ranges of parameters providing parabolic pulse formation at the femtosecond time scale are found depending on the initial pulse duration, chirp and energy. Applicability of different fibers for femtosecond pulse shaping is analyzed. Recommendation for shortest parabolic pulse formation is made based on the analysis presented. PMID- 23938651 TI - Nonlinear optics in the LP(02) higher-order mode of a fiber. AB - The distinct disperion properties of higher-order modes in optical fibers permit the nonlinear generation of radiation deeper into the ultraviolet than is possible with the fundamental mode. This is exploited using adiabatic, broadband mode convertors to couple light efficiently from an input fundamental mode and also to return the generated light to an output fundamental mode over a broad spectral range. For example, we generate visible and UV supercontinuum light in the LP(02) mode of a photonic crystal fiber from sub-ns pulses with a wavelength of 532 nm. PMID- 23938652 TI - Goya's artwork imaging with Terahertz waves. AB - In this paper we use a Terahertz (THz) time-domain system to image and analyze the structure of an artwork attributed to the Spanish artist Goya painted in 1771. The THz images show features that cannot be seen with optical inspection and complement data obtained with X-ray imaging that provide evidence of its authenticity, which is validated by other independent studies. For instance, a feature with a strong resemblance with one of Goya's known signatures is seen in the THz images. In particular, this paper demonstrates the potential of THz imaging as a complementary technique along with X-ray for the verification and authentication of artwork pieces through the detection of features that remain hidden to optical inspection. PMID- 23938653 TI - Carbon nanotube mode-locked optically-pumped semiconductor disk laser. AB - An optically pumped semiconductor disk laser was mode-locked for the first time by employing a single-walled carbon nanotube saturable absorber. Stable passive fundamental mode-locking was obtained at a repetition rate of 613 MHz with a pulse length of 1.23 ps. The mode-locked semiconductor disk laser in a compact geometry delivered a maximum average output power of 136 mW at 1074 nm. PMID- 23938654 TI - Dramatic size reduction of waveguide bends on a micron-scale silicon photonic platform. AB - We demonstrate theoretically and experimentally how highly multimodal high index contrast waveguides with micron-scale cores can be bent, on an ultra-broad band of operation, with bending radii below 10 um and losses for the fundamental mode below 0.02 dB/90 degrees . The bends have been designed based on the Euler spiral and fabricated on 4 um thick SOI. The proposed approach enabled also the realization of 180 degrees bends with 1.27 um effective radii and 0.09 dB loss, which are the smallest low-loss bends ever reported for an optical waveguide. These results pave the way for unprecedented integration density in most semiconductor platforms. PMID- 23938655 TI - Experimental direct estimation of nonlinear functionals of photonic quantum states via interferometry with a controlled-swap operation. AB - We propose a multi-photon interferometer with a generalized C-SWAP operation that can estimate Tr[rho(1)rho(2)...rho(n)], a nonlinear functional of n photonic density matrices. The scheme is demonstrated for three single-photon states whose overlap is experimentally measured as the interference visibility of a control qubit encoded into photonic paths. The validity of this method is verified by comparing the visibility with the results of Hong-Ou-Mandel experiments. PMID- 23938656 TI - Preparation of iridescent colloidal crystal coatings with variable structural colors. AB - Iridescent colloidal crystal coatings with variable structural colors were fabricated by incorporating carbon black nanoparticles (CB-NPs) into the voids of polystyrene (PS) colloidal crystals. The structural color of the colloid crystal coatings was not only greatly enhanced after the composition but also varied with observation angles. By changing the diameter of monodisperse PS colloids in the composites, colloidal crystal coatings with three primary colors for additive or subtractive combination were obtained. After incorporation of the PS/CB-NPs hybrid coatings into polydimethylsiloxane (PDMS) matrix, manmade opal jewelry with variable iridescent colors was made facilely. PMID- 23938657 TI - Dual-detection confocal fluorescence microscopy: fluorescence axial imaging without axial scanning. AB - We propose a new method for high-speed, three-dimensional (3-D) fluorescence imaging, which we refer to as dual-detection confocal fluorescence microscopy (DDCFM). In contrast to conventional beam-scanning confocal fluorescence microscopy, where the focal spot must be scanned either optically or mechanically over a sample volume to reconstruct a 3-D image, DDCFM can obtain the depth of a fluorescent emitter without depth scanning. DDCFM comprises two photodetectors, each with a pinhole of different size, in the confocal detection system. Axial information on fluorescent emitters can be measured by the axial response curve through the ratio of intensity signals. DDCFM can rapidly acquire a 3-D fluorescent image from a single two-dimensional scan with less phototoxicity and photobleaching than confocal fluorescence microscopy because no mechanical depth scans are needed. We demonstrated the feasibility of the proposed method by phantom studies. PMID- 23938658 TI - Retrieval of effective complex refractive index from intensive measurements of characteristics of ambient aerosols in the boundary layer. AB - Aerosol complex refractive index (ACRI) has attracted intensive attentions due to its significance in modeling aerosol radiative effects. Determinations of ACRI from surface measurements of aerosol scattering and absorption coefficients as well as number size distributions during June, 2008 based on an iterative Mie algorithm were performed. The aim of our study was to introduce an inversion approach with the merits of high time-resolutions to retrieve the optically effective ACRI, especially its imaginary part. Based on simultaneous measurements of aerosol characteristics, mean ACRI value of 1.50 ( +/- 0.34)-i0.025 ( +/- 0.015) at 550 nm in Hefei in summer was deducted. The lower imaginary parts with higher single scattering albedos and lower scattering Angstrom exponents were obtained for haze periods compared with nonhaze conditions with similar air-mass back-trajectories, indicating more large and scattering particles contributing to the formation of haze episodes. The derived imaginary parts of ACRI related to agricultural biomass burning were in the range from 0.013 to 0.029 at 550 nm. Significant negative correlations between retrieved imaginary parts of ACRI and measured single scattering albedos indicate that our retrieval approach is a reasonable method for determining the imaginary parts of complex refractive indices of aerosol particles. PMID- 23938659 TI - Magnetic field sensor using tilted fiber grating interacting with magnetic fluid. AB - A novel magnetic field sensor using tilted fiber Bragg grating (TFBG) interacting with magnetic fluid is proposed and experimentally demonstrated. The TFBG is surrounded by magnetic fluid whose complex refractive index changes with external magnetic field. The guiding properties of cladding modes excited by the TFBG are therefore modulated by the external magnetic field. As a result, the magnetic field strength measurement is successfully achieved within a range up to 196 Gauss by monitoring extinction ratio of cladding mode resonance. Furthermore, temperature variation can be obtained simultaneously from the wavelength shift of the TFBG transmission spectrum. PMID- 23938660 TI - Information-theoretic secure key distribution based on common random-signal induced synchronization in unidirectionally-coupled cascades of semiconductor lasers. AB - It has been proposed that a secure key distribution scheme using correlated random bit sequences can be implemented using common random-signal induced synchronization of semiconductor laser systems. In this scheme it is necessary to use laser systems consisting of multiple cascaded lasers to be secure against a powerful eavesdropper. In this paper, we report the results of an experimental study that demonstrate that the common random-signal induced synchronization is possible in cascaded semiconductor laser systems. We also show that the correlated random bit sequences generated in the synchronized cascaded laser systems can be used to create an information-theoretically secure key between two legitimate users. PMID- 23938661 TI - Experimental study of time-delay signature of chaos in mutually coupled vertical cavity surface-emitting lasers subject to polarization optical injection. AB - Time-delay signature of chaos in mutually coupled vertical-cavity surface emitting lasers subject to polarization rotated optical injection has been investigated experimentally. Autocorrelation function and permutation entropy are used to quantitatively identify the time-delay signature of chaos. The experiment results show that the time-delay signature is sensitive to the polarization rotated angle. Minimum time-delay signature has been observed in the intermediate polarization rotated angle for the lower bias current. This is in good agreement with the theoretical prediction. At higher bias currents, the lower time-delay signature has been obtained with parallel optical injection. PMID- 23938662 TI - Silicon mode multi/demultiplexer based on multimode grating-assisted couplers. AB - A simple and low-crosstalk 1 * 4 silicon mode (de)multiplexer based on multimode grating-assisted-couplers is proposed. Mode transitions can be flexibly controlled by designing the grating period at the phase-matching condition. Due to the contra-directional coupling, precise control of the coupling strength and the coupling length are not needed in the system. Calculation results show that the insertion loss and the 3 dB bandwidths of the device are 0.2 dB and 3.7 nm, 0.34 dB and 7.6 nm, and 0.21 dB and 11.8 nm for the channels which (de)multiplex to the 1st, 2nd, and 3rd modes of the bus waveguide, respectively. PMID- 23938663 TI - Fast-to-slow axis mode imaging for brightness enhancement of a broad-area laser diode array. AB - Broad-area laser (BAL) diodes have found use in numerous applications requiring multi-watt powers, but remain limited by poor spatial beam quality. A novel laser cavity that enhances the brightness of a BAL array has been demonstrated. Wavelength beam combining (WBC) is used to spatially overlap output from the emitters. Improved beam quality is achieved by imaging the fast-axis mode onto the slow axis of the BAL array. The brightness is enhanced twofold over a typical Littman-Metcalf WBC cavity, reaching 47 MW.cm(-2).sr(-1) at an output power of 1.16 W. PMID- 23938664 TI - Relative optical wavefront measurement in displacement measuring interferometer systems with sub-nm precision. AB - Many error sources can affect the accuracy of displacement measuring interferometer systems. In heterodyne interferometry two laser source frequencies constitute the finally detected wavefront. When the wavefronts of these source frequencies are non-ideal and one of them walks off the detector, the shape of the detected wavefront will vary. This leads to a change in measured phase at the detector resulting in increased measurement uncertainty. A new wavefront measurement tool described in this publication measures the relative phase difference between the two wavefronts of the two source frequencies of a coaxial heterodyne laser source as used in commercial heterodyne interferometer systems. The proposed measurement method uses standard commercial optics and operates with the same phase measurement equipment that is normally used for heterodyne displacement interferometry. In the presented method a bare tip of a multimode fiber represents the receiving detection aperture and is used for locally sampling the wavefront during a line scan. The difference in phase between the beating frequency of the scanning fiber and a reference beating frequency that results from integration over the entire beam, is used for the reconstruction of the wavefront. The method shows to have a phase resolution in the order of ~25 pm or ~lambda/25000 for lambda 632.8 nm, and a spatial resolution of ~60 um at a repeatability better than 1 nm over one week. PMID- 23938665 TI - Silicon-based optoelectronic integrated circuit for label-free bio/chemical sensor. AB - We demonstrate a silicon-based optoelectronic integrated circuit (OEIC) for label free bio/chemical sensing application. Such on-chip OEIC sensor system consists of optical grating couplers for vertical light coupling into silicon waveguides, a thermal-tunable microring as a tunable filter, an exposed microring as an optical label-free sensor, and a Ge photodetector for a direct electrical readout. Different from the conventional wavelength-scanning method, we adopt low cost broadband ASE light source, together with the on-chip tunable filter to generate sliced light source. The effective refractive index change of the sensing microring induced by the sensing target is traced by scanning the supplied electrical power applied onto the tracing microring, and the detected electrical signal is read out by the Ge photodetector. For bulk refractive index sensing, we demonstrate using such OEIC sensing system with a sensitivity of ~15 mW/RIU and a detection limit of 3.9 MU-RIU, while for surface sensing of biotin streptavidin, we obtain a surface mass sensitivity of S(m) = ~192 uW/ng.mm(-2) and a surface detection limit of 0.3 pg/mm(2). The presented OEIC sensing system is suitable for point-of-care applications. PMID- 23938666 TI - Ultra-fast transistor-based detectors for precise timing of near infrared and THz signals. AB - A whole class of two-color experiments involves intense, short Terahertz radiation pulses. A fast and moderately sensitive detector capable to resolve both near-infrared and Terahertz pulses at the same time is highly desirable. Here we present the first detector of this kind. The detector element is a GaAs based field effect transistor operated at room temperature. THz detection is successfully demonstrated at frequencies up to 4.9 THz. The THz detection time constant is shorter than 30 ps, the optical time constant is 150 ps. This detector is ideally suited for precise, simultaneous resolution of optical and THz pulses and for pulse characterization of high-power THz pulses up to tens of kW peak power levels. The dynamic range of the detector is as large as 65+/ 3dB/Hz, enabling applications in a large variety of experiments and setups, also including table-top systems. PMID- 23938667 TI - Discrete-like diffraction dynamics in free space. AB - We introduce a new class of paraxial optical beams exhibiting discrete-like diffraction patterns reminiscent to those observed in periodic evanescently coupled waveguide lattices. It is demonstrated that such paraxial beams are analytically described in terms of generalized Bessel functions. Such effects are elucidated via pertinent examples. PMID- 23938668 TI - Continuous-wave cavity ringdown spectroscopy based on the control of cavity reflection. AB - A new type of continuous-wave cavity ringdown spectrometer based on the control of cavity reflection for trace gas detection was designed and evaluated. The technique separated the acquisitions of the ringdown event and the trigger signal to optical switch by detecting the cavity reflection and transmission, respectively. A detailed description of the time sequence of the measurement process was presented. In order to avoid the wrong extraction of ringdown time encountered accidentally in fitting procedure, the laser frequency and cavity length were scanned synchronously. Based on the statistical analysis of measured ringdown times, the frequency normalized minimum detectable absorption in the reflection control mode was 1.7 * 10(-9)cm(-1)Hz(-1/2), which was 5.4 times smaller than that in the transmission control mode. However the signal-to-noise ratio of the absorption spectrum was only 3 times improved since the etalon effect existed. Finally, the peak absorption coefficients of the C(2)H(2) transition near 1530.9nm under different pressures showed a good agreement with the theoretical values. PMID- 23938669 TI - Light scattering by the Martian dust analog, palagonite, modeled with ellipsoids. AB - We have investigated the suitability of the ellipsoidal model particles to mimic scattering by Martian dust particles by comparing simulations against laboratory data for palagonite, a Mars analog sample. By optimizing the shape distribution of ellipsoids, a very good match with a laboratory-measured scattering matrix was obtained. Even an equiprobable distribution of ellipsoids performed well. The asymmetry parameter and single-scattering albedo were found to depend on the assumed shape distribution as much as on the typical uncertainties associated with refractive indices and size, suggesting that shape is an important parameter that potentially influences remote retrievals of dust particle properties. PMID- 23938670 TI - Interaction of pupil offset and fifth-order nodal aberration field properties in rotationally symmetric telescopes. AB - In this paper we succeeded in deriving changes in the nodal positions of aberrations that belong to the fifth-order class in pupil dependence by applying a system level pupil decentration vector. Our treatment is specifically for rotationally symmetric multi-mirror optical designs that simply use an offset pupil as a means of creating an unobscured optical design. When the pupil is offset, only the vectors to determine the node locations are modified by the pupil decentration vector, while the nodal properties originally developed for titled/decentered optical systems are retained. In general, the modifications to the nodal vectors for any particular aberration type are contributed only by terms of higher order pupil dependence. PMID- 23938671 TI - Thermal-induced two dimensional beam distortion in planar waveguide amplifiers. AB - Mode characteristics in the solid-state planar waveguide (PWG) laser amplifiers are investigated theoretically, in consideration of the temperature gradient generated by cooling across the thickness and by pumping inhomogeneity along the width direction. When variation of the refractive index along the width direction is dominated by the lower spatial frequencies, the vector wave equation is solved analytically by means of the perturbation method. It is similar to the zigzag slab amplifier in which the phase aberration depending on the width coordinate plays the most important role to cause degradation of the beam quality. The crossing mode distortions owing to two dimension nature of the index variations are illustrated, and that mode profile is varied by the index variation along both the thickness and the width directions. Modes in the single-mode or the few mode PWGs are shown to suffer weaker thermal-induced distortion across the thickness than those in the multi-mode PWGs. PMID- 23938672 TI - Increasing the darkfield contrast-to-noise ratio using a deconvolution-based information retrieval algorithm in X-ray grating-based phase-contrast imaging. AB - A novel information retrieval algorithm for X-ray grating-based phase-contrast imaging based on the deconvolution of the object and the reference phase stepping curve (PSC) as proposed by Modregger et al. was investigated in this paper. We applied the method for the first time on data obtained with a polychromatic spectrum and compared the results to those, received by applying the commonly used method, based on a Fourier analysis. We confirmed the expectation, that both methods deliver the same results for the absorption and the differential phase image. For the darkfield image, a mean contrast-to-noise ratio (CNR) increase by a factor of 1.17 using the new method was found. Furthermore, the dose saving potential was estimated for the deconvolution method experimentally. It is found, that for the conventional method a dose which is higher by a factor of 1.66 is needed to obtain a similar CNR value compared to the novel method. A further analysis of the data revealed, that the improvement in CNR and dose efficiency is due to the superior background noise properties of the deconvolution method, but at the cost of comparability between measurements at different applied dose values, as the mean value becomes dependent on the photon statistics used. PMID- 23938674 TI - Statistical characterization of the nonlinear noise in 2.8 Tbit/s PDM-16QAM CO OFDM system. AB - We show for the first time through comprehensive simulations under both uncompensated transmission (UT) and dispersion managed transmission (DMT) systems that the statistical distribution of the nonlinear interference (NLI) within the polarization multiplexed 16-state quadrature amplitude modulation (PM-16QAM) Coherent Optical OFDM (CO-OFDM) system deviates from Gaussian distribution in the absence of amplified spontaneous emission (ASE) noise. We also observe that the dependences of the variance of the NLI noise on both the launch power and the transmission distance (logrithm) seem to be in a simple linear way. PMID- 23938673 TI - Swept source optical coherence microscopy using a 1310 nm VCSEL light source. AB - We demonstrate high speed, swept source optical coherence microscopy (OCM) using a MEMS tunable vertical cavity surface-emitting laser (VCSEL) light source. The light source had a sweep rate of 280 kHz, providing a bidirectional axial scan rate of 560 kHz. The sweep bandwidth was 117 nm centered at 1310 nm, corresponding to an axial resolution of 13.1 um in air, corresponding to 8.1 um (9.6 um spectrally shaped) in tissue. Dispersion mismatch from different objectives was compensated numerically, enabling magnification and field of view to be easily changed. OCM images were acquired with transverse resolutions between 0.86 um - 3.42 um using interchangeable 40X, 20X and 10X objectives with ~600 um x 600 um, ~1 mm x 1 mm and ~2 mm x 2 mm field-of-view (FOV), respectively. Parasitic variations in path length with beam scanning were corrected numerically. These features enable swept source OCM to be integrated with a wide range of existing scanning microscopes. Large FOV mosaics were generated by serially acquiring adjacent overlapping microscopic fields and combining them in post-processing. Fresh human colon, thyroid and kidney specimens were imaged ex vivo and compared to matching histology sections, demonstrating the ability of OCM to image tissue specimens. PMID- 23938675 TI - Optical absorption characteristics of nanometer and submicron a-Si:H solar cells with two kinds of nano textures. AB - The optical absorption properties of a-Si:H have acquired much attention in solar cell(SC) research. In this paper, we studied enhancement of light absorption in the a-Si:H(10%H) SCs with thicknesses from 31.25nm to 2MUm and with nano textures of the column-shaped nanohole (CLNH) array and of the cone-shaped nanohole (CNNH) array, via the Finite Difference Time Domain (FDTD) simulation. For a given type of nano texture and film thickness, d, the ultimate efficiency, the ideal efficiency without considering carrier combinations, is optimized over array period, p, and filling fraction, f, and is defined as the optimized ultimate efficiency, eta(0). The simulation results demonstrated that: even for the CLNH textured a-Si:H(10%H) SCs as thin as 62.5 nm,eta(0) is 19.7%. When the a Si:H(10%H) SC is thinner than a critical depth of about 250nm, the CLNH texture is more efficient than the CNNH texture, and vice versa. When the thicknesses of SCs are very thin, especially smaller than 100nm, the efficiencies of the a Si:H(10%H) SCs are evidently higher than those of the c-Si SCs. For example, in the CLNH arrays, when d = 62.5nm, eta(0)for the a-Si:H(10%H) SCs is higher than the c-Si SCs by a factor of approximate 2.3. PMID- 23938676 TI - 110.9-Tbit/s SDM transmission over 6,370 km using a full C-band seven-core EDFA. AB - We confirm the feasibility of 100-Tbit/s-class trans-oceanic SDM transmission. Using seven-core fiber spans with seven-core full C-band EDFAs, 7 * 264-channel quasi-Nyquist-WDM 60-Gbit/s PDM-QPSK signals are transmitted over 6,370 km. PMID- 23938677 TI - Photoacoustic tomography extracted from speckle noise in acoustically inhomogeneous tissue. AB - Photoacoustic tomography is usually limited to acoustically homogeneous tissue. A hybrid scheme is developed to break this limitation by utilizing ultrasound to determine the unknown Green's function of inhomogeneous tissue. The method can effectively decrease the distortion and false contrast in images by extracting information from speckle noise. The method does not depend on the prior knowledge of tissue and the medium complexity. Moreover, the estimation of Green's function and the photoacoustic detection are performed by the same transducer. Therefore, the scheme could be easily integrated into a classical photoacoustic tomography system and extend its application in speckle environment. PMID- 23938678 TI - Temperature dependence of the fractional thermal load of Nd:YVO4 at 1064 nm lasing and its influence on laser performance. AB - Temperature dependence of thermal effect for neodymium doped yttrium orthovanadate crystal is quantified by measuring its dioptric power. With the boundary temperature range from 293 K to 353 K, the increase of fractional thermal load (lasing at 1064 nm, pumping at 888 nm) is from 16.9% to 24.9% with lasing, which is attributed to the rise of upconversion parameter and thermal conductivity. The influence of the boundary temperature on the output characteristic of a high-power single frequency laser is also investigated. The maximum output power decreases from 25.3 W to 13.5 W with the increase of boundary temperature from 293 K to 353 K. Analysis results indicate that further power scaling can be achieved by controlling the Nd:YVO(4) temperature to a lower. PMID- 23938679 TI - An endoscopic system adopting a liquid crystal lens with an electrically tunable depth-of-field. AB - Conventional endoscopic systems consisting of several solid lenses suffer from a fixed and limited depth-of-field (DOF). For practical applications, conventional endoscopes mechanically change the distance between the solid lenses of a lens module in order to change the focusing plane and DOF to see clearly in a scene. In this paper, we demonstrate an electrically tunable endoscopic system adopting a liquid crystal lens. By means of tunable focusing properties of the LC lens as a positive lens and a negative lens, the object at different objective distances can be imaged to the image sensor clearly and the corresponding depth-of-field can also help to enlarge the total spatial depth perception in a scene. The optical mechanism is discussed. In the experiments, under adjustment of three discrete lens powers of the LC lens, the viewing range or total spatial depth perception of the endoscopic system is from 76.4 mm to 12.4 mm which is 2x improved compared to the conventional one without LC lens. We believe this study can be extended to the applications of industrial and medical endoscopes. PMID- 23938680 TI - First multi-watt ribbon fiber oscillator in a high order mode. AB - Optical fibers in the ribbon geometry have the potential to reach powers well above the maximum anticipated power of a circular core fiber. In this paper we report the first doped silica high order mode ribbon fiber oscillator, with multimode power above 40 W with 71% slope efficiency and power in a single high order mode above 5 W with 44% slope efficiency. PMID- 23938681 TI - LCoS-based mode shaper for few-mode fiber. AB - Spatial light modulation can be used to address specific fiber modes, as required in mode-division multiplexed systems. We theoretically compare phase-only spatial light modulation to a combination of amplitude and phase spatial light modulation in terms of insertion loss and crosstalk for a fiber supporting 11 LP modes. We experimentally demonstrate selective mode excitation using a Liquid Crystal on Silicon (LCoS) spatial light modulator configured to as phase and amplitude modulator. PMID- 23938682 TI - Degenerate four wave mixing in large mode area hybrid photonic crystal fibers. AB - Spontaneous degenerate four wave mixing (FWM) is investigated in large mode area hybrid photonic crystal fibers, in which photonic bandgap guidance and index guidance is combined. Calculations show the parametric gain is maximum on the edge of a photonic bandgap, for a large range of pump wavelengths. The FWM products are observed on the edges of a transmission band experimentally, in good agreement with the numerical results. Thereby the bandedges can be used to control the spectral positions of FWM products through a proper fiber design. The parametric gain control combined with a large mode area fiber design potentially allows for power scaling of light at wavelengths not easily accessible with e.g. rare earth ions. PMID- 23938683 TI - Sparse ACEKF for phase reconstruction. AB - We propose a novel low-complexity recursive filter to efficiently recover quantitative phase from a series of noisy intensity images taken through focus. We first transform the wave propagation equation and nonlinear observation model (intensity measurement) into a complex augmented state space model. From the state space model, we derive a sparse augmented complex extended Kalman filter (ACEKF) to infer the complex optical field (amplitude and phase), and find that it converges under mild conditions. Our proposed method has a computational complexity of N(z)N logN and storage requirement of O(N), compared with the original ACEKF method, which has a computational complexity of O(NzN(3)) and storage requirement of O(N(2)), where Nz is the number of images and N is the number of pixels in each image. Thus, it is efficient, robust and recursive, and may be feasible for real-time phase recovery applications with high resolution images. PMID- 23938684 TI - Discrete linear canonical transform computation by adaptive method. AB - The linear canonical transform (LCT) describes the effect of quadratic phase systems on a wavefield and generalizes many optical transforms. In this paper, the computation method for the discrete LCT using the adaptive least-mean-square (LMS) algorithm is presented. The computation approaches of the block-based discrete LCT and the stream-based discrete LCT using the LMS algorithm are derived, and the implementation structures of these approaches by the adaptive filter system are considered. The proposed computation approaches have the inherent parallel structures which make them suitable for efficient VLSI implementations, and are robust to the propagation of possible errors in the computation process. PMID- 23938685 TI - Microwave assisted reconstruction of optical interferograms for distributed fiber optic sensing. AB - This paper reports a distributed fiber optic sensing technique through microwave assisted separation and reconstruction of optical interferograms in spectrum domain. The approach involves sending a microwave-modulated optical signal through cascaded fiber optic interferometers. The microwave signal was used to resolve the position and reflectivity of each sensor along the optical fiber. By sweeping the optical wavelength and detecting the modulation signal, the optical spectrum of each sensor can be reconstructed. Three cascaded fiber optic extrinsic Fabry-Perot interferometric sensors were used to prove the concept. Their microwave-reconstructed interferogram matched well with those recorded individually using an optical spectrum analyzer. The application in distributed strain measurement has also been demonstrated. PMID- 23938686 TI - Opto-VLSI-based N * M wavelength selective switch. AB - In this paper, we propose and experimentally demonstrate a novel N * M wavelength selective switch (WSS) architecture based on the use of an Opto-VLSI processor. Through a two-stage beamsteering process, wavelength channels from any input optical fiber port can be switched into any output optical fiber port. A proof-of concept 2 * 3 WSS structure is developed, demonstrating flexible wavelength selective switching with an insertion loss around 15 dB. PMID- 23938687 TI - Multi-span transmission using phase and amplitude regeneration in PPLN-based PSA. AB - We demonstrated multi-span transmission using a periodically poled LiNbO(3) (PPLN) based phase sensitive amplifier (PSA). An in-line PSA with a carrier recovery and phase locking system is implemented as a repeater amplifier in a recirculating loop. We achieved a PSA gain as high as + 18 dB and a high external gain of + 12 dB for the in-line PSA as a black box. The impairments caused by phase noise resulting from fiber nonlinearity and intensity noise caused by the amplified spontaneous emission (ASE) of an optical amplifier are largely suppressed using the phase and amplitude regeneration capabilities of the PSA. The ultra long-haul transmission of a 28-Gb/s binary phase shift keying (BPSK) signal over 5400 km was achieved with phase and amplitude regeneration. PMID- 23938688 TI - Tailor the surface-wave properties of a plasmonic metal by a metamaterial capping. AB - We show that putting an ultra-thin anisotropic metamaterial layer on a plasmonic surface significantly enriches the surface wave (SW) characteristics of the system, which now supports SWs with transverse-magnetic (TM) and transverse electric (TE) polarizations simultaneously. In addition, the generated SWs exhibit hybridized polarization characteristics in certain cases, and a SW band gap opens within a particular propagation direction range. We designed and fabricated a realistic structure based on the proposed model, and combined microwave experiments with full-wave simulations to verify the fascinating theoretical predictions. Several potential applications of the proposed system are discussed in the end. PMID- 23938689 TI - Accuracy improvement of quantitative analysis by spatial confinement in laser induced breakdown spectroscopy. AB - To improve the accuracy of quantitative analysis in laser-induced breakdown spectroscopy, the plasma produced by a Nd:YAG laser from steel targets was confined by a cavity. A number of elements with low concentrations, such as vanadium (V), chromium (Cr), and manganese (Mn), in the steel samples were investigated. After the optimization of the cavity dimension and laser fluence, significant enhancement factors of 4.2, 3.1, and 2.87 in the emission intensity of V, Cr, and Mn lines, respectively, were achieved at a laser fluence of 42.9 J/cm(2) using a hemispherical cavity (diameter: 5 mm). More importantly, the correlation coefficient of the V I 440.85/Fe I 438.35 nm was increased from 0.946 (without the cavity) to 0.981 (with the cavity); and similar results for Cr I 425.43/Fe I 425.08 nm and Mn I 476.64/Fe I 492.05 nm were also obtained. Therefore, it was demonstrated that the accuracy of quantitative analysis with low concentration elements in steel samples was improved, because the plasma became uniform with spatial confinement. The results of this study provide a new pathway for improving the accuracy of quantitative analysis of LIBS. PMID- 23938690 TI - Fluid tunable transition from trapping to discrete diffraction in waveguide arrays. AB - We report on the fluid tunable transition from trapping to discrete diffraction in planar polymer waveguide arrays. A novel optofluidic polymer waveguide array platform was engineered to allow a wavelength dependent transition from a localised state where light is trapped in a defect mode to delocalised state where light is spreading through discrete diffraction. The spectral location of this transition can be controlled through a variation of the fluid's refractive index. The platform is compatible with aqueous solutions, making it an interesting candidate for an integrated refractive index sensor to perform label free biosensing. PMID- 23938691 TI - Double-layer anti-reflection coating containing a nanoporous anodic aluminum oxide layer for GaAs solar cells. AB - Multilayer anti-reflection (AR) coatings can be used to improve the efficiency of Gallium Arsenide (GaAs) solar cells. We propose an alternate method to obtain optical thin films with specified refractive indices, which is using a self assembled nanoporous anodic aluminum oxide (AAO) template as an optical thin film whose effective refractive index can be tuned by pore-widening. Different kinds of double-layer AR coatings each containing an AAO layer were designed and investigated by finite difference time domain (FDTD) method. We demonstrate that a lambda /4n - lambda /4n AR coating consisting of a TiO(2) layer and an AAO layer whose effective refractive index is 1.32 realizes a 96.8% light absorption efficiency of the GaAs solar cell under AM1.5 solar spectrum (400 nm-860 nm). We also have concluded some design principles of the double-layer AR coating containing an AAO layer for GaAs solar cells. PMID- 23938692 TI - Photonic de Haas-van Alphen effect. AB - Based on the recently proposed concept of effective gauge potential and magnetic field for photons, we numerically demonstrate a photonic de Haas-van Alphen effect. We show that in a dynamically modulated photonic resonator lattice exhibiting an effect magnetic field, the trajectories of the light beam at a given frequency have the same shape as the constant energy contour for the photonic band structure of the lattice in the absence of the effective magnetic field. PMID- 23938693 TI - Analysis of imaging for laser triangulation sensors under Scheimpflug rule. AB - In this work a detailed analysis of the problem of imaging of objects lying in the plane tilted with respect to the optical axis of the rotationally symmetrical optical system is performed by means of geometrical optics theory. It is shown that the fulfillment of the so called Scheimpflug condition (Scheimpflug rule) does not guarantee the sharp image of the object as it is usually declared because of the fact that due to the dependence of aberrations of real optical systems on the object distance the image becomes blurred. The f-number of a given optical system also varies with the object distance. It is shown the influence of above mentioned effects on the accuracy of the laser triangulation sensors measurements. A detailed analysis of laser triangulation sensors, based on geometrical optics theory, is performed and relations for the calculation of measurement errors and construction parameters of laser triangulation sensors are derived. PMID- 23938694 TI - Vertical integration of high-Q silicon nitride microresonators into silicon-on insulator platform. AB - We demonstrate a vertical integration of high-Q silicon nitride microresonators into the silicon-on-insulator platform for applications at the telecommunication wavelengths. Low-loss silicon nitride films with a thickness of 400 nm are successfully grown, enabling compact silicon nitride microresonators with ultra high intrinsic Qs (~ 6 * 10(6) for 60 MUm radius and ~ 2 * 10(7) for 240 MUm radius). The coupling between the silicon nitride microresonator and the underneath silicon waveguide is based on evanescent coupling with silicon dioxide as buffer. Selective coupling to a desired radial mode of the silicon nitride microresonator is also achievable using a pulley coupling scheme. In this work, a 60-MUm-radius silicon nitride microresonator has been successfully integrated into the silicon-on-insulator platform, showing a single-mode operation with an intrinsic Q of 2 * 10(6). PMID- 23938695 TI - Single-shot detection of mid-infrared spectra by chirped-pulse upconversion with four-wave difference frequency generation in gases. AB - Single-shot detection of ultrabroadband mid-infrared spectra was demonstrated by using chirped-pulse upconversion technique with four-wave difference frequency generation in gases. Thanks to the low dispersion of the gas media, the bandwidth of the phase matching condition of the upconversion process becomes very broad and the entire mid-infrared spectrum spanning from 200 to 5500 cm(-1) was upconverted by using a 10 ps chirped pulse to visible wavelength radiation, which was detected with a conventional visible dispersive spectrometer. This method was demonstrated by the successful measurement of infrared absorption spectra of organic polymer films. PMID- 23938696 TI - Vibration modulated subaperture stitching interferometry. AB - A novel subaperture stitching interferometry is developed to measure the surface deformation of the lens by utilizing the mechanical vibration induced from a motorized stage. The interferograms of different subapertures are acquired on the fly while the tested optics is rotating against its symmetrical axis. The measurement throughput and the subaperture positioning accuracy are improved simultaneously by adopting both the synchronous rotational scanning mechanism and the non-uniform phase shifting algorithm. The experimental measurement shows the stitched phase RMS error of 0.0037 waves proving the feasibility of the proposed phase acquisition method. PMID- 23938697 TI - Digital pyramid wavefront sensor with tunable modulation. AB - The pyramid wavefront sensor is known for its high sensitivity and dynamic range that can be tuned by mechanically altering its modulation amplitude. Here, a novel modulating digital scheme employing a reflecting phase only spatial light modulator is demonstrated. The use of the modulator allows an easy reconfigurable pyramid with digital control of the apex angle and modulation geometry without the need of any mechanically moving parts. Aberrations introduced by a 140 actuator deformable mirror were simultaneously sensed with the help of a commercial Hartmann-Shack wavefront sensor. The wavefronts reconstructed using the digital pyramid wavefront sensor matched very closely with those sensed by the Hartmann-Shack. It is noted that a tunable modulation is necessary to operate the wavefront sensor in the linear regime and to accurately sense aberrations. Through simulations, it is shown that the wavefront sensor can be extended to astronomical applications as well. This novel digital pyramid wavefront sensor has the potential to become an attractive option in both open and closed loop adaptive optics systems. PMID- 23938698 TI - Polarimetric heterodyning fiber laser sensor for directional acoustic signal measurement. AB - A DBR fiber grating laser acoustic sensor based on polarization beat signal modulation analysis has been demonstrated for directional acoustic signal measurement. The acoustic sensor was fabricated in birefringent erbium-doped fiber, and the influences of external-acoustic pressure on fiber grating laser sensor were analyzed, considering the effect of relative orientation of the acoustic wave on the degrees of birefringence modulation. In experiment, the birefringence in sensing fiber was modulated by ultrasonic pressure. Agreement between theoretical and experimental results was obtained for ultrasound wave propagating from different directions (0-360 degrees in 15 degrees intervals) corresponding to a nonlinearly change in beat frequency modulation rates. The results demonstrate that the DBR fiber grating laser acoustic sensor has an orientation recognizable ability, offering a potential for acoustic vector signal detection. PMID- 23938699 TI - Up-conversion luminescence of Er(3+)-Yb3+ co-doped CaIn2O4. AB - Up-conversion emission spectra of Er(3+) singly and Er(3+)/Yb(3+) co-doped CaIn(2)O(4) were investigated under a 980 nm diode laser excitation. Double intense UC emission bands in green and red region are observed in Er(3+)/Yb(3+) co-doped CaIn(2)O(4), resulting in the tunable ratio of red to green and the chromaticity coordinates by adjusting the concentration of Er(3+) and Yb(3+). Based on the pump power dependence, the possible UC mechanism in Er(3+)/Yb(3+) co doped CaIn(2)O(4) was proposed, and lifetime measurements were also carried out to support our proposal. PMID- 23938700 TI - Grazing-incidence spectrometer for soft X-ray solar imaging spectroscopy. AB - The design and realization of a stigmatic grazing-incidence instrument for space applications to solar imaging spectroscopy is presented. We propose an optical layout in which imaging and spectral capabilities are decoupled by the use of crossed cylindrical mirrors. The design consists of a double telescope and a spectrograph: telescope I consists of a single cylindrical mirror with parabolic section, focusing the radiation on the entrance slit of the spectrograph in the spectral dispersion plane; telescope II consists of two cylindrical mirrors with aspherical section in Wolter configuration focusing the radiation on the spectrograph focal plane in the direction perpendicular to the spectral dispersion plane; the spectrograph consists of a grazing-incidence spherical variable-line-spaced grating with flat-field properties. Telescope II is crossed with respect to the grating and telescope I, i.e., is mounted with its tangential planes coincident with the grating equatorial plane, to decouple spectral and spatial focusing properties. The spectral resolution is preserved also for off axis angles. The instrument that has been realized operates in the 4-26 nm spectral range and has a field of view of 0.5 deg to image the full Sun disk. PMID- 23938701 TI - Effects of polarization and apodization on laser induced optical breakdown threshold. AB - We investigated the influence of polarization and apodization on laser induced optical breakdown threshold in transparent and diffuse media using linearly and radially polarized light. We demonstrate a lower irradiance threshold for optical breakdown using radially polarized light. The dominance of radial polarization in higher-order multiphoton ionization has important medical applications where a lower irradiance threshold may allow reaching deeper layers inside the skin with less risk of collateral damage and thereby improving safety and efficacy of treatment. PMID- 23938702 TI - Empirical study of the group delay dispersion achievable with multilayer mirrors. AB - With the help of the most advanced algorithms we obtained many dozens of multilayer dispersive mirror designs to empirically find limits for the maximum achievable negative value of the group delay dispersion (GDD). This value depends on the total thickness of coatings and layer material combination. Nb(2)O(5)/SiO(2) and Ta(2)O(50/SiO(2) combinations are studied in detail, for combinations HfO(2)/SiO(2) and TiO(2)/SiO(2) we obtained estimations for two bandwidths. We also show that reasonable values of third-order dispersion have no significant impact on the obtained results. Current state-of-the-art technology allows to produce designs with total physical thicknesses slightly higher than 10 um and to achieve maximum negative GDD values corresponding to this total design thickness. Designs with total physical thickness of 15 um and 20 um are not realized yet due to high sensitivity to deposition errors. PMID- 23938703 TI - Transmission-type photonic crystal structures for color filters. AB - A transmission-type structure based on woodpile photonic crystal layers is proposed for use in color filters. Selective bandpass filters for red, green, and blue wavelength bands are constructed using optimally designed multilayered woodpile photonic crystals. The R/G/B color filtering for a wide range of incidence angles of light is demonstrated numerically, and the operation principle and design method are described. PMID- 23938704 TI - A low-loss photonic silica nanofiber for higher-order modes. AB - Optical nanofibers confine light to subwavelength scales, and are of interest for the design, integration, and interconnection of nanophotonic devices. Here we demonstrate high transmission (> 97%) of the first family of excited modes through a 350 nm radius fiber, by appropriate choice of the fiber and precise control of the taper geometry. We can design the nanofibers so that these modes propagate with most of their energy outside the waist region. We also present an optical setup for selectively launching these modes with less than 1% fundamental mode contamination. Our experimental results are in good agreement with simulations of the propagation. Multimode optical nanofibers expand the photonic toolbox, and may aid in the realization of a fully integrated nanoscale device for communication science, laser science or other sensing applications. PMID- 23938705 TI - The enhancement of photo-thermo-electric conversion in tilted Bi2Sr2Co2O(y) thin films through coating a layer of single-wall carbon nanotubes light absorber. AB - Light-induced transverse thermoelectric effect has been investigated in c-axis tilted Bi(2)Sr(2)Co(2)O(y) thin films coated with a single-wall carbon nanotubes light absorption layer. Open-circuit voltage signals were detected when the sample surface was irradiated by different lasers with wavelengths ranging from ultraviolet to near-infrared and the voltage sensitivity was enhanced as a result of the increased light absorption at the carbon nanotubes layer. Moreover, the enhancement degree was found to be dependent on the laser wavelength as well as the absorption coating size. This work opens up new strategy toward the practical applications of layered cobaltites in photo-thermo-electric conversion devices. PMID- 23938706 TI - Understanding the plasmonic properties of dewetting formed Ag nanoparticles for large area solar cell applications. AB - The effects of substrates with technological interest for solar cell industry are examined on the plasmonic properties of Ag nanoparticles fabricated by dewetting technique. Both surface matching (boundary element) and propagator (finite difference time domain) methods are used in numerical simulations to describe plasmonic properties and to interpret experimental data. The uncertainty on the locations of nanoparticles by the substrate in experiment is explained by the simulations of various Ag nanoparticle configurations. The change in plasmon resonance due to the location of nanoparticles with respect to the substrate, interactions among them, their shapes, and sizes as well as dielectric properties of substrate are discussed theoretically and implications of these for the experiment are deliberated. PMID- 23938707 TI - Characterization of the stray light in a space borne atmospheric AOTF spectrometer. AB - Acousto-optic tunable filter (AOTF) spectrometers are being criticized for spectral leakage, distant side lobes of their spectral response function (SRF), or the stray light. SPICAM-IR is the AOTF spectrometer in the range of 1000-1700 nm with a resolving power of 1800-2200 operating on the Mars Express interplanetary probe. It is primarily dedicated to measurements of water vapor in the Martian atmosphere. SPICAM H(2)O retrievals are generally lower than simultaneous measurements with other instruments, the stray light suggested as a likely explanation. We report the results of laboratory measurements of water vapor in quantity characteristic for the Mars atmosphere (2-15 precipitable microns) with the Flight Spare model of SPICAM-IR. We simulated the measured spectra with HITRAN-based synthetic model, varying the water abundance, and the level of the stray light, and compared the results to the known amount of water in the cell. The retrieved level of the stray light, assumed uniformly spread over the spectral range, is below 1-1.3.10(-4). The stray may be responsible for the underestimation of water abundance of up to 8%, or 0.6 pr. um. The account for the stray light removes the bias completely; the overall accuracy to measure water vapor is ~0.2 pr. um. We demonstrate that the AOTF spectrometer dependably measures the water abundance and can be employed as an atmospheric spectrometer. PMID- 23938708 TI - A study on forward scattering Mueller matrix decomposition in anisotropic medium. AB - In this work, we apply Mueller matrix polar decomposition (MMPD) method in a forward scattering configuration on anisotropic scattering samples and look for the physics origin of depolarization and retardance. Using Monte Carlo simulations on the sphere-cylinder birefringence model (SCBM), and forward scattering experiments on samples containing polystyrene microspheres, well aligned glass fibers and polyacrylamide, we examine in detail the relationship between the MMPD parameters and the microscopic structure of the samples. The results show that the spherical scatterers and birefringent medium contribute to depolarization and retardance respectively, but the cylindrical scatterers contribute to both. Retardance due to the cylindrical scatterers changes with their density, size and order of alignment. Total retardance is a simple sum of both contributions when cylinders are in parallel to the extraordinary axis of birefringence. PMID- 23938709 TI - Squeezed light in an optical parametric oscillator network with coherent feedback quantum control. AB - We present squeezing and anti-squeezing spectra of the output from a degenerate optical parametric oscillator (OPO) network arranged in different coherent quantum feedback configurations. One OPO serves as a quantum plant, the other as a quantum controller. The addition of coherent feedback enables shaping of the output squeezing spectrum of the plant, and is found to be capable of pushing the frequency of maximum squeezing away from the optical driving frequency and broadening the spectrum over a wider frequency band. The experimental results are in excellent agreement with the developed theory, and illustrate the use of coherent quantum feedback to engineer the quantum-optical properties of the plant OPO output. PMID- 23938710 TI - Steady-state characteristics and transient response of MgZnO-based metal semiconductor-metal solar-blind ultraviolet photodetector with three types of electrode structures. AB - Detailed studies of MgZnO-based metal-semiconductor-metal (MSM) solar-blind ultraviolet photodetector with different electrode structures are performed. A two-dimensional physical model is established based on the Poisson's equation and time-dependent continuity equations, which is verified by our experimental data of conventional electrode MSM detector. The steady-state characteristics and transient response of semicircular and triangular electrode MSM detectors are also investigated by this model. Compared with the conventional electrode, semicircular and triangular electrode devices exhibit a substantial improvement on the photocurrent. At a bias of 10 V, the steady-state saturated photocurrents for semicircular and triangular electrode devices are 14.69 nA and 24.37 nA respectively, corresponding to a 20.5% and 100% increase over the conventional electrode detector. Meanwhile, the transient peak photocurrents reach 31.38 nA and 52.09 nA respectively, both of which are notably larger than that of conventional device. PMID- 23938711 TI - Energy-efficient utilization of bipolar optical forces in nano-optomechanical cavities. AB - Nanoscale all-optical circuits driven by optical forces have broad applications in future communication, computation, and sensing systems. Because human society faces huge challenges of energy saving and emission reduction, it is very important to develop energy-efficient nano-optomechanical devices. Due to their high quality (Q) factors, resonance modes of cavities are capable of generating much larger forces than waveguide modes. Here we experimentally demonstrate the use of resonance modes of double-coupled one-dimensional photonic crystal cavities to generate bipolar optical forces. Attractive and repulsive forces of 6.2 nN and 1.9 nN were obtained with respective launching powers of 0.81 mW and 0.87 mW in the waveguide just before cavities. Supported by flexible nanosprings (spring constant 0.166 N/m), one cavity is pulled to (pushed away from) the other cavity by 37.1 nm (11.4 nm). The shifts of the selected resonance modes of the device are mechanically and thermally calibrated with an integrated nanoelectromechanical system actuator and a temperature-controlled testing platform respectively. Based on these experimentally-obtained relations, probe mode shifts due to the optomechanical effect are decoupled from those due to the thermo-optic effect. Actuated by the third-order even pump mode, the optomechanical shift of the second-order even probe mode is found to be about 2.5 times its thermal shift, indicating a highly efficient conversion of light energy to mechanical energy. PMID- 23938712 TI - Anti-Stokes luminescence in bismuth-doped silica and germania-based fibers. AB - Luminescence excitation spectra of active centers in bismuth-doped vitreous SiO(2) and vitreous GeO(2) optical fibers under the two-step excitation have been obtained for the first time. The results revealed only one bismuth-related IR active center formed in each of these fibers. The observed IR luminescence bands at 1430 nm (1650 nm) and 830 nm (950 nm), yellow-orange (red) band at 580 nm (655 nm), violet (blue) band at 420 nm (480 nm) belong to this bismuth-related active center in the vitreous SiO(2) (vitreous GeO(2)), correspondingly. PMID- 23938713 TI - High-directional light source using photon recycling with a retro-reflective Dome incorporated with a textured LED die surface. AB - This paper demonstrates a novel retro-reflective dome that enhances the directionality of a light emitting diode (LED) by recycling photons reflected by a textured LED die surface. A simulation model is developed to describe both the photon recycling process within the dome and the role of specific pyramid patterns on the top surface of the LED die. Advanced simulations showed that a perfectly polished surface with 100% reflectivity potentially enhances the directionality of the dome by 340%, 250%, and 240% using reflective domes with 10 degrees , 20 degrees , and 30 degrees light cones, respectively. In the experiment, the directionality of the domes exhibiting surface imperfections is enhanced by approximately 160%, 150%, and 130% using 10 degrees , 20 degrees , and 30 degrees light cones, respectively. By incorporating a textured top surface on the LED die, the proposed dome effectively increases the directionality of the LED light source. PMID- 23938714 TI - Super-resolution complex amplitude reconstruction of nanostructured binary data using an interference microscope with pattern matching. AB - We propose a new method of optically reconstructing binary data formed by nanostructures with an elemental size several tens of nanometers smaller than the diffraction limit, implemented with an interference microscope and a complex amplitude image pattern matching method. We examine the size dependency of the data reconstruction capacity using a light propagation simulation based on the finite-difference time-domain (FDTD) method and the Fourier spatial frequency filtering method. We demonstrated that the readable size of the binary nanostructure depends on the magnitude of noise. PMID- 23938715 TI - Fiber-based free-space optical coherent receiver with vibration compensation mechanism. AB - We propose a novel fiber-based free-space optical (FSO) coherent receiver for inter-satellite communication. The receiver takes advantage of established fiber optic components and utilizes the fine-pointing subsystem installed in FSO terminals to minimize the influence of satellite platform vibrations. The received beam is coupled to a single-mode fiber, and the coupling efficiency of the system is investigated both analytically and experimentally. A receiving sensitivity of -38 dBm is obtained at the forward error correction limit with a transmission rate of 22.4 Gbit/s. The proposed receiver is shown to be a promising component for inter-satellite optical communication. PMID- 23938716 TI - Tetrad phase vortex structure in scattered SPP field produced by silver nano-ring slit under linearly polarized illumination. AB - We report the tetrad phase vortex structure in the scattered surface plasmon polariton (SPP) field produced by a silver nano-ring-slit with linearly polarized illumination. In the experiment, Mach-Zehnder type interferometer is constructed in which a microscopic objective (MO) is used to collect and image the scattered SPP field, and the phase map is extracted by Fourier transform of the interference intensity. To explain the formation of the tetrad phase vortices in the central area of the ring, we propose an empirical model for the ring-slit excited SPP source field by trial calculations with the Huygens-Fresnel principle for SPP propagations. It is shown that the azimuthal variation of the amplitude of the source SPP is roughly a half of a constant base, and the variation of the phase is a little greater than pi/2. The intensity and the phase distributions of the SSP field calculated with the formulations of this model phenomenologically conform the experimental results. PMID- 23938717 TI - Real time noise and wavelength correlations in octave-spanning supercontinuum generation. AB - We use dispersive Fourier transformation to measure shot-to-shot spectral instabilities in femtosecond supercontinuum generation. We study both the onset phase of supercontinuum generation with distinct dispersive wave generation, as well as a highly-unstable supercontinuum regime spanning an octave in bandwidth. Wavelength correlation maps allow interactions between separated spectral components to be identified, even when such interactions are not apparent in shot to-shot or average measurements. Experimental results are interpreted using numerical simulations. Our results show the clear advantages of dispersive Fourier transformation for studying spectral noise during supercontinuum generation. PMID- 23938718 TI - Polarization dependence of the self-organized microgratings induced in SrTiO3 crystal by a single femtosecond laser beam. AB - In this paper, self-organized microgratings are fabricated in SrTiO(3) crystal just by scanning the focus of a tightly-focused linearly-polarized femtosecond laser beam to form a single line. The polarization direction of the laser beam is rotated by a lambda/2 waveplate to check the effect of the polarization azimuth on the micrograting morphology. Fourier analyzing of the microscopic images of the microgratings indicates that the polarization plane azimuth of the laser beam does have influence on the microgratings in the aspects of groove orientation and groove spacing. A possible mechanism of polarization dependence is also proposed. PMID- 23938719 TI - Radially polarized Bessel-Gauss beams: decentered Gaussian beam analysis and experimental verification. AB - We derive solutions for radially polarized Bessel-Gauss beams in free-space by superimposing decentered Gaussian beams with differing polarization states. We numerically show that the analytical result is applicable even for large semi aperture angles, and we experimentally confirm the analytical expression by employing a fiber-based mode-converter. PMID- 23938720 TI - Disposable plasmonic plastic SERS sensor. AB - The 'KlariteTM' SERS sensor platform consisting of an array of gold coated inverted square pyramids patterned onto a silicon substrate has become the industry standard over the last decade, providing highly reproducible SERS signals. In this paper, we report successful transfer from silicon to plastic base platform of an optimized SERS substrate design which provides 8 times improvement in sensitivity for a Benzenethiol test molecule compared to standard production Klarite. Transfer is achieved using roll-to-roll and sheet-level nanoimprint fabrication techniques. The new generation plastic SERS sensors provide the added benefit of cheap low cost mass-manufacture, and easy disposal. The plastic replicated SERS sensors are shown to provide ~10(7) enhancement factor with good reproducibility (5%). PMID- 23938721 TI - All-optically controllable and highly efficient scattering mode light modulator based on azobenzene liquid crystals and poly(N-vinylcarbazole) films. AB - The present study reports that isothermal phase transition induced by photoisomerization of azobenzene liquid crystals (azo-LCs) from trans- to cis isomers results in the dissolution of poly(N-vinylcarbazole) (PVK) into azo-LCs. Transparent (scattering) states can be demonstrated using uniform (rough) morphologies of PVK generated by slow (rapid) phase separation of PVK and azo-LCs from cis- to trans-isomers. The PVK films were examined in detail using scanning electron microscopy. Scattering performance resulting from the rough PVK surface induced micron-sized LC domains, and transparent performance resulting from the reformed uniform PVK surface can be optically and reversibly switched. Finally, all-optically controllable and highly efficient (contrast ratio of 370:1) scattering mode light modulators based on azo-LCs and PVK films were demonstrated. PMID- 23938722 TI - Controlling ripples' periodicity using temporally delayed femtosecond laser double pulses. AB - We demonstrate the capability to control the ripple periodicity on polycrystalline ZnO films by applying temporally delayed femtosecond double pulses. It is shown that there is a characteristic pulse separation time for which one can switch from low- to high- spatial-frequency ripple formation. Results are interpreted based on the relation of the characteristic delay time with the electron-phonon relaxation time of the material. Our results indicate that temporal pulse shaping can be advantageously used as a mean to control the periodic nanoripples' formation and thus the outcome of laser assisted nanofabrication process, which is desirable for the applications of nanopatterned transparent semiconductors. PMID- 23938723 TI - Parametric model of the Mueller matrix of a Spectralon white reflectance standard deduced by polar decomposition techniques. AB - Decomposition methods have been applied to in-plane Mueller matrix ellipsometric scattering data of the Spectralon reflectance standard. Data were measured at the wavelengths 532 nm and 1500 nm, using an achromatic optimal Mueller matrix scatterometer applying a photomultiplier tube and a high gain InGaAs detector for the two wavelengths. A parametric model with physical significance was deduced through analysis of the product decomposed matrices. It is found that when the data are analyzed as a function of the scattering angle, similar to particle scattering, the matrix elements are largely independent of incidence angle. To the first order, we propose that a Guassian lineshape is appropriate to describe the polarization index, while the decomposed diagonal elements of the retardance matrix have a form resembling Rayleigh single scattering. New models are proposed for the off diagonal elements of the measured Mueller matrix. PMID- 23938725 TI - Ultra-broadband infrared luminescence of Bi-doped thin-films for integrated optics. AB - Ultra-broadband infrared luminescence has been observed in bismuth (Bi)-doped germanate thin-films prepared by pulsed laser deposition. The films are compatible with various types of substrates, including conventional dielectrics (LaAlO(3), silica) and semiconductors (Si, GaAs). The emission peak position of the films can be finely tuned by changing oxygen partial pressure during the deposition, while the excitation wavelength locates from ultra-violet to near infrared regions. The physical mechanism behind the observed infrared luminescence of the Bi-doped films, differing from that of the as-made glass, is discussed. PMID- 23938724 TI - Production of 70-nm Cr dots by laser-induced forward transfer. AB - The effect of donor film thickness and laser beam fluence on the size of laser induced forward transfer (LIFT) spots is studied to achieve sub-100 nm features. A 130 fs, 800 nm laser is focused on ultrathin Cr films, and the transfer and ablation thresholds of these films at various thicknesses are determined. The minimum transfer spot size decreases with decreasing donor film thickness and incident laser fluence. Minimum LIFT spots of 70-450 nm diameter are obtained from films of 20-80 nm thickness, respectively. The 70 nm diameter transfer spots obtained from sputtered continuous films are the smallest to date. PMID- 23938726 TI - Absolute instrument spectral response measurements using angle-resolved parametric fluorescence. AB - The broadband parametric fluorescence from a nonlinear crystal can be used as a compact primary source instead of a blackbody for absolute measurements of instrument spectral efficiency. We describe such a setup for measuring the instrument spectral response function in the wavelength range from 450 to 1000 nm. We perform angle-resolved imaging spectroscopy of conical parametric fluorescence in a beta-barium borate crystal pumped by a 405-nm diode laser. The experimental angle-resolved spectra and the generation efficiency of parametric down-conversion agree with a plane-wave theoretical analysis. PMID- 23938727 TI - Local bandgap control of germanium by silicon nitride stressor. AB - We have proposed a new approach to tune the operation wavelength of Franz-Keldysh Ge electro-absorption modulation in Si photonics by controlling the local strain environment to cover the whole range of C + L bands (1.53 - 1.62 MUm). The present paper shows a proof of strain-tuning modulator concept by the shift of the Ge absorption edge using SiN(x) stressor films and Franz-Keldysh effect in strain-controlled Ge. PMID- 23938728 TI - Understanding the contribution of mode area and slow light to the effective Kerr nonlinearity of waveguides. AB - We resolve the ambiguity in existing definitions of the effective area of a waveguide mode that have been reported in the literature by examining which definition leads to an accurate evaluation of the effective Kerr nonlinearity. We show that the effective nonlinear coefficient of a waveguide mode can be written as the product of a suitable average of the nonlinear coefficients of the waveguide's constituent materials, the mode's group velocity and a new suitably defined effective mode area. None of these parameters on their own completely describe the strength of the nonlinear effects of a waveguide. PMID- 23938729 TI - Theoretical analysis of obliquely excited surface plasmon self-interference. AB - We present the theoretical analysis of surface plasmon polaritons induced by a tightly focused light beam at oblique incidence. Firstly, we propose a geometrical model to explain the evolution of SPPs effect as light deviating from normal incidence, and introduce a concept of critical oblique angle (theta(co)) which is one of the key factors affecting the stability, efficiency and lateral resolution of SPPs. Secondly, the integral expressions for the transmitted SPP field excited by a linearly polarized vortex beam are derived, using angular spectrum representation and rotation matrix trans-formation, for the oblique directions as parallel and perpendicular to polarization plane. An interesting finding is that the system completely goes out of SPP self-interference resonance at an incident angle smaller than theta(co) at parallel obliquity, while larger than theta(co) at perpendicular obliquity. PMID- 23938730 TI - Spectral broadening in anatase titanium dioxide waveguides at telecommunication and near-visible wavelengths. AB - We observe spectral broadening of femtosecond pulses in single-mode anatase titanium dioxide (TiO(2)) waveguides at telecommunication and near-visible wavelengths (1565 and 794 nm). By fitting our data to nonlinear pulse propagation simulations, we quantify nonlinear optical parameters around 1565 nm. Our fitting yields a nonlinear refractive index of 0.16 * 10(-18) m(2)/W, no two-photon absorption, and stimulated Raman scattering from the 144 cm(-1) Raman line of anatase with a gain coefficient of 6.6 * 10(-12) m/W. Additionally, we report on asymmetric spectral broadening around 794 nm. The wide wavelength applicability and negligible two-photon absorption of TiO(2) make it a promising material for integrated photonics. PMID- 23938731 TI - Eclipsing thermal lens spectroscopy for fluorescence quantum yield measurement. AB - A modified spatial filtering method that improves the sensitivity of single-beam and mode-mismatched thermal lens spectroscopy (TLS) for fluorescence quantum yield measurement is presented. The method is based on the detection of the external part of a laser beam transmitted by the fluorescent sample (eclipsing detection mode). The experimental results show that the signal/noise (S/N) ratio of the absolute quantum yield of Rh6G can be enhanced up to ~1400% using the eclipsing detection mode on the TLS experimental setup. The method was evaluated by measuring the fluorescence quantum yield of varying concentration of ethanolic solutions of Rhodamine 6G. PMID- 23938735 TI - Alzheimer disease: Joining the dots between APOE epsilon4 and late-onset Alzheimer disease via integrative genomics. PMID- 23938737 TI - Dementia: Reduction in the prevalence of dementia in the past 20 years. PMID- 23938741 TI - Multiple sclerosis: Regenerative therapies for MS-hope on the horizon. PMID- 23938742 TI - Multiple sclerosis: Month of birth effect in MS--fact or artefact? PMID- 23938739 TI - Lysosomal storage diseases--the horizon expands. AB - Since the discovery of the lysosome in 1955, advances have been made in understanding the key roles and functions of this organelle. The concept of lysosomal storage diseases (LSDs)--disorders characterized by aberrant, excessive storage of cellular material in lysosomes--developed following the discovery of alpha-glucosidase deficiency as the cause of Pompe disease in 1963. Great strides have since been made in understanding the pathobiology of LSDs and the neuronal ceroid lipofuscinoses (NCLs). The NCLs are neurodegenerative disorders that display symptoms of cognitive and motor decline, seizures, blindness, early death, and accumulation of lipofuscin in various cell types, and also show some similarities to 'classic' LSDs. Defective lysosomal storage can occur in many cell types, but the CNS and PNS are particularly vulnerable to LSDs and NCLs, being affected in two-thirds of these disorders. Most LSDs are inherited in an autosomal recessive manner, with the exception of X-linked Hunter disease, Fabry disease and Danon disease, and a variant type of adult NCL (Kuf disease). This Review provides a summary of known LSDs, and the pathways affected in these disorders. Existing therapies and barriers to development of novel and improved treatments for LSDs and NCLs are also discussed. PMID- 23938744 TI - Multiple sclerosis: Gene-vitamin D interactions likely to influence pathogenesis and risk of relapse in multiple sclerosis. PMID- 23938746 TI - Dementia: Vascular and neurodegenerative pathways-will they meet? PMID- 23938747 TI - Paleovirology: inferring viral evolution from host genome sequence data. PMID- 23938748 TI - On the concept and elucidation of endogenous retroviruses. AB - Endogenous retrovirus (ERV) genomes integrated into the chromosomal DNA of the host were first detected in chickens and mice as Mendelian determinants of Gag and Env proteins and of the release of infectious virus particles. The presence of ERV was confirmed by DNA hybridization. With complete host genomes available for analysis, we can now see the great extent of viral invasion into the genomes of numerous vertebrate species, including humans. ERVs are found at many loci in host DNA and also in the genomes of large DNA viruses, such as herpesviruses and poxviruses. The evolution of xenotropism and cross-species infection is discussed in the light of the dynamic relationship between exogenous and endogenous retroviruses. PMID- 23938749 TI - Host gene evolution traces the evolutionary history of ancient primate lentiviruses. AB - Simian immunodeficiency viruses (SIVs) have infected primate species long before human immunodeficiency virus has infected humans. Dozens of species-specific lentiviruses are found in African primate species, including two strains that have repeatedly jumped into human populations within the past century. Traditional phylogenetic approaches have grossly underestimated the age of these primate lentiviruses. Instead, here we review how selective pressures imposed by these viruses have fundamentally altered the evolutionary trajectory of hosts genes and, even in cases where there now remains no trace of the viruses themselves, these evolutionary signatures can reveal the types of viruses that were once present. Examination of selection by ancient viruses on the adaptive evolution of host genes has been used to derive minimum age estimates for modern primate lentiviruses. This type of data suggests that ancestors of modern SIV existed in simian primates more than 10 Ma. Moreover, examples of host resistance and viral adaptation have implications not only for estimating the age and host range of ancient primate lentiviruses, but also the pathogenic potential of their modern counterparts. PMID- 23938750 TI - Apparent effect of rabbit endogenous lentivirus type K acquisition on retrovirus restriction by lagomorph Trim5alphas. AB - To test the hypothesis that rabbit endogenous lentivirus type K (RELIK) could play a role in shaping the evolution of TRIM5alpha, the susceptibility of viruses containing the RELIK capsid (CA) to TRIM5 restriction was evaluated. RELIK CA containing viruses were susceptible to the TRIM5alphas from Old World monkeys but were unaffected by most ape or New World monkey factors. TRIM5alphas from various lagomorph species were also isolated and tested for anti-retroviral activity. The TRIM5alphas from both cottontail rabbit and pika restrict a range of retroviruses, including HIV-1, HIV-2, FIV, EIAV and N-MLV. TRIM5alphas from the European and cottontail rabbit, which have previously been found to contain RELIK, also restricted RELIK CA-containing viruses, whereas a weaker restriction was observed with chimeric TRIM5alpha containing the B30.2 domain from the pika, which lacks RELIK. Taken together, these results could suggest that the pika had not been exposed to exogenous RELIK and that endogenized RELIK might exert a selective pressure on lagomorph TRIM5alpha. PMID- 23938751 TI - Comprehensive analysis of endogenous bornavirus-like elements in eukaryote genomes. AB - Bornaviruses are the only animal RNA viruses that establish a persistent infection in their host cell nucleus. Studies of bornaviruses have provided unique information about viral replication strategies and virus-host interactions. Although bornaviruses do not integrate into the host genome during their replication cycle, we and others have recently reported that there are DNA sequences derived from the mRNAs of ancient bornaviruses in the genomes of vertebrates, including humans, and these have been designated endogenous borna like (EBL) elements. Therefore, bornaviruses have been interacting with their hosts as driving forces in the evolution of host genomes in a previously unexpected way. Studies of EBL elements have provided new models for virology, evolutionary biology and general cell biology. In this review, we summarize the data on EBL elements including what we have newly identified in eukaryotes genomes, and discuss the biological significance of EBL elements, with a focus on EBL nucleoprotein elements in mammalian genomes. Surprisingly, EBL elements were detected in the genomes of invertebrates, suggesting that the host range of bornaviruses may be much wider than previously thought. We also review our new data on non-retroviral integration of Borna disease virus. PMID- 23938752 TI - Identification of an ancient endogenous retrovirus, predating the divergence of the placental mammals. AB - The evolutionary arms race between mammals and retroviruses has long been recognized as one of the oldest host-parasite interactions. Rapid evolution rates in exogenous retroviruses have often made accurate viral age estimations highly problematic. Endogenous retroviruses (ERVs), however, integrate into the germline of their hosts, and are subjected to their evolutionary rates. This study describes, for the first time, a retroviral orthologue predating the divergence of placental mammals, giving it a minimum age of 104-110 Myr. Simultaneously, other orthologous selfish genetic elements (SGEs), inserted into the ERV sequence, provide evidence for the oldest individual mammalian-wide interspersed repeat and medium-reiteration frequency interspersed repeat mammalian repeats, with the same minimum age. The combined use of shared SGEs and reconstruction of viral orthologies defines new limits and increases maximum 'lookback' times, with subsequent implications for the field of paleovirology. PMID- 23938754 TI - Exploring the effects of immunity and life history on the dynamics of an endogenous retrovirus. AB - Mammalian DNA is littered with the signatures of past retroviral infections. For example, at least 8% of the human genome can be attributed to endogenous retroviruses (ERVs). We take a single-locus approach to develop a simple susceptible-infected-recovered model to investigate the circumstances under which a disease-causing retrovirus can become incorporated into the host genome and spread through the host population if it were to confer an immunological advantage. In the absence of any fitness benefit provided by the long terminal repeat (LTR), we conclude that signatures of ERVs are likely to go to fixation within a population when the probability of evolving cellular/humoral immunity to a related exogenous version of the virus is extremely small. We extend this model to examine whether changing the speed of the host life history influences the likelihood that an exogenous retrovirus will incorporate and spread to fixation. Our results reveal the parameter space under which incorporation of exogenous retroviruses into a host genome may be beneficial to the host. In our final model, we find that the likelihood of an LTR reaching fixation in a host population is not strongly affected by host life history. PMID- 23938753 TI - 'There and back again': revisiting the pathophysiological roles of human endogenous retroviruses in the post-genomic era. AB - Almost 8% of the human genome comprises endogenous retroviruses (ERVs). While they have been shown to cause specific pathologies in animals, such as cancer, their association with disease in humans remains controversial. The limited evidence is partly due to the physical and bioethical restrictions surrounding the study of transposons in humans, coupled with the major experimental and bioinformatics challenges surrounding the association of ERVs with disease in general. Two biotechnological landmarks of the past decade provide us with unprecedented research artillery: (i) the ultra-fine sequencing of the human genome and (ii) the emergence of high-throughput sequencing technologies. Here, we critically assemble research about potential pathologies of ERVs in humans. We argue that the time is right to revisit the long-standing questions of human ERV pathogenesis within a robust and carefully structured framework that makes full use of genomic sequence data. We also pose two thought-provoking research questions on potential pathophysiological roles of ERVs with respect to immune escape and regulation. PMID- 23938755 TI - Pushing the endogenous envelope. AB - The majority of retroviral envelope glycoproteins characterized to date are typical of type I viral fusion proteins, having a receptor binding subunit associated with a fusion subunit. The fusion subunits of lentiviruses and alpha-, beta-, delta- and gammaretroviruses have a very conserved domain organization and conserved features of secondary structure, making them suitable for phylogenetic analyses. Such analyses, along with sequence comparisons, reveal evidence of numerous recombination events in which retroviruses have acquired envelope glycoproteins from heterologous sequences. Thus, the envelope gene (env) can have a history separate from that of the polymerase gene (pol), which is the most commonly used gene in phylogenetic analyses of retroviruses. Focusing on the fusion subunits of the genera listed above, we describe three distinct types of retroviral envelope glycoproteins, which we refer to as gamma-type, avian gamma type and beta-type. By tracing these types within the 'fossil record' provided by endogenous retroviruses, we show that they have surprisingly distinct evolutionary histories and dynamics, with important implications for cross species transmissions and the generation of novel lineages. These findings validate the utility of env sequences in contributing phylogenetic signal that enlarges our understanding of retrovirus evolution. PMID- 23938756 TI - Paleovirology of 'syncytins', retroviral env genes exapted for a role in placentation. AB - The development of the emerging field of 'paleovirology' allows biologists to reconstruct the evolutionary history of fossil endogenous retroviral sequences integrated within the genome of living organisms and has led to the retrieval of conserved, ancient retroviral genes 'exapted' by ancestral hosts to fulfil essential physiological roles, syncytin genes being undoubtedly among the most remarkable examples of such a phenomenon. Indeed, syncytins are 'new' genes encoding proteins derived from the envelope protein of endogenous retroviral elements that have been captured and domesticated on multiple occasions and independently in diverse mammalian species, through a process of convergent evolution. Knockout of syncytin genes in mice provided evidence for their absolute requirement for placenta development and embryo survival, via formation by cell-cell fusion of syncytial cell layers at the fetal-maternal interface. These genes of exogenous origin, acquired 'by chance' and yet still 'necessary' to carry out a basic function in placental mammals, may have been pivotal in the emergence of mammalian ancestors with a placenta from egg-laying animals via the capture of a founding retroviral env gene, subsequently replaced in the diverse mammalian lineages by new env-derived syncytin genes, each providing its host with a positive selective advantage. PMID- 23938757 TI - Functional endogenous viral elements in the genome of the parasitoid wasp Cotesia congregata: insights into the evolutionary dynamics of bracoviruses. AB - Bracoviruses represent the most complex endogenous viral elements (EVEs) described to date. Nudiviral genes have been hosted within parasitoid wasp genomes since approximately 100 Ma. They play a crucial role in the wasp life cycle as they produce bracovirus particles, which are injected into parasitized lepidopteran hosts during wasp oviposition. Bracovirus particles encapsidate multiple dsDNA circles encoding virulence genes. Their expression in parasitized caterpillars is essential for wasp parasitism success. Here, we report on the genomic organization of the proviral segments (i.e. master sequences used to produce the encapsidated dsDNA circles) present in the Cotesia congregata parasitoid wasp genome. The provirus is composed of a macrolocus, comprising two thirds of the proviral segments and of seven dispersed loci, each containing one to three segments. Comparative genomic analyses with closely related species gave insights into the evolutionary dynamics of bracovirus genomes. Conserved synteny in the different wasp genomes showed the orthology of the proviral macrolocus across different species. The nudiviral gene odv-e66-like1 is conserved within the macrolocus, suggesting an ancient co-localization of the nudiviral genome and bracovirus proviral segments. By contrast, the evolution of proviral segments within the macrolocus has involved a series of lineage-specific duplications. PMID- 23938758 TI - When parasitic wasps hijacked viruses: genomic and functional evolution of polydnaviruses. AB - The Polydnaviridae (PDV), including the Bracovirus (BV) and Ichnovirus genera, originated from the integration of unrelated viruses in the genomes of two parasitoid wasp lineages, in a remarkable example of convergent evolution. Functionally active PDVs represent the most compelling evolutionary success among endogenous viral elements (EVEs). BV evolved from the domestication by braconid wasps of a nudivirus 100 Ma. The nudivirus genome has become an EVE involved in BV particle production but is not encapsidated. Instead, BV genomes have co-opted virulence genes, used by the wasps to control the immunity and development of their hosts. Gene transfers and duplications have shaped BV genomes, now encoding hundreds of genes. Phylogenomic studies suggest that BVs contribute largely to wasp diversification and adaptation to their hosts. A genome evolution model explains how multidirectional wasp adaptation to different host species could have fostered PDV genome extension. Integrative studies linking ecological data on the wasp to genomic analyses should provide new insights into the adaptive role of particular BV genes. Forthcoming genomic advances should also indicate if the associations between endoparasitoid wasps and symbiotic viruses evolved because of their particularly intimate interactions with their hosts, or if similar domesticated EVEs could be uncovered in other parasites. PMID- 23938759 TI - Evolutionary analysis of hepatitis C virus gene sequences from 1953. AB - Reconstructing the transmission history of infectious diseases in the absence of medical or epidemiological records often relies on the evolutionary analysis of pathogen genetic sequences. The precision of evolutionary estimates of epidemic history can be increased by the inclusion of sequences derived from 'archived' samples that are genetically distinct from contemporary strains. Historical sequences are especially valuable for viral pathogens that circulated for many years before being formally identified, including HIV and the hepatitis C virus (HCV). However, surprisingly few HCV isolates sampled before discovery of the virus in 1989 are currently available. Here, we report and analyse two HCV subgenomic sequences obtained from infected individuals in 1953, which represent the oldest genetic evidence of HCV infection. The pairwise genetic diversity between the two sequences indicates a substantial period of HCV transmission prior to the 1950s, and their inclusion in evolutionary analyses provides new estimates of the common ancestor of HCV in the USA. To explore and validate the evolutionary information provided by these sequences, we used a new phylogenetic molecular clock method to estimate the date of sampling of the archived strains, plus the dates of four more contemporary reference genomes. Despite the short fragments available, we conclude that the archived sequences are consistent with a proposed sampling date of 1953, although statistical uncertainty is large. Our cross-validation analyses suggest that the bias and low statistical power observed here likely arise from a combination of high evolutionary rate heterogeneity and an unstructured, star-like phylogeny. We expect that attempts to date other historical viruses under similar circumstances will meet similar problems. PMID- 23938760 TI - Electromagnetic redesign of the HYPERcollar applicator: toward improved deep local head-and-neck hyperthermia. AB - Accumulating evidence shows that hyperthermia improves head-and-neck cancer treatment. Over the last decade, we introduced a radiofrequency applicator, named HYPERcollar, which enables local heating also of deep locations in this region. Based on clinical experience, we redesigned the HYPERcollar for improved comfort, reproducibility and operator handling. In the current study, we analyze the redesign from an electromagnetic point of view. We show that a higher number of antennas and their repositioning allow for a substantially improved treatment quality. Combined with the much better reproducibility of the water bolus, this will substantially minimize the risk of underexposure. All improvements combined enable a reduction of hot-spot prominence (hot-spot to target SAR quotient) by 32% at an average of 981 W, which drastically reduces the probability for system power to become a treatment limiting source. Moreover, the power deposited in the target selectively can be increased by more than twofold. Hence, we expect that the HYPERcollar redesign currently under construction allows us to double the clinically applied power to the target while reducing the hot-spots, resulting in higher temperatures and, consequently, better clinical outcome. PMID- 23938761 TI - The adjuvant effect of hypertension upon diabetic peripheral neuropathy in experimental type 2 diabetes. AB - Type 2 diabetes (DM) is the most common cause of peripheral neuropathy in the Western world. A comorbidity, hypertension, has been speculated to contribute to initiation or worsening of diabetic peripheral neuropathy. We studied adult rat models using genetic strains with DM (Zucker Diabetic Fat rats)+/-hypertension (HTN (ZSF-1 rats)) to investigate the relative contributions of DM and HTN and the potential for additive effects of HTN upon existing DM for the development of peripheral neuropathy. Long duration sensorimotor behavioral and electrophysiological testing was complemented by histological and molecular methods. Only DM led to tactile and thermal hyperalgesia and affected motor nerve electrophysiology. Although DM led to marked loss of sensory amplitudes and to sensory conduction slowing, a mild additive effect from HTN contributed after 6months of DM with worsening of slowing of sensory nerve conduction velocities, but without effect upon sensory amplitudes. At the sensory dominant sural nerve, mild (<10%) but greater degrees of myelin thinning were noted with DM and HTN combined, suggesting a mild additive effect. Matrix metalloproteinase (MMP) expression was increased only at the sural nerve in the presence of HTN with co localization to Schwann cells and myelin. The effects of DM and HTN upon peripheral nerve are dissimilar, with HTN contributing to MMP upregulation at the sites of myelin thinning at sensory nerve fibers, potentially worsening comorbid DM. Together, our results indicate that HTN has a mild additive contribution to diabetic peripheral neuropathy at sensory peripheral nerve fibers manifesting with the loss of myelin thickness. PMID- 23938762 TI - Neuronal firing activity and gene expression changes in the subthalamic nucleus after transplantation of dopamine neurons in hemiparkinsonian rats. AB - Dopamine (DA) depletion in the nigrostriatal system leads to basal ganglia dysfunction both in Parkinson's disease (PD) and in 6-hydroxy dopamine (6-OHDA) lesioned rats with neuronal hyperactivity in the subthalamic nucleus (STN), i.e. increased firing rate and burst activity, together with enhanced beta oscillatory activity. Moreover, intrastriatal transplantation of DA neurons has been shown to functionally re-innervate the host striatum and restore DA input. However, the effects of those transplanted cells on the STN are not well characterized. Therefore, we transplanted cells, derived from the ventral mesencephalon of E12 rat embryos, intrastriatally in the unilateral 6-OHDA-lesioned rat model of PD. We combined behavioral and histological findings with electrophysiological extracellular recordings in the STN, as well as qRT-PCR analyses of dopaminergic, GABAergic, and glutamatergic transporter and receptor genes in the striatum and the STN. Transplanted animals displayed improved rotational behavior after amphetamine injection by 50% in rats with small grafts (586+/-109 SEM dopamine cells), or even overcompensation by 116% in rats with large grafts (3486+/-548 SEM dopamine cells). Electrophysiological measurements revealed, that in rats with large grafts burst activity was not affected, while STN neuronal firing rate, as well as beta oscillatory activity was alleviated, whereas small grafts had less impact. Interestingly, both behavioral and electrophysiological measures were dependent on the number of surviving tyrosine hydroxylase positive cells. Although grafted rats displayed restored expression of the GABA synthesizing enzymes Gad65 and Gad67 in the striatum compared to naive rats, the grafts induced a decreased mRNA expression of dopamine receptor Drd2, glutamate receptors AMPA3, NMDA2A, and NMDA2B, and glutamate transporter Eaat3. Interestingly, the NMDA receptor subunit 2B and glutamate transporter Eaat3 were also less expressed in the STN of grafted animals compared to naive rats. In summary, DA grafts restore functional deficits and cause partial improvement of subthalamic neuronal activity. Incomplete recovery, however, may be due to decreased receptor gene expression induced by DA grafts in the striatum and in the STN. PMID- 23938763 TI - Pharmacological blockade of IL-1beta/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. AB - We studied whether pharmacological blockade of the IL-1beta-mediated signaling, rapidly activated in forebrain by epileptogenic injuries, affords neuroprotection in two different rat models of status epilepticus (SE). As secondary outcome, we measured treatment's effect on SE-induced epileptogenesis. IL-1beta signaling was blocked by systemic administration of two antiinflammatory drugs, namely human recombinant IL-1 receptor antagonist (anakinra), the naturally occurring and clinically used competitive IL-1 receptor type 1 antagonist, and VX-765 a specific non-peptide inhibitor of IL-1beta cleavage and release. Antiinflammatory drugs were given 60min after antiepileptic (AED) drug-controlled SE induced by pilocarpine, or 180min after unrestrained electrical SE, for 7days using a protocol yielding therapeutic drug levels in brain. This drug combination significantly decreased both IL-1beta expression in astrocytes and cell loss in rat forebrain. Neuroprotection and the antiinflammatory effect were more pronounced in the electrical SE model. Onset of epilepsy, and frequency and duration of seizures 3months after electrical SE were not significantly modified. Transcriptomic analysis in the hippocampus showed that the combined treatment did not affect the broad inflammatory response induced by SE during epileptogenesis. In particular, the treatment did not prevent the induction of the complement system and Toll-like receptors, both contributing to cell loss and seizure generation. We conclude that the IL-1beta signaling represents an important target for reducing cell loss after SE. The data highlight a new class of clinically tested agents affording neuroprotection after a delayed post-injury intervention. Earlier blockade of this rapid onset inflammatory pathway during SE, or concomitant treatment with antiinflammatory drugs targeting additional components of the broad inflammatory response to SE, or co-treatment with AEDs, is likely to be required for optimizing beneficial outcomes. PMID- 23938764 TI - Comparative antioxidant responses in liver of Carassius auratus exposed to phthalates: an integrated biomarker approach. AB - Phthalates (PAEs) are chemical agents typically used as plasticizers in numerous industrial products. They have become ubiquitous contaminants due to their tendency to release into the environment. The present study was conducted to investigate the comparative antioxidant responses in liver of freshwater goldfish Carassius auratus injected intraperitoneally with 17 different PAEs at a concentration of 10 mg/kg for 10 days. The results indicated that these PAEs can adversely affect the antioxidant status, confirmed by the significantly inhibited activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase). Especially, the latter two enzymes constituted the most affected antioxidant enzymes after the exposure, and the lowest values were recorded for the catalase activity. The toxicity order was proposed via the integrated biomarker response, with dicyclohexyl phthalate the most toxic and diethyl phthalate the least. Overall, these findings may contribute to the risk assessments of these chemicals on aquatic species. PMID- 23938765 TI - BRAF and KIT somatic mutations are present in amelanotic melanoma. AB - The genotypic profile of rare amelanotic melanomas (AMs) has been poorly investigated, thus preventing either an accurate identification as a distinctive melanoma subtype or therapy stratification. Here, we investigated the presence of the BRAF(V600E) mutation by real-time quantitative PCR and KIT mutations (exons 11 and 17) by sequencing analysis in 33 AMs. AMs included 'truly' amelanotic lesions (n = 19), with no melanin pigmentation upon dermoscopic inspection and hypomelanotic lesions (n = 14), by definition partially pigmented lesions showing a melanin pigmentation area of less than 25% of the total surface area. The frequency of the BRAF(V600E) mutation was 70.3% in the 33 cases, a percentage that increased to 89% when only the subgroup of thin melanomas (<= 1 mm in thickness, n = 9) was considered. KIT mutations were found in 12.1% of AMs, all of which developed in nonacral sites. The identification of a relatively high frequency of BRAF(V600E) and KIT mutations in AMs may have important consequences for implementation of the novel targeted therapies now available to treat this life-threatening disease. PMID- 23938766 TI - Remembering our origin: gender differences in spatial memory are reflected in gender differences in hippocampal lateralization. AB - Gender differences in spatial memory favoring men are frequently reported, and the involvement of the hippocampus in these functions is well-established. However, little is known of whether this behavioral gender difference is mirrored in a gender difference in hippocampal function. Here we assessed hippocampal activity, using functional MRI, while 24 men and women moved through three dimensional virtual mazes (navigation phase) of varying length, and at the end point estimated the direction of the starting-point (pointing phase). Men were indeed more accurate than women at estimating direction, and this was especially true in longer mazes. Both genders activated the posterior hippocampus throughout the whole task. During the navigation phase, men showed a larger activation in the right hippocampus than women, while in the pointing phase, women showed a larger activation in the left hippocampus than men. Right-lateralized activation during the navigation phase was associated with greater task performance, and may reflect a spatial strategy that is beneficial in this task. Left-sided activation during the pointing phase might reflect a less efficient post hoc verbal recapitulation of the route. This study is the first to identify neural correlates of the commonly observed male advantage in recalling one's original position, and points to hippocampal lateralization as a possible explanation for this behavioral gender difference. PMID- 23938767 TI - Band-gap expansion of tungsten oxide quantum dots synthesized in sub-nano porous silica. AB - The band-gap energy tuning of WO3 quantum dots was realized in the range of 2.6 eV (bulk) to 3.7 eV (sub-nano) by precise size control around one nanometer. Newly synthesized sub-nanoporous silicas act as excellent templates. In addition, single-electron reduction of oxygen under UV irradiation is now achievable with WO3. PMID- 23938768 TI - Reusable glucose sensing using carbon nanotube-based self-assembly. AB - Lipid functionalized single walled carbon nanotube-based self assembly forms a super-micellar structure. This assemblage has been exploited to trap glucose oxidase in a molecular cargo for glucose sensing. The advantage of such a molecular trap is that all components of this unique structure (both the trapping shell and the entrapped enzyme) are reusable and rechargeable. The unique feature of this sensing method lies in the solid state functionalization of single walled carbon nanotubes that facilitates liquid state immobilization of the enzyme. The method can be used for soft-immobilization (a new paradigm in enzyme immobilization) of enzymes with better thermostability that is imparted by the strong hydrophobic environment provided through encapsulation by the nanotubes. PMID- 23938770 TI - Sensitized terbium(III) macrocyclic-phthalimide complexes as luminescent pH switches. AB - Four new macrocyclic-phthalimide ligands were synthesised via the coupling of N (3-bromopropyl)phthalimide either to cyclen (1,4,7,10-tetraazacyclododecane) itself or its carboxylate-functionalized analogues, and photophysical studies were carried out on their corresponding Tb(III) complexes in aqueous media as a function of pH. Luminescence intensities of Tb.L1a-Tb.L3a were in 'switched off' mode under acidic conditions (pH < 4), and were activated on progression to basic conditions as the phthalimido functions therein were hydrolysed to their corresponding phthalamates Tb.L1b-Tb.L3b. Emission of phthalamate-based macrocyclic Tb(III) complexes Tb.L1b-Tb.L3b was in 'switched on' mode between pH 4 and 11, exhibiting high quantum yields (Phi) and long lifetimes (tau) of the order of milliseconds at pH ~ 6. Tb(III) emissions were found to decline with increasing number of chromophores. The values of Phi and tau were 46% and 2.4 ms respectively for Tb.L1b at pH ~ 6 when activated. This is the best pH-dependent sensor based on a Tb(III) complex reported to date, benefiting from the macrocyclic architecture of the ligand. PMID- 23938769 TI - "Click" dendrimers as efficient nanoreactors in aqueous solvent: Pd nanoparticle stabilization for sub-ppm Pd catalysis of Suzuki-Miyaura reactions of aryl bromides. AB - Palladium nanoparticles (PdNPs) with a size of 1.4 nm are stabilized by dendritic nanoreactors containing 1,2,3-triazole ligands with hydrophilic triethylene glycol (TEG) termini. These PdNPs are stable for months under air and are extremely active for the Suzuki-Miyaura reactions of aryl bromides down to sub ppm levels. PMID- 23938771 TI - Modern Vaccine Adjuvant/Formulation--Session 9: Adjuvants. AB - The Session 9 of the Modern Vaccine Adjuvant/Formulation meeting pointed out the permanent need for vaccine improvement and for adjuvant development. Indeed, the increasing use of recombinant subunit vaccines for both parenteral and mucosal vaccination necessitates the development of improved adjuvants. This session dealt with strategies for the development of new vaccine adjuvants with respect to the availability of new molecules targeting specifically the receptors of the systemic or mucosal immune system. PMID- 23938773 TI - Evaluation on the effect of different in-gel peptide isoelectric focusing parameters in global proteomic profiling. AB - Peptide isoelectric focusing (IEF) is a common technique used in two-dimensional liquid chromatography tandem mass spectrometry (2D-LC-MS/MS) proteomic workflow, in which the tryptic peptide is first pre-fractionated based on pI values before being subjected to reverse phase LC-MS analysis. Although this method has been widely used by many research groups, a systemic study on the optimal conditions and fundamental parameters influencing the experimental outcomes has been lacking, including the effect of peptide extraction methods, the extent of pre fractionation, and the choice of pH range. In this study, we compared the effect of different parameters on the numbers of peptides and proteins identified using two complex mouse proteomes. The results indicated that extraction of peptides from immobilized pH gradient (IPG) strips by sequential elution of increasingly organic solvents provided the highest number of peptide identification. In addition, we showed that approximately 45 more unique proteins were identified for every additional fraction collected during peptide IEF. Although narrow pH ranges provided higher resolution in peptide separation as expected, different pH ranges yielded similar numbers of peptide and protein identification. Overall, we demonstrated that the extraction solvent influenced the numbers of peptide and protein identification and quantitatively demonstrated the advantage of extensive fractionation and the performance of different pH ranges in practice. PMID- 23938772 TI - A quantitative method to identify microRNAs targeting a messenger RNA using a 3'UTR RNA affinity technique. AB - The identification of specific microRNAs (miRNAs) that target a given messenger RNA (mRNA) is essential for studies in gene regulation, but the available bioinformatic software programs are often unreliable. We have developed a unique experimental miRNA affinity assay whereby a 3'UTR RNA is end-labeled with biotin, immobilized, and then used as a bait sequence for affinity pull-down of miRNAs. After washes and release, cloning and sequencing identify the miRNAs. Binding affinity is quantitated by quantitative polymerase chain reaction (qPCR), comparing released and original input concentrations. As an initial demonstration, the TCF8/ZEB1 mRNA affinity pull-down yielded miR-200 family member miRs in the majority of clones, and binding affinity was approximately 100%; virtually all copies of miR-200c bound the immobilized mRNA transcript. For validation in cells, miR-200c strongly inhibited expression of a TCF8 luciferase reporter, native TCF8 mRNA, and protein levels, which contrasted with other recovered miRNAs with lower binding affinities. For Smad4 mRNA, miR-150 (and others) displayed a binding affinity of 39% (or less) yet did not inhibit a Smad4 reporter, native Smad4 mRNA, or protein levels. These results were not predicted by available software. This work demonstrates this miRNA binding affinity assay to be a novel yet facile experimental means of identification of miRNAs targeting a given mRNA. PMID- 23938774 TI - A liquid chromatography-tandem mass spectrometry assay for d-Ala-d-Lac: a key intermediate for vancomycin resistance in vancomycin-resistant enterococci. AB - Vancomycin exerts its antibacterial activity by binding to d-Ala-d-Ala in bacterial cell wall precursors. Vancomycin resistance in vancomycin-resistant enterococci (VRE) is due to an alternative cell wall biosynthesis pathway in which d-Ala-d-Ala is replaced, most commonly by d-Ala-d-Lac. In this study, we extend our recently developed Marfey's derivatization-based liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for l-Ala, d-Ala, and d-Ala-d-Ala to d Ala-d-Lac and apply it to the quantitation of these metabolites in VRE. The first step in this effort was the development of an effective washing method for removing medium components from VRE cells. Mar-d-Ala-d-Lac was well resolved chromatographically from Mar-d-Ala-d-Ala, a prerequisite for MS/MS quantitation of d-Ala-d-Ala and d-Ala-d-Lac. Mar-d-Ala-d-Lac gave similar detection parameters, sensitivity, and linearity as Mar-d-Ala-d-Ala. l-Ala, d-Ala, d-Ala-d Ala, and d-Ala-d-Lac levels in VRE were then determined in the presence of variable vancomycin levels. Exposure to vancomycin resulted in a dramatic reduction of d-Ala-d-Ala, with a response midpoint at approximately 0.06MUg/ml vancomycin and with a broad response profile up to 128MUg/ml vancomycin. In contrast, d-Ala-d-Lac was present in the absence of vancomycin, with its level constant up to 128MUg/ml vancomycin. This method will be useful for the discovery, characterization, and refinement of new agents targeting vancomycin resistance in VRE. PMID- 23938775 TI - A small-scale, inexpensive method for detecting formaldehyde or methanol in biochemical reactions containing interfering substances. AB - A simple, inexpensive microdistillation device is described for capturing methanol or formaldehyde as end products of biochemical reactions or in environmental samples. We demonstrate that the microdistillation protocol, coupled with the use of alcohol oxidase and the formaldehyde-sensitive reagent Purpald (4-amino-3-hydrazino-5-mercapto-1,2,4-triazole), serves as a quick and inexpensive alternative to chromatographic and mass spectrometer analyses for determining if formaldehyde or methanol is a product of reactions that contain substances that interfere with the Purpald reaction. These techniques were used to affirm formaldehyde as the end product of the dicamba monooxygenase-catalyzed O-demethylation of the herbicide dicamba (2-methoxy-3,6-dichlorobenzoic acid). PMID- 23938776 TI - Meningococcal X polysaccharide quantification by high-performance anion-exchange chromatography using synthetic N-acetylglucosamine-4-phosphate as standard. AB - A method for meningococcal X (MenX) polysaccharide quantification by high performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) is described. The polysaccharide is hydrolyzed by strong acidic treatment, and the peak of glucosamine-4-phosphate (4P-GlcN) is detected and measured after chromatography. In the selected conditions of hydrolysis, 4P-GlcN is the prevalent species formed, with GlcN detected for less than 5% in moles. As standard for the analysis, the monomeric unit of MenX polysaccharide, N acetylglucosamine-4-phosphate (4P-GlcNAc), was used. This method for MenX quantification is highly selective and sensitive, and it constitutes an important analytical tool for the development of a conjugate vaccine against MenX. PMID- 23938777 TI - Multi-tone parallel coherent matched detection for demultiplexing of superchannels. AB - This paper presents multi-tone parallel coherent matched detection that orthogonally detects superchannels without crosstalk between neighboring channels. The receiver consists of multiple sets of multi-tone coherent matched detector employed in parallel. In each detector, the received superchannels signal is homodyne mixed in multi frequency with locally generated multi-tone optical frequency comb; detected is a signal set that has the amplitude and phase exactly matched with the local comb. By launching orthogonal sets of local comb to the multiple parallel coherent matched detectors, the received superchannels are orthogonally downconverted to the baseband frequencies keeping the amplitude and phase information of all channels included. With an aid of n * n transform matrix, all channels are separately recovered from the downconverted signal sets. The system does not rely on any optical filters for channel demultiplexing and separation, with increased flexibility in wavelength arrangement. In addition, the parallel configuration equivalently enhance the bandwidth of the coherent matched detector keeping the speed in each tributary channel as high as possible. In this paper, it is experimentally demonstrated that even-odd interleaved 23 * 20-Gb/s QPSK superchannels are orthogonally demultiplexed and detected by two tone coherent matched detection. PMID- 23938778 TI - Plasmonic enhancement of second harmonic generation on metal coated nanoparticles. AB - Second Harmonic Generation (SHG) is a widely used tool to study surfaces. Here we investigate SHG from spherical nanoparticles consisting of a dielectric core (radius 100 nm) and a metallic shell of variable thickness. Plasmonic resonances occur that depend on the thickness of the nanoshells and boost the intensity of the Second Harmonic (SH) signal. The origin of the resonances is studied for the fundamental harmonic and the second harmonic frequencies. Mie resonances at the fundamental harmonic frequency dominate resonant effects of the SH-signal at low shell thickness. Resonances excited by a dipole emitting at SH frequency close to the surface explain the enhancement of the SHG-process at a larger shell thickness. All resonances are caused by surface plasmon polaritons, which run on the surface of the spherical particle and are in resonance with the circumference of the sphere. Because their wavelength critically depends on the properties of the metallic layer SHG resonances of core-shell nanoparticles can be easily tuned by varying the thickness of the shell. PMID- 23938779 TI - Polarization-resolved exact light backscattering by an ensemble of particles in air. AB - We present the first experimental observation of exact backscattering of light by an ensemble of particles in ambient air. Our experimental set-up operates in the far-field single scattering approximation, covers the exact backscattering direction with accuracy (theta = pi +/- epsilon with epsilon = 3.5 * 10(-3) rad) and efficiently collects the particles backscattering radiation, while minimizing any stray light. Moreover, by using scattering matrix formalism, the observation of the particles UV-backscattering signal allowed to measure the particles depolarization of water droplets and salt particles in air, for the first time, in the exact backscattering direction. We believe this result may be useful for comparison with the existing numerical models and for remote sensing field applications in radiative transfer and climatology. PMID- 23938780 TI - Improvement of diffraction efficiency of dielectric transmission gratings using anti-reflection coatings. AB - A novel method for increasing diffraction efficiency of transmission gratings is proposed. In this method, dielectric multilayers are inserted between a grating region and a substrate. These multilayers work as an anti-reflection coating for the transmission grating. It is presented that a grating with 1740 grooves/mm has the diffraction efficiency over 99% using this anti-reflection coating. PMID- 23938781 TI - Deflection and trapping of spatial solitons in linear photonic potentials. AB - We investigate the dynamics of spatial optical solitons launched in a medium with a finite perturbation of the refractive index. For longitudinally short perturbations of super-Gaussian transverse profile, as the input power varies we observe a transition from a wave-like behavior where solitons break up into multiple fringes to a particle-like behavior where solitons acquire a transverse velocity retaining their shape. For longitudinally long perturbations with an attractive potential solitons get trapped inside the well and propagate with transverse periodic oscillations, resulting in an efficient power-dependent angular steering or deflection. Using the Ehrenfest theorem we derive analytical expressions for soliton trajectory, and achieve excellent agreement between theory and numerical simulations for large powers, that is, narrow solitons. PMID- 23938782 TI - Enhanced sensitivity of photonic crystal slab transducers by oblique-angle layer deposition. AB - Photonic crystal slabs (PCS) are one of the major transducers for label-free, optical biosensing applications. In this paper we present oblique-angle layer deposition of the high index slab material as a method to improve the PCS sensitivity. In simulations and experiments we consider PCSs composed of a high index silicon monoxide layer on a nanostructured resist layer on a glass substrate. By mounting the substrate at an oblique angle with respect to the evaporation source, the high index material distribution on the nanostructured surface is modified due to shadowing effects. Finite-difference time-domain (FDTD) simulations were performed to predict bulk and surface sensitivities. In order to verify the simulation results we fabricated PCSs at various deposition angles using nanoimprint lithography to replicate a linear grating nanostructure into the resist layer and thermal evaporation for a 60-nm silicon monoxide deposition. The bulk sensitivities of these structures were measured using water glycerol dilutions. A sensitivity improvement of 281% was obtained for PCSs fabricated at 45 degrees deposition angle compared to normal incidence deposition. PMID- 23938783 TI - Enhancement of nonlinear Raman-Nath diffraction in two-dimensional optical superlattice. AB - We study second harmonic generation via nonlinear Raman-Nath diffraction in an optical superlattice that maintains a periodic modulation of the second-order nonlinear coefficient chi((2)) in transverse direction but undergoes random modulation in longitudinal direction. We show that the random chi((2)) modulation offers a continuous set of reciprocal lattice vectors to compensate for the phase mismatch of nonlinear Raman-Nath diffraction in the longitudinal direction, leading to more efficient harmonic generation for a wide range of wavelengths. We also characterize the intensity dependence of nonlinear Raman-Nath diffraction on the degree of randomness of the optical supperlattice. PMID- 23938784 TI - Integration, photostability and spontaneous emission rate enhancement of colloidal PbS nanocrystals for Si-based photonics at telecom wavelengths. AB - We experimentally investigate PbS nanocrystal (NC) photoluminescence (PL) coupled to all-integrated Si-based ring resonators and waveguides at telecom wavelengths. Dissolving the NCs into Novolak polymer significantly improves their stability in ambient atmosphere. Polymer-NC blends of various NC concentrations can be applied to and removed from the same device. For NC concentrations up to 4vol%, the spontaneous emission rate into ring-resonator modes is enhanced by a factor of ~13 with respect to that into a straight waveguide. The PL intensity shows a linear dependence on the excitation intensity up to 1.64kW/cm(2) and stable quality factors of ~2500. PMID- 23938785 TI - Multi-focus plasmonic lens design based on holography. AB - Multi-focus plasmonic lens with metallic nanoslits of variant widths have great potential applications in optical interconnection, integrated optics and nanophotonics. But the design method with simulated annealing algorithm or Yang Gu algorithm requires complex calculation and multi focuses are limited to be set on the same output plane. In this paper, we propose a design method based on holography. The desired light field distribution and the incident plane wave can be treated as object wave and reference wave, respectively. So the calculation is relative simple and multi focuses can be located in different output plane. Numerical simulation of multi-focus lens design is performed through finite difference time-domain (FDTD) method and the result confirms the feasibility of our method. PMID- 23938786 TI - A new approach to measure the volume scattering function. AB - We present a novel optical approach to measure the volume scattering function (VSF) by image detection. The instrument design, based upon a combination of two reflectors, uses a unique measurement principle and allows the rapid simultaneous determination of scattering at a wide range of angles. The advantages of the newly developed scattering meter are that: 1) it can determine the scattering function from 8 degrees to 172 degrees at 1 degrees intervals without changing the sensitivity of the detector, without moving any optical parts, and can do so within a few seconds, 2) the unique optical design facilitates determination of the spectral VSF over the full visible spectrum, i.e. it can obtain the VSF at a specific wavelength with an optional wavelength-resolution. Measurements under controlled conditions for the assessment of the instrument agreed well with theoretically predicted scattering functions. Measurements with cultured phytoplankton of different species revealed a significant variety of the VSF together with spectral variation. The observed results will stimulate and improve radiative transfer and/or two-flow models of light in the ocean, which is an important role for ocean color remote sensing algorithm development, particularly for coastal regions. PMID- 23938787 TI - Accurate and agile digital control of optical phase, amplitude and frequency for coherent atomic manipulation of atomic systems. AB - We demonstrate a system for fast and agile digital control of laser phase, amplitude and frequency for applications in coherent atomic systems. The full versatility of a direct digital synthesis radiofrequency source is faithfully transferred to laser radiation via acousto-optic modulation. Optical beatnotes are used to measure phase steps up to 2pi, which are accurately implemented with a resolution of <= 10 mrad. By linearizing the optical modulation process, amplitude-shaped pulses of durations ranging from 500 ns to 500 ms, in excellent agreement with the programmed functional form, are demonstrated. Pulse durations are limited only by the 30 ns rise time of the modulation process, and a measured extinction ratio of > 5 * 10(11) is achieved. The system presented here was developed specifically for controlling the quantum state of trapped ions with sequences of multiple laser pulses, including composite and bichromatic pulses. The demonstrated techniques are widely applicable to other atomic systems ranging across quantum information processing, frequency metrology, atom interferometry, and single-photon generation. PMID- 23938788 TI - 20 GHz spacing multi-wavelength generation of Brillouin-Raman fiber laser in a hybrid linear cavity. AB - We demonstrate a tunable multi-wavelength Brillouin-Raman fiber laser with 20 GHz wavelength spacing. The setup is arranged in a linear cavity by employing 7.2 and 11 km dispersion compensating fibers (DCF) in addition to a 30 cm Bismuth-oxide erbium doped fiber. In this experiment, for the purpose of increasing the Stokes lines, it is necessary to optimize Raman pump power and Brillouin pump power together with its corresponding wavelengths. At the specific Brillouin pump wavelength, it is found that the longer length of 11 km DCF with optimized parameters results in larger number of Stokes combs and optical signal to noise ratios (OSNRs). In this case, a total of 195 Brillouin Stokes combs are produced across 28 nm bandwidth at Brillouin pump power of -2 dBm and Raman pump power of 1000 mW. In addition, all Brillouin Stokes signals exhibit an average OSNR of 26 dB. PMID- 23938789 TI - Fabrication of metal-oxide nano-hairs for effective index optical elements. AB - We present a method for fabricating high aspect ratio metal-oxide, sub-wavelength grating structures. These "nano-hair" structures are composed of alumina cylindrical pillars, partially embedded in a supporting fused silica substrate. The fabricated nano-hair structures demonstrate phase control of the transmitted beam while maintaining a peak transmitted power greater than 93% around a central wavelength of lambda(o) = 1.55 um. Based on this principle, discrete and continuous phase functions can be encoded by controlling the lithographic process. PMID- 23938790 TI - Real-time capturing and 3D visualization method based on integral imaging. AB - We propose a real-time capturing and 3D visualization method based on integral imaging. We applied real-time conversion algorithm to conventional integral imaging pickup system. Gap control method with depth plane adjustment is also applied to improve image quality. Implemented system provides real-time 3D images with ultra high definition resolution in 20 frames per second, and the observer can change depth planes freely. Simulations and experimental results show the validity of proposed system. PMID- 23938791 TI - Stable radio-frequency transfer over optical fiber by phase-conjugate frequency mixing. AB - We demonstrate long-distance (>=100-km) synchronization of the phase of a radio frequency reference over an optical-fiber network without needing to actively stabilize the optical path length. Frequency mixing is used to achieve passive phase-conjugate cancellation of fiber-length fluctuations, ensuring that the phase difference between the reference and synchronized oscillators is independent of the link length. The fractional radio-frequency-transfer stability through a 100-km "real-world" urban optical-fiber network is 6 * 10(-17) with an averaging time of 10(4) s. Our compensation technique is robust, providing long term stability superior to that of a hydrogen maser. By combining our technique with the short-term stability provided by a remote, high-quality quartz oscillator, this system is potentially applicable to transcontinental optical fiber time and frequency dissemination where the optical round-trip propagation time is significant. PMID- 23938792 TI - Physical characteristics of localized surface plasmons resulting from nano-scale structured multi-layer thin films deposited on D-shaped optical fiber. AB - Novel surface plasmonic optical fiber sensors have been fabricated using multiple coatings deposited on a lapped section of a single mode fiber. UV laser irradiation processing with a phase mask produces a nano-scaled surface relief grating structure resembling nano-wires. The resulting individual corrugations produced by material compaction are approximately 20 MUm long with an average width at half maximum of 100 nm and generate localized surface plasmons. Experimental data are presented that show changes in the spectral characteristics after UV processing, coupled with an overall increase in the sensitivity of the devices to surrounding refractive index. Evidence is presented that there is an optimum UV dosage (48 joules) over which no significant additional optical change is observed. The devices are characterized with regards to change in refractive index, where significantly high spectral sensitivities in the aqueous index regime are found, ranging up to 4000 nm/RIU for wavelength and 800 dB/RIU for intensity. PMID- 23938793 TI - Applicability analysis of wavelet-transform profilometry. AB - The applicability of the wavelet-transform profilometry is examined in detail. The wavelet-ridge-based phase demodulation is an integral operation of the fringe signal in the spatial domain. The accuracy of the phase demodulation is related to the local linearity of the phase modulated by the object surface. We present a more robust applicability condition which is based on the evaluation of the local linearity. Since high carrier frequency leads to the phase demodulation integral in a narrow interval and the narrow interval results in the high local linearity of modulated phase, we propose to increase the carrier fringe frequency to improve the applicability of the wavelet-transform profilometry and the measurement accuracy. The numerical simulations and the experiment are presented. PMID- 23938794 TI - Generation of finite power Airy beams via initial field modulation. AB - We investigate the finite power Airy beams generated by finite extent input beams such as a Gaussian beam, a uniform beam of finite extent, and an inverse Gaussian beam. Each has different propagation behavior: A finite Airy beam generated by a uniform input beam keeps its Airy profile much longer than the conventional finite Airy beam. Also, an inverse Gaussian beam generates a finite Airy beam with a good bent focusing in free space. In this paper, the analysis and experimental results of finite Airy beams are presented. PMID- 23938795 TI - Young's experiment with a double slit of sub-wavelength dimensions. AB - We report that the interference pattern of Young's double-slit experiment changes as a function of polarization in the sub-wavelength diffraction regime. Experiments carried out with terahertz time-domain spectroscopy reveal that diffracted waves from sub-wavelength-scale slits exhibit either positive or negative phase shift with respect to Gouy phase depending on the polarization. Theoretical explanation based on the induction of electric current and magnetic dipole in the vicinity of the slits shows an excellent agreement with the experimental results. PMID- 23938796 TI - A 400G optical wireless integration delivery system. AB - We experimentally demonstrate a record 400G optical wireless integration system simultaneously delivering 2 * 112 Gb/s two-channel polarization-division multiplexing 16-ary quadrature amplitude modulation (PDM-16QAM) signal at 37.5 GHz wireless carrier and 2 * 108 Gb/s two-channel PDM quadrature phase shift keying (PDM-QPSK) signal at 100 GHz wireless carrier, adopting two millimeter wave (mm-wave) frequency bands, two orthogonal antenna polarizations, multiple input multiple-output (MIMO), photonic mm-wave generation and advanced digital signal processing (DSP). In the case of no fiber transmission, the bit error ratios (BERs) for both the 112 Gb/s PDM-16QAM signal after 1.5 m wireless delivery at 37.5 GHz and the 108 Gb/s PDM-QPSK signal after 0.7 m wireless delivery at 100 GHz are below the pre-forward-error-correction (pre-FEC) threshold of 3.8 * 10(-3). To our knowledge, this is the first demonstration of a 400G optical wireless integration system in mm-wave frequency bands and also a capacity record of wireless delivery. PMID- 23938797 TI - Adaptive Wiener filter super-resolution of color filter array images. AB - Digital color cameras using a single detector array with a Bayer color filter array (CFA) require interpolation or demosaicing to estimate missing color information and provide full-color images. However, demosaicing does not specifically address fundamental undersampling and aliasing inherent in typical camera designs. Fast non-uniform interpolation based super-resolution (SR) is an attractive approach to reduce or eliminate aliasing and its relatively low computational load is amenable to real-time applications. The adaptive Wiener filter (AWF) SR algorithm was initially developed for grayscale imaging and has not previously been applied to color SR demosaicing. Here, we develop a novel fast SR method for CFA cameras that is based on the AWF SR algorithm and uses global channel-to-channel statistical models. We apply this new method as a stand alone algorithm and also as an initialization image for a variational SR algorithm. This paper presents the theoretical development of the color AWF SR approach and applies it in performance comparisons to other SR techniques for both simulated and real data. PMID- 23938798 TI - 11 * 5 * 9.3Gb/s WDM-CAP-PON based on optical single-side band multi-level multi band carrier-less amplitude and phase modulation with direct detection. AB - We propose and demonstrate a novel WDM-CAP-PON based on optical single-side band (OSSB) multi-level multi-band carrier-less amplitude and phase modulation (MM CAP). To enable high-speed transmission with simplified optical network unit (ONU)-side digital signal processing, 4-level 5 sub-bands CAP-16 is used here, which is generated by the digital to analogue converter (DAC). Optical single side band (OSSB) technology is applied to extend the transmission distance against the spectrum fading effect. As a proof of concept, the experiment successfully demonstrates 11 WDM channels, 55 sub-bands, for 55 users with 9.3 Gb/s per user (after removing 7% overhead for forward error correction (FEC)) in the downstream over 40-km SMF. PMID- 23938799 TI - A hybrid approach to estimate chromophoric dissolved organic matter in turbid estuaries from satellite measurements: a case study for Tampa Bay. AB - Remote sensing of chromophoric dissolved organic matter (CDOM) from satellite measurements for estuaries has been problematic due to optical complexity of estuarine waters and uncertainties in satellite-derived remote sensing reflectance (Rrs, sr(-1)). Here we demonstrate a hybrid approach to combine empirical and semi-analytical algorithms to derive CDOM absorption coefficient at 443 nm (a(g)(443), m(-1)) in a turbid estuary (Tampa Bay) from MODIS Aqua (MODISA) and SeaWiFS measurements. The approach first used a validated empirical algorithm and a modified quasi-analytical algorithm (QAA) to derive chlorophyll-a concentration (Chla, mg m(-3)) and particulate backscattering coefficient at 443 nm (b(bp)(443), m(-1)), respectively, from which phytoplankton pigment and non algal particulate absorption coefficient at 443 nm (a(ph)(443) and a(d)(443), m( 1)) were derived with pre-determined bio-optical relationships. Then, the modified QAA was used to estimate the total absorption coefficient at 443 nm (a(t)(443), m(-1)). Finally, a(g)(443) was estimated as (a(t)(443) - a(ph)(443) - a(d)(443) - a(w)(443)) where a(w)(443) is the absorption coefficient of pure water (a constant). Using data collected from 71 field stations and 33 near concurrent satellite-field matchup data pairs covering a large dynamic range (0.3 - 8 m(-1)), the approach showed ~23% RMS uncertainties in retrieving a(g)(443) when in situ Rrs data (N = 71) were used. The same approach applied to satellite Rrs yielded much higher uncertainties of a(g)(443) (~85%) due to large errors in the satellite-retrieved Rrs(443). When the Rrs(443) was derived from the satellite-retrieved Rrs(550) and then used in the hybrid approach, uncertainties in the retrieved a(g)(443) reduced to ~30% (N = 33). Application of the approach to MODISA and SeaWiFS data led to a 15-year time series of monthly mean a(g)(443) distributions in Tampa Bay between 1998 and 2012. This time series showed significant seasonal and annual variations regulated mainly by river discharge. Testing of the approach over another turbid estuary (Chesapeake Bay, the largest estuary in the U.S.) demonstrated the potential (~25% uncertainties for a limited a(g)(443) range) of using this approach to establish long-term environmental data records (EDRs) of CDOM distributions in other estuaries with similar optical complexity. PMID- 23938800 TI - Common-path laser planar encoder. AB - This paper presents a common-path laser planar encoder (CLPE) for displacement measurements in the X- and Y- axes. The CLPE can effectively reduce the environmental disturbance to its lowest level. The experimental results of the CLPE match well with those of HP5529A for both short and long ranges. The CLPE can measure 2D displacement with high resolutions of 0.07 +/- 0.021 nm and 0.07 +/- 0.023 nm in the X- and Y- axes and also presents high system stabilities of 0.59 +/- 0.43 nm/h and -0.63 +/- 0.47 nm/h respectively in the X- and Y- axes. The CLPE has promising potential for nanometer resolution and large-range applications. PMID- 23938801 TI - Infrared differential interference contrast microscopy for 3D interconnect overlay metrology. AB - One of the main challenges for 3D interconnect metrology of bonded wafers is measuring through opaque silicon wafers using conventional optical microscopy. We demonstrate here the use infrared microscopy, enhanced by implementing the differential interference contrast (DIC) technique, to measure the wafer bonding overlay. A pair of two dimensional symmetric overlay marks were processed at both the front and back sides of thinned wafers to evaluate the bonding overlay. A self-developed analysis algorithm and theoretical fitting model was used to map the overlay error between the bonded wafers and the interconnect structures. The measurement accuracy was found to be better than 1.0 micron. PMID- 23938802 TI - Zero-frequency refractivity of water vapor, comparison of Debye and van-Vleck Weisskopf theory. AB - We show that the zero-frequency, refractivity of water vapor calculated by the van-Vleck Weisskopf theory via a summation over all the water lines from 22.2 GHz to 30 THz can explain all of the previous measurements from 0.5 MHz to microwave, mm-waves and THz frequencies. This result removes a long standing discrepancy in comparisons of measurements and theory, and is in excellent agreement with experiments. PMID- 23938803 TI - Characterization of azimuthal and longitudinal modes in rolled-up InGaAs/GaAs microtubes at telecom wavelengths. AB - We report on theoretical and experimental investigation of azimuthal and longitudinal modes in rolled-up microtubes at telecom wavelengths. These microtubes are fabricated by selectively releasing a coherently strained InGaAs/GaAs bilayer. We apply planar waveguide method and a quasi-potential model to analyze the azimuthal and longitudinal modes in the microtubes near 1550 nm. Then we demonstrate these modes in transmission spectrum by evanescent light coupling. The experimental observations agree well with the calculated results. Surface-scattering-induced mode splitting is also observed in both transmission and reflection spectra at ~1600 nm. The mode splitting is in essence the non degeneracy of clockwise and counter-clockwise whispering-gallery modes of the microtubes. This study is significant for understanding the physics of modes in microtubes and other microcavities with three-dimensional optical confinement, as well as for potential applications such as microtube-based photonic integrated devices and sensing purposes. PMID- 23938804 TI - Comparative study on the acousto-optic Q-switched pulse performances of 1520 and 1560 nm lasers in Er:Yb:RAl3(BO3)4 (R = Y and Lu) crystals. AB - 1520 and 1560 nm acousto-optic Q-switched pulse lasers with high peak power and narrow width were respectively realized in Er:Yb:RAl(3)(BO(3))(4) (R = Y and Lu) crystals end-pumped by a 970 nm diode laser. For Er:Yb:LuAl(3)(BO(3))(4) crystal, 1520 nm laser with 350 MUJ energy, 32 ns width and 10.9 kW peak power, and 1560 nm laser with 520 MUJ energy, 67 ns width and 7.8 kW peak power were respectively obtained at pulse repetition frequency of 1 kHz. For Er:Yb:YAl(3)(BO(3))(4) crystal, 1520 nm laser with 210 MUJ energy, 45 ns width and 4.7 kW peak power, and 1560 nm laser with 380 MUJ energy, 102 ns width and 3.7 kW peak power were respectively obtained at pulse repetition frequency of 1 kHz. Pulse performances of 1520 and 1560 nm lasers were compared and the narrower pulse width of 1520 nm laser was ascribed to the higher stimulated emission cross-section. PMID- 23938805 TI - Inner cladding microstructuration based on symmetry reduction for improvement of singlemode robustness in VLMA fiber. AB - Very large mode area, active optical fibers with a low high order mode content in the actively doped core region were designed by removing the inner cladding symmetry. The relevance of the numerical approach is demonstrated here by the investigation of a standard air-silica Large Pitch Fiber, used as a reference. A detailed study of all-solid structures is also performed. Finally, we propose new kinds of geometry for 50 MUm core, all-solid microstructured fibers enabling a robust singlemode laser emission from 400 nm to 2200 nm. PMID- 23938806 TI - Bidirectional fiber soliton laser mode-locked by single-wall carbon nanotubes. AB - We report on the experimental observation of a bidirectional fiber soliton laser passively mode-locked by single-wall carbon nanotubes. Two stable pulse trains in opposite directions are delivered simultaneously from the ring cavity. The counterpropagating pulses have different central wavelengths, pulse durations, and repetition rates. By adjusting the fiber birefringence and cavity length, the central wavelengths of two solitons can be the same or different. Experimental observations and analyses demonstrate that the different operating wavelengths result in the unequal repetition rates of two pulses. These unique features may be attributed to the cavity asymmetry and fiber birefringence. PMID- 23938807 TI - Temperature dependent red luminescence from a distorted Mn4+ site in CaAl4O7:Mn4+. AB - Thermal luminescence quenching behavior of a phosphor is essential for application in phosphor converted white light emitting diodes (pc-WLEDs) because the phosphor layer can be heated up to 473K in a working high power WLEDs. Here, we have confirmed indeed a red luminescence of Mn(4+) substituting for calcium sites rather than tetrahedral aluminum sites in CaAl(4)O(7):Mn which can be synthesized in pure phase even with boron acid as flux, and examined the low and high temperature luminescent properties in the range of 10 to 500K. We have revealed as well as thermal quenching mechanism that distorted octahedral Mn(4+) sites suffer severe thermal quenching. This work, thus, hints a strategy to find a new Mn(4+) phosphor with better resistance to thermal impact in the future. PMID- 23938808 TI - Halo-tellurite glass fiber with low OH content for 2-5um mid-infrared nonlinear applications. AB - We report the fabrication of new dehydrated halo-tellurite glass fibers with low OH content (1ppm in weight) and low OH-induced attenuation of 10dB/m in 3-4 um region. It shows halo-tellurite glass fibers a promising candidate for nonlinear applications in 2-5um region. PMID- 23938809 TI - Moving force of metal particle migration induced by laser irradiation in borosilicate glass. AB - We optically manipulated a metal particle in borosilicate glass. The glass in the neighborhood of the laser-heated metal particle softened; hence, the metal particle was able to migrate in the glass. In this letter, the driving force of the metal particle toward the light source in the glass provided by laser illumination was investigated. The variation in the surface tension of the glass at the interface between the glass and the metal particle induced by the temperature gradient was calculated via a numerical temperature calculation. It was found that the temperature at the laser-illuminated surface of a stainless steel particle with a radius of 40 MUm was ~320 K higher than that on the nonilluminated side. The force applied to the metal particle from the surrounding glass was calculated to be ~100 MUN, which was approximately equal to the viscous resistance force. In addition, the experimental and numerically calculated speeds of the moving particle, which was measured while varying the laser power, are discussed. PMID- 23938810 TI - Q-switched pulse laser generation from double-cladding Nd:YAG ceramics waveguides. AB - This work reports on the Q-switched pulsed laser generation from double-cladding Nd:YAG ceramic waveguides. Double-cladding waveguides with different combination of diameters were inscribed into a sample of Nd:YAG ceramic. With an additional semiconductor saturable absorber, stable pulsed laser emission at the wavelength of 1064 nm was achieved with pulses of 21 ns temporal duration and ~14 MUJ pulse energy at a repetition rate of 3.65 MHz. PMID- 23938811 TI - Graphene and nanotube mode-locked fiber laser emitting dissipative and conventional solitons. AB - We propose a bidirectional erbium-doped fiber laser mode-locked with a mixture of graphene and single-walled carbon nanotubes for the first time to our best knowledge. The fiber laser can deliver dissipative soliton (DS) and conventional soliton (CS), circulating in opposite directions. The net-cavity dispersion is normal in the clockwise direction and anomalous in counter clockwise direction, respectively, and then DS and CS are generated with the suitable adjustment of attenuators. The output DS and CS approximately have the same central wavelength, but exhibit different optical spectra, pulse durations, and repetition rates. The all-fiber switchable laser can provide two different pulse sources, which is convenient for practical applications. PMID- 23938812 TI - Enhancement of thermal damage threshold of carbon-nanotube-based saturable absorber by evanescent-field interaction on fiber end. AB - We present a scheme of fiber-connector-type carbon-nanotube-based saturable absorber (CNT-SA) with enhanced thermal damage threshold, in which the CNTs are deposited on the fiber connector end in a ring pattern for evanescent-field interaction instead of direct interaction. The thermal damage threshold of such CNT-SA is found to be increased by around 130% compared with an evenly deposited one. An all-fiber Fabry-Perot (FP) linear cavity passively mode-locked laser is further constructed incorporating the prepared CNT-SA, where the optical power is confined in a relatively short laser cavity to investigate the thermal damage threshold and the performance of the CNT-SA. Stable output pulses with a fundamental repetition rate of 211.84 MHz and a pulse width of 680 fs are generated from the fiber laser. The mode-locking operation can be maintained an intra-cavity average power of 30 mW, indicating that the CNT-SA can withstand a relatively high optical power without performance degradation. PMID- 23938813 TI - Range accuracy of photon heterodyne detection with laser pulse based on Geiger mode APD. AB - In this paper, we propose a combined system of heterodyne detection with laser pulse and photon counting based on Geiger-mode avalanche photodiode (GM-APD) that is designed to achieve the range of remote non-cooperative target. Based on the heterodyne principle and assuming that the creation of primary electrons in GM APD is Poisson-distributed, the range accuracy model is established. The factors that influence the range accuracy, namely pulse width, echo intensity, local oscillator (LO) intensity, noise, echo position, and beat frequency, are discussed. The results show that these six factors have significant influence on the range accuracy when the echo intensity is extremely weak. In case that the primary electrons of the echo signal are beyond 4, the pulse width and echo intensity are the main influence factors. It is also shown that the stronger echo intensity, narrower pulse width, low noise, large echo position, and small beat frequency produce higher range accuracy in a pulsed photon heterodyne detection system based on GM-APD. PMID- 23938814 TI - Simultaneous mode-locking at 1565 nm and 1944 nm in fiber laser based on common graphene saturable absorber. AB - We present for the first time to the best of our knowledge an all-fiber thulium (Tm) and erbium (Er) doped fiber laser simultaneously mode-locked by a common graphene saturable absorber. The laser consists of two ring resonators combined with a common saturable absorber (SA). The generated optical solitons have a full width at half maximum (FWHM) of 3.9 nm and 4.2 nm for Tm- and Er-doped laser, respectively. The used graphene layers were grown on copper foils by chemical vapor deposition (CVD) and transferred onto the fiber connector end. Broadband and flat absorption spectrum of used SA supports mode-locked operation at 1565 nm and 1944 nm. The repetition frequency of the resonator with Er-doped fiber was 20.19 MHz while the Tm-doped resonator was around 1 m longer and resulted with repetition rate of 18.43 MHz. The reported experiment unambiguously confirms one of the biggest advantage of the carbon nanomaterial (in this case graphene) SAs over semiconductor saturable absorption mirrors (SESAM), which is broadband operation range, allowing to mode-lock two lasers spectrally separated by almost 400 nm. PMID- 23938815 TI - Optical frequency comb interference profilometry using compressive sensing. AB - We describe a new optical system using an ultra-stable mode-locked frequency comb femtosecond laser and compressive sensing to measure an object's surface profile. The ultra-stable frequency comb laser was used to precisely measure an object with a large depth, over a wide dynamic range. The compressive sensing technique was able to obtain the spatial information of the object with two single-pixel fast photo-receivers, with no mechanical scanning and fewer measurements than the number of sampling points. An optical experiment was performed to verify the advantages of the proposed method. PMID- 23938816 TI - Second-harmonic generation in lithium niobate nanowires for local fluorescence excitation. AB - We study the nonlinear optical properties of lithium niobate (LiNbO(3)) nanowires (NWs) fabricated by a top-down ion beam enhanced etching method. First, we demonstrate generation and propagation of the second-harmonic (SH) light in LiNbO(3) NWs of typical rectangular cross-sections of 400 x 600 nm(2) and length from 10 to 50 MUm. Then, we show local fluorescent excitation of 4',6-diamidino-2 phenylindole (DAPI) dye with the propagated SH signal in standard concentrations as for biological applications. By measuring the detected average power of the propagated fundamental harmonic (FH) and the SH signal at the output of the NWs, we directly prove the dominating role of the SH signal over possible two-photon excitation processes with the FH in the DAPI dye. We estimate that 63 +/- 6 pW of the propagated SH average power is required for detectable dye excitation. Finally, we model the waveguiding of the SH light to determine the smallest NW cross-section (around 40x60 nm(2)) which is potentially able to excite fluorescence with a FH intensity below the cell damage threshold. PMID- 23938817 TI - InGaAs nano-photodetectors based on photonic crystal waveguide including ultracompact buried heterostructure. AB - Ultrasmall InGaAs photodetectors based on a photonic crystal waveguide with a buried heterostructure (BH) were demonstrated for the first time. A sufficiently high DC responsivity of ~1 A/W was achieved for the 3.4-MUm-long detector. The dynamic response revealed a 3-dB bandwidth of 6 GHz and a 10-Gb/s eye pattern. These results were thanks to the strong confinement of both photons and carriers in a small BH and will pave the way for unprecedented nano-photodetectors with a high quantum efficiency and small capacitance. Our device potentially has an ultrasmall junction capacitance of much less than 1 fF and may enable us to eliminate electrical amplifiers for future optical receivers and subsequent ultralow-power optical links on a chip. PMID- 23938818 TI - Silicon photonic slot waveguide Bragg gratings and resonators. AB - We present the design, fabrication, and characterization of integrated Bragg gratings in silicon-on-insulator slot waveguides. The Bragg gratings are formed with sidewall corrugations, either on the inside or on the outside of the waveguide. We demonstrate resonators implemented using phase-shifted Bragg gratings in slot waveguides, showing quality factors up to 3 * 10(4). Due to the strong optical confinement in the slot, these devices are promising for optical sensing applications. The devices were fabricated using a CMOS-compatible process, facilitating high-volume and low-cost production. PMID- 23938819 TI - Mode locking with enhanced nonlinearity--a detailed study. AB - We explore mode locked operation of a Ti:Sapphire laser with enhanced Kerr nonlinearity, where the threshold for pulsed operation can be continuously tuned down to the threshold for continuous-wave (CW) operation, and even below it. At the point of equality, even though a CW solution does not exist, pulsed oscillation can be realized directly from zero CW oscillation. We experimentally investigate the evolution of the mode locking mechanism towards this point and beyond it, and provide a qualitative theoretical model to explain the results. PMID- 23938820 TI - Squeezed quadrature fluctuations in a gravitational wave detector using squeezed light. AB - Squeezed states of light are an important tool for optical measurements below the shot noise limit and for optical realizations of quantum information systems. Recently, squeezed vacuum states were deployed to enhance the shot noise limited performance of gravitational wave detectors. In most practical implementations of squeezing enhancement, relative fluctuations between the squeezed quadrature angle and the measured quadrature (sometimes called squeezing angle jitter or phase noise) are one limit to the noise reduction that can be achieved. We present calculations of several effects that lead to quadrature fluctuations, and use these estimates to account for the observed quadrature fluctuations in a LIGO gravitational wave detector. We discuss the implications of this work for quantum enhanced advanced detectors and even more sensitive third generation detectors. PMID- 23938821 TI - Fitting freeform shapes with orthogonal bases. AB - Orthogonality is exploited for fitting analytically-specified freeform shapes in terms of orthogonal polynomials. The end result is expressed in terms of FFTs coupled to a simple explicit form of Gaussian quadrature. Its efficiency opens the possibilities for proceeding to arbitrary numbers of polynomial terms. This is shown to create promising options for quantifying and filtering the mid spatial frequency structure within circular domains from measurements of as-built parts. PMID- 23938822 TI - A broadband and omnidirectional electromagnetic wave concentrator with gradient woodpile structure. AB - We present the first realized three-dimensional (3D) practical implementation of the so called "optical black hole" in microwave frequencies, an electromagnetic (EM) concentrator. The 3D EM wave concentrator was designed with non-resonant gradient index (GRIN) 3D woodpile photonic crystals (PCs) structure in metamaterial regime, and fabricated by Stereolithography (SL) process. Omnidirectional EM wave capture and absorbing ability of the device in a broad bandwidth (12GHz-15GHz) were validated by full-wave simulation and experiments. Such devices may have applications in microwave energy harvesting and radiation detector. PMID- 23938823 TI - Trapping of light in solitonic cavities and its role in the supercontinuum generation. AB - We demonstrate that the fission of higher-order N-solitons with a subsequent ejection of fundamental quasi-solitons creates cavities formed by a pair of solitary waves with dispersive light trapped between them. As a result of multiple reflections of the trapped light from the bounding solitons which act as mirrors, they bend their trajectories and collide. In the spectral domain, the two solitons receive blue and red wavelength shifts, and the spectrum of the trapped light alters as well. This phenomenon strongly affects spectral characteristics of the generated supercontinuum. Consideration of the system's parameters which affect the creation of the cavity reveals possibilities of predicting and controlling soliton-soliton collisions induced by multiple reflections of the trapped light. PMID- 23938824 TI - VCSEL-powered and polarization-maintaining fiber-optic grating vector rotation sensor. AB - A compact fiber-optic vector rotation sensor in which a short section of polarization-maintaining (PM) fiber stub containing a straight fiber Bragg grating (FBG) is spliced to another single mode fiber without any lateral offset is proposed and experimentally demonstrated. Due to the intrinsic birefringence of the PM fiber, two well-defined resonances (i.e. orthogonally polarized FBG core modes) with wavelength separation of 0.5 nm have been achieved in reflection, and they exhibit a high sensitivity to fiber rotation. Both the orientation and the angle of rotation can be determined unambiguously via simple power detection of the relative amplitudes of the orthogonal core reflections. Meanwhile, instead of using a broadband source (BBS), the sensor is powered by a commercial vertical cavity surface emitting laser (VCSEL) with the laser wavelength matched to the PM-FBG core modes, which enables the sensor to work at much higher power levels (~15 dB better than BBS). This improves the signal-to noise ratio considerably (~50 dB), and makes a demodulation filter unnecessary. Vector rotation measurement with a sensitivity of 0.09 dB/deg has been achieved via cost-effective single detector real time power measurement, and the unwanted power fluctuations and temperature perturbations can be effectively referenced out. PMID- 23938825 TI - Layer-by-layer self-assembly of plexcitonic nanoparticles. AB - Colloidal suspensions of multilayer nanoparticles composed of a silver core, a polyelectrolyte spacer layer (inner shell), and a J-aggregate cyanine dye outer shell have been prepared for the first time. Absorption properties of the colloid were measured in the visible region. This multilayer architecture served as a framework for examining the coupling of the localized surface plasmon resonance exhibited by the silver core with the molecular exciton exhibited by the J aggregate outer shell. The polyelectrolyte spacer layer promotes the formation of an excitonic J-aggregate while serving as a means of controlling the plasmon exciton (i.e. plexciton) coupling strength through changing the distance between the core and the shell. An analytical expression based on Mie Theory and the Transfer Matrix Method was obtained for describing the optical response of these multilayered nanostructures. Computational and experimental results indicate that the absorption wavelength of the J-aggregate form of the dye is dependent on both the distance of the dye layer from the silver core and the degree of dye aggregation. PMID- 23938826 TI - Engineered surface waves in hyperbolic metamaterials. AB - We analyzed surface-wave propagation that takes place at the boundary between a semi-infinite dielectric and a multilayered metamaterial, the latter with indefinite permittivity and cut normally to the layers. Known hyperbolization of the dispersion curve is discussed within distinct spectral regimes, including the role of the surrounding material. Hybridization of surface waves enable tighter confinement near the interface in comparison with pure-TM surface-plasmon polaritons. We demonstrate that the effective-medium approach deviates severely in practical implementations. By using the finite-element method, we predict the existence of long-range oblique surface waves. PMID- 23938827 TI - Gerchberg-Saxton algorithm applied to a translational-variant optical setup. AB - The standard Gerchberg-Saxton (GS) algorithm is normally used to find the phase (measured on two different parallel planes) of a propagating optical field (usually far-field propagation), given that the irradiance information on those planes is known. This is mostly used to calculate the modulation function of a phase mask so that when illuminated by a plane wave, it produces a known far field irradiance distribution, or the equivalent, to calculate the phase mask to be used in a Fourier optical system so the desired pattern is obtained on the image plane. There are some extensions of the GS algorithm that can be used when the transformations that describe the optical setup are non-unitary, for example the Yang-Gu algorithm, but these are usually demonstrated using nonunitary translational-invariant optical systems. In this work a practical approach to use the GS algorithm is presented, where raytracing together with the Huygens-Fresnel principle are used to obtain the transformations that describe the optical system, so the calculation can be made when the field is propagated through a translational-variant optical system (TVOS) of arbitrary complexity. Some numerical results are shown for a system where a microscope objective composed by 5 lenses is used. PMID- 23938828 TI - Simultaneous compensation for aberration and axial elongation in three dimensional laser nanofabrication by a high numerical-aperture objective. AB - One of the challenges in laser direct writing with a high numerical-aperture objective is the severe axial focal elongation and the pronounced effect of the refractive-index mismatch aberration. We present the simultaneous compensation for the refractive-index mismatch aberration and the focal elongation in three dimensional laser nanofabrication by a high numerical-aperture objective. By the use of circularly polarized beam illumination and a spatial light modulator, a complex and dynamic slit pupil aperture can be produced to engineer the focal spot. Such a beam shaping method can result in circularly symmetric fabrication along the lateral directions as well as the dynamic compensation for the refractive-index mismatch aberration even when the laser beam is focused into the material of a refractive index up to 2.35. PMID- 23938829 TI - Hybridization of optical plasmonics with terahertz metamaterials to create multi spectral filters. AB - Multi-spectral imaging systems typically require the cumbersome integration of disparate filtering materials in order to work simultaneously in multiple spectral regions. We show for the first time how a single nano-patterned metal film can be used to filter multi-spectral content from the visible, near infrared and terahertz bands by hybridizing plasmonics and metamaterials. Plasmonic structures are well-suited to the visible band owing to the resonant dielectric properties of metals, whereas metamaterials are preferable at terahertz frequencies where metal conductivity is high. We present the simulated and experimental characteristics of our new hybrid synthetic multi-spectral material filters and demonstrate the independence of the metamaterial and plasmonic responses with respect to each other. PMID- 23938830 TI - Decoding the structure of granular and porous materials from speckled phase contrast X-ray images. AB - Imaging techniques for studying the structure of opaque, granular and porous materials are limited by temporal resolution and radiation dose. We present a technique for characterising the structure of such materials by decoding three dimensional structural information from single, propagation based phase contrast X-ray images. We demonstrate the technique by measuring the distribution of diameters of glass microspheres in packed samples. We also present synthetic data, which shows that our inverse method is stable and that accuracy is improved by phase contrast X-ray imaging. Compared to computed tomography, our technique has superior temporal resolution and lower radiation dose. PMID- 23938831 TI - Design of non-polarizing cut-off filters based on dielectric-metal-dielectric stacks. AB - Cut-off filters are usually operating at oblique incidence and exhibit polarization dependence properties. We propose a simple approach to design cut off filters with low linear polarization sensitivity (LPS) based on dielectric metal-dielectric (DMD) stacks. The designing method is derived from the theory of optical film characteristic matrix. The admittance loci of the film are adjusted to achieve similar spectral properties of s- and p-polarized light at oblique incidence. Different film structures are designed non-polarizing at different angles of incidence with the method. The results show that the designing method is efficient for designing non-polarizing cut-off filters, which are widely used in non-polarizing optical system. PMID- 23938832 TI - Bend compensated large-mode-area fibers: achieving robust single-modedness with transformation optics. AB - Fibers with symmetric bend compensated claddings are proposed, and demonstrate performance much better than conventional designs. These fibers can simultaneously achieve complete HOM suppression, negligible bend loss, and mode area >1000 square microns. The robust single-modedness of these fibers offers a path to overcoming mode instability limits on high-power amplifiers and lasers. The proposed designs achieve many of the advantages of our previous (asymmetric) bend compensation strategy in the regime of moderately large area, and are much easier to fabricate and utilize. PMID- 23938833 TI - Quantum cascade laser in a master oscillator power amplifier configuration with Watt-level optical output power. AB - We present the design and realization of short-wavelength (lambda = 4.53 MUm) and buried-heterostructure quantum cascade lasers in a master oscillator power amplifier configuration. Watt-level, singlemode peak optical output power is demonstrated for typical non-tapered 4 MUm wide and 5.25 mm long devices. Farfield measurements prove a symmetric, single transverse-mode emission in TM(00)-mode with typical divergences of 25 degrees and 27 degrees in and perpendicular to growth direction, respectively. We demonstrate singlemode tuning over a range of 7.9 cm(-1) for temperatures between 263K and 313K and also singlemode emission for different driving currents. The side mode suppression ratio is measured to be higher than 20 dB. PMID- 23938834 TI - Gradient field microscopy of unstained specimens: comment. AB - We comment on a recent paper by Kim et al. [Opt. Exp. 20(6) 6737-6745 (2012)], in which the authors claimed to present a new method for first-order differentiation of phase objects called gradient field microscopy (GFM). We consider that the method does not substantially differ from well-known Fourier methods discussed in textbooks. Also, we discuss some deficiencies of the paper. PMID- 23938835 TI - Gradient field microscopy of unstained specimens: reply to comment. AB - We reply to the comment written by Ferrari and Ayubi on our recent paper, Kim et al. [Opt. Express, 20, 6737 (2012)]. We maintain that our use of Fourier filtering methods lead to valuable intrinsic contrast live cell imaging. Judging by their comments regarding the limit sin(x)~x, it seems that the authors overlooked Fig. 2 in our paper, where we show results with sinusoidal masks of different periods. PMID- 23938836 TI - Characterization of the iridescence-causing multilayer structure of the Ceroglossus suturalis beetle using bio-inspired optimization strategies. AB - We investigate the iridescence exhibited by Ceroglossus suturalis beetles, which mostly live endemically in the southern end of South America. Two differently colored specimens have been studied. We observed and characterized the samples by different microscopy techniques, which revealed a multilayer structure within their cuticle. Using measured reflectance spectra as input data, we applied heuristic optimization techniques to estimate the refractive index values of the constituent materials, to be introduced within the theoretical model. The color of the samples was calculated for different incidence angles, showing that multilayer interference is the mechanism responsible for the observed iridescence. PMID- 23938837 TI - Performance comparison between electrical copper-based and optical fiber-based backplanes. AB - A performance comparison between the electrical Cu-based backplane and a full optical fiber-based backplane is presented in terms of capacity and power consumption. By means of systematic simulations we find the electrical configuration, which allows to optimize the Cu-based backplane by exploiting the best technologies available today. On the other hand, a fiber-based optical backplane is proposed by exploiting the most performing VCSEL sources. Limitations of the electrical and optical approaches are discussed, considering their capabilities to support up to about 25-Gb/s transmission and the possibility to evolve towards higher bit-rates. PMID- 23938838 TI - Spatial second-order interference of pseudothermal light in a Hong-Ou-Mandel interferometer. AB - The spatial second-order interference of two independent pseudothermal light beams in a Hong-Ou-Mandel interferometer is studied experimentally and theoretically. The similar cosine modulation in the second-order coherence function as the one with entangled-photon pairs in a Hong-Ou-Mandel interferometer is observed. Two-photon interference based on Feynman's path integral theory is employed to interpret the results. The experimental results and theoretical simulations agree with each other very well. PMID- 23938840 TI - Enhancement of Fano resonance in metal/dielectric/metal metamaterials at optical regime. AB - Fano resonance (FR) within the transmission spectrum is demonstrated in the near infrared (NIR) region using elliptical nanoholes array (ENA) embedding through metal-dielectric-metal (MDM) layers. For the symmetric MDM-ENA, it has been shown that a FR can be excited by the normally incident light. This FR response is attributed to the interplay between the bright modes and dark modes, where the bright modes originate from the electric resonance (localized surface plasmon resonance) caused by the ENA and the dark modes are due to the magnetic resonance (inductive-capacitive resonance) induced by the MDM multilayers. Displacement of the elliptical nanoholes from their centers breaks the structural symmetry to excite a double FR as a result of the coherent interaction of the electric resonance with two splitting sub-magnetic resonances at different wavelengths. Moreover,the degree of the asymmetry allows for the tuning of the amplitude and bandwidth of the double FR window. The sensitivity to the slight variations of the dielectric environment has been calculated and yields a figure-of-merit of 0.8RIU(-1) for the symmetric MDM-ENA and 3.0RIU(-1) for the asymmetric MDM-ENA. PMID- 23938839 TI - Space-division multiplexing optical coherence tomography. AB - High speed, high resolution and high sensitivity are desirable for optical coherence tomography (OCT). Here, we demonstrate a space-division multiplexing (SDM) technology that translates long coherence length of a commercially available wavelength tunable laser into high OCT imaging speed. We achieved an effective 800,000 A-scans/s imaging speed using a 100,000 Hz tunable vertical cavity surface-emitting laser (VCSEL). A sensitivity of 94.6 dB and a roll-off of < 2 dB over ~30 mm imaging depth were measured from a single channel in the prototype SDM-OCT system. An axial resolution of ~11 MUm in air (or ~8.3 MUm in tissue) was achieved throughout the entire depth range. An in vivo, 3D SDM-OCT volume of an entire Drosophila larva consisting of 400 x 605 A-scans was acquired in 0.37 seconds. Synchronized cross-sectional OCT imaging of three different segments of a beating Drosophila larva heart is demonstrated. The SDM technology provides a new orthogonal dimension for further speed improvement for OCT with favorable cost scaling. SDM-OCT also preserves image resolution and allows synchronized cross-sectional and three-dimensional (3D) imaging of biological samples, enabling new biomedical applications. PMID- 23938841 TI - Dynamics of Fourier domain mode-locked lasers. AB - An analysis of the dynamical features in the output of a Fourier Domain Mode Locked laser is presented. An experimental study of the wavelength sweep direction asymmetry in the output of such devices is undertaken. A mathematical model based on a set of delay differential equations is developed and shown to agree well with experiment. PMID- 23938842 TI - Universal quantum controlled phase gate on photonic qubits based on nitrogen vacancy centers and microcavity resonators. AB - Here we investigate a physical implementation of the universal quantum controlled phase (CPHASE) gate operation on photonic qubits by using nitrogen vacancy (N-V) centers and microcavity resonators. The quantum CPHASE gate can be achieved by sending the photons through the microcavity and interacting with the N-V center. The proposed scheme can be further used for scalable quantum computation. We show that this technique provides us a deterministic source of cluster state generation on photonic qubits. In this scheme, only single photons and single N-V center are required and the proposed schemes are feasible with the current experimental technology. PMID- 23938843 TI - Conductive optical-fiber STM probe for local excitation and collection of cathodoluminescence at semiconductor surfaces. AB - Luminescence imaging of semiconductor surfaces in nanometric resolution is a key to novel optoelectronic nano-devices, which requires local carrier excitation and local luminescence collection within the nanometric areas at the surfaces. However, there have not been a practical nanospectroscopies applicable to wide range of specimens. STM-cathodoluminescence (STM-CL) nanospectroscopy offers both high spatial resolution (of the order of 10 nm) and novel high carrier excitation power (up to ~1 mW), which enables local luminescence imaging of less-luminescent nano-structures. In this study, we advanced STM-CL technique by introducing a novel optical fiber probe with Cr thin film coating (Cr-FP), which was found to work as a STM probe, as an electron field-emitter for local carrier excitation, and as an alignment-free efficient local STM-CL collector which blinds luminescence after the minority carrier diffusion. PMID- 23938844 TI - Comparison of 128-SP-QAM and PM-16QAM in long-haul WDM transmission. AB - We investigate 128-level set-partitioning quadrature amplitude modulation (128-SP QAM) experimentally and compare the performance to polarization-multiplexed 16QAM both at the same bit rate and at the same symbol rate. Using a recirculating loop we study both single channel and wavelength-division multiplexing (WDM) transmission and demonstrate a reach of up to 2680 km at a bit-error rate of 10( 3) for 128-SP-QAM. We confirm that 128-SP-QAM has an increased sensitivity compared to PM-16QAM and show that the maximum transmission distance can be increased by more than 50 % at the same bit rate for both single channel and WDM transmission. We also investigate the performance at the same symbol rate as a possible fall back solution in a degrading link. PMID- 23938845 TI - Balanced detection for spectral domain optical coherence tomography. AB - The use and advantages of applying balanced-detection (BD) operation method to high speed spectral domain optical coherence tomography (SDOCT) are presented in this study, which we believe is the first such demonstration. Compared to conventional SDOCT, BD-SDOCT provides two unique advantages. First, the method can suppress background noise and autocorrelation artifacts in biological tissues. Second, it is a power-efficient method which is particularly helpful for high speed SDOCT to eliminate random intensity noise and to achieve shot noise limited detection. This performance allows in vivo three-dimensional tissue visualization with high imaging quality and high speed. PMID- 23938846 TI - Terahertz waveguide prism. AB - We present an easily fabricated waveguide prism for the terahertz (THz) frequency range. The prism is made of polypropylene and uses waveguide dispersion to spatially separate frequencies over the range of 0.1 to 0.7 THz. The diffraction properties of the prism were determined using electromagnetic field simulations and the waveguide parameters were optimized to maximize frequency dispersion. Angular-dependent measurements of two prisms designs were obtained in a terahertz time-domain goniometer setup. An excellent match between simulation and measurement was found. The prism can be used as a dispersive element in novel THz systems for a variety of applications. PMID- 23938847 TI - Laser cooling of CdS nanobelts: thickness matters. AB - We report on the thickness dependent laser cooling in CdS nanobelts pumped by a 532 nm green laser. The lowest achievable cooling temperature is found to strongly depend on thickness. No net cooling can be achieved in nanobelts with a thickness below 65 nm due to nearly zero absorption and larger surface nonradiative recombination. While for nanobelts thicker than ~120 nm, the reabsorption effect leads to the reduction of the cooling temperature. Based on the thickness dependent photoconductivity gain, mean emission energy and external quantum efficiency, the modeling of the normalized temperature change suggests a good agreement with the experimental results. PMID- 23938848 TI - Sub-5 nm hard x-ray point focusing by a combined Kirkpatrick-Baez mirror and multilayer zone plate. AB - Compound optics such as lens systems can overcome the limitations concerning resolution, efficiency, or aberrations which fabrication constraints would impose on any single optical element. In this work we demonstrate unprecedented sub-5 nm point focusing of hard x-rays, based on the combination of a high gain Kirkpatrick-Baez (KB) mirror system and a high resolution W/Si multilayer zone plate (MZP) for ultra-short focal length f. The pre-focusing allows limiting the MZP radius to below 2 MUm, compatible with the required 5 nm structure width and essentially unlimited aspect ratios, provided by enabling fabrication technology based on pulsed laser deposition (PLD) and focused ion beam (FIB). PMID- 23938849 TI - Master-slave interferometry for parallel spectral domain interferometry sensing and versatile 3D optical coherence tomography. AB - Conventional spectral domain interferometry (SDI) methods suffer from the need of data linearization. When applied to optical coherence tomography (OCT), conventional SDI methods are limited in their 3D capability, as they cannot deliver direct en-face cuts. Here we introduce a novel SDI method, which eliminates these disadvantages. We denote this method as Master - Slave Interferometry (MSI), because a signal is acquired by a slave interferometer for an optical path difference (OPD) value determined by a master interferometer. The MSI method radically changes the main building block of an SDI sensor and of a spectral domain OCT set-up. The serially provided signal in conventional technology is replaced by multiple signals, a signal for each OPD point in the object investigated. This opens novel avenues in parallel sensing and in parallelization of signal processing in 3D-OCT, with applications in high- resolution medical imaging and microscopy investigation of biosamples. Eliminating the need of linearization leads to lower cost OCT systems and opens potential avenues in increasing the speed of production of en-face OCT images in comparison with conventional SDI. PMID- 23938850 TI - Unidirectional III-V microdisk lasers heterogeneously integrated on SOI. AB - We demonstrate unidirectional bistability in microdisk lasers electrically pumped and heterogeneously integrated on SOI. The lasers operate in continuous wave regime at room temperature and are single mode. Integrating a passive distributed Bragg reflector (DBR) on the waveguide to which the microdisk is coupled feeds laser emission back into the laser cavity. This introduces an extra unidirectional gain and results in unidirectional emission of the laser, as demonstrated in simulations as well as in experiment. PMID- 23938851 TI - Investigation of the confocal wavefront sensor and its application to biological microscopy. AB - Wavefront sensing in the presence of background light sources is complicated by the need to restrict the effective depth of field of the wavefront sensor. This problem is particularly significant in direct wavefront sensing adaptive optic (AO) schemes for correcting imaging aberrations in biological microscopy. In this paper we investigate how a confocal pinhole can be used to reject out of focus light whilst still allowing effective wavefront sensing. Using a scaled set of phase screens with statistical properties derived from measurements of wavefront aberrations induced by C. elegans specimens, we investigate and quantify how the size of the pinhole and the aberration amplitude affect the transmitted wavefront. We suggest a lower bound for the pinhole size for a given aberration strength and quantify the optical sectioning provided by the system. For our measured aberration data we find that a pinhole of size approximately 3 Airy units represents a good compromise, allowing effective transmission of the wavefront and thin optical sections. Finally, we discuss some of the practical implications of confocal wavefront sensing for AO systems in microscopy. PMID- 23938852 TI - Long-wave infrared tunable thin-film perfect absorber utilizing highly doped silicon-on-sapphire. AB - We show that nearly perfect absorption can be achieved in a simple structure with highly doped silicon on a sapphire (SOS) substrate. An SOS structure with the n Si film being 600 nm thick and having doping concentration of 2e19 cm(-3) has an absorption peak of 96% in the film at a wavelength of 12.1 MUm. More generally, 95% absorption in the n-Si can be achieved and tailored to specific wavelengths in the range of 11.6-15.1 MUm utilizing dopings of 1-2.4e19 cm(-3) and film thicknesses of 600-1000 nm. Regions of 90% absorption can be achievable down to 11 MUm and up to as much as 22 MUm with tailoring of doping and film thickness. It is also shown that choice of substrate with large k/n (imaginary over real part of refractive index) is imperative for high absorption in the thin-film and will play a role in tailoring possibilities. Shown here are results for n-Si, but in general these results also apply to p-Si and the methods may be used to investigate structures with alternative films or substrates. This investigated SOS structure has high potential since desired film thickness and doping investigated here for perfect absorption can be purchased commercially and easily tuned by etching the silicon film. PMID- 23938853 TI - Passive mitigation strategies for mode instabilities in high-power fiber laser systems. AB - Mode instabilities have quickly become the most limiting effect when it comes to scaling the output average power of fiber laser systems. In consequence, there is an urgent need for effective strategies to mitigate it and, thus, to increase the power threshold at which it appears. Passive mitigation strategies can be classified into intrinsic, which are related to the fiber design, and extrinsic, which require a modification of the setup. In order to evaluate the impact of mitigation strategies, a means to calculate its power threshold and predict its behavior is required. In this paper we present a simple semi-analytic formula that is able to predict the changes of the mode instability threshold by analyzing the strength of the thermally-induced waveguide perturbations. Furthermore, we propose two passive mitigation strategies, one intrinsic and one extrinsic, that should lead to a significant increase of the power threshold of mode instabilities. PMID- 23938854 TI - Sub-Poissonian-light generation by postselection from twin beams. AB - States with sub-Poissonian photon-number statistics obtained by post-selection from twin beams are experimentally generated. States with Fano factors down to 0.62 and mean photon numbers around 12 are reached. Their quasi-distributions of integrated intensities attaining negative values are reconstructed. An intensified CCD camera with a quantum detection efficiency exceeding 20% is utilized both for post-selection and beam characterization. Experimental results are compared with theory that provides the optimum experimental conditions. PMID- 23938855 TI - A simple optical encryption based on shape merging technique in periodic diffraction correlation imaging. AB - In Periodic diffraction correlation imaging (PDCI), the images of several objects located in different spatial positions can be integrated into one image following certain rules, which is named shape merging. In this paper, we proposed and demonstrated this new technique. It can be realized without SLM or beam-splitter. And this effect can find novel application in optical encryption, enabling transmission of object information to a remote place secretly. PMID- 23938856 TI - A three-image algorithm for hard x-ray grating interferometry. AB - A three-image method to extract absorption, refraction and scattering information for hard x-ray grating interferometry is presented. The method comprises a post processing approach alternative to the conventional phase stepping procedure and is inspired by a similar three-image technique developed for analyzer-based x-ray imaging. Results obtained with this algorithm are quantitatively comparable with phase-stepping. This method can be further extended to samples with negligible scattering, where only two images are needed to separate absorption and refraction signal. Thanks to the limited number of images required, this technique is a viable route to bio-compatible imaging with x-ray grating interferometer. In addition our method elucidates and strengthens the formal and practical analogies between grating interferometry and the (non-interferometric) diffraction enhanced imaging technique. PMID- 23938857 TI - Advanced multi-contrast Jones matrix optical coherence tomography for Doppler and polarization sensitive imaging. AB - An advanced version of Jones matrix optical coherence tomography (JMT) is demonstrated for Doppler and polarization sensitive imaging of the posterior eye. JMT is capable of providing localized flow tomography by Doppler detection and investigating the birefringence property of tissue through a three-dimensional (3 D) Jones matrix measurement. Owing to an incident polarization multiplexing scheme based on passive optical components, this system is stable, safe in a clinical environment, and cost effective. Since the properties of this version of JMT provide intrinsic compensation for system imperfection, the system is easy to calibrate. Compared with the previous version of JMT, this advanced JMT achieves a sufficiently long depth measurement range for clinical cases of posterior eye disease. Furthermore, a fine spectral shift compensation method based on the cross-correlation of calibration signals was devised for stabilizing the phase of OCT, which enables a high sensitivity Doppler OCT measurement. In addition, a new theory of JMT which integrates the Jones matrix measurement, Doppler measurement, and scattering measurement is presented. This theory enables a sensitivity enhanced scattering OCT and high-sensitivity Doppler OCT. These new features enable the application of this system to clinical cases. A healthy subject and a geographic atrophy patient were measured in vivo, and simultaneous imaging of choroidal vasculature and birefringence structures are demonstrated. PMID- 23938858 TI - Validation of a power-law noise model for simulating small-scale breast tissue. AB - We have validated a small-scale breast tissue model based on power-law noise. A set of 110 patient images served as truth. The statistical model parameters were determined by matching the radially averaged power-spectrum of the projected simulated tissue with that of the central tomosynthesis patient breast projections. Observer performance in a signal-known exactly detection task in simulated and actual breast backgrounds was compared. Observers included human readers, a pre-whitening observer model and a channelized Hotelling observer model. For all observers, good agreement between performance in the simulated and actual backgrounds was found, both in the tomosynthesis central projections and the reconstructed images. This tissue model can be used for breast x-ray imaging system optimization. The complete statistical description of the model is provided. PMID- 23938861 TI - Development. EGR1 is a key factor in tendon development and healing. PMID- 23938859 TI - Drug therapy. Methotrexate normalizes folate pathway genes in RA. PMID- 23938864 TI - Bone diseases. Incident fractures during treatment for osteoporosis. AB - An incident fracture sustained during treatment for osteoporosis does not necessarily represent treatment failure, an outcome that was redefined in 2012. Predictors of the new definition have now been reported and include >=2 falls within the past year. Preventing fractures in the most at-risk patients, however, requires improved management strategies. PMID- 23938865 TI - Unintended consequences of regulatory initiatives in childhood cancer drug development. PMID- 23938866 TI - A "blush sign": radiological harbinger of delayed pseudoaneurysm formation after vein graft angioplasty. AB - Vein graft stenosis is a well-recognized complication of infrainguinal bypass surgery. Balloon angioplasty is an accepted method for managing vein graft stenosis in selected patients. This intervention is not without complication. We present 2 cases of delayed pseudoaneurysm formation after balloon angioplasty of vein graft stenoses. Both cases showed a persistent contrast stain or blush as an indication of vein wall damage and propose that this is a radiological harbinger of delayed rupture and pseudoaneurysm formation. PMID- 23938867 TI - Molecular evolution and patterns of duplication in the SEP/AGL6-like lineage of the Zingiberales: a proposed mechanism for floral diversification. AB - The diversity of floral forms in the plant order Zingiberales has evolved through alterations in floral organ morphology. One striking alteration is the shift from fertile, filamentous stamens to sterile, laminar (petaloid) organs in the stamen whorls, attributed to specific pollination syndromes. Here, we examine the role of the SEPALLATA (SEP) genes, known to be important in regulatory networks underlying floral development and organ identity, in the evolution of development of the diverse floral organs phenotypes in the Zingiberales. Phylogenetic analyses show that the SEP-like genes have undergone several duplication events giving rise to multiple copies. Selection tests on the SEP-like genes indicate that the two copies of SEP3 have mostly evolved under balancing selection, probably due to strong functional restrictions as a result of their critical role in floral organ specification. In contrast, the two LOFSEP copies have undergone differential positive selection, indicating neofunctionalization. Reverse transcriptase-polymerase chain reaction, gene expression from RNA-seq data, and in situ hybridization analyses show that the recovered genes have differential expression patterns across the various whorls and organ types found in the Zingiberales. Our data also suggest that AGL6, sister to the SEP-like genes, may play an important role in stamen morphology in the Zingiberales. Thus, the SEP like genes are likely to be involved in some of the unique morphogenetic patterns of floral organ development found among this diverse order of tropical monocots. This work contributes to a growing body of knowledge focused on understanding the role of gene duplications and the evolution of entire gene networks in the evolution of flower development. PMID- 23938868 TI - Genetic and nongenetic determinants of cell growth variation assessed by high throughput microscopy. AB - In microbial populations, growth initiation and proliferation rates are major components of fitness and therefore likely targets of selection. We used a high throughput microscopy assay, which enables simultaneous analysis of tens of thousands of microcolonies, to determine the sources and extent of growth rate variation in the budding yeast (Saccharomyces cerevisiae) in different glucose environments. We find that cell growth rates are regulated by the extracellular concentration of glucose as proposed by Monod (1949), but that significant heterogeneity in growth rates is observed among genetically identical individuals within an environment. Yeast strains isolated from different geographic locations and habitats differ in their growth rate responses to different glucose concentrations. Inheritance patterns suggest that the genetic determinants of growth rates in different glucose concentrations are distinct. In addition, we identified genotypes that differ in the extent of variation in growth rate within an environment despite nearly identical mean growth rates, providing evidence that alleles controlling phenotypic variability segregate in yeast populations. We find that the time to reinitiation of growth (lag) is negatively correlated with growth rate, yet this relationship is strain-dependent. Between environments, the respirative activity of individual cells negatively correlates with glucose abundance and growth rate, but within an environment respirative activity and growth rate show a positive correlation, which we propose reflects differences in protein expression capacity. Our study quantifies the sources of genetic and nongenetic variation in cell growth rates in different glucose environments with unprecedented precision, facilitating their molecular genetic dissection. PMID- 23938869 TI - Measuring ligand-receptor binding kinetics and dynamics using k-space image correlation spectroscopy. AB - Accurate measurements of kinetic rate constants for interacting biomolecules are crucial for understanding the mechanisms underlying intracellular signalling pathways. The magnitude of binding rates plays a very important molecular regulatory role which can lead to very different cellular physiological responses under different conditions. Here, we extend the k-space image correlation spectroscopy (kICS) technique to study the kinetic binding rates of systems wherein: (a) fluorescently labelled, free ligands in solution interact with unlabelled, diffusing receptors in the plasma membrane and (b) systems where labelled, diffusing receptors are allowed to bind/unbind and interconvert between two different diffusing states on the plasma membrane. We develop the necessary mathematical framework for the kICS analysis and demonstrate how to extract the relevant kinetic binding parameters of the underlying molecular system from fluorescence video-microscopy image time-series. Finally, by examining real data for two model experimental systems, we demonstrate how kICS can be a powerful tool to measure molecular transport coefficients and binding kinetics. PMID- 23938871 TI - Bilateral corneal infections associated with topical steroid therapy prophylaxis for cytarabine arabinoside-induced keratoconjunctivitis. PMID- 23938870 TI - Brain activation during anticipatory anxiety in social anxiety disorder. AB - Exaggerated anticipatory anxiety during expectation of performance-related situations is an important feature of the psychopathology of social anxiety disorder (SAD). The neural basis of anticipatory anxiety in SAD has not been investigated in controlled studies. The current study used functional magnetic resonance imaging (fMRI) to investigate the neural correlates during the anticipation of public and evaluated speaking vs a control condition in 17 SAD patients and 17 healthy control subjects. FMRI results show increased activation of the insula and decreased activation of the ventral striatum in SAD patients, compared to control subjects during anticipation of a speech vs the control condition. In addition, an activation of the amygdala in SAD patients during the first half of the anticipation phase in the speech condition was observed. Finally, the amount of anticipatory anxiety of SAD patients was negatively correlated to the activation of the ventral striatum. This suggests an association between incentive function, motivation and anticipatory anxiety when SAD patients expect a performance situation. PMID- 23938873 TI - Supramolecular chemistry of metal complexes in solution. AB - Building on established supramolecular chemistry, metal coordination and organometallic chemistry have been widely explored for supramolecular polymers and nanostructures. Increasingly, research has demonstrated that this approach is promising for the synthesis of novel materials with functions and properties derived from metal elements and their coordination structures. Unique self assembling behaviour and unexpected supramolecular structures are frequently discovered due to multiple non-covalent interactions in addition to metal coordination. However, an explicit understanding of the synergistic effects of non-covalent interactions for designed synthesis of metal containing assemblies with structure correlated properties remains a challenge to be addressed. Recent literature in the area is highlighted in this review in order to illustrate newly explored concepts and stress the importance of developing well understood and controlled supramolecular chemistry for designed synthesis. PMID- 23938874 TI - Synthesis, characterisation and biological activities of [(p-cym)RuX(pz4lut)]n+ and [{(p-cym)RuX}2(MU-pz4lut)]n+ (X = Cl, H2O and pz4lut = alpha,alpha,alpha',alpha'-tetra(pyrazol-1-yl)-2,6-lutidine). AB - Mononuclear [(p-cym)RuCl(pz4lut)]Cl (1) and dinuclear [{(p-cym)RuCl}2(MU pz4lut)]Cl2 (2) complexes (p-cym = 1-isopropyl-4-methylbenzene) comprising of bis(pyrazol-1-yl)methane based heteroscorpionate ligand alpha,alpha,alpha',alpha' tetra(pyrazol-1-yl)-2,6-lutidine (pz4lut) have been synthesised from pz4lut ligand and dimeric precursor complex [(p-cym)RuCl(MU-Cl)]2 in methanol. The aqua derivatives [(p-cym)Ru(H2O)(pz4lut)](ClO4)2 (3) and [{(p-cym)Ru(H2O)}2(MU pz4lut)](ClO4)4 (4) are obtained from 1 and 2, respectively, via Cl/H2O exchange process in presence of appropriate equivalents of AgClO4 in methanol-water mixture. The molecular structures of dinuclear complexes, 2 and 4 are authenticated by their single crystal X-ray structures. Cyclic voltammetry reveals negligible electronic communication between the metal centres in the ligand bridged complex 2. All four complexes have been tested for their anticancer activities in human breast (MCF7), lung (A549) and colon (HCT116) cancer cell lines. The complexes show dose dependent suppression of cell viability with moderately good IC50 values ranging from 3.5-92 MUM. Experimental results have revealed that the aqua derivatives, 3 and 4 exhibit better cytotoxic effect against all those cell lines as compared to the precursor chlorido complexes, 1 and 2. Results also demonstrate that the complexes are more potent against HCT116 cells as compared to other cell lines. PMID- 23938875 TI - Exploring the role of post-translational modifications on protein-protein interactions with survivin. AB - Survivin is a member of the inhibitor of apoptosis protein (IAP) family with crucial roles in apoptosis and cell cycle regulation. Post-translational modifications (PTMs) have a ubiquitous role in the regulation of a diverse range of proteins' cellular functions and survivin is not an exception. Phosphorylation, acetylation and ubiquitination seem to regulate survivin anti apoptotic and mitotic roles and also its nuclear localization. In the present review we explore the role of PTMs on protein-protein interactions focused on survivin to provide new insights into the functions and cell localization of this IAP in pathophysiological conditions, which might help the envisioning of novel targeted therapies for diseases characterized by impaired survivin activity. Protein-protein interaction analysis was performed with bioinformatics tools based on published data aiming to give an integrated perspective of this IAP's role in the cell. PMID- 23938876 TI - Computational study of porphyrin-based dyes with better performance. AB - Using density functional theory (DFT) and time-dependent DFT in different levels, we have systematically studied new porphyrin-based dyes with A-pi-D structures focusing on optical absorption, light harvest efficiency, ground state oxidation potential, excited state oxidation potential, and natural transition orbitals. Compared with existing dyes, we find that these new dyes have wide absorption regions (400-1000 nm) with high molar extinction coefficients, and display good energy level alignment for efficient injection of electrons and fast regeneration of the oxidized dyes. PMID- 23938877 TI - Psychophysiology in Australasia: selected papers from the 22nd annual meeting of the Australasian Society for Psychophysiology, ASP2012, held at the University of New South Wales, Sydney, Australia, 28-30 November 2012. PMID- 23938878 TI - Danger and disease: electrocortical responses to threat- and disgust-eliciting images. AB - Previous research suggests facilitated processing of evolutionarily significant stimuli (e.g., depictions of erotica, mutilation, threat), as reflected by augmented event-related potentials (ERPs), including the early posterior negativity (EPN) and late positive potential (LPP). Evolutionary models suggest that images that evoke disgust should be high in motivational salience, but evidence that the EPN and LPP are enhanced by disgusting images is lacking. Prior studies have employed only a small number of disgusting images that were limited in the types of content depicted. In the current study, participants viewed larger sets of disgusting, threatening, and neutral images with more varied content while electroencephalography (EEG) was recorded. Results showed that disgusting and threatening images elicited equivalent LPPs, which were both significantly increased relative to LPPs elicited by neutral images. EPN amplitudes were augmented for both disgusting and threatening relative to neutral images, though significantly more for disgust. These findings offer initial evidence that the EPN and the LPP are sensitive to disgust-eliciting pictures and that these pictures may receive processing that is at least on par with that of threatening images. Limitations of the current study and implications for future research are discussed. PMID- 23938879 TI - Strong coupling between plasmonic Fabry-Perot cavity mode and magnetic plasmon. AB - We demonstrate strong coupling between the Fabry-Perot cavity plasmons and magnetic nanowire plasmons. The strong coupling leads to drastic enhancement of magnetic field intensity beneath a silver nanowire inside a metallic cavity. A Rabi splitting of 280 meV and a magnetic field intensity enhancement of 845 times the incident is achieved using the proposed geometry. The theoretical prediction agrees well with rigorous full wave simulations. The effect provides efficient tools for applications such as magnetic nonlinearity and magnetic sensors. PMID- 23938880 TI - Thermal refractive index coefficients of nonlinear optical crystal CsB3O5. AB - The principal refractive indices of crystal CsB3O5 (CBO) at the wavelengths of 0.266, 0.355, 0.532, 0.473, 0.633, 1.064, and 1.338 MUm are accurately measured by using the autocollimation method within the temperature range from 40 degrees C to 190 degrees C. We derive and report equations of thermal refractive index coefficients as a function of wavelength that could be used to calculate the principal thermal refractive indices at different wavelengths. Sellmeier equations at different temperatures were derived and used to calculate the phase matching angles for the third-harmonic generation and the fourth-harmonic generation of CBO crystal at different temperatures. PMID- 23938881 TI - Ultraviolet imprinting and aligned ink-jet printing for multilayer patterning of electro-optic polymer modulators. AB - The present work demonstrates an electro-optic polymer-based Mach-Zehnder (MZ) modulator fabricated utilizing advanced ultraviolet (UV) imprinting and aligned ink-jet printing technologies for patterning and layer deposition. The bottom electrode layer is designed and directly ink-jet printed on the substrate to form the patterned layer. The waveguide structure is formed into a bottom cladding polymer using a transparent flexible mold-based UV imprinting method. All other layers can be ink-jet printed. The top electrode is aligned and printed over the MZ arm. The modulator demonstrates a V-pi of 8 V at 3 kHz. This technology shows great potential in minimizing the fabrication complexity and roll-to-roll compatibility for manufacturing low cost, lightweight, and conformal modulators at high throughput. PMID- 23938882 TI - Reconfigurable optical quadrature amplitude modulation converter/encoder using a tunable complex coefficient optical tapped delay line. AB - We experimentally demonstrate a reconfigurable optical converter/encoder for quadrature amplitude modulated (QAM) signals. The system utilizes nonlinear wavelength multicasting, conversion-dispersion delays, and simultaneous nonlinear multiplexing and sampling. We show baud rate tunability (31 and 20 Gbaud) and reconfigurable conversions from lower-order QAM signals to higher-order QAM signals (e.g., 64-QAM). PMID- 23938883 TI - Logarithmic axicon characterized by scanning optical probe system. AB - A scanning optical probe system is proposed to measure a logarithmic axicon (LA) with subwavelength resolution. Multiple plane intensity profiles measured by a fiber probe are interpreted by solving an optimization problem to get the phase retardation function (PRF) of the LA. Experimental results show that this approach can accurately obtain the PRF with which the optical path difference of the generated quasi-nondiffracting beam in the propagation is calculated. PMID- 23938884 TI - Thin low-loss dielectric coatings for free-space cloaking. AB - We report stereolithographic polymer-based fabrication and experimental operation of a microwave X-band cloaking device. The device is a relatively thin (about one wavelength thick) shell of an air-dielectric composite, in which the dielectric component has negligible loss and dispersion. In a finite band (9.7-10.1 GHz), the shell eliminates the shadow and strongly suppresses scattering from a conducting cylinder of six-wavelength diameter for TE-polarized free-space plane waves. The device does not require an immersion liquid or conducting ground planes for its operation. The dielectric constant of the polymer is low enough (epsilon=2.45) to suggest that this cloaking technique would be suitable for higher frequency radiation, including visible light. PMID- 23938885 TI - Demonstrating highly symmetric single-mode, single-photon heralding efficiency in spontaneous parametric downconversion. AB - We demonstrate a symmetric, single-spatial-mode, single-photon heralding efficiency of 84% for a type-II spontaneous parametric downconversion process. High-efficiency, single-spatial mode collection is key to enabling many quantum information processing and quantum metrology applications. PMID- 23938886 TI - Optical design of split-beam photonic crystal nanocavities. AB - We design high-quality-factor photonic crystal nanobeam cavities formed by two mechanically isolated cantilevers. These "split-beam" cavities have a physical gap at the center, allowing mechanical excitations of one or both of the cavity halves. They are designed by analyzing the optical band structures and mode profiles of waveguides perforated by elliptical holes and rectangular gaps and are predicted to support optical resonances with quality factors exceeding 10(6) at wavelengths of ~1.6 MUm. PMID- 23938887 TI - 100 kW peak power picosecond thulium-doped fiber amplifier system seeded by a gain-switched diode laser at 2 MUm. AB - We report on the generation of picosecond pulses at 2 MUm directly from a gain switched discrete-mode diode laser and their amplification in a multistage thulium-doped fiber amplifier chain. The system is capable of operating at repetition rates in the range of 2 MHz-1.5 GHz without change of configuration, delivering high-quality 33 ps pulses with up to 3.5 MUJ energy and 100 kW peak power, as well as up to 18 W of average power. These results represent a major technological advance and a 1 order of magnitude increase in peak power and pulse energy compared to existing picosecond sources at 2 MUm. PMID- 23938888 TI - Optical vortices in antiguides. AB - We address the question of whether an optical vortex can be trapped in a dielectric structure with a core of a lower refractive index than the cladding- namely an antiguide. Extensive numerical simulations seem to indicate that this inverse trapping of a vortex is not possible, at least in straightforward implementations. Yet, the interaction of a vortex beam with a curved antiguide produces interesting effects, namely a small but finite displacement of the optical energy center-of-mass and the creation of a symmetrical vortex-antivortex pair on the exterior of the antiguide. PMID- 23938889 TI - On-axis non-linear effects with programmable Dammann lenses under femtosecond illumination. AB - We demonstrate the utilization of Dammann lenses codified onto a spatial light modulator (SLM) for triggering non-linear effects. With continuous wave illumination Dammann lenses are binary phase optical elements that generate a set of equal intensity foci. We theoretically calculate the influence of ultrashort pulse illumination on the uniformity of the generated pattern, which is affected by chromatic aberration for pulses with temporal widths lower than 100 fs. The simulations also indicate that acceptable uniformity can be achieved for pulses of several fs by shortening the distance among foci which can be easily modified with the SLM. Multifocal second-harmonic generation (SHG) and on-axis multiple filamentation are produced and actively controlled in beta-BaB2O4 (BBO) and fused silica samples, respectively, with an amplified Ti: Sapphire femtosecond laser of 30 fs pulse duration. Experimental results are in very good agreement with theoretical calculations. PMID- 23938890 TI - Generation of self-mode-locked resembling pulses in a fast gain-switched thulium doped fiber laser. AB - We report on a generation of self-starting mode-locked resembling (MLR) pulses in an all-fiber, gain-switched Tm(3+)-doped fiber laser operating at 2 MUm wavelength, which we believe to be the first demonstration of such an approach. The laser delivers 100% modulated MLR pulses within an envelope of ~30 ns gain switched pulse at a repetition rate of 30 kHz. The maximum average output power is 0.4 W and the maximum peak-power of MLR pulses can be as high as 1.1 kW. The performance of the laser is described. PMID- 23938891 TI - Self-curable solid-state elastic dye lasers capable of mechanical stress probing. AB - Herein, a highly sensitive stress probe is reported based on pyrromethene 597 (PM597) doped elastic polydimethylsiloxane films. By sandwiching the dye doped elastic film with two plano dichromatic mirrors, a solid-sate microcavity laser with low laser threshold (~0.2 MUJ) is presented as a straightforward probing method for mechanical stress, which is monitored by the laser output spectra, demonstrating a resolution limit higher than 0.01 MPa. The photostability of PM597 doped into the microcavity laser is higher than 7222 GJ/mol, which is among the highest record ever reported to our knowledge and a fast self-recovery on the laser output in less than 1 h, attributed to diffusion of dye molecules is observed, indicating a practical durability for such stress probes. PMID- 23938892 TI - Directive antenna nanocoupler to plasmonic gap waveguides. AB - Optical nanocouplers matching a fiber microwaveguide to a plasmonic nanowaveguide are essential components for practical applications of nanophotonic systems. In this Letter we design an efficient nanocoupler using a directive nanoantenna in the visible range lambda0=0.65 MUm. The antenna has been optimized both in the configuration and in the matching element in order to achieve the maximum coupling efficiency (CE). In spite of the reduced size of the nanoantenna in comparison with the impinging fiber spot size (due to the localized plasmonic resonance at such high frequency), we have shown that a good efficiency can be achieved, improving the CE by a factor of 10 with respect to the nondirective antenna nanocouplers. PMID- 23938893 TI - High-power diode laser bars and shear strain. AB - The emitters at the edges of high-power laser bars tend to produce less power than emitters that are near the center of the bar. We suggest that shear strain, which owes to strain induced by bonding, creates through a photoelastic effect a weak birefringence that rotates the plane of polarization of the light. A rotation of the plane of polarization reduces the net gain for the lasing modes and hence leads to a lower output power for the emitters at the edges of the bars, where the shear strain is dominant. PMID- 23938894 TI - Tunable narrowband fiber laser with feedback based on whispering gallery mode resonances of a cylindrical microresonator. AB - Narrowband filtering based on whispering gallery modes of a slightly tapered cylindrical optical microresonator was used to implement a tunable narrowband erbium-doped fiber laser. The laser can be set to emit a single longitudinal cavity mode (single frequency), although the laser cavity is a few meters long. In the single-frequency regime the laser can emit a maximum power of 0.380 mW with a linewidth <35 kHz and a signal-to-noise ratio exceeding 50 dB. Tunability is achieved by sliding the excitation point along the microcylinder. A tuning range of 1.16 nm is demonstrated. PMID- 23938895 TI - Incomplete Airy beams: finite energy from a sharp spectral cutoff. AB - We present a mathematical analysis of the finite-energy Airy beam with a sharply truncated spectrum, which can be generated by a uniformly illuminated, finite sized spatial light modulator, or windowed cubic phase mask. The resulting "incomplete Airy beam" is tractable mathematically, and differs from an infinite energy Airy beam by an additional oscillating modulation and the decay of its fringes. Its propagation can be described explicitly using an incomplete Airy function, from which we derive simple expressions for the beam's total power and mean position. Asymptotic analysis reveals a simple connection between the cutoff and the region of the beam with Airy-like behavior. PMID- 23938896 TI - Cross mode modulation in multimode fibers. AB - We show that Kerr nonlinearity induced intermodal power transfer in a particular mode group of a multimode fiber can be formulated by the same type of equation used to describe the effect of cross polarization modulation in single-mode fibers. PMID- 23938897 TI - Generation of Airy-like wave with one-dimensional waveguide array. AB - We propose and demonstrate a approach for Airy-like wave generation using one dimensional arrayed waveguides instead of a cubic phase plate and a Fourier lens. We show that this Airy-like wave with quasi-Airy amplitude and quasi-cubic phase from arrayed waveguides end has abilities to remain quasi-nondiffracting and freely accelerating during propagation. We also study wave propagation in these waveguides based on supermode theory and beam propagation method. The numerical results are in good agreement with theoretical prediction. PMID- 23938898 TI - Competing wave-breaking mechanisms in quadratic media. AB - We show that second-harmonic generation in the regime of weak dispersion/diffraction can exhibit a coexistence of wave breaking mechanisms, such that a gradient catastrophe yielding a dispersive shock wave competes with modulational instability, leading to the generation of wavetrains with incommensurate frequencies and eventually to the destruction of the shock wave train. PMID- 23938899 TI - Asymmetric cryptosystem using random binary phase modulation based on mixture retrieval type of Yang-Gu algorithm. AB - We propose an asymmetric optical image encryption scheme that uses an amplitude and phase mixture retrieval of the Yang-Gu algorithm. The encryption process is realized by employing a cascaded Yang-Gu algorithm together with two random phase masks that serve as the public encryption keys. The two private keys are generated in the encryption process and are randomly distributed binary matrices to be used for performing one-way binary phase modulations. Without the private keys, illegal users cannot retrieve the secret image. Numerical simulations are carried out to demonstrate the validity and security of the proposed scheme. PMID- 23938900 TI - Broadband terahertz wave generation from a MgO:LiNbO3 ridge waveguide pumped by a 1.5 MUm femtosecond fiber laser. AB - Cherenkov phase-matched terahertz (THz) wave generation from a MgO:LiNbO3 ridge waveguide was studied using optical rectification. Pumping was achieved using 20 and 60 fs laser pulses from a fiber laser centered at 1.56 MUm. Time-domain spectroscopy (TDS) results showed a single-cycle pulse with 20 fs pulse pumping and a near-single-cycle pulse with 60 fs pulse pumping. The spectrum covered the range of 0.1-7 THz, with a signal-to-noise ratio of over 50 dB. The output power measured by a Si bolometer and a deuterated triglycine sulfate pyroelectric detector is shown and compared to that of a commercial photoconductive antenna. This system is believed to be a promising THz source for low-cost, compact, robust, and highly integrated TDS, THz imaging, and tomography systems. PMID- 23938902 TI - Accelerated single-beam wavefront reconstruction techniques based on relaxation and multiresolution strategies. AB - A previous Letter by Pedrini et al. [Opt. Lett. 30, 833 (2005)] proposed an iterative single-beam wavefront reconstruction algorithm that uses a sequence of interferograms recorded at different planes. In this Letter, the use of relaxation and multiresolution strategies is investigated in terms of accuracy and computational effort. It is shown that the convergence rate of the conventional iterative algorithm can be significantly improved with the use of relaxation techniques combined with a hierarchy of downsampled intensities that are used within a preconditioner. These techniques prove to be more robust, to achieve a higher accuracy, and to overcome the stagnation problem met in the iterative wavefront reconstruction. PMID- 23938901 TI - Athermalized channeled spectropolarimetry using a biaxial potassium titanyl phosphate crystal. AB - Channeled spectropolarimeters measure the polarization state of light as a function of wavelength. Typically, a channeled spectropolarimeter uses high-order retarders made of uniaxial crystal to amplitude modulate the measured spectrum with the Stokes polarization information. A primary limitation of these instruments is the thermal variability of the retarders, which necessitates frequent system recalibration. Past work has addressed this issue by implementing an athermalized retarder produced from two uniaxial crystals. However, reducing the complexity of an athermalized retarder is advantageous for minimizing size and weight requirements. In this Letter, a technique for producing a thermally stable channeled spectropolarimeter using biaxial retarders is presented. This technique preserves a constant phase over an appreciable temperature range. Proof of-concept results from a KTP-based athermal partial channeled spectropolarimeter are presented from 500 to 750 nm for temperature changes up to 26 degrees C. Spectropolarimetric reconstructions produced from this system vary by <=2.6% RMS when the retarder experiences a 13 degrees C increase in temperature above 21 degrees C ambient, <=5.2% for a 20 degrees C increase, and <=6.7% for a 26 degrees C increase. PMID- 23938903 TI - High-quality optical pulse train generator based on solitons on finite background. AB - We report a simple method to exploit the typical properties of solitons on a finite background in order to generate high-repetition-rate and high-quality optical pulse trains. We take advantage of the nonlinear evolution of a modulated continuous wave toward localized structures upon a nonzero background wave in anomalous dispersive fiber. After a stage of nonlinear compression, a delay-line interferometer enables the annihilation of the finite background and simultaneously allows the repetition-rate doubling of the pulse train. PMID- 23938904 TI - Temperature insensitive high-precision refractive-index sensor using two concatenated dual-resonance long-period gratings. AB - In this Letter we report on fabricating and analyzing a temperature insensitive refractometer based on two concatenated dual-resonance long-period gratings (LPGs) with an appropriate inter-grating space (IGS) in between. The IGS provides a temperature-dependent extra phase difference between the core and cladding modes, making the refractometer similar to a Mach-Zehnder interferometer with its arms phase shifted. We demonstrate that an appropriate IGS can produce temperature-insensitive resonance wavelengths. The interferometer is highly stable over a wide range of temperature (20 degrees C-100 degrees C). The measured refractive index sensitivity for aqueous solutions (1.333-1.343) is ~2583 nm/RIU, which is the highest reported so far for biological samples. The interferometer can be used for various other temperature-immune sensing applications also. PMID- 23938905 TI - Dye lasing in optically manipulated liquid aerosols. AB - We report lasing in airborne, rhodamine B-doped glycerol-water droplets with diameters ranging between 7.7 and 11.0 MUm, which were localized using optical tweezers. While being trapped near the focal point of an infrared laser, the droplets were pumped with a Q-switched green laser. Our experiments revealed nonlinear dependence of the intensity of the droplet whispering gallery modes (WGMs) on the pump laser fluence, indicating dye lasing. The average wavelength of the lasing WGMs could be tuned between 600 and 630 nm by changing the droplet size. These results may lead to new ways of probing airborne particles, exploiting the high sensitivity of stimulated emission to small perturbations in the droplet laser cavity and the gain medium. PMID- 23938906 TI - Demonstration of a miniature all-optical photoacoustic spectrometer based on ferrule-top technology. AB - We present a miniaturized photoacoustic (PA) spectrometer obtained by carving a micromachined flexural pressure transducer directly at the top of a glass ferrule. The ferrule is equipped with two optical fibers, one for laser excitation of the gas and one for interferometric readout of the transducer. To demonstrate the working principle and assess the sensitivity of the device, we performed a set of measurements of C2H2 traces in an Ar buffer atmosphere. The data acquired show that our ferrule-top scheme allows one to increase the minimum detectable concentration by more than one order of magnitude with respect to the other miniaturized PA spectrometers reported in the literature, while decreasing the integration time by a factor of 10. PMID- 23938908 TI - Influence of shadow removal on image classification in riverine environments. AB - Shadows in remote-sensor images can yield marked errors in classification of riverine environments. We propose use of a modified shadow-removal algorithm as a preprocessing step for remote-sensing image classification of riverine landscapes. To accommodate characterization of spatially complex river features in the image, we investigate an illumination suppression-based shadow-removal algorithm, modified to include a user-defined tiling approach. We quantitatively evaluate the influence of shadow removal from aerial photography on classification accuracy as such studies are currently lacking. Experimental results demonstrate that this modified shadow-removal method significantly increases classification accuracy and improves detection of small river channels partially obscured by shadow. PMID- 23938909 TI - Room temperature, high-efficiency, noncritical phase-matching fourth harmonic generation in partially deuterated ADP crystal. AB - High-efficiency frequency conversion into the deep ultraviolet in a partially deuterated ammonium dihydrogen phosphate (ADP) crystal is reported. For a 60% deuterated ADP crystal, the spontaneous Raman scattering intensity decreased by 38% compared with that of a pristine ADP crystal. At room temperature (24 degrees C), noncritical phase-matching fourth harmonic generation of a 1053 nm laser was realized. The angular acceptance was 55.7 mrad, and the external conversion efficiency from 526 to 263 nm reached 85.3%. PMID- 23938910 TI - Crossover from photodarkening to photobleaching in a-Ge(x)Se(100-x) thin films. AB - In this Letter, we present the interesting results of photodarkening (PD), transition toward photostability, and a slow crossover from PD to photobleaching when composition of the chalcogenide glassy thin film changes from Ge-deficient to rich. A subsequent Raman analysis on these as-prepared and irradiated samples provide the direct evidence of photoinduced structural rearrangement, i.e., photocrystallization of Se and the removal of edge-sharing GeSe4 tetrahedra. Further, our experimental results clearly demonstrate that light-induced effects can be effectively controlled by choosing the right composition and provide valuable information on synthesizing photostable/sensitive glasses. PMID- 23938911 TI - Quantum dot rolled-up microtube optoelectronic integrated circuit. AB - A rolled-up microtube optoelectronic integrated circuit operating as a phototransceiver is demonstrated. The microtube is made of a InGaAs/GaAs strained bilayer with InAs self-organized quantum dots inserted in the GaAs layer. The phototransceiver consists of an optically pumped microtube laser and a microtube photoconductive detector connected by an a-Si/SiO2 waveguide. The loss in the waveguide and responsivity of the entire phototransceiver circuit are 7.96 dB/cm and 34 mA/W, respectively. PMID- 23938912 TI - High-efficiency beam bending using graded photonic crystals. AB - We explore beam-bending properties of graded index (GRIN) waveguide with hyperbolic secant profile. The transmission efficiency and bandwidth features are extracted for GRIN photonic crystal (PC) media composed of dielectric rods. Light guiding performance of the GRIN PC medium is analyzed for 90 degrees and 180 degrees waveguide bends. The finite-difference time-domain method is deployed to investigate the performance of the designed GRIN waveguides. By the help of proposed photonic configuration, bending of light is achieved with a high efficiency within a broad bandwidth, which promotes the use of GRIN PC structures for efficient light-bending purposes. PMID- 23938913 TI - Mollow quintuplets from coherently excited quantum dots. AB - Charge-neutral excitons in semiconductor quantum dots (QDs) have a small finite energy separation caused by the anisotropic exchange splitting. Coherent excitation of neutral excitons will generally excite both exciton components, unless the excitation is parallel to one of the dipole axes. We present a polaron master equation model to describe two-exciton pumping using a coherent continuous wave pump field in the presence of a realistic anisotropic exchange splitting. We predict a five-peak incoherent spectrum, namely a Mollow quintuplet under general excitation conditions. We experimentally confirm such spectral quintuplets for In(Ga)As QDs and obtain very good agreement with theory. PMID- 23938914 TI - Lasing in hybrid metal-Bragg nanocavities. AB - We report room-temperature lasing from an optically pumped subwavelength-scale cylindrical InGaAsP pillar surrounded by circular Bragg reflectors on a metal substrate with a dielectric spacer layer. By taking advantage of wide in-plane photonic bandgaps and proper vertical antiresonances, three dielectric Bragg pairs produce a sufficient optical feedback capable of low threshold lasing from the fundamental TE011 mode. A large spontaneous emission coupling into the lasing mode is obtained from the cavity-enhanced Purcell effects and effective suppression of nonlasing modes. PMID- 23938916 TI - Multichannel transmission of intensity- and phase-modulated signals by optical phase conjugation using a quantum-dot semiconductor optical amplifier. AB - We report the demonstration of optical phase conjugation using a quantum-dot semiconductor optical amplifier. The transmission performance of wavelength multiplexed 10-Gbit/s intensity- and phase-modulated signals is investigated for different channel alignments. In a 100-km transmission, we have successfully achieved high transmission performance with low power penalties for all the transmitted signals. PMID- 23938915 TI - Fast flexible multiphoton fluorescence lifetime imaging using acousto-optic deflector. AB - We present a fast and flexible fluorescence lifetime imaging microscopy which uses a two-dimensional acousto-optic deflector to achieve fast beam scanning across the sample and provides random access to the regions of interests (ROI). Experimental results using standard fluorescent dye and biological samples show that this system can make addressable fluorescence lifetime measurements and perform fast and flexible fluorescence lifetime imaging particularly to the discontinuous ROI in the sample. PMID- 23938917 TI - Mach-Zehnder-based five-port silicon router for optical interconnects. AB - We propose and fabricate a five-port silicon optical router based on Mach-Zehnder interferometer switches. Only 10 switching elements and five low-loss waveguide crossings are required in our design. Through thermal control of the switching network, we successfully demonstrate 20 possible I/O paths of the five-port optical router at a data transmission rate of 32 Gb/s. The results here show great potential for application in ultrahigh-capacity optical interconnects. PMID- 23938918 TI - Defocus map estimation from a single image via spectrum contrast. AB - We present an effective method for defocus map estimation from a single natural image. It is inspired by the observation that defocusing can significantly affect the spectrum amplitude at the object edge locations in an image. By establishing the relationship between the amount of spatially varying defocus blur and spectrum contrast at edge locations, we first estimate the blur amount at these edge locations, then a full defocus map can be obtained by propagating the blur amount at edge locations over the entire image with a nonhomogeneous optimization procedure. The proposed method takes into consideration not only the affect of light refraction but also the blur texture of an image. Experimental results demonstrate that our proposed method is more reliable in defocus map estimation compared to various state-of-the-art methods. PMID- 23938919 TI - Near fundamental mode 1.1 kW Yb:YAG thin-disk laser. AB - We report on a Yb:YAG thin-disk laser with 1.1 kW output power and beam quality factor M2<1.4 using a simple stable resonator comprising just a single cavity mirror and a single thin disk, without the use of any aspherical elements or any adaptive optics. An optical-to-optical efficiency of 40% was obtained. The cavity was designed to give good beam quality and low misalignment sensitivity to maintain stable and robust laser operation throughout the changes in the thin disk curvature. To the best of the authors' knowledge, this is the first time an output power beyond 1 kW has been achieved from a single thin-disk laser in near fundamental mode operation (M2<1.4). PMID- 23938920 TI - Photonic microwave generation with high-power photodiodes. AB - We utilized and characterized high-power, high-linearity modified unitraveling carrier (MUTC) photodiodes for low-phase-noise photonic microwave generation based on optical frequency division (OFD). When illuminated with picosecond pulses from a repetition-rate-multiplied gigahertz Ti:sapphire modelocked laser, the photodiodes can achieve a 10 GHz signal power of +14 dBm. Using these diodes, we generated a 10 GHz microwave tone with less than 500 attoseconds absolute integrated timing jitter (1 Hz-10 MHz) and a phase noise floor of -177 dBc/Hz.We also characterized the electrical response, amplitude-to-phase conversion, saturation, and residual noise of the MUTC photodiodes. PMID- 23938921 TI - Intravascular optical coherence tomography imaging at 3200 frames per second. AB - We demonstrate intravascular optical coherence tomography (OCT) imaging with frame rate up to 3.2 kHz (192,000 rpm scanning). This was achieved by using a custom-built catheter in which the circumferential scanning was actuated by a 1.0 mm diameter synchronous motor. The OCT system, with an imaging depth of 3.7 mm (in air), is based on a Fourier domain mode locked laser operating at an A-line rate of 1.6 MHz. The diameter of the catheter is 1.1 mm at the tip. Ex vivo images of human coronary artery (78.4 mm length) were acquired at a pullback speed of 100 mm/s. True 3D volumetric imaging of the entire artery, with dense and isotropic sampling in all dimensions, was performed in <1 second acquisition time. PMID- 23938922 TI - Highly efficient counter-propagation-beams narrow-band ultraviolet frequency conversion in a quantum gas. AB - We show that highly efficient ultraviolet frequency up conversion can be established in a single-component quantum gas in the counter-propagating weak pump beam geometry where no frequency up conversion can occur in a normal gas. We also show that all light-wave mixing and scattering processes in quantum gases originating from elementary excitations characterized by efficient collective atomic recoil motion are stimulated Raman/hyper-Raman in nature. PMID- 23938923 TI - Phantom study of tear film dynamics with optical coherence tomography and maximum likelihood estimation. AB - In this Letter, we implement a maximum-likelihood estimator to interpret optical coherence tomography (OCT) data for the first time, based on Fourier-domain OCT and a two-interface tear film model. We use the root mean square error as a figure of merit to quantify the system performance of estimating the tear film thickness. With the methodology of task-based assessment, we study the trade-off between system imaging speed (temporal resolution of the dynamics) and the precision of the estimation. Finally, the estimator is validated with a digital tear-film dynamics phantom. PMID- 23938924 TI - Phase aberration compensation in digital holographic microscopy based on principal component analysis. AB - We present an effective, fast, and straightforward phase aberration compensation method in digital holographic microscopy based on principal component analysis. The proposed method decomposes the phase map into a set of values of uncorrelated variables called principal components, and then extracts the aberration terms from the first principal component obtained. It is effective, fully automatic, and does not require any prior knowledge of the object and the setup. The great performance and limited computational complexity make our approach a very attractive and promising technique for compensating phase aberration in digital holography under time-critical environments. PMID- 23938925 TI - Automatic salient object detection via maximum entropy estimation. AB - This Letter proposes a rapid method for automatic salient object detection inspired by the idea that an image consists of redundant information and novelty fluctuations. We believe object detection can be achieved by removing the nonsalient parts and focusing on the salient object. Considering the relation between the composition of the image and the aim of object detection, we constructed what we believe is a more reliable saliency map to evaluate the image composition. The local energy feature is combined with a simple biologically inspired model (color, intensity, orientation) to strengthen the integrity of the object in the saliency map. We estimated the entropy of the object via the maximum entropy method. Then, we removed pixels of minimal intensity from the original image and compute the entropy of the resulting images, correlating this entropy with the object entropy. Our experimental results show that the algorithm outperforms the state-of-the-art methods and is more suitable in real-time applications. PMID- 23938926 TI - Nonimaging achromatic shaped Fresnel lenses for ultrahigh solar concentration. AB - The maximum concentration ratio achievable with a solar concentrator made of a single refractive primary optics is much more limited by the chromatic aberration than by any other aberration. Therefore achromatic doublets made with poly(methyl methacrylate) and polycarbonate are of great interest to enhance the concentration ratio and to achieve a spectrally uniform flux on the receiver. In this Letter, shaped achromatic Fresnel lenses are investigated. One lossless design is of high interest since it provides spectrally and spatially uniform flux without being affected by soiling problems. With this design an optical concentration ratio of about 8500* can be achieved. PMID- 23938927 TI - Converting surface plasmon to spatial Airy beam by graded grating on metal surface. AB - A well-developed phase modulation method is utilized to design a nanogroove grating for a desired diffraction process, which gives rise to the conversion of a surface plasmon wave to an Airy-like radiation beam. Experiments and simulations revealed the unique characteristics of the generated Airy-like beam, such as nonspreading, self-bending, and self-healing. Our result confirms the validation of the diffraction strategy for beam engineering in conversions and possibly indicates wider applications in broader areas. PMID- 23938928 TI - Frequency stabilization of an ultraviolet semiconductor disk laser. AB - We report a tunable, narrow-linewidth UV laser based on intracavity second harmonic generation in a red semiconductor disk laser. Single-frequency operation is demonstrated with a total UV output power of 26 mW. By servo-locking the fundamental frequency to a reference Fabry-Perot cavity, the linewidth of the UV beam has been reduced to 16 kHz on short timescales and 50 kHz on a 1 s timescale, relative to the reference. PMID- 23938929 TI - Nonradiative energy transfer between two different activator sites in La(4 x)Ca(x)Si12O(3+x)N(18-x):Eu2+. AB - Energy transfer, which affects the entire performance of luminescent material, has been generally treated as an averaged parameter by assuming the host material to be a homogeneous continuum. However, energy transfer should be investigated in association with the crystallographic local structure around an activator site. To accomplish this, we established an analytical model and derived comprehensive rate equations, elucidating the relationship between the local structure and energy transfer behavior of La(4-x)Ca(x)Si12O(3+x)N(18-x):Eu2+, which is a recently discovered luminescent material for use in light-emitting diodes. Using the rate-equation model with the assistance of particle swarm optimization, the full-scale decay curves of donors and acceptors located at different crystallographic sites was computed. PMID- 23938930 TI - Angle-stable RGBW top-emitting organic light-emitting devices with Ag/Ge/Ag cathode. AB - Ag/Ge/Ag (AGA) is investigated as a transparent cathode for top-emitting organic light-emitting devices (TEOLEDs). TEOLEDs of different colors with excellent performances can be gained by simply adopting a corresponding emitting layer, without changing the thickness of the device and cathode. Especially, the blue and white TEOLEDs exhibit high efficiency as well as the bottom OLEDs and show an excellently angle-stable characteristic. The white TEOLED exhibits a maximum current efficiency of 12.4 cd/A, and the CIE coordinates at 6 V only shift by (0.048, 0.046) from 0 degrees to 60 degrees . It can be attributed to the less angle-dependent cavity emission of the TEOLED with AGA cathode. PMID- 23938931 TI - Sub-100-fs Cr:YAG laser mode-locked by monolayer graphene saturable absorber. AB - We report on mode-locking of a Cr:YAG laser at 1516 nm using a monolayer graphene based saturable absorber of transmission type generating 91 fs pulses with a Fourier product of 0.38 at an average output power exceeding 100 mW. Stable single-pulse mode-locked operation without any sign of Q-switching instabilities or multiple pulses is achieved. PMID- 23938932 TI - Enhancing spin-orbit interaction of light by plasmonic nanostructures. AB - The spin orbit interactions (SOI) of light mediated by single scattering from plasmon resonant metal nanoparticles (nanorods and nanospheres) are investigated using Jones and Mueller matrix polarimetry formalism. The effect of neighboring resonances in plasmonic nanostructures (e.g., orthogonal electric dipolar modes in rods or electric dipolar and quadrupolar modes in spheres) on the individual SOI effects are analyzed and interpreted via the Mueller matrix-derived polarimetry characteristics, namely, diattenuation d and retardance delta. The results clearly reveal that each of these can be controllably tuned and enhanced by exploiting the interference of neighboring modes. PMID- 23938933 TI - Thermally induced depolarization in TGG ceramics. AB - The thermal-birefringence-induced depolarization in terbium gallium garnet (TGG) ceramics has been investigated experimentally. The depolarization ratio of 6.1*10(-4) has been observed at the maximum input power of 117 W cw, which corresponds to a normalized laser power of p=0.14. As predicted by the previously proposed theory, the amount of depolarization ratio and its slope with respect to the laser power of the ceramic TGG was approximately the same as that previously reported for high-quality-cut <111> single crystal. PMID- 23938934 TI - Mechanical wave motion due to the radiation pressure on gain or absorptive rods. AB - The interaction of a light pulse with reflective and either a passive, lossy medium or an active medium with population inversion gives rise to elastic waves, already as a result of the change in the momentum carried by the incident light. We derived a 1D analytic displacement field that quantitatively predicts the shape and amplitude of such waves in semi-infinite and finite elastic rods in a half-space and infinite layer. The results are compatible with the conservation of momentum and energy of the light-matter system. They can be used as a signature for direct measurements of the radiation-pressure-induced elastic waves and to clarify the Abraham-Minkowski momentum dilemma. PMID- 23938935 TI - Detecting large copy number variants using exome genotyping arrays in a large Swedish schizophrenia sample. AB - Although copy number variants (CNVs) are important in genomic medicine, CNVs have not been systematically assessed for many complex traits. Several large rare CNVs increase risk for schizophrenia (SCZ) and autism and often demonstrate pleiotropic effects; however, their frequencies in the general population and other complex traits are unknown. Genotyping large numbers of samples is essential for progress. Large cohorts from many different diseases are being genotyped using exome-focused arrays designed to detect uncommon or rare protein altering sequence variation. Although these arrays were not designed for CNV detection, the hybridization intensity data generated in each experiment could, in principle, be used for gene-focused CNV analysis. Our goal was to evaluate the extent to which CNVs can be detected using data from one particular exome array (the Illumina Human Exome Bead Chip). We genotyped 9100 Swedish subjects (3962 cases with SCZ and 5138 controls) using both standard genome-wide association study (GWAS) and exome arrays. In comparison with CNVs detected using GWAS arrays, we observed high sensitivity and specificity for detecting genic CNVs ?400 kb including known pathogenic CNVs along with replicating the literature finding that cases with SCZ had greater enrichment for genic CNVs. Our data confirm the association of SCZ with 16p11.2 duplications and 22q11.2 deletions, and suggest a novel association with deletions at 11q12.2. Our results suggest the utility of exome-focused arrays in surveying large genic CNVs in very large samples; and thereby open the door for new opportunities such as conducting well powered CNV assessment and comparisons between different diseases. The use of a single platform also minimizes potential confounding factors that could impact accurate detection. PMID- 23938936 TI - Diffusion tensor image registration using polynomial expansion. AB - In this paper, we present a deformable registration framework for the diffusion tensor image (DTI) using polynomial expansion. The use of polynomial expansion in image registration has previously been shown to be beneficial due to fast convergence and high accuracy. However, earlier work was developed only for 3D scalar medical image registration. In this work, it is shown how polynomial expansion can be applied to DTI registration. A new measurement is proposed for DTI registration evaluation, which seems to be robust and sensitive in evaluating the result of DTI registration. We present the algorithms for DTI registration using polynomial expansion by the fractional anisotropy image, and an explicit tensor reorientation strategy is inherent to the registration process. Analytic transforms with high accuracy are derived from polynomial expansion and used for transforming the tensor's orientation. Three measurements for DTI registration evaluation are presented and compared in experimental results. The experiments for algorithm validation are designed from simple affine deformation to nonlinear deformation cases, and the algorithms using polynomial expansion give a good performance in both cases. Inter-subject DTI registration results are presented showing the utility of the proposed method. PMID- 23938937 TI - Oxygen vacancy induced band gap narrowing of ZnO nanostructures by an electrochemically active biofilm. AB - Band gap narrowing is important and advantageous for potential visible light photocatalytic applications involving metal oxide nanostructures. This paper reports a simple biogenic approach for the promotion of oxygen vacancies in pure zinc oxide (p-ZnO) nanostructures using an electrochemically active biofilm (EAB), which is different from traditional techniques for narrowing the band gap of nanomaterials. The novel protocol improved the visible photocatalytic activity of modified ZnO (m-ZnO) nanostructures through the promotion of oxygen vacancies, which resulted in band gap narrowing of the ZnO nanostructure (Eg = 3.05 eV) without dopants. X-ray diffraction, UV-visible diffuse reflectance spectroscopy, X-ray photoelectron spectroscopy, electron paramagnetic resonance spectroscopy, Raman spectroscopy, photoluminescence spectroscopy and high resolution transmission electron microscopy confirmed the oxygen vacancy and band gap narrowing of m-ZnO. m-ZnO enhanced the visible light catalytic activity for the degradation of different classes of dyes and 4-nitrophenol compared to p-ZnO, which confirmed the band gap narrowing because of oxygen defects. This study shed light on the modification of metal oxide nanostructures by EAB with a controlled band structure. PMID- 23938938 TI - HIV cure research: expanding the ethical considerations. PMID- 23938941 TI - Prostate cancer: MRI/US-guided biopsy--a viable alternative to TRUS-guidance. PMID- 23938942 TI - Kidney cancer: Rarity of hybrid tumours supports use of renal biopsy. PMID- 23938943 TI - Male factor infertility: Standardized diagram improves testicular cell identification. PMID- 23938945 TI - Prostate cancer: Prostate Health Index--improving screening in men with family history. PMID- 23938948 TI - In human retinoblastoma Y79 cells okadaic acid-parthenolide co-treatment induces synergistic apoptotic effects, with PTEN as a key player. AB - Retinoblastoma is the most common intraocular malignancy of childhood. In developing countries, treatment is limited, long-term survival rates are low and current chemotherapy causes significant morbidity to pediatric patients and significantly limits dosing. Therefore there is an urgent need to identify new therapeutic strategies to improve the clinical outcome of patients with retinoblastoma. Here, we investigated the effects of two natural compounds okadaic acid (OKA) and parthenolide (PN) on human retinoblastoma Y79 cells. For the first time we showed that OKA/PN combination at subtoxic doses induces potent synergistic apoptotic effects accompanied by lowering in p-Akt levels, increasing in the stabilized forms of p53 and potent decrease in pS166-Mdm2. We also showed the key involvement of PTEN which, after OKA/PN treatment, potently increased before p53, thus suggesting that p53 activation was under PTEN action. Moreover, after PTEN-knockdown p-Akt/ pS166Mdm2 increased over basal levels and p53 significantly lowered, while OKA/PN treatment failed both to lower p-Akt and pS166-Mdm2 and to increase p53 below/over their basal levels respectively. OKA/PN treatment potently increased ROS levels whereas decreased those of GSH. Reducing cellular GSH by l-butathionine-[S,R]-sulfoximine treatment significantly anticipated the cytotoxic effect exerted by OKA/PN. Furthermore, the effects of OKA/PN treatment on both GSH content and cell viability were less pronounced in PTEN silenced cells than in control cells. The results provide strong suggestion for combining a treatment approach that targets the PTEN/Akt/Mdm2/p53 pathway. PMID- 23938946 TI - Caveola-forming proteins caveolin-1 and PTRF in prostate cancer. AB - The expression of caveola-forming proteins is dysregulated in prostate cancer. Caveolae are flask-shaped invaginations of the plasma membrane that have roles in membrane trafficking and cell signalling. Members of two families of proteins- caveolins and cavins--are known to be required for the formation and functions of caveolae. Caveolin-1, the major structural protein of caveolae, is overexpresssed in prostate cancer and has been demonstrated to be involved in prostate cancer angiogenesis, growth and metastasis. Polymerase I and transcript release factor (PTRF) is the only cavin family member necessary for caveola formation. When exogenously expressed in prostate cancer cells, PTRF reduces aggressive potential, probably via both caveola-mediated and caveola-independent mechanisms. In addition, stromal PTRF expression decreases with progression of the disease. Evaluation of caveolin-1 antibodies in the clinical setting is underway and it is hoped that future studies will reveal the mechanisms of PTRF action, allowing its targeting for therapeutic purposes. PMID- 23938950 TI - Use of slow glucose feeding as supporting carbon source in lactose autoinduction medium improves the robustness of protein expression at different aeration conditions. AB - Recombinant protein expression from lac derived promoters by the autoinduction regime is based on diauxic growth of Escherichia coli on glucose and lactose. Glycerol is used as a supporting carbon source during the lactose-induced expression. While this glycerol-based formulation usually provides high cell densities, successful protein expression by autoinduction is often very dependent on correct aeration level. This complicates the reproducibility and scalability of the cultures. In this study we investigate the use of an alternative autoinduction formulation, in which the supporting carbon source is provided by fed-batch-like slow glucose feed from a biocatalytically degraded polysaccharide. The glucose feed as supporting carbon source allowed for high level of autoinduced target protein expression from T7lac promoter in E. coli BL21(DE3) and from T5lac promoter in E. coli K-12 RB791(lacI(q)) with lactose concentrations of 0.5-2gl(-1). Cell densities and protein yields per culture volume were similar to or higher than in the glycerol-based ZYM-5052 medium. In the glycerol-based medium, protein production was adversely influenced by high aeration level, resulting in 75-90% reduction in protein yield per cell compared to more moderately aerated conditions. The glucose fed-batch medium attenuated this oxygen-sensitivity and provided robust high-yield expression also under high aeration rates. It is concluded that the slow glucose feed as supporting carbon source mitigates aeration-related scale differences in autoinduced protein expression, and combined with the benefit of high product yields this makes the fed-batch autoinduction medium ideal for high-throughput screening and scale-up of the production process. PMID- 23938949 TI - Downregulation of HOPX controls metastatic behavior in sarcoma cells and identifies genes associated with metastasis. AB - Comparing the gene expression profiles of metastatic and nonmetastatic cells has the power to reveal candidate metastasis-associated genes, whose involvement in metastasis can be experimentally tested. In this study, differentially expressed genes were explored in the v-src-transformed metastatic cell line PR9692 and its nonmetastatic subclone PR9692-E9. First, the contribution of homeodomain only protein X (HOPX) in metastasis formation and development was assessed. HOPX specific knockdown decreased HOPX expression in the nonmetastatic subclone and displayed reduced cell motility in vitro. Critically, HOPX knockdown decreased the in vivo metastatic capacity in a syngeneic animal model system. Genomic analyses identified a cadre of genes affected by HOPX knockdown that intersected significantly with genes previously found to be differentially expressed in metastatic versus nonmetastatic cells. Furthermore, 232 genes were found in both screens with at least a two-fold change in gene expression, and a number of high confidence targets were validated for differential expression. Importantly, significant changes were demonstrated in the protein expression level of three metastatic-associated genes (NCAM, FOXG1, and ITGA4), and knockdown of one of the identified HOPX-regulated metastatic genes, ITGA4, showed marked inhibition of cell motility and metastasis formation. These data demonstrate that HOPX is a metastasis-associated gene and that its knockdown decreases the metastatic activity of v-src-transformed cells through altered gene expression patterns. IMPLICATIONS: This study provides new mechanistic insight into a HOPX-regulated metastatic dissemination signature. PMID- 23938951 TI - Antioxidant generation and regeneration in lipid bilayers: the amazing case of lipophilic thiosulfinates and hydrophilic thiols. AB - We demonstrate that the garlic-derived chemopreventive agent allicin and the related anamu-derived petivericin are poor radical-trapping antioxidants in lipid bilayers, but that the in situ reaction of a lipophilic analog and a hydrophilic thiol yields an extremely potent radical-trapping antioxidant that can be recycled in the presence of excess thiol. PMID- 23938953 TI - The moderating role of negative urgency on the prospective association between dietary restraint and binge eating. AB - It is well documented that negative urgency, a personality trait characterized by a tendency to act impulsively in the face of negative emotions, and dietary restraint independently increase risk to binge eat; however, it is unclear how these factors interact to alter risk for such behavior. It may be that individuals high on negative urgency, who also engage in dietary restraint, are at a greater risk to binge eat than individuals low on negative urgency. Accordingly, we sought to investigate whether negative urgency moderated the prospective association between dietary restraint and binge eating frequency among a sample of college women. We hypothesized that women who engaged in dietary restraint would report higher binge eating frequencies across the first semester of college and that this effect would be strengthened among individuals higher on negative urgency. Results indicated that negative urgency moderated the prospective association between dietary restraint and binge eating frequency. This effect was found to be "protective but reactive," such that low levels of dietary restraint protected against binge eating frequency at low to moderate levels of negative urgency, but this buffering effect was lost at high levels of negative urgency where binge eating frequency was equal across all levels of dietary restraint. These findings demonstrate that negative urgency and dietary restraint interact to differentially alter risk for binge eating frequency, and individuals high on negative urgency are at the greatest risk to engage in more frequent binge eating regardless of level of dietary restraint. PMID- 23938952 TI - Identifying and characterising the different structural length scales in liquids and glasses: an experimental approach. AB - The structure of several network-forming liquids and glasses is considered, where a focus is placed on the detailed information that is made available by using the method of neutron diffraction with isotope substitution (NDIS). In the case of binary network glass-forming materials with the MX2 stoichiometry (e.g. GeO2, GeSe2, ZnCl2), two different length scales at distances greater than the nearest neighbour distance manifest themselves by peaks in the measured diffraction patterns. The network properties are influenced by a competition between the ordering on these "intermediate" and "extended" length scales, which can be manipulated by changing the chemical identity of the atomic constituents or by varying state parameters such as the temperature and pressure. The extended-range ordering, which describes the decay of the pair-correlation functions at large-r, can be represented by making a pole analysis of the Ornstein-Zernike equations, an approach that can also be used to describe the large-r behaviour of the pair correlation functions for liquid and amorphous metals where packing constraints are important. The first applications are then described of the NDIS method to measure the detailed structure of aerodynamically-levitated laser-heated droplets of "fragile" glass-forming liquid oxides (CaAl2O4 and CaSiO3) at high temperatures (~2000 K) and the structure of a "strong" network-forming glass (GeO2) under pressures ranging from ambient to ~8 GPa. The high-temperature experiments show structural changes on multiple length scales when the oxides are vitrified. The high-pressure experiment offers insight into the density-driven mechanisms of network collapse in GeO2 glass, and parallels are drawn with the high-pressure behaviour of silica glass. Finally, the hydrogen-bonded network of water is considered, where the first application of the method of oxygen NDIS is used to measure the structures of light versus heavy water and a difference of approximately equal to 0.5% is found between the O-D and O-H intra-molecular bond lengths. The experimental data are best matched by using path integral molecular dynamics simulations with a flexible anharmonic water model, and the results support a competing quantum effects model for water in which its structural and dynamical properties are governed by an offset between intra-molecular and inter molecular quantum contributions. PMID- 23938954 TI - Prediction of the binding affinity of compounds with diverse scaffolds by MP CAFEE. AB - Accurate methods to predict the binding affinities of compounds for target molecules are powerful tools in structure-based drug design (SBDD). A recently developed method called massively parallel computation of absolute binding free energy with a well-equilibrated system (MP-CAFEE) successfully predicted the binding affinities of compounds with relatively similar scaffolds. We investigate the applicability of MP-CAFEE for predicting the affinity of compounds having more diverse scaffolds for the target p38alpha, a mitogen-activated protein kinase. The calculated and experimental binding affinities correlate well, showing that MP-CAFEE can accurately rank the compounds with diverse scaffolds. We propose a method to determine the optimal number of sampling runs with respect to a predefined level of accuracy, which is established according to the stage in the SBDD process being considered. The optimal number of sampling runs for two key stages-lead identification and lead optimization-is estimated to be five and eight or more, respectively, in our model system using Cochrans sample size formula. PMID- 23938955 TI - Computer modeling of the dynamic properties of the cAMP-dependent protein kinase catalytic subunit. AB - The structural dynamics of the cAMP-dependent protein kinase catalytic subunit were modeled using molecular dynamics computational methods. It was shown that the structure of this protein as well as its complexes with ATP and peptide ligand PKI(5-24) consisted of a large number of rapidly inter-converting conformations which could be grouped into subsets proceeding from their similarity. This cluster analysis revealed that conformations which correspond to the "opened" and "closed" structures of the protein were already present in the free enzyme, and most surprisingly co-existed in enzyme-ATP and enzyme-PKI(5-24) complexes as well as in the ternary complex, which included both of these ligands. The results also demonstrated that the most mobile structure segments of the protein were located in the regions of substrate binding sites and that their dynamics were most significantly affected by the binding of the ATP and peptide ligand. PMID- 23938956 TI - A structure-activity relationship study of flavonoids as inhibitors of E. coli by membrane interaction effect. AB - Flavonoids exhibit a broad range of biological activities including antibacterial activity. However, the mechanism of their antibacterial activity has not been fully investigated. The antibacterial activity and membrane interaction of 11 flavonoids (including 2 polymethoxyflavones and 4 isoflavonoids) against Escherichia coli were examined in this study. The antibacterial capacity was determined as flavonoids>polymethoxyflavones>isoflavonoids. Using fluorescence, it was observed that the 5 flavonoids rigidified the liposomal membrane, while the polymethoxyflavones and isoflavonoids increased membrane fluidity. There was a significant positive correlation between antibacterial capacity and membrane rigidification effect of the flavonoids. A quantitative structure-activity relationship (QSAR) study demonstrated that the activity of the flavonoid compounds can be related to molecular hydrophobicity (CLogP) and charges on C atom at position3 (C3). The QSAR model could be used to predict the antibacterial activity of flavonoids which could lead to natural compounds having important use in food and medical industry. PMID- 23938957 TI - Magneto-optical spaser. AB - We present an electrodynamical model of a quantum plasmonic device--the magneto optical (MO) spaser. It is shown that a spherical gain nanoparticle coated with a metallic MO shell can operate as a spaser amplifying circularly polarized surface plasmons. The MO spaser may be used in design of an optical isolator in plasmonic transmission lines as well as in spaser spectrometry of chiral molecules. PMID- 23938958 TI - Out-of-plane nanomechanical tuning of double-coupled one-dimensional photonic crystal cavities. AB - We demonstrate tuning of double-coupled one-dimensional photonic crystal cavities by their out-of-plane nanomechanical deformations. The coupled cavities are pulled by the vertical electrostatic force generated by the potential difference between the device layer and the handle layer in a silicon-on-insulator chip, and the induced deformations are analyzed by the finite element method. Applied with a voltage of 12 V, the cavities obtain a redshift of 0.0405 nm (twice the linewidth) for their second-order odd resonance mode and a blueshift of 0.0635 nm (three times the linewidth) for their second-order even resonance mode, which are mainly attributed to out-of-plane relative displacement. Out-of-plane tuning of coupled cavities does not need actuators and corresponding circuits; thus the device is succinct and compact. This working principle can be potentially applied in chip-level optoelectronic devices, such as sensors, switches, routers, and tunable filters. PMID- 23938959 TI - Optical tuning of silicon photonic structures with nematic liquid crystal claddings. AB - An analysis of and experimental demonstration of active optical tuning of silicon strip waveguides with methyl red doped nematic liquid crystal claddings is presented. Under low-power irradiation by polarized light, the reorientation of the nematic, the resulting index change, and phase shift produce a tuning range of 5.6 nm for the microresonator resonances. PMID- 23938960 TI - Noniterative data inversion of phase retrieval by omega oscillating filtering for optical arbitrary waveform measurement. AB - We propose a noniterative data inversion process for the phase retrieval by omega oscillating filtering method that could measure both isolated attosecond pulses and periodic optical arbitrary waveform (OAW). The built-in phase modulation depth recovery not only prevents the need of independent calibration (a critical advantage in the extreme ultraviolet regime) but provides a self-consistency check for the data integrity. Our experiments successfully retrieved OAW with ~100% duty cycle in the near infrared regime. PMID- 23938961 TI - Lens-free endoscopy probe for optical coherence tomography. AB - We present an ultrathin fiber-optic endoscopy probe for optical coherence tomography (OCT), which is made of a series of fused optical fibers instead of the conventional scheme based on an objective lens. The large-core fiber with a core diameter of 20 MUm was utilized for the probe, while a single-mode fiber of core diameter 8.2 MUm mainly delivered the OCT light. Those fibers were spliced with a bridge fiber of an intermediate core size. The guided light was stepwise converted to a beam of a large mode-field diameter to be radiated with a larger depth of focus. We obtained a 125 MUm thick all-fiber endoscopy probe with a side viewing capability implemented by an angled fiber end. Successful OCT imaging was demonstrated with a swept-source OCT system and showed the practical applicability of our lens-free endoscopy probe. PMID- 23938962 TI - Raman effect in self-focusing of few-cycle laser pulses in air. AB - Self-focusing of ultrashort pulses in air is investigated by means of numerical simulations. The role of the vibrational Raman effect and its dependence on pulse chirp is studied, with results shedding new light on the interpretation of the measurements of the critical self-focusing power. We also discuss computational modeling issues important specifically for few-cycle pulses. PMID- 23938963 TI - Splitting of levels in a cylindrical dielectric waveguide. AB - A splitting of modes in a cylindrical graded-index optical fiber is demonstrated by solving the full Maxwell equations using the perturbation analysis. It is shown that the degeneracy of vortex Laguerre-Gauss modes with distinct orbital angular momentum and polarization (spin) but the same total angular momentum is lifted due to the spin-orbit (vector) and tensor forces. Numerical estimations of group delays of modes in optical fiber and frequency splitting in Fabry-Perot and ring resonators are presented. PMID- 23938964 TI - Elimination of honeycomb patterns in fiber bundle imaging by a superimposition method. AB - A superimposition method for alleviating the characteristic artifact structure of an imaging fiber bundle is demonstrated. This method can reduce the inherent honeycomb patterns of fiber bundle images and restore hidden information by using pixelated images captured from neighboring locations. The pixelation effect is suppressed when multiple adjacent images, with centers separated by one core radius and arranged in a square pattern, are superimposed for summation. The restored image has preserved edge sharpness in cellular and vascular structure boundaries, compared to the reference image without pixelation and identical imaging modality, as found by optical coherence tomography. PMID- 23938965 TI - Comb-calibrated frequency-modulated continuous-wave ladar for absolute distance measurements. AB - We demonstrate a comb-calibrated frequency-modulated continuous-wave laser detection and ranging (FMCW ladar) system for absolute distance measurements. The FMCW ladar uses a compact external cavity laser that is swept quasi-sinusoidally over 1 THz at a 1 kHz rate. The system simultaneously records the heterodyne FMCW ladar signal and the instantaneous laser frequency at sweep rates up to 3400 THz/s, as measured against a free-running frequency comb (femtosecond fiber laser). Demodulation of the ladar signal against the instantaneous laser frequency yields the range to the target with 1 ms update rates, bandwidth limited 130 MUm resolution and a ~100 nm accuracy that is directly linked to the counted repetition rate of the comb. The precision is <100 nm at the 1 ms update rate and reaches ~6 nm for a 100 ms average. PMID- 23938966 TI - Theory of modal attraction in bimodal birefringent optical fibers. AB - Nonlinear mode coupling among two beams of different wavelength that copropagate in a bimodal highly birefringent optical fiber may lead to the effect of modal attraction. Under such circumstances, the modal distribution of light at a pump wavelength is replicated at the signal wavelength, nearly irrespective of the input mode excitation conditions of the signal. PMID- 23938967 TI - One-dimensional Fibonacci grating for far-field super-resolution imaging. AB - One-dimensional Fibonacci gratings are used to transform evanescent waves into propagating waves for far-field super-resolution imaging. By detecting far-field intensity distributions of light through objects in front of the Fibonacci grating in free space, we can observe the objects with nearly lambda/9 spatial resolution. Analytical results are verified by numerical simulations. We also discuss the effect of sampling error on imaging resolution of the system. PMID- 23938968 TI - Method of achieving a wide field-of-view head-mounted display with small distortion. AB - We present a method of achieving a wide-angle, lightweight, optical see-through, distortion-free head-mounted display (HMD) by using two similar ellipsoids. An HMD that achieves a single channel field-of-view (FOV) of 120 degrees *120 degrees with a 6 mm eye box and a total binocular FOV of 160 degrees *120 degrees with an 80 degrees field overlap is designed as an example. This method can solve the complex tiling problem and the distortion problem of other catadioptric structures. This structure is used to offset distortion and correct aberrations. PMID- 23938969 TI - Resolution below the point spread function for diffuse optical imaging using fluorescence lifetime multiplexing. AB - We show that asymptotic lifetime-based fluorescence tomography can localize multiple-lifetime targets separated well below the diffuse point spread function of a turbid medium. This is made possible due to a complete diagonalization of the time domain forward problem in the asymptotic limit. We also show that continuous wave or direct time gate approaches to fluorescence tomography are unable to achieve this separation, indicating the unique advantage of a decay amplitude-based approach for tomographic lifetime multiplexing with time domain data. PMID- 23938970 TI - Low-noise, single-frequency, single-polarization Brillouin/erbium fiber laser. AB - We demonstrate a low-noise Brillouin/erbium fiber laser (BEFL), which uses only 1.5 m polarization-maintaining erbium-doped fiber as both the Brillouin and erbium gain media. This BEFL presents a phase noise of -125 dB/Hz(1/2) at 1 kHz frequency, at 2 mW Brillouin pump (~3 MHz linewidth) power and 200 mW 980 nm pump power. The polarization extinction ratio of the laser output light is 31 dB. Stable (~2 h) single-mode operation is observed. This BEFL presents potential applications in distributed Brillouin fiber sensors, inteferometric fiber sensors, and optical communications. PMID- 23938971 TI - Integral three-dimensional image capture equipment with closely positioned lens array and image sensor. AB - We have developed a compact integral three-dimensional (3D) imaging equipment that positions the lens array and image sensor in close proximity to each other. In the conventional scheme, a camera lens is used to project the elemental images generated by the lens array onto the image sensor. In contrast, the imaging equipment presented here combines the lens array and image sensor into one unit and makes no use of a camera lens. This scheme eliminates the resolution deterioration and distortion caused by the use of a camera lens and improves, in principle, the quality of the reconstructed 3D image. We captured objects with this imaging equipment and displayed the reconstructed 3D images using display equipment consisting of a liquid crystal panel and a lens array. The reconstructed 3D images were found to have appropriate motion parallax. PMID- 23938972 TI - Bulk optical absorption of high resistivity silicon at 1550 nm. AB - We report on the measurement of the optical absorption of bulk crystalline silicon at 1550 nm. Using the photodeflection technique, absorption as low as 5 ppm/cm has been measured on a sample with a resistivity of 10 kOmega.cm. The absorption as a function of the resistivity has been derived for n-type silicon. PMID- 23938973 TI - Coherent anti-Stokes Raman spectroscopy in the presence of strong resonant signal from background molecules. AB - Spectroscopy of molecular mixtures with broadband femtosecond laser pulses often involves simultaneous excitation of multiple molecular species with close resonance frequencies. Interpreting the collective optical response typically requires Fourier analysis of time-resolved signals. We propose and demonstrate an alternative method of separating coherent Raman scattering signals from two molecular components with neighboring vibrational modes. We exploit "silence windows," which arise from coupling of the vibrational and rotational degrees of freedom in molecular dynamics. In silence windows, the detected signal stems solely from the minority species (here, CO2), while the strong resonant background from the dominant species (O2) is greatly suppressed. PMID- 23938974 TI - Enhancement of terahertz radiation from GaP emitters by subwavelength antireflective micropyramid structures. AB - Subwavelength antireflective micropyramid structures, designed by rigorous coupled-wave analysis and fabricated by precision micromachining, are used to enhance the terahertz (THz) radiation output of optical rectification in GaP crystal-based emitters. An average 16% increase in the THz radiation power emitted by a 3 mm GaP crystal is experimentally demonstrated using an antireflective micropyramid grating with a period of 60 MUm and a base angle of 55.5 degrees . Optimized pyramidal-frustum gratings are shown to operate as highly efficient antireflective structures within an ultrabroadband range of 0.5 5 THz. PMID- 23938975 TI - PQ:DMNA/PMMA photopolymer having amazing volume holographic recording at wavelength of insignificant absorption. AB - N, N-dimethyl-4-nitroaniline doping enables red-light holographic recording that was originally insensitive in thick phenanthrenequinone/poly(methyl methacrylate) photopolymer to have reasonable sensitivity. A volume hologram was recorded by a 647 nm laser with maximum diffraction efficiency of about 43% in a 2-mm-thick sample. A Bragg selectivity curve and an image hologram reconstruction are also demonstrated. These experimental results support recording material for volume holographic applications in an extended red spectral range. PMID- 23938976 TI - Optical coupling of an active microdisk to a passive one: effect on the lasing thresholds of the whispering-gallery supermodes. AB - The lasing spectra and thresholds of a selectively pumped photonic molecule composed of two microdisks is investigated using effective index approximation and full-wave 2-D electromagnetic equations. The lasing eigenvalue problem formulation is used to find modal frequencies and threshold values of material gain. The influence of the optical coupling between active and passive microdisks on the lasing eigenvalues and directionalities of emission is studied. It is shown that for strong coupling the effect of making one of the resonators passive leads to the doubling of the threshold. PMID- 23938977 TI - Optical feedback stabilized laser tuned by single-sideband modulation. AB - We report a subkilohertz-linewidth distributed-feedback diode laser that is optical-feedback locked to a highly stable V-shaped cavity with drift rates below 20 Hz/s. This source is continuously tunable over 1 THz around 1590 nm by selecting a cavity mode and using an innovative single-sideband modulation scheme, which allows for frequency shifting over up to 40 GHz with millihertz accuracy. This robust setup achieves high performance without advanced vibration isolation and will be a powerful tool for metrological applications, in particular a redetermination of the Boltzmann constant by molecular spectroscopy. PMID- 23938978 TI - On the physical realizability of highly focused electromagnetic field distributions. AB - A method to evaluate the physical realizability of an arbitrary three-dimensional vectorial field distribution in the focal area is proposed. A parameter that measures the similarity between the designed (target) field and the physically achievable beam is provided. This analysis is carried out within the framework of the closest electromagnetic field to a given vectorial function, and the procedure is applied to two illustrative cases. PMID- 23938979 TI - Scattering imaging method in transmission x-ray microscopy. AB - We present a x-ray microscopy technique based on structured illumination in a microscope that characterizes the size of the subresolution-limit features. The technique is effective for characterizing fine structures substantially beyond the Rayleigh resolution of the microscope. We carried out optical experiments to demonstrate the basic principle of this new technique. Experimental results show good agreement with theoretical predictions. This technique should find a wide range of important imaging applications with a feature size down to nanometer scale, such as oil and gas reservoir rocks, advanced composites, and functional nanodevices and materials. PMID- 23938980 TI - Soliton self-routing in a finite photonic potential. AB - We investigate power-dependent routing of one-dimensional Kerr-like spatial solitons in the presence of a finite photonic potential. Large self-deflections can be obtained using a trapping index well of limited length. PMID- 23938981 TI - Odd-symmetry phase gratings produce optical nulls uniquely insensitive to wavelength and depth. AB - This Letter presents the analysis of a new class of diffractive optical element, the odd-symmetry phase grating, which creates wavelength- and depth-robust features in its near-field diffraction pattern. PMID- 23938982 TI - High-power asynchronous midinfrared optical parametric oscillator frequency combs. AB - We introduce a new stabilization scheme providing a pair of high-power, carrier envelope-offset (CEO) frequency-stabilized, broadband, asynchronous frequency combs operating at 3.3 MUm. The two channels, each with 100 mW average power and originating from a single synchronously pumped optical parametric oscillator, share all the components for midinfrared generation and CEO-frequency detection, and can be stabilized independently at repetition frequencies up to 5 kHz apart. This unique source is fully compatible with midinfrared dual-comb spectroscopy, and the approach can be readily extended to other wavelengths. PMID- 23938983 TI - Zn(x)Cd(1-x)S quantum dots-based white light-emitting diodes. AB - In this study, two kinds of colloidal ternary semiconductor white light-emitting quantum dots (WQDs), Zn(0.5)Cd(0.5)S and Zn(0.8)Cd(0.2)S, are prepared and used as nanophosphors in a UV light-emitting diode (UV-LED) pumping device. When the weight ratio of Zn(0.5)Cd(0.5)S WQDs is 9.1 wt. % in silicone and the drive current is set at 20 mA, the chromaticity coordinates (CIE), correlated color temperature (CCT), color rendering index (CRI), and luminous efficiency are (0.43,0.37), 2830 K, 90, and 0.94 lm/W, respectively. On the other hand, under the same weight ratio in silicone, the CIE, CCT, CRI, and luminous efficiency of Zn(0.8)Cd(0.2)S WQDs are (0.36,0.33), 4240 K, 86, and 4.12 lm/W, respectively. Based on the above results, we can conclude that WQDs-based LED can be obtained by controlling the compositions of Zn(x)Cd(1-x)S QDs due to the coexistence of band-edge and surface state emission. PMID- 23938984 TI - Backward optical parametric efficiency in quasi-phase-matched GaN waveguide presenting stitching faults. AB - We model a backward mirrorless optical parametric oscillator in a fragmented GaN waveguide consisting of a sequence of submicronic periodically poled elements separated by uniformly polarized connection sections representing stitching errors. We find that the generated coherent phase of the backscattered wave locks the phases of the forward propagating waves in such a way that the dynamics is nonintuitivelly as efficient as for a uniform quasi-phase-matched waveguide. The best coherence transfer to the backward wave, obtained for perfect group-velocity matching of the forward propagating waves, requires a nanoscale poled periodicity, which is achieved in GaN through epitaxy. PMID- 23938985 TI - Characterizing weld pool surfaces from polarization state of thermal emissions. AB - In this Letter, a vision-based remote sensing methodology is proposed to measure the topography of weld pool surfaces from one single view. Thermal radiations emitted by the hot liquid metal at a wavelength within the arc plasma blind spectral window are acquired by a wavefront division polarimetric system. The refractive index of the liquid metal and the topography of the weld pool surface are inferred from the polarimetric state of the thermal radiations. PMID- 23938986 TI - Efficient second harmonic generation from mid-infrared to near-infrared regions in silicon-organic hybrid plasmonic waveguides with small fabrication-error sensitivity and a large bandwidth. AB - We theoretically investigate the quadratic nonlinear property of a silicon organic hybrid plasmonic waveguide with a thin polymer layer deposited on top of a silicon slab and covered by a metal cap. Due to the hybridization property of the waveguide modes, efficient phase-matched second harmonic generation (SHG) from mid-infrared (IR) (~3.1 MUm) to near-IR (~1.55 MUm) wavelengths are achieved with a small fabrication-error sensitivity (225 nm <= tolerated waveguide width <= 378 nm) and a large bandwidth (Deltalambda=100 nm). The SHG yield is as large as 8.8% for a pumping power of 100 mW. PMID- 23938987 TI - Tunneling of electromagnetic energy in multiple connected leads using epsilon near-zero materials. AB - A realization of a reflectionless power splitter is proposed by use of a metamaterial junction. To design the junction, the electromagnetic wave transmission in multiple connected leads is investigated theoretically and numerically. A closed analytical form is derived for the scattering matrix of any geometry of the interconnected leads. We show that the use of a junction made of epsilon-near-zero (ENZ) material allows production of perfect transmission. This can be achieved by reducing the area of the ENZ junction (squeezing effect) and by tuning the widths of the output leads with respect to the input lead. It is also shown that the same effect is obtained without squeezed junction by using a match impedance zero index material (MIZIM junction). PMID- 23938988 TI - Fast method for inverse determination of optical parameters from two measured signals. AB - Solving inverse problems requires multiple forward calculations of measured signals. We present a fast method combining graphic processing unit-accelerated Monte Carlo simulations of individual photons and a new perturbation scheme for a 300-fold speedup in comparison to conventional CPU-based approaches. The method allows rapid calculations of the diffuse reflectance and transmittance signals from a turbid sample of absorption coefficient MU(a), scattering coefficient MU(s), and anisotropy factor g based on the principle of correlated sampling. To demonstrate its strong utility, we have applied the method for determining the optical parameters of diluted intralipid samples with satisfactory results. PMID- 23938989 TI - Evaluation of a fast single-photon avalanche photodiode for measurement of early transmitted photons through diffusive media. AB - We tested the performance of a fast single-photon avalanche photodiode (SPAD) in measurement of early transmitted photons through diffusive media. In combination with a femtosecond titanium:sapphire laser, the overall instrument temporal response time was 59 ps. Using two experimental models, we showed that the SPAD allowed measurement of photon-density sensitivity functions that were approximately 65% narrower than the ungated continuous wave case at very early times. This exceeds the performance that we have previously achieved with photomultiplier-tube-based systems and approaches the theoretical maximum predicted by time-resolved Monte Carlo simulations. PMID- 23938990 TI - Shell thickness dependence of upconversion luminescence of beta-NaYF4:Yb, Er/beta NaYF4 core-shell nanocrystals. AB - NaYF4:Yb, Er/NaYF4 core-shell nanocrystals with different thickness shells were synthesized. The correlation between shell thickness and upconversion (UC) luminescence intensity was investigated experimentally and theoretically. We found that the UC fluorescence intensity of the core-shell nanocrystals is enhanced exponentially with shell thickness (d) in the form of (1-0.9 exp(-d/d0). For our core-shell nanocrystals, the d0 was determined as about 5.5 nm, corresponding to an enhancement of about 12 times for the 540 nm emission intensity. The d0 may be treated as the optimized shell thickness, which represents a balance between the conflict requirements of strong UC fluorescence intensity and small total crystal size for bioapplications. PMID- 23938991 TI - Flexible terahertz metamaterials for dual-axis strain sensing. AB - Utilizing an elastic polymer, we design and experimentally demonstrate a four fold symmetric flexible metamaterial operating at terahertz frequencies. The fabricated metamaterials exhibit good stretchability and recoverability. Two independent resonances can be observed when the structure is probed with linearly polarized terahertz waves in two orthogonal axes. Applying a stretching force along a main axis causes an observable frequency shift in the corresponding resonance, with minimal effect on the other. This study suggests a possible application of flexible metamaterials for dual-axis strain sensing. PMID- 23938992 TI - Diffractive digital lensless holographic microscopy with fine spectral tuning. AB - We experimentally demonstrate an all-diffractive optical setup for digital lensless holographic microscopy with easy wavelength line selection and micrometric resolution. In the proposed system, an ultrashort laser pulse is focused with a diffractive lens (DL) onto a pinhole of diameter close to its central wavelength to achieve a highly spatially coherent illumination cone as well as a spectral line with narrow width. To scan the complete spectrum of the light source the DL is displaced with respect to the pinhole plane. The proposed microscopy setup allows us to spectrally separate contributions from different sections of a sample, which may be attractive for several applications in life sciences. PMID- 23938993 TI - Quantum phase flip gate based on plasmonic double-bar resonators. AB - We demonstrate a quantum phase flip gate between two QDs that resonantly couple to plasmonic double-bar resonators with asymmetric coupling strengths. Large coupling strengths can be achieved due to the deep subwavelength mode volumes of the optical modes in plasmonic double-bar resonators. High fidelity (~98%) and high success probability of the phase gate operation have been obtained when the coupling strength ratio (g2/g1) and resonant mode decay rate (kappa/g1) are optimized. The subwavelength-scale plasmonic structures provide tremendous potential for solid-state quantum information processing. PMID- 23938994 TI - MgZnO p-n heterostructure light-emitting devices. AB - MgZnO heterostructure light-emitting devices (LEDs) have been fabricated from p Mg(0.35)Zn(0.65)O/n-Mg(0.20)Zn(0.80)O structures, and the p-type Mg(0.35)Zn(0.65)O film was realized using a lithium-nitrogen codoping method. Obvious ultraviolet emission peaked at around 355 nm dominates the electroluminescence (EL) spectra of the device at room temperature, which comes from the near-band-edge emission of the n-type Mg(0.20)Zn(0.80)O film. This is the first report on MgZnO heterostructured LEDs and the shortest EL emission ever reported in ZnO-based p-n junction LEDs to the best of our knowledge. PMID- 23938995 TI - Closed-form path loss model of non-line-of-sight ultraviolet single-scatter propagation. AB - Non-line-of-sight ultraviolet propagation models have been developed for both coplanar and noncoplanar geometries. Based on an exact integral-form single scatter model, this Letter proposes an approximate closed-form model for tractable analysis applicable to noncoplanar geometries with a narrow transmitter beam or receiver field of view. Numerical results on path loss are presented for various system geometries. These results are verified with the integral-form model and a previous approximate model, showing our model agrees well with the former and outperforms the latter. PMID- 23938996 TI - Quantum frequency conversion in nonlinear microcavities. AB - We study nonlinear microresonantors as potential implements for quantum frequency conversion of narrowband optical signals. Using silicon-nitride microdisks as a concrete example, we show that high-conversion performance can be achieved with relatively low pump power. Being chip integratable, such devices hold promise for use in large-scale quantum applications, including atomic-memory-based quantum repeaters. PMID- 23938997 TI - Two-color rubidium fiber frequency standard. AB - We demonstrate an optical frequency standard based on rubidium vapor loaded within a hollow-core photonic crystal fiber. We use the 5S(1/2)->5D(5/2) two photon transition, excited with two lasers at 780 and 776 nm. The sum-frequency of these lasers is stabilized to this transition using modulation transfer spectroscopy, demonstrating a fractional frequency stability of 9.8*10(-12) at 1 s. The current performance limitations are presented, along with a path to improving the performance by an order of magnitude. This technique will deliver a compact, robust standard with potential applications in commercial and industrial environments. PMID- 23938998 TI - Doubling transmission capacity in optical wireless system by antenna horizontal- and vertical-polarization multiplexing. AB - We experimentally demonstrate 2*56 Gb/s two-channel polarization-division multiplexing quadrature-phase-shift-keying signal delivery over 80 km single-mode fiber-28 and 2 m Q-band (33-50 GHz) wireless link, adopting antenna horizontal- (H-) and vertical-polarization (V-polarization) multiplexing. At the wireless receiver, classic constant-modulus-algorithm equalization based on digital signal processing can realize polarization demultiplexing and remove the crosstalk at the same antenna polarization. By adopting antenna polarization multiplexing, the signal baud rate and performance requirements for optical and wireless devices can be reduced but at the cost of double antennas and devices, while wireless transmission capacity can also be increased but at the cost of stricter requirements for V-polarization. The isolation is only about 19 dB when V polarization deviation approaches 10 degrees , which will affect high-speed (>50 Gb/s) wireless delivery. PMID- 23938999 TI - Modal characterization of fiber-to-fiber coupling processes. AB - We present a detailed experimental investigation of a fiber-to-fiber coupling process by characterizing the mode content at the output of the system. In our experiment a single-mode fiber is transversally scanned with respect to a multimode fiber, revealing position-dependent higher-order mode excitation. The outlined measurement system can be used for automated optimization of fundamental mode content and beam quality. Additionally, our approach characterizes the modal transmission properties of the multimode waveguide in its present state and is hence of high relevance for the conception of transport fibers and fiber laser systems. PMID- 23939000 TI - Full C-band tunable laser based on electroholography. AB - A tunable laser that spans the entire C band is presented. The laser consists of an Er-doped fiber amplifier gain medium, a fiber ring resonator, and an electroholography-based tuning mechanism. The electrohologram used is in the g44 configuration where the Bragg condition can be electrically tuned for a specific wavelength. Two laser architectures are presented, one in which the diffracting beam and one in which the direct beam of the electrohologram is used as the laser output. Switching time between wavelengths is limited by the gain medium relaxation time, since the electrohologram switching time is less than 1 ns. PMID- 23939001 TI - Optical bistability in a high-Q racetrack resonator based on small SU-8 ridge waveguides. AB - A racetrack resonator with a high Q value (~34,000) is demonstrated experimentally based on small SU-8 optical ridge waveguides, which were fabricated with an improved etchless process. Optical bistability is observed in the present racetrack resonator even with a low input optical power (5.6-7.3 mW), which is attributed to the significant thermal nonlinear optical effect due to the high Q value and the large negative thermo-optical coefficient of SU-8. Theoretical modeling for the optical bistability is also given, and it agrees well with the experimental result. PMID- 23939002 TI - Microwave synthesis from a continuous-wave terahertz oscillator using a photocarrier terahertz frequency comb. AB - We report low-noise microwave synthesis from radiation with a frequency of 0.3 THz using a photocarrier frequency comb in a photoconductive antenna. The synthesized microwave signal at 1 GHz is phase coherent to the 0.3 THz radiation and has a fractional instability of 1*10(-15) within 300 s averaging times and single-sideband phase noise of -105 dB/Hz at a 100 Hz offset from the carrier. This terahertz (THz)-to-microwave synthesizer is capable of being a THz frequency divider, which would be indispensable to not only THz metrology but also future high-speed wireless networks. PMID- 23939003 TI - Pulse-to-pulse alignment technique based on synthetic-wavelength interferometry of optical frequency combs for distance measurement. AB - A synthetic-wavelength interferometry of optical frequency combs is proposed for the pulse-to-pulse alignment in absolute distance measurement. The synthetic wavelength derived from the virtual second harmonic and the real second harmonic is used to bridge the interference intensity peak-finding method and the heterodyne interferometric phase measurement, so that the pulse-to-pulse alignment can be linked directly to single-wavelength heterodyne interferometry. The experimental results demonstrate that the distance measured by the peak finding method with micrometer accuracy can be improved to the nanometer level by applying the method proposed. PMID- 23939004 TI - High-speed secure key distribution over an optical network based on computational correlation imaging. AB - We present a protocol for an optical key distribution network based on computational correlation imaging, which can simultaneously realize privacy amplification and multiparty distribution. With current technology, the key distribution rate could reach hundreds of Mbit/s with suitable choice of parameters. The setup is simple and inexpensive, and may be employed in real networks where high-speed long-distance secure communication is required. PMID- 23939005 TI - Parametric four-wave mixing using a single cw laser. AB - Four-wave mixing can be used to generate coherent output beams, with frequencies difficult to acquire in commercial lasers. Here, a single narrow external cavity diode laser locked to the two photon 5s-5d transition in rubidium is combined with a tapered amplifier system to produce a high power cw beam at 778 nm and used to generate coherent light at 420 nm through parametric four-wave mixing. This process is analyzed in terms of the intensity and frequency of the incoming beam as well as the atomic density of the sample. The efficiency of the process is currently limited when on resonance due to the absorption of the 420 nm beam, and modifications should allow a significant increase in output power. PMID- 23939006 TI - 2.79 MUm high peak power LGS electro-optically Q-switched Cr,Er:YSGG laser. AB - A flash lamp pumped Cr,Er:YSGG laser utilizing a langasite (LGS) crystal as an electro-optic Q-switch is proposed and demonstrated. It is proved that a LGS crystal with relatively high damage threshold can be used as the electro-optic Q switch at 2.79 MUm, and 216 mJ pulse energy with 14.36 ns pulse width is achieved. Its corresponding peak power of pulse can reach 15 MW, to our knowledge the best result at a 2.79 MUm wavelength. PMID- 23939007 TI - Highly tunable self-assembled plasmonic lattices through nanosphere lithography. AB - This Letter reports a method to produce two-dimensional self-assembled plasmonic nanopillar (NP) arrays with independent control of the diameter (d), spacing (s), and height (h) of the NPs. A plasmonic lattice was designed and optimized for maximum plasmonic activity at 980 nm using three-dimensional finite-difference time-domain simulations. The optimized lattice with d=365 nm, s=410 nm, and h=70 nm was fabricated utilizing a self-assembled nanosphere lithography approach. Outstanding agreement between the observed and predicted results confirms the validity of the design process and the controllability and repeatability of the fabrication process. The excellent short-range order in the lattice structure suggests that this method can replace the electron-beam lithography approach in a scalable and cost-effective manner. PMID- 23939008 TI - In-plane focusing of terahertz surface waves on a gradient index metamaterial film. AB - We designed and implemented a gradient index metasurface for in-plane focusing of confined terahertz (THz) surface waves. We measured the spatial propagation of the surface waves by two-dimensional mapping of the complex electric field using a THz near-field spectroscope. The surface waves were focused to a diameter of 500 MUm after a focal length of approximately 2 mm. In the focus, we measured a field amplitude enhancement of a factor of 3. PMID- 23939010 TI - Pathogen profile in men with inflammation of paraurethral glands. AB - OBJECTIVE: To investigate the pathogen profile in men with inflammation of the paraurethral glands. METHODS: We enrolled 40 patients with first-onset, drug naive inflammation of the paraurethral glands. Discharge from the lesions was collected for Gram staining. Microscopy was performed for screening for trichomonads and detecting Gram-negative intracellular diplococci within phagocytes. Cultures for detection of Neisseria gonorrhoeae, Ureaplasma urealyticum and other bacteria, and Chlamydia-trachomatis-associated antigens were performed. PCR was conducted for herpes simplex virus type 1 or 2. RESULTS: From these 40 patients, there were nine microbial species, which included Gram negative bacteria (23 cases, 54.8%), Gram-positive bacteria (15 cases, 35.7%) and other pathogens (4 cases, 9.5%). The top three pathogens were gonococci (38.1%), Staphylococcus aureus (16.7%) and Escherichia coli (14.3%). CONCLUSIONS: Inflammation of paraurethral glands in men may be caused by a variety of pathogens and not just by gonococcal infection. PMID- 23939011 TI - Experimental verification of dose calculation using the simplified Monte Carlo method with an improved initial beam model for a beam-wobbling system. AB - A beam delivery system using a single-radius-beam-wobbling method has been used to form a conformal irradiation field for proton radiotherapy in Japan. A proton beam broadened by the beam-wobbling system provides a non-Gaussian distribution of projection angle different in two mutually orthogonal planes with a common beam central axis, at a certain position. However, the conventional initial beam model for dose calculations has been using an approximation of symmetric Gaussian angular distribution with the same variance in both planes (called here a Gaussian model with symmetric variance (GMSV)), instead of the accurate one. We have developed a more accurate initial beam model defined as a non-Gaussian model with asymmetric variance (NonGMAV), and applied it to dose calculations using the simplified Monte Carlo (SMC) method. The initial beam model takes into account the different distances of two beam-wobbling magnets from the iso-center and also the different amplitudes of kick angle given by each magnet. We have confirmed that the calculation using the SMC with NonGMAV reproduced the measured dose distribution formed in air by a mono-energetic proton beam passing through a square aperture collimator better than with the GMSV and with a Gaussian model with asymmetric variance (GMAV) in which different variances of angular distributions are used in the two mutually orthogonal planes. Measured dose distributions in a homogeneous phantom formed by a modulated proton beam passing through a range shifter and an L-shaped range compensator, were consistent with calculations using the SMC with GMAV and NonGMAV, but in disagreement with calculations using the SMC with GMSV. Measured lateral penumbrae in a lateral direction were reproduced better by calculations using the SMC with NonGMAV than by those with GMAV, when an aperture collimator with a smaller opening was used. We found that such a difference can be attributed to the non-Gaussian angular distribution of the initial beam at a lateral position for the beam-wobbling system. Calculations using the SMC with NonGMAV are effective to reproduce dose distributions formed by a beam-wobbling system more accurately than that with GMSV or that with GMAV. PMID- 23939012 TI - An unusual 1,2-aryl shift in palladium-catalyzed cross-coupling ethoxycarbonylation of arylboronic acids with alpha-iminoesters. AB - The Pd-catalyzed cross-coupling ethoxycarbonylation of aryl boronic acids with N aryl-alpha-iminoesters affords aryl carboxylic esters via carbonyl-imino sigma bond cleavage. This unprecedented mode of reaction allows regioselective installation of the ethoxycarbonyl group into target molecules. Mechanism studies have revealed that an unusual 1,2-aryl shift process is involved in the transformation. PMID- 23939013 TI - Using science to shape Medicare physician payment. PMID- 23939014 TI - Suppression of radiation-induced DNA double-strand break repair by MyD88 is accompanied by apoptosis and crypt loss in mouse colon. AB - Intestinal microbes promote the injurious effects of radiation on those tissues. However, the molecular factors mediating this effect are largely unknown. In this work, we explored the effects of orally administered antibiotics and MyD88, a key adapter molecule in toll-like receptor signaling, on molecular and cellular responses of mouse colon to radiation. Results show that oral antibiotics lowered radiation-induced colonic damage by protecting epithelial cells against radiation induced apoptosis, leading to increased survival of crypts. MyD88 deficiency partially phenocopied the effects of oral antibiotics on apoptosis and crypt survival, suggesting that colonic microbes exert their injurious effects in part via that molecule. Analysis of DNA double-strand breaks, the primary genotoxic lesions induced by radiation, showed that their early induction in mouse colon was unaffected by MyD88. However, MyD88 deficiency resulted in the later disappearance of DNA double-strand breaks. Loss of DNA double-strand breaks was accompanied by the evidence of increased activation of both the non-homologous end-joining and homologous recombination pathways of DNA repair in MyD88 deficient mice. These results show that colonic microbes and MyD88 regulate DNA double-strand break repair in irradiated mouse colon, effects which exert significant control over radiation-induced apoptosis and crypt survival. PMID- 23939015 TI - Mitophagy and neurodegeneration: the zebrafish model system. AB - Autophagy is responsible for the degradation of cytoplasmic components and organelles such as mitochondria. The selective degradation of damaged mitochondria by autophagy is termed mitophagy, and is an important quality control mechanism. Neurons, being highly specialized cells, are particularly susceptible to defects of autophagy. Impairments in mitochondrial function and their dynamics are present in many neurodegenerative diseases, and modulators of both mitochondrial physiology and autophagy present themselves as promising therapeutic targets. Zebrafish are now established as a valuable tool for disease modeling. A wide variety of genetic and molecular techniques can be employed to highlight pathogenic processes and dissect disease pathways. This review will explore the role that zebrafish have so far played in our understanding of mitophagy in neurodegeneration, and will discuss how they might be used to drive the wider mitophagy field forward. PMID- 23939016 TI - Images in vascular medicine. Endovascular repair of a post-traumatic right common carotid artery pseudoaneurysm. PMID- 23939017 TI - Images in vascular medicine. A challenging case of renovascular hypertension. PMID- 23939018 TI - Images in vascular medicine. Internal jugular vein phlebectasia. PMID- 23939019 TI - 3,4-ethylenedioxythiophene as an electron donor to construct arylamine sensitizers for highly efficient iodine-free dye-sensitized solar cells. AB - The development of arylamine photosensitizers with high extinction coefficients, and suitable electronic structures and steric properties is necessary for improving the efficiency of dye-sensitized solar cells (DSCs) employing iodine free redox shuttles. A new truxene-based organic sensitizer, M20, incorporating a 3,4-ethylenedioxythiophene (EDOT) moiety as an electron donor was synthesized and compared to its reference sensitizer, M4. M20 sensitized DSCs employing the Co(II/III) tris(1,10-phenanthroline)-based redox electrolyte exhibit a short circuit photocurrent of 11.8 mA cm(-2), an open circuit voltage of 903 mV, and a fill factor of 0.69, corresponding to an overall conversion efficiency of 7.35% under standard AM 1.5 sunlight, which is higher than that of 6.86% for equivalent M4 sensitized DSCs. The effects of 4-tert-butylpyridine (TBP) as an additive on the photovoltaic performance of truxene-dye-sensitized nanocrystallineTiO2 solar cells were also investigated. PMID- 23939020 TI - A multivariate analysis of age-related differences in functional networks supporting conflict resolution. AB - Functional neuroimaging studies demonstrate age-related differences in recruitment of a large-scale attentional network during interference resolution, especially within dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). These alterations in functional responses have been frequently observed despite equivalent task performance, suggesting age-related reallocation of neural resources, although direct evidence for a facilitating effect in aging is sparse. We used the multi-source interference task and multivariate partial least-squares to investigate age-related differences in the neuronal signature of conflict resolution, and their behavioral implications in younger and older adults. There were interference-related increases in activity, involving fronto parietal and basal ganglia networks that generalized across age. In addition an age-by-task interaction was observed within a distributed network, including DLPFC and ACC, with greater activity during interference in the old. Next, we combined brain-behavior and functional connectivity analyses to investigate whether compensatory brain changes were present in older adults, using DLPFC and ACC as regions of interest (i.e. seed regions). This analysis revealed two networks differentially related to performance across age groups. A structural analysis revealed age-related gray-matter losses in regions facilitating performance in the young, suggesting that functional reorganization may partly reflect structural alterations in aging. Collectively, these findings suggest that age-related structural changes contribute to reductions in the efficient recruitment of a youth-like interference network, which cascades into instantiation of a different network facilitating conflict resolution in elderly people. PMID- 23939021 TI - Top-down suppression of incompatible motor activations during response selection under conflict. AB - Top-down control is critical to select goal-directed actions in changeable environments, particularly when several options compete for selection. This control system is thought to involve a mechanism that suppresses activation of unwanted response representations. We tested this hypothesis, in humans, by measuring motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in a left finger muscle during motor preparation in an adapted Eriksen flanker task. Subjects reported, by a left or right button-press, the orientation of a left- or right-facing central arrow, flanked by two distractor arrows on each side. Central and peripheral arrows either pointed in the same (congruent trial) or in the opposite direction (incongruent trial). Top-down control was manipulated by changing the probability of congruent and incongruent trials in a given block. In the "mostly incongruent" (MI) blocks, 80% of trials were incongruent, producing a context in which subjects strongly anticipated that they would have to face conflict. In the "mostly congruent" (MC) blocks, 80% of trials were congruent and thus subjects barely anticipated conflict in that context. Thus, we assume that top-down control was stronger in the MI than in the MC condition. Accordingly, subjects displayed a lower error rate and shorter reaction times for the incongruent trials in the MI context than for similar trials in the MC context. More interestingly, we found that top-down control specifically reduced activation of the incompatible motor representation during response selection under high conflict. That is, when the central arrow specified a right hand response, left (non-selected) MEPs became smaller in the MI than in the MC condition, but only for incongruent trials, and this measure was positively correlated with performance. In contrast, MEPs elicited in the non selected hand during congruent trials, or during all trials in which the left hand was selected, tended to increase more after the imperative signal in the MI than the MC condition. Another important observation was that, overall, MEPs were already strongly suppressed at the onset of the imperative signal and that this effect was particularly pronounced in the MI context. Hence, suppression of motor excitability seems to be a key component of conflict resolution. PMID- 23939022 TI - Targeted drug delivery to intestinal macrophages by bioactive nanovesicles released from grapefruit. AB - The gut mucosal immune system is considered to play an important role in counteracting potential adverse effects of food-derived antigens including nanovesicles. Whether nanovesicles naturally released from edible fruit work in a coordinated manner with gut immune cells to maintain the gut in a noninflammatory status is not known. Here, as proof of concept, we demonstrate that grapefruit derived nanovesicles (GDNs) are selectively taken up by intestinal macrophages and ameliorate dextran sulfate sodium (DSS)-induced mouse colitis. These effects were mediated by upregulating the expression of heme oxygenase-1 (HO-1) and inhibiting the production of IL-1beta and TNF-alpha in intestinal macrophages. The inherent biocompatibility and biodegradability, stability at wide ranges of pH values, and targeting of intestinal macrophages led us to further develop a novel GDN-based oral delivery system. Incorporating methotrexate (MTX), an anti inflammatory drug, into GDNs and delivering the MTX-GDNs to mice significantly lowered the MTX toxicity when compared with free MTX, and remarkably increased its therapeutic effects in DSS-induced mouse colitis. These findings demonstrate that GDNs can serve as immune modulators in the intestine, maintain intestinal macrophage homeostasis, and can be developed for oral delivery of small molecule drugs to attenuate inflammatory responses in human disease. PMID- 23939023 TI - Antifibrotic properties of transarterial oncolytic VSV therapy for hepatocellular carcinoma in rats with thioacetamide-induced liver fibrosis. AB - Recombinant vesicular stomatitis virus (VSV) shows promise for the treatment of hepatocellular carcinoma (HCC), but its safety and efficacy when administered in a setting of hepatic fibrosis, which occurs in the majority of clinical cases, is unknown. We hypothesized that VSV could provide a novel benefit to the underlying fibrosis, due to its ability to replicate and cause cell death specifically in activated hepatic stellate cells. In addition to the ability of VSV to produce a significant oncolytic response in HCC-bearing rats in the background of thioacetamide-induced hepatic fibrosis without signs of hepatotoxicity, we observed a significant downgrading of fibrosis stage, a decrease in collagen content in the liver, and modulation of gene expression in favor of fibrotic regression. Together, this work suggests that VSV is not only safe and effective for the treatment of HCC with underlying fibrosis, but it could potentially be developed for clinical application as a novel antifibrotic agent. PMID- 23939024 TI - Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma. AB - Preclinical and early clinical studies have demonstrated that chimeric antigen receptor (CAR)-redirected T cells are highly promising in cancer therapy. We observed that targeting HER2 in a glioblastoma (GBM) cell line results in the emergence of HER2-null tumor cells that maintain the expression of nontargeted tumor-associated antigens. Combinational targeting of these tumor-associated antigens could therefore offset this escape mechanism. We studied the single-cell coexpression patterns of HER2, IL-13Ralpha2, and EphA2 in primary GBM samples using multicolor flow cytometry and immunofluorescence, and applied a binomial routine to the permutations of antigen expression and the related odds of complete tumor elimination. This mathematical model demonstrated that cotargeting HER2 and IL-13Ralpha2 could maximally expand the therapeutic reach of the T cell product in all primary tumors studied. Targeting a third antigen did not predict an added advantage in the tumor cohort studied. We therefore generated bispecific T cell products from healthy donors and from GBM patients by pooling T cells individually expressing HER2 and IL-13Ralpha2-specific CARs and by making individual T cells to coexpress both molecules. Both HER2/IL-13Ralpha2-bispecific T cell products offset antigen escape, producing enhanced effector activity in vitro immunoassays (against autologous glioma cells in the case of GBM patient products) and in an orthotopic xenogeneic murine model. Further, T cells coexpressing HER2 and IL-13Ralpha2-CARs exhibited accentuated yet antigen dependent downstream signaling and a particularly enhanced antitumor activity. PMID- 23939025 TI - Oversized AAV transductifon is mediated via a DNA-PKcs-independent, Rad51C dependent repair pathway. AB - A drawback of gene therapy using adeno-associated virus (AAV) is the DNA packaging restriction of the viral capsid (<4.7 kb). Recent observations demonstrate oversized AAV genome transduction through an unknown mechanism. Herein, AAV production using an oversized reporter (6.2 kb) resulted in chloroform and DNase-resistant particles harboring distinct "fragment" AAV (fAAV) genomes (5.0, 2.4, and 1.6 kb). Fractionation experiments determined that only the larger "fragments" mediated transduction in vitro, and relatively efficient transduction was also demonstrated in the muscle, the eye, and the liver. In contrast with concatemerization-dependent large-gene delivery by split AAV, fAAV transduction is independent of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in vitro and in vivo while disproportionately reliant on the DNA strand-annealing protein Rad51C. Importantly, fAAV's unique dependence on DNA repair proteins, compared with intact AAV, strongly suggests that the majority of oversized AAV transduction is mediated by fragmented genomes. Although fAAV transduction is less efficient than intact AAV, it is enhanced fourfold in muscle and sevenfold in the retina compared with split AAV transduction. Furthermore, fAAV carrying codon-optimized therapeutic dysferlin cDNA in a 7.5 kb expression cassette restored dysferlin levels in a dystrophic model. Collectively, oversized AAV genome transduction requires unique DNA repair pathways and offers an alternative, more efficient strategy for large-gene therapy. PMID- 23939026 TI - Generation of a chemical gradient across an array of 256 cell cultures in a single chip. AB - A microfluidic diffusion diluter to create stable chemical gradients across an array of cell cultures was demonstrated. The device enabled concentration based studies to be conducted at 256 different concentrations across individual, low shear cell cultures. A gradient of staurosporine on cells stained with Mitotracker Deep Red (MTDR) showed a concentration-based effect on cell apoptosis across the cell culture array. PMID- 23939027 TI - Glial cell line-derived neurotrophic factor (GDNF) induced migration of spermatogonial cells in vitro via MEK and NF-kB pathways. AB - Glial cell line-derived neurotrophic factor (GDNF) regulates spermatogonial stem cell (SSC) maintenance. In the present study, we examined the levels and the cellular origin of GDNF in mouse testes during age-development, and the capacity of GDNF to induce migration of enriched GFR-alpha1 positive cells in vitro. The involvement of MAP kinase (MEK) and NF-kB signal pathways were examined. Our results show high levels of GDNF in testicular tissue of one-week-old mice which significantly decreased with age when examined by ELISA, real time PCR (qPCR) and immunofluorescence staining (IF) analysis. GDNF receptor (GFR-alpha1) expression was similar to GDNF when examined by qPCR analysis. Only Sertoli cell cultures (SCs) from one-week-old mice produced GDNF compared to SCs from older mice. However, peritubular cells from all the examined ages did not produce GDNF. The addition of recombinant GDNF (rGDNF) or supernatant from SCs from one-week-old mice to GFR-alpha1 positive cells induced their migration in vitro. This effect was significantly reduced by the addition of inhibitors to MEK (PD98059, U0126), NF-kB (PDTC) and IkB protease inhibitor (TPCK). Our results show for the first time the capacity of rGDNF and supernatant from SCs to induce migration of enriched GFR-alpha1 positive cells, and the possible involvement of MEK, NF-kB and IkB in this process. This study may suggest a novel role for GDNF in the regulation SSC niches and spermatogenesis. PMID- 23939029 TI - Excessive sleepiness and sleep patterns in patients with epilepsy: a case-control study. AB - The aim of this study was to assess excessive daytime sleepiness (EDS), sleep quality, and sleep disorders in a cohort of patients with epilepsy in the city of Florianopolis in southern Brazil. One hundred and forty patients diagnosed with epilepsy were assessed by questionnaires that included demographic and clinical variables, the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale (SSS), and the Fletcher & Luckett Adapted Questionnaire (FLAQ). These data were then compared to data from a control group (n=85). Compared to controls, patients with epilepsy (PWE) had significantly higher scores on the ESS (p=0.003), higher scores on the "daytime dysfunction" domain of the PSQI (p=0.002), and more symptoms that suggested obstructive sleep apnea in the FLAQ (p<0.001). By performing multiple linear regression models, we demonstrated that age, male gender, the presence of secondarily generalized seizures, and phenobarbital use were slightly to moderately correlated with PSQI (r=0.38) and FLAQ (r=0.51) but not with SSS scores. We concluded that PWE had more EDS, daytime dysfunction, and sleep disorders compared to a control group. PMID- 23939028 TI - Structural characterization of the Saccharomyces cerevisiae autophagy regulatory complex Atg17-Atg31-Atg29. AB - Atg17, in complex with Atg29 and Atg31, constitutes a key module of the Atg1 kinase signaling complex and functions as an important organizer of the phagophore assembly site in the yeast Saccharomyces cerevisiae. We have determined the three-dimensional reconstruction of the full S. cerevisiae Atg17 Atg31-Atg29 complex by single-particle electron microscopy. Our structure shows that Atg17-Atg31-Atg29 is dimeric and adopts a relatively rigid and extended "S shape" architecture with an end-to-end distance of approximately 345 A. Subunit mapping analysis indicated that Atg17 mediates dimerization and generates a central rod-like scaffold, while Atg31 and Atg29 form two globular domains that are tethered to the concave sides of the scaffold at the terminal regions. Finally, our observation that Atg17 adopts multiple conformations in the absence of Atg31 and Atg29 suggests that the two smaller components play key roles in defining and maintaining the distinct curvature of the ternary complex. PMID- 23939030 TI - Racial differences in coping strategies among individuals with epilepsy. AB - PURPOSE: The purpose of this study was to determine whether racial differences exist in the coping styles of individuals with epilepsy. METHODS: This study utilized a survey of patients with epilepsy, including the Brief-COPE. RESULTS: One hundred thirteen Caucasians and 70 African-Americans comprised the study population. On univariate analysis, annual household income (p<0.01), receiving disability benefits (p<0.01), and number of AEDs being currently used (p=0.04) significantly distinguished Caucasians from African-Americans. African-Americans reported higher utilization of religion (p<0.01), denial (p<0.01), emotional support (p=0.02), positive reframing (p<0.01), and planning (p<0.01) as coping reactions compared to Caucasians. Using ordinal logistic regression, the association between being African-American and the higher utilization of religion, positive reframing, planning, and denial as coping strategies remained statistically significant. CONCLUSION: Among individuals with epilepsy, African Americans appear to utilize more engagement-type coping reactions when compared to Caucasians but also utilize more denial. PMID- 23939031 TI - Peri-ictal ECG changes in childhood epilepsy: implications for detection systems. AB - Early detection of seizures could reduce associated morbidity and mortality and improve the quality of life of patients with epilepsy. In this study, the aim was to investigate whether ictal tachycardia is present in focal and generalized epileptic seizures in children. We sought to predict in which type of seizures tachycardia can be identified before actual seizure onset. Electrocardiogram segments in 80 seizures were analyzed in time and frequency domains before and after the onset of epileptic seizures on EEG. These ECG parameters were analyzed to find the most informative ones that can be used for seizure detection. The algorithm of Leutmezer et al. was used to find the temporal relationship between the change in heart rate and seizure onset. In the time domain, the mean RR shows a significant difference before compared to after onset of the seizure in focal seizures. This can be observed in temporal lobe seizures as well as frontal lobe seizures. Calculation of mean RR interval has a high specificity for detection of ictal heart rate changes. Preictal heart rate changes are observed in 70% of the partial seizures. Ictal heart rate changes are present only in partial seizures in this childhood epilepsy study. The changes can be observed in temporal lobe seizures as well as in frontal lobe seizures. Heart rate changes precede seizure onset in 70% of the focal seizures, making seizure detection and closed-loop systems a possible therapeutic alternative in the population of children with refractory epilepsy. PMID- 23939032 TI - Pharmacological treatment of psychiatric comorbidity in patients with refractory epilepsy. AB - The purpose of the present study was to describe the use of psychopharmacological drugs for the treatment of a stated or presumed psychiatric comorbid condition in patients with refractory epilepsy and discuss the clinical implications of such treatment. The study was a retrospective descriptive study in patients admitted to the National Center for Epilepsy in Norway based on medication described in medical records. The mean age was 40 years (range: 9-90), and the gender ratio was 56/44% female/male. Psychotropic drugs (antidepressants and antipsychotics) were used to a lower extent than in the general population in Norway. Drugs for ADHD were predominantly used in children. The prevalence of patients treated with psychiatric comedication was 13% (143 of 1139 patients). The patients used two to eight concomitant CNS-active drugs, which calls for the close monitoring of potential pharmacodynamic and pharmacokinetic interactions and should challenge clinicians to achieve a less complex pharmacotherapy. Psychiatric comorbidity is an important concern in patients with refractory epilepsy and may be undertreated. PMID- 23939033 TI - Validation of a screening tool for attention and executive functions (EpiTrack Junior) in children and adolescents with absence epilepsy. AB - OBJECTIVE: Our prospective study aimed at the validation of EpiTrack Junior, a neuropsychological screening tool for attention and executive functions in children with epilepsy. METHODS: Twenty-two children with absence epilepsy aged 8 17 years underwent comprehensive neuropsychological evaluation including EpiTrack Junior and measures of intelligence, verbal and nonverbal memory, word fluency and visuoconstructive organization. Concurrent and discriminant validity of EpiTrack Junior subtests and total score as well as sensitivity and specificity of the total score were analyzed. RESULTS: EpiTrack Junior total score was impaired in 59% of participants. Concurrent validity was demonstrated in 4/6 subtests and for the total score. Discriminant validity was shown with respect to verbal and nonverbal long-term memory. Sensitivity was higher than specificity and highest for the "working memory index". CONCLUSION: EpiTrack Junior is recommended as a sensitive and time-efficient screening tool for attention and executive functions in children with epilepsy. Impaired results should be followed up with detailed evaluation including information from the parents and school as well as counseling where indicated. PMID- 23939034 TI - Possible nitric oxide mechanism in the protective effect of hesperidin against pentylenetetrazole (PTZ)-induced kindling and associated cognitive dysfunction in mice. AB - Epilepsy is a complex neurological disorder manifested by recurrent episodes of convulsive seizures, loss of consciousness, and sensory disturbances. Pentylenetetrazole (PTZ)-induced kindling primarily represents a model of generalized epilepsy. The present study has been undertaken to evaluate the neuroprotective potential of hesperidin and its interaction with nitric oxide modulators against PTZ-induced kindling and associated cognitive dysfunction in mice. The experimental protocol comprised of eleven groups (n=6), where a subconvulsive dose of PTZ (40 mg/kg, i.p.) had been administered every other day for a period of 12 days, and seizure episodes were noted after each PTZ injection over a period of 30 min. The memory performance tests were carried out on days 13 and 14 followed by the estimation of biochemical and mitochondrial parameters. Chronic administration of a subconvulsive dose of PTZ resulted in an increase in convulsive activity culminating in generalized clonic-tonic seizures, as revealed by a progressive increase in seizure score as well as alteration in antioxidant enzyme levels (lipid peroxidation, nitrite, glutathione, super oxide dismutase, and catalase) and mitochondrial complex (I, II, and IV) activities, whereas chronic treatment with hesperidin (200 mg/kg) significantly attenuated these behavioral, biochemical, and mitochondrial alterations. Further, treatment with l arginine (100 mg/kg) or l-NAME (10 mg/kg) in combination with hesperidin significantly modulated the protective effect of hesperidin which was significant as compared to their effects per se in PTZ-treated animals. Thus, the present study suggests a possible involvement of the NO-cGMP pathway in the neuroprotective effect of hesperidin in PTZ-kindled mice. PMID- 23939035 TI - Acceptance of epilepsy surgery in the pediatric age - what the parents think and what the doctors can do. AB - Epilepsy surgery (ES) in pediatrics is safe and effective but can be underutilized. Possible barriers could be parental resistance and doctor inertia. We surveyed 138 parents of pediatric patients with epilepsy and found that 25.2% were opposed to this treatment. However, upon completing the questionnaire that contained factual information about ES, 50.4% of the responders stated that they had become more favorable vs. 3.3% more contrary and 46.3% unchanged. Parents of prepubescent patients were most receptive (p=0.0343) and more likely to shift to a more favorable attitude. Thus, pediatric neurologists should not hesitate to discuss ES as soon as indicated, providing all necessary information to increase acceptance. However, among 60 child neurologists surveyed, 60% did not fully comply with guidelines or follow accepted standards of practice, indicating that they may not be apt to provide proper parental guidance. We conclude that education of both practicing neurologists and parents is needed to facilitate the process. PMID- 23939036 TI - Project Access: Strategies to improve care for children and youth with epilepsy: illustrations of recommendations in the IOM report on the epilepsies. AB - Project Access (PA), funded by the Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA), provided grants to state and local agencies to improve awareness, provide education, design, test, pilot and evaluate system changes, and improve quality of services and access to early diagnosis and comprehensive, coordinated health care and related services for children and youth with epilepsy residing in rural and medically underserved areas. In 2011, the Institute of Medicine of the National Academies (IOM) published a series of 13 recommendations addressing unmet psychosocial, medical, and public health needs of individuals with epilepsy, including children and youth. This paper examines the synergy between these two projects showing how the strategies utilized in the PA demonstration projects can address the IOM recommendations and how these recommendations can inform future initiatives for improving care for children and youth with epilepsy. PMID- 23939037 TI - Singlet 2-adamantylidene--an ambiphilic foiled carbene stabilized by hyperconjugation. AB - The EDA-NOCV analysis shows that the singlet 2-adamantylidene is a foiled-type carbene stabilized by the hyperconjugative interaction of one pair of the vicinal C-C sigma-MOs with the empty p-orbital on the carbene carbon atom. The high proton affinity and hydride affinity indicate the ambiphilic nature of 2 adamantylidene. PMID- 23939039 TI - Curcumin binds tubulin, induces mitotic catastrophe, and impedes normal endothelial cell proliferation. AB - Curcumin, a component of turmeric spice that imparts flavor and color to curry, is thought to possess anti-inflammatory and antioxidant properties in biological tissues. However, while such efficacies have been described in the context of carcinogenesis, the impact of curcumin on normal cell cycle regulation is poorly understood. Here, we provide evidence of curcumin toxicity in proliferating bovine aortic endothelial cells, at concentrations relevant to the diet and below those previously reported in cancer models. Upon confirming curcumin's ability to upregulate hemeoxygenase-1 in a dose-dependent fashion, we found the minimally efficacious curcumin concentration to also inhibit endothelial cell DNA synthesis. Moreover, curcumin concentrations below the minimum 2 MUM threshold required to induce hemeoxygenase-1 bound tubulin protein in vitro and triggered hallmark evidence of mitotic catastrophe in vivo. Concentrations as low as 0.1 MUM curcumin led to disproportionate DNA segregation, karyorrhexis, and micronucleation in proliferating endothelial cells. While suggesting a mechanism by which physiological curcumin concentrations inhibit cell cycle progression, these findings describe heretofore unappreciated curcumin toxicity with potential implications for endothelial growth, development, and tissue healing. PMID- 23939040 TI - Piperine inhibits the proliferation of human prostate cancer cells via induction of cell cycle arrest and autophagy. AB - Piperine, an alkaloid from black and long peppers (Piper nigrum Linn & Piper longum Linn), has been reported to exhibit antitumor activities in vitro and in vivo. To further understand the antitumor mechanism of piperine, we investigated the growth inhibitory effects of piperine on human prostate cancer DU145, PC-3 and LNCaP cells. Piperine treatment resulted in a dose-dependent inhibition of the proliferation of these cell lines. Cell cycle arrest at G0/G1 was induced and cyclin D1 and cyclin A were downregulated upon piperine treatment. Notably, the level of p21(Cip1) and p27(Kip1) was increased dose-dependently by piperine treatment in both LNCaP and DU145 but not in PC-3 cells, in line with more robust cell cycle arrest in the former two cell lines than the latter one. Although piperine induced low levels of apoptosis, it promoted autophagy as evidenced by the increased level of LC3B-II and the formation of LC3B puncta in LNCaP and PC-3 cells. The piperine-induced autophagic flux was further confirmed by assaying LC3 II accumulation and LC3B puncta formation in the presence of chloroquine, a well known autophagy inhibitor. Taken together, these results indicated that piperine exhibited anti-proliferative effect in human prostate cancer cells by inducing cell cycle arrest and autophagy. PMID- 23939041 TI - Influence of the method of production of eggs on the daily intake of polycyclic aromatic hydrocarbons and organochlorine contaminants: an independent study in the Canary Islands (Spain). AB - Analysis of 16 polycyclic aromatic hydrocarbons (PAHs), 20 organochlorine pesticides (OCPs) and 18 polychlorinated biphenyls (PCBs) were performed on eggs from three different production types (conventional, free-run and organic) collected from the markets of the Canary Islands (Spain). Unlike other studies we did not found differences in the content of PCBs or OCPs of eggs in relation to its production type. Median ?OCPs content was 3.87 ng g-1 fat, being dieldrin, dicofol, hexachlorobenzene, p,p'-DDE and p,p'-DDT the most frequently detected. Median ?PCBs value was 3.93 ng g-1 fat, with 79.9% of this amount coming from the marker PCBs. Two samples, one free-run and one organic, greatly exceeded the current European Commission (EC) limit of 2.5 pg TEQ(PCDD/F) g-1 lipid, but the rest were well below of this limit. The concentrations of PAHs in conventionally produced eggs were almost 4 times higher than in free-run or organic eggs. Mean dietary intake estimates of the organochlorine contaminants based on consumption of eggs, regardless of the type chosen, is negligible for the Canary Islands' population. However, the median dietary intake estimates of PAHs greatly depend on the type of eggs chosen, being much lower when free-run and organic eggs are consumed. PMID- 23939042 TI - A conserved domain in exon 2 coding for the human and murine ARF tumor suppressor protein is required for autophagy induction. AB - The ARF tumor suppressor, encoded by the CDKN2A gene, has a well-defined role regulating TP53 stability; this activity maps to exon 1beta of CDKN2A. In contrast, little is known about the function(s) of exon 2 of ARF, which contains the majority of mutations in human cancer. In addition to controlling TP53 stability, ARF also has a role in the induction of autophagy. However, whether the principal molecule involved is full-length ARF, or a small molecular weight variant called smARF, has been controversial. Additionally, whether tumor-derived mutations in exon 2 of CDKN2A affect ARF's autophagy function is unknown. Finally, whereas it is known that silencing or inhibiting TP53 induces autophagy, the contribution of ARF to this induction is unknown. In this report we used multiple autophagy assays to map a region located in the highly conserved 5' end of exon 2 of CDKN2A that is necessary for autophagy induction by both human and murine ARF. We showed that mutations in exon 2 of CDKN2A that affect the coding potential of ARF, but not p16INK4a, all impair the ability of ARF to induce autophagy. We showed that whereas full-length ARF can induce autophagy, our combined data suggest that smARF instead induces mitophagy (selective autophagy of mitochondria), thus potentially resolving some confusion regarding the role of these variants. Finally, we showed that silencing Tp53 induces autophagy in an ARF-dependent manner. Our data indicated that a conserved domain in ARF mediates autophagy, and for the first time they implicate autophagy in ARF's tumor suppressor function. PMID- 23939043 TI - Antibacterial activity and mechanism of action of epsilon-poly-L-lysine. AB - epsilon-Poly-L-lysine (epsilon-PL)(2) is widely used as an antibacterial agent because of its broad antimicrobial spectrum. However, the mechanism of epsilon-PL against pathogens at the molecular level has not been elucidated. This study investigated the antibacterial activity and mechanism of epsilon-PL against Escherichia coli O157:H7 CMCC44828. Propidium monoazide-PCR test results indicated that the threshold condition of epsilon-PL for complete membrane lysis of E. coli O157:H7 was 10 MUg/mL (90% mortality for 5 MUg/mL). Further verification of the destructive effect of epsilon-PL on cell structure was performed by atomic force microscopy and transmission electron microscopy. Results showed a positive correlation between reactive oxygen species (ROS)(3) levels and epsilon-PL concentration in E. coli O157:H7 cells. Moreover, the mortality of E. coli O157:H7 was reduced when antioxidant N-acetylcysteine was added. Results from real-time quantitative PCR (RT-qPCR)(4) indicated that the expression levels of oxidative stress genes sodA and oxyR were up-regulated 4- and 16-fold, respectively, whereas virulence genes eaeA and espA were down regulated after epsilon-PL treatment. Expression of DNA damage response (SOS response)(5) regulon genes recA and lexA were also affected by epsilon-PL. In conclusion, the antibacterial mechanism of epsilon-PL against E. coli O157:H7 may be attributed to disturbance on membrane integrity, oxidative stress by ROS, and effects on various gene expressions, such as regulation of oxidative stress, SOS response, and changes in virulence. PMID- 23939044 TI - Suppression of Wnt signaling by the miR-29 family is mediated by demethylation of WIF-1 in non-small-cell lung cancer. AB - Wnt inhibitory factor-1 (WIF-1) silencing induced by promoter hypermethylation is a common mechanism of aberrant activation of the Wnt signaling pathway in non small-cell lung cancer (NSCLC). However, the activity of regulators associated with the methylation of the WIF-1 gene remains unclear. Here, we investigated the role of three DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) in the expression of WIF-1. The three DNMTs were up-regulated in NSCLC tumor tissues and suppression of DNMT3A and DNMT3B restored the expression of WIF-1 in NSCLC cells. The miR-29 family (miR-29a, -29b, and -29c), which negatively regulates DNMT3A and DNMT3B, was examined in association with the Wnt/beta-catenin signaling pathway. A positive correlation between the expression of WIF-1 and that of MiR 29s was observed in NSCLC tissues. Methylation-specific PCR and Western blotting indicated that miR-29s positively regulate WIF-1 expression by inhibiting the methylation of its promoter. Furthermore, miR-29 overexpression downregulated beta-catenin expression, inhibited cell proliferation and induced apoptosis. The expression of miR-29a and miR-29b was partially regulated by DNMT3A and DNMT3B in a positive feedback loop. Taken together, our findings show that miR-29s suppress the Wnt signaling pathway through demethylation of WIF-1 in NSCLC. PMID- 23939045 TI - The gemin2-binding site on SMN protein: accessibility to antibody. AB - Reduced levels of SMN (survival-of-motor-neurons) protein are the cause of spinal muscular atrophy, an inherited disorder characterised by loss of motor neurons in early childhood. SMN associates with more than eight other proteins to form an RNA-binding complex involved in assembly of the spliceosome. Two monoclonal antibodies (mAbs), MANSMA1 and MANSMA12, have been widely-used in studies of SMN function and their precise binding sites on SMN have now been identified using a phage-displayed peptide library. The amino-acid residues in SMN required for antibody binding are the same as the five most important contact residues for interaction with gemin2. MANSMA12 immuno-precipitated SMN and gemin2 from HeLa cell extracts as efficiently as mAbs against other SMN epitopes or against gemin2. We explain this by showing that SMN exists as large multimeric complexes. This SMN epitope is highly-conserved and identical in human and mouse. To explain the vigorous immune response when mice are immunised with recombinant SMN alone, we suggest this region is masked by gemin2, or a related protein, throughout development, preventing its recognition as a "self-antigen". The epitope for a third mAb, MANSMA3, has been located to eight amino-acids in the proline-rich domain of SMN. PMID- 23939046 TI - Three-dimensional structure of a Bombyx mori Omega-class glutathione transferase. AB - Glutathione transferases (GSTs) are major phase II detoxification enzymes that play central roles in the defense against various environmental toxicants as well as oxidative stress. Here we report the crystal structure of an Omega-class glutathione transferase of Bombyx mori, bmGSTO, to gain insight into its catalytic mechanism. The structure of bmGSTO complexed with glutathione determined at a resolution of 2.5A reveals that it exists as a dimer and is structurally similar to Omega-class GSTs with respect to its secondary and tertiary structures. Analysis of a complex between bmGSTO and glutathione showed that bound glutathione was localized to the glutathione-binding site (G-site). Site-directed mutagenesis of bmGSTO mutants indicated that amino acid residues Leu62, Lys65, Lys77, Val78, Glu91 and Ser92 in the G-site contribute to catalytic activity. PMID- 23939047 TI - Borna disease virus nucleoprotein inhibits type I interferon induction through the interferon regulatory factor 7 pathway. AB - The expression of type I interferon (IFN) is one of the most potent innate defences against viral infection in higher vertebrates. Borna disease virus (BDV) establishes persistent, noncytolytic infections in animals and in cultured cells. Early studies have shown that the BDV phosphoprotein can inhibit the activation of type I IFN through the TBK1-IRF3 pathway. The function of the BDV nucleoprotein in the inhibition of IFN activity is not yet clear. In this study, we demonstrated IRF7 activation and increased IFN-alpha/beta expression in a BDV persistently infected human oligodendroglia cell line following RNA interference mediated BDV nucleoprotein silencing. Furthermore, we showed that BDV nucleoprotein prevented the nuclear localisation of IRF7 and inhibited endogenous IFN induction by poly(I:C), coxsackie virus B3 and IFN-beta. Our findings provide evidence for a previously undescribed mechanism by which the BDV nucleoprotein inhibits type I IFN expression by interfering with the IRF7 pathway. PMID- 23939048 TI - Neural differentiation of human embryonic stem cells as an in vitro tool for the study of the expression patterns of the neuronal cytoskeleton during neurogenesis. AB - The neural differentiation of human embryonic stem cells (ESCs) is a potential tool for elucidating the key mechanisms involved in human neurogenesis. Nestin and beta-III-tubulin, which are cytoskeleton proteins, are marker proteins of neural stem cells (NSCs) and neurons, respectively. However, the expression patterns of nestin and beta-III-tubulin in neural derivatives from human ESCs remain unclear. In this study, we found that neural progenitor cells (NPCs) derived from H9 cells express high levels of nestin and musashi-1. In contrast, beta-III-tubulin was weakly expressed in a few NPCs. Moreover, in these cells, nestin formed filament networks, whereas beta-III-tubulin was distributed randomly as small particles. As the differentiation proceeded, the nestin filament networks and the beta-III-tubulin particles were found in both the cell soma and the cellular processes. Moreover, the colocalization of nestin and beta III-tubulin was found mainly in the cell processes and neurite-like structures and not in the cell soma. These results may aid our understanding of the expression patterns of nestin and beta-III-tubulin during the neural differentiation of H9 cells. PMID- 23939049 TI - Three-dimensional modulation of cortical plasticity during pseudopodial protrusion of mouse leukocytes. AB - Leukocytes can rapidly migrate virtually within any substrate found in the body at speeds up to 100 times faster than mesenchymal cells that remain firmly attached to a substrate even when migrating. To understand the flexible migration strategy utilized by leukocytes, we experimentally investigated the three dimensional modulation of cortical plasticity during the formation of pseudopodial protrusions by mouse leukocytes isolated from blood. The surfaces of viable leukocytes were discretely labeled with fluorescent beads that were covalently conjugated with concanavalin A receptors. The movements of these fluorescent beads were different at the rear, central, and front surfaces. The beads initially present on the rear and central dorsal surfaces of the cell body flowed linearly toward the rear peripheral surface concomitant with a significant collapse of the cell body in the dorsal-ventral direction. In contrast, those beads initially on the front surface moved into a newly formed pseudopodium and exhibited rapid, random movements within this pseudopodium. Bead movements at the front surface were hypothesized to have resulted from rupture of the actin cytoskeleton and detachment of the plasma membrane from the actin cytoskeletal cortex, which allowed leukocytes to migrate while being minimally constrained by a substrate. PMID- 23939050 TI - Cholecalciferol treatment in older patients with isolated systolic hypertension. PMID- 23939051 TI - Multi-sensor magnetoencephalography with atomic magnetometers. AB - The authors have detected magnetic fields from the human brain with two independent, simultaneously operating rubidium spin-exchange-relaxation-free magnetometers. Evoked responses from auditory stimulation were recorded from multiple subjects with two multi-channel magnetometers located on opposite sides of the head. Signal processing techniques enabled by multi-channel measurements were used to improve signal quality. This is the first demonstration of multi sensor atomic magnetometer magnetoencephalography and provides a framework for developing a non-cryogenic, whole-head magnetoencephalography array for source localization. PMID- 23939052 TI - Efficient red organic electroluminescent devices by doping platinum(II) Schiff base emitter into two host materials with stepwise energy levels. AB - In this work, organic electroluminescent (EL) devices with double light-emitting layers (EMLs) having stepwise energy levels were designed to improve the EL performance of a red-light-emitting platinum(II) Schiff base complex. A series of devices with single or double EML(s) were fabricated and characterized. Compared with single-EML devices, double-EML devices showed improved EL efficiency and brightness, attributed to better balance in carriers. In addition, the stepwise distribution in energy levels of host materials is instrumental in broadening the recombination zone, thus delaying the roll-off of EL efficiency. The highest EL current efficiency and power efficiency of 17.36 cd/A and 14.73 lm/W, respectively, were achieved with the optimized double-EML devices. At high brightness of 1000 cd/m2, EL efficiency as high as 8.89 cd/A was retained. PMID- 23939053 TI - Flat lensing in the visible frequency range by woodpile photonic crystals. AB - We experimentally demonstrate full two-dimensional focalization of light beams at visible frequencies by a three-dimensional woodpile photonic crystal. The focalization (the flat lensing) with focal distances of the order of 50-70 MUm is experimentally demonstrated. Experimental results are compared with numerical calculations and interpreted by harmonic expansion studies. PMID- 23939054 TI - SOI based ultracompact polarization insensitive filter for PDM signal processing. AB - We propose and fabricate a scheme that combines a two-dimensional (2D) grating coupler and a delay interferometer (DI) in a loop configuration. According to the polarization states, the 2D grating coupler first splits the input signals into two paths, which copropagate in the loop and share a common DI, and then combines the two paths together to the same input port. The proposed device is polarization insensitive and can be used for polarization division multiplexed (PDM) signal processing. For demonstration, the PDM non return-to-zero differential-phase-shift-keying signals can be demodulated successfully. The bit error ratio measurements show an error free operation, reflecting the good performance and the practicability of the proposed device. PMID- 23939055 TI - Tunable dual-band terahertz metamaterial bandpass filters. AB - We report metamaterial terahertz (THz) bandpass filters with tunable dual-band selectivity. The shift in the center frequency of the device is achieved by actively modifying the effective length of the resonators. This was realized by introducing vanadium dioxide (VO2) bridges interconnecting specific regions of each resonator. Raising the temperature across the phase transition shifted the resonance frequency by ~32% due to changes in the electrical conductivity of the VO2. Measured THz transmission response of the proposed dual-band filter was in good correspondence with simulations. PMID- 23939056 TI - Dipole-dipole interaction in random electromagnetic fields. AB - We demonstrate that a nonvanishing interaction force exists between pairs of induced dipoles in a random, statistically stationary electromagnetic field. This new type of optical binding force leads to long-range interaction between dipolar particles even when placed in spatially incoherent fields. We also discuss several unique features of the dipole-dipole interaction in spatially incoherent Gaussian fields. PMID- 23939057 TI - Single-frequency fiber laser operating at 2.9 MUm. AB - We report the demonstration of a single-longitudinal-mode fiber laser operating at 2914 nm, which exhibits a spectrometer-limited linewidth of <0.4 nm, in a 49 mm long holmium/praseodymium co-doped ZBLAN fiber. Narrow-linewidth feedback is provided by a fiber Bragg grating inscribed directly in the ZBLAN fiber using the femtosecond laser point-by-point technique. Measurements of the temporal stability and coherence confirm that the laser is operating on a single longitudinal mode. PMID- 23939058 TI - Improvement of linearity in phase-modulated analog photonic link. AB - A method to improve the linearity of the analog photonic link is proposed and experimentally demonstrated, which consists of a phase modulator and an optical tunable bandpass filter. By carefully optimizing the bandwidth and center wavelength of the filter, we can significantly suppress the third-order intermodulation distortion by ~32 dB. Subsequently the spurious-free dynamic range of the link is improved by ~14 dB. PMID- 23939059 TI - High light-extracting efficiency for OLED directly fabricated on double-side nanotextured silica substrate. AB - One economical method for extracting the light loss from both the waveguide mode and substrate is demonstrated. Pillar arrays with different scales are created on the two sides of a silica substrate by inductively coupled plasma etching following a colloidal masking. The quasi-periodic Bragg scattering structure on a silica/ITO interface led to a two-fold current efficiency without introducing a spectral shift or directionality. Meanwhile, the subwavelength-scaled antireflection structure on a silica/air interface produced further increases in efficiency by 40%. The organic light-emitting device directly fabricated on the double-sided nanotextured silica substrate reached an overall enhancement factor of ~2.8 with the current efficiency. PMID- 23939060 TI - Electron relaxation effect on the sub-100-fs laser interaction with gold thin film. AB - The heating of a gold thin film by a single 10 fs laser pulse is modeled by a combined continuum-atomistic method considering the electron relaxation effect. Numerical results show that the temperature evolution and stress propagation proceed in the same manners as those for the subpicosecond laser irradiation. It is also found that the electron relaxation effect is insignificant and could be considerably overestimated by neglecting the ballistic energy transfer in the film. PMID- 23939061 TI - Correction of cell-induced optical aberrations in a fluorescence fluctuation microscope. AB - We describe the effect of optical aberrations on fluorescence fluctuations microscopy (FFM), when focusing through a single living cell. FFM measurements are performed in an aqueous fluorescent solution and prove to be a highly sensitive tool to assess the optical aberrations introduced by the cell. We demonstrate an adaptive optics (AO) system to remove the aberration-related bias in the FFM measurements. Our data show that AO is not only useful when imaging deep in tissues but also when performing FFM measurements through a single cellular layer. This work paves the way for the application of FFM to complex three-dimensional multicellular samples. PMID- 23939062 TI - Tapered InAs/InGaAs quantum dot semiconductor optical amplifier design for enhanced gain and beam quality. AB - In this Letter, a design for a tapered InAs/InGaAs quantum dot semiconductor optical amplifier is proposed and experimentally evaluated. The amplifier's geometry was optimized in order to reduce gain saturation effects and improve gain efficiency and beam quality. The experimental measurements confirm that the proposed amplifier allows for an elevated optical gain in the saturation regime, whereas a five-fold increase in the coupling efficiency to a standard single mode optical fiber is observed, due to the improvement in the beam quality factor M2 of the emitted beam. PMID- 23939063 TI - Regularization functional semi-automated incorporation of anatomical prior information in image-guided fluorescence tomography. AB - The use of anatomical priors in fluorescence tomography is known to improve image quality and accuracy significantly. However, the use of prior information is often implemented by incorporating user segmented structural images into the optical reconstruction algorithm, a process requiring significant time and expertise. We propose an automated implementation which encodes the gray-scale prior image directly into the regularization term, eliminating the need for direct prior image segmentation, which is extendable to any spatially defined prior data. The proposed method is supported by in vivo studies. PMID- 23939064 TI - Polarization conversion loss in birefringent crystalline resonators. AB - Whispering gallery modes in birefringent crystalline resonators are investigated. We experimentally investigate the XY-cut resonators made with LiNbO3, LiTaO3, and BBO and observe strong influence of the resonator's shape and birefringence on the quality factor of the extraordinary polarized modes. We show that extraordinary modes can have lower Q and even be suppressed owing to polarization conversion loss. The ordinary ray modes retain the high Q due to inhibited reflection phenomenon. PMID- 23939065 TI - Waveguide lasing from V-shaped ZnO microstructure. AB - A V-shaped optical resonance cavity was obtained from ZnO microstructures grown by thermal chemical vapor deposition. Strong laser emissions were observed in three regions--the tip of the two branches and the bottom facet of the V-shaped microstructures--under UV laser excitation at room temperature. In the region where the diameter of the branches was smaller than the wavelength of the laser light, light could not propagate into the tip due to the cutoff phenomenon, resulting in partial reflection. Quasi-Fabry-Perot resonance in the branch and light reflection at the bottom facet characterized the V-shaped microcavity. PMID- 23939066 TI - Abrupt polarization transition of vector autofocusing Airy beams. AB - We experimentally and theoretically study the abrupt polarization transitions of vector autofocusing Airy beams associated with the spin-orbit interactions. It is shown that when the topological charges of the polarization and the attached spiral phase are equal in number, the local polarizations undergo an abrupt transition from linear to circular polarizations at the focal point, and the associated orbital angular momentum partially converts into the spin of photons. The experimental results are theoretically explained from the far-field properties of the beams in terms of Hankel transformations. PMID- 23939067 TI - Stable radio-frequency delivery by lambda dispersion-induced optical tunable delay. AB - We propose and demonstrate a novel stable radio frequency (RF) delivery system based on a radio-over-fiber link. The proposed scheme acts as a long phase locking loop where an optical tunable delay line is involved to compensate dynamically for the time-delay variation that arises from fiber-link fluctuation. An optical carrier with variable wavelength under fiber-link dispersion results in the desired tunable delay. The tunable range is in proportion to the length of the fiber link, so a large phase-error correction capacity under long-distance delivery can be realized. The large as well as fine optical-delay tunability is experimentally demonstrated, and the RF reference of 2.42 GHz is transferred for 54 km where a time jitter compression factor of 588 is achieved. PMID- 23939068 TI - Precise measurements of the thermo-optical aberrations of an Yb:YAG thin-disk laser. AB - We report on interferometric measurements of the thermo-optical aberrations of the laser medium of an Yb:YAG thin-disk laser in pumped and cw lasing conditions at several pump-power levels with a mean repeatability of 5 nm. These measurements build the basis for future intracavity compensation of the aberrations with our deformable mirror in order to improve the fundamental-mode efficiency. PMID- 23939069 TI - Experimental demonstration and observation of a plasmon wave occuring at a GaAs Au-GaN interface. AB - Integration of surface plasmon structures using semiconductor materials is limited due to the difficulties encountered in maintaining the resonance conditions upon packaging. We propose here a technology process allowing us to bond two semiconductors, such as gallium nitride (GaN) and gallium arsenide (GaAs), through a thin metal layer. This solution allows the excitation of a surface plasmon wave in an integrated classical Kretschmann configuration. The Letter presents various metal bonding conditions employed for Au deposited on both GaN/sapphire and GaAs substrates aiming at semiconductor-metal-semiconductor interfaces transparent at telecom wavelengths. The process conditions for the bondings are optimized using Ti/Au (3 nm/30 nm) layers on each of the wafers to be bonded under an applied pressure of 500 mbar at a low temperature of 250 degrees C. PMID- 23939070 TI - Time-resolved tunable diode laser absorption spectroscopy of pulsed plasma. AB - A method for time-resolved tunable diode laser absorption spectroscopy (LAS) has been developed. In this Letter, we describe in detail a developed electronic module that controls the time resolution of the LAS system. The transistor transistor logic signal triggering the plasma pulse is used for generation of two signals: the first one triggers fine tuning of the laser wavelength and the second one controls time-defined signal sampling from the absorption detector. The described method and electronic system enable investigation of the temporal evolution of the density and temperature of selected particles in technological plasma systems. The high-power impulse magnetron sputtering system with a period of 10 ms and a duty cycle of 1% has been used to verify this method. The temporal evolution of argon metastable density was measured in the active part of the pulse and in the afterglow. The resulting density of Ar* displays a double-peak structure with a first peak in the plasma "ON" phase and a second peak in the afterglow approximately 1 ms after the end of the pulse. PMID- 23939071 TI - Resonantly pumped single-mode channel waveguide Er:YAG laser with nearly quantum defect limited efficiency. AB - We demonstrated the continuous-wave operation of a resonantly pumped Er:YAG single-mode channel waveguide laser with diffraction-limited output and nearly quantum defect limited efficiency. Using a longitudinally core-pumped, nearly square (61.2 MUm*61.6 MUm) Er3+:YAG waveguide embedded in an undoped YAG cladding, an output power of 9.1 W with a slope efficiency of 92.8% (versus absorbed pump power) has been obtained. To the best of our knowledge, this optical-to-optical efficiency is the highest ever demonstrated for a channel waveguide laser. PMID- 23939072 TI - High-sensitivity dynamical profilometry with a fiber-based composite interferometer. AB - We proposed and demonstrated a fiber-based composite interferometer, which can perform surface profile measurements with sensitivity at the nanometer scale. With the proposed phase-compensation mechanism, the phase deviation due to the instability of the optical delay component and environmental perturbations can be simultaneously compensated. The measurement sensitivity and imaging speed can be significantly improved such that the system can be used as a high-speed, high resolution, and wide-field dynamical imaging system. The axial precision of the system was examined to be 0.82 nm. High-resolution time-lapsed dynamical imaging of onion cells during dehydration processes were performed with this system with one frame captured in 75 s. PMID- 23939073 TI - Distributed fiber strain and vibration sensor based on Brillouin optical time domain reflectometry and polarization optical time-domain reflectometry. AB - A distributed fiber strain and vibration sensor which effectively combines Brillouin optical time-domain reflectometry and polarization optical time-domain reflectometry is proposed. Two reference beams with orthogonal polarization states are, respectively, used to perform the measurement. By using the signal obtained from either reference beam, the vibration of fiber can be measured from the polarization effect. After combining the signals obtained by both reference beams, the strain can be measured from the Brillouin effect. In the experiment, 10 m spatial resolution, 0.6 kHz frequency measurement range, 2.5 Hz frequency resolution, and 0.2 MHz uncertainty of Brillouin frequency measurement are realized for a 4 km sensing distance. PMID- 23939074 TI - Thermally tunable quadruple Vernier racetrack resonators. AB - The spectral responses of series-coupled racetrack resonators exhibiting the Vernier effect have many attractive features as compared to the spectral responses of identical series-coupled racetrack resonators, such as free spectral range (FSR) extension and enhanced wavelength tunability. Here we present experimental results of a thermally tunable quadruple series-coupled silicon racetrack resonator exhibiting the Vernier effect. We thermally tune two of the four racetrack resonators to enable discrete switching of the major peak by 15.54 nm. Also, our device has an interstitial peak suppression of 35.4 dB, a 3 dB bandwidth of 0.45 nm, and an extended FSR of 37.66 nm. PMID- 23939075 TI - Generation of a radially polarized laser beam in a single microchip Nd:YVO4 laser. AB - A radially polarized beam was generated in a microchip Nd:YVO4 laser by shaping the pump profile to be a group of focused plane waves, the directions of which are located on a conical surface. The oblique incident pump beam induces thermal lensing combined with birefringence to distinguish the radial ray from the azimuthal ray to achieve radial polarization. The average contrast ratio was 23.6 when the pump power was between 3.06 and 4.27 W. PMID- 23939076 TI - Highly efficient continuous-wave diode-pumped Er, Yb:GdAl3(BO3)4 laser. AB - We report the highly efficient continuous-wave diode-pumped laser operation of Er, Yb:GdAl3(BO3)4 crystal. Absorption and stimulated emission spectra, emission lifetimes, and efficiencies of energy transfer from Yb3+ to Er3+ ions were determined. A maximal output power of 780 mW was obtained at 1531 nm at absorbed pump power of 4 W with slope efficiency of 26%. PMID- 23939077 TI - Broadband spectrum generation using continuous-wave Raman scattering. AB - We experimentally demonstrate a continuous-wave ro-vibrational Raman spectrum that is two octaves wide with spectral components ranging from 0.8 to 3.2 MUm in wavelength. The spectrum is produced in low pressure molecular deuterium inside a high finesse cavity. PMID- 23939078 TI - Demonstration of coherent imaging through a phased array of single-mode optical fibers. AB - We demonstrate coherent imaging through a phased array of single-mode optical fibers. Specifically, we show that two laboratory point sources located within the individual-fiber single-mode acceptance angle can be resolved. Such techniques could eventually enable direct imaging with arrays of small collecting telescopes. PMID- 23939079 TI - Evanescent-wave-induced frequency shift for optical superresolution imaging. AB - We propose a method to enhance the resolution and break the diffraction limit. The superresolution imaging is realized by incorporating total internal reflection (TIR) illumination with a passive spatial frequency shift mechanism. Meanwhile, TIR supplies a surface field with a limited penetration depth, which demonstrates that the axial resolution can be improved simultaneously. The superresolution capability is confirmed both theoretically and experimentally. Compared with microfiber-based former work, this idea possesses promising merits, providing a wider viewing field and a simpler configuration for variable illumination orientations, thereby implying abundant application potentials. PMID- 23939080 TI - Spin Hall effect of light measured by interferometry. AB - We demonstrate a experimental method to measure the spin Hall effect of light (SHEL), which is based on the interference between two orthogonal circularly polarized beams with the help of a polarizer. Our method can measure the SHEL across the entire exit pupil, not only at the centroid as is the case with earlier methods, and hence one can scan the transverse section of the beam. We measured the SHEL of an aluminium mirror and a glass plate using a He-Ne laser at wavelength 633 nm, for incidence angles varying from 22 degrees to 70 degrees . The experimental results are in good agreement with theory. We also measured the shift across the transverse section of a Gaussian beam using same method. PMID- 23939081 TI - Space-bandwidth extension in parallel phase-shifting digital holography using a four-channel polarization-imaging camera. AB - We propose a method for extending the space bandwidth (SBW) available for recording an object wave in parallel phase-shifting digital holography using a four-channel polarization-imaging camera. A linear spatial carrier of the reference wave is introduced to an optical setup of parallel four-step phase shifting interferometry using a commercially available polarization-imaging camera that has four polarization-detection channels. Then a hologram required for parallel two-step phase shifting, which is a technique capable of recording the widest SBW in parallel phase shifting, can be obtained. The effectiveness of the proposed method was numerically and experimentally verified. PMID- 23939082 TI - Improved switching using Fano resonances in photonic crystal structures. AB - We present a simple and robust structure for realizing asymmetric Fano transmission characteristics in photonic crystal waveguide-cavity structures. The use of Fano resonances for optical switching is analyzed using temporal coupled mode theory in combination with three-dimensional finite difference time domain simulations taking into account the signal bandwidth. The results suggest a significant energy reduction by employing Fano resonances compared to more well established Lorentzian resonance structures. A specific example of a Kerr nonlinearity shows an order of magnitude energy reduction. PMID- 23939083 TI - Two-photon Lau effect. AB - The Lau effect is an interference phenomenon in which two transmission gratings are located in tandem and illuminated incoherently. Here we report the experimental observation of the quantum Lau effect using a two-photon entangled source. Two experimental schemes are proposed and performed. In one scheme, two gratings are nonlocally set in two different paths of two field modes. However, in the other scheme, only one grating is employed to receive the two-mode photons. In both schemes, the Lau interference patterns can be reproduced in a two-photon coincidence measurement where one photon is collected by a bucket detector. PMID- 23939084 TI - Raster-scan optoacoustic mesoscopy in the 25-125 MHz range. AB - We developed a raster-scan acoustic resolution broadband optoacoustic mesoscopy system and investigated the imaging performance using ultrasonic frequencies up to 125 MHz. The developed system achieves 7 MUm axial resolution and transverse resolution of 30 MUm reaching depths of at least 5 mm. This unprecedented performance is achieved by operating at out-of-focus ultrasonic detection and tomographic reconstruction. We demonstrate the limits reached due to the width of the laser pulse employed and showcase the technique on drosophila fly and drosophila pupae ex vivo. PMID- 23939085 TI - Linear cavity optical-feedback cavity-enhanced absorption spectroscopy with a quantum cascade laser. AB - A cw distributed feedback quantum cascade laser (DFB-QCL) coupled to a two-mirror linear optical cavity has been used to successfully demonstrate optical-feedback cavity-enhanced absorption spectroscopy (OF-CEAS) at 5.5 MUm. The noise equivalent absorption coefficient, alpha(min), was 2.4*10(-8) cm(-1) for 1 s averaging, limited by etalon-fringing. The temporal stability of the instrument allows NO detection down to 5 ppb in 2 s. PMID- 23939086 TI - Wavelength-tunable, sub-picosecond pulses from a passively Q-switched microchip laser system. AB - We present a novel concept to generate sub-picosecond pulses from a passively Q switched Nd:YVO4 microchip laser system with an adjustable wavelength shift up to a few tens of nanometers around the original emission wavelength of 1064 nm. This concept comprises two stages: one that carries out a nonlinear compression of fiber-amplified microchip pulses and a subsequent stage in which the compressed pulses are coupled into a further waveguide structure followed by a bandpass filter. In a proof-of-principle experiment, pedestal-free 0.62 ps long pulses have been demonstrated with a wavelength shift to 1045 nm. PMID- 23939087 TI - Experimental demonstration of lossy mode resonance generation for transverse magnetic and transverse-electric polarizations. AB - This Letter, presents the fabrication of lossy mode resonance (LMR) devices based on titanium dioxide (TiO2)/ poly(sodium 4-styrenesulfonate) (PSS) coatings deposited on side-polished D-shaped optical fibers. TiO2 thin films have been obtained by means of the layer-by-layer (LbL) self-assembly technique. LbL enables us to produce smooth and homogeneous coatings on the polished side of the fiber. This permits us to couple light from the waveguide to the TiO2 coating/external medium region at specific wavelength ranges. The generation of LMRs depends on the coating thickness, so that thicker coatings can produce more resonances. LMRs are sensitive to the external medium refractive index, which allows its utilization as refractometers. The characteristic D-shaped architecture of the devices employed in this Letter enables us to distinguish TE and TM polarizations, which had not been possible before with regular optical fibers due to their cylindrical symmetry. The results presented here show for the first time the experimental demonstration of the generation of LMRs produced by both TM and TE polarizations. More specifically, for these TiO2/PSS thin films, the TM and TM modes of the LMRs show a wavelength shift of 226 nm for the first order LMR and 56 nm for the second-order LMR. PMID- 23939088 TI - Type I and type II second harmonic generation of conically refracted beams. AB - Type I and type II second harmonic generation (SHG) of a beam transformed by the conical refraction phenomenon are presented. We show that, for type I, the second harmonic intensity pattern is a light ring with a point of null intensity while, for type II, the light ring possesses two dark regions. Taking into account the different two-photon processes involved in SHG, we have derived analytical expressions for the resulting transverse intensity patterns that are in good agreement with the experimental data. Finally, we have investigated the spatial evolution of the second harmonic signals, showing that they behave as conically refracted beams. PMID- 23939089 TI - Recursive formula to compute Zernike radial polynomials. AB - In optics, Zernike polynomials are widely used in testing, wavefront sensing, and aberration theory. This unique set of radial polynomials is orthogonal over the unit circle and finite on its boundary. This Letter presents a recursive formula to compute Zernike radial polynomials using a relationship between radial polynomials and Chebyshev polynomials of the second kind. Unlike the previous algorithms, the derived recurrence relation depends neither on the degree nor on the azimuthal order of the radial polynomials. This leads to a reduction in the computational complexity. PMID- 23939090 TI - Regenerated distributed Bragg reflector fiber lasers for high-temperature operation. AB - This Letter presents distributed Bragg reflector (DBR) fiber lasers for high temperature operation at 750 degrees C. Thermally regenerated fiber gratings were used as the feedback elements to construct an erbium-doped DBR fiber laser. The output power of the fiber laser can reach 1 mW at all operating temperatures. The output power fluctuation tested at 750 degrees C was 1.06% over a period of 7 hours. The thermal regeneration grating fabrication process opens new possibilities to design and to implement fiber laser sensors for extreme environments. PMID- 23939091 TI - Off-axis cyclic radial shearing interferometer for measurement of centrally blocked transient wavefront. AB - An off-axis cyclic radial shearing interferometer (OCRSI) to test a centrally blocked transient wavefront is proposed. Based on the standard cyclic radial shearing interferometer (CRSI), the OCRSI consists of a beam splitter, two folding mirrors, and a Galilean telescope. With the same but reversal tilt introduced to the two mirrors in OCRSI, the shearing interferogram can be obtained even when the central part of the test aperture is blocked. An improved wavefront retrieval method for OCRSI is employed, and a method to obtain the laterally sheared amount between the contracted and expanded beams is proposed. Numerical simulation and comparison experiments with a ZYGO GPI interferometer demonstrate that the OCRSI exhibits high precision and nice repeatability. PMID- 23939092 TI - Experimental demonstration of a hybrid III-V-on-silicon microlaser based on resonant grating cavity mirrors. AB - We present the experimental demonstration of a novel class of hybrid III-V-on silicon microlasers. We show that by coupling a silicon cavity to a III-V waveguide, the interaction between the propagating mode in the III-V waveguide and the cavity mode in the silicon resonator results in high, narrowband reflection back into the III-V waveguide, forming a so-called resonant mirror. By combining two such mirrors and providing optical gain in the III-V wire between these two mirrors, laser operation can be realized. This optically pumped device measures 55 by 2 MUm, requires microwatt-level threshold pump power, and shows single-mode laser emission with a side-mode suppression ratio of up to 39 dB. PMID- 23939093 TI - Inversion and tight focusing of Airy pulses under the action of third-order dispersion. AB - By means of direct simulations and theoretical analysis, we study the nonlinear propagation of truncated Airy pulses in an optical fiber exhibiting both anomalous second-order and strong positive third-order dispersions (TOD). It is found that the Airy pulse first reaches a finite-size focal area as determined by the relative strength of the two dispersion terms, and then undergoes an inversion transformation such that it continues to travel with an opposite acceleration. The system notably features tight focusing if the TOD is a dominant factor. These effects are partially reduced by Kerr nonlinearity. PMID- 23939094 TI - Orthogonal polarization Mirau interferometer using reflective-type waveplate. AB - This work proposes an orthogonal polarization Mirau interferometry using a reflective-type waveplate to generate different polarization orientations for broadband white light interferometry. The reflective-type half-waveplate is employed as the reference arm of the Mirau interferometer to convert polarization and it generates a reference light with an orientation orthogonal to the object light. An advantage of the proposed interferometer is its ability to control the ratio of light intensity between the object and reference arms to maximize the interferometric fringe contrast. Better, more accurate calibration of standard step height has been achieved by the developed interferometer, which also can measure solder bumps that traditional Mirau interferometers usually cannot measure. PMID- 23939095 TI - Inversion density threshold for Rabi oscillations and modified small-signal gain in extreme-ultraviolet lasers. AB - An expression is proposed for a threshold discriminating between classical quasi steady-state amplification and a strong pumping regime where a new dynamic behavior shows up in plasma-based extreme-ultraviolet (XUV) lasers. The criterion derived is applied to laser systems currently investigated in various laboratories. It is found that only high-gain XUV laser systems can be driven in that dynamic regime, associated with Rabi oscillations. For those systems, the small-signal dynamic gain accounting for the exponential amplification of the laser intensity is shown to be significantly smaller than the adiabatic value usually inferred from numerical simulations. PMID- 23939096 TI - Reconstruction guarantees for compressive tomographic holography. AB - Three-dimensional (3D) object tomography from a two-dimensional recorded hologram is a process of high-dimensional data inference from undersampled data. As such, recently, techniques developed in the field of compressive sensing and sparse representation have been applied for this task. While many applications of compressive sensing for tomography from digital holograms have been demonstrated in the past few years, the fundamental limits involved have not yet been addressed. We formulate the guarantees for compressive sensing-based recovery of 3D objects and show their relation to the physical attributes of the recording setup. PMID- 23939097 TI - Low-chirp high-extinction-ratio modulator based on graphene-silicon waveguide. AB - We present a hybrid graphene-silicon waveguide, which consists of a lateral slot waveguide with three layers of graphene flakes inside. Through a theoretical analysis, an effective index variation for about 0.05 is found in the waveguide by applying a voltage on the graphene. We designed a Mach-Zehnder modulator based on this waveguide and demonstrated it can process signals nearly chirp-free. The calculation shows that the driving voltage is only 1 V even if the length of the arm is shortened to be 43.54 MUm. An extinction up to 34.7 dB and a minimum chirp parameter of -0.006 are obtained. Its insertion loss is roughly -1.37 dB. This modulator consumes low power and has a small footprint. It can potentially be ultrafast as well as CMOS compatible. PMID- 23939099 TI - Nonlinearity induced critical coupling. AB - We study a critically coupled system [Opt. Lett. 32, 1483 (2007)] with a Kerr nonlinear spacer layer. Nonlinearity is shown to inhibit null scattering in a critically coupled system at low powers. However, a system detuned from critical coupling can exhibit near-complete suppression of scattering by means of nonlinearity-induced changes in refractive index. Our studies reveal clearly an important aspect of critical coupling as a delicate balance in both the amplitude and the phase relations, while a nonlinear resonance in dispersive bistability concerns only the phase. PMID- 23939100 TI - Visible wavelength silicon nitride focusing grating coupler with AlCu/TiN reflector. AB - High-performance silicon nitride focusing grating couplers with AlCu/TiN reflectors for a visible wavelength (660 nm) have been designed and fabricated in a standard complementary metal-oxide-semiconductor pilot line. The influence of the bottom oxide cladding thickness on the grating decay length and efficiency is theoretically and experimentally investigated. It is shown how the metal reflector not only increases the efficiency but also allows reduction of the radiated beam size. Coupling efficiencies above 59% have been measured for compact focusing gratings. PMID- 23939101 TI - Compressive holography with a single-pixel detector. AB - This Letter develops a framework for digital holography at optical wavelengths by merging phase-shifting interferometry with single-pixel optical imaging based on compressive sensing. The field diffracted by an input object is sampled by Hadamard patterns with a liquid crystal spatial light modulator. The concept of a single-pixel camera is then adapted to perform interferometric imaging of the sampled diffraction pattern by using a Mach-Zehnder interferometer. Phase shifting techniques together with the application of a backward light propagation algorithm allow the complex amplitude of the object under scrutiny to be resolved. A proof-of-concept experiment evaluating the phase distribution of an ophthalmic lens with compressive phase-shifting holography is provided. PMID- 23939102 TI - Single cut technique for adjustment of doubly resonant Brillouin laser cavities. AB - We report a simple technical solution for precise adjustment of short fiber cavities commonly used with Brillouin fiber lasers. The technique is based on recording the Brillouin response of the cavity to the frequency scanned laser radiation. The recorded traces are used to calculate the excess cavity length that needs to be removed from the original cavity to provide its precise adjustment to the Brillouin resonance at any preselected pump laser wavelength. The adjusted laser cavity is simultaneously resonant for pump and Stokes radiation. For demonstration of the approach, fine adjustment of a 4 m long ring cavity based on standard Corning SMF-28 fiber is performed. PMID- 23939103 TI - Fabrication of subwavelength periodic nanostructures using liquid immersion Lloyd's mirror interference lithography. AB - We have developed a liquid immersion Lloyd's mirror interference lithography system to fabricate subwavelength periodic nanostructures. In this approach, we construct the Lloyd's mirror interferometer within a liquid medium to increase the ambient index. The light wavelength is scaled by the refractive index of the immersion fluid, reducing the minimum interference pattern period and increasing the spatial resolution. The all-liquid system ensures continuous fluid contact with the sample without an external mechanism, allows rapid adjustment of pattern period with subwavelength resolution, and retains the passive vibration correction capability of Lloyd's mirror interferometers. Using this approach, we have successfully fabricated a grating structure with 112 nm period using a laser with 325 nm wavelength, attaining a numerical aperture of 1.45. The proposed immersion strategy can be adapted to improve pattern resolution of more complex interference lithography systems. PMID- 23939104 TI - Influence of temperature on upconversion multicolor luminescence in Ho3+/Yb3+/Tm(3+)-doped LiNbO3 single crystal. AB - The temperature dependence of upconversion luminescence in Ho3+/Yb3+/Tm3+ tri doped LiNbO3 single crystal was studied at different temperatures from 289 to 773 K under 980 nm excitation. The tri-doped LiNbO3 single crystal offers temperature dependent color tuning properties, and the white-light emission can be obtained by simply tuning the temperature. In addition, the competition between nonradiative transition and thermal population plays an important role in the upconversion process with temperature increase. This research has implications in the extension of research for optical temperature sensors and multicolor variable temperature display materials. PMID- 23939105 TI - Power scaling of high-efficiency 1.5 MUm cascaded Raman fiber lasers. AB - High-power fiber lasers operating at the 1.5 MUm wavelength region have attractive features, such as eye safety and atmospheric transparency, and cascaded Raman fiber lasers offer a convenient method to obtain high-power sources at these wavelengths. A limitation to power scaling, however, has been the lower conversion efficiency of these lasers. We recently introduced a high efficiency architecture for high-power cascaded Raman fiber lasers applicable for 1.5 MUm fiber lasers. Here we demonstrate further power scaling using this new architecture. Using numerical simulations, we identify the ideal operating conditions for the new architecture. We demonstrate a high-efficiency 1480 nm cascaded Raman fiber laser with an output power of 301 W, comparable to record power levels achieved with rare-earth-doped fiber lasers in the 1.5 MUm wavelength region. PMID- 23939106 TI - Photonic crystal nanofiber using an external grating. AB - We implemented a photonic crystal nanofiber device by reversibly combining an optical nanofiber and a nanofabricated grating. Using the finite-difference time domain method, we designed the system for minimal optical loss while tailoring the resonant wavelength and bandwidth of the device. Experimentally, we demonstrated that the combined system shows a strong photonic stop band in good agreement with numerical predictions. The resulting device may be used to realize strong light-matter coupling near the nanofiber surface. PMID- 23939107 TI - Physics-based simulation of the modulation transfer function in HgCdTe infrared detector arrays. AB - We have developed a numerical technique for performing physics-based simulations of the modulation transfer function (MTF) of infrared detector focal plane arrays. The finite-difference time-domain and finite element methods are employed to determine the electromagnetic and electrical response, respectively. We show how the total MTF can be decomposed to analyze the effect of lateral diffusion of charge carriers and present several methods for mitigation of such effects. We employ our numerical technique to analyze the MTF of a HgCdTe two-color bias selectable infrared detector array. PMID- 23939108 TI - Imaging performance of Bessel beam microscopy. AB - This Letter analyzes the imaging performance of Bessel beam microscopy (BBM), an imaging technique that places an axicon in the light path of a microscope. Like other superresolution imaging techniques that attempt to narrow the point spread function, in BBM there is a trade-off between spatial resolution and relative brightness of the images. The performance of BBM is analyzed using two parameters, gain and Strehl ratio, which measure the relative spatial resolution increase and relative brightness of the images, respectively. Analytical relationships for both of these parameters are provided and compared to results calculated from simulations. Finally, an optimized BBM system design is presented which has a gain of 0.7 and a Strehl ratio of 0.9. PMID- 23939109 TI - Subwavelength solitons and Faraday waves in two-dimensional lattices of metal nanoparticles. AB - We demonstrate that optically driven two-dimensional lattices of nonlinear metal nanoparticles can support a variety of dissipative localized modes including Faraday ripples, trapped and walking solitons, oscillons, and switching waves connecting different polarization states. PMID- 23939110 TI - Spectral coherence anomalies. AB - We describe the anomalous behavior of the spectral degree of coherence as a function of light frequency in the vicinity of phase singularities of partially spatially coherent, polychromatic wave fields. We distinguish the discovered spectral coherence anomalies from conventional spectral anomalies realized with fully spatially coherent optical fields. We also demonstrate how the previously reported spectral anomalies can be engineered in partially spatially coherent fields. PMID- 23939111 TI - Seventh-harmonic generation from tightly focused 2 MUm ultrashort pulses in air. AB - We report generation of third, fifth and seventh harmonics from air by using tightly focused, ultrashort pulses of short-wave infrared (2 MUm) radiation. We have measured the third- and fifth-harmonic efficiencies to be 5*10(-5) and ~1.4*10(-5), respectively, with the ratio of fifth-to-third-harmonic efficiency being close to 0.28. Our experimental results provide confirmation of expectations of the higher-order Kerr effect model. PMID- 23939112 TI - Ramsey spectroscopy with squeezed light. AB - Traditional Ramsey spectroscopy has the frequency resolution 2pi/T, where T is the time separation between two light fields. Using squeezed states and two-atom excitation joint detection, we present a new scheme achieving a higher resolution, pi/T. We use two-mode squeezed light, which exhibits strong entanglement. PMID- 23939113 TI - Third-harmonic generation in an elliptical-core ZBLAN fluoride fiber. AB - We demonstrate third-harmonic generation (THG) in an elliptical-core ZrF4-BaF2 LaF3-AlF3-NaF (ZBLAN) fluoride fiber, for the first time to our best knowledge. Linearly polarized THG around 523 nm is obtained when pumped by a pulse laser at 1560 nm. The extinction ratios of average power and peak power are ~6.7 and ~6.8 dB, respectively, in a 10 m long fiber. The extinction ratios are improved to ~11.1 and ~12.6 dB, respectively, when the fiber length is cut to 35 cm. Tunable THG from 605 to 740 nm is observed when pumped by an optical parametric oscillator with the pump wavelength changed from 1800 to 2200 nm. PMID- 23939114 TI - Defect-assisted plasmonic crystal sensor. AB - We demonstrate enhanced sensitivity of a nanostructured plasmonic sensor that utilizes resonance in intentional structural defects within a plasmonic crystal. The measured sensitivity of the fabricated nanosensor is ~500 nm/RIU showing improvement over traditional nanohole array sensors. Furthermore, the defects provide an additional design parameter to increase sensitivity by engineering plasmon lifetime. PMID- 23939115 TI - Imaging the electro-kinetic response of biological tissues with optical coherence tomography. AB - We demonstrate the feasibility of using optical coherence tomography (OCT) to detect and image an electro-kinetic response: electric-field induced optical changes (EIOC) in soft biological tissues. A low-frequency electric field was applied to ex vivo samples of porcine heart tissues, while OCT signals were acquired continuously. Experimental results show that the amplitude of the OCT signal change is proportional to the amplitude and inversely proportional to the frequency of the applied electric field. We show that the nonconductive component of the sample was eliminated in the normalized EIOC image. To the best our knowledge, this is the first time a two-dimensional image related to the electro kinetic response of soft tissues is obtained with depth resolution. Since electro kinetic properties can change during cancerogenesis, EIOC imaging can potentially be used for cancer detection. PMID- 23939116 TI - Optical vortices from closed-loop subwavelength slits. AB - We report on the singular shaping of light using closed-loop subwavelength slits whose shape is homeomorphic to the circle. Various sets of optical phase singularities can be generated depending on the given closed path whose geometry tailors the spin-orbit interaction for the light that passes through the curved slit. Here three families of closed-loop curves are considered--polygons, hypocycloids, and epicycloids. PMID- 23939117 TI - Cosine-Gaussian Schell-model sources. AB - We introduce a new class of partially coherent sources of Schell type with cosine Gaussian spectral degree of coherence and confirm that such sources are physically genuine. Further, we derive the expression for the cross-spectral density function of a beam generated by the novel source propagating in free space and analyze the evolution of the spectral density and the spectral degree of coherence. It is shown that at sufficiently large distances from the source the degree of coherence of the propagating beam assumes Gaussian shape while the spectral density takes on the dark-hollow profile. PMID- 23939118 TI - Optical tuning of dielectric properties of SrTiO3:Fe in the terahertz range. AB - Tuning of the dielectric permittivity spectra of iron-doped strontium titanate (SrTiO3:Fe) single crystals in an external optical field is investigated at room temperature by means of terahertz time-domain spectroscopy. Application of the optical field leads to an appreciable tuning of the permittivity, which reaches up to 3.8%. The observed behavior is interpreted in terms of soft-mode hardening due to the anharmonic character of its potential. We also find that the change of refractive index has a linear relationship on scale with the applied light power. These findings are attributed to the internal space charge field of photorefraction caused by the excited free carriers. PMID- 23939119 TI - Glossiness representation using binocular color difference. AB - We demonstrate that a binocular color difference can be used to express the surface glossiness of an object on 3D display devices without being accompanied by a specular reflection pattern. A simple image with a binocular color difference provides a similar surface appearance impression to a real object that has the same binocular color difference. It is found that human binocular perception is likely to interpret binocular color difference as spectral reflectance rather than as transparency. Binocular glossiness is caused not only by a binocular lightness difference but also by a chromatic or hue difference. PMID- 23939120 TI - Efficient 2.9 MUm fluorozirconate glass waveguide chip laser. AB - We report a large mode-area holmium-doped ZBLAN waveguide laser operating at 2.9 MUm, which was pumped by a 1150 nm diode laser. The laser is based on ultrafast laser inscribed depressed cladding waveguides fabricated in uniformly rare-earth doped bulk glass. It has a threshold of 28 mW and produced up to 27 mW of output power at an internal slope efficiency of approximately 20%. PMID- 23939122 TI - High-power high-repetition-rate subpicosecond monolithic Yb:KGW laser with self mode locking. AB - We report on a high-power subpicosecond monolithic self-mode-locked Yb:KGW laser with the pulse repetition rate up to several tens of gigahertz. Experimental results reveal that not only the repetition rate but also the pulse width depend on the length of the laser crystal. Using a coated Yb:KGW crystal with a length of 3.36 mm, mode-locked pulses with pulse duration of 850 fs at the repetition rate of 22.4 GHz have been achieved. With an incident pump power of 10.5 W, an average output power of 3.6 W was achieved which corresponds to the optical conversion efficiency of 34.3%. PMID- 23939121 TI - Optical clearing-aided photoacoustic microscopy with enhanced resolution and imaging depth. AB - Due to strong light scattering in tissue, both the spatial resolution and maximum penetration depth of optical-resolution photoacoustic microscopy (OR-PAM) deteriorate sharply with depth. To reduce tissue scattering, we propose to use glycerol as an optical clearing agent in OR-PAM. Our results show that the imaging performance of OR-PAM can be greatly enhanced by optical clearing both in vitro and in vivo. PMID- 23939123 TI - Vector solitons in parity-time-symmetric lattices. AB - I study vector solitons involving two incoherently coupled field components in periodic parity-time (PT)-symmetric optical lattices. The specific symmetry of the lattice imposes restrictions on the symmetry of available vector soliton states. While all configurations with asymmetric intensity distributions are prohibited, such lattices support multihump solitons with an equal number of "in phase" or "out-of-phase" spots in two components, residing on neighboring lattice channels. In the focusing medium, only the solitons containing out-of-phase spots in at least one component can be stable, while in the defocusing medium stability is achieved for structures consisting of in-phase spots. Mixed-gap vector solitons with components emerging from different gaps in the lattice spectrum also exist and can be stable in the PT-symmetric lattice. PMID- 23939124 TI - Tuning group-velocity dispersion by optical force. AB - We propose an optomechanical approach for dispersion dynamic tuning and microengineering by taking advantage of the optical force in nano-optomechanical structures. Simulations of a suspended coupled silicon waveguide show that the zero-dispersion wavelength can be tuned by 40 nm by an optical pump power of 3 mW. Our approach exhibits great potential for broad applications in dispersion sensitive processes, which not only offers a new root toward versatile tunable nonlinear photonics but may also open up a great avenue toward a new regime of nonlinear dynamics coupling between nonlinear optical and optomechanical effects. PMID- 23939125 TI - Controlled multiwavelength emission using semiconductor ring lasers with on-chip filtered optical feedback. AB - We report on an integrated approach to obtain multiwavelength emission from semiconductor ring lasers with filtered optical feedback. The filtered feedback is realized on-chip employing two arrayed-waveguide gratings to split/recombine light into different wavelength channels. Through experimental observations and numerical simulations, we find that the effective gain of the different modes is the key parameter which has to be balanced in order to achieve multiwavelength emission. This can be achieved by tuning the injection current in each amplifier. PMID- 23939126 TI - Transverse load sensing based on a dual-frequency optoelectronic oscillator. AB - We propose and experimentally demonstrate a fiber-optic sensor implemented based on a dual-frequency optoelectronic oscillator (OEO) for transverse load sensing. In the OEO loop, a phase-shifted fiber Bragg grating (PS-FBG) is employed to which a transverse load is applied to introduce a birefringence to create two orthogonally polarized notches, which leads to the generation of two oscillating frequencies. The beat frequency between the two oscillating frequencies is a function of the load force applied to the PS-FBG. The proposed sensor is experimentally demonstrated. The sensitivity and the minimal detectable load are measured to be as high as ~9.73 GHz/(N/mm) and 2.06*10(-4) N/mm, respectively. The high-frequency purity and stability of the generated microwave signal by the OEO permit extremely reliable and high-accuracy measurement. The frequency interrogation allows the system to operate at an ultra-high speed. In addition, the sensing signal is insensitive to the variations of both the environmental temperature and the optical carrier wavelength. PMID- 23939127 TI - 61 Gbits/s direct-detection optical OFDM based on blockwise signal phase switching with signal-to-signal beat noise cancellation. AB - We propose a scheme for a direct-detection optical orthogonal frequency-division multiplexing (OFDM) system based on blockwise signal-phase-switching (SPS). Experimental demonstration of 61 Gbits/s SPS direct-detection optical OFDM signal transmission over 80 km standard single-mode-fiber was successfully achieved with single polarization and a single photodetector. PMID- 23939128 TI - Mode division multiplexing technology for single-fiber optical trapping axial position adjustment. AB - We demonstrate trapped yeast cell axial-position adjustment without moving the optical fiber in a single-fiber optical trapping system. The dynamic axial position adjustment is realized by controlling the power ratio of the fundamental mode beam (LP01) and the low-order mode beam (LP11) generated in a normal single core fiber. In order to separate the trapping positions produced by the two mode beams, we fabricate a special fiber tapered tip with a selective two-step method. A yeast cell of 6 MUm diameter is moved along the optical axis direction for a distance of ~3 MUm. To the best of our knowledge, this is the first demonstration of the trapping position adjustment without moving the fiber for single-fiber optical tweezers. The excitation and utilization of multimode beams in a single fiber constitutes a new development for single-fiber optical trapping and makes possible more practical applications in biomedical research fields. PMID- 23939129 TI - Scattering of core-shell nanowires with the interference of electric and magnetic resonances. AB - We study the scattering of normally incident waves by core-shell nanowires, which support both electric and magnetic resonances. Within such nanowires, for p polarized incident waves, each electric resonance corresponds to two degenerate scattering channels while the magnetic resonance corresponds to only one channel. Consequently, when the electric dipole (ED) and magnetic dipole (MD) are tuned to overlap spectrally, the magnitude of the ED is twice that of the magnetic one, leading to a pair of angles of vanishing scattering. We further demonstrate that the scattering features of nanowires are polarization dependent, and vanishing scattering angles also can be induced by Fano resonances due to the interference of higher-order electric modes with the broad MD mode. PMID- 23939130 TI - Graphene-coated Si mold for precision glass optics molding. AB - Despite many attractive properties and well-developed micro/nano manufacturing technologies based on silicon (Si) wafers, severe adhesions between Si and glass at high temperature have limited its application as a mold material in precision glass molding. In this Letter, a coating using carbide-bonded graphene is introduced to build nonstick Si molds for glass molding. The coating has extraordinary mechanical properties and can effectively prevent Si-glass adhesion under high temperature. We demonstrated fabrications of a Fresnel lens and glass parts with micrometer pillars using graphene-coated Si molds. This newly developed process enables the use of Si as a mold material to fabricate sophisticated structures with high-precision dimensions that was not previously available. This technology will greatly improve precision glass molding process and allow high-precision low-cost glass optics to be manufactured in large quantity. PMID- 23939131 TI - Imaging of the interaction of low-frequency electric fields with biological tissues by optical coherence tomography. AB - Low-frequency electric fields propagating in ex vivo biological tissues have been observed by using double-correlation optical coherence tomography (OCT). An adaptive Wiener filtering approach has been used to remove background noise, and a Fourier domain correlation algorithm has been applied to the sequence of OCT images. The results present the first direct observation (to our knowledge) of the scope of the electric field influencing biological tissues with OCT. The results show that variation in voltage and frequency of the applied electric field relates exponentially to the magnitude of its influence on biological tissue. The magnitude of influence is about twice more for fresh tissue samples in comparison to nonfresh ones. The obtained results suggest that OCT can be used for observation and quantitative evaluation of the electrokinetic changes in biological tissues under different physiological conditions, functional electrical stimulation, and food quality control. PMID- 23939132 TI - Synthesis, photophysics, and reverse saturable absorption of platinum complexes bearing extended pi-conjugated C^N^N ligands. AB - The synthesis of ligands 1-L-6-L that feature the 6-[9,9-di(2-ethylhexyl)-7-R-9H fluoren-2-yl]-2,2'-bipyridine (C^N^N) core (R = 4-R'-phenylethynyl with R' = NO2, benzothiazol-2-yl (BTZ), H and OCH3 or R = 4'-BTZ-phenyl or BTZ) and their platinum complexes 1-6 were reported in this paper. The photophysical properties of these ligands and the Pt(II) complexes, including the UV-vis absorption spectra, emission characteristics at room temperature and at 77 K, and the triplet transient difference absorption spectra, were systematically investigated in order to understand the effects of the substituent at the 4-position of the 1 ethynylphenyl component and the extension of pi-conjugation between the C^N^N core and the BTZ substituent. Reverse saturable absorption (RSA) of complexes 1-6 was demonstrated at 532 nm using 4.1 ns laser pulses. The UV-vis absorption spectra of 1-L-6-L are featured by strong (1)pi,pi* transitions in the blue spectral region, and the absorption bands are effectively red-shifted by substitution at the 4-position of the ethynylphenyl motif and by the extended pi conjugation of the linkage. A similar effect was observed for the fluorescence spectra of these ligands in CH2Cl2 at room temperature, but the nature of the fluorescence varies from (1)pi,pi* fluorescence in 3-L and 6-L, to intraligand charge transfer ((1)ILCT) fluorescence in 1-L, 2-L and 5-L; while 4-L possesses mixed (1)pi,pi*/(1)ILCT characters. All ligands exhibit moderate triplet transient absorption (TA) in the visible spectral region, with substitution at the 4-position of the ethynylphenyl component broadening of the TA bands, while extended pi-conjugation of the linkage inducing red-shifts of the TA bands. For Pt(II) complexes 1-6, their UV-vis absorption spectra constitute red-shifted (1)pi,pi* transitions and low-energy metal-to-ligand charge transfer ((1)MLCT/(1)ILCT) tails. The emission of these complexes at room temperature in CH2Cl2 predominantly originates from the C^N^N core localized (3)pi,pi* state, probably mixed with minor (3)MLCT character. 4-Position substitution and extended pi-conjugation on the ligands exert a negligible effect on the shape and energy of the emission spectra. Similar to their respective ligands, 1-6 all exhibit broader and red-shifted TA spectra with respect to their ligands and both the 4 position substitution and extended pi-conjugation bathochromically shift the TA band maxima. The nonlinear transmission experiments carried out for 1-6 at 532 nm reveal that all complexes exhibit strong reverse saturable absorption (RSA), and the degree of RSA follows this trend: 6 <4 <5 <2 <=3 <1. The RSA performance is efficiently improved by electron-withdrawing substituents (NO2 and BTZ) and by extending the pi-conjugation; while electron-donating substituent (OCH3 in 4) decreases the RSA at 532 nm. PMID- 23939134 TI - Hide and seek: placing and finding an optimal tree for thousands of homoplasy rich sequences. AB - Finding optimal evolutionary trees from sequence data is typically an intractable problem, and there is usually no way of knowing how close to optimal the best tree from some search truly is. The problem would seem to be particularly acute when we have many taxa and when that data has high levels of homoplasy, in which the individual characters require many changes to fit on the best tree. However, a recent mathematical result has provided a precise tool to generate a short number of high-homoplasy characters for any given tree, so that this tree is provably the optimal tree under the maximum parsimony criterion. This provides, for the first time, a rigorous way to test tree search algorithms on homoplasy rich data, where we know in advance what the 'best' tree is. In this short note we consider just one search program (TNT) but show that it is able to locate the globally optimal tree correctly for 32,768 taxa, even though the characters in the dataset require, on average, 1148 state-changes each to fit on this tree, and the number of characters is only 57. PMID- 23939133 TI - Factors associated with improved biochemical response to neoadjuvant androgen deprivation therapy before definitive radiation therapy in prostate cancer patients. AB - BACKGROUND: In prostate cancer patients treated with androgen deprivation therapy (ADT) and radiation therapy (RT), a pre-RT PSA level ?0.5 ng ml(-1), determined after neoadjuvant ADT and before RT, predicts for worse survival measures. The present study sought to identify patient, tumor and treatment characteristics associated with the pre-RT PSA in prostate cancer patients. METHODS: We reviewed the charts of all patients diagnosed with intermediate- and high-risk prostate cancer and treated with a combination of neoadjuvant (median, 2.2 and 2.5 months, respectively), concurrent, and adjuvant ADT and RT between 1990 and 2011. RESULTS: A total of 170 intermediate- and 283 high-risk patients met inclusion criteria. On multivariate analysis, both intermediate- and high-risk patients with higher pre-treatment PSA (iPSA) were significantly less likely to achieve a pre-RT PSA <0.5 ng ml(-1) (iPSA 10.1-20 ng ml(-1): P=0.005 for intermediate risk; iPSA 10.1-20 ng ml(-1): P=0.005, iPSA >20 ng ml(-1): P<0.001 for high risk). High risk patients undergoing total androgen blockade were more likely to achieve a pre-RT PSA <0.5 ng ml(-1) (P=0.031). We observed an interaction between race and type of neoadjuvant ADT (P=0.074); whereas African-American men on total androgen blockade reached pre-RT PSA <0.5 ng ml(-1) as frequently as other men on total androgen blockade (P=0.999), African-American men on luteinizing hormone releasing hormone (LH-RH) agonist monotherapy/orchiectomy were significantly less likely to reach pre-RT PSA <0.5 ng ml(-1) compared with other men on LH-RH monotherapy/orchiectomy (P=0.001). CONCLUSIONS: Our findings suggest that total androgen blockade in the neoadjuvant period may be beneficial compared with LH-RH monotherapy for achieving a pre-RT PSA <0.5 ng ml(-1) in African-American men with high-risk prostate cancer. In addition, men with higher iPSA are more likely to have a pre-RT PSA greater than 0.5 ng ml(-1) in response to neoadjuvant ADT and are therefore candidates for clinical trials testing newer, more aggressive hormone-ablative therapies. PMID- 23939135 TI - Multi-locus species tree for the Amazonian peacock basses (Cichlidae: Cichla): emergent phylogenetic signal despite limited nuclear variation. AB - The inference of phylogenies of closely related species is obstructed by phenomena such as porous species boundaries and deep coalescence, and is often exacerbated by low levels of nucleotide variation among most loci surveyed in phylogenetic studies. We investigated the utility of twenty-one nuclear loci that had a range of 5-40 (median of 14) variable sites per locus to estimate the phylogeny of the genus Cichla, a group of 15 Neotropical cichlid fishes that began to diverge in the early to mid Miocene. We found that under a concatenated approach, the least variable loci, while contributing less to the overall phylogenetic signal (posterior node support), nevertheless provided information that increased support for the final tree. Moreover, this was not a result of misdirection by mutational noise, as the inference from all data was far superior to those from reduced datasets (those with more variable loci) in terms of the relative precision of posterior tree space. Phylogenetic methods that allowed each locus to have a separate genealogy, including Bayesian concordance analysis and a multispecies coalescent model, provided phylogenies that were also compatible with the concatenated tree in terms of the eight recently delimited species of Cichla, albeit with somewhat diminished support for some branches. In contrast, described species that still regularly exchange genes showed unstable relationships among analyses: not a surprising result from analyses that assume that gene tree heterogeneity results from incomplete lineage sorting and not gene flow. Importantly, we also observed that the confidence intervals for node ages in the coalescent analyses were quite wide, and likely susceptible to influence of the prior on node density (e.g. birth-death). PMID- 23939136 TI - Auditory click stimuli evoke event-related potentials in the visual cortex. AB - The objective of this study was to determine whether unimodal auditory stimuli evoke event-related potentials (ERPs) in brain areas normally designated as the visual cortex (VC). The topographical distribution of ERPs evoked by auditory click stimuli was measured from (a) electroencephalographic electrodes on the scalp of six neurologically normal adult human participants and (b) intracranial electrodes implanted on the cortex of one epileptic adult human participant. In all participants, unimodal click stimuli evoked ERPs over both the auditory cortex (AC) and the VC. Relative amplitudes of ERPs at different scalp electrodes did not support the idea that the ERPs over VC were volume-conducted versions of those over AC, and intracranial records confirmed the origin of some click-evoked ERPs in both V1 and other regions of VC. We conclude that unimodal auditory stimuli can evoke ERPs in VC. This finding adds to the earlier evidence for the effect of visual stimuli on AC by providing new evidence for bidirectional functional connectivity in the audio-visual network of the human brain. The implication is that not only do visual stimuli affect hearing; auditory stimuli also affect visual perception. PMID- 23939137 TI - P-chirogenic organocatalysts: application to the aza-Morita-Baylis-Hillman (aza MBH) reaction of ketimines. AB - The P-chirogenic organocatalysts were found to promote the enantioselective aza Morita-Baylis-Hillman reaction of ketimines derived from acyclic alpha-keto esters. In the P-chirogenic organocatalyzed aza-MBH reactions, alpha,alpha disubstituted alpha-amino acid derivatives were obtained in high yields with high enantioselectivities (up to 97% ee). PMID- 23939138 TI - Efficiency and equity in land conservation: the effects of policy scale. AB - This paper studies the effects of policy scale for land conservation schemes based on global objectives but implemented at local levels. They are explored in the classical reserve site selection framework for policy efficiency, to which we add the common social objective of equity between spatial units. We first analyze the role of the biophysical attributes of land available for conservation. These natural endowments are then combined with different implementation scales to improve a particular land-based social function: natural habitats for biodiversity. An empirical illustration, based on data from the Provence region of France, is used to explore what we identify as a policy scale trade-off between administrative units. This shows the importance of land availability in predicting the distribution of the costs and benefits of conservation schemes. In terms of equity, we find an interior solution that minimizes an inequality metric (the Gini coefficient) along policy scales. Our approach should lead to more socially acceptable conservation objectives, between the usual two extreme cases of autarky and specialization. PMID- 23939139 TI - Squaramide-catalysed enantioselective Michael addition of pyrazolin-5-ones to nitroalkenes. AB - An efficient chiral squaramide-catalysed enantioselective Michael addition of pyrazolin-5-ones to nitroalkenes has been developed. This reaction afforded the chiral pyrazol-3-ol derivatives in high to excellent yields (up to >99%) with high enantioselectivities (up to 94% ee) for most substrates under very low catalyst loading (0.25 mol%). This catalytic asymmetric reaction provides valuable and easy access to chiral pyrazol-3-ol derivatives, which possess potential pharmaceutical activity. PMID- 23939140 TI - Quantification of intramolecular cooperativity in polynuclear spin crossover Fe(II) complexes by density functional theory calculations. AB - The influence of the spin state of nearest neighbours on the spin transition of a given centre has been modelled with density functional theory methods for the linear oligomeric Fe(ii) complexes of 4-amino-1,2,4-triazole ligands. The calculated parameter Hcoop which is equal to the difference in the LS -> HS spin transition energy for a centre with two LS and two HS spin nearest neighbours, respectively, was found to be always positive, varying from 15 to 35 kJ mol(-1) depending on the applied model and exchange-correlation functional. On the other hand Hcoop was found to be of negligible value for a model of a linear Fe(ii) complex of the more flexible alkylene-bis-tetrazole ligands. This corresponds well to the observed cooperative behaviour of the spin transition for the complexes of triazole derivatives and the gradual transition for the above bis tetrazole ligands. The analysis of the bond distances in the optimised structures points towards elongation of the Fe-N bonds of the iron centre upon changing of the spin of the neighbours from low-spin to high-spin. This effect is related to the rigid nature of the bridging triazole ligand and is assumed to be the primary reason for the observed cooperativity. The presence of the next-to-nearest neighbour effects has been inferred. The effect of the softening of the Fe-N bonds in the LS centre distorted by the presence of the HS neighbours is also observed and its entropic effects are discussed. PMID- 23939141 TI - Autophagy induction promotes aristolochic acid-I-induced renal injury in vivo and in vitro. AB - Studies have found that ingestion of aristolochic acid (AA) causes nephropathy first by inducing renal tubular cell apoptosis acutely. It is currently unknown whether crosstalk between autophagy and apoptosis orchestrates the fate of tubular cells in acute AA nephropathy. We tested this hypothesis by acute administration of AA in vivo and in vitro. Autophagy was first induced in vivo through enhancing Atg5 and LC3-II expressions in kidneys of AA-I-treated rats. Punctuate LC3-GFP dots and autophagosomes were detected in this acute AA-I nephropathy rat model. We subsequently utilized normal rat renal proximal tubular epithelial cells (NRK52E) to study the autophagy mechanisms involved in acute AA I nephropathy, with 100MUM AA-I (median lethal dose 50) given in vitro. Cleavage of poly (ADP-ribose) polymerase (PARP), nuclear condensation, and fragmentation were demonstrated in the AA-I-treated NRK52E cells. Furthermore, AA-I induced Atg5 and LC3-II expressions and punctuated LC3-GFP dots. Autophagy flux by using lysosome inhibitor E64 induced the accumulation of LC3-II, which further promoted apoptosis through enhancing PARP cleavage. Inhibition of autophagy by 3-methyl adenine also led to the attenuation of AA-I-induced apoptosis, manifesting as decreased PARP cleavage, nuclei condensation, and decreased the number of cells negative for acridine orange/ethidium bromide staining. In addition, knockdown of Atg5 by short hairpin RNA attenuated LC3-II expression and PARP cleavage in NRK52E cells. Taken together, these findings suggested that the acute phase of AA I-induced nephropathy is associated with induction of Atg5-dependent autophagy, which promotes renal tubular cell apoptosis. PMID- 23939142 TI - A plea for risk assessment of endocrine disrupting chemicals. AB - Some recent EU Regulations have focused on the potential risks posed by the presence of endocrine disrupters (ED) into the environment. However there are conflicting opinions on how to assess the risk from exposure to these molecules that can reversibly modulate hormonal activity, endocrine active substances (EAS) rather than causing irreversible damage (ED). The present paper attempts to discuss that perturbation of normal endocrine homeostasis in itself may not be an adverse effect, since the endocrine system is naturally dynamic and responsive to various stimuli as part of its normal function and it is modulated according to the characteristic trend of the dose-response curve. EDs should be evaluated using a weight-of-evidence (WoE) approach. If a chemical meets the criteria to be defined as an ED in experimental animals, the relevance of observed effects to the human then needs to be addressed. Hazard-based risk management is therefore not justified since does not meet the criteria for a sound scientifically based assessment. PMID- 23939143 TI - Role of drug-independent stress factors in liver injury associated with diclofenac intake. AB - Although a basic understanding of the chemical and biological events leading to idiosyncratic drug toxicity is still lacking, it appears that drug-independent risk factors that increase reactive metabolite formation or alter cellular stress and immune response may be critical determinants in the response to an otherwise non-toxic drug. Thus, we were interested to determine the impact of various drug independent stress factors - lipopolysaccharide (LPS), poly I:C (PIC) or glutathione depletion via buthionine sulfoximine (BSO) - on the toxicity of diclofenac (Dcl), a model drug associated with rare but significant cases of serious hepatotoxicity, and to understand if enhanced toxicity occurs through alterations of drug metabolism and/or modulation of stress response pathways. Co treatment of rats repeatedly given therapeutic doses of Dcl for 7 days with a single dose of LPS 2h before the last Dcl dose resulted in severe liver toxicity. Neither LPS nor diclofenac alone or in combination with PIC or BSO had such an effect. While it is thought that bioactivation to reactive Dcl acyl glucuronides (AG) and subsequent protein adduct formation contribute to Dcl induced liver injury, LC-MS/MS analyses did not reveal increased formation of 4'- and 5-hydroxy Dcl, Dcl-AG or Dcl-AG dependent protein adducts in animals treated with LPS/Dcl. Hepatic gene expression analysis suggested enhanced activation of NFkappaB and MAPK pathways and up-regulation of co-stimulatory molecules (IL-1beta, TNF-alpha, CINC-1) by LPS/Dcl and PIC/Dcl, while protective factors (HSPs, SOD2) were down regulated. LPS/Dcl led to extensive release of pro-inflammatory cytokines (IL 1beta, IL-6, IFN-gamma, TNF-alpha) and factors thought to constitute danger signals (HMGB1, CINC-1) into plasma. Taken together, our results show that Dcl enhanced the inflammatory response induced by LPS - and to a lesser extent by PIC - through up-regulation of pro-inflammatory molecules and down-regulation of protective factors. This suggests sensitization of cells to cellular stress mediated by non-drug-related risk factors by therapeutic doses of Dcl, rather than potentiation of Dcl toxicity by the stress factors. PMID- 23939146 TI - Adequate margin definition for scanned particle therapy in the incidence of intrafractional motion. AB - Advanced 4D dose calculations (4DDCs) for scanned particle therapy show that in the incidence of motion, it is insufficient to use target contours defined on one reference CT phase. ICRU Report 62 (ICRU 1999 ICRU Report 62 (Bethesda, MD: ICRU)) advises that variations in size, shape and position of CTVs relative to anatomic reference points have to be considered for internal target volumes (ITVs). In addition to geometrical margin adaption, changes of water equivalent path length have to be considered for particle therapy. Different ITV concepts have been applied to six representative patients (liver and lung indications) based on 4DCT. Geometrical ITVs (gITV) were calculated by combining deformed CTVs over all motion phases. To take into account path length changes, range adapted ITVs (raITV) were established as the union of range adapted CTVs in all phases. For gated delivery, gat_gITVs and gat_raITVs were calculated. Extensive 4DDCs have been performed for two exemplary patients to illustrate that neither re scanning nor gating can sufficiently compensate for motion effects if no appropriate margins are employed and to evaluate the effectiveness of gITVs and raITVs. CTVs significantly differ from gITVs and raITVs in size (up to a factor 2 in volume). But also raITVs and gITVs differ significantly in size and are spatially displaced, particularly for lung patients. raITVs show a strong field dependence in shape. All volumes are reduced in size when gating is applied and considered during margin adaption. 4D dose distributions show big improvements when gITV or raITV are used compared to CTVs. However, the use of either gITVs or raITVs do not result in significant differences. If raITVs are used, slightly better target coverage is gained at the cost of more healthy tissue exposure. Our results emphasize that adapted target volumes have to be used for scanned particle therapy in the presence of motion. However, even though gITVs and raITVs differ significantly in shape and size, this difference does not necessarily translate into significant differences in the resultant 4D dose distributions. PMID- 23939144 TI - Srs2 prevents Rad51 filament formation by repetitive motion on DNA. AB - Srs2 dismantles presynaptic Rad51 filaments and prevents its re-formation as an anti-recombinase. However, the molecular mechanism by which Srs2 accomplishes these tasks remains unclear. Here we report a single-molecule fluorescence study of the dynamics of Rad51 filament formation and its disruption by Srs2. Rad51 forms filaments on single-stranded DNA by sequential binding of primarily monomers and dimers in a 5'-3' direction. One Rad51 molecule binds to three nucleotides, and six monomers are required to achieve a stable nucleation cluster. Srs2 exhibits ATP-dependent repetitive motion on single-stranded DNA and this activity prevents re-formation of the Rad51 filament. The same activity of Srs2 cannot prevent RecA filament formation, indicating its specificity for Rad51. Srs2's DNA-unwinding activity is greatly suppressed when Rad51 filaments form on duplex DNA. Taken together, our results reveal an exquisite and highly specific mechanism by which Srs2 regulates the Rad51 filament formation. PMID- 23939147 TI - Assigning site of origin in metastatic neuroendocrine neoplasms: a clinically significant application of diagnostic immunohistochemistry. AB - The neuroendocrine epithelial neoplasms (NENs) include well-differentiated neuroendocrine tumors (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs). Whereas PDNECs are highly lethal, with localized Merkel cell carcinoma somewhat of an exception, WDNETs exhibit a range of "indolent" biologic potentials-from benign to widely metastatic and eventually fatal. Within each of these 2 groups there is substantial morphologic overlap. In the metastatic setting, the site of origin of a WDNET has significant prognostic and therapeutic implications. In the skin, Merkel cell carcinoma must be distinguished from spread of a visceral PDNEC. This review intends to prove the thesis that determining the site of origin of a NEN is clinically vital and that diagnostic immunohistochemistry is well suited to the task. It will begin by reviewing current World Health Organization terminology for the NENs, as well as an embryologic and histologic pattern-based classification. It will present population-based data on the relative frequency and biology of WDNETs arising at various anatomic sites, including the frequency of metastases of unknown primary, and comment on limitations of contemporary imaging techniques, as a means of defining the scope of the problem. It will go on to discuss the therapeutic significance of site of origin. The heart of this review is a synthesis of data compiled from >100 manuscripts on the expression of individual markers in WDNETs and PDNECs, as regards site of origin. These include proteins that are considered "key markers" and others that are either useful "secondary markers," potentially very useful markers that need to be further vetted, or ones that are widely applied despite a lack of efficacy. It will conclude with my approach to the metastatic NEN of unknown origin. PMID- 23939148 TI - MYC/BCL2 double-hit high-grade B-cell lymphoma. AB - Double-hit lymphoma (DHL) has been defined by others as a B-cell lymphoma with MYC/8q24 rearrangement in combination with a translocation involving another gene, such as BCL2, BCL3, or BCL6. The most common form of DHL has translocations involving MYC and BCL2, also known as MYC/BCL2 DHL. In recent years, a number of case series of MYC/BCL2 DHL have been published. Most cases of MYC/BCL2 DHL morphologically resemble diffuse large B-cell lymphoma (DLBCL) or B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma. These tumors are of B-cell lineage, have a germinal center B-cell immunophenotype with a high proliferation rate, and a complex karyotype. Patients with these tumors have an aggressive clinical course and poor prognosis despite high-intensity chemotherapy. More recently, studies have suggested expanding the spectrum of MYC/BCL2 DHL to include cases that have concurrent MYC and BCL2 cytogenetic abnormalities, but not necessarily translocations. In addition, overexpression of MYC and BCL2 has been shown in an appreciable subset of DLBCL tumors. These tumors show overlap with MYC/BCL2 DHL, but are not equivalent. In this review, we discuss the clinicopathologic, immunophenotypic, cytogenetic, and prognostic features of MYC/BCL2 DHL. PMID- 23939149 TI - Is immunohistochemistry always required to diagnose lung cancer? AB - Non-small cell lung cancer is possibly the solid tumor with more potential drugable molecular targets, but the smallest tumor specimens. An optimization of tumor tissue handling is then mandatory. In this landscape, the precise definition of non-small cell lung cancer histologic type had a renewal role in selecting different therapeutic strategies, also leading to a large use of immunohistochemistry even in malignancies showing an overt morphologic differentiation. We suggest here 4 different clinicopathologic scenarios with some helpful rules aimed at preventing unnecessary and expensive immunostains, then underlining the ageless value of morphology and preserving tumor tissues for molecular investigations. PMID- 23939150 TI - What is new in adnexal tumors of the skin? AB - This article reviews the recent dermatopathology literature regarding cutaneous adnexal neoplasms, with emphasis on new and underrecognized entities, "old entities" with new findings, advances in immunohistochemistry, and new findings in relation to inherited disorders associated with cutaneous adnexal neoplasms. PMID- 23939151 TI - Well-differentiated adenocarcinoma-bronchioloalveolar carcinoma-in situ adenocarcinoma: a conundrum. AB - Over the last decade, considerable changes have been made to the classification of pulmonary adenocarcinoma, mainly with respect to the classification of small solitary tumors. The main goal seems to have been the identification of tumors that not only follow an indolent clinical course but that can also be treated more conservatively. Thus, the most important change to the classification of lung adenocarcinoma was proposed for a tumor no greater than 3.0 cm in size with a pure lepidic growth pattern and lacking stromal, vascular, or pleural invasion, which should now be categorized as in situ adenocarcinoma. At the same time, a category of minimally invasive adenocarcinoma was proposed for tumors with a predominantly lepidic growth pattern, <3 cm in size, and with <5 mm invasion in greatest dimension in any 1 focus. What is interesting about all these developments is the fact that all the publications on this issue have been presented under the terms of small adenocarcinomas or bronchioloalveolar carcinoma. Unfortunately, the literature reviews that have proposed the change in nomenclature to in situ adenocarcinoma have not offered a more in-depth assessment of these neoplasms. More recently, a publication of a large series of cases of small adenocarcinomas has offered a different view and underscored some of the important issues that need to be taken into account before a serious change in the nomenclature can be considered. PMID- 23939152 TI - Value of GATA3 immunostaining in tumor diagnosis: a review. AB - GATA3 is a member of a group of zinc-finger transcription factors that is involved in cell development and differentiation. Recent studies have shown that, among tumors, GATA3 is commonly expressed in both urothelial tumors and breast epithelial neoplasms. With the exception of salivary gland and parathyroid tumors, GATA3 has been reported to be either absent or only rarely expressed in other epithelial tumors. Owing to its restricted expression in urothelial and breast carcinomas, GATA3 has proved to be a useful immunohistochemical marker for assisting in distinguishing these 2 groups of neoplasms from other malignancies with which they may be confused. PMID- 23939153 TI - Selected case from the Arkadi M. Rywlin International Pathology Slide Club: aggressive angiomyxoma, left labial region in a postmenopausal woman. AB - Club members unanimously agreed with the diagnosis of an unencapsulated 8*2.5*3.6 cm aggressive angiomyxoma, which was invading the voluntary muscles of the pelvic floor beneath the left labium of a female aged 65. The tumor consisted of histologically bland, round, stellate to fusiform cells set in a myxocollagenous matrix with occasional mast cells, a few extravasated red cells, and prominent blood vessels varying from thin-walled capillaries 7 um in diameter to larger thick-walled vessels >250 um in diameter. The tumor cells stained positively for estrogen and progesterone receptors, vimentin, and desmin. A stain for the nuclear transcription factor HMGA2, which is emerging as a useful and relatively specific marker for aggressive angiomyxoma, was not performed. The tumor had not recurred 4 years after the surgical excision. One member commented that virtually all lesions diagnosed as aggressive angiomyxomas in superficial locations turn out to be either fibroepithelial stromal polyps or superficial angiomyxomas. None of the club had seen a metastasizing aggressive angiomyxoma nor had they any experience with gonadotropin hormone-releasing and luteinizing hormone-releasing agonists therapy, which have been reported to cause tumor regression. PMID- 23939154 TI - [Pathological and immunohistochemical analyses of 32 cases of nephrogenic adenoma]. AB - OBJECTIVE: To observe clinical and pathological features of nephrogenic adenoma (NA), and to find some useful immunohistochemical markers for its diagnosis. METHODS: The clinical features of 32 NA patients were obtained. Each case underwent microscopic observation and immumohistochemical staining. The primary antibodies were alpha-methylacyl-CoA racemase (AMACR, P504S), cytokeratin AE1/AE3, cytokeratin 7 (CK7), cytokeratin 20 (CK20), paired-box 2 (PAX2), paired box 8 (PAX8), vimentin, membrane metallo-endopeptidase (MME, CD10), prostate specific antigen (PSA), high molecular weight cytokeratin (34betaE12), P63 and carcinoembryonic antigen (CEA). RESULTS: NA mainly involved old men, and the bladder was the commonest location. The macroscopic features were prevalently small polypoid or papillary lesions, ranging from 1 mm to 10 mm (mean=4). The typical histological features included tubular, tubulocystic, polypoid and/or papillary. Immunohistochemistry for NA was positive for AMACR, AE1/AE3, PAX2, PAX8, CK7, vimentin and CD10. The negative immunostain for NA included P63, PSA and CEA. CONCLUSION: NA is a rare and easily misdiagnosed lesion. Careful histological examination is essential to accurately identify this lesion. A panel composed of AMACR (P504S), PAX8/PAX2, CK7, P63, PSA and CEA appears to be sensitive and specific in differentiating NA from its mimics of urothelial and prostatic origins. PMID- 23939155 TI - [Androgen receptor silencing by shRNA inhibits human prostate cancer xenograft growth in nude mice]. AB - OBJECTIVE: To investigate the inhibitory effect of silencing androgen receptor (AR) gene by AR short-hairpin RNA (shRNA) on the growth of human prostate cancer xenograft in nude mice. METHODS: Human 22RV1 prostate cancer cells were inoculated subcutaneously into nude mice to establish xenograft models of human prostate cancer. Meanwhile, a short-hairpin RNA that was capable of suppressing the expression of AR was constructed and then recombinant plasmids producing AR shRNA were prepared in a large number. The tumor-bearing mice were randomly divided into 2 groups: the control group and the experimental group. When the tumor volume grew to about 300 mm(3), the plasmids prepared previously were injected into the tail veins of the mice once at the dose of 2 MUg/g in the experimental group, whereas the mice in the control group was injected with the same amount of saline as control. The tumor volumes were monitored every other day until 14 days after the treatment.At the endpoint,the mice were sacrificed and the tumors were excised, weighed, fixed in buffered-formalin, and embedded in paraffin for the immunohistochemical analysis of AR,Ki-67 (a marker of proliferative cell) levels and apoptotic cell labeling by TUNEL (terminal deoxynucleotidyl transterase-mediated dUTP nick end labeling) assay. A semiquantitative immunohistochemical scoring system, HSCORE system, was used to evaluate the expression of AR and proliferative index/Ki-67 labeling index (PI/Ki 67 LI) and apoptotic index (AI) were used to assess the cell proliferation and cell apoptosis, respectively. RESULTS: Compared with the control group, the treatment induced an evident inhibitory effect on the tumor growth in the nude mice with prostate cancer. At the endpoint, the tumor volume of (1 199.56+/ 86.48) mm(3) in the experimental group was significantly smaller than that of (1 742.02+/-98.16) mm3 in the control group (P=0.002). The tumor weight of (1 006.2+/-79.1) mg in the experimental group significantly decreased compared with that of (1 383.4+/-74.8) mg in the control group (P=0.005). The AR HSCORE,PI and AI in the experimental group were 25.8+/-6.7, (26.0+/-3.1)%, (55.6+/-7.9)%, respectively, and those in the control group were 268.8+/- 18.7, (87.6+/-7.9)%, (27.2+/-3.9)%, respectively. There were significant differences between the two groups (all P<0.01). CONCLUSION: AR shRNA could be injected intravenously to suppress the expression of AR in vivo and hence inhibit the growth of human prostate cancer xenograft in nude mice. PMID- 23939156 TI - [Expression of circulating microRNAs in patients with bladder urothelial carcinoma]. AB - OBJECTIVE: To search for differentially expressed microRNAs in circulation and to explore their potential application as non-invasive biomarkers for bladder urothelial carcinoma. METHODS: Six bladder urothelial carcinoma patients were recruited into this study, and blood from seven non-tumor patients was included as the controls. Total small RNAs were isolated from the blood. By using high throughput sequencing technologies, we provided microRNA expression profiles of bladder urothelial carcinoma patients and the control group. The data were analyzed using T test of the SPSS17.0 software to study the expression differences of microRNAs between the two groups. RESULTS: The work identified some microRNAs with differential expression in circulation between the bladder urothelial carcinoma patients and the non-tumor patients. Five microRNAs (hsa-miR 378g, hsa-miR-942, hsa-miR-106a-5p, hsa-miR-142-3p and hsa-miR-374a) were identified to be upregulated in the patients, and the expressions of many other microRNAs were significantly downregulated. CONCLUSION: The study reveals that there is a variance of microRNA expression profile in circulation between bladder urothelial and non neoplastic populations,The results need further study by large samples. PMID- 23939157 TI - [Expressions of CMTM8 and E-cadherin in primary and metastatic clear cell renal cell carcinoma]. AB - OBJECTIVE: To investigate the expression and clinical pathological significance of CMTM8 and E-cadherin in primary and metastatic clear-cell renal cell carcinoma. METHODS: The immunohistochemistry was used to detect the expressions of CMTM8 and E-cadherin in 17 cases of primary clear-cell renal cell carcinoma, 8 cases of normal renal tissue, 9 cases of metastatic renal cell carcinoma in lungs and 10 cases of metastatic renal cell carcinoma in bones. RESULTS: The membranous staining intensities of CMTM8 and E-cadherin in normal renal tissue were strong, but reduced in low-grade clear-cell renal cell carcinoma. There were positive cytoplasmic stainings of CMTM8 and E-cadherin in high-grade clear-cell renal cell carcinoma. Increased cytoplasmic expression of CMTM8 was frequent in metastatic renal cell carcinoma, accompanied with reduced cell surface staining. The expression of E-cadherin could be negative or weakly positive at membrane and cytoplasma. CMTM8 and E-cadherin expressions were negatively correlated with development and metastasis in clear-cell renal cell carcinoma (r=-0.841 and r= 0.732, P<0.001). Moreover, CMTM8 was also correlated with the expression of E cadherin (r=0.694, P<0.001). CONCLUSION: CMTM8 and E-cadherin are negatively correlated with tumorgenesis and development in clear-cell renal cell carcinoma. The location and intensity of their expressions have significant association with the prognosis. PMID- 23939158 TI - [Urothelial carcinoma accompanied with other malignant tumor after renal transplantation: 9 cases report]. AB - OBJECTIVE: To investigate the patterns and control measures of the multiple malignancy occurring with urothelial carcinoma (UC) in patients after renal transplantation. METHODS: A retrospective analysis was made of 3 370 renal transplant recipients. Of all the subjects, 169 developed malignancy, of whom 9 patients developed other multiple malignant tumors occurring with UC, 8 patients were female and 1 male. The median age was 55 years (49-67 years), and the median diagnosis time of tumor after surgery was 38 months (8-80 months). All of them received operation as therapy. RESULTS: In 9 patients other multiple malignancy occurred with UC: 2 urothelial squamous cell carcinoma (SCC), 2 sarcoma, 2 colon adenocarcinoma, 1 skin SCC, 1 poorly differentiated adenocarcinoma combined with micro-papillary carcinoma of bladder and 1 renal chromophobe cell carcinoma. Of the 9 patients, 7 were alive in postoperative follow-ups for 32-172 months, of whom 2 received hemodialysis after the removal of dysfunctional allograft, and 5 were alive with functioned allograft. Two patients died of tumor metastasis in 6 months after operations. CONCLUSION: The multiple accompanying malignancy can happen in patients who have developed UC after renal transplantation. The possibility of multiple malignancy occurrences should be regarded among renal transplant recipients, since early diagnosis and treatment are essential to the improvement in the survival of the patients. PMID- 23939159 TI - [Combined application of 2 micron microwave resection and laparoscopy in treatment of urinary tumor in patients after renal transplantation]. AB - OBJECTIVE: To reduce the negative intervention for the transplant kidney and explore the optimal operational method for treating urinary tumor in patients after renal transplantation. METHODS: From March 2006 to March 2013, a total of 12 post renal transplantation patients with renal pelvis tumor/ureter tumor underwent operations. After the general anesthesia, the patient was placed in lithotomy position. The 2 micron microwave resection was performed, with the ureteral orifice as the center. After the ureteral wall section was resected, the resection was forwarded 6 cm. Then the patient was placed in lateral position. The laparoscopic radical nephrectomy was performed, and when this procedure was completed, the laparoscopy was converted to the other side to observe to the bladder side. Meanwhile, the operator pulled the ureter and maintained some tension, using the ultrasound knife to dissect the adjacent tissue and avoiding injuring the transplant kidney. With this method, the resected distal ureter and partial bladder were resected en bloc. In some condition, the uerteral tumor was tightly connected to the adjacent tissue, and the upper ureter failed to be removed completely, a short incision could be performed besides the musculus rectus abdominis. The Foley catheter had remained for 2 weeks after the operation. RESULTS: The 12 operations were successfully performed. The operation duration ranged from 110 to 290 minutes, and the bleeding volume was from 50 to 200 mL. Only one female patient developed secondary bleeding 18 hours after the operation, however, the secondary operation successfully stopped the bleeding. The mean hospital stay was 10.5 days. CONCLUSION: The combination use of 2 micron microwave resection and laparoscopy in the treatment of urinary tumor in patients after renal transplantation is effective, and has its advantages: lowering the risk of damaging the transplant kidney and easing the operation. Furthermore, this procedure is minimally invasive and safe. The patient could recover soon. PMID- 23939160 TI - [Surgical management and long-term outcomes of patients with renal cell carcinoma accompanied with venous tumor thrombus]. AB - OBJECTIVE: To evaluate the surgical management and long-term outcomes of patients with renal cell carcinoma and venous tumor thrombus. METHODS: From Aug. 2000 to Dec. 2011, 140 patients underwent radical nephrectomy and thrombectomy in our hospital, of whom, 80 were with renal vein tumor thrombus, 41 with inferior vena caval (IVC), level I tumor thrombus (below hepatic vein), 13 with IVC level II tumor thrombus (above hepatic vein but below diaphragm) and 6 with IVC level III tumor thrombus (above diaphragm). The overall and cancer-specific survival rates were analyzed with Kaplan-Meier survival curve method. RESULTS: The follow-up information of the 114 patients was gained. The median follow-up period for all the patients was 20.5 months (1-96). In the last follow-up, 47 patients died. The median survival time for all the patients was 51 months. The median survival time for the patients with renal vein tumor thrombus and IVC level Ito III tumor thrombus were 57, 43, 40 and 27 months. The 5 year overall survival (OS) and cancer-specific survival (CSS) rates for all the patients were 40.1% and 47.2%, respectively. The survival time of the patients with early tumor thrombus (below hepatic vein) was significantly longer than that of the patients with advanced tumor thrombus (above hepatic vein) (54.1+/-4.8 months vs. 26.9+/-5.7 months, P=0.049). CONCLUSION: Radical nephrectomy and thrombectomy are effective therapies for RCC patients with venous extension. The patients can obtain a relatively promising long-term outcome, which is comparable to previous western studies. Long-term outcome of the early tumor thrombus patients is significantly better than that of the advanced tumor thrombus patients. PMID- 23939161 TI - [Retrospective analysis of primary renal sarcoma: 17 cases report]. AB - OBJECTIVE: To investigate the clinical characteristics,prognosis, survival and diagnosis of primary renalsarcoma. METHODS: In the study,17 cases of renal sarcoma were reviewed and analyzed, the incidence, clinical manifestations, treatments and prognosis of renal sarcoma discussed and analyzed, and the correlated literature also reviewed. RESULTS: Radical nephrectomy was the main treatment for 16 cases, one case was punctured and pathologized. The distributions of pathology were leiomyosarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma, synoviosarcoma, liposarcoma, and clear-cell sarcoma. Thirteen of the subjects were followed-up, and the time of survival varied from 7 to 132 months. CONCLUSION: Renal sarcomas are rare and highly malignant and the prognosis is poor. Early diagnosis and radical nephrectomy can prolong the patient's life. PMID- 23939162 TI - [Necessity of prophylactic contralateral nephroureterectomy in the renal transplantation patients with transitional cell carcinoma of unilateral upper urinary tract]. AB - OBJECTIVE: To discuss the necessity of prophylactic contralateral nephroureterectomy in renal transplantation patients with upper urinary tract transitional cell carcinoma (TCC). METHODS: In our study 15 renal transplantation patients with upper urinary tract TCC were involved from Dec.2006 to May 2013. All the patients received prophylactic contralateral nephroureterectomy 3 months after their last nephroureterectomy. A retrospective analysis was performed. RESULTS: TCC of upper urinary tract was confirmed by postoperative pathology in all the 15 cases .Similarly, TCC of contralateral upper urinary tract was detected in 7 of these cases (46.7%), and 13 survived after 36 months' follow-up (86.7%). CONCLUSION: In the renal transplantation patient with unilateral upper urinary tract TCC, the possibility of contralateral upper urinary tract TCC is high, thus the necessity of prophylactic contratateral nephroureterectomy is certain. PMID- 23939163 TI - [Prognostic and long term follow-up analysis of sporadic bilateral renal cell carcinoma]. AB - OBJECTIVE: To investigate the pathological feature, therapy and prognosis of bilateral sporadic renal cell carcinoma. METHODS: The data of 59 bilateral sporadic renal cell carcinoma patients diagnosed from Apr. 1986 to Dec. 2009 were collected. We retrospectively analyzed the treatment, pathological features, long term survival and prognosis factors of the disease. RESULTS: We found 59 patients with bilateral sporadic renal cell carcinoma (RCC) in the database diagnosed from Apr. 1986 to Dec. 2009. The median age was 56 years. Of all the cases, 37 were bilateral synchronous sporadic renal cell carcinoma and 22 bilateral metachronous sporadic renal cell carcinoma. Forty-three patients underwent bilateral surgeries, 11 unilateral surgery, and 5 no treatment. There were 122 masses in the 59 patients and 109 masses had pathological reports. All the 59 cases were RCC, and clear cell carcinomas was the main subtype (96.6%). The median follow-up time was 62.1 months (range 4-277 months). Thirty-nine patients (66.1%) survived without tumor recurrence, 4 survived with tumors recurrence, and 16 (27.1%) died. Kaplan-Meier curve revealed that the 3-year and 5-year overall survival rates were 83.5% and 81.1%, respectively; the 3-year and 5-year cancer special survival rates were 73.1% and 64.8%, respectively. The disease-free survival rates of bilateral synchronous and bilateral metachronous RCC were similar. Multivariate regression suggested that post-operative application of interferon-alpha and bilateral surgeries were related with a better prognosis. CONCLUSION: The main subtype of bilateral sporadic renal cell carcinoma was clear cell carcinoma (96.6%). Bilateral synchronous and bilateral metachronous RCC both had a long time disease-free survival. Interferon-alpha application after surgery and bilateral surgeries were related with a better prognosis. PMID- 23939164 TI - [Tea polyphenol protects against HK-2 cell injury induced by oxalate and calcium oxalate monohydrate crystals]. AB - OBJECTIVE: To test whether the antioxidants tea polyphenol (TP) can provide protection against oxalate and calcium oxalate monohydrate (COM) crystals toxicity in HK-2 cells. METHODS: Four groups were chosen for the study: Negative control group, positive control group (COM+oxalate), TP group (TP+COM+oxalate), VitE group (vitamin E+COM+oxalate). HK-2 cells were exposed for 4, 8, 12 and 24 h. The viability of the cells was assessed by MTT. The cellular injury was assessed by the concentration of lactate dehydrogenase (LDH), hydrogen peroxide and viability of Na+/K+ ATP enzyme. The peroxidation level was assessed by malondialdehyde (MDA) content and viability of superoxide dismutase (SOD). The morphological changes of HK-2 cells after being exposed for 4 and 12 h in each group were observed by transmission electron microscope (TEM). RESULTS: The effects of TP and vitamin E on oxalate and COM exposed cells were tested. The HK 2 cells exposed to oxalate and COM showed a significant reduction in viability of cells, Na+/K+ ATPase and SOD. LDH release, MDA content and concentration of H2O2 were significantly increased. In TP group, the addition of TP significantly increased viability of cells, activity of Na+/K+ ATPase and SOD while LDH release, MDA content and concentration of H2O2 were significant decreased compared with the positive control group. In the Vitamn E group, compared with the positive control group, viability of cells, and activity of Na+/K+ ATPase were not significantly changed and after addition of vitamin E, SOD activity was restored, LDH release, MDA content and concentration of H2O2 were significant decreased compared with the positive control group. The morphological changes of HK-2 cells were observed by TEM in the positive control group, TP group and VitE group. In the VitE and TP groups, the amount of the cells with vacuoles formed in kytoplasms, mitochondria swelling, karyotheca dissolved and nucleolus disappearing were less than in the positive group. The morphological changes in the TP group were less than in the VitE group. CONCLUSION: TP and vitamin E administration may prevent oxalate and COM mediated peroxidative injury and restore intracellular antioxidant enzyme activity. The protection rendered by TP was greater than that of vitamin E. PMID- 23939165 TI - [Tubeless 24 F tract percutaneous nephrolithotomy in treatment of renal and proximal ureteral calculi]. AB - OBJECTIVE: To evaluate the feasibility and efficacy of tubeless 24 F (1 F=0.33 mm)tract percutaneous nephrolithotomy (PCNL) in the treatment of renal and proximal ureteral stones in Chinese patients. METHODS: In the study, 108 patients treated with tubless 24 F tract PCNLs during September 2009 and April 2013 in our department were retrospectively analyzed, of whom, 42 were with renal calculi (the max diameter of calculi 2-4 cm, including 4 with simple staghorn stones), 41 with upper ureteral stones (the max diameter of calculi more than 1.5 cm or failure treated with extracorporeal shock wave lithotripsy), and 25 with upper ureteral stones combined with simple renal stones. Tubeless 24 F tract PCNL was performed when serious renal infection, obstraction in the distal of stone, the thickness of cortex less than 5 mm, operation time more than 90 min, residual stones needing second PCNL, severe bleeding during operation, pelvic perforation and obvious urinous infiltration were excluded. RESULTS: All the 108 patients were treated successfully with tubeless 24 F tract PCNL. Residual stone(about 5 mm in diameter)was found only 1 patient's lower calyces. The stone clearance rate was 99.1%, the average operation time was (40.5+/-9.1) min, the mean VAS on the first day postoperation was 3.0+/-1.6, the preoperative and postoperative hemoglobin decrease was (4.8+/-2.7) g/L, no blood transfusion and angiography and embolization needed, no pleural and other adjacent organ injury occurred. One patient got fever postoperatively (>38.5 degrees C). No perirenal hematoma and urine leakage were found. The average postoperative hospital stay was (2.4+/-0.6) days. All the patients were followed up for 1 month, and no other complication occurred. CONCLUSION: Tubeless 24 F tract PCNL can be a feasible way for renal stones and upper ureteral stones treatment, based on the severity candidate, perfect operative procedures and precise judgment at the end of the operation. PMID- 23939166 TI - [Technical improvement of transumbilical laparoendoscopic single-site nephrectomy]. AB - OBJECTIVE: To summarize the technical modification and experiences of transumbilical laparoendoscopic single-site nephrectomy (LESS-N) by homemade device. METHODS: The clinical data of LESS nephrectomy performed from June 2010 to April 2013 in Peking University Third Hospital were analyzed retrospectively. All the cases were divided into two groups according to the technique method and operative date. Group 1 included 10 cases that underwent LESS radical nephrectomy and 2 that received LESS simple nephrectomy from June 2010 to April 2011. Group 2 included 7 cases that underwent LESS radical nephrectomy and 3 that received LESS simple nephrectomy from May 2011 to April 2013. The data on the general presentation, tumor size, tumor location, operative time, blood loss, complications, Visual Analog Pain Scale (VAPS), postoperative hospital stay, pathological results were collected to compare between the two groups. The modified technique included homemade single-ring glove technique, fast access to the pedicle, pulling-up technique to retract the kidney or liver. The kidney was dissociated after the renal vessel was cut off and extracted through the umbilical incision. RESULTS: All the procedures were finished without conversion to open radical nephrectomy. Compared with group 1, operative time showed significant difference in group 2 [Group 1:(220.6+/-51.0) min; Group 2: (178.9+/ 34.0) min; P=0.04],and no difference was noted in other factors (P>0.05). There was no secondary bleeding, wound infection, intestinal obstruction, incision hernia and other severe postoperative complications. follow-up of 2 to 36 months showed no local recurrence. CONCLUSION: Transumbilical LESS-N is feasible, effective and safe. It gives a more mini-invasive and cosmetic option for young or female patients. Learning curve and operative time can be reduced by modified techniques, such as single-ring glove technique and pulling-up technique. PMID- 23939167 TI - [Complications of laparoscopic surgery: a 11-year single institute experience]. AB - OBJECTIVE: To analyze the complications of laparoscopic surgery for the past 11 years in the Urology Department of Peking Union Medical College Hospital. METHODS: The laparoscopic surgery of 5 386 cases from Jan. 2002 to Dec. 2012 was statistically analyzed. The patient's gender, age, surgery mode, blood loss, complications, total length of hospital stay, postoperative hospital stay and other data were analyzed. RESULTS: There were 5 386 cases in this group aged 8-86 years (the mean age: 49.0 years; 2 651 cases were male and 2 735 female). Of all the cases, 2 411 were of adrenal surgery, accounting for 44.7%, 167 of retroperitoneal tumor resection , accounting for 3.1%, 763 of radical nephrectomy surgery, accounting for 14.2%, 441 of partial nephrectomy surgery, accounting for 8.2%, 784 of renal cyst surgery, accounting for 14.6%; 279 of semi-urinary tract resection, accounting for 5.2%; 74 of renal pelvis and ureter plasty, accounting for 1.4%; 141 of radical prostatectomy surgery, accounting for 2.6%, 71 of cystectomy surgery, accounting for 1.3% and 255 of other surgery, accounting for 4.7%. The blood loss was 10-3 000 mL (average: 97.5 mL ) and the surgery requiring blood transfusion treatment involved 270 patients. The total hospital stay was 3-133 days (average: 18 days) and postoperative hospital stay was 2-35 days (average: 6.3 days). All kinds of complications occured in 346 cases (6.42%), of which 198 were of peritoneal injury, 12 of pleural injury; 72 of subcutaneous emphysema, 24 of urinary fistula, 15 of inferior vena cava injury, 6 of pancreatic fistula 10,of lymphatic fistula, 8 of wound delayed healing and 1 of, intestinal fistula. The incidence of the complications and blood transfusion showed a downward trend according to stratified analysis each year. CONCLUSION: The laparoscopic surgery coveres almost all treatment of urological diseases. The complications are different in different types of surgery at different times, but generally no serious complications occurr. The incidence of complications is in a downward trend as the laparoscopic technique level improves. PMID- 23939168 TI - [Endoscopic therapy combined antegrade percutaneous approach and retrograde transurethral approach for ureteral obstruction after kidney transplantation]. AB - OBJECTIVE: To evaluate the method and efficacy of endoscopic therapy combined with antegrade percutaneous approach and retrograde transurethral approach for ureteral obstruction after kidney transplantation. METHODS: Eight cases were analyzed retrospectively who received endoscopic therapy combined with antegrade percutaneous approach and retrograde transurethral approach when they had been diagnosed with ureteral obstruction in the transplant kidney from February 2007 to March 2013 in Department of Urology, Peking University Third Hospital. The cases included three males and five females, with the average age being 44 years (30-64 years). The interval between ureteral obstruction and kidney transplantation ranged from one month to 12 months. Four cases presented with increased serum creatine, two with anuria and two with urinary leakage. The stricture site was located in ureter terminal part in seven cases, and middle part in 1 case. In three cases, percutaneous nephrostomy were carried out immediately while endoscopic therapy combined with antegrade percutaneous approach and retrograde transurethral approach were carried out later. The remaining five cases were treated simultaneously. RESULTS: The average serum creatine decreased from (237+/-43) MUmol/L to (121+/-29) MUmol/L (P<0.05) after the therapy. No perioperative complications occurred. Two urinary fistula healed. Six cases were treated successfully with two cases that failed followed by percutaneous nephrostomy. The ureteral obstruction recurred in one case after six months with recurrence rate of 17% (1/6). CONCLUSION: Endoscopic therapy combined with antegrade percutaneous approach and retrograde transurethral approach is an effective therapeutic approach to treat ureteral obstruction in transplant kidney which shows good clinical results. PMID- 23939169 TI - [Comparison of the diode laser and the thulium laser in transurethral enucleation of the prostate for treatment of benign prostatic hyperplasia]. AB - OBJECTIVE: To compare the validity and safety of diode laser and thulium laser transurethral enucleation of the prostate in benign prostatic hyperplasia (BPH) patients. METHODS: In our study, 63 BPH patients treated with transurethral enucleation of the prostate were divided randomly into 2 groups by diode laser (Di group) or thulium laser (Thu group) respectively. The operation time, bleeding volume, electrolyte, international prostatic symptomatic score (IPSS), post-voiding residual volume (PVR) and maximum urine flow rate (Qmax) were recorded and compared. RESULTS: No difference was found in the 2 groups in basic preoperative characteristics. Di group was superior to Thu group in mean operation time [(61.5+/-19.6) min vs. (71.4+/-16.5) min, P=0.026] notwithstanding little clinical sense. The mean time of removing catheter was 2.1 d and 2.3 d respectively. No difference in either electrolyte decrease or hemoglobin decrease [(5.0+/-1.1 g/L) vs. (4.4+/-0.9) g/L, P=0.32] peri-operation between the 2 groups were found and no transurethral resection (TUR) syndrome was encountered. Lower urinary tract symptom (LUTS) in both the groups were released the 1st and 3nd months post-operation effectively in IPSS, PVR and Qmax respectively and comparable (P>0.05). CONCLUSION: Both the Diode laser and the Thulium laser transurethral enucleation of the prostate released the LUTS effectively in BPH patients and comparable in the short-time follow-up. Further study about late complications related to enucleation is necessary. PMID- 23939170 TI - [Efficacy of microsurgical vasectomy reversal on patients after vasectomy]. AB - OBJECTIVE: To evaluate the efficacy of microsurgical vasectomy reversal on patients after vasectomy. METHODS: In the study, 41 patients after vasectomy were admitted for microsurgical vasectomy reversal. The mean (range) age was 45 (29 to 66) years for the men. The mean duration of obstruction was 12 years. All the patients were seen by the surgeon for a complete history and physical examination. Semen analyses proved azoopermia, and their serum levels of sexual hormone were normal. They were all offered scrotal exploration. Microvasovasostomy was performed if the sperm was found in the material coming from the proximal vas lumen. The decision for microvasoepididymostomy was made during surgery, if the fluid was creamy, containing only debris or there was no fluid whatsoever when the vas was milked toward the cut end. Microvasovasostomy was performed in 40 patients, of whom 6 were with lateral microvasoepididymostomy and 1 with bilateral microvasoepididymostomy. The initial semen analysis was then done after usually 3 months postoperatively. Patency was arbitrarily defined as>10 000 sperm/mL in ejaculate in at least one semen analysis after surgery. Postoperative patency rate and postoperative impregnation rate were followed. RESULTS: The 41 patients were followed up for 3 to 72 months, and 5 cases were lost. In the 28 patients who had obstructions for less than 15 years, 3 were lost. Sperm was found by semen analysis in 21 patients. Their sperm density was 2*10(6) to 46*10(6) sperms/mL and motility was 0% to 60%. The semen analysis revealed azoospermia in 2 patients after 12 months, who were advised to undergo intracytoplasmic sperm injection. Natural conception occurred in 6 patients followed for more than 12 months. The overall patency rate was 84% (21/25). Among the patients with a follow-up of >6 months, the natural paternity rate was 29% (6/21). In the 13 patients who had obstructions for more than 15 years, 2 were lost. The patency and pregnancy rates were 64% (7/11) and 14% (1/7) respectively. Their sperm density was 0.02*10(6) to 30* 10(6) sperms/mL and motility was 0% to 43%. CONCLUSION: Microsurgical vasectomy reversal is an effective method to treat vasal obstruction due to vasectomy. The patency and pregnancy rates are related to the time of vasectomy. The patency and pregnancy rates are higher in patients with obstruction for less than 15 years than those for more than 15 years. PMID- 23939171 TI - [Epidemiology and clinical features of renal tuberculosis: 239 cases report]. AB - OBJECTIVE: To study the changes in the status of genitourinary tuberculosis, especially in renal tuberculosis. METHODS: In the study, 239 cases of renal tuberculosis from 2000 to 2010 were retrospectively reviewed. The patients with 3 or more than 3 kinds of common clinical manifestations of genitourinary tuberculosis were regarded as typical group (145 cases), and otherwise, as atypical group (94 cases). RESULTS: The cases of renal tuberculosis constituted 0.89% of the urological inpatients in a duration of 11 years from 2000 to 2010. The incidence rates were higher in the 40-60 years old patients (45.61%). 48% of the patients were farmers or the unemployed. The most common clinical manifestations included frequency (151 cases), urgency (124 cases), odynuria (120 cases), flank pain (97 cases), and hematuria (76 cases). However, flank pain (34.04%) turned into the main complaint of the atypical group. We found that 125 cases had a history of pulmonary tuberculosis or an abnormal chest radiography, 30 patients were diagnosed as contracted bladder (typical group/atypical group: 26/4, P<0.05), and 20 patients (8.4%) were diagnosed as contralateral hydronephrosis. And 198 cases were examined by acid-fast stain, with a positive diagnostic rate of 47.98%. Also 202 cases of the 205 patients who had an ultrasonography had an abnormal outcome and 135 cases of them were definitively diagnosed. Surgical treatments were performed among almost all the patients, while 21 cases only had antituberculosis drugs. CONCLUSION: Socio-economic issues still affect the status of genitourinary tuberculosis. The history of pulmonary tuberculosis or an abnormal outcome of chest radiography can provide an important clue during the diagnostic process. Acid-fast stain and ultrasonography remain as effective screening tests. Though the treatment with antituberculosis drugs has become the "mainstream", the surgical treatment is needed for advanced renal tuberculosis. PMID- 23939172 TI - [Perioperative treatment of patients with pheochromocytoma combined severe catecholamine cardiomyopathy: 5 cases report]. AB - OBJECTIVE: To discuss perioperative treatment and cardiac function changes after medicine and surgical treatment of pheochromocytoma patients with severe catecholamine cardiomyopathy. METHODS: Five pheochromocytoma patients with severe catecholamine cardiomyopathy in our hospital for the past 5 years were studied, their general characteristics, clinical manifestations, diagnosis tests summarized and the cardiac function changes before and after the treatment evaluated. RESULTS: All the 5 patients were diagnosed definitely before operation. After medication, left ventricular ejection fraction (LVEF) of the 5 patients improved and 4 patients' LVEF increased 7-10 days after operation compared with after medication, and one patient's LVEF improved after 3 months. CONCLUSION: Pheochromocytoma patients with severe catecholamine cardiomyopathy should have adequate medication, and their abnormal cardiac function would be reversed after surgical treatment. PMID- 23939173 TI - Association of depression/anxiety with lower urinary tract symptoms and erectile dysfunction in Chinese men aged from 22 to 50 years. AB - OBJECTIVE: To examine the relationships among lower urinary tract symptoms (LUTS), erectile dysfunction (ED) and mental health in Chinese men aged from 22 to 50. METHODS: The subjects were 907 men aged between 22 and 50 years. The symptoms of mental distress were evaluated by the Zung Self-rating Depression Scale questionnaires and Zung Self-rating Anxiety Scale questionnaires. The symptoms of chronic prostatitis/chronic pelvic pain syndrome (CPPS), LUTS and ED were assessed by the US National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function 5 (IIEF-5) score. RESULTS: In the study, 894 subjects had their complete data. Their mean NIH-CPSI score was higher for the men with depression and anxiety than for those without (6.2+/-6.2 vs. 5.0+/ 5.8, P=0.015; 8.7+/-8.1 vs. 4.7+/- 5.3, P<0.001), with the mean IPSS score (5.9+/ 6.6 vs. 4.7+/-5.8, P=0.029; 8.4+/-8.0 vs. 4.4+/-5.5, P<0.001). The mean IIEF-5 score was lower for the men with depression and anxiety than for those without (18.3+/-4.4 vs. 20.2+/-3.5; 17.2+/-4.1 vs. 20.1+/-3.6, both P<0.001). The proportion of total ED was higher for the men with depression and anxiety than for those without (69.7% vs. 57.8%, P=0.002; 81.1% vs. 57.0%, P<0.001). CONCLUSION: Our study reveals associations among depression, anxiety, and CPPS, LUTS and ED in Chinese men aged 50 years and younger. PMID- 23939174 TI - [Neutralization of interleukin-17 aggravates respiratory infection induced by Chlamydia trachomatis in mice]. AB - OBJECTIVE: To evaluate the role of interleukin-17 (IL-17) in respiratory infection with Chlamydia trachomatis in mice. METHODS: (1) In the study, 32 mice were randomly divided into the following 4 groups (8 mice/group): neutralizing antibody group (NG), isotype-matched control antibody group (IG), compensating recombinant mouse IL-17 group (CG) and PBS control group (PG), respectively. The mice in all the groups were induced by intranasal inoculation with high dose of inclusion-forming unit (IFU) Chlamydia trachomatis mouse pneumonitis (MoPn). Meanwhile, they were injected intraperitoneally with neutralizing rat antimouse IL-17 mAb, or control rat IgG, or neutralizing rat antimouse IL-17 mAb plus recombinant mouse IL-17 or PBS alone every 48 h starting on day 1 before chlamydial infecton. The mice were monitored daily for body weight change and survival rates. (2) Another 32 mice were randomly divided into 4 groups as method (1),and intranasally infected with moderate dose of MoPn, and the following steps were taken as the same as method (1). The bronchial alveolar lavage fluids (BALF) were collected for counting neutrophils, macrophages, and lymphocytes on day 8 postinfection. At the same time, the chlamydial growth in the lung, kidney and spleen were assessed by inoculating HeLa cell monolayer with homogenates followed by immunofluoresent assay (IFA). RESULTS: After being infected by high dose of MoPn and neutralized with anti-IL-17 mAb, the average body weight change decreased obviously in all the groups and began to increase 12 d after infection in IG, CG and PG, but only the mice in NG continued to lose their body weight till all died. The survival rate of the mice decreased significantly in NG and all died on day 21 postinfection. There were significant differences compared with IG, CG and PG groups (chi(2)= 11.096,10.575,13.781, respectively, P<0.05). But the survival rates of the mice were 75%, 75% and 87.5% for IG, CG and PG respectively, and there were no significant differences among the three groups. After being infected by moderate dose of MoPn, the chlymadia growth in the lung and the spread to the kidney and spleen significantly increased in NG (6.85+/ 0.12, 1.85+/-0.35, and 1.59+/-0.35, P<0.05), compared with IG (6.03+/-0.25, 0.86+/-0.80, 0.57+/-0.42), CG (5.42+/-0.66, 0.43+/-0.23, 0.21+/-0.15) and PG (5.65+/-0.29, 0.68+/-0.39, but not detected in the spleen), these data were expressed as lg IFUs/organ. The results of BALF cell differentials were calculated as the percentage of the total cells and the final results of neutrophils, macrophages, and lymphocytes were 54.17%+/-5.29%, 26.92%+/-6.28%, 18.90%+/-5.01% for NG, 74.50%+/-7.33%, 13.43%+/-5.69%, 12.06%+/-6.64% for IG, 76.13%+/-8.12%, 12.31%+/-7.73%, 11.56%+/-7.25% for CG, and 69.97%+/-6.45%, 14.55%+/-6.59%, and 15.48%+/-6.11% for PG. The ratios of neutrophils, macrophages, and lymphocytes in BALF of NG had significant differences compared with the other groups (P<0.001). The neutrophil population in the BALF was significantly decreased in NG than that of the other groups. CONCLUSION: After the endogenous IL-17 activity had been neutralized, the mice showed greater body weight loss, less survival rate, higher bacterial growth in the lung and more spread to other organs, and less neutrophils inflitration. These data suggest that IL-17 plays a critical protective role in the host defense against chlamydial infection. PMID- 23939175 TI - [Effects of kidney stem cells on injure-recovery of human renal tubular epithelial cells]. AB - OBJECTIVE: To investigate the protective effects and the mechanism of kidney stem cells (KSC) on the injured tubular epithelial cells. METHODS: KSC were isolated from rat renal papilla. The human kidney epithelial cells (HKC) injury model was induced with 0.1 MUmol/L antimycin A for 30 minutes. The injured HKC were co cultured with KSC or supernatant of cultured KSC. The apoptosis of HKC were detected by flow cytometry. The changes of ATP in the HKC and the level of malondialdehyde (MDA), superoxide dismutase (SOD) and lactate dehydrogenase (LDH) in the supernatant of cultured HKC were detected after being co-cultured with KSC. RESULTS: The study of the co-culture showed that KSC was less capable to migrate through the micropores of Transwell compared with bone marrow stem cells. However, after being co-cultured with the KSC conditional supernatant, ATP content of injured HKC, total SOD value in the supernatant of injured HKC were increased, and the MDA and LDH in the supernatant of injured HKC decreased. CONCLUSION: KSC have protected effects and participate in the repair of injured HKC. PMID- 23939176 TI - [Evaluation of optimal dosage of heparin in hemodialysis patients by thromboelastograph]. AB - OBJECTIVE: To assess the blood coagulation function and investigate the appropriate dose of unfractionated heparin by thromboelastograph in maintenance hemodialysis (MHD) patients. METHODS: Thirty MHD patients were enrolled in this study and divided into two groups. The total dose of unfractionated heparin was below 80 u/kg in the low-dose group (LH, n=16), while it exceeded 80 u/kg in the high-dose group (HH, n=14). Blood routine tests and conventional coagulation examinations were measured before hemodialysis. TEG and activated partial thromboplastin time (APTT) were examined at the beginning and the end of hemodialysis at the arterial circuit, and the second hour (h 2) at the venous circuit. RESULTS: The initial bolus dose of unfractionated heparin for LH and HH groups were (26.6+/-6.2) u/kg vs. (42.3+/-8.2) u/kg and the repeated maintenance dose for both the groups were (13.7+/-5.1) u/kg/h vs. (18.2+/-4.3) u/kg/h. No significant difference was noticed in results from blood routine tests and conventional coagulation parameters between the two groups. In LH group, the increase of APTT at h 2 of hemodialysis was significant compared with the baseline, while it recovered partly at the end of hemodialysis. R value prolonged at h 2 and the end of hemodialysis. CI value was more negative at the end of hemodialysis. In HH group, APTT obviously prolonged at h 2 and the end of hemodialysis. R value also obviously prolonged at h 2 of hemodialysis. At the end of hemodialysis, R and K values prolonged, MA value reduced, and CI value was more negative. APTT was significantly different between the two groups at h 2 of hemodialysis. At the end of hemodialysis, APTT was still extended in HH group, but there was no significant difference. R value at h 2, and R, K, MA, CI values at the end of hemodialysis were significantly different between the two groups. R values at the end of hemodialysis had a direct correlation with the dose of unfractionated heparin (r=0.403, P=0.041), but APTT had not. There was no significant difference in transmembrane pressure, venous pressure and filter clotting between the two groups. CONCLUSION: Low-dose heparin is effective and safe as anticoagulant in hemodialysis. TEG shows that the blood coagulation function is more sensitive than conventional coagulation parameters and is useful to anticoagulant therapy in MHD patients. PMID- 23939177 TI - [Plasma osteopontin level and left ventricular remodeling in patients with acute myocardial infarction]. AB - OBJECTIVE: To investigate the change of plasma osteopontin level during the progress of acute ST-segment elevation myocardial infarction, as well as its association with the left ventricular remodeling and prognosis. METHODS: In the study, 61 patients with acute ST-segment elevation myocardial infarction were recruited. Blood samples were taken at admission, on the 3rd day and 7th day of admission, while 63 healthy blood donors were employed as normal controls. There plasma osteopontin levels were measured by ELSIA. RESULTS: Compared with the normal controls, the plasma osteopontin levels of the patients with acute ST segment elevation myocardial infarction were significantly higher at admission [(96.51+/-37.22) MUg/L vs. (54.50+/-28.17) MU g/L, P<0.001], reached the peak value on the 3rd day, and dropped down on the 7th day. The correlation analysis showed that the plasma osteopontin level positively correlated with age and left ventricular end-systolic volume index 3 months after acute myocardial infarction, and negatively correlated with left ventricular ejection fraction 3 months after acute myocardial infarction. The follow-up study found that the plasma osteopontin level did not predict mortality, re-infarction, stroke, revascularization or hospitalization due to heart failure. CONCLUSION: In patients with acute ST-segment elevation myocardial infarction, the elevated plasma level of osteopontin might be associated with the left ventricular remodeling. PMID- 23939178 TI - [Peri-operative management and follow-up outcomes of cardiac surgery in dialysis dependent patients with end stage renal disease]. AB - OBJECTIVE: To summarize the perioperative management experience of patients with end-stage renal diseases (ESRD) undergoing cardiac surgery and the follow-up outcomes. METHODS: From September 2004 to February 2012, 18 dialysis-dependent patients with ESRD received cardiac surgery in Department of Cardiac Surgery, Peking University First Hospital. A series of methods were employed to maintain water-electrolyte and acid-base balance and coagulation function. We followed up the patients by clinic service or telephone. RESULTS: The spectra of surgical interventions included isolated coronary artery bypass graft (CABG, n=13), isolated valve replacement (VR, n=2) and concomitant CABG and VR (n=3). Of the 18 patients, 3 died within the Peri-operative period and 15 recovered and were discharged. The follow up period was 6-91 months [(27.6+/-27.5) months]. Within the follow up period, 2 patients died (66th month and 76th month), non-fatal complications occurred in 3 patients. Cardiac functions of the survived patients were good according to the New York Heart Association (NYHA) classification, 4 of them were within NYHA class I and 9 within NYHA class II. CONCLUSION: Dialysis dependent patients with end-stage renal diseases are a high risk group receiving cardiac surgery, but a comprehensive Peri-operative management of water electrolyte and acid-base balance and coagulation function could yield a better outcome. PMID- 23939179 TI - [Efficacy of early consecutive lumbar puncture treatment in aneurysmal subarachnoid hemorrhage after embolization]. AB - OBJECTIVE: To summarize the significance of lumbar punctures in remedy for aneurysmal subarachnoid hemorrhage (aSAH) after embolization. METHODS: From December 2002 to September 2011, 43 cases of aSAH underwent aneurysm embolization at department of interventional radiology and vascular surgery, Peking University Third Hospital. After the embolization,consecutive lumbar punctures were undertaken everyday, by which we measured proper cerebrospinal fluid pressure and slow drainage of cerebrospinal fluid. In accordance with the lumbar puncture results we determined the control of blood pressure, dehydration and rehydration therapy procedures. RESULTS: Two patients died. Only one patient in the 41 cases of the survived patients developed cerebral vasospasm, cerebral infarction and obstructive hydrocephalus, but by ventriculo-peritoneal shunt, obstructive hydrocephalus was relieved. The remaining 39 patients recovered well. After the mean follow-up of (26.0+/-5.8) months, no new neurological symptoms were found. CONCLUSION: Early consecutive lumbar puncture treatment in ASH after embolization is significant. PMID- 23939180 TI - [Is preoperative regular laboratory test necessary for gynecological ambulatory surgery?]. AB - OBJECTIVE: To investigate whether preoperative regular laboratory tests are necessary to all patients in ambulatory gynecological surgery settings. METHODS: This is a retrospective cohort study. Patients who underwent selective ambulatory gynecological surgery in Peking University First Hospital during January 2012 and May 2012 were enrolled. Regular preoperative laboratory tests including complete blood count (21 items), biochemical test (8 items), bleeding & clotting test (10 items) and urine test (12 items) were recorded. An expert group criticized on all abnormal items according to referred normal range and decided if the abnormal items had clinical significance. The demographic data, perioperative related data, complications (intraoperative and postoperative 7 days) and mortality in postoperative 7 days were also recorded. RESULTS: In the study, 708 patients were enrolled and no death case in postoperative 7 days. Of all the patients, 610 (86.2%) showed one or more laboratory test abnormalities. The incidence of complete blood count abnormality was 68.8% (487/708), of biochemical test 48.2% (341/708), of coagulation test 24.2% (171/708) and of urine test 37.3% (264/708). But only a few of them needed clinical treatment or intervention. There was no statistical significance between the normal patients and abnormal patients in the incidence of surgical complications. Multi Logistic analysis showed that age, hypertension, arrhythmia, coronary artery disease and diabetes were independent risk factors of complications. No patient died in postoperative 7 days. CONCLUSION: The incidence of abnormal regular laboratory tests is very high, but only a few of them have clinical significance or need clinical treatment. The occurrence of abnormal regular laboratory tests is not related with complications. PMID- 23939181 TI - [Evaluation of digital subtraction angiography rabbit VX2 hepatic carcinoma model with modified hepatic artery catheterization]. AB - OBJECTIVE: To modify the success rate of establishing VX2 transplanted tumor model with different methods in rabbits, and access new typed modification and improved technique in catheterization. METHODS: In the study, 30 rabbits were randomly divided into 2 groups. In prophase, tumor cell suspension was implanted in group I, while tumor tissue particles were implanted into liver under direct vision, to establish VX2 transplanted tumor model. The rabbits were catheterized from femoral artery to selective hepatic artery under DSA, by using conventional modification with Seldinger technique in group I and by using new typed modification with improved technique in group II. The imaging and histological features of VX2 tumor were evaluated by combining pathology and DSA, then the success rate, operation time and postoperative complications were compared and evaluated. RESULTS: The success rates of the liver tumor model were 60.0% and 93.3%; the disposable success rates of catheterization were 66.7% and 92.8%; the operation time of catheterization were (35.6+/-5.8) min and (27.4+/-5.3) min; the incidence rates of adverse reaction were 22.5% and 18.0%; the differences between the two groups in the experimental rabbits were significant (P<0.05) statistically. CONCLUSION: The efficiency of tumor tissue particles implanted is better than that of tumor cell suspension implanted in establishing VX2 transplanted tumor model under direct vision. The cathetenzation quality and outcomes of new typed modification by improved technique, from femoral artery to selective hepatic artery, is superior to those of conventional modification with Seldinger technique. PMID- 23939182 TI - [Clinical character of metanephric adenoma of the kidney: a case report]. AB - To investigate the clinicopathological characteristics of metanephric adenoma (MA), we analyzed the clinical and pathological data of metanephric adenoma. A 39 year old woman with asymptomatic right kidney tumor for 4 years was admitted to the hospital. A tumor with the largest diameter of 28 mm in the right kidney was homogeneously enhanced on CT. The tumor was distinctly increased as compared with 4 years before. The diagnosis was right kidney tumor. Nephron-sparing surgery was given after general anaesthesia. And the relative literature was reviewed. The tumor was homogeneous, with integrity tegument, and a grey cutting surface. Histopathologically, the tumor cells formed an adenoid or papillary pattern and contained psammoma bodies. Immunohistologically, they were positive for AE1/AE3, vimentin and WT1, negative for CK7, EMA and RCC. Pathological diagnosis was metanephric adenoma. The follow-up data of 24 months were available and without recurrence. MA is peculiar. It is difficult to get the final diagnosis of MA only by imaging characters. Nephron-sparing surgery is eligible for the treatment of MA. Considering the uncertainty of the biological behavior and cellular origin of MA, a long-term active surveillance is necessary. PMID- 23939183 TI - [Progress of low-energy shockwave therapy in clinical application]. AB - A shock wave is a transient pressure disturbance that propagates rapidly in three dimensional space. It is associated with a sudden rise from ambient pressure to its maximum pressure. Shock wave therapy in urology is primarily used to disintegrate urolithiasis. Recently, low-energy shock wave therapy (LESWT), which is a novel convenient and cost-effective therapeutic modality, is extended to treat other pathological conditions including coronary heart disease, musculoskeletal disorders and erectile dysfunction. However, the exact therapeutic mechanisms and clinical safety and efficacy of LESWT remain to be investigated. Based on the results of previous studies, it is suggested that LESWT could regulate angiogenesis-related growth factors expression including endothelial nitric oxide synthase (eNOS), vessel endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA), which might induce the ingrowth of neovascularization that improves blood supply and increases cell proliferation and eventual tissue regeneration for restore pathological changes. The further studies on cellular and molecular biological changes by LESWT for clarification its mechanism and clinical safety and efficacy studies are recommended. PMID- 23939184 TI - [Recent advances in molecular mechanisms of supernumerary tooth formation]. AB - Despite advances in the knowledge of tooth morphogenesis and differentiation, little is relatively known about the aetiology and molecular mechanisms underlying supernumerary tooth formation. Mice, which are commonly used for studying tooth development, only exhibit one dentition. However, a number of mouse models are now starting to provide some insight into the mechanisms that control overall tooth number within the dentition. This review describes recent advances in our understanding of the molecular mechanisms of supernumerary tooth formation. Indeed, many of the molecular signaling pathways known to be involved in normal development of the tooth germ can also give rise to supernumerary teeth if inappropriately regulated. These include components of the Hedgehog, FGF, Wnt and BMP families, which may potentially play a role in human supernumerary tooth formation. PMID- 23939185 TI - Treatment implications of the altered cytokine-insulin axis in neurodegenerative disease. AB - The disappointments of a series of large anti-amyloid trials have brought home the point that until the driving force behind Alzheimer's disease, and the way it causes harm, are firmly established and accepted, researchers will remain ill equipped to find a way to treat patients successfully. The origin of inflammation in neurodegenerative diseases is still an open question. We champion and expand the argument that a shift in intracellular location of alpha-synuclein, thereby moving a key methylation enzyme from the nucleus, provides global hypomethylation of patients' cerebral DNA that, through being sensed by TLR9, initiates production of the cytokines that drive these cerebral inflammatory states. After providing a background on the relevant inflammatory cytokines, this commentary then discusses many of the known alternatives to the primary amyloid argument of the pathogenesis of Alzheimer's disease, and the treatment approaches they provide. A key point to appreciate is the weight of evidence that inflammatory cytokines, largely through increasing insulin resistance and thereby reducing the strength of the ubiquitously important signaling mediated by insulin, bring together most of these treatments under development for neurodegenerative disease under the one roof. Moreover, the principles involved apply to a wide range of inflammatory diseases on both sides of the blood brain barrier. PMID- 23939188 TI - Nickel(III) complexes of di-amidato-di-phenolato ligands: effect of H-bonding. AB - The one-electron oxidation of the dianionic diamido-diphenoxo Ni(II) complexes involving H-bonding (1(2-)), or not (2(2-)), yields the corresponding Ni(III) species; the formation, stability and electronic structures of which are affected by the H-bonding interactions. PMID- 23939189 TI - Young-onset dementia: unanswered questions and unmet needs. PMID- 23939186 TI - Transcriptional regulation by nicotine in dopaminergic neurons. AB - Dopaminergic neurons in the substantia nigra pars compacta (SNc) degenerate in Parkinson's disease. These neurons robustly express several nicotinic acetylcholine receptor (nAChR) subtypes. Smoking appears to be neuroprotective for Parkinson's disease but the mechanism is unknown. To determine whether chronic nicotine-induced changes in gene expression contribute to the neuroprotective effects of smoking, we develop methods to measure the effect of prolonged nicotine exposure on the SNc neuronal transcriptome in an unbiased manner. Twenty neurons were collected using laser-capture microscopy and transcriptional changes were assessed using RNA deep sequencing. These results are the first whole-transcriptome analyses of chronic nicotine treatment in SNc neurons. Overall, 129 genes were significantly regulated: 67 upregulated, 62 downregulated. Nicotine-induced relief of endoplasmic reticulum (ER) stress has been postulated as a potential mechanism for the neuroprotective effects of smoking. Chronic nicotine did not significantly affect the expression of ER stress-related genes, nor of dopamine-related or nAChR genes, but it did modulate expression of 129 genes that could be relevant to the neuroprotective effects of smoking, including genes involved in (1) the ubiquitin-proteasome pathway, (2) cell cycle regulation, (3) chromatin modification, and (4) DNA binding and RNA regulation. We also report preliminary transcriptome data for single-cell dopaminergic and GABAergic neurons isolated from midbrain cultures. These novel techniques will facilitate advances in understanding the mechanisms taking place at the cellular level and may have applications elsewhere in the fields of neuroscience and molecular biology. The results give an emerging picture of the role of nicotine on the SNc and on dopaminergic neurons. PMID- 23939187 TI - Choline transporter hemizygosity results in diminished basal extracellular dopamine levels in nucleus accumbens and blunts dopamine elevations following cocaine or nicotine. AB - Dopamine (DA) signaling in the central nervous system mediates the addictive capacities of multiple commonly abused substances, including cocaine, amphetamine, heroin and nicotine. The firing of DA neurons residing in the ventral tegmental area (VTA), and the release of DA by the projections of these neurons in the nucleus accumbens (NAc), is under tight control by cholinergic signaling mediated by nicotinic acetylcholine (ACh) receptors (nAChRs). The capacity for cholinergic signaling is dictated by the availability and activity of the presynaptic, high-affinity, choline transporter (CHT, SLC5A7) that acquires choline in an activity-dependent matter to sustain ACh synthesis. Here, we present evidence that a constitutive loss of CHT expression, mediated by genetic elimination of one copy of the Slc5a7 gene in mice (CHT+/-), leads to a significant reduction in basal extracellular DA levels in the NAc, as measured by in vivo microdialysis. Moreover, CHT heterozygosity results in blunted DA elevations following systemic nicotine or cocaine administration. These findings reinforce a critical role of ACh signaling capacity in both tonic and drug modulated DA signaling and argue that genetically imposed reductions in CHT that lead to diminished DA signaling may lead to poor responses to reinforcing stimuli, possibly contributing to disorders linked to perturbed cholinergic signaling including depression and attention-deficit hyperactivity disorder (ADHD). PMID- 23939190 TI - Residual urine volumes after intermittent catheterization in men with spinal cord injury. AB - STUDY DESIGN: Prospective cross-sectional study. OBJECTIVES: To investigate residual urine volumes after intermittent catheterization (IC) in men with spinal cord injury (SCI) and the effect of residual urine on the rate of symptomatic urinary tract infections (UTIs). SETTING: Single SCI rehabilitation center in Switzerland. METHODS: Sixty men experienced in IC (>= 6 months) emptied their bladder twice by IC. Immediately after catheterization, residual urine was determined by ultrasonography. Personal characteristics and bladder diary details (annual UTI rate, catheter type) were also collected. RESULTS: The median residual urine volume was 7.0 ml (lower quartile (LQ): 0.0, upper quartile (UQ): 20.3 ml). No residual urine was observed after 42% (n=50) of all catheterizations (n=120). Unsatisfactory residual volumes (that is, >50 ml) were observed after 9% (n=11) of all catheterizations. There was no significant (P=0.95) difference between the median residual urine volume of men with recurrent (>2 UTIs per year) UTIs (2.5 ml, LQ: 0.0, UQ: 29.3 ml) and the volume of those with sporadic (<= 2 UTIs per year) UTIs (6.0 ml, LQ: 0.0, UQ: 20.0 ml). CONCLUSIONS: Bladder evacuation by IC is an efficient method, resulting in zero or small residual urine volumes. The small residual urine volumes generally observed after IC do not predispose for UTIs. PMID- 23939191 TI - Comparison of urodynamic findings in patients with upper and lower cervical spinal cord injury. AB - STUDY DESIGN: Retrospective study. OBJECTIVES: To analyze the neurogenic bladder characteristics and treatment approaches in patients with upper and lower cervical spinal cord injury (SCI) in order to make proper and reasonable decisions to the relevant patients. SETTING: Rehabilitation center in Ankara, Turkey. METHOD: Ninety patients with cervical SCI were included. The urodynamic analyses of the patients were conducted retrospectively by using the urodynamic laboratory records. The patients were divided into two groups as the upper cervical SCI (UCSCI) group (C1-C5) and lower cervical SCI (LCSCI) group (C6-C8). RESULTS: In this study, 82 male (91.1%) and 8 (8.9%) female patients were included. There were 51 UCSCI patients with the mean age of 34.2 +/- 16.1 years and 39 LCSCI patients with the mean age of 30.4 +/- 12.5 years. Detrusor overactivity and preservation of the bladder-filling sensation were significantly more frequent in the UCSCI group than in the LCSCI group (P=0.048, P=0.000 respectively). Moreover, there were statistically significant differences between the groups regarding the bladder-emptying methods, residual volume and the frequency of anticholinergic and alpha blocker use (all P<0.05). No significant difference was found between the groups regarding the frequency of autonomic dysreflexia, detrusor hypocompliancy and the bladder-storage and -emptying disorders (all P>0.05). CONCLUSION: Our results demonstrate that there are differences in the upper and lower SCI cases in terms of neurogenic bladder characteristics and treatment approaches. PMID- 23939192 TI - Functional implications of corticospinal tract impairment on gait after spinal cord injury. AB - OBJECTIVE: Maximum toe elevation during walking is an objective measure of foot drop and reflects the impairment of the corticospinal tract (CST) in persons with spinal cord injury (SCI). To determine if this measurement is functionally relevant to ambulatory abilities, we correlated maximum toe elevation with clinical physiotherapy tests. SETTING: Cross-sectional study, laboratory and clinical settings. METHODS: A total of 24 individuals with SCI (American Spinal Injury Association (ASIA) Impairment Scale D) were recruited. Maximum toe elevation during the swing phase of treadmill gait was measured with a kinematic system. CST function was assessed in a sitting position by measuring the motor evoked potentials (MEPs) induced in tibialis anterior muscle with transcranial magnetic stimulation over the motor cortex. Clinical tests performed were 10-m and 6-min walk test (6MWT), Timed-Up and Go (TUG), Walking Index for Spinal Cord Injury, Berg Balance Scale, Lower Extremity Motor Score (LEMS) and sensory score of the L4, L5 and S1 dermatomes. RESULTS: Participants with lower toe elevation during gait walked at a slower speed, took more time to perform the TUG test, and covered a shorter distance in the 6MWT. They also scored lower on the LEMS and showed impaired superficial sensitivity of the dermatomes around the ankles. Few correlations were observed between CST function and clinical tests, but the presence of MEP at rest was indicative of faster speed and longer distance in the 6MWT. CONCLUSION: These results indicate that maximum toe elevation, which is directly correlated with CST impairment, is functionally relevant as it also correlates with timed clinical tests, LEMS and sensory scores. PMID- 23939193 TI - Constructing phylogenies in the presence of intra-individual site polymorphisms (2ISPs) with a focus on the nuclear ribosomal cistron. AB - Nuclear DNA is widely used to estimate phylogenetic and phylogeographic relationships. Nuclear gene variants may be present in an individual's genome, and these result in Intra-Individual Site Polymorphisms (2ISP; pronounced "twisp") in direct-PCR or individual-consensus sequences based on a sample of clones or fragment sequences from next generation sequencing (NGS). 2ISPs can occur fairly often, especially within, but not restricted to, high-copy-number regions such as the widely used internal transcribed spacers of the nuclear ribosomal cistron. Dealing with 2ISPs has been problematic as phylogeny reconstruction optimality criteria generally do not take account of this variation. Here we test whether an approach that treats 2ISPs as additional (termed "informative"), rather than ambiguous, characters offers improved support in three common criteria used for phylogenetic inference: Minimum Evolution (via Neighbour Joining), Maximum Parsimony, and Maximum Likelihood. We demonstrate significant improvements using the 2ISP-informative treatment with simulated, real-world, and case-study data sets. We envisage that this 2ISP-informative approach will greatly aid phylogenetic inference using any nuclear DNA regions that contain polymorphisms within individuals (including consensus sequences generated from NGS), especially at the intrageneric or intraspecific level. PMID- 23939194 TI - Therapeutic drug monitoring of ciclosporin A and tacrolimus in heart lung transplant patients using dried blood spots. AB - BACKGROUND: Therapeutic drug monitoring of ciclosporin A (CsA) and tacrolimus is traditionally performed using venous whole blood sampling. A number of reports have described development of ultra high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) methods for the quantitation of CsA and tacrolimus from dried blood spots (DBS), which may offer a convenient alternative. As yet, no such reports have validated this methodology using fingerprick capillary DBS samples collected from transplant patients. METHODS: Capillary fingerprick DBS were collected from heart and lung transplant patients in a specialist cardiothoracic transplant centre. We utilized our previously published method for the extraction and simultaneous quantitation of CsA and tacrolimus from DBS using UPLC-MS/MS. Drug concentrations measured from DBS were compared to concentrations measured in venous whole blood by our routine clinical UPLC-MS/MS assay. RESULTS: In total, 91 heart or lung transplant patients were enrolled onto the study; 46 patients were on CsA therapy and 45 on tacrolimus therapy. Passing-Bablock analysis demonstrated excellent agreement between capillary fingerprick DBS samples and venous whole blood samples. There was a mean positive bias of 2.6 ug/L (95% confidence interval (CI) -2.2 to 7.5 ug/L) for CsA (n = 45) and mean negative bias of -0.7 ug/L (95% CI -1.1 to -0.3 ug/L) for tacrolimus (n = 42). CONCLUSIONS: We demonstrate utility of DBS for serial monitoring of CsA and tacrolimus using UPLC-MS/MS in heart and lung transplant patients. This may offer significant advantages for these patients including the ability to take capillary DBS samples in the community prior to clinic visits. PMID- 23939196 TI - Direct monitoring of self-assembly of copolymeric micelles by a luminescent molecular rotor. AB - The detailed analysis of the time resolved luminescence of a specifically designed fluorescent molecular rotor enables the direct monitoring of the self assembly of a poly(N,N-dimethylacrylamide)-block-polystyrene (PDMA-b-PS) copolymer into core-corona nanoparticles. Comparison with bulk PS indicates hard confinement of the micelle core, due to the solvation of the hydrophilic PDMA corona. PMID- 23939195 TI - The biochemical utility of chromogranin A, chromogranin B and cocaine- and amphetamine-regulated transcript for neuroendocrine neoplasia. AB - Neuroendocrine neoplasia (NEN) is a heterogeneous group of tumours and often represents a therapeutic challenge to clinicians. The peptides chromogranin A (CgA), chromogranin B (CgB) and cocaine- and amphetamine-regulated transcript (CART) are widely distributed throughout the neuroendocrine system. CgA and CgB have been used as general NEN biomarkers for many years, while CART has only recently been identified. Of these biomarkers, CgA is the most commonly used. However, circulating CgA concentrations exhibit considerable intra-individual biological variation, are altered by proton pump inhibitors (PPIs) and somatostatin analogues and are elevated in non-NEN malignancies. Therefore, interpretation of CgA results must be in the context of these confounding factors. The effects of treatment and non-NEN conditions on circulating CgB and CART concentrations are less well understood. CgB is less affected by impaired renal function and PPIs than CgA; while, circulating CART concentrations lack a diurnal variation in humans and are more reliable markers of pancreatic NEN malignancy than CgA. The utility of circulating CgA measurements in NEN prognosis, surveillance and disease recurrence has been widely investigated. However, the utility of CgB and CART in NEN management is yet to be elucidated. Further studies are needed to establish whether CgB and CART are useful alternatives to CgA. PMID- 23939197 TI - Have we found freedom for all? PMID- 23939199 TI - Immunologic recovery in children after alternative donor allogeneic transplantation for hematologic malignancies: comparison of recipients of partially T cell-depleted peripheral blood stem cells and umbilical cord blood. AB - Impaired immunologic recovery (IR) after hematopoietic stem cell transplantation (HSCT) is associated with increased risk for infections and relapse. Stem cell source and graft manipulation influence the kinetics of IR. Partial T cell depletion of peripheral blood stem cell (PBSC) grafts is a novel alternative method of graft manipulation for children. We compared IR in children undergoing HSCT for hematologic malignancies receiving either T cell-depleted (TCD)-PBSCs (n = 55) or umbilical cord blood (UCB) (n = 21) over a 7-year period at a single institution. PBSC grafts underwent ex vivo negative selection for CD3(+) cells using the CliniMACS system with partial T cell add-back. Recovery of CD4(+) T cells was significantly delayed in TCD-PBSC recipients compared with UCB recipients, owing to impaired CD4(+)/CD45RA(+) (naive) T cell lymphopoiesis. Recovery of total CD3(+) cells and CD3(+)/CD8(+) cells was similar in the 2 groups. The TCD-PBSC recipients had a marked deficit in CD19(+) and, to a lesser extent, IgA/IgM, owing to the need for B cell depletion of these grafts to attenuate the risk of lymphoproliferative disease after TCD HSCT. There were no significant between-group differences in response to mitogen stimulation, time to independence from intravenous immunoglobulin supplementation, or incidence of viral reactivation. Transplantation outcomes of relapse, transplantation-related mortality, event-free survival, and overall survival were similar in the 2 groups. Efforts to enhance IR after partial TCD-PBSC transplantation, such as selective alphabeta T cell depletion, hold promise for further improvement of this transplantation approach. PMID- 23939200 TI - Pressurized liquid extraction coupled with countercurrent chromatography for systematic isolation of chemical constituents by preprogrammed automatic control. AB - Pressurized liquid extraction (PLE) coupled with high-speed countercurrent chromatography (HSCCC) via an automated procedure was firstly developed to extract and isolate ginsenosides from Panax quinquefolium. The experiments were designed under the guidance of mathematical model. The partition coefficient (K) values of the target compounds and resolutions of peak profiles were employed as the research indicators, and exponential function and binomial formulas were used to optimizing the solvent systems and flow rates of the mobile phases in a three stage separation. In the first stage, ethyl acetate, n-butanol, and water were simultaneously pumped into the solvent separator at the flow rates 11.0, 10.0, and 23.0mL/min, respectively. The upper phase of the solvent system in the solvent separator was used as both the PLE solvent and the HSCCC stationary phase, followed by elution with the lower phase of the corresponding solvent system to separate the common ginsenosides. In the second and third stages, rare ginsenosides were first separated by elution with ethyl acetate, n-butanol, methanol, and water (flow rates: 20.0, 3.0, 5.0, and 11.0mL/min, respectively), then with n-heptane, n-butanol, methanol, and water (flow rates: 17.5, 6.0, 5.0, and 22.5mL/min, respectively). Nine target compounds, with purities exceeding 95.0%, and three non-target compounds, with purities above 84.48%, were successfully separated at the semipreparative scale in 450min. The separation results prove that the PLE/HSCCC parameters calculated via mathematical model and formulas were accurately and scientifically. This research has opened up great prospects for industrial automation application. PMID- 23939201 TI - Application of a high performance liquid chromatography-tandem mass spectrometry method for determination of buflomedil in human plasma for a bioequivalence study. AB - A rapid, simple and sensitive method based on ultra fast liquid chromatography tandem spectrometry for the determination of buflomedil in human plasma has been developed and validated using carbamazepine as internal standard. After the precipitation of plasma sample with methanol, the analyte and IS were separated on an Ultimate C18 column (5MUm, 2.1mm*50mm, MD, USA) with an isocratic mobile phase composed of acetonitrile and 5mM ammonium acetate in water (60:40, v/v) at a flow rate of 0.25ml/min. The analyte and IS were detected with proton adducts at m/z 308.3-237.1 and m/z 237.2-194.2 in positive ion electrospray ionization and multiple reaction monitoring acquisition mode, respectively. The lower limit of quantification of the method was 23.64ng/ml with a linear dynamic range of 23.64-1182ng/ml for buflomedil. The intra- and inter-batch precisions were less than 5.8%. The developed method was successfully applied to a bioequivalence study of two buflomedil hydrochloride preparations (150mg) in 22 healthy Chinese male volunteers. PMID- 23939198 TI - Trends in utilization and outcomes of autologous transplantation as early therapy for multiple myeloma. AB - The impact of novel drugs for treating multiple myeloma (MM) on the utilization and outcomes of autologous hematopoietic progenitor cell transplantation (AHPCT) is unknown. We reviewed characteristics and outcomes of 20,278 patients who underwent AHPCT within 12 months of diagnosis of MM in the United States and Canada and registered at the Center for International Blood and Marrow Transplant Research (CIBMTR) in 3 time cohorts reflecting the increasing availability of novel drugs: 1995 to 1999 (n = 2226), 2000 to 2004 (n = 6408), and 2005 to 2010 (n = 11,644). In the United States, the number of AHPCTs performed increased at a greater rate than new MM cases. Patients in recent cohorts were older, less likely to have stage 3 MM, and more likely to have received previous thalidomide, lenalidomide, or bortezomib. On multivariate analysis, AHPCT in the 2000 to 2004 cohort (HR = 0.77) or in the 2005 to 2010 cohort (HR = 0.68) were associated with lower risk of death. Survival at 60 months post-AHPCT improved from 47% in 1995 to 1999 to 55% in 2000 to 2004 and to 57% in 2005 to 2010, owing less to improvement in progression-free survival (50% versus 55% versus 57% at 24 months) than to postrelapse/progression survival (58% versus 65% versus 72% at 24 months). AHPCT and new biological agents are complementary, nonredundant therapies and should be combined in the management of MM in suitable patients. PMID- 23939202 TI - A simple and robust high-performance liquid chromatography coupled to a diode array detector method for the analysis of genistein in mouse tissues. AB - A simple liquid-liquid extraction procedure and quantification by high performance liquid chromatography (HPLC) method coupled to a diode-array detector (DAD) of genistein (GEN) was developed in various mouse biological matrices. 7 ethoxycoumarin was used as internal standard (IS) and peaks were optimally separated using a Kinetex C18 column (2.6MUm, 150mm*2.10mm I.D.) at 40 degrees C with an isocratic elution of mobile phase with sodium dihydrogen phosphate 0.01M in water at pH 2.5 and methanol (55:45, v/v), at a flow rate of 0.25mL/min. The injection volume was 10MUL. In all cases, the range of GEN recovery was higher than 61%. The low limit of quantification (LLOQ) was 25ng/mL. The linearity of the calibration curves was satisfactory in all cases as shown by correlation coefficients >0.996. The within-day and between-day precisions were <15% and the accuracy ranged in all cases between 90.14% and 106.05%. This method was successfully applied to quantify GEN in liver, spleen, kidney and plasma after intravenous administration of a single dose (30mg/kg) in female BALB/C mice. PMID- 23939203 TI - A semiconductor/mixed ion and electron conductor heterojunction for elevated temperature water splitting. AB - Photoelectrochemical cells (PECs) have been studied extensively for dissociating water into hydrogen and oxygen. Key bottlenecks for achieving high solar-to hydrogen efficiency in PECs include increasing solar spectrum utilization, surmounting overpotential losses, and aligning the absorber/electrochemical redox levels. We propose a new class of solid-state PECs based on mixed ionic and electronic conducting (MIEC) oxides that operates at temperatures significantly above ambient and utilizes both the light and thermal energy available from concentrated sunlight to dissociate water vapor. Unlike thermochemical and hybrid photo-thermochemical water-splitting routes, the elevated-temperature PEC is a single-step approach operating isothermally. At the heart of the solid-state PEC is a semiconductor light absorber coated with a thin MIEC layer for improved catalytic activity, electrochemical stability, and ionic conduction. The MIEC, placed between the gas phase and the semiconductor light absorber, provides a facile path for minority carriers to reach the water vapor as well as a path for the ionic carriers to reach the solid electrolyte. Elevated temperature operation allows reasonable band misalignments at the interfaces to be overcome, reduces the required overpotential, and facilitates rapid product diffusion away from the surface. In this work, we simulate the behavior of an oxygen-ion-conducting photocathode in 1-D. Using the detailed-balance approach, in conjunction with recombination and electrochemical reaction rates, the practical efficiency is calculated as a function of temperature, solar flux, and select material properties. For a non-degenerate light absorber with a 2.0 eV band-gap and an uphill band offset of 0.3 eV, an efficiency of 17% and 11% is predicted at 723 and 873 K, respectively. PMID- 23939204 TI - Observation by NMR of cationic Wheland-like intermediates in the deiodination of protected 1-iodonaphthalene-2,4-diamines in acidic media. AB - 1-Iodonaphthalene-2,4-diamines in trifluoroacetic acid/chloroform give stable Wheland-like tetrahedral cationic species observable by NMR, through an initial intramolecular protonation. Dynamic equilibria allow proton-deuterium exchange of aromatic protons and provide a mechanism for deiodination of 1-iodonaphthalene 2,4-diamines. PMID- 23939205 TI - Identification and design principles of low hole effective mass p-type transparent conducting oxides. AB - The development of high-performance transparent conducting oxides is critical to many technologies from transparent electronics to solar cells. Whereas n-type transparent conducting oxides are present in many devices, their p-type counterparts are not largely commercialized, as they exhibit much lower carrier mobilities due to the large hole effective masses of most oxides. Here we conduct a high-throughput computational search on thousands of binary and ternary oxides and identify several highly promising compounds displaying exceptionally low hole effective masses (up to an order of magnitude lower than state-of-the-art p-type transparent conducting oxides), as well as wide band gaps. In addition to the discovery of specific compounds, the chemical rationalization of our findings opens new directions, beyond current Cu-based chemistries, for the design and development of future p-type transparent conducting oxides. PMID- 23939206 TI - Concentrations and congener profiles of polybrominated diphenyl ethers (PBDEs) in blood plasma from Hong Kong: implications for sources and exposure route. AB - There was limited information about bioaccumulation of polybrominated diphenyl ethers (PBDEs) in humans of the general population of Hong Kong. Therefore, the present study was conducted to determine concentrations and congener profiles of PBDEs in blood plasma from Hong Kong, evaluate their sources and correlations with other organobrominated compounds, and investigate exposure routes from fish and dust. Concentrations of ?PBDE22 ranged from 0.56 to 92 ng g(-1), lipid weight (lw), with a median of 5.4 ng g(-1). BDE-47 was the dominant congener, accounting for 26% of ?PBDE22. Concentrations of PBDE congeners in market fish were significantly (r(2)=0.89, p<0.001) correlated with plasma. Positive but no significant correlations were observed, between concentrations of PBDE congeners in indoor dust from workplaces (r(2)=0.46, p=0.081) and homes (r(2)=0.49, p=0.10), with concentrations of PBDE in human blood plasma. The results indicated that dietary exposure, particularly consumption of fish, is a major pathway through which people in Hong Kong are exposed to PBDEs. Furthermore, our data revealed a spatial distribution and terrestrial source of BDE-28 for local people. Results of the present study, which was the first systematic study to investigate concentrations of PBDEs in blood of Hong Kong people, provides useful information to which future measurements can be compared. PMID- 23939207 TI - Chemical characteristics and risk assessment of typical municipal solid waste incineration (MSWI) fly ash in China. AB - The release of heavy metals in municipal solid waste incineration (MSWI) fly ash has become a worrying issue while fly ash is utilized or landfilled. This work investigated the potential mobility of heavy metals in the fly ashes from 15 typical MSWI plants in Chinese mainland by the characterization of distribution, chemical speciation and leaching behavior of heavy metals. The results showed that total content of heavy metals decreased in the order Zn>Pb>Cu>Cr>Ni>Cd in samples. The toxicity characteristics leaching procedure (TCLP) of fly ash indicated that the amount of leached Cd in 67% of samples exceeded the regulated limit. Also, the excess amount of leached Zn and Pb was observed in 40% and 53% of samples, respectively. The chemical speciation analysis revealed that this excess of heavy metal leached in TCLP was contributed to the high content of acid soluble fraction (F1) and reducible fraction (F2) of heavy metal. Moreover, the great positive relevance between leaching behavior of heavy metals and F1 fraction was supported by principal component analysis (PCA). Risk assessment code (RAC) results suggested that Cd and Pb showed a very high risk class to the environment. PMID- 23939208 TI - Tick-borne relapsing fever in pregnancy. PMID- 23939209 TI - Second Wi-Fi panel member's conflicts are problematic. PMID- 23939210 TI - Introducing deprescribing into culture of medication. PMID- 23939211 TI - Pharma influence widespread at medical schools: study. PMID- 23939212 TI - Croup in children. PMID- 23939213 TI - End funding for liberation therapy, say New Brunswick MDs. PMID- 23939214 TI - Incentives to increase patient satisfaction: are we doing more harm than good? PMID- 23939217 TI - Time to rethink refusing kidney transplants for obese patients. PMID- 23939215 TI - Effect of the Low Risk Ankle Rule on the frequency of radiography in children with ankle injuries. AB - BACKGROUND: The Low Risk Ankle Rule is a validated clinical decision rule that has the potential to safely reduce radiography in children with acute ankle injuries. We performed a phased implementation of the Low Risk Ankle Rule and evaluated its effectiveness in reducing the frequency of radiography in children with ankle injuries. METHODS: Six Canadian emergency departments participated in the study from Jan. 1, 2009, to Aug. 31, 2011. At the 3 intervention sites, there were 3 consecutive 26-week phases. In phase 1, no interventions were implemented. In phase 2, we activated strategies to implement the ankle rule, including physician education, reminders and a computerized decision support system. In phase 3, we included only the decision support system. No interventions were introduced at the 3 pair-matched control sites. We examined the management of ankle injuries among children aged 3-16 years. The primary outcome was the proportion of children undergoing radiography. RESULTS: We enrolled 2151 children with ankle injuries, 1055 at intervention and 1096 at control hospitals. During phase 1, the baseline frequency of pediatric ankle radiography at intervention and control sites was 96.5% and 90.2%, respectively. During phase 2, the frequency of ankle radiography decreased significantly at intervention sites relative to control sites (between-group difference -21.9% [95% confidence interval [CI] -28.6% to -15.2%]), without significant differences in patient or physician satisfaction. All effects were sustained in phase 3. The sensitivity of the Low Risk Ankle Rule during implementation was 100% (95% CI 85.4% to 100%), and the specificity was 53.1% (95% CI 48.1% to 58.1%). INTERPRETATION: Implementation of the Low Risk Ankle Rule in several different emergency department settings reduced the rate of pediatric ankle radiography significantly and safely, without an accompanying change in physician or patient satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT00785876. PMID- 23939219 TI - Design of D-pi-A type photoacid generators for high efficiency excitation at 405 nm and 800 nm. AB - New sulfonium salts with diphenylamino asymmetrically substituted stilbene as a D pi-A conjugated system have been synthesized. The resulting photoacid generators exhibit a highly efficient acid photogeneration process by either one-photon 405 nm or two-photon 800 nm excitation. PMID- 23939218 TI - Effectiveness of group medical visits for improving diabetes care: a systematic review and meta-analysis. AB - BACKGROUND: Group medical visits, whereby health care professionals meet with groups of patients who have the same disease, have been introduced in primary care as a way to meet the increasing demand for health care delivery to patients with chronic diseases. We performed a systematic review and meta-analysis of the evidence on the effectiveness of such visits for patients with diabetes. METHODS: We conducted a systematic review of all relevant studies published from 1947 to February 2012 identified in a search of electronic databases and grey literature. We included randomized controlled trials (RCTs) and observational studies published in English that included patients aged 16-80 years with type 1 or 2 diabetes and that had group medical visits as the intervention. These studies were assessed for methodologic quality. We included data only from the RCTs in the meta-analysis. RESULTS: Of the 94 studies identified, we selected 26 that met our inclusion criteria, 13 of which were RCTs. Group medical visits had a positive effect on clinical and patient-reported outcomes, with significant reductions in glycated hemoglobin (HbA1c reduction -0.46%, 95% confidence interval -0.80% to -0.31%). We were unable to assess the effect of group medical visits on processes of care because of an insufficient number of RCTs that reported on this outcome. INTERPRETATION: Group medical visits for patients with diabetes were found to be effective in terms of reducing HbA1c. The results of our meta-analysis suggest that wider implementation of group medical visits for patients with diabetes will have a positive effect on patient outcomes. PMID- 23939220 TI - DspA from Strongylocentrotus purpuratus: The first biochemically characterized haloalkane dehalogenase of non-microbial origin. AB - Haloalkane dehalogenases are known as bacterial enzymes cleaving a carbon-halogen bond in halogenated compounds. Here we report the first biochemically characterized non-microbial haloalkane dehalogenase DspA from Strongylocentrotus purpuratus. The enzyme shows a preference for terminally brominated hydrocarbons and enantioselectivity towards beta-brominated alkanes. Moreover, we identified other putative haloalkane dehalogenases of eukaryotic origin, representing targets for future experiments to discover dehalogenases with novel catalytic properties. PMID- 23939221 TI - Small molecule modulators of eukaryotic initiation factor 2alpha kinases, the key regulators of protein synthesis. AB - Eukaryotic initiation factor 2 alpha kinases (eIF-2alpha kinases) are key mediators of stress response in cells. In mammalian cells, there are four eIF 2alpha kinases, namely HRI (Heme-Regulated Inhibitor), PKR (RNA-dependent Protein Kinase), PERK (PKR-like ER Kinase) and GCN2 (General Control Non-derepressible 2). These kinases get activated during diverse cytoplasmic stress conditions and phosphorylate the alpha-subunit of eIF2, leading to global protein synthesis inhibition. Therefore, eIF-2alpha kinases play a vital role in various cellular processes such as proliferation, differentiation, apoptosis and cell signaling. Deregulation of eIF-2alpha kinases and protein synthesis has been linked to numerous pathological conditions such as certain cancers, anemia and neurodegenerative disorders. Thus, modulation of these kinases by small molecules holds a great therapeutic promise. In this review we have compiled the available information on inhibitors and activators of these four eIF-2alpha kinases. The review concludes with a note on the selectivity issue of currently available modulators and future perspectives for the design of specific small molecule probes. PMID- 23939222 TI - Early postnatal GFAP-expressing cells produce multilineage progeny in cerebrum and astrocytes in cerebellum of adult mice. AB - Early postnatal GFAP-expressing cells are thought to be immature astrocytes. However, it is not clear if they possess multilineage capacity and if they can generate different lineages (astrocytes, neurons and oligodendrocytes) in the brain of adult mice. In order to identify the fate of astroglial cells in the postnatal brain, hGFAP-Cre-ER(T2) transgenic mice were crossed with the R26R Cre reporter mouse strains which exhibit constitutive expression of beta galactosidase (beta-gal). Mice carrying the hGFAP-Cre-ER(T2)/R26R transgene were treated with Tamoxifen to induce Cre recombination in astroglial cells at postnatal (P) day 6 and Cre recombinase-expressing cells were identified by X-gal staining. Immunohistochemical staining was used to identify the type(s) of these reporter-tagged cells. Sixty days after recombination, X-gal-positive cells in different cerebral regions of the adult mice expressed the astroglial markers Blbp and GFAP, the neuronal marker NeuN, the oligodendrocyte precursor cell marker NG2 and the mature oligodendrocyte marker CC1. X-gal-positive cells in the cerebellum coexpressed the astroglial marker Blbp, but not the granule cell marker NeuN, Purkinje cell marker Calbindin or oligodendrocyte precursor cell marker NG2. Our genetic fate mapping data demonstrated that early postnatal GFAP positive cells possessed multilineage potential and eventually differentiated into neurons, astrocytes, and oligodendrocyte precursor cells in the cerebrum and into astrocytes (including Bergmann glia) in the cerebellum of adult mice. PMID- 23939224 TI - Motor-related cortical activity after cervical spinal cord injury: multifaceted EEG analysis of isometric elbow flexion contractions. AB - Electroencephalographic (EEG) studies have well established that motor cortex (M1) activity ~20 Hz decreases during muscular contraction and increases as soon as contraction stops, which are known as event-related desynchronization (ERD) and event-related synchronization (ERS), respectively. ERD is supposed to reflect M1 activation, sending information to recruited muscles, while the process underlying ERS is interpreted either as active cortical inhibition or as processing of sensory inputs. Investigation of the process behind ERD/ERS in people with spinal cord injury (SCI) would be particularly relevant since their M1 remains effective despite decreased sensorimotor abilities. In this study, we recorded net joint torque and EEG in 6 participants with cervical SCI and 8 healthy participants who performed isometric elbow flexion at 3 force levels. Multifaceted EEG analysis was introduced to assess ERD/ERS according to their amplitude, frequency range and duration. The results revealed that net joint torque increased with the required force level for all participants and time to contraction inhibition was longer in the SCI group. At the cortical level, ERD/ERS frequency ranges increased with the required force level in all participants, indicating that the modulation of cortical activity with force level is preserved after SCI. However, ERS amplitude decreased only in SCI participants, which may be linked to delayed contraction inhibition. All in all, cortical modulation of frequency range and amplitude could reflect two different kinds of neural communication. PMID- 23939223 TI - Gene-environment interactions affect long-term depression (LTD) through changes in dopamine receptor affinity in Snap25 deficient mice. AB - Genes and environmental conditions interact in the development of cognitive capacities and each plays an important role in neuropsychiatric disorders such as attention deficit/hyperactivity disorder (ADHD) and schizophrenia. Multiple studies have indicated that the gene for the SNARE protein SNAP-25 is a candidate susceptibility gene for ADHD, as well as schizophrenia, while maternal smoking is a candidate environmental risk factor for ADHD. We utilized mice heterozygous for a Snap25 null allele and deficient in SNAP-25 expression to model genetic effects in combination with prenatal exposure to nicotine to explore genetic and environmental interactions in synaptic plasticity and behavior. We show that SNAP 25 deficient mice exposed to prenatal nicotine exhibit hyperactivity and deficits in social interaction. Using a high frequency stimulus electrophysiological paradigm for long-term depression (LTD) induction, we examined the roles of dopaminergic D2 receptors (D2Rs) and cannabinoid CB1 receptors (CB1Rs), both critical for LTD induction in the striatum. We found that prenatal exposure to nicotine in Snap25 heterozygote null mice produced a deficit in the D2R-dependent induction of LTD, although CB1R regulation of plasticity was not impaired. We also show that prenatal nicotine exposure altered the affinity and/or receptor coupling of D2Rs, but not the number of these receptors in heterozygote null Snap25 mutants. These results refine the observations made in the coloboma mouse mutant, a proposed mouse model of ADHD, and illustrate how gene*environmental influences can interact to perturb neural functions that regulate behavior. PMID- 23939225 TI - Therapeutic hypercapnia improves functional recovery and attenuates injury via antiapoptotic mechanisms in a rat focal cerebral ischemia/reperfusion model. AB - Recent studies have demonstrated neuroprotective effects of therapeutic hypercapnia for different forms of brain injury. However, few studies have assessed the neuroprotective and neurobehavioral effects of hypercapnia in focal cerebral ischemia, and the underlying mechanisms are still unclear. Here, we investigated the effects of therapeutic hypercapnia in focal cerebral ischemia in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model. Adult male Sprague Dawley rats were subjected to 90 min of MCAO/R and subsequently exposed to increased carbon dioxide (CO2) levels to maintain arterial blood CO2 tension (PaCO2) between 80 and 100 mmHg for 2h. Neurological deficits were evaluated with the corner test at days 1, 7, 14, and 28. Infarction volume and apoptotic changes were assessed by 2, 3, 7-triphenyltetrazolium chloride (TTC) staining, and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate biotin nick end labeling (TUNEL) staining at 24h after reperfusion. Apoptosis related proteins (Bcl-2, Bax, cytochrome c, and caspase-3) were investigated by western blotting. The results of this study showed that therapeutic hypercapnia significantly reduced infarct volume and improved neurological scores after MCAO/R. Moreover, hypercapnia treatment increased the survival rate at 28 days after reperfusion. The TUNEL-positive neurons in the ipsilateral cortex were significantly decreased in the hypercapnia group. Mitochondrial Bcl-2 and Bax cortical expression levels were significantly higher and lower, respectively, in hypercapnia-treated rats. In addition, hypercapnia treatment decreased cytosolic cytochrome c and cleaved caspase-3 expression and increased cytosolic Bax expression. These findings indicate that therapeutic hypercapnia preserves brain tissue and promotes functional neurological recovery through antiapoptotic mechanisms. PMID- 23939226 TI - Nested theta to gamma oscillations and precise spatiotemporal firing during memory retrieval in a simulated attractor network. AB - Nested oscillations, where the phase of the underlying slow rhythm modulates the power of faster oscillations, have recently attracted considerable research attention as the increased phase-coupling of cross-frequency oscillations has been shown to relate to memory processes. Here we investigate the hypothesis that reactivations of memory patterns, induced by either external stimuli or internal dynamics, are manifested as distributed cell assemblies oscillating at gamma-like frequencies with life-times on a theta scale. For this purpose, we study the spatiotemporal oscillatory dynamics of a previously developed meso-scale attractor network model as a correlate of its memory function. The focus is on a hierarchical nested organization of neural oscillations in delta/theta (2-5Hz) and gamma frequency bands (25-35Hz), and in some conditions even in lower alpha band (8-12Hz), which emerge in the synthesized field potentials during attractor memory retrieval. We also examine spiking behavior of the network in close relation to oscillations. Despite highly irregular firing during memory retrieval and random connectivity within each cell assembly, we observe precise spatiotemporal firing patterns that repeat across memory activations at a rate higher than expected from random firing. In contrast to earlier studies aimed at modeling neural oscillations, our attractor memory network allows us to elaborate on the functional context of emerging rhythms and discuss their relevance. We provide support for the hypothesis that the dynamics of coherent delta/theta oscillations constitute an important aspect of the formation and replay of neuronal assemblies. This article is part of a Special Issue entitled Neural Coding 2012. PMID- 23939227 TI - Moving dietary management of diabetes forward. PMID- 23939228 TI - Evaluation of the dependence of CEST-EPI measurement on repetition time, RF irradiation duty cycle and imaging flip angle for enhanced pH sensitivity. AB - Chemical exchange saturation transfer (CEST) is a magnetic resonance imaging (MRI) contrast mechanism that can detect dilute CEST agents and microenvironmental properties, with a host of promising applications. Experimental measurement of the CEST effect is complex, and depends on not only CEST agent concentration and exchange rate, but also experimental parameters such as RF irradiation amplitude and scheme. Although echo planar imaging (EPI) has been increasingly used for CEST MRI, the relationship between CEST effect and repetition time (TR), RF irradiation duty cycle (DC) and EPI flip angle (alpha) has not been fully evaluated and optimized to enhance CEST MRI sensitivity. In addition, our study evaluated gradient echo CEST-EPI by quantifying the CEST effect and its signal-to-noise ratio per unit time (SNRput) as functions of TR, DC and alpha. We found that CEST effect increased with TR and DC but decreased with alpha. Importantly, we found that SNRput peaked at intermediate TRs of about twice the T1 and alpha, at approximately 75 degrees , and increased with RF DC. The simulation results were validated using a dual-pH creatine-gel CEST phantom. In summary, our study provides a useful framework for optimizing CEST MRI experiments. PMID- 23939229 TI - Characterization of fatty acid delta-6 desaturase gene in Nile tilapia and heterogenous expression in Saccharomyces cerevisiae. AB - Fatty acid delta-6 desaturase (fads2)-like gene from Nile tilapia (Oreochromis niloticus) was characterized and designated as oni-fads2. The Oni-FADS2 showed the typical structure of microsomal FADS2. The presence of oni-fads2 transcripts in unfertilized eggs demonstrated the maternal role of Nile tilapia in providing the oni-fads2 transcript in their eggs. In addition, the expression of oni-fads2 was detectable in embryos throughout the hatching stage. Real-time reverse transcription-PCR revealed that oni-fads2 was expressed at a high level in all the brain regions, liver, and testis. Recombinant yeast (RY) was generated by transformation of Saccharomyces cerevisiae with the plasmid containing oni-fads2 driven by the Gal1 promoter (pYoni-fads2). The conspicuous expression of RY was detectable by RT-PCR after induction with galactose for 24h. When RY was induced with galactose, it exhibited 39% and 7% of delta-6 desaturase (?6) activity toward C18:2n6 and C18:3n3, respectively. Additionally, it displayed 4% of delta 5 desaturase (?5) activity toward C20:3n6, indicating that Oni-FADS2 had ?5 and ?6 bifunction. PMID- 23939230 TI - Virtual screening and experimental validation reveal novel small-molecule inhibitors of 14-3-3 protein-protein interactions. AB - We report first non-covalent and exclusively extracellular inhibitors of 14-3-3 protein-protein interactions identified by virtual screening. Optimization by crystal structure analysis and in vitro binding assays yielded compounds capable of disrupting the interaction of 14-3-3sigma with aminopeptidase N in a cellular assay. PMID- 23939231 TI - Engineering nanocolumnar defect configurations for optimized vortex pinning in high temperature superconducting nanocomposite wires. AB - We report microstructural design via control of BaZrO3 (BZO) defect density in high temperature superconducting (HTS) wires based on epitaxial YBa2Cu3O7-delta (YBCO) films to achieve the highest critical current density, Jc, at different fields, H. We find the occurrence of Jc(H) cross-over between the films with 1-4 vol% BZO, indicating that optimal BZO doping is strongly field-dependent. The matching fields, Bphi, estimated by the number density of BZO nanocolumns are matched to the field ranges for which 1-4 vol% BZO-doped films exhibit the highest Jc(H). With incorporation of BZO defects with the controlled density, we fabricate 4-MUm-thick single layer, YBCO + BZO nanocomposite film having the critical current (Ic) of ~1000 A cm(-1) at 77 K, self-field and the record minimum Ic, Ic(min), of 455 A cm(-1) at 65 K and 3 T for all field angles. This Ic(min) is the largest value ever reported from HTS films fabricated on metallic templates. PMID- 23939232 TI - The photochemistry of rhenium(I) tricarbonyl N-heterocyclic carbene complexes. AB - The photophysical and photochemical properties of the new tricarbonyl rhenium(I) complexes bound to N-heterocyclic carbene ligands (NHC), fac-[Re(CO)3(N^C)X] (N^C = 1-phenyl-3-(2-pyridyl)imidazole or 1-quinolinyl-3-(2-pyridyl)imidazole; X = Cl or Br), are reported. The photophysics of these complexes highlight phosphorescent emission from triplet metal-to-ligand ((3)MLCT) excited states, typical of tricarbonyl rhenium(I) complexes, with the pyridyl-bound species displaying a ten-fold shorter excited state lifetime. On the other hand, these pyridyl-bound species display solvent-dependent photochemical CO dissociation following what appear to be two different mechanisms, with a key step being the formation of cationic tricarbonyl solvato-complexes, being themselves photochemically active. The photochemical mechanisms are illustrated with a combination of NMR, IR, UV-Vis, emission and X-ray structural characterization techniques, clearly demonstrating that the presence of the NHC ligand is responsible for the previously unobserved photochemical behavior in other photoactive tricarbonyl rhenium(I) species. The complexes bound to the quinolinyl NHC ligand (which possess a lower-energy (3)MLCT) are photostable, suggesting that the photoreactive excited state is not any longer thermally accessible. The photochemistry of the pyridyl complexes was investigated in acetonitrile solutions and also in the presence of triethylphosphite, showing a competing and bifurcated photoreactivity promoted by the trans effect of both the NHC and phosphite ligands. PMID- 23939233 TI - Human leukocyte antigen B*57 does not fully explain hepatitis C clearance in HIV controllers. AB - OBJECTIVE: HIV controllers demonstrate high rates of spontaneous clearance of hepatitis C virus (HCV) infection. The objective of this study was to evaluate the role of human leukocyte antigen (HLA) B*57 and other genetic polymorphisms on HCV clearance in HIV controllers. DESIGN: This is a prospective cohort study. METHODS: Patients in the Study of the Consequences of Protease Inhibitor Era (SCOPE) were tested for anti-HCV using enzyme immunoassay (EIA3) and HCV RNA using discriminatory HCV transcription-mediated amplification assay (Norvatis). We compared the proportion of HIV controllers and noncontrollers demonstrating HCV clearance and fitted multivariable Poisson regression models with robust standard errors to estimate adjusted prevalence ratios (APRs) and assessed genetic and immunologic predictors of HCV clearance. RESULTS: Of 279 HIV/HCV seropositive individuals, 48 were HIV controllers. HIV controllers compared to HIV noncontrollers, were significantly more likely to have HLA B*57 (33 vs. 10%, P < 0.01). In multivariate analyses, adjusting for HLAB57, IL28B genotype, age, sex and race/ethnicity, HCV clearance was significantly more likely in HIV controllers than HIV noncontrollers [APR 1.78; 95% confidence interval (CI) 1.06 3.0; P = 0.03]. HLA B*57 did not explain the increased proportion of HCV clearance in HIV controllers, but IL28B CC genotype was independently associated with spontaneous HCV clearance (APR 2.76; 95% CI 1.85-4.11; P < 0.001). CONCLUSION: Although enriched in HIV controllers, HLA B*57 does not explain the increased HCV clearance. Further identification of host immunologic or genetic factors that contribute to control of HIV and HCV may support the development of novel treatments for and effective vaccines against both viruses. PMID- 23939235 TI - Structure-specific glial response in a macaque model of neuroAIDS: multivoxel proton magnetic resonance spectroscopic imaging at 3 Tesla. AB - OBJECTIVE: As ~40% of persons with HIV also suffer neurocognitive decline, we sought to assess metabolic dysfunction in the brains of simian immunodeficiency virus (SIV)-infected rhesus macaques, an advanced animal model, in structures involved in cognitive function. We test the hypothesis that SIV-infection produces proton-magnetic resonance spectroscopic imaging (H-MRSI)-observed decline in the neuronal marker, N-acetylaspartate (NAA), and elevations in the glial marker, myo-inositol (mI), and associated creatine (Cr) and choline (Cho) in these structures. DESIGN: Pre- and 4-6 weeks post-SIV infection (with CD8 T lymphocyte depletion) was monitored with T2-weighted quantitative MRI and 16*16*4 multivoxel H-MRSI (TE/TR = 33/1400 ms) in the brains of five rhesus macaques. METHODS: Exploiting the high-resolution H-MRSI grid, we obtained absolute, cerebrospinal fluid partial volume-corrected NAA, Cr, Cho and mI concentrations from centrum semiovale, caudate nucleus, putamen, thalamus and hippocampus regions. RESULTS: Pre- to post-infection mean Cr increased in the thalamus: 7.2+/ 0.4 to 8.0+/-0.8 mmol/l (+11%, P<0.05); mI increased in the centrum semiovale: 5.1+/-0.8 to 6.6+/-0.8 mmol/l, caudate: 5.7+/-0.7 to 7.3+/-0.5 mmol/l, thalamus: 6.8+/-0.8 to 8.5+/-0.8 mmol/l and hippocampus: 7.7+/-1.2 to 9.9+/-0.4 mmol/l (+29%, +27%, +24% and +29%, all P<0.05). NAA and Cho changes were not significant. CONCLUSION: SIV-infection appears to cause brain injury indirectly, through glial activation, while the deep gray matter structures' neuronal cell bodies are relatively spared. Treatment regimens to reduce gliosis may, therefore, prevent neuronal damage and its associated neurocognitive impairment. PMID- 23939236 TI - Variation in IFNL4 genotype and response to interferon-based therapy of hepatitis C in HIV-positive patients with acute and chronic hepatitis C. AB - The IFNL4 ss469415590 polymorphism has recently be shown to better predict treatment response in chronic hepatitis than the IL28B rs12979860 variant. However, no data exist in patients with HIV/hepatitis C virus (HCV) coinfection. Analysing 206 HCV(+)/HIV(+) and 162 HCV(+)/HIV(-) patients, we found that compared with IL28B rs12979860, IFNL4 ss469415590 was strongly associated with response to interferon/ribavirin therapy in HCV(+)/HIV(-) individuals but not in HIV(+)/HCV(+) patients. Thus, effects of the IFNL4 variant may differ in HIV(+) and HIV(-) patients. PMID- 23939234 TI - Longitudinal assessment of associations between food insecurity, antiretroviral adherence and HIV treatment outcomes in rural Uganda. AB - INTRODUCTION: Food insecurity is a potentially important barrier to the success of antiretroviral therapy (ART) programs in resource-limited settings. We undertook a longitudinal study in rural Uganda to estimate the associations between food insecurity and HIV treatment outcomes. DESIGN: Longitudinal cohort study. METHODS: Participants were from the Uganda AIDS Rural Treatment Outcomes study and were followed quarterly for blood draws and structured interviews. We measured food insecurity with the validated Household Food Insecurity Access Scale. Our primary outcomes were: ART nonadherence (adherence <90%) measured by visual analog scale; incomplete viral load suppression (>400 copies/ml); and low CD4 T-cell count (<350 cells/MUl). We used generalized estimating equations to estimate the associations, adjusting for socio-demographic and clinical variables. RESULTS: We followed 438 participants for a median of 33 months; 78.5% were food insecure at baseline. In adjusted analyses, food insecurity was associated with higher odds of ART nonadherence [adjusted odds ratio (AOR) 1.56, 95% confidence interval (CI) 1.10-2.20, P < 0.05], incomplete viral suppression (AOR 1.52, 95% CI 1.18-1.96, P < 0.01), and CD4 T-cell count less than 350 (AOR 1.47, 95% CI 1.24-1.74, P < 0.01). Adding adherence as a covariate to the latter two models removed the association between food insecurity and viral suppression, but not between food insecurity and CD4 T-cell count. CONCLUSIONS: Food insecurity is longitudinally associated with poor HIV outcomes in rural Uganda. Intervention research is needed to determine the extent to which improved food security is causally related to improved HIV outcomes and to identify the most effective policies and programs to improve food security and health. PMID- 23939237 TI - Preexposure prophylaxis will have a limited impact on HIV-1 drug resistance in sub-Saharan Africa: a comparison of mathematical models. AB - BACKGROUND: Preexposure prophylaxis (PrEP) with tenofovir and emtricitabine can prevent new HIV-1 infections, but there is a concern that use of PrEP could increase HIV drug resistance resulting in loss of treatment options. We compared standardized outcomes from three independent mathematical models simulating the impact of PrEP on HIV transmission and drug resistance in sub-Saharan African countries. METHODS: All models assume that people using PrEP receive an HIV test every 3-6 months. The models vary in structure and parameter choices for PrEP coverage, effectiveness of PrEP (at different adherence levels) and the rate with which HIV drug resistance emerges and is transmitted. RESULTS: The models predict that the use of PrEP in conjunction with antiretroviral therapy will result in a lower prevalence of HIV than when only antiretroviral therapy is used. With or without PrEP, all models suggest that HIV drug resistance will increase over the next 20 years due to antiretroviral therapy. PrEP will increase the absolute prevalence of drug resistance in the total population by less than 0.5% and amongst infected individuals by at most 7%. Twenty years after the introduction of PrEP, the majority of drug-resistant infections is due to antiretroviral therapy (50-63% across models), whereas 40-50% will be due to transmission of drug resistance, and less than 4% to the use of PrEP. CONCLUSION: HIV drug resistance resulting from antiretroviral therapy is predicted to far exceed that resulting from PrEP. Concern over drug resistance should not be a reason to limit the use of PrEP. PMID- 23939238 TI - Graves' disease as immune reconstitution disease in HIV-positive patients is associated with naive and primary thymic emigrant CD4(+) T-cell recovery. AB - OBJECTIVE: Immune restoration disease (IRD) can develop in HIV-infected patients following antiretroviral therapy (ART) initiation as unmasking or paradoxical worsening of opportunistic infections and, rarely, autoimmune phenomena. Although IRD usually occurs in the first months of ART during memory CD4 T-cell recovery, Graves' disease occurs as a distinctive late-onset IRD and its pathogenesis is unclear. DESIGN: Seven patients who developed Graves' disease following ART initiation from the primary HIV care clinic at the National Institutes of Health were retrospectively identified and each was matched with two HIV-infected controls based on age, sex, and baseline CD4 T-cell count. Laboratory evaluations on stored cryopreserved samples were performed. METHODS: Immunophenotyping of peripheral blood mononuclear cells (PBMCs), T-cell receptor excision circle (TREC) analysis in PBMCs, measurement of serum cytokines, and luciferase immunoprecipitation systems (LIPS) analysis for autoimmune antibodies were performed on stored samples for cases and controls at baseline and longitudinally following ART initiation. TSH/thyrotropin receptor (TSH-R) antibody testing was performed on serum from cases. Data were analyzed using nonparametric testing. RESULTS: In comparison with controls, the proportion of naive CD4 T cells increased significantly (P = 0.0027) in the Graves' disease-IRD patients. TREC/10 PBMCs also increased significantly following ART in Graves' disease-IRD patients compared with controls (P = 0.0071). Similarly, LIPS analysis demonstrated increases in nonthyroid-related autoantibody titers over time following ART in cases compared with controls. CONCLUSION: Our data suggest that Graves' disease IRD, in contrast to early-onset IRD, is associated with naive and primary thymic emigrant CD4 T-cell recovery and inappropriate autoantibody production. PMID- 23939239 TI - Evidence for continuing cross-species transmission of SIVsmm to humans: characterization of a new HIV-2 lineage in rural Cote d'Ivoire. AB - HIV types 1 and 2 (HIV-1 and HIV-2) are the result of multiple cross-species transmissions of their simian counterparts (SIVs) to humans. We studied whether new SIVs lineages have been transmitted to humans in rural Cote d'Ivoire and identified a novel HIV-2 variant (HIV-2-07IC-TNP03) not related to any of the previously defined HIV-2 groups. This finding shows that sooty mangabey viruses continue to be transmitted to humans, causing new zoonotic outbreaks. PMID- 23939240 TI - Highlights on HIV eradication in 2013. PMID- 23939241 TI - Successful anti-hepatitis C virus therapy with telaprevir in an HIV/hepatitis C virus co-infected patient with a severe recurrence of hepatitis C virus infection on the liver graft. AB - We report, for the first time, the outcome of anti-hepatitis C virus (HCV) triple therapy with telaprevir in an HIV/HCV co-infected transplanted patient. After liver transplantation, the patient experienced a severe HCV recurrence with fibrosing cholestatic hepatitis, and anti-HCV therapy with pegylated interferon alpha 2a, ribavirin and telaprevir was initiated. A sustained virological response was achieved after 48 weeks of anti-HCV therapy. Drug-drug interactions between antiretroviral therapy, immunosuppressive agents and anti-HCV therapy could be managed. PMID- 23939242 TI - Who is taking up voluntary medical male circumcision? Early evidence from Tanzania. AB - We examined the impacts of nationwide voluntary medical male circumcision efforts in Tanzania. Using Demographic and Health Surveys data, we found that circumcision rates increased from 37% to 47% in regions targeted by the program. Those who took up medical male circumcision were younger, more educated, wealthier, and more likely to use condoms. Efforts going forward should focus on stimulating circumcision demand among more vulnerable men. PMID- 23939243 TI - Physicians' lack of awareness of how they are paid: implications for new models of reimbursement. PMID- 23939244 TI - Confirmation of quasi-static approximation in SAR evaluation for a wireless power transfer system. AB - The present study discusses the applicability of the magneto-quasi-static approximation to the calculation of the specific absorption rate (SAR) in a cylindrical model for a wireless power transfer system. Resonant coils with different parameters were considered in the 10 MHz band. A two-step quasi-static method that is comprised of the method of moments and the scalar-potential finite difference methods is applied, which can consider the effects of electric and magnetic fields on the induced SAR separately. From our computational results, the SARs obtained from our quasi-static method are found to be in good agreement with full-wave analysis for different positions of the cylindrical model relative to the wireless power transfer system, confirming the applicability of the quasi static approximation in the 10 MHz band. The SAR induced by the external electric field is found to be marginal as compared to that induced by the magnetic field. Thus, the dosimetry for the external magnetic field, which may be marginally perturbed by the presence of biological tissue, is confirmed to be essential for SAR compliance in the 10 MHz band or lower. This confirmation also suggests that the current in the coil rather than the transferred power is essential for SAR compliance. PMID- 23939245 TI - What's your legacy? PMID- 23939246 TI - Waste to real energy: the first MFC powered mobile phone. AB - This communication reports for the first time the charging of a commercially available mobile phone, using Microbial Fuel Cells (MFCs) fed with real neat urine. The membrane-less MFCs were made out of ceramic material and employed plain carbon based electrodes. PMID- 23939247 TI - Mitochondrial phosphate transport during nutrient stimulation of INS-1E insulinoma cells. AB - Here, we have investigated the role of inorganic phosphate (Pi) transport in mitochondria of rat clonal beta-cells. In alpha-toxin-permeabilized INS-1E cells, succinate and glycerol-3-phosphate increased mitochondrial ATP release which depends on exogenous ADP and Pi. In the presence of substrates, addition of Pi caused mitochondrial matrix acidification and hyperpolarisation which promoted ATP export. Dissipation of the mitochondrial pH gradient or pharmacological inhibition of Pi transport blocked the effects of Pi on electrochemical gradient and ATP export. Knock-down of the phosphate transporter PiC, however, neither prevented Pi-induced mitochondrial activation nor glucose-induced insulin secretion. Using (31)P NMR we observed reduction of Pi pools during nutrient stimulation of INS-1E cells. Interestingly, Pi loss was less pronounced in mitochondria than in the cytosol. We conclude that matrix alkalinisation is necessary to maintain a mitochondrial Pi pool, at levels sufficient to stimulate energy metabolism in insulin-secreting cells beyond its role as a substrate for ATP synthesis. PMID- 23939248 TI - Orthogonal aerobic conversion of N-benzyl amidoximes to 1,2,4-oxadiazoles or quinazolinones. AB - Concise synthesis of 1,2,4-oxadiazoles was achieved by heating N-benzyl amidoximes with K3PO4 in DMF at 60 degrees C under an O2 atmosphere via benzylic C-H oxygenation. On the other hand, aerobic treatment of N-benzyl amidoximes with Cs2CO3 in DMSO at 100 degrees C could result in oxidative skeletal rearrangement to deliver quinazolinones as a major product. This orthogonal product selectivity could be realized by difference of the reaction temperature as well as selection of the solvents and inorganic bases. PMID- 23939250 TI - Reversible thermally-responsive electrochemical energy storage based on smart LDH@P(NIPAM-co-SPMA) films. AB - A smart supercapacitor was fabricated by loading a thermosensitive polymer P(NIPAM-co-SPMA) onto the surface of NiAl-layered double hydroxide (LDH) nanowalls grown on a flexible Ni foil substrate, which displays temperature triggered on-off ion channels for controlling the electrochemical behavior. PMID- 23939249 TI - Overexpression of Atg5 in mice activates autophagy and extends lifespan. AB - Autophagy has been implicated in the ageing process, but whether autophagy activation extends lifespan in mammals is unknown. Here we show that ubiquitous overexpression of Atg5, a protein essential for autophagosome formation, extends median lifespan of mice by 17.2%. We demonstrate that moderate overexpression of Atg5 in mice enhances autophagy, and that Atg5 transgenic mice showed anti-ageing phenotypes, including leanness, increased insulin sensitivity and improved motor function. Furthermore, mouse embryonic fibroblasts cultured from Atg5 transgenic mice are more tolerant to oxidative damage and cell death induced by oxidative stress, and this tolerance was reversible by treatment with an autophagy inhibitor. Our observations suggest that the leanness and lifespan extension in Atg5 transgenic mice may be the result of increased autophagic activity. PMID- 23939251 TI - Salivary mental stress proteins. AB - Of the major diagnostic specimen types, saliva is one of the most easily collected. Many studies have focused on the evaluation of salivary proteins secreted by healthy people and patients with various diseases during responses to acute mental stress. In particular, such studies have focused on cortisol, alpha amylase, chromogranin A (CgA), and immunoglobulin A (IgA) as salivary stress markers. Each of these salivary stress markers has its own strengths and weaknesses as well as data gaps related to many factors including collection technique. In this review, we summarize the critical knowledge of the positive and negative attributes and data gaps pertaining to each salivary stress marker. PMID- 23939252 TI - Voltammetric and spectroscopic characterization of early intermediates in the Co(II)-polypyridyl-catalyzed reduction of water. AB - Early intermediates of catalytic water reduction by a Co(II)-polypyridyl species have been characterized. Electrochemical detection of the Co(III)-hydride and time-resolved spectroscopic detection of the Co(I)-ligand intermediates provide an understanding of their reactivity in electrolytic or light-driven reduction of protons to hydrogen. PMID- 23939253 TI - Facile synthesis of highly efficient and recyclable magnetic solid acid from biomass waste. AB - In this work, sawdust, a biomass waste, is converted into a magnetic porous carbonaceous (MPC) solid acid catalyst by an integrated fast pyrolysis sulfonation process. The resultant magnetic solid acid has a porous structure with high surface area of 296.4 m(2) g(-1), which can be attributed to the catalytic effect of Fe. The catalytic activity and recyclability of the solid acid catalyst are evaluated during three typical acid-catalyzed reactions: esterification, dehydration, and hydrolysis. The favorable catalytic performance in all three reactions is attributed to the acid's high strength with 2.57 mmol g(-1) of total acid sites. Moreover, the solid acid can be reused five times without a noticeable decrease in catalytic activity, indicating the stability of the porous carbon (PC)-sulfonic acid group structure. The findings in the present work offer effective alternatives for environmentally friendly utilization of abundant biomass waste. PMID- 23939254 TI - Productivity and impact of the top 100 cited Parkinson's disease investigators since 1985. AB - We have compiled a list of the 100 most cited researchers in Parkinson's disease since 1985 together with H-Indices as a means to assess productivity and impact. Within the total-citations ranking, "broad impact" citations are used as a way of identifying those researchers whose work is cited widely beyond the Parkinson's disease research community. Finally, we present a table of the most cited researchers this decade for a comparison of the two with analysis. PMID- 23939255 TI - Use of a refined drug tracer algorithm to estimate prevalence and incidence of Parkinson's disease in a large israeli population. AB - Estimating rates of Parkinson's disease (PD) is essential for health services planning and studies of disease determinants. However, few PD registries exist. We aimed to estimate annual prevalence and incidence of PD in a large Israeli population over the past decade using computerized drug purchase data. Based on profiles of anti-parkinsonian drugs, age at first purchase, purchase density, and follow-up time, we developed a refined algorithm for PD assessment (definite, probable or possible) and validated it against clinical diagnoses. We used the prescription database of the second largest Health Maintenance Organization in Israel (covers ~25% of population), for the years 1998-2008. PD rates by age, gender and year were calculated and compared using Poisson models. The algorithm was found to be highly sensitive (96%) for detecting PD cases. We identified 7,134 prevalent cases (67% definite/probable), and 5,288 incident cases (65% definite/probable), with mean age at first purchase 69 +/- 13 years. Over the years 2000-2007, PD incidence rate of 33/100,000 was stable, and the prevalence rate increased from 170/100,000 to 256/100,000. For ages 50+, 60+, 70+, median prevalence rates were 1%, 2%, 3%, respectively. Incidence rates also increased with age (RR = 1.76, 95%CI 1.75-1.77, ages 50+, 5-year interval). For ages 50+, rates were higher among men for both prevalence (RR = 1.38, 95%CI 1.37-1.39) and incidence (RR = 1.45, 95%CI 1.42-1.48). In conclusion, our refined algorithm for PD assessment, based on computerized drug purchases data, may be a reliable tool for population-based studies. The findings indicate a burden of PD in Israel higher than previously assumed. PMID- 23939256 TI - Restorative effects of platelet derived growth factor-BB in rodent models of Parkinson's disease. AB - Parkinson's disease is characterized by motor deficits caused by loss of midbrain dopaminergic neurons. Neurotrophic factors and cell transplantation have partially restored function in models of Parkinson's disease, but have had limited effects in humans. Here we show that intracerebroventricular administration of platelet-derived growth factor-BB can offer an alternative strategy to restore function in Parkinson's disease; In animal models of nigrostriatal injury, a two weeks treatment with platelet-derived growth factor BB resulted in long-lasting restoration of striatal dopamine transporter binding sites and expression of nigral tyrosine hydroxylase. It also normalized amphetamine-induced rotational behavior in 6-hydroxydopamine lesioned rats. Platelet-derived growth factor-BB promoted proliferation of neural progenitor cells in the subventricular zone. The effects on dopaminergic neurons and functional recovery could be blocked by co-infusion with a proliferation inhibitor, indicating a link between the proliferative and anti-parkinsonian effects. Based on the current data, we consider platelet-derived growth factor-BB a clinical candidate drug for treatment of Parkinson's disease. PMID- 23939257 TI - Gastrointestinal disorders in Parkinson's disease: prevalence and health outcomes in a US claims database. AB - The majority of patients with Parkinson's Disease (PD) will eventually develop gastrointestinal disorders (GIDs) such as dysphagia, constipation and gastroesophageal reflux. The objectives of this study were to examine the incidence of GIDs in PD patients in a US population, and to examine subsequent PD related outcomes in patients with GIDs. In a US administrative health claims database, GID incidence increased over time to reach 65% at four years after PD diagnosis. To further investigate this relationship, a subset of patients was analysed in greater detail. Continuously treated PD patients with and without GIDs were matched by age, gender, comorbidities, treatment regime, US region and plan type. Their emerging health outcomes were followed up for two years. Outcomes included neuropsychiatric, motor and urogenital disturbances, as well as healthcare utilization and costs. Patients with GIDs had higher rates of psychosexual dysfunction, anxiety, depression, ataxia, pain, movement disorders, urinary incontinence and falls. Emergency room admissions, the number of drugs for pain, sleep and depression, PD-related healthcare costs and non PD-related healthcare costs also increased during the observation period in GID patients. This study indicated that GIDs may be associated with deleterious effects on some PD-related outcomes. PMID- 23939258 TI - The factor structure of the UPDRS as an index of disease progression in Parkinson's disease. AB - The optimum method for evaluating disease progression in Parkinson's disease (PD) has not been established, and this has implications for clinical trials. The majority of previous studies have utilized change on the Unified Parkinson's disease Rating Scale (UPDRS) as an index of progression. However, the UPDRS has not been validated for this purpose. We utilized exploratory factor analysis (EFA) to evaluate the longitudinal properties of the UPDRS as an index of disease progression in PD. Data was derived from a representative cohort of 122 PD patients followed from diagnosis and assessed every 18-24 months for up to 7.9 years. For each subject the rate of change of each item on the UPDRS-3 was calculated and an EFA was performed using this data. Results were compared with those of previously published EFAs in cross-sectional PD cohorts. The UPDRS-3 retains a stable factor structure when used as an index of disease evolution. The 27 items reduced to 6 factors which accounted for 61.0% of the variance in disease progression. A dominant factor was identified which incorporated axial (gait/postural stability) symptoms and signs. Our analysis indicates that the UPDRS captures meaningful aspects of disease progression in PD, and that it is possible to identify symptom/sign complexes which evolve independently of one another. Progression in PD is predominantly characterized by the development of axial symptoms and signs. This result has implications for pathogenesis and should also inform natural history models of PD thereby allowing identification of meaningful outcome measures for clinical trials of disease-modifying therapies. PMID- 23939259 TI - Signs of degeneration in 12-22-year old grafts of mesencephalic dopamine neurons in patients with Parkinson's disease. AB - We demonstrate that grafted human fetal mesencephalic neurons can survive and extend axons for 22 years in the brain of a patient with Parkinson's disease (PD). In this patient, the overall survival and fiber outgrowth of the grafts were, however, relatively poor, which is consistent with the lack of significant clinical graft-induced benefit. We have compared the morphology of neurons in the 22-year old grafts with those in two younger grafts (16- and 12-year old), which were sequentially implanted in another PD patient. In the case with the 22-year old transplant, a high proportion (up to 38%) of the grafted dopaminergic (pigment-granule containing) neurons do not express tyrosine hydroxylase and dopamine transporter and their perikarya appear atrophic. The proportion of pigmented neurons not expressing these markers is lower in the 12-16 year old grafts. Furthermore, in the 22-year-old graft, 49% of the pigmented neurons display alpha-synuclein immunoreactivity in the cell body and 1.2% of them contain Lewy bodies. In conclusion, our results show that grafted dopaminergic neurons can survive for more than two decades. However, over time an increasing proportion of grafted neurons exhibit signs of degeneration. PMID- 23939260 TI - Striatal dopamine depletion induces forelimb motor impairments and disrupts forelimb movement representations within the motor cortex. AB - While limb motor deficits of Parkinson's disease are well characterized, the effects of striatal dopamine depletion on the motor cortex is poorly understood. We therefore aimed to 1) examine the effects of striatal dopamine depletion on forelimb function and cortical motor map topography and 2) explore potential relationships between forelimb function and cortical movement representations in an animal model of PD. Twenty-four male Long Evans rats were randomized to control or 6-hydroxydopamine (6-OHDA) groups. Animals in the 6-OHDA group underwent four unilateral 6-OHDA infusions into the striatum to induce striatal dopamine depletion. Four weeks later, animals were tested on a comprehensive battery of behavioral limb motor tasks followed by intracortical microstimulation to derive high-resolution topographic maps of forelimb movement representations. Standard tyrosine hydroxylase (TH) immunohistochemistry was performed and near infrared densitometry analysis utilized to assess TH depletion. Unilateral striatal dopamine depletion induced significant reductions in limb motor function that were reflected neurophysiologically as a reduction in cortical forelimb movement representations. Voluntary forelimb use, pasta handling, sunflower seed manipulation, and forelimb motor maps were all significantly impaired in 6-OHDA animals. A positive correlation was observed between forelimb function and motor map size, as well as two negative correlations between TH depletion with 1) motor map size and 2) forelimb function. The results clearly show how dysfunction within the basal ganglia thalamocortical loop resulting from nigrostriatal dopamine depletion disrupts corticospinal function. PMID- 23939261 TI - Design and evaluation of levodopa methyl ester intranasal delivery systems. AB - OBJECTIVES: This study aimed to examine the feasibility of nasal powder formulations for the delivery of levodopa (L-dopa) into the brain using highly water-soluble levodopa methyl ester hydrochloride (LDME). METHODS: For designing nasal LDME powders, pH-rate stabilities of LDME in buffer solutions and their enzymatic degradations in rabbit nasal mucosal and serosal extracts were investigated. In vitro permeation studies were carried out with four LDME nasal powders. RESULTS: LDME was degraded fast in weakly acidic and neutral solutions, but relatively stable in acidic solutions. In nasal extracts, LDME (50 and 200 MUg/mL) was rapidly hydrolyzed, forming L-dopa, and there were no significant differences in first-order degradation rates between mucosal and serosal extracts. From the in vitro permeation studies, LDME powder formulations resulted in faster appearance rates (1.07 +/- 0.39 mg/cm2/hr) of L-dopa than solution formulations (0.35 +/- 0.08 mg/cm2/hr). CONCLUSIONS: These results suggested that LDME nasal powder formulations could be useful delivery systems of L-dopa. PMID- 23939262 TI - A novel compound heterozygous tyrosine hydroxylase mutation (p.R441P) with complex phenotype. AB - Tyrosine hydroxylase (TH) is a tetrahydrobiopterin (BH4) dependent enzyme that catalyses the conversion of L-tyrosine to L-dopa, the rate-limiting step in the biosynthesis of dopamine. Autosomal recessive mutations in the TH gene cause impaired TH activity and are associated with phenotypes ranging from autosomal recessive dopa-responsive dystonia (DRD) to progressive infantile encephalopathy. Herein, we present a patient with TH-deficiency due to two compound heterozygous missense mutations in the TH/gene, one of which is novel (p.R441P). A clinical update on TH-deficiency and clues on how to achieve a timely diagnosis of this highly treatable disorder is provided. PMID- 23939263 TI - Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial. AB - IMPORTANCE: Observational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people. OBJECTIVE: To test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension. DESIGN: Parallel group, double-blind, placebo-controlled randomized trial. SETTING: Primary care clinics and hospital clinics. PARTICIPANTS: Patients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011. INTERVENTIONS: A total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year. MAIN OUTCOMES AND MEASURES: Difference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months. RESULTS: A total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P < .001). No significant treatment effect was seen for mean (95% CI) office blood pressure (-1 [-6 to 4]/-2 [-4 to 1] mm Hg at 3 months and 1 [-2 to 4]/0 [-2 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24 hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P = .24). CONCLUSIONS AND RELEVANCE: Vitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN92186858. PMID- 23939264 TI - Retinal vascular dysfunction relates to cognitive impairment in Alzheimer disease. PMID- 23939265 TI - Evaluation and comparison of Ga-68 DOTA-TATE and Ga-68 DOTA-NOC PET/CT imaging in well-differentiated thyroid cancer. AB - BACKGROUND: Somatostatin receptor (Sstr) scintigraphy with radiolabelled somatostatin analogues has been used extensively for the diagnosis and therapy of Sstr-expressing tumours. It has been shown that well-differentiated thyroid cancer (WDTC) cells have a high expression of Sstr2, Sstr3 and Sstr5. Hence, WDTC cells could be an ideal target for the evaluation of lesion uptake of Ga-68 DOTA 1-NaI3-octreotide (DOTA-NOC), which has a high affinity not only to Sstr2 but also to Sstr3 and Sstr5. The aim of the present study was to evaluate the value of Ga-68 DOTA-NOC as a target for Sstr2-expressing, Sstr3-expressing and Sstr5 expressing tumours in WDTC patients and to compare the results with those of Ga 68 DOTA-TATE in the same patient population. METHOD: Thirteen patients with WDTC were included in our study: nine with papillary thyroid cancer, three with Hurthle cell carcinoma and one with follicular thyroid carcinoma. All patients had elevated serum thyroglobulin levels and negative post-therapeutic I-131 whole body scans, which were obtained after the last radioiodine treatment. All patients had undergone two consecutive PET imaging studies with Ga-68 DOTA-D-Phe1 Tyr3-octreotate (DOTA-TATE) and Ga-68 DOTA-NOC, respectively. All images were evaluated visually, and maximum standardized uptake values were calculated. RESULTS: Both Ga-68 DOTA-TATE and Ga-68 DOTA-NOC PET images gave comparable results. Among the 13 patients, imaging with both Ga-68 DOTA-TATE and Ga-68 DOTA NOC gave negative results in five (38%) patients and positive results in eight (62%) patients. A total of 45 lesions were identified on Ga-68 DOTA-TATE images and 42 on Ga-68 DOTA-NOC images; three lesions were missed. Lesion uptake was significantly higher on Ga-68 DOTA-TATE images. Maximum standardized uptake values of Ga-68 DOTA-TATE and Ga-68 DOTA-NOC were 12.9+/-9.1 and 6.3+/-4.1 (n=54, P<0.001), respectively. CONCLUSION: Our study suggested that Ga-68 DOTA-TATE has a higher lesion uptake even in WDTC patients and may have potential advantage over Ga-68 DOTA-NOC. PMID- 23939266 TI - Endothelial cells mitigate DNA damage and promote the regeneration of hematopoietic stem cells after radiation injury. AB - Endothelial cells (ECs) are an essential component of the hematopoietic microenvironment, which maintains and regulates hematopoietic stem cells (HSCs). Although ECs can support the regeneration of otherwise lethally-irradiated HSCs, the mechanisms are not well understood. To further understand this phenomenon, we studied HSC regeneration from irradiated bone marrow using co-culture with human aortic ECs (HAECs). Co-culture with HAECs induced a 24-fold expansion of long term HSCs (CD150(+), lineage(lo), Sca-1(+), c-Kit(+); CD150(+)LSK cells) in vitro. These cells gave rise to functional hematopoietic stem and progenitor cells (HSPCs) with colony-forming activity, multilineage reconstitution and serial transplantation potential. Furthermore, HAECs significantly reduced DNA damage in irradiated LSK cells within 24h. Remarkably, we were able to delay the exposure of irradiated bone marrow to the regenerative, HAEC-derived signals for up to 48h and still rescue functional HSCs. G-CSF is the gold standard for promoting hematopoietic regeneration in vivo. However, when compared to HAECs, in vitro G-CSF treatment promoted lineage differentiation and regenerated 5-fold fewer CD150(+)LSK cells. Together, our results show that HAECs are powerful, direct mitigators of HSC injury and DNA damage. Identification of the HAEC derived factors that rescue HSCs may lead to improved therapies for hematopoietic regeneration after radiation injury. PMID- 23939268 TI - Influence of previous experience on the preference, food utilization and performance of Ascia monuste orseis wild larvae (Godart) (Lepidoptera: Pieridae) for three different hosts. AB - The exhaustion of food resources which occurs during the ontogenetic growth of Ascia monuste orseis (Godart) results in the dispersion of older larvae to nearby plants in order to complete their development, which might expose these animals to the nutritional variation of the hosts found. This study aimed to verify whether the food ingested in the beginning of the development influences the larvae host preference and whether the shift to a new host can affect the digestion and performance of A. monuste orseis, using two natural hosts: kale (Brassica oleracea var. acephala) and rocket (Eruca sativa), or kale and cabbage (B. oleracea var. capitata). Larvae were reared throughout their larval development on a single host or on two different hosts. When a host change was tested, larvae were reared for four instars on a host, and offered the other host plant in the fifth instar. Development time, percentage of pupation and emergence, pupal weight, fecundity and digestive indices were evaluated. The change in feeding preference for kale and for rocket in the fourth instar, when those were the original hosts, respectively, shows that prior experience plays a major role in food preference of immature A. monuste orseis. The shift can be beneficial for larval development, depending on the order of the hosts; in general, larvae fed on kale at the end of the development showed better performance. Our results presented strong evidence of a considerable phenotypic plasticity in A. monuste orseis for host preferences. PMID- 23939269 TI - Fauna and stratification of male orchid bees (Hymenoptera: Apidae) and their preference for odor baits in a forest fragment. AB - This is a study of the population fluctuation of euglossine species, as well as their preferences for scent baits (cineole, eugenol, vanillin and methyl salicylate) in two forest strata (canopy and understory) at the Reserva Florestal do Azulao, a forest fragment located in the municipality of Dourados, MS, Brazil (22 degrees 12'S, 54 degrees 55'W). We collected a total of 529 males from four genera and eight species. Diversity and equitability for both strata (understory: H' = 1.195 and J' = 0.6139; canopy: H' = 1.193 and J' = 0.6131) did not show a significant difference and a high similarity index was found (P = 87.5%). On the other hand, abundance was substantially higher in the canopy (n = 358) than in the understory (n = 171). From the scents used, eugenol attracted a larger number of individuals (n = 225), but cineole and vanillin attracted a higher number of species. PMID- 23939267 TI - Glycogen shortage during fasting triggers liver-brain-adipose neurocircuitry to facilitate fat utilization. AB - During fasting, animals maintain their energy balance by shifting their energy source from carbohydrates to triglycerides. However, the trigger for this switch has not yet been entirely elucidated. Here we show that a selective hepatic vagotomy slows the speed of fat consumption by attenuating sympathetic nerve mediated lipolysis in adipose tissue. Hepatic glycogen pre-loading by the adenoviral overexpression of glycogen synthase or the transcription factor TFE3 abolished this liver-brain-adipose axis activation. Moreover, the blockade of glycogenolysis [corrected] through the knockdown of the glycogen phosphorylase gene and the resulting elevation in the glycogen content abolished the lipolytic signal from the liver, indicating that glycogen is the key to triggering this neurocircuitry. These results demonstrate that liver glycogen shortage activates a liver-brain-adipose neural axis that has an important role in switching the fuel source from glycogen to triglycerides under prolonged fasting conditions. PMID- 23939270 TI - Geographical transition zone of Solenopsis fire ants (Hymenoptera: Formicidae) and Pseudacteon fly parasitoids (Diptera: Phoridae) in the state of Sao Paulo, Brazil. AB - Solenopsis saevissima (Smith) and Solenopsis invicta Buren are the most abundant and widely distributed fire ants in Brazil. The occurrence of the two fire ant species and of their parasitoids Pseudacteon spp. is described for a climatic and phytophysiognomic transition area in the state of Sao Paulo. Both fire ant species have a parapatric distribution, apparently determined by the climate: S. saevissima predominates in the north part of Sao Paulo (Aw climate), while S. invicta in the south (Cfa climate). A sympatric area is observed between the latitudes 21oS and 23oS. Two different communities of parasitic decapitating flies were associated with S. saevissima in the north and with S. invicta in the south, with a sympatric area in the municipality of Sao Carlos (21o58'S 47o53'W). The possible causes of this biogeographic pattern are discussed. Preference tests with Pseudacteon flies challenge the association of P. litoralis Borgmeier, P. curvatus Borgmeier, P. wasmanni Schmitz, P. pradei Borgmeier and P. obtusus Borgmeier with S. saevissima, and P. dentiger Borgmeier, P. disneyi Pesquero and P. lenkoi Borgmeier & Prado with S. invicta. PMID- 23939271 TI - An adaptive view of caste differentiation in the neotropical wasp Polybia (Trichothorax) sericea Olivier (Hymenoptera: Vespidae). AB - The tribe Epiponini comprehends the swarm-founding Neotropical wasps, with several species endemic to Brazil, which are extremely important in studies of social evolution of wasps. The Epiponini diverge in several ways from the definitions of high eusociality, since caste syndromes range from species without morphological caste differentiation to those with complete caste dimorphism, and all species are polygynous. Frequently, indirect studies based on morphometry and physiology are the only solutions to collect data regarding the natural history and caste system in this tribe, since most species are extremely aggressive and build enveloped nests, usually in places of difficult access. We analyzed morphological parameters in seven colonies of the Epiponini species Polybia (Trichothorax) sericea Olivier in different phases of colonial development. Nine body variables were taken and females were classified according to their ovary development and spermathecal contents. The results showed that caste differences in this species are based on a contrast among variables: queens have larger mesosoma and abdomen, but are smaller in head width and wing length. These results suggest that morphological caste differentiation in this species is based mainly on body shape. We considered this combination of characters as being adaptive. We also showed that caste differences varied according to the colony cycle, with more conspicuous differences when queen number is reduced. PMID- 23939272 TI - Body size, symmetry and abundance of Euxesta stigmatias (Loew) and Euxesta sororcula (Wiedemann) (Diptera: Ulidiidae) in a natural reserve and in a guava orchard in Uberlandia, MG, Brazil. AB - The aim of this study was to comparatively characterize the monthly variation and the sex ratio of Euxesta stigmatias (Loew) and Euxesta sororcula (Wiedermann) populations from a natural reserve and from a guava orchard. It was also investigated whether density and the climate factors affected the individuals' size and fluctuating asymmetry (FA). In both environments, E. sororcula predominated over E. stigmatias. The number of individuals of E. sororcula collected in the ecological station was significantly lower than the number of individuals caught in the orchard. However, the number of captured individuals of E. stigmatias did not differ between environments. Significant sex ratio differences were detected between the collection sites. Female's frequency of E. stigmatias was significantly higher than male's frequency in the ecological station, but not in the orchard. An opposite pattern was encountered for E. sororcula population, showing a significant larger number of females only in the orchard. The species populations also differed in the degree of asymmetry presented. Euxesta stigmatias individuals showed no change on size or on FA along the captures and between environments. Moreover, E. sororcula tended to be more susceptible to climatic variations, considering the significant observed correlation between temperature and body size and the expressive body size and FA variations. This study illustrates the influence of the environment in some structural and dynamic parameters of the studied populations. PMID- 23939273 TI - The endangered butterfly Charonias theano (Boisduval) (Lepidoptera: Pieridae): current status, threats and its rediscovery in the state of Sao Paulo, southeastern Brazil. AB - The pierid Charonias theano (Boisduval), an endangered butterfly species, has been rarely observed in nature, and has not been recorded in the state of Sao Paulo in the last 50 years despite numerous efforts to locate extant colonies. Based on museum specimens and personal information, C. theano was known from 26 sites in southeastern and southern Brazil. Recently, an apparently viable population was recorded in a new locality, at Serra do Japi, Jundiai, Sao Paulo, with several individuals observed during two weeks in April, 2011. The existence of this population at Serra do Japi is an important finding, since this site represents one of the few large forested protected areas where the species could potentially persist not only in the state of Sao Paulo, but within its entire historical distribution. PMID- 23939274 TI - Morphometry of the midgut of Melipona quadrifasciata anthidioides (Lepeletier) (Hymenoptera: Apidae) during metamorphosis. AB - In Hymenoptera, midgut changes begin in the last instar. At this stage, the larval epithelial digestive cells degenerate, leaving only the basal membrane and the regenerative cells which will develop into a new epithelium during the pupal stage and in the adult. Epithelium renewal is followed by changes in volume and shape of the midgut. Morphometric analysis of digestive cells and total midgut volume of Melipona quadrifasciata anthidioides (Lepeletier) were conducted to verify whether cell volume increase are sufficient to account for the total midgut volume increase that occurs during metamorphosis. An increase in midgut volume was verified in spite of the scarcity of cell proliferation found during metamorphosis. At the end of metamorphosis, the increase in cell volume was not sufficient to explain the increase in volume of the midgut, indicating that an increase in the number of digestive cells is apparently necessary. Nevertheless, the mechanism by which regenerative cells reconstitute the epithelium during metamorphosis remains unknown. PMID- 23939275 TI - Leptohyphidae (Insecta: Ephemeroptera) from northeastern Brazil. AB - New records of Leptohyphidae for Northeastern Brazil are provided. Previously, only Tricorythopsis bahiensis Dias, Salles & Ferreira had been recorded in this region, but we now record one species of Amanahyphes Salles & Molineri, one of Leptohyphes Eaton, three of Traverhyphes Molineri, three of Tricorythodes Ulmer, and seven of Tricorythopsis Traver. Two of these species are recorded for the first time in Brazil. As all of these species are reported, the Northeastern Brazil became the second most diverse geographic region in Brazil in Leptohyphidae. PMID- 23939276 TI - First record of Alloxysta Forster (Hymenoptera: Figitidae) from Costa Rica, with description of four new species. AB - Four new species of Alloxysta Forster are described (A. andrewsi Ferrer-Suay & Pujade-Villar n. sp., A. costaricensis Ferrer-Suay & Pujade-Villar n. sp., A. hansoni Pujade-Villar n. sp. and A. luismii Ferrer-Suay n. sp.) from Costa Rica being the first records of this genus in this area. Their morphological features and diagnostic characters are illustrated. We provide a diagnosis of Apocharips hansoni Menke with a detailed description of the radial cell, which expands the characteristics of the genus Apocharips. PMID- 23939277 TI - Description of the female of Navicordulia aemulatrix Pinto & Lamas and additional notes on the male (Odonata: Corduliidae). AB - The female of Navicordulia aemulatrix Pinto & Lamas is described and illustrated for the first time based on a single specimen from the same locality of the type series (state of Santa Catarina, [municipality of Sao Bento do Sul, 26 degrees 14'58"S, 49 degrees 22'59"W, railroad station] Rio Vermelho, 29.I.1952, in MZSP). In addition, further morphological notes for the male are provided based on three specimens collected at the type locality and at a new locality in the state of Santa Catarina (Timbo municipality). The pronotal process present in N. aemulatrix is re-evaluated and considered non-homologous to that found in Neocordulia setifera (Hagen in Selys) as previously suggested. PMID- 23939278 TI - An invasive pentatomid pest in Argentina: neotropical brown stink bug, Euschistus heros (F.) (Hemiptera: Pentatomidae). AB - This is the first record on the invasion of the Neotropical brown stink bug, Euschistus heros (F.) in Parana County (latitude 31o 51' 9.6" S, longitude 60o 32' 11.2" W), Entre Rios province, Argentina. Five adults were intercepted in 2009/2010, one in crop residues and four on soybean fields. The expanding range in the distribution of E. heros in the Southern Hemisphere is believed to be due to the increased commercial trade among countries, increase in the area cultivated with soybean, and the adoption of no-tillage cropping systems. PMID- 23939279 TI - First record of Anastrepha serpentina (Wiedemann) (Diptera: Tephritidae) in citrus in Brazil. AB - Anastrepha serpentina (Wiedemann) is recorded for the first time in citrus (Rutaceae) in Brazil. Specimens were obtained from sweet orange (Citrus sinensis) sampled in the municipalities of Belem and Capitao Poco, and from mandarin orange (Citrus reticulata) from Tome-Acu, state of Para, Brazil. PMID- 23939280 TI - Behavioral evidence of an ectoparasitic interaction between Triatoma pseudomaculata Correa e Espinola (Heteroptera: Reduviidae) and Periplaneta americana (L.) (Blattodea: Blattidae). AB - The present work tested whether Triatoma pseudomaculata Correa & Espinola shows behavioral traits indicating that it is capable of feeding on arthropods. We consistently observed nymphs extending their proboscis in the direction of cockroaches and attempting to bite. Insects presented a preference for biting specific cockroach body parts. Our results suggest that arthropod hemolymph represents an alternative source of food that increases the survival of T. pseudomaculata individuals undergoing long starvation. PMID- 23939281 TI - First record of the fruit fly parasitoid Doryctobracon crawfordi (Viereck) (Hymenoptera: Braconidae) in Brazil. AB - Doryctobracon crawfordi (Viereck) was recorded in the states of Amapa and Roraima, Brazil. This is also the first time that this parasitoid is associated with Anastrepha atrigona Hendel from Geissospermum argenteum. PMID- 23939282 TI - Au/ZnS core/shell nanocrystals as an efficient anode photocatalyst in direct methanol fuel cells. AB - Au/ZnS core/shell nanocrystals with controllable shell thicknesses were synthesized using a cysteine-assisted hydrothermal method. Incorporating Au/ZnS nanocrystals into the traditional Pt-catalyzed half-cell reaction led to a 43.3% increase in methanol oxidation current under light illumination, demonstrating their promising potential for metal/semiconductor hybrid nanocrystals as the anode photocatalyst in direct methanol fuel cells. PMID- 23939283 TI - Dose-dense FEC followed by dose-dense ixabepilone as neoadjuvant treatment for breast cancer patients: a feasibility study. AB - BACKGROUND: Ixabepilone is an effective chemotherapy in metastatic breast cancer that has been pretreated with anthracyclines and is resistant or refractory to taxanes. Adjuvant dose-dense (DD) chemotherapy is more effective than regimens administered every 3 weeks, especially in hormonal receptor (HR)-negative tumors. METHODS: A feasibility study of neoadjuvant DD ixabepilone was conducted in breast cancer patients with tumors measuring at least 2 cm. Patients received 5 fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 600 mg/m(2) ("FEC" in combination) administered intravenously on day 1 every 14 days with granulocyte-colony stimulating factor (filgrastim) followed by ixabepilone 40 mg/m(2) administered intravenously on day 1 every 14 days with granulocyte-colony stimulating factor. The study's primary endpoint was feasibility, and the secondary endpoint was pathologic complete response. A two-stage Simon's design was adopted. RESULTS: Forty-seven patients were enrolled, and 42 were evaluable. For 10 of 42 patients, DD ixabepilone was not feasible. Six (14%) required ixabepilone interruption, and four (9.5%) required ixabepilone dose reduction of 25%. One toxic death occurred. Hematologic grade 3-4 toxicities included anemia (9.5%), grade 4 neutropenia (2.4%), febrile neutropenia (4.8%), and thrombocytopenia (2.4%). Nonhematologic grade 3-4 toxicities consisted of fatigue (14.3%), mucositis (14.3%), sensory neuropathy (7.1%), onychopathy (7.1%), and liver toxicity (4.8%). Grade 2 sensory neuropathy lasting longer than 7 days was recorded in 11.9% of patients. Pathologic complete response was observed in 16 of 42 patients (38.1%), including 11 of 23 (47.8%) with HR-negative tumors and 5 of 19 (26.3%) with HR-positive tumors. CONCLUSION: Despite high activity, DD ixabepilone after DD FEC is poorly tolerated. PMID- 23939285 TI - Ternary self-assemblies in water: forming a pentanuclear ReLn4 assembly by association of binuclear lanthanide binding pockets with fac Re(CO)3(dinicotinate)2Cl. AB - The self-assembly of higher order structures in water is realised by using the association of 1,3-biscarboxylates to binuclear meta-xylyl bridged DO3A complexes. Two dinicotinate binding sites are placed at a right-angle in a rhenium complex, which is shown to form a 1 : 2 complex with alpha,alpha' bis(Eu.DO3A)-5-amino-m-xylene. PMID- 23939286 TI - Inhibitory deficit in semantic conflict in obsessive-compulsive disorder: an event-related potential study. AB - The present study examines the inhibitory function of patients with obsessive compulsive disorder (OCD) involved in semantic conflict using event-related potentials (ERPs). EPRs were recorded in a group of 18 medicine-free OCD patients and 18 normal controls using a modified Stroop paradigm in which the participants were asked to make a judgment of congruent or incongruent stimuli. The reaction time to color-word incongruent stimuli in the OCD group was significantly longer than the reaction time to congruent stimuli. In the OCD group, a significant negativity shift was discovered in P350 amplitude and N450 amplitude in response to incongruent stimuli, a shift not present in the control group. The amplitude of difference waveform was significantly higher for OCD than for control subjects. The findings probably revealed an inhibitory deficit in patients with OCD when performing semantic conflict tasks. The results suggest that this type of inhibitory deficit may be the cause of increased Stroop effects in patients with OCD, and one of contributors to the pathophysiology of OCD. PMID- 23939284 TI - Disparities in breast cancer treatment and outcomes: biological, social, and health system determinants and opportunities for research. AB - Racial disparities in breast cancer mortality have been widely documented for several decades and persist despite advances in receipt of mammography across racial groups. This persistence leads to questions about the roles of biological, social, and health system determinants of poor outcomes. Cancer outcomes are a function not only of innate biological factors but also of modifiable characteristics of individual behavior and decision making as well as characteristics of patient-health system interaction and the health system itself. Attempts to explain persistent racial disparities have mostly been limited to discussion of differences in insurance coverage, socioeconomic status, tumor stage at diagnosis, comorbidity, and molecular subtype of the tumor. This article summarizes existing literature exploring reasons for racial disparities in breast cancer mortality, with an emphasis on treatment disparities and opportunities for future research. Because breast cancer care requires a high degree of multidisciplinary team collaboration, ensuring that guideline recommended treatment (such as endocrine therapy for hormone receptor positive patients) is received by all racial/ethnic groups is critical and requires coordination across multiple providers and health care settings. Recognition that variation in cancer care quality may be correlated with race (and socioeconomic and health system factors) may assist policy makers in identifying strategies to more equally distribute clinical expertise and health infrastructure across multiple user populations. PMID- 23939287 TI - Intrathecal adrenomedullin modulates acute inflammatory pain in the rat formalin test. AB - Adrenomedullin (AM), a member of the calcitonin gene-related peptide (CGRP) family, has been demonstrated to be a pronociceptive mediator. This study was undertaken to investigate the role of AM in acute inflammatory pain induced by formalin injection in rats. Interestingly Cerebrospinal fluid (CSF) levels of AM increased 45 min after formalin injection and a selective AM receptor antagonist, AM22-52, administered intrathecally (i.t.) decreased phase 2 flinching in a dose dependent manner but not phase 1 flinching during the formalin test. This anti hyperalgesic effect of i.t. AM22-52 lasted for 4 h or more. AM in the CSF contributes to the modulation of acute inflammatory pain in the formalin test, and blocking downstream signaling effects of the AM receptor has the potential to relieve pain associated with acute inflammation. PMID- 23939288 TI - NBPF is a potential DNA-binding transcription factor that is directly regulated by NF-kappaB. AB - The neuroblastoma breakpoint family (NBPF) has been reported to play potential roles in the development of neuroblastoma and human evolution. However, the exact regulation and function of this family is still unknown. In this study, the genes of NBPF family were found to be densely covered by many high-confidence ChIP-Seq peaks of NF-kappaB. The expressions of NBPF genes were thus deduced to be regulated by this transcription factor. The activities of NF-kappaB in HeLa, HepG2 and ECa109 cells were then manipulated with NF-kappaB activator (TNFalpha) and inhibitors (BAY11-7082 or p65 siRNA), and the expressions of NBPF genes in these cells were checked. As result, it was found that the expressions of NBPF genes were regulated by NF-kappaB in HeLa and HepG2 cells. Therefore, the genes of NBPF family were identified as new bona fide direct target genes of NF-kappaB. In addition, NBPF was also identified as a nuclear protein by in silico prediction and immunolocalization. Finally, the bioinformatics analysis revealed that most of NBPF proteins contained classical nuclear localization signals (NLSs) and a conserved DNA-binding domain similar to the transcription factor stat3b/dna complex or stat-1/dna complex in their N-terminals. Therefore, this study concluded that NBPF was nuclear protein that contained classical NLSs and conserved known DNA-binding domain, and its expression was regulated by another important transcription factor, NF-kappaB. These findings suggest that NBPF may function as DNA-binding transcription factor in nucleus, which provides important new insight into the functions of NBPF genes in the human cells. PMID- 23939289 TI - Interference with the mitochondrial bioenergetics fuels reprogramming to pluripotency via facilitation of the glycolytic transition. AB - The switch in cell metabolism from oxidative phosphorylation to glycolysis is critical for the reprogramming of cells to pluripotency. Here, we demonstrate that the disturbance of mitochondrial metabolism by canonical mitochondrial inhibitors enhances metabolic reprogramming toward a glycolytic state, enabling the highly efficient generation of induced pluripotent stem cells. This interference with mitochondrial bioenergetics resulted in enriched reprogrammable subpopulations and accelerated the conversion of refractory intermediates to pluripotent states without requiring additional genetic or epigenetic modifications. Conversely, the reprogramming efficiency and accelerated reprogramming kinetics promoted by mitochondrial inhibition were obstructed by glycolysis inhibitors. We suggest that changes in mitochondrial bioenergetics are a novel mechanism involved in the regulation of cell fate and, more importantly, in the reprogramming of cells to pluripotency. PMID- 23939290 TI - Synthesis of pyridine-capped diketopyrrolopyrrole and its use as a building block of low band-gap polymers for efficient polymer solar cells. AB - A new building block for low band-gap polymers, diketopyrrolopyrrole (DPP) flanked by pyridine (PyDPP), has been synthesized via a simple synthetic route. PyDPP was polymerized with bithiophene (BT) to afford a low band-gap copolymer (PBTPyDPP) which was used as an electron donor of the active layer in polymer solar cells. The solar cell device based on PBTPyDPP exhibited a promising PCE of 4.9% with a high VOC over 0.9 V, which is one of the highest values among DPP based polymer solar cells. PMID- 23939291 TI - Corneal sensitivity with contact lenses of different mechanical properties. AB - PURPOSE: To examine the changes in corneal sensitivity after overnight wear of contact lenses with different mechanical properties. METHODS: Twenty young-adult subjects wore a silicone hydrogel, rigid gas-permeable, or orthokeratology (OK) contact lens in randomized order for a single night of wear in the right eye only. All lenses were matched in Dk/t (~46 ISO Fatt). Changes in corneal apical radius r(o), asphericity Q, and corneal refractive power (Medmont E300) were measured. Changes in central corneal sensitivity were also measured by a masked investigator using two instruments: Cochet-Bonnet (COBO) aesthesiometer and Non Contact Corneal Aesthesiometer (NCCA). RESULTS: There were significant differences in corneal topographic change from baseline between the lens types for r(o), Q, and corneal refractive power. There were also significant differences in the change from baseline (mean +/- SD) in corneal sensitivity between lens types using the COBO (silicone hydrogel, 0.02 +/- 0.17 g/mm(2); rigid gas-permeable, 0.03 +/- 0.20 g/mm; OK, 0.22 +/- 0.33 g/mm(2)). A significant increase in threshold from baseline was only seen in the OK lenses (p = 0.006). There was no change in sensitivity thresholds from baseline for any lens type using the NCCA (p > 0.05). CONCLUSIONS: Central corneal sensitivity is reduced after a single overnight wear of OK lenses, as measured using the COBO aesthesiometer. This suggests that the mechanical force exerted by contact lenses may influence corneal sensitivity. PMID- 23939292 TI - Adverse events during 2 years of daily wear of silicone hydrogels in children. AB - PURPOSE: Type and incidence of adverse events and rate of discontinuations for 2 years of daily wear with silicone hydrogel contact lenses in Chinese children with myopia. METHODS: Two hundred forty children aged 7 to 14 years were enrolled in a prospective randomized clinical trial from November 2008 to April 2009. Children with myopia of up to -3.50 diopters (D) spherical equivalent with astigmatism less than or equal to -0.75 D were randomized to one commercial and three experimental lens designs of Lotrafilcon B silicone hydrogel lenses (four groups) used bilaterally on a daily wear, monthly replacement schedule. The main outcome measures were incidence per 100 patient-years (incidence, in percentage) of adverse events and rate of discontinuations. RESULTS: There were no events of microbial keratitis. Fifty-five adverse events (incidence, 14.2%) were seen. There were also 12 recurrent events. The type and incidence percentage were contact lens papillary conjunctivitis (16 events, 4.1%), superior epithelial arcuate lesions (SEALs, six events, 1.5%), corneal erosions (eight events, 2.1%), infiltrative keratitis (five events, 1.3%), asymptomatic infiltrative keratitis (seven events, 1.8%), and asymptomatic infiltrates (13 events, 3.42%). There were differences in the incidence of SEALs between groups (p = 0.023), with the incidence of SEALs being greater with one of the experimental designs. No event resulted in any vision loss. Seventy participants (29.2%) discontinued, with one third (26 participants, 10.8%) occurring in the first month of lens wear. Discomfort and non-lens-related reasons such as safety concern and disinterest were frequently cited reasons for discontinuations. CONCLUSIONS: Adverse events with daily wear of silicone hydrogels in children were mainly mechanical in nature, and significant infiltrative events were few. The large number of dropouts in the early days of lens wear and their reasons for discontinuation suggest that adaptation and patient motivation are critical for survival in lens wear. PMID- 23939293 TI - Noninvasive tear breakup times and ocular surface disease. AB - PURPOSE: To investigate the correlation between the Ocular Surface Disease Index (OSDI) Questionnaire and noninvasive tear breakup times (NITBUTs) obtained by the Keratograph 4 (Oculus, Wetzlar, Germany) device. METHODS: A prospective sequential study of subjects (N = 99) unmatched for sex and without a significant difference in age by sex was performed. Testing included administration of OSDI, followed by Keratograph 4 measurements of the first NITBUT (NITBUT(f)) and average NITBUT (NITBUT(av)). RESULTS: The NITBUT(f) was significantly shorter than NITBUT(av), as tested by Mann-Whitney statistic (U = 7331.5, <0.0001). The NITBUT(f) and NITBUT(av) demonstrated identical statistically significant Spearman correlations with OSDI (r(s) = -0.20, p = 0.05). CONCLUSIONS: Ocular Surface Disease Index and NITBUT testing by Keratograph 4 device demonstrate a weak, but statistically significant, negative correlation. PMID- 23939294 TI - Orbscan topography in primary open-angle glaucoma. AB - PURPOSE: To compare anterior and posterior corneal curvatures between eyes with primary open-angle glaucoma (POAG) and healthy eyes. METHODS: This is a prospective, cross-sectional, observer-masked study. A total of 138 white subjects (one eye per patient) were consecutively recruited; 69 eyes had POAG (study group), and the other 69 comprised a group of healthy control eyes matched for age and central corneal pachymetry with the study ones. Exclusion criteria included any corneal or ocular inflammatory disease, previous ocular surgery, or treatment with carbonic anhydrase inhibitors. The same masked observer performed Goldmann applanation tonometry, ultrasound pachymetry, and Orbscan II topography in all cases. Central corneal thickness, intraocular pressure, and anterior and posterior topographic elevation maps were analyzed and compared between both groups. RESULTS: Patients with POAG had greater forward shifting of the posterior corneal surface than that in healthy control eyes (p < 0.01). Significant differences in anterior corneal elevation between controls and POAG eyes were also found (p < 0.01). CONCLUSIONS: Primary open-angle glaucoma eyes have a higher elevation of the posterior corneal surface than that in central corneal thickness-matched nonglaucomatous eyes. PMID- 23939295 TI - Clinical findings and management of multiple evanescent white dot syndrome. AB - PURPOSE: This case report presents the diagnosis and management of a patient who was ultimately diagnosed as having multiple evanescent white dot syndrome (MEWDS), a rare retinal inflammatory disorder classified under the white dot syndromes. CASE REPORT: A 34-year-old Hispanic woman presented with chief complaints of flickering lights and spots in her right eye that started 2 weeks earlier. Retinal examination revealed multiple white dots scattered across the retina, with an accompanying foveal granularity. Spectral domain optical coherence tomography and fundus autofluorescence were performed, which confirmed the diagnosis of MEWDS. The patient was monitored without treatment until resolution. CONCLUSIONS: The etiology and pathogenesis of MEWDS remain unknown; fortunately, the natural course of the disease is favorable because almost all patients retain a good outcome without the need for treatment. This case highlights the importance of considering MEWDS and other white dot syndromes in the differential diagnosis of patients who present with a history of photopsia. Because many clinical findings are absent or very subtle when patients present, the clinician should consider supplemental testing such as spectral domain optical coherence tomography and fundus autofluorescence in aiding in the diagnosis. PMID- 23939296 TI - Corneal sensation after corneal refractive surgery with small incision lenticule extraction. AB - PURPOSE: To compare effects of small-incision lenticule extraction (SMILE) and femtosecond laser-assisted in situ keratomileusis (F-LASIK) on corneal sensation and dry eye parameters. METHODS: In this prospective, randomized, contralateral eye study, 28 patients with myopia or myopic astigmatism in both eyes were enrolled. One eye of each patient was treated by SMILE, and the fellow eye was treated by F-LASIK. Mean outcome measures Cochet-Bonnet esthesiometry, Schirmer test with anesthesia, tear breakup time, and tear film osmolarity were evaluated preoperatively as well as 1 week, 1 month, 3 months, and 6 months after surgery. RESULTS: Corneal sensation was reduced after both SMILE and F-LASIK surgeries 1 week, 1 month, and 3 months after surgery (p < 0.05 in both groups). Corneal sensation was significantly lower after F-LASIK than after SMILE at postoperative 1 week, 1 month, and 3 months (p < 0.01 for all points). Dry eye parameters such as tear breakup time, Schirmer test, and tear film osmolarity did not change significantly in any of the procedures and were not significantly different between the procedures at any follow-up visits. CONCLUSIONS: The findings of the study revealed that, although both F-LASIK and SMILE procedures changed the corneal sensation 1 week, 1 month, and 3 months after surgery, they did not affect the dry eye parameters at any point. PMID- 23939300 TI - Dry mouth: an overlooked autonomic symptom of Parkinson's disease. AB - There is involvement of salivary glands by alpha-synuclein pathology in PD. However, the prevalence of dry mouth has not been systematically assessed in these patients. We studied 97 PD patients and 86 controls using a structured questionnaire. Dry mouth was reported by 60.8% of PD patients and 27.9% of controls (p < 0.0001). Dry mouth and drooling coexisted in 30% of cases. Only 12% of patients had reported dry mouth to their physicians. Dry mouth is a frequent but underreported symptom and may be an early manifestation of autonomic involvement in PD. PMID- 23939299 TI - Association of depression with adverse cardiovascular events after percutaneous coronary intervention. AB - OBJECTIVE: The aim of this study was to investigate the impact of depression on the clinical outcomes of patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). METHODS: A total of 400 patients treated with PCI were assessed using the Mini-International Neuropsychiatric Interview 1 day before and 2 weeks after the procedure. All patients were followed up for 3 years after the procedure. The primary endpoint was a major adverse cardiovascular event (MACE) including mortality, nonfatal myocardial infarction, or repeat revascularization. RESULTS: Depression was present in 38.5% (n=154) of patients after the procedure, which was significantly higher than that before the procedure (25.5%, P<0.001). Patients with postprocedure depression had a higher rate of MACE (27.3 vs. 13.0%, P<0.001), mortality (5.8 vs. 2.0%, P=0.044), and repeat revascularization (13.0 vs. 6.5%, P=0.027) compared with patients without depression during the 3 years of follow-up. After adjustment for other factors that affect cardiovascular outcomes, postprocedure depression was seen to be an independent predictor of 3-year MACE [hazard ratio: 2.51, 95% confidence interval (CI): 1.57-4.02, P<0.001], mortality (3.60, 95% CI: 1.16 11.22, P=0.027), and repeat revascularization (hazard ratio: 2.22, 95% CI: 1.09 4.51, P=0.029). CONCLUSION: Depression is common among patients treated with PCI. Postprocedure depression is an independent predictor of 3-year MACE, mortality, and repeat revascularization. PMID- 23939298 TI - A dynamic spatiotemporal extracellular matrix facilitates epicardial-mediated vertebrate heart regeneration. AB - Unlike humans, certain adult vertebrates such as newts and zebrafish possess extraordinary abilities to functionally regenerate lost appendages and injured organs, including cardiac muscle. Here, we present new evidence that a remodeled extracellular matrix (ECM) directs cell activities essential for cardiac muscle regeneration. Comprehensive mining of DNA microarrays and Gene Ontology term enrichment analyses for regenerating newt and zebrafish hearts revealed that distinct ECM components and ECM-modifying proteases are among the most significantly enriched genes in response to local injury. In contrast, data analyses for mammalian cardiac injury models indicated that inflammation and metabolic processes are the most significantly activated gene groups. In the regenerating newt heart, we show dynamic spatial and temporal changes in tenascin C, hyaluronic acid, and fibronectin ECM distribution as early as 3 days postamputation. Linked to distinct matrix remodeling, we demonstrate a myocardium wide proliferative response and radial migration of progenitor cells. In particular, we report dramatic upregulation of a regeneration-specific matrix in the epicardium that precedes the accumulation and migration of progenitor cells. For the first time, we show that the regenerative ECM component tenascin-C significantly increases newt cardiomyocyte cell cycle reentry in vitro. Thus, the engineering of nature-tested extracellular matrices may provide new strategic opportunities for the enhancement of regenerative responses in mammals. PMID- 23939302 TI - Porous copper surfaces with improved superhydrophobicity under oil and their application in oil separation and capture from water. AB - The repeatable wettability of the facile-to-fabricate porous copper surface shows superhydrophobicity in air and improved superhydrophobicity under oil. The resultant 3D copper foam can separate and capture oils from water with high separation efficiency, fast capture kinetics, fine mechanical resistance to water impact, and good recyclability. PMID- 23939301 TI - Ultrahigh gas storage both at low and high pressures in KOH-activated carbonized porous aromatic frameworks. AB - The carbonized PAF-1 derivatives formed by high-temperature KOH activation showed a unique bimodal microporous structure located at 0.6 nm and 1.2 nm and high surface area. These robust micropores were confirmed by nitrogen sorption experiment and high-resolution transmission electron microscopy (TEM). Carbon dioxide, methane and hydrogen sorption experiments indicated that these novel porous carbon materials have significant gas sorption abilities in both low pressure and high-pressure environments. Moreover the methane storage ability of K-PAF-1-750 is among the best at 35 bars, and its low-pressure gas adsorption abilities are also comparable to the best porous materials in the world. Combined with excellent physicochemical stability, these materials are very promising for industrial applications such as carbon dioxide capture and high-density clean energy storage. PMID- 23939303 TI - Mouse models of cognitive deficits due to alpha-synuclein pathology. AB - Synucleopathies are neurodegenerative disorders characterized by abnormal accumulation of alpha-synuclein, most often in neurons. Familial forms are due to mutations or multiplications of the gene encoding for alpha-synuclein but most synucleopathies occur sporadically. They include Parkinson's disease (PD) and dementia with Lewy Bodies (DLB), which are both linked to cognitive decline. In DLB, dementia dominates the symptoms whereas in PD, subtle cognitive deficits are frequent and may appear even before motor symptoms, but only a fraction of patients develop severe dementia-type cognitive deficits. Several lines of mice were developed to model human synucleopathies by over-expressing the wild type or the mutated human alpha-synuclein under a variety of promoters. In addition, mice lacking alpha-synuclein have been used to determine the role of this protein in cognitive function. This chapter will review cognitive alterations observed in these models and discuss how they may help understand the various forms and stages of cognitive deficits observed in patients with synucleopathies. PMID- 23939304 TI - Loss-of-function rodent models for parkin and PINK1. AB - Parkinson's disease is a common neurodegenerative disorder whose aetiology is not yet fully understood. In the past ten years, the discovery of genes linked to hereditary forms of the disease has impelled the development of animal models. These should lead to the identification of novel pathways that provide insight into the functionality of the proteins involved and the pathogenesis of the sporadic forms of the disease. In particular, loss-of-function mutations in the parkin and PINK1 (phosphatase and tensin homolog (PTEN)-induced kinase 1) genes account for most of the cases of familial autosomal recessive parkinsonism. Both parkin and PINK1 knockout rodent models are now available, which display an overall mild phenotype consisting of a mitochondrial dysfunction together with changes in dopamine metabolism and oxidative stress. However, up till now these models fail to reproduce the main hallmarks of Parkinson's disease: the dopaminergic cell loss in the substantia nigra and the presence of cytoplasmic inclusions, named Lewy bodies, in the remaining dopaminergic neurons. We here review the most important knockout and knockdown rodent models generated so far for these two recessive Parkinson's disease-causing genes. We critically feature their main characteristics and their impact on the research field, and propose some future directions for the study and modelling of the loss of function of parkin and PINK1 in rodents. PMID- 23939305 TI - Examination of the UPDRS bradykinesia subscale: equivalence, reliability and validity. AB - Administering items or subscales separately from the measure for which they were designed to be a part may have unintended consequences for research and practice in Parkinson's disease (PD). The current study tested the equivalence of the bradykinesia subscale when administered alone versus as a component of the full 14-item Unified Parkinson's Disease Rating Scale (UPDRS) motor examination, as well as examined the reliability and validity of the bradykinesia subscale. The study sample consisted of 112 patients with PD. Patients were randomly assigned to either the bradykinesia subscale alone group (n = 56), who were administered the bradykinesia subscale separately from the rest of the UPDRS motor examination, or the full scale group (n = 56), who were administered the UPDRS motor examination in its standard format. The two one-sided t-test (TOST) procedure was used to test for mean equivalency between the two administration groups. Additionally, reliability and validity analyses were performed. The bradykinesia subscale mean scores from the full scale group and the subscale alone group were not statistically equivalent. However, in both groups, the bradykinesia subscale had exceptional reliability and was strongly and similarly related to age, activities of daily living, disability, and other assessments of motor symptom severity. The bradykinesia subscale is a valid and reliable assessment when administered separately from the rest of the UPDRS motor examination; however, caution should be taken when comparing mean scores across studies or occasions when different administrations are used. PMID- 23939306 TI - The effects of medication on turning in people with Parkinson disease with and without freezing of gait. AB - Turning difficulty is prevalent in Parkinson disease (PD) and may lead to falls or freezing. Medication improves motor symptoms of PD, but its effects on turning in people with PD with (PD+FOG) and without (PD-FOG) freezing of gait are unclear. This study evaluated the effects of medication on turning in PD compared to healthy older adults (controls), and in PD+FOG compared to PD-FOG. We assessed timed-up-and-go (TUG), and in-place turns in 16 controls and 20 people with PD (10 PD+FOG, 10 PD-FOG) OFF and ON medication. PD+FOG performed worse than PD-FOG (p < 0.05) in TUG, turn duration, step count, and had earlier head rotation onset (HTO). These measures improved ON medication in PD+FOG and PD-FOG (p < 0.05). Turn duration and step count improved more with medication in PD+FOG than PD-FOG (p < 0.005). There were subtle differences in gastrocnemius and sternocleidomastoid onsets, with PD OFF or ON activating muscles earlier than controls. Tibialis anterior, gastrocnemius, and sternocleidomastoid initial onset times were similar between PD+FOG and PD-FOG. Though medication improved turning, turn duration and step count impairments still existed in PD ON, compared to controls. Relative to PD-FOG, PD+FOG turned worse, but improved more with medication, potentially because PD+FOG were initially more impaired than PD-FOG or were taking higher medication dosages. Further treatment options may be needed to address ON medication turning deficits. PMID- 23939307 TI - Interaction between alpha-synuclein and tau genotypes and the progression of Parkinson's disease. AB - OBJECTIVE: To determine whether alpha-synuclein NACP-Rep1 and tau genotypes can predict the rate of progression of Parkinson's disease. METHODS: 123 Parkinson's disease cases were recruited for neurological examination and DNA donation. The rate of progression was assessed as the motor Unified Parkinson's disease Rating Score divided by symptom duration at the time of assessment and associations determined with alpha-synuclein NACP-Rep1 and tau genotypes. RESULTS: There was a significant effect of genotype on the rate of progression of Parkinson's disease. In MAPT H2 haplotype carriers, some NACP-Rep1 genotypes, thought to be associated with increasing alpha-synuclein expression, were linked with a higher rate of progression. In NACP-Rep1 0/0 genotype carriers, patients without MAPT H2 haplotype had a higher rate of progression of Parkinson's disease. The relative risk to develop a more rapid disease progression in these genotypes reached 5.8. CONCLUSION: Genetic factors not only influence the risk of Parkinson's disease, but also the progression of Parkinson's disease. PMID- 23939309 TI - Predicting outcomes in Parkinson's disease: comparison of simple motor performance measures and The Unified Parkinson's Disease Rating Scale-III. AB - The Unified Parkinson's Disease Rating Scale (UPDRS) part III is the principal motor assessment method for Parkinson's disease (PD), but has recognized limitations including subjectivity and insensitivity. Easy to administer, objective, quantitative tests that are good indicators of PD progression could offer advantages in both clinical and research settings. We administered four simple, motor performance measures--functional reach, timed hall walk, a timed block sort task, and timed dotting--as well as the UPDRS to 609 PD patients of a single neurologist. The unadjusted Spearman correlations of these performance measures with the UPDRS motor score (UPDRS III) ranged from 0.29 to 0.49. Moreover, these measures generally had high reliability on repeated testing. We defined specific outcomes in PD--overall disability, gait instability and falls, as well as non-motor outcomes of depression, dementia, and psychosis, and assessed the ability of the measures to predict these outcomes over the entire follow-up of the cohort (average: 2.4 years) and over the first year of follow up. The associations between the measures and the outcomes were generally stronger and more precise for the performance measures than for the UPDRS III. A summary score of the performance measures was a particularly good predictor of the outcomes. These motor performance measures could provide a rapid, simple means of assessing PD progression that could benefit both clinical and research endeavors. PMID- 23939310 TI - Peroxiredoxins as biomarkers of oxidative stress. AB - BACKGROUND: Peroxiredoxins (Prxs) are a class of abundant thiol peroxidases that degrade hydroperoxides to water. Prxs are sensitive to oxidation, and it is hypothesized that they also act as redox sensors. The accumulation of oxidized Prxs may indicate disruption of cellular redox homeostasis. SCOPE OF REVIEW: This review discusses the biochemical properties of the Prxs that make them suitable as endogenous biomarkers of oxidative stress, and describes the methodology available for measuring Prx oxidation in biological systems. MAJOR CONCLUSIONS: Two Prx oxidation products accumulate in cells under increased oxidative stress: an intermolecular disulfide and a hyperoxidized form. Methodologies are available for measuring both of these redox states, and oxidation has been reported in cells and tissues under oxidative stress from external or internal sources. GENERAL SIGNIFICANCE: Monitoring the oxidation state of Prxs provides insight into disturbances of cellular redox homeostasis, and complements the use of exogenous probes of oxidative stress. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. PMID- 23939311 TI - NMR reveals molecular interactions and dynamics of fatty acid binding to albumin. AB - BACKGROUND: The molecular details of fatty acid (FA) interactions with albumin are fundamental to understanding transport in the plasma and cellular utilization of these key nutrients and building blocks of membranes. SCOPE OF REVIEW: This review focuses on the development and application of NMR methods to study FA binding to albumin [bovine (BSA) and human (HSA)]. The key strategy was to use (13)C enrichment of a specific carbon in the FA as a non-perturbing probe to permit visualization of the small ligand complexed to the very large protein. NMR contributions to illuminating molecular interactions and FA dynamics are summarized from three decades of studies. MAJOR CONCLUSIONS: Our early studies detected multiple binding sites that we hypothesized were distinguished because of the unique tertiary structure of the protein in close proximity to the FA labeled carbon in each site. Later crystallographic structures revealed the presence of polar and charged amino acid side chains near the carboxyl carbon of the FA and unique tertiary structures lining all of the FA binding pockets. In collaboration with the crystallography group, several FA sites in the crystalline state were matched with NMR resonances in the solution state. With the newest application of NMR, 2D NMR spectroscopy detected nine binding sites, and three were located in the crystal structure through displacement of drugs with identified sites. GENERAL SIGNIFICANCE: NMR spectroscopy utilizing the FA as a probe allows characterization of site-specific interactions, molecular motions within binding sites, the order of filling and removal of FA from sites. This article is part of a Special Issue entitled Serum Albumin. PMID- 23939308 TI - Disentangling the relationship between lewy bodies and nigral neuronal loss in Parkinson's disease. AB - Progressive rostral spread of Lewy body (LB) pathology is thought to reflect the clinical course of Parkinson's disease (PD) although several studies have suggested that LBs are not the toxic species responsible for cell death. We investigated the relationship between nigral dopaminergic cell loss, distribution and density of alpha-synuclein-immunoreactive LBs and duration of motor symptoms in 97 patients with PD. Density of pigmented neurons was measured in a single section of one half of the substantia nigra (SN) with delineation of the dorsal and ventral tiers whereas the cortical and nigral LB densities were determined using a morphometric approach. The density of nigral neurons was estimated to decrease by 2% each year after confirmation of the clinical diagnosis of PD but showed marked heterogeneity with some PD patients with longer duration of illness still possessing a significant number of preserved pigmented nigral neurons at the time of death. An average 15% of surviving nigral neurones contained LBs and the age-adjusted proportion of LB-bearing neurons appeared relatively stable throughout the disease duration. No difference was observed in the age at death or duration of disease with respect to Braak PD stages. The nigral neuronal density was unrelated to either the Braak PD stage or to cortical LB densities. We conclude that nigral neuronal loss is slow and shows considerable variation in PD. Our data also provides no support for a primary pathogenic role of LBs as neither their distribution nor density was associated with the severity of nigral cell loss. PMID- 23939312 TI - Doppler echocardiographic criteria in patency assessment of composite grafts from left internal thoracic artery. AB - OBJECTIVES: The purpose of our study was to establish, with an entirely noninvasive method, transthoracic Doppler echocardiography, criteria for patency of composite left internal thoracic artery grafts when placed on the left anterior descending artery and other branches of the left coronary system. METHODS: The control group comprised 20 patients with single graft and 20 patients with composite graft; all forty having their patency confirmed by coronary angiogram (CA). In this control group, two Doppler echocardiographic variables, diastolic mean velocity-time and integral diastolic peak velocity to systolic peak velocity ratio were recorded. For each variable, established cut off points were established, using the ROC (Receiver Operator Characteristic) curves, to identify criteria which could differentiate the composite grafts. Only patients with composite grafts were included in the 159-patients study group. The criteria established by the cut-off points in the control group were then applied to detect patency using a diastolic fraction of > 0.5 as the gold standard. The sensitivity, specificity, and positive and negative predictive values of these two criteria were determined. RESULTS: In the control group, cut-off points of 0.71 and 0.09 m were established for the diastolic peak velocity/systolic peak velocity ratio and for diastolic mean velocity-time integral, respectively. In the study group phase, the sensitivity and negative predictive value of the diastolic peak velocity/systolic peak velocity > 0.71 criterion were 36% and 11%, respectively. Diastolic mean velocity-time integral > 0.09 m criterion, were 40% and 10.48%. The specificities and positive predictive values of each criterion were 100%. CONCLUSION: Values reaching the criteria established for each variable indicate high probability of composite graft patency. Lower values have a large proportion of false negatives and are not conclusive as patency criteria. PMID- 23939313 TI - Results of Castro Bernardes intraluminal ring in surgery for ascending aortic aneurysms and dissections. AB - OBJECTIVE: To demonstrate surgical results using Castro Bernardes intraluminal ring in ascending aorta surgery, instead of conventional suture. METHODS: 95 patients underwent ascending aorta surgery from December 2008 to April 2011 at Madre Tereza Hospital (Belo Horizonte, MG, Brazil), using Castro Bernardes intraluminal ring instead of conventional suture of the aorta. RESULTS: Ninety five patients underwent ascending aorta surgery with Castro-Bernardes intraluminal ring. Thirty patients presented acute dissection and 65 aneurism. Overall postoperative mortality was 15.78% (15/95). Nine patients in 15 (60%) died due to acute type A dissection. For acute type A dissection, mortality was 30% and for aneurism mortality was 9.23%. The intraluminal ring was inserted in distal position in 89 patients and in proximal and distal position in 6 patients. Mortality was related to Bentall & De Bono or Cabrol associated techniques. Average extracorporeal circulation time was 57.4 minutes and average aortic cross clamping time was 37 minutes. CONCLUSION: The use of Castro Bernardes intraluminal ring in ascending aortic surgery avoiding conventional suture reduces extracorporeal circulation time and aortic cross-clamping time, improving surgical results. This approach simplifies ascending aortic surgery whether the disease is type A dissection or aneurysm, and may be considered a good alternative technique. PMID- 23939314 TI - Impact of autologous blood transfusion on the use of pack of red blood cells in coronary artery bypass grafting surgery. AB - OBJECTIVE: To evaluate the impact of Cell Saver autologous blood transfusion system (CS) on the use of packed red blood cells (pRBC) in coronary artery bypass grafting (CABG) surgery. METHODS: We carried out a retrospective cross-sectional study in 87 patients undergoing primary elective CABG with miniaturized cardiopulmonary bypass (miniCPB), divided in two groups: 44 without-CS and 43 with-CS. We investigated the necessity of absolute use and the volume of packed red blood cells (pRBC) in each group, as well as cardiovascular risk factors, presurgical variables and intraoperative surgical parameters. All data were collected from medical records and there was no randomization or intervention on group selection. Statistical analysis was performed with Student t-test, Mann Whitney U-test and chi2 test, with a 5% significance level. RESULTS: There were no significant differences between the two groups in terms of cardiovascular risk factors and pre and intraoperative variables. Evaluating the absolute use of pRBC during surgery, there was a statistically significant difference (P=0.00008) between the groups without-CS (21/44 cases; 47.7%) and with-CS (4/43 cases; 9.3%). There was also a statistically significant difference (P=0.000117) in the volumes of pRBC between the groups without-CS (198.651258.65 ml) and with-CS (35.061125.67 ml). On the other hand, in the early postoperative period (up to 24h) there was no difference regarding either the absolute use or the volumes of pRBC between both studied groups. CONCLUSION: Autologous erythrocyte transfusion with CS use reduces the use of intraoperative homologous pRBC in coronary artery bypass grafting surgeries associated with miniCPB. PMID- 23939315 TI - Reinforced aortic root reconstruction for acute type A aortic dissection involving the aortic root. AB - OBJECTIVE: There are debates regarding the optimal approach for AAAD involving the aortic root. We described a modified reinforced aortic root reconstruction approach for treating AAAD involving the aortic root. METHODS: A total of 161 patients with AAAD involving the aortic root were treated by our modified reinforced aortic root reconstruction approach from January 1998 to December 2008. Key features of our modified approach were placement of an autologous pericardial patch in the false lumen, lining of the sinotubular junction lumen with a polyester vascular ring, and wrapping of the vessel with Teflon strips. Outcome measures included post-operative mortality, survival, complications, and level of aortic regurgitation. RESULTS: A total of 161 patients were included in the study (mean age: 43.3 1 15.5 years). The mean duration of follow-up was 5.1 1 2.96 years (2-12 years). A total of 10 (6.2%) and 11 (6.8%) patients died during hospitalization and during follow-up, respectively. Thirty-one (19.3%) patients experienced postoperative complications. The 1-, 3-, 5-, and 10-year survival rates were 99.3%, 98%, 93.8%, and 75.5%, respectively. There were no instances of recurrent aortic dissection, aortic aneurysm, or pseudoaneurysm during the entire study period. The severity of aortic regurgitation dramatically decreased immediately after surgery (from 28.6% to 0% grade 3-4) and thereafter slightly increased (from 0% to 7.2% at 5 years and 9.1% at 10 years). CONCLUSION: This modified reinforced aortic root reconstruction was feasible, safe and durable/effective, as indicated by its low mortality, low postoperative complications and high survival rate. PMID- 23939316 TI - Mediastinitis: mortality rate comparing single-stage surgical approach and preconditioning of wound. AB - OBJECTIVE: This study aims to compare hospital mortality rate of surgical debridement followed by primary wound closure versus surgical debridement with closure after preconditioning of the wound. METHODS: A historical cohort of 43 patients with postoperative mediastinitis type III and IV between 2000 and 2008. The diagnosis of mediastinitis was based on physical examination and laboratory tests. Patients were divided into two groups: patients who received the protocol of preconditioning of the wound (Group 2) and those who did not (Group 1). RESULTS: Of the 43 patients, 15 received the protocol and were assigned to Group 2, and 28 patients to Group 1. Myocardial revascularisation was the surgical intervention most affected by infection, accounting for 69.8% of patients in Group 1 and 64.3% in Group 2.Staphylococcus aureus was the predominant pathogen, accounting for 58.1% of all cases, 50% in Group 1 and 73.3% in Group 2. Hospital mortality rate was 42.9% in Group 1 and 20% in Group 2 (P=1.86), with relative risk of 2.14 and CI [0.714-6.043]. Among the 28 (65.1%) patients who underwent single-stage surgical approach, 12 (27.9%) underwent primary wound closure with irrigation, seven (16.3%) only primary closure, six (14%) omental flap, and three (7%) pectoralis muscle flap. CONCLUSION: Due to the lack of established guidelines, the choice of the surgical approach is based largely on low-level evidence references. Preconditioning of the wound appears to lead to a reduction in mortality in these patients, being a good surgical option. PMID- 23939317 TI - Initial and pioneer experience of transcatheter aortic valve implantation (Inovare) through femoral or iliac artery. AB - OBJECTIVE: This paper demonstrates the initial and pioneering experience implant of the Inovare prosthesis implant through transfemoral or iliac artery route. METHODS: Six patients underwent transcatheter aortic valve implantation. The access was femoral or iliac through which the delivery device, a latex balloon catheter with the crimped prosthesis, was inserted. Through the femoral introducer 24 Fr Gore(r) DrySeal sheath, an extra stiff guide wire with non traumatic tip was positioned in the left ventricle by passing through the valve ring. After balloon valvuloplasty, in cases of native valve stenosis, the prosthesis implantation was performed after hypotension induced by tachycardia and controlled by temporary pacemaker. The valve positioning was guided by TEE (transesophageal ecocardiography) and fluoroscopy, aiming to position a third of the length of the prosthesis into the left ventricle cavity. RESULTS: The successful valve implantation was possible in six cases. There was no need of conversion to open surgery due to inability to access or graft migration. There were no intraoperative or hospital deaths. We observed a significant reduction in the mean gradient of 66.84115.46 mmHg to 19.74110.61 mm Hg postoperatively (P=0.002), a reduction of 70.46%. CONCLUSION: Inovare prosthesis, implanted by femoral or iliac artery was feasible, and determined adequate hemodynamic performance in the postoperative follow-up, showing no mortality in this small series. PMID- 23939318 TI - Pulsatile stent graft: a new alternative in chronic ventricular assistance. AB - OBJECTIVE: Heart failure is currently one of the most common hospitalization causes. Several chronic circulatory assist devices have been tested and are highly complex. The objective is the description of a pulsatile endoprosthesis capable of applying a chronic pulse within the descending aorta, similar to that produced by intra-aortic balloon. METHODS: Pulsatile stents composed of nickel titanium were built and positioned to engage latex tubes simulating the aorta. Different electric currents were applied to units connected in series in order to cause structure contraction and displacement of a liquid column. There were two sequence tests: first composed of two metallic cages and the second composed of five cages. At first sequence tests was applied a voltage of 16.3 volts and a current of 5 amperes. In the second, voltage of 15 volts and current of 07 amperes. RESULTS: In the first sequence was obtained the pulsatile effect of stent, with contraction of the tube and displacement of the water column sufficient to validate the pulsating effect of the endoprosthesis. The two structures ejected a volume of 2.6 ml per cycle, with a range of 29 mm in height of the column of water equivalent to 8% shrinkage during the pulse. In the second sequence, it reachead a variation of 7.4 mL per cycle. CONCLUSION: The results obtained confirm the stent pulsatile contractility activated by electrical current. The continuity of the study and material improvement are necessary to obtain more efficient model from the point of view of energy and pulse, to allow ejection volumes comparable with the intra-aortic balloons. PMID- 23939319 TI - Comparison between the Doppler flowmetry and the free flow of dog's internal thoracic artery with and without use norepinephrine. AB - OBJECTIVE: This work aims to study comparatively the free flow and the Doppler flowmetry of the internal thoracic artery in anesthetized dogs, with and without continuous intravenous administration of norepinephrine. METHODS: The sample was made up of ten mongrel dogs, which dissected the left and right internal thoracic arteries and evaluated your stream; first, by Doppler flowmetry and then by free flow. The mean arterial pressure and the diameter of the arteries at the beginning of the procedure were registered. The workflow checks by two methods occurred in three times: time zero, 10 and 25 minutes. After the first check in time zero, the continuous infusion of norepinephrine in the right atrium; other checks were made in the same way that the first time, to 10 and 25 minutes, in the same arteries and by two methods, each one in his artery, noting the results, as well as the corresponding average blood pressure. RESULTS: The results of the scan of the stream, between Doppler flowmetry and free flow, there were similar; being the first, zero times, ten and twenty-five minutes, respectively, 183, 230.1 and 237 ml/min compared to seconds, 168.6, 226.8 and 226.4 ml/min (P = 0.285). The mean arterial pressures of three times and the average diameter of the arteries, showed no statistically significant differences between the methods, so did not influence on the comparison of the results. CONCLUSION: The evaluations, both from Doppler flowmetry and free flow, were similar in three times checked. PMID- 23939320 TI - Acute kidney injury after coronary artery bypass grafting: assessment using RIFLE and AKIN criteria. AB - OBJECTIVE: To compare the RIFLE (Risk, Injury, Failure, Loss and End-stage Renal Failure) and AKIN (Acute Kidney Injury Network) criteria for diagnosis of acute kidney injury after coronary artery bypass grafting. METHODS: Retrospective cohort. 169 patients who underwent coronary artery bypass grafting from January 2007 through December 2008 were analyzed. Information was entered into a database and analyzed using STATA 9.0. RESULTS: Patients' mean age was 63.43 1 9.01 years old. Predominantly male patients (66.86%) were studied. Acute Kidney Injury was present in 33.14% by AKIN and in 29.59% by RIFLE. Hemodialysis was required by 3.57% and 4.0% of the patients when AKIN and RIFLE were applied respectively. There was 4.0% and 3.57% mortality of patients with Acute Kidney Injury according to the RIFLE and AKIN criteria, respectively. In 88.76% of the cases, there was good agreement between the two methods in the detection (kappa=0.7380) and stratification (kappa=0.7515) of Acute Kidney Injury. CONCLUSION: This study showed that the RIFLE and AKIN criteria have a good agreement in the detection and stratification of acute kidney injury after coronary artery bypass grafting. PMID- 23939321 TI - Cardiovascular prevention in coronary heart disease patients: guidelines implementation in clinical practice. AB - OBJECTIVE: To demonstrate the utilization of a clinical improvement program in stable coronary artery disease patients to increase the evidence-proven treatment utilization, and to describe the ongoing clinical practice and lifestyle change counseling. METHODS: Cross-sectional study followed by a longitudinal component in which the tools utilization to improve clinical practice was assessed by means of additional cross-sectional data collection. 710 consecutive patients were included (Phase 1). After tools implementation, within 6 months period, 705 patients were included (Phase 2) for comparative analysis. Randomly, 318 patients from Phase 1 were selected, 6-12 months after the first evaluation (Phase 3). RESULTS: Phase 1 to Phase 2: there were improvement on smoking cessation (P=0.019), dyslipidemia (P<0.001), hypertension and physical activity (P<0.001). There was significant difference on angiotensin converting enzyme inhibitors - ACEI (67.2% vs. 56.8%, P<0.001); angiotensin II receptor blockers - ARB II (25.4% vs. 32.9%, P=0.002) and beta-blocker (88.7% vs. 91.9%, P=0.047). Phase 1 to Phase 3: there was both weight (P=0.044), and blood pressure reduction (P<0.001). There was statistical significant difference on ACEI (64.8% vs. 61.6%, P=0.011) and ARB II (27.0% vs. 31.3%, P=0.035). CONCLUSION: There was no significant change on the evidence-based pharmacological treatment utilization between pre and post intervention phases; there was significant improvement concerning smoking and physical activity in phase 2; substantial improvement on blood pressure levels in both comparisons (Phase 1 to 2 and Phase 1 to 3). The inclusion of a case-manager for the process management was crucial for program efficacy. Comprehensive programs for clinical practice should be pursued for longer follow-up period. PMID- 23939322 TI - Cardiac surgery: the infinite quest. Part III--pediatric cardiac surgery: a discipline on its own. AB - Although there are common grounds with adult cardiac surgery, it is important to understand the differences in the business plan, paths, manpower, mindset, training, and infrastructure that are essential in those institutions where pediatric cardiac surgery can and should be performed. Time to start thinking, it is not what we can do, but should we do it? PMID- 23939323 TI - Regionalization of Brazilian pediatric cardiovascular surgery. PMID- 23939324 TI - Heart surgery programs innovation using surgical risk stratification at the Sao Paulo State Public Healthcare System: SP-SCORE-SUS study. AB - Cardiovascular diseases represent the greatest burden of morbidity and mortality for the health system and cardiac surgery has an important impact on their resolutivity. The association and correlation of patients' demographic and clinical relevant information with the resources required for each stratum represent the possibility to adapt, improve and innovate into the healthcare programs. This project aims to remodel the "InsCor" risk score for the formulation of the SP-SCORE (Sao Paulo System for Cardiac Operative Risk Evaluation) in order to better reflects the complexity of cardiac surgical care. The participating hospitals include the Health Technology Assessment Centers in of the Health Secretariat' HTA Network of Sao Paulo State (HTA-NATSs / SES-SP). The SP-SCORE will use 10 variables of the InsCor model and others 8 variables with presumed influence in Brazil. The primary endpoints are morbidity and mortality. Bootstrap technique besides automated selection of variables (stepwise) will be used to develop a parsimonious model by multiple logistic regression. This project will contribute for the SUS-SP regionalized health-care (RRAS) sustainability and financing of the CABG and/or heart valve surgery programs promoting equitable allocation, increasing access and effectiveness, as well as characterizing the magnitude of available resources and its impact. PMID- 23939325 TI - Clinical and ultramicroscopic myocardial randomized study of beating versus arrested heart for mitral surgery. AB - INTRODUCTION: Beating heart surgery on normothermic bypass simulates physiologic cardiac status. OBJECTIVES: This study compared clinical and transmission electron microscopic aspects of myocardial protection during mitral valve replacement using warm retrograde perfusion in empty beating versus arrested heart with cold blood anterograde cardioplegia. METHODS: Randomized study to evaluate myocardial cellular ischemia-reperfusion of both techniques to replace the mitral valve. Thirty-four patients were randomly assigned into group A (beating heart) and group B (arrested heart). The following parameters were assessed: echocardiography, blood chemistry, hemoglobin, lactate. During the surgical procedure a total of 102 myocardial biopsies were performed for ultrastructural analysis from anterior left ventricular wall: before cardiopulmonary bypass, before aortic desclamping and 10 minutes after reperfusion. RESULTS: Elevation of lactate at 3 hours during the procedure was higher in group A, but similar at the end of surgery (P=0.06). Cardioversion was necessary in 5/17 (A) vs. 13/17 (B) P=0.07. Median intraoperative systemic temperature was significantly lower in the group B compared to A (32 degrees C vs. 36 degrees C), P<0.001. There was no significant difference of the ultramicroscopic aspects of the heart biopsies before, during and after surgery in both groups. Cellular and mitochondrial transient abnormalities such as mitochondrial swelling, glycogen loss and cytosol swelling were detected independently of the moment of the biopsies. CONCLUSION: Myocardial protection and ultrastructural abnormalities were similar for both types of mitral valve replacement beating or arrested heart techniques. PMID- 23939326 TI - The use of the virtual reality as intervention tool in the postoperative of cardiac surgery. AB - INTRODUCTION: Cardiac surgery has been the intervention of choice in many cases of cardiovascular diseases. Susceptibility to postoperative complications, cardiac rehabilitation is indicated. Therapeutic resources, such as virtual reality has been helping the rehabilitational process. The aim of the study was to evaluate the use of virtual reality in the functional rehabilitation of patients in the postoperative period. METHODS: Patients were randomized into two groups, Virtual Reality (VRG, n = 30) and Control (CG, n = 30). The response to treatment was assessed through the functional independence measure (FIM), by the 6-minute walk test (6MWT) and the Nottingham Health Profile (NHP). Evaluations were performed preoperatively and postoperatively. RESULTS: On the first day after surgery, patients in both groups showed decreased functional performance. However, the VRG showed lower reduction (45.712.3) when compared to CG (35.0612.09, P<0.05) in first postoperative day, and no significant difference in performance on discharge day (P>0.05). In evaluating the NHP field, we observed a significant decrease in pain score at third assessment (P<0.05). These patients also had a higher energy level in the first evaluation (P<0.05). There were no differences with statistical significance for emotional reactions, physical ability, and social interaction. The length of stay was significantly shorter in patients of VRG (9.410.5 days vs. 12.2 1 0.9 days, P<0.05), which also had a higher 6MWD (319.9119.3 meters vs. 263.5115.4 meters, P<0.02). CONCLUSION: Adjunctive treatment with virtual reality demonstrated benefits, with better functional performance in patients undergoing cardiac surgery. PMID- 23939327 TI - Cardiogenic shock due to coronary artery disease associated with interrupted aortic arch. AB - Acute pulmonary edema is a serious event. Its occurrence in association with interrupted aortic arch and coronary heart disease is rare. Recently, an old patient developed cardiogenic shock and acute pulmonary edema due to acute coronary insufficiency, associated with interrupted aortic arch. The coronary angiography revealed occlusion of the right coronary artery and 95% obstruction in the left main coronary artery, associated with interruption of the descending aorta. Coronary artery bypass graft was performed, without extracorporeal circulation, to the anterior descending coronary artery. We discuss the initial management, given the seriousness of the case. PMID- 23939297 TI - Diet and kidney disease in high-risk individuals with type 2 diabetes mellitus. AB - IMPORTANCE: Type 2 diabetes mellitus and associated chronic kidney disease (CKD) have become major public health problems. Little is known about the influence of diet on the incidence or progression of CKD among individuals with type 2 diabetes. OBJECTIVE: To examine the association between (healthy) diet, alcohol, protein, and sodium intake, and incidence or progression of CKD among individuals with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: All 6213 individuals with type 2 diabetes without macroalbuminuria from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) were included in this observational study. Recruitment spanned from January 2002 to July 2003, with prospective follow-up through January 2008. MAIN OUTCOMES AND MEASURES: Chronic kidney disease was defined as new microalbuminuria or macroalbuminuria or glomerular filtration rate decline of more than 5% per year at 5.5 years of follow-up. We assessed diet using the modified Alternate Healthy Eating Index (mAHEI). The analyses were adjusted for known risk factors, and competing risk of death was considered. RESULTS: After 5.5 years of follow-up, 31.7% of participants had developed CKD and 8.3% had died. Compared with participants in the least healthy tertile of mAHEI score, participants in the healthiest tertile had a lower risk of CKD (adjusted odds ratio [OR], 0.74; 95% CI, 0.64-0.84) and lower risk of mortality (OR, 0.61; 95% CI, 0.48-0.78). Participants consuming more than 3 servings of fruits per week had a lower risk of CKD compared with participants consuming these food items less frequently. Participants in the lowest tertile of total and animal protein intake had an increased risk of CKD compared with participants in the highest tertile (total protein OR, 1.16; 95% CI, 1.05-1.30). Sodium intake was not associated with CKD. Moderate alcohol intake reduced the risk of CKD (OR, 0.75; 95% CI, 0.65-0.87) and mortality (OR, 0.69; 95% CI, 0.53-0.89). CONCLUSIONS AND RELEVANCE: A healthy diet and moderate intake of alcohol may decrease the incidence or progression of CKD among individuals with type 2 diabetes. Sodium intake, within a wide range, and normal protein intake are not associated with CKD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00153101. PMID- 23939328 TI - Extracorporeal membrane oxygenation as a support for TGA/IVS with low cardiac output syndrome and pulmonary hemorrhage. AB - A 15-day-old neonate with complete transposition of the great arteries/intact ventricular septum was admitted with life-threatening hypoxemia and heart arrest. After successful resuscitation, heart beat recovered but blood lactate began to arise and maintained above 15 mmol/L 6 hours later. Emergency arterial switch operation was done at 20 hours after resuscitation. Planned extracorporeal membrane oxygenation support was employed postoperatively. The baby experienced severe pulmonary hemorrhage and severe hypoxemia after weaning from cardiopulmonary bypass, which were treated with extracorporeal membrane oxygenation support. PMID- 23939329 TI - Use of autologous pericardium for mitral leaflet reconstruction in a child with endocarditis. AB - We present a case of successful repair of the mitral valve for active infective endocarditis. Mitral valve repair was performed through debridement of vegetation and abscess, resection and repair of the posterior mitral leaflet and posterior repair with autologous pericardium. Postoperative period was uneventfully, with no evidence of recurrent infection, and echocardiogram showed mitral valve competence with mild mitral regurgitation. We demonstrate that valve repair is a feasible choice in cases of active endocarditis in children. PMID- 23939330 TI - Extracorporeal Circulation System. DeWall Oxygenator (1955). PMID- 23939331 TI - Scientists can tell an accurate story. Interview by Frances Jones. PMID- 23939332 TI - Technical modification for total cavopulmonary connection in a 9-year-old girl: a 20-year postoperative approach. PMID- 23939333 TI - Authorship in the scientific paper: defining the role of each one. PMID- 23939334 TI - SYNTAX from the evidence to the disobedience. PMID- 23939335 TI - A debt with our nation's health: the case of congenital heart diseases. PMID- 23939336 TI - Pre-deployment daytime and nighttime sleep complaints as predictors of post deployment PTSD and depression in National Guard troops. AB - There is growing evidence that disturbed sleep is a risk factor for the development of a number of psychiatric diagnoses including depression, PTSD and substance use. The goal of this study was to use a subset of participants from a larger prospective longitudinal study to examine whether preexisting daytime and nighttime sleep disturbances predict depression, PTSD and substance use in US National Guard Soldiers deployed to Iraq. Data on daytime and nighttime sleep complaints, baseline symptoms and personality variables were gathered prior to deployment to Iraq. Measures of psychopathology were collected at three time points post-deployment over the course of two years using both questionnaires and interviews. Multiple regressions were used to predict diagnoses and symptoms of depression, PTSD and substance use. Pre-deployment daytime and nighttime sleep complaints contributed significantly to the prediction of PTSD and depression up to two years after deployment, but not substance use. This study suggests that daytime and nighttime sleep complaints are a risk factor for internalizing disorders including PTSD and depression. PMID- 23939338 TI - Fine-scale niche structure of Neotropical forests reflects a legacy of the Great American Biotic Interchange. AB - The tendency of species to retain their ancestral niches may link processes that determine community assembly with biogeographic histories that span geological time scales. Biogeographic history is likely to have had a particularly strong impact on Neotropical forests because of the influence of the Great American Biotic Interchange, which followed emergence of a land connection between North and South America ~3 Ma. Here we examine the community structure, ancestral niches and ancestral distributions of the related, hyperdiverse woody plant genera Psychotria and Palicourea (Rubiaceae) in Panama. We find that 49% of the variation in hydraulic traits, a strong determinant of community structure, is explained by species' origins in climatically distinct biogeographic regions. Niche evolution models for a regional sample of 152 species indicate that ancestral climatic niches are associated with species' habitat distributions, and hence local community structure and composition, even millions of years after dispersal into new geographic regions. PMID- 23939339 TI - Highly active gauze-supported skeletal nickel catalysts. AB - Gauze-supported skeletal nickel catalysts were prepared by electrodeposition of Ni-Zn alloys from an acetamide-DMSO2-NiCl2-ZnCl2 quaternary melt, followed by chemical or electrochemical leaching of zinc from the alloys. The activity and selectivity of the structured RANEY(r) nickel surpass those of commercial RANEY(r) nickel in the hydrogenation of acetophenone. PMID- 23939337 TI - Rational design of chemical genetic probes of RNA function and lead therapeutics targeting repeating transcripts. AB - RNA is an important yet vastly underexploited target for small molecule chemical probes or lead therapeutics. Small molecules have been used successfully to modulate the function of the bacterial ribosome, viral RNAs and riboswitches. These RNAs are either highly expressed or can be targeted using substrate mimicry, a mainstay in the design of enzyme inhibitors. However, most cellular RNAs are neither highly expressed nor have a lead small molecule inhibitor, a significant challenge for drug discovery efforts. Herein, I describe the design of small molecules targeting expanded repeating transcripts that cause myotonic muscular dystrophy (DM). These test cases illustrate the challenges of designing small molecules that target RNA and the advantages of targeting repeating transcripts. Lastly, I discuss how small molecules might be more advantageous than oligonucleotides for targeting RNA. PMID- 23939340 TI - The computerized medical record as a tool for clinical governance in Australian primary care. AB - BACKGROUND: Computerized medical records (CMR) are used in most Australian general practices. Although CMRs have the capacity to amalgamate and provide data to the clinician about their standard of care, there is little research on the way in which they may be used to support clinical governance: the process of ensuring quality and accountability that incorporates the obligation that patients are treated according to best evidence. OBJECTIVE: The objective of this study was to explore the capability, capacity, and acceptability of CMRs to support clinical governance. METHODS: We conducted a realist review of the role of seven CMR systems in implementing clinical governance, developing a four-level maturity model for the CMR. We took Australian primary care as the context, CMR to be the mechanism, and looked at outcomes for individual patients, localities, and for the population in terms of known evidence-based surrogates or true outcome measures. RESULTS: The lack of standardization of CMRs makes national and international benchmarking challenging. The use of the CMR was largely at level two of our maturity model, indicating a relatively simple system in which most of the process takes place outside of the CMR, and which has little capacity to support benchmarking, practice comparisons, and population-level activities. Although national standards for coding and projects for record access are proposed, they are not operationalized. CONCLUSIONS: The current CMR systems can support clinical governance activities; however, unless the standardization and data quality issues are addressed, it will not be possible for current systems to work at higher levels. PMID- 23939341 TI - Quantitation of Li2O2 stored in Li-O2 batteries based on its reaction with an oxoammonium salt. AB - Precise knowledge of the discharge and charge reactions within Li-O2 batteries is an important aspect of developing highly efficient, rechargeable Li-O2 cells. We describe an analytical method capable of determining the quantity of Li2O2 in the cathode on the basis of the reaction of Li2O2 with an oxoammonium salt. PMID- 23939342 TI - Assessing drug-induced dyskinesia in the clinic, the laboratory and the natural environment of patients. AB - The assessment of drug-induced dyskinesia (DID) in Parkinson's disease represents a formidable challenge for clinicians and researchers alike. The present review describes the current assessment tools used in the clinic, where different scales have been developed for monitoring levels of DID in patients. We also review laboratory tools used to assess the quantity and characteristics of DID. Finally, we review assessment methods currently in development for monitoring DID and voluntary mobility in the natural living environment of patients. Here, we discuss the strengths and weaknesses of these tools as it pertains to their efficacy in assessing the quantity of DID, its characteristics, as well as its impact on the quality of life of patients. Finally, we discuss ongoing challenges and research questions that may guide future development of assessment methods aimed at monitoring DID and its impact on daily lives of patients. PMID- 23939344 TI - Rab1A over-expression prevents Golgi apparatus fragmentation and partially corrects motor deficits in an alpha-synuclein based rat model of Parkinson's disease. AB - Although the overabundance of human alpha-synuclein in nigral dopaminergic neurons is considered to play a pathogenic role in Parkinson's disease (PD), it remains unclear how alpha-synuclein leads to neuronal degeneration and motor symptoms. Here, we explored the effect of human alpha-synuclein in the rat substantia nigra following AAV-mediated gene delivery inducing a moderate loss of dopaminergic neurons together with motor impairments. A significant fraction of the surviving nigral neurons were found to express human alphaSyn and displayed a pathological fragmentation of the Golgi apparatus. This observation prompted further investigation on the role of the secretory pathway, in particular at the ER/Golgi level, in alpha-synuclein toxicity. To address this question, we co expressed human alpha-synuclein with Rab1A, a regulator of ER-to-Golgi vesicular trafficking, and found a significant reduction of Golgi fragmentation. Rab1A did not protect the dopaminergic neurons from the alpha-synuclein-induced degeneration that occurred within several months following vector injection. However, we observed in animals co-expressing Rab1A an improvement of motor behavior that correlates with the rescue of normal Golgi morphology in alpha synuclein-expressing dopaminergic neurons. The non-prenylable mutant Rab1A DeltaCC did not produce any of the effects observed with the wild-type form of Rab1A, linking the protective role of Rab1A with its activity in ER-to-Golgi vesicular trafficking. In conclusion, Rab1A can rescue the Golgi fragmentation caused by the overabundance of alpha-synuclein in nigral dopaminergic neurons, improving the ability of the surviving neurons to control motor function in hemiparkinsonian animals. PMID- 23939343 TI - Activation of metabotropic glutamate 4 receptors decreases L-DOPA-induced dyskinesia in a mouse model of Parkinson's disease. AB - Group III metabotropic glutamate (mGlu) receptors modulate glutamatergic and GABAergic transmission in the basal ganglia. In this study, we examined a novel orthosteric agonist at the mGlu4 receptor, LSP1-2111, for its ability to affect L DOPA-induced dyskinesia (LID), in a mouse model. In 6-OHDA-lesioned mice treated with L-DOPA, chronic co-administration of LSP1-2111 significantly attenuated the development of abnormal involuntary movements, which are regarded as a marker of dyskinesia. In contrast, a single injection of LSP1-2111 did not modify the expression of LID, once this condition had been established by previous administration of L-DOPA. LSP1-2111 did not affect L-DOPA-induced cAMP and extracellular signal-regulated protein kinase signaling, which have been previoulsy implicated in dyskinesia. These results indicate that co administration of LSP1-2111 may improve the efficacy of standard L-DOPA therapy by attenuating its liability for dyskinesia. PMID- 23939345 TI - Colonic neuropathology is independent of olfactory dysfunction in Parkinson's disease. AB - Olfactory dysfunction (OD) and constipation are two frequent and early non-motor features of Parkinson's disease (PD). Colonic PD neuropathology, the putative cause of constipation, can be analyzed and quantified using routine colonic biopsies and parallels disease severity. The present study was aimed at investigating whether the severity of neuropathology in the colon in PD is related to OD. Twenty-six PD patients were included. Colonic neuropathology, i.e., the density of Lewy pathology and the number of submucosal neurons, was unrelated to OD as assessed using the University of Pennsylvania Smell Identification. This suggests that unlike colonic Lewy pathology, OD is unrelated to disease severity. PMID- 23939346 TI - Signaling pathways regulating ectodermal cell fate choices. AB - Although embryonic patterning and early development of the nervous system have been studied for decades, our understanding of how signals instruct ectodermal derivatives to acquire specific identities has only recently started to form a coherent picture. In this mini-review, we summarize recent findings and models of how a handful of well-known secreted signals influence progenitor cells in successive binary decisions to adopt various cell type specific differentiation programs. PMID- 23939347 TI - Risk factors in late adolescence for young-onset dementia in men: a nationwide cohort study. AB - IMPORTANCE: Young-onset dementia (YOD), that is, dementia diagnosed before 65 years of age, has been related to genetic mutations in affected families. The identification of other risk factors could improve the understanding of this heterogeneous group of syndromes. OBJECTIVE: To evaluate risk factors in late adolescence for the development of YOD later in life. DESIGN: We identified the study cohort from the Swedish Military Service Conscription Register from January 1, 1969, through December 31, 1979. Potential risk factors, such as cognitive function and different physical characteristics, were assessed at conscription. We collected other risk factors, including dementia in parents, through national register linkage. PARTICIPANTS: All Swedish men conscripted for mandatory military service (n=488,484) with a mean age of 18 years. SETTING: Predominantly Swedish men born from January 1, 1950, through December 31, 1960. EXPOSURE: Potential risk factors for dementia based on those found in previous studies, data available, and quality of register data. MAIN OUTCOMES AND MEASURE: All forms of YOD. RESULTS: During a median follow-up of 37 years, 487 men were diagnosed as having YOD at a median age of 54 years. In multivariate Cox regression analysis, significant risk factors (all P< .05) for YOD included alcohol intoxication (hazard ratio, 4.82 [95% CI, 3.83-6.05]); population attributable risk, 0.28), stroke (2.96 [2.02-4.35]; 0.04), use of antipsychotics (2.75 [2.09-3.60]; 0.12), depression (1.89 [1.53-2.34]; 0.28), father's dementia (1.65 [1.22-2.24]; 0.04), drug intoxication other than alcohol (1.54 [1.06-2.24]; 0.03), low cognitive function at conscription (1.26 per 1-SD decrease [1.14 1.40]; 0.29), low height at conscription (1.16 per 1-SD decrease [1.04-1.29]; 0.16), and high systolic blood pressure at conscription (0.90 per 1-SD decrease [0.82-0.99]; 0.06). The population-attributable risk associated with all 9 risk factors was 68%. Men with at least 2 of these risk factors and in the lowest third of overall cognitive function were found to have a 20-fold increased risk of YOD during follow-up (hazard ratio, 20.38 [95% CI, 13.64-30.44]). CONCLUSIONS AND RELEVANCE: In this nationwide cohort, 9 independent risk factors were identified that accounted for most cases of YOD in men. These risk factors were multiplicative, most were potentially modifiable, and most could be traced to adolescence, suggesting excellent opportunities for early prevention. PMID- 23939348 TI - Inhibition of IKKbeta in enterocytes exacerbates sepsis-induced intestinal injury and worsens mortality. AB - OBJECTIVES: Nuclear factor-kappaB is a critical regulator of cell-survival genes and the host inflammatory response. The purpose of this study was to investigate the role of enterocyte-specific NF-kB in sepsis through selective ablation of IkB kinase. DESIGN: Prospective, randomized controlled study. SETTING: Animal laboratories in university medical centers. SUBJECTS AND INTERVENTIONS: Mice lacking functional NF-kB in their intestinal epithelium (Vil-Cre/Ikkbeta) and wild-type mice were subjected to sham laparotomy or cecal ligation and puncture. Animals were killed at 24 hours or followed 7 days for survival. MEASUREMENTS AND MAIN RESULTS: Septic wild-type mice had decreased villus length compared with sham mice, whereas villus atrophy was further exacerbated in septic Vil Cre/Ikkbeta mice. Sepsis induced an increase in intestinal epithelial apoptosis compared with sham mice, which was further exacerbated in Vil-Cre/Ikkbeta mice. Sepsis induced intestinal hyperpermeability in wild-type mice compared with sham mice, which was further exacerbated in septic Vil-Cre/Ikkbeta mice. This was associated with increased intestinal expression of claudin-2 in septic wild-type mice, which was further increased in septic Vil-Cre/Ikkbeta mice. Both, pro inflammatory and anti-inflammatory cytokines were increased in serum following cecal ligation and puncture, and interleukin 10 and monocyte chemoattractant protein-1 levels were higher in septic Vil-Cre/Ikkbeta mice than in septic wild type mice. All septic mice were bacteremic, but no differences in bacterial load were identified between wild-type and Vil-Cre/Ikkbeta mice. To determine the functional significance of these results, animals were followed for survival. Septic wild-type mice had lower mortality than septic Vil-Cre/Ikkbeta mice (47% vs 80%, p<0.05). Antitumor necrosis factor administration decreased intestinal apoptosis, permeability, and mortality in wild-type septic mice, and a similar improvement in intestinal integrity and survival were seen when antitumor necrosis factor was given to Vil-Cre/Ikkbeta mice. CONCLUSIONS: Enterocyte specific NF-kB has a beneficial role in sepsis by partially preventing sepsis induced increases in apoptosis and permeability, which are associated with worsening mortality. PMID- 23939349 TI - Choosing and using screening criteria for palliative care consultation in the ICU: a report from the Improving Palliative Care in the ICU (IPAL-ICU) Advisory Board. AB - OBJECTIVE: To review the use of screening criteria (also known as "triggers") as a mechanism for engaging palliative care consultants to assist with care of critically ill patients and their families in the ICU. DATA SOURCES: We searched the MEDLINE database from inception to December 2012 for all English-language articles using the terms "trigger," "screen," "referral," "tool," "triage," "case finding," "assessment," "checklist," "proactive," or "consultation," together with "intensive care" or "critical care" and "palliative care," "supportive care," "end-of-life care," or "ethics." We also hand-searched reference lists and author files and relevant tools on the Center to Advance Palliative Care website. STUDY SELECTION: Two members (a physician and a nurse with expertise in clinical research, intensive care, and palliative care) of the interdisciplinary Improving Palliative Care in the ICU Project Advisory Board presented studies and tools to the full Board, which made final selections by consensus. DATA EXTRACTION: We critically reviewed the existing data and tools to identify screening criteria for palliative care consultation, to describe methods for selecting, implementing, and evaluating such criteria, and to consider alternative strategies for increasing access of ICU patients and families to high-quality palliative care. DATA SYNTHESIS: The Improving Palliative Care in the ICU Advisory Board used data and experience to address key questions relating to: existing screening criteria; optimal methods for selection, implementation, and evaluation of such criteria; and appropriateness of the screening approach for a particular ICU. CONCLUSIONS: Use of specific criteria to prompt proactive referral for palliative care consultation seems to help reduce utilization of ICU resources without changing mortality, while increasing involvement of palliative care specialists for critically ill patients and families in need. Existing data and resources can be used in developing such criteria, which should be tailored for a specific ICU, implemented through an organized process involving key stakeholders, and evaluated by appropriate measures. In some settings, other strategies for increasing access to palliative care may be more appropriate. PMID- 23939350 TI - RBC transfusion practices among critically ill patients: has evidence changed practice? AB - OBJECTIVE: Increasing evidence, including publication of the Transfusion Requirements in Critical Care trial in 1999, supports a lower hemoglobin threshold for RBC transfusion in ICU patients. However, little is known regarding the influence of this evidence on clinical practice over time in a large population-based cohort. DESIGN: Retrospective population-based cohort study. SETTING: Thirty-five Maryland hospitals. PATIENTS: Seventy-three thousand three hundred eighty-five nonsurgical adults with an ICU stay greater than 1 day between 1994 and 2007. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The unadjusted odds of patients receiving an RBC transfusion increased from 7.9% during the pre-Transfusion Requirements in Critical Care baseline period (1994 1998) to 14.7% during the post-Transfusion Requirements in Critical Care period (1999-2007). A logistic regression model, including 40 relevant patient and hospital characteristics, compared the annual trend in the adjusted odds of RBC transfusion during the pre- versus post-Transfusion Requirements in Critical Care periods. During the pre-Transfusion Requirements in Critical Care period, the trend in the adjusted odds of RBC transfusion did not differ between hospitals averaging>200 annual ICU discharges and hospitals averaging<=200 annual ICU discharges (odds ratio, 1.07 [95% CI, 1.01-1.13] annually and 1.03 [95% CI, 0.99 1.07] annually, respectively; p=0.401). However, during the post-Transfusion Requirements in Critical Care period, the adjusted odds of RBC transfusion decreased over time in higher ICU volume hospitals (odds ratio, 0.96 [95% CI, 0.93-0.98] annually) but continued to increase in lower ICU volume hospitals (odds ratio, 1.10 [95% CI, 1.08-1.13] annually), p<0.001. CONCLUSIONS: In this population-based cohort of ICU patients, the unadjusted odds of RBC transfusion increased in both higher and lower ICU volume hospitals both before and after Transfusion Requirements in Critical Care publication. After adjusting for relevant characteristics, the odds continued to increase in lower ICU volume hospitals in the post-Transfusion Requirements in Critical Care period, but it decreased in higher ICU volume hospitals. This suggests that evidence supporting restrictive RBC transfusion thresholds may not be uniformly translated into practice in different hospital settings. PMID- 23939351 TI - Restrictive versus liberal transfusion strategies for older mechanically ventilated critically ill patients: a randomized pilot trial. AB - OBJECTIVES: To compare hemoglobin concentration (Hb), RBC use, and patient outcomes when restrictive or liberal blood transfusion strategies are used to treat anemic (Hb<=90 g/L) critically ill patients of age>=55 years requiring>=4 days of mechanical ventilation in ICU. DESIGN: Parallel-group randomized multicenter pilot trial. SETTING: Six ICUs in the United Kingdom participated between August 2009 and December 2010. PATIENTS: One hundred patients (51 restrictive and 49 liberal groups). INTERVENTIONS: Patients were randomized to a restrictive (Hb trigger, 70 g/L; target, 71-90 g/L) or liberal (90 g/L; target, 91-110 g/L) transfusion strategy for 14 days or the remainder of ICU stay, whichever was longest. MEASUREMENTS AND MAIN RESULTS: Baseline comorbidity rates and illness severity were high, notably for ischemic heart disease (32%). The Hb difference among groups was 13.8 g/L (95% CI, 11.5-16.0 g/L); p<0.0001); mean Hb during intervention was 81.9 (SD, 5.1) versus 95.7 (6.3) g/L; 21.6% fewer patients in the restrictive group were transfused postrandomization (p<0.001) and received a median 1 (95% CI, 1-2; p=0.002) fewer RBC units. Protocol compliance was high. No major differences in organ dysfunction, duration of ventilation, infections, or cardiovascular complications were observed during intensive care and hospital follow-up. Mortality at 180 days postrandomization trended toward higher rates in the liberal group (55%) than in the restrictive group (37%); relative risk was 0.68 (95% CI, 0.44-1.05; p=0.073). This trend remained in a survival model adjusted for age, gender, ischemic heart disease, Acute Physiology and Chronic Health Evaluation II score, and total non-neurologic Sequential Organ Failure Assessment score at baseline (hazard ratio, 0.54 [95% CI, 0.28-1.03]; p=0.061). CONCLUSIONS: A large trial of transfusion strategies in older mechanically ventilated patients is feasible. This pilot trial found a nonsignificant trend toward lower mortality with restrictive transfusion practice. PMID- 23939352 TI - Impact of a national multimodal intervention to prevent catheter-related bloodstream infection in the ICU: the Spanish experience. AB - OBJECTIVE: Prevention of catheter-related bloodstream infection is a basic objective to optimize patient safety in the ICU. Building on the early success of a patient safety unit-based comprehensive intervention (the Keystone ICU project in Michigan), the Bacteremia Zero project aimed to assess its effectiveness after contextual adaptation at large-scale implementation in Spanish ICUs. DESIGN: Prospective time series. SETTING: A total of 192 ICUs throughout Spain. PATIENTS: All patients admitted to the participating ICUs during the study period (baseline April 1 to June 30, 2008; intervention period from January 1, 2009, to June 30, 2010). INTERVENTION: Engagement, education, execution, and evaluation were key program features. Main components of the intervention included a bundle of evidence-based clinical practices during insertion and maintenance of catheters and a unit-based safety program (including patient safety training and identification and analysis of errors through patient safety rounds) to improve the safety culture. MEASUREMENTS AND MAIN RESULTS: The number of catheter-related bloodstream infections was expressed as median and interquartile range. Poisson distribution was used to calculate incidence rates and risk estimates. The participating ICUs accounted for 68% of all ICUs in Spain. Catheter-related bloodstream infection was reduced after 16-18 months of participation (median 3.07 vs 1.12 episodes per 1,000 catheter-days, p<0.001). The adjusted incidence rate of bacteremia showed a 50% risk reduction (95% CI, 0.39-0.63) at the end of the follow-up period compared with baseline. The reduction was independent of hospital size and type. CONCLUSIONS: Results of the Bacteremia Zero project confirmed that the intervention significantly reduced catheter-related bloodstream infection after large-scale implementation in Spanish ICUs. This study suggests that the intervention can also be effective in different socioeconomic contexts even with decentralized health systems. PMID- 23939353 TI - Prognostic and diagnostic value of plasma soluble suppression of tumorigenicity-2 concentrations in acute respiratory distress syndrome. AB - OBJECTIVES: Soluble suppression of tumorigenicity-2 is a biomarker of myocardial strain and inflammation. The characteristics of acute respiratory distress syndrome include inflammation and cardiovascular dysfunction. We sought to determine whether plasma soluble suppression of tumorigenicity-2 concentration is associated with outcome and response to conservative fluid management and whether soluble suppression of tumorigenicity-2 concentration discriminates acute respiratory distress syndrome from decompensated heart failure. DESIGN: A retrospective analysis of the Fluid and Catheter Treatment Trial, a multi-center randomized controlled trial of conservative fluid management in the acute respiratory distress syndrome, as well as of a cohort of patients with decompensated heart failure. SETTING: Twenty acute care hospitals. PATIENTS: Eight hundred twenty-six patients with acute respiratory distress syndrome and 209 patients with acutely decompensated heart failure. MEASUREMENTS AND MAIN RESULTS: Nonsurvivors had higher day 0 (p < 0.0001) and day 3 (p < 0.0001) soluble suppression of tumorigenicity-2 concentrations. After adjustment for severity of illness, higher soluble suppression of tumorigenicity-2 concentration was associated with mortality, with odds ratioadj 1.47 (95% CI, 0.99-2.20; p = 0.06) at day 0, 2.94 (95% CI, 2.00-4.33; p < 0.0001) at day 3, and 3.63 (95% CI, 2.38-5.53; p < 0.0001) if soluble suppression of tumorigenicity-2 increased between days. Cumulative fluid balance was more positive among patients with higher day 0 (median, 5,212 mL [interquartile range, 200-12,284 mL] vs median, 2,020 mL [interquartile range, -2,034 to 7,091 mL]; p < 0.0001) and day 3 soluble suppression of tumorigenicity-2 (median, 7,678 mL [interquartile range, 2,217 14,278 mL] vs median, 1,492 mL [interquartile range, -2,384 to 6,239 mL]; p < 0.0001). Soluble suppression of tumorigenicity-2 showed excellent discriminative ability between the Fluid and Catheter Treatment Trial and heart failure populations (area under receiver-operating characteristic curve = 0.98; p < 0.0001). CONCLUSIONS: Higher soluble suppression of tumorigenicity-2 concentrations are associated with worse outcome in acute respiratory distress syndrome and may have value for discriminating acute respiratory distress syndrome from heart failure. PMID- 23939354 TI - A clinical trial comparing physician prompting with an unprompted automated electronic checklist to reduce empirical antibiotic utilization. AB - OBJECTIVES: To determine whether face-to-face prompting of critical care physicians reduces empirical antibiotic utilization compared to an unprompted electronic checklist embedded within the electronic health record. DESIGN: Random allocation design. SETTING: Medical ICU with high-intensity intensivist coverage at a tertiary care urban medical center. PATIENTS: Two hundred ninety-six critically ill patients treated with at least 1 day of empirical antibiotics. INTERVENTIONS: For one medical ICU team, face-to-face prompting of critical care physicians if they did not address empirical antibiotic utilization during a patient's daily rounds. On a separate medical ICU team, attendings and fellows were trained once to complete an electronic health record-embedded checklist daily for each patient, including a question asking whether listed empirical antibiotics could be discontinued. MEASUREMENTS AND MAIN RESULTS: Prompting led to a more than four-fold increase in discontinuing or narrowing of empirical antibiotics compared to use of the electronic checklist. Prompted group patients had a lower proportion of patient-days on which empirical antibiotics were administered compared to electronic checklist group patients (63.1% vs 70.0%, p = 0.002). Mean proportion of antibiotic-days on which empirical antibiotics were used was also lower in the prompted group, although not statistically significant (0.78 [0.27] vs 0.83 [0.27], p = 0.093). Each additional day of empirical antibiotics predicted higher risk-adjusted mortality (odds ratio, 1.14; 95% CI, 1.05-1.23). Risk-adjusted ICU length of stay and hospital mortality were not significantly different between the two groups. CONCLUSIONS: Face-to-face prompting was superior to an unprompted electronic health record-based checklist at reducing empirical antibiotic utilization. Sustained culture change may have contributed to the electronic checklist having similar empirical antibiotic utilization to a prompted group in the same medical ICU 2 years prior. Future studies should investigate the integration of an automated prompting mechanism with a more generalizable electronic health record-based checklist. PMID- 23939355 TI - The short-term prognosis of cardiogenic shock can be determined using hemodynamic variables: a retrospective cohort study*. AB - OBJECTIVES: Few reports address the relationship between hemodynamic variables and the cardiogenic shock outcome in critically ill patients. The present study aimed to investigate the association between hemodynamic variables and early cardiogenic shock mortality in critically ill patients. DESIGN: Retrospective, single-center cohort study. SETTING: Tertiary academic hospital's 36-bed multidisciplinary intensive care. PATIENTS: Initial presentation with cardiogenic shock. MEASUREMENTS AND MAIN RESULTS: The authors retrospectively analyzed medical information and the hemodynamic variables (recorded during the first 24 hr following admission to the ICU) of patients with cardiogenic shock. For all the patients, the Simplified Acute Physiology Score II, cardiac index, cardiac power index, and continuous hemodynamic values following the first 24 hours of admission were reviewed. Mortality within 28 days was the primary endpoint. All the variables were then compared with survival and nonsurvival status and those variables with a significant association in the univariate analysis were entered into a multivariate logistic regression model. Seventy-one patients were included. Among them, 26 (37%) died within 28 days after ICU admission and were classified as "nonsurvivors." The minimum value for diastolic arterial blood pressure during the first 24 hours was independently associated with the 28-day mortality in the univariate and multivariate analyses model. This model performed better than the model using the Simplified Acute Physiology Score II, even when assessing the effect of inotrope and vasoactive treatments at 24, 48, and 72 hours. CONCLUSIONS: In the first 24 hours of an ICU admission, the minimum diastolic arterial blood pressure was a hemodynamic variable that was independently associated with 28-day mortality in cardiogenic shock patients. PMID- 23939356 TI - Knowledge translation interventions for critically ill patients: a systematic review*. AB - OBJECTIVE: We systematically reviewed ICU-based knowledge translation studies to assess the impact of knowledge translation interventions on processes and outcomes of care. DATA SOURCES: We searched electronic databases (to July, 2010) without language restrictions and hand-searched reference lists of relevant studies and reviews. STUDY SELECTION: Two reviewers independently identified randomized controlled trials and observational studies comparing any ICU-based knowledge translation intervention (e.g., protocols, guidelines, and audit and feedback) to management without a knowledge translation intervention. We focused on clinical topics that were addressed in greater than or equal to five studies. DATA EXTRACTION: Pairs of reviewers abstracted data on the clinical topic, knowledge translation intervention(s), process of care measures, and patient outcomes. For each individual or combination of knowledge translation intervention(s) addressed in greater than or equal to three studies, we summarized each study using median risk ratio for dichotomous and standardized mean difference for continuous process measures. We used random-effects models. Anticipating a small number of randomized controlled trials, our primary meta analyses included randomized controlled trials and observational studies. In separate sensitivity analyses, we excluded randomized controlled trials and collapsed protocols, guidelines, and bundles into one category of intervention. We conducted meta-analyses for clinical outcomes (ICU and hospital mortality, ventilator-associated pneumonia, duration of mechanical ventilation, and ICU length of stay) related to interventions that were associated with improvements in processes of care. DATA SYNTHESIS: From 11,742 publications, we included 119 investigations (seven randomized controlled trials, 112 observational studies) on nine clinical topics. Interventions that included protocols with or without education improved continuous process measures (seven observational studies and one randomized controlled trial; standardized mean difference [95% CI]: 0.26 [0.1, 0.42]; p = 0.001 and four observational studies and one randomized controlled trial; 0.83 [0.37, 1.29]; p = 0.0004, respectively). Heterogeneity among studies within topics ranged from low to extreme. The exclusion of randomized controlled trials did not change our results. Single-intervention and lower-quality studies had higher standardized mean differences compared to multiple-intervention and higher-quality studies (p = 0.013 and 0.016, respectively). There were no associated improvements in clinical outcomes. CONCLUSIONS: Knowledge translation interventions in the ICU that include protocols with or without education are associated with the greatest improvements in processes of critical care. PMID- 23939357 TI - Validity of low-intensity continuous renal replacement therapy*. AB - OBJECTIVE: To study the hospital mortality of patients with severe acute kidney injury treated with low-intensity continuous renal replacement therapy. DESIGN: Multicenter retrospective observational study (Japanese Society for Physicians and Trainees in Intensive Care), combined with previously conducted multinational prospective observational study (Beginning and Ending Supportive Therapy). SETTING: Fourteen Japanese ICUs in 12 tertiary hospitals (Japanese Society for Physicians and Trainees in Intensive Care) and 54 ICUs in 23 countries (Beginning and Ending Supportive Therapy). PATIENTS: Consecutive adult patients with severe acute kidney injury requiring continuous renal replacement therapy admitted to the participating ICUs in 2010 (Japanese Society for Physicians and Trainees in Intensive Care, n = 343) and 2001 (Beginning and Ending Supportive Therapy Beginning and Ending Supportive Therapy, n = 1,006). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, variables at continuous renal replacement therapy initiation, continuous renal replacement therapy settings, and outcomes (ICU and hospital mortality and renal replacement therapy requirement at hospital discharge) were collected. Continuous renal replacement therapy intensity was arbitrarily classified into seven subclasses: less than 10, 10-15, 15-20, 20-25, 25-30, 30-35, and more than 35 mL/kg/hr. Multivariable logistic regression analysis was conducted to investigate risk factors for hospital mortality. The continuous renal replacement therapy dose in the Japanese Society for Physicians and Trainees in Intensive Care database was less than half of the Beginning and Ending Supportive Therapy database (800 mL/hr vs 2,000 mL/hr, p < 0.001). Even after adjusting for the body weight and dilution factor, continuous renal replacement therapy intensity was statistically different (14.3 mL/kg/hr vs 20.4 mL/kg/hr, p < 0.001). Patients in the Japanese Society for Physicians and Trainees in Intensive Care database had a lower ICU mortality (46.1% vs 55.3%, p = 0.003) and hospital mortality (58.6% vs 64.2%, p = 0.070) compared with patients in the Beginning and Ending Supportive Therapy database. In multivariable regression analysis after combining the two databases, no continuous renal replacement therapy intensity subclasses were found to be statistically different from the reference intensity (20-25 mL/kg/hr). Several sensitivity analyses (patients with sepsis, patients from Western countries in the Beginning and Ending Supportive Therapy database) confirmed no intensity outcome relationship. CONCLUSIONS: Continuous renal replacement therapy at a mean intensity of 14.3 mL/kg/hr did not have worse outcome compared with 20-25 mL/kg/hr of continuous renal replacement therapy, currently considered the standard intensity. However, our study is insufficient to support the use of low intensity continuous renal replacement therapy, and more studies are needed to confirm our findings. PMID- 23939358 TI - Effects of sitting position and applied positive end-expiratory pressure on respiratory mechanics of critically ill obese patients receiving mechanical ventilation*. AB - OBJECTIVE: To evaluate the extent to which sitting position and applied positive end-expiratory pressure improve respiratory mechanics of severely obese patients under mechanical ventilation. DESIGN: Prospective cohort study. SETTINGS: A 15 bed ICU of a tertiary hospital. PARTICIPANTS: Fifteen consecutive critically ill patients with a body mass index (the weight in kilograms divided by the square of the height in meters) above 35 were compared to 15 controls with body mass index less than 30. INTERVENTIONS: Respiratory mechanics was first assessed in the supine position, at zero end-expiratory pressure, and then at positive end expiratory pressure set at the level of auto-positive endexpiratory pressure. Second, all measures were repeated in the sitting position. MEASUREMENTS AND MAIN RESULTS: Assessment of respiratory mechanics included plateau pressure, auto positive end-expiratory pressure, and flow-limited volume during manual compression of the abdomen, expressed as percentage of tidal volume to evaluate expiratory flow limitation. In supine position at zero end-expiratory pressure, all critically ill obese patients demonstrated expiratory flow limitation (flow limited volume, 59.4% [51.3-81.4%] vs 0% [0-0%] in controls; p < 0.0001) and greater auto-positive end-expiratory pressure (10 [5-12.5] vs 0.7 [0.4-1.25] cm H2O in controls; p < 0.0001). Applied positive end-expiratory pressure reverses expiratory flow limitation (flow-limited volume, 0% [0-21%] vs 59.4% [51-81.4%] at zero end-expiratory pressure; p < 0.001) in almost all the obese patients, without increasing plateau pressure (24 [19-25] vs 22 [18-24] cm H2O at zero end expiratory pressure; p = 0.94). Sitting position not only reverses partially or completely expiratory flow limitation at zero end-expiratory pressure (flow limited volume, 0% [0-58%] vs 59.4% [51-81.4%] in supine obese patients; p < 0.001) but also results in a significant drop in auto-positive end-expiratory pressure (1.2 [0.6-4] vs 10 [5-12.5] cm H2O in supine obese patients; p < 0.001) and plateau pressure (15.6 [14-17] vs 22 [18-24] cm H2O in supine obese patients; p < 0.001). CONCLUSIONS: In critically ill obese patients under mechanical ventilation, sitting position constantly and significantly relieved expiratory flow limitation and auto-positive end-expiratory pressure resulting in a dramatic drop in alveolar pressures. Combining sitting position and applied positive end expiratory pressure provides the best strategy. PMID- 23939359 TI - Prediction of death in less than 60 minutes following withdrawal of cardiorespiratory support in ICUs. AB - OBJECTIVES: Half of all ICU patients die within 60 minutes of withdrawal of cardiorespiratory support. Prediction of which patients die before and after 60 minutes would allow changes in service organization to improve patient palliation, family grieving, and allocation of ICU beds. This study tested various predictors of death within 60 minutes and explored which clinical variables ICU specialists used to make their prediction. DESIGN AND SETTINGS: Prospective longitudinal cohort design (n = 765) of consecutive adult patients having withdrawal of cardiorespiratory support, in 28 ICUs in Australia. Primary outcome was death within 60 minutes following withdrawal of cardiorespiratory support. A random split-half method was used to make two independent samples for development and testing of the predictive indices. The secondary outcome was ICU Specialist prediction of death within 60 minutes. MEASUREMENTS AND MAIN RESULTS: Death within 60 minutes of withdrawal of cardiorespiratory support occurred in 377 (49.3%). ICU specialist opinion was the best individual predictor, with an unadjusted odds ratio of 15.42 (95% CI, 9.33-25.49) and an adjusted odds ratio of 8.44 (4.30-16.58). A predictive index incorporating the ICU specialist opinion and clinical variables had an area under the curve of 0.89 (0.86-0.92) and 0.84 (0.80-0.88) in the development and test sets, respectively; and a second index using only clinical variables had an area under the curve of 0.86 (0.82-0.89) and 0.78 (0.73-0.83). The ICU specialist prediction of death within 60 minutes was independently associated with five clinical variables: pH, Glasgow Coma Scale, spontaneous respiratory rate, positive end-expiratory pressure, and systolic blood pressure. CONCLUSION: ICU specialist opinion is probably the current clinical standard for predicting death within 60 minutes of withdrawal of cardiorespiratory support. This approach is supported by this study, although predictive indices restricted to clinical variables are only marginally inferior. Either approach has a clinically useful level of prediction that would allow ICU service organization to be modified to improve care for patients and families and use ICU beds more efficiently. PMID- 23939360 TI - Should we rescue patients with the death rattle? PMID- 23939361 TI - ICU-acquired swallowing disorders. AB - OBJECTIVES: Patients hospitalized in the ICU can frequently develop swallowing disorders, resulting in an inability to effectively transfer food, liquids, and pills from their mouth to stomach. The complications of these disorders can be devastating, including aspiration, reintubation, pneumonia, and a prolonged hospital length of stay. As a result, critical care practitioners should understand the optimal diagnostic strategies, proposed mechanisms, and downstream complications of these ICU-acquired swallowing disorders. DATA SOURCES: Database searches and a review of the relevant medical literature. DATA SYNTHESIS: A significant portion of the estimated 400,000 patients who annually develop acute respiratory failure, require endotracheal intubation, and survive to be extubated are determined to have dysfunctional swallowing. This group of swallowing disorders has multiple etiologies, including local effects of endotracheal tubes, neuromuscular weakness, and an altered sensorium. The diagnosis of dysfunctional swallowing is usually made by a speech-language pathologist using a bedside swallowing evaluation. Major complications of swallowing disorders in hospitalized patients include aspiration, reintubation, pneumonia, and increased hospitalization. The national yearly cost of swallowing disorders in hospitalized patients is estimated to be over $500 million. Treatment modalities focus on changing the consistency of food, changing mealtime position, and/or placing feeding tubes to prevent aspiration. CONCLUSIONS: Swallowing disorders are costly and clinically important in a large population of ICU patients. The development of effective screening strategies and national diagnostic standards will enable further studies aimed at understanding the precise mechanisms for these disorders. Further research should also concentrate on identifying modifiable risk factors and developing novel treatments aimed at reducing the significant burden of swallowing dysfunction in critical illness survivors. PMID- 23939362 TI - Effectiveness of lipid-lowering therapy among a sample of patients in Colombia. AB - OBJECTIVE: To determine the effectiveness of lipid-lowering therapy in a sample of patients affiliated with the Sistema General de Seguridad Social en Salud (the Colombian health system). METHODS: A cross-sectional study was conducted from 1 January 2010-30 June 2011. From a total of 8 316 patients in 10 cities, a random sample of 600 was stratified according to dyslipidemia. Information on sociodemographic and anthropometric characteristics, risk factors, and pharmacological and laboratory variables were obtained from medical records. RESULTS: Subjects were predominantly female (56.2%), with a mean age of 65.1 +/- 11.5 years; 93.2% had hypertension; 29.0%, diabetes mellitus; and 10.2%, a history of myocardial infarction. The patients were being treated with lovastatin (84.1%) or gemfibrozil (12.3%)-both at doses below what is recommended-or atorvastatin (1.8%). In patients with high cardiovascular risk, 38.6% achieved goals for low-density lipoprotein cholesterol (LDL-C) levels (<100 mg/dL). Among those at moderate risk, 49.4% reached the target level (< 130 mg/dL). On average, there was a 4.9% reduction in LDL-C. Sex, age, history of cardiovascular disease and/or diabetes mellitus, use of hydrochlorothiazide, and poor therapy adherence were statistically associated with a lack of dyslipidemia control. CONCLUSIONS: Because a lack LDL-C control occurred in patients with two or more of the following variables: male, more than 55 years of age, diabetes and/or a history of cardiovascular disease, received lower doses of lovastatin, or non-adherent to treatment, it is recommended that medication be increased based on clearly defined therapeutic goals and that comorbidities be assessed and effectively treated. PMID- 23939363 TI - [Innovation in the organization of health services delivery within the Metropolitan System of Solidarity in Peru]. AB - OBJECTIVE: Based on the results achieved to date by the Metropolitan System of Solidarity (SISOL) in Peru, this study undertook to analyze the extent to which SISOL has contributed to innovation in the organization of health services delivery. METHODS: SISOL performance indicators were analyzed and compared with those of other health services delivery models in Peru, drawing on data from a survey of 4 570 SISOL users conducted in the last quarter of 2011, National Household Surveys from 2003 through 2011, and statistical data from the Peruvian Ministry of Health and Social Security. RESULTS: SISOL rated high in terms of growth of the demand served in Lima, productivity of human resources in office visits, and levels of user satisfaction. These results are attributed to: (a) the presence of specialists at the first level of care; (b) an innovative public private structure, as opposed to outsourcing; and (c) a system of incentives based on shared risk management. CONCLUSIONS: The findings support the need for primary health care renewal, especially in urban areas to reduce the proliferation of unnecessary levels and sublevels of care. They also point to the possibility of developing synergistic public-private partnerships in which both sectors share risks and act in collaboration within a single service system. And finally, they indicate that primary care needs to be articulated into the segmented models. PMID- 23939364 TI - Small area variation in diabetes prevalence in Puerto Rico. AB - OBJECTIVE: To estimate the 2009 prevalence of diagnosed diabetes in Puerto Rico among adults >= 20 years of age in order to gain a better understanding of its geographic distribution so that policymakers can more efficiently target prevention and control programs. METHODS: A Bayesian multilevel model was fitted to the combined 2008-2010 Behavioral Risk Factor Surveillance System and 2009 United States Census data to estimate diabetes prevalence for each of the 78 municipios (counties) in Puerto Rico. RESULTS: The mean unadjusted estimate for all counties was 14.3% (range by county, 9.9%-18.0%). The average width of the confidence intervals was 6.2%. Adjusted and unadjusted estimates differed little. CONCLUSIONS: These 78 county estimates are higher on average and showed less variability (i.e., had a smaller range) than the previously published estimates of the 2008 diabetes prevalence for all United States counties (mean, 9.9%; range, 3.0%-18.2%). PMID- 23939365 TI - [Trend in cervical cancer mortality in Chile: application of joinpoint regression models]. AB - OBJECTIVE: To identify and model changes in the cervical cancer mortality trend in Chile between 1990 and 2009 in order to contribute to the design of health policies on cervical cancer. METHODS: The study analyzed deaths from cervical cancer in Chile between 1990 and 2009. The cases were identified by the codes ICD 9 180 and ICD-10 C-53. The population at risk was calculated on the basis of projections by the National Statistics Institute of Chile. Mortality was modeled using Poisson regression analysis, including the variables of age in decades starting at age 30 and time interval in calendar periods and the term of interaction between the two variables. A joinpoint regression model, stratified by age group, was used to assess changes in the trend. In both models, the annual percentage of change (APC) was used as a summary measure. RESULTS: During the period studied, the APC in Chile was -4%. Women aged 40 to 49 experienced the greatest reduction in mortality (incidence rate ratio = 0.98; P < 0.05) (reference group: women aged 30 to 39). Those with the least reduction in mortality were women over 80 (APC -1.18%). The joinpoint model identified six significant changes in the time trend for the women studied: the greatest reductions occurred in 1999-2002 and 2003-2009, with APCs of -6.9 and -4%, respectively. CONCLUSIONS: Mortality from cervical cancer exhibited a downward trend during the period studied, and the trend was more pronounced among women in the youngest age group. PMID- 23939366 TI - Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in Mexico. AB - OBJECTIVE: To assess the safety and immune responses induced by a 13-valent pneumococcal conjugate vaccine (PCV13) after immunization of infants in Mexico. METHODS: PCV13 was given with other routine childhood vaccinations to 225 infants in Mexico at ages 2, 4, 6, and 12 months. RESULTS: The proportions of subjects achieving immunoglobulin G (IgG) concentrations >=0.35 ug/mL after the infant series and toddler dose were >=93.1% and >=96.7%, respectively, for all 13 serotypes. The serotype-specific pneumococcal IgG geometric mean concentrations after the infant series and toddler dose ranged from 1.18 to 9.13 ug/mL and from 1.62 to 15.41 ug/mL, respectively. The most common local reaction and systemic event after each dose were tenderness and irritability, respectively. Most fever was mild; no fever >40.0 degrees C (i.e., severe) was reported. One subject withdrew because of Kawasaki disease 5 days after the first dose of vaccines, but this condition was not considered related to PCV13. CONCLUSIONS: Overall, PCV13 administered with routine pediatric vaccines was immunogenic and safe in healthy infants in Mexico. PMID- 23939367 TI - Molecular characterization of Streptococcus pneumoniae serotype 1 invasive isolates in Colombia. AB - OBJECTIVE: To determine the genetic relationship between Streptococcus pneumoniae serotype 1 Colombian isolates recovered from invasive disease between 1994 and 2011 and recognized serotype 1 international clones. METHODS: A total of 135 S. pneumoniae serotype 1 isolates with epidemiological and antimicrobial susceptibility data (Clinical and Laboratory Standards Institute, 2012) were studied. The genetic relationship with recognized international clones was established by pulsed-field gel electrophoresis (PFGE) with SmaI restriction enzyme. Multilocus sequence typing (MLST) was standardized to determine the sequence type (ST) in seven isolates representing different clonal groups. Control and reference strain R6, and clones Sweden1 ST217, Sweden1 ST304, Sweden1 ST306, and USA1 ST615, were used. RESULTS: PFGE revealed that 89.7% of the isolates were associated with Sweden1 ST306, 3.7% were associated with Sweden1 ST304, and 6.6% were not clonally related. Using MLST, ST306 was confirmed in six isolates and ST304 in one. CONCLUSIONS: In contrast to Brazil and the United States, where clones Sweden1 ST304 and ST227 prevail, invasive disease caused by S. pneumoniae serotype 1 in Colombia is principally associated with the dispersion of isolates related to clone Sweden1 ST306. PMID- 23939368 TI - Oral rapid test: an alternative to traditional HIV screening in Chile. AB - OBJECTIVE: To compare the sensitivity and specificity of an Oral Rapid Test (ORT) to that of the Enzyme-Linked Immunosorbent Assay (ELISA) for HIV testing in Santiago, Chile; to track the number of study participants returning for ELISA testing results; and to analyze the participants' perceptions of the ORT compared to the ELISA. METHODS: A total of 497 people were recruited in Santiago, Chile: 153 had previously tested positive for HIV, and 344 were of unknown status. Participants were tested for HIV using both the ELISA and the ORT to examine and compare specificity and sensitivity. Qualitative data were collected from 22 participants to compare perceptions of the testing experience with ORT versus ELISA. RESULTS: The ELISA reported 184 (37%) of the 497 participants as being "positive" for HIV antibodies; the ORT showed 181 (36.4%) as being "reactive" for HIV. The ORT showed a sensitivity of 98.4% (95.7%-99.9%, 95% Confidence Interval) and specificity of 100%. The Kappa test produced K = 0.983 (P < 0.0001). Of the 344 participants whose HIV status was unknown at the start of the study, 55 failed to return for their ELISA results. Participants positively perceived ORT as having reduced both waiting time and anxiety over obtaining their test results. ORT oral swabbing appeared more practical and less invasive than drawing blood for the ELISA. CONCLUSIONS: The ORT and ELISA were statistically equal in specificity and sensitivity. ORT provides quicker results, potentially ensuring that more people receive them, and does not require handling of or exposure to potentially hazardous blood products. PMID- 23939369 TI - [Correlation between socioeconomic factors and in-hospital mortality from ischemic stroke in a hospital cohort in Colombia, 2003-2006]. AB - OBJECTIVE: To determine if there is a correlation between socioeconomic conditions and in-hospital mortality (IHM) from ischemic stroke in a sample of the Colombian population and identify the chain of events that determine that association. METHODS: Prospective study of a hospital cohort of patients with ischemic stroke in four Colombian clinical referral institutions-located in Floridablanca, Bucaramanga, Bogota, and Medellin-between February 2003 and December 2006. Hierarchical analysis was used to group the socioeconomic variables into three levels, and their relationship to IHM due to ischemic stroke was assessed in a Cox proportional hazards model. RESULTS: The IHM rate was 9.4% in the 253 patients included in the study. In the analysis by levels, mortality was inversely associated with educational level (advanced to primary), monthly income (>= minimum wage), and participation in the contributory health system. When the three levels were combined in the hierarchical analysis, affiliation with the contributory system was the only association that maintained its statistical significance (RR 0.35; CI 95%: 0.13-0.96; P = 0.04). CONCLUSIONS: The results indicate that, in Colombia, being affiliated with the contributory health system is an independent protective factor against IHM after an ischemic stroke. The education-income-access to health services sequence is a possible explanation for the relationship between socioeconomic conditions and the clinical outcome of these events. Strategies should be designed to mitigate the differences in the quality and distribution of health services in the Colombian population. PMID- 23939370 TI - [Self-rating of oral health according to the Oral Health Impact Profile and associated factors: a systematic review]. AB - OBJECTIVE: To systematically evaluate the literature to investigate associations between social, demographic, economic, psychosocial, and behavioral factors and the self-perception of oral health measured using the Oral Health Impact Profile (OHIP). METHODS: In this systematic review of the literature, the Preferred Reporting Items for Systematic Reviews (PRISMA) were adapted for the performance of a qualitative metasummary, without meta-analysis. Articles about oral health and associated factors with implications for quality of life were selected, with a focus on the tool for self-rating of the oral health-disease process, the OHIP. Pubmed/National Library of Medicine (NLM) and the Virtual Health Library (Biblioteca Virtual em Saude - BVS/BIREME) were searched. Articles published between 2001 and 2011 were included. The following Medical Subject Headings (MeSH) were employed: oral health, quality of life, sickness impact profile, and socioeconomic factors. RESULTS: Of 57 articles identified, 20 met the inclusion criteria. The metasummary revealed that a poor self-perception of oral health was associated with unfavorable social, economic, demographic, and psychosocial factors, as well as with undesirable habits and poor clinical oral conditions. CONCLUSIONS: There is consensus in the literature about the influence of the investigated factors on the self-perception of oral health and on quality of life. The OHIP is an important aid for determining oral health needs and for developing strategies to control/reduce disease and promote oral health, with a consequent positive impact on quality of life. PMID- 23939371 TI - Influenza among the elderly in the Americas: a consensus statement. AB - Influenza exacts a heavy burden on the elderly, a segment of the population that is estimated to experience rapid growth in the near future. In the past decade most developed and several developing countries have recommended influenza vaccination for those > 65 years of age. The World Health Organization (WHO) set a goal of 75% influenza vaccination coverage among the elderly by 2010, but it was not achieved. In 2011, the Technical Advisory Group at the Pan American Health Organization, Regional Office of WHO for the Americas, reiterated the influenza vaccine recommendation for older adults. Relatively little information has been compiled on the immunological aspect of aging or on reducing its impact, information particularly relevant for clinicians and gerontologist with firsthand experience confronting its effects. To fill this data gap, in 2012 the Americas Health Foundation (Washington, D.C., United States) and the nonprofit, Fighting Infectious Diseases in Emerging Countries (Miami, Florida, United States), convened a panel of Latin American clinicians and gerontologists with expertise in influenza to discuss key issues and develop a consensus statement. The major recommendations were to improve influenza surveillance throughout Latin America so that its impact can be quantified; and to conduct laboratory confirmation of influenza for all patients who have flu-like symptoms and are frail, immunosuppressed, have comorbidities, are respiratory compromised, or have been admitted to a hospital. The panel also noted that: since evidence for antivirals in the elderly is unclear, their use should be handled on a case-by-case basis; despite decreased immunological response, influenza vaccination in older adults is still crucial; indirect immunization strategies should be encouraged; and traditional infection control measures are essential in long-term care facilities. PMID- 23939372 TI - New insights into hydrothermal vent processes in the unique shallow-submarine arc volcano, Kolumbo (Santorini), Greece. AB - We report on integrated geomorphological, mineralogical, geochemical and biological investigations of the hydrothermal vent field located on the floor of the density-stratified acidic (pH ~ 5) crater of the Kolumbo shallow-submarine arc-volcano, near Santorini. Kolumbo features rare geodynamic setting at convergent boundaries, where arc-volcanism and seafloor hydrothermal activity are occurring in thinned continental crust. Special focus is given to unique enrichments of polymetallic spires in Sb and Tl (+/-Hg, As, Au, Ag, Zn) indicating a new hybrid seafloor analogue of epithermal-to-volcanic-hosted massive-sulphide deposits. Iron microbial-mat analyses reveal dominating ferrihydrite-type phases, and high-proportion of microbial sequences akin to "Nitrosopumilus maritimus", a mesophilic Thaumarchaeota strain capable of chemoautotrophic growth on hydrothermal ammonia and CO2. Our findings highlight that acidic shallow-submarine hydrothermal vents nourish marine ecosystems in which nitrifying Archaea are important and suggest ferrihydrite-type Fe(3+) (hydrated)-oxyhydroxides in associated low-temperature iron mats are formed by anaerobic Fe(2+)-oxidation, dependent on microbially produced nitrate. PMID- 23939373 TI - The spatial and sequential immobilisation of cytochrome c at adjacent electrodes. AB - Two adjacent electrode surfaces were modified in a sequential manner with self assembled thiol layers from the same solution using conditions (aqueous buffer at neutral pH) suitable for applications with proteins. A faradaic response was obtained from the redox protein, cytochrome c, independently immobilised at each surface. PMID- 23939374 TI - Characterization of a new class of androgen receptor antagonists with potential therapeutic application in advanced prostate cancer. AB - The human androgen receptor plays a major role in the development and progression of prostate cancer and represents a well-established drug target. All clinically approved androgen receptor antagonists possess similar chemical structures and exhibit the same mode of action on the androgen receptor. Although initially effective, resistance to these androgen receptor antagonists usually develops and the cancer quickly progresses to castration-resistant and metastatic states. Yet even in these late-stage patients, the androgen receptor is critical for the progression of the disease. Thus, there is a continuing need for novel chemical classes of androgen receptor antagonists that could help overcome the problem of resistance. In this study, we implemented and used the synergetic combination of virtual and experimental screening to discover a number of new 10-benzylidene-10H anthracen-9-ones that not only effectively inhibit androgen receptor transcriptional activity, but also induce almost complete degradation of the androgen receptor. Of these 10-benzylidene-10H-anthracen-9-one analogues, a lead compound (VPC-3033) was identified that showed strong androgen displacement potency, effectively inhibited androgen receptor transcriptional activity, and possesses a profound ability to cause degradation of androgen receptor. Notably, VPC-3033 exhibited significant activity against prostate cancer cells that have already developed resistance to the second-generation antiandrogen enzalutamide (formerly known as MDV3100). VPC-3033 also showed strong antiandrogen receptor activity in the LNCaP in vivo xenograft model. These results provide a foundation for the development of a new class of androgen receptor antagonists that can help address the problem of antiandrogen resistance in prostate cancer. PMID- 23939375 TI - Overcoming platinum resistance in preclinical models of ovarian cancer using the neddylation inhibitor MLN4924. AB - The nearly ubiquitous development of chemoresistant disease remains a major obstacle against improving outcomes for patients with ovarian cancer. In this investigation, we evaluated the preclinical activity of MLN4924, an investigational inhibitor of the NEDD8-activating enzyme, in ovarian cancer cells. Efficacy of MLN4924 both alone and in combination with platinum was assessed. Overall, single-agent MLN4924 exhibited moderate activity in ovarian cancer cell lines. However, the combination of MLN4924 with cisplatin or carboplatin produced synergistic effects in SKOV3 and ES2 cells, as well as in primary ovarian cancer cell lines established from high-grade serous, clear cell, and serous borderline ovarian tumors. The efficacy of cisplatin plus MLN4924 was also evident in several in vitro models of platinum-resistant ovarian cancer. Mechanistically, the combination of cisplatin and MLN4924 was not associated with DNA re-replication, altered platinum-DNA adduct formation, abrogation of FANCD2 monoubiquitination, or CHK1 phosphorylation. An siRNA screen was used to investigate the contribution of each member of the cullin RING ligase (CRL) family of E3 ubiquitin ligases, the best-characterized downstream mediators of MLN4924's biologic effects. Cisplatin-induced cytotoxicity was augmented by depletion of CUL3, and antagonized by siCUL1 in both ES2 and SKOV3 ovarian cancer cells. This investigation identifies inhibition of neddylation as a novel mechanism for overcoming platinum resistance in vitro, and provides a strong rationale for clinical investigations of platinum and MLN4924 combinations in ovarian cancer. PMID- 23939376 TI - A urokinase receptor-derived peptide inhibiting VEGF-dependent directional migration and vascular sprouting. AB - The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration, and uPAR88-92 is the minimal sequence required to induce cell motility. We previously showed that soluble forms of uPAR elicit angiogenic responses through their uPAR88-92 chemotactic sequence and that the synthetic peptide SRSRY exerts similar effects. By a drug design approach, based on the conformational analysis of the uPAR88-92 sequence, we developed peptides (pERERY, RERY, and RERF) that potently inhibit signaling triggered by uPAR88-92. In this study, we present evidence that these peptides are endowed also with a clear-cut antiangiogenic activity, although to different extents. The most active, RERF, prevents tube formation by human endothelial cells exposed to SRSRY. RERF also inhibits VEGF-triggered endothelial cell migration and cord-like formation in a dose-dependent manner, starting in the femtomolar range. RERF prevents F-actin polymerization, recruitment of alphavbeta3 integrin at focal adhesions, and alphavbeta3/VEGFR2 complex formation in endothelial cells exposed to VEGF. At molecular level, the inhibitory effect of RERF on VEGF signaling is shown by the decreased amount of phospho-FAK and phospho-Akt in VEGF-treated cells. In vivo, RERF prevents VEGF-dependent capillary sprouts originating from the host vessels that invaded angioreactors implanted in mice and neovascularization induced by subcorneal implantation of pellets containing VEGF in rabbits. Consistently, RERF reduced the growth and vascularization rate of tumors formed by HT1080 cells injected subcutaneously in the flanks of nude mice, indicating that RERF is a promising therapeutic agent for the control of diseases fuelled by excessive angiogenesis such as cancer. PMID- 23939377 TI - PI3K stimulates DNA synthesis and cell-cycle progression via its p55PIK regulatory subunit interaction with PCNA. AB - Previously, we have shown that p55PIK, an isoform of class I(A) phosphoinositide 3-kinase (PI3K), specifically interacts with important cell-cycle regulators, such as retinoblastoma (Rb), to promote cell-cycle progression. Here, we used the glutathione S-transferase pull-down assay to identify other p55PIK-interacting proteins besides Rb in a Rb-deficient cell line and found that p55PIK interacted with proliferation cell nuclear antigen (PCNA), which plays a key role in coordinating both initiation of the leading strand DNA replication and discontinuous lagging strand synthesis. Overexpression of p55PIK increased, and knockdown decreased, DNA synthesis and DNA replication by modulating the binding of DNA polymerase delta (Poldelta) to PCNA. Moreover, a cell-permeable peptide containing the N-terminal-binding domain of p55PIK (TAT-N24) disrupted the p55PIK PCNA interaction in cancer cells, and also inhibited the DNA synthesis and tumor growth in cell culture and in vivo. Altogether, our results show that the p55PIK PCNA interaction is important in regulating DNA synthesis and contributes to tumorigenesis. Furthermore, the p55PIK-PCNA interaction provides a potential new target for anticancer drug development. PMID- 23939378 TI - EGFR inhibition promotes an aggressive invasion pattern mediated by mesenchymal like tumor cells within squamous cell carcinomas. AB - Squamous cell carcinomas (SCC) with an infiltrative invasion pattern carry a higher risk of treatment failure. Such infiltrative invasion may be mediated by a mesenchymal-like subpopulation of malignant cells that we have previously shown to arise from epithelial-mesenchymal transition (EMT) and resist epidermal growth factor receptor (EGFR) targeting. Here, we show that SCCs with infiltrative, high risk invasion patterns contain abundant mesenchymal-like cells, which are rare in tumors with low-risk patterns. This cellular heterogeneity was modeled accurately in three-dimensional culture using collagen-embedded SCC spheroids, which revealed distinct invasive fronts created by collective migration of E-cadherin positive cells versus infiltrative migration of individual mesenchymal-like cells. Because EGFR expression by mesenchymal-like cells was diminished in the spheroid model and in human SCCs, we hypothesized that SCCs shift toward infiltrative invasion mediated by this subpopulation during anti-EGFR therapy. Anti-EGFR treatment of spheroids using erlotinib or cetuximab enhanced infiltrative invasion by targeting collective migration by E-cadherin-positive cells while sparing mesenchymal-like cells; by contrast, spheroid invasion in absence of mesenchymal-like cells was abrogated by erlotinib. Similarly, cetuximab treatment of xenografts containing mesenchymal-like cells created an infiltrative invasive front composed of this subpopulation, whereas no such shift was observed upon treating xenografts lacking these cells. These results implicate mesenchymal-like SCC cells as key mediators of the infiltrative invasion seen in tumors with locally aggressive behavior. They further show that EGFR inhibition can promote an infiltrative invasion front composed of mesenchymal-like cells preferentially in tumors where they are abundant before therapy. PMID- 23939379 TI - Histone deacetylase regulation of ATM-mediated DNA damage signaling. AB - Ataxia-telangiectasia mutated (ATM) is a major regulator of the DNA damage response. ATM promotes the activation of BRCA1, CHK2, and p53 leading to the induction of response genes such as CDKN1A (p21), GADD45A, and RRM2B that promote cell-cycle arrest and DNA repair. The upregulation of these response genes may contribute to resistance of cancer cells to genotoxic therapies. Here, we show that histone deacetylases (HDAC) play a major role in mitigating the response of the ATM pathway to DNA damage. HDAC inhibition decreased ATM activation and expression, and attenuated the activation of p53 in vitro and in vivo. Select depletion of HDAC1 and HDAC2 was sufficient to modulate ATM activation, reduce GADD45A and RRM2B induction, and increase sensitivity to DNA strand breaks. The regulation of ATM by HDAC enzymes therefore suggests a vital role for HDAC1 and HDAC2 in the DNA damage response, and the potential use of the ATM pathway as a pharmacodynamic marker for combination therapies involving HDAC inhibitors. PMID- 23939380 TI - Novel inhibitors of cyclin-dependent kinases combat hepatocellular carcinoma without inducing chemoresistance. AB - Treatment options for hepatocellular carcinoma using chemotherapeutics at intermediate and advanced stages of disease are limited as patients most rapidly escape from therapy and succumb to disease progression. Mechanisms of the hepatic xenobiotic metabolism are mostly involved in providing chemoresistance to therapeutic compounds. Given the fact that the aberrant activation of cyclin dependent kinases (CDK) is frequently observed in hepatocellular carcinomas, we focused on the efficacy of the novel compounds BA-12 and BP-14 that antagonize CDK1/2/5/7 and CDK9. Inhibition of those CDKs in human hepatocellular carcinoma cell lines reduced the clonogenicity by arresting cells in S-G2 and G2-M phase of the cell cycle and inducing apoptosis. In contrast, primary human hepatocytes failed to show cytotoxicity and apoptosis. No loss of chemosensitivity was observed in hepatocellular carcinoma cells after long-term exposure to inhibitors. In vivo, treatment of xenografted human hepatocellular carcinomas with BA-12 or BP-14 effectively repressed tumor formation. Moreover, BA-12 or BP 14 significantly diminished diethylnitrosamine (DEN)-induced hepatoma development in mice. These data show that BA-12 or BP-14 exhibit strong antitumorigenic effects in the absence of chemoresistance, resulting in a superior efficacy compared with currently used chemotherapeutics in hepatocellular carcinomas. PMID- 23939381 TI - Ventricular dilatation in ex-prematures: only confined to the occipital region? MRI-based normative standards for 19-year-old ex-prematures without major handicaps. AB - BACKGROUND: Premature birth may be associated with white matter injury later developing with widening of the ventricles. However, population-based data on normal ventricular size by age are sparse, making the evaluation of possible ventricular dilatation difficult. PURPOSE: To present the linear measurements of the ventricular system, to compare these to subjectively assessed ventricular size, and to examine differences in ventricular size between ex-prematures and controls. MATERIAL AND METHODS: Eligible survivors (n = 113) from the initial birth cohort (n = 217, born in 1986-1988, birth weight <2000 g) underwent MRI during 2006-2007. One hundred and three were ex-premature and included in the study. The ventricular size was subjectively judged by a pediatric neuroradiologist, and scored as normal, mildly, moderately, or severely dilated. Objective measurements, including width and depth of the frontal and occipital horns, were performed in a blinded fashion, by a pediatric radiologist. RESULTS: The normative standards for different parts of the ventricular system in ex premature young adults varied considerably. We found significant associations between the objective measurements and the subjectively classification of ventricular dilatation. Ex-prematures had smaller heads than those born term (control group). After adjustment for head circumference, there were no significant group differences regarding the frontal horns, but the occipital horns were proportionately wider among ex-prematures. CONCLUSION: Young adults born prematurely, with a birth weight <2000 g, do not have larger lateral ventricles than healthy controls born term, even after correcting for a smaller head size. However, they do have larger occipital horns, confirming previous studies and strengthening our belief of a specific vulnerability of the occipital region. PMID- 23939382 TI - MRI findings before and after prolapse surgery. AB - BACKGROUND: Therapeutical outcome after prolapse surgery is evaluated using a standardized grading system based on maximum prolapse extent, which might not provide the full picture of the patient's subjective outcome. We therefore applied an evaluation method, which is detached from a grading system. PURPOSE: To evaluate the impact of pelvic organ mobility in dynamic magnetic resonance imaging (MRI) before and after mesh-repair surgery in patients with symptomatic pelvic organ prolapse. MATERIAL AND METHODS: To obtain measurements, we performed parasagittal T2-weighted turbo spin echo sequence at rest (TR, 3460 ms; TE, 85 ms; matrix, 512; slice thickness [ST], 5 mm), parasagittal T2-weighted true fast imaging with steady-state precession (TrueFISP) single-shot sequence during straining (TR, 397.4 ms; TE, 1.5 ms; matrix, 256; ST, 8 mm), and parasagittal T2 weighted TrueFISP sequence at maximum strain (TR, 4.3 ms; TE, 2.15 ms; matrix, 256; ST, 5 mm) at 1.5 T MRI. Pelvic organ prolapse (anatomical landmarks: bladder, cervix, pouch, rectum) was measured perpendicularly with reference to the pubococcygeal and the midpubic line. Pelvic organ mobility was defined as the difference between the measured distance at rest and at maximum strain for each anatomical landmark. All patients underwent mesh-repair procedure. Eighty patients could be included in this short-term follow-up study. Due to the physical diagnosis of pelvic organ prolapse, 51 underwent anterior mesh repair, 16 underwent posterior mesh repair, and 13 underwent total mesh repair. Surgery was performed by one surgeon, using mesh implants from several manufacturers. RESULTS: Median values of maximum organ prolapse for bladder, cervix, pouch, and rectum preoperatively were 2.54 cm, 0.33 cm, 2.47 cm, and 0.32 cm, respectively, and 12 weeks postoperatively 0.87 cm, -1.79 cm, 1.49 cm, and 0.49 cm, respectively. Highly significant improvement (P < 0.001) of pelvic organ mobility was observed in the treated compartment at 4- and 12-week follow-up. Physical evaluation 12 weeks after mesh-repair showed an asymptomatic POP-Q stage I, if any. CONCLUSION: Dynamic MRI is useful in visualizing the maximum extent of pelvic organ prolapse, as the evaluation of pelvic organ mobility documents the intraindividual therapeutic outcome detached from a grading system based on maximal prolapse values. PMID- 23939383 TI - The costs and effects of contrast-enhanced magnetic resonance angiography and digital substraction angiography on quality of life in patients with peripheral arterial disease. AB - BACKGROUND: Contrast-enhanced magnetic resonance angiography (MRA) and intra arterial digital subtraction angiography (DSA) both have a high diagnostic performance in the imaging of peripheral arterial occlusive disease (PAOD). However, little is known about the effects of initial, preoperative imaging using MRA or DSA on quality of life (QoL) in relation to costs (cost-utility). PURPOSE: To compare cost-utility of treatment strategies using either MRA or DSA as the principal imaging tool, related to QoL, in patients with PAOD. MATERIAL AND METHODS: In a prospective subgroup analysis of patients randomized between MRA and DSA (n = 79) for preoperative imaging, QoL questionnaires (SF-36) were obtained at randomization and at 4-month follow-up. Cost-effectiveness from hospital perspective was subsequently compared between groups and the difference in gained or lost QoL per ? spent assessed using bootstrap analysis. RESULTS: No difference in quality of life was found. A treatment trajectory employing MRA as the principal imaging modality was almost 20% cheaper, leading to a better cost utility ratio in favor of MRA. CONCLUSION: A treatment plan for peripheral arterial occlusive disease employing MRA versus DSA as the principal imaging modality yields a better cost/QoL ratio for MRA. PMID- 23939384 TI - Regional variations and age-related changes in arginine metabolism in the rat brain stem and spinal cord. AB - Accumulating evidence suggests that the metabolism of l-arginine, a metabolically versatile amino acid, is critically involved in the aging process. The present study compared the activity and protein expression of nitric oxide synthase (NOS) and arginase, and the levels of l-arginine and its eight down-stream metabolites in the brain stem (pons and medulla) and the cervical spinal cord in 3- (young) and 22- (aged) month-old male Sprague-Dawley rats. Total NOS activity was significantly reduced with age in the spinal cord (but not brain stem), and there were no age-related changes in arginase activity in both regions. Western blot revealed decreased protein expression of endothelial NOS, but not neuronal NOS, with age in both regions. Furthermore, there were significantly decreased l arginine, glutamate, GABA and spermine levels and increased putrescine and spermidine levels with age in both regions. Although the absolute concentrations of l-arginine and six metabolites were significantly different between the brain stem and spinal cord in both age groups, there were similar clusters between l arginine and its three main metabolites (l-citrulline, l-ornithine and agmatine) in both regions, which changed as a function of age. These findings, for the first time, demonstrate the regional variations and age-related changes in arginine metabolism in the rat brain stem and spinal cord. Future research is required to understand the functional significance of these changes and the underlying mechanisms. PMID- 23939385 TI - Visualizing short-range charge transfer at the interfaces between ferromagnetic and superconducting oxides. AB - The interplay between antagonistic superconductivity and ferromagnetism has been a interesting playground to explore the interaction between competing ground states. Although this effect in systems of conventional superconductors is better understood, the framework of the proximity effect at complex-oxide-based superconductor/ferromagnet interfaces is not so clear. The main difficulty originates from the lack of experimental tools capable of probing the interfaces directly with high spatial resolution. Here we harness cross-sectional scanning tunnelling microscopy and spectroscopy together with atomic-resolution electron microscopy to understand the buried interfaces between cuprate and manganite layers. The results show that the fundamental length scale of the electronic evolution between YBa2Cu3O(7-delta) (YBCO) and La2/3Ca1/3MnO3 (LCMO) is confined to the subnanometre range. Our findings provide a complete and direct microscopic picture of the electronic transition across the YBCO/LCMO interfaces, which is an important step towards understanding the competition between ferromagnetism and superconductivity in complex-oxide heterostructures. PMID- 23939386 TI - Direct gravimetric sensing of GBL by a molecular recognition process in organic cage compounds. AB - Organic cages were identified as highly potent affinity materials for the tracing of gamma-butyrolactone. The selectivity over ethanol and water is based on the interior functional groups which allow preferential hydrogen bonding to the target analyte. PMID- 23939387 TI - Female university students' physical activity levels and associated factors--a cross-sectional study in southwestern Saudi Arabia. AB - BACKGROUND: The high prevalence of physical inactivity in Saudi Arabia is a growing challenge to public health. This study aimed to examine the prevalence of physical activity (PA) and associated factors among female university students. METHODS: This cross-sectional study involved 663 randomly selected female university students who completed the Arab Teens Life Style questionnaire. Data included measurements of anthropometric, socioeconomic and environmental factors, as well as self-reported PA. Ordinal regression was used to identify associated factors with low, moderate and high PA levels. RESULTS: The mean age of participants was 20.4 years (SD 1.5). Mean BMI of the students in relation to PA were 23.0, 22.9, 22.1 for high, moderate and low levels of activity, respectively. The analysis revealed significantly higher PA levels among married students, those with high educated mothers, and those who lived far from parks, and lower activity levels among underweight students. CONCLUSIONS: This study raises four important determinants for female university students' PA levels. These factors could be of great importance in the endeavor to prevent the health threatening increase in physical inactivity patterns and thus non-communicable diseases and obesity where the focus should be on the specific situation and needs of women in Saudi Arabia. PMID- 23939388 TI - A review of programs that targeted environmental determinants of Aboriginal and Torres Strait Islander health. AB - OBJECTIVE: Effective interventions to improve population and individual health require environmental change as well as strategies that target individual behaviours and clinical factors. This is the basis of implementing an ecological approach to health programs and health promotion. For Aboriginal People and Torres Strait Islanders, colonisation has made the physical and social environment particularly detrimental for health. METHODS AND RESULTS: We conducted a literature review to identify Aboriginal health interventions that targeted environmental determinants of health, identifying 21 different health programs. Program activities that targeted environmental determinants of health included: Caring for Country; changes to food supply and/or policy; infrastructure for physical activity; housing construction and maintenance; anti smoking policies; increased workforce capacity; continuous quality improvement of clinical systems; petrol substitution; and income management. Targets were categorised according to Miller's Living Systems Theory. Researchers using an Indigenous community based perspective more often identified interpersonal and community-level targets than were identified using a Western academic perspective. CONCLUSIONS: Although there are relatively few papers describing interventions that target environmental determinants of health, many of these addressed such determinants at multiple levels, consistent to some degree with an ecological approach. Interpretation of program targets sometimes differed between academic and community-based perspectives, and was limited by the type of data reported in the journal articles, highlighting the need for local Indigenous knowledge for accurate program evaluation. IMPLICATIONS: While an ecological approach to Indigenous health is increasingly evident in the health research literature, the design and evaluation of such programs requires a wide breadth of expertise, including local Indigenous knowledge. PMID- 23939390 TI - Travel mode and physical activity at Sydney University. AB - How staff and students travel to university can impact their physical activity level. An online survey of physical activity and travel behaviour was conducted in early November 2012 to inform planning of physical activity and active travel promotion programs at the University of Sydney, Australia as part of the "Sit Less, Move More" sub-committee of the Healthy University Initiative, and as baseline data for evaluation. There were 3,737 useable responses, 60% of which were from students. Four out of five respondents travelled to the University on the day of interest (Tuesday, November 30, 2012). The most frequently used travel modes were train (32%), car as driver (22%), bus (17%), walking (17%) and cycling (6%). Staff were twice as likely to drive as students, and also slightly more likely to use active transport, defined as walking and cycling (26% versus 22%). Overall, 41% of respondents were sufficiently active (defined by meeting physical activity recommendations of 150 min per week). Participants were more likely to meet physical activity recommendations if they travelled actively to the University. With a high proportion of respondents using active travel modes or public transport already, increasing the physical activity levels and increasing the use of sustainable travel modes would mean a mode shift from public transport to walking and cycling for students is needed and a mode shift from driving to public transport or active travel for University staff. Strategies to achieve this are discussed. PMID- 23939389 TI - Environmental drivers of West Nile fever epidemiology in Europe and Western Asia- a review. AB - Abiotic and biotic conditions are both important determinants of West Nile Fever (WNF) epidemiology. Ambient temperature plays an important role in the growth rates of vector populations, the interval between blood meals, viral replication rates and transmission of West Nile Virus (WNV). The contribution of precipitation is more complex and less well understood. In this paper we discuss impacts of climatic parameters (temperature, relative humidity, precipitation) and other environmental drivers (such as bird migration, land use) on WNV transmission in Europe. WNV recently became established in southeastern Europe, with a large outbreak in the summer of 2010 and recurrent outbreaks in 2011 and 2012. Abundant competent mosquito vectors, bridge vectors, infected (viremic) migrating and local (amplifying) birds are all important characteristics of WNV transmission. In addition, certain key climatic factors, such as increased ambient temperatures, and by extension climate change, may also favor WNF transmission, and they should be taken into account when evaluating the risk of disease spread in the coming years. Monitoring epidemic precursors of WNF, such as significant temperature deviations in high risk areas, could be used to trigger vector control programs and public education campaigns. PMID- 23939391 TI - Sexual and reproductive health among unmarried rural-urban female migrants in Shanghai China: a comparative analysis. AB - We compared sexual and reproductive health (SRH)-related knowledge, attitude and behavior among unmarried rural-urban female migrants in Shanghai coming from different regions of China. A total of 944 unmarried rural-urban female migrants were recruited from three districts of Shanghai. We used an interviewer administered structured questionnaire to collect information from each participant and a multivariate logistic regression to examine the association between premarital sex and risk factors. We found the rates of premarital sex, pregnancy and abortion among unmarried rural-urban female migrants were 28.2%, 5.2% and 5.0%, respectively. Participants from the east of China were more likely to engage in premarital sex than those from the mid-west (p < 0.001). The analysis showed premarital sex was associated with age, hometown, education, current residential type, knowledge of sexual physiology and safe sex, attitude to SRH and safe sex, and permissive attitude to sex. Unmarried rural-urban female migrants lack SRH related knowledge and the data suggests high levels of occurrence of premarital sex. The results indicate that programs to promote safe sex, especially to those migrants coming from eastern China, should be a priority. PMID- 23939392 TI - Lactate-induced release of GABA in the ventromedial hypothalamus contributes to counterregulatory failure in recurrent hypoglycemia and diabetes. AB - Suppression of GABAergic neurotransmission in the ventromedial hypothalamus (VMH) is crucial for full activation of counterregulatory responses to hypoglycemia, and increased gamma-aminobutyric acid (GABA) output contributes to counterregulatory failure in recurrently hypoglycemic (RH) and diabetic rats. The goal of this study was to establish whether lactate contributes to raising VMH GABA levels in these two conditions. We used microdialysis to deliver artificial extracellular fluid or L-lactate into the VMH and sample for GABA. We then microinjected a GABAA receptor antagonist, an inhibitor of lactate transport (4CIN), or an inhibitor of lactate dehydrogenase, oxamate (OX), into the VMH prior to inducing hypoglycemia. To assess whether lactate contributes to raising GABA in RH and diabetes, we injected 4CIN or OX into the VMH of RH and diabetic rats before inducing hypoglycemia. L-lactate raised VMH GABA levels and suppressed counterregulatory responses to hypoglycemia. While blocking GABAA receptors did not prevent the lactate-induced rise in GABA, inhibition of lactate transport or utilization did, despite the presence of lactate. All three treatments restored the counterregulatory responses, suggesting that lactate suppresses these responses by enhancing GABA release. Both RH and diabetic rats had higher baseline GABA levels and were unable to reduce GABA levels sufficiently to fully activate counterregulatory responses during hypoglycemia. 4CIN or OX lowered VMH GABA levels in both RH and diabetic rats and restored the counterregulatory responses. Lactate likely contributes to counterregulatory failure in RH and diabetes by increasing VMH GABA levels. PMID- 23939394 TI - Downregulation of CPPED1 expression improves glucose metabolism in vitro in adipocytes. AB - We have previously demonstrated that the expression of calcineurin-like phosphoesterase domain containing 1 (CPPED1) decreases in adipose tissue (AT) after weight reduction. However, the function of CPPED1 in AT is unknown. Therefore, we investigated whether the change in CPPED1 expression is connected to changes in adipocyte glucose metabolism. First, we confirmed that the expression of CPPED1 decreased after weight loss in subcutaneous AT. Second, the expression of CPPED1 did not change during adipocyte differentiation. Third, CPPED1 knockdown with small interfering RNA increased expression of genes involved in glucose metabolism (adiponectin, adiponectin receptor 1, and GLUT4) and improved insulin-stimulated glucose uptake. To conclude, CPPED1 is a novel molecule involved in AT biology, and CPPED1 is involved in glucose uptake in adipocytes. PMID- 23939393 TI - STAT4 deficiency reduces obesity-induced insulin resistance and adipose tissue inflammation. AB - Signal transducer and activator of transcription (STAT) 4 is one of the seven members of the STAT family. STAT4 has a prominent role in mediating interleukin 12-induced T-helper cell type 1 lineage differentiation. T cells are key players in the maintenance of adipose tissue (AT) inflammation. The role of STAT4 in obesity and AT inflammation is unknown. We sought to determine the role of STAT4 in AT inflammation in obesity-induced insulin resistance. We studied STAT4-null mice on the C57Bl6/J background. We have found that STAT4(-/-)C57Bl6/J mice develop high-fat diet-induced obesity (DIO) similar to wild-type controls, but that they have significantly improved insulin sensitivity and better glucose tolerance. Using flow cytometry and real-time PCR, we show that STAT4(-/-) mice with DIO produce significantly reduced numbers of inflammatory cytokines and chemokines in adipocytes, have reduced numbers of CD8(+) cells, and display increased alternative (M2) macrophage polarization. CD8(+) cells, but not CD4(+) cells, from STAT4(-/-) mice displayed reduced in vitro migration. Also, we found that adipocyte inflammation is reduced and insulin signaling is improved in STAT4(-/-) mice with DIO. We have identified STAT4 as a key contributor to insulin resistance and AT inflammation in DIO. Targeting STAT4 activation could be a novel approach to reducing AT inflammation and insulin resistance in obesity. PMID- 23939396 TI - Novel off-target effect of tamoxifen--inhibition of acid ceramidase activity in cancer cells. AB - Acid ceramidase (AC), EC 3.5.1.23, a lysosomal enzyme, catalyzes the hydrolysis of ceramide to constituent sphingoid base, sphingosine, and fatty acid. Because AC regulates the levels of pro-apoptotic ceramide and mitogenic sphingosine-1 phosphate, it is considered an apt target in cancer therapy. The present study reveals, for the first time, that the prominent antiestrogen, tamoxifen, is a pan effective AC inhibitor in the low, single digit micromolar range, as demonstrated in a wide spectrum of cancer cell types, prostate, pancreatic, colorectal, and breast. Prostate cancer cells were chosen for the detailed investigations. Treatment of intact PC-3 cells with tamoxifen produced time- and dose-dependent inhibition of AC activity. Tamoxifen did not impact cell viability nor did it inhibit AC activity in cell-free assays. In pursuit of mechanism of action, we demonstrate that tamoxifen induced time-, as early as 5min, and dose-dependent, as low as 5MUM, increases in lysosomal membrane permeability (LMP), and time- and dose-dependent downregulation of AC protein expression. Assessing various protease inhibitors revealed that a cathepsin B inhibitor blocked tamoxifen elicited downregulation of AC protein; however, this action failed to restore AC activity unless assayed in a cell-free system at pH4.5. In addition, pretreatment with tamoxifen inhibited PC-3 cell migration. Toremifene, an antiestrogen structurally similar to tamoxifen, was also a potent inhibitor of AC activity. This study reveals a new, off-target action of tamoxifen that may be of benefit to enhance anticancer therapies that either incorporate ceramide or target ceramide metabolism. PMID- 23939398 TI - Heat shock protein-27 attenuates foam cell formation and atherogenesis by down regulating scavenger receptor-A expression via NF-kappaB signaling. AB - Previously, we showed an inverse correlation between HSP27 serum levels and experimental atherogenesis in ApoE(-/-) mice that over-express HSP27 and speculated that the apparent binding of HSP27 to scavenger receptor-A (SR-A) was of mechanistic importance in attenuating foam cell formation. However, the nature and importance of the interplay between HSP27 and SR-A in atheroprotection remained unclear. Treatment of THP-1 macrophages with recombinant HSP27 (rHSP27) inhibited acLDL binding (-34%; p<0.005) and uptake (-38%, p<0.05). rHSP27 reduced SR-A mRNA (-39%, p=0.02), total protein (-56%, p=0.01) and cell surface (-53%, p<0.001) expression. The reduction in SR-A expression by rHSP27 was associated with a 4-fold increase in nuclear factor-kappa B (NF-kappaB) signaling (p<0.001 versus control), while an inhibitor of NF-kappaB signaling, BAY11-7082, attenuated the negative effects of rHSP27 on both SR-A expression and lipid uptake. To determine if SR-A is required for HSP27 mediated atheroprotection in vivo, ApoE(-/-) and ApoE(-/-) SR-A(-/-) mice fed with a high fat diet were treated for 3weeks with rHSP25. Compared to controls, rHSP25 therapy reduced aortic en face and aortic sinus atherosclerotic lesion size in ApoE(-/-) mice by 39% and 36% (p<0.05), respectively, but not in ApoE(-/-)SR-A(-/-) mice. In conclusion, rHSP27 diminishes SR-A expression, resulting in attenuated foam cell formation in vitro. Regulation of SR-A by HSP27 may involve the participation of NF-kappaB signaling. Lastly, SR-A is required for HSP27-mediated atheroprotection in vivo. PMID- 23939397 TI - HDL endocytosis and resecretion. AB - HDL removes excess cholesterol from peripheral tissues and delivers it to the liver and steroidogenic tissues via selective lipid uptake without catabolism of the HDL particle itself. In addition, endocytosis of HDL holo-particles has been debated for nearly 40years. However, neither the connection between HDL endocytosis and selective lipid uptake, nor the physiological relevance of HDL uptake has been delineated clearly. This review will focus on HDL endocytosis and resecretion and its relation to cholesterol transfer. We will discuss the role of HDL endocytosis in maintaining cholesterol homeostasis in tissues and cell types involved in atherosclerosis, focusing on liver, macrophages and endothelium. We will critically summarize the current knowledge on the receptors mediating HDL endocytosis including SR-BI, F1-ATPase and CD36 and on intracellular HDL transport routes. Dependent on the tissue, HDL is either resecreted (retro endocytosis) or degraded after endocytosis. Finally, findings on HDL transcytosis across the endothelial barrier will be summarized. We suggest that HDL endocytosis and resecretion is a rather redundant pathway under physiologic conditions. In case of disturbed lipid metabolism, however, HDL retro-endocytosis represents an alternative pathway that enables tissues to maintain cellular cholesterol homeostasis. PMID- 23939400 TI - Electronic cigarettes. PMID- 23939399 TI - Ethnic differences in respiratory impairment. AB - OBJECTIVE: Spirometric Z scores by lambda-mu-sigma (LMS) rigorously account for age-related changes in lung function. Recently, the Global Lung Function Initiative (GLI) expanded LMS spirometric Z scores to multiple ethnicities. Hence, in aging populations, the GLI provides an opportunity to rigorously evaluate ethnic differences in respiratory impairment, including airflow limitation and restrictive pattern. METHODS: Using data from the Third National Health and Nutrition Examination Survey, including participants aged 40-80, we evaluated ethnic differences in GLI-defined respiratory impairment, including prevalence and associations with mortality and respiratory symptoms. RESULTS: Among 3506 white Americans, 1860 African Americans and 1749 Mexican Americans, the prevalence of airflow limitation was 15.1% (13.9% to 16.4%), 12.4% (10.7% to 14.0%) and 8.2% (6.7% to 9.8%), and restrictive pattern was 5.6% (4.6% to 6.5%), 8.0% (6.9% to 9.0%) and 5.7% (4.5% to 6.9%), respectively. Airflow limitation was associated with mortality in white Americans, African Americans and Mexican Americans-adjusted HR (aHR) 1.66 (1.23 to 2.25), 1.60 (1.09 to 2.36) and 1.80 (1.17 to 2.76), respectively, but associated with respiratory symptoms only in white Americans-adjusted OR (aOR) 2.15 (1.70 to 2.73). Restrictive pattern was associated with mortality but only in white Americans and African Americans-aHR 2.56 (1.84 to 3.55) and 3.23 (2.06 to 5.05), and associated with respiratory symptoms but only in white Americans and Mexican Americans-aOR 2.16 (1.51 to 3.07) and 2.12 (1.45 to 3.08), respectively. CONCLUSIONS: In an aging population, we found ethnic differences in GLI-defined respiratory impairment. In particular, African Americans had high rates of respiratory impairment that were associated with mortality but not respiratory symptoms. PMID- 23939402 TI - Genetics and the neurodegenerations: musings of a gadfly. AB - An elderly perplexed clinician who has lived through the molecular revolution briefly considers the potential of genetics in elucidating the causes of neurodegenerations and expresses certain reservations. PMID- 23939401 TI - Tablet-based strength-balance training to motivate and improve adherence to exercise in independently living older people: a phase II preclinical exploratory trial. AB - BACKGROUND: Reaction time, coordination, and cognition performance typically diminish in older adults, which may lead to gait impairments, falls, and injuries. Regular strength-balance exercises are highly recommended to reduce this problem and to improve health, well-being, and independence in old age. However, many older people face a lack of motivation in addition to other strong barriers to exercise. We developed ActiveLifestyle, an information technology (IT)-based system for active and healthy aging aiming at improving balance and strength. ActiveLifestyle is a training app that runs on a tablet and assists, monitors, and motivates older people to follow personalized training plans autonomously at home. OBJECTIVE: The objectives were to (1) investigate which IT mediated motivation strategies increase adherence to physical exercise training plans in older people, (2) assess the impact of ActiveLifestyle on physical activity behavior change, and (3) demonstrate the effectiveness of the ActiveLifestyle training to improve gait speed. METHODS: A total of 44 older adults followed personalized, 12-week strength and balance training plans. All participants performed the exercises autonomously at home. Questionnaires were used to assess the technological familiarity and stage of behavior change, as well as the effectiveness of the motivation instruments adopted by ActiveLifestyle. Adherence to the exercise plan was evaluated using performance data collected by the app and through information given by the participants during the study. Pretests and posttests were performed to evaluate gait speed of the participants before and after the study. RESULTS: Participants were 75 years (SD 6), predominantly female (64%), held a trade or professional diploma (54%), and their past profession was in a sitting position (43%). Of the 44 participants who enrolled, 33 (75%) completed the study. The app proved to assist and motivate independently living and healthy older adults to autonomously perform strength balance exercises (median 6 on a 7-point Likert scale). Social motivation strategies proved more effective than individual strategies to stimulate the participants to comply with the training plan, as well as to change their behavior permanently toward a more physically active lifestyle. The exercises were effective to improve preferred and fast gait speed. CONCLUSIONS: ActiveLifestyle assisted and motivated independently living and healthy older people to autonomously perform strength-balance exercises over 12 weeks and had low dropout rates. The social motivation strategies were more effective to stimulate the participants to comply with the training plan and remain on the intervention. The adoption of assistive technology devices for physical intervention tends to motivate and retain older people exercising for longer periods of time. PMID- 23939403 TI - Difference in MSA phenotype distribution between populations: genetics or environment? AB - The reasons for the differences in emphasis on striatonigral or olivopontocerebellar involvement in multiple system atrophy (MSA) remain to be determined. Semi-quantitative pathological analyses carried out in the United Kingdom and Japan demonstrated that olivopontocerebellar-predominant pathology was more frequent in Japanese MSA than British MSA. This observation provides evidence for a difference in phenotype distribution between British and Japanese patients with definite MSA. Studies of the natural history and epidemiology of MSA carried out in various populations have revealed that the relative prevalences of clinical subtypes of MSA probably differ among populations; the majority of MSA patients diagnosed in Europe have predominant parkinsonism (MSA P), while the majority of MSA patients diagnosed in Asia have predominant cerebellar ataxia (MSA-C). Although potential drawbacks to the published frequencies of clinical subtypes and pathological subtypes should be considered because of selection biases, the difference demonstrated in pathological subtype is also consistent with the differences in clinical subtype of MSA demonstrated between Europe and Asia. Modest alterations in susceptibility factors may contribute to the difference in MSA phenotype distribution between populations. Synergistic interactions between genetic risk variants and environmental toxins responsible for parkinsonism or cerebellar dysfunction should therefore be explored. Further investigations are needed to determine the environmental, genetic, and epigenetic factors that account for the differences in clinicopathological phenotype of MSA among different populations. PMID- 23939404 TI - Motor imagery of gait tasks in individuals with Parkinson disease. AB - We developed a questionnaire to assess motor imagery (MI) of gait and administered it to 33 controls and 28 individuals with PD. Our goals were: 1) compare gait MI in individuals with and without PD, 2) determine whether walking performance relates to gait MI and 3) compare gait MI in individuals with PD with and without freezing of gait. Gait MI was not different between PD and controls. There was no correlation between walking performance and gait MI, and no difference in gait MI between freezers and nonfreezers. The gait imagery questionnaire may be useful for imaging studies involving imagined gait. PMID- 23939405 TI - Vibration therapy for Parkinson's disease: Charcot's studies revisited. AB - The 19th century neurologist, J-M Charcot, used a vibration chair for treating Parkinson's disease (PD). He documented improvement, but few subsequent studies examined vibration treatment. Using a specialized lounge chair, we conducted a rater blinded, randomized trial of body vibration vs. no vibration in 23 PD patients. The primary outcome measure was change from baseline in the motor section of the MDS-UPDRS. Both vibration and no vibration groups significantly improved after one month of daily treatments. However, there was no significant difference between the two treatment groups, suggesting that non-specific or placebo factors had an effect on PD motor function. PMID- 23939406 TI - Selective left, right and bilateral stimulation of subthalamic nuclei in Parkinson's disease: differential effects on motor, speech and language function. AB - Deep brain stimulation (DBS) of the subthalamic nucleus improves the motor symptoms of Parkinson's disease, but may produce a worsening of speech and language performance at rates and amplitudes typically selected in clinical practice. The possibility that these dissociated effects might be modulated by selective stimulation of left and right STN has never been systematically investigated. To address this issue, we analyzed motor, speech and language functions of 12 patients implanted with bilateral stimulators configured for optimal motor responses. Behavioral responses were quantified under four stimulator conditions: bilateral DBS, right-only DBS, left-only DBS and no DBS. Under bilateral and left-only DBS conditions, our results exhibited a significant improvement in motor symptoms but worsening of speech and language. These findings contribute to the growing body of literature demonstrating that bilateral STN DBS compromises speech and language function and suggests that these negative effects may be principally due to left-sided stimulation. These findings may have practical clinical consequences, suggesting that clinicians might optimize motor, speech and language functions by carefully adjusting left- and right-sided stimulation parameters. PMID- 23939407 TI - Changes in sphingomyelin level affect alpha-synuclein and ABCA5 expression. AB - The pathological hallmark of Parkinson's disease (PD) is the presence of aggregated alpha-synuclein associated with lipids. Substantial evidence now exists to indicate that alpha-synuclein binds and interacts with regions of membranes that are enriched in lipids (lipid rafts). Lipids are transported around the brain by a group of proteins called ATP-Binding Cassette subfamily A (ABCA) transporters and in recent years there has been mounting evidence indicating that ABCA transporters regulate a number of neurodegenerative disease processes. Only recently a genome-wide association study reported that ABCA5 was genetically associated with a reduced risk for PD. However, very little is known about the role of lipids and ABCA5 in the pathological process of PD. In this study we investigate the impact of the lipid-raft lipid sphingomyelin on alpha synuclein and ABCA5 expression. We also investigate in which primary human brain cells ABCA5 is expressed and whether the expression of ABCA5 is altered in PD brain. When SK-N-SH neuronal cells were treated with sphingomyelin the expression of both alpha-synuclein and ABCA5 was significantly increased, indicating sphingomyelin as a potential substrate for the ABCA5 transporter. ABCA5 was strongly expressed in neurons and moderately in microglia, with only weak expression observed in astrocytes and oligodendrocytes. The expression of ABCA5 was significantly elevated in PD brains compared to age- and gender-matched control brains, possibly as a protective response to the disease. These data provide new evidence indicating that lipid is important for alpha-synuclein pathology in PD. PMID- 23939408 TI - Automated assessment of bradykinesia and dyskinesia in Parkinson's disease. AB - There is a need for objective measures of dyskinesia and bradykinesia of Parkinson's disease (PD) that are continuous throughout the day and related to levodopa dosing. The output of an algorithm that calculates dyskinesia and bradykinesia scores every two minutes over 10 days (PKG: Global Kinetics Corporation) was compared with conventional rating scales for PD in PD subjects. The algorithm recognises bradykinesia as movements made with lower acceleration and amplitude and with longer intervals between movement. Similarly the algorithm recognises dyskinesia as having movements of normal amplitude and acceleration but with shorter periods without movement. The distribution of the bradykinesia and dyskinesia scores from PD subjects differed from that of normal subjects. The algorithm predicted the clinical dyskinesia rating scale AIMS with a 95% margin of error of 3.2 units compared with the inter-rater 95% limits of agreement from 3 neurologists of -3.4 to +4.3 units. Similarly the algorithm predicted the UPDRS III score with a margin of error similar to the inter-rater limits of agreement. Improvement in scores in response to changes in medication could be assessed statistically in individual patients. This algorithm provides objective, continuous and automated assessment of the clinical features of bradykinesia and dyskinesia in PD. PMID- 23939409 TI - Impaired complex-I mitochondrial biogenesis in Parkinson disease frontal cortex. AB - Parkinson's disease (PD) can include a progressive frontal lobe alpha synucleinopathy with disability from cognitive decline and cortico-limbic dysregulation that may arise from bioenergetic impairments. We examined in PD frontal cortex regulation of mitochondrial biogenesis (mitobiogenesis) and its effects on Complex-I. We quantified expression of 33 nuclear genome (nDNA) encoded and 7 mitochondrial genome (mtDNA)-encoded Complex-I genes, 6 Complex-I assembly factors and multiple mitobiogenesis genes. We related these findings to levels of Complex-I proteins and NADH-driven electron flow in mitochondria from these same specimens reported in earlier studies. We found widespread, decreased expression of nDNA Complex-I genes that correlated in some cases with mitochondrial Complex-I protein levels, and of ACAD9, a Complex-I assembly factor. mtDNA-transcribed Complex-I genes showed ~ constant expression within each PD sample but variable expression across PD samples that correlated with NRF1. Relationships among PGC-1alpha and its downstream targets NRF1 and TFAM were very similar in PD and CTL and were related to mitochondrial NADH-driven electron flow. MicroRNA arrays revealed multiple miRNA's regulated >2-fold predicted to interact with PGC-1alpha or its upstream regulators. Exposure of cultured human neurons to NO, rotenone and TNF-alpha partially reproduced mitobiogenesis down-regulation. In PD frontal cortex mitobiogenesis signaling relationships are maintained but down-regulated, correlate with impaired mitochondrial NADH-driven electron flow and may arise from combinations of nitrosative/oxidative stresses, inflammatory cytokines, altered levels of mitobiogenesis gene-interacting microRNA's, or other unknown mechanisms. Stimulation of mitobiogenesis in PD may inhibit rostral disease progression and appearance of secondary symptoms referable to frontal cortex. PMID- 23939410 TI - Tissue-type plasminogen activator is an extracellular mediator of Purkinje cell damage and altered gait. AB - Purkinje neurons are a sensitive and specialised cell type important for fine motor movement and coordination. Purkinje cell damage manifests as motor incoordination and ataxia - a prominent feature of many human disorders including spinocerebellar ataxia and Huntington's disease. A correlation between Purkinje degeneration and excess cerebellar levels of tissue-type plasminogen activator (tPA) has been observed in multiple genetically-distinct models of ataxia. Here we show that Purkinje loss in a mouse model of Huntington's disease also correlates with a 200% increase in cerebellar tPA activity. That elevated tPA levels arise in a variety of ataxia models suggests that tPA is a common mediator of Purkinje damage. To address the specific contribution of tPA to cerebellar dysfunction we studied the T4 mice line that overexpresses murine tPA in postnatal neurons through the Thy1.2 gene promoter, which directs preferential expression to Purkinje cells within the cerebellum. Here we show that T4 mice develop signs of cerebellar damage within 10 weeks of birth including atrophy of Purkinje cell soma and dendrites, astrogliosis, reduced molecular layer volume and altered gait. In contrast, T4 mice displayed no evidence of microgliosis, nor any changes in interneuron density, nor alteration in the cerebellar granular neuron layer. Thus, excess tPA levels may be sufficient to cause targeted Purkinje cell degeneration and ataxia. We propose that elevated cerebellar tPA levels exert a common pathway of Purkinje cell damage. Therapeutically lowering cerebellar tPA levels may represent a novel means of preserving Purkinje cell integrity and motor coordination across a wide range of neurodegenerative diseases. PMID- 23939411 TI - Medicare payment for cognitive vs procedural care: minding the gap. AB - IMPORTANCE: Health care costs in the United States are rising rapidly, and consensus exists that we are not achieving sufficient value for this investment. Historically, US physicians have been paid more for performing costly procedures that drive up spending and less for cognitive services that may conserve costs and promote population health. OBJECTIVE: To quantify the Medicare payment gap between representative cognitive and procedural services, each requiring similar amounts of physician time. DESIGN: Observational analytical study comparing the hourly revenue generated by a physician performing cognitive services (Current Procedural Terminology [CPT] code 99214) and billing by time with that generated by physicians performing screening colonoscopy (Healthcare Common Procedure Coding System code G0121) or cataract extraction (CPT code 66984) for Medicare beneficiaries. SETTING: Outpatient medical practice. PARTICIPANTS: Medical care providers of outpatient services. EXPOSURE: Work relative-value unit assigned to physician services. MAIN OUTCOME AND MEASURES: Payment for physician services. RESULTS: The revenue for physician time spent on 2 common procedures (colonoscopy and cataract extraction) was 368% and 486%, respectively, of the revenue for a similar amount of physician time spent on cognitive care. CONCLUSIONS AND RELEVANCE: Our analysis indicates that Medicare reimburses physicians 3 to 5 times more for common procedural care than for cognitive care and illustrates the financial pressures that may contribute to the US health care system's emphasis on procedural care. We demonstrate that 2 common specialty procedures can generate more revenue in 1 to 2 hours of total time than a primary care physician receives for an entire day's work. PMID- 23939412 TI - Ethnic disparities in asthma treatment and outcomes in children aged under 15 years in New Zealand: analysis of national databases. AB - BACKGROUND: Maori and Pacific children experience poorer outcomes relating to asthma management than other ethnicities. AIMS: To measure recommended treatment and outcomes for asthma in all New Zealand children by age, sex, and ethnic group. METHODS: Children aged <15 years dispensed >2 asthma medicines (N=80,514) were identified from the national pharmaceutical claims database. We measured the number of children dispensed oral steroids >2 times and hospital admissions with a primary diagnosis of asthma and compared asthma treatment steps and hospitalisation by age and ethnicity. RESULTS: 16.0% of children were dispensed asthma medicines, 9.2% were dispensed medicine >2 times, 3.6% of children were hospitalised at least once for asthma and 98.9% of admissions were acute. Maori (OR 1.46, 95% CI 1.41 to 1.51) and Pacific children (OR 2.38, 95% CI 2.28 to 2.47) were more likely to remain on the lowest step of treatment. At all steps of treatment, Maori and Pacific children had higher rates of oral steroid use. In all age groups, more Maori children (5.1%, OR 1.88, 95% CI 1.73 to 2.04) and Pacific children (5.6%, OR 2.05, 95% CI 1.84 to 2.29) were hospitalised for asthma than children of other ethnicities (2.8%). CONCLUSIONS: Maori and Pacific children are less likely to have their treatment escalated to a higher step than other children. They are also more likely to use oral steroids to control asthma exacerbations and be admitted to hospital for severe asthma episodes. New Zealand databases can be used to monitor these outcomes. PMID- 23939414 TI - A supramolecular synthon approach to aid the discovery of architectures sustained by C-H...M hydrogen bonds. AB - Hydrogen bonding in the form of eight-membered {...HCNM}2 synthons is identified in the crystal structures of nickel and copper complexes. These C-H...M interactions lead to the formation of well-defined zero-, one- and even two dimensional supramolecular aggregation patterns. PMID- 23939413 TI - Age-dependent alterations of decorin glycosaminoglycans in human skin. AB - Proteoglycans, a family of glycosaminoglycan (GAG) conjugated proteins, are important constituents of human skin connective tissue (dermis) and are essential for maintaining mechanical strength of the skin. Age-related alterations of dermal proteoglycans have not been fully elucidated. We quantified transcripts of 20 known interstitial proteoglycans in human skin and found that decorin was the most highly expressed. Decorin was predominantly produced by dermal fibroblasts. Decorin was localized in dermal extracellular matrix with GAG bound to type I collagen fibrils. Analysis of decorin extracted from young (21-30 years) and aged (>80 years) sun-protected human buttock skin revealed that decorin molecular size in aged skin is significantly smaller than in young skin. The average size of decorin protein did not alter, indicating size of GAG chain is reduced in aged, compared to young skin. This age-dependent alteration of decorin GAG may contribute to skin fragility of elderly people. PMID- 23939415 TI - Nonlinear mixed effects modeling of the diurnal blood pressure profile in a multiracial population. AB - BACKGROUND: Cardiac and cerebrovascular events in hypertensive patients are related to specific features of the 24-hour diurnal blood pressure (BP) profile (i.e., daytime and nighttime BP, nocturnal dip (ND), and morning surge (MS)). This investigation aimed to characterize 24-hour diurnal systolic BP (SBP) with parameters that correlate directly with daytime and nighttime SBP, ND, and MS using nonlinear mixed effects modeling. METHODS: Ambulatory 24-hour SBP measurements (ABPM) of 196 nontreated subjects from three ethnic groups were available. A population model was parameterized in NONMEM to estimate and evaluate the parameters baseline SBP (BSL), nadir (minimum SBP during the night), and change (SBP difference between day and night). Associations were tested between these parameters and patient-related factors to explain interindividual variability. RESULTS: The diurnal SBP profile was adequately described as the sum of 2 cosine functions. The following typical values (interindividual variability) were found: BSL = 139 mm Hg (11%); nadir = 122 mm Hg (14%); change = 25 mm Hg (52%), and residual error = 12 mm Hg. The model parameters correlate well with daytime and nighttime SBP, ND, and MS (R (2) = 0.50-0.92). During covariate analysis, ethnicity was found to be associated with change; change was 40% higher in white Dutch subjects and 26.8% higher in South Asians than in blacks. CONCLUSIONS: The developed population model allows simultaneous estimation of BSL, nadir, and change for all individuals in the investigated population, regardless of individual number of SBP measurements. Ethnicity was associated with change. The model provides a tool to evaluate and optimize the sampling frequency for 24-hour ABPM. PMID- 23939416 TI - Determination of sex differences in activities of angiotensin-converting enzyme 2 (ACE2) requires an activity assay that doesn't underestimate ACE2. PMID- 23939417 TI - Response to "Determination of sex differences in activities of angiotensin converting enzyme 2 (ACE2) requires an activity assay that doesn't underestimate ACE2". PMID- 23939418 TI - Angiotensin-(1-7) in the central nervous system regulation of blood pressure and renin-angiotensin system. PMID- 23939419 TI - Response to "Angiotensin-(1-7) in the central regulation of blood pressure and renin-angiotensin system". PMID- 23939421 TI - Adsorption, structural alteration and elution of peptides at pendant PEO layers. AB - An experimentally based, quantitative understanding of the entrapment and function of small peptides within PEO brush layers does not currently exist. Earlier work provided a rationale for expecting that an ordered, compact peptide will enter the PEO phase more readily than a peptide of similar size that adopts a less ordered, less compact form, and that amphiphilicity will promote peptide retention within the hydrophobic region of the PEO brush. Here we more deliberately describe criteria for peptide integration and structural change within the PEO brush, and discuss the reversibility of peptide entrapment with changing solvent conditions. For this purpose, circular dichroism (CD) was used to record the adsorption and conformational changes of (amphiphilic) WLBU2 and (non-amphiphilic) polyarginine peptides at uncoated (hydrophobic) and PEO-coated silica nanoparticles. Peptide conformation was controlled between disordered and alpha-helical forms by varying the concentration of perchlorate ion. We show an initially more ordered (alpha-helical) structure promotes peptide adsorption into the PEO layer. Further, a partially helical peptide undergoes an increase in helicity after entry, likely due to concomitant loss of capacity for peptide solvent hydrogen bonding. Peptide interaction with the PEO chains resulted in entrapment and conformational change that was irreversible to elution with changing solution conditions in the case of the amphiphilic peptide. In contrast, the adsorption and conformational change of the non-amphiphilic peptide was reversible. These results indicate that responsive drug delivery systems based on peptide-loaded PEO layers can be controlled by modulation of solution conditions and peptide amphiphilicity. PMID- 23939422 TI - Ocular biocompatibility and tolerance study of biodegradable polymeric micelles in the rabbit eye. AB - Polymeric nanoparticles have been developed to improve the bioavailability of drugs applied in ocular drug delivery. However, there are few information on ocular biocompatibility of polymeric nanoparticles applied topically onto the eye. In this paper, the ocular biocompatibility and tolerance of methoxy poly(ethylene glycol)-poly(E-caprolactone) (MPEG-PCL) micelles (~50nm) were investigated in rabbit eyes after a single intracameral and intravitreal injections. In vitro cytotoxicity assays showed that MPEG-PCL micelles had no apparent cytotoxicity against human corneal epithelial cells (HCEC), human lens epithelial cells (HLEC), and retinal pigment epithelial cells (RPE cells) at micelle concentrations of 0-2mg/mL. After a single intracameral injection of 0.2mL MPEG-PCL micelles (200mg/mL) into rabbit eyes, MPEG-PCL micelles were slowly removed from aqueous humor in a period of 14 days, while the intraocular pressure (IOP) was maintained at nearly the same level for 15 days. Three days after intracameral injection, dual staining of corneal endothelium showed that the endothelial cells were nearly regular hexagon-shape with well-defined organization, similar to normal endothelial cells. Hematoxylin and eosin staining indicated that there was absence of any obvious changes in microstructure of the corneal tissue and retina after a single intracameral and intravitreal injection of 0.2mL MPEG-PCL micelles (100mg/mL, 150mg/mL, and 200mg/mL). This study provides valuable information (safety and biocompatibility) for biomedical researchers to develop MPEG-PCL micelles as candidates for ocular drug delivery. PMID- 23939423 TI - Actein induces calcium release in human breast cancer cells. AB - BACKGROUND: The triterpene glycoside actein from the herb black cohosh preferentially inhibits the growth of breast cancer cells and activates the ER stress response. The ER IP3 receptor and Na,K-ATPase form a signaling microdomain. Since actein is lipophilic, its action may be limited by bioavailability. PURPOSE: To develop actein to prevent and treat cancer, we examined the primary targets and combinations with chemotherapy agents, as well as the ability of nanoparticles to enhance the activity. MATERIALS AND METHODS: To reveal signaling pathways, we treated human breast and colon cancer, as well as 293T and 293T (NF-kappaB), cells with actein, and measured effects using the MTT, luciferase promoter, Western blot and histology assays. To assess effects on calcium release, we preloaded cells with the calcium sensitive dye Fura-2. To enhance bioavailability, we conjugated actein to nanoparticle liposomes. RESULTS: Actein strongly inhibited the growth of human breast cancer cells and induced a dose dependent release of calcium into the cytoplasm. The ER IP3 receptor antagonist heparin blocked this release, indicating that the receptor is required for activity. Heparin partially blocked the growth inhibitory effect, while the MEK inhibitor U0126 enhanced it. Consistent with this, actein synergized with the ER mobilizer thapsigargin. Further, actein preferentially inhibited the growth of 293T (NF-kappaB) cells. Nanoparticle liposomes increased the growth inhibitory activity of actein. CONCLUSIONS: Actein alters the activity of the ER IP3 receptor and Na,K-ATPase, induces calcium release and modulates the NF-kappaB and MEK pathways and may be worthwhile to explore to prevent and treat breast cancer. PMID- 23939425 TI - Probing the reactivity of o-phthalaldehydic acid/methyl ester: synthesis of N isoindolinones and 3-arylaminophthalides. AB - A new method for the synthesis of N-substituted isoindolinones and 3 arylaminophthalides was developed through aza-Wittig/cyclisation. The reaction of o-phthalaldehydic acid methyl ester with benzylic, aromatic and aliphatic azides gave N-isoindolinones whereas reaction of o-phthalaldehydic acid with the aromatic azides gave 3-arylaminophthalides. PMID- 23939424 TI - Functional status of the serotonin 5-HT2C receptor (5-HT2CR) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence. AB - Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues ('cue reactivity'). The serotonin (5 hydroxytryptamine, 5-HT) 5-HT2C receptor (5-HT2CR) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT2CR functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT2CR macromolecular protein complex, and editing of the 5 HT2CR pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT2CR membrane protein levels concomitant with higher levels of 5-HT2CR:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT2CR mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT2CR induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT2CR tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5 HT2CR functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors. PMID- 23939426 TI - Structural variations in articular cartilage matrix are associated with early onset osteoarthritis in the spondyloepiphyseal dysplasia congenita (sedc) mouse. AB - Heterozgyous spondyloepiphyseal dysplasia congenita (sedc/+) mice expressing a missense mutation in col2a1 exhibit a normal skeletal morphology but early-onset osteoarthritis (OA). We have recently examined knee articular cartilage obtained from homozygous (sedc/sedc) mice, which express a Stickler-like phenotype including dwarfism. We examined sedc/sedc mice at various levels to better understand the mechanistic process resulting in OA. Mutant sedc/sedc, and control (+/+) cartilages were compared at two, six and nine months of age. Tissues were fixed, decalcified, processed to paraffin sections, and stained with hematoxylin/eosin and safranin O/fast green. Samples were analyzed under the light microscope and the modified Mankin and OARSI scoring system was used to quantify the OA-like changes. Knees were stained with 1C10 antibody to detect the presence and distribution of type II collagen. Electron microscopy was used to study chondrocyte morphology and collagen fibril diameter. Compared with controls, mutant articular cartilage displayed decreased fibril diameter concomitant with increases in size of the pericellular space, Mankin and OARSI scores, cartilage thickness, chondrocyte clustering, proteoglycan staining and horizontal fissuring. In conclusion, homozygous sedc mice are subject to early onset knee OA. We conclude that collagen in the mutant's articular cartilage (both heterozygote and homozygote) fails to provide the normal meshwork required for matrix integrity and overall cartilage stability. PMID- 23939427 TI - Mechanisms of Lin28-mediated miRNA and mRNA regulation--a structural and functional perspective. AB - Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis and by modulating the translation of target mRNAs. Both activities strongly depend on Lin28's RNA-binding domains (RBDs), an N-terminal cold-shock domain (CSD) and a C-terminal Zn-knuckle domain (ZKD). Recent biochemical and structural studies revealed the mechanisms of how Lin28 controls let-7 biogenesis. Lin28 binds to the terminal loop of pri- and pre-let-7 miRNA and represses their processing by Drosha and Dicer. Several biochemical and structural studies showed that the specificity of this interaction is mainly mediated by the ZKD with a conserved GGAGA or GGAGA-like motif. Further RNA crosslinking and immunoprecipitation coupled to high-throughput sequencing (CLIP seq) studies confirmed this binding motif and uncovered a large number of new mRNA binding sites. Here we review exciting recent progress in our understanding of how Lin28 binds structurally diverse RNAs and fulfills its pleiotropic functions. PMID- 23939428 TI - Skp2 regulates subcellular localization of PPARgamma by MEK signaling pathways in human breast cancer. AB - Nuclear hormone receptor family member PPARgamma plays an important role in mammary gland tumorigenesis. Previous studies have shown PPARgamma has cytoplasmic activities upon tetradecanoyl phorbol acetate (TPA) stimulation. However, the clinical pathological significance of cytoplasmic PPARgamma is not completely understood in human breast cancer. Skp2 is oncogenic, and its frequent amplification and overexpression correlated with the grade of malignancy. In this study, the role of cytoplasmic PPARgamma and Skp2 expression was investigated in human breast cancer progression. Therefore, immunohistochemical analysis was performed on formalin-fixed paraffin sections of 70 specimens. Furthermore, Western blot and immunofluorescence microscopy analysis were used to study the relationship between expression of cytoplasmic PPARgamma and Skp2 expression in human breast cancer cells in vitro. Results showed that the expression of cytoplasmic PPARgamma was positively correlated with Skp2 expression (p < 0.05), and correlated significantly with estrogen receptor (p = 0.026) and pathological grade (p = 0.029), respectively. In addition, Skp2 overexpression can provoke cytoplasmic localization of PPARgamma upon MEK1-dependent mechanisms in human breast cancer cells by nuclear-cytosolic fractionation technology and immunofluorescence microscopy analysis. Using RNA interference technology, we also found that down-regulated Skp2 reduced the phosphorylation level of MEK1 and significantly reversed TPA-induced nuclear export of PPARgamma in MDA-MB-231 cells. The changes in the subcellular localization of PPARgamma may represent a novel target for selective interference in patients with breast cancer. PMID- 23939431 TI - Bleeding left hepatic artery pseudoaneurysm: a complication of endoscopic ultrasound-guided hepaticogastrostomy. PMID- 23939432 TI - Suppression of the external mitochondrial NADPH dehydrogenase, NDB1, in Arabidopsis thaliana affects central metabolism and vegetative growth. AB - Ca(2+)-dependent oxidation of cytosolic NADPH is mediated by NDB1, which is an external type II NADPH dehydrogenase in the plant mitochondrial electron transport chain. Using RNA interference, the NDB1 transcript was suppressed by 80% in Arabidopsis thaliana plants, and external Ca(2+)-dependent NADPH dehydrogenase activity became undetectable in isolated mitochondria. This was linked to a decreased level of NADP(+) in rosettes of the transgenic lines. Sterile-grown transgenic seedlings displayed decreased growth specifically on glucose, and respiratory metabolism of (14)C-glucose was increased. On soil, NDB1 suppressing plants had a decreased vegetative biomass, but leaf maximum quantum efficiency of photosystem II and CO2 assimilation rates, as well as total respiration, were similar to the wild-type. The in vivo alternative oxidase activity and capacity were also similar in all genotypes. Metabolic profiling revealed decreased levels of sugars, citric acid cycle intermediates, and amino acids in the transgenic lines. The NDB1-suppression induced transcriptomic changes associated with protein synthesis and glucosinolate and jasmonate metabolism. The transcriptomic changes also overlapped with changes observed in a mutant lacking ABAINSENSITIVE4 and in A. thaliana overexpressing stress tolerance genes from rice. The results thus indicate that A. thaliana NDB1 modulates NADP(H) reduction levels, which in turn affect central metabolism and growth, and interact with defense signaling. PMID- 23939435 TI - The integrative care of Parkinson's disease: a systematic review. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, and it is characterized by a complex variety of both motor and neuropsychiatric issues. Effective treatment of PD symptoms requires a combination of pharmacotherapy and allied health therapies; however, treatment is generally monodisciplinary, with the neurologist referring out to varied therapists as needed. In order to more effectively manage PD as it progresses over time, clinics are beginning to implement and advocate the use of more integrative models of care for PD. In order to understand the effectiveness of these models, a comprehensive literature review was conducted through electronic searches of PubMed, Academic Search Premier, PsycINFO, Health Source: Nursing/Academic Edition, AgeLine, AMED (Alternative Medicine), Health and Psychosocial Instruments, Health Source - Consumer Edition, and Social Work Abstracts databases. The review identified only two published studies, both of which only evaluated the effectiveness of multidisciplinary care in outpatient settings. The results of the studies indicated that multidisciplinary treatment led to marked improvement in patient outcomes; however, these results are limited as they measured short term outcomes only. The limited available evidence on the efficacy of integrative healthcare delivery models in PD should serve as a call to-action for clinicians to work to improve the care, and subsequently the quality of life, of PD patients through streamlining PD-specialized care with multiple complementary clinicians and incorporating patient preferences and goals into treatment. PMID- 23939434 TI - Alteration of endothelial proteoglycan and heparanase gene expression by high glucose, insulin and heparin. AB - Heparan sulfate proteoglycans (HSPGs) contain a core protein with glycosaminoglycans attached. Reduced glycosaminoglycan, in endothelial HSPGs syndecan and perlecan, is associated with diabetic cardiovascular complications but changes in core protein remain controversial. Since heparanase degrades heparan sulfate, we wished to determine if changes in endothelial heparanase mRNA, by high glucose (HG), correlate with changes in syndecan and perlecan core proteins, and to observe effects of heparin or insulin. RNA was isolated from cultured human aortic endothelial cells treated with HG (30mM), insulin (0.01 units/mL), heparin (0.5MUg/mL), HG plus heparin and/or insulin for 24h. Real time PCR revealed that HG alone significantly increased heparanase, decreased syndecan with no effect on perlecan mRNA. Heparin or insulin significantly prevented the increase in heparanase but decreased perlecan mRNA while heparin, but not insulin, prevented the decrease in syndecan mRNA in HG treated cells. HG plus heparin and insulin increased heparanase and syndecan mRNA compared to all other treatments and decreased perlecan mRNA compared to control and HG alone. Heparin may protect endothelium from HG injury by reducing heparanase and increasing syndecan while insulin inhibits heparanase expression. Effects with insulin plus heparin suggest interference in transcriptional regulation of heparanase and syndecan genes. PMID- 23939433 TI - WOX5-IAA17 feedback circuit-mediated cellular auxin response is crucial for the patterning of root stem cell niches in Arabidopsis. AB - In plants, the patterning of stem cell-enriched meristems requires a graded auxin response maximum that emerges from the concerted action of polar auxin transport, auxin biosynthesis, auxin metabolism, and cellular auxin response machinery. However, mechanisms underlying this auxin response maximum-mediated root stem cell maintenance are not fully understood. Here, we present unexpected evidence that WUSCHEL-RELATED HOMEOBOX 5 (WOX5) transcription factor modulates expression of auxin biosynthetic genes in the quiescent center (QC) of the root and thus provides a robust mechanism for the maintenance of auxin response maximum in the root tip. This WOX5 action is balanced through the activity of indole-3-acetic acid 17 (IAA17) auxin response repressor. Our combined genetic, cell biology, and computational modeling studies revealed a previously uncharacterized feedback loop linking WOX5-mediated auxin production to IAA17-dependent repression of auxin responses. This WOX5-IAA17 feedback circuit further assures the maintenance of auxin response maximum in the root tip and thereby contributes to the maintenance of distal stem cell (DSC) populations. Our experimental studies and in silico computer simulations both demonstrate that the WOX5-IAA17 feedback circuit is essential for the maintenance of auxin gradient in the root tip and the auxin-mediated root DSC differentiation. PMID- 23939429 TI - Development of quorum-based anti-virulence therapeutics targeting Gram-negative bacterial pathogens. AB - Quorum sensing is a cell density-dependent signaling phenomenon used by bacteria for coordination of population-wide phenotypes, such as expression of virulence genes, antibiotic resistance and biofilm formation. Lately, disruption of bacterial communication has emerged as an anti-virulence strategy with enormous therapeutic potential given the increasing incidences of drug resistance in pathogenic bacteria. The quorum quenching therapeutic approach promises a lower risk of resistance development, since interference with virulence generally does not affect the growth and fitness of the bacteria and, hence, does not exert an associated selection pressure for drug-resistant strains. With better understanding of bacterial communication networks and mechanisms, many quorum quenching methods have been developed against various clinically significant bacterial pathogens. In particular, Gram-negative bacteria are an important group of pathogens, because, collectively, they are responsible for the majority of hospital-acquired infections. Here, we discuss the current understanding of existing quorum sensing mechanisms and present important inhibitory strategies that have been developed against this group of pathogenic bacteria. PMID- 23939436 TI - Studies of depression-related states in animal models of Parkinsonism. AB - The diagnosis of Parkinson's disease (PD) is solely based on movement disorders, but several non-motor deficits are common in PD. Depression often precedes the movement dysfunctions and continues to be a major concern during all stages of the disease. The pathophysiology of parkinsonian depression is largely unknown, but appears to partly differ from depression in patients without PD. Because of the increased awareness of the negative impact of depression on the quality of life of PD patients, there is a growing interest in developing animal models of parkinsonism that also recapitulate the depressive-like symptomatology. This review introduces paradigms for measurement of depression-like behaviors in rodents and summarizes data on behavioral, neurochemical and pharmacological changes in experimental PD models with relevance for depression-related states. PMID- 23939437 TI - Effects of levodopa on vividness of motor imagery in Parkinson disease. AB - INTRODUCTION: Motor imagery during functional magnetic resonance imaging is commonly used to understand the neural underpinnings of complex movements. This approach has recently been applied to individuals with Parkinson disease (PD) to better understand how brain function may relate to movement dysfunction. However, the ability of individuals with PD to imagine movements when "Off" dopamine replacement medication is poorly understood. Therefore, the primary purpose of the current study is to test the ability of people with PD to imagine movements while "On" and "Off" anti-Parkinson medication. METHODS: Vividness of imagery was assessed in 28 individuals with mild to moderate PD (Hoehn and Yahr stages 1-3) via the Kinesthetic Visual Imagery Questionnaire (KVIQ-20) both "On" and "Off" anti-Parkinson medication. Vividness of imagery of 32 age-matched older adults was also assessed. RESULTS: No differences in vividness of imagery were observed between "Off" and "On" medication states (p = 0.15). Imagery was similar between controls and PD both "Off" (p = 0.25) and "On" (p = 0.46) anti-Parkinson medication. A significant correlation was observed between imagery and disease severity while "On" anti-Parkinson medication (r = -0.49; p = 0.008). DISCUSSION AND CONCLUSIONS: Vividness of movement imagery was not different between "Off" and "On" anti-Parkinson medications or between PD and controls. These results suggest that people with PD are able to imagine similarly to older adults both when "On" and "Off" anti-Parkinson medication, and supports the use of motor imagery in the "Off" medication state. PMID- 23939438 TI - Cognitive behavioral therapy for depression and anxiety in Parkinson's disease: a clinical review. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is generally defined by its progressive motor features; but increased attention is being paid to its non-motor neuropsychiatric symptoms, which profoundly impact quality of life for patients and caregivers. Anxiety and depression are particularly problematic and are the strongest predictors of quality of life in PD. Recent research has focused on non-pharmacological approaches to treating depression and anxiety in patients with PD. Cognitive-behavioral therapy (CBT) is a potentially efficacious non-pharmacological treatment for mood and anxiety symptoms associated with PD. Accordingly, this review examines empirical studies of CBT-based treatments for depression and anxiety symptoms in PD. Medical Subject Headings were used in searches of PsychInfo and PubMed of English language articles published in peer-reviewed journals, resulting in the identification of 10 articles. Four additional articles were identified from the references of these articles and upon the suggestions of experts, for 15 articles in all. Results of individual studies varied significantly; however, the randomized controlled trials showed encouraging results and support the need for further investigation of the utility of CBT for depressed and anxious patients with PD. CBT is potentially a useful treatment for patients with PD and comorbid depression and/or anxiety, but more systematic research will be necessary to measure its effects. PMID- 23939439 TI - Declining quality of life in Parkinson disease before and after diagnosis. AB - We sought to assess the quality of life in PD patients before the diagnosis, in comparison to age-matched individuals free of PD, among participants in two large prospective cohorts of men and women. Components of the Short-Form Health Status Survey (SF36) were administered to all participants in 1996 and 2008 in the Health Professionals Follow-up Study (HPFS), and in 1992, 1996, 2000 and 2004 in the Nurses' Health Study (NHS). We used scores in 7 health-related quality of life-dimensions, that were rated from 1(worst) to 100(best) points. We fitted a multivariate mixed-effect model with repeated measures to estimate the expected decline with age and compared that to the decline observed among PD cases by time to diagnosis. 454 men and 414 women with PD contributed data to the analyses. A decline in physical function in PD patients relative to the whole cohort began approximately 7.5 years prior to diagnosis in women and 3 years prior to diagnosis in men, and continued to decline thereafter with a rate of 2.35 and 1.43 points per year in women and men respectively (p < 0.001 for both). For comparison, the average yearly decline in individuals without PD was 0.42 and 0.23 points per year in women and men respectively. Other measures of quality of life (only available in women) declined in a similar pattern to physical function. In summary, the quality of life in PD patients begins to decline years before the diagnosis. PMID- 23939440 TI - Dimensions of apathy in Parkinson's disease: exploratory factor analysis of the apathy scale. AB - Apathy, an intrinsic disorder of motivation, can manifest in cognitive, affective, and behavioral domains. Recent attempts to formalize diagnostic criteria for apathy have advocated this triadic structure. The Apathy Scale (AS) is the only recommended measure for assessing apathy in Parkinson's disease (PD) by a Movement Disorders task force. We tested the hypothesis that the AS distinctly measures the three proposed domains of apathy in PD. Participants were 226 non-demented PD patients. Apathy Scale data were examined with exploratory factor analysis (EFA). The three factor solution resembled the triadic structure of cognitive, behavioral, and affective domains; however, adjustments to the AS may be appropriate. PMID- 23939441 TI - Sleep benefit in Parkinson's disease: time to revive an enigma? AB - Some patients with Parkinson's disease (PD) reportedly experience 'sleep benefit': an improved motor functioning upon awaking in the morning. In this questionnaire study, 114 out of 243 consecutive outpatients with PD (46.9%) subjectively experienced sleep benefit. Among those patients that regularly took an afternoon nap, 33.7% experienced sleep benefit after the nap as well. Between patients with and without sleep benefit, there were no differences in demographic or clinical variables, including age, disease duration, dopaminergic treatment, and nocturnal sleep quality. Sleep benefit remains an intriguing but elusive phenomenon, which deserves renewed attention and further research. PMID- 23939442 TI - MRI diffusion in Parkinson's disease: using the technique's inherent directional information to study the olfactory bulb and substantia nigra. AB - Pathological studies have shown that Parkinson's disease (PD) at early stages affects the olfactory bulb (OB) followed by an involvement of substantia nigra (SN) and other brain regions. Emerging imaging methodologies detect alterations in certain brain regions of living PD patients, which may support proper diagnosis and monitor disease progression. Here we used a novel approach of diffusion tensor imaging (DTI), taking advantage of the technique's inherent diffusion directional information, for region of interest (ROI) placement and diffusion measurements in the OB and SN. 16 healthy individuals and 18 early moderate patients with PD, supported by reduced 123I-Ioflupane putaminal binding, were examined with two identical DTI series. Olfaction was assessed with the 40 item UPSIT and Parkinsonian severity with UPDRS and Hoehn&Yahr. DTI measurements showed reduced fractional anisotropy (FA) for SN in the PD group in both DTI series. In OBs there was reduced FA in the PD group in the first series, but not in the second. As OBs are located in an area susceptible to artifacts, the coefficient of variation between the two DTI series was higher than for other brain regions. The UPSIT scores were much lower in the PD group than in healthy individuals. In conclusion, we describe a novel approach for more objective ROI placement in DTI, which enabled us to detect altered diffusion in the SN and OBs in PD. These data provides further support that diffusion MRI can be of high clinical utility as a biomarker to facilitate diagnosis and follow disease progression in PD. PMID- 23939443 TI - The truth about cigarette price increases in Britain. PMID- 23939445 TI - Hard-to-diagnose headache: practical tips for diagnosis and treatment. PMID- 23939446 TI - Approach to acute headache in adults. AB - Approximately one-half of the adult population worldwide is affected by a headache disorder. The International Headache Society classification and diagnostic criteria can help physicians differentiate primary headaches (e.g., tension, migraine, cluster) from secondary headaches (e.g., those caused by infection or vascular disease). A thorough history and physical examination, and an understanding of the typical features of primary headaches, can reduce the need for neuroimaging, lumbar puncture, or other studies. Some red flag signs and symptoms identified in the history or during a physical examination can indicate serious underlying pathology and will require neuroimaging or other testing to evaluate the cause of headache. Red flag signs and symptoms include focal neurologic signs, papilledema, neck stiffness, an immunocompromised state, sudden onset of the worst headache in the patient's life, personality changes, headache after trauma, and headache that is worse with exercise. If an intracranial hemorrhage is suspected, head computed tomography without contrast media is recommended. For most other dangerous causes of headache, magnetic resonance imaging or computed tomography is acceptable. PMID- 23939447 TI - Sick sinus syndrome: a review. AB - Sick sinus syndrome refers to a collection of disorders marked by the heart's inability to perform its pacemaking function. Predominantly affecting older adults, sick sinus syndrome comprises various arrhythmias, including bradyarrhythmias with or without accompanying tachyarrhythmias. At least 50 percent of patients with sick sinus syndrome develop alternating bradycardia and tachycardia, also known as tachy-brady syndrome. Sick sinus syndrome results from intrinsic causes, or may be exacerbated or mimicked by extrinsic factors. Intrinsic causes include degenerative fibrosis, ion channel dysfunction, and remodeling of the sinoatrial node. Extrinsic factors can be pharmacologic, metabolic, or autonomic. Signs and symptoms are often subtle early on and become more obvious as the disease progresses. They are commonly related to end-organ hypoperfusion. Cerebral hypoperfusion is most common, with syncope or near fainting occurring in about one-half of patients. Diagnosis may be challenging, and is ultimately made by electrocardiographic identification of the arrhythmia in conjunction with the presence of symptoms. If electrocardiography does not yield a diagnosis, inpatient telemetry monitoring, outpatient Holter monitoring, event monitoring, or loop monitoring may be used. Electrophysiologic studies also may be used but are not routinely needed. Treatment of sick sinus syndrome includes removing extrinsic factors, when possible, and pacemaker placement. Pacemakers do not reduce mortality, but they can decrease symptoms and improve quality of life. PMID- 23939449 TI - Screening for ovarian cancer. PMID- 23939448 TI - Ulcerative colitis. AB - Ulcerative colitis is a chronic inflammatory disease of the colon. The etiology is unknown. Risk factors include a history of recent infection with Salmonella or Campylobacter, living in Western industrialized nations and at higher latitudes, and a family history of the disease. The incidence peaks in early adulthood, but patients can develop the disorder from early childhood through adulthood. Ulcerative colitis often presents with abdominal pain, diarrhea, and hematochezia. It is important to exclude infectious etiologies. Anemia and an elevated erythrocyte sedimentation rate or C-reactive protein level may suggest inflammatory bowel disease, but the absence of laboratory abnormalities does not rule out ulcerative colitis. The diagnosis is suspected clinically and confirmed through endoscopic biopsy. First-line treatment is therapy with 5-aminosalicylic acid. Corticosteroids may be added if 5-aminosalicylic acid therapy is ineffective. Infliximab can be added to induce and sustain remission. Patients with severe or nonresponsive ulcerative colitis should be hospitalized, and intravenous corticosteroids should be given. If medical management has been ineffective, surgical intervention is indicated for severe disease. Patients with ulcerative colitis have an increased risk of colon cancer and should have periodic colonoscopy beginning eight to 10 years after diagnosis. PMID- 23939450 TI - Multiple sclerosis. PMID- 23939451 TI - Bromocriptine mesylate (Cycloset) for type 2 diabetes mellitus. PMID- 23939452 TI - Photo quiz. Pruritic rash in a pregnant woman. PMID- 23939453 TI - Treatments for urinary incontinence in women. PMID- 23939455 TI - AHA/ASA publish advisory on oral antithrombotics for stroke prevention in nonvalvular artial fibrillation. PMID- 23939456 TI - FPIN's clinical inquiries. Dipstick urinalysis for the diagnosis of acute UTI. PMID- 23939457 TI - Screening for ovarian cancer: reaffirmation recommendation statement. PMID- 23939458 TI - Mating enhances the probability of winning aggressive encounters in male lobster cockroaches. AB - In the present study, we report that contact with isolated female antenna significantly increases both the pheromone 3-hydroxy-2-butanone (3H-2B) release and the hemolymph JH III level in all examined aggressive posture-adopting (AP) and NP (non-AP-adopting) socially naive males, with significantly faster concomitant pre-mating wing-raising behavior in AP as compared to NP males. 3H-2B release and JH III level were significantly increased after mating in both AP and NP males. A positive correlation was observed between mating experience and dominant status. Furthermore, mated-AP males initiated fights more rapidly and fought for a significantly longer duration than mated-NP males; retention with the paired female for 24h did not affect this increase. JH III level and 3H-2B release were significantly increased in dominant males as compared to subordinates. These results suggest that prior mating experience in invertebrates may enhance aggression in subsequent male-male encounters, with accompanying physiological (hormone and pheromone) responses. PMID- 23939459 TI - Mamma mia: a feasibility study of a web-based intervention to reduce the risk of postpartum depression and enhance subjective well-being. AB - BACKGROUND: Currently, 10-15% of women giving birth suffer from symptoms of postpartum depression. Due to a lack of knowledge of this condition and the stigma associated with it, as well as few treatment options, a large proportion of postpartum women with depression remain untreated. Internet-based interventions have been found effective in treating depression, anxiety, phobias, and addictions. Hence, we developed such program ("Mamma Mia") with the aim of reducing the risk for postpartum depression and enhance subjective well-being. Mamma Mia is based on positive psychology, metacognitive therapy, and couples therapy. It starts in gestational week 22, and lasts until 6 months after birth. During pregnancy, Mamma Mia is delivered weekly (every Monday). After birth, Mamma Mia is delivered three times per week for six weeks. The remaining weeks, the program is delivered more sporadically. In total, Mamma Mia consists of 44 sessions. The program is individualized, interactive, and tunneled (ie, the user is guided through the program in a pre-determined manner). OBJECTIVE: The purpose of the present study was to pilot test the intervention in order to assess the feasibility and acceptance among program users. METHODS: The present paper reports a feasibility study that combined quantitative survey data with semi structured interviews. Participants (N=103) were recruited via hospitals, well baby clinics, and Facebook. Due to time constraint in completing the current study, our results were based on participation in one of the two phases: pregnancy or maternity. Participants in the pregnancy phase were surveyed 4 and 8 weeks after intervention enrollment, and participants in the postnatal phase were surveyed 2 and 4 weeks after intervention enrollment. The survey assessed perceived usefulness, ease-of-use, credibility, and unobtrusiveness. All measures were filled in by participants at both measurement occasions. Data were analyzed by running descriptives and frequencies with corresponding percentages. Binomial tests were carried out to investigate whether demographics differed significantly from a 50/50 distribution. Paired sample t tests were used to examine differences between time 1 and 2. Four participants were interviewed in the qualitative follow-up study, where they were given the opportunity to address and elaborate on similar aspects as assessed in the survey. RESULTS: More than two-thirds of users found Mamma Mia to be of high quality and would recommend Mamma Mia to others. By far, most also found the amount of information and frequency of the intervention schedule to be appropriate. Mamma Mia was perceived as a user friendly and credible intervention. CONCLUSIONS: Overall, the user acceptance of Mamma Mia was good and our findings add to the feasibility of the program. The effect of Mamma Mia on depression and subjective well-being will be evaluated in a large randomized controlled trial, and if found to be effective, Mamma Mia could serve as a low-threshold prevention program. PMID- 23939460 TI - Fractional tunnelling resonance in plasmonic media. AB - Metals can transmit light by tunnelling when they possess skin-depth thickness. Tunnelling can be resonantly enhanced if resonators are added to each side of a metal film, such as additional dielectric layers or periodic structures on a metal surface. Here we show that, even with no additional resonators, tunnelling resonance can arise if the metal film is confined and fractionally thin. In a slit waveguide filled with a negative permittivity metallic slab of thickness L, resonance is shown to arise at fractional thicknesses (L = Const./m; m = 1,2,3,...) by the excitation of 'vortex plasmons'. We experimentally demonstrate fractional tunnelling resonance and vortex plasmons using microwave and negative permittivity metamaterials. The measured spectral peaks of the fractional tunnelling resonance and modes of the vortex plasmons agree with theoretical predictions. Fractional tunnelling resonance and vortex plasmons open new perspectives in resonance physics and promise potential applications in nanotechnology. PMID- 23939461 TI - Mandatory anesthesia. PMID- 23939462 TI - Effect of green tea catechins on breast carcinogenesis: a systematic review of in vitro and in-vivo experimental studies. AB - Catechins (flavan-3-oils) are the main flavonoids present in green tea. The potential cancer chemopreventive and therapeutic properties of green tea catechins have been the focus of research efforts in the last two decades. This systematic review aims to generate in vitro and in vivo data on the effect of green tea catechins on breast carcinogenesis. Electronic databases were searched with the appropriate search terms. Existing evidence suggests that green tea catechins modulate breast cell carcinogenesis. The effect of green tea catechins on breast cell carcinogenesis has been investigated in different experimental models and under different experimental conditions, that is, carcinogen investigated, green tea catechin dosage regimen, treatment with green tea extract versus pure synthetic EGCG, and time point of treatment with green tea catechins in relation to the exposure to the carcinogen. Although the effect of green tea catechins was not always statistically significant, the protective effect of green tea catechins was demonstrated in all the trials, suggesting that treatment with green tea catechins should be further investigated in the clinical setting of chemoprevention of high-risk women. However, it should be emphasized that the reported actions of green tea catechins are observed in high concentrations that are difficult to achieve in the clinical setting. This drawback could be overcome by designing green tea catechins with better bioavailability and/or by cotreatment combining breast cancer endocrine treatment with green tea catechins. PMID- 23939463 TI - Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy cataplexy. AB - IMPORTANCE: Idiopathic narcolepsy with cataplexy is thought to be an autoimmune disorder targeting hypothalamic hypocretin neurons. Symptomatic narcolepsy with low hypocretin level has been described in Ma antibody-associated encephalitis; however, the mechanisms underlying such an association remain unknown. OBSERVATIONS: We described a 63-year-old man with clinical criteria for diencephalic encephalitis with sleepiness, cataplexy, hypocretin deficiency, and central hypothyroidism, together with brainstem encephalitis reflected by supranuclear ophtalmoparesis and rapid eye movement sleep behavior disorder with underlying abnormalities on brain magnetic resonance imaging. An autoimmune process was demonstrated by the detection of antibodies against Ma protein. Death occurred 4 months after disease onset without any tumor detected. Neuropathology, immunohistochemistry, and immunoreactivity results were compared with those obtained in idiopathic narcolepsy-cataplexy and with normal control brains. The principal findings revealed almost exclusive inflammation and tissue injury in the hypothalamus. The type of inflammatory reaction suggests cytotoxic CD8+ T lymphocytes being responsible for the induction of tissue injury. Inflammation was associated with complete loss of hypocretinergic neurons. Autoantibodies of the patient predominantly stained neurons in the hypothalamus and could be absorbed with Ma2. CONCLUSIONS AND RELEVANCE: The encephalitic process, responsible for narcolepsy-cataplexy and hypocretin deficiency, reflects a CD8+ inflammatory-mediated response against hypocretin neurons. PMID- 23939464 TI - Facile synthesis of quantum dots/mesoporous silica/quantum dots core/shell/shell hybrid microspheres for ratiometric fluorescence detection of 5-fluorouracil in human serum. AB - Compared to single photoluminescence (PL) intensity-based sensors, dual-emitting based ratiometric PL sensors are more preferable because the influence from PL fluctuation in the reagents and background PL can be reduced to a minimum. However, so far no report has been directed to the ratiometric PL detection of 5 fluorouracil (5-FU). In this study, for the first time, high-quality quantum dots (QD1)/mesoporous silica (SiO2)/quantum dots (QD2) core/shell/shell hybrid microspheres (QD1/SiO2/QD2) were prepared by self-assembly, and further developed toward a ratiometric PL sensor of 5-FU. The addition of 5-FU induced regular PL quenching of QD2, but hardly influenced on the PL of QD1 in the microspheres. Based on the linear relationship (R = -0.9994) between the ratiometric PL intensity (IQD2/IQD1) and the molar concentration of 5-FU (0-1 MUM), a ratiometric PL sensor for 5-FU was achieved and displays a low limit of detection (20 nM). Experimental results testified that this sensor for the detection of 5 FU in human serum samples was highly sensitive and selective over other inorganic ions and biological molecules. Compared with conventional analysis techniques and other spectrofluorimetric methods reported previously, this proposed ratiometric PL sensor could be a good candidate for the highly efficient detection of 5-FU. PMID- 23939465 TI - WITHDRAWN: Uncoupling protein 2 gene polymorphisms in association with overweight and obesity susceptibility: A meta-analysis. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23939466 TI - Protein sequence comparison based on K-string dictionary. AB - The current K-string-based protein sequence comparisons require large amounts of computer memory because the dimension of the protein vector representation grows exponentially with K. In this paper, we propose a novel concept, the "K-string dictionary", to solve this high-dimensional problem. It allows us to use a much lower dimensional K-string-based frequency or probability vector to represent a protein, and thus significantly reduce the computer memory requirements for their implementation. Furthermore, based on this new concept, we use Singular Value Decomposition to analyze real protein datasets, and the improved protein vector representation allows us to obtain accurate gene trees. PMID- 23939467 TI - Genome-wide identification and expression analysis of MAPK and MAPKK gene family in Malus domestica. AB - MAPK signal transduction modules play crucial roles in regulating many biological processes in plants, which are composed of three classes of hierarchically organized protein kinases, namely MAPKKKs, MAPKKs, and MAPKs. Although genome wide analysis of this family has been carried out in some species, little is known about MAPK and MAPKK genes in apple (Malus domestica). In this study, a total of 26 putative apple MAPK genes (MdMPKs) and 9 putative apple MAPKK genes (MdMKKs) have been identified and located within the apple genome. Phylogenetic analysis revealed that MdMAPKs and MdMAPKKs could be divided into 4 subfamilies (groups A, B, C and D), respectively. The predicted MdMAPKs and MdMAPKKs were distributed across 13 out of 17 chromosomes with different densities. In addition, analysis of exon-intron junctions and of intron phase inside the predicted coding region of each candidate gene has revealed high levels of conservation within and between phylogenetic groups. According to the microarray and expressed sequence tag (EST) analysis, the different expression patterns indicate that they may play different roles during fruit development and rootstock-scion interaction process. Moreover, MAPK and MAPKK genes were performed expression profile analyses in different tissues (root, stem, leaf, flower and fruit), and all of the selected genes were expressed in at least one of the tissues tested, indicating that the MAPKs and MAPKKs are involved in various aspects of physiological and developmental processes of apple. To our knowledge, this is the first report of a genome-wide analysis of the apple MAPK and MAPKK gene family. This study provides valuable information for understanding the classification and putative functions of the MAPK signal in apple. PMID- 23939469 TI - The associations between the Val158Met in the catechol-O-methyltransferase (COMT) gene and the risk of uterine leiomyoma (ULM). AB - The Val158Met polymorphism of the COMT gene has been implicated in susceptibility to uterine leiomyoma (ULM), but the reported results were inconclusive. The aim of the study was to evaluate the Val158Met polymorphism of the COMT gene and the risk of ULM by meta-analysis. A comprehensive electronic search for relevant articles was conducted in Pubmed, Embase, CNKI, Wanfang, and Weipu databases. Statistical analysis was performed by using the Revman4.2 software and Stata10.0 software. A total of 7 articles including 12 case-control studies were identified in this meta-analysis. The results showed that the polymorphism was associated with decreased risk of ULM (Met/Met+Val/Met vs. Met/Met: OR=0.84, 95% CI=0.70 0.99, Z=2.07, p=0.04). In the subgroup analyses by ethnicity, significant decreased risk was found among the black populations (OR=0.68, 95% CI=0.48-0.97, Z=2.15, p=0.03). The current meta-analysis suggested that the Val158Met polymorphism in the COMT gene was associated with decreased risk of ULM, especially in the black population. Future studies are needed to validate our conclusions. PMID- 23939468 TI - Novel SLC20A2 mutations identified in southern Chinese patients with idiopathic basal ganglia calcification. AB - Idiopathic basal ganglia calcification (IBGC) is a rare neuropsychiatric disorder characterized by bilateral and symmetric cerebral calcifications. Recently, SLC20A2 was identified as a causative gene for familial IBGC, and three mutations were reported in a northern Chinese population. Here, we aimed to explore the mutation spectrum of SLC20A2 in a southern Chinese population. Sanger sequencing was employed to screen mutations within SLC20A2 in two IBGC families and 14 sporadic IBGC cases from a southern Han Chinese population. Four novel mutations (c.82G>A p.D28N, c.185T>C p.L62P, c.1470_1478delGCAGGTCCT p.Q491_L493del and c.935-1G>A) were identified in two families and two sporadic cases, respectively; none were detected in 200 unrelated controls. No mutation was found in the remaining 12 patients. Different mutations may result in varied phenotypes, including brain calcification and clinical manifestations. Our study supports the hypothesis that SLC20A2 is a causative gene of IBGC and expands the mutation spectrum of SLC20A2, which facilitates the understanding of the genotype phenotype correlation of IBGC. PMID- 23939470 TI - Start Codon Targeted (SCoT) marker reveals genetic diversity of Dendrobium nobile Lindl., an endangered medicinal orchid species. AB - Genetic variability in the wild genotypes of Dendrobium nobile Lindl. collected from different parts of Northeast India, was analyzed using a Start Codon Targeted (SCoT) marker system. A total of sixty individuals comprising of six natural populations were investigated for the existing natural genetic diversity. One hundred and thirty two (132) amplicons were produced by SCoT marker generating 96.21% polymorphism. The PIC value of the SCoT marker system was 0.78 and the Rp values of the primers ranged between 4.43 and 7.50. The percentage of polymorphic loci (Pp) ranging from 25% to 56.82%, Nei's gene diversity (h) from 0.08 to 0.15 with mean Nei's gene diversity of 0.28, and Shannon's information index (I) values ranging from 0.13 to 0.24 with an average value of 0.43 were recorded. The gene flow value (0.37) and the diversity among populations (0.57) demonstrated higher genetic variation among the populations. Analysis of molecular variance (AMOVA) showed 43.37% of variation within the populations, whereas 56.63% variation was recorded among the populations. Cluster analysis also reveals high genetic variation among the genotypes. Present investigation suggests the effectiveness of SCoT marker system to estimate the genetic diversity of D. nobile and that it can be seen as a preliminary point for future research on the population and evolutionary genetics of this endangered orchid species of medicinal importance. PMID- 23939471 TI - Screening for possible miRNA-mRNA associations in a colon cancer cell line. AB - MicroRNAs (miRNAs) are small non-coding RNAs mediating the regulation of gene expression in various biological contexts, including carcinogenesis. Here, we screened putative associations between 34, 45, and 103 miRNAs and 164, 391, and 81 mRNAs via Argonaute1 (Ago1) or Ago2 immunoprecipitation (IP) experiments in a colon cancer cell line. We used a combination of RIP Seq analysis. RNAs that were co-immunoprecipitated with Ago1 or Ago2 were used for massively parallel small RNA and mRNA sequencing. The detected miRNAs and mRNAs were further associated with one another based on in silico target predictions. Analysis of the putative associations indicated that, although Ago1 and Ago2 shared a similar repertory of miRNAs, the mRNAs possibly regulated by those miRNAs seemed different. The mRNAs detected with Ago1 IP were indicated to be frequently associated with genes having constitutive cellular functions, regulated by a smaller number of miRNAs, and appeared to receive more stringent translational regulation. In contrast, putative miRNA-mRNA associations detected with Ago2 IP appeared to be related to signal transduction genes, which had a larger number of possible miRNA binding sites. We then conducted a similar analysis using the colon cancer cells cultured under hypoxia and identified potential hypoxia-induced miRNA-mRNA associations, which included several well-characterized cancer-related genes as novel putative miRNA targets. PMID- 23939472 TI - Novel genes FAM134C, C3orf10 and ENOX1 are regulated by NRF-1 and differentially regulate neurite outgrowth in neuroblastoma cells and hippocampal neurons. AB - Nuclear respiratory factor-1 (NRF-1) is a major transcription factor in the human genome and functions in neurite outgrowth in neuroblastoma cells. Whether genes downstream from NRF-1 differentially regulate axonal and dendritic outgrowth in neurons remains largely unknown. Three hypothetical genes, C3orf10, FAM134C, and ENOX1, were investigated because their NRF-1 response elements are 100% conserved in humans and mice. We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. FAM134C but not C3orf10 mediates NRF-1-enhanced neurite outgrowth. In primary rat hippocampal neurons, Fam134c is predominantly expressed in the axon hillock and C3orf10 is ubiquitously expressed in all neurites and cell bodies at different developmental stages, suggesting their roles in axonal and dendritic outgrowth. Knockdown of Fam134c decreased both axonal length and the number of axonal collaterals and dendrites, however, knockdown of C3orf10 only increased the number of axonal collaterals and dendrites. Overall, we annotated FAM134C, C3orf10, and ENOX1 as NRF-1-regulated genes, which have differential effects on neurite outgrowth in neuroblastoma cells as well as neurons. This study provided an effective platform for annotating hypothetical genes in the human genome and increasing our knowledge in the molecular network underlying neuronal differentiation. PMID- 23939473 TI - Preparation of graphene nanoplatelet-titanate nanotube composite and its advantages over the two single components as biosensor immobilization materials. AB - A novel nanocomposite consisting of graphene nanoplatelets (GNPs) and titanate nanotubes (TNTs) have been synthesized successfully utilizing the hydrothermal method. The GNP-TNT composite was characterized by transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy and electrochemical impedance spectroscopy. The voltammetric characterization of GNP TNT composite, pure GNPs and pure TNTs modified horseradish peroxidase (HRP) biosensors were conducted to select the most suitable electrode immobilization material for enzyme biosensors. The GNPs was firstly eliminated owing to its extremely high background charging current, distinct electrochemical interference from its surface functional groups and low signal to noise ratio. Next, the direct electron transfer of HRP on electrode and the catalytic current of HRP towards H2O2 was increased around 45% and 72% respectively on GNP-TNT composite modified electrodes compared with those on pure TNTs modified electrodes. GNP-TNT composite modified HRP biosensor also exhibited superiority over pure TNTs modified HRP biosensor in the analytical performance. The precision and stability study provided additional evidence for the feasibility of using GNP-TNT composite as electrode modification material. PMID- 23939474 TI - Dual-mode tracking of tumor-cell-specific drug delivery using fluorescence and label-free SERS techniques. AB - We developed a dual-mode detection method for tumor cell specific targeting and intracellular delivery of the chemotherapeutic agent Doxorubicin (DOX) using folic acid functionalized mesoporous silica nanoparticles (FA-MSNs) as carrier systems. In this method, label free surface enhanced Raman scattering (SERS) spectra were utilized to monitor the dynamic release of DOX inside tumor cells in combination with fluorescence images. To investigate the targeting delivery performance of the carrier system, both normal cells (MRC-5) and tumor cells (HeLa) were used as the model cells. The real-time release of DOX from FA-MSNs inside MRC-5 and HeLa cells was monitored. As demonstrated by both fluorescence and SERS results, the DOX loaded FA-MSNs can actively target FA receptor overexpressed tumor cells. Moreover, the releasing behavior of DOX from FA-MSNs in tumor and in normal cells was quantitatively analyzed. Compared with the traditional sole fluorescence or SERS method, this dual-mode detection is more powerful and more accurate, which should have a potential application in drug tracking in living cells. PMID- 23939475 TI - Retrospective study of hepatocellular adenomas based on the phenotypic classification system: A report from China. AB - A molecular and pathological classification system for hepatocellular adenomas (HCAs) was recently introduced in Europe, resulting in four major identified subgroups. Asian countries have a considerably lower incidence of HCA as well as a different etiology. We aimed to characterize HCAs in a Chinese population based on this new classification system. A series of 30 patients with HCA were analyzed based on the phenotypic classification system using immunohistochemical analysis. Investigated antigens included liver-fatty acid binding protein (L-FABP), glutamine synthetase (GS), beta-catenin, serum amyloid A (SAA), and C-reactive protein (CRP). Of the 30 cases (20 female) included in this study, only one had a history of oral contraceptive use. We identified 9 (30%) hepatocyte nuclear factor (HNF)-1alpha-inactivated HCAs, 3 (10%) beta-catenin-activated HCAs, 11 (36.7%) inflammatory HCAs, and 7 (23.3%) unclassified HCAs. In the inflammatory HCA group, 2 cases demonstrated concurrent beta-catenin-activation. Homogeneous steatosis (6/9) and microadenomas (2/9) were more frequently observed in HNF1alpha-inactivated HCAs. A body mass index (BMI) of greater than 25 (5/11), alcohol use (4/11), and steatosis in background liver (3/11) were more frequent in inflammatory HCAs. beta-catenin-activated HCAs were larger than those of other subgroups. Despite obvious differences in etiology and gender proportion compared with Western countries, the clinical and pathological characteristics of HCA subgroups in China are similar to those in Europe. The phenotypic classification system could be reliably applied to Chinese patients as a meaningful tool for HCA management. PMID- 23939477 TI - Three-dimensional electron-accepting compounds containing perylene bis(dicarboximide)s as n-type organic photovoltaic materials. AB - The synthesis of three-dimensional compounds containing perylene bis(dicarboximide) for application as acceptor materials in organic photovoltaics is reported. Physicochemical measurements as well as device evaluations revealed that the characteristic properties of these materials are derived from their three-dimensional structure. PMID- 23939476 TI - Okadaic acid meet and greet: an insight into detection methods, response strategies and genotoxic effects in marine invertebrates. AB - Harmful Algal Blooms (HABs) constitute one of the most important sources of contamination in the oceans, producing high concentrations of potentially harmful biotoxins that are accumulated across the food chains. One such biotoxin, Okadaic Acid (OA), is produced by marine dinoflagellates and subsequently accumulated within the tissues of filtering marine organisms feeding on HABs, rapidly spreading to their predators in the food chain and eventually reaching human consumers causing Diarrhetic Shellfish Poisoning (DSP) syndrome. While numerous studies have thoroughly evaluated the effects of OA in mammals, the attention drawn to marine organisms in this regard has been scarce, even though they constitute primary targets for this biotoxin. With this in mind, the present work aimed to provide a timely and comprehensive insight into the current literature on the effect of OA in marine invertebrates, along with the strategies developed by these organisms to respond to its toxic effect together with the most important methods and techniques used for OA detection and evaluation. PMID- 23939478 TI - Risk factors: Kidney stones associated with increased CHD risk in women. PMID- 23939479 TI - Interventional cardiology: Platelet reactivity after stenting. PMID- 23939480 TI - Public health: Echocardiography--no role in population screening. PMID- 23939482 TI - Hypertension: Riociguat therapy for pulmonary hypertension. PMID- 23939481 TI - Cardiac contractility modulation therapy in advanced systolic heart failure. AB - Cardiac contractility modulation (CCM) is the application of nonexcitatory electrical signals to the myocardium, during the absolute refractory period of the action potential, to elicit a positive inotropic effect without increasing myocardial oxygen consumption. These effects are independent of QRS duration; consequently, CCM device therapy might benefit symptomatic patients with reduced left ventricular ejection fraction who are not candidates for cardiac resynchronization therapy. Preclinical studies have demonstrated a rapid positive inotropic effect of CCM, which seems to be mediated by modulation of cardiomyocyte Ca(2+) fluxes and alterations in the phosphorylation of cardiac phospholamban. In vivo translational and clinical studies that utilized double biphasic voltage pulses to the right ventricular aspect of the interventricular septum have demonstrated positive global effects on cardiac reverse remodelling and contractility. Long-term application of CCM seems to improve patients' exercise tolerance and quality of life. These benefits are apparently accomplished with an acceptable safety profile; however, to date, no data have demonstrated reductions in hospitalizations for heart failure or mortality. CCM is currently available in Europe and ongoing studies are attempting to identify the ideal target population and accumulate additional outcome data. PMID- 23939483 TI - Genetics: Potassium channelopathy implicated in the pathogenesis of familial PAH. PMID- 23939484 TI - Phosphorescence from a pure organic fluorene derivative in solution at room temperature. AB - A fluorene derivative having both bromo and formyl groups exhibited bright phosphorescence emission in common organic solvents at room temperature. The absolute phosphorescence quantum yield reached 5.9% in chloroform at 298 K. When the fluorene derivative was incorporated into a poly(methyl methacrylate) film, the phosphorescence emission was similarly observed even under air at room temperature for over five days. PMID- 23939485 TI - Using AHRQ patient safety indicators to detect postdischarge adverse events in the Veterans Health Administration. AB - Patient safety indicators (PSIs) use inpatient administrative data to flag cases with potentially preventable adverse events (AEs) attributable to hospital care. This study explored how many AEs the PSIs identified in the 30 days post discharge. PSI software was run on Veterans Health Administration 2003-2007 administrative data for 10 recently validated PSIs. Among PSI-eligible index hospitalizations not flagged with an AE, this study evaluated how many AEs occurred within 1 to 14 and 15 to 30 days post discharge using inpatient and outpatient administrative data. Considering all PSI-eligible index hospitalizations, 11 141 postdischarge AEs were identified, compared with 40 578 inpatient-flagged AEs. More than 60% of postdischarge AEs were detected within 14 days of discharge. The majority of postdischarge AEs were decubitus ulcers and postoperative pulmonary embolisms or deep vein thromboses. Extending PSI algorithms to the postdischarge period may provide a more complete picture of hospital quality. Future work should use chart review to validate postdischarge PSI events. PMID- 23939487 TI - Progress in patient safety: a glass fuller than it seems. PMID- 23939486 TI - Factors Influencing the Increasing Disparity in LDL Cholesterol Control Between White and Black Patients With Diabetes in a Context of Active Quality Improvement. AB - After implementing a multifaceted physician-directed quality improvement (QI) initiative, an increased disparity in low-density lipoprotein (LDL) cholesterol control between white and black diabetes patients was observed. To examine possible causes, a retrospective analysis of 962 black and white patients treated continuously between 2008 and 2010 was performed. At baseline, 55.0% of whites and 49.8% of blacks were controlled (5.2% disparity). The disparity increased, with 61.8% of whites and 44.6% of blacks having control in 2010 (17.2% disparity). Among patients uncontrolled at baseline, blacks were less likely to become controlled. Among patients controlled at baseline, blacks were less likely to remain controlled; accounting for patient characteristics and changes in lipid lowering drug prescription regimens did not attenuate these relationships. Physician-facing, general QI interventions may be insufficient to produce equity in LDL cholesterol control. Helping patients maintain prior success controlling cholesterol appears as important in addressing this disparity as is helping uncontrolled patients achieve control. PMID- 23939488 TI - Which outpatient wait-time measures are related to patient satisfaction? AB - Long waits for appointments decrease patient satisfaction. Administrative wait time measures are used by managers, but relationships between these measures and satisfaction have not been studied. Data from the Veterans Health Administration are used to examine the relationship between wait times and satisfaction. Outcome measures include patient-reported satisfaction and timely appointment access. Capacity and retrospective and prospective time stamp measures are calculated separately for new and returning patients. The time stamp measures consist of the date when the appointment was created in the scheduling system (create date [CD]) or the date the appointment was desired as the start date for wait-time computation. Logistic regression models predict patient satisfaction using these measures. The new-patient capacity, new-patient time stamp measures using CD, and the returning-patient desired-date prospective measure were significantly associated with patient satisfaction. Standard practices can be improved by targeting wait-time measures to patient subpopulations. PMID- 23939489 TI - Dependence of All-Cause Standardized In-Hospital Mortality on Sepsis Mortality Between 2005 and 2010. AB - Sepsis is the 11th leading cause of death in the United States. The authors evaluated the dependence of all-cause in-hospital mortality on sepsis mortality. A retrospective observational cohort design and All Patient Refined Diagnosis Related Groups were used to evaluate 150 410 patients (>17 years of age) over 6 years. The hospital standardized mortality ratio (HSMR) decreased from 0.80 +/- 0.04 to 0.65 +/- 0.04 (observed/expected [O/E]). The HSMR was correlated with the standardized sepsis mortality ratio (SSMR), accounting for 61% of the variation (P < .0001). The mortality rate for sepsis declined from 14.54 +/- 1.60% to 8.57 +/- 1.88% (P < .002), and the SSMR decreased from 0.82 +/- 0.09 to 0.48 +/- 0.07 (O/E; P < .002). The months of sepsis mortality matched the months of hospital mortality for the lowest of each (odds ratio = 0.30, 95% confidence interval = 0.14-0.65; P < .003) and the highest of each (odds ratio = 1.47, 95% confidence interval = 1.18-1.84; P < .0007). Monitoring monthly mortality of sepsis can provide insight for timely intervention into variation of total in-hospital mortality. PMID- 23939490 TI - Effect of high free fatty acids on the anti-contractile response of perivascular adipose tissue in rat aorta. AB - To determine whether high free fatty acids (FFA) could affect the anti contractile properties of perivascular adipose tissue (PVAT) in rat aortas. Wistar rats were divided into normal, obesity and fenofibrate groups and fed a normal, high-fat, and high-fat plus fenofibrate diet, respectively. Thoracic aortas with or without PVAT (PVAT+ and PVAT-) were prepared with either intact endothelium (E+) or with endothelium removed (E-). Aortas pre-treated with either 500MUmol/L of palmitic acid (PA) or physiological salt solution (PSS), as a control, were used for in vitro study. Concentration-dependent responses of aortas to norepinephrine were measured. The anti-contractile effects of PVAT were attenuated in both obese rats with high FFA levels and in the PA group in the presence of endothelium, but not in the absence of endothelium. The attenuation of the anti-contractile effect was restored by reducing FFA levels in the fenofibrate group (P<0.05). Incubation of aortas (PVAT+ E+) with nitric oxide (NO) synthase inhibitor and tumor necrosis factor-alpha (TNF-alpha) in the normal group caused attenuation of the anti-contractile effect of PVAT (P<0.05). Incubation of aortas (PVAT+ E+) in the obese and PA groups with a NO donor, anti TNF-alpha antibodies or free radical scavengers partially restored the anti contractile effect of PVAT (P<0.05). Under both acute and chronic conditions, high FFA levels could attenuate the anti-contractile properties of PVAT by an endothelium-dependent rather than an endothelium-independent mechanism, in which inflammation and oxidative stress may play important roles. PMID- 23939491 TI - Overexpression of microRNA-1 promotes cardiomyocyte commitment from human cardiovascular progenitors via suppressing WNT and FGF signaling pathways. AB - Early heart development takes place through a complex series of steps, including the induction of cardiac mesoderm, formation of the cardiovascular progenitor cells and the commitment of cardiovascular lineage cells, such as cardiomyocytes (CMs), smooth muscle cells (SMCs) and endothelial cells (ECs). Recently, microRNAs, a family of endogenous, small non-coding RNAs, have been identified as critical regulators in cardiogenesis and cardiovascular disease. Previous studies demonstrated that microRNA-1 (miR-1) could promote cardiac differentiation from mouse and human embryonic stem (ES) cells. However, the underlying mechanism remained largely unclear. We performed microRNA deep sequencing among human ES cells, ES cell derived-multipotent cardiovascular progenitors (MCPs), and MCP specified CMs, ECs, and SMCs. A specific enrichment of miR-1 was found in CMs, not in SMCs or ECs, implying a key role of miR-1 in determining cardiovascular commitment from MCPs. When overexpressed in human induced pluripotent stem cells, miR-1 enhanced the expression of key cardiac transcriptional factors and sarcomeric genes. Importantly, we found miR-1 promoted CM differentiation and suppressed EC commitment from MCPs by modulating the activities of WNT and FGF signaling pathways. FZD7 and FRS2 were confirmed as miR-1 targets using luciferase reporter assay and western blot. Overall, this study reveals a fate switching role of miR-1 at early human cardiovascular commitment stage via suppressing both WNT and FGF signaling pathways. PMID- 23939494 TI - Health literacy and prescribing: it is time to change old habits. PMID- 23939495 TI - Diabetes: taking control of my health. PMID- 23939492 TI - BET acetyl-lysine binding proteins control pathological cardiac hypertrophy. AB - Cardiac hypertrophy is an independent predictor of adverse outcomes in patients with heart failure, and thus represents an attractive target for novel therapeutic intervention. JQ1, a small molecule inhibitor of bromodomain and extraterminal (BET) acetyl-lysine reader proteins, was identified in a high throughput screen designed to discover novel small molecule regulators of cardiomyocyte hypertrophy. JQ1 dose-dependently blocked agonist-dependent hypertrophy of cultured neonatal rat ventricular myocytes (NRVMs) and reversed the prototypical gene program associated with pathological cardiac hypertrophy. JQ1 also blocked left ventricular hypertrophy (LVH) and improved cardiac function in adult mice subjected to transverse aortic constriction (TAC). The BET family consists of BRD2, BRD3, BRD4 and BRDT. BRD4 protein expression was increased during cardiac hypertrophy, and hypertrophic stimuli promoted recruitment of BRD4 to the transcriptional start site (TSS) of the gene encoding atrial natriuretic factor (ANF). Binding of BRD4 to the ANF TSS was associated with increased phosphorylation of local RNA polymerase II. These findings define a novel function for BET proteins as signal-responsive regulators of cardiac hypertrophy, and suggest that small molecule inhibitors of these epigenetic reader proteins have potential as therapeutics for heart failure. PMID- 23939496 TI - Oxytocin augmentation during labor with epidural analgesia. PMID- 23939497 TI - Contraceptive education for women after childbirth. PMID- 23939498 TI - Pharmacologic therapy for acute pain. AB - The approach to patients with acute pain begins by identifying the underlying cause and a disease-specific treatment. The first-line pharmacologic agent for the symptomatic treatment of mild to moderate pain is acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). The choice between these two medications depends on the type of pain and patient risk factors for NSAID related adverse effects (e.g., gastrointestinal, renovascular, or cardiovascular effects). Different NSAIDs have similar analgesic effects. However, cyclooxygenase-2 selective NSAIDs (e.g., celecoxib) must be used with caution in patients with cardiovascular risk factors and are more expensive than nonselective NSAIDs. If these first-line agents are not sufficient for mild to moderate pain, medications that target separate pathways simultaneously, such as an acetaminophen/opioid combination, are reasonable choices. Severe acute pain is typically treated with potent opioids. At each step, adjuvant medications directed at the underlying condition can be used. Newer medications with dual actions (e.g., tapentadol) are also an option. There is little evidence that one opioid is superior for pain control, but there are some pharmacologic differences among opioids. Because of the growing misuse and diversion of controlled substances, caution should be used when prescribing opioids, even for short-term treatment. Patients should be advised to properly dispose of unused medications. PMID- 23939499 TI - Evaluation of primary immunodeficiency disease in children. AB - One in 2,000 children younger than 18 years is thought to have a primary immunodeficiency disease. Antibody, combined B-cell and T-cell, phagocytic, and complement disorders are the most common types. Children with these diseases tend to have bacterial or fungal infections with unusual organisms, or unusually severe and recurrent infections with common organisms. A family history of primary immunodeficiency disease is the strongest predictor of a person having this type of disease. When an immunodeficiency disease is suspected, initial laboratory screening should include a complete blood count with differential and measurement of serum immunoglobulin and complement levels. The presence of lymphocytopenia on complete blood count suggests a T-cell disorder, whereas a finding of neutropenia suggests a phagocytic disorder. Abnormal serum immunoglobulin levels suggest a B-cell disorder. Abnormalities on assay of the classic or alternative complement pathways suggest a complement disorder. If laboratory results are abnormal, or if clinical suspicion continues despite normal laboratory results, children should be referred for further evaluation. Human immunodeficiency virus infection should also be considered, and testing should be performed, if appropriate; this infection often clinically resembles a T-cell disorder. PMID- 23939500 TI - Amenorrhea: an approach to diagnosis and management. AB - Although amenorrhea may result from a number of different conditions, a systematic evaluation including a detailed history, physical examination, and laboratory assessment of selected serum hormone levels can usually identify the underlying cause. Primary amenorrhea, which by definition is failure to reach menarche, is often the result of chromosomal irregularities leading to primary ovarian insufficiency (e.g., Turner syndrome) or anatomic abnormalities (e.g., Mullerian agenesis). Secondary amenorrhea is defined as the cessation of regular menses for three months or the cessation of irregular menses for six months. Most cases of secondary amenorrhea can be attributed to polycystic ovary syndrome, hypothalamic amenorrhea, hyperprolactinemia, or primary ovarian insufficiency. Pregnancy should be excluded in all cases. Initial workup of primary and secondary amenorrhea includes a pregnancy test and serum levels of luteinizing hormone, follicle-stimulating hormone, prolactin, and thyroid-stimulating hormone. Patients with primary ovarian insufficiency can maintain unpredictable ovarian function and should not be presumed infertile. Patients with hypothalamic amenorrhea should be evaluated for eating disorders and are at risk for decreased bone density. Patients with polycystic ovary syndrome are at risk for glucose intolerance, dyslipidemia, and other aspects of metabolic syndrome. Patients with Turner syndrome (or variant) should be treated by a physician familiar with the appropriate screening and treatment measures. Treatment goals for patients with amenorrhea may vary considerably, and depend on the patient and the specific diagnosis. PMID- 23939501 TI - Photo quiz. Toddler with a worsening rash. PMID- 23939502 TI - Caring for colleagues, VIPs, friends, and family members. PMID- 23939507 TI - Unequal distribution of the U.S. primary care workforce. PMID- 23939508 TI - Amenorrhea. Page for Patients. PMID- 23939509 TI - A prospective cohort study evaluating a novel colonoscopy platform featuring full spectrum endoscopy. AB - BACKGROUND AND STUDY AIMS: Although colonoscopy is the criterion standard for detecting colorectal adenomas and cancers, a significant percentage of adenomas are missed with this technique. We aimed to establish the feasibility, usability, and safety of a novel colonoscopy platform featuring full-spectrum endoscopy (FUSE). PATIENTS AND METHODS: This was a prospective, single-center pilot and feasibility study. In total, 50 individuals, ages 18 - 70 years, underwent colonoscopy featuring FUSE (up to 330 degrees field of view) for colorectal cancer screening, polyp surveillance, or diagnostic evaluation. Study end points included success of cecal intubation, time to cecal intubation, withdrawal time, total procedure time, success of therapeutic interventions, adverse events, and endoscopists' subjective evaluation of FUSE. RESULTS: Cecal intubation was achieved in 50/50 individuals (100 %). Time to cecum (minutes, mean +/- SD) was 3.1 +/- 1.5 minutes, withdrawal time 12.7 +/- 4.4 minutes, and total procedure time 15.3 +/- 4.6 minutes. In 22/50 cases (44 %), 26 therapeutic interventions were performed: 19 (73.1 %) biopsies and 7 (26.9 %) polypectomies. No acute or delayed adverse events were observed. Patient satisfaction and endoscopist subjective evaluation were high. CONCLUSIONS: A colonoscopy platform featuring full-spectrum endoscopy appears feasible, usable, and safe. These results represent an important advance in colonoscopy imaging technology and should be further pursued in comparative human studies. PMID- 23939510 TI - Improving depression treatment for women: integrating a collaborative care depression intervention into OB-GYN care. AB - BACKGROUND: Women have higher rates of depression and often experience depression symptoms during critical reproductive periods, including adolescence, pregnancy, postpartum, and menopause. Collaborative care intervention models for mood disorders in patients receiving care in an OB-GYN clinic setting have not been evaluated. Study design and methodology for a randomized controlled trial of collaborative care depression management versus usual care in OB-GYN clinics and the details of the adapted collaborative care intervention and model implementation are described in this paper. METHODS: Women over age 18 years with clinically significant symptoms of depression, as measured by a Patient Health Questionnaire-9 (PHQ-9) score >=10 and a clinical diagnosis of major depression or dysthymia, were randomized to the study intervention or to usual care and were followed for 18 months. The primary outcome assessed was change over time in the SCL-20 depression scale between baseline and 12 months. BASELINE RESULTS: Two hundred five women were randomized: 57% white, 20% African American, 9% Asian or Pacific Islander, 7% Hispanic, and 6% Native American. Mean age was 39 years. 4.6% were pregnant and 7.5% were within 12 months postpartum. The majority were single (52%), and 95% had at least the equivalent of a high school diploma. Almost all patients met DSM IV criteria for major depression (99%) and approximately 33% met criteria for dysthymia. CONCLUSIONS: An OB-GYN collaborative care team, including a social worker, a psychiatrist, and an OB-GYN physician, who met weekly and used an electronic tracking system for patients was the essential element of the proposed depression care treatment model described here. Further study of models that improve quality of depression care that are adapted to the unique OB-GYN setting is needed. PMID- 23939511 TI - The efficacy and biobehavioural basis of baclofen in the treatment of alcoholic liver disease (BacALD): study protocol for a randomised controlled trial. AB - BACKGROUND: Effective treatments for alcohol use disorders in those with significant liver disease are critically lacking. The primary aim of the current study is to explore the effectiveness and biobehavioural basis of low and high dose baclofen in improving treatment outcomes for alcohol dependence in people with alcoholic liver disease (The BacALD study). METHODS: This double-blind, placebo-controlled study will randomize 180 participants to a 12-week regime of either baclofen (30 mg/day baclofen, 75 mg/day baclofen) or placebo. Participants must meet the ICD-10 criteria for alcohol dependence in addition to alcoholic liver disease (ALD) defined as the presence of symptoms and/or signs referable to liver disease or its complications with or without cirrhosis. Primary outcome measures will include total abstinence duration, and time to lapse and relapse. Furthermore, 60 of the ALD patients enrolled in the trial will also participate in a pharmacokinetic and cue-reactivity component, along with an additional 30 healthy volunteers matched for age and gender randomised to a 1 week regime of either 30 mg/day baclofen or 75 mg/day baclofen. At week 1, plasma levels of baclofen and beta-p-chlorophenol-gamma-hydroxybutric acid will be measured at 0, 1 and 4 h following baclofen administration and psychophysiological responses to alcohol-associated stimuli will be assessed in a cue reactivity paradigm. Recruitment commenced in late March 2013. CONCLUSIONS: This trial will demonstrate the efficacy and safety of two doses of baclofen in patients with alcoholic liver disease and will explore the biobehavioural mechanisms of the treatment effect. PMID- 23939512 TI - Enhancing exposure therapy for PTSD with yohimbine HCL: protocol for a double blind, randomized controlled study implementing subjective and objective measures of treatment outcome. AB - Prolonged exposure (PE) therapy is considered a gold standard protocol for the treatment of PTSD, and it is associated with large treatment effect sizes in combat veteran samples. However, considering high rates of PTSD in the present veteran population, ongoing research work is important toward improving treatment efficiency by decreasing time to symptom amelioration and increasing the amount of symptom amelioration. The proposed research aims to enhance exposure therapy outcomes for veterans with PTSD via combination treatment with PE and yohimbine hydrochloride (HCL), an alpha-2 adrenergic receptor antagonist. The proposed investigation entails a randomized, placebo-controlled trial investigating the effect of a single administration of yohimbine HCL (paired with the first session of imaginal exposure) on outcome of PE in 40 veterans with PTSD. An additional goal is to establish a pragmatic method of tracking psychophysiological measures over the course of therapy for incorporation into future clinical psychotherapy trials. Thus, in addition to traditional self- and clinician-reported psychological outcomes, heart rate and skin conductance reactivity will be measured during a standard trauma-specific imagery task before, during, and after PE treatment. We will further investigate whether changes in psychophysiological measures predict changes in patient- and clinician-reported outcome measures. PMID- 23939515 TI - Promoting "low T": a medical writer's perspective. AB - Despite progress in raising the level of transparency about funding, conflicts of interest, and ghostwriting, drug companies remain free to pursue subtle and, therefore, effective means of marketing. Continuing medical education programs and "consensus" panels continue to be funded by companies selling products directly tied to the messages being conveyed by the resulting "educational" materials. And patient education materials continue to be created that, while factually accurate, subtly shift attitudes by including only selected facts and/or omitting ideas that would undermine the funder's preferred paradigm. PMID- 23939516 TI - Low "T" as in "template": how to sell disease. PMID- 23939517 TI - Trends in androgen prescribing in the United States, 2001 to 2011. PMID- 23939518 TI - Perceptions of safety are shaped by the hospital environment. PMID- 23939519 TI - Why physicians favored lipitor over simvastatin. PMID- 23939520 TI - The case for generic statins: not if they don't work so well. PMID- 23939522 TI - Does managed problem solving work and in what setting? PMID- 23939523 TI - Reply: To PMID 23303273. PMID- 23939524 TI - Reply: To PMID 23358784. PMID- 23939525 TI - Is 81-mg aspirin associated with age-related macular degeneration risk? PMID- 23939526 TI - Reply: To PMID 23337937. PMID- 23939531 TI - Patterns of cortical input to the primary motor area in the marmoset monkey. AB - In primates the primary motor cortex (M1) forms a topographic map of the body, whereby neurons in the medial part of this area control movements involving trunk and hindlimb muscles, those in the intermediate part control movements involving forelimb muscles, and those in the lateral part control movements of facial and other head muscles. This topography is accompanied by changes in cytoarchitectural characteristics, raising the question of whether the anatomical connections also vary between different parts of M1. To address this issue, we compared the patterns of cortical afferents revealed by retrograde tracer injections in different locations within M1 of marmoset monkeys. We found that the entire extent of this area is unified by projections from the dorsocaudal and medial subdivisions of premotor cortex (areas 6DC and 6M), from somatosensory areas 3a, 3b, 1/2, and S2, and from posterior parietal area PE. While cingulate areas projected to all subdivisions, they preferentially targeted the medial part of M1. Conversely, the ventral premotor areas were preferentially connected with the lateral part of M1. Smaller but consistent inputs originated in frontal area 6DR, ventral posterior parietal cortex, the retroinsular cortex, and area TPt. Connections with intraparietal, prefrontal, and temporal areas were very sparse, and variable. Our results demonstrate that M1 is unified by a consistent pattern of major connections, but also shows regional variations in terms of minor inputs. These differences likely reflect requirements for control of voluntary movement involving different body parts. PMID- 23939533 TI - Locked-in or locked-out, but present. PMID- 23939534 TI - Colour and odour drive fruit selection and seed dispersal by mouse lemurs. AB - Animals and fruiting plants are involved in a complex set of interactions, with animals relying on fruiting trees as food resources, and fruiting trees relying on animals for seed dispersal. This interdependence shapes fruit signals such as colour and odour, to increase fruit detectability, and animal sensory systems, such as colour vision and olfaction to facilitate food identification and selection. Despite the ecological and evolutionary importance of plant-animal interactions for shaping animal sensory adaptations and plant characteristics, the details of the relationship are poorly understood. Here we examine the role of fruit chromaticity, luminance and odour on seed dispersal by mouse lemurs. We show that both fruit colour and odour significantly predict fruit consumption and seed dispersal by Microcebus ravelobensis and M. murinus. Our study is the first to quantify and examine the role of bimodal fruit signals on seed dispersal in light of the sensory abilities of the disperser. PMID- 23939535 TI - The impact of relative humidity during electrospinning on the morphology and mechanical properties of nanofibers. AB - Electrospinning is an efficient and flexible method for nanofiber production, but it is influenced by many systemic, process, and environmental parameters that govern the electrospun product morphology. This study systematically investigates the influence of relative humidity (RH) on the electrospinning process. The results showed that the morphology of the electrospun product (shape and diameter) can be manipulated with precise regulation of RH during electrospinning. Because the diameter of nanofibers correlates with their rigidity, it was shown that RH control can lead to manipulation of material mechanical properties. Finally, based on the solution's rheological parameter namely, phase shift angle-we were able to predict the loss of homogenous nanofiber structure in correlation with RH conditions during electrospinning. This research addresses the mechanism of RH impact on the electrospinning process and offers the background to exploit it in order to better control nanomaterial properties and alter its applicability. PMID- 23939537 TI - Influence of food on pharmacokinetics of zolpidem from fast dissolving sublingual zolpidem tartrate tablets. AB - Ingesting food can impact the pharmacokinetics of sedative-hypnotic drugs. A buffered zolpidem sublingual tablet (ZST) recently became available for the treatment of middle-of-the-night awakening. In this randomized, open-label, single-site study, the pharmacokinetic profile of ZST was evaluated when administered while fasting and following a standard high-fat meal (fed state). Healthy adults aged 18-64 years received a single morning dose of 3.5 mg ZST in the fed or fasting state. From 20 min to 3 h post-dose, zolpidem plasma levels were lower in the fed state compared to the fasting state. After 4 h post-dose (corresponding to "morning wake time"), higher zolpidem plasma levels were evident in the fed state. Area under the concentration-time curve (AUC) values for the 0-8 h interval were 160 ng/mL h in the fed state and 203 ng/mL h in the fasting state (P < .001). In the fed versus fasting states, Cmax was 32.0 ng/mL versus 57.3 ng/mL (P < .001), respectively, and Tmax was 3.0 h versus 0.92 h (P < .001), respectively. Together these data suggest that administration of ZST in the fed state is not optimal for maximizing the likelihood of therapeutic benefit and minimizing the probability of residual sedation. PMID- 23939538 TI - A pillar[6]arene with mono(ethylene oxide) substituents: synthesis and complexation with diquat. AB - A pillar[6]arene with mono(ethylene oxide) groups was synthesized and it formed a highly stable inclusion complex with diquat, while the pillar[5]arene analogue did not. PMID- 23939536 TI - Vitamin C: a novel regulator of neutrophil extracellular trap formation. AB - INTRODUCTION: Neutrophil extracellular trap (NET) formation was recently identified as a novel mechanism to kill pathogens. However, excessive NET formation in sepsis can injure host tissues. We have recently shown that parenteral vitamin C (VitC) is protective in sepsis. Whether VitC alters NETosis is unknown. METHODS: We used Gulo-/- mice as they lack the ability to synthesize VitC. Sepsis was induced by intraperitoneal infusion of a fecal stem solution (abdominal peritonitis, FIP). Some VitC deficient Gulo-/- mice received an infusion of ascorbic acid (AscA, 200 mg/kg) 30 min after induction of FIP. NETosis was assessed histologically and by quantification for circulating free DNA (cf-DNA) in serum. Autophagy, histone citrullination, endoplasmic reticulum (ER) stress, NFkappaB activation and apoptosis were investigated in peritoneal PMNs. RESULTS: Sepsis produced significant NETs in the lungs of VitC deficient Gulo-/- mice and increased circulating cf-DNA. This was attenuated in the VitC sufficient Gulo-/- mice and in VitC deficient Gulo-/- mice infused with AscA. Polymorphonuclear neutrophils (PMNs) from VitC deficient Gulo-/- mice demonstrated increased activation of ER stress, autophagy, histone citrullination, and NFkappaB activation, while apoptosis was inhibited. VitC also significantly attenuated PMA induced NETosis in PMNs from healthy human volunteers. CONCLUSIONS: Our in vitro and in vivo findings identify VitC as a novel regulator of NET formation in sepsis. This study complements the notion that VitC is protective in sepsis settings. PMID- 23939539 TI - Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. AB - OBJECTIVE: Type 2 diabetes (T2DM) is associated with brain atrophy and cerebrovascular disease. We aimed to define the regional distribution of brain atrophy in T2DM and to examine whether atrophy or cerebrovascular lesions are feasible links between T2DM and cognitive function. RESEARCH DESIGN AND METHODS: This cross-sectional study used magnetic resonance imaging (MRI) scans and cognitive tests in 350 participants with T2DM and 363 participants without T2DM. With voxel-based morphometry, we studied the regional distribution of atrophy in T2DM. We measured cerebrovascular lesions (infarcts, microbleeds, and white matter hyperintensity [WMH] volume) and atrophy (gray matter, white matter, and hippocampal volumes) while blinded to T2DM status. With use of multivariable regression, we examined for mediation or effect modification of the association between T2DM and cognitive measures by MRI measures. RESULTS: T2DM was associated with more cerebral infarcts and lower total gray, white, and hippocampal volumes (all P < 0.05) but not with microbleeds or WMH. T2DM-related gray matter loss was distributed mainly in medial temporal, anterior cingulate, and medial frontal lobes, and white matter loss was distributed in frontal and temporal regions. T2DM was associated with poorer visuospatial construction, planning, visual memory, and speed (P <= 0.05) independent of age, sex, education, and vascular risk factors. The strength of these associations was attenuated by almost one half when adjusted for hippocampal and total gray volumes but was unchanged by adjustment for cerebrovascular lesions or white matter volume. CONCLUSIONS: Cortical atrophy in T2DM resembles patterns seen in preclinical Alzheimer disease. Neurodegeneration rather than cerebrovascular lesions may play a key role in T2DM-related cognitive impairment. PMID- 23939540 TI - Vital signs, QT prolongation, and newly diagnosed cardiovascular disease during severe hypoglycemia in type 1 and type 2 diabetic patients. AB - OBJECTIVE To assess vital signs, QT intervals, and newly diagnosed cardiovascular disease during severe hypoglycemia in diabetic patients. RESEARCH DESIGN AND METHODS From January 2006 to March 2012, we conducted a retrospective cohort study to assess type 1 and type 2 diabetic patients with severe hypoglycemia at a national center in Japan. Severe hypoglycemia was defined as the presence of any hypoglycemic symptoms that could not be resolved by the patients themselves in prehospital settings. RESULTS A total of 59,602 cases that visited the emergency room by ambulance were screened, and 414 cases of severe hypoglycemia were analyzed. The median (interquartile range) blood glucose levels were not significantly different between the type 1 diabetes mellitus (T1DM) (n = 88) and type 2 diabetes mellitus (T2DM) (n = 326) groups (32 [24-42] vs. 31 [24-39] mg/dL, P = 0.59). During severe hypoglycemia, the incidences of severe hypertension (>=180/120 mmHg), hypokalemia (<3.5 mEq/L), and QT prolongation were 19.8 and 38.8% (P = 0.001), 42.4 and 36.3% (P = 0.30), and 50.0 and 59.9% (P = 0.29) in the T1DM and T2DM groups, respectively. Newly diagnosed cardiovascular disease during severe hypoglycemia and death were only observed in the T2DM group (1.5 and 1.8%, respectively). Blood glucose levels between the deceased and surviving patients in the T2DM group were significantly different (18 [14-33] vs. 31 [24-39] mg/dL, P = 0.02). CONCLUSIONS T1DM and T2DM patients with severe hypoglycemia experienced many critical problems that could lead to cardiovascular disease, fatal arrhythmia, and death. PMID- 23939541 TI - Potential efficiency benefits of nonmydriatic ultrawide field retinal imaging in an ocular telehealth diabetic retinopathy program. AB - OBJECTIVE To compare efficiency of nonmydriatic ultrawide field retinal imaging (UWFI) and nonmydriatic fundus photography (NMFP) in a diabetic retinopathy (DR) ocular telehealth program. RESEARCH DESIGN AND METHODS Patients in this retrospective, comparative cohort study underwent NMFP and UWFI between 1 November 2011 and 1 November 2012. Images were evaluated for DR and diabetic macular edema (DME) by certified graders using a standard protocol at a centralized reading center. Identification of DR, image evaluation time, and rate of ungradable eyes were compared. RESULTS NMFP and UWFI were performed in 1,633 and 2,170 consecutive patients, respectively. No statistically significant differences were found between groups regarding age, diabetes duration, sex, ethnicity, or insulin use. The ungradable rate per patient for DR (2.9 vs. 9.9%, P < 0.0001) and DME (3.8 vs. 8.8%, P < 0.0001) was lower with UWFI than with NMFP. With UWFI, the median image evaluation time per patient was reduced from 12.8 to 9.2 min (P < 0.0001). The identification of patients with DR (38.4 vs. 33.8%) and vision-threatening DR (14.5 vs. 11.9%) was increased with UWFI versus NMFP. In a consecutive subgroup of 502 eyes of 301 patients with DR, the distribution of peripheral retinal lesions outside Early Treatment Diabetic Retinopathy Study fields suggested a more severe DR level in 9.0% (45 eyes). CONCLUSIONS In a standardized DR ocular telehealth program, nonmydriatic UWFI reduced the ungradable rate by 71% (to <3%) and reduced image evaluation time by 28%. DR was identified 17% more frequently after UWFI, and DR peripheral lesions suggested a more severe DR level in 9%. These data suggest that UWFI may improve efficiency of ocular telehealth programs evaluating DR and DME. PMID- 23939542 TI - Dietary energy intake is associated with type 2 diabetes risk markers in children. AB - OBJECTIVE Energy intake, energy density, and nutrient intakes are implicated in type 2 diabetes risk in adults, but little is known about their influence on emerging type 2 diabetes risk in childhood. We examined these associations in a multiethnic population of children. RESEARCH DESIGN AND METHODS This was a cross sectional study of 2,017 children predominantly of white European, South Asian, and black African-Caribbean origin aged 9-10 years who had a detailed 24-h dietary recall and measurements of body composition and provided a fasting blood sample for measurements of plasma glucose, HbA1c, and serum insulin; homeostasis model assessment of insulin resistance was also derived. RESULTS Energy intake was positively associated with insulin resistance. After the removal of 176 participants with implausible energy intakes (unlikely to be representative of habitual intake), energy intake was more strongly associated with insulin resistance and was also associated with glucose and fat mass index. Energy density was also positively associated with insulin resistance and fat mass index. However, in mutually adjusted analyses, the associations for energy intake remained while those for energy density became nonsignificant. Individual nutrient intakes showed no associations with type 2 diabetes risk markers. CONCLUSIONS Higher total energy intake was strongly associated with high levels of insulin resistance and may help to explain emerging type 2 diabetes risk in childhood. Studies are needed to establish whether reducing energy intake produces sustained favorable changes in insulin resistance and circulating glucose levels. PMID- 23939543 TI - Early progressive renal decline precedes the onset of microalbuminuria and its progression to macroalbuminuria. AB - OBJECTIVE Progressive decrease in the glomerular filtration rate (GFR), or renal decline, in type 1 diabetes (T1D) is observed in patients with macroalbuminuria. However, it is unknown whether this decline begins during microalbuminuria (MA) or normoalbuminuria (NA). RESEARCH DESIGN AND METHODS The study group (second Joslin Kidney Study) comprises patients with T1D and NA (n = 286) or MA (n = 248) who were followed for 4-10 years (median 8 years). Serial measurements (median 6, range 3-16) of serum creatinine and cystatin C were used jointly to estimate GFR (eGFRcr-cys) and assess its trajectories during follow-up. RESULTS Renal decline (progressive eGFRcr-cys loss of at least 3.3% per year) occurred in 10% of the NA and 35% of the MA (P < 0.001). In both groups, the strongest determinants of renal decline were baseline serum concentrations of uric acid (P < 0.001) and tumor necrosis factor receptor 1 or 2 (TNFR-1 or -2, P < 0.001). Other significant risk factors included baseline HbA1c, age/diabetes duration, and systolic blood pressure. Relative impacts of these determinants were similar in NA and MA. Renal decline was not associated with sex or baseline serum concentration of TNF-alpha, IL-6, IL-8, IP-10, MCP-1, VCAM, ICAM, Fas, or FasL. CONCLUSIONS Renal decline in T1D begins during NA and it is determined by multiple factors, similar to MA. Thus, this early decline is the primary disease process leading to impaired renal function in T1D. Changes in albumin excretion rate, such as the onset of MA or its progression to macroalbuminuria, are either caused by or develop in parallel to the early renal decline. PMID- 23939544 TI - Acute metabolic effects of exenatide in patients with type 1 diabetes with and without residual insulin to oral and intravenous glucose challenges. AB - OBJECTIVE Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the gastrointestinal tract. Treatment with GLP-1 analogs has proven to be of clinical use for patients with type 2 diabetes. Patients with type 1 diabetes, particularly those with residual beta-cell function, may also respond to treatment, but the acute metabolic effects of GLP-1 analogs on these patients in reaction to both oral and intravenous glucose challenges are not well understood. RESEARCH DESIGN AND METHODS Seventeen patients with type 1 diabetes, half of whom had residual insulin production, underwent two mixed-meal tolerance tests (MMTTs) and two intravenous glucose tolerance tests (IVGTTs), with and without pretreatment with exenatide. No exogenous bolus insulin was administered for the studies. Glucose excursions, insulin secretion rates (ISRs), and levels of glucagon, endogenous GLP-1, and gastric inhibitory polypeptide were measured after the meal or glucose loads. RESULTS During the MMTT, glucose levels were suppressed with exenatide in patients with or without residual insulin production (P = 0.0003). Exenatide treatment did not change the absolute ISR, but the ISR to glucose levels were increased (P = 0.0078). Gastric emptying was delayed (P = 0.0017), and glucagon was suppressed (P = 0.0015). None of these hormonal or glucose changes were detected during the IVGTT with exenatide administration. CONCLUSIONS Exenatide showed a significant antidiabetogenic effect prior to an oral meal in patients with type 1 diabetes involving glucagon suppression and gastric emptying, while preserving increased insulin secretion. GLP-1 analogs may be useful as an adjunctive treatment in type 1 diabetes. PMID- 23939549 TI - Breast cancer: Mutations in breast cancer stem cells correlate with metastases. PMID- 23939550 TI - Palliative care: Steroids to combat fatigue. PMID- 23939548 TI - Advances in the treatment of neurofibromatosis-associated tumours. AB - Neurofibromatosis (NF) comprises two distinct genetic disorders-neurofibromatosis type 1 and 2 (NF1 and NF2)-in which affected individuals develop both benign and malignant tumours. NF1 results from germline mutations in the NF1 gene that encodes neurofibromin, while NF2 results from germline mutations in the NF2 gene that encodes merlin (or schwannomin). The major tumour types arising in individuals with NF1 include neurofibromas, malignant peripheral nerve sheath tumours, and gliomas, whereas NF2 is characterized by the formation of schwannomas, meningiomas, and ependymomas. With the identification of the NF1 and NF2 genes and the generation of robust preclinical mouse models of NF-associated neoplasms, novel treatments that specifically target the growth control pathways deregulated in these tumours have been discovered, some of which are now being tested in clinical trials in individuals with NF1 and NF2. In this Review, we will highlight the key clinical features of NF1 and NF2 and the advances in future clinical management based on an improved understanding of the function of the NF1 and NF2 genes and the development of small-animal models. PMID- 23939551 TI - White-light emitting dye micelles in aqueous solution. AB - Biscarbazole-loaded perylene bisimide (PBI) dye micelles in water afforded a fluorescence resonance energy transfer (FRET)-based white-light emitting nano luminary system with biscarbazoles as energy donors and PBI micelles as acceptors. PMID- 23939552 TI - Chimeric repressor of PtSND2 severely affects wood formation in transgenic Populus. AB - NAC domain transcription factors are important regulators that activate the secondary wall biosynthesis in wood formation. In this work, we investigated the possible functions of an NAC family member SECONDARY WALL-ASSOCIATED NAC DOMAIN PROTEIN2 (PtSND2) using chimeric repressor silencing technology. Reverse transcription-polymerase chain reaction, subcellular localization and transcriptional activation analyses indicated that PtSND2 is a wood-associated transcriptional factor with the predicted transcriptional activation activity, which could be inhibited by the repression domain SUPERMAN REPRESSION DOMAIN X (SRDX) in yeast. Wood formation was severely repressed in transgenic poplar plants overexpressing PtSND2-SRDX. Meanwhile, the secondary cell wall thickness of xylem fibers was restrained, and the contents of cellulose and lignin were obviously decreased in the stems of transgenic plants. Further studies indicated that expressions of a number of wood-associated genes were down-regulated in the stems of transgenic plants. Our results suggest that PtSND2 may play important roles during the secondary growth of stems in poplar. PMID- 23939553 TI - Dehydration and osmotic adjustment in apple stem tissue during winter as it relates to the frost resistance of buds. AB - In deciduous trees, measurement of stem water potential can be difficult during the leafless period in winter. By using thermocouple psychrometry, osmotic water potentials (Psio; actual Psio: Psio(act); Psio at full saturation: Psio(sat)) of expressed sap of bark and bud tissue were measured in order to test if the severity of winter desiccation in apple stems could be sufficiently assessed with Psio. Water potentials were related to frost resistance and freezing behaviour of buds. The determination of Psio reliably allowed winter desiccation and osmotic adjustments in apple stem tissue to be assessed. In winter in bark tissue, a pronounced decrease in Psio(act) and Psio(sat) was found. Decreased Psio(sat) indicates active osmotic adjustment in the bark as observed earlier in the leaves of evergreen woody plants. In terminal bud meristems, no significant osmotic adjustments occurred and dehydration during winter was much less. Osmotic water potentials, Psio(act) and Psio(sat), of bud tissue were always less negative than in the bark. To prevent water movement and dehydration of the bud tissue via this osmotic gradient, it must be compensated for either by a sufficiently high turgor pressure (Psip) in bark tissue or by the isolation of the bud tissue from the bark during midwinter. During freezing of apple buds, freeze dehydration and extra-organ freezing could be demonstrated by significantly reduced Psio(act) values of bud meristems that had been excised in the frozen state. Infrared video thermography was used to monitor freezing patterns in apple twigs. During extracellular freezing of intact and longitudinally dissected stems, infrared differential thermal analysis (IDTA) images showed that the bud meristem remains ice free. Even if cooled to temperatures below the frost-killing temperature, no freezing event could be detected in bud meristems during winter. In contrast, after bud break, terminal buds showed a second freezing at the frost-killing temperature that indicates deep supercooling. Our results demonstrate the applicability of thermocouple psychrometry for the assessment of winter desiccation in stem tissues of deciduous trees and corroborate the finding that dormant apple buds survive by extra-organ freezing and do not deep supercool. In addition, they indicate that significant changes of the frost-survival mechanism can occur during the apple bud development in spring. PMID- 23939554 TI - Pathological correlates of magnetic resonance imaging texture heterogeneity in multiple sclerosis. AB - OBJECTIVE: To analyze the texture of T2-weighted magnetic resonance imaging (MRI) of postmortem multiple sclerosis (MS) brain, and to determine whether and how MRI texture correlates with tissue pathology. METHODS: Ten brain samples from 3 subjects with MS were examined. Areas of complete, partial, or no loss of Luxol fast blue (myelin) and Bielschowsky (axons) staining were marked on histological images, and matched on corresponding MRI as lesions, diffusely abnormal white matter (DAWM), and normal-appearing white matter (NAWM). The number of CD45(+) cells (inflammation) was also counted. MRI texture was computed using polar Stockwell transform and compared to histology. RESULTS: Thirty-four lesions, 17 DAWM regions, and 36 NAWM regions were identified. After mixed effects modeling, MRI texture heterogeneity was greater in lesions than in DAWM (p < 0.001) and NAWM (p < 0.001), and was greater in DAWM than in NAWM (p < 0.001); the number of CD45+ cells was greater in both lesions (p < 0.001) and DAWM (p = 0.005) than in NAWM. In MRI, a gradient of texture heterogeneity was detected in lesions, with gradual tapering toward perilesional NAWM. Moreover, besides univariate correlation with histological markers, texture heterogeneity correlated independently with normalized myelin density (p < 0.01) when random effects were considered. Within sample, MRI texture correlated with myelin and axonal density in 7 of 10 samples (p < 0.01). INTERPRETATION: Texture analysis performed on routine clinical magnetic resonance images may be a potential measure of tissue integrity. Tissues with more severe myelin and axonal pathology are associated with greater texture heterogeneity. PMID- 23939555 TI - The prognostic impact of tumor-associated macrophages and intra-tumoral apoptosis in non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung malignancies. Tumor associated macrophages (TAM) are abundant components of NSCLC. Although under certain conditions TAM can kill tumor cells, they can also act as tumor promoters secreting a variety of factors that directly stimulate tumor invasion and metastasis. TAM presents two distinct phenotypes: the classically activated (or M1) phenotype, which is highly pro-inflammatory (phagocytic and cytotoxic), and the alternatively activated (or M2) phenotype, which has anti-inflammatory and pro-tumoral properties. The polarization status of TAM depends on stimulating factors from the tumor microenvironment, and some in vitro evidence implies that the phagocytosis of apoptotic bodies derived from tumoral cells is a key factor in M1/M2 modulation, raising the question of whether the evaluation of the apoptotic index (AI) and macrophage polarization have a prognostic role in NSCLC patient survival. The present article systematically reviewed the published series of clinical data that correlated the AI and/or macrophage densities and polarization status (M1/M2) with the outcome of non-small cell lung cancer patients. Even though an overwhelming body of clinical data support that TAM's density, micro-anatomical localization, phenotype and intra-tumoral AI are independent predictors of survival time, no study to date has been conducted to evaluate the impact of these parameters altogether in NSCLC patient outcome. Joint analysis of these biologic factors in future studies might reveal their prognostic value in the management of NSCLC cases. PMID- 23939556 TI - [Is neurology a care-giving specialty?]. PMID- 23939557 TI - [Pharmacological treatment for patients with borderline personality disorder: practice and study results]. AB - Many patients with borderline personality disorder (BPD) receive pharmacological treatment. On account of the few treatment guidelines and the often changing symptoms, different substances are used. The present article summarises treatment practice and study results concerning the pharmacological treatment of BPD. PMID- 23939558 TI - [Assessing activities of daily living in patients with epilepsy]. AB - BACKGROUND: Objective cognitive assessment and subjective self-assessment do not sufficiently reflect actual daily routines and everyday functioning of patients with epilepsy. The study at hand examined whether a questionnaire assessing the activities of daily living provides additional diagnostic information. METHODS: A total of 180 consecutive patients with epilepsy received a questionnaire addressing (i) mood, (ii) subjective cognitive performance as well as (iii) frequencies of subjective problems in everyday life and (iv) 36 activities of daily living (ADL-Track). Normative data were based on 536 healthy volunteers. Analysis focused on the interrelation among these subjective measures as well as their relation to objective neuropsychological performance. RESULTS: Compared to the normative sample, social activities, home activities, and mobility were reduced in 25 - 34 % of the patients (OR = 2.07 - 2.79). Frequencies of activities of daily living reflect the results of subjective performance ratings ("attention", "praxia") and objective performance in attention, language, intelligence and memory. A negative mood showed highly significant correlations with subjective complaints and increased the risk of reduced activities by a factor of 2 - 3. Multiple regression analyses explained between 9 - 22 % of the variance of the ADL-Track scales. CONCLUSION: The ADL-Track, a questionnaire on frequencies of activities of daily living, appears more independent from mood than subjective complaints and it shows relevant correlations with subjective and even more with objective cognitive measures. Moreover, it indicates a behavioural domain in epilepsy which is not yet covered by standard diagnostics. When applied longitudinally, the ADL-Track may well turn out to be a valuable longer-term outcome parameter with regard to epilepsy and its treatment. PMID- 23939559 TI - [Poststroke-bipolar affective disorder]. AB - A few weeks after suffering from a basal ganglia infarction (globus pallidus) with left-sided hemiplegia, a 23-year-old woman exhibited for the first time a pronounced mania with self-endangerment. The use of oral contraceptives was the only determinable risk factor. During the further course, the mother also developed a depressive disorder. Thus a certain genetic predisposition for affective disorders may be relevant, although this would not explain the outbreak by itself. An association between the right-sided basal ganglia infarction and the occurrence of a bipolar affective disorder has been described in the literature. Vascular or, respectively, inflammatory risk factors in synopsis with the aetiopathogenesis of bipolar affective disorders are also discussed in depth in this case report. PMID- 23939560 TI - [Treatment-resistant schizophrenia - biological treatments]. PMID- 23939562 TI - Risks of deep brain stimulation for Parkinson disease. PMID- 23939561 TI - A practical guide to epidemiological practice and standards in the identification and validation of diagnostic markers using a bladder cancer example. AB - Technical advances to analyze biological markers have generated a plethora of promising new marker candidates for early detection of cancer. However, in subsequent analyses only few could be successfully validated as being predictive, clinically useful, or effective. This failure is partially due to rapid publication of results that were detected in early stages of biomarker research. Methodological considerations are a major concern when carrying out molecular epidemiological studies of diagnostic markers to avoid errors that increase the potential for bias. Although guidelines for conducting studies and reporting of results have been published to improve the quality of marker studies, their planning and execution still need to be improved. We will discuss different sources of bias in study design, handling of specimens, and statistical analysis to illustrate possible pitfalls associated with marker research, and present legal, ethical, and technical considerations associated with storage and handling of specimens. This article presents a guide to epidemiological standards in marker research using bladder cancer as an example. Because of the possibility to detect early cancer stages due to leakage of molecular markers from the target organ or exfoliation of tumor cells into the urine, bladder cancer is particularly useful to study diagnostic markers. To improve the overall quality of marker research, future developments should focus on networks of studies and tissue banks according to uniform legal, ethical, methodological, and technical standards. This article is part of a Special Issue entitled: Computational Proteomics in the Post-Identification Era. Guest Editors: Martin Eisenacher and Christian Stephan. PMID- 23939564 TI - Immunizations in pregnancy. PMID- 23939565 TI - Gynecologic procedures: colposcopy, treatments for cervical intraepithelial neoplasia and endometrial assessment. AB - Women who have abnormal Papanicolaou test results may undergo colposcopy to determine the biopsy site for histologic evaluation. Traditional grading systems do not accurately assess lesion severity because colposcopic impression alone is unreliable for diagnosis. The likelihood of finding cervical intraepithelial neoplasia grade 2 or higher increases when two or more cervical biopsies are performed. Excisional and ablative methods have similar treatment outcomes for the eradication of cervical intraepithelial neoplasia. However, diagnostic excisional methods, including loop electrosurgical excision procedure and cold knife conization, are associated with an increased risk of adverse obstetric outcomes, such as preterm labor and low birth weight. Methods of endometrial assessment have a high sensitivity for detecting endometrial carcinoma and benign causes of uterine bleeding without unnecessary procedures. Endometrial biopsy can reliably detect carcinoma involving a large portion of the endometrium, but is suboptimal for diagnosing focal lesions. A 3- to 4-mm cutoff for endometrial thickness on transvaginal ultrasonography yields the highest sensitivity to exclude endometrial carcinoma in postmenopausal women. Saline infusion sonohysteroscopy can differentiate globally thickened endometrium amenable to endometrial biopsy from focal abnormalities best assessed by hysteroscopy. Hysteroscopy with directed biopsy is the most sensitive and specific method of diagnosing endometrial carcinoma, other than hysterectomy. PMID- 23939566 TI - Inguinal hernias: diagnosis and management. AB - Inguinal hernias are one of the most common reasons a primary care patient may need referral for surgical intervention. The history and physical examination are usually sufficient to make the diagnosis. Symptomatic patients often have groin pain, which can sometimes be severe. Inguinal hernias may cause a burning, gurgling, or aching sensation in the groin, and a heavy or dragging sensation may worsen toward the end of the day and after prolonged activity. An abdominal bulge may disappear when the patient is in the prone position. Examination involves feeling for a bulge or impulse while the patient coughs or strains. Although imaging is rarely warranted, ultrasonography or magnetic resonance imaging can help diagnose a hernia in an athlete without a palpable impulse or bulge on physical examination. Ultrasonography may also be indicated with a recurrent hernia or suspected hydrocele, when the diagnosis is uncertain, or if there are surgical complications. Although most hernias are repaired, surgical intervention is not always necessary, such as with a small, minimally symptomatic hernia. If repair is necessary, the patient should be counseled about whether an open or laparoscopic technique is best. Surgical complications and hernia recurrences are uncommon. However, a patient with a recurrent hernia should be referred to the original surgeon, if possible. PMID- 23939567 TI - Dermatologic conditions in skin of color: part I. Special considerations for common skin disorders. AB - Skin of color traditionally refers to that of persons of African, Asian, Native American, Middle Eastern, and Hispanic backgrounds. Differences in cutaneous structure and function can result in skin conditions with distinct presentations and varying prevalence that require unique treatment. Skin cancers have different presentations in these populations. The ability to recognize and diagnose skin cancer in a timely manner is important for reducing morbidity and mortality. Basal cell carcinoma often is pigmented, squamous cell carcinoma occurs in areas of chronic scarring and inflammation, and melanoma presents in non-sun-exposed areas, such as the soles and nail beds. Diagnosis requires biopsy, with the technique depending on size and location of the lesion. Treatment options range from topical to surgical. Acne commonly results in postinflammatory hyperpigmentation and keloids. Combination therapy with topical antibiotics and benzoyl peroxide is generally more effective than monotherapy for treating acne. Use of retinoids at lower concentrations and at less frequent dosing can help prevent postinflammatory hyperpigmentation. PMID- 23939568 TI - Dermatologic conditions in skin of color: part II. Disorders occurring predominately in skin of color. AB - Several skin conditions are more common in persons with skin of color, including dermatosis papulosa nigra, pseudofolliculitis barbae, acne keloidalis nuchae, and keloids. Dermatosis papulosa nigra is a common benign condition characterized by skin lesions that do not require treatment, although several options are available for removal to address cosmetic concerns. Pseudofolliculitis barbae occurs as a result of hair removal. Altering shaving techniques helps prevent lesions from recurring. In acne keloidalis nuchae, keloidal lesions are found on the occipital scalp and posterior neck. Early treatment with steroids, antibiotics, and retinoids prevents progression. A key part of the management of keloids is prevention. First-line medical therapy includes intralesional steroid injections. The distinct structure of the hair follicle in blacks results in hair care practices that can lead to common scalp disorders. For example, chemical relaxers decrease the strength of hair and may cause breakage. Better patient education, with early diagnosis and treatment, often leads to better outcomes. PMID- 23939569 TI - Behavioral counseling interventions to promote a healthful diet and physical activity for cardiovascular disease prevention in adults. PMID- 23939570 TI - Is rivaroxaban noninferior to standard warfarin therapy in preventing recurrent PE and DVT? PMID- 23939572 TI - Intracranial lesion with fever and headaches. Toxoplasmic encephalitis. PMID- 23939573 TI - FPIN's clinical inquiries. Pharmacologic therapy for eustachian tube dysfunction. PMID- 23939576 TI - Patient information. Common conditions in skin of color. PMID- 23939577 TI - Patient information. Inguinal (groin) hernias. PMID- 23939579 TI - Long-term oropharyngeal colonization by C. albicans in children with cystic fibrosis. AB - This longitudinal prospective study aimed to determine the prevalence of oropharyngeal colonization by C. albicans in children with cystic fibrosis (CF), and observe the continuity of candidal colonization and the changes in production of virulence factors, susceptibility to antifungal agents and RAPD patterns of the isolates. Thirty-seven children with CF were followed-up for oropharyngeal C. albicans colonization for 18 months. The colonization rate was detected in 54%. All isolates were susceptible to amphotericin B, but those isolated from one patient were resistant to fluconazole. Biofilm production, secretory acid proteinase, phospholipase and esterase activity rates were 30%, 60%, 75% and 80%, respectively. RAPD analysis with the primers OPE-03 and OPE-18 was performed for genotyping. RAPD patterns of the strains isolated from the same patient were related to each other, whereas they were not related with other strains isolated from different patients. Two C. albicans strains isolated from the same patient were found to be unrelated to one another. As a result, long-lasting colonization of the oropharyngeal mucosa of children with CF by endogenous C. albicans isolates having the same RAPD pattern was demonstrated. Colonization prevalance and development of resistance to antifungal agents and the increased production of virulence factors were not correlated. PMID- 23939580 TI - Increasing awareness in unawareness. PMID- 23939581 TI - Digital Video Broadcast-Terrestrial (DVB-T) single frequency networks positioning in dynamic scenarios. AB - Since Global Navigation Satellite Systems (GNSS) show degraded performance in dense urban and indoor areas, a positioning sensor based on Digital Video Broadcast-Terrestrial (DVB-T) systems is presented in this paper. DVB-T signals can be considered as signals-of-opportunity for positioning, due to their good properties. One of the challenges to overcome is to distinguish the signals from different emitters. Here, we suppose that the user can first compute his position by GNSS during an initialization phase, which is used for solving all the ambiguities concerning DVB-T emitters. Starting from there, DVB-T signals can be used for aiding positioning when the user enters a GNSS-blocked area, up to a limit case, where all the GNSS satellites are not in view and only DVB-T signals are used for positioning. We tested this method by simulation, by adopting the Hata model for the emitter attenuations and the Rayleigh model for multipath. The obtained results show good performance if the receiver correctly associates the signal to the user's motion. PMID- 23939582 TI - On maximizing the lifetime of Wireless Sensor Networks by optimally assigning energy supplies. AB - The extension of the network lifetime of Wireless Sensor Networks (WSN) is an important issue that has not been appropriately solved yet. This paper addresses this concern and proposes some techniques to plan an arbitrary WSN. To this end, we suggest a hierarchical network architecture, similar to realistic scenarios, where nodes with renewable energy sources (denoted as primary nodes) carry out most message delivery tasks, and nodes equipped with conventional chemical batteries (denoted as secondary nodes) are those with less communication demands. The key design issue of this network architecture is the development of a new optimization framework to calculate the optimal assignment of renewable energy supplies (primary node assignment) to maximize network lifetime, obtaining the minimum number of energy supplies and their node assignment. We also conduct a second optimization step to additionally minimize the number of packet hops between the source and the sink. In this work, we present an algorithm that approaches the results of the optimization framework, but with much faster execution speed, which is a good alternative for large-scale WSN networks. Finally, the network model, the optimization process and the designed algorithm are further evaluated and validated by means of computer simulation under realistic conditions. The results obtained are discussed comparatively. PMID- 23939583 TI - On-line flatness measurement in the steelmaking industry. AB - Shape is a key characteristic to determine the quality of outgoing flat-rolled products in the steel industry. It is greatly influenced by flatness, a feature to describe how the surface of a rolled product approaches a plane. Flatness is of the utmost importance in steelmaking, since it is used by most downstream processes and customers for the acceptance or rejection of rolled products. Flatness sensors compute flatness measurements based on comparing the length of several longitudinal fibers of the surface of the product under inspection. Two main different approaches are commonly used. On the one hand, most mechanical sensors measure the tensile stress across the width of the rolled product, while manufacturing and estimating the fiber lengths from this stress. On the other hand, optical sensors measure the length of the fibers by means of light patterns projected onto the product surface. In this paper, we review the techniques and the main sensors used in the steelmaking industry to measure and quantify flatness defects in steel plates, sheets and strips. Most of these techniques and sensors can be used in other industries involving rolling mills or continuous production lines, such as aluminum, copper and paper, to name a few. Encompassed in the special issue, State-of-the-Art Sensors Technology in Spain 2013, this paper also reviews the most important flatness sensors designed and developed for the steelmaking industry in Spain. PMID- 23939584 TI - Recognizing the degree of human attention using EEG signals from mobile sensors. AB - During the learning process, whether students remain attentive throughout instruction generally influences their learning efficacy. If teachers can instantly identify whether students are attentive they can be suitably reminded to remain focused, thereby improving their learning effects. Traditional teaching methods generally require that teachers observe students' expressions to determine whether they are attentively learning. However, this method is often inaccurate and increases the burden on teachers. With the development of electroencephalography (EEG) detection tools, mobile brainwave sensors have become mature and affordable equipment. Therefore, in this study, whether students are attentive or inattentive during instruction is determined by observing their EEG signals. Because distinguishing between attentiveness and inattentiveness is challenging, two scenarios were developed for this study to measure the subjects' EEG signals when attentive and inattentive. After collecting EEG data using mobile sensors, various common features were extracted from the raw data. A support vector machine (SVM) classifier was used to calculate and analyze these features to identify the combination of features that best indicates whether students are attentive. Based on the experiment results, the method proposed in this study provides a classification accuracy of up to 76.82%. The study results can be used as a reference for learning system designs in the future. PMID- 23939585 TI - Monitoring sintering burn-through point using infrared thermography. AB - Sintering is a complex industrial process that applies heat to fine particles of iron ore and other materials to produce sinter, a solidified porous material used in blast furnaces. The sintering process needs to be carefully adjusted, so that the combustion zone reaches the bottom of the material just before the discharge end. This is known as the burn-through point. Many different parameters need to be finely tuned, including the speed and the quantities of the materials mixed. However, in order to achieve good results, sintering control requires precise feedback to adjust these parameters. This work presents a sensor to monitor the sintering burn-through point based on infrared thermography. The proposed procedure is based on the acquisition of infrared images at the end of the sintering process. At this position, infrared images contain the cross-section temperatures of the mixture. The objective of this work is to process this information to extract relevant features about the sintering process. The proposed procedure is based on four steps: key frame detection, region of interest detection, segmentation and feature extraction. The results indicate that the proposed procedure is very robust and reliable, providing features that can be used effectively to control the sintering process. PMID- 23939586 TI - A subcarrier-pair based resource allocation scheme using proportional fairness for cooperative OFDM-based cognitive radio networks. AB - The paper presents a joint subcarrier-pair based resource allocation algorithm in order to improve the efficiency and fairness of cooperative multiuser orthogonal frequency division multiplexing (MU-OFDM) cognitive radio (CR) systems. A communication model where one source node communicates with one destination node assisted by one half-duplex decode-and-forward (DF) relay is considered in the paper. An interference-limited environment is considered, with the constraint of transmitted sum-power over all channels and aggregate average interference towards multiple primary users (PUs). The proposed resource allocation algorithm is capable of maximizing both the system transmission efficiency and fairness among secondary users (SUs). Besides, the proposed algorithm can also keep the interference introduced to the PU bands below a threshold. A proportional fairness constraint is used to assure that each SU can achieve a required data rate, with quality of service guarantees. Moreover, we extend the analysis to the scenario where each cooperative SU has no channel state information (CSI) about non-adjacent links. We analyzed the throughput and fairness tradeoff in CR system. A detailed analysis of the performance of the proposed algorithm is presented with the simulation results. PMID- 23939588 TI - How many molecular layers of polar solvent molecules control chemistry? The concept of compensating dipoles. AB - The extension of the solvent influence of the shell into the volume of a polar medium was examined by means of anti-collinear dipoles on the basis of the E(T)(30) solvent polarity scale (i.e., the molar energy of excitation of a pyridinium-N-phenolatebetaine dye; generally: E(T) =28,591 nm kcal mol( 1)/lambdamax) where no compensation effects were found. As a consequence, solvent polarity effects are concentrated to a very thin layer of a few thousand picometres around the solute where extensions into the bulk solvent become unimportant. A parallelism to the thin surface layer of water to the gas phase is discussed. PMID- 23939587 TI - Mesenchymal stem cells exploit extracellular matrix as mechanotransducer. AB - While stem cells can sense and respond to physical properties of their environment, the molecular aspects how physical information is translated into biochemical signals remain unknown. Here we show that human mesenchymal stem cells (hMSCs) harvest and assemble plasma fibronectin into their extracellular matrix (ECM) fibrils within 24 hours. hMSCs pro-actively pull on newly assembled fibronectin ECM fibrils, and the fibers are more stretched on rigid than on soft fibronectin-coated polyacrylamide gels. Culturing hMSCs on single stretched fibronectin fibers upregulates hMSC osteogenesis. Osteogenesis was increased when alphavbeta3 integrins were blocked on relaxed fibronectin fibers, and decreased when alpha5beta1 integrins were blocked or when epidermal growth factor (EGF) receptor signaling was inhibited on stretched fibronectin fibers. This suggests that hMSCs utilize their own contractile forces to translate environmental cues into differential biochemical signals by stretching fibronectin fibrils. Mechanoregulation of fibronectin fibrils may thus serve as check point to regulate hMSC osteogenesis. PMID- 23939591 TI - Sleep evaluation by actigraphy for patients with Alzheimer disease. PMID- 23939592 TI - Sleep evaluation by actigraphy for patients with Alzheimer disease--reply. PMID- 23939594 TI - Hydroacid complexes: a new class of draw solutes to promote forward osmosis (FO) processes. AB - A new class of draw solutes from hydroacid complexes is presented. With hydroacid complexes as draw solutes in FO, superior performance is achieved in terms of high water fluxes and negligible reverse solute fluxes. The characteristics of expanded configurations, abundant hydrophilic groups and ionic species are essential for hydroacid complexes as competent draw solutes. PMID- 23939595 TI - Cognitive exposure versus avoidance in patients with chronic pain: adherence matters. AB - BACKGROUND: Behavioural exposure methods can reduce pain-avoidance behaviours, but outcomes vary. One possible explanation is that patients employ cognitive (experiential) avoidance during behavioural exposure. If so, reducing cognitive avoidance during behavioural exposure should help. One option is interoceptive exposure (IE), which involves sustained exposure (via attention) to pain sensations. In order to test if IE could improve outcomes from behavioural exposure, this study with mixed chronic pain patients compared outcomes from a cognitive behavioural therapy (CBT) pain management programme incorporating either IE or distraction from pain. METHODS: One hundred forty chronic pain patients were randomly assigned to CBT + IE or CBT + distraction. Outcome measures included pain, disability, depression and medication. Measures reflecting degree of threat of pain were also employed (catastrophizing, fear avoidance, pain self-efficacy and pain acceptance). An intention-to-treat approach, using mixed-effects model repeated measures, as well as conventional inferential statistical tests, effect sizes and reliable change indices were employed to evaluate the outcomes up to 1-year post-treatment. RESULTS: Significant improvements were achieved by both treatment conditions on all outcome measures and on measures reflecting the threatening nature of pain, with no differences between treatment conditions. CONCLUSIONS: The addition of IE to behavioural exposure did not improve outcomes. However, higher adherence to either attentional strategy was associated with larger effect sizes on all measures, suggesting factors shared by the two treatments could have contributed to the outcomes. Taken as a whole, the results suggest that increasing adherence to treatment strategies, possibly by motivational measures, would improve the overall outcomes of these interventions. PMID- 23939597 TI - Catalytic stereospecific alkylation of malononitriles with enantioenriched primary allylic amines. AB - An unprecedented alkylation reaction of malononitriles with enantioenriched primary allylic amines has been developed in a stereospecific manner through palladium-catalyzed sp(3) C-N bond cleavage without additives at room temperature. PMID- 23939596 TI - Diffusion tensor imaging detects treatment effects of FTY720 in experimental autoimmune encephalomyelitis mice. AB - Fingolimod (FTY720) is an orally available sphingosine-1-phosphate (S1P) receptor modulator reducing relapse frequency in patients with relapsing-remitting multiple sclerosis (RRMS). In addition to immunosuppression, neuronal protection by FTY720 has also been suggested, but remains controversial. Axial and radial diffusivities derived from in vivo diffusion tensor imaging (DTI) were employed as noninvasive biomarkers of axonal injury and demyelination to assess axonal protection by FTY720 in experimental autoimmune encephalomyelitis (EAE) mice. EAE was induced through active immunization of C57BL/6 mice using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55)). We evaluated both the prophylactic and therapeutic treatment effect of FTY720 at doses of 3 and 10 mg/kg on EAE mice by daily clinical scoring and end-point in vivo DTI. Prophylactic administration of FTY720 suppressed the disease onset and prevented axon and myelin damage when compared with EAE mice without treatment. Therapeutic treatment by FTY720 did not prevent EAE onset, but reduced disease severity, improving axial and radial diffusivity towards the control values without statistical significance. Consistent with previous findings, in vivo DTI-derived axial and radial diffusivity correlated with clinical scores in EAE mice. The results support the use of in vivo DTI as an effective outcome measure for preclinical drug development. PMID- 23939598 TI - Increased cancer risk associated with CT in childhood. PMID- 23939600 TI - Uncommon adverse effects of commonly abused illicit drugs. PMID- 23939601 TI - Text message appointment reminders. PMID- 23939602 TI - Pharmacotherapy for mild hypertension. PMID- 23939603 TI - Postexposure prophylaxis for common infectious diseases. AB - Postexposure prophylaxis (PEP) is effective in preventing illness after potential or documented exposure to a variety of microbial pathogens and in reducing the risk of secondary spread of infection. Guidelines have been published by the Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practices for proper use of PEP for bloodborne pathogens, for microorganisms transmitted by either airborne or droplet spread or through direct contact, and for infections acquired after traumatic injuries. Depending on the type of exposure, different forms of PEP are available, including vaccines, immune globulins, antibiotics, and antiviral medications. Physicians should assess a patient's potential need for PEP based on several factors, including the type of exposure, the timing and severity of illness in the source patient, the exposed person's susceptibility to infectious diseases of concern, and the relative risks and benefits of the PEP regimen in an individual situation. Immunity to certain infectious diseases can be ensured with prior infection or vaccination, and by serologic testing in patients with a negative or uncertain history. PEP should be given to persons exposed to index cases of pertussis and invasive meningococcal infection regardless of immunization history, and should be given following rabies and tetanus exposure regardless of the length of delay. In general, PEP should be given as soon as possible following a high-risk exposure. Persons exposed to bloodborne pathogens should have baseline testing for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus antibodies, and follow-up testing at six weeks, three months, and six months postexposure. PMID- 23939604 TI - Nonalcoholic fatty liver disease: diagnosis and management. AB - Nonalcoholic fatty liver disease is characterized by excessive fat accumulation in the liver (hepatic steatosis). Nonalcoholic steatohepatitis is characterized by steatosis, liver cell injury, and inflammation. The mechanism of nonalcoholic fatty liver disease is unknown but involves the development of insulin resistance, steatosis, inflammatory cytokines, and oxidative stress. Nonalcoholic fatty liver disease is associated with physical inactivity, obesity, and metabolic syndrome. Screening is not recommended in the general population. The diagnosis is usually made after an incidental discovery of unexplained elevation of liver enzyme levels or when steatosis is noted on imaging (e.g., ultrasonography). Patients are often asymptomatic and the physical examination is often unremarkable. No single laboratory test is diagnostic, but tests of liver function, tests for metabolic syndrome, and tests to exclude other causes of abnormal liver enzyme levels are routinely performed. Imaging studies, such as ultrasonography, computed tomography, and magnetic resonance imaging, can assess hepatic fat, measure liver and spleen size, and exclude other diseases. Liver biopsy remains the criterion standard for the diagnosis of nonalcoholic steatohepatitis. Noninvasive tests are available and may reduce the need for liver biopsy. A healthy diet, weight loss, and exercise are first-line therapeutic measures to reduce insulin resistance. There is insufficient evidence to support bariatric surgery, metformin, thiazolidinediones, bile acids, or antioxidant supplements for the treatment of nonalcoholic fatty liver disease. The long-term prognosis is not associated with an increased risk of all-cause mortality, cardiovascular disease, cancer, or liver disease. PMID- 23939605 TI - Early recognition and management of sepsis in adults: the first six hours. AB - Sepsis is a complication of severe infection characterized by a systemic inflammatory response. Mortality rates from sepsis range between 25% to 30% for severe sepsis and 40% to 70% for septic shock. The clinical presentation of sepsis is highly variable depending on the etiology. The most common sites of infection are the respiratory, genitourinary, and gastrointestinal systems, as well as the skin and soft tissue. Fever is often the first manifestation of sepsis, with pneumonia being the most common presentation leading to sepsis. Early goal-directed therapy completed within the first six hours of sepsis recognition significantly decreases in-hospital mortality. Initial management includes respiratory stabilization followed by aggressive fluid resuscitation. Vasopressor therapy is indicated when fluid resuscitation fails to restore adequate mean arterial pressure and organ perfusion. Early antibiotic therapy can improve clinical outcomes, and should be given within one hour of suspected sepsis. Blood product therapy may be required in some cases to correct coagulopathy and anemia, and to improve the central venous oxygen saturation. Insulin therapy may be required to maintain serum glucose levels less than 180 mg per dL. Initiation of low-dose corticosteroids may further improve survival in patients with septic shock that does not respond to vasopressor therapy. Timely initiation of evidence-based protocols should improve sepsis outcomes. PMID- 23939606 TI - Arm rash and swelling in a child. PMID- 23939611 TI - Topical antibiotics and benzoyl peroxide for treatment of acne. PMID- 23939612 TI - Nonalcoholic fatty liver disease. PMID- 23939613 TI - A self-powered polymeric material that responds autonomously and continuously to fleeting stimuli. PMID- 23939614 TI - Differentiating reversible cerebral vasoconstriction syndrome with subarachnoid hemorrhage from other causes of subarachnoid hemorrhage. AB - IMPORTANCE: Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical angiographic syndrome characterized by recurrent thunderclap headaches and reversible segmental multifocal cerebral artery narrowing. More than 30% of patients with RCVS develop subarachnoid hemorrhage (SAH). Patients with RCVS with SAH (RCVS-SAH) are often misdiagnosed as having potentially ominous conditions such as aneurysmal SAH (aSAH) or cryptogenic "angiogram-negative" SAH (cSAH) owing to overlapping clinical and imaging features. OBJECTIVE: To identify predictors that can distinguish RCVS-SAH from aSAH and cSAH at the time of clinical presentation. DESIGN: Retrospective analysis of 3 patient cohorts: patients with RCVS (1998-2009), patients with aSAH (1995-2003), and patients with cSAH (1995-2003). SETTING: Academic hospital and tertiary referral center. PARTICIPANTS: Consecutive patients with RCVS-SAH (n = 38), aSAH (n = 515), or cSAH (n = 93) whose conditions were diagnosed using standard criteria. MAIN OUTCOMES AND MEASURES: Multivariate logistic regression analysis was used to identify predictors that differentiate RCVS-SAH from aSAH and cSAH. RESULTS: Predictors differentiating RCVS-SAH from aSAH were younger age, chronic headache disorder, prior depression, prior chronic obstructive pulmonary disease, lower Hunt-Hess grade, lower Fisher SAH group, higher number of affected arteries, and the presence of bilateral arterial narrowing. Predictors differentiating RCVS-SAH from cSAH were younger age, female sex, prior hypertension, chronic headache disorder, lower Hunt-Hess grade, lower Fisher SAH group, and the presence of bilateral arterial narrowing. CONCLUSIONS AND RELEVANCE: We identified important clinical and imaging differences between RCVS-SAH, aSAH, and cSAH that may be useful for improving diagnostic accuracy, clinical management, and resource utilization. PMID- 23939615 TI - Placental growth factor and soluble Fms-like tyrosine kinase 1 in diabetic pregnancy: A possible relation to distal villous immaturity. AB - This study aimed to describe the prevalence of chorionic distal villous immaturity (DVI) in overt diabetic/gestational diabetic (OD/GD) women compared with normoglycemic ones and to analyze the relation of DVI index (DVII) to placental growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1). Three groups were studied; normoglycemics (n=21), OD (n=17) and GD (n=20). Maternal blood samples were evaluated regarding serum levels of PlGF and sFlt-1. Immunohistochemical methodologies were employed in term placentae of all subjects to assess DVII and area% of PlGF and sFlt-1 immunostaining. We found that mean Hemoglobin A1c (HbA1c) is 5.22+/-0.15 in normoglycemics, 6.2+/-0.3 in OD, and 5.70+/-0.23 in GD with significant differences between groups (p=0.012). DVII was significantly higher in OD (66.6+/-4.7) and GD (72.4+/-4.5) compared to controls (11.6+/-2.5; p=0.000). Healthy women have significantly lower levels of PlGF (86.6+/-14.5) compared to OD (166.6+/-22.4, p=0.000) and GD (150.3+/-23.97, p=0.000) and their placentae expressed a significantly lower area% of PlGF (6.5+/ 0.8) compared to OD (14.8+/-1.0, p=0.000) and GD (18.8+/-1.3, p=0.000). Also, normoglycemic women have significantly lower levels of sFlt-1 (108.9+/-12.1) compared to OD (226.5+/-18.6, p=0.000) or GD (197.2+/-16.8, p=0.000) and their placentae expressed a significantly lower area% of sFlt-1 (3.2+/-0.3) compared to OD (15.4+/-1.7, p=0.000) and GD (16.9+/-1.2, p=0.000). There was significant correlation between DVII and both serum level and area% of PlGF and sFlt-1 expression in the 3 groups. This study provided a new score for evaluating DVI in normal and diabetic placentae and suggested a role for PlGF and sFlt-1 in regulation of DVI in diabetic pregnancies. PMID- 23939616 TI - Lab-on-CMOS integration of microfluidics and electrochemical sensors. AB - This paper introduces a CMOS-microfluidics integration scheme for electrochemical microsystems. A CMOS chip was embedded into a micro-machined silicon carrier. By leveling the CMOS chip and carrier surface to within 100 nm, an expanded obstacle free surface suitable for photolithography was achieved. Thin film metal planar interconnects were microfabricated to bridge CMOS pads to the perimeter of the carrier, leaving a flat and smooth surface for integrating microfluidic structures. A model device containing SU-8 microfluidic mixers and detection channels crossing over microelectrodes on a CMOS integrated circuit was constructed using the chip-carrier assembly scheme. Functional integrity of microfluidic structures and on-CMOS electrodes was verified by a simultaneous sample dilution and electrochemical detection experiment within multi-channel microfluidics. This lab-on-CMOS integration process is capable of high packing density, is suitable for wafer-level batch production, and opens new opportunities to combine the performance benefits of on-CMOS sensors with lab-on chip platforms. PMID- 23939617 TI - Metal ion as both a cofactor and a probe of metal-binding sites in a uranyl specific DNAzyme: a uranyl photocleavage study. AB - DNAzymes are known to bind metal ions specifically to carry out catalytic functions. Despite many studies since DNAzymes were discovered nearly two decades ago, the metal-binding sites in DNAzymes are not fully understood. Herein, we adopt uranyl photocleavage to probe specific uranyl-binding sites in the 39E DNAzyme with catalytically relevant concentrations of uranyl. The results indicate that uranyl binds between T23 and C25 in the bulge loop, G11 and T12 in the stem loop of the enzyme strand, as well as between T2.4 and G3 close to the cleavage site in the substrate strand. Control experiments using two 39E DNAzyme mutants revealed a different cleavage pattern of the mutated region. Another DNAzyme, the 8-17 DNAzyme, which has a similar secondary structure but shows no activity in the presence of uranyl, indicated a different uranyl-dependent photocleavage as well. In addition, a close correlation between the concentration dependent photocleavage and enzymatic activities is also demonstrated. Together, these experiments suggest that uranyl photocleavage has been successfully used to probe catalytically relevant uranyl-binding sites in the 39E DNAzyme. As uranyl is the cofactor of the 39E DNAzyme as well as the probe, specific uranyl binding has now been identified without disruption of the structure. PMID- 23939618 TI - PCNA promotes processive DNA end resection by Exo1. AB - Exo1-mediated resection of DNA double-strand break ends generates 3' single stranded DNA overhangs required for homology-based DNA repair and activation of the ATR-dependent checkpoint. Despite its critical importance in inducing the overall DNA damage response, the mechanisms and regulation of the Exo1 resection pathway remain incompletely understood. Here, we identify the ring-shaped DNA clamp PCNA as a new factor in the Exo1 resection pathway. Using mammalian cells, Xenopus nuclear extracts and purified proteins, we show that after DNA damage, PCNA loads onto double-strand breaks and promotes Exo1 damage association through direct interaction with Exo1. By tethering Exo1 to the DNA substrate, PCNA confers processivity to Exo1 in resection. This role of PCNA in DNA resection is analogous to its function in DNA replication where PCNA serves as a processivity co-factor for DNA polymerases. PMID- 23939619 TI - Interaction of bacterial fatty-acid-displaced regulators with DNA is interrupted by tyrosine phosphorylation in the helix-turn-helix domain. AB - Bacteria possess transcription regulators (of the TetR family) specifically dedicated to repressing genes for cytochrome P450, involved in oxidation of polyunsaturated fatty acids. Interaction of these repressors with operator sequences is disrupted in the presence of fatty acids, and they are therefore known as fatty-acid-displaced regulators. Here, we describe a novel mechanism of inactivating the interaction of these proteins with DNA, illustrated by the example of Bacillus subtilis regulator FatR. FatR was found to interact in a two hybrid assay with TkmA, an activator of the protein-tyrosine kinase PtkA. We show that FatR is phosphorylated specifically at the residue tyrosine 45 in its helix turn-helix domain by the kinase PtkA. Structural modelling reveals that the hydroxyl group of tyrosine 45 interacts with DNA, and we show that this phosphorylation reduces FatR DNA binding capacity. Point mutants mimicking phosphorylation of FatR in vivo lead to a strong derepression of the fatR operon, indicating that this regulatory mechanism works independently of derepression by polyunsaturated fatty acids. Tyrosine 45 is a highly conserved residue, and PtkA from B. subtilis can phosphorylate FatR homologues from other bacteria. This indicates that phosphorylation of tyrosine 45 may be a general mechanism of switching off bacterial fatty-acid-displaced regulators. PMID- 23939620 TI - Tracking in atomic detail the functional specializations in viral RecA helicases that occur during evolution. AB - Many complex viruses package their genomes into empty protein shells and bacteriophages of the Cystoviridae family provide some of the simplest models for this. The cystoviral hexameric NTPase, P4, uses chemical energy to translocate single-stranded RNA genomic precursors into the procapsid. We previously dissected the mechanism of RNA translocation for one such phage, 12, and have now investigated three further highly divergent, cystoviral P4 NTPases (from 6, 8 and 13). High-resolution crystal structures of the set of P4s allow a structure-based phylogenetic analysis, which reveals that these proteins form a distinct subfamily of the RecA-type ATPases. Although the proteins share a common catalytic core, they have different specificities and control mechanisms, which we map onto divergent N- and C-terminal domains. Thus, the RNA loading and tight coupling of NTPase activity with RNA translocation in 8 P4 is due to a remarkable C-terminal structure, which wraps right around the outside of the molecule to insert into the central hole where RNA binds to coupled L1 and L2 loops, whereas in 12 P4, a C-terminal residue, serine 282, forms a specific hydrogen bond to the N7 of purines ring to confer purine specificity for the 12 enzyme. PMID- 23939621 TI - Model of the Mediator middle module based on protein cross-linking. AB - The essential core of the transcription coactivator Mediator consists of two conserved multiprotein modules, the head and middle modules. Whereas the structure of the head module is known, the structure of the middle module is lacking. Here we report a 3D model of a 6-subunit Mediator middle module. The model was obtained by arranging crystal structures and homology models of parts of the module based on lysine-lysine cross-links obtained by mass spectrometric analysis. The model contains a central tetramer formed by the heterodimers Med4/Med9 and Med7/Med21. The Med7/Med21 heterodimer is flanked by subunits Med10 and Med31. The model is highly extended, suggests that the middle module is flexible and contributes to a molecular basis for detailed structure-function studies of RNA polymerase II regulation. PMID- 23939622 TI - CRISPR/Cas9 systems targeting beta-globin and CCR5 genes have substantial off target activity. AB - The ability to precisely modify endogenous genes can significantly facilitate biological studies and disease treatment, and the clustered regularly interspaced short palindromic repeats (CRISPR) systems have the potential to be powerful tools for genome engineering. However, the target specificity of CRISPR systems is largely unknown. Here we demonstrate that CRISPR/Cas9 systems targeting the human hemoglobin beta and C-C chemokine receptor type 5 genes have substantial off-target cleavage, especially within the hemoglobin delta and C-C chemokine receptor type 2 genes, respectively, causing gross chromosomal deletions. The guide strands of the CRISPR/Cas9 systems were designed to have a range of mismatches with the sequences of potential off-target sites. Off-target analysis was performed using the T7 endonuclease I mutation detection assay and Sanger sequencing. We found that the repair of the on-and off-target cleavage resulted in a wide variety of insertions, deletions and point mutations. Therefore, CRISPR/Cas9 systems need to be carefully designed to avoid potential off-target cleavage sites, including those with mismatches to the 12-bases proximal to the guide strand protospacer-adjacent motif. PMID- 23939624 TI - When epitaxy meets plasma: a path to ordered nanosheets arrays. AB - The possibility of a controlled assembly of 2-dimensional (2D) nanosheets (NSs) into ordered arrays or even more sophisticated structures offers tremendous opportunities in the context of fabrication of a variety of NSs based devices. Reports of such ordered NSs are rare and all conventional "top-down" methods typically led to coarse structures exhibiting only limited surface quality. In this work, we demonstrate a path to directly synthesis ordered NSs arrays in a plasma activated chemical vapor deposition technique utilizing planar defects formed during hetero-epitaxial growth of crystals featuring a close-packed lattice. As an example, the synthesis of 3C-SiC NSs arrays with well-defined orientation on (001) and (111) Si substrates is shown. A detailed analysis identifies planar defects and the plasma environment as key factors determining the resulting 2D NSs arrays. Consequently, a "planar defects induced selective growth" effect is proposed to elucidate the corresponding growth mechanism. PMID- 23939623 TI - Functional determinants of gate-DNA selection and cleavage by bacterial type II topoisomerases. AB - Antibacterial fluoroquinolones trap a cleavage complex of gyrase and topoisomerase (topo) IV inducing site-specific DNA breakage within a bent DNA gate engaged in DNA transport. Despite its importance for drug action and in revealing potential sites of topoisomerase catalysis, the mechanism of DNA selectivity is poorly understood. To explore its functional basis, we generated mutant versions of the strongly cleaved E-site and used a novel competitive assay to examine their gemifloxacin-mediated DNA breakage by Streptococcus pneumoniae topo IV and gyrase. Parallel studies of Ca(2+)-induced cleavage distinguished 'intrinsic recognition' of DNA cleavage sites by topo IV from drug-induced preferences. Analysis revealed strong enzyme-determined requirements for -4G, -2A and -1T bases preceding the breakage site (between -1 and +1) and enzyme-unique or degenerate determinants at -3, plus drug-specific preferences at +2/+3 and for +1 purines associated with drug intercalation. Similar cleavage rules were seen additionally at the novel V-site identified here in ColE1-derived plasmids. In concert with DNA binding data, our results provide functional evidence for DNA, enzyme and drug contributions to DNA cleavage at the gate, suggest a mechanism for DNA discrimination involving enzyme-induced DNA bending/helix distortion and cleavage complex stabilization and advance understanding of fluoroquinolones as important cleavage-enhancing therapeutics. PMID- 23939625 TI - Clonal selection and persistence in dysplastic Barrett's esophagus and intramucosal cancers after failed radiofrequency ablation. AB - OBJECTIVES: Radiofrequency ablation (RFA) is used to successfully eliminate Barrett's esophagus (BE)-related dysplasia or intramucosal carcinoma and aims to cause reversion to squamous epithelium. However, in 20% of cases RFA fails to return the epithelium to squamous phenotype. Follow-up studies show a similar dysplasia recurrence rate. We hypothesize that failed RFA is due to clonally mutated epithelial populations harbored in RFA-privileged sites and that RFA can select for the mutant clonal expansion. METHODS: A longitudinal case series of 19 patients with BE and high-grade dysplasia or intramucosal carcinoma were studied. DNA was extracted from individual Barrett's glands, deep esophageal glands within mucosal resections and biopsy specimens before and after RFA. Mutations were identified by targeted sequencing of genes commonly mutated in Barrett's adenocarcinoma. RESULTS: Five patients demonstrated persistent post-RFA pathology with persistent mutations, sometimes detected in deep esophageal glands or neighboring squamous epithelium after several rounds of RFA preceded by mucosal resection. Recurrence of pathology in three other patients was characterized by de novo mutations. CONCLUSIONS: Protumorigenic mutations can be found in post ablation squamous mucosa as well as in mutant deep esophageal glands; both are associated with dysplasia recurrence. Following RFA, non-dysplastic Barrett's epithelium can contain mutant clones that are found in a subsequent adenocarcinoma. Ablation may also drive the clonal expansion of pre-existing clones after a "bottleneck" created by the RFA. Overall, recurrence of dysplasia post RFA reflects the multicentric origins of Barrett's clones and highlights the role of clonal selection in carcinogenesis. PMID- 23939626 TI - Mortality and cancer in pediatric-onset inflammatory bowel disease: a population based study. AB - OBJECTIVES: Although the incidence of pediatric inflammatory bowel disease (IBD) continues to rise in Northern France, the risks of death and cancer in this population have not been characterized. METHODS: All patients <17 years, recorded in EPIMAD registry, and diagnosed between 1988 and 2004 with Crohn's disease (CD) or ulcerative colitis (UC) were included. The observed incidences of death and cancer were compared with those expected in the regional general population obtained by French Statistical Institute (INSEE) and the cancer Registry from Lille. Comparisons were performed using Fisher's exact test and were expressed using the standardized mortality ratios (SMRs) and standardized incidence ratios. RESULTS: A total of 698 patients (538 with CD and 160 with UC) were identified; 360 (52%) were men, the median age at IBD diagnosis was 14 years (12-16) and the median follow-up time was 11.5 years (7-15). During follow-up, the mortality rate was 0.84% (6/698) and did not differ from that in the reference population (SMR=1.4 (0.5-3.0); P=0.27). After a median follow-up of 15 years (10-17), 1.3% of patients (9/698) had a cancer: colon (n=2), biliary tract (cholangiocarcinoma; n=1), uterine cervix (n=1), prepuce (n=1), skin (basal cell carcinoma (n=2), hematological (acute leukemia; n=1), and small bowel carcinoid (n=1). There was a significantly increased risk of cancer regardless of gender and age (standardized incidence ratio=3.0 (1.3-5.9); P<0.02). Four out of nine patients who developed a cancer had received immunosuppressants or anti-tumor necrosis factor-alpha therapy (including combination therapy in three patients). CONCLUSIONS: In this large pediatric population-based IBD cohort, mortality did not differ from that of the general population but there was a significant threefold increased risk of neoplasia. PMID- 23939627 TI - Protective value of TIPS against the development of hydrothorax/ascites and upper gastrointestinal bleeding after balloon-occluded retrograde transvenous obliteration (BRTO). AB - OBJECTIVES: The objective of this study was to evaluate the incidence of post balloon-occluded retrograde transvenous obliteration (BRTO) ascites/hepatic hydrothorax and rebleeding rate (variceal and non-variceal) in the presence and absence of a transjugular intrahepatic portosystemic shunt (TIPS). METHODS: A retrospective audit of consecutive patients undergoing BRTO was performed (August 2007-October 2010). The population was divided into two groups: patients who underwent BRTO only (BRTO-only group) and those who underwent BRTO in the presence of TIPS (BRTO+TIPS group). Post-BRTO rebleeding was categorized for the source of bleeding. Ascites and/or hepatic hydrothorax were categorized according to clinical severity. Comparisons, utilizing the Kaplan-Meier method, between both groups were made for patient survival, incidence of ascites/hydrothorax, and rebleeding. RESULTS: Thirty-nine patients underwent BRTO (three technical failures of BRTO-only group). Of the 36 technically successful BRTO procedures, 27 patients (75%) underwent BRTO-only and 9 patients (25%) underwent BRTO in the presence of a TIPS. Pre-BRTO ascites/hydrothorax resolved in BRTO-only vs. BRTO+TIPS in 7% (N=2/27) and 56% (N=5/9), respectively (P=0.006). The ascites/hydrothorax free rate at 6, 12, and 24 months after BRTO for BRTO-only vs. BRTO+TIPS was 58%, 43%, 29%, and 100%, 100%, 100%, respectively (P=0.01). Recurrent hemorrhage for BRTO-only vs. BRTO+TIPS groups, and for the same time periods was 9%, 9%, 21% vs. 0%, 0%, 0%, respectively (P=0.03). The 1-year patient survival of both groups (80-88%) was similar (P>0.05). CONCLUSIONS: This study concludes that the presence of TIPS has a protective value against the development of post-BRTO ascites/hydrothorax as well as recurrent hemorrhage but this does not translate to improved patient survival. PMID- 23939628 TI - Heat waves, incidence of infectious gastroenteritis, and relapse rates of inflammatory bowel disease: a retrospective controlled observational study. AB - OBJECTIVES: The objective of this study was to evaluate the effect of heat waves on flares of inflammatory bowel disease (IBD) and infectious gastroenteritis (IG). METHODS: In this retrospective controlled observational study, data from 738 IBD and 786 IG patients admitted to the University Hospital of Zurich in the years 2001-2005, as well as from 506 other noninfectious chronic intestinal inflammations, which were used as control, were collected. Climate data were obtained from the Swiss Federal Office for Meteorology and Climatology. RESULTS: The presence of a heat wave increased the risk of IBD flares by 4.6% (95% confidence interval (CI): 1.6-7.4%, P=0.0035) and of IG flares by 4.7% (95% CI: 1.8-7.4%, P=0.0020) for every additional day within a heat wave period. In the control group there was no significant effect (95% CI: -6.2-2.9%, P=0.53). Screening of alternative forms for the effect of heat waves suggested that for IG the effect is strongest when lagged by 7 days (risk increase per day: 7.2%, 95% CI: 4.6-9.7%, P<0.0001), whereas for IBD no such transformation was required. Other formulations with additive effects, interactions between heat waves and time of the year, and additional adjustments for daily average temperature did not show any improvement in model fit. CONCLUSIONS: In this retrospective controlled observational study, we found a substantial increase in hospital admissions because of flares of IBD and IG during heat wave periods. Whereas the effect on IG is strongest with a delay of 7 days, the effect on IBD flares is immediate, suggesting different mechanisms. PMID- 23939629 TI - Therapeutic advances in muscular dystrophy. AB - The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Each of these disorders represents a different class of genetic disease (monogenic, epigenetic, and repeat expansion disorders), and the approach to therapy addresses the diverse and complex molecular mechanisms involved in these diseases. The large number of novel pharmacologic agents in development with good biologic rationale and strong proof of concept suggests there will be an improved quality of life for individuals with muscular dystrophy. PMID- 23939631 TI - Multiple-dose, safety, pharmacokinetic, and pharmacodynamic study of sotatercept (ActRIIA-IgG1), a novel erythropoietic agent, in healthy postmenopausal women. AB - Ligands of the transforming growth factor-beta superfamily and activin-receptor signaling play an important role in erythropoiesis. Sotatercept, an activin receptor type IIA (ActRIIA) ligand trap, is a novel, recombinant, fusion protein comprising the extracellular domain of human ActRIIA linked to the Fc portion of human immunoglobulin G1. Sotatercept, originally developed to increase bone mineral density, was noted to have robust effects on erythropoiesis. Here, we evaluated the safety, pharmacokinetic properties, and pharmacodynamic effects of sotatercept in 31 healthy postmenopausal women. Sotatercept was administered at dose level 0.1, 0.3, or 1 mg/kg every 28 days subcutaneously for up to four doses. Sotatercept was generally safe and well tolerated, and elicited clinically significant, dose-dependent increases in hemoglobin, hematocrit, and red blood cell counts that persisted for up to 4 months. The effect of sotatercept on hemoglobin was dose-limiting. Sotatercept also increased bone mineral density and biomarkers of bone formation. The sotatercept serum exposure-dose relationship was linear, with a mean terminal half-life of approximately 23 days. ActRIIA ligands are important regulators of erythrocyte production in healthy individuals. Clinical studies are ongoing to explore the potential of sotatercept to treat anemia and diseases of ineffective erythropoiesis as well as an agent to increase bone mineral density. PMID- 23939630 TI - Variable temporoinsular cortex neuroanatomy in primates suggests a bottleneck effect in eastern gorillas. AB - We describe an atypical neuroanatomical feature present in several primate species that involves a fusion between the temporal lobe (often including Heschl's gyrus in great apes) and the posterior dorsal insula, such that a portion of insular cortex forms an isolated pocket medial to the Sylvian fissure. We assessed the frequency of this fusion in 56 primate species (including apes, Old World monkeys, New World monkeys, and strepsirrhines) by using either magnetic resonance images or histological sections. A fusion between temporal cortex and posterior insula was present in 22 species (seven apes, two Old World monkeys, four New World monkeys, and nine strepsirrhines). The temporoinsular fusion was observed in most eastern gorilla (Gorilla beringei beringei and G. b. graueri) specimens (62% and 100% of cases, respectively) but was seen less frequently in other great apes and was never found in humans. We further explored the histology of this fusion in eastern gorillas by examining the cyto- and myeloarchitecture within this region and observed that the degree to which deep cortical layers and white matter are incorporated into the fusion varies among individuals within a species. We suggest that fusion between temporal and insular cortex is an example of a relatively rare neuroanatomical feature that has become more common in eastern gorillas, possibly as the result of a population bottleneck effect. Characterizing the phylogenetic distribution of this morphology highlights a derived feature of these great apes. PMID- 23939632 TI - Mutation of the CgPDR16 gene attenuates azole tolerance and biofilm production in pathogenic Candida glabrata. AB - The PDR16 gene encodes the homologue of Sec14p, participating in protein secretion, regulation of lipid synthesis and turnover in vivo and acting as a phosphatidylinositol transfer protein in vitro. This gene is also involved in the regulation of multidrug resistance in Saccharomyces cerevisiae and pathogenic yeasts. Here we report the results of functional analysis of the CgPDR16 gene, whose mutation has been previously shown to enhance fluconazole sensitivity in Candida glabrata mutant cells. We have cloned the CgPDR16 gene, which was able to complement the pdr16Delta mutation in both C. glabrata and S. cerevisiae. Along with fluconazole, the pdr16Delta mutation resulted in increased susceptibility of mutant cells to several azole antifungals without changes in sensitivity to polyene antibiotics, cycloheximide, NQO, 5-fluorocytosine and oxidants inducing the intracellular formation of reactive oxygen species. The susceptibility of the pdr16Delta mutant strain to itraconazole and 5-fluorocytosine was enhanced by CTBT [7-chlorotetrazolo(5,1-c)benzo(1,2,4)triazine] inducing oxidative stress. The pdr16Delta mutation increased the accumulation of rhodamine 6G in mutant cells, decreased the level of itraconazole resistance caused by gain-of-function mutations in the CgPDR1 gene, and reduced cell surface hydrophobicity and biofilm production. These results point to the pleiotropic phenotype of the pdr16Delta mutant and support the role of the CgPDR16 gene in the control of drug susceptibility and virulence in the pathogenic C. glabrata. PMID- 23939633 TI - Towards molecular ribbons of corannulene. AB - Herein, we explore the synthesis of corannulene-based ribbon-shaped molecules through a repetitive Diels-Alder strategy. For this, appropriate corannulene based dienes and dienophiles were identified and synthesized. These building blocks could be combined in a modular way to obtain the dimeric and trimeric segments of the hypothetical molecular ribbons. 1D and 2D NMR measurements, along with crystal-structure analyses, allowed the structures and geometries of the synthesized compounds to be determined. PMID- 23939634 TI - Making every word count for nonresponsive patients. AB - IMPORTANCE: Despite the apparent absence of external signs of consciousness, a significant small proportion of patients with disorders of consciousness can respond to commands by willfully modulating their brain activity, even respond to yes or no questions, by performing mental imagery tasks. However, little is known about the mental life of such responsive patients, for example, with regard to whether they can have coherent thoughts or selectively maintain attention to specific events in their environment. The ability to selectively pay attention would provide evidence of a patient's preserved cognition and a method for brain based communication, thus far untested with functional magnetic resonance imaging in this patient group. OBJECTIVE: To test whether selective auditory attention can be used to detect conscious awareness and communicate with behaviorally nonresponsive patients. DESIGN, SETTING, AND PARTICIPANTS: Case study performed in 3 patients with severe brain injury, 2 diagnosed as being in a minimally conscious state and 1 as being in a vegetative state. The patients constituted a convenience sample. MAIN OUTCOMES AND MEASURES: Functional magnetic resonance imaging data were acquired as the patients were asked to selectively attend to auditory stimuli, thereby conveying their ability to follow commands and communicate. RESULTS: All patients demonstrated command following according to instructions. Two patients (1 in a minimally conscious state and 1 in a vegetative state) were also able to guide their attention to repeatedly communicate correct answers to binary (yes or no) questions. CONCLUSIONS AND RELEVANCE: To our knowledge, we show for the first time with functional magnetic resonance imaging that behaviorally nonresponsive patients can use selective auditory attention to convey their ability to follow commands and communicate. One patient in a minimally conscious state was able to use attention to establish functional communication in the scanner, despite his inability to produce any communication responses in repeated bedside examinations. More important, 1 patient, who had been in a vegetative state for 12 years before the scanning and subsequent to it, was able to use attention to correctly communicate answers to several binary questions. The technique may be useful in establishing basic communication with patients who appear unresponsive to bedside examinations and cannot respond with existing neuroimaging methods. PMID- 23939635 TI - Nickel foam supported mesoporous MnO2 nanosheet arrays with superior lithium storage performance. AB - Mesoporous MnO2 nanosheet arrays have been directly grown on nickel foam current collectors and exhibited a reversible capacity as high as 1690 mA h g(-1) even after one hundred cycles at 100 mA g(-1). They also reveal good rate capability and excellent cycling stability. PMID- 23939636 TI - Anisotropic overgrowth of metal heterostructures induced by a site-selective silica coating. PMID- 23939639 TI - Bullying among adolescents: a challenge in primary care. PMID- 23939637 TI - Smart-phone based computational microscopy using multi-frame contact imaging on a fiber-optic array. AB - We demonstrate a cellphone based contact microscopy platform, termed Contact Scope, which can image highly dense or connected samples in transmission mode. Weighing approximately 76 grams, this portable and compact microscope is installed on the existing camera unit of a cellphone using an opto-mechanical add on, where planar samples of interest are placed in contact with the top facet of a tapered fiber-optic array. This glass-based tapered fiber array has ~9 fold higher density of fiber optic cables on its top facet compared to the bottom one and is illuminated by an incoherent light source, e.g., a simple light-emitting diode (LED). The transmitted light pattern through the object is then sampled by this array of fiber optic cables, delivering a transmission image of the sample onto the other side of the taper, with ~3* magnification in each direction. This magnified image of the object, located at the bottom facet of the fiber array, is then projected onto the CMOS image sensor of the cellphone using two lenses. While keeping the sample and the cellphone camera at a fixed position, the fiber optic array is then manually rotated with discrete angular increments of e.g., 1 2 degrees. At each angular position of the fiber-optic array, contact images are captured using the cellphone camera, creating a sequence of transmission images for the same sample. These multi-frame images are digitally fused together based on a shift-and-add algorithm through a custom-developed Android application running on the smart-phone, providing the final microscopic image of the sample, visualized through the screen of the phone. This final computation step improves the resolution and also removes spatial artefacts that arise due to non-uniform sampling of the transmission intensity at the fiber optic array surface. We validated the performance of this cellphone based Contact Scope by imaging resolution test charts and blood smears. PMID- 23939640 TI - Pulmonary embolism rule-out criteria: a clinical decision rule that works. PMID- 23939641 TI - Edema: diagnosis and management. AB - Edema is an accumulation of fluid in the interstitial space that occurs as the capillary filtration exceeds the limits of lymphatic drainage, producing noticeable clinical signs and symptoms. The rapid development of generalized pitting edema associated with systemic disease requires timely diagnosis and management. The chronic accumulation of edema in one or both lower extremities often indicates venous insufficiency, especially in the presence of dependent edema and hemosiderin deposition. Skin care is crucial in preventing skin breakdown and venous ulcers. Eczematous (stasis) dermatitis can be managed with emollients and topical steroid creams. Patients who have had deep venous thrombosis should wear compression stockings to prevent postthrombotic syndrome. If clinical suspicion for deep venous thrombosis remains high after negative results are noted on duplex ultrasonography, further investigation may include magnetic resonance venography to rule out pelvic or thigh proximal venous thrombosis or compression. Obstructive sleep apnea may cause bilateral leg edema even in the absence of pulmonary hypertension. Brawny, nonpitting skin with edema characterizes lymphedema, which can present in one or both lower extremities. Possible secondary causes of lymphedema include tumor, trauma, previous pelvic surgery, inguinal lymphadenectomy, and previous radiation therapy. Use of pneumatic compression devices or compression stockings may be helpful in these cases. PMID- 23939642 TI - A primary care approach to substance misuse. AB - Substance misuse is common among patients in primary care settings. Although it has a substantial health impact, physicians report low levels of preparedness to identify and assist patients with substance use disorders. An effective approach to office-based treatment includes a coherent framework for identifying and managing substance use disorders and specific strategies to promote behavior change. Brief validated screening tools allow rapid and efficient identification of problematic drug use, including prescription medication misuse. After a positive screening, a brief assessment should be performed to stratify patients into three categories: hazardous use, substance abuse, or substance dependence. Patients with hazardous use benefit from brief counseling by a physician. For patients with substance abuse, brief counseling is also indicated, with the addition of more intensive ongoing follow-up and reevaluation. In patients with substance dependence, best practices include a combination of counseling, referral to specialty treatment, and pharmacotherapy (e.g., drug tapering, naltrexone, buprenorphine, methadone). Comorbid mental illness and intimate partner violence are common in patients with substance use disorders. The use of a motivational rather than a confrontational communication style during screening, counseling, and treatment is important to improve patient outcomes. PMID- 23939643 TI - Cluster headache. AB - Cluster headache causes severe unilateral temporal or periorbital pain, lasting 15 to 180 minutes and accompanied by autonomic symptoms in the nose, eyes, and face. Headaches often recur at the same time each day during the cluster period, which can last for weeks to months. Some patients have chronic cluster headache without remission periods. The pathophysiology of cluster headache is not fully understood, but may include a genetic component. Cluster headache is more prevalent in men and typically begins between 20 and 40 years of age. Treatment focuses on avoiding triggers and includes abortive therapies, prophylaxis during the cluster period, and long-term treatment in patients with chronic cluster headache. Evidence supports the use of supplemental oxygen, sumatriptan, and zolmitriptan for acute treatment of episodic cluster headache. Verapamil is first line prophylactic therapy and can also be used to treat chronic cluster headache. More invasive treatments, including nerve stimulation and surgery, may be helpful in refractory cases. PMID- 23939644 TI - Acute asthma and other recurrent wheezing disorders in children. PMID- 23939645 TI - Photo quiz. Pigmented lesion on the sole in a child. PMID- 23939648 TI - Treating patients with borderline personality disorder in the medical office. PMID- 23939649 TI - Endocrine society releases guidelines on diagnosis and management of hypertriglyceridemia. PMID- 23939650 TI - FPIN's clinical inquiries. Corticosteroids for presumed pneumocystis pneumonia in patients with HIV infection. PMID- 23939651 TI - Cluster headache. PMID- 23939652 TI - Percutaneous cholecystostomy for high-risk surgical patients with acute calculous cholecystitis. AB - BACKGROUND: The management of people at high risk of perioperative death due to their general condition (high-risk surgical patients) with acute calculous cholecystitis is controversial, with no clear guidelines. In particular, the role of percutaneous cholecystostomy in these patients has not been defined. OBJECTIVES: To compare the benefits (temporary or permanent relief of symptoms) and harms (recurrence of symptoms, procedure-related morbidity) of percutaneous cholecystostomy in the management of high-risk individuals with symptomatic gallstones. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded to December 2012 to identify the randomised clinical trials. We also handsearched the references lists of identified trials. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or publication status) addressing this issue. DATA COLLECTION AND ANALYSIS: Two review authors collected data independently. For each outcome, we calculated the P values using Fisher's exact test or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: We included two trials with 156 participants for this review. The comparisons included in these two trials were percutaneous cholecystostomy followed by early laparoscopic cholecystectomy versus delayed laparoscopic cholecystectomy (1 trial; 70 participants) and percutaneous cholecystostomy versus conservative treatment (1 trial; 86 participants). Both trials had high risk of bias. Percutaneous cholecystostomy with early laparoscopic cholecystectomy versus delayed laparoscopic cholecystectomy: There was no significant difference in mortality between the two intervention groups (0/37 versus 1/33; Fisher's exact test: P value = 0.47). There was no significant difference in overall morbidity between the two intervention groups (1/31 versus 2/30; Fisher's exact test: P value = 0.61). This trial did not report on quality of life. There was no significant difference in the proportion of participants requiring conversion to open cholecystectomy between the two intervention groups (2/31 percutaneous cholecystostomy followed by early laparoscopic cholecystectomy versus 4/30 delayed laparoscopic cholecystectomy; Fisher's exact test: P value = 0.43). The mean total hospital stay was significantly lower in the percutaneous cholecystostomy followed by early laparoscopic cholecystectomy group compared with the delayed laparoscopic cholecystectomy group (1 trial; 61 participants; MD -9.90 days; 95% CI -12.31 to 7.49). The mean total costs were significantly lower in the percutaneous cholecystostomy followed by early laparoscopic cholecystectomy group compared with the delayed laparoscopic cholecystectomy group (1 trial; 61 participants; MD -1123.00 USD; 95% CI -1336.60 to -909.40). Percutaneous cholecystostomy versus conservative treatment: Nine of the 44 participants underwent delayed cholecystectomy in the percutaneous cholecystostomy group. Seven of the 42 participants underwent delayed cholecystectomy in the conservative treatment group. There was no significant difference in mortality between the two intervention groups (6/44 versus 7/42; Fisher's exact test: P value = 0.77). There was no significant difference in overall morbidity between the two intervention groups (6/44 versus 3/42; Fisher's exact test: P value = 0.49). The number of participants who underwent laparoscopic cholecystectomy was not reported in this trial. Therefore, we were unable to calculate the proportion of participants who underwent conversion to open cholecystectomy. The other outcomes, total hospital stay, quality of life, and total costs, were not reported in this trial. AUTHORS' CONCLUSIONS: Based on the current available evidence from randomised clinical trials, we are unable to determine the role of percutaneous cholecystostomy in the clinical management of high-risk surgical patients with acute cholecystitis. There is a need for adequately powered randomised clinical trials of low risk of bias on this issue. PMID- 23939653 TI - How is radiating leg pain defined in randomized controlled trials of conservative treatments in primary care? A systematic review. AB - Many terms exist to describe radiating leg pain or symptoms associated with back pain (e.g., sciatica or radiculopathy) and it appears that these terms are used inconsistently. We examined the terms used to describe, and the eligibility criteria used to define, radiating leg pain in randomized controlled trials of conservative treatments, and evaluated how the eligibility criteria compared to an international pain taxonomy. Eligible studies were identified from two systematic reviews and an updated search of their search strategy. Studies were included if they recruited adults with radiating leg pain associated with back pain. Two independent reviewers screened the studies and extracted data. Studies were grouped according to the terms used to describe radiating leg pain. Thirty one of the seventy-seven included studies used multiple terms to describe radiating leg pain; the most commonly used terms were sciatica (60 studies) and disc herniation (19 studies). Most studies that used the term sciatica included pain distribution in the eligibility criteria, but studies were inconsistent in including signs (e.g., neurological deficits) and imaging findings. Similarly, studies that used other terms to describe radiating leg pain used inconsistent eligibility criteria between studies and to the pain taxonomy, except that positive imaging findings were required for almost all studies that used disc herniation to describe radiating leg pain. In view of the varying terms to describe, and eligibility criteria to define, radiating leg pain, consensus needs to be reached for each of communication and comparison between studies. PMID- 23939654 TI - The facile synthesis of the 5Z,9Z-dienoic acids and their topoisomerase I inhibitory activity. AB - An original, effective approach to the synthesis of natural and synthetic 5Z,9Z dienoic acids in high yields (61-67%) and with high selectivity (>98%) was developed. The approach is based on the use of the new intermolecular catalytic cross cyclomagnesiation of terminal aliphatic and oxygenated 1,2-dienes upon treatment with Grignard reagents in the presence of the Cp2TiCl2 catalyst. High activity of (5Z,9Z)-5,9-eicosadienoic acid as a human topoisomerase I inhibitor at concentrations above 0.1 MUM was elucidated. PMID- 23939655 TI - Synthesis, structure and light scattering properties of tetraalkylammonium metal isothiocyanate salts. AB - A series of ammonium and tetraalkylammonium metal isothiocyanate salts of the type Q(y)[M(NCS)x] (M = Cr(III), x = 6, y = 3, Q = NH4(+), Me4N(+), Et4N(+), n Bu4N(+); M = Mn(II), x = 6, y = 4, Q = Me4N(+); M = Mn(II), x = 5, y = 3, Q = Et4N(+); M = Fe(III), x = 6, y = 3, Q = Me4N(+), Et4N(+), n-Bu4N(+); M = Co(II), x = 4, y = 2, Q = n-Bu4N(+); M = Eu(III), Gd(III), Dy(III), x = 6, y = 3, Q = Bu4N(+)) has been synthesized and structurally characterized. The octahedral Cr(III) salts are isostructural to previously and newly reported Fe(III) salts. The Ln(III)-containing anions are also octahedral. For Mn(II), although the Me4N(+) salt is octahedral, the Et4N(+) salt [Mn(NCS)5](3-) possesses a distorted trigonal bipyramidal geometry. For (Et4N)3[Fe(NCS)6] and (n-Bu4N)3[Fe(NCS)6], a solid-state size-dependent change in colour from red to green was observed and was attributed to a light scattering phenomenon in the crystalline samples. PMID- 23939656 TI - Psychosocial work characteristics and sleep quality: a systematic review of longitudinal and intervention research. AB - OBJECTIVES: The objective of this study was to review longitudinal and intervention studies examining the association between psychosocial work characteristics (eg, job demands, job control, and social support) and sleep quality. Our main research aims were to examine whether (i) psychosocial work characteristics are a predictor of sleep quality, and (ii) sleep quality, in turn, is a predictor of psychosocial work characteristics. METHODS: A systematic literature search resulted in 20 relevant papers, of which 16 were longitudinal studies and 3 were intervention studies (1 study was discussed in separate papers). To quantify results, we assessed the strength of evidence of all examined associations and subsequently evaluated the studies' research quality based on predefined quality criteria. RESULTS: One intervention and three longitudinal studies studies were categorized as being of high-quality. In longitudinal studies, we found consistent and strong evidence for a negative relation between job demands and sleep quality as well as evidence for a positive relation between job control and sleep quality. Other psychosocial work characteristics were examined in an insufficient number of (high-quality) studies. Moreover, both intervention studies as well as studies investigating reversed and reciprocal relations are rare, which further limits the possibility of drawing conclusions on causality. CONCLUSIONS: Based on the current literature, it can be concluded that high job demands and low job control are predictors of poor sleep quality. More high-quality research is needed to examine the possible causal relationship between these and other psychosocial work characteristics with sleep quality, in addition to research focusing on reversed and reciprocal relations. PMID- 23939657 TI - Evaluation of dimethyl sulfoxide and dexamethasone on pulmonary contusion in experimental blunt thoracic trauma. AB - BACKGROUND: A thoracic trauma model was designed to evaluate the effect of dimethyl sulfoxide (DMSO) and dexamethasone (DX) on histopathologic and oxidative changes in lung parenchyma seen after pulmonary contusion. METHODS: Twenty-four Wistar albino rats were included in the study. They were allocated into control (CG, n=6), sham (SG, n=6), DX (DXG, n=6), and DMSO (DMG, n=6) groups. Only a lung biopsy was performed in CG. In the experimental groups, blunt thoracic trauma was induced by dropping a cylindrical metal weight (0.5 kg) through a stainless steel tube onto the right hemithorax from a height of 0.4 m (E=1.96 J). In the SG, 1 mL of physiologic saline was injected intraperitoneally, in the DXG 10 mg/kg of DX was injected intraperitoneally, and in the DMG 1.2 g/mL of DMSO was injected intraperitoneally 15 minutes after trauma. After 6 hours, lung biopsy was performed for histopathologic and oxidative injury markers. RESULTS: Histopathologically, congestion, hemorrhage, neutrophil infiltration, endothelial nitric oxide synthase (E-NoS), and total pathologic score were significantly higher in SG, DXG, and DMG when compared with CG (p<0.05). Neutrophil infiltration, total pathologic score, and E-NoS were significantly decreased in DMG when compared with SG and DXG (p<0.05). Biochemically, superoxide dismutase (SOD) level was significantly higher in SG, DXG, and DMG than in CG. SOD level was significantly lower in DXG and DMG than in SG (p<0.05). CONCLUSION: DMSO prevents further injury by decreasing neutrophil infiltration and endothelial injury in lung contusions. DX may have a role in the progression of inflammation but not in preventing the pathologic disruption of pulmonary parenchyma. PMID- 23939658 TI - Progressive changes in cerebral perfusion after carotid stenting: a dynamic susceptibility contrast perfusion weighted imaging study. AB - BACKGROUND: We aimed to assess baseline inter-hemispheric perfusion differences, before carotid artery stenting (CAS), of severe internal carotid artery (ICA) stenosis, and to evaluate perfusion changes over time after CAS by means of perfusion weighted imaging (PWI). METHODS: Dynamic susceptibility contrast PWI was performed in 33 patients with severe ICA stenosis 1 day before and 1 day after CAS, and repeated in 23 patients 30 days after CAS. Cerebral blood volume, cerebral blood flow, arrival time (T0), mean transit time, and time to peak (TTP) relative values comparing symptomatic and asymptomatic hemispheres before CAS were obtained. Pre- and post-CAS values were also compared in the treated hemisphere and middle cerebral artery (MCA) territories. The influence of collateral circulation and contralateral ICA stenosis were evaluated. RESULTS: Before CAS, TTP was significantly increased in the affected hemisphere and MCA territory in all patients (p=0.007 and p=0.021, respectively). After treatment, normalization was observed for TTP and T0 30 days after CAS in all patients, mainly in patients with any grade of contralateral stenosis and with one or both functioning communicating arteries (42.4% of patients had both, and 42.4% showed only one-anterior communicating artery=11 patients (78.6%) and posterior communicating artery=3 patients (21.4%)). CONCLUSIONS: Inter-hemispheric perfusion differences in patients with severe ICA stenosis normalize after CAS in the long term, up to 30 days after the procedure. PMID- 23939660 TI - Understanding the impacts of allocation approaches during process-based life cycle assessment of water treatment chemicals. AB - Chemicals are an important component of advanced water treatment operations not only in terms of economics but also from an environmental standpoint. Tools such as life cycle assessment (LCA) are useful for estimating the environmental impacts of water treatment operations. At the same time, LCA analysts must manage several fundamental and as yet unresolved methodological challenges, one of which is the question of how best to "allocate" environmental burdens in multifunctional processes. Using water treatment chemicals as a case study example, this article aims to quantify the variability in greenhouse gas emissions estimates stemming from methodological choices made in respect of allocation during LCA. The chemicals investigated and reported here are those most important to coagulation and disinfection processes, and the outcomes are illustrated on the basis of treating 1000 ML of noncoagulated and nondisinfected water. Recent process and economic data for the production of these chemicals is used and methodological alternatives for solving the multifunctionality problem, including system expansion and mass, exergy, and economic allocation, are applied to data from chlor-alkali plants. In addition, Monte Carlo simulation is included to provide a comprehensive picture of the robustness of economic allocation results to changes in the market price of these industrial commodities. For disinfection, results demonstrate that chlorine gas has a lower global warming potential (GWP) than sodium hypochlorite regardless of the technique used to solve allocation issues. For coagulation, when mass or economic allocation is used to solve the multifunctionality problem in the chlor-alkali facility, ferric chloride was found to have a higher GWP than aluminum sulfate and a slightly lower burden where system expansion or exergy allocation are applied instead. Monte Carlo results demonstrate that when economic allocation is used, GWP results were relatively robust and resilient to the changes in commodity prices encountered during the study period, with standard deviations less than 6% for all chlor-alkali-produced chemicals reported here. Overall outcomes from the study demonstrate the potential variability in LCA results according to the allocation approach taken and emphasize the need for a consensus approach to water sector LCAs. PMID- 23939661 TI - Regioselectivity and competition of the Paterno-Buchi reaction and triplet triplet energy transfer between triplet benzophenones and pyrimidines: control by triplet energy levels. AB - The photochemical reaction of a pyrimidine and a ketone occurs either as a Paterno-Buchi (PB) reaction or as energy transfer (ET) from the triplet ketone to the pyrimidine. It is rare for the two types of reactions to occur concurrently, and their competitive mechanism remains unknown. In this work, two classes of products, regioisomeric oxetane(s) (2, 3) from a PB reaction and three isomeric dimers of 5-fluoro-1,3-dimethyl uracil (FDMU) (4-6) from a photosensitized dimerization of FDMU, are obtained through the UV irradiation of FDMU with various benzophenones (BPs). The ratio of the two products (oxetanes to dimers) reveals that the two competitive reactions depend strongly on the triplet energy levels (ET ) of the BPs. The BPs with higher ET values lead to higher proportions of dimers, whereas those with lower ET values give higher proportions of oxetane(s), with the generation of just two regioisomeric oxetanes for the BP with the lowest ET of the eight BPs investigated. The ratio of the two oxetanes (2:3) decreases with the BP ET value. The competitive mechanism for the two types of photochemical reactions is demonstrated through quenching experiments and investigation of temperature effects. Kinetic analysis shows that the rate constants of the two [2+2] photocycloadditions are comparable. Furthermore, in combination with the results of previous studies, we have gained insight into the dependence of the photochemical type and the regioselectivity in the PB reaction on the triplet energy gaps (DeltaE) between the pyrimidines and ketones. For ketones with higher ET values than the pyrimidines, the photochemical reaction is a photosensitized dimerization of the pyrimidine. In the opposite case, a PB reaction occurs, and the lower the ET of the ketones, the lower the ratio of oxetanes (2:3). When the ET of values of the ketones are close to those of the pyrimidines, the two reactions occur concurrently, and the higher the ET of the ketones, the higher the proportion of the dimers. The ratio of oxetanes (2:3) decreases with the ET value of the BPs. PMID- 23939659 TI - Spinal muscular atrophy: development and implementation of potential treatments. AB - In neurodegenerative disorders, effective treatments are urgently needed, along with methods to determine whether treatment worked. In this review, we discuss the rapid progress in the understanding of recessive proximal spinal muscular atrophy and how this is leading to exciting potential treatments of the disease. Spinal muscular atrophy is caused by loss of the survival motor neuron 1 (SMN1) gene and reduced levels of SMN protein. The critical downstream targets of SMN deficiency that result in motor neuron loss are not known. However, increasing SMN levels has a marked impact in mouse models, and these therapeutics are rapidly moving toward clinical trials. Promising preclinical therapies, the varying degree of impact on the mouse models, and potential measures of treatment effect are reviewed. One key issue discussed is the variable outcome of increasing SMN at different stages of disease progression. PMID- 23939662 TI - Valorization of humin-based byproducts from biomass processing-a route to sustainable hydrogen. AB - The synthesis of biomass-based top value-added chemical platforms, for example, 5 hydroxymethyl furfural, furfural, or levulinic acid from the acid-catalyzed dehydration of sugars results in high yields of insoluble by-products, referred to as humin. Valorization of humin by steam reforming for H2 is discussed. Both thermal and catalytic steam gasification were investigated systematically. Humin undergoes drastic changes under thermal pre-treatment to the gasification temperature. Alkali-metal-based catalysts were screened for the reactions. Na2 CO3 showed the highest activity and was selected for further study. The presence of Na2 CO3 enhances the gasification rate drastically, and gas-product analysis shows that the selectivity to CO and CO2 is 75% and 25%, respectively, which is a H2 /CO ratio of 2 (corresponding to 81.3% H2 as compared to the thermodynamic equilibrium). A possible process for the complete, efficient conversion of humin is outlined. PMID- 23939663 TI - Reduced exposure variability of the CYP3A substrate simvastatin by dose individualization to CYP3A activity. AB - This study aimed to demonstrate that the dose of a CYP3A substrate (simvastatin) can be adapted individually on the basis of CYP3A activity as assessed by midazolam metabolic clearance. In 18 healthy participants individual CYP3A activity was quantified using midazolam metabolic clearance both alone and during CYP3A inhibition with 40 mg ritonavir. Thereafter, simvastatin acid exposure was determined after a simvastatin standard dose (40 mg) and doses adapted to individual CYP3A activity at baseline and during CYP3A inhibition. Interindividual variability of CYP3A activity and simvastatin acid AUC0-24 was large and both correlated (r(2) = 0.745, P < .001). The adapted simvastatin doses ranged from 25 to 80 mg and their administration reduced simvastatin variability fivefold. Despite the low adapted simvastatin dose of 12 mg during CYP3A inhibition with ritonavir, exposure increased (point estimate of 4.2 [90% CI: 3.15-5.61]) probably caused by additional OATP1B1 inhibition. CYP3A activity based dose adaptation can be used to reduce interindividual variability in simvastatin exposure. PMID- 23939664 TI - Nitrate uptake by p-phosphonic acid calix[8]arene stabilized graphene. AB - In situ sonic probe exfoliated graphene sheets in the presence of various concentrations of p-phosphonic acid calix[8]arene are effective in removing nitrate from aquatic effluents, with the efficiency increasing for higher ratios of calixarene to graphite. Mild sonication of the nitrate-adsorbed material releases some nitrate ions back to the effluent. PMID- 23939665 TI - Analysis of reactive oxygen species in the guard cell of wheat stoma with confocal microscope. AB - Recently, the laser-scanning confocal microscope has become a routine technique and indispensable tool for cell biological studies. Previous studies indicated that reactive oxygen species (ROS) were generated in tobacco epidermal cells with confocal microscope. In the present studies, the probe 2',7'-dichlorof luorescein diacetate (H2DCF-DA) was used to research the change of ROS in the guard cell of wheat stoma, and catalase (CAT) was used to demonstrate that ROS had been labeled. The laser-scanning mode of confocal microscope was XYT, and the time interval between two sections was 1.6351 s. Sixty optical sections were acquired with the laser-scanning confocal microscope, and CAT (60,000 U mg-1) was added after four optical sections were scanned. Furthermore, the region of interest (ROI) was circled and the fluorescence intensity of ROS was quantified with Leica Confocal Software. The quantitative data were exported and the trend chart was made with software Excell. The results indicated that ROS were produced intracellularly in stomatal guard cells, and the quantified fluorescence intensity of ROS was declined with CAT added. It is a good method to research the instantaneous change of ROS in plant cells with confocal microscope and fluorescence probe H2DCF-DA. PMID- 23939666 TI - Estimating the physical cluster-size distribution within materials using atom probe. AB - A limiting characteristic of the atom-probe technique is the nondetection of ions and this embodies a significant "missing information" problem in investigations of atomic clustering phenomena causing difficulty in the interpretation of any atom-probe experiment. It is shown that the measurable cluster-size distribution can be modeled by a mixed binomial distribution. A deconvolution method based upon expectation-maximization (EM) algorithm is presented to obtain the original physical distribution from an efficiency-degraded distribution, thereby providing means to calculate accurate cluster number densities from atom probe results. The accuracy of this restoration was predominantly dependent upon the detector efficiency and was proved to be highly accurate in the case of conventional atom probe detector efficiencies (epsilon = 57%). Such considerations and measures are absolutely necessary when the number density of clusters and small precipitates is in any way regarded as important. We conclude that limitations in detector efficiency are more limiting for cluster-finding analyses via atom-probe techniques than spatial resolution issues, and therefore the current endeavors for improving detector technologies are well found. PMID- 23939667 TI - FLIM and FCS detection in laser-scanning microscopes: increased efficiency by GaAsP hybrid detectors. AB - Photon counting detectors currently used in fluorescence lifetime microscopy have a number of deficiencies that result in less-than-ideal signal-to-noise ratio of the lifetimes obtained: either the quantum efficiency is unsatisfactory or the active area is too small, and afterpulsing or tails in the temporal response contribute to overall timing inaccuracy. We have therefore developed a new FLIM detector based on a GaAsP hybrid photomultiplier. Compared with conventional PMTs and SPADs, GaAsP hybrid detectors have a number of advantages: The detection quantum efficiency reaches or surpasses the efficiency of fast SPADs, and the active area is on the order of 5 mm2, compared with 2.5 10-3 mm2 for a SPAD. The TCSPC response is clean, without the bumps and the diffusion tails typical for PMTs and SPADs. Most important, the hybrid detector is intrinsically free of afterpulsing. FLIM results are therefore free of signal-dependent background, and FCS curves are free of the known afterpulsing peak. We demonstrate the performance of the new detector for multiphoton NDD FLIM and for FCS. PMID- 23939668 TI - New details on the fine structure of the rhoptry of Toxoplasma gondii. AB - Rhoptries are organelles that have important, complex roles in Apicomplexa biology. During Toxoplasma gondii infection, these organelles take part in several essential and complex processes that include host cell entry and parasite development. Using different electron microscopy techniques, we characterized the fine morphology of the rhoptries of two of the most important life stages of T. gondii: the tachyzoite and the bradyzoite forms. The observed tachyzoite and bradyzoite rhoptries had delimited regions characterized by a dark and electron dense neck, an amorphous and less electron-dense bulb, and a region of intermediate electron density, which connects the bulb to the neck. Metal replicas of frozen-fractured tachyzoites showed intramembranous particles of different densities and sizes on the fractured faces of rhoptry membranes. Both in tachyzoites and bradyzoites, the intramembranous particles were arranged in distinctive parallel arrays that decorated most part of these organelles. Tubulo vesicular subcompartments and free particles within the rhoptry lumen were observed on freeze-fractured replicas. Cryo-fixed, deep-etched samples showed several pore-like structures localized in the bulb portion. No obvious evidence was found of a possible connection between rhoptries and micronemes. PMID- 23939669 TI - The distribution of T lymphocytes, B lymphocytes, and dendritic-like cells of the anal tonsil in the laboratory shrew, Suncus murinus. AB - We investigated the distribution of T lymphocytes, B lymphocytes, and S-100 protein-immunoreactive dendritic-like in the anal tonsil of the laboratory shrew, Suncus murinus. In adult animals, T lymphocytes were located mainly at the periphery of the anal tonsil, especially around small blood vessels. B lymphocytes were located in the central and subepithelial region of the anal tonsil, which includes primary lymphoid follicles, and in which there are small numbers of scattered T lymphocytes. B and T lymphocytes were distributed over 72.7 and 27.3% of the tonsillar area, respectively. However, their areas of distribution were not clearly distinguished. The areas containing B lymphocytes were enriched in S-100 protein antibody-immunoreactive cells, which exhibited a dendritic shape. These S-100-positive cells appeared to be identical to the follicular dendritic cells (FDC) seen in the follicles of lymphoid organs. These results suggest that the anal tonsils constitute one of the gut-associated lymphoid tissues (GALT), and that a function of the anal tonsil includes the capture of intruding antigens that would generate protective antibody responses. PMID- 23939670 TI - Enhanced effects of nonisotopic hafnium chloride in methanol as a substitute for uranyl acetate in TEM contrast of ultrastructure of fungal and plant cells. AB - This ultrastructural study showed that nonisotopic methanolic hafnium chloride and aqueous lead solution was an excellent new electron stain for enhancing TEM contrasts of fungal and plant cell structures. The ultrastructural definition provided by the new stain was often superior to that provided by conventional staining with uranyl acetate and lead. Definition of fine ultrastructure was also supported by quantitative data on TEM contrast ratios of organelles and components in fungal and plant cells. In particular, polysaccharides, which were localized in cell walls, glycogen particles, starch grains, and plant Golgi vesicle components, were much more reactive to the new stain than to the conventional one. The new nonisotopic stain is useful for enhancing the contrast of ultrastructure in biological tissues and is a safer alternative to uranyl acetate. PMID- 23939671 TI - Compensation of inhomogeneous fluorescence signal distribution in 2D images acquired by confocal microscopy. AB - In images acquired by confocal laser scanning microscopy (CLSM), regions corresponding to the same concentration of fluorophores in the specimen should be mapped to the same grayscale levels. However, in practice, due to multiple distortion effects, CLSM images of even homogeneous specimen regions suffer from irregular brightness variations, e.g., darkening of image edges and lightening of the center. The effects are yet more pronounced in images of real biological specimens. A spatially varying grayscale map complicates image postprocessing, e.g., in alignment of overlapping regions of two images and in 3D reconstructions, since measures of similarity usually assume a spatially independent grayscale map. We present a fast correction method based on estimating a spatially variable illumination gain, and multiplying acquired CLSM images by the inverse of the estimated gain. The method does not require any special calibration of reference images since the gain estimate is extracted from the CLSM image being corrected itself. The proposed approach exploits two types of morphological filters: the median filter and the upper Lipschitz cover. The presented correction method, tested on images of both artificial (homogeneous fluorescent layer) and real biological specimens, namely sections of a rat embryo and a rat brain, proved to be very fast and yielded a significant visual improvement. PMID- 23939672 TI - Energy dispersive X-ray spectrometry study of the protective effects of fluoride varnish and gel on enamel erosion. AB - BACKGROUND: Dental erosion is a risk factor for dental health, introduced by today's lifestyle. Topical fluoride applications in the form of varnishes and gel may lead to deposition of fluoride on enamel. PURPOSE: This in vitro study aimed to evaluate the effect of two fluoride varnishes and one fluoride gel on the dissolution of bovine enamel by acids. METHODS: Enamel samples (72) were divided (n = 8): artificial saliva (control-G1), Pepsi Twist(r) (G2), orange juice (G3), Duraphat(r) + Pepsi Twist(r) (G4), Duraphat(r) + orange juice (G5), Duofluorid(r) + Pepsi Twist(r) (G6), Duofluorid(r) + orange juice (G7), fluoride gel + Pepsi Twist(r) (G8), and fluoride gel + orange juice (G9). Fluoride gel was applied for 4 min and the varnishes were applied and removed after 6 h. The samples were submitted to six cycles (demineralization: Pepsi Twist(r) or orange juice, 10 min; remineralization: saliva, 1 h). Samples were analyzed by energy-dispersive X ray fluorescence (144 line-scanning). RESULTS: The amount of Ca and P decreased significantly in the samples of G2 and G3, and the Ca/P ratio decreased in G3. Mineral gain (Ca) was greater in G9 samples than in G4 > G3 > G5 > G1, and (P) greater in G7 samples than in G9 > G4-6 > G2-3. CONCLUSIONS: The protective effect of Duofluorid(r) was significantly lower than fluoride gel against orange juice. The fluoride varnishes can interfere positively with the dissolution of dental enamel in the presence of acidic beverages. Fluoride gel showed the best protection level to extrinsic erosion with low costs. PMID- 23939673 TI - Utilization of laser-assisted analytical methods for monitoring of lead and nutrition elements distribution in fresh and dried Capsicum annuum l. leaves. AB - Laser induced breakdown spectroscopy (LIBS) and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) have been applied for high resolution mapping of accumulation and distribution of heavy metal (lead) and nutrition elements (potassium, manganese) in leaves of Capsicum annuum L. samples. Lead was added in a form of Pb(NO3)2 at concentration up to 10 mmol L-1 into the vessels that contained tap water and where the 2-months old Capsicum annuum L. plants were grown another seven days. Two dimensional maps of the elements are presented for both laser-assisted analytical methods. Elemental mapping performed on fresh (frozen) and dried Capsicum annuum L. leaves are compared. PMID- 23939674 TI - Rhyncophorus palmarum L. (Linnaeus, 1758): a morphological and histological study of the female reproductive system. AB - Rhyncophorus palmarum (Coleoptera) is a pest of great economic importance because of the damage caused in the plants of the Palmae family. This study showed that the female reproductive system of this beetle is composed of two ovaries of the telotrophic meroistic type invariably containing two ovarioles per ovary. Each ovariole is home to about 50 oocytes at different stages of maturation. The proximal region of the ovary is rather peculiar because it houses inside it a large quantity of bacilliform structures immersed in a glycolipoprotein substance, which has never before been described in the literature. The function of these structures is still unknown. However, it is suggested that they can function as a method of neutralizing the resistance of the plant because these insects are responsible for the transmission of the red ring disease to the palm plants. PMID- 23939675 TI - Morphology and lectin-binding sites of pyloric caeca epithelium in normal and GnRH-treated Atlantic bluefin tuna (Thunnus thynnus) Linnaeus 1758. AB - Mucosal epithelium of pyloric caeca was studied in normal and in GnRH-treated Atlantic bluefin tuna Thunnus thynnus L., using morphological analysis, conventional and lectin glycohistochemistry. The lining epithelium consisted of columnar (absorptive) cells, goblet cells and intraepithelial leucocytes. The epithelium from normal animals was significantly taller than GnRH-treated samples. Conventional histochemistry displayed the same staining pattern in normal and hormone-treated specimens which showed a mixture of neutral and sulphated acidic glycoconjugates in the luminal surface and goblet cells, and neutral glycans in apical granules of enterocytes. Lectin histochemistry revealed a different glycoconjugate pattern in normal and GnRH-treated tunas. In normal specimens the luminal surface expressed sialoglycoconjugates which bound MAL II, SNA, KOH-sialidase-PNA, KOH-sialidase-SBA as well as asialoglycans stained with HPA, SBA, GSA I-B4 , LTA. N-linked glycans were highlighted by Con A and KOH sialidase-WGA. In GnRH-treated tunas the luminal surface did not react with SNA, SBA and LTA. The columnar cells of normal tunas bound KOH-sialisase-PNA in the apical region, KOH-sialidase-PNA, KOH-sialidase-DBA, HPA, SBA, KOH-sialidase-SBA and KOH-sialidase-WGA in apical granules, GSA I-B4 and LTA in the supranuclear region. GnRH-treated specimens showed some columnar cells that stained with KOH sialidase-WGA in the apical granules and with GSA I-B4 in the supranuclear region. The goblet cells of normal animals produced mucins positive to PNA, HPA, KOH-sialidase-DBA, SBA, GSA II. The latter three binding sites lacked in GnRH treated tunas. The results suggest that the mucosal epithelium of Thunnus thynnus L. pyloric caeca expresses a complex glycan pattern that is affected by GnRH treatment. PMID- 23939676 TI - MDMA (ecstasy) enhances loud noise-induced morphofunctional alterations in heart and adrenal gland. AB - Noise is an environmental stressor increasingly more present in modern life and, in particular, in a variety of recreational contexts. The aim of this work is to show the effects of noise on the myocardium and adrenal gland, through a careful review of the literature dealing with the peripheral effects of noise exposure in experimental and clinical studies. Noise induces adverse effects in human health, principally involving the cardiovascular and autonomic nervous systems, and the endocrine apparatus. Several factors in recreational environments potentially worsen the effects induced by loud noise. Among these, the intake of 3,4 methylenedioxymethamphetamine (MDMA) is frequently associated with noise exposure in recreational situations, because of its high compliance within social and relaxation settings. For this reason, MDMA is defined as a club drug--as its intake by young people often occurs in association with other factors, such as aggregation, high temperatures, and noise. It is known that self-administration of MDMA by humans causes severe toxicity. In particular, the myocardium is affected early after MDMA intake--resulting in tachycardia, hypertension, and arrhythmia. Furthermore, MDMA alters the activity of the adrenal glands by elevating catecholamines and corticosterone levels. This review shows that combining MDMA and loud noise exposure potentiates the effects that are produced by each single stimulant alone as seen in experimental animal models. The convergence of the effects of prolonged loud noise exposure and the consumption of MDMA on the same system might explain the sudden fatal events that happen in recreational situations. PMID- 23939677 TI - Lay therapist-delivered manualised CBT improves anger coping in people with intellectual disability and anger problems, but effects on anger measures mixed. PMID- 23939678 TI - Depression and use of antidepressants is associated with increased risk of Clostridium difficile infection. PMID- 23939679 TI - Review: computerised CBT improves adult depression in the short-term, but its effect may have been overestimated previously. PMID- 23939680 TI - Electrophysiological mapping of the temporal branch of the facial nerve. AB - BACKGROUND: Minimized frontal and frontolateral approaches have been proposed for the clipping of aneurysms and for removal of deep-seated supra- and parasellar lesions. To avoid postoperative facial nerve palsy, anatomical studies have been conducted; however, only one electrophysiological investigation has been reported. We studied the course of the facial nerve in the temporal region and identify the optimal pterional keyhole craniotomy from the perspective of facial nerve protection. MATERIALS AND METHODS: We stimulated the temporal branch of the facial nerve in nine healthy volunteers and identified its course electrophysiologically. Electromyographic (EMG) responses were recorded from the superior orbicularis oculi, corrugator, and frontal muscles. The course of the temporal branch of the facial nerve was identified by tracking the stimulation points that elicited the best EMG responses. RESULTS AND CONCLUSION: The distances from the tragus to the canthus, the tragus to the point where the facial nerve crosses over the zygomatic arch, the tragus to the first nerve bifurcation, the tragus to the second nerve bifurcation, and from the orbit to the middle rami were 80.8 +/- 1.8 mm, 40.2 +/- 1.6 mm, 58.1 +/- 2.8 mm, 79.1 +/- 3.4 mm, and 16.4 +/- 0.9 mm, respectively. We found that the temporal branch of the facial nerve innervates each muscle in posterior-anterior direction. Based on these results, we prefer the pterional keyhole approach and incise the skin at a site posterior to the temporal branch of the facial nerve. PMID- 23939681 TI - Transventricular fenestration of the lamina terminalis: the value of a flexible endoscope: technical note. AB - BACKGROUND: Recently, the authors demonstrated the technical feasibility of a transventricular translaminar terminalis ventriculostomy with a rigid endoscope. A major problem with this technique remains the contusion of the fornix at the foramen of Monro. Here, the authors evaluated alternative approaches and techniques, including the use of a flexible endoscope. MATERIAL AND METHODS: Feasibility of two approaches-anterior and posterior of the coronal suture-was evaluated on magnetic resonance images and in cadaveric brains. Two different trajectories were selected. Lamina terminalis (LT) fenestration was performed with a rigid and a flexible endoscope using two approaches in 10 fixed cadaver brains. RESULTS: Using the posterior approach 2 cm behind the coronal suture with the two endoscopes caused moderate to severe damage to foramen and fornix. Using the standard approach (Kocher point) with the flexible endoscope avoided damage of these structures. After completion of the anatomical investigation, the authors successfully performed a transventricular fenestration of the LT with the flexible endoscope in one clinical case. CONCLUSION: Rigid scopes provide brilliant optics and safe manipulation with the instruments. However, with the rigid scope, a transventricular opening of the LT is only possible with acceptance of structural damage to the foramen of Monro and the fornix. In contrast, opening of the LT via a transventricular route with preservation of the anatomical structures can be achieved with a flexible steerable endoscope even via a standard burr hole. Thus, if a standard third ventriculostomy is not feasible, endoscopic opening of the LT might represent an alternative, particularly with a flexible scope in experienced hands. PMID- 23939682 TI - Are we doing enough to prevent the perfect storm?: novice drivers, ADHD, and distracted driving. PMID- 23939683 TI - Ternary complex formation and competition quench fluorescence of ZnAF family zinc sensors. AB - Our current understanding of the intracellular thermodynamics and kinetics of Zn(ii) ions is largely based on the application of fluorescent sensor molecules, used to study and visualize the concentration, distribution and transport of Zn(ii) ions in real time. Such agents are designed for high selectivity for zinc in respect to other biological metal ions. However, the issue of their sensitivity to physiological levels of low molecular weight Zn(ii) ligands (LMWLs) has not been addressed. We followed the effects of eight such compounds on the fluorescence of ZnAF-1 and ZnAF-2F, two representatives of the ZnAF family of fluorescein-based zinc sensors containing the N,N-bis(2 pyridylmethyl)ethylenediamine chelating unit. Fluorescence titrations of equimolar Zn(ii)-ZnAF-1 and Zn(ii)-ZnAF-2F solutions with acetate, phosphate, citrate, glycine, glutamic acid, histidine, ATP and GSH demonstrated strong fluorescence quenching. These results are interpreted in terms of an interplay of the formation of the [ZnAF-Zn(ii)-LMWL] ternary complexes and the competition for Zn(ii) between ZnAF and LMWLs. UV-vis spectroscopic titrations revealed the existence of supramolecular interactions between the fluorescein moiety of ZnAF-1 and ATP and His, which, however, did not contribute to fluorescence quenching. Therefore, the obtained results show that the ZnAF sensors, other currently used zinc sensors containing the N,N-bis(2-pyridylmethyl)ethylenediamine unit, and, in general, all sensors that do not saturate the Zn(ii) coordination sphere may co report cellular metabolites and Zn(ii) ions, leading to misrepresentations of the concentrations and fluxes of biological zinc. PMID- 23939684 TI - Autophagy and neurodegeneration - genetic findings in SENDA syndrome, a subtype of neurodegeneration with brain iron accumulation, provide a novel link. PMID- 23939686 TI - 'Mediterranean' dietary pattern for the primary prevention of cardiovascular disease. AB - BACKGROUND: The Seven Countries study in the 1960s showed that populations in the Mediterranean region experienced lower cardiovascular disease (CVD) mortality probably as a result of different dietary patterns. Later observational studies have confirmed the benefits of adherence to a Mediterranean dietary pattern on CVD risk factors. Clinical trial evidence is limited, and is mostly in secondary prevention. OBJECTIVES: To determine the effectiveness of a Mediterranean dietary pattern for the primary prevention of CVD. SEARCH METHODS: We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 9 of 12, September 2012); MEDLINE (Ovid, 1946 to October week 1 2012); EMBASE (Ovid, 1980 to 2012 week 41); ISI Web of Science (1970 to 16 October 2012); Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database and Health Economics Evaluations Database (Issue 3 of 12, September 2012). We searched trial registers and reference lists of reviews and applied no language restrictions. SELECTION CRITERIA: We selected randomised controlled trials in healthy adults and adults at high risk of CVD. A Mediterranean dietary pattern was defined as comprising at least two of the following components: (1) high monounsaturated/saturated fat ratio, (2) low to moderate red wine consumption, (3) high consumption of legumes, (4) high consumption of grains and cereals, (5) high consumption of fruits and vegetables, (6) low consumption of meat and meat products and increased consumption of fish, and (7) moderate consumption of milk and dairy products. The comparison group received either no intervention or minimal intervention. Outcomes included clinical events and CVD risk factors. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and contacted chief investigators to request additional relevant information. MAIN RESULTS: We included 11 trials (15 papers) (52,044 participants randomised). Trials were heterogeneous in the participants recruited, in the number of dietary components and follow-up periods. Seven trials described the intervention as a Mediterranean diet. Clinical events were reported in only one trial (Women's Health Initiative 48,835 postmenopausal women, intervention not described as a Mediterranean diet but increased fruit and vegetable and cereal intake) where no statistically significant effects of the intervention were seen on fatal and non-fatal endpoints at eight years. Small reductions in total cholesterol (-0.16 mmol/L, 95% confidence interval (CI) -0.26 to -0.06; random-effects model) and low-density lipoprotein (LDL) cholesterol ( 0.07 mmol/L, 95% CI -0.13 to -0.01) were seen with the intervention. Subgroup analyses revealed statistically significant greater reductions in total cholesterol in those trials describing the intervention as a Mediterranean diet ( 0.23 mmol/L, 95% CI -0.27 to -0.2) compared with control (-0.06 mmol/L, 95% CI 0.13 to 0.01). Heterogeneity precluded meta-analyses for other outcomes. Reductions in blood pressure were seen in three of five trials reporting this outcome. None of the trials reported adverse events. AUTHORS' CONCLUSIONS: The limited evidence to date suggests some favourable effects on cardiovascular risk factors. More comprehensive interventions describing themselves as the Mediterranean diet may produce more beneficial effects on lipid levels than those interventions with fewer dietary components. More trials are needed to examine the impact of heterogeneity of both participants and the intervention on outcomes. PMID- 23939687 TI - Connexin 35b expression in the spinal cord of Danio rerio embryos and larvae. AB - Electrical synapses are expressed prominently in the developing and mature nervous systems. Unlike chemical synapses, little is known about the developmental role of electrical synapses, reflecting the limitations imposed by the lack of selective pharmacological blockers. At a molecular level, the building blocks of electrical synapses are connexin proteins. In this study, we report the expression pattern for neuronally expressed connexin 35b (cx35b), the zebrafish orthologue of mammalian connexin (Cx) 36. We find that cx35b is expressed at the time of neural induction, indicating a possible early role in neural progenitor cells. Additionally, cx35b localizes to the ventral spinal cord during embryonic and early larval stages. We detect cx35b mRNA in secondary motor neurons (SMNs) and interneurons. We identified the premotor circumferential descending (CiD) interneuron as one interneuron subtype expressing cx35b. In addition, cx35b is present in other ventral interneurons of unknown subtype(s). This early expression of cx35b in SMNs and CiDs suggests a possible role in motor network function during embryonic and larval stages. PMID- 23939689 TI - Sodium ions template the formation of rotaxanes from BPX26C6 and nonconjugated amide and urea functionalities. PMID- 23939690 TI - Physicians need more education about natural family planning. PMID- 23939688 TI - From microRNA functions to microRNA therapeutics: novel targets and novel drugs in breast cancer research and treatment (Review). AB - MicroRNAs (miRNAs or miRs) are a family of small non-coding RNAs that regulate gene expression by the sequence-selective targeting of mRNAs, leading to translational repression or mRNA degradation, depending on the degree of complementarity with target mRNA sequences. miRNAs play a crucial role in cancer. In the case of breast tumors, several studies have demonstrated a correlation between: i) the expression profile of oncogenic miRNAs (oncomiRs) and tumor suppressor miRNAs; and ii) the tumorigenic potential of triple-negative [estrogen receptor (ER), progesterone receptor (PR) and Her2/neu] primary breast cancers. Among the miRNAs involved in breast cancer, miR-221 plays a crucial role for the following reasons: i) miR-221 is significantly overexpressed in triple-negative primary breast cancer; ii) the oncosuppressor p27Kip1, a validated miR-221 target is downregulated in aggressive cancer cell lines; and iii) the upregulation of a key transcription factor, Slug, appears to be crucial, since it binds to the miR 221/miR-222 promoter and is responsible for the high expression of the miR 221/miR-222 cluster in breast cancer cells. A Slug/miR-221 network has been suggested, linking miR-221 activity with the downregulation of a Slug repressor, leading to Slug/miR-221 upregulation and p27Kip1 downregulation. Interference with this process can be achieved using antisense miRNA (antagomiR) molecules targeting miR-221, inducing the downregulation of Slug and the upregulation of p27Kip1. PMID- 23939693 TI - Choosing Wisely: more good clinical recommendations to improve health care quality and reduce harm. PMID- 23939694 TI - Back to baseline. PMID- 23939695 TI - Antiretroviral preexposure prophylaxis for preventing HIV infection in high-risk individuals. PMID- 23939696 TI - Diabetic foot infections. AB - Diabetic foot infection, defined as soft tissue or bone infection below the malleoli, is the most common complication of diabetes mellitus leading to hospitalization and the most frequent cause of nontraumatic lower extremity amputation. Diabetic foot infections are diagnosed clinically based on the presence of at least two classic findings of inflammation or purulence. Infections are classified as mild, moderate, or severe. Most diabetic foot infections are polymicrobial. The most common pathogens are aerobic gram-positive cocci, mainly Staphylococcus species. Osteomyelitis is a serious complication of diabetic foot infection that increases the likelihood of surgical intervention. Treatment is based on the extent and severity of the infection and comorbid conditions. Mild infections are treated with oral antibiotics, wound care, and pressure off-loading in the outpatient setting. Selected patients with moderate infections and all patients with severe infections should be hospitalized, given intravenous antibiotics, and evaluated for possible surgical intervention. Peripheral arterial disease is present in up to 40% of patients with diabetic foot infections, making evaluation of the vascular supply critical. All patients with diabetes should undergo a systematic foot examination at least once a year, and more frequently if risk factors for diabetic foot ulcers exist. Preventive measures include patient education on proper foot care, glycemic and blood pressure control, smoking cessation, use of prescription footwear, intensive care from a podiatrist, and evaluation for surgical interventions as indicated. PMID- 23939697 TI - Signs and symptoms of childhood cancer: a guide for early recognition. AB - Although cancer in children is rare, it is the second most common cause of childhood mortality in developed countries. It often presents with nonspecific symptoms similar to those of benign conditions, leading to delays in the diagnosis and initiation of appropriate treatment. Primary care physicians should have a raised index of suspicion and explore the possibility of cancer in children who have worrisome or persisting signs and symptoms. Red flag signs for leukemia or lymphoma include unexplained and protracted pallor, malaise, fever, anorexia, weight loss, lymphadenopathy, hemorrhagic diathesis, and hepatosplenomegaly. New onset or persistent morning headaches associated with vomiting, neurologic symptoms, or back pain should raise concern for tumors of the central nervous system. Palpable masses in the abdomen or soft tissues, and persistent bone pain that awakens the child are red flags for abdominal, soft tissue, and bone tumors. Leukokoria is a red flag for retinoblastoma. Endocrine symptoms such as growth arrest, diabetes insipidus, and precocious or delayed puberty may be signs of endocranial or germ cell tumors. Paraneoplastic manifestations such as opsoclonus-myoclonus syndrome, rheumatic symptoms, or hypertension are rare and may be related to neuroblastoma, leukemia, or Wilms tumor, respectively. Increased suspicion is also warranted for conditions associated with a higher risk of childhood cancer, including immunodeficiency syndromes and previous malignancies, as well as with certain genetic conditions and familial cancer syndromes such as Down syndrome, Li-Fraumeni syndrome, hemihypertrophy, neurofibromatosis, and retinoblastoma. PMID- 23939698 TI - Thyroid nodules. AB - Thyroid nodules are a common finding in the general population. They may present with symptoms of pressure in the neck or may be discovered during physical examination. Although the risk of cancer is small, it is the main reason for workup of these lesions. Measurement of thyroid-stimulating hormone can identify conditions that may cause hyperfunctioning of the thyroid. For all other conditions, ultrasonography and fine-needle aspiration are central to the diagnosis. Lesions larger than 1 cm should be biopsied. Lesions with features suggestive of malignancy and those in patients with risk factors for thyroid cancer should be biopsied, regardless of size. Smaller lesions and those with benign histology can be followed and reevaluated if they grow. The evaluation of thyroid nodules in euthyroid and hypothyroid pregnant women is the same as in other adults. Thyroid nodules are uncommon in children, but the malignancy rate is much higher than in adults. Fine-needle aspiration is less accurate in children, so more aggressive surgical excision may be preferable. PMID- 23939702 TI - Preventing diabetic foot infections. PMID- 23939699 TI - Dyspnea in an older patient. PMID- 23939703 TI - Thyroid nodules. PMID- 23939704 TI - Hydrothermal synthesis of a crystalline rutile TiO2 nanorod based network for efficient dye-sensitized solar cells. AB - One-dimensional (1D) TiO2 nanostructures are desirable as photoanodes in dye sensitized solar cells (DSSCs) due to their superior electron-transport capability. However, making use of the DSSC performance of 1D rutile TiO2 photoanodes remains challenging, mainly due to the small surface area and consequently low dye loading. Herein, a new type of photoanode with a three dimensional (3D) rutile-nanorod-based network structure directly grown on fluorine-doped tin oxide (FTO) substrates was developed by using a facile two step hydrothermal process. The resultant photoanode possesses oriented rutile nanorod arrays for fast electron transport as the bottom layer and radially packed rutile head-caps with an improved large surface area for efficient dye adsorption. The diffuse reflectance spectra showed that with the radially packed top layer, the light-harvesting efficiency was increased due to an enhanced light scattering effect. A combination of electrochemical impedance spectroscopy (EIS), dark current, and open-circuit voltage decay (OCVD) analyses confirmed that the electron-recombiantion rate was reduced on formation of the nanorod-based 3D network for fast electron transport. As a resut, a light-to-electricity conversion efficiency of 6.31% was achieved with this photoanode in DSSCs, which is comparable to the best DSSC efficiencies that have been reported to date for 1D rutile TiO2 . PMID- 23939705 TI - Hypoxia preconditioning of mesenchymal stromal cells enhances PC3 cell lymphatic metastasis accompanied by VEGFR-3/CCR7 activation. AB - Mesenchymal stromal cells (MSCs) in bone marrow may enhance tumor metastases through the secretion of chemokines. MSCs have been reported to home toward the hypoxic tumor microenvironment in vivo. In this study, we investigated prostate cancer PC3 cell behavior under the influence of hypoxia preconditioned MSCs and explored the related mechanism of prostate cancer lymphatic metastases in mice. Transwell assays revealed that VEGF-C receptor, VEGFR-3, as well as chemokine CCL21 receptor, CC chemokine receptor 7 (CCR7), were responsible for the migration of PC3 cells toward hypoxia preconditioned MSCs. Knock-in Ccr7 in PC3 cells also improved cell migration in vitro. Furthermore, when PC3 cells were labeled using the hrGfp-lentiviral vector, and were combined with hypoxia preconditioned MSCs for xenografting, it resulted in an enhancement of lymph node metastases accompanied by up-regulation of VEGFR-3 and CCR7 in primary tumors. Both PI3K/Akt/IkappaBalpha and JAK2/STAT3 signaling pathways were activated in xenografts in the presence of hypoxia-preconditioned MSCs. Unexpectedly, the p VEGFR-2/VEGFR-2 ratio was attenuated accompanied by decreased JAK1 expression, indicating a switching-off of potential vascular signal within xenografts in the presence of hypoxia-preconditioned MSCs. Unlike results from other studies, VEGF C maintained a stable expression in both conditions, which indicated that hypoxia preconditioning of MSCs did not influence VEGF-C secretion. Our results provide the new insights into the functional molecular events and signalings influencing prostate tumor metastases, suggesting a hopeful diagnosis and treatment in new approaches. PMID- 23939706 TI - Climate and leishmaniasis in French Guiana. AB - To study the link between climatic variables and the incidence of leishmaniasis a study was conducted in Cayenne, French Guiana. Patients infected between January 1994 and December 2010. Meteorological data were studied in relation to the incidence of leishmaniasis using an ARIMA model. In the final model, the infections were negatively correlated with rainfall (with a 2-month lag) and with the number of days with rainfall > 50 mm (lags of 4 and 7 months). The variables that were positively correlated were temperature and the Multivariate El Nino Southern Oscillation Index with lags of 8 and 4 months, respectively. Significantly greater correlations were observed in March for rainfall and in November for the Multivariate El Nino/Southern Oscillation Index. Climate thus seems to be a non-negligible explanatory variable for the fluctuations of leishmaniasis. A decrease in rainfall is linked to increased cases 2 months later. This easily perceptible point could lead to an interesting prevention message. PMID- 23939707 TI - Impact of regular soap provision to primary schools on hand washing and E. coli hand contamination among pupils in Nyanza Province, Kenya: a cluster-randomized trial. AB - We assessed whether supplying soap to primary schools on a regular basis increased pupil hand washing and decreased Escherichia coli hand contamination. Multiple rounds of structured observations of hand washing events after latrine use were conducted in 60 Kenyan schools, and hand rinse samples were collected one time in a subset of schools. The proportion of pupils observed practicing hand washing with soap (HWWS) events was significantly higher in schools that received a soap provision intervention (32%) and schools that received soap and latrine cleaning materials (38%) compared with controls (3%). Girls and boys had similar hand washing rates. There were non-significant reductions in E. coli contamination among intervention school pupils compared with controls. Removing the barrier of soap procurement can significantly increase availability of soap and hand washing among pupils; however, we discuss limitations in the enabling policy and institutional environment that may have prevented reaching desired levels of HWWS. PMID- 23939708 TI - Community-wide distribution of long-lasting insecticidal nets can halt transmission of lymphatic filariasis in southeastern Nigeria. AB - Lymphatic filariasis (LF) in rural southeastern Nigeria is transmitted mainly by Anopheles spp. mosquitoes. Potential coinfection with Loa loa in this area has prevented use of ivermectin in the mass drug administration (MDA) strategy for LF elimination because of potential severe adverse L. loa-related reactions. This study determined if long-lasting insecticidal net (LLIN) distribution programs for malaria would interrupt LF transmission in such areas, without need for MDA. Monthly entomologic monitoring was conducted in sentinel villages before and after LLIN distribution to all households and all age groups (full coverage) in two districts, and to pregnant women and children less than five years of age in the other two districts. No change in human LF microfilaremia prevalence was observed, but mosquito studies showed a statistically significant decrease in LF infection and infectivity with full-coverage LLIN distribution. We conclude that LF transmission can be halted in southeastern Nigeria by full-coverage LLIN distribution, without MDA. PMID- 23939709 TI - Short report: Exposing laboratory-reared fleas to soil and wild flea feces increases transmission of Yersinia pestis. AB - Laboratory-reared Oropsylla montana were exposed to soil and wild-caught Oropsylla montana feces for 1 week. Fleas from these two treatments and a control group of laboratory-reared fleas were infected with Yersinia pestis, the etiological agent of plague. Fleas exposed to soil transmitted Y. pestis to mice at a significantly greater rate (50.0% of mice were infected) than control fleas (23.3% of mice were infected). Although the concentration of Y. pestis in fleas did not differ among treatments, the minimum transmission efficiency of fleas from the soil and wild flea feces treatments (6.9% and 7.6%, respectively) were more than three times higher than in control fleas (2.2%). Our results suggest that exposing laboratory-reared fleas to diverse microbes alters transmission of Y. pestis. PMID- 23939710 TI - Predictive factors of HTLV1-HIV coinfections in French Guiana. AB - French Guiana, the French territory most affected by human immunodeficiency virus (HIV) (1.3% of pregnant women), is also endemic for human T lymphotropic virus 1 (HTLV1). The objective of this study was to determine if the HTLV1/HIV coinfected patients had particular characteristics. All HIV-infected patients having a computerized medical file containing an HTLV1 serology were included: there were 1,333 HIV monoinfections and 76 HTLV1/VIH coinfections. The prevalence of HTLV1/HIV coinfections was 5.39%. Women (odds ratio [OR] = 1.91[1.13-3.24]), subjects > 40 years of age, and patients of Surinamese origin (OR = 2.65 [1.25 5.61]) were overrepresented among the coinfected. CD4 count at the time of diagnosis and viral loads were higher among coinfected patients. The clinical stage was not significantly different between the two groups. The number of CD4 cells was not higher among the coinfected, unlike most reports from the literature. Prevalence of HTLV1 among HIV-infected patients is high in French Guiana, and physicians seem to omit the prescription of serology for this potentially serious coinfection. PMID- 23939711 TI - Nonaqueous lithium-ion capacitors with high energy densities using trigol-reduced graphene oxide nanosheets as cathode-active material. AB - One HEC of a material: The use of trigol-reduced graphene oxide nanosheets as cathode material in hybrid lithium-ion electrochemical capacitors (Li-HECs) results in an energy density of 45 Wh kg(-1) ; much enhanced when compared to similar devices. The mass loading of the active materials is optimized, and the devices show good cycling performance. Li-HECs employing these materials outperform other supercapacitors, making them attractive for use in power sources. PMID- 23939712 TI - Testing the hypothesis of morphological integration on a skull of a vertebrate with a biphasic life cycle: a case study of the alpine newt. AB - In this article, we explore the possible influences of the developmental and functional relationships between skeletal elements on the pattern of morphological integration in the adult skull of the alpine newt. Like many tailed amphibians, the alpine newt has a biphasic life cycle, which implies the possibility that two distinct sets of constraints on development and function of the cranial skeleton may act at different times. We study how trait covariation, resulting from processes early in development, affects patterns of covariation at the adult stage. We test whether the observed patterns of integration are consistent with those predicted from three a priori hypothesized sources of integration: developmental timing, hormonally mediated growth/remodeling during metamorphosis, and developmental and functional relationships. The analyses of the covariation among the landmarks in the dorsal and ventral alpine newt craniums yield somewhat contrasting results. Our results do not indicate a clear correspondence between the observed variations in the skull shape and any of the three proposed hypotheses. No traceable reflection of hypothesized developmental relationships in the pattern of morphological integration/modularity in the adult skull indicate that covariation structure is continually restructured by overlaying variation introduced through developmental and environmental factors at different stages of development. This finding supports the recently elaborated palimpsest view of morphological integration. Also, our results indicate that the allometry-free shape data have an even higher level of morphological integration than the data that contain the allometric component of the shape variation. PMID- 23939714 TI - Dynamics and partitioning of the ionome in seeds and germinating seedlings of winter oilseed rape. AB - Germination and seedling establishment are among the most critical phases in the development of plants, and seed vigour has become an important trait for the selection of robust crop cultivars. Little is known about the potentially limiting role of mineral nutrients in early metabolic and developmental processes during germination. Therefore, we assessed the ionome and relative distribution of mineral elements in different seed and seedling tissues of oilseed rape (Brassica napus L.) and monitored the internal allocation of nutrients during germination. In seeds, cotyledons harboured the main pool of K, P, S, Mg, Fe, Mn and Zn, whereas the seed coat contained most of the Ca, Na, B, Cu and Mo. Although the early root and hypocotyl tissue expanded first, concentrations of most elements were initially low. Re-allocation of elements to the root/hypocotyl tissue from other pools set in two days after seed imbibition and was most rapid for K. Relative to the critical deficiency levels of vegetative tissues, seed tissues were particularly low in B, K and Fe. Further analyses of the ionome of seeds and seedlings, grouped according to their germination efficiency, indicated that in particular low S, Mg and Ca coincided with germination failure. This study documents highly dynamic changes in the ionome of seed and seedling tissues and provides evidence for potentially limiting elements during early germination and seedling establishment in rapeseed. PMID- 23939715 TI - The validity of the instrument to evaluate social network in the ageing population: the Collaborative Research on Ageing in Europe Social Network Index. AB - The aim of the study was to create a simplified, easy implementable multidimensional instrument to assess all relevant elements of the structure and function of social network within individuals across different European countries and to provide the tool for health professionals and policy makers. The analysis was based on the sample of 10 446 non-institutionalized adult population from Finland, Poland and Spain. The Social Network Questionnaire Collaborative Research on Ageing in Europe Social Network Index (COURAGE-SNI) was part of the COURAGE questionnaire. The indicators of the functioning of social network ties (close relations), frequency of direct contact and general support were evaluated. Functions were assess within the main structural components as spouse, parents, children, grandchildren, other relatives, friends, coworkers and neighbours. The exploratory factor analysis revealed five main latent components of social network with one component composed of hierarchical part. The confirmatory factor analysis provided an acceptable fit for the model. The generalize partial credit model was used to calculate factor scores for five components of the COURAGE-SNI considering the social networks of 'spouse/partner', 'parents', 'other family members', 'neighbours' and 'friends and co-workers'. The scores for every component were recalculated so as to provide the social network saturation ranged from 0 (the lowest) to 100% (the highest possible). Finally, the COURAGE-SNI score was obtained as the sum of weighted information calculated by the item response theory procedure for every aforementioned component. In summary, the COURAGE-SNI showed good reliability and content validity and seems to be a promising tool for the assessment of the social network phenomenon across European countries. KEY PRACTITIONER MESSAGE: The Courage-SNI is a new tool to assess the construct of social network in population studies. The Courage-SNI is an instrument useful to identify high risk groups or populations whose social network is poorer. PMID- 23939716 TI - Breastfeeding and childhood obesity: where do we go from here? PMID- 23939717 TI - Fetal laryngoscopy to evaluate vocal folds in a fetus with congenital high airway obstruction syndrome (CHAOS). PMID- 23939718 TI - Parkinson's disease: "Braak" to the future. PMID- 23939719 TI - Nursing interventions for smoking cessation. AB - BACKGROUND: Healthcare professionals, including nurses, frequently advise people to improve their health by stopping smoking. Such advice may be brief, or part of more intensive interventions. OBJECTIVES: To determine the effectiveness of nursing-delivered smoking cessation interventions. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group specialized Register and CINAHL in June 2013. SELECTION CRITERIA: Randomized trials of smoking cessation interventions delivered by nurses or health visitors with follow-up of at least six months. DATA COLLECTION AND ANALYSIS: Two authors extracted data independently. The main outcome measure was abstinence from smoking after at least six months of follow up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Where statistically and clinically appropriate, we pooled studies using a Mantel-Haenszel fixed-effect model and reported the outcome as a risk ratio (RR) with a 95% confidence interval (CI). MAIN RESULTS: Forty-nine studies met the inclusion criteria. Pooling 35 studies (over 17,000 participants) comparing a nursing intervention to a control or to usual care, we found the intervention to increase the likelihood of quitting (RR 1.29; 95% CI 1.20 to 1.39). In a subgroup analysis the estimated effect size was similar for the group of seven studies using a particularly low intensity intervention but the confidence interval was wider. There was limited indirect evidence that interventions were more effective for hospital inpatients with cardiovascular disease than for inpatients with other conditions. Interventions in non-hospitalized adults also showed evidence of benefit. Eleven studies comparing different nurse-delivered interventions failed to detect significant benefit from using additional components. Six studies of nurse counselling on smoking cessation during a screening health check or as part of multifactorial secondary prevention in general practice (not included in the main meta-analysis) found nursing intervention to have less effect under these conditions. AUTHORS' CONCLUSIONS: The results indicate the potential benefits of smoking cessation advice and/or counselling given by nurses, with reasonable evidence that intervention is effective. The evidence for an effect is weaker when interventions are brief and are provided by nurses whose main role is not health promotion or smoking cessation. The challenge will be to incorporate smoking behaviour monitoring and smoking cessation interventions as part of standard practice so that all patients are given an opportunity to be asked about their tobacco use and to be given advice and/or counselling to quit along with reinforcement and follow-up. PMID- 23939720 TI - Assessing pediatric patient's risk of distress during health-care encounters: The psychometric properties of the Psychosocial Risk Assessment in Pediatrics. AB - The aim of this study was to examine the psychometric properties of the Psychosocial Risk Assessment in Pediatrics (PRAP). PRAP is a screening tool designed to assess pediatric patients who are at risk of experiencing elevated distress during health-care encounters. A cross-sectional observational study was conducted with 200 pediatric patients. Patient's distress levels were observed during their health-care encounter using the Children's Emotional Manifestation Scale (CEMS). Health-care staff and parents were asked to rate the patient's level of cooperation and stress. Exploratory factor analysis supported a single latent factor structure of the PRAP tool. Cronbach's alpha for internal reliability was .83. PRAP score was strongly correlated with CEMS score with r = .82 (p < .0001). The PRAP is a standardized, reliable, and valid method for health-care providers to assess a patient's risk of experiencing significant distress during treatment or testing. PMID- 23939721 TI - Meaning of caring in pediatric intensive care unit from the perspective of parents: A qualitative study. AB - When children are critically ill, parents still strive to be present and participate in the care of their child. Pediatric intensive care differs from other realms of pediatric care as the nature of care is technically advanced and rather obstructing than encouraging parental involvement or closeness, either physically or emotionally, with the critically ill child. The aim of this study was to elucidate the meaning of caring in the pediatric intensive care unit from the perspective of parents. The design of this study followed Benner's interpretive phenomenological method. Eleven parents of seven children participated in observations and interviews. The following aspects of caring were illustrated in the themes arising from the findings: being a bridge to the child on the edge, building a sheltered atmosphere, meeting the child's needs, and adapting the environment for family life. The overall impression is that the phenomenon of caring is experienced exclusively when it is directed toward the exposed child. The conclusion drawn is that caring is present when providing expert physical care combined with fulfilling emotional needs and supporting continuing daily parental care for the child in an inviting environment. PMID- 23939722 TI - Development of personal identity among refugee adolescents: Facilitating elements and obstacles. AB - This qualitative study examines what contributes to the development of personal identity among refugee adolescents of African origin who have immigrated to Quebec. For this purpose, 12 adolescents participated in individual interviews and in self-recorded interviews. The research findings show that the development of young people's personal identity is directly and indirectly influenced by personal characteristics, the environmental, and the interpersonal relationships. We identify both elements that facilitate the development of personal identity and obstacles to such development so as to provide better support for health education among refugee adolescents. PMID- 23939723 TI - Pain reports in children and adolescents with type 1 diabetes mellitus. AB - The purpose of this study is to examine prevalence rates of pain reports in youth with type 1 diabetes mellitus (T1DM) and potential predictors of pain. Pain is a common and debilitating symptom of diabetic polyneuropathies. There is currently little research regarding pain in youth with T1DM. It was predicted that self care and general health factors would predict pain as suggested by the general pain literature. Participants (N = 269) ranged in age from 13 to 17 years; youth had a mean time since diagnosis of 5.8 years. Data collected included diabetes self-management variables, ratings of the patient's current functioning and pain intensity ('current'), and information collected about experiences that occurred in the time preceding each appointment ('interim'). About half of the youth (n = 121, 49.0%) reported any interim pain across both appointments. Female adolescents and those individuals who were physically active and/or utilized health-care system more acutely were more likely to report interim central nervous system pain. Improved diabetes self-management and increased level of physical activity may reduce experiences of pain and increase the quality of life of youth with T1DM. Regular monitoring of both current and interim pain experiences of youth with T1DM is recommended. PMID- 23939724 TI - Comparison of utility scores from the Visual Analog Scale and Health Utilities Index 3 in children following pediatric intensive care unit admission. AB - Indirect and direct health-related quality of life (HRQoL) measures are intended to assess the same underlying constructs. There is evidence that the two types of assessments can show important differences. We assessed the agreement between the utilities of direct and indirect HRQoL measurements in children following pediatric intensive care unit (PICU) admission. We collected Health Utilities Index 3 (HUI-3) and Visual Analog Scale (VAS) ratings of children who were urgently admitted to the PICU of a university-affiliated pediatric hospital at ICU admission (baseline) and one month post-ICU admission. The mean (SD) VAS converted standard gamble and HUI-3 utilities were 0.82 (+/-0.19) and 0.70 (+/ 0.39), respectively, at baseline (n = 51), and 0.81 (+/-0.15) and 0.58 (+/-0.39) at one month (n = 36). The VAS utilities were significantly greater than the HUI 3 utilities (p = 0.009). At baseline, the intraclass coefficient (95% confidence interval) was 0.49 (0.25-0.68), representing moderate agreement, and at one month, was 0.18 (-0.87 to 0.45), representing negligible agreement. There were significant differences between indirect and direct measures, and inconsistent agreement between utilities derived from the two measures. These data illustrate the potential impact of HRQoL assessment techniques on economic analyses used to inform health policy decision-making for pediatric critical care. PMID- 23939725 TI - Developing indicators of service integration for child health: perceptions of service providers and families of young children in a region of high need in New Zealand. AB - Children in many areas of New Zealand have poor health indices; statistics indicate health inequalities. Existing international indicators of child health currently take little account of local context. There are few composite indicators of how child health services are integrated at a community level. This study aimed to explore what local people consider would be useful indicators of better child health. Data for this qualitative study were collected via 24 individual interviews and two focus groups in a rural area of New Zealand. A total of 13 in-depth interviews were conducted with parents/families of small children. Participants were asked about wide-ranging aspects of child health. Also, 11 interviews and two focus groups were conducted with front line health professionals/stakeholders. Key themes from the content thematic analysis: include child health should be measured in multidimensional ways; essential interdependence of family-child health; universal access to culturally appropriate care, free primary care services and parenting education and support is needed; and there is a lack of integration and communication between health, education and social services. There is an important need to measure and monitor communication/integration across existing health, education and social services, provide better parenting support and health education and improve access to culturally appropriate primary care. PMID- 23939726 TI - Examination of parent-child adjustment in juvenile rheumatic diseases using depression-specific indices of parent and youth functioning. AB - Studies demonstrate a link between parental distress, youth illness appraisals, and depression symptoms in youth with juvenile rheumatic diseases. However, the exclusive use of broadband (i.e. general) measures of parental distress in these studies has resulted in conceptual and clinical imprecision regarding the parent child adjustment process. Our aim was to reanalyze previously published data (i.e. Wagner et al., 2003) using a depression-specific scale derived from the general adult distress measure in the original study. Parents completed the Brief Symptom Inventory (BSI), youth completed the Child Depression Inventory (CDI), and the Illness Intrusiveness Scale (IIS-C). Thirteen Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) depression-specific items from the BSI comprised the parent measure of Depressive Symptoms Scale (DS). Consistent with Wagner et al. (2003), adult DS scores were associated with youth CDI scores. However, youth illness appraisals had unique effects on the parent-child depression relation. Elevated youth perceptions of illness intrusiveness amplified the negative effect of parent depressive symptoms on youth depressive symptoms; decreased illness intrusiveness buffered the negative effect of parent depression. The empirical and clinical implications of assessing parent and youth adjustment in a domain-specific manner are discussed. PMID- 23939727 TI - Comparative metabolomic analysis of an alternative biosynthetic pathway to pseudosugars in Actinosynnema mirum DSM 43827. PMID- 23939728 TI - Transitional care management: why bother? PMID- 23939729 TI - Making EHR notes more readable. PMID- 23939730 TI - Medication adherence. PMID- 23939731 TI - Use templates for procedures. PMID- 23939732 TI - Embrace change. PMID- 23939733 TI - Long-term relationships. PMID- 23939734 TI - Transitional care management services: new codes, new requirements. PMID- 23939735 TI - HIPAA again: confronting the updated privacy and security rules. PMID- 23939736 TI - The use of symptom diaries in outpatient care. PMID- 23939737 TI - Generation gap: effectively leading physicians of all ages. PMID- 23939738 TI - Engaging patients in collaborative care plans. PMID- 23939739 TI - Health coaching: teaching patients how to fish. PMID- 23939748 TI - "All I wanted was something for the cough". PMID- 23939749 TI - Genetic analysis of a 12-year-old boy with X-linked ichthyosis in association with sclerosing glomerulonephritis. AB - In this study, we report the case of a 12-year-old male with X-linked ichthyosis (XLI) in association with glomerular sclerosis, and our investigation into the deletion pattern of the STS gene and the flanking regions in DNA samples of family members. We observed no features typical of renal osteodystrophy or rickets, with the exception of short stature, in the three afffected male family members. Audiometry, visual acuity and olfactory sensation were normal. By performing PCR analysis of the steroid sulfatase (STS) gene and flanking regions on our patients, we discovered a complete deletion that involved the entire region from DXS1139 to DXF22S1. Further studies are required to determine whether the STS gene or the co-deleted flanking sequences are the cause of renal disease associated with XLI. PMID- 23939750 TI - Laminar and subcellular heterogeneity of GLAST and GLT-1 immunoreactivity in the developing postnatal mouse hippocampus. AB - Astrocytes express two sodium-coupled transporters, glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), which are essential for the maintenance of low extracellular glutamate levels. We performed a comparative analysis of the laminar and subcellular expression profile of GLAST and GLT-1 in the developing postnatal mouse hippocampus by using immunohistochemistry and western blotting and employing high-resolution fluorescence microscopy. Astrocytes were identified by costaining with glial fibrillary acidic protein (GFAP) or S100beta. In CA1, the density of GFAP-positive cells and GFAP expression rose during the first 2 weeks after birth, paralleled by a steady increase in GLAST immunoreactivity and protein content. Upregulation of GLT-1 was completed only at postnatal days (P) P20-25 and was thus delayed by about 10 days. GLAST staining was highest along the stratum pyramidale and was especially prominent in astrocytes at P3-5. GLAST immunoreactivity indicated no preferential localization to a specific cellular compartment. GLT-1 exhibited a laminar expression pattern from P10-15 on, with the highest immunoreactivity in the stratum lacunosum-moleculare. At the cellular level, GLT-1 immunoreactivity did not entirely cover astrocyte somata and exhibited clusters at processes. In neonatal and juvenile animals, discrete clusters of GLT-1 were also detected at perivascular endfeet. From these results, we conclude there is a remarkable subcellular heterogeneity of GLAST and GLT-1 expression in the developing hippocampus. The clustering of GLT-1 at astrocyte endfeet indicates that it might serve a specialized functional role at the blood-brain barrier during formation of the hippocampal network. PMID- 23939751 TI - Diesel and alkane fuels from biomass by organocatalysis and metal-acid tandem catalysis. AB - Combo deal: Biomass furaldehydes are upgraded into oxygenated diesel and high quality C10-12 linear alkane fuels. The first of two steps involves solvent-free self-condensation (Umpolung) through organocatalysis using an N-heterocyclic carbene (NHC), yielding C10 -C12 furoin intermediates. In the metal-acid tandem catalysis step, in water, the furoin intermediates are converted into oxygenated biodiesel by hydrogenation, etherification or esterification; or into premium alkane jet fuels by hydrodeoxygenation. PMID- 23939752 TI - Preparation and functions of hybrid membranes with rings of Ag NPs anchored at the edges of highly ordered honeycomb-patterned pores. AB - We report a new, simple strategy to apply honeycomb films for the patterning of colloidal particles. By combination of a "bottom-up" breath figure method and the electrochemical properties of the honeycomb films of ferrocenyl-based oligomers, highly ordered hybrid membranes coated with ring-like patterning of 0D- and 1D-Ag nanoparticles (NPs) have been fabricated. One interesting phenomenon is that the nucleation and adsorption of Ag dots occurred preferentially at the edges of the micropores. The hybrid membranes exhibited richly electrochemical activities towards reduction of iodate and enhanced effectively catalytic reduction of organic dyes. We believe that this method can be used to decorate and/or assemble functional metal NPs such as Au, Pd, and Cu on honeycomb-patterned materials for the further applications of photonics, sensors, and catalysis. PMID- 23939753 TI - Sensitivity and specificity of blood leukocyte counts as an indicator of mortality in horses after colic surgery. AB - The objectives of this study were to describe and relate perioperative changes in blood leukocyte counts to the outcome of surgical colic horses, determine a cut off value in the early postoperative period to obtain an indicator of the outcome, and compare the obtained value to a validation population of horses. Fifty-three horses undergoing colic surgery were included in the descriptive part of the study. Total leukocyte counts were performed before, during and serially after surgery. A receiver operating characteristic analysis was performed on the leukocyte counts of 45 of these horses to determine a cut-off value for the outcome. The results obtained were validated on a second set of 50 horses that underwent colic surgery in similar conditions. The kinetics of blood leukocytes in survivors was higher than in non-survivors during the first days. Non-survivor horses were more likely to have at least one blood leukocyte count <= 3.9 * 10(3)/mm(3) between 28 and 60 hours after surgery than survivor horses. This cut off value was confirmed in the validation population. These results suggest that routine values of blood leukocyte counts can be used as an additional prognostic indicator after colic surgery alongside other predictors previously associated with the outcome. PMID- 23939754 TI - Fetal right ventricular contraction and relaxation times at 11-13 weeks' gestation on speckle tracking imaging. AB - OBJECTIVE: To examine the contraction time and relaxation time of the right ventricle at 11-13 weeks' gestation in trisomy 21 and euploid fetuses by speckle tracking ultrasound imaging. METHODS: Measurement of fetal nuchal translucency (NT) thickness, Doppler assessment for tricuspid regurgitation and reversed A wave in the ductus venosus (DV) and fetal echocardiography were performed immediately before chorionic villus sampling for fetal karyotyping at 11-13 weeks' gestation. Digital videoclips of the four-chamber view of the fetal heart were recorded and analyzed offline using speckle tracking imaging software. The contraction time, which is the time between the highest and lowest peaks in the right ventricular area, and relaxation time, which is the time between the lowest and the subsequent highest area peak, were measured and expressed as a percentage of the duration of the cardiac cycle. Values in trisomy 21 and euploid fetuses were compared. RESULTS: Mean contraction time and relaxation time in 119 euploid fetuses were 52.1% (95% CI, 51.6-52.8%) and 47.8% (95% CI, 47.2-48.4%), respectively. In 21 trisomy 21 fetuses, mean contraction time was significantly higher (57.0% (95% CI, 55.2-58.9%); P<0.01) and relaxation time lower (42.9% (95% CI, 41.1-44.8%); P<0.01) than in euploid fetuses. Multiple regression analysis showed that significant contributions to contraction time and relaxation time were provided by fetal karyotype, NT and tricuspid regurgitation, but not by reversed A-wave in the DV or the presence of a cardiac defect. CONCLUSION: In first-trimester fetuses with trisomy 21 and in euploid fetuses with increased NT and tricuspid regurgitation there is evidence of increased right ventricular contraction time and shortening of the relaxation time. PMID- 23939755 TI - Asymmetric hydrogenation of ketones with H2 and ruthenium catalysts containing chiral tetradentate S2N2 ligands. PMID- 23939756 TI - Placental lipoprotein lipase (LPL) gene expression in a placentotrophic lizard, Pseudemoia entrecasteauxii. AB - Viviparity (live birth) relies on a functional placenta, which is formed by cooperating maternal and embryonic tissues. In some viviparous lineages, mothers use this placenta to transport nutrients to feed developing embryos through pregnancy (placentotrophy). The Australian lizard, Pseudemoia entrecasteauxii, provides approximately 60% of the lipid for embryonic growth and metabolism to embryos across the placenta. Lipoprotein lipase (LPL) is an important enzyme in lipid transport in vertebrates. We examined patterns of LPL gene expression to identify its role in the uterus of pregnant P. entrecasteauxii. We used reverse transcription quantitative real time PCR to measure the expression of the LPL gene in the uterine tissue throughout reproduction and compared uterine LPL expression in chorioallantoic and yolk-sac placentae. Expression of the LPL gene is significantly higher in the uterus of late pregnant compared to non-pregnant and early pregnant P. entrecasteauxii, indicating a greater capacity for lipid transport towards the end of pregnancy. The period of high LPL gene expression correlates with the time that developing embryos are undergoing the greatest growth and have the highest metabolic rate. LPL gene expression is significantly higher in the uterine tissue of the yolk-sac placenta than the chorioallantoic placenta, providing the first molecular evidence that the yolk-sac placenta is the major site of lipid transport in pregnant P. entrecasteauxii. PMID- 23939757 TI - The balance mediated by miRNAs and the heme oxygenase 1 feedback loop contributes to biological effects. AB - Heme oxygenase-1 (HMOX1) is a ubiquitously expressed inducible enzyme that degrades heme to carbon monoxide, biliverdin, and free iron ions. Since 1950, many studies have revealed the role of HMOX1 in reducing the impact of oxidative stress in many types of diseases, such as Alzheimer's disease, heart disease, and the development of tumors. These effects arise as a result of the removal of heme, the biological activities of the products of HMOX1 and the activity of HMOX1 itself. However, HMOX1 has some contradictory effects. The discovery of microRNAs (miRNAs) and their relationship with HMOX1 has provided a new direction for research in this field. Here, we discuss the role of a potential regulatory feedback loop between HMOX1 and miRNAs in pathological processes based on recently published data. We hope to describe a new mechanism for HMOX1 function based on miRNAs to address the contradictory results reported in the literature. PMID- 23939758 TI - Impact of distraction on the driving performance of adolescents with and without attention-deficit/hyperactivity disorder. AB - IMPORTANCE: This study extends the literature regarding attention deficit/hyperactivity disorder (ADHD)-related driving impairments to a newly licensed, adolescent population. OBJECTIVE: To investigate the combined risks of adolescence, ADHD, and distracted driving (cell phone conversation and text messaging) on driving performance. DESIGN, SETTING, AND PARTICIPANTS: Adolescents aged 16 to 17 years with (n = 28) and without (n = 33) ADHD engaged in a simulated drive under 3 conditions (no distraction, cell phone conversation, and texting). During each condition, one unexpected event (eg, another car suddenly merging into driver's lane) was introduced. INTERVENTIONS: Cell phone conversation, texting, and no distraction while driving. MAIN OUTCOMES AND MEASURES: Self-report of driving history, average speed, standard deviation of speed, standard deviation of lateral position, and braking reaction time during driving simulation. RESULTS: Adolescents with ADHD reported fewer months of driving experience and a higher proportion of driving violations than control subjects. After controlling for months of driving history, adolescents with ADHD demonstrated more variability in speed and lane position than control subjects. There were no group differences for braking reaction time. Furthermore, texting negatively impacted the driving performance of all participants as evidenced by increased variability in speed and lane position. CONCLUSIONS: To our knowledge, this study is one of the first to investigate distracted driving in adolescents with ADHD and adds to a growing body of literature documenting that individuals with ADHD are at increased risk for negative driving outcomes. Furthermore, texting significantly impairs the driving performance of all adolescents and increases existing driving-related impairment in adolescents with ADHD, highlighting the need for education and enforcement of regulations against texting for this age group. PMID- 23939759 TI - Oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is defined as pneumonia developing in persons who have received mechanical ventilation for at least 48 hours. VAP is a potentially serious complication in these patients who are already critically ill. Oral hygiene care (OHC), using either a mouthrinse, gel, toothbrush, or combination, together with aspiration of secretions may reduce the risk of VAP in these patients. OBJECTIVES: To assess the effects of OHC on the incidence of VAP in critically ill patients receiving mechanical ventilation in intensive care units (ICUs) in hospitals. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register (to 14 January 2013), CENTRAL (The Cochrane Library 2012, Issue 12), MEDLINE (OVID) (1946 to 14 January 2013), EMBASE (OVID) (1980 to 14 January 2013), LILACS (BIREME) (1982 to 14 January 2013), CINAHL (EBSCO) (1980 to 14 January 2013), Chinese Biomedical Literature Database (1978 to 14 January 2013), China National Knowledge Infrastructure (1994 to 14 January 2013), Wan Fang Database (January 1984 to 14 January 2013), OpenGrey and ClinicalTrials.gov (to 14 January 2013). There were no restrictions regarding language or date of publication. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating the effects of OHC (mouthrinse, swab, toothbrush or combination) in critically ill patients receiving mechanical ventilation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all search results, extracted data and undertook risk of bias. We contacted study authors for additional information. Trials with similar interventions and outcomes were pooled reporting odds ratios (OR) for dichotomous outcomes and mean differences (MD) for continuous outcomes using random-effects models unless there were fewer than four studies. MAIN RESULTS: Thirty-five RCTs (5374 participants) were included. Five trials (14%) were assessed at low risk of bias, 17 studies (49%) were at high risk of bias, and 13 studies (37%) were assessed at unclear risk of bias in at least one domain. There were four main comparisons: chlorhexidine (CHX mouthrinse or gel) versus placebo/usual care, toothbrushing versus no toothbrushing, powered versus manual toothbrushing and comparisons of oral care solutions.There is moderate quality evidence from 17 RCTs (2402 participants, two at high, 11 at unclear and four at low risk of bias) that CHX mouthrinse or gel, as part of OHC, compared to placebo or usual care is associated with a reduction in VAP (OR 0.60, 95% confidence intervals (CI) 0.47 to 0.77, P < 0.001, I(2) = 21%). This is equivalent to a number needed to treat (NNT) of 15 (95% CI 10 to 34) indicating that for every 15 ventilated patients in intensive care receiving OHC including chlorhexidine, one outcome of VAP will be prevented. There is no evidence of a difference between CHX and placebo/usual care in the outcomes of mortality (OR 1.10, 95% CI 0.87 to 1.38, P = 0.44, I(2) = 2%, 15 RCTs, moderate quality evidence), duration of mechanical ventilation (MD 0.09, 95% CI -0.84 to 1.01 days, P = 0.85, I(2) = 24%, six RCTs, moderate quality evidence), or duration of ICU stay (MD -0.21, 95% CI -1.48 to 1.89 days, P = 0.81, I(2) = 9%, six RCTs, moderate quality evidence). There was insufficient evidence to determine whether there is a difference between CHX and placebo/usual care in the outcomes of duration of use of systemic antibiotics, oral health indices, microbiological cultures, caregivers preferences or cost. Only three studies reported any adverse effects, and these were mild with similar frequency in CHX and control groups.From three trials of children aged from 0 to 15 years (342 participants, moderate quality evidence) there is no evidence of a difference between OHC with CHX and placebo for the outcomes of VAP (OR 1.07, 95% CI 0.65 to 1.77, P = 0.79, I(2) = 0%), or mortality (OR 0.73, 95% CI 0.41 to 1.30, P = 0.28, I(2) = 0%), and insufficient evidence to determine the effect on the outcomes of duration of ventilation, duration of ICU stay, use of systemic antibiotics, plaque index, microbiological cultures or adverse effects, in children.Based on four RCTs (828 participants, low quality evidence) there is no evidence of a difference between OHC including toothbrushing (+/- CHX) compared to OHC without toothbrushing (+/- CHX) for the outcome of VAP (OR 0.69, 95% CI 0.36 to 1.29, P = 0.24 , I(2) = 64%) and no evidence of a difference for mortality (OR 0.85, 95% CI 0.62 to 1.16, P = 0.31, I(2) = 0%, four RCTs, moderate quality evidence). There is insufficient evidence to determine whether there is a difference due to toothbrushing for the outcomes of duration of mechanical ventilation, duration of ICU stay, use of systemic antibiotics, oral health indices, microbiological cultures, adverse effects, caregivers preferences or cost.Only one trial compared use of a powered toothbrush with a manual toothbrush providing insufficient evidence to determine the effect on any of the outcomes of this review.A range of other oral care solutions were compared. There is some weak evidence that povidone iodine mouthrinse is more effective than saline in reducing VAP (OR 0.35, 95% CI 0.19 to 0.65, P = 0.0009, I(2) = 53%) (two studies, 206 participants, high risk of bias). Due to the variation in comparisons and outcomes among the trials in this group there is insufficient evidence concerning the effects of other oral care solutions on the outcomes of this review. AUTHORS' CONCLUSIONS: Effective OHC is important for ventilated patients in intensive care. OHC that includes either chlorhexidine mouthwash or gel is associated with a 40% reduction in the odds of developing ventilator-associated pneumonia in critically ill adults. However, there is no evidence of a difference in the outcomes of mortality, duration of mechanical ventilation or duration of ICU stay. There is no evidence that OHC including both CHX and toothbrushing is different from OHC with CHX alone, and some weak evidence to suggest that povidone iodine mouthrinse is more effective than saline in reducing VAP. There is insufficient evidence to determine whether powered toothbrushing or other oral care solutions are effective in reducing VAP. PMID- 23939760 TI - Patient and public involvement in the implementation of evidence into practice. PMID- 23939761 TI - Five to seven years after breast cancer treatment, over a third of women (37%) report persistent pain. PMID- 23939762 TI - Use of multifaceted strategies and processes at multiple levels, and passionate frontline leaders are associated with uptake of best practice guidelines on breastfeeding. PMID- 23939763 TI - Multiple oxidative routes towards the maturation of nosiheptide. PMID- 23939764 TI - Making sense of the trend toward hospital employment. PMID- 23939765 TI - Quiet space is needed for thinking. PMID- 23939766 TI - Respect each other. PMID- 23939767 TI - Advancing multidisciplinary team care. PMID- 23939768 TI - Personal issues to consider before leaving independent practice. PMID- 23939769 TI - Easing into your new practice after residency: tips for success. PMID- 23939770 TI - Optimizing the role of nursing staff to enhance physician productivity: one physician's journey. PMID- 23939771 TI - Do you know what is (or isn't) in your documentation? PMID- 23939781 TI - HITIOS: why cynicism is helpful when working with health IT. PMID- 23939782 TI - Harnessing reversible oxidative addition: application of diiodinated aromatic compounds in the carboiodination process. AB - An I for an I: Conditions for the intramolecular carboiodination and the simultaneous convergent intramolecular carboiodination/intermolecular Heck reaction of various diiodoarenes were developed. The ability of the Pd(0)/QPhos catalyst/ligand combination to undergo reversible oxidative addition allows these reactions to proceed well, thus increasing both the appeal and utility of this class of substrates in site-selective cross-coupling reactions. PMID- 23939783 TI - Ethylenedithio-tetrathiafulvalene-helicenes: electroactive helical precursors with switchable chiroptical properties. AB - Electroactive fused ethylenedithio-tetrathiafulvalene-[4]helicene and [6]helicenes have been synthesized through a strategy that involved the preparation of 2,3-dibromo-helicene derivatives as intermediates. The dihedral angles between the terminal helicenes, as determined by single-crystal X-ray analysis, are 22.7 degrees and 50.7 degrees for the [4]helicene and [6]helicene, respectively. Their solid-state architectures show interplay between S???S and pi???pi intermolecular interactions. The chiroptical properties of the enantiopure EDT-TTF-[6]helicene derivatives have been investigated and supported by TDDFT calculations. Remarkable redox switching of the circular dichroism (CD) signal between the neutral and radical-cation species has been achieved. PMID- 23939784 TI - Relevance of class 1 integrons and extended-spectrum beta-lactamases in drug resistant Escherichia coli. AB - Escherichia coli is a common cause of community- and hospital-acquired urinary tract infections, and class 1 integrons are the prior elements of gene transference in the capture and distribution of gene cassettes among clinical gram-negative bacillus. In the present study, the resistance of Escherichia coli to antimicrobial agents was investigated. A total of 97 isolates were found to be susceptible to 16 antimicrobial agents and were detected in the production of extended beta-lactamases (ESBLs), distribution of CTX-M-type beta-lactamases, presence and characterization of class 1 integrons and a variable region of integron-positive isolates. Escherichia coli isolates possessing CTX-M (31; 32%) were detected in 19 isolates (61.5%). The presence of ESBLs was associated with resistance to penicillins, third-generation cephalosporins, ciprofloxacin, aminoglycosides and monocyclic beta-lactam antibiotics. Escherichia coli isolates (69; 71.1%) possessed class 1 integrons associated with resistance to ciprofloxacin and numerous third-generation cephalosporins, penicillins, tobramycin and trimethoprim-sulfamethoxazole. The four gene cassette arrangements were as follows: dfrA17-aadA5, aadA1, aacC4-cmlA1 and dfr2d, and 8 carried two disparate class 1 integrons. Five isolates presented class 1 integrons containing no gene cassettes. The distribution of ESBLs and class 1 integrons in Escherichia coli were prevalent with drug resistance in Chengdu. In addition, the resistance range of Escherichia coli isolates that harboured ESBLs and carried class 1 integrons were similar. The current study demonstrated the presence of class 1 integrons and ESBLs, which jointly mediate the resistance of Escherichia coli isolates to a number of antibacterial agents. PMID- 23939785 TI - Castration-induced upregulation of muscle ERalpha supports estrogen sensitivity of motoneuron dendrites in a sexually dimorphic neuromuscular system. AB - The spinal cord of rats contains the sexually dimorphic motoneurons of the spinal nucleus of the bulbocavernosus (SNB). In males, SNB dendrites fail to grow after castration, but androgen or estrogen treatment supports dendritic growth in castrated males. Estrogenic support of SNB dendrite growth is mediated by estrogen receptors (ER) in the target muscle. ERalpha expression in cells lacking a basal lamina (referred to as "extra-muscle fiber cells") of the SNB target musculature coincides with the period of estrogen-dependent SNB dendrite growth. In the SNB target muscle, extra-muscle fiber ERalpha expression declines with age and is typically absent after postnatal (P) day 21 (P21). Given that estradiol downregulates ERalpha in skeletal muscle, we tested the hypothesis that depleting gonadal hormones would prevent the postnatal decline in ERalpha expression in the SNB target musculature. We castrated male rats at P7 and assessed ERalpha immunolabeling at P21; ERalpha expression was significantly greater in castrated males compared with normal animals. Because ERalpha expression in SNB target muscles mediates estrogen-dependent SNB dendrogenesis, we further hypothesized that the castration-induced increase in muscle ERalpha would heighten the estrogen sensitivity of SNB dendrites. Male rats were castrated at P7 and treated with estradiol from P21 to P28; estradiol treatment in castrates resulted in dendritic hypertrophy in SNB motoneurons compared with normal males. We conclude that early castration results in an increase in ERalpha expression in the SNB target muscle, and this upregulation of ERalpha supports estrogen sensitivity of SNB dendrites, allowing for hypermasculinization of SNB dendritic arbors. PMID- 23939787 TI - Breastfeeding and obesity among schoolchildren: a nationwide longitudinal survey in Japan. AB - IMPORTANCE: Although it is suggested that breastfeeding is protective against obesity in children, the evidence remains inconclusive because of possible residual confounding by socioeconomic status or children's lifestyle factors. Most of the participants in the previous studies were children in Western developed countries, so studies in a different context are awaited. OBJECTIVE: To examine the associations of breastfeeding with overweight and obesity among schoolchildren in Japan, with adjustment for the potential confounders. DESIGN: Secondary data analyses of a nationwide longitudinal survey ongoing since 2001, with results collected from 2001 to 2009. SETTING: All over Japan. PARTICIPANTS: A total of 43,367 singleton children who were born after 37 gestational weeks and had information on their feeding during infancy. EXPOSURES: Five mutually exclusive infant feeding practice categories. MAIN OUTCOMES AND MEASURES: Underweight, normal weight (referent group), overweight, and obesity at 7 and 8 years of age defined by using international cutoff points of body mass index by sex and age. RESULTS: In multinomial logistic regression models with adjustment for children's factors (sex, television viewing time, and computer game playing time) and maternal factors (educational attainment, smoking status, and working status), exclusive breastfeeding at 6 to 7 months of age was associated with decreased risk of overweight and obesity compared with formula feeding. The adjusted odds ratios were 0.85 (95% CI, 0.69-1.05) and 0.55 (95% CI, 0.39-0.78) for overweight and obesity, respectively, at 7 years of age. Similar results were observed at 8 years of age. CONCLUSIONS AND RELEVANCE: Breastfeeding is associated with decreased risk of overweight and obesity among schoolchildren in Japan. Therefore, it would be better to encourage breastfeeding even in developed countries. PMID- 23939786 TI - Rax regulates hypothalamic tanycyte differentiation and barrier function in mice. AB - The wall of the ventral third ventricle is composed of two distinct cell populations: tanycytes and ependymal cells. Tanycytes regulate many aspects of hypothalamic physiology, but little is known about the transcriptional network that regulates their development and function. We observed that the retina and anterior neural fold homeobox transcription factor (Rax) is selectively expressed in hypothalamic tanycytes, and showed a complementary pattern of expression to markers of hypothalamic ependymal cells, such as Rarres2 (retinoic acid receptor responder [tazarotene induced] 2). To determine whether Rax controls tanycyte differentiation and function, we generated Rax haploinsufficient mice and examined their cellular and molecular phenotype in adulthood. These mice appeared grossly normal, but careful examination revealed a thinning of the third ventricular wall and reduction of both tanycyte and ependymal markers. These experiments show that Rax is required for hypothalamic tanycyte and ependymal cell differentiation. Rax haploinsufficiency also resulted in the ectopic presence of ependymal cells in the alpha2 tanycytic zone, where few ependymal cells are normally found, suggesting that Rax is selectively required for alpha2 tanycyte differentiation. These changes in the ventricular wall were associated with reduced diffusion of Evans Blue tracer from the ventricle to the hypothalamic parenchyma, with no apparent repercussion on the gross anatomical or behavioral phenotype of these mice. In conclusion, we have provided evidence that Rax is required for the normal differentiation and patterning of hypothalamic tanycytes and ependymal cells, as well as for maintenance of the cerebrospinal fluid-hypothalamus barrier. PMID- 23939788 TI - Optimization of random PEGylation reactions by means of high throughput screening. AB - Since the first FDA approval of a PEGylated product in 1990, so called random PEGylation reactions are still used to increase the efficacy of biopharmaceuticals and represent the major technology of all approved PEG modified drugs. However, the great influence of process parameters on PEGylation degree and the PEG-binding site results in a lack of reaction specificity which can have severe impact on the product profile. Consequently, reproducible and well characterized processes are essential to meet increasing regulative requirements resulting from the quality-by-design (QbD) initiative, especially for this kind of modification type. In this study we present a general approach which combines the simple chemistry of random PEGylation reactions with high throughput experimentation (HTE) to achieve a well-defined process. Robotic based batch experiments have been established in a 96-well plate format and were analyzed to investigate the influence of different PEGylation conditions for lysozyme as model protein. With common SEC analytics highly reproducible reaction kinetics were measured and a significant influence of PEG-excess, buffer pH, and reaction time could be investigated. Additional mono-PEG-lysozyme analytics showed the impact of varying buffer pH on the isoform distribution, which allowed us to identify optimal process parameters to get a maximum concentration of each isoform. Employing Micrococcus lysodeikticus based activity assays, PEG lysozyme33 was identified to be the isoform with the highest residual activity, followed by PEG-lysozyme1 . Based on these results, a control space for a PEGylation reaction was defined with respect to an optimal overall volumetric activity of mono-PEG-lysozyme isoform mixtures. PMID- 23939789 TI - Common use of high doses of antipsychotic medications in older Asian patients with schizophrenia (2001-2009). AB - OBJECTIVE: This study aimed to examine the use of high doses of antipsychotic medications (>=600 mg/day chlorpromazine equivalent) in older Asian patients with schizophrenia and its demographic and clinical correlates. METHOD: Information on hospitalized patients with schizophrenia aged >=50 years was extracted from the database of the Research on Asian Psychotropic Prescription Patterns study (2001 2009). Data on 2203 patients in six Asian countries and territories, including China, Hong Kong, Japan, Korea, Singapore and Taiwan, were analyzed. Socio demographic and clinical characteristics and antipsychotic prescriptions were recorded. RESULTS: The frequency for high-dose antipsychotic medications was 36.0% overall, with 38.4% in 2001, 33.3% in 2004 and 36.0% in 2009. Multiple logistic regression analysis of the whole sample showed that compared to patients receiving low-medium antipsychotic doses, those on high doses had a longer illness duration (odds ratio (OR): 2.0, 95% confidence interval (CI):1.2-3.3, p = 0.008), were more likely in the 50-59-year group (OR: 0.95, 95% CI: 0.94-0.97, p < 0.001), more often had current positive (OR: 1.5, 95% CI: 1.2-1.8, p < 0.001) or negative symptoms (OR: 1.3, 95% CI: 1.03-1.6, p = 0.03), and more commonly received antipsychotic polypharmacy (OR: 5.3, 95% CI: 4.1-6.7, p < 0.001). Extrapyramidal symptoms (p = 0.25) and tardive dyskinesia (p = 0.92) were not more frequent in the high-dose group. CONCLUSIONS: High doses of antipsychotic medications were used in more than one third of older Asian patients with schizophrenia. The reasons for the frequent use of high antipsychotic doses in older Asian patients warrant further investigation. PMID- 23939790 TI - Studies on the chemical constituents and biological activities of ixeris. PMID- 23939791 TI - Natural friedelanes. AB - This review covers the occurrence and biological activities of all natural friedelane triterpenoids found between 1977 and March 2011. The biogeneses of dimeric friedelanes and several rearranged friedelanes are discussed. The pharmacological properties of representative compounds, including celastrol and correolide, have also been compiled, on the basis of 344 references. PMID- 23939792 TI - Alkaloids from corals. AB - Alkaloids, which are generally basic N-containing compounds, have been found in a variety of natural sources. Recently, the interest in alkaloids from corals increased significantly due to their remarkable bioactivities. This review deals with the chemical structures and biological activities of alkaloids in corals. The literature has been covered up to June 2011, and a total of 102 alkaloids from the 51 publications are discussed and reviewed. Some of these compounds showed various biological properties, such as cytotoxic, antibacterial, insecticidal, antifouling, and other activities. PMID- 23939793 TI - Biological activities of phenolic compounds and triterpenoids from the galls of Terminalia chebula. AB - Nine phenolic compounds, including two phenolic carboxylic acids, 1 and 2, seven hydrolyzable tannins, 3-9, eight triterpenoids, including four oleanane-type triterpene acids, 10-13, and four of their glucosides, 14-17, isolated from a MeOH extract of the gall of Terminalia chebula Retz. (myrobalan tree; Combretaceae), were evaluated for their inhibitory activities against melanogenesis in B16 melanoma cells induced by alpha-melanocyte-stimulating hormone (alpha-MSH), against the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) in Raji cells, and against TPA-induced inflammation in mice. Their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activities and cytotoxic activities against four human cancer cell lines were also evaluated. Compounds 6-9 and 12 exhibited potent inhibitory activities against melanogenesis (39.3-66.3% melanin content) with low toxicity to the cells (74.5-105.9% cell viability) at a concentration of 10 MUM. Western-blot analysis revealed that isoterchebulin (8) reduced the protein levels of MITF (=microphtalmia-associated transcription factor), tyrosinase, and TRP-1 (=tyrosine-related protein 1), mostly in a concentration-dependent manner. Eight triterpenoids, 10-17, showed potent inhibitory effects on EBV-EA induction with the IC50 values in the range of 269-363 mol ratio/32 pmol TPA, while these compounds exhibited no DPPH scavenging activities (IC50 >100 MUM). On the other hand, the nine phenolic compounds, 1-9, exhibited potent radical-scavenging activities (IC50 1.4-10.9 MUM) with weak inhibitory effects on EBV-EA induction (IC50 460-518 mol ratio/32 pmol TPA). The tannin 6 and seven triterpenoids, 10 16, have been shown to inhibit TPA-induced inflammation (1 MUg/ear) in mice with the ID50 values in the range of 0.06-0.33 MUmol/ear. Arjungenin (10) exhibited inhibitory effect on skin-tumor promotion in an in vivo two-stage mouse-skin carcinogenesis test based on 7,12-dimethylbenz[a]anthracene (DMBA) as initiator and with TPA as promoter. Compounds 1, 2, 4, 5, 7-9, 12, and 13, against HL60 cell line, compounds 1 and 4, against AZ521 cell line, and compounds 1, 11, and 12, against SK-BR-3 cell line, showed moderate cytotoxic activities (IC50 13.9 73.2 MUM). PMID- 23939794 TI - Chemopreventive and antioxidant activity of the chamazulene-rich essential oil obtained from Artemisia arborescens L. growing on the Isle of La Maddalena, Sardinia, Italy. AB - The essential oils of Artemisia arborescens growing in Sardinia (Italy), collected during three plant growth stages, i.e., from the vegetative stage to post-blooming time, were characterized. Moreover, the in vitro antiproliferative and antioxidant activities of the oil isolated from aerial parts collected in February were evaluated. The essential oils belonged to the beta thujone/chamazulene chemotype, notably with the highest amount of chamazulene (ca. 52%) ever detected up to now in the genus Artemisia and, in general, in essential oils. Quantitative variations in the oil composition were observed as the plant passes from the vegetative to the blooming stage. The oil was tested for its potential tumor cell growth-inhibitory effect on T98G, MDA-MB 435S, A375, and HCT116 human cell lines, using the MTT (=3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl-2H-tetrazolium bromide) assay. The highest activity was observed on A375 and HCT116 cell lines, with IC50 values of 14 MUg/ml. Moreover, the in vitro antioxidant and free radical-scavenging assays revealed the oil to be an effective scavenger of the ABTS radical cation, with an activity comparable to that of Trolox((r)) . These results support the use of A. arborescens oil for the treatment of inflamed skin conditions. Finally, the composition of the polar fraction of the A. arborescens aerial parts was also examined, and the main component detected was 5-O-caffeoylquinic acid, which was identified for the first time in this plant. PMID- 23939795 TI - Photodynamic activity of plant extracts from Sarawak, Borneo. AB - Photodynamic therapy (PDT) is a medical treatment that involves the irradiation of an administered photosensitizing drug with light of a particular wavelength to activate the photosensitizer to kill abnormal cells. To date, only a small number of photosensitizers have been clinically approved for PDT, and researchers continue to look for new molecules that have more desirable properties for clinical applications. Natural products have long been important sources of pharmaceuticals, and there is a great potential for discovery of novel chemotypes from under-explored biodiversities in the world. The objective of this study is to mine the terrestrial plants in Sarawak, Borneo Island, for new photosensitizers for PDT. In a screening program from 2004 to 2008, we prepared and studied 2,400 extracts from 888 plants for their photosensitizing activities. This report details the bioprospecting process, preparation and testing of extracts, analysis of the active samples, fractionation of four samples, and isolation and characterization of photosensitizers. PMID- 23939796 TI - Cytotoxic ent-kaurane diterpenoids from Isodon nervosus. AB - Four new ent-kaurane diterpenoids, rabdonervosins G-J (1-4, resp.), were isolated from the leaves and stems of Isodon nervosus. Their structures were elucidated by extensive spectroscopic analyses, including 1D-, 2D-NMR and HR mass spectra. Compound 2 showed potent cytotoxicity against the HepG2 and PC-9/ZD cell lines with IC50 values of 2.36 and 6.07 MUM, respectively, and compound 3 exhibited cytotoxicity against the HepG2 and CNE2 cell lines with IC50 values of 8.64 and 9.77 MUM, respectively. PMID- 23939797 TI - Abietane diterpenes from Hyptis suaveolens. AB - Investigation of the constituents of the whole plant of Hyptis suaveolens led to the isolation of three new abietane diterpenes, isosuaveolic acid (1), 8alpha,9alpha-epoxysuaveolic acid (2), and 14-O-methylsuaveolic acid (3), together with eleven known compounds. The structures of 1-3 were established by spectroscopic methods and chemical correlations. Some isolates were tested for their antimycobacterial and cytotoxic activities. PMID- 23939798 TI - 11alpha-Ethoxy-beta-boswellic acid and nizwanone, a new boswellic acid derivative and a new triterpene, respectively, from Boswellia sacra. AB - A new boswellic acid derivative, 11alpha-ethoxy-beta-boswellic acid (EBA; 1) and a new ursane-type triterpene, named nizwanone (2), were isolated from Omani frankincense Boswellia sacra Flueck. together with two known compounds papyriogenin B and rigidenol. The structures of 1 and 2 were elucidated by detailed spectroscopic analysis using (1) H- and (13) C-NMR, (1) H,(1) H-COSY, HMQC, HMBC, and HR-EI-MS techniques. The relative configurations of 1 and 2 were assigned by comparative analysis of the NMR spectral data with those of known analogs together with NOESY experiments. Structures of known compounds were identified by comparison with the reported data. PMID- 23939799 TI - Chemotaxonomic significance of the terpene composition in natural populations of Pinus nigra J.F.Arnold from Serbia. AB - The essential-oil variability in seven native populations belonging to different infraspecific taxa of Pinus nigra (ssp. nigra, var. gocensis, ssp. pallasiana, and var. banatica) growing wild in Serbia was analyzed. In the needles of 195 trees from seven populations, 58 essential-oil components were identified. The major components were alpha-pinene (43.6%) and germacrene D (29.8%), comprising together 73.4% of the total oil composition. Based on the average chemical profile of the main terpene components (with contents >5%), the studied populations were found to be the most similar to populations from central Italy and Greece (ssp. nigra). Cluster analysis showed the division of the populations into three principal groups: the first group consisted of Populations I, II, III, IV, and V (considered as ssp. nigra group), the second of Population VI (ssp. pallasiana group), and the third of Population VII, which had the most distinct oil composition (ssp. banatica group). The taxonomic implications of the essential-oil profiles of the investigated taxa of this very complex species are discussed. PMID- 23939800 TI - Developmental changes in the sterol composition and the glycerol content of cuticular and internal lipids of three species of flies. AB - The glycerol concentration and the composition of cuticular and internal sterols in three medically and forensically important fly species, viz., Musca domestica, Sarcophaga carnaria, and Calliphora vicina, were analyzed. The cuticular and internal lipid extracts were separated by HPLC-LLSD, after which the sterol fraction was characterized by GC/MS in total ion current (TIC) mode. The cuticular lipids of M. domestica larvae contained seven sterols, while in pupae and females, six sterols were identified. Five sterols were found in the cuticular lipids of M. domestica males. The internal lipids of M. domestica larvae and pupae contained six and seven sterols, respectively, while those of male and female flies contained only five sterols. Sitosterol, cholesterol, and campesterol were the dominant sterols in M. domestica, while campestanol, stigmasterol, sitostanol, and fucosterol were identified in low concentrations or in traces. In contrast, cuticular and internal lipids of S. carnaria and C. vicina contained only cholesterol. Glycerol was identified in all stages of M. domestica, S. carnaria, and C. vicina. For all the three examined fly species, the present study clearly showed species-specific developmental changes in the composition of cuticular and internal sterols as well as in the glycerol concentration. PMID- 23939801 TI - An eco-friendly enantioselective access to (R)-naringenin as inhibitor of proinflammatory cytokine release. AB - (RS)-Naringenin is a flavanone well-known for its beneficial health-related properties, such as its anti-inflammatory activity. The preparative enantioselective chromatographic resolution of commercial (RS)-naringenin was performed on a Chiralpak AD-H column (500*50 mm i.d., dp 20 MUm) using MeOH as eluent. The developed method is in accordance with the principles of green chemistry, since the environmental impact was lowered by recycling of the eluent, and allowed the production of gram amounts of each enantiomer with high purity (chemical purity >99%, enantiomeric excess (ee) >94%). Racemic and enantiomeric naringenin were subjected to an exhaustive in vitro investigation of anti inflammatory activity, aimed at evaluating the relevance of chirality. The assay with cultured human peripheral blood mononuclear cells (hPBMC) activated by phytohemagglutinin A revealed that (R)-naringenin was more effective in inhibiting T-cell proliferation than the (S)-enantiomer and the racemate. Moreover, (R)-naringenin significantly reduced proinflammatory cytokine levels such as those of TNF-alpha and, with less potency, IL-6. These results evidenced the anti-inflammatory potential of naringenin and the higher capacity of (R) naringenin to inhibit both in vitro hPBMC proliferation and cytokine secretion at non toxic doses. Thus, (R)-naringenin is a promising candidate for in vivo investigation. PMID- 23939802 TI - Allelopathic potential of Rapanea umbellata leaf extracts. AB - The stressful conditions associated with the Brazilian savanna (Cerrado) environment were supposed to favor higher levels of allelochemicals in Rapanea umbellata from this ecosystem. The allelopathic potential of R. umbellata leaf extracts was studied using the etiolated wheat coleoptile and standard phytotoxicity bioassays. The most active extract was selected to perform a bioassay-guided isolation, which allowed identifying lutein (1) and (-)-catechin (2) as potential allelochemicals. Finally, the general bioactivity of the two compounds was studied, which indicated that the presence of 1 might be part of the defense mechanisms of this plant. PMID- 23939803 TI - Bioorganic diversity of rare Coriandrum sativum L. honey: unusual chromatographic profiles containing derivatives of linalool/oxygenated methoxybenzene. AB - The compounds responsible for highly individual aroma profile of Coriandrum sativum L. honey were isolated by headspace solid-phase microextraction (HS-SPME; used fibers: A: polydimethylsiloxane (PDMS)/divinylbenzene (DVB) and B: divinylbenzene/carboxen/polydimethylsiloxane), as well as ultrasonic solvent extraction (USE; used solvents: A: pentane/Et2 O 1 : 2 (v/v) and B: CH2 Cl2 ) and analyzed by gas chromatography (GC) and mass spectrometry (MS). Unusual chromatographic profiles were obtained containing derivatives of linalool/oxygenated methoxybenzene. trans-Linalool oxide (11.1%; 14.6%) dominated in the headspace, followed by other linalool derivatives (such as cis/trans anhydrolinalool oxide (5.0%; 5.9%), isomers of lilac aldehyde/alcohol (14.9%; 13.8%) or p-menth-1-en-9-al (15.6%; 18.5%)), octanal, and several low-molecular weight esters. The major compounds in the solvent extracts were oxygenated methoxybenzene derivatives such as 3,4,5-trimethoxybenzyl alcohol (26.3%; 24.7%), methyl syringate (23.8%; 11.7%), and 3,4-dimethoxybenzyl alcohol (5.6%; 13.9%). Another group of abundant compounds in the extracts were derivatives of linalool (e.g., (E)/(Z)-2,6-dimethylocta-2,7-diene-1,6-diol (17.8%; 16.1%)). Among the compounds identified, cis/trans-anhydrolinalool oxides and 3,4,5-trimethoxybenzyl alcohol can be useful as chemical markers of coriander honey. PMID- 23939804 TI - Intra- and interobserver reliability of levator ani muscle biometry and avulsion using three-dimensional endovaginal ultrasonography. AB - OBJECTIVES: To test intra- and interobserver reliability of assessment of levator ani muscle (LAM) biometry and avulsion using antenatal and postnatal three dimensional (3D) endovaginal ultrasonography (EVUS), and to determine levator urethra gap (LUG) values on EVUS. METHODS: Primigravid women were scanned prior to delivery, early postpartum and 3 months postpartum, with EVUS performed at rest using a standardized protocol. During post-processing, measurements were taken in the plane of minimal hiatal dimensions by two independent investigators blinded to the clinical information and each other's results. LAM attachment to the pubic bone was assessed at the pubococcygeus and puborectalis levels using a score system: (1) intact; (2) partial avulsion (< 50%); (3) partial avulsion (>= 50%); and (4) complete avulsion. Intraclass correlation coefficients (ICCs) and limits of agreement (LOAs) were calculated for each time point, with intraobserver analysis conducted in a random sample of 20 women scanned 3 months following delivery. RESULTS: One hundred and sixty-nine antenatal scans, 83 early postpartum scans and 75 scans at 3 months postpartum were performed. The intra- and interobserver ICCs, respectively, were 0.95 and 0.86-0.88 for hiatal area, 0.90 and 0.16-0.74 for hiatal transverse diameter, 0.91 and 0.73-0.80 for hiatal anteroposterior diameter, 0.50 and 0.32-0.52 for LAM thickness at the '9 o'clock position' and 0.55 and 0.33-0.45 for LAM thickness at the '3 o'clock position'. Both intra- and interobserver analysis revealed acceptable LOAs for hiatal measurements, but the LOAs were wide for thickness measurements. The correlation of LAM avulsion score was excellent on intra- and interobserver analysis. Antenatal mean +/- SD LUGs were 18.8 +/- 2.4 mm and 19.2 +/- 2.3 mm on right and left sides, respectively; the intraobserver ICC was 0.82-0.91 but LOAs were wide, while interobserver ICC was 0.13-0.68 and also had wide LOAs. CONCLUSIONS: 3D EVUS is a reliable tool for the assessment of hiatal measurements and LAM avulsion in women during pregnancy and after delivery, but performs less well for measurements of LAM thickness and LUG. EVUS can therefore be used in research studies involving childbirth and recurrent prolapse. PMID- 23939805 TI - FBP1 and p27kip1 expression after sciatic nerve injury: implications for Schwann cells proliferation and differentiation. AB - Far Upstream Element (FUSE) Binding Protein 1 (FBP1), first identified as a single-stranded DNA (ssDNA) binding protein that binds to the FUSE, could modulate c-myc mRNA levels and also has been shown to regulate tumor cell proliferation and replication of virus. Typically, FBP1 could active the translation of p27kip1 (p27) and participate in tumor growth. However, the expression and roles of FBP1 in peripheral system lesions and repair are still unknown. In our study, we found that FBP1 protein levels was relatively higher in the normal sciatic nerves, significantly decreased and reached a minimal level at Day 3, and then returned to the normal level at 4 weeks. Spatially, we observed that FBP1 had a major colocation in Schwann cells and FBP1 was connected with Ki 67 and Oct-6. In vitro, we detected the decreased level of FBP1 and p27 in the TNF-alpha-induced Schwann cells proliferation model, while increased expression in cAMP-induced Schwann cells differentiation system. Specially, FBP1-specific siRNA-transfected SCs did not show fine and longer morphological change after cAMP treatment and had a decreased motility compared with normal. At 3 days after cAMP treatment and SC/neuron co-cultures, p27 was transported to cytoplasm to form CDK4/6-p27 to participate in SCs differentiation. In conclusion, we speculated that FBP1 and p27 were involved in SCs proliferation and the following differentiation in the sciatic nerve after crush by transporting p27 from nucleus to cytoplasm. PMID- 23939806 TI - Bond Fukui indices: comparison of frozen molecular orbital and finite differences through Mulliken populations. AB - Bond Fukui functions and matrices are introduced for ab initio levels of theory using a Mulliken atoms in molecules model. It is shown how these indices may be obtained from first-order density matrix derivatives without need for going to second-order density matrices as in a previous work. The importance of taking into account the nonorthogonality of the basis in ab initio calculations is shown, contrasting the present results with previous work based on Huckel theory. It is shown how the extension of Fukui functions to Fukui matrices allows getting more insight into the nature of bond Fukui functions. All presently introduced indices respect the necessary normalization conditions and include the classical single atom condensed Fukui functions. PMID- 23939807 TI - Caspase-3 modulates regenerative response after stroke. AB - Stroke is a leading cause of long-lasting disability in humans. However, currently there are still no effective therapies available for promoting stroke recovery. Recent studies have shown that the adult brain has the capacity to regenerate neurons after stroke. Although this neurogenic response may be functionally important for brain repair after injury, the mechanisms underlying stroke-induced neurogenesis are not known. Caspase-3 is a major executioner and has been identified as a key mediator of neuronal death in the acute stage of stroke. Recently, however, accumulating data indicate that caspase-3 also participates in various biological processes that do not cause cell death. Here, we show that cleaved caspase-3 was increased in newborn neuronal precursor cells (NPCs) in the subventricular zone (SVZ) and the dentate gyrus during the period of stroke recovery, with no evidence of apoptosis. We observed that cleaved caspase-3 was expressed by NPCs and limited its self-renewal without triggering apoptosis in cultured NPCs from the SVZ of ischemic mice. Moreover, we revealed that caspase-3 negatively regulated the proliferation of NPCs through reducing the phosphorylation of Akt. Importantly, we demonstrated that peptide inhibition of caspase-3 activity significantly promoted the proliferation and migration of SVZ NPCs and resulted in a significant increase in subsequent neuronal regeneration and functional recovery after stroke. Together, our data identify a previously unknown caspase-3-dependent mechanism that constrains stroke-induced endogenous neurogenesis and should revitalize interest in targeting caspase-3 for treatment of stroke. PMID- 23939808 TI - One-step preparation of macroporous polymer particles with multiple interconnected chambers: a candidate for trapping biomacromolecules. AB - Taking advantage of photothermal conversion, the surface pores of water dispersible single-walled carbon nanotubes assembled on polymer particles were rapidly closed by NIR irradiation to produce macroporous polymeric microspheres with multiple interconnected chambers. These particles can act as smart containers to encapsulate and hold DNA molecules. PMID- 23939809 TI - Forests on thawing permafrost: fragmentation, edge effects, and net forest loss. AB - Much of the world's boreal forest occurs on permafrost (perennially cryotic ground). As such, changes in permafrost conditions have implications for forest function and, within the zone of discontinuous permafrost (30-80% permafrost in areal extent), distribution. Here, forested peat plateaus underlain by permafrost are elevated above the surrounding permafrost-free wetlands; as permafrost thaws, ground surface subsidence leads to waterlogging at forest margins. Within the North American subarctic, recent warming has produced rapid, widespread permafrost thaw and corresponding forest loss. Although permafrost thaw-induced forest loss provides a natural analogue to deforestation occurring in more southerly locations, we know little about how fragmentation relates to subsequent permafrost thaw and forest loss or the role of changing conditions at the edges of forested plateaus. We address these knowledge gaps by (i) examining the relationship of forest loss to the degree of fragmentation in a boreal peatland in the Northwest Territories, Canada; and (ii) quantifying associated biotic and abiotic changes occurring across forest-wetland transitions and extending into the forested plateaus (i.e., edge effects). We demonstrate that the rate of forest loss correlates positively with the degree of fragmentation as quantified by perimeter to area ratio of peat plateaus (edge : area). Changes in depth of seasonal thaw, soil moisture, and effective leaf area index (LAIe ) penetrated the plateau forests by 3-15 m. Water uptake by trees was sevenfold greater in the plateau interior than at the edges with direct implications for tree radial growth. A negative relationship existed between LAIe and soil moisture, suggesting that changes in vegetation physiological function may contribute to changing edge conditions while simultaneously being affected by these changes. Enhancing our understanding of mechanisms contributing to differential rates of permafrost thaw and associated forest loss is critical for predicting future interactions between the land surface processes and the climate system in high latitude regions. PMID- 23939810 TI - High expression of SGTA in esophageal squamous cell carcinoma correlates with proliferation and poor prognosis. AB - Receptor tyrosine kinases (RTKs) expression and the growth factor such as platelet-derived growth factor (PDGF) and their receptors have been considered relevant in the process of angiogenesis and dissemination in esophageal squamous cell carcinoma (ESCC). Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA) downstream of RTK signaling was a critical regulator of PDGF receptors (PDGFR) stability. The aim of the present study was to examine the expression of SGTA and to elucidate its clinicopathologic significance in ESCC. Immunohistochemistry and western blot analysis were performed for SGTA in ESCC samples. SGTA was up-regulated in ESCC as compared with the adjacent normal tissue. High expression of SGTA was associated with tumor grade (P < 0.01), and SGTA was positively correlated with proliferation marker Ki-67 (P < 0.05). Univariate analysis showed that SGTA expression did has a remarkable prediction for poor prognosis (P = 0.016). Knockdown or overexpression of SGTA affected ESCC cells proliferation and cell cycle. Additionally, after ESCC cells silenced for SGTA were treated with cisplatin (an anti-ESCC agent), the cell growth was down regulated. These findings suggested that SGTA was involved in the pathogenesis of ESCC and might indicate a poor prognosis for ESCC patients. PMID- 23939811 TI - Tunable self-assembly of triazole-linked porphyrin-polymer conjugates. AB - The convergence of supramolecular chemistry and polymer science offers many powerful approaches for building functional nanostructures with well-defined dynamic behaviour. Herein we report the efficient "click" synthesis and self assembly of AB2 - and AB4 -type multitopic porphyrin-polymer conjugates (PPCs). PPCs were prepared using the copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) reaction, and consisted of linear polystyrene, poly(butyl acrylate), or poly(tert-butyl acrylate) arms attached to a zinc(II) porphyrin core via triazole linkages. We exploit the presence of the triazole groups obtained from CuAAC coupling to direct the self-assembly of the PPCs into short oligomers (2-6 units in length) via intermolecular porphyrinatozinc-triazole coordination. By altering the length and grafting density of the polymer arms, we demonstrate that the association constant of the porphyrinatozinc-triazole complex can be systematically tuned over two orders of magnitude. Self-assembly of the PPCs also resulted in a 6 K increase in the glass transition temperature of the bulk material compared to a non-assembling PPC. The modular synthesis and tunable self assembly of the triazole-linked PPCs thus represents a powerful supramolecular platform for building functional nanostructured materials. PMID- 23939812 TI - Tandem orthogonal chemically induced dimerization. PMID- 23939813 TI - Predictors of suicidal ideation in older individuals receiving home-care services. AB - OBJECTIVES: Despite the importance of tending to older individuals who are vulnerable to suicide, little is known about suicidal ideation in the portion of this population receiving home-care services in Asian countries. The objective of this cross-sectional study was to examine predictors of suicidal ideation in older individuals using home-care service. METHOD: Participants were randomly selected from the individuals 50 years old and over using home-care services across Jeollabuk-do Province, Korea. A total of 697 subjects participated in this study. Each participant completed the short version of the Geriatric Depression Scale, the Scale for Suicidal Ideation, the Multidimensional Scale of Perceived Social Support, and the World Health Organization Disability Assessment Schedule II. RESULTS: Hierarchical regression analyses revealed that depression, perceived social support, and disability were significant predictors of suicidal ideation, whereas the roles of subjective health status and fish consumption remained ambiguous in this regard. In terms of social support, we also found that less perceived social support from family members was related to higher levels of suicidal ideation. The associations between various categories of disability and suicidal ideation disappeared after controlling for depression. Our investigation of the mediating effect of depression on the relationship between disability and suicidal ideation revealed that depression was either a complete (disability related to cognition, self-care, getting along with others, and life activities) or partial (disability related to participation) mediator. CONCLUSIONS: Preventive strategies focusing on depression, social support, and disability should be emphasized during encounters with older people receiving home-care services. PMID- 23939815 TI - Plant species identity surpasses species richness as a key driver of N(2)O emissions from grassland. AB - Grassland ecosystems worldwide not only provide many important ecosystem services but they also function as a major source of the greenhouse gas nitrous oxide (N2O), especially in response to nitrogen deposition by grazing animals. To explore the role of plants as mediators of these emissions, we tested whether and how N2O emissions are dependent on grass species richness and/or specific grass species composition in the absence and presence of urine deposition. We hypothesized that: (i) N2O emissions relate negatively to plant productivity; (ii) four-species mixtures have lower emissions than monocultures (as they are expected to be more productive); (iii) emissions are lowest in combinations of species with diverging root morphology and high root biomass; and (iv) the identity of the key species that reduce N2O emissions is dependent on urine deposition. We established monocultures and two- and four-species mixtures of common grass species with diverging functional traits: Lolium perenne L. (Lp), Festuca arundinacea Schreb. (Fa), Phleum pratense L. (Php) and Poa trivialis L. (Pt), and quantified N2O emissions for 42 days. We found no relation between plant species richness and N2O emissions. However, N2O emissions were significantly reduced in specific plant species combinations. In the absence of urine, plant communities of Fa+Php acted as a sink for N2O, whereas the monocultures of these species constituted a N2O source. With urine application Lp+Pt plant communities reduced (P < 0.001) N2O emissions by 44% compared to monocultures of Lp. Reductions in N2O emissions by species mixtures could be explained by total biomass productivity and by complementarity in root morphology. This study shows that plant species composition is a key component underlying N2O emissions from grassland ecosystems. Selection of specific grass species combinations in the context of the expected nitrogen deposition regimes may therefore provide a key for mitigation of N2O emissions. PMID- 23939814 TI - Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. AB - We previously found that human mesenchymal stem cells (MSC) or its conditioned medium restored lung protein permeability and reduced alveolar inflammation following Escherichia coli endotoxin-induced acute lung injury (ALI) in an ex vivo perfused human lung in part through the secretion of soluble factors such as keratinocyte growth factor (KGF). Recently, MSC were found to release microvesicles (MVs) that were biologically active because of the presence of mRNA or miRNA with reparative properties. MVs are circular fragments of membrane released from the endosomal compartment as exosomes or shed from the surface membranes. These studies were designed to determine if MVs released by human bone marrow derived MSCs would be effective in restoring lung protein permeability and reducing inflammation in E. coli endotoxin-induced ALI in C57BL/6 mice. The intratracheal instillation of MVs improved several indices of ALI at 48 hours. Compared to endotoxin-injured mice, MVs reduced extravascular lung water by 43% and reduced total protein levels in the bronchoalveolar lavage (BAL) fluid by 35%, demonstrating a reduction in pulmonary edema and lung protein permeability. MVs also reduced the influx of neutrophils and macrophage inflammatory protein-2 levels in the BAL fluid by 73% and 49%, respectively, demonstrating a reduction in inflammation. KGF siRNA-pretreatment of MSC partially eliminated the therapeutic effects of MVs released by MSCs, suggesting that KGF protein expression was important for the underlying mechanism. In summary, human MSC derived MVs were therapeutically effective following E. coli endotoxin-induced ALI in mice in part through the expression of KGF mRNA in the injured alveolus. PMID- 23939816 TI - Taurine improves obesity-induced inflammatory responses and modulates the unbalanced phenotype of adipose tissue macrophages. AB - SCOPE: It is increasingly accepted that chronic inflammation is a feature of obesity. Obesity-induced inflammation triggers enhanced recruitment of macrophages into the adipose tissue. Depending on their phenotype, macrophages can be designated either as pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. We have therefore investigated the effects of taurine, a sulfated amino acid that is abundant in seafood, on obesity-related inflammation. METHODS AND RESULTS: In high-fat diet fed C57BL/6J mice, taurine treatment reduced the infiltration of macrophages and promoted an M2-like phenotype of macrophages in adipose tissues. In addition, taurine decreased the production of inflammatory cytokines, and suppressed the development of hyperglycemia in diet-induced obese mice. Moreover, in vitro experiments that involved bone marrow derived macrophages indicated that taurine treatment induced alternative M2 macrophage activation, and its chloride, taurine chloramines, inhibited classical M1 macrophage activation. CONCLUSION: Our findings indicate that taurine treatment attenuates the infiltration of adipose tissue by macrophages and modulates the phenotype of macrophages, which suggest that taurine is a valuable food constituent with a potential to attenuate chronic inflammation in adipose tissue and improve obesity-related insulin resistance. PMID- 23939817 TI - A computational methodology for accurate predictions of rate constants in solution: application to the assessment of primary antioxidant activity. AB - The accurate prediction of rate constants for chemical reactions in solution, using computational methods, is a challenging task. In this work, a computational protocol designed to be a reliable tool in the study of radical-molecule reactions in solution is presented. It is referred to as quantum mechanics-based test for overall free radical scavenging activity (QM-ORSA) because it is mainly intended to provide a universal and quantitative way of evaluating the free radical scavenging activity of chemical compounds. That is, its primary antioxidant activity. However, it can also be successfully applied to obtain accurate kinetic data for other chemical reactions in solution. The QM-ORSA protocol has been validated by comparison with experimental results, and its uncertainties have been proven to be no larger than those arising from experiments. Further applications of QM-ORSA are expected to contribute increasing the kinetic data for free radical-molecule reactions relevant to oxidative stress, which is currently rather scarce. PMID- 23939818 TI - Surface patterning using two-phase laminar flow and in situ formation of aryldiazonium salts. PMID- 23939819 TI - Model predictions of toxaphene degradation in the atmosphere over North America. AB - Technical toxaphene, a broad-spectrum pesticide mixture, degrades in the environment, resulting in potential changes in toxicity. The present study uses a multimedia model that the authors developed to estimate toxaphene degradation in the atmosphere over North America. The predicted degradation has strong spatial and temporal variability determined by processes such as emission and transport of technical toxaphene, as well as the complex interactions among many species (e.g., toxaphene, hydroxyl [OH] radicals, and ozone). More toxaphene is degraded in warmer months due to higher concentrations of technical toxaphene (primarily due to higher technical toxaphene emissions in the southeastern United States and transport to other regions) and OH radicals. In the model, OH radicals are created primarily through the reactions of water vapor with the excited oxygen atom, O(1D), generated by the photolysis of ozone, which is produced primarily by reactions of volatile organic compounds and nitrogen oxides (NOx) in the presence of sunlight. The higher OH concentrations in warmer months are primarily the result of higher solar radiation and ozone concentrations. The spatial distribution of degradation depends on the distribution of technical toxaphene soil residues as well as atmospheric transport and chemistry; significant chemical degradation occurs in the southeastern United States where soils are most heavily contaminated by past applications of toxaphene. PMID- 23939823 TI - Monoliths: special issue in a new package. AB - Regular special issues concerning monoliths have always been a stronghold of the Journal of Separation Science. Typically, we issued a call for papers, collected and processed the submitted manuscripts, and all of them were then printed in a single issue of the journal. This approach worked to a certain limit quite acceptably but there was always a longer waiting time between the early submissions and publication. This is why we decided to do it this year differently. I claimed in my 2013 New Years Editorial: "We are living in the electronic era! Why not to make an advantage of that?" And we do. As a result, all manuscript submitted for publication in the special issue Monoliths have already been published in regular issues as soon as they were accepted. The first page of these papers includes a footnote: "This paper is included in the virtual special issue Monoliths available at the Journal of Separation Science website." All papers published with this footnote were collected in a virtual special issue accessible through the internet. This concept ruled out possible delays in publication of contributions submitted early. Since we did not have any real "special issue", there was no need for any hard deadline for submission. We just collected manuscripts submitted for the special issue Monoliths published from January to July 2013 and included them in the virtual special issue. This new approach worked very well and we published 22 excellent papers that are included in the issue available now at this website: http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1615 9314/homepage/virtual_special_issue__monoliths.htm. PMID- 23939822 TI - Stress-induced dopamine release in human medial prefrontal cortex--18F fallypride/PET study in healthy volunteers. AB - BACKGROUND: In laboratory animals, environmental stressors markedly activate the mesocortical dopamine system. The present study tested whether this occurs in humans. METHODS: The effects of a laboratory psychological stressor (Montreal Imaging Stress Task, MIST) on mesocortical dopamine release in healthy young adults (11 males, mean age +/- SD, 20.6 +/- 2.4 years) was measured using positron emission tomography and [(18)F]fallypride. Each subject was scanned in two separate days in counterbalanced order: one with the MIST and one with the control task. Binding potential (BP ND ) maps of the whole brain were calculated for each scan, using a simplified reference tissue compartmental model. Then BP ND was compared between subjects. Heart rate, galvanic skin response, and salivary cortisol level were measured during the scans. RESULTS: The psychological stressor significantly decreased [(18)F]fallypride binding values in the dorsal part of the medial prefrontal cortex (dmPFC), corresponding to the rostal part of the cingulate motor zone. The greater the stress-induced decrease in [(18)F]fallypride binding in the dmPFC, the greater the stress-induced increases in heart rate. CONCLUSIONS: The present study provides evidence of stress-induced dopamine release in the mPFC in humans, in vivo. PMID- 23939826 TI - Solvation dynamics of a radical ion pair in micro-heterogeneous binary solvents: a semi-quantitative study utilizing MARY line-broadening experiments. AB - This work aims at elucidating the mechanism of solvation of a radical ion pair (RIP) in a micro-heterogeneous binary solvent mixture using magnetically affected reaction yield (MARY) spectroscopy. For the exciplex-forming 9,10 dimethylanthracene/N,N-dimethylaniline system a comparative, composition dependent MARY line-broadening study is undertaken in a heterogeneous (toluene/dimethylsulfoxide) and a quasi-homogenous (propyl acetate/butyronitrile) solvent mixture. The half-saturation field extrapolated to zero-quencher concentration, B(1/2), and the self-exchange rate constants are analyzed in the light of solvent dynamical properties of the mixtures and a dielectric continuum solvation model. The dependence of B(1/2) on the solvent composition is explained by cluster formation giving rise to shortened RIP lifetimes. The results are in qualitative agreement with the continuum solvation model suggesting that it could serve as a theoretical basis for quantitative modeling. PMID- 23939827 TI - Insights into the oxidative dehydrogenation of amines with nanoparticulate iridium oxide. AB - The aerobic oxidation of amines offers a promising route towards many versatile chemical compounds. Within this contribution, we extend our previous investigations of iridium oxide-catalyzed alcohol oxidation to amine substrates. In addition to demonstrating the versatility of this catalyst, particular attention is focused on the mechanisms of the reaction. Herein, we demonstrate that although amines are oxidized slower than the corresponding alcohols, the catalyst has a preference for amine substrates, and oxidizes various amines at turnover frequencies greater than other systems found in the open literature. Furthermore, the competition between double amine dehydrogenation, to yield the corresponding nitrile, and amine-imine coupling, to yield the corresponding coupled imine, has been found to arise from a competitive reaction pathway, and stems from an effect of substrate-to-metal ratio. Finally, the mechanism responsible for the formation of N-benzylidene-1-phenylmethanamine was examined, and attributed to the coupling of free benzyl amine substrate and benzaldehyde, formed in situ through hydrolysis of the primary reaction product, benzyl imine. PMID- 23939828 TI - Crosslinked poly(ethylene oxide) as a versatile alignment medium for the measurement of residual anisotropic NMR parameters. PMID- 23939820 TI - The rachitic tooth. AB - Teeth are mineralized organs composed of three unique hard tissues, enamel, dentin, and cementum, and supported by the surrounding alveolar bone. Although odontogenesis differs from osteogenesis in several respects, tooth mineralization is susceptible to similar developmental failures as bone. Here we discuss conditions fitting under the umbrella of rickets, which traditionally referred to skeletal disease associated with vitamin D deficiency but has been more recently expanded to include newly identified factors involved in endocrine regulation of vitamin D, phosphate, and calcium, including phosphate-regulating endopeptidase homolog, X-linked, fibroblast growth factor 23, and dentin matrix protein 1. Systemic mineral metabolism intersects with local regulation of mineralization, and factors including tissue nonspecific alkaline phosphatase are necessary for proper mineralization, where rickets can result from loss of activity of tissue nonspecific alkaline phosphatase. Individuals suffering from rickets often bear the additional burden of a defective dentition, and transgenic mouse models have aided in understanding the nature and mechanisms involved in tooth defects, which may or may not parallel rachitic bone defects. This report reviews dental effects of the range of rachitic disorders, including discussion of etiologies of hereditary forms of rickets, a survey of resulting bone and tooth mineralization disorders, and a discussion of mechanisms, known and hypothesized, involved in the observed dental pathologies. Descriptions of human pathology are augmented by analysis of transgenic mouse models, and new interpretations are brought to bear on questions of how teeth are affected under conditions of rickets. In short, the rachitic tooth will be revealed. PMID- 23939829 TI - Cytological criteria of high-grade epithelial atypia in the cyst fluid of pancreatic intraductal papillary mucinous neoplasms. AB - BACKGROUND: The recognition of epithelial cells with high-grade atypia (HGA) in the cyst fluid of an intraductal papillary mucinous neoplasm (IPMN) identifies a cyst at high risk of invasive carcinoma. To the best of the authors' knowledge, the cytological features of HGA have not been systematically analyzed to define diagnostic criteria. METHODS: Cell groups from patients with histologically confirmed branch-duct IPMNs were evaluated by 2 cytopathologists with expertise in pancreatic cytology. A consensus interpretation categorized the cell groups as having either low-grade (LG) or high-grade (HG) morphology. Characteristics regarding cell size and architecture, nuclear and cytoplasmic features, and background necrosis were analyzed. Performance characteristics were assessed using the Fisher exact test at 95% confidence intervals. RESULTS: Sixty cell groups yielded 27 LG and 25 HG morphological groups. No consensus was reached for 8 groups, which were excluded from statistical analysis. Five features that were found to be significantly different between the LG and HG groups included: 1) cell size < a 12-MUm duodenal enterocyte for HG and size equal for LG; 2) an increased nuclear-to-cytoplasmic (N/C) ratio; 3) marked nuclear membrane abnormalities; 4) abnormal chromatin pattern; and 5) background necrosis. The 3 most accurate features for the identification of HGA were background necrosis (88%), abnormal chromatin pattern (84%), and an increased N/C ratio (82%). CONCLUSIONS: IPMN cyst fluid at high-risk of malignancy can be recognized most accurately by the presence of epithelial cells with HGA showing an increased N/C ratio, an abnormal chromatin pattern, and background necrosis. PMID- 23939830 TI - Detection of genetic abnormalities by using CVS and FISH prior to fetal reduction in sonographically normal appearing fetuses. AB - OBJECTIVE: To examine the ability of chorionic villus sampling (CVS) and fluorescence in situ hybridization (FISH) to detect aneuploidy before first trimester fetal reduction (FR) in sonographically normal-appearing fetuses. METHODS: A retrospective review of 470 patients referred to our unit for FR from January 2007-March 2011. Prenatal diagnosis was offered to all. FR was performed after next-day FISH results. Abnormalities were categorized by ultrasound, FISH, and/or karyotype. Sensitivity, specificity, positive predictive value, and negative predictive value of pre-FR FISH were calculated. RESULTS: Four hundred thirty-two of 470 patients seen were first trimester. 24/432 (5.2%) were excluded for abnormal ultrasound findings, including nuchal translucency (NT) > 3.0 mm, and 360 (88.2%) underwent CVS before FR. Ten fetuses were then excluded for euploid sex mosaicism. 10/350 (2.9%) patients with normal ultrasounds had abnormal FISH confirmed by karyotype. 9/350 (2.6%) patients with normal FISH had an abnormal karyotype necessitating follow up amniocentesis in which the clinically relevant discordancy was confirmed in one case (1/350, 0.3%). Pre-FR FISH had a 90% sensitivity, 99.4% specificity, 83.3% positive predictive value, and 99.7% negative predictive value. CONCLUSIONS: 3.1% of patients with normal appearing fetuses prior to first trimester FR had a fetus with an abnormal karyotype of which FISH detected 90%. CVS with FISH prior to FR adds significant information that can guide reduction decisions. PMID- 23939831 TI - Effects of temperature and copper pollution on soil community--extreme temperature events can lead to community extinction. AB - Global warming affects ecosystems and species' diversity. The physiology of individual species is highly influenced by changes in temperature. The effects on species communities are less studied; they are virtually unknown when combining effects of pollution and temperature. To assess the effects of temperature and pollution in the soil community, a 2-factorial soil mesocosms multispecies experiment was performed. Three exposure periods (28 d, 61 d, and 84 d) and 4 temperatures (19 degrees C, 23 degrees C, 26 degrees C, and 29 degrees C) were tested, resembling the mean annual values for southern Europe countries and extreme events. The soil used was from a field site, clean, or spiked with Cu (100 mg Cu/kg). Results showed clear differences between 29 degrees C treatment and all other temperature treatments, with a decrease in overall abundance of organisms, further potentiated by the increase in exposure time. Folsomia candida was the most abundant species and Enchytraeus crypticus was the most sensitive to Cu toxicity. Differences in species optimum temperatures were adequately covered: 19 degrees C for Hypoaspis aculeifer or 26 degrees C for E. crypticus. The temperature effects were more pronounced the longer the exposure time. Feeding activity decreased with higher temperature and exposure time, following the decrease in invertebrate abundance, whereas for the same conditions the organic matter turnover increased. Hence, negative impacts on ecosystem services because of temperature increase can be expected by changes on soil function and as consequence of biodiversity loss. PMID- 23939833 TI - Acid-catalyzed direct conjugate alkenylation of alpha,beta-unsaturated ketones. AB - New tricks, old reaction: The title reaction proceeds under mild and transition metal-free conditions (see scheme; Tf=trifluoromethanesulfonyl). Various combinations of substrates are applicable to the synthesis of gamma,delta unsaturated ketones by employing silicon substituents at the beta-position of the enones. The silicon substituents play a key role in stabilization of the cationic intermediate by hyperconjugation. PMID- 23939832 TI - MiR-26b is down-regulated in carcinoma-associated fibroblasts from ER-positive breast cancers leading to enhanced cell migration and invasion. AB - Carcinoma-associated fibroblasts (CAFs) influence the behaviour of cancer cells but the roles of microRNAs in this interaction are unknown. We report microRNAs that are differentially expressed between breast normal fibroblasts and CAFs of oestrogen receptor-positive cancers, and explore the influences of one of these, miR-26b, on breast cancer biology. We identified differentially expressed microRNAs by expression profiling of clinical samples and a tissue culture model: miR-26b was the most highly deregulated microRNA. Using qPCR, miR-26b was confirmed as down-regulated in fibroblasts from 15 of 18 further breast cancers. Next, we examined whether manipulation of miR-26b expression changed breast fibroblast behaviour. Reduced miR-26b expression caused fibroblast migration and invasion to increase by up to three-fold in scratch-closure and trans-well assays. Furthermore, in co-culture with MCF7 breast cancer epithelial cells, fibroblasts with reduced miR-26b expression enhanced both MCF7 migration in trans well assays and MCF7 invasion from three-dimensional spheroids by up to five fold. Mass spectrometry was used to identify expression changes associated with the reduction of miR-26b expression in fibroblasts. Pathway analyses of differentially expressed proteins revealed that glycolysis/TCA cycle and cytoskeletal regulation by Rho GTPases are downstream of miR-26b. In addition, three novel miR-26b targets were identified (TNKS1BP1, CPSF7, COL12A1) and the expression of each in cancer stroma was shown to be significantly associated with breast cancer recurrence. MiR-26b in breast CAFs is a potent regulator of cancer behaviour in oestrogen receptor-positive cancers, and we have identified key genes and molecular pathways that act downstream of miR-26b in CAFs. PMID- 23939834 TI - Pigment epithelium-derived factor enhances differentiation and mineral deposition of human mesenchymal stem cells. AB - Pigment epithelium-derived factor (PEDF) is a potent antiangiogenic factor found in a wide variety of tissues. Recent findings indicated that lack of PEDF leads to osteogenesis imperfecta type VI whose hallmark is a defect in mineralization. We investigated the effects of PEDF on human mesenchymal stem cells (hMSCs) and signaling pathways through which PEDF displays its activities in hMSCs. hMSCs incubated in a medium supplemented with PEDF induced expression of osteoblastic related genes. In addition, PEDF induced alkaline phosphatase (ALP) activity in MSCs at 14 days of incubation in maintenance medium; hMSCs incubated in osteogenic medium in presence of PEDF expressed 19% more ALP activity (35.655 +/- 1.827 U/mg protein, p = .041 than cells incubated in the same medium without PEDF supplementation (29.956 +/- 2.100 U/MUg protein). hMSCs incubated in osteogenic medium in presence of PEDF deposited 50% more mineral (2.108 +/- 0.306 OD/ml per well per 1 * 10(4) cells per square centimeter, p = .017) than MSCs incubated in absence of the protein (1.398 +/- 0.098 OD/ml per well per 1 * 10(4) cells per square centimeter) as determined by Alizarin Red quantitation. Reduction in PEDF expression in MSCs by siRNA led to decreased ALP activity (33.552 +/- 2.009 U/ng protein of knockdown group vs. 39.269 +/- 3.533 U/ng protein of scrambled siRNA group, p = .039) and significant reduction in mineral deposition (0.654 +/- 0.050 OD/ml per well per 1 * 10(4) cells per square centimeter of knockdown group vs. 1.152 +/- 0.132 OD/ml per well per 1 * 10(4) cells per square centimeter of wild type group, p = .010). Decreased ALP activity and mineral deposition were restored by supplementation with exogenous PEDF protein. PEDF activated ERK and AKT signaling pathways in MSCs to induce expression of osteoblastic-related genes. These data suggest that PEDF is involved in MSCs osteoblastic differentiation. PMID- 23939835 TI - Use of sulfated cyclofructan 6 and sulfated cyclodextrins for the chiral separation of four basic pharmaceuticals by capillary electrophoresis. AB - Sulfated cyclofructan 6 (S-CF6) and sulfated cyclodextrins (S-alpha-, beta-, gamma-CDs) are highly selective chiral selectors for the enantioseparation of basic solutes. In this study, S-CF6 was introduced for the enantiomeric separation of four basic pharmaceuticals (including tamsulosin, tiropramide, bupivacaine, and norephedrine) by capillary electrophoresis (CE), and the enantiomeric separation performance was compared with S-alpha-, beta-, gamma-CDs. The effects of the chiral selector type, chiral selector concentration, operating voltage, and column temperature were examined and optimized. Excellent resolutions were obtained for all solutes on these chiral selectors. PMID- 23939836 TI - Hollow-fiber liquid-phase microextraction combined with capillary HPLC for the selective determination of six sulfonylurea herbicides in environmental waters. AB - A three-phase hollow-fiber liquid-phase microextraction combined with a capillary LC method using diode array detection was proposed for the determination of six sulfonylurea herbicides, triasulfuron, metsulfuron-methyl, chlorsulfuron, flazasulfuron, chlorimuron-ethyl, and primisulfuron-methyl, in environmental water samples. Different factors that can affect the extraction process such as extraction solvent, acidity of the donor phase, composition and pH of the acceptor phase, salt addition, stirring speed, and extraction time were optimized. Under the optimum conditions, detection and quantitation limits between 0.1-1.7 and 0.3-5.7 MUg/L, respectively, and enrichment factors ranging from 71 to 548 were obtained. The calibration curves were linear within the range of 0.3-40 MUg/L. Intra- and interday RSDs were <6.3 and 8.4%, respectively. The relative recoveries of the spiked ground and river water samples were in the range of 69.4-119.2 and 77.4-111.7%, respectively. The results of the study revealed that the developed methodology involves an efficient sample pretreatment allowing the preconcentration of analytes, combined with the use of a miniaturized separation technique, suitable for the accurate determination of sulfonylurea herbicides in water. PMID- 23939837 TI - Tunable emissive lanthanidomesogen derived from a room-temperature liquid crystalline Schiff-base ligand. AB - A novel photoluminescent room-temperature liquid-crystalline salicylaldimine Schiff base with a short alkoxy substituent and a series of lanthanide(III) complexes of the type [Ln(LH)3(NO3)3] (Ln = La, Pr, Sm, Gd, Tb, Dy; LH = (E)-5 (hexyloxy)-2-[{2-(2-hydroxyethylamino)ethylimino]methyl}phenol) have been synthesized and characterized by FTIR, (1)H and (13)C NMR, UV/Vis, and FAB-MS analyses. The ligand coordinates to the metal ions in its zwitterionic form. The thermal behavior of the compounds was investigated by polarizing optical microscopy (POM) and differential scanning calorimetry (DSC). The ligand exhibits an enantiotropic hexagonal columnar (Col(h)) mesophase at room temperature and the complexes show an enantiotropic lamellar columnar (Col(L)) phase at around 120 degrees C with high thermal stability. Based on XRD results, different space filling models have been proposed for the ligand and complexes to account for the columnar mesomorphism. The ligand exhibits intense blue emission both in solution and in the condensed state. The most intense emissions were observed for the samarium and terbium complexes, with the samarium complex glowing with a bright orange light (ca. 560-644 nm) and the terbium complex emitting green light (ca. 490-622 nm) upon UV irradiation. DFT calculations performed by using the DMol3 program at the BLYP/DNP level of theory revealed a nine-coordinate structure for the lanthanide complexes. PMID- 23939838 TI - Surgical safety. PMID- 23939839 TI - Preoperative indicators of the systemic inflammatory response in the treatment of patients with gastrointestinal cancer. PMID- 23939821 TI - Key role of CRF in the skin stress response system. AB - The discovery of corticotropin-releasing factor (CRF) or CRH defining the upper regulatory arm of the hypothalamic-pituitary-adrenal (HPA) axis, along with the identification of the corresponding receptors (CRFRs 1 and 2), represents a milestone in our understanding of central mechanisms regulating body and local homeostasis. We focused on the CRF-led signaling systems in the skin and offer a model for regulation of peripheral homeostasis based on the interaction of CRF and the structurally related urocortins with corresponding receptors and the resulting direct or indirect phenotypic effects that include regulation of epidermal barrier function, skin immune, pigmentary, adnexal, and dermal functions necessary to maintain local and systemic homeostasis. The regulatory modes of action include the classical CRF-led cutaneous equivalent of the central HPA axis, the expression and function of CRF and related peptides, and the stimulation of pro-opiomelanocortin peptides or cytokines. The key regulatory role is assigned to the CRFR-1alpha receptor, with other isoforms having modulatory effects. CRF can be released from sensory nerves and immune cells in response to emotional and environmental stressors. The expression sequence of peptides includes urocortin/CRF->pro-opiomelanocortin->ACTH, MSH, and beta endorphin. Expression of these peptides and of CRFR-1alpha is environmentally regulated, and their dysfunction can lead to skin and systemic diseases. Environmentally stressed skin can activate both the central and local HPA axis through either sensory nerves or humoral factors to turn on homeostatic responses counteracting cutaneous and systemic environmental damage. CRF and CRFR-1 may constitute novel targets through the use of specific agonists or antagonists, especially for therapy of skin diseases that worsen with stress, such as atopic dermatitis and psoriasis. PMID- 23939840 TI - Type II endoleak after endovascular aneurysm repair. AB - BACKGROUND: The aim was to assess the risk of rupture, and determine the benefits of intervention for the treatment of type II endoleak after endovascular abdominal aortic aneurysm repair (EVAR). METHODS: This systematic review was done according to PRISMA guidelines. Outcome data included incidence, spontaneous resolution, sac expansion, interventions, clinical success, and complications including conversion to open repair, and rupture. RESULTS: Thirty-two non randomized retrospective studies were included, totalling 21 744 patients who underwent EVAR. There were 1515 type II endoleaks and 393 interventions. Type II endoleak was seen in 10.2 per cent of patients after EVAR; 35.4 per cent resolved spontaneously. Fourteen patients (0.9 per cent) with isolated type II endoleak had ruptured abdominal aortic aneurysm; six of these did not have known aneurysm sac expansion. Of 393 interventions for type II endoleak, 28.5 per cent were unsuccessful. Translumbar embolization had a higher clinical success rate than transarterial embolization (81 versus 62.5 per cent respectively; P = 0.024) and fewer recurrent endoleaks were reported (19 versus 35.8 per cent; P = 0.036). Transarterial embolization also had a higher rate of complications (9.2 per cent versus none; P = 0.043). CONCLUSION: Aortic aneurysm rupture after EVAR secondary to an isolated type II endoleak is rare (less than 1 per cent), but over a third occur in the absence of sac expansion. Translumbar embolization had a higher success rate with a lower risk of complications. PMID- 23939841 TI - Randomized clinical trial of a simple pulmonary recruitment manoeuvre to reduce pain after laparoscopy. AB - BACKGROUND: Shoulder tip and abdominal pain following laparoscopic procedures are well recognized causes of postoperative morbidity. In this double-blind randomized clinical trial attempts were made to reduce postoperative pain in patients undergoing laparoscopic surgery by implementing a simple intraoperative technique. METHODS: Patients undergoing elective laparoscopic cholecystectomy or laparoscopic transabdominal preperitoneal inguinal hernia repair were randomized to receive either the current standard treatment (control group) or an intervention to remove residual carbon dioxide. In the intervention group, the pneumoperitoneum was removed at the end of the operation by placing the patient in the Trendelenburg position and utilizing a pulmonary recruitment manoeuvre consisting of two manual inflations to a maximum pressure of 60 cmH2 O. In the control group, residual pneumoperitoneum was evacuated at the end of the procedure by passive decompression via the open operative ports. RESULTS: Seventy six randomly assigned patients, 37 in the intervention group and 39 in the control group, were recruited. Overall postoperative pain scores were significantly lower in the intervention group (P = 0.001). Median (interquartile range) pain scores were significantly lower in the intervention group compared with the control group at both 12 h (3.5 versus 5; P < 0.010) and 24 h (3 versus 4.5; P < 0.010). CONCLUSION: Active evacuation of residual pneumoperitoneum following laparoscopic procedures, by means of two pulmonary recruitment manoeuvres in the Trendelenburg position, reduces postoperative pain significantly. This simple and safe technique can be implemented routinely after abdominal laparoscopy. REGISTRATION NUMBER: NCT01720433 (http://www.clinical trials.gov). PMID- 23939842 TI - Randomized clinical trial of the benefit of laparoscopy with closure of loop ileostomy. AB - BACKGROUND: The aim was to compare reversal and laparoscopy with standard reversal of loop ileostomy in terms of hospital stay and morbidity in a randomized study. METHODS: Patients having reversal of a loop ileostomy were randomized to either standard reversal of ileostomy or reversal and laparoscopy. Strict discharge criteria were applied: toleration of two meals without nausea and vomiting, passing a bowel motion, and attaining adequate pain control with oral analgesia. Morbidity and cost were also compared between the two groups. RESULTS: A total of 74 patients (reversal and laparoscopy 40, standard reversal 34) with a median age of 61 years underwent loop ileostomy reversal; there were 45 men (61 per cent). Ileostomy was most commonly carried out after laparoscopic low anterior resection (36 patients). Median length of stay, based on discharge criteria, was significantly shorter in the reversal and laparoscopy group than in the standard group: 4 (interquartile range 3-4) versus 5 (4-6) days (P = 0.003). The overall morbidity rate was also lower in patients who had ileostomy reversal and laparoscopy: 10 versus 32 per cent (P = 0.023). The median cost per patient was lower in the reversal and laparoscopy group: ?3450 (interquartile range 2766 3450) versus ?4527 (3843-7263) (P = 0.015). There was no statistically significant difference in American Society of Anesthesiologists fitness grade or time to reversal between the two groups. CONCLUSION: Reversal of loop ileostomy with laparoscopy was associated with a shorter hospital stay, lower morbidity and reduced cost compared with the standard technique. REGISTRATION NUMBER: ISRCTN46101203 (http://www.controlled-trials.com). PMID- 23939843 TI - Factors predictive of lymph node metastasis in the follicular variant of papillary thyroid carcinoma. AB - BACKGROUND: The treatment of papillary thyroid carcinomas larger than 1 cm usually consists of total thyroidectomy and central lymph node dissection (LND). In patients with the follicular variant of papillary thyroid carcinoma (FVPTC), preoperative cytology and intraoperative frozen-section analysis cannot always establish the diagnosis. The aim of this study was to evaluate predictive factors for lymph node metastasis in patients with FVPTC and to identify patients who might benefit from LND. METHODS: The study included patients with FVPTC treated by total thyroidectomy and LND between 2000 and 2010 in four departments. When fewer than six non-involved lymph nodes were removed, the patient was excluded from the analysis. RESULTS: Some 199 patients were included. The median tumour size was 17 (range 1-85) mm, and tumours were classified as T1a in 28 patients, T1b in 40, T2 in 53, and T3 in 78. Eighty-one patients (40.7 per cent) had lymph node metastasis (51 classified as N1a and 30 as N1b). Four risk factors were predictive of lymph node metastasis in the multivariable analysis: multifocality (odds ratio (OR) 2.36, 95 per cent confidence interval 1.15 to 4.86), angiolymphatic invasion (OR 3.67, 1.01 to 13.36), absence of tumour capsule (OR 3.00, 1.47 to 6.14) and tumour involvement of perithyroid tissue (OR 3.89, 1.85 to 8.18). The rate of lymph node metastasis varied between 14 and 94 per cent depending on the presence of risk factors. CONCLUSION: The rate of lymph node metastasis in patients with FVPTC varies widely according to the presence or absence of predictive risk factors. PMID- 23939844 TI - Economic impact of an enhanced recovery pathway for oesophagectomy. AB - BACKGROUND: Data are lacking to support the cost-effectiveness of enhanced recovery pathways (ERP) for oesophagectomy. The aim of this study was to investigate the impact of an ERP on medical costs for oesophagectomy. METHODS: This study investigated all patients undergoing elective oesophagectomy between June 2009 and December 2011 at a single high-volume university hospital. From June 2010, all patients were enrolled in an ERP. Clinical outcomes were recorded for up to 30 days. Deviation-based cost modelling was used to compare costs between the traditional care and ERP groups. RESULTS: A total of 106 patients were included (47 traditional care, 59 ERP). There were no differences in patient, pathological and operative characteristics between the groups. Median length of hospital stay (LOS) was lower in the ERP group (8 (interquartile range 7-18) days versus 10 (9-18) days with traditional care; P = 0.019). There was no difference in 30-day complication rates (59 per cent with ERP versus 62 per cent with traditional care; P = 0.803), and the 30-day or in-hospital mortality rate was low (3.8 per cent, 4 of 106). Costs in the on-course and minor-deviation groups were significantly lower after implementation of the ERP. The pathway dependent cost saving per patient was ?1055 and the overall cost saving per patient was ?2013. One-way sensitivity analysis demonstrated that the ERP was cost-neutral or more costly only at extreme values of ward, operating and intensive care costs. CONCLUSION: A multidisciplinary ERP for oesophagectomy was associated with cost savings, with no increase in morbidity or mortality. PMID- 23939845 TI - Body mass index and outcomes following gastrointestinal cancer surgery in Japan. AB - BACKGROUND: Recent studies in the USA have shown a lower postoperative mortality rate in mildly obese patients, described as the 'obesity paradox'. The results from the relatively obese population in Western countries may not be generalizable to Asian countries, prompting the present study to investigate the relationship between body mass index (BMI) and outcomes after gastrointestinal surgery. METHODS: Patients who underwent gastrectomy or colorectal resection for stage I-III cancer between July and December 2010 were identified from a nationwide inpatient database in Japan. Multivariable logistic regression models for in-hospital mortality and postoperative complications, and a linear regression model for total costs were established, with adjustment for age, sex, co-morbidities, cancer stage and BMI. Restricted cubic spline functions were used to consider potential non-linear associations between BMI and the outcomes. RESULTS: Among 30 765 eligible patients, associations between BMI and the outcomes were U-shaped, with the lowest mortality, morbidity and total costs in patients with a BMI of around 23.0 kg/m(2) . A BMI of 18.5 kg/m(2) was associated with significantly greater mortality (odds ratio (OR) 2.04, 95 per cent confidence interval 1.64 to 2.55), postoperative complications (OR 1.10, 1.03 to 1.18) and total costs (difference ?1389, 1139 to 1640) compared with a BMI of 23.0 kg/m(2) . Patients with a BMI exceeding 30.0 kg/m(2) had significantly higher rates of postoperative complications and total costs than those with a BMI of 23.0 kg/m(2) , but no significant association was evident between a BMI of more than 23.0 kg/m(2) and in-hospital death. CONCLUSION: Unlike previous studies in the USA, in the present national Japanese cohort of patients undergoing surgery for gastrointestinal cancer, those who were either underweight or overweight had more postoperative complications and greater perioperative costs than those of normal weight. PMID- 23939846 TI - Outcomes following surgery for perforating Crohn's disease. AB - BACKGROUND: The most common indications for surgery for patients with ileocolic Crohn's disease are fibrostenotic or perforating disease. The objective was to compare surgical outcomes of patients with perforating versus non-perforating disease following ileocolic resection. METHODS: This was a retrospective review of all patients who had their first ileocolic resection between 1990 and 2010, identified from a prospectively maintained inflammatory bowel disease database. Demographic information, preoperative medication, intraoperative findings and postoperative outcome data were collected. Outcomes in patients who had an abscess drained before surgery or were found to have a fistula or abscess at surgery or at pathology were compared with outcomes in all others. RESULTS: A total of 434 patients (56.2 per cent women) were included, 293 with perforating and 141 with non-perforating disease. Median age, tobacco use, and preoperative steroid and biological agent use were similar in the two groups. Forty patients (13.7 per cent) in the perforating group had abscesses drained before surgery and 251 patients had at least one fistula, most commonly to the sigmoid colon. Patients with perforating disease were more likely to require preoperative total parenteral nutrition, need another resection, have an ileostomy and a longer mean postoperative stay, and less likely to undergo a laparoscopic procedure. Patients in this group also developed more postoperative abscesses or leaks (4.8 versus 0 per cent; P = 0.006). The reoperation rate was similar (3.1 versus 0.7 per cent; P = 0.178). CONCLUSION: Patients with penetrating Crohn's disease are more likely to require a more complex procedure, and an ileostomy, and to a have longer postoperative stay. PMID- 23939847 TI - Planned versus unplanned portal vein resections during pancreaticoduodenectomy for adenocarcinoma. AB - BACKGROUND: The management of portal vein (PV) involvement by pancreatic adenocarcinoma during pancreaticoduodenectomy (PD) is controversial. The aim of this study was to compare the outcomes of unplanned and planned PV resections as part of PD. METHODS: An analysis of PD over 11 years was performed. Patients who had undergone PV resection (PV-PD) were identified, and categorized into those who had undergone planned or unplanned resection. Postoperative and oncological outcomes were compared. RESULTS: Of 249 patients who underwent PD for pancreatic adenocarcinoma, 66 (26.5 per cent) had PV-PD, including 27 (41 per cent) planned and 39 (59 per cent) unplanned PV resections. Twenty-five of 27 planned PV resections were circumferential PV-PD, whereas 25 of 39 unplanned PV resections were partial PV-PD. Planned PV resections were performed in slightly younger patients (mean(s.d.) 60(9) versus 65(10) years; P = 0.031), and associated with longer operating times (mean(s.d.) 602(131) versus 458(83) min; P < 0.001) and more major complications (26 versus 5 per cent; P = 0.026). Planned PV resections were associated with a lower rate of positive margins (4 versus 44 per cent; P < 0.001) despite being carried out for larger tumours (mean(s.d.) 3.9(1.4) versus 2.9(1.0) cm; P = 0.002). There was no difference in survival between the two groups (P = 0.998). On multivariable analysis, margin status was a significant predictor of survival. CONCLUSION: Although planned PV resections for pancreatic adenocarcinoma were associated with higher rates of postoperative morbidity than unplanned resections, R0 resection rates were better. PMID- 23939848 TI - Extent and completeness of mesorectal excision evaluated by postoperative magnetic resonance imaging. AB - BACKGROUND: The major advance in rectal cancer management over the past 20 years has been the standardization of mesorectal excision. The aim of this study was to determine the prevalence and localization of inadvertent residual mesorectum detected on magnetic resonance imaging (MRI) after rectal cancer surgery. METHODS: Postoperative T2-weighted MRI of the pelvis was performed on patients following mesorectal excision. A multidisciplinary team radiologist evaluated the images with regard to residual mesorectum and distal margin. Only mesorectum above the level of the anastomosis perpendicular to the bowel was regarded as inadvertent residual mesorectum after partial mesorectal excision. Histopathological records, standardized photographs and clinical records were assessed. The pathology and MRI findings were evaluated independently in a blinded fashion. RESULTS: MRI-detected residual mesorectum was identified in 54 (39.7 per cent) of 136 patients. There was agreement with the pathology findings in 88 patients (64.7 per cent). Residual mesorectum was more frequent in patients treated with partial mesorectal excision (63 per cent) than those who had total mesorectal excision (36 per cent) or abdominoperineal resection (13 per cent) (P < 0.001). Pathology and MRI findings both showed that the distal resection margin after partial mesorectal excision was less than 5 cm in more than three-quarters of patients, and less than 3 cm in more than one-third. CONCLUSION: Inadvertent residual mesorectum was commonly found on postoperative MRI, especially after partial mesorectal excision. PMID- 23939849 TI - Outcome following laparoscopic and open total mesorectal excision for rectal cancer. AB - BACKGROUND: There are few reports on the oncological quality of resection and outcome after laparoscopic versus open total mesorectal excision (TME) for rectal cancer in everyday surgical practice. METHODS: Between January 2006 and October 2011, data for patients with mid or low rectal adenocarcinoma who underwent elective TME were recorded in the PROCARE database. A multivariable model and the propensity score as a co-variable in Cox or logistic regression models were used for adjustment of differences in patient mix and non-random assignment of surgical approach. RESULTS: Data for 2660 patients from 82 hospitals were recorded. Implementation of laparoscopic TME was highly variable. The oncological quality of resection was similar in the laparoscopic and the open group: incomplete mesorectal excision in 13.2 and 11.4 per cent respectively, circumferential resection margin positivity in 18.1 per cent, and a median of 11 lymph nodes examined per specimen in both groups. The hazard ratio for survival after laparoscopic versus open TME was 1.05 (95 per cent confidence interval 0.88 to 1.24) after correction for differences in patient mix, and 1.06 (0.89 to 1.25) after correction for the propensity score. The definitive colostomy rate was similar in the two groups: 31.0 per cent after open and 31.4 per cent after laparoscopic TME. Postoperative morbidity was lower and length of stay was shorter after laparoscopic TME compared with open TME. Survival was not negatively affected by converted laparoscopic resection, whereas postoperative morbidity, mortality and length of stay after converted laparoscopy were comparable with those after open TME. CONCLUSION: Oncological outcome is comparable after laparoscopic and open TME in everyday surgical practice. PMID- 23939850 TI - Outcome following laparoscopic and open total mesorectal excision for rectal cancer (Br J Surg 2013; 100: 1368-1375). PMID- 23939851 TI - Impact of bowel dysfunction on quality of life after sphincter-preserving resection for rectal cancer. AB - BACKGROUND: Bowel dysfunction after sphincter-preserving surgery for rectal cancer is a common complication, with the potential to affect quality of life (QoL) strongly. The aim of this study was to examine the extent of bowel dysfunction and impact on health-related QoL after curative sphincter-preserving resection for rectal cancer. METHODS: QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire, and bowel function using a validated questionnaire, including the recently developed low anterior resection syndrome (LARS) score. Assessments were carried out at the time of diagnosis, and at 3 and 12 months after surgery. RESULTS: A total of 260 patients were included in the study. At 3 months, 58.0 per cent of patients had a LARS score of 30 or more (major LARS), which declined to 45.9 per cent at 12 months (P < 0.001). The risk of major LARS was significantly increased in patients who received neoadjuvant therapy (odds ratio 2.41, 95 per cent confidence interval 1.00 to 5.83), and after total versus partial mesorectal excision (odds ratio 2.81, 1.35 to 5.88). Global health status was closely associated with LARS, and significant differences in global health status, functional and symptom scales of QoL were found between patients without LARS and those with major LARS. CONCLUSION: Bowel dysfunction is a major problem with an immense impact on QoL following sphincter-preserving resection. The risk of major LARS was significantly increased after neoadjuvant therapy and total mesorectal excision. PMID- 23939852 TI - Contribution of surgical specialization to improved colorectal cancer survival. AB - BACKGROUND: Reorganization of colorectal cancer services has led to surgery being increasingly, but not exclusively, delivered by specialist surgeons. Outcomes from colorectal cancer surgery have improved, but the exact determinants remain unclear. This study explored the determinants of outcome after colorectal cancer surgery over time. METHODS: Postoperative mortality (within 30 days of surgery) and 5-year relative survival rates for patients in the West of Scotland undergoing surgery for colorectal cancer between 1991 and 1994 were compared with rates for those having surgery between 2001 and 2004. RESULTS: The 1823 patients who had surgery in 2001-2004 were more likely to have had stage I or III tumours, and to have undergone surgery with curative intent than the 1715 patients operated on in 1991-1994. The proportion of patients presenting electively who received surgery by a specialist surgeon increased over time (from 14.9 to 72.8 per cent; P < 0.001). Postoperative mortality increased among patients treated by non-specialists over time (from 7.4 to 10.3 per cent; P = 0.026). Non-specialist surgery was associated with an increased risk of postoperative death (adjusted odds ratio 1.72, 95 per cent confidence interval (c.i.) 1.17 to 2.55; P = 0.006) compared with specialist surgery. The 5-year relative survival rate increased over time and was higher among those treated by specialist compared with non specialist surgeons (62.1 versus 53.0 per cent; P < 0.001). Compared with the earlier period, the adjusted relative excess risk ratio for the later period was 0.69 (95 per cent c.i. 0.61 to 0.79; P < 0.001). Increased surgical specialization accounted for 18.9 per cent of the observed survival improvement. CONCLUSION: Increased surgical specialization contributed significantly to the observed improvement in longer-term survival following colorectal cancer surgery. PMID- 23939853 TI - Author's reply: the effect of sacral nerve stimulation on distal colonic motility in patients with faecal incontinence (Br J Surg 2013; 100: 959-968). PMID- 23939854 TI - The effect of sacral nerve stimulation on distal colonic motility in patients with faecal incontinence (Br J Surg 2013; 100: 959-968). PMID- 23939855 TI - Authors' reply: systematic review and meta-analysis of the early and late outcomes of open and endovascular repair of abdominal aortic aneurysm (Br J Surg 2013; 100: 863-872). PMID- 23939856 TI - Systematic review and meta-analysis of the early and late outcomes of open and endovascular repair of abdominal aortic aneurysm (Br J Surg 2013; 100: 863-872). PMID- 23939857 TI - Authors' reply: systematic review and meta-analysis of intraoperative peritoneal lavage for colorectal cancer staging (Br J Surg 2013; 100: 853-862). PMID- 23939858 TI - Systematic review and meta-analysis of intraoperative peritoneal lavage for colorectal cancer staging (Br J Surg 2013; 100: 853-862). PMID- 23939859 TI - Causes of false-negative sentinel node biopsy in patients with breast cancer (Br J Surg 2013; 100: 775-783). PMID- 23939860 TI - Authors' reply: causes of false-negative sentinel node biopsy in patients with breast cancer (Br J Surg 2013; 100: 775-783). PMID- 23939862 TI - Ligand-induced conformational changes of the multidrug resistance transporter EmrE probed by oriented solid-state NMR spectroscopy. PMID- 23939863 TI - Distribution of pyrethroid insecticides in secondary wastewater effluent. AB - Although the freely dissolved form of hydrophobic organic chemicals may best predict aquatic toxicity, differentiating between dissolved and particle-bound forms is challenging at environmentally relevant concentrations for compounds with low toxicity thresholds such as pyrethroid insecticides. The authors investigated the distribution of pyrethroids among 3 forms: freely dissolved, complexed with dissolved organic carbon, and sorbed to suspended particulate matter, during a yearlong study at a secondary wastewater treatment plant. Effluent was fractionated by laboratory centrifugation to determine whether sorption was driven by particle size. Linear distribution coefficients were estimated for pyrethroid sorption to suspended particulate matter (K(id)) and dissolved organic carbon (K(idoc)) at environmentally relevant pyrethroid concentrations. Resulting K(id) values were higher than those reported for other environmental solids, and variation between sampling events correlated well with available particle surface area. Fractionation results suggest that no more than 40% of the pyrethroid remaining in secondary effluent could be removed by extending settling periods. Less than 6% of the total pyrethroid load in wastewater effluent was present in the dissolved form across all sampling events and chemicals. PMID- 23939864 TI - Artd1/Parp1 regulates reprogramming by transcriptional regulation of Fgf4 via Sox2 ADP-ribosylation. AB - The recently established reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by Takahashi and Yamanaka represents a valuable tool for future therapeutic applications. To date, the mechanisms underlying this process are still largely unknown. In particular, the mechanisms how the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc) directly drive reprogramming and which additional components are involved are still not yet understood. In this study, we aimed at analyzing the role of ADP-ribosyltransferase diphtheria toxin-like one (Artd1; formerly called poly(ADP-ribose) polymerase 1 [Parp1]) during reprogramming. We found that poly(ADP-ribosylation) (PARylation) of the reprogramming factor Sox2 by Artd1 plays an important role during the first days upon transduction with the reprogramming factors. A process that happens before Artd1 in conjunction with 10 11 translocation-2 (Tet2) mediates the histone modifications necessary for the establishment of an activated chromatin state at pluripotency loci (e.g., Nanog and Essrb) [Nature 2012;488:652-655]. Wild-type (WT) fibroblasts treated with an Artd1 inhibitor as well as fibroblasts deficient for Artd1 (Artd1-/-) show strongly decreased reprogramming capacity. Our data indicate that Artd1-mediated PARylation of Sox2 favors its binding to the fibroblast growth factor 4 (Fgf4) enhancer, thereby activating Fgf4 expression. The importance of Fgf4 during the first 4 days upon initiation of reprogramming was also highlighted by the observation that exogenous addition of Fgf4 was sufficient to restore the reprogramming capacity of Artd1-/- fibroblast to WT levels. In conclusion, our data clearly show that the interaction between Artd1 and Sox2 is crucial for the first steps of the reprogramming process and that early expression of Fgf4 (day 2 to day 4) is an essential component for the successful generation of iPSCs. PMID- 23939866 TI - Simultaneous determination of chlordiazepoxide and selected antidepressants using CZE. AB - A simple CE method was developed and validated for the simultaneous determination of chlordiazepoxide (CHL), amitriptyline, and nortriptyline (mixture I) or the determination of CHL and imipramine (mixture II) using the same BGE. Sertraline and amitriptyline were used as internal standards for the first and second mixtures, respectively. The method allows amitriptyline to be completely separated from its impurity and main metabolite nortriptyline, which can be quantified from 0.2 MUg/mL. The separation was achieved using 20 mM potassium phosphate buffer pH 5 containing 12 mM beta-cyclodextrin and 1 mM carboxymethyl beta-cyclodextrin. UV detection was performed at 200 nm and a voltage of 15 kV was applied on an uncoated fused-silica capillary at 25 degrees C. These experimental conditions allowed separation of the compounds to be obtained in 7 min. Calibration graphs proved the linearity up to 40 MUg/mL for CHL, up to 100 MUg/mL for amitriptyline and imipramine, and up to 5 MUg/mL for nortriptyline. The accuracy and precision of the method have been determined by analyzing synthetic mixtures and pharmaceutical formulations. The analytical results were quite good in all cases indicating that the method was linear, sensitive, precise, accurate, and selective for both mixtures. PMID- 23939867 TI - Local anesthesia and pain perception during amniocentesis: a randomized double blind placebo-controlled trial. AB - OBJECTIVE: To determine the effect of local anesthesia on the maternal pain perception from amniocentesis. METHODS: We conducted a randomized double blind placebo controlled trial comparing use of local anesthesia (1% lidocaine) with placebo with regards to maternal perception of pain among women undergoing genetic amniocentesis. The primary outcome was the intensity of perceived maternal pain as measured by the Visual Analogue Scale (VAS) as well a 101 point Numerical Rating Scale. RESULTS: Seventy six women participated in the trial. 36 (47.4%) women were randomized to lidocaine, whereas 40 (52.6%) were randomized to placebo. There were no statistically significant differences between the groups in terms of baseline sociodemographic and clinical characteristics. However, pain perception as characterized by the median 9.5 (2.1-21.0) VSA scores was significantly lower among women in the lidocaine group compared with among women in the placebo group [18.4 (12.9-31.3), P = 0.005]. Similarly the mean VSA scores was significantly lower in the lidocaine group (P = 0.02). A trend toward lower scores was also observed when maternal pain perception was measured by the Numerical Rating Scale. CONCLUSION: Local anesthetic lidocaine significantly lowers maternal perceived pain during genetic amniocentesis. PMID- 23939868 TI - Fine-needle aspirations of pancreatic serous cystadenomas: improving diagnostic yield with cell blocks and alpha-inhibin immunohistochemistry. AB - BACKGROUND: The diagnosis of serous cystadenoma (SCA), a rare benign pancreatic neoplasm, can alter the management of patients with pancreatic masses. Although characteristic imaging findings and fluid chemical analysis have been described, SCAs are not always recognized preoperatively. Furthermore, scant cellular yield on fine-needle aspiration (FNA) often leads to a nondiagnostic or nonspecific benign diagnosis. alpha-Inhibin (AI), a sensitive marker for SCA, is infrequently required for diagnosis in surgical specimens due to their characteristic histologic appearance. The objective of the current study was to determine whether AI staining can improve SCA diagnosis on FNA specimens. METHODS: Fifteen confirmed cases of SCA with prior FNA specimens were selected for this study. FNAs were evaluated for cellularity, cellular arrangement, and cytomorphology. Resection specimens were reviewed. RESULTS: Of the 15 FNA cases, approximately 75% demonstrated scant cellularity (11 of 15 cases). On smears, the cells were arranged as flat sheets, corresponding to strips of cells on cell block sections. The cells were small and round to cuboidal, with clear cytoplasm; occasional plasmacytoid cells and oncocytic cells were identified. Flattened cells, corresponding to attenuated epithelial cells lining macrocysts on the resections, were also noted. Stromal fragments were present in 5 FNAs and correlated with the hyalinized stroma in the resection specimens. AI immunostaining was positive in 88% of cases (7 of 8 of cases), thereby supporting the diagnosis of SCA. CONCLUSIONS: The results of the current study indicate that low cellularity and bland cytology are inherent to SCAs. Performing cell blocks and AI staining on FNA specimens is useful for establishing the diagnosis of SCA. An immunohistochemical panel including AI, chromogranin, and synaptophysin may enhance the diagnostic accuracy of pancreatic FNA specimens. PMID- 23939869 TI - Cooperative use of VCD and XRD for the determination of tetrahydrobenzoisoquinolines absolute configuration: a reliable proof of memory of chirality and retention of configuration in enediyne rearrangements. AB - The absolute configurations (AC) of azaheterocylic compounds resulting from the cascade rearrangement of enediynes involving only light atoms were unambiguously assigned by the joint use of vibrational circular dichroism (VCD) and copper radiation single crystal X-ray diffraction (XRD). These AC determinations proved that the rearrangements of enediynes proceeded with memory of chirality and retention of configuration. PMID- 23939870 TI - Tuning anion-functionalized ionic liquids for improved SO2 capture. AB - You can have your cake and eat it too: A "dual-tuning" strategy for improving the capture of SO2 was developed by introducing electron-withdrawing sites on the anions to produce several kinds of functionalized ionic liquids. Those functionalized with a halogen group exhibited improved performance over their non halogenated counterparts, leading to highly efficient and reversible capture. PMID- 23939872 TI - Autistic traits modulate mimicry of social but not nonsocial rewards. AB - Autism Spectrum Conditions (ASC) are associated with diminished responsiveness to social stimuli, and especially to social rewards such as smiles. Atypical responsiveness to social rewards, which reinforce socially appropriate behavior in children, can potentially lead to a cascade of deficits in social behavior. Individuals with ASC often show diminished spontaneous mimicry of social stimuli in a natural setting. In the general population, mimicry is modulated both by the reward value and the sociality of the stimulus (i.e., whether the stimulus is perceived to belong to a conspecific or an inanimate object). Since empathy and autistic traits are distributed continuously in the general population, this study aimed to test if and how these traits modulated automatic mimicry of rewarded social and nonsocial stimuli. High and low rewards were associated with human and robot hands using a conditioned learning paradigm. Thirty-six participants from the general population then completed a mimicry task involving performing a prespecified hand movement which was either compatible or incompatible with a hand movement presented to the participant. High autistic traits (measured using the Autism Spectrum Quotient, AQ) predicted lesser mimicry of high-reward than low-reward conditioned human hands, whereas trait empathy showed an opposite pattern of correlations. No such relations were observed for high-reward vs. low-reward conditioned robot hands. These results demonstrate how autistic traits and empathy modulate the effects of reward on mimicry of social compared to nonsocial stimuli. This evidence suggests a potential role for the reward system in underlying the atypical social behavior in individuals with ASC, who constitute the extreme end of the spectrum of autistic traits. PMID- 23939871 TI - Hippocampal correlates of depression in healthy elderly adults. AB - Mixed findings have been reported on the relationship between hippocampal integrity and major depression in clinical populations. Few neuroimaging studies have investigated associations between hippocampal measures and depressive symptoms in nondemented older adults. Here, we address this issue by imaging 36 nondemented adults over age 70 from the Einstein Aging Study, a community-based sample from the Bronx, NY. Depressive symptoms were assessed using the 15-item Geriatric Depression scale (GDS). Clinically significant depression was defined using a cut-off score of 5 or greater. Hippocampal data included MRI-derived volume data normalized to midsagittal area and MRS-derived N-acetylaspartate to creatine ratios (NAA/Cr). Our result indicates that smaller total hippocampal volume was associated with higher GDS scores, but there were no significant association between hippocampal NAA/Cr and GDS score. These effects were consistent after controlling for age, education, and gender. Reduction in hippocampal volume could represent a risk factor or a consequence of depression in older adults. Further studies are needed to better understand the role of the hippocampus in the development and experience of depression in older adults. PMID- 23939873 TI - Dietary bioavailability of cadmium presented to the gastropod Peringia ulvae as quantum dots and in ionic form. AB - For quantum dots (QDs) synthesized in solvents that are immiscible in water, dietary, rather than aqueous, exposure is expected to be the primary route of uptake. The estuarine snail Peringia ulvae was presented with mats of simulated detritus spiked with oleic acid capped cadmium sulfide (CdS; 3.1 +/- 0.4 nm) or cadmium selenide (CdSe; 4.2 +/- 0.8 nm) nanoparticles, synthesized using a microfluidics method, or Cd(2+) (added as Cd[NO3 ]2 ) as a control. A biodynamic modeling approach was used to quantify parameters that describe the dietary accumulation of the Cd forms. Ingestion rates decreased across treatments at higher exposure concentrations, indicating a metal-induced stress response related to Cd dose rather than form. Although Cd was bioavailable from both CdS and CdSe QDs, uptake rate constants from diet were significantly lower than that of Cd(2+) (p < 0.05). After 72 h depuration, however, no loss of Cd was observed from snails that had accumulated Cd from either type of QD. In comparison, snails ingesting Cd(2+) -spiked detritus eliminated 39% of their accumulated body burden per day. The almost identical uptake and efflux rates for Cd in both QDs suggest no effect of the chalcogenide conjugates (S or Se). The findings of the present study indicate that the availability of Cd in the form of nanoparticles and its apparent in vivo persistence will lead to bioaccumulation. The implications of this are discussed. PMID- 23939874 TI - A general palladium-catalyzed carbonylative synthesis of chromenones from salicylic aldehydes and benzyl chlorides. AB - Cute CO! An interesting and straightforward procedure for the carbonylative synthesis of chromenones from readily available salicylic aldehydes and benzyl chlorides has been developed (see scheme; DPPP = 1,3 bis(diphenylphosphino)propane). In the presence of a palladium catalyst, various coumarins were produced in good to excellent yields. PMID- 23939875 TI - Superposition, entanglement, and raising Schrodinger's cat (Nobel Lecture). PMID- 23939876 TI - Multiplug filtration clean-up with multiwalled carbon nanotubes in the analysis of pesticide residues using LC-ESI-MS/MS. AB - A novel design for a rapid clean-up method was developed for the analysis of pesticide residues in fruit and vegetables followed by LC-ESI-MS/MS. The acetonitrile-based sample extraction technique was used to obtain the extracts, and further clean-up was carried out by applying the streamlined procedure on a multiplug filtration clean-up column coupled with a syringe. The sorbent used for clean-up in this research is multiwalled carbon nanotubes, which was mixed with anhydrous magnesium sulfate to remove water from the extracts. This method was validated on 40 representative pesticides and apple, cabbage, and potato sample matrices spiked at two concentration levels of 10 and 100 MUg/kg. It exhibited recoveries between 71 and 117% for most pesticides with RSDs < 15%. Matrix matched calibrations were performed with the coefficients of determination >0.995 for most studied pesticides between concentration levels of 10-500 MUg/L. The LOQs for 40 pesticides ranged from 2 to 50 MUg/kg. The developed method was successfully applied to the determination of pesticide residues in market fruit and vegetable samples. PMID- 23939877 TI - Impact of carbon ion radiotherapy for primary spinal sarcoma. AB - BACKGROUND: Spinal sarcomas have been one of the most challenging diseases for orthopedic surgeons. The objective of this study was to retrospectively analyze carbon ion radiotherapy (CIRT) treatment results for spinal sarcoma. METHODS: Forty-seven patients with 48 medically unresectable spinal sarcomas, excluding sacral tumors, received treatment with CIRT between 1996 and 2011. All patients were enrolled in phase 1/2 and phase 2 clinical trials of CIRT for bone and soft tissue sarcoma. The applied dose ranged from 52.8 gray equivalents (GyE) to 70.4 GyE (median, 64.0 GyE) in 16 fixed fractions over 4 weeks. RESULTS: The median patient age was 54 years, and the cohort included 24 men and 23 women. Thirty five patients were without prior treatment, and 12 patients had locally recurrent tumors after previous resection. The median follow-up was 25 months, and the median survival was 44 months (range, 5.2-148 months). The 5-year local control, overall survival, and progression free rates were 79%, 52%, and 48%, respectively. None of the 15 patients who had tumors measuring <100 cm(3) had a local recurrence. No fatal toxicities occurred during follow-up. One patient each had a grade 3 late skin reaction and a grade 4 late skin reaction. Vertebral body compression was observed in 7 patients. One patient had a grade 3 late spinal cord reaction. Twenty-two of the surviving 28 patients who had primary tumors remained ambulatory without supportive devices. CONCLUSIONS: CIRT appears to be both effective and safe for the treatment of patients with unresectable spinal sarcoma. PMID- 23939878 TI - Outcome and etiologies of fetal megacystis according to the gestational age at diagnosis. AB - OBJECTIVE: To investigate the gestational age-specific outcomes and the different etiologies of megacystis diagnosed at screening ultrasound. METHODS: A retrospective single-center study was conducted between 1989 and 2009. We identified all consecutive cases of megacystis prenatally diagnosed during routine ultrasound screening. Outcome, final diagnosis, and renal function were recorded. RESULTS: Eighty-four patients were included. An isolated lower urinary tract obstruction was observed in 38/84 (45.2%), ureterovesical reflux in 9/84 (10.7%), an associated congenital abnormality in 32/84 (38.1%) and a normal bladder in 5/84 (6%). Increased gestational age at diagnosis was correlated with an increased rate of live born children (P < 0.01). No cases of megacystis diagnosed in the first trimester were born alive. When diagnosis of posterior urethral valves (PUV) was made in the third trimester, the ultimate survival rate was 11/13 (84.6%) compared with 3/12 (25%) for a diagnosis made in the second trimester (P = 0.02). CONCLUSION: Lower urinary tract obstruction is the main etiology of megacystis. Megacystis can also be part of more complex malformations. Outcome of megacystis detected in the first trimester is poor. PUV detected in the third trimester had a better overall survival rate than PUV detected in the second trimester. PMID- 23939879 TI - Transplants of adult mesenchymal and neural stem cells provide neuroprotection and behavioral sparing in a transgenic rat model of Huntington's disease. AB - Stem cells have gained significant interest as a potential treatment of neurodegenerative diseases, including Huntington's disease (HD). One source of these cells is adult neural stem cells (aNSCs), which differentiate easily into neuronal lineages. However, these cells are vulnerable to immune responses following transplantation. Another source is bone-marrow-derived mesenchymal stem cells (MSCs), which release neurotrophic factors and anti-inflammatory cytokines following transplantation, and are less vulnerable to rejection. The goal of this study was to compare the efficacy of transplants of MSCs, aNSCs, or cotransplants of MSCs and aNSCs for reducing deficits in a transgenic rat model of HD. HD rats received intrastriatal transplantations of 400,000 MSCs, aNSCs, or a combination of MSCs/aNSCs, while wild-type and HD controls were given vehicle. Rats were tested on the rotarod over the course of 20 weeks. The results indicated that transplants of: (a) aNSCs produced a strong immune response and conferred short term behavioral benefits; (b) MSCs elicited a relatively weak immune response, and provided a longer term behavioral benefit; and (c) combined MSCs and aNSCs conferred long-term behavioral benefits and increased survival of the transplanted aNSCs. The finding that cotransplanting MSCs with aNSCs can prolong aNSC survival and provide greater behavioral sparing than when the transplants contains only aNSCs suggests that MSCs are capable of creating a more suitable microenvironment for aNSC survival. This cotransplantation strategy may be useful as a future therapeutic option for treating HD, especially if long-term survival of differentiated cells proves to be critically important for preserving lasting functional outcomes. PMID- 23939880 TI - Solubility profiling of HIV protease inhibitors in human intestinal fluids. AB - The present study pursued to profile the intestinal solubility of nine HIV protease inhibitors (PIs) in fasted- and fed-state human intestinal fluids (FaHIF, FeHIF) aspirated from four volunteers. In addition, the ability of fasted and fed-state simulated intestinal fluids (FaSSIF, FeSSIF) to predict the intestinal solubility was evaluated. All PIs were poorly soluble in FaHIF (from 7 MUM for ritonavir to 327 MUM for darunavir) and FeHIF (from 15 MUM for atazanavir to 409MUM for darunavir). For four of nine PIs, food intake significantly enhanced the solubilizing capacity of intestinal fluids (up to 18.4-fold increase for ritonavir). The intersubject variability (average coefficient of variance CVfed = 60.6%, CVfasted = 40.4%) was higher as compared with the intrasubject variability (CVfed = 41.3%, CVfasted = 20.5%). PI solubilities correlated reasonably well between FaSSIF and FaHIF (R = 0.817), but not between FeSSIF and FeHIF (R = 0.617). To conclude, postprandial conditions increased the inter- and intrasubject variability of the PIs. The inability of FeSSIF to accurately predict the FeHIF solubility emphasizes the need for a multivariate approach to determine solubility profiles, taking into account solid-state characteristics, pH, mixed bile acid/phospholipid micelles, and digestive products. PMID- 23939881 TI - Enantioselective toxic effects and degradation of myclobutanil enantiomers in Scenedesmus obliquus. AB - Research on the enantioselective environmental behavior of chiral pesticides has been a hot spot of environmental chemistry recently. In this study, the acute toxicity of myclobutanil enantiomers was investigated with the aquatic algae Scendesmus obliquus. After exposure for 96 h, the EC50 values for (-) myclobutanil, rac-myclobutanil and (+)-myclobutanil were 3.951, 2.760, and 2.128 mg/L, respectively. The photosynthetic pigment (chlorophyll a, chlorophyll b, and carotenoids) and antioxidant enzyme activities catalase (CAT) were determined to evaluate the different toxic effects when S. obliquus were exposed to 1.5, 5 and 15 mg/L of rac-myclobutanil, (-)-myclobutanil, and (+)-myclobutanil for 96 h, respectively. In addition, the degradation of myclobutanil enantiomers in S. obliquus was also studied. Myclobutanil in the medium inoculated with algae degraded faster than in the uninoculated medium. The degradation of (-) myclobutanil was faster than that of (+)-myclobutanil at a concentration of 3 mg/L. On the basis of these data, the acute toxicity and toxic effects of myclobutanil against S. obliquus were concluded to be enantioselective, and such enantiomeric differences should be taken into consideration in pesticide risk assessment. PMID- 23939882 TI - Effect of low concentration 17beta-estradiol on the emissions of CH4 and CO2 in anaerobic sediments. AB - The estrogen17beta-estradiol (E2) is one of the most widely distributed natural estrogens and is the most potent estrogen in the environment. For the present study, methanogenic bacteria communities were chosen as study objects to analyze the effects of E2 on the production of methane and carbon dioxide. Microecological systems in anaerobic pore water were constructed in the laboratory. The results show that E2 played an enhancing role in methanogenic activity when the concentrations were <=0.5 ng/L. The enhancement was the strongest at 0.3 ng/L. However, when the E2 concentration exceeded 1.0 ng/L, it inhibited the methanogenic activities of bacteria. The inhibition effect persisted for up to 264 h, beyond which the trend became unclear. On the other hand, E2 has an inhibition effect on CO2 production in anaerobic sediments, which indicates that E2 had a significant inhibition effect on microbial activities under anaerobic conditions. Based on these experiments, the authors believe that E2 in anaerobic sediments can affect sediment microbial activities and therefore influence the self-purification of water bodies and methane ebullition. PMID- 23939883 TI - F3/Contactin promotes hippocampal neurogenesis, synaptic plasticity, and memory in adult mice. AB - F3/contactin, a cell-adhesion molecule belonging to the immunoglobulin supergene family, is involved in several aspects of neural development including synapse building, maintenance and functioning. Here, we examine F3/contactin function in adult hippocampal neurogenesis, synaptic plasticity, and memory, using as a model TAG/F3 transgenic mice, where F3/contactin overexpression was induced under control of regulatory sequences from the human TAG-1 (TAX-1) gene. Transgenic mice aged 5 (M5) and 12 (M12) months exhibited an increase in hippocampal size, which correlated with positive effects on precursor proliferation and NeuN expression, these data suggesting a possible role for F3/contactin in promoting adult hippocampal neurogenesis. On the functional level, TAG/F3 mice exhibited increased CA1 long-term potentiation and improved spatial and object recognition memory, notably at 12 months of age. Interestingly, these mice showed an increased expression of the phosphorylated transcription factor CREB, which may represent the main molecular correlate of the observed morphological and functional effects. Altogether, these findings indicate for the first time that F3/contactin plays a role in promoting adult hippocampal neurogenesis and that this effect correlates with improved synaptic function and memory. PMID- 23939884 TI - Detection of individual vapors and their mixtures using a selectivity-tunable three-dimensional network of plasmonic nanoparticles. PMID- 23939885 TI - Ultrasmall metal nanoclusters for bio-related applications. AB - The study of ultrasmall metal nanoclusters (NCs, ranging from subnanometer to ca 2 nm) is evidently a quickly evolving field in current nanoscience and nanotechnology research. Metal NCs, typically composed of several to hundreds of metal atoms, have attracted great interest in recent years owing to their unique properties including ultrasmall size and enhanced photoluminescence, together with other properties such as excellent photostability, low toxicity, and good biocompatibility desired for biological applications. This review summarizes recent advances in the field of bio-related applications of metal NCs materials. We highlight the applications of metal NCs for biosensor development, fluorescent biological imaging, and biomedical research, and finally discuss briefly some current challenges and future work. PMID- 23939886 TI - Multilocus sequence typing reveals genetic diversity of carbapenem- or ceftazidime-nonsusceptible Pseudomonas aeruginosa in China. AB - It is unclear whether the genetic background of drug-resistant Pseudomonas aeruginosa was disseminated from a certain clone. Thus, we performed MLST (multilocus sequence typing) of 896 P. aeruginosa isolates that were nonsusceptible to imipenem, meropenem, or ceftazidime. This revealed 254 sequence types (STs), including 104 new STs and 34 STs with novel alleles. Thirty-three clonal complexes and 404 singletons were found. In conclusion, drug-resistant P. aeruginosa clones can be developed from diverse genetic backgrounds. PMID- 23939887 TI - Nontoxigenic Clostridium difficile protects hamsters against challenge with historic and epidemic strains of toxigenic BI/NAP1/027 C. difficile. AB - Nontoxigenic Clostridium difficile (NTCD) has been shown to prevent fatal C. difficile infection in the hamster model when hamsters are challenged with standard toxigenic C. difficile strains. The purpose of this study was to determine if NTCD can prevent C. difficile infection in the hamster model when hamsters are challenged with restriction endonuclease analysis group BI C. difficile strains. Groups of 10 hamsters were given oral clindamycin, followed on day 2 by 10(6) CFU of spores of NTCD strain M3 or T7, and were challenged on day 5 with 100 CFU of spores of BI1 or BI6. To conserve animals, results for control hamsters challenged with BI1 or BI6 from the present study and controls from previous identical experiments were combined for statistical comparisons. NTCD strains M3 and T7 achieved 100% colonization and were 100% protective against challenge with BI1 (P <= 0.001). M3 colonized 9/10 hamsters and protected against BI6 challenge in the colonized hamsters (P = 0.0003). T7 colonized 10/10 hamsters, but following BI6 challenge, cocolonization occurred in 5 hamsters, 4 of which died, for protection of 6/10 animals (P = 0.02). NTCD colonization provides protection against challenge with toxigenic BI group strains. M3 is more effective than T7 in preventing C. difficile infection caused by the BI6 epidemic strain. Prevention of C. difficile infection caused by the epidemic BI6 strain may be more challenging than that of infections caused by historic BI1 and non-BI C. difficile strains. PMID- 23939889 TI - In vitro activity of fosfomycin against a collection of clinical Pseudomonas aeruginosa isolates from 16 Spanish hospitals: establishing the validity of standard broth microdilution as susceptibility testing method. AB - The broth microdilution method for fosfomycin and Pseudomonas aeruginosa was assessed and compared with the approved agar dilution method in 206 genetically unrelated P. aeruginosa clinical isolates. Essential agreement between the two methods was 84%, and categorical agreement was 89.3%. Additionally, Etest and disk diffusion assays were performed. Results validate broth microdilution as a reliable susceptibility testing method for fosfomycin against P. aeruginosa. Conversely, unacceptable concordance was established between Etest and disk diffusion results with agar dilution results. PMID- 23939888 TI - Mutations of the ompK36 porin gene and promoter impact responses of sequence type 258, KPC-2-producing Klebsiella pneumoniae strains to doripenem and doripenem colistin. AB - Doripenem-colistin exerts synergy against some, but not all, Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains in vitro. We determined if doripenem MICs and/or ompK36 porin gene mutations impacted the responses of 23 sequence type 258 (ST258), KPC-2-producing strains to the combination of doripenem (8 MUg/ml) and colistin (2 MUg/ml) during time-kill assays. The median doripenem and colistin MICs were 32 and 4 MUg/ml. Doripenem MICs did not correlate with KPC-2 expression levels. Five and 18 strains had wild type and mutant ompK36, respectively. The most common mutations were IS5 promoter insertions (n = 7) and insertions encoding glycine and aspartic acid at amino acid (aa) positions 134 and 135 (ins aa134-135 GD; n = 8), which were associated with higher doripenem MICs than other mutations or wild-type ompK36 (all P values <= 0.04). Bactericidal activity (24 h) was achieved by doripenem-colistin against 12%, 43%, and 75% of ins aa134-135 GD, IS5, and wild-type/other mutants, respectively (P = 0.04). Doripenem-colistin was more active in time-kill studies than colistin at 12 and 24 h if the doripenem MIC was <=8 MUg/ml (P = 0.0007 and 0.09, respectively), but not if the MIC was >8 MUg/ml (P = 0.10 and 0.16). Likewise, doripenem-colistin was more active at 12 and 24 h against the wild type/other mutants than ins aa134-135 GD or IS5 mutants (P = 0.007 and 0.0007). By multivariate analysis, the absence of ins aa134-135 GD or IS5 mutations was the only independent predictor of doripenem-colistin responses at 24 h (P = 0.002). In conclusion, ompK36 genotypes identified ST258 KPC-K. pneumoniae strains that were most likely to respond to doripenem-colistin. PMID- 23939890 TI - Antimicrobial resistance and molecular typing of Neisseria gonorrhoeae isolates in Kyoto and Osaka, Japan, 2010 to 2012: intensified surveillance after identification of the first strain (H041) with high-level ceftriaxone resistance. AB - In 2009, the first high-level ceftriaxone-resistant Neisseria gonorrhoeae strain (H041) was isolated in Kyoto, Japan. The present study describes an intensified surveillance (antimicrobial resistance and molecular typing) of Neisseria gonorrhoeae isolates in Kyoto and its neighboring prefecture Osaka, Japan, in 2010 to 2012, which was initiated after the identification of H041. From April 2010 to March 2012, 193 N. gonorrhoeae isolates were collected and the MICs (MUg/ml) to six antimicrobials, including ceftriaxone, were determined. All isolates showed susceptibility to ceftriaxone and cefixime (MIC values, <0.5 MUg/ml), and spectinomycin. The rates of resistance (intermediate susceptibility) to azithromycin, penicillin G, and ciprofloxacin were 3.6% (19.7%), 24.4% (71.0%), and 78.2% (0.5%), respectively. Multilocus sequence typing (MLST) showed that 40.9%, 19.2%, and 17.1% of isolates belonged to ST1901, ST7359, and ST7363, respectively. Furthermore, N. gonorrhoeae multiantigen sequence typing (NG-MAST) revealed that 12 (63%) of the 19 isolates with decreased susceptibility to ceftriaxone (MIC > 0.064 MUg/ml) were of ST1407. NG-MAST ST1407 was also the most prevalent ST (16.1%; 31 of 193 isolates). In those NG-MAST ST1407 strains, several mosaic type penA alleles were found, including SF-A type (penicillin binding protein 2 allele XXXIV) and its derivatives. These were confirmed using transformation of the penA mosaic alleles as critical determinants for enhanced cefixime and ceftriaxone MICs. The intensified surveillance in Kyoto and Osaka, Japan, did not identify any dissemination of the high-level ceftriaxone-resistant N. gonorrhoeae strain H041, suggesting that H041 might have caused only a sporadic case and has not spread further. PMID- 23939891 TI - Transduction of staphylococcal cassette chromosome mec elements between strains of Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a well-known public health concern. However, the means by which methicillin resistance genes are transferred among staphylococci in nature remains unknown. Older scientific literature suggests transduction as a means of mecA transfer, but the optimal conditions are reported to require plasmids and potentially a lysogenic phage. These reports preceded discovery of the staphylococcal cassette chromosome mec (SCCmec) elements. We undertook studies to confirm and clarify the conditions promoting transduction of SCCmec in S. aureus populations using well-characterized donor and recipient strains primarily of the USA300 lineage. Both bacteriophages 80alpha and 29 were capable of transducing SCCmec type IV and SCCmec type I to recipient strains of S. aureus. Pulsed-field gel electrophoresis and mec associated dru typing were used to confirm the identity of the transductants. Transfer of mecA via transduction occurred at low frequency and required extended selection times for mecA gene expression and the presence of a penicillinase plasmid in the recipient. However, interference with the process by clavulanic acid and the necessity of lysogeny with 11 in the recipient or the presence of a small (4-kb) tetracycline resistance plasmid, as previously reported, were not confirmed. SCCmec transduction was occasionally associated with substantial deletions or truncation of SCCmec and the arginine catabolic metabolic element in USA300 recipients. Overall, these data clarify the conditions required for SCCmec transduction and document that rearrangements may occur during the process. PMID- 23939893 TI - Microcalorimetry assay for rapid detection of voriconazole resistance in Aspergillus fumigatus. AB - We describe a calorimetric assay for detection of voriconazole-resistant Aspergillus fumigatus within 8 h. Among 27 genetically distinct strains, all 21 resistant and all 6 susceptible strains were correctly identified by measurement of fungal heat production in the presence of voriconazole. This proof-of-concept study demonstrates the potential of microcalorimetry for rapid detection of azole resistance in A. fumigatus. PMID- 23939892 TI - Spread of carbapenem-resistant Acinetobacter baumannii global clone 2 in Asia and AbaR-type resistance islands. AB - In this surveillance study, we identified the genotypes, carbapenem resistance determinants, and structural variations of AbaR-type resistance islands among carbapenem-resistant Acinetobacter baumannii (CRAB) isolates from nine Asian locales. Clonal complex 92 (CC92), corresponding to global clone 2 (GC2), was the most prevalent in most Asian locales (83/108 isolates; 76.9%). CC108, or GC1, was a predominant clone in India. OXA-23 oxacillinase was detected in CRAB isolates from most Asian locales except Taiwan. blaOXA-24 was found in CRAB isolates from Taiwan. AbaR4-type resistance islands, which were divided into six subtypes, were identified in most CRAB isolates investigated. Five isolates from India, Malaysia, Singapore, and Hong Kong contained AbaR3-type resistance islands. Of these, three isolates harbored both AbaR3- and AbaR4-type resistance islands simultaneously. In this study, GC2 was revealed as a prevalent clone in most Asian locales, with the AbaR4-type resistance island predominant, with diverse variants. The significance of this study lies in identifying the spread of global clones of carbapenem-resistant A. baumannii in Asia. PMID- 23939894 TI - Contribution of efflux pumps, porins, and beta-lactamases to multidrug resistance in clinical isolates of Acinetobacter baumannii. AB - We investigated the mechanisms of resistance to carbapenems, aminoglycosides, glycylcyclines, tetracyclines, and quinolones in 90 multiresistant clinical strains of Acinetobacter baumannii isolated from two genetically unrelated A. baumannii clones: clone PFGE-ROC-1 (53 strains producing the OXA-58 beta lactamase enzyme and 18 strains with the OXA-24 beta-lactamase) and clone PFGE HUI-1 (19 strains susceptible to carbapenems). We used real-time reverse transcriptase PCR to correlate antimicrobial resistance (MICs) with expression of genes encoding chromosomal beta-lactamases (AmpC and OXA-51), porins (OmpA, CarO, Omp33, Dcap-like, OprB, Omp25, OprC, OprD, and OmpW), and proteins integral to six efflux systems (AdeABC, AdeIJK, AdeFGH, CraA, AbeM, and AmvA). Overexpression of the AdeABC system (level of expression relative to that by A. baumannii ATCC 17978, 30- to 45-fold) was significantly associated with resistance to tigecycline, minocycline, and gentamicin and other biological functions. However, hyperexpression of the AdeIJK efflux pump (level of expression relative to that by A. baumannii ATCC 17978, 8- to 10-fold) was significantly associated only with resistance to tigecycline and minocycline (to which the TetB efflux system also contributed). TetB and TetA(39) efflux pumps were detected in clinical strains and were associated with resistance to tetracyclines and doxycycline. The absence of the AdeABC system and the lack of expression of other mechanisms suggest that tigecycline-resistant strains of the PFGE-HUI-1 clone may be associated with a novel resistance-nodulation-cell efflux pump (decreased MICs in the presence of the inhibitor Phe-Arg beta-naphthylamide dihydrochloride) and the TetA(39) system. PMID- 23939895 TI - In vitro activity of ceftolozane-tazobactam against Pseudomonas aeruginosa isolates obtained from patients in Canadian hospitals in the CANWARD study, 2007 to 2012. AB - The in vitro activity of ceftolozane in combination with tazobactam (fixed concentration of 4 MUg/ml) was evaluated against 2,435 Pseudomonas aeruginosa clinical isolates obtained from across Canada using Clinical and Laboratory Standards Institute broth microdilution methods. The MIC50 and MIC90 values for ceftolozane-tazobactam were 0.5 MUg/ml and 1 MUg/ml, respectively (a 32-fold lower MIC90 than that for ceftazidime). Eighty-nine percent (141/158) of multidrug-resistant isolates were inhibited by <=8 MUg/ml of ceftolozane tazobactam. PMID- 23939896 TI - In vitro characterization of GSK2485852, a novel hepatitis C virus polymerase inhibitor. AB - GSK2485852 (referred to here as GSK5852) is a hepatitis C virus (HCV) NS5B polymerase inhibitor with 50% effective concentrations (EC50s) in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell culture system. We have characterized the antiviral activity of GSK5852 using chimeric replicon systems with NS5B genes from additional genotypes as well as NS5B sequences from clinical isolates of patients infected with HCV of genotypes 1a and 1b. The inhibitory activity of GSK5852 remained unchanged in these intergenotypic and intragenotypic replicon systems. GSK5852 furthermore displays an excellent resistance profile and shows a <5-fold potency loss across the clinically important NS5B resistance mutations P495L, M423T, C316Y, and Y448H. Testing of a diverse mutant panel also revealed a lack of cross resistance against known resistance mutations in other viral proteins. Data from both the newer 454 sequencing method and traditional population sequencing showed a pattern of mutations arising in the NS5B RNA-dependent RNA polymerase in replicon cells exposed to GSK5852. GSK5852 was more potent than HCV-796, an earlier inhibitor in this class, and showed greater reductions in HCV RNA during long-term treatment of replicons. GSK5852 is similar to HCV-796 in its activity against multiple genotypes, but its superior resistance profile suggests that it could be an attractive component of an all-oral regimen for treating HCV. PMID- 23939897 TI - Ex vivo susceptibility of Plasmodium falciparum to antimalarial drugs in western, northern, and eastern Cambodia, 2011-2012: association with molecular markers. AB - In 2008, dihydroartemisinin (DHA)-piperaquine (PPQ) became the first-line treatment for uncomplicated Plasmodium falciparum malaria in western Cambodia. Recent reports of increased treatment failure rates after DHA-PPQ therapy in this region suggest that parasite resistance to DHA, PPQ, or both is now adversely affecting treatment. While artemisinin (ART) resistance is established in western Cambodia, there is no evidence of PPQ resistance. To monitor for resistance to PPQ and other antimalarials, we measured drug susceptibilities for parasites collected in 2011 and 2012 from Pursat, Preah Vihear, and Ratanakiri, in western, northern, and eastern Cambodia, respectively. Using a SYBR green I fluorescence assay, we calculated the ex vivo 50% inhibitory concentrations (IC50s) of 310 parasites to six antimalarials: chloroquine (CQ), mefloquine (MQ), quinine (QN), PPQ, artesunate (ATS), and DHA. Geometric mean IC50s (GMIC50s) for all drugs (except PPQ) were significantly higher in Pursat and Preah Vihear than in Ratanakiri (P <= 0.001). An increased copy number of P. falciparum mdr1 (pfmdr1), an MQ resistance marker, was more prevalent in Pursat and Preah Vihear than in Ratanakiri and was associated with higher GMIC50s for MQ, QN, ATS, and DHA. An increased copy number of a chromosome 5 region (X5r), a candidate PPQ resistance marker, was detected in Pursat but was not associated with reduced susceptibility to PPQ. The ex vivo IC50 and pfmdr1 copy number are important tools in the surveillance of multidrug-resistant (MDR) parasites in Cambodia. While MDR P. falciparum is prevalent in western and northern Cambodia, there is no evidence for PPQ resistance, suggesting that DHA-PPQ treatment failures result mainly from ART resistance. PMID- 23939898 TI - Quantification of brain voriconazole levels in healthy adults using fluorine magnetic resonance spectroscopy. AB - Voriconazole is more effective for aspergillosis infections with central nervous system involvement than other antifungal agents. The clinical efficacy of voriconazole for central nervous system infections has been attributed to its ability to cross the blood-brain barrier. However, pharmacokinetic studies are limited to plasma and cerebrospinal fluid, so it remains unclear how much of the drug enters the brain. Fluorinated compounds such as voriconazole can be quantified in the brain using fluorine-19 magnetic resonance spectroscopy (MRS). Twelve healthy adult males participated in a pharmacokinetic analysis of voriconazole levels in the brain and plasma. Open-label voriconazole was dosed per clinical protocol with a loading dose of 400 mg every 12 h on day 1, followed by 200 mg every 12 h administered orally over a 3-day period. MRS was performed before and after dosing on the third day. Voriconazole levels in the brain exceeded the MIC for Aspergillus. The brain/plasma ratios were 3.0 at steady state on day 3 (predose) and 1.9 postdose. We found that voriconazole is able to penetrate the brain tissue, which can be quantified using a noninvasive MRS technique. (This study has been registered at ClinicalTrials.gov under registration no. NCT00300677.). PMID- 23939899 TI - Preclinical characterization of the novel hepatitis C virus NS3 protease inhibitor GS-9451. AB - GS-9451 is a selective hepatitis C virus (HCV) NS3 protease inhibitor in development for the treatment of genotype 1 (GT1) HCV infection. Key preclinical properties of GS-9451, including in vitro antiviral activity, selectivity, cross resistance, and combination activity, as well as pharmacokinetic properties, were determined. In multiple GT1a and GT1b replicon cell lines, GS-9451 had mean 50% effective concentrations (EC50s) of 13 and 5.4 nM, respectively, with minimal cytotoxicity; similar potency was observed in chimeric replicons encoding the NS3 protease gene of GT1 clinical isolates. GS-9451 was less active in GT2a replicon cells (EC50 = 316 nM). Additive to synergistic in vitro antiviral activity was observed when GS-9451 was combined with other agents, including alpha interferon, ribavirin, and the polymerase inhibitors GS-6620 and tegobuvir (GS-9190), as well as the NS5A inhibitor ledipasvir (GS-5885). GS-9451 retained wild-type activity against multiple classes of NS5B and NS5A inhibitor resistance mutations. GS-9451 was stable in hepatic microsomes and hepatocytes from human and three other tested species. Systemic clearance was low in dogs and monkeys but high in rats. GS-9451 showed good oral bioavailability in all three species tested. In rats, GS 9451 levels were ~40-fold higher in liver than plasma after intravenous dosing, and elimination of GS-9451 was primarily through biliary excretion. Together, these results are consistent with the antiviral activity observed in a recent phase 1b study. The results of in vitro cross-resistance and combination antiviral assays support the ongoing development of GS-9451 in combination with other agents for the treatment of chronic HCV infection. PMID- 23939900 TI - Systematic review and meta-analysis of antimicrobial treatment effect estimation in complicated urinary tract infection. AB - Noninferiority trial design and analyses are commonly used to establish the effectiveness of a new antimicrobial drug for treatment of serious infections such as complicated urinary tract infection (cUTI). A systematic review and meta analysis were conducted to estimate the treatment effects of three potential active comparator drugs for the design of a noninferiority trial. The systematic review identified no placebo trials of cUTI, four clinical trials of cUTI with uncomplicated urinary tract infection as a proxy for placebo, and nine trials with reports of treatment effect estimates for doripenem, levofloxacin, or imipenem-cilastatin. In the meta-analysis, the primary efficacy endpoint of interest was the microbiological eradication rate at the test-of-cure visit in the microbiological intent-to-treat population. The estimated eradication rates and corresponding 95% confidence intervals (CI) were 31.8% (26.5% to 37.2%) for placebo, 81% (77.7% to 84.2%) for doripenem, 79% (75.9% to 82.2%) for levofloxacin, and 80.5% (71.9% to 89.1%) for imipenem-cilastatin. The treatment effect estimates were 40.5% for doripenem, 38.7% for levofloxacin, 34.7% for imipenem-cilastatin, and 40.8% overall. These treatment effect estimates can be used to inform the design and analysis of future noninferiority trials in cUTI study populations. PMID- 23939901 TI - Activities of psilostachyin A and cynaropicrin against Trypanosoma cruzi in vitro and in vivo. AB - In vitro and in vivo activities against Trypanosoma cruzi were evaluated for two sesquiterpene lactones: psilostachyin A and cynaropicrin. Cynaropicrin had previously been shown to potently inhibit African trypanosomes in vivo, and psilostachyin A had been reported to show in vivo effects against T. cruzi, albeit in another test design. In vitro data showed that cynaropicrin was more effective than psilostachyin A. Ultrastructural alterations induced by cynaropicrin included shedding events, detachment of large portions of the plasma membrane, and vesicular bodies and large vacuoles containing membranous structures, suggestive of parasite autophagy. Acute toxicity studies showed that one of two mice died at a cynaropicrin dose of 400 mg/kg of body weight given intraperitoneally (i.p.). Although no major plasma biochemical alterations could be detected, histopathology demonstrated that the liver was the most affected organ in cynaropicrin-treated animals. Although cynaropicrin was as effective as benznidazole against trypomastigotes in vitro, the treatment (once or twice a day) of T. cruzi-infected mice (up to 50 mg/kg/day cynaropicrin) did not suppress parasitemia or protect against mortality induced by the Y and Colombiana strains. Psilostachyin A (0.5 to 50 mg/kg/day given once a day) was not effective in the acute model of T. cruzi infection (Y strain), reaching 100% animal mortality. Our data demonstrate that although it is very promising against African trypanosomes, cynaropicrin does not show efficacy compared to benznidazole in acute mouse models of T. cruzi infection. PMID- 23939903 TI - In vitro and in vivo activities of antibiotic PM181104. AB - Drug resistance has become a global threat that, if not addressed, may return us to the preantibiotic era. A way to overcome the problem of growing incidence of global antibiotic resistance is to introduce compounds belonging to classes that are new to the clinic. During a screening of the marine microbial extract library for new antibiotics, one of the extracts showed promising antibacterial activity against Gram-positive organisms. Bioactivity-guided isolation and characterization of active metabolites led to the discovery of a novel thiazolyl cyclic-peptide antibiotic, PM181104. It was isolated and characterized from a marine sponge-associated actinobacterium strain of the genus Kocuria (MTCC 5269). The compound exhibited a potent in vitro antibacterial activity against a broad range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The MIC values evaluated for the compound were found to be in the single-digit nanomolar range. In in vivo studies of PM181104 in a BALB/c murine septicemia model, the compound displayed 100% effective dose (ED100) values of 2.5 and 5.0 mg/kg of body weight against MRSA and 10.0 mg/kg against VRE. In this report, in vitro and in vivo studies of PM181104 are described. PMID- 23939902 TI - Nucleic acid polymers inhibit duck hepatitis B virus infection in vitro. AB - Nucleic acid polymers (NAPs) utilize the sequence-independent properties of phosphorothioate oligonucleotides (PS-ONs) to target protein interactions involved in viral replication. NAPs are broadly active against a diverse range of enveloped viruses that use type I entry mechanisms. The antiviral activity of NAPs against hepatitis B virus (HBV) infection was assessed in vitro in duck hepatitis B virus (DHBV)-infected primary duck hepatocytes (PDH). NAPs efficiently entered PDH in the absence of any transfection agent and displayed antiviral activity at concentrations of 0.01 to 10 MUM, measured by their ability to prevent the intracellular accumulation of DHBV surface antigen, which was independent of their nucleotide sequence and was specifically dependent on phosphorothioation. Higher levels of antiviral activity were observed with NAPs 40 nucleotides in length or longer. The fully degenerate NAP (REP 2006) was active during DHBV infection or when added 12 h after infection. In contrast, an acidic-pH-sensitive NAP (REP 2031) that was broadly active against other viruses displayed antiviral activity when present during DHBV infection but no activity when added 12 h after infection, suggesting that NAPs exert their postentry effect in an acidic environment unique to DHBV infection. Both REP 2006 and REP 2031 displayed negligible cytotoxicity in PDH at concentrations of up to 10 MUM, as assessed using an XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H tetrazolium-5-carboxanilide] cytotoxicity assay. The antiviral activity of NAPs against DHBV in vitro was strictly dependent on their amphipathic character, suggesting that NAPs interact with amphipathic target(s) that are important for DHBV entry and postentry mechanisms required for infection. PMID- 23939904 TI - Nucleic acid polymers prevent the establishment of duck hepatitis B virus infection in vivo. AB - Nucleic acid polymers (NAPs) are novel, broad-spectrum antiviral compounds that use the sequence-independent properties of phosphorothioate oligonucleotides (PS ONs) as amphipathic polymers to block amphipathic interactions involved in viral entry. Using the duck hepatitis B virus (DHBV) model of human hepatitis B virus infection, NAPs have been shown to have both entry and postentry antiviral activity against DHBV infection in vitro in primary duck hepatocytes (PDH). In the current study, various NAPs were assessed for their prophylactic activity in vivo against DHBV infection in ducks. The degenerate NAP REP 2006 prevented the development of widespread and persistent DHBV infection in 14-day-old ducks, while the acidic-pH-sensitive NAP REP 2031 had little or no prophylactic effect. REP 2006 displayed significant toxicity in ducks, which was attributed to CpG mediated proinflammation, while REP 2031 (which has no CpG motifs) displayed no toxicity. A third NAP, REP 2055, which was designed to retain amphipathic activity at acidic pH and contained no CpG motifs, was well tolerated and displayed prophylactic activity against DHBV infection at doses as low as 1 mg/kg of body weight/day. These studies suggest that NAPs can be easily and predictably tailored to retain anti-DHBV activity and to have minimal toxic effects in vivo. Future studies are planned to establish the therapeutic efficacy of NAPs against persistent DHBV infection. PMID- 23939905 TI - A common intermediate for N2 formation in enzymes and zeolites: side-on Cu nitrosyl complexes. AB - Side on! Combined FTIR and NMR studies revealed the presence of a side-on nitrosyl species in the zeolite Cu-SSZ-13. This intermediate is very similar to those found in nitrite reductase enzyme systems. The identification of this intermediate led to the proposal of a reaction mechanism that is fully consistent with the results of both kinetic and spectroscopic studies. PMID- 23939906 TI - Total synthesis of enantiopure pyrrhoxanthin: alternative methods for the stereoselective preparation of 4-alkylidenebutenolides. AB - A new stereocontrolled total synthesis of the configurationally labile C37 norcarotenoid pyrrhoxanthin in enantiopure form has been completed. A highly stereoselective Horner-Wadsworth-Emmons (HWE) condensation of a C17 allylphosphonate and a C20-aldehyde was used as the last conjunctive step. Both a Sonogashira reaction to form the C17-phosphonate and the final HWE condensation proved to be compatible with the sensitive C7-C10 enyne E configuration. Regioselective (5-exo-dig) silver-promoted lactonization reactions of three alternative pent-2-en-4-ynoic acid precursors with increased complexity, including a fully functionalized C20-fragment, were explored for the preparation of the gamma-alkylidenebutenolide fragment. This survey extends the existing methodologies for the preparation of oxygen-containing carotenoids (xanthophylls) and streamlines the synthesis of additional members of the C37-norcarotenoid butenolide family of natural products. PMID- 23939907 TI - Separation and purification of four compounds from Desmodium styracifolium using off-line two-dimensional high-speed counter-current chromatography. AB - An off-line 2D high-speed counter-current chromatography technique in preparative scale has been successfully applied to separate and purify the main compounds from the ethyl acetate extract of Desmodium styracifolium. A two-phase solvent system composed of n-hexane/ethyl acetate/methanol/water at an optimized volume ratio of 1:2:1:2 v/v/v/v was used. Conventional high-speed counter-current chromatography was used as the first dimension, and the upper phase of the solvent system was used as the stationary phase in the head-to-tail elution mode at a flow rate of 2.0 mL/min and a rotation speed of 900 rpm. Recycling high speed counter-current chromatography served as the second dimension to separate an impure fraction of the first dimension. A total of four well-separated substances including vanillic acid (1), beta-sitosterol (2), formononetin (3), and aromadendrin (4) were obtained, and their purities and structures were identified by HPLC-MS and (1) H NMR spectroscopy. The results illustrated that off-line 2D high-speed counter-current chromatography is an effective way to isolate compounds in complex samples. PMID- 23939909 TI - Organic and hybrid materials for flexible electronics. PMID- 23939908 TI - Unveiling the critical role of REX1 in the regulation of human stem cell pluripotency. AB - Reduced expression 1 (REX1) is a widely used pluripotency marker, but little is known about its roles in pluripotency. Here, we show that REX1 is functionally important in the reacquisition and maintenance of pluripotency. REX1-depleted human pluripotent stem cells (hPSCs) lose their self-renewal capacity and full differentiation potential, especially their mesoderm lineage potential. Cyclin B1/B2 expression was found to parallel that of REX1. REX1 positively regulates the transcriptional activity of cyclin B1/B2 through binding to their promoters. REX1 induces the phosphorylation of DRP1 at Ser616 by cyclin B/CDK1, which leads to mitochondrial fission and appears to be important for meeting the high-energy demands of highly glycolytic hPSCs. During reprogramming to pluripotency by defined factors (OCT4, SOX2, KLF4, and c-MYC), the reprogramming kinetics and efficiency are markedly improved by adding REX1 or replacing KLF4 with REX1. These improvements are achieved by lowering reprogramming barriers (growth arrest and apoptosis), by enhancing mitochondrial fission, and by conversion to glycolytic metabolism, dependent on the cyclin B1/B2-DRP1 pathway. Our results show that a novel pluripotency regulator, REX1, is essential for pluripotency and reprogramming. PMID- 23939910 TI - Blocking the peroxisome proliferator-activated receptor (PPAR): an overview. AB - Peroxisome proliferator-activated receptors (PPARs) have been studied extensively over the last few decades and have been assessed as molecular targets for the development of drugs against metabolic disorders. A rapid increase in understanding of the physiology and pharmacology of these receptors has occurred, together with the identification of novel chemical structures that are able to activate the various PPAR subtypes. More recent evidence suggests that moderate activation of these receptors could be favorable in pathological situations due to a decrease in the side effects brought about by PPAR agonists. PPAR partial agonists and antagonists are interesting tools that are currently used to better elucidate the biological processes modulated by this family of nuclear receptors. Herein we present an overview of the various molecular structures that are able to block each of the PPAR subtypes, with a focus on promising therapeutic applications. PMID- 23939911 TI - Proline substitution independently enhances H-2D(b) complex stabilization and TCR recognition of melanoma-associated peptides. AB - The immunogenicity of H-2D(b) (D(b)) restricted epitopes can be significantly increased by substituting peptide position 3 to a proline (p3P). The p3P modification enhances MHC stability without altering the conformation of the modified epitope allowing for T-cell cross-reactivity with the native peptide. The present study reveals how specific interactions between p3P and the highly conserved MHC heavy chain residue Y159 increase the stability of D(b) in complex with an optimized version of the melanoma-associated epitope gp10025-33 . Furthermore, the p3P modification directly increased the affinity of the D(b)/gp10025-33 -specific T-cell receptor (TCR) pMel. Surprisingly, the enhanced TCR binding was independent from the observed increased stability of the optimized D(b)/gp10025-33 complex and from the interactions formed between p3P and Y159, indicating a direct effect of the p3P modification on TCR recognition. PMID- 23939912 TI - Comparison between self-report of cannabis use and toxicological detection of THC/THCCOOH in blood and THC in oral fluid in drivers in a roadside survey. AB - The objective of this study was to compare the number of drivers who self reported cannabis use by questionnaires to the results of toxicological analysis. During roadside surveys, 2957 respondents driving a personal car or van completed a questionnaire to report their use of drugs and medicines during the previous two weeks and to indicate the time of their last intake. Cannabis was analyzed in oral fluid by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), in blood by gas chromatography-mass spectrometry (GC-MS). Frequencies in the time categories were calculated and compared with toxicological results. Diagnostic values were calculated for the time categories in which positive findings were to be expected (<4 h and <2 4h, respectively for tetrahydrocannabinol (THC) and delta9-tetrahydrocannabinol (THCCOOH) in blood, <12 h for THC in oral fluid). Most self-reported cannabis use was more than 12 h before driving. The sensitivity of the questionnaire was low, while the specificity and accuracy were high. Kappa statistics revealed a fair agreement between self-report and positive findings for THC in oral fluid and blood and moderate agreement with THCCOOH in blood. Self-report largely underestimates driving under the influence of cannabis, particularly recent cannabis use; therefore analysis of biological samples is necessary. PMID- 23939913 TI - Mapping functional interaction sites of human prune C-terminal domain by NMR spectroscopy in human cell lysates. AB - Get well prune: The C-terminal third domain of h-prune is largely unfolded and involved in relevant protein-protein interactions, particularly with Nm23-H1 (see figure), GSK-3beta and gelsolin. This study shows that protein functions mediated by protein-protein interactions can be accurately followed in cell lysates by using fast NMR spectroscopy, which could be easily used for a very efficient NMR drug-discovery strategy. PMID- 23939914 TI - Concise review: bone marrow autotransplants for liver disease? AB - There are increasing reports of using bone marrow-derived stem cells to treat advanced liver disease. We consider several critical issues that underlie this approach. For example, are there multipotent stem cell populations in human adult bone marrow? Can they develop into liver cells or supporting cell types? What are stromal stem/progenitor cells, and can they promote tissue repair without replacing hepatocytes? Does reversal of end-stage liver disease require new hepatocytes, a new liver microenvironment, both, neither or something else? Although many of these questions are unanswered, we consider the conceptual and experimental bases underlying these issues and critically analyze results of clinical trials of stem cell therapy of end-stage liver disease. PMID- 23939915 TI - Utility of noninvasive biomatrices in pharmacokinetic studies. AB - Blood and plasma are the biomatrices traditionally used for drug monitoring and their pharmacokinetic profiling. Blood is the circulating fluid in contact with all organs and tissues of body and thus is the most representative fluid for measuring systemic drug levels. However, venipuncture suffers from the caveat of being an invasive technique which often makes people reluctant to participate in clinical studies. Thus, there is a need for noninvasive bio-fluids that are ethically appropriate, cost-efficient and toxicologically relevant. These alternate bio-fluids may prove clinically useful as alternatives to plasma/serum in therapeutic drug monitoring, pharmacokinetic and toxicokinetic studies, doping control in sports medicine and to monitor local adverse effects. These may be of particular interest in the case of special population groups such as neonates, children, the elderly, terminally ill patients and pregnant or lactating women, and offer the advantage of circumvention of the demand for specialized personnel for sample collection. This review describes such noninvasive bio-fluids (saliva, sweat, tears and milk) that have been considered for pharmacokinetic drug analysis, emphasizing their sample preparation, its associated difficulties and their correlation with plasma. PMID- 23939916 TI - A 10-year analysis of thyrotoxic periodic paralysis in 135 patients: focus on symptomatology and precipitants. AB - BACKGROUND: A comprehensive analysis has not been performed on patients with thyrotoxic periodic paralysis (TPP) characterized by acute hypokalemia and paralysis in the setting of thyrotoxicosis. PURPOSE: The aim of this study was to analyze the detailed symptomatology of thyrotoxicosis and precipitating factors for the attack in a large cohort of TPP patients. PATIENTS AND METHODS: A prospective observational study enrolled patients with TPP consecutively over 10 years at an academic medical center. Clinical features, including signs/symptoms of thyrotoxicosis and precipitating factors, were analyzed. The Wayne's index was used to assess the severity of thyrotoxicosis at presentation. Patients who agreed to receive an oral glucose-loading test after recovery were evaluated. RESULTS: Among the 135 TPP patients (male:female, 130:5), 70% of paralytic attacks occurred in the morning, especially during the seasons of summer and fall. Two-thirds of patients did not have a known family or personal history of hyperthyroidism. Only 17% of TPP patients manifested overt signs/symptoms of thyrotoxicosis (Wayne's index >19). A clear precipitating factor, such as high carbohydrate load, acute upper respiratory tract infection, strenuous exercise, high-salt diet, or the use of steroids or bronchodilators, was identified in only 34% of TPP patients. A glucose load to stimulate insulin secretion induced acute hypokalemia (K(+)2.47+/-0.6 mmol/l) with reparalysis in only 18% (10/55) of TPP patients. CONCLUSIONS: Most TPP patients have only subtle clinical signs/symptoms of thyrotoxicosis and only a small fraction has clear precipitating factors. In addition to the effects of hyperinsulinemia, other insulin-independent mechanisms may participate in the pathogenesis of TPP. PMID- 23939917 TI - Second primary malignancies following thyroid cancer: a population-based study in Taiwan. AB - OBJECTIVE: Most studies on second primary malignancies (SPMs) after primary thyroid cancer were conducted in USA or Europe. The discrepancy between SPMs in these studies could be attributed to geographical and ethnic heterogeneity. Thus, there is a clear need for another large-scale epidemiological study, particularly in Asian countries, to define the incidence and risk of SPMs in thyroid cancer survivors. DESIGN: A population-based study was conducted using the nation-wide database from Taiwan Cancer Registry between 1979 and 2006. METHODS: We quantified standardized incidence ratios (SIRs) and cumulative incidence of SPMs among 19,068 individuals (4205 males and 14,863 females) with primary thyroid cancer. RESULTS: A total of 644 cases (3.38%) developed at least a SPM during 134,678 person-years of follow-up. The risk for subsequent SPMs was significantly greater than that of the general population (SIR=1.33, 95% CI 1.23-1.44). There was a greater risk of developing major salivary glands, nasopharyngeal, lung, thymus, breast (females), bladder, and brain cancers, and leukemia and lymphoma. We observed that the risk was highest within the first 5 years of diagnosis of thyroid cancer (SIR=5.29, 1.68, and 0.68 for <= 5, 5-10, and >10 respectively) and in the younger patients (SIR=1.81 vs 1.61 for <50 and >= 50 respectively). The median overall survival for primary thyroid cancer patients was 23.28 years, but it was only 4.73 years for those who developed SPMs. CONCLUSION: Thyroid cancer is associated with a 33% risk increment of SPMs, which had a negative impact on survival. There are sites of SPMs in the Asian population that are distinctive from those in the Western population, suggesting that other genetic predisposition or environmental factors may play a role. PMID- 23939918 TI - Ultrasensitive serum thyroglobulin measurement is useful for the follow-up of patients treated with total thyroidectomy without radioactive iodine ablation. AB - CONTEXT: Thyroglobulin (Tg) measurement is a major tool for the follow-up of differentiated thyroid cancer (DTC) patients; however, in patients who do not undergo radioactive iodine (RAI) ablation, normal ultrasensitive Tg levels measured under levothyroxine treatment (usTg/l-T4) are not well defined. OBJECTIVE AND DESIGN: This single-center retrospective study assessed usTg/l-T4 level in 86 consecutive patients treated with total thyroidectomy without RAI ablation for low-risk DTC (n=77) or for tumors of uncertain malignant potential (TUMP) (n=9). RESULTS: DTCS were classified as PT1, PT2, and PT3 in 75, 1, and 1 case respectively and PN0, PN1, and PNX in 40, 6, and 31 respectively. following surgery, ten patients had TG antibodieS (TGAB). Among those without TGAB, the first USTG/L-T4 determination obtained at a mean time of 9 months after surgery was 0.1NG/ML in 62% of cases, 0.3NG/ML in 82% of cases, 1NG/ML in 91%, and 2NG/ML in 96% of cases. after a median follow-up of 2.5 years (range: 0.6-7.2 years), one patient had persistent disease with an usTg/l-T4 at 11 ng/ml and an abnormal neck ultrasonography (US) and two patients had usTg/l-T4 level >2 ng/ml (3.9 and 4.9 ng/ml) with a normal neck US. Within the first 2 years following total thyroidectomy without RAI ablation, usTg/l-T4 level is <=2 ng/ml in 96% of the cases. CONCLUSION: After total thyroidectomy, sensitive serum Tg/l-T4 level is <=2 ng/ml in most patients and can be used for patient follow-up. PMID- 23939919 TI - Pathogenesis of type 2 diabetes in South Asians. AB - The risk of developing type 2 diabetes mellitus (T2DM) is exceptionally high among both native and migrant South Asians. T2DM occurs more often and at a younger age and lower BMI, and the risk of coronary artery and cerebrovascular disease, and renal complications is higher for South Asians compared with people of White Caucasian descent. The high prevalence of T2DM and its related complications in South Asians, which comprise one-fifth of the total world's population, poses a major health and socioeconomic burden. The underlying cause of this excess risk, however, is still not completely understood. Therefore, gaining insight into the pathogenesis of T2DM in South Asians is of great importance. The predominant mechanism, in this ethnicity seems to be insulin resistance (IR) rather than an impaired beta-cell function. In this systematic review, we describe several possible mechanisms that may underlie or contribute to the increased IR observed in South Asians. PMID- 23939921 TI - Mortality in Cushing's syndrome: data from 386 patients from a single tertiary referral center. AB - OBJECTIVE: Data on the incidence, mortality, and causes of death in patients with Cushing's syndrome (CS) are scarce, due to the rarity of CS. The aim of the study was to analyze mortality in a large cohort of patients of all etiologies and to determine the cause of death. DESIGN: This was a retrospective study of patients with CS, treated over a period of 45 years in the main tertiary referral center in Bulgaria. METHODS: Three hundred and eighty-six patients with CS of all etiologies were included. The main outcome measures were the standardized mortality ratio (SMR) and the cause of death. RESULTS: Mean (S.D.) age at diagnosis was 3813 years; 84% of patients were women; mean follow-up was 85 months (rangE: 0-494 months). The SMR in the CS cohort was 4.05 (95% CI 2.50 5.80) (P<0.0001). The following subgroups did not have a significantly increased SMR: patients with Cushing's disease SMR - 1.88 (95% CI 0.69-4.08), adrenal adenomas 1.67 (95% CI 0.20-6.02), and ACTH-independent bilateral adrenal hyperplasia 1.14 (95% CI 0.21-6.34). Patients with adrenal carcinomas, ectopic CS, and those with CS of undetermined etiology had significantly increased SMR: 48.00 (95% CI 30.75-71.42), 13.33 (95% CI 0.00-24.59), and 4.00 (95% CI 0.48 14.45) respectively (P<0.0001). The significant predictors for mortality were active disease at death, age, male sex, etiology of the disease, and the overall duration of active disease. The major causes of death were vascular events (40%) cardiovascular 29%, and cerebrovascular 11% - followed by infections (12%). CONCLUSIONS: Patients with CS have increased mortality due to vascular events and infections. PMID- 23939922 TI - 8-Aminoquinoline: a powerful directing group in metal-catalyzed direct functionalization of C-H bonds. AB - Chelate me if you can: Over the last decade, strategies for the functionalization of both C(sp2)-H and C(sp3)-H bonds have witnessed an increasing use of a simple, yet powerful directing group, 8-aminoquinoline (in blue). This auxiliary is very efficient in a wide range of metal-mediated reactions, and can be readily removed to afford the desired carboxylic acids or corresponding derivatives. PMID- 23939920 TI - Monocentric study of 112 consecutive patients with childhood onset GH deficiency around and after transition. AB - OBJECTIVES: Our aim was to analyze a large cohort of childhood onset GH deficiency (CO-GHD) adults from a unique adult center, in order to analyze their clinical management and to study the metabolic and bone status in relation to GHD and to the other pituitary deficits, and to evaluate these parameters during the long-term follow-up. DESIGN AND METHODS: Observational retrospective cohort study on 112 consecutive CO-GHD adults transferred to our unit from 1st January 1994 to 1st March 2012. Evaluation of GHD in pediatrics and after transition was conducted following consensus guidelines. Data recorded from pediatric and adult files were GH doses, pituitary magnetic resonance imaging and function, and metabolic and bone status. RESULTS: Most patients presented with severe CO-GHD (64%) associated with other pituitary deficits (66%). CO-GHD was acquired in 56%, congenital in 33%, and idiopathic in 11% cases. Most patients (83%) stopped GH before transfer, at 16.3 years (median), despite persistence of GHD. Median age at transfer was 19.4 years. After transfer, GHD persisted in 101 patients and four of the 11 resolutive GHD were non idiopathic. IGF1 level was <-2 SDS in 70% of treated patients at transfer and in 34% of them after 3 years of treatment. Follow-up showed improvement in lipid profile and bone mineral density in severely persistent GHD patients under GH therapy. In multivariate analysis, the associated pituitary deficits seemed stronger determinant factors of metabolic and bone status than GHD. CONCLUSIONS: This study raises concern about discontinuation of GH replacement therapy in pediatrics in severely persistent GHD patients and about the often insufficient dose of GH in the treatment of adult patients. PMID- 23939923 TI - Targeting the K-Ras/PDEdelta protein-protein interaction: the solution for Ras driven cancers or just another therapeutic mirage? AB - The holy grail, finally? After years of unsuccessful attempts at drugging the Ras oncogene, a recent paper by Zimmerman et al. has revealed the possibility of inhibiting Ras signaling on a clinically relevant level by blocking the K Ras/PDEdelta protein-protein interaction. The results, reported in Nature, are highlighted herein with future implications and directions to evaluate the full clinical potential of this research. PMID- 23939924 TI - Maternal transfer of inorganic mercury and methylmercury in aquatic and terrestrial arthropods. AB - The transfer of mercury from females to their offspring plays an important role in mercury accumulation and toxicity during early development. To quantify the transfer of inorganic mercury and methylmercury from female arthropods to their eggs, the authors collected and analyzed brine shrimp (Artemia franciscana), wolf spiders (Alopecosa spp.), and their attached eggs from aquatic and terrestrial ecosystems at the Great Salt Lake, Utah, USA. Essentially all of the mercury in both the female brine shrimp and their eggs was methylmercury (94 +/- 17% and 90 +/- 21%, respectively). The brine shrimp eggs had methylmercury concentrations that were 84 +/- 2% lower than in the females, reflecting the fact that females transferred 45 +/- 4% of their total body mass but only 11 +/- 3% of their methylmercury burden to their eggs. As a result of this sequestration, the concentration of methylmercury in the female brine shrimp increased by 62 +/- 8% during egg formation. The percentage of the total mercury that was methylmercury in female wolf spiders (77 +/- 21%) was similar to that in their egg masses (81 +/- 19%), indicating similar maternal transfer efficiencies for inorganic mercury and methylmercury in these invertebrates. The concentration of inorganic mercury and methylmercury in the female spiders was the same as in their eggs. These arachnids transferred 48 +/- 9% of their total body mass, 55 +/- 13% of their inorganic mercury, and 50 +/- 9% of their methylmercury to their egg masses. Thus, female wolf spiders do not have the ability to reduce the transfer of methylmercury to their eggs, nor does this process represent an important pathway for the depuration of mercury. The present study demonstrates that although some arthropods have mechanisms to minimize the transfer of methylmercury to their eggs and reduce the potential for mercury toxicity during early development, other arthropods do not. PMID- 23939926 TI - Photoinduced gold(I)-gold(I) chemical bonding in dicyanoaurate oligomers. PMID- 23939925 TI - Caudate nucleus-dependent navigational strategies are associated with increased use of addictive drugs. AB - This study aimed to investigate the relationship between navigational strategies and the use of abused substances in a sample of healthy young adults. Navigational strategies were assessed with the 4-on-8 virtual maze (4/8VM), a task previously shown to dissociate between hippocampal-dependent spatial navigational strategies and caudate nucleus-dependent stimulus-response navigational strategies. Spatial strategies involve learning the spatial relationships between the landmarks in an environment, while response learning strategies involve learning a rigid set of stimulus-response type associations, e.g., see the tree, turn left. We have shown that spatial learners have increased gray matter and fMRI activity in the hippocampus compared with response learners, while response learners have increased gray matter and fMRI activity in the caudate nucleus. We were interested in the prevalence of use of substances of abuse in spatial and response learners because of the evidence that people who score high on traits such as novelty seeking, sensation seeking, reward seeking, and impulsivity, are more cue-responsive and more likely to use substances of abuse. Since response learners show increased activity and gray matter in the caudate nucleus of the striatum, which is a brain area involved in addiction, we hypothesized that response learners would have a greater use of abused substances than spatial learners. Fifty-five young adults were tested on the 4/8VM and completed a time-line follow-back assessment of drug and alcohol use. We found that response learners had smoked a significantly greater number of cigarettes in their lifetime than spatial learners, were more likely to have used cannabis, and had double the lifetime alcohol consumption. We discuss the possible relationship between substance abuse and response strategies as well as the implications for the hippocampus, risks of neurological and psychiatric disorders, and healthy cognition. PMID- 23939927 TI - Fullerene derivative-doped zinc oxide nanofilm as the cathode of inverted polymer solar cells with low-bandgap polymer (PTB7-Th) for high performance. AB - Modification of a ZnO cathode by doping it with a hydroxyl-containing derivative giving a ZnO-C60 cathode - provides a fullerene-derivative-rich surface and enhanced electron conduction. Inverted polymer solar cells with the ZnO-C60 cathode display markedly improved power conversion efficiency compared to those with a pristine ZnO cathode, especially when the active layer includes the low bandgap polymer PTB7-Th. PMID- 23939930 TI - Synthesis of zwitterionic cobaltocenium borate and borata-alkene derivatives from a borole-radical anion. AB - Chemical single-electron reduction of 1-mesityl-2,3,4,5-tetraphenylborole (3) gave a stable radical anion [CoCp*2 ][3] as shown in earlier investigations. Herein, we present the reaction of [CoCp*2 ][3] with the 2,2,6,6 tetramethylpiperidine-N-oxyl radical (TEMPO), a common radical trap. Instead of radical recombination, the reaction proceeds through a redox pathway involving oxidation of the borole radical anion combined with reduction of TEMPO. This electron-transfer process is accompanied by a deprotonation reaction of the cobaltocenium counterion by the base TEMPO(-) to give TEMPO-H and a neutral cobalt(I) fulvene complex (7). The latter was not observed directly during the reaction, because it instantaneously reacts as a nucleophile attacking at the boron center of the in situ generated borole 3 to give the borate 6. However, 7 was synthesized independently by deprotonation of [CoCp*2 ][PF6 ]. In addition, the obtained zwitterionic cobaltocenium borate 6 undergoes a photolytic rearrangement to form the borata-alkene derivative 9 that thermally transforms to the chiral cobaltocenium borate 12. Our investigations are based on spectroscopic evidence, X-ray crystallography, elemental analysis, as well as DFT calculations. PMID- 23939929 TI - Interference with Ca(2+) release activated Ca(2+) (CRAC) channel function delays T-cell arrest in vivo. AB - Entry of lymphocytes into secondary lymphoid organs (SLOs) involves intravascular arrest and intracellular calcium ion ([Ca(2+)]i) elevation. TCR activation triggers increased [Ca(2+)]i and can arrest T-cell motility in vitro. However, the requirement for [Ca(2+)]i elevation in arresting T cells in vivo has not been tested. Here, we have manipulated the Ca(2+) release-activated Ca(2+) (CRAC) channel pathway required for [Ca(2+)]i elevation in T cells through genetic deletion of stromal interaction molecule (STIM) 1 or by expression of a dominant negative ORAI1 channel subunit (ORAI1-DN). Interestingly, the absence of CRAC did not interfere with homing of naive CD4(+) T cells to SLOs and only moderately reduced crawling speeds in vivo. T cells expressing ORAI1-DN lacked TCR activation induced [Ca(2+)]i elevation, yet arrested motility similar to control T cells in vitro. In contrast, antigen-specific ORAI1-DN T cells had a twofold delayed onset of arrest following injection of OVA peptide in vivo. CRAC channel function is not required for homing to SLOs, but enhances spatiotemporal coordination of TCR signaling and motility arrest. PMID- 23939931 TI - Adsorption of polycyclic aromatic hydrocarbons on graphene oxides and reduced graphene oxides. AB - Graphene has attracted increasing attention in multidisciplinary studies because of its unique physical and chemical properties. Herein, the adsorption of polycyclic aromatic hydrocarbons (PAHs), such as naphthalene (NAP), anthracene (ANT), and pyrene (PYR), on reduced graphene oxides (rGOs) and graphene oxides (GOs) as a function of pH, humic acid (HA), and temperature were elucidated by means of a batch technique. For comparison, nonpolar and nonporous graphite were also employed in this study. The increasing of pH from 2 to 11 did not influence the adsorption of PAHs on rGOs, whereas the suppressed adsorption of NAP on rGOs was observed both in the presence of HA and under high-temperature conditions. Adsorption isotherms of PAHs on rGOs were in accordance with the Polanyi-Dubinin Ashtahhov (PDA) model, providing evidence that pore filling and flat surface adsorption were involved. The saturated adsorbed capacities (in mmol g(-1)) of rGOs for PAHs calculated from the PDA model significantly decreased in the order of NAP>PYR>ANT, which was comparable to the results of theoretical calculations. The pore-filling mechanism dominates the adsorption of NAP on rGOs, but the adsorption mechanisms of ANT and PYR on rGOs are flat surface adsorption. PMID- 23939933 TI - Vinylsulfonamide and acrylamide modification of DNA for cross-linking with proteins. AB - Bioorthogonal covalent cross-linking of DNA-binding proteins (p53) to DNA was achieved through novel DNA probes bearing a reactive vinylsulfonamide (VS) group. The VS-modified dCTP served as building block for polymerase synthesis of modified DNA, which was readily conjugated with cysteine-containing peptides and proteins by Michael addition. PMID- 23939932 TI - Crosstalk between mesenchymal stem cells and endothelial cells leads to downregulation of cytokine-induced leukocyte recruitment. AB - Mesenchymal stem cells (MSC) have immunomodulatory properties, but their effects on endothelial cells (EC) and recruitment of leukocytes are unknown. We cocultured human bone marrow-derived MSC with EC and found that MSC could downregulate adhesion of flowing neutrophils or lymphocytes and their subsequent transendothelial migration. This applied for EC treated with tumor necrosis factor-alpha (TNF), interleukin-1beta (IL-1), or TNF and interferon-gamma combined. Supernatant from cocultures also inhibited endothelial responses. This supernatant had much higher levels of IL-6 than supernatant from cultures of the individual cells, which also lacked inhibitory functions. Addition of neutralizing antibody against IL-6 removed the bioactivity of the supernatant and also the immunomodulatory effects of coculture. Studies using siRNA showed that IL-6 came mainly from the MSC in coculture, and reduction in production in MSC alone was sufficient to impair the protective effects of coculture. Interestingly, siRNA knockdown of IL-6-receptor expression in MSC as well as EC inhibited anti-inflammatory effects. This was explained when we detected soluble IL-6R receptor in supernatants and showed that receptor removal reduced the potency of supernatant. Neutralization of transforming growth factor-beta indicated that activation of this factor in coculture contributed to IL-6 production. Thus, crosstalk between MSC and EC caused upregulation of production of IL-6 by MSC which in turn downregulated the response of EC to inflammatory cytokines, an effect potentiated by MSC release of soluble IL-6R. These studies establish a novel mechanism by which MSC might have protective effects against inflammatory pathology and cardiovascular disease. PMID- 23939934 TI - Effects of lentivirus-mediated CREB expression in the dorsolateral striatum: memory enhancement and evidence for competitive and cooperative interactions with the hippocampus. AB - Neural systems specialized for memory may interact during memory formation or recall, and the results of interactions are important determinants of how systems control behavioral output. In two experiments, we used lentivirus-mediated expression of the transcription factor CREB (LV-CREB) to test if localized manipulations of cellular plasticity influence interactions between the hippocampus and dorsolateral striatum. In Experiment 1, we tested the hypothesis that infusion of LV-CREB in the dorsolateral striatum facilitates memory for response learning, and impairs memory for place learning. LV-CREB in the dorsolateral striatum had no effect on response learning, but impaired place memory; a finding consistent with competition between the striatum and hippocampus. In Experiment 2, we tested the hypothesis that infusion of LV-CREB in the dorsolateral striatum facilitates memory for cue learning, and impairs memory for contextual fear conditioning. LV-CREB in the dorsolateral striatum enhanced memory for cue learning and, in contrast to our prediction, also enhanced memory for contextual fear conditioning, consistent with a cooperative interaction between the striatum and hippocampus. Overall, the current experiments demonstrate that infusion of LV-CREB in the dorsolateral striatum (1) increases levels of CREB protein locally, (2) does not alter acquisition of place, response, cue, or contextual fear conditioning, (3) facilitates memory for cue learning and contextual fear conditioning, and (4) impairs memory for place learning. Taken together, the present results provide evidence that LV-CREB in the dorsolateral striatum can enhance memory formation and cause both competitive and cooperative interactions with the hippocampus. PMID- 23939936 TI - Microcrystalline organic thin-film solar cells. AB - Microcrystalline organic films with tunable thickness are produced directly on an indium-tin-oxide substrate, by crystallizing a thin amorphous rubrene film followed by its use as a template for subsequent homoepitaxial growth. These films, with exciton diffusion lengths exceeding 200 nm, produce solar cells with increasing photocurrents at thicknesses up to 400 nm with a fill factor >65%, demonstrating significant potential for microcrystalline organic electronic devices. PMID- 23939935 TI - Tendon gradient mineralization for tendon to bone interface integration. AB - Tendon-to-bone integration is a great challenge for tendon or ligament reconstruction regardless of use of autograft or allograft tendons. We mineralized the tendon, thus transforming the tendon-to-bone into a "bone-to bone" interface for healing. Sixty dog flexor digitorum profundus (FDP) tendons were divided randomly into five groups: (1) normal FDP tendon, (2) CaP (non extraction and mineralization without fetuin), (3) CaPEXT (Extraction by Na2 HPO4 and mineralization without fetuin), (4) CaPFetuin (non-extraction and mineralization with fetuin), and (5) CaPEXTFetuin (extraction and mineralization with fetuin). The calcium and phosphate content significantly increased in tendons treated with combination of extraction and fetuin compared to the other treatments. Histology also revealed a dense mineral deposition throughout the tendon outer layers and penetrated into the tendon to a depth of 200 um in a graded manner. Compressive moduli were significantly lower in the four mineralized groups compared with normal control group. No significant differences in maximum failure strength or stiffness were found in the suture pull-out test among all groups. Mineralization of tendon alters the interface from tendon to bone into mineralized tendon to bone, which may facilitate tendon-to-bone junction healing following tendon or ligament reconstruction. PMID- 23939937 TI - Selective deficit in spatial memory strategies contrast to intact response strategies in patients with schizophrenia spectrum disorders tested in a virtual navigation task. AB - Spatial memory is impaired among persons with schizophrenia (SCZ). However, different strategies may be used to solve most spatial memory and navigation tasks. This study investigated the hypothesis that participants with schizophrenia-spectrum disorders (SSD) would demonstrate differential impairment during acquisition and retrieval of target locations when using a hippocampal dependent spatial strategy, but not a response strategy, which is more associated with caudate function. Healthy control (CON) and SSD participants were tested using the 4-on-8 virtual maze (4/8VM), a virtual navigation task designed to differentiate between participants' use of spatial and response strategies. Consistent with our predictions, SSD participants demonstrated a differential deficit such that those who navigated using a spatial strategy made more errors and took longer to locate targets. In contrast, SSD participants who spontaneously used a response strategy performed as well as CON participants. The differential pattern of spatial-memory impairment in SSD provides only indirect support for underlying hippocampal dysfunction. These findings emphasize the importance of considering individual strategies when investigating SSD-related memory and navigation performance. Future cognitive intervention protocols may harness SSD participants' intact ability to navigate using a response strategy and/or train the deficient ability to navigate using a spatial strategy to improve navigation and memory abilities in participants with SSD. PMID- 23939938 TI - Polysaccharides from Liriopes Radix ameliorates hyperglycemia via various potential mechanisms in diabetic rats. AB - BACKGROUND: Liriopes Radix, which is regarded as both drug and healthy diet, is drunk as tea and used in traditional Chinese medicine to treat diabetes. Based on our previous studies, investigated the hypoglycemic effects and explored the mechanisms of total polysaccharides from Liriope spicata var. prolifera (Liriopes Radix) in a diabetic rat model. RESULTS: TLSP reduced hyperglycemia in diabetic rats. The oral glucose tolerance test showed that TLSP could improve the glucose tolerance of diabetic rats. Damage to liver and pancreas tissue was inhibited after treatment with TLSP. Moreover, TLSP increased glycogen content, glucokinase (GK) and glycogen synthetase (GS) activities, and suppressed the elevation of glucose-6-phosphatase (G6Pase) and glycogen phosphorylase (GP) activities in liver. Compared with the diabetic control group, GK and GS mRNA expression were significantly elevated, while G6Pase and GP mRNA expression were decreased in TLSP groups. In addition, TLSP could inhibit glycogen synthase kinase-3beta expression and increase insulin receptor, insulin receptor substrate-1, phosphoinositide 3-kinase, protein kinase B and glucose transport protein-4 expression in liver. CONCLUSION: TLSP showed hypoglycemic function. Improvement of glucose metabolism and insulin-signaling transduction were possible mechanisms. PMID- 23939939 TI - A photoelectrochemical investigation on the synergetic effect between CdS and reduced graphene oxide for solar-energy conversion. AB - CdS modified with reduced graphene oxide (RGO) has been widely demonstrated to be effective in the field of solar-energy conversion. However, the inherent mechanism of this superior property is still not thoroughly understood. Thus the photoelectrochemical method was employed to systemically investigate the synergetic effect between CdS and RGO. The result shows that the photoelectrochemical properties of RGO/CdS samples are sensitive to the relative ratio of RGO to CdS, and the photoelectrode with 1.0 wt% ratio of RGO possesses the best photoelectrochemical performance. Further investigation demonstrates that the synergetic effect between CdS and RGO directly influences the charge transport property and band-structure of the composite, which is also supported by the X-ray photoelectron spectroscopy data and first-principle simulation, respectively. PMID- 23939940 TI - Using magnetic levitation to separate mixtures of crystal polymorphs. PMID- 23939941 TI - Polymerization of polyanthrylene on a titanium dioxide (011)-(2*1) surface. PMID- 23939942 TI - Hepatic oxidative stress activates the Gadd45b gene by way of degradation of the transcriptional repressor STAT3. AB - Growth arrest and DNA damage-inducible beta (GADD45b) plays an important role in many intracellular events, such as cell cycle arrest, DNA repair, cell survival, apoptosis, and senescence. However, its mechanism of transcriptional regulation remains unclear. In this study the mechanism of peroxisome proliferator-activated receptor alpha (PPARalpha) ligand induction of the Gadd45b gene in mouse liver was investigated. Gadd45b messenger RNA (mRNA) was markedly induced by the PPARalpha agonist Wy-14,643 in wild-type mice but not in Ppara-null mice. Signal transducer and activator of transcription 3 (STAT3) was found to be a repressor of the Gadd45b gene through binding to upstream regulatory elements. The role of STAT3 in control of Gadd45b was confirmed using liver-specific Stat3-null mice. Wy-14,643 treatment stimulated STAT3 ubiquitination leading to activation of the Gadd45b gene as a result of loss of Gadd45b repression by STAT3. STAT3 degradation was induced by forced overexpression of the PPARalpha target gene encoded enzyme ACOX1, which produces increased H(2)O(2) as a byproduct of fatty acid beta-oxidation. H(2)O(2) also stimulated expression of Gadd45b in cultured cells. CONCLUSION: PPARalpha indirectly induces the Gadd45b gene in liver through promoting degradation of the repressor STAT3 as a result of elevated oxidative stress. PMID- 23939943 TI - Highly photoluminescent amino-functionalized graphene quantum dots used for sensing copper ions. AB - Herein, we report a new kind of highly fluorescent probe for Cu(2+) sensing generated by hydrothermal treatment of graphene quantum dots (GQDs). After hydrothermal treatment in ammonia, the greenish-yellow fluorescent GQDs (gGQDs) with a low quantum yield (QY, 2.5%) are converted to amino-functionalized GQDs (afGQDs) with a high QY (16.4%). Due to the fact that Cu(2+) ions have a higher binding affinity and faster chelating kinetics with N and O on the surface of afGQDs than other transition-metal ions, the selectivity of afGQDs for Cu(2+) is much higher than that of gGQDs. Furthermore, afGQDs are biocompatible and eco friendly, and the afGQDs with a positive charge can be easily taken up by cells, which makes it possible to sense Cu(2+) in living cells. The strategy presented here is simple in design, economical, and offers a "mix-and-detect" protocol without dye-modified oligonucleotides or complex chemical modification. PMID- 23939945 TI - The accuracy of alternative triage rules for identification of significant traumatic brain injury: a diagnostic cohort study. AB - INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of death and disability in young adults. Reorganisation of trauma services with direct triage of suspected head injury patients to trauma centres may improve outcomes following TBI. This study aimed to determine the sensitivity of principal English triage tools for identifying significant TBI. METHODS: We performed a diagnostic cohort study using data prospectively collated from the Trauma Audit and Research Network database between 2005 and 2011. Adult head injury patients were retrospectively classified according to London Ambulance Service (LAS) and Head Injury Transportation Straight to Neurosurgery study (HITS-NS) triage criteria. Sensitivity and specificity were then calculated against a reference standard of significant TBI, comprising head region abbreviated injury score (AIS) >=3 or neurosurgical operation. RESULTS: 6559 patients were included in complete case analyses. The LAS and HITS-NS triage tools demonstrated sensitivities of 44.5% (95% CI 43.2 to 45.9) and 32.6% (95% CI 31.4 to 33.9), respectively, for identifying significant TBI patients. False negative significant TBI cases were relatively older, more likely to be female, more frequently secondary to low level falls, and were less likely to have very severe AIS five or six head injuries, p<0.01. CONCLUSIONS: A considerable proportion of significant head injury patients may not be triaged directly to trauma centres. Investment is therefore necessary to improve the accuracy of existing triage rules and maintain expertise in TBI diagnosis and management in non-specialist emergency departments. PMID- 23939944 TI - Generation of functional, antigen-specific CD8+ human T cells from cord blood stem cells using exogenous Notch and tetramer-TCR signaling. AB - In vitro differentiation of mouse and human stem cells into early T cells has been successfully demonstrated using artificial Notch signaling systems. However, generation of mature, antigen-specific, functional T cells, directly from human stem cells has remained elusive, except when using stromal coculture of stem cells retrovirally transfected with antigen-specific T cell receptors (TCRs). Here we show that human umbilical cord blood (UCB)-derived CD34+CD38-/low hematopoietic stem cells can be successfully differentiated into functional, antigen-specific cytotoxic CD8+ T cells without direct stromal coculture or retroviral TCR transfection. Surface-immobilized Notch ligands (DLL1) and stromal cell conditioned medium successfully induced the development of CD1a+CD7+ and CD4+CD8+ early T cells. These cells, upon continued culture with cytomegalovirus (CMV) or influenza-A virus M1 (GIL) epitope-loaded human leukocyte antigen (HLA) A*0201 tetramers, resulted in the generation of a polyclonal population of CMV specific or GIL-specific CD8+ T cells, respectively. Upon further activation with antigen-loaded target cells, these antigen-specific, stem cell-derived T cells exhibited cytolytic functionality, specifically CD107a surface mobilization, interferon gamma (IFNg) production, and Granzyme B secretion. Such scalable, in vitro generation of functional, antigen-specific T cells from human stem cells could eventually provide a readily available cell source for adoptive transfer immunotherapies and also allow better understanding of human T cell development. PMID- 23939946 TI - Histological confirmation and biological significance of cartilage canals demonstrated using high field MRI in swine at predilection sites of osteochondrosis. AB - Cartilage canal vessels in epiphyseal cartilage have a pivotal role in the pathogenesis of osteochondrosis/osteochondritis dissecans. The present study aimed to validate high field magnetic resonance imaging (MRI) methods to visualize these vessels in young pigs. Osteochondral samples from the distal femur and distal humerus (predilection sites of osteochondrosis) of piglets were imaged post-mortem: (1) using susceptibility-weighted imaging (SWI) in an MRI scanner, followed by histological evaluation; and (2) after barium perfusion using uCT, followed by clearing techniques. In addition, both stifle joints of a 25-day-old piglet were imaged in vivo using SWI and gadolinium enhanced T1 weighted MRI, after which distal femoral samples were harvested and evaluated using uCT and histology. Histological sections were compared to corresponding MRI slices, and three-dimensional visualizations of vessels identified using MRI were compared to those obtained using uCT and to the cleared specimens. Vessels contained in cartilage canals were identified using MRI, both ex vivo and in vivo; their locations matched those observed in the histological sections, uCT images, and cleared specimens of barium-perfused tissues. The ability to visualize cartilage canal blood vessels by MRI, without using a contrast agent, will allow future longitudinal studies to evaluate their role in developmental orthopedic disease. PMID- 23939947 TI - Evidence of subgroup-specific treatment effect in the absence of an overall effect: is there really a contradiction? AB - PURPOSE: Interaction and subgroup analyses remain controversial topics in epidemiology. A recent theoretical paper suggested that a combination of no overall treatment-outcome association and treatment effect limited to a single subgroup would imply a clinically implausible interaction, with opposite treatment effects in the two subgroups. However, this argument was based entirely on point estimates and ignored sampling error and statistical inference. METHODS: We simulated hypothetical studies in which treatment truly affected the outcome in only one subgroup, with no effect in the other subgroup. We generated 1000 random samples for three study designs (small clinical study, case-control, and large cohort), and different values of total sample size (N), relative size of the affected subgroup, and treatment effect. We estimated the frequency of significant results for tests of overall and subgroup-specific treatment effects, and treatment-by-subgroup interaction. RESULTS: Combination of statistically non significant overall treatment effect and significant treatment-by-subgroup interaction occurred frequently, especially if the affected subgroup was proportionally smaller, even in studies with high power to detect the overall effect (e.g. in 37.1% of samples with N = 20 000, with 600 outcomes, and an effect (odds ratio of 1.5) limited to 30% of subjects). Furthermore, in most samples with a significant interaction, subgroup analyses correctly indicated that the significant effect was limited to one subgroup. CONCLUSION: In studies where the treatment truly affects the risks in only one subgroup, a non significant overall effect will often coincide with a statistically significant treatment-by-subgroup interaction. Thus, a non-significant overall effect should not prevent testing plausible interactions. PMID- 23939948 TI - SWCNT/graphite nanoplatelet hybrid thin films for self-temperature-compensated, highly sensitive, and extensible piezoresistive sensors. AB - Highly sensitive single-wall carbon nanotube/graphite nanoplatelet (SWCNT/GNP) hybrid thin-film sensors are developed, which possess the unique capability for self-temperature compensation. This unique property in combination with their high gauge sensitivity and large reversible extensibility promises the SWCNT/GNP hybrid thin film piezoresistive sensors for a wide range applications, such as in man-machine interaction and body monitoring. PMID- 23939949 TI - Effect of two Spanish breeds and diet on beef quality including consumer preferences. AB - BACKGROUND: Farmers in dry mountain areas are changing their management strategies to improve livestock farming efficiency, by using different forages or different breeds. The effect of breed (Parda de Montana vs. Pirenaica) and finishing diet (grazing on meadows vs. a total mixed ration (50% alfalfa, 40% maize grain, 10% straw)) on carcass characteristics and meat quality of steers was studied. RESULTS: Parda de Montana had a greater (P < 0.01) amount of intramuscular fat than Pirenaica. The finishing diet did not influence carcass fat color, but fatty acid composition was slightly affected. Finishing steers on a total mixed ration increased the percentage of fat of the 10th rib (P < 0.001). Supplementation with concentrates increased the diet energy concentration and also increased the dressing percentage. CONCLUSIONS: Both breeds had similar carcass characteristics. Consumers preferred beef from the Pirenaica breed because of its greater tenderness. Consumers did not differentiate between beef from animals fed different finishing diets. However, consumers who like meat very much preferred meat aged in a cooler at 4 degrees C for 15 days rather than 8 days. PMID- 23939950 TI - Rhodium-catalyzed oxygenative addition to terminal alkynes for the synthesis of esters, amides, and carboxylic acids. AB - A gem of a couple: The title reaction of terminal alkynes with O and N nucleophiles proceeds in the presence of [{Rh(cod)Cl}2], P(4-FC6H4)3, and 4 picoline N-oxide. Alcohols, amines, and water add to the terminal alkynes to give esters, amides, and carboxylic acids, respectively. The reaction involves formation of a rhodium vinylidene, oxidation to a ketene by oxygen transfer, and nucleophilic addition. PMID- 23939951 TI - Direct peptide lipidation through thiol-ene coupling enables rapid synthesis and evaluation of self-adjuvanting vaccine candidates. AB - A radical lipidation: Application of a novel thiol-ene lipidation enables the one step synthesis of self-adjuvanting antigenic peptides as vaccine candidates. The resultant monoacyl lipopeptides are shown to activate monocytes in a robust manner. PMID- 23939952 TI - EBV-encoded LMP-1 sensitizes nasopharyngeal carcinoma cells to genotoxic drugs by down-regulating Cabin1 expression. AB - The oncogenic latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is involved in the pathogenesis of human nasopharyngeal carcinoma (NPC) and lymphoma. We and other authors have shown earlier that LMP1 induces apoptosis and inhibits xenograft tumor growth in mice, but the mechanism underlying these processes has not been investigated so far. In the present study, we show that knockdown of LMP1 renders the EBV-positive NPC cell line CG-1 resistant to various genotoxic drugs (cisplatin, etoposide, and adriamycin). LMP1 inhibits the expression of Cabin1, a Ca(2+) regulated protein shown earlier to inhibit calcineurin. Knockdown of calcineurin binding protein (Cabin1) with small hairpin RNA sensitizes CG-1 cells to genotoxic drugs. In contrast, LMP1 overexpression reduces Cabin1 level and renders both CG-1 cells and EBV-negative NPC cell lines sensitive to cisplatin. The c-Jun-N-terminal kinase (JNK) and ERK pathways are required for LMP1-induced suppression of Cabin1 at the transcriptional level. Chromatin immunoprecipitation assays further confirm that the JNK-activated transcription factor AP-1 mediates the LMP1-induced down-regulation of Cabin1 gene expression. LMP1 knockdown also increases the resistance of xenograph tumors to cisplatin in mice, therefore confirming the relevance of our findings in vivo. This study reveals the molecular mechanism underlying the pro-apoptotic activity of LMP1 during cisplatin-based NPC chemotherapy. PMID- 23939953 TI - No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. AB - One major challenge in the treatment of chronic hepatitis B is to maintain long term viral suppression without promoting the selection of drug-resistant mutations. We analyzed data from 347 hepatitis B e antigen-negative and 238 hepatitis B e antigen positive patients receiving tenofovir disoproxil fumarate (TDF) in an open-label, longterm extension of two phase 3 studies. To date, resistance analyses have been completed for patients receiving up to 288 weeks (6 years) of TDF. Population sequencing of hepatitis B virus (HBV) polymerase/reverse transcriptase (pol/RT) was attempted for all patients at baseline, and any patient who remained viremic (HBV DNA 400 copies/mL [69 IU/mL]) at week 288 or at the end of treatment with TDF (n552) or emtricitabine(FTC)/TDF (n57). Phenotypic analyses were performed in HepG2 cells using recombinant HBV containing patient pol/RT sequences. Approximately half of the patients on open label treatment who qualified for genotyping had pol/RT sequence changes compared to baseline (23/52 [44%] on TDF, 4/7 [57%] on FTC/TDF). Most changes were at polymorphic sites and none were associated with TDF resistance. Virologic breakthrough occurred infrequently and was associated with nonadherence to study medication in the majority of cases (12/16, 75%). Per protocol, 57 patients (10%)were eligible to switch to FTC/TDF; the majority had HBV DNA <400 copies/mL at their last study visit regardless of whether they switched to FTC/TDF (n534) or maintained TDF monotherapy (n517). No patient exhibited persistent viremia (HBV DNA never <400 copies/mL) after week 240. CONCLUSION: TDF monotherapy maintains effective suppression of HBV DNA through 288 weeks of treatment with no evidence of TDF resistance. PMID- 23939954 TI - Core cross-linked micelle-based nanoreactors for efficient photocatalysis. AB - Stable nanoscale cross-linked polymer micelles containing Ru complexes (Ru-CMs) were prepared from monomethoxy[poly(ethylene glycol)]-block-poly(L-lysine) (MPEG PLys) and [(bpy)2Ru(fmbpy)](PF6)2 (bpy=bipyridine, fmbpy=5-formy-5'-methyl-2,2' bipyridine). To stabilize the micelles, bifunctional glutaraldehyde was used as a cross-linker to react with the free amino groups of the PLys block. After that, the Ru-CMs showed very good stability in common solvents. The Ru-CMs showed photocatalytic activity and selectivity in the oxidation of sulfides that were as high as those of the well-known [Ru(bpy)3(PF6)2] complex, because the micelles were swollen in the methanol-sulfide mixture. Moreover, because of the nanoscale size of the particles and their high stability, the Ru-CM photocatalysts can be readily recovered by ultrafiltration and reused without loss of photocatalytic activity. This work highlights the potential of using cross-linked micelles as a platform for developing highly efficient heterogeneous photocatalysts for a number of important organic transformations. PMID- 23939955 TI - Identification of imidacloprid metabolites in onion (Allium cepa L.) using high resolution mass spectrometry and accurate mass tools. AB - RATIONALE: Imidacloprid is a potent and widely used insecticide on vegetable crops, such as onion (Allium cepa L.). Because of possible toxicity to beneficial insects, imidacloprid and several metabolites have raised safety concerns for pollenating insects, such as honey bees. Thus, imidacloprid metabolites continue to be an important subject for new methods that better understand its dissipation and fate in plants, such as onions. METHODS: One month after a single addition of imidacloprid to soil containing onion plants, imidacloprid and its metabolites were extracted from pulverized onion with a methanol/water-buffer mixture and analyzed by liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/QTOF-MS) using a labeled imidacloprid internal standard and tandem mass spectrometric (MS/MS) analysis. RESULTS: Accurate mass tools were developed and applied to detect seven new metabolites of imidacloprid with the goal to better understand its fate in onion. The accurate mass tools include: database searching, diagnostic ions, chlorine mass filters, Mass Profiler software, and manual use of metabolic analogy. The new metabolites discovered included an amine reduction product (m/z 226.0854), and its methylated analogue (m/z 240.1010), and five other metabolites, all of unknown toxicity to insects. CONCLUSIONS: The accurate mass tools were combined with LC/QTOF-MS and were able to detect both known and new metabolites of imidacloprid using fragmentation studies of both parent and labeled standards. New metabolites and their structures were inferred from these MS/MS studies with accurate mass, which makes it possible to better understand imidacloprid metabolism in onion as well as new metabolite targets for toxicity studies. PMID- 23939957 TI - Tandem mass spectrometric analysis of isosorbide-1,4-cyclohexane-dicarboxylic acid polyester oligomer cations using ion-trap mass spectrometry. AB - RATIONALE: Isosorbide is a promising biomass-derived molecule that can be used as a replacement for fossil resource-derived diol monomers used in polyester synthesis. Due to its increased use in sustainable development, it is useful to understand the tandem mass spectrometric (MS/MS) fragmentation pathways of the isosorbide-based copolymer as an aid to interpreting the MS/MS spectra of other isosorbide-containing copolymers. METHODS: Collision-activated dissociation (CAD) experiments were performed on the sodiated/protonated molecules, [(AB)(n)A+Na(or H)](+), n = 2-5, of isosorbide (A)-1,4-cyclohexanedicarboxylic acid (B) oligomers formed by ion-trap electrospray ionization (ESI). RESULTS: Product ions arose from cleavage of the bonds between isosorbide and 1,4-cyclohexanedicarboxylic acid. In the MS/MS spectra, f(n)'' product ions were most abundant, followed by e(n) ions. McLafferty rearrangement appeared to provide the most facile pathway to yield the abundant f(n)'' and e(n) ions. In addition, a(n), b(n)'', f(n)''u(n)'', and en (+) ions were observed. Inductive cleavage and beta elimination were suggested to be the pathways involved in generating e(n)(+)- and e(n)/b(n)''-type ions, respectively. CONCLUSIONS: Based on the obtained CAD spectra, the alternating sequences of two copolymer building blocks, A and B, were unambiguously determined. The fragmentation pathways leading to the observed product ion types were also established. PMID- 23939956 TI - Hydrogen isotope ratio mass spectrometry and high-resolution/high-accuracy mass spectrometry in metabolite identification studies: detecting target compounds for sports drug testing. AB - RATIONALE: In sports drug testing, comprehensive studies on the metabolism of therapeutic agents with misuse potential are necessary to identify metabolites that provide utmost retrospectivity and specificity. By commonly employed approaches minor and/or long-term metabolites in urine might remain undetected. Hence, an alternative strategy to unambiguously identify the majority of urinary metabolites including low-abundance representatives is desirable. METHODS: Urine samples were collected for 20 days during an elimination study with an oral dose of 5 mg of 17alpha-C(2)H3-metandienone. The specimens were processed according to established sample preparation procedures (including fractionation and deconjugation) and subjected to gas chromatography/hydrogen isotope ratio mass spectrometry (GC/IRMS) analysis. Due to the deuteration of the administered drug, urinary metabolites bearing the deuterium label yield abundant and specific signals on the GC/IRMS instrument resulting from the substantially altered (2)H/(1)H ratio. The sample aliquots were measured by gas chromatography/time-of flight (GC/Q-TOF) mass spectrometry using identical GC conditions, allowing high resolution/high-accuracy mass data to be obtained on all urinary metabolites previously identified by IRMS. RESULTS: Within the IRMS chromatograms, labeled metabolites were identified up to 20 days after administration at urinary concentration down to 0.25 ng/mL. More than 50 metabolites were observed with the earlier described long-term metabolite of metandienone, 18-nor-17beta hyroxymethyl,17alpha-methyl-androst-1,4,13-trien-3-one, being the most prominent glucuronidated metabolite in the studied time window. In the sulfoconjugated steroids fraction, a yet unknown metabolite was observed at m/z 283.1997 comprising the experimentally determined elemental composition of C20H21(2)H3O. CONCLUSIONS: Combining IRMS with high-resolution mass spectrometry considerably facilitates and accelerates metabolite identification of deuterium-labeled compounds in urine. Of particular relevance in doping control, the principle is applicable also to other arenas of drug research, allowing the preparation and administration of e.g. radioactively labeled substances to be omitted. PMID- 23939958 TI - Strontium concentrations and isotope ratios in enamel of healthy and carious teeth in southern Shaanxi, China. AB - RATIONALE: As the trace element strontium (Sr) plays a significant role in dental health, it is important to determine the Sr concentration and isotope composition ((87)Sr/(86)Sr) of teeth and whether these values are related to caries formation, age and sex. METHODS: A total of 160 permanent teeth were collected from 7- to 79-year-old people from the southern Shaanxi area of China, including 100 healthy teeth and 60 carious teeth (men and women each accounted for half of the samples). The concentration and isotope composition of Sr elements in the dental enamel of the teeth were measured using inductively coupled plasma mass spectrometry (ICP-MS) and thermal ionization mass spectrometry (TIMS). RESULTS: A significantly lower Sr concentration was found in the enamel of the carious teeth than in that of the healthy teeth for individuals of varying ages and sex. The Sr concentration in human carious teeth ranged between 79.70 ug/g and 85.80 ug/g; while the Sr concentration in healthy teeth ranged between 128 ug/g and 156.77 ug/g. Our results also demonstrated that the (87)Sr/(86)Sr ratio did not appear to be affected by the caries formation, age or sex. The (87)Sr/(86)Sr ratio in the enamel of the healthy and carious teeth of individuals of varying ages and genders ranged between 0.710935 and 0.711037, which falls into the range of (87)Sr/(86)Sr ratios found in the local, naturally occurring water, soils and rocks. CONCLUSIONS: Sr plays a significant role in dental health, and there is a negative correlation between Sr and the occurrence of dental caries. The (87)Sr/(86)Sr ratio of teeth reflects the (87)Sr/(86)Sr ratio of the associated environment, and there is no significant relationship with the frequency of dental caries, age or sex. PMID- 23939959 TI - Quantification of docetaxel and its metabolites in human plasma by liquid chromatography/tandem mass spectrometry. AB - RATIONALE: During drug development accurate quantification of metabolites in biological samples using mass spectrometry is often hampered by the lack of metabolites of chemically pure quality. However, quantification of metabolites can be useful for assessment and interpretation of (pre)clinical data. We now describe an approach to quantify docetaxel metabolites in human plasma by liquid chromatography/tandem mass spectrometry (LC/MS/MS) using docetaxel calibration standards. METHODS: Metabolites (M1/M3, M2 and M4) were generated using microsomal incubations. Retention times of docetaxel and its metabolites were assessed using an LC/UV assay and peak identification was performed by LC/MS(n). Samples containing isolated metabolites from human faeces were quantified by LC/UV and used as references for spiking human plasma samples. LC/MS/MS was applied to sensitively quantify docetaxel and its metabolites in human plasma using docetaxel calibration standards in a range of 0.25-500 ng/mL. RESULTS: Because ionisation of docetaxel and its metabolites differed, correction factors were established to quantify the metabolites using docetaxel calibration samples. During method validation, accuracy and precision of the metabolites were within +/-7.7% and <=17.6%, respectively, and within +/-14.3% and <=10.1%, respectively, for docetaxel. Metabolites were found to be unstable in human plasma at ambient temperature. After storage up to 1 year at -20 degrees C, recovered metabolite concentrations were within +/-25%. CONCLUSIONS: Development and validation of an LC/MS/MS assay for the quantification of docetaxel and its metabolites M1/M3, M2 and M4 using docetaxel calibration standards is described. The same approach may be used for quantification of metabolites of other drugs by LC/MS/MS when chemically pure reference substances are unavailable. PMID- 23939960 TI - Simultaneous characterization of methane and carbon dioxide produced by cultured methanogens using gas chromatography/isotope ratio mass spectrometry and gas chromatography/mass spectrometry. AB - RATIONALE: The stable carbon isotope ratios of methanogen-produced CH4 and CO2 are useful information for identifying and quantifying methanogenic pathways. Isotope ratio mass spectrometry combined with gas chromatography (GC/IRMS) is a very attractive tool for performing high-precision compound-specific isotope analysis. However, no GC/IRMS techniques have yet been available or been validated that give baseline separation of methanogen-produced CH4 and CO2 from N2/N-oxides and H2O vapor at ambient temperature and compatibility with analysis by mass spectrometry. METHODS: Microbe-produced CH4 and CO2 in headspace gases were separated from N2/N-oxides and H2O vapor in a single run on a GS-CarbonPLOT column at 35 degrees C and with a maximum operating temperature of 120-140 degrees C. The simultaneous characterization of CH4 and CO2 was then performed by GC/IRMS using an optimized backflush time to eliminate the interference from N2/N oxides and H2O vapor, and by GC/MS due to there being no interference from O2 gas in the culture. RESULTS: GC/MS and GC/IRMS were used to calculate the ionization efficiency of CO2 as 8.22-8.84 times that of CH4 in GC/MS analysis, and it was deduced that the N-oxides, which can potentially interfere with delta(13)C analysis, were probably produced mainly in the source of the isotope ratio mass spectrometer. We also determined the aceticlastic methanogenic pathway. CONCLUSIONS: The established GC/MS and GC/IRMS techniques are suitable for characterizing the gaseous carbon-containing compounds produced by microbial cultures. Through high-precision carbon isotope analysis by GC/IRMS combined with low concentrations of (13)C-labelled substrates, the technique has great potential for identifying and quantifying methanogen-mediated carbon metabolic processes and pathways. PMID- 23939961 TI - Advantages of using fecal samples for stable isotope analysis in bats: evidence from a triple isotopic experiment. AB - RATIONALE: Stable isotope analysis in ecological studies is usually conducted on biomaterials, e.g. muscle and blood, that require catching the animals. Feces are rarely used for stable isotope analysis, despite the possibility of non-invasive sampling and short-term responsiveness to dietary changes. This promising method is neglected due to a lack of calibration experiments and unknown diet-feces isotopic difference (Delta(diet-feces)). METHODS: To fill this gap, we simulated trophic changes occurring in nature when animals switch feeding habitats, e.g. by moving from freshwater to terrestrial systems, from cultivated areas to forests or changing distance from marine environments. In a controlled experiment, the diet of two bat species (Myotis myotis, Rhinolophus ferrumequinum) was altered to an isotopically distinct one. We measured stable nitrogen, carbon and the rarely used sulfur isotope in feces, and calculated Delta(diet-feces) values. RESULTS: The feces acquired the new dietary signature within 2-3 h from food ingestion; thus, they are suited for detecting recent and rapid dietary changes. The Delta(diet-feces) (Delta) did not differ between species or diet (overall means +/- standard deviation (sd)): Delta(15)N: 1.47 +/- 1.510/00, Delta(13)C: -0.11 +/ 0.800/00, Delta(34)S: 0.74 +/- 1.100/00. Only Delta(15)N for M. myotis was significantly different from zero and only Delta(13) C differed among the days of the experiment. CONCLUSIONS: Fecal stable isotopes can be now further applied in mammalian ecology. This includes a range of applications, such as studying changes in trophic level, resource or habitat use, on a short time-scale. Such information is gaining importance for monitoring rapidly changing ecosystems under anthropogenic influence. PMID- 23939962 TI - Imidazolium salts with varying anions as charge carriers for detection of neutral bis(triphenylphosphine)palladium(II) dichloride in electrospray ionization mass spectrometry. AB - RATIONALE: While electrospray ionization is a popular technique for mass analysis, without a charged species it is ineffective. This coupled with solvent restrictions hinders the analysis of organometallic complexes. Detecting neutral species whose solubility is limited to nonconventional solvents is a problem that can be overcome with the right charge carrier, which is described in this study. METHODS: Ionic liquids were synthesized and analyzed by electrospray ionization quadrupole ion trap mass spectrometry. The neutral palladium complex was also analyzed using different imidazolium salts as the charge carrier with the same method and instrumentation. Theoretical complements were also performed using Gaussian 09 at the density functional theory levels, using B3LYP functionals and the 6-31 g (d,p) basis set for geometry optimizations. RESULTS: Low concentration imidazolium salts in methanol showed aggregation behavior of the ionic liquid, where the cation peak and [cation](n+1)[anion]n peaks were observed in positive mode, while the [cation]n[anion](n+1) peaks were seen in negative mode. The unbound anion was observed in all the negative mode spectra except for the salt with the SCN anion when in THF. Solutions of PdCl2(PPh3)2 and a small amount of ionic liquid in THF showed the palladium complex adducted with the imidazolium cation for each of the ionic liquids studied. CONCLUSIONS: A charge carrier for a neutral organometallic complex was found in imidazolium salts, where the cation was observed as the ionizing agent. Differing ion intensities of the complex adduct peak resulted from the anions ability to dissociate from the cation. PMID- 23939963 TI - Variability of 13C-labeling in plant leaves. AB - RATIONALE: Plant tissues artificially labeled with (13)C are increasingly used in environmental studies to unravel biogeochemical and ecophysiological processes. However, the variability of (13)C-content in labeled tissues has never been carefully investigated. Hence, this study aimed at documenting the variability of (13)C-content in artificially labeled leaves. METHODS: European beech and Italian ryegrass were subjected to long-term (13)C-labeling in a controlled-environment growth chamber. The (13)C-content of the leaves obtained after several months labeling was determined by isotope ratio mass spectrometry. RESULTS: The (13)C content of the labeled leaves exhibited inter- and intra-leaf variability much higher than those naturally occurring in unlabeled plants, which do not exceed a few per mil. This variability was correlated with labeling intensity: the isotope composition of leaves varied in ranges of ca 600/00 and 900/00 for experiments that led to average leaf (13)C-content of ca +150/00 and +4500/00, respectively. CONCLUSIONS: The reported variability of isotope composition in (13)C-enriched leaves is critical, and should be taken into account in subsequent experimental investigations of environmental processes using (13)C-labeled plant tissues. PMID- 23939964 TI - Carbon disulfide as a dopant in photon-induced chemical ionization mass spectrometry. AB - RATIONALE: The addition of a dopant to an Atmospheric Pressure PhotoIonization (APPI) source of a mass spectrometer has been shown to enhance the degree of analyte ionization. A series of different dopants has been successfully utilized; however, there has been very little published on the characteristics of a good dopant. We have proposed carbon disulfide (CS2) as a novel new dopant based on its absorption cross-section for the VUV photon's energy used and its unique gas phase ion chemistry, notably the fact that it does not contain a proton. METHODS: The ability of CS2 to enhance the ionization effectiveness of APPI was tested by using a group of compounds that have different proton affinities (PAs) and electron affinities (EAs). These results were compared to results obtained using the commonly used dopants, toluene and anisole. Particular attention was paid to the formation of [M](+) ions relative to [M+H](+) ions. Mass spectra were collected using a Waters Quattro Premier liquid chromatography/tandem mass spectrometry (LC/MS/MS) system equipped with a commercial PhotomateTM photoionization source. RESULTS: The results show that CS2 increases the ionization efficiency of most of the analytes studied in this work comparably to toluene and anisole. CS2 promotes both ionization routes of [M](+) and [M+H](+). In addition, due to the higher ionization energy (IE) of CS2 (10.01) compared to the IEs of toluene (8.83) and anisole (8.20), CS2 can enhance the ionization efficiency of analytes that cannot be enhanced with toluene and anisole. CONCLUSIONS: We have determined that CS2 is a viable dopant for use in APPI sources. For some analytes, significant [M+H](+) ion signals are observed; therefore, the donated proton must come from either water clusters or solvents. In addition, CS2 promotes the ionization of analytes with low PAs and higher IEs than that of toluene and anisole. PMID- 23939965 TI - Improved optimization of the Fourier transform ion cyclotron resonance mass spectrometry phase correction function using a genetic algorithm. AB - RATIONALE: Fourier Transform Ion Cyclotron Resonance mass spectra exhibit improved resolving power, mass accuracy and signal-to-noise ratio when presented in absorption mode; a process which requires calculation of a phase correction function. Mass spectrometric images can contain many thousands of pixels; hence methods of decreasing the time required to solve for a phase correction function will result in significant improvements in this application. METHODS: A genetic algorithm approach for optimizing the phase correction function has been developed and compared with a previously described convergent iteration technique. RESULTS: The genetic algorithm method has been shown to offer a five fold improvement in processing speed compared with the previous iterative approach used in the Autophaser algorithm, while maintaining the levels of accuracy. This translates to an 11 hour improvement in processing for a 20 000 pixel mass spectrometric image. CONCLUSIONS: The genetic algorithm method described in this manuscript offers significant processing speed advantages over the previously described convergent iteration technique. This improvement is key to allowing the future routine use of absorption mode mass spectrometric images. PMID- 23939966 TI - Quantification of pentane in exhaled breath, a potential biomarker of bowel disease, using selected ion flow tube mass spectrometry. AB - RATIONALE: Inflammatory bowel disease has a relatively large incidence in modern populations and the current diagnostic methods are either invasive or have limited sensitivity or specificity. Thus, there is a need for new non-invasive methods for its diagnosis and therapeutic monitoring, and breath analysis represents a promising direction in this area of research. Specifically, a method is needed for the absolute quantification of pentane in human breath. METHODS: Selected ion flow tube mass spectrometry (SIFT-MS) has been used to study the kinetics of the O2(+) reaction with pentane. Product ions at m/z 42 and 72 were chosen as characteristic ions useful for the quantification of pentane and the reactivity of these ions with water vapour was characterized. A pilot study has been carried out of pentane in the exhaled breath of patients with Crohn's disease (CD) and ulcerative colitis (UC) and of healthy volunteers. RESULTS: Accurate data on the kinetics of the gas phase reaction of the O2(+*) ions with pentane have been obtained: rate coefficient 8 * 10(-10) cm(3) s(-1) (+/-5%) and branching ratios into the following product ions C5H12(+*) (m/z 72, 31%); C4H9(+) (m/z 57, 8%); C3H7(+) (m/z 43, 40%), C3H6(+*) (m/z 42, 21%). A method of calculation of absolute pentane concentration in exhaled breath was formulated using the count rates of the ions at m/z 32, 42, 55 and 72. Pentane was found to be significantly elevated in the breath of both the CD (mean 114 ppbv) and the UC patients (mean 84 ppbv) relative to the healthy controls (mean 40 ppbv). CONCLUSIONS: SIFT-MS can be used to quantify pentane in human breath in real time avoiding sample storage. This method of analysis can ultimately form the basis of non-invasive screening of inflammatory processes, including inflammatory bowel disease. PMID- 23939967 TI - Clustering of simple aminosulfonic acids--electrospray ionization mass spectrometric study. AB - RATIONALE: Aminosulfonic acids are structurally related to amino acids as bifunctional compounds. Some of them like taurine and homotaurine play important roles in biology. Although there is a vast literature devoted to the electrospray ionization mass spectrometric (ESI-MS) study of amino acid aggregation, no such study has been performed so far for aminosulfonic acids. METHODS: A gas-phase clustering study was performed for aminomethanesulfonic acid (AMS), taurine (Tau), homotaurine (HT), and cysteic acid (CA) from water and methanol/water solutions, using a Bruker TOF-Q spectrometer equipped with an ESI source, in the negative-ion mode. For selected anionic clusters the tandem mass (MS/MS) spectra were recorded and the breakdown curves were obtained. The cluster formation abilities (ACS parameter) of the studied molecules were calculated. RESULTS: Both singly and doubly charged clusters were formed when the acids were electrosprayed from water solutions; they may be described as [(H3N-R-SO3)n-zH](z-), where z = 1 or 2. The largest identified clusters are built of 20, 22, 20 and 4 monomers of AMS, Tau, HT and CA, respectively. The doubly negatively charged clusters were observed for n >=9, 12, 14 in the case of AMS, Tau and HT. AMS pentamers and Tau, HT tetramers and hexamers show higher stabilities than the other clusters. CONCLUSIONS: The results indicate that aminosulfonic acids form large stable clusters, similarly to aminocarboxylic acids. The cluster formation ability decreases with an increase in CH2 chain length within the series of the studied compounds. The large singly and doubly charged aggregates are formed under the conditions of the experiment, possibly in the droplets. Taurine dissolved in water seems to be a good calibrant for electrospray instruments in negative ion mode. PMID- 23939968 TI - Structural elucidation of palytoxin analogs produced by the dinoflagellate Ostreopsis ovata IK2 strain by complementary use of positive and negative ion liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - RATIONALE: The ovatoxins are palytoxin analogs of a dinoflagellate origin implicated in human intoxication. The structures of ovatoxin-a, ovatoxin-d, and ovatoxin-e produced by the IK2 strain of Ostreopsis ovata collected in Japan were elucidated using liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/QTOFMS). The novel structures and a new insight into the spectral data are presented. METHODS: The structural elucidations were carried out by complementary use of positive and negative ion LC/QTOFMS. Ostreocin-D (C127H219N3O53), another palytoxin congener previously elucidated by negative fast-atom bombardment collision-induced tandem mass spectrometry (FAB CID MS/MS), was used as a reference. RESULTS: Positive ion spectra allowed deduction of hydroxyl positions based on the conjugated polyene structures produced, while the negative ion spectra allowed assignments of cleavage sites of C-C bonds. The analysis could be performed using a small sample without extensive purification. CONCLUSIONS: Ovatoxin-a IK2 (C129H223N3O52), ovatoxin-d IK2 (C129H223N3O53), and ovatoxin-e IK2 (C129H223N3O53) were tentatively assigned to 42-hydroxy-17,44,70 trideoxypalytoxin, 42-hydroxy-17,70-dideoxypalytoxin and 42,82-dihydroxy-17,44,70 trideoxypalytoxin, respectively. The wide applicability of the method was suggested. PMID- 23939969 TI - Multi-allergen quantification of fining-related egg and milk proteins in white wines by high-resolution mass spectrometry. AB - RATIONALE: A method based on High-Resolution Mass Spectrometry was developed for the simultaneous determination of fining agents containing potentially allergenic milk (casein) and egg-white (lysozyme and ovalbumin) proteins, added to commercial white wines at sub-ppm levels. Selected tryptic peptides were used as quantitative markers. An evaluation of protein digestion yields was also performed by implementing the (15)N-valine-labelled analogues of the best peptide markers identified for alphaS1 -casein and ovalbumin. METHODS: The method was based on the combination of ultrafiltration (UF) of protein-containing wines, tryptic digestion of the dialyzed wine extracts and liquid chromatography/high resolution mass spectrometry (LC/HRMS) analysis of tryptic digests. Peptides providing the most intense electrospray ionization (ESI)-MS response were chosen as quantitative markers of the proteins under investigation. RESULTS: Six-point calibrations were performed by adding caseinate and egg-white powder in the concentration range between 0.25 and 10 ug/mL, to an allergen-free white wine. The following three peptide markers, LTEWTSSNVMEER, GGLEPINFQTAADQAR and ELINSWVESQTNGIIR, were highlighted as best markers for ovalbumin, while GTDVQAWIR and NTDGSTDYGILQINSR for lysozyme and YLGYLEQLLR, GPFPIIV and FFVAPFPEVFGK for caseinate. Limits of detection (LODs) ranged from 0.4 to 1.1 ug/mL. CONCLUSIONS: The developed method is suited for assessing the contemporary presence of allergenic milk and egg proteins characterizing egg white and caseinate, fining agents typically employed for wine clarification. The LODs of the method enable the detection of sub-ppm concentrations of residual fining agents, that could represent a potential risk for allergic consumers. PMID- 23939970 TI - The relationship between electrospray ionization behavior and cytotoxic activity of [M(I)(P)4](+)-type complexes (M = Cu, Ag and Au; P = tertiary phosphine). AB - RATIONALE: To try to find a correlation between the antiproliferative activity of a series of [M(I)(P)4](+) complexes (M = Cu, Ag and Au; P = tertiary phosphine) and their stability at micromolar concentration under mass spectrometric conditions. METHODS: [M(I)(P)4](+) complexes were investigated by positive ion electrospray ionization mass spectrometry with multiple collisional experiments using an ion trap mass spectrometer. RESULTS: The displacement of P from native [M(I)(P)4](+), previously described for the copper derivative, is common for the triad complexes leading to the formation of [M(P)3](+) and [M(P)2](+) adducts. Further dissociation of [M(P)2](+) depends on the nature of the metal (Cu ~ Ag > Au). More labile [Cu(P)2](+) and [Ag(P)2](+) are more cytotoxic against HCT-15 human colon carcinoma cells compared to less labile [Au(P)2](+) species. CONCLUSIONS: The dissociation of P ligand(s) from the [M(I)(P)4](+) complexes is the driving force for the triggering of the antiproliferative activity. The more favored is the displacement of P from the [M(P)2](+) active form, the more favored is in turn the possibility for the metal to interact with biological substrates related to cancer proliferation. PMID- 23939971 TI - Mapping the protein-binding sites for novel iridium(III) anticancer complexes using electron capture dissociation. AB - RATIONALE: Application of Fourier transform ion cyclotron (FT-ICR) tandem mass spectrometry reveals the binding sites for novel cyclopentadienyl Ir(III) anticancer complexes on calmodulin. The conventional fragmentation methods, collisionally activated dissociation (CAD) and infrared multiphoton dissociation (IRMPD), failed to define the Ir modification, but these binding sites were located via electron capture dissociation (ECD). METHODS: A combination of top down and bottom-up methods was used to generate detailed information about the reaction of these compounds with a common signalling protein, calmodulin. RESULTS: The research shows that such Ir-based complexes preferentially bind to methionine sites in the protein, and interestingly, the very low efficiency of the Ir modification is different compared to reactions of Pt(II) complexes, which can lead to protein crosslinking. CONCLUSIONS: This is the first report on reactions of novel Ir-based anticancer complexes with proteins, which provides helpful information for studying the protein targets of this category of metallodrug and the transportation mechanisms which allow them to inhibit cancer cell growth. PMID- 23939972 TI - Mass spectral studies of diamide compounds obtained by the Ugi reaction. PMID- 23939974 TI - Arterivirus molecular biology and pathogenesis. AB - Arteriviruses are positive-stranded RNA viruses that infect mammals. They can cause persistent or asymptomatic infections, but also acute disease associated with a respiratory syndrome, abortion or lethal haemorrhagic fever. During the past two decades, porcine reproductive and respiratory syndrome virus (PRRSV) and, to a lesser extent, equine arteritis virus (EAV) have attracted attention as veterinary pathogens with significant economic impact. Particularly noteworthy were the 'porcine high fever disease' outbreaks in South-East Asia and the emergence of new virulent PRRSV strains in the USA. Recently, the family was expanded with several previously unknown arteriviruses isolated from different African monkey species. At the molecular level, arteriviruses share an intriguing but distant evolutionary relationship with coronaviruses and other members of the order Nidovirales. Nevertheless, several of their characteristics are unique, including virion composition and structure, and the conservation of only a subset of the replicase domains encountered in nidoviruses with larger genomes. During the past 15 years, the advent of reverse genetics systems for EAV and PRRSV has changed and accelerated the structure-function analysis of arterivirus RNA and protein sequences. These systems now also facilitate studies into host immune responses and arterivirus immune evasion and pathogenesis. In this review, we have summarized recent advances in the areas of arterivirus genome expression, RNA and protein functions, virion architecture, virus-host interactions, immunity, and pathogenesis. We have also briefly reviewed the impact of these advances on disease management, the engineering of novel candidate live vaccines and the diagnosis of arterivirus infection. PMID- 23939973 TI - Wnt5a regulates hematopoietic stem cell proliferation and repopulation through the Ryk receptor. AB - Proper regulation of the balance between hematopoietic stem cell (HSC) proliferation, self-renewal, and differentiation is necessary to maintain hematopoiesis throughout life. The Wnt family of ligands has been implicated as critical regulators of these processes through a network of signaling pathways. Previously, we have demonstrated that the Wnt5a ligand can induce HSC quiescence through a noncanonical Wnt pathway, resulting in an increased ability to reconstitute hematopoiesis. In this study, we tested the hypothesis that the Ryk protein, a Wnt ligand receptor that can bind the Wnt5a ligand, regulated the response of HSCs to Wnt5a. We observed that inhibiting Ryk blocked the ability of Wnt5a to induce HSC quiescence and enhance short-term and long-term hematopoietic repopulation. We found that Wnt5a suppressed production of reactive oxygen species, a known inducer of HSC proliferation. The ability of Wnt5a to inhibit ROS production was also regulated by Ryk. From these data, we propose that Wnt5a regulates HSC quiescence and hematopoietic repopulation through the Ryk receptor and that this process is mediated by suppression of reactive oxygen species. PMID- 23939975 TI - Reassortment and migration analysis of Crimean-Congo haemorrhagic fever virus. AB - Crimean-Congo haemorrhagic fever virus (CCHFV) is a tick-borne virus with high pathogenicity to humans. CCHFV contains a three-segment [small (S), medium (M) and large (L)] genome and is prone to reassortment. Investigation of identified reassortment events can yield insight into the evolutionary history of the virus, while migration events reflect its geographical dissemination. While many studies have already considered these issues, they have investigated small numbers of isolates and lack statistical support for their findings. Here, we consider a larger set of 30 full genomes to investigate reassortment using recombination methods, as well as two sets of partial S segments comprising 393 isolates, reflecting a broader geographical range, to investigate migration events. Phylogenetic analysis revealed that the S segment showed strong geographical subdivision, but this was less apparent in the M and L segments. A total of 16 reassortment events with 22 isolates were identified with strong statistical support. Migration analysis on the partial S segments identified both long- and short-range migration events that spanned the entire geographical region in which the CCHFV has been isolated, reflecting the complex processes associated with the dissemination of the virus. PMID- 23939976 TI - Isolation and molecular characterization of Fikirini rhabdovirus, a novel virus from a Kenyan bat. AB - Zoonotic and vector-borne pathogens have comprised a significant component of emerging human infections in recent decades, and bats are increasingly recognized as reservoirs for many of these disease agents. To identify novel pathogens associated with bats, we screened tissues of bats collected in Kenya. Virus isolates were identified by next generation sequencing of viral nucleic acid preparations from the infected cell culture supernatant and characterized. Here we report the identification of Fikirini rhabdovirus, a novel rhabdovirus isolated from a bat, Hipposideros vittatus, captured along the Kenyan coast. PMID- 23939977 TI - Human cytomegalovirus directly modulates expression of chemokine CCL2 (MCP-1) during viral replication. AB - Human cytomegalovirus (CMV) infects monocytes and other haematopoietic progenitor cells which then act as reservoirs for latency and virus dissemination. The chemokine CCL2 (monocyte chemotactic protein-1 or MCP-1) exhibits potent chemotactic activity for monocytes and is a likely target for CMV-induced immunomodulation. In this study, we demonstrate CMV modulates CCL2 expression in MRC-5 fibroblasts with multiplicity-dependent kinetics, where CCL2 is upregulated during early stage infection, followed by CCL2 inhibition at late stage infection. This CMV-induced CCL2 modulation was dependent upon virus replication, as UV-inactivated virus did not elicit any changes in CCL2 levels. Dual immunofluorescence staining showed CMV strains AD169, purified AD169, Merlin, FIX WT (FLAG-US28/WT) and pUS28-deficient FIX (FIX-DeltaUS28) all induced upregulation of CCL2 primarily within infected cells. Focal upregulation of CCL2 within FIX-DeltaUS28-infected cells demonstrated intracellular CCL2 accumulation was independent of CCL2 sequestration by the CMV-encoded chemokine receptor US28. Infection with purified virus confirmed CMV-induced CCL2 upregulation was not due to any CCL2-inducing factors contained within non-purified virus stocks. The CMV induced CCL2 expression kinetics occurred concurrently with modulation of the CCL2 transcriptional activators NF-kappaB, interferon regulatory factor 3 and cytokine IFN-beta, independent of virus strain, and with the establishment of viral replication compartments within infected cell nuclei. This is the first report to our knowledge to demonstrate CMV modulation of CCL2 expression within infected cells during viral replication. This immune modulation may facilitate virus dissemination, establishment of latency and pathogenesis of CMV-induced host disease. PMID- 23939978 TI - Barkedji virus, a novel mosquito-borne flavivirus identified in Culex perexiguus mosquitoes, Israel, 2011. AB - Barkedji virus, named after the area of its first identification in Senegal, is a newly discovered flavivirus (FV), for which we propose the abbreviation BJV. In the present study, we report the first-time detection of BJV in Culex perexiguus mosquitoes in Israel in 2011 and determination of its almost complete polyprotein gene sequence. We characterized the BJV genome and defined putative mature proteins, conserved structural elements and potential enzyme motifs along the polyprotein precursor. By comparing polyproteins and individual proteins of BJV with several other FVs, a distant relationship of BJV to Nounane virus (NOUV), a recently described African FV, is demonstrated. Phylogenetic analysis of 55 selected flaviviral polyprotein gene sequences exhibits two major clusters, one made up of the classical three clades of FVs: mosquito-borne, tick-borne and those without known vectors. The other cluster exclusively contains so-called 'insect-specific' FVs, which do not replicate in vertebrate cells. Based on our phylogenetic analysis, BJV is related to other members of the mosquito-borne clade with yet unknown vertebrate hosts, such as NOUV, Donggang virus, Chaoyang virus and Lammi virus. However, with a maximum identity of only 54 % to NOUV, BJV represents a distinct new virus species. PMID- 23939979 TI - Characterization of messenger RNA termini in Schmallenberg virus and related Simbuviruses. AB - Schmallenberg virus (SBV) is an emerging arbovirus infecting ruminants in Europe. SBV belongs to the Bunyaviridae family within the Simbu serogroup. Its genome comprises three segments, small (S), medium (M) and large (L), that together encode six proteins and contain NTRs. NTRs are involved in initiation and termination of transcription and in genome packaging. This study explored the 3' mRNA termini of SBV and related Simbuviruses. In addition, the 5' termini of SBV messenger RNA (mRNA) were characterized. For the three SBV segments, cap snatching was found to initiate mRNA transcription both in vivo and in vitro. The presence of extraneous nucleotides between host RNA leaders and the viral termini fits with the previously described prime-and-realign theory. At the 3' termini, common features were identified for SBV and related Simbuviruses. However, different patterns were observed for the termini of the three segments from the same virus type. PMID- 23939980 TI - Reduced sphingosine kinase 1 activity in dengue virus type-2 infected cells can be mediated by the 3' untranslated region of dengue virus type-2 RNA. AB - Sphingosine kinase 1 (SphK1) is a lipid kinase with important roles including regulation of cell survival. We have previously shown reduced SphK1 activity in cells with an established dengue virus type-2 (DENV-2) infection. In this study, we examined the effect of alterations in SphK1 activity on DENV-2 replication and cell death and determined the mechanisms of the reduction in SphK1 activity. Chemical inhibition or overexpression of SphK1 after established DENV-2 infection had no effect on infectious DENV-2 production, although inhibition of SphK1 resulted in enhanced DENV-2-induced cell death. Reduced SphK1 activity was observed in multiple cell types, regardless of the ability of DENV-2 infection to be cytopathic, and was mediated by a post-translational mechanism. Unlike bovine viral diarrhea virus, where SphK1 activity is decreased by the NS3 protein, SphK1 activity was not affected by DENV-2 NS3 but, instead, was reduced by expression of the terminal 396 bases of the 3' UTR of DENV-2 RNA. We have previously shown that eukaryotic elongation factor 1A (eEF1A) is a direct activator of SphK1 and here DENV-2 RNA co-localized and co-precipitated with eEF1A from infected cells. We propose that the reduction in SphK1 activity late in DENV-2-infected cells is a consequence of DENV-2 out-competing SphK1 for eEF1A binding and hijacking cellular eEF1A for its own replication strategy, rather than a specific host or virus-induced change in SphK1 to modulate viral replication. Nonetheless, reduced SphK1 activity may have important consequences for survival or death of the infected cell. PMID- 23939981 TI - Co-incorporation of the PB2 and PA polymerase subunits from human H3N2 influenza virus is a critical determinant of the replication of reassortant ribonucleoprotein complexes. AB - The influenza virus RNA polymerase, composed of the PB1, PB2 and PA subunits, has a potential role in influencing genetic reassortment. Recent studies on the reassortment of human H3N2 strains suggest that the co-incorporation of PB2 and PA from the same H3N2 strain appears to be important for efficient virus replication; however, the underlying mechanism remains unclear. Here, we reconstituted reassortant ribonucleoprotein (RNP) complexes and demonstrated that the RNP activity was severely impaired when the PA subunit of H3N2 strain A/NT/60/1968 (NT PA) was introduced into H1N1 or H5N1 polymerase. The NT PA did not affect the correct assembly of the polymerase trimeric complex, but it significantly reduced replication-initiation activity when provided with a vRNA promoter and severely impaired the accumulation of RNP, which led to the loss of RNP activity. Mutational analysis demonstrated that PA residues 184N and 383N were the major determinants of the inhibitory effect of NT PA and 184N/383N sequences were unique to human H3N2 strains. Significantly, NT PB2 specifically relieved the inhibitory effect of NT PA, and the PB2 residue 627K played a key role. Our results suggest that PB2 from the same H3N2 strain might be required for overcoming the inhibitory effect of H3N2 PA in the genetic reassortment of influenza virus. PMID- 23939982 TI - Analysis of Soybean mosaic virus genetic diversity in Iran allows the characterization of a new mutation resulting in overcoming Rsv4-resistance. AB - The genetic variation and population structure of Soybean mosaic virus (SMV) in Iran was analysed through the characterization of a set of isolates collected in the soybean-growing provinces of Iran. The partial nucleotide sequence of these isolates showed a single, undifferentiated population with low genetic diversity, highly differentiated from other SMV world populations. These traits are compatible with a population bottleneck associated with the recent introduction of SMV in Iran. Phylogenetic analyses suggest that SMV was introduced into Iran from East Asia, with at least three introduction events. The limited genetic diversification of SMV in Iran may be explained by strong negative selection in most viral genes eliminating the majority of mutations, together with recombination purging deleterious mutations. The pathogenicity of Iranian SMV isolates was typified on a set of soybean differential lines either susceptible or carrying different resistance genes or alleles to SMV. Two pathotypes were distinguished according to the ability to overcome Rsv4 resistance in line V94 5152. Amino acid sequence comparisons of virulent and avirulent isolates on V94 5152 (Rsv4), plus site-directed mutagenesis in a biologically active cDNA clone, identified mutation S1053N in the P3 protein as the determinant for virulence on V94-5152. Codon 1053 was shown to be under positive selection, and S1053N determined Rsv4-virulence occurred in isolates with different genealogies. The V94-5152 (Rsv4)-virulence determinant in Iranian isolates maps into a different amino acid position in the P3 protein than those previously reported, indicating different evolutionary pathways towards resistance breaking that might be conditioned by sequence context. PMID- 23939983 TI - Polymorphisms in BMP4 and FGFR1 genes are associated with fracture non-union. AB - Fracture healing is a complex process influenced by a multitude of factors and expression of several thousand genes. Polymorphisms in these genes can lead to an extended healing process and explain why certain patients are more susceptible to develop non-union. A total of 16 SNPs within five genes involved in bone repair pathogenesis (FAM5C, BMP4, FGF3, FGF10, and FGFR1) were investigated in 167 patients with long bone fractures, 101 with uneventful healing, and 66 presenting aseptic non-unions. Exclusion criteria were patients presenting pathological fractures, osteoporosis, hypertrophic and infected non-unions, pregnancy, and children. All genetic markers were genotyped using TaqMan real-time PCR. Chi square test was used to compare genotypes, allele frequencies, and haplotype differences between groups. Binary logistic regression analyzed the significance of many covariates and the incidence of non-union. Statistical analysis revealed open fracture to be a risk factor for non-union development (p < 0.001, OR 3.6 [1.70-7.67]). A significant association of haplotype GTAA in BMP4 (p = 0.01) and FGFR1 rs13317 (p = 0.005) with NU could be observed. Also, uneventful healing showed association with FAM5C rs1342913 (p = 0.04). Our work supported the role of BMP4 and FGFR1 in NU fracture independently of the presence of previously described risk factors. PMID- 23939984 TI - Beta sheets with a twist: the conformation of helical polyisocyanopeptides determined by using vibrational circular dichroism. AB - Detailed information on the architecture of polyisocyanopeptides based on vibrational circular dichroism (VCD) spectroscopy in combination with DFT calculations is presented. It is demonstrated that the screw sense of the helical polyisocyanides can be determined directly from the C=N-stretch vibrational region of the VCD spectrum. Analysis of the VCD signals associated with the amide I and amide II modes provides detailed information on the peptide side-chain arrangement in the polymer and indicates the presence of a helical beta-sheet architecture, in which the dihedral angles are slightly different to those of natural beta-sheet helices. PMID- 23939986 TI - Activation of H2 by a multiply bonded amido-digermyne: evidence for the formation of a hydrido-germylene. PMID- 23939985 TI - Current issues in dietary acrylamide: formation, mitigation and risk assessment. AB - Acrylamide (AA) is known as a neurotoxin in humans and it is classified as a probable human carcinogen by the International Agency of Research on Cancer. AA is produced as by-product of the Maillard reaction in starchy foods processed at high temperatures (>120 degrees C). This review includes the investigation of AA precursors, mechanisms of AA formation and AA mitigation technologies in potato, cereal and coffee products. Additionally, most relevant issues of AA risk assessment are discussed. New technologies tested from laboratory to industrial scale face, as a major challenge, the reduction of AA content of browned food, while still maintaining its attractive organoleptic properties. Reducing sugars such as glucose and fructose are the major contributors to AA in potato-based products. On the other hand, the limiting substrate of AA formation in cereals and coffee is the free amino acid asparagine. For some products the addition of glycine or asparaginase reduces AA formation during baking. Since, for potatoes, the limiting substrate is reducing sugars, increases in sugar content in potatoes during storage then introduce some difficulties and potentially quite large variations in the AA content of the final product. Sugars in potatoes may be reduced by blanching. Levels of AA in different foods show large variations and no general upper limit is easily applicable, since some formation will always occur. Current policy is that practical measures should be taken voluntarily to reduce AA formation in vulnerable foods since AA is considered a health risk at the concentrations found in foods. PMID- 23939987 TI - Visible-light hypervalent iodide carboxylate photo(trifluoro)methylations and controlled radical polymerization of fluorinated alkenes. AB - IFAB-ulous trifluoromethylation: (CX3COO)2I(III) h (X=F, H) and (CH3COO)3I(V)(C6H4COO) are introduced as CX3./CX3I precursors for metal-free, visible-light, radical (trifluoro)(iodo)methylations of alkenes, illustrated by their use as photoinitiators for the controlled radical polymerization of vinylidene fluoride with external (I(CF2)6I) and in situ generated (CF3I) iodine chain transfer agents, and for block copolymer synthesis. PMID- 23939988 TI - Characterization of a French series of female cases of mesothelioma. AB - BACKGROUND: More than 80% of mesothelioma cases in men are attributable to occupational asbestos exposure compared to only 40% in women. The objective of the study was to characterize a series of female pleural mesotheliomas according to known and suspected risk factors. METHODS: From the exhaustive recording of 318 female mesothelioma cases in the French National Mesothelioma Surveillance Program between 1998 and 2009, multiple correspondence analysis and hybrid clustering were performed to characterize these cases according to expert assessed occupational and non-occupational exposure to asbestos and man-made vitreous fibers, X-ray exposure, and history of cancer and non-malignant respiratory diseases. RESULTS: Four clusters were identified: (1) occupational exposure to asbestos and man-made vitreous fibers (7.9% of subjects); (2) radiation exposure during radiotherapy (12.9%); (3) increased asbestos exposure (19.8%); and (4) "non-exposure" characteristics (59.4%). CONCLUSION: These results will allow hypotheses to be generated about associations between mesothelioma and non-occupational asbestos exposure, X-ray exposure and history of respiratory disease. PMID- 23939989 TI - The merged basins of signal transduction pathways in spatiotemporal cell biology. AB - Numerous evidences have indicated that a signal system is composed by signal pathways, each pathway is composed by sub-pathways, and the sub-pathway is composed by the original signal terminals initiated with a protein/gene. We infer the terminal signals merged signal transduction system as "signal basin". In this article, we discussed the composition and regulation of signal basins, and the relationship between the signal basin control and triple W of spatiotemporal cell biology. Finally, we evaluated the importance of the systemic regulation to gene expression by signal basins under triple W. We hope our discussion will be the beginning to cause the attention for this area from the scientists of life science. PMID- 23939990 TI - Fasting increases aggression and differentially modulates local and systemic steroid levels in male zebra finches. AB - Aggression enables individuals to obtain and retain limited resources. Studies of the neuroendocrine regulation of aggression have focused on territorial and reproductive contexts. By contrast, little is understood concerning the neuroendocrine regulation of aggression over other resources, such as food. Here, we developed a paradigm to examine the role of steroids in food-related aggression. In groups of male zebra finches, a 6-hour fast decreased body mass and increased aggressive interactions among subjects that competed for a point source feeder. Fasting also dramatically altered circulating steroid levels by decreasing plasma testosterone but not estradiol (E2). By contrast, both plasma corticosterone and dehydroepiandrosterone (DHEA) concentrations were elevated with fasting. Interestingly, short-term access to food (15 minutes) after fasting normalized circulating steroid levels. Fasting increased corticosterone levels in a wide range of peripheral tissues but increased DHEA levels specifically in adrenal glands and liver; these effects were quickly normalized with refeeding. DHEA can be metabolized within specific brain regions to testosterone and E2, which promote the expression of aggression. We measured E2 in microdissected brain regions and found that fasting specifically increased local E2 levels in 3 regions: the periaqueductal gray, ventral tegmental area, and ventromedial nucleus of the hypothalamus. These regions are part of the vertebrate social behavior network and regulate the expression of aggression. Together, these data suggest that fasting stimulates secretion of DHEA from the adrenals and liver and subsequent conversion of DHEA to E2 within specific brain regions, to enable individuals to compete for limited food resources. PMID- 23939993 TI - Structural design of ionic conduction paths in molecular crystals for selective and enhanced lithium ion conduction. AB - The molecular crystals [Li{N(SO2CF3)2}{C6H4(OCH3)2}2] and [Li{N(SO2CF3)2}{C6F2H2(OCH3)2}2] with solid-state lithium ion conductivity have been synthesized by the addition of two equivalents of 1,2-dimethoxybenzene or 1,2-difluoro-4,5-dimethoxybenzene to Li{N(SO2CF3)2}, respectively. Single-crystal X-ray diffraction analysis revealed the formation of ionic conduction paths with an ordered arrangement of lithium ions in these crystal structures, afforded by the self- assembled stacking of molecular-based channels consisting of N(SO2CF3)2 anion and 1,2-dimethoxybenzene frameworks as a result of intermolecular aromatic and hydrogen interactions. These compounds show selective lithium ion conductivity as the anions behave as a component unit of the conduction paths. The relationship between the crystal structure and ionic conductivity of the molecular crystals provides a clue to the development of novel solid electrolytes based on molecular crystals showing fast and selective lithium ion conduction. PMID- 23939991 TI - Simulated moving bed chromatography: separation and recovery of sugars and ionic liquid from biomass hydrolysates. AB - Separation from bed, not board: Simulated moving bed chromatography, a continuous separation method, enables the nearly quantitative recovery of sugar products and ionic liquid solvent from chemical hydrolysates of biomass. The ensuing sugars support microbial growth, and the residual lignin from the process is intact. PMID- 23939994 TI - Collagen scaffold meniscus implant integration in a canine model: a histological analysis. AB - In the situation of an irreparable meniscus tear, an implant comparable to a normal meniscus is an attractive option. Using a canine model, we assessed the early and late histologic response to a tissue engineered meniscal collagen scaffold (CS). All animals received bilateral arthrotomies, and all joints receiving the CS had an 80% resection of the meniscus. Animals were sacrificed at 3 and 6 weeks, and 12, 13, and 17 months. The CS/tissue complex and host meniscal rim were sectioned for histologic examination with specific focus on the extracellular matrix, angiogenesis, cellular resorption of the scaffold, scaffold appearance, and CS/Host integration. Early histologic samples (3-6 weeks) revealed active angiogenesis and fibrin clots evolving into cellular granulation type tissue. At 12 months, a mature fibrochondrocytic matrix was depositing with gradations of dissolution and integration of the CS implant. Maturing CS/host integration was observed at 18 months. Active cellular resorption of the implant decreased over time. Four cases showed a mild non-specific chronic inflammation and one additional case showed inflammatory engulfment of the scaffold with giant cells at 3 weeks. No evidence of infection either clinically or histologically was observed at any time point. Overall, this histologic analysis demonstrated the active integration of a meniscal like cartilage into a tissue engineered biological scaffold in a canine model. PMID- 23939995 TI - FGFR1 signaling stimulates proliferation of human mesenchymal stem cells by inhibiting the cyclin-dependent kinase inhibitors p21(Waf1) and p27(Kip1). AB - Signaling through fibroblast growth factor receptor one (FGFR1) is a known inducer of proliferation in both embryonic and human adult mesenchymal stem cells (hMSCs) and positively regulates maintenance of stem cell viability. Leveraging the mitogenic potential of FGF2/FGFR1 signaling in stem cells for therapeutic applications necessitates a mechanistic understanding of how this receptor stimulates cell cycle progression. Using small interfering RNA (siRNA) depletion, antibody-inhibition, and small molecule inhibition, we establish that FGFR1 activity is rate limiting for self-renewal of hMSCs. We show that FGFR1 promotes stem cell proliferation through multiple mechanisms that unite to antagonize cyclin-dependent kinase (CDK) inhibitors. FGFR1 not only stimulates c-Myc to suppress transcription of the CDK inhibitors p21(Waf1) and p27(Kip1), thus promoting cell cycle progression but also increases the activity of protein kinase B (AKT) and the level of S-phase kinase-associated protein 2 (Skp2), resulting in the nuclear exclusion and reduction of p21(Waf1). The in vivo importance of FGFR1 signaling for the control of proliferation in mesenchymal progenitor populations is underscored by defects in ventral mesoderm formation during development upon inhibition of its signaling. Collectively, these studies demonstrate that FGFR1 signaling mediates the continuation of MSC growth and establishes a receptor target for enhancing the expansion of mesenchymal progenitors while maintaining their multilineage potential. PMID- 23939997 TI - The galliform (Turkey thigh) model for resident training in facial plastic surgery. PMID- 23939996 TI - TALE transcription factors during early development of the vertebrate brain and eye. AB - Our brain's cognitive performance arises from the coordinated activities of billions of nerve cells. Despite a high degree of morphological and functional differences, all neurons of the vertebrate central nervous system (CNS) arise from a common field of multipotent progenitors. Cell fate specification and differentiation are directed by multistep processes that include inductive/external cues, such as the extracellular matrix or growth factors, and cell-intrinsic determinants, such as transcription factors and epigenetic modulators of proteins and DNA. Here we review recent findings implicating TALE homeodomain proteins in these processes. Although originally identified as HOX cofactors, TALE proteins also contribute to many physiological processes that do not require HOX-activity. Particular focus is, therefore, given to HOX-dependent and -independent functions of TALE proteins during early vertebrate brain development. Additionally, we provide an overview about known upstream and downstream factors of TALE proteins in the developing vertebrate brain and discuss general concepts of how TALE proteins function to modulate neuronal cell fate specification. PMID- 23939998 TI - Trifluoromethanesulfonic acid catalyzed synergetic oxidative/[3+2] cyclization of quinones with olefins. PMID- 23939999 TI - Selective nitrate binding in competitive hydrogen bonding solvents: do anion-pi interactions facilitate nitrate selectivity? PMID- 23940000 TI - Efficacy of topical atorvastatin for the treatment of pressure ulcers: a randomized clinical trial. AB - STUDY OBJECTIVE: To evaluate the effects of topical atorvastatin on the healing process of pressure ulcers in critically ill patients. DESIGN: Randomized, double blind, placebo-controlled clinical trial. SETTING: Medical-surgical intensive care unit of a university-affiliated teaching hospital in Tehran, Iran. PATIENTS: One hundred four patients with stage I or II pressure ulcers, graded according to the 2-digit Stirling Pressure Sore Severity Scale. INTERVENTION: Patients were randomized to receive topical atorvastatin 1% ointment (51 patients [atorvastatin group]) or placebo ointment (53 patients [control group]) applied once/day to pressure ulcers for 14 days in addition to standard care for pressure ulcers. MEASUREMENTS AND MAIN RESULTS: The efficacy of each treatment was assessed on days 7 and 14. Efficacy was determined based on the degree of healing of the existing pressure ulcer by using the 2-digit Stirling scale. The baseline stage of the pressure ulcers did not differ significantly between the control and atorvastatin groups. However, the mean +/- SD stage of pressure ulcers significantly decreased in the atorvastatin group compared with the control group on day 7 (0.97 +/- 0.76 vs 1.74 +/- 0.75, p<0.01) and day 14 (0.42 +/- 0.67 vs 1.71 +/- 0.78, p<0.01) of treatment. In addition, the mean +/- SD surface areas of ulcers in the atorvastatin group were significantly declined compared with the control group after 7 days (5.55 +/- 4.55 vs 9.41 +/- 5.03 cm2, p<0.01) and 14 days (3.72 +/- 4.45 vs 10.41 +/- 6.41 cm2, p<0.01) of treatment. CONCLUSION: Topical application of atorvastatin ointment 1% for 14 days in addition to standard care significantly accelerated the healing of stage I or II pressure ulcers in critically ill patients. PMID- 23940001 TI - Synthesis of alpha-amino acids from glucosamine-HCl and its derivatives by aerobic oxidation in water catalyzed by Au nanoparticles on basic supports. AB - The golden wonder: Various alpha-amino acids such as glucosaminic acid, galactosaminic acid, or N-acetyl-glucosaminic acid can be obtained from the corresponding glucosamine derivatives (amino sugars). This is achieved through an aqueous oxidation that catalyzed by Au nanoparticles dispersed on basic support under mild reaction conditions in water. PMID- 23940005 TI - Determination of enantioselectivity and enantiomeric excess by mass spectrometry in the absence of chiral chromatographic separation: an overview. AB - This review describes the principles and instrumentation for the screening of asymmetric reactions by mass spectrometry. These techniques witnessed a significant advancement in the last few years. Although some of them are still at the proof-of-concept development stage, several applications might be foreseen in the field of combinatorial, high-throughput parallel catalyst screening. PMID- 23940002 TI - Analysis of microRNAs expressions in chondrosarcoma. AB - MicroRNAs (miRNAs) are small non-coding RNAs capable of inhibiting gene expression post-transcriptionally and expression profiling can provide therapeutic targets and tools for cancer diagnosis. Chondrosarcoma is a mesenchymal tumor with unknown cause and differentiation status. Here, we profiled miRNA expression of chondrosarcoma, namely clinical samples from human conventional chondrosarcoma tissue, established chondrosarcoma cell lines, and primary non-tumorous adult articular chondrocytes, by miRNA array and quantitative real-time PCR. A wide variety of miRNAs were differently downregulated in chondrosarcoma compared to non-tumorous articular chondrocytes; 27 miRNAs: miR-10b, 23b, 24-1*, 27b, 100, 134, 136, 136*, 138, 181d, 186, 193b, 221*, 222, 335, 337-5p, 376a, 376a*, 376b, 376c, 377, 454, 495, 497, 505, 574-3p, and 660, were significantly downregulated in chondrosarcoma and only 2: miR-96 and 183, were upregulated. We further validated the expression levels of miRNAs by quantitative real-time PCR for miR-181a, let-7a, 100, 222, 136, 376a, and 335 in extended number of chondrosarcoma clinical samples. Among them, all except miR 181a were found to be significantly downregulated in chondrosarcoma derived samples. The findings provide potential diagnostic value and new molecular understanding of chondrosarcoma. PMID- 23940003 TI - Generation and characterization of spiking and nonspiking oligodendroglial progenitor cells from embryonic stem cells. AB - Pluripotent stem cells (PSCs) have been differentiated into oligodendroglial progenitor cells (OPCs), providing promising cell replacement therapies for many central nervous system disorders. Studies from rodents have shown that brain OPCs express a variety of ion channels, and that a subset of brain OPCs express voltage-gated sodium channel (NaV ), mediating the spiking properties of OPCs. However, it is unclear whether PSC-derived OPCs exhibit electrophysiological properties similar to brain OPCs and the role of NaV in the functional maturation of OPCs is unknown. Here, using a mouse embryonic stem cell (mESC) green fluorescent protein (GFP)-Olig2 knockin reporter line, we demonstrated that unlike brain OPCs, all the GFP(+) /Olig2(+) mESC-derived OPCs (mESC-OPCs) did not express functional NaV and failed to generate spikes (hence termed "nonspiking mESC-OPCs"), while expressing the delayed rectifier and inactivating potassium currents. By ectopically expressing NaV 1.2 alpha subunit via viral transduction, we successfully generated mESC-OPCs with spiking properties (termed "spiking mESC OPCs"). After transplantation into the spinal cord and brain of myelin-deficient shiverer mice, the spiking mESC-OPCs demonstrated better capability in differentiating into myelin basic protein expressing oligodendrocytes and in myelinating axons in vivo than the nonspiking mESC-OPCs. Thus, by generating spiking and nonspiking mESC-OPCs, this study reveals a novel function of NaV in OPCs in their functional maturation and myelination, and sheds new light on ways to effectively develop PSC-derived OPCs for future clinical applications. PMID- 23940006 TI - Single glutamate to aspartate mutation makes ferric uptake regulator (Fur) as sensitive to H2O2 as peroxide resistance regulator (PerR). PMID- 23940007 TI - Impact of the JUPITER trial on statin prescribing for primary prevention. AB - STUDY OBJECTIVE: As the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial identified a new population of individuals with cholesterol levels below traditional treatment thresholds but with elevated high-sensitivity C-reactive protein (hs-CRP) levels who may benefit from primary prevention with statin therapy, we sought to evaluate the impact of this trial on the incident prescription rates of rosuvastatin alone as well as all statins in a primary prevention population. DESIGN: Population-based, cross-sectional time-series analysis. DATA SOURCE: Administrative health care databases in Ontario, Canada. PATIENTS: A total of 299,809 incident statin users 66 years or older were identified during the study period, from January 1, 2003, to March 31, 2011, who were prescribed statin therapy for primary prevention. MEASUREMENTS AND MAIN RESULTS: We evaluated the incident rate of rosuvastatin and all statin use during each quarter of the study period. Overall, no significant trends in all incident statin use were observed (p=0.99). Furthermore, no significant differences were observed in incident rates of rosuvastatin (p=0.21) or all statin (p=0.41) use after the publication of the JUPITER trial. Despite the lack of impact of the JUPITER trial on rosuvastatin or all statin utilization, the relative market share of rosuvastatin increased from 9% to 65% over the study period. CONCLUSION: The publication of the JUPITER trial did not significantly affect trends in overall statin and rosuvastatin prescribing patterns for primary prevention in this study. Increases in the relative market share of rosuvastatin may be attributed to the impact of the pharmaceutical industry on prescribing patterns. Our results highlight the need to further improve the integration of evidence-based prescribing into cost effective clinical practice. PMID- 23940008 TI - Apparent diffusion coefficient of pediatric cerebellar tumors: a biomarker of tumor grade? AB - BACKGROUND: The role of diffusion weighted imaging (DWI) to reliably differentiate tumor types and grades in pediatric cerebellar tumors is controversial. We aimed to clarify the discrepancy reported in previous articles. PROCEDURES: We retrospectively evaluated the apparent diffusion coefficient (ADC) values of the enhancing, solid parts of cerebellar tumors and correlated the absolute tumor ADC values and cerebellar and thalamic ratios with histology in a cohort of children with cerebellar tumors. RESULTS: Twenty-four children (12 females) were included in the study. The median age at pre-surgical MRI was 10 years (range 29 days-18.5 years). Absolute ADC values (mean 1.49, SD 0.25 vs. 0.63 +/- 0.18), cerebellar (2.04 +/- 0.33 vs. 0.83 +/- 0.25), and thalamic ratio (1.98 +/- 0.35 vs. 0.79 +/- 0.23) were significantly higher in low- than in high grade tumors (P < 0.0001). Absolute ADC values and cerebellar and thalamic ratios were significantly higher in low-grade astrocytomas than in MBs. Overlap was seen for WHO grade II and III ependymomas. One hundred percent specific cutoff ADC values of >1.2 * 10(3) and <0.8 * 10(-3) mm(2) /s were established for low- and high-grade tumors. CONCLUSION: ADC analysis of the solid, contrast enhancing components of pediatric cerebellar tumors may facilitate differentiation between various tumor histologies. PMID- 23940009 TI - The heterogeneous structural behavior of E7 from HPV16 revealed by NMR spectroscopy. AB - The E7 protein from human papillomavirus (HPV) plays a key role in oncogenesis; for this reason, it is a target of great biomedical interest. To date, no high resolution information is available for the full protein. We present here the NMR characterization of the entire E7 from HPV16, one of the most oncogenic variants of the virus. The protein is very heterogeneous in terms of structural and dynamic properties with a highly flexible N-terminal module and a more structured C terminus. This opens possibilities for studies of molecular-level interactions and post-translational modifications of the protein to unravel functional details that might be linked to its highly oncogenic potential. PMID- 23940010 TI - Population pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes. AB - Data from five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with type 2 diabetes mellitus (T2DM; N = 974; 1-100 mg q.d.; <=12 weeks) were used to develop a population pharmacokinetic (PK) model for empagliflozin. The model consisted of two-compartmental disposition, lagged first-order absorption and first-order elimination, and incorporated appropriate covariates. Population estimates (interindividual variance, CV%) of oral apparent clearance, central and peripheral volumes of distribution, and inter compartmental clearance were 9.87 L/h (26.9%), 3.02 L, 60.4 L (30.8%), and 5.16 L/h, respectively. An imposed allometric weight effect was the most influential PK covariate effect, with a maximum effect on exposure of +/-30%, using 2.5th and 97.5th percentiles of observed weights, relative to the median observed weight. Sex and race did not lend additional description to PK variability beyond allometric weight effects, other than ~25% greater oral absorption rate constant for Asian patients. Age, total protein, and smoking/alcohol history did not affect PK parameters. Predictive check plots were consistent with observed data, implying an adequate description of empagliflozin PKs following multiple dosing in patients with T2DM. The lack of marked covariate effects, including weight, suggests that no exposure-based dose adjustments were required within the study population and dose range. PMID- 23940011 TI - A new look at cytoskeletal NOS-1 and beta-dystroglycan changes in developing muscle and brain in control and mdx dystrophic mice. AB - BACKGROUND: Loss of dystrophin profoundly affects muscle function and cognition. Changes in the dystrophin-glycoprotein complex (DGC) including disruption of nitric oxide synthase (NOS-1) may result from loss of dystrophin or secondarily after muscle damage. Disruptions in NOS-1 and beta-dystroglycan (bDG) were examined in developing diaphragm, quadriceps, and two brain regions between control and mdx mice at embryonic day E18 and postnatal days P1, P10, and P28. Age-dependent differential muscle loading allowed us to test the hypothesis that DGC changes are dependent on muscle use. RESULTS: Muscle development, including loss of central nucleation and the localization of NOS-1 and bDG, was earlier in diaphragm than quadriceps; these features were differentially disrupted in dystrophic muscles. The NOS-1/bDG ratio, an index of DGC stability, was higher in dystrophic diaphragm (P10-P28) and quadriceps (P28) than controls. There were also distinct regional differences in NOS-1 and bDG in brain tissues with age and strain. NOS-1 increased with age in control forebrain and cerebellum, and in mdx cerebellum; NOS-1 and bDG were higher in control than mdx mouse forebrain. CONCLUSIONS: Important developmental changes in structure and muscle DGC preceded the hallmarks of dystrophy, and are consistent with the impact of muscle-specific differential loading during maturation. PMID- 23940012 TI - Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations. AB - Germline aryl hydrocarbon receptor interacting protein (AIP) gene mutations confer a predisposition to pituitary adenoma (PA), predominantly GH-secreting (GH PA). As recent data suggest a role for AIP in the pathogenesis of sporadic GH-PA and their response to somatostatin analogues (SSA), the expression of AIP and its partner, aryl hydrocarbon receptor (AHR), was determined by semiquantitative immunohistochemistry scoring in 62 sporadic GH-PA (37 treated with SSA preoperatively). The influence of Gsp status was studied in a subset of tumours (n=39, 14 Gsp(+)) and six GH-PA were available for primary cultures. AIP and AHR were detected in most cases, with a positive correlation between AIP and cytoplasmic AHR (P=0.012). Low AIP expression was significantly more frequent in untreated vs SSA-treated tumours (44.0 vs 20.5%, P=0.016). AHR expression or localisation did not differ between the two groups. Similarly, in vitro octreotide induced a median twofold increase in AIP expression (range 1.2-13.9, P=0.027) in GH-PA. In SSA-treated tumours, the AIP score was significantly higher in the presence of preoperative IGF1 decrease or tumour shrinkage (P=0.008 and P=0.014 respectively). In untreated tumours, low AIP expression was significantly associated with invasiveness (P=0.028) and suprasellar extension (P=0.019). The only effect of Gsp status was a significantly lower nuclear AHR score in Gsp(+) vs Gsp(-) tumours (P=0.025), irrespective of SSA. In conclusion, AIP is involved in the aggressiveness of sporadic GH-PA, regardless of Gsp status, and AIP up regulation in SSA-treated tumours is associated with a better preoperative response, with no clear role for AHR. PMID- 23940014 TI - Quantitative measures of damage to subchondral bone are associated with functional outcome following treatment of displaced acetabular fractures. AB - Current analysis of displaced acetabular fractures is limited in its ability to predict functional outcome. This study aimed to (1) quantify initial acetabular damage following acetabular fracture through measurement of subchondral bone density and fracture lines, and (2) evaluate associations between acetabular damage and functional outcomes following fracture. Subchondral bone intensity maps were created for 24 patients with unilateral acetabular fractures. Measures of crack length and density differences between corresponding regions in the fractured acetabuli, normalized by the unfractured side, were generated from preoperative CT images. Damage measures were compared to quality of life survey data collected for each patient at least 2 years post-injury (Musculoskeletal Functional Assessment [MFA] and Short Form-36 [SF-36], with specific focus on parameters that best describe patients' physical health). CT image quantification of initial damage to acetabular subchondral bone was associated with functional outcome post-injury. In general, damage as quantified through differences in density in the superior dome region (zones 8 and 12) and the central anterior region of the acetabulum (zone 3) were found to be the strongest significant predictors of functional outcome (adjusted R(2) = 0.3-0.45, p < 0.05). Damage to the superior dome was predictive of worse functional outcome whereas damage to the central anterior region indicated a better functional outcome. Once automated, this approach may form a basis to score acetabular fractures toward improving clinical prognoses. PMID- 23940015 TI - Shape- and size-controlled nanomaterials for artificial photosynthesis. AB - Nanomaterials with various shapes and sizes have been developed to mimic functions of photosynthesis in which solar energy conversion is achieved by using nanosized proteins with controlled shapes and sizes. Artificial photosynthesis consists of light-harvesting and charge-separation processes together with catalytic units of water oxidation and reduction. Nanosized mesoporous silica alumina was utilized to encapsulate organic charge-separation molecules inside the nanospace to elongate the lifetimes of the charge-separated states, as observed in the photosynthetic reaction centers. Metal nanoparticles with controlled shapes and sizes have also been utilized as efficient catalysts for photocatalytic hydrogen evolution from water with reductants by using electron donor-acceptor organic molecules as photocatalysts. The control of the shape and size of metal nanoparticles plays a very important role in achieving high catalytic performance in catalytic hydrogen evolution in water reduction and also in catalytic oxygen evolution in water oxidation. PMID- 23940016 TI - Quantitative magnetization transfer MRI of desmoplasia in pancreatic ductal adenocarcinoma xenografts. AB - Quantitative assessment of desmoplasia in pancreatic ductal adenocarcinoma (PDAC) may be critical for staging or prediction of response to therapy. We performed quantitative magnetization transfer (qMT) MRI measurements in 18 mouse xenograft tumors generated from three PDAC cell lines. The qMT parameter bound proton fraction (BPF) was found to be significantly higher in tumors grown using the BxPC-3 cell line (5.31 +/- 0.87, mean +/- standard deviation) compared with the BPF measured for tumors grown from Panc-1 (3.65 +/- 0.60) and Capan-1 (1.50 +/- 0.58) cell lines (P < 0.05 for each comparison). Histologic measurements demonstrated a similar trend; BxPC-3 tumors had significantly higher fibrosis levels (percentage of fibrotic tissue area, 6.21 +/- 2.10) compared with Panc-1 (2.88 +/- 1.13) and Capan-1 (1.69 +/- 1.01) tumors. BPF was well correlated with quantitative fibrosis levels (r = 0.77, P < 0.01). Our results indicate that qMT measurements offer the potential to noninvasively quantify fibrosis levels in PDAC mouse xenograft models and thus serve as a valuable in vivo biomarker of desmoplasia in PDAC. PMID- 23940018 TI - alpha-Oligofurans: a computational study. AB - Recently, alpha-oligofurans have emerged as interesting and promising organic electronic materials that have certain advantages over alpha-oligothiophenes. In this work, alpha-oligofurans were studied computationally, and their properties were compared systematically with those of the corresponding oligothiophenes. Although the two materials share similar electronic structures, overall, this study revealed important differences between alpha-oligofurans and alpha oligothiophenes. Twisting studies on oligofurans revealed them to be significantly more rigid than oligothiophenes in the ground state and first excited state. Neutral alpha-oligofurans have more quinoid character, higher frontier orbital energies, and higher HOMO-LUMO gaps than their alpha oligothiophene counterparts. The theoretical results suggest that oligofurans (and subsequently polyfuran) have lower ionization potentials than the corresponding oligothiophenes (and polythiophene), which in turn predicts that oligofurans can be lightly doped more easily than oligothiophenes. Oligofuran dications (8 F(2+)-14 F(2+)) of medium-sized and longer chain lengths show a polaron-pair character, and the polycations of alpha-oligofurans cannot accommodate high positive charges as easily as their thiophene analogues. PMID- 23940017 TI - A small molecule p75(NTR) ligand protects neurogenesis after traumatic brain injury. AB - The p75 neurotrophin receptor (p75(NTR)) influences the proliferation, survival, and differentiation of neuronal precursors and its expression is induced in injured brain, where it regulates cell survival. Here, we test the hypotheses that pharmacologic modulation of p75(NTR) signaling will promote neural progenitor survival and proliferation, and improve outcomes of traumatic brain injury (TBI). LM11A-31, an orally available, blood-brain barrier-permeant small molecule p75(NTR) signaling modulator, significantly increased proliferation and survival, and decreased JNK phosphorylation, in hippocampal neural stem/progenitor cells in culture expressing wild-type p75(NTR), but had no effect on cells expressing a mutant neurotrophin-unresponsive form of the receptor. The compound also enhanced the production of mature neurons from adult hippocampal neural progenitors in vitro. In vivo, intranasal administration of LM11A-31 decreased postinjury hippocampal and cortical neuronal death, neural progenitor cell death, gliogenesis, and microglial activation, and enhanced long-term hippocampal neurogenesis and reversed spatial memory impairments. LM11A-31 diminished the postinjury increase of SOX2-expressing early progenitor cells, but protected and increased the proliferation of endogenous polysialylated-neural cell adhesion molecule positive intermediate progenitors, and restored the long term production of mature granule neurons. These findings suggest that modulation of p75(NTR) actions using small molecules such as LM11A-31 may constitute a potent therapeutic strategy for TBI. PMID- 23940019 TI - Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia in Saudi Arabia: a multi-institutional retrospective national collaborative study. AB - BACKGROUND: Treatment of childhood acute lymphoblastic leukemia (ALL) has been available in Saudi Arabia (SA) for over 30 years; however, only limited data have been published from there. This study was conducted to establish processes for collaborative data collection and provide clinical characteristics and outcome of children with ALL in SA. PROCEDURE: Clinical data for patients diagnosed from 2004 to 2008 were retrospectively collected at eight institutions and entered remotely into a custom-built database. Statistics regarding clinical and genetic characteristics and treatment outcome were calculated. RESULTS: The 594 evaluable patients had a median age of 4.37 years and 56.4% were boys. Majority of patients had B-precursor ALL while 10.7% had T-ALL. CNS leukemia was present in 5.2% of patients. The distribution of common genetic abnormalities was similar to that reported from western populations, with 24.6% hyperdiploidy, 21% RUNX1-ETV6 positivity, 4.2% BCR-ABL1 positivity, and 2.5% with MLL gene rearrangement. Patients received risk-adapted therapy according to various protocols, although treatment strategies for the majority were similar. Five-year OS, RFS and EFS were 86.9%, 79.1%, and 73.3%, respectively. The OS for patients with pre-B ALL was significantly higher than for T-ALL (88.0% vs. 71.8%; P = 0.019, Log-Rank test). Patients with pre-B ALL categorized as low-risk by NCI/Rome criteria and those with hyperdiploidy had OS of 93.4% and 95.8%, respectively. CONCLUSIONS: The characteristics of childhood ALL in SA are similar to those observed in developed countries. Future prospective studies utilizing unified national protocols are needed to further improve the outcome of our patients. PMID- 23940020 TI - Naming vs knowing faces in primary progressive aphasia: a tale of 2 hemispheres. AB - OBJECTIVES: This study examines the anatomical correlates of naming vs recognizing faces using a novel measure that utilizes culturally relevant and age appropriate items, the Northwestern University Famous Faces (NUFFACE) Test, in primary progressive aphasia (PPA), a syndrome characterized by progressive language deficits and associated with cortical atrophy in areas important for word and object representations. METHODS: NUFFACE Test performance of 27 controls (mean age 62.3 years) was compared with that of 30 patients with PPA (mean age 62 years). Associations between NUFFACE Test performance and cortical thickness measures were quantified within the PPA group. RESULTS: Patients with PPA displayed significant impairment on the NUFFACE Test, demonstrating that it is a useful measure of famous-face identification for individuals with relatively young-onset dementias. Despite widespread distribution of atrophy in the PPA group, face naming impairments were correlated with atrophy of the left anterior temporal lobe while face recognition impairments were correlated with bitemporal atrophy. CONCLUSIONS: In addition to their clinical relevance for highlighting the distinction between face naming and recognition impairments in individuals with young-onset dementia, these findings add new insights into the dissociable clinico-anatomical substrates of lexical retrieval and object knowledge. PMID- 23940021 TI - Sleep apnea and snoring. PMID- 23940022 TI - Screening for impulse control symptoms in patients with de novo Parkinson disease: a case-control study. PMID- 23940023 TI - Clinical course of idiopathic intracranial hypertension with transverse sinus stenosis. PMID- 23940024 TI - Mystery case: an unexpected complication of IV thrombolysis for acute ischemic stroke. PMID- 23940025 TI - Teaching NeuroImages: characteristic phenotype of Ullrich congenital muscular dystrophy. PMID- 23940026 TI - Teaching NeuroImages: diffuse cerebral neurosarcoidosis mimicking gliomatosis cerebri. PMID- 23940027 TI - Kinetic resolution of secondary alcohols catalyzed by chiral phosphoric acids. PMID- 23940028 TI - Phlorizin pretreatment reduces acute renal toxicity in a mouse model for diabetic nephropathy. AB - Streptozotocin (STZ) is widely used as diabetogenic agent in animal models for diabetic nephropathy (DN). However, it is also directly cytotoxic to kidneys, making it difficult to distinguish between DN-related and STZ-induced nephropathy. Therefore, an improved protocol to generate mice for DN studies, with a quick and robust achievement of the diabetic state, without direct kidney toxicity is required. To investigate the mechanism leading to STZ-induced nephropathy, kidney damage was induced with a high dose of STZ. This resulted in delayed gastric emptying, at least partially caused by impaired desacyl ghrelin clearance. STZ uptake in the kidneys is to a large extent mediated by the sodium/glucose cotransporters (Sglts) because the Sglt inhibitor phlorizin could reduce STZ uptake in the kidneys. Consequently, the direct toxic effects in the kidney and the gastric dilatation were resolved without interfering with the beta cell toxicity. Furthermore, pancreatic STZ uptake was increased, hereby decreasing the threshold for beta-cell toxicity, allowing for single low non nephrotoxic STZ doses (70 mg/kg). In conclusion, this study provides novel insights into the mechanism of STZ toxicity in kidneys and suggests a more efficient regime to induce DN with little or no toxic side effects. PMID- 23940029 TI - Dynamics of cleft closure of the GluA2 ligand-binding domain in the presence of full and partial agonists revealed by hydrogen-deuterium exchange. AB - The majority of excitatory neurotransmission in the CNS is mediated by tetrameric AMPA receptors. Channel activation begins with a series of interactions with an agonist that binds to the cleft between the two lobes of the ligand-binding domain of each subunit. Binding leads to a series of conformational transitions, including the closure of the two lobes of the binding domain around the ligand, culminating in ion channel opening. Although a great deal has been learned from crystal structures, determining the molecular details of channel activation, deactivation, and desensitization requires measures of dynamics and stabilities of hydrogen bonds that stabilize cleft closure. The use of hydrogen-deuterium exchange at low pH provides a measure of the variation of stability of specific hydrogen bonds among agonists of different efficacy. Here, we used NMR measurements of hydrogen-deuterium exchange to determine the stability of hydrogen bonds in the GluA2 (AMPA receptor) ligand-binding domain in the presence of several full and partial agonists. The results suggest that the stabilization of hydrogen bonds between the two lobes of the binding domain is weaker for partial than for full agonists, and efficacy is correlated with the stability of these hydrogen bonds. The closure of the lobes around the agonists leads to a destabilization of the hydrogen bonding in another portion of the lobe interface, and removing an electrostatic interaction in Lobe 2 can relieve the strain. These results provide new details of transitions in the binding domain that are associated with channel activation and desensitization. PMID- 23940030 TI - The F-box protein FBXO25 promotes the proteasome-dependent degradation of ELK-1 protein. AB - FBXO25 is one of the 69 known human F-box proteins that serve as specificity factors for a family of ubiquitin ligases composed of SKP1, Rbx1, Cullin1, and F box protein (SCF1) that are involved in targeting proteins for degradation across the ubiquitin proteasome system. However, the substrates of most SCF E3 ligases remain unknown. Here, we applied an in chip ubiquitination screen using a human protein microarray to uncover putative substrates for the FBXO25 protein. Among several novel putative targets identified, the c-fos protooncogene regulator ELK 1 was characterized as the first endogenous substrate for SCF1(FBXO25) E3 ligase. FBXO25 interacted with and mediated the ubiquitination and proteasomal degradation of ELK-1 in HEK293T cells. In addition, FBXO25 overexpression suppressed induction of two ELK-1 target genes, c-fos and egr-1, in response to phorbol 12-myristate 13-acetate. Together, our findings show that FBXO25 mediates ELK-1 degradation through the ubiquitin proteasome system and thereby plays a role in regulating the activation of ELK-1 pathway in response to mitogens. PMID- 23940031 TI - Human mitochondrial chaperone (mtHSP70) and cysteine desulfurase (NFS1) bind preferentially to the disordered conformation, whereas co-chaperone (HSC20) binds to the structured conformation of the iron-sulfur cluster scaffold protein (ISCU). AB - Human ISCU is the scaffold protein for mitochondrial iron-sulfur (Fe-S) cluster biogenesis and transfer. NMR spectra have revealed that ISCU populates two conformational states; that is, a more structured state (S) and a partially disordered state (D). We identified two single amino acid substitutions (D39V and N90A) that stabilize the S-state and two (D39A and H105A) that stabilize the D state. We isolated the two constituent proteins of the human cysteine desulfurase complex (NFS1 and ISD11) separately and used NMR spectroscopy to investigate their interaction with ISCU. We found that ISD11 does not interact directly with ISCU. By contrast, NFS1 binds preferentially to the D-state of ISCU as does the NFS1-ISD11 complex. An in vitro Fe-S cluster assembly assay showed that [2Fe-2S] and [4Fe-4S] clusters are assembled on ISCU when catalyzed by NFS1 alone and at a higher rate when catalyzed by the NFS1-ISD11 complex. The DnaK-type chaperone (mtHSP70) and DnaJ-type co-chaperone (HSC20) are involved in the transfer of clusters bound to ISCU to acceptor proteins in an ATP-dependent reaction. We found that the ATPase activity of mtHSP70 is accelerated by HSC20 and further accelerated by HSC20 plus ISCU. NMR studies have shown that mtHSP70 binds preferentially to the D-state of ISCU and that HSC20 binds preferentially to the S-state of ISCU. PMID- 23940032 TI - A constitutively activating mutation alters the dynamics and energetics of a key conformational change in a ligand-free G protein-coupled receptor. AB - G protein-coupled receptors (GPCRs) undergo dynamic transitions between active and inactive conformations. Usually, these conversions are triggered when the receptor detects an external signal, but some so-called constitutively activating mutations, or CAMs, induce a GPCR to bind and activate G proteins in the absence of external stimulation, in ways still not fully understood. Here, we investigated how a CAM alters the structure of a GPCR and the dynamics involved as the receptor transitions between different conformations. Our approach used site-directed fluorescence labeling (SDFL) spectroscopy to compare opsin, the ligand-free form of the GPCR rhodopsin, with opsin containing the CAM M257Y, focusing specifically on key movements that occur in the sixth transmembrane helix (TM6) during GPCR activation. The site-directed fluorescence labeling data indicate opsin is constrained to an inactive conformation both in detergent micelles and lipid membranes, but when it contains the M257Y CAM, opsin is more dynamic and can interact with a G protein mimetic. Further study of these receptors using tryptophan-induced quenching (TrIQ) methods indicates that in detergent, the CAM significantly increases the population of receptors in the active state, but not in lipids. Subsequent Arrhenius analysis of the TrIQ data suggests that, both in detergent and lipids, the CAM lowers the energy barrier for TM6 movement, a key transition required for conversion between the inactive and active conformations. Together, these data suggest that the lowered energy barrier is a primary effect of the CAM on the receptor dynamics and energetics. PMID- 23940033 TI - The severe autosomal dominant retinitis pigmentosa rhodopsin mutant Ter349Glu mislocalizes and induces rapid rod cell death. AB - Mutations in the rhodopsin gene cause approximately one-tenth of retinitis pigmentosa cases worldwide, and most result in endoplasmic reticulum retention and apoptosis. Other rhodopsin mutations cause receptor mislocalization, diminished/constitutive activity, or faulty protein-protein interactions. The purpose of this study was to test for mechanisms by which the autosomal dominant rhodopsin mutation Ter349Glu causes an early, rapid retinal degeneration in patients. The mutation adds an additional 51 amino acids to the C terminus of the protein. Folding and ligand interaction of Ter349Glu rhodopsin were tested by ultraviolet-visible (UV-visible) spectrophotometry. The ability of the mutant to initiate phototransduction was tested using a radioactive filter binding assay. Photoreceptor localization was assessed both in vitro and in vivo utilizing fluorescent immunochemistry on transfected cells, transgenic Xenopus laevis, and knock-in mice. Photoreceptor ultrastructure was observed by transmission electron microscopy. Spectrally, Ter349Glu rhodopsin behaves similarly to wild-type rhodopsin, absorbing maximally at 500 nm. The mutant protein also displays in vitro G protein activation similar to that of WT. In cultured cells, mislocalization was observed at high expression levels whereas ciliary localization occurred at low expression levels. Similarly, transgenic X. laevis expressing Ter349Glu rhodopsin exhibited partial mislocalization. Analysis of the Ter349Glu rhodopsin knock-in mouse showed a rapid, early onset degeneration in homozygotes with a loss of proper rod outer segment development and improper disc formation. Together, the data show that both mislocalization and rod outer segment morphogenesis are likely associated with the human phenotype. PMID- 23940034 TI - Identification of the C3a receptor (C3AR1) as the target of the VGF-derived peptide TLQP-21 in rodent cells. AB - TLQP-21, a peptide derived from VGF (non-acronymic) by proteolytic processing, has been shown to modulate energy metabolism, differentiation, and cellular response to stress. Although extensively investigated, the receptor for this endogenous peptide has not previously been described. This study describes the use of a series of studies that show G protein-coupled receptor-mediated biological activity of TLQP-21 signaling in CHO-K1 cells. Unbiased genome-wide sequencing of the transcriptome from responsive CHO-K1 cells identified a prioritized list of possible G protein-coupled receptors bringing about this activity. Further experiments using a series of defined receptor antagonists and siRNAs led to the identification of complement C3a receptor-1 (C3AR1) as a target for TLQP-21 in rodents. We have not been able to demonstrate so far that this finding is translatable to the human receptor. Our results are in line with a large number of physiological observations in rodent models of food intake and metabolic control, where TLQP-21 shows activity. In addition, the sensitivity of TLQP-21 signaling to pertussis toxin is consistent with the known signaling pathway of C3AR1. The binding of TLQP-21 to C3AR1 not only has effects on signaling but also modulates cellular functions, as TLQP-21 was shown to have a role in directing migration of mouse RAW264.7 cells. PMID- 23940035 TI - Structural snapshots from the oxidative half-reaction of a copper amine oxidase: implications for O2 activation. AB - The mechanism of molecular oxygen activation is the subject of controversy in the copper amine oxidase family. At their active sites, copper amine oxidases contain both a mononuclear copper ion and a protein-derived quinone cofactor. Proposals have been made for the activation of molecular oxygen via both a Cu(II) aminoquinol catalytic intermediate and a Cu(I)-semiquinone intermediate. Using protein crystallographic freeze-trapping methods under low oxygen conditions combined with single-crystal microspectrophotometry, we have determined structures corresponding to the iminoquinone and semiquinone forms of the enzyme. Methylamine reduction at acidic or neutral pH has revealed protonated and deprotonated forms of the iminoquinone that are accompanied by a bound oxygen species that is likely hydrogen peroxide. However, methylamine reduction at pH 8.5 has revealed a copper-ligated cofactor proposed to be the semiquinone form. A copper-ligated orientation, be it the sole identity of the semiquinone or not, blocks the oxygen-binding site, suggesting that accessibility of Cu(I) may be the basis of partitioning O2 activation between the aminoquinol and Cu(I). PMID- 23940036 TI - Heterochromatic gene silencing by activator interference and a transcription elongation barrier. AB - Heterochromatin silences transcription, contributing to development, differentiation, and genome stability in eukaryotic organisms. Budding yeast heterochromatic silencing is strictly dependent on the silent information regulator (SIR) complex composed of the Sir2 histone deacetylase and the chromatin-interacting proteins Sir3 and Sir4. We use reconstituted SIR heterochromatin to characterize the steps in transcription that are disrupted to achieve silencing. Transcriptional activator binding is permitted before and after heterochromatin assembly. A comprehensive proteomic approach identified heterochromatin-mediated disruption of activator interactions with coactivator complexes. We also find that if RNA polymerase II (Pol II) is allowed to initiate transcription, the SIR complex blocks elongation on chromatin while maintaining Pol II in a halted conformation. This Pol II elongation barrier functions for even one nucleosome, is more effective when assembled with multiple nucleosomes, and is sensitive to a histone mutation that is known to disrupt silencing. This dual mechanism of silencing suggests a conserved principle of heterochromatin in assembling a specific structure that targets multiple steps to achieve repression. PMID- 23940037 TI - The phosphatase Ptc7 induces coenzyme Q biosynthesis by activating the hydroxylase Coq7 in yeast. AB - The study of the components of mitochondrial metabolism has potential benefits for health span and lifespan because the maintenance of efficient mitochondrial function and antioxidant capacity is associated with improved health and survival. In yeast, mitochondrial function requires the tight control of several metabolic processes such as coenzyme Q biosynthesis, assuring an appropriate energy supply and antioxidant functions. Many mitochondrial processes are regulated by phosphorylation cycles mediated by protein kinases and phosphatases. In this study, we determined that the mitochondrial phosphatase Ptc7p, a Ser/Thr phosphatase, was required to regulate coenzyme Q6 biosynthesis, which in turn activated aerobic metabolism and enhanced oxidative stress resistance. We showed that Ptc7p phosphatase specifically activated coenzyme Q6 biosynthesis through the dephosphorylation of the demethoxy-Q6 hydroxylase Coq7p. The current findings revealed that Ptc7p is a regulator of mitochondrial metabolism that is essential to maintain proper function of the mitochondria by regulating energy metabolism and oxidative stress resistance. PMID- 23940039 TI - Increased expression of fibroblast growth factor 21 (FGF21) during chronic undernutrition causes growth hormone insensitivity in chondrocytes by inducing leptin receptor overlapping transcript (LEPROT) and leptin receptor overlapping transcript-like 1 (LEPROTL1) expression. AB - During calorie restriction in mice, increased expression of FGF21 causes growth attenuation and growth hormone (GH) insensitivity. Previous evidence also indicates that fasting-associated increased expression of leptin receptor overlapping transcript (LEPROT) and LEPROT-like 1 (LEPROTL1) (two proteins that regulate intracellular protein trafficking) reduces GH receptor cell-surface expression in the liver. Thus, we hypothesized that FGF21 causes GH insensitivity through regulation of LEPROT and/or LEPROTL1 expression. After 4 weeks of food restriction, LEPROT and LEPROTL1 mRNA expression in the liver and in the tibial growth plate of wild-type (WT) mice was increased compared with WT mice fed ad libitum. In Fgf21 knock-out (KO) mice, LEPROT and LEPROTL1 mRNA expression in food-restricted and fed ad libitum was similar, with the exception of a subgroup of food-restricted Fgf21 KO mice treated with recombinant human (rh) FGF21 that experienced increased LEPROT and LEPROTL1 mRNA expression compared with untreated food-restricted Fgf21 KO mice. In cultured growth plate chondrocytes, FGF21 stimulated LEPROT and LEPROTL1 mRNA expression, with such effect being prevented in chondrocytes transfected with FGFR1 siRNA or ERK1 siRNA. In cells transfected with control siRNA, GH increased [(3)H]thymidine incorporation, collagen X, and IGF-1 mRNA expression, with all effects being prevented by rhFGF21. In addition, rhFGF21 decreased (125)I-GH binding. In LEPROT siRNA- and/or LEPROTL1 siRNA transfected cells, rhFGF21 did not prevent the GH stimulatory effects on thymidine incorporation, collagen X, and IGF-1 expression; furthermore, rhFGF21 did not prevent (125)I-GH binding. Consistent with the effects of rhFGF21, LEPROT overexpression in chondrocytes resulted in the inhibition of GH action. Our findings indicate that the increased expression of FGF21 during chronic undernutrition inhibits GH action on chondrocytes by activating LEPROT and LEPROTL1. PMID- 23940038 TI - An intrinsically disordered photosystem II subunit, PsbO, provides a structural template and a sensor of the hydrogen-bonding network in photosynthetic water oxidation. AB - Photosystem II (PSII) is a membrane-bound enzyme that utilizes solar energy to catalyze the photooxidation of water. Molecular oxygen is evolved after four sequential light-driven oxidation reactions at the Mn4CaO5 oxygen-evolving complex, producing five sequentially oxidized states, Sn. PSII is composed of 17 membrane-spanning subunits and three extrinsic subunits, PsbP, PsbQ, and PsbO. PsbO is intrinsically disordered and plays a role in facilitation of the water oxidizing cycle. Native PsbO can be removed and substituted with recombinant PsbO, thereby restoring steady-state activity. In this report, we used reaction induced Fourier transform infrared spectroscopy to obtain information concerning the role of PsbP, PsbQ, and PsbO during the S state cycle. Light-minus-dark difference spectra were acquired, monitoring structural changes associated with each accessible flash-induced S state transition in a highly purified plant PSII preparation (Triton X-100, octylthioglucoside). A comparison of S2 minus S1 spectra revealed that removal of PsbP and PsbQ had no significant effect on the data, whereas amide frequency and intensity changes were associated with PsbO removal. These data suggest that PsbO acts as an organizational template for the PSII reaction center. To identify any coupled conformational changes arising directly from PsbO, global (13)C-PsbO isotope editing was employed. The reaction induced Fourier transform infrared spectra of accessible S states provide evidence that PsbO spectral contributions are temperature (263 and 277 K) and S state dependent. These experiments show that PsbO undergoes catalytically relevant structural dynamics, which are coupled over long distance to hydrogen bonding changes at the Mn4CaO5 cluster. PMID- 23940040 TI - Link protein N-terminal peptide binds to bone morphogenetic protein (BMP) type II receptor and drives matrix protein expression in rabbit intervertebral disc cells. AB - Intervertebral disc (IVD) degeneration and associated spinal disorders are leading sources of morbidity, and they can be responsible for chronic low back pain. Treatments for degenerative disc diseases continue to be a challenge. Intensive research is now focusing on promoting regeneration of degenerated discs by stimulating production of the disc matrix. Link protein N-terminal peptide (LPP) is a proteolytic fragment of link protein, an important cross-linker and stabilizer of the major structural components of cartilage, aggrecan and hyaluronan. In this study we investigated LPP action in rabbit primary intervertebral disc cells cultured ex vivo in a three-dimensional alginate matrix. Our data reveal that LPP promotes disc matrix production, which was evidenced by increased expression of the chondrocyte-specific transcription factor SOX9 and the extracellular matrix macromolecules aggrecan and collagen II. Using colocalization and pulldown studies we further document a noggin insensitive direct peptide-protein association between LPP and BMP-RII. This association mediated Smad signaling that converges on BMP genes leading to expression of BMP-4 and BMP-7. Furthermore, through a cell-autonomous loop BMP-4 and BMP-7 intensified Smad1/5 signaling though a feedforward circuit involving BMP-RI, ultimately promoting expression of SOX9 and downstream aggrecan and collagen II genes. Our data define a complex regulatory signaling cascade initiated by LPP and suggest that LPP may be a useful therapeutic substitute for direct BMP administration to treat IVD degeneration and to ameliorate IVD associated chronic low back pain. PMID- 23940041 TI - The allosteric role of the AAA+ domain of ChlD protein from the magnesium chelatase of synechocystis species PCC 6803. AB - Magnesium chelatase is an AAA(+) ATPase that catalyzes the first step in chlorophyll biosynthesis, the energetically unfavorable insertion of a magnesium ion into a porphyrin ring. This enzyme contains two AAA(+) domains, one active in the ChlI protein and one inactive in the ChlD protein. Using a series of mutants in the AAA(+) domain of ChlD, we show that this site is essential for magnesium chelation and allosterically regulates Mg(2+) and MgATP(2-) binding. PMID- 23940042 TI - Interplay between clathrin and Rab5 controls the early phagocytic trafficking and intracellular survival of Brucella abortus within HeLa cells. AB - Lipid raft-associated clathrin is essential for host-pathogen interactions during infection. Brucella abortus is an intracellular pathogen that circumvents host defenses, but little is known about the precise infection mechanisms that involve interaction with lipid raft-associated mediators. The aim of this study was to elucidate the clathrin-mediated phagocytic mechanisms of B. abortus. The clathrin dependence of B. abortus infection in HeLa cells was investigated using an infection assay and immunofluorescence microscopy. The redistribution of clathrin in the membrane and in phagosomes was investigated using sucrose gradient fractionation of lipid rafts and the isolation of B. abortus-containing vacuoles, respectively. Clathrin and dynamin were concentrated into lipid rafts during B. abortus infection, and the entry and intracellular survival of B. abortus within HeLa cells were abrogated by clathrin inhibition. Clathrin disruption decreased actin polymerization and the colocalization of B. abortus-containing vacuoles with clathrin and Rab5 but not lysosome-associated membrane protein 1 (LAMP-1). Thus, our data demonstrate that clathrin plays a fundamental role in the entry and intracellular survival of B. abortus via interaction with lipid rafts and actin rearrangement. This process facilitates the early intracellular trafficking of B. abortus to safe replicative vacuoles. PMID- 23940043 TI - Structural insight into Golgi membrane stacking by GRASP65 and GRASP55 proteins. AB - The stacking of Golgi cisternae involves GRASP65 and GRASP55. The oligomerization of the N-terminal GRASP domain of these proteins, which consists of two tandem PDZ domains, is required to tether the Golgi membranes. However, the molecular basis for GRASP assembly is unclear. Here, we determined the crystal structures of the GRASP domain of GRASP65 and GRASP55. The structures reveal similar homotypic interactions: the GRASP domain forms a dimer in which the peptide binding pockets of the two neighboring PDZ2 domains face each other, and the dimers are further connected by the C-terminal tail of one GRASP domain inserting into the binding pocket of the PDZ1 domain in another dimer. Biochemical analysis suggests that both types of contacts are relatively weak but are needed in combination for GRASP-mediated Golgi stacking. Our results unveil a novel mode of membrane tethering by GRASP proteins and provide insight into the mechanism of Golgi stacking. PMID- 23940044 TI - Engraftment of a galactose receptor footprint onto adeno-associated viral capsids improves transduction efficiency. AB - New viral strains can be evolved to recognize different host glycans through mutagenesis and experimental adaptation. However, such mutants generally harbor amino acid changes that affect viral binding to a single class of carbohydrate receptors. We describe the rational design and synthesis of novel, chimeric adeno associated virus (AAV) strains that exploit an orthogonal glycan receptor for transduction. A dual glycan-binding AAV strain was first engineered as proof of concept by grafting a galactose (Gal)-binding footprint from AAV serotype 9 onto the heparan sulfate-binding AAV serotype 2. The resulting chimera, AAV2G9, continues to bind heparin affinity columns but interchangeably exploits Gal and heparan sulfate receptors for infection, as evidenced by competitive inhibition assays with lectins, glycans, and parental AAV strains. Although remaining hepatotropic like AAV2, the AAV2G9 chimera mediates rapid onset and higher transgene expression in mice. Similarly, engraftment of the Gal footprint onto the laboratory-derived strain AAV2i8 yielded an enhanced AAV2i8G9 chimera. This new strain remains liver-detargeted like AAV2i8 while selectively transducing muscle tissues at high efficiency, comparable with AAV9. The AAV2i8G9 chimera is a promising vector candidate for targeted gene therapy of cardiac and musculoskeletal diseases. In addition to demonstrating the modularity of glycan receptor footprints on viral capsids, our approach provides design strategies to expand the AAV vector toolkit. PMID- 23940045 TI - Hydroquinone increases 5-hydroxymethylcytosine formation through ten eleven translocation 1 (TET1) 5-methylcytosine dioxygenase. AB - DNA methylation regulates gene expression throughout development and in a wide range of pathologies such as cancer and neurological disorders. Pathways controlling the dynamic levels and targets of methylation are known to be disrupted by chemicals and are therefore of great interest in both prevention and clinical contexts. Benzene and its metabolite hydroquinone have been shown to lead to decreased levels of DNA methylation, although the mechanism is not known. This study employs a cell culture model to investigate the mechanism of hydroquinone-mediated changes in DNA methylation. Exposures that do not affect HEK293 cell viability led to genomic and methylated reporter DNA demethylation. Hydroquinone caused reactivation of a methylated reporter plasmid that was prevented by the addition of N-acetylcysteine. Hydroquinone also caused an increase in Ten Eleven Translocation 1 activity and global levels of 5 hydroxymethylcytosine. 5-Hydroxymethylcytosine was found enriched at LINE-1 prior to a decrease in both 5-hydroxymethylcytosine and 5-methylcytosine. Ten Eleven Translocation-1 knockdown decreased 5-hydroxymethylcytosine formation following hydroquinone exposure as well as the induction of glutamate-cysteine ligase catalytic subunit and 14-3-3sigma. Finally, Ten Eleven Translocation 1 knockdown decreased the percentage of cells accumulating in G2+M following hydroquinone exposure, indicating that it may have a role in cell cycle changes in response to toxicants. This work demonstrates that hydroquinone exposure leads to active and functional DNA demethylation in HEK293 cells in a mechanism involving reactive oxygen species and Ten Eleven Translocation 1 5-methylcytosine dioxygenase. PMID- 23940046 TI - Histone deacetylase inhibition promotes osteoblast maturation by altering the histone H4 epigenome and reduces Akt phosphorylation. AB - Bone has remarkable regenerative capacity, but this ability diminishes during aging. Histone deacetylase inhibitors (HDIs) promote terminal osteoblast differentiation and extracellular matrix production in culture. The epigenetic events altered by HDIs in osteoblasts may hold clues for the development of new anabolic treatments for osteoporosis and other conditions of low bone mass. To assess how HDIs affect the epigenome of committed osteoblasts, MC3T3 cells were treated with suberoylanilide hydroxamic acid (SAHA) and subjected to microarray gene expression profiling and high-throughput ChIP-Seq analysis. As expected, SAHA induced differentiation and matrix calcification of osteoblasts in vitro. ChIP-Seq analysis revealed that SAHA increased histone H4 acetylation genome-wide and in differentially regulated genes, except for the 500 bp upstream of transcriptional start sites. Pathway analysis indicated that SAHA increased the expression of insulin signaling modulators, including Slc9a3r1. SAHA decreased phosphorylation of insulin receptor beta, Akt, and the Akt substrate FoxO1, resulting in FoxO1 stabilization. Thus, SAHA induces genome-wide H4 acetylation and modulates the insulin/Akt/FoxO1 signaling axis, whereas it promotes terminal osteoblast differentiation in vitro. PMID- 23940047 TI - Nicotinamide adenine dinucleotide-induced multimerization of the co-repressor CtBP1 relies on a switching tryptophan. AB - The transcriptional co-repressor C-terminal binding protein (CtBP) interacts with a number of repressor proteins and chromatin modifying enzymes. How the biochemical properties including binding of dinucleotide, oligomerization, and dehydrogenase domains of CtBP1 direct the assembly of a functional co-repressor to influence gene expression is not well understood. In the current study we demonstrate that CtBP1 assembles into a tetramer in a NAD(H)-dependent manner, proceeding through a dimeric intermediate. We find that NAD-dependent oligomerization correlates with NAD(+) binding affinity and that the carboxyl terminus is required for assembly of a dimer of dimers. Mutant CtBP1 proteins that abrogate dinucleotide-binding retain wild type affinity for the PXDLS motif, but do not self-associate either in vitro or in vivo. CtBP1 proteins with mutations in the dehydrogenase domain still retain the ability to self-associate and bind target proteins. Both co-immunoprecipitation and mammalian two-hybrid experiments demonstrate that CtBP1 self-association occurs within the nucleus, and depends on dinucleotide binding. Repression of transcription does not depend on dinucleotide binding or an intact dehydrogenase domain, but rather depends on the amino-terminal domain that recruits PXDLS containing targets. We show that tryptophan 318 (Trp(318)) is a critical residue for tetramer assembly and likely functions as a switch for effective dimerization following NAD(+) binding. These results suggest that dinucleotide binding permits CtBP1 to form an intranuclear homodimer through a Trp(318) switch, creating a nucleation site for multimerization through the C-terminal domain for tetramerization to form an effective repression complex. PMID- 23940048 TI - Semaphorin 3A binds to the perineuronal nets via chondroitin sulfate type E motifs in rodent brains. AB - Chondroitin sulfate (CS) and the CS-rich extracellular matrix structures called perineuronal nets (PNNs) restrict plasticity and regeneration in the CNS. Plasticity is enhanced by chondroitinase ABC treatment that removes CS from its core protein in the chondroitin sulfate proteoglycans or by preventing the formation of PNNs, suggesting that chondroitin sulfate proteoglycans in the PNNs control plasticity. Recently, we have shown that semaphorin3A (Sema3A), a repulsive axon guidance molecule, localizes to the PNNs and is removed by chondroitinase ABC treatment (Vo, T., Carulli, D., Ehlert, E. M., Kwok, J. C., Dick, G., Mecollari, V., Moloney, E. B., Neufeld, G., de Winter, F., Fawcett, J. W., and Verhaagen, J. (2013) Mol. Cell. Neurosci. 56C, 186-200). Sema3A is therefore a candidate for a PNN effector in controlling plasticity. Here, we characterize the interaction of Sema3A with CS of the PNNs. Recombinant Sema3A interacts with CS type E (CS-E), and this interaction is involved in the binding of Sema3A to rat brain-derived PNN glycosaminoglycans, as demonstrated by the use of CS-E blocking antibody GD3G7. In addition, we investigate the release of endogenous Sema3A from rat brain by biochemical and enzymatic extractions. Our results confirm the interaction of Sema3A with CS-E containing glycosaminoglycans in the dense extracellular matrix of rat brain. We also demonstrate that the combination of Sema3A and PNN GAGs is a potent inhibitor of axon growth, and this inhibition is reduced by the CS-E blocking antibody. In conclusion, Sema3A binding to CS-E in the PNNs may be a mechanism whereby PNNs restrict growth and plasticity and may represent a possible point of intervention to facilitate neuronal plasticity. PMID- 23940050 TI - Membrane binding by prothrombin mediates its constrained presentation to prothrombinase for cleavage. AB - Long-standing dogma proposes a profound contribution of membrane binding by prothrombin in determining the rate at which it is converted to thrombin by prothrombinase. We have examined the action of prothrombinase on full-length prothrombin variants lacking gamma-carboxyglutamate modifications (desGla) with impaired membrane binding. We show an unexpectedly modest decrease in the rate of thrombin formation for desGla prothrombin but with a major effect on the pathway for substrate cleavage. Using desGla prothrombin variants in which the individual cleavage sites have been singly rendered uncleavable, we find that loss of membrane binding and other Gla-dependent functions in the substrate leads to a decrease in the rate of cleavage at Arg(320) and a surprising increase in the rate of cleavage at Arg(271). These compensating effects arise from a loss in the membrane component of exosite-dependent tethering of substrate to prothrombinase and a relaxation in the constrained presentation of the individual cleavage sites for active site docking and catalysis. Loss of constraint is evident as a switch in the pathway for prothrombin cleavage and the intermediate produced but without the expected profound decrease in rate. Extension of these findings to the action of prothrombinase assembled on platelets and endothelial cells on fully carboxylated prothrombin reveals new mechanistic insights into function on physiological membranes. Cell-dependent enzyme function is probably governed by a differential ability to support prothrombin binding and the variable accumulation of intermediates from the two possible pathways of prothrombin activation. PMID- 23940049 TI - Nox4 NADPH oxidase mediates peroxynitrite-dependent uncoupling of endothelial nitric-oxide synthase and fibronectin expression in response to angiotensin II: role of mitochondrial reactive oxygen species. AB - Activation of glomerular mesangial cells (MCs) by angiotensin II (Ang II) leads to extracellular matrix accumulation. Here, we demonstrate that, in MCs, Ang II induces endothelial nitric-oxide synthase (eNOS) uncoupling with enhanced generation of reactive oxygen species (ROS) and decreased production of NO. Ang II promotes a rapid increase in 3-nitrotyrosine formation, and uric acid attenuates Ang II-induced decrease in NO bioavailability, demonstrating that peroxynitrite mediates the effects of Ang II on eNOS dysfunction. Ang II rapidly up-regulates Nox4 protein. Inhibition of Nox4 abolishes the increase in ROS and peroxynitrite generation as well as eNOS uncoupling triggered by Ang II, indicating that Nox4 is upstream of eNOS. This pathway contributes to Ang II mediated fibronectin accumulation in MCs. Ang II also elicits an increase in mitochondrial abundance of Nox4 protein, and the oxidase contributes to ROS production in mitochondria. Overexpression of mitochondrial manganese superoxide dismutase prevents the stimulatory effects of Ang II on mitochondrial ROS production, loss of NO availability, and MC fibronectin accumulation, whereas manganese superoxide dismutase depletion increases mitochondrial ROS, NO deficiency, and fibronectin synthesis basally and in cells exposed to Ang II. This work provides the first evidence that uncoupled eNOS is responsible for Ang II-induced MC fibronectin accumulation and identifies Nox4 and mitochondrial ROS as mediators of eNOS dysfunction. These data shed light on molecular processes underlying the oxidative signaling cascade engaged by Ang II and identify potential targets for intervention to prevent renal fibrosis. PMID- 23940051 TI - Cluster of differentiation 38 (CD38) mediates bile acid-induced acinar cell injury and pancreatitis through cyclic ADP-ribose and intracellular calcium release. AB - Aberrant Ca(2+) signals within pancreatic acinar cells are an early and critical feature in acute pancreatitis, yet it is unclear how these signals are generated. An important mediator of the aberrant Ca(2+) signals due to bile acid exposure is the intracellular Ca(2+) channel ryanodine receptor. One putative activator of the ryanodine receptor is the nucleotide second messenger cyclic ADP-ribose (cADPR), which is generated by an ectoenzyme ADP-ribosyl cyclase, CD38. In this study, we examined the role of CD38 and cADPR in acinar cell Ca(2+) signals and acinar injury due to bile acids using pharmacologic inhibitors of CD38 and cADPR as well as mice deficient in Cd38 (Cd38(-/-)). Cytosolic Ca(2+) signals were imaged using live time-lapse confocal microscopy in freshly isolated mouse acinar cells during perifusion with the bile acid taurolithocholic acid 3-sulfate (TLCS; 500 MUM). To focus on intracellular Ca(2+) release and to specifically exclude Ca(2+) influx, cells were perifused in Ca(2+)-free medium. Cell injury was assessed by lactate dehydrogenase leakage and propidium iodide uptake. Pretreatment with either nicotinamide (20 mM) or the cADPR antagonist 8-Br-cADPR (30 MUM) abrogated TLCS-induced Ca(2+) signals and cell injury. TLCS-induced Ca(2+) release and cell injury were reduced by 30 and 95%, respectively, in Cd38 deficient acinar cells compared with wild-type cells (p < 0.05). Cd38-deficient mice were protected against a model of bile acid infusion pancreatitis. In summary, these data indicate that CD38-cADPR mediates bile acid-induced pancreatitis and acinar cell injury through aberrant intracellular Ca(2+) signaling. PMID- 23940052 TI - Cell survival during complete nutrient deprivation depends on lipid droplet fueled beta-oxidation of fatty acids. AB - Cells exposed to stress of different origins synthesize triacylglycerols and generate lipid droplets (LD), but the physiological relevance of this response is uncertain. Using complete nutrient deprivation of cells in culture as a simple model of stress, we have addressed whether LD biogenesis has a protective role in cells committed to die. Complete nutrient deprivation induced the biogenesis of LD in human LN18 glioblastoma and HeLa cells and also in CHO and rat primary astrocytes. In all cell types, death was associated with LD depletion and was accelerated by blocking LD biogenesis after pharmacological inhibition of Group IVA phospholipase A2 (cPLA2alpha) or down-regulation of ceramide kinase. Nutrient deprivation also induced beta-oxidation of fatty acids that was sensitive to cPLA2alpha inhibition, and cell survival in these conditions became strictly dependent on fatty acid catabolism. These results show that, during nutrient deprivation, cell viability is sustained by beta-oxidation of fatty acids that requires biogenesis and mobilization of LD. PMID- 23940053 TI - Assembly of functional ribonucleoprotein complexes by AU-rich element RNA-binding protein 1 (AUF1) requires base-dependent and -independent RNA contacts. AB - AU-rich element RNA-binding protein 1 (AUF1) regulates the stability and/or translational efficiency of diverse mRNA targets, including many encoding products controlling the cell cycle, apoptosis, and inflammation by associating with AU-rich elements residing in their 3'-untranslated regions. Previous biochemical studies showed that optimal AUF1 binding requires 33-34 nucleotides with a strong preference for U-rich RNA despite observations that few AUF1 associated cellular mRNAs contain such extended U-rich domains. Using the smallest AUF1 isoform (p37(AUF1)) as a model, we employed fluorescence anisotropy based approaches to define thermodynamic parameters describing AUF1 ribonucleoprotein (RNP) complex formation across a panel of RNA substrates. These data demonstrated that 15 nucleotides of AU-rich sequence were sufficient to nucleate high affinity p37(AUF1) RNP complexes within a larger RNA context. In particular, p37(AUF1) binding to short AU-rich RNA targets was significantly stabilized by interactions with a 3'-purine residue and largely base-independent but non-ionic contacts 5' of the AU-rich site. RNP stabilization by the upstream RNA domain was associated with an enhanced negative change in heat capacity consistent with conformational changes in protein and/or RNA components, and fluorescence resonance energy transfer-based assays demonstrated that these contacts were required for p37(AUF1) to remodel local RNA structure. Finally, reporter mRNAs containing minimal high affinity p37(AUF1) target sequences associated with AUF1 and were destabilized in a p37(AUF1)-dependent manner in cells. These findings provide a mechanistic explanation for the diverse population of AUF1 target mRNAs but also suggest how AUF1 binding could regulate protein and/or microRNA binding events at adjacent sites. PMID- 23940054 TI - Control by potassium of the size distribution of Escherichia coli FtsZ polymers is independent of GTPase activity. AB - The influence of potassium content (at neutral pH and millimolar Mg(2+)) on the size distribution of FtsZ polymers formed in the presence of constantly replenished GTP under steady-state conditions was studied by a combination of biophysical methods. The size of the GTP-FtsZ polymers decreased with lower potassium concentration, in contrast with the increase in the mass of the GDP FtsZ oligomers, whereas no effect was observed on FtsZ GTPase activity and critical concentration of polymerization. Remarkably, the concerted formation of a narrow size distribution of GTP-FtsZ polymers previously observed at high salt concentration was maintained in all KCl concentrations tested. Polymers induced with guanosine 5'-(alpha,beta-methylene)triphosphate, a slowly hydrolyzable analog of GTP, became larger and polydisperse as the potassium concentration was decreased. Our results suggest that the potassium dependence of the GTP-FtsZ polymer size may be related to changes in the subunit turnover rate that are independent of the GTP hydrolysis rate. The formation of a narrow size distribution of FtsZ polymers under very different solution conditions indicates that it is an inherent feature of FtsZ, not observed in other filament-forming proteins, with potential implications in the structural organization of the functional Z-ring. PMID- 23940055 TI - Global shapes of F-actin depolymerization-competent minimal gelsolins: insight into the role of g2-g3 linker in pH/Ca2+ insensitivity of the first half. AB - Because of its ability to rapidly depolymerize F-actin, plasma gelsolin has emerged as a therapeutic molecule in different disease conditions. High amounts of exogenous gelsolin are, however, required to treat animal models of different diseases. Knowing that the F-actin depolymerizing property of gelsolin resides in its N terminus, we made several truncated versions of plasma gelsolin. The smaller versions, particularly the one composed of the first 28-161 residues, depolymerized the F-actin much faster than the native gelsolin and other truncates at the same molar ratios. Although G1-G3 loses its dependence on Ca(2+) or low pH for the actin depolymerization function, interestingly, G1-G2 and its smaller versions were found to regain this requirement. Small angle x-ray scattering-based shape reconstructions revealed that G1-G3 adopts an open shape in both the presence and the absence of Ca(2+) as well as low pH, whereas G1-G2 and residues 28-161 prefer collapsed states in Ca(2+)-free conditions at pH 8. The mutations in the g2-g3 linker resulted in the calcium sensitivity of the mutant G1-G3 for F-actin depolymerization activity, although the F-actin-binding sites remained exposed in the mutant G1-G3 as well as in the smaller truncates even in the Ca(2+)-free conditions at pH 8. Furthermore, unlike wild type G1-G3, calcium-sensitive mutants of G1-G3 acquired closed shapes in the absence of free calcium, implying a role of g2-g3 linker in determining the open F-actin depolymerizing-competent shape of G1-G3 in this condition. We demonstrate that the mobility of the G1 domain, essential for F-actin depolymerization, is indirectly regulated by the gelsolin-like sequence of g2-g3 linker. PMID- 23940056 TI - The lymphocyte to monocyte ratio improves the IPI-risk definition of diffuse large B-cell lymphoma when rituximab is added to chemotherapy. AB - The peripheral blood lymphocyte to monocyte ratio (LMR) at diagnosis can be clinically relevant in patients with diffuse large B-cell lymphoma (DLBCL). We reviewed the outcome of 1,057 DLBCL patients followed from 1984 to 2012 at four centers. LMR was analyzed as a clinical biomarker by receiver-operating characteristic (ROC) analysis and Harrell's C-statistics. Patients were characterized by a median age of 61 years, International Prognostic Index (IPI) score of >2 in 39%, and were treated with a rituximab-containing chemotherapy in 66%. LMR proved strongly predictive for survival in patients treated with rituximab-based programs, but not in those receiving chemotherapy alone. Additionally, an LMR value of <=2.6 (as determined by ROC analysis) was associated with a worst performance status, a higher lactate dehydrogenase (LDH) level, an advanced clinical stage, and a higher IPI score (P = 0.000). In patients treated with rituximab-supplemented chemotherapy programs, an LMR value of <2.6 was found in most of the primary refractory patients (75%) which proved as the best cutoff to predict both response and survival (P = 0.018). Finally, multivariate analysis and Harrell's C-statistics confirmed the IPI-independent role of LMR on survival (P = 0.0000). In conclusion, LMR is a potent predictor of clinical response and survival in DLBCL treated with rituximab-containing chemotherapy. PMID- 23940057 TI - Photophysics of structurally modified flavin derivatives in the blue-light photoreceptor YtvA: a combined experimental and theoretical study. AB - The light-induced processes of two flavin mononucleotide derivatives (1- and 5 deaza flavin mononucleotide, 1DFMN and 5DFMN), incorporated into the LOV domain of YtvA protein from Bacillus subtilis, were studied by a combination of experimental and computational methods. Quantum mechanics/molecular mechanics (QM/MM) calculations were carried out in which the QM part was treated by density functional theory (DFT) using the B3LYP functional for geometry optimizations and the DFT/MRCI method for spectroscopic properties, whereas the MM part was described by the CHARMM force field. 1DFMN is incorporated into the protein binding site, yielding a red-shifted absorption band (lambda(max) =530 nm compared to YtvA wild-type lambda(max) =445 nm), but does not undergo any LOV typical photoreactions such as triplet and photoadduct formation. QM/MM computations confirmed the absence of a channel for triplet formation and located a radiation-free channel (through an S1/S0 conical intersection) along a hydrogen transfer path that might allow for fast deactivation. By contrast, 5DFMN-YtvA-LOV shows a blue-shifted absorption (lambda(max) =410 nm) and undergoes similar photochemical processes to FMN in the wild-type protein, both with regard to the photophysics and the formation of a photoadduct with a flavin-cysteinyl covalent bond. The QM/MM calculations predict a mechanism that involves hydrogen transfer in the T1 state, followed by intersystem crossing and adduct formation in the S0 state for the forward reaction. Experimentally, in contrast to wild-type YtvA, dark-state recovery in 5DFMN-YtvA-LOV is not thermally driven but can only be accomplished after absorption of a second photon by the photoadduct, again via the triplet state. The QM/MM calculations suggest a photochemical mechanism for dark-state recovery that is accessible only for the adduct with a C4a--S bond but not for alternative adducts with a C5--S bond. PMID- 23940059 TI - Howell-Jolly body interference in reticulocyte counts. PMID- 23940058 TI - Twenty-fold acceleration of 3D projection reconstruction MPI. AB - We experimentally demonstrate a 20-fold improvement in acquisition time in projection reconstruction (PR) magnetic particle imaging (MPI) relative to the state-of-the-art PR MPI imaging results. We achieve this acceleration in our imaging system by introducing an additional Helmholtz electromagnet pair, which creates a slow shift (focus) field. Because of magnetostimulation limits in humans, we show that scan time with three-dimensional (3D) PR MPI is theoretically within the same order of magnitude as 3D MPI with a field free point; however, PR MPI has an order of magnitude signal-to-noise ratio gain. PMID- 23940060 TI - Frontiers in research on the Maillard reaction in aging and chronic disease. PMID- 23940061 TI - The value of clinical and laboratory diagnostics for chest pain patients at the emergency department. AB - BACKGROUND: The focus during the diagnostic process for patients with acute chest pain is to discriminate patients who can be safely discharged from those who are at risk for an acute coronary syndrome (ACS). In this study the diagnostic value of the clinical examination is compared with laboratory testing of troponin. METHODS: This study included 710 chest pain patients who presented at the ED of two hospitals in the Netherlands. Clinical examination and laboratory testing were combined in the recently developed HEART-score. The diagnostic values of clinical presentation, troponin and the HEART-score for a major adverse coronary event (MACE) and an ACS within 6 weeks were assessed. Furthermore, the improvement of HEART with the second troponin measurement after 6 h was assessed using the net reclassification improvement (NRI). RESULTS: The use of HEART (AUCMACE: 0.77; AUCACS: 0.82) obtains a higher diagnostic value than troponin (AUCMACE: 0.72; AUCACS: 0.74) or clinical evaluation (AUCMACE: 0.69; AUCACS: 0.74). Statistical significant different AUCs were obtained when HEART is compared to troponin or clinical evaluation (p<0.01). The use of the second troponin test (after 6 h of admission) within HEART resulted in an improvement of 8.0%. CONCLUSIONS: The HEART-score combines clinical evaluation and results from laboratory testing, which should be used together, to discriminate patients at risk of a cardiac event from patients who can be safely discharged. In addition, it is shown that a second troponin measurement slightly improves the discriminative ability of the HEART-score. PMID- 23940062 TI - Double heterozygosity in the BRCA1 and BRCA2 genes in Italian family. AB - BACKGROUND: Double heterozygosity (DH) is an extremely rare event in which both BRCA1 and BRCA2 are mutated simultaneously in a family. To date, few cases of DH have been reported, especially in Ashkenazi populations. In Italy some cases of DH have been reported. In this study, we have described an Italian family with double heterozygosity in the BRCA genes. METHODS: The proband is a 43-year-old woman with bilateral breast cancer. She presented two pathogenic mutations in both BRCA genes, IVS8+2T>A (c.547+2T>A;p.Gln148Aspfsx51) in BRCA1, K944X (c.2830A>T;p.Lys944X) in BRCA2 and a novel variant IVS4-57A>G (c.426-57A>G) in BRCA2, not previously described. Both mutations were inherited from the paternal lineage in the proband's family. We investigated all available members of this family and we identified other two family members with DH. RESULTS AND CONCLUSIONS: Our observations support the hypothesis of a non-specific severe phenotype in DH carriers in terms of age of disease onset, cumulative lifetime risk and multiple primary tumours. Furthermore, our findings confirm that in order to identify all cases of DH, it is important not to limit the identification of mutations in a single gene, but extend the analysis to BRCA1 and BRCA2 and other breast cancer susceptibility genes. PMID- 23940063 TI - The futility of thrombophilia testing. AB - There has been increasing recognition of various laboratory markers of thrombophilia that are associated with increased risk of thrombosis either through hereditary (especially Factor V Leiden, prothrombin G20210A mutation, and protein C, S and antithrombin deficiencies) and/or acquired means (e.g., antiphospholipid antibodies) over past decades. This has led to an explosion of clinical requests for these markers, that has now become virtually uncontrolled, and seemingly inclusive of everyone who has had a thrombotic event. Although these haemostasis-related defects should be assessed in selective cases, the overuse (or misuse) of testing causes serious adverse outcomes and leads to the conclusion that, in general, testing for thrombophilia is futile. PMID- 23940064 TI - Identification of an important potential confound in CSF AD studies: aliquot volume. AB - BACKGROUND: Cerebrospinal fluid (CSF) amyloid beta1-42 (Abeta1-42), total tau (T tau) and phosphorylated tau181 (P-tau) are finding increasing utility as biomarkers of Alzheimer's disease (AD). The purpose of this study was to determine whether measured CSF biomarker concentrations were affected by aliquot storage volume and whether addition of detergent-containing buffer mitigates any observed effects. METHODS: AD and control CSF was distributed into polypropylene tubes in aliquots of different volumes (50-1500 MUL). Abeta1-42, T-tau and P-tau were measured with and without addition of Tween 20 (0.05%). RESULTS: Measured concentrations of Abeta1-42 increased two-fold with aliquot storage volume. A volume increase of 10 uL caused an Abeta1-42 increase of 0.95 pg/mL [95% confidence interval (CI) 0.36-1.50, p=0.02] in controls, and 0.60 pg/mL (CI 0.23 0.98 pg/mL, p=0.003) in AD samples. Following addition of Tween 20, the positive relationship between Abeta1-42 and aliquot volume disappeared. T-tau and P-tau were not significantly affected. CONCLUSIONS: CSF aliquot storage volume has a significant impact on the measured concentration of Abeta1-42. The introduction of a buffer detergent at the initial aliquoting stage may be an effective solution to this problem. PMID- 23940065 TI - Development and validation of a rapid and reliable high-performance liquid chromatography method for methadone quantification in human plasma and saliva. PMID- 23940066 TI - Thrombophilia testing. Useful or hype? PMID- 23940067 TI - Recent advances in physiological lipoprotein metabolism. AB - Research into lipoprotein metabolism has developed because understanding lipoprotein metabolism has important clinical indications. Lipoproteins are risk factors for cardiovascular disease. Recent advances include the identification of factors in the synthesis and secretion of triglyceride rich lipoproteins, chylomicrons (CM) and very low density lipoproteins (VLDL). These included the identification of microsomal transfer protein, the cotranslational targeting of apoproteinB (apoB) for degradation regulated by the availability of lipids, and the characterization of transport vesicles transporting primordial apoB containing particles to the Golgi. The lipase maturation factor 1, glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 and an angiopoietin-like protein play a role in lipoprotein lipase (LPL)-mediated hydrolysis of secreted CMs and VLDL so that the right amount of fatty acid is delivered to the right tissue at the right time. Expression of the low density lipoprotein (LDL) receptor is regulated at both transcriptional and post transcriptional level. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has a pivotal role in the degradation of LDL receptor. Plasma remnant lipoproteins bind to specific receptors in the liver, the LDL receptor, VLDL receptor and LDL receptor-like proteins prior to removal from the plasma. Reverse cholesterol transport occurs when lipid free apoAI recruits cholesterol and phospholipid to assemble high density lipoprotein (HDL) particles. The discovery of ABC transporters (ABCA1 and ABCG1) and scavenger receptor class B type I (SR-BI) provided further information on the biogenesis of HDL. In humans HDL-cholesterol can be returned to the liver either by direct uptake by SR-BI or through cholesteryl ester transfer protein exchange of cholesteryl ester for triglycerides in apoB lipoproteins, followed by hepatic uptake of apoB containing particles. Cholesterol content in cells is regulated by several transcription factors, including the liver X receptor and sterol regulatory element binding protein. This review summarizes recent advances in knowledge of the molecular mechanisms regulating lipoprotein metabolism. PMID- 23940068 TI - The rare bipolar-contracted red cell significance and correlation with red cell volume. PMID- 23940069 TI - SAA1 genetic polymorphisms are associated with plasma glucose concentration in non-diabetic subjects. AB - BACKGROUND: Serum amyloid A (SAA) was reported to be associated with insulin resistance and type-2 diabetes. The present study aimed to investigate the association of SAA genetic polymorphisms with plasma glucose levels in non diabetic subjects. METHODS: All participants (n=1220) were selected from subjects participating in the Cardiovascular Risk Survey (CRS) study. Five single nucleotide polymorphisms (SNPs) (rs2229338, rs12218, rs4638289, rs7131332 and rs11603089) of SAA gene were genotyped using polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) analysis. RESULTS: In the present study, we found rs2229338, rs4638289 and rs12218 were significantly associated with plasma glucose levels in a dominate model, recessive model or additive model before and after multivariate adjustment (all p<0.05). These associations were not found in rs7131332 and rs11603089 before and after adjustment of key co variants. CONCLUSIONS: The genetic polymorphisms of SAA1 were associated with plasma glucose levels in non-diabetic subjects. PMID- 23940070 TI - Semiparametric regression analysis of clustered interval-censored failure time data with informative cluster size. AB - Clustered interval-censored failure time data are commonly encountered in many medical settings. In such situations, one issue that often arises in practice is that the cluster size is related to the risk for the outcome of interest. It is well-known that ignoring the informativeness of the cluster size can result in biased parameter estimates. In this article, we consider regression analysis of clustered interval-censored data with informative cluster size with the focus on semiparametric methods. For the problem, two approaches are presented and investigated. One is a within-cluster resampling procedure and the other is a weighted estimating equation approach. Unlike previously published methods, the new approaches take into account cluster sizes and heterogeneous correlation structures without imposing strong parametric assumptions. A simulation experiment is carried out to evaluate the performance of the proposed approaches and indicates that they perform well for practical situations. The approaches are applied to a lymphatic filariasis study that motivated this study. PMID- 23940071 TI - The effects of the "physical BEMER(r) vascular therapy", a method for the physical stimulation of the vasomotion of precapillary microvessels in case of impaired microcirculation, on sleep, pain and quality of life of patients with different clinical pictures on the basis of three scientifically validated scales. AB - As part of the statutory market monitoring of certified medical devices, 658 valid patient questionnaires were evaluated between April 2011 and March 2013. The questions consisted mainly of three scientifically recognized scales for assessing the changes of sleep, pain and quality of life in patients who had used the "physical BEMER(r) vascular therapy" for different diseases over 6 weeks. The result clearly shows that there are significant improvements in all areas surveyed through the application of this complementary treatment option, regardless of the underlying disease. PMID- 23940072 TI - Waste not, want not: mild and selective catalytic oxidation of uronic acids. AB - And isn't it uronic: A mild, highly efficient and selective catalytic oxidation of pectin-derived uronic acids to the corresponding aldaric acids is reported. Fast, quantitative conversions (>99%) of the starting materials are achieved with high selectivity (>97%) at room temperature, using supported gold catalysts and air as oxidizing agent. PMID- 23940073 TI - Beverage preferences and associated drinking patterns, consequences and other substance use behaviours. AB - BACKGROUND: Studies about beverage preferences in a country in which wine drinking is relatively widespread (like Switzerland) are scarce. Therefore, the main aims of the present study were to examine the associations between beverage preferences and drinking patterns, alcohol-related consequences and the use of other substances among Swiss young men. METHODS: The analytical sample consisted of 5399 Swiss men who participated in the Cohort Study on Substance Use Risk Factors (C-SURF) and had been drinking alcohol over the preceding 12 months. Logistic regression analyses were conducted to study the associations between preference for a particular beverage and (i) drinking patterns, (ii) negative alcohol-related consequences and (iii) the (at-risk) use of cigarettes, cannabis and other illicit drugs. RESULTS: Preference for beer was associated with risky drinking patterns and, comparable with a preference for strong alcohol, with the use of illicit substances (cannabis and other illicit drugs). In contrast, a preference for wine was associated with low-risk alcohol consumption and a reduced likelihood of experiencing at least four negative alcohol-related consequences or of daily cigarette smoking. Furthermore, the likelihood of negative outcomes (alcohol-related consequences; use of other substances) increased among people with risky drinking behaviours, independent of beverage preference. CONCLUSIONS: In our survey, beer preference was associated with risky drinking patterns and illicit drug use. Alcohol polices to prevent large quantities of alcohol consumption, especially of cheaper spirits like beer, should be considered to reduce total alcohol consumption and the negative consequences associated with these beverage types. PMID- 23940074 TI - The IDO1-induced kynurenines play a major role in the antimicrobial effect of human myeloid cells against Listeria monocytogenes. AB - Induction of indoleamine 2,3-dioxygenase (IDO1) is an established cellular response to infection with numerous pathogens. Several mechanisms, such as IDO1 mediated tryptophan (Trp) depletion, but also accumulation of Trp catabolites, have been associated with the antimicrobial effects of IDO(+) cells. Recent findings of IDO1 as an immunoinhibitory and signaling molecule extended these previous observations. Using infection of professional phagocytes with Listeria monocytogenes (L.m.) as a model, we illustrate that IDO1 induction is a species specific event observed in human, but not murine myeloid, cells. Knockdown and inhibition experiments indicate that IDO1 enzymatic activity is required for the anti-L.m. effect. Surprisingly, the IDO1-mediated antimicrobial effect is less prominent when Trp is depleted, but can be significantly amplified by tryptophan excess, leading to increased accumulation of catabolites that promote enhanced bactericidal activity. We observed a pathogen-specific pattern with kynurenine and 3-hydroxy-kynurenine being most potent against L.m., but not against other bacteria. Hence, apparent discrepant findings concerning IDO1-mediated antimicrobial mechanisms can be reconciled by a model of species and pathogen specificity of IDO1 function. Our findings highlight the necessity to consider species- and pathogen-specific aspects of host-pathogen interactions when elucidating the individual role of antimicrobial proteins such as IDO1. PMID- 23940075 TI - The role of TLR2 and 4 in Behcet's disease pathogenesis. AB - TLRs are PRRs that play a pivotal role in sensing exogenous pathogens and endogenous danger signals. Their role in the pathogenesis of inflammatory and immune-related diseases is gradually being unravelled. TLR2 and TLR4 are capable of sensing the oral microbial community, which is considered a potential trigger for Behcet's disease (BD). This study aimed to investigate the expression and function of TLR2 and TLR4 in the oral mucosa of BD. A total of 87 patients was included: 55 BD, 24 healthy controls and eight recurrent aphthous stomatitis. Total RNA was purified from non-lesional oral mucosal brush biopsies and analysed for the presence of TLR2 and TLR4 mRNA, along with their splice variants. The response of peripheral blood mononuclear cells to classical TLR2 and TLR4 agonists was also investigated. TLR2b, TLR2d, TLR2e, TLR4.3 and TLR4.4 were significantly elevated in relapsed BD. A significant defect in the response to cognate agonists of TLR1/2 heterodimer and TLR4 was also observed in BD. The expression of unusual splice variants of TLR2 and TLR4 might explain the observed defect in these receptors' function in BD. PMID- 23940076 TI - Cytokine gene polymorphism among Indigenous Australians. AB - The health profile of Indigenous Australians is characterised by high rates of classic 'lifestyle' diseases. Potential roles of inflammation in pathophysiology of these diseases requires investigation. It is not clear if genetic regulation of inflammation in Indigenous Australians is similar to other populations. This study characterised frequencies of single nucleotide polymorphisms (SNPs) for eight cytokine genes for 100 individuals from a remote Indigenous Australian community and assessed novel genetic variants in four cytokine genes. We used a commercially-available allelic discrimination assay for SNP genotyping; re sequencing was undertaken by standard Sanger sequencing methodologies for 26 samples. Frequencies of cytokine gene SNPs differed significantly from the Caucasian population (P < 0.001-0.044). Twenty-five novel variants were identified across four re-sequenced genes; frequencies ranged from <5% to 100%. Genotype frequencies observed in Indigenous Australians did not consistently resemble reported HapMap frequencies in Northern and Western European populations, Yoruba Nigerian or Han Chinese. Our findings indicate Indigenous Australians might have an inherited propensity for strong inflammatory responses. Preliminary evidence of novel genetic variants highlights the need to catalogue the extent of genetic variation in specific population groups. Improved understanding of differences in genetic variation between specific population groups could assist in assessment of risk for lifestyle diseases. PMID- 23940077 TI - LTbetaR expression on hematopoietic cells regulates acute inflammation and influences maturation of myeloid subpopulations. AB - Lymphotoxin beta-receptor (LTbetaR) is involved in the formation and maintenance of secondary lymphoid structures, as well as in the regulation of inflammatory responses. Because LTbetaR lymphoid structure formation continues to develop in infants, we compared two different chimera models: one using adult mice and the other using a transplantation model of neonatal mice. To elucidate the function of LTbetaR on lymphoid and non-lymphoid cells, we generated bone marrow chimeras on the wild type C57Bl/6 and the LTbetaR-deficient (LTbetaR(-/-)) background, and reconstituted the mice with bone marrow cells reciprocally. These chimeric mice were analyzed in the experimental model of acute dextran sulfate sodium-induced colitis. Interestingly, both models revealed not only equal reconstitution levels but also similar immunological responses: LTbetaR expression on stromal cells is essential for lymph node formation, whereas LTBR on hematopoietic cells is crucial for a decrease in inflammation. In addition, mice lacking LTbetaR on hematopoietic cells revealed (a) an increase of immature granulocytic cells in the spleen and (b) a reduced proportion of myeloid cells in peripheral blood and spleen expressing CD11b(+)Ly6C(+)Ly6G(-) (myeloid-derived suppressor cells expression profile). In conclusion, LTbetaR expression on hematopoietic cells seems to be involved in the down-regulation of acute inflammatory reactions paralleled by the appearance of immature myeloid cells. PMID- 23940078 TI - Synthesis of poly(benzothiadiazole-co-dithienobenzodithiophenes) and effect of thiophene insertion for high-performance polymer solar cells. AB - We describe herein the synthesis of novel donor-acceptor conjugated polymers with dithienobenzodithiophenes (DTBDT) as the electron donor and 2,1,3 benzothiadiazole as the electron acceptor for high-performance organic photovoltaics (OPVs). We studied the effects of strategically inserting thiophene into the DTBDT as a substituent on the skeletal structure on the opto-electronic performances of fabricated devices. From UV/Vis absorption, electrochemical, and field-effect transistor analyses, we found that the thiophene-containing DTBDT derivative can substantially increase the orbital overlap area between adjacent conjugated chains and thus dramatically enhance charge-carrier mobility up to 0.55 cm(2) V(-1) s(-1). The outstanding charge-transport characteristics of this polymer allowed the realization of high-performance organic solar cells with a power conversion efficiency (PCE) of 5.1 %. Detailed studies on the morphological factors that enable the maximum PCE of the polymer solar cells are discussed along with a hole/electron mobility analysis based on the space-charge limited current model. PMID- 23940079 TI - Changes in the NMR characteristics of 3,6-di-tert-butylquinone on formation of paramagnetic complexes. AB - High-resolution NMR spectra of 3,6-di-tert-butylquinone were recorded and analyzed for the first time in a wide range of temperatures. The spectra were transformed by paramagnetic additives of cobalt, nickel, and copper complexes synthesized on the basis of metal semiquinolates. Chloroform, dimethylsulfoxide, toluene, and acetone were used as solvents. It was shown that the spectra changed by paramagnetic additives can contain valuable information on the nature of a superfine interaction in paramagnetic complexes and on peculiarities of intramolecular dynamics inherent in these compounds. PMID- 23940080 TI - Effect of taxane-based neoadjuvant chemotherapy on fibroglandular tissue volume and percent breast density in the contralateral normal breast evaluated by 3T MR. AB - The aim of this study was to evaluate the change of breast density in the normal breast of patients receiving neoadjuvant chemotherapy (NAC). Forty-four breast cancer patients were studied. MRI acquisition was performed before treatment (baseline), and 4 and 12 weeks after treatment. A computer-algorithm-based program was used to segment breast tissue and calculate breast volume (BV), fibroglandular tissue volume (FV), and percent density (PD) (the ratio of FV over BV * 100%). The reduction of FV and PD after treatment was compared with baseline using paired t-tests with a Bonferroni-Holm correction. The association of density reduction with age was analyzed. FV and PD after NAC showed significant decreases compared with the baseline. FV was 110.0 ml (67.2, 189.8) (geometric mean (interquartile range)) at baseline, 104.3 ml (66.6, 164.4) after 4 weeks (p < 0.0001), and 94.7 ml (60.2, 144.4) after 12 weeks (comparison with baseline, p < 0.0001; comparison with 4 weeks, p = 0.016). PD was 11.2% (6.4, 22.4) at baseline, 10.6% (6.6, 20.3) after 4 weeks (p < 0.0001), and 9.7% (6.2, 17.9) after 12 weeks (comparison with baseline, p = 0.0001; comparison with 4 weeks, p = 0.018). Younger patients tended to show a higher density reduction, but overall correlation with age was only moderate (r = 0.28 for FV, p = 0.07, and r = 0.52 for PD, p = 0.0003). Our study showed that breast density measured from MR images acquired at 3T MR can be accurately quantified using a robust computer-aided algorithm based on non-parametric non-uniformity normalization (N3) and an adaptive fuzzy C-means algorithm. Similar to doxorubicin and cyclophosphamide regimens, the taxane-based NAC regimen also caused density atrophy in the normal breast and showed reduction in FV and PD. The effect of breast density reduction was age related and duration related. PMID- 23940081 TI - The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer. AB - Tumor cells have long been observed to share several biological characteristics with normal stem/progenitor cells; however, the oncogenic mechanisms underlying the lung stem/progenitor cell signaling remain elusive. Here, we report that SOX2, a self-renewal factor in lung stem/progenitor cells, is highly expressed in a subclass of lung cancer cells, the proliferation, survival, and chemoresistance of which are dependent on SOX2 signaling. Overexpression of SOX2 promotes oncogenic phenotypes in lung cancer cells; knockdown of SOX2 attenuated cell proliferation. We observed that SOX2 increased the expression of epidermal growth factor receptor (EGFR), and EGFR activation further upregulated SOX2 levels, forming a positive feedback loop. SOX2 expression promoted chemoresistance, and silencing of SOX2 perturbed mitochondrial function, causing marked apoptosis and autophagy. SOX2 induced BCL2L1, the ectopic expression of which rescued the effects of SOX2 silencing on apoptosis, autophagy, and mitochondrial function. SOX2 promoted tumor formation, along with increased cell proliferation in a xenograft mouse model. SOX2 expression is associated with poor prognosis in lung cancer patients; moreover, SOX2, EGFR, and BCL2L1 expression levels were significantly correlated in lung tumors. Our findings support the emerging role of SOX2 in cell proliferation and survival by eliciting oncogenic EGFR and BCL2L1 signaling with potential applications as a prognosis marker and a therapeutic target in lung cancer. PMID- 23940082 TI - Synthesis of dibenzopyranones through palladium-catalyzed directed C-H activation/carbonylation of 2-arylphenols. AB - Dibenzopyranones were synthesized by a palladium-catalyzed phenol-directed C-H activation/carbonylation of 2-phenylphenol derivatives in the presence of CO. Pd(OAc)2 was used as a catalyst and Cu(OAc)2 as a catalytic oxidant in the presence of air. PMID- 23940083 TI - Overcoming resistance to Sonic Hedgehog inhibition by targeting p90 ribosomal S6 kinase in pediatric medulloblastoma. AB - BACKGROUND: Molecular subtyping has allowed for the beginning of personalized treatment in children suffering from medulloblastoma (MB). However, resistance inevitably emerges against these therapies, particularly in the Sonic Hedgehog (SHH) subtype. We found that children with SHH subtype have the worst outcome underscoring the need to identify new therapeutic targets. PROCEDURE: High content screening of a 129 compound library identified agents that inhibited SHH MB growth. Lead molecular target levels, p90 ribosomal S6 kinase (RSK) were characterized by immunoblotting and qRT-PCR. Comparisons were made to human neural stem cells (hNSC). Impact of inhibiting RSK with the small molecule BI D1870 or siRNA was assessed in growth assays (monolayer, neurosphere, and soft agar). NanoString was used to detect RSK in a cohort of 66 patients with MB. To determine BI-D1870 pharmacokinetics/pharmacodynamics, 100 mg/kg was I.P. injected into mice and tissues were collected at various time points. RESULTS: Daoy, ONS76, UW228, and UW426 MB cells were exquisitely sensitive to BI-D1870 but unresponsive to SHH inhibitors. Anti-tumor growth corresponded with inactivation of RSK in MB cells. BI-D1870 had no effect on hNSCs. Inhibiting RSK with siRNA or BI-D1870 suppressed growth, induced apoptosis, and sensitized cells to SHH agents. Notably, RSK expression is correlated with SHH patients. In mice, BI D1870 was well-tolerated and crossed the blood-brain barrier (BBB). CONCLUSIONS: RSK inhibitors are promising because they target RSK which is correlated with SHH patients as well as cause high levels of apoptosis to only MB cells. Importantly, BI-D1870 crosses the BBB, acting as a scaffold for development of more long-lived RSK inhibitors. PMID- 23940084 TI - TET2 mutations, myelodysplastic features, and a distinct immunoprofile characterize blastic plasmacytoid dendritic cell neoplasm in the bone marrow. AB - Distinguishing blastic plasmacytoid dendritic cell neoplasm (BPDCN) from acute myeloid leukemia (AML) is gaining increased importance because of emerging differences in therapeutic approaches, and this distinction can be problematic in bone marrow specimens. We identified retrospectively 16 patients with bone marrow involvement by BPDCN: 11 men and 5 women with a median age of 62.5 years (range, 19-86 years). Myelodysplastic changes were observed in five patients. Immunophenotypic analysis showed that the neoplastic cells were positive for CD4, CD123, TCL-1, and HLA-DR and were negative for CD3, CD8, CD13, CD19, CD34, and myeloperoxidase. Other antigens expressed by subsets of BPDCN cases included the following: CD56 (13/15; 81%), CD33 (7/10; 70%), CD7 (11/14; 69%), TdT (5/15; 33%), CD2 (5/11; 31%), CD117 (2/9; 22%), and CD5 (2/13; 15%). Conventional cytogenetic analysis showed chromosomal abnormalities in 6 of 13 (46%) cases analyzed, of which 3 cases had -13/13q-. Targeted next-generation sequencing performed on five BPDCN cases identified TET2 (ten eleven translocation 2) mutations and no other AML-associated mutations. In conclusion, BPDCN in the bone marrow has a characteristic immunoprofile (CD4+, CD56+, CD123+, and TCL-1+) and appears to be commonly associated with myelodysplastic features and a high frequency of TET2 mutations in the absence of other mutations commonly observed in AML. PMID- 23940085 TI - Different circadian expression of major matrix-related genes in various types of cartilage: modulation by light-dark conditions. AB - We screened circadian-regulated genes in rat cartilage by using a DNA microarray analysis. In rib growth-plate cartilage, numerous genes showed statistically significant circadian mRNA expression under both 12:12 h light-dark and constant darkness conditions. Type II collagen and aggrecan genes--along with several genes essential for post-translational modifications of collagen and aggrecan, including prolyl 4-hydroxylase 1, lysyl oxidase, lysyl oxidase-like 2 and 3' phosphoadenosine 5'-phosphosulphate synthase 2--showed the same circadian phase. In addition, the mRNA level of SOX9, a master transcription factor for the synthesis of type II collagen and aggrecan, has a similar phase of circadian rhythms. The circadian expression of the matrix-related genes may be critical in the development and the growth of various cartilages, because similar circadian expression of the matrix-related genes was observed in hip joint cartilage. However, the circadian phase of the major matrix-related genes in the rib permanent cartilage was almost the converse of that in the rib growth-plate cartilage under light-dark conditions. We also found that half of the oscillating genes had conserved clock-regulatory elements, indicating contribution of the elements to the clock outputs. These findings suggest that the synthesis of the cartilage matrix macromolecules is controlled by cell-autonomous clocks depending upon the in vivo location of cartilage. PMID- 23940086 TI - Heparin modulates the mitogenic activity of fibroblast growth factor by inducing dimerization of its receptor. a 3D view by using NMR. AB - In vitro mitogenesis assays have shown that sulfated glycosaminoglycans (GAGs; heparin and heparan sulfate) cause an enhancement of the mitogenic activity of fibroblast growth factors (FGFs). Herein, we report that the simultaneous presence of FGF and the GAG is not an essential requisite for this event to take place. Indeed, preincubation with heparin (just before FGF addition) of cells lacking heparan sulfate produced an enhancing effect equivalent to that observed when the GAG and the protein are simultaneously added. A first structural characterization of this effect by analytical ultracentrifugation of a soluble preparation of the heparin-binding domain of fibroblast growth factor receptor 2 (FGFR2) and a low molecular weight (3 kDa) heparin showed that the GAG induces dimerization of FGFR2. To derive a high resolution structural picture of this molecular recognition process, the interactions of a soluble heparin-binding domain of FGFR2 with two different homogeneous, synthetic, and mitogenically active sulfated GAGs were analyzed by NMR spectroscopy. These studies, assisted by docking protocols and molecular dynamics simulations, have demonstrated that the interactions of these GAGs with the soluble heparin-binding domain of FGFR induces formation of an FGFR dimer; its architecture is equivalent to that in one of the two distinct crystallographic structures of FGFR in complex with both heparin and FGF1. This preformation of the FGFR dimer (with similar topology to that of the signaling complex) should favor incorporation of the FGF component to form the final assemblage of the signaling complex, without major entropy penalty. This cascade of events is probably at the heart of the observed activating effect of heparin in FGF-driven mitogenesis. PMID- 23940087 TI - Effect of antioxidants on functional recovery after in vitro-induced ischemia and long-term potentiation recorded in the pyramidal layer of the CA1 area of rat hippocampus. AB - Ischemic stroke is one of the leading causes of cognitive impairment. Antioxidants may be beneficial in brain diseases in which oxidative stress can be assumed. The effect of two antioxidants, stobadine and its new derivative coded SMe1EC2, was studied on post-ischemic functional recovery in the hippocampus of young and 18-month-old rats. The synaptic transmission was apparently absent after 6-min hypoxia/hypoglycemia in both age groups. Re-oxygenation resulted in negligible functional recovery in untreated slices, yet the presence of pyridoindoles tested elicited improved recovery upon re-oxygenation. SMe1EC2 was found more effective in post-ischemic functional recovery and was further tested in the hippocampus of 15-month-old rats in long-term potentiation (LTP) experiments, a synaptic model of learning and memory mechanisms. In slices of aged rats, 3.5-min hypoxia/hypoglycemia resulted in depression of the LTP induction phase (immediately after high frequency stimulation) and this was prevented in the presence of SMe1EC2 (3 umol/l). Upon "normoxia", marked amelioration of LTP was recorded in the presence of the antioxidant in about 1.5 order lower concentration. These results suggest a possible application of the pyridoindole in the management of brain ischemia and cognitive impairment. PMID- 23940088 TI - Interactions of y+LAT1 and 4F2hc in the y+l amino acid transporter complex: consequences of lysinuric protein intolerance-causing mutations. AB - Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by recessive mutations in the SLC7A7 gene encoding y+L amino acid transporter 1 (y+LAT1), which combines with 4F2hc to generate an active transporter responsible for the system y+L amino acid transport. We have previously shown that the y+LAT1 proteins with point mutations are expressed in the plasma membrane, while those with frameshift mutations are retained in the cytoplasm. This finding has prompted us to study whether the difference in localization is due to the inability of the structurally altered mutant y+LAT1 proteins to heteromerize with 4F2hc. For this purpose, we utilized FACS technique to reveal fluorescence resonance energy transfer (FRET) in cells expressing wild type or LPI-mutant CFP tagged y+LAT1 and YFP-tagged 4F2hc. The heteromerization of y+LAT1 and 4F2hc within the cell is not disrupted by any of the tested LPI mutations. In addition, the expression rate of the LPI mutant y+LAT1 proteins was significantly lower and cellular mortality was markedly increased than that of the wild type y+LAT1 in transfected samples. Our results indicate that the FACS-FRET method provides an alternative approach for screening of potential protein associations. PMID- 23940089 TI - ABT-737 accelerates butyrate-induced death of HL-60 cells. Involvement of mitochondrial apoptosis pathway. AB - The aim of presented study was to determine effect of NaBu in combination with ABT-737 on cell survival of leukemic cell line HL-60. In addition, analysis of molecular mechanism of NaBu action with a focus on mitochondrial apoptosis was performed. Both NaBu and ABT-737 are inducing death of HL-60 cells with different kinetics. ABT-737-induced cell death is fast while NaBu-induced death preceded by cell cycle arrest in G2 phase is rather slow. Cell viability preceded by cell cycle arrest in G2 phase was significantly decreased after 48 hours of incubation with 2 and 5 mmol/l of NaBu while it was significantly decreased after 24 hours of incubation with 1 MUmol/l of ABT-737 combined with 2 and 5 mmol/l of NaBu. Incubation of HL-60 cells with NaBu was associated with increased level of pro apoptotic protein BIMEL and decreased levels of anti-apoptotic proteins of Bcl-2 family as well as GRP78 involved in ER stress signalling. It seems that ABT-737 accelerates NaBu-induced death of HL-60 cells due to mitochondrial apoptosis resulting from ABT-737-mediated inhibition of functions and NaBu-induced decrease of the levels of anti-apoptotic Bcl-2 family proteins as well as due to accelerated decrease of GRP78 observed after the treatment of cells with combination of NaBu and ABT-737. The effect of combination of both drugs on survival of HL-60 cells seems to be synergistic at high concentrations of NaBu (2 and 5 mmol/) while it is rather antagonistic at concentrations of NaBu less than 1 mmol/l. Finally, it might be assumed that NaBu is capable to induce cell death with mechanisms independent from mitochondrial apoptosis. PMID- 23940090 TI - Protective effects of Artemisia campestris upon fenthion-induced nephrotoxicity in adult rats and their progeny. AB - The purpose of this study was to assess the possible protective effects of Artemisia campestris against fenthion-induced nephrotoxicity in adult rats and their progeny. Fenthion was administered orally at a dose of 551 ppm, which represented 1/4 of LD50, for 21 consecutive days to pregnant and lactating rats. Oxidative stress was monitored in the kidney by measuring malondialdehyde (MDA), GSH levels, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase activities (GPx). Fenthion caused a significant induction of oxidative damage in kidney as evidenced by increased MDA levels from 5.32 +/- 0.47 nmol/100 mg tissue to 11.72 +/- 0.83 nmol/100 mg tissue for pups and from 5.18 +/- 0.45 nmol/100 mg tissue to 10.84 +/- 1.67 nmol/100 mg tissue for dams (p < 0.001). A significant increase (p < 0.001) in the activities of SOD, CAT and GPx was observed. Co administration of Artemisia c. at a dose of 5% (w/w) in the diet of fenthion treated rats showed a significant reno-protection against fenthion-induced cytotoxic effects. It could be concluded that Artemisia c. is promising as a protective agent against nephrotoxicity during the exposure to fenthion. PMID- 23940091 TI - Quantitative estimation of transmembrane ion transport in rat renal collecting duct principal cells. AB - Kidney collecting duct principal cells play a key role in regulated tubular reabsorption of water and sodium and secretion of potassium. The importance of this function for the maintenance of the osmotic homeostasis of the whole organism motivates extensive study of the ion transport properties of collecting duct principal cells. We performed experimental measurements of cell volume and intracellular sodium concentration in rat renal collecting duct principal cells from the outer medulla (OMCD) and used a mathematical model describing transmembrane ion fluxes to analyze the experimental data. The sodium and chloride concentrations ([Na+]in = 37.3 +/- 3.3 mM, [Cl-]in = 32.2 +/- 4.0 mM) in OMCD cells were quantitatively estimated. Correspondence between the experimentally measured cell physiological characteristics and the values of model permeability parameters was established. Plasma membrane permeabilities and the rates of transmembrane fluxes for sodium, potassium and chloride ions were estimated on the basis of ion substitution experiments and model predictions. In particular, calculated sodium (PNa), potassium (PK) and chloride (PCl) permeabilities were equal to 3.2 * 10-6 cm/s, 1.0 * 10-5 cm/s and 3.0 * 10-6 cm/s, respectively. This approach sets grounds for utilization of experimental measurements of intracellular sodium concentration and cell volume to quantify the ion permeabilities of OMCD principal cells and aids us in understanding the physiology of the adjustment of renal sodium and potassium excretion. PMID- 23940093 TI - Gender differences in ghrelin response to chronic immobilization stress in rats: possible role of estrogen. AB - Ghrelin is a peptidergic hormone known to be one of the main hormones involved in the regulation of energy balance. Here we evaluated ghrelin response to stress in rats after ovariectomy and during estradiol benzoate (EB) therapy and compared results of males and females, to know whether ghrelin is involved in disordered eating behaviors in response to stress, and for understanding differences between males and females in food intake and weight gain especially during stress. 96 adult rats were classified into; male, female, ovariectomized (Ovx), Ovx with EB. Half animals of each group were exposed to immobilization stress 20 min/day for 21 days. We found that chronic stress significantly augments serum ghrelin levels in both males and females, which is correlated with an increase in food intake and body weight. Females displayed significant higher ghrelin than males especially in response to stress, ovariectomy suppresses serum ghrelin in both unstressed and stressed females which is rescued by replacement with EB. EB replacement augments ghrelin response to stress in Ovx female, and reduces food intake and body weight. In conclusion, there is a clear sex difference in ghrelin secretion in response to stress caused by EB, since it amplifies ghrelin response to stress in females. PMID- 23940092 TI - Attenuated vascular responsiveness to K+ channel openers in diabetes mellitus: the differential role of reactive oxygen species. AB - The current study examined the responsiveness of blood vessels from diabetic rats to K+ channel openers and explored whether ROS might be involved in any changes. Responses were measured in aortic rings isolated from four weeks streptozotocin (65 mg/kg)-induced diabetic rats. Relaxation to levcromakalim (ATP-sensitive potassium channel KATP opener, 10(-9)-10(-5) mol/l) and (+/-)-naringenin (large conductance calcium-activated channel BKCa opener, 10(-8)-10(-3) mol/l) were recorded in phenylephrine (1 umol/l) pre-contracted segments in the absence and presence of superoxide dismutase (SOD, 100 umol/l) and apocynin (an antioxidant and inhibitor of NADPH oxidase, 100 umol/l). Contractions to phenylephrine (10( 9)-10(-5) mol/l) and relaxation to acetylcholine (ACh, 10(-9)-10(-5) mol/l) were also recorded. Relaxation curves for levcromakalim, naringenin and ACh for the diabetic group were shifted to the right (p < 0.05) compared with the control. Contractions to phenylephrine were enhanced in the diabetic group (p < 0.01). SOD restored the ACh response but not those of K+ channel openers. On the other hand, apocynin restored the relaxation to naringenin but had no effect on both levcromakalim and ACh responses. The results suggest that both KATP and BKCa activities are attenuated in diabetes mellitus and that ROS appears to contribute only to the change in BKCa function. PMID- 23940094 TI - Comparative spectroscopic studies on liposomes containing chlorophyll a and chlorophyllide a. AB - Chlorophyll a (Chla) and chlorophyllyde a (Chlida) - a derivative of Chla, have been incorporated in the lipid bilayers of two types of liposomes, small unilamellar vesicles (SUV) and multilamelar vesicles (MLV). The objective of the present work was to compare the spectral behaviour of Chla and Chlida incorporated in the lipid bilayers and their sensing behaviour at molecular level. The VIS absorption and fluorescence emission presented differences depending on the type of liposomes and inserted pigment, reflecting the different localization of porphyrin macrocycle in the lipid moieties. The temperature dependence of emission anisotropy and fluorescence intensity, for both Chla and Chlida incorporated in DPPC SUV, revealed the presence of different lipid phases. The degree of incorporation of quercetin (QCT) in liposome membrane was studied by using Chla and Chlida as molecular sensors. The fluorescence polarisation data and the fluorescence quenching process provided arguments for the insertion of the QCT at the interface lipid/water, in the vicinity of lipid polar heads and porphyrin macrocycle. The phytyl chain of Chla penetrating in the hydrophobic core of the lipid bilayers is responsible for the observed differences among Chla and Chlida in sensing the lipid phase transition and the fluorescence quenching process induced by QCT. PMID- 23940095 TI - Distal ulnar changes in children with thalassemia and deferiprone related arthropathy. AB - BACKGROUND: Regular blood transfusion and iron chelation are the standard of care for children with thalassemia. Deferiprone is an effective oral iron chelator but is known to cause significant arthropathy. Though clinical and radiographic features of deferiprone related arthropathy have been described, the long-term effects are not known. PROCEDURE: Routine radiographs of left wrist and hand done for bone age estimation in 40 children with thalassemia were evaluated and revealed unique radiographic changes in 13 children (10 males: 3 females) with previous or current deferiprone related arthropathy. Subsequently, these children underwent radiographs of both the knee joints. RESULTS: The changes on wrist X ray included lucency and thinning of the ulnar metaphysis, small ulnar epiphysis, deformation and impaired growth of the physeal cartilage leading to reduced distance between the epiphysis and metaphysis. The knee radiograph showed subchondral flattening of femoral and tibial condyles with irregular articular margins. CONCLUSIONS: Bony dysplasia, deformation and impaired growth of ulnar epiphyses, metaphyses and physes may be an expression of deferiprone related arthropathy in children with thalassemia major. PMID- 23940097 TI - Manipulating the kinetics of seeded growth for edge-selective metal deposition and the formation of concave au nanocrystals. AB - By manipulating the kinetics of seeded growth through judicious control of reaction conditions, edge-selective metal deposition can be achieved to synthesize new Au nanostructures with face-centered concavities, referred to herein as Au overgrown trisoctahedra. These nanostructures display higher sensitivity to changes in refractive index compared to both Au traditional trisoctahedra and the Au nanocube seeds from which they are grown. Often, concave nanostructures are achieved by selective etching processes or corner-selective overgrowth and adopt a stellated profile rather than a profile with face-centered concavities. The presented results illustrate another strategy toward concave nanostructures and can facilitate the synthesis of new concave nanostructures for applications in catalysis and chemical sensing. PMID- 23940096 TI - The role of metabolic imaging in radiation therapy of prostate cancer. AB - The goal of this study was to correlate prostatic metabolite concentrations from snap-frozen patient biopsies of recurrent cancer after failed radiation therapy with histopathological findings, including Ki-67 immunohistochemistry and pathologic grade, in order to identify quantitative metabolic biomarkers that predict for residual aggressive versus indolent cancer. A total of 124 snap frozen transrectal ultrasound (TRUS)-guided biopsies were acquired from 47 men with untreated prostate cancer and from 39 men with a rising prostate-specific antigen and recurrent prostate cancer following radiation therapy. Biopsy tissues with Ki-67 labeling index <= 5% were classified as indolent cancer, while biopsy tissues with Ki-67 labeling index > 5% were classified as aggressive cancer. The majority (15 out of 17) of cancers classified as aggressive had a primary Gleason 4 pattern (Gleason score >= 4 + 3). The concentrations of choline-containing phospholipid metabolites (PC, GPC, and free Cho) and lactate were significantly elevated in recurrent cancer relative to surrounding benign tissues. There was also a significant increase in [PC] and reduction in [GPC] between untreated and irradiated prostate cancer biopsies. The concentration of the choline-containing phospholipid metabolites was significantly higher in recurrent aggressive (~ twofold) than in recurrent indolent cancer biopsies, and the receiver operating characteristic (ROC) curve analysis of total choline to creatine ratio (tCho/Cr) demonstrated an accuracy of 95% (confidence interval = 0.88-1.00) for predicting aggressive recurrent disease. The tCho/Cr was significantly higher for identifying recurrent aggressive versus indolent cancer (tCho/Cr = 2.4 +/- 0.4 versus 1.5 +/- 0.2), suggesting that use of a higher threshold tCho/Cr ratio in future in vivo (1)H MRSI studies could improve the selection and therapeutic planning for patients who would benefit most from salvage focal therapy after failed radiation therapy. PMID- 23940098 TI - Fluorinated pseudopeptide analogues of the neuropeptide 26RFa: synthesis, biological, and structural studies. AB - A series of four fluorinated dipeptide analogues each containing a fluoro-olefin moiety as peptide bond surrogate has been designed and synthesized. These motifs have been successfully introduced into the bioactive C-terminal heptapeptide of the neuropeptide 26RFa by conventional SPPS. We then evaluated the ability of the generated pseudopeptides to increase [Ca2+](i) in GPR103-transfected cells. For these fluorinated analogues, greater stability in human serum was observed. Their conformations were also investigated, leading to the valuable identification of differences depending on the position of the fluoro-olefin moiety in the sequence. PMID- 23940099 TI - Phylogenomic distance method for analyzing transcriptome evolution based on RNA seq data. AB - Thanks to the microarray technology, our understanding of transcriptome evolution at the genome level has been considerably advanced in the past decade. Yet, further investigation was challenged by several technical limitations of this technology. Recent innovation of next-generation sequencing, particularly the invention of RNA-seq technology, has shed insightful lights on resolving this problem. Though a number of statistical and computational methods have been developed to analyze RNA-seq data, the analytical framework specifically designed for evolutionary genomics remains an open question. In this article we develop a new method for estimating the genome expression distance from the RNA-seq data, which has explicit interpretations under the model of gene expression evolution. Moreover, this distance measure takes the data overdispersion, gene length variation, and sequencing depth variation into account so that it can be applied to multiple genomes from different species. Using mammalian RNA-seq data as example, we demonstrated that this expression distance is useful in phylogenomic analysis. PMID- 23940100 TI - Palindromic genes in the linear mitochondrial genome of the nonphotosynthetic green alga Polytomella magna. AB - Organelle DNA is no stranger to palindromic repeats. But never has a mitochondrial or plastid genome been described in which every coding region is part of a distinct palindromic unit. While sequencing the mitochondrial DNA of the nonphotosynthetic green alga Polytomella magna, we uncovered precisely this type of genic arrangement. The P. magna mitochondrial genome is linear and made up entirely of palindromes, each containing 1-7 unique coding regions. Consequently, every gene in the genome is duplicated and in an inverted orientation relative to its partner. And when these palindromic genes are folded into putative stem-loops, their predicted translational start sites are often positioned in the apex of the loop. Gel electrophoresis results support the linear, 28-kb monomeric conformation of the P. magna mitochondrial genome. Analyses of other Polytomella taxa suggest that palindromic mitochondrial genes were present in the ancestor of the Polytomella lineage and lost or retained to various degrees in extant species. The possible origins and consequences of this bizarre genomic architecture are discussed. PMID- 23940101 TI - The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study. AB - BACKGROUND: Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses. METHODS: We compared the performance of the Cyclophosphamide Equivalent Dose (CED), a unit for quantifying alkylating agent exposure independent of study population, to the AAD. Comparisons included associations from three Childhood Cancer Survivor Study (CCSS) outcome analyses, receiver operator characteristic (ROC) curves and goodness of fit based on the Akaike's Information Criterion (AIC). RESULTS: The CED and AAD performed essentially identically in analyses of risk for pregnancy among the partners of male CCSS participants, risk for adverse dental outcomes among all CCSS participants and risk for premature menopause among female CCSS participants, based on similar associations, lack of statistically significant differences between the areas under the ROC curves and similar model fit values for the AIC between models including the two measures of exposure. CONCLUSION: The CED is easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. We recommend the use of the CED in future research assessing cumulative alkylating agent exposure. PMID- 23940102 TI - The Liebenberg syndrome: in depth analysis of the original family. AB - The Liebenberg syndrome was first described in 1973 in a five- generation family. A sixth generation was added in 2001, and in 2009 a hitherto unknown branch of the same family with similar anomalies extended the family tree significantly. This article describes the clinical findings and illustrates the abnormalities with radiographs and three-dimensional computed tomography scans. We discuss the genetic abnormality that causes Liebenberg syndrome, the genomic rearrangement at the PITX1 locus on chromosome 5.The structural variations seem to result in an ectopic expression of paired-like homeodomain transcription factor 1 (PITX1) in the forelimb causing a partial arm-to-leg transformation in these patients. PMID- 23940103 TI - Intercostal and pectoral nerve transfers to re-innervate the biceps muscle in obstetric brachial plexus lesions. AB - In obstetric brachial plexus lesions with avulsion injury, nerve grafting for biceps muscle re-innervation may not be possible owing to the unavailability of a proximal stump. In such cases, the intercostal nerves or medial pectoral nerve can serve as donor nerves in an end-to-end transfer to the musculocutaneous nerve. The present study reports the results of both techniques from a single institution in a consecutive series of 42 patients between 1995 and 2008. From 1995 to 2000 we always used the intercostal nerve transfer, and from 2001 to 2008 both techniques were used. Biceps muscle force >= Medical Research Council Grade 3 was achieved in 37 of 42 patients after a mean follow-up of 44 months. There was no statistical difference in the results in the medial pectoral nerve transfer group (n = 25) and the intercostal nerve transfer group (n = 17). PMID- 23940104 TI - 'Living' PEGylation on gold nanoparticles to optimize cancer cell uptake by controlling targeting ligand and charge densities. AB - We report and demonstrate biomedical applications of a new technique--'living' PEGylation--that allows control of the density and composition of heterobifunctional PEG (HS-PEG-R; thiol-terminated poly(ethylene glycol)) on gold nanoparticles (AuNPs). We first establish 'living' PEGylation by incubating HS PEG5000-COOH with AuNPs (~20 nm) at increasing molar ratios from zero to 2000. This causes the hydrodynamic layer thickness to differentially increase up to 26 nm. The controlled, gradual increase in PEG-COOH density is revealed after centrifugation, based on the ability to re-suspend the pellet and increase the AuNP absorption. Using a fluorescamine-based assay we quantify differential HS PEG5000-NH2 binding to AuNPs, revealing that it is highly efficient until AuNP saturation is reached. Furthermore, the zeta potential incrementally changes from -44.9 to +52.2 mV and becomes constant upon saturation. Using 'living' PEGylation we prepare AuNPs with different ratios of HS-PEG-RGD (RGD: Arg-Gly-Asp) and incubate them with U-87 MG (malignant glioblastoma) and non-target cells, demonstrating that targeting ligand density is critical to maximizing the efficiency of targeting of AuNPs to cancer cells. We also sequentially control the HS-PEG-R density to develop multifunctional nanoparticles, conjugating positively charged HS-PEG-NH2 at increasing ratios to AuNPs containing negatively charged HS-PEG-COOH to reduce uptake by macrophage cells. This ability to minimize non-specific binding/uptake by healthy cells could further improve targeted nanoparticle efficacy. PMID- 23940106 TI - Pressure-assisted low-temperature sintering for paper-based writing electronics. AB - With the aim of preparing paper-based writing electronics, a kind of conductive pen was made with nano-silver ink as the conductive component and a rollerball pen as the writing implement. This was used to direct-write conductive patterns on Epson photo paper. In order to decrease the sintering temperature, pressure was introduced to enhance the driving forces for sintering. Compared with hot sintering without pressure, hot-pressure can effectively improve the conductivity of silver coatings, reduce the sintering time and thus improve productivity. Importantly, pressure can achieve a more uniform and denser microstructure, which increases the connection strength of the silver coating. At the optimum hot pressure condition (sintering temperature 120 degrees C/sintering pressure 25 MPa/sintering time 15 min), a typical measured resistivity value was 1.43 * 10-7 Omega m, nine greater than that of bulk silver. This heat treatment process is compatible with paper and does not cause any damage to the paper substrates. Even after several thousand bending cycles, the resistivity values of writing tracks by hot-pressure sintering stay almost the same (from 1.43 * 10-7 to 1.57 * 10-7 Omega m). The stability and flexibility of the writing circuits are good, which demonstrates the promising future of writing electronics. PMID- 23940105 TI - Photochemical control of DNA structure through radical disproportionation. AB - Photolysis of an aryl sulfide-containing 5,6-dihydropyrimidine (1) at 350 nm produces high yields of thymidine and products resulting from trapping of a 5,6 dihydrothymidin-5-yl radical by O2 or thiols. Thymidine is believed to result from disproportionation of the radical pair originally generated from C--S bond homolysis of 1 on the microsecond timescale, which is significantly shorter than other photochemical transformations of modified nucleotides into their native forms. Duplex DNA containing 1 is destabilized, presumably due to disruption of pi-stacking. Incorporation of 1 within the binding site of the restriction endonuclease EcoRV provides a photochemical switch for turning on the enzyme's activity. In contrast, 1 is a substrate for endonuclease VIII and serves as a photochemical off switch for this base excision repair enzyme. Modification 1 also modulates the activity of the 10-23 DNAzyme, despite its incorporation into a nonduplex region. Overall, dihydropyrimidine 1 shows promise as a tool to provide spatiotemporal control over DNA structure on the miscrosecond timescale. PMID- 23940107 TI - Association between religious and socio-economic background of parents of children with solid tumors and DNR orders. AB - BACKGROUND: The influence of socio-economic and religious background on decisions made by parents of children with incurable cancer regarding DNR orders is not fully understood. PROCEDURE: A retrospective analysis of medical charts of patients who died between January 2000 and January 2011 was performed. The following data were sought: written evidence of DNR discussion with parents, religious background, educational level, monthly income. RESULTS: There was evidence of a discussion on DNR in 73/90 charts. DNR consent was obtained in 14/17 (82.4%) cases where at least one parent had >15 years of education versus in only 24/45 (53.3%) cases where both parents had <=15 years education as determined by univariate analysis (P = 0.03). DNR consent was also more likely to be obtained among parents of children with income >10,000 NIS (24/30, 80.0% vs. 20/38, 52.6%, P = 0.013). Parents of Jewish (22/30, 73.3%), Islamic (16/26, 61.5%), and Christian (8/9, 88.9%) background were equally likely to provide DNR consent. However, Druze families were less likely to do so (2/8, 25.0%, P = 0.036). CONCLUSIONS: The process of decision-making to a DNR request was associated with parents' educational level and monthly family income, and not by religious background, with the exception of Druze families. PMID- 23940109 TI - Increasing use of less-invasive hemodynamic monitoring in 3 specialty surgical intensive care units: a 5-year experience at a tertiary medical center. AB - INTRODUCTION: Less-invasive hemodynamic monitoring (eg, esophageal doppler monitoring [EDM] and arterial pressure contour analysis, FloTrac) is increasingly used as an alternative to pulmonary artery catheters (PACs) in critically ill intensive care unit (ICU). HYPOTHESIS: The decrease in use of PACs is not associated with increased mortality. METHODS: Five-year retrospective review of 1894 hemodynamically monitored patients admitted to 3 surgical ICUs in a university-affiliate, tertiary care urban hospital. Data included the number of admissions, diagnosis-related group discharge case mix, length of stay, insertion of monitoring devices (PAC, EDM, and FloTrac probes), administered intravenous vasoactive agents (beta-predominant agonists--dobutamine, epinephrine, and dopamine; vasopressors--norepinephrine and phenylephrine), and mortality. Data from hospital administrative databases were compiled to create patient characteristic and monitoring variables across a 5-year time period, 2005 to 2009 inclusive. Chi-square for independent proportions, 1-way analysis of variance, and Kruskal-Wallis tests were used; tests for trend were conducted. An alpha level of .05 was considered significant. Statistical Package for the Social Sciences v14 was used for all statistical testing. RESULTS: There was a significant change in the type of hemodynamic monitors inserted in 2 of the 3 surgical ICUs (in the general surgery and neurointensive care but not in the cardiac ICU) from PACs to less-invasive devices (FloTrac or EDM) during the 5 year study period (P < .001). There was no change in mortality rate over the time period (P = .492). There was an overall increase in the proportion of monitored patients who received intravenous vasoactive agents (P < .001) with a progressive shift from beta-agonists to vasopressors (P < .002). Multivariate analyses indicated that age, case mix, and use of vasoactive agents were all independent predictors of inhospital mortality (P = .001) but that type of monitoring was not (P = .638). CONCLUSIONS: In a 5-year period, the decreased insertions of PACs were replaced by increased utilization of less-invasive hemodynamic monitoring devices. This change in practice did not adversely impact mortality. PMID- 23940108 TI - Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer. AB - Deregulated E2F transcription factor activity occurs in the vast majority of human tumors and has been solidly implicated in disturbances of cell cycle control, proliferation, and apoptosis. Aberrant E2F regulatory activity is often caused by impairment of control through pRB function, but little is known about the interplay of other oncoproteins with E2F. Here we show that ETS transcription factor fusions resulting from disease driving rearrangements in Ewing sarcoma (ES) and prostate cancer (PC) are one such class of oncoproteins. We performed an integrative study of genome-wide DNA-binding and transcription data in EWSR1/FLI1 expressing ES and TMPRSS2/ERG containing PC cells. Supported by promoter activity and mutation analyses, we demonstrate that a large fraction of E2F3 target genes are synergistically coregulated by these aberrant ETS proteins. We propose that the oncogenic effect of ETS fusion oncoproteins is in part mediated by the disruptive effect of the E2F-ETS interaction on cell cycle control. Additionally, a detailed analysis of the regulatory targets of the characteristic EWSR1/FLI1 fusion in ES identifies two functionally distinct gene sets. While synergistic regulation in concert with E2F in the promoter of target genes has a generally activating effect, EWSR1/FLI1 binding independent of E2F3 is predominantly associated with repressed differentiation genes. Thus, EWSR1/FLI1 appears to promote oncogenesis by simultaneously promoting cell proliferation and perturbing differentiation. PMID- 23940110 TI - A novel IL2RG mutation presenting with atypical T(-)B(+)NK+ phenotype: rapid elucidation of NK cell origin. PMID- 23940111 TI - Design guideline of Si nanohole/PEDOT:PSS hybrid structure for solar cell application. AB - The finite element method is used to simulate light absorption in periodic hybrid Si nanohole (SiNH)/PEDOT:PSS arrays. The structural periodicity (P) and hole diameter (D) of the hybrid SiNH structure are varied to maximize light absorption. In terms of the solar cell performance under the AM1.5G spectrum, the highest ultimate efficiency achieved is 30.5%, when the D/P ratio is 0.8 and P is 600 nm. We have successfully fabricated the SiNH structure based on a low cost electroless chemical etching approach using a silver catalyst. The SiNH diameters formed vary from ~200 to 300 nm, with periodicities from ~300 to 1000 nm. The SiNH structure reveals a low average reflectance of 4% for incident light in the range 300 to 1100 nm. PMID- 23940112 TI - An ecological approach to seeking and utilising the views of young people with intellectual disabilities in transition planning. AB - Transition planning using a person-centred approach has, in the main, failed to shape service provision. We offer an alternative based on an ecological understanding of human development linked to public health approaches that prioritise whole system planning. A total of 43 young people with intellectual disabilities, in Bradford, England, who were approaching transition from school or college were recruited to a qualitative study. Their ethnic breakdown was as follows: 16 white British, 24 Pakistani, 2 Bangladeshi and 1 Black African. Each young person was interviewed twice, at recruitment and a year later, to observe any changes in their social networks during transition. Interviews were undertaken with a semi-structured interview schedule and with the pictorial approach of Talking Mats. Both the networks the young people live within, and their sense of what the future might hold for them, are described and linked to Bronfenbrenner's ecological model of human development. The importance of the family and school is emphasised, as is the absence of engagement in leisure activities and work. Transition planning needs to start with mapping the systems individuals live within, areas of strength should be supported and parts of the system, which are not fit for purpose for these young people, should be prioritised for interventions. PMID- 23940113 TI - The role of SIOP as a platform for communication in the global response to childhood cancer. AB - Since the year 2000, there has been a 35% annual decrease in mortality among children under the age of five worldwide. The decrease is mainly attributed to the decrease in childhood epidemic infections, for example, due to vaccination programs. In the near future, this decrease will draw attention to paediatric non communicable diseases (NCDs), and cancer is one of the most common. Access to care for children with cancer and survival rates have improved dramatically in high-income countries. However, it is important that a global perspective addresses problems in developing countries in particular. To meet this challenge, it is critical that emphasis is placed on demands such as access to care and drugs that are known to be effective, and which can be safely administered in resource-limited settings. Additionally, cancer registries and improved health care structures that include care for children with cancer, are paramount for further progress to increase awareness and the survival of children with cancer. The purpose of this paper is to describe current worldwide interventions to improve childhood cancer from the perspective of the International Society of Paediatric Oncology (SIOP). This global perspective will serve as an introduction to a series of papers from six SIOP continental branches, which will highlight the specific and/or common issues related to children with cancer worldwide. To strengthen the communication among and synergistic effects of various paediatric cancer stakeholders, SIOP could serve as a global platform for a proposed Global Paediatric Cancer Network through the interaction of its continental branches and partner collaborations. PMID- 23940114 TI - Salvage therapy for refractory or recurrent pediatric germ cell tumors: the French SFCE experience. AB - PURPOSE: Some children with extracranial germ cell tumors (GCT) relapse after or do not respond to first-line treatment combining chemotherapy and surgery, of whom very few experience long-term survival despite multimodal salvage treatment. METHODS: This prospective study, part of the French TGM95 Protocol for non seminomatous GCT (NSGCT), included 19 (7%) children with malignant refractory or recurrent extracranial NSGCT who were studied to identify prognostic factors and determine the best salvage treatment. RESULTS: At the end of the first-line treatment, 10 and 9 children were in complete and incomplete remission, respectively. Events occurred within 2 years (5-23 months) after initial diagnosis. A progression was observed in 13 patients at least in one site initially involved. Two patients had a purely biological relapse (increase in isolated markers), and four patients had a purely metastatic relapse (brain location in three cases). After salvage treatment combining surgery and various types of chemotherapy (including high-dose chemotherapy (HDCT) in 10 cases), the 5-year event-free survival and overall survival rates were of 26% (95%CI: 9.6 46.8%) and 32% (95%CI: 12.9-52.2%), respectively. Patients who underwent complete surgery (or without any detectable tumor) had higher survival rate than patients who underwent partial surgery or for whom surgery was not feasible (P = 0.0003) at first relapse while this rate was similar between patients treated or not with HDCT. CONCLUSION: In pediatric recurrent or refractory NSGCT, complete excision of the tumor appears essential. The role of HDCT remains debated. PMID- 23940115 TI - Aurora B suppresses microtubule dynamics and limits central spindle size by locally activating KIF4A. AB - Anaphase central spindle formation is controlled by the microtubule-stabilizing factor PRC1 and the kinesin KIF4A. We show that an MKlp2-dependent pool of Aurora B at the central spindle, rather than global Aurora B activity, regulates KIF4A accumulation at the central spindle. KIF4A phosphorylation by Aurora B stimulates the maximal microtubule-dependent ATPase activity of KIF4A and promotes its interaction with PRC1. In the presence of phosphorylated KIF4A, microtubules grew more slowly and showed long pauses in growth, resulting in the generation of shorter PRC1-stabilized microtubule overlaps in vitro. Cells expressing only mutant forms of KIF4A lacking the Aurora B phosphorylation site overextended the anaphase central spindle, demonstrating that this regulation is crucial for microtubule length control in vivo. Aurora B therefore ensures that suppression of microtubule dynamic instability by KIF4A is restricted to a specific subset of microtubules and thereby contributes to central spindle size control in anaphase. PMID- 23940116 TI - hGAAP promotes cell adhesion and migration via the stimulation of store-operated Ca2+ entry and calpain 2. AB - Golgi antiapoptotic proteins (GAAPs) are highly conserved Golgi membrane proteins that inhibit apoptosis and promote Ca(2+) release from intracellular stores. Given the role of Ca(2+) in controlling cell adhesion and motility, we hypothesized that human GAAP (hGAAP) might influence these events. In this paper, we present evidence that hGAAP increased cell adhesion, spreading, and migration in a manner that depended on the C-terminal domain of hGAAP. We show that hGAAP increased store-operated Ca(2+) entry and thereby the activity of calpain at newly forming protrusions. These hGAAP-dependent effects regulated focal adhesion dynamics and cell migration. Indeed, inhibition or knockdown of calpain 2 abrogated the effects of hGAAP on cell spreading and migration. Our data reveal that hGAAP is a novel regulator of focal adhesion dynamics, cell adhesion, and migration by controlling localized Ca(2+)-dependent activation of calpain. PMID- 23940117 TI - Atg18 phosphoregulation controls organellar dynamics by modulating its phosphoinositide-binding activity. AB - The PROPPIN family member Atg18 is a phosphoinositide-binding protein that is composed of a seven beta-propeller motif and is part of the conserved autophagy machinery. Here, we report that the Atg18 phosphorylation in the loops in the propellar structure of blade 6 and blade 7 decreases its binding affinity to phosphatidylinositol 3,5-bisphosphate in the yeast Pichia pastoris. Dephosphorylation of Atg18 was necessary for its association with the vacuolar membrane and caused septation of the vacuole. Upon or after dissociation from the vacuolar membrane, Atg18 was rephosphorylated, and the vacuoles fused and formed a single rounded structure. Vacuolar dynamics were regulated according to osmotic changes, oxidative stresses, and nutrient conditions inducing micropexophagy via modulation of Atg18 phosphorylation. This study reveals how the phosphoinositide binding activity of the PROPPIN family protein Atg18 is regulated at the membrane association domain and highlights the importance of such phosphoregulation in coordinated intracellular reorganization. PMID- 23940118 TI - Epiblast integrity requires CLASP and Dystroglycan-mediated microtubule anchoring to the basal cortex. AB - Amniote epiblast cells differentiate into mesoderm and endoderm lineages during gastrulation through a process called epithelial-to-mesenchymal transition (EMT). Molecular regulation of gastrulation EMT is poorly understood. Here we show that epiblast epithelial status was maintained by anchoring microtubules to the basal cortex via CLIP-associated protein (CLASP), a microtubule plus-end tracking protein, and Dystroglycan, a transmembrane protein that bridges the cytoskeleton and basement membrane (BM). Mesoderm formation required down-regulation of CLASP and Dystroglycan, and reducing CLASP activity in pregastrulation epiblast cells caused ectopic BM breakdown and disrupted epiblast integrity. These effects were mediated through the CLASP-binding partner LL5. Live-imaging using EB1-enhanced GFP (eGFP) revealed that reducing CLASP and LL5 levels in the epiblast destabilized basal microtubules. We further show that Dystroglycan is localized to basolateral membrane in epiblast cells. Basal but not lateral localization of Dystroglycan was regulated by CLASP. We propose that epiblast-BM interaction requires CLASP- and Dystroglycan-mediated cortical microtubule anchoring, the disruption of which initiates gastrulation EMT. PMID- 23940121 TI - The role of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea. AB - For the treatment of Clostridium difficile-associated diarrhea (CDAD), metronidazole and vancomycin remain the most commonly used agents. The major advantage of metronidazole is its low cost, while the advantage of oral vancomycin is a more favorable pharmacokinetic profile. The epidemiology and clinical severity of CDAD have changed due to the emergence of a hypervirulent strain (BI/NAP1/027). In 2010, the Infectious Diseases Society of America/Society for Health Care Epidemiology of America expert panel defined severe CDAD and recommended oral vancomycin to treat these patients. Metronidazole remains the preferred agent for treatment of mild to moderate CDAD. PMID- 23940119 TI - The GEF Bcr activates RhoA/MAL signaling to promote keratinocyte differentiation via desmoglein-1. AB - Although much is known about signaling factors downstream of Rho GTPases that contribute to epidermal differentiation, little is known about which upstream regulatory proteins (guanine nucleotide exchange factors [GEFs] or GTPase activating proteins [GAPs]) are involved in coordinating Rho signaling in keratinocytes. Here we identify the GEF breakpoint cluster region (Bcr) as a major upstream regulator of RhoA activity, stress fibers, and focal adhesion formation in keratinocytes. Loss of Bcr reduced expression of multiple markers of differentiation (such as desmoglein-1 [Dsg1], keratin-1, and loricrin) and abrogated MAL/SRF signaling in differentiating keratinocytes. We further demonstrated that loss of Bcr or MAL reduced levels of Dsg1 mRNA in keratinocytes, and ectopic expression of Dsg1 rescued defects in differentiation seen upon loss of Bcr or MAL signaling. Taken together, these data identify the GEF Bcr as a regulator of RhoA/MAL signaling in keratinocytes, which in turn promotes differentiation through the desmosomal cadherin Dsg1. PMID- 23940123 TI - Scientists and the 3Rs: attitudes to animal use in biomedical research and the effect of mandatory training in laboratory animal science. AB - The 3Rs principle of replacement, reduction, and refinement has increasingly been endorsed by legislators and regulatory bodies as the best approach to tackle the ethical dilemma presented by animal experimentation in which the potential benefits for humans stand against the costs borne by the animals. Even when animal use is tightly regulated and supervised, the individual researcher's responsibility is still decisive in the implementation of the 3Rs. Training in laboratory animal science (LAS) aims to raise researchers' awareness and increase their knowledge, but its effect on scientists' attitudes and practice has not so far been systematically assessed. Participants (n = 206) in eight LAS courses (following the Federation of European Laboratory Animal Science Associations category C recommendations) in Portugal were surveyed in a self-administered questionnaire during the course. Questions were related mainly to the 3Rs and their application, attitudes to animal use and the ethical review of animal experiments. One year later, all the respondents were asked to answer a similar questionnaire (57% response rate) with added self-evaluation questions on the impact of training. Our results suggest that the course is effective in promoting awareness and increasing knowledge of the 3Rs, particularly with regard to refinement. However, participation in the course did not change perceptions on the current and future needs for animal use in research. PMID- 23940122 TI - Antimicrobial selection and its impact on the incidence of Clostridium difficile associated diarrhea. AB - The study objective was to determine which antimicrobials place patients at a higher risk for Clostridium difficile-associated diarrhea (CDAD) and which interventions can reduce their risk. All patients with diarrhea and a positive toxin assay for Clostridium difficile for 3 months were included in the study. Patients were broken down into either community-acquired infection or health care associated infection based on symptom onset, antibiotic usage prior to admission, and where the patient was admitted from. Physicians were educated on antimicrobials that place patients at higher risk for CDAD and alternative agents to use. Physician education consisted of in-service presentations, posters, Medical Grand Rounds, and an article in the physician newsletter highlighting the initial results of this study and alternative antimicrobial regimens. After implementation of educational programs, a repeat sample of patients was reviewed to determine effectiveness of the physician education. Cases of CDAD increased secondary to testing changes at our facility. Implicated antimicrobial usage did decrease after educational program implementation. PMID- 23940124 TI - The perioperative care of lambs and ewes when the former undergo major experimental (scoliotic) surgery. AB - The purpose of the study was to optimize postoperative comfort in lambs anaesthetized for the surgical creation of scoliosis while maintaining the ewe lamb relationship to miminize rejection rates. The first management plan produced six scoliotic lambs but intraoperative hypoventilation and hypovolaemia followed by postoperative dyspnoea, pain, monitoring and nursing difficulties, hypothermia, hypoglycaemia and tympany were encountered. Three of eight lambs (38%) were rejected by their ewes. Perioperative management was amended which, combined with improved surgical technique, produced 16 scoliotic lambs. The lambs recovered more rapidly (mean time to standing after discontinuation of anaesthesia was reduced from 12 h to 70 min) and appeared to be more comfortable. No rejections occurred after the refinements were implemented. PMID- 23940125 TI - A diagnosis not to be missed: nonclassic steroid 11beta-hydroxylase deficiency presenting with premature adrenarche and hirsutism. AB - CONTEXT: Steroid 11beta-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia. Milder nonclassic forms are rare and at risk to be missed. OBJECTIVE: The objective of the study was to demonstrate the challenges in diagnosing nonclassic 11OHD. PATIENTS AND METHODS: Patient 1, a 10-year-old boy, presented with high-normal blood pressure and previously unexplained exaggerated adrenarche from age 4 years. Previous tests at the age of 8 years showed normal 17-hydroxyprogesterone concentrations with increased androgens. Patient 2, a 14-year-old female, presented with facial hirsutism, primary amenorrhea, and high-normal blood pressure. Novel CYP11B1 mutations were functionally analyzed in transiently transfected COS7 cells measuring the conversion of 11-deoxycortisol to cortisol by liquid chromatography tandem mass spectrometry. RESULTS: Biochemical findings including urinary steroid metabolite analysis by gas chromatography-mass spectrometry were suggestive of 11OHD in all patients. CYP11B1 mutation analysis revealed compound heterozygosity in patient 1 (g.235T>A, p.F79I/g.2608C>T, p.R138C) and a homozygous mutation in patient 2 and two siblings (g.2623C>T, p.R143W). Functional in vitro analysis demonstrated partially impaired CYP11B1 activity compared with wild-type (p.F79I: 8.8% +/- 0.8% (SEM); p.R138C: 9.8% +/- 0.8%; p.R143W: 10.6% +/- 1.2%). CONCLUSION: In addition to nonclassic 21-hydroxylase deficiency and steroid secreting tumors, nonclassic 11OHD should be considered as an important differential diagnosis in patients with unexplained hyperandrogenism without 46,XX disorder of sex development. Nonclassic 11OHD is likely to be missed when relying on measuring standard steroid hormone panels. This diagnosis needs to be established early in life to avoid long-term health problems such as short stature, hyperandrogenism-related metabolic complications, potentially severe arterial hypertension, and cardiovascular consequences. PMID- 23940126 TI - An adult female with resistance to thyroid hormone mediated by defective thyroid hormone receptor alpha. AB - CONTEXT: The first human cases (female, age 6 y; father and daughter, ages 47 and 11 y, respectively) with growth retardation/short stature, skeletal dysplasia, constipation, and defective thyroid receptor alpha (TRalpha) have been recently described. OBJECTIVE: A 45-year-old, short, overweight female with cognitive impairment, epilepsy, and constipation was investigated. DESIGN AND INTERVENTION: Clinical, biochemical, and radiological assessment and THRA sequencing were undertaken. The patient's thyroid status and her biochemical and physiological parameters were evaluated at baseline and after T4 therapy. RESULTS: The patient exhibits disproportionate short stature, macrocephaly, low free T4/free T3 ratio and rT3 levels, together with subnormal heart and basal metabolic rate. She is heterozygous for a novel frameshift/premature stop (Ala382ProfsX7) THRA mutation, generating a mutant TRalpha with constitutive corepressor binding and negligible coactivator recruitment, which inhibits its wild-type counterpart in a dominant negative manner-both in vitro and in mutation-containing patient blood mononuclear cells studied ex vivo. Her alertness and constipation responded to T4 therapy, which readily suppressed TSH levels, raised basal metabolic rate, and normalized elevated muscle creatine kinase, but cardiac parameters (heart rate, contractility) remained relatively refractory. The patient and a previous childhood case showed reduced red cell mass with macrocytosis unresponsive to T4 therapy. CONCLUSIONS: Clinical (short stature, macrocephaly, constipation) and biochemical (low free T4/free T3 ratio, subnormal rT3) findings that are congruent with previous cases and newly recognized features (epilepsy) in this adult female with defective TRalpha define a shared phenotype in TRalpha-mediated resistance to thyroid hormone, with differential tissue responses to T4 treatment. PMID- 23940127 TI - Serum 1,25(OH)D level increases after elimination of periodontal inflammation in T1DM subjects. AB - OBJECTIVES: The aim of the present study was to investigate associations between serum concentrations of vitamin D metabolites, 25-hydroxyvitamin D [25(OH)D], and its active form, 1,25-dihydroxyvitamin D [1,25(OH)D], and the severity of chronic periodontitis. SUBJECTS AND DESIGN: Presence of dental plaque, probing pocket depth (PD), and attachment level in 80 type 1 diabetes mellitus subjects were recorded. The serum levels of 25(OH)D, 1,25(OH)D, ultrasensitive C-reactive protein, IL-6, TNF-alpha, high-density lipoprotein cholesterol, and glycosylated hemoglobin (percentage) were determined. Multivariate regression models were used to explore the associations between serum 25(OH)D (nanomoles per liter) and 1,25(OH)D (picomoles per liter) levels and periodontal health status. INTERVENTION: Antiinfective periodontal therapies were delivered and the clinical examination and laboratory analyses were repeated 8 weeks after the therapies. RESULTS: A statistically significant association was found between the serum level of 1,25(OH)D (odds ratio 1.06, 95% confidence interval 1.02-1.11) and periodontal health at the baseline; subjects with a high level were more likely to belong to the group of no or mild periodontitis. The serum level of 1,25(OH)D showed a statistically significant increase after antiinfective periodontal therapy in both no or mild (P = .001) and moderate or severe periodontitis (P < .001) subjects. The association between serum 25(OH)D level and periodontal health was negligible. CONCLUSION: This study has shown a significant positive association between the serum 1,25(OH)D level and periodontal health status. To what extent this association is causal in nature remains to be confirmed. PMID- 23940129 TI - Cardiovascular disease in menopause: does the obstetric history have any bearing? AB - Cardiovascular disease remains a leading cause of morbidity and mortality in menopausal women in spite of the overall reduction in age-adjusted mortality from the disease in the last few years. It is now clear that mechanisms of cardiovascular disease in menopausal women are similar to men and rather than midlife acceleration of cardiovascular disease in women, the final impact of cardiovascular disease in later life may be a reflection of cardiovascular changes during reproductive years as a result of woman's obstetric history. A decade after the Women's Health Initiative trial, there is upcoming evidence to suggest that hormone replacement therapy in young recently menopausal women has a cardioprotective effect. Cardiovascular changes during normal pregnancy or pregnancy complications such as preeclampsia may affect a woman's long-term cardiovascular health. Therefore, it is plausible that the cardioprotective benefit of hormone replacement therapy depends on occult pre-existing cardiovascular risks in women in relation to their previous obstetric history. In this review, we describe the cardiovascular changes during and after pregnancy in obstetric complications such as recurrent miscarriage, preeclampsia, intrauterine growth restriction, preterm labour and gestational diabetes; existing evidence regarding their association with cardiovascular disease later in life, and hypothesize possible mechanisms. Our aim is to improve the understanding and highlight the importance of including obstetric history in risk assessment in menopausal women and individualizing their risks before prescribing hormone replacement therapy. Future research in risk benefit assessment of hormone replacement therapy should also account for a woman's background cardiovascular risk in the light of her obstetric history. PMID- 23940128 TI - Isolated prolactin deficiency associated with serum autoantibodies against prolactin-secreting cells. AB - CONTEXT: Isolated prolactin (PRL) deficiency is a rare entity of unknown etiology manifesting as failure of puerperal lactogenesis. OBJECTIVE: The aim of the study was to determine the cause of isolated PRL deficiency in an affected woman. DESIGN AND SETTING: We examined genetic and autoimmune causes of isolated PRL deficiency at academic medical centers. PATIENT: The patient was a 39-year-old woman with puerperal alactogenesis after two deliveries and undetectable PRL. The other pituitary axes, serum calcium levels, and cranial magnetic resonance imaging were normal. INTERVENTION: Recombinant human PRL (r-hPRL) was administered to the patient. MAIN OUTCOME MEASURES: We measured the sequencing of candidate genes and immunofluorescence analysis of autoantibodies directed against pituitary endocrine cells. RESULTS: There were no rare sequence variants in the genes encoding for PRL, putative PRL-releasing peptide, putative PRL releasing peptide receptor, or in other genes important for lactotroph lineage development (POU1F1, PROP1, LHX3, LHX4, HESX1, OTX2, and LSD1). The patient serum, on the contrary, contained autoantibodies that specifically recognized a subset of PRL-secreting cells but not PRL itself or any other pituitary cells or hormones. The mother was able to lactate fully after 17 days of treatment with r hPRL 60 MUg/kg every 12 hours, but alactogenesis resumed after treatment was completed. CONCLUSIONS: These studies report a new autoimmune etiology for women with isolated PRL deficiency and puerperal alactogenesis. PMID- 23940130 TI - Non-alcoholic fatty liver disease: non-invasive investigation and risk stratification. AB - Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum of liver disease, from simple steatosis through to cirrhosis. As the worldwide rates of obesity have increased, NAFLD has become the commonest cause of liver disease in many developed countries, affecting up to a third of the population. The majority of patients have simple steatosis that carries a relatively benign prognosis. However, a significant minority have non-alcoholic steatohepatitis, and have increased liver related and cardiovascular mortality. Identifying those at risk of progressive disease is crucial. Liver biopsy remains the gold standard investigation for assessing stage of disease but its invasive nature makes it impractical for widespread use as a prognostic tool. Non-invasive tools for diagnosis and disease staging are required, reserving liver biopsy for those patients where it offers clinically relevant additional information. This review discusses the non-invasive modalities available for assessing steatosis, steatohepatitis and fibrosis. We propose a pragmatic approach for the assessment of patients with NAFLD to identify those at high risk of progressive disease who require referral to specialist services. PMID- 23940132 TI - Gene of the month: E-cadherin (CDH1). PMID- 23940131 TI - Immune activation in HIV/HCV-infected patients is associated with low-level expression of liver expressed antimicrobial peptide-2 (LEAP-2). AB - BACKGROUND: Immune activation is one of the main features of HIV/Hepatitis C virus (HCV) infections and has been linked to the disturbance of the gut associated lymphoid tissue (GALT). In chronic HIV infection, loss of GALT integrity results in translocation of microbial products and chronic immune activation. We explored the relationship between bacterial translocation and specific colonic proteins, including liver expressed antimicrobial peptide (LEAP 2) which may play a role in modulating the bacterial translocation process. METHODS: A total of 40 subjects (10 HIV/HCV, 10 HIV, 10 HCV-infected patients and 10 controls) were enrolled and underwent serum and colonic tissue sampling. The levels of immune activation were evaluated by measuring plasma sCD27, and the levels of selected proinflammatory, Th2 and regulatory cytokines in both the plasma and supernatant of CD3-stimulated intraepithelial lymphocytes. We also evaluated LEAP-2 expression in the colon biopsies using Affymetrix Human Gene 1.0 ST (HuGene) and fluorescent immunohistochemistry. RESULTS: Increased levels of sCD27 were observed in HIV/HCV coinfected (p=0.03) and HIV monoinfected (p=0.04) patients compared with controls consistent with the presence of immune activation. The chip array identified LEAP-2 expression as a key marker associated with immune activation. LEAP-2 expression in HIV, HCV and HIV/HCV infected patients was significantly lower compared with controls, and was significantly negatively correlated (p=0.03, r=-0.44) with sCD27. CONCLUSIONS: Our data suggests that HCV and HIV infections are associated with decreased expression of LEAP-2 in colonic tissue. This may represent a key mechanism for enhanced microbial translocation and immune activation in HIV/HCV-infected patients. PMID- 23940133 TI - What is the point of tips? AB - AIMS: To look at the incidence of tip margin involvement in skin excisions for basal cell carcinomas (BCCs) and to examine if any factors might be used to predict margin involvement. METHODS AND RESULTS: All reports of BCCs by a single dermatopathologist were reviewed and 793 excisions were included from 642 patients. Whether there was BCC in the tip and whether this tip was involved were recorded together with macroscopic and microscopic factors based on the Royal College of Pathologists' (RCPath) dataset. Statistical analysis was carried out to determine associations between these factors and tip involvement. In 43 (5%) specimens the tip margin was involved and in 35 (4%) cases the peripheral lateral margin was involved. Risk factors for tip margin involvement were a lesion that was non-discernible macroscopically and most importantly, involvement of a peripheral lateral margin. CONCLUSIONS: The incidence of tip margin involvement is small and it appears unnecessary to embed the tips unless the lesion is non discernible macroscopically or if the peripheral lateral margin is involved. PMID- 23940134 TI - Postmortem serum tryptase levels in anaphylactic and non-anaphylactic deaths. AB - BACKGROUND: The postmortem diagnosis of anaphylaxis remains difficult due to the lack of specific biomarkers. Mast cell tryptase (MCT) levels are used as a marker of mast cell degranulation in living patients and elevated levels have also been described in postmortem serum samples in anaphylaxis-associated deaths, although elevated levels may also be seen in non-anaphylaxis-associated deaths. OBJECTIVE: To investigate the effects of cause of death, site of blood sampling, degree of sample haemolysis and the presence of opiates on postmortem MCT levels. METHOD: We obtained sera from three collection sites from 189 non-suspicious coronial postmortems and aortic samples from 10 anaphylactic deaths to characterise postmortem MCT. RESULTS: MCT were elevated (>11.4 MUg/L) in 57% of aortic samples, 58% of femoral samples and 30% of subclavian samples. In aortic samples, there were significantly higher levels of MCT in anaphylaxis-associated deaths compared with other causes of death. Aortic MCT levels >110 MUg/L had a sensitivity of 80% and specificity of 92.1% for anaphylaxis-associated deaths. There was a significant correlation between MCT and degree of sample haemolysis but no correlation with the presence of opiates. CONCLUSIONS: Moderately elevated MCT levels are common in postmortem sera. Aortic values >110 MUg/L may support a diagnosis of anaphylaxis-associated death, although the diagnosis should not be based on this test alone. There was significant variation between sample sites and reference ranges for individual sample sites should be established. PMID- 23940135 TI - Clinical significance of micropapillary urothelial carcinoma of the upper urinary tract. AB - BACKGROUND: The aim of this study was to improve understanding of the characteristics of micropapillary urothelial carcinoma (MPUC) in the renal pelvis and ureter, and to compare oncological outcomes between MPUC and non-MPUC. METHODS: From September 1994 to October 2010, 418 patients underwent nephroureterectomy with bladder excision due to presumed urothelial carcinoma. Pathological review of all specimens was done by one uropathologist. Perioperative data from these patients were reviewed retrospectively. Patients were divided into MPUC and non-MPUC groups. Oncological outcomes were compared between the two groups via progression-free survival (PFS) and cancer-specific survival (CSS) rates. RESULTS: A total of 386 patients were included in the study. Of these, seven patients (1.81%) had MPUC. The median follow-up duration was 39.0 months (IQR range 21.1-70.6). All MPUC patients were men and had lymphovascular invasion, and six patients (85.7%) had grade III and T3 disease. On univariable analysis, MPUC showed significantly worse prognosis with regard to disease progression (p<0.001). In the subgroup analysis confined to T3 or T4 disease, MPUC showed worse prognosis than non-MPUC in terms of PFS and CSS, respectively (p<0.05). In the multivariable model, MPUC still remained a statistically significant independent predictor for PFS (HR (95% CI)=3.85 (1.59 9.32), p=0.003). MPUC was associated with poorer CSS than non-MPUC (p<0.001). CONCLUSIONS: We have observed that upper tract MPUC is associated with poor oncological outcomes in terms of PFS and CSS. MPUC was an independent prognostic factor for PFS in multivariable analysis. PMID- 23940136 TI - Complete blood counts with differential: more accurate reference ranges based on circadian leukocyte trafficking. PMID- 23940192 TI - Dampness and mould in schools and respiratory symptoms. PMID- 23940193 TI - The health effects of major organisational changes. PMID- 23940194 TI - Hypertensive retinopathy and risk of stroke. AB - Although assessment of hypertensive retinopathy signs has been recommended for determining end-organ damage and stratifying vascular risk in persons with hypertension, its value remains unclear. In this study, we examine whether hypertensive retinopathy predicts the long-term risk of stroke in those with hypertension. A total of 2907 participants with hypertension aged 50 to 73 years at the 1993 to 1995 examination, who had gradable retinal photographs, no history of diabetes mellitus, stroke, and coronary heart disease at baseline and data on incident stroke, were included from the Atherosclerosis Risk in Communities (ARIC) Study. Retinal photographs were assessed for hypertensive retinopathy signs and classified as none, mild, and moderate/severe. Incident events of any stroke, cerebral infarction, and hemorrhagic stroke were identified and validated. After a mean follow-up period of 13.0 years, 165 persons developed incident stroke (146 cerebral infarctions and 15 hemorrhagic strokes). After adjusting for age, sex, blood pressure, and other risk factors, persons with moderate hypertensive retinopathy were more likely to have stroke (moderate versus no retinopathy: multivariable hazard ratios, 2.37 [95% confidence interval, 1.39-4.02]). In participants with hypertension on medication with good control of blood pressure, hypertensive retinopathy was related to an increased risk of cerebral infarction (mild retinopathy: hazard ratio, 1.96 [95% confidence interval, 1.09-3.55]; and moderate retinopathy: hazard ratio, 2.98 [95% confidence interval, 1.01-8.83]). Hypertensive retinopathy predicts the long-term risk of stroke, independent of blood pressure, even in treated patients with hypertension with good hypertension control. Retinal photographic assessment of hypertensive retinopathy signs may be useful for assessment of stroke risk. PMID- 23940195 TI - Walking and running produce similar reductions in cause-specific disease mortality in hypertensives. AB - To test prospectively in hypertensives whether moderate and vigorous exercise produces equivalent reductions in mortality, Cox-proportional hazard analyses were applied to energy expenditure (metabolic equivalents hours/d [METh/d]) in 6973 walkers and 3907 runners who used hypertensive medications at baseline. A total of 1121 died during 10.2-year follow-up: 695 cardiovascular disease (International Classification of Diseases, Tenth Revision [ICD10] I00-99; 465 underlying cause and 230 contributing cause), 124 cerebrovascular disease, 353 ischemic heart disease (ICD10 I20-25; 257 underlying and 96 contributing), 122 heart failure (ICD10 I50; 24 underlying and 98 contributing), and 260 dysrhythmias (ICD10 I46-49; 24 underlying and 236 contributing). Relative to <1.07 METh/d, running or walking 1.8 to 3.6 METh/d produced significantly lower all-cause (29% reduction; 95% confidence interval [CI], 17%-39%; P=0.0001), cardiovascular disease (34% reduction; 95% CI, 20%-46%; P=0.0001), cerebrovascular disease (55% reduction; 95% CI, 27%-73%; P=0.001), dysrhythmia (47% reduction; 95% CI, 27%-62%; P=0.0001), and heart failure mortality (51% reduction; 95% CI, 21%-70%; P=0.003), as did >= 3.6 METh/d with all-cause (22% reduction; 95% CI, 6%-35%; P=0.005), cardiovascular disease (36% reduction; 95% CI, 19%-50%; P=0.0002), cerebrovascular disease (47% reduction; 95% CI, 6%-71%; P=0.03), and dysrhythmia mortality (43% reduction; 95% CI, 16%-62%; P=0.004). Diabetes mellitus and chronic kidney disease mortality also decreased significantly with METh/d. All results remained significant when body mass index adjusted. Merely meeting guideline levels (1.07-1.8 METh/d) did not significantly reduced mortality. The dose-response was significantly nonlinear for all end points except diabetes mellitus, and cerebrovascular and chronic kidney disease. Results did not differ between running and walking. Thus, walking and running produce similar reductions in mortality in hypertensives. PMID- 23940196 TI - Prenatal hypoxia causes long-term alterations in vascular endothelin-1 function in aged male, but not female, offspring. AB - Prenatal hypoxia can alter the growth trajectory of the fetus and cause lasting health complications including vascular dysfunction. We hypothesized that offspring that were intrauterine growth restricted (IUGR) because of prenatal hypoxia would exhibit altered vascular endothelin-1 (ET-1) signaling in later life. Isolated mesenteric artery responses to big ET-1 (bET-1) and ET-1 were assessed by using wire myography. Male IUGR offspring had 3-fold greater bET-1 induced vasoconstriction compared with controls (n=7 per group; P<0.001); NO synthase inhibition with L-N(G)-nitro-arginine-methyl ester potentiated bET-1 induced vasoconstriction, albeit this effect was 2-fold greater (P<0.05) in male control compared with IUGR offspring. Vascular responses to bET-1 were similar between female IUGR and control offspring (n=9-11 per group). In the presence of L-N(G)-nitro-arginine-methyl ester, pretreatment with the chymase inhibitor chymostatin, the gelatinase inhibitor GM6001, or the neutral endopeptidase inhibitor thiorphan did not alter responses to bET-1; however, the ET-converting enzyme inhibitor CGS35066 almost completely abolished vascular responses to bET-1 in control and IUGR groups. Systolic blood pressure in IUGR male offspring was more responsive to ET-1 antagonism in vivo compared with controls (-9 versus -4 mm Hg; n=5 per group; P=0.02); no such differences were observed in female offspring (n=5-6 per group). These results demonstrate that vascular ET-1 function is programmed by prenatal hypoxia and provide further insights into the sex differences in the long-term vascular effects of developmental stressors. PMID- 23940197 TI - Is masked hypertension related to diabetes mellitus? PMID- 23940198 TI - Masked hypertension in untreated and treated patients with diabetes mellitus: attractive but questionable interpretations. PMID- 23940199 TI - Retinal vasculature: a window on the brain. PMID- 23940200 TI - Are sildenafil derivatives useful even in unborn males? PMID- 23940202 TI - Restoration of the meniscus: form and function. AB - Over the past 2 decades there has been a profound shift in our perception of the role of the meniscus in the knee joint. Orthopaedic opinion now favors salvaging and restoring the damaged meniscus where possible. Basic science is characterizing its form (anatomy) and functionality (biological and biomechanical) in an attempt to understand the effect of meniscal injury and repair on the knee joint as a whole. The meniscus is a complex tissue and has warranted extensive basic science, translational, and clinical research to identify techniques to augment healing and even replace the meniscus. The application of quantitative magnetic resonance image sequencing to the meniscus and articular cartilage of the affected compartment promises to add a quantifiable outcome measure to the body of clinical evidence that supports restoration of the meniscus. This article discusses the recent advances and outcomes in the pursuit of meniscal restoration with particular focus on the use of augmentation strategies in meniscal repair, meniscal imaging, and translational strategies. PMID- 23940201 TI - Amelioration of angiotensin II-induced salt-sensitive hypertension by liver-type fatty acid-binding protein in proximal tubules. AB - Inappropriate activation of the intrarenal renin-angiotensin system induces generation of reactive oxygen species and tubulointerstitial inflammation, which contribute to salt-sensitive hypertension (SSHT). Liver-type fatty acid-binding protein is expressed in proximal tubules in humans, but not in rodents, and may play an endogenous antioxidative role. The objective of the present study was to examine the antioxidative effect of liver-type fatty acid-binding protein on post angiotensin II SSHT model in transgenic mice with selective overexpression of human liver-type fatty acid-binding protein in the proximal tubules. The transgenic mice showed marked protection against angiotensin II-induced SSHT. Overexpression of tubular liver-type fatty acid-binding protein prevented intrarenal T-cell infiltration and also reduced reactive oxygen species generation, intrarenal renin-angiotensin system activation, and monocyte chemotactic protein-1 expression. We also performed an in vitro study using the murine proximal tubular cell lines with or without recombinant liver-type fatty acid-binding protein and murine proximal tubular cell lines transfected with human liver-type fatty acid-binding protein, and found that gene transfection of liver-type fatty acid-binding protein and, in part, recombinant liver-type fatty acid-binding protein administration had significantly attenuated angiotensin II induced reactive oxygen species generation and the expression of angiotensinogen and monocyte chemotactic protein-1 in murine proximal tubular cell lines. These findings indicated that liver-type fatty acid-binding protein in the proximal tubules may protect against angiotensin II-induced SSHT by attenuating activation of the intrarenal renin-angiotensin system and reducing oxidative stress and tubulointerstitial inflammation. Present data suggest that liver-type fatty acid binding protein in the proximal tubules may be a novel therapeutic target for SSHT. PMID- 23940203 TI - The GraftLink ulnar collateral ligament reconstruction: biomechanical comparison with the docking technique in both kinematics and failure tests. AB - BACKGROUND: Ulnar collateral ligament (UCL) reconstruction aims to restore valgus stability, and numerous techniques have been described in the literature. HYPOTHESIS/ PURPOSE: To biomechanically compare the GraftLink (GL) technique with traditional bone tunnels used in the docking (DO) technique. It is hypothesized that the GL method will offer a stiffer, less lax construct compared with the DO. STUDY DESIGN: Controlled laboratory study. METHODS: Native and reconstructed states were tested in 7 matched pairs of cadaveric arms. To test kinematics, a 1.5-N.m valgus torque was applied and the resultant displacement at 15 degrees to 90 degrees of flexion was measured. Dissipated energy and the torque at the peak of the 10th cycle of preconditioning were analyzed during kinematic tests. Failure testing was performed by internal rotation of the humerus at 4.5 deg/s in 70 degrees of flexion. Ulnotrochlear joint (UTJ) gapping was quantified during failure tests by use of video tracking. RESULTS: Kinematics testing revealed no differences between the native state and the reconstructed state in either the DO or the GL group at any flexion angle. Stiffness was lower in the reconstructed specimens in both the DO (39.92 N.m/rad) and GL (50.74 N.m/rad) groups compared with their matched native states (DO Native, 71.41 N.m/rad, P = .005; GL Native, 86.36 N.m/rad, P = .002). There was no difference in stiffness between DO and GL. Reconstructed specimens in the GL group had lower torque at failure compared with native specimens (17.404 N.m vs 24.63 N.m, P = .038), but there was no difference in the DO group at failure. There was no difference in torque at failure between DO and GL. The DO exhibited higher angular displacement at failure compared with the native state (34.21 degrees vs 21.79 degrees , P = .010) and compared with the GL when normalized (1.58-fold vs 1.19-fold, P = .039). Compared with their native states, both DO and GL had significantly higher UTJ gapping at 3 N.m and at failure. The DO had significantly higher normalized UTJ gapping than the GL at 3 N.m (P = .037) and at failure (P = .043). CONCLUSION: The DO and GL both restored joint kinematics under low loading conditions. Although less stiff, the GL exhibited lower joint gapping and laxity than did the DO. CLINICAL RELEVANCE: Understanding the biomechanics of UCL reconstruction has significant implications for postoperative management as it relates to early rehabilitation. Biomechanically inferior constructs could risk graft failure or early loosening during rehabilitation, and comparing the biomechanics of new techniques to established, widely used procedures such as the docking technique can provide important information about the immediate postoperative performance. PMID- 23940204 TI - The microvascular volume of the Achilles tendon is increased in patients with tendinopathy at rest and after a 1-hour treadmill run. AB - BACKGROUND: Achilles tendinopathy (AT) is initiated asymptomatically and is therefore often discovered at a very late stage. PURPOSE: To elucidate whether the microvascular volume (MV) of the Achilles tendon is elevated in patients with AT compared with healthy controls during pre-exercise rest, after acute exercise, and 24 hours after exercise. Additionally, this study investigated the muscle activation pattern of the gastrocnemius muscle and the relative elasticity of the Achilles tendon during a 1-hour treadmill run in healthy patients and in patients with AT. STUDY DESIGN: Controlled laboratory study. METHODS: Real-time harmonic contrast-enhanced ultrasound (CEU) measurements of the MV of the Achilles tendon were taken in 18 volunteers (9 patients with AT, 9 healthy controls). The CEU analyses were conducted before exercise, immediately after a 1-hour treadmill run, and 24 hours after exercise. Surface electromyography (EMG) signals of the gastrocnemius were recorded continuously during the 1-hour treadmill run. RESULTS: In both the controls and the patients with AT, the MV of the Achilles tendon was increased after exercise as compared with before exercise (P < .005). Additionally, the MV signal was significantly larger in the patients with AT before, immediately after, and 24 hours after the running exercise compared with values in healthy controls (P < .0001). The muscle activation pattern differed in patients with AT compared with controls in that controls had increased EMG amplitudes at the end of the 1-hour treadmill run in the medial and lateral gastrocnemius (P < .0001). Moreover, patients with AT had approximately 15% less elastic Achilles tendons at the beginning of the 1-hour treadmill run, a condition that did not change because of exercise. CONCLUSION: Acute exercise increases the MV of the Achilles tendon in healthy patients and patients with AT in a similar manner. However, patients with AT have a significantly larger MV at all time points compared with healthy patients, supporting the hypothesis that microvascular changes may be involved in the pathogenesis of tendinopathy. CLINICAL RELEVANCE: This study underlines that tendon flexibility is altered in patients with AT and that CEU is a promising tool to establish the early diagnosis of this condition. PMID- 23940205 TI - Coverage of the anterior cruciate ligament femoral footprint using 3 different approaches in single-bundle reconstruction: a cadaveric study analyzed by 3 dimensional computed tomography. AB - BACKGROUND: Performing a single-bundle anterior cruciate ligament (ACL) reconstruction within the femoral footprint is important to obtain a functional graft and a stable knee. HYPOTHESIS: There will be a significant difference in the ability of 3 ACL reconstruction techniques to reach and cover the native femoral footprint. STUDY DESIGN: Controlled laboratory study. METHODS: The percentage of the ACL footprint covered by the femoral tunnel was compared after 3 different techniques to target the footprint: transtibial (TT), inside out/anteromedial (IO), and outside-in/transfemoral (OI). Fourteen cadaveric knee specimens with a mean age of 67.5 years were used. For each knee, the TT technique utilized a 7.5-mm offset guide, the IO technique was performed through an accessory anteromedial portal, and the OI technique was carried out through the femur from the external wall of the lateral condyle. Entry points in the footprint were spotted with markers, and orientations (sagittal and frontal) of each drill guide were noted. The distal femurs were sawed and scanned, and 3 dimensional image reconstructions were analyzed. The virtual drilled area (reamer diameter, 8 mm) depending on the entry point and the sagittal/frontal orientation of the drill guide was calculated and reported for each of the 3 techniques. The distance from the tunnel center to the ACL center, percentage of the femoral tunnel within the ACL footprint, and percentage of the ACL footprint covered by the tunnel were calculated and statistically compared (analysis of variance and t test). RESULTS: The average distance to the native femoral footprint center was 6.8 +/- 2.68 mm for the TT, 2.84 +/- 1.26 mm for the IO, and 2.56 +/- 1.39 mm for the OI techniques. Average percentages of the femoral tunnel within the ACL footprint were 32%, 76%, and 78%, and average percentages of the ACL footprint covered by the tunnel were 35%, 54%, and 47%, for the TT, IO, and OI techniques, respectively. No significant difference was observed between the IO and OI techniques (P = .11). The TT approach gave less satisfactory coverage on all testing criteria. CONCLUSION: The IO and OI techniques allowed for creation of a tunnel closest to the ACL femoral footprint center. Despite this fact and even if the average percentage of the drilled area included in the femoral footprint was close to 80% for these 2 techniques, the average percentage of the ACL footprint covered by the tunnels was <55% for all 3 techniques. Coverage of the ACL footprint depended on the entry point, orientation, and diameter of the drilling but also on the size of the footprint. CLINICAL RELEVANCE: To improve the coverage of the native femoral footprint with a single-bundle graft, in addition to the entry point it may also be necessary to consider the orientation of the drilling to increase the dimensions of the area while respecting the anatomic constraints of the femoral bone and graft geometry. PMID- 23940206 TI - Cytoadherence of Plasmodium berghei-infected red blood cells to murine brain and lung microvascular endothelial cells in vitro. AB - Sequestration of infected red blood cells (iRBC) within the cerebral and pulmonary microvasculature is a hallmark of human cerebral malaria (hCM). The interaction between iRBC and the endothelium in hCM has been studied extensively and is linked to the severity of malaria. Experimental CM (eCM) caused by Plasmodium berghei ANKA reproduces most features of hCM, although the sequestration of RBC infected by P. berghei ANKA (PbA-iRBC) has not been completely delineated. The role of PbA-iRBC sequestration in the severity of eCM is not well characterized. Using static and flow cytoadherence assays, we provide the first direct in vitro evidence for the binding of PbA-iRBC to murine brain and lung microvascular endothelial cells (MVEC). We found that basal PbA-iRBC cytoadherence to MVECs was significantly higher than that of normal red blood cells (NRBC) and of RBC infected with P. berghei K173 (PbK173-iRBC), a strain that causes noncerebral malaria (NCM). MVEC prestimulation with tumor necrosis factor (TNF) failed to promote any further significant increase in mixed-stage iRBC adherence. Interestingly, enrichment of the blood for mature parasites significantly increased PbA-iRBC binding to the MVECs prestimulated with TNF, while blockade of VCAM-1 reduced this adhesion. Our study provides evidence for the firm, flow-resistant binding to endothelial cells of iRBC from strain ANKA infected mice, which develop CM, and for less binding of iRBC from strain K173 infected mice, which develop NCM. An understanding of P. berghei cytoadherence may help elucidate the importance of sequestration in the development of CM and aid the development of antibinding therapies to help reduce the burden of this syndrome. PMID- 23940207 TI - Augmentation of epithelial resistance to invading bacteria by using mRNA transfections. AB - To protect against invading bacteria, oral epithelial cells appear to use two effector antimicrobial peptides (AMPs): calprotectin (S100A8-S100A9 heterodimer [S100A8/A9]) in the cytosol and cathelicidin antimicrobial protein (CAMP) in endosomes. We sought to learn whether innate immunity might be augmented benignly to increase resistance against invasive bacteria. Epithelial cells were transiently transfected with mRNA constructs containing either the CAMP, S100A8, and S100A9 open reading frames, A8-IRES-A9 (fusion sequence), or A8-nIRES-A9 (fusion with native internal ribosome entry site [IRES] sequence). CAMP, S100A8, and S100A9 protein levels generally peaked between 16 and 44 h after mRNA transfection, depending on the construct; CAMP was processed to LL-37 over time. Following transfection with the respective mRNAs, CAMP and S100A8/A9 each independently increased resistance of epithelial cells to invasion by Listeria and Salmonella for up to 48 h; tandem S100A8/A9 constructs were also effective. Cotransfection to express S100A8/A9 and CAMP together augmented resistance, but synergy was not seen. Independent of the new proteins produced, transfection reduced cell viability after 48 h by 20%, with only 2% attributable to apoptosis. Taken together, these results suggest that epithelial cell resistance to invasive pathogens can be augmented by transient transfection of antimicrobial mRNAs into epithelial cells. PMID- 23940208 TI - No holes barred: invasion of the intestinal mucosa by Mycobacterium avium subsp. paratuberculosis. AB - The infection biology of Mycobacterium avium subsp. paratuberculosis has recently crystallized, with added details surrounding intestinal invasion. The involvement of pathogen-derived effector proteins such as the major membrane protein, oxidoreductase, and fibronectin attachment proteins have been uncovered. Mutations constructed in this pathogen have also shed light on genes needed for invasion. The host cell types that are susceptible to invasion have been defined, along with their transcriptional response. Recent details have given a new appreciation for the dynamic interplay between the host and bacterium that occurs at the outset of infection. An initial look at the global expression pathways of the host has shown a circumvention of the cell communication pathway by M. avium subsp. paratuberculosis, which loosens the integrity of the tight junctions. We now know that M. avium subsp. paratuberculosis activates the epithelial layer and also actively recruits macrophages to the site of infection. These notable findings are summarized along with added mechanistic details of the early infection model. We conclude by proposing critical next steps to further elucidate the process of M. avium subsp. paratuberculosis invasion. PMID- 23940209 TI - Identification of a human monoclonal antibody to replace equine diphtheria antitoxin for treatment of diphtheria intoxication. AB - Diphtheria antitoxin (DAT) has been the cornerstone of the treatment of Corynebacterium diphtheriae infection for more than 100 years. Although the global incidence of diphtheria has declined steadily over the last quarter of the 20th century, the disease remains endemic in many parts of the world, and significant outbreaks still occur. DAT is an equine polyclonal antibody that is not commercially available in the United States and is in short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we obtained human monoclonal antibodies (hMAbs) directly from antibody-secreting cells in the circulation of immunized human volunteers. We isolated a panel of diverse hMAbs that recognized diphtheria toxoid, as well as a variety of recombinant protein fragments of diphtheria toxin. Forty-five unique hMAbs were tested for neutralization of diphtheria toxin in in vitro cytotoxicity assays with a 50% effective concentration of 0.65 ng/ml for the lead candidate hMAb, 315C4. In addition, 25 MUg of 315C4 completely protected guinea pigs from intoxication in an in vivo lethality model, yielding an estimated relative potency of 64 IU/mg. In comparison, 1.6 IU of DAT was necessary for full protection from morbidity and mortality in this model. We further established that our lead candidate hMAb binds to the receptor-binding domain of diphtheria toxin and physically blocks the toxin from binding to the putative receptor, heparin-binding epidermal growth factor-like growth factor. The discovery of a specific and potent human neutralizing antibody against diphtheria toxin holds promise as a potential therapeutic. PMID- 23940210 TI - Fracture of mobile unicompartmental knee bearings: a parametric finite element study. AB - Cases of fractured mobile unicompartmental knee bearings have recently been reported. The purpose of this study was to understand the mechanics behind these fractures and to examine the influence of different design modifications. A parametric finite element model was used to examine the influence of different geometrical factors on the stresses within the bearing. Crack initiation occurred clinically in the centre of the bearing; this correlated with the position of the maximum von Mises stress. Tensile stresses, thought to propagate the fatigue crack, were maximal at the medial-lateral sides of the bearing, and the tensile vectors were normal to the fracture direction observed clinically. Fully congruent femoral articulation on the bearing, use of a thicker bearing size, and minimising wear of the component reduced the risk of fracture. For example, an unworn 6.5-mm-thick bearing (no clinical fractures reported) had 21.6% lower medial-lateral tensile stress compared to an unworn 3.5 mm bearing (five clinical fractures reported). In turn, an unworn 3.5 mm bearing had 34.3% lower tensile stress compared to a 3.5 mm bearing after 1.9 mm wear (average linear wear reported for clinically fractured bearings). The fracture risk was also reduced when the radio-opaque marker wire was positioned further from the centre of the bearing, and when marker balls were used instead of marker wires (19% reduction in tensile stress in some regions). These results indicate the importance of minimising component wear; the data also support the current component design which uses posterior marker balls instead of marker wires, and the continuing use of a congruous femoral component. PMID- 23940212 TI - Ultrasound definition of tendon damage in patients with rheumatoid arthritis. Results of a OMERACT consensus-based ultrasound score focussing on the diagnostic reliability. AB - OBJECTIVE: To develop the first ultrasound scoring system of tendon damage in rheumatoid arthritis (RA) and assess its intraobserver and interobserver reliability. METHODS: We conducted a Delphi study on ultrasound-defined tendon damage and ultrasound scoring system of tendon damage in RA among 35 international rheumatologists with experience in musculoskeletal ultrasound. Twelve patients with RA were included and assessed twice by 12 rheumatologists sonographers. Ultrasound examination for tendon damage in B mode of five wrist extensor compartments (extensor carpi radialis brevis and longus; extensor pollicis longus; extensor digitorum communis; extensor digiti minimi; extensor carpi ulnaris) and one ankle tendon (tibialis posterior) was performed blindly, independently and bilaterally in each patient. Intraobserver and interobserver reliability were calculated by kappa coefficients. RESULTS: A three-grade semiquantitative scoring system was agreed for scoring tendon damage in B mode. The mean intraobserver reliability for tendon damage scoring was excellent (kappa value 0.91). The mean interobserver reliability assessment showed good kappa values (kappa value 0.75). The most reliable were the extensor digiti minimi, the extensor carpi ulnaris, and the tibialis posterior tendons. An ultrasound reference image atlas of tenosynovitis and tendon damage was also developed. CONCLUSIONS: Ultrasound is a reproducible tool for evaluating tendon damage in RA. This study strongly supports a new reliable ultrasound scoring system for tendon damage. PMID- 23940211 TI - Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis. AB - OBJECTIVES: The EULAR (European League Against Rheumatism) Scleroderma Trials and Research Group (EUSTAR) has identified preliminary criteria for very early diagnosis of systemic sclerosis (SSc). Our aim was to assess the prevalence of each proposed diagnostic item in a large observational patient cohort with Raynaud's phenomenon (RP). METHODS: Baseline data of 469 RP patients enrolled into the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) cohort are presented. RESULTS: 68% of all RP patients were antinuclear antibody (ANA) positive. ANA+ RP patients more frequently had previous or current puffy fingers (PuFi) (38.5% and 23.3%, p<0.01) and an SSc pattern on nailfold capillaroscopy (NC) (53.6% and 13.4%, p<0.001) than ANA- patients. Telangiectasia, current digital ulcers and digital pitting scars were also commoner in ANA+ RP patients. 38% of ANA+ patients presented with all three features, which should raise suspicion of very early SSc (ANA+RP+PuFi constitutes a 'red flag'). These patients more frequently exhibited an NC SSc pattern, sclerodactyly and telangiectases compared to ANA+ patients without PuFi. Almost 90% of patients with 'red flags' had anti-centromere or anti-topoisomerase I antibodies and/or an NC SSc pattern, and fulfilled the EUSTAR criteria for very early SSc. Previous or current PuFi were present in 23.3% of ANA- RP patients, eight of whom also had an NC SSc pattern. CONCLUSIONS: In addition to well-characterised predictive factors, PuFi is an important sign raising suspicion for underlying very early SSc in patients with RP. The relevance of PuFi in ANA- RP patients should be clarified. PMID- 23940214 TI - EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) is sensitive to show efficacy of rituximab treatment in a randomised controlled trial. PMID- 23940213 TI - Variations in criteria regulating treatment with reimbursed biologic DMARDs across European countries. Are differences related to country's wealth? AB - OBJECTIVES: To explore criteria regulating treatment with reimbursed biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) across Europe and to relate criteria to indicators of national socioeconomic welfare. METHODS: A cross-sectional study among 46 European countries. One expert from each country completed a questionnaire on criteria regulating the start, maintenance/stop and switch of reimbursed bDMARDs. A composite score was developed to evaluate the level of restrictions in prescription of a first bDMARD (0=highly restricted, 5=most liberal). The level of restrictiveness was correlated with national socioeconomic welfare indicators. RESULTS: In 10 countries (22%), no bDMARD was reimbursed. Among 36 countries with at least one biologic reimbursed, 23(64%) had no requirement for disease duration to initiate a biologic. Half of the countries required a failure of two synthetic DMARDs to qualify for therapy. 31 countries specified a minimum level of disease activity to be fulfilled and in 20 (56%) countries cut-off for disease activity score with 28-joint assessment was higher than 3.2. Four countries (11%) had the maximum composite score (most liberal) and 20 (56%) scored between 0 and 2 (more restrictive). Criteria for initiation of a bDMARD were negatively associated with countries' socioeconomic welfare (-0.34 to -0.64), and a moderate positive correlation was found between the composite score and welfare indicators (0.59 0.72). Only some countries had regulations for stopping (n=14(39%)) or switching (n=19(53%)). CONCLUSIONS: Clinical criteria regulating prescription of bDMARDs in RA differ significantly across Europe. Countries with lower socioeconomic welfare tend to have stricter eligibility criteria, pointing to inequities in access to treatment. PMID- 23940215 TI - Long-term intake of dietary long-chain n-3 polyunsaturated fatty acids and risk of rheumatoid arthritis: a prospective cohort study of women. AB - OBJECTIVES: To analyse the association between dietary long-chain n-3 polyunsaturated fatty acids (PUFAs) and incidence of rheumatoid arthritis (RA) in middle-aged and older women from the Swedish Mammography Cohort, a population based prospective study. METHODS: Data on diet were collected in 1987 and 1997 via a self-administered food-frequency questionnaire (FFQ). The risk of RA associated with dietary long-chain n-3 PUFAs and fish intake was estimated using Cox proportional hazard regression models, adjusted for age, cigarette smoking, alcohol intake, use of aspirin and energy intake. RESULTS: Among 32 232 women born 1914-1948, 205 RA cases were identified during a mean follow-up of 7.5 years (1 January 2003 to 31 December 2010; 2 41 120 person-years). An intake of dietary long-chain n-3 PUFAs (FFQ1997) of more than 0.21 g/day (lowest quintile) was associated with a 35% decreased risk of developing RA (multivariable adjusted relative risk (RR) 0.65; 95% CI 0.48 to 0.90) compared with a lower intake. Long term intake consistently higher than 0.21 g/day (according to both FFQ1987 and FFQ1997) was associated with a 52% (95% CI 29% to 67%) decreased risk. Consistent long-term consumption (FFQ1987 and FFQ1997) of fish >=1 serving per week compared with<1 was associated with a 29% decrease in risk (RR 0.71; 95% CI 0.48 to 1.04). CONCLUSIONS: This prospective study of women supports the hypothesis that dietary intake of long-chain n-3 PUFAs may play a role in aetiology of RA. PMID- 23940217 TI - Gene expression profiling of localized prostate cancer: getting answers to the questions that really matter. PMID- 23940216 TI - Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. AB - PURPOSE: A randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recent in in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. PATIENTS AND METHODS: Patients (N = 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) cediranib (30 mg) monotherapy; (2) cediranib (20 mg) plus lomustine (110 mg/m(2)); (3) lomustine (110 mg/m(2)) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans. RESULTS: The primary end point of progression-free survival (PFS) was not significantly different for either cediranib alone (hazard ratio [HR] = 1.05; 95% CI, 0.74 to 1.50; two-sided P = .90) or cediranib in combination with lomustine (HR = 0.76; 95% CI, 0.53 to 1.08; two-sided P = .16) versus lomustine based on independent or local review of postcontrast T1-weighted MRI. CONCLUSION: This study did not meet its primary end point of PFS prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary end points including time to deterioration in neurologic status and corticosteroid-sparing effects. PMID- 23940219 TI - Diagnosis and treatment of KIT-mutant metastatic melanoma. AB - A 52-year-old man has unresectable locally recurrent melanoma of the left foot (Fig 1) and pulmonary metastases. Nine months before this presentation, he underwent a wide local excision and sentinel node biopsy for an acral melanoma on his left heel. Pathology disclosed Breslow thickness of 4.8 mm, Clark level IV, and tumor ulceration with a mitotic rate of 37 mitoses/mm(2). Both sentinel nodes in the left groin were positive for melanoma cells, which expressed S100, HMB45, and melan A. At subsequent left inguinal dissection, seven more nodes showed no additional nodal metastases. Within 3 months of his original surgery, the patient developed a local recurrence in the foot, and over the subsequent 6 months, he underwent serial local excisions and topical diphencyprone treatment. A recent staging scan showed at least 20 foci of in-transit disease in the left lower leg and foot, as well as a solitary lung metastasis (12 mm). His Eastern Cooperative Oncology Group performance status is 1, with no significant comorbidities. High resolution melt followed by sequencing of an in-transit metastasis showed there is no BRAF exon 15 mutation. However, Sanger sequencing of KIT exons 9, 11, 13, and 17, performed as screening for a clinical trial enrolling patients with metastatic acral and mucosal melanomas, showed an exon 13 K642E mutation. PMID- 23940218 TI - Histologic and clinical characteristics can guide staging evaluations for children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. AB - PURPOSE: To simplify the recommended staging evaluation by correlating tumor and clinical features with patterns of distant metastasis in newly diagnosed patients with embryonal rhabdomyosarcoma (ERMS) or alveolar rhabdomyosarcoma (ARMS). PATIENTS AND METHODS: Patient data from the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group over two periods were analyzed: 1991 to 1997 and 1999 to 2004. We used recursive partitioning analyses to identify factors (including histology, age, regional nodal and distant metastatic status, tumor size, local invasiveness, and primary site) that divided patients into subsets with the most different rates of metastatic disease. RESULTS: Of the 1,687 patients analyzed, 5.7% had lung metastases, 4.8% had bone involvement, and 6% had bone marrow (BM) involvement. Rhabdomyosarcoma (RMS) without local invasion (T1) had a low rate of metastasis for all distant sites, especially ERMS (0% bone, 0% BM). ARMS with local invasion (T2) had a higher rate of metastasis for all distant sites (13% lung, 18% bone, 23% BM). ERMS, T2 also had a higher rate of metastatic lung involvement (9%). The likelihood of bone or BM involvement increased in the presence of lung metastases (41% with, 6% without). Regional nodal metastases (N1) predicted a high rate of metastasis in all distant sites (14% lung, 14% bone, 18% BM). A staging algorithm was developed. CONCLUSION: Staging studies in childhood RMS can be tailored to patients' presenting characteristics. Bone marrow aspirate and biopsy and bone scan are unnecessary in at least one third of patients with RMS. PMID- 23940220 TI - Risk-directed treatment intensification significantly reduces the risk of relapse among children and adolescents with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21: a comparison of the MRC ALL97/99 and UKALL2003 trials. AB - PURPOSE: To evaluate the effect on outcome of intensifying therapy for patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21). PATIENTS AND METHODS: We report two cohorts of patients treated on Medical Research Council ALL97 or United Kingdom (UK) ALL2003. iAMP21 was identified retrospectively in ALL97 and was not used to guide therapy. However, in UKALL2003, iAMP21 was determined prospectively, and patients were allocated to the most intensive treatment arm (regimen C), which included augmented Berlin-Frankfurt-Munster consolidation, escalating Capizzi maintenance, double delayed intensification, and an option for first remission transplantation. The presence of iAMP21 was determined by fluorescence in situ hybridization using probes specific for the RUNX1 gene. RESULTS: iAMP21 was identified in 2% of patients with B-cell precursor ALL treated on UKALL2003 and ALL97. The event-free survival, relapse, and overall survival rates at 5 years for iAMP21 patients treated on ALL97 and UKALL2003 were 29% and 78%, 70% and 16%, and 67% and 89%, respectively (all P < .01). Patients treated on ALL97 had an increased risk of relapse compared with patients treated on UKALL2003 (hazard ratio, 7.2; 95% CI, 2.91 to 17.87; P < .001). CONCLUSION: iAMP21 patients with ALL benefitted from receiving more intensive therapy in UKALL2003. In UKALL2011, they will continue to be treated as cytogenetic high risk, receive intensive chemotherapy (regimen C), and will only be recommended for transplantation if they do not achieve a complete remission by the end of induction therapy. This study illustrates how the discovery and characterization of disease-specific genetic aberrations can be used to tailor therapy more precisely. PMID- 23940222 TI - Evaluation of treatment benefit: randomized controlled trials and population based observational research. PMID- 23940221 TI - Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk children's oncology group studies: a report from the children's oncology group. AB - PURPOSE: Five-year overall survival (OS) for children with B-cell precursor acute lymphoblastic leukemia (B-ALL) exceeds 90% with risk-adapted therapy. Age, initial WBC count, genetic aberrations, and minimal residual disease (MRD) are used for risk stratification. Intrachromosomal amplification of a region of chromosome 21 (iAMP21; three or more extra copies of RUNX1 on an abnormal chromosome 21) is a recently identified recurrent genomic lesion associated with inferior outcome in some studies. We investigated the impact of iAMP21 in a large cohort treated in contemporary Children's Oncology Group (COG) ALL trials. PATIENTS AND METHODS: Fluorescent in situ hybridization for specific genetic aberrations was required at diagnosis. MRD was measured by flow cytometry at end induction. Outcome was measured as event-free survival (EFS) and OS. RESULTS: iAMP21 was found in 158 (2%) of 7,793 patients with B-ALL age >= 1 year; 74 (1.5%) of 5,057 standard-risk (SR) patients, and 84 (3.1%) of 2,736 high-risk (HR) patients. iAMP21 was associated with age >= 10 years, WBC less than 50,000/MUL, female sex, and detectable MRD at day 29. Four-year EFS and OS were significantly worse for patients with iAMP21 and SR B-ALL, but iAMP21 was not a statistically significant prognostic factor in HR patients. There was no interaction between MRD and iAMP21. Among SR patients, day 29 MRD >= 0.01% and iAMP21 were associated with the poorest EFS and OS; absence of both was associated with the best outcome. CONCLUSION: iAMP21 is associated with inferior outcome in pediatric B-ALL, particularly SR patients who require more intensive therapy and are now treated on HR COG ALL protocols. PMID- 23940223 TI - Epidermal growth factor receptor tyrosine kinase inhibitor treatment in patients with EGFR wild-type non-small-cell lung cancer: the never-ending story. PMID- 23940224 TI - Targeting activated KIT signaling for melanoma therapy. PMID- 23940226 TI - Another option in our KIT of effective therapies for advanced melanoma. PMID- 23940225 TI - Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. AB - PURPOSE: Anthracycline- and taxane-based three-drug chemotherapy regimens have proven benefit as adjuvant therapy for early-stage breast cancer. This trial (NSABP B-38; Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Positive Breast Cancer) asked whether the incorporation of a fourth drug could improve outcomes relative to two standard regimens and provided a direct comparison of those two regimens. PATIENTS AND METHODS: We randomly assigned 4,894 women with node-positive early-stage breast cancer to six cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC), four cycles of dose-dense (DD) doxorubicin and cyclophosphamide followed by four cycles of DD paclitaxel (P; DD AC->P), or DD AC->P with four cycles of gemcitabine (G) added to the DD paclitaxel (DD AC->PG). Primary granulocyte colony-stimulating factor support was required; erythropoiesis-stimulating agents (ESAs) were used at the investigator's discretion. RESULTS: There were no significant differences in 5 year disease-free survival (DFS) between DD AC->PG and DD AC->P (80.6% v 82.2%; HR, 1.07; P = .41), between DD AC->PG and TAC (80.6% v 80.1%; HR, 0.93; P = .39), in 5-year overall survival (OS) between DD AC->PG and DD AC->P (90.8% v 89.1%; HR, 0.85; P = .13), between DD AC->PG and TAC (90.8% v 89.6%; HR, 0.86; P = .17), or between DD AC->P versus TAC for DFS (HR, 0.87; P = .07) and OS (HR, 1.01; P = .96). Grade 3 to 4 toxicities for TAC, DD AC->P, and DD AC->PG, respectively, were febrile neutropenia (9%, 3%, 3%; P < .001), sensory neuropathy (< 1%, 7%, 6%; P < .001), and diarrhea (7%, 2%, 2%; P < .001). Exploratory analyses for ESAs showed no association with DFS events (HR, 1.02; P = .95). CONCLUSION: Adding G to DD AC->P did not improve outcomes. No significant differences in efficacy were identified between DD AC->P and TAC, although toxicity profiles differed. PMID- 23940227 TI - Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. AB - PURPOSE: Treatment outcomes in younger patients with acute myeloid leukemia (AML) have improved, but optimization and new combinations are needed. We assess three combinations in induction and consolidation. PATIENTS AND METHODS: Younger untreated patients with AML (median age, 49 years; range, 0 to 73 years) were randomly allocated to two induction courses of daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = 1983) or ADE versus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida; n = 1268), and to amsacrine, cytarabine, etoposide, and then mitoxantrone/cytarabine (MACE MidAC) or high-dose cytarabine (n = 1,445) 3 g/m(2) or 1.5 g/m(2) (n = 657) in consolidation, and finally to a fifth course (cytarabine) or not (n = 227). RESULTS: Overall remission rates were similar for DA versus ADE (84% v 86%; P = .14) and ADE versus FLAG-Ida (86% v 85%; P = .7), with more course 1 remissions after FLAG-Ida (77%) reducing relapse (38% v 55%; P < .001) and improving relapse free survival (45% v 34%; P = .01), overall and in subgroups, but with increased myelosuppression, reducing participation in the consolidation randomization. Overall outcomes were similar between MACE/MidAc and high-dose cytarabine (1.5/3.0 g/m(2)), but cytarabine required less supportive care. MACE/MidAc was superior for high-risk patients. A fifth course provided no benefit. The outcome for recipients of only two FLAG-Ida courses were not different from that with DA/ADE with consolidation. CONCLUSION: FLAG-Ida is an effective remission induction treatment, with a high complete remission rate after course 1 and reduced relapse. Consolidation with MACE/MidAc is similar overall to high-dose cytarabine, but superior in high-risk patients. Cytarabine at 1.5 g/m(2) is equivalent to a 3 g/m(2) dose. A fifth course is unnecessary. In patients receiving FLAG-Ida (two courses) and cytarabine (two courses), 8-year survival was 63% for patients with intermediate-risk and 95% for those with favorable-risk disease. PMID- 23940228 TI - Project connect online: randomized trial of an internet-based program to chronicle the cancer experience and facilitate communication. AB - PURPOSE: Evidence suggests that expressing emotions related to cancer and receiving interpersonal support can promote psychological and physical health in women diagnosed with breast cancer. However, adaptive expression of feelings and communication with one's social network can pose challenges for patients with cancer. We report on a randomized controlled trial of an intervention, Project Connect Online, for patients with breast cancer to create personal Web sites to chronicle their experience and communicate with their social network. PATIENTS AND METHODS: Women (N = 88) diagnosed with breast cancer (any stage, any interval since diagnosis) were randomly assigned to participate in a 3-hour workshop for hands-on creation of personal Web sites with a follow-up call to facilitate Web site use, or to a waiting-list control. Assessed before randomization and 6 months after the intervention, dependent variables included depressive symptoms, positive and negative mood, cancer-related intrusive thoughts, and perceived cancer-related benefits in life appreciation and strengthened relationships. RESULTS: Relative to control participants, women randomly assigned to Project Connect Online evidenced significant benefit 6 months later on depressive symptoms, positive mood, and life appreciation, but not negative mood, perceived strengthened relationships, or intrusive thoughts. Treatment status moderated the intervention effects, such that women currently undergoing medical treatment for cancer benefitted significantly more from the intervention on depressive symptoms and positive mood than did women not receiving treatment. CONCLUSION: Findings suggest the promise of an intervention to facilitate the ability of women diagnosed with breast cancer to chronicle their experience and communicate with their social network via the Internet. PMID- 23940229 TI - Ten-year survival in patients with BRCA1-negative and BRCA1-positive breast cancer. AB - PURPOSE: To estimate 10-year overall survival (OS) rates for patients with early onset breast cancer, with and without a BRCA1 mutation, and to identify prognostic factors among those with BRCA1-positive breast cancer. PATIENTS AND METHODS: A total of 3,345 women with stage I to III breast cancer, age <= 50 years, were tested for three founder mutations in BRCA1. Information on tumor characteristics and treatments received was retrieved from medical records. Dates of death were obtained from the vital statistics registry. Survival curves for the mutation-positive and -negative subcohorts were compared. Predictors of OS were determined using the Cox proportional hazards model. RESULTS: Of the 3,345 patients enrolled onto the study, 233 (7.0%) carried a BRCA1 mutation. The 10 year survival rate for mutation carriers was 80.9% (95% CI, 75.4% to 86.4%); for noncarriers, it was 82.2% (95% CI, 80.5% to 83.7%). The adjusted hazard ratio (HR) associated with carrying a BRCA1 mutation was 1.81 (95% CI, 1.26 to 2.61). Among BRCA1 carriers with a small (< 2 cm) node-negative tumor, the 10-year survival rate was 89.9%. Among BRCA1 mutation carriers, positive lymph node status was a strong predictor of mortality (adjusted HR, 4.1; 95% CI, 1.8 to 8.9). Oophorectomy was associated with improved survival in BRCA1 carriers (adjusted HR, 0.30; 95% CI, 0.12 to 0.75). CONCLUSION: The 10-year survival rate among women with breast cancer and a BRCA1 mutation is similar to that of patients without a BRCA1 mutation. Among women with a BRCA1 mutation, survival was much improved after oophorectomy. PMID- 23940230 TI - Explicit prognostic information and reassurance about nonabandonment when entering palliative breast cancer care: findings from a scripted video-vignette study. AB - PURPOSE: When discussing the transition to palliative care for patients with breast cancer, oncologists have to find a balance between giving explicit information while not overwhelming patients and being realistic while remaining hopeful. It is unclear whether patients prefer more or less explicit prognostic information, and reassuring patients that they will not be abandoned may provide realistic hope. We assessed the effect of explicit prognostic information and reassurance about nonabandonment at the transition to palliative care. PATIENTS AND METHODS: An experimental 2 * 2 study was used. Four scripted videos of a bad news conversation were created that differed only in the level of "explicitness of prognosis" and "reassurance about nonabandonment" (high v low). Patients with and survivors of breast cancer (n = 51) and healthy women (n = 53) watched the video-vignettes. The effects of the different communications on participants' anxiety, uncertainty, self-efficacy, and satisfaction were assessed by using multilevel analyses that explored the moderating influences of monitoring/blunting scores. RESULTS: The highly explicit/highly reassuring video yielded the most positive outcomes, and the less explicit/less reassuring video, the most negative (P <= .05 for all outcome measures except anxiety). The main effects found were that explicitness and reassurance decreased participants' uncertainty (P < .001 and P = .002, respectively) and anxiety (only after reassurance; P = .001) while increasing self-efficacy (P = .004 and P < .001, respectively) and satisfaction (P < .001 and P < .001, respectively). High monitors seemed least positive, mainly following explicitness. CONCLUSION: Explicit prognostic information may lead to better outcomes than general information. In addition, reassurance about nonabandonment might provide realistic hope but should be lived up to. More research is needed to translate these findings into clinical care. PMID- 23940232 TI - Parenting as a reaction evoked by children's genotype: a meta-analysis of children-as-twins studies. AB - Parenting has been extensively studied but mostly as a causal factor influencing child outcomes. The aim of the current article is to examine the child's side of the relationship by meta-analyzing studies which used quantitative genetic methods that provide leverage in understanding causality. A meta-analysis of 32 children-as-twins studies of parenting revealed a heritability estimate of 23%, thus indicating that genetically influenced behaviors of the child affect and shape parental behavior. The shared- and nonshared-environmental estimates, which amounted to 43% and 34%, respectively, indicate not only substantial consistency in parental behavior but also differential treatment within the family. Assessment method, age, and parenting dimension were found to be significant moderators of these influences. Our findings stress the importance of accounting for genotype-environment correlations in child-development studies and call into question previous research that interpreted correlational results in unidirectional terms with parenting as the sole causal factor. PMID- 23940233 TI - The collective origins of valued originality: a social identity approach to creativity. AB - Prevailing approaches to individual and group creativity have focused on personal factors that contribute to creative behavior (e.g., personality, intelligence, motivation), and the processes of behaving creatively and appreciating creativity are understood to be largely unrelated. This article uses social identity and self-categorization theories as the basis for a model of creativity that addresses these lacunae by emphasizing the role that groups play in stimulating and shaping creative acts and in determining the reception they are given. We argue that shared social identity (or lack of it) motivates individuals to rise to particular creative challenges and provides a basis for certain forms of creativity to be recognized (or disregarded). Empirical work informed by this approach supports eight novel hypotheses relating to individual, group, and systemic dimensions of the creativity process. These also provide an agenda for future creativity research. PMID- 23940231 TI - Multicenter, randomized controlled trial of yoga for sleep quality among cancer survivors. AB - PURPOSE: Thirty percent to 90% of cancer survivors report impaired sleep quality post-treatment, which can be severe enough to increase morbidity and mortality. Lifestyle interventions, such as exercise, are recommended in conjunction with drugs and cognitive behavioral therapy for the treatment of impaired sleep. Preliminary evidence indicates that yoga-a mind-body practice and form of exercise-may improve sleep among cancer survivors. The primary aim of this randomized, controlled clinical trial was to determine the efficacy of a standardized yoga intervention compared with standard care for improving global sleep quality (primary outcome) among post-treatment cancer survivors. PATIENTS AND METHODS: In all, 410 survivors suffering from moderate or greater sleep disruption between 2 and 24 months after surgery, chemotherapy, and/or radiation therapy were randomly assigned to standard care or standard care plus the 4-week yoga intervention. The yoga intervention used the Yoga for Cancer Survivors (YOCAS) program consisting of pranayama (breathing exercises), 16 Gentle Hatha and Restorative yoga asanas (postures), and meditation. Participants attended two 75-minute sessions per week. Sleep quality was assessed by using the Pittsburgh Sleep Quality Index and actigraphy pre- and postintervention. RESULTS: In all, 410 survivors were accrued (96% female; mean age, 54 years; 75% had breast cancer). Yoga participants demonstrated greater improvements in global sleep quality and, secondarily, subjective sleep quality, daytime dysfunction, wake after sleep onset, sleep efficiency, and medication use at postintervention (all P <= .05) compared with standard care participants. CONCLUSION: Yoga, specifically the YOCAS program, is a useful treatment for improving sleep quality and reducing sleep medication use among cancer survivors. PMID- 23940234 TI - Pneumococcal vaccine reduces US hospital admissions. PMID- 23940235 TI - Nutritional assessment of acute medical admissions is still done badly despite 'nutrition screening'. PMID- 23940236 TI - Enterovirus and the hygiene hypothesis. PMID- 23940238 TI - Home visiting and outcomes of preterm infants: a systematic review. AB - BACKGROUND AND OBJECTIVES: Home visiting is 1 strategy to improve child health and parenting. Since implementation of home visiting trials 2 decades ago, US preterm births (<37 weeks) have risen by 20%. The objective of this study was to review evidence regarding home visiting and outcomes of preterm infants METHODS: Searches of Medline, Cumulative Index to Nursing and Allied Health Literature, Cochrane Database of Systematic Reviews, Cochrane Controlled Trial Register, PsycINFO, and Embase were conducted. Criteria for inclusion were (1) cohort or controlled trial designs; (2) home-based, preventive services for infants at medical or social risk; and (3) outcomes reported for infants born preterm or low birth weight (<2500 g). Data from eligible reports were abstracted by 2 reviewers. Random effects meta-analysis was used to synthesize data for developmental and parent interaction measures. RESULTS: Seventeen studies (15 controlled trials, 2 cohort studies) were reviewed. Five outcome domains were identified: infant development, parent-infant interaction, morbidity, abuse/neglect, and growth/nutrition. Six studies (n = 336) demonstrated a pooled standardized mean difference of 0.79 (95% confidence interval 0.57 to 1.02) in Home Observation for Measurement of the Environment Inventory scores at 1 year in the home-visited groups versus control. Evidence for other outcomes was limited. Methodological limitations were common. CONCLUSIONS: Reviewed studies suggest that home visiting for preterm infants promotes improved parent-infant interaction. Further study of interventions targeting preterm infants within existing programs may strengthen the impact and cost benefits of home visiting in at-risk populations. PMID- 23940237 TI - Two-year outcomes of a randomized controlled trial of inhaled nitric oxide in premature infants. AB - BACKGROUND AND OBJECTIVES: The European Union Nitric Oxide trial was designed to assess the potential benefits of inhaled nitric oxide (iNO) compared with placebo in infants with respiratory failure. This follow-up study evaluated respiratory, neurodevelopmental, and other outcomes for infants entered into the European Union Nitric Oxide trial to age 2 years. METHODS: In a multicenter, randomized, double-blind study, preterm infants born at <29 weeks' gestation with moderate respiratory failure were allocated to receive iNO (5 ppm) or placebo for 7 to 21 days. Subjects underwent assessments at 1 and 2 years corrected for prematurity. RESULTS: At 36 weeks' postmenstrual age, 696 of 792 infants were alive; 4 in the iNO arm subsequently died before age 2 years compared with 7 in the control arm. We evaluated 95% of the survivors at 12 months and 90% at 2 years. In the iNO arm, 244 of 363 (67.2%) infants had survived without disability at age 2 years compared with 270 of 374 (72.2%) who received placebo (P = .094). Mean (SD) cognitive composite scores (Bayley Scales of Infant and Toddler Development, third edition) were 94 (13) in the iNO group and 95 (14) in the placebo group; in the iNO group, 19% scored <85 and 9.5% developed cerebral palsy compared with 13.3% and 9%, respectively. There were no significant differences in hospitalizations overall or due to respiratory illness in use of home oxygen therapy or respiratory medications, in growth, or in other health outcomes. CONCLUSIONS: At 2 years of age, low-dose (5 ppm) iNO started early (<24 hours after birth) for a median of 20 days did not affect neurodevelopmental or other health outcomes. PMID- 23940239 TI - Unexpected relationship between tympanometry and mortality in children with nontraumatic coma. AB - OBJECTIVE: We sought to further examine the relationship between tympanometry and mortality after noting an unexpected association on assessment of baseline data of a study whose primary aim was to investigate the utility of noninvasive tympanic membrane displacement measurement for monitoring intracranial pressure in childhood coma. METHODS: We recruited children who presented with acute nontraumatic coma to the high-dependency unit of Kilifi District Hospital on the rural coast of Kenya. We excluded children with sickle cell disease, epilepsy, and neurodevelopmental delay. We performed tympanometry on the right ear before tympanic membrane displacement analyzer measurements. All children were managed according to standard World Health Organization guidelines. RESULTS: We recruited 72 children with a median age of 3.2 years (interquartile range [IQR]: 2.0-4.3 years); 31 (43%) were female. Thirty-eight (53%) had cerebral malaria, 8 (11%) acute bacterial meningitis, 4 (6%) sepsis, and 22 (30%) encephalopathy of unknown etiology. Twenty (28%) children died. Tympanometry was normal in 25 (35%) children. Adjusting for diagnosis and clinical features of increased intracranial pressure, both associated with death on univariable analysis, children with abnormal tympanometry had greater odds of dying than did those with normal tympanometry (adjusted odds ratio: 17.0; 95% confidence interval: 1.9-152.4; P = .01). Children who died had a lower compliance (0.29 mL; IQR: 0.09-0.33 mL) compared with those who survived (0.48 mL; IQR: 0.29-0.70 mL) (P < .01). CONCLUSIONS: Abnormal tympanometry appears to be significantly associated with death in children with acute nontraumatic coma. This finding needs to be explored further through a prospective study that incorporates imaging and intensive physiologic monitoring. PMID- 23940241 TI - Adolescent and young adult male health: a review. AB - Adolescent and young adult male health receives little attention, despite the potential for positive effects on adult quality and length of life and reduction of health disparities and social inequalities. Pediatric providers, as the medical home for adolescents, are well positioned to address young men's health needs. This review has 2 primary objectives. The first is to review the literature on young men's health, focusing on morbidity and mortality in key areas of health and well-being. The second is to provide a clinically relevant review of the best practices in young men's health. This review covers male health issues related to health care access and the Centers for Disease Control and Prevention's Healthy 2020 objectives for adolescents and young adults, focusing on the objectives for chronic illness, mortality, unintentional injury and violence, mental health and substance use, and reproductive and sexual health. We focus, in particular, on gender-specific issues, particularly in reproductive and sexual health. The review provides recommendations for the overall care of adolescent and young adult males. PMID- 23940240 TI - Ethnic differences in the link between insulin resistance and elevated ALT. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) exhibits tight links with insulin resistance (IR) and the metabolic syndrome (MetS), a cluster of cardiovascular risk factors. Compared with non-Hispanic whites, non-Hispanic black adolescents have more IR but a lower prevalence of NAFLD and MetS. Our hypothesis was that IR would be a better predictor of alanine aminotransferase (ALT) elevations than is MetS among non-Hispanic blacks. METHODS: We analyzed data from 4124 adolescents aged 12 to 19 years in the 1999 to 2010 NHANES, using unexplained elevations in ALT (>30 U/L) to characterize presumed NAFLD and using a pediatric adaptation of the Adult Treatment Panel III definition of MetS. RESULTS: Prevalence of elevated ALT varied by race/ethnicity (Hispanics 13.7%, non-Hispanic white 8.6%, non-Hispanic blacks 5.4%, P < .0001). Among non-Hispanic whites and Hispanics, a classification of MetS performed well in identifying adolescents with elevated ALT (odds ratios [ORs] 9.53 and 5.56, respectively), as did MetS-related indices. However, among non-Hispanic blacks, the association between MetS and ALT elevations was smaller in magnitude and technically nonsignificant (OR = 3.24, P = .051). Furthermore, among non-Hispanic blacks, the presence of IR and elevated waist circumference performed more poorly at identifying ALT elevations (ORs 3.93 and 2.28, respectively: significantly smaller than ORs for non-Hispanic whites, P < .05), with triglyceride elevations being a better predictor (OR = 4.44). CONCLUSIONS: Non-Hispanic black adolescents exhibit a lower relationship between IR and elevated ALT, supporting racial/ethnic differences in the link between MetS and NAFLD. These data may have implications regarding triggers for screening for NAFLD among non-Hispanic black adolescents, focusing particularly on those with triglyceride elevations. PMID- 23940242 TI - Gender differences in physiologic markers and health behaviors associated with childhood obesity. AB - BACKGROUND: Previous studies have demonstrated gender-related differences in body composition, physical activity, and diet. This observational study assesses gender variance in independent predictors for obesity to determine targeted areas for intervention. METHODS: Data from 1714 sixth-grade students enrolled in Project Healthy Schools were compared by using health behaviors and physiologic markers (lipids, random glucose, blood pressure, and resting and recovery heart rates). Students were stratified by gender and obesity (BMI >=95th percentile by age and gender). Physiologic markers and behaviors were compared by using chi(2) analysis. Univariate associations with P < .10 were included in a stepwise logistic regression model to determine independent predictors for obesity by gender. RESULTS: Nonobese students (both boys and girls) showed significantly healthier physiologic parameters compared with their obese counterparts. Two behaviors independently correlated with obesity in both boys and girls: regularly eating school lunches (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.01 1.64; OR 1.27, 95% CI 1.00-1.62, respectively) and watching >=2 hours of television per day (OR 1.19, 95% CI 1.07-1.32; OR 1.19, 95% CI 1.06-1.34, respectively). Vigorous physical activity and involvement in school sports teams appeared to be protective against obesity in boys (OR 0.90, 95% CI 0.82-0.98; OR 0.77, 95% CI 0.64-0.94, respectively), whereas milk consumption appeared protective in girls (OR 0.81, 95% CI 0.67-0.98). CONCLUSIONS: Among middle-school children, we observed gender-related differences in factors associated with obesity. Additional research is warranted to determine the beneficial impact of improving school lunches and decreasing screen time, while improving our understanding of gender-related differences in milk consumption and physical activities in relation to BMI. PMID- 23940243 TI - Pushing the boundaries in adolescent health and disease. PMID- 23940244 TI - Functional abdominal pain in childhood and long-term vulnerability to anxiety disorders. AB - BACKGROUND: Cross-sectional studies link functional abdominal pain (FAP) to anxiety and depression in childhood, but no prospective study has evaluated psychiatric status in adulthood or its relation to pain persistence. METHODS: Pediatric patients with FAP (n = 332) and control subjects (n = 147) were tracked prospectively and evaluated for psychiatric disorders and functional gastrointestinal disorders (FGIDs) at follow-up in adolescence and young adulthood (mean age = 20.01 years). Participants were classified according to presence (FGID-POS) or absence (FGID-NEG) of FGIDs at follow-up. RESULTS: Lifetime and current risk of anxiety disorders was higher in FAP than controls (lifetime: 51% vs 20%; current: 30% vs 12%). Controlling for gender and age, the odds ratio was 4.9 (confidence interval = 2.83-7.43) for lifetime anxiety disorder and 3.57 (confidence interval = 2.00-6.36) for current anxiety disorder at follow-up for FAP versus controls. Lifetime risk of depressive disorder was significantly higher in FAP versus controls (40% vs. 16%); current risk did not differ. In most cases, initial onset of anxiety disorders was before pediatric FAP evaluation; onset of depressive disorders was subsequent to FAP evaluation. Within the FAP group, risk of current anxiety disorders at follow-up was significantly higher for FGID-POS versus FGID-NEG (40% vs 24%), and both were higher than controls (12%); current depressive disorders did not differ across FGID-POS, FGID-NEG, and controls. CONCLUSIONS: Patients with FAP carry long-term vulnerability to anxiety that begins in childhood and persists into late adolescence and early adulthood, even if abdominal pain resolves. PMID- 23940245 TI - Electronic health record identification of nephrotoxin exposure and associated acute kidney injury. AB - BACKGROUND AND OBJECTIVE: Nephrotoxic medication exposure represents a common cause of acute kidney injury (nephrotoxin-AKI) in hospitalized children. Systematic serum creatinine (SCr) screening has not been routinely performed in children receiving nephrotoxins, potentially leading to underestimating nephrotoxin-AKI rates. We aimed to accurately determine nephrotoxin exposure and nephrotoxin-AKI rates to drive appropriate interventions in non-critically ill hospitalized children. METHODS: We conducted a prospective quality improvement project implementing a systematic electronic health record (EHR) screening and decision support process (trigger) at a single quaternary pediatric hospital. Patients were all noncritically ill hospitalized children receiving an intravenous aminoglycoside for >=3 days or >=3 nephrotoxins simultaneously (exposure). Pharmacists recommended daily SCr monitoring in exposed patients. AKI was defined by the modified pediatric Risk, Injury, Failure, Loss and End-stage Renal Disease criteria (>=25% decrease in estimated creatinine clearance). We developed 4 novel metrics: exposure rate per 1000 patient-days, AKI rate per 1000 patient-days, AKI rate (%) per high nephrotoxin admission, and AKI days per 100 exposure days (AKI intensity). RESULTS: This study included 21 807 patients accounting for 27 711 admissions. A total of 726 (3.3%) unique exposed patients accounted for 945 hospital admissions (6713 patient-days). AKI occurred in 25% of unique exposed patients and 31% of exposure admissions (1974 patient-days). Our EHR-driven SCr nephrotoxin-AKI surveillance process was associated with a 42% reduction in AKI intensity. CONCLUSIONS: Nephrotoxin-AKI rates are high in noncritically ill children; systematic screening for nephrotoxic medication exposure and AKI detection was accomplished reliably through an EHR based trigger tool. PMID- 23940246 TI - Hypocretin-1 deficiency in a girl with ROHHAD syndrome. AB - Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare and complex pediatric syndrome, essentially caused by dysfunction of 3 vital systems regulating endocrine, respiratory, and autonomic nervous system functioning. The clinical spectrum of ROHHAD is broad, but sleep/wake disorders have received relatively little attention so far, although the central hypothalamic dysfunction would make the occurrence of sleep symptoms likely. In this case report, we expand the phenotype of ROHHAD with a number of striking sleep symptoms that together can be classified as a secondary form of narcolepsy. We present a 7-year-old girl with ROHHAD who displayed the classic features of narcolepsy with cataplexy: excessive daytime sleepiness with daytime naps, visual hallucinations, and partial cataplexy reflected in intermittent loss of facial muscle tone. Nocturnal polysomnography revealed sleep fragmentation and a sleep-onset REM period characteristic for narcolepsy. The diagnosis was confirmed by showing an absence of hypocretin-1 in the cerebrospinal fluid. We discuss potential pathophysiological implications as well as symptomatic treatment options. PMID- 23940247 TI - First successful use of eltrombopag before surgery in a child with MYH9-related thrombocytopenia. AB - MYH9-related disease (MYH9-RD) is one of the most frequent autosomal-dominant forms of inherited macrothrombocytopenias and is caused by mutations in MYH9 (nonmuscle myosin IIA), the gene coding for the heavy chain of the nonmuscle myosin IIA. Affected individuals can present with isolated thrombocytopenia, and whereas only some will have bleeding events requiring intervention, nearly all will require the use of prophylactic platelet transfusions before surgery. Here we report the first prophylactic use of eltrombopag before surgery in a child with MYH9-RD. Our patient was a 13-year-old girl with an MYH9 S96L missense mutation who required a tympanoplasty due to chronic otitis media. Pretreatment microscopic platelet count was 10 * 10(9)/L. The child was treated with eltrombopag starting 4 weeks before her planned surgery. On the day of surgery her platelet count was 70 * 10(9)/L. She required no platelet transfusions and no abnormal bleeding was reported either during surgery or postoperatively. Given these results, the first reported in a child, we suggest that the use of this thrombopoietic agent should be further evaluated as a useful presurgical prophylactic option in this hereditary thrombocytopenia, thus avoiding the use of platelet transfusions and their associated risks, which include alloimmunization and the transmission of infectious agents. PMID- 23940248 TI - Rotavirus vaccination of very low birth weight infants at discharge from the NICU. AB - OBJECTIVE: Preterm infants are at increased risk of severe rotavirus gastroenteritis. Although immunization with rotavirus vaccine is safe and effective, age restrictions limit the number of infants eligible for vaccination at discharge from the NICU. The objectives of this study were to assess the implementation of the rotavirus vaccine program in our NICU, recognize missed opportunities for vaccination, and document how often very low birth weight (VLBW; birth weight <=1500 g) and extremely low birth weight (ELBW; birth weight <1000 g) infants were eligible to receive rotavirus vaccine at the time of NICU discharge. METHODS: This study reports on a prospective, observational cohort of all VLBW infants who were discharged from the NICU at Parkland Memorial Hospital from May 2008 to April 2010. Medical records were reviewed and data collected regarding the number of infants who were eligible for and received rotavirus vaccination at discharge. RESULTS: A total of 63% (135 of 213) of VLBW infants did not receive rotavirus vaccine. The reasons for not providing vaccine included the following: <42 days of age at discharge (56 of 213; 26%), >84 or 104 days of age at discharge (48 of 213; 23%), or missed (35 of 213; 16%). The majority (75%) who were too old for vaccination at the time of discharge were ELBW. CONCLUSIONS: The current age restrictions for rotavirus immunization resulted in more than half of ELBW infants being ineligible for vaccination at the time of discharge from the NICU. Alternative strategies for rotavirus immunization in this population are needed. PMID- 23940249 TI - Factors associated with late detection of critical congenital heart disease in newborns. AB - OBJECTIVES: Critical congenital heart disease (CCHD) was recently added to the US Recommended Uniform Screening Panel for newborns. This study assessed whether maternal/household and infant characteristics were associated with late CCHD detection. METHODS: This was a statewide, population-based, retrospective, observational study of infants with CCHD born between 1998 and 2007 identified by using the Florida Birth Defects Registry. We examined 12 CCHD conditions that are primary and secondary targets of newborn CCHD screening using pulse oximetry. We used Poisson regression models to analyze associations between selected characteristics (eg, CCHD type, birth hospital nursery level [highest level available in the hospital]) and late CCHD detection (defined as diagnosis after the birth hospitalization). RESULTS: Of 3603 infants with CCHD and linked hospitalizations, CCHD was not detected during the birth hospitalization for 22.9% (n = 825) of infants. The likelihood of late detection varied by CCHD condition. Infants born in a birth hospital with a level I nursery only (adjusted prevalence ratio: 1.9 [95% confidence interval: 1.6-2.2]) or level II nursery (adjusted prevalence ratio: 1.5 [95% confidence interval: 1.3-1.7]) were significantly more likely to have late-detected CCHD compared with infants born in a birth hospital with a level III (highest) nursery. CONCLUSIONS: After controlling for the selected characteristics, hospital nursery level seems to have an independent association with late CCHD detection. Thus, perhaps universal newborn screening for CCHD could be particularly beneficial in level I and II nurseries and may reduce differences in the frequency of late diagnosis between birth hospital facilities. PMID- 23940250 TI - Modelling the effects of low indoor temperatures on the lung function of children with asthma. AB - INTRODUCTION: While many epidemiological studies have shown that low outdoor temperatures are associated with increased rates of hospitalisation and mortality (especially for respiratory or cardiovascular disease), very few studies have looked at the association between indoor temperatures and health. Such studies are clearly warranted, as people have greater exposure to the indoor environment than the outdoor environment. OBJECTIVES: To examine the relationship between various metrics of indoor temperature and lung function in children with asthma. Our specific research questions were: (1) In which room of the home is temperature most strongly associated with lung function? (2) Which exposure metric best describes the relationship between indoor temperature and lung function? (3) Over what lag/time period does indoor air temperature affect lung function most strongly? METHODS: The Heating Housing and Health Study was a randomised controlled trial that investigated the effect of installing heaters in the homes of children with asthma. This study collected measurements of lung function (daily) and indoor temperature (hourly). Lung function and indoor temperature were measured for 309 children over 12 049 child-days. Statistical models were fitted to identify the best measures and metrics. RESULTS: The strongest association with lung function was found for the severity of exposure to low bedroom temperatures averaged over the preceding periods of 0-7 to 0-12 days. A 1 degrees C increase in temperature was associated with an average increase of 0.010, 0.008, 10.06, 12.06, in our four measures of lung function (peak expiratory flow rate (PEFR) morning, PEFR evening, forced expiratory volume in 1 s (FEV1) morning and FEV1 evening). CONCLUSIONS: Indoor temperatures have a small, but significant, association with short-term variations in the lung function of children with asthma. PMID- 23940251 TI - Badger--an accessible genome exploration environment. AB - SUMMARY: High-quality draft genomes are now easy to generate, as sequencing and assembly costs have dropped dramatically. However, building a user-friendly searchable Web site and database for a newly annotated genome is not straightforward. Here we present Badger, a lightweight and easy-to-install genome exploration environment designed for next generation non-model organism genomes. AVAILABILITY: Badger is released under the GPL and is available at http://badger.bio.ed.ac.uk/. We show two working examples: (i) a test dataset included with the source code, and (ii) a collection of four filarial nematode genomes. CONTACT: mark.blaxter@ed.ac.uk. PMID- 23940252 TI - ROBNCA: robust network component analysis for recovering transcription factor activities. AB - MOTIVATION: Network component analysis (NCA) is an efficient method of reconstructing the transcription factor activity (TFA), which makes use of the gene expression data and prior information available about transcription factor (TF)-gene regulations. Most of the contemporary algorithms either exhibit the drawback of inconsistency and poor reliability, or suffer from prohibitive computational complexity. In addition, the existing algorithms do not possess the ability to counteract the presence of outliers in the microarray data. Hence, robust and computationally efficient algorithms are needed to enable practical applications. RESULTS: We propose ROBust Network Component Analysis (ROBNCA), a novel iterative algorithm that explicitly models the possible outliers in the microarray data. An attractive feature of the ROBNCA algorithm is the derivation of a closed form solution for estimating the connectivity matrix, which was not available in prior contributions. The ROBNCA algorithm is compared with FastNCA and the non-iterative NCA (NI-NCA). ROBNCA estimates the TF activity profiles as well as the TF-gene control strength matrix with a much higher degree of accuracy than FastNCA and NI-NCA, irrespective of varying noise, correlation and/or amount of outliers in case of synthetic data. The ROBNCA algorithm is also tested on Saccharomyces cerevisiae data and Escherichia coli data, and it is observed to outperform the existing algorithms. The run time of the ROBNCA algorithm is comparable with that of FastNCA, and is hundreds of times faster than NI-NCA. AVAILABILITY: The ROBNCA software is available at http://people.tamu.edu/~amina/ROBNCA PMID- 23940253 TI - A novel proteinase, SNOWY COTYLEDON4, is required for photosynthetic acclimation to higher light intensities in Arabidopsis. AB - Excess light can have a negative impact on photosynthesis; thus, plants have evolved many different ways to adapt to different light conditions to both optimize energy use and avoid damage caused by excess light. Analysis of the Arabidopsis (Arabidopsis thaliana) mutant snowy cotyledon4 (sco4) revealed a mutation in a chloroplast-targeted protein that shares limited homology with CaaX type endopeptidases. The SCO4 protein possesses an important function in photosynthesis and development, with point mutations rendering the seedlings and adult plants susceptible to photooxidative stress. The sco4 mutation impairs the acclimation of chloroplasts and their photosystems to excess light, evidenced in a reduction in photosystem I function, decreased linear electron transfer, yet increased nonphotochemical quenching. SCO4 is localized to the chloroplasts, which suggests the existence of an unreported type of protein modification within this organelle. Phylogenetic and yeast complementation analyses of SCO4-like proteins reveal that SCO4 is a member of an unknown group of higher plant specific proteinases quite distinct from the well-described CaaX-type endopeptidases RAS Converting Enzyme1 (RCE1) and zinc metallopeptidase STE24 and lacks canonical CaaX activity. Therefore, we hypothesize that SCO4 is a novel endopeptidase required for critical protein modifications within chloroplasts, influencing the function of proteins involved in photosynthesis required for tolerance to excess light. PMID- 23940254 TI - The ureide-degrading reactions of purine ring catabolism employ three amidohydrolases and one aminohydrolase in Arabidopsis, soybean, and rice. AB - Several ureides are intermediates of purine base catabolism, releasing nitrogen from the purine nucleotides for reassimilation into amino acids. In some legumes like soybean (Glycine max), ureides are used for nodule-to-shoot translocation of fixed nitrogen. Four enzymes of Arabidopsis (Arabidopsis thaliana), (1) allantoinase, (2) allantoate amidohydrolase (AAH), (3) ureidoglycine aminohydrolase, and (4) ureidoglycolate amidohydrolase (UAH), catalyze the complete hydrolysis of the ureide allantoin in vitro. However, the metabolic route in vivo remains controversial. Here, in growth and metabolite analyses of Arabidopsis mutants, we demonstrate that these enzymes are required for allantoin degradation in vivo. Orthologous enzymes are present in soybean, encoded by one to four gene copies. All isoenzymes are active in vitro, while some may be inefficiently translated in vivo. Surprisingly, transcript and protein amounts are not significantly regulated by nitrogen fixation or leaf ureide content. A requirement for soybean AAH and UAH for ureide catabolism in leaves has been demonstrated by the use of virus-induced gene silencing. Functional AAH, ureidoglycine aminohydrolase, and UAH are also present in rice (Oryza sativa), and orthologous genes occur in all other plant genomes sequenced to date, indicating that the amidohydrolase route of ureide degradation is universal in plants, including mosses (e.g. Physcomitrella patens) and algae (e.g. Chlamydomomas reinhardtii). PMID- 23940255 TI - Multicolor fate mapping of Langerhans cell homeostasis. AB - Langerhans cells (LCs) constitute a network of immune sentinels in the skin epidermis that is seeded during embryogenesis. Whereas the development of LCs has been extensively studied, much less is known about the homeostatic renewal of adult LCs in "nonmanipulated" animals. Here, we present a new multicolor fluorescent fate mapping system and quantification approach to investigate adult LC homeostasis. This novel approach enables us to propose and provide evidence for a model in which the adult epidermal LC network is not formed by mature coequal LCs endowed with proliferative capabilities, but rather constituted by adjacent proliferative units composed of "dividing" LCs and their terminally differentiated daughter cells. Altogether, our results demonstrate the general utility of our novel fate-mapping system to follow cell population dynamics in vivo and to establish an alternative model for LC homeostasis. PMID- 23940256 TI - Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease. AB - Interleukin (IL) 12 and IL23 are two related heterodimeric cytokines produced by antigen-presenting cells. The balance between these two cytokines plays a crucial role in the control of Th1/Th17 responses and autoimmune inflammation. Most studies focused on their transcriptional regulation. Herein, we explored the role of the adenine and uridine-rich element (ARE)-binding protein tristetraprolin (TTP) in influencing mRNA stability of IL12p35, IL12/23p40, and IL23p19 subunits. LPS-stimulated bone marrow-derived dendritic cells (BMDCs) from TTP(-/-) mice produced normal levels of IL12/23p40. Production of IL12p70 was modestly increased in these conditions. In contrast, we observed a strong impact of TTP on IL23 production and IL23p19 mRNA stability through several AREs in the 3' untranslated region. TTP(-/-) mice spontaneously develop an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis. We observed IL23p19 expression within skin lesions associated with exacerbated IL17A and IL22 production by infiltrating gammadelta T cells and draining lymph node CD4 T cells. We demonstrate that the clinical and immunological parameters associated with TTP deficiency were completely dependent on the IL23-IL17A axis. We conclude that tight control of IL23 mRNA stability by TTP is critical to avoid severe inflammation. PMID- 23940257 TI - Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide-MHC. AB - Recent work has demonstrated that nonstimulatory endogenous peptides can enhance T cell recognition of antigen, but MHCI- and MHCII-restricted systems have generated very different results. MHCII-restricted TCRs need to interact with the nonstimulatory peptide-MHC (pMHC), showing peptide specificity for activation enhancers or coagonists. In contrast, the MHCI-restricted cells studied to date show no such peptide specificity for coagonists, suggesting that CD8 binding to noncognate MHCI is more important. Here we show how this dichotomy can be resolved by varying CD8 and TCR binding to agonist and coagonists coupled with computer simulations, and we identify two distinct mechanisms by which CD8 influences the peptide specificity of coagonism. Mechanism 1 identifies the requirement of CD8 binding to noncognate ligand and suggests a direct relationship between the magnitude of coagonism and CD8 affinity for coagonist pMHCI. Mechanism 2 describes how the affinity of CD8 for agonist pMHCI changes the requirement for specific coagonist peptides. MHCs that bind CD8 strongly were tolerant of all or most peptides as coagonists, but weaker CD8-binding MHCs required stronger TCR binding to coagonist, limiting the potential coagonist peptides. These findings in MHCI systems also explain peptide-specific coagonism in MHCII-restricted cells, as CD4-MHCII interaction is generally weaker than CD8 MHCI. PMID- 23940259 TI - A role for gut-associated lymphoid tissue in shaping the human B cell repertoire. AB - We have tracked the fate of immature human B cells at a critical stage in their development when the mature B cell repertoire is shaped. We show that a major subset of bone marrow emigrant immature human B cells, the transitional 2 (T2) B cells, homes to gut-associated lymphoid tissue (GALT) and that most T2 B cells isolated from human GALT are activated. Activation in GALT is a previously unknown potential fate for immature human B cells. The process of maturation from immature transitional B cell through to mature naive B cell includes the removal of autoreactive cells from the developing repertoire, a process which is known to fail in systemic lupus erythematosus (SLE). We observe that immature B cells in SLE are poorly equipped to access the gut and that gut immune compartments are depleted in SLE. Thus, activation of immature B cells in GALT may function as a checkpoint that protects against autoimmunity. In healthy individuals, this pathway may be involved in generating the vast population of IgA plasma cells and also the enigmatic marginal zone B cell subset that is poorly understood in humans. PMID- 23940258 TI - Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome. AB - The ubiquitously expressed iron storage protein ferritin plays a central role in maintaining cellular iron homeostasis. Cytosolic ferritins are composed of heavy (H) and light (L) subunits that co-assemble into a hollow spherical shell with an internal cavity where iron is stored. The ferroxidase activity of the ferritin H chain is critical to store iron in its Fe3+ oxidation state, while the L chain shows iron nucleation properties. We describe a unique case of a 23-yr-old female patient affected by a homozygous loss of function mutation in the L-ferritin gene, idiopathic generalized seizures, and atypical restless leg syndrome (RLS). We show that L chain ferritin is undetectable in primary fibroblasts from the patient, and thus ferritin consists only of H chains. Increased iron incorporation into the FtH homopolymer leads to reduced cellular iron availability, diminished levels of cytosolic catalase, SOD1 protein levels, enhanced ROS production and higher levels of oxidized proteins. Importantly, key phenotypic features observed in fibroblasts are also mirrored in reprogrammed neurons from the patient's fibroblasts. Our results demonstrate for the first time the pathophysiological consequences of L-ferritin deficiency in a human and help to define the concept for a new disease entity hallmarked by idiopathic generalized seizure and atypical RLS. PMID- 23940260 TI - Q/R site interactions with the M3 helix in GluK2 kainate receptor channels revealed by thermodynamic mutant cycles. AB - RNA editing at the Q/R site near the apex of the pore loop of AMPA and kainate receptors controls a diverse array of channel properties, including ion selectivity and unitary conductance and susceptibility to inhibition by polyamines and cis-unsaturated fatty acids, as well as subunit assembly into tetramers and regulation by auxiliary subunits. How these different aspects of channel function are all determined by a single amino acid substitution remains poorly understood; however, several lines of evidence suggest that interaction between the pore helix (M2) and adjacent segments of the transmembrane inner (M3) and outer (M1) helices may be involved. In the present study, we have used double mutant cycle analysis to test for energetic coupling between the Q/R site residue and amino acid side chains along the M3 helix. Our results demonstrate interaction with several M3 locations and particularly strong coupling to substitution for L614 at the level of the central cavity. In this location, replacement with smaller side chains completely and selectively reverses the effect of fatty acids on gating of edited channels, converting strong inhibition of wild-type GluK2(R) to nearly 10-fold potentiation of GluK2(R) L614A. PMID- 23940261 TI - Interactions among DIV voltage-sensor movement, fast inactivation, and resurgent Na current induced by the NaVbeta4 open-channel blocking peptide. AB - Resurgent Na current flows as voltage-gated Na channels recover through open states from block by an endogenous open-channel blocking protein, such as the NaVbeta4 subunit. The open-channel blocker and fast-inactivation gate apparently compete directly, as slowing the onset of fast inactivation increases resurgent currents by favoring binding of the blocker. Here, we tested whether open-channel block is also sensitive to deployment of the DIV voltage sensor, which facilitates fast inactivation. We expressed NaV1.4 channels in HEK293t cells and assessed block by a free peptide replicating the cytoplasmic tail of NaVbeta4 (the "beta4 peptide"). Macroscopic fast inactivation was disrupted by mutations of DIS6 (L443C/A444W; "CW" channels), which reduce fast-inactivation gate binding, and/or by the site-3 toxin ATX-II, which interferes with DIV movement. In wild-type channels, the beta4 peptide competed poorly with fast inactivation, but block was enhanced by ATX. With the CW mutation, large peptide-induced resurgent currents were present even without ATX, consistent with increased open channel block upon depolarization and slower deactivation after blocker unbinding upon repolarization. The addition of ATX greatly increased transient current amplitudes and further enlarged resurgent currents, suggesting that pore access by the blocker is actually decreased by full deployment of the DIV voltage sensor. ATX accelerated recovery from block at hyperpolarized potentials, however, suggesting that the peptide unbinds more readily when DIV voltage-sensor deployment is disrupted. These results are consistent with two open states in Na channels, dependent on the DIV voltage-sensor position, which differ in affinity for the blocking protein. PMID- 23940262 TI - Antibody-guided photoablation of voltage-gated potassium currents. AB - A family of 40 mammalian voltage-gated potassium (Kv) channels control membrane excitability in electrically excitable cells. The contribution of individual Kv channel types to electrophysiological signaling has been difficult to assign, as few selective inhibitors exist for individual Kv subunits. Guided by the exquisite selectivity of immune system interactions, we find potential for antibody conjugates as selective Kv inhibitors. Here, functionally benign anti-Kv channel monoclonal antibodies (mAbs) were chemically modified to facilitate photoablation of K currents. Antibodies were conjugated to porphyrin compounds that upon photostimulation inflict localized oxidative damage. Anti-Kv4.2 mAb porphyrin conjugates facilitated photoablation of Kv4.2 currents. The degree of K current ablation was dependent on photon dose and conjugate concentration. Kv channel photoablation was selective for Kv4.2 over Kv4.3 or Kv2.1, yielding specificity not present in existing neurotoxins or other Kv channel inhibitors. We conclude that antibody-porphyrin conjugates are capable of selective photoablation of Kv currents. These findings demonstrate that subtype-specific mAbs that in themselves do not modulate ion channel function are capable of delivering functional payloads to specific ion channel targets. PMID- 23940263 TI - The i5K Initiative: advancing arthropod genomics for knowledge, human health, agriculture, and the environment. AB - Insects and their arthropod relatives including mites, spiders, and crustaceans play major roles in the world's terrestrial, aquatic, and marine ecosystems. Arthropods compete with humans for food and transmit devastating diseases. They also comprise the most diverse and successful branch of metazoan evolution, with millions of extant species. Here, we describe an international effort to guide arthropod genomic efforts, from species prioritization to methodology and informatics. The 5000 arthropod genomes initiative (i5K) community met formally in 2012 to discuss a roadmap for sequencing and analyzing 5000 high-priority arthropods and is continuing this effort via pilot projects, the development of standard operating procedures, and training of students and career scientists. With university, governmental, and industry support, the i5K Consortium aspires to deliver sequences and analytical tools for each of the arthropod branches and each of the species having beneficial and negative effects on humankind. PMID- 23940269 TI - Physiological utility of ultrasound biomicroscopy in the lacrimal drainage system. AB - OBJECTIVE: To evaluate lacrimal sac (LS) pump failure in patients with lower motor neuron facial nerve palsy (FNP) using ultrasound biomicroscopy (UBM). METHODS: This was a prospective observational case series. Patients with unilateral lower motor neuron FNP of different aetiologies, age groups and gender were enrolled in this study. Anatomical patency was confirmed through irrigation of the lacrimal drainage system. The degree of lagophthalmos and House-Brackmann grade (HBG) were evaluated, and the dye disappearance test performed. UBM evaluation of the LS during opening and closure of the eyelids was performed for both sides; the control side and the side with assumed lacrimal pump failure (attributed to FNP). Any changes in the orbicularis oculi muscle and fluid turbulence within the sac were reported. RESULTS: A total of 17 patients with unilateral lower motor neuron FNP were evaluated. The average age (+/- SD) was 33.2 +/- 20.1 years. UBM evaluation of control side LS showed obvious fluid turbulence of different patterns within the sac during opening and closure of the eyelids. Fluid turbulence was absent in the LS with HBG V and VI FNP and reduced in the LS with HBG III and IV FNP. CONCLUSIONS: UBM can be used as a safe, non invasive and office-based tool to evaluate the LS pump. PMID- 23940270 TI - Exercise prescription for people with osteoporotic vertebral fracture. PMID- 23940271 TI - The FIFA medical emergency bag and FIFA 11 steps to prevent sudden cardiac death: setting a global standard and promoting consistent football field emergency care. AB - Life-threatening medical emergencies are an infrequent but regular occurrence on the football field. Proper prevention strategies, emergency medical planning and timely access to emergency equipment are required to prevent catastrophic outcomes. In a continuing commitment to player safety during football, this paper presents the FIFA Medical Emergency Bag and FIFA 11 Steps to prevent sudden cardiac death. These recommendations are intended to create a global standard for emergency preparedness and the medical response to serious or catastrophic on field injuries in football. PMID- 23940272 TI - Blockade of TGF-beta signaling greatly enhances the efficacy of TCR gene therapy of cancer. AB - TCR gene therapy is a promising approach for the treatment of various human malignancies. However, the tumoricidal activity of TCR-modified T cells may be limited by local immunosuppressive mechanisms within the tumor environment. In particular, many malignancies induce T cell suppression in their microenvironment by TGF-beta secretion. In this study, we evaluate whether blockade of TGF-beta signaling in TCR-modified T cells enhances TCR gene therapy efficacy in an autochthonous mouse tumor model. Treatment of mice with advanced prostate cancer with T cells genetically engineered to express a tumor-reactive TCR and a dominant-negative TGF-beta receptor II induces complete and sustained tumor regression, enhances survival, and leads to restored differentiation of prostate epithelium. These data demonstrate the potential to tailor the activity of TCR modified T cells by additional genetic modification and provide a strong rationale for the clinical testing of TGF-beta signaling blockade to enhance TCR gene therapy against advanced cancers. PMID- 23940274 TI - The rate of immune escape vanishes when multiple immune responses control an HIV infection. AB - During the first months of HIV infection, the virus typically evolves several immune escape mutations. These mutations are found in epitopes in viral proteins and reduce the impact of the CD8+ T cells specific for these epitopes. Recent data show that only a subset of the epitopes escapes, that most of these escapes evolve early, and that the rate of immune escape slows down considerably. To investigate why the evolution of immune escape slows down over the time of infection, we have extended a consensus mathematical model to allow several immune responses to control the virus together. In the extended model, most escapes also occur early, and the immune escape rate becomes small later, and typically only a minority of the epitopes escape. We show that escaping one of the many immune responses provides little advantage after viral setpoint has been approached because the total killing rate hardly depends on the breadth of the immune response. If the breadth of the immune response slowly wanes during disease progression, the model predicts an increase in the rate of immune escape at late stages of infection. Overall, the most striking prediction of the model is that HIV evolves a small number of immune escapes, in both relative and absolute terms, when the CTL immune response is broad. PMID- 23940273 TI - B cells from knock-in mice expressing broadly neutralizing HIV antibody b12 carry an innocuous B cell receptor responsive to HIV vaccine candidates. AB - Broadly neutralizing Abs against HIV protect from infection, but their routine elicitation by vaccination has not been achieved. To generate small animal models to test vaccine candidates, we have generated targeted transgenic ("knock-in") mice expressing, in the physiological Ig H and L chain loci, two well-studied broadly neutralizing Abs: 4E10, which interacts with the membrane proximal external region of gp41, and b12, which binds to the CD4 binding site on gp120. 4E10HL mice are described in the companion article (Doyle-Cooper et al., J. Immunol. 191: 3186-3191). In this article, we describe b12 mice. B cells in b12HL mice, in contrast to the case in 4E10 mice, were abundant and essentially monoclonal, retaining the b12 specificity. In cell culture, b12HL B cells responded avidly to HIV envelope gp140 trimers and to BCR ligands. Upon transfer to wild-type recipients, b12HL B cells responded robustly to vaccination with gp140 trimers. Vaccinated b12H mice, although generating abundant precursors and Abs with affinity for Env, were unable to rapidly generate neutralizing Abs, highlighting the importance of developing Ag forms that better focus responses to neutralizing epitopes. The b12HL and b12H mice should be useful in optimizing HIV vaccine candidates to elicit a neutralizing response while avoiding nonprotective specificities. PMID- 23940275 TI - CD8+ T cells produce the chemokine CXCL10 in response to CD27/CD70 costimulation to promote generation of the CD8+ effector T cell pool. AB - Various cell types can produce the chemokine CXCL10 in response to IFN-gamma stimulation. CXCL10 is generally viewed as a proinflammatory chemokine that promotes recruitment of CD8/ and Th1-type CD4/ effector T cells to infected or inflamed nonlymphoid tissues. We show that CXCL10 plays a role during CD8/ T cell priming in the mouse. Genome-wide expression profiling revealed the Cxcl10 gene as a target of CD27/CD70 costimulation in newly activated CD8/ T cells. CD27/CD70 costimulation is known to promote activated T cell survival, but CXCL10 did not affect survival or proliferation of primed CD8/ T cells in vitro. Accordingly, CXCL10 could not fully rescue CD27 deficiency in mice infected with influenza virus. Rather, CXCL10 acted as chemoattractant for other activated CD8+ T cells. It signaled downstream of CD27 in a paracrine fashion to promote generation of the CD8/ effector T cell pool in the Ag-draining lymph nodes. Consistently, CD8/ T cells required expression of the CXCL10 receptor CXCR3 for their clonal expansion in a CD27/CD70-dependent peptide-immunization model. Our findings indicate that CXCL10, produced by primed CD8/ T cells in response to CD27/CD70 costimulation, signals to other primed CD8+ T cells in the lymph node microenvironment to facilitate their participation in the CD8/ effector T cell pool. PMID- 23940277 TI - Dermal regulatory T cells display distinct migratory behavior that is modulated during adaptive and innate inflammation. AB - Regulatory T cells (Tregs) are important in controlling skin inflammation, an effect dependent on their ability to home to this organ. However, little is known regarding their behavior in the skin. In this study, we used multiphoton imaging in Foxp3-GFP mice to examine the behavior of endogenous Tregs in resting and inflamed skin. Although Tregs were readily detectable in the uninflamed dermis, most were nonmotile. Induction of contact sensitivity increased the proportion of motile Tregs, and also induced Treg recruitment. This response was significantly blunted in mice challenged with an irrelevant hapten, or by inhibition of effector cell recruitment, indicating a role for T cell-dependent inflammation in induction of Treg migration. Moreover, induction of Treg migration was inhibited by local injection of a CCR4 antagonist, indicating a role for CCR4 in this response. Exposure of naive mice to hapten also induced an increase in the proportion of migratory Tregs, demonstrating that innate signals can also induce Treg migration. Simultaneous examination of the migration of CD4+ effector cells and Tregs in the same region of uninflamed skin demonstrated that effector cells behaved differently, being uniformly highly migratory. These findings indicate that Treg behavior in skin differs from that of CD4+ effector cells, in that only a low proportion of Tregs is migratory under resting conditions. However, in response to both adaptive and innate inflammation, the proportion of migratory Tregs increases, raising the possibility that this response is important in multiple forms of skin inflammation. PMID- 23940276 TI - Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10. AB - A major goal of HIV research is to develop vaccines reproducibly eliciting broadly neutralizing Abs (bNAbs); however, this has proved to be challenging. One suggested explanation for this difficulty is that epitopes seen by bNAbs mimic self, leading to immune tolerance. We generated knock-in mice expressing bNAb 4E10, which recognizes the membrane proximal external region of gp41. Unlike b12 knock-in mice, described in the companion article (Ota et al. 2013. J. Immunol. 191: 3179-3185), 4E10HL mice were found to undergo profound negative selection of B cells, indicating that 4E10 is, to a physiologically significant extent, autoreactive. Negative selection occurred by various mechanisms, including receptor editing, clonal deletion, and receptor downregulation. Despite significant deletion, small amounts of IgM and IgG anti-gp41 were found in the sera of 4E10HL mice. On a Rag1-/- background, 4E10HL mice had virtually no serum Ig of any kind. These results are consistent with a model in which B cells with 4E10 specificity are counterselected, raising the question of how 4E10 was generated in the patient from whom it was isolated. This represents the second example of a membrane proximal external region-directed bNAb that is apparently autoreactive in a physiological setting. The relative conservation in HIV of the 4E10 epitope might reflect the fact that it is under less intense immunological selection as a result of B cell self-tolerance. The safety and desirability of targeting this epitope by a vaccine is discussed in light of the newly described bNAb 10E8. PMID- 23940278 TI - Ubiquitin-specific protease 13 regulates IFN signaling by stabilizing STAT1. AB - The IFN immune system comprises type I, II, and III IFNs, signals through the JAK STAT pathway, and plays central roles in host defense against viral infection. Posttranslational modifications such as ubiquitination regulate diverse molecules in the IFN pathway. To search for the deubiquitinating enzymes (DUBs) involved in the antiviral activity of IFN, we used RNA interference screening to identify a human DUB, ubiquitin-specific protease (USP) 13, whose expression modulates the antiviral activity of IFN-alpha against dengue virus serotype 2 (DEN-2). The signaling events and anti-DEN-2 activities of IFN-alpha and IFN-gamma were reduced in cells with USP13 knockdown but enhanced with USP13 overexpression. USP13 may regulate STAT1 protein because the protein level and stability of STAT1 were increased with USP13 overexpression. Furthermore, STAT1 ubiquitination was reduced in cells with USP13 overexpression and increased with USP13 knockdown regardless of with or without IFN-alpha treatment. Thus, USP13 positively regulates type I and type II IFN signaling by deubiquitinating and stabilizing STAT1 protein. Overall, to our knowledge, USP13 is the first DUB identified to modulate STAT1 and play a role in the antiviral activity of IFN against DEN-2 replication. PMID- 23940279 TI - Characterization of the novel duplicated PRLR gene at the late-feathering K locus in Lohmann chickens. AB - A partial duplication of the prolactin (PRL) receptor gene (designated as dPRLR) has been identified at the late-feathering (LF) K locus on chromosome Z of some chicken strains recently, implying that dPRLR is probably a candidate gene associated with LF development in chickens. However, little is known about the structure, functionality, and spatiotemporal expression of the dPRLR gene in chickens. In this study, using 3'-RACE and RT-PCR, the full-length cDNA of the dPRLR obtained from the kidneys of male Lohmann layer chickens carrying a K allele was cloned. The cloned dPRLR is predicted to encode a membrane-spanning receptor of 683 amino acids, which is nearly identical to the original PRLR, except for its lack of a 149-amino acid C-terminal tail. Using a 5* STAT5 Luciferase reporter system and western blot analysis, we demonstrated that dPRLR expressed in HepG2 cells could be potently activated by chicken PRL and functionally coupled to the intracellular STAT5 signaling pathway, suggesting that dPRLR may function as a novel receptor for PRL. RT-PCR assays revealed that similar to the original PRLR gene, dPRLR mRNA is widely expressed in all embryonic and adult tissues examined including the skin of male Lohmann chickens with a K allele. These findings, together with the expression of PRL mRNA detected in the skin of embryos at embryonic day 20 and 1-week-old chicks, suggest that skin-expressed dPRLR and PRLR, together with plasma and skin-derived PRL, may be involved in the control of the LF development of chicks at hatching. Moreover, the wide tissue expression of dPRLR implies that dPRLR may regulate other physiological processes of chickens carrying the K allele. PMID- 23940280 TI - Clonal genetic and hematopoietic heterogeneity among human-induced pluripotent stem cell lines. AB - Induced pluripotent stem cells (iPSCs) hold great promise for modeling human hematopoietic diseases. However, intrinsic variability in the capacities of different iPSC lines for hematopoietic development complicates comparative studies and is currently unexplained. We created and analyzed 3 separate iPSC clones from fibroblasts of 3 different normal individuals using a standardized approach that included excision of integrated reprogramming genes by Cre-Lox mediated recombination. Gene expression profiling and hematopoietic differentiation assays showed that independent lines from the same individual were generally more similar to one another than those from different individuals. However, one iPSC line (WT2.1) exhibited a distinctly different gene expression, proliferation rate, and hematopoietic developmental potential relative to all other iPSC lines. This "outlier" clone also acquired extensive copy number variations (CNVs) during reprogramming, which may be responsible for its divergent properties. Our data indicate how inherent and acquired genetic differences can influence iPSC properties, including hematopoietic potential. PMID- 23940281 TI - Pivotal role of HIV and EBV replication in the long-term persistence of monoclonal gammopathy in patients on antiretroviral therapy. AB - A high prevalence of monoclonal gammopathy (MG) has been observed in HIV-infected patients. We explored the conditions associated with long-term persistence of serum monoclonal protein (M protein) in HIV-infected patients on antiretroviral therapy (ART). Of 21 patients with MG, M protein disappeared in 12 patients (58%) over 5 years of ART. Higher level of serum gamma-globulin and higher percentages of circulating plasmablasts and plasma cells were observed in patients with persistent MG compared with patients with transient MG. MG persistence was associated with the cumulative time of detectable plasma HIV RNA after ART initiation, detection of Epstein-Barr virus (EBV) DNA in plasma, and a high level of EBV DNA in B cells. Poor control of HIV replication and detectable EBV replication in plasma were both associated with long-term MG persistence in patients on ART. In the case of viral control, MG associated with HIV infection is usually transient. PMID- 23940282 TI - Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. AB - Ibrutinib (PCI-32765) is a highly potent oral Bruton tyrosine kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR- and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLCgamma2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This trial was registered at www.clinicaltrials.gov as #NCT00114738. PMID- 23940284 TI - Congenital dyserythropoietic anemias: molecular insights and diagnostic approach. AB - The congenital dyserythropoietic anemias (CDAs) are hereditary disorders characterized by distinct morphologic abnormalities of marrow erythroblasts. The unveiling of the genes mutated in the major CDA subgroups (I-CDAN1 and II-SEC23B) has now been completed with the recent identification of the CDA III gene (KIF23). KIF23 encodes mitotic kinesin-like protein 1, which plays a critical role in cytokinesis, whereas the cellular role of the proteins encoded by CDAN1 and SEC23B is still unknown. CDA variants with mutations in erythroid transcription factor genes (KLF1 and GATA-1) have been recently identified. Molecular diagnosis of CDA is now possible in most patients. PMID- 23940283 TI - PARP-1 regulates expression of TGF-beta receptors in T cells. AB - Transforming growth factor-beta (TGF-beta) receptors (TbetaRs) are essential components for TGF-beta signal transduction in T cells, yet the mechanisms by which the receptors are regulated remain poorly understood. We show here that Poly(ADP-ribose) polymerase-1 (PARP-1) regulates TGF-beta receptor I (TbetaRI) and II (TbetaRII) expression in CD4(+) T cells and subsequently affects Smad2/3 mediated TGF-beta signal transduction. Inhibition of PARP-1 led to the upregulation of both TbetaRI and TbetaRII, yet the underlying molecular mechanisms were distinct. PARP-1 selectively bound to the promoter of TbetaRII, whereas the enzymatic activity of PARP-1 was responsible for the inhibition of TbetaRI expression. Importantly, inhibition of PARP-1 also enhanced expression of TbetaRs in human CD4(+) T cells. Thus, PARP-1 regulates TbetaR expression and TGF beta signaling in T cells. PMID- 23940285 TI - Cost-effectiveness of screening women with familial risk for breast cancer with magnetic resonance imaging. AB - BACKGROUND: To reduce mortality, women with a family history of breast cancer are often screened with mammography before age 50 years. Additional magnetic resonance imaging (MRI) improves sensitivity and is cost-effective for BRCA1/2 mutation carriers. However, for women with a family history without a proven mutation, cost-effectiveness is unclear. METHODS: We evaluated data of the largest prospective MRI screening study (MRISC). Between 1999 and 2007, 1597 women (8370 woman-years at risk) aged 25 to 70 years with an estimated cumulative lifetime risk of 15% to 50% for breast cancer were screened with clinical breast examination every 6 months and with annual mammography and MRI. We calculated the cost per detected and treated breast cancer. After incorporating MRISC data into a microsimulation screening analysis model (MISCAN), different schemes were evaluated, and cost per life-year gained (LYG) was estimated in comparison with the Dutch nationwide breast cancer screening program (biennial mammography from age 50 to 75 years). All statistical tests were two-sided. RESULTS: Forty-seven breast cancers (9 ductal carcinoma in situ) were detected. Screening with additional MRI costs $123 672 (?93 639) per detected breast cancer. In increasing age-cohorts, costs per detected and treated breast cancer decreased, but, unexpectedly, the percentage of MRI-only detected cancers increased. Screening under the MRISC-scheme from age 35 to 50 years was estimated to reduce breast cancer mortality by 25% at $134 932 (?102 164) per LYG (3.5% discounting) compared with 17% mortality reduction at $54 665 (?41 390) per LYG with mammography only. CONCLUSIONS: Screening with MRI may improve survival for women with familial risk for breast cancer but is expensive, especially in the youngest age categories. PMID- 23940286 TI - Investigation of complement activation product c4d as a diagnostic and prognostic biomarker for lung cancer. AB - BACKGROUND: There is a medical need for diagnostic biomarkers in lung cancer. We evaluated the diagnostic performance of complement activation fragments. METHODS: We assessed complement activation in four bronchial epithelial and seven lung cancer cell lines. C4d, a degradation product of complement activation, was determined in 90 primary lung tumors; bronchoalveolar lavage supernatants from patients with lung cancer (n = 50) and nonmalignant respiratory diseases (n = 22); and plasma samples from advanced (n = 50) and early lung cancer patients (n = 84) subjects with inflammatory lung diseases (n = 133), and asymptomatic individuals enrolled in a lung cancer computed tomography screening program (n = 190). Two-sided P values were calculated by Mann-Whitney U test. RESULTS: Lung cancer cells activated the classical complement pathway mediated by C1q binding that was inhibited by phosphomonoesters. Survival was decreased in patients with high C4d deposition in tumors (hazard ratio [HR] = 3.06; 95% confidence interval [CI] = 1.18 to 7.91). C4d levels were increased in bronchoalveolar lavage fluid from lung cancer patients compared with patients with nonmalignant respiratory diseases (0.61 +/- 0.87 vs 0.16 +/- 0.11 ug/mL; P < .001). C4d levels in plasma samples from lung cancer patients at both advanced and early stages were also increased compared with control subjects (4.13 +/- 2.02 vs 1.86 +/- 0.95 ug/mL, P < 0.001; 3.18 +/- 3.20 vs 1.13 +/- 0.69 ug/mL, P < .001, respectively). C4d plasma levels were associated with shorter survival in patients at advanced (HR = 1.59; 95% CI = 0.97 to 2.60) and early stages (HR = 5.57; 95% CI = 1.60 to 19.39). Plasma C4d levels were reduced after surgical removal of lung tumors (P < .001) and were associated with increased lung cancer risk in asymptomatic individuals with (n = 32) or without lung cancer (n = 158) (odds ratio = 4.38; 95% CI = 1.61 to 11.93). CONCLUSIONS: Complement fragment C4d may serve as a biomarker for early diagnosis and prognosis of lung cancer. PMID- 23940287 TI - Effects of the selective MPS1 inhibitor MPS1-IN-3 on glioblastoma sensitivity to antimitotic drugs. AB - BACKGROUND: Glioblastomas exhibit a high level of chemotherapeutic resistance, including to the antimitotic agents vincristine and taxol. During the mitotic agent-induced arrest, glioblastoma cells are able to perform damage-control and self-repair to continue proliferation. Monopolar spindle 1 (MPS1/TTK) is a checkpoint kinase and a gatekeeper of the mitotic arrest. METHODS: We used glioblastoma cells to determine the expression of MPS1 and to determine the effects of MPS1 inhibition on mitotic errors and cell viability in combination with vincristine and taxol. The effect of MPS1 inhibition was assessed in different orthotopic glioblastoma mouse models (n = 3-7 mice/group). MPS1 expression levels were examined in relation to patient survival. RESULTS: Using publicly available gene expression data, we determined that MPS1 overexpression corresponds positively with tumor grade and negatively with patient survival (two sided t test, P < .001). Patients with high MPS1 expression (n = 203) had a median and mean survival of 487 and 913 days (95% confidence intervals [CI] = 751 to 1075), respectively, and a 2-year survival rate of 35%, whereas patients with intermediate MPS1 expression (n = 140) had a median and mean survival of 858 and 1183 days (95% CI = 1177 to 1189), respectively, and a 2-year survival rate of 56%. We demonstrate that MPS1 inhibition by RNAi results in sensitization to antimitotic agents. We developed a selective small-molecule inhibitor of MPS1, MPS1-IN-3, which caused mitotic aberrancies in glioblastoma cells and, in combination with vincristine, induced mitotic checkpoint override, increased aneuploidy, and augmented cell death. MPS1-IN-3 sensitizes glioblastoma cells to vincristine in orthotopic mouse models (two-sided log-rank test, P < .01), resulting in prolonged survival without toxicity. CONCLUSIONS: Our results collectively demonstrate that MPS1, a putative therapeutic target in glioblastoma, can be selectively inhibited by MPS1-IN-3 sensitizing glioblastoma cells to antimitotic drugs. PMID- 23940288 TI - Threats to validity of nonrandomized studies of postdiagnosis exposures on cancer recurrence and survival. AB - Studies of the effects of exposures after cancer diagnosis on cancer recurrence and survival can provide important information to the growing group of cancer survivors. Observational studies that address this issue generally fall into one of two categories: 1) those using health plan automated data that contain "continuous" information on exposures, such as studies that use pharmacy records; and 2) survey or interview studies that collect information directly from patients once or periodically postdiagnosis. Reverse causation, confounding, selection bias, and information bias are common in observational studies of cancer outcomes in relation to exposures after cancer diagnosis. We describe these biases, focusing on sources of bias specific to these types of studies, and we discuss approaches for reducing them. Attention to known challenges in epidemiologic research is critical for the validity of studies of postdiagnosis exposures and cancer outcomes. PMID- 23940291 TI - Fault lines: resolving clinical negligence claims. PMID- 23940292 TI - Charging patients fees is bad medicine. PMID- 23940293 TI - Most statins prescribed in the UK go to the wrong patients, study finds. PMID- 23940294 TI - Intravenous vaccine shows promise against malaria. PMID- 23940290 TI - Predictors of severe H1N1 infection in children presenting within Pediatric Emergency Research Networks (PERN): retrospective case-control study. AB - OBJECTIVE: To identify historical and clinical findings at emergency department presentation associated with severe H1N1 outcome in children presenting with influenza-like illness. DESIGN: Multicentre retrospective case-control study. SETTING: 79 emergency departments of hospitals associated with the Pediatric Emergency Research Networks in 12 countries. PARTICIPANTS: 265 children (<16 years), presenting between 16 April and 31 December 2009, who fulfilled Centers for Disease Control and Prevention criteria for influenza-like illness and developed severe outcomes from laboratory confirmed H1N1 infection. For each case, two controls presenting with influenza-like illness but without severe outcomes were included: one random control and one age matched control. MAIN OUTCOME MEASURES: Severe outcomes included death or admission to intensive care for assisted ventilation, inotropic support, or both. Multivariable conditional logistic regression was used to compare cases and controls, with effect sizes measured as adjusted odds ratios. RESULTS: 151 (57%) of the 265 cases were male, the median age was 6 (interquartile range 2.3-10.0) years, and 27 (10%) died. Six factors were associated with severe outcomes in children presenting with influenza-like illness: history of chronic lung disease (odds ratio 10.3, 95% confidence interval 1.5 to 69.8), history of cerebral palsy/developmental delay (10.2, 2.0 to 51.4), signs of chest retractions (9.6, 3.2 to 29.0), signs of dehydration (8.8, 1.6 to 49.3), requirement for oxygen (5.8, 2.0 to 16.2), and tachycardia relative to age). CONCLUSION: These independent risk factors may alert clinicians to children at risk of severe outcomes when presenting with influenza-like illness during future pandemics. PMID- 23940289 TI - Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction. AB - Many solid tumors, including pheochromocytoma (PHEO) and paraganglioma (PGL), are characterized by a (pseudo)hypoxic signature. (Pseudo)hypoxia has been shown to promote both tumor progression and resistance to therapy. The major mediators of the transcriptional hypoxic response are hypoxia-inducible factors (HIFs). High levels of HIFs lead to transcription of hypoxia-responsive genes, which are involved in tumorigenesis. PHEOs and PGLs are catecholamine-producing tumors arising from sympathetic- or parasympathetic-derived chromaffin tissue. In recent years, substantial progress has been made in understanding the metabolic disturbances present in PHEO and PGL, especially because of the identification of some disease-susceptibility genes. To date, fifteen PHEO and PGL susceptibility genes have been identified. Based on the main transcription signatures of the mutated genes, PHEOs and PGLs have been divided into two clusters, pseudohypoxic cluster 1 and cluster 2, rich in kinase receptor signaling and protein translation pathways. Although these two clusters seem to show distinct signaling pathways, recent data suggest that both clusters are interconnected by HIF signaling as the important driver in their tumorigenesis, and mutations in most PHEO and PGL susceptibility genes seem to affect HIF-alpha regulation and its downstream signaling pathways. HIF signaling appears to play an important role in the development and growth of PHEOs and PGLs, which could suggest new therapeutic approaches for the treatment of these tumors. PMID- 23940295 TI - Pregnancy screening strategies for diagnostic nuclear medicine: survey results from Australia and New Zealand. AB - The ionizing radiation used in diagnostic nuclear medicine procedures has the potential to cause biologic harm to a fetus. Although the risks are relatively small, it is recommended that all female patients of childbearing age be questioned regarding their pregnancy status before administration of the radiopharmaceutical. This can be a sensitive situation especially for certain types of patients, such as teenagers. Currently, there are no guidelines that detail how to question the patient. Previous studies have revealed the lack of a consistent approach in this area. The aim of this study was to investigate current practice for pregnancy screening before diagnostic nuclear medicine procedures in Australia and New Zealand and to determine whether a standardized practice guideline is required. METHODS: An online survey was administered via SurveyMonkey from October to December 2011. Members of the Australian and New Zealand Society of Nuclear Medicine were invited to participate. The survey consisted of 30 questions divided into 4 sections: demographics, policy and regulations, current practice, and open-ended clinical scenarios. RESULTS: Three hundred thirty-five responses were recorded from participants in all states and territories of Australia and New Zealand; 90% were nuclear medicine technologists. Participants reported a low awareness of radiation policy and regulations but demonstrated good knowledge of the relative risk to the fetus from commonly performed procedures. The most common minimum and maximum age to question patients was 12 y (32%) and 55 y (42%), respectively, although the range was from 10 to 60 y. Verbal questioning (44%) was the most commonly used approach. Pregnancy testing was used by 72%, usually if the patient indicated she was unsure of her pregnancy status. Responses to clinical scenarios were varied, and these will be discussed in a subsequent paper. CONCLUSION: The survey revealed a lack of awareness of government regulations and departmental policy regarding radiation protection. The study demonstrated wide variety in pregnancy screening strategies used to determine the pregnancy status of patients before diagnostic nuclear medicine procedures, indicating that a standardized practice guideline is required for Australia and New Zealand. PMID- 23940296 TI - Surgery and amyotrophic lateral sclerosis: avoid the surgeon. PMID- 23940297 TI - Doctors will feed into review of children's heart services. PMID- 23940298 TI - Sanofi is investigated for allegedly bribing doctors in China. PMID- 23940299 TI - Double minute chromosomes in glioblastoma multiforme are revealed by precise reconstruction of oncogenic amplicons. AB - DNA sequencing offers a powerful tool in oncology based on the precise definition of structural rearrangements and copy number in tumor genomes. Here, we describe the development of methods to compute copy number and detect structural variants to locally reconstruct highly rearranged regions of the tumor genome with high precision from standard, short-read, paired-end sequencing datasets. We find that circular assemblies are the most parsimonious explanation for a set of highly amplified tumor regions in a subset of glioblastoma multiforme samples sequenced by The Cancer Genome Atlas (TCGA) consortium, revealing evidence for double minute chromosomes in these tumors. Further, we find that some samples harbor multiple circular amplicons and, in some cases, further rearrangements occurred after the initial amplicon-generating event. Fluorescence in situ hybridization analysis offered an initial confirmation of the presence of double minute chromosomes. Gene content in these assemblies helps identify likely driver oncogenes for these amplicons. RNA-seq data available for one double minute chromosome offered additional support for our local tumor genome assemblies, and identified the birth of a novel exon made possible through rearranged sequences present in the double minute chromosomes. Our method was also useful for analysis of a larger set of glioblastoma multiforme tumors for which exome sequencing data are available, finding evidence for oncogenic double minute chromosomes in more than 20% of clinical specimens examined, a frequency consistent with previous estimates. PMID- 23940300 TI - Nm23-h1 binds to gelsolin and inactivates its actin-severing capacity to promote tumor cell motility and metastasis. AB - Nm23-H1 has been identified as a metastasis suppressor gene, but its protein interactions have yet to be understood with any mechanistic clarity. In this study, we evaluated the proteomic spectrum of interactions made by Nm23-H1 in 4T1 murine breast cancer cells derived from tissue culture, primary mammary tumors, and pulmonary metastases. By this approach, we identified the actin-severing protein Gelsolin as binding partner for Nm23-H1, verifying their interaction by coimmunoprecipitation in 4T1 cells as well as in human MCF7, MDA-MB-231T, and MDA MB-435 breast cancer cells. In Gelsolin-transfected cells, coexpression of Nm23 H1 abrogated the actin-severing activity of Gelsolin. Conversely, actin severing by Gelsolin was abrogated by RNA interference-mediated silencing of endogenous Nm23-H1. Tumor cell motility was negatively affected in parallel with Gelsolin activity, suggesting that Nm23-H1 binding inactivated the actin-depolymerizing function of Gelsolin to inhibit cell motility. Using indirect immunoflourescence to monitor complexes formed by Gelsolin and Nm23-H1 in living cells, we observed their colocalization in a perinuclear cytoplasmic compartment that was associated with the presence of disrupted actin stress fibers. In vivo analyses revealed that Gelsolin overexpression increased the metastasis of orthotopically implanted 4T1 or tail vein-injected MDA-MB-231T cells (P = 0.001 and 0.04, respectively), along with the proportion of mice with diffuse liver metastases, an effect ablated by coexpression of Nm23-H1. We observed no variation in proliferation among lung metastases. Our findings suggest a new actin-based mechanism that can suppress tumor metastasis. PMID- 23940301 TI - Repeatable noninvasive measurement of mouse myocardial glucose uptake with 18F FDG: evaluation of tracer kinetics in a type 1 diabetes model. AB - A noninvasive and repeatable method for assessing mouse myocardial glucose uptake with (18)F-FDG PET and Patlak kinetic analysis was systematically assessed using the vena cava image-derived blood input function (IDIF). METHODS: Contrast CT and computer modeling was used to determine the vena cava recovery coefficient. Vena cava IDIF (n = 7) was compared with the left ventricular cavity IDIF, with blood and liver activity measured ex vivo at 60 min. The test-retest repeatability (n = 9) of Patlak influx constant K(i) at 10-40 min was assessed quantitatively using Bland-Altman analysis. Myocardial glucose uptake rates (rMGU) using the vena cava IDIF were calculated at baseline (n = 8), after induction of type 1 diabetes (streptozotocin [50 mg/kg] intraperitoneally, 5 d), and after acute insulin stimulation (0.08 mU/kg of body weight intraperitoneally). These changes were analyzed with a standardized uptake value calculation at 20 and 40 min after injection to correlate to the Patlak time interval. RESULTS: The proximal mouse vena cava diameter was 2.54 +/- 0.30 mm. The estimated recovery coefficient, calculated using nonlinear image reconstruction, decreased from 0.76 initially (time 0 to peak activity) to 0.61 for the duration of the scan. There was a 17% difference in the image-derived vena cava blood activity at 60 min, compared with the ex vivo blood activity measured in the gamma-counter. The coefficient of variability for Patlak K(i) values between mice was found to be 23% with the proposed method, compared with 51% when using the left ventricular cavity IDIF (P < 0.05). No significant bias in K(i) was found between repeated scans with a coefficient of repeatability of 0.16 mL/min/g. Calculated rMGU values were reduced by 60% in type 1 diabetic mice from baseline scans (P < 0.03, ANOVA), with a subsequent increase of 40% to a level not significantly different from baseline after acute insulin treatment. These results were confirmed with a standardized uptake value measured at 20 and 40 min. CONCLUSION: The mouse vena cava IDIF provides repeatable assessment of the blood time-activity curve for Patlak kinetic modeling of rMGU. An expected significant reduction in myocardial glucose uptake was demonstrated in a type 1 diabetic mouse model, with significant recovery after acute insulin treatment, using a mouse vena cava IDIF approach. PMID- 23940302 TI - Standards for reporting PET clinical trials. PMID- 23940303 TI - In vivo responses of human A375M melanoma to a sigma ligand: 18F-FDG PET imaging. AB - sigma-ligands can kill tumor cells. Previously we have shown that a short in vitro incubation of C6 tumor cells with sigma-ligands (24 h) results in a dose dependent increase of cellular (18)F-FDG uptake and that the magnitude of this increase is predictive of subsequent cell death. Here, we aimed to assess whether the sigma-ligand rimcazole inhibits growth of A375M melanoma xenografts in nude mice and whether rimcazole treatment changes (18)F-FDG uptake in vivo. METHODS: Athymic mice were inoculated with A375M melanoma cells. After 2 wk, tumors had reached a size of 41 +/- 6 mm(3). We then started a 14-d treatment schedule with daily drug dosing. Control animals were injected with water and treated animals with rimcazole (26 mg/kg) in water. Three small-animal PET scans with (18)F-FDG were obtained: on days 0, 7, and 14 of treatment. After the last scan, animals were terminated, and a biodistribution study was performed. RESULTS: Rimcazole treatment resulted in a greater than 4-fold reduction of tumor weight in comparison to controls at day 14 (100 +/- 26 vs. 436 +/- 117 mg, respectively, P < 0.03). Treatment did not affect the levels of (nonradioactive) glucose in blood, sigma-1 and sigma-2 receptor expression in the tumor, animal weight, behavior, or appearance. Antitumor activity of rimcazole was accompanied by a transient increase of the tumor uptake of (18)F-FDG (measured at day 7). Significant increases of (18)F-FDG uptake at day 14 were observed in the liver and pancreas. CONCLUSION: Rimcazole strongly inhibited the growth of A375M melanoma xenografts. This growth inhibition is accompanied by an early increase of (18)F-FDG uptake in the tumor. PMID- 23940304 TI - Longitudinal amyloid imaging using 11C-PiB: methodologic considerations. AB - Several methods are in use for analyzing (11)C-Pittsburgh compound-B ((11)C-PiB) data. The objective of this study was to identify the method of choice for measuring longitudinal changes in specific (11)C-PiB binding. METHODS: Dynamic 90 min (11)C-PiB baseline and follow-up scans (interval, 30 +/- 5 mo) were obtained for 7 Alzheimer disease (AD) patients, 11 patients with mild cognitive impairment (MCI), and 11 healthy controls. Parametric images were generated using reference parametric mapping (RPM2), reference Logan values, and standardized uptake value volume ratios (SUVr), the latter for intervals between 60 and 90 (SUVr(60-90)) and 40 and 60 (SUVr(40-60)) minutes after injection. In all analyses, cerebellar gray matter was used as a reference region. A global cortical volume of interest was defined using a probability map-based template. Percentage change between baseline and follow-up was derived for all analytic methods. RESULTS: SUVr(60-90) and SUVr(40-60) overestimated binding with 13% and 10%, respectively, compared with RPM2. Reference Logan values were on average 6% lower than RPM2. Both SUVr measures showed high intersubject variability. Over time, R1, the delivery of tracer to the cortex relative to that to the cerebellum, decreased in AD patients (P < 0.05) but not in MCI patients and controls. Simulations showed that SUVr, but not RPM2 and reference Logan values, was highly dependent on uptake period and that changes in SUVr over time were sensitive to changes in flow. CONCLUSION: To reliably assess amyloid binding over time--for example, in drug intervention studies--it is essential to use fully quantitative methods for data acquisition and analysis. PMID- 23940305 TI - Detection of obstructive coronary artery disease using regadenoson stress and 82Rb PET/CT myocardial perfusion imaging. AB - Our objective was to study the diagnostic performance of regadenoson (82)Rb myocardial perfusion PET imaging to detect obstructive coronary artery disease (CAD). METHODS: We studied 134 patients (mean age, 63 +/- 12 y; mean body mass index, 31 +/- 9 kg/m(2)) without known CAD (96 with coronary angiography and 38 with low pretest likelihood of CAD). Stress left ventricular ejection fraction (LVEF) minus rest LVEF defined LVEF reserve. The Duke score was used to estimate the anatomic extent of jeopardized myocardium. RESULTS: Regadenoson PET had a high sensitivity, 92% (95% confidence interval [CI], 83%-97%), in detecting obstructive CAD, with a normalcy rate of 97% (95% CI, 86%-99%), specificity of 77% (54/70 patients; 95% CI, 66%-86%), and area under the receiver-operator characteristic curve of 0.847 (95% CI, 0.774-0.903; P < 0.001). Regadenoson PET demonstrated high sensitivity to detect CAD in patients with single-vessel CAD (89%; 95% CI, 70%-98%). The mean LVEF reserve was significantly higher in patients with normal myocardial perfusion imaging results (6.5% +/- 5.4%) than in those with mild (4.3 +/- 5.1, P = 0.03) and moderate to severe reversible defects (-0.2% +/- 8.4%, P = 0.001). Also, mean LVEF reserve was significantly higher in patients with a low likelihood of CAD (7.2% +/- 4.5%, P < 0.0001) and mild or moderate jeopardized myocardium than in those with significant jeopardized myocardium (score >= 6), -2.8% +/- 8.3%. CONCLUSION: Regadenoson (82)Rb myocardial perfusion imaging is accurate for the detection of obstructive CAD. LVEF reserve is high in patients without significant ischemia or significant angiographic jeopardized myocardium. PMID- 23940306 TI - Assessing compound carcinogenicity in vitro using connectivity mapping. AB - One of the main challenges of toxicology is the accurate prediction of compound carcinogenicity. The default test model for assessing chemical carcinogenicity, the 2 year rodent cancer bioassay, is currently criticized because of its limited specificity. With increased societal attention and new legislation against animal testing, toxicologists urgently need an alternative to the current rodent bioassays for chemical cancer risk assessment. Toxicogenomics approaches propose to use global high-throughput technologies (transcriptomics, proteomics and metabolomics) to study the toxic effect of compounds on a biological system. Here, we demonstrate the improvement of transcriptomics assay consisting of primary human hepatocytes to predict the putative liver carcinogenicity of several compounds by applying the connectivity map methodology. Our analyses underline that connectivity mapping is useful for predicting compound carcinogenicity by connecting in vivo expression profiles from human cancer tissue samples with in vitro toxicogenomics data sets. Furthermore, the importance of time and dose effect on carcinogenicity prediction is demonstrated, showing best prediction for low dose and 24 h exposure of potential carcinogens. PMID- 23940307 TI - Race influences the safety and efficacy of spironolactone in severe heart failure. AB - BACKGROUND: The incidence of hyperkalemia caused by mineralocorticoid receptor antagonists may vary by race, but whether race influences efficacy of mineralocorticoid receptor antagonists in heart failure (HF) is unknown. METHODS AND RESULTS: We assessed hyperkalemia and outcomes in African Americans (AAs; n=120) and non-AAs (n=1543; white 93%) with New York Heart Association (NYHA) class III or IV HF and left ventricular dysfunction who were randomized to spironolactone, titrated to 25 or 50 mg daily or placebo, in the Randomized Aldactone Evaluation Study (RALES). AA participants were significantly younger, less likely to have an ischemic HF pathogenesis, more likely to be NYHA functional class IV, and more likely to have a higher estimated glomerular filtration rate and heart rate, less hypertension, diabetes mellitus, or history of myocardial infarction compared with non-AA participants. Potassium increased with spironolactone in non-AAs (4.29+/-0.5-4.55+/-0.49 mmol/L) but not in AAs (4.32+/-0.54-4.31+/-0.49 mmol/L; race by treatment interaction, P=0.03) during the first month and remained higher throughout the trial. Compared with AAs, non AAs were more likely to attain maximal spironolactone dose (13.9% versus 5.8%; P=0.04) and had higher rates of hyperkalemia (potassium>5.5 mmol/L; 9.7% versus 4.2%; P<0.046), as well as lower rates of hypokalemia (potassium<3.5 mmol/L; 5.6% versus 17.9%; P<0.001). After adjustment for differences in baseline characteristics and achieved study drug dose, spironolactone reduced the combined end point of death or hospitalization for HF in non-AAs (hazard ratio, 0.63; 95% confidence interval, 0.55-0.73) but not in AAs (hazard ratio, 1.07; 95% confidence interval, 0.67-1.71; P value for interaction=0.032). CONCLUSIONS: AAs with HF exhibited less hyperkalemia and more hypokalemia with spironolactone compared with non-AAs and seemed to derive less clinical benefit. These hypothesis-generating findings suggest that safety and efficacy of mineralocorticoid receptor antagonists may differ by race. PMID- 23940308 TI - Differential translocation of the fatty acid transporter, FAT/CD36, and the glucose transporter, GLUT4, coordinates changes in cardiac substrate metabolism during ischemia and reperfusion. AB - BACKGROUND: Fatty acid and glucose transporters translocate between the sarcolemma and intracellular compartments to regulate substrate metabolism acutely. We hypothesised that during ischemia fatty acid translocase (FAT/CD36) would translocate away from the sarcolemma to limit fatty acid uptake when fatty acid oxidation is inhibited. METHODS AND RESULTS: Wistar rat hearts were perfused during preischemia, low-flow ischemia, and reperfusion, using (3)H-substrates for measurement of metabolic rates, followed by metabolomic analysis and subcellular fractionation. During ischemia, there was a 32% decrease in sarcolemmal FAT/CD36 accompanied by a 95% decrease in fatty acid oxidation rates, with no change in intramyocardial lipids. Concomitantly, the sarcolemmal content of the glucose transporter, GLUT4, increased by 90% during ischemia, associated with an 86% increase in glycolytic rates, 45% decrease in glycogen content, and a 3-fold increase in phosphorylated AMP-activated protein kinase. Following reperfusion, decreased sarcolemmal FAT/CD36 persisted, but fatty acid oxidation rates returned to preischemic levels, resulting in a 35% decrease in myocardial triglyceride content. Elevated sarcolemmal GLUT4 persisted during reperfusion; in contrast, glycolytic rates decreased to 30% of preischemic rates, accompanied by a 5-fold increase in intracellular citrate levels and restoration of glycogen content. CONCLUSIONS: During ischemia, FAT/CD36 moved away from the sarcolemma as GLUT4 moved toward the sarcolemma, associated with a shift from fatty acid oxidation to glycolysis, while intramyocardial lipid accumulation was prevented. This relocation was maintained during reperfusion, which was associated with replenishing glycogen stores as a priority, occurring at the expense of glycolysis and mediated by an increase in citrate levels. PMID- 23940310 TI - Bridging the gap between science and decision making. AB - All decisions, whether they are personal, public, or business-related, are based on the decision maker's beliefs and values. Science can and should help decision makers by shaping their beliefs. Unfortunately, science is not easily accessible to decision makers, and scientists often do not understand decision makers' information needs. This article presents a framework for bridging the gap between science and decision making and illustrates it with two examples. The first example is a personal health decision. It shows how a formal representation of the beliefs and values can reflect scientific inputs by a physician to combine with the values held by the decision maker to inform a medical choice. The second example is a public policy decision about managing a potential environmental hazard. It illustrates how controversial beliefs can be reflected as uncertainties and informed by science to make better decisions. Both examples use decision analysis to bridge science and decisions. The conclusions suggest that this can be a helpful process that requires skills in both science and decision making. PMID- 23940312 TI - Gap between science and media revisited: scientists as public communicators. AB - The present article presents an up-to-date account of the current media relations of scientists, based on a comprehensive analysis of relevant surveys. The evidence suggests that most scientists consider visibility in the media important and responding to journalists a professional duty--an attitude that is reinforced by universities and other science organizations. Scientific communities continue to regulate media contacts with their members by certain norms that compete with the motivating and regulating influences of public information departments. Most scientists assume a two-arena model with a gap between the arenas of internal scientific and public communication. They want to meet the public in the public arena, not in the arena of internal scientific communication. Despite obvious changes in science and in the media system, the orientations of scientists toward the media, as well as the patterns of interaction with journalists, have their roots in the early 1980s. Although there is more influence on public communication from the science organizations and more emphasis on strategic considerations today, the available data do not indicate abrupt changes in communication practices or in the relevant beliefs and attitudes of scientists in the past 30 y. Changes in the science-media interface may be expected from the ongoing structural transformation of the public communication system. However, as yet, there is little evidence of an erosion of the dominant orientation toward the public and public communication within the younger generation of scientists. PMID- 23940309 TI - Reactive hyperemia occurs via activation of inwardly rectifying potassium channels and Na+/K+-ATPase in humans. AB - RATIONALE: Reactive hyperemia (RH) in the forearm circulation is an important marker of cardiovascular health, yet the underlying vasodilator signaling pathways are controversial and thus remain unclear. OBJECTIVE: We hypothesized that RH occurs via activation of inwardly rectifying potassium (KIR) channels and Na(+)/K(+)-ATPase and is largely independent of the combined production of the endothelial autocoids nitric oxide (NO) and prostaglandins in young healthy humans. METHODS AND RESULTS: In 24 (23+/-1 years) subjects, we performed RH trials by measuring forearm blood flow (FBF; venous occlusion plethysmography) after 5 minutes of arterial occlusion. In protocol 1, we studied 2 groups of 8 subjects and assessed RH in the following conditions. For group 1, we studied control (saline), KIR channel inhibition (BaCl2), combined inhibition of KIR channels and Na(+)/K(+)-ATPase (BaCl2 and ouabain, respectively), and combined inhibition of KIR channels, Na(+)/K(+)-ATPase, NO, and prostaglandins (BaCl2, ouabain, L-NMMA [N(G)-monomethyl-L-arginine] and ketorolac, respectively). Group 2 received ouabain rather than BaCl2 in the second trial. In protocol 2 (n=8), the following 3 RH trials were performed: control; L-NMMA plus ketorolac; and L NMMA plus ketorolac plus BaCl2 plus ouabain. All infusions were intra-arterial (brachial). Compared with control, BaCl2 significantly reduced peak FBF (-50+/ 6%; P<0.05), whereas ouabain and L-NMMA plus ketorolac did not. Total FBF (area under the curve) was attenuated by BaCl2 (-61+/-3%) and ouabain (-44+/-12%) alone, and this effect was enhanced when combined (-87+/-4%), nearly abolishing RH. L-NMMA plus ketorolac did not impact total RH FBF before or after administration of BaCl2 plus ouabain. CONCLUSIONS: Activation of KIR channels is the primary determinant of peak RH, whereas activation of both KIR channels and Na(+)/K(+)-ATPase explains nearly all of the total (AUC) RH in humans. PMID- 23940311 TI - Metalloproteases meprin alpha and meprin beta are C- and N-procollagen proteinases important for collagen assembly and tensile strength. AB - Type I fibrillar collagen is the most abundant protein in the human body, crucial for the formation and strength of bones, skin, and tendon. Proteolytic enzymes are essential for initiation of the assembly of collagen fibrils by cleaving off the propeptides. We report that Mep1a(-/-) and Mep1b(-/-) mice revealed lower amounts of mature collagen I compared with WT mice and exhibited significantly reduced collagen deposition in skin, along with markedly decreased tissue tensile strength. While exploring the mechanism of this phenotype, we found that cleavage of full-length human procollagen I heterotrimers by either meprin alpha or meprin beta led to the generation of mature collagen molecules that spontaneously assembled into collagen fibrils. Thus, meprin alpha and meprin beta are unique in their ability to process and release both C- and N-propeptides from type I procollagen in vitro and in vivo and contribute to the integrity of connective tissue in skin, with consequent implications for inherited connective tissue disorders. PMID- 23940313 TI - DNA motifs determining the efficiency of adaptation into the Escherichia coli CRISPR array. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) and their associated proteins constitute a recently identified prokaryotic defense system against invading nucleic acids. DNA segments, termed protospacers, are integrated into the CRISPR array in a process called adaptation. Here, we establish a PCR based assay that enables evaluating the adaptation efficiency of specific spacers into the type I-E Escherichia coli CRISPR array. Using this assay, we provide direct evidence that the protospacer adjacent motif along with the first base of the protospacer (5'-AAG) partially affect the efficiency of spacer acquisition. Remarkably, we identified a unique dinucleotide, 5'-AA, positioned at the 3' end of the spacer, that enhances efficiency of the spacer's acquisition. Insertion of this dinucleotide increased acquisition efficiency of two different spacers. DNA sequencing of newly adapted CRISPR arrays revealed that the position of the newly identified motif with respect to the 5'-AAG is important for affecting acquisition efficiency. Analysis of approximately 1 million spacers showed that this motif is overrepresented in frequently acquired spacers compared with those acquired rarely. Our results represent an example of a short nonprotospacer adjacent motif sequence that affects acquisition efficiency and suggest that other as yet unknown motifs affect acquisition efficiency in other CRISPR systems as well. PMID- 23940314 TI - Cytoplasmic streaming in plant cells emerges naturally by microfilament self organization. AB - Many cells exhibit large-scale active circulation of their entire fluid contents, a process termed cytoplasmic streaming. This phenomenon is particularly prevalent in plant cells, often presenting strikingly regimented flow patterns. The driving mechanism in such cells is known: myosin-coated organelles entrain cytoplasm as they process along actin filament bundles fixed at the periphery. Still unknown, however, is the developmental process that constructs the well-ordered actin configurations required for coherent cell-scale flow. Previous experimental works on streaming regeneration in cells of Characean algae, whose longitudinal flow is perhaps the most regimented of all, hint at an autonomous process of microfilament self-organization driving the formation of streaming patterns during morphogenesis. Working from first principles, we propose a robust model of streaming emergence that combines motor dynamics with both microscopic and macroscopic hydrodynamics to explain how several independent processes, each ineffectual on its own, can reinforce to ultimately develop the patterns of streaming observed in the Characeae and other streaming species. PMID- 23940316 TI - New media landscapes and the science information consumer. AB - Individuals are increasingly turning to online environments to find information about science and to follow scientific developments. It is therefore crucial for scientists and scientific institutions to consider empirical findings from research in online science communication when thinking about science in the public sphere. After providing a snapshot of the current media landscape, this paper reviews recent major research findings related to science communication in the online environment and their implications for science in the 21st century. Particular emphasis is given to the bias introduced by search engines, the nature of scientific content encountered online, and the potential impact of the Internet on audiences' knowledge and attitudes toward science. PMID- 23940315 TI - Cryoelectron tomography reveals the sequential assembly of bacterial flagella in Borrelia burgdorferi. AB - Periplasmic flagella are essential for the distinctive morphology, motility, and infectious life cycle of the Lyme disease spirochete Borrelia burgdorferi. In this study, we genetically trapped intermediates in flagellar assembly and determined the 3D structures of the intermediates to 4-nm resolution by cryoelectron tomography. We provide structural evidence that secretion of rod substrates triggers remodeling of the central channel in the flagellar secretion apparatus from a closed to an open conformation. This open channel then serves as both a gateway and a template for flagellar rod assembly. The individual proteins assemble sequentially to form a modular rod. The hook cap initiates hook assembly on completion of the rod, and the filament cap facilitates filament assembly after formation of the mature hook. Cryoelectron tomography and mutational analysis thus combine synergistically to provide a unique structural blueprint of the assembly process of this intricate molecular machine in intact cells. PMID- 23940317 TI - Competing molecular interactions of aPKC isoforms regulate neuronal polarity. AB - Atypical protein kinase C (aPKC) isoforms zeta and lambda interact with polarity complex protein Par3 and are evolutionarily conserved regulators of cell polarity. Prkcz encodes aPKC-zeta and PKM-zeta, a truncated, neuron-specific alternative transcript, and Prkcl encodes aPKC-lambda. Here we show that, in embryonic hippocampal neurons, two aPKC isoforms, aPKC-lambda and PKM-zeta, are expressed. The localization of these isoforms is spatially distinct in a polarized neuron. aPKC-lambda, as well as Par3, localizes at the presumptive axon, whereas PKM-zeta and Par3 are distributed at non-axon-forming neurites. PKM zeta competes with aPKC-lambda for binding to Par3 and disrupts the aPKC-lambda Par3 complex. Silencing of PKM-zeta or overexpression of aPKC-lambda in hippocampal neurons alters neuronal polarity, resulting in neurons with supernumerary axons. In contrast, the overexpression of PKM-zeta prevents axon specification. Our studies suggest a molecular model wherein mutually antagonistic intermolecular competition between aPKC isoforms directs the establishment of neuronal polarity. PMID- 23940318 TI - Availability of public goods shapes the evolution of competing metabolic strategies. AB - Tradeoffs provide a rationale for the outcome of natural selection. A prominent example is the negative correlation between the growth rate and the biomass yield in unicellular organisms. This tradeoff leads to a dilemma, where the optimization of growth rate is advantageous for an individual, whereas the optimization of the biomass yield would be advantageous for a population. High rate strategies are observed in a broad variety of organisms such as Escherichia coli, yeast, and cancer cells. Growth in suspension cultures favors fast-growing organisms, whereas spatial structure is of importance for the evolution of high yield strategies. Despite this realization, experimental methods to directly select for increased yield are lacking. We here show that the serial propagation of a microbial population in a water-in-oil emulsion allows selection of strains with increased biomass yield. The propagation in emulsion creates a spatially structured environment where the growth-limiting substrate is privatized for populations founded by individual cells. Experimental evolution of several isogenic Lactococcus lactis strains demonstrated the existence of a tradeoff between growth rate and biomass yield as an apparent Pareto front. The underlying mutations altered glucose transport and led to major shifts between homofermentative and heterofermentative metabolism, accounting for the changes in metabolic efficiency. The results demonstrated the impact of privatizing a public good on the evolutionary outcome between competing metabolic strategies. The presented approach allows the investigation of fundamental questions in biology such as the evolution of cooperation, cell-cell interactions, and the relationships between environmental and metabolic constraints. PMID- 23940319 TI - Tandem oleosin genes in a cluster acquired in Brassicaceae created tapetosomes and conferred additive benefit of pollen vigor. AB - During evolution, genomes expanded via whole-genome, segmental, tandem, and individual-gene duplications, and the emerged redundant paralogs would be eliminated or retained owing to selective neutrality or adaptive benefit and further functional divergence. Here we show that tandem paralogs can contribute adaptive quantitative benefit and thus have been retained in a lineage-specific manner. In Brassicaceae, a tandem oleosin gene cluster of five to nine paralogs encodes ample tapetum-specific oleosins located in abundant organelles called tapetosomes in flower anthers. Tapetosomes coordinate the storage of lipids and flavonoids and their transport to the adjacent maturing pollen as the coat to serve various functions. Transfer-DNA and siRNA mutants of Arabidopsis thaliana with knockout and knockdown of different tandem oleosin paralogs had quantitative and correlated loss of organized structures of the tapetosomes, pollen-coat materials, and pollen tolerance to dehydration. Complementation with the knockout paralog restored the losses. Cleomaceae is the family closest to Brassicaceae. Cleome species did not contain the tandem oleosin gene cluster, tapetum oleosin transcripts, tapetosomes, or pollen tolerant to dehydration. Cleome hassleriana transformed with an Arabidopsis oleosin gene for tapetum expression possessed primitive tapetosomes and pollen tolerant to dehydration. We propose that during early evolution of Brassicaceae, a duplicate oleosin gene mutated from expression in seed to the tapetum. The tapetum oleosin generated primitive tapetosomes that organized stored lipids and flavonoids for their effective transfer to the pollen surface for greater pollen vitality. The resulting adaptive benefit led to retention of tandem-duplicated oleosin genes for production of more oleosin and modern tapetosomes. PMID- 23940320 TI - Nonclassical MHC class I-dependent invariant T cells are evolutionarily conserved and prominent from early development in amphibians. AB - Human and murine MHC nonclassical class Ib-restricted invariant T (iT) cell subsets, such as invariant natural killer T cells (iNKT) and mucosal-associated invariant T cells, have specialized functions early in immune responses, especially in modulating subsequent adaptive immune responses. Here, we characterize a prominent iT population in the amphibian Xenopus laevis and show the requirement of the class Ib molecule, Xenopus nonclassical gene 10, in its differentiation and function. Using Xenopus nonclassical gene 10 tetramers and RNAi loss of function by transgenesis, we identified a large class Ib-dependent CD8(-)/CD4(-) iT subset in unmanipulated frogs and tadpoles. This population is critical for antiviral immunity during early larval stages when classical MHC class Ia function is suboptimal. Furthermore, in young tadpoles with low class Ia expression, deep sequencing revealed additional preponderant invariant T cell receptor (TCR)alpha rearrangements, implying other iT cell subsets and a predominant selection process mediated by other class Ib molecules. The restriction and requirement of class Ib molecules for development and antiviral immunity of a mammalian iNKT or mucosal-associated invariant T cell counterpart in the amphibian Xenopus show the importance of iT cells in the emergence and evolution of the adaptive immune system. PMID- 23940321 TI - Biochemical analysis of a multifunctional cytochrome P450 (CYP51) enzyme required for synthesis of antimicrobial triterpenes in plants. AB - Members of the cytochromes P450 superfamily (P450s) catalyze a huge variety of oxidation reactions in microbes and higher organisms. Most P450 families are highly divergent, but in contrast the cytochrome P450 14alpha-sterol demethylase (CYP51) family is one of the most ancient and conserved, catalyzing sterol 14alpha-demethylase reactions required for essential sterol synthesis across the fungal, animal, and plant kingdoms. Oats (Avena spp.) produce antimicrobial compounds, avenacins, that provide protection against disease. Avenacins are synthesized from the simple triterpene, beta-amyrin. Previously we identified a gene encoding a member of the CYP51 family of cytochromes P450, AsCyp51H10 (also known as Saponin-deficient 2, Sad2), that is required for avenacin synthesis in a forward screen for avenacin-deficient oat mutants. sad2 mutants accumulate beta amyrin, suggesting that they are blocked early in the pathway. Here, using a transient plant expression system, we show that AsCYP51H10 is a multifunctional P450 capable of modifying both the C and D rings of the pentacyclic triterpene scaffold to give 12,13beta-epoxy-3beta,16beta-dihydroxy-oleanane (12,13beta-epoxy 16beta-hydroxy-beta-amyrin). Molecular modeling and docking experiments indicate that C16 hydroxylation is likely to precede C12,13 epoxidation. Our computational modeling, in combination with analysis of a suite of sad2 mutants, provides insights into the unusual catalytic behavior of AsCYP51H10 and its active site mutants. Fungal bioassays show that the C12,13 epoxy group is an important determinant of antifungal activity. Accordingly, the oat AsCYP51H10 enzyme has been recruited from primary metabolism and has acquired a different function compared to other characterized members of the plant CYP51 family--as a multifunctional stereo- and regio-specific hydroxylase in plant specialized metabolism. PMID- 23940322 TI - Dissecting yield-associated loci in super hybrid rice by resequencing recombinant inbred lines and improving parental genome sequences. AB - The growing world population and shrinkage of arable land demand yield improvement of rice, one of the most important staple crops. To elucidate the genetic basis of yield and uncover its associated loci in rice, we resequenced the core recombinant inbred lines of Liang-You-Pei-Jiu, the widely cultivated super hybrid rice, and constructed a high-resolution linkage map. We detected 43 yield-associated quantitative trait loci, of which 20 are unique. Based on the high-density physical map, the genome sequences of paternal variety 93-11 and maternal cultivar PA64s of Liang-You-Pei-Jiu were significantly improved. The large recombinant inbred line population combined with plentiful high-quality single nucleotide polymorphisms and insertions/deletions between parental genomes allowed us to fine-map two quantitative trait loci, qSN8 and qSPB1, and to identify days to heading8 and lax panicle1 as candidate genes, respectively. The quantitative trait locus qSN8 was further confirmed to be days to heading8 by a complementation test. Our study provided an ideal platform for molecular breeding by targeting and dissecting yield-associated loci in rice. PMID- 23940323 TI - Language can boost otherwise unseen objects into visual awareness. AB - Linguistic labels (e.g., "chair") seem to activate visual properties of the objects to which they refer. Here we investigated whether language-based activation of visual representations can affect the ability to simply detect the presence of an object. We used continuous flash suppression to suppress visual awareness of familiar objects while they were continuously presented to one eye. Participants made simple detection decisions, indicating whether they saw any image. Hearing a verbal label before the simple detection task changed performance relative to an uninformative cue baseline. Valid labels improved performance relative to no-label baseline trials. Invalid labels decreased performance. Labels affected both sensitivity (d') and response times. In addition, we found that the effectiveness of labels varied predictably as a function of the match between the shape of the stimulus and the shape denoted by the label. Together, the findings suggest that facilitated detection of invisible objects due to language occurs at a perceptual rather than semantic locus. We hypothesize that when information associated with verbal labels matches stimulus driven activity, language can provide a boost to perception, propelling an otherwise invisible image into awareness. PMID- 23940324 TI - Distinctive topology of age-associated epigenetic drift in the human interactome. AB - Recently, it has been demonstrated that DNA methylation, a covalent modification of DNA that can regulate gene expression, is modified as a function of age. However, the biological and clinical significance of this age-associated epigenetic drift is unclear. To shed light on the potential biological significance, we here adopt a systems approach and study the genes undergoing age associated changes in DNA methylation in the context of a protein interaction network, focusing on their topological properties. In contrast to what has been observed for other age-related gene classes, including longevity- and disease associated genes, as well as genes undergoing age-associated changes in gene expression, we here demonstrate that age-associated epigenetic drift occurs preferentially in genes that occupy peripheral network positions of exceptionally low connectivity. In addition, we show that these genes synergize topologically with disease and longevity genes, forming unexpectedly large network communities. Thus, these results point toward a potentially distinct mechanistic and biological role of DNA methylation in dictating the complex aging and disease phenotypes. PMID- 23940326 TI - Isothermal amplification method for next-generation sequencing. AB - We report an approach for generating immobilized monoclonal templates for next- generation sequencing applications. Our isothermal amplification method is based on a template walking mechanism using a pair of low-melting temperature (Tm) solid-surface homopolymer primers and a low-Tm solution phase primer. The method can generate more than one billion submicrometer-sized colonies in a single lane of a next-generation sequencing flowchip. An alternative paired-end sequencing method using interstrand DNA photo cross-linking to covalently link the complementary strands of the original templates to the solid surface is also demonstrated. PMID- 23940325 TI - In vivo genetic dissection of O2-evoked cGMP dynamics in a Caenorhabditis elegans gas sensor. AB - cGMP signaling is widespread in the nervous system. However, it has proved difficult to visualize and genetically probe endogenously evoked cGMP dynamics in neurons in vivo. Here, we combine cGMP and Ca(2+) biosensors to image and dissect a cGMP signaling network in a Caenorhabditis elegans oxygen-sensing neuron. We show that a rise in O2 can evoke a tonic increase in cGMP that requires an atypical O2-binding soluble guanylate cyclase and that is sustained until oxygen levels fall. Increased cGMP leads to a sustained Ca(2+) response in the neuron that depends on cGMP-gated ion channels. Elevated levels of cGMP and Ca(2+) stimulate competing negative feedback loops that shape cGMP dynamics. Ca(2+) dependent negative feedback loops, including activation of phosphodiesterase-1 (PDE-1), dampen the rise of cGMP. A different negative feedback loop, mediated by phosphodiesterase-2 (PDE-2) and stimulated by cGMP-dependent kinase (PKG), unexpectedly promotes cGMP accumulation following a rise in O2, apparently by keeping in check gating of cGMP channels and limiting activation of Ca(2+) dependent negative feedback loops. Simultaneous imaging of Ca(2+) and cGMP suggests that cGMP levels can rise close to cGMP channels while falling elsewhere. O2-evoked cGMP and Ca(2+) responses are highly reproducible when the same neuron in an individual animal is stimulated repeatedly, suggesting that cGMP transduction has high intrinsic reliability. However, responses vary substantially across individuals, despite animals being genetically identical and similarly reared. This variability may reflect stochastic differences in expression of cGMP signaling components. Our work provides in vivo insights into the architecture of neuronal cGMP signaling. PMID- 23940327 TI - A closure scheme for chemical master equations. AB - Probability reigns in biology, with random molecular events dictating the fate of individual organisms, and propelling populations of species through evolution. In principle, the master probability equation provides the most complete model of probabilistic behavior in biomolecular networks. In practice, master equations describing complex reaction networks have remained unsolved for over 70 years. This practical challenge is a reason why master equations, for all their potential, have not inspired biological discovery. Herein, we present a closure scheme that solves the master probability equation of networks of chemical or biochemical reactions. We cast the master equation in terms of ordinary differential equations that describe the time evolution of probability distribution moments. We postulate that a finite number of moments capture all of the necessary information, and compute the probability distribution and higher order moments by maximizing the information entropy of the system. An accurate order closure is selected, and the dynamic evolution of molecular populations is simulated. Comparison with kinetic Monte Carlo simulations, which merely sample the probability distribution, demonstrates this closure scheme is accurate for several small reaction networks. The importance of this result notwithstanding, a most striking finding is that the steady state of stochastic reaction networks can now be readily computed in a single-step calculation, without the need to simulate the evolution of the probability distribution in time. PMID- 23940328 TI - An integrated model of communication influence on beliefs. AB - How do people develop and maintain their beliefs about science? Decades of social science research exist to help us answer this question. The Integrated Model of Communication Influence on Beliefs presented here combines multiple theories that have considered aspects of this process into a comprehensive model to explain how individuals arrive at their scientific beliefs. In this article, we (i) summarize what is known about how science is presented in various news and entertainment media forms; (ii) describe how individuals differ in their choices to be exposed to various forms and sources of communication; (iii) discuss the implications of how individuals mentally process information on the effects of communication; (iv) consider how communication effects can be altered depending on background characteristics and motivations of individuals; and (v) emphasize that the process of belief formation is not unidirectional but rather, feeds back on itself over time. We conclude by applying the Integrated Model of Communication Influence on Beliefs to the complex issue of beliefs about climate change. PMID- 23940329 TI - Human circulating influenza-CD4+ ICOS1+IL-21+ T cells expand after vaccination, exert helper function, and predict antibody responses. AB - Protection against influenza is mediated by neutralizing antibodies, and their induction at high and sustained titers is key for successful vaccination. Optimal B cells activation requires delivery of help from CD4(+) T lymphocytes. In lymph nodes and tonsils, T-follicular helper cells have been identified as the T cells subset specialized in helping B lymphocytes, with interleukin-21 (IL-21) and inducible costimulatory molecule (ICOS1) playing a central role for this function. We followed the expansion of antigen-specific IL-21(+) CD4(+) T cells upon influenza vaccination in adults. We show that, after an overnight in vitro stimulation, influenza-specific IL-21(+) CD4(+) T cells can be measured in human blood, accumulate in the CXCR5(-)ICOS1(+) population, and increase in frequency after vaccination. The expansion of influenza-specific ICOS1(+)IL-21(+) CD4(+) T cells associates with and predicts the rise of functionally active antibodies to avian H5N1. We also show that blood-derived CXCR5(-)ICOS1(+) CD4(+) T cells exert helper function in vitro and support the differentiation of influenza specific B cells in an ICOS1- and IL-21-dependent manner. We propose that the expansion of antigen-specific ICOS1(+)IL-21(+) CD4(+) T cells in blood is an early marker of vaccine immunogenicity and an important immune parameter for the evaluation of novel vaccination strategies. PMID- 23940330 TI - Germ-line variant of human NTH1 DNA glycosylase induces genomic instability and cellular transformation. AB - Base excision repair (BER) removes at least 20,000 DNA lesions per human cell per day and is critical for the maintenance of genomic stability. We hypothesize that aberrant BER, resulting from mutations in BER genes, can lead to genomic instability and cancer. The first step in BER is catalyzed by DNA N-glycosylases. One of these, n(th) endonuclease III-like (NTH1), removes oxidized pyrimidines from DNA, including thymine glycol. The rs3087468 single nucleotide polymorphism of the NTH1 gene is a G-to-T base substitution that results in the NTH1 D239Y variant protein that occurs in ~6.2% of the global population and is found in Europeans, Asians, and sub-Saharan Africans. In this study, we functionally characterize the effect of the D239Y variant expressed in immortal but nontransformed human and mouse mammary epithelial cells. We demonstrate that expression of the D239Y variant in cells also expressing wild-type NTH1 leads to genomic instability and cellular transformation as assessed by anchorage independent growth, focus formation, invasion, and chromosomal aberrations. We also show that cells expressing the D239Y variant are sensitive to ionizing radiation and hydrogen peroxide and accumulate double strand breaks after treatment with these agents. The DNA damage response is also activated in D239Y expressing cells. In combination, our data suggest that individuals possessing the D239Y variant are at risk for genomic instability and cancer. PMID- 23940331 TI - Unexpected variations in the triple oxygen isotope composition of stratospheric carbon dioxide. AB - We report observations of stratospheric CO2 that reveal surprisingly large anomalous enrichments in (17)O that vary systematically with latitude, altitude, and season. The triple isotope slopes reached 1.95 +/- 0.05(1sigma) in the middle stratosphere and 2.22 +/- 0.07 in the Arctic vortex versus 1.71 +/- 0.03 from previous observations and a remarkable factor of 4 larger than the mass-dependent value of 0.52. Kinetics modeling of laboratory measurements of photochemical ozone-CO2 isotope exchange demonstrates that non-mass-dependent isotope effects in ozone formation alone quantitatively account for the (17)O anomaly in CO2 in the laboratory, resolving long-standing discrepancies between models and laboratory measurements. Model sensitivities to hypothetical mass-dependent isotope effects in reactions involving O3, O((1)D), or CO2 and to an empirically derived temperature dependence of the anomalous kinetic isotope effects in ozone formation then provide a conceptual framework for understanding the differences in the isotopic composition and the triple isotope slopes between the laboratory and the stratosphere and between different regions of the stratosphere. This understanding in turn provides a firmer foundation for the diverse biogeochemical and paleoclimate applications of (17)O anomalies in tropospheric CO2, O2, mineral sulfates, and fossil bones and teeth, which all derive from stratospheric CO2. PMID- 23940332 TI - The allosteric communication pathways in KIX domain of CBP. AB - Allosteric regulation plays an important role in a myriad of biomacromolecular processes. Specifically, in a protein, the process of allostery refers to the transmission of a local perturbation, such as ligand binding, to a distant site. Decades after the discovery of this phenomenon, models built on static images of proteins are being reconsidered with the knowledge that protein dynamics plays an important role in its function. Molecular dynamics simulations are a valuable tool for studying complex biomolecular systems, providing an atomistic description of their structure and dynamics. Unfortunately, their predictive power has been limited by the complexity of the biomolecule free-energy surface and by the length of the allosteric timescale (in the order of milliseconds). In this work, we are able to probe the origins of the allosteric changes that transcription factor mixed lineage leukemia (MLL) causes to the interactions of KIX domain of CREB-binding protein (CBP) with phosphorylated kinase inducible domain (pKID), by combing all-atom molecular dynamics with enhanced sampling methods recently developed in our group. We discuss our results in relation to previous NMR studies. We also develop a general simulations protocol to study allosteric phenomena and many other biological processes that occur in the micro/milliseconds timescale. PMID- 23940333 TI - Neandertals made the first specialized bone tools in Europe. AB - Modern humans replaced Neandertals ~40,000 y ago. Close to the time of replacement, Neandertals show behaviors similar to those of the modern humans arriving into Europe, including the use of specialized bone tools, body ornaments, and small blades. It is highly debated whether these modern behaviors developed before or as a result of contact with modern humans. Here we report the identification of a type of specialized bone tool, lissoir, previously only associated with modern humans. The microwear preserved on one of these lissoir is consistent with the use of lissoir in modern times to obtain supple, lustrous, and more impermeable hides. These tools are from a Neandertal context proceeding the replacement period and are the oldest specialized bone tools in Europe. As such, they are either a demonstration of independent invention by Neandertals or an indication that modern humans started influencing European Neandertals much earlier than previously believed. Because these finds clearly predate the oldest known age for the use of similar objects in Europe by anatomically modern humans, they could also be evidence for cultural diffusion from Neandertals to modern humans. PMID- 23940334 TI - AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons. AB - NMDA receptor activation promotes endocytosis of AMPA receptors, which is an important mechanism underlying long-term synaptic depression. The pH-sensitive GFP variant pHluorin fused to the N terminus of GluA2 (pH-GluA2) has been used to assay NMDA-mediated AMPA receptor endocytosis and recycling. Here, we demonstrate that in somatic and dendritic regions of hippocampal neurons a large fraction of the fluorescent signal originates from intracellular pH-GluA2, and that the decline in fluorescence in response to NMDA and AMPA primarily describes an intracellular acidification, which quenches the pHluorin signal from intracellular receptor pools. Neurons expressing an endoplasmic reticulum retained mutant of GluA2 (pH-GluA2 DeltaC49) displayed a larger response to NMDA than neurons expressing wild-type pH-GluA2. A similar NMDA-elicited decline in pHluorin signal was observed by expressing cytosolic pHluorin alone without fusion to GluA2 (cyto-pHluorin). Intracellular acidification in response to NMDA was further confirmed by using the ratiometric pH indicator carboxy-SNARF-1. The NMDA-induced decline was followed by rapid recovery of the fluorescent signal from both cyto-pHluorin and pH-GluA2. The recovery was sodium-dependent and sensitive to Na(+)/H(+)-exchanger (NHE) inhibitors. Moreover, recovery was more rapid after shRNA-mediated knockdown of the GluA2 binding PDZ domain-containing protein interacting with C kinase 1 (PICK1). Interestingly, the accelerating effect of PICK1 knockdown on the fluorescence recovery was eliminated in the presence of the NHE1 inhibitor zoniporide. Our results indicate that the pH-GluA2 recycling assay is an unreliable assay for studying AMPA receptor trafficking and also suggest a role for PICK1 in regulating intracellular pH via modulation of NHE activity. PMID- 23940336 TI - Communicating science in politicized environments. AB - Many members of the scientific community attempt to convey information to policymakers and the public. Much of this information is ignored or misinterpreted. This article describes why these outcomes occur and how science communicators can achieve better outcomes. The article focuses on two challenges associated with communicating scientific information to such audiences. One challenge is that people have less capacity to pay attention to scientific presentations than many communicators anticipate. A second challenge is that people in politicized environments often make different choices about whom to believe than do people in other settings. Together, these challenges cause policymakers and the public to be less responsive to scientific information than many communicators desire. Research on attention and source credibility can help science communicators better adapt to these challenges. Attention research clarifies when, and to what type of stimuli, people do (and do not) pay attention. Source credibility research clarifies the conditions under which an audience will believe scientists' descriptions of phenomena rather than the descriptions of less-valid sources. Such research can help communicators stay true to their science while making their findings more memorable and more believable to more audiences. PMID- 23940335 TI - Reconciling migration models to the Americas with the variation of North American native mitogenomes. AB - In this study we evaluated migration models to the Americas by using the information contained in native mitochondrial genomes (mitogenomes) from North America. Molecular and phylogeographic analyses of B2a mitogenomes, which are absent in Eskimo-Aleut and northern Na-Dene speakers, revealed that this haplogroup arose in North America ~11-13 ka from one of the founder Paleo-Indian B2 mitogenomes. In contrast, haplogroup A2a, which is typical of Eskimo-Aleuts and Na-Dene, but also present in the easternmost Siberian groups, originated only 4-7 ka in Alaska, led to the first Paleo-Eskimo settlement of northern Canada and Greenland, and contributed to the formation of the Na-Dene gene pool. However, mitogenomes also show that Amerindians from northern North America, without any distinction between Na-Dene and non-Na-Dene, were heavily affected by an additional and distinctive Beringian genetic input. In conclusion, most mtDNA variation (along the double-continent) stems from the first wave from Beringia, which followed the Pacific coastal route. This was accompanied or followed by a second inland migratory event, marked by haplogroups X2a and C4c, which affected all Amerindian groups of Northern North America. Much later, the ancestral A2a carriers spread from Alaska, undertaking both a westward migration to Asia and an eastward expansion into the circumpolar regions of Canada. Thus, the first American founders left the greatest genetic mark but the original maternal makeup of North American Natives was subsequently reshaped by additional streams of gene flow and local population dynamics, making a three-wave view too simplistic. PMID- 23940337 TI - Enhanced basal lubrication and the contribution of the Greenland ice sheet to future sea-level rise. AB - We assess the effect of enhanced basal sliding on the flow and mass budget of the Greenland ice sheet, using a newly developed parameterization of the relation between meltwater runoff and ice flow. A wide range of observations suggest that water generated by melt at the surface of the ice sheet reaches its bed by both fracture and drainage through moulins. Once at the bed, this water is likely to affect lubrication, although current observations are insufficient to determine whether changes in subglacial hydraulics will limit the potential for the speedup of flow. An uncertainty analysis based on our best-fit parameterization admits both possibilities: continuously increasing or bounded lubrication. We apply the parameterization to four higher-order ice-sheet models in a series of experiments forced by changes in both lubrication and surface mass budget and determine the additional mass loss brought about by lubrication in comparison with experiments forced only by changes in surface mass balance. We use forcing from a regional climate model, itself forced by output from the European Centre Hamburg Model (ECHAM5) global climate model run under scenario A1B. Although changes in lubrication generate widespread effects on the flow and form of the ice sheet, they do not affect substantial net mass loss; increase in the ice sheet's contribution to sea-level rise from basal lubrication is projected by all models to be no more than 5% of the contribution from surface mass budget forcing alone. PMID- 23940338 TI - What do we mean? On the importance of not abandoning scientific rigor when talking about science education. AB - Although the "science of science communication" usually refers to the flow of scientific knowledge from scientists to the public, scientists direct most of their communications not to the public, but instead to other scientists in their field. This paper presents a case study on this understudied type of communication: within a discipline, among its practitioners. I argue that many of the contentious disagreements that exist today in the field in which I conduct my research--early science education--derive from a lack of operational definitions, such that when competing claims are made for the efficacy of one type of science instruction vs. another, the arguments are hopelessly disjointed. The aim of the paper is not to resolve the current claims and counterclaims about the most effective pedagogies in science education, but rather to note that the assessment of one approach vs. the other is all too often defended on the basis of strongly held beliefs, rather than on the results of replicable experiments, designed around operational definitions of the teaching methods being investigated. A detailed example of operational definitions from my own research on elementary school science instruction is provided. In addition, the paper addresses the issue of how casual use of labels-both within the discipline and when communicating with the public-may inadvertently "undo" the benefits of operational definitions. PMID- 23940339 TI - Soil food web properties explain ecosystem services across European land use systems. AB - Intensive land use reduces the diversity and abundance of many soil biota, with consequences for the processes that they govern and the ecosystem services that these processes underpin. Relationships between soil biota and ecosystem processes have mostly been found in laboratory experiments and rarely are found in the field. Here, we quantified, across four countries of contrasting climatic and soil conditions in Europe, how differences in soil food web composition resulting from land use systems (intensive wheat rotation, extensive rotation, and permanent grassland) influence the functioning of soils and the ecosystem services that they deliver. Intensive wheat rotation consistently reduced the biomass of all components of the soil food web across all countries. Soil food web properties strongly and consistently predicted processes of C and N cycling across land use systems and geographic locations, and they were a better predictor of these processes than land use. Processes of carbon loss increased with soil food web properties that correlated with soil C content, such as earthworm biomass and fungal/bacterial energy channel ratio, and were greatest in permanent grassland. In contrast, processes of N cycling were explained by soil food web properties independent of land use, such as arbuscular mycorrhizal fungi and bacterial channel biomass. Our quantification of the contribution of soil organisms to processes of C and N cycling across land use systems and geographic locations shows that soil biota need to be included in C and N cycling models and highlights the need to map and conserve soil biodiversity across the world. PMID- 23940341 TI - Communicating science in social settings. AB - This essay examines the societal dynamics surrounding modern science. It first discusses a number of challenges facing any effort to communicate science in social environments: lay publics with varying levels of preparedness for fully understanding new scientific breakthroughs; the deterioration of traditional media infrastructures; and an increasingly complex set of emerging technologies that are surrounded by a host of ethical, legal, and social considerations. Based on this overview, I discuss four areas in which empirical social science helps clarify intuitive but sometimes faulty assumptions about the social-level mechanisms of science communication and outline an agenda for bench and social scientists--driven by current social-scientific research in the field of science communication--to guide more effective communication efforts at the societal level in the future. PMID- 23940340 TI - Surge of neurophysiological coherence and connectivity in the dying brain. AB - The brain is assumed to be hypoactive during cardiac arrest. However, the neurophysiological state of the brain immediately following cardiac arrest has not been systematically investigated. In this study, we performed continuous electroencephalography in rats undergoing experimental cardiac arrest and analyzed changes in power density, coherence, directed connectivity, and cross frequency coupling. We identified a transient surge of synchronous gamma oscillations that occurred within the first 30 s after cardiac arrest and preceded isoelectric electroencephalogram. Gamma oscillations during cardiac arrest were global and highly coherent; moreover, this frequency band exhibited a striking increase in anterior-posterior-directed connectivity and tight phase coupling to both theta and alpha waves. High-frequency neurophysiological activity in the near-death state exceeded levels found during the conscious waking state. These data demonstrate that the mammalian brain can, albeit paradoxically, generate neural correlates of heightened conscious processing at near-death. PMID- 23940342 TI - Core foundations of abstract geometry. AB - Human adults from diverse cultures share intuitions about the points, lines, and figures of Euclidean geometry. Do children develop these intuitions by drawing on phylogenetically ancient and developmentally precocious geometric representations that guide their navigation and their analysis of object shape? In what way might these early-arising representations support later-developing Euclidean intuitions? To approach these questions, we investigated the relations among young children's use of geometry in tasks assessing: navigation; visual form analysis; and the interpretation of symbolic, purely geometric maps. Children's navigation depended on the distance and directional relations of the surface layout and predicted their use of a symbolic map with targets designated by surface distances. In contrast, children's analysis of visual forms depended on the size-invariant shape relations of objects and predicted their use of the same map but with targets designated by corner angles. Even though the two map tasks used identical instructions and map displays, children's performance on these tasks showed no evidence of integrated representations of distance and angle. Instead, young children flexibly recruited geometric representations of either navigable layouts or objects to interpret the same spatial symbols. These findings reveal a link between the early-arising geometric representations that humans share with diverse animals and the flexible geometric intuitions that give rise to human knowledge at its highest reaches. Although young children do not appear to integrate core geometric representations, children's use of the abstract geometry in spatial symbols such as maps may provide the earliest clues to the later construction of Euclidean geometry. PMID- 23940343 TI - Direct atomic structure determination by the inspection of structural phase. AB - A century has passed since Bragg solved the first atomic structure using diffraction. As with this first structure, all atomic structures to date have been deduced from the measurement of many diffracted intensities using iterative and statistical methods. We show that centrosymmetric atomic structures can be determined without the need to measure or even record a diffracted intensity. Instead, atomic structures can be determined directly and quickly from the observation of crystallographic phases in electron diffraction patterns. Furthermore, only a few phases are required to achieve high resolution. This represents a paradigm shift in structure determination methods, which we demonstrate with the moderately complex alpha-Al2O3. We show that the observation of just nine phases enables the location of all atoms with a resolution of better than 0.1 A. This level of certainty previously required the measurement of thousands of diffracted intensities. PMID- 23940344 TI - Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation. AB - Deletion of lyn, a Src-family tyrosine kinase expressed by B, myeloid, and dendritic cells (DCs), triggers lupus-like disease in mice, characterized by autoantibody production and renal immune complex deposition leading to chronic glomerulonephritis. B cells from these mice are hyperactive to antigen-receptor stimulation owing to a loss of inhibitory signaling mediated by Lyn kinase. The hyperactive B-cell responses are thought to underlie the development of autoimmunity in this model. Lyn-deficient mice also manifest significant myeloexpansion. To test the contribution of different immune cell types to the lupus-like disease in this model, we generated a lyn(flox/flox) transgenic mouse strain. To our surprise, when we crossed these mice to Cd11c-cre animals, generating DC-specific deletion of Lyn, the animals developed spontaneous B- and T-cell activation and subsequent production of autoantibodies and severe nephritis. Remarkably, the DC-specific Lyn-deficient mice also developed severe tissue inflammatory disease, which was not present in the global lyn(-/-) strain. Lyn-deficient DCs were hyperactivated and hyperresponsive to Toll-like receptor agonists and IL-1beta. To test whether dysregulation of these signaling pathways in DCs contributed to the inflammatory/autoimmune phenotype, we crossed the lyn(f/f) Cd11c-cre(+) mice to myd88(f/f) animals, generating double-mutant mice lacking both Lyn and the adaptor protein myeloid differentiation factor 88 (MyD88) in DCs, specifically. Deletion of MyD88 in DCs alone completely reversed the inflammatory autoimmunity in the DC-specific Lyn-mutant mice. Thus, we demonstrate that hyperactivation of MyD88-dependent signaling in DCs is sufficient to drive pathogenesis of lupus-like disease, illuminating the fact that dysregulation in innate immune cells alone can lead to autoimmunity. PMID- 23940345 TI - Neutral and weakly nonneutral sequence variants may define individuality. AB - Large-scale computational analyses of the growing wealth of genome-variation data consistently tell two distinct stories. The first is expected: coding variants reported in disease-related databases significantly alter the function of affected proteins. The second is surprising: the genomes of healthy individuals appear to carry many variants that are predicted to have some effect on function. As long as the complete experimental analysis of all human genome variants remains impossible, computational methods, such as PolyPhen, SNAP, and SIFT, might provide important insights. These methods capture the effects of particular variants very well and can highlight trends in populations of variants. Diseases are, arguably, extreme phenotypic variations and are often attributable to one or a few severely functionally disruptive variants. Our findings suggest a genomic basis of the different nondisease phenotypes. Prediction methods indicate that variants in seemingly healthy individuals tend to be neutral or weakly disruptive for protein molecular function. These variant effects are predicted to be largely either experimentally undetectable or are not deemed significant enough to be published. This may suggest that nondisease phenotypes arise through combinations of many variants whose effects are weakly nonneutral (damaging or enhancing) to the molecular protein function but fall within the wild-type range of overall physiological function. PMID- 23940346 TI - Rapid structural change in synaptosomal-associated protein 25 (SNAP25) precedes the fusion of single vesicles with the plasma membrane in live chromaffin cells. AB - The SNARE complex consists of the three proteins synaptobrevin-2, syntaxin, and synaptosomal-associated protein 25 (SNAP25) and is thought to execute a large conformational change as it drives membrane fusion and exocytosis. The relation between changes in the SNARE complex and fusion pore opening is, however, still unknown. We report here a direct measurement relating a change in the SNARE complex to vesicle fusion on the millisecond time scale. In individual chromaffin cells, we tracked conformational changes in SNAP25 by total internal reflection fluorescence resonance energy transfer (FRET) microscopy while exocytotic catecholamine release from single vesicles was simultaneously recorded using a microfabricated electrochemical detector array. A local rapid and transient FRET change occurred precisely where individual vesicles released catecholamine. To overcome the low time resolution of the imaging frames needed to collect sufficient signal intensity, a method named event correlation microscopy was developed, which revealed that the FRET change was abrupt and preceded the opening of an exocytotic fusion pore by ~90 ms. The FRET change correlated temporally with the opening of the fusion pore and not with its dilation. PMID- 23940347 TI - Live-cell imaging of Marburg virus-infected cells uncovers actin-dependent transport of nucleocapsids over long distances. AB - Transport of large viral nucleocapsids from replication centers to assembly sites requires contributions from the host cytoskeleton via cellular adaptor and motor proteins. For the Marburg and Ebola viruses, related viruses that cause severe hemorrhagic fevers, the mechanism of nucleocapsid transport remains poorly understood. Here we developed and used live-cell imaging of fluorescently labeled viral and host proteins to characterize the dynamics and molecular requirements of nucleocapsid transport in Marburg virus-infected cells under biosafety level 4 conditions. The study showed a complex actin-based transport of nucleocapsids over long distances from the viral replication centers to the budding sites. Only after the nucleocapsids had associated with the matrix viral protein VP40 at the plasma membrane were they recruited into filopodia and cotransported with host motor myosin 10 toward the budding sites at the tip or side of the long cellular protrusions. Three different transport modes and velocities were identified: (i) Along actin filaments in the cytosol, nucleocapsids were transported at ~200 nm/s; (ii) nucleocapsids migrated from one actin filament to another at ~400 nm/s; and (iii) VP40-associated nucleocapsids moved inside filopodia at 100 nm/s. Unique insights into the spatiotemporal dynamics of nucleocapsids and their interaction with the cytoskeleton and motor proteins can lead to novel classes of antivirals that interfere with the trafficking and subsequent release of the Marburg virus from infected cells. PMID- 23940348 TI - CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. AB - A characteristic of memory T (TM) cells is their ability to mount faster and stronger responses to reinfection than naive T (TN) cells do in response to an initial infection. However, the mechanisms that allow this rapid recall are not completely understood. We found that CD8 TM cells have more mitochondrial mass than CD8 TN cells and, that upon activation, the resulting secondary effector T (TE) cells proliferate more quickly, produce more cytokines, and maintain greater ATP levels than primary effector T cells. We also found that after activation, TM cells increase oxidative phosphorylation and aerobic glycolysis and sustain this increase to a greater extent than TN cells, suggesting that greater mitochondrial mass in TM cells not only promotes oxidative capacity, but also glycolytic capacity. We show that mitochondrial ATP is essential for the rapid induction of glycolysis in response to activation and the initiation of proliferation of both TN and TM cells. We also found that fatty acid oxidation is needed for TM cells to rapidly respond upon restimulation. Finally, we show that dissociation of the glycolysis enzyme hexokinase from mitochondria impairs proliferation and blocks the rapid induction of glycolysis upon T-cell receptor stimulation in TM cells. Our results demonstrate that greater mitochondrial mass endows TM cells with a bioenergetic advantage that underlies their ability to rapidly recall in response to reinfection. PMID- 23940350 TI - Bringing values and deliberation to science communication. AB - Decisions always involve both facts and values, whereas most science communication focuses only on facts. If science communication is intended to inform decisions, it must be competent with regard to both facts and values. Public participation inevitably involves both facts and values. Research on public participation suggests that linking scientific analysis to public deliberation in an iterative process can help decision making deal effectively with both facts and values. Thus, linked analysis and deliberation can be an effective tool for science communication. However, challenges remain in conducting such process at the national and global scales, in enhancing trust, and in reconciling diverse values. PMID- 23940349 TI - Immunomodulatory effect of a decellularized skeletal muscle scaffold in a discordant xenotransplantation model. AB - Decellularized (acellular) scaffolds, composed of natural extracellular matrix, form the basis of an emerging generation of tissue-engineered organ and tissue replacements capable of transforming healthcare. Prime requirements for allogeneic, or xenogeneic, decellularized scaffolds are biocompatibility and absence of rejection. The humoral immune response to decellularized scaffolds has been well documented, but there is a lack of data on the cell-mediated immune response toward them in vitro and in vivo. Skeletal muscle scaffolds were decellularized, characterized in vitro, and xenotransplanted. The cellular immune response toward scaffolds was evaluated by immunohistochemistry and quantified stereologically. T-cell proliferation and cytokines, as assessed by flow cytometry using carboxy-fluorescein diacetate succinimidyl ester dye and cytometric bead array, formed an in vitro surrogate marker and correlate of the in vivo host immune response toward the scaffold. Decellularized scaffolds were free of major histocompatibility complex class I and II antigens and were found to exert anti-inflammatory and immunosuppressive effects, as evidenced by delayed biodegradation time in vivo; reduced sensitized T-cell proliferative activity in vitro; reduced IL-2, IFN-gamma, and raised IL-10 levels in cell-culture supernatants; polarization of the macrophage response in vivo toward an M2 phenotype; and improved survival of donor-derived xenogeneic cells at 2 and 4 wk in vivo. Decellularized scaffolds polarize host responses away from a classical TH1-proinflammatory profile and appear to down-regulate T-cell xeno responses and TH1 effector function by inducing a state of peripheral T-cell hyporesponsiveness. These results have substantial implications for the future clinical application of tissue-engineered therapies. PMID- 23940352 TI - Cavity cooling of an optically levitated submicron particle. AB - The coupling of a levitated submicron particle and an optical cavity field promises access to a unique parameter regime both for macroscopic quantum experiments and for high-precision force sensing. We report a demonstration of such controlled interactions by cavity cooling the center-of-mass motion of an optically trapped submicron particle. This paves the way for a light-matter interface that can enable room-temperature quantum experiments with mesoscopic mechanical systems. PMID- 23940351 TI - High-resolution crystal structure reveals molecular details of target recognition by bacitracin. AB - Bacitracin is a metalloantibiotic agent that is widely used as a medicine and feed additive. It interferes with bacterial cell-wall biosynthesis by binding undecaprenyl-pyrophosphate, a lipid carrier that serves as a critical intermediate in cell wall production. Despite bacitracin's broad use, the molecular details of its target recognition have not been elucidated. Here we report a crystal structure for the ternary complex of bacitracin A, zinc, and a geranyl-pyrophosphate ligand at a resolution of 1.1 A. The antibiotic forms a compact structure that completely envelopes the ligand's pyrophosphate group, together with flanking zinc and sodium ions. The complex adopts a highly amphipathic conformation that offers clues to antibiotic function in the context of bacterial membranes. Bacitracin's efficient sequestration of its target represents a previously unseen mode for the recognition of lipid pyrophosphates, and suggests new directions for the design of next-generation antimicrobial agents. PMID- 23940354 TI - Differential mobilization of terrestrial carbon pools in Eurasian Arctic river basins. AB - Mobilization of Arctic permafrost carbon is expected to increase with warming induced thawing. However, this effect is challenging to assess due to the diverse processes controlling the release of various organic carbon (OC) pools from heterogeneous Arctic landscapes. Here, by radiocarbon dating various terrestrial OC components in fluvially and coastally integrated estuarine sediments, we present a unique framework for deconvoluting the contrasting mobilization mechanisms of surface vs. deep (permafrost) carbon pools across the climosequence of the Eurasian Arctic. Vascular plant-derived lignin phenol (14)C contents reveal significant inputs of young carbon from surface sources whose delivery is dominantly controlled by river runoff. In contrast, plant wax lipids predominantly trace ancient (permafrost) OC that is preferentially mobilized from discontinuous permafrost regions, where hydrological conduits penetrate deeper into soils and thermokarst erosion occurs more frequently. Because river runoff has significantly increased across the Eurasian Arctic in recent decades, we estimate from an isotopic mixing model that, in tandem with an increased transfer of young surface carbon, the proportion of mobilized terrestrial OC accounted for by ancient carbon has increased by 3-6% between 1985 and 2004. These findings suggest that although partly masked by surface carbon export, climate change induced mobilization of old permafrost carbon is well underway in the Arctic. PMID- 23940353 TI - Structural basis for membrane recruitment and allosteric activation of cytohesin family Arf GTPase exchange factors. AB - Membrane recruitment of cytohesin family Arf guanine nucleotide exchange factors depends on interactions with phosphoinositides and active Arf GTPases that, in turn, relieve autoinhibition of the catalytic Sec7 domain through an unknown structural mechanism. Here, we show that Arf6-GTP relieves autoinhibition by binding to an allosteric site that includes the autoinhibitory elements in addition to the PH domain. The crystal structure of a cytohesin-3 construct encompassing the allosteric site in complex with the head group of phosphatidyl inositol 3,4,5-trisphosphate and N-terminally truncated Arf6-GTP reveals a large conformational rearrangement, whereby autoinhibition can be relieved by competitive sequestration of the autoinhibitory elements in grooves at the Arf6/PH domain interface. Disposition of the known membrane targeting determinants on a common surface is compatible with multivalent membrane docking and subsequent activation of Arf substrates, suggesting a plausible model through which membrane recruitment and allosteric activation could be structurally integrated. PMID- 23940355 TI - RasGRF2 Rac-GEF activity couples NMDA receptor calcium flux to enhanced synaptic transmission. AB - Dendritic spines are the primary sites of excitatory synaptic transmission in the vertebrate brain, and the morphology of these actin-rich structures correlates with synaptic function. Here we demonstrate a unique method for inducing spine enlargement and synaptic potentiation in dispersed hippocampal neurons, and use this technique to identify a coordinator of these processes; Ras-specific guanine nucleotide releasing factor 2 (RasGRF2). RasGRF2 is a dual Ras/Rac guanine nucleotide exchange factor (GEF) that is known to be necessary for long-term potentiation in situ. Contrary to the prevailing assumption, we find RasGRF2's Rac-GEF activity to be essential for synaptic potentiation by using a molecular replacement strategy designed to dissociate Rac- from Ras-GEF activities. Furthermore, we demonstrate that Rac1 activity itself is sufficient to rapidly modulate postsynaptic strength by using a photoactivatable derivative of this small GTPase. Because Rac1 is a major actin regulator, our results support a model where the initial phase of long-term potentiation is driven by the cytoskeleton. PMID- 23940357 TI - Near-term climate mitigation by short-lived forcers. AB - Emissions reductions focused on anthropogenic climate-forcing agents with relatively short atmospheric lifetimes, such as methane (CH4) and black carbon, have been suggested as a strategy to reduce the rate of climate change over the next several decades. We find that reductions of methane and black carbon would likely have only a modest impact on near-term global climate warming. Even with maximally feasible reductions phased in from 2015 to 2035, global mean temperatures in 2050 would be reduced by 0.16 degrees C, with a range of 0.04 0.35 degrees C because of uncertainties in carbonaceous aerosol emissions and aerosol forcing per unit of emissions. The high end of this range is only possible if total historical aerosol forcing is relatively small. More realistic emission reductions would likely provide an even smaller climate benefit. We find that the climate benefit from reductions in short-lived forcing agents are smaller than previously estimated. These near-term climate benefits of targeted reductions in short-lived forcers are not substantially different in magnitude from the benefits from a comprehensive climate policy. PMID- 23940356 TI - Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. AB - Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2(+)), PIK3CA(H1047R)-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in the mammary epithelium developed tumors with shorter latencies compared with mice expressing either oncogene alone. HER2 and mutant PIK3CA also cooperated to promote lung metastases. By microarray analysis, HER2-driven tumors clustered with luminal breast cancers, whereas mutant PIK3CA tumors were associated with claudin-low breast cancers. PIK3CA and HER2(+)/PIK3CA tumors expressed elevated transcripts encoding markers of epithelial-to-mesenchymal transition and stem cells. Cells from HER2(+)/PIK3CA tumors more efficiently formed mammospheres and lung metastases. Finally, HER2(+)/PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. Both drug resistance and enhanced mammosphere formation were reversed by treatment with a PI3K inhibitor. In sum, PIK3CA(H1047R) accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies. PMID- 23940358 TI - Attenuation of the posttranslational oscillator via transcription-translation feedback enhances circadian-phase shifts in Synechococcus. AB - Circadian rhythms are endogenous biological timing processes that are ubiquitous in organisms ranging from cyanobacteria to humans. In the photoautotrophic unicellular cyanobacterium Synechococcus elongatus PCC 7942, under continuous light (LL) conditions, the transcription-translation feedback loop (TTFL) of KaiC generates a rhythmic change in the accumulation of KaiC relative to KaiA clock proteins (KaiC/KaiA ratio), which peak and trough at subjective dawn and dusk, respectively. However, the role of TTFL in the cyanobacterial circadian system remains unclear because it is not an essential requirement for the basic oscillation driven by the Kai-based posttranslational oscillator (PTO) and the transcriptional output mechanisms. Here, we show that TTFL is important for the circadian photic resetting property in Synechococcus. The robustness of PTO, which is exemplified by the amplitude of the KaiC phosphorylation cycle, changed depending on the KaiC/KaiA ratio, which was cyclic under LL. After cells were transferred from LL to the dark, the clock protein levels remained constant in the dark. When cells were transferred from LL to continuous dark at subjective dawn, the KaiC phosphorylation cycle was attenuated with a lower KaiC/KaiA ratio, a higher KaiC phosphorylation level, and a lower amplitude than that in cells transferred at subjective dusk. We also found that the greater the degree to which PTO was attenuated in continuous dark, the greater the phase shifts upon the subsequent light exposure. Based on these results, we propose that TTFL enhances resetting of the Kai-based PTO in Synechococcus. PMID- 23940359 TI - Transient, afferent input-dependent, postnatal niche for neural progenitor cells in the cochlear nucleus. AB - In the cochlear nucleus (CN), the first central relay of the auditory pathway, the survival of neurons during the first weeks after birth depends on afferent innervation from the cochlea. Although input-dependent neuron survival has been extensively studied in the CN, neurogenesis has not been evaluated as a possible mechanism of postnatal plasticity. Here we show that new neurons are born in the CN during the critical period of postnatal plasticity. Coincidently, we found a population of neural progenitor cells that are controlled by a complex interplay of Wnt, Notch, and TGFbeta/BMP signaling, in which low levels of TGFbeta/BMP signaling are permissive for progenitor proliferation that is promoted by Wnt and Notch activation. We further show that cells with activated Wnt signaling reside in the CN and that these cells have high propensity for neurosphere formation. Cochlear ablation resulted in diminishment of progenitors and Wnt/beta-catenin active cells, suggesting that the neonatal CN maintains an afferent innervation dependent population of progenitor cells that display active canonical Wnt signaling. PMID- 23940360 TI - Efficient genome engineering in human pluripotent stem cells using Cas9 from Neisseria meningitidis. AB - Genome engineering in human pluripotent stem cells (hPSCs) holds great promise for biomedical research and regenerative medicine. Recently, an RNA-guided, DNA cleaving interference pathway from bacteria [the type II clustered, regularly interspaced, short palindromic repeats (CRISPR)-CRISPR-associated (Cas) pathway] has been adapted for use in eukaryotic cells, greatly facilitating genome editing. Only two CRISPR-Cas systems (from Streptococcus pyogenes and Streptococcus thermophilus), each with their own distinct targeting requirements and limitations, have been developed for genome editing thus far. Furthermore, limited information exists about homology-directed repair (HDR)-mediated gene targeting using long donor DNA templates in hPSCs with these systems. Here, using a distinct CRISPR-Cas system from Neisseria meningitidis, we demonstrate efficient targeting of an endogenous gene in three hPSC lines using HDR. The Cas9 RNA-guided endonuclease from N. meningitidis (NmCas9) recognizes a 5'-NNNNGATT-3' protospacer adjacent motif (PAM) different from those recognized by Cas9 proteins from S. pyogenes and S. thermophilus (SpCas9 and StCas9, respectively). Similar to SpCas9, NmCas9 is able to use a single-guide RNA (sgRNA) to direct its activity. Because of its distinct protospacer adjacent motif, the N. meningitidis CRISPR-Cas machinery increases the sequence contexts amenable to RNA-directed genome editing. PMID- 23940361 TI - An alternative polyadenylation mechanism coopted to the Arabidopsis RPP7 gene through intronic retrotransposon domestication. AB - Transposable elements (TEs) can drive evolution by creating genetic and epigenetic variation. Although examples of adaptive TE insertions are accumulating, proof that epigenetic information carried by such "domesticated" TEs has been coopted to control host gene function is still limited. We show that COPIA-R7, a TE inserted into the Arabidopsis thaliana disease resistance gene RPP7 recruited the histone mark H3K9me2 to this locus. H3K9me2 levels at COPIA-R7 affect the choice between two alternative RPP7 polyadenylation sites in the pre mRNA and, thereby, influence the critical balance between RPP7-coding and non RPP7-coding transcript isoforms. Function of RPP7 is fully dependent on high levels of H3K9me2 at COPIA-R7. We present a direct in vivo demonstration for cooption of a TE-associated histone mark to the epigenetic control of pre-mRNA processing and establish a unique mechanism for regulation of plant immune surveillance gene expression. Our results functionally link a histone mark to alternative polyadenylation and the balance between distinct transcript isoforms from a single gene. PMID- 23940362 TI - Process of inducing pores in membranes by melittin. AB - Melittin is a prototype of the ubiquitous antimicrobial peptides that induce pores in membranes. It is commonly used as a molecular device for membrane permeabilization. Even at concentrations in the nanomolar range, melittin can induce transient pores that allow transmembrane conduction of atomic ions but not leakage of glucose or larger molecules. At micromolar concentrations, melittin induces stable pores allowing transmembrane leakage of molecules up to tens of kilodaltons, corresponding to its antimicrobial activities. Despite extensive studies, aspects of the molecular mechanism for pore formation remain unclear. To clarify the mechanism, one must know the states of the melittin-bound membrane before and after the process. By correlating experiments using giant unilamellar vesicles with those of peptide-lipid multilayers, we found that melittin bound on the vesicle translocated and redistributed to both sides of the membrane before the formation of stable pores. Furthermore, stable pores are formed only above a critical peptide-to-lipid ratio. The initial states for transient and stable pores are different, which implies different mechanisms at low and high peptide concentrations. To determine the lipidic structure of the pore, the pores in peptide-lipid multilayers were induced to form a lattice and examined by anomalous X-ray diffraction. The electron density distribution of lipid labels shows that the pore is formed by merging of two interfaces through a hole. The molecular property of melittin is such that it adsorbs strongly to the bilayer interface. Pore formation can be viewed as the bilayer adopting a lipid configuration to accommodate its excessive interfacial area. PMID- 23940363 TI - Tuning a riboswitch response through structural extension of a pseudoknot. AB - Structural and dynamic features of RNA folding landscapes represent critical aspects of RNA function in the cell and are particularly central to riboswitch mediated control of gene expression. Here, using single-molecule fluorescence energy transfer imaging, we explore the folding dynamics of the preQ1 class II riboswitch, an upstream mRNA element that regulates downstream encoded modification enzymes of queuosine biosynthesis. For reasons that are not presently understood, the classical pseudoknot fold of this system harbors an extra stem-loop structure within its 3'-terminal region immediately upstream of the Shine-Dalgarno sequence that contributes to formation of the ligand-bound state. By imaging ligand-dependent preQ1 riboswitch folding from multiple structural perspectives, we reveal that the extra stem-loop strongly influences pseudoknot dynamics in a manner that decreases its propensity to spontaneously fold and increases its responsiveness to ligand binding. We conclude that the extra stem-loop sensitizes this RNA to broaden the dynamic range of the ON/OFF regulatory switch. PMID- 23940364 TI - WNK1-related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron. AB - Large deletions in the first intron of the With No lysine (K) 1 (WNK1) gene are responsible for Familial Hyperkalemic Hypertension (FHHt), a rare form of human hypertension associated with hyperkalemia and hyperchloremic metabolic acidosis. We generated a mouse model of WNK1-associated FHHt to explore the consequences of this intronic deletion. WNK1(+/FHHt) mice display all clinical and biological signs of FHHt. This phenotype results from increased expression of long WNK1 (L WNK1), the ubiquitous kinase isoform of WNK1, in the distal convoluted tubule, which in turn, stimulates the activity of the Na-Cl cotransporter. We also show that the activity of the epithelial sodium channel is not altered in FHHt mice, suggesting that other mechanisms are responsible for the hyperkalemia and acidosis in this model. Finally, we observe a decreased expression of the renal outer medullary potassium channel in the late distal convoluted tubule of WNK1(+/FHHt) mice, which could contribute to the hyperkalemia. In summary, our study provides insights into the in vivo mechanisms underlying the pathogenesis of WNK1-mediated FHHt and further corroborates the importance of WNK1 in ion homeostasis and blood pressure. PMID- 23940365 TI - Knots and nonorientable surfaces in chiral nematics. AB - Knots and knotted fields enrich physical phenomena ranging from DNA and molecular chemistry to the vortices of fluid flows and textures of ordered media. Liquid crystals provide an ideal setting for exploring such topological phenomena through control of their characteristic defects. The use of colloids in generating defects and knotted configurations in liquid crystals has been demonstrated for spherical and toroidal particles and shows promise for the development of novel photonic devices. Extending this existing work, we describe the full topological implications of colloids representing nonorientable surfaces and use it to construct torus knots and links of type (p,2) around multiply twisted Mobius strips. PMID- 23940366 TI - Growth hormone is a cellular senescence target in pituitary and nonpituitary cells. AB - Premature proliferative arrest in benign or early-stage tumors induced by oncoproteins, chromosomal instability, or DNA damage is associated with p53/p21 activation, culminating in either senescence or apoptosis, depending on cell context. Growth hormone (GH) elicits direct peripheral metabolic actions as well as growth effects mediated by insulin-like growth factor 1 (IGF1). Locally produced peripheral tissue GH, in contrast to circulating pituitary-derived endocrine GH, has been proposed to be both proapoptotic and prooncogenic. Pituitary adenomas expressing and secreting GH are invariably benign and exhibit DNA damage and a senescent phenotype. We therefore tested effects of nutlin induced p53-mediated senescence in rat and human pituitary cells. We show that DNA damage senescence induced by nutlin triggers the p53/p21 senescent pathway, with subsequent marked induction of intracellular pituitary GH in vitro. In contrast, GH is not induced in cells devoid of p53. Furthermore we show that p53 binds specific GH promoter motifs and enhances GH transcription and secretion in senescent pituitary adenoma cells and also in nonpituitary (human breast and colon) cells. In vivo, treatment with nutlin results in up-regulation of both p53 and GH in the pituitary gland, as well as increased GH expression in nonpituitary tissues (lung and liver). Intracrine GH acts in pituitary cells as an apoptosis switch for p53-mediated senescence, likely protecting the pituitary adenoma from progression to malignancy. Unlike in the pituitary, in nonpituitary cells GH exerts antiapoptotic properties. Thus, the results show that GH is a direct p53 transcriptional target and fulfills criteria as a p53 target gene. Induced GH is a readily measurable cell marker for p53-mediated cellular senescence. PMID- 23940367 TI - Caspase-dependent regulation of the ubiquitin-proteasome system through direct substrate targeting. AB - Drosophila inhibitor of apoptosis (IAP) 1 (DIAP1) is an E3 ubiquitin ligase that regulates apoptosis in flies, in large part through direct inhibition and/or ubiquitinylation of caspases. IAP antagonists, such as Reaper, Hid, and Grim, are thought to induce cell death by displacing active caspases from baculovirus IAP repeat domains in DIAP1, but can themselves become targets of DIAP1-mediated ubiquitinylation. Herein, we demonstrate that Grim self-associates in cells and is ubiquitinylated by DIAP1 at Lys136 in an UbcD1-dependent manner, resulting in its rapid turnover. K48-linked ubiquitin chains are added almost exclusively to BIR2-bound Grim as a result of its structural proximity to DIAP1's RING domain. However, active caspases can simultaneously cleave Grim at Asp132, removing the lysine necessary for ubiquitinylation as well as any existing ubiquitin conjugates. Cleavage therefore enhances the stability of Grim and initiates a feed-forward caspase amplification loop, resulting in greater cell death. In summary, Grim is a caspase substrate whose cleavage promotes apoptosis by limiting, in a target-specific fashion, its ubiquitinylation and turnover by the proteasome. PMID- 23940368 TI - Oxidation of ethanol in the rat brain and effects associated with chronic ethanol exposure. AB - It has been reported that chronic and acute alcohol exposure decreases cerebral glucose metabolism and increases acetate oxidation. However, it remains unknown how much ethanol the living brain can oxidize directly and whether such a process would be affected by alcohol exposure. The questions have implications for reward, oxidative damage, and long-term adaptation to drinking. One group of adult male Sprague-Dawley rats was treated with ethanol vapor and the other given room air. After 3 wk the rats received i.v. [2-(13)C]ethanol and [1, 2 (13)C2]acetate for 2 h, and then the brain was fixed, removed, and divided into neocortex and subcortical tissues for measurement of (13)C isotopic labeling of glutamate and glutamine by magnetic resonance spectroscopy. Ethanol oxidation was seen to occur both in the cortex and the subcortex. In ethanol-naive rats, cortical oxidation of ethanol occurred at rates of 0.017 +/- 0.002 umol/min/g in astroglia and 0.014 +/- 0.003 umol/min/g in neurons, and chronic alcohol exposure increased the astroglial ethanol oxidation to 0.028 +/- 0.002 umol/min/g (P = 0.001) with an insignificant effect on neuronal ethanol oxidation. Compared with published rates of overall oxidative metabolism in astroglia and neurons, ethanol provided 12.3 +/- 1.4% of cortical astroglial oxidation in ethanol-naive rats and 20.2 +/- 1.5% in ethanol-treated rats. For cortical astroglia and neurons combined, the ethanol oxidation for naive and treated rats was 3.2 +/- 0.3% and 3.8 +/- 0.2% of total oxidation, respectively. (13)C labeling from subcortical oxidation of ethanol was similar to that seen in cortex but was not affected by chronic ethanol exposure. PMID- 23940369 TI - Transcription termination controls prophage maintenance in Escherichia coli genomes. AB - Prophages represent a large fraction of prokaryotic genomes and often provide new functions to their hosts, in particular virulence and fitness. How prokaryotic cells maintain such gene providers is central for understanding bacterial genome evolution by horizontal transfer. Prophage excision occurs through site-specific recombination mediated by a prophage-encoded integrase. In addition, a recombination directionality factor (or excisionase) directs the reaction toward excision and prevents the phage genome from being reintegrated. In this work, we describe the role of the transcription termination factor Rho in prophage maintenance through control of the synthesis of transcripts that mediate recombination directionality factor expression and, thus, excisive recombination. We show that Rho inhibition by bicyclomycin allows for the expression of prophage genes that lead to excisive recombination. Thus, besides its role in the silencing of horizontally acquired genes, Rho also maintains lysogeny of defective and functional prophages. PMID- 23940370 TI - Dirigent domain-containing protein is part of the machinery required for formation of the lignin-based Casparian strip in the root. AB - The endodermis acts as a "second skin" in plant roots by providing the cellular control necessary for the selective entry of water and solutes into the vascular system. To enable such control, Casparian strips span the cell wall of adjacent endodermal cells to form a tight junction that blocks extracellular diffusion across the endodermis. This junction is composed of lignin that is polymerized by oxidative coupling of monolignols through the action of a NADPH oxidase and peroxidases. Casparian strip domain proteins (CASPs) correctly position this biosynthetic machinery by forming a protein scaffold in the plasma membrane at the site where the Casparian strip forms. Here, we show that the dirigent-domain containing protein, enhanced suberin1 (ESB1), is part of this machinery, playing an essential role in the correct formation of Casparian strips. ESB1 is localized to Casparian strips in a CASP-dependent manner, and in the absence of ESB1, disordered and defective Casparian strips are formed. In addition, loss of ESB1 disrupts the localization of the CASP1 protein at the casparian strip domain, suggesting a reciprocal requirement for both ESB1 and CASPs in forming the casparian strip domain. PMID- 23940371 TI - Human NAIP and mouse NAIP1 recognize bacterial type III secretion needle protein for inflammasome activation. AB - Inflammasome mediated by central nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) protein is critical for defense against bacterial infection. Here we show that type III secretion system (T3SS) needle proteins from several bacterial pathogens, including Salmonella typhimurium, enterohemorrhagic Escherichia coli, Shigella flexneri, and Burkholderia spp., can induce robust inflammasome activation in both human monocyte-derived and mouse bone marrow macrophages. Needle protein activation of human NRL family CARD domain containing 4 (NLRC4) inflammasome requires the sole human neuronal apoptosis inhibitory protein (hNAIP). Among the seven mouse NAIPs, NAIP1 functions as the mouse counterpart of hNAIP. We found that NAIP1 recognition of T3SS needle proteins was more robust in mouse dendritic cells than in bone marrow macrophages. Needle proteins, as well as flagellin and rod proteins from five different bacteria, exhibited differential and cell type-dependent inflammasome stimulating activity. Comprehensive profiling of the three types of NAIP ligands revealed that NAIP1 sensing of the needle protein dominated S. flexneri-induced inflammasome activation, particularly in dendritic cells. hNAIP/NAIP1 and NAIP2/5 formed a large oligomeric complex with NLRC4 in the presence of corresponding bacterial ligands, and could support reconstitution of the NLRC4 inflammasome in a ligand-specific manner. PMID- 23940372 TI - Mechanistic patient-specific predictive correlation of tumor drug response with microenvironment and perfusion measurements. AB - Physical properties of the microenvironment influence penetration of drugs into tumors. Here, we develop a mathematical model to predict the outcome of chemotherapy based on the physical laws of diffusion. The most important parameters in the model are the volume fraction occupied by tumor blood vessels and their average diameter. Drug delivery to cells, and kill thereof, are mediated by these microenvironmental properties and affected by the diffusion penetration distance after extravasation. To calculate parameter values we fit the model to histopathology measurements of the fraction of tumor killed after chemotherapy in human patients with colorectal cancer metastatic to liver (coefficient of determination R(2) = 0.94). To validate the model in a different tumor type, we input patient-specific model parameter values from glioblastoma; the model successfully predicts extent of tumor kill after chemotherapy (R(2) = 0.7-0.91). Toward prospective clinical translation, we calculate blood volume fraction parameter values from in vivo contrast-enhanced computed tomography imaging from a separate cohort of patients with colorectal cancer metastatic to liver, and demonstrate accurate model predictions of individual patient responses (average relative error = 15%). Here, patient-specific data from either in vivo imaging or histopathology drives output of the model's formulas. Values obtained from standard clinical diagnostic measurements for each individual are entered into the model, producing accurate predictions of tumor kill after chemotherapy. Clinical translation will enable the rational design of individualized treatment strategies such as amount, frequency, and delivery platform of drug and the need for ancillary non-drug-based treatment. PMID- 23940374 TI - Hemiplegic shoulder pain: a common clinical consequence of stroke. AB - Hemiplegic shoulder pain is common in stroke survivors, developing in up to 54% of patients. The underlying mechanisms include soft tissue lesions, impaired motor function and central nervous system-related phenomena. Hemiplegic shoulder pain has many underlying causes and is challenging to manage, requiring a team approach, including physicians, therapists and caregivers. The management strategy must target the underlying causes. Preventative measures, such as positioning and handling, can reduce the risk of developing hemiplegic shoulder pain. We have reviewed the literature on hemiplegic shoulder pain, and used this to categorise the underlying mechanisms, and to explore the best management strategies. PMID- 23940373 TI - let-7 and miR-140 microRNAs coordinately regulate skeletal development. AB - MicroRNAs (miRNAs) play critical roles in multiple processes of skeletal development. A global reduction of miRNAs in growth plate chondrocytes results in defects in both proliferation and differentiation; however, specific microRNAs responsible for these defects have not been identified. In this study, we provide evidence that let-7 miRNAs and microRNA-140 (miR-140), among other miRNAs expressed in chondrocytes, play major roles in endochondral bone development. We overexpressed lin-28 homolog A (Lin28a) to inhibit let-7 miRNA biogenesis in growth plate chondrocytes. Lin28a overexpression efficiently and specifically reduced let-7 miRNAs and up-regulated let-7 target genes. However, unlike the previous notion that let-7 miRNAs inhibit proliferation and growth, suppression of let-7 miRNAs via Lin28a overexpression decreased proliferation in growth plate chondrocytes, likely through up-regulation of the let-7 target cell cycle regulators cell division cycle 34 (Cdc34) and E2F transcription factor 5 (E2F5). Deficiency of the chondrocyte-specific miRNA, miR-140, causes a differentiation defect in growth plate chondrocytes. Although either Lin28a overexpression or miR 140 deficiency alone caused only mild growth impairment, mice with both miR-140 deficiency and Lin28a overexpression in chondrocytes showed a dramatic growth defect. Deregulation of distinct processes in the absence of these miRNAs synergistically decreased the proliferating chondrocyte mass; miR-140 deficiency reduced differentiation into proliferating chondrocytes, whereas Lin28a overexpression decreased proliferation per se. PMID- 23940375 TI - Home care: more than just a visiting nurse. PMID- 23940376 TI - Modulation of synaptic depression of the calyx of Held synapse by GABA(B) receptors and spontaneous activity. AB - The calyx of Held synapse of the medial nucleus of the trapezoid body is a giant axosomatic synapse in the auditory brainstem, which acts as a relay synapse showing little dependence of its synaptic strength on firing frequency. The main mechanism that is responsible for its resistance to synaptic depression is its large number of release sites with low release probability. Here, we investigated the contribution of presynaptic GABA(B) receptors and spontaneous activity to release probability both in vivo and in vitro in young-adult mice. Maximal activation of presynaptic GABA(B) receptors by baclofen reduced synaptic output by about 45% in whole-cell voltage clamp slice recordings, which was accompanied by a reduction in short-term depression. A similar reduction in transmission was observed when baclofen was applied in vivo by microiontophoresis during juxtacellular recordings using piggyback electrodes. No significant change in synaptic transmission was observed during application of the GABA(B) receptor antagonist CGP54626 both during in vivo and slice recordings, suggesting a low ambient GABA concentration. Interestingly, we observed that synapses with a high spontaneous frequency showed almost no synaptic depression during auditory stimulation, whereas synapses with a low spontaneous frequency did depress during noise bursts. Our data thus suggest that spontaneous firing can tonically reduce release probability in vivo. In addition, our data show that the ambient GABA concentration in the auditory brainstem is too low to activate the GABA(B) receptor at the calyx of Held significantly, but that activation of GABA(B) receptors can reduce sound-evoked synaptic depression. PMID- 23940377 TI - Ba2+- and bupivacaine-sensitive background K+ conductances mediate rapid EPSP attenuation in oligodendrocyte precursor cells. AB - Glutamatergic transmission onto oligodendrocyte precursor cells (OPCs) may regulate OPC proliferation, migration and differentiation. Dendritic integration of excitatory postsynaptic potentials (EPSPs) is critical for neuronal functions, and mechanisms regulating dendritic propagation and summation of EPSPs are well understood. However, little is known about EPSP attenuation and integration in OPCs. We developed realistic OPC models for synaptic integration, based on passive membrane responses of OPCs obtained by simultaneous dual whole-cell patch pipette recordings. Compared with neurons, OPCs have a very low value of membrane resistivity, which is largely mediated by Ba(2+)- and bupivacaine-sensitive background K(+) conductances. The very low membrane resistivity not only leads to rapid EPSP attenuation along OPC processes but also sharpens EPSPs and narrows the temporal window for EPSP summation. Thus, background K(+) conductances regulate synaptic responses and integration in OPCs, thereby affecting activity dependent neuronal control of OPC development and function. PMID- 23940378 TI - Antioxidant treatment improves neonatal survival and prevents impaired cardiac function at adulthood following neonatal glucocorticoid therapy. AB - Glucocorticoids are widely used to treat chronic lung disease in premature infants but their longer-term adverse effects on the cardiovascular system raise concerns. We reported that neonatal dexamethasone treatment in rats induced in the short term molecular indices of cardiac oxidative stress and cardiovascular tissue remodelling at weaning, and that neonatal combined antioxidant and dexamethasone treatment was protective at this time. In this study, we investigated whether such effects of neonatal dexamethasone have adverse consequences for NO bioavailability and cardiovascular function at adulthood, and whether neonatal combined antioxidant and dexamethasone treatment is protective in the adult. Newborn rat pups received daily i.p. injections of a human-relevant tapering dose of dexamethasone (D; n = 8; 0.5, 0.3, 0.1 MUg g(-1)) or D with vitamins C and E (DCE; n = 8; 200 and 100 mg kg(-1), respectively) on postnatal days 1-3 (P1-3); vitamins were continued from P4 to P6. Controls received equal volumes of vehicle from P1 to P6 (C; n = 8). A fourth group received vitamins alone (CCE; n = 8). At P100, plasma NO metabolites (NOx) was measured and isolated hearts were assessed under both Working and Langendorff preparations. Relative to controls, neonatal dexamethasone therapy increased mortality by 18% (P < 0.05). Surviving D pups at adulthood had lower plasma NOx concentrations (10.6 +/- 0.8 vs. 28.0 +/- 1.5 MUM), an increased relative left ventricular (LV) mass (70 +/- 2 vs. 63 +/- 1%), enhanced LV end-diastolic pressure (14 +/- 2 vs. 8 +/- 1 mmHg) and these hearts failed to adapt output with increased preload (cardiac output: 2.9 +/- 2.0 vs. 10.6 +/- 1.2 ml min(-1)) or afterload (cardiac output: -5.3 +/- 2.0 vs.1.4 +/- 1.2 ml min(-1)); all P < 0.05. Combined neonatal dexamethasone with antioxidant vitamins improved postnatal survival, restored plasma NOx and protected against cardiac dysfunction at adulthood. In conclusion, neonatal dexamethasone therapy promotes cardiac dysfunction at adulthood. Combined neonatal treatment with antioxidant vitamins is an effective intervention. PMID- 23940380 TI - Online correction of licking-induced brain motion during two-photon imaging with a tunable lens. AB - Two-photon calcium imaging in awake, head-fixed animals enables the measurement of neuronal activity during behaviour. Often, licking for the retrieval of water reward is used as a measurable report of the animal's decision during reward driven behaviour. However, licking behaviour can induce severe motion artifacts that interfere with two-photon imaging of cellular activity. Here, we describe a simple method for the online correction of licking-induced focus shifts for two photon calcium imaging of neocortical neurons in the head-fixed mouse. We found that licking causes a stereotyped drop of neocortical tissue, shifting neurons up to 20 MUm out of focus. Based on the measurement of licking with a piezo film sensor, we developed a feedback model, which provides a corrective signal for fast optical focus adjustments with an electrically tunable lens. Using online correction with this feedback model, we demonstrate a reduction of licking related focus changes below 3 MUm, minimizing motion artifact contamination of cellular calcium signals. Focus correction with a tunable lens is a simple and effective method to improve the ability to monitor neuronal activity during reward-based behaviour. PMID- 23940381 TI - Segmentation of the mouse fourth deep lumbrical muscle connectome reveals concentric organisation of motor units. AB - Connectomic analysis of the nervous system aims to discover and establish principles that underpin normal and abnormal neural connectivity and function. Here we performed image analysis of motor unit connectivity in the fourth deep lumbrical muscle (4DL) of mice, using transgenic expression of fluorescent protein in motor neurones as a morphological reporter. We developed a method that accelerated segmentation of confocal image projections of 4DL motor units, by applying high resolution (63*, 1.4 NA objective) imaging or deconvolution only where either proved necessary, in order to resolve axon crossings that produced ambiguities in the correct assignment of axon terminals to identified motor units imaged at lower optical resolution (40*, 1.3 NA). The 4DL muscles contained between 4 and 9 motor units and motor unit sizes ranged in distribution from 3 to 111 motor nerve terminals per unit. Several structural properties of the motor units were consistent with those reported in other muscles, including suboptimal wiring length and distribution of motor unit size. Surprisingly, however, small motor units were confined to a region of the muscle near the nerve entry point, whereas their larger counterparts were progressively more widely dispersed, suggesting a previously unrecognised form of segregated motor innervation in this muscle. We also found small but significant differences in variance of motor endplate length in motor units, which correlated weakly with their motor unit size. Thus, our connectomic analysis has revealed a pattern of concentric innervation that may perhaps also exist in other, cylindrical muscles that have not previously been thought to show segregated motor unit organisation. This organisation may be the outcome of competition during postnatal development based on intrinsic neuronal differences in synaptic size or synaptic strength that generates a territorial hierarchy in motor unit size and disposition. PMID- 23940382 TI - Short-term exercise training augments 2-adrenoreceptor-mediated sympathetic vasoconstriction in resting and contracting skeletal muscle. AB - We hypothesized that exercise training (ET) would alter alpha2-adrenoreceptor mediated sympathetic vasoconstriction. Sprague-Dawley rats (n = 30) were randomized to sedentary (S), mild- (M) or heavy-intensity (H) treadmill ET groups (5 days per week for 4 weeks). Following the ET component of the study, rats were anaesthetized, and instrumented for lumbar sympathetic chain stimulation, triceps surae muscle contraction and measurement of femoral vascular conductance (FVC). The percentage change of FVC in response to sympathetic stimulation was determined at rest and during contraction in control, alpha2 blockade (yohimbine) and combined alpha2 + nitric oxide (NO) synthase (NOS) blockade (N-nitro-L arginine methyl ester hydrochloride, L-NAME) conditions. ET augmented (P < 0.05) sympathetic vasoconstrictor responses at rest and during contraction. Yohimbine reduced (P < 0.05) the vasoconstrictor response in ET rats at rest (M: 2 Hz: 8 +/ 2%, 5 Hz: 9 +/- 4%; H: 2 Hz: 14 +/- 5%, 5 Hz: 11 +/- 6%) and during contraction (M: 2 Hz: 9 +/- 2%, 5 Hz: 9 +/- 5%; H: 2 Hz: 8 +/- 3%, 5 Hz: 6 +/- 6%) but did not change the response in S rats. The addition of L-NAME caused a larger increase (P < 0.05) in the vasoconstrictor response in ET than in S rats at rest (2 Hz: S: 8 +/- 2%, M: 15 +/- 3%, H: 23 +/- 7%; 5 Hz: S: 8 +/- 5%, M: 15 +/- 3%, H: 17 +/- 5%) and during contraction (2 Hz: S: 9 +/- 3%, M: 18 +/- 3%, H: 22 +/- 6%; 5 Hz: S: 9 +/- 5%, M: 22 +/- 4%, H:26 +/- 9%). Sympatholysis was greater (P < 0.05) in ET than in S rats. Blockade of alpha2-adrenoreceptors and NOS reduced (P < 0.05) sympatholysis in ET rats, but had no effect on sympatholysis in S rats. In conclusion, ET increased alpha2-mediated vasoconstriction at rest and during contraction. PMID- 23940383 TI - The fast exercise drive to breathe. AB - This paper presents a personal view of research into the exercise drive to breathe that can be observed to act immediately to increase breathing at the start of rhythmic exercise. It is based on a talk given at the Experimental Biology 2013 meeting in a session entitled 'Recent advances in understanding mechanisms regulating breathing during exercise'. This drive to breathe has its origin in a combination of central command, whereby voluntary motor commands to the exercising muscles produce a concurrent respiratory drive, and afferent feedback, whereby afferent information from the exercising muscles affects breathing. The drive at the start and end of rhythmic exercise is proportional to limb movement frequency, and its magnitude decays as exercise continues so that the immediate decrease of ventilation at the end of exercise is about 60% of the immediate increase at the start. With such evidence for the effect of this fast drive to breathe at the start and end of rhythmic exercise, its existence during exercise is hypothesised. Experiments to test this hypothesis have, however, provided debatable evidence. A fast drive to breathe during both ramp and sine wave changes in treadmill exercise speed and grade appears to be present in some individuals, but is not as evident in the general population. Recent sine-wave cycling experiments show that when cadence is varied sinusoidally the ventilation response lags by about 10 s, whereas when pedal loading is varied ventilation lags by about 30 s. It therefore appears that limb movement frequency is effective in influencing ventilation during exercise as well as at the start and end of exercise. PMID- 23940384 TI - Properties of myenteric neurones and mucosal functions in the distal colon of diet-induced obese mice. AB - Colonic transit and mucosal integrity are believed to be impaired in obesity. However, a comprehensive assessment of altered colonic functions, inflammatory changes and neuronal signalling of obese animals is missing. In mice, we studied the impact of diet-induced obesity (DIO) on: (i) in vivo colonic transit; (ii) signalling in the myenteric plexus by recording responses to nicotine and 2 methyl-5-hydroxytryptamine (2-methyl-5-HT), together with the expression of tryptophan hydroxylase (TPH) 1 and 2, serotonin reuptake transporter, choline acetyltransferase and the paired box gene 4; and (iii) expression of proinflammatory cytokines, epithelial permeability and density of macrophages, mast cells and enterochromaffin cells. Compared with controls, colon transit and neuronal sensitivity to nicotine and 2-methyl-5-HT were enhanced in DIO mice fed for 12 weeks. This was associated with increased tissue acetylcholine and 5 hydroxytryptamine (5-HT) content, and increased expression of TPH1 and TPH2. In DIO mice, upregulation of proinflammatory cytokines was found in fat tissue, but not in the gut wall. Accordingly, mucosal permeability or integrity was unaltered without signs of immune cell infiltration in the gut wall. Body weight showed positive correlations with adipocyte markers, tissue levels of 5-HT and acetylcholine, and the degree of neuronal sensitization. DIO mice fed for 4 weeks showed no neuronal sensitization, had no signs of gut wall inflammation and showed a smaller increase in leptin, interleukin-6 and monocyte chemoattractant protein 1 expression in fat tissue. DIO is associated with faster colonic transit and impacts on acetylcholine and 5-HT metabolism with enhanced responsiveness of enteric neurones to both mediators after 12 weeks of feeding. Our study demonstrates neuronal plasticity in DIO prior to the development of a pathological histology or abnormal mucosal functions. This questions the common assumption that increased mucosal inflammation and permeability initiate functional disorders in obesity. PMID- 23940385 TI - Influence of bovine sperm DNA fragmentation and oxidative stress on early embryo in vitro development outcome. AB - Sperm chromatin fragmentation may be caused by a number of factors, the most significant of which is reactive oxygen species. However, little is known about the effect of sperm oxidative stress (OS) on DNA integrity, fertilization, and embryonic development in cattle. Therefore, the goal of this study was to evaluate the influence of sperm OS susceptibility on the DNA fragmentation rate and in vitro embryo production (IVP) in a population of bulls. Groups of cryopreserved sperm samples were divided into four groups, based on their susceptibility to OS (G1, low OS; G2, average OS; G3, high OS; and G4, highest OS). Our results demonstrated that the sperm DNA integrity was compromised in response to increased OS susceptibility. Furthermore, semen samples with lower susceptibility to OS were also less susceptible to DNA damage (G1, 4.06%; G2, 6.09%; G3, 6.19%; and G4, 6.20%). In addition, embryo IVP provided evidence that the embryo cleavage rate decreased as the OS increased (G1, 70.18%; G2, 62.24%; G3, 55.85%; and G4, 50.93%), but no significant difference in the blastocyst rate or the number of blastomeres was observed among the groups. The groups with greater sensitivity to OS were also associated with a greater percentage of apoptotic cells (G1, 2.6%; G2, 2.76%; G3, 5.59%; and G4, 4.49%). In conclusion, we demonstrated that an increased susceptibility to OS compromises sperm DNA integrity and consequently reduces embryo quality. PMID- 23940386 TI - Nanometer scale pores similar in size to the entrance of the ribosomal exit cavity are a common feature of large RNAs. AB - The highly conserved peptidyl transferase center (PTC) of the ribosome contains an RNA pore that serves as the entrance to the exit tunnel. Analysis of available ribosome crystal structures has revealed the presence of multiple additional well defined pores of comparable size in the ribosomal (rRNA) RNAs. These typically have dimensions of 1-2 nm, with a total area of ~100 A(2) or more, and most are associated with one or more ribosomal proteins. The PTC example and the other rRNA pores result from the packing of helices. However, in the non-PTC cases the nitrogenous bases do not protrude into the pore, thereby limiting the potential for hydrogen bonding within the pore. Instead, it is the RNA backbone that largely defines the pore likely resulting in a negatively charged environment. In many but not all cases, ribosomal proteins are associated with the pores to a greater or lesser extent. With the exception of the PTC case, the large subunit pores are not found in what are thought to be the evolutionarily oldest regions of the 23S rRNA. The unusual nature of the PTC pore may reflect a history of being created by hybridization between two or more RNAs early in evolution rather than simple folding of a single RNA. An initial survey of nonribosomal RNA crystal structures revealed additional pores, thereby showing that they are likely a general feature of RNA tertiary structure. PMID- 23940387 TI - Right ventricular systolic dysfunction in young adults born preterm. AB - BACKGROUND: Young adults born preterm have distinct differences in left ventricular mass, function, and geometry. Animal studies suggest that cardiomyocyte changes are evident in both ventricles after preterm birth; therefore, we investigated whether these young adults also have differences in their right ventricular structure and function. METHODS AND RESULTS: We studied 102 preterm-born young adults followed up prospectively since birth and 132 term born control subjects born to uncomplicated pregnancies. We quantified right ventricular structure and function by cardiovascular magnetic resonance on a 1.5 T Siemens scanner using Argus and TomTec postprocessing software. Preterm birth was associated with a small right ventricle (end diastolic volume, 79.8+/-13.2 versus 88.5+/-11.8 mL/m(2); P<0.001) but greater right ventricular mass (24.5+/ 3.5 versus 20.4+/-3.4 g/m2; P<0.001) compared with term-born controls, with the severity of differences proportional to gestational age (r=-0.47, P<0.001). Differences in right ventricular mass and function were proportionally greater than previously reported for the left ventricle. This was most apparent for systolic function; young adults born preterm had significantly lower right ventricular ejection fraction (57+/-8% versus 60+/-5%; P=0.006). Indeed, 21% had values below the lower limit observed in the term-born adults and 6% had mild systolic dysfunction (<45%). Postnatal ventilation accounted for some of the variation in mass but not function. CONCLUSIONS: Preterm birth is associated with global myocardial structural and functional differences in adult life, including smaller right ventricular size and greater mass. The changes are greater in the right ventricle than previously observed in the left ventricle, with potentially clinically significant impairment in right ventricular systolic function. PMID- 23940388 TI - The promise of pharmacoepidemiology in helping clinicians assess drug risk. PMID- 23940389 TI - Management of patients after endovascular interventions for peripheral artery disease. PMID- 23940391 TI - Demonstration of prosthetic aortic valve dehiscence in a patient with noninfectious aortitis by multimodality imaging: findings of echocardiography and computed tomography. PMID- 23940392 TI - Letter by Xue et al regarding article, "Duration of cardiopulmonary resuscitation and illness category impact survival and neurologic outcomes for in-hospital pediatric cardiac arrests". PMID- 23940393 TI - Letter by Joffe et al regarding article, "Duration of cardiopulmonary resuscitation and illness category impact survival and neurologic outcomes for in hospital pediatric cardiac arrests". PMID- 23940394 TI - Right ventricular tachycardia: common presentation versus common disease. PMID- 23940396 TI - Population pharmacokinetics of enoxaparin during the antenatal period. AB - BACKGROUND: The optimal dosing strategy of low-molecular-weight heparins for the treatment of antenatal venous thromboembolism is not known. The physiological changes associated with pregnancy alter the pharmacokinetic profile of low molecular-weight heparins, which has led to controversy and subsequent variation in practice, when pregnant women with venous thromboembolism are treated with low molecular-weight heparins. Our objective was to develop a robust pharmacokinetic model of enoxaparin during the antenatal period to address this problem. METHOD AND RESULTS: Women prescribed antenatal enoxaparin were eligible to enroll in the study. Recruited women were reviewed monthly and had up to 3 anti-Xa activities (trough and 1 and 3 hours after dose) drawn at each clinic attendance. Compartmental pharmacokinetic modeling was conducted using nonlinear mixed effects modeling. One hundred twenty-three patients contributed 795 anti-Xa activities for pharmacokinetic modeling purposes. Both enoxaparin clearance and volume of distribution were increased during pregnancy. Simulations of once- versus twice-daily enoxaparin administration demonstrated that both dosing regimens would reach target 3-hour plasma concentrations throughout the duration of the pregnancy. When trough anti-Xa activity was simulated, both once- and twice-daily regimens exhibited an increase in trough anti-Xa activity with the progression of pregnancy. This is explained by the significant increase in volume of distribution observed during pregnancy. CONCLUSIONS: The half-life of enoxaparin is prolonged with the progression of pregnancy, and our work provides compelling evidence for prescribing once-daily enoxaparin for the treatment of antenatal venous thromboembolism. National and international guideline recommendations should be reconsidered. PMID- 23940398 TI - Universal health coverage and universal access. PMID- 23940399 TI - Public health round-up. PMID- 23940400 TI - Europe's visible epidemic. PMID- 23940401 TI - All-of-government approach needed to tackle obesity. Interview by Fiona Fleck. PMID- 23940402 TI - Prioritizing hazardous pollutants in two Nigerian water supply schemes: a risk based approach. AB - OBJECTIVE: To rank pollutants in two Nigerian water supply schemes according to their effect on human health using a risk-based approach. METHODS: Hazardous pollutants in drinking-water in the study area were identified from a literature search and selected pollutants were monitored from April 2010 to December 2011 in catchments, treatment works and consumer taps. The disease burden due to each pollutant was estimated in disability-adjusted life years (DALYs) using data on the pollutant's concentration, exposure to the pollutant, the severity of its health effects and the consumer population. FINDINGS: The pollutants identified were microbial organisms, cadmium, cobalt, chromium, copper, iron, manganese, nickel, lead and zinc. All were detected in the catchments but only cadmium, cobalt, chromium, manganese and lead exceeded World Health Organization (WHO) guideline values after water treatment. Post-treatment contamination was observed. The estimated disease burden was greatest for chromium in both schemes, followed in decreasing order by cadmium, lead, manganese and cobalt. The total disease burden of all pollutants in the two schemes was 46 000 and 9500 DALYs per year or 0.14 and 0.088 DALYs per person per year, respectively, much higher than the WHO reference level of 1 * 10(-6) DALYs per person per year. For each metal, the disease burden exceeded the reference level and was comparable with that due to microbial contamination reported elsewhere in Africa. CONCLUSION: The estimated disease burden of metal contamination of two Nigerian water supply systems was high. It could best be reduced by protection of water catchment and pretreatment by electrocoagulation. PMID- 23940403 TI - The epidemiology of child homicides in South Africa. AB - OBJECTIVE: To describe age- and sex-specific rates of child homicide in South Africa. METHODS: A cross-sectional mortuary-based study was conducted in a national sample of 38 medicolegal laboratories operating in 2009. These were sampled in inverse proportion to the number that were operational in each of three strata defined by autopsy volume: < 500, 500-1499 or > 1499 annual autopsies. Child homicide data were collected from mortuary files, autopsy reports and police interviews. Cause of death, evidence of abuse and neglect or of sexual assault, perpetrator characteristics and circumstances surrounding the death were investigated. FINDINGS: An estimated 1018 (95% confidence interval, CI: 843-1187) child homicides occurred in 2009, for a rate of 5.5 (95% CI: 4.6 6.4) homicides per 100 000 children younger than 18 years. The homicide rate was much higher in boys (6.9 per 100 000; 95% CI: 5.6-8.3) than in girls (3.9 per 100 000; 95% CI: 3.2-4.7). Child abuse and neglect had preceded nearly half (44.5%) of all homicides, but three times more often among girls than among boys. In children aged 15 to 17 years, the homicide rate among boys (21.7 per 100 000; 95% CI: 14.2-29.2) was nearly five times higher than the homicide rate among girls (4.6 per 100 000; 95% CI: 2.4-6.8). CONCLUSION: South Africa's child homicide rate is more than twice the global estimate. Since a background of child abuse and neglect is common, improvement of parenting skills should be part of primary prevention efforts. PMID- 23940404 TI - Adverse events attributed to traditional Korean medical practices: 1999-2010. AB - OBJECTIVE: To investigate adverse events attributed to traditional medical treatments in the Republic of Korea. METHODS: Adverse events recorded in the Republic of Korea between 1999 and 2010 - by the Food and Drug Administration, the Consumer Agency or the Association of Traditional Korean Medicine - were reviewed. Records of adverse events attributed to the use of traditional medical practices, including reports of medicinal accidents and consumers' complaints, were investigated. FINDINGS: Overall, 9624 records of adverse events attributed to traditional medical practices - including 522 linked to herbal treatments - were identified. Liver problems were the most frequently reported adverse events. Only eight of the adverse events were recorded by the pharmacovigilance system run by the Food and Drug Administration. Of the 9624 events, 1389 - mostly infections, cases of pneumothorax and burns - were linked to physical therapy (n = 285) or acupuncture/moxibustion (n = 1104). CONCLUSION: In the Republic of Korea, traditional medical practices often appear to have adverse effects, yet almost all of the adverse events attributed to such practices between 1999 and 2010 were missed by the national pharmacovigilance system. The Consumer Agency and the Association of Traditional Korean Medicine should be included in the national pharmacovigilance system. PMID- 23940405 TI - Hospital admissions as a function of temperature, other weather phenomena and pollution levels in an urban setting in China. AB - OBJECTIVE: To explore the relationship between weather phenomena and pollution levels and daily hospital admissions (as an approximation to morbidity patterns) in Hong Kong Special Administrative Region (SAR), China, in 1998-2009. METHODS: Generalized additive models and lag models were constructed with data from official sources on hospital admissions and on mean daily temperature, mean daily wind speed, mean relative humidity, daily total global solar radiation, total daily rainfall and daily pollution levels. FINDINGS: During the hot season, admissions increased by 4.5% for every increase of 1 degrees C above 29 degrees C; during the cold season, admissions increased by 1.4% for every decrease of 1 degrees C within the 8.2-26.9 degrees C range. In subgroup analyses, admissions for respiratory and infectious diseases increased during extreme heat and cold, but cardiovascular disease admissions increased only during cold temperatures. For every increase of 1 degrees C above 29 degrees C, admissions for unintentional injuries increased by 1.9%. During the cold season, for every decrease of 1 degrees C within the 8.2-26.9 degrees C range, admissions for cardiovascular diseases and intentional injuries rose by 2.1% and 2.4%, respectively. Admission patterns were not sensitive to sex. Admissions for respiratory diseases rose during hot and cold temperatures among children but only during cold temperatures among the elderly. In people aged 75 years or older, admissions for infectious diseases rose during both temperature extremes. CONCLUSION: In Hong Kong SAR, hospitalizations rise during extreme temperatures. Public health interventions should be developed to protect children, the elderly and other vulnerable groups from excessive heat and cold. PMID- 23940406 TI - Delivery cost of human papillomavirus vaccination of young adolescent girls in Peru, Uganda and Viet Nam. AB - OBJECTIVE: To estimate the incremental delivery cost of human papillomavirus (HPV) vaccination of young adolescent girls in Peru, Uganda and Viet Nam. METHODS: Data were collected from a sample of facilities that participated in five demonstration projects for hpv vaccine delivery: school-based delivery was used in Peru, Uganda and Viet Nam; health-centre-based delivery was also used in Viet Nam; and integrated delivery, which involved existing health services, was also used in Uganda. Microcosting methods were used to guide data collection on the use of resources (i.e. staff, supplies and equipment) and data were obtained from government, demonstration project and health centre administrative records. Delivery costs were expressed in 2009 United States dollars (US$). Exclusively project-related expenses and the cost of the vaccine were excluded. FINDINGS: The economic delivery cost per vaccine dose ranged from US$ 1.44 for integrated outreach in Uganda to US$ 3.88 for school-based delivery in Peru. In Viet Nam, the lowest cost per dose was US$ 1.92 for health-centre-based delivery. Cost profiles revealed that, in general, the largest contributing factors were project start-up costs and recurrent personnel costs. The delivery cost of HPV vaccine was higher than published costs for traditional vaccines recommended by the Expanded Programme on Immunization (EPI). CONCLUSION: The cost of delivering HPV vaccine to young adolescent girls in Peru, Uganda and Viet Nam was higher than that for vaccines currently in the EPI schedule. The cost per vaccine dose was lower when delivery was integrated into existing health services. PMID- 23940408 TI - Health financing for universal coverage and health system performance: concepts and implications for policy. AB - Unless the concept is clearly understood, "universal coverage" (or universal health coverage, UHC) can be used to justify practically any health financing reform or scheme. This paper unpacks the definition of health financing for universal coverage as used in the World Health Organization's World health report 2010 to show how UHC embodies specific health system goals and intermediate objectives and, broadly, how health financing reforms can influence these. All countries seek to improve equity in the use of health services, service quality and financial protection for their populations. Hence, the pursuit of UHC is relevant to every country. Health financing policy is an integral part of efforts to move towards UHC, but for health financing policy to be aligned with the pursuit of UHC, health system reforms need to be aimed explicitly at improving coverage and the intermediate objectives linked to it, namely, efficiency, equity in health resource distribution and transparency and accountability. The unit of analysis for goals and objectives must be the population and health system as a whole. What matters is not how a particular financing scheme affects its individual members, but rather, how it influences progress towards UHC at the population level. Concern only with specific schemes is incompatible with a universal coverage approach and may even undermine UHC, particularly in terms of equity. Conversely, if a scheme is fully oriented towards system-level goals and objectives, it can further progress towards UHC. Policy and policy analysis need to shift from the scheme to the system level. PMID- 23940407 TI - Interventions for common perinatal mental disorders in women in low- and middle income countries: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the effectiveness of interventions to improve the mental health of women in the perinatal period and to evaluate any effect on the health, growth and development of their offspring, in low- and middle-income (LAMI) countries. METHODS: Seven electronic bibliographic databases were systematically searched for papers published up to May 2012 describing controlled trials of interventions designed to improve mental health outcomes in women who were pregnant or had recently given birth. The main outcomes of interest were rates of common perinatal mental disorders (CPMDs), primarily postpartum depression or anxiety; measures of the quality of the mother-infant relationship; and measures of infant or child health, growth and cognitive development. Meta-analysis was conducted to obtain a summary measure of the clinical effectiveness of the interventions. FINDINGS: Thirteen trials representing 20 092 participants were identified. In all studies, supervised, non-specialist health and community workers delivered the interventions, which proved more beneficial than routine care for both mothers and children. The pooled effect size for maternal depression was -0.38 (95% confidence interval: -0.56 to -0.21; I (2) = 79.9%). Where assessed, benefits to the child included improved mother-infant interaction, better cognitive development and growth, reduced diarrhoeal episodes and increased immunization rates. CONCLUSION: In LAMI countries, the burden of CPMDs can be reduced through mental health interventions delivered by supervised non-specialists. Such interventions benefit both women and their children, but further studies are needed to understand how they can be scaled up in the highly diverse settings that exist in LAMI countries. PMID- 23940409 TI - Protecting and improving breastfeeding practices during a major emergency: lessons learnt from the baby tents in Haiti. AB - PROBLEM: The 2010 earthquake in Haiti displaced about 1.5 million people, many of them into camps for internally displaced persons. It was expected that disruption of breastfeeding practices would lead to increased infant morbidity, malnutrition and mortality. APPROACH: Haiti's health ministry and the United Nations Children's Fund, in collaboration with local and international nongovernmental organizations, established baby tents in the areas affected by the earthquake. The tents provided a safe place for mothers to breastfeed and for non-breastfed infants to receive ready-to-use infant formula. Such a large and coordinated baby tent response in an emergency context had never been mounted before anywhere in the world. LOCAL SETTING: Baby tents were set up in five cities but mainly in Port-au-Prince, where the majority of Haiti's 1555 camps for displaced persons had been established. RELEVANT CHANGES: Between February 2010 and June 2012, 193 baby tents were set up; 180 499 mother-infant pairs and 52 503 pregnant women were registered in the baby tent programme. Of infants younger than 6 months, 70% were reported to be exclusively breastfed and 10% of the "mixed feeders" moved to exclusive breastfeeding while enrolled. In 2010, 13.5% of registered infants could not be breastfed. These infants received ready-to-use infant formula. LESSONS LEARNT: Thanks to rapid programme scale-up, breastfeeding practices remained undisrupted. However, better evaluation methods and comprehensive guidance on the implementation and monitoring of baby tents are needed for future emergencies, along with a clear strategy for transitioning baby tent activities into facility and community programmes. PMID- 23940410 TI - Debating the scope of a health research and development convention. PMID- 23940411 TI - Expressed Likelihood as Motivator: Creating Value through Engaging What's Real. AB - Our research tested two predictions regarding how likelihood can have motivational effects as a function of how a probability is expressed. We predicted that describing the probability of a future event that could be either A or B using the language of high likelihood ("80% A") rather than low likelihood ("20% B"), i.e., high rather than low expressed likelihood, would make a present activity more real and engaging, as long as the future event had properties relevant to the present activity. We also predicted that strengthening engagement from the high (vs. low) expressed likelihood of a future event would intensify the value of present positive and negative objects (in opposite directions). Both predictions were supported. There was also evidence that this intensification effect from expressed likelihood was independent of the actual probability or valence of the future event. What mattered was whether high versus low likelihood language was used to describe the future event. PMID- 23940412 TI - Unique Contributions of Fathering to Emerging Self Regulation in Low-Income Ethnic Minority Preschoolers. AB - Self regulation ability is an important component of school readiness and predictor of academic success, but few studies of self regulation examine contributions of fathering to the emergence of self regulation in low-income ethnic minority preschoolers. Associations were examined between parental child oriented parenting support and preschoolers' emerging self regulation abilities in 224 low-income African American (n=86) and Latino (n=138) children observed at age 30 months in father-child and mother-child interactions to determine unique predictions from fathering qualities. Child-oriented mothering but not fathering predicted greater simple response inhibition for both African American and Latino children. Fathering but not mothering quality uniquely predicted greater complex response inhibition, but only for the African American children. The culture specific fathering effects could not be explained by differences in father involvement. PMID- 23940414 TI - Ocular pharmacokinetics of bimatoprost formulated in DuraSite compared to bimatoprost 0.03% ophthalmic solution in pigmented rabbit eyes. AB - PURPOSE: To compare the aqueous humor (AH) and iris-ciliary body (ICB) concentration of bimatoprost in rabbit eyes treated with ISV-215 (0.03% bimatoprost formulated in DuraSite) with the marketed product bimatoprost 0.03% ophthalmic solution. METHODS: The left eye of rabbits received a single topical instillation of either ISV-215 (n = 32 eyes) or bimatoprost 0.03% (n = 32 eyes). At predetermined time points, levels of bimatoprost and bimatoprost acid in the AH and the ICB were quantified by HPLC-MS/MS. RESULTS: Both bimatoprost and bimatoprost acid were detected in the AH and the ICB within 15 minutes of dosing. Bimatoprost acid concentrations in both compartments were markedly higher than bimatoprost. There was a statistically significant (P < 0.01) increase in the concentration of the prodrug in the AH and its acid form in the ICB in animals treated with ISV-215 compared to bimatoprost 0.03%. In the ISV-215-treated rabbit eyes, the highest concentrations of bimatoprost and bimatoprost acid were in the ICB and AH, respectively, while in the bimatoprost 0.03%-treated eyes, no differences in the drug content of the selected ocular tissues were observed. CONCLUSIONS: Bimatoprost 0.03% formulated in DuraSite has superior ocular distribution and area under the curve compared to bimatoprost 0.03% in rabbit eyes. This improvement in the pharmacokinetic parameters of ISV-215 may provide us with a better platform to optimize a bimatoprost formulation that offers the same degree of efficacy in lowering intraocular pressure and improved therapeutic index in glaucomatous patients by lessening the ocular side effects associated with long-term use of topical prostaglandin F2alpha analogs. PMID- 23940415 TI - The effectiveness of acupuncture on the sleep quality of elderly with dementia: a within-subjects trial. AB - PURPOSE: Elderly with dementia are often afflicted with sleep problems. Recent studies have suggested that acupuncture may be a feasible alternative to traditional sleep medicine for treating sleep disturbance. This study investigated the effectiveness of acupuncture on sleep quality of elderly with dementia. PATIENTS AND METHODS: Nineteen elders with dementia were followed through a control period and an acupuncture treatment period, each lasting 6 weeks. Outcome measures were subjects' sleep quality and cognitive function. Sleep parameters were recorded by wrist actigraphy. Cognitive function was assessed by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). Pretests and posttests were conducted immediately before and after the control and treatment periods. Changes in the outcome measures between control and treatment periods were compared. RESULTS: Wilcoxon signed rank tests revealed that the subjects gained significantly more resting time and total sleep time in the treatment period than in the control period (P < 0.05). A nonsignificant trend for improvement in sleep efficiency was observed. Improvement in cognitive function was not statistically significant. A total of 86% of the subjects completed the treatment regime. CONCLUSION: Results reveal that acupuncture was effective in improving some domains of sleep quality of elderly with dementia, and the subjects showed acceptance towards the intervention. Strengths and limitations of the present study as well as suggestions for further studies were considered. PMID- 23940416 TI - Pronounced induction of endoplasmic reticulum stress and tumor suppression by surfactant-free poly(lactic-co-glycolic acid) nanoparticles via modulation of the PI3K signaling pathway. AB - BACKGROUND: Y294002 (LY) is a potent inhibitor of phosphatidylinositol 3-kinases (PI3Ks); however, biological applications of LY are limited by its poor solubility and pharmacokinetic profile. This study aimed at developing LY-loaded surfactant-free poly(lactic-co-glycolic acid) (PLGA) nanoparticles (SF-LY NPs) to improve the therapeutic efficacy of LY. MATERIALS AND METHODS: Cellular viability was measured by MTT assay. The subcellular distribution of NPs was studied using an ultraviolet-visible spectrophotometer and confocal microscope. The expression of cell-death-associated proteins was determined using Western blotting and the in vivo activity of SF-LY NPs was tested in a xenograft animal model. RESULTS: SF LY NPs enhanced the intracellular level of LY, induced sustained suppression of AKT, and induced marked cancer cell death. In addition, SF-LY NPs tended to accumulate in the endoplasmic reticulum (ER) and induce pronounced ER stress. Finally, SF-LY NPs exhibited a prominent antitumor effect in vivo. CONCLUSION: The surfactant-free formulation of PLGA is critical to the promising anticancer activity of SF-LY NPs. PMID- 23940418 TI - Age as a factor in sensory integration function in Taiwanese children. AB - OBJECTIVE: Sensory integration progresses along a normal developmental sequence. However, few studies have explored how age difference affects the way sensory integration functions in Taiwanese children as they develop. Therefore, this study aims to pinpoint the role of age in sensory integration. METHOD: A purposive sampling plan was employed. The study population comprised 1,000 Chinese children aged 36 to 131 months (mean = 74.48 months, standard deviation = 25.69 months). Subjects were scored on seven subsets of the Test of Sensory Integration Function (TSIF). An analysis of variance (ANOVA) was used to identify differences between four age groups (ages 3-4, 5-6, 7-8, and 9-10 years), in the categories of the TSIF. RESULTS: ANOVA revealed that age is a significant factor in each of the seven tasks of sensory integration associated with various stages of development. The effect of age was significant in all four groups for the subscale of Bilateral Integration Sequences. The function of sensory integration for the children aged 5-8 years did not produce statistically significant results for the subscale of Postural Movement, Sensory Discrimination, Sensory Seeking, or Attention and Activity. For the subscale of Sensory Modulation and Emotional Behavior, the effect of age was significant in only group 1 (children aged 3-4 years) and group 2 (children aged 5-6 years). CONCLUSION: There was significant difference between group 1 and group 2 for seven categories. Significant differences were contributed by the differences from group 1 (3-4 years) and group 4 (9-10 years) in five subscales (Postural Movement, Bilateral Integration Sequences, Sensory Discrimination, Sensory Seeking, and Attention and Activity). There were three developmental trends in the seven categories of the TSIF. PMID- 23940417 TI - Green chemistry approach for the synthesis of biocompatible graphene. AB - BACKGROUND: Graphene is a single-atom thick, two-dimensional sheet of hexagonally arranged carbon atoms isolated from its three-dimensional parent material, graphite. One of the most common methods for preparation of graphene is chemical exfoliation of graphite using powerful oxidizing agents. Generally, graphene is synthesized through deoxygenation of graphene oxide (GO) by using hydrazine, which is one of the most widespread and strongest reducing agents. Due to the high toxicity of hydrazine, it is not a promising reducing agent in large-scale production of graphene; therefore, this study focused on a green or sustainable synthesis of graphene and the biocompatibility of graphene in primary mouse embryonic fibroblast cells (PMEFs). METHODS: Here, we demonstrated a simple, rapid, and green chemistry approach for the synthesis of reduced GO (rGO) from GO using triethylamine (TEA) as a reducing agent and stabilizing agent. The obtained TEA reduced GO (TEA-rGO) was characterized by ultraviolet (UV)-visible absorption spectroscopy, X-ray diffraction (XRD), particle size dynamic light scattering (DLS), scanning electron microscopy (SEM), Raman spectroscopy, and atomic force microscopy (AFM). RESULTS: The transition of graphene oxide to graphene was confirmed by UV-visible spectroscopy. XRD and SEM were used to investigate the crystallinity of graphene and the surface morphologies of prepared graphene respectively. The formation of defects further supports the functionalization of graphene as indicated in the Raman spectrum of TEA-rGO. Surface morphology and the thickness of the GO and TEA-rGO were analyzed using AFM. The presented results suggest that TEA-rGO shows significantly more biocompatibility with PMEFs cells than GO. CONCLUSION: This is the first report about using TEA as a reducing as well as a stabilizing agent for the preparation of biocompatible graphene. The proposed safe and green method offers substitute routes for large-scale production of graphene for several biomedical applications. PMID- 23940419 TI - Anatomic connections of the diaphragm: influence of respiration on the body system. AB - The article explains the scientific reasons for the diaphragm muscle being an important crossroads for information involving the entire body. The diaphragm muscle extends from the trigeminal system to the pelvic floor, passing from the thoracic diaphragm to the floor of the mouth. Like many structures in the human body, the diaphragm muscle has more than one function, and has links throughout the body, and provides the network necessary for breathing. To assess and treat this muscle effectively, it is necessary to be aware of its anatomic, fascial, and neurologic complexity in the control of breathing. The patient is never a symptom localized, but a system that adapts to a corporeal dysfunction. PMID- 23940420 TI - Update on oncolytic viral therapy - targeting angiogenesis. AB - Oncolytic viruses (OVs) have the ability to selectively replicate in and lyse cancer cells. Angiogenesis is an essential requirement for tumor growth. Like OVs, the therapeutic effect of many angiogenesis inhibitors has been limited, leading to the development of more effective approaches to combine antiangiogenic therapy with OVs. Angiogenesis can be targeted either directly by OV infection of vascular endothelial cells, or by arming OVs with antiangiogenic transgenes, which are subsequently expressed locally in the tumor microenvironment. In this review, we describe the development and targeting of OVs, the role of angiogenesis in cancer, and the progress made in arming viruses with antiangiogenic transgenes. Future developments required to optimize this approach are addressed. PMID- 23940422 TI - Noninvasive prediction of the exercise-induced elevation in left ventricular filling pressure in post-heart transplant patients with normal left ventricular ejection fraction. AB - OBJECTIVES: At present, there are conflicting data on the ability of echocardiographic parameters to predict the exercise-induced elevation of left ventricular (LV) filling pressure. The purpose of the present study was to validate the ratio of early diastolic transmitral (E) to mitral annular velocity (e') obtained at peak exercise in its capacity to determine the exercise-induced elevation of pulmonary capillary wedge pressure (PCWP) and to reveal new noninvasive parameters with such capacity. METHODS: Sixty-one patients who had undergone heart transplantation with normal LV ejection fraction underwent simultaneous exercise echocardiography and right heart catheterization. RESULTS: In 50 patients with a normal PCWP at rest, exercise E/e' >=8.5 predicted exercise PCWP >=25 mmHg with a sensitivity of 64.3% and a specificity of 84.2% (area under the curve [AUC]=0.74). A comparable or slightly better prediction was achieved by exercise E/peak systolic mitral annular velocity (s') >=11.0 (sensitivity 79.3%; specificity 57.9%; AUC=0.75) and exercise E/LV systolic longitudinal strain rate <=-105 cm (sensitivity 78.9%; specificity 78.6%; AUC=0.87). Combined, exercise E/s' and exercise E/e' resulted in a trend toward a slightly more precise prediction (sensitivity 53.6%; specificity 89.5%; AUC=0.78) than did either variable alone. CONCLUSIONS: Exercise E/e', used as a sole parameter, is not sufficiently precise to predict the exercise-induced elevation of PCWP. Exercise E/s', E/LV systolic longitudinal strain rate or combinations of these parameters may represent further promising possibilities for predicting exercise PCWP elevation. PMID- 23940421 TI - Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma. AB - Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC. PMID- 23940423 TI - Using sheathless standard guiding catheters for transradial percutaneous coronary intervention to treat bifurcation lesions. AB - OBJECTIVE: To investigate the feasibility and safety of using sheathless standard guiding catheters for transradial percutaneous coronary intervention (PCI) to treat bifurcation lesions. METHODS: Coronary bifurcation lesions were identified using angiography in 43 patients with coronary artery disease. These patients underwent transradial PCI using sheathless standard guiding catheters, and the procedural success and complication rates were recorded. RESULTS: All 43 patients underwent successful PCI. The Culotte stenting technique was used in 22 (51.2%) subjects, the Crush stenting technique was used in eight (18.8%) subjects and the crossover stenting implantation technique was used in 13 (30.0%) subjects. Of the 43 coronary artery bifurcation lesions, the final kissing balloon technique was performed in 39 (90.1%) lesions. Adjunctive devices used in the cohort included intravascular ultrasound for 32 (74.4%) patients, thrombus aspiration catheters for two patients and cutting balloon for five patients. During the perioperative period, no major complications associated with vessel puncture or adverse cardiac or cerebrovascular events occurred in any of the 43 patients enrolled in the present study. At day 30, radial artery occlusion was detected in only three (2.5%) patients and radial artery stenosis in four (9.3%) patients. At six-month follow-up, 24 (55.8%) patients exhibited coronary artery patency with no significant intimal hyperplasia. CONCLUSIONS: Transradial PCI using the sheathless technique may be a feasible and safe technique to treat coronary bifurcation lesions. PMID- 23940424 TI - The seasonal variation in hospitalizations due to chronic systolic heart failure correlates with blood sodium levels and cardiac function. AB - BACKGROUND: Although seasonal variation in hospitalizations due to chronic heart failure is recognized, the possible contributors to such variability are less well documented. METHODS: Records from all admissions to 12 hospitals in Hubei province, China, over a 10-year period with diagnostic codes for chronic systolic heart failure (CSHF) were reviewed. A total of 16,145 patients with CSHF were analyzed. RESULTS: There was a marked seasonal variation in the number of hospitalizations due to CSHF, with two peaks in the monthly rate of hospitalization due to CSHF occurring in December and August compared with the spring and autumn months. Monthly hospitalizations due to CSHF for patients with New York Heart Association class III and IV ranged from a peak of 40.4% and 23.3% above average in December and August, respectively, to 18.6% below average in November, while hospitalizations due to CSHF for patients with New York Heart Association class I and II exhibited no obvious seasonal variation. Blood sodium level (95% CI 2.132 to 2.144; P=0.036) was an independent risk factor for hospitalizations due to CSHF in August. CONCLUSION: The number of hospitalizations due to CSHF increased during the colder and warmer months in China. A low blood sodium level was associated with the peak in hospitalizations in August. PMID- 23940426 TI - Monitoring biventricular pacing parameters depending on the left ventricle lead configuration. AB - OBJECTIVES: To evaluate whether pacing or sensing configuration has an effect on pacing parameters or their time progression. Three left ventricular (LV) pacing parameters were monitored - the LV pacing threshold, pacing impedance and intrinsic R-wave amplitude. METHODS: DATA WERE COLLECTED AT THREE INTERVALS: during implantation; between the second and fifth month after implantation (first follow-up); and between the eighth and 15th month after implantation (second follow-up). Repeated-measures ANOVA was used for the statistical analysis. RESULTS: The impedance, but not its time progression, was significantly higher for the LV tip to LV ring configuration than for other configurations. R-wave amplitude and impedance increased significantly (without dependance on configurations) between implantation and first follow-up, as expected. The time progression of any parameter was not dependent on configuration of the LV lead. CONCLUSIONS: LV tip to LV ring is the best configuration for maintaining a high impedance level. It is better to maintain an individual approach for pacing threshold and R-wave amplitude, and their settings. PMID- 23940425 TI - Routine pretreatment with abciximab versus standard periprocedural therapy in mechanically ventilated cardiogenic shock patients undergoing primary percutaneous coronary intervention: Subanalysis of the PRAGUE-7 study. AB - BACKGROUND: The clinical outcome of patients with myocardial infarction (MI) complicated by cardiogenic shock (CS) who require mechanical ventilation (MV) is poor. OBJECTIVE: To analyze the impact of abciximab pretreatment in this high risk population of MI patients. METHODS: The present study was a retrospective subanalysis of the multicentre randomized Routine Upfront Abciximab Versus Standard Peri-Procedural Therapy in Patients Undergoing Percutaneous Coronary Intervention for Cardiogenic Shock (PRAGUE-7) study, which included 80 MI patients in CS undergoing primary percutaneous coronary intervention (PCI). Patients were randomly assigned into group A (routine pretreatment with an abciximab bolus followed by a 1 h abciximab infusion) and group B (standard therapy). The subanalysis included 37 patients requiring MV. Seventeen patients were in group A and 20 were in group B. The primary end point (death/stroke/reinfarction/new severe renal failure) at 30 days, procedural success (thrombosis in myocardial infarction [TIMI] flow) and frequency of bleeding were assessed. The chi(2) and Student's t tests were used for statistical analysis; P<0.05 was considered to be statistically significant. RESULTS: The primary end point occurred in nine (53%) patients in group A and 12 (60%) patients in group B (P=0.66). TIMI flow after primary PCI was higher in group A (2.75 versus 2.31; P<0.05). Major bleeding occurred in 12% of patients in group A versus 10% of patients in group B (P=0.86). Minor or minimal bleeding was more common in group A (29%) compared with group B (5%; P<0.05). CONCLUSION: The results of the present study suggest that routine pretreatment with abciximab before primary PCI in mechanically ventilated patients with MI complicated by cardiogenic shock was associated with better angiographic results but also with a higher incidence of bleeding. PMID- 23940427 TI - An analysis of the risk factors for premature coronary artery disease in young and middle-age Chinese patients with hypertension. AB - BACKGROUND: Hypertension has become prevalent among young and middle-age individuals. Many studies have identified a variety of risk factors for cardiovascular diseases, yet there have been few reports focusing on the young and middle-age hypertensive population. OBJECTIVE: To investigate the epidemiological characteristics of conventional risk factors of premature coronary artery disease (PCAD) in patients with hypertension. METHODS: The clinical and laboratory data of 267 hypertensive patients with PCAD and 96 hypertensive patients without any visible coronary disease according to angiography were compared. Potential coronary risk factors were analyzed using logistic regression. RESULTS: The PCAD group had lower levels of high-density lipoprotein cholesterol (HDL-C) (P<0.05). Multivariate logistic analysis showed positive family history, low HDL-C, hypertriglyceridemia, duration of diabetes mellitus and male sex were significantly associated with PCAD (P<0.05), with ORs of 12.317, 3.267, 2.894, 1.140 and 0.088, respectively. Plasma renin activities in PCAD patients were significantly higher than in control hypertensive patients (P=0.027), but there was no significant difference in angiotensin II and aldosterone levels between the two groups. CONCLUSION: Low HDL-C and hypertriglyceridemia are important coronary risk factors in Chinese individuals with hypertension. PMID- 23940428 TI - Enlargement of the aorta: An occupational disease? AB - BACKGROUND: Aortic dilation may critically precede progression to thoracic aortic aneurysm (TAA). Prolonged or repetitive isometric-type heavier strenuous activities resulting from the nature of some professions may be an important causative factor for TAA. METHOD: The echocardiographic measurement data of middle-age subjects who were isometric-type daily strenuous activity trainers or ordinary activity trainers were retrospectively analyzed. Clinical features and echocardiographic parameters of the left ventricle and left atrium (LA), aortic root (AR) and ascending aorta (AA) were compared between the groups. RESULTS: AR (35.6+/-3.0 mm versus 33.5+/-1.9 mm), AA (36.8+/-3.0 mm versus 34.4+/-1.9 mm) and LA (37.4+/-2.2 mm versus 36.2+/-2.2 mm) diameters were significantly enlarged in the strenuous activity trainer group versus the ordinary activity group. Diastolic blood pressure was significantly lower (73.8+/-5.9 mmHg versus 78.3+/ 6.0 mmHg) in this group. AR diameter was correlated with height (beta=0.460; P=0.004) and LA diameter (beta=0.280; P=0.008) while AA diameter was correlated with type of profession (beta=0.309; P=0.003), left ventricular systolic diameter (beta=0.500; P=0.001) and LA diameter (beta=0.272; P=0.005) in regression analysis. CONCLUSION: Aortic dilation and, subsequently, TAA may be an occupational disease due to nature of some professions (eg, the military, security, weight lifters, athletes, heavy workers, etc). Echocardiography is a convenient method of imaging that could be easily applied either during preparticipation screening or during periodical examination of these subjects. Earlier detection of TAA and limitation of such strenuous activities in these individuals may be initial lifesaving measures for the prevention of future cases of aortic aneurysm and dissection. PMID- 23940429 TI - Comparison of the diagnostic accuracy of ischemia-modified albumin and echocardiography in patients with acute chest pain. AB - BACKGROUND: Several imaging tests and biomarkers have been proposed for the identification of patients with unstable angina among those presenting to the emergency department with acute chest pain. Preliminary data suggest that ischemia-modified albumin (IMA) may represent a potentially useful biomarker in these patients. OBJECTIVE: To compare IMA and echocardiography in excluding unstable angina in patients with acute chest pain. METHODS: Thirty-three patients (mean [+/- SD] age 59.8+/-10.8 years; 28 men) presenting to the emergency department with acute chest pain lasting <3 h suggestive of acute coronary syndrome, with normal or non-diagnostic electrocardiograms, and creatine kinase MB and troponin levels within the normal range, were included in the present study. RESULTS: After further diagnostic evaluation, five patients (15.2%) were diagnosed with unstable angina. The sensitivity, specificity, positive predictive value and negative predictive (NPV) value of echocardiography for diagnosing unstable angina was 60.0%, 89.3%, 50.0% and 92.6%, respectively. The area under the ROC curve for diagnosing unstable angina based on the serum IMA levels was 0.193 (95% CI 0.047 to 0.339; P<0.05). Based on ROC curve analysis, serum IMA levels >=31.95 IU/mL yielded the optimal combination of sensitivity and specificity for diagnosing unstable angina. The sensitivity, specificity, positive predictive value and NPV of serum IMA levels >=31.95 IU/mL for diagnosing unstable angina was 40.0%, 28.6%, 9.1% and 72.7%, respectively. CONCLUSIONS: Measurement of serum IMA levels appears to represent a useful tool for excluding unstable angina in patients presenting to the emergency department with acute chest pain. Moreover, IMA shows an NPV that is comparable with echocardiography. PMID- 23940430 TI - Correlation between CHADS2 score and anticoagulant use in atrial fibrillation: Results of a mini-survey. AB - Quality assurance in atrial fibrillation is related to the appropriate use of anticoagulation. The CHADS2 score is widely used to determine which patients should or should not be anticoagulated. The authors hypothesized that as thromboembolic risk and, therefore, the CHADS2 score increases, so should the rate of anticoagulant prescription. The authors found a positive correlation between CHADS2 score and anticoagulant prescription (r=0.8) in a mini-survey. Although anticoagulant use at CHADS2 score = 0 was presumed to be very low, it was found to be higher than expected. This was readily explained by a group of low-risk patients being anticoagulated before cardioversion. Cardioverted patients were then examined as a group and it was found that the rate of rhythm control decreased with CHADS2 score (r= -0.89), a finding that has not been reported in the literature and may warrant further investigation. PMID- 23940431 TI - The relationship between atrial septal aneurysm and autonomic dysfunction. AB - BACKGROUND: Systemic thromboembolism is a serious, major complication in patients with an atrial septal aneurysm (ASA). Atrial dysfunction resulting from paroxysmal atrial fibrillation is more common in patients with ASA than in the general population. The autonomic nervous system plays an important role in the initiation of atrial fibrillation. OBJECTIVE: To investigate autonomic function and its impact on ventricular and atrial arrhythmia in a group of ASA patients compared with a control group of healthy volunteers. METHODS: The study group consisted of 40 patients with ASA; the control group consisted of 30 age-, sex- and body mass index-matched healthy volunteers. All patients and control subjects underwent echocardiographic examination. Autonomic function was assessed by determining heart rate variability (HRV) indexes. RESULTS: HRV time and frequency domain indexes were lower in patients with ASA compared with healthy controls (188+/-32 ms(2) and 323+/-42 ms(2) for low-frequency HRV; 195+/-39 ms(2) and 377+/-43 ms(2) for high-frequency HRV; P<0.001 for all). Statistically significant differences with respect to other HRV indexes were also found between the two groups. CONCLUSION: ASA appears to be associated with cardiac autonomic dysfunction; however, the mechanisms of this association are not known in detail. PMID- 23940432 TI - Neutrophil gelatinase-associated lipocalin as a biomarker for acute kidney injury in patients undergoing coronary artery bypass grafting. AB - BACKGROUND/OBJECTIVE: The development of acute renal injury (ARI) is an important indicator of clinical outcomes after cardiac surgery. Neutrophil gelatinase associated lipocalin (NGAL) has been certified as a predictive biomarker of hypoxic ARI. The present study aimed to determine the predictive role of NGAL in coronary bypass graft (CABG) surgery. METHOD: A total of 72 consecutive patients undergoing elective CABG were enrolled in the study. NGAL levels were determined preoperatively and postoperatively after 6 h, 24 h and 72 h for all participants. The participants were then divided into two groups according to their preoperative creatinine levels (group I, creatinine 111.38 MUmol/L to 361.55 MUmol/L; group II, creatinine <111.38 MUmol/L). RESULTS: There was no statistically significant difference between the groups according to their NGAL values (P>0.05), except at 6 h (P=0.045). Three patients required continuous hemodialysis. Comparison of the NGAL levels of these three patients with those of the other participants did not reveal any correlation with serum creatinine levels. In contrast, the NGAL levels were significantly lower in the continuous hemodialysis patients (1.9+/-1 ng/mL) compared with those of the other participants (22.6+/-12.8 ng/mL; P=0.001). CONCLUSION: NGAL is one of the most frequently used biomarkers for ARI after cardiac operations, especially in younger patients. The participants in the present study were coronary artery disease patients and were, therefore, older than patients in previous reports. These results support the view that NGAL is not a relevant predictive factor for ARI in patients with CABG, including older patients. PMID- 23940433 TI - Increased QT dispersion and P wave dispersion in major depressive disorder. AB - BACKGROUND: QT and P wave dispersion parameters can indicate abnormalities in autonomic nervous system and cardiac functioning. OBJECTIVES: To determine QT and P wave dispersion in patients with major depressive disorder compared with healthy volunteers. METHODS: Fifty newly diagnosed patients with major depressive disorder and 50 age- and sex-matched healthy volunteers underwent 12-lead electrocardiography. QT interval, QT dispersion, heart rate-corrected QT dispersion and P wave dispersions were calculated manually by a blinded specialist. RESULTS: Groups were comparable in terms of age, sex, body mass index, smoking status, metabolic diseases and left ventricular ejection fraction. The major depressive disorder group had significantly higher QT dispersion (58.5+/-9.9 versus 41.7+/-3.8; P<0.001), heart rate-corrected QT dispersion (62.5+/-10.0 versus 45.2+/-4.3; P<0.001) and P wave dispersion (46.9+/-4.8 versus 41.5+/-5.1; P<0.001). CONCLUSION: Increased QT dispersion, heart-rate corrected QT dispersion and P wave dispersion in major depressive disorder patients may be indicative of autonomic imbalance and increased risk of cardiac morbidity and mortality. PMID- 23940434 TI - Low albumin levels and high impedance ratio as risk factors for worsening kidney function during hospitalization of decompensated heart failure patients. AB - BACKGROUND: Patients hospitalized for decompensated heart failure (DHF) frequently experience worsening of renal function (WRF), leading to volume overload and resistance to diuretics. OBJECTIVE: To investigate whether albumin levels and whole-body impedance ratio, as an indicator of water distribution, were associated with WRF in patients with DHF. METHODS: A total of 80 patients hospitalized for DHF were consecutively included in the present longitudinal study. WRF during hospitalization was defined as an increase of >=0.3 mg/dL (>=26.52 MUmol/L) or 25% of baseline serum creatinine. Clinical and echocardiographic characteristics were assessed at baseline. Whole-body bioelectrical impedance was measured using tetrapolar and multiple-frequency equipment to obtain the ratio of impedance at 200 kHz to that at 5 kHz. Serum albumin levels were also evaluated. Baseline characteristics were compared between patients with and without deteriorating renal function using a t test or chi(2) test. Subsequently, a logistic regression analysis was performed to obtain the independent variables associated with WRF. RESULTS: The incidence of WRF during hospitalization was 26%. Independent risk factors associated with WRF were low serum albumin (RR=0.11; P=0.04); impedance ratio >0.85 (RR=5.3; P=0.05), systolic blood pressure >160 mmHg (RR=12; P=0.02) and maximum dose of continuous intravenous furosemide required >80 mg/day during hospitalization (RR=5.7, P=0.015). CONCLUSIONS: WRF is frequent in patients with DHF. It results from the inability to effectively regulate volume status because hypoalbuminemia induces water loss from the vascular space (high impedance ratio), and high diuretic doses lower circulatory volumes and reduce renal blood flow, leading to a decline in renal filtration function. PMID- 23940435 TI - In vitro effects of L-carnitine on coronary artery bypass grafts. AB - BACKGROUND: The gold standard treatment for multivessel coronary revascularization is coronary artery bypass grafting. The internal mammary artery and saphenous vein grafts are the conduits most frequently used for these operations. Spasm of arterial and venous grafts is a significant problem during the operation. OBJECTIVES: To evaluate the acute in vitro effects of L-carnitine on internal mammary artery and saphenous vein grafts using a tissue bath. METHODS: Ten consecutive patients who underwent elective coronary artery bypass grafting were enrolled in the present study (nine men, one woman; mean [+/- SD] age 62+/-9.1 years). Samples from left internal mammary artery and saphenous vein grafts were collected from each patient. Submaximal smooth muscle contraction was achieved by adding 1 MUM phenylephrine, and L-carnitine was then added to the solution. The concentration-response curves of the vasodilation response were obtained. RESULTS: In the internal mammary graft samples, the vasodilation response to L-carnitine was 64.3+/-11.1% at a concentration of 5 mM. In the saphenous vein graft samples, the vasodilation response to L-carnitine was 41.5+/ 11.4% at a concentration of 5 mM. There was a statistically significant difference (P<0.001) between the response of the internal mammary artery and saphenous vein grafts in the in vitro tissue bath system. CONCLUSIONS: These results indicate that L-carnitine is a potential vasodilatory drug for internal mammary artery and saphenous vein grafts. PMID- 23940436 TI - The primary anomalies of coronary artery origin and course: A coronary angiographic analysis of 16,573 patients. AB - BACKGROUND/OBJECTIVES: Coronary artery anomalies are present at birth, but relatively few are symptomatic. The majority are discovered incidentally. In the present study, coronary angiograms performed in the authors' centre (Ondokuz Mayis University Hospital, Samsun, Turkey) were analyzed to determine the prevalence and types of coronary artery origin and course anomalies. METHODS: Coronary angiographic data of 16,573 patients were analyzed. Anomalous origins and courses of coronary arteries were assessed. RESULTS: Anomalous coronary arteries were detected in 48 (0.29%) of 16,573 patients. The origin of the circumflex (Cx) artery from the right coronary artery (RCA) or right sinus of Valsalva was the most common anomaly (28 patients [58.3%]). An anomalous RCA originating from the left anterior descending artery (LAD) or Cx artery was observed in six patients (12.5%). The left coronary artery originated from the right sinus of Valsalva in five patients, and the LAD originated from the RCA or the right sinus of Valsalva in five patients. The RCA originated from the left sinus of Valsalva in three patients and from an ectopic ostium in the ascending aorta in one patient. CONCLUSIONS: The most frequent anomaly observed in the present study was related to the Cx artery, which is consistent with previous reports. Although coronary artery anomalies are rare, they may cause difficulties during coronary interventions or cardiac surgery and may occasionally result in sudden cardiac death. Therefore, the recognition and diagnosis of these anomalies is important and requires specialization in coronary angiographic techniques and other imaging modalities. PMID- 23940437 TI - High-sensitivity C-reactive protein levels and treadmill exercise test responses in men and women without overt heart disease. AB - BACKGROUND: C-reactive protein (CRP) is a marker of systemic inflammatory activity and may be modulated by physical fitness. Treadmill exercise testing is used to evaluate cardiovascular health through different variables including exercise capacity, heart rate and blood pressure responses. It was hypothesized that CRP levels are associated with these variables in men and women without overt heart disease. METHODS: A total of 584 asymptomatic subjects (317 [54.3%] women and 267 [45.7%] men) were enrolled in the present study and underwent clinical evaluation. CRP levels in men and women were examined relative to clinical characteristics and to variables of treadmill exercise testing: peak heart rate, exercise systolic blood pressure, exercise time, chronotropic reserve and heart rate recovery at the first and second minutes after exercise. Multivariate analysis was performed using a log-linear regression model. RESULTS: In women, exercise time on the treadmill exercise test (P=0.009) and high-density lipoprotein cholesterol levels (P=0.002) were inversely associated with CRP levels. Body mass index (P<0.001) and total cholesterol levels (P=0.005) were positively associated with CRP levels. In men, exercise time on the treadmill exercise test was inversely associated with CRP levels (P=0.015). Body mass index (P=0.001) and leukocyte count (P=0.002) were positively associated with CRP levels. CRP levels were not associated with peak heart rate, chronotropic reserve, heart rate recovery at the first and second minutes, or exercise systolic blood pressure. CONCLUSIONS: These findings contribute to the evidence that CRP is lower in individuals with better exercise capacity and demonstrate that this relationship is also apparent in individuals without overt heart disease undergoing cardiovascular evaluation through the treadmill exercise test. Lowering inflammatory markers may be an additional reason to stimulate sedentary individuals with low exercise capacity in the treadmill exercise test to improve physical conditioning through regular exercise. PMID- 23940438 TI - Pulmonary embolism, part I: Epidemiology, risk factors and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism. AB - Pulmonary embolism is an important clinical entity with considerable mortality despite advances in diagnosis and treatment. In the present article, the authors offer a comprehensive review focused mainly on epidemiology, risk factors, risk stratification, pathophysiological considerations and clinical presentation. Diagnosis based on assessment of clinical likelihood, electrocardiography, chest x-ray, D-dimer levels, markers of myocardial injury and overload, and blood gases is discussed in detail. Special attention is devoted to the clinical use of computed tomography, pulmonary angiography and echocardiography in the setting of pulmonary embolism. PMID- 23940439 TI - Pulmonary embolism, part II: Management. AB - Acute pulmonary embolism (PE) bears a significant burden on health and survival. Rapid and accurate risk stratification and management are of paramount importance to ensure the highest quality of care. This present article summarizes currently available and emerging management strategies for the disease. The authors not only review current evidence regarding early therapy of acute PE, including supportive care, anticoagulation, thrombolysis, surgical and catheter-based treatment, but also the possible role of mechanical circulatory support in PE. The authors also discuss complications related to PE and its management. PMID- 23940440 TI - Chronic diarrhea as the initial clinical manifestation of light-chain amyloidosis with cardiac involvement despite negative duodenal and rectal biopsies. AB - Early and accurate diagnosis and a prompt initiation of treatment are critical for the prognosis of light-chain amyloidosis. The present article describes a case involving a 62-year-old patient who experienced unexplained, chronic diarrhea with negative duodenal and rectal biopsies. Serum immunofixation, a free light-chain assay, electrocardiography and echocardiography were performed after the patient developed syncope. The results of these diagnostic investigations showed characteristic signs of systemic amyloidosis. Cardiac and bone marrow biopsies confirmed the diagnosis of systemic light-chain amyloidosis. The chronic diarrhea was found to be due to an autonomic neuropathy of the enteric nervous system. PMID- 23940441 TI - Myocardial inflammation in polymyalgia rheumatica assessed using cardiac magnetic resonance imaging. PMID- 23940442 TI - Wenxin Keli suppresses atrial substrate remodelling after epicardial ganglionic plexi ablation. AB - BACKGROUND: The chronic effects of ganglionic plexi (GP) ablation on atrial fibrillation (AF) inducibility have not been elucidated. OBJECTIVE: To investigate the effect of Wenxin Keli (WK) on the inducibility of AF and atrial substrate remodelling after epicardial GP ablation. METHODS: Twenty dogs were randomly divided into a sham-operated group, a GP ablation group and a WK-treated group. All animals underwent a left thoracotomy at the fourth intercostal space. AF inducibility was assessed by burst rapid pacing at the right atrium. Both the GP ablation group and the WK-treated group received four major GP ablations. In the WK-treated group, dogs were treated with oral WK once per day, and all animals were allowed to recover for eight weeks, after which AF inducibility and AF duration were measured again. RESULTS: After eight weeks of WK treatment, AF inducibility was lower than in the GP ablation group, and was similar to that of the sham-operated group. Compared with the sham-operated group, the levels of atrial natriuretic peptide (ANP), tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 in right atrial tissues were increased in GP ablation group (143.6+/-33.7 pg/mg versus 206.2+/-41.4 pg/mg, P=0.02; 75.3+/-12.1 pg/mg versus 141.3+/-64 pg/mg, P=0.03; and 175.1+/-42.5 pg/mg versus 351.7+/-101 pg/mg, P<0.01, respectively). There were no significant differences in levels of ANP, TNF-alpha and IL-6 in atrial tissues between the sham-operated group and WK treated group. Expression of connexin 43 in atrial tissues was increased after eight weeks of GP ablation, while WK administration inhibited connexin 43 remodelling. CONCLUSIONS: Epicardial GP ablation can induce atrial substrate remodelling, including Cx43 upregulation and increased levels of ANP, TNF-alpha and IL-6. These changes may be suppressed by long-term oral WK administration. PMID- 23940443 TI - Substrate-dependent modulation of oxidative phosphorylation in isolated mitochondria following in vitro hypoxia and reoxygenation injury. AB - BACKGROUND/OBJECTIVES: Previous studies using isolated mitochondria have provided new insight into the mechanisms and interventions for ischemia and reperfusion (I/R) injury. In in vitro experiments involving isolated mitochondria, hypoxia and reoxygenation (H/R) has been widely used to mimic I/R injury. However, in in vitro H/R mitochondrial experiments, the effects of various substrates on mitochondrial oxidative phosphorylation are unclear. In the present study, the effects of in vitro I/R injury on mitochondrial oxidative phosphorylation under different substrate conditions were investigated. METHODS: Hypoxia was achieved following complete consumption of oxygen by mitochondria isolated from rat heart tissue in an experimental chamber. The H/R protocol involved 30 min hypoxia followed by 15 min reoxygenation in a chamber opened to the atmosphere. Mitochondrial respiration and respiratory control ratio (RCR) were measured. RESULTS: When pyruvate/malate were used as substrates, H/R significantly decreased state 3 respiration (28.2+/-12 nmol O2/min/mg protein) and RCR (2.7+/ 0.8) compared with the control (121.4+/-32.5 nmol O2/mg protein/min and 7.8+/ 1.2, respectively). In contrast, when succinate was used without rotenone, H/R significantly increased state 3 respiration (57.0+/-11.2 nmol O2/mg protein/min) and RCR (2.0+/-0.3) compared with the control (48.2+/-12.3 nmol O2/mg protein/min and 1.3+/-0.2, respectively). CONCLUSIONS: The present study demonstrated that mitochondrial oxidative phosphorylation can be modulated by H/R in vitro depending on substrate conditions. PMID- 23940444 TI - Effect of metoprolol on myocardial apoptosis and caspase-9 activation after coronary microembolization in rats. AB - OBJECTIVE: To explore the effect of metoprolol on myocardial apoptosis and caspase-9 activation after coronary microembolization (CME) in rats. METHODS: Forty rats were randomly divided into four groups (n=10 each): a sham operation (control) group, CME plus saline (CME) group, CME plus metoprolol (metoprolol) group and caspase-9 inhibitor Z-LEHD-FMK (ZLF) group. CME was induced by injecting 3000 polyethylene microspheres (42 MUm diameter) into the left ventricle during a 10 s occlusion of the ascending aorta. Echocardiography, terminal deoxynucleotidyl transferase dUTP nick end labelling and Western blotting were used to evaluate cardiac function, apoptosis and activation of caspase-9/caspase-3, respectively, 6 h after CME. RESULTS: The echocardiographic parameters of left ventricular function were significantly decreased in the CME group compared with the control group (P<0.05); however, the metoprolol group and ZLF group showed significantly improved cardiac function compared with CME alone (P<0.05). Compared with the control group, the myocardial apoptosis rate and the levels of activated caspase-9 and -3 increased significantly in the CME group (P<0.05). Again, these effects were ameliorated by metoprolol and ZLF (P<0.05). CONCLUSIONS: The present study demonstrates that metoprolol and ZLF can protect the rat myocardium during CME by inhibiting apoptosis and improving cardiac function, likely by inhibiting apoptosis/ mitochondrial apoptotic pathway. These results suggest that antiapoptotic therapies may be useful in treating CME. PMID- 23940445 TI - Effectiveness of a new inflatable balloon device for gluing dissected layers in an experimental model of aortic dissection. AB - OBJECTIVES: In the surgical treatment of acute aortic dissection, tissue glues are widely used to reinforce the adhesion between the dissected aortic layers. A new inflatable balloon device was developed to compress the dissected aortic wall during gluing to increase adhesion between the dissected layers. The present study used an ex vivo experimental animal model to test the hypothesis that this device is effective when gluing the true and false channels of dissected aortas. METHODS: In the ex vivo experimental model, aortic dissection was simulated surgically on 12 fresh bovine aorta samples. In six samples (group I), the inflatable balloon device was inserted into the aorta to reinforce and fuse the dissected layers during gluing. The other six fresh bovine aortic samples (group II) were compressed between the surgeon's fingers during gluing. Aortic samples were evaluated and compared macroscopically and histologically. RESULTS: In group I, adhesion between the dissected layers was easily achieved during gluing. All false cavities were perfectly closed, with no deleterious effects related to the device. In group II, the adhesion between the dissected layers was not complete and some false cavities remained patent. CONCLUSIONS: The inflatable balloon device can increase the adhesive effect of tissue glues via homogenous compression of the dissected aortic layers. In addition, the balloon can prevent distal embolization of the glue. PMID- 23940446 TI - The effects of cyclooxygenase and nitric oxide synthase inhibition on cardiodynamic parameters and coronary flow in isolated rat hearts. AB - BACKGROUND: Despite the widespread clinical use of cyclooxygenase (COX) inhibitors, dilemmas regarding the potential impact of these drugs on the cardiovascular system persist. OBJECTIVE: To estimate the effects of different COX inhibitors (meloxicam, acetylsalicylic acid [ASA] and SC-560) on cardiac function and coronary flow in isolated rat hearts, with special focus on the L arginine/nitric oxide system. METHODS: The hearts of eight-week-old male Wistar albino rats (n=72; 12 rats per group; body mass 180 g to 200 g) were retrogradely perfused according to the Langendorff technique at gradually increased perfusion pressure (40 cmH2O to 120 cmH2O). After control experiments, the hearts were perfused with the following drugs: 100 MUM ASA, alone or in combination with 30 MUM N(omega)-nitro-L-arginine monomethyl ester (L-NAME), 0.3 MUM meloxicam with or without 30 MUM L-NAME, 3 MUM meloxicam with or without 30 MUM L-NAME, 30 MUM L NAME and 0.25 MUM SC-560. In the control and experimental groups, the following parameters of heart function were continuously recorded: maximum rate of left ventricular pressure development, minimum rate of left ventricular pressure development, systolic left ventricular pressure, diastolic left ventricular pressure, heart rate and mean blood pressure. Coronary flow was measured flowmetrically. The amount of released NO2 (-) was determined spectrophotometrically in coronary venous effluent. RESULTS: While meloxicam and SC-560 were found to have an adverse influence on cardiac function and coronary perfusion, ASA did not negatively affect the intact model of the heart. CONCLUSION: It appeared that interaction between COX and the L-arginine/nitric oxide system truly exists in coronary circulation and may explain the causes of the observed effects. PMID- 23940447 TI - The effect of trans-resveratrol on platelet-neutrophil complex formation and neutrophil burst in hypercholesterolemic rats. AB - Transresveratrol (t-resveratrol; 3,5,4'-trihydroxy-trans-stilbene) is a polyphenolic compound found in fresh grapes, grape juice and wine, and has been found to reduce the total cholesterol level in hypercholesterolemic rats. The objective of the present study was to assess the effects of t-resveratrol on platelet-neutrophil complex formation and neutrophil reactive oxygen species (ROS) status in control and hypercholesterolemic rats using a modified flow cytometric method. Rats (n=80) were divided into five groups (control, ethanol, resveratrol, hypercholesterolemic and resveratrol-administered hypercholesterolemic groups), comprising 16 animals per group. Serum levels of lipids and H2O2 were determined using commercially available kits, while platelet neutrophil complex formation and neutrophil ROS status were determined using a modified flow cytometric method. Serum total cholesterol and low-density lipoprotein cholesterol levels were found to be increased and the high-density lipoprotein cholesterol level was found to be decreased in the HC group compared with the control group (P<0.001). Treatment of HC rats with t-resveratrol significantly lowered total cholesterol and low-density lipoprotein cholesterol levels (P<0.001). In the hypercholesterolemic group, levels of serum H2O2 platelet-neutrophil complex formation and neutrophil ROS status were significantly increased (P<0.001). On the other hand, in the resveratrol administered hypercholesterolemic group, serum H2O2 levels, platelet-neutrophil complex formation and neutrophil ROS status were decreased compared with the hypercholesterolemic group (P<0.001). Serum H2O2 levels, platelet-neutrophil complex and neutrophil ROS status were positively correlated with one another. The present study is the first to demonstrate the protective effect of t resveratrol against hypercholesterolemia-induced platelet-neutrophil complex formation and neutrophil ROS burst. Further investigations on its plausible role in antihypercholesterolemic treatment are warranted. PMID- 23940448 TI - A modified murine model for the study of reverse cardiac remodelling. AB - BACKGROUND: The authors previously reported a murine model of left ventricular hypertrophy (LVH) and regression using a suture technique of transverse aortic arch constriction and subsequent removal. A number of issues have limited the widespread adoption of this method. The present study assessed a modification of this model using a titanium clip. METHODS: Male C57BL/6 mice (n=95) underwent minimally invasive aortic banding for three, four or six weeks with or without subsequent band removal for one week. Hearts were evaluated both structurally and functionally using heart weight/body weight ratios, transthoracic echocardiography and direct left ventricular pressure measured using catheterization. RESULTS: Clip banding resulted in a threefold gradient across the transverse aortic arch. Pressure overload induced concentric LVH by three weeks that progressively decompensated. By six weeks, hearts were significantly dilated, with poor left ventricular function. Clips were removed in a minimally invasive procedure after each time point. When overloaded for either three or four weeks, removal of the clip with subsequent pressure relief enabled regression of LVH and restoration of function. When removed after six weeks of banding, mouse hearts were unable to reverse remodel and maintained elevated left ventricular end-diastolic pressures and lung congestion. CONCLUSIONS: The application and removal of a titanium clip successfully induced pressure overload and relief associated with the serial development and reversal of LVH. Compared with similar models using suture ligation and release, this method was found to be a simple, effective (no slipped bands) and reproducible method to study murine LVH, heart failure and its regression. PMID- 23940449 TI - Functions of cyclophilin A in atherosclerosis. AB - Cyclophilin A (CypA) is a ubiquitously distributed protein present both in intracellular and extracellular spaces. In atherosclerosis, various cells, including endothelial cells, monocytes, vascular smooth muscle cells and platelets, secrete CypA in response to excessive levels of reactive oxygen species. Atherosclerosis, a complicated disease, is the result of the interplay of different risk factors. Researchers have found that CypA links many risk factors, including hyperlipidemia, hypertension and diabetes, to atherosclerosis that develop into a vicious cycle. Furthermore, most studies have shown that secreted CypA participates in the developmental process of atherosclerosis via many important intracellular mechanisms. CypA can cause injury to and apoptosis of endothelial cells, leading to dysfunction of the endothelium. CypA may also induce the activation and migration of leukocytes, producing proinflammatory cytokines that promote inflammation in blood vessels. In addition, CypA can promote the proliferation of monocytes/macrophages and vascular smooth muscle cells, leading to the formation of foam cells and the remodelling of the vascular wall. Studies investigating the roles of CypA in atherosclerosis may provide new direction for preventive and interventional treatment strategies in atherosclerosis. PMID- 23940450 TI - Correlation between major adverse cardiac events and coronary plaque characteristics. AB - BACKGROUND: Unstable plaque is believed to be responsible for major adverse cardiac events (MACE). OBJECTIVE: To determine whether coronary computed tomography angiography (CCTA) could be used to predict future MACE. METHODS: Patients undergoing CCTA between January 2008 and February 2010 were consecutively enrolled in the study. The hospital database was screened for patients who later developed acute ST segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) or cardiac death. Plaque scores were calculated and analyzed using one-way ANOVA to examine the relationship between plaque scores and MACE. RESULTS: Of the 8557 patients who underwent CCTA, 1055 had hospital records available for follow-up. During follow-up, 25 patients experienced MACE including death (six patients), heart failure (two patients), STEMI (11 patients) and NSTEMI (six patients). The plaque scores were significantly increased in patients who later died, developed heart failure or experienced STEMI (P<0.05). Calcification, erosion and severe stenosis were responsible for the events (P<0.05). Mild and moderate lesions, positive remodelling, drug-eluting stent placement, occlusion and diffuse lesions were not predictive of MACE (P>0.05). CONCLUSION: Severe calcification, erosion and severe stenosis predict death, heart failure and STEMI. PMID- 23940451 TI - Predictors of preinterventional patency of infarct-related artery in patients with ST-segment elevation myocardial infarction: Importance of neutrophil to lymphocyte ratio and uric acid level. AB - BACKGROUND: Patients with ST-segment elevation myocardial infarction (STEMI) and a patent infarct-related artery (IRA) experience lower mortality and better clinical outcome, but little is known about the predictors of IRA patency before primary percutaneous coronary intervention (PCI) in the setting of STEMI. OBJECTIVE: To assess possible predictors of patency of IRA before primary PCI in patients with STEMI. METHODS: A total of 880 patients with STEMI undergoing primary PCI were prospectively included (646 male, 234 female; mean [+/- SD] age 58.5+/-12.4 years). Blood samples were obtained on admission to investigate biochemical markers. Preinterventional thrombolysis in myocardial infarction (TIMI) flow was assessed in all patients. The patients were divided into two groups according to the pre-PCI TIMI flow as impaired flow group (TIMI flow 0, 1 and 2) and normal flow group (TIMI flow 3). Transthoracic echocardiography was performed in all patients. RESULTS: Eighty-three (9.43%) patients had pre-PCI TIMI 3 flow in IRA. Uric acid levels and neutrophil to lymphocyte (N to L) ratio in the normal flow group were lower than in the impaired flow group (P<0.001 for both). However, ejection fraction (EF) was higher in the normal flow group than in the impaired flow group. Multivariate logistic regression analysis showed that IRA patency was independently associated with serum uric acid level (beta 0.673 [95% CI 0.548 to 0.826]; P<0.001), N to L ratio (beta 0.783 [95% CI 0.683 to 0.897]; P<0.001) and EF (beta 1.033 [95% CI 1.006 to 1.061]; P=0.016). CONCLUSION: Serum uric acid level, N to L ratio and EF are independent predictors of the pre-PCI patency of IRA in patients with STEMI undergoing primary PCI. PMID- 23940452 TI - Nitrate-induced paradoxical ischemia predicts adverse outcomes in elderly patients with healed myocardial infarcts. AB - BACKGROUND: It is well known that nitrates can induce paradoxical myocardial ischemia. METHODS AND RESULTS: Fifty patients (median age 73 years; range 67 to 78 years; 80% male) with healed myocardial infarcts were selected. All patients underwent resting single-photon emission computed tomography (SPECT) and resting baseline gated-SPECT using sestamibi or thallium-201 after the sublingual administration of 5 mg isosorbide dinitrate (ISD). Forty-eight per cent (24 of 50) of the patients demonstrated ISD-induced peri-infarct ischemia as observed by SPECT. Compared with patients without ISD-induced ischemia, patients with ISD induced ischemia presented larger infarcts as determined by the extent of perfusion defects (mean [+/- SD] 27+/-12 pixels versus 11+/-9 pixels; P<0.0001), lower ejection fractions (39+/-17% versus 50+/-15%; P<0.02) and a higher incidence of severe coronary artery disease (P<0.04). At five years, the survival probability on Kaplan-Meier analysis was 42% and 96% for patients with and without ISD-induced ischemia, respectively (HR 5.6 [95% CI 1.6 to 20]; P=0.009). CONCLUSIONS: Nitrates may have low efficacy in improving blood flow through the coronary vessels that supply large myocardial infarcts with high-resistance microvascular damage. At the same time, nitrates induce dilation and blood pressure decrease in remotely patent or mildly stenotic vessels. The blood pressure gradient elicited between the high- and low-resistance coronary vessels may provide the force for a blood flow steal from the viable zones of the infarct toward the healthy myocardium. The resultant nitrate-induced paradoxical ischemia could be a silent marker of myocardial instability and adverse outcomes in elderly patients with healed myocardial infarcts. PMID- 23940453 TI - Oxidative stress: Predictive marker for coronary artery disease. AB - The role of oxidative stress in cardiovascular disease processes, such as atherogenesis, ischemic-reperfusion injury and cardiac remodelling, has been increasingly recognized in the past few decades. Currently, an increasing number of studies suggest that levels of oxidative stress markers in body fluids correlate with atherosclerotic disease activity. This finding may lead to novel clinical approaches in patients with coronary artery disease. Assessment of oxidative stress markers could modify risk stratification and treatment of patients with suspected coronary artery disease or myocardial infarction. PMID- 23940454 TI - Exercise-induced ST-segment elevation during the recovery phase of an exercise stress test. AB - To the authors' knowledge, the present report represents the first case in the medical literature in which an ST-segment elevation during the recovery phase of an exercise stress test indicated significant left main coronary artery stenosis. Although the patient did not complain of chest pain during the test, the ST segment elevation persisted 20 min into recovery. PMID- 23940455 TI - Effects of low-dose hydroxychloroquine on expression of phosphorylated Akt and p53 proteins and cardiomyocyte apoptosis in peri-infarct myocardium in rats. AB - BACKGROUND: Low-dose hydroxychloroquine (HCQ) and ataxia-telangiectasia-mutated (ATM) protein kinase have recently been postulated to be beneficial for the prevention of the age-associated metabolic syndrome including hypertension, hypercholesterolemia and glucose intolerance; however, the effects of low-dose HCQ on the expression of ATM downstream phosphorylated Akt (protein kinase B) and p53 proteins and cardiomyocyte apoptosis in the peri-infarct myocardium remain unclear. OBJECTIVE: To explore the effects of low-dose HCQ on the expression of phosphorylated Akt and p53 proteins and cardiomyocyte apoptosis in the peri infarct myocardium in a rat model. METHODS: Myocardial infarction (MI) was induced experimentally in a subset of rats, while others underwent sham operation (sham). Three days after operation, surviving Sprague-Dawley male rats were divided into MI+HCQ, MI, sham+HCQ and sham groups. MI+HCQ and sham + HCQ groups were treated with HCQ (3.4 mg/kg); and MI and sham groups were treated with phosphate buffered (ie, physiological) saline (10 mL/kg) by gavage every day for 12 weeks. The expression of phosphorylated Akt and p53 proteins and cardiomyocyte apoptosis in the peri-infarct myocardium was detected by Western blot and terminal deoxynucleotidyl transferase dUTP nick end labelling, respectively. RESULTS: Twelve weeks after treatment, the expression of phosphorylated Akt protein was significantly increased (P<0.05). Expression of phosphorylated p53 protein was not significantly different (P>0.05) in the peri-infarct myocardium of the MI+HCQ group from that in the MI group. The cardiomyocyte apoptosis rate in the peri-infarct myocardium was significantly decreased in the MI+HCQ group compared with the MI group (P<0.05). CONCLUSION: Low-dose HCQ can significantly increase the expression of phosphorylated Akt protein without significantly impacting expression of phosphorylated p53 protein in the peri-infarct myocardium. Accordingly, it can inhibit cardiomyocyte apoptosis in the peri infarct myocardium. PMID- 23940456 TI - Ischemic postconditioning decreases matrix metalloproteinase-2 expression during ischemia-reperfusion of myocardium in a rabbit model: A preliminary report. AB - OBJECTIVE: To investigate the effect of ischemic postconditioning on the expression of matrix metalloproteinase (MMP)-2 during ischemia-reperfusion of myocardium in a rabbit model. METHODS: Thirty-six male New Zealand white rabbits were randomly divided into sham, ischemia-reperfusion and ischemic postconditioning groups. Myocardial ischemia-reperfusion was created by ligating the left anterior descending coronary artery for 30 min followed by 3 h of reperfusion. Myocardial infarction sizes were determined by dual staining with triphenyltetrazolium chloride and trypan blue. Plasma levels of MMP-2 were measured using ELISA. Myocardial MMP-2 messenger RNA was analyzed by reverse transcription polymerase chain reaction. RESULTS: The mean (+/- SD) infarct size in the ischemic postconditioning group was significantly smaller compared with the ischemia-reperfusion group (37.1+/-3.8% versus 57.5+/-1.9%; P=0.02). The incidence of ventricular tachycardia in the ischemic postconditioning group was also lower than in the ischemia-reperfusion group (8.5% versus 75%; P=0.003). MMP 2 messenger RNA expression in the ischemic postconditioning group was significantly lower compared with the ischemia-reperfusion group (0.4944+/-0.0476 versus 0.6989+/-0.0694; P=0.02). CONCLUSION: Ischemic postconditioning reduces myocardial ischemia-reperfusion injury, possibly by inhibiting the expression of MMP-2. PMID- 23940459 TI - Bursting with randomness: a simple model for stochastic control of gene expression. PMID- 23940457 TI - Par-1 regulates tissue growth by influencing hippo phosphorylation status and hippo-salvador association. AB - The evolutionarily conserved Hippo (Hpo) signaling pathway plays a pivotal role in organ size control by balancing cell proliferation and cell death. Here, we reported the identification of Par-1 as a regulator of the Hpo signaling pathway using a gain-of-function EP screen in Drosophila melanogaster. Overexpression of Par-1 elevated Yorkie activity, resulting in increased Hpo target gene expression and tissue overgrowth, while loss of Par-1 diminished Hpo target gene expression and reduced organ size. We demonstrated that par-1 functioned downstream of fat and expanded and upstream of hpo and salvador (sav). In addition, we also found that Par-1 physically interacted with Hpo and Sav and regulated the phosphorylation of Hpo at Ser30 to restrict its activity. Par-1 also inhibited the association of Hpo and Sav, resulting in Sav dephosphorylation and destabilization. Furthermore, we provided evidence that Par-1-induced Hpo regulation is conserved in mammalian cells. Taken together, our findings identified Par-1 as a novel component of the Hpo signaling network. PMID- 23940458 TI - Linking stochastic fluctuations in chromatin structure and gene expression. AB - The number of mRNA and protein molecules expressed from a single gene molecule fluctuates over time. These fluctuations have been attributed, in part, to the random transitioning of promoters between transcriptionally active and inactive states, causing transcription to occur in bursts. However, the molecular basis of transcriptional bursting remains poorly understood. By electron microscopy of single PHO5 gene molecules from yeast, we show that the "activated" promoter assumes alternative nucleosome configurations at steady state, including the maximally repressive, fully nucleosomal, and the maximally non-repressive, nucleosome-free, configuration. We demonstrate that the observed probabilities of promoter nucleosome configurations are obtained from a simple, intrinsically stochastic process of nucleosome assembly, disassembly, and position-specific sliding; and we show that gene expression and promoter nucleosome configuration can be mechanistically coupled, relating promoter nucleosome dynamics and gene expression fluctuations. Together, our findings suggest a structural basis for transcriptional bursting, and offer new insights into the mechanism of transcriptional regulation and the kinetics of promoter nucleosome transitions. PMID- 23940460 TI - Sonic Hedgehog promotes tumor cell survival by inhibiting CDON pro-apoptotic activity. AB - The Hedgehog signaling is a determinant pathway for tumor progression. However, while inhibition of the Hedgehog canonical pathway-Patched-Smoothened-Gli-has proved efficient in human tumors with activating mutations in this pathway, recent clinical data have failed to show any benefit in other cancers, even though Sonic Hedgehog (SHH) expression is detected in these cancers. Cell adhesion molecule-related/down-regulated by Oncogenes (CDON), a positive regulator of skeletal muscle development, was recently identified as a receptor for SHH. We show here that CDON behaves as a SHH dependence receptor: it actively triggers apoptosis in the absence of SHH. The pro-apoptotic activity of unbound CDON requires a proteolytic cleavage in its intracellular domain, allowing the recruitment and activation of caspase-9. We show that by inducing apoptosis in settings of SHH limitation, CDON expression constrains tumor progression, and as such, decreased CDON expression observed in a large fraction of human colorectal cancer is associated in mice with intestinal tumor progression. Reciprocally, we propose that the SHH expression, detected in human cancers and previously considered as a mechanism for activation of the canonical pathway in an autocrine or paracrine manner, actually provides a selective tumor growth advantage by blocking CDON-induced apoptosis. In support of this notion, we present the preclinical demonstration that interference with the SHH-CDON interaction triggers a CDON-dependent apoptosis in vitro and tumor growth inhibition in vivo. The latter observation qualifies CDON as a relevant alternative target for anticancer therapy in SHH-expressing tumors. PMID- 23940462 TI - Public engagement in health priority setting in low- and middle-income countries: current trends and considerations for policy. PMID- 23940463 TI - What is patient-centred care? / Que sont les soins axes sur le patient? PMID- 23940464 TI - Wasted medications, wasted resource. PMID- 23940461 TI - Switching HIV treatment in adults based on CD4 count versus viral load monitoring: a randomized, non-inferiority trial in Thailand. AB - BACKGROUND: Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand. METHODS AND FINDINGS: The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4 only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naive HIV-infected adults (CD4 count 50-250/mm(3)) initiating non nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm(3). The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6-11.4) in VL versus 7.4% (5.1-10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2-8.4) in VL versus 7.5% (5.0-11.1) in CD4 (p=0.097). Median time from treatment initiation to switch was 11.7 months (7.7-19.4) in VL and 24.7 months (15.9-35.0) in CD4 (p=0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8-8.0) in VL versus 15.8 months (8.5-20.4) in CD4 (p=0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported. CONCLUSIONS: The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource limited settings. TRIAL REGISTRATION: ClinicalTrials.govNCT00162682 Please see later in the article for the Editors' Summary. PMID- 23940465 TI - Report says extending use of pharmacists and generic drugs can save health care system up to $11 billion over 3 years. PMID- 23940466 TI - PEI PharmaCheck program. PMID- 23940467 TI - Physicians and pharmacists call for more rapid implementation of e-prescribing in Canada. PMID- 23940468 TI - Distribution of diluted chemo drugs leads to new oversight in Ontario: OCP receives broader inspection powers. PMID- 23940469 TI - Still some short-term pain for New Brunswick pharmacists but NBPA sees encouraging signs from the province. PMID- 23940470 TI - Alberta College of Pharmacists confirms it will proceed with inducements ban but enabling mechanism still under review. PMID- 23940471 TI - Pace of growth in drug expenditures slows to lowest level in 16 years: CIHI. PMID- 23940472 TI - Another successful University of Saskatchewan Pharmacy Student Business Plan Competition. PMID- 23940473 TI - Public health watch. PMID- 23940474 TI - The use of pregabalin in the treatment of hot flashes. PMID- 23940475 TI - A mixed-methods evaluation of a nurse-pharmacist-managed pain clinic: Design, rationale and limitations. PMID- 23940476 TI - How well do pharmacists know their patients? A case report highlighting natural health product disclosure. PMID- 23940477 TI - Domperidone withdrawal in a breastfeeding woman. PMID- 23940478 TI - Review of the top 5 cardiology studies of 2011-12. PMID- 23940479 TI - Pharmacist and physician views on collaborative practice: Findings from the community pharmaceutical care project. AB - BACKGROUND: Strong working relationships between pharmacists and physicians are needed to optimize patient care. Understanding attitudes and barriers to collaboration between pharmacists and physicians may help with delivery of primary health care services. The objective of this study was to capture the opinions of family physicians and community pharmacists in Newfoundland and Labrador (NL) regarding collaborative practice. METHODS: Two parallel surveys were offered to all community pharmacists and family physicians in NL. Surveys assessed the following: attitudes and experience with collaborative practice, preferred communication methods, perceived role of pharmacists, areas for more collaboration and barriers to collaborative practice. Results for both groups were analyzed separately, with comparisons between groups to compare responses with similar questions. RESULTS: Survey response rates were 78.6% and 7.1% for pharmacists and physicians, respectively. Both groups overwhelmingly agreed that collaborative practice could result in improved patient outcomes and agreed that major barriers were lack of time and compensation and the need to deal with multiple pharmacists/physicians. Physicians indicated they would like more collaboration for insurance approvals and patient counselling, while pharmacists want to assist with identifying and managing patients' drug-related problems. Both groups want more collaboration to improve patient adherence. CONCLUSION: Both groups agree that collaborative practice can positively affect patient outcomes and would like more collaboration opportunities. However, physicians and pharmacists disagree about the areas where they would like to collaborate to deliver care. Changes to reimbursement models and infrastructure are needed to facilitate enhanced collaboration between pharmacists and physicians in the community setting. PMID- 23940481 TI - CPhA's Pharmacist of the Year: Diane Lamarre. PMID- 23940480 TI - Satisfaction with student pharmacists administering vaccinations in the University of Alberta annual influenza campaign. AB - OBJECTIVE: To evaluate University of Alberta staff and students' acceptance of and satisfaction with receiving influenza vaccinations from student pharmacists during the university's annual influenza campaign. MATERIAL AND METHODS: A patient survey was created to collect patient demographics, influenza history and feedback on the services provided by pharmacy students and to measure willingness to receive vaccinations from a pharmacist in a community pharmacy. The 13 question survey was distributed to patients who received an influenza vaccination from a student pharmacist during the influenza campaign. KEY FINDINGS: A total of 1555 staff and students completed the satisfaction survey. Almost all (n = 1533, 99%) survey participants were satisfied or very satisfied with the service provided by student pharmacists. A total of 1437 (92%) participants agreed or strongly agreed that based on this experience, they would be willing to receive vaccinations from a pharmacist in a community pharmacy and 1526 (98%) participants rated their overall experience at the flu clinic as very good or excellent. CONCLUSIONS: Positive responses to the survey suggest that University of Alberta staff and students are satisfied with the service provided by student pharmacists. Their willingness to receive vaccines from a pharmacist in a community pharmacy highlighted public acceptance of the expanding role of pharmacists as immunizers. PMID- 23940482 TI - Closing words from CPhA's Executive Director. PMID- 23940483 TI - Health care in Canada and the role of the federal government: What's your take? PMID- 23940484 TI - Antibacterial substantivity of Carvacrol and sodium hypochlorite in infected bovine root dentin. AB - INTRODUCTION: Various methods commonly used for cleaning and shaping root canals have not been successful in completely eradicating bacteria due to anatomic complexity and root canals irregularities. Disinfecting the canals with intracanal irrigants in addition to proper cleaning and shaping can produce a successful outcome. Antimicrobials with sustained antibacterial activity would be desirable for irrigation. The purpose of this study was to compare the antimicrobial substantivity of Carvacrol and 5.25% NaOCl in infected bovine root dentin. MATERIALS AND METHODS: One hundred and twenty dentin tubes prepared from bovine incisors were infected in vitro for 14 days with Enterococcus (E) faecalis. The specimens were divided into four groups including 1) Carvacrol, 2) NaOCl, 3) infected dentin tubes (positive control); and 4) sterile dentin tubes (negative control). Dentin chips were collected at five intervals (days 0, 1, 3, 7 and 28) using round burs with sequentially increasing diameters (which includes five layers of dentin) into Brain Heart Infusion (BHI) broth. In order to compare the pre- and post-irrigation antimicrobial activity of the irrigants the colony forming units (CFU) were counted and classified as 'CFU-before' and 'CFU-after'. After culturing, the number of CFU with the various experimental time and dentinal layers was recounted. Two-way ANOVA test was used to analyze the effects of time and materials. One-way ANOVA and supplemental Tukey HSD test were used for pair comparison. RESULTS: CFU was significantly reduced in NaOCl group when compared to all other experimental groups (P<0.05). CONCLUSION: The substantivity of NaOCl was significantly greater than Carvacrol. Further studies are required to investigate and approve Carvacrol as a final irrigant. PMID- 23940485 TI - Dental pulp reaction to exposure at different time intervals in open apex canine teeth of cats. AB - INTRODUCTION: Open-apex teeth with irreversible pulpitis require complex and difficult treatment. Providing the right environment for apexogenesis and pulp protection is vital for their long term prognosis. The young pulp of open apex tooth, however, is better equipped against irritation and assault. The aim of this study was to evaluate pulp inflammation in open apex canine teeth of cats. MATERIALS AND METHODS: In this in vivo study, twelve cats with open apex canines were used. Pulps were iatrogenically exposed and the animals were sacrificed at one, seven, thirty and ninety days after pulp exposure. Samples were prepared for histological evaluations. RESULTS: During the first and seventh day, changes were limited to acute inflammation in the coronal pulp. During the first month pulp changes in 45.5% of samples were similar to the seventh day. In the other samples necrosis and abscess spread to the end of the root, and internal resorption and periapical abscess were observed. In 45.5% of samples in the apical region vital tissue was barely observed (during 90 days); in 54.5% of samples however, complete pulp necrosis, internal resorption and a large periapical lesion was observed. CONCLUSION: In one and seven-day periods pulp tissue was vital, however, in the thirty and ninety-day periods, minority of the pulp samples were vital. PMID- 23940486 TI - Root canal cleaning efficacy of rotary and hand files instrumentation in primary molars. AB - INTRODUCTION: Pulpectomy of primary teeth is commonly carried out with hand files and broaches; a tricky and time consuming procedure. The purpose of this in vitro study was to compare the cleaning efficacy and time taken for instrumentation of deciduous molars using hand K-files and Flex Master rotary system. MATERIALS AND METHODS: In this study, 68 canals of 23 extracted primary molars with at least two third intact roots and 7-12 mm length were selected. After preparing an access cavity, K-file size #15 was introduced into the root canal and India ink was injected with an insulin syringe. Sixty samples were randomly divided in to experimental groups in group I (n=30), root canals were prepared with hand K files; in group II (n=30), rotary Flex Master files were used for instrumentation, and in group III 8 remained samples were considered as negative controls. After clearing and root sectioning, the removal of India ink from cervical, middle, and apical thirds was scored. Data was analyzed using student's T-test and Mann-Whitney U test. RESULTS: There was no significant difference between experimental groups cleaning efficacy at the cervical, middle and apical root canal thirds. Only the coronal third scored higher in the hand instrumented group (P<0.001). Instrumentation with Flex Master rotary files was significantly less time consuming (P<0.001). CONCLUSION: Although there was no difference in cleanliness efficacy at the apical and middle thirds, the coronal third was more effectively cleaned with hand files. Predictably, time efficiency was a significant advantage with rotary technique. PMID- 23940487 TI - Efficacy of MTAD, Glyde and EDTA in debridement of curved root canals. AB - INTRODUCTION: This study aimed to compare the efficacy of MTAD, Glyde and EDTA in removing the post-preparation smear layer and debris produced in apical third of curved molar root canals. MATERIALS AND METHODS: Forty extracted human maxillary first molars with curved mesiobuccal canals (30-35), similar root lengths and morphologies were divided into 3 experimental groups (n=12) and one control group (n=4). Canals were prepared by RaCe rotary files and were treated with the following materials between each two files: Group A (control group); 5 mL of distilled water, Group B; 1 mL of 17% ethylenediamine tetra-acetic acid (EDTA) for 1 min, Group C; BioPure(TM) MTAD (according to the manufacturer's instruction; 5mL for 5 min), and Group D; Glyde File Prep alternated with sodium hypochlorite (NaOCl) between each two files. Debridement of the apical third was evaluated using scanning electron microscope (SEM) (*5000). The data were statistically analyzed using the Kruskal-Wallis and Mann-Whitney U tests (P<0.05). RESULTS: Statistical analysis of the data showed that MTAD and 17% EDTA were effective in removing smear layer and debris from the apical thirds. MTAD was more effective than EDTA in smear layer removal. Glyde did not adequately debride curved root canals of molar teeth. CONCLUSION: MTAD and 17% EDTA were effective in debriding the apical third of curved molar root canals during endodontic treatment, whereas Glyde File Prep does not provide adequate debridement. PMID- 23940489 TI - Comparison of removed dentin thickness with hand and rotary instruments. AB - INTRODUCTION: The aim of this study was to evaluate the amount of dentine removed after canal preparation using stainless steel (SS) hand instruments or rotary ProFile instruments. MATERIALS AND METHODS: Thirty-six extracted human teeth with root canal curvatures less than 30o were embedded in clear polyester resin. The roots were cut horizontally at apical 2, 4 and 7 mm. Dentin thickness was measured at each section and the sections were accurately reassembled using a muffle. Root canals were randomly prepared by SS hand instruments or rotary ProFile instruments. Root sections were again separated, and the remaining dentin thickness was measured. Mann-Whitney U and t tests were performed for analytic comparison of the results. RESULTS: The thickness of removed dentin was significantly different between the two used methods (P<0.05). Significantly greater amounts of dentin was removed mesially in all sections in hand instrumentation group (P<0.001). CONCLUSION: ProFile rotary instrumentation prepares root canals with a greater conservation of tooth structure. PMID- 23940488 TI - Evaluation of the antimicrobial effects of MTAD, NaOCl against selected endodontic pathogens. AB - INTRODUCTION: The aim of this study was to compare the antimicrobial effects of MTAD, sodium hypochlorite (NaOCl) and their combination on endodontic micro organisms. MATERIALS AND METHODS: Zone of Inhibition (ZI) and Minimum Inhibitory Concentration (MIC) were the techniques used. In ZI technique blood agar plates were inoculated with organisms, paper discs were soaked with irrigants and maximum zones of bacterial inhibition were recorded. In the MIC technique the irrigants were serially diluted in TSB tubes and 0.1 mL of the tested microbe solutions were added. Results were obtained on the basis of turbidity and growth on agar plates. Statistical analyses were carried out using ANOVA and Tukey tests. RESULTS: In ZI technique, we investigated 120 specimens including 5 microbial species, 3 irrigants and their control groups, each with 6 repetitions. The results demonstrated MTAD greater antimicrobial efficacy compared to NaOCl, and their mixture (M+N) against Staphylococcus (S) aureus, Enteric (E) bacteria and Enterococcus (E) faecalis (P<0.001). NaOCl was more effective in eradicating Candida (C) albicans than the others (P<0.01). MIC method (155 tubes) showed MTAD to be more effective against E. bacteria and S. aureus. MTAD and NaOCl were equally effective against E. faecalis; however, NaOCl was more effective against C. albicans. CONCLUSION: Bacterial species were more susceptible to MTAD than NaOCl, C. albicans, however, was more susceptible to NaOCl. The advantage of NaOCl is that it has broad spectrum antimicrobial activity. The joint solution (M+N) did not prove to be more effective than their individual use. PMID- 23940490 TI - Ion release and pH of a new endodontic cement, MTA and Portland cement. AB - INTRODUCTION: This in vitro study measured and compared pH and phosphate and calcium ions release of a new endodontic material (CEM cement), mineral trioxide aggregate (MTA), and Portland cement (PC) using UV-visible technique, atomic absorption spectrophotometry methods, and pH meter, respectively. MATERIALS AND METHODS: Each material was placed in a plastic tube (n=10) and immersed in a glass flask containing deionized water. Half of the samples were tested for determining pH and released ions after 1h, 3h, 24h, 48h, 7d and 28d. Remaining samples (n=5), were evaluated after 28d. Data was analyzed using one way ANOVA and Tukey tests. RESULTS: Results indicated that all materials were highly alkaline and released calcium and low concentration of phosphate ions in all the time intervals. CEM cement released considerably higher concentration of phosphate during the first hour (P<0.05). CONCLUSION: This novel endodontic cement promoted alkaline pH in a similar manner to MTA and released calcium and phosphate. These conditions can stimulate the calcification process and explain the basic physico-chemical mechanisms of hard tissue regeneration of CEM cement. PMID- 23940491 TI - Endodontic treatment of two-canalled maxillary central and lateral incisors: a case report. AB - Familiarity with the intricacies and variations of root canal morphology is essential for successful endodontic treatment. Maxillary central and lateral incisors are known to be single-rooted with one canal, however, this case report describes endodontic treatment of maxillary central and lateral incisors with two buccopalatal root canals. PMID- 23940492 TI - Erythrodermic mycosis fungoides with hypereosinophilic syndrome: a rare presentation. AB - Mycosis fungoides (MF) is the most common variant of primary cutaneous T-cell lymphoma (CTCL). It is generally associated with an indolent clinical course and characterised by well-defined clinicopathological features. Although rare, CTCLs constitute 65% of all cutaneous lymphoid malignancies, of which 50% are patients with MF. The erythrodermic variants of MF, a malignancy of mature, skin homing and clonal T lymphocytes, usually present in mid to late adulthood. Association with hypereosinophilia is important in prognosis. We report a case of erythrodermic MF with hypereosinophilic syndrome in a 22-year-old female presenting with gradually progressive intractable erythroderma with intensely pruritic multiple papules, plaques, and nodules involving more than 90% of body surface area. Diagnosis was confirmed by histopathological examination and immunophenotyping from multiple skin biopsies. PMID- 23940493 TI - Cancer incidence in Rabat, Morocco: 2006-2008. AB - INTRODUCTION: No population-based data of cancer incidence from Morocco have been published before. This is the first report of cancer incidence in Rabat from a population-based cancer registry for the period 2006-2008. MATERIALS AND METHODS: The cancer registry collects data on all new cases of cancer diagnosed in the resident population of the Rabat area. Data collection is an active process involving visits by registry staff to all data sources, essentially hospitals, pathological laboratories, and private clinics in Rabat. RESULTS: A total of 2,473 new cases of cancer were registered among residents in Rabat during the period 2006-2008. The overall world age-standardised rate (ASR) for all sites combined was 136.6/100,000 for men and 114.5/100,000 for women. The most frequently diagnosed malignancies in males were lung cancer (19.0%, ASR 24.8/10(5)), followed by prostate cancer (15.5%, ASR 22.9/10(5)), colorectal cancer (8.8%, ASR 12.0/10(5)), bladder cancer (6.9%, ASR 9.7/10(5)), and non Hodgkin's lymphoma (NHL) (6.0%, ASR 8.2/10(5)). In females, the most frequently reported malignancies were breast cancer (39.9%, ASR 43.4/10(5)), followed by cervix uteri cancer (11.4%, ASR 13.0/10(5)), colorectal cancer (7.5%, ASR 9.0/10(5)), NHL (3.4, ASR 4.2/10(5)), and thyroid cancer (3.4%, ASR 3.9/10(5)). Of all cancers, 2% are observed in childhood (0-14 years), and ~43% of them are malignant haemopathies. CONCLUSION: The data reported by Rabat Cancer Registry indicate that cancers of the breast, cervix, uteri, and colon and rectum in females and the lung, prostate, and colon and rectum in men are major cancers in the population of Rabat. The Incidences observed are sometimes different from those observed in the neighbouring North African countries. PMID- 23940494 TI - Salmonella paratyphi B meningitis in an infant. AB - We report a case of Salmonella paratyphi B meningitis in a 90 day-old male infant who was admitted with complaints of fever, vomiting and one episode of vacant stare. Clinically, the infant was found to be toxic and dull with a bulging anterior fontanelle. Subsequently, blood and cerebrospinal fluid cultures demonstrated the presence of Salmonella Paratyphi B organism. PMID- 23940495 TI - Baseline antibody titres against Salmonella typhi in apparently asymptomatic HIV positive individuals in a tertiary care hospital. AB - BACKGROUND: Enteric fever is common in tropical regions and is caused by Salmonella enterica serotype typhi (S typhi ). For diagnosis of enteric fever, the Widal test is the most widely used test after blood culture. In HIV infected individuals false positive and false negative Widal reactions are common. The result is variable titres and baseline titres that are unusual in this patient population. AIMS: This study was done to determine the baseline antibody titres for S typhi among HIV infected individuals. METHOD: Average baseline antibody titres against O and H antigens of S typhi were measured by standard Widal test in 200 HIV positive asymptomatic individuals, as well as 200 age and sex-matched controls. The results were compiled and statistically analysed. RESULTS: A total of 84 (42%) of the cases had an H antibody titre of >1:20 and 105 (52.5%) had a titre of >1:20 against O antigen. This implies that positive titre of H and O antigen is significantly associated with HIV positive cases with P<0.001. Correlation of CD4 count with antibody titres shows that there is no significant association between CD4 counts and antibody titres against either H (P=0.634) or O antigen (P=0.765). CONCLUSION: This study shows that HIV infected individuals had increased titres of antibodies against S typhi from the baseline. This indicates a need for evaluation of current cut-off values of diagnostic titres for this group. We also suggest that it is best to perform baseline titres against S t yphi for each patient at the time of diagnosis of HIV status, and to use this for future reference. PMID- 23940496 TI - 'I mean I expect that it's pretty safe': Perceptions of food trust in pregnancy - implications for primary health care practice. AB - BACKGROUND: Pregnancy is a time in which food choice is of particular importance. Trust in the food supply and those who regulate it is receiving greater acknowledgement because of the influence of trust on food choice. No prior investigation into pregnant women and food trust has been conducted. AIMS: This paper identifies factors that determine the nature and extent of pregnant women's trust in food; sources of information which influence pregnant women's food choices; and how trust impacts on pregnant women's food choices. METHOD: In-depth interviews were conducted with 13 pregnant women; nine were pregnant with their first child and four were in their second or subsequent pregnancy. RESULTS: Food choices of pregnant women were predominantly influenced by nutrition and perceived quality of food. Risktaking behaviour, such as the consumption of foods considered high risk during pregnancy, was common amongst participants. The sample was characterised by a dependence on expert information, limited reflexivity in relation to food safety, and contradictory practice such as risk taking behaviours in regard to high risk foods were observed. CONCLUSION: Further research is needed to confirm findings in this study. Research into consumption of high-risk foods and the information received from healthcare providers would be useful in creating a clearer understanding of whether provision of information is sufficient in communicating risks and promoting a healthy pregnancy. PMID- 23940497 TI - Difficulties in diagnosing tuberculosis of the cervix in a post menopausal woman: Case report and literature review. AB - Tuberculosis (TB) of the cervix is a rare disease, especially in developed countries. We presented a patient with primary TB of the cervix with no concurrent immune deficiency or HIV infections. The case clinically mimicked carcinoma of the cervix. Difficulties in diagnosis have been discussed. Given the recent increase in migration patterns including travel from TB endemic areas, an abnormal-looking cervix should be regarded with a degree of suspicion for TB. PMID- 23940498 TI - Forgotten but not gone - Scrofuloderma in a migrant student from India. AB - A 34-year-old Indian student who immigrated to Australia five years ago presented with a four-week history of neck pain. Physical examination revealed two firm fixed cervical lymph nodes in the anterior triangle and midline region which were tender on palpation and erythematous on inspection. Cording phenomenon was found on ZN staining of FNA sample and mycobacterium tuberculosis (M.tb ) PCR confirmed the diagnosis with incomplete resistance to isoniazid. Patient was treated with other three first line antituberculosis medications for nine months with an excellent outcome. Prednisolone was also used as adjunctive therapy and tapered during the course of treatment. PMID- 23940499 TI - Subcutaneous zygomycosis caused by Mucor hiemalis in an immunocompetent patient. AB - Zygomycosis is an opportunistic fungal infection with a high mortality rate. It is known to cause invasive disease in immunocompromised hosts but it may produce only cutaneous/ subcutaneous infections in immunocompetent hosts. Treatment is difficult due to its fulminant course and lack of effective anti-fungal drugs. Here, we report a rare case of subcutaneous zygomycosis caused by Mucor hiemalis in an immunocompetent patient without any debilitating illness. The patient was successfully treated by aggressive surgical debridement and anti-fungal therapy. PMID- 23940500 TI - Modern microbiology - a quiet revolution with many benefits. AB - In the clinical microbiology laboratory, classical culture and identification methods are rapidly giving way to molecular techniques with many benefits for clinicians and patients. Building on the discovery of the structure of DNA and the genetic code, four main scientific advances have been made which underpin these techniques (hybridisation probes, polymerase chain reaction, the observation that the microbial species signature can be read in the ribosomal genes and also in the proteins). Early discoveries have paved the way for new diagnostic methods, which are rapid, highly sensitive and specific. Automation has provided high throughput for large numbers of clinical specimens combined with reasonable cost. The benefits for the clinician and patient include confirmation of clinical diagnoses and information about antimicrobial susceptibility within hours compared to days for conventional methods. In resource-poor settings, molecular techniques and automated systems may seem unaffordable but new public-private partnerships, initiatives by the World Health Organization and new, innovative laboratory methods offer the promise of benefit for all. PMID- 23940501 TI - Convenient quantification of methanol concentration detection utilizing an integrated microfluidic chip. AB - A rapid and simple technique is proposed for methanol concentration detection using a PMMA (Polymethyl-Methacrylate) microfluidic chip patterned using a commercially available CO2 laser scriber. In the proposed device, methanol and methanol oxidase (MOX) are injected into a three-dimensional circular chamber and are mixed via a vortex stirring effect. The mixture is heated to prompt the formation of formaldehyde and is flowed into a rectangular chamber, to which fuchsin-sulphurous acid is then added. Finally, the microchip is transferred to a UV spectrophotometer for methanol detection purposes. The experimental results show that a correlation coefficient of R(2) = 0.9940 is obtained when plotting the optical density against the methanol concentration for samples and an accuracy as high as 93.1% are compared with the determined by the high quality gas chromatography with concentrations in the range of 2 ~ 100 ppm. The methanol concentrations of four commercial red wines are successfully detected using the developed device. Overall, the results show that the proposed device provides a rapid and accurate means of detecting the methanol concentration for a variety of applications in the alcoholic beverage inspection and control field. PMID- 23940502 TI - Quantification of the specific membrane capacitance of single cells using a microfluidic device and impedance spectroscopy measurement. AB - The specific membrane capacitance (SMC) is an electrical parameter that correlates with both the electrical activity and morphology of the plasma membrane, which are physiological markers for cellular phenotype and health. We have developed a microfluidic device that enables impedance spectroscopy measurements of the SMC of single biological cells. Impedance spectra induced by single cells aspirated into the device are captured over a moderate frequency range (5 kHz-1 MHz). Maximum impedance sensitivity is achieved using a tapered microfluidic channel, which effectively routes electric fields across the cell membranes. The SMC is extracted by curve-fitting impedance spectra to an equivalent circuit model. From our measurement, acute myeloid leukemia (AML) cells are found to exhibit larger SMC values in hypertonic solutions as compared with those in isotonic solutions. In addition, AML cell phenotypes (AML2 and NB4) exhibiting varying metastatic potential yield distinct SMC values (AML2: 16.9 +/- 1.9 mF/m(2) (n = 23); NB4: 22.5 +/- 4.7 mF/m(2) (n = 23)). Three-dimensional finite element simulations of the microfluidic device confirm the feasibility of this approach. PMID- 23940503 TI - Biomarker-free dielectrophoretic sorting of differentiating myoblast multipotent progenitor cells and their membrane analysis by Raman spectroscopy. AB - Myoblasts are muscle derived mesenchymal stem cell progenitors that have great potential for use in regenerative medicine, especially for cardiomyogenesis grafts and intracardiac cell transplantation. To utilise such cells for pre clinical and clinical applications, and especially for personalized medicine, it is essential to generate a synchronised, homogenous, population of cells that display phenotypic and genotypic homogeneity within a population of cells. We demonstrate that the biomarker-free technique of dielectrophoresis (DEP) can be used to discriminate cells between stages of differentiation in the C2C12 myoblast multipotent mouse model. Terminally differentiated myotubes were separated from C2C12 myoblasts to better than 96% purity, a result validated by flow cytometry and Western blotting. To determine the extent to which cell membrane capacitance, rather than cell size, determined the DEP response of a cell, C2C12 myoblasts were co-cultured with GFP-expressing MRC-5 fibroblasts of comparable size distributions (mean diameter ~10 MUm). A DEP sorting efficiency greater than 98% was achieved for these two cell types, a result concluded to arise from the fibroblasts possessing a larger membrane capacitance than the myoblasts. It is currently assumed that differences in membrane capacitance primarily reflect differences in the extent of folding or surface features of the membrane. However, our finding by Raman spectroscopy that the fibroblast membranes contained a smaller proportion of saturated lipids than those of the myoblasts suggests that the membrane chemistry should also be taken into account. PMID- 23940504 TI - Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis. AB - BACKGROUND: Retinal dystrophies (RD) are a group of hereditary diseases that lead to debilitating visual impairment and are usually transmitted as a Mendelian trait. Pathogenic mutations can occur in any of the 100 or more disease genes identified so far, making molecular diagnosis a rather laborious process. In this work we explored the use of whole exome sequencing (WES) as a tool for identification of RD mutations, with the aim of assessing its applicability in a diagnostic context. METHODOLOGY/PRINCIPAL FINDINGS: We ascertained 12 Spanish families with seemingly recessive RD. All of the index patients underwent mutational pre-screening by chip-based sequence hybridization and resulted to be negative for known RD mutations. With the exception of one pedigree, to simulate a standard diagnostic scenario we processed by WES only the DNA from the index patient of each family, followed by in silico data analysis. We successfully identified causative mutations in patients from 10 different families, which were later verified by Sanger sequencing and co-segregation analyses. Specifically, we detected pathogenic DNA variants (~50% novel mutations) in the genes RP1, USH2A, CNGB3, NMNAT1, CHM, and ABCA4, responsible for retinitis pigmentosa, Usher syndrome, achromatopsia, Leber congenital amaurosis, choroideremia, or recessive Stargardt/cone-rod dystrophy cases. CONCLUSIONS/SIGNIFICANCE: Despite the absence of genetic information from other family members that could help excluding nonpathogenic DNA variants, we could detect causative mutations in a variety of genes known to represent a wide spectrum of clinical phenotypes in 83% of the patients analyzed. Considering the constant drop in costs for human exome sequencing and the relative simplicity of the analyses made, this technique could represent a valuable tool for molecular diagnostics or genetic research, even in cases for which no genotypes from family members are available. PMID- 23940507 TI - Protection by an oral disubstituted hydroxylamine derivative against loss of retinal ganglion cell differentiation following optic nerve crush. AB - Thy-1 is a cell surface protein that is expressed during the differentiation of retinal ganglion cells (RGCs). Optic nerve injury induces progressive loss in the number of RGCs expressing Thy-1. The rate of this loss is fastest during the first week after optic nerve injury and slower in subsequent weeks. This study was undertaken to determine whether oral treatment with a water-soluble N-hydroxy 2,2,6,6-tetramethylpiperidine derivative (OT-440) protects against loss of Thy-1 promoter activation following optic nerve crush and whether this effect targets the earlier quick phase or the later slow phase. The retina of mice expressing cyan fluorescent protein under control of the Thy-1 promoter (Thy1-CFP mice) was imaged using a blue-light confocal scanning laser ophthalmoscope (bCSLO). These mice then received oral OT-440 prepared in cream cheese or dissolved in water, or plain vehicle, for two weeks and were imaged again prior to unilateral optic nerve crush. Treatments and weekly imaging continued for four more weeks. Fluorescent neurons were counted in the same defined retinal areas imaged at each time point in a masked fashion. When the counts at each time point were directly compared, the numbers of fluorescent cells at each time point were greater in the animals that received OT-440 in cream cheese by 8%, 27%, 52% and 60% than in corresponding control animals at 1, 2, 3 and 4 weeks after optic nerve crush. Similar results were obtained when the vehicle was water. Rate analysis indicated the protective effect of OT-440 was greatest during the first two weeks and was maintained in the second two weeks after crush for both the cream cheese vehicle study and water vehicle study. Because most of the fluorescent cells detected by bCSLO are RGCs, these findings suggest that oral OT-440 can either protect against or delay early degenerative responses occurring in RGCs following optic nerve injury. PMID- 23940509 TI - Adaptive geometric tessellation for 3D reconstruction of anisotropically developing cells in multilayer tissues from sparse volumetric microscopy images. AB - The need for quantification of cell growth patterns in a multilayer, multi cellular tissue necessitates the development of a 3D reconstruction technique that can estimate 3D shapes and sizes of individual cells from Confocal Microscopy (CLSM) image slices. However, the current methods of 3D reconstruction using CLSM imaging require large number of image slices per cell. But, in case of Live Cell Imaging of an actively developing tissue, large depth resolution is not feasible in order to avoid damage to cells from prolonged exposure to laser radiation. In the present work, we have proposed an anisotropic Voronoi tessellation based 3D reconstruction framework for a tightly packed multilayer tissue with extreme z-sparsity (2-4 slices/cell) and wide range of cell shapes and sizes. The proposed method, named as the 'Adaptive Quadratic Voronoi Tessellation' (AQVT), is capable of handling both the sparsity problem and the non-uniformity in cell shapes by estimating the tessellation parameters for each cell from the sparse data-points on its boundaries. We have tested the proposed 3D reconstruction method on time-lapse CLSM image stacks of the Arabidopsis Shoot Apical Meristem (SAM) and have shown that the AQVT based reconstruction method can correctly estimate the 3D shapes of a large number of SAM cells. PMID- 23940508 TI - Nitric oxide synthetic pathway in red blood cells is impaired in coronary artery disease. AB - BACKGROUND: All the enzymatic factors/cofactors involved in nitric oxide (NO) metabolism have been recently found in red blood cells. Increased oxidative stress impairs NO bioavailability and has been described in plasma of coronary artery disease (CAD) patients. The aim of the study was to highlight a potential dysfunction of the metabolic profile of NO in red blood cells and in plasma from CAD patients compared with healthy controls. METHODS: We determined L-arginine/NO pathway by liquid-chromatography tandem mass spectrometry and high performance liquid chromatography methods. The ratio of oxidized and reduced forms of glutathione, as index of oxidative stress, was measured by liquid-chromatography tandem mass spectrometry method. NO synthase expression and activity were evaluated by immunofluorescence staining and ex-vivo experiments of L [(15)N2]arginine conversion to L-[(15)N]citrulline respectively. RESULTS: Increased amounts of asymmetric and symmetric dimethylarginines were found both in red blood cells and in plasma of CAD patients in respect to controls. Interestingly NO synthase expression and activity were reduced in CAD red blood cells. In contrast, oxidized/reduced glutathione ratio was increased in CAD and was associated to arginase activity. CONCLUSION: Our study analyzed for the first time the whole metabolic pathway of L-arginine/NO, both in red blood cells and in plasma, highlighting an impairment of NO pathway in erythrocytes from CAD patients, associated with decreased NO synthase expression/activity and increased oxidative stress. PMID- 23940511 TI - Vibrot, a simple device for the conversion of vibration into rotation mediated by friction: preliminary evaluation. AB - While "vibrational noise" induced by rotating components of machinery is a common problem constantly faced by engineers, the controlled conversion of translational into rotational motion or vice-versa is a desirable goal in many scenarios ranging from internal combustion engines to ultrasonic motors. In this work, we describe the underlying physics after isolating a single degree of freedom, focusing on devices that convert a vibration along the vertical axis into a rotation around this axis. A typical Vibrot (as we label these devices) consists of a rigid body with three or more cantilevered elastic legs attached to its bottom at an angle. We show that these legs are capable of transforming vibration into rotation by a "ratchet effect", which is caused by the anisotropic stick slip-flight motion of the leg tips against the ground. Drawing an analogy with the Froude number used to classify the locomotion dynamics of legged animals, we discuss the walking regime of these robots. We are able to control the rotation frequency of the Vibrot by manipulating the shaking amplitude, frequency or waveform. Furthermore, we have been able to excite Vibrots with acoustic waves, which allows speculating about the possibility of reducing the size of the devices so they can perform tasks into the human body, excited by ultrasound waves from the outside. PMID- 23940510 TI - Non-linear interactions between consumers and flow determine the probability of plant community dominance on Maine rocky shores. AB - Although consumers can strongly influence community recovery from disturbance, few studies have explored the effects of consumer identity and density and how they may vary across abiotic gradients. On rocky shores in Maine, recent experiments suggest that recovery of plant- or animal- dominated community states is governed by rates of water movement and consumer pressure. To further elucidate the mechanisms of consumer control, we examined the species-specific and density-dependent effects of rocky shore consumers (crabs and snails) on community recovery under both high (mussel dominated) and low flow (plant dominated) conditions. By partitioning the direct impacts of predators (crabs) and grazers (snails) on community recovery across a flow gradient, we found that grazers, but not predators, are likely the primary agent of consumer control and that their impact is highly non-linear. Manipulating snail densities revealed that herbivorous and bull-dozing snails (Littorina littorea) alone can control recovery of high and low flow communities. After ~1.5 years of recovery, snail density explained a significant amount of the variation in macroalgal coverage at low flow sites and also mussel recovery at high flow sites. These density dependent grazer effects were were both non-linear and flow-dependent, with low abundance thresholds needed to suppress plant community recovery, and much higher levels needed to control mussel bed development. Our study suggests that consumer density and identity are key in regulating both plant and animal community recovery and that physical conditions can determine the functional forms of these consumer effects. PMID- 23940512 TI - Dental informatics to characterize patients with dentofacial deformities. AB - Relevant statistical modeling and analysis of dental data can improve diagnostic and treatment procedures. The purpose of this study is to demonstrate the use of various data mining algorithms to characterize patients with dentofacial deformities. A total of 72 patients with skeletal malocclusions who had completed orthodontic and orthognathic surgical treatments were examined. Each patient was characterized by 22 measurements related to dentofacial deformities. Clustering analysis and visualization grouped the patients into three different patterns of dentofacial deformities. A feature selection approach based on a false discovery rate was used to identify a subset of 22 measurements important in categorizing these three clusters. Finally, classification was performed to evaluate the quality of the measurements selected by the feature selection approach. The results showed that feature selection improved classification accuracy while simultaneously determining which measurements were relevant. PMID- 23940513 TI - Does stress increase the risk of atopic dermatitis in adolescents? results of the Korea Youth Risk Behavior Web-based Survey (KYRBWS-VI). AB - This study investigated the relationship between level of stress in middle and high school students aged 12-18 and risk of atopic dermatitis. Data from the Sixth Korea Youth Risk Behavior Web-based Survey (KYRBWS-VI), a cross-sectional study among 74,980 students in 800 middle schools and high schools with a response rate of 97.7%, were analyzed. Ordinal logistic regression analyses were conducted to determine the relationship between stress and atopic dermatitis with severity. A total of 5,550 boys and 6,964 girls reported having been diagnosed with atopic dermatitis. Younger students were more likely to have atopic dermatitis. Interestingly, the educational level of parents was found to be associated with having atopic dermatitis and having more severe condition. In particular, girls with mothers with at least college education had a 41% higher risk of having atopic dermatitis and severe atopic condition (odds ratio (OR)) = 1.41, 95% CI, 1.22-1.63; P<0.0001) compared with those with mothers who had attended middle school at most. Similar trend was shown among both boys and girls for their father's education level. The stress level was found to be significantly associated with the risk of atopic dermatitis. Compared to boys with who reported "no stress", boys with "very high" stress had 46% higher the risk of having more severe atopic dermatitis (OR = 1.46, 95% CI, 1.20-1.78; P<0.0001), 44% higher (OR = 1.44, 95% CI, 1.19-1.73; P<0.0001) with "high" stress, and 21% higher (OR = 1.21, 95% CI, 1.00-1.45; P = 0.05) with "moderate" stress. In contrast, we found no statistically significant relationship between stress and atopic dermatitis in girls. This study suggests that stress and parents' education level were associated with atopic dermatitis. Specifically, degree of stress is positively correlated with likelihood of being diagnosed with this condition and increasing the severity. PMID- 23940514 TI - NT pro BNP plasma level and atrial volume are linked to the severity of liver cirrhosis. AB - BACKGROUND AND AIMS: Plasma levels of NT-pro-BNP, a natriuretic peptide precursor, are raised in the presence of fluid retention of cardiac origin and can be used as markers of cardiac dysfunction. Recent studies showed high levels of NT pro BNP in patients with cirrhosis. We assessed NT pro-BNP and other parameters of cardiac dysfunction in patients with cirrhosis, with or without ascites, in order to determine whether the behaviour of NT pro BNP is linked to the stage of liver disease or to secondary cardiac dysfunction. METHODS: Fifty eight consecutive hospitalized patients mostly with viral or NAFLD-related cirrhosis were studied. All underwent abdominal ultrasound and upper GI endoscopy. Cardiac morpho-functional changes were evaluated by echocardiography and NT-pro-BNP plasma levels determined upon admission. Twenty-eight hypertensive patients, without evidence of liver disease served as controls. RESULTS: Fifty eight cirrhotic patients (72% men) with a median age of 62 years (11% with mild arterial hypertension and 31% with type 2 diabetes) had a normal renal function (mean creatinine 0.9 mg/dl, range 0.7-1.06). As compared to controls, cirrhotic patients had higher NT pro-BNP plasma levels (365.2+/-365.2 vs 70.8+/-70.6 pg/ml; p<0.001). Left atrial volume (LAV) (61.8+/-26.3 vs 43.5+/-14.1 ml; p = 0.001), and left ventricular ejection fraction (62.7+/-6.9 vs. 65.5+/-4%,; p = 0.05) were also altered in cirrhotic patients that in controls. Patients with F2-F3 oesophageal varices as compared to F0/F1, showed higher e' velocity (0.91+/-0.23 vs 0.66+/-0.19 m/s, p<0.001), and accordingly a higher E/A ratio (1.21+/-0.46 vs 0.89+/-0.33 m/s., p = 0.006). CONCLUSION: NT-pro-BNP plasma levels are increased proportionally to the stage of chronic liver disease. Advanced cirrhosis and high NT-pro-BNP levels are significantly associated to increased LAV and to signs of cardiac diastolic dysfunction. NT pro-BNP levels could hence be an useful prognostic indicators of early decompensation of cirrhosis. PMID- 23940515 TI - Parathyroidectomy improves survival in patients with severe hyperparathyroidism: a comparative study. AB - BACKGROUND AND OBJECTIVES: Secondary hyperparathyroidism (SHPT) in CKD is associated with an increased risk for mortality, but definitive data showing that parathormone control decreases mortality is still lacking. This study aimed to compare the mortality of patients with severe SHPT submitted to parathyroidectomy(PTX) with those who did not have access to surgery. METHODS: This is a retrospective study in a cohort of 251 CKD patients with severe SHPT who were referred to a CKD-MBD Center for PTX from 2005 until 2012. RESULTS: Most of our patients had indication of PTX, but only 49% of them had access to this surgical procedure. After a mean follow-up of 23 months, 72 patients had died. Non-survivors were older; more often had diabetes, lower serum 25 vitamin D and mostly had not been submitted to surgery. The relative risk of death was lower in the PTX patients (0.428; 95% CI, 0.28 to 0.67; p<0.0001). After adjustments, mortality risk was dependent on age (1.04; 95% CI, 1.01 to 1.07; p = 0.002), 25 vitamin D (0.43; 95% CI, 0.24 to 0.81; p = 0.006) and no access to PTX (4.13; 95% CI, 2.16 to 7.88; p<0.0001). Results remained the same in a second model using the PTX date as the study start date for the PTX group. CONCLUSIONS: Our data confirms the benefit of PTX on mortality in patients with severe SHPT. The high mortality encountered in our population is significant and urges the need to better treat these patients. PMID- 23940516 TI - Radiation therapy-induced tumor invasiveness is associated with SDF-1-regulated macrophage mobilization and vasculogenesis. AB - Radiation therapy (RT) remains the front-line treatment for high-grade gliomas; however, tumor recurrence remains the main obstacle for the clinical success of RT. Using a murine astrocytoma tumor cell line, ALTS1C1, the present study demonstrates that whole brain irradiation prolonged the survival of tumor-bearing mice, although the mice eventually died associated with increased tumor infiltration. Immunohistochemical (IHC) analysis indicated that RT decreased the microvascular density (MVD) of the primary tumor core, but increased the MVD of the tumor invasion front. RT also increased the number of tumor-associated macrophages (TAMs) and the expression of stromal cell-derived factor-1 (SDF-1) and hypoxia-inducible factor-1 (HIF-1) at the tumor invasion front. SDF-1 expression suppressed by siRNA (SDFkd tumors) showed a decrease in RT-enhanced tumor invasiveness, leading to prolonged survival of mice bearing these tumors. The invasion front in SDFkd tumors showed a lower MVD and TAM density than that in the islands of the control or irradiated ALTS1C1 tumors. Our results indicate that tumor-secreted SDF-1 is one key factor in RT-induced tumor invasiveness, and that it exerts its effect likely through macrophage mobilization and tumor revascularization. PMID- 23940517 TI - Personality of wild male crested macaques (Macaca nigra). AB - Animal personalities, i.e. consistent differences in behavior across time and/or context, have received increased attention of behavioral biologists over the last years. Recent research shows that personalities represent traits on which natural and sexual selection work and which can have substantial fitness consequences. The aim of this study is to establish the personality structure of crested macaque (Macaca nigra) males as foundation for future studies on its adaptive value. We collected behavioral data through focal animal sampling and additionally conducted two sets of playback experiments. Results of a factor analysis on the behavioral data revealed a four factor structure with components we labeled Anxiety, Sociability, Connectedness and Aggressiveness. Results from the experiments revealed an additional and independent Boldness factor but the absence of Neophilia. Overall, this structure resembles other macaque and animal species with the exception of Connectedness, which might be a consequence of the species' tolerant social style. Our results thus not only form the basis for future studies on the adaptive value of personality in crested macaques but also contribute an important data point for investigating the evolution of personality structure from a comparative perspective by refining, for example, which personality factors characterized the last common ancestor of hominids and macaques. PMID- 23940518 TI - Repulsion between oppositely charged planar macroions. AB - The repulsive interaction between oppositely charged macroions is investigated using Grand Canonical Monte Carlo simulations of an unrestricted primitive model, including the effect of inhomogeneous surface charge and its density, the depth of surface charge, the cation size, and the dielectric permittivity of solvent and macroions, and their contrast. The origin of the repulsion is a combination of osmotic pressure and ionic screening resulting from excess salt between the macroions. The excess charge over-reduces the electrostatic attraction between macroions and raises the entropic repulsion. The magnitude of the repulsion increases when the dielectric constant of the solvent is lowered (below that of water) and/or the surface charge density is increased, in good agreement with experiment. Smaller size of surface charge and the cation, their discreteness and mobility are other factors that enhance the repulsion and charge inversion phenomenons. PMID- 23940519 TI - Effects of fertility on gene expression and function of the bovine endometrium. AB - Infertility and subfertility are important and pervasive reproductive problems in both domestic animals and humans. The majority of embryonic loss occurs during the first three weeks of pregnancy in cattle and women due, in part, to inadequate endometrial receptivity for support of embryo implantation. To identify heifers of contrasting fertility, serial rounds of artificial insemination (AI) were conducted in 201 synchronized crossbred beef heifers. The heifers were then fertility classified based on number of pregnancies detected on day 35 in four AI opportunities. Heifers, classified as having high fertility, subfertility or infertility, were selected for further study. The fertility classified heifers were superovulated and flushed, and the recovered embryos were graded and then transferred to synchronized recipients. Quantity of embryos recovered per flush, embryo quality, and subsequent recipient pregnancy rates did not differ by fertility classification. Two in vivo-produced bovine embryos (stage 4 or 5, grade 1 or 2) were then transferred into each heifer on day 7 post estrus. Pregnancy rates were greater in high fertility than lower fertility heifers when heifers were used as embryo recipients. The reproductive tracts of the classified heifers were obtained on day 14 of the estrous cycle. No obvious morphological differences in reproductive tract structures and histology of the uterus were observed in the heifers. Microarray analysis revealed differences in the endometrial transcriptome based on fertility classification. A genome-wide association study, based on SNP genotyping, detected 7 moderate associations with fertility across 6 different chromosomes. Collectively, these studies support the idea that innate differences in uterine function underlie fertility and early pregnancy loss in ruminants. Cattle with defined early pregnancy success or loss is useful to elucidate the complex biological and genetic mechanisms governing endometrial receptivity and uterine competency for pregnancy. PMID- 23940520 TI - The complete mitochondrial genome of Gossypium hirsutum and evolutionary analysis of higher plant mitochondrial genomes. AB - BACKGROUND: Mitochondria are the main manufacturers of cellular ATP in eukaryotes. The plant mitochondrial genome contains large number of foreign DNA and repeated sequences undergone frequently intramolecular recombination. Upland Cotton (Gossypium hirsutum L.) is one of the main natural fiber crops and also an important oil-producing plant in the world. Sequencing of the cotton mitochondrial (mt) genome could be helpful for the evolution research of plant mt genomes. METHODOLOGY/PRINCIPAL FINDINGS: We utilized 454 technology for sequencing and combined with Fosmid library of the Gossypium hirsutum mt genome screening and positive clones sequencing and conducted a series of evolutionary analysis on Cycas taitungensis and 24 angiosperms mt genomes. After data assembling and contigs joining, the complete mitochondrial genome sequence of G. hirsutum was obtained. The completed G.hirsutum mt genome is 621,884 bp in length, and contained 68 genes, including 35 protein genes, four rRNA genes and 29 tRNA genes. Five gene clusters are found conserved in all plant mt genomes; one and four clusters are specifically conserved in monocots and dicots, respectively. Homologous sequences are distributed along the plant mt genomes and species closely related share the most homologous sequences. For species that have both mt and chloroplast genome sequences available, we checked the location of cp-like migration and found several fragments closely linked with mitochondrial genes. CONCLUSION: The G. hirsutum mt genome possesses most of the common characters of higher plant mt genomes. The existence of syntenic gene clusters, as well as the conservation of some intergenic sequences and genic content among the plant mt genomes suggest that evolution of mt genomes is consistent with plant taxonomy but independent among different species. PMID- 23940521 TI - Copper oxide nanoparticles induced mitochondria mediated apoptosis in human hepatocarcinoma cells. AB - Copper oxide nanoparticles (CuO NPs) are heavily utilized in semiconductor devices, gas sensor, batteries, solar energy converter, microelectronics and heat transfer fluids. It has been reported that liver is one of the target organs for nanoparticles after they gain entry into the body through any of the possible routes. Recent studies have shown cytotoxic response of CuO NPs in liver cells. However, the underlying mechanism of apoptosis in liver cells due to CuO NPs exposure is largely lacking. We explored the possible mechanisms of apoptosis induced by CuO NPs in human hepatocellular carcinoma HepG2 cells. Prepared CuO NPs were spherical in shape with a smooth surface and had an average diameter of 22 nm. CuO NPs (concentration range 2-50 ug/ml) were found to induce cytotoxicity in HepG2 cells in dose-dependent manner, which was likely to be mediated through reactive oxygen species generation and oxidative stress. Tumor suppressor gene p53 and apoptotic gene caspase-3 were up-regulated due to CuO NPs exposure. Decrease in mitochondrial membrane potential with a concomitant increase in the gene expression of bax/bcl2 ratio suggested that mitochondria mediated pathway involved in CuO NPs induced apoptosis. This study has provided valuable insights into the possible mechanism of apoptosis caused by CuO NPs at in vitro level. Underlying mechanism(s) of apoptosis due to CuO NPs exposure should be further invested at in vivo level. PMID- 23940522 TI - Adherence to drug label recommendations for avoiding drug interactions causing statin-induced myopathy--a nationwide register study. AB - PURPOSE: To investigate the extent to which clinicians avoid well-established drug-drug interactions that cause statin-induced myopathy. We hypothesised that clinicians would avoid combining erythromycin or verapamil/diltiazem respectively with atorvastatin or simvastatin. In patients with statin-fibrate combination therapy, we hypothesised that gemfibrozil was avoided to the preference of bezafibrate or fenofibrate. When combined with verapamil/diltiazem or fibrates, we hypothesized that the dispensed doses of atorvastatin/simvastatin would be decreased. METHODS: Cross-sectional analysis of nationwide dispensing data. Odds ratios of interacting erythromycin, verapamil/diltiazem versus respective prevalence of comparator drugs doxycycline, amlodipine/felodipine in patients co dispensed interacting statins simvastatin/atorvastatin versus patients unexposed (pravastatin/fluvastatin/rosuvastatin) was calculated. For fibrates, OR of gemfibrozil versus fenofibrate/bezafibrate in patients co-dispensed any statin was assessed. RESULTS: OR of interacting erythromycin versus comparator doxycycline did not differ between patients on interacting and comparator statins either in patients dispensed high or low statin doses (adjusted OR 0.87; 95% CI 0.60-1.25 and 0.92; 95% CI 0.69-1.23). Interacting statins were less common among patients dispensed verapamil/diltiazem as compared to patients on amlodipine/felodipine (OR high dose 0.62; CI 0.56-0.68 and low dose 0.63; CI 0.58 0.68). Patients on any statin were to a lesser extent dispensed gemfibrozil compared to patients not dispensed a statin (OR high dose 0.65; CI 0.55-0.76 and low dose 0.70; CI 0.63-0.78). Mean DDD (SD) for any statin was substantially higher in patients co-dispensed gemfibrozil 178 (149) compared to patients on statin monotherapy 127 (93), (p<0.001). CONCLUSIONS: Prescribers may to some extent avoid co-prescription of statins with calcium blockers and fibrates with an increased risk of myopathy. We found no evidence for avoiding co-prescriptions of statins and antibiotics with an increased risk of statin-induced adverse drug reactions. Co-prescription of statins and gemfibrozil is paradoxically associated with a marked increased statin dose, further aggravating the risk for severe myopathy. PMID- 23940523 TI - XRCC3 Thr241Met polymorphism and clinical outcomes of NSCLC patients receiving platinum-based chemotherapy: a systematic review and meta-analysis. AB - INTRODUCTION: X-ray repair cross-complementing protein 3 (XRCC3) is an essential gene involved in the double-strand break repair pathway. Published evidence has shown controversial results about the relationship between XRCC3 Thr241Met polymorphism and clinical outcomes of non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy. METHODS: A systematic review and meta analysis was performed to evaluate the predictive value of XRCC3 Thr241Met polymorphism on clinical outcomes of advanced NSCLC receiving platinum-based chemotherapy. Response to chemotherapy, overall survival (OS) and progression free survival (PFS) were analyzed. RESULTS: A number of 11 eligible studies were identified according to the inclusion criteria. Carriers of the variant XRCC3 241Met allele were significantly associated with good response to platinum-based chemotherapy (ThrMet/MetMet vs. ThrThr: OR = 1.509, 95% CI: 1.099-2.072, Pheterogeneity = 0.618). The XRCC3 Thr241Met polymorphism was not associated with OS (MetMet vs. ThrThr, HR = 0.939, 95% CI:0.651-1.356, Pheterogeneity = 0.112) or PFS (MetMet vs. ThrThr, HR = 0.960, 95% CI: 0.539-1.710, Pheterogeneity = 0.198). Additionally, no evidence of publication bias was observed. CONCLUSIONS: This systematic review and meta-analysis shows that carriers of the XRCC3 241Met allele are associated with good response to platinum based chemotherapy in advanced NSCLC, while the XRCC3 Thr241Met polymorphism is not associated with OS or PFS. PMID- 23940524 TI - Headaches in multiple sclerosis patients might imply an inflammatorial process. AB - Recent studies on Multiple Sclerosis (MS) pathology mention the involvement of "tertiary B cell follicles" in MS pathogenesis. This inflammatory process, which occurs with interindividually great variance, might be a link between MS pathology and headaches. The aim of this study was to detect the prevalence of headaches and of subtypes of headaches (migraine, cluster, tension-type headache [TTH]) in an unselected MS collective and to compile possibly influencing factors. Unselected MS patients (n = 180) with and without headache were examined by a semi-structured interview using a questionnaire about headache, depression and the health status. Additionally clinical MS data (expanded disability state score [EDSS], MS course, medication, disease duration) were gathered. N = 98 MS patients (55.4%) reported headaches in the previous 4 weeks. We subsequently grouped headache patients according to the IHS criteria and detected 16 (16.3%) MS patients suffering from migraine (migraine with aura: 2 [2%]; migraine without aura: 14 [14.3%]), 23 (23.5%) suffering from TTH and none with a cluster headache. Thus, headaches of 59 (60.2%) MS patients remained unclassified. When comparing MS patients with and without headaches significant differences in age, gender, MS course, physical functioning, pain and social functioning occurred. MS patients with headaches were significantly younger of age (p = 0.001), female (p = 0.001) and reported more often of a clinically isolated syndrome (CIS) and relapsing/remitting MS (RRMS) instead of secondary chronic progressive MS (SCP). EDSS was significantly lower in MS patients suffering from headaches compared to the MS patients without headaches (p = 0.001). In conclusion headache in MS patients is a relevant symptom, especially in early stages of the MS disease. Especially unclassified headache seems to represent an important symptom in MS course and requires increased attention. PMID- 23940525 TI - Distance to the scaling law: a useful approach for unveiling relationships between crime and urban metrics. AB - We report on a quantitative analysis of relationships between the number of homicides, population size and ten other urban metrics. By using data from Brazilian cities, we show that well-defined average scaling laws with the population size emerge when investigating the relations between population and number of homicides as well as population and urban metrics. We also show that the fluctuations around the scaling laws are log-normally distributed, which enabled us to model these scaling laws by a stochastic-like equation driven by a multiplicative and log-normally distributed noise. Because of the scaling laws, we argue that it is better to employ logarithms in order to describe the number of homicides in function of the urban metrics via regression analysis. In addition to the regression analysis, we propose an approach to correlate crime and urban metrics via the evaluation of the distance between the actual value of the number of homicides (as well as the value of the urban metrics) and the value that is expected by the scaling law with the population size. This approach has proved to be robust and useful for unveiling relationships/behaviors that were not properly carried out by the regression analysis, such as [Formula: see text] the non-explanatory potential of the elderly population when the number of homicides is much above or much below the scaling law, [Formula: see text] the fact that unemployment has explanatory potential only when the number of homicides is considerably larger than the expected by the power law, and [Formula: see text] a gender difference in number of homicides, where cities with female population below the scaling law are characterized by a number of homicides above the power law. PMID- 23940526 TI - Age-specific mortality during the 1918 influenza pandemic: unravelling the mystery of high young adult mortality. AB - The worldwide spread of a novel influenza A (H1N1) virus in 2009 showed that influenza remains a significant health threat, even for individuals in the prime of life. This paper focuses on the unusually high young adult mortality observed during the Spanish flu pandemic of 1918. Using historical records from Canada and the U.S., we report a peak of mortality at the exact age of 28 during the pandemic and argue that this increased mortality resulted from an early life exposure to influenza during the previous Russian flu pandemic of 1889-90. We posit that in specific instances, development of immunological memory to an influenza virus strain in early life may lead to a dysregulated immune response to antigenically novel strains encountered in later life, thereby increasing the risk of death. Exposure during critical periods of development could also create holes in the T cell repertoire and impair fetal maturation in general, thereby increasing mortality from infectious diseases later in life. Knowledge of the age pattern of susceptibility to mortality from influenza could improve crisis management during future influenza pandemics. PMID- 23940527 TI - Zebrafish guanylate cyclase type 3 signaling in cone photoreceptors. AB - The zebrafish guanylate cyclase type 3 (zGC3) is specifically expressed in cone cells. A specifc antibody directed against zGC3 revealed expression at the protein level at 3.5 dpf in outer and inner retinal layers, which increased in intensity between 3.5 and 7 dpf. This expression pattern differed from sections of the adult retina showing strong immunostaining in outer segments of double cones and short single cones, less intense immunoreactivity in long single cones, but no staining in the inner retina. Although transcription and protein expression levels of zGC3 are similar to that of the cyclase regulator guanylate cyclase-activating protein 3 (zGCAP3), we surprisingly found that zGCAP3 is present in a 28-fold molar excess over zGC3 in zebrafish retinae. Further, zGCAP3 was an efficient regulator of guanylate cyclases activity in native zebrafish retinal membrane preparations. Therefore, we investigated the physiological function of zGCAP3 by two different behavioral assays. Using the morpholino antisense technique, we knocked down expression of zGCAP3 and recorded the optokinetic and optomotor responses of morphants, control morphants, and wild type fish at 5-6 dpf. No significant differences in behavioral responses among wild type, morphants and control morphants were found, indicating that a loss of zGCAP3 has no consequences in primary visual processing in the larval retina despite its prominent expression pattern. Its physiological function is therefore compensated by other zGCAP isoforms. PMID- 23940528 TI - Heterogeneity of astrocytes: from development to injury - single cell gene expression. AB - Astrocytes perform control and regulatory functions in the central nervous system; heterogeneity among them is still a matter of debate due to limited knowledge of their gene expression profiles and functional diversity. To unravel astrocyte heterogeneity during postnatal development and after focal cerebral ischemia, we employed single-cell gene expression profiling in acutely isolated cortical GFAP/EGFP-positive cells. Using a microfluidic qPCR platform, we profiled 47 genes encoding glial markers and ion channels/transporters/receptors participating in maintaining K(+) and glutamate homeostasis per cell. Self organizing maps and principal component analyses revealed three subpopulations within 10-50 days of postnatal development (P10-P50). The first subpopulation, mainly immature glia from P10, was characterized by high transcriptional activity of all studied genes, including polydendrocytic markers. The second subpopulation (mostly from P20) was characterized by low gene transcript levels, while the third subpopulation encompassed mature astrocytes (mainly from P30, P50). Within 14 days after ischemia (D3, D7, D14), additional astrocytic subpopulations were identified: resting glia (mostly from P50 and D3), transcriptionally active early reactive glia (mainly from D7) and permanent reactive glia (solely from D14). Following focal cerebral ischemia, reactive astrocytes underwent pronounced changes in the expression of aquaporins, nonspecific cationic and potassium channels, glutamate receptors and reactive astrocyte markers. PMID- 23940529 TI - Roles of genetic polymorphisms in the folate pathway in childhood acute lymphoblastic leukemia evaluated by Bayesian relevance and effect size analysis. AB - In this study we investigated whether polymorphisms in the folate pathway influenced the risk of childhood acute lymphoblastic leukemia (ALL) or the survival rate of the patients. For this we selected and genotyped 67 SNPs in 15 genes in the folate pathway in 543 children with ALL and 529 controls. The results were evaluated by gender adjusted logistic regression and by the Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) methods. Bayesian structure based odds ratios for the relevant variables and interactions were also calculated. Altogether 9 SNPs in 8 genes were associated with altered susceptibility to ALL. After correction for multiple testing, two associations remained significant. The genotype distribution of the MTHFD1 rs1076991 differed significantly between the ALL and control population. Analyzing the subtypes of the disease the GG genotype increased only the risk of B-cell ALL (p = 3.52*10( 4); OR = 2.00). The GG genotype of the rs3776455 SNP in the MTRR gene was associated with a significantly reduced risk to ALL (p = 1.21*10(-3); OR = 0.55), which resulted mainly from the reduced risk to B-cell and hyperdiploid-ALL. The TC genotype of the rs9909104 SNP in the SHMT1 gene was associated with a lower survival rate comparing it to the TT genotype (80.2% vs. 88.8%; p = 0.01). The BN BMLA confirmed the main findings of the frequentist-based analysis and showed structural interactional maps and the probabilities of the different structural association types of the relevant SNPs especially in the hyperdiploid-ALL, involving additional SNPs in genes like TYMS, DHFR and GGH. We also investigated the statistical interactions and redundancies using structural model properties. These results gave further evidence that polymorphisms in the folate pathway could influence the ALL risk and the effectiveness of the therapy. It was also shown that in gene association studies the BN-BMLA could be a useful supplementary to the traditional frequentist-based statistical method. PMID- 23940530 TI - MATIN: a random network coding based framework for high quality peer-to-peer live video streaming. AB - In recent years, Random Network Coding (RNC) has emerged as a promising solution for efficient Peer-to-Peer (P2P) video multicasting over the Internet. This probably refers to this fact that RNC noticeably increases the error resiliency and throughput of the network. However, high transmission overhead arising from sending large coefficients vector as header has been the most important challenge of the RNC. Moreover, due to employing the Gauss-Jordan elimination method, considerable computational complexity can be imposed on peers in decoding the encoded blocks and checking linear dependency among the coefficients vectors. In order to address these challenges, this study introduces MATIN which is a random network coding based framework for efficient P2P video streaming. The MATIN includes a novel coefficients matrix generation method so that there is no linear dependency in the generated coefficients matrix. Using the proposed framework, each peer encapsulates one instead of n coefficients entries into the generated encoded packet which results in very low transmission overhead. It is also possible to obtain the inverted coefficients matrix using a bit number of simple arithmetic operations. In this regard, peers sustain very low computational complexities. As a result, the MATIN permits random network coding to be more efficient in P2P video streaming systems. The results obtained from simulation using OMNET++ show that it substantially outperforms the RNC which uses the Gauss Jordan elimination method by providing better video quality on peers in terms of the four important performance metrics including video distortion, dependency distortion, End-to-End delay and Initial Startup delay. PMID- 23940531 TI - Somatic maintenance resources in the honeybee worker fat body are distributed to withstand the most life-threatening challenges at each life stage. AB - In a global transcriptome analysis of three natural and three manipulated honeybee worker phenotypes at different ages, we have investigated the distribution of investment in somatic maintenance of the fat body. Gene expression is modulated so that the bees are able to resist the most life threatening challenges at the actual life stage. Different modes of maintenance and repair are regulated, apparently to meet the environmental challenges most detrimental to survival and reproductive potential for the hive. We observed a broad down-regulation of genomic and cellular maintenance in the short-lived foragers and nurse bees compared to the long-lived winter bees. Our results show that survival and reproduction of the entire hive is given priority over the individual bees, hence supporting the idea of the honeybee society as a superorganism. Our results also fit the disposable soma theory of aging. PMID- 23940532 TI - Exposure to odors of rivals enhances sexual motivation in male giant pandas. AB - Males will alter their mating behavior to cope with the presence of their competitors. Even exposure to odors from potential competitors can greatly increase male ejaculate expenditure in a variety of animals including insects, fishes, birds and rodents. Major efforts have been made to examine males' plastic responses to sperm competition and its fitness benefits. However, the effects of competitor absence on male's sexual motivation and behaviors remain unclear, which has been proposed to be one of the causes for the poor sexual performance of some captive mammals. This study revealed that sexual motivation can be greatly enhanced in captive male giant pandas (Ailuropoda melanoleuca) by exposure to chemosensory cues from either one or three conspecifics males. It had been shown that potential rivals' odors increased males' chemosensory investigation behavior, as well as their observing, following and sniffing behaviors towards estrous females. Behaviors changed regardless of the number of rivals (one or three). Our results demonstrate the effects of potential competition on male giant pandas' sexual motivation and behavioral coping strategy. We anticipate that our research will provide a fresh insight into the mechanisms underlying poor sexual performance in male captive mammals, and valuable information for the practical management and ex situ conservation of endangered species. PMID- 23940533 TI - A comparison of structural and evolutionary attributes of Escherichia coli and Thermus thermophilus small ribosomal subunits: signatures of thermal adaptation. AB - Here we compare the structural and evolutionary attributes of Thermus thermophilus and Escherichia coli small ribosomal subunits (SSU). Our results indicate that with few exceptions, thermophilic 16S ribosomal RNA (16S rRNA) is densely packed compared to that of mesophilic at most of the analogous spatial regions. In addition, we have located species-specific cavity clusters (SSCCs) in both species. E. coli SSCCs are numerous and larger compared to T. thermophilus SSCCs, which again indicates densely packed thermophilic 16S rRNA. Thermophilic ribosomal proteins (r-proteins) have longer disordered regions than their mesophilic homologs and they experience larger disorder-to-order transitions during SSU-assembly. This is reflected in the predicted higher conformational changes of thermophilic r-proteins compared to their mesophilic homologs during SSU-assembly. This high conformational change of thermophilic r-proteins may help them to associate with the 16S ribosomal RNA with high complementary interfaces, larger interface areas, and denser molecular contacts, compared to those of mesophilic. Thus, thermophilic protein-rRNA interfaces are tightly associated with 16S rRNA than their mesophilic homologs. Densely packed 16S rRNA interior and tight protein-rRNA binding of T. thermophilus (compared to those of E. coli) are likely the signatures of its thermal adaptation. We have found a linear correlation between the free energy of protein-RNA interface formation, interface size, and square of conformational changes, which is followed in both prokaryotic and eukaryotic SSU. Disorder is associated with high protein-RNA interface polarity. We have found an evolutionary tendency to maintain high polarity (thereby disorder) at protein-rRNA interfaces, than that at rest of the protein structures. However, some proteins exhibit exceptions to this general trend. PMID- 23940534 TI - Intravitreal transplantation of human umbilical cord blood stem cells protects rats from traumatic optic neuropathy. AB - OBJECTIVES: To treat traumatic optic neuropathy (TON) with transplantation of human umbilical cord blood stem cells (hUCBSC) and explore how transplanted stem cells participate in the neuron repairing process. METHODS: A total of 195 Sprague-Dawley rats were randomly assigned to three groups: sham-surgery, optic nerve injury, and stem cell transplant group. Optic nerve injury was established in rats by directly clamping the optic nerve for 30 seconds. hUCBSC was microinjected into the vitreous cavity of injured rats. Optic nerve function was evaluated by flash visual evoked potentials (F-VEP). Apoptosis in retina tissues was detected by TUNEL staining. GRP78 and CHOP gene expression was measured by RT PCR. RESULTS: After injury, transplantation of hUCBSC significantly blunted a reduction in optic nerve function indicated by smaller decreases in amplitude and smaller increases in peak latency of F-VEP waveform compared to the injury alone group. Also, significant more in retinal ganglion cell (RGC) count and less in RGC apoptosis were detected after transplantation compared to injured rats. The protective effect correlated with upregulated GRP78 and downregulated CHOP mRNA expression. CONCLUSION: Intravitreal transplantation of hUCBSCs significantly blunted a reduction in optic nerve function through increasing RGC survival and decreasing retinal cell apoptosis. The protective role of transplantation was associated with upregulation of GRP78 expression and downregulation of CHOP expression in retinal cells. PMID- 23940535 TI - Autonomic substrates of the response to pups in male prairie voles. AB - Caregiving by nonparents (alloparenting) and fathers is a defining aspect of human social behavior, yet this phenomenon is rare among mammals. Male prairie voles (Microtus ochrogaster) spontaneously exhibit high levels of alloparental care, even in the absence of reproductive experience. In previous studies, exposure to a pup was selectively associated with increased activity in oxytocin and vasopressin neurons along with decreased plasma corticosterone. In the present study, physiological, pharmacological and neuroanatomical methods were used to explore the autonomic and behavioral consequences of exposing male prairie voles to a pup. Reproductively naive, adult male prairie voles were implanted with radiotransmitters used for recording ECG, temperature and activity. Males responded with a sustained increase in heart-rate during pup exposure. This prolonged increase in heart rate was not explained by novelty, locomotion or thermoregulation. Although heart rate was elevated during pup exposure, respiratory sinus arrhythmia (RSA) did not differ between these males and males exposed to control stimuli indicating that vagal inhibition of the heart was maintained. Blockade of beta-adrenergic receptors with atenolol abolished the pup-induced heart rate increase, implicating sympathetic activity in the pup-induced increase in heart rate. Blockade of vagal input to the heart delayed the males' approach to the pup. Increased activity in brainstem autonomic regulatory nuclei was also observed in males exposed to pups. Together, these findings suggest that exposure to a pup activates both vagal and sympathetic systems. This unique physiological state (i.e. increased sympathetic excitation of the heart, while maintaining some vagal cardiac tone) associated with male caregiving behavior may allow males to both nurture and protect infants. PMID- 23940536 TI - Design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors. AB - Targeting papain family cysteine proteases is one of the novel strategies in the development of chemotherapy for a number of diseases. Novel cysteine protease inhibitors derived from 1-pyridylimidazo[1,5-a]pyridine representing pharmacologically important class of compounds are being reported here for the first time. The derivatives were initially designed and screened in silico by molecular docking studies against papain to explore the possible mode of action. The molecular interaction between the compounds and cysteine protease (papain) was found to be very similar to the interactions observed with the respective epoxide inhibitor (E-64c) of papain. Subsequently, compounds were synthesized to validate their efficacy in wet lab experiments. When characterized kinetically, these compounds show their Ki and IC50 values in the range of 13.75 to 99.30 uM and 13.40 to 96.50 uM, respectively. The thermodynamics studies suggest their binding with papain hydrophobically and entropically driven. These inhibitors also inhibit the growth of clinically important different types of Gram positive and Gram negative bacteria having MIC50 values in the range of 0.6-1.4 ug/ml. Based on Lipinski's rule of Five, we also propose these compounds as potent antibacterial prodrugs. The most active antibacterial compound was found to be 1 (2-pyridyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine (3a). PMID- 23940537 TI - Interleukin-5 supports the expansion of fas ligand-expressing killer B cells that induce antigen-specific apoptosis of CD4(+) T cells and secrete interleukin-10. AB - Beyond their critical role in humoral immunity, B lymphocytes can employ a variety of immunomodulatory mechanisms including expression of the apoptosis inducing molecule Fas ligand (FasL; CD178). Here, we extensively characterized the surface phenotype of FasL(+) killer B cells, showing they are enriched in the IgM(high)CD5(+)CD1d(high) B cell subset previously reported to contain a higher frequency of B cells producing interleukin-10 (IL-10). A rare population of B cells expressing IL-10 was present among FasL(+) B cells, but most FasL(+) B cells did not produce IL-10. We also identify interleukin-5 (IL-5) as a novel inducer of killer B cell function. Constitutively FasL(+) B cells expressed higher levels of the IL-5 receptor, and treating B cells with IL-5 and CD40L resulted in the expansion of a B cell population enriched for FasL(+) cells. B cells stimulated with IL-5 and CD40L were potent inducers of apoptosis in activated primary CD4(+) T cells, and this killing function was antigen-specific and dependent upon FasL. IL-5 also enhanced IL-10 secretion in B cells stimulated with CD40L. Taken together these findings elucidate the relationship of FasL(+) B cells and IL-10-producing B cells and demonstrate that IL-5 can induce or enhance both killer B cell activity and IL-10 secretion in B cells. Finally, we found that the killer B cell activity induced by IL-5 was completely blocked by IL-4, suggesting the existence of a previously unknown antagonistic relationship between these type-2 cytokines in modulating the activity of killer B cells. Targeting this IL-5/IL-4 signaling axis may therefore represent a novel area of drug discovery in inflammatory disorders. PMID- 23940538 TI - Enzymatic assays for the diagnosis of bradykinin-dependent angioedema. AB - BACKGROUND: The kinins (primarily bradykinin, BK) represent the mediators responsible for local increase of vascular permeability in hereditary angioedema (HAE), HAE I-II associated with alterations of the SERPING1 gene and HAE with normal C1-Inhibitor function (HAE-nC1INH). Besides C1-Inhibitor function and concentration, no biological assay of kinin metabolism is actually available to help physicians for the diagnosis of angioedema (AE). We describe enzymatic tests on the plasma for diagnosis of BK-dependent AE. METHODS: The plasma amidase assays are performed using the Pro-Phe-Arg-p-nitroanilide peptide substrate to evaluate the spontaneous amidase activity and the proenzyme activation. We analyzed data of 872 patients presenting with BK-dependent AE or BK-unrelated diseases, compared to 303 controls. Anti-high MW kininogen (HK) immunoblot was achieved to confirm HK cleavage in exemplary samples. Reproducibility, repeatability, limit of blank, limit of detection, precision, linearity and receiver operating characteristics (ROC) were used to calculate the diagnostic performance of the assays. RESULTS: Spontaneous amidase activity was significantly increased in all BK-dependent AE, associated with the acute phase of disease in HAE-nC1INH, but preserved in BK-unrelated disorders. The increase of the amidase activity was associated to HK proteolysis, indicating its relevance to identify kininogenase activity. The oestrogens, known for precipitating AE episodes, were found as triggers of enzymatic activity. Calculations from ROC curves gave the optimum diagnostic cut-off for women (9.3 nmol?min(-1)?mL(-1), area under curve [AUC] 92.1%, sensitivity 80.0%, and specificity 90.1%) and for men (6.6 nmol.min(-1)?mL(-1), AUC 91.0%, sensitivity 87.0% and specificity 81.2%). CONCLUSION: The amidase assay represents a diagnostic tool to help physicians in the decision to distinguish between BK related and -unrelated AE. PMID- 23940539 TI - Gene expression changes in the olfactory bulb of mice induced by exposure to diesel exhaust are dependent on animal rearing environment. AB - There is an emerging concern that particulate air pollution increases the risk of cranial nerve disease onset. Small nanoparticles, mainly derived from diesel exhaust particles reach the olfactory bulb by their nasal depositions. It has been reported that diesel exhaust inhalation causes inflammation of the olfactory bulb and other brain regions. However, these toxicological studies have not evaluated animal rearing environment. We hypothesized that rearing environment can change mice phenotypes and thus might alter toxicological study results. In this study, we exposed mice to diesel exhaust inhalation at 90 ug/m(3), 8 hours/day, for 28 consecutive days after rearing in a standard cage or environmental enrichment conditions. Microarray analysis found that expression levels of 112 genes were changed by diesel exhaust inhalation. Functional analysis using Gene Ontology revealed that the dysregulated genes were involved in inflammation and immune response. This result was supported by pathway analysis. Quantitative RT-PCR analysis confirmed 10 genes. Interestingly, background gene expression of the olfactory bulb of mice reared in a standard cage environment was changed by diesel exhaust inhalation, whereas there was no significant effect of diesel exhaust exposure on gene expression levels of mice reared with environmental enrichment. The results indicate for the first time that the effect of diesel exhaust exposure on gene expression of the olfactory bulb was influenced by rearing environment. Rearing environment, such as environmental enrichment, may be an important contributive factor to causation in evaluating still undefined toxic environmental substances such as diesel exhaust. PMID- 23940540 TI - Filtering for compound heterozygous sequence variants in non-consanguineous pedigrees. AB - The identification of disease-causing mutations in next-generation sequencing (NGS) data requires efficient filtering techniques. In patients with rare recessive diseases, compound heterozygosity of pathogenic mutations is the most likely inheritance model if the parents are non-consanguineous. We developed a web-based compound heterozygous filter that is suited for data from NGS projects and that is easy to use for non-bioinformaticians. We analyzed the power of compound heterozygous mutation filtering by deriving background distributions for healthy individuals from different ethnicities and studied the effectiveness in trios as well as more complex pedigree structures. While usually more then 30 genes harbor potential compound heterozygotes in single exomes, this number can be markedly reduced with every additional member of the pedigree that is included in the analysis. In a real data set with exomes of four family members, two sisters affected by Mabry syndrome and their healthy parents, the disease-causing gene PIGO, which harbors the pathogenic compound heterozygous variants, could be readily identified. Compound heterozygous filtering is an efficient means to reduce the number of candidate mutations in studies aiming at identifying recessive disease genes in non-consanguineous families. A web-server is provided to make this filtering strategy available at www.gene-talk.de. PMID- 23940541 TI - The effect of music on the human stress response. AB - BACKGROUND: Music listening has been suggested to beneficially impact health via stress-reducing effects. However, the existing literature presents itself with a limited number of investigations and with discrepancies in reported findings that may result from methodological shortcomings (e.g. small sample size, no valid stressor). It was the aim of the current study to address this gap in knowledge and overcome previous shortcomings by thoroughly examining music effects across endocrine, autonomic, cognitive, and emotional domains of the human stress response. METHODS: Sixty healthy female volunteers (mean age = 25 years) were exposed to a standardized psychosocial stress test after having been randomly assigned to one of three different conditions prior to the stress test: 1) relaxing music ('Miserere', Allegri) (RM), 2) sound of rippling water (SW), and 3) rest without acoustic stimulation (R). Salivary cortisol and salivary alpha amylase (sAA), heart rate (HR), respiratory sinus arrhythmia (RSA), subjective stress perception and anxiety were repeatedly assessed in all subjects. We hypothesized that listening to RM prior to the stress test, compared to SW or R would result in a decreased stress response across all measured parameters. RESULTS: The three conditions significantly differed regarding cortisol response (p = 0.025) to the stressor, with highest concentrations in the RM and lowest in the SW condition. After the stressor, sAA (p=0.026) baseline values were reached considerably faster in the RM group than in the R group. HR and psychological measures did not significantly differ between groups. CONCLUSION: Our findings indicate that music listening impacted the psychobiological stress system. Listening to music prior to a standardized stressor predominantly affected the autonomic nervous system (in terms of a faster recovery), and to a lesser degree the endocrine and psychological stress response. These findings may help better understanding the beneficial effects of music on the human body. PMID- 23940542 TI - Analysis and prediction of highly effective antiviral peptides based on random forests. AB - The goal of this study was to examine and predict antiviral peptides. Although antiviral peptides hold great potential in antiviral drug discovery, little is done in antiviral peptide prediction. In this study, we demonstrate that a physicochemical model using random forests outperform in distinguishing antiviral peptides. On the experimental benchmark, our physicochemical model aided with aggregation and secondary structural features reaches 90% accuracy and 0.79 Matthew's correlation coefficient, which exceeds the previous models. The results suggest that aggregation could be an important feature for identifying antiviral peptides. In addition, our analysis reveals the characteristics of the antiviral peptides such as the importance of lysine and the abundance of alpha-helical secondary structures. PMID- 23940543 TI - Inter-population movements of steller sea lions in Alaska with implications for population separation. AB - Genetic studies and differing population trends support the separation of Steller sea lions (Eumetopias jubatus) into a western distinct population segment (WDPS) and an eastern DPS (EDPS) with the dividing line between populations at 144 degrees W. Despite little exchange for thousands of years, the gap between the breeding ranges narrowed during the past 15-30 years with the formation of new rookeries near the DPS boundary. We analyzed >22,000 sightings of 4,172 sea lions branded as pups in each DPS from 2000-2010 to estimate probabilities of a sea lion born in one DPS being seen within the range of the other DPS (either 'West' or 'East'). Males from both populations regularly traveled across the DPS boundary; probabilities were highest at ages 2-5 and for males born in Prince William Sound and southern Southeast Alaska. The probability of WDPS females being in the East at age 5 was 0.067 but 0 for EDPS females which rarely traveled to the West. Prince William Sound-born females had high probabilities of being in the East during breeding and non-breeding seasons. We present strong evidence that WDPS females have permanently emigrated to the East, reproducing at two 'mixing zone' rookeries. We documented breeding bulls that traveled >6,500 km round trip from their natal rookery in southern Alaska to the northern Bering Sea and central Aleutian Islands and back within one year. WDPS animals began moving East in the 1990s, following steep population declines in the central Gulf of Alaska. Results of our study, and others documenting high survival and rapid population growth in northern Southeast Alaska suggest that conditions in this mixing zone region have been optimal for sea lions. It is unclear whether eastward movement across the DPS boundary is due to less-optimal conditions in the West or a reflection of favorable conditions in the East. PMID- 23940544 TI - Rotation-invariant features for multi-oriented text detection in natural images. AB - Texts in natural scenes carry rich semantic information, which can be used to assist a wide range of applications, such as object recognition, image/video retrieval, mapping/navigation, and human computer interaction. However, most existing systems are designed to detect and recognize horizontal (or near horizontal) texts. Due to the increasing popularity of mobile-computing devices and applications, detecting texts of varying orientations from natural images under less controlled conditions has become an important but challenging task. In this paper, we propose a new algorithm to detect texts of varying orientations. Our algorithm is based on a two-level classification scheme and two sets of features specially designed for capturing the intrinsic characteristics of texts. To better evaluate the proposed method and compare it with the competing algorithms, we generate a comprehensive dataset with various types of texts in diverse real-world scenes. We also propose a new evaluation protocol, which is more suitable for benchmarking algorithms for detecting texts in varying orientations. Experiments on benchmark datasets demonstrate that our system compares favorably with the state-of-the-art algorithms when handling horizontal texts and achieves significantly enhanced performance on variant texts in complex natural scenes. PMID- 23940545 TI - Enhancement of natural killer cell cytotoxicity by sodium/iodide symporter gene mediated radioiodine pretreatment in breast cancer cells. AB - A phase II study of NK cell therapy in treatment of patients with recurrent breast cancer has recently been reported. However, because of the complexities of tumor microenvironments, effective therapeutic effects have not been achieved in NK cell therapy. Radioiodine (I-131) therapy inhibits cancer growth by inducing the apoptosis and necrosis of cancer cells. Furthermore, it can modify cancer cell phenotypes and enhance the effect of immunotherapy against cancer cells. The present study showed that I-131 therapy can modulate microenvironment of breast cancer and improve the therapeutic effect by enhancing NK cell cytotoxicity to the tumor cells. The susceptibility of breast cancer cells to NK cell was increased by precedent I-131 treatment in vitro. Tumor burden in mice treated with I-131 plus NK cell was significantly lower than that in mice treated with NK cell or I-131 alone. The up-regulation of Fas, DR5 and MIC A/B on irradiated tumor cells could be the explanation for the enhancement of NK cell cytotoxicity to tumor cells. It can be applied to breast cancer patients with iodine avid metastatic lesions that are non-responsive to conventional treatments. PMID- 23940546 TI - Visual evoked cortical potential (VECP) elicited by sinusoidal gratings controlled by pseudo-random stimulation. AB - The contributions of contrast detection mechanisms to the visual cortical evoked potential (VECP) have been investigated studying the contrast-response and spatial frequency-response functions. Previously, the use of m-sequences for stimulus control has been almost restricted to multifocal electrophysiology stimulation and, in some aspects, it substantially differs from conventional VECPs. Single stimulation with spatial contrast temporally controlled by m sequences has not been extensively tested or compared to multifocal techniques. Our purpose was to evaluate the influence of spatial frequency and contrast of sinusoidal gratings on the VECP elicited by pseudo-random stimulation. Nine normal subjects were stimulated by achromatic sinusoidal gratings driven by pseudo random binary m-sequence at seven spatial frequencies (0.4-10 cpd) and three stimulus sizes (4 degrees , 8 degrees , and 16 degrees of visual angle). At 8 degrees subtence, six contrast levels were used (3.12-99%). The first order kernel (K1) did not provide a consistent measurable signal across spatial frequencies and contrasts that were tested-signal was very small or absent-while the second order kernel first (K2.1) and second (K2.2) slices exhibited reliable responses for the stimulus range. The main differences between results obtained with the K2.1 and K2.2 were in the contrast gain as measured in the amplitude versus contrast and amplitude versus spatial frequency functions. The results indicated that K2.1 was dominated by M-pathway, but for some stimulus condition some P-pathway contribution could be found, while the second slice reflected the P-pathway contribution. The present work extended previous findings of the visual pathways contribution to VECP elicited by pseudorandom stimulation for a wider range of spatial frequencies. PMID- 23940547 TI - The morphology of corneal cap and its relation to refractive outcomes in femtosecond laser small incision lenticule extraction (SMILE) with anterior segment optical coherence tomography observation. AB - PURPOSE: To investigate the morphology of corneal caps in femtosecond laser small incision lenticule extraction (SMILE) and its relation to the refractive outcomes. METHODS: A prospective study of fifty-four corneal caps created with VisuMax femtosecond laser were examined using an Fourier-domain optical coherence tomography at 1 day, 1 week, 1 month and 6 months after SMILE. The cap thickness at nine points on each of the four meridians (0 degrees , 45 degrees , 90 degrees , 135 degrees ) and the diameter were measured. Cap morphology, changes over time and its correlation with refractive outcomes were assessed. RESULTS: The mean achieved central cap thickness were (108.74+/-5.06) um at 6 months and (107.32+/ 4.81 ) um at 1 month postoperatively, significantly thinner than that at 1 day (110.81+/-7.95) um and 1 week (109.58+/-7.48 ) um (P<0.05). The mean diameter on 0 degrees meridian was (7.61+/-0.07) mm, significantly larger than that on 90 degrees meridian (7.57+/-0.06) mm (P = 0.001). Cap morphology showed good regularity, except that the differences of points in two pairs were significant at 1 day postoperatively. The uniformity was consistent over time and the central cap thickness was thinner than those in the paracentral and peripheral areas. The refractive outcomes stabilized within 1 month. Uncorrected distance visual acuity (UDVA) was correlated to the central cap thickness at 1 day and 1 week (both rs = 0.33, p<0.05). The uniformity index was correlated with UDVA (rs = 0.34, p<0.05) and corrected distance visual acuity (rs = 0.32, p<0.05) at 1 week postoperatively. CONCLUSIONS: Corneal caps of SMILE are predictable with good reproducibility, regularity and uniformity. Cap morphology might have a mild effect on refractive outcomes in the early stage. Further study should focus on the impact on the visual quality. PMID- 23940548 TI - Intervention-based stochastic disease eradication. AB - Disease control is of paramount importance in public health, with infectious disease extinction as the ultimate goal. Although diseases may go extinct due to random loss of effective contacts where the infection is transmitted to new susceptible individuals, the time to extinction in the absence of control may be prohibitively long. Intervention controls are typically defined on a deterministic schedule. In reality, however, such policies are administered as a random process, while still possessing a mean period. Here, we consider the effect of randomly distributed intervention as disease control on large finite populations. We show explicitly how intervention control, based on mean period and treatment fraction, modulates the average extinction times as a function of population size and rate of infection spread. In particular, our results show an exponential improvement in extinction times even though the controls are implemented using a random Poisson distribution. Finally, we discover those parameter regimes where random treatment yields an exponential improvement in extinction times over the application of strictly periodic intervention. The implication of our results is discussed in light of the availability of limited resources for control. PMID- 23940549 TI - Wnt activation of immortalized brain endothelial cells as a tool for generating a standardized model of the blood brain barrier in vitro. AB - Reproducing the characteristics and the functional responses of the blood-brain barrier (BBB) in vitro represents an important task for the research community, and would be a critical biotechnological breakthrough. Pharmaceutical and biotechnology industries provide strong demand for inexpensive and easy-to-handle in vitro BBB models to screen novel drug candidates. Recently, it was shown that canonical Wnt signaling is responsible for the induction of the BBB properties in the neonatal brain microvasculature in vivo. In the present study, following on from earlier observations, we have developed a novel model of the BBB in vitro that may be suitable for large scale screening assays. This model is based on immortalized endothelial cell lines derived from murine and human brain, with no need for co-culture with astrocytes. To maintain the BBB endothelial cell properties, the cell lines are cultured in the presence of Wnt3a or drugs that stabilize beta-catenin, or they are infected with a transcriptionally active form of beta-catenin. Upon these treatments, the cell lines maintain expression of BBB specific markers, which results in elevated transendothelial electrical resistance and reduced cell permeability. Importantly, these properties are retained for several passages in culture, and they can be reproduced and maintained in different laboratories over time. We conclude that the brain derived endothelial cell lines that we have investigated gain their specialized characteristics upon activation of the canonical Wnt pathway. This model may be thus suitable to test the BBB permeability to chemicals or large molecular weight proteins, transmigration of inflammatory cells, treatments with cytokines, and genetic manipulation. PMID- 23940550 TI - Testosterone delivered with a scaffold is as effective as bone morphologic protein-2 in promoting the repair of critical-size segmental defect of femoral bone in mice. AB - Loss of large bone segments due to fracture resulting from trauma or tumor removal is a common clinical problem. The goal of this study was to evaluate the use of scaffolds containing testosterone, bone morphogenetic protein-2 (BMP-2), or a combination of both for treatment of critical-size segmental bone defects in mice. A 2.5-mm wide osteotomy was created on the left femur of wildtype and androgen receptor knockout (ARKO) mice. Testosterone, BMP-2, or both were delivered locally using a scaffold that bridged the fracture. Results of X-ray imaging showed that in both wildtype and ARKO mice, BMP-2 treatment induced callus formation within 14 days after initiation of the treatment. Testosterone treatment also induced callus formation within 14 days in wildtype but not in ARKO mice. Micro-computed tomography and histological examinations revealed that testosterone treatment caused similar degrees of callus formation as BMP-2 treatment in wildtype mice, but had no such effect in ARKO mice, suggesting that the androgen receptor is required for testosterone to initiate fracture healing. These results demonstrate that testosterone is as effective as BMP-2 in promoting the healing of critical-size segmental defects and that combination therapy with testosterone and BMP-2 is superior to single therapy. Results of this study may provide a foundation to develop a cost effective and efficient therapeutic modality for treatment of bone fractures with segmental defects. PMID- 23940551 TI - Comprehensive genomic characterization of campylobacter genus reveals some underlying mechanisms for its genomic diversification. AB - Campylobacter species.are phenotypically diverse in many aspects including host habitats and pathogenicities, which demands comprehensive characterization of the entire Campylobacter genus to study their underlying genetic diversification. Up to now, 34 Campylobacter strains have been sequenced and published in public databases, providing good opportunity to systemically analyze their genomic diversities. In this study, we first conducted genomic characterization, which includes genome-wide alignments, pan-genome analysis, and phylogenetic identification, to depict the genetic diversity of Campylobacter genus. Afterward, we improved the tetranucleotide usage pattern-based naive Bayesian classifier to identify the abnormal composition fragments (ACFs, fragments with significantly different tetranucleotide frequency profiles from its genomic tetranucleotide frequency profiles) including horizontal gene transfers (HGTs) to explore the mechanisms for the genetic diversity of this organism. Finally, we analyzed the HGTs transferred via bacteriophage transductions. To our knowledge, this study is the first to use single nucleotide polymorphism information to construct liable microevolution phylogeny of 21 Campylobacter jejuni strains. Combined with the phylogeny of all the collected Campylobacter species based on genome-wide core gene information, comprehensive phylogenetic inference of all 34 Campylobacter organisms was determined. It was found that C. jejuni harbors a high fraction of ACFs possibly through intraspecies recombination, whereas other Campylobacter members possess numerous ACFs possibly via intragenus recombination. Furthermore, some Campylobacter strains have undergone significant ancient viral integration during their evolution process. The improved method is a powerful tool for bacterial genomic analysis. Moreover, the findings would provide useful information for future research on Campylobacter genus. PMID- 23940552 TI - Attachment patterns trigger differential neural signature of emotional processing in adolescents. AB - BACKGROUND: Research suggests that individuals with different attachment patterns process social information differently, especially in terms of facial emotion recognition. However, few studies have explored social information processes in adolescents. This study examined the behavioral and ERP correlates of emotional processing in adolescents with different attachment orientations (insecure attachment group and secure attachment group; IAG and SAG, respectively). This study also explored the association of these correlates to individual neuropsychological profiles. METHODOLOGY/PRINCIPAL FINDINGS: We used a modified version of the dual valence task (DVT), in which participants classify stimuli (faces and words) according to emotional valence (positive or negative). Results showed that the IAG performed significantly worse than SAG on tests of executive function (EF attention, processing speed, visuospatial abilities and cognitive flexibility). In the behavioral DVT, the IAG presented lower performance and accuracy. The IAG also exhibited slower RTs for stimuli with negative valence. Compared to the SAG, the IAG showed a negative bias for faces; a larger P1 and attenuated N170 component over the right hemisphere was observed. A negative bias was also observed in the IAG for word stimuli, which was demonstrated by comparing the N170 amplitude of the IAG with the valence of the SAG. Finally, the amplitude of the N170 elicited by the facial stimuli correlated with EF in both groups (and negative valence with EF in the IAG). CONCLUSIONS/SIGNIFICANCE: Our results suggest that individuals with different attachment patterns process key emotional information and corresponding EF differently. This is evidenced by an early modulation of ERP components' amplitudes, which are correlated with behavioral and neuropsychological effects. In brief, attachments patterns appear to impact multiple domains, such as emotional processing and EFs. PMID- 23940553 TI - Synthetic surface for expansion of human mesenchymal stem cells in xeno-free, chemically defined culture conditions. AB - Human mesenchymal stem cells (HMSCS) possess three properties of great interest for the development of cell therapies and tissue engineering: multilineage differentiation, immunomodulation, and production of trophic factors. Efficient ex vivo expansion of hMSCs is a challenging requirement for large scale production of clinical grade cells. Low-cost, robust, scalable culture methods using chemically defined materials need to be developed to address this need. This study describes the use of a xeno-free synthetic peptide acrylate surface, the Corning(r) Synthemax(r) Surface, for culture of hMSCs in serum-free, defined medium. Cell performance on the Corning Synthemax Surface was compared to cells cultured on biological extracellular matrix (ECM) coatings in xeno-free defined medium and in traditional conditions on tissue culture treated (TCT) plastic in fetal bovine serum (FBS) supplemented medium. Our results show successful maintenance of hMSCs on Corning Synthemax Surface for eight passages, with cell expansion rate comparable to cells cultured on ECM and significantly higher than for cells in TCT/FBS condition. Importantly, on the Corning Synthemax Surface, cells maintained elongated, spindle-like morphology, typical hMSC marker profile and in vitro multilineage differentiation potential. We believe the Corning Synthemax Surface, in combination with defined media, provides a complete synthetic, xeno-free, cell culture system for scalable production of hMSCs. PMID- 23940554 TI - Stability of whole brain and regional network topology within and between resting and cognitive states. AB - BACKGROUND: Graph-theory based analyses of resting state functional Magnetic Resonance Imaging (fMRI) data have been used to map the network organization of the brain. While numerous analyses of resting state brain organization exist, many questions remain unexplored. The present study examines the stability of findings based on this approach over repeated resting state and working memory state sessions within the same individuals. This allows assessment of stability of network topology within the same state for both rest and working memory, and between rest and working memory as well. METHODOLOGY/PRINCIPAL FINDINGS: fMRI scans were performed on five participants while at rest and while performing the 2-back working memory task five times each, with task state alternating while they were in the scanner. Voxel-based whole brain network analyses were performed on the resulting data along with analyses of functional connectivity in regions associated with resting state and working memory. Network topology was fairly stable across repeated sessions of the same task, but varied significantly between rest and working memory. In the whole brain analysis, local efficiency, Eloc, differed significantly between rest and working memory. Analyses of network statistics for the precuneus and dorsolateral prefrontal cortex revealed significant differences in degree as a function of task state for both regions and in local efficiency for the precuneus. Conversely, no significant differences were observed across repeated sessions of the same state. CONCLUSIONS/SIGNIFICANCE: These findings suggest that network topology is fairly stable within individuals across time for the same state, but also fluid between states. Whole brain voxel-based network analyses may prove to be a valuable tool for exploring how functional connectivity changes in response to task demands. PMID- 23940555 TI - Ethylene response factor 6 is a regulator of reactive oxygen species signaling in Arabidopsis. AB - Reactive oxygen species (ROS) are produced in plant cells in response to diverse biotic and abiotic stresses as well as during normal growth and development. Although a large number of transcription factor (TF) genes are up- or down regulated by ROS, currently very little is known about the functions of these TFs during oxidative stress. In this work, we examined the role of ERF6 (ETHYLENE RESPONSE FACTOR6), an AP2/ERF domain-containing TF, during oxidative stress responses in Arabidopsis. Mutant analyses showed that NADPH oxidase (RbohD) and calcium signaling are required for ROS-responsive expression of ERF6. erf6 insertion mutant plants showed reduced growth and increased H2O2 and anthocyanin levels. Expression analyses of selected ROS-responsive genes during oxidative stress identified several differentially expressed genes in the erf6 mutant. In particular, a number of ROS responsive genes, such as ZAT12, HSFs, WRKYs, MAPKs, RBOHs, DHAR1, APX4, and CAT1 were more strongly induced by H2O2 in erf6 plants than in wild-type. In contrast, MDAR3, CAT3, VTC2 and EX1 showed reduced expression levels in the erf6 mutant. Taken together, our results indicate that ERF6 plays an important role as a positive antioxidant regulator during plant growth and in response to biotic and abiotic stresses. PMID- 23940556 TI - MiR-124 suppresses growth of human colorectal cancer by inhibiting STAT3. AB - Emerging evidence indicate that microRNAs (miRNAs) may play important roles in cancer. Aberrant expression of miRNAs has been frequently identified in different human malignancies, including colorectal cancer (CRC). However, the mechanism by which deregulated miRNAs impact the development of CRC remains largely elusive. In this study, we show that miR-124 is significantly down-regulated in CRC compared to adjacent non-tumor colorectal tissues. MiR-124 suppresses the expression of STAT3 by directly binding to its 3'-untranslated region (3'-UTR). Overexpression of miR-124 led to increased apoptosis of CRC cells and reduced tumor growth in vitro and in vivo. Knocking down STAT3 expression by specific siRNA suppressed the growth of CRC cells in vitro and in vivo, resembling that of miR-124 overexpression. Moreover, overexpression of STAT3 in miR-124-transfected CRC cells effectively rescued the inhibition of cell proliferation caused by miR 124. These data suggest that miR-124 serves as a tumor suppressor by targeting STAT3, and call for the use of miR-124 as a potential therapeutic tool for CRC, where STAT3 is often hyper-activated. PMID- 23940557 TI - Mycobacterium tuberculosis bacteremia in a cohort of hiv-infected patients hospitalized with severe sepsis in uganda-high frequency, low clinical suspicion [corrected] and derivation of a clinical prediction score. AB - BACKGROUND: When manifested as Mycobacterium tuberculosis (MTB) bacteremia, disseminated MTB infection clinically mimics other serious blood stream infections often hindering early diagnosis and initiation of potentially life saving anti-tuberculosis therapy. In a cohort of hospitalized HIV-infected Ugandan patients with severe sepsis, we report the frequency, management and outcomes of patients with MTB bacteremia and propose a risk score based on clinical predictors of MTB bacteremia. METHODS: We prospectively enrolled adult patients with severe sepsis at two Ugandan hospitals and obtained blood cultures for MTB identification. Multivariable logistic regression modeling was used to determine predictors of MTB bacteremia and to inform the stratification of patients into MTB bacteremia risk categories based on relevant patient characteristics. RESULTS: Among 368 HIV-infected patients with a syndrome of severe sepsis, eighty-six (23%) had MTB bacteremia. Patients with MTB bacteremia had a significantly lower median CD4 count (17 vs 64 lymphocytes/mm(3), p<0.001) and a higher 30-day mortality (53% vs 32%, p = 0.001) than patients without MTB bacteremia. A minority of patients with MTB bacteremia underwent standard MTB diagnostic testing (24%) or received empiric anti-tuberculosis therapy (15%). Independent factors associated with MTB bacteremia included male sex, increased heart rate, low CD4 count, absence of highly active anti-retroviral therapy, chief complaint of fever, low serum sodium and low hemoglobin. A risk score derived from a model containing these independent predictors had good predictive accuracy [area under the curve = 0.85, 95% CI 0.80-0.89]. CONCLUSIONS: Nearly 1 in 4 adult HIV-infected patients hospitalized with severe sepsis in 2 Ugandan hospitals had MTB bacteremia. Among patients in whom MTB was suspected, standard tests for diagnosing pulmonary MTB were inaccurate for correctly classifying patients with or without bloodstream MTB infection. A MTB bacteremia risk score can improve early diagnosis of MTB bacteremia particularly in settings with increased HIV and MTB co-infection. PMID- 23940558 TI - Targeted re-sequencing identified rs3106189 at the 5' UTR of TAPBP and rs1052918 at the 3' UTR of TCF3 to be associated with the overall survival of colorectal cancer patients. AB - Recent studies have demonstrated the power of deep re-sequencing of the whole genome or exome in understanding cancer genomes. However, targeted capture of selected genomic whole gene-body regions, rather than the whole exome, have several advantages: 1) the genes can be selected based on biology or a hypothesis; 2) mutations in promoter and intronic regions, which have important regulatory roles, can be investigated; and 3) less expensive than whole genome or whole exome sequencing. Therefore, we designed custom high-density oligonucleotide microarrays (NimbleGen Inc.) to capture approximately 1.7 Mb target regions comprising the genomic regions of 28 genes related to colorectal cancer including genes belonging to the WNT signaling pathway, as well as important transcription factors or colon-specific genes that are over expressed in colorectal cancer (CRC). The 1.7 Mb targeted regions were sequenced with a coverage ranged from 32* to 45* for the 28 genes. We identified a total of 2342 sequence variations in the CRC and corresponding adjacent normal tissues. Among them, 738 were novel sequence variations based on comparisons with the SNP database (dbSNP135). We validated 56 of 66 SNPs in a separate cohort of 30 CRC tissues using Sequenom MassARRAY iPLEX Platform, suggesting a validation rate of at least 85% (56/66). We found 15 missense mutations among the exonic variations, 21 synonymous SNPs that were predicted to change the exonic splicing motifs, 31 UTR SNPs that were predicted to occur at the transcription factor binding sites, 20 intronic SNPs located near the splicing sites, 43 SNPs in conserved transcription factor binding sites and 32 in CpG islands. Finally, we determined that rs3106189, localized to the 5' UTR of antigen presenting tapasin binding protein (TAPBP), and rs1052918, localized to the 3' UTR of transcription factor 3 (TCF3), were associated with overall survival of CRC patients. PMID- 23940559 TI - The weight of cognitions in panic: the link between misinterpretations and panic attacks. AB - In cognitive theory it is hypothesized that panic attacks are provoked by catastrophic misinterpretations of bodily sensations. The aim of the present study was to investigate the ability of associated word pairs referring to catastrophic thinking (e.g. palpitations-heart attack) in producing panic attacks. Patients with PD (n = 20), patients with mixed anxiety disorders (n = 20), and a healthy control group (n = 30) participated in the present study. To enhance ecological validity we first conducted a stimulus validation experiment. Subsequently, nine suitable panic and neutral word pairs were presented in block to the participants. Anxiety levels were assessed before and after the presentation. PD patients were more anxious when reading these word pairs, compared to neutral word pairs. However, none of the participants experienced a panic attack upon reading the word pairs. From the present results it seems that catastrophic thinking is rather related to the anticipatory anxiety for panic attacks, but not necessarily with the occurrence of the panic attacks themselves. PMID- 23940560 TI - Reconstruction of active regular motion in amoeba extract: dynamic cooperation between sol and gel states. AB - Amoeboid locomotion is one of the typical modes of biological cell migration. Cytoplasmic sol-gel conversion of an actomyosin system is thought to play an important role in locomotion. However, the mechanisms underlying sol-gel conversion, including trigger, signal, and regulating factors, remain unclear. We developed a novel model system in which an actomyosin fraction moves like an amoeba in a cytoplasmic extract. Rheological study of this model system revealed that the actomyosin fraction exhibits shear banding: the sol-gel state of actomyosin can be regulated by shear rate or mechanical force. Furthermore, study of the living cell indicated that the shear-banding property also causes sol-gel conversion with the same order of magnitude as that of shear rate. Our results suggest that the inherent sol-gel transition property plays an essential role in the self-regulation of autonomous translational motion in amoeba. PMID- 23940561 TI - Polymorphism of ORM1 is associated with the pharmacokinetics of telmisartan. AB - BACKGROUND: The pharmacokinetics (PKs) and pharmacodynamics (PDs) of telmisartan varies among the individuals, and the main causes remain unknown. The aim of this study was to evaluate the impact of ORM1, as well as ABCC2, ABCB1, ABCG2 and SLCO1B3 polymorphisms, on the disposition of the drug and BP change after taking 40 mg telmisartan in 48 healthy Chinese males. METHOD: A total of 48 healthy males were included in this trial. Every volunteer ingested a single dose of 40 mg telmisartan, and the plasma drug concentration and blood pressure (BP) were measured up to 48 h. RESULT: In this study, the area under the plasma concentration-time curve (AUC) in the heterozygotes of ORM1 113AG was higher than that in the wild-type homozygotes, AUC(0-48) (113AA vs. 113AG, 1,549.18+/-859.84 ng.h/ml vs. 2,313.54+/-1,257.71 ng.h/ml, P = 0.033), AUC(0-infinity) (113AA vs. 113AG, 1,753.13+/-1,060.60 ng.h/ml vs. 2,686.90+/-1,401.87 ng.h/ml, P = 0.016), and the change(%) of the diastolic blood pressure (DBP) from the baseline BP value also showed a significant difference between the ORM1 113AG and 113AA genotypes at 5 h after taking telmisartan (P = 0.026). This study also showed that the allele of ABCC2 C3972T would affected the disposition of telmsiartan and the DBP change significantly after taking the drug. However, the common SNPs of ABCG2 C421, ABCB1 C3435T, and SLCO1B3 T334G showed no impacts on the PKs of telmisartan or BP change(%) in our trial. CONCLUSION: The ORM1 A113G polymorphism was associated with the PKs variability after taking telmsiartan, as well as ABCC2 C3972T. The heterozygotes of ORM1 113AG showed a larger AUC and a notable BP change(%) from the baseline compared with the wild-type. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TNC-10000898. PMID- 23940562 TI - Possible involvement of cone opsins in distinct photoresponses of intrinsically photosensitive dermal chromatophores in tilapia Oreochromis niloticus. AB - Dermal specialized pigment cells (chromatophores) are thought to be one type of extraretinal photoreceptors responsible for a wide variety of sensory tasks, including adjusting body coloration. Unlike the well-studied image-forming function in retinal photoreceptors, direct evidence characterizing the mechanism of chromatophore photoresponses is less understood, particularly at the molecular and cellular levels. In the present study, cone opsin expression was detected in tilapia caudal fin where photosensitive chromatophores exist. Single-cell RT-PCR revealed co-existence of different cone opsins within melanophores and erythrophores. By stimulating cells with six wavelengths ranging from 380 to 580 nm, we found melanophores and erythrophores showed distinct photoresponses. After exposed to light, regardless of wavelength presentation, melanophores dispersed and maintained cell shape in an expansion stage by shuttling pigment granules. Conversely, erythrophores aggregated or dispersed pigment granules when exposed to short- or middle/long-wavelength light, respectively. These results suggest that diverse molecular mechanisms and light-detecting strategies may be employed by different types of tilapia chromatophores, which are instrumental in pigment pattern formation. PMID- 23940563 TI - MRI phantoms - are there alternatives to agar? AB - The suitability of different gelling agents as MRI phantoms was evaluated in terms of homogeneity, gel stability and reproducibility. Time and effort for preparation were also taken into account. The relaxation times of various gel compositions were estimated. Carbomer-980 and Carbopol-974P were determined to be promising novel phantom materials. These gelling agents are readily available, inexpensive and easy to handle given that thermal treatment is not required. Furthermore, the viscoelasticity of their polymer network is pH-dependent. With such characteristics, it was even possible to embed sensitive objects and retrieve them after testing. This was demonstrated with a fiber phantom for Diffusion Weighted MRI applications. Since Carbomer-980 and Carbopol-974P are non hazardous, they are also suitable for multimodal setups (e.g., MRI as well as ultrasonic imaging). PMID- 23940564 TI - Combination of intratumoral invariant natural killer T cells and interferon-gamma is associated with prognosis of hepatocellular carcinoma after curative resection. AB - PURPOSE: To investigate the prognostic value of intratumoral invariant natural killer T (iNKT) cells and interferon-gamma (IFN-gamma) in hepatocellular carcinoma (HCC) after curative resection. EXPERIMENTAL DESIGN: Expression of TRAV10, encoding the Valpha24 domain of iNKT cells, and IFN-gamma mRNA were assessed by quantitative real-time polymerase chain reaction in tumor from 224 HCC patients undergoing curative resection. The prognostic value of these two and other clinicopathologic factors was evaluated. RESULTS: Either intratumoral iNKT cells and IFN-gamma alone or their combination was an independent prognostic factor for OS (P = 0.001) and RFS (P = 0.001) by multivariate Cox proportional hazards analysis. Patients with concurrent low levels of iNKT cells and IFN-gamma had a hazard ratio (HR) of 2.784 for OS and 2.673 for RFS. The areas under the curve of iNKT cells, IFN-gammaand their combination were 0.618 vs 0.608 vs 0.654 for death and 0.591 vs 0.604 vs 0.633 for recurrence respectively by receiver operating characteristic curve analysis. The prognosis was the worst for HCC patients with concurrent low levels of iNKT cells and IFN-gamma, which might be related with more advanced pTNM stage and more vascular invasion. CONCLUSIONS: Combination of intratumoral iNKT cells and IFN-gamma is a promising independent predictor for recurrence and survival in HCC, which has a better power to predict HCC patients' outcome compared with intratumoral iNKT cells or IFN-gamma alone. PMID- 23940565 TI - Subtracted diversity array identifies novel molecular markers including retrotransposons for fingerprinting Echinacea species. AB - Echinacea, native to the Canadian prairies and the prairie states of the United States, has a long tradition as a folk medicine for the Native Americans. Currently, Echinacea are among the top 10 selling herbal medicines in the U.S. and Europe, due to increasing popularity for the treatment of common cold and ability to stimulate the immune system. However, the genetic relationship within the species of this genus is unclear, making the authentication of the species used for the medicinal industry more difficult. We report the construction of a novel Subtracted Diversity Array (SDA) for Echinacea species and demonstrate the potential of this array for isolating highly polymorphic sequences. In order to selectively isolate Echinacea-specific sequences, a Suppression Subtractive Hybridization (SSH) was performed between a pool of twenty-four Echinacea genotypes and a pool of other angiosperms and non-angiosperms. A total of 283 subtracted genomic DNA (gDNA) fragments were amplified and arrayed. Twenty-seven Echinacea genotypes including four that were not used in the array construction could be successfully discriminated. Interestingly, unknown samples of E. paradoxa and E. purpurea could be unambiguously identified from the cluster analysis. Furthermore, this Echinacea-specific SDA was also able to isolate highly polymorphic retrotransposon sequences. Five out of the eleven most discriminatory features matched to known retrotransposons. This is the first time retrotransposon sequences have been used to fingerprint Echinacea, highlighting the potential of retrotransposons as based molecular markers useful for fingerprinting and studying diversity patterns in Echinacea. PMID- 23940566 TI - Human papillomavirus-associated subsequent malignancies among long-term survivors of pediatric and young adult cancers. AB - Long-term survivors of pediatric and young adult (PAYA) cancers have a high incidence of subsequent neoplasms, but few risk factors other than cancer treatment have been identified. We aimed to describe the burden of human papillomavirus (HPV)-associated malignancies among survivors of PAYA cancers to assess whether HPV infections might be a reasonable area of future etiologic research on subsequent malignancies in this population. We used longitudinal data from 9 population-based registries of the Surveillance, Epidemiology, and End Results program collected between 1973 and 2010 to assemble a cohort of individuals who were diagnosed with any cancer between the ages of 0 and 29 years and survived at least 5 years post-diagnosis. We estimated sex-specific standardized incidence ratios (SIRs) with corresponding 95% confidence limits (CL) of HPV-associated subsequent malignancies (cervical, vaginal, vulvar, penile, anal, tongue, tonsillar, and oropharyngeal). Our study population comprised 64,547 long-term survivors of PAYA cancers diagnosed between 1973 and 2010. Compared with females in the general US population, female PAYA cancer survivors had a 40% relative excess of HPV-associated malignancies overall (SIR = 1.4, 95% CL: 1.2, 1.8). Compared with males in the general US population, male PAYA cancer survivors had a 150% relative excess of HPV-associated malignancies overall (SIR = 2.5, 95% CL: 1.9, 3.4). Our findings suggest an excess of HPV associated malignancies among PAYA cancer survivors compared with the general US population. We hypothesize that a portion of subsequent malignancies among PAYA cancer survivors may be directly attributable to HPV infection. This hypothesis warrants exploration in future studies. PMID- 23940567 TI - Possible role of the glycogen synthase kinase-3 signaling pathway in trimethyltin induced hippocampal neurodegeneration in mice. AB - Trimethyltin (TMT) is an organotin compound with potent neurotoxic effects characterized by neuronal destruction in selective regions, including the hippocampus. Glycogen synthase kinase-3 (GSK-3) regulates many cellular processes, and is implicated in several neurodegenerative disorders. In this study, we evaluated the therapeutic effect of lithium, a selective GSK-3 inhibitor, on the hippocampus of adult C57BL/6 mice with TMT treatment (2.6 mg/kg, intraperitoneal [i.p.]) and on cultured hippocampal neurons (12 days in vitro) with TMT treatment (5 uM). Lithium (50 mg/kg, i.p., 0 and 24 h after TMT injection) significantly attenuated TMT-induced hippocampal cell degeneration, seizure, and memory deficits in mice. In cultured hippocampal neurons, lithium treatment (0-10 mM; 1 h before TMT application) significantly reduced TMT-induced cytotoxicity in a dose-dependent manner. Additionally, the dynamic changes in GSK 3/beta-catenin signaling were observed in the mouse hippocampus and cultured hippocampal neurons after TMT treatment with or without lithium. Therefore, lithium inhibited the detrimental effects of TMT on the hippocampal neurons in vivo and in vitro, suggesting involvement of the GSK-3/beta-catenin signaling pathway in TMT-induced hippocampal cell degeneration and dysfunction. PMID- 23940568 TI - Microarray analysis of gene expression profiles of Schistosoma japonicum derived from less-susceptible host water buffalo and susceptible host goat. AB - BACKGROUND: Water buffalo and goats are natural hosts for S. japonicum in endemic areas of China. The susceptibility of these two hosts to schistosome infection is different, as water buffalo are less conducive to S. japonicum growth and development. To identify genes that may affect schistosome development and survival, we compared gene expression profiles of schistosomes derived from these two natural hosts using high-throughput microarray technology. RESULTS: The worm recovery rate was lower and the length and width of worms from water buffalo were smaller compared to those from goats following S. japonicum infection for 7 weeks. Besides obvious morphological difference between the schistosomes derived from the two hosts, differences were also observed by scanning and transmission electron microscopy. Microarray analysis showed differentially expressed gene patterns for parasites from the two hosts, which revealed that genes related to lipid and nucleotide metabolism, as well as protein folding, sorting, and degradation were upregulated, while others associated with signal transduction, endocrine function, development, immune function, endocytosis, and amino acid/carbohydrate/glycan metabolism were downregulated in schistosomes from water buffalo. KEGG pathway analysis deduced that the differentially expressed genes mainly involved lipid metabolism, the MAPK and ErbB signaling pathways, progesterone-mediated oocyte maturation, dorso-ventral axis formation, reproduction, and endocytosis, etc. CONCLUSION: The microarray gene analysis in schistosomes derived from water buffalo and goats provide a useful platform to disclose differences determining S. japonicum host compatibility to better understand the interplay between natural hosts and parasites, and identify schistosome target genes associated with susceptibility to screen vaccine candidates. PMID- 23940569 TI - Arf induction by Tgfbeta is influenced by Sp1 and C/ebpbeta in opposing directions. AB - Recent studies show that Arf, a bona fide tumor suppressor, also plays an essential role during mouse eye development. Tgfbeta is required for Arf promoter activation in developing mouse eyes, and its capacity to induce Arf depends on Smads 2/3 as well as p38 Mapk. Substantial delay between activation of these pathways and increased Arf transcription imply that changes in the binding of additional transcription factors help orchestrate changes in Arf expression. Focusing on proteins with putative DNA binding elements near the mouse Arf transcription start, we now show that Tgfbeta induction of this gene correlated with decreased expression and DNA binding of C/ebpbeta to the proximal Arf promoter. Ectopic expression of C/ebpbeta in mouse embryo fibroblasts (MEFs) blocked Arf induction by Tgfbeta. Although basal levels of Arf mRNA were increased by C/ebpbeta loss in MEFs and in the developing eye, Tgfbeta was still able to increase Arf, indicating that derepression was not the sole factor. Chromatin immunoprecipitation (ChIP) assay showed increased Sp1 binding to the Arf promotor at 24 and 48 hours after Tgfbeta treatment, at which time points Arf expression was significantly induced by Tgfbeta. Chemical inhibition of Sp1 and its knockdown by RNA interference blocked Arf induction by Tgfbeta in MEFs. In summary, our results indicate that C/ebpbeta and Sp1 are negative and positive Arf regulators that are influenced by Tgfbeta. PMID- 23940570 TI - Interstitial fluid flow and drug delivery in vascularized tumors: a computational model. AB - Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider-with the help of a theoretical model-the tumor IFP, interstitial fluid flow (IFF) and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law) and sources (vessels) and sinks (lymphatics) for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss various strategies to increase drug exposure time of tumor cells. PMID- 23940571 TI - Gastrin: a distinct fate of neurogenin3 positive progenitor cells in the embryonic pancreas. AB - Neurogenin3(+) (Ngn3(+)) progenitor cells in the developing pancreas give rise to five endocrine cell types secreting insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. Gastrin is a hormone produced primarily by G-cells in the stomach, where it functions to stimulate acid secretion by gastric parietal cells. Gastrin is expressed in the embryonic pancreas and is common in islet cell tumors, but the lineage and regulators of pancreatic gastrin(+) cells are not known. We report that gastrin is abundantly expressed in the embryonic pancreas and disappears soon after birth. Some gastrin(+) cells in the developing pancreas co-express glucagon, ghrelin or pancreatic polypeptide, but many gastrin(+) cells do not express any other islet hormone. Pancreatic gastrin(+) cells express the transcription factors Nkx6.1, Nkx2.2 and low levels of Pdx1, and derive from Ngn3(+) endocrine progenitor cells as shown by genetic lineage tracing. Using mice deficient for key transcription factors we show that gastrin expression depends on Ngn3, Nkx2.2, NeuroD1 and Arx, but not Pax4 or Pax6. Finally, gastrin expression is induced upon differentiation of human embryonic stem cells to pancreatic endocrine cells expressing insulin. Thus, gastrin(+) cells are a distinct endocrine cell type in the pancreas and an alternative fate of Ngn3+ cells. PMID- 23940572 TI - mGluR5 ablation in cortical glutamatergic neurons increases novelty-induced locomotion. AB - The group I metabotropic glutamate receptor 5 (mGluR5) has been implicated in the pathology of various neurological disorders including schizophrenia, ADHD, and autism. mGluR5-dependent synaptic plasticity has been described at a variety of neural connections and its signaling has been implicated in several behaviors. These behaviors include locomotor reactivity to novel environment, sensorimotor gating, anxiety, and cognition. mGluR5 is expressed in glutamatergic neurons, inhibitory neurons, and glia in various brain regions. In this study, we show that deleting mGluR5 expression only in principal cortical neurons leads to defective cannabinoid receptor 1 (CB1R) dependent synaptic plasticity in the prefrontal cortex. These cortical glutamatergic mGluR5 knockout mice exhibit increased novelty-induced locomotion, and their locomotion can be further enhanced by treatment with the psychostimulant methylphenidate. Despite a modest reduction in repetitive behaviors, cortical glutamatergic mGluR5 knockout mice are normal in sensorimotor gating, anxiety, motor balance/learning and fear conditioning behaviors. These results show that mGluR5 signaling in cortical glutamatergic neurons is required for precisely modulating locomotor reactivity to a novel environment but not for sensorimotor gating, anxiety, motor coordination, several forms of learning or social interactions. PMID- 23940573 TI - A biodegradable, sustained-released, prednisolone acetate microfilm drug delivery system effectively prolongs corneal allograft survival in the rat keratoplasty model. AB - Frequent and long-term use of topical corticosteroids after corneal transplantation is necessary to prevent graft rejection. However, it relies heavily on patient compliance, and sustained therapeutic drug levels are often not achieved with administration of topical eye drops. A biodegradable drug delivery system with a controlled and sustained drug release may circumvent these limitations. In this study, we investigated the efficacy of a prednisolone acetate (PA)-loaded poly (d,l-lactide-co-epsilon-caprolactone) (PLC) microfilm drug delivery system on promoting the survival of allogeneic grafts after penetrating keratoplasty (PK) using a rat model. The drug release profiles of the microfilms were characterized (group 1). Subsequently, forty-eight PK were performed in four experimental groups: syngeneic control grafts (group 2), allogeneic control grafts (group 3), allogeneic grafts with subconjunctivally implanted PA microfilm (group 4), and allogeneic grafts with PA eye drops (group 5; n = 12 in each). PA-loaded microfilm achieved a sustained and steady release at a rate of 0.006-0.009 mg/day, with a consistent aqueous drug concentration of 207-209 ng/ml. The mean survival days was >28 days in group 2, 9.9+/-0.8 days in group 3, 26.8+/-2.7 days in group 4, and 26.4+/-3.4 days in group 5 (P = 0.023 and P = 0.027 compared with group 3). Statistically significant decrease in CD4+, CD163+, CD 25+, and CD54+ cell infiltration was observed in group 4 and group 5 compared with group 3 (P<0.001). There was no significant difference in the mean survival and immunohistochemical analysis between group 4 and group 5. These results showed that sustained PA-loaded microfilm effectively prolongs corneal allograft survival. It is as effective as conventional PA eye drops, providing a promising clinically applicable alternative for patients undergoing corneal transplantation. PMID- 23940574 TI - Regulators of global genome repair do not respond to DNA damaging therapy but correlate with survival in melanoma. AB - Nucleotide excision repair (NER) orchestrates the repair of helix distorting DNA damage, induced by both ultraviolet radiation (UVR) and cisplatin. There is evidence that the global genome repair (GGR) arm of NER is dysfunctional in melanoma and it is known to have limited induction in melanoma cell lines after cisplatin treatment. The aims of this study were to examine mRNA transcript levels of regulators of GGR and to investigate the downstream effect on global transcript expression in melanoma cell lines after cisplatin treatment and in melanoma tumours. The GGR regulators, BRCA1 and PCNA, were induced in melanocytes after cisplatin, but not in melanoma cell lines. Transcripts associated with BRCA1, BRCA2, ATM and CHEK2 showed altered expression in melanoma cell lines after cisplatin treatment. In melanoma tumour tissue BRCA1 transcript expression correlated with poor survival and XPB expression correlated with solar elastosis levels. Taken together, these findings provide evidence of the mechanisms underlying NER deficiency in melanoma. PMID- 23940576 TI - Effects of rate-limiting steps in transcription initiation on genetic filter motifs. AB - The behavior of genetic motifs is determined not only by the gene-gene interactions, but also by the expression patterns of the constituent genes. Live single-molecule measurements have provided evidence that transcription initiation is a sequential process, whose kinetics plays a key role in the dynamics of mRNA and protein numbers. The extent to which it affects the behavior of cellular motifs is unknown. Here, we examine how the kinetics of transcription initiation affects the behavior of motifs performing filtering in amplitude and frequency domain. We find that the performance of each filter is degraded as transcript levels are lowered. This effect can be reduced by having a transcription process with more steps. In addition, we show that the kinetics of the stepwise transcription initiation process affects features such as filter cutoffs. These results constitute an assessment of the range of behaviors of genetic motifs as a function of the kinetics of transcription initiation, and thus will aid in tuning of synthetic motifs to attain specific characteristics without affecting their protein products. PMID- 23940575 TI - Effects of wheat and oat-based whole grain foods on serum lipoprotein size and distribution in overweight middle aged people: a randomised controlled trial. AB - INTRODUCTION: Epidemiological studies suggest three daily servings of whole-grain foods (WGF) might lower cardiovascular disease risk, at least partly by lowering serum lipid levels. We have assessed the effects of consuming three daily portions of wholegrain food (provided as wheat or a mixture of wheat and oats) on lipoprotein subclass size and concentration in a dietary randomised controlled trial involving middle aged healthy individuals. METHODS: After a 4-week run-in period on a refined diet, volunteers were randomly allocated to a control (refined diet), wheat, or wheat + oats group for 12 weeks. Our servings were determined in order to significantly increase the intakes of non starch polysaccharides to the UK Dietary Reference Value of 18 g per day in the whole grain groups (18.5 g and 16.8 g per day in the wheat and wheat + oats groups respectively in comparison with 11.3 g per day in the control group). Outcome measures were serum lipoprotein subclasses' size and concentration. Habitual dietary intake was assessed prior and during the intervention. Of the 233 volunteers recruited, 24 withdrew and 3 were excluded. RESULTS: At baseline, significant associations were found between lipoprotein size and subclasses' concentrations and some markers of cardiovascular risk such as insulin resistance, blood pressure and serum Inter cellular adhesion molecule 1 concentration. Furthermore, alcohol and vitamin C intake were positively associated with an anti-atherogenic lipoprotein profile, with regards to lipoprotein size and subclasses' distribution. However, none of the interventions with whole grain affected lipoprotein size and profile. CONCLUSION: Our results indicate that three portions of wholegrain foods, irrelevant of the type (wheat or oat-based) do not reduce cardiovascular risk by beneficially altering the size and distribution of lipoprotein subclasses. TRIAL REGISTRATION: www.Controlled Trials.com ISRCTN 27657880. PMID- 23940578 TI - A multi-year longitudinal study of water quality parameters in four salmon bearing and recreational streams on mount hood, Oregon. AB - Four streams-Clear Fork, Lost Creek, Camp Creek and Still Creek-in northwestern Oregon's Sandy River Basin were monitored for temperature, dissolved oxygen levels, and fecal bacterial concentrations in a multi-year analysis examining stream health for recreational users and anchor habitat for Pacific Salmon. Temperatures were recorded using micro -T temperature loggers at 15 locations, during 22 July - 5 September 2006, 2 July - 4 September 2007, 20 June - 7 September 2008, 23 June - 9 September 2009, and 2 July -9 September 2010. The Seven-Day Average Maximum water temperature (7-DAM) of 13 degrees C was used as a reference value for the biological limit governing suitable salmonid spawning and egg incubation conditions. The maximum 7-DAM temperatures occurred on different dates and all streams neared or exceeded the 13 degrees C standard at least once each summer. Dissolved oxygen levels were measured at weekly or longer intervals in 2006, 2007, 2008, and 2009. Dissolved oxygen levels fell below the 9.0 ppm standard for Clear Fork on almost half the sampling dates in 2006, 2007, and 2009. Concentrations of the bacterial genus Enterococcus were measured as an indicator of fecal contamination. Samples were collected at 15 sites along the four streams. Weekly samples were collected during a 9 week period from July - September 2007, an 11 week period from June - September 2008, and an 11 week period from June - September 2009. Enterococcus counts exceeded the federal recommended national criterion value of 61 colony forming units (CFU) per 100 mL every year in Camp Creek and occasionally elsewhere, with exceedances trending towards late summer. PMID- 23940577 TI - Surface display and bioactivity of Bombyx mori acetylcholinesterase on Pichia pastoris. AB - A Pichia pastoris (P. pastoris) cell surface display system of Bombyx mori acetylcholinesterase (BmAChE) was constructed and its bioactivity was studied. The modified Bombyx mori acetylcholinesterase gene (bmace) was fused with the anchor protein (AGalpha1) from Saccharomyces cerevisiae and transformed into P. pastoris strain GS115. The recombinant strain harboring the fusion gene bmace AGalpha1 was induced to display BmAChE on the P. pastoris cell surface. Fluorescence microscopy and flow cytometry assays revealed that the BmAChE was successfully displayed on the cell surface of P. pastoris GS115. The enzyme activity of the displayed BmAChE was detected by the Ellman method at 787.7 U/g (wet cell weight). In addition, bioactivity of the displayed BmAChE was verified by inhibition tests conducted with eserine, and with carbamate and organophosphorus pesticides. The displayed BmAChE had an IC50 of 4.17*10(-8) M and was highly sensitive to eserine and five carbamate pesticides, as well as seven organophosphorus pesticides. Results suggest that the displayed BmAChE had good bioactivity. PMID- 23940579 TI - Angiopoietin-2 is critical for cytokine-induced vascular leakage. AB - Genetic experiments (loss-of-function and gain-of-function) have established the role of Angiopoietin/Tie ligand/receptor tyrosine kinase system as a regulator of vessel maturation and quiescence. Angiopoietin-2 (Ang-2) acts on Tie2-expressing resting endothelial cells as an antagonistic ligand to negatively interfere with the vessel stabilizing effects of constitutive Ang-1/Tie-2 signaling. Ang-2 thereby controls the vascular response to inflammation-inducing as well as angiogenesis-inducing cytokines. This study was aimed at assessing the role of Ang-2 as an autocrine (i.e. endothelial-derived) regulator of rapid vascular responses (within minutes) caused by permeability-inducing agents. Employing two independent in vivo assays to quantitatively assess vascular leakage (tracheal microsphere assay, 1-5 min and Miles assay, 20 min), the immediate vascular response to histamine, bradykinin and VEGF was analyzed in Ang-2-deficient (Ang 2(-/-)) mice. In comparison to the wild type control mice, the Ang2(-/-) mice demonstrated a significantly attenuated response. The Ang-2(-/-) phenotype was rescued by systemic administration (paracrine) of an adenovirus encoding Ang-2. Furthermore, cytokine-induced intracellular calcium influx was impaired in Ang-2( /-) endothelioma cells, consistent with reduced phospholipase activation in vivo. Additionally, recombinant human Ang-2 (rhAng-2) alone was unable to induce vascular leakage. In summary, we report here in a definite genetic setting that Ang-2 is critical for multiple vascular permeability-inducing cytokines. PMID- 23940580 TI - Increased cellular senescence and vascular rarefaction exacerbate the progression of kidney fibrosis in aged mice following transient ischemic injury. AB - Recent findings indicate that elderly patients with acute kidney injury (AKI) have an increased incidence of progression to chronic kidney disease (CKD) due to incomplete recovery from an acute insult. In the current study, a co-morbid model of AKI was developed to better mimic the patient population and to investigate whether age exacerbates the fibrosis and inflammation that develop in the sequelae of progressive kidney disease following acute injury. Young (8-10 weeks) and aged (46-49 weeks) C57BL/6 mice were subjected to 30 min bilateral renal ischemia-reperfusion (I/R) to induce AKI. The aged animals have greater mortality and prolonged elevation of plasma creatinine correlating with less tubular epithelial cell proliferation compared to the young. Six weeks post-reperfusion, interstitial fibrosis is greater in aged kidneys based on picrosirius red staining and immunolocalization of cellular fibronectin, collagen III and collagen IV. Aged kidneys 6 weeks post-reperfusion also express higher levels of p53 and p21 compared to the young, correlating with greater increases in senescence associated (SA) beta-galactosidase, a known marker of cellular senescence. A higher influx of F4/80(+) macrophages and CD4(+) T lymphocytes is measured and is accompanied by increases in mRNA of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha). Importantly, microvascular density is significantly less, correlating with an increase in nitro-tyrosine, a marker of oxidative stress. Collectively, these data demonstrate that prolonged acute injury in the aged animals results in an accelerated progression of kidney disease in a chronic state. PMID- 23940581 TI - Temperament and character in the Child and Adolescent Twin Study in Sweden (CATSS): comparison to the general population, and genetic structure analysis. AB - BACKGROUND: The Child and Adolescent Twin Study in Sweden (CATSS) is an on-going, large population-based longitudinal twin study. We aimed (1) to investigate the reliability of two different versions (125-items and 238-items) of Cloninger's Temperament and Character Inventory (TCI) used in the CATSS and the validity of extracting the short version from the long version, (2) to compare these personality dimensions between twins and adolescents from the general population, and (3) to investigate the genetic structure of Cloninger's model. METHOD: Reliability and correlation analyses were conducted for both TCI versions, 2,714 CATSS-twins were compared to 631 adolescents from the general population, and the genetic structure was investigated through univariate genetic analyses, using a model-fitting approach with structural equation-modeling techniques based on same sex twin pairs from the CATSS (423 monozygotic and 408 dizygotic pairs). RESULTS: The TCI scores from the short and long versions showed comparable reliability coefficients and were strongly correlated. Twins scored about half a standard deviation higher in the character scales. Three of the four temperament dimensions (Novelty Seeking, Harm Avoidance, and Persistence) had strong genetic and non-shared environmental effects, while Reward Dependence and the three character dimensions had moderate genetic effects, and both shared and non-shared environmental effects. CONCLUSIONS: Twins showed higher scores in character dimensions compared to adolescents from the general population. At least among adolescents there is a shared environmental influence for all of the character dimensions, but only for one of the temperament dimensions (i.e., Reward Dependence). This specific finding regarding the existence of shared environmental factors behind the character dimensions in adolescence, together with earlier findings showing a small shared environmental effects on character among young adults and no shared environmental effects on character among adults, suggest that there is a shift in type of environmental influence from adolescence to adulthood regarding character. PMID- 23940582 TI - Longitudinal nasopharyngeal carriage and antibiotic resistance of respiratory bacteria in indigenous Australian and Alaska native children with bronchiectasis. AB - BACKGROUND: Indigenous children in Australia and Alaska have very high rates of chronic suppurative lung disease (CSLD)/bronchiectasis. Antibiotics, including frequent or long-term azithromycin in Australia and short-term beta-lactam therapy in both countries, are often prescribed to treat these patients. In the Bronchiectasis Observational Study we examined over several years the nasopharyngeal carriage and antibiotic resistance of respiratory bacteria in these two PCV7-vaccinated populations. METHODS: Indigenous children aged 0.5-8.9 years with CSLD/bronchiectasis from remote Australia (n = 79) and Alaska (n = 41) were enrolled in a prospective cohort study during 2004-8. At scheduled study visits until 2010 antibiotic use in the preceding 2-weeks was recorded and nasopharyngeal swabs collected for culture and antimicrobial susceptibility testing. Analysis of respiratory bacterial carriage and antibiotic resistance was by baseline and final swabs, and total swabs by year. RESULTS: Streptococcus pneumoniae carriage changed little over time. In contrast, carriage of Haemophilus influenzae declined and Staphylococcus aureus increased (from 0% in 2005-6 to 23% in 2010 in Alaskan children); these changes were associated with increasing age. Moraxella catarrhalis carriage declined significantly in Australian, but not Alaskan, children (from 64% in 2004-6 to 11% in 2010). While beta-lactam antibiotic use was similar in the two cohorts, Australian children received more azithromycin. Macrolide resistance was significantly higher in Australian compared to Alaskan children, while H. influenzae beta-lactam resistance was higher in Alaskan children. Azithromycin use coincided significantly with reduced carriage of S. pneumoniae, H. influenzae and M. catarrhalis, but increased carriage of S. aureus and macrolide-resistant strains of S. pneumoniae and S. aureus (proportion of carriers and all swabs), in a 'cumulative dose-response' relationship. CONCLUSIONS: Over time, similar (possibly age-related) changes in nasopharyngeal bacterial carriage were observed in Australian and Alaskan children with CSLD/bronchiectasis. However, there were also significant frequency-dependent differences in carriage and antibiotic resistance that coincided with azithromycin use. PMID- 23940583 TI - Voting-based cancer module identification by combining topological and data driven properties. AB - Recently, computational approaches integrating copy number aberrations (CNAs) and gene expression (GE) have been extensively studied to identify cancer-related genes and pathways. In this work, we integrate these two data sets with protein protein interaction (PPI) information to find cancer-related functional modules. To integrate CNA and GE data, we first built a gene-gene relationship network from a set of seed genes by enumerating all types of pairwise correlations, e.g. GE-GE, CNA-GE, and CNA-CNA, over multiple patients. Next, we propose a voting based cancer module identification algorithm by combining topological and data driven properties (VToD algorithm) by using the gene-gene relationship network as a source of data-driven information, and the PPI data as topological information. We applied the VToD algorithm to 266 glioblastoma multiforme (GBM) and 96 ovarian carcinoma (OVC) samples that have both expression and copy number measurements, and identified 22 GBM modules and 23 OVC modules. Among 22 GBM modules, 15, 12, and 20 modules were significantly enriched with cancer-related KEGG, BioCarta pathways, and GO terms, respectively. Among 23 OVC modules, 19, 18, and 23 modules were significantly enriched with cancer-related KEGG, BioCarta pathways, and GO terms, respectively. Similarly, we also observed that 9 and 2 GBM modules and 15 and 18 OVC modules were enriched with cancer gene census (CGC) and specific cancer driver genes, respectively. Our proposed module-detection algorithm significantly outperformed other existing methods in terms of both functional and cancer gene set enrichments. Most of the cancer-related pathways from both cancer data sets found in our algorithm contained more than two types of gene-gene relationships, showing strong positive correlations between the number of different types of relationship and CGC enrichment [Formula: see text] values (0.64 for GBM and 0.49 for OVC). This study suggests that identified modules containing both expression changes and CNAs can explain cancer-related activities with greater insights. PMID- 23940584 TI - Sparstolonin B inhibits pro-angiogenic functions and blocks cell cycle progression in endothelial cells. AB - Sparstolonin B (SsnB) is a novel bioactive compound isolated from Sparganium stoloniferum, an herb historically used in Traditional Chinese Medicine as an anti-tumor agent. Angiogenesis, the process of new capillary formation from existing blood vessels, is dysregulated in many pathological disorders, including diabetic retinopathy, tumor growth, and atherosclerosis. In functional assays, SsnB inhibited endothelial cell tube formation (Matrigel method) and cell migration (Transwell method) in a dose-dependent manner. Microarray experiments with human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells (HCAECs) demonstrated differential expression of several hundred genes in response to SsnB exposure (916 and 356 genes, respectively, with fold change >=2, p<0.05, unpaired t-test). Microarray data from both cell types showed significant overlap, including genes associated with cell proliferation and cell cycle. Flow cytometric cell cycle analysis of HUVECs treated with SsnB showed an increase of cells in the G1 phase and a decrease of cells in the S phase. Cyclin E2 (CCNE2) and Cell division cycle 6 (CDC6) are regulatory proteins that control cell cycle progression through the G1/S checkpoint. Both CCNE2 and CDC6 were downregulated in the microarray data. Real Time quantitative PCR confirmed that gene expression of CCNE2 and CDC6 in HUVECs was downregulated after SsnB exposure, to 64% and 35% of controls, respectively. The data suggest that SsnB may exert its anti-angiogenic properties in part by downregulating CCNE2 and CDC6, halting progression through the G1/S checkpoint. In the chick chorioallantoic membrane (CAM) assay, SsnB caused significant reduction in capillary length and branching number relative to the vehicle control group. Overall, SsnB caused a significant reduction in angiogenesis (ANOVA, p<0.05), demonstrating its ex vivo efficacy. PMID- 23940585 TI - Mouse strain determines cardiac growth potential. AB - RATIONALE: The extent of heart disease varies from person to person, suggesting that genetic background is important in pathology. Genetic background is also important when selecting appropriate mouse models to study heart disease. This study examines heart growth as a function of strain, specifically C57BL/6 and DBA/2 mouse strains. OBJECTIVE: In this study, we test the hypothesis that two strains of mice, C57BL/6 and DBA/2, will produce varying degrees of heart growth in both physiological and pathological settings. METHODS AND RESULTS: Differences in heart dimensions are detectable by echocardiography at 8 weeks of age. Percentages of cardiac progenitor cells (c-kit+ cells) and mononucleated cells were found to be in a higher percentage in DBA/2 mice, and more tri- and quad nucleated cells were in C57BL/6 mice. Cardiomyocyte turnover shows no significant changes in mitotic activity, however, there is more apoptotic activity in DBA/2 mice. Cardiomyocyte cell size increased with age, but increased more in DBA/2 mice, although percentages of nucleated cells remained the same in both strains. Two-week isoproterenol stimulation showed an increase in heart growth in DBA/2 mice, both at cardiomyocyte and whole heart level. In isoproterenol-treated DBA/2 mice, there was also a greater expression level of the hypertrophy marker, ANF, compared to C57BL/6 mice. CONCLUSION: We conclude that the DBA/2 mouse strain has a more immature cardiac phenotype, which correlates to a cardiac protective response to hypertrophy in both physiological and pathological stimulations. PMID- 23940586 TI - Increased PRAME-specific CTL killing of acute myeloid leukemia cells by either a novel histone deacetylase inhibitor chidamide alone or combined treatment with decitabine. AB - As one of the best known cancer testis antigens, PRAME is overexpressed exclusively in germ line tissues such as the testis as well as in a variety of solid and hematological malignant cells including acute myeloid leukemia. Therefore, PRAME has been recognized as a promising target for both active and adoptive anti-leukemia immunotherapy. However, in most patients with PRAME expressing acute myeloid leukemia, PRAME antigen-specific CD8(+) CTL response are either undetectable or too weak to exert immune surveillance presumably due to the inadequate PRAME antigen expression and PRAME-specific antigen presentation by leukemia cells. In this study, we observed remarkably increased PRAME mRNA expression in human acute myeloid leukemia cell lines and primary acute myeloid leukemia cells after treatment with a novel subtype-selective histone deacetylase inhibitor chidamide in vitro. PRAME expression was further enhanced in acute myeloid leukemia cell lines after combined treatment with chidamide and DNA demethylating agent decitabine. Pre-treatment of an HLA-A0201(+) acute myeloid leukemia cell line THP-1 with chidamide and/or decitabine increased sensitivity to purified CTLs that recognize PRAME(100-108) or PRAME(300-309) peptide presented by HLA-A0201. Chidamide-induced epigenetic upregulation of CD86 also contributed to increased cytotoxicity of PRAME antigen-specific CTLs. Our data thus provide a new line of evidence that epigenetic upregulation of cancer testis antigens by a subtype-selective HDAC inhibitor or in combination with hypomethylating agent increases CTL cytotoxicity and may represent a new opportunity in future design of treatment strategy targeting specifically PRAME expressing acute myeloid leukemia. PMID- 23940587 TI - Pirfenidone nanoparticles improve corneal wound healing and prevent scarring following alkali burn. AB - PURPOSE: To evaluate the effects of pirfenidone nanoparticles on corneal re epithelialization and scarring, major clinical challenges after alkali burn. METHODS: Effect of pirfenidone on collagen I and alpha-smooth muscle actin (alpha SMA) synthesis by TGFbeta induced primary corneal fibroblast cells was evaluated by immunoblotting and immunocytochemistry. Pirfenidone loaded poly (lactide-co glycolide) (PLGA) nanoparticles were prepared, characterized and their cellular entry was examined in primary corneal fibroblast cells by fluorescence microscopy. Alkali burn was induced in one eye of Sprague Dawley rats followed by daily topical treatment with free pirfenidone, pirfenidone nanoparticles or vehicle. Corneal re-epithelialization was assessed daily by flourescein dye test; absence of stained area indicated complete re-epithelialization and the time for complete re-epithelialization was determined. Corneal haze was assessed daily for 7 days under slit lamp microscope and graded using a standard method. After 7 days, collagen I deposition in the superficial layer of cornea was examined by immunohistochemistry. RESULTS: Pirfenidone prevented (P<0.05) increase in TGF beta induced collagen I and alpha-SMA synthesis by corneal fibroblasts in a dose dependent manner. Pirfenidone could be loaded successfully within PLGA nanoparticles, which entered the corneal fibroblasts within 5 minutes. Pirfenidone nanoparticles but not free pirfenidone significantly (P<0.05) reduced collagen I level, corneal haze and the time for corneal re-epithelialization following alkali burn. CONCLUSION: Pirfenidone decreases collagen synthesis and prevents myofibroblast formation. Pirfenidone nanoparticles improve corneal wound healing and prevent fibrosis. Pirfenidone nanoparticles are of potential value in treating corneal chemical burns and other corneal fibrotic diseases. PMID- 23940588 TI - Urinary calcium and oxalate excretion in healthy adult cats are not affected by increasing dietary levels of bone meal in a canned diet. AB - This study aimed to investigate the impact of dietary calcium (Ca) and phosphorus (P), derived from bone meal, on the feline urine composition and the urinary pH, allowing a risk assessment for the formation of calcium oxalate (CaOx) uroliths in cats. Eight healthy adult cats received 3 canned diets, containing 12.2 (A), 18.5 (B) and 27.0 g Ca/kg dry matter (C) and 16.1 (A), 17.6 (B) and 21.1 g P/kg dry matter (C). Each diet was fed over 17 days. After a 7 days adaptation period, urine and faeces were collected over 2*4 days (with a two-day rest between), and blood samples were taken. Urinary and faecal minerals, urinary oxalate (Ox), the urinary pH and the concentrations of serum Ca, phosphate and parathyroid hormone (PTH) were analyzed. Moreover, the urine was microscopically examined for CaOx uroliths. The results demonstrated that increasing levels of dietary Ca led to decreased serum PTH and Ca and increased faecal Ca and P concentrations, but did not affect the urinary Ca or Ox concentrations or the urinary fasting pH. The urinary postprandial pH slightly increased when the diet C was compared to the diet B. No CaOx crystals were detected in the urine of the cats. In conclusion, urinary Ca excretion in cats seems to be widely independent of the dietary Ca levels when Ca is added as bone meal to a typical canned diet, implicating that raw materials with higher contents of bones are of subordinate importance as risk factors for the formation of urinary CaOx crystals. PMID- 23940589 TI - Effect of static and dynamic stretching on the diurnal variations of jump performance in soccer players. AB - PURPOSE: The present study addressed the lack of data on the effect of different types of stretching on diurnal variations in vertical jump height - i.e., squat jump (SJ) and countermovement-jump (CMJ). We hypothesized that dynamic stretching could affect the diurnal variations of jump height by producing a greater increase in short-term maximal performance in the morning than the evening through increasing core temperature at this time-of-day. METHODS: Twenty male soccer players (age, 18.6+/-1.3 yrs; height, 174.6+/-3.8 cm; body-mass, 71.1+/ 8.6 kg; mean +/- SD) completed the SJ and CMJ tests either after static stretching, dynamic stretching or no-stretching protocols at two times of day, 07:00 h and 17:00 h, with a minimum of 48 hours between testing sessions. One minute after warming-up for 5 minutes by light jogging and performing one of the three stretching protocols (i.e., static stretching, dynamic stretching or no stretching) for 8 minutes, each subject completed the SJ and CMJ tests. Jumping heights were recorded and analyzed using a two-way analysis of variance with repeated measures (3 [stretching]*2 [time-of-day]). RESULTS: The SJ and CMJ heights were significantly higher at 17:00 than 07:00 h (p<0.01) after the no stretching protocol. These daily variations disappeared (i.e., the diurnal gain decreased from 4.2+/-2.81% (p<0.01) to 1.81+/-4.39% (not-significant) for SJ and from 3.99+/-3.43% (p<0.01) to 1.51+/-3.83% (not-significant) for CMJ) after dynamic stretching due to greater increases in SJ and CMJ heights in the morning than the evening (8.4+/-6.36% vs. 4.4+/-2.64%, p<0.05 for SJ and 10.61+/-5.49% vs. 6.03+/-3.14%, p<0.05 for CMJ). However, no significant effect of static stretching on the diurnal variations of SJ and CMJ heights was observed. CONCLUSION: Dynamic stretching affects the typical diurnal variations of SJ and CMJ and helps to counteract the lower morning values in vertical jump height. PMID- 23940590 TI - Shigella flexneri 3a outer membrane protein C epitope is recognized by human umbilical cord sera and associated with protective activity. AB - Shigella flexneri 3a is one of the five major strains of the Shigella genus responsible for dysentery, especially among children, in regions of high poverty and poor sanitation. The outer membrane proteins (OMP) of this bacterium elicit immunological responses and are considered a prime target for vaccine development. When injected into mice they elicit a protective immunological response against a lethal dose of the pathogen. The OMPs from S. flexneri 3a were isolated and resolved by two-dimension-SDS-PAGE. Two 38-kDa spots were of particular interest since in our earlier studies OMPs of such molecular mass were found to interact with umbilical cord sera. These two spots were identified as OmpC by ESI-MS/MS spectrometry. By DNA sequencing, the ompC gene from S. flexneri 3a was identical to ompC from S. flexneri 2a [Gene Bank: 24113600]. A 3D model of OmpC was built and used to predict B-cell type (discontinuous) antigenic epitopes. Six epitopes bearing the highest score were selected and the corresponding peptides were synthesized. Only the peptides representing loop V of OmpC reacted strongly with the umbilical cord serum immunoglobulins. To determine which amino acids are essential for the antigenic activity of the epitope, the loop V was scanned with a series of dodecapeptides. The peptide RYDERY was identified as a minimal sequence for the loop V epitope. Truncation at either the C- or N-terminus rendered this peptide inactive. Apart from C-terminal tyrosine, substitution of each of the remaining five amino acids with glycine, led to a precipitous loss of immunological activity. This peptide may serve as a ligand in affinity chromatography of OmpC-specific antibodies and as a component of a vaccine designed to boost human immune defenses against enterobacterial infections. PMID- 23940591 TI - Human voltage-gated proton channel hv1: a new potential biomarker for diagnosis and prognosis of colorectal cancer. AB - Solid tumors exist in a hypoxic microenvironment, and possess high-glycolytic metabolites. To avoid the acidosis, tumor cells must exhibit a dynamic cytosolic pH regulation mechanism(s). The voltage-gated proton channel Hv1 mediates NADPH oxidase function by compensating cellular loss of electrons with protons. Here, we showed for the first time, that Hv1 expression is increased in colorectal tumor tissues and cell lines, associated with poor prognosis. Immunohistochemistry showed that Hv1 is strongly expressed in adenocarcinomas but not or lowly expressed in normal colorectal or hyperplastic polyps. Hv1 expression in colorectal cancer is significantly associated with the tumor size, tumor classification, lymph node status, clinical stage and p53 status. High Hv1 expression is associated significantly with shorter overall and recurrence-free survival. Furthermore, real-time RT-PCR and immunocytochemistry showed that Hv1 is highly expressed in colorectal cancer cell lines, SW620, HT29, LS174T and Colo205, but not in SW480. Inhibitions of Hv1 expression and activity in the highly metastatic SW620 cells by small interfering RNA (siRNA) and Zn(2+) respectively, markedly decrease the cell invasion and migration, restraint proton extrusion and the intracellular pH recovery. Our results suggest that Hv1 may be used as a potential biomarker for diagnosis and prognosis of colorectal carcinoma, and a potential target for anticancer drugs in colorectal cancer therapy. PMID- 23940592 TI - Dynamic parameters of balance which correlate to elderly persons with a history of falls. AB - Poor balance in older persons contributes to a rise in fall risk and serious injury, yet no consensus has developed on which measures of postural sway can identify those at greatest risk of falling. Postural sway was measured in 161 elderly individuals (81.8y+/-7.4), 24 of which had at least one self-reported fall in the prior six months, and compared to sway measured in 37 young adults (34.9y+/-7.1). Center of pressure (COP) was measured during 4 minutes of quiet stance with eyes opened. In the elderly with fall history, all measures but one were worse than those taken from young adults (e.g., maximal COP velocity was 2.7* greater in fallers than young adults; p<0.05), while three measures of balance were significantly worse in fallers as compared to older persons with no recent fall history (COP Displacement, Short Term Diffusion Coefficient, and Critical Displacement). Variance of elderly subjects' COP measures from the young adult cohort were weighted to establish a balance score ("B-score") algorithm designed to distinguish subjects with a fall history from those more sure on their feet. Relative to a young adult B-score of zero, elderly "non-fallers" had a B-score of 0.334, compared to 0.645 for those with a fall history (p<0.001). A weighted amalgam of postural sway elements may identify individuals at greatest risk of falling, allowing interventions to target those with greatest need of attention. PMID- 23940593 TI - Comparison of prediction model for cardiovascular autonomic dysfunction using artificial neural network and logistic regression analysis. AB - BACKGROUND: This study aimed to develop the artificial neural network (ANN) and multivariable logistic regression (LR) analyses for prediction modeling of cardiovascular autonomic (CA) dysfunction in the general population, and compare the prediction models using the two approaches. METHODS AND MATERIALS: We analyzed a previous dataset based on a Chinese population sample consisting of 2,092 individuals aged 30-80 years. The prediction models were derived from an exploratory set using ANN and LR analysis, and were tested in the validation set. Performances of these prediction models were then compared. RESULTS: Univariate analysis indicated that 14 risk factors showed statistically significant association with the prevalence of CA dysfunction (P<0.05). The mean area under the receiver-operating curve was 0.758 (95% CI 0.724-0.793) for LR and 0.762 (95% CI 0.732-0.793) for ANN analysis, but noninferiority result was found (P<0.001). The similar results were found in comparisons of sensitivity, specificity, and predictive values in the prediction models between the LR and ANN analyses. CONCLUSION: The prediction models for CA dysfunction were developed using ANN and LR. ANN and LR are two effective tools for developing prediction models based on our dataset. PMID- 23940594 TI - Competitive outcome of Daphnia-Simocephalus experimental microcosms: salinity versus priority effects. AB - Competition is a major driving force in freshwaters, especially given the cyclic nature and dynamics of pelagic food webs. Competition is especially important in the initial species assortment during colonization and re-colonization events, which depends strongly on the environmental context. Subtle changes, such as saline intrusion, may disrupt competitive relationships and, thus, influence community composition. Bearing this in mind, our objective was to assess whether low salinity levels (using NaCl as a proxy) alter the competitive outcome (measured as the rate of population biomass increase) of Daphnia-Simocephalus experimental microcosms, taking into account interactions with priority effects (sequential species arrival order). With this approach, we aimed to experimentally demonstrate a putative mechanism of differential species sorting in brackish environments or in freshwaters facing secondary salinization. Experiments considered three salinity levels, regarding NaCl added (0.00, 0.75 and 1.50 g L(-1)), crossed with three competition scenarios (no priority, priority of Daphnia over Simocephalus, and vice-versa). At lower NaCl concentrations (0.00 and 0.75 g L(-1)), Daphnia was a significantly superior competitor, irrespective of the species inoculation order, suggesting negligible priority effects. However, the strong decrease in Daphnia population growth at 1.50 g L(-1) alleviated the competitive pressure on Simocephalus, causing an inversion of the competitive outcome in favour of Simocephalus. The intensity of this inversion depended on the competition scenario. This salinity-mediated disruption of the competitive outcome demonstrates that subtle environmental changes produce indirect effects in key ecological mechanisms, thus altering community composition, which may lead to serious implications in terms of ecosystem functioning (e.g. lake regime shifts due to reduced grazing) and biodiversity. PMID- 23940595 TI - Generating a non-integrating human induced pluripotent stem cell bank from urine derived cells. AB - Induced pluripotent stem cell (iPS cell) holds great potential for applications in regenerative medicine, drug discovery, and disease modeling. We describe here a practical method to generate human iPS cells from urine-derived cells (UCs) under feeder-free, virus-free, serum-free condition and without oncogene c-MYC. We showed that this approach could be applied in a large population with different genetic backgrounds. UCs are easily accessible and exhibit high reprogramming efficiency, offering advantages over other cell types used for the purpose of iPS generation. Using the approach described in this study, we have generated 93 iPS cell lines from 20 donors with diverse genetic backgrounds. The non-viral iPS cell bank with these cell lines provides a valuable resource for iPS cells research, facilitating future applications of human iPS cells. PMID- 23940596 TI - Mito-tempol and dexrazoxane exhibit cardioprotective and chemotherapeutic effects through specific protein oxidation and autophagy in a syngeneic breast tumor preclinical model. AB - Several front-line chemotherapeutics cause mitochondria-derived, oxidative stress mediated cardiotoxicity. Iron chelators and other antioxidants have not completely succeeded in mitigating this effect. One hindrance to the development of cardioprotectants is the lack of physiologically-relevant animal models to simultaneously study antitumor activity and cardioprotection. Therefore, we optimized a syngeneic rat model and examined the mechanisms by which oxidative stress affects outcome. Immune-competent spontaneously hypertensive rats (SHRs) were implanted with passaged, SHR-derived, breast tumor cell line, SST-2. Tumor growth and cytokine responses (IL-1A, MCP-1, TNF-alpha) were observed for two weeks post-implantation. To demonstrate the utility of the SHR/SST-2 model for monitoring both anticancer efficacy and cardiotoxicity, we tested cardiotoxic doxorubicin alone and in combination with an established cardioprotectant, dexrazoxane, or a nitroxide conjugated to a triphenylphosphonium cation, Mito Tempol (4) [Mito-T (4)]. As predicted, tumor reduction and cardiomyopathy were demonstrated by doxorubicin. We confirmed mitochondrial accumulation of Mito-T (4) in tumor and cardiac tissue. Dexrazoxane and Mito-T (4) ameliorated doxorubicin-induced cardiomyopathy without altering the antitumor activity. Both agents increased the pro-survival autophagy marker LC3-II and decreased the apoptosis marker caspase-3 in the heart, independently and in combination with doxorubicin. Histopathology and transmission electron microscopy demonstrated apoptosis, autophagy, and necrosis corresponding to cytotoxicity in the tumor and cardioprotection in the heart. Changes in serum levels of 8-oxo-dG-modified DNA and total protein carbonylation corresponded to cardioprotective activity. Finally, 2D-electrophoresis/mass spectrometry identified specific serum proteins oxidized under cardiotoxic conditions. Our results demonstrate the utility of the SHR/SST-2 model and the potential of mitochondrially-directed agents to mitigate oxidative stress-induced cardiotoxicity. Our findings also emphasize the novel role of specific protein oxidation markers and autophagic mechanisms for cardioprotection. PMID- 23940597 TI - P2X7 receptor activation impairs exogenous MHC class I oligopeptides presentation in antigen presenting cells. AB - Major histocompatibility complex class I (MHC I) on antigen presenting cells (APCs) is a potent molecule to activate CD8(+) T cells and initiate immunity. P2X7 receptors (P2X7Rs) are present on the plasma membrane of APCs to sense the extracellular danger signal adenosine-5'-triphosphate (ATP). P2X7R activates the inflammasome and the release of IL-1beta in macrophages and other immune cells to initiate the inflammatory response. Here we show that P2X7R stimulation by ATP in APCs decreased the amount of MHC I at the plasma membrane. Specific antagonism or genetic ablation of P2X7R inhibited the effects of ATP on levels of cellular MHC I. Furthermore, P2X7R stimulation was able to inhibit activation of CD8(+) T cells via specific MHC I-oligopeptide complexes. Our study suggests that P2X7R activation on APCs is a novel inhibitor of adaptive CD8(+) T cell immunity. PMID- 23940598 TI - TGF-beta2-induced invadosomes in human trabecular meshwork cells. AB - Primary open-angle glaucoma (POAG) is a leading cause of blindness due to chronic degeneration of retinal ganglion cells and their optic nerve axons. It is associated with disturbed regulation of intraocular pressure, elevated intraocular levels of TGF-beta2, aberrant extracellular matrix (ECM) deposition and increased outflow resistance in the trabecular meshwork (TM). The mechanisms underlying these changes are not fully understood. Cell-matrix interactions have a decisive role in TM maintenance and it has been suggested that TGF-beta-induced inhibition of matrix metalloproteases may drive aberrant ECM deposition in POAG. Invadopodia and podosomes (invadosomes) are distinct sites of cell-matrix interaction and localized matrix-metalloprotease (MMP) activity. Here, we report on the effects of TGF-beta2 on invadosomes in human trabecular meshwork cells. Human TM (HTM) cells were derived from donor tissue and pretreated with vehicle or TGF-beta2 (2 ng/ml) for 3d. Invadosomes were studied in ECM degradation assays, protein expression and MMP-2 activity were assessed by western blot and zymography and ECM protein transcription was detected by RT-qPCR. HTM cells spontaneously formed podosomes and invadopodia as detected by colocalization of Grb2 or Nck1 to sites of gelatinolysis. Pretreatment with TGF-beta2 enhanced invadosomal proteolysis and zymographic MMP-2 activity as well as MMP-2, TIMP-2 and PAI-1 levels in HTM cell culture supernatants. Rho-kinase inhibition by H1152 blocked the effects of TGF-beta2. Concomitant transcription of fibronectin and collagens-1, -4 and -6 was increased by TGF-beta2 and fibrillar fibronectin deposits were observed in areas of invadosomal ECM remodelling. In contrast to a current hypothesis, our data indicate that TGF-beta2 induces an active ECM remodelling process in TM cells, characterized by concurrent increases in localized ECM digestion and ECM expression, rather than a mere buildup of material due to a lack of degradation. Invadosomal cell adhesion and signaling may thus have a role in POAG pathophysiology. PMID- 23940599 TI - Study on different molecular weights of chitosan as an immobilization matrix for a glucose biosensor. AB - Two chitosan samples (medium molecular weight (MMCHI) and low molecular weight (LMCHI)) were investigated as an enzyme immobilization matrix for the fabrication of a glucose biosensor. Chitosan membranes prepared from acetic acid were flexible, transparent, smooth and quick-drying. The FTIR spectra showed the existence of intermolecular interactions between chitosan and glucose oxidase (GOD). Higher catalytic activities were observed on for GOD-MMCHI than GOD-LMCHI and for those crosslinked with glutaraldehyde than using the adsorption technique. Enzyme loading greater than 0.6 mg decreased the activity. Under optimum conditions (pH 6.0, 35 degrees C and applied potential of 0.6 V) response times of 85 s and 65 s were observed for medium molecular weight chitosan glucose biosensor (GOD-MMCHI/PT) and low molecular weight chitosan glucose biosensor (GOD LMCHI/PT), respectively. The apparent Michaelis-Menten constant ([Formula: see text]) was found to be 12.737 mM for GOD-MMCHI/PT and 17.692 mM for GOD-LMCHI/PT. This indicated that GOD-MMCHI/PT had greater affinity for the enzyme. Moreover, GOD-MMCHI/PT showed higher sensitivity (52.3666 nA/mM glucose) when compared with GOD-LMCHI/PT (9.8579 nA/mM glucose) at S/N>3. Better repeatability and reproducibility were achieved with GOD-MMCHI/PT than GOD-LMCHI/PT regarding glucose measurement. GOD-MMCHI/PT was found to give the highest enzymatic activity among the electrodes under investigation. The extent of interference encountered by GOD-MMCHI/PT and GOD-LMCHI/PT was not significantly different. Although the Nafion coated biosensor significantly reduced the signal due to the interferents under study, it also significantly reduced the response to glucose. The performance of the biosensors in the determination of glucose in rat serum was evaluated. Comparatively better accuracy and recovery results were obtained for GOD-MMCHI/PT. Hence, GOD-MMCHI/PT showed a better performance when compared with GOD-LMCHI/PT. In conclusion, chitosan membranes shave the potential to be a suitable matrix for the development of glucose biosensors. PMID- 23940600 TI - A novel color change mechanism for breast cancer biomarker detection: naphthoquinones as specific ligands of human arylamine N-acetyltransferase 1. AB - Human arylamine N-acetyltransferase 1 (hNAT1) has become an attractive potential biomarker for estrogen-receptor-positive breast cancers. We describe here the mechanism of action of a selective non-covalent colorimetric biosensor for the recognition of hNAT1 and its murine homologue, mNat2, over their respective isoenzymes, leading to new opportunities in diagnosis. On interaction with the enzyme, the naphthoquinone probe undergoes an instantaneous and striking visible color change from red to blue. Spectroscopic, chemical, molecular modelling and biochemical studies reported here show that the color change is mediated by selective recognition between the conjugate base of the sulfonamide group within the probe and the conjugate acid of the arginine residue within the active site of both hNAT1 and mNat2. This represents a new mechanism for selective biomarker sensing and may be exploited as a general approach to the specific detection of biomarkers in disease. PMID- 23940601 TI - Do children who move home and school frequently have poorer educational outcomes in their early years at school? An anonymised cohort study. AB - Frequent mobility has been linked to poorer educational attainment. We investigated the association between moving home and moving school frequently and the early childhood formal educational achievement. We carried out a cohort analysis of 121,422 children with anonymised linked records. Our exposure measures were: 1) the number of residential moves registered with a health care provider, and 2) number of school moves. Our outcome was the formal educational assessment at age 6-7. Binary regression modeling was used to examine residential moves within the three time periods: 0 - <1 year; 1 - <4 years and 4 - <6 years. School moves were examined from age 4 to age 6. We adjusted for demographics, residential moves at different times, school moves and birth related variables. Children who moved home frequently were more likely not to achieve in formal assessments compared with children not moving. Adjusted odds ratios were significant for 3 or more moves within the time period 1 -<4 years and for any number of residential moves within the time period 4-<6 years. There was a dose response relationship, with increased odds ratios with increased frequency of residential moves (2 or more moves at 4-<6 years, adjusted odds ratio 1.16 (1.03, 1.29). The most marked effect was seen with frequent school moves where 2 or more moves resulted in an adjusted odds ratio of 2.33 (1.82, 2.98). This is the first study to examine the relationship between residential and school moves in early childhood and the effect on educational attainment. Children experiencing frequent mobility may be disadvantaged and should be closely monitored. Additional educational support services should be afforded to children, particularly those who frequently change school, in order to help them achieve the expected educational standards. PMID- 23940602 TI - Identification and validation of reference genes for transcript normalization in strawberry (Fragaria * ananassa) defense responses. AB - Strawberry (Fragaria spp) is an emerging model for the development of basic genomics and recombinant DNA studies among rosaceous crops. Functional genomic and molecular studies involve relative quantification of gene expression under experimental conditions of interest. Accuracy and reliability are dependent upon the choice of an optimal reference control transcript. There is no information available on validated endogenous reference genes for use in studies testing strawberry-pathogen interactions. Thirteen potential pre-selected strawberry reference genes were tested against different tissues, strawberry cultivars, biotic stresses, ripening and senescent conditions, and SA/JA treatments. Evaluation of reference candidate's suitability was analyzed by five different methodologies, and information was merged to identify best reference transcripts. A combination of all five methods was used for selective classification of reference genes. The resulting superior reference genes, FaRIB413, FaACTIN, FaEF1alpha and FaGAPDH2 are strongly recommended as control genes for relative quantification of gene expression in strawberry. This report constitutes the first systematic study to identify and validate optimal reference genes for accurate normalization of gene expression in strawberry plant defense response studies. PMID- 23940603 TI - Metabolomics reveals the heterogeneous secretome of two entomopathogenic fungi to ex vivo cultured insect tissues. AB - Fungal entomopathogens rely on cellular heterogeneity during the different stages of insect host infection. Their pathogenicity is exhibited through the secretion of secondary metabolites, which implies that the infection life history of this group of environmentally important fungi can be revealed using metabolomics. Here metabolomic analysis in combination with ex vivo insect tissue culturing shows that two generalist isolates of the genus Metarhizium and Beauveria, commonly used as biological pesticides, employ significantly different arrays of secondary metabolites during infectious and saprophytic growth. It also reveals that both fungi exhibit tissue specific strategies by a distinguishable metabolite secretion on the insect tissues tested in this study. In addition to showing the important heterogeneous nature of these two entomopathogens, this study also resulted in the discovery of several novel destruxins and beauverolides that have not been described before, most likely because previous surveys did not use insect tissues as a culturing system. While Beauveria secreted these cyclic depsipeptides when encountering live insect tissues, Metarhizium employed them primarily on dead tissue. This implies that, while these fungi employ comparable strategies when it comes to entomopathogenesis, there are most certainly significant differences at the molecular level that deserve to be studied. PMID- 23940604 TI - Pharmacokinetics of rifabutin in Japanese HIV-infected patients with or without antiretroviral therapy. AB - OBJECTIVE: Based on drug-drug interaction, dose reduction of rifabutin is recommended when co-administered with HIV protease inhibitors for human immunodeficiency virus (HIV)-associated mycobacterial infection. The aim of this study was to compare the pharmacokinetics of rifabutin administered at 300 mg/day alone to that at 150 mg every other day combined with lopinavir-ritonavir in Japanese patients with HIV/mycobacterium co-infection. METHODS: Plasma concentrations of rifabutin and its biologically active metabolite, 25-O desacetyl rifabutin were measured in 16 cases with HIV-mycobacterial coinfection. Nine were treated with 300 mg/day rifabutin and 7 with 150 mg rifabutin every other day combined with lopinavir-ritonavir antiretroviral therapy (ART). Samples were collected at a median of 15 days (range, 5-63) of rifabutin use. RESULTS: The mean Cmax and AUC0-24 of rifabutin in patients on rifabutin 150 mg every other day were 36% and 26% lower than on 300 mg/day rifabutin, while the mean Cmax and AUC0-24 of 25-O-desacetyl rifabutin were 186% and 152% higher, respectively. The plasma concentrations of rifabutin plus its metabolite were similar between the groups within the first 24 hours, but it remained low during subsequent 24 to 48 hours under rifabutin 150 mg alternate day dosing. CONCLUSION: Rifabutin dose of 150 mg every other day combined with lopinavir ritonavir seems to be associated with lower exposure to rifabutin and its metabolite compared with rifabutin 300 mg/day alone in Japanese patients. Further studies are needed to establish the optimal rifabutin dose during ART. The results highlight the importance of monitoring rifabutin plasma concentration during ART. TRIAL REGISTRATION: UMIN-CTR (https://upload.umin.ac.jp/cgi-open bin/ctr/ctr.cgi?function=search&action=input&language=E) UMIN000001102. PMID- 23940605 TI - Kidney stones in primary hyperoxaluria: new lessons learnt. AB - To investigate potential differences in stone composition with regard to the type of Primary Hyperoxaluria (PH), and in relation to the patient's medical therapy (treatment naive patients versus those on preventive medication) we examined twelve kidney stones from ten PH I and six stones from four PH III patients. Unfortunately, no PH II stones were available for analysis. The study on this set of stones indicates a more diverse composition of PH stones than previously reported and a potential dynamic response of morphology and composition of calculi to treatment with crystallization inhibitors (citrate, magnesium) in PH I. Stones formed by PH I patients under treatment are more compact and consist predominantly of calcium-oxalate monohydrate (COM, whewellite), while calcium oxalate dihydrate (COD, weddellite) is only rarely present. In contrast, the single stone available from a treatment naive PH I patient as well as stones from PH III patients prior to and under treatment with alkali citrate contained a wide size range of aggregated COD crystals. No significant effects of the treatment were noted in PH III stones. In disagreement with findings from previous studies, stones from patients with primary hyperoxaluria did not exclusively consist of COM. Progressive replacement of COD by small COM crystals could be caused by prolonged stone growth and residence times in the urinary tract, eventually resulting in complete replacement of calcium-oxalate dihydrate by the monohydrate form. The noted difference to the naive PH I stone may reflect a reduced growth rate in response to treatment. This pilot study highlights the importance of detailed stone diagnostics and could be of therapeutic relevance in calcium oxalates urolithiasis, provided that the effects of treatment can be reproduced in subsequent larger studies. PMID- 23940606 TI - Therapeutic potential of caspofungin combined with trimethoprim-sulfamethoxazole for pneumocystis pneumonia: a pilot study in mice. AB - Pneumocystis pneumonia (PcP) is a major cause of mortality and morbidity in immunocompromised patients. There are limited alternative therapeutic choices to trimethoprim-sulfamethoxazole (TMP-SMX) which is the standard first line therapy/prophylaxis for PcP. The efficacy of low doses of caspofungin and caspofungin in association with TMP-SMX standard-prophylactic dose was evaluated in an experimental model of Pneumocystis. Susceptibility of Pneumocystis spp. to low doses of caspofungin and caspofungin/TMP-SMX was evaluated in Balb/c immunosuppressed mice, infected intranasally with P. murina. Caspofungin was administered once daily at 0.1 mg/kg, 0.05 mg/kg, and 0.001 mg/kg and TMP-SMX was administered by oral gavage (12.25 mg/62.5 mg/day), for 21 days. Efficacy was calculated based on the reduction in organism burden determined through quantitative fluorescent-based real-time PCR (qPCR). Serum beta-1,3-D-glucan was measured as an additional marker of infection. The present data showed that caspofungin demonstrated anti-Pneumomocystis effect. However, the doses administrated were too low to achieve Pneumocystis eradication, which suggests that echinocandin treatment should not be administrated as mono-therapy. After 21 days of treatment, P. murina was not detected in the lungs of mice with either TMP-SMX or caspofungin/TMP-SMX. The results showed that, even at the lowest concentrations tested, the efficacy of caspofungin in association with TMP-SMX was higher than the efficacy of either drug used alone. The administration of caspofungin/TMP-SMX was at least 1.4 times more effective against P. murina infection than TMP-SMX used alone. The most promising result was achieved with the combination of caspofungin 0.05 mg/kg/day with TMP-SMX 12.5 mg-62.5 mg/day, which reduced the parasite burden to undetectable levels immediately at the 14(th) day of treatment, showing a highly marked anti-Pneumomocystis effect. These data suggest that the administration of low doses of caspofungin in combination with low doses of TMP-SMX may provide an improved treatment protocol for Pneumocystis infection clearance. PMID- 23940607 TI - The MUC5B variant is associated with idiopathic pulmonary fibrosis but not with systemic sclerosis interstitial lung disease in the European Caucasian population. AB - A polymorphism on the MUC5B promoter (rs35705950) has been associated with idiopathic pulmonary fibrosis (IPF) but not with systemic sclerosis (SSc) with interstitial lung disease (ILD). We genotyped the MUC5B promoter in the first 142 patients of the French national prospective cohort of IPF, in 981 French patients with SSc (346 ILD), 598 Italian patients with SSc (207 ILD), 1383 French controls and 494 Italian controls. A meta-analysis was performed including all American data available. The T risk allele was present in 41.9% of the IPF patients, 10.8% of the controls (P = 2 * 10(-44)), OR 6.3 [4.6-8.7] for heterozygous patients and OR 21.7 [10.4-45.3] for homozygous patients. Prevalence of the T allele was not modified according to age, gender, smoking in IPF patients. However, none of the black patients with IPF presented the T allele. The prevalence of the T risk allele was similar between French (10%) and Italian (12%) cohorts of SSc whatever the presence of an ILD (11.1% and 13.5%, respectively). Meta-analysis confirmed the similarity between French, Italian and American cohorts of IPF or SSc-ILD. This study confirms 1) an association between the T allele risk and IPF, 2) an absence of association with SSc-ILD, suggesting different pathophysiology. PMID- 23940608 TI - Genome annotation of Burkholderia sp. SJ98 with special focus on chemotaxis genes. AB - Burkholderia sp. strain SJ98 has the chemotactic activity towards nitroaromatic and chloronitroaromatic compounds. Recently our group published draft genome of strain SJ98. In this study, we further sequence and annotate the genome of stain SJ98 to exploit the potential of this bacterium. We specifically annotate its chemotaxis genes and methyl accepting chemotaxis proteins. Genome of Burkholderia sp. SJ98 was annotated using PGAAP pipeline that predicts 7,268 CDSs, 52 tRNAs and 3 rRNAs. Our analysis based on phylogenetic and comparative genomics suggest that Burkholderia sp. YI23 is closest neighbor of the strain SJ98. The genes involved in the chemotaxis of strain SJ98 were compared with genes of closely related Burkholderia strains (i.e. YI23, CCGE 1001, CCGE 1002, CCGE 1003) and with well characterized bacterium E. coli K12. It was found that strain SJ98 has 37 che genes including 19 methyl accepting chemotaxis proteins that involved in sensing of different attractants. Chemotaxis genes have been found in a cluster along with the flagellar motor proteins. We also developed a web resource that provides comprehensive information on strain SJ98 that includes all analysis data (http://crdd.osdd.net/raghava/genomesrs/burkholderia/). PMID- 23940609 TI - Juvenile idiopathic arthritis-associated uveitis: a nationwide population-based study in Taiwan. AB - OBJECTIVE: The incidence and prevalence of juvenile idiopathic arthritis (JIA) vary widely across the world but data in East Asia is lacking. Uveitis is a serious cause of morbidity in JIA. This study aimed to analyze the incidence and prevalence of JIA, and the characteristics of JIA-associated uveitis in Taiwan. METHODS: A population-based cohort study was conducted using the Taiwan National Health Insurance Research Database. Each patient was individually tracked from 1999 to 2009 to identify the diagnosis of JIA and uveitis using the International Classification of Diseases diagnostic codes. Multivariate logistic regression was used to determine the risk factors and complications of uveitis in patients with JIA. RESULTS: The study cohort had 2636 cases of JIA and included juvenile rheumatoid arthritis (57.7%), enthesitis-related arthritis (ERA) (39.2%), and psoriatic arthritis (3.1%). The average annual incidence of JIA and JIA associated uveitis were 4.93 (range, 3.93-6.23) and 0.25 (range, 0.12-0.37) cases per 100,000 population, respectively. The average period prevalence of JIA was 33.8 cases per 100,000 population. Uveitis occurred in 4.7% of patients with JIA, while JIA-associated uveitis was complicated by cataract (11.2%) and glaucoma (24.8%). Enthesitis-related arthritis was significantly associated with uveitis (OR: 3.47; 95% CI: 2.24-5.37) (p<0.0001). Uveitis diagnosed before JIA was the most significant risk factor for complications of glaucoma or cataract (OR: 3.54; 95% CI: 1.44-8.72) (p = 0.006). CONCLUSIONS: The incidence of JIA is low but that of JIA-associated uveitis is increasing. Higher percentage of males in patients with ERA and the strong association between ERA and uveitis are unique for children with JIA in Taiwan. Uveitis diagnosed before arthritis is an important risk factor for complications. Continuous ophthalmologic follow-up is needed for children with JIA or uveitis of unknown etiology. PMID- 23940610 TI - Predictive factors of late venous aortocoronary graft failure: ultrastructural studies. AB - BACKGROUND: Venous aortocoronary graft arterialization may precede a preterm occlusion in some coronary artery bypass grafting (CABG) patients. The aim of the present study was to identify ultrastructural variations in the saphenous vein wall that may have an impact on the development of venous graft disease in CABG patients. METHODS: The study involved 365 consecutive patients with a mean age of 62.9 +/- 9.4 years who underwent isolated CABG. The thickness and area of the whole venous wall, the tunica intima, the tunica media and the adventitia and the number and shape (length, thickness and length/thickness ratio) of the nuclei in the medial smooth muscle cells nuclei in the distal saphenous vein segments were evaluated by ultrastructural studies. Patients were followed up for 41 to 50 months (mean 45.1 +/- 5.1). Saphenous vein graft patency was assessed by follow up coronary angiography. Logistic regression models were used to identify independent risk factors for late graft failure. RESULTS: In 71 patients significant lesions in the saphenous vein grafts were observed. The whole venous wall thickness (437.5 um vs. 405.5 um), tunica media thickness (257.2 um vs. 211.5 um), whole venous wall area (2.23 mm(2) vs. 2.02 mm(2)) and tunica media area (1.09 mm(2) vs. 0.93 mm(2)) were significantly larger for this group of patients than for those without graft disease. In the latter group more elongated smooth muscle cell nuclei (higher length/thickness ratio) were found in the tunica media of the saphenous vein segments. Thickening of the saphenous vein tunica media and chunky smooth muscle cell nuclei were identified as independent risk factors for graft disease development. CONCLUSIONS: Saphenous vein tunica media hypertrophy (resulting in wall thickening) and chunky smooth muscle cell nuclei might predict the development of venous graft disease. PMID- 23940611 TI - Transcriptional blood signatures distinguish pulmonary tuberculosis, pulmonary sarcoidosis, pneumonias and lung cancers. AB - RATIONALE: New approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations. OBJECTIVES: To determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases. METHODS: We compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations. MEASUREMENTS AND MAIN RESULTS: An Interferon inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls. CONCLUSIONS: Tuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment. PMID- 23940613 TI - Dynamin-2 regulates fusion pore expansion and quantal release through a mechanism that involves actin dynamics in neuroendocrine chromaffin cells. AB - Over the past years, dynamin has been implicated in tuning the amount and nature of transmitter released during exocytosis. However, the mechanism involved remains poorly understood. Here, using bovine adrenal chromaffin cells, we investigated whether this mechanism rely on dynamin's ability to remodel actin cytoskeleton. According to this idea, inhibition of dynamin GTPase activity suppressed the calcium-dependent de novo cortical actin and altered the cortical actin network. Similarly, expression of a small interfering RNA directed against dynamin-2, an isoform highly expressed in chromaffin cells, changed the cortical actin network pattern. Disruption of dynamin-2 function, as well as the pharmacological inhibition of actin polymerization with cytochalasine-D, slowed down fusion pore expansion and increased the quantal size of individual exocytotic events. The effects of cytochalasine-D and dynamin-2 disruption were not additive indicating that dynamin-2 and F-actin regulate the late steps of exocytosis by a common mechanism. Together our data support a model in which dynamin-2 directs actin polymerization at the exocytosis site where both, in concert, adjust the hormone quantal release to efficiently respond to physiological demands. PMID- 23940614 TI - Threatened and endangered subspecies with vulnerable ecological traits also have high susceptibility to sea level rise and habitat fragmentation. AB - The presence of multiple interacting threats to biodiversity and the increasing rate of species extinction make it critical to prioritize management efforts on species and communities that maximize conservation success. We implemented a multi-step approach that coupled vulnerability assessments evaluating threats to Florida taxa such as climate change, sea-level rise, and habitat fragmentation with in-depth literature surveys of taxon-specific ecological traits. The vulnerability, adaptive capacity, and ecological traits of 12 threatened and endangered subspecies were compared to non-listed subspecies of the same parent species. Overall, the threatened and endangered subspecies showed high vulnerability and low adaptive capacity, in particular to sea level rise and habitat fragmentation. They also exhibited larger home ranges and greater dispersal limitation compared to non-endangered subspecies, which may inhibit their ability to track changing climate in fragmented landscapes. There was evidence for lower reproductive capacity in some of the threatened or endangered taxa, but not for most. Taxa located in the Florida Keys or in other low coastal areas were most vulnerable to sea level rise, and also showed low levels of adaptive capacity, indicating they may have a lower probability of conservation success. Our analysis of at-risk subspecies and closely related non-endangered subspecies demonstrates that ecological traits help to explain observed differences in vulnerability and adaptive capacity. This study points to the importance of assessing the relative contributions of multiple threats and evaluating conservation value at the species (or subspecies) level when resources are limited and several factors affect conservation success. PMID- 23940612 TI - Toxoplasma gondii sporozoites invade host cells using two novel paralogues of RON2 and AMA1. AB - Toxoplasma gondii is an obligate intracellular parasite of the phylum Apicomplexa. The interaction of two well-studied proteins, Apical Membrane Antigen 1 (AMA1) and Rhoptry Neck protein 2 (RON2), has been shown to be critical for invasion by the asexual tachyzoite stage. Recently, two paralogues of these proteins, dubbed sporoAMA1 and sporoRON2 (or RON2L2), respectively, have been identified but not further characterized in proteomic and transcriptomic analyses of Toxoplasma sporozoites. Here, we show that sporoAMA1 and sporoRON2 localize to the apical region of sporozoites and that, in vitro, they interact specifically and exclusively, with no detectable interaction of sporoAMA1 with generic RON2 or sporoRON2 with generic AMA1. Structural studies of the interacting domains of sporoRON2 and sporoAMA1 indicate a novel pairing that is similar in overall form but distinct in detail from the previously described interaction of the generic pairing. Most notably, binding of sporoRON2 domain 3 to domains I/II of sporoAMA1 results in major alterations in the latter protein at the site of binding and allosterically in the membrane-proximal domain III of sporoAMA1 suggesting a possible role in signaling. Lastly, pretreatment of sporozoites with domain 3 of sporoRON2 substantially impedes their invasion into host cells while having no effect on tachyzoites, and vice versa for domain 3 of generic RON2 (which inhibits tachyzoite but not sporozoite invasion). These data indicate that sporozoites and tachyzoites each use a distinct pair of paralogous AMA1 and RON2 proteins for invasion into host cells, possibly due to the very different environment in which they each must function. PMID- 23940615 TI - An intronic miRNA regulates expression of the human endothelial nitric oxide synthase gene and proliferation of endothelial cells by a mechanism related to the transcription factor SP-1. AB - OBJECTIVE: This study was to investigate the molecular mechanisms underlying the 27nt-miRNA-mediated regulation of expression of the endothelial nitric oxide synthase (eNOS) gene. METHODS: Cell lines overexpressing 27nt-miRNA or its mutant were established by transfecting the miRNA expression vector into the endothelial cells. eNOS mRNA and protein expression were examined by RT-PCR and Western Blotting, respectively. Luciferase activity reporter system was used to study the target of 27nt-miRNA. RESULTS: The results showed that overexpression of 27nt miRNA significantly inhibited eNOS mRNA level and protein expression, and reduced the eNOS transcriptional efficiency. Such inhibitory effects of 27nt-miRNA were attenuated by the sequence mutations in 27nt-miRNA. Interestingly, the transcription factor SP-1 expression was reduced by 27nt-miRNA. Meanwhile, overxpression of SP-1 protein partially restored eNOS expression, and rescued the 27nt-miRNA-mediated reduction of endothelial cell proliferation. Moreover, certain sites in the SP-1 mRNA were found to be the direct target of 27nt-miRNA by a luciferase reporter system. CONCLUSIONS: These results demonstrate that the 27nt-miRNA suppresses eNOS gene expression and SP-1 expression in vascular endothelial cells. The 27nt-miRNA directly target to SP-1 mRNA, thereby contributing to proliferation of endothelial cells. PMID- 23940616 TI - Role of PTPalpha in the destruction of periodontal connective tissues. AB - IL-1beta contributes to connective tissue destruction in part by up-regulating stromelysin-1 (MMP-3), which in fibroblasts is a focal adhesion-dependent process. Protein tyrosine phosphatase-alpha (PTPalpha) is enriched in and regulates the formation of focal adhesions, but the role of PTPalpha in connective tissue destruction is not defined. We first examined destruction of periodontal connective tissues in adult PTPalpha(+/+) and PTPalpha(-/-) mice subjected to ligature-induced periodontitis, which increases the levels of multiple cytokines, including IL-1beta. Three weeks after ligation, maxillae were processed for morphometry, micro-computed tomography and histomorphometry. Compared with unligated controls, there was ~1.5-3 times greater bone loss as well as 3-fold reduction of the thickness of the gingival lamina propria and 20 fold reduction of the amount of collagen fibers in WT than PTPalpha(-/-) mice. Immunohistochemical staining of periodontal tissue showed elevated expression of MMP-3 at ligated sites. Second, to examine mechanisms by which PTPalpha may regulate matrix degradation, human MMP arrays were used to screen conditioned media from human gingival fibroblasts treated with vehicle, IL-1beta or TNFalpha. Although MMP-3 was upregulated by both cytokines, only IL-1beta stimulated ERK activation in human gingival fibroblasts plated on fibronectin. TIRF microscopy and immunoblotting analyses of cells depleted of PTPalpha activity with the use of various mutated constructs or with siRNA or PTPalpha(KO) and matched wild type fibroblasts were plated on fibronectin to enable focal adhesion formation and stimulated with IL-1beta. These data showed that the catalytic and adaptor functions of PTPalpha were required for IL-1beta-induced focal adhesion formation, ERK activation and MMP-3 release. We conclude that inflammation induced connective tissue degradation involving fibroblasts requires functionally active PTPalpha and in part is mediated by IL-1beta signaling through focal adhesions. PMID- 23940617 TI - Variation in thermal sensitivity and thermal tolerances in an invasive species across a climatic gradient: lessons from the land snail Cornu aspersum. AB - The ability of organisms to perform at different temperatures could be described by a continuous nonlinear reaction norm (i.e., thermal performance curve, TPC), in which the phenotypic trait value varies as a function of temperature. Almost any shift in the parameters of this performance curve could highlight the direct effect of temperature on organism fitness, providing a powerful framework for testing thermal adaptation hypotheses. Inter-and intraspecific differences in this performance curve are also reflected in thermal tolerances limits (e.g., critical and lethal limits), influencing the biogeographic patterns of species' distribution. Within this context, here we investigated the intraspecific variation in thermal sensitivities and thermal tolerances in three populations of the invasive snail Cornu aspersum across a geographical gradient, characterized by different climatic conditions. Thus, we examined population differentiation in the TPCs, thermal-coma recovery times, expression of heat-shock proteins and standard metabolic rate (i.e., energetic costs of physiological differentiation). We tested two competing hypotheses regarding thermal adaptation (the "hotter is better" and the generalist-specialist trade-offs). Our results show that the differences in thermal sensitivity among populations of C. aspersum follow a latitudinal pattern, which is likely the result of a combination of thermodynamic constraints ("hotter is better") and thermal adaptations to their local environments (generalist-specialist trade-offs). This finding is also consistent with some thermal tolerance indices such as the Heat-Shock Protein Response and the recovery time from chill-coma. However, mixed responses in the evaluated traits suggest that thermal adaptation in this species is not complete, as we were not able to detect any differences in neither energetic costs of physiological differentiation among populations, nor in the heat-coma recovery. PMID- 23940618 TI - Increased 4-hydroxynonenal formation contributes to obesity-related lipolytic activation in adipocytes. AB - Oxidative stress in adipose tissue plays an etiological role in a variety of obesity-related metabolic disorders. We previously reported that increased adipose tissue 4-hydroxynonenal (4-HNE) contents contributed to obesity-related plasma adiponectin decline in mice. In the present study, we investigated the effects of intracellular 4-HNE accumulation on lipolytic response in adipocytes/adipose tissues and underlying mechanisms. In both fully differentiated 3T3-L1 and primary adipocytes, a 5-hour 4-HNE exposure elevated lipolytic reaction in a dose-dependent manner at both basal and isoproterenol stimulated conditions, evidenced by significantly increased glycerol and fatty acids releases. This conclusion was corroborated by the comparable observations when the minced human visceral adipose tissues were used. Mechanistic investigations revealed that 4-HNE-stimulated lipolytic activation is multifactorial. 4-HNE exposure quickly increased intracellular cyclic AMP (cAMP) level, which was concomitant with increased phosphorylations of protein kinase A (PKA) and its direct downstream target, hormone sensitive lipase (HSL). Pre incubation with H89, a potent PKA inhibitor, prevented 4-HNE stimulated glycerol release, suggesting that enhanced lipolytic action in response to 4-HNE increase is mediated mainly by cAMP/PKA signal pathway in adipocytes. In addition to activating cAMP/PKA/HSL pathway, 4-HNE exposure also suppresses AMP-activated protein kinase (AMPK), a suppressive pathway for lipolysis, measured by both Western blotting for phosphorylated form of AMPK and ELISA for enzyme activity. Furthermore, 5-Aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR), a pharmacological AMPK activator, alleviated 4-HNE-induced lipolysis, suggesting that AMPK suppression also contributes to 4-HNE elicited lipolytic response. In conclusion, our findings indicate that increased intracellular 4-HNE accumulation in adipocytes/adipose tissues contributes to obesity-related lipolytic activation. PMID- 23940619 TI - Fatty acid composition at the base of aquatic food webs is influenced by habitat type and watershed land use. AB - Spatial variation in food resources strongly influences many aspects of aquatic consumer ecology. Although large-scale controls over spatial variation in many aspects of food resources are well known, others have received little study. Here we investigated variation in the fatty acid (FA) composition of seston and primary consumers within (i.e., among habitats) and among tributary systems of Lake Michigan, USA. FA composition of food is important because all metazoans require certain FAs for proper growth and development that cannot be produced de novo, including many polyunsaturated fatty acids (PUFAs). Here we sampled three habitat types (river, rivermouth and nearshore zone) in 11 tributaries of Lake Michigan to assess the amount of FA in seston and primary consumers of seston. We hypothesize that among-system and among-habitat variation in FAs at the base of food webs would be related to algal production, which in turn is influenced by three land cover characteristics: 1) combined agriculture and urban lands (an indication of anthropogenic nutrient inputs that fuel algal production), 2) the proportion of surface waters (an indication of water residence times that allow algal producers to accumulate) and 3) the extent of riparian forested buffers (an indication of stream shading that reduces algal production). Of these three land cover characteristics, only intense land use appeared to strongly related to seston and consumer FA and this effect was only strong in rivermouth and nearshore lake sites. River seston and consumer FA composition was highly variable, but that variation does not appear to be driven by the watershed land cover characteristics investigated here. Whether the spatial variation in FA content at the base of these food webs significantly influences the production of economically important species higher in the food web should be a focus of future research. PMID- 23940620 TI - Anthropometric measures and physical activity and the risk of lung cancer in never-smokers: a prospective cohort study. AB - Worldwide, lung cancer in never-smokers is ranked the seventh most common cause of cancer death; however, the etiology of lung cancer in never-smokers is unclear. We investigated associations for body mass index (BMI) at various ages, waist circumference, hip circumference, and physical activity with lung cancer in 158,415 never-smokers of the NIH-AARP Diet and Health Study. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from Cox proportional hazards models. Over 11 years of follow-up, 532 lung cancer cases occurred. The risk estimate for obese (BMI >= 30 kg/m(2)) participants at baseline was 1.21 (95%CI = 0.95-1.53) relative to those with a normal BMI between 18.5 <= BMI<25.0. Overweight (25.0 <= BMI<30.0) at age 18 (HR(overweight-vs normal) = 1.51;95%CI = 1.01-2.26) and time spent sitting (HR(>= 3 hrs-vs-<3 hrs) = 1.32;95%CI = 1.00-1.73) was each associated with lung cancer after adjustment for baseline BMI, as was waist (HR(Q4-vs-Q1) = 1.75;95%CI = 1.09-2.79) and hip circumference (HRQ4-vs-Q1 = 0.62;95%CI = 0.39-0.99), after mutual adjustment for each other and baseline BMI. No associations were observed for vigorous activity or television watching. In summary, using a large prospective cohort study, we found no evidence that BMI at baseline or middle age was associated with decreased lung cancer risk in never smokers. If anything, we observed some evidence for positive associations with a larger BMI or waist circumference. PMID- 23940621 TI - Anterior segment optical coherence tomography for the quantitative evaluation of the anterior segment following Boston keratoprosthesis. AB - OBJECTIVE: To quantitatively evaluate the anterior segment using anterior segment optical coherence tomography (AS-OCT) following Boston keratoprosthesis type 1. METHODS: A retrospective study consisted of AS-OCT imaging at a single time point postoperatively in 52 eyes. Main outcomes measures include anatomical and functional anterior chamber depth (ACD), angle (ACA) and peripheral and proximal synechiae. RESULTS: The mean time point of imaging was 19.3 months postoperatively. Average anatomical and functional ACD was 2.0 and 0.21 mm respectively, and mean ACA ranged from 2.5 degrees to 6.14 degrees in representative meridians. An average of 8.7 clock hours of angle closure was observed in the 25 eyes in which all meridians were imaged. The majority of eyes showed peripheral (86.5%) and proximal (67.3%) synechiae. CONCLUSIONS: AS-OCT is a useful tool for quantitative evaluation of anterior segment and angle after keratoprosthesis, which is otherwise poorly visible. The majority of eyes showed shallow ACD, extensive angle closure and synechiae formation. PMID- 23940622 TI - A temporal signature of epidermal growth factor signaling regulates the differentiation of germline cells in testes of Drosophila melanogaster. AB - Tissue replenishment from stem cells follows a precise cascade of events, during which stem cell daughters first proliferate by mitotic transit amplifying divisions and then enter terminal differentiation. Here we address how stem cell daughters are guided through the early steps of development. In Drosophila testes, somatic cyst cells enclose the proliferating and differentiating germline cells and the units of germline and surrounding cyst cells are commonly referred to as cysts. By characterizing flies with reduced or increased Epidermal Growth Factor (EGF) signaling we show that EGF triggers different responses in the cysts dependent on its dose. In addition to the previously reported requirement for EGF signaling in cyst formation, a low dose of EGF signaling is required for the progression of the germline cells through transit amplifying divisions, and a high dose of EGF signaling promotes terminal differentiation. Terminal differentiation was promoted in testes expressing a constitutively active EGF Receptor (EGFR) and in testes expressing both a secreted EGF and the EGFR in the cyst cells, but not in testes expressing either only EGF or only EGFR. We propose that as the cysts develop, a temporal signature of EGF signaling is created by the coordinated increase of both the production of active ligands by the germline cells and the amount of available receptor molecules on the cyst cells. PMID- 23940623 TI - Chewing betel quid and the risk of metabolic disease, cardiovascular disease, and all-cause mortality: a meta-analysis. AB - BACKGROUND: Betel nut (Areca nut) is the fruit of the Areca catechu tree. Approximately 700 million individuals regularly chew betel nut (or betel quid) worldwide and it is a known risk factor for oral cancer and esophageal cancer. We performed a meta-analysis to assess the influence of chewing betel quid on metabolic diseases, cardiovascular disease, and all-cause mortality. METHODOLOGY/PRINCIPAL FINDINGS: We searched Medline, Cochrane Library, Web of Science, and Science Direct for pertinent articles (including the references) published between 1951 and 2013. The adjusted relative risk (RR) and 95% confidence interval were calculated using the random effect model. Sex was used as an independent category for comparison. RESULTS: Of 580 potentially relevant studies, 17 studies from Asia (5 cohort studies and 12 case-control studies) covering 388,134 subjects (range: 94 to 97,244) were selected. Seven studies (N = 121,585) showed significant dose-response relationships between betel quid consumption and the risk of events. According to pooled analysis, the adjusted RR of betel quid chewers vs. non-chewers was 1.47 (P<0.001) for obesity (N = 30,623), 1.51 (P = 0.01) for metabolic syndrome (N = 23,291), 1.47 (P<0.001) for diabetes (N = 51,412), 1.45 (P = 0.06) for hypertension (N = 89,051), 1.2 (P = 0.02) for cardiovascular disease (N = 201,488), and 1.21 (P = 0.02) for all-cause mortality (N = 179,582). CONCLUSION/SIGNIFICANCE: Betel quid chewing is associated with an increased risk of metabolic disease, cardiovascular disease, and all-cause mortality. Thus, in addition to preventing oral cancer, stopping betel quid use could be a valuable public health measure for metabolic diseases that are showing a rapid increase in South-East Asia and the Western Pacific. PMID- 23940624 TI - Low intensity ultrasound promotes the sensitivity of rat brain glioma to Doxorubicin by down-regulating the expressions of p-glucoprotein and multidrug resistance protein 1 in vitro and in vivo. AB - The overall prognosis for malignant glioma is extremely poor, and treatment options are limited in part because of multidrug resistant proteins. Our previous findings suggest low intensity ultrasound (LIUS) can induce apoptosis of glioma cells. Given this finding, we were interested in determining if LIUS could help treat glioma by inhibiting multidrug resistant proteins, and if so, which pathways are involved. In this study, the toxicity sensitivity and multidrug resistance proteins of glioma induced by LIUS were investigated using CCK-8, immunohistochemistry, immunofluorency, and RT-PCR in tissue samples and cultured cells. LIUS inhibited increase of C6 cells in an intensity- and time-dependent manner. The toxicity sensitivity of C6 cells increased significantly after LIUS sonication (intensity of 142.0 mW/cm(2)) or Doxorubicin (DOX) at different concentration, particularly by the combination of LIUS sonication and DOX. The expressions of P-gp and MRP1 decreased significantly post-sonication at intensity of 142.0 mW/cm(2) both in vitro and in vivo. The expressions of p110 delta (PI3K), NF-kappaB-p65, Akt/PKB, and p-Akt/PKB were downregulated by LIUS sonication and DOX treatment separately or in combination at the same parameters in rat glioma. These results indicate that LIUS could increase the toxicity sensitivity of glioma by down-regulating the expressions of P-gp and MRP1, which might be mediated by the PI3K/Akt/NF-kappaB pathway. PMID- 23940625 TI - Microbial electricity generation enhances decabromodiphenyl ether (BDE-209) degradation. AB - Due to environmental persistence and biotoxicity of polybrominated diphenyl ethers (PBDEs), it is urgent to develop potential technologies to remediate PBDEs. Introducing electrodes for microbial electricity generation to stimulate the anaerobic degradation of organic pollutants is highly promising for bioremediation. However, it is still not clear whether the degradation of PBDEs could be promoted by this strategy. In this study, we hypothesized that the degradation of PBDEs (e.g., BDE-209) would be enhanced under microbial electricity generation condition. The functional compositions and structures of microbial communities in closed-circuit microbial fuel cell (c-MFC) and open circuit microbial fuel cell (o-MFC) systems for BDE-209 degradation were detected by a comprehensive functional gene array, GeoChip 4.0, and linked with PBDE degradations. The results indicated that distinctly different microbial community structures were formed between c-MFCs and o-MFCs, and that lower concentrations of BDE-209 and the resulting lower brominated PBDE products were detected in c MFCs after 70-day performance. The diversity and abundance of a variety of functional genes in c-MFCs were significantly higher than those in o-MFCs. Most genes involved in chlorinated solvent reductive dechlorination, hydroxylation, methoxylation and aromatic hydrocarbon degradation were highly enriched in c-MFCs and significantly positively correlated with the removal of PBDEs. Various other microbial functional genes for carbon, nitrogen, phosphorus and sulfur cycling, as well as energy transformation process, were also significantly increased in c MFCs. Together, these results suggest that PBDE degradation could be enhanced by introducing the electrodes for microbial electricity generation and by specifically stimulating microbial functional genes. PMID- 23940626 TI - Rapid global fitting of large fluorescence lifetime imaging microscopy datasets. AB - Fluorescence lifetime imaging (FLIM) is widely applied to obtain quantitative information from fluorescence signals, particularly using Forster Resonant Energy Transfer (FRET) measurements to map, for example, protein-protein interactions. Extracting FRET efficiencies or population fractions typically entails fitting data to complex fluorescence decay models but such experiments are frequently photon constrained, particularly for live cell or in vivo imaging, and this leads to unacceptable errors when analysing data on a pixel-wise basis. Lifetimes and population fractions may, however, be more robustly extracted using global analysis to simultaneously fit the fluorescence decay data of all pixels in an image or dataset to a multi-exponential model under the assumption that the lifetime components are invariant across the image (dataset). This approach is often considered to be prohibitively slow and/or computationally expensive but we present here a computationally efficient global analysis algorithm for the analysis of time-correlated single photon counting (TCSPC) or time-gated FLIM data based on variable projection. It makes efficient use of both computer processor and memory resources, requiring less than a minute to analyse time series and multiwell plate datasets with hundreds of FLIM images on standard personal computers. This lifetime analysis takes account of repetitive excitation, including fluorescence photons excited by earlier pulses contributing to the fit, and is able to accommodate time-varying backgrounds and instrument response functions. We demonstrate that this global approach allows us to readily fit time-resolved fluorescence data to complex models including a four exponential model of a FRET system, for which the FRET efficiencies of the two species of a bi-exponential donor are linked, and polarisation-resolved lifetime data, where a fluorescence intensity and bi-exponential anisotropy decay model is applied to the analysis of live cell homo-FRET data. A software package implementing this algorithm, FLIMfit, is available under an open source licence through the Open Microscopy Environment. PMID- 23940627 TI - B7-H3 is overexpressed in patients suffering osteosarcoma and associated with tumor aggressiveness and metastasis. AB - B7-H3 is a member of the B7-family of co-stimulatory molecules, which has been shown to be broadly expressed in various tumor tissues, and which plays an important role in adaptive immune responses. The role of B7-H3 in osteosarcoma, however, remains unknown. In this study we used immunohistochemistry to analyze B7-H3 expression in 61 primary osteosarcoma tissues with case-matched adjacent normal tissues, and 37 osteochondroma and 20 bone fibrous dysplasia tissues. B7 H3 expression was expressed in 91.8% (56/61) of the osteosarcoma lesions, and the intensity of B7-H3 expression in osteosarcoma was significantly increased compared with adjacent normal tissues, osteochondroma and bone fibrous dysplasia tissues (p<0.001). Patients with high tumor B7-H3 levels had a significantly shorter survival time and recurrence time than patients with low tumor B7-H3 levels (p<0.001). Moreover, tumor B7-H3 expression inversely correlated with the number of tumor-infiltrating CD8(+) T cells (p<0.05). In vitro, increasing expression of B7-H3 promotes osteosarcoma cell invasion, at least in part by upregulating matrix metalloproteinase-2 (MMP-2). In conclusion, our study provides the first evidence of B7-H3 expression in osteosarcoma cells as a potential mechanism controlling tumor immunity and invasive malignancy, and which is correlated with patients' survival and metastasis. PMID- 23940628 TI - Fatty acid amide hydrolase-dependent generation of antinociceptive drug metabolites acting on TRPV1 in the brain. AB - The discovery that paracetamol is metabolized to the potent TRPV1 activator N-(4 hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404) and that this metabolite contributes to paracetamol's antinociceptive effect in rodents via activation of TRPV1 in the central nervous system (CNS) has provided a potential strategy for developing novel analgesics. Here we validated this strategy by examining the metabolism and antinociceptive activity of the de-acetylated paracetamol metabolite 4-aminophenol and 4-hydroxy-3-methoxybenzylamine (HMBA), both of which may undergo a fatty acid amide hydrolase (FAAH)-dependent biotransformation to potent TRPV1 activators in the brain. Systemic administration of 4-aminophenol and HMBA led to a dose-dependent formation of AM404 plus N-(4-hydroxyphenyl)-9Z octadecenamide (HPODA) and arvanil plus olvanil in the mouse brain, respectively. The order of potency of these lipid metabolites as TRPV1 activators was arvanil = olvanil>>AM404> HPODA. Both 4-aminophenol and HMBA displayed antinociceptive activity in various rodent pain tests. The formation of AM404, arvanil and olvanil, but not HPODA, and the antinociceptive effects of 4-aminophenol and HMBA were substantially reduced or disappeared in FAAH null mice. The activity of 4 aminophenol in the mouse formalin, von Frey and tail immersion tests was also lost in TRPV1 null mice. Intracerebroventricular injection of the TRPV1 blocker capsazepine eliminated the antinociceptive effects of 4-aminophenol and HMBA in the mouse formalin test. In the rat, pharmacological inhibition of FAAH, TRPV1, cannabinoid CB1 receptors and spinal 5-HT3 or 5-HT1A receptors, and chemical deletion of bulbospinal serotonergic pathways prevented the antinociceptive action of 4-aminophenol. Thus, the pharmacological profile of 4-aminophenol was identical to that previously reported for paracetamol, supporting our suggestion that this drug metabolite contributes to paracetamol's analgesic activity via activation of bulbospinal pathways. Our findings demonstrate that it is possible to construct novel antinociceptive drugs based on fatty acid conjugation as a metabolic pathway for the generation of TRPV1 modulators in the CNS. PMID- 23940629 TI - Global changes in DNA methylation in seeds and seedlings of Pyrus communis after seed desiccation and storage. AB - The effects of storage and deep desiccation on structural changes of DNA in orthodox seeds are poorly characterized. In this study we analyzed the 5 methylcytosine (m(5)C) global content of DNA isolated from seeds of common pear (Pyrus communis L.) that had been subjected to extreme desiccation, and the seedlings derived from these seeds. Germination and seedling emergence tests were applied to determine seed viability after their desiccation. In parallel, analysis of the global content of m(5)C in dried seeds and DNA of seedlings obtained from such seeds was performed with a 2D TLC method. Desiccation of fresh seeds to 5.3% moisture content (mc) resulted in a slight reduction of DNA methylation, whereas severe desiccation down to 2-3% mc increased DNA methylation. Strong desiccation of seeds resulted in the subsequent generation of seedlings of shorter height. A 1-year period of seed storage induced a significant increase in the level of DNA methylation in seeds. It is possible that alterations in the m(5)C content of DNA in strongly desiccated pear seeds reflect a reaction of desiccation-tolerant (orthodox) seeds to severe desiccation. Epigenetic changes were observed not only in severely desiccated seeds but also in 3-month old seedlings obtained from these seeds. With regard to seed storage practices, epigenetic assessment could be used by gene banks for early detection of structural changes in the DNA of stored seeds. PMID- 23940630 TI - Association between genetic polymorphisms in Ca(v)2.3 (R-type) Ca2+ channels and fentanyl sensitivity in patients undergoing painful cosmetic surgery. AB - Individual differences in the sensitivity to fentanyl, a widely used opioid analgesic, lead to different proper doses of fentanyl, which can hamper effective pain treatment. Voltage-activated Ca(2+) channels (VACCs) play a crucial role in the nervous system by controlling membrane excitability and calcium signaling. Ca(v)2.3 (R-type) VACCs have been especially thought to play critical roles in pain pathways and the analgesic effects of opioids. However, unknown is whether single-nucleotide polymorphisms (SNPs) of the human CACNA1E (calcium channel, voltage-dependent, R type, alpha 1E subunit) gene that encodes Cav2.3 VACCs influence the analgesic effects of opioids. Thus, the present study examined associations between fentanyl sensitivity and SNPs in the human CACNA1E gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery, including bone dissection. We first conducted linkage disequilibrium (LD) analyses of 223 SNPs in a region that contains the CACNA1E gene using genomic samples from 100 patients, and a total of 13 LD blocks with 42 Tag SNPs were observed within and around the CACNA1E gene region. In the preliminary study using the same 100 genomic samples, only the rs3845446 A/G SNP was significantly associated with perioperative fentanyl use among these 42 Tag SNPs. In a confirmatory study using the other 255 genomic samples, this SNP was also significantly associated with perioperative fentanyl use. Thus, we further analyzed associations between genotypes of this SNP and all of the clinical data using a total of 355 samples. The rs3845446 A/G SNP was associated with intraoperative fentanyl use, 24 h postoperative fentanyl requirements, and perioperative fentanyl use. Subjects who carried the minor G allele required significantly less fentanyl for pain control compared with subjects who did not carry this allele. Although further validation is needed, the present findings show the possibility of the involvement of CACNA1E gene polymorphisms in fentanyl sensitivity. PMID- 23940631 TI - Noninvasive fMRI investigation of interaural level difference processing in the rat auditory subcortex. AB - OBJECTIVE: Interaural level difference (ILD) is the difference in sound pressure level (SPL) between the two ears and is one of the key physical cues used by the auditory system in sound localization. Our current understanding of ILD encoding has come primarily from invasive studies of individual structures, which have implicated subcortical structures such as the cochlear nucleus (CN), superior olivary complex (SOC), lateral lemniscus (LL), and inferior colliculus (IC). Noninvasive brain imaging enables studying ILD processing in multiple structures simultaneously. METHODS: In this study, blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is used for the first time to measure changes in the hemodynamic responses in the adult Sprague-Dawley rat subcortex during binaural stimulation with different ILDs. RESULTS AND SIGNIFICANCE: Consistent responses are observed in the CN, SOC, LL, and IC in both hemispheres. Voxel-by-voxel analysis of the change of the response amplitude with ILD indicates statistically significant ILD dependence in dorsal LL, IC, and a region containing parts of the SOC and LL. For all three regions, the larger amplitude response is located in the hemisphere contralateral from the higher SPL stimulus. These findings are supported by region of interest analysis. fMRI shows that ILD dependence occurs in both hemispheres and multiple subcortical levels of the auditory system. This study is the first step towards future studies examining subcortical binaural processing and sound localization in animal models of hearing. PMID- 23940632 TI - Study design and quality of reporting of randomized controlled trials of chronic idiopathic or autoimmune urticaria: review. AB - BACKGROUND: The recommended first-line therapy of chronic urticaria is second generation antihistamines, but the modalities of treatment remains unclear. Numerous recommendations with heterogeneous conclusions have been published. We wondered whether such heterogeneous conclusions were linked to the quality of published studies and their reporting. OBJECTIVE: To review the study design and quality of reporting of randomized control trials investigating pharmacological treatment of autoimmune or idiopathic chronic urticaria. METHODOLOGY/PRINCIPAL FINDINGS: MEDLINE and EMBASE were searched for pharmacological randomized controlled trials involving patients with chronic autoimmune or idiopathic urticaria, with the main outcome being treatment efficacy. Data were collected on general characteristics of the studies, internal validity, studied treatments, design of the trial, outcome measures and "spin" strategy in interpreting results. Spin was defined as use of specific reporting strategies to highlight that the experimental treatment is beneficial, despite statistically nonsignificant results. We evaluated 52 articles that met our criteria. Patients were reported as blinded in 42 articles (81%) and the outcome assessor was blinded in 37 (71%). A placebo was the only comparator in 13 (25%) studies. The study duration was <8 weeks in 39 articles (75%), with no follow-up after discontinuation of treatment in 37 (71%). In 4 articles (8%), blinding was clear because they described blinding of the outcome assessor, the treatment was not recognizable (identical or double-dummy) or had no major secondary effects, and computed randomization was centralized. The primary outcome was specified in 33 articles (63%) and was a score in 31. In total, 15 different scores were used. A spin strategy was used for 10 of 12 studies with a nonsignificant primary outcome. CONCLUSION: For establishing guidelines in treatment of chronic urticaria, studies should focus on choosing clinically relevant and reproducible primary outcomes, long-term follow-up, limited use of placebo and avoiding spin strategies. PMID- 23940633 TI - Measuring the intangibles: a metrics for the economic complexity of countries and products. AB - We investigate a recent methodology we have proposed to extract valuable information on the competitiveness of countries and complexity of products from trade data. Standard economic theories predict a high level of specialization of countries in specific industrial sectors. However, a direct analysis of the official databases of exported products by all countries shows that the actual situation is very different. Countries commonly considered as developed ones are extremely diversified, exporting a large variety of products from very simple to very complex. At the same time countries generally considered as less developed export only the products also exported by the majority of countries. This situation calls for the introduction of a non-monetary and non-income-based measure for country economy complexity which uncovers the hidden potential for development and growth. The statistical approach we present here consists of coupled non-linear maps relating the competitiveness/fitness of countries to the complexity of their products. The fixed point of this transformation defines a metrics for the fitness of countries and the complexity of products. We argue that the key point to properly extract the economic information is the non linearity of the map which is necessary to bound the complexity of products by the fitness of the less competitive countries exporting them. We present a detailed comparison of the results of this approach directly with those of the Method of Reflections by Hidalgo and Hausmann, showing the better performance of our method and a more solid economic, scientific and consistent foundation. PMID- 23940634 TI - Effects of the dopamine D2 allosteric modulator, PAOPA, on the expression of GRK2, arrestin-3, ERK1/2, and on receptor internalization. AB - The activity of G protein-coupled receptors (GPCRs) is intricately regulated by a range of intracellular proteins, including G protein-coupled kinases (GRKs) and arrestins. Understanding the effects of ligands on these signaling pathways could provide insights into disease pathophysiologies and treatment. The dopamine D2 receptor is a GPCR strongly implicated in the pathophysiology of a range of neurological and neuropsychiatric disorders, particularly schizophrenia. Previous studies from our lab have shown the preclinical efficacy of a novel allosteric drug, 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA), in attenuating schizophrenia-like behavioural abnormalities in rodent models of the disease. As an allosteric modulator, PAOPA binds to a site on the D2 receptor, which is distinct from the endogenous ligand-binding site, in order to modulate the binding of the D2 receptor ligand, dopamine. The exact signaling pathways affected by this allosteric modulator are currently unknown. The objectives of this study were to decipher the in vivo effects, in rats, of chronic PAOPA administration on D2 receptor regulatory and downstream molecules, including GRK2, arrestin-3 and extracellular receptor kinase (ERK) 1/2. Additionally, an in vitro cellular model was also used to study PAOPA's effects on D2 receptor internalization. Results from western immunoblots showed that chronic PAOPA treatment increased the striatal expression of GRK2 by 41%, arrestin-3 by 34%, phospho-ERK1 by 51% and phospho-ERK2 by 36%. Results also showed that the addition of PAOPA to agonist treatment in cells increased D2 receptor internalization by 33%. This study provides the foundational evidence of putative signaling pathways, and changes in receptor localization, affected by treatment with PAOPA. It improves our understanding on the diverse mechanisms of action of allosteric modulators, while advancing PAOPA's development into a novel drug for the improved treatment of schizophrenia. PMID- 23940635 TI - Chemoirradiation for glioblastoma multiforme: the national cancer institute experience. AB - PURPOSE: Standard treatment for glioblastoma (GBM) is surgery followed by radiation (RT) and temozolomide (TMZ). While there is variability in survival based on several established prognostic factors, the prognostic utility of other factors such as tumor size and location are not well established. EXPERIMENTAL DESIGN: The charts of ninety two patients with GBM treated with RT at the National Cancer Institute (NCI) between 1998 and 2012 were retrospectively reviewed. Most patients received RT with concurrent and adjuvant TMZ. Topographic locations were classified using preoperative imaging. Gross tumor volumes were contoured using treatment planning systems utilizing both pre-operative and post operative MR imaging. RESULTS: At a median follow-up of 18.7 months, the median overall survival (OS) and progression-free survival (PFS) for all patients was 17.9 and 7.6 months. Patients with the smallest tumors had a median OS of 52.3 months compared to 16.3 months among patients with the largest tumors, P = 0.006. The patients who received bevacizumab after recurrence had a median OS of 23.3 months, compared to 16.3 months in patients who did not receive it, P = 0.0284. The median PFS and OS in patients with periventricular tumors was 5.7 and 17.5 months, versus 8.9 and 23.3 months in patients with non-periventricular tumors, P = 0.005. CONCLUSIONS: Survival in our cohort was comparable to the outcome of the defining EORTC-NCIC trial establishing the use of RT+TMZ. This study also identifies several potential prognostic factors that may be useful in stratifying patients. PMID- 23940636 TI - TGFA and IRF6 contribute to the risk of nonsyndromic cleft lip with or without cleft palate in northeast China. AB - Nonsyndromic cleft lip with or without cleft palate (NSCL/P) are common birth defects with a complex etiology. Multiple interacting loci and possible environmental factors influence the risk of NSCL/P. 12 single nucleotide polymorphisms (SNPs) in 7 candidate genes were tested using an allele-specific primer extension for case-control and case-parent analyses in northeast China in 236 unrelated patients, 185 mothers and 154 fathers, including 128 complete trios, and 400 control individuals. TGFA and IRF6 genes showed a significant association with NSCL/P. In IRF6, statistical evidence of an association between rs2235371 (p = 0.003), rs2013162 (p<0.0001) and NSCL/P was observed in case control analyses. Family based association tests (FBATs) showed over-transmission of the C allele at the rs2235371 polymorphism (p = 0.007). In TGFA, associations between rs3771494, rs3771523 (G3822A), rs11466285 (T3851C) and NSCL/P were observed in case-control and FBAT analyses. Associations between other genes (BCL3, TGFB3, MTHFR, PVRL1 and SUMO1) and NSCL/P were not detected. PMID- 23940638 TI - HIV infection in fishing communities of Lake Victoria Basin of Uganda--a cross sectional sero-behavioral survey. AB - BACKGROUND: Uganda's first AIDS case was reported in a fishing village. Thereafter, due to varying risk factors, the epidemic spread heterogeneously to all regions, with some populations more affected. Given the recent rising trends in HIV infection in Uganda, it is crucial to know the risk factors in different populations. The aim of this study was to determine the prevalence and risk factors of HIV infection among fishing communities. METHODOLOGY: A cross sectional survey of 46 fishing communities was conducted in 2010. Following written consent, 911 randomly selected respondents age 15-59 years were interviewed and gave blood for HIV testing. HIV testing was conducted in the field and central laboratory according to national algorithm. Survey protocol was approved by the Science and Ethics Committee of Uganda Virus Research Institute, and cleared by Uganda National Council for Science and Technology. Data was captured by EPIINFO and statistical analysis done in SPSS. FINDINGS: Overall HIV prevalence was 22%; there was no difference by sex (x (2) test, p>0.05). Association with HIV infection was determined by x (2) test, p<0.5. Never married respondents had lower HIV prevalence (6.2%) than the ever married (24.1%). HIV prevalence was lower in younger respondents, age 15-24 years (10.8%) than in age group 25 years and above (26.1%). Muslims had lower HIV prevalence (14.4%) than Christians (25.2%). HIV prevalence was higher among respondents reporting 3 or more lifetime sexual partners (25.3%) than in those reporting less numbers (10.8%). HIV prevalence was higher among uncircumcised men (27%) than in circumcised men (11%). Multivariate analysis identified 4 risk factors for HIV infection; age, religion, ever condom use and number of lifetime sexual partners. CONCLUSIONS: HIV prevalence in the surveyed communities was three times higher than of general population. This underscores the need for tailor made HIV combination prevention interventions targeting fishing communities. PMID- 23940639 TI - The effects of glucosinolates and their breakdown products on necrotrophic fungi. AB - Glucosinolates are a diverse class of S- and N-containing secondary metabolites that play a variety of roles in plant defense. In this study, we used Arabidopsis thaliana mutants that contain different amounts of glucosinolates and glucosinolate-breakdown products to study the effects of these phytochemicals on phytopathogenic fungi. We compared the fungus Botrytis cinerea, which infects a variety of hosts, with the Brassicaceae-specific fungus Alternaria brassicicola. B. cinerea isolates showed variable composition-dependent sensitivity to glucosinolates and their hydrolysis products, while A. brassicicola was more strongly affected by aliphatic glucosinolates and isothiocyanates as decomposition products. We also found that B. cinerea stimulates the accumulation of glucosinolates to a greater extent than A. brassicicola. In our work with A. brassicicola, we found that the type of glucosinolate-breakdown product is more important than the type of glucosinolate from which that product was derived, as demonstrated by the sensitivity of the Ler background and the sensitivity gained in Col-0 plants expressing epithiospecifier protein both of which accumulate simple nitrile and epithionitriles, but not isothiocyanates. Furthermore, in vivo, hydrolysis products of indole glucosinolates were found to be involved in defense against B. cinerea, but not in the host response to A. brassicicola. We suggest that the Brassicaceae-specialist A. brassicicola has adapted to the presence of indolic glucosinolates and can cope with their hydrolysis products. In contrast, some isolates of the generalist B. cinerea are more sensitive to these phytochemicals. PMID- 23940637 TI - Mitochondrial genome analysis of primary open angle glaucoma patients. AB - Primary open angle glaucoma (POAG) is a multi-factorial optic disc neuropathy characterized by accelerating damage of the retinal ganglion cells and atrophy of the optic nerve head. The vulnerability of the optic nerve damage leading to POAG has been postulated to result from oxidative stress and mitochondrial dysfunction. In this study, we investigated the possible involvement of the mitochondrial genomic variants in 101 patients and 71 controls by direct sequencing of the entire mitochondrial genome. The number of variable positions in the mtDNA with respect to the revised Cambridge Reference Sequence (rCRS), have been designated "Segregating Sites". The segregating sites present only in the patients or controls have been designated "Unique Segregating Sites (USS)". The population mutation rate (theta = 4NeMU) as estimated by Watterson's theta (thetaw), considering only the USS, was significantly higher among the patients (p = 9.8 * 10(-15)) compared to controls. The difference in thetaw and the number of USS were more pronounced when restricted to the coding region (p<1.31 * 10( 21) and p = 0.006607, respectively). Further analysis of the region revealed non synonymous variations were significantly higher in Complex I among the patients (p = 0.0053). Similar trends were retained when USS was considered only within complex I (frequency 0.49 vs 0.31 with p<0.0001 and mutation rate p-value <1.49*10(-43)) and ND5 within its gene cluster (frequency 0.47 vs 0.23 with p<0.0001 and mutation rate p-value <4.42*10(-47)). ND5 is involved in the proton pumping mechanism. Incidentally, glaucomatous trabecular meshwork cells have been reported to be more sensitive to inhibition of complex I activity. Thus mutations in ND5, expected to inhibit complex I activity, could lead to generation of oxidative stress and favor glaucomatous condition. PMID- 23940640 TI - Low glucose but not galactose enhances oxidative mitochondrial metabolism in C2C12 myoblasts and myotubes. AB - BACKGROUND: Substituting galactose for glucose in cell culture media has been suggested to enhance mitochondrial metabolism in a variety of cell lines. We studied the effects of carbohydrate availability on growth, differentiation and metabolism of C2C12 myoblasts and myotubes. METHODOLOGY/PRINCIPAL FINDINGS: We measured growth rates, ability to differentiate, citrate synthase and respiratory chain activities and several parameters of mitochondrial respiration in C2C12 cells grown in media with varying carbohydrate availability (5 g/l glucose, 1 g/l glucose, 1 g/l galactose, and no added carbohydrates). C2C12 myoblasts grow more slowly without glucose irrespective of the presence of galactose, which is not consumed by the cells, and they fail to differentiate without glucose in the medium. Cells grown in a no-glucose medium (with or without galactose) have lower maximal respiration and spare respiratory capacity than cells grown in the presence of glucose. However, increasing glucose concentration above physiological levels decreases the achievable maximal respiration. C2C12 myotubes differentiated at a high glucose concentration showed higher dependency on oxidative respiration under basal conditions but had lower maximal and spare respiratory capacity when compared to cells differentiated under low glucose condition. Citrate synthase activity or mitochondrial yield were not significantly affected by changes in the available substrate concentration but a trend towards a higher respiratory chain activity was observed at reduced glucose levels. CONCLUSIONS/SIGNIFICANCE: Our results show that using galactose to increase oxidative metabolism may not be applicable to every cell line, and the changes in mitochondrial respiratory parameters associated with treating cells with galactose are mainly due to glucose deprivation. Moderate concentrations of glucose (1 g/l) in a growth medium are optimal for mitochondrial respiration in C2C12 cell line while supraphysiological concentrations of glucose cause mitochondrial dysfunction in C2C12 myoblasts and myotubes. PMID- 23940643 TI - Measurement of the infection and dissemination of bluetongue virus in culicoides biting midges using a semi-quantitative rt-PCR assay and isolation of infectious virus. AB - BACKGROUND: Culicoides biting midges (Diptera: Ceratopogonidae) are the biological vectors of globally significant arboviruses of livestock including bluetongue virus (BTV), African horse sickness virus (AHSV) and the recently emerging Schmallenberg virus (SBV). From 2006-2009 outbreaks of BTV in northern Europe inflicted major disruption and economic losses to farmers and several attempts were made to implicate Palaearctic Culicoides species as vectors. Results from these studies were difficult to interpret as they used semi quantitative RT-PCR (sqPCR) assays as the major diagnostic tool, a technique that had not been validated for use in this role. In this study we validate the use of these assays by carrying out time-series detection of BTV RNA in two colony species of Culicoides and compare the results with the more traditional isolation of infectious BTV on cell culture. METHODOLOGY/PRINCIPAL FINDINGS: A BTV serotype 1 strain mixed with horse blood was fed to several hundred individuals of Culicoides sonorensis (Wirth & Jones) and C. nubeculosus (Mg.) using a membrane based assay and replete individuals were then incubated at 25 degrees C. At daily intervals 25 Culicoides of each species were removed from incubation, homogenised and BTV quantified in each individual using sqPCR (Cq values) and virus isolation on a KC-C. sonorensis embryonic cell line, followed by antigen enzyme-linked immunosorbent assay (ELISA). In addition, comparisons were also drawn between the results obtained with whole C. sonorensis and with individually dissected individuals to determine the level of BTV dissemination. CONCLUSIONS/SIGNIFICANCE: Cq values generated from time-series infection experiments in both C. sonorensis and C. nubeculosus confirmed previous studies that relied upon the isolation and detection of infectious BTV. Implications on the testing of field-collected Culicoides as potential virus vectors by PCR assays and the use of such assays as front-line tools for use in diagnostic laboratories in this role are discussed. PMID- 23940641 TI - Topical rosiglitazone is an effective anti-scarring agent in the cornea. AB - Corneal scarring remains a major cause of blindness world-wide, with limited treatment options, all of which have side-effects. Here, we tested the hypothesis that topical application of Rosiglitazone, a Thiazolidinedione and ligand of peroxisome proliferator activated receptor gamma (PPARgamma), can effectively block scar formation in a cat model of corneal damage. Adult cats underwent bilateral epithelial debridement followed by excimer laser ablation of the central corneal stroma to a depth of ~160 um as a means of experimentally inducing a reproducible wound. Eyes were then left untreated, or received 50 ul of either 10 uM Rosiglitazone in DMSO/Celluvisc, DMSO/Celluvisc vehicle or Celluvisc vehicle twice daily for 2 weeks. Cellular aspects of corneal wound healing were evaluated with in vivo confocal imaging and post-mortem immunohistochemistry for alpha smooth muscle actin (alphaSMA). Impacts of the wound and treatments on optical quality were assessed using wavefront sensing and optical coherence tomography at 2, 4, 8 and 12 weeks post-operatively. In parallel, cat corneal fibroblasts were cultured to assess the effects of Rosiglitazone on TGFbeta-induced alphaSMA expression. Topical application of Rosiglitazone to cat eyes after injury decreased alphaSMA expression and haze, as well as the induction of lower-order and residual, higher-order wavefront aberrations compared to vehicle-treated eyes. Rosiglitazone also inhibited TGFbeta-induced alphaSMA expression in cultured corneal fibroblasts. In conclusion, Rosiglitazone effectively controlled corneal fibrosis in vivo and in vitro, while restoring corneal thickness and optics. Its topical application may represent an effective, new avenue for the prevention of corneal scarring with distinct advantages for pathologically thin corneas. PMID- 23940642 TI - Early prefrontal brain responses to the Hedonic quality of emotional words--a simultaneous EEG and MEG study. AB - The hedonic meaning of words affects word recognition, as shown by behavioral, functional imaging, and event-related potential (ERP) studies. However, the spatiotemporal dynamics and cognitive functions behind are elusive, partly due to methodological limitations of previous studies. Here, we account for these difficulties by computing combined electro-magnetoencephalographic (EEG/MEG) source localization techniques. Participants covertly read emotionally high arousing positive and negative nouns, while EEG and MEG were recorded simultaneously. Combined EEG/MEG current-density reconstructions for the P1 (80 120 ms), P2 (150-190 ms) and EPN component (200-300 ms) were computed using realistic individual head models, with a cortical constraint. Relative to negative words, the P1 to positive words predominantly involved language-related structures (left middle temporal and inferior frontal regions), and posterior structures related to directed attention (occipital and parietal regions). Effects shifted to the right hemisphere in the P2 component. By contrast, negative words received more activation in the P1 time-range only, recruiting prefrontal regions, including the anterior cingulate cortex (ACC). Effects in the EPN were not statistically significant. These findings show that different neuronal networks are active when positive versus negative words are processed. We account for these effects in terms of an "emotional tagging" of word forms during language acquisition. These tags then give rise to different processing strategies, including enhanced lexical processing of positive words and a very fast language-independent alert response to negative words. The valence-specific recruitment of different networks might underlie fast adaptive responses to both approach- and withdrawal-related stimuli, be they acquired or biological. PMID- 23940644 TI - Functional gene polymorphism to reveal species history: the case of the CRTISO gene in cultivated carrots. AB - BACKGROUND: Carrot is a vegetable cultivated worldwide for the consumption of its root. Historical data indicate that root colour has been differentially selected over time and according to geographical areas. Root pigmentation depends on the relative proportion of different carotenoids for the white, yellow, orange and red types but only internally for the purple one. The genetic control for root carotenoid content might be partially associated with carotenoid biosynthetic genes. Carotenoid isomerase (CRTISO) has emerged as a regulatory step in the carotenoid biosynthesis pathway and could be a good candidate to show how a metabolic pathway gene reflects a species genetic history. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the nucleotide polymorphism and the linkage disequilibrium among the complete CRTISO sequence, and the deviation from neutral expectation were analysed by considering population subdivision revealed with 17 microsatellite markers. A sample of 39 accessions, which represented different geographical origins and root colours, was used. Cultivated carrot was divided into two genetic groups: one from Middle East and Asia (Eastern group), and another one mainly from Europe (Western group). The Western and Eastern genetic groups were suggested to be differentially affected by selection: a signature of balancing selection was detected within the first group whereas the second one showed no selection. A focus on orange-rooted carrots revealed that cultivars cultivated in Asia were mainly assigned to the Western group but showed CRTISO haplotypes common to Eastern carrots. CONCLUSION: The carotenoid pathway CRTISO gene data proved to be complementary to neutral markers in order to bring critical insight in the cultivated carrot history. We confirmed the occurrence of two migration events since domestication. Our results showed a European background in material from Japan and Central Asia. While confirming the introduction of European carrots in Japanese resources, the history of Central Asia material remains unclear. PMID- 23940645 TI - Stool microbiome and metabolome differences between colorectal cancer patients and healthy adults. AB - In this study we used stool profiling to identify intestinal bacteria and metabolites that are differentially represented in humans with colorectal cancer (CRC) compared to healthy controls to identify how microbial functions may influence CRC development. Stool samples were collected from healthy adults (n = 10) and colorectal cancer patients (n = 11) prior to colon resection surgery at the University of Colorado Health-Poudre Valley Hospital in Fort Collins, CO. The V4 region of the 16s rRNA gene was pyrosequenced and both short chain fatty acids and global stool metabolites were extracted and analyzed utilizing Gas Chromatography-Mass Spectrometry (GC-MS). There were no significant differences in the overall microbial community structure associated with the disease state, but several bacterial genera, particularly butyrate-producing species, were under represented in the CRC samples, while a mucin-degrading species, Akkermansia muciniphila, was about 4-fold higher in CRC (p<0.01). Proportionately higher amounts of butyrate were seen in stool of healthy individuals while relative concentrations of acetate were higher in stools of CRC patients. GC-MS profiling revealed higher concentrations of amino acids in stool samples from CRC patients and higher poly and monounsaturated fatty acids and ursodeoxycholic acid, a conjugated bile acid in stool samples from healthy adults (p<0.01). Correlative analysis between the combined datasets revealed some potential relationships between stool metabolites and certain bacterial species. These associations could provide insight into microbial functions occurring in a cancer environment and will help direct future mechanistic studies. Using integrated "omics" approaches may prove a useful tool in identifying functional groups of gastrointestinal bacteria and their associated metabolites as novel therapeutic and chemopreventive targets. PMID- 23940647 TI - C-src enriched serum microvesicles are generated in malignant plasma cell dyscrasia. AB - Plasma cell dyscrasias are immunosecretory disorders that can lead to hematological malignancies such as Multiple Myeloma (MM). MM accounts for 15% of all hematologic cancers, and those diagnosed with MM typically become severely ill and have a low life expectancy. Monoclonal immunoglobulin Free Light Chains (FLC) are present in the serum and urine of many patients with plasma cell diseases. The biological differences between monoclonal FLCs, produced under malignant or benign dyscrasias, has not yet been characterized. In the present study, we show that endothelial and heart muscle cell lines internalize kappa and lambda FLCs. After internalization, FLCs are rerouted in the extracellular space via microvesicles and exosomes that can be re-internalized in contiguous cells. Only FLCs secreted from malignant B Lymphocytes were carried in Hsp70, annexin V, and c-src positive vesicles. In both MM and AL Amyloidosis patients we observed an increase in microvesicle and exosome production. Isolated serum vesicles from MM, AL Amyloidosis and monoclonal gammopathy of undetermined significance (MGUS) patients contained FLCs. Furthermore MM and AL amyloidosis vesicles were strongly positive for Hsp70, annexin V, and c-src compared to MGUS and control patients. These are the first data implying that FLCs reroute via microvesicles in the blood stream, and also suggest a potential novel mechanism of c-src activation in plasma cell dyscrasia. PMID- 23940646 TI - Permissivity of primary human hepatocytes and different hepatoma cell lines to cell culture adapted hepatitis C virus. AB - Significant progress has been made in Hepatitis C virus (HCV) culture since the JFH1 strain cloning. However, developing efficient and physiologically relevant culture systems for all viral genotypes remains an important goal. In this work, we aimed at producing a high titer JFH1 derived virus to test different hepatic cells' permissivity. To this end, we performed successive infections and obtained a JFH1 derived virus reaching high titers. Six potential adaptive mutations were identified (I599V in E2, R1373Q and M1611T in NS3, S2364P and C2441S in NS5A and R2523K in NS5B) and the effect of these mutations on HCV replication and infectious particle production was investigated. This cell culture adapted virus enabled us to efficiently infect primary human hepatocytes, as demonstrated using the RFP-NLS-IPS reporter protein and intracellular HCV RNA quantification. However, the induction of a strong type III interferon response in these cells was responsible for HCV inhibition. The disruption of this innate immune response led to a strong infection enhancement and permitted the detection of viral protein expression by western blotting as well as progeny virus production. This cell culture adapted virus also enabled us to easily compare the permissivity of seven hepatoma cell lines. In particular, we demonstrated that HuH-7, HepG2-CD81, PLC/PRF/5 and Hep3B cells were permissive to HCV entry, replication and secretion even if the efficiency was very low in PLC/PRF/5 and Hep3B cells. In contrast, we did not observe any infection of SNU-182, SNU-398 and SNU-449 hepatoma cells. Using iodixanol density gradients, we also demonstrated that the density profiles of HCV particles produced by PLC/PRF/5 and Hep3B cells were different from that of HuH-7 and HepG2-CD81 derived virions. These results will help the development of a physiologically relevant culture system for HCV patient isolates. PMID- 23940648 TI - Analysis of variations in the glutamate receptor, N-methyl D-aspartate 2A (GRIN2A) gene reveals their relative importance as genetic susceptibility factors for heroin addiction. AB - The glutamate receptor, N-methyl D-aspartate 2A (GRIN2A) gene that encodes the 2A subunit of the N-methyl D-aspartate (NMDA) receptor was recently shown to be involved in the development of opiate addiction. Genetic polymorphisms in GRIN2A have a plausible role in modulating the risk of heroin addiction. An association of GRIN2A single-nucleotide polymorphisms (SNPs) with heroin addiction was found earlier in African Americans. To identify markers that contribute to the genetic susceptibility to heroin addiction, we examined the potential association between heroin addiction and forty polymorphisms of the GRIN2A gene using the MassARRAY system and GeneScan in this study. The frequency of the (GT)26 repeats (rs3219790) in the heroin addiction group was significantly higher than that in the control group (chi(2) = 5.360, P = 0.021). The allele frequencies of three polymorphisms (rs1102972, rs1650420, and rs3104703 in intron 3) were strongly associated with heroin addiction (P<0.001, 0.0002, and <0.001, after Bonferroni correction). Three additional SNPs from the same intron (rs1071502, rs6497730, and rs1070487) had nominally significant P values for association (P<0.05), but did not pass the threshold value. Haplotype analysis revealed that the G-C-T-C-C T-A (block 6) and T-T (block 10) haplotypes of the GRIN2A gene displayed a protective effect (P = <0.001 and 0.003). These findings point to a role for GRIN2A polymorphisms in heroin addiction among the Han Chinese from Shaanxi province, and may be informative for future genetic or neurobiological studies on heroin addiction. PMID- 23940649 TI - Phospholipid metabolism in an industry microalga Chlorella sorokiniana: the impact of inoculum sizes. AB - Chlorella sorokiniana is an important industry microalga potential for biofuel production. Inoculum size is one of the important factors in algal large-scale culture, and has great effects on the growth, lipid accumulation and metabolism of microalgae. As the first barrier of cell contents, membrane plays a vital role in algal inoculum-related metabolism. The knowledge of phospholipids, the main membrane component and high accumulation of phospholipids as the major content of total lipids mass in some microalgae, is necessary to understand the role of membrane in cell growth and metabolism under different inoculum density. Profiling of C. sorokiniana phospholipids with LC-MS led to the identification of 119 phospholipid species. To discover the phospholipid molecules most related to change of inoculum sizes, Partial Least Squares Discriminant Analysis (PLS-DA) was employed and the results revealed that inoculum sizes significantly affected phospholipid profiling. Phosphatidylglycerol (PG), phosphatidyl- ethanolamine (PE) and several phosphatidylcholine (PC) species might play an important role under our experimental conditions. Further analysis of these biomarkers indicated that cell membrane status of C. sorokiniana might play an important role in the adaption to the inoculum sizes. And the culture with inoculum size of 1 * 10(6) cells mL(-1) presented the best membrane status with the highest content of PC and PG, and the lowest content of PE. We discovered that the inoculum size of 1 * 10(6) cells mL(-1) might provide the best growth condition for C. sorokiniana. Also we proposed that PG, PE and several PC may play an important role in inoculum-related metabolism in C. sorokiniana, which may work through thylakoid membrane and photosynthetic pathway. Thus this study would provide more potential targets for metabolic engineering to improve biofuel production and productivity in microalgae. PMID- 23940650 TI - The putative thiosulfate sulfurtransferases PspE and GlpE contribute to virulence of Salmonella Typhimurium in the mouse model of systemic disease. AB - The phage-shock protein PspE and GlpE of the glycerol 3-phosphate regulon of Salmonella enterica serovar Typhimurium are predicted to belong to the class of thiosulfate sulfurtransferases, enzymes that traffic sulfur between molecules. In the present study we demonstrated that the two genes contribute to S. Typhimurium virulence, as a glpE and pspE double deletion strain showed significantly decreased virulence in a mouse model of systemic infection. However, challenge of cultured epithelial cells and macrophages did not reveal any virulence-associated phenotypes. We hypothesized that their contribution to virulence could be in sulfur metabolism or by contributing to resistance to nitric oxide, oxidative stress, or cyanide detoxification. In vitro studies demonstrated that glpE but not pspE was important for resistance to H2O2. Since the double mutant, which was the one affected in virulence, was not affected in this assay, we concluded that resistance to oxidative stress and the virulence phenotype was most likely not linked. The two genes did not contribute to nitric oxid stress, to synthesis of essential sulfur containing amino acids, nor to detoxification of cyanide. Currently, the precise mechanism by which they contribute to virulence remains elusive. PMID- 23940651 TI - Syntenic relationships between the U and M genomes of Aegilops, wheat and the model species Brachypodium and rice as revealed by COS markers. AB - Diploid Aegilops umbellulata and Ae. comosa and their natural allotetraploid hybrids Ae. biuncialis and Ae. geniculata are important wild gene sources for wheat. With the aim of assisting in alien gene transfer, this study provides gene based conserved orthologous set (COS) markers for the U and M genome chromosomes. Out of the 140 markers tested on a series of wheat-Aegilops chromosome introgression lines and flow-sorted subgenomic chromosome fractions, 100 were assigned to Aegilops chromosomes and six and seven duplications were identified in the U and M genomes, respectively. The marker-specific EST sequences were BLAST-ed to Brachypodium and rice genomic sequences to investigate macrosyntenic relationships between the U and M genomes of Aegilops, wheat and the model species. Five syntenic regions of Brachypodium identified genome rearrangements differentiating the U genome from the M genome and from the D genome of wheat. All of them seem to have evolved at the diploid level and to have been modified differentially in the polyploid species Ae. biuncialis and Ae. geniculata. A certain level of wheat-Aegilops homology was detected for group 1, 2, 3 and 5 chromosomes, while a clearly rearranged structure was showed for the group 4, 6 and 7 Aegilops chromosomes relative to wheat. The conserved orthologous set markers assigned to Aegilops chromosomes promise to accelerate gene introgression by facilitating the identification of alien chromatin. The syntenic relationships between the Aegilops species, wheat and model species will facilitate the targeted development of new markers specific for U and M genomic regions and will contribute to the understanding of molecular processes related to allopolyploidization. PMID- 23940652 TI - Development of a system to monitor laryngeal movement during swallowing using a bend sensor. AB - BACKGROUND: Swallowing dysfunction (also known as dysphagia), which results in a deterioration of nutritional intake, slows rehabilitation and causes aspiration pneumonia, is very common following neurological impairments. Although videofluorographic (VF) examination is widely used for detecting aspiration, an objective and non-invasive method for assessing swallowing function has yet to be established because of a lack of adequate devices and protocols. In this paper, a bend sensor whose resistance is altered by bending was introduced to monitor swallowing-related laryngeal movement. METHODS: Six healthy male volunteers were recruited in the present study. Specific time points on the signal waveform produced by the bend sensor were defined to describe laryngeal movement by differential analysis. Additionally, the physiological significance of the obtained waveform was confirmed by analyzing the sequential correlations between the signal waveform from the bend sensor and hyoid bone kinetics simultaneously recorded by VF. RESULTS: Seven time points were successfully defined on the signal waveform to reference laryngeal movement. Each time point was well correlated with certain VF events, with evidence of no significant time lags, and there were positive correlations between waveform time points and matched VF events. Furthermore, obvious similarities were noticed between the duration of each phase on the signal waveform and the duration of the matched hyoid bone activity. CONCLUSIONS: The present monitoring system using a bend sensor might be useful for observing the temporal aspects of laryngeal movement during swallowing, and it was well coordinated with hyoid bone movement. PMID- 23940653 TI - Brain characterization using normalized quantitative magnetic resonance imaging. AB - OBJECTIVES: To present a method for generating reference maps of typical brain characteristics of groups of subjects using a novel combination of rapid quantitative Magnetic Resonance Imaging (qMRI) and brain normalization. The reference maps can be used to detect significant tissue differences in patients, both locally and globally. MATERIALS AND METHODS: A rapid qMRI method was used to obtain the longitudinal relaxation rate (R1), the transverse relaxation rate (R2) and the proton density (PD). These three tissue properties were measured in the brains of 32 healthy subjects and in one patient diagnosed with Multiple Sclerosis (MS). The maps were normalized to a standard brain template using a linear affine registration. The differences of the mean value ofR1, R2 and PD of 31 healthy subjects in comparison to the oldest healthy subject and in comparison to an MS patient were calculated. Larger anatomical structures were characterized using a standard atlas. The vector sum of the normalized differences was used to show significant tissue differences. RESULTS: The coefficient of variation of the reference maps was high at the edges of the brain and the ventricles, moderate in the cortical grey matter and low in white matter and the deep grey matter structures. The elderly subject mainly showed significantly lower R1 and R2 and higher PD values along all sulci. The MS patient showed significantly lower R1 and R2 and higher PD values at the edges of the ventricular system as well as throughout the periventricular white matter, at the internal and external capsules and at each of the MS lesions. CONCLUSION: Brain normalization of rapid qMRI is a promising new method to generate reference maps of typical brain characteristics and to automatically detect deviating tissue properties in the brain. PMID- 23940654 TI - Dynamic localisation of mature microRNAs in Human nucleoli is influenced by exogenous genetic materials. AB - Although microRNAs are commonly known to function as a component of RNA-induced silencing complexes in the cytoplasm, they have been detected in other organelles, notably the nucleus and the nucleolus, of mammalian cells. We have conducted a systematic search for miRNAs in HeLa cell nucleoli, and identified 11 abundant miRNAs with a high level of nucleolar accumulation. Through in situ hybridisation, we have localised these miRNAs, including miR-191 and miR-484, in the nucleolus of a diversity of human and rodent cell lines. The nucleolar association of these miRNAs is resistant to various cellular stresses, but highly sensitive to the presence of exogenous nucleic acids. Introduction of both single and double-stranded DNA as well as double stranded RNA rapidly induce the redistribution of nucleolar miRNAs to the cytoplasm. A similar change in subcellular distribution is also observed in cells infected with the influenza A virus. The partition of miRNAs between the nucleolus and the cytoplasm is affected by Leptomycin B, suggesting a role of Exportin-1 in the intracellular shuttling of miRNAs. This study reveals a previously unknown aspect of miRNA biology, and suggests a possible link between these small noncoding RNAs and the cellular management of foreign genetic materials. PMID- 23940656 TI - Revised vertebral count in the "longest-necked vertebrate" Elasmosaurus platyurus Cope 1868, and clarification of the cervical-dorsal transition in Plesiosauria. AB - Elasmosaurid plesiosaurians are renowned for their immensely long necks, and indeed, possessed the highest number of cervical vertebrae for any known vertebrate. Historically, the largest count has been attributed to the iconic Elasmosaurus platyurus from the Late Cretaceous of Kansas, but estimates for the total neck series in this taxon have varied between published reports. Accurately determining the number of vertebral centra vis-a-vis the maximum length of the neck in plesiosaurians has significant implications for phylogenetic character designations, as well as the inconsistent terminology applied to some osteological structures. With these issues in mind, we reassessed the holotype of E. platyurus as a model for standardizing the debated cervical-dorsal transition in plesiosaurians, and during this procedure, documented a "lost" cervical centrum. Our revision also advocates retention of the term "pectorals" to describe the usually three or more distinctive vertebrae close to the cranial margin of the forelimb girdle that bear a functional rib facet transected by the neurocentral suture, and thus conjointly formed by both the parapophysis on the centrum body and diapophysis from the neural arch (irrespective of rib length). This morphology is unambiguously distinguishable from standard cervicals, in which the functional rib facet is borne exclusively on the centrum, and dorsals in which the rib articulation is situated above the neurocentral suture and functionally borne only by the transverse process of the neural arch. Given these easily distinguishable definitions, the maximum number of neck vertebrae preserved in E. platyurus is 72; this is only three vertebrae shorter than the recently described Albertonectes, which together with E. platyurus constitute the "longest necked" animals ever to have lived. PMID- 23940655 TI - Growth monitoring: a survey of current practices of primary care paediatricians in Europe. AB - OBJECTIVE: We aimed to study current practices in growth monitoring by European primary care paediatricians and to explore their perceived needs in this field. METHODS: We developed a cross-sectional, anonymous on-line survey and contacted primary care paediatricians listed in national directories in the 18 European countries with a confederation of primary care paediatricians. Paediatricians participated in the survey between April and September 2011. RESULTS: Of the 1,198 paediatricians from 11 European countries (response rate 13%) who participated, 29% used the 2006 World Health Organization Multicentre Growth Reference Study growth charts, 69% used national growth charts; 61% used software to draw growth charts and 79% did not use a formal algorithm to detect abnormal growth on growth charts. Among the 21% of paediatricians who used algorithms, many used non-algorithmic simple thresholds for height and weight and none used the algorithms published in the international literature. In all, 69% of paediatricians declared that a validated algorithm to monitor growth would be useful in daily practice. We found important between-country variations. CONCLUSION: The varied growth-monitoring practices declared by primary care paediatricians reveals the need for standardization and evidence-based algorithms to define abnormal growth and the development of software that would use such algorithms. PMID- 23940657 TI - Insights into the N-sulfation mechanism: molecular dynamics simulations of the N sulfotransferase domain of NDST1 and mutants. AB - Sulfation patterns along glycosaminoglycan (GAG) chains dictate their functional role. The N-deacetylase N-sulfotransferase family (NDST) catalyzes the initial downstream modification of heparan sulfate and heparin chains by removing acetyl groups from subsets of N-acetylglucosamine units and, subsequently, sulfating the residual free amino groups. These enzymes transfer the sulfuryl group from 3' phosphoadenosine-5'-phosphosulfate (PAPS), yielding sulfated sugar chains and 3' phosphoadenosine-5'-phosphate (PAP). For the N-sulfotransferase domain of NDST1, Lys833 has been implicated to play a role in holding the substrate glycan moiety close to the PAPS cofactor. Additionally, Lys833 together with His716 interact with the sulfonate group, stabilizing the transition state. Such a role seems to be shared by Lys614 through donation of a proton to the bridging oxygen of the cofactor, thereby acting as a catalytic acid. However, the relevance of these boundary residues at the hydrophobic cleft is still unclear. Moreover, whether Lys833, His716 and Lys614 play a role in both glycan recognition and glycan sulfation remains elusive. In this study we evaluate the contribution of NDST mutants (Lys833, His716 and Lys614) to dynamical effects during sulfate transfer using comprehensive combined docking and essential dynamics. In addition, the binding location of the glycan moiety, PAPS and PAP within the active site of NDST1 throughout the sulfate transfer were determined by intermediate state analysis. Furthermore, NDST1 mutants unveiled Lys833 as vital for both the glycan binding and subsequent N-sulfotransferase activity of NDST1. PMID- 23940659 TI - Analysis of herpes simplex virion tegument ICP4 derived from infected cells and ICP4-expressing cells. AB - ICP4 is the major transcriptional regulatory protein of herpes simplex virus (HSV). It is expressed in infected cells with immediate early kinetics and is essential for viral growth. ICP4 is also a structural component of the virion tegument layer. Herpesviral tegument proteins exert regulatory functions important for takeover of the host cell. Tegument ICP4 has not been well characterized. We examined the ICP4 present in HSV-1 virions that were either derived from wild type infected cells or from ICP4-expressing (E5) cells infected with ICP4 deletion virus d120. Limited proteolysis demonstrated that virion associated ICP4 from particles derived from E5 cells was indeed an internal component of the virion. A similar subset of virion structural proteins was detected in viral particles regardless of the cellular origin of ICP4. Genotypically ICP4-negative virions complemented with tegument ICP4 entered cells via a proteasome-dependent, pH-dependent pathway similar to wild type virions. In infected cells, ICP4 was distributed predominantly in intranuclear replication compartments regardless of whether it was expressed from a transgene or from the HSV genome. PMID- 23940658 TI - Neurotoxicity of prion peptides mimicking the central domain of the cellular prion protein. AB - The physiological functions of PrP(C) remain enigmatic, but the central domain, comprising highly conserved regions of the protein may play an important role. Indeed, a large number of studies indicate that synthetic peptides containing residues 106-126 (CR) located in the central domain (CD, 95-133) of PrP(C) are neurotoxic. The central domain comprises two chemically distinct subdomains, the charge cluster (CC, 95-110) and a hydrophobic region (HR, 112-133). The aim of the present study was to establish the individual cytotoxicity of CC, HR and CD. Our results show that only the CD peptide is neurotoxic. Biochemical, Transmission Electron Microscopy and Atomic Force Microscopy experiments demonstrated that the CD peptide is able to activate caspase-3 and disrupt the cell membrane, leading to cell death. PMID- 23940660 TI - Akt-induced phosphorylation of N-CoR at serine 1450 contributes to its misfolded conformational dependent loss (MCDL) in acute myeloid leukemia of the M5 subtype. AB - The nuclear receptor co-repressor (N-CoR) is a key component of the generic co repressor complex that plays an important role in the control of cellular growth and differentiation. As shown by us recently, the growth suppressive function of N-CoR largely relies on its capacity to repress Flt3, a key regulator of cellular gorwth during normal and malignant hematopoesis. We further demonstrated how de repression of Flt3 due to the misfolded conformation dependent loss (MCDL) of N CoR contributed to malignant growth in acute myeloid leukemia (AML). However, the molecular mechanism underlying the MCDL of N-CoR and its implication in AML pathogenesis is not fully understood. Here, we report that Akt-induced phosphorylation of N-CoR at the consensus Akt motif is crucial for its misfolding and subsequent loss in AML (AML-M5). N-CoR displayed significantly higher level of serine specific phosphorylation in almost all AML-M5 derived cells and was subjected to processing by AML-M5 specific aberrant protease activity. To identify the kinase linked to N-CoR phosphorylation, a library of activated kinases was screened with the extracts of AML cells; leading to the identification of Akt as the putative kinase linked to N-CoR phosphorylation. Consistent with this finding, a constitutively active Akt consistently phosphorylated N-CoR leading to its misfolding; while the therapeutic and genetic ablation of Akt largely abrogated the MCDL of N-CoR in AML-M5 cells. Site directed mutagenic analysis of N-CoR identified serine 1450 as the crucial residue whose phosphorylation by Akt was essential for the misfolding and loss of N-CoR protein. Moreover, Akt-induced phosphorylation of N-CoR contributed to the de-repression of Flt3, suggesting a cross talk between Akt signaling and N-CoR misfolding pathway in the pathogenesis of AML-M5. The N-CoR misfolding pathway could be the common downstream thread of pleiotropic Akt signaling activated by various oncogenic insults in some subtypes of leukemia and solid tumors. PMID- 23940661 TI - Structures of an apo and a binary complex of an evolved archeal B family DNA polymerase capable of synthesising highly cy-dye labelled DNA. AB - Thermophilic DNA polymerases of the polB family are of great importance in biotechnological applications including high-fidelity PCR. Of particular interest is the relative promiscuity of engineered versions of the exo- form of polymerases from the Thermo- and Pyrococcales families towards non-canonical substrates, which enables key advances in Next-generation sequencing. Despite this there is a paucity of structural information to guide further engineering of this group of polymerases. Here we report two structures, of the apo form and of a binary complex of a previously described variant (E10) of Pyrococcus furiosus (Pfu) polymerase with an ability to fully replace dCTP with Cyanine dye-labeled dCTP (Cy3-dCTP or Cy5-dCTP) in PCR and synthesise highly fluorescent "CyDNA" densely decorated with cyanine dye heterocycles. The apo form of Pfu-E10 closely matches reported apo form structures of wild-type Pfu. In contrast, the binary complex (in the replicative state with a duplex DNA oligonucleotide) reveals a closing movement of the thumb domain, increasing the contact surface with the nascent DNA duplex strand. Modelling based on the binary complex suggests how bulky fluorophores may be accommodated during processive synthesis and has aided the identification of residues important for the synthesis of unnatural nucleic acid polymers. PMID- 23940662 TI - Estimating temporal causal interaction between spike trains with permutation and transfer entropy. AB - Estimating the causal interaction between neurons is very important for better understanding the functional connectivity in neuronal networks. We propose a method called normalized permutation transfer entropy (NPTE) to evaluate the temporal causal interaction between spike trains, which quantifies the fraction of ordinal information in a neuron that has presented in another one. The performance of this method is evaluated with the spike trains generated by an Izhikevich's neuronal model. Results show that the NPTE method can effectively estimate the causal interaction between two neurons without influence of data length. Considering both the precision of time delay estimated and the robustness of information flow estimated against neuronal firing rate, the NPTE method is superior to other information theoretic method including normalized transfer entropy, symbolic transfer entropy and permutation conditional mutual information. To test the performance of NPTE on analyzing simulated biophysically realistic synapses, an Izhikevich's cortical network that based on the neuronal model is employed. It is found that the NPTE method is able to characterize mutual interactions and identify spurious causality in a network of three neurons exactly. We conclude that the proposed method can obtain more reliable comparison of interactions between different pairs of neurons and is a promising tool to uncover more details on the neural coding. PMID- 23940663 TI - A preconscious neural mechanism of hypnotically altered colors: a double case study. AB - Hypnotic suggestions may change the perceived color of objects. Given that chromatic stimulus information is processed rapidly and automatically by the visual system, how can hypnotic suggestions affect perceived colors in a seemingly immediate fashion? We studied the mechanisms of such color alterations by measuring electroencephalography in two highly suggestible participants as they perceived briefly presented visual shapes under posthypnotic color alternation suggestions such as "all the squares are blue". One participant consistently reported seeing the suggested colors. Her reports correlated with enhanced evoked upper beta-band activity (22 Hz) 70-120 ms after stimulus in response to the shapes mentioned in the suggestion. This effect was not observed in a control condition where the participants merely tried to simulate the effects of the suggestion on behavior. The second participant neither reported color alterations nor showed the evoked beta activity, although her subjective experience and event-related potentials were changed by the suggestions. The results indicate a preconscious mechanism that first compares early visual input with a memory representation of the suggestion and consequently triggers the color alteration process in response to the objects specified by the suggestion. Conscious color experience is not purely the result of bottom-up processing but it can be modulated, at least in some individuals, by top-down factors such as hypnotic suggestions. PMID- 23940664 TI - A decision analytic approach to exposure-based chemical prioritization. AB - The manufacture of novel synthetic chemicals has increased in volume and variety, but often the environmental and health risks are not fully understood in terms of toxicity and, in particular, exposure. While efforts to assess risks have generally been effective when sufficient data are available, the hazard and exposure data necessary to assess risks adequately are unavailable for the vast majority of chemicals in commerce. The US Environmental Protection Agency has initiated the ExpoCast Program to develop tools for rapid chemical evaluation based on potential for exposure. In this context, a model is presented in which chemicals are evaluated based on inherent chemical properties and behaviorally based usage characteristics over the chemical's life cycle. These criteria are assessed and integrated within a decision analytic framework, facilitating rapid assessment and prioritization for future targeted testing and systems modeling. A case study outlines the prioritization process using 51 chemicals. The results show a preliminary relative ranking of chemicals based on exposure potential. The strength of this approach is the ability to integrate relevant statistical and mechanistic data with expert judgment, allowing for an initial tier assessment that can further inform targeted testing and risk management strategies. PMID- 23940665 TI - Clinical prediction in early pregnancy of infants small for gestational age by customised birthweight centiles: findings from a healthy nulliparous cohort. AB - OBJECTIVE: Small for gestational age (SGA) infants comprise up to 50% of all stillbirths and a minority are detected before birth. We aimed to develop and validate early pregnancy predictive models for SGA infants. METHODS: 5628 participants from SCOPE, a prospective study of nulliparous pregnant women, were interviewed at 15 +/- 1 weeks' gestation. Fetal anthropometry, uterine and umbilical Doppler studies were performed at 20 +/- 1 weeks'. The cohort was divided into training (n = 3735) and validation datasets (n = 1871). All-SGA (birthweight <10th customised centile), Normotensive-SGA (SGA with normotensive mother) and Hypertensive-SGA (SGA with mother who developed hypertension) were the primary outcomes. Multivariable analysis was performed using stepwise logistic regression firstly using clinical variables and then with clinical and ultrasound variables. Receiver operator curves were constructed and areas under the curve (AUC) calculated. RESULTS: 633 infants (11.3%) in the whole cohort were SGA; 465 (8.3%) Normotensive-SGA and 165 (3.0%) Hypertensive-SGA. In the training dataset risk factors for All-SGA at 15 +/- 1 weeks' included: family history of coronary heart disease, maternal birthweight <3000 g and 3000 g to 3499 g compared with >= 3500 g, >12 months to conceive, university student, cigarette smoking, proteinuria, daily vigorous exercise and diastolic blood pressure >= 80. Recreational walking >= 4 times weekly, rhesus negative blood group and increasing random glucose were protective. AUC for clinical risk factors was 0.63. Fetal abdominal or head circumference z scores <10(th) centile and increasing uterine artery Doppler resistance at 20 +/- 1 weeks' were associated with increased risk. Addition of these parameters increased the AUC to 0.69. Clinical predictors of Normotensive and Hypertensive-SGA were sub-groups of All SGA predictors and were quite different. The combined clinical and ultrasound AUC for Normotensive and Hypertensive-SGA were 0.69 and 0.82 respectively. CONCLUSION: Predictors for SGA of relevance to clinical practice were identified. The identity and predictive potential differed in normotensive women and those who developed hypertension. PMID- 23940666 TI - Basolateral amygdala lesion inhibits the development of pain chronicity in neuropathic pain rats. AB - BACKGROUND: Chronicity of pain is one of the most interesting questions in chronic pain study. Clinical and experimental data suggest that supraspinal areas responsible for negative emotions such as depression and anxiety contribute to the chronicity of pain. The amygdala is suspected to be a potential structure for the pain chronicity due to its critical role in processing negative emotions and pain information. OBJECTIVE: This study aimed to investigate whether amygdala or its subregions, the basolateral amygdala (BLA) and the central medial amygdala (CeA), contributes to the pain chronicity in the spared nerve injury (SNI) induced neuropathic pain model of rats. METHODOLOGY/PRINCIPAL FINDINGS: (1) Before the establishment of the SNI-induced neuropathic pain model of rats, lesion of the amygdaloid complex with stereotaxic injection of ibotenic acid (IBO) alleviated mechanical allodynia significantly at days 7 and 14, even no mechanical allodynia at day 28 after SNI; Lesion of the BLA, but not the CeA had similar effects; (2) however, 7 days after SNI when the neuropathic pain model was established, lesion of the amygdala complex or the BLA or the CeA, mechanical allodynia was not affected. CONCLUSION: These results suggest that BLA activities in the early stage after nerve injury might be crucial to the development of pain chronicity, and amygdala-related negative emotions and pain-related memories could promote pain chronicity. PMID- 23940667 TI - A computational module assembled from different protease family motifs identifies PI PLC from Bacillus cereus as a putative prolyl peptidase with a serine protease scaffold. AB - Proteolytic enzymes have evolved several mechanisms to cleave peptide bonds. These distinct types have been systematically categorized in the MEROPS database. While a BLAST search on these proteases identifies homologous proteins, sequence alignment methods often fail to identify relationships arising from convergent evolution, exon shuffling, and modular reuse of catalytic units. We have previously established a computational method to detect functions in proteins based on the spatial and electrostatic properties of the catalytic residues (CLASP). CLASP identified a promiscuous serine protease scaffold in alkaline phosphatases (AP) and a scaffold recognizing a beta-lactam (imipenem) in a cold active Vibrio AP. Subsequently, we defined a methodology to quantify promiscuous activities in a wide range of proteins. Here, we assemble a module which encapsulates the multifarious motifs used by protease families listed in the MEROPS database. Since APs and proteases are an integral component of outer membrane vesicles (OMV), we sought to query other OMV proteins, like phospholipase C (PLC), using this search module. Our analysis indicated that phosphoinositide-specific PLC from Bacillus cereus is a serine protease. This was validated by protease assays, mass spectrometry and by inhibition of the native phospholipase activity of PI-PLC by the well-known serine protease inhibitor AEBSF (IC50 = 0.018 mM). Edman degradation analysis linked the specificity of the protease activity to a proline in the amino terminal, suggesting that the PI-PLC is a prolyl peptidase. Thus, we propose a computational method of extending protein families based on the spatial and electrostatic congruence of active site residues. PMID- 23940668 TI - Classical estrogen receptors and ERalpha splice variants in the mouse. AB - Estrogens exert a variety of effects in both reproductive and non-reproductive tissues. With the discovery of ERalpha splice variants, prior assumptions concerning tissue-specific estrogen signaling need to be re-evaluated. Accordingly, we sought to determine the expression of the classical estrogen receptors and ERalpha splice variants across reproductive and non-reproductive tissues of male and female mice. Western blotting revealed that the full-length ERalpha66 was mainly present in female reproductive tissues but was also found in non-reproductive tissues at lower levels. ERalpha46 was most highly expressed in the heart of both sexes. ERalpha36 was highly expressed in the kidneys and liver of female mice but not in the kidneys of males. ERbeta was most abundant in non reproductive tissues and in the ovaries. Because the kidney has been reported to be the most estrogenic non-reproductive organ, we sought to elucidate ER renal expression and localization. Immunofluorescence studies revealed ERalpha66 in the vasculature and the glomerulus. It was also found in the brush border of the proximal tubule and in the cortical collecting duct of female mice. ERalpha36 was evident in mesangial cells and tubular epithelial cells of both sexes, as well as podocytes of females but not males. ERbeta was found primarily in the podocytes in female mice but was also present in the mesangial cells in both sexes. Within the renal cortex, ERalpha46 and ERalpha36 were mainly located in the membrane fraction although they were also present in the cytosolic fraction. Given the variability of expression patterns demonstrated herein, identification of the specific estrogen receptors expressed in a tissue is necessary for interpreting estrogenic effects. As this study revealed expression of the ERalpha splice variants at multiple sites within the kidney, further studies are warranted in order to elucidate the contribution of these receptors to renal estrogen responsiveness. PMID- 23940669 TI - Microglial P2Y12 deficiency/inhibition protects against brain ischemia. AB - OBJECTIVE: Microglia are among the first immune cells to respond to ischemic insults. Triggering of this inflammatory response may involve the microglial purinergic GPCR, P2Y12, activation via extracellular release of nucleotides from injured cells. It is also the inhibitory target of the widely used antiplatelet drug, clopidogrel. Thus, inhibiting this GPCR in microglia should inhibit microglial mediated neurotoxicity following ischemic brain injury. METHODS: Experimental cerebral ischemia was induced, in vitro with oxygen-glucose deprivation (OGD), or in vivo via bilateral common carotid artery occlusion (BCCAO). Genetic knock-down in vitro via siRNA, or in vivo P2Y12 transgenic mice (P2Y12-/- or P2Y12+/-), or in vivo treatment with clopidogrel, were used to manipulate the receptor. Neuron death, microglial activation, and microglial migration were assessed. RESULTS: The addition of microglia to neuron-astrocyte cultures increases neurotoxicity following OGD, which is mitigated by microglial P2Y12 deficiency (P<0.05). Wildtype microglia form clusters around these neurons following injury, which is also prevented in P2Y12 deficient microglia (P<0.01). P2Y12 knock-out microglia migrated less than WT controls in response to OGD conditioned neuronal supernatant. P2Y12 (+/-) or clopidogrel treated mice subjected to global cerebral ischemia suffered less neuronal injury (P<0.01, P<0.001) compared to wild-type littermates or placebo treated controls. There were also fewer microglia surrounding areas of injury, and less activation of the pro-inflammatory transcription factor, nuclear factor Kappa B (NFkB). INTERPRETATION: P2Y12 participates in ischemia related inflammation by mediating microglial migration and potentiation of neurotoxicity. These data also suggest an additional anti-inflammatory, neuroprotective benefit of clopidogrel. PMID- 23940670 TI - Downscaling the analysis of complex transmembrane signaling cascades to closed attoliter volumes. AB - Cellular signaling is classically investigated by measuring optical or electrical properties of single or populations of living cells. Here we show that ligand binding to cell surface receptors and subsequent activation of signaling cascades can be monitored in single, (sub-)micrometer sized native vesicles with single molecule sensitivity. The vesicles are derived from live mammalian cells using chemicals or optical tweezers. They comprise parts of a cell's plasma membrane and cytosol and represent the smallest autonomous containers performing cellular signaling reactions thus functioning like minimized cells. Using fluorescence microscopies, we measured in individual vesicles the different steps of G-protein coupled receptor mediated signaling like ligand binding to receptors, subsequent G-protein activation and finally arrestin translocation indicating receptor deactivation. Observing cellular signaling reactions in individual vesicles opens the door for downscaling bioanalysis of cellular functions to the attoliter range, multiplexing single cell analysis, and investigating receptor mediated signaling in multiarray format. PMID- 23940671 TI - Gender-mediated differences in vertical transmission of a nucleopolyhedrovirus. AB - With the development of sensitive molecular techniques for detection of low levels of asymptomatic pathogens, it becoming clear that vertical transmission is a common feature of some insect pathogenic viruses, and likely to be essential to virus survival when opportunities for horizontal transmission are unfavorable. Vertical transmission of Spodoptera exigua multiple nucleopolyhedrovirus (SeMNPV) is common in natural populations of S. exigua. To assess whether gender affected transgenerational virus transmission, four mating group treatments were performed using healthy and sublethally infected insects: i) healthy males (H?) * healthy females (H?); ii) infected males (I?) * healthy females (H?); iii) healthy males (H?) * infected females (I?) and iv) infected males (I?) * infected females (I?). Experimental adults and their offspring were analyzed by qPCR to determine the prevalence of infection. Both males and females were able to transmit the infection to the next generation, although female-mediated transmission resulted in a higher prevalence of infected offspring. Male-mediated venereal transmission was half as efficient as maternally-mediated transmission. Egg surface decontamination studies indicated that the main route of transmission is likely transovarial rather than transovum. Both male and female offspring were infected by their parents in similar proportions. Incorporating vertically-transmitted genotypes into virus-based insecticides could provide moderate levels of transgenerational pest control, thereby extending the periods between bioinsecticide applications. PMID- 23940672 TI - Activation of GSK-3beta and caspase-3 occurs in Nigral dopamine neurons during the development of apoptosis activated by a striatal injection of 6 hydroxydopamine. AB - The 6-Hydroxydopamine (6-OHDA) rat model of Parkinson's disease is essential for a better understanding of the pathological processes underlying the human disease and for the evaluation of promising therapeutic interventions. This work evaluated whether a single striatal injection of 6-OHDA causes progressive apoptosis of dopamine (DA) neurons and activation of glycogen synthase kinase 3beta (GSK-3beta) and caspase-3 in the substantia nigra compacta (SNc). The loss of DA neurons was shown by three neuron markers; tyrosine hydroxylase (TH), NeuN, and beta-III tubulin. Apoptosis activation was determined using Apostain and immunostaining against cleaved caspase-3 and GSK-3beta pY216. We also explored the possibility that cleaved caspase-3 is produced by microglia and astrocytes. Our results showed that the 6-OHDA caused loss of nigral TH(+) cells, progressing mainly in rostrocaudal and lateromedial directions. In the neostriatum, a severe loss of TH(+) terminals occurred from day 3 after lesion. The disappearance of TH(+) cells was associated with a decrease in NeuN and beta-III tubulin immunoreactivity and an increase in Apostain, cleaved caspase-3, and GSK-3beta pY216 in the SNc. Apostain immunoreactivity was observed from days 3 to 21 postlesion. Increased levels of caspase-3 immunoreactivity in TH(+) cells were detected from days 1 to 15, and the levels then decreased to day 30 postlesion. The cleaved caspase-3 also collocated with microglia and astrocytes indicating its participation in glial activation. Our results suggest that caspase-3 and GSK 3beta pY216 activation might participate in the DA cell death and that the active caspase-3 might also participate in the neuroinflammation caused by the striatal 6-OHDA injection. PMID- 23940673 TI - Neuronal apoptosis and motor deficits in mice with genetic inhibition of GSK-3 are Fas-dependent. AB - Glycogen synthase kinase-3 (GSK-3) inhibitors have been postulated as useful therapeutic tools for the treatment of chronic neurodegenerative and neuropsychiatric diseases. Nevertheless the clinical use of these inhibitors has been limited by their common side effects. Lithium, a non-selective GSK-3 inhibitor has been classically administered to treat bipolar patients but its prescription is decreasing due to its frequent side effects such as hand tremor. This toxicity seems to be higher in the elderly and a clinical trial with lithium for Alzheimer's disease was stopped due to high rate of discontinuation. We have previously described a mechanism for the adverse effects of chronic lithium that involves neuronal apoptosis via Fas signaling. As lithium inhibits many other enzymatic activities such as inositol monophosphatase and histone deacetylase, here we aim to genetically test whether GSK-3 inhibition induces those adverse effects through Fas receptor. For this purpose we took advantage of a transgenic mouse line with decreased GSK-3 activity (Tet/DN-GSK-3 mice) that shows increased rate of neuronal apoptosis as well as motor deficits and brought it to a Fas deficient background (lpr mice). We found that apoptosis induced by GSK-3 inhibition was absent in Fas deficient background. Interestingly, motor deficits were also absent in Fas deficient Tet/DN-GSK-3 mice. These results demonstrate that Fas signaling contributes to the neurological toxicity of GSK-3 inhibition and suggest that a combination of GSK-3 inhibitors with blockers of Fas signaling could help to improve the application of GSK-3 inhibitors to clinics. PMID- 23940674 TI - Prognostic value of CD166 expression in cancers of the digestive system: a systematic review and meta-analysis. AB - OBJECTIVE: Many studies have reported the prognostic predictive value of CD166 as a cancer stem cell marker in cancers of the digestive system; however, its predictive value remains controversial. Here, we investigate the correlation between CD166 positivity in digestive system cancers and clinicopathological features using meta-analysis. METHODS: A comprehensive search in PubMed and ISI Web of Science through March of 2013 was performed. Only articles containing CD166 antigen immunohistochemical staining in cancers of the digestive system were included,including pancreatic cancer, esophageal cancer, gastric cancer and colorectal cancer. Data comparing 3- and 5-year overall survival along with other clinicopathological features were collected. RESULTS: Nine studies with 2553 patients who met the inclusion criteria were included for the analysis. The median rate of CD166 immunohistochemical staining expression was 56% (25.4% 76.3%). In colorectal cancer specifically, the results of a fixed-effects model indicated that CD166-positive expression was an independent marker associated with a smaller tumor burden (T category; RR = 0.93, 95%, CI: 0.88-0.98) but worse spread to nearby lymph nodes (N category; RR = 1.17, 95% CI: 1.05-1.30). The 5 year overall survival rate was showed relationship with cytoplasmic positive staining of CD166 (RR = 1.47 95% 1.21-1.79), but no significant association was found in the pool or any other stratified analysis with 3- or 5- year overall survival rate. CONCLUSION: Based on the published studies, different cellular location of CD166 has distinct prognostic value and cytoplasmic positive expression is associated with worse prognosis outcome. Besides, our results also find CD166 expression indicate advanced T category and N-positive status in colorectal cancer specifically. PMID- 23940675 TI - Elderly men have low levels of anti-Mullerian hormone and inhibin B, but with high interpersonal variation: a cross-sectional study of the sertoli cell hormones in 615 community-dwelling men. AB - The Sertoli cells of the testes secrete anti-Mullerian hormone (Mullerian inhibiting Substance, AMH) and inhibin B (InhB). AMH triggers the degeneration of the uterine precursor in male embryos, whereas InhB is part of the gonadal pituitary axis for the regulation of sperm production in adults. However, both hormones are also putative regulators of homeostasis, and age-related changes in these hormones may therefore be important to the health status of elderly men. The levels of AMH in elderly men are unknown, with limited information being available about age-related changes in InhB. We have therefore used ELISAs to measure Sertoli cell hormone levels in 3 cohorts of community-dwelling men in New Zealand. In total, 615 men were examined, 493 of which were aged 65 or older. Serum AMH and InhB levels inversely correlated with age in men older than 50 years (p<0.001) but not in the younger men. A minority of elderly men had undetectable levels of AMH and InhB. The variation in hormone levels between similarly aged men increased with the age of men. AMH and InhB partially correlated with each other as expected (r = 0.48, p<0.001). However, the ratio of the two Sertoli hormones varied significantly between men, with this variation increasing with age. Elderly men selected for the absence of cardiovascular disease had AMH levels similar to those of young men whereas their InhB levels did not differ from aged-matched controls. These data suggests that Sertoli cell number and function changes with age, but with the extent and nature of the changes varying between men. PMID- 23940676 TI - The synergistic immunoregulatory effects of culture-expanded mesenchymal stromal cells and CD4(+)25(+)Foxp3+ regulatory T cells on skin allograft rejection. AB - Mesenchymal stromal cells (MSCs) are seen as an ideal source of cells to induce graft acceptance; however, some reports have shown that MSCs can be immunogenic rather than immunosuppressive. We speculate that the immunomodulatory effects of regulatory T cells (Tregs) can aid the maintenance of immunoregulatory functions of MSCs, and that a combinatorial approach to cell therapy can have synergistic immunomodulatory effects on allograft rejection. After preconditioning with Fludarabine, followed by total body irradiation and anti-asialo-GM-1(ASGM-1), tail skin grafts from C57BL/6 (H-2k(b)) mice were grafted onto the lateral thoracic wall of BALB/c (H-2k(d)) mice. Group A mice (control group, n = 9) did not receive any further treatment after preconditioning, whereas groups B and C (n = 9) received cell therapy with MSCs or Tregs, respectively, on days -1, +6 and +13 relative to the skin transplantation. Group D (n = 10) received cell therapy with MSCs and Tregs on days -1, +6 and +13. Cell suspensions were obtained from the spleens of five randomly chosen mice from each group on day +7, and the immunomodulatory effects of the cell therapy were evaluated by flow cytometry and real-time PCR. Our results show that allograft survival was significantly longer in group D compared to the control group (group A). Flow cytometric analysis and real-time PCR for splenocytes revealed that the Th2 subpopulation in group D increased significantly compared to the group B. Also, the expression of Foxp3 and STAT 5 increased significantly in group D compared to the conventional cell therapy groups (B and C). Taken together, these data suggest that a combined cell therapy approach with MSCs and Tregs has a synergistic effect on immunoregulatory function in vivo, and might provide a novel strategy for improving survival in allograft transplantation. PMID- 23940677 TI - Efficiency of household reactive case detection for malaria in rural Southern Zambia: simulations based on cross-sectional surveys from two epidemiological settings. AB - BACKGROUND: Case detection and treatment are critical to malaria control and elimination as infected individuals who do not seek medical care can serve as persistent reservoirs for transmission. METHODS: Household malaria surveys were conducted in two study areas within Southern Province, Zambia in 2007 and 2008. Cross-sectional surveys were conducted approximately five times throughout the year in each of the two study areas. During study visits, adults and caretakers of children were administered a questionnaire and a blood sample was obtained for a rapid diagnostic test (RDT) for malaria. These data were used to estimate the proportions of individuals with malaria potentially identified through passive case detection at health care facilities and those potentially identified through reactive case finding. Simulations were performed to extrapolate data from sampled to non-sampled households. Radii of increasing size surrounding households with an index case were examined to determine the proportion of households with an infected individual that would be identified through reactive case detection. RESULTS: In the 2007 high transmission setting, with a parasite prevalence of 23%, screening neighboring households within 500 meters of an index case could have identified 89% of all households with an RDT positive resident and 90% of all RDT positive individuals. In the 2008 low transmission setting, with a parasite prevalence of 8%, screening neighboring households within 500 meters of a household with an index case could have identified 77% of all households with an RDT positive resident and 76% of all RDT positive individuals. CONCLUSIONS: Testing and treating individuals residing within a defined radius from an index case has the potential to be an effective strategy to identify and treat a large proportion of infected individuals who do not seek medical care, although the efficiency of this strategy is likely to decrease with declining parasite prevalence. PMID- 23940678 TI - Phylogeographic pattern and extensive mitochondrial DNA divergence disclose a species complex within the Chagas disease vector Triatoma dimidiata. AB - BACKGROUND: Triatoma dimidiata is among the main vectors of Chagas disease in Latin America. However, and despite important advances, there is no consensus about the taxonomic status of phenotypically divergent T. dimidiata populations, which in most recent papers are regarded as subspecies. METHODOLOGY AND FINDINGS: A total of 126 cyt b sequences (621 bp long) were produced for specimens from across the species range. Forty-seven selected specimens representing the main cyt b clades observed (after a preliminary phylogenetic analysis) were also sequenced for an ND4 fragment (554 bp long) and concatenated with their respective cyt b sequences to produce a combined data set totalling 1175 bp/individual. Bayesian and Maximum-Likelihood phylogenetic analyses of both data sets (cyt b, and cyt b+ND4) disclosed four strongly divergent (all pairwise Kimura 2-parameter distances >0.08), monophyletic groups: Group I occurs from Southern Mexico through Central America into Colombia, with Ecuadorian specimens resembling Nicaraguan material; Group II includes samples from Western Southwestern Mexico; Group III comprises specimens from the Yucatan peninsula; and Group IV consists of sylvatic samples from Belize. The closely-related, yet formally recognized species T. hegneri from the island of Cozumel falls within the divergence range of the T. dimidiata populations studied. CONCLUSIONS: We propose that Groups I-IV, as well as T. hegneri, should be regarded as separate species. In the Peten of Guatemala, representatives of Groups I, II, and III occur in sympatry; the absence of haplotypes with intermediate genetic distances, as shown by multimodal mismatch distribution plots, clearly indicates that reproductive barriers actively promote within-group cohesion. Some sylvatic specimens from Belize belong to a different species - likely the basal lineage of the T. dimidiata complex, originated ~8.25 Mya. The evidence presented here strongly supports the proposition that T. dimidiata is a complex of five cryptic species (Groups I-IV plus T. hegneri) that play different roles as vectors of Chagas disease in the region. PMID- 23940679 TI - Hemocyte density increases with developmental stage in an immune-challenged forest caterpillar. AB - The cellular arm of the insect immune response is mediated by the activity of hemocytes. While hemocytes have been well-characterized morphologically and functionally in model insects, few studies have characterized the hemocytes of non-model insects. Further, the role of ontogeny in mediating immune response is not well understood in non-model invertebrate systems. The goals of the current study were to (1) determine the effects of caterpillar size (and age) on hemocyte density in naive caterpillars and caterpillars challenged with non-pathogenic bacteria, and (2) characterize the hemocyte activity and diversity of cell types present in two forest caterpillars: Euclea delphinii and Lithacodes fasciola (Limacodidae). We found that although early and late instar (small and large size, respectively) naive caterpillars had similar constitutive hemocyte densities in both species, late instar Lithacodes caterpillars injected with non pathogenic E. coli produced more than a twofold greater density of hemocytes than those in early instars. We also found that both caterpillar species contained plasmatocytes, granulocytes and oenocytoids, all of which are found in other lepidopteran species, but lacked spherulocytes. Granulocytes and plasmatocytes were found to be strongly phagocytic in both species, but granulocytes exhibited a higher phagocytic activity than plasmatocytes. Our results strongly suggest that for at least one measure of immunological response, the production of hemocytes in response to infection, response magnitudes can increase over ontogeny. While the underlying raison d' etre for this improvement remains unclear, these findings may be useful in explaining natural patterns of stage dependent parasitism and pathogen infection. PMID- 23940680 TI - Association between bone mineral density and incidence of breast cancer. AB - INTRODUCTION: Previous studies have suggested an inverse relationship between bone mineral density (BMD) and breast cancer incidence. The primary objective of this study was to assess whether BMD is associated with risk of subsequent breast cancer occurrence in the female population of southern Israel. METHODS: The electronic medical charts of women who underwent BMD at the Soroka Medical Center (SMC) between February 2003 and March 2011 were screened for subsequent breast cancer diagnoses. Women were divided by tertiles of BMD at 3 skeletal sites: lumbar spine (LS, L1-4), total hip (TH) and femoral neck (FN). The incidence of breast cancer was calculated. RESULTS: Of 15268 women who underwent BMD testing, 86 were subsequently diagnosed with breast cancer. Most women in the study were older than 50 years (94.2% and 92.7%, respectively; p = 0.597). Women who subsequently developed breast cancer had a higher mean body-mass index (BMI) (30.9 +/- 5.5 vs. 29.1 +/- 5.7 p = 0.004) and the mean BMD Z-score was significantly higher than in those without breast cancer for all 3 skeletal sites (LS: 0.36 +/- 1.58 vs. -0.12 +/- 1.42, p = 0.002; TH: 0.37 +/- 1.08 vs. 0.03 +/- 1.02, p = 0.002; FN: 0.04 +/- 0.99 vs. -0.18 +/- 0.94; p = 0.026). Women in the highest Z-score tertiles at the FN and TH had a higher chance of developing breast cancer compared to the lowest tertile; odds ratio of 2.15, 2.02, respectively (P = 0.004 and 0.01 respectively). No association was found between the BMD Z-score and the stage, histology, grade or survival from breast cancer. CONCLUSIONS: This study provides additional support for an inverse association between BMD and the risk of breast cancer. PMID- 23940681 TI - Correlation of cutaneous immunoreactants in lesional skin with the serological disorders and disease activity of systemic lupus erythematosus. AB - Detection of immunoreactants including IgG, IgM, IgA, and C3 by direct immunofluorescence (DIF) from skin is useful for distinguishing lupus lesions from other skin disorders. Despite their diagnostic value, the type and number of cutaneous immunoreactants as they relate to serological disorders and disease severity has been poorly studied. We examined 36 patients with systemic lupus erythematosis (SLE) with positive DIF (DIF+) and 28 patients with negative DIF (DIF-) tests performed on lesional skin. Among DIF+ patients, the most frequent patterns of immunoreactants were IgM alone (36%) and the coexistence of IgM with C3 (28%). IgM was the highest detected individual immunoreactant (86%). As classified by number, 17 of 36 DIF+ patients had one immunoreactant (= 1), while the remaining patients had two to four immunoreactants (>1). Compared with DIF- patients, DIF+ patients were more likely to have severe disease as indicated by lower serum C3 levels and a higher SLE disease activity index (SLEDAI). The coexistence of IgM with any other immunoreactants indicated a more severe disease than that present in the DIF- group, whereas the IgM-alone group was comparable with the DIF- group in both serum C3 levels and SLEDAI. These findings were also applicable in the comparison of patients with more than one (>1) immunoreactant and patients with no (DIF-) and one ( = 1) immunoreactant. Collectively, the presence of multiple immunoreactants in lesional skin implies a more severe disease activity of SLE, while a single immunoreactant may be equal to the absence of immunoreactants (DIF-) in terms of predicting disease activity. PMID- 23940682 TI - Targeted routine antenatal anti-D prophylaxis in the prevention of RhD immunisation--outcome of a new antenatal screening and prevention program. AB - OBJECTIVE: To estimate the incidence of RhD immunisation after implementation of first trimester non-invasive fetal RHD screening to select only RhD negative women carrying RHD positive fetuses for routine antenatal anti-D prophylaxis (RAADP). MATERIALS AND METHODS: We present a population-based prospective observational cohort study with historic controls including all maternity care centres and delivery hospitals in the Stockholm region, Sweden. All RhD negative pregnant women were screened for fetal RHD genotype in the first trimester of pregnancy. Anti-D immunoglobulin (250-300 ug) was administered intramuscularly in gestational week 28-30 to participants with RHD positive fetuses. Main outcome measure was the incidence of RhD immunisation developing during or after pregnancy. RESULTS: During the study period 9380 RhD negative women gave birth in Stockholm. Non-invasive fetal RHD genotyping using cell-free fetal DNA in maternal plasma was performed in 8374 pregnancies of which 5104 (61%) were RHD positive and 3270 (39%) RHD negative. In 4590 pregnancies with an RHD positive test the women received antenatal anti-D prophylaxis. The incidence of RhD immunisation in the study cohort was 0.26 percent (24/9380) (95% CI 0.15-0.36%) compared to 0.46 percent (86/18546) (95% CI 0.37 to 0.56%) in the reference cohort. The risk ratio (RR) for sensitisation was 0.55 (95% CI 0.35 to 0.87) and the risk reduction was statistically significant (p = 0.009). The absolute risk difference was 0.20 percent, corresponding to a number needed to treat (NNT) of 500. CONCLUSIONS: Using first trimester non-invasive antenatal screening for fetal RHD to target routine antenatal anti-D prophylaxis selectively to RhD negative women with RHD positive fetuses significantly reduces the incidence of new RhD immunisation. The risk reduction is comparable to that reported in studies evaluating the outcome of non selective RAADP to all RhD negative women. The cost-effectiveness of this targeted approach remains to be studied. PMID- 23940683 TI - Consideration of chronic pain in trials to promote physical activity for diabetes: a systematic review of randomized controlled trials. AB - BACKGROUND: Chronic pain has been estimated to affect 60% of patients with diabetes and is strongly associated with reduced activity tolerance. We systematically reviewed randomized controlled trials (RCTs) that explored interventions to improve physical activity among patients with diabetes to establish whether co-morbid chronic pain was captured at baseline or explored as an effect modifier and if trials reported a component designed to target chronic pain. METHODOLOGY/PRINCIPAL FINDINGS: We searched CINAHL, Cochrane Central Registry of Controlled Trials, EMBASE, ERIC, MEDLINE, SPORTDiscus and PsycInfo from inception of each database to March 2012 for RCTs that enrolled patients with diabetes and randomly assigned them to an intervention designed to promote physical activity. Two reviewers independently selected trials and abstracted data. We identified 136 trials meeting our inclusion criteria, only one of which that reported capturing chronic pain measures at baseline. No trial reported on specific interventions to address chronic pain as a competing demand, or as an effect modifier. CONCLUSION/SIGNIFICANCE: Only 1 trial identified that aimed to promote physical activity among patients with diabetes reported that co-morbid chronic pain was captured at baseline. No trials reported exploring chronic pain as an effect modifier or targeting it as part of its intervention. PMID- 23940684 TI - Exposure of clinical MRSA heterogeneous strains to beta-lactams redirects metabolism to optimize energy production through the TCA cycle. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as one of the most important pathogens both in health care and community-onset infections. The prerequisite for methicillin resistance is mecA, which encodes a beta-lactam insensitive penicillin binding protein PBP2a. A characteristic of MRSA strains from hospital and community associated infections is their heterogeneous expression of resistance to beta-lactam (HeR) in which only a small portion (<= 0.1%) of the population expresses resistance to oxacillin (OXA) >= 10 ug/ml, while in other isolates, most of the population expresses resistance to a high level (homotypic resistance, HoR). The mechanism associated with heterogeneous expression requires both increase expression of mecA and a mutational event that involved the triggering of a beta-lactam-mediated SOS response and related lexA and recA genes. In the present study we investigated the cellular physiology of HeR-MRSA strains during the process of beta-lactam-mediated HeR/HoR selection at sub-inhibitory concentrations by using a combinatorial approach of microarray analyses and global biochemical profiling employing gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) to investigate changes in metabolic pathways and the metabolome associated with beta lactam-mediated HeR/HoR selection in clinically relevant heterogeneous MRSA. We found unique features present in the oxacillin-selected SA13011-HoR derivative when compared to the corresponding SA13011-HeR parental strain that included significant increases in tricarboxyl citric acid (TCA) cycle intermediates and a concomitant decrease in fermentative pathways. Inactivation of the TCA cycle enzyme cis-aconitase gene in the SA13011-HeR strain abolished beta-lactam mediated HeR/HoR selection demonstrating the significance of altered TCA cycle activity during the HeR/HoR selection. These results provide evidence of both the metabolic cost and the adaptation that HeR-MRSA clinical strains undergo when exposed to beta-lactam pressure, indicating that the energy production is redirected to supply the cell wall synthesis/metabolism, which in turn contributes to the survival response in the presence of beta-lactam antibiotics. PMID- 23940685 TI - A cellular pathway involved in Clara cell to alveolar type II cell differentiation after severe lung injury. AB - Regeneration of alveolar epithelia following severe pulmonary damage is critical for lung function. We and others have previously shown that Scgb1a1-expressing cells, most likely Clara cells, can give rise to newly generated alveolar type 2 cells (AT2s) in response to severe lung damage induced by either influenza virus infection or bleomycin treatment. In this study, we have investigated cellular pathway underlying the Clara cell to AT2 differentiation. We show that the initial intermediates are bronchiolar epithelial cells that exhibit Clara cell morphology and express Clara cell marker, Scgb1a1, as well as the AT2 cell marker, pro-surfactant protein C (pro-SPC). These cells, referred to as pro SPC(+) bronchiolar epithelial cells (or SBECs), gradually lose Scgb1a1 expression and give rise to pro-SPC(+) cells in the ring structures in the damaged parenchyma, which appear to differentiate into AT2s via a process sharing some features with that observed during alveolar epithelial development in the embryonic lung. These findings suggest that SBECs are intermediates of Clara cell to AT2 differentiation during the repair of alveolar epithelia following severe pulmonary injury. PMID- 23940686 TI - Role of DNA methylation in cell cycle arrest induced by Cr (VI) in two cell lines. AB - Hexavalent chromium [Cr(IV)], a well-known industrial waste product and an environmental pollutant, is recognized as a human carcinogen. But its mechanisms of carcinogenicity remain unclear, and recent studies suggest that DNA methylation may play an important role in the carcinogenesis of Cr(IV). The aim of our study was to investigate the effects of Cr(IV) on cell cycle progress, global DNA methylation, and DNA methylation of p16 gene. A human B lymphoblastoid cell line and a human lung cell line A549 were exposed to 5-15 uM potassium dichromate or 1.25-5 ug/cm2 lead chromate for 2-24 hours. Cell cycle was arrested at G1 phase by both compounds in 24 hours exposure group, but global hypomethylation occurred earlier than cell cycle arrest, and the hypomethylation status maintained for more than 20 hours. The mRNA expression of p16 was significantly up-regulated by Cr(IV), especially by potassium dichromate, and the mRNA expression of cyclin-dependent kinases (CDK4 and CDK6) was significantly down-regulated. But protein expression analysis showed very little change of p16 gene. Both qualitative and quantitative results showed that DNA methylation status of p16 remained unchanged. Collectively, our data suggested that global hypomethylation was possibly responsible for Cr(IV)-induced G1 phase arrest, but DNA methylation might not be related to up-regulation of p16 gene by Cr(IV). PMID- 23940687 TI - Immuno-regulatory function of indoleamine 2,3 dioxygenase through modulation of innate immune responses. AB - Successful long-term treatment of type-1 diabetes mainly relies on replacement of beta-cells via islet transplantation. Donor shortage is one of the main obstacles preventing transplantation from becoming the treatment of choice. Although animal organs could be an alternative source for transplantation, common immunosuppressive treatments demonstrate low efficacy in preventing xenorejection. Immunoprotective effects of indoleamine 2,3-dioxygenase (IDO) on T cell mediated allorejection has been extensively studied. Our studies revealed that IDO expression by fibroblasts, induced apoptosis in T-cells while not affecting non-immune cell survival/function. Since macrophages play a pivotal role in xenograft rejection, herein we investigated the effect of IDO-induced tryptophan deficiency/kynurenine accumulation on macrophage function/survival. Moreover, we evaluated the local immunosuppressive effect of IDO on islet xenograft protection. Our results indicated that IDO expression by bystander fibroblasts significantly reduced the viability of primary macrophages via apoptosis induction. Treatment of peritoneal macrophages by IDO-expressing fibroblast conditioned medium significantly reduced their proinflammatory activity through inhibition of iNOS expression. To determine whether IDO-induced tryptophan starvation or kynurenine accumulation is responsible for macrophage apoptosis and inhibition of their proinflammatory activity, Raw264.7 cell viability and proinflammatory responses were evaluated in tryptophan deficient medium or in the presence of kynurenine. Tryptophan deficiency, but not kynurenine accumulation, reduced Raw264.7 cell viability and suppressed their proinflammatory activity. Next a three-dimensional islet-xenograft was engineered by embedding rat islets within either control or IDO-expressing fibroblast populated collagen matrix. Islets morphology and immune cell infiltration were then studied in the xenografts transplanted into the C57BL/6 mouse renal sub capsular space. Local IDO significantly decreased the number of infiltrating macrophages (11 +/- 1.47 vs. 70.5 +/- 7.57 cells/HPF), T-cells (8.75 +/- 1.03 vs. 75.75 +/- 5.72 cells/HPF) and iNOS expression in IDO-expressing xenografts versus controls. Islet morphology remained intact in IDO-expressing grafts and islets were strongly stained for insulin/glucagon compared to control. These findings support the immunosuppressive role of IDO on macrophage-mediated xeno-rejection. PMID- 23940688 TI - Adverse drug events in older hospitalized patients: results and reliability of a comprehensive and structured identification strategy. AB - BACKGROUND: Older patients are at high risk for experiencing Adverse Drug Events (ADEs) during hospitalization. To be able to reduce ADEs in these vulnerable patients, hospitals first need to measure the occurrence of ADEs, especially those that are preventable. However, data on preventable ADEs (pADEs) occurring during hospitalization in older patients are scarce, and no 'gold standard' for the identification of ADEs exists. METHODOLOGY: The study was conducted in three hospitals in the Netherlands in 2007. ADEs were retrospectively identified by a team of experts using a comprehensive and structured patient chart review (PCR) combined with a trigger-tool as an aid. This ADE identification strategy was applied to a cohort of 250 older hospitalized patients. To estimate the intra- and inter-rater reliabilities, Cohen's kappa values were calculated. PRINCIPAL FINDINGS: In total, 118 ADEs were detected which occurred in 62 patients. This ADE yield was 1.1 to 2.7 times higher in comparison to other ADE studies in older hospitalized patients. Of the 118 ADEs, 83 (70.3%) were pADEs; 51 pADEs (43.2% of all ADEs identified) caused serious patient harm. Patient harm caused by ADEs resulted in various events. The overall intra-rater agreement of the developed strategy was substantial (kappa = 0.74); the overall inter-rater agreement was only fair (kappa = 0.24). CONCLUSIONS/SIGNIFICANCE: The ADE identification strategy provided a detailed insight into the scope of ADEs occurring in older hospitalized patients, and showed that the majority of (serious) ADEs can be prevented. Several strategy related aspects, as well as setting/study specific aspects, may have contributed to the results gained. These aspects should be considered whenever ADE measurements need to be conducted. The results regarding pADEs can be used to design tailored interventions to effectively reduce harm caused by medication errors. Improvement of the inter-rater reliability of a PCR remains challenging. PMID- 23940689 TI - Excess mortality and long-term disability from healthcare-associated staphylococcus aureus infections: a population-based matched cohort study. AB - BACKGROUND: Staphylococcus aureus is a leading cause of healthcare-associated infections (HAIs), but the impact of S. aureus HAIs on the long-term survival and functional status of hospitalized patients remain unknown. This study aimed to examine whether S. aureus HAIs increase the risks for long-term mortality and disability. METHODS: We conducted a retrospective population-based matched cohort study of inpatients at 8 medical centers, 43 regional hospitals, and 63 local hospitals which participated in the Taiwan Nosocomial Infection Surveillance (TNIS). We individually matched 3070 patients with S. aureus HAIs to 6140 inpatients without HAIs at a 1?2 ratio by age, gender, hospital, specialty, underlying diseases, and the length of stay before onset of the S. aureus HAI. Main outcome measures are one-year excess risks for mortality, new-onset chronic ventilator dependence, and new-onset dialysis-dependent end-stage renal disease. RESULTS: We found that patients with S. aureus HAIs had an excess one-year mortality of 20.2% compared with matched uninfected inpatients (P<0.001). The excess risk for new-onset chronic ventilator dependence and dialysis-dependent end-stage renal disease was 7.3% and 2.6%, respectively (Ps<0.001). S. aureus HAIs were also associated with an excess hospital stay of 12 days and an extra cost of $5978 (Ps<0.001). CONCLUSION: S. aureus HAIs have substantial negative effect on the long-term outcome of hospitalized patients in terms of both mortality and disability, which should be taken into consideration in future cost effectiveness studies of the control and prevention interventions for S. aureus HAIs. PMID- 23940690 TI - Single administration of tripeptide alpha-MSH(11-13) attenuates brain damage by reduced inflammation and apoptosis after experimental traumatic brain injury in mice. AB - Following traumatic brain injury (TBI) neuroinflammatory processes promote neuronal cell loss. Alpha-melanocyte-stimulating hormone (alpha-MSH) is a neuropeptide with immunomodulatory properties, which may offer neuroprotection. Due to short half-life and pigmentary side-effects of alpha-MSH, the C-terminal tripeptide alpha-MSH(11-13) may be an anti-inflammatory alternative. The present study investigated the mRNA concentrations of the precursor hormone proopiomelanocortin (POMC) and of melanocortin receptors 1 and 4 (MC1R/MC4R) in naive mice and 15 min, 6, 12, 24, and 48 h after controlled cortical impact (CCI). Regulation of POMC and MC4R expression did not change after trauma, while MC1R levels increased over time with a 3-fold maximum at 12 h compared to naive brain tissue. The effect of alpha-MSH(11-13) on secondary lesion volume determined in cresyl violet stained sections (intraperitoneal injection 30 min after insult of 1 mg/kg alpha-MSH(11-13) or 0.9% NaCl) showed a considerable smaller trauma in alpha-MSH(11-13) injected mice. The expression of the inflammatory markers TNF-alpha and IL-1beta as well as the total amount of Iba-1 positive cells were not reduced. However, cell branch counting of Iba-1 positive cells revealed a reduced activation of microglia. Furthermore, tripeptide injection reduced neuronal apoptosis analyzed by cleaved caspase-3 and NeuN staining. Based on the results single alpha-MSH(11-13) administration offers a promising neuroprotective property by modulation of inflammation and prevention of apoptosis after traumatic brain injury. PMID- 23940691 TI - A human in vitro whole blood assay to predict the systemic cytokine response to therapeutic oligonucleotides including siRNA. AB - Therapeutic oligonucleotides including siRNA and immunostimulatory ligands of Toll-like receptors (TLR) or RIG-I like helicases (RLH) are a promising novel class of drugs. They are in clinical development for a broad spectrum of applications, e.g. as adjuvants in vaccines and for the immunotherapy of cancer. Species-specific immune activation leading to cytokine release is characteristic for therapeutic oligonucleotides either as an unwanted side effect or intended pharmacology. Reliable in vitro tests designed for therapeutic oligonucleotides are therefore urgently needed in order to predict clinical efficacy and to prevent unexpected harmful effects in clinical development. To serve this purpose, we here established a human whole blood assay (WBA) that is fast and easy to perform. Its response to synthetic TLR ligands (R848: TLR7/8, LPS: TLR4) was on a comparable threshold to the more time consuming peripheral blood mononuclear cell (PBMC) based assay. By contrast, the type I IFN profile provoked by intravenous CpG-DNA (TLR9 ligand) in humans in vivo was more precisely replicated in the WBA than in stimulated PBMC. Since Heparin and EDTA, but not Hirudin, displaced oligonucleotides from their delivery agent, only Hirudin qualified as the anticoagulant to be used in the WBA. The Hirudin WBA exhibited a similar capacity as the PBMC assay to distinguish between TLR7-activating and modified non-stimulatory siRNA sequences. RNA-based immunoactivating TLR7/8- and RIG-I-ligands induced substantial amounts of IFN-alpha in the Hirudin-WBA dependent on delivery agent used. In conclusion, we present a human Hirudin WBA to determine therapeutic oligonucleotide-induced cytokine release during preclinical development that can readily be performed and offers a close reflection of human cytokine response in vivo. PMID- 23940692 TI - CD44 gene polymorphisms in breast cancer risk and prognosis: a study in North Indian population. AB - BACKGROUND: Cell surface biomarker CD44 plays an important role in breast cancer cell growth, differentiation, invasion, angiogenesis and tumour metastasis. Therefore, we aimed to investigate the role of CD44 gene polymorphisms in breast cancer risk and prognosis in North Indian population. MATERIALS & METHODS: A total of 258 breast cancer patients and 241 healthy controls were included in the case-control study for risk prediction. According to RECIST, 114 patients who received neo-adjuvant chemotherapy were recruited for the evaluation of breast cancer prognosis. We examined the association of tagging SNP (rs353639) of Hapmap Gujrati Indians in Houston (GIH population) in CD44 gene along with a significant reported SNP (rs13347) in Chinese population by genotyping using Taqman allelic discrimination assays. Statistical analysis was done using SPSS software, version 17. In-silico analysis for prediction of functional effects was done using F-SNP and FAST-SNP. RESULTS: No significant association of both the genetic variants of the CD44 gene polymorphisms was found with breast cancer risk. On performing univariate analysis with clinicopathological characteristics and treatment response, we found significant association of genotype (CT+TT) of rs13347 polymorphism with earlier age of onset (P = 0.029, OR = 0.037). However, significance was lost in multivariate analysis. For rs353639 polymorphism, significant association was seen with clinical tumour size, both at the genotypic (AC+CC) (P = 0.039, OR = 3.02) as well as the allelic (C) (P = 0.042, OR = 2.87) levels. On performing multivariate analysis, increased significance of variant genotype (P = 0.017, OR = 4.29) and allele (P = 0.025, OR = 3.34) of rs353639 was found with clinical tumour size. In-silico analysis using F-SNP, showed altered transcriptional regulation for rs353639 polymorphism. CONCLUSIONS: These findings suggest that CD44 rs353639 genetic variants may have significant effect in breast cancer prognosis. However, both the polymorphisms- rs13347 and rs353639 had no effect on breast cancer susceptibility. PMID- 23940693 TI - Heparin-binding haemagglutinin, a new tool for the detection of latent Mycobacterium tuberculosis infection in hemodialysis patients. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) and latently infected with Mycobacterium tuberculosis (LTBI) are at higher risk to develop tuberculosis (TB) than healthy subjects. Interferon-gamma release assays (IGRAs) were reported to be more sensitive than tuberculin skin tests for the detection of infected individuals in dialysis patients. METHODS: On 143 dialysis patients prospectively enrolled, we compared the results from the QuantiFERON(r)-TB Gold assay (QFT), to those of an IGRA in response to in vitro stimulation of circulating mononuclear cells with the mycobacterial latency antigen Heparin-Binding Haemagglutinin purified from Mycobacterium bovis BCG (native HBHA, nHBHA). RESULTS: Seven patients had a past history of active TB and 1 had an undetermined result with both IGRAs. Among the other 135 patients, 94 had concordant results with the QFT and nHBHA-IGRA, 40.0% being negative and therefore not latently infected, and 29.6% being positive and thus LTBI. Discrepant results between these tests were found for 36 patients positive only with the nHBHA-IGRA and 5 only with the QFT. CONCLUSIONS: The nHBHA-IGRA is more sensitive than the QFT for the detection of LTBI dialysis patients, and follow-up of the patients will allow us to define the clinical significance of discrepant results between the nHBHA-IGRA and the QFT. PMID- 23940694 TI - A high diet quality is associated with lower incidence of cardiovascular events in the Malmo diet and cancer cohort. AB - AIMS: To investigate if diet quality is related to incidence of cardiovascular (CV) events. SUBJECTS AND METHODS: A diet quality index based on the 2005 Swedish Nutrition Recommendations and the Swedish Dietary Guidelines was created and included six dietary components: saturated fatty acids, polyunsaturated fatty acids, fish and shellfish, dietary fiber, fruit and vegetables, and sucrose. The index ranked 17126 participants (59% women) of the population-based Malmo Diet and Cancer cohort (Sweden) on their dietary intakes. Total index score was categorized as low, medium or high. Cox proportional hazard regression was used to model associations between index score categories and index components with risk of incident CV events, with adjustment for potential confounders. The incidence of first CV events (non-fatal or fatal myocardial infarction or ischemic stroke or death from ischemic heart disease) was monitored from baseline (1991-1996) until December 31, 2008; 703 CV events occurred in women and 1093 in men. RESULTS: A high diet quality was associated with decreased risk of CV events when compared to a low diet quality. In multivariate analysis, the risk reduction was 32% (hazard ratio = 0.68, 95% confidence interval: 0.49-0.73) in men and 27% (hazard ratio = 0.73, 95% confidence interval: 0.59-0.91) in women. When examined separately and mutually adjusted for each other, the individual components were either not associated with CV risk or marginally decreased risks were seen. CONCLUSION: High quality diets in line with current recommendations may reduce the risk of CV events. This study illustrates the importance of considering a combination of dietary factors when evaluating diet-disease associations. PMID- 23940695 TI - Prolonged treatment with DNMT inhibitors induces distinct effects in promoters and gene-bodies. AB - Treatment with the demethylating drugs 5-azacytidine (AZA) and decitabine (DAC) is now recognised as an effective therapy for patients with Myelodysplastic Syndromes (MDS), a range of disorders arising in clones of hematopoietic progenitor cells. A variety of cell models have been used to study the effect of these drugs on the methylation of promoter regions of tumour suppressor genes, with recent efforts focusing on the ability of these drugs to inhibit DNA methylation at low doses. However, it is still not clear how nano-molar drug treatment exerts its effects on the methylome. In this study, we have characterised changes in DNA methylation caused by prolonged low-dose treatment in a leukemic cell model (SKM-1), and present a genome-wide analysis of the effects of AZA and DAC. At nano-molar dosages, a one-month continuous treatment halved the total number of hypermethylated probes in leukemic cells and our analysis identified 803 candidate regions with significant demethylation after treatment. Demethylated regions were enriched in promoter sequences whereas gene body CGIs were more resistant to the demethylation process. CGI methylation in promoters was strongly correlated with gene expression but this correlation was lost after treatment. Our results indicate that CGI demethylation occurs preferentially at promoters, but that it is not generally sufficient to modify expression patterns, and emphasises the roles of other means of maintaining cell state. PMID- 23940696 TI - Proteome of human stem cells from periodontal ligament and dental pulp. AB - BACKGROUND: Many adult tissues contain a population of stem cells with the ability to regenerate structures similar to the microenvironments from which they are derived in vivo and represent a promising therapy for the regeneration of complex tissues in the clinical disorder. Human adult stem cells (SCs) including bone marrow stem cells (BMSCs), dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) have been characterized for their high proliferative potential, expression of characteristic SC-associated markers and for the plasticity to differentiate in different lineage in vitro. METHODOLOGY/PRINCIPAL FINDINGS: The aim of this study is to define the molecular features of stem cells from oral tissue by comparing the proteomic profiles obtained with 2-DE followed by MALDI-TOF/TOF of ex-vivo cultured human PDLSCs, DPSCs and BMSCs. Our results showed qualitative similarities in the proteome profiles among the SCs examined including some significant quantitative differences. To enrich the knowledge of oral SCs proteome we performed an analysis in narrow range pH 4-7 and 6-9, and we found that DPSCs vs PDLSCs express differentially regulated proteins that are potentially related to growth, regulation and genesis of neuronal cells, suggesting that SCs derived from oral tissue source populations may possess the potential ability of neuronal differentiation which is very consistent with their neural crest origin. CONCLUSION/SIGNIFICANCE: This study identifies some differentially expressed proteins by using comparative analysis between DPSCs and PDLSCs and BMSCs and suggests that stem cells from oral tissue could have a different cell lineage potency compared to BMSCs. PMID- 23940697 TI - Communicating risk to aboriginal peoples: first nations and Metis responses to H1N1 risk messages. AB - Developing appropriate risk messages during challenging situations like public health outbreaks is complicated. The focus of this paper is on how First Nations and Metis people in Manitoba, Canada, responded to the public health management of pandemic H1N1, using a focus group methodology (n = 23 focus groups). Focus group conversations explored participant reactions to messaging regarding the identification of H1N1 virus risk groups, the H1N1 vaccine and how priority groups to receive the vaccine were established. To better contextualize the intentions of public health professionals, key informant interviews (n = 20) were conducted with different health decision makers (e.g., public health officials, people responsible for communications, representatives from some First Nations and Metis self-governing organizations). While risk communication practice has improved, 'one size' messaging campaigns do not work effectively, particularly when communicating about who is most 'at-risk'. Public health agencies need to pay more attention to the specific socio-economic, historical and cultural contexts of First Nations and Metis citizens when planning for, communicating and managing responses associated with pandemic outbreaks to better tailor both the messages and delivery. More attention is needed to directly engage First Nations and Metis communities in the development and dissemination of risk messaging. PMID- 23940698 TI - A novel support vector machine-based approach for rare variant detection. AB - Advances in next-generation sequencing technologies have enabled the identification of multiple rare single nucleotide polymorphisms involved in diseases or traits. Several strategies for identifying rare variants that contribute to disease susceptibility have recently been proposed. An important feature of many of these statistical methods is the pooling or collapsing of multiple rare single nucleotide variants to achieve a reasonably high frequency and effect. However, if the pooled rare variants are associated with the trait in different directions, then the pooling may weaken the signal, thereby reducing its statistical power. In the present paper, we propose a backward support vector machine (BSVM)-based variant selection procedure to identify informative disease associated rare variants. In the selection procedure, the rare variants are weighted and collapsed according to their positive or negative associations with the disease, which may be associated with common variants and rare variants with protective, deleterious, or neutral effects. This nonparametric variant selection procedure is able to account for confounding factors and can also be adopted in other regression frameworks. The results of a simulation study and a data example show that the proposed BSVM approach is more powerful than four other approaches under the considered scenarios, while maintaining valid type I errors. PMID- 23940699 TI - Month 2 culture status and treatment duration as predictors of tuberculosis relapse risk in a meta-regression model. AB - BACKGROUND: New drugs and regimens with the potential to transform tuberculosis treatment are presently in early stage clinical trials. OBJECTIVE: The goal of the present study was to infer the required duration of these treatments. METHOD: A meta-regression model was developed to predict relapse risk using treatment duration and month 2 sputum culture positive rate as predictors, based on published historical data from 24 studies describing 58 regimens in 7793 patients. Regimens in which rifampin was administered for the first 2 months but not subsequently were excluded. The model treated study as a random effect. RESULTS: The model predicted that new regimens of 4 or 5 months duration with rates of culture positivity after 2 months of 1% or 3%, would yield relapse rates of 4.0% or 4.1%, respectively. In both cases, the upper limit of the 2-sided 80% prediction interval for relapse for a hypothetical trial with 680 subjects per arm was <10%. Analysis using this model of published month 2 data for moxifloxacin-containing regimens indicated they would result in relapse rates similar to standard therapy only if administered for >=5 months. CONCLUSIONS: This model is proposed to inform the required duration of treatment of new TB regimens, potentially hastening their accelerated approval by several years. PMID- 23940700 TI - Integrating evolution into ecological modelling: accommodating phenotypic changes in agent based models. AB - Evolutionary change is a characteristic of living organisms and forms one of the ways in which species adapt to changed conditions. However, most ecological models do not incorporate this ubiquitous phenomenon. We have developed a model that takes a 'phenotypic gambit' approach and focuses on changes in the frequency of phenotypes (which differ in timing of breeding and fecundity) within a population, using, as an example, seasonal breeding. Fitness per phenotype calculated as the individual's contribution to population growth on an annual basis coincide with the population dynamics per phenotype. Simplified model variants were explored to examine whether the complexity included in the model is justified. Outputs from the spatially implicit model underestimated the number of individuals across all phenotypes. When no phenotype transitions are included (i.e. offspring always inherit their parent's phenotype) numbers of all individuals are always underestimated. We conclude that by using a phenotypic gambit approach evolutionary dynamics can be incorporated into individual based models, and that all that is required is an understanding of the probability of offspring inheriting the parental phenotype. PMID- 23940701 TI - The curcumin analog EF24 targets NF-kappaB and miRNA-21, and has potent anticancer activity in vitro and in vivo. AB - EF24 is a curcumin analog that has improved anticancer activity over curcumin, but its therapeutic potential and mechanism of action is unknown, which is important to address as curcumin targets multiple signaling pathways. EF24 inhibits the NF-kappaB but not the JAK-STAT signaling pathway in DU145 human prostate cancer cells and B16 murine melanoma cells. EF24 induces apoptosis in these cells apparently by inhibiting miR-21 expression, and also enhances the expression of several miR-21 target genes, PTEN and PDCD4. EF24 treatment significantly suppressed the growth of DU145 prostate cancer xenografts in immunocompromised mice and resulted in tumor regression. EF24 enhanced the expression of the miR-21 target PTEN in DU145 tumor tissue, but suppressed the expression of markers of proliferating cells (cyclin D1 and Ki67). In syngeneic mice injected with B16 cells, EF24 treatment inhibited the formation of lung metastasis, prolonged animal survival, inhibited miR-21 expression and increased the expression of miR-21 target genes. Expression profiling of miRNAs regulated by EF24 in vitro and in vivo showed that the antitumor activity of EF24 reflected the enhanced expression of potential tumor suppressor miRNAs as well as the suppressed expression of oncogenic miRNAs, including miR-21. Taken together, our data suggest that EF24 is a potent anticancer agent and selectively targets NF kappaB signaling and miRNA expression, indicating that EF24 has significant potential as a therapeutic agent in various cancers. PMID- 23940703 TI - Developing transgenic Jatropha using the SbNHX1 gene from an extreme halophyte for cultivation in saline wasteland. AB - Jatropha is an important second-generation biofuel plant. Salinity is a major factor adversely impacting the growth and yield of several plants including Jatropha. SbNHX1 is a vacuolar Na+/H+ antiporter gene that compartmentalises excess Na+ ions into the vacuole and maintains ion homeostasis. We have previously cloned and characterised the SbNHX1 gene from an extreme halophyte, Salicornia brachiata. Transgenic plants of Jatropha curcas with the SbNHX1 gene were developed using microprojectile bombardment mediated transformation. Integration of the transgene was confirmed by PCR and Rt-PCR and the copy number was determined by real time qPCR. The present study of engineering salt tolerance in Jatropha is the first report to date. Salt tolerance of the transgenic lines JL2, JL8 and JL19 was confirmed by leaf senescence assay, chlorophyll estimation, plant growth, ion content, electrolyte leakage and malondialdehyde (MDA) content analysis. Transgenic lines showed better salt tolerance than WT up to 200 mM NaCl. Imparting salt tolerance to Jatropha using the SbNHX1 gene may open up the possibility of cultivating it in marginal salty land, releasing arable land presently under Jatropha cultivation for agriculture purposes. Apart from this, transgenic Jatropha can be cultivated with brackish water, opening up the possibility of sustainable cultivation of this biofuel plant in salty coastal areas. PMID- 23940702 TI - Frequent intra-subtype recombination among HIV-1 circulating in Tanzania. AB - The study estimated the prevalence of HIV-1 intra-subtype recombinant variants among female bar and hotel workers in Tanzania. While intra-subtype recombination occurs in HIV-1, it is generally underestimated. HIV-1 env gp120 V1-C5 quasispecies from 45 subjects were generated by single-genome amplification and sequencing (median (IQR) of 38 (28-50) sequences per subject). Recombination analysis was performed using seven methods implemented within the recombination detection program version 3, RDP3. HIV-1 sequences were considered recombinant if recombination signals were detected by at least three methods with p-values of <=0.05 after Bonferroni correction for multiple comparisons. HIV-1 in 38 (84%) subjects showed evidence for intra-subtype recombination including 22 with HIV-1 subtype A1, 13 with HIV-1 subtype C, and 3 with HIV-1 subtype D. The distribution of intra-patient recombination breakpoints suggested ongoing recombination and showed selective enrichment of recombinant variants in 23 (60%) subjects. The number of subjects with evidence of intra-subtype recombination increased from 29 (69%) to 36 (82%) over one year of follow-up, although the increase did not reach statistical significance. Adjustment for intra-subtype recombination is important for the analysis of multiplicity of HIV infection. This is the first report of high prevalence of intra-subtype recombination in the HIV/AIDS epidemic in Tanzania, a region where multiple HIV-1 subtypes co-circulate. HIV-1 intra subtype recombination increases viral diversity and presents additional challenges for HIV-1 vaccine design. PMID- 23940704 TI - Requirement for the eIF4E binding proteins for the synergistic down-regulation of protein synthesis by hypertonic conditions and mTOR inhibition. AB - The protein kinase mammalian target of rapamycin (mTOR) regulates the phosphorylation and activity of several proteins that have the potential to control translation, including p70S6 kinase and the eIF4E binding proteins 4E-BP1 and 4E-BP2. In spite of this, in exponentially growing cells overall protein synthesis is often resistant to mTOR inhibitors. We report here that sensitivity of wild-type mouse embryonic fibroblasts (MEFs) to mTOR inhibitors can be greatly increased when the cells are subjected to the physiological stress imposed by hypertonic conditions. In contrast, protein synthesis in MEFs with a double knockout of 4E-BP1 and 4E-BP2 remains resistant to mTOR inhibitors under these conditions. Phosphorylation of p70S6 kinase and protein kinase B (Akt) is blocked by the mTOR inhibitor Ku0063794 equally well in both wild-type and 4E-BP knockout cells, under both normal and hypertonic conditions. The response of protein synthesis to hypertonic stress itself does not require the 4E-BPs. These data suggest that under certain stress conditions: (i) translation has a greater requirement for mTOR activity and (ii) there is an absolute requirement for the 4E-BPs for regulation by mTOR. Importantly, dephosphorylation of p70S6 kinase and Akt is not sufficient to affect protein synthesis acutely. PMID- 23940705 TI - Sarcoptes scabiei mites modulate gene expression in human skin equivalents. AB - The ectoparasitic mite, Sarcoptes scabiei that burrows in the epidermis of mammalian skin has a long co-evolution with its hosts. Phenotypic studies show that the mites have the ability to modulate cytokine secretion and expression of cell adhesion molecules in cells of the skin and other cells of the innate and adaptive immune systems that may assist the mites to survive in the skin. The purpose of this study was to identify genes in keratinocytes and fibroblasts in human skin equivalents (HSEs) that changed expression in response to the burrowing of live scabies mites. Overall, of the more than 25,800 genes measured, 189 genes were up-regulated >2-fold in response to scabies mite burrowing while 152 genes were down-regulated to the same degree. HSEs differentially expressed large numbers of genes that were related to host protective responses including those involved in immune response, defense response, cytokine activity, taxis, response to other organisms, and cell adhesion. Genes for the expression of interleukin-1alpha (IL-1alpha) precursor, IL-1beta, granulocyte/macrophage-colony stimulating factor (GM-CSF) precursor, and G-CSF precursor were up-regulated 2.8- to 7.4-fold, paralleling cytokine secretion profiles. A large number of genes involved in epithelium development and keratinization were also differentially expressed in response to live scabies mites. Thus, these skin cells are directly responding as expected in an inflammatory response to products of the mites and the disruption of the skin's protective barrier caused by burrowing. This suggests that in vivo the interplay among these skin cells and other cell types, including Langerhans cells, dendritic cells, lymphocytes and endothelial cells, is responsible for depressing the host's protective response allowing these mites to survive in the skin. PMID- 23940706 TI - Optic neuritis is associated with inner nuclear layer thickening and microcystic macular edema independently of multiple sclerosis. AB - BACKGROUND: Microcystic macular edema (MME) and inner nuclear layer thickening (INL) were described in multiple sclerosis (MS) and neuromyelitis optica (NMO) patients using optical coherence tomography (OCT). The cause of these findings is currently unknown and a relation to inflammatory or degenerative processes in the optic nerve is discussed. OBJECTIVE: The aim of our study was to investigate whether INL thickening and MME are related to optic neuritis (ON) in various neuro-inflammatory disorders causingON: MS, NMO and chronic inflammatory optic neuropathy. METHODS: We retrospectively analyzed data from 216 MS patients, 39 patients with a clinically isolated syndrome, 20 NMO spectrum disorder patients, 9 patients with chronic inflammatory optic neuropathy and 121 healthy subjects. Intra-retinal layer segmentation was performed for the eyes of patients with unilateral ON. Scanning laser ophthalmoscopy (SLO) images were reviewed for characteristic ocular fundus changes. RESULTS: Intra-retinal layer segmentation showed that eyes with a history of ON displayed MME independent INL thickening compared to contralateral eyes without previous ON. MME was detected in 22 eyes from 15 patients (5.3% of all screened patients), including 7 patients with bilateral edema. Of these, 21 had a prior history of ON (95%). The SLO images of all 22 MME-affected eyes showed crescent-shaped texture changes which were visible in the perifoveal region. A second grader who was blinded to the results of the OCT classified all SLO images for the presence of these characteristic fundus changes. All MME eyes were correctly classified (sensitivity = 100%) with high specificity (95.2%). CONCLUSION: This study shows that both MME and INL thickening occur in various neuro-inflammatory disorders associated with ON. We also demonstrate that detection and analysis of MME by OCT is not limited to B scans, but also possible using SLO images. PMID- 23940708 TI - Comparison of toxicity of benzene metabolite hydroquinone in hematopoietic stem cells derived from murine embryonic yolk sac and adult bone marrow. AB - Benzene is an occupational toxicant and an environmental pollutant that potentially causes hematotoxicity and leukemia in exposed populations. Epidemiological studies suggest an association between an increased incidence of childhood leukemia and benzene exposure during the early stages of pregnancy. However, experimental evidence supporting the association is lacking at the present time. It is believed that benzene and its metabolites target hematopoietic stem cells (HSCs) to cause toxicity and cancer in the hematopoietic system. In the current study, we compared the effects of hydroquinone (HQ), a major metabolite of benzene in humans and animals, on mouse embryonic yolk sac hematopoietic stem cells (YS-HSCs) and adult bone marrow hematopoietic stem cells (BM-HSCs). YS-HSCs and BM-HSCs were isolated and enriched, and were exposed to HQ at increasing concentrations. HQ reduced the proliferation and the differentiation and colony formation, but increased the apoptosis of both YS-HSCs and BM-HSCs. However, the cytotoxic and apoptotic effects of HQ were more apparent and reduction of colony formation by HQ was more severe in YS-HSCs than in BM-HSCs. Differences in gene expression profiles were observed in HQ-treated YS-HSCs and BM-HSCs. Cyp4f18 was induced by HQ both in YS-HSCs and BM-HSCs, whereas DNA-PKcs was induced in BM-HSCs only. The results revealed differential effects of benzene metabolites on embryonic and adult HSCs. The study established an experimental system for comparison of the hematopoietic toxicity and leukemogenicity of benzene and metabolites during mouse embryonic development and adulthood. PMID- 23940709 TI - Shorter lines facilitate reading in those who struggle. AB - People with dyslexia, who ordinarily struggle to read, sometimes remark that reading is easier when e-readers are used. Here, we used eye tracking to observe high school students with dyslexia as they read using these devices. Among the factors investigated, we found that reading using a small device resulted in substantial benefits, improving reading speeds by 27%, reducing the number of fixations by 11%, and importantly, reducing the number of regressive saccades by more than a factor of 2, with no cost to comprehension. Given that an expected trade-off between horizontal and vertical regression was not observed when line lengths were altered, we speculate that these effects occur because sluggish attention spreads perception to the left as the gaze shifts during reading. Short lines eliminate crowded text to the left, reducing regression. The effects of attention modulation by the hand, and of increased letter spacing to reduce crowding, were also found to modulate the oculomotor dynamics in reading, but whether these factors resulted in benefits or costs depended on characteristics, such as visual attention span, that varied within our sample. PMID- 23940710 TI - Associations of proanthocyanidin intake with renal function and clinical outcomes in elderly women. AB - BACKGROUND: Progression to chronic renal failure involves accelerated atherosclerosis and vascular calcification. Oxidative stress and endothelial dysfunction play a role in renal failure pathophysiology. In addition to improving vascular health and function, proanthocyanidins have been shown to exert renoprotective effects in animal models. Thus we hypothesize that proanthocyanidins may contribute to the maintenance of healthy renal function. OBJECTIVE: Determine the association of habitual proanthocyanidin intake with renal function and the risk of clinical renal outcomes in a population of elderly women. DESIGN: 948 women aged over 75 y, free of prevalent renal disease at baseline, were randomly selected from ambulant Caucasian women. Proanthocyanidin consumption was determined using a validated food frequency questionnaire and the United States Department of Agriculture proanthocyanidin food content database. Fasting serum cystatin C and creatinine were assessed at baseline. Renal failure hospitalisations and deaths were assessed over 5 years of follow-up through the Western Australia Data Linkage System. RESULTS: Compared to participants with low consumption, participants in the highest tertile of proanthocyanidin intake had a 9% lower cystatin C concentration (P<0.001). High proanthocyanidin consumers were at 50% lower risk of moderate chronic kidney insufficiency, and 65% lower risk of experiencing a 5-year renal disease event (P<0.05). These relationships remained significant following adjustment for renal disease risk factors and diet-related potential confounders. CONCLUSION: Increased consumption of proanthocyanidins was associated with better renal function and substantially reduced renal associated events, which has been supported by mechanistic and animal model data. Proanthocyanidin intake should be further examined as a dietary contributor to better renal health. PMID- 23940711 TI - Temporal alcohol availability predicts first-time drunk driving, but not repeat offending. AB - Alcohol availability has been linked to drunk driving, but research has not examined whether this relationship is the same for first-time and repeat offenses. We examined the relationship between the business hours of alcohol outlets licensed to serve alcohol for on-premises consumption and misdemeanor level (first offense) and felony-level drunk driving (repeat offense) charges in New York State in 2009. Longer outlet business hours were associated with more misdemeanor drunk driving charges, but were not associated with felony drunk driving charges. The per capita density of on-premises alcohol outlets did not affect misdemeanor or felony drunk driving charges. The results suggest that temporal alcohol availability may be an impelling factor for first-time drunk driving, but other factors likely influence repeat drunk driving behaviors. PMID- 23940712 TI - Macaque cardiac physiology is sensitive to the valence of passively viewed sensory stimuli. AB - Autonomic nervous system activity is an important component of affective experience. We demonstrate in the rhesus monkey that both the sympathetic and parasympathetic branches of the autonomic nervous system respond differentially to the affective valence of passively viewed video stimuli. We recorded cardiac impedance and an electrocardiogram while adult macaques watched a series of 300 30-second videos that varied in their affective content. We found that sympathetic activity (as measured by cardiac pre-ejection period) increased and parasympathetic activity (as measured by respiratory sinus arrhythmia) decreased as video content changes from positive to negative. These findings parallel the relationship between autonomic nervous system responsivity and valence of stimuli in humans. Given the relationship between human cardiac physiology and affective processing, these findings suggest that macaque cardiac physiology may be an index of affect in nonverbal animals. PMID- 23940707 TI - Ancient dispersal of the human fungal pathogen Cryptococcus gattii from the Amazon rainforest. AB - Over the past two decades, several fungal outbreaks have occurred, including the high-profile 'Vancouver Island' and 'Pacific Northwest' outbreaks, caused by Cryptococcus gattii, which has affected hundreds of otherwise healthy humans and animals. Over the same time period, C. gattii was the cause of several additional case clusters at localities outside of the tropical and subtropical climate zones where the species normally occurs. In every case, the causative agent belongs to a previously rare genotype of C. gattii called AFLP6/VGII, but the origin of the outbreak clades remains enigmatic. Here we used phylogenetic and recombination analyses, based on AFLP and multiple MLST datasets, and coalescence gene genealogy to demonstrate that these outbreaks have arisen from a highly recombining C. gattii population in the native rainforest of Northern Brazil. Thus the modern virulent C. gattii AFLP6/VGII outbreak lineages derived from mating events in South America and then dispersed to temperate regions where they cause serious infections in humans and animals. PMID- 23940713 TI - Developing prediction equations and a mobile phone application to identify infants at risk of obesity. AB - BACKGROUND: Advancements in knowledge of obesity aetiology and mobile phone technology have created the opportunity to develop an electronic tool to predict an infant's risk of childhood obesity. The study aims were to develop and validate equations for the prediction of childhood obesity and integrate them into a mobile phone application (App). METHODS AND FINDINGS: Anthropometry and childhood obesity risk data were obtained for 1868 UK-born White or South Asian infants in the Born in Bradford cohort. Logistic regression was used to develop prediction equations (at 6 +/- 1.5, 9 +/- 1.5 and 12 +/- 1.5 months) for risk of childhood obesity (BMI at 2 years >91(st) centile and weight gain from 0-2 years >1 centile band) incorporating sex, birth weight, and weight gain as predictors. The discrimination accuracy of the equations was assessed by the area under the curve (AUC); internal validity by comparing area under the curve to those obtained in bootstrapped samples; and external validity by applying the equations to an external sample. An App was built to incorporate six final equations (two at each age, one of which included maternal BMI). The equations had good discrimination (AUCs 86-91%), with the addition of maternal BMI marginally improving prediction. The AUCs in the bootstrapped and external validation samples were similar to those obtained in the development sample. The App is user friendly, requires a minimum amount of information, and provides a risk assessment of low, medium, or high accompanied by advice and website links to government recommendations. CONCLUSIONS: Prediction equations for risk of childhood obesity have been developed and incorporated into a novel App, thereby providing proof of concept that childhood obesity prediction research can be integrated with advancements in technology. PMID- 23940714 TI - TLR2, TLR4 and the MyD88 signaling are crucial for the in vivo generation and the longevity of long-lived antibody-secreting cells. AB - This study was undertaken to gain better insights into the role of TLRs and MyD88 in the development and differentiation of memory B cells, especially of ASC, during the Th2 polarized memory response induced by Natterins. Our in vivo findings demonstrated that the anaphylactic IgG1 production is dependent on TLR2 and MyD88 signaling, and that TLR4 acts as adjuvant accelerating the synthesis of high affinity-IgE. Also, TLR4 (MyD88-independent) modulated the migration of innate-like B cells (B1a and B2) out of the peritoneal cavity, and the emigration from the spleen of B1b and B2 cells. TLR4 (MyD88-independent) modulated the emigration from the spleen of Bmem as well as ASC B220(pos). TLR2 triggered to the egress from the peritoneum of Bmem (MyD88-dependent) and ASC B220(pos) (MyD88 independent). We showed that TLR4 regulates the degree of expansion of Bmem in the peritoneum (MyD88-dependent) and in BM (MyD88-independent) as well as of ASC B220(neg) in the spleen (MyD88-independent). TLR2 regulated the intensity of the expansion of Bmem (MyD88-independent) and ASC B220(pos) (MyD88-dependent) in BM. Finally, TLR4 signals sustained the longevity of ASC B220(pos) (MyD88 independent) and ASC B220(neg) into the peritoneum (MyD88-dependent) and TLR2 MyD88-dependent signaling supported the persistence of B2 cells in BM, Bmem in the spleen and ASC B220(neg) in peritoneum and BM. Terminally differentiated ASC B220(neg) required the cooperation of both signals through TLR2/TLR4 via MyD88 for longevity in peritoneum, whereas Bmem required only TLR2/MyD88 to stay in spleen, and ASC B220(pos) rested in peritoneum dependent on TLR4 signaling. Our data sustain that earlier events on memory B cells differentiation induced in secondary immune response against Natterins, after secondary lymph organs influx and egress, may be the key to determining peripheral localization of innate-like B cells and memory B cells as ASC B220(pos) and ASC B220(neg). PMID- 23940715 TI - Intratumoral alpha-SMA enhances the prognostic potency of CD34 associated with maintenance of microvessel integrity in hepatocellular carcinoma and pancreatic cancer. AB - Microvessel density (MVD) as an angiogenesis predictor is inefficient per se in cancer prognosis. We evaluated prognostic values of combining intratumoral alpha smooth muscle actin (alpha-SMA)-positive stromal cell density and MVD after curative resection in hypervascular hepatocellular carcinoma (HCC) and hypovascular pancreatic cancer (PC). Tissue microarrays were constructed from tumors of 305 HCC and 57 PC patients who underwent curative resection and analyzed for alpha-SMA and CD34 expression by immunostaining. Prognostic values of these two proteins and other clinicopathological features were examined. Both low alpha-SMA density and high MVD-CD34 were associated in HCC with the presence of intrahepatic metastasis and microvascular invasion, and they were related to lymph node involvement and microvascular invasion in PC (p<0.05). Although CD34 alone, but not alpha-SMA, was an independent prognostic factor for overall survival and recurrence-free survival, the combination of low alpha-SMA and high CD34 was a predictor of worst prognosis for both types of tumors and had a better power to predict patient death and early recurrence (p<0.01). Furthermore, the results show that distribution of most of the alpha-SMA-positive cells and vascular endothelial cells overlap, showing major colocalization on vascular walls. Poor microvessel integrity, as indicated by high MVD, together with low perivascular alpha-SMA-positive cell coverage is associated with early recurrence, unfavorable metastasis, and short survival after tumor resection. This finding highlights the significance of vascular quality in tumor progression, which provides an optimized complement to vascular quantity in prognosis of postoperative patients. PMID- 23940716 TI - Prioritizing disease candidate proteins in cardiomyopathy-specific protein protein interaction networks based on "guilt by association" analysis. AB - The cardiomyopathies are a group of heart muscle diseases which can be inherited (familial). Identifying potential disease-related proteins is important to understand mechanisms of cardiomyopathies. Experimental identification of cardiomyophthies is costly and labour-intensive. In contrast, bioinformatics approach has a competitive advantage over experimental method. Based on "guilt by association" analysis, we prioritized candidate proteins involving in human cardiomyopathies. We first built weighted human cardiomyopathy-specific protein protein interaction networks for three subtypes of cardiomyopathies using the known disease proteins from Online Mendelian Inheritance in Man as seeds. We then developed a method in prioritizing disease candidate proteins to rank candidate proteins in the network based on "guilt by association" analysis. It was found that most candidate proteins with high scores shared disease-related pathways with disease seed proteins. These top ranked candidate proteins were related with the corresponding disease subtypes, and were potential disease-related proteins. Cross-validation and comparison with other methods indicated that our approach could be used for the identification of potentially novel disease proteins, which may provide insights into cardiomyopathy-related mechanisms in a more comprehensive and integrated way. PMID- 23940717 TI - Pharmacological reversal of histone methylation presensitizes pancreatic cancer cells to nucleoside drugs: in vitro optimization and novel nanoparticle delivery studies. AB - We evaluated the potential of an investigational histone methylation reversal agent, 3-deazaneplanocin A (DZNep), in improving the chemosensitivity of pancreatic cancer to nucleoside analogs (i.e., gemcitabine). DZNep brought delayed but selective cytotoxicity to pancreatic cancer cells without affecting normal human pancreatic ductal epithelial (HPDE) cells. Co-exposure of DZNep and gemcitabine induced cytotoxic additivity or synergism in both well- and poorly differentiated pancreatic cell lines by increased apoptosis. In contrast, DZNep exerted antagonism with gemcitabine against HPDE cells with significant reduction in cytotoxicity compared with the gemcitabine-alone regimen. DZNep marginally depended on purine nucleoside transporters for its cytotoxicity, but the transport dependence was circumvented by acyl derivatization. Drug exposure studies revealed that a short priming with DZNep followed by gemcitabine treatment rather than co-treatment of both agents to produce a maximal chemosensitization response in both gemcitabine-sensitive and gemcitabine resistant pancreatic cancer cells. DZNep rapidly and reversibly decreased trimethylation of histone H3 lysine 27 but increased trimethylation of lysine 9 in an EZH2- and JMJD1A/2C-dependent manner, respectively. However, DZNep potentiation of nucleoside analog chemosensitization was found to be temporally coupled to trimethylation changes in lysine 27 and not lysine 9. Polymeric nanoparticles engineered to chronologically release DZNep followed by gemcitabine produced pronounced chemosensitization and dose-lowering effects. Together, our results identify that an optimized DZNep exposure can presensitize pancreatic cancer cells to anticancer nucleoside analogs through the reversal of histone methylation, emphasizing the promising clinical utilities of epigenetic reversal agents in future pancreatic cancer combination therapies. PMID- 23940718 TI - Properties of local interactions and their potential value in complementing genome-wide association studies. AB - Local interactions between neighbouring SNPs are hypothesized to be able to capture variants missing from genome-wide association studies (GWAS) via haplotype effects but have not been thoroughly explored. We have used a new high throughput analysis tool to probe this underexplored area through full pair-wise genome scans and conventional GWAS in diastolic and systolic blood pressure and six metabolic traits in the Northern Finland Birth Cohort 1966 (NFBC1966) and the Atherosclerosis Risk in Communities study cohort (ARIC). Genome-wide significant interactions were detected in ARIC for systolic blood pressure between PLEKHA7 (a known GWAS locus for blood pressure) and GPR180 (which plays a role in vascular remodelling), and also for triglycerides as local interactions within the 11q23.3 region (replicated significantly in NFBC1966), which notably harbours several loci (BUD13, ZNF259 and APOA5) contributing to triglyceride levels. Tests of the local interactions within the 11q23.3 region conditional on the top GWAS signal suggested the presence of two independent functional variants, each with supportive evidence for their roles in gene regulation. Local interactions captured 9 additional GWAS loci identified in this study (3 significantly replicated) and 73 from previous GWAS (24 in the eight traits and 49 in related traits). We conclude that the detection of local interactions requires adequate SNP coverage of the genome and that such interactions are only likely to be detectable between SNPs in low linkage disequilibrium. Analysing local interactions is a potentially valuable complement to GWAS and can provide new insights into the biology underlying variation in complex traits. PMID- 23940719 TI - Intra and interobserver reliability and agreement of semiquantitative vertebral fracture assessment on chest computed tomography. AB - OBJECTIVES: To evaluate the reliability of semiquantitative Vertebral Fracture Assessment (VFA) on chest Computed Tomography (CT). METHODS: Four observers performed VFA twice upon sagittal reconstructions of 50 routine clinical chest CTs. Intra- and interobserver agreement (absolute agreement or 95% Limits of Agreement) and reliability (Cohen's kappa or intraclass correlation coefficient(ICC)) were calculated for the visual VFA measures (fracture present, worst fracture grade, cumulative fracture grade on patient level) and for percentage height loss of each fractured vertebra compared to the adjacent vertebrae. RESULTS: Observers classified 24-38% patients as having at least one vertebral fracture, giving rise to kappa's of 0.73-0.84 (intraobserver) and 0.56 0.81 (interobserver). For worst fracture grade we found good intraobserver (76 88%) and interobserver (74-88%) agreement, and excellent reliability with square weighted kappa's of 0.84-0.90 (intraobserver) and 0.84-0.94 (interobserver). For cumulative fracture grade the 95% Limits of Agreement were maximally +/-1,99 (intraobserver) and +/-2,69 (interobserver) and the reliability (ICC) varied from 0.84-0.94 (intraobserver) and 0.74-0.94 (interobserver). For percentage height loss on a vertebral level the 95% Limits of Agreement were maximally +/-11,75% (intraobserver) and +/-12,53% (interobserver). The ICC was 0.59-0.90 (intraobserver) and 0.53-0-82 (interobserver). Further investigation is needed to evaluate the prognostic value of this approach. CONCLUSION: In conclusion, these results demonstrate acceptable reproducibility of VFA on CT. PMID- 23940720 TI - Contribution of NADPH oxidase to membrane CD38 internalization and activation in coronary arterial myocytes. AB - The CD38-ADP-ribosylcyclase-mediated Ca(2+) signaling pathway importantly contributes to the vasomotor response in different arteries. Although there is evidence indicating that the activation of CD38-ADP-ribosylcyclase is associated with CD38 internalization, the molecular mechanism mediating CD38 internalization and consequent activation in response to a variety of physiological and pathological stimuli remains poorly understood. Recent studies have shown that CD38 may sense redox signals and is thereby activated to produce cellular response and that the NADPH oxidase isoform, NOX1, is a major resource to produce superoxide (O2.-)) in coronary arterial myocytes (CAMs) in response to muscarinic receptor agonist, which uses CD38-ADP-ribosylcyclase signaling pathway to exert its action in these CAMs. These findings led us hypothesize that NOX1-derived O2. serves in an autocrine fashion to enhance CD38 internalization, leading to redox activation of CD38-ADP-ribosylcyclase activity in mouse CAMs. To test this hypothesis, confocal microscopy, flow cytometry and a membrane protein biotinylation assay were used in the present study. We first demonstrated that CD38 internalization induced by endothelin-1 (ET-1) was inhibited by silencing of NOX1 gene, but not NOX4 gene. Correspondingly, NOX1 gene silencing abolished ET-1 induced O2.- production and increased CD38-ADP-ribosylcyclase activity in CAMs, while activation of NOX1 by overexpression of Rac1 or Vav2 or administration of exogenous O2.- significantly increased CD38 internalization in CAMs. Lastly, ET-1 was found to markedly increase membrane raft clustering as shown by increased colocalization of cholera toxin-B with CD38 and NOX1. Taken together, these results provide direct evidence that Rac1-NOX1-dependent O2.- production mediates CD38 internalization in CAMs, which may represent an important mechanism linking receptor activation with CD38 activity in these cells. PMID- 23940721 TI - Exogenous calcium alleviates photoinhibition of PSII by improving the xanthophyll cycle in peanut (Arachis hypogaea) leaves during heat stress under high irradiance. AB - Peanut is one of the calciphilous plants. Calcium (Ca) serves as a ubiquitous central hub in a large number of signaling pathways. The effect of exogenous calcium nitrate [Ca(NO3)2] (6 mM) on the dissipation of excess excitation energy in the photosystem II (PSII) antenna, especially on the level of D1 protein and the xanthophyll cycle in peanut plants under heat (40 degrees C) and high irradiance (HI) (1 200 umol m(-2) s(-1)) stress were investigated. Compared with the control plants [cultivated in 0 mM Ca(NO3)2 medium], the maximal photochemical efficiency of PSII (Fv/Fm) in Ca(2+)-treated plants showed a slighter decrease after 5 h of stress, accompanied by higher non-photochemical quenching (NPQ), higher expression of antioxidative genes and less reactive oxygen species (ROS) accumulation. Meanwhile, higher content of D1 protein and higher ratio of (A+Z)/(V+A+Z) were also detected in Ca(2+)-treated plants under such stress. These results showed that Ca(2+) could help protect the peanut photosynthetic system from severe photoinhibition under heat and HI stress by accelerating the repair of D1 protein and improving the de-epoxidation ratio of the xanthophyll cycle. Furthermore, EGTA (a chelant of Ca ion), LaCl3 (a blocker of Ca(2+) channel in cytoplasmic membrane), and CPZ [a calmodulin (CaM) antagonist] were used to analyze the effects of Ca(2+)/CaM on the variation of (A+Z)/(V+A+Z) (%) and the expression of violaxanthin de-epoxidase (VDE). The results indicated that CaM, an important component of the Ca(2+) signal transduction pathway, mediated the expression of the VDE gene in the presence of Ca to improve the xanthophyll cycle. PMID- 23940722 TI - Exercise-induced blood lactate increase does not change red blood cell deformability in cyclists. AB - BACKGROUND: The effect of exercise-induced lactate production on red blood cell deformability and other blood rheological changes is controversial, given heavy exercise induces biochemical processes (e.g., oxidative stress) known to perturb haemorheology. The aim of the present study was to examine the haemorheological response to a short-duration cycling protocol designed to increase blood lactate concentration, but of duration insufficient to induce significant oxidative stress. METHODS: Male cyclists and triathletes (n = 6; 27+/-7 yr; body mass index: 23.7+/-3.0 kg/m2; peak oxygen uptake 4.02+/-0.51 L/min) performed unloaded (0 W), moderate-intensity, and heavy-intensity cycling. Blood was sampled at rest and during the final minute of each cycling bout. Blood chemistry, blood viscosity, red blood cell aggregation and red blood cell deformability were measured. RESULTS: Blood lactate concentration increased significantly during heavy-intensity cycling, when compared with all other conditions. Methaemoglobin fraction did not change during any exercise bout when compared with rest. Blood viscosity at native haematocrit increased during heavy-intensity cycling at higher-shear rates when compared with rest, unloaded and moderate-intensity cycling. Heavy-intensity exercise increased the amplitude of red blood cell aggregation in native haematocrit samples when compared with all other conditions. Red blood cell deformability was not changed by exercise. CONCLUSION: Acute exercise perturbs haemorheology in an intensity dose-response fashion; however, many of the haemorheological effects appear to be secondary to haemoconcentration, rather than increased lactate concentration. PMID- 23940723 TI - Electron microscopic, genetic and protein expression analyses of Helicobacter acinonychis strains from a Bengal tiger. AB - Colonization by Helicobacter species is commonly noted in many mammals. These infections often remain unrecognized, but can cause severe health complications or more subtle host immune perturbations. The aim of this study was to isolate and characterize putative novel Helicobacter spp. from Bengal tigers in Thailand. Morphological investigation (Gram-staining and electron microscopy) and genetic studies (16SrRNA, 23SrRNA, flagellin, urease and prophage gene analyses, RAPD DNA fingerprinting and restriction fragment polymorphisms) as well as Western blotting were used to characterize the isolated Helicobacters. Electron microscopy revealed spiral-shaped bacteria, which varied in length (2.5-6 um) and contained up to four monopolar sheathed flagella. The 16SrRNA, 23SrRNA, sequencing and protein expression analyses identified novel H. acinonychis isolates closely related to H. pylori. These Asian isolates are genetically very similar to H. acinonychis strains of other big cats (cheetahs, lions, lion-tiger hybrid and other tigers) from North America and Europe, which is remarkable in the context of the great genetic diversity among worldwide H. pylori strains. We also found by immunoblotting that the Bengal tiger isolates express UreaseA/B, flagellin, BabA adhesin, neutrophil-activating protein NapA, HtrA protease, gamma glutamyl-transpeptidase GGT, Slt lytic transglycosylase and two DNA transfer relaxase orthologs that were known from H. pylori, but not the cag pathogenicity island, nor CagA, VacA, SabA, DupA or OipA proteins. These results give fresh insights into H. acinonychis genetics and the expression of potential pathogenicity-associated factors and their possible pathophysiological relevance in related gastric infections. PMID- 23940724 TI - Heterologous immunity triggered by a single, latent virus in Mus musculus: combined costimulation- and adhesion- blockade decrease rejection. AB - The mechanisms underlying latent-virus-mediated heterologous immunity, and subsequent transplant rejection, especially in the setting of T cell costimulation blockade, remain undetermined. To address this, we have utilized MHV68 to develop a rodent model of latent virus-induced heterologous alloimmunity. MHV68 infection was correlated with multimodal immune deviation, which included increased secretion of CXCL9 and CXCL10, and with the expansion of a CD8(dim) T cell population. CD8(dim) T cells exhibited decreased expression of multiple costimulation molecules and increased expression of two adhesion molecules, LFA-1 and VLA-4. In the setting of MHV68 latency, recipients demonstrated accelerated costimulation blockade-resistant rejection of skin allografts compared to non-infected animals (MST 13.5 d in infected animals vs 22 d in non-infected animals, p<.0001). In contrast, the duration of graft acceptance was equivalent between non-infected and infected animals when treated with combined anti-LFA-1/anti-VLA-4 adhesion blockade (MST 24 d for non-infected and 27 d for infected, p = n.s.). The combination of CTLA-4-Ig/anti-CD154-based costimulation blockade+anti-LFA-1/anti-VLA-4-based adhesion blockade led to prolonged graft acceptance in both non-infected and infected cohorts (MST>100 d for both, p<.0001 versus costimulation blockade for either). While in the non infected cohort, either CTLA-4-Ig or anti-CD154 alone could effectively pair with adhesion blockade to prolong allograft acceptance, in infected animals, the prolonged acceptance of skin grafts could only be recapitulated when anti-LFA-1 and anti-VLA-4 antibodies were combined with anti-CD154 (without CTLA-4-Ig, MST>100 d). Graft acceptance was significantly impaired when CTLA-4-Ig alone (no anti-CD154) was combined with adhesion blockade (MST 41 d). These results suggest that in the setting of MHV68 infection, synergy occurs predominantly between adhesion pathways and CD154-based costimulation, and that combined targeting of both pathways may be required to overcome the increased risk of rejection that occurs in the setting of latent-virus-mediated immune deviation. PMID- 23940725 TI - Identification of an imprinted gene cluster in the X-inactivation center. AB - Mammalian development is strongly influenced by the epigenetic phenomenon called genomic imprinting, in which either the paternal or the maternal allele of imprinted genes is expressed. Paternally expressed Xist, an imprinted gene, has been considered as a single cis-acting factor to inactivate the paternally inherited X chromosome (Xp) in preimplantation mouse embryos. This means that X chromosome inactivation also entails gene imprinting at a very early developmental stage. However, the precise mechanism of imprinted X-chromosome inactivation remains unknown and there is little information about imprinted genes on X chromosomes. In this study, we examined whether there are other imprinted genes than Xist expressed from the inactive paternal X chromosome and expressed in female embryos at the preimplantation stage. We focused on small RNAs and compared their expression patterns between sexes by tagging the female X chromosome with green fluorescent protein. As a result, we identified two micro (mi)RNAs-miR-374-5p and miR-421-3p-mapped adjacent to Xist that were predominantly expressed in female blastocysts. Allelic expression analysis revealed that these miRNAs were indeed imprinted and expressed from the Xp. Further analysis of the imprinting status of adjacent locus led to the discovery of a large cluster of imprinted genes expressed from the Xp: Jpx, Ftx and Zcchc13. To our knowledge, this is the first identified cluster of imprinted genes in the cis-acting regulatory region termed the X-inactivation center. This finding may help in understanding the molecular mechanisms regulating imprinted X chromosome inactivation during early mammalian development. PMID- 23940726 TI - Two variants of the C-reactive protein gene are associated with risk of pre eclampsia in an American Indian population. AB - BACKGROUND: The etiology of pre-eclampsia (PE) is unknown; but it is accepted that normal pregnancy represents a distinctive challenge to the maternal immune system. C-reactive protein is a prominent component of the innate immune system; and we previously reported an association between PE and the CRP polymorphism, rs1205. Our aim was to explore the effects of additional CRP variants. The IBC (Cardiochip) genotyping microarray focuses on candidate genes and pathways related to the pathophysiology of cardiovascular disease. METHODS: This study recruited 140 cases of PE and 270 matched controls, of which 95 cases met criteria as severe PE, from an American Indian community. IBC array genotypes from 10 suitable CRP SNPs were analyzed. A replication sample of 178 cases and 427 controls of European ancestry was also genotyped. RESULTS: A nominally significant difference (p value <0.05) was seen in the distribution of discordant matched pairs for rs3093068; and Bonferroni corrected differences (P<0.005) were seen for rs876538, rs2794521, and rs3091244. Univariate conditional logistic regression odds ratios (OR) were nominally significant for rs3093068 and rs876538 models only. Multivariate logistic models with adjustment for mother's age, nulliparity and BMI attenuated the effect (OR 1.58, P = 0.066, 95% CI 0.97-2.58) for rs876538 and (OR 2.59, P = 0.050, 95% CI 1.00-6.68) for rs3093068. An additive risk score of the above two risk genotypes shows a multivariate adjusted OR of 2.04 (P = 0.013, 95% CI 1.16-3.56). The replication sample also demonstrated significant association between PE and the rs876538 allele (OR = 1.55, P = 0.01, 95% CI 2.16-1.10). We also show putative functionality for the rs876538 and rs3093068 CRP variants. CONCLUSION: The CRP variants, rs876538 and rs3093068, previously associated with other cardiovascular disease phenotypes, show suggestive association with PE in this American Indian population, further supporting a possible role for CRP in PE. PMID- 23940727 TI - Assessment of human sleep depth is being de-standardized by recently advised EEG electrode locations. AB - Human sleep depth was traditionally assessed by scoring electro-encephalographic slow-wave amplitudes at the globally standardized C4-M1 electrode derivation. Since 2007, the American Association of Sleep Medicine (AASM) has accepted three additional derivations for the same purpose. These might well differ in slow wave amplitudes which would bias the scorings. Some derivations might also introduce large inter-individual variability. We compared mean and variability of slow wave amplitudes between six derivations including the four AASM ones. Slow wave amplitudes in those derivations were simultaneously measured using automated analysis in 29 patients. Each amplitude was divided by the average from the six derivations, thus removing shared factors such as age, gender and sleep depth while retaining factors that differ between the derivations such as caused by local skull characteristics, electrode distance and neuronal dipole orientation. The remaining inter-individual variability differed significantly and up to a factor of two between the AASM derivations. The amplitudes differed significantly and up to 60% between the AASM derivations, causing substantial scoring bias between centres using different derivations. The resulting de-standardization most likely affects any patient group because the amplitude differences were consistent over diagnoses, genders, and age. Derivation-dependent amplitude thresholds were proposed to reduce the scoring bias. However, it would be better to settle on just one derivation, for instance Cz-Oz or Fpz-Cz because these have lowest variability while matching the traditional C4-M1 amplitudes. PMID- 23940728 TI - AMD-associated genes encoding stress-activated MAPK pathway constituents are identified by interval-based enrichment analysis. AB - PURPOSE: To determine whether common DNA sequence variants within groups of genes encoding elements of stress-activated mitogen-activated protein kinase (MAPK) signaling pathways are, in aggregate, associated with advanced AMD (AAMD). METHODS: We used meta-regression and exact testing methods to identify AAMD associated SNPs in 1177 people with AAMD and 1024 AMD-free elderly peers from 3 large-scale genotyping projects on the molecular genetics of AMD. SNPs spanning independent AAMD-associated genomic intervals were examined with a multi-locus testing method (INRICH) for enrichment within five sets of genes encoding constituents of stress-activated MAPK signaling cascades. RESULTS: Four-of-five pathway gene sets showed enrichment with AAMD-associated SNPs; findings persisted after adjustment for multiple testing in two. Strongest enrichment signals (P = 0.006) existed in a c-Jun N-terminal kinase (JNK)/MAPK cascade (Science Signaling, STKE CMP_10827). In this pathway, seven independent AAMD-associated regions were resident in 6 of 25 genes examined. These included sequence variants in: 1) three MAP kinase kinase kinases (MAP3K4, MAP3K5, MAP3K9) that phosphorylate and activate the MAP kinase kinases MAP2K4 and MAP2K7 (molecules that phosphorylate threonine and tyrosine residues within the activation loop of JNK); 2) a target of MAP2K7 (JNK3A1) that activates complexes involved in transcriptional regulation of stress related genes influencing cell proliferation, apoptosis, motility, metabolism and DNA repair; and 3) NR2C2, a transcription factor activated by JNK1A1 (a drugable molecule influencing retinal cell viability in model systems). We also observed AAMD-related sequence variants resident in genes encoding PPP3CA (a drugable molecule that inactivates MAP3K5), and two genes (TGFB2, TGFBR2) encoding factors involved in MAPK sensing of growth factors/cytokines. CONCLUSIONS: Linkage disequilibrium (LD)-independent genomic enrichment analysis yielded associations of AAMD with aggregates of functionally related genes encoding constituents of the JNK MAPK signaling pathway. FDA approved drugs now exist to target constituents of stress-activated MAPK pathways and may offer reasonable approaches to preventing or treating AAMD. PMID- 23940729 TI - Conscious sedation procedures using intravenous midazolam for dental care in patients with different cognitive profiles: a prospective study of effectiveness and safety. AB - The use of midazolam for dental care in patients with intellectual disability is poorly documented. This study aimed to evaluate the effectiveness and safety of conscious sedation procedures using intravenous midazolam in adults and children with intellectual disability (ID) compared to dentally anxious patients (DA). Ninety-eight patients with ID and 44 patients with DA programmed for intravenous midazolam participated in the study over 187 and 133 sessions, respectively. Evaluation criteria were success of dental treatment, cooperation level (modified Venham scale), and occurrence of adverse effects. The mean intravenous dose administered was 8.8+/-4.9 mg and 9.8+/-4.1 mg in ID and DA sessions respectively (t-test, NS). 50% N2O/O2 was administered during cannulation in 51% of ID sessions and 61% of DA sessions (NS, Fisher exact test). Oral or rectal midazolam premedication was administered for cannulation in 31% of ID sessions and 3% of DA sessions (p<0,001, Fisher exact test). Dental treatment was successful in 9 out of 10 sessions for both groups. Minor adverse effects occurred in 16.6% and 6.8% of ID and DA sessions respectively (p = 0.01, Fisher exact test). Patients with ID were more often very disturbed during cannulation (25.4% ID vs. 3.9% DA sessions) and were less often relaxed after induction (58.9% ID vs. 90.3% DA) and during dental treatment (39.5% ID vs. 59.7% DA) (p<0.001, Fisher exact test) than patients with DA. When midazolam sedation was repeated, cooperation improved for both groups. Conscious sedation procedures using intravenous midazolam, with or without premedication and/or inhalation sedation (50% N2O/O2), were shown to be safe and effective in patients with intellectual disability when administered by dentists. PMID- 23940730 TI - Comparison of steroid-free immunosuppression and standard immunosuppression for liver transplant patients with hepatocellular carcinoma. AB - Immunosuppression therapy following liver transplantation often includes steroids. However, extended corticosteroid therapy is associated with numerous complications. This study evaluated the efficacy and safety of using basiliximab in place of a corticosteroid for immunosuppression following liver transplantation for hepatocellular carcinoma (HCC) in Chinese patients. The records of 178 patients with HCC who underwent orthotopic liver transplantation from January 2003 to December 2009 were retrospectively reviewed. All patients received immunosuppression therapy that contained either basiliximab (n = 78) or steroids (n = 100) in addition to tacrolimus and mycophenolate mofetil. Assessments included complications related to liver transplantation, occurrence of steroid side effects, recurrence of HCC, and patient and graft survival. A smaller proportion of patients receiving basiliximab compared with steroids experienced de novo diabetes (38.7% vs. 91.0%, respectively) or long-term de novo diabetes mellitus (7.7% vs. 38.0%, respectively) (both, P<0.0001). The median overall and disease free survival was similar between basiliximab (50.8 months and 19.6 months, respectively) and steroid treated patients (64.2 months and 23.8 months, respectively). The 5-year overall survival and disease free survival rates was also similar between the basiliximab (42.5% and 38.9%, respectively) and steroid (50.5% and 39.2%) groups (all, P>0.730). However, in patients who met the Milan criteria basiliximab was associated with greater 5-year overall survival rate as compared with steroid therapy (88.9% vs. 57.4%, respectively, P = 0.022). These findings provide further evidence of the negative impact of steroids as a part of immunosuppression therapy following liver transplantation for HCC. PMID- 23940731 TI - Requirement of retinoic acid receptor beta for genipin derivative-induced optic nerve regeneration in adult rat retina. AB - Like other CNS neurons, mature retinal ganglion cells (RGCs) are unable to regenerate their axons after nerve injury due to a diminished intrinsic regenerative capacity. One of the reasons why they lose the capacity for axon regeneration seems to be associated with a dramatic shift in RGCs' program of gene expression by epigenetic modulation. We recently reported that (1R) isoPropyloxygenipin (IPRG001), a genipin derivative, has both neuroprotective and neurite outgrowth activities in murine RGC-5 retinal precursor cells. These effects were both mediated by nitric oxide (NO)/S-nitrosylation signaling. Neuritogenic activity was mediated by S-nitrosylation of histone deacetylase-2 (HDAC2), which subsequently induced retinoic acid receptor beta (RARbeta) expression via chromatin remodeling in vitro. RARbeta plays important roles of neural growth and differentiation in development. However, the role of RARbeta expression during adult rat optic nerve regeneration is not clear. In the present study, we extended this hypothesis to examine optic nerve regeneration by IPRG001 in adult rat RGCs in vivo. We found a correlation between RARbeta expression and neurite outgrowth with age in the developing rat retina. Moreover, we found that IPRG001 significantly induced RARbeta expression in adult rat RGCs through the S nitrosylation of HDAC2 processing mechanism. Concomitant with RARbeta expression, adult rat RGCs displayed a regenerative capacity for optic axons in vivo by IPRG001 treatment. These neuritogenic effects of IPRG001 were specifically suppressed by siRNA for RARbeta. Thus, the dual neuroprotective and neuritogenic actions of genipin via S-nitrosylation might offer a powerful therapeutic tool for the treatment of RGC degenerative disorders. PMID- 23940732 TI - Combined effects of energy development and disease on greater sage-grouse. AB - Species of conservation concern are increasingly threatened by multiple, anthropogenic stressors which are outside their evolutionary experience. Greater sage-grouse are highly susceptible to the impacts of two such stressors: oil and gas (energy) development and West Nile virus (WNv). However, the combined effects of these stressors and their potential interactions have not been quantified. We used lek (breeding ground) counts across a landscape encompassing extensive local and regional variation in the intensity of energy development to quantify the effects of energy development on lek counts, in years with widespread WNv outbreaks and in years without widespread outbreaks. We then predicted the effects of well density and WNv outbreak years on sage-grouse in northeast Wyoming. Absent an outbreak year, drilling an undeveloped landscape to a high permitting level (3.1 wells/km2) resulted in a 61% reduction in the total number of males counted in northeast Wyoming (total count). This was similar in magnitude to the 55% total count reduction that resulted from an outbreak year alone. However, energy-associated reductions in the total count resulted from a decrease in the mean count at active leks, whereas outbreak-associated reductions resulted from a near doubling of the lek inactivity rate (proportion of leks with a last count = 0). Lek inactivity quadrupled when 3.1 wells/km2 was combined with an outbreak year, compared to no energy development and no outbreak. Conservation measures should maintain sagebrush landscapes large and intact enough so that leks are not chronically reduced in size due to energy development, and therefore vulnerable to becoming inactive due to additional stressors. PMID- 23940733 TI - Differential actions of the endocytic collagen receptor uPARAP/Endo180 and the collagenase MMP-2 in bone homeostasis. AB - A well-coordinated remodeling of uncalcified collagen matrices is a pre-requisite for bone development and homeostasis. Collagen turnover proceeds through different pathways, either involving extracellular reactions exclusively, or being dependent on endocytic processes. Extracellular collagen degradation requires the action of secreted or membrane attached collagenolytic proteases, whereas the alternative collagen degradation pathway proceeds intracellularly after receptor-mediated uptake and delivery to the lysosomes. In this study we have examined the functional interplay between the extracellular collagenase, MMP 2, and the endocytic collagen receptor, uPARAP, by generating mice with combined deficiency of both components. In both uPARAP-deficient and MMP-2-deficient adult mice the length of the tibia and femur was decreased, along with a reduced bone mineral density and trabecular bone quality. An additional decrease in bone length was observed when combining the two deficiencies, pointing to both components being important for the remodeling processes in long bone growth. In agreement with results found by others, a different effect of MMP-2 deficiency was observed in the distinct bone structures of the calvaria. These membranous bones were found to be thickened in MMP-2-deficient mice, an effect likely to be related to an accompanying defect in the canalicular system. Surprisingly, both of the latter defects in MMP-2-deficient mice were counteracted by concurrent uPARAP deficiency, demonstrating that the collagen receptor does not support the same matrix remodeling processes as the MMP in the growth of the skull. We conclude that both uPARAP and MMP-2 take part in matrix turnover processes important for bone growth. However, in some physiological situations, these two components do not support the same step in the growth process. PMID- 23940734 TI - Hypoxia-ischemia or excitotoxin-induced tissue plasminogen activator- dependent gelatinase activation in mice neonate brain microvessels. AB - Hypoxia-ischemia (HI) and excitotoxicity are validated causes of neonatal brain injuries and tissue plasminogen activator (t-PA) participates in the processes through proteolytic and receptor-mediated pathways. Brain microvascular endothelial cells from neonates in culture, contain and release more t-PA and gelatinases upon glutamate challenge than adult cells. We have studied t-PA to gelatinase (MMP-2 and MMP-9) activity links in HI and excitotoxicity lesion models in 5 day-old pups in wild type and in t-PA or its inhibitor (PAI-1) genes inactivated mice. Gelatinolytic activities were detected in SDS-PAGE zymograms and by in situ fluorescent DQ-gelatin microscopic zymographies. HI was achieved by unilateral carotid ligature followed by a 40 min hypoxia (8%O2). Excitotoxic lesions were produced by intra parenchymal cortical (i.c.) injections of 10 ug ibotenate (Ibo). Gel zymograms in WT cortex revealed progressive extinction of MMP-2 and MMP-9 activities near day 15 or day 8 respectively. MMP-2 expression was the same in all strains while MMP-9 activity was barely detectable in t-PA-/- and enhanced in PAI-1-/- mice. HI or Ibo produced activation of MMP-2 activities 6 hours post-insult, in cortices of WT mice but not in t-PA-/- mice. In PAI-1-/- mice, HI or vehicle i.c. injection increased MMP-2 and MMP-9 activities. In situ zymograms using DQ-gelatin revealed vessel associated gelatinolytic activity in lesioned areas in PAI-1-/- and in WT mice. In WT brain slices incubated ex vivo, glutamate (200 uM) induced DQ-gelatin activation in vessels. The effect was not detected in t-PA-/- mice, but was restored by concomitant exposure to recombinant t-PA (20 ug/mL). In summary, neonatal brain lesion paradigms and ex vivo excitotoxic glutamate evoked t-PA-dependent gelatinases activation in vessels. Both MMP-2 and MMP-9 activities appeared t-PA-dependent. The data suggest that vascular directed protease inhibition may have neuroprotection potential against neonatal brain injuries. PMID- 23940736 TI - Newly standing infants increase postural stability when performing a supra postural task. AB - Independent stance is one of the most difficult motor milestones to achieve. Newly standing infants exhibit exaggerated body movements and can only stand for a brief amount of time. Given the difficult nature of bipedal stance, these unstable characteristics are slow to improve. However, we demonstrate that infants can increase their stability when engaged in a standing goal-directed task. Infants' balance was measured while standing and while standing and holding a visually attractive toy. When holding the toy, infants stood for a longer period of time, exhibited less body sway, and more mature postural dynamics. These results demonstrate that even with limited standing experience, infants can stabilize posture to facilitate performance of a concurrent task. PMID- 23940735 TI - Epitope mapping and in silico characterization of interactions between Der p 7 allergen and MoAb WH9. AB - Der p 7 is an important house dust mite allergen. However, antigenic determinants of Der p 7 are largely unknown. The purpose of this study is to analyze the determinants of Der p 7 and determine the structural basis of interactions between Der p 7 and WH9, an IgE-binding inhibition mouse monoclonal antibody (MoAb). IgE and WH9-reactive determinant(s) was identified by immunoblot using allergen mutants. A 3-D binary complex structure of Der p 7 and WH9 was simulated with homology modeling and docking methods. Our results obtained showed that among the five Der p 7 mutants (S156A, I157A, L158A, D159A, P160A), serum no. 1045 with IgE-binding against Der p 7 exhibited a reduced IgE immunoblot reactivity against Der p 7 L158A and D159A mutants. WH9 showed reduced immunoblot reactivity against S156A, L158A, D159A and P160A and the observation was confirmed by immunoblot inhibition. The WH9-binding determinant on Der p 7 containing S156, L158, D159 and P160 assumes a loop-like structure. The structural model of the Der p 7-WH9 complex suggests residues S156, I157, L158, D159 and P160 of Der p 7 contribute to WH9 binding via potential hydrogen bonds, electrostatic and hydrophobic interactions. In conclusion, MoAb WH9 interacts with critical residues L158 and D159 of Der p 7 and inhibits IgE-binding to Der p 7. Results obtained advance our understanding on molecular and structural bases of the antigenicity of Der p 7, its interactions with MoAb WH9 and facilitate the design of safer immunotherapy of human atopic disorders. PMID- 23940737 TI - Highly heterogeneous bacterial communities associated with the South China Sea reef corals Porites lutea, Galaxea fascicularis and Acropora millepora. AB - Coral harbor diverse and specific bacteria play significant roles in coral holobiont function. Bacteria associated with three of the common and phylogenetically divergent reef-building corals in the South China Sea, Porites lutea, Galaxea fascicularis and Acropora millepora, were investigated using 454 barcoded-pyrosequencing. Three colonies of each species were sampled, and 16S rRNA gene libraries were constructed individually. Analysis of pyrosequencing libraries showed that bacterial communities associated with the three coral species were more diverse than previous estimates based on corals from the Caribbean Sea, Indo-Pacific reefs and the Red Sea. Three candidate phyla, including BRC1, OD1 and SR1, were found for the first time in corals. Bacterial communities were separated into three groups: P. lutea and G. fascicular, A. millepora and seawater. P. lutea and G. fascicular displayed more similar bacterial communities, and bacterial communities associated with A. millepora differed from the other two coral species. The three coral species shared only 22 OTUs, which were distributed in Alphaproteobacteria, Deltaproteobacteria, Gammaproteobacteria, Chloroflexi, Actinobacteria, Acidobacteria and an unclassified bacterial group. The composition of bacterial communities within each colony of each coral species also showed variation. The relatively small common and large specific bacterial communities in these corals implies that bacterial associations may be structured by multiple factors at different scales and that corals may associate with microbes in terms of similar function, rather than identical species. PMID- 23940738 TI - Population level inference for multivariate MEG analysis. AB - Multivariate analysis is a very general and powerful technique for analysing Magnetoencephalography (MEG) data. An outstanding problem however is how to make inferences that are consistent over a group of subjects as to whether there are condition-specific differences in data features, and what are those features that maximise these differences. Here we propose a solution based on Canonical Variates Analysis (CVA) model scoring at the subject level and random effects Bayesian model selection at the group level. We apply this approach to beamformer reconstructed MEG data in source space. CVA estimates those multivariate patterns of activation that correlate most highly with the experimental design; the order of a CVA model is then determined by the number of significant canonical vectors. Random effects Bayesian model comparison then provides machinery for inferring the optimal order over the group of subjects. Absence of a multivariate dependence is indicated by the null model being the most likely. This approach can also be applied to CVA models with a fixed number of canonical vectors but supplied with different feature sets. We illustrate the method by identifying feature sets based on variable-dimension MEG power spectra in the primary visual cortex and fusiform gyrus that are maximally discriminative of data epochs before versus after visual stimulation. PMID- 23940739 TI - The epidemiology of hospitalization for pneumonia in children under five in the rural western region of Nepal: a descriptive study. AB - Pneumonia is one of the major public health problems in children under five years of age. The aim of this study was to analyze the time, place, and characteristics of the distribution of pneumonia in hospitalized children under five years of age at the Dhaulagiri Zonal Hospital (DZH) in Nepal. A descriptive cross-sectional study was carried out at DZH from July 16, 2008 to August 17, 2011 for hospitalized children under five years of age and diagnosed with pneumonia. The main bacterial cause of pneumonia was Streptococcus pneumoniae and the main viral cause was Respiratory Syntical Virus (RSV). The majority of children admitted for treatment of pneumonia were males (60%), from upper class ethnic groups, and common among those aged 29 days to one year (49.1% of overall pneumonia cases). Data from this study show that pneumonia episodes in DZH occurred throughout the year with a sharp increase in the occurrence at the end of August to September. More cases were recorded during the rainy seasons and winter months in all three study years. The cases were from households most concentrated in Baglung municipality where the hospital is located. Pneumonia was found in higher proportions among hospitalized male children, those aged 29 days to one year, and in upper ethnic groups, during the rainy seasons and in winter months, and among local populations near the hospital in the rural western region of Nepal. Strengthening community-based case management, prevention strategies, and health care delivery system would help reduce pneumonia cases and the overall burden associated with it. PMID- 23940740 TI - Absence of the common gamma chain (gamma(c)), a critical component of the Type I IL-4 receptor, increases the severity of allergic lung inflammation. AB - The T(H)2 cytokines, IL-4 and IL-13, play critical roles in inducing allergic lung inflammation and drive the alternative activation of macrophages (AAM). Although both cytokines share receptor subunits, IL-4 and IL-13 have differential roles in asthma pathogenesis: IL-4 regulates T(H)2 cell differentiation, while IL 13 regulates airway hyperreactivity and mucus production. Aside from controlling T(H)2 differentiation, the unique contribution of IL-4 signaling via the Type I receptor in airway inflammation remains unclear. Therefore, we analyzed responses in mice deficient in gamma c (gamma(c)) to elucidate the role of the Type I IL-4 receptor. OVA primed CD4+ OT-II T cells were adoptively transferred into RAG2-/- and gamma(c)-/- mice and allergic lung disease was induced. Both gamma(c)-/- and gammacxRAG2-/- mice developed increased pulmonary inflammation and eosinophilia upon OVA challenge, compared to RAG2-/- mice. Characteristic AAM proteins FIZZ1 and YM1 were expressed in lung epithelial cells in both mouse strains, but greater numbers of FIZZ1+ or YM1+ airways were present in gamma(c)-/- mice. Absence of gammac in macrophages, however, resulted in reduced YM1 expression. We observed higher T(H)2 cytokine levels in the BAL and an altered DC phenotype in the gamma(c)-/- recipient mice suggesting the potential for dysregulated T cell and dendritic cell (DC) activation in the gamma(c)-deficient environment. These results demonstrate that in absence of the Type I IL-4R, the Type II R can mediate allergic responses in the presence of T(H)2 effectors. However, the Type I R regulates AAM protein expression in macrophages. PMID- 23940741 TI - Prognostic value of EGFR mutation and ERCC1 in patients with non-small cell lung cancer undergoing platinum-based chemotherapy. AB - BACKGROUND: In order to improve the outcome of patients with non-small cell lung cancer (NSCLC), a biomarker that can predict the efficacy of chemotherapy is needed. The aim of this study was to assess the role of EGFR mutations and ERCC1 in predicting the efficacy of platinum-based chemotherapy and the outcome of patients with NSCLC. METHODS: We conducted a retrospective study to analyze the relationships between EGFR mutations or ERCC1 expression and progression-free survival (PFS) in patients with NSCLC who received platinum-based chemotherapy. EGFR mutation status was determined using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method, and immunohistochemistry was used to examine the expression of ERCC1 in tumor samples obtained from the patients. RESULTS: Among the NSCLC patients who received platinum-based chemotherapy, the median PFS was significantly better in those who had never smoked and those with exon 19 deletion, and the median overall survival (OS) was significantly better in those who had never smoked, those with exon 19 deletion, and women. Cox regression analysis revealed that exon 19 deletion and having never smoked were significantly associated with both PFS and OS. Subset analysis revealed a significant correlation between ERCC1 expression and EGFR mutation, and ERCC1 negative patients with exon 19 deletion had a longer PFS than the other patients; ERCC1-positive patients without exon 19 deletion had a shorter PFS than the other patients. CONCLUSIONS: Our results indicate that among NSCLC patients receiving platinum-based chemotherapy, those with exon 19 deletion have a longer PFS and OS. Our findings suggest that platinum-based chemotherapy is more effective against ERCC1-negative and exon 19-positive NSCLC. PMID- 23940742 TI - Increased B cell-activating factor promotes tumor invasion and metastasis in human pancreatic cancer. AB - B cell-activating factor (BAFF) is a cytokine belonging to the tumor necrosis factor (TNF) superfamily. It has been reported that BAFF is elevated in patients with autoimmune pancreatitis and contributes to the malignant potential of blood cancers and solid tumors. In this study, clinical evidence of increased BAFF levels in patients with pancreatic ductal adenocarcinoma (PDAC) was obtained, and the roles and mechanisms of BAFF in PDAC were clarified in human tissues of PDAC and from in vitro data of PDAC cell lines. Serum levels of BAFF in patients with PDAC were significantly higher than in healthy subjects (p = 0.0121). Patients with UICC stage IV PDAC (T1-4, N0-1, M1) had significantly higher levels of serum BAFF compared to patients with PDAC (p = 0.0182). BAFF was remarkably expressed in infiltrating B lymphocytes surrounding pancreatic cancer in human pancreatic tissues, suggesting that BAFF may play a role in progression of pancreatic cancer. PDAC cell lines were cultured with human recombinant BAFF, and morphology and gene expression were analyzed; pancreatic cancer cells changed to a fibroblast-like morphology, and showed altered gene expression of E-cadherin, vimentin and Snail. These BAFF-induced changes reflect enhanced cell motility and invasion. BAFF-R-overexpressing cell clones confirmed the association between these BAFF-induced changes and epithelial-mesenchymal transition (EMT)-related genes. BAFF was elevated in patients with metastatic advanced PDAC and induced alterations in PDAC cells via regulation of EMT-related genes. Elucidation of the precise role and mechanism of control of BAFF may lead to new therapeutic approaches with the aim of improving pancreatic cancer survival. PMID- 23940743 TI - Clinical and economic burden of community-acquired pneumonia among adults in the Czech Republic, Hungary, Poland and Slovakia. AB - We estimate and describe the incidence rates, mortality, and cost of CAP (community-acquired pneumonia), in both inpatient and outpatient settings, in the Czech Republic (CZ), Slovakia (SK), Poland (PL), and Hungary (HU). A retrospective analysis was conducted on administrative data from the health ministry and insurance reimbursement claims with a primary diagnosis of pneumonia in 2009 to determine hospitalization rates, costs, and mortality in adults >=50 years of age. Patient chart reviews were conducted to estimate the number of outpatient cases. Among all adults >=50 years, the incidence of hospitalized CAP per 100,000 person years was: 456.6 (CZ), 504.6 (SK), 363.9 (PL), and 845.3 (HU). The average fatality rate for all adults >=50 is 19.1%, and for each country; 21.7% (CZ), 20.9% (SK), 18.6% (PL), 17.8% (HU). Incidence, fatality, and likelihood of hospitalization increased with advancing age. Total healthcare costs of CAP in EUR was 12,579,543 (CZ); 9,160,774 (SK); 22,409,085 (PL); and 18,298,449 (HU); with hospitalization representing over 90% of the direct costs of treatment. The burden of CAP increases with advancing age in four CEE countries, with hospitalizations driving the costs of CAP upwards in the elderly population. Mortality rates are generally higher than reported in Western EU countries. PMID- 23940744 TI - A cost-utility analysis of lung cancer screening and the additional benefits of incorporating smoking cessation interventions. AB - BACKGROUND: A 2011 report from the National Lung Screening Trial indicates that three annual low-dose computed tomography (LDCT) screenings for lung cancer reduced lung cancer mortality by 20% compared to chest X-ray among older individuals at high risk for lung cancer. Discussion has shifted from clinical proof to financial feasibility. The goal of this study was to determine whether LDCT screening for lung cancer in a commercially-insured population (aged 50-64) at high risk for lung cancer is cost-effective and to quantify the additional benefits of incorporating smoking cessation interventions in a lung cancer screening program. METHODS AND FINDINGS: The current study builds upon a previous simulation model to estimate the cost-utility of annual, repeated LDCT screenings over 15 years in a high risk hypothetical cohort of 18 million adults between age 50 and 64 with 30+ pack-years of smoking history. In the base case, the lung cancer screening intervention cost $27.8 billion over 15 years and yielded 985,284 quality-adjusted life years (QALYs) gained for a cost-utility ratio of $28,240 per QALY gained. Adding smoking cessation to these annual screenings resulted in increases in both the costs and QALYs saved, reflected in cost utility ratios ranging from $16,198 per QALY gained to $23,185 per QALY gained. Annual LDCT lung cancer screening in this high risk population remained cost effective across all sensitivity analyses. CONCLUSIONS: The findings of this study indicate that repeat annual lung cancer screening in a high risk cohort of adults aged 50-64 is highly cost-effective. Offering smoking cessation interventions with the annual screening program improved the cost-effectiveness of lung cancer screening between 20% and 45%. The cost-utility ratios estimated in this study were in line with other accepted cancer screening interventions and support inclusion of annual LDCT screening for lung cancer in a high risk population in clinical recommendations. PMID- 23940745 TI - Trade-offs between predation risk and growth benefits in the copepod Eurytemora affinis with contrasting pigmentation. AB - Intraspecific variation in body pigmentation is an ecologically and evolutionary important trait; however, the pigmentation related trade-offs in marine zooplankton are poorly understood. We tested the effects of intrapopulation phenotypic variation in the pigmentation of the copepod Eurytemora affinis on predation risk, foraging, growth, metabolic activity and antioxidant capacity. Using pigmented and unpigmented specimens, we compared (1) predation and selectivity by the invertebrate predator Cercopagis pengoi, (2) feeding activity of the copepods measured as grazing rate in experiments and gut fluorescence in situ, (3) metabolic activity assayed as RNA:DNA ratio in both experimental and field-collected copepods, (4) reproductive output estimated as egg ratio in the population, and (5) total antioxidant capacity. Moreover, mitochondrial DNA (mtDNA) COI gene variation was analysed. The pigmented individuals were at higher predation risk as evidenced by significantly higher predation rate by C. pengoi on pigmented individuals and positive selection by the predator fed pigmented and unpigmented copepods in a mixture. However, the antioxidant capacity, RNA:DNA and egg ratio values were significantly higher in the pigmented copepods, whereas neither feeding rate nor gut fluorescence differed between the pigmented and unpigmented copepods. The phenotypic variation in pigmentation was not associated with any specific mtDNA genotype. Together, these results support the metabolic stimulation hypothesis to explain variation in E. affinis pigmentation, which translates into beneficial increase in growth via enhanced metabolism and antioxidant protective capacity, together with disadvantageous increase in predation risk. We also suggest an alternative mechanism for the metabolic stimulation via elevated antioxidant levels as a primary means of increasing metabolism without the increase in heat absorbance. The observed trade-offs are relevant to evolutionary mechanisms underlying plasticity and adaptation and have the capacity to modify strength of complex trophic interactions. PMID- 23940746 TI - Molecular detection of Rickettsia typhi in cats and fleas. AB - BACKGROUND: Rickettsiatyphi is the etiological agent of murine typhus (MT), a disease transmitted by two cycles: rat-flea-rat, and peridomestic cycle. Murine typhus is often misdiagnosed and underreported. A correct diagnosis is important because MT can cause severe illness and death. Our previous seroprevalence results pointed to presence of human R. typhi infection in our region; however, no clinical case has been reported. Although cats have been related to MT, no naturally infected cat has been described. The aim of the study is to confirm the existence of R. typhi in our location analyzing its presence in cats and fleas. METHODOLOGY/PRINCIPAL FINDINGS: 221 cats and 80 fleas were collected from Veterinary clinics, shelters, and the street (2001-2009). Variables surveyed were: date of collection, age, sex, municipality, living place, outdoor activities, demographic area, healthy status, contact with animals, and ectoparasite infestation. IgG against R. typhi were evaluated by indirect immunofluorescence assay. Molecular detection in cats and fleas was performed by real-time PCR. Cultures were performed in those cats with positive molecular detection. Statistical analysis was carried out using SPSS. A p < 0.05 was considered significant. Thirty-five (15.8%) cats were seropositive. There were no significant associations among seropositivity and any variables. R. typhi was detected in 5 blood and 2 cultures. High titres and molecular detection were observed in stray cats and pets, as well as in spring and winter. All fleas were Ctenocephalides felis. R. typhi was detected in 44 fleas (55%), from shelters and pets. Co-infection with R. felis was observed. CONCLUSIONS: Although no clinical case has been described in this area, the presence of R. typhi in cats and fleas is demonstrated. Moreover, a considerable percentage of those animals lived in households. To our knowledge, this is the first time R. typhi is detected in naturally infected cats. PMID- 23940747 TI - MyD88 deficiency markedly worsens tissue inflammation and bacterial clearance in mice infected with Treponema pallidum, the agent of syphilis. AB - Research on syphilis, a sexually transmitted infection caused by the non cultivatable spirochete Treponema pallidum, has been hampered by the lack of an inbred animal model. We hypothesized that Toll-like receptor (TLR)-dependent responses are essential for clearance of T. pallidum and, consequently, compared infection in wild-type (WT) mice and animals lacking MyD88, the adaptor molecule required for signaling by most TLRs. MyD88-deficient mice had significantly higher pathogen burdens and more extensive inflammation than control animals. Whereas tissue infiltrates in WT mice consisted of mixed mononuclear and plasma cells, infiltrates in MyD88-deficient animals were predominantly neutrophilic. Although both WT and MyD88-deficient mice produced antibodies that promoted uptake of treponemes by WT macrophages, MyD88-deficient macrophages were deficient in opsonophagocytosis of treponemes. Our results demonstrate that TLR mediated responses are major contributors to the resistance of mice to syphilitic disease and that MyD88 signaling and FcR-mediated opsonophagocytosis are linked to the macrophage-mediated clearance of treponemes. PMID- 23940748 TI - Shadows alter facial expressions of Noh masks. AB - BACKGROUND: A Noh mask, worn by expert actors during performance on the Japanese traditional Noh drama, conveys various emotional expressions despite its fixed physical properties. How does the mask change its expressions? Shadows change subtly during the actual Noh drama, which plays a key role in creating elusive artistic enchantment. We here describe evidence from two experiments regarding how attached shadows of the Noh masks influence the observers' recognition of the emotional expressions. METHODOLOGY/PRINCIPAL FINDINGS: In Experiment 1, neutral faced Noh masks having the attached shadows of the happy/sad masks were recognized as bearing happy/sad expressions, respectively. This was true for all four types of masks each of which represented a character differing in sex and age, even though the original characteristics of the masks also greatly influenced the evaluation of emotions. Experiment 2 further revealed that frontal Noh mask images having shadows of upward/downward tilted masks were evaluated as sad/happy, respectively. This was consistent with outcomes from preceding studies using actually tilted Noh mask images. CONCLUSIONS/SIGNIFICANCE: Results from the two experiments concur that purely manipulating attached shadows of the different types of Noh masks significantly alters the emotion recognition. These findings go in line with the mysterious facial expressions observed in Western paintings, such as the elusive qualities of Mona Lisa's smile. They also agree with the aesthetic principle of Japanese traditional art "yugen (profound grace and subtlety)", which highly appreciates subtle emotional expressions in the darkness. PMID- 23940749 TI - Uremic pruritus, dialysis adequacy, and metabolic profiles in hemodialysis patients: a prospective 5-year cohort study. AB - BACKGROUND: Uremic pruritus is a common and intractable symptom in patients on chronic hemodialysis, but factors associated with the severity of pruritus remain unclear. This study aimed to explore the associations of metabolic factors and dialysis adequacy with the aggravation of pruritus. METHODS: We conducted a 5 year prospective cohort study on patients with maintenance hemodialysis. A visual analogue scale (VAS) was used to assess the intensity of pruritus. Patient demographic and clinical characteristics, laboratory parameters, dialysis adequacy (assessed by Kt/V), and pruritus intensity were recorded at baseline and follow-up. Change score analysis of the difference score of VAS between baseline and follow-up was performed using multiple linear regression models. The optimal threshold of Kt/V, which is associated with the aggravation of uremic pruritus, was determined by generalized additive models and receiver operating characteristic analysis. RESULTS: A total of 111 patients completed the study. Linear regression analysis showed that lower Kt/V and use of low-flux dialyzer were significantly associated with the aggravation of pruritus after adjusting for the baseline pruritus intensity and a variety of confounding factors. The optimal threshold value of Kt/V for pruritus was 1.5 suggested by both generalized additive models and receiver operating characteristic analysis. CONCLUSIONS: Hemodialysis with the target of Kt/V >=1.5 and use of high-flux dialyzer may reduce the intensity of pruritus in patients on chronic hemodialysis. Further clinical trials are required to determine the optimal dialysis dose and regimen for uremic pruritus. PMID- 23940750 TI - Susceptibility of human placenta derived mesenchymal stromal/stem cells to human herpesviruses infection. AB - Fetal membranes (FM) derived mesenchymal stromal/stem cells (MSCs) are higher in number, expansion and differentiation abilities compared with those obtained from adult tissues, including bone marrow. Upon systemic administration, ex vivo expanded FM-MSCs preferentially home to damaged tissues promoting regenerative processes through their unique biological properties. These characteristics together with their immune-privileged nature and immune suppressive activity, a low infection rate and young age of placenta compared to other sources of SCs make FM-MSCs an attractive target for cell-based therapy and a valuable tool in regenerative medicine, currently being evaluated in clinical trials. In the present study we investigated the permissivity of FM-MSCs to all members of the human Herpesviridae family, an issue which is relevant to their purification, propagation, conservation and therapeutic use, as well as to their potential role in the vertical transmission of viral agents to the fetus and to their potential viral vector-mediated genetic modification. We present here evidence that FM-MSCs are fully permissive to infection with Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Varicella zoster virus (VZV), and Human Cytomegalovirus (HCMV), but not with Epstein-Barr virus (EBV), Human Herpesvirus-6, 7 and 8 (HHV-6, 7, 8) although these viruses are capable of entering FM-MSCs and transient, limited viral gene expression occurs. Our findings therefore strongly suggest that FM MSCs should be screened for the presence of herpesviruses before xenotransplantation. In addition, they suggest that herpesviruses may be indicated as viral vectors for gene expression in MSCs both in gene therapy applications and in the selective induction of differentiation. PMID- 23940751 TI - Auditory responses of engrailed and invected-expressing Johnston's Organ neurons in Drosophila melanogaster. AB - The roles of the transcription factor Engrailed (En), and its paralogue Invected (Inv), in adult Drosophila Johnston's Organ sensory neurons are unknown. We used en-GAL4 driven CD8-GFP and antibody staining to characterize these neurons in the pedicel (second antennal segment). The majority of En and Inv-expressing Johnston's Organ neurons (En-JONs) are located in the ventral part of the posterior group of JONs, with only a few in the medial group. Anatomical classification of En-JON axon projections shows they are mainly type A and E, with a few type B. Extracellular recording of sound-evoked potentials (SEPs) from the antennal nerve was used along with Kir2.1 silencing to assess the contribution that En-JONs make to the auditory response to pure-tone sound stimuli. Silencing En-JONs reduces the SEP amplitude at the onset of the stimulus by about half at 100, 200 and 400 Hz, and also reduces the steady-state response to 200 Hz. En-JONs respond to 82 dB and 92 dB sounds but not 98 dB. Despite their asymmetrical distribution in the Johnston's Organ they respond equally strongly to both directions of movement of the arista. This implies that individual neurons are excited in both directions, a conclusion supported by reanalysis of the morphology of the pedicel-funicular joint. Other methods of silencing the JONs were also used: RNAi against the voltage-gated Na+ channel encoded by the para gene, expression of attenuated diphtheria toxin, and expression of a modified influenza toxin M2(H37A). Only the latter was found to be more effective than Kir2.1. Three additional JON subsets were characterized using Flylight GAL4 lines. inv-GAL4 88B12 and Gycbeta100B-GAL4 12G03 express in different subsets of A group neurons and CG12484-GAL4 91G04 is expressed in B neurons. All three contribute to the auditory response to 200 Hz tones. PMID- 23940752 TI - Cations form sequence selective motifs within DNA grooves via a combination of cation-pi and ion-dipole/hydrogen bond interactions. AB - The fine conformational subtleties of DNA structure modulate many fundamental cellular processes including gene activation/repression, cellular division, and DNA repair. Most of these cellular processes rely on the conformational heterogeneity of specific DNA sequences. Factors including those structural characteristics inherent in the particular base sequence as well as those induced through interaction with solvent components combine to produce fine DNA structural variation including helical flexibility and conformation. Cation-pi interactions between solvent cations or their first hydration shell waters and the faces of DNA bases form sequence selectively and contribute to DNA structural heterogeneity. In this paper, we detect and characterize the binding patterns found in cation-pi interactions between solvent cations and DNA bases in a set of high resolution x-ray crystal structures. Specifically, we found that monovalent cations (Tl+) and the polarized first hydration shell waters of divalent cations (Mg2+, Ca2+) form cation-pi interactions with DNA bases stabilizing unstacked conformations. When these cation-pi interactions are combined with electrostatic interactions a pattern of specific binding motifs is formed within the grooves. PMID- 23940753 TI - Equal contributions and credit: an emerging trend in the characterization of authorship in major anaesthesia journals during a 10-yr period. AB - BACKGROUND: The practice of giving certain authors equal credit in original research publications was increasingly common in some specialty. This study aimed to investigate the prevalence and characteristics of designating some authors with equally credited authors (ECAs) in major anaesthesia journals. METHODOLOGY/PRINCIPAL FINDINGS: The practice of giving authors equal credit was searched and identified in the three major anaesthesia journals between January 1, 2002 and December 31, 2011. Papers with ECAs had a higher proportion of the total number of articles in 2011 versus published in 2002 (Anesthesiology, 8.8% vs. 0.9%; British Journal of Anaesthesia, 8.8% vs. 0%; Anesthesia & Analgesia, 3.4% vs. 0.3%; totally, 6.4% vs. 0.4%). A significant increasing trend in annual proportion of articles with ECA was found in the three journals. The first two authors listed in the byline had equal credit in most cases. CONCLUSIONS/SIGNIFICANCE: The practice of giving authors equal credit in original research papers is increasingly common in major anaesthesia journals. It may be warranted for the journals to guide the authors how to regard this practice. PMID- 23940754 TI - Whey protein reduces early life weight gain in mice fed a high-fat diet. AB - An increasing number of studies indicate that dairy products, including whey protein, alleviate several disorders of the metabolic syndrome. Here, we investigated the effects of whey protein isolate (whey) in mice fed a high-fat diet hypothesising that the metabolic effects of whey would be associated with changes in the gut microbiota composition. Five-week-old male C57BL/6 mice were fed a high-fat diet ad libitum for 14 weeks with the protein source being either whey or casein. Faeces were collected at week 0, 7, and 13 and the fecal microbiota was analysed by denaturing gradient gel electrophoresis analyses of PCR-derived 16S rRNA gene (V3-region) amplicons. At the end of the study, plasma samples were collected and assayed for glucose, insulin and lipids. Whey significantly reduced body weight gain during the first four weeks of the study compared with casein (P<0.001-0.05). Hereafter weight gain was similar resulting in a 15% lower final body weight in the whey group relative to casein (34.0+/-1.0 g vs. 40.2+/-1.3 g, P<0.001). Food intake was unaffected by protein source throughout the study period. Fasting insulin was lower in the whey group (P<0.01) and glucose clearance was improved after an oral glucose challenge (P<0.05). Plasma cholesterol was lowered by whey compared to casein (P<0.001). The composition of the fecal microbiota differed between high- and low-fat groups at 13 weeks (P<0.05) whereas no difference was seen between whey and casein. In conclusion, whey initially reduced weight gain in young C57BL/6 mice fed a high fat diet compared to casein. Although the effect on weight gain ceased, whey alleviated glucose intolerance, improved insulin sensitivity and reduced plasma cholesterol. These findings could not be explained by changes in food intake or gut microbiota composition. Further studies are needed to clarify the mechanisms behind the metabolic effects of whey. PMID- 23940755 TI - Api5 contributes to E2F1 control of the G1/S cell cycle phase transition. AB - BACKGROUND: The E2f transcription factor family has a pivotal role in controlling the cell fate in general, and in particular cancer development, by regulating the expression of several genes required for S phase entry and progression through the cell cycle. It has become clear that the transcriptional activation of at least one member of the family, E2F1, can also induce apoptosis. An appropriate balance of positive and negative regulators appears to be necessary to modulate E2F1 transcriptional activity, and thus cell fate. METHODOLOGY/PRINCIPAL FINDINGS: In this report, we show that Api5, already known as a regulator of E2F1 induced-apoptosis, is required for the E2F1 transcriptional activation of G1/S transition genes, and consequently, for cell cycle progression and cell proliferation. Api5 appears to be a cell cycle regulated protein. Removal of Api5 reduces cyclin E, cyclin A, cyclin D1 and Cdk2 levels, causing G1 cell cycle arrest and cell cycle delay. Luciferase assays established that Api5 directly regulates the expression of several G1/S genes under E2F1 control. Using protein/protein and protein/DNA immunoprecipitation studies, we demonstrate that Api5, even if not physically interacting with E2F1, contributes positively to E2F1 transcriptional activity by increasing E2F1 binding to its target promoters, through an indirect mechanism. CONCLUSION/SIGNIFICANCE: The results described here support the pivotal role of cell cycle related proteins, that like E2F1, may act as tumor suppressors or as proto-oncogenes during cancer development, depending on the behavior of their positive and negative regulators. According to our findings, Api5 contributes to E2F1 transcriptional activation of cell cycle associated genes by facilitating E2F1 recruitment onto its target promoters and thus E2F1 target gene transcription. PMID- 23940756 TI - Cathepsin G-dependent modulation of platelet thrombus formation in vivo by blood neutrophils. AB - Neutrophils are consistently associated with arterial thrombotic morbidity in human clinical studies but the causal basis for this association is unclear. We tested the hypothesis that neutrophils modulate platelet activation and thrombus formation in vivo in a cathepsin G-dependent manner. Neutrophils enhanced aggregation of human platelets in vitro in dose-dependent fashion and this effect was diminished by pharmacologic inhibition of cathepsin G activity and knockdown of cathepsin G expression. Tail bleeding time in the mouse was prolonged by a cathepsin G inhibitor and in cathepsin G knockout mice, and formation of neutrophil-platelet conjugates in blood that was shed from transected tails was reduced in the absence of cathepsin G. Bleeding time was highly correlated with blood neutrophil count in wildtype but not cathepsin G deficient mice. In the presence of elevated blood neutrophil counts, the anti-thrombotic effect of cathepsin G inhibition was greater than that of aspirin and additive to it when administered in combination. Both pharmacologic inhibition of cathepsin G and its congenital absence prolonged the time for platelet thrombus to form in ferric chloride-injured mouse mesenteric arterioles. In a vaso-occlusive model of ischemic stroke, inhibition of cathepsin G and its congenital absence improved cerebral blood flow, reduced histologic brain injury, and improved neurobehavioral outcome. These experiments demonstrate that neutrophil cathepsin G is a physiologic modulator of platelet thrombus formation in vivo and has potential as a target for novel anti-thrombotic therapies. PMID- 23940757 TI - Impact of contextual factors and substance characteristics on perspectives toward cognitive enhancement. AB - Enhancing cognitive performance with substances--especially prescription drugs- is a fiercely debated topic among scholars and in the media. The empirical basis for these discussions is limited, given that the actual nature of factors that influence the acceptability of and willingness to use cognitive enhancement substances remains unclear. In an online factorial survey, contextual and substance-specific characteristics of substances that improve academic performance were varied experimentally and presented to respondents. Students in four German universities rated their willingness to use and moral acceptance of different substances for cognitive enhancement. We found that the overall willingness to use performance enhancing substances is low. Most respondents considered the use of these substances as morally unacceptable. Situational influences such as peer pressure, policies concerning substance use, relative performance level of peers, but also characteristics of the substance, such as perceptions of substance safety, shape the willingness and acceptability of using a substance to enhance academic performance. Among the findings is evidence of a contagion effect meaning that the willingness was higher when the respondents have more CE drug users in their social network. We also found deterrence effects from strong side effects of using the substance, as well as from policy regulations and sanctions. Regulations might activate social norms against usage and sanctions can be seen as costly to users. Moreover, enhancement substances seem to be most tempting to low performers to catch up with others compared to high performers. By identifying contextual factors and substance characteristics influencing the willingness and acceptability of cognitive enhancers, policy approaches could consider these insights to better manage the use of such substances. PMID- 23940758 TI - Quantifying beetle-mediated effects on gas fluxes from dung pats. AB - Agriculture is one of the largest contributors of the anthropogenic greenhouse gases (GHGs) responsible for global warming. Measurements of gas fluxes from dung pats suggest that dung is a source of GHGs, but whether these emissions are modified by arthropods has not been studied. A closed chamber system was used to measure the fluxes of carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) from dung pats with and without dung beetles on a grass sward. The presence of dung beetles significantly affected the fluxes of GHGs from dung pats. Most importantly, fresh dung pats emitted higher amounts of CO2 and lower amounts of CH4 per day in the presence than absence of beetles. Emissions of N2O showed a distinct peak three weeks after the start of the experiment--a pattern detected only in the presence of beetles. When summed over the main grazing season (June July), total emissions of CH4 proved significantly lower, and total emissions of N2O significantly higher in the presence than absence of beetles. While clearly conditional on the experimental conditions, the patterns observed here reveal a potential impact of dung beetles on gas fluxes realized at a small spatial scale, and thereby suggest that arthropods may have an overall effect on gas fluxes from agriculture. Dissecting the exact mechanisms behind these effects, mapping out the range of conditions under which they occur, and quantifying effect sizes under variable environmental conditions emerge as key priorities for further research. PMID- 23940759 TI - Sleepless in town--drivers of the temporal shift in dawn song in urban European blackbirds. AB - Organisms living in urban environments are exposed to different environmental conditions compared to their rural conspecifics. Especially anthropogenic noise and artificial night light are closely linked to urbanization and pose new challenges to urban species. Songbirds are particularly affected by these factors, because they rely on the spread of acoustic information and adjust their behaviour to the rhythm of night and day, e.g. time their dawn song according to changing light intensities. Our aim was to clarify the specific contributions of artificial night light and traffic noise on the timing of dawn song of urban European Blackbirds (Turdus merula). We investigated the onset of blackbird dawn song along a steep urban gradient ranging from an urban forest to the city centre of Leipzig, Germany. This gradient of anthropogenic noise and artificial night light was reflected in the timing of dawn song. In the city centre, blackbirds started their dawn song up to 5 hours earlier compared to those in semi-natural habitats. We found traffic noise to be the driving factor of the shift of dawn song into true night, although it was not completely separable from the effects of ambient night light. We additionally included meteorological conditions into the analysis and found an effect on the song onset. Cloudy and cold weather delayed the onset, but cloud cover was assumed to reflect night light emissions, thus, amplified sky luminance and increased the effect of artificial night light. Beside these temporal effects, we also found differences in the spatial autocorrelation of dawn song onset showing a much higher variability in noisy city areas than in rural parks and forests. These findings indicate that urban hazards such as ambient noise and light pollution show a manifold interference with naturally evolved cycles and have significant effects on the activity patterns of urban blackbirds. PMID- 23940760 TI - TNF-Alpha may mediate inflammasome activation in the absence of bacterial infection in more than one way. AB - Members of the mammalian nucleotide binding domain, leucine-rich repeat (LRR) containing receptor family of proteins are key modulators of innate immunity regulating inflammation. To date, microbial pathogen-associated molecules and toxins have been identified as key triggers of activation of inflammasomes. However, recently, environmental, and neurodegenerative stimuli have been identified that lead to IL-1beta release by means of inflammasomes. IL-1beta plays a crucial role during brain inflammation, and caspase-1 appears to be a key modulator of IL-1beta bioactivity and the consequent transcriptional regulation of gene expression within the brain during inflammation. We show here that exposure of a human neuroblastoma cell line (SK-N-MC cells) to TNF-alpha promotes ROS-mediated caspase-1 activation and IL-1beta secretion. The involvement of NF kappaB in the regulation of IL-1beta synthesis is investigated through specific inhibition of this transcription factor. The effect of TNF-alpha was abolished in the presence of ROS inhibitors as NAC, or DPI. Remarkably, SK-N-MC cells do not respond to ATP stimulation in spite of P2X7R expression. These results provide a mechanism by which danger signals and particulate matter mediate inflammation via the inflammasome in the absence of microbial infection. PMID- 23940761 TI - Multiparametric, longitudinal optical coherence tomography imaging reveals acute injury and chronic recovery in experimental ischemic stroke. AB - Progress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties. PMID- 23940762 TI - Family-based behavioural intervention program for obese children: an observational study of child and parent lifestyle interpretations. AB - BACKGROUND: Family-based behavioural intervention programs (FBIPs) against childhood obesity have shown promising results, but the mediating mechanisms have not been identified. The aim of this study was to examine changes in obese childrens lifestyle habits during a 2-year FBIP according to their own and parents' reports, the concordance between these reports and the correlations to change in post-intervention z-BMI. METHODS: An observational study of 26 children (8.3-12.0 years) and their parents participating in a 2-year FBIP was performed. Weight and height were measured from baseline to 12 months after the end of the program. Eating habits and physical- and sedentary activity were reported separately by children and parents. Data were analysed with regard to concordance between parents' and children's reports and association between the lifestyle reports and change in z-BMI at the study endpoint using descriptive statistics and parametric and non-parametric tests. RESULTS: According to both children's and parents' reports, the level of physical activity among the children had increased after the intervention as well as the agreement between the informants' reports. According to the children, eating habits had improved, while the parents' reports showed an improvement only with regard to binge eating. The concordance between children and parents regarding eating habits was slight to fair also after the intervention. No statistically significant associations between changes in lifestyle reports and changes in z-BMI were observed. CONCLUSIONS: Child and parent reports of physical activity were found to converge and display an improvement in a 2-year FBIP, while the reports on eating habits showed a more refractory pattern. Changes in concordance and agreement between children and parents reports did not correlate with weight reduction. Further methods development and studies of the processes during family-based interventions against childhood obesity are warranted. PMID- 23940763 TI - Metagenomic guilt by association: an operonic perspective. AB - Next-generation sequencing projects continue to drive a vast accumulation of metagenomic sequence data. Given the growth rate of this data, automated approaches to functional annotation are indispensable and a cornerstone heuristic of many computational protocols is the concept of guilt by association. The guilt by association paradigm has been heavily exploited by genomic context methods that offer functional predictions that are complementary to homology-based annotations, thereby offering a means to extend functional annotation. In particular, operon methods that exploit co-directional intergenic distances can provide homology-free functional annotation through the transfer of functions among co-operonic genes, under the assumption that guilt by association is indeed applicable. Although guilt by association is a well-accepted annotative device, its applicability to metagenomic functional annotation has not been definitively demonstrated. Here a large-scale assessment of metagenomic guilt by association is undertaken where functional associations are predicted on the basis of co directional intergenic distances. Specifically, functional annotations are compared within pairs of adjacent co-directional genes, as well as operons of various lengths (i.e. number of member genes), in order to reveal new information about annotative cohesion versus operon length. The results suggests that co directional gene pairs offer reduced confidence for metagenomic guilt by association due to difficulty in resolving the existence of functional associations when intergenic distance is the sole predictor of pairwise gene interactions. However, metagenomic operons, particularly those with substantial lengths, appear to be capable of providing a superior basis for metagenomic guilt by association due to increased annotative stability. The need for improved recognition of metagenomic operons is discussed, as well as the limitations of the present work. PMID- 23940764 TI - Serum can overcome contact inhibition in confluent human pulmonary artery smooth muscle cells. AB - Pulmonary artery endothelial cells (PAEC) in an intact vessel are continually exposed to serum, but unless injured, do not proliferate, constrained by confluence. In contrast, pulmonary artery smooth muscle cells (PASMC) attain, and maintain, confluence in the presence of minimal serum, protected from serum's stimulatory effects except when the endothelial barrier becomes more permeable. We hypothesized therefore, that confluent PASMC may be less constrained by contact inhibition in the presence of serum than PAEC and tested this idea by exposing confluent non-transformed human PAEC and PASMC to media containing increasing concentrations of fetal bovine serum (FBS) and determining cell growth over 7 days. PAEC that had attained confluence in low serum did not proliferate even when exposed to 5% serum, the highest concentration tested. In contrast, PASMC that attained confluence in low serum did proliferate once serum levels were increased, an effect that was dose dependent. Consistent with this observation, PASMC had more BrdU incorporation and a greater percentage of cells in S phase in 5% compared to 0.2% FBS, whereas no such difference was seen in PAEC. These results suggest that confluent human PAEC are resistant to the stimulatory effects of serum, whereas confluent PASMC can proliferate when serum levels are increased, an effect mediated in part by differences in phosphoinositide 3-kinase activation. This observation may be relevant to understanding the PASMC hyperplasia observed in humans and animals with pulmonary hypertension in which changes in endothelial permeability due to hypoxia or injury expose the underlying smooth muscle to serum. PMID- 23940765 TI - A Monte Carlo permutation test for random mating using genome sequences. AB - Testing for random mating of a population is important in population genetics, because deviations from randomness of mating may indicate inbreeding, population stratification, natural selection, or sampling bias. However, current methods use only observed numbers of genotypes and alleles, and do not take advantage of the fact that the advent of sequencing technology provides an opportunity to investigate this topic in unprecedented detail. To address this opportunity, a novel statistical test for random mating is required in population genomics studies for which large sequencing datasets are generally available. Here, we propose a Monte-Carlo-based-permutation test (MCP) as an approach to detect random mating. Computer simulations used to evaluate the performance of the permutation test indicate that its type I error is well controlled and that its statistical power is greater than that of the commonly used chi-square test (CHI). Our simulation study shows the power of our test is greater for datasets characterized by lower levels of migration between subpopulations. In addition, test power increases with increasing recombination rate, sample size, and divergence time of subpopulations. For populations exhibiting limited migration and having average levels of population divergence, the statistical power approaches 1 for sequences longer than 1 Mbp and for samples of 400 individuals or more. Taken together, our results suggest that our permutation test is a valuable tool to detect random mating of populations, especially in population genomics studies. PMID- 23940766 TI - Population status of Pan troglodytes verus in Lagoas de Cufada Natural Park, Guinea-Bissau. AB - The western chimpanzee, Pan troglodytes verus, has been classified as Endangered on the IUCN Red List since 1988. Intensive agriculture, commercial plantations, logging, and mining have eliminated or degraded the habitats suitable for P. t. verus over a large part of its range. In this study we assessed the effect of land-use change on the population size and density of chimpanzees at Lagoas de Cufada Natural Park (LCNP), Guinea-Bissau. We further explored chimpanzee distribution in relation to landscape-level proxies of human disturbance. Nest count and distance-sampling methods were employed along 11 systematically placed linear transects in 2010 and 2011. Estimated nest decay rate was 293.9 days (%CV = 58.8). Based on this estimate of decay time and using the Standing-Crop Nest Count Method, we obtained a habitat-weighted average chimpanzee density estimate for 2011 of 0.22 nest building chimpanzees/km(2) (95% CI 0.08-0.62), corresponding to 137 (95% CI 51.0-390.0) chimpanzees for LCNP. Human disturbance had a negative influence on chimpanzee distribution as nests were built farther away from human settlements, roads, and rivers than if they were randomly distributed, coinciding with the distribution of the remaining patches of dense canopy forest. We conclude that the continuous disappearance of suitable habitat (e.g. the replacement of LCNP's dense forests by monocultures of cashew plantations) may be compromising the future of one of the most threatened Guinean coastal chimpanzee populations. We discuss strategies to ensure long-term conservation in this important refuge for this chimpanzee subspecies at its westernmost margin of geographic distribution. PMID- 23940767 TI - The Fas/Fas ligand death receptor pathway contributes to phenylalanine-induced apoptosis in cortical neurons. AB - Phenylketonuria (PKU), an autosomal recessive disorder of amino acid metabolism caused by mutations in the phenylalanine hydroxylase (PAH) gene, leads to childhood mental retardation by exposing neurons to cytotoxic levels of phenylalanine (Phe). A recent study showed that the mitochondria-mediated (intrinsic) apoptotic pathway is involved in Phe-induced apoptosis in cultured cortical neurons, but it is not known if the death receptor (extrinsic) apoptotic pathway and endoplasmic reticulum (ER) stress-associated apoptosis also contribute to neurodegeneration in PKU. To answer this question, we used specific inhibitors to block each apoptotic pathway in cortical neurons under neurotoxic levels of Phe. The caspase-8 inhibitor Z-IETD-FMK strongly attenuated apoptosis in Phe-treated neurons (0.9 mM, 18 h), suggesting involvement of the Fas receptor (FasR)-mediated cell death receptor pathway in Phe toxicity. In addition, Phe significantly increased cell surface Fas expression and formation of the Fas/FasL complex. Blocking Fas/FasL signaling using an anti-Fas antibody markedly inhibited apoptosis caused by Phe. In contrast, blocking the ER stress-induced cell death pathway with salubrinal had no effect on apoptosis in Phe-treated cortical neurons. These experiments demonstrate that the Fas death receptor pathway contributes to Phe-induced apoptosis and suggest that inhibition of the death receptor pathway may be a novel target for neuroprotection in PKU patients. PMID- 23940769 TI - 18F-FDG PET metabolic parameters and MRI perfusion and diffusion parameters in hepatocellular carcinoma: a preliminary study. AB - OBJECTIVES: Glucose metabolism, perfusion, and water diffusion may have a relationship or affect each other in the same tumor. The understanding of their relationship could expand the knowledge of tumor characteristics and contribute to the field of oncologic imaging. The purpose of this study was to evaluate the relationships between metabolism, vasculature and cellularity of advanced hepatocellular carcinoma (HCC), using multimodality imaging such as 18F-FDG positron emission tomography (PET), dynamic contrast enhanced (DCE)-MRI, and diffusion weighted imaging(DWI). MATERIALS AND METHODS: Twenty-one patients with advanced HCC underwent 18F-FDG PET, DCE-MRI, and DWI before treatment. Maximum standard uptake values (SUV(max)) from 18F-FDG-PET, variables of the volume transfer constant (K(trans)) from DCE-MRI and apparent diffusion coefficient (ADC) from DWI were obtained for the tumor and their relationships were examined by Spearman's correlation analysis. The influence of portal vein thrombosis on SUV(max) and variables of K(trans) and ADC was evaluated by Mann-Whitney test. RESULTS: SUV(max) showed significant negative correlation with K(trans)(max) (rho = -0.622, p = 0.002). However, variables of ADC showed no relationship with variables of K(trans) or SUV(max) (p>0.05). Whether portal vein thrombosis was present or not did not influence the SUV max and variables of ADC and K(trans) (p>0.05). CONCLUSION: In this study, SUV was shown to be correlated with K(trans) in advanced HCCs; the higher the glucose metabolism a tumor had, the lower the perfusion it had, which might help in guiding target therapy. PMID- 23940768 TI - Global transcriptome analysis of orange wheat blossom midge, Sitodiplosis mosellana (Gehin) (Diptera: Cecidomyiidae) to identify candidate transcripts regulating diapause. AB - BACKGROUND: Many insects enter a developmental arrest (diapause) that allows them to survive harsh seasonal conditions. Despite the well-established ecological significance of diapause, the molecular basis of this crucial adaptation remains largely unresolved. Sitodiplosis mosellana (Gehin), the orange wheat blossom midge (OWBM), causes serious damage to wheat throughout the northern hemisphere, and sporadic outbreaks occur in the world. Traits related to diapause appear to be important factors contributing to their rapid spread and outbreak. To better understand the diapause mechanisms of OWBM, we sequenced the transcriptome and determined the gene expression profile of this species. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we performed de novo transcriptome analysis using short read sequencing technology (Illumina) and gene expression analysis with a tag based digital gene expression (DGE) system. The sequencing results generated 89,117 contigs, and 45,713 unigenes. These unigenes were annotated by Blastx alignment against the NCBI non-redundant (nr), Clusters of orthologous groups (COG), gene orthology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. 20,802 unigenes (45.5% of the total) matched with protein in the NCBI nr database. Two digital gene expression (DGE) libraries were constructed to determine differences in gene expression profiles during diapause and non-diapause developmental stages. Genes related to diapause were analyzed in detail and in addition, nine diapause-related genes were analyzed by real time PCR. CONCLUSIONS/SIGNIFICANCE: The OWBM transcriptome greatly improves our genetic understanding and provides a platform for functional genomics research of this species. The DGE profiling data provides comprehensive information at the transcriptional level that facilitates our understanding of the molecular mechanisms of various physiological aspects including development and diapause stages in OWBM. From this study it is evident that various genes coding metabolic enzymes are crucial for diapause and metamorphosis. PMID- 23940770 TI - Expression and function of the lipocalin-2 (24p3/NGAL) receptor in rodent and human intestinal epithelia. AB - The lipocalin 2//NGAL/24p3 receptor (NGAL-R/24p3-R) is expressed in rodent distal nephron where it mediates protein endocytosis. The mechanisms of apical endocytosis and transcytosis of proteins and peptides in the intestine are poorly understood. In the present study, the expression and localization of rodent 24p3 R (r24p3-R) and human NGAL-R (hNGAL-R) was investigated in intestinal segments by immunofluorescence and confocal laser scanning microscopy, immunohistochemistry and immunoblotting. r24p3-R/hNGAL-R was also studied in human Caco-2 BBE cells and CHO cells transiently transfected with r24p3-R by immunofluorescence microscopy, RT-PCR and immunoblotting of plasma membrane enriched vesicles (PM). To assay function, endocytosis/transcytosis of putative ligands phytochelatin (PC3), metallothionein (MT) and transferrin (Tf) was assayed by measuring internalization of fluorescence-labelled ligands in Caco-2 BBE cells grown on plastic or as monolayers on Transwell inserts. The binding affinity of Alexa 488 PC3 to colon-like Caco-2 BBE PM was quantified by microscale thermophoresis (MST). r24p3-R/hNGAL-R expression was detected apically in all intestinal segments but showed the highest expression in ileum and colon. Colon-like, but not duodenum-like, Caco-2 BBE cells expressed hNGAL-R on their surface. Colon like Caco-2 BBE cells or r24p3-R transfected CHO cells internalized fluorescence labelled PC3 or MT with half-maximal saturation at submicromolar concentrations. Uptake of PC3 and MT (0.7 uM) by Caco-2 BBE cells was partially blocked by hNGAL (500 pM) and an EC50 of 18.6 +/- 12.2 nM was determined for binding of Alexa 488 PC3 to PM vesicles by MST. Transwell experiments showed rapid (0.5-2 h) apical uptake and basolateral delivery of fluorescent PC3/MT/Tf (0.7 uM). Apical uptake of ligands was significantly blocked by 500 pM hNGAL. hNGAL-R dependent uptake was more prominent with MT but transcytosis efficiency was reduced compared to PC3 and Tf. Hence, r24p3-R/hNGAL-R may represent a high-affinity multi-ligand receptor for apical internalization and transcytosis of intact proteins/peptides by the lower intestine. PMID- 23940771 TI - Cellular apoptosis of hemocytes from Dendrolimus tabulaeformis Tsai et Liu larvae induced with the secondary metabolites of Beauveria brongniartii (Sacc.) Petch. AB - To investigate the effect of the secondary metabolites of entomopathogenic fungus on the hemocyte immunity of host insect, the secondary metabolite complex (SMC) of Beauveriabrongniartii was used in three concentrations (5.5, 55, and 550 ug/mL), and the 4(th) instar larvae of the pine caterpillar Dendrolimustabulaeformis were employed as host insects. The larvae were inoculated with the SMC solutions by injection in bioassays. Apoptosis of the larval hemocytes was observed using fluorescence microscopy (FM), transmission electron microscopy (TEM), and flow cytometry (FCM). The FM results showed that in the treated groups, larval hemocytes exhibited symptoms of early apoptosis at 6 h post-treatment by radiating a non-uniform kelly fluorescence and exhibited symptoms of late apoptosis at 12 h post-treatment by radiating a non-uniform orange fluorescence. Under TEM, the following ultra-structural changes associated with apoptosis of the larval hemocytes were observed in the treated groups: the nuclei were hypertrophied, slight folds were on the nuclear envelope, the chromatin became concentrated, the mitochondrial cristae disappeared or were disorderly, most cells developed blebs, and fibrillar aggregation appeared and accumulated in the cytoplasm. Apoptosis of the larval hemocytes was detected by FCM at 6 h post-treatment; the percentage of early apoptotic cells in the SMC 5.5, 55, and 550 ug/mL treatment groups were 11.93%, 13.10%, and 18.42%, respectively. Late apoptosis first occurred at 12 h post-treatment; the highest rate of apoptosis was 36.54 +/- 4.37% at 24 h post-treatment in the SMC 55 ug/mL treatment group. In general, the cellular apoptosis rate was positively correlated with the SMC concentration and the time post-treatment. These results indicate that secondary metabolites of B. brongniartii are able to attack the hemocytes of D. tabulaeformis larvae and induce cellular apoptosis, thereby providing new evidence that secondary metabolites of mycopathogens can act on host immune systems. PMID- 23940772 TI - Hard-on-hard lubrication in the artificial hip under dynamic loading conditions. AB - The tribological performance of an artificial hip joint has a particularly strong influence on its success. The principle causes for failure are adverse short- and long-term reactions to wear debris and high frictional torque in the case of poor lubrication that may cause loosening of the implant. Therefore, using experimental and theoretical approaches models have been developed to evaluate lubrication under standardized conditions. A steady-state numerical model has been extended with dynamic experimental data for hard-on-hard bearings used in total hip replacements to verify the tribological relevance of the ISO 14242-1 gait cycle in comparison to experimental data from the Orthoload database and instrumented gait analysis for three additional loading conditions: normal walking, climbing stairs and descending stairs. Ceramic-on-ceramic bearing partners show superior lubrication potential compared to hard-on-hard bearings that work with at least one articulating metal component. Lubrication regimes during the investigated activities are shown to strongly depend on the kinematics and loading conditions. The outcome from the ISO gait is not fully confirmed by the normal walking data and more challenging conditions show evidence of inferior lubrication. These findings may help to explain the differences between the in vitro predictions using the ISO gait cycle and the clinical outcome of some hard on-hard bearings, e.g., using metal-on-metal. PMID- 23940773 TI - Who learns more? Cultural differences in implicit sequence learning. AB - BACKGROUND: It is well documented that East Asians differ from Westerners in conscious perception and attention. However, few studies have explored cultural differences in unconscious processes such as implicit learning. METHODOLOGY/PRINCIPAL FINDINGS: The global-local Navon letters were adopted in the serial reaction time (SRT) task, during which Chinese and British participants were instructed to respond to global or local letters, to investigate whether culture influences what people acquire in implicit sequence learning. Our results showed that from the beginning British expressed a greater local bias in perception than Chinese, confirming a cultural difference in perception. Further, over extended exposure, the Chinese learned the target regularity better than the British when the targets were global, indicating a global advantage for Chinese in implicit learning. Moreover, Chinese participants acquired greater unconscious knowledge of an irrelevant regularity than British participants, indicating that the Chinese were more sensitive to contextual regularities than the British. CONCLUSIONS/SIGNIFICANCE: The results suggest that cultural biases can profoundly influence both what people consciously perceive and unconsciously learn. PMID- 23940774 TI - Do older professional musicians have cognitive advantages? AB - The current study investigates whether long-term music training and practice are associated with enhancement of general cognitive abilities in late middle-aged to older adults. Professional musicians and non-musicians who were matched on age, education, vocabulary, and general health were compared on a near-transfer task involving auditory processing and on far-transfer tasks that measured spatial span and aspects of cognitive control. Musicians outperformed non-musicians on the near-transfer task, on most but not all of the far-transfer tasks, and on a composite measure of cognitive control. The results suggest that sustained music training or involvement is associated with improved aspects of cognitive functioning in older adults. PMID- 23940775 TI - TNF-alpha acts as an immunoregulator in the mouse brain by reducing the incidence of severe disease following Japanese encephalitis virus infection. AB - Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from mild to fatal outcome. Comparison of the pathogenetic response between severe and mild cases of JaOArS982-infected mice revealed increased levels of TNF-alpha in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-alpha KO mice was significantly increased compared with that of WT mice, indicating that TNF-alpha plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-alpha KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-alpha KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-alpha KO mice. Our findings therefore provide the first evidence that TNF-alpha has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease. Thus, we propose that the increased level of TNF-alpha in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease. In future, further elucidation of the immunoregulatory mechanism of TNF-alpha will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis. PMID- 23940776 TI - Functional analysis of Tcl1 using Tcl1-deficient mouse embryonic stem cells. AB - Tcl1 is highly expressed in embryonic stem (ES) cells, but its expression rapidly decreases following differentiation. To assess Tcl1's roles in ES cells, we generated Tcl1-deficient and -overexpressing mouse ES cell lines. We found that Tcl1 was neither essential nor sufficient for maintaining the undifferentiated state. Tcl1 is reported to activate Akt and to enhance cell proliferation. We found that Tcl1 expression levels correlated positively with the proliferation rate and negatively with the apoptosis of ES cells, but did not affect Akt phosphorylation. On the other hand, the phosphorylation level of beta-catenin decreased in response to Tcl1 overexpression. We measured the beta-catenin activity using the TOPflash reporter assay, and found that wild-type ES cells had low activity, which Tcl1 overexpression enhanced 1.8-fold. When the canonical Wnt signaling is activated by beta-catenin stabilization, it reportedly helps maintain ES cells in the undifferentiated state. We then performed DNA microarray analyses between the Tcl1-deficient and -expressing ES cells. The results revealed that Tcl1 expression downregulated a distinct group of genes, including Ndp52, whose expression is very high in blastocysts but reduced in the primitive ectoderm. Based on these results, we discuss the possible roles of Tcl1 in ES cells. PMID- 23940777 TI - Oviduct infection and hydrosalpinx in DBA1/j mice is induced by intracervical but not intravaginal inoculation with Chlamydia muridarum. AB - Intravaginal infection with C. muridarum in mice often results in hydrosalpinx similar to that found in women urogenitally infected with C. trachomatis, making the C. muridarum lower genital tract infection murine model suitable for studying C. trachomatis pathogenesis. To our surprise, DBA1/j mice were highly resistant to hydrosalpinx following an intravaginal infection with C. muridarum although these mice were as susceptible to lower genital tract infection as other mouse strains. A significantly lower level of C. muridarum organisms was recovered from the oviduct of DBA1/j mice, correlating the resistance to hydrosalpinx with reduced ascension of C. muridarum to the oviduct. The DBA1/j resistance to hydrosalpinx was effectively overcome by intracervical inoculation with C. muridarum. The intracervically inoculated DBA1/j mice developed severe hydrosalpinx with the highest levels of live C. muridarum organisms recovered from uterine tissue on day 3 and oviduct tissue on day 7 post inoculation while in intravaginally inoculated DBA1/j mice, the peak of live organism recovery from uterine tissue was delayed to day 7 with no rise in the amount of live organisms recovered from the oviduct. These observations have not only validated the correlation between hydrosalpinx and live organism invasion in the oviduct but also demonstrated that the intracervical inoculation, by promoting rapid chlamydial replication in the uterine epithelial cells and ascension to the oviduct of DBA1/j mice, may be used for further understanding chlamydial pathogenic mechanisms. The above findings also suggest that strategies aimed at reducing tubal infection may be most effective in blocking tubal pathology. PMID- 23940778 TI - Proteomic analysis of signaling network regulation in renal cell carcinomas with differential hypoxia-inducible factor-2alpha expression. AB - BACKGROUND: The loss of von Hippel-Lindau (VHL) protein function leads to highly vascular renal tumors characterized by an aggressive course of disease and refractoriness to chemotherapy and radiotherapy. Loss of VHL in renal tumors also differs from tumors of other organs in that the oncogenic cascade is mediated by an increase in the levels of hypoxia-inducible factor-2alpha (HIF2alpha) instead of hypoxia-inducible factor-1alpha (HIF1alpha). METHODS AND PRINCIPAL FINDINGS: We used renal carcinoma cell lines that recapitulate the differences between mutant VHL and wild-type VHL genotypes. Utilizing a method relying on extracted peptide intensities as a label-free approach for quantitation by liquid chromatography-mass spectrometry, our proteomics study revealed regulation of key proteins important for cancer cell survival, proliferation and stress-resistance, and implicated differential regulation of signaling networks in VHL-mutant renal cell carcinoma. We also observed upregulation of cellular energy pathway enzymes and the stress-responsive mitochondrial 60-kDa heat shock protein. Finding reliance on glutaminolysis in VHL-mutant renal cell carcinoma was of particular significance, given the generally predominant dependence of tumors on glycolysis. The data have been deposited to the ProteomeXchange with identifier PXD000335. CONCLUSIONS AND SIGNIFICANCE: Pathway analyses provided corroborative evidence for differential regulation of molecular and cellular functions influencing cancer energetics, metabolism and cell proliferation in renal cell carcinoma with distinct VHL genotype. Collectively, the differentially regulated proteome characterized by this study can potentially guide translational research specifically aimed at effective clinical interventions for advanced VHL-mutant, HIF2alpha-over-expressing tumors. PMID- 23940779 TI - Identification of bicluster regions in a binary matrix and its applications. AB - Biclustering has emerged as an important approach to the analysis of large-scale datasets. A biclustering technique identifies a subset of rows that exhibit similar patterns on a subset of columns in a data matrix. Many biclustering methods have been proposed, and most, if not all, algorithms are developed to detect regions of "coherence" patterns. These methods perform unsatisfactorily if the purpose is to identify biclusters of a constant level. This paper presents a two-step biclustering method to identify constant level biclusters for binary or quantitative data. This algorithm identifies the maximal dimensional submatrix such that the proportion of non-signals is less than a pre-specified tolerance delta. The proposed method has much higher sensitivity and slightly lower specificity than several prominent biclustering methods from the analysis of two synthetic datasets. It was further compared with the Bimax method for two real datasets. The proposed method was shown to perform the most robust in terms of sensitivity, number of biclusters and number of serotype-specific biclusters identified. However, dichotomization using different signal level thresholds usually leads to different sets of biclusters; this also occurs in the present analysis. PMID- 23940780 TI - Low levels of aflatoxin B1, ricin, and milk enhance recombinant protein production in mammalian cells. AB - Gene expression in transduced mammalian cells correlates with virus titer, but high doses of vector for gene therapy leads to toxicity in humans and in animals. Changing the optimal tissue culture medium by adding low levels of environmental stressors, such as 1 uM of the fungal toxin aflatoxin B1 (AFB1), 1 ng of the castor bean protein toxin ricin, or 1% reconstituted milk, enhances transcription and increases production of proteins in transduced mammalian cells as demonstrated by production of the following three recombinant proteins: firefly luciferase, beta-galactosidase, and green fluorescent protein (GFP). Higher concentrations of the stress-producing substances damage the cells beyond recovery, resulting in inhibited gene expression and cell death. We also evaluated the effect of the stressor substances on the enhanced infectivity of virus. The presented findings extend methods for large-scale transient recombinant protein production in mammalian cells and suggest that it may be possible to reduce the cytotoxicity of the adenovirus by reducing the virus titer without adversely affecting gene expression levels. PMID- 23940781 TI - Visualising androgen receptor activity in male and female mice. AB - Androgens, required for normal development and fertility of males and females, have vital roles in the reproductive tract, brain, cardiovascular system, smooth muscle and bone. Androgens function via the androgen receptor (AR), a ligand dependent transcription factor. To assay and localise AR activity in vivo we generated the transgenic "ARE-Luc" mouse, expressing a luciferase reporter gene under the control of activated endogenous AR. In vivo imaging of androgen mediated luciferase activity revealed several strongly expressing tissues in the male mouse as expected and also in certain female tissues. In males the testes, prostate, seminal vesicles and bone marrow all showed high AR activity. In females, strong activity was seen in the ovaries, uterus, omentum tissue and mammary glands. In both sexes AR expression and activity was also found in salivary glands, the eye (and associated glands), adipose tissue, spleen and, notably, regions of the brain. Luciferase protein expression was found in the same cell layers as androgen receptor expression. Additionally, mouse AR expression and activity correlated well with AR expression in human tissues. The anti-androgen bicalutamide reduced luciferase signal in all tissues. Our model demonstrates that androgens can act in these tissues directly via AR, rather than exclusively via androgen aromatisation to estrogens and activation of the estrogen receptor. Additionally, it visually demonstrates the fundamental importance of AR signalling outside the normal role in the reproductive organs. This model represents an important tool for physiological and developmental analysis of androgen signalling, and for characterization of known and novel androgenic or antiandrogenic compounds. PMID- 23940782 TI - The impact of choice of NNRTI on short-term treatment outcomes among HIV-infected patients prescribed tenofovir and lamivudine in Johannesburg, South Africa. AB - INTRODUCTION: Recent WHO guidelines for resource-limited settings recommend tenofovir in first-line antiretroviral therapy (ART) yet there are suggestions that patients receiving nevirapine with tenofovir have worse outcomes than those receiving efavirenz. We sought to compare outcomes among those taking nevirapine vs. efavirenz with tenofovir and lamivudine. METHODS: We analyzed data on ART naive, non-pregnant patients, >= 18 years old without tuberculosis co-infection, initiating tenofovir with lamivudine and either nevirapine or efavirenz between April 1, 2010 and July 31, 2011 (when South Africa's public-sector use of tenofovir began) at Themba Lethu Clinic in South Africa. We measured virologic suppression (viral load <400 copies/ml), virologic failure (2 consecutive viral loads >1000 copies/ml), and attrition (death/loss to follow-up) all at 12 months after ART initiation. Modified Poisson regression with robust error estimation was used to estimate risk ratios (RR) and 95% confidence intervals (CI) for predictors of each outcome. RESULTS: 2,254 patients were prescribed efavirenz, 131 nevirapine. Patients were followed a median (range) of 12.0 (0.1-12.0) person months. 62.2% were female and median (IQR) age was 37.7 years (31.5-44.1). Patients prescribed efavirenz had similar initiating CD4 counts (median 132 for both regimens) but were somewhat more likely to be WHO Stage III or IV (39.6% vs. 33.6%) than those prescribed nevirapine. No difference in attrition was found (aRR: 0.83; 95% CI: 0.49-1.41). Among patients with >= 1 viral load within 1 year on ART, those prescribed nevirapine were as likely to reach virologic suppression (aRR: 0.97; 95% CI: 0.88-1.07) but more likely to experience virologic failure (aRR: 1.84; 95% CI: 1.02-3.31) than those prescribed efavirenz. CONCLUSIONS: Our results support the notion that, among patients prescribed tenofovir and lamivudine, virologic failure is more common among those taking nevirapine than among those taking efavirenz. Longer-term follow up and larger studies will be needed to confirm this finding. PMID- 23940783 TI - Poly (C)-binding protein 1 regulates p63 expression through mRNA stability. AB - p63, a transcription factor and p53 family protein, plays a crucial role in tumor suppression and development of various epithelial tissues. While p63 expression is controlled mostly by post-translational modifications, recent studies indicate that transcriptional and posttranscriptional regulations are essential for proper p63 expression. Here, we investigated the regulation of p63 expression by poly (C)-binding protein 1 (PCBP1, also known as hnRNP-E1 and alphaCP1). We found that knockdown of PCBP1 decreases the level of p63 transcript and protein. We also found that PCBP1 regulates the stability of p63 mRNA via binding to p63 3'UTR. Additionally, we found that a CU-rich element (CUE) in p63 3'UTR is bound by and responsive to PCBP1. Together, we conclude that PCBP1 regulates p63 expression via mRNA stability. PMID- 23940785 TI - Pomalidomide shows significant therapeutic activity against CNS lymphoma with a major impact on the tumor microenvironment in murine models. AB - Primary CNS lymphoma carries a poor prognosis. Novel therapeutic agents are urgently needed. Pomalidomide (POM) is a novel immunomodulatory drug with anti lymphoma activity. CNS pharmacokinetic analysis was performed in rats to assess the CNS penetration of POM. Preclinical evaluation of POM was performed in two murine models to assess its therapeutic activity against CNS lymphoma. The impact of POM on the CNS lymphoma immune microenvironment was evaluated by immunohistochemistry and immunofluorescence. In vitro cell culture experiments were carried out to further investigate the impact of POM on the biology of macrophages. POM crosses the blood brain barrier with CNS penetration of ~ 39%. Preclinical evaluations showed that it had significant therapeutic activity against CNS lymphoma with significant reduction in tumor growth rate and prolongation of survival, that it had a major impact on the tumor microenvironment with an increase in macrophages and natural killer cells, and that it decreased M2-polarized tumor-associated macrophages and increased M1 polarized macrophages when macrophages were evaluated based on polarization status. In vitro studies using various macrophage models showed that POM converted the polarization status of IL4-stimulated macrophages from M2 to M1, that M2 to M1 conversion by POM in the polarization status of lymphoma-associated macrophages is dependent on the presence of NK cells, that POM induced M2 to M1 conversion in the polarization of macrophages by inactivating STAT6 signaling and activating STAT1 signaling, and that POM functionally increased the phagocytic activity of macrophages. Based on our findings, POM is a promising therapeutic agent for CNS lymphoma with excellent CNS penetration, significant preclinical therapeutic activity, and a major impact on the tumor microenvironment. It can induce significant biological changes in tumor-associated macrophages, which likely play a major role in its therapeutic activity against CNS lymphoma. POM should be further evaluated in clinical trials. PMID- 23940784 TI - Aromatic L-amino acid decarboxylase (AADC) is crucial for brain development and motor functions. AB - Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric neuro metabolic disease in children. Due to the lack of an animal model, its pathogenetic mechanism is poorly understood. To study the role of AADC in brain development, a zebrafish model of AADC deficiency was generated. We identified an aadc gene homolog, dopa decarboxylase (ddc), in the zebrafish genome. Whole-mount in situ hybridization analysis showed that the ddc gene is expressed in the epiphysis, locus caeruleus, diencephalic catecholaminergic clusters, and raphe nuclei of 36-h post-fertilization (hpf) zebrafish embryos. Inhibition of Ddc by AADC inhibitor NSD-1015 or anti-sense morpholino oligonucleotides (MO) reduced brain volume and body length. We observed increased brain cell apoptosis and loss of dipencephalic catecholaminergic cluster neurons in ddc morphants (ddc MO injected embryos). Seizure-like activity was also detected in ddc morphants in a dose-dependent manner. ddc morphants had less sensitive touch response and impaired swimming activity that could be rescued by injection of ddc plasmids. In addition, eye movement was also significantly impaired in ddc morphants. Collectively, loss of Ddc appears to result in similar phenotypes as that of ADCC deficiency, thus zebrafish could be a good model for investigating pathogenetic mechanisms of AADC deficiency in children. PMID- 23940786 TI - Ellagitannins from Rubus berries for the control of gastric inflammation: in vitro and in vivo studies. AB - Ellagitannins have shown anti-inflammatory and anti-Helicobacter pylori properties; however, their anti-inflammatory activity at gastric level was not previously investigated. The aim of this research was to evaluate the effects of ellagitannins from Rubus berries on gastric inflammation. Ellagitannin enriched extracts (ETs) were prepared from Rubus fruticosus L. (blackberry) and Rubus idaeus L. (raspberry). The anti-inflammatory activity was tested on gastric cell line AGS stimulated by TNF-alpha and IL-1beta for evaluating the effect on NF-kB driven transcription, nuclear translocation and IL-8 secretion. In vivo the protective effect of ellagitannins was evaluated in a rat model of ethanol induced gastric lesions. Rats were treated orally for ten days with 20 mg/kg/day of ETs, and ethanol was given one hour before the sacrifice. Gastric mucosa was isolated and used for the determination of IL-8 release, NF-kB nuclear translocation, Trolox equivalents, superoxide dismutase and catalase activities. In vitro, ETs inhibited TNF-alpha induced NF-kB driven transcription (IC50: 0.67 1.73 ug/mL) and reduced TNF-alpha-induced NF-kB nuclear translocation (57%-67% at 2 ug/mL). ETs inhibited IL-8 secretion induced by TNF-alpha and IL-1beta at low concentrations (IC50 range of 0.7-4 ug/mL). Sanguiin H-6 and lambertianin C, the major ETs present in the extracts, were found to be responsible, at least in part, for the effect of the mixtures. ETs of blackberry and raspberry decreased Ulcer Index by 88% and 75% respectively and protected from the ethanol induced oxidative stress in rats. CINC-1 (the rat homologue of IL-8) secretion in the gastric mucosa was reduced in the animals receiving blackberry and raspberry ETs. The effect of ETs on CINC-1 was associated to a decrease of NF-kappaB nuclear translocation in ETs treated animals. The results of the present study report for the first time the preventing effect of ETs in gastric inflammation and support for their use in dietary regimens against peptic ulcer. PMID- 23940787 TI - A qualitative study of alcohol, health and identities among UK adults in later life. AB - Increasing alcohol consumption among older individuals is a public health concern. Lay understandings of health risks and stigma around alcohol problems may explain why public health messages have not reduced rates of heavy drinking in this sector. A qualitative study aimed to elucidate older people's reasoning about drinking in later life and how this interacted with health concerns, in order to inform future, targeted, prevention in this group. In 2010 a diverse sample of older adults in North East England (ages 50-95) participated in interviews (n = 24, 12 male, 12 female) and three focus groups (participants n = 27, 6 male, 21 female). Data were analysed using grounded theory and discursive psychology methods. When talking about alcohol use older people oriented strongly towards opposed identities of normal or problematic drinker, defined by propriety rather than health considerations. Each of these identities could be applied in older people's accounts of either moderate or heavy drinking. Older adults portrayed drinking less alcohol as an appropriate response if one experienced impaired health. However continued heavy drinking was also presented as normal behaviour for someone experiencing relative wellbeing in later life, or if ill health was construed as unrelated to alcohol consumption. Older people displayed scepticism about health advice on alcohol when avoiding stigmatised identity as a drinker. Drinking patterns did not appear to be strongly defined by gender, although some gendered expectations of drinking were described. Identities offer a useful theoretical concept to explain the rises in heavy drinking among older populations, and can inform preventive approaches to tackle this. Interventions should engage and foster positive identities to sustain healthier drinking and encourage at the community level the identification of heavy drinking as neither healthy nor synonymous with dependence. Future research should test and assess such approaches. PMID- 23940788 TI - Patterns of horse-rider coordination during endurance race: a dynamical system approach. AB - In riding, most biomechanical studies have focused on the description of the horse locomotion in unridden condition. In this study, we draw the prospect of how the basic principles established in inter-personal coordination by the theory of Coordination Dynamics may provide a conceptual and methodological framework for understanding the horse-rider coupling. The recent development of mobile technologies allows combined horse and rider recordings during long lasting natural events such as endurance races. Six international horse-rider dyads were thus recorded during a 120 km race by using two tri-axial accelerometers placed on the horses and riders, respectively. The analysis concentrated on their combined vertical displacements. The obtained shapes and angles of Lissajous plots together with values of relative phase between horse and rider displacements at lower reversal point allowed us to characterize four coordination patterns, reflecting the use of two riding techniques per horse's gait (trot and canter). The present study shows that the concepts, methods and tools of self-organizing dynamic system approach offer new directions for understanding horse-rider coordination. The identification of the horse-rider coupling patterns constitutes a firm basis to further study the coalition of multiple constraints that determine their emergence and their dynamics in endurance race. PMID- 23940789 TI - Effect of leaf type and pesticide exposure on abundance of bacterial taxa in mosquito larval habitats. AB - Lentic freshwater systems including those inhabited by aquatic stages of mosquitoes derive most of their carbon inputs from terrestrial organic matter mainly leaf litter. The leaf litter is colonized by microbial communities that provide the resource base for mosquito larvae. While the microbial biomass associated with different leaf species in container aquatic habitats is well documented, the taxonomic composition of these microbes and their response to common environmental stressors is poorly understood. We used indoor aquatic microcosms to determine the abundances of major taxonomic groups of bacteria in leaf litters from seven plant species and their responses to low concentrations of four pesticides with different modes of action on the target organisms; permethrin, malathion, atrazine and glyphosate. We tested the hypotheses that leaf species support different quantities of major taxonomic groups of bacteria and that exposure to pesticides at environmentally relevant concentrations alters bacterial abundance and community structure in mosquito larval habitats. We found support for both hypotheses suggesting that leaf litter identity and chemical contamination may alter the quality and quantity of mosquito food base (microbial communities) in larval habitats. The effect of pesticides on microbial communities varied significantly among leaf types, suggesting that the impact of pesticides on natural microbial communities may be highly complex and difficult to predict. Collectively, these findings demonstrate the potential for detritus composition within mosquito larval habitats and exposure to pesticides to influence the quality of mosquito larval habitats. PMID- 23940790 TI - Analysis of mutations in Neurospora crassa ERMES components reveals specific functions related to beta-barrel protein assembly and maintenance of mitochondrial morphology. AB - The endoplasmic reticulum mitochondria encounter structure (ERMES) tethers the er to mitochondria and contains four structural components: Mmm1, Mdm12, Mdm10, and Mmm2 (Mdm34). The Gem1 protein may play a role in regulating ERMES function. Saccharomyces cerevisiae and Neurospora crassa strains lacking any of Mmm1, Mdm12, or Mdm10 are known to show a variety of phenotypic defects including altered mitochondrial morphology and defects in the assembly of beta-barrel proteins into the mitochondrial outer membrane. Here we examine ERMES complex components in N. crassa and show that Mmm1 is an ER membrane protein containing a Cys residue near its N-terminus that is conserved in the class Sordariomycetes. The residue occurs in the ER-lumen domain of the protein and is involved in the formation of disulphide bonds that give rise to Mmm1 dimers. Dimer formation is required for efficient assembly of Tom40 into the TOM complex. However, no effects are seen on porin assembly or mitochondrial morphology. This demonstrates a specificity of function and suggests a direct role for Mmm1 in Tom40 assembly. Mutation of a highly conserved region in the cytosolic domain of Mmm1 results in moderate defects in Tom40 and porin assembly, as well as a slight morphological phenotype. Previous reports have not examined the role of Mmm2 with respect to mitochondrial protein import and assembly. Here we show that absence of Mmm2 affects assembly of beta-barrel proteins and that lack of any ERMES structural component results in defects in Tom22 assembly. Loss of N. crassa Gem1 has no effect on the assembly of these proteins but does affect mitochondrial morphology. PMID- 23940792 TI - Mitochondrial haplogroups modify the risk of developing hypertrophic cardiomyopathy in a Danish population. AB - Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in genes coding for proteins involved in sarcomere function. The disease is associated with mitochondrial dysfunction. Evolutionarily developed variation in mitochondrial DNA (mtDNA), defining mtDNA haplogroups and haplogroup clusters, is associated with functional differences in mitochondrial function and susceptibility to various diseases, including ischemic cardiomyopathy. We hypothesized that mtDNA haplogroups, in particular H, J and K, might modify disease susceptibility to HCM. Mitochondrial DNA, isolated from blood, was sequenced and haplogroups identified in 91 probands with HCM. The association with HCM was ascertained using two Danish control populations. Haplogroup H was more prevalent in HCM patients, 60% versus 46% (p = 0.006) and 41% (p = 0.003), in the two control populations. Haplogroup J was less prevalent, 3% vs. 12.4% (p = 0.017) and 9.1%, (p = 0.06). Likewise, the UK haplogroup cluster was less prevalent in HCM, 11% vs. 22.1% (p = 0.02) and 22.8% (p = 0.04). These results indicate that haplogroup H constitutes a susceptibility factor and that haplogroup J and haplogroup cluster UK are protective factors in the development of HCM. Thus, constitutive differences in mitochondrial function may influence the occurrence and clinical presentation of HCM. This could explain some of the phenotypic variability in HCM. The fact that haplogroup H and J are also modifying factors in ischemic cardiomyopathy suggests that mtDNA haplotypes may be of significance in determining whether a physiological hypertrophy develops into myopathy. mtDNA haplotypes may have the potential of becoming significant biomarkers in cardiomyopathy. PMID- 23940791 TI - Amelioration of murine passive immune thrombocytopenia by IVIg and a therapeutic monoclonal CD44 antibody does not require the Myd88 signaling pathway. AB - Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by a low platelet count and the production of anti-platelet antibodies. The majority of ITP patients have antibodies to platelet integrin alpha(IIb)beta3 (GPIIbIIIa) which can direct platelet phagocytosis by macrophages. One effective treatment for patients with ITP is intravenous immunoglobulin (IVIg) which rapidly reverses thrombocytopenia. The exact mechanism of IVIg action in human patients is unclear, although in mouse models of passive ITP, IVIg can rapidly increase platelet counts in the absence of adaptive immunity. Another antibody therapeutic that can similarly increase platelet counts independent of adaptive immunity are CD44 antibodies. Toll-like receptors (TLRs) are pattern recognition receptors which play a central role in helping direct the innate immune system. Dendritic cells, which are notable for their expression of TLRs, have been directly implicated in IVIg function as an initiator cell, while CD44 can associate with TLR2 and TLR4. We therefore questioned whether IVIg, or the therapeutic CD44 antibody KM114, mediate their ameliorative effects in a manner dependent upon normal TLR function. Here, we demonstrate that the TLR4 agonist LPS does not inhibit IVIg or KM114 amelioration of antibody-induced thrombocytopenia, and that these therapeutics do not ameliorate LPS-induced thrombocytopenia. IVIg was able to significantly ameliorate murine ITP in C3H/HeJ mice which have defective TLR4. All known murine TLRs except TLR3 utilize the Myd88 adapter protein to drive TLR signaling. Employing Myd88 deficient mice, we found that both IVIg and KM114 ameliorate murine ITP in Myd88 deficient mice to the same extent as normal mice. Thus both IVIg and anti-CD44 antibody can mediate their ameliorative effects in murine passive ITP independent of the Myd88 signaling pathway. These data help shed light on the mechanism of action of IVIg and KM114 in the amelioration of murine ITP. PMID- 23940793 TI - Changes in soil carbon and nitrogen following land abandonment of farmland on the Loess Plateau, China. AB - The revegetation of abandoned farmland significantly influences soil organic C (SOC) and total N (TN). However, the dynamics of both soil OC and N storage following the abandonment of farmland are not well understood. To learn more about soil C and N storages dynamics 30 years after the conversion of farmland to grassland, we measured SOC and TN content in paired grassland and farmland sites in the Zhifanggou watershed on the Loess Plateau, China. The grassland sites were established on farmland abandoned for 1, 7, 13, 20, and 30 years. Top soil OC and TN were higher in older grassland, especially in the 0-5 cm soil depths; deeper soil OC and TN was lower in younger grasslands (<20 yr), and higher in older grasslands (30 yr). Soil OC and N storage (0-100 cm) was significantly lower in the younger grasslands (<20 yr), had increased in the older grasslands (30 yr), and at 30 years SOC had increased to pre-abandonment levels. For a thirty year period following abandonment the soil C/N value remained at 10. Our results indicate that soil C and TN were significantly and positively correlated, indicating that studies on the storage of soil OC and TN needs to focus on deeper soil and not be restricted to the uppermost (0-30 cm) soil levels. PMID- 23940794 TI - Smoking, radiotherapy, diabetes and osteoporosis as risk factors for dental implant failure: a meta-analysis. AB - BACKGROUND: There are conflicting reports as to the association between smoking, radiotherapy, diabetes and osteoporosis and the risk of dental implant failure. We undertook a meta-analysis to evaluate the association between smoking, radiotherapy, diabetes and osteoporosis and the risk of dental implant failure. METHODS: A comprehensive research on MEDLINE and EMBASE, up to January 2013, was conducted to identify potential studies. References of relevant studies were also searched. Screening, data extraction and quality assessment were conducted independently and in duplicate. A random-effects meta-analysis was used to pool estimates of relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: A total of 51 studies were identified in this meta-analysis, with more than 40,000 dental implants placed under risk-threatening conditions. The pooled RRs showed a direct association between smoking (n = 33; RR = 1.92; 95% CI, 1.67-2.21) and radiotherapy (n = 16; RR = 2.28; 95% CI, 1.49-3.51) and the risk of dental implant failure, whereas no inverse impact of diabetes (n = 5; RR = 0.90; 95% CI, 0.62-1.32) on the risk of dental implant failure was found. The influence of osteoporosis on the risk of dental implant failure was direct but not significant (n = 4; RR = 1.09; 95% CI, 0.79-1.52). The subgroup analysis indicated no influence of study design, geographical location, length of follow-up, sample size, or mean age of recruited patients. CONCLUSIONS: Smoking and radiotherapy were associated with an increased risk of dental implant failure. The relationship between diabetes and osteoporosis and the risk of implant failure warrant further study. PMID- 23940795 TI - Phosphorylation of the actin binding protein Drebrin at S647 is regulated by neuronal activity and PTEN. AB - Defects in actin dynamics affect activity-dependent modulation of synaptic transmission and neuronal plasticity, and can cause cognitive impairment. A salient candidate actin-binding protein linking synaptic dysfunction to cognitive deficits is Drebrin (DBN). However, the specific mode of how DBN is regulated at the central synapse is largely unknown. In this study we identify and characterize the interaction of the PTEN tumor suppressor with DBN. Our results demonstrate that PTEN binds DBN and that this interaction results in the dephosphorylation of a site present in the DBN C-terminus--serine 647. PTEN and pS647-DBN segregate into distinct and complimentary compartments in neurons, supporting the idea that PTEN negatively regulates DBN phosphorylation at this site. We further demonstrate that neuronal activity increases phosphorylation of DBN at S647 in hippocampal neurons in vitro and in ex vivo hippocampus slices exhibiting seizure activity, potentially by inducing rapid dissociation of the PTEN:DBN complex. Our results identify a novel mechanism by which PTEN is required to maintain DBN phosphorylation at dynamic range and signifies an unusual regulation of an actin-binding protein linked to cognitive decline and degenerative conditions at the CNS synapse. PMID- 23940796 TI - Enhanced synthesis and diminished degradation of hydrogen sulfide in experimental colitis: a site-specific, pro-resolution mechanism. AB - Hydrogen sulfide (H2S) is produced throughout the gastrointestinal tract, and it contributes to maintenance of mucosal integrity, resolution of inflammation, and repair of damaged tissue. H2S synthesis is elevated in inflamed and damaged colonic tissue, but the enzymatic sources of that synthesis are not completely understood. In the present study, the contributions of three enzymatic pathways to colonic H2S synthesis were determined, with tissues taken from healthy rats and rats with colitis. The ability of the colonic tissue to inactivate H2S was also determined. Colonic tissue from rats with hapten-induced colitis produced significantly more H2S than tissue from healthy controls. The largest source of the H2S synthesis was the pathway involving cysteine amino transferase and 3 mercaptopyruvate sulfurtransferase (an alpha-ketoglutarate-dependent pathway). Elevated H2S synthesis occurred specifically at sites of mucosal ulceration, and was not related to the extent of granulocyte infiltration into the tissue. Inactivation of H2S by colonic tissue occurred rapidly, and was significantly reduced at sites of mucosal ulceration. This correlated with a marked decrease in the expression of sulfide quinone reductase in these regions. Together, the increased production and decreased inactivation of H2S at sites of mucosal ulceration would result in higher H2S levels at these sites, which promotes of resolution of inflammation and repair of damaged tissue. PMID- 23940797 TI - Farnesyl phosphatase, a Corpora allata enzyme involved in juvenile hormone biosynthesis in Aedes aegypti. AB - BACKGROUND: The juvenile hormones (JHs) are sesquiterpenoid compounds that play a central role in insect reproduction, development and behavior. The late steps of JH III biosynthesis in the mosquito Aedes aegypti involve the hydrolysis of farnesyl pyrophosphate (FPP) to farnesol (FOL), which is then successively oxidized to farnesal and farnesoic acid, methylated to form methyl farnesoate and finally transformed to JH III by a P450 epoxidase. The only recognized FPP phosphatase (FPPase) expressed in the corpora allata (CA) of an insect was recently described in Drosophila melanogaster (DmFPPase). In the present study we sought to molecularly and biochemically characterize the FPP phosphatase responsible for the transformation of FPP into FOL in the CA of A. aegypti. METHODS: A search for orthologs of the DmFPPase in Aedes aegypti led to the identification of 3 putative FPPase paralogs expressed in the CA of the mosquito (AaFPPases-1, -2, and -3). The activities of recombinant AaFPPases were tested against general phosphatase substrates and isoprenoid pyrophosphates. Using a newly developed assay utilizing fluorescent tags, we analyzed AaFPPase activities in CA of sugar and blood-fed females. Double-stranded RNA (dsRNA) was used to evaluate the effect of reduction of AaFPPase mRNAs on JH biosynthesis. CONCLUSIONS: AaFPPase-1 and AaFPPase-2 are members of the NagD family of the Class IIA C2 cap-containing haloalkanoic acid dehalogenase (HAD) super family and efficiently hydrolyzed FPP into FOL. AaFPPase activities were different in CA of sugar and blood-fed females. Injection of dsRNAs resulted in a significant reduction of AaFPPase-1 and AaFPPase-2 mRNAs, but only reduction of AaFPPase-1 caused a significant decrease of JH biosynthesis. These results suggest that AaFPPase-1 is predominantly involved in the catalysis of FPP into FOL in the CA of A. aegypti. PMID- 23940798 TI - Polymorphisms in the mTOR gene and risk of sporadic prostate cancer in an Eastern Chinese population. AB - BACKGROUND: The mTOR gene regulates cell growth by controlling mRNA translation, ribosome biogenesis, autophagy, and metabolism. Abnormally increased expression of mTOR was associated with carcinogenesis, and its functional single nucleotide polymorphisms (SNPs) may regulate the expression of mTOR and thus contribute to cancer risk. METHODOLOGY/PRINCIPAL FINDINGS: In a hospital-based case-control study of 1004 prostate cancer (PCa) cases and 1051 cancer-free controls, we genotyped six potentially functional SNPs of mTOR (rs2536 T>C, rs1883965 G>A, rs1034528 G>C, rs17036508 T>C, rs3806317 A>G, and rs2295080 T>G) and assessed their associations with risk of PCa by using logistic regression analysis. CONCLUSIONS/SIGNIFICANCES: In the single-locus analysis, we found a significantly increased risk of PCa associated with mTOR rs2536 CT/CC and rs1034528 CG/CC genotypes [adjusted OR = 1.42 (1.13-1.78), P = 0.003 and 1.29 (1.07-1.55), P = 0.007), respectively], compared with their common homozygous genotypes, whereas mTOR rs2295080 GT/GG genotypes were associated with a decreased risk of PCa [adjusted OR = 0.76 (0.64-0.92), P = 0.003], compared with wild-type TT genotypes. In the combined analysis of the six SNPs, we found that individuals carrying two or more adverse genotypes had an increased risk of PCa [adjusted OR = 1.24 (1.04-1.47), P = 0.016], compared with individuals carrying less than two adverse genotypes. In the multiple dimension reduction analysis, body mass index (BMI) was the best one-factor model with the highest CVC (100%) and the lowest prediction error (42.7%) among all seven factors. The model including an interaction among BMI, rs17036508, and rs2536 was the best three-factor model with the highest CVC (100%) and the lowest prediction error of 41.9%. These findings suggested that mTOR SNPs may contribute to the risk of PCa in Eastern Chinese men, but the effect was weak and needs further validation by larger population-based studies. PMID- 23940799 TI - Fisetin inhibits migration and invasion of human cervical cancer cells by down regulating urokinase plasminogen activator expression through suppressing the p38 MAPK-dependent NF-kappaB signaling pathway. AB - Fisetin (3,3',4',7-tetrahydroxyflavone), a naturally occurring flavonoid, has been reported to inhibit proliferation and induce apoptosis in several cancer types. However, its effect on the anti-metastatic potential of cervical cancer cells remains unclear. In the present study, we found that fisetin inhibits the invasion and migration of cervical cancer cells. The expression and activity of urokinase plasminogen activator (uPA) was significantly suppressed by fisetin in a dose-dependent manner. We also demonstrated that fisetin reduces the phosphorylation of p38 MAPK, but not that of ERK1/2, JNK1/2, or AKT. Addition of a p38 MAPK inhibitor, SB203580, further enhanced the inhibitory effect of fisetin on the expression and activity of uPA and the invasion and motility in cervical cancer cells. Fisetin suppressed the TPA (tetradecanoylphorbol-13-acetate) induced activation of p38 MAPK and uPA, and inhibited the TPA-enhanced migratory and invasive abilities. Furthermore, the promoter activity of the uPA gene was dramatically repressed by fisetin, which disrupted the nuclear translocation of NF-kappaB and its binding amount on the promoter of the uPA gene, and these suppressive effects could be further enhanced by SB203580. This study provides strong evidence for the molecular mechanism of fisetin in inhibiting the aggressive phenotypes by repression of uPA via interruption of p38 MAPK-dependent NF-kappaB signaling pathway in cervical cancer cells and thus contributes insight to the potential of using fisetin as a therapeutic strategy against cervical cancer by inhibiting migration and invasion. PMID- 23940800 TI - Genetic inactivation of pyruvate dehydrogenase kinases improves hepatic insulin resistance induced diabetes. AB - Pyruvate dehydrogenase kinases (PDK1-4) play a critical role in the inhibition of the mitochondrial pyruvate dehydrogenase complex especially when blood glucose levels are low and pyruvate can be conserved for gluconeogenesis. Under diabetic conditions, the Pdk genes, particularly Pdk4, are often induced, and the elevation of the Pdk4 gene expression has been implicated in the increased gluconeogenesis in the liver and the decreased glucose utilization in the peripheral tissues. However, there is no direct evidence yet to show to what extent that the dysregulation of hepatic Pdk genes attributes to hyperglycemia and insulin resistance in vivo. To address this question, we crossed Pdk2 or Pdk4 null mice with a diabetic model that is deficient in hepatic insulin receptor substrates 1 and 2 (Irs1/2). Metabolic analyses reveal that deletion of the Pdk4 gene had better improvement in hyperglycemia and glucose tolerance than knockout of the Pdk2 gene whereas the Pdk2 gene deletion showed better insulin tolerance as compared to the Pdk4 gene inactivation on the Irs1/2 knockout genetic background. To examine the specific hepatic effects of Pdks on diabetes, we also knocked down the Pdk2 or Pdk4 gene using specific shRNAs. The data also indicate that the Pdk4 gene knockdown led to better glucose tolerance than the Pdk2 gene knockdown. In conclusion, our data suggest that hepatic Pdk4 may be critically involved in the pathogenesis of diabetes. PMID- 23940801 TI - Mycobacterium tuberculosis Beijing genotype is associated with HIV infection in Mozambique. AB - The Beijing genotype is a lineage of Mycobacterium tuberculosis that is distributed worldwide and responsible for large epidemics, associated with multidrug-resistance. However, its distribution in Africa is less understood due to the lack of data. Our aim was to investigate the prevalence and possible transmission of Beijing strains in Mozambique by a multivariate analysis of genotypic, geographic and demographic data. A total of 543 M. tuberculosis isolates from Mozambique were spoligotyped. Of these, 33 were of the Beijing lineage. The genetic relationship between the Beijing isolates were studied by identification of genomic deletions within some Regions of Difference (RD), Restriction Fragment Length Polymorphism (RFLP) and Mycobacterial Interspersed Repetivie Unit - variable number tandem repeat (MIRU-VNTR). Beijing strains from South Africa, representing different sublineages were included as reference strains. The association between Beijing genotype, Human Immunodeficiency Virus (HIV) serology and baseline demographic data was investigated. HIV positive serostatus was significantly (p=0.023) more common in patients with Beijing strains than in patients with non-Beijing strains in a multivariable analysis adjusted for age, sex and province (14 (10.9%) of the 129 HIV positive patients had Beijing strains while 6/141 (4.3%) of HIV negative patients had Beijing strains). The majority of Beijing strains were found in the Southern region of Mozambique, particularly in Maputo City (17%). Only one Beijing strain was drug resistant (multi-drug resistant). By combined use of RD and spoligotyping, three genetic sublineages could be tentatively identified where a distinct group of four isolates had deletion of RD150, a signature of the "sublineage 7" recently emerging in South Africa. The same group was very similar to South African "sublineage 7" by RFLP and MIRU-VNTR, suggesting that this sublineage could have been recently introduced in Mozambique from South Africa, in association with HIV infection. PMID- 23940802 TI - Role of musclin in the pathogenesis of hypertension in rat. AB - Musclin is a novel skeletal muscle-derived secretory factor found in the signal sequence trap of mouse skeletal muscle cDNAs. Musclin possesses a region homologous to the natriuretic peptide family. Thus, musclin is found to bind with the natriuretic peptide clearance receptors. However, the role of musclin in vascular regulation remains unclear. In this study, we aim to investigate the direct effect of musclin on vascular tone and to analyze its role in hypertension using the spontaneously hypertensive rats (SHR). In aortic strips isolated from SHR, musclin induced contractions in a dose-dependent manner. We found that the musclin-induced vasoconstriction was more marked in SHR than in normal rats (WKY). Moreover, this contraction was reduced by blockade of natriuretic peptide receptor C using the ab14355 antibody. Therefore, mediation of the natriuretic peptide receptor in musclin-induced vasoconstriction can be considered. In addition, similar to the natriuretic peptide receptor, expression of the musclin gene in blood vessels was higher in SHR than in WKY. Injection of musclin markedly increased the blood pressure in rats that can be inhibited by anti musclin antibodies. Musclin-induced vasoconstriction was more pronounced in SHR than in WKY as in its expression. Taken together, these results suggest that musclin is involved in blood pressure regulation. The higher expression of musclin in hypertension indicates that musclin could be used as a new target for the treatment of hypertension in the future. PMID- 23940803 TI - Influence of pollen nutrition on honey bee health: do pollen quality and diversity matter? AB - Honey bee colonies are highly dependent upon the availability of floral resources from which they get the nutrients (notably pollen) necessary to their development and survival. However, foraging areas are currently affected by the intensification of agriculture and landscape alteration. Bees are therefore confronted to disparities in time and space of floral resource abundance, type and diversity, which might provide inadequate nutrition and endanger colonies. The beneficial influence of pollen availability on bee health is well-established but whether quality and diversity of pollen diets can modify bee health remains largely unknown. We therefore tested the influence of pollen diet quality (different monofloral pollens) and diversity (polyfloral pollen diet) on the physiology of young nurse bees, which have a distinct nutritional physiology (e.g. hypopharyngeal gland development and vitellogenin level), and on the tolerance to the microsporidian parasite Nosemaceranae by measuring bee survival and the activity of different enzymes potentially involved in bee health and defense response (glutathione-S-transferase (detoxification), phenoloxidase (immunity) and alkaline phosphatase (metabolism)). We found that both nurse bee physiology and the tolerance to the parasite were affected by pollen quality. Pollen diet diversity had no effect on the nurse bee physiology and the survival of healthy bees. However, when parasitized, bees fed with the polyfloral blend lived longer than bees fed with monofloral pollens, excepted for the protein richest monofloral pollen. Furthermore, the survival was positively correlated to alkaline phosphatase activity in healthy bees and to phenoloxydase activities in infected bees. Our results support the idea that both the quality and diversity (in a specific context) of pollen can shape bee physiology and might help to better understand the influence of agriculture and land-use intensification on bee nutrition and health. PMID- 23940804 TI - ARLTS1 and prostate cancer risk--analysis of expression and regulation. AB - Prostate cancer (PCa) is a heterogeneous trait for which several susceptibility loci have been implicated by genome-wide linkage and association studies. The genomic region 13q14 is frequently deleted in tumour tissues of both sporadic and familial PCa patients and is consequently recognised as a possible locus of tumour suppressor gene(s). Deletions of this region have been found in many other cancers. Recently, we showed that homozygous carriers for the T442C variant of the ARLTS1 gene (ADP-ribosylation factor-like tumour suppressor protein 1 or ARL11, located at 13q14) are associated with an increased risk for both unselected and familial PCa. Furthermore, the variant T442C was observed in greater frequency among malignant tissue samples, PCa cell lines and xenografts, supporting its role in PCa tumourigenesis. In this study, 84 PCa cases and 15 controls were analysed for ARLTS1 expression status in blood-derived RNA. A statistically significant (p = 0.0037) decrease of ARLTS1 expression in PCa cases was detected. Regulation of ARLTS1 expression was analysed with eQTL (expression quantitative trait loci) methods. Altogether fourteen significant cis-eQTLs affecting the ARLTS1 expression level were found. In addition, epistatic interactions of ARLTS1 genomic variants with genes involved in immune system processes were predicted with the MDR program. In conclusion, this study further supports the role of ARLTS1 as a tumour suppressor gene and reveals that the expression is regulated through variants localised in regulatory regions. PMID- 23940805 TI - Mapping sub-antarctic cushion plants using random forests to combine very high resolution satellite imagery and terrain modelling. AB - Monitoring changes in the distribution and density of plant species often requires accurate and high-resolution baseline maps of those species. Detecting such change at the landscape scale is often problematic, particularly in remote areas. We examine a new technique to improve accuracy and objectivity in mapping vegetation, combining species distribution modelling and satellite image classification on a remote sub-Antarctic island. In this study, we combine spectral data from very high resolution WorldView-2 satellite imagery and terrain variables from a high resolution digital elevation model to improve mapping accuracy, in both pixel- and object-based classifications. Random forest classification was used to explore the effectiveness of these approaches on mapping the distribution of the critically endangered cushion plant Azorella macquariensis Orchard (Apiaceae) on sub-Antarctic Macquarie Island. Both pixel- and object-based classifications of the distribution of Azorella achieved very high overall validation accuracies (91.6-96.3%, kappa = 0.849-0.924). Both two class and three-class classifications were able to accurately and consistently identify the areas where Azorella was absent, indicating that these maps provide a suitable baseline for monitoring expected change in the distribution of the cushion plants. Detecting such change is critical given the threats this species is currently facing under altering environmental conditions. The method presented here has applications to monitoring a range of species, particularly in remote and isolated environments. PMID- 23940807 TI - Quantitatively increased somatic transposition of transposable elements in Drosophila strains compromised for RNAi. AB - In Drosophila melanogaster, small RNAs homologous to transposable elements (TEs) are of two types: piRNA (piwi-interacting RNA) with size 23-29nt and siRNA (small interfering RNA) with size 19-22nt. The siRNA pathway is suggested to silence TE activities in somatic tissues based on TE expression profiles, but direct evidence of transposition is lacking. Here we developed an efficient FISH (fluorescence in Situ hybridization) based method for polytene chromosomes from larval salivary glands to reveal new TE insertions. Analysis of the LTR retrotransposon 297 and the non-LTR retroposon DOC shows that in the argonaut 2 (Ago2) and Dicer 2 (Dcr2) mutant strains, new transposition events are much more frequent than in heterozygous strains or wild type strains. The data demonstrate that the siRNA pathway represses TE transposition in somatic cells. Nevertheless, we found that loss of one functional copy of Ago2 or Dcr2 increases somatic transpositions of the elements at a lower level depending on the genetic background, suggesting a quantitative role for RNAi core components on mutation frequency. PMID- 23940806 TI - Predicting functional recovery after acute ankle sprain. AB - INTRODUCTION: Ankle sprains are among the most common acute musculoskeletal conditions presenting to primary care. Their clinical course is variable but there are limited recommendations on prognostic factors. Our primary aim was to identify clinical predictors of short and medium term functional recovery after ankle sprain. METHODS: A secondary analysis of data from adult participants (N = 85) with an acute ankle sprain, enrolled in a randomized controlled trial was undertaken. The predictive value of variables (age, BMI, gender, injury mechanism, previous injury, weight-bearing status, medial joint line pain, pain during weight-bearing dorsiflexion and lateral hop test) recorded at baseline and at 4 weeks post injury were investigated for their prognostic ability. Recovery was determined from measures of subjective ankle function at short (4 weeks) and medium term (4 months) follow ups. Multivariate stepwise linear regression analyses were undertaken to evaluate the association between the aforementioned variables and functional recovery. RESULTS: Greater age, greater injury grade and weight-bearing status at baseline were associated with lower function at 4 weeks post injury (p<0.01; adjusted R square=0.34). Greater age, weight-bearing status at baseline and non-inversion injury mechanisms were associated with lower function at 4 months (p<0.01; adjusted R square=0.20). Pain on medial palpation and pain on dorsiflexion at 4 weeks were the most valuable prognostic indicators of function at 4 months (p< 0.01; adjusted R square=0.49). CONCLUSION: The results of the present study provide further evidence that ankle sprains have a variable clinical course. Age, injury grade, mechanism and weight-bearing status at baseline provide some prognostic information for short and medium term recovery. Clinical assessment variables at 4 weeks were the strongest predictors of recovery, explaining 50% of the variance in ankle function at 4 months. Further prospective research is required to highlight the factors that best inform the expected convalescent period, and risk of recurrence. PMID- 23940808 TI - BARE retrotransposons are translated and replicated via distinct RNA pools. AB - The replication of Long Terminal Repeat (LTR) retrotransposons, which can constitute over 80% of higher plant genomes, resembles that of retroviruses. A major question for retrotransposons and retroviruses is how the two conflicting roles of their transcripts, in translation and reverse transcription, are balanced. Here, we show that the BARE retrotransposon, despite its organization into just one open reading frame, produces three distinct classes of transcripts. One is capped, polyadenylated, and translated, but cannot be copied into cDNA. The second is not capped or polyadenylated, but is destined for packaging and ultimate reverse transcription. The third class is capped, polyadenylated, and spliced to favor production of a subgenomic RNA encoding only Gag, the protein forming virus-like particles. Moreover, the BARE2 subfamily, which cannot synthesize Gag and is parasitic on BARE1, does not produce the spliced sub genomic RNA for translation but does make the replication competent transcripts, which are packaged into BARE1 particles. To our knowledge, this is first demonstration of distinct RNA pools for translation and transcription for any retrotransposon. PMID- 23940809 TI - Clonal expansion analysis of transposon insertions by high-throughput sequencing identifies candidate cancer genes in a PiggyBac mutagenesis screen. AB - Somatic transposon mutagenesis in mice is an efficient strategy to investigate the genetic mechanisms of tumorigenesis. The identification of tumor driving transposon insertions traditionally requires the generation of large tumor cohorts to obtain information about common insertion sites. Tumor driving insertions are also characterized by their clonal expansion in tumor tissue, a phenomenon that is facilitated by the slow and evolving transformation process of transposon mutagenesis. We describe here an improved approach for the detection of tumor driving insertions that assesses the clonal expansion of insertions by quantifying the relative proportion of sequence reads obtained in individual tumors. To this end, we have developed a protocol for insertion site sequencing that utilizes acoustic shearing of tumor DNA and Illumina sequencing. We analyzed various solid tumors generated by PiggyBac mutagenesis and for each tumor >106 reads corresponding to >104 insertion sites were obtained. In each tumor, 9 to 25 insertions stood out by their enriched sequence read frequencies when compared to frequencies obtained from tail DNA controls. These enriched insertions are potential clonally expanded tumor driving insertions, and thus identify candidate cancer genes. The candidate cancer genes of our study comprised many established cancer genes, but also novel candidate genes such as Mastermind-like1 (Mamld1) and Diacylglycerolkinase delta (Dgkd). We show that clonal expansion analysis by high-throughput sequencing is a robust approach for the identification of candidate cancer genes in insertional mutagenesis screens on the level of individual tumors. PMID- 23940810 TI - Serum levels of fibroblast growth factor 19 are inversely associated with coronary artery disease in chinese individuals. AB - BACKGROUND: The fibroblast growth factor 19 (FGF19) has been implicated in recent studies as a potential regulator of glucose and lipid metabolism, which may lead to atherosclerosis. Here, we investigated the association of FGF19 with the presence and severity of coronary artery disease (CAD) in a Chinese population. METHODS: A total of 315 patients with suspected or established CAD, including 205 males and 110 postmenopausal females, were enrolled and assessed by coronary angiography. CAD severity was determined by the Gensini score. Serum FGF19 was measured by quantitative sandwich ELISA. RESULTS: FGF19 levels were not significantly different between male and female patients (median [interquartile range], 143.40 [87.96-250.80] vs. 141.60 [87.13-226.32] pg/mL, P = 0.773). CAD patients had lower levels of FGF19 than those without CAD (128.20 [80.62-226.58] vs. 188.00 [105.10-284.70] pg/mL, P = 0.007). FGF19 was negatively correlated with 2hPG (r = -0.150, P = 0.008), FINS (r = -0.169, P = 0.004), HOMA-IR (r = 0.171, P = 0.004), and the Gensini score (r = -0.141, P = 0.012), but positively correlated with HDL-c (r = 0.116, P = 0.041) and adiponectin (r = 0.128, P = 0.024). Moreover, FGF19 was found to be independently correlated with 2hPG (beta = -0.146, P = 0.022) and adiponectin (beta = 0.154, P = 0.016). After adjusting for other CAD risk factors, FGF19 was demonstrated to be an independent factor for Gensini score (beta = -0.140, P = 0.019) and the presence of CAD (beta = 1.248, P = 0.036). CONCLUSIONS: Serum FGF19 is associated with the presence and severity of CAD in a Chinese population. PMID- 23940811 TI - Silica desiccant packets for storage and transport of Streptococcus pneumoniae and other clinically relevant species. AB - Bacterial isolates are often transported between laboratories for research and diagnostic purposes. Silica desiccant packets (SDPs), which are inexpensive and do not require freezing, were evaluated for storage and recovery of bacterial isolates. Conditions such as inoculum size, swab type and temperature of storage were investigated using ten Streptococcus pneumoniae isolates. The optimized protocol was then tested using 49 additional S. pneumoniae isolates representing 40 serogroups. Overall, S. pneumoniae growth was considered satisfactory (>100 colony forming units) for 98/109 (89.9%) and 20/20 (100%) swabs after 14 days at room temperature or 28 days at 4 degrees C, respectively. Storage in SDPs did not impact on the ability of S. pneumoniae isolates to be subsequently serotyped. When the survival of nine other clinically relevant bacterial species was tested, seven were viable after 28 days at room temperature, the exceptions being Neisseria gonorrhoeae and Haemophilus influenzae. SDPs are suitable for transport and short-term storage of bacterial species including S. pneumoniae. PMID- 23940813 TI - Evolution of Peromyscus leucopus mice in response to a captive environment. AB - Many wildlife species are propagated in captivity as models for behavioral, physiological, and genetic research or to provide assurance populations to protect threatened species. However, very little is known about how animals evolve in the novel environment of captivity. The histories of most laboratory strains are poorly documented, and protected populations of wildlife species are usually too small and too short-term to allow robust statistical analysis. To document the evolutionary change in captive breeding programs, we monitored reproduction and behavior across 18 generations in six experimental populations of Peromyscusleucopus mice started from a common set of 20 wild-caught founders. The mice were propagated under three breeding protocols: a strategy to retain maximal genetic diversity, artificial selection against stereotypic behaviors that were hypothesized to reflect poor adaptation to captivity, and random bred controls. Two replicates were maintained with each protocol, and inter-replicate crosses at generations 19 and 20 were used to reverse accumulated inbreeding. We found that one of the stereotypic behaviors (repetitive flipping) was positively associated with reproductive fitness, while the other (gnawing) was relatively invariant. Selection to reduce these stereotypic behaviors caused marked reduction in reproduction, and populations not under artificial selection to reduce these behaviors responded with large increases in flipping. In non selected populations, there was rapid evolution toward much higher proportion of pairs breeding and more rapid conception. Litter size, pup survival, and weaning mass all declined slowly, to the extent that would be predicted based on inbreeding depression. Inter-crossing between replicate populations reversed these declines in fitness components but did not reverse the changes in behavior or the accelerated breeding. These findings indicate that adaptation to captivity can be rapid, affecting reproductive patterns and behaviors, even under breeding protocols designed to minimize the rate of genetic change due to random drift and inadvertent selection. PMID- 23940812 TI - GATA-2 transduces LPS-induced il-1beta gene expression in macrophages via a toll like receptor 4/MD88/MAPK-dependent mechanism. AB - Lipopolysaccharide (LPS) is a critical factor for inducing acute lung injury. GATA-2, a transcription factor, contributes to the control of cell activity and function. Exposure of RAW 264.7 cells to LPS induced interleukin (IL)-1beta mRNA and protein expression and GATA-2 translocation from the cytoplasm to nuclei in concentration- and time-dependent manners. A bioinformatic search revealed that GATA-2-specific binding elements exist in the 5'-promoter region of the il-1beta gene. LPS could enhance the transactivation activity of GATA-2 in macrophages. Knocking-down translation of GATA-2 mRNA using RNA interference significantly alleviated LPS-induced IL-1beta mRNA and protein expression. As to the mechanism, transfection of toll-like receptor (TLR) 4 small interfering (si)RNA into macrophages concurrently decreased LPS-caused increases in nuclear GATA-2 levels. Sequentially, treatment with myeloid differentiation factor 88 (MyD88) siRNA decreased LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs) kinase 1/2 and subsequent translocation of GATA-2. Reducing MAPK activities using specific inhibitors simultaneously decreased GATA-2 activation. Furthermore, exposure of primary macrophages to LPS significantly increased the transactivation activities of GATA-2 and IL-1beta mRNA and protein expression. Transfection of GATA-2 siRNA inhibited LPS-induced IL-1beta mRNA expression. Results of this study show that LPS induction of il-1beta gene expression in macrophages is mediated by GATA-2 via activation of TLR4, MyD88, and MAPKs. PMID- 23940814 TI - CD11c+ cells partially mediate the renoprotective effect induced by bone marrow derived mesenchymal stem cells. AB - Previous studies have shown that induction of immune tolerance by mesenchymal stem cells (MSCs) is partially mediated via monocytes or dendritic cells (DCs). The purpose of this study was to determine the role of CD11c+ cells in MSC induced effects on ischemia/reperfusion injury (IRI). IRI was induced in wildtype (WT) mice and CD11c+-depleted mice following pretreatment with or without MSCs. In the in-vitro experiments, the MSC-treated CD11c+ cells acquired regulatory phenotype with increased intracellular IL-10 production. Although splenocytes cocultured with MSCs showed reduced T cell proliferation and expansion of CD4+FoxP3+ regulatory T cells (Tregs), depletion of CD11c+ cells was associated with partial loss of MSCs effect on T cells. In in-vivo experiment, MSCs' renoprotective effect was also associated with induction of more immature CD11c+ cells and increased FoxP3 expression in I/R kidneys. However all these effects induced by the MSCs were partially abrogated when CD11c+ cells were depleted in the CD11c+-DTR transgenic mice. In addition, the observation that adoptive transfer of WT CD11c+ cells partially restored the beneficial effect of the MSCs, while transferring IL-10 deficient CD11c+ cells did not, strongly suggest the important contribution of IL-10 producing CD11c+ cells in attenuating kidney injury by MSCs. Our results suggest that the CD11c+ cell-Tregs play critical role in mediating renoprotective effect of MSCs. PMID- 23940815 TI - Molecular characterization of larval peripheral thermosensory responses of the malaria vector mosquito Anopheles gambiae. AB - Thermosensation provides vital inputs for the malaria vector mosquito, Anopheles gambiae which utilizes heat-sensitivity within a broad spectrum of behaviors, most notably, the localization of human hosts for blood feeding. In this study, we examine thermosensory behaviors in larval-stage An. gambiae, which as a result of their obligate aquatic habitats and importance for vectorial capacity, represents an opportunistic target for vector control as part of the global campaign to eliminate malaria. As is the case for adults, immature mosquitoes respond differentially to a diverse array of external heat stimuli. In addition, larvae exhibit a striking phenotypic plasticity in thermal-driven behaviors that are established by temperature at which embryonic development occurs. Within this spectrum, RNAi-directed gene-silencing studies provide evidence for the essential role of the Transient Receptor Potential sub-family A1 (TRPA1) channel in mediating larval thermal-induced locomotion and thermal preference within a discrete upper range of ambient temperatures. PMID- 23940816 TI - Genetic diversity and geographic population structure of bovine Neospora caninum determined by microsatellite genotyping analysis. AB - The cyst-forming protozoan parasite Neosporacaninum is one of the main causes of bovine abortion worldwide and is of great economic importance in the cattle industry. Recent studies have revealed extensive genetic variation among N. caninum isolates based on microsatellite sequences (MSs). MSs may be suitable molecular markers for inferring the diversity of parasite populations, molecular epidemiology and the basis for phenotypic variations in N. caninum, which have been poorly defined. In this study, we evaluated nine MS markers using a panel of 11 N. caninum-derived reference isolates from around the world and 96 N. caninum bovine clinical samples and one ovine clinical sample collected from four countries on two continents, including Spain, Argentina, Germany and Scotland, over a 10-year period. These markers were used as molecular tools to investigate the genetic diversity, geographic distribution and population structure of N. caninum. Multilocus microsatellite genotyping based on 7 loci demonstrated high levels of genetic diversity in the samples from all of the different countries, with 96 microsatellite multilocus genotypes (MLGs) identified from 108 N. caninum samples. Geographic sub-structuring was present in the country populations according to pairwise F(ST). Principal component analysis (PCA) and Neighbor Joining tree topologies also suggested MLG segregation partially associated with geographical origin. An analysis of the MLG relationships, using eBURST, confirmed that the close genetic relationship observed between the Spanish and Argentinean populations may be the result of parasite migration (i.e., the introduction of novel MLGs from Spain to South America) due to cattle movement. The eBURST relationships also revealed genetically different clusters associated with the abortion. The presence of linkage disequilibrium, the co-existence of specific MLGs to individual farms and eBURST MLG relationships suggest a predominant clonal propagation for Spanish N. caninum MLGs in cattle. PMID- 23940817 TI - Generation of mouse small intestinal epithelial cell lines that allow the analysis of specific innate immune functions. AB - Cell lines derived from the small intestine that reflect authentic properties of the originating intestinal epithelium are of high value for studies on mucosal immunology and host microbial homeostasis. A novel immortalization procedure was applied to generate continuously proliferating cell lines from murine E19 embryonic small intestinal tissue. The obtained cell lines form a tight and polarized epithelial cell layer, display characteristic tight junction, microvilli and surface protein expression and generate increasing transepithelial electrical resistance during in vitro culture. Significant up-regulation of Cxcl2 and Cxcl5 chemokine expression upon exposure to defined microbial innate immune stimuli and endogenous cytokines is observed. Cell lines were also generated from a transgenic interferon reporter (Mx2-Luciferase) mouse, allowing reporter technology-based quantification of the cellular response to type I and III interferon. Thus, the newly created cell lines mimic properties of the natural epithelium and can be used for diverse studies including testing of the absorption of drug candidates. The reproducibility of the method to create such cell lines from wild type and transgenic mice provides a new tool to study molecular and cellular processes of the epithelial barrier. PMID- 23940818 TI - ERManI is a target of miR-125b and promotes transformation phenotypes in hepatocellular carcinoma (HCC). AB - The MAN1B1 gene product, designated ER alpha-1, 2-mannosidase (ERManI), is an enzyme localized in the Golgi complex of mammalian cells. By functioning as a "gate keeper" to prevent the inappropriate secretion of misfolded glycoproteins, it plays a critical role in maintaining protein homeostasis in the mammalian secretory pathway. In the present study, we identified that a conserved motif within the 3'UTR of ERManI is a target of miR-125b, a microRNA frequently down regulated in numerous types of cancers, including hepatocellular carcinoma (HCC). As predicted, the expression of ERManI is significantly elevated in HCC, as measured by immunohistochemistry in a liver spectrum tissue microarray. Additional analyses using several hepatoma cell lines demonstrated that the elevated ERManI inversely correlates with a diminished intracellular concentration of miR-125b. Moreover, functional studies indicated that RNAi mediated knock-down of endogenous ERManI was sufficient to inhibit proliferation, migration, and invasion of hepatoma cells. These phenotypical changes occurred in the absence of alterations in global glycoprotein secretion or ER-stress status. Together, these results revealed a novel post-transcriptional regulatory mechanism for ERManI and implied that this molecule contributes to the regulation of carcinogenesis in HCC independent of its function in glycoprotein quality control. PMID- 23940819 TI - CD200R/CD200 inhibits osteoclastogenesis: new mechanism of osteoclast control by mesenchymal stem cells in human. AB - Bone homeostasis is maintained by the balance between bone-forming osteoblasts and bone-degrading osteoclasts. Osteoblasts have a mesenchymal origin whereas osteoclasts belong to the myeloid lineage. Osteoclast and osteoblast communication occurs through soluble factors secretion, cell-bone interaction and cell-cell contact, which modulate their activities. CD200 is an immunoglobulin superfamilly member expressed on various types of cells including mesenchymal stem cells (MSCs). CD200 receptor (CD200R) is expressed on myeloid cells such as monocytes/macrophages. We assume that CD200 could be a new molecule involved in the control of osteoclastogenesis and could play a role in MSC-osteoclast communication in humans. In this study, we demonstrated that soluble CD200 inhibited the differentiation of osteoclast precursors as well as their maturation in bone-resorbing cells in vitro. Soluble CD200 did not modify the monocyte phenotype but inhibited the receptor activator of nuclear factor kappa-B ligand (RANKL) signaling pathway as well as the gene expression of osteoclast markers such as osteoclast-associated receptor (OSCAR) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Moreover, MSCs inhibited osteoclast formation, which depended on cell-cell contact and was associated with CD200 expression on the MSC surface. Our results clearly demonstrate that MSCs, through the expression of CD200, play a major role in the regulation of bone resorption and bone physiology and that the CD200-CD200R couple could be a new target to control bone diseases. PMID- 23940820 TI - Functional metagenomic investigations of microbial communities in a shallow-sea hydrothermal system. AB - Little is known about the functional capability of microbial communities in shallow-sea hydrothermal systems (water depth of <200 m). This study analyzed two high-throughput pyrosequencing metagenomic datasets from the vent and the surface water in the shallow-sea hydrothermal system offshore NE Taiwan. This system exhibited distinct geochemical parameters. Metagenomic data revealed that the vent and the surface water were predominated by Epsilonproteobacteria (Nautiliales-like organisms) and Gammaproteobacteria (Thiomicrospira-like organisms), respectively. A significant difference in microbial carbon fixation and sulfur metabolism was found between the vent and the surface water. The chemoautotrophic microorganisms in the vent and in the surface water might possess the reverse tricarboxylic acid cycle and the Calvin-Bassham-Benson cycle for carbon fixation in response to carbon dioxide highly enriched in the environment, which is possibly fueled by geochemical energy with sulfur and hydrogen. Comparative analyses of metagenomes showed that the shallow-sea metagenomes contained some genes similar to those present in other extreme environments. This study may serve as a basis for deeply understanding the genetic network and functional capability of the microbial members of shallow-sea hydrothermal systems. PMID- 23940821 TI - Persistent infection of human fetal endothelial cells with rubella virus. AB - Cardiovascular abnormalities are the leading cause of neonatal death among patients with congenital rubella syndrome (CRS). Although persistence of rubella virus (RV) in fetal endothelium has been repeatedly suggested as a possible cause of cardiovascular birth defects, evidence of the permissiveness of fetal endothelial cells to RV is lacking. In this study we evaluated the ability of RV to infect and persist in primary fetal endothelial cells derived from human umbilical vein (HUVEC). We found that wild type (wt) low passage clinical RV productively infected HUVEC cultures without producing cytopathology or ultrastructural changes. RV did not inhibit host cell protein synthesis, cell proliferation, or interfere with the cell cycle. Persistently infected cultures were easily established at low and high multiplicities of infection (MOI) with both laboratory and wt clinical RV strains. However, synchronous infections of entire HUVEC monolayers were only observed with clinical RV strains. The release of infectious virions into media remained at consistently high levels for several subcultures of infected HUVEC. The results indicate that macrovascular fetal endothelial cells are highly permissive to RV and allow slow persistent RV replication. The findings provide more evidence for the suggestion that vascular pathologies in CRS are triggered by persistent rubella virus infection of the endothelium. PMID- 23940822 TI - T1-weighted sodium MRI of the articulator cartilage in osteoarthritis: a cross sectional and longitudinal study. AB - Structural magnetic resonance imaging (MRI) has shown great utility in diagnosing soft tissue burden in osteoarthritis (OA), though MRI measures of cartilage integrity have proven more elusive. Sodium MRI can reflect the proteoglycan content of cartilage; however, it requires specialized hardware, acquisition sequences, and long imaging times. This study was designed to assess the potential of a clinically feasible sodium MRI acquisition to detect differences in the knee cartilage of subjects with OA versus healthy controls (HC), and to determine whether longitudinal changes in sodium content are observed at 3 and 6 months. 28 subjects with primary knee OA and 19 HC subjects age and gender matched were enrolled in this ethically-approved study. At baseline, 3 and 6 months subjects underwent structural MRI and a 0.4ms echo time 3D T1-weighted sodium scan as well as the knee injury and osteoarthritis outcome score (KOOS) and knee pain by visual analogue score (VAS). A standing radiograph of the knee was taken for Kellgren-Lawrence (K-L) scoring. A blinded reader outlined the cartilage on the structural images which was used to determine median T1-weighted sodium concentrations in each region of interest on the co-registered sodium scans. VAS, K-L, and KOOS all significantly separated the OA and HC groups. OA subjects had higher T1-weighted sodium concentrations, most strongly observed in the lateral tibial, lateral femoral and medial patella ROIs. There were no significant changes in cartilage volume or sodium concentration over 6 months. This study has shown that a clinically-feasible sodium MRI at a moderate 3T field strength and imaging time with fluid attenuation by T1 weighting significantly separated HCs from OA subjects. PMID- 23940823 TI - Central nervous system involvement of primary renal lymphoma with diffuse large B cell type lymphoma. AB - PATIENT: Female, 27 FINAL DIAGNOSIS: Central nervous system leukemia Symptoms: Abdominal mass * fever * nausea * vomitting MEDICATION: - Clinical Procedure: - Specialty: Hematology. OBJECTIVE: Unusual clinical course. BACKGROUND: Primary lymphoma of urinary system is an uncommon entity including primary renal lymphoma, primary ureter lymphoma, bladder lymphoma, and urethra (including prostate) lymphoma. The pathology of PRL is usually diffuse large B-cell lymphoma. CASE REPORT: In this study we describe a 27-year-old Chinese woman with central nervous system leukemia due to PRL. It was classified as diffuse large B cell lymphoma non-GCB type according to kidney biopsy. We selected R-CHOP as a regimen and it showed good curative effect. However, the patient suffered recurrence involving the central nervous system with complaint of intolerable iliac-sacral pain at 26 days after 6 courses of R-CHOP. CONCLUSIONS: This case shows that prognosis of PRL is poorer than nodal lymphoma. There is an urgent need for a more effective strategy with higher blood-brain barrier permeability. PMID- 23940824 TI - Mediastinal mass and pericardial tamponade in a renal transplant recipient: A rare case of nocardia infection. AB - PATIENT: Female, 30 FINAL DIAGNOSIS: Nocardiosis Symptoms: Cardiac tamponade * cough * dyspnea * hoarseness * mediastinal mass * pericardial effusion * short of breath MEDICATION: - Clinical Procedure: - Specialty: Transplantology. OBJECTIVE: Rare disease. BACKGROUND: Nocardia infections can complicate solid organ transplantation. The usual clinical presentations include pulmonary infiltrates with or without cavitation and subcutaneous and brain abscesses. We report an unusual case of nocardia infection in a kidney transplant recipient that presented as mediastinal mass and was associated with pericardial tamponade. CASE REPORT: A 30 year old African American renal transplant recipient presented with cough, hoarseness and shortness of breath nine months after kidney transplantation. She received basiliximab perioperatively and her maintenance immunosuppression included tacrolimus, mycophenolate mofetil and prednisone. Computed tomography (CT) showed a large mediastinal mass with a large pericardial effusion. An echocardiogram revealed collapse of the right ventricle consistent with tamponade. We performed emergent pericardiocentesis to treat the tamponade. A mediastinoscopic biopsy of the mediastinal mass was done to establish a diagnosis. The mediastinal biopsy confirmed the growth of Nocardia. After 2 weeks of imipenem and 6 weeks of linezolid, there was marked radiographic improvement in the size of the mediastinal mass. CONCLUSIONS: We report a rare case of a large mediastinal mass associated with pericardial tamponade from nocardia infection in a renal transplant recipient. An invasive approach may be necessary to obtain tissue diagnosis to direct treatment in these cases. Prompt and appropriate medical therapy leads to marked radiographic improvement. PMID- 23940825 TI - New twist to nuclear import: When two travel together. AB - Ribosomes are the nanomachines that synthesize all cellular proteins from mRNA templates. In eukaryotes, ribosomes, which are composed of ribosomal proteins and rRNA, are mainly assembled in the nucleus. Thus, ribosomal proteins require a nuclear transport step from their place of synthesis in the cytoplasm to their site of assembly in the nucleus. Recognition of import substrates is mediated by different types of nuclear localization signals, which are either directly recognized by import receptors or recruited to these via adaptor proteins. The novel transport adaptor Syo1 (Symportin), which is dedicated to the synchronous import of two functionally related ribosomal proteins, has recently been described. In this review, we highlight and discuss these findings in the context of our current knowledge of ribosome assembly and nucleocytoplasmic transport. We propose that nuclear co-import of functionally and topologically linked cargo could be a widespread strategy to streamline assembly of macromolecular complexes in the nucleus. PMID- 23940826 TI - High resolution anatomical mapping confirms the absence of a magnetic sense system in the rostral upper beak of pigeons. AB - The cells that are responsible for detecting magnetic fields in animals remain undiscovered. Previous studies have proposed that pigeons employ a magnetic sense system that consists of six bilateral patches of magnetite containing dendrites located in the rostral subepidermis of the upper beak. We have challenged this hypothesis arguing that clusters of iron-rich cells in this region are macrophages, not magnetosensitive neurons. Here we present additional data in support of this conclusion. We have undertaken high resolution anatomical mapping of iron-rich cells in the rostral upper beak of pigeons, excluding the possibility that a conserved six-loci magnetic sense system exists. In addition we have extended our immunohistochemical studies to a second cohort of pigeons, confirming that iron rich cells in the upper beak are positive for MHCII and CD44, which are expressed by macrophages. We argue that it is important to critically assess conclusions that have been made in the past, while keeping an open mind as the search for the magnetoreceptor continues. PMID- 23940827 TI - GSK-3 and lysosomes meet in Alzheimer's disease. AB - Aberrant regulation of glycogen synthase kinase-3 (GSK-3) is implicated in Alzheimer's disease (AD), but the mechanisms involved remain elusive. Our recent study shows that GSK-3 impairs lysosomal acidification and that inhibition of GSK 3 re-acidified lysosomes in brains of AD mice. This effect was accompanied by reductions in beta-amyloid pathology and amelioration of cognitive deficits. Presenilin-1 (PS1) is an essential factor in lysosomal acidification. To determine whether the inhibition of GSK-3 restores lysosomal malfunction caused by dysfunctional PS1, we treated MEF cells deficient in presenilin proteins (MEF PS1/2(-/-)) with a selective substrate competitive GSK-3 inhibitor, L803-mts. L803-mts enhanced the acidic lysosomal pool in MEF-PS1/2(-/-) cells and increased levels of activated cathepsin D in the lysosomes. We conclude that GSK-3 and PS1 operate via similar mechanisms to disrupt lysosomal acidification. Importantly, these data indicate that GSK-3 inhibitors have potential in treatment of conditions associated with defective PS1. PMID- 23940828 TI - List of guest reviewers. PMID- 23940830 TI - Lacosamide adjunctive therapy for partial-onset seizures: a meta-analysis. AB - Background. The relative efficacy and safety of lacosamide as adjunctive therapy compared to other antiepileptic drugs has not been well established. Objective. To determine if lacosamide provides improved efficacy and safety, reduced length of hospital stay and improved quality of life compared with other anti-epileptic therapies for adults with partial-onset seizures. Data Sources. A systematic review of the medical literature using Medline (1946-Week 4, 2012), EMBASE (1980 Week 3, 2012), Cochrane Central Register of Controlled Trials (Issue 1 of 12, January 2012). Additional studies were identified (through to February 7, 2012) by searching bibliographies, the FDA drug approval files, clinical trial registries and major national and international neurology meeting abstracts. No restrictions on publication status or language were applied. Study Selection. Randomized controlled trials of lacosamide in adults with partial-onset seizures were included. Data Extraction. Study selection, extraction and risk of bias assessment were performed independently by two authors. Authors of studies were contacted for missing data. Data Synthesis. All pooled analyses used the random effects model. Results. Three trials (1311 patients) met inclusion criteria. Lacosamide increased the 50% responder rate compared to placebo (RR 1.68 [95% CI 1.36 to 2.08]; I(2) = 0%). Discontinuation due to adverse events was statistically significantly higher in the lacosamide arm (RR3.13 [95% CI 1.94 to 5.06]; I(2) = 0%). Individual adverse events (ataxia, dizziness, fatigue, and nausea) were also significantly higher in the lacosamide group. Limitations. All dosage arms from the included studies were pooled to make a single pair-wise comparison to placebo. Selective reporting of outcomes was found in all of the included RCTs. Conclusions. Lacosamide as adjunctive therapy in patients with partial-onset seizures increases the 50% responder rate but with significantly more adverse events compared to the placebo. PMID- 23940831 TI - Rapid quantitative pharmacodynamic imaging by a novel method: theory, simulation testing and proof of principle. AB - Pharmacological challenge imaging has mapped, but rarely quantified, the sensitivity of a biological system to a given drug. We describe a novel method called rapid quantitative pharmacodynamic imaging. This method combines pharmacokinetic-pharmacodynamic modeling, repeated small doses of a challenge drug over a short time scale, and functional imaging to rapidly provide quantitative estimates of drug sensitivity including EC 50 (the concentration of drug that produces half the maximum possible effect). We first test the method with simulated data, assuming a typical sigmoidal dose-response curve and assuming imperfect imaging that includes artifactual baseline signal drift and random error. With these few assumptions, rapid quantitative pharmacodynamic imaging reliably estimates EC 50 from the simulated data, except when noise overwhelms the drug effect or when the effect occurs only at high doses. In preliminary fMRI studies of primate brain using a dopamine agonist, the observed noise level is modest compared with observed drug effects, and a quantitative EC 50 can be obtained from some regional time-signal curves. Taken together, these results suggest that research and clinical applications for rapid quantitative pharmacodynamic imaging are realistic. PMID- 23940832 TI - Microsaccades restore the visibility of minute foveal targets. AB - Stationary targets can fade perceptually during steady visual fixation, a phenomenon known as Troxler fading. Recent research found that microsaccades small, involuntary saccades produced during attempted fixation-can restore the visibility of faded targets, both in the visual periphery and in the fovea. Because the targets tested previously extended beyond the foveal area, however, the ability of microsaccades to restore the visibility of foveally-contained targets remains unclear. Here, subjects reported the visibility of low-to moderate contrast targets contained entirely within the fovea during attempted fixation. The targets did not change physically, but their visibility varied intermittently during fixation, in an illusory fashion (i.e., foveal Troxler fading). Microsaccade rates increased significantly before the targets became visible, and decreased significantly before the targets faded, for a variety of target contrasts. These results support previous research linking microsaccade onsets to the visual restoration of peripheral and foveal targets, and extend the former conclusions to minute targets contained entirely within the fovea. Our findings suggest that the involuntary eye movements produced during attempted fixation do not always prevent fading-in either the fovea or the periphery-and that microsaccades can restore perception, when fading does occur. Therefore, microsaccades are relevant to human perception of foveal stimuli. PMID- 23940833 TI - Playing with heart and soul...and genomes: sports implications and applications of personal genomics. AB - Whether the integration of genetic/omic technologies in sports contexts will facilitate player success, promote player safety, or spur genetic discrimination depends largely upon the game rules established by those currently designing genomic sports medicine programs. The integration has already begun, but there is not yet a playbook for best practices. Thus far discussions have focused largely on whether the integration would occur and how to prevent the integration from occurring, rather than how it could occur in such a way that maximizes benefits, minimizes risks, and avoids the exacerbation of racial disparities. Previous empirical research has identified members of the personal genomics industry offering sports-related DNA tests, and previous legal research has explored the impact of collective bargaining in professional sports as it relates to the employment protections of the Genetic Information Nondiscrimination Act (GINA). Building upon that research and upon participant observations with specific sports-related DNA tests purchased from four direct-to-consumer companies in 2011 and broader personal genomics (PGx) services, this anthropological, legal, and ethical (ALE) discussion highlights fundamental issues that must be addressed by those developing personal genomic sports medicine programs, either independently or through collaborations with commercial providers. For example, the vulnerability of student-athletes creates a number of issues that require careful, deliberate consideration. More broadly, however, this ALE discussion highlights potential sports-related implications (that ultimately might mitigate or, conversely, exacerbate racial disparities among athletes) of whole exome/genome sequencing conducted by biomedical researchers and clinicians for non-sports purposes. For example, the possibility that exome/genome sequencing of individuals who are considered to be non-patients, asymptomatic, normal, etc. will reveal the presence of variants of unknown significance in any one of the genes associated with hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS), Marfan's syndrome, and other conditions is not inconsequential, and how this information is reported, interpreted, and used may ultimately prevent the individual from participation in competitive sports. Due to the distribution of genetic diversity that reflects our evolutionary and demographic history (including the discernible effects of restricted gene flow and genetic drift associated with cultural constructs of race) and in recognition of previous policies for "leveling" the playing field in competitive sports based on "natural" athletic abilities, preliminary recommendations are provided to discourage genetic segregation of sports and to develop best practice guidelines for genomic sports medicine programs that will facilitate player success, promote player safety, and avoid genetic discrimination within and beyond the program. PMID- 23940834 TI - Towards objectively quantifying sensory hypersensitivity: a pilot study of the "Ariana effect". AB - Background. Normally one habituates rapidly to steady, faint sensations. People with sensory hypersensitivity (SH), by contrast, continue to attend to such stimuli and find them noxious. SH is common in Tourette syndrome (TS) and autism, and methods to quantify SH may lead to better understanding of these disorders. In an attempt to objectively quantify SH severity, the authors tested whether a choice reaction time (CRT) task was a sensitive enough measure to detect significant distraction from a steady tactile stimulus, and to detect significantly greater distraction in subjects with more severe SH. Methods. Nineteen ambulatory adult volunteers with varying scores on the Adult Sensory Questionnaire (ASQ), a clinical measure of SH, completed a CRT task in the alternating presence and absence of tactile stimulation. Results. Tactile stimulation interfered with attention (i.e., produced longer reaction times), and this effect was significantly greater in participants with more SH (higher ASQ scores). Accuracy on the CRT was high in blocks with and without stimulation. Habituation within stimulation blocks was not detected. Conclusion. This approach can detect distraction from a cognitive task by a steady, faint tactile stimulus that does not degrade response accuracy. The method was also sensitive to the hypothesized enhancement of this effect by SH. These results support the potential utility of this approach to quantifying SH, and suggest possible refinements for future studies. PMID- 23940836 TI - Adding propensity scores to pure prediction models fails to improve predictive performance. AB - Background. Propensity score usage seems to be growing in popularity leading researchers to question the possible role of propensity scores in prediction modeling, despite the lack of a theoretical rationale. It is suspected that such requests are due to the lack of differentiation regarding the goals of predictive modeling versus causal inference modeling. Therefore, the purpose of this study is to formally examine the effect of propensity scores on predictive performance. Our hypothesis is that a multivariable regression model that adjusts for all covariates will perform as well as or better than those models utilizing propensity scores with respect to model discrimination and calibration. Methods. The most commonly encountered statistical scenarios for medical prediction (logistic and proportional hazards regression) were used to investigate this research question. Random cross-validation was performed 500 times to correct for optimism. The multivariable regression models adjusting for all covariates were compared with models that included adjustment for or weighting with the propensity scores. The methods were compared based on three predictive performance measures: (1) concordance indices; (2) Brier scores; and (3) calibration curves. Results. Multivariable models adjusting for all covariates had the highest average concordance index, the lowest average Brier score, and the best calibration. Propensity score adjustment and inverse probability weighting models without adjustment for all covariates performed worse than full models and failed to improve predictive performance with full covariate adjustment. Conclusion. Propensity score techniques did not improve prediction performance measures beyond multivariable adjustment. Propensity scores are not recommended if the analytical goal is pure prediction modeling. PMID- 23940835 TI - Bile acids induce apoptosis selectively in androgen-dependent and -independent prostate cancer cells. AB - Prostate cancer is a prevalent age-related disease in North America, accounting for about 15% of all diagnosed cancers. We have previously identified lithocholic acid (LCA) as a potential chemotherapeutic compound that selectively kills neuroblastoma cells while sparing normal human neurons. Now, we report that LCA inhibits the proliferation of androgen-dependent (AD) LNCaP prostate cancer cells and that LCA is the most potent bile acid with respect to inducing apoptosis in LNCaP as well as androgen-independent (AI) PC-3 cells, without killing RWPE-1 immortalized normal prostate epithelial cells. In LNCaP and PC-3 cells, LCA triggered the extrinsic pathway of apoptosis and cell death induced by LCA was partially dependent on the activation of caspase-8 and -3. Moreover, LCA increased cleavage of Bid and Bax, down-regulation of Bcl-2, permeabilization of the mitochondrial outer membrane and activation of caspase-9. The cytotoxic actions of LCA occurred despite the inability of this bile acid to enter the prostate cancer cells with about 98% of the nominal test concentrations present in the extracellular culture medium. With our findings, we provide evidence to support a mechanism of action underlying the broad anticancer activity of LCA in various human tissues. PMID- 23940837 TI - The variability of inner ear orientation in saurischian dinosaurs: testing the use of semicircular canals as a reference system for comparative anatomy. AB - The vestibular system of the inner ear houses three semicircular canals-oriented on three nearly-orthogonal planes-that respond to angular acceleration stimuli. In recent years, the orientation of the lateral semicircular canal (LSC) has been regularly used to determine skull orientations for comparative purposes in studies of non-avian dinosaurs. Such orientations have been inferred based on fixing the LSC to a common set of coordinates (parallel to the Earth's horizon), given that the orientation to gravity of this sensory system is assumed constant among taxa. Under this assumption, the LSC is used as a baseline (a reference system) both to estimate how the animals held their heads and to describe craniofacial variation among dinosaurs. However, the available data in living birds (extant saurischian dinosaurs) suggests that the orientation of the LSC in non-avian saurischian dinosaurs could have been very variable and taxon-specific. If such were the case, using the LSC as a comparative reference system would cause inappropriate visual perceptions of craniofacial organization, leading to significant descriptive inconsistencies among taxa. Here, we used Procrustes methods (Geometric Morphometrics), a suite of analytical tools that compares morphology on the basis of shared landmark homology, to show that the variability of LSC relative to skull landmarks is large (ca. 50 degrees ) and likely unpredictable, thus making it an inconsistent reference system for comparing and describing the skulls of saurischian (sauropodomorph and theropod) dinosaurs. In light of our results, the lateral semicircular canal is an inconsistent baseline for comparative studies of craniofacial morphology in dinosaurs. PMID- 23940838 TI - Kinome Render: a stand-alone and web-accessible tool to annotate the human protein kinome tree. AB - Human protein kinases play fundamental roles mediating the majority of signal transduction pathways in eukaryotic cells as well as a multitude of other processes involved in metabolism, cell-cycle regulation, cellular shape, motility, differentiation and apoptosis. The human protein kinome contains 518 members. Most studies that focus on the human kinome require, at some point, the visualization of large amounts of data. The visualization of such data within the framework of a phylogenetic tree may help identify key relationships between different protein kinases in view of their evolutionary distance and the information used to annotate the kinome tree. For example, studies that focus on the promiscuity of kinase inhibitors can benefit from the annotations to depict binding affinities across kinase groups. Images involving the mapping of information into the kinome tree are common. However, producing such figures manually can be a long arduous process prone to errors. To circumvent this issue, we have developed a web-based tool called Kinome Render (KR) that produces customized annotations on the human kinome tree. KR allows the creation and automatic overlay of customizable text or shape-based annotations of different sizes and colors on the human kinome tree. The web interface can be accessed at: http://bcb.med.usherbrooke.ca/kinomerender. A stand-alone version is also available and can be run locally. PMID- 23940839 TI - How age influences phonotaxis in virgin female Jamaican field crickets (Gryllus assimilis). AB - Female mating preference can be a dominant force shaping the evolution of sexual signals. However, females rarely have consistent mating preferences throughout their lives. Preference flexibility results from complex interactions of predation risk, social and sexual experience, and age. Because residual reproductive value should theoretically decline with age, older females should not be as choosy as younger females. We explored how age influences phonotaxis towards a standard mate attraction signal using a spherical treadmill (trackball) and a no-choice experimental protocol. Female Jamaican field crickets, Gryllus assimilis, were highly variable in their phonotaxis; age explained up to 64% of this variation. Females 10 days post imaginal eclosion and older oriented toward the mate attraction signal, with 10- and 13-day females exhibiting the greatest movement in the direction of the signal. Our study suggests 10- and 13-day old females would be most responsive when quantifying the preference landscape for G. assimilis sexual signals. PMID- 23940840 TI - Indicators of food and water security in an Arctic Health context--results from an international workshop discussion. AB - In August 2012, a literature search with the aim of describing indicators on food and water security in an Arctic health context was initialized in collaboration between the Arctic Human Health Expert Group, SDWG/AHHEG and the AMAP (Arctic Monitoring and Assessment Programme within the Arctic Council) Human Health Assessment Group, AMAP/HHAG. In December 2012, workshop discussions were performed with representatives from both of these organizations, including 7 Arctic countries. The aim of this article is to describe the workshop discussions and the rational for the 12 indicators selected and the 9 rejected and to discuss the potential feasibility of these. Advantages and disadvantages of candidate indicators were listed. Informative value and costs for collecting were estimated separately on a 3-level scale: low, medium and high. Based on these reviews, the final selection of promoted and rejected indicators was performed and summarized in tables. Among 10 suggested indicators of food security, 6 were promoted: healthy weight, traditional food proportion in diet, monetary food costs, non monetary food accessibility, food-borne diseases and food-related contaminants. Four were rejected: per-person dietary energy supply, food security modules, self estimated food safety and healthy eating. Among 10 suggested indicators of water security, 6 were promoted: per-capita renewable water, accessibility of running water, waterborne diseases, drinking-water-related contaminants, authorized water quality assurance and water safety plans. Four were rejected: water consumption, types of water sources, periodic water shortages and household water costs. PMID- 23940841 TI - Ethnic differences in leptin and adiponectin levels between Greenlandic Inuit and Danish children. AB - OBJECTIVE: In a recent study, we found that Greenlandic Inuit children had a more adverse metabolic profile than Danish children. Aerobic fitness and adiposity could only partly account for the differences. Therefore, we set out to evaluate and compare plasma leptin and adiponectin levels in Danish and Inuit children. METHODS: In total, 187 Inuit and 132 Danish children (5.7-17.1 years) had examinations of anthropometrics, body fat content, pubertal staging, fasting blood and aerobic fitness. RESULTS: Plasma leptin was higher in Danish boys [3,774 (4,741-3,005)] [pg/mL unadjusted geometric mean (95% CI)] compared to both northern [2,076 (2,525-1,706)] (p < 0.001) and southern (2,515 (3,137-2,016)) (p < 0.001) living Inuit boys and higher in Danish girls [6,988 (8,353-5,847)] compared to southern living Inuit girls [4,910 (6,370-3,785)] (p = 0.021) and tended to be higher compared to northern living Inuit girls [5,131 (6,444-4,085)] (p = 0.052). Plasma adiponectin was higher for both Danish boys [22,359 (2,573 19,428)] [ng/mL unadjusted geometric mean (95% CI)] and girls [26,609 (28,994 24,420)] compared to southern living Inuit boys [15,306 (18,406-12,728)] and girls [18,864 (22,640-15,717)] (both p < 0.001), respectively. All differences remained after adjustment for body fat percentage (BF%), aerobic fitness, age and puberty. The leptin/adiponectin ratio was higher in Danish boys and tended to be higher in Danish girls compared to northern living Inuit boys and girls, respectively. These differences were eliminated after adjustment for BF%, aerobic fitness, age and puberty. CONCLUSIONS: In contrast to our hypothesis, plasma leptin was higher in Danish children despite a more healthy metabolic profile compared to Inuit children. As expected, plasma adiponectin was lowest in Inuit children with the most adverse metabolic profile. PMID- 23940842 TI - Reply to Errera and Campbell: No, low salinity shock does not increase brevetoxins in Karenia brevis. PMID- 23940843 TI - Reply to Mottershead et al.: GDF9:BMP15 heterodimers are potent regulators of ovarian functions. PMID- 23940844 TI - Reply to Harris et al.: Differential impacts of omega-3 fatty acids and their derivatives on blood pressure. PMID- 23940845 TI - Reply.Re: Zyluk A. and Szlosser Z. The results of carpal tunnel release for carpal tunnel syndrome diagnosed on clinical grounds, with or without electrophysiological investigations: a randomized study. J Hand Surg Eur. 2013, 38: 44-9. PMID- 23940846 TI - Reply. Re: A. Sierakowski and D. Elliot. Amputation for pain in a thumb - not an advisable treatment. J Hand Surg Eur. 2013, 38: 331-3. PMID- 23940847 TI - Reply: response to the letter by Drs Berman and Case. PMID- 23940848 TI - Thailand's migrant sex workers struggle to access health care. PMID- 23940849 TI - Gene patents remain controversial in biomedical research. PMID- 23940850 TI - [Oral Rivaroxaban for the treatment of symptomatic pulmonary embolism]. PMID- 23940851 TI - [Rivaroxaban for thromboprophylaxis inpatients with acute medical illness]. PMID- 23940852 TI - [Transfusion strategies in acute upper gastrointestinal bleeding]. PMID- 23940855 TI - A novel fluoroscopy-free, resuscitative endovascular aortic balloon occlusion system in a model of hemorrhagic shock. AB - BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a potentially lifesaving maneuver in the setting of hemorrhagic shock. However, emergent use of REBOA is limited by existing technology, which requires large sheath arterial access and fluoroscopy-guided balloon positioning. The objectives of this study were to describe a new, fluoroscopy-free REBOA system and to compare its efficacy to existing technology. An additional objective was to characterize the survivability of 60 minutes of REBOA using these systems in a model of hemorrhagic shock. METHODS: Swine (70-88 kg) in shock underwent 60 minutes of REBOA using either a self-centering, one component prototype balloon system (PBS, n = 8) inserted (8 Fr) and inflated without fluoroscopy or a two component, commercially available balloon system (CBS, n = 8) inserted (14 Fr) with fluoroscopic guidance. Following REBOA, resuscitation occurred for 48 hours with blood, crystalloid, and vasopressors. End points included accurate balloon positioning, hemodynamics, markers of ischemia, resuscitation requirements, and mortality. RESULTS: Posthemorrhage mean arterial pressure (mm Hg) was similar in the CBS and PBS groups (35 [8] vs. 34 [5]; p = 0.89). Accurate balloon positioning and inflation occurred in 100% of the CBS and 88% of the PBS group. Following REBOA, mean arterial pressure increased comparably in the CBS and PBS groups (81 [20] vs. 89 [16]; p = 0.21). Lactate peaked in the CBS and PBS groups (10.8 [1.4] mmol/L vs. 13.2 [2.1] mmol/L; p = 0.01) 45 minutes following balloon deflation but returned to baseline by 24 hours. Mortality was similar between the CBS and PBS groups (12% vs. 25%, p = 0.50). CONCLUSION: This study reports the feasibility and efficacy of a novel, fluoroscopy-free REBOA system in a model of shock. Despite a significant physiologic insult, 60 minutes of REBOA is tolerated and recoverable. Development of lower profile, fluoroscopy-free endovascular balloon occlusion catheters may allow proactive aortic control in patients at risk for hemorrhagic shock and cardiovascular collapse. PMID- 23940856 TI - Uncontrolled hemorrhagic shock results in a hypercoagulable state modulated by initial fluid resuscitation regimens. AB - BACKGROUND: Previous studies have shown large-volume resuscitation modulates coagulopathy and inflammation. Our objective was to analyze the effects of initial bolus fluids used in military and civilian settings on coagulation and inflammation in a prospective, randomized, blinded trial of resuscitation of uncontrolled hemorrhage. METHODS: Fifty swine were anesthetized, intubated, and ventilated and had monitoring lines placed. A Grade V liver injury was performed followed by 30 minutes of hemorrhage. After 30 minutes, the liver was packed, and randomized fluid resuscitation was initiated during a 12-minute period with 2 L of normal saline, 2 L of lactated Ringer's solution, 250 mL of 7.5% saline with 3% Dextran, 500 mL of Hextend, or no fluid (NF). Animals were monitored for 2 hours after injury. Thrombelastograms (TEGs), prothrombin time (PT), partial thromboplastin time, fibrinogen as well as serum interleukin 6, interleukin 8, and tumor necrosis factor alpha levels were drawn at baseline and after 1 hour and 2 hours. RESULTS: The NF group had less posttreatment blood loss compared with other groups (p < 0.01). Blood loss was similar in the other groups. TEG R values in each group decreased from baseline at 1 and 2 hours (p < 0.02). The groups receiving 2 L of normal saline, 250 mL of 7.5% saline with 3% Dextran, or 500 mL of Hextend had lower TEG maximum amplitude values compared with NF group (p < 0.02). All fluids except lactated Ringer's solution resulted in significant increases in PT compared with NF, whereas all fluids resulted in significant decreases in fibrinogen compared with NF (p < 0.02). Fluid resuscitation groups as well as NF group demonstrated significant increases in inflammatory cytokines from baseline to 1 hour and baseline to 2 hours. There were no significant differences in inflammatory cytokines between groups at 2 hours. CONCLUSION: Withholding fluid resulted in the least significant change in PT, fibrinogen, and maximum amplitude and in the lowest posttreatment blood loss. Resuscitation with different initial fluid resuscitation strategies did not result in increased proinflammatory mediators compared with animals that did not receive fluid. PMID- 23940857 TI - Evaluation of the risk of noncontiguous fractures of the spine in blunt trauma. AB - BACKGROUND: There is significant debate over the risk of additional noncontiguous (NC) fractures among blunt trauma patients with an identified spinal column injury, often prompting routine full-spine imaging. We sought to determine the incidence of NC spinal fractures and the relationship between injury pattern and mechanism. METHODS: A review of all adult blunt trauma patients from the 2010 National Trauma Data Bank with a spine fracture. Patient demographics, mechanism of injury, and frequencies of all combinations of spinal fractures were analyzed. RESULTS: Among 654,052 blunt trauma patients, 83,338 (13%) had a diagnosed spine fracture. The mean (SD) Injury Severity Score (ISS) was 15 (11). Of these, 7% (5,496) sustained spinal cord injury, and 17% (14,413) underwent spinal surgery during their index hospitalization. Among those with spinal column fractures, the overall incidence of NC fractures was 19% and was associated with severe truncal injuries, primarily involving the chest. The relative incidences of cervical, thoracic, and lumbar fractures were 41% (34,480), 37% (30,383), and 43% (35,778), respectively. Rates of NC fractures of the spine included 9% cervicothoracic (7,406), 4% cervicolumbar (3,415), and 10% thoracolumbar (7,929). The slight majority (57%) of patients with spinal fractures sustained high-velocity trauma compared with 43% associated with low-velocity trauma. However, NC fractures of the spine were strongly associated with high-velocity trauma. CONCLUSION: Spine fractures are relatively common with blunt trauma, and approximately 20% of patients with a spinal column fracture will have an NC fracture. NC fractures were associated with other severe injuries and should be mainly suspected and investigated in high-velocity mechanisms. PMID- 23940858 TI - Not all mechanisms are created equal: a single-center experience with the national guidelines for field triage of injured patients. AB - BACKGROUND: Trauma systems use prehospital evaluation of anatomic and physiologic criteria and mechanism of injury (MOI) to determine trauma center need (TCN). MOI criteria are established nationally in a collaborative effort between the Centers for Disease Control and Prevention and the American College of Surgeons' Committee on Trauma and have been revised several times, most recently in 2011. Controversy exists as to which MOI criteria truly predict TCN. We review our single-center experience with past and present National Trauma Triage Criteria to determine which MOI predict TCN. METHODS: The trauma registry of an urban Level I trauma center was reviewed from 2001 to 2011 for all patients meeting only MOI criteria. Patients meeting any anatomic and physiologic criteria were excluded. TCN was defined as death, Injury Severity Score (ISS) of greater than 15, emergency department transfusion, intensive care unit admission, need for laparotomy/thoracotomy/vascular surgery within 24 hours of arrival, pelvic fracture, 2 or more proximal long bone fractures, or neurosurgical intervention during admission. Logistic regression analysis was used to identify which MOI predict TCN. RESULTS: A total of 3,569 patients were transported to our trauma center who met only MOI criteria and had the MOI recorded in the registry; 821 MOI patients (23%) were identified who met our definition of TCN. Significant predictors of TCN included death in the same passenger compartment, ejection from vehicle, extrication time of more than 20 minutes, fall from more than 20 feet, and pedestrian thrown/runover. Criteria not meeting TCN include vehicle intrusion, rollover motor vehicle collision, speed of more than 40 mph, injury from autopedestrian/autobicycle of more than 5 mph, and both of the motorcycle crash (MCC) criteria. CONCLUSION: With the exception of vehicle intrusion and MCC, the new National Trauma Triage Criteria accurately predicts TCN. In addition, extrication time of more than 20 minutes was a positive predictor of TCN in our system. Elimination of the vehicle intrusion and MCC criteria and reevaluation of extrication time merits further study. PMID- 23940860 TI - Repositioning endotracheal tubes in the intensive care unit: depth changes poorly correlate with postrepositioning radiographic location. AB - BACKGROUND: Suboptimal positioning of endotracheal tubes (ETs) is often identified on routine chest radiographs prompting adjustment. The accuracy of ET adjustments based on tube measurement markings at the incisors has not been reported. METHODS: We performed a 1-year prospective observational study of all surgical intensive care unit patients requiring repositioning of their ET based on chest x-ray (CXR) study. The ET was repositioned by a respiratory therapist using tube markings at the incisors, and follow-up CXR images were obtained within 2 hours. ET tube locations were compared with the planned intervention. Mean, median, interquartile range (IQR) and [chi]2 results are reported. RESULTS: Fifty-five patients met inclusion criteria and had a complete set of data (80% male). ET advancement was the most commonly required intervention (80%). For advancement, the median starting position was 7.10 cm (IQR, 2.20 cm) from the carina, with a median planned advancement of 2.00 cm. The actual advancement was a median of 1.15 cm, achieving 57.5% of the goal. Patients requiring ET withdrawal were more likely female (8 of 11, p < 0.001). For the withdrawal group, the median starting position was 0.70 cm (IQR, 1.05 cm) from the carina with a planned median withdrawal of 2.00 cm (IQR, 0.75 cm). The actual withdrawal was a median of 1.00 cm, achieving 50.0% of the goal. Overall, the mean difference between the planned and actual intervention was 1.55 cm (95% confidence interval, 1.16-1.95 cm) differing by a mean of 40% from the planned intervention (95% confidence interval, 29.0-51.0%). There was no correlation between the original location or the planned intervention and the accuracy of the intervention. In three cases, the ET moved opposite of the planned intervention. CONCLUSION: ET repositioning based on measurement at the incisors is inaccurate and the magnitude of the intervention does not correlate with the degree of error. Repositioning of ETs based on measurements at the incisors should be abandoned, or follow-up CXR images should be obtained. PMID- 23940861 TI - Vented versus unvented chest seals for treatment of pneumothorax and prevention of tension pneumothorax in a swine model. AB - BACKGROUND: Unvented chest seals (CSs) are currently recommended for the management of penetrating thoracic injuries in the battlefield. Since no supporting data exist, we compared the efficacy of a preferred unvented with that of a vented CS in a novel swine model of pneumothorax (PTx). METHODS: An open chest wound was created in the left thorax of spontaneously air-breathing anesthetized pigs (n = 8). A CS was applied over the injury, then tension PTx was induced by incremental air injections (0.2 L) into the pleural cavity via a cannula that was also used to measure intrapleural pressure (IP). Both CS were tested on each pig in series. Tidal volume (V(T)), respiratory rate, IP, heart rate, mean arterial pressure, cardiac output, central venous pressure, pulmonary arterial pressure, venous and peripheral oxygen saturations (SvO2, SpO2) were recorded. Tension PTx was defined as a mean IP equal to or greater than +1 mm Hg plus significant (20-30%) deviation in baseline levels of the previously mentioned parameters and confirmed by chest x-ray study. PaO2 and PaCo2 were also measured. RESULTS: PTx produced immediate breathing difficulty and significant rises in IP and pulmonary arterial pressure and falls in V(T), SpO2, and SvO2. Both CSs returned these parameters to near baseline within 5 minutes of application. After vented CS was applied, serial air injections up to 2 L resulted in no significant change in the previously mentioned parameters. After unvented CS application, progressive deterioration of all respiratory parameters and onset of tension PTx were observed in all subjects after approximately 1.4-L air injection. CONCLUSION: Both vented and unvented CSs provided immediate improvements in breathing and blood oxygenation in our model of penetrating thoracic trauma. However, in the presence of ongoing intrapleural air accumulation, the unvented CS led to tension PTx, hypoxemia, and possible respiratory arrest, while the vented CS prevented these outcomes. PMID- 23940862 TI - Increased morbidity and mortality of traumatic brain injury in victims of nonaccidental trauma. AB - BACKGROUND: The purpose of this study was to determine if the morbidity and mortality associated with traumatic brain injury (TBI) are worse in children who experienced nonaccidental trauma (NAT) compared with TBI from other traumatic mechanisms. METHODS: We identified all pediatric patients admitted with the diagnosis of TBI between 2001 and 2010 in our institutional trauma registry with an Abbreviated Injury Scale (AIS) score greater than 1. Patients were divided into groups based on a nonaccidental (NAT) or accidental mechanism of injury. Need for gastrostomy tube insertion was used as a marker of more severe neurologic morbidity in survivors of TBI. Group comparisons were made using Fisher's exact tests. RESULTS: A total of 2,782 patients with TBI were included; 315 (11.3%) patients had TBI secondary to NAT. Overall mortality and AIS-specific mortality were higher in patients with TBI secondary to NAT. In comparison with patients with TBI secondary to accidental mechanisms, patients with TBI secondary to NAT were younger (mean, 1 year vs. 8 years), had longer intensive care unit stays (mean, 3 days vs. 1 day), and required gastrostomy tubes more often (6% vs. 1%, p < 0.0001). Even among the subgroup of patients with severe TBI, (AIS score 4 and 5), patients with NAT required gastrostomy tubes more often (5% vs. 2%, p = 0.014). CONCLUSION: Patients with TBI from NAT have increased morbidity and mortality compared with patients with TBI from accidental mechanisms; these differences are present at all levels of severity of injury. Patients with TBI from NAT represent a vulnerable group of pediatric trauma patients who are at increased risk for death and worse outcome and who will require greater short- and long-term medical resources. PMID- 23940863 TI - Mortality increases with recurrent episodes of nonaccidental trauma in children. AB - BACKGROUND: Nonaccidental trauma (NAT) is a leading cause of childhood traumatic injury and death. Our objectives were to compare the mortality rates of children who experience recurrent episodes of NAT (rNAT) with children who experience a single episode of NAT and to identify factors associated with rNAT and increased mortality from rNAT. METHODS: Patients of NAT and rNAT in the Ohio State Trauma Registry were identified by matching date of birth, race, and sex between records of patients younger than 16 years between 2000 and 2010 with an DRG International Classification of Diseases--9th Rev. e-code for child abuse (E967-E967.9). Statistical comparisons were made using Fisher's exact and Wilcoxon rank-sum tests. RESULTS: A total of 1,572 patients of NAT were identified, with 53 patients meeting criteria for rNAT. Compared with patients with single-episode NAT, patients with rNAT were more commonly male (66% vs. 52%, p = 0.05), were white (83% vs. 65%, p = 0.02), were evaluated at a pediatric trauma center (87% vs. 69%, p = 0.008), and had higher mortality (24.5% vs. 9.9%, p = 0.002). Compared with rNAT patients who did not die, those who died with rNAT had a longer interval from initial episode to second episode (median [interquartile range], 527 days [83-1,099] vs. 166 days [52-502]; p = 0.07) and were older during their second episode (1 year [<6 months to 3 years] vs. <6 months [<6 months to 1 year]; p = 0.06). At initial presentation, lower-extremity fractures (p = 0.09) and liver injuries (p = 0.06) were reported more commonly in nonsurvivors of rNAT. CONCLUSION: Mortality is significantly higher in children who experience rNAT. Therefore, it is critically important to effectively intervene with appropriate resources and follow-up after a child's initial episode of NAT to prevent a future catastrophic episode. PMID- 23940865 TI - "It takes a village" to raise research productivity: impact of a Trauma Interdisciplinary Group for Research at an urban, Level 1 trauma center. AB - BACKGROUND: Few interdisciplinary research groups include basic scientists, pharmacists, therapists, nutritionists, laboratory technicians, as well as trauma patients and families, in addition to clinicians. Increasing interprofessional diversity within scientific teams working to improve trauma care is a goal of national organizations and federal funding agencies such as the National Institutes of Health (NIH). This article describes the design, implementation, and outcomes of a Trauma Interdisciplinary Group for Research (TIGR) at a Level 1 trauma center as it relates to increasing research productivity, with specific examples excerpted from an ongoing NIH-funded study. METHODS: We used a pretest/posttest design with objectives aimed at measuring increases in research productivity following a targeted intervention. A SWOT (strengths, weaknesses, opportunities, and threats) analysis was used to develop the intervention, which included research skill-building activities, accomplished by adding multidisciplinary investigators to an existing NIH-funded project. The NIH project aimed to test the hypothesis that accelerated biologic aging from chronic stress increases baseline inflammation and reduces inflammatory response to trauma (projected n = 150). Pre-TIGR/post-TIGR data related to participant screening, recruitment, consent, and research processes were compared. Research productivity was measured through abstracts, publications, and investigator initiated projects. RESULTS: Research products increased from 12 to 42 (approximately 400%). Research proposals for federal funding increased from 0 to 3, with success rate of 66%. Participant screenings for the NIH-funded study increased from 40 to 313. Consents increased from 14 to 70. Laboratory service fees were reduced from $300 per participant to $5 per participant. CONCLUSION: Adding diversity to our scientific team via TIGR was exponentially successful in (1) improving research productivity, (2) reducing research costs, and (3) increasing research products and mentoring activities that the team before TIGR had not entertained. The team is now well positioned to apply for more federally funded projects, and more trauma clinicians are considering research careers than before. PMID- 23940864 TI - Reliability adjustment: a necessity for trauma center ranking and benchmarking. AB - BACKGROUND: Currently, trauma center quality benchmarking is based on risk adjusted observed-expected (O/E) mortality ratios. However, failure to account for number of patients has been recently shown to produce unreliable mortality estimates, especially for low-volume centers. This study explores the effect of reliability adjustment (RA), a statistical technique developed to eliminate bias introduced by low volume on risk-adjusted trauma center benchmarking. METHODS: Analysis of the National Trauma Data Bank 2010 was performed. Patients 16 years or older with blunt or penetrating trauma and an Injury Severity Score (ISS) of 9 or greater were included. Based on the statistically accepted standards of the Trauma Quality Improvement Program methodology, risk-adjusted mortality rates were generated for each center and used to rank them accordingly. Hierarchical logistic regression modeling was then performed to adjust these rates for reliability using an empiric Bayes approach. The impact of RA was examined by (1) recalculating interfacility variations in adjusted mortality rates and (2) comparing adjusted hospital mortality quintile rankings before and after RA. RESULTS: A total of 557 facilities (with 278,558 patients) were included. RA significantly reduced the variation in risk-adjusted mortality rates between centers from 14-fold (0.7-9.8%) to only 2-fold (4.4-9.6%) after RA. This reduction in variation was most profound for smaller centers. A total of 68 "best" hospitals and 18 "worst" hospitals based on current risk adjustment methods were reclassified after performing RA. CONCLUSION: "Reliability adjustment" dramatically reduces variations in risk-adjusted mortality arising from statistical noise, especially for lower volume centers. Moreover, the absence of RA had a profound impact on hospital performance assessment, suggesting that nearly one of every six hospitals in National Trauma Data Bank would have been inappropriately placed among the very best or very worst quintile of rankings. RA should be considered while benchmarking trauma centers based on mortality. PMID- 23940866 TI - Does caring for trauma patients lead to psychological stress in surgeons? AB - BACKGROUND: Symptoms identical to posttraumatic stress disorder (PTSD) have been shown to occur in caregivers of trauma patients. Secondary traumatic stress (STS) characterizes those who exhibit PTSD symptoms related to indirect exposure to a stressor. We hypothesized that caring for trauma patients is associated with symptoms of PTSD/STS. METHODS: Surgeons in various specialties (n = 133) were surveyed from January to May 2012 at two regional surgical conferences. Symptoms of PTSD were identified using the Secondary Traumatic Stress Scale (STSS) using specific diagnostic criteria to measure the psychological impact of exposure to trauma patients. Resilience was measured using the Connor-Davidson Resilience Scale 10 items. The amount of time caring for trauma patients was used as a measure of risk exposure. The relationship between STSS, resilience, and exposure to trauma patients was measured with p < 0.05 considered significant. RESULTS: Twenty-eight surgeons (22%) met diagnostic symptom criteria for PTSD as measured by the STSS. Approximately two thirds of the surgeons (86 of 133, 65%) exhibited at least one symptom of STS. However, the magnitude of exposure to trauma patients was similar between surgeons with and without PTSD symptoms (p = 0.2177). Higher resilience scores were associated with lower STS scores (r = 0.369, p < 0.0001). Most importantly, surgeons who met symptom criteria for PTSD exhibited significantly lower resilience scores (31 [3.4] vs. 34 [3.9], p < 0.0001). CONCLUSION: Symptoms of PTSD as measured by the STSS were reported in two thirds of study participants but did not correlate with time spent for caring for trauma patients. One in five reported symptoms consistent with a PTSD. Lower resilience scores correlated with risk of symptoms and may be used to identify those surgeons most at risk. Efforts to better identify, address, and moderate these psychological consequences of surgical care may improve both the emotional well-being and the vocational performance of surgeons. PMID- 23940867 TI - Hit the floor running. PMID- 23940868 TI - The autism spectrum. PMID- 23940869 TI - How a mother's age at menopause predicts her daughter's ovarian reserve. PMID- 23940870 TI - Hospitals bristle as MedPAC warns of controversial billing initiative. PMID- 23940871 TI - Part D's underuse of generics wastes $1B per year. PMID- 23940872 TI - Stroke-related costs to double by 2030. PMID- 23940873 TI - [Cholecalciferol hydroxylation in rat hepatocytes under the influence of prednisolone]. AB - Glucocorticoid therapy is accompanied by development of processes typical of steroid osteoporosis. Indirect effects of glucocorticoids on the bone tissue are due to changes in mineral metabolism, which is regulated by vitamin D3. In this connection, we studied the influence of prednisolone on cholecalciferol metabolism. The study has shown that prednisolone action causes impairment of cholecalciferol metabolism in hepatocytes due to inhibiting vitamin D3 25 hydroxylase activity. Microsomal (CYP2R1) and mitochondrial (CYP27A1) isoenzymes of vitamin D3 25-hydroxylase were found to function at different concentrations of the substrate. The relative protein contents of the isoenzymes greatly differed in the liver with the prevalence of CYP27A1 over CYP2R1. Prednisolone administration resulted in the lowering of both mitochondrial and microsomal isoenzymes of vitamin D3 25-hydroxylase. The inhibition of vitamin D3 25 hydroxylating system in hepatocytes contributed to a significant reduction in blood serum 25OHD3. PMID- 23940874 TI - [Peculiarities of antioxidant defense system in erythroid cells and tissues of pigs under action of chromium chloride]. AB - The influence of CrCI3 in the amount of 400 mg Cr/kg of feed on antioxidant defense in populations of erythrocytes, erythroid bone marrow cells and tissues of pigs was studied. The increasing of the antioxidant defense of swine organism, as evidenced by the increase in superoxide dismutase and glutathione peroxidase activity in the fractions of "young" erythrocytes, was shown. Superoxide dismutase activity decreases, while glutathione and catalase activity increases in the erythroid cells of the bone marrow after of CrCl3 action. Oxidative processes are intensified in the liver of pigs of the experimental group, in contrast to other tissues, leading to the increase of content of TBARS-products, growth of superoxide dismutase activity and reduction of glutathione peroxidase activity. At the same time, the action of CrCl3 in other tissues activates antioxidant system, including the kidneys, lungs and myocardium, increases superoxide dismutase activity, and catalase activity in the spleen and kidneys. A decrease of content of TBARS-products and reduction of superoxide dismutase activity, as well as the increase of katalase activity and reduction of glutathione content were discovered in the skeletal muscles of pigs of the experimental group. As a result of research it is suggested to add CrCl3 to the diet of pigs to enhance antioxidant defense during their intensive growth. PMID- 23940875 TI - [Q & A. An aged patient with ileal stenosis and suffering from sudden abdominal pain and vomiting]. PMID- 23940876 TI - Response. PMID- 23940877 TI - Emergency physician should have omnidirectional thinking. PMID- 23940878 TI - [Invasive pulmonary aspergillosis after hematopoietic stem cell transplantation]. PMID- 23940879 TI - [Corynebacterium striatum]. PMID- 23940880 TI - [Fever and pancytopenia after a trip]. PMID- 23940881 TI - [Drug induced hypersensitivity syndrome (DIHS)]. PMID- 23940882 TI - Tar heel footprints in health care: Troy Roberson. PMID- 23940883 TI - Verifying influenza and pneumococcal immunization status of children in 2009-2010 from primary care practice records and from the North Carolina Immunization Registry. AB - BACKGROUND: The North Carolina Immunization Registry (NCIR) has been available since 2004. We sought to measure its utilization among practices that provide primary care for children who are enrolled in a prospective influenza surveillance study. METHODS: This study included children aged 0.5-17 years who presented with fever or acute respiratory symptoms to an emergency department or inpatient setting in Winston-Salem, North Carolina, from September 1, 2009, through May 19, 2010. Study team members verified influenza and pneumococcal immunization status by requesting records from each child's primary care practice and by independently reviewing the NCIR. We assessed agreement of nonregistry immunization medical records with NCIR data using the kappa statistic. RESULTS: Fifty-six practices confirmed the immunization status of 292 study-enrolled children. For most children (238/292, 82%), practices verified the child's immunizations by providing a copy of the NCIR record. For 54 children whose practices verified their immunizations by providing practice records alone, agreement with the NCIR by the kappa statistic was 0.6-0.7 for seasonal and monovalent H1N1 influenza vaccines and 0.8-0.9 for pneumococcal conjugate and polysaccharide vaccines. A total of 221 (98%) of 226 enrolled children younger than 6 years of age had 2 or more immunizations documented in the NCIR. LIMITATIONS: NCIR usage may vary in other regions of North Carolina. CONCLUSION: More than 95% of children younger than 6 years of age had 2 or more immunizations documented in the NCIR; thus, the Centers for Disease Control and Prevention 2010 goal for immunization information systems was met in this population. We found substantial agreement between practice records and the NCIR for influenza and pneumococcal immunizations in children. PMID- 23940884 TI - North Carolina health professionals' communication with adolescents about smoking. AB - BACKGROUND: The middle school and high school years are a time when adolescents are at high risk for initiation of smoking and progression to nicotine addiction. This research examines the prevalence with which North Carolina students receive smoking-related communication from health professionals and how such communication relates to smoking behaviors. METHODS: Data are from the 2009 North Carolina Youth Tobacco Survey (NCYTS), a biennial public and charter school-based survey of students in grades 6-12. The overall response rate was 78.2% (n = 3,301) for high school students and 79.2% (n = 3,805) for middle school students. Weighted multivariable logistic regression models were used to identify variables that are significantly related to health professionals' communication about smoking and/or advice against smoking. RESULTS: A majority of respondents reported that they had not been asked about or advised against smoking. Middle school and high school students who had tried to quit smoking in the past 12 months were significantly more likely to report having been asked about smoking (OR = 2.00 [95% CI, 1.23-3.28], OR = 1.96 [95% CI,1.44-2.661, respectively) or advised against smoking (OR = 2.25 [95% CI,1.13-4.50], OR = 2.02 [95% CI, 1.31 3.14], respectively) than were students who had not tried to quit. LIMITATIONS: This research is based on a cross-sectional survey and is subject to the honesty of the participants. Results may not generalize beyond public and charter school students in North Carolina. CONCLUSIONS: North Carolina health professionals need to increase communication with adolescents in order to sustain the historically low rates of smoking in this age group. PMID- 23940885 TI - Treating chronic pain. Introduction. PMID- 23940886 TI - Chronic pain: challenges and opportunities for relieving suffering. AB - This issue of the NCMJ addresses the problem of chronic pain in North Carolina; its diagnosis and management in primary and specialty care; and the need to balance efficacy and safety when prescribing opioid medications, as these drugs are associated with significant potential for misuse and abuse. The commentaries in this issue not only address the use of opioids for the management of chronic pain but also explore various alternatives, including medical marijuana, epidural and other injections, surgery, acupuncture, and other integrative therapies. Articles in this issue also describe the management of chronic pain in palliative care, the ways in which mental health affects pain, and the unintended consequences of chronic pain management. Finally, this issue describes several initiatives across the state that are addressing the epidemic of prescription drug abuse; these initiatives are effecting systematic changes in clinical practice to more effectively manage chronic pain, protect patients, and minimize the negative impact of prescription drug abuse on communities. PMID- 23940887 TI - Long-term opioid therapy for chronic pain: optimizing management, minimizing risk. AB - Opioid analgesics are commonly used for the management of chronic noncancer pain. Although they can be beneficial for select patients, opioids are also at the heart of a nationwide epidemic of misuse and diversion. PMID- 23940888 TI - Alternatives and adjuncts to opioids for the treatment of chronic pain. AB - The use of opioids to treat chronic noncancer pain is controversial because of concerns about safety, efficacy, and the potential for addiction and abuse. Clinicians must therefore continue to seek out alternatives to opioids, such as nonsteroidal anti-inflammatory drugs, acetaminophen, muscle relaxants, benzodiazepines, and antidepressants. PMID- 23940889 TI - Medical marijuana for chronic pain. PMID- 23940890 TI - The needle in a haystack: appropriate use of interventional techniques in the management of chronic pain. AB - Management of chronic pain is often difficult. Interventional approaches, such as joint injections and nerve blocks, can reduce dependence on opioid therapy, polypharmacy, and long-term costs; they can also dramatically improve pain control and function. However, interventional techniques must be used ethically and judiciously as part of a comprehensive approach to patient-centered care. PMID- 23940891 TI - Total hip or knee replacement in patients with chronic pain. AB - Patients with advanced degenerative joint disease of the hip or knee often experience chronic pain that can be effectively treated with joint replacement surgery. Joint replacement surgery remains beneficial even if patients have concurrent extrinsic pain or they are taking narcotics long term, although these groups are at higher risk for persistent pain and for dissatisfaction with their surgical results. PMID- 23940892 TI - Acupuncture for the treatment or management of chronic pain. AB - Evidence supports the safety and efficacy of acupuncture compared with no treatment, but it is unclear what role the placebo effect plays in acupuncture's efficacy. In determining whether acupuncture is indicated for a given individual or patient population, clinicians should consider acupuncture's effectiveness compared with no acupuncture--as well as the effectiveness, safety, and cost of alternative types of treatment. PMID- 23940893 TI - Pain management: lessons from palliative care. AB - Reducing suffering and helping patients to control their symptoms are key components of palliative care. This commentary will offer a comprehensive definition of palliative care and will present a case history to illustrate how palliative care can benefit patients with chronic pain. PMID- 23940894 TI - Chronic pain and mental health: moving beyond the conceptualization of pain as the fifth vital sign. AB - Current approaches to the assessment and treatment of chronic pain continue to rely predominantly on the medical model. However, the comorbidity of chronic pain with psychiatric conditions underscores the need for a biopsychosocial and interdisciplinary approach to pain that can bridge the gap between scientific understanding and medical practice. PMID- 23940895 TI - Safe and practical: a guide for reducing the risks of opioids in the treatment of chronic pain. AB - Health care providers often face the challenge of deciding when and how to prescribe opioids for patients with chronic noncancer pain. In patients for whom opioid treatment is appropriate, the risks can be mitigated by an initial risk assessment, informed consent, regular monitoring, and treatment within a medical home. PMID- 23940896 TI - Educating medical practitioners about safe opioid prescribing: training from the Governor's Institute on Substance Abuse. PMID- 23940897 TI - The chronic pain initiative and community care of North Carolina. AB - The rate of unintentional deaths from opioid poisoning has reached epidemic proportions. One model of successful intervention is Project Lazarus, an integrated-care pilot program in Wilkes County, North Carolina. Community Care of North Carolina, supported by a grant of $1.3 million from the Kate B. Reynolds Charitable Trust and matching funds of $1.3 million from the North Carolina Office of Rural Health and Community Care, is now expanding the Project Lazarus approach statewide. PMID- 23940898 TI - Challenges of chronic pain management: public health consequences and considered responses. AB - This article reviews the public health consequences of current approaches to chronic pain management, particularly those related to prescription of opioid analgesics and other controlled medications. This article also reviews factors contributing to these negative trends and discusses potential strategies for reversing them. PMID- 23940899 TI - Prescription drug overdose and misuse: data from Carolinas Poison Center. PMID- 23940900 TI - Prescription drug diversion: a law enforcement perspective. PMID- 23940901 TI - The North Carolina Controlled Substances Reporting System: a valuable tool for combating prescription drug misuse. AB - Prescription drug misuse is a growing problem that is resulting in increased morbidity and mortality throughout the United States. The North Carolina Controlled Substances Reporting System has proven to be an effective tool that allows health care providers to make more informed decisions when they prescribe or dispense controlled substances. PMID- 23940902 TI - Emergency department and hospital utilization for treatment of chronic pain in North Carolina. PMID- 23940903 TI - Project Lazarus: an innovative community response to prescription drug overdose. PMID- 23940904 TI - Foundation investments in palliative care. PMID- 23940905 TI - [Abdominal pain, vomits and weight loss]. PMID- 23940906 TI - [Infrequent etiology of a common symptom]. PMID- 23940907 TI - [Auguste Nelaton]. PMID- 23940908 TI - [Endoscopic versus endoscopic plus octreotide treatment for acute variceal bleeding. Benefit according to severity at admission]. AB - Vasoactive agents plus endoscopic treatment was recommended in esophageal variceal bleeding (EVB). However, the use according to severity on admission has been poorly evaluated OBJECTIVES: To evaluate the efficacy of endoscopic versus endoscopic plus octreotide treatment in patients with EVB according to severity on admission. METHODS: Between June 2001 and December 2011, 247 patients with EVB were treated using endoscopic or combined endoscopic plus octreotide treatment. Patients were analyzed according to the following cohorts: all patients, those with and without active bleeding, and by Child classes. Initial hemostatic failure, in-hospital rebleeding and in-hospital mortality were compared with both treatments. RESULTS: All patients with combined treatment had less initial hemostatic failure (P = 0.0157) and rebleeding (P = 0.0011) when compared to endoscopic treatment. Active bleeding patients and Child C patients had a significant reduction of initial hemostatic failure when receiving combined treatment vs endoscopic treatment (P = 0.0479 and P = 0.0222, respectively). Child C patients and patients without active bleeding significantly decreased rebleeding with combined treatment (P = 0.0139 and P = 0.0056, respectively). Global mortality was 17%, and did not differ between treatments. None patient in Child A died. CONCLUSIONS: Combined endoscopic plus octreotide treatment in patients with EVB resulted in a reduction of initial hemostatic failure and rebleeding. Moreover, the most relevant effect of combined treatment in decreasing initial hemostatic failure was seen in Child C and active bleeding patients, and for in-hospital rebleeding the same effect was seen in Child C and in patients without active bleeding. Mortality did not differ with both mentioned treatments. PMID- 23940909 TI - Prevalence of cholelithiasis in Buenos Aires, Argentina. AB - BACKGROUND: Cholelithiasis is an important cause of morbidity in the world and it varies significantly depending on the region of study. OBJECTIVE: To assess the prevalence of cholelithiasis in Buenos Aires. MATERIAL AND METHODS: This is a cross-sectional, descriptive, observational study performed in a public hospital with tertiary care in Gastrointestinal Surgery. From July 2010 to December 2011, 1,875 healthy volunteers who underwent liver, gallbladder and pancreas ultrasound imaging were included and a questionnaire containing the individual's medical history was administered. The presence of cholelithiasis and its eventual risk factors were studied. RESULTS: Of 1,875 individuals, 866 were males (46.2%) and 1,009 females (53.8%), older than 20 years old with an average age of 46.1 + 16.7 years. Cholelithiasis was found in 410 inidviduals (21.9%); 285 (15.2%) diagnosed at the time of the study and 125 (67%) who had already undergone a cholecystectomy due to gallstones. CONCLUSIONS: The prevalence of cholelithiasis in Buenos Aires, capital city of Argentina, is 21.9%. A significant association was found between cholelithiasis and female gender, age, body mass index, history of colic pain, family history of cholelithiasis, smoking, fatty liver and number of pregnancies. PMID- 23940910 TI - [Hepatocellular carcinoma within Milan criteria and beyond: outcomes of liver transplantation in a single Argentinian institution]. AB - Hepatocellular carcinoma (HCC) recurrence following liver transplantation is associated to bad prognosis. We retrospectively analyzed the data of 95 patients who underwent liver transplantation for HCC. Recurrence rate and variables associated with recurrence were reviewed. According to the findings on the explanted livers they were divided in two groups: Milan (M) 67% and non-Milan (NM) 33%. Global recurrence rate, and M-group and NM-group recurrence rates were 19%; 12% and 32%, respectively (P = 0.001). Although in the univariate analysis we found some factors associated to recurrence (hemocromathosis, year of transplant, bilobar distribution, vascular invasion and previous chemoembolization), they were not independent predictors of recurrence in the multivariate analysis. Actuarial survival in cirrhotic patients with and without HCC at 1, 3 and 5 years was 86% and 91% (NS), 77% and 88% (NS), and 67% and 86% (P = 0.002), respectively; whereas actuarial survival of the M and NM groups was 86% and 71%; 82% and 61%, and 78% and 58%, respectively (P = 0.02). We had a satisfactory five-year global survival in our series even though one third of our patients grafted for HCC were outside Milan criteria. PMID- 23940911 TI - [The Argentine experience with human immune deficiency virus positive patients in the waiting list for liver transplantation: preliminary analysis]. AB - After the introduction of high active antiretroviral therapy (HAART), the human immunodeficiency virus (HIV) was no longer considered a contraindication for transplantation. Yet, liver disease in this population is characterized by an accelerated course that may impact on the waiting list. OBJECTIVE: To evaluate the experience in Argentina with HIV positive patients listed for liver transplantation. PATIENTS AND METHODS: We analyzed 52 HIV positive patients listed between July 2005 and March 2010 (Group HIV positive). Results were compared with 462 HIV negative patients included during the same period (Group HIV negative). Data were obtained from INCUCAI, the Argentinian procurement organism and from the Transplantation Centers. RESULTS: The etiology of liver disease in the Group HIV positive was hepatitis C 40, HBV 3, fulminant hepatitis 3, alcohol 2, retrasplant 2 and others 2. The mean MELD at the time of listing was 1615 (lower than 19 in 40 cases, higher than 19 in 8, emergency in 3) in the group HIV positive and 16.64 in the group HIV negative (NS). The outcome in the waiting list for HIV positive and negative patients respectively was: death 14 (27%) vs 61 (18.7%) (P < 0.05), cadaveric donor transplant 10 (13%) vs 95 (29.4%) (P < 0.001), living donor transplant 0 (0%) vs 5 (1.1%) (NS), mean time from listing to death 270.70 298.11 days vs 267.29 266.53 days (NS), mean time from listing to transplant 70.26 74.05 vs 261 187.6 days (P < 0.01), mean MELD at the time of death 12.54 (13 cases lower than 15, 1 higher than 19) vs 19.6 9.7 (P < 0.05), mean MELD at the time of transplantation 24.33 vs 24.1 7.6 (NS). CONCLUSION: HIV positive patients have high mortality in the waiting list and low access to liver transplantation. MELD score underscores the severity of liver disease in this population when compared to HIV negative patients. PMID- 23940912 TI - [Efficacy of the association of a single dose of hepatitis B hyperimmune gammaglobulin and entecavir in the prophylaxis of hepatitis B after liver transplantation: experience of a single center in Argentina]. AB - The present study reports the effectiveness of the association of a single dose of hepatitis B immunoglobulin (HBIg) associated to entecavir in the prophylaxis of hepatitis B in patients who have undergone liver transplantation. Six patients that had been transplanted because of hepatitis B liver disease were retrospectively evaluated. Three of them developed non-oncological complications related to liver cirrhosis, two had hepatocellular carcinoma and another one had fulminant HBV hepatitis. The mean follow-up was 22 months (range: 7-52 months). The 6 patients received entecavir as prophylactic treatment before transplantation. The pretransplant viral load was undetectable in all patients. HBsAg seroconversion was observed in four of the six patients. Three patients died during follow-up, two because of recurrent hepatocellular carcinoma, none of them had detectable HBV serum viral load. In a small series of patients we could demonstrate that a regimen with a single dose of gamma globulin entecavir is effective in the post-transplant management of patients with liver disease associated with HBV. Future studies will be able to demonstrate the effectiveness of specific gamma globulin-free regimens. PMID- 23940913 TI - Intestinal intussusception in adults: tomographic findings and report of two cases. AB - Intestinal intussusception is infrequent in adults. Unlike what happens in kids, it shows a demonstrable etiology in most cases: polyps, lipomas, hamartomas, malignancies, etc. Among diagnostic methods, CT scan is the study that yields the best results for the diagnosis, giving forth pathognomonic signs and favoring therapeutic decision-making. Two cases of intestinal intussusception in adults secondary to benign pathology are analyzed, stressing mainly the tomographic findings and some considerations about therapeutic decision-making based on tomographic results. PMID- 23940914 TI - [Acute necrotizing esophagitis. Case report]. AB - Acute necrotizing esophagitis, also known as black esophagus, represents an extremely rare clinical entity, defined by the black pigmentation of the esophagus, secondary to necrosis of the mucosa and detected at endoscopy. We present a clinical case of this rare disease, with its manifestation, diagnosis, treatment, and we perform a review of the literature. PMID- 23940915 TI - [Robotic total mesorectal excision for rectal cancer]. AB - Laparoscopic total mesorectal excision (TME) has proven to be feasible and safe. However, it represents a major technical challenge, since it involves the dissection of the rectum in a confined space such as the bony pelvis using un ergonomic surgical devices. This difficulty is accentuated in patients with distal tumors and high body mass index (BMI), in which the surgical margins and the hypogastric nerves may be affected. Therefore, robotic surgery aims to overcome these limitations that conspire against the mininvasive surgical approach of rectal cancer. We present an obese (BMI = 32 kg/m2) 82-year-old man with a history of smoking and prostate cancer that was recently diagnosed with a middle rectal adenocarcinoma at 9 cm from the anal verge. Rectal examination evidenced a mobile lesion. Computed tomography scan ruled out metastases and at the local staging by MRI, the tumor was considered as T3-N0 with free circumferential margins. Surgical treatment was decided and a hybrid technique was used combining an initial laparoscopic approach followed by the robotic TME. The patient had a full recovery and was discharged three days after surgery without complications. Pathological examination revealed a low-grade adenocarcinoma with mesorectal invasion, free circumferential and distal margins, and 24 negative lymph nodes (pT3-pN0-pM0/Stage II). Robotic TME was performed safely in an obese patient. It facilitated dissection maneuvers in a confined space with proper identification and preservation of the hypogastric nerves, allowing retrieving an intact mesorectum. Prospective randomized trials will define the role of this new technology. PMID- 23940916 TI - [Solid pseudopapillary tumor of the pancreas: a case report and a review of the literature]. AB - The solid pseudopapillary tumor of the pancreas is a rare neoplasm, representing 0.13% to 2.7% of all pancreatic tumors. This neoplasm is more common in young women between the third and fourth decade of life. It may produce nonspecific symptoms and in many cases is asymptomatic, being diagnosed incidentally. A 28 year-old woman with no previous medical history presented epigastric pain for the last 3 months. Physical examination was normal. When an upper gastrointestinal endoscopy was performed, a submucosal lesion was observed in the posterior wall of the stomach. A computed tomography and a magnetic resonance imaging were done and both showed a 2.8 cm-diameter tumor in the body of the pancreas. She underwent a spleen-preserving distal pancreatectomy (Warshaw surgery), evolved favourably and was discharged at the sixth postoperative day. The pathological diagnosis of the surgical specimen was a solid pseudopapillary tumor of the pancreas. Surgery is the gold-standard treatment for this condition, given the facts that no other treatment have proven being effective and often surgical treatment is curative because of the tumor's low malignant potential. PMID- 23940917 TI - [Hepatitis E: an infrequent virus or an unfrecuently investigated agent?]. AB - Two cases of hepatitis E that were assisted in our Unit of Hepatology and Liver Transplantation are described in this article. The first patient had prior hepatic involvement and therefore a more severe course, whereas the second case, with normal liver function, only developed a self-limited acute hepatitis. PMID- 23940918 TI - [Cholangitis secondary to migrated metallic coils in the common bile duct]. AB - Biliary obstructions are infrequently caused by foreign bodies. We present an unusual case of angiographically placed metallic coils into the intrahepatic arteries to provide hemostasis, that subsequently eroded into the common bile duct leading to obstructive jaundice and cholangitis a year later. In patients with history of invasive procedures, the possibility of foreign body migration into the common bile duct should always be considered in the differential diagnosis of obstructive jaundice and cholangitis. PMID- 23940919 TI - [Update on colorectal cancer screening: "guiding" the guides of the last years]. PMID- 23940920 TI - [Anesthesia safety in diagnostic and therapeutic endoscopic procedures. Professional relationship between endoscopists and anesthesists]. PMID- 23940921 TI - Mandatory reporting; you are in trouble if you don't! PMID- 23940922 TI - Organized dentistry prepared to protect our members and our profession. PMID- 23940923 TI - ADA partnering with the LDA and NODA for a mission of mercy (MOM). PMID- 23940924 TI - 2013 legislative session comes to an end. PMID- 23940925 TI - ADA/LDA top ten list. PMID- 23940926 TI - Follow DPA to avoid disciplinary action. PMID- 23940927 TI - Beyond dental education. PMID- 23940928 TI - Chancellor's news could be much worse. PMID- 23940929 TI - Regulator has improved, but is still failing to meet key standards. PMID- 23940930 TI - Every nurse urged to wage war on obesity and high blood pressure. PMID- 23940931 TI - Nurses angered by chancellor's slur on public sector workers. PMID- 23940932 TI - Calls for whistleblowing lead and standardised policy at every trust. PMID- 23940933 TI - European influx helps plug the gaps, but for how much longer? PMID- 23940934 TI - Lessons in delivering good care. AB - Education is at the heart of St Christopher's Hospice's mission to make palliative care widely available--it is now one of the largest providers of end of life care education. Its approach influenced Mid Staffs public inquiry chair Robert Francis's recommendations on nurse training. PMID- 23940935 TI - Recovery through suggestion. AB - Nurse Helen Bremner established a hypnotherapy service for patients with irritable bowel syndrome in 2010. Despite achieving impressive results, funding was withdrawn in April this year. PMID- 23940936 TI - Care at just a touch. AB - As NHS trusts across the UK strive to make better use of information technology to improve patient safety, some nurses are using an electronic observation system called Wardware on iPod Touch devices. It not only saves time on paperwork and reduces errors, but alerts nurses when action needs to be taken and allows patient data to be shared at once with doctors. PMID- 23940937 TI - The role of nurses in medicine administration errors. AB - This article explores the commonly held belief that nurses are to blame for the high rate of medication administration errors in health care. The article argues for a need to move away from a culture of blame and to consider changes to medicine and the increasing complexity of administration as potential reasons for error. Medicine administration should be viewed within the wider context of health care rather than as an isolated process in order to develop effective solutions to reduce medicine-related errors. PMID- 23940938 TI - Prevention and management of incontinence-associated dermatitis. AB - Maintaining skin integrity in people with incontinence is challenging. Incontinence is common in older people and those compromised by medical or surgical comorbidities. Urinary and faecal incontinence can result in skin breakdown, which is characterised by erosion of the epidermis, creating a moist, macerated appearance to the skin. Incontinence and associated skin breakdown can have a considerable effect on an individual's physical and psychological wellbeing. This article discusses the aetiology of incontinence-associated dermatitis and considers the best options for the prevention, management and treatment of this condition. PMID- 23940939 TI - Patient safety: threats and solutions. AB - The recent landmark report into the care failings at Stafford Hospital has called for sweeping changes to end the NHS's neglect of patient safety (Francis 2013). The report calls for a 'fundamental change' in culture so that patients are always put first, and it makes 290 recommendations covering a broad range of issues relating to patient care and safety in the NHS. This article explores issues surrounding patient safety, including the terminology associated with harm and error. The types of patient safety incidents that occur in different care environments are discussed. It offers insight into why patient safety incidents occur and describes some of the underlying factors. It also discusses preventive strategies and the role of patients and family members in enhancing safety. PMID- 23940941 TI - Stand out in a crowd. PMID- 23940940 TI - Ethical practice. PMID- 23940942 TI - Could you be a research nurse? PMID- 23940943 TI - Priorities for placements. PMID- 23940944 TI - [The effects of autophagy on cell survival under different hypoxia]. AB - OBJECTIVE: To investigate the regulation of different hypoxia on cell survival and autophagy. METHODS: PC12 cells were treated with different hypoxia. The cell survival was measured by MTT assay, expressions of LC3 and p62 were marked for autophagy detected by Western Blot, and the level of reactive oxygen species (ROS) was analyzed by flow cytometry. RESULTS: The cell viability was different under different hypoxia: moderate hypoxia promoted cell viability, and severe hypoxia caused a decrease in cell viability; autophagy marker molecules, p62 and LC3-II expressions were different: moderate hypoxia increased p62 and LC3-II expressions, in contrast, severe hypoxia led to the decrease of p62 and LC3-II expressions; compared to normoxia, moderate hypoxia did not change the levels of ROS, while severe hypoxia increased the levels; 3-MA, the inhibitor of autophagy, elevated the levels of ROS in the three oxygen concentrations, additionally, the increased amplitudes in the moderate and severe hypoxia groups were higher than that in the normoxia group. CONCLUSION: Moderate hypoxia promotes cell survival, severe hypoxia causes the cell death, and the autophagy activity may mediate the effects of different hypoxia. PMID- 23940945 TI - [The expressions of endoplasmic reticulum molecular chaperone proteins in pressure ulcer on the different stage of ischemic injury]. PMID- 23940946 TI - [Effects of endothelial progenitor cell-conditioned medium on the proliferation, adhesion and migration of vascular smooth muscle cells]. AB - OBJECTIVE: To investigate the effects of endothelia progenitor cells conditioned medium (EPC-CM) on the migration, adhesion and proliferation of vascular smooth muscle cells (VSMCs). METHODS: Mononuclear cells were isolated from rat bone marrow by density gradient centrifugation,plated on dishes precoated with 5% fibronectin, and then cultured with complete M199 medium (including 15% fetal calf serum, 10 microg/L VEGF and 5 microg/L bFGF). EPC-CM was collected and used to incubate VSMCs isolated from rat arteriae aorta. After 24 h, VSMCs proliferation, adhesion and migration were assayed with CCK-8, adhesion test and modified Boyden chamber assay, respectively. RESULTS: The proliferation, adhesion and migration of VSMCs were obviously decreased when the cells were cultured with EPC-CM. CONCLUSION: EPC-CM could inhibit VSMC functions, which would be one of the mechanisms against atherosclerosis by EPCs. PMID- 23940947 TI - [Beta-arrestin 1 induces CRFR1 internalization in the cortex of rat during hypoxia]. PMID- 23940948 TI - [Effects of ATP-sensitive potassium channel opener iptakalim against ventricular remodeling and its mechanisms of endothelial protection]. AB - OBJECTIVE: To study the effects of iptakalim (Ipt), an ATP-sensitive potassium channel opener, on cardiac remodeling induced by isoproterenol (ISO) in Wistar rats. METHODS: ISO was given subcutaneously (85 mg/(kg x d), sc, 7 days) to induce cardiac remodeling in rats. The rats in Ipt treated group were administrated with Ipt 3 mg/kg (po) after ISO injection. After treated with Ipt for 6 weeks, the hemodynamic parameters were tested by an eight channel physiological recorder (RM-6000). Then the heart weight was weighed and the cardiac remodeling index was calculated. HE stain and Masson's stain were employed to perform histological analysis, the hydroxyproline(Hyp) content in cardiac tissue was detected by colorimetric method, radioimmunoassay was used to measure the plasma levels of endothelin-1 (ET-1) and prostacyclin (PGI2). RESULTS: Six weeks after ISO injection, the cardiac functions of model group were damaged markedly compared with those of normal group. The characteristics of ventricular remodeling in model group included that the heart weight index, myocyte cross-sectional area, myocardial fibrosis, and the hydroxyproline content in cardiac tissue were all increased significantly. The plasma level of ET-1 was increased, while the plasma level of PGI2 was decreased significantly. These changes could be reversed by Ipt treatment (3 mg/(kg x d) for 6 weeks). CONCLUSION: Ipt can reverse cardiac remodeling induced by isoproterenol in rats. The endothelial protective effect regulating effects of Ipt on the balance between the ET-1 and PGI2 system may be involved in its mechanisms. PMID- 23940949 TI - [The changes of inducible nitric oxide synthase activity and apoptosis-related gene expression in endotoxemia-induced rat diaphragm]. AB - OBJECTIVE: To study the changes of inducible nitric oxide synthase (iNOS) activity and apoptosis-related genes Bcl-2, Bax and caspase-3 mRNA expressions in endotoxemia-induced rat diaphragm injury and analyze the related apoptosis mechanism. METHODS: Thirty-two male SD rats were randomly divided into 4 groups (n = 8): control group (saline 0.5 ml ip), endotoxin 24 h, 48 h and 96 h group (endotoxin 12 mg/kg ip, animals were killed either 24, 48 or 96 h after injections). Body weight were measured, the ratio between diaphragm weight and body weight, activities of constitutive nitric oxide syntheses (cNOS), iNOS and succinate dehydrogenase (SDH) were also measured. The expressions of Bcl-2, Bax and caspase-3 mRNA were detected by RT-PCR analysis. RESULTS: Endotoxin induced significant reductions in diaphragm mass in endotoxin 96 h group (P < 0.05). Endotoxin increased diaphragm cNOS or iNOS activities, and they were significantly higher in endotoxin 96 h group than those in endotoxin 24 h and 48 h groups, diaphragm SDH activity was reduced, and it was lower in endotoxin 96 h group than that in endotoxin 24 h and 48 h groups (P < 0.01). Endotoxin significantly increased Bax and caspase-3 mRNA expressions, and they were higher in endotoxin 48 h and 96 h groups than those in endotoxin 24 h group (P < 0.01). Endotoxin significantly reduced Bcl-2 mRNA expression and the ratio of Bcl-2/Bax, and they were lower in endotoxin 48 h and 96 h groups than those in endotoxin 24 h group (P < 0.01). CONCLUSION: iNOS is activated in endotoxemia-induced rat diaphragm injury. It damages mitochondria, upregulates Bax expression and downregulates Bcl-2 expression, then induces caspase-3 related apoptotic pathway. These changes may cause diaphragm injury and atrophy. PMID- 23940950 TI - [The role of TLR2/4 in the IL-10 expression in synoviocytes of rheumatoid arthritis induced by Hsp72]. PMID- 23940951 TI - [Changes in expression of tyrosine hydroxylase by CD4+ T lymphocytes in lymphoid tissues of DBA/1 mice with collagen-induced arthritis]. AB - OBJECTIVE: To show the involvement of lymphocyte-derived catecholamines in the pathogenesis of rheumatoid arthritis (RA), we investigated the change in expression of tyrosine hydroxylase (TH), a rate-limiting enzyme of catecholamine synthesis, by CD4+ T lymphocytes in lymphoid tissues of DBA/1 mice with collagen induced arthritis (CIA). METHODS: CIA model was induced by chicken type II collagen in DBA/1 mice. The joints of the mice were observed for clinical score of swelling on and after the 22nd day of primary immunization. Pathological changes of ankles were examined by staining of tissue sections with hematoxylin and eosin on the 35th and 55th day following primary immunization. Immunofluorescent histochemistry was used to identify the number of TH-positive, CD4-positive, and double-labeled cells in the mesenteric lymph nodes and the spleen. RESULTS: Paw-swelling onset was on days 29 - 32 after the first immunization in DBA/1 mice. Clinical score for swelling of the paws reached peak on day 46 after the first immunization. Compared with the ankles of intact or vehicle mice, the joints of CIA mice had these characteristics: increased inflammatory cells in the synovial tissues, proliferated synoviocytes in the multilayers, narrowed articular space, and destructed articular cartilages. Simultaneously, the number of TH-positive, CD4-positive, and double-labeled cells in the mesenteric lymph nodes and the spleen was significantly increased on days 35 and 55 following the first immunization. Between day 35 and day 55 post immunization, there was no significant difference in the number of these positive cells. CONCLUSION: CD4+ T lymphocytes up-regulate TH expression in the process of CIA and therefore, it is suggested that endogenous catecholamines of lymphocytes involve in the pathogenesis of RA. PMID- 23940952 TI - [The damage effects of hypothermia combined with hypoxia on rat pulmonary microvascular endothelial cells]. AB - OBJECTIVE: To study the synergistic effects of hypothermia and hypoxia on the damage of pulmonary microvascular endothelial cells (PMVEC) in rat. METHODS: Primary PMVECs were obtained by complex phosphoesterasum digesting from isolated lung tissues of Wistar rats, the PMVECs were identified by phase contrast microscope and immunofluorescence studies for CD31 antigen and bandeiraea simplicifolia isolectin (BSI) binding test. Factorial design was adopted in trial according to hypothermia and hypoxia existing or not. Using corresponding kit measured the levels of lactate dehydrogenase (LDH) activity in cell medium. Level of nitric oxide (NO) concentration was measured by Griess Assay. RT-PCR was used to examine the expression of vascular endothelial growth factor (VEGF), endothelin-1 (ET-1) mRNA in PMVECs. RESULTS: The monolayer of cultured PMVECs displayed the shape of pavingstone. CD31 antigen and binding BSI results by fluorescence microscope identified the cultured cells were PMVECs. Compared to the control group, LDH activity and VEGF, ET-1 expression levels were significantly increased in hypothermia group, hypoxia group and hypoxia combined with hypothermia group. And the levels of NO concentration were reduced in these three groups. The results of One-way ANOVA showed that there was a synergistic effect between hypothermia and hypoxia. CONCLUSION: Hypothermia and hypoxia both have an effect on PMVECs whether in altering the cell permeability or in releasing of vasoactive substances including NO and ET-1. In addition, there is a synergistic effect between hypothermia and hypoxia. PMID- 23940953 TI - [Effect of Morinda officinalis how (MOH) on free radical metabolism and physical ability in mouse myocardium]. PMID- 23940954 TI - [Effect of hypoxia on gastric cancer cell proliferation and LINE-1 endonuclease variant GCRG213 expression]. AB - OBJECTIVE: To investigate the change of gastric cancer cell proliferation and the expression of gastric cancer related gene 213 (GCRG213), a long interspersed nuclear element-1 (LINE-1) endonuclease variant, during hypoxia. METHODS: Normal gastric mucosa cell GES-1 and gastric cancer cell BGC-823 were cultured in 20% or 3% oxygen concentrations, respectively. MTT test was used to analyze the proliferation of the GES-1 and BGC-823 cells. The change of GCRG213 mRNA and protein expression in GES-1 and BGC-823 cells was detected by using RT-PCR and Western blot analysis. Blast was used at the NCBI Blast server to identify GCRG213 sequence to any alignment in the GeneBank databases. RESULTS: Compared with 20% oxygen condition, 3% oxygen concentration could promote cell growth. Mean-while, the expression of GCRG213 at mRNA and protein levels was increased. GCRG213 sequence shared high homology with LINE-1 endonuclease sequence. CONCLUSION: GCRG213 is a variant of LINE-1 endonuclease. Hypoxia as in 3% oxygen condition can promote cell proliferation and lead to GCRG213 overexpression. PMID- 23940955 TI - [Choline promotes angiogenesis in chick embryo chorioallantoic membrane]. AB - OBJECTIVE: To investigate choline promoting angiogenesis on chick embryo chorioallantoic membrane (CAM). METHODS: CAM model was prepared, the choline chloride, human vascular endothelial growth factor (hVEGF) and normal saline were added respectively onto the carrier on the CAM, the state of angiogenesis was observed and the number of new blood vessels was counted. RESULTS: Choline chloride was tested at the concentrations of 0.5 nmol/L - 1 mmol/L in this experiment, when its concentrations were increased to 0.01 micromol/L - 1 000 micromol/L, it could stimulate angiogenesis, the minimum effective concentration was tested as 0.01 micromol/L, and its effect for promoting the angiogenesis was equivalent to that of hVEGF, the potent stimulator for angiogenesis. CONCLUSION: The result shows that choline can promote angiogenesis in the chick embryo chorioallantoic membrane. PMID- 23940956 TI - [Construction of inducible lentiviral vector containing human Notch1 and EGFP gene and its expression in PC12 cells]. AB - OBJECTIVE: To construct inducible lentiviral vector containing human Notch1 intracellular domain (NICD) gene and enhanced green fluorescent protein (EGFP), and to study its expression in PC12 cells. METHODS: NICD cDNA was amplified by RT PCR from human placenta tissue. EGFP gene was amplified by PCR from pEGFP-C1. Both NICD and EGFP were cloned into pcDNA 3.1 (+) plasmid to form pcDNA3.1-Notch1 EGFP. Then the Notch1-EGFP fragment was separated and cloned into pLVX-Tight-puro to form pLVX-Notch1-EGFP. The lentivirus were packaged and harvested, which were used to infect PC12 cells. After antibody selection for 2 weeks, the PC12 cells were induced by doxycycline (Dox). The expression of Notch1-EGFP was detected by fluorescence microscope and flow cytometry. RESULTS: The recombinant inducible lentiviral vectors (pLVX-Notch1-EGFP) were success fully constructed. The EGFP positive cell percentage was over 90% in transfected PC12 cells after 500 ng/ml Dox induction for 36 h. The expression of Notch1 was posited correlated to the Dox concentration. The expression of Notch1 increased with the duration of Dox induction, which got the peak at 36 h after Dox induction. CONCLUSION: The recombinant inducible lentiviral vectors containing Notch1 and EGFP gene are successfully constructed, which provides an effective and simple method to regulate the expression of Notch1 in PC12 cells. PMID- 23940957 TI - [Effect of ischemic preconditioning on the expression of P-selectin in the lung injury following ischemia/reperfusion in the hind limbs of rats]. PMID- 23940958 TI - [The combined effects of beta-sheet breaker and hUCMSC on APP transgenic mice]. AB - OBJECTIVE: To study the effect of combining the injection of beta-sheet breaker H102 with human umbilical cord mesenchymal stem cell (hUCMSC) on APP transgenic mice behavior, P-tau, apoptosis and the expression of relevant enzymes in the brain. METHODS: APP transgenic mice were randomly divided into model group, hUCMSC group, H102 group, H102 with hUCMSC group and a group of C57BL/6J mice with the same age and background was set as normal. After two weeks and four weeks, the ability of spatial reference memory was tested by Morris Water Maze. After four weeks, immunohistochemical stain and Western blot were done to detect the content of Bad, Bax, Bcl-2, Bcl-xl, P-tau, GSK-3beta, PP-2A and PP-1 in mice brain. RESULTS: The ability of memory of hUCMSC in 2 weeks group was slightly improved than that in the model group. hUCMSC in four weeks group, H102 group and H102 with hUCMSC group significantly improved the ability of and memory, and reduced the phosphorylation of tau and brain cell's apoptosis of the Alzheimer disease (AD) mice. CONCLUSION: Beta-sheet breaker H102 together with transplanting hUCMSC is an effective therapeutic strategy for AD. PMID- 23940959 TI - [The role of mitochondrial dysfunction in apoptosis of mouse glomerular podocytes exposed to high glucose]. PMID- 23940960 TI - [Attenuation of cardiac ischemia/reperfusion injury by transient low hydroperoxide pretreatment in rat]. AB - OBJECTIVE: To investigate how transient low dose of hydroperoxide pretreatment prevents cardiac ischemia/reperfusion injury. METHODS: SD rats were divided into 4 groups: sham operation (Sham), standard ischemia/reperfusion (I/R), ischemic preconditioning (IPC) and IR preceded by low H2O2 treatment. Cardiac function and injury parameter were compared among groups. RESULTS: IPC protected reperfusion injury and improved cardiac function. Low H2O2 treatment played a role in cardioprotection similar to IPC. Low H2O2 was indeed generated in the early phase of simulated ischemia and attenuated cytochrome c release induced by high Ca2+ in isolated mitochondria. CONCLUSION: Low H2O2 plays a critical role in cardioprotection probably by inhibiting mitochondrial permeability transition. PMID- 23940961 TI - [The effect of 18beta-glycyrrhetinic acid on gap junction among cerebral arteriolar smooth muscle cells in Wistar rat and spontaneously hypertensive rat]. AB - OBJECTIVE: This study compared Wistar rat with spontaneously hypertensive rat (SHR) on the electrophysiology and coupling force of the smooth muscle cells in the cerebral arteriolar segments and observe the influence of 18beta glycyrrhetinic acid(18beta-GA) on the gap junctions between the arterial smooth muscle cells. METHODS: The outer layer's connective tissue of the cerebral arteriolar segments was removed. Whole-cell patch clamp recordings were used to observe the 18beta-GA's impaction on the arteriolar segment membrane's input capacitance (C(input)), input conductance (G(input)) and input resistance (R(input)) of the smooth muscle cells. RESULTS: (1) The C(input) and G(input) of the SHR arteriolar segment smooth muscle cells was much higher than the Wistar rats, there was significant difference (P < 0.05). (2) 18beta-GA concentration dependently reduced C(input) and G(input) (or increase R(input)) on smooth muscle cells in arteriolar segment. IC50 of 18beta-GA suppression's G(input) of the Wistar rat and SHR were 1.7 and 2.0 micromol/L respectively, there was not significant difference (P > 0.05). After application of 18beta-GA concentration > or = 100 micrmol/L, the C(input), G(input) and R(input) of the single smooth muscle cells was very close. CONCLUSION: Gap junctional coupling is enhanced in the SHR cerebral arterial smooth muscle cells. 18beta-GA concentration-dependent inhibits Wistar rat's and SHR cerebral arteriolar gap junctions between arterial smooth muscle cells. The inhibitory potency is similar between the two different rats. When 18beta-GA concentration is > or = 100 micromol/L, it can completely block gap junctions between arteriolar smooth muscle cells. PMID- 23940962 TI - [Effect of neurotrophin p75 receptor activation on transmural dispersion repolarization in rabbits with myocardial infarction]. AB - OBJECTIVE: To elucidate the effect of neurotrophin p75 receptor (p75NTR)on transmural dispersion repolarization (TDR) of the layers of left ventricular myocytes in rabbits with myocardial infarction (MI). METHODS: Forty Japanese rabbits were divided into four groups (n = 10): (1) Sham group, (2) Heald myocardial infarction (HMI) group, (3) p75 NTR activation group, (4) p75 NTR inhibition group. Cardiomyocytes were isolated with enzyme digestion and the currents were recorded by whole-cell patch-clamp technique. RESULTS: Compared with those in the sham group, the duration of 90% action potential repolarization (APD90) and transmural dispersion repolarization of three layers of left ventricular myocytes were obviously raised (P < 0.05). But significant reduction was observed in p75NTR(-) group. Current densities of Ito and I(Ks, tail) in the p75NTR(+) group and HMI group were significantly reduced (P < 0.05), especially in mid myocytes. And no obvious changes were observed in p75NTR(-) group. CONCLUSION: Activation of p75NTR(+) increases transmural dispersion repolarization, which may lead to the incidence of arrhythmia. PMID- 23940963 TI - [Application of SEMG to study the effects of imagery training on back-style high jump]. PMID- 23940964 TI - [Effects of ropivacaine on GABA-activated currents in isolated dorsal root ganglion neurons in rats]. AB - OBJECTIVE: To investigate the effects of ropivacaine on Gamma-aminobutyric acid(GABA)-activated currents in dorsal root ganglion (DRG) neurons in rats and discuss the analgesia mechanism of ropivacaine. METHODS: By means of using whole cell patch-clamp technique, to investigate the modulatory effects of ropivacaine on GABA-activated currents (I(GABA)) in acutely isolated dorsal root ganglion neurons. RESULTS: (1) In 48 out of 73DRG cells (65.7%, 48/73), to perfusion ropivacaine bromide (0.1 - 1 000 micromol/L) were sensitive. Which produce in 0 to 380 pA current. (2) The majority of the neurons examined (74.5%, 73/98) were sensitive to GABA. Concentration of 1 - 1 000 micromol/L GABA could activate a concentration-dependent inward current, which manifested obvious desensitization, and the inward currents could be blocked byGABA-receptor selective antagonist of bicuculline (100 micromol/L). (3) After the neurons were treated with ropivacaine (0.1 - 1000 micromol/L) prior to the application of GABA (100 micromol/L) 30 s, GABA currents were obviously increased. Ropivacaine could make dose-response curve of the GABA up, EC50 is 23.46 micromol/L. Ropivacaine shifted the GABA dose response curve upward and increased the maximum response to the contrast about 153%. CONCLUSION: The enhancement of ropivacaine to DRG neurons activation of GABA current, can lead to enhancement of pre-synaptic inhibition at the spinal cord level. This may be one of the reasons for the anesthetic effect and analgesia for ropivacaine in epidural anesthesia. PMID- 23940965 TI - [Study on fatigue of pilots during simulated flight training based on electroencephalogram]. AB - OBJECTIVE: To study EEG during simulated flight training, then to explore the situational character of mental fatigue of the pilots. METHODS: Fifty male pilots were randomly choice to be recorded their EEG including rest,flight and recovery phase. Then the band waves of EEG were analysed among the three phase. RESULTS: (1) During flight, the amplitude of alpha, beta, SMR, theta, gamma waves tended to increase. These changes seemed obviously in SMR, theta waves. (2) After flight, all the amplitude of the waves declined except for beta wave of the right lobe,and most of them were still higher than those before flight (P < 0.05); (3) The right brain showed a higher cerebration than the left, especially in theta wave. CONCLUSION: Mental fatigue is started during the flight training, and the right lobe has a severe mental fatigue than the left. After flight, mental fatigue showed a slow recovery. PMID- 23940966 TI - [Research about the effect of exercise on the vascular endothelial cells AMPK activated in atherosclerotic rat]. AB - OBJECTIVE: To study the molecular mechanism of exercise to improve cardiovascular health, and exploring the effect of different intensity exercise on AMP activated protein kinase (AMPK) protein expression and phosphorylation of vascular endothelial cells in rat. METHODS: Forty-eight Wistar rats were divided into control group (group C), model group (group AS), low intensity exercise model group (ASL) and high intensity exercise model group (ASH). The serum inflammatory factor concentrations such as IL-6, TNF-alpha, CRP were studied, and the endothelial cell total AMPK and p-AMPK protein were checked by means of Western blot. RESULTS: (1) The level of IL-6 between AS group and control group had no significant difference, the value of ASH group was markedly increased and had significant difference compared with that of the control group or AS group. The serum TNF-alpha levels of AS group and ASL group were significantly higher than those in control group, but the value of ASH and ASL was significantly lower than that in AS group. The serum concentration of CRP after the AS molding was significantly higher than that of the control group, there was no statistical difference between that of ASL and ASH groups. (2) The total AMPK protein content of ASL and ASH groups was significantly higher than that in control group. When compared between the two groups, there was statistical significance. (3) The value of p-AMPK protein of ASL and ASH groups was significantly higher than that of AS group, the value of p-AMPK protein of ASH group was significantly higher than that of the control group at the same time. CONCLUSION: Exercise can reduce the serum levels of inflammatory factors in atherosclerosis rat, and increase AMPK protein expression and phosphorylation level in endothelial cell. PMID- 23940967 TI - [Inhibition of Jumi extraction on growth of human cervical cancer cell line HeLa]. AB - OBJECTIVE: To explore the inhibition of Jumi (traditional Chinese medicine) extraction on the growth of human cervical cancer cell line HeLa. METHODS: Nude mouse model of human cervical cancer HeLa cell transplantation was established. The nude mice bearing cancer were randomly divided into control group and Jumi treated groups with different concentration (0.001, 0.002, 0.005, 0.01 mg/ml). The growth of cervical cancer cell in experimental mice were measured. Cultured HeLa cells were incubated in culture media with or without Jumi extract for 48 hours. Cell proliferation rate, cell apoptosis, caspase-3/7 and caspase-6 activity were determined by MTT colorimetric assay, flow cytometry analysis and spectrophotometric detection, respectively. RESULTS: With the increase of the concentration of Jumi extract, tumor-bearing mice tumor inhibition rate gradually increased. The proliferation of cultured HeLa cells were significantly inhibited by Jumi extract in a dose-dependent manner. IC50 was 0.004 mg/ml. Apoptosis rates in the cells treated with Jumi extract were higher than those of the control group. Compared with the control group, except for lower Jumi treated group (0.001 mg/ml), caspase-3/7 and caspase-6 activity were significantly increased in the all Jumi treated groups. CONCLUSION: Jumi extract can inhibit the proliferation of human cervical cancer cell line HeLa in vitro in a dose dependent manner and promote cell apoptosis through caspase-3, caspase-7 and caspase-6 pathway. PMID- 23940968 TI - [The effect of exercises on TNF-alpha, IL-6 and adiponectin in different fat diet rats]. AB - OBJECTIVE: To evaluate the role of serum tumor necrosis factor-alpha (TNF-alpha) and adiponectin on insulin resistance in different fat diet rats. METHODS: Thirty weanling female rats were randomly divided into 3 group (n = 10): a low-fat soybean oil (LFS; 22% of total energy fed as fat), high-fat soybean oil (HFS; 40% of total energy fed as fat), or high-fat soybean oil and swimming training at the same time (HFS + T). After fed for 10 weeks, the level of TNF-alpha, adiponectin in serum of rats were observed. RESULTS: (1) The body weight, percentage of body fat of HFS group increased compared with that of LFS group (P < 0.05), however those of HFS + T group were decreased (P < 0.05). (2) The level of serum insulin and ISI in HFS group were increased by LFS group (P < 0.05), in HFS+ T group the levels decreased. (3) And the serum level of TNF-alpha and IL-6 in HFS group were higher than those in LFS group (P < 0.05), the serum levels of adiponectin in HFS group were lower than those in LFS rats, and in HFS+ T group the levels of TNF alpha and IL-6 were lower than those in HFS group (P < 0.05), the adiponectin level was higher than that in HFS group, and there were no significant difference between LFS group and HFS + T group. CONCLUSION: Exercises training could improve sugar and fat metabolism disorders, which also contributes to improving insulin resistance caused by high-fat diet. PMID- 23940969 TI - [Investigation on the difference of intolerance to food between southern and northern middle-aged Chinese and its association with eating habits]. AB - OBJECTIVE: The aim of the present study was to investigate the difference of intolerance to food between southern and northern middle-aged Chinese, and furthermore analyze its association with eating habits in both study population. METHODS: ELISA was applied to determine the serum concentrations of specific IgG of 14 food anaphylactogen in 1568 healthy subjects from totally 9 districts in both southern and northern China. Life style questionnaire was also applied to investigate the daily intake of six categorizes of food associated with food intolerance. RESULTS: 45.8% of all subjects were found to be intolerant to certain food. 62.3% of subjects from southern China and 40.4% of subjects from northern China were found to be intolerant to certain food, the difference between southern and northern Chinese was statistically significant. Top three foods intolerant by southern Chinese were crab, egg, and cold fish, while top three food intolerant by northern Chinese were egg, crab, and milk. The differences of intolerance to crab, cold fish, soy bean, rice, and tomato between southern and northern Chinese were statistically significant. Investigation on eating habits revealed that cereals and fish were the major food consumed by subjects in our study. There was no certain association between food intolerance and eating habits. CONCLUSION: Considering that there are differences between southern and northern Chinese, southern and northern Chinese should pay attention to their daily food in order to avoid food allergy. PMID- 23940970 TI - [Changes in electrophysiology of rabbits exposed to rush decompression]. PMID- 23940971 TI - Public and private language ideologies as reflected in language attitudes on the Island of Korcula. AB - Since languages are such powerful means of group identification, they may be considered as constitutive of communities. Attitudes expressed toward certain linguistic varieties may thus be perceived as attitudes held toward respective community-members. However, as attitudes are not always easily accessible, and are rarely one-dimensional but rather multi-layered, an insight into overt (publicly proclaimed) and covert (privately held) ideologies can enhance understanding of language attitudes and their meaning. This paper brings the analysis of these two types of attitudes held by adolescents in three most populated places on the island of Korcula, Croatia. The analysis is based on the results obtained by means of a questionnaire eliciting, among other things, overt attitudes toward six local, regional and supra-regional varieties, and covert attitudes toward judges' local speech and the Standard variety of Croatian. Although the results confirm some expected tendencies in the evaluation of different varieties, subsequently conducted analysis of speech recognition rates offers some valuable insights and interesting implications for further interpretation of the results. PMID- 23940972 TI - Dietary patterns in adults from an Adriatic Island of Croatia and their associations with metabolic syndrome and its components. AB - Adriatic islanders have a high prevalence of metabolic syndrome (MetS) although they have traditionally practiced an active lifestyle and adhered to a Mediterranean diet. We performed a cross-sectional study to identify dietary patterns in a sample of 1442 adults from the island of Hvar, and determined whether MetS and its components: waist-circumference, serum triglycerides, fasting plasma glucose, HDL-cholesterol, and blood pressure, were related to an altered pattern of the traditional Mediterranean diet. Dietary intake was assessed by a food frequency questionnaire. MetS was defined using the International Diabetes Federation criteria. Our study showed that dietary patterns in this population have diversified from the traditional diet. Principal component analysis identified three major patterns. The meat, alcohol, and fish pattern (MAFp), sweets, grains, and fats pattern (SGFp), and an olive-oil, vegetables, and fruits pattern (OVFp) explained 30.6% of total dietary variance. The MAFp associated significantly with MetS (p = 0.027) and high plasma glucose (p = 0.006). PMID- 23940973 TI - Changes in the genetic variance and heritability of the body mass index and skinfolds among Polish twins aged 8-18 years. AB - Body Mass Index (BMI) and skinfolds are common indicators of adiposity. Many studies have shown relationships between the BMI in childhood and adolescence and the BMI in adulthood. Similar correlations were observed for the skinfolds, although they tend to be lower. The aim of this study was to estimate changes with age in the genetic variance and heritability of the BMI and skinfolds among Polish twins born between 1959 and 1965. Observations involved male and female monozygotic (MZ) and dizygotic (DZ) twins, who were measured annually between 8 and 18 years of age. Body Mass Index and skinfold thicknesses at the triceps (TSF), subscapular (SSF) and suprailiac (SIF) sites were measured. Genetic variance and heritability were estimated for individual skinfold thicknesses, the sum of three skinfolds (SUMSF) and BM, separately by age classes for both sexes. Intraclass correlations were significantly higher for MZ twins than for DZ twins in both sexes and across all ages. Heritability estimates were significant for all indicators of adiposity, but varied with age and had different ranges for boys and girls. Estimates of genetic variance were significant for all indicators of adiposity and were higher for girls than for boys. PMID- 23940974 TI - A measure of obesity: BMI versus subcutaneous fat patterns in young athletes and nonathletes. AB - Although the body mass index (BMI, kg/m2) is widely used as a surrogate measure of adiposity, it is a measure of excess weight, rather than excess body fat, relative to height. The BMI classification system is derived from cut points obtained from the general population. The influence of large muscle mass on BMI in athletes and young adults may misclassify these individuals as overweight and obese. Therefore, the use of subcutaneous adipose tissue topography (SAT-Top) may be more effective than BMI in assessing obesity in physically active people and young adults. The purposes of this study were 1) to describe the relationship between the BMI and SAT-Top of young athletes and nonathletes, and 2) to determine the accuracy of the BMI as a measure of overweight. Height, weight, BMI and SAT-Top were determined in 64 males (25.0 +/- 6.7) and 42 females (24.8 +/- 7.0), who were subsequently separated into two even groups (athletes and non athletes). The optical Lipometer device was applied to measure the thickness of subcutaneous adipose tissue (SAT). While BMI was similar, male athletes showed a 50.3% lower total SAT thickness compared to their male nonathlete controls. Even though female athletes had significantly higher BMI and weight scores, their total SAT thickness was 34.9% lower than their nonathlete controls. These results suggest subcutaneous fat patterns are a better screening tool to characterize fatness in physically active young people. PMID- 23940975 TI - Evaluation of lifestyle of underweight, normal weight and overweight young women. AB - The aim of this study was to compare eating and lifestyle habits between underweight, normal weight and overweight young women. Data obtained from a survey of 1129 students of the three higher education institutions in Kielce, Krakow and Opole (Southern Poland) were analysed. BMI was used to define underweight, overweight and obesity. Eating and lifestyle habits were assessed based on the information received from surveyed students. The study group consisted of women of childbearing-age and a special attention was paid to analyse habits correlated with the risk factor for pregnant women (low consumption of dairy products, meat, fish, fruits and vegetables, cigarette smoking, alcohol and caffeine intake). In the studied group, the prevalence of underweight was higher than the prevalence of overweight and obesity (11.1% vs. 7.0%). There were no significant differences in nutritional habits between the three weight groups. The responding students, regardless their weight status, presented numerous unhealthy eating habits. Underweight students more frequently took multivitamin supplements, less frequently followed an alternative diet, smoked cigarettes or drank larger amounts of coffee than normal weight and overweight women. Underweight and normal weight women more frequently participated in sports activities than overweight and obese women. However, 39.2 percent of the surveyed women declared that they seldom or never perform any sport activities. The results show that majority of young women present numerous unhealthy behaviours. Unhealthy habits occur with the same frequency among underweight students as among normal weight students or overweight ones. PMID- 23940976 TI - Preliminary report of hypoglycemic response in obese metabolic syndrome males treated with metformin after weight loss intervention. AB - We conducted this study to determine the degree of obesity influence on the hypoglycemic response of growth hormone and cortisol after weight loss of 5%. A total of 45 non-diabetic, male subjects followed in the outpatient endocrinological departments were divided into three groups comprising 15 subjects in each group, based upon body mass index (BMI) to healthy, overweight and obese group. Metformin was administered in the dose of 50 mg daily to the overweight and obese participants. Cortisol was measured at 0, 60 and 120 minutes. Growth hormone (GH) was measured at -15, 0, 30, 60, 90 and 120 minutes. Values of cortisol and GH were compared upon changes in hypothalamo-pituitary adrenal (HPA) response to insulin induced hypoglycemia initially and after weight loss of 5% for overweight and obese participants. The BMI of the healthy group ranged 20.0-24.5 kg/m2 (median: 22.8); overweight group ranged 25.9-29.7 kg/m2 (median: 28.3); and obese group ranged 30.9-34.6 kg/m2 (median: 32.6). There were no significant differences of cortisol values among groups at 0 (chi2 = 2.0; p = 0.365); 60 (chi2 = 0.754; P = 0.686) and at 120 minutes (chi2 = 0.466; p = 0.792). The comparisons among groups were significant for differences of GH values at -15 (chi2 = 25.0; p < 0.01); 0 (chi2 = 16.2; p < 0.01); 30 (chi2 = 16.2; p < 0.01); 60 (chi2 = 32.8; p < 0.01); 90 (chi2 = 30.2; p < 0.01) and at 120 minutes (chi2 = 27.3; p < 0.01). Healthy and obese subjects significantly differed in growth hormone response at -15 (Z = 4.67; p < 0.01); 0 (Z = 3.83; p < 0.01); 60 (Z = 2.78; p = 0.05); 90 (Z = 4.67; p < 0.01) and at 120 minutes (Z = 4.23; p < 0.01). Changes on the various levels of HPA axis, when it is activated by a stress as it is the case in insulin-induced hypoglycemia correspond to the degree of obesity. Weight loss of 5% was not enough for restoration of a normal stimulated growth hormone release and did not influence on the level of cortisol. PMID- 23940977 TI - Clinical scoring systems in predicting health-related quality of life of children with injuries. AB - The aim of the study was to explore the association between Glasgow Coma Scale (GCS), Paediatric Index of Mortality (PIM2) and Injury Severity Score (ISS), and the long-term outcome of children with injuries. The health related quality of life (HRQL) was assessed by using the Royal Alexandra Hospital for children Measure of Function (RAHC MOF), 12 months post discharge. Out of 118 children with injuries (9% of all patients), 75 had injury of the head as the leading injury. There were no significant differences at admission in the severity of clinical condition, as expressed by PIM2 and ISS, between patients with head injuries and patients with other injured leading body regions. Children with head injuries had significantly worse HRQOL than children with other leading injured body region (p < 0.045), and children from road traffic accidents had significantly worse HRQL (p = 0.004), compared to other mechanisms of injury. HRQL correlated significantly with GCS (p = 0.027), but not with ISS and PIM2. As the conclusion, among all scoring systems applied, only GCS, which demonstrates severity of head injury, showed significant impact on long-term outcome of injured children. PMID- 23940978 TI - Shift work, quality of life and work ability among Croatian hospital nurses. AB - This paper is a report of a study of the associations of shift work with work ability and quality of life (QoL) among clinical nurses. A cross-sectional study was conducted in 2007-2008 on 1124 nurses using the Work Ability Index Questionnaire and the Quality of Life Questionnaire (WHOQOL-BREF). Lower education was a predictor for low level of work ability and low physical health domain of QoL. Older age and having no partner were statistically significantly related to lower social interaction. Predictors significantly related to low environment domain of QoL were low education and shift work. Shift workers had higher level of level of work ability, but clinically insignificant. The study provides no evidence of a significant association between shift work and work ability or quality of life. Education has a positive association with nurses' work ability and quality of life. PMID- 23940979 TI - How to measure muscular endurance in children: a new approach. AB - The aim of this study was primarily to determine the reliability and factor validity of four muscular endurance tests, and secondly, to identify gender differences in muscular endurance tests. For this purpose, a new muscular endurance test was constructed for pupils aged between seven and eight (CROCO). The research was done on a sample of 71 pupils aged between seven and eight (35 girls and 36 boys), their body height being 129.2 +/- 1.3 cm for boys and 127.1 +/- 1.4 cm for girls, body weight 29.3 +/- 7.2 kg for boys and 27.1 +/- 6.5 for girls. According to the results, all tests have shown a good level of reliability and factor validity. Also, the present study confirmed the expected gender differences (p < or = 0.05). In all muscular endurance tests, the boys were slightly better than girls (p < or = 0.05). The authors recommend the implementation of the CROCO test and other muscular endurance tests used in this study, both for the implementation in the primary school curricula and in sports because of these tests' satisfactory level of reliability and factor validity. The school curricula need to be adjusted to the age and gender differences of children in order to promote positive health behavior from the earliest age on the one hand, and on the other to be able to objectively measure muscular endurance. PMID- 23940980 TI - Effects of an additional basketball and volleyball program on motor abilities of fifth grade elementary school students. AB - The aim was to evaluate the transformational effects of an additional weekly PE session based on team sports (basketball and volleyball) on students' motor status. The research was conducted on a sample of 125 eleven-year-old boys divided into three groups (two experimental and one control) which were examined by 12 motor tests at the beginning and at the end of the 9-month period. The tests included evaluation of explosive power dynamic and static strength endurance, co-ordination, flexibility and hand frequency motion. Although all three treatments together, complemented by the natural growth and developmental factors, induced significant quantitative changes, the results showed the highest motor improvements in the basketball experimental group, followed by the volleyball experimental group. While explosive power mainly contributed toward significant difference between the control and experimental groups in the final measurement, univarate test results also showed distinctive improvements in dynamic strength, hand frequency motion and various factors of co-ordination within experimental groups. The general conclusion points to the fact that even one additional PE session per week of the given program is sufficient to produce significant changes in motor abilities of elementary school fifth graders. Therefore the authors' support the legal provisions of mandatory implementation of extra-curricular forms of physical activity in elementary schools. PMID- 23940981 TI - Comparison of somatotype values of football players in two professional league football teams according to the positions. AB - This study compared the somatotype values of football players according to their playing positions. The study aimed to determine the physical profiles of players and to analyze the relationships between somatotypes and playing positions. Study participants were members of two teams in the Turkey Professional Football League, Genclerbirligi Sports Team (GB) (N = 24) and Genclerbirligi Oftas Sports Team (GBO) (N = 24). Anthropometric measurements of the players were performed according to techniques suggested by the Anthropometric Standardization Reference Manual (ASRM) and International Biological Program (IBP). In somatotype calculations, triceps, subscapular, supraspinale and calf skinfold thickness, humerus bicondylar, femur bicondylar, biceps circumference, calf circumference and body weight and height were used. Statistical analysis of the data was performed using the Graph Pad prism Version 5.00 for Windows (Graph Pad Software, San Diego California USA); somatotype calculations and analyses used the Somatotype 1.1 program and graphical representations of the results were produced. Analysis of non-parametric (two independent samples) Mann-Whitney U Test of the player data showed that there were no statistically significant differences between the two teams. The measurements indicated that, when all of the GB and GBO players were evaluated collectively, their average somatotypes were balanced mesomorph. The somatotypes of GBO goalkeepers were generally ectomorphic mesomorph; GB goalkeepers were balanced mesomorphic, although they were slightly endomorphic. PMID- 23940982 TI - Factors related to oral health related quality of life in TMD patients. AB - The aims of the study were to determine the impact of temporomandibular disorders (TMD) on self-percieved oral health related quality of life (OHRQoL) and to compare OHRQoL of patients with TMD with a control group. A total of 81 TMD patients participated in a study group and 400 adults served as the control group. The mean OHIP summary scores were computed for all patients with the same diagnosis and the same subgroup of axis I according to the RDC/TMD exam form. The mean OHIP subscores for all seven domains of the OHIP questionnaire were compared between the study and the control group. The hierarchical linear regression model was used to assess the most important variables according to the RDC/TMD protocol that contribute to OHRQoL in TMD patients with the OHIP summary score as dependent variable. According to this study, TMD had a high association with reduced OHRQoL (p < 0.001). More diagnoses of axis I according to the RDC/TMD protocol (p < 0.001), higher age of TMD patients (p < 0.001) and diagnoses associated with limited jaw movements contributed to more impaired OHRQoL (p = 0.008 and p = 0.030, respectively). Female TMD patients had no significantly different OHRQoL compared to male patients (p = 0.436). According to regression analysis, higher age (p < 0.001), more physical diagnoses (p = 0.018) and diagnosis Ib (p = 0.169) explained 39.1% of the variability (p < 0.001) of the OHIP summary score in TMD patients. PMID- 23940983 TI - Nasopharyngeal bacterial flora in healthy preschool children during winter-spring months. AB - The paper aimed to determine the incidence of colonization of Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis in the nasopharynges of healthy children in two preschool institutions during winter and spring months, without using antimicrobial treatment or serotyping of these bacteria. In addition to colonization of the above bacteria, the research that continued for 3 months monitored the length of their persistence in and disappearance from children's nasopharynges, children's health statuses, and provision of adequate medical interventions in children demonstrating clinical signs of disease. The ultimate aim of the paper was based on contributing to clearer and more accurate determination of a medical procedure in case of a positive result for bacteria intended to be found in the nasopharynx of a healthy child who spends time in a preschool institution. PMID- 23940984 TI - Prosthetic modalities used to treat cleft palate patients in a university clinic: a 10-year review. AB - Cleft palate patients are not usually seen in general dental clinics, but this congenital anomaly is one of the most frequent of cases. General dental practitioners are usually unwilling or/and not sufficiently trained to treat such patients for whom rehabilitation and interdisciplinary cooperation is often needed. The aim of this study was to determine the incidence of prosthetic modalities most frequently used by licensed prosthodontists for prosthetic rehabilitation of cleft palate patients. Participants in this study were 56 cleft palate patients (aged 23-66 years) who received prosthetic treatment between 2000 and 2010. Patients' dental status and prosthetic modalities used were noted from patient records archived at Department of Prosthodontics, School of Dental Medicine, University of Zagreb. Data analyses revealed that combined prosthetic constructions (fixed + removable, p < 0.05) were the most frequently used. In a group of molar teeth, the most frequent fixed prosthetic modalities were crowns with rests; in a group of premolar teeth, telescopic crowns; on canines, metal ceramic crowns and telescopic crowns; and in a group of incisors, metal ceramic pontics (p < 0.05). Understanding the distribution of prosthetic modalities for cleft palate patients could serve to guide dental practitioners towards planning adequate prosthetic treatment for their patients since only a well-planned prosthetic therapy will result in satisfactory function and alleviation of the deformities. PMID- 23940985 TI - Microleakage along glass-fibre posts cemented with three different materials after cyclic loading: a pilot study. AB - The purpose of this in vitro study was to evaluate microleakage along glass-fibre posts cemented with three different cements after cyclic loading. After post space preparation, fifty obturated root canals were randomly divided into three experimental groups and two control groups. In group 1, Glassix posts were cemented using Harvard cement, in group 2, Fuji PLUS cement was used and in group 3, Variolink II was used for post cementation. The specimens were artificially aged by loading in a special testing machine. Coronal leakage was evaluated using a fluid transport system. Posts cemented with Variolink II, showed significantly higher failure rate after loading, compared to group 1 and 2 (p = 0.009). Comparing microleakage in samples that have not failed, specimens cemented with Variolink II showed significantly less fluid transport than specimens cemented with zinc phosphate and glass ionomer cements (p = 0.04 and p = 0.006, respectively). Variolink II cement exibited significantly less fluid movement compared with Harvard and Fuji PLUS cement. PMID- 23940986 TI - An in vitro morphological investigation of the endodontic spaces of third molars. AB - Aim of this paper was to investigate the particular anatomic features of the endodontic space of third molars in the general population of Croatia. A total of 106 fully developed third molars (56 maxillar and 50 mandibular) has been analyzed. The respective number of roots and of root canals, the structure of the roots, and the curvature and absolute length of the root-canals were analyzed. In most cases, upper third molars had three roots (83.9%), while most of the lower molars were single rooted (56.0%). Upper third molars had mostly three root canals (75.1%), lower third molars two (90.0%). In both jaws, most third molars had curved canals (60.7% in the upper and 84.0% in the lower jaw). 12.5% of upper third molars had lateral and accessory canals, whereas only 4.0% of the lower third molars were found to have them. The Student t-test showed statistically significant differences (p < 0.05) in the length of the root-canals, mesiobuccal and distobuccal canals being significantly shorter than palatinal canals. The same test showed that in the lower third molars the mesial root canals were significantly longer that the distal ones, although slightly. The results obtained are in compliance with similar results by other authors; however, they tend to show some specific population-related features. PMID- 23940987 TI - Mucositis grades and yeast species. AB - Surgically treated patients with oral, head and neck cancer commonly develop mucositis during additional irradiation therapy. Oral mucosa inflammation other than irradiation is mostly caused by Candida albicans, yeast of Candida genus. This study evaluated possible connection between grades of oral mucositis and oral yeast profile in irradiated patients before, during and after irradiation. In 25 examined patients mucosits grades "0" to "2" before irradiation with 20% positive smears and only two different species of yeasts (C. krusei 4%, C. albicans 16%) during the irradiation changed into "0" to "4" and 36% positive smears with five different species of oral yeasts (C. albicans 12%, C. glabrata 12%, C. parapsilosis 4%, C. guilliermondii 4% and Saccharomyces cerevisiae 4%). Three weeks after irradiation was finished mucositis decreased into "1" to "3" with 20% positive smears and again only two species of yeasts (C. albicans 16%, C. guilliermondii 4%). Mucositis grades was increased significantly (p = 0.0037) with changes in fungi profile. PMID- 23940988 TI - Antibiotic prescription rate for upper respiratory tract infections and risks for unnecessary prescription in Croatia. AB - Overprescribing of antibiotics in primary care has been recognized as public health problem. We investigated visits prescription rate of antibiotics to patients with upper respiratory tract infections (URTI) and unnecessary prescription for tonsillopharyngitis, in Croatia. In prospective observational study in November 2007. 25 GPs in Croatia recorded all patients' visits with URTI episode according ICPC-2. Clinical status of patients with tonsillopharyngitis were categorized according to Centor Criteria. 689 visits were analysed, 82% of visits were initial. Antibiotics were prescribed in 44.7% visits with URTI. There were no significant differences in antibiotic prescription rates regarding non clinical factors. Antibiotics were prescribed to patients with tonsillopharyngitis in 62.2% visits. Unnecessary antibiotics were prescribed (Centor 1,2) in 49.6% visits with tonsillopharyngitis. Logistic regression analysis showed significant differences in unnecessary antibiotic prescription rates only with respect to the workday--Wednesday, CI (1.117-2.671), p = 0.0139. Leading antibiotic was amoxicillin + clavulonic acid, second was amoxicillin, the third were macrolides, the fourth was narrow spectrum penicillin and fifth were cephalosporins. This study shows over prescription for URTI. Unnecessary prescription for tonsillopharyngitis depend on non clinical factor--day of the week. This should be further explored and help to improved prescribe antibiotics. PMID- 23940989 TI - Risk factors for sexually transmitted infections among young adolescents. AB - Significant numbers of adolescents are initiating sexual activity at age 17 and younger. Little is known about this younger population of adolescents. This includes risk or protective factors for sexual activity and sexually transmitted infection (STI) acquisition. To safeguard all adolescents from the consequences of risky sexual behaviors, and to insure age appropriate and effective interventions, further study is critical to address risky behaviors specific to early adolescents. This study was a retrospective chart review of 155 sexually active adolescent girls. Students were divided into those who never had a documented STI and those who had 1 or more STIs. Data were collected from a sexual history questionnaire. These data were grouped into risk or protective domains. Domains were made up of 5 items of protective factors, 3 items of peer risks, 2 items of family risks, and 7 items of individual risks. STI outcomes were compared to these characteristics. One hundred fifty-five sexually active adolescents were studied. A univariate and multivariate analysis of risk and protective factors for testing positive for an STI demonstrated that high levels of protective factors reduced the risk of STIs. This suggests that STI prevention programs should focus on increasing protective factors among young adolescents in addition to reducing risk factors. PMID- 23940990 TI - Clinical and patohistological factors affecting the 5 year survival rate in a population of Croatian women with invasive ductal breast carcinoma. AB - Breast carcinoma falls into a heterogeneous group of diseases which can be determined by various prognostic factors. The identification of clinical and histopathologic factors is of great value in predicting the progression of tumor growth and survival outcome. Due to a high degree of cell proliferation in breast tumors and high genetic instability of these tumors, as a consequence of defective DNA repair mechanisms, chemotherapy as a treatment option often renders very successful results. During our scientific study of the expression of genes responsible for mismatch repair of DNA in cells of invasive ductal carcinoma we also compared the patient survival rate with the major prognostic factors. This study included 108 patients who were surgically treated for invasive breast cancer at the Department of Plastic, Reconstructive and Aesthetic Surgery, University Hospital "Dubrava". The overall survival rate was compared to factors such as initial tumor stage, regional lymph node involvement and distant metastasis. The overall five year survival rate of our patients was 78.7%. Patients without the presence of distant metastasis, a lower rate of local lymph node involvement and a lower. tumor stage statistically had a longer overall survival period. It is important that physicians recognize the various clinico pathohistological factors in patients with breast carcinoma. This study confirms that this prognostic factors determine the type of treatment required and most important, the patient overall survival period. PMID- 23940991 TI - Clinical, hormonal and metabolic characteristics of polycystic ovary syndrome among obese and nonobese women in the Croatian population. AB - Obesity has a deteriorating impact on women with PCOS, although prevalence and the impact of specific traits of PCOS remain inconstant in different populations. Therefore, the aim of this study was to explore the differences in clinical, hormonal and metabolic features between obese and nonobese Croatian women diagnosed as having PCOS according to Rotterdam consensus criteria. The study included 74 obese and 208 nonobese women with PCOS. Clinical, biochemical and metabolic variables were compared among those PCOS subgroups. Obese subjects with PCOS had a higher risk of developing oligo-amenorrhea (OR 3.7; 95% CI, 1.1-12.5) and lower risk for developing hirsutism and acne (OR 0.2; 95% CI, 0.1-0.3 and OR 0.8; 95% CI 0.5-1.4, respectively). Obese PCOS subjects also had a higher risk of developing hyperandrogenemia (OR 2.5; CI 95% 0.9-6.7), insulin resistance (OR 4.5; CI 95%, 2.6-7.9), hypercholesterolemia (OR 5.0, CI 95% 2.5-10.2), hypertriglyceridemia (OR 5.2; 95% CI, 2.9-9.2) as well as elevated serum CRP levels (OR 4.1; 95% CI 1.4-12.2) compared to nonobese PCOS women. In conclusion, nonobese Croatian women with PCOS are more inclined to cosmetic problems associated with PCOS then metabolic ones. This is the first study to report the impact of obesity on acne and irregular menses as a study outcome. Obesity deteriorates menstrual regularity, insulin sensitivity and lipid profile in Croatian women with PCOS; therefore one of the fundamental treatment strategies of PCOS should be obesity prevention. PMID- 23940992 TI - Hyperfiltration in normoalbuminuric type 1 diabetic patients: relationship with urinary albumin excretion rate. AB - Hyperfiltration has been documented in type 1 diabetes and may contribute to the high risk for development of albuminuria and progression of nephropathy. However, recent studies suggest that the risk of progression to albuminuria in type 1 diabetes was not increased by hyperfiltration. We investigated associations of estimated glomerular filtration rate (eGFR) and urinary albumin excretion rate (UAE) in normoalbuminuric type 1 diabetic patients. Study included 313 normoalbuminuric patients with type 1 diabetes, none showed signs of adrenal, renal, or cardiovascular diseases. GFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Glomerular hyperfiltration was defined as eGFR > or = 125 mL min(-1) 1.73 m(-2). Renal hyperfiltration was present in 12% of the study group. Subjects with eGFR > or = 125 mL min(-1) 1.73 m(-2) were younger, had shorter duration of diabetes, lower levels of total and LDL cholesterol, and higher HbA1c than subjects with an eGFR below 125 mL min(-1) 1.73 m(-2). Type 1 diabetic patients with hyperfiltration also had significantly lower UAE. In a multiple logistic regression analysis, higher eGFR was associated with lower UAE. Our results indicate that normoalbuminuric type 1 diabetic patients with hyperfiltration have lower UAE than those with renal function in the normal range. Together with other recent studies this may suggest that creatinine-based estimates of GFR indicating hyperfiltration is not associated with higher UAE and subsequent development of microalbuminuria. PMID- 23940993 TI - Characteristics of different phenotypes of polycystic ovary syndrome based on the Rotterdam criteria in the Croatian population. AB - The aim of this study was to calculate the relative prevalence of all phenotypes of polycystic ovary syndrome (PCOS) and to compare them for anthropometrical, hormonal and metabolic differences according to the Rotterdam Criteria. A total of 300 women with PCOS aged 26.7 +/- 5.6 years (mean +/- SD) and 100 women aged 28.3 +/- 4.1 years (mean +/- SD) were included in a control group. Anthropometrical, hormonal and metabolic parameters were compared between the groups. The most prevalent phenotype in our population was the most severe, phenotype A (56.7%), followed by phenotype D (26.7%) and phenotype C (14.3%). Phenotype B was present in only 2.3% of patients. The four main phenotypes did not differ in age, BMI and WHR. Women with phenotypes A and C had increased levels of LH and an increased LH/FSH ratio along with elevated androgen levels compared to the other groups. Serum glucose levels did not differ between the groups studied, however, higher levels of insulin, GIR and HOMA-IR were found between phenotype A and the control group. Phenotype C PCOS or ovulatory PCOS have the same characteristics as classic PCOS, however in a more mild form, which represents a transition between the classic form and the control group. Compared to the control group, phenotype D had higher mean levels of serum testosterone (still within normal range) along with elevated LH levels and LH/FSH ratio, similar to classic PCOS. However, compared with women diagnosed with PCOS based on hyperandrogenism, oligo-ovulation and polycystic ovaries, these patients demonstrated milder endocrine and metabolic abnormalities. Therefore, from an endocrine point of view, our study supports the inclusion of a normoandrogenic anovulatory phenotype in PCOS diagnostic criteria. PMID- 23940994 TI - Pregnant women's knowledge and attitudes to prenatal screening for fetal chromosomal abnormalities: Croatian multicentric survey. AB - We aimed to assess opinion and preferences of Croatian pregnant women regarding the prenatal screening tests for trisomies. The study was conducted in Zagreb, Split, Cakovec, Nova Gradiska, Gospic and Zlatar. It was organized in the public primary healthcare centers, among the pregnant volunteers during their first visit to an antenatal clinic (7-12 weeks pregnant). The respondents filled anonymous questionnaire reflecting their knowledge and attitudes to the screening options. In total, 437 completed questionnaires were selected. The average maternal age and the level of education differed significantly between the respondents in the respective cities (P < 0.001). Of the respondents with positive attitude towards screening, the majority would prefer the first trimester combined test (160/219; 73.1%), while 37/219 (16.9%) opted for the second-trimester biochemical screening. The remaining 22/219 (10.0%) would accept only the ultrasound screening. Among the 224 respondents, who would accept the combined first-trimester test, 95 (42.4%) held a college and university degree, whereas among 59 women, who would choose the second-trimester biochemical screening, 14 were highly educated (23.7%). The difference was statistically significant (P = 0.016). The univariate regression analysis showed that age, level of education and previous information were significant variables predictive for the choice of the test; the level of education and previous knowledge remained significant in the multivariate model. The survey has revealed some of the points that should be improved in the future concept of screening program in Croatia. Health professionals should persist to mend women's knowledge about prenatal screening, taking into consideration women's preferences as well. PMID- 23940995 TI - P2RY12 gene polymorphisms and effect of clopidogrel on platelet aggregation. AB - Objective of this study was to assess platelet response to clopidogrel and its association with certain single nucleotide polymorphisms (SNPs) of the P2RY12 gene. Several studies have shown that patients with poor in vitro response to clopidogrel have worse outcomes after coronary interventions. Pharmacological response to clopidogrel is mediated by the P2Y12 platelet receptor, therefore, SNPs of the P2RY12 gene may account for some of the observed variability in the cardiovascular risk. Fifty patients with stable coronary heart disease, undergoing percutaneous coronary intervention were included in this study. Response to clopidogrel was analysed using light transmitted aggregometry before, and 5 days after the initation of therapy. SNPs analysed: c.-15+742C > T, c. 180+2739T > C and c.18C > T. A higher proportion of non-responders to clopidogrel were noted in carriers of 18C > T[T/T] (p = 0.05), and lower prevalence in carriers of 742C > T[T/T] (p = 0.05). Participants with 742C > T[T/T] had significantly higher change in aggregation compared to other 742C > T variants ([C/C] = 20.5 +/- 21.9%; [C/T] = 20.0 +/- 31.2%; [T/T] = 48.6 +/- 21.3%; p = 0.03). Those carrying 18C > T[T/T] had smaller change in aggregation (7.6 +/- 15.0%) compared to other variants, but the difference was not statistically significant (p = 0.15). Analysis of variance showed 18C > T[T/T] was a statistically significant predictor of poor response to antiaggregation therapy, independent from other clinical and demographic variables. There was no relation between poor response to clopidogrel and any other genetic variant. Our results suggest that 18C > T SNP of the P2RY12 gene may be an independent predictor of pharmacological response to clopidogrel. Larger prospective studies are needed to confirm this link and assess its possible clinical consequences. PMID- 23940996 TI - Risks for first nonfatal myocardial infarction in Belgrade. AB - The aim of this study was to investigate which one among possible risk factors are independently related to first nonfatal myocardial infarction (MI) in Belgrade population. Case-control study was conducted in Belgrade during the period 2005-2006. Case group comprised 100 subjects 35-80 years old who were hospitalized because of first nonfatal MI at the coronary care unit in Urgent Center, Belgrade. Control group consisted of 100 persons chosen among patients treated during the same period at the Institute of Rheumatology, Institute for Gastroenterology, and Clinic for Orthopedics, Belgrade, Serbia. Cases and controls were individually matched by sex, age (+/- 2 years) and place of residence (urban/rural communities of Belgrade). According to the multivariate analysis risk factors for MI occurrence were "good" socioeconomic conditions (OR = 2.76), total alcohol consumption (OR = 2.62) and consumption of brandy (OR = 6.73), stressful life events taken together (OR = 3.13) and stress because of close relative Ns death (OR = 3.35), great financial problems (OR = 31.64) and small financial problems (OR = 8.47), hypertension (OR = 2.39), MI among all relatives (OR = 3.66), MI in father (OR = 6.24), and low level of high density lipoprotein cholesterol (OR = 152.41). Amateur sport activity in the past was negatively associated with MI development. The results obtained are mainly in accordance with other studies results and can be of help in development of strategy for coronary heart disease prevention in Serbia. PMID- 23940997 TI - The impact of delayed cardiac surgery on the postnatal growth of children with congenital heart disease in Bosnia and Herzegovina. AB - The aim of this study was to evaluate preoperative and postoperative growth in children with congenital heart disease (CHD) when cardio-surgical treatment is delayed. Growth data were analysed on 116 children with various types of CHD (cyanotic lesions (Group 1), left to right shunt (Group 2) and obstructive lesions (Group 3)), who underwent cardiac surgery after a certain period of waiting. Preoperatively, during the time (median 1.13 (0.55-2.39)) years of waiting for surgery, their mean weight z-score decreased from -1.38 (+/- 1.19) to -1.41 (+/- 1.28), and their mean height z-score from -0.65 (+/- 1.41) to -0.81 (+/- 1.36). Children in Group 1 developed a significant linear growth deficit, in Group 2 weight was more affected than height, while in Group 3 both growth parameters were gradually slowly, but not significantly reduced. Postoperatively weight and height z scores, although they showed a linear trend of improvement for all three groups, remained significantly reduced for two years after surgery. At the time of the last examination at the age 9.11 (5.66-13.10) years, the mean height z score -0.16 (+/- 1.28), was significantly reduced p < 0.0001, than predicted height 0.23 (+/- 0.82). Growth catch-up was related to age at surgery and preoperative growth deficit. Delayed cardiac surgery in children with CHD aggravated growth deficit and caused slow and incomplete postoperative growth catch-up. PMID- 23940998 TI - Characteristics of stroke in young adults in Tuzla Canton, Bosnia and Herzegovina. AB - The aim of the study was to analyze stroke in young adults in Tuzla Canton, Bosnia and Herzegovina. From January 2001 to December 2005, 3864 patients with first-ever stroke were admitted at the Department of Neurology Tuzla. A retrospective analysis of risk factors, stroke types, severity and one month outcome in all young adults (18-45 years of age) with first-ever stroke was carried out. Out of total, there were 154 (4%) young adults with stroke. Mean age was 38.8 +/- 5.7 years and 47% were women. The leading risk factors were smoking (56%) and hypertension (45%). Subarachnoid hemorrhage (SAH) was more frequent in young adults compared with older patients (> 45 years of age) (22% vs. 3.5%, p < 0.0001), intracerebral hemorrhage (ICH) was similar in both groups (16.9% vs. 15.8%, p = 0.7), but ischemic stroke (IS) was predominant stroke type in the older group (61% vs. 74%, p = 0.0004). Young adults had more frequent lacunar stroke (26.6% vs. 16.1%, p = 0.01) and stroke due to other etiology (8.5% vs. 1.8%, p = 0.0004) than stroke patients over 45 years of age. Stroke severity at admission was lower in young adults than in older patients (p < 0.0001), as well as mortality at one month (11% vs. 30%, p < 0.0001). Favorable outcome (modified Rankin Scale < or = 2) had 71% of young adults compared with only 53% of patients in the older group (p = 0.0003). Stroke in young adults in Tuzla Canton is rare. Risk factors profile, stroke types, severity and outcome at one month in young adults are different from those in older patients. PMID- 23940999 TI - Monosystem multifocal Langerhans cell histiocytosis (multifocal eosinophilic granulomas of the bone) in a 36-year old patient: case report, therapeutic doubts and review of literature. AB - Our aim is to provide review of available studies on Langerhans cell histiocytosis (LCH) and discuss treatment for polyostotic monosystem form of disease based on our clinical experience. LCH is an enigmatic disease with insufficiently understood etiology, pathophysiology, and variety of clinical presentations ranging from solitary eosinophilic granuloma to severe multisystem disease. It is marked by formation of granuloma in practically any organ. We present rare case of multifocal bone disease in 36-year old patient without visceral involvement. Treatment protocols for adult LCH patients, especially for uncommon form in our case have not yet been defined. Our therapeutical trial with corticosteroids showed limited success with numerous side-effects. We conclude that LCH treatment can commence only after diagnosis and staging of the disease. Other factors like patient's age, comorbidity, general condition, severity of symptoms and contraindications for therapy modalities should also be considered. In our experience expectative approach has better clinical outcome than immunosuppressive therapy in patients suffering from polyostotic multifocal form LCH with mild symptoms. PMID- 23941000 TI - Quality of pain in herpes zoster patients. AB - Pain typically accompanies acute herpes zoster and persists well beyond rash healing. Different types of pain are reported by patients with herpes zoster. Current studies show that these types of pain vary with respect to their presence, location, duration, intensity and quality, hence pain needs to be analyzed more thoroughly. The aim of the study was to assess different components of pain in patients with herpes zoster. The study subjects were 46 patients diagnosed with herpes zoster and selected out of 493 patients treated at the Pain Therapy Clinic, the outpatient facility of Zagreb Clinic for Traumatology, in 2010. Measures used to assess pain and daily activities were the following: SF McGill Pain Questionnaire, Visual Analogue Scale, Self-Assessment of Life Satisfaction, Health Satisfaction and Enjoyment in Life. Analgesic treatment together with demographic and clinical characteristics of patients were also taken into account. The results have shown that the patients report about spontaneous pain mostly in terms of the following qualities of high level pain intensity: throbbing, aching, hot-burning and sharp. The results also demonstrate that herpes zoster pain significantly affects the patients' everyday living quality and their emotional health. Comprehensive assessment of pain is necessary for clinical research about the epidemiology, natural history, pathophysiologic mechanisms, treatment, and prevention of pain in herpes zoster. PMID- 23941001 TI - Wildlife-vehicle collisions in Croatia--a hazard for humans and animals. AB - Wildlife-vehicle collisions (WVC) have increased and now there is a world-wide problem related to significant mortality of wildlife, habitat fragmentation, change in behavior and even disappearance of local endangered populations. Along with these deleterious effects on wildlife, WVC can also result in injuries and deaths of humans. During the three-year monitoring, a total of 7,495 wildlife vehicle collisions were recorded, including mainly roe deer (73%), while other species were less frequently affected (wild boar--9%; brown hare--5%; and red deer and pheasant each with 4%). Incidence of wildlife-vehicle collisions were observed according to territorial distribution, seasonal and daily occurrence and type of road (total and per 1 km). PMID- 23941002 TI - Inheritance of dermatoglyphic asymmetry and diversity traits in twins based on factor: variance decomposition analysis. AB - Dermatoglyphic asymmetry and diversity traits from a large number of twins (MZ and DZ) were analyzed based on principal factors to evaluate genetic effects and common familial environmental influences on twin data by the use of maximum likelihood-based Variance decomposition analysis. Sample consists of monozygotic (MZ) twins of two sexes (102 male pairs and 138 female pairs) and 120 pairs of dizygotic (DZ) female twins. All asymmetry (DA and FA) and diversity of dermatoglyphic traits were clearly separated into factors. These are perfectly corroborated with the earlier studies in different ethnic populations, which indicate a common biological validity perhaps exists of the underlying component structures of dermatoglyphic characters. Our heritability result in twins clearly showed that DA_F2 is inherited mostly in dominant type (28.0%) and FA_F1 is additive (60.7%), but no significant difference in sexes was observed for these factors. Inheritance is also very prominent in diversity Factor 1, which is exactly corroborated with our previous findings. The present results are similar with the earlier results of finger ridge count diversity in twin data, which suggested that finger ridge count diversity is under genetic control. PMID- 23941003 TI - Position of the mental foramen in Kosovarian population. AB - The aim of this study was to determine the position, shape, number and radiographic appearance of the mental foramen in a selected Kosovarian population. Five hundred panoramic radiographs of dental Kosovarian patients were selected and analyzed according to the mental foramen position, shape, radiographic appearance, number and symmetry. The mean distance in the horizontal plane of the mental foramen to the posterior border of the mandibular ramus was 67.5 mm and for distance from the mental foramen to symphysis menti 24.84 mm. In the vertical plane the mean distance of the mental foramen to alveolar crest was 20.38 mm and 14.68 mm for distance of the mental foramen to the lower border of mandible. The majority of mental foramen was oval in shape and the most frequent radiographic appearance was the separated type. Accessory mental foramina were detected in < 1% of the cases and the mental foramen was not bilaterally symmetrical but no statistical differences were found. This study showed that the most common position of the mental foramen investigated using panoramic radiographs from a selected group in Kosovarian population was between the first and second mandibular premolars with distinct tendency to be positioned near to the second mandibular premolar. PMID- 23941004 TI - Intrinsic deficiencies of lectures as a teaching method. AB - Lectures were, still are and seem to remain a dominant form of teaching, despite an increased research and use of other methods of teaching and leverage of technology aimed at improving teaching results and efficiency. Learning, as the result of a lecture, greatly depends on the subject, the competence and abilities of the lecturer as well as on other transient causes. However, lectures also have some intrinsic deficiencies as a teaching method pertinent to their very nature. In order to fully understand the teaching value of lectures and their role and proper use in educational systems, their deficiencies have been studied in a theoretical analysis from the perspective of cognitive learning theories. Fifteen deficiencies have been identified and clustered in three categories based on root causes of deficiencies: synchronicity problems, time constraint and individual student abilities, needs and knowledge. These findings can be used to adjust expected learning outcomes of lectures, to properly (re)design lecture content and process and to design other learning and teaching activities that would compensate and complement lectures. Recommendations are given on replacing and amending lectures with other instructional methods, amending lectures in the course of delivery with additional content and tools and complementing lectures after delivery with content, tools and activities. Suggestions on the use of information technology that could substitute, reduce or eliminate at least some of the deficiencies are made. Lecture captures seem to be valuable supplement for live lectures compensating in all three categories of deficiencies. Suggestions and directions for further research are given. PMID- 23941005 TI - Primary uterine cervical cancer: correlation of preoperative magnetic resonance imaging and clinical staging (FIGO) with histopathology findings. AB - The most commonly used staging system for cervical cancer is based on the International Federation of Gynaecology and Obstetrics (FIGO) staging system. Magnetic resonance imaging (MRI) has been accepted as the optimal tool for evaluation of the main prognostic factors and selection of therapeutic strategy. The purpose of this study was to compare the preoperative clinical examination FIGO staging findings with MRI and postoperative pathology report in females with primary cancer of the cervix. The study prospectively included 46 females consecutively hospitalized at the Department of Gynaecology and Obstetrics at the "Sestre milosrdnice" University Hospital Center in Zagreb. Interviews, clinical examination, transvaginal ultrasound and MRI were performed in all patients. In selected patients the surgical procedure was done and the correlation of clinical findings according to FIGO classifications, MRI and histopathological findings was completed. According to FIGO classification, positive clinical findings for stage IIA were found in 26/46 (55.5%) and stage IIB in 20/46 (44.5%)patients. FIGO MR modified classification confirmed stage IIA in 30/46 (66.6%) and stage IIB in 16/46 (33.4%) patients. Surgery (Wertheim radical hysterectomy with bilateral pelvic and selective para-aortic lymphadenectomy) was performed in 33/46 (71%) patients with clinically, MR, cytologically and pathohistologically confirmed findings of cervical cancer: 26 patients with IIA clinically FIGO stage and 7 with IIB stage. MRI examination proved better than clinical examination in staging of cervical carcinoma with 90.9% versus 79.0% accuracy rate. We suggest the application of the following MR protocol in all clinically staged FIGO IIA and IIB patients: T1W, T2WI and postcontrast dynamic T1WI after 3 and 60 seconds and after 5 minutes, performed on 1.5T MR machine. PMID- 23941006 TI - Visual persuasion and politics: ideology and symbols of the totalitarian regimes' -case study: hammer and sickle. AB - Unlike all other autocracies, authoritarian regimes are, as the ultimate form of authoritarianism, a distinct phenomenon of the modern era. Caused by the crisis of liberal democracy and industrial capitalism of the early twentieth century, and led by radical populist political movements/parties and their leaders, they established themselves as the regimes which marked one of the greatest degrees of unfreedom. The article analyzes the specific sociostructural, sociocultural and sociopsychological aspects of the formation of totalitarian regimes (particularly communism), as well as their political system, ideological foundations and modus operandi. In doing so, it particularly emphasizes the dissolution of civil society and its substitution by a political society as a key structural determinant, authoritarianism and fear as a sociopsychological basis, and repression as the functional basis of operation for totalitarian regimes. In that context, it analyzes the political, anthropological and visual aspects of the symbols of totalitarian regimes, their archetypal (mythological, religious, ethnic, cultural, historical) meaning, and explains their function (political, anthropological, sociocultural, and sociopsychological) in the development and preservation of totalitarian regimes. Using the example of the hammer and sickle, a typical symbol of communism, it shows a substantial and communicational (particularly visual) dimension of symbol, by breakdown by the elements of semiotics (signum, designatum, interpretant) and its sub-disciplines (semantics, pragmatics, sintactics). On this basis, it tries to show the decisive power of political symbols over the political perceptions and political behavior of individuals and entire social groups, i.e. their manipulative power by meanings assigned to them by totalitarian authorities and forms of their communication, with the goal of preserving the totalitarian regime. PMID- 23941007 TI - Thermography--a feasible method for screening breast cancer? AB - Potential use of thermography for more effective detection of breast carcinoma was evaluated on 26 patients scheduled for breast carcinoma surgery. Ultrasonographic scan, mammography and thermography were performed at the University Hospital for Tumors. Thermographic imaging was performed using a new generation of digital thermal cameras with high sensitivity and resolution (ThermoTracer TH7102WL, NEC). Five images for each patient were recorded: front, right semi-oblique, right oblique, left- semi oblique and left oblique. While mammography detected 31 changes in 26 patients, thermography was more sensitive and detected 6 more changes in the same patients. All 37 changes were subjected to the cytological analysis and it was found that 16 of samples were malignant, 8 were suspected malignant and 11 were benign with atypia or proliferation while only 2 samples had benign findings. The pathohistological method (PHD) recorded 75.75% malignant changes within the total number of samples. Statistical analysis of the data has shown a probability of a correct mammographic finding in 85% of the cases (sensitivity of 85%, specificity of 84%) and a probability of a correct thermographic finding in 92% of the cases (sensitivity of 100%, specificity of 79%). As breast cancer remains the most prevalent cancer in women and thermography exhibited superior sensitivity, we believe that thermography should immediately find its place in the screening programs for early detection of breast carcinoma, in order to reduce the sufferings from this devastating disease. PMID- 23941008 TI - Thermography is not a feasible method for breast cancer screening. AB - Breast cancer is a common malignancy causing high mortality in women especially in developed countries. Due to the contribution of mammographic screening and improvements in therapy, the mortality rate from breast cancer has decreased considerably. An imaging-based early detection of breast cancer improves the treatment outcome. Mammography is generally established not only as diagnostic but also as screening tool, while breast ultrasound plays a major role in the diagnostic setting in distinguishing solid lesions from cysts and in guiding tissue sampling. Several indications are established for contrast-enhanced magnetic resonance imaging. Thermography was not validated as a screening tool and the only study performed long ago for evaluating this technology in the screening setting demonstrated very poor results. The conclusion that thermography might be feasible for screening cannot be derived from studies with small sample size, unclear selection of patients, and in which mammography and thermography were not blindly compared as screening modalities. Thermography can not be used to aspirate, biopsy or localize lesions preoperatively since no method so far was described to accurately transpose the thermographic location of the lesion to the mammogram or ultrasound and to surgical specimen. Thermography cannot be proclaimed as a screening method, without any evidence whatsoever. PMID- 23941009 TI - Recent trend and perspectives in forensic anthropology: a bibliometric analysis. AB - This paper evaluates research in Forensic Anthropology (FA) in order to report on the state of this field of science. In particular, we carried out a review of all PubMed-listed scientific studies in the past decades using "forensic anthropology" as the keyword. In our "meta-analysis", we observed variation in the number of publications per 2-year interval throughout the study period. In total, 1589 studies were found in the database and 1292 of them were published in the period 2000-2009. There was a significant positive correlation between the number of published articles and time (subdivided into 2-year intervals). The rate of increase was lower in the last decade. Based on the observed trend, we expect that the phenomenon will continue in the near future, reaching a number close to 400 FA publications in PubMed in the biennium 2012-13. We also carried out a specific content analysis of all FA papers published in the journal Forensic Science International in the last decade. During this period, the majority of FA papers concerned skeletal biology, although there was a positive shift toward virtual anthropological studies. PMID- 23941010 TI - Analysis of purity profiles of generic lisinopril tablets marketed in Croatia. AB - In view of an increasing number of generic drugs emerging, a comparative study was performed including the approved lisinopril preparations in the form of tablets marketed in Croatia, to compare purity profiles of generic drugs versus the original medicinal product. Several batches of each individual medicinal product at different stages of their shelf life were analyzed. Impurities were determined by means of high performance liquid chromatography (HPLC). Impurity profiles were demonstrated to be specific for each individual drug. Original drug, as compared to its generic copies, had the lowest values and also the lowest variability of all the tested parameters--type, total number and content of impurities--suggesting that its manufacturing process is to certain degree better controlled compared to other manufacturers. A characteristic impurity C appearing in all the assessed preparations has the lowest levels in the original drug, whereas the amount of the highest unknown impurity does not exceed 0.10% in any of the analyzed preparations. Although the original drug stands out from all the generic preparations with its purity, it can be generally concluded that, as regarding impurities levels, all the analyzed medicinal products are within the ranges of specification limits; accordingly, it is therefore not expected that, in case of lisinopril tablets, administration of the original drug as compared to any of its generic drugs, will be safer for the patient. PMID- 23941011 TI - Kikuchi-Fujimoto disease: the first reported case in Croatia. AB - Kikuchi-Fujimoto disease (KFD) is an extremely rare disease known to have a worldwide distribution with higher prevalence among Japanese and other Asiatic individuals. KFD presents as benign and self-limited disorder, characterized by regional cervical lymphadenopathy with tenderness, usually accompanied with mild to high fever and night sweats. Less frequent symptoms include weight loss, nausea, vomiting and sore throat. Final diagnosis can only be determined on the basis of typical morphological changes in the lymph node, therefore lymph node biopsy is crucial for proving the diagnosis. Here we present a 16-year-old, native Croatian, Caucasian girl with KFD, as a first case of KFD reported in Croatia. We suggest that this disease should be considered as a possible cause of fever of the unknown origin followed by lymphadenopathy. PMID- 23941012 TI - Unrecognized malaria and its consequences--a case report of severe malaria with acute renal failure. AB - Severe malaria is a medical emergency that requires urgent recognition and treatment, because it may rapidly progress to serious complications and death. We report a case of imported severe malaria tropica in an adult traveller, with a parasitemia of 20%, complicated by acute renal failure. Patient was initially misdiagnosed by a physician unaware of the importance of patients travel history, as having a viral infection. Despite the treatment delay, the patient was successfully cured with parenteral artemether combined with peroral mefloquine and vigorous supportive measures including renal replacement therapy. PMID- 23941013 TI - Gastric tube ulcer perforating the pericardium after subtotal esophagectomy. AB - Subtotal esophagectomy with retrosternal transposition of the gastric tube to the neck was performed in a 62-year-old patient with squamous cell carcinoma of the proximal third of the esophagus. He developed a salivatory fistula in the early postoperative period that healed spontaneously. Five months later, the patient developed partial stenosis of the esophagogastric anastomosis which required recervicotomy and excision, after numerous failed dilatation attempts. Eighteen months later, the patient presented to the hospital for severe pain in the upper abdomen. Clinical work-up revealed pericardial perforation by the gastric tube ulcer necessitating emergent surgery and gastric tube removal. We present a patient who developed both early and late complications of subtotal esophagectomy with gastric tube transposition as well as a review of the literature. PMID- 23941014 TI - Cryptococcus neoformans meningoencephalitis in a patient with idiopathic CD4+ T lymphocytopenia. AB - Cryptococcus neoformans is a leading cause of invasive cryptoccocal infections which include meningitis/meningoencephalitis, cerebral cryptococcoma, invasive pulmonary and mediastinal infection. Invasive infection is mainly diagnosed in immunocompromised patients, especially in HIV-infected individuals. There is a rising number of patients with invasive cryptococcal infections in immunocompromised patients who are HIV-negative. Among several primary immunodeficiency syndromes, considered as possible reasons for these invasive infections, idiopathic CD4+ T lymphocytopenia (ICL) is most frequently diagnosed. The pathogenesis of this rare syndrome is still unknown, while its clinical spectrum ranges from an asymptomatic laboratory abnormality to life-threatening opportunistic infections. Here we present an HIV-negative young man suffering from cryptococcal meningoencephalitis in whom ICL was diagnosed. PMID- 23941015 TI - Primary extragastrointestinal stromal tumor of the sigmoid mesocolon with metastatic spread to greater omentum: case report. AB - A 71-year-old female complained of abdominal pain, weight loss and abdominal distension. Gynecologic examination revealed a hardly movable, palpable mass in the lower abdomen, reaching the umbilicus. An abdominal ultrasound and computed tomography (CT) scan suggested a large abdominal mass with the possible origin in the left ovary and without significant lymph node enlargements. The patient subsequently underwent complete evacuation of tumor tissue, omentectomy and total abdominal hysterectomy and bilateral salpingo-ovariectomy. Immunohistochemical examination revealed strongly positive staining of tumor cells for CD117. The final pathologic diagnosis was a primary extragastrointestinal stromal tumor (EGIST) of the sigmoid mesocolon with omental metastasis. The differential diagnosis of the tumor presented in the lower abdomen should consider the EGIST as well. PMID- 23941016 TI - Renal adenocarcinoma presenting as a spontaneous perirenal hematoma in a patient on warfarin therapy--case report and literature review. AB - We are presenting a rare case of a spontaneous extensive perirenal hematoma caused by ruptured renal adenocarcinoma in a patient who was on warfarin therapy because she had atrial fibrillation and three myocardial infarctions. A 77-year old woman was admitted to our department with acute right flank pain and hemorrhagic shock. The anamnestic data revealed no trauma and hematuria. Abdominal ultrasonography and computed tomography scan showed large retroperitoneal hematoma. The patient underwent urgent surgery and radical nephrectomy was performed. A large retroperitoneal hematoma was found originating from a ruptured renal neoplasm in the upper pole of the right kidney. The pathohistological diagnosis was chromophobe renal cell carcinoma. The clinical, diagnostic and therapeutic peculiarities of this rare condition are presented, along with the literature review on the topic. PMID- 23941017 TI - Synovial chondromatosis of the elbow. AB - Synovial chondromatosis (SC) is a rare, mostly benign proliferation of the synovium of the joint, tendon or bursa which results in the formation of loose bodies. It can appear in one of 33 described localisations, but it is most common in the knee. In our study we gathered a group of 7 patients (6 male and 1 female) with SC of the elbow, which underwent arthroscopic surgery of the elbow, performing both removal of the loose bodies and complete synovectomy. Mayo Elbow Performance Score (MEPS) was used to evaluate and compare the patients' condition before the operation and at the final follow-up, 31 months, on average, after the operation (range 18-56 months). All patients had poor MEPS before the operation, with an average of 40.7 (range 15-50 points). At the final follow-up, 6 patients had a good or excellent MEPS, while a poor MEPS was present in a single patient. The average MEPS was 85 (range 45-100 points). The one patient who's MEPS remained poor developed heterotopic ossification in the same elbow shortly after arthroscopic surgery. This patient was reoperated 8 months later using an open technique. No other complications occurred in the rest of the operated patients and no recurrence of SC occurred in any of the operated patients. Our results confirm that arthroscopic removal of loose bodies and complete synovectomy should be the treatment of choice for SC of the elbow. PMID- 23941018 TI - Section for Interventional Radiology--sIRcro 10 years of existence and organised activities (2000-2010). AB - Shortly after the Roentgen's discovery (1895), X-rays were applied for depicting vascular system (Lindenthal and Haschek 1896). But it took rather long time before another brilliant idea (Seldinger 1953) for percutaneous puncture and catheterization of superficial artery was developed instead of these previously performed and the surgical arteriotomy. The percutaneous puncture enabled another idea to emerge, i.e. percutaneous transluminal angioplasty--PTA (Dotter/Judkins 1964). Thus it was proved that catheter could be used not only in diagnostics but also in therapy, and the method was applied to other organs and organic systems. The application of interventional radiology in Croatia started in late 1970s and early 1980s. The number and type of procedures increased rapidly in the four largest hospitals and educational centres (Zagreb, Split, Rijeka, Osijek), so that the need was felt to establish a Section for Interventional Radiology of the Croatian Society of Radiology (2000). PMID- 23941019 TI - Pathophysiology of osteonecrosis of the jaw in patients treated with bisphosphonate. AB - Apart from the well-known mechanism of bisphosphonates' cellular effect, embryonic development and the specific features of alveolar bone homeostasis have been discussed. The unique ethiopathogenic mechanism which relates osteonecrosis of the jaw and bisphosphonates treatment has not been explained. The emphasis lies on the toxicological effects of bisphosphonates on the physiology of the alveolar bone and on the lasting effect of tooth extraction followed by an infection of the extraction wound and consequent progression into deeper layers of osseous tissue. Epithelial infection includes microbiological findings of Actinomyces species. The risk is pronounced in oncological patients treated with bisphosphonates intravenously in relatively large doses and during a longer period of time, especially with highly potent nitrogen-containing bisphosphonates pamidronate and zoledronate. This review of bisphosphonate-related osteonecrosis of the jaw stresses the significance of some other risk factors (corticosteroids, chemotherapy, tumour tissue etc.) of necrosis development--more precisely of osteomyelitis of the jaw if the microbiological component of the diseases has been taken into account, while the role of the bisphosphonates becomes minor. There is no gold standard for the treatment of jaw osteonecrosis; rather, palliative and minimally invasive treatment is applied, without subsequent oral surgical interventions. Since there is a significant risk of jaw osteonecrosis in oncological patients, the level of oral health is an important factor for the indication of intravenous bisphosphonates treatment. PMID- 23941020 TI - Spontaneous ovarian hyperstimulation syndrome. AB - Spontaneous forms of the ovarian hyperstimulation syndrome (sOHSS) are nearly always reported between 8 and 14 weeks of pregnancy and also with follicle stimulating hormone (FSH) producing pituitary adenoma. The syndrome has been previously reported in rare instances of increased production of human chorionic gonadotrophin (hCG) such as multiple pregnancies, hydatiforme mole, polycystic ovary disease and elevated concentrations of thyroid-stimulating hormone (TSH) in hypothyreoidism. High levels of these hormones are able to stimulate by natural promiscuous activation the wild-type FSHr, resulting in sporadic presentations of the syndrome. Since 2003, only six different activating FSHr gene mutations have been reported in cases of familial or habitual sOHSS. In addition to five mutations which have been found in the transmembrane helices (Asp567Asn, Asp567Gly, Thr449Ile, Thr449Ala, Ile545Thr), the first germline mutation (c.383C > A, p. Ser 128 Tyr) in the extracelullar domain was identified. All five mutants were abnormally activated by TSH and normal levels of hCG while displaying constitutive activity. In contrast to these mutations, the p.Ser128Tyr mutant displayed an increase in sensitivity only toward hCG. Accordingly, the mutated FSHrs, may be hyperstimulated by the pregnancy-derived hCG or TSH, inducing the occurrence of the syndrome. In the differential diagnosis, malignancy, pregnancy luteoma and hyperreactio luteinalis would have to be excluded. In almost all of the cases the disease regresses spontaneously and could be managed expectantly or conservatively, but with termination of pregnancy or surgery in cases of complications. PMID- 23941021 TI - Fertility in the aging male: molecular pathways in the anthropology of aging. AB - The aging process is a normal stage in development characterized by the gradual deterioration of all life functions. As far as reproduction is concerned, aging is characterized by a significant limitation of fertility in both sexes. This process is, at least partially, attributed to the action (or loss of action) of sex steroids, coinciding with low activity of the pituitary-gonad axis. From an anthropological point of view, the study of reproductive aging is a unique opportunity to investigate various environmental and endogenous factors influencing sexual behavior and, thus, playing a significant role in human biology. Various techniques are now widely available to allow the detailed examination of reproductive hazards using only minor samples of genetic material. These methods are highly sensitive and specific and allow the characterization of distortions at subcellular and even molecular level. This short review briefly summarizes the current understanding of reproductive aging, as well as its potential clinical and anthropological impact. PMID- 23941022 TI - Draw the line... your personal choice. PMID- 23941023 TI - Class III correction of a non-growing patient. AB - The purpose of this article is to suggest that the previously held postulation that we cannot functionally treat non-growing individuals may not be entirely true. It contains a class III case treated after stage 5 growth and possibly into stage 6. PMID- 23941024 TI - Lefort 1 osteotomy in a beta-thalassemia major patient--a case report. AB - Maxillary setback of patients with protruded maxilla is a complex procedure. This complexity is aggravated when combined with thalassemia. The Aim of this case report was to treat a beta-thalassemia major girl with severe maxillary protrusion. A 16 year-old beta-thalassemia major girl presented with excessive maxilla, incompetent lips and an everted upper lip was referred for treatment. She had her spleen removed at the age of 9 and her blood transfusion was stopped 3 month before referral. After leveling and aligning with 018 standard edgewise system the patient was sent for Lefort 1 osteotomy. Segmental osteotomy was denied due to excessive bleeding in the procedure. The results showed that the thalassemic patient was effectively treated with presurgical orthodontics, Lefort 1 osteotomy followed by post surgical orthodontics. Very satisfactory esthetic results were obtained in the patient after 4.5 years of active treatment. PMID- 23941025 TI - Composite lingual buttons for correction of rotated premolar teeth. AB - Composite lingual buttons can be an invaluable alternative for bondable stainless steel lingual buttons on the lingual surfaces of rotated premolars as these surfaces are more vulnerable for bond failures due to their varied morphology, inadequate bonding surfaces, aprismatic enamel, salivary contamination and inferior etch pattern. Their use can also be extended to the molars and other teeth as they can be used as attachments for correction of cross-bites. PMID- 23941026 TI - Efficacy of planas direct tracks for early treatment of skeletal Class II malocclusion--a clinical and cephalometric study. AB - OBJECTIVE: To evaluate the efficacy of Planas Direct Tracks in the treatment of skeletal Class II malocclusion due to retrognathic mandible in the intermediate mixed dentition stage clinically and cephalometrically. MATERIALS AND METHOD: A six month cross sectional comparative study consisted of 40 subjects (21 males and 19 females) with a mean age of 9.8 + 1.3 years. The total sample was classified into control group (20 patients which were not subjected to treatment with Planas Direct Tracks (PDT) which were observed over a period of six months) and experimental group (20 patients subjected to treatment with Planas Direct Tracks and were observed over a period of six months). Records were taken before treatment and at the end of six months for comparative analysis. RESULT: The experimental group showed a a significant increase in mandibular length, and a significant improvement in maxillo-mandibular sagittal skeletal relationships. They exhibited a significant reduction in overjet and an improvement in molar relationship. CONCLUSIONS: The PDT protocol is effective in early treatment of skeletal Class II malocclusion. PMID- 23941027 TI - Mandibular symphyseal distraction osteogenesis--simplified. AB - The limb lengthening technique of distraction osteogenesis (DO) used in orthopedic surgery is a well established procedure. DO has been adapted to the facial skeleton to change the anterior-posterior position of the jaws. Historically, the mandibular arch transverse dimension has been considered immutable. Mandibular arch expansion is done with a variety of methods including Schwarz plates, lingual arches, functional appliances and arch wires; these methods produce limited dimensional change with questionable long-term stability. Adapting the Ilizarov treatment protocol to the mandibular symphysis can produce a regenerate bone thereby adding dimension to the innate basal bone. This can then be used to produce a potentially greater effect than the conventional modes of mandibular expansion. The modified mandibular symphyseal distraction device used by the authors is a tooth borne device fabricated with a Schwartz screw and self cured acrylic resin coverage over all the erupted mandibular teeth. The appliance used by the authors has been found to be very economical, easy to fabricate and clinically efficient. The surgical approach used, requiring surgery under local anesthesia in the outpatient department obviates need of hospital admission and the cost and time factors associated with in-patient therapy Mandibular Symphyseal Distraction Osteogenesis (MSDO) with this innovative low cost approach may be compared in a multi centric study with other established methods of MSDO. PMID- 23941028 TI - Resin pad thickness in conventional and in plain wire lingual systems: a comparative study. AB - The purpose was to compare resin pad thickness in conventional and plain wire lingual systems, considering archwire form. Resin pads were smaller in plain wire for all studied teeth, except canines and second premolars; which provide better torque control. Archwire was flat/square in anterior region for plain wire system. PMID- 23941029 TI - Management of pseudo Class III malocclusion--synergistic approach with fixed and functional appliance. AB - Class III malocclusion has been divided into two subtypes: skeletal and pseudo Class III. A pseudo Class III malocclusion should be treated as early as possible to reduce the functional shift of the mandible and increase maxillary arch length. A case of pseudo-Class III malocclusion was presented here. A 11-year-old boy came with an anterior cross bite, the treatment was done with Fixed appliance (Roth prescription) and Reverse Twin block therapy. This case demonstrated that an anterior cross bite was corrected after 10 months of treatment. PMID- 23941030 TI - Treatment of Class II Div I malocclusion with two phase therapy--a case report. AB - In our opinion, the main goal of orthodontic treatment has now shifted from attaining normal occlusion to achieving a pleasing soft tissue profile. The following case report presents a case in which normal dental and skeletal relations as well as a pleasing soft tissue profile was achieved. The female growing patient presented with convex profile and incompetent lips with deep mentolabial sulcus. On examination she exhibited a normal maxilla, deficient mandible with a horizontal growth pattern and Class II, Div I malocclusion dentally. Her growth potential was utilized fully with the twin block functional appliance followed by fixed orthodontic treatment. A favorable skeletal, dental and soft tissue relationship was achieved using this two phase therapy. PMID- 23941031 TI - Treatment of impacted, rotated central incisors with removable appliance. AB - A 12-year-old girl was referred to the orthodontic department of Kerman dental school with a chief complaint of two unerupted upper left & right front teeth. Patient had no significant medical & Dental history. Intra oral and radiographic examination revealed missing of two maxillary permanent central incisors. Orthodontic treatment involved two phases: Phase 1 Impacted maxillary central incisors: surgical exposure and force eruption with removable appliance. Phase 2: whip appliance is used to correct rotation of right permanent maxillary incisor. PMID- 23941033 TI - Fifth alternative for replacement of maxillary first molar. AB - There are occasions when the patient is missing only one first molar or the first molar is slated for an odontectomy (extraction). Most of the time, there are only four common avenues for replacement: partial removable prosthesis, Maryland bridge, ceramic or ceramic to metal fixed prosthesis and osseo-integrated implant supported crown. In this article, the author discusses the least common avenue for replacement of missing maxillary first molar--an orthodontic closure. He discusses and demonstrates; Maximum, Medium and Minimum Anchorage strategies on acrylic models. Preserving the anchorage is necessary for successful execution of this orthodontic procedure. This demonstration is followed by presentation of the actual case. PMID- 23941032 TI - Treatment of an impacted supernumerary tooth using limited fixed orthodontic appliances. AB - A 42-year and 9-month-old female with an impacted supernumerary tooth was treated with limited fixed orthodontic appliances. As seen in this case, it is possible to successfully treat impacted teeth in adults even though the most common time to treat impactions is during adolescence. PMID- 23941034 TI - An interim bite raiser. AB - Patients with deep bites or crossbites often need temporary bite opening to prevent mandibular brackets from being sheared off and to allow unobstructed tooth movement. Here we present a simple auxiliary occlusal extension for temporary bite opening to correct an anterior crossbite. The bite plane is hygienic, less intrusive to the tongue space and prevents supra-eruption of the adjacent as well as opposing teeth. PMID- 23941035 TI - The nurse as an instrument of healing. PMID- 23941036 TI - Reflections on the holistic journey. PMID- 23941037 TI - Gardens that heal. PMID- 23941038 TI - Mind the gap: healing environments start with nourished nurses. PMID- 23941039 TI - Forest immersion experience: Mother Nature promotes introspection and healing. PMID- 23941040 TI - Nurturing healing environments. PMID- 23941041 TI - Creating healing spaces with words & imagery: a nursing intervention in pain management. PMID- 23941042 TI - Seizure-sensitivity in Drosophila is ameliorated by dorsal vessel injection of the antiepileptic drug valproate. AB - Drosophila is a powerful model organism that can be used for the development of new drugs directed against human disease. A limitation is the ability to deliver drugs for testing. We report on a novel delivery system for treating Drosophila neurological mutants, direct injection into the circulatory system. Using this method, we show that injection of the antiepileptic drug valproate can ameliorate seizure-sensitive phenotypes in several mutant genotypes in the bang-sensitive (BS) paralytic mutant class, sda, eas, and para(bss1). This drug-injection method is superior to drug-feeding methods that we have employed previously, presumably because it bypasses potent detoxification systems present in the fly. In addition, we find that utilizing blood-brain barrier mutations in the background may further improve the injection results under certain circumstances. We propose that this method of drug delivery is especially effective when using Drosophila to model human pathologies, especially neurological syndromes. PMID- 23941043 TI - Sesterterpenoids isolated from a northeastern Pacific Phorbas sp. AB - Four new sesterterpenoids, ansellone B (4), phorbadione (5), secoepoxyansellone A (6), and alotaketal C (7), have been isolated from specimens of the sponge Phorbas sp. collected in British Columbia. Ansellone B (4) has an unprecedented heterocyclic skeleton featuring an oxocane ring, and secoepoxyansellone A (6) is the first example of the degraded "secoansellane" sesterterpenoid carbon skeleton. Alotaketal C (7) is an activator of cAMP signaling in HEK cells. PMID- 23941044 TI - Substituted tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor. AB - Increasing evidence implicates the orexin 1 (OX1) receptor in reward processes, suggesting OX1 antagonism could be therapeutic in drug addiction. In a program to develop an OX1 selective antagonist, we designed and synthesized a series of substituted tetrahydroisoquinolines and determined their potency in OX1 and OX2 calcium mobilization assays. Structure-activity relationship (SAR) studies revealed limited steric tolerance and a preference for electron deficiency at the 7-position. Pyridylmethyl groups were shown to be optimal for activity at the acetamide position. Computational studies resulted in a pharmacophore model and confirmed the SAR results. Compound 72 significantly attenuated the development of place preference for cocaine in rats. PMID- 23941045 TI - New helpers in TF-dependent migration. PMID- 23941046 TI - Health care and personal responsibility. PMID- 23941047 TI - Measuring the triple aim: a call for action. PMID- 23941048 TI - Mobile health care operations and return on investment in predominantly underserved children with asthma: the breathmobile program. AB - Underserved populations have limited access to care. Improved access to effective asthma care potentially improves quality of life and reduces costs associated with emergency department (ED) visits. The purpose of this study is to examine return on investment (ROI) for the Breathmobile Program in terms of improved patient quality-adjusted life years saved and reduced costs attributed to preventable ED visits for 2010, with extrapolation to previous years of operation. It also examines cost-benefit related to reduced morbidity (ED visits, hospitalizations, and school absenteeism) for new patients to the Breathmobile Program during 2008-2009 who engaged in care (>=3 visits). This is a retrospective analysis of data for 15,986 pediatric patients, covering 88,865 visits, participating in 4 Southern California Breathmobile Programs (November 16, 1995-December 31, 2010). The ROI calculation expressed the cost-benefit ratio as the net benefits (ED costs avoided+relative value of quality-adjusted life years saved) over the per annum program costs (~$500,000 per mobile). The ROI across the 4 California programs in 2010 was $6.73 per dollar invested. Annual estimated emergency costs avoided in the 4 regions were $2,541,639. The relative value of quality-adjusted life years saved was $24,381,000. For patients new to the Breathmobile Program during 2008-2009 who engaged in care (>=3 visits), total annual morbidity costs avoided per patient were $1395. This study suggests that mobile health care is a cost-effective strategy to deliver medical care to underserved populations, consistent with the Triple Aims of Therapy. PMID- 23941049 TI - The real value of wellness programs: a comprehensive review of the literature. PMID- 23941050 TI - Does the way we organise anaesthesia departments matter? What should be the measures of outcome? PMID- 23941052 TI - Systematic study of the thermophysical properties of imidazolium-based ionic liquids with cyano-functionalized anions. AB - In the past few years, ionic liquids (ILs) with cyano-functionalized anions have shown to be improved candidates for electrochemical and separation applications. Nevertheless, only scattered data exist hitherto and a broad analysis of their structure-property relationship has yet to be attempted. Therefore, in this work, a systematic study of the densities, viscosities and refractive indices of imidazolium-based ILs with cyano-functionalized anions was carried out at 0.1 MPa within a broad temperature range (from 278 to 363 K). The ILs under study are based on 1-alkyl-3-methylimidazolium cations (alkyl = ethyl, butyl and hexyl) combined with the [SCN](-), [N(CN)2](-), [C(CN)3](-) and [B(CN)4](-) anions. The selected matrix of cation/anion combinations allows us to provide a detailed and comprehensive investigation of the influence of the -CN group through an analysis of the thermophysical properties of the related ILs. The results show that, regardless of the cation, the densities decrease with an increase in the number of cyano groups or anion molecular weight. Moreover, for a fixed cation and temperature, the refractive index of the ILs decreases according to the rank: [SCN](-) > [N(CN)2](-) ~ [C(CN)3](-) > [B(CN)4](-). On the other hand, no clear trend was observed for the viscosity of ILs and the respective number of -CN groups. The viscosity dependence on the cyano-functionalized anions decreases in the order: [SCN](-) > [B(CN)4](-) > [N(CN)2](-) > [C(CN)3](-). The isobaric thermal expansion coefficient, the derived molar refraction, the free volume, and the viscosity energy barrier of all compounds were estimated from the experimental data and are presented and discussed. Finally, group contribution models were applied, and new group contribution parameters are presented, extending these methods to the prediction of the ILs properties. PMID- 23941054 TI - Comment on: Stanley D. (2012) Celluloid devils: a research study of male nurses in feature films. Journal of Advanced Nursing 68(11), 2526-2537. PMID- 23941053 TI - Mindfulness training for stress management: a randomised controlled study of medical and psychology students. AB - BACKGROUND: Distress and burnout among medical and psychology professionals are commonly reported and have implications for the quality of patient care delivered. Already in the course of university studies, medicine and psychology students report mental distress and low life satisfaction. There is a need for interventions that promote better coping skills in students in order to prevent distress and future burnout. This study examines the effect of a seven-week Mindfulness-Based Stress Reduction (MBSR) programme on mental distress, study stress, burnout, subjective well-being, and mindfulness of medical and psychology students. METHODS: A total of 288 students (mean age = 23 years, 76% female) from the University of Oslo and the University of Tromso were randomly allocated to an intervention or control group. The control group continued with their standard university courses and received no intervention. Participants were evaluated using self-reported measures both before and after the intervention. These were: the 'General Health Questionnaire, Maslach Burnout Inventory Student version, Perceived Medical School Stress, Subjective Well-being, and Five Facet Mindfulness Questionnaire' and additional indices of compliance. RESULTS: Following the intervention, a moderate effect on mental distress (Hedges'g 0.65, CI = .41, .88), and a small effect on both subjective well-being (Hedges'g 0.40, CI = .27, .63) and the mindfulness facet 'non-reacting' (Hedges'g 0.33, CI = .10, .56) were found in the intervention group compared with the control group. A higher level of programme attendance and reported mindfulness exercises predicted these changes. Significant effects were only found for female students who additionally reported reduced study stress and an increase in the mindfulness facet 'non-judging'. Gender specific effects of participation in the MBSR programme have not previously been reported, and gender differences in the present study are discussed. CONCLUSION: Female medical and psychology students experienced significant positive improvements in mental distress, study stress, subjective well-being and mindfulness after participating in the MBSR programme. TRIAL REGISTRATION: NCT00892138. PMID- 23941055 TI - Reply: To PMID 22409605. PMID- 23941057 TI - An international prevalence measurement of care problems: study protocol. AB - AIM: The aim of this article was to describe the design of an international audit of the prevalence of care problems in different healthcare sectors using identical methodologies. BACKGROUND: Audits, defined as a monitor of quality of health care, are increasingly applied in many countries as a strategy to improve professional practice and quality and safety of care. A prerequisite to enable a reliable comparison of quality of care audits is the use of identical instruments and methodology. DESIGN: Annual cross-sectional multi-centre point prevalence survey. METHOD: This international prevalence measurement of care problems in hospitals, care homes and home care is performed in the Netherlands, Austria, Switzerland and New Zealand. This study is based on a prevalence measurement of care problems originally performed in the Netherlands. For each care problem (pressure ulcer, incontinence, malnutrition, falls and restraints) at patient level, next to patient characteristics, data are gathered about the prevalence, prevention and treatment of each care problem. In addition, at ward/department and institution level, specific quality indicators are measured related to the care problems. After the measurement, institutions enter their data into a web based data-entry program. Institutions receive an overview of their own results and results at national level to enable a process of benchmarking. DISCUSSION: A uniform way of measuring the prevalence of care problems internationally is a significant step forward in gaining insight into the quality of basic care in different healthcare settings in different countries and may lead to more awareness and improvement programmes. PMID- 23941058 TI - The LPZ project. PMID- 23941059 TI - International prevalence measurement of care problems: results. AB - AIM: This report describes the results from the last international prevalence measurement of care problems in the Netherlands, Austria and Switzerland, including the course of the prevalence rates during the past 4 years. BACKGROUND: Basic care problems such as pressure ulcers, malnutrition and falls occur frequently in healthcare organizations. Measuring these care problems provides insight into their occurrence, and, while a measurement is included of the prevention, treatment and structural quality indicators, this gives institutions the possibility of improving their care regarding these care problems. DESIGN: An annual cross-sectional multicentre study. METHOD: The prevalence measurement of care problems is conducted annually on one specific day in different healthcare settings, among which are hospitals and care homes. Data are collected by means of a comprehensive, standardized questionnaire that comprises three levels: institutional, ward/department and patient level. RESULTS: Besides general characteristics of patients, results are presented for prevalence rates, prevention, treatment and quality indicators regarding each care problem for each country. PMID- 23941060 TI - Circulating levels and subcutaneous adipose tissue gene expression of pigment epithelium-derived factor in polycystic ovary syndrome and normal women: a case control study. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) has been recognized as a metabolic disorder, manifested by abdominal obesity, insulin resistance, dyslipidemia and hypertension. Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor family, is a pleiotropic protein known for its antiangiogenic, antioxidant, and neuroprotective properties and has been shown to induce insulin resistance and play a role in glucose metabolism. Recent studies investigating circulating PEDF levels show elevated serum PEDF in association with insulin resistance in normal-weight women with PCOS, but not in obese PCOS patients. The aims of this study were 1) to assess PEDF gene expression in subcutaneous adipose tissue (scAT) from women with PCOS and nonhirsute, ovulatory controls, and 2) to determine the circulating levels of PEDF in these groups. METHODS: Total RNA was extracted from adipose tissue biopsy samples and reverse-transcribed to cDNA. Real-time quantitative PCR was performed to determine relative gene expression levels. RESULTS: The 22 women with PCOS and 14 non-PCOS controls included in the study had similar age, BMI, and fasting glucose, triglycerides, and HDL cholesterol levels. Participants with PCOS exhibited higher 2 h oral glucose tolerance test levels (p = 0.006), total (p = 0.026) and LDL-cholesterol (p = 0.036), Ferriman-Gallwey score (p = 0.003) and total testosterone (p = 0.001) as compared to controls. BMI-adjusted PEDF serum levels and scAT gene expression were similar in the PCOS and control groups (p = 0.622 and p = 0.509, respectively). Circulating PEDF levels were not associated with scAT PEDF gene expression. Multiple regression analysis revealed that, in women with PCOS, insulin contributed positively and significantly to serum PEDF (p = 0.027), independently of testosterone. CONCLUSION: Serum PEDF levels and scAT gene expression were associated with metabolic risk factors, but did not differ between women with PCOS and age- and BMI-matched controls. Circulating levels and scAT gene expression of PEDF were not associated in the study subjects, suggesting additional sources for PEDF in addition to or instead of fat tissue. PMID- 23941061 TI - Long-term outcome in stroke survivors after discharge from a convalescent rehabilitation ward. AB - AIM: The aim of this study was to investigate the long-term mortality, daily living activities, social activity, and symptoms of depression, in post-stroke patients discharged to their homes from a convalescent rehabilitation ward, and to determine the relationship between demographic variables and long-term outcome. METHODS: This study included 252 consecutive stroke patients (140 men; mean age, 72.4 +/- 10.8 years) who had been admitted to a convalescent rehabilitation ward for inpatient rehabilitation. Follow-up assessment was made by postal questionnaire for up to >1 year after discharge, and included the modified Rankin scale, Frenchay activities index (FAI), and Geriatric Depression Scale. RESULTS: Of the 192 respondents (76.2%), 160 (83.3%) were living at home. Eighty-three (51.8%) were independent. Cumulative post-stroke mortality at 1 and 3 years was 3.7% and 19.4%, respectively.Mean total FAI score was 26.5 +/- 10.9, suggesting that social inactivity was common. The estimated prevalence of depression was 21.6%. Coronary artery disease and motor functional independence measures were significantly associated with mortality, whereas age, recurrent stroke, severity of paralysis, and motor functional independence measures were significant predictors of independence. In the cross-sectional logistic model, depression symptoms were inversely associated with FAI score. CONCLUSIONS: The mortality rate of patients discharged to their home following inpatient rehabilitation is relatively low. Social inactivity and depression symptoms, however, remain common during the chronic phase, and the severity of depression and restriction of participation were interrelated. PMID- 23941063 TI - Effect of anxiety, competition, and failure on performance of a complex motor task. AB - The effect of anxiety on learning and performance of a complex motor task was determined. In addition the effects of two stressors-competition and failure-and the interactions between these stressors and anxiety were investigated. 40 high and 40 low anxiety Ss (selected by the Taylor Manifest Anxiety Scale) learned and performed a coincident timing task. Competition was presented by offering the Ss a monetary reward for the best performance, while failure was manipulated by giving false knowledge of results and indicating that the performance level was inferior. Results showed that Ss low in anxiety performed significantly better than Ss high in anxiety during the initial learning of a complex motor task. No difference was found between Ss extreme in anxiety once the task was well learned. Competition and failure did not affect performance or interact with the anxiety level of Ss. PMID- 23941064 TI - Experimental hybrid-computer automation in perceptual-motor and social behaviorial research. AB - A hybrid-computer laboratory has made possible systematic procedures of experimental automation by computer programming methods. In studies of visual manual tracking, eyemovement-yoked visual tracking, and social tracking and feedback control, such a system has been programmed to control experimentally the signal, space, and time feedback compliances between motor response and sensory input, make experimental calibrations, measure response variables, control feedback displays, and perform other experimental operations automatically. A number of research projects have indicated that all aspects of behavior motorsensory performance, perception, learning, psychophysiological integration, motivation, development and aging-may be investigated by partial automation in terms of the multivariant feedback mechanisms that govern them. PMID- 23941065 TI - Proactive interference in short-term motor retention. AB - Proactive inhibition (PI) in motor short-term memory (STM) was investigated to determine if the PI effects commonly found in verbal STM are also present in motor STM. A simple linear positioning task was used in which a criterion position was presented to the blind-folded S (N = 72), with recall of the criterion after either 10 or 120 sec. The variable of greatest interest was the number (either 0, 2, or 4) of similar positions presented prior to the criterion, the previous positions and the criterion being recalled in reverse order following the retention interval. With 4 previous positions, Ss displayed greater absolute error and greater undershooting with algebraic error than with either 0 or 2 previous positions, indicating that PI effects were present in motor STM and that verbal and motor STM may be governed by the same set of laws. PMID- 23941062 TI - TRPA1 and other TRP channels in migraine. AB - Ever since their identification, interest in the role of transient receptor potential (TRP) channels in health and disease has steadily increased. Robust evidence has underlined the role of TRP channels expressed in a subset of primary sensory neurons of the trigeminal ganglion to promote, by neuronal excitation, nociceptive responses, allodynia and hyperalgesia. In particular, the TRP vanilloid 1 (TRPV1) and the TRP ankyrin 1 (TRPA1) are expressed in nociceptive neurons, which also express the sensory neuropeptides, tachykinins, and calcitonin gene-related peptide (CGRP), which mediate neurogenic inflammatory responses. Of interest, CGRP released from the trigeminovascular network of neurons is currently recognized as a main contributing mechanism of migraine attack. The ability of TRPA1 to sense and to be activated by an unprecedented series of exogenous and endogenous reactive molecules has now been extensively documented. Several of the TRPA1 activators are also known as triggers of migraine attack. Thus, TRP channels, and particularly TRPA1, may be proposed as novel pathways in migraine pathophysiology and as possible new targets for its treatment. PMID- 23941066 TI - Short term motor retention as a function of response-similarity. AB - The present study examined short-term retention in a simple leverpositioning task. The basic variables were the degree of similarity of prior responses about a target (+/- 5 deg., +/- 15 deg., and +/- 25 deg.) and the length of retention interval (5, 15, and 50 sec.). It was found that the absolute errors at recall were inversely related to the similarity of the prior responses about the target position. In all conditions, forgetting was found to be an increasing function of the retention interval. The loss of retention over short periods of time was interpreted as being consistent with verbal short-term memory studies. The results on the similarity of responses were in direct opposition to the findings usually observed in verbal tasks. Comparisons with verbal responses are difficult to make since the nature of retention measurement is different in verbal tasks. PMID- 23941067 TI - Specificity versus generality of motor response consistency. AB - The hypothesis that tasks are specific and not based upon general underlying factors (specificity hypothesis) was tested for motor response consistency, or intra-individual variability, SD(intra). Four motor tasks involving rapid speed of movement were administered to 46 Ss. The reliability of SD(intra) ranged from .45 to .78 indicating that there are reliable individual differences in SD(intra) and that inconsistency is not simply random error. Also, the reliability of SD(intra) increased as the number of trials/S increased. Even though the mean score correlations indicated a moderate degree of generality, inter-correlations among tasks using response consistency scores were very low indicating specificity of response consistency. PMID- 23941068 TI - Intertrial correlations and intertrial periods of rest. AB - Eight groups of 40 basic airmen each worked the Manual Crank for an initial period of 5 min., rested, and then worked for a final period of 3 min. The eight groups were distinguished according to the load (heavy or light) against which they worked in the two periods and the rest interval (30 sec. or 4 min.) between them. Response was scored in revolutions of the crank handle in each 20 sec. interval (trial). None of the main effects had any bearing on the intertrial correlations within or between the periods of cranking. The results lend further support to the proposition that intertrial correlations are invariant under rest interval (distribution of practice) and the force required to make a response. PMID- 23941069 TI - A note on verbal reinforcement combinations. AB - The hypothesis that "right" is weaker as a positive reinforcer than "wrong" as a negative reinforcer can be dismissed on logical grounds for the kind of task in which it originated. Both actual and hypotheicai data indicate that the characteristic difference between trials to criterion in rn ("right" for correct choices, nothing said after incorrect choices) and nw combinations (nothing for correct choices, "wrong" for incorrect choices) is produced by the nothings, not by the "rights" and "wrongs." PMID- 23941070 TI - A note on the conscious controls of motor units by children under six. AB - A simple form of training the conscious control of motor units in skeletal muscle has been demonstrated in a series of children under age 6. Easy boredom is the chief deterrent in the very young. So long as a child understands and cooperates, he can learn to isolate single units in a period of about 30 min. PMID- 23941071 TI - Association of genetic polymorphisms with warfarin dose requirements in Chinese patients. AB - OBJECTIVE: Warfarin is a commonly used anticoagulant with a narrow therapeutic range and large interindividual differences in dosing requirements. Previously, studies have identified that the interindividual variability was influenced by varieties of factors, including age, body size, vitamin K intake, interacting medications, as well as genetic variants. We aimed to investigate the effect of single-nucleotide polymorphisms (SNPs) on the interindividual variability of warfarin dose requirements in Chinese patients. METHODS: The study population consisted of 300 patients with a stable maintenance dose of warfarin. We examined SNPs in eight genes involving in the biotransformation and mode of action of warfarin (i.e., CYP4F2, CYP2C19, APOE, CALU, EPHX1, PROC, CYP2C9, and GGCX) using the SNaPshot assay. RESULTS: The mean daily warfarin dose in patients carrying CYP2C19 rs3814637CC, CYP2C9 rs1057910AA, and GGCX rs699664AA genotype was 3.39, 3.34, and 3.51 mg/day, respectively, which was higher than those carrying CYP2C19 rs3814637TT, CYP2C9 rs1057910CC, and rs699664GG genotype (2.00, 0.81, and 3.09 mg/day, respectively). CONCLUSION: These findings indicate that individuals carrying the CYP2C19 rs3814637CC or CYP2C9 rs1057910AA or GGCX rs699664AA genotype needed higher warfarin doses in the Chinese population. PMID- 23941072 TI - Variations of the COL1A1 gene promoter and the relation to developmental dysplasia of the hip. AB - AIM: Developmental dysplasia of the hip (DDH) is one of the most common hip deformities in children. Since the COL1A1 gene is located in the DDH relating region, we investigated the COL1A1 promoter variations in the development of DDH. RESULTS: We collected 154 unrelated female patients and 180 matched healthy female children, and then sequenced the COL1A1 gene promoter for detection of variations. Three variations in the COL1A1 gene promoter were detected in ten patients (T-139C, C-106T, and C-35T [rs113647555]), but none of the 180 health controls. The chi-square test showed that the rate of total variations in COL1A1 gene contributed to DDH (p=0.0016). CONCLUSION: We detected three variations in the COL1A1 gene promoter in patients and first demonstrated that the higher rate of total variations of COL1A1 gene contributed to DDH in Chinese female children; thus, the COL1A1 gene is a new candidate gene for DDH disease. PMID- 23941073 TI - The importance of patient engagement. PMID- 23941074 TI - Graphene/acid coassisted synthesis of ultrathin MoS2 nanosheets with outstanding rate capability for a lithium battery anode. AB - Morphology-controlled MoS2 nanosheets were successfully synthesized with the aid of graphene/acid coexistence by a one-pot hydrothermal method. The ultrathin MoS2 nanosheets were self-assembled into a cockscomb-like structure with an exposed (100) facet on graphene sheets, which is in strong contrast to large aggregate MoS2 plates grown freely on graphene sheets without acetic acid. The ultrathin MoS2 nanosheets displayed excellent rate performance for Li storage (709 mAh.g( 1) capacity at 8320 mA.g(-1) discharging rate) and superior charge/discharge cyclability. PMID- 23941075 TI - Neighboring-cation substitution tuning of photoluminescence by remote-controlled activator in phosphor lattice. AB - Highly efficient red phosphors with superior intrinsic properties that are excited by ultraviolet or blue light-emitting diodes are important white light sources for our daily life. Nitride-based phosphors, such as Sr2Si5N8:Eu(2+) and CaAlSiN3:Eu(2+), are commonly more red-shifted in photoluminescence and have better thermal/chemical stability than oxides. Cation substitutions are usually performed to optimize photoluminescence and thermal quenching behavior. However, the underlying mechanisms are unclear in most cases. Here we show that neighboring-cation substitution systematically controls temperature-dependent photoluminescence behavior in CaAlSiN3:Eu(2+) lattice. Trivalent cation substitution at the Ca(2+) site degrades the photoluminescence in high temperature environments but achieves better thermal stability when the substituted cation turns monovalent. The neighboring-cation control of lifetime decay is also observed. A remote control effect that guides Eu(2+) activators in selective Ca(2+) sites is proposed for neighboring-cation substitution while the compositional Si(4+)/Al(3+) ratio adjusts to the valence of M(n+) (n = 1-3) cation. In the remote control effect, the Eu(2+) activators are surrounded with nitride anions which neighbor with M(3+)-dominant and Si(4+)/Al(3+)-equivalent coordination when M is trivalent, but shift to the site where surrounded nitride anions neighbor with M(+)-dominant and Si-rich coordination when M is monovalent. This mechanism can efficiently tune optical properties, especially thermal stability, and could be general to luminescent materials, which are sensitive to valence variation in local environments. PMID- 23941077 TI - Recurrent hospitalisation with pneumonia is associated with higher 1-year mortality in frail older people. AB - BACKGROUND: Previous studies persistently showed that functional dependence was associated with higher long-term (>=1 year) mortality of older patients hospitalised with community-acquired pneumonia (CAP). The importance of other factors was, however, not well reported. AIM: This study aimed to investigate the relative contributions of comorbidity, nutritional status and frailty to 1-year mortality. METHODS: We prospectively recruited older patients, aged >=65 years, hospitalised with CAP from October 2009 to September 2010 at the Prince of Wales Hospital, Hong Kong. Demographics, Charlson's Comorbidity Index, mid-arm circumference (MAC) and Clinical Frailty Scale (CFS) were recorded as baseline characteristics. The severity of pneumonia was evaluated by the CURB score (confusion, blood urea nitrogen, respiratory rate and low blood pressure). The surviving patients were followed for 1 year since discharge to monitor readmission for CAP and all-cause mortality. We entered the following variables into the multivariate Cox regression model to identify independent predictors of 1-year all-cause mortality: age, sex, residential status, MAC, Charlson's Comorbidity Index, CFS and readmission for CAP. RESULTS: The final cohort consisted of 428 patients who were discharged from hospital. Within 1 year after hospital discharge, all-cause mortality and readmission for CAP were 22.4% and 32.0% respectively. Independent predictors of 1-year mortality were male sex (hazard ratio (HR) = 1.57, 95% confidence interval (CI) = 1.02-2.48), severe under-nutrition (MAC <=21 cm) (HR = 3.75, 95% CI = 1.66-8.46), frailty (CFS >=5) (HR = 2.36, 95% CI = 1.29-4.27) and readmission for CAP (HR = 4.50, 95% CI = 2.82 7.17). CONCLUSIONS: Recurrent pneumonia may be a terminal life event of frail older people so that advance care planning should be considered in those with recurrent admission for pneumonia. PMID- 23941078 TI - Editorial. AB - No abstract available for this article. PMID- 23941076 TI - Identification of neglected cestode Taenia multiceps microRNAs by illumina sequencing and bioinformatic analysis. AB - BACKGROUND: Worldwide, but especially in developing countries, coenurosis of sheep and other livestock is caused by Taenia multiceps larvae, and zoonotic infections occur in humans. Infections frequently lead to host death, resulting in huge socioeconomic losses. MicroRNAs (miRNAs) have important roles in the post transcriptional regulation of a large number of animal genes by imperfectly binding target mRNAs. To date, there have been no reports of miRNAs in T. multiceps. RESULTS: In this study, we obtained 12.8 million high quality raw reads from adult T. multiceps small RNA library using Illumina sequencing technology. A total of 796 conserved miRNA families (containing 1,006 miRNAs) from 170,888 unique miRNAs were characterized using miRBase (Release 17.0). Here, we selected three conserved miRNA/miRNA* (antisense strand) duplexes at random and amplified their corresponding precursors using a PCR-based method. Furthermore, 20 candidate novel miRNA precursors were verified by genomic PCR. Among these, six corresponding T. multiceps miRNAs are considered specific for Taeniidae because no homologs were found in other species annotated in miRBase. In addition, 181,077 target sites within T. multiceps transcriptome were predicted for 20 candidate newly miRNAs. CONCLUSIONS: Our large-scale investigation of miRNAs in adult T. multiceps provides a substantial platform for improving our understanding of the molecular regulation of T. multiceps and other cestodes development. PMID- 23941079 TI - Stated versus Observed Performance Levels in Patients with Chronic Low Back Pain. AB - This study examined the relationship between perceived (stated) levels of function and the measured (observed) performance in squatting and stair climbing activities of 20 patients with chronic low back pain (CLBP) and 20 healthy volunteers. Subjects were asked through an interview to self-assess their ability to comfortably perform stair climbing and squatting as well as other tolerances. The subjects were then asked to perform the activities and their performance levels were recorded. Results revealed that patients' estimate of squatting and stair climbing abilities as well as their demonstrated levels were significantly lower (p < 0.001) than those of the healthy subjects. There was a significant difference between groups in terms of the time required to perform squatting but not stair climbing. Both groups underestimated their physical capabilities. Findings indicate that the use of actual performance measurement combined with self-report of functional abilities is needed when assessing performance levels of healthy subjects as well as patients with CLBP. PMID- 23941080 TI - Motor-learning theory and the neurodevelopmental treatment approach:. AB - The neurodevelopmental treatment approach is frequently used by occupational therapists to supplement occupational therapy treatment techniques. As little empirical evidence exists to support the efficacy of this treatment approach, several authors have advocated incorporating motor-learning theory into occupational therapy intervention for people with motor-control disorders. This paper will review the basic principles of motor-learning theory and the neurodevelopmental treatment approach as related to the occupational therapy process. The review will include a description of the theoretical concepts, treatment applications, and research related to each approach. The two approaches will be compared and contrasted and methods for incorporating both approaches into occupational therapy will be described. PMID- 23941082 TI - Stroke:. AB - No abstract available for this article. PMID- 23941081 TI - Usage and effectiveness of rails, bathing and toileting AIDS. AB - There is a lack of systematic follow-up on the usage or effectiveness of rails and aids to elderly persons or persons with disability. One hundred and forty four persons, mostly elderly, responded to a mailed questionnaire. Factors associated with usage and non-usage of commonly used bathing and toileting aids and rails, and rails used for access to and from the home were investigated, including reasons for non-usage, equipment acceptance, perceived benefit, ergonomic factors and equipment reliability. The questionnaire was shown to have high internal consistency. Usage rates were high, 86% for rails and 76% for aids. Non-usage was largely attributed to change in functional status. There were also some specific areas of dissatisfaction indicated, including issues of aid prescription, methods of assessing rail placement, and design of equipment. PMID- 23941083 TI - Spinal cord injury:. AB - No abstract available for this article. PMID- 23941085 TI - Why do we need to use a zero reference? Reference influences on the ERPs of audiovisual effects. AB - Using ERPs in the audiovisual stimulus, the current study is the first to investigate the influence of the reference on experimental effects (between two conditions). Three references, the average reference (AR), the mean mastoid (MM), and a new infinity zero reference (IR), were comparatively investigated via ERPs, statistical parametric scalp mappings (SPSM), and LORETA. Specifically, for the N1 (170-190 ms), the SPSM results showed an anterior distribution for MM, a posterior distribution for IR, and both anterior and posterior distributions for AR. However, the circumstantial evidence provided by LORETA is consistent with SPSM of IR. These results indicated that the newly developed IR could provide increased accuracy; thus, we recommend IR for future ERP studies. PMID- 23941087 TI - Electronic optional guidelines as a tool to improve the process of referring patients to specialized care: an intervention study. AB - OBJECTIVE: The main objective of this paper is to investigate whether incorporating an electronic optional guideline tool (EOGT) in the standardized referral template used by general practitioners (GPs) when referring patients to specialized care can improve outpatient referral appropriateness. DESIGN: Intervention study with an intervention and a control group. SETTING: 210 GPs in the municipality of Bergen and the Department of Thoracic Medicine at Haukeland University Hospital. SUBJECTS: 2400 patients referred to the Department of Thoracic Medicine at Haukeland University Hospital. RESULTS: An electronic optional guideline tool (EOGT) was implemented on 93 of 210 GPs' computer systems. The referral quality and the time spent reviewing each referral were evaluated by the hospital specialists. The GPs did not know that their referrals were being evaluated. The specialists were blinded with regard to information concerning the intervention and the control group. The specialists reported significantly higher referral quality and considerably less time spent on evaluating referrals when using the EOGT, with an overall time reduction of 34%. Likewise, GPs also reported that the EOGT was easy to use, time-saving and led to an improved quality of their referrals. CONCLUSION: This study documents an improvement in the quality of the referrals. Since the GPs save time by using the EOGT, there is no reason to believe that they will discontinue using it. In fact, the tool may be even more beneficial for the GP. The authors believe that it is possible to implement the EOGT as a standard referral tool within various fields of medicine and are currently in the process of developing these tools. PMID- 23941086 TI - "I'm Dr Jekyll and Mr Hyde": are GPs' antibiotic prescribing patterns contextually dependent? A qualitative focus group study. AB - OBJECTIVE: To explore factors and circumstances contributing to prudent antibiotic prescribing for respiratory tract infections in primary care. DESIGN: Two focus groups representing rural and urban areas. A semi-structured interview guide with open-ended questions and an editing analysis style was used. They were examined to identify meaning units that were sorted into categories in an iterative process throughout the analysis. SETTING: Primary health care in two counties in southern Sweden. SUBJECTS: Two groups including seven and six general practitioners (GPs) respectively, men and women of different ages with different professional experiences. MAIN OUTCOME MEASURES: Exploration of categories, determination of themes, construction of models. RESULTS: The decision to prescribe antibiotics takes place in the encounter between GP and patient, initially characterized by harmony or fight and the subsequent process by collaboration or negotiation, resulting in agreement, compromise, or disagreement. Several factors influence the meeting and contribute to enhancing the conditions for rational prescribing. These conditions are connected to the GP, the relationship, and the setting; organization as well as professional culture. The findings indicate synergies between the factors, and that one factor can sometimes compensate for lack of another. Continuity and mutual trust can make a brief consultation successful, but lack of continuity can eliminate the effects of knowledge and professional skills. CONCLUSIONS: The findings emphasize the importance of the encounter between the GP and the patient for prudent antibiotic prescribing. Furthermore, the importance of an appropriate organization of primary care, which promotes continuity and encourages professional autonomy, is demonstrated. PMID- 23941089 TI - Adaptation to reversal of retinal feedback of eyemovements. AB - Both optical and hybrid-computer methods were devised to reverse the visual feedback which the eye gets of its own movements. Optical reversal by a contact lens device caused persisting, unstable, skittered, blurred vision, to which the subject made no effective adaptation. Using a hybrid analog-digital-analog computer, eyemovement-retinal feedback was reversed by yoking oscilloscope targets to the transduced electrical signals of ocular movements and reversing the sign of input-output control of the computer system. Vision with such computer-reversed feedback from ocular movements duplicated the experiences with the contact-lens method. Practice over five sessions of 50 trials indicated that three Ss showed no significant improvement in eye-tracking accuracy with the reversed vision. Perception of direction in vision and the basic signal processes of vision were thus found to be dependent on built-in direction specificity of eyemovement-retinal feedback interactions which also govern dynamic specialization and control of pursuit, saccadic, and fixation movements. PMID- 23941088 TI - Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: a population-based register study. AB - OBJECTIVE: This study aimed to investigate the association of lipoprotein and triglyceride levels with all-cause mortality in a population free from diabetes and cardiovascular disease (CVD) at baseline. The European Guidelines on cardiovascular disease prevention state that in general total cholesterol (TC) should be < 5 mmol/L (190 mg/dL) and low-density lipoprotein cholesterol (LDL-C) should be < 3 mmol/L (115 mg/dL). DESIGN: A population-based register study in the period 1999-2007 including 118 160 subjects aged 50 + without statin use at baseline. All-cause mortality was related to lipoprotein and triglyceride levels and adjusted for statin use after inclusion. RESULTS: All-cause mortality was lower in the groups with TC or LDL-C above the recommended levels. Compared with subjects with TC < 5 mmol/L, adjusted hazard ratios for the group aged 60-70 years ranged from 0.68 (95% confidence interval (CI) 0.61-0.77) for TC 5-5.99 mmol/L to 0.67 (95% CI 0.59-0.75) for TC 6-7.99 mmol/L and 1.02 (95% CI 0.68 1.53) for TC >= 8 mmol/L in males and from 0.57 (95% CI 0.48-0.67) to 0.59 (95% CI 0.50-0.68) and 1.02 (95% CI: 0.77-1.37) in females. For triglycerides, ratios compared with the group < 1 mmol/L in the females aged 60-70 years ranged from 1.04 (95% CI 0.88-1.23) to 1.35 (95% CI 1.10-1.66) and 1.25 (95% CI 1.05-1.48) for triglycerides 1-1.39 mmol/L, 1.4-1.69 mmol/L, and >= 1.7 mmol/L, respectively. Statin treatment after inclusion provided a survival benefit. CONCLUSION: These associations indicate that high lipoprotein levels do not seem to be definitely harmful in the general population. However, high triglyceride levels in females are associated with decreased survival. PMID- 23941090 TI - Intra-limb specificity of motor response consistency. AB - Two separate experiment using motor responses evaluated the specificity vs. generality of response consistency when the various tasks used the same limb for response. In Exp. I four similar tasks requiring rapid right arm movement were defined and, in Exp. II, Ss had to "hit" a moving target with either a maximal or moderately fast right hand movement. Although the mean intercorrelations among tasks were generally moderate to low (mean r = .85 and .30, respectively for Exp. I and II) the intercorrelations using response consistency scores (the SD of S's responses about his own mean) were lower for Exp. I (mean r = .54) and similar for Exp. II (mean r = .30). These findings provided little support for a notion of a general within-limb factor of motor response consistency. PMID- 23941091 TI - Analysis of memory as a feedforward control mechanism. AB - The properties of memory as a feedforward control mechanism of perception and motion have been investigated by requiring Ss to project in active space-time an observed stimulus wave pattern. Memory error was measured under conditions in which the visual feedback of the memory response was delayed and interrupted (sampled) at five time magnitudes (0.0, 0.2, 0.4, 0.6, and 0.8 sec). In addition, memory performance was measured under conditions of temporal pacing by an auditory clock and no such pacing. Results confirmed the hypotheses that memory error in projecting an observed stimulus target on a space-time basis would be improved by time pacing and systematically degraded by variable magnitudes of feedback delay and interruption of the projected movement patterns. The results indicate that memory, as well as learning, may be organized on a spacetime basis and that the critical time factors are related to feedback-and feedforward control timing in temporally spanning past response and experience through learning and in projecting such space-time control of acquisition in-memory. PMID- 23941092 TI - Control dynamics and timing a discrete motor response. AB - Altering the resistive dynamics of a handle moved 60 cm. to fill a 2-sec. interval manipulated the proprioceptive feedback (PFB) from the response. Spelling aloud 2-, 3-, and 4-letter words during the motor response prevented overt counting. 84 11-14 year old boys were given immediate KR, the lapsed time for the motor response, for 50 or 60 trials according to the design. Only the condition reducing time varying PFB to a minimum, no movement and no spelling, prevented accurate timing of the responses, but above the minimal level, accuracy, consistency and rapidity of learning was increased by the addition of large resistances varying with velocity and acceleration. PMID- 23941093 TI - The rate of handling information. AB - Several tests were given to determine the rate of transmission of information through the human channel when the information was encoded in one to five flashing lights and S's output was pressing corresponding keys. All possible stimulus bulbs were equally probable and any number could be lighted simultaneously. (1) Increasing the stimulus rate increased the information transmission rate only up to a point where S was making a few errors. (2) Increasing the number of possible light bulbs from one through five more than tripled the maximum transmission rate. (3) Reaction time was not a function of stimulus rate. (4) The reaction time increased with the number of possible light bulbs in the stimulus but not linearly. (5) Maximum transmission occurred at a rate very close numerically to the reciprocal of the reaction time. (6) The self pacing test resulted in as high transmission as the forced rate tests. PMID- 23941094 TI - Varied input stimuli and motor learning . AB - 75 apparatus-naive undergraduate Ss were assigned to one of five groups differentiated according to training display associated with a modified rotary pursuit (RP) apparatus. Performance of two control groups, one practicing an unaided reference task and the other a pathmarked RP task, was compared with that of groups that received either path-marked or mechanically guided practice during training, and where path-marked and mechanical guidance display was removed during transfer. It was found that the path-marked display produced superior results only during initial stages of practice, and retarded improvement in performance after transfer to the reference task. Mechanical guidance resulted in better performance on the path-marked condition than the unaided RP task, but in both cases performance dropped upon transfer. The results are discussed in the light of hypothesized learning strategies influenced by different training conditions. PMID- 23941095 TI - Handedness. AB - A 36 year-old man with unusual handwriting difficulties was tested for writing ability with the right and left hands shortly before and after a spontaneous change of writing habits. After only 10 mos. practice with the previously non preferred (left) hand, handwriting speed and legibility was comparable on the two sides. PMID- 23941097 TI - Impact of promotions on awareness, trial, and likelihood of trial of new dissolvable tobacco. AB - PURPOSE: To determine test market awareness and promotional effects of Camel dissolvable tobacco. DESIGN: Cross-sectional survey. SETTING: Indiana test market. SUBJECTS: Stratified sample of Indiana adults (N = 472). MEASURES: Data were poststratified and weighted to account for the sampling and demographics. ANALYSIS: Descriptive statistics and multivariate analysis. RESULTS: The study results indicate that 31.2% of participants were aware of Camel Dissolvables, 4.5% had tried them, and 8.3% were likely to try them. Tobacco use was a significant predictor of all outcomes; dual (cigarettes and smokeless tobacco) users were more likely to be familiar with, try, and be interested in trying Camel Dissolvables than single tobacco users and nonusers (p < .05). Male gender was a significant predictor only for likelihood of trial (p < .05). Education was a significant predictor only of actual trial (p < .05). Familiarity was predicted by in-store, magazine, and mail promotions. Trial was predicted by having seen magazine ads. Web site exposure predicted likelihood of trial. Of those who reported trying Camel Dissolvables (N = 37), 49% no longer used them, 43% used them some days, and 8% used them daily. Continued use was reported by 87% of dual users and 26% of single tobacco users (p < .01). CONCLUSION: Smokers and male dual tobacco users appear most affected by Camel Dissolvables promotions. PMID- 23941096 TI - Comparing human papillomavirus prevalences in women with normal cytology or invasive cervical cancer to rank genotypes according to their oncogenic potential: a meta-analysis of observational studies. AB - BACKGROUND: Mucosal human papillomavirus (HPV) infection is a necessary cause of cervical cancer. Vaccine and non-vaccine genotype prevalences may change after vaccine introduction. Therefore, it appears essential to rank HPV genotypes according to their oncogenic potential for invasive cervical cancer, independently of their respective prevalences. METHODS: We performed meta analyses of published observational studies and estimated pooled odds ratios with random-effects models for 32 HPV genotypes, using HPV-16 as the reference. RESULTS: Twenty-seven studies yielded 9,252 HPV-infected women: 2,902 diagnosed with invasive cervical cancer and 6,350 with normal cytology. Expressed as (odds ratio [95% confidence interval]), HPV-18 (0.63 [0.51, 0.78]) ranked closest to HPV-16, while other genotypes showed continuously decreasing relative oncogenic potentials: HPV-45 (0.35 [0.22, 0.55]), HPV-69 (0.28 [0.09, 0.92]), HPV-58 (0.24 [0.15, 0.38]), HPV-31 (0.22 [0.14, 0.35]), HPV-33 (0.22 [0.12, 0.38]), HPV-34 (0.21 [0.06, 0.80]), HPV-67 (0.21 [0.06, 0.67]), HPV-39 (0.17 [0.09, 0.30]), HPV 59 (0.17 [0.09, 0.31]), HPV-73 (0.16 [0.06, 0.41]), and HPV-52 (0.16 [0.11, 0.23]). CONCLUSIONS: Our results support the markedly higher oncogenic potentials of HPV-16 and -18, followed by HPV-31, -33, -39, -45, -52, -58 and -59, and highlight the need for further investigation of HPV-34, -67, -69 and -73. Overall, these findings could have important implications for the prevention of cervical cancer. PMID- 23941098 TI - Trust in health information sources differs between young/middle and oldest old. AB - PURPOSE: Examine differences in trust of health information sources between the oldest old and young/middle old. DESIGN: Cross-sectional survey using convenience sampling. SETTING: Eleven retirement communities. SUBJECTS: Older adults >=65 years (N = 353). MEASURES: Self-rated trust in health information sources. ANALYSIS: Mann-Whitney U-test or Fisher exact test to compare trust between age groups; multinomial ordered logistic regression analyses to model trust in Internet information sources. RESULTS: The overall survey response rate was 26.6%. Differences in trust were identified between oldest old (n = 108) and young/middle old (n = 245) for pharmacist (p < .05), Internet (p < .001), television (p < .05), radio (p < .001), and newspaper (p < .05) sources. In the oldest old, we found associations between levels of trust in Internet sources and frequency of Internet use (beta = 4.13, p < .001). CONCLUSION: Understanding where differences in trust arise can inform the design of resources to support the information-seeking process. When planning widespread distribution of health information to these distinct groups, program developers need to consider these differences. PMID- 23941099 TI - Is the dose-response relationship between body mass and hip bone mineral density in women influenced by diet, physical activity, or menopause? AB - PURPOSE: Investigate the relationship between body mass and hip bone mineral density (BMD) and the extent to which this association is influenced by potential mediating factors. DESIGN: Cross-sectional. SETTING: Approximately 20 cities in Utah and Wyoming. SUBJECTS: Subjects were 262 apparently healthy, nonsmoking females. MEASURES: Hip BMD was assessed using dual energy X-ray absorptiometry. Physical activity (PA) was measured objectively using accelerometers. Calcium and vitamin D were measured using the Block food frequency questionnaire. Menopause status and bone drug use were measured using a questionnaire. ANALYSIS: General linear models and partial correlations. RESULTS: With body mass divided into three categories, hip BMD differed significantly across the groups in a dose response manner: low mass (mean +/- standard deviation [SD]), .876 +/- .085 g/cm(2); moderate, .932 +/- .109 g/cm(2); and high mass, .995 +/- .112 g/cm(2) (F = 21.5, p < .0001). The relationship between mass and hip BMD was not affected by differences in age, height, menopause status, calcium or vitamin D intake, PA, or use of bone prescription drugs. CONCLUSION: These findings suggest that women with low body mass tend to have low hip BMD and those with high mass tend to have high BMD. Controlling for the potential mediating variables did not influence the dose-response relationship between mass and BMD. It appears that lifestyle may not influence the body mass and BMD relationship, making it a challenge for women with low mass to avoid risk of low BMD. PMID- 23941100 TI - Scales of smoking-related self-efficacy, beliefs, and intention: assessing measurement invariance among intermittent and daily high school smokers. AB - PURPOSE: To examine the factorial validity and measurement invariance of scales that measure smoking-related self-efficacy, beliefs, and intention between daily and intermittent adolescent smokers. DESIGN: Cross-sectional survey design. SETTING: Selected high schools in eastern Texas. SUBJECTS: Subjects were 2888 high school current smokers; mean age 16.2 years; 53.5% male; 67.4% White, 17.8% Hispanic, 6.2% Black, 8.6% "other." Daily smokers comprised 37.9% of the sample (i.e., smoked at least one cigarette every day 30 days prior to the survey). MEASURES: Smoking-related self-efficacy and intention were measured by three items; beliefs were measured by four items. ANALYSIS: Confirmatory factor analyses were conducted to test the invariance of the measures between daily and intermittent smokers. Fit indices included comparative fit index (CFI), nonnormed fix index (NNFI), and root mean square error of approximation (RMSEA). RESULTS: The three-factor measurement model had good fit for daily (CFI = .97, NNFI = .95, RMSEA = .09) and intermittent (CFI = .96, NNFI = .95, RMSEA = .09) smokers. Evidence of strong factorial invariance was found for the factors between the smoking subgroups (CFI = .96, NNFI = .96, RMSEA = .08). CONCLUSION: These measures may be used to capture and compare scores on self-efficacy to resist smoking, beliefs about benefits of smoking, and intention to smoke between daily and intermittent adolescent smokers. PMID- 23941101 TI - Physiological and psychological effects of a Himalayan singing bowl in meditation practice: a quantitative analysis. AB - PURPOSE: To determine the physiological and psychological effects of adding a Himalayan singing bowl (HSB) to a directed relaxation (DR) session. DESIGN: Randomized crossover study. SETTING: Community-based counseling practice. SUBJECTS: Fifty-one participants completed two randomly assigned sessions beginning with either 12 minutes of HSB or silence, followed by a 20-minute DR session. INTERVENTION: Random order of HSB intervention/silence prior to DR. MEASURES: Blood pressure (BP), heart rate (HR), Positive and Negative Affect Schedule (PANAS) scores measured before and after both sessions. ANALYSIS: Analysis of variance (ANOVA) compared differences between variables over time between both study days, and analysis of covariance (ANCOVA) analyzed changes from baseline, controlling for baseline, age, and sex. RESULTS: Fifty-one participants completed both sessions. There was a greater decline in systolic BP (p = .044) and HR (p = .003) with HSB compared to silence prior to DR. Changes in diastolic BP were greater with HSB, with a nonsignificant trend (p = .073). Hypertensive subjects (n = 20) had similar and significant BP changes with HSB and silence when compared to normotensive subjects (n = 31). PANAS scores fell significantly with both interventions. CONCLUSIONS: BP and HR responses were enhanced by HSB exposure. HSB may be used as an adjunct to DR to produce physiological and psychological responses prior to DR. PMID- 23941102 TI - Social support may protect against development of posttraumatic stress disorder: findings from the Heart and Soul Study. AB - PURPOSE: No prospective studies have examined the association of poor social support and development of posttraumatic stress disorder (PTSD) in patients with chronic illness. This study addresses this knowledge gap. DESIGN: This prospective study examines the relationship of social support to the subsequent development of PTSD during a 5-year period. SETTING: San Francisco Veterans Affairs Medical Center. SUBJECTS: A total of 579 participants with cardiovascular disease did not have PTSD at baseline and returned for the 5-year follow-up examination. MEASURES: PTSD measured by Computerized Diagnostic Interview Schedule for DSM-IV. Social support measured by Interpersonal Support Evaluation List (ISEL). ANALYSIS: Unconditional ordered logistic regression analyses were performed to yield the odds ratio of developing PTSD for a one-standard-deviation change in ISEL score. RESULTS: Of 579 participants who did not have PTSD at baseline, approximately 6.4% (n = 37) developed PTSD. Higher baseline perceived social support was strongly protective against development of PTSD (OR = .60, p = .001). Results remained significant after adjustment for age, sex, race, income, and depression (OR = .69, p = .04). Of social support types examined, the "tangible" and "belonging" domains were most strongly associated with future PTSD status. CONCLUSION: Social support may impact development of PTSD. Interventions that optimize social support may be part of a PTSD prevention program designed to help individuals at risk of developing PTSD. PMID- 23941103 TI - Eat for life: a work site feasibility study of a novel mindfulness-based intuitive eating intervention. AB - PURPOSE: To examine the efficacy of a novel intervention for problematic eating behaviors and body dissatisfaction. DESIGN: Participants enrolled in the intervention or waitlist comparison group were assessed at pre and post 10 weeks. SETTING: Midwestern university. SUBJECTS: One hundred twenty-four female employees or partners/spouses. INTERVENTION: Eat for Life is a 10-week group intervention integrating mindfulness and intuitive eating skills. MEASURES: Self report questionnaires included the Intuitive Eating Scale, Body Appreciation Scale, Five-Facet Mindfulness Questionnaire, Questionnaire for Eating Disorder Diagnoses, and an author-constructed supplemental and demographic questionnaire. ANALYSIS: Analyses of covariance and ordinal regression measured group differences. Structural equation modeling examined mediation effects. Results . Significant differences between groups were observed for body appreciation (F1,121 = 40.17, p = .000, partial eta squared = .25), intuitive eating (F1,121 = 67.44, p = .000, partial eta squared = .36), and mindfulness (F1,121 = 30.50, p = .000, partial eta squared = .20), with mean scores significantly higher in the intervention group than waitlist comparison group after 10 weeks. The intervention group was 3.65 times more likely to be asymptomatic for disordered eating than the comparison group. Mindfulness served as a partial mediator. CONCLUSION: The study provides support for an intervention combining intuitive eating and mindfulness for treatment of problematic eating behaviors and body dissatisfaction, with limitations including self-selection and lack of active control group. PMID- 23941104 TI - Local concentration of fast-food outlets is associated with poor nutrition and obesity. AB - PURPOSE: We investigated the relationship of the local availability of fast-food restaurant locations with diet and obesity. DESIGN: We geocoded addresses of survey respondents and fast-food restaurant locations to assess the association between the local concentration of fast-food outlets, BMI, and fruit and vegetable consumption. SETTING: The survey was conducted in Genesee County, Michigan. SUBJECTS: There were 1345 individuals included in this analysis, and the response rate was 25%. MEASURES: The Speak to Your Health! Community Survey included fruit and vegetable consumption items from the Behavioral Risk Factor Surveillance System, height, weight, and demographics. We used ArcGIS to map fast food outlets and survey respondents. ANALYSIS: Stepwise linear regressions identified unique predictors of body mass index (BMI) and fruit and vegetable consumption. RESULTS: Survey respondents had 8 +/- 7 fast-food outlets within 2 miles of their home. Individuals living in close proximity to fast-food restaurants had higher BMIs t(1342) = 3.21, p < .001, and lower fruit and vegetable consumption, t(1342) = 2.67, p = .008. CONCLUSION: Individuals may be at greater risk for adverse consequences of poor nutrition because of the patterns in local food availability, which may constrain the success of nutrition promotion efforts. Efforts to decrease the local availability of unhealthy foods as well as programs to help consumers identify strategies for obtaining healthy meals at fast-food outlets may improve health outcomes. PMID- 23941105 TI - Psychosocial predictors of diet and physical activity in African-Americans: results from the Delta Body and Soul effectiveness trial, 2010-2011. AB - PURPOSE: To examine associations among psychosocial constructs of behavior change and postintervention changes in diet and physical activity (PA). DESIGN: Quasi experimental with cluster (church) treatment assignment. SETTING: Churches (n = 8) in a rural, southern region of the United States. SUBJECTS: A total of 403 African-American adults participating in the Delta Body and Soul study. INTERVENTION: Six-month diet and PA intervention consisting of monthly didactic educational sessions with specific emphasis on increasing consumption of fruits, vegetables, and whole grains, and decreasing consumption of added sugars. Self directed PA was promoted throughout the intervention. MEASURES: Validated surveys for all dietary, PA, and psychosocial measures. ANALYSIS: Secondary analysis using generalized linear mixed models to test for significant intervention effects on psychosocial constructs and for significant associations between changes in psychosocial constructs and changes in diet and PA outcomes after controlling for covariates. RESULTS: Intervention effects were apparent for several dietary psychosocial constructs (improvements ranging from .5 to 2.0 points), but only one PA construct (decisional balance for exercise). Changes in psychosocial constructs, including self-efficacy, social support, and decisional balance, were significant predictors of dietary outcome changes (model coefficients ranging from .03 to .42), but not PA changes. CONCLUSION: Understanding which psychosocial constructs predict improvements in dietary and PA behaviors helps inform theoretical mechanisms of action and identify social and behavioral processes to target in faith-based interventions. PMID- 23941106 TI - Associations between healthy lifestyle behaviors and academic performance in U.S. undergraduates: a secondary analysis of the American College Health Association's National College Health Assessment II. AB - PURPOSE: To examine associations between academic performance and moderate vigorous physical activity, strength training, fruit and vegetable intake, and sleep. DESIGN: Cross-sectional observational study. SETTING: Forty U.S. colleges and universities participating in the Fall 2008 National College Health Assessment-II (NCHA-II) (median response, 27%). SUBJECTS: A total of 16,095 undergraduate students (18-24 years; 70.3% female). MEASURES: Self-reported lifestyle variables from the NCHA-II questions were dichotomized as meeting or not meeting public health recommendations. Grade average ranged from 1.00 to 4.00 points. ANALYSIS: Linear regression, adjusting for sociodemographic and health related variables. RESULTS: The prevalence of meeting public health recommendations was as follows: moderate-vigorous physical activity, 41.9%; strength training, 32.4%; fruit and vegetable intake, 4.6%; and sleep, 23.6 %. Grade average was higher in students meeting moderate-vigorous physical activity, fruit and vegetable intake, and sleep recommendations (p <= .019). If moderate vigorous physical activity was met, grade average was higher by .03 points, .15 points higher when meeting fruit and vegetable intake recommendations, and .06 points higher for sleep. There was no significant change in grade average in those meeting strength-training recommendations. CONCLUSION: College students who adhere to public health recommendations for lifestyle behaviors have modestly higher grade averages after adjusting for sociodemographic and negative health behaviors. PMID- 23941107 TI - Lexical category influences in Persian children who stutter. AB - This article explores the effect that words from different lexical categories have on disfluency in 12 Persian children, ten boys and two girls, who stutter. They were aged 7 years 5 months to 10 years 6 months. Words from the participants' narrative and reading samples (sub-tests of the Reading and Dyslexia Test validated for Persian school-aged children) were categorized as content, function, or content-function, and stuttering-like disfluencies were coded in each speech sample. Content and content-function words were significantly more likely to show stuttering-like disfluencies than function words. The distribution of symptom types over content and content-function words was similar, and differed from the distribution seen in function words. The symptom type analysis also supported the view that whole-word repetitions should not be grouped with other stuttering-like disfluencies. PMID- 23941108 TI - Casuarinines A-J, lycodine-type alkaloids from Lycopodiastrum casuarinoides. AB - Ten new lycodine-type alkaloids, named casuarinines A-J (1-10), along with eight known analogues (11-18), were isolated from the whole plant of Lycopodiastrum casuarinoides . The new structures were established by spectroscopic methods and chemical transformations. Casuarinines A-D (1-4) and J (10) are common lycodine alkaloids possessing four connected six-membered rings, while tricyclic casuarinines E-H (5-8) are the piperidine ring cleavage products. In particular, casuarinine I (9) has an unprecedented five-membered tetrahydropyrrole ring instead of the piperidine ring. A plausible biosynthetic pathway to 9 is proposed. Among the compounds reported, casuarinine H (8) exhibited significant neuroprotective effect against hydrogen peroxide (H2O2)-induced neuronal cell damage in human neuroblastoma SH-SY5Y cells, while casuarinines C (3) and I (9) showed moderate inhibitory activity against acetylcholinesterase (AChE). PMID- 23941109 TI - Human BDH2, an anti-apoptosis factor, is a novel poor prognostic factor for de novo cytogenetically normal acute myeloid leukemia. AB - BACKGROUND: The relevance of recurrent molecular abnormalities in cytogenetically normal (CN) acute myeloid leukemia (AML) was recently acknowledged by the inclusion of molecular markers such as NPM1, FLT3, and CEBPA as a complement to cytogenetic information within both the World Health Organization and the European Leukemia Net classifications. Mitochondrial metabolism is different in cancer and normal cells. A novel cytosolic type 2-hydroxybutyrate dehydrogenase, BDH2, originally named DHRS6, plays a physiological role in the cytosolic utilization of ketone bodies, which can subsequently enter mitochondria and the tricarboxylic acid cycle. Moreover, BDH2 catalyzes the production of 2, 3-DHBA during enterobactin biosynthesis and participates in 24p3 (LCN2)-mediated iron transport and apoptosis. RESULTS: We observed that BDH2 expression is an independent poor prognostic factor for CN-AML, with an anti-apoptotic role. Patients with high BDH2 expression have relatively shorter overall survival (P = 0.007) and a low complete response rate (P = 0.032). BDH2-knockdown (BDH2-KD) in THP1 and HL60 cells increased the apoptosis rate under reactive oxygen species stimulation. Decrease inducible survivin, a member of the inhibitors of apoptosis family, but not members of the Bcl-2 family, induced apoptosis via a caspase-3 independent pathway upon BDH2-KD. CONCLUSIONS: BDH2 is a novel independent poor prognostic marker for CN-AML, with the role of anti-apoptosis, through surviving. PMID- 23941111 TI - Subunit variation to uncover properties of polyazine-bridged Ru(II), Pt(II) supramolecules with low lying charge separated states providing insight into the functioning as H2O reduction photocatalysts to produce H2. AB - Two new structurally diverse polyazine-bridged Ru(II),Pt(II) tetrametallic complexes, [{(Ph2phen)2Ru(dpp)}2Ru(dpp)PtCl2](PF6)6 (1a) and [{(Ph2phen)2Ru(dpp)}2Ru(dpq)PtCl2](PF6)6 (2a) (Ph2phen = 4,7-diphenyl-1,10 phenanthroline, dpp = 2,3-bis(2-pyridyl)pyrazine, dpq = 2,3-bis(2 pyridyl)quinoxaline), as well as their trimetallic precursors have been synthesized to provide a comparison for detailed analysis to elucidate component effects in the previously reported photocatalyst [{(phen)2Ru(dpp)}2Ru(dpq)PtCl2](PF6)6 (4a) (phen = 1,10-phenanthroline). Electrochemistry shows terminal Ru based highest occupied molecular orbitals (HOMOs) with remote BL' (BL' = bridging ligand coupling central Ru and cis-PtCl2 moiety) based lowest unoccupied molecular orbitals (LUMOs). Population of a lowest-lying charge separated ((3)CS) excited state with oxidized terminal Ru and reduced remote BL' via intramolecular electron transfer is predicted by electrochemical analysis and is observed through steady-state and time-resolved emission studies as well as emission excitation profiles which display unusual nonunity population of the lowest lying emissive Ru->dpp (3)MLCT (metal-to-ligand charge transfer) state. Each tetrametallic complex is an active photocatalyst for H2 production from H2O with 2a showing the highest activity (94 TON (turnover number) in 10 h, where TON = mol H2/mol catalyst). The nature of the bridging ligand coupling the trimetallic light absorber to the cis-PtCl2 moiety has a significant impact on the catalyst activity, correlated to the degree of population of the (3)CS excited state. The choice of terminal ligand affects visible light absorption and has a minor influence on photocatalytic H2 production from H2O. Evidence that an intact supramolecule functions as the photocatalyst includes a strong dependence of the photocatalysis on the identity of BL', an insensitivity to Hg(l), no detectable H2 production from the systems with the trimetallic synthons and cis-[PtCl2(DMSO)2] as well as spectroscopic analysis of the photocatalytic system. PMID- 23941110 TI - Addressing potentially inappropriate prescribing in older patients: development and pilot study of an intervention in primary care (the OPTI-SCRIPT study). AB - BACKGROUND: Potentially inappropriate prescribing (PIP) in older people is common in primary care and can result in increased morbidity, adverse drug events, hospitalizations and mortality. The prevalence of PIP in Ireland is estimated at 36% with an associated expenditure of over ?45 million in 2007. The aim of this paper is to describe the application of the Medical Research Council (MRC) framework to the development of an intervention to decrease PIP in Irish primary care. METHODS: The MRC framework for the design and evaluation of complex interventions guided the development of the study intervention. In the development stage, literature was reviewed and combined with information obtained from experts in the field using a consensus based methodology and patient cases to define the main components of the intervention. In the pilot stage, five GPs tested the proposed intervention. Qualitative interviews were conducted with the GPs to inform the development and implementation of the intervention for the main randomised controlled trial. RESULTS: The literature review identified PIP criteria for inclusion in the study and two initial intervention components - academic detailing and medicines review supported by therapeutic treatment algorithms. Through patient case studies and a focus group with a group of 8 GPs, these components were refined and a third component of the intervention identified - patient information leaflets. The intervention was tested in a pilot study. In total, eight medicine reviews were conducted across five GP practices. These reviews addressed ten instances of PIP, nine of which were addressed in the form of either a dose reduction or a discontinuation of a targeted medication. Qualitative interviews highlighted that GPs were receptive to the intervention but patient preference and time needed both to prepare for and conduct the medicines review, emerged as potential barriers. Findings from the pilot study allowed further refinement to produce the finalised intervention of academic detailing with a pharmacist, medicines review with web-based therapeutic treatment algorithms and tailored patient information leaflets. CONCLUSIONS: The MRC framework was used in the development of the OPTI-SCRIPT intervention to decrease the level of PIP in primary care in Ireland. Its application ensured that the intervention was developed using the best available evidence, was acceptable to GPs and feasible to deliver in the clinical setting. The effectiveness of this intervention is currently being tested in a pragmatic cluster randomised controlled trial. TRIAL REGISTRATION: Current controlled trials ISRCTN41694007. PMID- 23941112 TI - Bovine tuberculosis and brucellosis prevalence in cattle from selected milk cooperatives in Arsi zone, Oromia region, Ethiopia. AB - BACKGROUND: Bovine tuberculosis (BTB) and bovine brucellosis are two important milk-borne zoonoses that have been shown to be prevalent to various degrees in Ethiopian cattle. The study was carried out in four Woredas (districts) around Asella town, Arsi Zone between October 2011 and March 2012 and included 318 small holders in 13 dairy cooperatives that marketed the delivered milk. The aims of the study were i) to assess the prevalence of the two diseases in cattle in a cross-sectional study, ii) to assess potential risk factors of BTB and brucellosis to humans as well as the knowledge-attitude-practice (KAP) among these farmers towards these diseases. RESULTS: BTB testing using the comparative intradermal skin test (CIDT) was done on 584 milking cows, out of which 417 were serologically tested for brucellosis using the Rose Bengal Plate Test and reactors confirmed with an indirect ELISA test (PrioCHECK(r)). The individual animal prevalence was 0.3% (95% CI 0.1% to 1.3%) for BTB, 1.7% (95% CI 0.8% to 3.5%) for brucellosis and 8.9% (95% CI 6.8% to 11.5%) for MAC (Mycobacterium avium complex). Of the 13 milk cooperatives, two had at least one positive BTB reactor and five had animals positive for brucellosis. Cross-breeds accounted for 100% and 71.4% of the BTB and brucellosis reactors respectively. For both diseases, there were prevalence variations depending on Woreda. No animal was concomitant reactor for BTB and brucellosis. Raw milk was consumed by 55.4% of the respondents. 79.2% of the respondents reported touching the afterbirth with bare hands. The latter was fed to dogs in 83% of the households. One cow among the herds of the 130 interviewees had aborted in the last 12 months. Among the interviewees, 77% stated knowing tuberculosis in general but 42 out of the 130 respondents (32.3%) did not know that BTB was transmitted by livestock. Less than half (47.7%) of the respondents knew about brucellosis. CONCLUSIONS: Low prevalence of both diseases reflected the potential for the area to compete with the growing milk demand. The authors discussed the possible control strategies for the area. PMID- 23941113 TI - Thickness-controlled synthesis of ultrathin Au sheets and surface plasmonic property. AB - Thickness-controlled synthesis of nanosheets of nonlayered materials is of scientific significance yet greatly underdeveloped because of the lack of controllable means of inducing anisotropic growth of 2D structures. Here we report a novel 2D template-directed synthesis of ultrathin single-crystalline Au nanosheets with well-tuned thicknesses of several to tens of nanometers, large areas (>100 MUm(2)), and atomically flat surfaces. The 2D template is composed of hundred-nanometer-thick water layers sandwiched by lamellar bilayer membranes of a self-assembled nonionic surfactant, dodecylglyceryl itaconate, which appears as an iridescent solution as a result of Bragg reflection of visible light from the periodic lamellar planes. The large-area, ultrathin single-crystalline Au nanosheets enable the fabrication of plasmonic devices. For the first time, the property of surface plasmon polaritons on a patterned single-crystalline Au nanosheet was investigated, and a long propagation length approaching the theoretical expectation was found. PMID- 23941114 TI - A relationship between the aggregation rates of alpha-synuclein variants and the beta-sheet populations in their monomeric forms. AB - Intrinsically disordered proteins constitute a significant part of the human proteome and carry out a wide range of different functions, including in particular signaling and regulation. Several of these proteins are vulnerable to aggregation, and their aberrant assemblies have been associated with a variety of neurodegenerative and systemic diseases. It remains unclear, however, the extent to which the conformational properties of intrinsically disordered proteins in their monomeric states influence the aggregation behavior of these molecules. Here we report a relationship between aggregation rates and secondary structure populations in the soluble monomeric states of a series of mutational variants of alpha-synuclein. Overall, we found a correlation of over 90% between the changes in beta-sheet populations calculated from NMR chemical shift data and the changes in aggregation rates for eight human-to-mouse chimeric mutants. These results provide support to the idea of investigating therapeutic strategies based on the stabilization of the monomeric form of intrinsically disordered proteins through the alteration of their conformational properties. PMID- 23941116 TI - Asymmetrical/symmetrical D-pi-A/D-pi-D thiazole-containing aromatic heterocyclic fluorescent compounds having the same triphenylamino chromophores. AB - A family of linear asymmetrical D-pi-A and symmetrical D-pi-D types of thiazole based aromatic heterocyclic fluorescent compounds bearing various electron donating and electron-withdrawing tails (bromo, triphenylamino, pyridyl, thienyl and benzoic acid) have been designed and prepared successfully. Synthetic, structural, thermal, spectral and computational comparisons have been carried out for related compounds because of their adjustable electronic properties. It is interesting to mention that compound 2 can be prepared from 5-bromothiazole by one-pot Suzuki-Miyaura coupling and subsequent C-H activation reactions via a 5 TPA-substituted thiazole intermediate 1. X-ray single-crystal structures of six compounds indicate that they all crystallize in the triclinic P1 space group and the thiazole core exhibits different dihedral angles with its adjacent benzene ring of the triphenylamino group (3.6(3)-40.8(3) degrees ). The photophysical and electrochemical results demonstrate that compound 7 exhibits high electrochemical activity with a green fluorescence emission. Meanwhile, compounds 1, 2, and 6 show high luminescence quantum yields, and compound 8 exhibits excellent thermal stability (T(d(10)) = 503 degrees C). PMID- 23941117 TI - Skin temperature measured by infrared thermography after ultrasound-guided blockade of the sciatic nerve. AB - BACKGROUND: In the present study, we assessed the relationship between subgluteal sciatic nerve blocking and skin temperature by infrared thermography in the lower extremity. We hypothesized that blocking the sciatic nerve will lead to an increase in temperature, and that this will correlate with existing sensory block tests. METHODS: We studied 18 healthy individuals undergoing orthopaedic surgery of the foot under ultrasound-guided subgluteal blockade of the sciatic nerve with 30 ml ropivacaine 7.5 mg/ml. Skin temperature was measured on the toes, the dorsal and plantar side of the foot, the malleoli, and the lateral side of the lower leg, just before sciatic nerve blockade and at 10-min intervals thereafter. RESULTS: Baseline skin temperatures showed a significant distal-to-proximal gradient. After sciatic block, temperatures on the blocked side increased significantly in the toes and foot. When comparing pinprick to skin temperature in a receiver operating curve, there was an AUC of 85.9% (95% confidence interval = 83.7-88.2%, P < 0.001). The medial malleolus (not being innervated by the sciatic nerve) showed no significant difference to the lateral. CONCLUSIONS: After sciatic nerve block, temperatures of the foot increased significantly. There was a good correlation between pinprick testing and infrared temperature measurement. This makes infrared skin temperature measuring a good test in determining block success when sensory testing is impossible. PMID- 23941115 TI - Utilization of TREC and KREC quantification for the monitoring of early T- and B cell neogenesis in adult patients after allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: After hematopoietic stem cell transplantation (HSCT) T- and B-cell reconstitution from primary lymphoid organs are a prerequisite for an effective early lymphocyte reconstitution and a long-term survival for adult patients suffering from acute leukemia. Here, we asked whether quantification of T cell receptor excision circle, (TREC) and kappa-deleting recombination excision circle (KREC) before and within six month after allogeneic HSCT could be used to measure the thymic and bone marrow outputs in such patients. METHODS: We used a duplex real time PCR assay to quantify the absolute copy counts of TREC and KREC, and correlated the data with absolute cell counts of CD3+CD4+ T-cell and CD19+ B-cell subsets determined by flow cytometry, respectively. RESULTS: By comparing two recently proposed naive T cell subsets, CD31+ naive and CD31- naive T cells, we found a better correlation for the CD31+ subset with TREC level post alloHSCT, in line with the assumption that it contained T cells recently derived from the thymus, indicating that TREC levels reflected real thymic de novo production. Transitional as well as naive B cells highly correlated with KREC levels, which suggested an association of KREC levels with ongoing bone marrow B cell output. CD45RO+ memory T cells and CD27+ memory B cells were significantly less correlated with TREC and KREC recovery, respectively. CONCLUSION: We conclude that simultaneous TREC/ KREC quantification is as a suitable and practicable method to monitor thymic and bone marrow output post alloHSCT in adult patients diagnosed with acute leukemia. PMID- 23941118 TI - Patients' preferences when comparing analogue implant impressions using a polyether impression material versus digital impressions (Intraoral Scan) of dental implants. AB - OBJECTIVES: The primary objective of this clinical study was to assess the patients' perception of the difference between an analogue impression approach on the one hand and an intra-oral scan (IO scan) on the other when restoring implants in the non-aesthetic zone. A second objective was to analyse the difference in time needed to perform these two procedures. MATERIALS AND METHODS: Thirty consecutive patients who had received 41 implants (Straumann tissue level) in the non-aesthetic zone in an implant-based referral practice setting in the Netherlands. As they were to receive crown and or bridge work on the implants, in one session, the final impressions were taken with both an analogue technique and with an intraoral scan. Patients were also asked if, directly after the treatment was carried out, they would be prepared to fill out a questionnaire on their perception of both techniques. The time involved following these two procedures was also recorded. RESULTS: The preparatory activities of the treatment, the taste of the impression material and the overall preference of the patients were significantly in favour of the IO scan. The bite registration, the scan head and gag reflex positively tended to the IO scan, but none of these effects were significant. The overall time involved with the IO scan was more negatively perceived than the analogue impression. Overall less time was involved when following the analogue impression technique than with the IO scan. CONCLUSIONS: The overall preference of the patients in our sample is significantly in favour of the approach using the IO scan. This preference relates mainly to the differences between the compared approaches with respect to taste effects and their preparatory activities. The patients did perceive the duration of IO scan more negatively than the analogue impression approach. PMID- 23941119 TI - Use of Admission Criteria to Predict Performance of Students in an Entry-Level Master's Program on Fieldwork Placements and in Academic Courses. AB - The relationships among clinical outcomes, academic success, and predictors used to screen applicants for entrance into a Master in Occupational Therapy Program (MOT) were examined. The dependent variables were grade point average in occupational therapy courses (OT-GPA), client therapy outcomes at the clinic, and ratings of MOT students by Level II Fieldwork supervisors. Predictor variables included undergraduate GPA, scores on the Graduate Record Examination (GRE), and an essay. Both undergraduate GPA and scores on the GRE were found to predict OT GPA. The analytical section of the GRE was also positively correlated with fieldwork supervisors' ratings of students. PMID- 23941120 TI - Clinical reasoning and reflective practice: implications of fieldwork activities. AB - Objectives. Theories and research suggest that learning clinical reasoning skills requires students to be reflective in their practice. To explain this proposition, five research questions were developed to examine the effect of: (a) the fieldwork experience on clinical reasoning skills, (b) degree of participation in different clinical reasoning activities on clinical reasoning skills, and (c) the total number of clinical reasoning activities in which students participated related to clinical reasoning. Method. Data (n = 70) were collected using a researcher-developed case analysis test, the Adaptive Style Inventory, and a questionnaire. Paired t tests, ANCOVA, and multiple regressions were used to analyze the data from the research questions. Results. Fieldwork does improve clinical reasoning skills (large effect size). Participation in activities thought to develop clinical reasoning skills was mixed. Conclusion. The results support the improvement of fieldwork as a mode of developing clinical reasoning skills in occupational therapy students. PMID- 23941121 TI - Application of motor learning principles with stroke survivors. AB - The purpose of this study was to determine the relationship between type of task and type of environment on retention and transfer of motor skills when applied to stroke survivors, as measured by time to complete the task and the number of errors. It was expected that those performing a purposeful task in a familiar environment (home) would demonstrate greater retention and transfer of the motor task; however, data was inconclusive. PMID- 23941122 TI - The effect of leisure activity on depression in the elderly: implications for the field of occupational therapy. AB - The purpose of this annotated review of literature was to examine the effect of leisure activity on depression in the elderly. Despite some limitations, the literature, in general, suggests an inverse correlation between leisure activity and depression in the elderly. Individuals who engaged in leisure activity, whether it was physical exercise or more sedentary activity such as card games, were less depressed than individuals who did not engage in leisure activity. More scientific research is needed, however, to confirm this effect. Further studies could serve to define leisure activity as a tool for treatment in the field of occupational therapy. PMID- 23941123 TI - Follow-up: bridging the gap between discharge and home. AB - This article reports the results of a survey conducted in order to find out how occupational therapists aid their clients in transition back into the community. A brief description of the current follow-up practices of occupational therapists in the state of Michigan is provided and a discussion regarding the value of follow-up as perceived by these therapists is described. Occupational therapists were asked to identify which discipline they felt would best deliver follow-up services in their facilities. The results of this study showed that 17% of occupational therapists in Michigan followed-up with all of their clients. Results showed that among the OT practitioners who follow-up their clients post discharge, only 38% did so since follow-up and continuation of care was standard in their work sites. However, all therapists surveyed valued follow-up as a critical final step to client care. These therapists expressed the need for follow-up especially in certain percentage of their clients who are in critical need for follow-up in order to monitor their continued functional independence. Some solutions to the lack of follow-up service delivery are offered. PMID- 23941124 TI - The application of constructivism to concepts of occupation using a group process approach. AB - Students in an undergraduate occupational therapy program used the concepts of constructivism and the group process to select and decoupage chairs depicting varieties of occupations for one of four life span segments: infancy, adolescence, young adulthood and older adulthood. Students were not provided a set of specific guidelines to follow during the process but constructed their learning according to their creativity and hands-on application of classroom concepts. Student feedback indicated that, while they found the experience challenging, they enjoyed the process and learned a great deal not only about the group process but also about how to approach and solve unfamiliar problems. Results suggest the similarity between principles underlying good education and those underlying occupational performance. Implications for classroom instruction are discussed. PMID- 23941125 TI - Moderate alcohol intake is related to increased heart rate variability in young adults: implications for health and well-being. AB - Epidemiological literature indicates that the relationship between alcohol consumption and health outcomes reflects a J-shaped curve such that moderate alcohol consumption confers a protective effect in comparison to abstinence, while heavy consumption is associated with poorer health. While heart rate variability (HRV) may underpin the relationship between drinking and poor health in heavy drinkers, it is unclear whether HRV is increased in moderate, habitual drinkers relative to nonhabitual drinkers. HRV and drinking habits were assessed in 47 volunteers. Results supported hypotheses suggesting that moderate, habitual drinking increases HRV. Although not supported by a significant interaction between drinking group and sex, planned follow-up analysis also revealed that these findings may be specific to males. Regardless, results highlight HRV as a candidate mechanism for the findings reported in the epidemiological literature. PMID- 23941126 TI - Diabetes, physical activity participation and exercise capacity in patients with schizophrenia. AB - AIM: The aim of this study was to determine if in schizophrenia patients the presence of diabetes is associated with lower physical activity participation and lower exercise capacity compared to patients with pre-diabetes and to patients without (pre-) diabetes. METHODS: Schizophrenia patients without (pre-)diabetes (n = 86) were compared with pre-diabetic (n = 10) and diabetic patients (n = 10). Patients were assessed on physical activity participation using the Baecke physical activity questionnaire and on exercise capacity using a 6-min walk test (6MWT). RESULTS: The three groups were similar in age, sex, mean antipsychotic medication dose, negative and depressive symptoms and smoking behavior. Distance achieved on the 6MWT, however, was approximately 15% shorter (P < 0.05) in patients withdiabetes than in patients without (pre-)diabetes (500.3 +/- 76.9 m vs 590.7 +/- 101.8 m). Patients with diabetes were also significantly less physically active (P < 0.05). No differences between diabetic and pre-diabetic patients were found. Pre-diabetic patients had a higher body mass index (BMI) than non-diabetic patients (30.0 +/- 7.3 vs 24.3 +/- 4.3, P < 0.05). An interaction effect with BMI for differences in Baecke (F = 29.9, P < 0.001) and 6MWT (F = 13.0, P < 0.001) scores was seen between diabetic and non-diabetic patients on univariate ANCOVA. CONCLUSION: The additive burden of diabetes might place patients with schizophrenia at an even greater risk for functional limitations in daily life. PMID- 23941127 TI - Evaluation of the need for routine clinical testing of PALB2 c.1592delT mutation in BRCA negative Northern Finnish breast cancer families. AB - BACKGROUND: Testing for mutations in the BRCA1 and BRCA2 genes among high-risk breast cancer patients has become a routine practice among clinical geneticists. Unfortunately, however, the genetic background of a majority of the cases coming to the clinics remains currently unexplained, making genetic counseling rather challenging. In recent years it has become evident world-wide that also women carrying a heterozygous germline mutation in PALB2 are at significantly increased risk of getting breast cancer. We have previously studied the clinical as well as biological impact of the PALB2 c.1592delT founder mutation occurring in about 1% of Finnish breast cancer patients unselected for their family history of disease, and our results demonstrated a 40% increased breast cancer risk by age 70 for female mutation carriers. Thus, this relatively common mutation in PALB2 is associated with a high risk of developing breast cancer. The aim of the current study was to analyze whether female index individuals of breast cancer families who had tested negative for germline mutations in BRCA1/BRCA2 as part of genetic counseling services should be offered mutation testing for PALB2 c.1592delT. METHODS: The study cohort consisted of altogether 223 individuals who had contacted the Department of Clinical Genetics at the Oulu University Hospital in Finland between the years 1997 and 2011 for counseling on hereditary breast and/or ovarian cancer risk. 101 of them met our inclusion criteria. Of these, 10 persons were now deceased, but 6 of them had participated in one of our previous studies on PALB2. Seventy (77%) of the remaining 91 persons responded positively to our study invitation. Chart review of updated pedigree data led to the exclusion of 14 further individuals not meeting the selection criteria. RESULT: Of the 56 alive affected female individuals screened for PALB2 c.1592delT, altogether two (3.6%) tested positive for this mutation. In addition, of the previously tested but now deceased 6 persons eligible for the current study, one more mutation carrier was observed. Therefore, overall 4.8% (3/62) of the tested individuals belonging to the Northern Finnish 1997-2011 study cohort turned out to be carriers of the PALB2 c.1592delT allele. CONCLUSIONS: Given the potential benefits versus harms of this testing, the result of our study suggest that PALB2 c.1592delT should be a routine part of the genetic counseling protocol for Finnish high-risk breast cancer cases tested negative for mutations in BRCA1/BRCA2. PMID- 23941128 TI - Higher risk of kidney graft failure in the presence of anti-angiotensin II type-1 receptor antibodies. AB - Reports have associated non-HLA antibodies, specifically those against angiotensin II type-1 receptor (AT1R), with antibody-mediated kidney graft rejection. However, association of anti-AT1R with graft failure had not been demonstrated. We tested anti-AT1R and donor-specific HLA antibodies (DSA) in pre- and posttransplant sera from 351 consecutive kidney recipients: 134 with biopsy proven rejection and/or lesions (abnormal biopsy group [ABG]) and 217 control group (CG) patients. The ABG's rate of anti-AT1R was significantly higher than the CG's (18% vs. 6%, p < 0.001). Moreover, 79% of ABG patients with anti-AT1R lost their grafts (vs. 0%, CG), anti-AT1R levels in 58% of those failed grafts increasing posttransplant. With anti-AT1R detectable before DSA, time to graft failure was 31 months-but 63 months with DSA detectable before anti-AT1R. Patients with both anti-AT1R and DSA had lower graft survival than those with DSA alone (log-rank p = 0.007). Multivariate analysis showed that de novo anti-AT1R was an independent predictor of graft failure in the ABG, alone (HR: 6.6), and in the entire population (HR: 5.4). In conclusion, this study found significant association of anti-AT1R with graft failure. Further study is needed to establish causality between anti-AT1R and graft failure and, thus, the importance of routine anti-AT1R monitoring and therapeutic targeting. PMID- 23941129 TI - Does subjective evaluation of the frequency of salty food intake predict the risk of incident hypertension? A 4-year follow-up study in a middle-aged population. AB - BACKGROUND: Excess salt intake increases blood pressure (BP). Identifying individuals with excess salt intake is, therefore, important for the prevention of hypertension. AIM: To examine the predictive value of subjective evaluation of salty foods intake for the risk of incident hypertension in a middle-aged population. METHODS: A total of 970 non-hypertensive workers (mean age, 44 +/- 6 years) was followed for a maximum period of 4 years, and their BP was measured annually. At baseline, all participants were asked about their subjective frequency of salty foods intake (seldom, sometimes or always), and they were divided into three groups according to their answers. Hypertension was defined as systolic/diastolic BP >= 140/90 mmHg or use of antihypertensive medications. RESULTS: There were no significant differences in the 4-year cumulative incident rate of hypertension among the 'seldom', 'sometimes' and 'always' groups (15.8%, 14.3% and 10.3%, respectively, log-rank test P = 0.44). In a multivariate Cox proportional hazards model, age, body mass index and the baseline BP category were independent predictors for developing hypertension, whereas the frequency of salty foods intake was not a predictor (adjusted hazard ratio (95% confidence interval), 0.99 (0.64-1.54) in the 'sometimes' group and 0.64 (0.33-1.28) in the 'always' group as compared with the 'seldom' group). CONCLUSION: The subjective evaluation of salty foods intake did not predict the 4-year risk of incident hypertension in this study population. Further investigations with a longer follow-up period are needed to clarify whether the present insignificant results are maintained for more than 4 years. PMID- 23941130 TI - Risk, resilience, and the rorschach: a longitudinal study of children who experienced sexual abuse. AB - Experiencing sexual abuse increases the risk that children will report or otherwise demonstrate problems with emotion, behavior, and health. This longitudinal study of 44 children who experienced sexual abuse examined whether information processing as assessed via the Rorschach Inkblot Test was associated with child-reported depression symptoms assessed via the Children's Depression Inventory (Kovacs, 1992) concurrently and an average of 15 months later. Children whose Rorschach protocols were relatively free of scores suggesting intense distress, complex processing, and sexual content were more likely to experience remission of depression symptoms at follow-up. Findings provide incremental validity for certain Rorschach indexes to inform prognosis regarding depression symptoms and perhaps their treatment. PMID- 23941131 TI - The goal circuit model: a hierarchical multi-route model of the acquisition and control of routine sequential action in humans. AB - Human control of action in routine situations involves a flexible interplay between (a) task-dependent serial ordering constraints; (b) top-down, or intentional, control processes; and (c) bottom-up, or environmentally triggered, affordances. In addition, the interaction between these influences is modulated by learning mechanisms that, over time, appear to reduce the need for top-down control processes while still allowing those processes to intervene at any point if necessary or if desired. We present a model of the acquisition and control of goal-directed action that goes beyond existing models by operationalizing an interface between two putative systems-a routine and a non-routine system-thereby demonstrating how explicitly represented goals can interact with the emergent task representations that develop through learning in the routine system. The gradual emergence of task representations offers an explanation for the transfer of control with experience from the non-routine goal-based system to the routine system. At the same time it allows action selection to be sensitive both to environmental triggers and to biasing from multiple levels within the goal system. PMID- 23941133 TI - Statins in patients with chronic kidney disease - an attempt at recommendations. PMID- 23941134 TI - Acquisition of a simple motor response as influenced by the presence or absence of action visual feedback. AB - Two experiments were performed to evaluate the learning properties of action visual feedback in comparison to standard terminal feedback, in Exp. 1, 144 Ss practiced for 0, 4, or 12 trials with action feedback on a simple motor task and were then transferred to terminal feedback. Amount of transfer was a negatively accelerated growth function of number of trials devoted to action feedback training. In Exp. 2, 122 Ss were trained under one of four conditions of action or terminal feedback and were then tested without information feedback (IF). No group showed a significant deterioration in accuracy during the no-IF test period. In addition, action IF + 1 responses during training compared favorably with the corresponding responses of a standard terminal IF condition. Previously reported failures of action IF to benefit learning are discussed, with emphasis directed toward the need for more analytic considerations of task intrinsic sources of IF. PMID- 23941132 TI - Carcinoembryonic antigen (CEA)-related cell adhesion molecules are co-expressed in the human lung and their expression can be modulated in bronchial epithelial cells by non-typable Haemophilus influenzae, Moraxella catarrhalis, TLR3, and type I and II interferons. AB - BACKGROUND: The carcinoembryonic antigen (CEA)-related cell adhesion molecules CEACAM1 (BGP, CD66a), CEACAM5 (CEA, CD66e) and CEACAM6 (NCA, CD66c) are expressed in human lung. They play a role in innate and adaptive immunity and are targets for various bacterial and viral adhesins. Two pathogens that colonize the normally sterile lower respiratory tract in patients with chronic obstructive pulmonary disease (COPD) are non-typable Haemophilus influenzae (NTHI) and Moraxella catarrhalis. Both pathogens bind to CEACAMs and elicit a variety of cellular reactions, including bacterial internalization, cell adhesion and apoptosis. METHODS: To analyze the (co-) expression of CEACAM1, CEACAM5 and CEACAM6 in different lung tissues with respect to COPD, smoking status and granulocyte infiltration, immunohistochemically stained paraffin sections of 19 donors were studied. To address short-term effects of cigarette smoke and acute inflammation, transcriptional regulation of CEACAM5, CEACAM6 and different CEACAM1 isoforms by cigarette smoke extract, interferons, Toll-like receptor agonists, and bacteria was tested in normal human bronchial epithelial (NHBE) cells by quantitative PCR. Corresponding CEACAM protein levels were determined by flow cytometry. RESULTS: Immunohistochemical analysis of lung sections showed the most frequent and intense staining for CEACAM1, CEACAM5 and CEACAM6 in bronchial and alveolar epithelium, but revealed no significant differences in connection with COPD, smoking status and granulocyte infiltration. In NHBE cells, mRNA expression of CEACAM1 isoforms CEACAM1-4L, CEACAM1-4S, CEACAM1-3L and CEACAM1-3S were up-regulated by interferons alpha, beta and gamma, as well as the TLR3 agonist polyinosinic:polycytidylic acid (poly I:C). Interferon-gamma also increased CEACAM5 expression. These results were confirmed on protein level by FACS analysis. Importantly, also NTHI and M. catarrhalis increased CEACAM1 mRNA levels. This effect was independent of the ability to bind to CEACAM1. The expression of CEACAM6 was not affected by any treatment or bacterial infection. CONCLUSIONS: While we did not find a direct correlation between CEACAM1 expression and COPD, the COPD-associated bacteria NTHi and M. catarrhalis were able to increase the expression of their own receptor on host cells. Further, the data suggest a role for CEACAM1 and CEACAM5 in the phenomenon of increased host susceptibility to bacterial infection upon viral challenge in the human respiratory tract. PMID- 23941135 TI - Some physiological concomitants of pursuit rotor performance and reminiscence. AB - A frustration theory of pursuit rotor performance and reminiscence has previously been presented (Costello, 1967; Costello & Discipio, 1967). The theory was reformulated in terms of arousal theory and the following hypotheses were tested: (1) an inverted "U" relationship exists between level of arousal and performance level; (2) reminiscence results when S during the rest period moves closer to his optimum level of arousal; (3) massed practice produces a higher level of arousal than spaced practice; (4) experimental conditions producing a high drive state will also increase his arousal level. Findings in line with these hypotheses were found for EMG measures but not for GSR and pulse rate. In view of what appears to be the task-specific nature of the physiological results it was concluded that there was no particular advantage in reformulating the frustration theory in terms of arousal theory. PMID- 23941136 TI - Reacquisition and transfer of motor skills with sensory feedback reduction. AB - Reacquisition and transfer of Morse key tapping and finger circling under total peripheral feedback reduction were investigated. 23 medical students were tested. Kinesthetic and tactile feedback were reduced by compression block. The results showed that tapping performance was reacquired to 56.4% of normal and circling to 26.4% by the tenth preshift trials. Strong positive transfer was found for both tasks in Groups 1 and 2. This positive transfer indicated the existence of central, general programming operations. With trials alternating between the two tasks (Group 3) reacquisition curves followed the preshift trials for tapping and circling, showing absence of adverse emotional influence of the block technique. Marked individual differences in performance in the absence of peripheral information were observed, grouping Ss into two distinct categories. PMID- 23941137 TI - The influence of competition on the efficiency of an isometric muscle contraction. AB - 36 male Ss from collegiate intramural athletic teams were asked to maintain 50% of their maximum voluntary contraction on an iso-metric handle as long as possible. Ss were divided into 2 groups. One group performed individually while the other group, in teams of 3 Ss each, competed for a team prize. During the session, the active muscle was continuously monitored by EMG. The introduction of the motivational factors of competition and team presence did not increase the mean endurance time, but muscle EMG activity was significantly increased when additional motivational factors were introduced. It was concluded that team presence and competition are better described as stress factors which reduce the efficiency of the muscles. The reduction of efficiency is explained both in terms of increased activity of the antagonistic muscles and an increase in S's general arousal level. PMID- 23941138 TI - Response speed and accuracy during anticipatory stress. AB - Response speed and accuracy of 48 general aviation pilots were determined under condition of anticipatory physical threat stress (APTS). Variables included unpleasantness of the event (electrical shock), proximity of the event, and relationship of Ss' performance to the occurrence of the event. The data support inclusion of these variables in Wherry's model of APTS. Ss who believed they could avoid the shock by an adequate performance were able to maintain or improve that performance while the performance of Ss who perceived the shock as inevitable was deteriorating. Two possible modifications of the APTS model were discussed: (1) weighting APTS determiners according to their effectiveness in generating anticipatory stress, (2) recognizing the interaction of the APTS variables with S's personality structure. PMID- 23941139 TI - Strength recovery patterns following isometric and isotonic exercise. AB - 31 male Ss performed 2 bouts of hand-gripping exercise on a hand ergograph. The first exercise consisted of isotonic contractions performed for 3 min. at the rate of 30/min. The second bout was an isometric contraction held maximally until strength was depressed to the level established in the isotonic exercise. Recovery in both conditions was followed for 10 min., during which maximal strength tests were performed every 60 sec. The only significant difference observed during recovery was at the end of the first min. at which time the strength level following isotonic exercise was higher than that after the isometric bout Mathematical differences were found in the recovery curve constants after the first min, the recovery rate being approximately 35% faster following isometric exercise. PMID- 23941141 TI - Phosphinodi(benzylsilane) PhP{(o-C6H4CH2)SiMe2H}2: a versatile "PSi2Hx" pincer type ligand at ruthenium. AB - The synthesis of the new phosphinodi(benzylsilane) compound PhP{(o C6H4CH2)SiMe2H}2 (1) is achieved in a one-pot reaction from the corresponding phenylbis(o-tolylphosphine). Compound 1 acts as a pincer-type ligand capable of adopting different coordination modes at Ru through different extents of Si-H bond activation as demonstrated by a combination of X-ray diffraction analysis, density functional theory calculations, and multinuclear NMR spectroscopy. Reaction of 1 with RuH2(H2)2(PCy3)2 (2) yields quantitatively [RuH2{[eta(2) (HSiMe2)-CH2-o-C6H4]2PPh}(PCy3)] (3), a complex stabilized by two rare high order epsilon-agostic Si-H bonds and involved in terminal hydride/eta(2)-Si-H exchange processes. A small free energy of reaction (DeltarG298 = +16.9 kJ mol(-1)) was computed for dihydrogen loss from 3 with concomitant formation of the 16-electron species [RuH{[eta(2)-(HSiMe2)-CH2-o-C6H4]PPh[CH2-o-C6H4SiMe2]}(PCy3)] (4). Complex 4 features an unprecedented (29)Si NMR decoalescence process. The dehydrogenation process is fully reversible under standard conditions (1 bar, 298 K). PMID- 23941140 TI - Cancer diagnosed by emergency admission in England: an observational study using the general practice research database. AB - BACKGROUND: Patients diagnosed with cancer by the emergency route often have more advanced diseases and poorer outcomes. Rates of cancer diagnosed through unplanned admissions vary within and between countries, suggesting potential inconsistencies in the quality of care. To reduce diagnoses by this route and improve patient outcomes, high risk patient groups must be identified. This cross sectional observational study determined the incidence of first-ever diagnoses of cancer by emergency (unplanned) admission and identified patient-level risk factors for these diagnoses in England. METHODS: Data for 74,763 randomly selected patients at 457 general practices between 1999 and 2008 were obtained from the General Practice Research Database (GPRD), including integrated Hospital Episode Statistics (HES) data and Office for National Statistics (ONS) mortality data. The proportion of first-ever diagnoses by emergency admission out of all recorded first cancer diagnoses by any route was analysed by patient characteristics. RESULTS: Diagnosis by emergency admission was recorded in 13.9% of patients diagnosed with cancer for the first time (n = 817/5870). The incidence of first cases by the emergency route was 2.51 patients per 10,000 person years. In adjusted regression analyses, patients of older age (p < 0.0001), living in the most deprived areas (RR 1.93, 95% CI 1.51 to 2.47; p < 0.0001) or who had a total Charlson score of 1 compared to 0 (RR 1.34, 95% CI 1.06 to 1.69; p = 0.014) were most at risk of diagnosis by emergency admission. Patients with more prior (all-cause) emergency admissions were less at risk of subsequent diagnosis by the emergency route (RR 0.31 per prior emergency admission, 95% CI 0.20 to 0.46; p < 0.0001). CONCLUSIONS: A much lower incidence of first-ever cancer diagnoses by emergency admission was found compared with previous studies. Identified high risk groups may benefit from interventions to reduce delayed diagnosis. Further studies should include screening and cancer staging data to improve understanding of delayed or untimely diagnosis and patient care pathways. PMID- 23941142 TI - Evaluation of eating and rumination behaviour in cows using a noseband pressure sensor. AB - BACKGROUND: An automated technique for recording eating and rumination behaviour was evaluated in ten lactating Brown Swiss cows by comparing data obtained from a pressure sensor with data obtained via direct observation over a 24-hour period. The recording device involved a pressure sensor integrated in the noseband of a halter. The analysed variables included number and duration of individual rumination, eating and resting phases, total daily length of these phases and number of cuds chewed per day. RESULTS: Eating and rumination phases were readily differentiated based on characteristic pressure profiles. Chewing movements during rumination were regular and generated regular waveforms with uniform amplitudes, whereas eating generated irregular waveforms with variable amplitudes. There was complete or almost complete agreement and no significant differences between data obtained via direct observation and pressure sensor technique. Both methods yielded an average of 16 daily eating phases with a mean duration of 28.3 minutes. Total time spent eating was 445.0 minutes for direct observation and 445.4 minutes for the pressure sensor technique. Both techniques recorded an average of 13.3 rumination phases with a mean duration of 30.3 (direct observation) and of 30.2 (pressure sensor) minutes. Total time spent ruminating per day, number of cuds per day and chewing cycles per cud were 389.3 and 388.3 minutes, 410.1 and 410.0 and 60.0 and 60.3 for direct observation and pressure sensor technique, respectively. There was a significant difference between the two methods with respect to mean number of chewing cycles per day (24'669, direct observation vs. 24'751, pressure sensor, P < 0.05, paired t test). There were strong correlations between the two recording methods with correlation coefficients ranging from 0.98 to 1.00. CONCLUSIONS: The results confirmed that measurements of eating and rumination variables obtained via the pressure sensor technique are in excellent agreement with data obtained via direct observation. PMID- 23941143 TI - Exercise in children with joint hypermobility syndrome and knee pain: a randomised controlled trial comparing exercise into hypermobile versus neutral knee extension. AB - BACKGROUND: Knee pain in children with Joint Hypermobility Syndrome (JHS) is traditionally managed with exercise, however the supporting evidence for this is scarce. No trial has previously examined whether exercising to neutral or into the hypermobile range affects outcomes. This study aimed to (i) determine if a physiotherapist-prescribed exercise programme focused on knee joint strength and control is effective in reducing knee pain in children with JHS compared to no treatment, and (ii) whether the range in which these exercises are performed affects outcomes. METHODS: A prospective, parallel-group, randomised controlled trial conducted in a tertiary hospital in Sydney, Australia compared an 8 week exercise programme performed into either the full hypermobile range or only to neutral knee extension, following a minimum 2 week baseline period without treatment. Randomisation was computer-generated, with allocation concealed by sequentially numbered opaque sealed envelopes. Knee pain was the primary outcome. Quality of life, thigh muscle strength, and function were also measured at (i) initial assessment, (ii) following the baseline period and (iii) post treatment. Assessors were blinded to the participants' treatment allocation and participants blinded to the difference in the treatments. RESULTS: Children with JHS and knee pain (n=26) aged 7-16 years were randomly assigned to the hypermobile (n=12) or neutral (n=14) treatment group. Significant improvements in child-reported maximal knee pain were found following treatment, regardless of group allocation with a mean 14.5 mm reduction on the visual analogue scale (95% CI 5.2 - 23.8 mm, p=0.003). Significant differences between treatment groups were noted for parent reported overall psychosocial health (p=0.009), specifically self-esteem (p=0.034), mental health (p=0.001) and behaviour (p=0.019), in favour of exercising into the hypermobile range (n=11) compared to neutral only (n=14). Conversely, parent-reported overall physical health significantly favoured exercising only to neutral (p=0.037). No other differences were found between groups and no adverse events occurred. CONCLUSIONS: Parents perceive improved child psychosocial health when children exercise into the hypermobile range, while exercising to neutral only is perceived to favour the child's physical health. A physiotherapist prescribed, supervised, individualised and progressed exercise programme effectively reduces knee pain in children with JHS. TRIAL REGISTRATION: Australia & New Zealand Clinical Trials Registry; ACTRN12606000109505. PMID- 23941144 TI - Targeted disruption of transcriptional regulators in Chaetomium globosum activates biosynthetic pathways and reveals transcriptional regulator-like behavior of aureonitol. AB - Postgenomic analysis revealed that many microorganisms carry numerous secondary metabolite biosynthetic genes on their genome. However, activities of those putative genes are not clearly reflected in the metabolic profile of the microorganisms, especially in fungi. A recent genome mining effort is promising in discovering new natural products. However, many fungi and other organisms are not amenable to molecular genetics manipulations, making the study difficult. Here we report successful engineering of Chaetomium globosum, a known producer of various valuable natural products, that allows its genetic manipulation via targeted homologous recombination. This strain permitted us to abolish transcriptional regulators associated with epigenetic silencing of secondary metabolite biosynthetic pathways, leading to the identification of the products generated by different gene clusters and isolation of novel secondary metabolites. We were able to identify six gene clusters that are responsible for the biosynthesis of 11 natural products previously known to be produced by C. globosum, including one cytochalasan and six azaphilone-type compounds. In addition, we isolated two new compounds, mollipilin A and B, that were only recently identified in a related Chaetomium species. Furthermore, our investigation into the mechanism of biosynthesis of those natural products in C. globosum also led to the discovery of a secondary metabolite, aureonitol, that acts like a transcriptional regulator for the biosynthesis of other secondary metabolites. Similar approaches should facilitate exploration of the untapped potential of fungal biosynthetic capability and identification of various unique biological functions that those secondary metabolites possess. PMID- 23941145 TI - Association between intramuscular fat in the arm following arm training and INSIG2. AB - Insulin-induced gene 2 (INSIG2) single-nucleotide polymorphism (SNP rs7566605) is linked to lipid metabolism, and this study assessed its potential influence on fat in the upper arm following arm training. Twenty healthy sedentary volunteers (22.0 +/- 1.1 years, body mass index 25.4 +/- 4.0 kg/m(2) ; mean +/- standard deviation) carried out a 12-week two-arm elbow extensor training (10 maximal extensions with 1 min recovery between bouts) five times per day, five times per week. For 17 volunteers, upper arm muscle and adipose tissue [subcutaneous (SCAT) and intramuscular (IMAT)] volumes were evaluated by magnetic resonance imaging before, immediately after, and 12 months after training and variables were related to the subjects' INSIG2 SNP rs7566605 genotype. Muscle volume and SCAT for the upper arm, as the decrease in IMAT during training were not related to INSIG2 SNP rs7566605: GG: %IMAT 1.0 +/- 0.9%; GC/CC: %IMAT 0.6 +/- 0.5% (P > 0.05). However, in the year following the training, accumulation of upper arm IMAT was twice as large in participants homozygous for the G allele (GG: Delta%IMAT +2.5 +/- 0.8%; GC/CC: Delta%IMAT +1.1 +/- 0.7%; P < 0.01). This study suggests that the G allele in the INSIG2 SNP rs7566605 is more relevant for changes in IMAT following training than for the amount of subcutaneous fat. PMID- 23941146 TI - Test-retest reliability of a student self-assessment of professional behaviors. AB - The test-retest reliability of the University of Indianapolis School of Occupational Therapy Student Self-Assessment for Professional Behaviors was investigated. Twenty-seven first year and 31 second year students participated in the study. Results indicated that 31 (83.78%) of 37 academic questions answered by first year students were significant for test-retest reliability and 6 (16.22%) of 37 questions were not significant at alpha level 0.05. Of the 74 combined academic and clinical questions answered by second year students, 56 (75.68%) were significant for test-rest reliability and 18 (24.32%) were not significant at alpha level 0.05. To further examine results, 5 second year students participated in a focus group. Focus group results revealed themes regarding tool impressions, individual differences, and question display. Findings emphasized areas for revision to enhance test-retest reliability of the self-assessment tool. PMID- 23941147 TI - The good beginnings clinic: an interdisciplinary collaboration. AB - The purpose of this paper is to present the development, implementation and outcomes of an interdisciplinary clinic that models "best practices" in pediatric occupational therapy and speech language pathology. The collaborative process is presented through the use of a case example as well as information about the program's logistics, benefits, limitations and future goals. PMID- 23941148 TI - Keyboarding and visual-motor skills in elementary students: a pilot study. AB - With the increased integration of technology in public school settings, occupational therapists have utilized computers in their role as related special education service providers. Although computers are used as an intervention tool, no studies have documented the efficacy of computer training on functional skills in students. PURPOSE: The purpose of this pilot study was to investigate the effect of a structured keyboarding (typing) program on visual-motor (eye-hand coordination) and written communication skills in children enrolled in second grade public school classrooms. METHOD: Sixty-six children participated in the study. Thirty-two children received typing instruction on a daily basis for eight months and thirty-four students served as control children receiving no formal instruction. RESULTS: RESULTS of a mixed ANOVA with repeated factor showed a significant difference in visual-motor abilities in students who received keyboarding instruction as compared to control children. In addition, average typing speeds approached handwriting speeds at this grade level. These preliminary results support the use of keyboarding as a compensatory handwriting approach in the classroom. Further investigation of the use of keyboarding for students with milder disorders such as learning disabilities is recommended. PMID- 23941149 TI - Enhancing motor learning through peer tutoring. AB - The purpose of this study was to examine the efficacy of incorporating mnemonic memory aids and having a subject teach another person a given task (peer tutoring) as a method of enhancing task acquisition and recall by the subject and to discuss the implications for occupational therapists who instruct clients in motor tasks such as therapeutic exercise programs. Sixty-seven college students were randomly assigned to one of three groups using different teaching methods for the purpose of learning a motor task, specifically the American Sign Language alphabet. Subjects who were taught using mnemonics and peer tutoring scored significantly better on post-testing two days following instruction than did the control groups. Use of these techniques did not increase direct teaching time by the instructor, nor did they incur additional costs. Thus, these techniques may be easily incorporated into client education to improve recall and performance. PMID- 23941150 TI - A pilot study of the delivery of occupational therapy in long term care settings under the medicare prospective payment system. AB - OBJECTIVE: The purpose of this pilot study was to examine occupational therapists' perceptions of practice in skilled nursing facilities since the implementation of the Medicare Prospective Payment System (PPS). METHOD: A survey was sent to 250 randomly selected occupational therapists who had worked or were currently working in skilled nursing facilities for a minimum of two years. RESULTS: A majority of therapists reported an increase in caseload size since the implementation of the new prospective payment system. Most also noted increasing expectations to maintain patients on their caseloads for longer periods of time. Many reported that their facilities were decreasing the number of level II fieldwork students they were accepting. An even greater number reported that their facilities were decreasing the amounts of their continuing education budgets. A significant number also reported that they felt the quality of life for their residents had decreased since the implementation of prospective payment. CONCLUSION: This pilot survey may indicate some problematic trends in occupational therapists' perceptions of practice in skilled nursing facilities. There may be a relationship between these trends and the implementation of prospective payment in these settings. Further studies are recommended to more deeply assess occupational therapists' practice perceptions, as well as the quality of life of patients in skilled nursing facilities. Research is also needed to determine if occupational therapists' perceptions of practice in skilled nursing facilities changes or stabilizes under the prospective payment system. PMID- 23941151 TI - The emotional effects of writing about stressful experiences: an exploration of moderators. AB - The emotional effects of writing about stressful experiences was studied using a quasi-experimental design in which ninety-one college students, who journaled for fifteen minutes on two occasions, were compared to 71 participants in a comparison group. Locus of control, extroversion, and previous experience with journaling were considered as moderating variables. The results indicated greater improvements in emotional health for the treatment group, with males benefiting to a greater degree than females. These findings suggest the short-term effectiveness of brief journaling interventions across the personality dimensions considered. The relevance of these findings for occupational therapists is considered. PMID- 23941152 TI - Iatrogenesis within long term care facilities. AB - Seniors living within long term care facilities have higher incidences of frailness, chronic disease, and deterioration as compared with seniors living in the community. There is increasing evidence within the literature that some of this deterioration is caused by the very facilities they are living in. This article discusses the iatrogenic factors associated with living in long term care facilities and the consequences of such factors on older adults. Following this, an exploration of the relevancy of this issue for occupational therapists will take place. Occupational therapists must be particularly alert to the dangers of iatrogenic effects and be concerned with making changes within the long term care system to prevent further harm to older adults and work on promoting an environment that promotes optimal health. PMID- 23941153 TI - A new addition to occupational therapy in health care! PMID- 23941154 TI - Copyright laws and occupational therapy education. AB - Faculty are often confused about the laws of copyright and when copies of articles can be made for students. Copyright laws protect authors of text, art, film, and software from unfair use. Educational settings must comply with copyright laws and are not exempt because of educational status. This article summarizes copyright laws that affect college campuses and suggests practical solutions for compliance. PMID- 23941155 TI - Collaboration in the community: a capstone experience. AB - At York College, a six-week capstone experience, focused on community-based intervention, is required of all occupational therapy students following their traditional fieldwork placements. In this article, the program is described, and implications for the future of occupational therapy are discussed. PMID- 23941157 TI - Placenta accreta and beyond: Aesop's fables. PMID- 23941158 TI - Influence of solvent on ion aggregation and transport in PY15TFSI ionic liquid aprotic solvent mixtures. AB - Molecular dynamics (MD) simulations using a many-body polarizable APPLE&P force field have been performed on mixtures of the N-methyl-N-pentylpyrrolidinium bis(trifluoromethanesulfonyl)imide (PY15TFSI) ionic liquid (IL) with three molecular solvents: propylene carbonate (PC), dimethyl carbonate (DMC), and acetonitrile (AN). The MD simulations predict density, viscosity, and ionic conductivity values that agree well with the experimental results. In the solvent rich regime, the ionic conductivity of the PY15TFSI-AN mixtures was found to be significantly higher than the conductivity of the corresponding -PC and -DMC mixtures, despite the similar viscosity values obtained from both the MD simulations and experiments for the -DMC and -AN mixtures. The significantly lower conductivity of the PY15TFSI-DMC mixtures, as compared to those for PY15TFSI-AN, in the solvent-rich regime was attributed to the more extensive ion aggregation observed for the -DMC mixtures. The PY15TFSI-DMC mixtures present an interesting case where the addition of the organic solvent to the IL results in an increase in the cation-anion correlations, in contrast to what is found for the mixtures with PC and AN, where ion motion became increasingly uncorrelated with addition of solvent. A combination of pfg-NMR and conductivity measurements confirmed the MD simulation predictions. Further insight into the molecular interactions and properties was also obtained using the MD simulations by examining the solvent distribution in the IL-solvent mixtures and the mixture excess properties. PMID- 23941159 TI - Influence of patient characteristics on duration of seclusion/restrain in acute psychiatric settings in Japan. AB - AIM: The aim of this study was to investigate the current state of duration of seclusion/restraint in acute psychiatric settings in Japan and the effect of patient characteristics on duration of seclusion/restraint. METHODS: During an 8 month period starting from November 2008, duration of seclusion/restraint and patient characteristics were investigated in 694 psychiatric inpatients who experienced seclusion/restraint in three emergency and three acute wards at four psychiatric hospitals. Reasons for starting seclusion/restraint were also assessed. Analysis was performed using generalized linear models, with the duration of seclusion/restraint as the dependent variable and patient characteristics and reasons for starting seclusion/restraint as independent variables. RESULTS: Of the patients secluded/restrained, 58.6% had a primary diagnosis of schizophrenia (F20-F29) and a large proportion (37.9%) were secluded/restrained due to hurting others. Median hours ofseclusion/restraint were 204 and 82 h, respectively. The duration of seclusion was longer for patients with F20-F29 than those with disorders due to psychoactive substance use (F10-F19) or other diagnoses (F40-F99), and when the reason was danger of hurting others. In contrast, the duration of restraint in female patients and in patients with F10-F19 diagnosis was shorter. CONCLUSION: The duration of seclusion/restraint at acute psychiatric care wards in Japan are much longer than those reported by previous overseas studies. Although Japanese structure issues such as more patients per ward and a lower ratio of nurses need to be considered, skills for dealing with patients with primary diagnosis of F20-F29 secluded due to danger posed to others should be improved. PMID- 23941161 TI - Nonaffective motivation modulates the sustained LPP (1,000-2,000 ms). AB - Past work has demonstrated that the sustained late positive potential (LPP) is modulated by motivational demands of affective content. The current experiment sought to investigate how motivational demands in nonaffective tasks would modulate the sustained LPP. Using a modified oddball paradigm, participants either counted the number of appearances of a nonaffective target or determined the duration length of the target. Results showed that targets in both the counted and duration tasks produced larger LPPs in the early window (400-1,000 ms) than the neutral standard. Only the duration target produced larger LPPs in the late time window (1,000-2,000 ms) than the neutral standard. These results suggest that the late LPP is a measure of persistent motivated attentional processing and can be modulated by nonaffective motivation. PMID- 23941160 TI - RACK1 scaffold proteins influence miRNA abundance in Arabidopsis. AB - MicroRNAs (miRNAs) regulate plant development by post-transcriptional regulation of target genes. In Arabidopsis thaliana, DCL1 processes precursors (pri-miRNAs) to miRNA duplexes, which associate with AGO1. Additional proteins act in concert with DCL1 (e.g. HYL1 and SERRATE) or AGO1 to facilitate efficient and precise pri miRNA processing and miRNA loading, respectively. In this study, we show that the accumulation of plant microRNAs depends on RECEPTOR FOR ACTIVATED C KINASE 1 (RACK1), a scaffold protein that is found in all higher eukaryotes. miRNA levels are reduced in rack1 mutants, and our data suggest that RACK1 affects the microRNA pathway via several distinct mechanisms involving direct interactions with known microRNA factors: RACK1 ensures the accumulation and processing of some pri-miRNAs, directly interacts with SERRATE and is part of an AGO1 complex. As a result, mutations in RACK1 lead to over-accumulation of miRNA target mRNAs, which are important for ABA responses and phyllotaxy, for example. In conclusion, our study identified complex functioning of RACK1 proteins in the Arabidopsis miRNA pathway; these proteins are important for miRNA production and therefore plant development. PMID- 23941162 TI - Switchable reporter enzymes based on mutually exclusive domain interactions allow antibody detection directly in solution. AB - Detection of antibodies is essential for the diagnosis of many diseases including infections, allergies, and autoimmune diseases. Current heterogeneous immunoassays require multiple time-consuming binding and washing steps, which limits their application in point-of-care diagnostics and high-throughput screening. Here, we report switchable reporter enzymes that allow simple colorimetric detection of antibodies directly in solution. Our approach is based on the antibody-induced disruption of an intramolecular interaction between TEM1 beta-lactamase and its inhibitor protein BLIP. Using the HIV1-p17 antibody as an initial target, the interaction between enzyme and inhibitor was carefully tuned to yield a reporter enzyme whose activity increased 10-fold in the presence of pM antibody concentrations. Reporter enzymes for two other antibodies (HA-tag and Dengue virus type I) were obtained by simply replacing the epitope sequences. This new sensor design represents a modular and generic approach to construct antibody reporter enzymes without the cumbersome optimization required by previous engineering strategies. PMID- 23941163 TI - Warfarin use in hemodialysis patients with atrial fibrillation: decisions based on uncertainty. AB - BACKGROUND: Warfarin prescribing patterns for hemodialysis patients with atrial fibrillation vary widely amongst nephrologists. This may be due to a paucity of guiding evidence, but also due to concerns of increased risks of warfarin use in this population. The literature lacks clarity on the balance of warfarin therapy between prevention of thrombotic strokes and the increased risks of bleeding in hemodialysis patients with atrial fibrillation. METHODS: We performed a survey of Canadian Nephrologists, assessing warfarin prescribing practice, and measured the certainty in making these choices. RESULTS: Respondents were consistently uncertain about warfarin use for atrial fibrillation. This uncertainty increased with a history of falls or starting hemodialysis, even when a high CHADS2 or CHA2DS2VASc score was present. The majority of respondents agreed that clinical equipoise existed about the use of oral anticoagulation in hemodialysis patients with atrial fibrillation (72.2%) and that the results of a randomized controlled trial would be relevant to their practice (98.2%). CONCLUSIONS: A randomized controlled trial of warfarin use in hemodialysis patients with atrial fibrillation would clarify the risks and benefits of warfarin use in this population. PMID- 23941164 TI - Genetic variation in oxytocin rs2740210 and early adversity associated with postpartum depression and breastfeeding duration. AB - Mothers vary in duration of breastfeeding. These individual differences are related to a variety of demographic and individual maternal factors including maternal hormones, mood and early experiences. However, little is known about the role of genetic factors. We studied single-nucleotide polymorphisms (SNPs) in the OXT peptide gene (rs2740210; rs4813627) and the OXT receptor gene (OXTR rs237885) in two samples of mothers from the Maternal adversity, Vulnerability and Neurodevelopment study (MAVAN), a multicenter (Hamilton and Montreal, Canada) study following mothers and their children from pregnancy until 7 years of age. Data from the Hamilton site was the primary sample (n = 201) and data from Montreal was the replication sample (n = 151). Breastfeeding duration, maternal mood (measured by the CES-D scale) and early life adversity (measured by the CTQ scale) were established during 12 months postpartum. In our primary sample, polymorphisms in OXT rs2740210, but not the other SNPs, interacted with early life adversity to predict variation in breastfeeding duration (overall F8,125 = 2.361, P = 0.021; interaction effect b = -8.12, t = -2.3, P = 0.023) and depression (overall F8,118 = 5.751, P <= 0.001; interaction effect b = 6.06, t = 3.13, P = 0.002). A moderated mediation model showed that higher levels of depression mediated the inverse relation of high levels of early life adversity to breastfeeding duration, but only in women possessing the CC genotype [effect a' = -3.3401, 95% confidence interval (CI) = -7.9466 to -0.0015] of the OXT SNP and not in women with the AA/AC genotype (a' = -1.2942, ns). The latter findings (moderated mediation model) were replicated in our Montreal sample (a' = -0.277, 95% CI = -0.7987 to -0.0348 for CC; a' = -0.1820, ns for AA/AC). PMID- 23941165 TI - Impact of emergency access targets on admissions to general medicine: a retrospective cohort study. AB - BACKGROUND: Emergency access targets have been implemented Australia-wide following recent retrospective cohort studies linking emergency department (ED) overcrowding and excess mortality. AIM: To examine the impact of ED access targets on the characteristics and health service utilisation of general medicine (GM) inpatients at the Royal Melbourne Hospital. METHODS: A retrospective cohort study was conducted on all patient episodes admitted from ED to GM units from January 2009 to December 2012 (n = 15562), compared in two cohorts for 24 months before (n = 7393) and after (n = 8169) the implementation of the '4-h rule'. The main outcome measures were age, comorbidity, clinical urgency at presentation (Australasian Triage Score), ED and inpatient length of stay, diagnosis at discharge, and in-hospital complications. RESULTS: After the implementation of the '4-h rule', there was an increased proportion of younger patients aged <=50 years (7.7-9.1%), urgent Australasian Triage Scale 3 (45.6-49.7%) and semi-urgent Australasian Triage Scale 4 (21.8-27.6%) patients admitted to GM. On average, GM patients had fewer comorbid conditions (proportion with Charlson score >=6 decreased from 14.2% to 11.9%), and higher proportions (21.8-24.7%) were admitted for less than 48 h. CONCLUSION: Implementation of a 4-h access target has been associated with changes to the characteristics of patients admitted to GM, including higher proportions of younger patients, with fewer comorbid conditions and lower clinical urgency at presentation, although the latter may be explained by a coincidental change in the way that ED patients were triaged, as well as a greater number of these patients presenting to ED overall. PMID- 23941166 TI - The MMPI-2-RF Personality Psychopathology Five (PSY-5-RF) scales: development and validity research. AB - This article describes the development, internal psychometric, and external validation studies on scales designed to measure the Personality Psychopathology Five (PSY-5) from MMPI-2 Restructured Form (MMPI-2-RF) items. Diverse and comprehensive data sets, representing various clinical and nonclinical populations, were classified into development and validation research samples. Item selection, retention, and exclusion procedures are detailed. The final set of PSY-5-RF scales contain 104 items, with no item overlap between scales (same as the original MMPI-2 PSY-5 scales), and no item overlap with the Demoralization scale. Internal consistency estimates are comparable to the longer MMPI-2 PSY-5 scales. Appropriate convergent and discriminant validity findings utilizing various self-report, collateral rating, and record review data are reported and discussed. A particular emphasis is offered for the unique aspects of the PSY-5 model: psychoticism and disconstraint. The findings are connected to the broader PSY-5 literature and the recommended review of systems (Harkness, Reynolds, & Lilienfeld, this issue) presented in this series of articles. PMID- 23941167 TI - ArkMAP: integrating genomic maps across species and data sources. AB - BACKGROUND: The visualisation of genetic and genomic maps aligned within and between species and across data sources can be used to inform studies of genome evolution, assist genome assembly projects and aid gene discovery and identification. Whilst annotation, integration and exploration of assembled genome sequences is well supported, there are fewer tools available which can display genetic maps for less well-characterized species, and integrate these maps with annotated reference genomes to support cross species comparisons. RESULTS: We have developed a desktop application to draw and align genetic and genomic maps, retrieved from remote data sources or loaded as local files. Maps can be retrieved from our public map database ArkDB or from any Ensembl data source (i.e. Ensembl and Ensembl Genomes). By using the JEnsembl API, maps can be drawn for any release version of any of the thousands of species present in Ensembl data sources, allowing not only inter-specific comparisons, but also comparisons between different versions/revisions of assembled genomes. Maps can be aligned by relating identical or synonymous markers across maps, or through the gene homology/orthology relationship data stored in the Ensembl Compara databases, allowing ready visualization of regions of conserved synteny between species. The map drawing canvas is highly configurable, supports interactive exploration of maps, markers and relationships and allows export of publication quality graphics. CONCLUSIONS: ArkMAP allows users to draw and interactively explore gene and variation maps for any version of any annotated genome curated in the Ensembl data sources, and to integrate local mapping data. The maps and inter-map relationships drawn are highly configurable and ArkMAP may be used to produce publication quality graphics. ArkMAP is freely available as an auto updating Java 'Web Start' application, or as a standalone archived application. PMID- 23941168 TI - Discovering the sequential structure of thought. AB - Multi-voxel pattern recognition techniques combined with Hidden Markov models can be used to discover the mental states that people go through in performing a task. The combined method identifies both the mental states and how their durations vary with experimental conditions. We apply this method to a task where participants solve novel mathematical problems. We identify four states in the solution of these problems: Encoding, Planning, Solving, and Respond. The method allows us to interpret what participants are doing on individual problem-solving trials. The duration of the planning state varies on a trial-to-trial basis with novelty of the problem. The duration of solution stage similarly varies with the amount of computation needed to produce a solution once a plan is devised. The response stage similarly varies with the complexity of the answer produced. In addition, we identified a number of effects that ran counter to a prior model of the task. Thus, we were able to decompose the overall problem-solving time into estimates of its components and in way that serves to guide theory. PMID- 23941169 TI - Reduced attention and the performance of "automated" movements. AB - 3 repetitive movements were studied. These were a blind movement between 2 stops, a visually guided movement to a line and a blind movement which had to be terminated at a previously learned position. Previous work had shown that the first of the three caused no interference with RT to a secondary signal presented during the movement, while the other two did interfere. Ss either performed the movement task alone, together with an attention demanding key positioning task, or under an instruction to think about something else. The variability of movement and pause time was used to score the movement tasks. When the movement was performed alone, variability was least for the blind movement between stops and most for the blind movement with a remembered target All tasks showed increased variability when performed with the subsidiary key task. The instruction to think about something else generally increased variability but not significantly. The task component showing the least influence of the secondary task was the variability of movement distance in the blind task without stops. PMID- 23941170 TI - A comparison of selected behaviors of identical twins, one blind from birth. AB - The purpose of this study was to compare differences in mental-emotional, fine perceptual-motor and gross motor behaviors of a set of 13 year-old identical twins, one of whom was blind from birth. In general, the blind twin was superior in performances where total body involvements were minimal and fine manipulative movements of the hands and/or fingers were stressed. The blind twin also appeared to be more well-adjusted emotionally than the sighted twin. PMID- 23941171 TI - Reliability and specificity of individual differences in reminiscence. AB - In investigating Eysenck's (1965) suggestion of the specificity of reminiscence, 50 high school boys were tested on 2 gross motorcoordination tasks-one involving tracking and the other balance. In the practice schedule, which was identical for both tasks, all Ss were given 20 50-sec. trials with a 10-sec. intertrial rest. A 5-min. interpolated rest was given after every fourth trial. The reliability of individual differences in reminiscence for both tasks was found to be extremely low. While Eysenck's hypothesis was not necessarily weakened, doubt was cast upon the specificity of reminiscence in the usual context of the word. PMID- 23941172 TI - Practice to an asymptote? AB - Certain experimental designs are based upon the assumption that performance level becomes stabilized after a prolonged period of practice. This assumption was tested by taking a long series of repeated measurements upon a single S for the performance of each of several constant tasks, each task being tested singly in a separate series of measurements. Results showed that after thousands of practice trials on a simple task S may still be learning or showing other sequential effects in performance. These effects may disappear on one day only to reappear on the next. Therefore it is extremely doubtful that "practice to an asymptote" should be regarded as either an efficient or an effective method of eliminating sequential effects from an experiment proper. PMID- 23941173 TI - Adaptation to combined reversal and delay of eyemovement-retinal feedback. AB - A real-time computer system was used to calibrate eye position with respect to the position of an oscilloscope target, to yoke transduced eyemovement signals to the target, and to program variable feedback reversal and delays into the closed eyemovement-retinal interaction. S was required to compensate a sine-wave movement of the target by opposed movements of the eyes. Experimental transmission lags of 0.0, 0.1, and 0.2 sec. were introduced into the closed eyemovement-retinal yoke. Results indicated that both reversal and delay of eyemovement-retinal feedback degraded primary visual processes and their ocular control by pursuit, saccadic, and fixation motions, causing blurred, skittered, and unstable vision, and that there was limited adaptation to distortion of eyemovement-retinal feedback timing as well as to the spatial reversal of such feedback. PMID- 23941174 TI - Individual differences in intra-individual variability. AB - For each of 75 Ss several estimates of intra-individual variations were calculated for each of 4 motor skills. The reliability of intra-individual variation for these data, estimated from Pearson productmoment correlations, ranged from r = .31 to r = .51 (in all cases p < .05). It was also found that in 3 of the 4 skills, intra-individual variation correlated significantly (r = .36, .54, .55) with mean performance level. Second order partial correlations, holding constant the effect of mean performance level, were then used to estimate the reliability of intravariation. These correlations were statistically significant and ranged from r = .27 to r = .34. When correlations of intra-individual variation were calculated among the four skills it was demonstrated that intra individual variation was approximately 95 to 100% task specific. PMID- 23941175 TI - Transfer variables in tracking skills. AB - In the present work the effect of two task variables on transfer were studied: shape of the track-circular or triangular; and target speed-constant or variable. One or both of these variables was changed on transfer. Experimental conditions were (a) 10 preshift and 10 post-shift trials, and (b) 20 single-trial alternations of two tasks. 22 groups of 12 Ss each were tested. Condition (a) showed positive transfer with single variable change and zero or negative transfer with simultaneous change in two variables, and condition (b) annulled all transfer effects. Results are discussed in terms of commonality between tasks and receptor and perceptual anticipation. PMID- 23941176 TI - Knowledge of results and intertrial correlations in a simple motor task. AB - Lever positioning is a simple motor task, one of a very few, in which the intertrial correlations do not ordinarily show strong superdiagonal patterning. However, if knowledge of results (KR) is withheld, superdiagonal pattern appears. If KR is given every 3rd, 4th, or 10th trial, superdiagonal pattern appears in blocks of trials without KR. The pattern is strongest in the first block of trials without KR and in gradually weakening strength in subsequent blocks. It appears, therefore, that in lever-positioning an inverse relation holds between learning and superdiagonal pattern. In proportion as learning progresses (because KR is given) superdiagonal pattern degenerates. When KR is given after every trial, the pattern is vestigial at best. These results are attributed to the terminal effects of practice in a very simple task. PMID- 23941177 TI - A note on the inferiority of retardates' motor performance. AB - It is suggested that the general inferiority of retardates on tests of motor performance is due to contamination of the test with cognitive elements, that, by definition, are inferior in the retardate. This contamination hypothesis seems worthy of investigation since educable mentally handicapped children learned and performed a discrete novel motor task similarly to normal Ss matched to them on CA and MA, when this contamination was minimized by the procedure. PMID- 23941178 TI - Roles of the Lewis acid and base in the chemical reduction of CO2 catalyzed by frustrated Lewis pairs. AB - We employ quantum chemical calculations to discover how frustrated Lewis pairs (FLP) catalyze the reduction of CO2 by ammonia borane (AB); specifically, we examine how the Lewis acid (LA) and Lewis base (LB) of an FLP activate CO2 for reduction. We find that the LA (trichloroaluminum, AlCl3) alone catalyzes hydride transfer (HT) to CO2 while the LB (trimesitylenephosphine, PMes3) actually hinders HT; inclusion of the LB increases the HT barrier by ~8 kcal/mol relative to the reaction catalyzed by LAs only. The LB hinders HT by donating its lone pair to the LUMO of CO2, increasing the electron density on the C atom and thus lowering its hydride affinity. Although the LB hinders HT, it nonetheless plays a crucial role by stabilizing the active FLP.CO2 complex relative to the LA dimer, free CO2, and free LB. This greatly increases the concentration of the reactive complex in the form FLP.CO2 and thus increases the rate of reaction. We expect that the principles we describe will aid in understanding other catalytic CO2 reductions. PMID- 23941179 TI - Provider connectedness and communication patterns: extending continuity of care in the context of the circle of care. AB - BACKGROUND: Continuity is an important aspect of quality of care, especially for complex patients in the community. We explored provider perceptions of continuity through a system's lens. The circle of care was used as the system. METHODS: Soft systems methodology was used to understand and improve continuity for end of life patients in two communities. PARTICIPANTS: Physicians, nurses, pharmacists in two communities in British Columbia, involved in end of life care. Two debates/discussion groups were completed after the interviews and initial analysis to confirm findings. Interview recordings were qualitatively analyzed to extract components and enablers of continuity. RESULTS: 32 provider interviews were completed. Findings from this study support the three types of continuity described by Haggerty and Reid (information, management, and relationship continuity). This work extends their model by adding features of the circle of care that influence and enable continuity: Provider Connectedness the sense of knowing and trust between providers who share care of a patient; a set of ten communication patterns that are used to support continuity across the circle of care; and environmental factors outside the circle that can indirectly influence continuity. CONCLUSIONS: We present an extended model of continuity of care. The components in the model can support health planners consider how health care is organized to promote continuity and by researchers when considering future continuity research. PMID- 23941180 TI - Risk disparities in the globalisation of assisted reproductive technology: the case of Asia. AB - This paper analyses the disparities in risks associated with biomedical technology focusing on the results of assisted reproductive technology (ART). ART among biomedical technologies transferred to Asia is a representative case that reveals in its clinical use and related scientific research the global politics of technology. This study notes the global politics at work in the recognition of and reaction to such risks. While many Asian countries aggressively pursue technological development, weak legislative and administrative regulations have created various problems and controversial cases. This study asserts that risks associated with technology are characterised as social facts not natural ones or mere 'side effects', since technological development and risk are closely intertwined. PMID- 23941181 TI - Pharmacokinetics of flunixin meglumine in mature swine after intravenous, intramuscular and oral administration. AB - BACKGROUND: The purpose of this study was to determine intravenous (IV), intramuscular (IM) and oral (PO) FM PK in mature swine. Appropriate pain management for lameness in swine is a critical control point for veterinarians and producers, but science-based guidance on optimal housing, management and treatment of lameness is deficient. Six mature swine (121-168 kg) were administered an IV, IM, or PO dose of flunixin meglumine at a target dose of 2.2 mg/kg in a cross-over design with a 10 day washout period between treatments. Plasma samples collected up to 48 hours post-administration were analyzed by high pressure liquid chromatography and mass spectrometry (HPLC-MS) followed by non compartmental pharmacokinetic analysis. RESULTS: No adverse effects were observed with flunixin meglumine administration for all routes. Flunixin meglumine was administered at an actual mean dose of 2.21 mg/kg (range: 2.05-2.48 mg/kg) IV, IM and PO. A mean peak plasma concentration (CMAX) for IM and PO administration was 3748 ng/ml (range: 2749-6004 ng/ml) and 946 ng/ml (range: 554-1593 ng/ml), respectively. TMAX was recorded at 1.00 hour (range: 0.50-2.00 hours) and 0.61 hours (range: 0.17-2.00 hours) after PO and IM administration. Half-life (T 1/2 lambdaz) for IV, IM and PO administration was 6.29 hours (range: 4.84-8.34 hours), 7.49 hours (range: 5.55-12.98 hours) and 7.08 hours (range: 5.29-9.15 hours) respectively. In comparison, bioavailability (F) for PO administration was 22% (range: 11-44%) compared to IM F at 76% (range: 54-92%). CONCLUSIONS: The results of the present study suggest that FM oral administration is not the most effective administration route for mature swine when compared to IV and IM. Lower F and Cmax of PO-FM in comparison to IM-FM suggest that PO-FM is less likely to be an effective therapeutic administration route. PMID- 23941183 TI - Molecular crowding stabilizes both the intrinsically disordered calcium-free state and the folded calcium-bound state of a repeat in toxin (RTX) protein. AB - Macromolecular crowding affects most chemical equilibria in living cells, as the presence of high concentrations of macromolecules sterically restricts the available space. Here, we characterized the influence of crowding on a prototypical RTX protein, RC(L). RTX (Repeat in ToXin) motifs are calcium-binding nonapeptide sequences that are found in many virulence factors produced by Gram negative bacteria and secreted by dedicated type 1 secretion systems. RC(L) is an attractive model to investigate the effect of molecular crowding on ligand induced protein folding, as it shifts from intrinsically disordered conformations (apo-form) to a stable structure upon calcium binding (holo-form). It thus offers the rare opportunity to characterize the crowding effects on the same polypeptide chain under two drastically distinct folding states. We showed that the crowding agent Ficoll70 did not affect the structural content of the apo-state and holo state of RC(L) but increased the protein affinity for calcium. Moreover, Ficoll70 strongly stabilized both states of RC(L), increasing their half-melting temperature, without affecting enthalpy changes. The power law dependence of the melting temperature increase (DeltaT(m)) on the volume fraction (phi) followed theoretical excluded volume predictions and allowed the estimation of the Flory exponent (nu) of the thermally unfolded polypeptide chain in both states. Altogether, our data suggest that, in the apo-state as found in the crowded bacterial cytosol, RTX proteins adopt extended unfolded conformations that may facilitate protein export by the type I secretion machinery. Subsequently, crowding also enhances the calcium-dependent folding and stability of RTX proteins once secreted in the extracellular milieu. PMID- 23941185 TI - A message from the editor. PMID- 23941184 TI - Black silicon with self-cleaning surface prepared by wetting processes. AB - This paper reports on a simple method to prepare a hydrophobic surface on black silicon, which is fabricated by metal-assisted wet etching. To increase the reaction rate, the reaction device was placed in a heat collection-constant temperature type magnetic stirrer and set at room temperature. It was demonstrated that the micro- and nanoscale spikes on the black silicon made the surface become hydrophobic. As the reaction rate increases, the surface hydrophobicity becomes more outstanding and presents self-cleaning until the very end. The reflectance of the black silicon is drastically suppressed over a broad spectral range due to the unique geometry, which is effective for the enhancement of absorption. PMID- 23941186 TI - The relationship between strength, pain, and community integration in wheelchair users: a pilot study. AB - The purpose of this pilot study was to determine the differences between wheelchair users and their matched able-bodied controls in grip strength, pain (as expressed by scores on the McGill Pain Questionnaire [MPQ]), and community integration (as expressed by scores on the Craig Handicap Assessment and Reporting Technique [CHART]). We also explored the relationships among community integration, pain, strength, and demographic variables. Thirteen wheelchair users and 13 able-bodied participants were matched for gender, age, and activity level. The wheelchair-user group had significantly greater scores on the MPQ and significantly lower scores on the CHART. Step-wise multiple regression analyses revealed that the best predictor for pain was age for the wheelchair-user group and activity for the able-bodied group. The best predictor of the CHART for the wheelchair-user group was grip strength. In conclusion, pain was associated with age for the wheelchair-user group and with activity for the able-bodied group. In addition, grip strength was associated with community integration for the wheelchair-user group. PMID- 23941187 TI - Therapeutic humor: attitudes and actions by occupational therapists in adult physical disabilities settings. AB - This study examined attitudes and uses of humor by occupational therapists with their adult clients with physical disabilities. A cross-sectional survey of randomly selected occupational therapists from the American Occupational Therapy Association's Physical Disabilities Special Interest Section was used; 283 surveys qualified for the study. All of the respondents had positive attitudes towards humor and a large majority reported using humor. Four key areas of humor were further analyzed: relationships, coping, promoting physical health, and treatment compliance. While a large majority professed to value humor in each area, only about one-third reported using it in the last two areas. Humor attitudes and humor behaviors in each area showed a moderate positive correlation. Both spontaneous and planned use was reported. The results of this survey support humor use in occupational therapy practice to help clients rehabilitate. PMID- 23941188 TI - Goal attainment scaling allows program evaluation of a home-based occupational therapy program. AB - A problem for occupational therapists involved in home-based rehabilitation is the dichotomy between traditional functional status measures, which are commonly reported by therapists to have insufficient flexibility and poor clinical sensitivity, and individualized methods (which do not allow inter-patient comparison for program evaluation). This study used Goal Attainment Scaling (GAS) to evaluate both individual and program change. The study demonstrates that GAS was a simple, clinically meaningful measure of change which evaluated patient centered outcomes and program effects concurrently. In addition, this measure was applied to a traditionally challenging service, that of a home-based rehabilitation program. Goal Attainment Scaling was demonstrated to be useful as an outcome measure for patients with multiple, complex rehabilitation needs, such as those served by a home-based rehabilitation occupational therapy service. It was able to accurately detect meaningful change (necessary for demonstrating clinically significant improvement at the level of the individual patient), be administered in a time-effective manner, and also allow the clinician to evaluate program effectiveness. PMID- 23941189 TI - Occupational therapists in rural healthcare: a "jack of all trades". AB - Rural areas are often perceived to have limitations in healthcare resources. The literature indicates that shortages of occupational therapy resources exist within rural health areas. This study reports on a survey that was distributed to rehabilitation departments in Nebraska, excluding only the metropolitan areas of Omaha and Lincoln. Forty-four of the ninety-three surveys sent were completed and returned (47.3%). The survey examined the occupational therapy resources available and those diagnoses treated in the designated geographical area. Although the survey results do not support the literature regarding limitations of occupational therapy resources, results do demonstrate a variety of challenges faced by therapists practicing in isolated areas. PMID- 23941190 TI - Burnout among occupational therapists. AB - Objectives. Using Maslach's Burnout Inventory (MBI), this study examined burnout among full-time staff occupational therapists including the extent of their burnout; how occupational therapists' burnout compared to four health care professions, and if type of health care setting impacts their level of burnout. Method. The MBI was mailed to each subject in the random sample (n = 3000) of occupational therapists who were American Occupational Therapy Association (AOTA) members. Results. Occupational therapists displayed a higher level of emotional exhaustion, and lower levels of depersonalization and personal accomplishment. Differences were found in the levels of occupational therapists' burnout when compared to four health care professions. Occupational therapists working in chronic care health care settings demonstrated higher levels of burnout than those working in other health care settings. Conclusion. The occupational therapist should strive to match their skills, interests, life style, and experience to the appropriate health care setting to promote a good person environment fit to decrease burnout and promote quality patient care and personal health. PMID- 23941191 TI - From the internet editor. PMID- 23941193 TI - Eccentric/concentric training of ankle evertor and dorsiflexors in recreational athletes: muscle latency and strength. AB - The aim of this study was to investigate the effects of a combined eccentric concentric exercise program of the ankle evertors and dorsiflexors on the latency time of the peroneus longus and tibialis anterior muscles. Twenty-four healthy male recreational athletes were admitted to this study and were randomly assigned to either the exercise group (n = 12) or the control group (n = 12). Subjects in the exercise group performed an isokinetic exercise program of the ankle evertors and dorsiflexors in a combined eccentric-concentric mode for 3 days per week for 6 weeks. Before and after the exercise program, muscle reaction times of the peroneus longus and tibialis anterior muscles to sudden supinating maneuvers on a tilting platform, and isokinetic strength of the ankle joint musculature were evaluated. The peroneus longus and tibialis anterior reaction times showed significant (P < 0.01-0.05) reductions following six weeks of intervention in the exercise group. Additionally, eccentric peak torques for the ankle evertor and dorsiflexors represented significant (P < 0.05) increases in the exercise group compared with the control group. The results of this study suggest that it is possible to reduce peroneal and anterior tibial reaction times following a six week eccentric/concentric isokinetic training program in healthy ankles. PMID- 23941194 TI - Uterine compression sutures with intrauterine balloon tamponade. PMID- 23941195 TI - Fracture of the penis: an atypical presentation. AB - BACKGROUND: Fracture of the penis is an uncommon injury presenting to the emergency department (ED). Personal embarrassment and social scenarios associated with this condition may result in underreporting. Patients often delay seeking medical attention, and even when they do, as in our case report, they may withhold the condition for a significant time. ED physicians need to be aware of the social inhibitions and the need for early diagnosis and prompt treatment. A delay in treatment increases the risk of complications such as ischemia, necrosis and penile deformity.Fracture of the penis is caused by rupture of the tunica albuginea of one or both corpora cavernosa by a blunt trauma to the erect penis. Diagnosis is usually clinical as evident by the characteristic history and clinical presentation. Diagnostic modalities aid in the management of the fracture and associated injuries if present. But promptness in the recognition and initiation of treatment can significantly reduce the chances of post-injury complications. FINDINGS: We present a case of penile fracture in a young male who presented to the ED with abdominal pain, but careful history and physical examination revealed penile fracture. A delay in diagnosis could have led to complications. CONCLUSION: Our case report is an attempt to emphasize the need to suspect injury to the penis in a young adult who might present to the emergency department with an entirely different complaint and also to treat any penile trauma as an emergency. This report provides evidence of an uncommon and underreported clinical entity. A review of the pertinent literature is included. PMID- 23941196 TI - Independent versus cooperative binding in polyethylenimine-DNA and Poly(L-lysine) DNA polyplexes. AB - The mechanism of polyethylenimine-DNA and poly(L-lysine)-DNA complex formation at pH 5.2 and 7.4 was studied by a time-resolved spectroscopic method. The formation of a polyplex core was observed to be complete at approximately N/P = 2, at which point nearly all DNA phosphate groups were bound by polymer amine groups. The data were analyzed further both by an independent binding model and by a cooperative model for multivalent ligand binding to multisubunit substrate. At pH 5.2, the polyplex formation was cooperative at all N/P ratios, whereas for pH 7.4 at N/P < 0.6 the polyplex formation followed independent binding changing to cooperative binding at higher N/Ps. PMID- 23941198 TI - One-year follow up after admission to an emergency department for drug overdose in Japan. AB - AIM: The aim of the study was to investigate the incidence of and risk factors for repetition of suicidal behavior within a year after admission for drug overdose in Japan. METHODS: Patients admitted to the emergency department of a general public hospital in Tokyo for drug overdose of prescribed medicine and/or over-the-counter drugs between March 2008 and February 2009 were followed up after 1 year. Demographic characteristics, previous suicide attempts, and mental health state were examined by self-report questionnaire and interview at recovery from the initial attempt. Information about suicidal behavior during the follow up period was obtained from the outpatient psychiatrists by postal questionnaire 1 year after discharge. RESULTS: Of 190 patients admitted to the emergency department, 132 patients answered the questionnaire and had the interview. Information about thefollow-up period for 66 patients was obtained. Of the 66 patients, 28 patients attempted suicide again and two patients committed suicide during the 1-year follow-up period. Psychiatric diagnosis of personality disorder and denial of suicidal intent at the time of recovery were associated with increased risk for another suicide attempt. Lethality levels of suicidal behaviors before and after admission were associated with each other. CONCLUSION: The rate of fatal and non-fatal suicide attempt within a year after admission for self-poisoning was substantial. Psychiatric diagnosis of personality disorder was a risk factor for repetition of suicide attempt. Clinicians should pay attention to the means of previous suicide attempts even though the patient denies suicidal intent at recovery. PMID- 23941199 TI - An integrative model of the control of ovule primordia formation. AB - Upon hormonal signaling, ovules develop as lateral organs from the placenta. Ovule numbers ultimately determine the number of seeds that develop, and thereby contribute to the final seed yield in crop plants. We demonstrate here that CUP SHAPED COTYLEDON 1 (CUC1), CUC2 and AINTEGUMENTA (ANT) have additive effects on ovule primordia formation. We show that expression of the CUC1 and CUC2 genes is required to redundantly regulate expression of PINFORMED1 (PIN1), which in turn is required for ovule primordia formation. Furthermore, our results suggest that the auxin response factor MONOPTEROS (MP/ARF5) may directly bind ANT, CUC1 and CUC2 and promote their transcription. Based on our findings, we propose an integrative model to describe the molecular mechanisms of the early stages of ovule development. PMID- 23941200 TI - An antibody CDR3-erythropoietin fusion protein. AB - X-ray crystallographic analysis of a bovine antibody (BLV1H12) revealed a unique scaffold in its ultralong heavy chain complementarity determining region 3 (CDR3H) that folds into a solvent exposed, antiparallel beta-stranded "stalk" fused with a disulfide cross-linked "knob" domain. This unusual variable region motif provides a novel approach for generating chimeric antibodies with novel activities. Toward this end, human erythropoietin (hEPO) was substituted for the "knob" domain in this antibody to afford an antibody-hEPO (Ab-hEPO) fusion protein that efficiently expresses in mammalian cells. Ab-hEPO proliferated TF-1 cells with a potency comparable to that of hEPO (EC50 ~ 0.03 nM) and exhibits a significantly extended plasma half-life (>6 days) in mice relative to hEPO (~4 h). Mice treated with the Ab-hEPO fusion protein show sustained elevated hematocrit for more than two weeks. This work demonstrates the utility of BLV1H12 CDR3 fusions as a novel approach for generating potent polypeptides with enhanced pharmacological properties. PMID- 23941201 TI - Effect of salinity and temperature on marine leech, Zeylanicobdella arugamensis (De Silva) under laboratory conditions. AB - The high prevalence (80-100%) of the marine leech Zeylanicobdella arugamensis (De Silva) on cage-cultured Asian sea bass Lates calcarifer (Bloch) led us to investigate the percentage of juvenile leeches hatched from deposited cocoons, survival of juvenile and adult marine leeches at different salinity and temperature. The results showed that the hatching percentage of juvenile leeches was highest at salinity of 30 ppt (32.5 +/- 2.8%) followed by 20 ppt (18.0 +/- 4.3%) and 10 ppt (12.1 +/- 1.4%), respectively. It was found that the adult and juvenile leeches could live up to an average range of 4-7 days at salinity ranging from 10 to 40 ppt. The juvenile leeches were able to hatch at temperature ranging from 25 to 35 degrees C but unable to hatch at 40 degrees C. The survival period of adult and juvenile leeches ranged from 11 to 16 days at 25 degrees C, which was comparatively longer than 5-13 days and 10 h--5 days at 27 30 degrees C and 35-40 degrees C, respectively. The study provided the information on the physical parameters of salinity and temperature which are most optimal for the marine leech Z. arugamensis to propagate. PMID- 23941203 TI - Quality of intrapartum care at Mulago national referral hospital, Uganda: clients' perspective. AB - BACKGROUND: Quality of intrapartum care is an important intervention towards increasing clients' utilization of skilled attendance at birth and accelerating improvements in newborn's and maternal survival and wellbeing. Ensuring quality of care is one of the key challenges facing maternal and neonatal services in Uganda. The study assessed quality of intrapartum care services in the general labor ward of the Mulago national referral and teaching hospital in Uganda from clients' perspective. METHODS: A cross sectional study was conducted using face to face interviews at discharge with 384 systematically selected clients, who delivered in general labor ward at Mulago hospital during May, 2012. Data analysis was done using STATA Version (10) software. Means and median general index scores for quality of intrapartum care services were calculated. Linear regression models were used to determine factors associated with quality of care. RESULTS: Overall, quality of intrapartum care mean index score was 49.4 (standard deviation (sd) 15.46, and the median (interquartile range (IQR)) was 49.1 (37.5 58.9). Median index scores (IQR) per selected quality of care indicators were; dignity and respect 75 (50-87.5); relief of pain and suffering 71.4 (42.8-85.7); information 42.1 (31.6-55.3); privacy and confidentiality 33.3 (1-66.7); and involvement in decision making 16.7 (1-33.3). On average, higher educational level (college/university) (beta: 6.81, 95% CI: 0.85-15.46) and rural residence of clients (beta: 5.67, 95% CI: 0.95-10.3) were statistically associated with higher quality scores. CONCLUSION: This study has revealed that quality of intrapartum care services from clients' perspective was low. Improvements should be focused on involving clients in decision making, provision of information about their conditions and care, and provision of privacy and confidentiality. There is also need to improve the number and availability of health care providers in the labor ward. PMID- 23941202 TI - Lithium treatment alleviates impaired cognition in a mouse model of fragile X syndrome. AB - Fragile X syndrome (FXS) is caused by suppressed expression of fragile X mental retardation protein (FMRP), which results in intellectual disability accompanied by many variably manifested characteristics, such as hyperactivity, seizures and autistic-like behaviors. Treatment of mice that lack FMRP, Fmr1 knockout (KO) mice, with lithium has been reported to ameliorate locomotor hyperactivity, prevent hypersensitivity to audiogenic seizures, improve passive avoidance behavior and attenuate sociability deficits. To focus on the defining characteristic of FXS, which is cognitive impairment, we tested if lithium treatment ameliorated impairments in four cognitive tasks in Fmr1 KO mice, tested if the response to lithium differed in adolescent and adult mice and tested if therapeutic effects persisted after discontinuation of lithium administration. Fmr1 KO mice displayed impaired cognition in the novel object detection task, temporal ordering for objects task and coordinate and categorical spatial processing tasks. Chronic lithium treatment of adolescent (from 4 to 8 weeks of age) and adult (from 8 to 12 weeks of age) mice abolished cognitive impairments in all four cognitive tasks. Cognitive deficits returned after lithium treatment was discontinued for 4 weeks. These results show that Fmr1 KO mice exhibit severe impairments in these cognitive tasks, that lithium is equally effective in normalizing cognition in these tasks whether it is administered to young or adult mice and that lithium administration must be continued for the cognitive improvements to be sustained. These findings provide further evidence that lithium administration may be beneficial for individuals with FXS. PMID- 23941204 TI - A review of systems for psychology and psychiatry: adaptive systems, personality psychopathology five (PSY-5), and the DSM-5. AB - We outline a crisis in clinical description, in which atheoretical categorical descriptors, as in the Diagnostic and Statistical Manual of Mental Disorders (DSM), has turned focus away from the obvious: evolved major adaptive systems. Adaptive systems, at the core of a medical review of systems (ROS), allow models of pathology to be layered over an understanding of systems as they normally function. We argue that clinical psychology and psychiatry would develop more programmatically by incorporating 5 systems evolved for adaptation to the external environment: reality modeling for action, short-term danger detection, long-term cost-benefit projection, resource acquisition, and agenda protection. These systems, although not exhaustive, coincide with great historical issues in psychology, psychopathology, and individual differences. Readers of this journal should be interested in this approach because personality is seen as a relatively stable property of these systems. Thus, an essential starting point in ROS-based clinical description involves personality assessment. But this approach also places demands on scientist-practitioners to integrate across sciences. An ROS promotes theories that are (a) compositional, answering the question: What elements comprise the system?; (b) dynamic, answering: How do the elements and other systems interact?; and (c) developmental: How do systems change over time? The proposed ROS corresponds well with the National Institute of Mental Health's recent research domain criteria (RDoC) approach. We urge that in the RDoC approach, measurement variables should be treated as falsifiable and theory-laden markers, not unfalsifiable criteria. We argue that our proposed ROS promotes integration across sciences, rather than fostering the isolation of sciences allowed by atheoretical observation terms, as in the DSM. PMID- 23941205 TI - Towards a better understanding of bone bridge formation in the growth plate - an immunohistochemical approach. AB - The growth plate at the end of long bones is the cartilaginous organ responsible for longitudinal bone growth in children. Trauma to the growth plate, i.e. fractures, can severely impair longitudinal bone growth, leading to growth disorders due to destruction of the epiphyseal circulation and formation of a bone bridge. From the clinical experience it is known that in some patients this bone bridge eventually disappears during the growth process. However, the molecular mechanisms involved in bone bridge formation and dissolution have not been clarified yet. The aim of this study was to investigate the spatial and temporal protein level of molecules potentially involved in these processes, i.e. RANKL, OPG, DKK-1, Coll 10, BMP-2 and IL-6, in an experimental rat model using an immunohistochemical approach. The results from our study suggest that bone bridge formation might be an early event starting immediately after growth plate injury and involving several pro-osteoblastic molecules, i.e. IL-6, BMP-2 as well as OPG and Coll X. In the late studied time points 3- and 9-month post-injury expression of anti-osteoblastic proteins, i.e. DKK1 and RANKL, was increased. This indicates that bone bridge dissolution might be a late event and potentially linked to Wnt signaling inhibition and RANK/RANKL signaling activation. PMID- 23941207 TI - PKIS: computational identification of protein kinases for experimentally discovered protein phosphorylation sites. AB - BACKGROUND: Dynamic protein phosphorylation is an essential regulatory mechanism in various organisms. In this capacity, it is involved in a multitude of signal transduction pathways. Kinase-specific phosphorylation data lay the foundation for reconstruction of signal transduction networks. For this reason, precise annotation of phosphorylated proteins is the first step toward simulating cell signaling pathways. However, the vast majority of kinase-specific phosphorylation data remain undiscovered and existing experimental methods and computational phosphorylation site (P-site) prediction tools have various limitations with respect to addressing this problem. RESULTS: To address this issue, a novel protein kinase identification web server, PKIS, is here presented for the identification of the protein kinases responsible for experimentally verified P sites at high specificity, which incorporates the composition of monomer spectrum (CMS) encoding strategy and support vector machines (SVMs). Compared to widely used P-site prediction tools including KinasePhos 2.0, Musite, and GPS2.1, PKIS largely outperformed these tools in identifying protein kinases associated with known P-sites. In addition, PKIS was used on all the P-sites in Phospho.ELM that currently lack kinase information. It successfully identified 14 potential SYK substrates with 36 known P-sites. Further literature search showed that 5 of them were indeed phosphorylated by SYK. Finally, an enrichment analysis was performed and 6 significant SYK-related signal pathways were identified. CONCLUSIONS: In general, PKIS can identify protein kinases for experimental phosphorylation sites efficiently. It is a valuable bioinformatics tool suitable for the study of protein phosphorylation. The PKIS web server is freely available at http://bioinformatics.ustc.edu.cn/pkis. PMID- 23941209 TI - Consistency of arm and leg coordination measures. AB - Reliability and objectivity coefficients were computed for test items purportedly measuring arm and leg coordination. Data was collected from 96 resident high school students at Lincoln School, Simpsonville, Kentucky. Reliability coefficients ranged from .421 to .909. Objectivity coefficients ranged from .923 to .970, indicating high objectivity. PMID- 23941208 TI - Children use temporal cues to learn causal directionality. AB - The ability to learn the direction of causal relations is critical for understanding and acting in the world. We investigated how children learn causal directionality in situations in which the states of variables are temporally dependent (i.e., autocorrelated). In Experiment 1, children learned about causal direction by comparing the states of one variable before versus after an intervention on another variable. In Experiment 2, children reliably inferred causal directionality merely from observing how two variables change over time; they interpreted Y changing without a change in X as evidence that Y does not influence X. Both of these strategies make sense if one believes the variables to be temporally dependent. We discuss the implications of these results for interpreting previous findings. More broadly, given that many real-world environments are characterized by temporal dependency, these results suggest strategies that children may use to learn the causal structure of their environments. PMID- 23941206 TI - The location-specific role of proteoglycans in the flexor carpi ulnaris tendon. AB - Tendons like the flexor carpi ulnaris (FCU) that contain region-specific distributions of proteoglycans (PGs) as a result of the heterogeneous, multi axial loads they are subjected to in vivo provide valuable models for understanding structure-function relationships in connective tissues. However, the contributions of specific PGs to FCU tendon mechanical properties are unknown. Therefore, the objective of this study was to determine how the location dependent, viscoelastic mechanical properties of the FCU tendon are impacted individually by PG-associated glycosaminoglycans (GAGs) and by two small leucine rich proteoglycans (SLRPs), biglycan and decorin. Full length FCU tendons from biglycan- and decorin-null mice were compared to wild-type (WT) mice to evaluate the effects of specific SLRPs, while chondroitinase ABC digestion of isolated specimens removed from the tendon midsubstance was used to determine how chondroitin/dermatan sulfate (CS/DS) GAGs impact mechanics in mature FCU tendons. A novel combined genetic knockout/digestion technique also was employed to compare SLRP-null and WT tendons in the absence of CS/DS GAGs that may impact properties in the mature state. In all genotypes, mechanical properties in the FCU tendon midsubstance were not affected by GAG digestion. Full-length tendons exhibited complex, multi-axial deformation under tension that may be associated with their in vivo loading environment. Mechanical properties were adversely affected by the absence of biglycan, and a decreased modulus localized in the center of the tendon was measured. These results help elucidate the role that local alterations in PG levels may play in processes that adversely impact tendon functionality including injury and pathology. PMID- 23941210 TI - Toward a process-oriented theory of human skilled performance. AB - Skilled perceptual-motor performance should be approached from a point of view of the processing operations performed by S in a skilled task. This perspective is emphasized in recent attempts to develop analytic or computer-simulation models of tracking tasks. These models are illustrated, and it is argued that a model that has a discrete correction compensatory path and a continuously programmed pursuit path may form one starting point for a more general representation. This representation needs to incorporate as yet undefined processing and storage units to handle coherence prediction, memorized movement patterns, and compensation for external system dynamics. PMID- 23941211 TI - Effects of visual feedback delay on simulated automobile steering. AB - Visual feedback delay in simulated automobile steering was investigated by means of a televised road display and a laboratory real-time computer system for producing steering delays. Transmission lags of 0.2 and 0.4 sec. were used, which were assumed to approximate feedback delays which occur in driving modern passenger cars with powered steering. A non-confounding experimental design was used to compare learning and transfer of learning under three conditions of delayed steering feedback of 0.0, 0.2, and 0.4 sec. Results showed that the steering delays severely impaired driving accuracy and learning in the simulated driving situation and that delayed steering feedback, rather than the stimulus controlled reaction time of the driver, is a primary factor in loss of control of a car in emergency and difficult driving situations. PMID- 23941212 TI - Functional properties of supplementary feedback stimuli. AB - Performance on a psychomotor learning task was facilitated by supplementary feedback stimuli which had been endowed with special significance by a preliminary sensitization procedure, but it was un-affected by these stimuli in the absence of such experience. The persistence of the facilitative effect well beyond the termination of feedback supports the inference that the sensitization experience invested the stimuli with reinforcing properties. PMID- 23941213 TI - Recovery of lost transfer effects. AB - Tracking tasks known to facilitate or interfere with one another were investigated under various sequences of alternation. Double and treble alternating sequences of 2 tasks were used. 6 groups of 12 Ss practiced for 20 10 sec. trials, with 50-sec. intertrial intervals. Trend analyses were employed in comparing the results of the double and treble alternating sequences with the single alternating sequence and postshift trials of the previous study (Laszlo & Pritchard, 1969). The results showed that facilitation or interference lost with single alternation was recovered with double or treble alternating sequences. Rate and degree of recovery appeared to depend upon the degree of transfer between tasks and strategies employed by S. These results were discussed in terms of motor program consolidation. PMID- 23941214 TI - Subject and experimenter errors in behavioral research with particular reference to motor behavior. AB - Sources of error stemming from S and E and their interaction were identified, their prevalence in behavioral science research discussed, and means for eliminating or discounting them suggested. The findings reviewed indicated that E may bias his findings by indicating to S the demand characteristics of the experimental situation. S errors include such behavior as trying to be over helpful, attempting to defeat E's intentions, and the Hawthorne effect. Errors from E may arise by transmitting subtle cues to S as to the hypothesized outcome of the experiment, E's various characteristics, situational factors, and intentional errors. The applicability of these errors to mo tor behavior research was discussed. PMID- 23941215 TI - Homochiral helical metal-organic frameworks of group 1 metals. AB - The reactions of (S)-2-(1,8-naphthalimido)propanoic acid (HL(ala)) and (S)-2-(1,8 naphthalimido)-3-hydroxypropanoic acid (HL(ser)), protonated forms of ligands that contain a carboxylate donor group, an enantiopure chiral center, and a 1,8 naphthalimide pi...pi stacking supramolecular tecton and in the case of HL(ser) an alcohol functional group, with the appropriate alkali metal hydroxide followed by a variety of crystallization methods leads to the formation of crystalline K(L(ala))(MeOH) (1), K(L(ala))(H2O) (2), Na(L(ala))(H2O) (3), KL(ser) (4), CsL(ser) (5), and CsL(ala) (6). Each of these new complexes has a solid state structure based on six-coordinate metals linked into homochiral helical rod secondary building unit (SBU) central cores. In addition to the bonding of the carboxylate and solvent (in the case of L(ser) the ligand alcohol) to the metals, both oxygens on the 1,8-naphthalimide act as donor groups. One naphthalimide oxygen bonds to the same helical rod SBU as the carboxylate group of that ligand forming a chelate ring. The other naphthalimide oxygen bonds to adjacent SBUs. In complexes 1-3, this inter-rod link has a square arrangement bonding four other rods forming a three-dimensional enantiopure metal-organic framework (MOF) structure, whereas in 4-6 this link has a linear arrangement bonding two other rods forming a two-dimensional, sheet structure. In the latter case, the third dimension is supported exclusively by interdigitated pi...pi stacking interactions of the naphthalimide supramolecular tecton, forming enantiopure supramolecular MOF solids. Compounds 1-3 lose the coordinated solvent when heating above 100 degrees C. For 1, the polycrystalline powder reverts to 1 only by recrystallization from methanol, whereas compounds 2 and 3 undergo gas/solid, single-crystal to single-crystal transformations to form dehydrated compounds 2* and 3*, and rehydration occurs when crystals of these new complexes are left out in air. The reversible single-crystal to single-crystal transformation of 2 involves the dissociation/coordination of a terminal water ligand, but the case of 3 is remarkable considering that the water that is lost is the only bridging ligand between the metals in the helical rod SBU and a carboxylate oxygen that is a terminal ligand in 3 moves into a bridging position in 3* to maintain the homochiral helical rods. Both 2* and 3* contain five-coordinate metals. There are no coordinated solvents in compounds 4-6, in two cases by designed ligand modification, which allows them to have high thermal stability. Compounds 1-3 did not exhibit observable Second Harmonic Generation (SHG) efficiency at an incident wavelength of 1064 nm, but compounds 4-6 did exhibit modest SHG efficiency for MOF-like compounds in the range of 30 * alpha-SiO2. PMID- 23941216 TI - Comparison of transmission parameters between Anopheles argyritarsis and Anopheles pseudopunctipennis in two ecologically different localities of Bolivia. AB - BACKGROUND: Anopheles (Anopheles) pseudopunctipennis is a recognized malaria vector in the slopes of the Andes of Bolivia. There, other species might be involved in malaria transmission and one candidate could be Anopheles argyritarsis. Although it is generally admitted that this species is not a malaria vector in the neotropical region, its potential role in transmission is still controversial and this situation has to be cleared, at least for Bolivia. Comparing the vectorial efficiency of An. pseudopunctipennis with that of An. argyritarsis could solve the question. METHODS: The two species were sampled throughout Bolivia to estimate their degree of co-existence in their distribution range. Vectorial efficiencies of the two species were compared in two ecologically different localities where the species were sympatric by analysing their vectorial capacities and components (i e, human biting rates, human biting index, survival, durations of the gonotrophic cycle and extrinsic cycle), and the entomological inoculation rates (EIR). Mosquitoes were sampled monthly during more than one year in the two localities. A monthly sample consisted in hourly captures in four houses (inside and outside) in each locality, during four consecutive nights. Climatic variables (temperature, humidity, potential evapo transpiration and precipitations) were recorded to better understand variability in the entomological parameters. Relationships were analysed using multivariate methods. RESULTS: Anopheles pseudopunctipennis and An. argyritarsis are "altitude" species, sharing the same geographical distribution range in the Andes of Bolivia. No Plasmodium parasite was identified in An. argyritarsis and estimates of the vectorial capacity indicated that it is not a malaria vector in the two studied localities, unlike An. pseudopunctipennis which showed positive EIRs. This latter species, although not a very good malaria vector, exhibited better life traits values and better behavioural characteristics in favour of transmission as compared to An. argyritarsis. CONCLUSIONS: In the Andes of Bolivia, above 1000 m of altitude, An. pseudopunctipennis is likely to be the only malaria vector. There, it is present almost everywhere and priority control effort should be directed toward this species. Below 1000 m of altitude, vector incrimination should also be focused on other sympatric species (likely not An. argyritarsis) that might be locally important. From the present study, candidates would be among Anopheles rangeli, Anopheles triannulatus s.l., Anopheles trinkae, Anopheles nuneztovari s.l., Anopheles oswaldoi s.l. and Anopheles benarrochi s.l. PMID- 23941218 TI - Introduction: occupational therapy practice and research with persons with multiple sclerosis. PMID- 23941219 TI - Multiple perspectives on the health service need, use, and variability among older adults with multiple sclerosis. AB - SUMMARY The purpose of this paper is to present the findings from the first phase of a large study that is examining the unmet health-related service needs of people aging with MS. Fifty-one volunteers participated in seven focus groups five with individuals with MS and their family members, and two with health care professionals. Content analysis indicated health promotion (both physical and social), community accessibility, and support to remain at home as the most commonly identified health-related service needs. Differences were observed between the groups of individuals with MS/family members and health professionals. Findings point to the importance of using a client-centered approach when working with persons with multiple sclerosis and their family members. PMID- 23941217 TI - Community perceptions of mental distress in a post-conflict setting: a qualitative study in Burundi. AB - There is scant documentation of the mental health characteristics of low-income communities recovering from armed conflict. To prepare for quantitative health surveys and health service planning in Burundi, we implemented a qualitative study to explore concepts related to mental distress and coping among adults. Mental distress was defined as problems related to feelings, thinking, behaviour and physical stress. Using free listing and key informant interviews with a range of community members, we triangulated data to identify salient issues. Thirty eight free list respondents and 23 key informants were interviewed in 5 rural communities in Burundi using 2 interview guides from the WHO Toolkit for Mental Health Assessment in Humanitarian Settings. Based on these interviews, we identified four locally defined idioms/terms relating to mental distress: ihahamuka (anxiety spectrum illnesses), ukutiyemera (a mix of depression and anxiety-like syndrome), akabonge (depression/grief-like syndrome) and kwamana ubwoba burengeje (anxiety-like syndrome). Mental distress terms were perceived as important problems impacting community development. Affected individuals sought help from several sources within the community, including community leaders and traditional healers. We discuss how local expressions of distress can be used to tailor health research and service integration from the bottom up. PMID- 23941220 TI - Analysis of symptoms, functional impairments, and participation in occupational therapy for individuals with multiple sclerosis. AB - SUMMARY The aim of this study was to identify client factors that may influence physicians' decision to refer individuals with multiple sclerosis (MS) to occupational therapy (OT). Study participants were seen in an MS clinic in which a physician referral was required prior to receipt of OT services. The symptoms and functional impairments of 40 individuals with MS who were either seen or not seen for OT services were compared. Findings show that individuals with MS who were referred to OT reported more difficulties with speaking or swallowing, hand tremors, uncontrolled urinary urgency, weakness of the legs, and performing functional activities than individuals with MS who did not receive OT services. Results also suggest that difficulties in functional mobility, work, community mobility and meal preparation were more likely to prompt OT referral and subsequent therapy for individuals who had attended the MS Clinic than any specific sign or symptom. PMID- 23941221 TI - Self-report assessment of fatigue in multiple sclerosis: a critical evaluation. AB - SUMMARY Fatigue is among the most common and disabling symptoms of multiple sclerosis. Clinicians usually assess fatigue by asking people to describe and rate their fatigue in a self-report instrument. This paper evaluates the clinical usefulness and the scientific properties of a selection of various self-report instruments for fatigue. To be selected, instruments had to assess fatigue or a related concept, have some published information on reliability and validity, be used in at least one clinical trial of fatigue with people with multiple sclerosis, and demonstrate validity in people with MS. Five fatigue specific scales and four subscales of quality of life instruments were selected and evaluated. In occupational therapy, the fatigue subscales or items of quality of life measurements give limited information about the quality of fatigue. The selection of an instrument may depend on the clinical setting or trial design. PMID- 23941222 TI - The effect of wheelchair use on the quality of life of persons with multiple sclerosis. AB - SUMMARY This pilot study describes the effect of wheelchair use on the quality of life of persons with multiple sclerosis (MS), and examines the clinical utility of the Psychosocial Impact of Assistive Devices Scale (PIADS) as an outcome measure for use by occupational therapists. Sixteen hospitalized adults with MS were interviewed using the PIADS. Descriptive comparisons of PIADS subscale scores (competence, adaptability, self-esteem) were conducted for participants using different types of wheelchairs, daily versus non-daily wheelchair users, and participants who required different levels of assistance to propel their wheelchairs. Results suggest that using a wheelchair has a positive impact on the quality of life of persons with MS. The PIADS was found to be clinically useful for exploring person-environment interactions and appears to be well suited to the goals and values of occupational therapy. Recommendations for future research and for incorporating the PIADS into occupational therapy practice are discussed. PMID- 23941223 TI - Interference of upper limb tremor on daily life activities in people with multiple sclerosis. AB - SUMMARY The interference of upper limb intention tremor on activities of daily living was described in 32 persons with multiple sclerosis. Ratings about their degree of impairment and disability (Functional Systems, Expanded Disability Status Scale, Functional Independence Measure) was obtained from the multidisciplinary rehabilitation team. The individuals were interviewed using a questionnaire, mainly based on the items of the FIM scale, about the interference of tremor during activities of daily life. Intention tremor is rarely an isolated symptom. It is extremely disabling and was reported to interfere the most with activities of daily life such as eating, drinking, grooming and dressing. A variety of aids and strategies to compensate for specific disabilities were reported reflecting the important counseling role of the occupational therapist in assisting persons to cope more effectively with tremor. PMID- 23941224 TI - Developing and implementing lifestyle management programs(c) with people with multiple sclerosis. AB - SUMMARY This paper describes the development and use of Lifestyle Management Programs(c) (LMPs) by occupational therapists at the Multiple Sclerosis Society of New South Wales, Australia. A case study is used to demonstrate how the program is applied in an individual situation. LMPs are used with people with MS, or their support people, to enable management of the impact of fluctuating and interactive physical, sensory and cognitive symptoms. LMPs are flexible and adaptable systems, allowing integration of information and strategies for managing symptoms. LMPs assist clients to sustain meaningful activities and life roles. Subjective client feedback supports the effectiveness of the programs in meeting specific individual goals. Formal outcome measures are being explored. PMID- 23941225 TI - In their own words: coping processes among women aging with multiple sclerosis. AB - SUMMARY People with multiple sclerosis (MS) employ a variety of coping mechanisms throughout the process of managing their disease. This study describes the coping processes used by women aging with MS. Participants in the study included 23 women living in the Chicago area aged 55 years or older and diagnosed with MS for a minimum of 15 years. Data were gathered through in-depth semi-structured qualitative interviews. Findings suggest that participants who reported integrating MS into their lives, had confidence in their abilities to cope with stress, and had a positive outlook on life appeared to employ action-oriented strategies to cope with their disease. Findings from the study offer ideas and direction for occupational therapy interventions for women aging with multiple sclerosis. PMID- 23941226 TI - Occupational Therapy Practice and Research with Persons with MS: Final Reflections. PMID- 23941227 TI - Preface: Perspectives of an MS Researcher. PMID- 23941228 TI - Foreword: a note of appreciation from a grateful recipient. PMID- 23941229 TI - Survey of bluetongue virus infection in free-ranging wild ruminants in Switzerland. AB - BACKGROUND: In 2006, bluetongue virus serotype 8 (BTV-8) was detected for the first time in central Europe. Measures to control the infection in livestock were implemented in Switzerland but the question was raised whether free-ranging wildlife could be a maintenance host for BTV-8. Furthermore Toggenburg orbivirus (TOV), considered as a potential 25th BTV serotype, was detected in 2007 in domestic goats in Switzerland and wild ruminants were considered a potential source of infection. To assess prevalences of BTV-8 and TOV infections in wildlife, we conducted a serological and virological survey in red deer, roe deer, Alpine chamois and Alpine ibex between 2009 and 2011. Because samples originating from wildlife carcasses are often of poor quality, we also documented the influence of hemolysis on test results, and evaluated the usefulness of confirmatory tests. RESULTS: Ten out of 1,898 animals (0.5%, 95% confidence interval 0.3-1.0%) had detectable antibodies against BTV-8 and BTV-8 RNA was found in two chamois and one roe deer (0.3%, 0.1-0.8%). Seroprevalence was highest among red deer, and the majority of positive wild animals were sampled close to areas where outbreaks had been reported in livestock. Most samples were hemolytic and the range of the optical density percentage values obtained in the screening test increased with increasing hemolysis. Confirmatory tests significantly increased specificity of the testing procedure and proved to be applicable even on poor quality samples. Nearly all samples confirmed as positive had an optical density percentage value greater than 50% in the ELISA screening. CONCLUSIONS: Prevalence of BTV-8 infection was low, and none of the tested animals were positive for TOV. Currently, wild ruminants are apparently not a reservoir for these viruses in Switzerland. However, we report for the first time BTV-8 RNA in Alpine chamois. This animal was found at high altitude and far from a domestic outbreak, which suggests that the virus could spread into/through the Alps. Regarding testing procedures, hemolysis did not significantly affect test results but confirmatory tests proved to be necessary to obtain reliable prevalence estimates. The cut-off value recommended by the manufacturer for the screening test was applicable for wildlife samples. PMID- 23941230 TI - Nucleic acid sample preparation using spontaneous biphasic plug flow. AB - Nucleic acid (NA) extraction and purification has become a common technique in both research and clinical laboratories. Current methods require repetitive wash steps with a pipet that are laborious and time-consuming, making the procedure inefficient for clinical settings. We present here a simple technique that relies on spontaneous biphasic plug flow inside a capillary to achieve sample preparation. By filling the sample with oil, aqueous contaminants were displaced from the captured NA without pipetting wash buffers or use of external force and equipment. mRNA from mammalian cell culture was purified, and polymerase chain reaction (PCR) amplification showed similar threshold cycle values as those obtained from a commercially available kit. Human immunodeficiency virus (HIV) viral-like particles were spiked into serum and a 5-fold increase in viral RNA extraction yield was achieved compared to the conventional wash method. In addition, viral RNA was successfully purified from human whole blood, and a limit of detection of approximately 14 copies of RNA extracted per sample was determined. The results demonstrate the utility of the current technique for nucleic acid purification for clinical purposes, and the overall approach provides a potential method to implement nucleic acid testing in low-resource settings. PMID- 23941231 TI - Secondary analysis of publicly available data reveals superoxide and oxygen radical pathways are enriched for associations between type 2 diabetes and low frequency variants. AB - Genome-wide association studies explain at most 5%-10% of the heritable components of type 2 diabetes. Some of the "missing type 2 diabetes heritability" could be explained by low-frequency variants. We examined the associations between low-frequency variants and type 2 diabetes, using data from 2538 diabetic and 2977 nondiabetic subjects in the publicly available database of Genotypes and Phenotypes. We applied two approaches. First, we combined information from all low-frequency (1%-5%) variants at a locus in a gene-centric analysis of associations with diabetes. Next, we searched for gene ontology (GO) biological processes that were enriched for gene-centric associations, after correcting for multiple testing to control the false discovery rate (FDR). We found three GO biological processes that were significantly enriched for associations to diabetes: "response to superoxide" (FDR-adjusted p=2.7*10(-3)), "response to oxygen radical" (FDR-adjusted p=2.7*10(-3)), and "heart contraction" (FDR adjusted p=2.6*10(-2)). There were three genes that contributed to "response to superoxide" and "oxygen radical" pathways, including the SOD1 gene. Gene-centric tests of association with low-frequency variants, followed by analysis to evaluate which biological pathways are enriched for these associations has the potential to recover, at least some proportion of, the "missing heritability" of type 2 diabetes. PMID- 23941234 TI - Fabrication of cobalt-nickel binary nanowires in a highly ordered alumina template via AC electrodeposition. AB - Cobalt-nickel (Co-Ni) binary alloy nanowires of different compositions were co deposited in the nanopores of highly ordered anodic aluminum oxide (AAO) templates from a single sulfate bath using alternating current (AC) electrodeposition. AC electrodeposition was accomplished without modifying or removing the barrier layer. Field emission scanning electron microscope was used to study the morphology of templates and alloy nanowires. Energy-dispersive X-ray analysis confirmed the deposition of Co-Ni alloy nanowires in the AAO templates. Average diameter of the alloy nanowires was approximately 40 nm which is equal to the diameter of nanopore. X-ray diffraction analysis showed that the alloy nanowires consisted of both hexagonal close-packed and face-centered cubic phases. Magnetic measurements showed that the easy x-axis of magnetization is parallel to the nanowires with coercivity of approximately 706 Oe. AC electrodeposition is very simple, fast, and is useful for the homogenous deposition of various secondary nanostuctured materials into the nanopores of AAO. PMID- 23941232 TI - Manufacturing porcine islets: culture at 22 degrees C has no advantage above culture at 37 degrees C: a gene expression evaluation. AB - BACKGROUND: The manufacturing process of islets includes a culture step which was originally introduced to ease the logistics of procedures in preparing the graft and transplant recipient. It has been suggested that culture at room temperature has an advantage over culture at 37 degrees C, in part by reducing immunogenicity via preferential elimination of contaminating cells (such as passenger leukocytes) within islets. We investigated this using islets isolated from pancreata of adult pigs. METHODS: Porcine islets were isolated from three donors and cultured at 37 degrees C for 1 day, and then under three different conditions: 37 degrees C for 6 days (condition A); 22 degrees C for 6 days (condition B); or 22 degrees C for 5 days followed by 37 degrees C for 1 day (condition C). Recovery was assessed by DNA measurement, viability by oxygen consumption rate normalized for DNA (OCR/DNA), and gene expression by RT-PCR for a series of 9 lymphocyte markers, 11 lymphokines and chemokines, and 14 apoptotic and stress markers. RESULTS: Post-culture islet recoveries were similar for the three culture conditions. Average OCR/DNA values were 129-159 nmol/min.mgDNA before culture, and 259-291, 204-212, and 207-228 nmol/min.mgDNA, respectively, for culture under conditions A, B, and C, respectively. Irrespective of culture condition, examined gene expression in all three series of lymphocyte markers, lymphokines and chemokines, and apoptotic and stress markers manifested a statistically significant decrease upon culture for 7 days. This decrease was most dramatic for condition A: in particular, most of lymphocyte markers showed a >10-fold reduction and also six markers in the lymphokine and chemokine series; these reductions are consistent with the elimination of immune cells present within islets during culture. The reduction was less for apoptotic and stress markers. For culture under condition B, the reduction in gene expression was less, and culture under condition C resulted in gene expression levels similar to those under condition A: this indicates that 24 h at 37 degrees C is sufficient to re-equilibrate gene expression levels from those in islets cultured at 22 degrees C to those in islets cultured at 37 degrees C. Results were consistent among the preparations from the three donors. CONCLUSIONS: Culture of porcine islets at 37 degrees C provides benefits over culture at 22 degrees C with respect to OCR/DNA outcomes and reduced expression of genes encoding lymphocyte markers, lymphokines and chemokines, and markers for apoptosis and stress. PMID- 23941233 TI - Association of Hg2+ with aqueous (C60)n aggregates facilitates increased bioavailability of Hg2+ in Zebrafish (Danio rerio). AB - Manufactured nanoparticles (NPs) can associate with toxicants in the aqueous phase and these associations can influence the environmental fate, transport, and bioavailability of these toxicants in organisms. Dissolved metals (e.g., Hg(2+)) can be toxic in aquatic organisms, and, if metals associate with NPs in the aqueous phase, changes in bioavailability and toxicology may result. Here we demonstrated that Hg(2+) (25 MUg/L) can associate with aqueous (C60)n (termed nC60) and increase aggregate size and settlement of nC60 aggregates out of the water column over 24 h. The concentration of C60 was directly related to concentration of Hg for nC60 aggregates that settled to the bottom of the container. Bioavailability of Hg(2+) in larval zebrafish Danio rerio, evaluated by assessment of metallothionein gene (mt2) expression, was reduced in the water column when nC60was present. However, zebrafish residing at the container bottom and exposed to nC60 aggregates with associated Hg(2+) had elevated expression of mt2 when compared to fish exposed to 25 MUg/L Hg(2+) preparations without nC60, which indicated nC60 led to a localized increase in Hg(2+) bioavailability. Results indicate that aqueous nC60 can sorb Hg(2+), transport Hg(2+) to substrate surface, and increase concentrations of bioavailable Hg(2+) in organisms located where settled nC60 aggregates accumulate. PMID- 23941235 TI - Design and evaluation of an i-motif-based allosteric control mechanism in DNA hairpin molecular devices. AB - Molecular devices designed to assess and manipulate biologically relevant conditions with required accuracy and precision play an essential role in life sciences research. Incorporating allosteric regulation mechanism is an attractive strategy toward more efficient artificial sensing and switching systems. Herein, we report on a new principle of regulating switching parameters of a DNA-based molecular device based on allosteric interaction between spatially separated hairpin stem and a tetraplexed fragment (i.e., i-motif). We characterized thermodynamic and kinetic effects arising from interaction between functional domains of the device and demonstrated the potential of applying the allosteric control principle for rational design of sensors and switches with precisely defined operational characteristics. PMID- 23941236 TI - Comparison of whole genome amplification and nested-PCR methods for preimplantation genetic diagnosis for BRCA1 gene mutation on unfertilized oocytes a pilot study. AB - BACKGROUND: Preimplantation genetic diagnosis (PGD) remains nowadays a valid alternative for couples at high-risk of having a child with a genetic disease and for women older than 37-40 years with the high risk of chromosomal aneuploidies in the embryos. However the use of PGD for high penetrance recessive, dominant and X-liked disorders occurring in early life is documented, debate exists regarding its appropriateness in lower penetrance and late-onset cancer susceptibility syndromes. The data regarding the efficacy of different molecular techniques used in PGD are still lacking. We therefore sought to assess the different molecular techniques used in PGD for detecting three most frequent BRCA1 gene mutations: 5382insC, 185delAG and C61G. METHODS: Anonymous donors of the oocytes and control healthy blood samples were extracted and analyzed in the Fertility and Reproductive Center Invicta in Gdansk. Preimplantation genetic diagnosis for the most frequent mutations: 185delAG, 5382insC, C61G in BRCA 1 gene was carried out on single, unfertilized oocytes, in metaphase of second meiotic division, not qualified to IVF. Positive mutation controls were represented by cell lines from the Coriell Institute for Medical Research: GM14090 (185delAG), GM14097 (C61G), GM13715 (5382insC). RESULTS: Repeatability of the results acquired from the WGA analysis for the mutation 5382insC was 38%. The repeatability of the nested-PCR analysis in the second round of the amplification was labile for the mutation 5382insC and 185delAG and was ranged from 47% to 57%. However, the repeatability for the mutation C61G was 100%. CONCLUSIONS: Our results suggest that the nested-PCR technique remains more sensitive and specific method as compared to WGA. WGA performed on the single cells did not reflect expected results. The repeatability of the WGA methodology remains questionable, and any analysis attempt does not guarantee reliable results. Further evaluation is strongly needed to propose the most accurate molecular technique used in PGD for detecting three most frequent BRCA1 gene mutations: 5382insC, 185delAG and C61G. PMID- 23941237 TI - Mucosal microfolds augment mixing at the wall of the distal ileum of the brushtail possum. AB - BACKGROUND: Recent work suggests that mixing in the small intestine takes place in central luminal and peripheral compartments. However, while movements of villi have been described, the mechanisms by which peripheral mixing are engendered remain unclear. METHODS: We examined the disposition and movement of mucosa and associated villi during contractions of the everted terminal ileum of the brushtail possum. We then simulated the effect of these movements on peripheral mixing. KEY RESULTS: Compression of the intestinal mucosa by phasic longitudinal or radial contractions created short-lived microfolds, which were of similar scale to the attached villi. The packing density of the villous tips increased in the concavities and decreased on the crests of these microfolds. Simulations showed that these caused liquid digesta to be expelled from, or drawn into, intervillous spaces, significantly augmenting peripheral, but not bulk, luminal mixing. CONCLUSIONS & INFERENCES: We describe a mechanism by which peripheral mixing may be engendered by mucosal microfolds without requiring the coordinated contraction of individual villi or groups of villi. PMID- 23941238 TI - Bonding with parallel spins: high-spin clusters of monovalent metal atoms. AB - Bonding is a glue of chemical matter and is also a useful concept for designing new molecules. Despite the fact that electron pairing remains the bonding mechanism in the great majority of molecules, in the past few decades scientists have had a growing interest in discovering novel bonding motifs. As this Account shows, monovalent metallic atoms having exclusively parallel spins, such as (11)Li10, (11)Au10, and (11)Cu10, can nevertheless form strongly bound clusters, without having even one traditional bond due to electron pairing. These clusters, which also can be made chiral, have high magnetic moments. We refer to this type as no-pair ferromagnetic (NPFM) bonding, which characterizes the (n+1)Mn clusters, which were all predicted by theoretical computations. The small NPFM alkali clusters that have been "synthesized" to date, using cold-atom techniques, support the computational predictions. In this Account, we describe the origins of NPFM bonding using a valence bond (VB) analysis, which shows that this bonding motif arises from bound triplet electron pairs that spread over all the close neighbors of a given atom in the cluster. The bound triplet pair owes its stabilization to the resonance energy provided by the mixing of the local ionic configurations, [(3)M(??)(-)]M(+) and M(+)[(3)M(??)(-)], and the various excited covalent configurations (involving pz and dz(2) atomic orbitals) into the repulsive covalent structure (3)(M??M) with the s(1)s(1) electronic configuration. The NPFM bond of the bound triplet is described by a resonating wave function with "in-out" and "out-in" pointing hybrids. The VB model accounts for the tendency of NPFM clusters to assume polyhedral shapes with rather high symmetry. In addition, this model explains the very steep rise of the bonding energy per atom (De/n), which starts out small in the (3)M2 dimer (<1 kcal/mol) and reaches 12-19 kcal/mol for clusters with 10 atoms. The model further predicts that usage of heteroatomic clusters should increase the bonding energy of an NPFM cluster. These NPFM clusters are excited state species. We suggest here stabilizing these states and making them accessible, for example, by using magnetic fields, or a combination of magnetic and electric fields. The advent of NPFM clusters offers new horizons in chemistry and enriches the scope of chemical bonding. These prospects form a strong incentive to investigate the origins of the bound triplet pairs and further chart the territory of NPFM clusters, for example, in clusters of Be, Mg, or Zn, possibly in clusters of their monosubstituted species, and the group III metalloids, such as B, Al, as well as in transition metals such as Sc. PMID- 23941240 TI - A quantitative empirical analysis of the abstract/concrete distinction. AB - This study presents original evidence that abstract and concrete concepts are organized and represented differently in the mind, based on analyses of thousands of concepts in publicly available data sets and computational resources. First, we show that abstract and concrete concepts have differing patterns of association with other concepts. Second, we test recent hypotheses that abstract concepts are organized according to association, whereas concrete concepts are organized according to (semantic) similarity. Third, we present evidence suggesting that concrete representations are more strongly feature-based than abstract concepts. We argue that degree of feature-based structure may fundamentally determine concreteness, and we discuss implications for cognitive and computational models of meaning. PMID- 23941239 TI - Pleiotropic effect of sigE over-expression on cell morphology, photosynthesis and hydrogen production in Synechocystis sp. PCC 6803. AB - Over-expression of sigE, a gene encoding an RNA polymerase sigma factor in the unicellular cyanobacterium Synechocystis sp. PCC 6803, is known to activate sugar catabolism and bioplastic production. In this study, we investigated the effects of sigE over-expression on cell morphology, photosynthesis and hydrogen production in this cyanobacterium. Transmission electron and scanning probe microscopic analyses revealed that sigE over-expression increased the cell size, possibly as a result of aberrant cell division. Over-expression of sigE reduced respiration and photosynthesis activities via changes in gene expression and chlorophyll fluorescence. Hydrogen production under micro-oxic conditions is enhanced in sigE over-expressing cells. Despite these pleiotropic phenotypes, the sigE over-expressing strain showed normal cell viability under both nitrogen replete and nitrogen-depleted conditions. These results provide insights into the inter-relationship among metabolism, cell morphology, photosynthesis and hydrogen production in this unicellular cyanobacterium. PMID- 23941241 TI - Fluorescent dye cocktail for multiplex drug-site mapping on human serum albumin. AB - Elucidating how molecules bind to HSA is fundamental for predicting drug incompatibilities. Through combinatorial screening, we identified a novel fluorescent dye (BD140) with turn-on fluorescence emission and specific binding at HSA drug site 2. We further combined it with dansylamide to develop a fluorescent dye cocktail for high-throughput mapping of the interaction between therapeutics at HSA drug-binding sites. PMID- 23941242 TI - Transcranial high intensity focused ultrasound therapy guided by 7 TESLA MRI in a rat brain tumour model: a feasibility study. AB - PURPOSE: Transcranial high intensity focused ultrasound (HIFU) therapy guided by magnetic resonance imaging (MRI) is a promising approach for the treatment of brain tumours. Our objective is to validate a dedicated therapy monitoring system for rodents for transcranial HIFU therapy under MRI guidance in an in vivo brain tumour model. MATERIALS AND METHODS: A dedicated MR-compatible ultrasound therapy system and positioning frame was developed. Three MR-compatible prefocused ultrasonic monoelement transducers were designed, operating at 1.5 MHz and 2.5 MHz with different geometries. A full protocol of transcranial HIFU brain therapy under MRI guidance was applied in n = 19 rats without and n = 6 rats with transplanted tumours (RG2). Different heating strategies were tested. After treatment, histological study of the brain was performed in order to confirm thermal lesions. RESULTS: Relying on a larger aperture and a higher frequency, the 2.5 MHz transducer was found to give better results than other ones. This single element transducer optimised the ratio of the temperature elevation at the focus to the one at the skull surface. Using optimised transducer and heating strategies enabled thermal necrosis both in normal and tumour tissues as verified by histology while limiting overheating in the tissues in contact with the skull. CONCLUSIONS: In this study, a system for transcranial HIFU therapy guided by MRI was developed and tested in an in vivo rat brain tumour model. The feasibility of this therapy set-up to induce thermal lesions within brain tumours was demonstrated. PMID- 23941243 TI - Comment on Jackson et al. 'impact of Lepeophtheirus salmonis infestations on migrating Atlantic salmon, Salmo salar L., smolts at eight locations in Ireland with an analysis of lice-induced marine mortality'. PMID- 23941245 TI - Too much surgery and too little benefit? Sentinel node biopsy for melanoma as it currently stands. PMID- 23941244 TI - Differential gene expression profiles of PPP2R5C-siRNA-treated malignant T cells. AB - Recently, alterations in the expression pattern of PPP2R5C associated with malignant transformation have been characterized, and PPP2R5C overexpression was demonstrated in leukemias. To confirm the role of PPP2R5C in proliferation and its molecular mechanism, three PPP2R5C-siRNAs and a scrambled nonsilencing siRNA control were used to treat Molt-4 and Jurkat T cells. After nucleofection, PPP2R5C expression and biological consequences based on a highly efficient and specific PPP2R5C-siRNA were demonstrated by qRT-PCR, CCK-8 assay, Annexin V/PI, and flow cytometry. The global gene expression profile of PPP2R5C-siRNA-treated Jurkat T cells was established. A significant reduction in the PPP2R5C mRNA level was observed at 24 to 72 h in Molt-4 and Jurkat T cells with all of the PPP2R5C siRNAs. The proliferation rate of Molt-4 and Jurkat T cells transfected with different PPP2R5C-siRNAs was significantly decreased at 72 h compared with the control (p<0.05). However, the transfected cells did not show a significant increase in Annexin V/PI-positive cells (apoptosis). The highly efficient PPP2R5C siRNA2 was used to treat Jurkat T cells for gene expression profile analysis. In total, 439 genes were upregulated, and 524 genes were downregulated at least twofold in PPP2R5C-siRNA-treated Jurkat T cells. Changes in signaling pathway genes closely related to the TCR, Wnt, calcium, MAPK, and p53 signaling pathways were observed. In conclusion, the suppression of PPP2R5C by RNA interference could effectively inhibit the proliferation of leukemic T cells, the PPP2R5C siRNA treatment altered gene expression profiles, and the differential expression of the glycogen synthase kinase 3 beta (GSK-3beta), ataxia telangiectasia mutated (ATM), and Mdm2 p53 binding protein homolog (MDM2) genes may play an important role in the effects of PPP2R5C knockdown in Jurkat T cells. PMID- 23941246 TI - Sunbeds and young people: an easy target for legislation? PMID- 23941247 TI - The British Journal of Dermatology: 125 years, 28 editors, enduring values. PMID- 23941248 TI - Oral vitamin D supplementation vs. ultraviolet B exposure: what is appropriate to achieve a sufficient vitamin D level? PMID- 23941249 TI - Seeing is believing. PMID- 23941250 TI - Predicting response to anti-interleukin 12/23 treatment in psoriasis. PMID- 23941251 TI - Patient empowerment increases capacity and widens access to phototherapy. PMID- 23941252 TI - The mechanistic basis for psoriasis immunopathogenesis: translating genotype to phenotype. Report of a workshop, Venice, 2012. AB - The International Psoriasis Council, a global nonprofit organization dedicated to advancing psoriasis research and treatment, led an initiative to better define the pathogenic mechanisms that constitute psoriasis. In September 2012, a workshop was held at the 42nd Annual European Society for Dermatological Research in Venice, Italy. By assembling a panel of global dermatology and immunology experts, the objective was to evaluate the current status of the science explaining the mechanism of disease in psoriasis, e.g. dysregulation of the skin immune system and perturbations of epidermal homeostasis. The workshop consisted of four oral presentations, which addressed key topics in psoriasis, delivered by Herve Bachelez (Paris, France), Antonio Costanzo (Rome, Italy), Michelle Lowes (New York, NY, U.S.A.) and Frank Nestle (London, U.K.). A global expert panel was assembled to stimulate dialogue and debate: Kevin Cooper (Cleveland, OH, U.S.A.), Michel Gilliet (Lausanne, Switzerland), Joerg Prinz (Munich, Germany), Martin Rocken (Tubingen, Germany), Jens Schroeder (Kiel, Germany), Manuelle Viguier (Paris, France), Mayte Suarez-Farinas (New York, NY, U.S.A.) and Cristina Zielinski (Berlin, Germany). Collectively, the presentations demonstrated the significant advances in understanding immune regulation that have occurred over the past decade by virtue of the study of psoriasis subtypes, phenotypic manifestations and genetic associations. Elucidating the pathogenic and genetic basis of psoriasis holds the promise of a complete understanding of disease mechanisms, predictors of treatment response, novel drug development strategies and customized therapeutic regimens for the individual patient. PMID- 23941254 TI - Breastfeeding and maternal weight changes during 24 months post-partum: a cohort study. AB - The relationship between breastfeeding and the loss of weight gained during pregnancy remains unclear. This study aimed to investigate the association between breastfeeding and maternal weight changes during 24 months post-partum. We studied a dynamic cohort comprising 315 women living in two cities in the state of Bahia, Brazil. The outcome variable was change in the post-partum weight; the exposure variable was the duration and intensity of breastfeeding. Demographic, socio-economic, environmental, reproductive and lifestyle factors were integrated in the analysis as covariates. The data were analysed using multiple linear regression and linear mixed-effects models. The average cumulative weight loss at 6 months post-partum was 2.561 kg (SD 4.585), increasing at 12 months (3.066 kg; SD 5.098) and decreasing at 18 months (1.993 kg; SD 5.340), being 1.353 kg (SD, 5.574) at 24 months post-partum. After adjustment, the data indicated that for every 1-point increase in breastfeeding score, the estimated average post-partum weight loss observed was 0.191 kg at 6 months (P = 0.03), 0.090 kg at 12 months (P = 0.043), 0.123 kg at 18 months (P < 0.001) and 0.077 kg at 24 months (P = 0.001). Based on these results, we concluded that despite the low expressiveness, the intensity and duration of breastfeeding was associated with post-partum weight loss at all stages of the study during the 24-month follow-up. PMID- 23941256 TI - Efavirenz-induced gynecomastia in a prepubertal girl with human immunodeficiency virus infection: a case report. AB - BACKGROUND: Prepubertal gynecomastia is a rare condition and most frequently classified as idiopathic. In HIV-infected adults gynecomastia is a recognised but infrequent side-effect of antiretroviral treatment (ART) and mostly attributed to efavirenz use. Gynecomastia should be distinguished from pseudogynecomastia as part of the lipodystrophy syndrome caused by Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to avoid incorrect substitution of drugs. In the medical literature only five cases of prepubertal gynecomastia in children taking ART are described and underlying pathogenesis was unknown. The occurrence of adverse effects of ART may interfere with therapy adherence and long-term prognosis and for that reason requires attention. We report the first case of prepubertal gynecomastia in a young girl attributed to efavirenz use. CASE PRESENTATION: A seven-year-old African girl presented with true gynecomastia four months after initiation on ART (abacavir, lamivudine, efavirenz). History, physical examination and laboratory tests excluded known causes of gynecomastia and efavirenz was considered as the most likely cause. Six weeks after withdrawal of efavirenz the breast enlargement had completely resolved. CONCLUSIONS: Efavirenz induced gynecomastia may occur in children as well as in adults. With the increasing access to ART, the possibility of efavirenz-exposure and the potential occurrence of its associated side-effects may be high. In resource-poor settings, empirical change from efavirenz to nevirapine may be considered, providing no other known or alarming cause is identified, as efavirenz-induced gynecomastia can resolve quickly after withdrawal of the drug. Timely recognition of gynecomastia as a side-effect of efavirenz is important in order to intervene while the condition may still be reversible, to sustain adherence to ART and to maintain the sociopsychological health of the child. PMID- 23941255 TI - Changes in sub-cellular localisation of trophoblast and inner cell mass specific transcription factors during bovine preimplantation development. AB - BACKGROUND: Preimplantation bovine development is emerging as an attractive experimental model, yet little is known about the mechanisms underlying trophoblast (TE)/inner cell mass (ICM) segregation in cattle. To gain an insight into these processes we have studied protein and mRNA distribution during the crucial stages of bovine development. Protein distribution of lineage specific markers OCT4, NANOG, CDX2 were analysed in 5-cell, 8-16 cell, morula and blastocyst stage embryos. ICM/TE mRNA levels were compared in hatched blastocysts and included: OCT4, NANOG, FN-1, KLF4, c-MYC, REX1, CDX2, KRT-18 and GATA6. RESULTS: At the mRNA level the observed distribution patterns agree with the mouse model. CDX2 and OCT4 proteins were first detected in 5-cell stage embryos. NANOG appeared at the morula stage and was located in the cytoplasm forming characteristic rings around the nuclei. Changes in sub-cellular localisation of OCT4, NANOG and CDX2 were noted from the 8-16 cell onwards. CDX2 initially co localised with OCT4, but at the blastocyst stage a clear lineage segregation could be observed. Interestingly, we have observed in a small proportion of embryos (2%) that CDX2 immunolabelling overlapped with mitotic chromosomes. CONCLUSIONS: Cell fate specification in cattle become evident earlier than presently anticipated - around the time of bovine embryonic genome activation. There is an intriguing possibility that for proper lineage determination certain transcription factors (such as CDX2) may need to occupy specific regions of chromatin prior to its activation in the interphase nucleus. Our observation suggests a possible role of CDX2 in the process of epigenetic regulation of embryonic cell fate. PMID- 23941257 TI - Mechanisms of action of otilonium bromide (OB) in human cultured smooth muscle cells and rat colonic strips. AB - BACKGROUND: The pharmacological properties of otilonium bromide (OB) have been investigated using different experimental models, techniques, and conditions, and consequently, the results are not always easy to compare. The aim of the present work was to investigate the pharmacological properties of OB in human cultured colonic smooth muscle cells (HCSMCs), which is the main target of the drug 'in vivo'. Rat colonic strips were used to confirm the pharmacological properties. METHODS: Human cultured colonic smooth muscle cells were studied using the calcium imaging technique. Microelectrodes and muscle bath experiments were performed in rat colonic strips. KEY RESULTS: Otilonium bromide (OB) concentration dependently inhibited nifedipine-sensitive calcium transients induced by KCl (EC50 = 3.6 MUM) and BayK8644 (EC50 = 4.0 MUM). All the following experiments were performed in the presence of nifedipine. In HCSMC, carbachol-induced calcium transients were inhibited by OB (EC50 = 8.4 MUM). Carbachol evoked 1-a smooth muscle depolarization (10 mV) that was antagonized by 100 MUM OB; and 2-a contraction that was inhibited by OB (EC50 = 13.0 MUM). 'Non nitrergic (L-NNA 1 mM) non-purinergic (MRS2500 1 MUM)' conditions were used to elicit endogenous excitatory responses. Electrical field stimulation caused 1-an atropine-sensitive excitatory junction potential that was inhibited by OB (EC50 = 8.9 MUM) and 2-an atropine-sensitive contraction that was inhibited by OB (EC50 = 7.3 MUM). In HCSMC, neurokinin A (NKA) and CaCl2 induced calcium transients that were inhibited by OB (NKA: EC50 = 11.7 MUM; CaCl2 : EC50 = 17.5 MUM). CONCLUSIONS & INFERENCES: Otilonium bromide causes inhibition of L-/T-type calcium channels, muscarinic, and tachykininergic responses that acting together explain the pharmacological properties of the compound. PMID- 23941258 TI - Plasmodium knowlesi and HIV co-infection in a German traveller to Thailand. AB - A case of Plasmodium knowlesi and HIV co-infection is reported in a German traveller returning from Thailand. The 54 year-old patient presented to the Institute of Tropical Medicine in Tubingen with a 11-day history of daily fever and chills. Initial microscopic evaluation of Giemsa-stained thin blood smears was suggestive of a mixed infection with Plasmodium falciparum and Plasmodium malariae. However, PCR amplification of small subunit ribosomal RNA gene revealed a P. knowlesi infection. Parasitaemia was 473 parasites/MUl and the platelet count was within the normal range. Oral treatment with Malarone(r) was initiated and resulted in a fast recovery without any complications. As part of routine screening the patient also underwent HIV testing and was found to be HIV positive with a CD4 cell count of 115/MUl and a viral load of 34,799 copies/ml. A follow up measurement of the viral load seven days after the first quantification revealed an increase to 102,000 copies/ml. Three months after the first quantification the viral load had dropped to 10,000 copies/ml without the initiation of antiretroviral treatment. This suggests the possibility of a P. knowlesi malaria-induced temporary elevation of viral load similar to that reported for P. falciparum and HIV co-infection. PMID- 23941259 TI - Hypercholesterolemia boosts joint destruction in chronic arthritis. An experimental model aggravated by foam macrophage infiltration. AB - OBJECTIVE: The aim of this study was to determine whether hypercholesterolemia increases articular damage in a rabbit model of chronic arthritis. METHODS: Hypercholesterolemia was induced in 18 rabbits by administrating a high-fat diet (HFD). Fifteen rabbits were fed normal chow as controls. Chronic antigen-induced arthritis (AIA) was induced in half of the HFD and control rabbits, previously immunized, by intra-articular injections of ovalbumin. After sacrifice, lipid and systemic inflammation markers were analyzed in blood serum. Synovium was analyzed by Krenn score, multinucleated cell counting, immunohistochemistry of RAM11 and CD31, and TNF-alpha and macrophage chemoattractant protein-1 (MCP-1) gene expression. Active bone resorption was assessed by protein expression of receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) and quantification of cathepsin K, contact surface and the invasive area of pannus into bone. RESULTS: Rabbits receiving the HFD showed higher total serum cholesterol, HDL, triglycerides and CRP levels than rabbits fed a normal diet. Synovitis score was increased in HFD, and particularly in AIA and AIA + HFD groups. AIA + HFD synovium was characterized by a massive infiltration of RAM11+ cells, higher presence of multinucleated foam cells and bigger vascularization than AIA. Cathepsin K+ osteoclasts and the contact surface of bone resorbing pannus were also increased in rabbits with AIA + HFD compared with AIA alone. Synovial TNF-alpha and MCP-1 gene expression was increased in AIA and HFD rabbits compared with healthy animals. RANKL protein expression in AIA and AIA + HFD groups was higher compared with either HFD or normal groups. CONCLUSIONS: This experimental model demonstrates that hypercholesterolemia increments joint tissue damage in chronic arthritis, with foam macrophages being key players in this process. PMID- 23941260 TI - SETX mutations are a frequent genetic cause of juvenile and adult onset cerebellar ataxia with neuropathy and elevated serum alpha-fetoprotein. AB - OBJECTIVES/BACKGROUND: Ataxia with oculomotor apraxia defines a group of genetically distinct recessive ataxias including ataxia-telangectasia (A-T, ATM gene), ataxia with oculomotor apraxia type 1 (AOA1, APTX gene) and type 2 (AOA2, SETX gene). Although, a few unique clinical features differentiate each of these forms, the patients also share common clinical signs, such as the presence of cerebellar atrophy, sensorimotor axonal neuropathy, and elevated alpha fetoprotein (AFP) serum level. MATERIALS AND METHODS: We selected 22 Italian patients from 21 families, presenting progressive cerebellar ataxia, axonal neuropathy, and elevated serum AFP. We screened the coding regions of ATM, APTX and SETX genes for point mutations by direct sequencing or DHPLC, and searched genomic rearrangements in SETX by MLPA analysis. In selected cases, quantification of ATM and senataxin proteins was performed by Western blot. Clinical, neurophysiological, and neuroimaging data were collected. RESULTS: Thirteen patients (12 families) carried SETX mutations (AOA2, 57%), two were mutated in ATM (A-T), and three in APTX (AOA1). In three remaining patients, we could not find pathogenic mutations, and in one case we found, in homozygosis, the SETX p.K992R polymorphism (population frequency 1-2%). In AOA2 cases, we identified 14 novel and three reported SETX mutations. Signs at onset were gait ataxia and facial dyskinesia, and the age ranged between 11 and 18 years. None had obvious oculomotor apraxia at the latest examination (age 14-45 years). The patient carrying the p.K992R SETX polymorphism had a phenotype similar to that of the diagnosed AOA2 patients, while the other three undiagnosed subjects had a very late onset and a few distinguishing clinical features. DISCUSSION AND CONCLUSIONS: We describe a large series of 13 AOA2 Italian patients. The phenotype was consistent with previous descriptions of AOA2, except for a higher frequency of strabism, and for the absence of oculomotor apraxia. In our survey ~60% of juvenile-to-adult cases with cerebellar ataxia, sensorimotor neuropathy and increased AFP are due to mutations in the SETX gene, and a smaller percentage to APTX and ATM gene mutations. PMID- 23941261 TI - Multicenter study on endoscopic ultrasound-guided expandable biliary metal stent placement: choice of access route, direction of stent insertion, and drainage route. AB - BACKGROUND AND AIM: Endoscopic ultrasonography-guided biliary drainage (EUS-BD) using expandable biliary metal stents has emerged as an acceptable alternative in patients with failed endoscopic retrograde cholangiopancreatography for malignant biliary obstruction. However, there is no consensus over the preferred access route (transhepatic or extrahepatic), direction of stent insertion (antegrade or retrograde) or drainage route (transluminal or transpapillary) in patients potentially suitable for multiple methods. The present study compares success and complication rates in patients undergoing EUS-BD via different methods. METHODS: This was a multicenter retrospective analysis. Records of patients who underwent EUS-BD for malignant obstructive jaundice at four centers were entered in a standard database. Success and complications were compared for different techniques. RESULTS: Sixty-eight patients were analyzed. EUS-BD was successful in 65 patients (95.6%). There was no significant difference in the success rates of different techniques. Complications were seen in 14 patients (20.6%) and mortality in three patients (4.4%). Complications were significantly higher for the transhepatic route compared to the transduodenal route (30.5% vs 9.3%, P=0.03). There was no significant difference in complication rates among transluminal and transpapillary stent placements, or direct and rendezvous stenting. Logistic regression analysis showed transhepatic access to be the only independent risk factor for complications (P=0.031, t=2.2). CONCLUSION: EUS-BD can be carried out with high success rates regardless of the choice of access route, stent direction or drainage route. However, complications are significantly higher with transhepatic access. The transduodenal route should be chosen for EUS-guided and rendezvous stent placements, when both routes are available. PMID- 23941262 TI - Antigenic variation and transmission fitness as drivers of bacterial strain structure. AB - Shifts in microbial strain structure underlie both emergence of new pathogens and shifts in patterns of infection and disease of known agents. Understanding the selective pressures at a population level as well as the mechanisms at the molecular level represent significant gaps in our knowledge regarding microbial epidemiology. Highly antigenically variant pathogens, which are broadly represented among microbial taxa, are most commonly viewed through the mechanistic lens of how they evade immune clearance within the host. However, equally important are mechanisms that allow pathogens to evade immunity at the population level. The selective pressure of immunity at both the level of the individual host and the population is a driver of diversification within a pathogen strain. Using Anaplasma marginale as a model highly antigenically variable bacterial pathogen, we review how immunity selects for genetic diversification in alleles encoding outer membrane proteins both within and among strains. Importantly, genomic comparisons among strains isolated from diverse epidemiological settings elucidates the counterbalancing pressures for diversification and conservation, driven by immune escape and transmission fitness, respectively, and how these shape pathogen strain structure. PMID- 23941264 TI - Factor structure of intellectual, visual perception, and visuomotor performance of poorly co-ordinated boys. AB - A battery of intellectual, visual perception, and visuomotor tests yielding 15 subtest scores were factor analyzed to determine the factorial structure of these tests in poorly coordinated boys. 5 rotated orthogonal factors were identified accounting for 76% of the variance in the battery. 3 of the factors were primarily intellectual, including one performance factor and 2 general intellectual factors. The remaining 2 factors were primarily visual, with one being most clearly represented by the Bender-Gestalt and interpreted as a form reproduction factor. The other factor was less clearly interpretable involving both eye-hand coordination and discrimination of position in space. PMID- 23941265 TI - The effect of remoteness on intertrial correlations in pursuit rotor performance. AB - 120 male university students were tested on a Koerth pursuit rotor. One group of 60 Ss was tested on each of 6 days spaced throughout a 3-wk. period. Another group of 60 Ss performed the same task in an identical manner for test-retest days only, with the retest day following by 3 wk. One group had a large amount of practice while the other did not within a comparable time period. Each practice session consisted of 60 15-sec. trials. The effects of both practice and layoff on intertrial correlations separated by increasing remoteness was investigated. The findings indicated, as others have found, that correlations decrease in size as remoteness increases. Adjacent trial correlations were found to increase as practice increased. PMID- 23941263 TI - Cumulative and recent psychiatric symptoms as predictors of substance use onset: does timing matter? AB - AIMS: We examined two questions about the relationship between conduct disorder (CD), depression and anxiety symptoms and substance use onset: (i) what is the relative influence of recent and more chronic psychiatric symptoms on alcohol and marijuana use initiation and (ii) are there sensitive developmental periods when psychiatric symptoms have a stronger influence on substance use initiation? DESIGN: Secondary analysis of longitudinal data from the Pittsburgh Youth Study, a cohort study of boys followed annually from 7 to 19 years of age. SETTING: Recruitment occurred in public schools in Pittsburgh, Pennsylvania, USA. PARTICIPANTS: A total of 503 boys. MEASUREMENTS: The primary outcomes were age of alcohol and marijuana use onset. Discrete-time hazard models were used to determine whether (i) recent (prior year); and (ii) cumulative (from age 7 until 2 years prior to substance use onset) psychiatric symptoms were associated with substance use onset. FINDINGS: Recent anxiety symptoms [hazard ratio (HR) = 1.10, 95% confidence interval (CI) = 1.03-1.17], recent (HR = 1.59, 95% CI = 1.35 1.87), cumulative (HR = 1.45, 95% CI = 1.03-2.03) CD symptoms, and cumulative depression symptoms (HR = 1.04, 95% CI = 1.01-1.08) were associated with earlier alcohol use onset. Recent (HR = 1.39, 95% CI = 1.22-1.58) and cumulative CD symptoms (HR = 1.38, 95% CI = 1.02-1.85) were associated with marijuana use onset. Recent anxiety symptoms were only associated with alcohol use onset among black participants. CONCLUSIONS: Timing matters in the relationship between psychiatric symptoms and substance use onset in childhood and adolescence, and the psychiatric predictors of onset are substance-specific. There is no single sensitive developmental period for the influence of psychiatric symptoms on alcohol and marijuana use initiation. PMID- 23941266 TI - Effect of an audience on performance of a motor task. AB - 40 College Ss were placed in 4 groups and tested on a star-tracing task on 2 occasions under the following conditions: spectators-no-spectators; spectators spectators; no-spectators-no-spectators; no-spectators-spectators. It was found that the presence or absence of spectators had no noticeable effect on the initial learning phase as contrasted to later stages of performance. When conditions remained the same on both testing occasions, less errors were made. Speed was generally quicker under altered task conditions. PMID- 23941267 TI - Premotor and motor reaction time as a function of preliminary muscular tension. AB - Ss squeezed a hand grip device to 1 of 3 submaximal tensions, and reacted to either a light (Exp. I, N = 30) or to a buzzer (Exp. II, N = 24) by squeezing as quickly and forcefully as possible. Total RT was the time from stimulus to the change in tension, and this was divided into Premotor RT (stimulus to change in EMG) and Motor RT (change in EMG to change in tension) to determine the locus of changes in Total RT found by Clarke (1968). Whereas Total RT was unaffected by increased pre-tension, Premotor RT shortened and Motor RT lengthened. Partial programming or activation hypotheses were tenable for the Premotor RT changes, whereas changes in the contractile component, but not in the series elastic component, were tenable for the Motor RT changes. PMID- 23941268 TI - The role of motor programming, command, and standard in the central control of skilled movement. AB - Central control of skilled movement was investigated in a tapping task under total reduction of peripheral feedback with a nerve compression block. Practice conditions including no practice, tapping with normal feedback with either hand, or writing were manipulated prior to application of the block and were given in random order over 8 experimental trials to 48 Ss, followed by 6 further training trials. 2 control groups (12 and 11 Ss) were trained with constant practice conditions. Learning was dependent on constant practice conditions throughout the trial series. Findings were discussed in terms of central closed-loop systems, i.e., motor programming, or standards-programming units. The utilization of these units involves different strategies. Ss were classified as alpha or beta according to their ability to utilize these units. PMID- 23941269 TI - Proprioception as a basis for the temporal anticipation of motor responses . AB - The present study attempted to distinguish between the proprioceptive Decay and proprioceptive Input Hypotheses of motor timing behavior. The hypothesis that an increased level of proprioceptive cues results in more proficient temporal anticipation was also tested. 90 male Ss were required to anticipate (no preview) the coincidence of a moving pointer and a stationary one. The timing response was executed with the right hand while 3 levels of proprioceptive cues were indirectly manipulated in the left arm. While results were unable to distinguish between the hypotheses, support was found for the hypothesis that an increased level of proprioceptive feedback administered during the interval can increase anticipatory response consistency. PMID- 23941270 TI - The human movement factor (m) in the rorschach, motor activity, and behavior. AB - The relationship between the M response and one of its basic theoretical components, overt motor activity, measured by participation in varsity level sports and related activities, was determined. 114 Ss were assigned to a participant group and 108 Ss to a non-participant group. The Group Rorschach, the Group Form of Coan's Individual Movement Cards, and the Guilford-Zimmerman Temperament Survey were administered. The results failed to confirm Rorschach's theory that overt motor activity inhibits kinesthetic perception. Flexor movement was significantly associated with non-participation. The participant group scored significantly higher in Factors G (General Activity), A (Ascendance), S (Sociability), and E (Emotional Stability) of the Guilford-Zimmerman Temperament Survey. Intellectual functioning appeared as the most important factor in M production. PMID- 23941271 TI - Efficiency of learning as a function of practice schedule and initial ability. AB - 2 groups of 50 Ss practiced a pursuit rotor skill under different schedules of practice. A massed practice (MP) group (40 sec. work, 20 sec. rest) performed just as well as a distributed practice (DP) group (20 sec. work, 20 sec. rest) on the first day of practice. However, after 24 hr. of interpolated rest MP Ss demonstrated significantly greater amounts of learning. A further analysis of the 15 high initial ability and 15 low initial ability Ss from each of the two main groups resulted in no statistical differences among these subgroups in Day 1 performance that could be attributed to the practice schedules; however, a significant Ability Level * Practice Schedule interaction was obtained for Day 2 performance. It was caused by the low ability Ss under MP learning relatively more than the high ability Ss under MP when compared to the two DP groups. Thus learning was seen as being a function not only of schedule of practice but also of initial ability level. PMID- 23941272 TI - Searching for control: priming randomness increases the evaluation of ritual efficacy. AB - Reestablishing feelings of control after experiencing uncertainty has long been considered a fundamental motive for human behavior. We propose that rituals (i.e., socially stipulated, causally opaque practices) provide a means for coping with the aversive feelings associated with randomness due to the perception of a connection between ritual action and a desired outcome. Two experiments were conducted (one in Brazil [n = 40] and another in the United States [n = 94]) to evaluate how the perceived efficacy of rituals is affected by feelings of randomness. In a between-subjects design, the Scramble Sentence Task was used as a priming procedure in three conditions (i.e., randomness, negativity, and neutral) and participants were then asked to rate the efficacy of rituals used for problem-solving purposes. The results demonstrate that priming randomness increased participants' perception of ritual efficacy relative to negativity and neutral conditions. Implications for increasing our understanding of the relationship between perceived control and ritualistic behavior are discussed. PMID- 23941273 TI - A survey on Tetracapsuloides bryosalmonae infections in Slovene fresh waters. AB - Slovenia has no history of health problems related to proliferative kidney disease (PKD) either in farmed or in wild fish. However, due to the past molecular evidence for the presence of Tetracapsuloides bryosalmonae DNA in tissues of some fish from open waters, a survey was conducted on wild salmonids that were primarily sampled for other purposes. In winter 2010-2011, specimens from a total of 244 rainbow trout, Oncorhynchus mykiss (Walbaum), and brown trout, Salmo trutta L., from 30 bodies of fresh water were examined for T. bryosalmonae using a PCR method. The sampled fish showed no clinical signs or gross pathological lesions characteristic of PKD. Nineteen (7.8%) fish from seven (23.3%) fresh waters were positive for T. bryosalmonae. The identity of PCR amplicons was confirmed by sequencing. With one exception, all the positive fish were found in waters from the regions where the average yearly temperatures and the environmental pollution are higher. This preliminary countrywide survey provided the first insight into the situation regarding T. bryosalmonae infection of wild salmonids in Slovenia. PMID- 23941274 TI - VirD: a virion display array for profiling functional membrane proteins. AB - To facilitate high-throughput biochemical analyses of membrane proteins, we have developed a novel display technology in a microarray format. Both single-pass (cluster of differentiation 4, CD4) and multiple-pass (G protein-coupled receptor 77, GPR77) human transmembrane proteins were engineered to be displayed in the membrane envelop of herpes simplex virions. These viruses produce large spherical virions displaying multiple copies of envelop proteins. Our aim was to engineer this virus to express these human proteins during the virus productive cycle and incorporate the human proteins into the virion during the assembly process. Another strategy presented includes engineering a fusion of glycoprotein C (gC), a major constituent of herpes simplex virus type 1 (HSV-1) virions, by hijacking the cis-acting signals to direct incorporation of the chimeric protein into the virion. The expression of the human proteins in infected cells, at the cell surface and in purified virions, is in the correct transmembrane orientation, and the proteins are biochemically functional. Purified virions printed on glass slides form a high-density Virion Display (VirD) Array, and the displayed proteins were demonstrated to retain their native conformations and interactions on the VirD Array judging by similar assays, such as antibody staining, as well as lectin and ligand binding. This method can be readily scaled or tailored for different modalities including a high-content, high-throughput platform for screening ligands and drugs of human membrane proteins. PMID- 23941277 TI - Dispersed three-pulse infrared photon echoes of nitrous oxide in water and octanol. AB - Dispersed IR three-pulse photon echoes due to the antisymmetric (nu3) stretch mode of N2O dissolved in H2O and 1-octanol at room temperature are reported and analyzed. The experimentally determined transition frequency-frequency correlation function (FFCF) in these two solvents is explained in terms of inertial solvent contributions, hydrogen bond network fluctuations, and, for octanol, the motions of the alkyl chains. The H2O hydrogen bond fluctuations result in 1.5 ps FFCF decay, in agreement with relaxation rates determined from photon echo based measurements of other aqueous solutions including salt solutions. In octanol, hydrogen bond fluctuations decay on a slower time scale of 3.3 ps and alkyl chain motions result in an inhomogeneous broadening contribution to the nu3 absorption spectrum that decays on a 35 ps time scale. Rotational reorientation of N2O is nearly 3 times faster in octanol as compared to water. Although the vibrational nu3 N2O absorption line shapes in water and octanol are similar, the line widths result from different coherence loss mechanisms. A hot band contribution in the N2O in octanol solution is found to have a significant effect on the echo spectrum due to its correspondingly stronger transition moment than that of the fundamental transition. The dephasing dynamics of the N2O nu3 stretch mode is of interest as a probe in ultrafast studies of complex or nanoconfined systems with both hydrophobic and hydrophilic regions such as phospholipids, nucleic acids, and proteins. These results demonstrate the value of the N2O molecule to act as a reporter of equilibrium fluctuations in such complex systems particularly due to its solubility characteristics and long vibrational lifetime. PMID- 23941276 TI - Endothelin-1 and endothelin-2 initiate and maintain contractile responses by different mechanisms in rat mesenteric and cerebral arteries. AB - BACKGROUND AND PURPOSE: Endothelin (ET)-1 and ET-2 cause potent long-lasting vasoconstrictions by tight binding to smooth muscle ETA receptors. We tested the hypotheses that different mechanisms mediate initiation and maintenance of arterial contractile responses to ET-1 and ET-2 and that this differs among vascular beds. EXPERIMENTAL APPROACH: Segments of rat mesenteric resistance artery (MRA) and basilar artery (BA) were studied in wire myographs with and without functional antagonists. KEY RESULTS: Sensitivity and maximum of MRA contractile responses to ET-1 were not, or only moderately, reduced by stimulation of soluble GC, AC or K(+) -channels and by an inhibitor of receptor operated ion channels. However, each of these reduced maintenance of ET-1 effects and relaxed ET-1-induced contractions in MRA. A calcium channel antagonist did not alter sensitivity, maximum and maintenance of ET-1 effects, but relaxed ET-1 induced contractions in MRA. A PLC inhibitor prevented contractile responses to ET-1 and ET-2 in MRA and BA, and relaxed ET-1- and ET-2-induced responses in MRA and ET-1 effects in BA. A Rho-kinase inhibitor did not modify sensitivity, maximum and maintenance of responses to both peptides in both arteries but relaxed ET-2, but not ET-1, effects in MRA and ET-1 effects in BA. CONCLUSIONS AND IMPLICATIONS: PLC played a key role in arterial contractile responses to ETs, but ET-1 and ET-2 initiated and maintained vasoconstriction through different mechanisms, and these differed between MRA and BA. Selective functional antagonism may be considered for agonist- and vascular bed selective pharmacotherapy of ET-related diseases. PMID- 23941279 TI - PEGylated insulin Lispro, (LY2605541)--a new basal insulin analogue. AB - There is a clinical rationale for a basal insulin with a predictable action and low inter- and intra-individual variability coupled with an improved side effect and metabolic profile. Since insulin therapy is anabolic and its initiation is commonly associated with weight gain, an insulin preparation associated with a beneficial weight profile would represent a particularly valuable therapeutic entity. LY2605541, or PEGylated insulin Lispro, has a large hydrodynamic size while still exerting the metabolic effects of insulin. This may reduce absorption and clearance of the compound following subcutaneous administration. A number of preclinical and clinical studies have been constructed to evaluate the utility of this novel insulin. The currently available data from preclinical, phase I and phase II studies suggests LY2605541 has a non-inferior glucose-lowering efficacy compared to insulin glargine in people with type 1 and type 2 diabetes and may afford a weight-loss advantage. Pre-clinical studies indicate that LY2605541 has low mitogenic potency, exerting a preferential hepatic effect on glucose homeostasis. LY2605541 appears to cause elevated transaminases and derangement of lipid profiles. On the basis of these initial observations, LY2605541 requires further extensive clinical evaluation to fully assess its risk/benefit profile in the management in people with diabetes. PMID- 23941275 TI - Personalizing health care: feasibility and future implications. AB - Considerable variety in how patients respond to treatments, driven by differences in their geno- and/ or phenotypes, calls for a more tailored approach. This is already happening, and will accelerate with developments in personalized medicine. However, its promise has not always translated into improvements in patient care due to the complexities involved. There are also concerns that advice for tests has been reversed, current tests can be costly, there is fragmentation of funding of care, and companies may seek high prices for new targeted drugs. There is a need to integrate current knowledge from a payer's perspective to provide future guidance. Multiple findings including general considerations; influence of pharmacogenomics on response and toxicity of drug therapies; value of biomarker tests; limitations and costs of tests; and potentially high acquisition costs of new targeted therapies help to give guidance on potential ways forward for all stakeholder groups. Overall, personalized medicine has the potential to revolutionize care. However, current challenges and concerns need to be addressed to enhance its uptake and funding to benefit patients. PMID- 23941280 TI - Nature of noncovalent interactions in catenane supramolecular complexes: calibrating the MM3 force field with ab initio, DFT, and SAPT methods. AB - The design and assembly of mechanically interlocked molecules, such as catenanes and rotaxanes, are dictated by various types of noncovalent interactions. In particular, [C-H...O] hydrogen-bonding and pi-pi stacking interactions in these supramolecular complexes have been identified as important noncovalent interactions. With this in mind, we examined the [3]catenane 2.4PF6 using molecular mechanics (MM3), ab initio methods (HF, MP2), several versions of density functional theory (DFT) (B3LYP, M0X), and the dispersion-corrected method DFT-D3. Symmetry adapted perturbation theory (DFT-SAPT) provides the highest level of theory considered, and we use the DFT-SAPT results both to calibrate the other electronic structure methods, and the empirical potential MM3 force field that is often used to describe larger catenane and rotaxane structures where [C H...O] hydrogen-bonding and pi-pi stacking interactions play a role. Our results indicate that the MM3 calculated complexation energies agree qualitatively with the energetic ordering from DFT-SAPT calculations with an aug-cc-pVTZ basis, both for structures dominated by [C-H...O] hydrogen-bonding and pi-pi stacking interactions. When the DFT-SAPT energies are decomposed into components, we find that electrostatic interactions dominate the [C-H...O] hydrogen-bonding interactions, while dispersion makes a significant contribution to pi-pi stacking. Another important conclusion is that DFT-D3 based on M06 or M06-2X provides interaction energies that are in near-quantitative agreement with DFT SAPT. DFT results without the D3 correction have important differences compared to DFT-SAPT, while HF and even MP2 results are in poor agreement with DFT-SAPT. PMID- 23941278 TI - Human growth is associated with distinct patterns of gene expression in evolutionarily conserved networks. AB - BACKGROUND: A co-ordinated tissue-independent gene expression profile associated with growth is present in rodent models and this is hypothesised to extend to all mammals. Growth in humans has similarities to other mammals but the return to active long bone growth in the pubertal growth spurt is a distinctly human growth event. The aim of this study was to describe gene expression and biological pathways associated with stages of growth in children and to assess tissue independent expression patterns in relation to human growth. RESULTS: We conducted gene expression analysis on a library of datasets from normal children with age annotation, collated from the NCBI Gene Expression Omnibus (GEO) and EBI Arrayexpress databases. A primary data set was generated using cells of lymphoid origin from normal children; the expression of 688 genes (ANOVA false discovery rate modified p-value, q < 0.1) was associated with age, and subsets of these genes formed clusters that correlated with the phases of growth--infancy, childhood, puberty and final height. Network analysis on these clusters identified evolutionarily conserved growth pathways (NOTCH, VEGF, TGFB, WNT and glucocorticoid receptor--Hyper-geometric test, q < 0.05). The greatest degree of network 'connectivity' and hence functional significance was present in infancy (Wilcoxon test, p < 0.05), which then decreased through to adulthood. These observations were confirmed in a separate validation data set from lymphoid tissue. Similar biological pathways were observed to be associated with development-related gene expression in other tissues (conjunctival epithelia, temporal lobe brain tissue and bone marrow) suggesting the existence of a tissue independent genetic program for human growth and maturation. CONCLUSIONS: Similar evolutionarily conserved pathways have been associated with gene expression and child growth in multiple tissues. These expression profiles associate with the developmental phases of growth including the return to active long bone growth in puberty, a distinctly human event. These observations also have direct medical relevance to pathological changes that induce disease in children. Taking into account development-dependent gene expression profiles for normal children will be key to the appropriate selection of genes and pathways as potential biomarkers of disease or as drug targets. PMID- 23941281 TI - Performance of microscopy and RDTs in the context of a malaria prevalence survey in Angola: a comparison using PCR as the gold standard. AB - BACKGROUND: Accurate identification of Plasmodium infections in community surveys is essential to successful malaria control. Microscopy and rapid diagnostic tests (RDTs) are the main techniques used to diagnose malaria in field-based surveys. While microscopy is still considered the gold standard, RDTs are growing in popularity as they allow for rapid and inexpensive diagnosis. Using data from a prevalence survey conducted in north-western Angola in 2010, the authors aimed to compare the performance of microscopy and RDTs in identifying Plasmodium falciparum infections, using polymerase chain reaction (PCR) as the gold standard. METHODS: Results from 3,307 subjects (1,225 preschool-aged children (zero to five year olds), 1,134 school-aged children (six to 15 year olds) and 948 mothers/caregivers (>15 years of age)), tested for P. falciparum infections, were utilized. The sensitivity, specificity, positive, and negative predictive values (PPV and NPV) of microscopy and Paracheck-Pf(r) were compared using the McNemar's test and the weighted generalized score Chi-squared test for paired data. RESULTS: The prevalence of P. falciparum infections determined by PCR and microscopy was 15.9% and by Paracheck- Pf(r) was 16.3%. Compared to microscopy, Paracheck-Pf(r) had significantly higher sensitivity (72.8% versus 60%), specificity (94.3% versus 92.5%), PPV (70.7% versus 60%) and NPV (94.8% versus 92.5%). Both tests had significantly lower sensitivity in mothers (36.8% for microscopy and 43.7% for Paracheck-Pf(r)) than in their children (68.4% in zero to five years-old and 60.6% in six to 15 years-old for microscopy and 80.4% in zero to five year-olds and 76.5% in six to 15 year-olds for Paracheck-Pf(r)). CONCLUSION: Both microscopy and RDTs performed suboptimally when compared to PCR. False negativity could be associated with the low parasite density profile of the samples. False positivity may be related to the well-described limitations of those techniques such as level of expertise of microscopists or persistent antigenicity from previous infections in the case of RDTs. Nevertheless, RDTs had enhanced performance comparatively to microscopy in detecting malaria infections, favouring their use in community cross-sectional malaria surveys, where expert performance of microscopy is hard to accomplish. PMID- 23941282 TI - Biomechanical changes in the pharynx and upper esophageal sphincter after modified balloon dilatation in brainstem stroke patients with dysphagia. AB - BACKGROUND: Few studies have investigated the biomechanical changes in the upper esophageal sphincter (UES) and pharyngeal function after successful dilatation therapy for dysphagia. Using high-resolution manometry (HRM), we examined the biomechanical properties of swallowing in brainstem stroke patients with dysphagia following modified balloon dilation therapy. METHODS: 30 brainstem stroke patients with dysphagia were included. Patients in the experimental group received 3 weeks of modified balloon dilatation treatment and regular dysphagia therapy. Patients in the control group received 3 weeks of regular dysphagia therapy only. Efficacy of treatment was evaluated before and following intervention. Functional oral intake was measured using the Functional Oral Intake Scale (FOIS). Pharyngeal maximum pressures and duration, UES residual pressure and duration during swallowing were measured using HRM. KEY RESULTS: In the experimental group, the feeding tube was able to be removed in 12 of 15 patients, vs 2 of 15 patients in the control group. The experimental group had 4 point median improvement, while control groups only had 1-point improvement in FOIS scores. In the experimental group, posttreatment UES relaxation and pharyngeal propulsion were both significantly improved for the three materials (p < 0.05) and UES resting pressure approximated normal. In the control group, pharyngeal propulsion was improved for water and thick liquids (p < 0.05) but not for paste material; there was no improvement in posttreatment UES relaxation for all three materials (p > 0.05). CONCLUSIONS & INFERENCES: Dysphagia therapy with modified dilatation improved UES relaxation, strengthened pharyngeal propulsion, restored UES resting pressure and improved functional oral intake to a greater extent than regular therapy alone. PMID- 23941284 TI - Low-dose CT in clinical diagnostics. AB - INTRODUCTION: Computed tomography (CT) has become key for patient management due to its outstanding capabilities for detecting disease processes and assessing treatment response, which has led to expansion in CT imaging for diagnostic and image-guided therapeutic interventions. Despite these benefits, the growing use of CT has raised concerns as radiation risks associated with radiation exposure. AREAS COVERED: The purpose of this article is to familiarize the reader with fundamental concepts of dose metrics for assessing radiation exposure and weighting radiation-associated risks. The article also discusses general approaches for reducing radiation dose while preserving diagnostic quality. The authors provide additional insight for undertaking protocol optimization, customizing scanning techniques based on the patients' clinical scenario and demographics. Supplemental strategies are postulated using more advanced post processing techniques for achieving further dose improvements. EXPERT OPINION: The technologic offerings of CT are integral to modern medicine and its role will continue to evolve. Although, the estimated risks from low levels of radiation of a single CT exam are uncertain, it is prudent to minimize the dose from CT by applying common sense solutions and using other simple strategies as well as exploiting technologic innovations. These efforts will enable us to take advantage of all the clinical benefits of CT while minimizing the likelihood of harm to patients. PMID- 23941283 TI - Genetics of amyotrophic lateral sclerosis: an update. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the disease neuropathogenesis. PMID- 23941285 TI - Transcutaneous monitoring of partial pressure of carbon dioxide during endoscopic retrograde cholangiopancreatography using a double-balloon endoscope with carbon dioxide insufflation under conscious sedation. AB - BACKGROUND AND AIM: A double-balloon (DB) endoscope can be selectively inserted into the afferent loop to carry out endoscopic retrograde cholangiopancreatography (ERCP) in patients with surgically altered anatomy, allowing various types of endoscopic treatments for pancreaticobiliary diseases to be successfully carried out. In order to make such a lengthy procedure more comfortable and safe, sedatives and carbon dioxide (CO2 ) insufflation are widely used for gastrointestinal endoscopy. However, these techniques can increase the risk of CO2 retention. Recently, a new sensor for transcutaneous measurement of partial pressure of carbon dioxide (PCO2 ) has been introduced. The aim of the present study was to evaluate the changes in transcutaneous PCO2 (PtcCO2 ) during DB-ERCP with CO2 insufflation under conscious sedation and assess any complications related to sedation and CO2 insufflation. METHODS: A total of 312 patients underwent DB-ERCP with CO2 insufflation at our hospital between March 2009 and December 2012. The patients were moderately sedated using midazolam with or without pentazocine. PtcCO2 was measured by a non-invasive sensor throughout DB-ERCP in all patients. RESULTS: The mean peak PtcCO2 during the procedure was significantly higher than the mean PtcCO2 value before and after DB-ERCP. Body mass index, procedure time and dose of pentazocine were significantly higher in the CO2 retention group (peak PtcCO2 >= 50 mmHg). CO2 narcosis was observed in one case. CONCLUSIONS: DB-ERCP with CO2 insufflation under conscious sedation might have the potential to increase the risk of CO2 retention. Hence, non invasive and continuous PtcCO2 measurement is useful for early detection of hypercapnia. PMID- 23941286 TI - Engagement with the criminal justice system among opioid-dependent people: a retrospective cohort study. AB - AIMS: Studies of offending among people who use drugs typically focus upon small and potentially unrepresentative samples. We examined an entire population of opioid-dependent clients' contact with the criminal justice system to develop more accurate population-wide measures of offending among opioid-dependent people in Australia. DESIGN: Retrospective data linkage study. SETTING: All entrants to opioid substitution therapy (OST) for opioid dependence in New South Wales, Australia, between 1985 and 2010, with data on court appearances from 1 December 1993 to 31 March 2011. PARTICIPANTS: All 48 069 valid cohort members who received OST between 1985 and 2010. MEASUREMENTS: Person-years (PY) of observation and charge rates for major crime categories estimated by sex, age and time. FINDINGS: A total of 638 545 charges were laid against cohort members between 1993 and 2011. Eight in 10 males (79.7%) and 67.9% of females had at least one charge; rates were 94.15 per 100 PY [95% confidence interval (CI) = 93.89-94.41] among males, and 53.19 per 100 PY (95% CI = 52.91-53.46) among females, and highest at 15-19 years [175.74/100 PY males (95% CI = 174.45-177.03), 75.60/100 PY females (95% CI = 74.46-76.76)] and 20-24 years [144.61/100 PY males (95% CI = 143.70 145.53), 84.50/100 PY females (95% CI = 83.53-85.48)]. The most frequent charges were theft (24.5% of charges), traffic/vehicle (16.3%), offences against justice (10.5%), illicit drug (10.0%), intentional injury (9.9%) and public order offences (8.9%). Overall, 20.8% of the cohort accounted for 67.4% of charges. The most frequently appearing 5.6% of the cohort accounted for 24.3% of costs ($75.5 million). CONCLUSIONS: Among opioid-dependent people in Australia, a minority account for the majority of the criminal justice contact and levels of offending are not consistent over time, sex or age. PMID- 23941287 TI - Childhood body mass index and subsequent physician-diagnosed asthma: a systematic review and meta-analysis of prospective cohort studies. AB - BACKGROUND: Childhood asthma and obesity prevalence have increased in recent years suggesting a potential association. However, the direction of any association is poorly understood and the potential causal-relationship is unknown. METHODS: We examined the association between overweight/obesity, defined by body mass index (BMI) <18 years of age, and subsequent physician-diagnosed incident asthma at least one year after BMI assessment. We sought to explore potential effect modification by sex. PubMed and Embase were searched using keywords and restricted to subjects aged 0-18 years. There were no date or language restrictions. From each study we extracted: authors, publication date, location, overweight/obesity definitions, asthma definitions, number of participants, recruitment duration, description of cohort, follow-up time, adjusted effect estimates (with 95% CI) and estimates of subgroup analysis. RESULTS: Six prospective cohort studies which focused on children <18 years of age met criteria for inclusion. The combined risk ratio (RR) of overweight was associated with asthma (RR = 1.35; 95% CI = 1.15, 1.58). In boys, the combined RR of overweight on asthma was significant (RR = 1.41; 95% CI = 1.05, 1.88). For girls, when BMI was defined by Z-score, the combined RR of overweight on asthma was also significant (RR = 1.19; 95% CI = 1.06, 1.34). The combined risk ratio (RR) of obesity was associated with asthma in both boys and girls (RR = 1.50; 95% CI = 1.22, 1.83), in boys only (RR = 1.40; 95% CI = 1.01, 1.93) and in girls only (RR = 1.53; 95% CI = 1.09, 2.14). CONCLUSIONS: Overweight and, especially, obese children are at increased risk of subsequent physician diagnosed asthma in comparison to normal weight children. Except for sex, no studies reported any other potential effect modifiers. The observed sex effects were inconsistent. PMID- 23941288 TI - In vitro batch cultures of gut microbiota from healthy and ulcerative colitis (UC) subjects suggest that sulphate-reducing bacteria levels are raised in UC and by a protein-rich diet. AB - Imbalances in gut microbiota composition during ulcerative colitis (UC) indicate a role for the microbiota in propagating the disorder. Such effects were investigated using in vitro batch cultures (with/without mucin, peptone or starch) inoculated with faecal slurries from healthy or UC patients; the growth of five bacterial groups was monitored along with short-chain fatty acid (SCFA) production. Healthy cultures gave two-fold higher growth and SCFA levels with up to ten-fold higher butyrate production. Starch gave the highest growth and SCFA production (particularly butyrate), indicating starch-enhanced saccharolytic activity. Sulphate-reducing bacteria (SRB) were the predominant bacterial group (of five examined) for UC inocula whereas they were the minority group for the healthy inocula. Furthermore, SRB growth was stimulated by peptone presumably due to the presence of sulphur-rich amino acids. The results suggest raised SRB levels in UC, which could contribute to the condition through release of toxic sulphide. PMID- 23941289 TI - Human umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis: safety and efficacy. AB - This study was designed to assess the safety and efficacy of human umbilical cord mesenchymal stem cells (UC-MSCs) in the treatment of rheumatoid arthritis (RA). In this ongoing cohort, 172 patients with active RA who had inadequate responses to traditional medication were enrolled. Patients were divided into two groups for different treatment: disease-modifying anti-rheumatic drugs (DMARDs) plus medium without UC-MSCs, or DMARDs plus UC-MSCs group (4*10(7) cells per time) via intravenous injection. Adverse events and the clinical information were recorded. Tests for serological markers to assess safety and disease activity were conducted. Serum levels of inflammatory chemokines/cytokines were measured, and lymphocyte subsets in peripheral blood were analyzed. No serious adverse effects were observed during or after infusion. The serum levels of tumor necrosis factor alpha and interleukin-6 decreased after the first UC-MSCs treatment (P<0.05). The percentage of CD4(+)CD25(+)Foxp3(+) regulatory T cells of peripheral blood was increased (P<0.05). The treatment induced a significant remission of disease according to the American College of Rheumatology improvement criteria, the 28 joint disease activity score, and the Health Assessment Questionnaire. The therapeutic effects maintained for 3-6 months without continuous administration, correlating with the increased percentage of regulatory T cells of peripheral blood. Repeated infusion after this period can enhance the therapeutic efficacy. In comparison, there were no such benefits observed in control group of DMARDS plus medium without UC-MSCs. Thus, our data indicate that treatment with DMARDs plus UC-MSCs may provide safe, significant, and persistent clinical benefits for patients with active RA. PMID- 23941290 TI - 'Sometimes they fail to keep their faith in us': community health worker perceptions of structural barriers to quality of care and community utilisation of services in Bangladesh. AB - Community health workers (CHWs) have strong potential to extend health and nutrition services to underserved populations. However, CHWs face complex challenges when working within weak health systems and among communities with limited abilities to access and utilise CHW services. It is crucial to understand these challenges to improve programme support mechanisms. This study describes the results of qualitative investigations into CHW perceptions of barriers to quality of care among two groups of workers implementing community case management of acute respiratory infection, diarrhoea and severe acute malnutrition in southern Bangladesh. We explored systemic barriers to service delivery, pertaining to communities and health systems, which limited the usefulness and effectiveness of CHW services. Focus group discussions (n = 10) were conducted in March 2010. Discussions were analysed for themes related to CHWs' work challenges. Findings highlight several perceived barriers to effective service provision, including community poverty constraining uptake of recommended practices, irregular supplies of medicine from the health facility and poor quality of care for CHW referrals sent there. This study further documents interactions between demand-side and supply-side constraints including the influence of health system resource constraints on community trust in CHW services, and the influence of community resource constraints on the utilisation and effectiveness of CHW services. By documenting service delivery challenges from the perspective of the frontline workers themselves, this article contributes evidence to help identify appropriate support mechanisms for these workers, in order to develop scalable and sustainable CHW programmes in countries with under-resourced public health care infrastructure. PMID- 23941292 TI - Visual-propriocetive correspondence in the para-median plane. AB - 2 experiments in which Ss matched a proprioceptively perceived stylus to a visual target in the para-median plane show that Ss make idiosyncratic errors which are stable over periods of at least several days. A technique for comparing visual and proprioceptive spaces is used to Show how matching errors vary within the para-median plane. These errors are interpreted as the result of inadequate inter calibration of visual and proprioceptive space perception, and their implications for movement control are discussed. PMID- 23941291 TI - Identification of three new cis-regulatory IRF5 polymorphisms: in vitro studies. AB - BACKGROUND: Polymorphisms in the interferon regulatory factor 5 (IRF5) gene are associated with susceptibility to systemic lupus erythematosus, rheumatoid arthritis and other diseases through independent risk and protective haplotypes. Several functional polymorphisms are already known, but they do not account for the protective haplotypes that are tagged by the minor allele of rs729302. METHODS: Polymorphisms in linkage disequilibrium (LD) with rs729302 or particularly associated with IRF5 expression were selected for functional screening, which involved electrophoretic mobility shift assays (EMSAs) and reporter gene assays. RESULTS: A total of 54 single-nucleotide polymorphisms in the 5' region of IRF5 were genotyped. Twenty-four of them were selected for functional screening because of their high LD with rs729302 or protective haplotypes. In addition, two polymorphisms were selected for their prominent association with IRF5 expression. Seven of these twenty-six polymorphisms showed reproducible allele differences in EMSA. The seven were subsequently analyzed in gene reporter assays, and three of them showed significant differences between their two alleles: rs729302, rs13245639 and rs11269962. Haplotypes including the cis-regulatory polymorphisms correlated very well with IRF5 mRNA expression in an analysis based on previous data. CONCLUSION: We have found that three polymorphisms in LD with the protective haplotypes of IRF5 have differential allele effects in EMSA and in reporter gene assays. Identification of these cis regulatory polymorphisms will allow more accurate analysis of transcriptional regulation of IRF5 expression, more powerful genetic association studies and deeper insight into the role of IRF5 in disease susceptibility. PMID- 23941293 TI - Pre-motor and motor reaction time differences associated with stretching of the hamstring muscles. AB - Pre-motor and motor RT scores were obtained from 24 male Ss using a knee flexion task. It was predicted that an increased arousal state due to proprioceptive feedback from stretched hamstring muscles would shorten pre-motor RT while motor RT would shorten because of changes in muscle tension development due to changes in the series elastic and/or contractile components of the muscle tissue. A finger RT task was also included in order to determine whether other factors not related to changes in the stretch of the hamstring muscles were operative. Motor RT decreased with increased muscle stretch and constituted 46% of leg RT. Pre motor RT as well as finger RT increased rather than decreased with increased muscle stretch. No relationship was found between pre-motor and motor RT indicating that lags in CNS processing are independent of lags associated with the rate of muscular tension development. PMID- 23941294 TI - Perceived occurrence of the second of two closely spaced stimuli in a long movement. AB - A 75-deg. movement of the arm in the vertical plane was used to examine the conscious perception of the apparent time of occurrence of a reversal signal S2. A marked perceptual delay was found whether S2 occurred during or after the reaction time to the first stimulus. This finding was consistent with Henry's memory drum theory of neuromotor response, as well as with the efference theory of conscious perception proposed by Festinger and associates. PMID- 23941295 TI - Kinesthetic recall and information bold>reduction activity. AB - 2 experiments are reported in which interpolated motor activity requiring either information reduction (1.86 bits) or no reduction was compared to a control to examine their effects on kinesthetic retention. Exp. 1 used an independent groups design and found only absolute error to increase over the delay intervals. Information reduction activity did not affect kinesthetic retention and there was increasing negative error for longer movements, with positive response sets for short movements and negative response sets for long movements. Exp. 2 replicated the retention interval conditions using a within-Ss design. No difference between conditions was found for either absolute or algebraic error, but an effect of Retention Intervals was found for absolute error. For both studies, the Interpolated Activity X Retention Interval interaction failed significance. No evidence was found to support interference or available processing capacity expalanation for the loss of retention. PMID- 23941296 TI - Weight and velocity influences on kinesthetic learning and transfer of learning. AB - 80 Ss performed a horizontal adduction movement of the arm attempting to approximate a velocity of 6 or 10 ft/sec with or without a 2-lb. weight in the hand, and Ss were randomly divided into 4 equal subgroups based upon the possible velocity-weight combinations. Ss were blindfolded and received only verbal cues as to the direction of error. After 60 trials on the initial task, each group was divided into 4 subgroups, based upon the original velocity-weight combinations, and performed 60 transfer trials. The two groups approximating the faster velocity were significantly more accurate on the initial task while weight had no effect on accuracy. Negative transfer occurred from the faster movement to the slower, more difficult movement. PMID- 23941297 TI - Hearing-loss effects on a procedural task sequence. AB - 40 deaf and 40 hearing children representing 2 age groups were blindfolded and presented with 3 high-relief finger mazes of increasing complexity. It was found that young deaf children performed the most difficult task more efficiently than comparable hearing children. Contrary to previous findings, hearing children showed no advantage over deaf children on any of the three tasks as a result of their supposed greater facility with verbal conceptual mediators. The results were interpreted as supporting the idea that deaf children compensate for their auditory lack and verbal deficiency by developing problem solving skills that maximize sensitivity to other sensory modalities. PMID- 23941298 TI - Notes and comments the role of action feedback in the acquisition of simple motor responses. AB - The use of visual action feedback (AIF) in learning a simple motor response can sometimes be as effective as the more conventional terminal feedback (TIF) but sometimes leads to gross overshooting errors when AIF is removed. Both the amplitude of movement and the gain of the AIF have strong and systematic effects on the error in attempted reproductions. Percent overestimation increases linearly with fog. gain and decreases linearly with log. amplitude. This may be due to an intersensory effect in which visual and kinesthetic feedback sum to form a unitary impression of the movement on which subsequent attempts at reproduction are based. PMID- 23941299 TI - Learning under conditions of action information feedback. AB - Methodological and empirical issues in research on action information feedback (AIF) are discussed, with particular reference to the procedures and results of Annett (1970). Positioning responses practiced under conditions of AIF training are learned, though generally less well than under terminal IF conditions. Effects obtained as a result of AIF training may be subject to variations in movement extent required, gain and other transformations, frequency, temporal locus, and mode of augmentation, many aspects of which remain to be systematically studied. PMID- 23941300 TI - Laser-induced carbene-carbene rearrangement in solution: the diphenylcarbene fluorene rearrangement. AB - Diphenylcarbene (DPC) generated by high-intensity laser photolysis of diphenyldiazomethane rearranges to fluorene (FL) by two distinct mechanisms as revealed by methyl-group labeling. Thus, excimer laser irradiation of p,p' dimethyldiphenyldiazomethane generates 3,6-dimethylfluorene (3,6-DMF) and 2,7 dimethylfluorene (2,7-DMF), which were identified by fluorescence measurements as well as GC-MS and comparison with authentic materials. 3,6-DMF corresponds to direct bond formation between ortho positions in DPC, referred to as ortho,ortho' coupling. 2,7-DMF corresponds to a carbene-carbene rearrangement, whereby DPC undergoes ring expansion to phenylcycloheptatetraene (PhCHT) followed by ring contraction to o-biphenylylcarbene (o-BPC), which then cyclizes to FL. The carbene-carbene rearrangement dominates over the ortho,ortho' coupling under all conditions employed. The ortho,ortho' coupling must take place in a higher excited state (most likely S2 or T1) of DPC, because it is not observed at all under thermolysis conditions, where only S1 and T0 are populated. The carbene carbene rearrangement may take place either in a hot S1 state or more likely in a higher excited state (S2 or T1). PMID- 23941301 TI - Hydrophilic polydopamine-coated graphene for metal ion immobilization as a novel immobilized metal ion affinity chromatography platform for phosphoproteome analysis. AB - To discover trace phosphorylated proteins or peptides with great biological significance for in-depth phosphoproteome analysis, it is urgent to develop a novel technique for highly selective and effective enrichment of phosphopeptides. In this work, an IMAC (immobilized metal ion affinity chromatography) material with polydopamine coated on the surface of graphene and functionalized with titanium ions (denoted as Ti(4+)-G@PD) was initially designed and synthesized. The newly prepared Ti(4+)-G@PD with enhanced hydrophilicity and biological compatibility was characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and infrared (IR), and its performance for selective and effective enrichment of phosphopeptide was evaluated with both standard peptide mixtures and human serum. PMID- 23941303 TI - Ichthyophonus-infected walleye pollock Theragra chalcogramma (Pallas) in the eastern Bering Sea: a potential reservoir of infections in the North Pacific. AB - In 2003, the Alaska walleye pollock industry reported product quality issues attributed to an unspecified parasite in fish muscle. Using molecular and histological methods, we identified the parasite in Bering Sea pollock as Ichthyophonus. Infected pollock were identified throughout the study area, and prevalence was greater in adults than in juveniles. This study not only provides the first documented report of Ichthyophonus in any fish species captured in the Bering Sea, but also reveals that the parasite has been present in this region for nearly 20 years and is not a recent introduction. Sequence analysis of 18S rDNA from Ichthyophonus in pollock revealed that consensus sequences were identical to published parasite sequences from Pacific herring and Yukon River Chinook salmon. Results from this study suggest potential for Ichthyophonus exposures from infected pollock via two trophic pathways; feeding on whole fish as prey and scavenging on industry-discharged offal. Considering the notable Ichthyophonus levels in pollock, the low host specificity of the parasite and the role of this host as a central prey item in the Bering Sea, pollock likely serve as a key Ichthyophonus reservoir for other susceptible hosts in the North Pacific. PMID- 23941302 TI - Penta-O-galloyl-beta-D-glucose ameliorates inflammation by inhibiting MyD88/NF kappaB and MyD88/MAPK signalling pathways. AB - BACKGROUND AND PURPOSE: The gallnut of Rhus chinensis MILL and its main constituent penta-O-galloyl-beta-D-glucose (PGG) inhibited NF-kappaB activation in LPS-stimulated peritoneal and colonic macrophages. Here we have investigated PGG mechanisms underlying anti-inflammatory effects of PGG in vitro and in vivo. EXPERIMENTAL APPROACH: Male C57BL/6 mice (18-22 g, 6 weeks old) were used to prepare peritoneal and colonic macrophages and for the induction of colitis by intrarectal administration of 2,3,4-trinitrobenzene sulphonic acid (TNBS). A range of inflammatory markers and transcription factors were evaluated by elisa, immunoblotting, flow cytometry and confocal microscopy. KEY RESULTS: Expression of Toll-like receptor (TLR)-4 or Lipopolysaccharide (LPS) binding to TLR-4 in LPS stimulated peritoneal macrophages was not affected by PGG. However PGG inhibited binding of an anti-MyD88 antibody to peritoneal macrophages, but did not reduce binding of anti-IL-1 receptor-associated kinase (IRAK1) and IRAK4 antibodies to the macrophages with or without transfection with MyD88 siRNA. PGG potently reduced the activation of IRAK1, NF-kappaB, and MAPKs in LPS- or pepetidoglycan stimulated peritoneal and colonic macrophages. PGG suppressed IL-1beta, TNF-alpha and IL-6 in LPS-stimulated peritoneal macrophages, while increasing expression of the anti-inflammatorycytokine IL-10. Oral administration of PGG inhibited colon shortening and myeloperoxidase activity in mice with TNBS-induced colitis, along with reducing NF-kappaB activation and IL-1beta, TNF-alpha, and IL-6 levels, whereas it increased IL-10. CONCLUSIONS AND IMPLICATIONS: PGG reduced activation of NF-kappaB and MAPK signalling pathways by directly interacting with the MyD88 adaptor protein. PGG may ameliorate inflammatory diseases such as colitis. PMID- 23941305 TI - Ultraviolet resonance Raman observations of the structural dynamics of rhizobial oxygen sensor FixL on ligand recognition. AB - FixL is a heme-based oxygen-sensing histidine kinase that induces expression of nitrogen fixation genes under hypoxic conditions. Oxygen binding to heme iron in the sensor domain of FixL initiates protein conformational changes that are transmitted to the histidine kinase domain, inactivating autophosphorylation activity. Although FixL also can bind other diatomic ligands such as CO, the CO bound FixL represents incomplete inhibition of kinase activity. Ultraviolet resonance Raman (UVRR) spectra revealed that oxygen binding to the truncated sensor domain of FixL markedly decreased the intensity of the Y8a band arising from Falpha-10 Tyr. In contrast, no appreciable change in intensity of the Y8a band occurred after CO binding, and time-resolved UVRR spectra of the sensor domain of FixL upon O2 dissociation indicated that structural changes near Falpha 10 Tyr occurred at ~0.1 MUs. These results suggest that O2 dissociation from FixL changes the protein conformation near the Falpha-10 Tyr residue within a microsecond. The conformational changes of FixL upon O2 dissociation and the underlying sensing mechanism also are discussed. PMID- 23941304 TI - Clonal amplification and maternal-infant transmission of nevirapine-resistant HIV 1 variants in breast milk following single-dose nevirapine prophylaxis. AB - BACKGROUND: Intrapartum administration of single-dose nevirapine (sdNVP) reduces perinatal HIV-1 transmission in resource-limiting settings by half. Yet this strategy has limited effect on subsequent breast milk transmission, making the case for new treatment approaches to extend maternal/infant antiretroviral prophylaxis through the period of lactation. Maternal and transmitted infant HIV 1 variants frequently develop NVP resistance mutations following sdNVP, complicating subsequent treatment/prophylaxis regimens. However, it is not clear whether NVP-resistant viruses are transmitted via breastfeeding or arise de novo in the infant. FINDINGS: We performed a detailed HIV genetic analysis using single genome sequencing to identify the origin of drug-resistant variants in an sdNVP-treated postnatally-transmitting mother-infant pair. Phylogenetic analysis of HIV sequences from the child revealed low-diversity variants indicating infection by a subtype C single transmitted/founder virus that shared full-length sequence identity with a clonally-amplified maternal breast milk virus variant harboring the K103N NVP resistance mutation. CONCLUSION: In this mother/child pair, clonal amplification of maternal NVP-resistant HIV variants present in systemic and mammary gland compartments following intrapartum sdNVP represents one source of transmitted NVP-resistant variants that is responsible for the acquisition of drug resistant virus by the breastfeeding infant. This finding emphasizes the need for combination antiretroviral prophylaxis to prevent mother to-child HIV transmission. PMID- 23941307 TI - Early postoperative complications after stapled vs handsewn restorative proctocolectomy with ileal pouch-anal anastomosis in 148 patients with familial adenomatous polyposis coli: a matched-pair analysis. AB - AIM: Restorative proctocolectomy with ileal pouch-anal anastomosis for patients with familial adenomatous polyposis (FAP) and ulcerative colitis (UC) has been modified from a transanal hand-suture after mucosectomy to a stapled ileal pouch anal anastomosis (IPAA) without mucosectomy. Better functional results favour stapled anastomosis; however, stapled anastomosis results in higher rates of adenomas in persisting anorectal mucosa. The purpose of this study was to compare the two techniques of pouch-anal anastomosis with respect to early postoperative complications in a collective of FAP patients. METHOD: The study was performed as a matched-pair analysis. Data were obtained from a prospectively collected database. RESULTS: The overall rate of postoperative complications was higher after stapled IPAA (31% stapled vs 23% handsewn), with anastomotic stricture occurring in 24.3% (stapled) and 16.2% (handsewn) (P = 0.22). Any leakage or pelvic abscess formation after stapled anastomosis occurred within 30 days in almost all patients, whereas these were mainly diagnosed between 30 days and 6 months after handsewn IPAA. A laparoscopic approach was used in 56.7% of patients in the stapled group but in only two patients in the handsewn group. Intra operative blood loss was significantly higher in the handsewn group (mean +/- SD: 699 +/- 511 ml vs 369 +/- 343 ml; P < 0.0001), as was the volume of blood transfused (mean +/- SD: 205 +/- 365 ml vs 8 +/- 49 ml; P < 0.0001). Function did not differ between the groups. CONCLUSION: There was a nonstatistically significant tendency towards a higher rate of early postoperative complications after stapled IPAA. The timing of anastomotic leakage and abscess formation differed between the groups. PMID- 23941306 TI - De novo characterization of Larix gmelinii (Rupr.) Rupr. transcriptome and analysis of its gene expression induced by jasmonates. AB - BACKGROUND: Larix gmelinii is a dominant tree species in China's boreal forests and plays an important role in the coniferous ecosystem. It is also one of the most economically important tree species in the Chinese timber industry due to excellent water resistance and anti-corrosion of its wood products. Unfortunately, in Northeast China, L. gmelinii often suffers from serious attacks by diseases and insects. The application of exogenous volatile semiochemicals may induce and enhance its resistance against insect or disease attacks; however, little is known regarding the genes and molecular mechanisms related to induced resistance. RESULTS: We performed de novo sequencing and assembly of the L. gmelinii transcriptome using a short read sequencing technology (Illumina). Chemical defenses of L. gmelinii seedlings were induced with jasmonic acid (JA) or methyl jasmonate (MeJA) for 6 hours. Transcriptomes were compared between seedlings induced by JA, MeJA and untreated controls using a tag-based digital gene expression profiling system. In a single run, 25,977,782 short reads were produced and 51,157 unigenes were obtained with a mean length of 517 nt. We sequenced 3 digital gene expression libraries and generated between 3.5 and 5.9 million raw tags, and obtained 52,040 reliable reference genes after removing redundancy. The expression of disease/insect-resistance genes (e.g., phenylalanine ammonialyase, coumarate 3-hydroxylase, lipoxygenase, allene oxide synthase and allene oxide cyclase) was up-regulated. The expression profiles of some abundant genes under different elicitor treatment were studied by using real time qRT-PCR.The results showed that the expression levels of disease/insect resistance genes in the seedling samples induced by JA and MeJA were higher than those in the control group. The seedlings induced with MeJA elicited the strongest increases in disease/insect-resistance genes. CONCLUSIONS: Both JA and MeJA induced seedlings of L. gmelinii showed significantly increased expression of disease/insect-resistance genes. MeJA seemed to have a stronger induction effect than JA on expression of disease/insect-resistance related genes. This study provides sequence resources for L. gmelinii research and will help us to better understand the functions of disease/insect-resistance genes and the molecular mechanisms of secondary metabolisms in L. gmelinii. PMID- 23941308 TI - Theoretical study of interactions between halogen-substituted s-triazine and halide anions. AB - The interactions between halogen-substituted s-trazine (C3H2N3X) and halide anions (Y(-)) have been investigated at the MP2/aug-cc-pVDZ (aug-cc-pVDZ-PP) level. C3H2N3X can interact with halide anions to form five types of complexes (C3H2N3X.Y(-)): a strong sigma-type interaction complex, a weak sigma-type interaction complex, an anion-pi interaction complex, a hydrogen-bonding complex, and a halogen-bonding complex. The binding energies, structures, and bonding characteristics of these complexes have been discussed. The local details of potential energy surfaces around the binding sites for some selected complexes have been depicted. The results indicate that the binding behavior of F(-) is quite different from that of Cl(-), Br(-), and I(-). The potential energy surface is separated into two parts, the HB-sigma-pi region and the XB region, by a relatively high energy barrier for complexes C3H2N3Cl.Cl(-), C3H2N3Br.Cl(-), and C3H2N3I.Cl(-). The HB-sigma-pi region is characterized by the flat potential energy surface, indicating that the binding strength is retained when the anion is held over the HB-sigma-pi region. The XB region is characterized by the steeper potential energy surface, indicating that the binding strength is more sensitive to the anion position in this region. The binding strength of the HB sigma-pi region is stronger than that of the XB region for C3H2N3Cl.Cl(-) and C3H2N3Br.Cl(-), whereas the binding strength of the XB region is stronger than that of the HB-sigma-pi region for C3H2N3I.Cl(-). PMID- 23941310 TI - Myotonic dystrophy is not only a disease affecting the muscles, it is also a CNS disorder. PMID- 23941309 TI - Association of supermarket characteristics with the body mass index of their shoppers. AB - BACKGROUND: Research on the built food environment and weight status has mostly focused on the presence/absence of food outlets while ignoring their internal features or where residents actually shop. We explored associations of distance travelled to supermarkets and supermarket characteristics with shoppers' body mass index (BMI). METHODS: Shoppers (n=555) of five supermarkets situated in different income areas in the city were surveyed for food shopping habits, demographics, home postal code, height and weight. Associations of minimum distance to a supermarket (along road network, objectively measured using ArcGIS), its size, food variety and food basket price with shoppers' BMI were investigated. The 'food basket' was defined as the mixture of several food items commonly consumed by residents and available in all supermarkets. RESULTS: Supermarkets ranged in total floor space (7500-135,000 square feet) and had similar varieties of fruits, vegetables and cereals. The majority of participants shopped at the surveyed supermarket more than once per week (mean range 1.2 +/- 0.8 to 2.3 +/- 2.1 times per week across the five supermarkets, p < 0.001), and identified it as their primary store for food (52% overall). Mean participant BMI of the five supermarkets ranged from 23.7 +/- 4.3 kg/m2 to 27.1 +/- 4.3 kg/m2 (p < 0.001). Median minimum distance from the shoppers' residence to the supermarket they shopped at ranged from 0.96 (0.57, 2.31) km to 4.30 (2.83, 5.75) km (p < 0.001). A negative association was found between food basket price and BMI. There were no associations between BMI and minimum distance to the supermarket, or other supermarket characteristics. After adjusting for age, sex, dissemination area median individual income and car ownership, BMI of individuals who shopped at Store 1 and Store 2, the supermarkets with lowest price of the 'food basket', was 3.66 kg/m2 and 3.73 kg/m2 higher compared to their counterparts who shopped at the supermarket where the 'food basket' price was highest (p < 0.001). CONCLUSIONS: The food basket price in supermarkets was inversely associated with BMI of their shoppers. Our results suggest that careful manipulation of food prices may be used as an intervention for decreasing BMI. PMID- 23941311 TI - Factors influencing women's selection of combined hormonal contraceptive methods after counselling in 11 countries: results from a subanalysis of the CHOICE study. AB - OBJECTIVES: To investigate which characteristics of women and healthcare professionals (HCPs) were associated with changing to another combined hormonal contraceptive (CHC) method after contraceptive counselling. METHODS: CHOICE was a cross-sectional survey in which 18,787 women were counselled about combined hormonal contraceptives, during which their contraceptive methods preferred both prior to and after counselling were recorded. In this subanalysis, characteristics associated with changing the method after counselling were determined using logistic regression models. RESULTS: The probability of intending to change from the pill to another method was associated with being older; university-educated; being in a steady relationship; a prior unintended pregnancy; a younger HCP or one who recommended methods other than the pill. Changing to the patch was associated with a female HCP or a HCP who recommended the patch or an injectable. Changing to the ring was associated with being over 21 years; university-educated; being in a relationship; previous hormonal method use; and counselling by a female HCP, a HCP < 60 years old, or a HCP who recommended the ring or an implant. The country of residence influenced these changes in a complex pattern. CONCLUSIONS: Women's choice of CHC methods after contraceptive counselling are influenced by their age, educational background, relationship status, prior unplanned pregnancies and country of residence, as well as age, gender and preferences of their HCP. PMID- 23941312 TI - Knowledge and practices of general surgeons and residents regarding spilled gallstones lost during laparoscopic cholecystectomy: a cross sectional survey. AB - BACKGROUND: Gall bladder perforation, gallstone spillage and loss are commonly reported from Laparoscopic Cholecystectomy (LC). Though rare, lost gallstones can cause a variety of complications presenting variably from within 1 month to 20 years postoperatively. Our objective was to investigate knowledge and practices of surgeons and surgical residents regarding spilled gallstones lost during laparoscopic cholecystectomy. METHODS: An observational, cross-sectional survey, using a questionnaire based on 13 self-answered close-ended questions, was conducted at 6 different post-graduate centers in Karachi, Pakistan. RESULTS: Of the 82 participants, 23 (28%) were consultant surgeons while 59 (72%) were general surgery residents. 86% of participants were aware that stones lost during LC can cause complications. Out of the 18 reported complications presented, only 20% participants identified more than 8 complications for which they can consider lost gallstones causal. 28% of participants weren't aware about the expected postoperative duration for presentation of complications. Only 15% of our participants expected complications beyond 5 years of the procedure. 72% of participants will not convert to open cholecystectomy to retrieve lost gallstones. While 88% of participants agreed that lost gallstones should be documented in operative notes, only 70% reported that it's actually done in practice. 55% of participants agreed to have possibility of lost gallstones as part of the informed consent but in practice it's included according to only 31% of participants. 68% of participants believe that patients should be informed if gallstones are lost but in actual practice only 41% participants inform patients when gallstones are lost during procedure. CONCLUSIONS: We conclude that there is a dearth of awareness regarding diversity of complications from lost gallstones and about their variable postoperative duration of presentation. The practices involving lost gallstones management, documentation and patient information were found to vary widely. Proper awareness is imperative as it may compel surgeons to undertake all possible measures to retrieve spilled gallstones and progress towards better and standardized practices in managing lost gallstones. PMID- 23941314 TI - Variation of health-related quality of life assessed by caregivers and patients affected by severe childhood infections. AB - BACKGROUND: The agreement between self-reported and proxy measures of health status in ill children is not well established. This study aimed to quantify the variation in health-related quality of life (HRQOL) derived from young patients and their carers using different instruments. METHODS: A hospital-based cross sectional survey was conducted between August 2010 and March 2011. Children with meningitis, bacteremia, pneumonia, acute otitis media, hearing loss, chronic lung disease, epilepsy, mild mental retardation, severe mental retardation, and mental retardation combined with epilepsy, aged between five to 14 years in seven tertiary hospitals were selected for participation in this study. The Health Utilities Index Mark 2 (HUI2), and Mark 3 (HUI3), and the EuroQoL Descriptive System (EQ-5D) and Visual Analogue Scale (EQ-VAS) were applied to both paediatric patients (self-assessment) and caregivers (proxy-assessment). RESULTS: The EQ-5D scores were lowest for acute conditions such as meningitis, bacteremia, and pneumonia, whereas the HUI3 scores were lowest for most chronic conditions such as hearing loss and severe mental retardation. Comparing patient and proxy scores (n = 74), the EQ-5D exhibited high correlation (r = 0.77) while in the HUI2 and HUI3 patient and caregiver scores were moderately correlated (r = 0.58 and 0.67 respectively). The mean difference between self and proxy-assessment using the HUI2, HUI3, EQ-5D and EQ-VAS scores were 0.03, 0.05, -0.03 and -0.02, respectively. In hearing-impaired and chronic lung patients the self-rated HRQOL differed significantly from their caregivers. CONCLUSIONS: The use of caregivers as proxies for measuring HRQOL in young patients affected by pneumococcal infection and its sequelae should be employed with caution. Given the high correlation between instruments, each of the HRQOL instruments appears acceptable apart from the EQ-VAS which exhibited low correlation with the others. PMID- 23941313 TI - Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: results from two randomized clinical trials of bupropion. AB - AIMS: To evaluate the associations of treatment and an additive genetic efficacy score (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled into two randomized clinical trials of smoking cessation therapies. DESIGN: Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support. SETTING: Two hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2). PARTICIPANTS: A total of 792 self-identified white treatment-seeking smokers aged >=18 years smoking >=10 cigarettes per day over the last year. MEASUREMENTS: Age, gender, Fagerstrom Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 variable number of tandem repeats polymorphism [DRD4 VNTR], SLC6A3,3' VNTR) analyzed both separately and as part of an AGES, time to first lapse and point prevalence abstinence at end of treatment. FINDINGS: Significant associations of the AGES (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.06-1.14, P = 0.009) and of the DRD4 VNTR (HR = 1.29, 95% CI = 1.17-1.41, P = 0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (beta standard error = -0.18 [0.07], P = 0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo. CONCLUSIONS: A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion. PMID- 23941315 TI - How significant is upgrade in Gleason score between prostate biopsy and radical prostatectomy pathology while discussing less invasive treatment options? AB - OBJECTIVE: This study aimed to assess the oncological outcomes of patients experiencing an upgrade from their initial biopsy pathology, and to determine whether these tumours have characteristics resembling their initial biopsy Gleason score (GS) or final radical prostatectomy (RP) GS. MATERIAL AND METHODS: Data on 632 patients undergoing open retropubic RP between January 1994 and May 2011 at Ankara University were investigated retrospectively. Data included age, preoperative prostate-specific antigen (PSA), clinical stage, biopsy GS, prostate volume, RP specimen GS, surgical margin positivity, pathological T stage and biochemical recurrence. Biochemical recurrence of GS concordant and upgraded tumours was compared. RESULTS: GS concordance was found in 378 cases (59.8%) and GS upgrading was observed in 183 patients (28.9%). GS upgraded tumours were found to have higher biochemical recurrence rates than their corresponding concomitant GS group. Multivariate analysis revealed that serum PSA level, pathological T stage and GS upgrading were independent prognostic factors for biochemical recurrence. Age and prostate volume were not found to be independent prognostic factors. CONCLUSION: Upgrade in biopsy GS is a predictor for aggressive tumours with a higher risk for biochemical recurrence than concordant tumours. It may be observed in about a quarter of patients. As it was not possible to identify correctly those patients who may experience an upgrade in GS, patients who are candidates for less invasive treatment options must be informed about the risk of upgrading and the possibility of a worse clinical course. PMID- 23941316 TI - 'It was caused by the carelessness of the parents': cultural models of child malnutrition in southern Malawi. AB - Parents' conceptions of child growth, health and malnutrition are culturally bound, making information about local understandings of malnutrition and its causes necessary for designing effective nutrition programmes. This study used ethnographic methods to elucidate cultural models of child care and malnutrition among the Yao of southern Malawi. Data were collected in six rural villages from 28 key informant interviews with village chiefs and traditional healers among others and 18 focus group discussions with parents and grandmothers of young children. For the Yao, lack of parental care is a key cause of poor child health and can lead to thinness (kunyililika) or swelling (kuimbangana). Parents are said to be careless if they are not attentive to the child's needs, are unable to provide adequate quality or quantity of food, or fail to follow sexual abstinence rules. Maintaining abstinence protects the family and failure to do so causes the transfer of 'heat' from a sexually active parent to a 'cold' child and results in child health problems, including signs and symptoms of malnutrition. These findings indicate that the Yao understanding of care is much broader than the concept of care during feeding described in the nutrition literature. In addition, the Yao note the importance of several key feeding practices supported by international agencies and understand the influence of illness on child nutritional status. These congruencies with the public health frame should be used together with information about the cultural context to design more socially and emotionally relevant care and nutrition programmes among the Yao. PMID- 23941317 TI - Serial organization and timing in a motor skill. AB - The temporal and serial organization (or timing) of responses in motor skill was investigated in a repetitive motor task, resisted hand cranking. Both positional timing and serial timing were analyzed using strain-gauge techniques and were related to the performance of the preferred and non-preferred hands. The results demonstrated the superiority of the preferred hand on the serial timing criteria and supported the hypothesis that skilled performance is characterized by more effective temporal structuring of the components of the response. PMID- 23941318 TI - An examination of the selection of criterion scores for the study of motor learning and retention. AB - 150 Ss were given 50 practice trials on the stabilometer over a period of 4 days (20 trials on Day 1 followed by a 1-day rest, 10 trials on Day 2, followed by a 7 day rest, 10 trials on Day 3 followed by a 14-day rest, and 10 trials on Day 4). A series of learning scores reflecting improvement in performance over the 4 days and retention scores reflecting loss of performance between days were obtained. The reliability of individual differences in these scores were calculated using the odd-even method and by progressively increasing the number of trials included in the measure of initial and final performance level. On the basis of the findings obtained it was concluded that using 4 - 6 trials in initial and final ability levels results in a difference (criterion) score which combines relatively high reliability with a relatively high estimate of the amount of change in performance. PMID- 23941319 TI - Uncertainty, timekeeping, and simple reaction time. AB - Implications of the hypothesis that effects on simple RT of event and time uncertainty are due to S's unwillingness to prepare for an unlikely event were tested. In 2 experiments, RT was compared for the foreperiod method and the new transit-signal method. Alternative hypotheses based on faulty reinstatement of foreperiods were invalidated. The inverse relation of RT to event uncertainty persisted for the transit-signal method which is free of memory effects. With time uncertainty the initial gradient of RT was steeper with the transit-signal method. There S had before him exact time information for estimating momentary probability of a signal. The uncertainty effect occurred even though it was evident that S could overcome it, so the term unwillingness is appropriate. Consequences of inaccurate timekeeping were examined; the contention that it simply and invariably increases RT was not supported. Unwillingness was examined in terms of the utility associated with preparation. PMID- 23941320 TI - Bilateral transfer in tapping skill in the absence of peripheral information. AB - Bilateral transfer in a fast tapping task was investigated under normal (+FB) and reduced (-FB) feedback conditions, in the -FB experiment 36 Ss were assigned to 3 groups: preferred (PH) to non-preferred (NPH) shift; NPH to PH; and alternating trials of PH and NPH. With + FB 2 further groups of 12 Ss transferred PH to NPH or NPH to PH. 8 preshift and 8 postshift trials were given. The alternating group had 8 PH and 8 NPH trials. In preshift performance increment was found in ail groups except in +FB with NPH. With +FB some facilitation in transfer was obtained for the NPH; under -FB marked positive transfer was found for the PH. Alternating PH and NPH performance conformed to preshift levels. Results were discussed in terms of differential central control processes for the two hands. PMID- 23941321 TI - A test of the adams-creamer decay hypothesis for the timing of motor responses. AB - The Adams-Creamer hypothesis states that S uses the decay of proprioceptive feedback from an early portion of a movement to cue a timed response at some later time. This hypothesis was tested by creating passive left-arm movement in one group and withholding it from another, and having Ss make a right-hand response when exactly 2.0 sec. had elapsed since the end of the movement Ss with left-arm feedback had less absolute and algebraic error, and greater within-S consistency than did the no-movement control Ss and, when KR was withdrawn, Ss with left-arm movement regressed less than did Ss without the left-arm movement, which provided 2 lines of support for the decay hypothesis. PMID- 23941322 TI - Laterality of champion athletes. AB - Laterality questionnaire responses of 144 nationally known male champion athletes and 160 university upper-classmen were compared. For each of 19 significant handedness and footedness items (in a list of 150) the percentage of "right" (R) responses of champions was less than that of students whose interest in athletics was assumed to be nominal. Difference between mean Index of Dominance score of champion is (+.420) and that of students (+.477) was not significant. PMID- 23941323 TI - Carbon nanotube yarn electrodes for enhanced detection of neurotransmitter dynamics in live brain tissue. AB - This work demonstrates the potential of nanoscale carbon electrode materials for improved detection of electroactive neurotransmitter dynamics in the brain. Individual multiwalled carbon nanotubes were synthesized via chemical vapor deposition, spun into yarns, and used in the fabrication of disk microelectrodes that were subsequently characterized using scanning electron and atomic force microscopies. The carbon nanotube yarn electrodes were coupled with fast-scan cyclic voltammetry and used to discriminately detect rapid neurotransmitter fluctuations in acute brain slices. The results demonstrate that the distinct structural and electronic properties of the nanotubes result in improved selectivity, sensitivity, and spatial resolution, as well as faster apparent electron transfer kinetics when compared to the conventional carbon-fiber microelectrodes typically used in vivo. PMID- 23941324 TI - Improved exercise performance and increased aerobic capacity after endurance training of patients with stable polymyositis and dermatomyositis. AB - INTRODUCTION: This randomized, controlled study on patients with polymyositis or dermatomyositis was based on three hypotheses: patients display impaired endurance due to reduced aerobic capacity and muscle weakness, endurance training improves their exercise performance by increasing the aerobic capacity, and endurance training has general beneficial effects on their health status. METHODS: In the first part of this study, we compared 23 patients with polymyositis or dermatomyositis with 12 age- and gender-matched healthy controls. A subgroup of patients were randomized to perform a 12-week endurance training program (exercise group, n = 9) or to a non-exercising control group (n = 6). We measured maximal oxygen uptake (VO2 max) and the associated power output during a progressive cycling test. Endurance was assessed as the cycling time to exhaustion at 65% of VO2 max. Lactate levels in the vastus lateralis muscle were measured with microdialysis. Mitochondrial function was assessed by measuring citrate synthase (CS) and beta-hydroxyacyl-CoA dehydrogenase (beta-HAD) activities in muscle biopsies. Clinical improvement was assessed according to the International Myositis Assessment and Clinical Studies Group (IMACS) improvement criteria. All assessors were blinded to the type of intervention (that is, training or control). RESULTS: Exercise performance and aerobic capacity were lower in patients than in healthy controls, whereas lactate levels at exhaustion were similar. Patients in the exercise group increased their cycling time, aerobic capacity and CS and beta-HAD activities, whereas lactate levels at exhaustion decreased. Six of nine patients in the exercise group met the IMACS improvement criteria. Patients in the control group did not show any consistent changes during the 12-week study. CONCLUSIONS: Polymyositis and dermatomyositis patients have impaired endurance, which could be improved by 12 weeks of endurance training. The clinical improvement corresponds to increases in aerobic capacity and muscle mitochondrial enzyme activities. The results emphasize the importance of endurance exercise in addition to immunosuppressive treatment of patients with polymyositis or dermatomyositis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01184625. PMID- 23941325 TI - UDP induces intestinal epithelial migration via the P2Y6 receptor. AB - BACKGROUND AND PURPOSE: Extracellular nucleotides are released at high concentrations from damaged cells and function through P2 receptor activation. Intestinal epithelial restitution, which is defined as cell migration independent of cell proliferation, is an important initial step in the process of wound healing. In this study, we investigated the role of extracellular nucleotides in intestinal epithelial migratory responses. EXPERIMENTAL APPROACH: Wound-healing and trans-well migration assays were performed with a rat intestinal epithelial cell line (IEC-6). The concentrations of extracellular nucleotides released from injured IEC-6 cells were measured by HPLC. TGF-beta expression was assessed by RT PCR and elisa. KEY RESULTS: Scratching the monolayer of IEC-6 cells induced cell migration. Pretreatment with apyrase or MRS2578, a selective P2Y6 antagonist, inhibited the wound-induced cell migration. Among the cellular nucleotides, only ATP and uridine 5'-diphosphate (UDP) were detected in the culture medium after cell wounding. Exogenously applied UDP dose-dependently enhanced the migration more effectively than ATP but did not induce proliferation. In addition, cell wounding and UDP increased the expression of TGF-beta, and both the wound-induced and UDP-enhanced migration were inhibited by MRS2578 or ALK5Inhibitor (ALK5i), a TGF-beta receptor blocker. Furthermore, cell wounding and UDP stimulation up regulated the expression of P2Y6 receptor mRNA, and this effect was suppressed by MRS2578 or ALK5i. CONCLUSION AND IMPLICATIONS: Wound-induced UDP evokes intestinal epithelial restitution by activation of P2Y6 receptors, which mediates de novo synthesis of TGF-beta. In addition, the expression of P2Y6 receptors is increased by cell wounding and UDP, which constitutes a positive-feedback loop for mucosal repair. PMID- 23941326 TI - Enhanced sensitivity employing zwitterionic and pI balancing dyes (Z-CyDyes) optimized for 2D-gel electrophoresis based on side chain modifications of CyDye fluorophores. New tools for use in proteomics and diagnostics. AB - The CyDye family of fluorescent dyes is currently the overwhelming choice for applications in proteomic analysis, using two-dimensional difference gel electrophoresis (2D-DIGE). Protein labeling with CyDyes is hampered by protein precipitation and gel smearing when used above minimal labeling. The solubility of labeled protein may be improved by introducing water solubilizing groups on the dye such as cysteic acids. However, addition of a negatively charged functionality will have the undesired effect of shifting the pI in relation to the unlabeled protein. These limitations have been addressed through the synthesis of highly water-soluble and pI balancing zwitterionic CyDye fluorophores (Z-CyDyes). The new dyes feature a cysteic acid motif, a titratable amine functionality and a NHS activated ester group. In side by side 2D-DIGE comparisons of Z-CyDyes and CyDyes, the new dyes significantly enhanced protein spot volume and the number of spots that were detected. Z-CyDyes have the potential to enhance the depth of proteome coverage and provide a general strategy for improving the performance of protein tagging reagents. PMID- 23941327 TI - Application of loop analysis for the qualitative assessment of surveillance and control in veterinary epidemiology. AB - BACKGROUND: Systems for animal disease mitigation involve both surveillance activities and interventions to control the disease. They are complex organizations that are described by partial or imprecise data, making it difficult to evaluate them or make decisions to improve them. A mathematical method, called loop analysis, can be used to model qualitatively the structure and the behavior of dynamic systems; it relies on the study of the sign of the interactions between the components of the system. This method, currently widely used by ecologists, has to our knowledge never been applied in the context of animal disease mitigation systems. The objective of the study was to assess whether loop analysis could be applied to this new context. We first developed a generic model that restricted the applicability of the method to event-based surveillance systems of endemic diseases, excluding the emergence and eradication phases. Then we chose the mitigation system of highly pathogenic avian influenza (HPAI) H5N1 in Cambodia as an example of such system to study the application of loop analysis to a real disease mitigation system. RESULTS: Breaking down the generic model, we constructed a 6-variables model to represent the HPAI H5N1 mitigation system in Cambodia. This construction work improved our understanding of this system, highlighting the link between surveillance and control which is unclear in traditional representations of this system. Then we analyzed the effect of the perturbations to this HPAI H5N1 mitigation system that we interpreted in terms of investment in a given compartment. This study suggested that increasing intervention at a local level can optimize the system's efficiency. Indeed, this perturbation both decreases surveillance and intervention costs and reduces the disease's occurrence. CONCLUSION: Loop analysis can be applied to disease mitigation systems. Its main strength is that it is easy to design, focusing on the signs of the interactions. It is a simple and flexible tool that could be used as a precursor to large-scale quantitative studies, to support reflection about disease mitigation systems structure and functioning. PMID- 23941328 TI - Direct imaging of atomic scale structure and electronic properties of GaAs wurtzite and zinc blende nanowire surfaces. AB - Using scanning tunneling microscopy and spectroscopy we study the atomic scale geometry and electronic structure of GaAs nanowires exhibiting controlled axial stacking of wurtzite (Wz) and zinc blende (Zb) crystal segments. We find that the nonpolar low-index surfaces {110}, {101[overline]0}, and {112[overline]0} are unreconstructed, unpinned, and without states in the band gap region. Direct comparison between Wz and Zb GaAs reveal a type-II band alignment and a Wz GaAs band gap of 1.52 eV. PMID- 23941330 TI - Corneal collagen cross-linking as treatment for infectious and noninfectious corneal melting in cats and dogs: results of a prospective, nonrandomized, controlled trial. AB - OBJECTIVE: UV-A/Riboflavin cross-linking of corneal collagen fibers (CXL) is a highly promising therapy for corneal melting in humans. A prospective interventional, nonrandomized, controlled study was conducted to compare the stabilizing effect of CXL treatment on melting keratitis in dogs and cats and the complication rate of CXL to those of standardized intensive medical treatment. PROCEDURES: Forty-nine eyes with melting keratitis were included in the study between October 2009 and October 2012. All eyes were treated according to the same medical treatment protocol. Nineteen eyes were CXL-treated, and 30 eyes were not. Follow-up included slit-lamp examination, fluorescein staining, ulcer size measurement, stromal stability evaluation, photographic documentation, and documentation of complications. RESULTS: Five of 19 eyes in the CXL group and 9/30 eyes in the control group required rescue stabilization due to continued melting. Seven of the nine control group corneas stabilized after rescue CXL treatment. At initial presentation, the ulcers in the canine CXL group were significantly deeper and larger than in the control group. Ulcer deepening during follow-up was more pronounced in the canine control group than in the canine CXL group. CXL treatment-related complications were not observed. CONCLUSIONS: Based on the similar failure rates in the control and CXL treatment groups despite the poorer initial situation in the CXL group, the tendency for the ulcers in the control group to deepen and the stabilization of all corneas receiving CXL rescue treatment, we believe that CXL has its place as an adjunctive therapy for melting keratitis in veterinary ophthalmology. PMID- 23941329 TI - Global transcriptional response of Caulobacter crescentus to iron availability. AB - BACKGROUND: In the alpha subclass of proteobacteria iron homeostasis is controlled by diverse iron responsive regulators. Caulobacter crescentus, an important freshwater alpha-proteobacterium, uses the ferric uptake repressor (Fur) for such purpose. However, the impact of the iron availability on the C. crescentus transcriptome and an overall perspective of the regulatory networks involved remain unknown. RESULTS: In this work we report the identification of iron-responsive and Fur-regulated genes in C. crescentus using microarray-based global transcriptional analyses. We identified 42 genes that were strongly upregulated both by mutation of fur and by iron limitation condition. Among them, there are genes involved in iron uptake (four TonB-dependent receptor gene clusters, and feoAB), riboflavin biosynthesis and genes encoding hypothetical proteins. Most of these genes are associated with predicted Fur binding sites, implicating them as direct targets of Fur-mediated repression. These data were validated by beta-galactosidase and EMSA assays for two operons encoding putative transporters. The role of Fur as a positive regulator is also evident, given that 27 genes were downregulated both by mutation of fur and under low-iron condition. As expected, this group includes many genes involved in energy metabolism, mostly iron-using enzymes. Surprisingly, included in this group are also TonB-dependent receptors genes and the genes fixK, fixT and ftrB encoding an oxygen signaling network required for growth during hypoxia. Bioinformatics analyses suggest that positive regulation by Fur is mainly indirect. In addition to the Fur modulon, iron limitation altered expression of 113 more genes, including induction of genes involved in Fe-S cluster assembly, oxidative stress and heat shock response, as well as repression of genes implicated in amino acid metabolism, chemotaxis and motility. CONCLUSIONS: Using a global transcriptional approach, we determined the C. crescentus iron stimulon. Many but not all of iron responsive genes were directly or indirectly controlled by Fur. The iron limitation stimulon overlaps with other regulatory systems, such as the RpoH and FixK regulons. Altogether, our results showed that adaptation of C. crescentus to iron limitation not only involves increasing the transcription of iron-acquisition systems and decreasing the production of iron-using proteins, but also includes novel genes and regulatory mechanisms. PMID- 23941332 TI - Limbic encephalitis: a clinical-radiological comparison between herpetic and autoimmune etiologies. AB - BACKGROUND: Herpetic (HE) and autoimmune (AE) encephalitis share clinical and radiological features. We compared both types of encephalitis with the aim of making a differential clinical-radiological pattern. MATERIALS AND METHODS: All cases with a clinical diagnosis of encephalitis who attended our hospital between 1999 and 2012 were reviewed. We selected those cases with positive polymerase chain reaction for herpes simplex virus 1 (HSV-1) in the cerebrospinal fluid (CSF), and those with antineuronal antibodies or paraneoplastic etiology. We compared epidemiological, clinical, CSF, electroencephalographic and radiological findings. RESULTS: Twelve patients with positive polymerase chain reaction for HSV-1, and 10 patients with antineuronal antibody or paraneoplastic etiology were found. The only features found exclusively in one group were the presence of psychiatric symptoms and tumors in AE. Acute onset of symptoms, fever and aphasia were more frequent in HE, which showed higher level of proteins and erythrocyte count in CSF. Neuroimaging was abnormal in all cases of HE, but only in 60% of AE. Insular and diffuse temporal lobe involvement and absence of basal ganglia involvement were more frequent in HE, and mesial temporal involvement in AE. The highest diagnostic values for differentiating HE from AE were the association of acute onset of symptoms and fever (sensitivity 0.92, specificity 1), and the absence of basal ganglia involvement (sensitivity 0.82, specificity 1). CONCLUSIONS: There are few differences between HE and AE. Psychiatric symptoms and association with tumors were unique for AE. Acute onset with fever and absence of basal ganglia involvement in magnetic resonance imaging support a diagnosis of HE. PMID- 23941331 TI - The relationship between baseline nutritional status with subsequent parenteral nutrition and clinical outcomes in cancer patients undergoing hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising treatment option for selected patients with peritoneal carcinomatosis. This retrospective study investigated the relationship between baseline nutritional assessment with subsequent parenteral nutritional (PN) and clinical outcomes in cancer patients undergoing CRS and HIPEC. METHODS: A consecutive series of 60 patients undergoing CRS and HIPEC at our institution between January 2009 and May 2011. Subjective Global Assessment (SGA) was used to assess nutritional status. Patients were classified preoperatively as: well nourished (SGA-A), mildly-moderately malnourished (SGA B), and severely malnourished (SGA-C). For PN, patients were divided into 2 groups: those who received PN (PN+) and those who did not receive PN (PN-). The primary outcomes of interest were length of stay (LOS), postoperative complications, ECOG performance status (PS) and survival. LOS was calculated as the number of days in the hospital post surgery. Performance status was measured on a scale of 0-4. Survival was calculated from the date of first visit to the date of death/last contact. RESULTS: Of 60 patients, 19 were males and 41 females. The mean age at presentation was 50.3 years. The most common cancer types were colorectal (n = 24) and gynecologic (n = 19) with the majority of patients (n = 47) treated previously before coming to our institution. 33 patients were SGA-A, 22 SGA-B and 5 SGA-C prior to surgery. Of a total of 60 patients, 31 received PN. Mean LOS for the entire cohort was 16.2 days (SD = 9.8). Mean LOS for preoperative SGA-A, SGA-B and SGA-C were 15.0, 15.2 and 27.8 days respectively (ANOVA p = 0.02). Overall incidence of complications was 26.7% (16/60). Complications were recorded in 9 of 33 (27.3%) preoperative SGA-A patients and 7 of 27 (25.9%) SGA-B + C patients (p = 0.91). The median overall survival was 17.5 months (95% CI = 13.0 to 22.1 months). Median survival for preoperative SGA-A and SGA-B + C cohorts was 22.4 and 10.4 months respectively (p = 0.006). CONCLUSIONS: The preoperative SGA predicts LOS and survival in cancer patients undergoing HIPEC. Future randomized clinical trials in this patient population should investigate the systematic provision of PN to all malnourished patients in the preoperative period for a minimum of 7-10 days with the continuation of PN in the postoperative period. PMID- 23941333 TI - Previous exposure to musical auditory stimulation immediately influences the cardiac autonomic responses to the postural change maneuver in women. AB - BACKGROUND: Chronic exposure to musical auditory stimulation has been reported to improve cardiac autonomic regulation. However, it is not clear if music acutely influences it in response to autonomic tests. We evaluated the acute effects of music on heart rate variability (HRV) responses to the postural change maneuver (PCM) in women. METHOD: We evaluated 12 healthy women between 18 and 28 years old and HRV was analyzed in the time (SDNN, RMSSD, NN50 and pNN50) and frequency (LF, HF and LF/HF ratio) domains. In the control protocol, the women remained at seated rest for 10 minutes and quickly stood up within three seconds and remained standing still for 15 minutes. In the music protocol, the women remained at seated rest for 10 minutes, were exposed to music for 10 minutes and quickly stood up within three seconds and remained standing still for 15 minutes. HRV was recorded at the following time: rest, music (music protocol) 0-5, 5-10 and 10-15 min during standing. RESULTS: In the control protocol the SDNN, RMSSD and pNN50 indexes were reduced at 10-15 minutes after the volunteers stood up, while the LF (nu) index was increased at the same moment compared to seated rest. In the protocol with music, the indexes were not different from control but the RMSSD, pNN50 and LF (nu) were different from the music period. CONCLUSION: Musical auditory stimulation attenuates the cardiac autonomic responses to the PCM. PMID- 23941334 TI - Acute alcohol-related dysfunction as a predictor of employment status in a longitudinal study of working-age men in Izhevsk, Russia. AB - AIMS: To investigate longitudinally the effect of alcohol consumption and related acute alcohol-related dysfunction on employment status. DESIGN, SETTING AND PARTICIPANTS: A total of 1143 men aged 25-55 years in regular paid employment and resident in the city of Izhevsk, Russia were interviewed between 2003-06 and then re-interviewed (2008-09) and their employment status ascertained. MEASUREMENTS: Exposures of interest were baseline alcohol intake (yearly total volume of ethanol consumed and non-beverage alcohols) and alcohol-related dysfunction, measured by a latent variable defined in terms of frequency of alcohol-related dysfunctional behaviours and by one or more episodes of zapoi (a period of continuous drunkenness lasting 2 or more days). The outcome of interest was whether or not men were still in regular paid employment at follow-up. The inter relationship between these variables was investigated using structural equation modelling. FINDINGS: Total volume of ethanol consumed had no substantive effect on future employment status; however, taking into account education and other socio-demographic factors, there was strong evidence that loss of regular paid employment at follow-up was influenced by non-beverage alcohol consumption [odds ratio = 2.30 for non-beverage drinkers compared with beverage-only drinkers, 95% confidence interval (CI) = 1.21, 4.40)], latent acute alcohol-related dysfunction (odds ratio = 1.50 per standard deviation increase in dysfunction score, 95% CI = 1.20, 1.88) and zapoi (odds ratio = 3.08, 95% CI = 1.71, 5.55). Acute alcohol related dysfunction was an important mediator of the relationship between non beverage alcohol use and employment status. CONCLUSIONS: Acute alcohol-related dysfunction is an important factor in determining whether men remain in employment and an important mediator of the effects of alcohol intake. PMID- 23941336 TI - The evolution of our understanding of endo-xenobiotic crosstalk and cytochrome P450 regulation and the therapeutic implications. AB - INTRODUCTION: Over the past years, there has been increasing evidence that, at least in vertebrates, cytochrome P450-dependent monooxygenases (CYPs) are governed by a most complex regulation. The respective mechanisms comprise structural features such as domain movements, allostery, enzyme-oligomerization as well as numerous transcription factors, non-coding RNAs and extensive regulatory crosstalk. AREAS COVERED: This review summarizes the recent aspects of structural and molecular CYP regulation and discusses the respective consequences and implications. The authors, further, examine the evolutionary origins of CYP regulation in light of their role as endogenous and xenobiotic enzymes. Finally, the article aims to elucidate the potential of CYP regulation as a pharmaceutical target. EXPERT OPINION: Studies on CYP regulation paint an increasingly complex picture of a layered set of regulatory mechanisms. These start structurally on single molecule level, continue with cooperativity and oligomerization of enzyme complexes and finally include a multifaceted regulation of expression control and crossregulation. The respective regulatory network is a key to cellular plasticity and adaptivity. However, it can also be the cause for pathological conditions as well as resistance to medical treatment. A better understanding of the regulatory aspects of CYP biology is, thus, not only of academic interest but promises to be highly rewarding. Even with the limited knowledge available, CYP regulation and CYP crosstalk are already promising pharmacological targets. PMID- 23941335 TI - Association between interleukin 1beta and interleukin 10 concentrations: a cross sectional study in young adolescents in Taiwan. AB - BACKGROUND: In adults, low circulating interleukin 10 (IL10) has been associated with obesity and type 2 diabetes. However, studies investigating IL10 in overweight and obese children have yielded conflicting results. The aim of this study was to investigate factors associated with serum IL10 concentration in young Chinese adolescents. METHODS: Young adolescents (n=325) ages 13.33+/-1.10 years were recruited into the cross-sectional study from 2010 to 2011. Parameters of obesity, individual components of MetS, iron status and serum IL10 were evaluated. RESULTS: Compared with their normal weight counterparts, overweight adolescents had lower serum IL10 but higher TNFalpha, nitric oxide (NO) and IL1beta concentrations (all p<0.05). Obese adolescents had increased IL1beta but decreased hepcidin concentration compared with normal weight (p<0.01 and p<0.05; respectively). A strong inverse relationship (p<0.0001) was found between IL10 and pro-inflammatory cytokines (TNFalpha and IL1beta). Multivariate linear regression analysis showed serum IL1beta was significantly correlated with IL10 (beta=-0.156, p<0.0001). When overweight and obese adolescents were assessed separately from normal weight, only IL1beta was inversely associated with serum IL10 (beta=-0.231, p=0.0009). The association between IL10 and IL1beta was weaker in adolescents with normal weight (beta=-0.157, p=0.0002), after adjusting for gender, TNFalpha, IFNgamma and NO. CONCLUSIONS: Our study confirmed that low IL10 concentration is associated with overweight and obesity in young adolescents. We also demonstrated for the first time that pro-inflammatory cytokine IL1beta is independently associated with IL10. A decline in IL10 concentration in overweight and obese adolescents may further contribute to the IL1beta-mediated inflammatory environment associated with obesity. PMID- 23941337 TI - Client-centered occupational therapy for individuals with spinal cord injury. AB - A randomized controlled trial investigated the effect of client-centered Occupational Therapy on individuals with spinal cord injuries (SCI). Twenty-one subjects, 4 to 6 months post acute rehabilitation, received eight in-home, client centered Occupational Therapy sessions or eight visits from social visitors. The Functional Independence Measure (FIM), the Craig Handicap Reporting and Assessment Technique (CHART), the Role Checklist and the Life Satisfaction Inventory-A (LSIA) were administered pre and post interventions. Analyses showed no differences between groups on the CHART and the FIM; the Role Checklist showed the Occupational Therapy group took on a limited number of new life roles; however, a statistically significant difference was found between groups post intervention for LSIA (p < 0.05). PMID- 23941338 TI - Mentoring in Occupational Therapy: One State's Status. AB - Although mentoring is considered a powerful tool for professional development and critical to strengthening the profession of occupational therapy little is known about the frequency among practitioners with which it occurs or the supports needed to sustain it. This study describes the status of Ohio Occupational Therapy State Association members with active E-mail addresses who were selected randomly and responded to a telephone survey. Of the 130 respondents, the incidence of serving as a mentor or mentee in the past was higher than the current rate. More respondents currently not serving in either role desired to serve in the role of mentor than mentee. Supports for participating in a mentoring relationship included identification of ideal mentor and/or mentee "characteristics," "linkage" to connect the two parties, and "resources" such as knowledge, time, positive environment, and incentives. The results of this study may serve useful to those involved in facilitating and supporting mentoring initiatives as mentoring strengthens not only individual practitioners but the profession as a whole. PMID- 23941339 TI - Surviving Domestic Violence: Rebuilding One's Life. AB - The purpose of this study was to contribute to occupational therapists' understanding of the experience of domestic violence, its impact on the lives of women, and the needs of these women as they journey towards independent and abuse free lives. A phenomenological design was used to explore the experiences of five women living at a battered women's shelter and five women who had been at the shelter and were now living on their own, free of abuse. Five themes emerged to describe the women's experiences of rebuilding their lives: (1) "You owe yourself a life," (2) "It's really all about connecting the dots," (3) "I don't have an ounce of time to myself," (4) "It gets hard," and (5) "That was the road I traveled but this is now the road that I'm on." The experiences of these women compel the occupational therapists to pause and reflect upon their role in working with survivor's of domestic violence. PMID- 23941340 TI - Occupational therapy and substance use disorders: are practitioners addressing these disorders in practice? AB - Occupational therapy practitioners across all practice settings were surveyed in order to determine whether practitioners were assessing substance use disorders, and what interventions were used with clients who have or were suspected to have substance use disorders. Reasons practitioners did not address a clients' substance use disorder were explored. The perceptions of practitioners regarding their competence to assess and treat substance use disorders were also examined. The results of this study indicated that the majority of occupational therapy practitioners sampled outside the mental health setting did not routinely assess or treat substance use disorders. The findings of this study suggest that practitioners need to incorporate assessment and treatment of substance use disorders and their subsequent occupational performance deficits into daily practice regardless of practice area to assure holistic and comprehensive treatment. PMID- 23941341 TI - Moving the classroom to the clinic: the experiences of occupational therapy students during a "living lab". AB - This paper describes an experiential learning lab which emerged from designing a "living lab" that was embedded into an intervention course. The lab resulted in a teaching-learning experience that provided students with consistent opportunity to engage in clinical application of theory with feedback from peers and professionals. Results of a qualitative program evaluation indicated that this experience had a positive effect on the professional growth and development of the students and increased their ability to apply clinical reasoning skills. It also provided the students with the opportunity to examine their emotions and their change of emotions over time as they were presented with clinical challenges. A surprise outcome identified by the students was their clarity and understanding about disability. Recommendations for future community experiences for occupational therapy students as well as suggestions for program evaluation of such experiences are provided. PMID- 23941342 TI - From the internet editor. PMID- 23941344 TI - The activity-set hypothesis for warm-up decrement. AB - An alternative to the set hypothesis for warm-up decrement (WU) is proposed which states that WU is due to the loss over rest of an activity-set consisting of proper adjustment of activation, attention to relevant sources of feedback, etc. Force estimation (Exp. 1) and arm positioning (Exp. 2 and 3) were used as criterion tasks. During an interpolated rest period, activities were introduced which were intended to reinstate the lost activity-set but which would not contribute habit strength to the criterion task. WU on subsequent criterion task performance was nearly eliminated in one task (Exp. 1) and greatly reduced in another (Exp. 2 and 3), and the evidence strongly supported the activity-set hypothesis. PMID- 23941345 TI - Serial isometric fatigue functions with variable intertrial intervals. AB - The maximum voluntary strength of 60 Ss was measured during 10 successive 25-sec. trials separated by rest periods of 25, 50, or 100 sec. The intertrial intervals within a session were constant. The adjustment to the various work-rest schedules occurred early in the trial series. When the reduction in mean output was taken as 100% for each rest condition, the loss between the first 2 trials was 33%, 35%, and 24% for the 25-, 50, and 100-sec. conditions, respectively. An equation derived by a multiple regression analysis with the number of previous trials, intertrial intervals, and contraction time as independent variables produced a set of predicted values which correlated .99 with the actual means. This analysis indicated that the fatigue functions may be assumed to be identical in form for the various trials at the different intertrial intervals. Strength was significantly correlated with absolute decrement but not with relative decrement. PMID- 23941346 TI - Multivariate relationships between motor and personality measures in culturally deprived high school pupils. AB - The relationship between personality, as measured by the IPAT-HSPQ, and certain motor performance variables was studied by utilizing the multivariate technique of canonical correlation. Ss for the study were 91 culturally deprived high school students who were achieving well below their expected capacity. A significant canonical relationship was not found between the domains of personality and motor performance. Also, no significant relationships between motor sub-domains and personality were found. It was thus concluded that for the population under study, the domains of motor performance and personality were independent Some discussion of the multivariate technique of canonical correlation was offered and compared with univariate procedures. PMID- 23941347 TI - The effect of interpolated motor activities in short-term motor memory. AB - This experiment examined the effect of an interpolated motor response on short term retention of a blind positioning movement. The interpolated response was varied in degree of similarity to the response length (+/- 25, +/- 50, and +/- 100 mm.), in number of repetitions (0, 1, or 5), and in temporal position (immediate or delayed), with a retention interval of 25 sec. Absolute error was not affected but a systematic change in response bias due to interpolated motor activity was found. When an interpolated response was longer than the response length, the tendency to undershoot decreased. The defay of the interpolated response was relatively more important than the number of repetitions in producing a positive shift in response bias. These results are interpreted as evidence for a form of interference in short-term motor memory. PMID- 23941348 TI - Subjective assessment of effort in dynamic work. AB - 18 male Ss were instructed to walk as long as possible at 75% of their maximum walking speed on a motor driven treadmill. Each S walked for 8 sessions. During the sessions Ss were instructed to report on a 5-point scale the increase in the amount of effort required by the walking task. The obtained effort scales were linear as had been reported for shorter duration isometric muscle contractions. Correlations between the endurance scores and various physical and psychological measures suggested that while maximum walking speed was primarily related to physique, endurance appeared to be related more to other variables. PMID- 23941349 TI - A reappraisal of the concept of cerebral dominance. AB - The traditional concept of cerebral dominance relies for support on the facts of handedness and the association of propositional speech with the leading hemisphere. This is regarded as evidence for specialization but not that the hemispheres are involved in an unchanging dominance relationship. The fact that the corpus callosum forms a bridge between the hemispheres means that they are not isolated units and that one may work through the other to control the functions of the limbs. Control however may be switched as the tasks demand the respective specializations of each hemisphere. PMID- 23941350 TI - The effect of fatigue on learning and performance of a gross motor task. AB - 40 college males were sequentially assigned to 1 of 2 groups to examine the effects of induced physical fatigue upon the performance and learning of a gross motor task, the stabilometer. All Ss were given 32 practice trials over 3 practice sessions, with 48 hr. rest interpolated between sessions. Trials 1 and 2 were performed under control conditions (no fatigue) for both groups. The Experimental Group was then required to perform under conditions of physical fatigue during Trials 3-26. Trials 27-32 (Session 3) were performed under control conditions. The condition of fatigue was achieved on Trials 3-26 by having Ss pedal a bicycle ergometer until a heart rate of 180 beats/min was attained prior to each trial. The Control Group cancelled vowels. The results indicated that physical fatigue was detrimental to the performance and learning of the Experimental Group. PMID- 23941351 TI - An informational analysis of active kinesthesis as measured by amplitude of movement. AB - 5 blindfolded Ss were required to make absolute judgments of the extent to which their extended right arm was voluntarily moved in the horizontal plane. The first experiment entailed the judgment of 20 different amplitudes and from these data a scale of equal discriminability was constructed for each S. From these individual scales amplitudes were selected for 5 additional absolute judgment experiments where the number of amplitudes were varied from 4 to 16. Analysis of the mean equal discriminability scale showed that kinesthetic sensitivity varied over the continuum of movements. The primary analysis of information transfer between number of amplitudes of movement and responses indicated that information transfer varied considerably over the 5 experiments with a maximum transfer of 2.48 bits occurring when 16 amplitudes were used. These results were discussed in terms of the possible cues involved in movement discrimination and whether kinesthetic cues could be used in a closed-loop model of voluntary movement control. PMID- 23941352 TI - Individual differences in various parameters of motor learning. AB - 60 Ss practiced 6 days on the stabilometer. No reminiscence or warm-up decrement was found; loss of skill occurred from 1-day layoffs which lessened as learning progressed. A 3-component exponential equation fitted the learning trend (including relearning). Both individual differences and intra-individual variations decreased exponentially with practice, but the ratio of individual differences to mean score increased. Practice had little influence on adjacent trial rs. Between scores in any particular pair of separated trials, r decreased when increasing number of trials separated them. Averaging 8 initial and 8 final trials gave optimum learning score reliability (r = .95). Individual rates of learning were not appreciably correlated with amounts of learning (r = .23). Final performance levels could only be predicted 50% from initial skill and cumulated amounts of learning unless more than half of the total practice (i.e., more than 90% of the potential learning) had been accomplished. The pattern of zero order rs between amount of learning and initial and final skill levels differed markedly from that previously observed in learning the ladder climb. PMID- 23941353 TI - Low dose of amino-modified nanoparticles induces cell cycle arrest. AB - The interaction of nanoscaled materials with biological systems is currently the focus of a fast-growing area of investigation. Though many nanoparticles interact with cells without acute toxic responses, amino-modified polystyrene nanoparticles are known to induce cell death. We have found that by lowering their dose, cell death remains low for several days while, interestingly, cell cycle progression is arrested. In this scenario, nanoparticle uptake, which we have recently shown to be affected by cell cycle progression, develops differently over time due to the absence of cell division. This suggests that the same nanoparticles can trigger different pathways depending on exposure conditions and the dose accumulated. PMID- 23941354 TI - Dairy intensification, mothers and children: an exploration of infant and young child feeding practices among rural dairy farmers in Kenya. AB - Agricultural strategies such as dairy intensification have potential to improve human nutrition through increased household food security. Increasing dairy productivity could also adversely affect infant and young child feeding (IYCF) practices because of increased maternal stress, demands on maternal time, and beliefs about the timing and appropriate types of complementary foods. Yet, few studies have looked rigorously at how interventions can affect young children (0 60 months). The study explores, within the context of rural dairy farming in Kenya, the relationship between level of household dairy production and selected IYCF practices using a mixed-methods approach. Six focus group discussions with women involved in dairy farming investigated their attitudes towards breastfeeding, introduction of complementary foods and child diets. Ninety-two households involved in three levels of dairy production with at least one child 0 60 months participated in a household survey. Quantitative results indicated that women from higher dairy producing households were more likely to introduce cow's milk to infants before they reached 6 months than women from households not producing any dairy. Themes from the focus group discussions demonstrated that women were familiar with exclusive breastfeeding recommendations, but indicated a preference for mixed feeding of infants. Evidence from this study can inform nutrition education programmes targeted to farmers participating in dairy interventions in rural, low-income settings to minimise potential harm to the nutritional status of children. PMID- 23941356 TI - Do warning calls boost survival of signal recipients? Evidence from a field experiment in a group-living bird species. AB - INTRODUCTION: Warning calls are a widespread anti-predator adaptation, which can signal unprofitability to predators or alert other potential targets of the predator. Although it is tacitly assumed that the recipients of warning calls experience a reduction in predation risk, this crucial assumption remains untested. Here I tested this hypothesis with a field experiment in the group living Siberian jay, Perisoreus infaustus. I exposed male or female breeding adults that were foraging together with a non-breeder (related or unrelated) to a model of their main predator (goshawk Accipiter gentilis) in autumn. I then recorded the warning call response of breeders as well as the reaction time of non-breeders, and followed the subsequent survival of non-breeders until spring. RESULTS: In most experiments (73%), non-breeders were warned by the more experienced breeders. Warning calls almost halved the reaction time of non breeders during the experiment and influenced the survival of call recipients: non-breeders that were warned had a higher subsequent survival (19 out of 23) than non-breeders that were not warned (2 out of 5). However, neither kinship, group size, the age of the non-breeder, or the habitat structure of the territory had an influence on the survival subsequent to the experiments. CONCLUSIONS: Since earlier studies showed that breeders are consistent in their warning call investment across different contexts, breeders that did warn non-breeders in the experiment were likely to have done so in subsequent, natural attacks. Consequently non-breeders living with breeders that called had a better chance of surviving predator attacks. Thus, these results suggest that warning calls have the potential to boost the survival of signal recipients, confirming a pivotal, yet hitherto untested assumption of the effect of warning calls. PMID- 23941357 TI - Local control of cis-peptidyl-prolyl bonds mediated by CH...pi interactions: the Xaa-Pro-Tyr motif. AB - Compared to generic peptide bonds, the peptidyl-prolyl bond shows a strong propensity for the cis conformer. The presence of a sequence-contiguous aromatic (Aro) residue can further stabilize the cis conformer, as observed for the Aro Pro motif. The cis propensity of the reverse sequence motif, Pro-Aro, is not so well understood, especially the effect of N-capping the Pro-Aro motif with different amino acid residues. From a comparative nuclear magnetic resonance study of two peptide series with the general sequences Ac-Xaa-Pro-Tyr-NH2 and Ac Xaa-Pro-Ala-NH2, we present a relative thermodynamic scale that reflects how the nature of the Xaa side chain influences the cis propensity of the Xaa-Pro-Tyr motif, with Gly, Pro, and Ala at position Xaa giving the greatest enhancement of the cis-peptidyl-prolyl population. We also show that CH...pi interaction between Xaa and Tyr is responsible for the enhanced cis population. However, the mere presence of the CH...pi interaction does not guarantee that the peptidyl-prolyl bond will have a higher cis content in Xaa-Pro-Tyr than in Xaa-Pro-Ala. Xaa dependent intramolecular interactions present in Xaa-trans-Pro-Tyr can nullify favorable CH...pi interactions in Xaa-cis-Pro-Tyr. The relative cis-peptidyl prolyl stabilizing propensities of Xaa (Xaa-Pro-Tyr) in proteins and in our peptide series show strong linear correlation except when Xaa is aromatic. We also explore the Xaa-Pro-Gly-Tyr sequence motif and show that mediated by a Pro Tyr CH...pi interaction, the cis-peptidyl-prolyl bond in the motif is stabilized when Xaa is Pro. PMID- 23941355 TI - Glycine receptor mouse mutants: model systems for human hyperekplexia. AB - Human hyperekplexia is a neuromotor disorder caused by disturbances in inhibitory glycine-mediated neurotransmission. Mutations in genes encoding for glycine receptor subunits or associated proteins, such as GLRA1, GLRB, GPHN and ARHGEF9, have been detected in patients suffering from hyperekplexia. Classical symptoms are exaggerated startle attacks upon unexpected acoustic or tactile stimuli, massive tremor, loss of postural control during startle and apnoea. Usually patients are treated with clonazepam, this helps to dampen the severe symptoms most probably by up-regulating GABAergic responses. However, the mechanism is not completely understood. Similar neuromotor phenotypes have been observed in mouse models that carry glycine receptor mutations. These mouse models serve as excellent tools for analysing the underlying pathomechanisms. Yet, studies in mutant mice looking for postsynaptic compensation of glycinergic dysfunction via an up-regulation in GABAA receptor numbers have failed, as expression levels were similar to those in wild-type mice. However, presynaptic adaptation mechanisms with an unusual switch from mixed GABA/glycinergic to GABAergic presynaptic terminals have been observed. Whether this presynaptic adaptation explains the improvement in symptoms or other compensation mechanisms exist is still under investigation. With the help of spontaneous glycine receptor mouse mutants, knock in and knock-out studies, it is possible to associate behavioural changes with pharmacological differences in glycinergic inhibition. This review focuses on the structural and functional characteristics of the various mouse models used to elucidate the underlying signal transduction pathways and adaptation processes and describes a novel route that uses gene-therapeutic modulation of mutated receptors to overcome loss of function mutations. PMID- 23941358 TI - Express optical analysis of epitaxial graphene on SiC: impact of morphology on quantum transport. AB - We show that inspection with an optical microscope allows surprisingly simple and accurate identification of single and multilayer graphene domains in epitaxial graphene on silicon carbide (SiC/G) and is informative about nanoscopic details of the SiC topography, making it ideal for rapid and noninvasive quality control of as-grown SiC/G. As an illustration of the power of the method, we apply it to demonstrate the correlations between graphene morphology and its electronic properties by quantum magneto-transport. PMID- 23941360 TI - Comparative transcriptomics as a tool for the identification of root branching genes in maize. AB - The root system is fundamental for plant development, is crucial for overall plant growth and is recently being recognized as the key for future crop productivity improvement. A major determinant of root system architecture is the initiation of lateral roots. While knowledge of the genetic and molecular mechanisms regulating lateral root initiation has mainly been achieved in the dicotyledonous plant Arabidopsis thaliana, only scarce data are available for major crop species, generally monocotyledonous plants. The existence of both similarities and differences at the morphological and anatomical level between plant species from both clades raises the question whether regulation of lateral root initiation may or may not be conserved through evolution. Here, we performed a targeted genome-wide transcriptome analysis during lateral root initiation both in primary and in adventitious roots of Zea mays and found evidence for the existence of common transcriptional regulation. Further, based on a comparative analysis with Arabidopsis transcriptome data, a core of genes putatively conserved across angiosperms could be identified. Therefore, it is plausible that common regulatory mechanisms for lateral root initiation are at play in maize and Arabidopsis, a finding that might encourage the extrapolation of knowledge obtained in Arabidopsis to crop species at the level of root system architecture. PMID- 23941359 TI - Barnacle: detecting and characterizing tandem duplications and fusions in transcriptome assemblies. AB - BACKGROUND: Chimeric transcripts, including partial and internal tandem duplications (PTDs, ITDs) and gene fusions, are important in the detection, prognosis, and treatment of human cancers. RESULTS: We describe Barnacle, a production-grade analysis tool that detects such chimeras in de novo assemblies of RNA-seq data, and supports prioritizing them for review and validation by reporting the relative coverage of co-occurring chimeric and wild-type transcripts. We demonstrate applications in large-scale disease studies, by identifying PTDs in MLL, ITDs in FLT3, and reciprocal fusions between PML and RARA, in two deeply sequenced acute myeloid leukemia (AML) RNA-seq datasets. CONCLUSIONS: Our analyses of real and simulated data sets show that, with appropriate filter settings, Barnacle makes highly specific predictions for three types of chimeric transcripts that are important in a range of cancers: PTDs, ITDs, and fusions. High specificity makes manual review and validation efficient, which is necessary in large-scale disease studies. Characterizing an extended range of chimera types will help generate insights into progression, treatment, and outcomes for complex diseases. PMID- 23941362 TI - Effects of lifestyle changes including specific dietary intervention and physical activity in the management of patients with chronic hepatitis C--a randomized trial. AB - BACKGROUND: In patients with chronic hepatitis C (CHC), obesity is involved in the pathogenesis of insulin resistance, fatty liver disease and progression of fibrosis. The objective of this study was to compare a normoglucidic low-calorie diet (NGLCD) with a low-fat diet (LFD) among participants with CHC. Aimed to measure the impact of dietary changes in reduction of insulin resistance, obesity but also in steatosis and fibrosis. METHODS: Randomized, controlled trial in three medical centers with assessments at baseline, 6 months and 12 months. Participants were patients over 35 years with chronic hepatitis C (n = 120) with BMI over 25 kg/m2. We evaluated the effects of NGLCD vs. LFD in weight management and metabolic improvement. The primary endpoint was to measure the impact of dietary changes through nutritional intervention in reversibility of insulin resistance, obesity, steatosis, and fibrosis. We performed anthropometric measurements, fasting glucose profile, serum lipids, liver profile, blood count at baseline, 6 and 12 months. Steatosis was evaluated using ultrasonographic criteria. Liver fibrosis was non-invasively assessed. RESULTS: After 6 and 12 months of intervention, both groups had a significant decrease in caloric consumption. At 6 months, weight loss was greater in the NGLCD group (-5.02 +/- 3.43 kg vs. -4.1 +/- 2.6 kg; p = 0.002) compared to the LFD group. At 1-year, however, weight loss was similar in both groups (-3.9 +/- 3.3 kg vs. -3.1 +/- 2.6 kg; p = 0.139). At 12 months, fasting plasma glucose, fasting plasma insulin, and HOMA-IR had significant improvements in both groups. With both diets aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT) decreased with significant differences; also there were significant improvements in AST/ALT ratio, Forns fibrosis index. The two diets were associated with reduction of both the prevalence and the severity of steatosis (all p < 0.001). At 12 months, total cholesterol, HDL-cholesterol, triglycerides improved in both groups (all p < 0.05). CONCLUSIONS: The present study establishes the benefits of low-calorie diet and low-fat diet in management of patients with hepatitis C regarding improvement of insulin resistance, steatosis and also fibrosis.Overweight or obese patients with CHC undergoing a lifestyle intervention (specific dietary intervention and physical activity) for 1-year had significant improvements in body weight, lipid and hepatic profile. TRIAL REGISTRATION: PNCI2-3343/41008/2007. PMID- 23941363 TI - Trend analysis and modelling of gender-specific age, period and birth cohort effects on alcohol abstention and consumption level for drinkers in Great Britain using the General Lifestyle Survey 1984-2009. AB - BACKGROUND AND AIMS: British alcohol consumption and abstinence rates have increased substantially in the last 3 decades. This study aims to disentangle age, period and birth cohort effects to improve our understanding of these trends and suggest groups for targeted interventions to reduce resultant harms. DESIGN: Age, period, cohort analysis of repeated cross-sectional surveys using separate logistic and negative binomial models for each gender. SETTING: Great Britain 1984-2009. PARTICIPANTS: Annual nationally representative samples of approximately 20 000 adults (16+) within 13 000 households. MEASUREMENTS: Age (eight groups: 16-17 to 75+ years), period (six groups: 1980-84 to 2005-09) and birth cohorts (19 groups: 1900-04 to 1990-94). Outcome measures were abstinence and average weekly alcohol consumption. Controls were income, education, ethnicity and country. FINDINGS: After accounting for period and cohort trends, 18-24-year-olds have the highest consumption levels (incident rate ratio = 1.18 1.15) and lower abstention rates (odds ratio = 0.67-0.87). Consumption generally decreases and abstention rates increase in later life. Until recently, successive birth cohorts' consumption levels were also increasing. However, for those born post-1985, abstention rates are increasing and male consumption is falling relative to preceding cohorts. In contrast, female drinking behaviours have polarized over the study period, with increasing abstention rates accompanying increases in drinkers' consumption levels. CONCLUSIONS: Rising female consumption of alcohol and progression of higher-consuming birth cohorts through the life course are key drivers of increased per capita alcohol consumption in the United Kingdom. Recent declines in alcohol consumption appear to be attributable to reduced consumption and increased abstinence rates among the most recent birth cohorts, especially males, and general increased rates of abstention across the study period. PMID- 23941364 TI - An integrated analysis of SOCS1 down-regulation in HBV infection-related hepatocellular carcinoma. AB - Persistent inflammation together with genetic/epigenetic aberrations is strongly associated with chronic Hepatitis B virus (HBV) infection-related hepatocarcinogenesis. Here, we investigated the alterations of the suppressor of cytokine signalling (SOCS) family genes in HBV-related hepatocellular carcinoma (HCC). A total of 116 patients with HCC were enrolled in this study. The methylation statuses of SOCS1-7 and CISH genes were quantitatively measured and clinicopathological significance of SOCS1 methylation was statistically analysed. The gene copy number variation was assayed by aCGH. Luciferase reporter assay and Western blot were used to detect the involvement of SOCS1 in p53 signalling. We found high frequencies of SOCS1 gene hypermethylation in both tumour (56.03%) and adjacent nontumour tissues (54.31%), but tumour tissues exhibited increased methylation intensity (24.01% vs 13.11%, P < 0.0001), particularly in patients with larger tumour size or cirrhosis background (P < 0.0001). In addition, the frequency and intensity of SOCS1 hypermethylation in tumour tissues were both significantly higher than those in nontumour tissues in male gender patients and in patients >=45 years old (P = 0.0214 and P < 0.0001, P = 0.0232 and P < 0.0001, respectively). SOCS1 gene deletion was found in 8 of 25 aCGH assayed tumour specimens, which was associated with lower SOCS1 mRNA expression (P = 0.0448). Furthermore, ectopic SOCS1 overexpression could activate the p53 signalling pathway in HCC cell lines. Hypermethylation of SOCS2-7 and CISH genes was seldom found in HCC. Our results suggested that the gene loss and epigenetic silencing of SOCS1 were strongly associated with HBV-related HCC. PMID- 23941365 TI - Occipital lobe epilepsy secondary to posterior reversible encephalopathy syndrome (PRES) during a post-partum eclampsia in Mali (West Africa). AB - BACKGROUND: Eclampsia is known to cause posterior reversible encephalopathy syndrome (PRES) that is often associated with an extensive neurovascular damage affecting preferably posterior regions, often leading to reversible cortical blindness. In spite the magnitude of these lesions, post eclamptic symptomatic epilepsy is rare. We therefore report a case of symptomatic occipital lobe epilepsy secondary to PRES. CASE PRESENTATION: A 39-year-old female right handed teacher who presented with headache of progressive onset, phosphenes, rapid decline of visual acuity to blindness, vomiting, repeated generalized tonic clonic seizures followed by altered consciousness and very high blood pressure (HBP) of 240/120 mmHg, all of which started about 12 hours following a normal delivery. Nine months later, the patient presented with paroxysmal visual symptoms predominating in the right visual field followed by partial tonic clonic seizures with secondary generalization and recurrence of partial occipital lobe seizures. The pathophysiologic mechanism of irreversible tissue damage during PRES syndrome could result from a combination of events including the delay for early treatment, inadequate antihypertensive drugs that could worsen the brain damage by hypo perfusion, inadequate or delayed treatment for seizures or status epilepticus. CONCLUSION: Despite its high incidence in the third world, eclampsia is not a usual cause of epilepsy. Our case is the first description of post eclamptic occipital lobe epilepsy in Africa. With this report, we draw practitioners' attention on this rare complication. PMID- 23941367 TI - Minimizing the instant and accumulative effects of salt permeability to sustain ultrahigh osmotic power density. AB - We have investigated the instant and accumulative effects of salt permeability on the sustainability of high power density in the pressure-retarded osmosis (PRO) process experimentally and theoretically. Thin-film composite (TFC) hollow-fiber membranes were prepared. A critical wall thickness was observed to ensure sufficient mechanical stability and hence a low salt permeability, B. The experimental results revealed that a lower B was essential to enhance the maximum power density from 15.3 W/m(2) to as high as 24.3 W/m(2) when 1 M NaCl and deionized water were feeds. Modeling work showed that a large B not only causes an instant drop in the initial water flux but also accelerates the flux decline at high hydraulic pressures, leading to reduced optimal operating pressure and maximal power density. However, the optimal operating pressure to harvest energy can be greater than one-half of the osmotic pressure gradient across the membrane if one can carefully design a PRO membrane with a large water permeability, small B value, and reasonably small structural parameter. It was also found that a high B accumulates salts in the feed, leads to the oversalinization of the feed, and largely lowers both the water flux and power density along the membrane module. Therefore, a low salt permeability is highly desirable to sustain high power density not only locally but also throughout the whole module. PMID- 23941369 TI - International efforts to disseminate and develop the model of human occupation. AB - This paper documents efforts in Canada, France, Finland, Germany, Hispanoamerica, Israel, Japan, The Netherlands, and Taiwan to disseminate the Model of Human Occupation (MOHO). We aim to characterize the challenges involved, the strategies used, and the impact of these efforts in diverse cultural and social conditions. PMID- 23941368 TI - Risk of low Apgar scores and socioeconomic status over a 30-year period. AB - OBJECTIVE: The aim of this study was to investigate the stability of associations between social factors, as assessed by maternal occupation and education, and poor birth condition (an Apgar score of below 7 at 1 and 5 minutes) over a 30 year period in Sweden. METHODS: The dataset was based on infants born in Sweden between 1973 and 2002. Poor birth condition was defined as an Apgar score below 7 at 1 and 5 minutes. Logistic regression was used to investigate the association of between socioeconomic status and poor birth condition. RESULTS: In the adjusted model, mothers in non-manual occupations (OR 0.91 (0.88, 0.95)) or with higher educational status (OR 0.88 (0.84, 0.93)) were less likely to have an infant born in poor condition than the reference group. Limiting the analysis to the last decade showed less evidence for an association (OR 0.94 (0.86, 1.02) and OR 0.94 (0.82, 1.09), respectively). CONCLUSIONS: While maternity, delivery and child healthcare are free of charge in Sweden, poor birth condition was more common among infants of mothers in manual occupations or low levels of education. However, this association appeared to attenuate over the calendar period studied. PMID- 23941370 TI - Usefulness of the model of human occupation in the Hong Kong chinese context. AB - Questions have been raised about the applicability of Western theory in an Eastern context. Two case studies are used to illustrate how the Model of Human Occupation (MOHO) is useful in problem identification and intervention planning in Hong Kong. The cases illustrate that MOHO provides useful insights to how Chinese culture influences participation of persons with disabilities. PMID- 23941366 TI - Environmental determinants of islet autoimmunity (ENDIA): a pregnancy to early life cohort study in children at-risk of type 1 diabetes. AB - BACKGROUND: The incidence of type 1 diabetes has increased worldwide, particularly in younger children and those with lower genetic susceptibility. These observations suggest factors in the modern environment promote pancreatic islet autoimmunity and destruction of insulin-producing beta cells. The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is investigating candidate environmental exposures and gene-environment interactions that may contribute to the development of islet autoimmunity and type 1 diabetes. METHODS/DESIGN: ENDIA is the only prospective pregnancy/birth cohort study in the Southern Hemisphere investigating the determinants of type 1 diabetes in at-risk children. The study will recruit 1,400 unborn infants or infants less than six months of age with a first-degree relative (i.e. mother, father or sibling) with type 1 diabetes, across five Australian states. Pregnant mothers/infants will be followed prospectively from early pregnancy through childhood to investigate relationships between genotype, the development of islet autoimmunity (and subsequently type 1 diabetes), and prenatal and postnatal environmental factors. ENDIA will evaluate the microbiome, nutrition, bodyweight/composition, metabolome lipidome, insulin resistance, innate and adaptive immune function and viral infections. A systems biology approach will be used to integrate these data. Investigation will be by 3-monthly assessments of the mother during pregnancy, then 3-monthly assessments of the child until 24 months of age and 6-monthly thereafter. The primary outcome measure is persistent islet autoimmunity, defined as the presence of autoantibodies to one or more islet autoantigens on consecutive tests. DISCUSSION: Defining gene-environment interactions that initiate and/or promote destruction of the insulin-producing beta cells in early life will inform approaches to primary prevention of type 1 diabetes. The strength of ENDIA is the prospective, comprehensive and frequent systems-wide profiling from early pregnancy through to early childhood, to capture dynamic environmental exposures that may shape the development of islet autoimmunity. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12613000794707. PMID- 23941371 TI - Program Redesign Based on the Model of Human Occupation: Inpatient Services for People Experiencing Acute Mental Illness in the UK. AB - This paper discusses the current context of the UK mental health service system and the resulting need for program change within acute-care inpatient hospitals. The primary focus is to illustrate through practice example what can be done to support the delivery of client treatment packages by using the concepts described by the Model of Human Occupation (MOHO). The paper concentrates on explaining how MOHO has helped to guide program redesign and develop an Occupational Therapy Care Pathway to support occupation-focused services. The example given is of a hospital service in Gloucestershire, England, which provides inpatient care for people experiencing acute mental illness. PMID- 23941372 TI - Using the model of human occupation to conceptualize an occupational therapy program for blind persons in South Africa. AB - The diversity within South African society encourages innovative occupational therapy practice. This paper illustrates how the Model of Human Occupation (MOHO) was used as a guiding framework for an innovative program for unemployed blind adults. The program allowed these clients to participate in income-generating projects and illustrates how factors related to South Africa's cultural, economic, and social conditions influence the use of MOHO in occupational therapy practice. PMID- 23941373 TI - Application of the Model of Human Occupation Screening Tool (MOHOST Assessment) in an Acute Psychiatric Setting. AB - The Model of Human Occupation Screening Tool (MOHOST) plays a key role in the occupational therapy assessment protocol at an acute psychiatric unit in Britain. This paper incorporates a case study and discussions with the occupational therapists to explore how the assessment influences practice from initial assessment to final outcome measure and how single observation forms and prototype self-assessment forms based on the MOHOST have contributed to the assessment process. PMID- 23941374 TI - Assessing employment needs of bulgarian youths with intellectual impairments. AB - This paper illustrates how the Model of Human Occupation provided a conceptual framework to inform the development of a work-related program for Bulgarian youths with intellectual impairments who are also socially disadvantaged. The paper describes the process of conducting a needs assessment guided by this model. Information was gathered on participants from the target group to create a holistic profile of their strengths and challenges/barriers. This information, in turn, was used to identify key needs which will guide next steps in program development. PMID- 23941375 TI - Addressing the needs of elderly clients whose lives have been compounded by traumatic histories. AB - This paper presents a community-based group intervention for elderly women in Israel. The intervention, based on the Model of Human Occupation (MOHO), addresses problems of aging clients whose lives have been compounded by traumatic histories. The unique contribution of MOHO concepts to this population is illustrated and discussed. PMID- 23941376 TI - Using the model of human occupation to nurture an occupational focus in the clinical reasoning of experienced therapists. AB - Best ooccupational therapy practice requires a commitment to ongoing learning to enhance clinical reasoning. This paper describes a five-step cooperative learning process to advance clinical reasoning based on the Model of Human Occupation (MOHO). During the five-step process the MOHO concepts and assessments provide opportunities for therapists to develop occupation-focused clinical reasoning and deepen their knowledge of the theory and its application in practice. PMID- 23941377 TI - Psychosocial programming in ireland based on the model of human occupation: a program evaluation study. AB - The Model of Human Occupation (MOHO) is frequently used to guide mental health psychosocial programs. However, the benefits of these programs are not fully understood. This study explores the impact of a program that addresses the volition, habituation, and skill challenges reported by those with mental health problems. Follow-up data were collected 32 weeks and 1 year after initial assessment. Based on follow-up data for 28 participants, improvements in the areas targeted by the intervention were found at both time periods. PMID- 23941378 TI - Canadian therapists' experiences while implementing the model of human occupation remotivation process. AB - This paper presents the results of a qualitative study conducted in Quebec, Canada, with occupational therapists working in mental health. Data were gathered through self-reported narratives of four occupational therapists over the 2 years it took to implement the Remotivation Process ( de las Heras, Llerena, & Kielhofner, 2003 ) and develop a research protocol. Through the descriptive analysis of their narratives, the positive changes this intervention approach had on clients and on occupational therapy practice are highlighted. The experience of the therapists in developing a research protocol is addressed. Finally, the research protocol evaluating the effect of the Remotivation Process on the recovery process of people with depression is presented. PMID- 23941379 TI - A study of the relationship between variables from the model of human occupation and subjective well-being among university students in jordan. AB - The occupational role of a university student can create challenges that negatively affect subjective well-being. Cultural factors can make these problems particularly acute for students from Arab backgrounds. This study examined the relationship between variables derived from the Model of Human Occupation (MOHO) and Jordanian university students' subjective well-being. Using cluster sampling, a total of 670 participants were recruited from the undergraduate student body at the University of Jordan. Data were collected from these students using the Role checklist, the Occupational Self-Assessment, the Affectometer 2, and the Satisfaction with Life Scale. As hypothesized, reported roles, valuation of roles, perceived competence in volition, habituation, performance capacity/skills, and the environment were significantly correlated with subjective well-being. A discriminant analysis using the most strongly correlated items significantly classified students into known groups of high and low subjective well-being. Overall, MOHO-based variables offered an effective explanation of factors that influence subjective well-being in Jordanian university students. PMID- 23941380 TI - A process for translating and validating model of human occupation assessments in the danish context. AB - The aim of the study was to validate the Danish translation of The Assessment of Communication and Interaction Skills (ACIS) and The Occupational Self-Assessment (OSA). The validation process followed four research steps where pilot versions were tested by occupational therapists in practice, peer-reviewed, and back translated. The result of the study was two validated assessment tools based on the Model of Human Occupation (MOHO) available for Danish occupational therapy practice, education, and research. Future studies should enlighten how to maintain the validity and reliability of assessments when translations are made into other languages. PMID- 23941381 TI - Assessing interests in Japanese elders: a descriptive study. AB - This study investigated use of the Japanese Interest Checklist for the Elderly (JICE). An interview that followed administration of the checklist illuminated the reasons for interests among 65 participants. Examining the reasons behind levels of interest is a potential avenue of research that may add to our understanding of the nature of interests. PMID- 23941382 TI - Utilization and Content Validity of the Swedish Version of the Volitional Questionnaire (VQ-S). AB - The aim of this study was to examine the utility and content validity of the Swedish version of the Volitional Questionnaire (VQ-S). The participants in this study were thirteen occupational therapists selected because they worked with clients for whom the VQ-S is appropriate (in this case, adults with intellectual impairments) and because they had knowledge of the Model of Human Occupation. These participants completed a demographic questionnaire at the beginning of the study. Each therapist then used the VQ-S a total of six times and after each time they completed a questionnaire concerning the utility and content validity of the instrument. After having administered the instrument six times they completed a third questionnaire that assessed their perceptions of the VQ-S based on their total experience. Data from these questionnaires and the six assessment forms with the actual client ratings were analyzed using both quantitative and qualitative procedures. The findings indicate that the VQ-S has clinical relevance and potential for implementation with adults with intellectual impairments. They also support the content validity of the VQ-S. PMID- 23941383 TI - A psychometric study of the chinese version of the assessment of communication and interaction skills. AB - This study examined the dependability of the Assessment of Communication and Interaction Skills-Chinese version (ACIS-C) with psychiatric participants in Taiwan. A convenience sample of 101 participants diagnosed with psychiatric illness were recruited from four day-care wards in northern and eastern Taiwan. The results of the Rasch analysis showed that the ACIS-C items coalesced to form a measure of communication/interaction and the 4-point rating scale functioned as intended. The ACIS-C differentiated participants into six levels of communication and interaction skills. The findings support the conclusion that the ACIS-C is a valid and sensitive tool when used with Chinese clients. Moreover the study supports the generalizability of the Model of Human Occupation concept of communication and interaction skills to an Eastern context. PMID- 23941384 TI - Construct Validity and Factor Structure of the Persian Occupational Self Assessment (OSA) With Iranian Students. AB - This study aimed to investigate construct validity and factor structure of the Persian Occupational Self-Assessment (OSA; Baron, Kielhofner, Iyenger, Goldhammer, & Wolenski, 2003 ) based on the model of human occupation (MOHO). Three hundred and thirty-six (179 male and 157 female) Iranian junior high students were measured using the OSA. The data were analyzed using a Confirmatory Factor Analysis (CFA) and the Rasch Rating Scale Model (RSM). In combination, the CFA and RSM results provided strong evidence for the construct validity of the Persian version. The CFA indicated that the hypothesized second-order model could explain the relationship of the OSA items to the latent variables of occupational competence and value for occupations. However, RSM item hierarchies did not replicate those found in previous international studies. PMID- 23941385 TI - The fourth edition of Gary Kielhofner's book, Model of Human Occupation: Theory and Application. PMID- 23941386 TI - Beyond internalised stigma: daily moralities and subjectivity among self identified kothis in Karnataka, South India. AB - The Bill and Melinda Gates Foundation has poured a tremendous amount of resources into epidemic prevention in India's high HIV prevalence zones, through their Avahan initiative. These community-centred programmes operate under the assumption that fostering community-based organisational development and empowering the community to take charge of HIV prevention and education will help to transform the wider social inequalities that inhibit access to health services. Focusing on the South Indian state of Karnataka, this paper explores a troubling set of local narratives that, we contend, hold broader implications for future programme planning and implementation. Although confronting stigma and discrimination has become a hallmark in community mobilisation discourse, communities of self-identified kothis (feminine men) who were involved in Avahan programme activities continued to articulate highly negative attitudes about their own sexualities in relation to various spheres of social life. Rather than framing an understanding of these narratives in psychological terms of 'internalized stigma', we draw upon medical anthropological approaches to the study of stigma that emphasise how social, cultural and moral processes create stigmatising conditions in the everyday lives of people. The way stigma continues to manifest itself in the self-perceptions of participants points to an area that warrants critical public health attention. PMID- 23941387 TI - Modular strategy for the synthesis of functionalized aryl-fused azabicyclo[2.2.2]octanes via sequential Cu/Pd/Ru catalysis. AB - Aryl-fused 2-azabicyclo[2.2.2]octanes were prepared by a novel sequence of Cu catalyzed three-component coupling of diversely substituted N-benzyl o-bromoaryl imines with methacryloyl chloride and vinyltributyl stannane followed by Pd catalyzed Heck annulation. Subsequent diversification of the aryl-fused 2 azabicyclo[2.2.2]octane core was achieved by attaching a flexible linker and a potential second pharmacophore via Ru-catalyzed cross-metathesis and a nucleophilic substitution. PMID- 23941388 TI - The effects of video-taped feedback on form, accuracy, and latency in an open and closed environment. AB - 40 college women performed a modification of the classical fencing lunge against 2 laterally-arranged targets, under closed and open environmental conditions. Form (rating scale), accuracy (proximity to target center), and response latency were taken to measure the effects of video-taped feedback (VT). Administration of VT with specific instructions to direct S's attention to parts of the display resulted in closer approximation of the externally-imposed form, higher accuracy, and shorter response latency. Performing the skill in the closed environmental condition resulted in less deviation from the imposed form, higher accuracy scores, and longer response latency. No significant correlations were found between imposed form and accuracy. PMID- 23941389 TI - Refractoriness of on extended movement to directional change. AB - An extended movement was used to compare the memory-drum and single-channel definitions of psychological refractoriness. The basic movement In response to the first signal (S1) was a forward lunge and a concurrent arm swing through a target string. The response to the second signal (S2) was a reversal of the original movement The interstimulus Interval (ISI) ranged from .10 - .70 sec. in .10-sec. steps. The hypothesis that refractoriness of the reversal movement would decrease as ISI shortened was confirmed by the fact that error frequencies decreased significantly and substantially with decreasing IS I. The availability of some residual capacity to deal with S2 during the refractory period was also indicated by an examination of the relationship between RT2 and the interval between S2 and RT1. This departure from the classical single-channel model shows some agreement with the neuromotor-programming theory. PMID- 23941390 TI - The persistence of psychological refractoriness. AB - The view that psychological refractoriness is a fundamental characteristic of human performance was supported by its survival of a determined attempt to eliminate it through training. An S was given practice for 87 days on a successive choice-response task with a constant inter-signal interval of 100 msec. Although his performance became better than any exhibited by Ss with more typical practice, he was not able to reduce psychological refractoriness to less than 20 or 25 msec. Moreover, when S was then shifted to variable inter-signal intervals he showed greater than the usual amount of psychological refractoriness at the intervals next longer than 100 msec. This indicated that he had learned a special skill rather than a generally "less refractory" mode of response (or merely better technique on the separate tasks). Training was found to be an effective way of eliminating holding back on the first response. PMID- 23941391 TI - The compression block technique. PMID- 23941392 TI - The activity-set hypothesis for warm-up decrement in a movement-speed task. AB - The activity-set hypothesis that warm-up decrement (WUD) is caused by loss over rest of a generalized readiness to respond was tested using a right-hand movement time task. 34 university males practiced 20 trials of the right-hand task, and then had a 10-min. no-practice period during which they either rested (Condition REST) or rested plus practiced a left-hand movement-time task, (Condition ACT). When Ss were transferred to the right-hand task, Condition REST produced large WUD which was quickly eliminated, whereas Condition ACT produced no WUD. This supported the hypothesis that the left-hand task reinstated the activity set for movement speed, and that WUD is the loss of a generalized non-habit readiness to respond. Implications for rival hypotheses for WUD were discussed. PMID- 23941393 TI - Dynamic and static balancing ability of preschool children. AB - Performance differences in dynamic and static balance ability of 150 preschool Ss aged 3,4, and 5 yr. were studied. Ss performed 4 balance-beam tasks and 2 balance board tasks. An Age by Sex (3 * 2) factorial, design employing both univariate and multivariate ANOVA techniques were the statistics used. For both dynamic and static balance Age was highly significant, and the use of multivariate ANOVA indicated significant sex differences on the static balance tasks. The appropriateness of multivariate techniques where more than one dependent variable is measured on the same population was discussed, and the need to take into account the relationship between these variables when analyzing the data was noted. PMID- 23941394 TI - Tailoring ZnSe-CdSe colloidal quantum dots via cation exchange: from core/shell to alloy nanocrystals. AB - We report a study of Zn(2+) by Cd(2+) cation exchange (CE) in colloidal ZnSe nanocrystals (NCs). Our results reveal that CE in ZnSe NCs is a thermally activated isotropic process. The CE efficiency (i.e., fraction of Cd(2+) ions originally in solution, Cdsol, that is incorporated in the ZnSe NC) increases with temperature and depends also on the Cdsol/ZnSe ratio. Interestingly, the reaction temperature can be used as a sensitive parameter to tailor both the composition and the elemental distribution profile of the product (Zn,Cd)Se NCs. At 150 degrees C ZnSe/CdSe core/shell hetero-NCs (HNCs) are obtained, while higher temperatures (200 and 220 degrees C) produce (Zn1-xCdx)Se gradient alloy NCs, with increasingly smoother gradients as the temperature increases, until homogeneous alloy NCs are obtained at T >= 240 degrees C. Remarkably, sequential heating (150 degrees C followed by 220 degrees C) leads to ZnSe/CdSe core/shell HNCs with thicker shells, rather than (Zn1-xCdx)Se gradient alloy NCs. Thermal treatment at 250 degrees C converts the ZnSe/CdSe core/shell HNCs into (Zn1 xCdx)Se homogeneous alloy NCs, while preserving the NC shape. A mechanism for the cation exchange in ZnSe NCs is proposed, in which fast CE takes place at the NC surface, and is followed by relatively slower thermally activated solid-state cation diffusion, which is mediated by Frenkel defects. The findings presented here demonstrate that cation exchange in colloidal ZnSe NCs provides a very sensitive tool to tailor the nature and localization regime of the electron and hole wave functions and the optoelectronic properties of colloidal ZnSe-CdSe NCs. PMID- 23941395 TI - Predicted implications of using percentage weight gain as single discharge criterion in management of acute malnutrition in rural southern Ethiopia. AB - Mid-upper arm circumference (MUAC) is increasingly used in identifying and admitting children with acute malnutrition for treatment. It is easy to use because it does not involve height assessment, but its use calls for alternative discharge criteria. This study examined how use of percentage weight gain as discharge criterion would affect the nutritional status of children admitted into a community-based management programme for acute malnutrition in rural southern Ethiopia. Non-oedematous children (n = 631) aged 6-59 months and having a MUAC of <125 mm were studied. By simulation, 10%, 15% and 20% weight was added to admission weight and their nutritional status by weight-for-height z-score (WHZ) was determined at each target. Moderate and severe wasting according to World Health Organization WHZ definitions was used as outcome. Applying the most commonly recommended target of 15% weight gain resulted in 9% of children with admission MUAC <115 mm still being moderately or severely wasted at theoretical discharge. In children with admission MUAC 115-124 mm, 10% of weight gain was sufficient to generate a similar result. Children failing to recover were the ones with the poorest nutritional status at admission. Increasing the percentage weight gain targets in the two groups to 20% and 15%, respectively, would largely resolve wasting but likely lead to increased programme costs by keeping already recovered children in the programme. Further research is needed on appropriate discharge procedures in programmes using MUAC for screening and admission. PMID- 23941396 TI - Relationship between clinical and instrumental balance assessments in chronic post-stroke hemiparesis subjects. AB - BACKGROUND: Stroke is often associated with balance deficits that increase the risk of falls and may lead to severe mobility disfunctions or death. The purpose of this study is to establish the relation between the outcome of instrumented posturography and of the most commonly used clinical balance tests, and investigate their role for obtaining reliable feedback on stroke patients' balance impairment. METHODS: Romberg test was performed on 20 subjects, 10 hemiplegic post-stroke subjects (SS, 69.4 +/- 8.2 years old) and 10 control subjects (CS, 61.6 +/- 8.6 years old), with 1 Bertec force plate. The following parameters were estimated from the centre of pressure (CoP) trajectory, which can be used to define subjects' performance during the balance task: sway area; ellipse (containing 95% of the data); mean CoP path and velocity in the anterior posterior and medio-lateral directions. The following clinical scales and tests were administered to the subjects: Tinetti Balance test (TB); Berg Balance test (BBT); Time up and go test (TUG), Fugl-Meyer (lower limbs) (FM), Motricity Index (lower limbs), Trunk Control Test, Functional Independence Measure. Comparison between SS and CS subjects was performed by using the Student t-test. The Pearson Correlation coefficient was computed between instrumental and clinical parameters. RESULTS: Mean +/- standard deviation for the balance scales scores of SS were: 12.5 +/- 3.6 for TB, 42.9 +/- 13.1 for BBT, 24 s and 75 cent +/- 25 s and 70 cent for TUG. Correlation was found among some CoP parameters and both BBT and TUG in the eyes open and closed conditions (0.9 <= R <= 0.8). Sway area correlated only with TUG. Statistically significant differences were found between SS and CS in all CoP parameters in eyes open condition (p < 0.04); whereas in eyes closed condition only CoP path and velocity (p < 0.02) differed significantly. CONCLUSIONS: Correlation was found only among some of the clinical and instrumental balance outcomes, indicating that they might measure different aspects of balance control. Consistently with previous findings in healthy and pathological subjects, our results suggest that instrumented posturography should be recommended for use in clinical practice in addition to clinical functional tests. PMID- 23941397 TI - Lengthening the intersubunit linker of procaspase 3 leads to constitutive activation. AB - The conformational ensemble of procaspase 3, the primary executioner in apoptosis, contains two major forms, inactive and active, with the inactive state favored in the native ensemble. A region of the protein known as the intersubunit linker (IL) is cleaved during maturation, resulting in movement of the IL out of the dimer interface and subsequent active site formation (activation-by-cleavage mechanism). We examined two models for the role of the IL in maintaining the inactive conformer, an IL-extension model versus a hydrophobic cluster model, and we show that increasing the length of the IL by introducing 3-5 alanines results in constitutively active procaspases. Active site labeling and subsequent analyses by mass spectrometry show that the full-length zymogen is enzymatically active. We also show that minor populations of alternately cleaved procaspase result from processing at D169 when the normal cleavage site, D175, is unavailable. Importantly, the alternately cleaved proteins have little to no activity, but increased flexibility of the linker increases the exposure of D169. The data show that releasing the strain of the short IL, in and of itself, is not sufficient to populate the active conformer of the native ensemble. The IL must also allow for interactions that stabilize the active site, possibly from a combination of optimal length, flexibility in the IL, and specific contacts between the IL and interface. The results provide further evidence that substantial energy is required to shift the protein to the active conformer. As a result, the activation-by-cleavage mechanism dominates in the cell. PMID- 23941398 TI - Mechanisms of the thermal and catalytic redistributions, oligomerizations, and polymerizations of linear diborazanes. AB - Linear diborazanes R3N-BH2-NR2-BH3 (R = alkyl or H) are often implicated as key intermediates in the dehydrocoupling/dehydrogenation of amine-boranes to form oligo- and polyaminoboranes. Here we report detailed studies of the reactivity of three related examples: Me3N-BH2-NMe2-BH3 (1), Me3N-BH2-NHMe-BH3 (2), and MeNH2 BH2-NHMe-BH3 (3). The mechanisms of the thermal and catalytic redistributions of 1 were investigated in depth using temporal-concentration studies, deuterium labeling, and DFT calculations. The results indicated that, although the products formed under both thermal and catalytic regimes are identical (Me3N.BH3 (8) and [Me2N-BH2]2 (9a)), the mechanisms of their formation differ significantly. The thermal pathway was found to involve the dissociation of the terminal amine to form [H2B(MU-H)(MU-NMe2)BH2] (5) and NMe3 as intermediates, with the former operating as a catalyst and accelerating the redistribution of 1. Intermediate 5 was then transformed to amine-borane 8 and the cyclic diborazane 9a by two different mechanisms. In contrast, under catalytic conditions (0.3-2 mol % IrH2POCOP (POCOP = kappa(3)-1,3-(OPtBu2)2C6H3)), 8 was found to inhibit the redistribution of 1 by coordination to the Ir-center. Furthermore, the catalytic pathway involved direct formation of 8 and Me2N?BH2 (9b), which spontaneously dimerizes to give 9a, with the absence of 5 and BH3 as intermediates. The mechanisms elucidated for 1 are also likely to be applicable to other diborazanes, for example, 2 and 3, for which detailed mechanistic studies are impaired by complex post-redistribution chemistry. This includes both metal-free and metal-mediated oligomerization of MeNH?BH2 (10) to form oligoaminoborane [MeNH-BH2]x (11) or polyaminoborane [MeNH-BH2]n (16) following the initial redistribution reaction. PMID- 23941399 TI - Overweight and obesity are associated with musculoskeletal complaints as early as childhood: a systematic review. AB - In order to examine (i) the association between weight status and musculoskeletal complaints (MSC) in children, and (ii) whether overweight and obese children have a higher risk of developing MSC than normal-weight children Medline, Embase, Web of Science and Cochrane were searched (all years up to 2 January 2013) for observational studies studying direct associations between body mass index (or weight status) and MSC in children. Forty studies, together studying over one million children, were included. There was moderate quality of evidence that being overweight in childhood is positively associated with musculoskeletal pain (risk ratio [RR] 1.26; 95% confidence interval [CI]: 1.09-1.45). In addition, low quality of evidence was found for a positive association between overweight and low back pain (RR 1.42; 95% CI: 1.03-1.97) and between overweight and injuries and fractures (RR 1.08; 95% CI: 1.03-1.14). Although the risk of developing an injury was significantly higher for overweight than for normal-weight adolescents (RR: 2.41, 95% CI: 1.42 to 4.10), this evidence was of very low quality. Overweight and obesity are associated with musculoskeletal pain, injuries and fractures as early as childhood. More high-quality prospective cohort studies are needed to study the nature of this relationship. PMID- 23941400 TI - Image based evaluation of mediastinal constraints for the development of a pulsatile total artificial heart. AB - BACKGROUND: Good anatomical compatibility is an important aspect in the development of cardiovascular implants. This work analyzes the interaction of the pump unit of an electrically driven pulsatile Total Artificial Heart (TAH) and the mediastinum. For an adequate compliance, both overall dimensions and alignment of inlets and outlets must be matched. METHODS: Cross-sectional medical image data of 27 individuals, including male and female patients suffering from end stage heart failure, was segmented and reconstructed to three dimensional (3D) surface models. Dimensions and orientations of relevant structures were identified and analyzed. The TAH surface model was virtually placed in orthotopic position and aligned with atrioventricular valves and big vessels. Additionally seven conventional cadaver studies were performed to validate different pump chamber designs based on virtual findings. Thereby 3D-coordinates were captured and introduced to the virtual environment to allow quantitative comparison between different individuals. RESULTS: Spatial parameters varied more in male patients with higher values if heart failure persists. Good correlation of the virtual analysis both to literature data and conventional cadaver studies could be shown. The full data of the 27 individuals as well as the summarized values found in literature are enclosed in the appendix. By superimposing the TAH-volume model to the anatomy, various misalignments were found and the TAH-design was adjusted. CONCLUSIONS: Virtual fitting allows implant design adjustments in realistic anatomy which has not been influenced by thoracotomy. Higher numbers of relevant individuals can be reasonably investigated in the virtual environment and quantitatively correlated. Using this approach, conventional cadaver studies can be significantly reduced but not obviated, due to the unavailable haptic feedback and immobility of potentially compressed structures. PMID- 23941401 TI - Influence of work-related characteristics and work ability on changing employer or leaving the profession among nursing staff. AB - AIM: To investigate how work-related characteristics and work ability influence nursing staff decisions to change employer or leave the profession. BACKGROUND: Previous cross-sectional studies have indicated that decreased work ability and unfavourable work-related characteristics are important determinants for the intention to leave the profession among nursing staff. METHODS: A 1-year longitudinal study, using data from the European Nurses' Early Exit Study. The study population consisted of 9927 (66%) members of the eligible nursing staff of which 345 left their current employer. Work-related characteristics, work ability and employment status were assessed by questionnaires. RESULTS: Nursing staff with a low work ability were more likely to either change employer or leave the profession. Among nursing staff with a low work ability the risk of changing employer increased significantly with unfavourable work-related characteristics. However, among nursing staff with a good work ability the risk of changing employer barely changed with unfavourable work-related characteristics. CONCLUSION: The negative effects of decreased work ability on changing employer and leaving the profession are partly counterbalanced by favourable psychological and physical work-related characteristics. IMPLICATIONS FOR NURSING MANAGEMENT: Managers should implement strategies that focus on promoting the work ability of nursing staff in combination with improving work-related characteristics in order to prevent unnecessary changes of employment. PMID- 23941402 TI - Comparative genomic and transcriptome analyses of pathotypes of Xanthomonas citri subsp. citri provide insights into mechanisms of bacterial virulence and host range. AB - BACKGROUND: Citrus bacterial canker is a disease that has severe economic impact on citrus industries worldwide and is caused by a few species and pathotypes of Xanthomonas. X. citri subsp. citri strain 306 (XccA306) is a type A (Asiatic) strain with a wide host range, whereas its variant X. citri subsp. citri strain A(w)12879 (Xcaw12879, Wellington strain) is restricted to Mexican lime. RESULTS: To characterize the mechanism for the differences in host range of XccA and Xcaw, the genome of Xcaw12879 that was completed recently was compared with XccA306 genome. Effectors xopAF and avrGf1 are present in Xcaw12879, but were absent in XccA306. AvrGf1 was shown previously for Xcaw to cause hypersensitive response in Duncan grapefruit. Mutation analysis of xopAF indicates that the gene contributes to Xcaw growth in Mexican lime but does not contribute to the limited host range of Xcaw. RNA-Seq analysis was conducted to compare the expression profiles of Xcaw12879 and XccA306 in Nutrient Broth (NB) medium and XVM2 medium, which induces hrp gene expression. Two hundred ninety two and 281 genes showed differential expression in XVM2 compared to in NB for XccA306 and Xcaw12879, respectively. Twenty-five type 3 secretion system genes were up-regulated in XVM2 for both XccA and Xcaw. Among the 4,370 common genes of Xcaw12879 compared to XccA306, 603 genes in NB and 450 genes in XVM2 conditions were differentially regulated. Xcaw12879 showed higher protease activity than XccA306 whereas Xcaw12879 showed lower pectate lyase activity in comparison to XccA306. CONCLUSIONS: Comparative genomic analysis of XccA306 and Xcaw12879 identified strain specific genes. Our study indicated that AvrGf1 contributes to the host range limitation of Xcaw12879 whereas XopAF contributes to virulence. Transcriptome analyses of XccA306 and Xcaw12879 presented insights into the expression of the two closely related strains of X. citri subsp. citri. Virulence genes including genes encoding T3SS components and effectors are induced in XVM2 medium. Numerous genes with differential expression in Xcaw12879 and XccA306 were identified. This study provided the foundation to further characterize the mechanisms for virulence and host range of pathotypes of X. citri subsp. citri. PMID- 23941403 TI - Multilocus sequence typing and biocide tolerance of Arcobacter butzleri from Danish broiler carcasses. AB - BACKGROUND: Arcobacter spp. have in recent years received increasing interest as potential emerging enteropathogens and zoonotic agents. They are associated with various animals including poultry and can be isolated from meat products. The possibilities of persistence and cross-contamination in slaughterhouses during meat processing are not well established. We have evaluated the occurrence and persistence of Arcobacter spp. in a Danish slaughterhouse and determined the sensitivity of isolates to sodium hypochlorite, a commonly used biocide. RESULTS: Arcobacter contamination was examined in a broiler slaughterhouse by selective enrichment of 235 swabs from the processing line during two production days and after sanitizing in between. In total 13.6% of samples were positive for A. butzleri with the majority (29 of 32 isolates) originating from the evisceration machine. No Arcobacter spp. was isolated after cleaning. A. butzleri isolates confirmed by PCR were typed by multilocus sequence typing (MLST) resulting in 10 new sequence types (STs). Two sequence types were isolated on both processing days. Minimum inhibitory concentration (MIC) to sodium hypochlorite was determined to 0.5% hypochlorite biocide (500 ppm chlorine) for most isolates, which allows growth of A. butzleri within the working concentration of the biocide (0.2 - 0.5%). CONCLUSIONS: A. butzleri was readily isolated from a Danish broiler slaughterhouse, primarily in the evisceration machine. Typing by MLST showed high strain variability but the recurrence of two STs indicate that some persistence or cross-contamination takes place. Importantly, the isolates tolerated sodium hypochlorite, a biocide commonly employed in slaughterhouse sanitizing, at levels close to the disinfection concentration, and thus, A. butzleri may survive the disinfection process although this was not observed in our study. PMID- 23941404 TI - Reliability and validity of the German version of the Structured Interview of Personality Organization (STIPO). AB - BACKGROUND: The assessment of personality organization and its observable behavioral manifestations, i.e. personality functioning, has a long tradition in psychodynamic psychiatry. Recently, the DSM-5 Levels of Personality Functioning Scale has moved it into the focus of psychiatric diagnostics. Based on Kernberg's concept of personality organization the Structured Interview of Personality Organization (STIPO) was developed for diagnosing personality functioning. The STIPO covers seven dimensions: (1) identity, (2) object relations, (3) primitive defenses, (4) coping/rigidity, (5) aggression, (6) moral values, and (7) reality testing and perceptual distortions. The English version of the STIPO has previously revealed satisfying psychometric properties. METHODS: Validity and reliability of the German version of the 100-item instrument have been evaluated in 122 psychiatric patients. All patients were diagnosed according to the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV) and were assessed by means of the STIPO. Moreover, all patients completed eight questionnaires that served as criteria for external validity of the STIPO. RESULTS: Interrater reliability varied between intraclass correlations of .89 and 1.0, Crohnbach's alpha for the seven dimensions was .69 to .93. All a priori selected questionnaire scales correlated significantly with the corresponding STIPO dimensions. Patients with personality disorder (PD) revealed significantly higher STIPO scores (i.e. worse personality functioning) than patients without PD; patients cluster B PD showed significantly higher STIPO scores than patients with cluster C PD. CONCLUSIONS: Interrater reliability, Crohnbach's alpha, concurrent validity, and differential validity of the STIPO are satisfying. The STIPO represents an appropriate instrument for the assessment of personality functioning in clinical and research settings. PMID- 23941407 TI - From the editor's desk. AB - No abstract available for this article. PMID- 23941408 TI - Risk taking in occupational therapy. AB - No abstract available for this article. PMID- 23941405 TI - Balancing the rates of new bone formation and polymer degradation enhances healing of weight-bearing allograft/polyurethane composites in rabbit femoral defects. AB - There is a compelling clinical need for bone grafts with initial bone-like mechanical properties that actively remodel for repair of weight-bearing bone defects, such as fractures of the tibial plateau and vertebrae. However, there is a paucity of studies investigating remodeling of weight-bearing bone grafts in preclinical models, and consequently there is limited understanding of the mechanisms by which these grafts remodel in vivo. In this study, we investigated the effects of the rates of new bone formation, matrix resorption, and polymer degradation on healing of settable weight-bearing polyurethane/allograft composites in a rabbit femoral condyle defect model. The grafts induced progressive healing in vivo, as evidenced by an increase in new bone formation, as well as a decrease in residual allograft and polymer from 6 to 12 weeks. However, the mismatch between the rates of autocatalytic polymer degradation and zero-order (independent of time) new bone formation resulted in incomplete healing in the interior of the composite. Augmentation of the grafts with recombinant human bone morphogenetic protein-2 not only increased the rate of new bone formation, but also altered the degradation mechanism of the polymer to approximate a zero-order process. The consequent matching of the rates of new bone formation and polymer degradation resulted in more extensive healing at later time points in all regions of the graft. These observations underscore the importance of balancing the rates of new bone formation and degradation to promote healing of settable weight-bearing bone grafts that maintain bone-like strength, while actively remodeling. PMID- 23941406 TI - Alterations in placental pendrin expression in pre-eclampsia. AB - INTRODUCTION: Pendrin is an integral membrane protein and plays a key role in extracellular fluid volume and blood pressure control. We aimed to investigate the relationship between pendrin immunostaining intensity in normal and pre eclamptic placental tissue. METHODS: Fifty-six placental tissues, of which 26 were in pre-eclamptic, and 30 were in control group were evaluated by immunohistochemical staining. Positive immunostaining was evaluated using a semiquantitative score: 0, negative; +, mild; ++, moderate; and +++, intense. RESULTS: There was more positive immunstaining in the pre-eclamptic placenta compared to the controls (p<0.001). A significant positive correlation was observed between immunostaining level and diastolic blood pressure (r=0.533, p=0.005) in the pre-eclamptic group. However, no significant correlation was observed between any condition and immunostaining level in the control group. CONCLUSIONS: Placentas in the pre-eclamptic group were significantly more immunostained with pendrin than were those in the control group. In addition, a positive correlation between immunostaining intensity with pendrin and both systolic and diastolic blood pressure were observed. Pendrin may play a role in the mechanism of severe hypertension in women with pre-eclampsia. PMID- 23941409 TI - Tidal surge and private practice. AB - There are historic changes occuring in American society and not least among them is a veritable transformation of the delivery of health care. Many circumstances, historical and economic, including a growing enlightenment among the public, are demanding innovation on a greater scale than ever before, and the private practitioner is responding with historic pervasive innovation. PMID- 23941410 TI - Community occupational therapy associates. AB - This article describes the creation and evolution of an occupational therapy practice agency in Canada. It explains how the agency has grown to meet the needs of both patients and therapists, and gives case examples as illustrations of successful intervention. PMID- 23941411 TI - A new arena for private practice in occupational therapy. AB - The "occupational therapist in private practice" during the last decade seems to be an expected topic for conventions, task forces and cocktail clutches among therapists. Manuals have been published, seminars given and a list of consultatns has been made available for those asking the big question "Should I set up my own practice?" Still, the letters and phone calls persist. "How do I start?" Occupational therapists' nonetheless now are numerous in the private sector and represent many different models of practice. The intent of this article is to introduce the role and function of the private practice occupational therapist in evaluation, treatment, consultation and testimony for worker's compensation or personal injury cases. The definition of private practice for this paper is a sole proprietorship, staffed by independent contracting therapists providing direct services in the private practice office. Certain aspects of business administration will also be included. PMID- 23941412 TI - One Person's Experience in Private Practice. AB - This article will focus in a very personal way on a practice, its organization and composition, and on the procedures initiated in closing this large, full-time occupational therapy program. The practice has dealt exclusively with the treatment of childhood learning disorders, as well as with adolescents and adults identified under the current nomenclature of Attention Deficit Disorders. Because the author was one of the first, if not the first, to establish a private practice in the treatment of learning disabilities, it is felt that all therapists can benefit from her unique personal experiences. The author cites what, in restrospect, might have been done differently, and offers concrete suggestions for therapists in establishing, maintaining and terminating a private practice in occupational therapy. PMID- 23941413 TI - Developing pediatric programming in a private occupational therapy practice. AB - The purpose of this paper is to suggest to occupational therapists some introductory guidelines which might be followed in developing a private occupational therapy practice. Elements of a treatment program are discussed and examples drawn from a currently successful pediatric program which uses a sensory integrative approach in offering services. Components of program development addressed in this paper include the purpose and content of screening as a recruitment device, how to structure an initial evaluation and parent conference, general treatment planning and goal setting, incorporating a theoretical frame of reference into practice, as well as clinic equipment in the private setting, documentation, discharge planning and finally, concepts of marketing for the beginning practice. PMID- 23941414 TI - The airplane. AB - As a rural private practice in occupational therapy expanded to meet the service requests in a large, sparsely populated area, the need for fast, efficient transportation became obvious. A private pilot's license was acquired and then an airplane was purchased to meet that transportation need. The private practice, geographical area and the intervention methods are reviewed. The efficiency, cost, safety and practicality of flying, and its effect on the success of the private practice are then described. PMID- 23941415 TI - Occupational therapists as publishers and trainers in the field of aging. AB - This is an account of how two occupational therapists, specialists in the field of aging, formed a publishing company to disseminate their ideas in an effort to help change attitudes about aging. The paper touches briefly on the organization, financing and staffing, the acquisition of manuscripts and materials, and how distribution by mail order was developed. Further there are descriptions of the development of workshops, inservice training activities and audio-visual materials. The authors show how community outreach has led to the expansion of their business into unforeseen areas including work with children on aging parents, intergenerational groups and a public school curriculum. PMID- 23941416 TI - Marketing occupational therapy services. AB - The ability to understand and appropriately apply business skills is a key component in the development of a successful private practice. Marketing is one of the business skills occupational therapists need to have in order to take full advantage of the opportunities available to entrepeneurs in the health care industry. The purpose of this article is to present a structured approach to marketing occupational therapy services through the use of a marketing plan. The four components of a marketing plan, a situation analysis, the identification of problems, opportunities, and target markets, the development of a marketing strategy for each targeted market, and a method to monitor the plan, are discussed. Applications to occupational therapy practice are suggested. The use of a marketing plan as a method for organizing and focusing marketing efforts is an effective means of supporting and enhancing the development of a private practice. PMID- 23941417 TI - Computers and the private practitioner in occupational therapy. AB - Computer application to thc area of occupational therapy practice is a relatively recent undertaking. Because of the absence of pertinent literature, suggestions given for potential uses are derived from imagination and from recent experience. As a therapist in private practice, concerned with cost and efficiency as well as quality treatment, the computer is examined as an administrative and research tool. Therapists are given guidelines so as to choose whether and where to initiate computer use. Next, computers and tasks are subjected to activity analysis, suggesting idaptations for use and proposing some treatment applications. Potential hazards and future needs are discussed, including computer literacy in education of therapists, compatibility of hardware/software, and communication between therapists. PMID- 23941419 TI - Laparoendoscopic single-site retroperitoneoscopic adrenalectomy for pheochromocytoma: case selection, surgical technique, and short-term outcome. AB - PURPOSE: To present our experience with case selection and operative skills of laparoendoscopic single-site (LESS) retroperitoneoscopic adrenalectomy for pheochromocytoma and evaluate its feasibility. PATIENTS AND METHODS: Between June 2011 and December 2012, we performed LESS retroperitoneoscopic adrenalectomy for 16 patients with pheochromocytoma. In all patients, the diameter of the pheochromocytoma was less than 4.0 cm. During the operation, a single-port access was inserted through a 2.5-3.0 cm transverse incision below the tip of the 12th rib. Internally, the operative procedure duplicates the conventional retroperitoneoscopic adrenalectomy for pheochromocytoma. RESULTS: No conversions to open surgery or standard laparoscopy with additional trocars were necessary. The mean operative duration was 68.1 minutes (range 41-125 min). The mean blood loss was negligible (<50 mL), and no patient needed blood transfusion. Intraoperative hypertension (SBP>180 mmHg) occurred in 12.5% (2/16) of the patients. No patient had sustained hypertension, and none experienced intraoperative hypotension (systolic blood pressure <80 mm Hg). The only postoperative complication was one case of pneumonia successfully treated with antibiotics. The average postoperative hospital stay was 3.1 days (range 2-5 days). All patients left the hospital with a good cosmetic appearance. CONCLUSIONS: In properly selected patients, LESS retroperitoneoscopic adrenalectomy is a feasible and safe procedure for pheochromocytoma. PMID- 23941421 TI - Evaluation of a seven state criminal history screening pilot program for long term care workers. AB - This article summarizes results from an evaluation of a federally sponsored criminal history screening (CHS) pilot program to improve screening for workers in long-term care settings. The evaluation addressed eight key issues specified through enabling legislation, including efficiency, costs, and outcomes of screening procedures. Of the 204,339 completed screenings, 3.7% were disqualified due to criminal history, and 18.8% were withdrawn prior to completion for reasons that may include relevant criminal history. Lessons learned from the pilot program experiences may inform a new national background check demonstration program. PMID- 23941420 TI - Distinct activation phenotype of a highly conserved novel HLA-B57-restricted epitope during dengue virus infection. AB - Variation in the sequence of T-cell epitopes between dengue virus (DENV) serotypes is believed to alter memory T-cell responses during second heterologous infections. We identified a highly conserved, novel, HLA-B57-restricted epitope on the DENV NS1 protein. We predicted higher frequencies of B57-NS1(26-34) specific CD8(+) T cells in peripheral blood mononuclear cells from individuals undergoing secondary rather than primary DENV infection. However, high tetramer positive T-cell frequencies during acute infection were seen in only one of nine subjects with secondary infection. B57-NS1(26-34) -specific and other DENV epitope-specific CD8(+) T cells, as well as total CD8(+) T cells, expressed an activated phenotype (CD69(+) and/or CD38(+)) during acute infection. In contrast, expression of CD71 was largely limited to DENV epitope-specific CD8(+) T cells. In vitro stimulation of cell lines indicated that CD71 expression was differentially sensitive to stimulation by homologous and heterologous variant peptides. CD71 may represent a useful marker of antigen-specific T-cell activation. PMID- 23941422 TI - What is "elder abuse"? Voices from the margin: the views of underrepresented Canadian older adults. AB - We know relatively little about the definitions and perceptions of elder abuse held by marginalized groups of older adults in Canada. The current study used focus group methodology to explore perceptions of elder abuse among marginalized groups such as Aboriginal persons, immigrants, refugees, and lesbians. We found both similarities and differences in perceptions of elder abuse across groups. Groups identified traditional forms of elder abuse (i.e., physical, sexual, psychological/emotional, financial abuse, and neglect) as well as less frequently identified types of abuse such as disrespect and government or systemic abuse. Groups also discussed issues related to immigrant sponsorship arrangements and abuse in nursing homes. PMID- 23941423 TI - Financial exploitation of older adults in rural settings: a family perspective. AB - Federal agencies responsible for funding protective services to older adults are increasingly concerned with the growing incidence of financial exploitation in rural areas. The Wall Street Journal recently has reported an increasing trend of unemployed adult children migrating from urban centers to smaller rural towns and countrysides to live with their parents since 2008. This current study explores the attitudes of family caregivers regarding management of financial matters for their elderly care recipients. The major findings of the study include that adult children often (1) overestimate their parents' ability to manage their finances; (2) prefer to manage their parents' finances informally, as opposed to using legal options like power of attorney; and (3) tend to think of their parents' assets as "almost theirs." The study concludes with recommendations on the critical need for information to help families make important decisions about helping elderly parents with their finances. This information would not only promote the use of safeguards against abuse, but could potentially provide caregivers with greater confidence and protection. PMID- 23941424 TI - "Do they think I am a pack rat?". AB - This case study presents details of the life of one older man who lived in seclusion and squalor, surrounded by hoarded possessions. This man was one participant of a focused ethnography of eight older adults who received home care. All participants in the original ethnography were identified by their community care coordinators as exhibiting hoarding behaviors. The case study presented here provides rich narrative and photographic detail in order to add strength to what has already been presented in previous research articles about compulsive acquisition. The narratives reveal examples of debilitating dysfunction, distress associated with decision making, broad acquisition of free things, compulsive buying, and ritualistic discarding. Quotes included in the case study stem from the original ethnography. PMID- 23941425 TI - Competing values in serving older and vulnerable adults: adult protective services, mandated reporting, and domestic violence programs. AB - State mandatory reporting statutes may directly or indirectly list domestic violence programs as among those that are mandated reporters of cases of suspected abuse, neglect, or exploitation of older individuals and those with disabilities. Domestic violence programs, however, may not consider themselves to be mandated reporters, because the responsibility of reporting abuse may be contrary to their programmatic philosophy. In the Commonwealth of Virginia, the potential conflict between domestic violence programs and Adult Protective Services about the issue of mandated reporting has created tension between these organizations as each entity continues interpreting the issues and policies of mandated reporting through its own lens. The authors draw out some of the reasons for the conflict as well as make recommendations for improving relationships between the two organizations, which will ultimately benefit vulnerable adults who are experiencing abuse. PMID- 23941427 TI - Duck Tembusu virus exhibits neurovirulence in BALB/c mice. AB - BACKGROUND: Duck Tembusu virus is a member of the Ntaya group in the genus Flavivirus. The virus has been responsible for severe duck egg-drop syndrome in China since 2010. Its emergence and rapid spread have caused great economic loss for the poultry industry. The epidemiology of the virus infection and the potential threat to public health is of great concern because of the infective and zoonotic nature of flaviviruses. RESULTS: In this study, the pathogenicity of duck Tembusu virus in BALB/c mice was investigated. Infected mice developed clinical signs, including loss of appetite, ruffled hair, weight loss, disorientation, blindness and paralysis of hind limbs from six days post- infection following intracerebral inoculation. Morbidity was 100%, with mortality ranging from 20 to 80% in three- to eight-week-old mice. High virus titers were recovered from the brain, and the virus was distributed in several organs. Histologically, there was widespread non-suppurative encephalitis in the brain. Lymphocyte depletion in the spleen was observed, along with fatty degeneration in the liver and kidney. CONCLUSIONS: Our results demonstrate, for the first time, that duck Tembusu virus is highly neurovirulent in BALB/c mice. The mouse model used in this work was able to produce Tembusu virus infection and could be useful for elucidating some of the aspects of the pathophysiology of other flavivirus infections. PMID- 23941428 TI - Triplet state of the semiquinone-Rieske cluster as an intermediate of electronic bifurcation catalyzed by cytochrome bc1. AB - Efficient energy conversion often requires stabilization of one-electron intermediates within catalytic sites of redox enzymes. While quinol oxidoreductases are known to stabilize semiquinones, one of the famous exceptions includes the quinol oxidation site of cytochrome bc1 (Qo), for which detection of any intermediate states is extremely difficult. Here we discover a semiquinone at the Qo site (SQo) that is coupled to the reduced Rieske cluster (FeS) via spin spin exchange interaction. This interaction creates a new electron paramagnetic resonance (EPR) transitions with the most prominent g = 1.94 signal shifting to 1.96 with an increase in the EPR frequency from X- to Q-band. The estimated value of isotropic spin-spin exchange interaction (|J0| = 3500 MHz) indicates that at a lower magnetic field (typical of X-band) the SQo-FeS coupled centers can be described as a triplet state. Concomitantly with the appearance of the SQo-FeS triplet state, we detected a g = 2.0045 radical signal that corresponded to the population of unusually fast-relaxing SQo for which spin-spin exchange does not exist or is too small to be resolved. The g = 1.94 and g = 2.0045 signals reached up to 20% of cytochrome bc1 monomers under aerobic conditions, challenging the paradigm of the high reactivity of SQo toward molecular oxygen. Recognition of stable SQo reflected in g = 1.94 and g = 2.0045 signals offers a new perspective on understanding the mechanism of Qo site catalysis. The frequency-dependent EPR transitions of the SQo-FeS coupled system establish a new spectroscopic approach for the detection of SQo in mitochondria and other bioenergetic systems. PMID- 23941430 TI - Does screening for pre-eclampsia make sense? PMID- 23941431 TI - Meeting the challenge of interpreting high-resolution single nucleotide polymorphism array data: does increased diagnostic power outweigh the dilemma of rare variants. PMID- 23941432 TI - Lymphadenectomy in ovarian cancer--an overrated procedure? PMID- 23941433 TI - Authors' response to: Meeting the challenge of interpreting high-resolution single nucleotide polymorphism array data: does increased diagnostic power outweigh the dilemma of rare variants. PMID- 23941434 TI - Authors' response to: Lymphadenectomy in ovarian cancer--an overrated procedure? PMID- 23941435 TI - Medical versus surgical termination of pregnancy in primigravid women--is the next delivery differently at risk? PMID- 23941436 TI - A report from #BlueJC: does mental rehearsal help a novice surgeon? PMID- 23941437 TI - Authors' response to: Medical versus surgical termination of pregnancy in primigravid women--is the next delivery differently at risk? PMID- 23941439 TI - 25 GHz embedded-gate graphene transistors with high-k dielectrics on extremely flexible plastic sheets. AB - Despite the widespread interest in graphene electronics over the past decade, high-performance graphene field-effect transistors (GFETs) on flexible substrates have been rarely achieved, even though this atomic sheet is widely understood to have greater prospects for flexible electronic systems. In this article, we report detailed studies on the electrical and mechanical properties of vapor synthesized high-quality monolayer graphene integrated onto flexible polyimide substrates. Flexible graphene transistors with high-k dielectric afforded intrinsic gain, maximum carrier mobilities of 3900 cm(2)/V.s, and importantly, 25 GHz cutoff frequency, which is more than a factor of 2.5 times higher than prior results. Mechanical studies reveal robust transistor performance under repeated bending, down to 0.7 mm bending radius, whose tensile strain is a factor of 2-5 times higher than in prior studies. In addition, integration of functional coatings such as highly hydrophobic fluoropolymers combined with the self passivation properties of the polyimide substrate provides water-resistant protection without compromising flexibility, which is an important advancement for the realization of future robust flexible systems based on graphene. PMID- 23941440 TI - De novo assembly and characterization of fruit transcriptome in Litchi chinensis Sonn and analysis of differentially regulated genes in fruit in response to shading. AB - BACKGROUND: Litchi (Litchi chinensis Sonn.) is one of the most important fruit trees cultivated in tropical and subtropical areas. However, a lack of transcriptomic and genomic information hinders our understanding of the molecular mechanisms underlying fruit set and fruit development in litchi. Shading during early fruit development decreases fruit growth and induces fruit abscission. Here, high-throughput RNA sequencing (RNA-Seq) was employed for the de novo assembly and characterization of the fruit transcriptome in litchi, and differentially regulated genes, which are responsive to shading, were also investigated using digital transcript abundance(DTA)profiling. RESULTS: More than 53 million paired-end reads were generated and assembled into 57,050 unigenes with an average length of 601 bp. These unigenes were annotated by querying against various public databases, with 34,029 unigenes found to be homologous to genes in the NCBI GenBank database and 22,945 unigenes annotated based on known proteins in the Swiss-Prot database. In further orthologous analyses, 5,885 unigenes were assigned with one or more Gene Ontology terms, 10,234 hits were aligned to the 24 Clusters of Orthologous Groups classifications and 15,330 unigenes were classified into 266 Kyoto Encyclopedia of Genes and Genomes pathways. Based on the newly assembled transcriptome, the DTA profiling approach was applied to investigate the differentially expressed genes related to shading stress. A total of 3.6 million and 3.5 million high-quality tags were generated from shaded and non-shaded libraries, respectively. As many as 1,039 unigenes were shown to be significantly differentially regulated. Eleven of the 14 differentially regulated unigenes, which were randomly selected for more detailed expression comparison during the course of shading treatment, were identified as being likely to be involved in the process of fruitlet abscission in litchi. CONCLUSIONS: The assembled transcriptome of litchi fruit provides a global description of expressed genes in litchi fruit development, and could serve as an ideal repository for future functional characterization of specific genes. The DTA analysis revealed that more than 1000 differentially regulated unigenes respond to the shading signal, some of which might be involved in the fruitlet abscission process in litchi, shedding new light on the molecular mechanisms underlying organ abscission. PMID- 23941442 TI - Online N2O measurement: the next standard for controlling biological ammonia oxidation? PMID- 23941443 TI - C-H functionalization of cyclopropanes: a practical approach employing a picolinamide auxiliary. AB - A Pd-catalyzed, picolinamide-enabled, and efficient C-H arylation of cyclopropanes is described. The reaction can be promoted by either a silver additive or catalytic pivalic acid in the presence of a carbonate base. Various aryl iodides can be employed as coupling partners, providing exclusively cis substituted cyclopropylpicolinamides. PMID- 23941441 TI - BRAF V600E mutation is associated with mTOR signaling activation in glioneuronal tumors. AB - BRAF V600E mutations have been recently reported in glioneuronal tumors (GNTs). To evaluate the expression of the BRAF V600E mutated protein and its association with activation of the mammalian target of rapamycin (mTOR) pathway, immunophenotype and clinical characteristics in GNTs, we investigated a cohort of 174 GNTs. The presence of BRAF V600E mutations was detected by direct DNA sequencing and BRAF V600E immunohistochemical detection. Expression of BRAF mutated protein was detected in 38/93 (40.8%) gangliogliomas (GGs), 2/4 (50%) desmoplastic infantile gangliogliomas (DIGs) and 23/77 (29.8%) dysembryoplastic neuroepithelial tumors (DNTs) by immunohistochemistry. In both GGs and DNTs, the presence of BRAF V600E mutation was significantly associated with the expression of CD34, phosphorylated ribosomal S6 protein (pS6; marker of mTOR pathway activation) in dysplastic neurons and synaptophysin (P < 0.05). In GGs, the presence of lymphocytic cuffs was more frequent in BRAF-mutated cases (31 vs. 15.8%; P=0.001). The expression of both BRAF V600E and pS6 was associated with a worse postoperative seizure outcome in GNT (P < 0.001). Immunohistochemical detection of BRAF V600E-mutated protein may be valuable in the diagnostic evaluation of these glioneuronal lesions and the observed association with mTOR activation may aid in the development of targeted treatment involving specific pathogenic pathways. PMID- 23941444 TI - Comparative evaluation of a two-reagent cold stain method with Ziehl-Nelseen method for pulmonary tuberculosis diagnosis. AB - BACKGROUND: Bacteriological examination of sputum is the cornerstone in diagnosis of pulmonary tuberculosis in developing world, which is usually done using a Ziehl-Nelseen (ZN) method. However, due to limited laboratory facilities that can satisfy the procedure, applicability of this procedure appears to be adversely affected in field conditions and at peripheral health institutions. Hence, it has become necessary to look for a procedure which can be used as alternative in such conditions.In a cross-sectional study, using convenient sampling technique 362 pulmonary tuberculosis suspected patients who attended at Mekelle University Hospital (MUH) between November 2011 and February 2012 were included. After obtaining an informed consent, spot-morning-spot sputum samples were collected from suspected patients. Then a set of duplicate slides, of which one was allocated to a two-reagent cold method (a method of staining which requires carbol fuchsine as a primary stain and Gabbet's methylene blue both as a decolorizer and counter stain) and the other to the Zeihl-Nelseen method were smeared evenly from representative portion of each specimen using the protocol for duplicate smear preparation. Stained smears were read blindly by two technologists at different occasions. Finally to assure quality, all positive smears and 25% of the negative smears were cross checked by senior experienced examiner. FINDINGS: Overall concordance between the two methods was 99.7% (kappa (kappa) = 0.98; 95%, confidence interval 0.93-1.00), and the observed agreement was statistically significant (p<0.001). When evaluated against Ziehl-Nelseen method, sensitivity and specificity of the two-reagent cold staining method were 95.8% (95% confidence interval 93.7-97.9) and 100% respectively. Positive and negative predictive values of the two-reagent cold staining method were respectively 100% and 99.7%. Positive and negative agreements between the two techniques were respectively 97.9% and 99.9%. CONCLUSION: The two-reagent cold staining method was found to be a suitable alternative to the conventional Ziehl Nelseen method; it was at least as specific as Ziehl-Neelsen method although somewhat less sensitive. However, large scale multicentric studies need to be performed for further evaluation of this cold staining method. PMID- 23941447 TI - From the editor's desk. AB - No abstract available for this article. PMID- 23941448 TI - Energy. AB - Historically occupational therapists have planned treatment programs requiring activity involving different and diverse amounts of energy use by patients. Also, many energy saving methods and devices, now commonly applied by therapists, were developed empirically to make activities possible for paralyzed patients. For the energy deficient patient physiological concepts of energy may not apply because both psychological and sociological factors may influence how individuals convert food to energy for maintenance of homeostasis and musculoskeletal activity. Energy conservation measures identified with occupational therapy may be supplemented with Brief, Isometric, Maximal Exercise (BRIME) to enhancec energy reserves, and reflex mechanisms may also be used to facilitate movement for the energy deficient person. The older person with low energy but without serious medical problems may need thorough investigation of life style and environment in order to plan appropriate occupational therapy intervention. PMID- 23941449 TI - Designing environments for the elderly. AB - Planning living environments for the elderly is a challenge due to the variety of characteristics and the changing health status of this special population. An occupational therapist's knowledge and understanding of the aging process, as well as the profession's philosophy of maximizing health through active living can contribute to the design of retirement centers. The concepts and basic principles involved in such collaborative planning are discussed. This paper concludes with an invocation for more occupational therapists to seek opportunities to be involved in facility planning for the elderly. PMID- 23941445 TI - Pharmacotherapy for bipolar disorder and concordance with treatment guidelines: survey of a general population sample referred to a tertiary care service. AB - BACKGROUND: Many new approaches have been adopted for the treatment of bipolar disorder (BD) in the past few years, which strived to produce more positive outcomes. To enhance the quality of care, several guideline recommendations have been developed. For study purposes, we monitored the prescription of psychotropic drugs administered to bipolar patients who had been referred to tertiary care services, and assessed the degree to which treatment met specific guidelines. METHODS: Between December 2006 and February 2009, we assessed 113 individuals suffering from BD who had been referred to the Royal Ottawa Mental Health Centre (ROMHC) Mood Disorders Program by physicians within the community, mostly general practitioners. The Structured Clinical Interview for DSM-IV-TR was used to assess diagnosis. The prescribed treatment was compared with specific Canadian guidelines (CANMAT, 2009). Univariate analyses and logistic regression were used to assess the contribution of demographic and clinical factors for concordance of treatment with guidelines. RESULTS: Thirty-two subjects had BD type I (BD-I), and 81 subjects had BD type II (BD-II). All subjects with BD-I, and 90% of the BD-II group were given at least one psychotropic treatment. Lithium was more often prescribed for subjects with BD-I (62%) than those with BD-II (19%). Antidepressants were the most frequently prescribed class of psychotropics. Sixty eight percent of subjects received treatment concordant with guidelines by medication and dose. The presence of a current hypomanic episode was independently associated with poorer concordance to guidelines. In more than half the cases, the inappropriate use of antidepressants was at the origin of the non concordance of treatment with respect to guidelines. Absence of psychotropic treatment in bipolar II patients and inadequate dosage of mood stabilizers were the two other main causes of non concordance with guidelines. CONCLUSIONS: The factors related to treatment not concordant with guidelines should be further explored to determine appropriate strategies in implementing the use of guidelines in clinical practice. PMID- 23941450 TI - Outcomes of a problem-solving approach to independence in children with multiple limb deficiencies. AB - Occupational therapists can play a unique role in helping children with disabilities develop a positive history of mastery of skills and habits necessary for continued movement along the developmental continuum throughout the life cycle. An independent problem-solving approach to treatment is suggested as a method of facilitating development of skills and habits which will continue to support independence. A case history of a 27-year-old woman who as a child participated in a program using this approach illustrates how her use of independent problem-solving to master competent performance of adult roles. PMID- 23941451 TI - Using purpose to engage the patient with depression. AB - At the very heart of occupational therapy practice is the active engagement of the patient with purposeful activities. The lack of energy displayed by some psychiatric patients is often viewed by occupational therapists as a barrier to the very treatment process they are trying to implement. When patients fail to participate in treatment, therapists are often frustrated and confused about what steps to take next. This paper will examine the process of involving the low energy psychiatric patients in activity across four dimensions: imparting purpose, the role of choice, meeting expectations and interaction with peers. Treatment implications are outlined and discussed in respect to three case studies. PMID- 23941452 TI - Psychic energy - the activator of the low energy patient. AB - The article presents a description of a theoretical basis for how psychic energy can be harnessed to activate the low energy patient to physical performance which otherwise would be unobtainable. It shows how this vitalizer varies with each individual and how it varies over time for one individual. A longitudinal case study, in log form, illustrates the progression of change in one patient at various levels of diminished physical energy and performance. For the occupational therapist treating patients with difficult restorable clinical symptoms and/or poor prognosis, psychic energy and its potentials is seen as a useful tool. PMID- 23941453 TI - Occupational therapy as part of a pulmonary rehabilitation program. AB - In the City of Hope Medical Respiratory Care (MRC) program occupational therapy is a dynamic, integral part of the rehabilitation process. Three broad and varying aspects of occupational therapy are covered. These consist of upper extremity exercises using both an arm argometer and gravity resistive exercises, relaxation and stress management training, and a multifaceted approach to activities of daily living (ADL) training. The ADL training is carried out in both individual and group sessions and includes techniques or work efficiency and motion economy, proper body mechanics, and proper breathing techniques during daily activities. The occupational therapist is a member of the MRC treatment team and would be unable to function effectively with these patients without the support and assistance of other members. The studies referred to in this paper validate this use of occupational therapy in a Pulmonary Rehabilitation Program. PMID- 23941454 TI - A Subjective ADL Rating Scale for the Pulmonary Rehabilitation Patient. AB - A subjective rating scale to measure changes in performance of activities of daily living before and after participation in an out-patient multidisciplinary pulmonary rehabilitation program is presented. Results of a small pilot study using the scale is reported in which the scores of patients in ADL are compared with one measure of their pulmonary function. The use of the scale as an adjunct to planning occupational therapy programs is proposed and suggestions are made both for its change and for improving its usefulness to other therapists. PMID- 23941455 TI - Monitored dressing evaluation. AB - The ability to measure changes in self care status for patients with cardiovascular disease is difficult to quantify since their independence is usually not limited by the need for physical assistance. Instead, limitations may include changes in vital signs that indicate excessive workload for the cardiovascular system, abnormally slow work pace, or inability to perform other tasks due to fatigue after self care is completed. Typical parameters that have been used to measure improvement in work tolerance, such as the ability to work for longer periods of time at progressively higher workloads, do not apply to self care. The purpose of this paper is to describe a monitored dressing evaluation that includes a scale to grade functional work tolerance. The scoring system provides a more objective way than usually available to measure improvements in tolerance for dressing. It is especially useful for the patient at a low level of functioning. PMID- 23941456 TI - Cardiac rehabilitation. AB - Occupational therapy plays a significant role in helping patients with coronary artery disease move to restored health and function and in facilitating their change from states of crisis to adaptation. Treatment begun early and carried out both in group and individual sessions, addresses cardiac function and risk factors in all phases of daily activities with emphasis on managing stress. Activities of daily living groups particularly emphasize energy conservation techniques in both vocational and avocational pursuits. Staff also teach and encourage appropriate lifestyle modifications. PMID- 23941458 TI - Creation of "all about aging". AB - No abstract available for this article. PMID- 23941457 TI - Adapting to life after a stroke. AB - This article provides a patient's perspective on the physical and psychological adaptations necessitated by a stroke. The subject of the article is 70 year old woman who has suffered two severe strokes. Her efforts in adapting to energy deficits and relearning how to walk, write, speak, carry out the activities of daily living, and resume her exercise program are all detailed. In addition, the psychological adaptations that she has made in order to cope with the strokes are described. The subject's extremely positive attitude and determination are highlighted, along with her perceptions of how therapists can help other people who have had strokes develop a similar positive attitude. PMID- 23941459 TI - A preliminary critique. AB - No abstract available for this article. PMID- 23941460 TI - Assessment of the agreement between photoplethysmographic and arterial waveform respiratory variation in patients undergoing spine surgery. AB - Respiratory variation in the arterial blood pressure and photoplethysmographic (PPG) waveforms have both been shown to predict the haemodynamic response to volume administration. Whether or not the two can be considered interchangeable is controversial. Twenty-three patients undergoing spine surgery received both a 20 gauge intra-arterial catheter and a Masimo adult adhesive SpHb sensor connected to a Radical-7 monitor. Pulse pressure variation (PPV) was calculated off-line at 1-min intervals. Pleth Variability Index (PVI) and Perfusion Index data were recorded. After exclusion of outliers, agreement between PPV and PVI was assessed using a repeated measures Bland-Altman approach. Concordance between changes in PPV and PVI was assessed using a four-quadrant plot with a 20% zone of exclusion. In total, 6549 min of data were collected. Repeated measures Bland Altman analysis identified a bias of 2.2% and 95% confidence intervals of +/ 15.3% (limits of agreement -13.1 and +17.6%). The concordance rate between changes in PPV and changes in PVI was 51%. The agreement between respiratory variation in the arterial blood pressure and PPG waveforms is poor and these two should not be considered interchangeable. Changes in PPV are unrelated to changes in PVI. The data, combined with recently published work from other authors, suggests that the low frequency oscillations in the PPG waveform are not related to the low frequency oscillation in the systemic arterial blood pressure tracing and may be related to changes in venous pressure, peripheral tone or other physiologic phenomena yet to be described. PMID- 23941461 TI - Protein kinase inhibitors in metastatic colorectal cancer. Let's pick patients, tumors, and kinase inhibitors to piece the puzzle together! AB - INTRODUCTION: Increased understanding in intracellular signaling pathways leading to carcinogenesis, proliferation, migration, invasion, angiogenesis, and anti apoptosis of colorectal cancer cells has been critical for target identification and drug development. Specific protein kinase inhibitors (KIs) have been developed to block activated pathways associated with tumor growth and progression. Although showing promising activity in preclinical models, until now, the majority of KIs were not able to demonstrate clinically meaningful efficacy in Phase II/III trials. AREAS COVERED: The major pathways altered in colorectal cancer will be highlighted, and molecularly defined targets will be discussed. The mechanisms of action and the proof of principle demonstrated in preclinical models of KIs and the disappointing efficacy in clinical trials will be reviewed. EXPERT OPINION: Despite recent negative study results, KIs have the potential to be the next class of therapeutics in the treatment of metastatic colorectal cancer. Molecular classification of the individual tumors and identification of molecular escape mechanisms for primary (intrinsic) and secondary resistances to KI treatment is critical to select the patients' most likely to benefit. Appropriate drug combinations based on those mechanisms of resistance have to be tested in selected patient populations to ensure progress and efficacy with the goal to lead to a clinically meaningful prolongation of patients' lives. PMID- 23941462 TI - Poplar calcineurin B-like proteins PtCBL10A and PtCBL10B regulate shoot salt tolerance through interaction with PtSOS2 in the vacuolar membrane. AB - The calcineurin B-like protein (CBL) family represents a unique group of calcium sensors in plants. In Arabidopsis, CBL10 functions as a shoot-specific regulator in salt tolerance. We have identified two CBL10 homologs, PtCBL10A and PtCBL10B, from the poplar (Populus trichocarpa) genome. While PtCBL10A was ubiquitously expressed at low levels, PtCBL10B was preferentially expressed in the green aerial tissues of poplar. Both PtCBL10A and PtCBL10B were targeted to the tonoplast and expression of either one in the Arabidopsis cbl10 mutant could rescue its shoot salt-sensitive phenotype. Like PtSOS3, both PtCBL10s physically interacted with the salt-tolerance component PtSOS2. But in contrast to the SOS3 SOS2 complex at the plasma membrane, the PtCBL10-SOS2 interaction was primarily associated with vacuolar compartments. Furthermore, overexpression of either PtCBL10A or PtCBL10B conferred salt tolerance on transgenic poplar plants by maintaining ion homeostasis in shoot tissues under salinity stress. These results not only suggest a crucial role of PtCBL10s in shoot responses to salt toxicity in poplar, but also provide a molecular basis for genetic engineering of salt tolerant tree species. PMID- 23941463 TI - Optimization of compound ranking for structure-based virtual ligand screening using an established FRED-Surflex consensus approach. AB - The use of multiple target conformers has been applied successfully in virtual screening campaigns; however, a study on how to best combine scores for multiple targets in a hierarchic method that combines rigid and flexible docking is not available. In this study, we used a data set of 59 479 compounds to screen multiple conformers of four distinct protein targets to obtain an adapted and optimized combination of an established hierarchic method that employs the programs FRED and Surflex. Our study was extended and verified by application of our protocol to ten different data sets from the directory of useful decoys (DUD). We quantitated overall method performance in ensemble docking and compared several consensus scoring methods to improve the enrichment during virtual ligand screening. We conclude that one of the methods used, which employs a consensus weighted scoring of multiple target conformers, performs consistently better than methods that do not include such consensus scoring. For optimal overall performance in ensemble docking, it is advisable to first calculate a consensus of FRED results and use this consensus as a sub-data set for Surflex screening. Furthermore, we identified an optimal method for each of the chosen targets and propose how to optimize the enrichment for any target. PMID- 23941464 TI - Liver steatosis in Chinese HIV-infected patients with hypertriglyceridemia: characteristics and independent risk factors. AB - BACKGROUND: Since Highly Active Antiretroviral Therapy (HAART) medications were made available in 2002, multiple serious side effects have been observed. However, no study has yet systematically evaluated the prevalence of liver steatosis, a very serious but treatable side effect. OBJECTIVES: This study examined the prevalence of and independent risk factors for liver steatosis in Chinese HIV-infected, HAART-experienced patients who had been diagnosed with hypertriglyceridemia. METHODS: In this cross-sectional observational study, the prevalence of liver steatosis was determined by ultrasound imaging that detected diffusion in hepatic echogenicity. The risk factors associated with steatosis were evaluated with a proportional odds logistic regression model. RESULTS: Among 163 HIV-infected patients with hypertriglyceridemia and past HAART experience, 75(46%) patients were determined to have liver steatosis. In multivariable logistic regression model, the risk factors associated with liver steatosis were: higher triglyceride level (OR = 1.086, P = 0.026), metabolic syndromes (OR = 2.092, P = 0.024) and exposure to nucleoside reverse transcriptase inhibitor (NRTIs) ((OR = 2.11, P = 0.001) and Stavudine (OR = 3.75, P = 0.01)). Exposure to Nevirapine (OR = 0 .41, P = 0.003) was a favorable factor for lipid metabolism in vivo and was a protective factors for liver steatosis. CONCLUSIONS: Chinese HIV infected patients with hypertriglyceridemia appear to be prone to liver steatosis, especially those on NRTIs. Routine screening should be considered on their lipid panels. PMID- 23941465 TI - Intermediate partitioning kinetic isotope effects for the NIH shift of 4 hydroxyphenylpyruvate dioxygenase and the hydroxylation reaction of hydroxymandelate synthase reveal mechanistic complexity. AB - 4-Hydroxyphenylpyruvate dioxygenase (HPPD) and hydroxymandelate synthase (HMS) are similar enzymes that catalyze complex dioxygenation reactions using the substrates 4-hydroxyphenylpyruvate (HPP) and dioxygen. Both enzymes decarboxylate HPP and then hydroxylate the resulting hydroxyphenylacetate (HPA). The hydroxylation reaction catalyzed by HPPD displaces the aceto substituent of HPA in a 1,2-shift to form 2,5-dihydroxyphenylacetate (homogentisate, HG), whereas the hydroxylation reaction of HMS places a hydroxyl on the benzylic carbon forming 3'-hydroxyphenylacetate (S-hydroxymandelate, HMA) without ensuing chemistry. The wild-type form of HPPD and variants of both enzymes uncouple to form both native and non-native products. We have used intermediate partitioning to probe bifurcating steps that form these products by substituting deuteriums for protiums at the benzylic position of the HPP substrate. These substitutions result in altered ratios of products that can be used to calculate kinetic isotope effects (KIE) for the formation of a specific product. For HPPD, secondary normal KIEs indicate that cleavage of the bond in the displacement reaction prior to the shift occurs by a homolytic mechanism. NMR analysis of HG derived from HPPD reacting with enantiomerically pure R-3'-deutero-HPP indicates that no rotation about the bond to the radical occurs, suggesting that collapse of the biradical intermediate is rapid. The production of HMA was observed in HMS and HPPD variant reactions. HMS hydroxylates to form exclusively S hydroxymandelate. When HMS is reacted with R-3'-deutero-HPP, the observed kinetic isotope effect represents geometry changes in the initial transition state for the nonabstracted proton. These data show evidence of sp(3) hybridization in a HPPD variant and sp(2) hybridization in HMS variants, suggesting that HMS stabilizes a more advanced transition state in order to catalyze H-atom abstraction. PMID- 23941466 TI - In situ transmission electron microscopy observations of sublimation in silver nanoparticles. AB - In situ heating experiments were performed in a transmission electron microscope (TEM) to monitor the thermal stability of silver nanoparticles. The sublimation kinetics from isothermal experiments on individual nanoparticles was used to assess the actual temperatures of the nanoparticles by considering the localized heating from the electron beam. For isolated nanoparticles, beam heating under normal TEM operating conditions was found to increase the temperature by tens of degrees. For nominally isothermal experiments, the observed sublimation temperatures generally decreased with decreasing particle size, in agreement with the predictions from the Kelvin equation. However, sublimation of smaller nanoparticles was often observed to occur in discrete steps, which led to faceting of the nanoparticles. This discrete behavior differs from that predicted by conventional theory as well as from experimental observations in larger nanoparticles where sublimation was continuous. A hypothesis that explains the mechanism for this size-dependent behavior is proposed. PMID- 23941467 TI - Isotopic biosignatures in carbonate-rich, cyanobacteria-dominated microbial mats of the Cariboo Plateau, B.C. AB - Photosynthetic activity in carbonate-rich benthic microbial mats located in saline, alkaline lakes on the Cariboo Plateau, B.C. resulted in pCO2 below equilibrium and delta(13) CDIC values up to +6.00/00 above predicted carbon dioxide (CO2 ) equilibrium values, representing a biosignature of photosynthesis. Mat-associated delta(13) Ccarb values ranged from ~4 to 80/00 within any individual lake, with observations of both enrichments (up to 3.80/00) and depletions (up to 11.60/00) relative to the concurrent dissolved inorganic carbon (DIC). Seasonal and annual variations in delta(13) C values reflected the balance between photosynthetic (13) C-enrichment and heterotrophic inputs of (13) C depleted DIC. Mat microelectrode profiles identified oxic zones where delta(13) Ccarb was within 0.20/00 of surface DIC overlying anoxic zones associated with sulphate reduction where delta(13) Ccarb was depleted by up to 50/00 relative to surface DIC reflecting inputs of (13) C-depleted DIC. delta(13) C values of sulphate reducing bacteria biomarker phospholipid fatty acids (PLFA) were depleted relative to the bulk organic matter by ~40/00, consistent with heterotrophic synthesis, while the majority of PLFA had larger offsets consistent with autotrophy. Mean delta(13) Corg values ranged from -18.7 +/- 0.1 to -25.3 +/ 1.00/00 with mean Delta(13) Cinorg-org values ranging from 21.1 to 24.20/00, consistent with non-CO2 -limited photosynthesis, suggesting that Precambrian delta(13) Corg values of ~-260/00 do not necessitate higher atmospheric CO2 concentrations. Rather, it is likely that the high DIC and carbonate content of these systems provide a non-limiting carbon source allowing for expression of large photosynthetic offsets, in contrast to the smaller offsets observed in saline, organic-rich and hot spring microbial mats. PMID- 23941468 TI - Density profile in thin films of polybutadiene on silicon oxide substrates: a TOF NR study. AB - We have investigated thin films from fully deuterated polybutadiene (PB-d6) on silicon substrates with the aim of detecting and characterizing a possible interphase in the polymer film near the substrate using time-of-flight neutron reflectometry (TOF-NR). As substrates, thermally oxidized silicon wafers were either used as such or they were coated with triethylethoxysilyl modified 1,2-PB prior to deposition of the PB-d6 film. TOF-NR reveals that, for both substrates, the scattering length density (SLD) of the PB films decreases near the solid interface. The reduction of SLD is converted to an excess fraction of free volume. To further verify the existence of the interphase in PB-d6, we attempt to model the TOF-NR curves with density profiles which do not feature an interphase. These density profiles do not describe the TOF-NR curves adequately. We conclude that, near the solid interface, an interphase having an SLD lower than the bulk of the film is present. PMID- 23941469 TI - Computed tomographic characteristics of the cisterna chyli in dogs. AB - Previous lymphangiographic studies have investigated the use of computed tomography (CT) for characterizing the thoracic duct and its tributaries in dogs. However, there is limited published information on the appearance of the canine cisterna chyli using CT. The objective of this retrospective study was to describe the features of the canine cisterna chyli in pre- and post-contrast abdominal CT studies. The presence, location, shape, maximum width, size compared with the aortic diameter (Ao:cisterna chyli ratio) and mean attenuation of the cisterna chyli were recorded from archived abdominal CT scans of 30 dogs. Breed, age, sex and neutering status were also noted. A cisterna chyli was identified in 26 of the dogs (87%). In 22 cases a cisterna chyli could be reliably identified prior to intravenous contrast administration and in all 26 cases in postcontrast images. The cisterna chyli was most commonly located right dorsolateral to the abdominal aorta between L1 and L4. Shape varied on transverse images from crescent-like to globular and maximum diameters ranged from 5 to 9 mm. The Ao:cisterna chyli ratio varied between 0.29 and 0.71 (mean value-males: 0.32; females: 0.38). On pre-contrast images the mean Hounsfield units were 21.3HU (range: -3.8 to 64.25). Mild enhancement of the cisterna chyli post-contrast was observed in 24 dogs (80%). Findings supported the use of pre- and post-contrast abdominal CT as a non-invasive method for assessing qualitative and quantitative characteristics of the canine cisterna chyli. PMID- 23941470 TI - Informing the design of a randomised controlled trial of an exercise-based programme for long term stroke survivors: lessons from a before-and-after case series study. AB - BACKGROUND: To inform the design of a randomised controlled trial (RCT) of an exercise-based programme for long term stroke survivors, we conducted a mixed methods before-and-after case series with assessment at three time points. We evaluated Action for Rehabilitation from Neurological Injury (ARNI), a personalised, functionally-focussed programme. It was delivered through 24 hours of one-to-one training by an Exercise Professional (EP), plus at least 2 hours weekly unsupervised exercise, over 12- 14 weeks. Assessment was by patient-rated questionnaires addressing function, physical activity, confidence, fatigue and health-related quality of life; objective assessment of gait quality and speed; qualitative individual interviews conducted with participants. Data were collected at baseline, 3 months and 6 months. Fidelity and acceptability was assessed by participant interviews, audit of participant and EP records, and observation of training. FINDINGS: Four of six enrolled participants completed the exercise programme. Quantitative data demonstrated little change across the sample, but marked changes on some measures for some individuals. Qualitative interviews suggested that small benefits in physical outcomes could be of great psychological significance to participants. Participant-reported fatigue levels commonly increased, and non-completers said they found the programme too demanding. Most key components of the intervention were delivered, but there were several potentially important departures from intervention fidelity. DISCUSSION: The study provided data and experience that are helping to inform the design of an RCT of this intervention. It suggested the need for a broader recruitment strategy; indicated areas that could be explored in more depth in the qualitative component of the trial; and highlighted issues that should be addressed to enhance and evaluate fidelity, particularly in the preparation and monitoring of intervention providers. The experience illustrates the value of even small sample before-and-after studies in the development of trials of complex interventions. PMID- 23941471 TI - Bisphenol-A (BPA), BPA glucuronide, and BPA sulfate in midgestation umbilical cord serum in a northern and central California population. AB - Bisphenol-A (BPA) is an endocrine disrupting chemical used in numerous consumer products, resulting in universal exposure in the United States. Prenatal exposure to BPA is associated with numerous reproductive and developmental effects in animals. However, little is known about human fetal exposure or metabolism of BPA during midgestation. In the present study, we present a new liquid chromatography tandem mass spectrometry method to directly measure concentrations of BPA and two predominant metabolic conjugates-BPA glucuronide and BPA sulfate-in umbilical cord serum collected from elective second trimester pregnancy terminations. We detected at least one form of BPA in all umbilical cord serum samples: BPA (GM 0.16, range T>A) gene polymorphism and IgG antibodies. AB - BACKGROUND: C-reactive protein (CRP) is a nonspecific, acute-phase protein that rises in response to infectious and non-infectious inflammatory processes. Infections are the single largest cause of neonatal deaths globally.The primary aim of this study is to examine the association between CRP gene polymorphism and serum levels of CRP in correlation with early onset sepsis (EOS) infection in newborns living in Taif city, Saudi Arabia. The second aim is to examine the relationship between specific IgG/IgG subclasses and early onset sepsis (EOS) infection among these newborns. METHODS: Staphylococcus aureus (S. aureus) is one of the most common organisms related to sepsis infection in the newborn at King Abdel Aziz Specialist Hospital (KAASH). This study was conducted in Taif city, at KAASH's neonatal intensive care unit between March and August 2012. Neonates were consecutively enrolled onto the study having met our inclusion criteria (as per our research protocol).The CRP concentration level was analysed using NycoCard CRP Single Test. CRP -286 (C>T>A) A polymorphisms were analyzed using Pyrosequencing technology for CRP genotyping. IgG subclasses were analysed in the study population using ELISA. RESULT: Logistic regression analyses showed that the AA and AC genotypes were negatively associated amongst EOS neonates compared to suspected neonates. The frequency of CC and CT were significantly associated with the EOS neonates compared to the suspected group. The levels of specific IgG1, IgG2 and IgG3 antibodies were significantly lower amongst EOS compared to the suspected group. CONCLUSIONS: Taken together, the CRP-286 (C>T>A) A genotype polymorphism and specific IgG antibodies isotype levels can contribute to a reduced risk of EOS. Furthermore, CRP has a potential use in detecting EOS in neonates, which may mean earlier detection and management of EOS and subsequently better clinical outcome. PMID- 23941475 TI - Wrist postures and forces in tree planters during three tree unloading conditions. AB - The aims of this study were to investigate wrist postures and forces while operating the shovel during tree planting and to determine if different tree unloading techniques result in variations in wrist postures and forces. Experienced tree planters performed the planting task in a laboratory environment for three conditions: (1) symmetric tree unloading, and asymmetric unloading resulting in (2) right-loaded planting bags and (3) left-loaded planting bags. An optoelectric system and a shovel instrumented with strain gauges captured wrist posture and forces at the wrist, respectively. Wrist extension of up to 45 degrees was observed, and this posture, in combination with varying degrees of wrist deviation, may be a primary risk factor for musculoskeletal pain. Average resultant forces at the wrist were moderately high (>30 N) for each unloading condition, indicating increased risk for the development of repetitive strain injuries such as carpal tunnel syndrome. No significant differences in wrist posture or forces existed between unloading conditions. PRACTITIONER SUMMARY: Wrist pain is a major musculoskeletal complaint among tree planters. This study measured wrist postures and forces at the wrist while operating the shovel during tree planting. The wrist extension observed, in combination with deviation, may be a key risk factor for musculoskeletal pain. Forces at the wrist indicate increased risk for repetitive strain injuries. PMID- 23941474 TI - Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: a protocol for a randomised, independent, pragmatic, multicentre, parallel-group, superiority clinical trial. AB - BACKGROUND: Data on therapeutic interventions following deliberate self harm (DSH) in patients with treatment-resistant depression (TRD) are very scant and there is no unanimous consensus on the best pharmacological option for these patients. There is some evidence that lithium treatment might be effective in reducing the risk of completed suicide in adult patients with unipolar affective disorders, however no clear cut results have been found so far. The primary aim of the present study is to assess whether adding lithium to standard therapy is an effective treatment strategy to reduce the risk of suicidal behaviour in long term treatment of people with TRD and previous history of DSH. METHODS/DESIGN: We will carry out a randomised, parallel group, assessor-blinded superiority clinical trial. Adults with a diagnosis of major depression, an episode of DSH in the previous 12 months and inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode will be allocated to add lithium to current therapy (intervention arm) or not (control arm). Following randomisation, treatment is to be taken daily for 1 year unless some clear reason to stop develops. Suicide completion and acts of DSH during the 12 months of follow-up will constitute the composite primary outcome. To preserve outcome assessor blindness, an independent adjudicating committee, blind to treatment allocation, will anonymously review all outcome events. DISCUSSION: The results of this study should indicate whether lithium treatment is associated with lower risk of completed suicide and DSH in adult patients with treatment resistant unipolar depression, who recently attempted suicide. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00927550. PMID- 23941476 TI - From the Editor's Desk. AB - No abstract available for this article. PMID- 23941477 TI - From the co-editor. AB - No abstract available for this article. PMID- 23941478 TI - Supervision of the certified occupational therapy assistant. AB - Children with autism vary greatly in their individual learning styles, their problem areas, and their response to treatment. Since children with this diagnosis present a relatively unique clinical picture, innovative approaches to treatment are required. The purpose of this paper is to encourage therapist to employ a variety of treatment techniques according to the traditional frames of reference described in the occupational therapy literature (Tiffany, 1983; Matsutsuyu, 1983; Ayres, 1979; Pedretti and Pasquelli-Estrada, 1985). These include the following approaches: developmental, occupational behavior, sensory intenrative, acquisitional, biomechanical, rehabilitative, and psychoandytic. Each frarne of reference will be described in. terms of its theoretical base, state of dysfunction. and focus of intervention in order to assist the therapist in develophg a structured approach in initiating treatment. In addition, a theoretical case study will be presented and each frame of reference applied with an emphasis on principles for treatment and sample long and short term goals. Suggestions will also be provided for establishing a therapeutic environment for children with autism. PMID- 23941479 TI - Going to the source. AB - A small but growing body of occupational therapy literature identifies the value of qualitative research methodology, which is useful with relatively unstudied or complex phenomena. This paper describes the use of qualitative research to obtain insight into the world of adults with significantly limiting cerebral palsy, as seen from their own perspective. The first author conducted extended, guided interviews with five adults who live independently with attendant care. The resulting data, synthesized into recurring themes, suggested guidelines for occupational therapy practice. In this paper, the study methodology is described in depth, and directions for further qualitative and quantitative research are presented. PMID- 23941480 TI - Occupational therapy and epilepsy. AB - Epilepsy and its varied seizure types effect the physical, social, emotional, recreational and vocational functioning of individuals and their families. This article addresses the varlous components of seizure disorders and discusses the importance of occupational therapy intervention in each of these areas. Epilepsy first aid, safe and activities of daily living, and the role of the occupational therapist in education and vocational exploration are discussed, along with a concise description of epilepsy and its seizure types. PMID- 23941481 TI - Early intervention. AB - This paper provides an overview of the critical nced for early intervention services, the specific role of occupational therapists in early intervention settings, and the training implications for the preparation of occupational Therapists with expanded roles, responsibilities and skills. An intervention approach that is multidisciplinary, culturally relevant, and family centered in nature is proposed as one way of redefining the occupational therapist's contribution and strategy in early intervention settings. Recommendations are presented regarding the education and preparation of occupational thera ists for their new directions in early intervention and the potenliarincrease in demands for their services. PMID- 23941482 TI - Occupational therapy in a regional comprehensive service system. AB - This paper provides an overview of the diverse roles played by occupational therapists in a large regional comprehensive service system for persons with developmental disabilities. A brief description of the system is followed by a look at how occupational therapy services are provided within the regional center itself and a review of work training and day activities services as the service recipient moves toward greater independence and a lesser restrictive setting. In the community setting the occupational therapists roles are that of arranging for, monitoring and assuring delivery of appropriate services. PMID- 23941483 TI - On the formative stages of the adult screening questionnaire. AB - This article describes the formative stages of a screening tool for developmentally disabled adults, the Adult Screening Questionnaire (ASQ). ASQ offers occupational therapists a uniform approach for screening clients. Employing the ASQ will result with a client profile that leads to improved capability in screening outcomes for service delivery: prioritizing caseloads, identifying domains of need for comprehensive evaluation, facilitating clinical decision making, and reporting population needs. to administrators. These screcning outcomes contribute to determining the client evaluation and program intervention necessary for the service delivery process. Reported are rationale for the developmentluse of the instrument, previous validity studies, modifications, and pilot study testin for reliability. The Clients Profile will enable the clinicians to establish three priority levels according to clients' needs. In addition, each clients' needs are identified on nine domains of occupational therapy programmatic concern. A summay,of fipdings for five outcomes for service delivery is introduced. imltatlons and plans for further modification and study are discussed. PMID- 23941484 TI - Intervention Strategies for Promoting Feeding Skills in Infants with sensory Deficits. AB - Feeding is multi-sensory, highly stimulating experience for infants and young children. Feeding interactions with children who have oral sensory processing deficits may be therapeutic and pleasurable or may be stressful and disorganizing. Specific oral motor and feeding problems in hyposensilive/hypotonic children and hypersensitivethy ertonic children are described. Occupational therapy intervention t k' at emphasizes sensory stimulation related to the environment, handling before and during feeding, and the sensory qualities of food is explained. PMID- 23941485 TI - Clinical management of Dysphagia in the developmentally disabled adult. AB - As a member of a dysphagia team, the occupational therapist contributes a major part in both the assessment and treatment of swallowing disorders. Dysphagia referrals for developmentally disabled adults may range from aspiration and chokin to ruminatlon and refusal to eat. Using observations during mealtime, the therapist establishes a baseline for treatment planning. Related variables provide the focus and parameters of treatment. Although medical evaluations such as videoflouroscopy may provide expanded information, they are generally not critical In implementing an effective program. The primary treatment objective, in most cases, is to develop active participation of the individual in the eating process. Most of these adults have never experienced "normal" mature eating patterns and may never achieve this level through treatment. The achievement of a functional level of eating will not only assist in maintaining the person's medical and nutritional status, but will facilitate a more positive mealtime experience. PMID- 23941486 TI - Development and implementation of a Dysphagia program in a mental retardation residential facility. AB - This paper describes the implementation of a dysphagia program in a residential mental retardation (MR) setting. Five program phases are presented describing the staff requirements, inservice and other procedures necessary to establish the program, the evaluation procedures, treatment approaches, and documentation patterns. Specific recommendations developed at Caswell to improve implementation of such a program with a residential, multi- Randicapped population are discussed, and our initial results with evaluation procedures and therapeutic interventions in 56 residents are presented. In particular, a detailed analysis of 24 clients whose intervention was based on videofluoroscopic examination are also presented. PMID- 23941487 TI - Pre-vocational programming in a pediatric skilled care facility. AB - This article describes a pre-vocational program that was developed in a private residential skilled care pediatric facility, under the guidance of an occupational therapy consultant. This "Special Training Program" was designed to meet the needs of the few higher functioning adolescents and young adults residing within the facility who did not participate in daily community school programs. This paper presents the philosophical issues related to developing a pre-vocational program; the criteria for selecting program participants; the program structure (implementation details, work sample selection, production rate data records, program supervision, participant remuneration, physical set-up and start-up costs); and an evaluation of the benefits and disadvantages of the program following one year of the Special Training Program's initiation date. PMID- 23941488 TI - Developmental Growth in "ACTION". AB - This paper describes a pilot program in a work acrivity center. Called the "ACTION Group," the project involved six c ients whose selection was based on low productivity rates on work assignments. The purpose of the "ACTION Group" was to allow clients who were experiencing failure to be motivated by tasks structured to their performance needs. The hypothesis is that productivity improves when clients are presented with purposeful and appealing activities at their developmental level. PMID- 23941489 TI - Options. AB - This article discusses a grant-funded occu~ational therapy independent living skills transition program for adoiesccnts with develo~mental disabilities on a non-mainstreamed high school campus. The Options Program was designed to provide intensive transition services through its emphasis on exploring and broadening the range of individuals' choices' about employment, living arrangements, and social activities. The assessment procedure, program model, curriculum goals, and intervention strategies are presented. PMID- 23941490 TI - Grip strength and dexterity in adults with developmental delays. AB - The purpose of this study was to determine the usefulness of dexterity and grip strength assessments by comparing the scores of adults with developmental delays with adult norms. A second purpose was to determine the correlations among the assessment instruments. Fifty-six developmentally disabled adults performed the box and block test, the nine hole peg test, and grip strength. Males performed significantly better on grip strength than females, but there was no significant difference on dexterity scores. Males scored significantly lower than established norms on all tests except the left nine hole peg test. Females scores were significantly lower than norms on all tests except the left and right nine hole peg test. Dexterity test scores on one side of the body were highly correlated with those on the other side, but grip strength was not highly correlated with dexterity. This suggests that occupational therap~sts need to treat dexterity and grip as separate entitles. The present results may provide guidelines to determine average performance for adults with developmental delays. PMID- 23941492 TI - The importance of program evaluation. AB - No abstract available for this article. PMID- 23941491 TI - Occupational therapy in operation outreach. AB - A mobile outreach program is presented here as a response to the rapidly expanding demand for occupational therapy services in the field of developmental disabilties. Histroical overview of Operation Outreach will include discussion of societal trends influencing the program as well as factual information specific to the Indiana University (IU) experience. Demand for increased productivity and efficiency with cost containment led to IU's modified truck, housing a complete mobile adapted equipment laboratory, for convenient on-site evaluations and service of Wheelchair and custom designed posistioning equipment. Operation Outreach was designed for the developmental disabled to help address the needs of the whole person in his own enviornment, to enhance wellness, and to improve quality of life. PMID- 23941493 TI - An Exchange of Services programfor Adults with Developmental Disabilities. AB - A randomized controlled trial was conducted to evaluate a community program to train, match and place developmentally disabled adults with elderly people who needed help with housekeeping, personal care and companionship. Program goals were not acheived, as employment of persons with developmental disabilities did not increase and institutionalization of elderly people was not delayed. The program did improve feelings of well-being. Program cost exceeded $200 per person month. Attrition was high, and survival analysis indentified critical periods for retention in the program. PMID- 23941495 TI - Behaviour of four diarrheagenic Escherichia coli pathotypes on carrots and in unpasteurized carrot juice. AB - The behaviours of Shiga toxin-producing Escherichia coli (STEC), enteroinvasive E. coli (EIEC), enteropathogenic E. coli (EPEC) and enterotoxigenic E. coli (ETEC) strains on raw carrots at 3 +/- 1 and 30 +/- 1 degrees C, and in unpasteurized carrot juice at 3 +/- 1, 12 +/- 1, 20 +/- 1, 30 +/- 1 degrees C and 37 +/- 1 degrees C were determined. Raw carrots were purchased in a local market. Fresh juice was obtained from raw carrots in the laboratory. On whole carrots stored at 30 +/- 1 or 3 +/- 1 degrees C, no growth was observed for any of the diarrheagenic E. coli pathotype (DEPs) strains studied. After 15 days at 30 +/- 1 degrees C, the tested DEPs had decreased from an initial inoculum level of approximately 6 log colony-forming units (CFU) to approximately 3.5 log CFU on whole carrots, while at 3 +/- 1 degrees C, they decreased from approximately 2.4 log to 1.6 log CFU. All these DEPs grew in fresh carrot juice at 12 +/- 1, 20 +/- 1, 30 +/- 1 and 37 +/- 1 degrees C, reaching counts of approximately 4.2 log, 5.8 log, 6.7 log and 7.5 log CFU ml(-1) , respectively, after 24 h. At 3 +/- 1 degrees C, the DEP growth was inhibited at least during 7 days. Thus, storage of carrot juice at unrefrigerated temperatures can result in DEP growth to levels likely to represent a risk to consumers. SIGNIFICANCE AND IMPACT OF THE STUDY: The information presented shows the potential of Shiga toxin-producing Escherichia coli, enteroinvasive E. coli, enteropathogenic E. coli and enterotoxigenic E. coli strains for survival on carrots and growth in carrot juice at warmer temperatures. The information can help food processors in plants and restaurants understand the importance of the implementation of hazard analysis and critical control point (HACCP) strategies for preventing potential diarrheagenic E. coli pathotypes (DEPs) contamination and growth in carrot juice. This is the first report regarding the behaviour these DEPs on carrots and in carrot juice. PMID- 23941496 TI - Ex vivo cytokine production in peripheral blood mononuclear cells after their stimulation with dsRNA of natural origin. AB - Double-stranded RNA (dsRNA) is a pathogen-associated molecular pattern, known for its ability to induce antiviral response and enhance communication between cells mediating innate and adaptive immune responses. The aim of this study was to characterize the effect of the dsRNA-containing product Larifan on the production of a wide spectrum of cytokines and chemokines in ex vivo cultivated peripheral blood mononuclear cells. Concentrations of 29 different cytokines were detected by a Luminex(r) 200TM System using three Milliplex MAP Multiplex Assay Kits. Larifan caused strong induction of chemokine macrophage inflammatory protein 1beta, I-309, and TARC, proinflammatory cytokines IL-6, tumor necrosis factor alpha, granulocyte macrophage colony-stimulating factor, anti-inflammatory IL-10, and cellular immunity mediating factors IL-23 and interferon-gamma. Considerable suppression of IL-16 and chemokine stromal cell-derived factor 1 a+b and interferon gamma-induced protein 10 was also observed. The network of molecules responding to the presence of Larifan revealed the pleiotropic effect this product exerts on immune response. PMID- 23941497 TI - Determination of sensitizer regeneration efficiency in dye-sensitized solar cells. AB - Regeneration of the sensitizing dye in dye-sensitized solar cells (DSCs) is frequently studied using the transient absorption (TA) technique. However, TA measurements are generally not performed using complete DSCs at the maximum power point (MPP) on the current-voltage (j-V) characteristic, and the electron concentration in the nanocrystalline TiO2 films used in these devices is often not well characterized, which may lead to results that are not relevant to actual solar cell operation. Here, dye regeneration kinetics were studied at the MPP and at open circuit (where interpretation of results is simpler) in DSCs employing a "robust" nonvolatile 3-methoxypropionitrile-based electrolyte solution. Using a combination of TA, differential incident photon-to-current efficiency measurements, and impedance spectroscopy, the dependence of electron-dye recombination rate and overall sensitizer regeneration efficiency on TiO2 electron concentration is unambiguously demonstrated. We also examine the validity of a commonly used approach for determining regeneration efficiency in which the electron-dye recombination rate constant is estimated from TA decays of cells employing a redox-inactive electrolyte solution. We find evidence that this widespread practice may be unsuitable for accurate determination of the regeneration rate constant or efficiency. We go on to show that, despite near quantitative regeneration at short circuit or low photovoltage, power conversion efficiency is limited by inefficient regeneration in stable DSCs with practically relevant electrolyte solutions. PMID- 23941498 TI - Targeting protein-bound uremic toxins in chronic kidney disease. AB - INTRODUCTION: Protein-bound uremic toxins such as indoxyl sulfate cannot be removed efficiently by hemodialysis. These protein-bound uremic toxins have emerged as important risk factors for the progression of chronic kidney disease (CKD) as well as cardiovascular disease (CVD). AREAS COVERED: Indoxyl sulfate shows toxic effects on a variety of cells such as renal proximal tubular cells, glomerular mesangial cells, vascular smooth muscle cells, vascular endothelial cells, cardiomyocytes, cardiac fibroblasts, monocytes, osteoblasts and osteoclasts. This review overviews the cellular toxicity of indoxyl sulfate, its molecular mechanism and its role in the progression of CKD and CVD. Further, this review summarizes the clinical effects of AST-120 and the other strategies to reduce serum levels of indoxyl sulfate. EXPERT OPINION: Protein-bound uremic toxins such as indoxyl sulfate have emerged as target molecules for therapeutic intervention of not only CKD but also CVD. An oral sorbent AST-120 reduces serum level of indoxyl sulfate by adsorbing indole in the intestine. The modulation of intestinal bacteria by prebiotics/probiotics might be effective in reducing the production of indole in the intestine followed by reduced serum levels of indoxyl sulfate. An alternative approach might be antagonist which can counteract indoxyl sulfate-induced cellular effects and signaling pathways. PMID- 23941499 TI - Effects of fructose-containing caloric sweeteners on resting energy expenditure and energy efficiency: a review of human trials. AB - Epidemiological studies indicate that the consumption of fructose-containing caloric sweeteners (FCCS: mainly sucrose and high-fructose corn syrup) is associated with obesity. The hypothesis that FCCS plays a causal role in the development of obesity however implies that they would impair energy balance to a larger extent than other nutrients, either by increasing food intake, or by decreasing energy expenditure. We therefore reviewed the literature comparing a) diet-induced thermogenesis (DIT) after ingestion of isocaloric FCCS vs glucose meals, and b) basal metabolic rate (BMR) or c) post-prandial energy expenditure after consuming a high FCCS diet for > 3 days vs basal,weight-maintenance low FCCS diet. Nine studies compared the effects of single isocaloric FCCS and glucose meals on DIT; of them, six studies reported that DIT was significantly higher with FCCS than with glucose, 2 reported a non-significant increase with FCCS, and one reported no difference. The higher DIT with fructose than glucose can be explained by the low energy efficiency associated with fructose metabolism. Five studies compared BMR after consumption of a high FCCS vs a low FCCS diet for > 3 days. Four studies reported no change after 4-7 day on a high FCCS diet, and only one study reported a 7% decrease after 12 week on a high FCCS diet. Three studies compared post-prandial EE after consumption of a high FCCS vs a low FCCS diet for > 3 days, and did not report any significant difference. One study compared 24-EE in subjects fed a weight-maintenance diet and hypercaloric diets with 50% excess energy as fructose, sucrose and glucose during 4 days: 24 EE was increased with all 3 hypercaloric diets, but there was no difference between fructose, sucrose and glucose. We conclude that fructose has lower energy efficiency than glucose. Based on available studies, there is presently no hint that dietary FCCS may decrease EE. Larger, well controlled studies are however needed to assess the longer term effects of FCCS on EE. PMID- 23941500 TI - Combined 3D-QSAR, molecular docking, molecular dynamics simulation, and binding free energy calculation studies on the 5-hydroxy-2H-pyridazin-3-one derivatives as HCV NS5B polymerase inhibitors. AB - The NS5B RNA-dependent RNA polymerase (RdRP) is a promising therapeutic target for developing novel anti-hepatitis C virus (HCV) drugs. In this work, a combined molecular modeling study was performed on a series of 193 5-hydroxy-2H-pyridazin 3-one derivatives as inhibitors of HCV NS5B Polymerase. The best 3D-QSAR models, including CoMFA and CoMSIA, are based on receptor (or docking). Furthermore, a 40 ns molecular dynamics (MD) simulation and binding free energy calculations using docked structures of NS5B with ten compounds, which have diverse structures and pIC50 values, were employed to determine the detailed binding process and to compare the binding modes of the inhibitors with different activities. On one side, the stability and rationality of molecular docking and 3D-QSAR results were validated by MD simulation. The binding free energies calculated by the MM-PBSA method gave a good correlation with the experimental biological activity. On the other side, by analyzing some differences between the molecular docking and the MD simulation results, we can find that the MD simulation could also remedy the defects of molecular docking. The analyses of the combined molecular modeling results have identified that Tyr448, Ser556, and Asp318 are the key amino acid residues in the NS5B binding pocket. The results from this study can provide some insights into the development of novel potent NS5B inhibitors. PMID- 23941501 TI - Characterization of the interdomain motions in hen lysozyme using residual dipolar couplings as replica-averaged structural restraints in molecular dynamics simulations. AB - Hen lysozyme is an enzyme characterized by the presence of two domains whose relative motions are involved in the mechanism of binding and release of the substrates. By using residual dipolar couplings as replica-averaged structural restraints in molecular dynamics simulations, we characterize the breathing motions describing the interdomain fluctuations of this protein. We found that the ensemble of conformations that we determined spans the entire range of structures of hen lysozyme deposited in the Protein Data Bank, including both the free and bound states, suggesting that the thermal motions in the free state provide access to the structures populated upon binding. The approach that we present illustrates how the use of residual dipolar couplings as replica-averaged structural restraints in molecular dynamics simulations makes it possible to explore conformational fluctuations of a relatively large amplitude in proteins. PMID- 23941503 TI - Synthetic self-localizing ligands that control the spatial location of proteins in living cells. AB - Small-molecule ligands that control the spatial location of proteins in living cells would be valuable tools for regulating biological systems. However, the creation of such molecules remains almost unexplored because of the lack of a design methodology. Here we introduce a conceptually new type of synthetic ligands, self-localizing ligands (SLLs), which spontaneously localize to specific subcellular regions in mammalian cells. We show that SLLs bind their target proteins and relocate (tether) them rapidly from the cytoplasm to their targeting sites, thus serving as synthetic protein translocators. SLL-induced protein translocation enables us to manipulate diverse synthetic/endogenous signaling pathways. The method is also applicable to reversible protein translocation and allows control of multiple proteins at different times and locations in the same cell. These results demonstrate the usefulness of SLLs in the spatial (and temporal) control of intracellular protein distribution and biological processes, opening a new direction in the design of small-molecule tools or drugs for cell regulation. PMID- 23941502 TI - Maintenance of muscle mass and load-induced growth in Muscle RING Finger 1 null mice with age. AB - Age-related loss of muscle mass occurs to varying degrees in all individuals and has a detrimental effect on morbidity and mortality. Muscle RING Finger 1 (MuRF1), a muscle-specific E3 ubiquitin ligase, is believed to mediate muscle atrophy through the ubiquitin proteasome system (UPS). Deletion of MuRF1 (KO) in mice attenuates the loss of muscle mass following denervation, disuse, and glucocorticoid treatment; however, its role in age-related muscle loss is unknown. In this study, skeletal muscle from male wild-type (WT) and MuRF1 KO mice was studied up to the age of 24 months. Muscle mass and fiber cross sectional area decreased significantly with age in WT, but not in KO mice. In aged WT muscle, significant decreases in proteasome activities, especially 20S and 26S beta5 (20-40% decrease), were measured and were associated with significant increases in the maladaptive endoplasmic reticulum (ER) stress marker, CHOP. Conversely, in aged MuRF1 KO mice, 20S or 26S beta5 proteasome activity was maintained or decreased to a lesser extent than in WT mice, and no increase in CHOP expression was measured. Examination of the growth response of older (18 months) mice to functional overload revealed that old WT mice had significantly less growth relative to young mice (1.37- vs. 1.83-fold), whereas old MuRF1 KO mice had a normal growth response (1.74- vs. 1.90-fold). These data collectively suggest that with age, MuRF1 plays an important role in the control of skeletal muscle mass and growth capacity through the regulation of cellular stress. PMID- 23941504 TI - Identification of molecular phenotypic descriptors of breast capsular contracture formation using informatics analysis of the whole genome transcriptome. AB - Breast capsular contracture formation following silicone implant augmentation/reconstruction is a common complication that remains poorly understood. The aim of this study was to identify potential biomarkers implicated in breast capsular contracture formation by using, for the first time, whole genome arrays. Biopsy samples were taken from 18 patients (23 breast capsules) with Baker Grade I-II (Control) and Baker Grade III-IV (Contracted). Whole genome microarrays were performed and six significantly dysregulated genes were selected for further validation with quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Hematoxylin and eosin was also carried out to compare the histological characteristics of control and contracted samples. Microarray results showed that aggrecan, tissue inhibitor of metalloproteinase 4 (TIMP4), and tumor necrosis factor superfamily (ligand) member 11 were significantly down-regulated in contracted capsules; while matrix metallopeptidase 12, serum amyloid A 1, and interleukin 8 (IL8) were significantly up-regulated. The dysregulation of aggrecan, tumor necrosis factor superfamily (ligand) member 11, TIMP4, and IL8 was validated by quantitative reverse transcriptase polymerase chain reaction (p < 0.05). Immunohistochemistry confirmed an increased protein expression for IL8 and matrix metallopeptidase 12 in contracted capsules (p < 0.05), and decreased protein expression of TIMP4 (p < 0.05). This study has shown, for the first time, a number of unique biomarkers of significance in capsular contracture formation. IL8 and TIMP4 may serve as potential key diagnostic, therapeutic, and prognostic biomarkers in capsular contracture formation. PMID- 23941505 TI - Development of an in vitro drug sensitivity assay based on newly excysted larvae of Echinostoma caproni. AB - BACKGROUND: Echinostomiasis is one of the major food-borne trematodiases and the species Echinostoma caproni serves as a useful model for trematocidal drug discovery. The current in vitro drug sensitivity assay uses adult E. caproni worms that are incubated with candidate drugs and scored microscopically for viability at 72 hrs. The aim of this study was to investigate the use of newly excysted larvae (NEL) of E. caproni for in vitro drug testing, which would be faster, more cost effective and more ethical compared to adult worm assays. METHODS: Larvae were obtained by collecting metacercariae from snails and triggering their excystation using the trypsin-bile salt excystation method. Studies concerning various parameters of this chemical transformation process as well as appropriate NEL culturing conditions were carried out and findings evaluated. NEL and adult worms were incubated with praziquantel, tribendimidine, albendazole and quinine and evaluated microscopically 72 hrs post-incubation. In addition, the colorimetric markers resazurin, CellTiter-Glo(r) and Vybrant(r) were tested as an alternative assay read-out method. RESULTS: The chemical excystation method successfully induced E. caproni metacercariae to excyst at a rate of about 20-60%. NEL remained viable in culture medium for 5-7 days. The results of an in vitro drug assay using NEL mirrored the results of an assay using adult worms incubated with the same drugs. None of the markers could reliably produce signals proportional to NEL viability or cytotoxicity without significant complications. CONCLUSION: NEL are adequate for in vitro drug testing. Challenges remain in further improving the excystation yield and the practicability of the assay setup. Resolving these issues could also improve read outs using colorimetric markers. Using NEL is in alignment with the 3 R rules of the ethical use of laboratory animals and can greatly increase the rate and affordability with which drugs are screened in vitro against this intestinal trematode. PMID- 23941506 TI - Underutilized chokeberry (Aronia melanocarpa, Aronia arbutifolia, Aronia prunifolia) accessions are rich sources of anthocyanins, flavonoids, hydroxycinnamic acids, and proanthocyanidins. AB - Polyphenols from underutilized black, purple, and red aronia (Aronia melanocarpa, Aronia prunifolia, and Aronia arbutifolia) and 'Viking' (Aronia mitschurinii) berries were characterized. Anthocyanin and nonanthocyanin flavonoids were quantitated by UHPLC-DAD-MS and proanthocyanidins by normal-phase HPLC. On a dry weight basis, anthocyanins were mainly cyanidin-3-galactoside, highest in black aronia (3.4-14.8 mg/g) and lowest in red aronia (0.5-0.8 mg/g) as cyandin-3 galactoside equivalents. Berries from 'Viking' and the red accession UC021 had substantially more proanthocyanidins than the other accessions, with 3.3 and 3.8 mg catechin equiv/g, respectively. Chlorogenic acids and quercetin glycosides were most abundant in purple UC047 berries, at 17.3 and 1.3 mg/g, respectively. In contrast to anthocyanin content, total phenol values were highest in berries from red and purple accessions and attributed to phenolic acid and proanthocyanin content. Thus, red, purple, and black aronia berries are rich sources of polyphenols with various levels of polyphenol classes. PMID- 23941507 TI - Plasma klotho levels were inversely associated with subclinical carotid atherosclerosis in HIV-infected patients receiving combined antiretroviral therapy. AB - Combined antiretroviral therapy (cART) has significantly improved the survival rate in HIV-infected individuals, but it contributes to the development of various metabolic complications. Klotho is a novel antiaging gene that encodes a protein with pleiotropic functions, including an emerging role in cardiovascular disease (CVD). The protective effect of higher plasma klotho levels against CVD was recently observed in non-HIV-infected adults. We aimed to assess whether plasma-secreted alpha-klotho is associated with subclinical carotid atherosclerosis in HIV-infected patients receiving cART. We prospectively examined the association of circulating plasma alpha-klotho in 120 HIV-infected patients who had received cART for >=6 months with intima-media thickness (IMT) in the carotid artery and other metabolic variables. The subclinical carotid atherosclerosis was defined as an increased mean IMT level of >=75th percentile for the matched age, sex, and race and/or the presence of carotid plaque. Thirty four (28.3%) of 120 had subclinical carotid atherosclerosis. The higher plasma levels of alpha-klotho had protective effect against subclinical carotid atherosclerosis (OR 0.006, p=0.034) in multivariate regression analysis. Plasma alpha-klotho levels had a significantly negative correlation with fasting glucose levels (r=-0.216, p=0.018) and mean IMT (r=-0.258, p=0.004) in multiple stepwise regression analyses. The optimal cutoff values of plasma alpha-klotho levels for the greatest sensitivity and specificity were calculated as 2.83 log10 [pg/ml] (sensitivity, 48.7%; specificity, 90.5%). These results show that plasma klotho levels were inversely associated with subclinical carotid atherosclerosis in HIV infected patients receiving cART. PMID- 23941508 TI - Laboratory study on the hygroscopic behavior of external and internal C2-C4 dicarboxylic acid-NaCl mixtures. AB - Atmospheric aerosol is usually found to be a mixture of various inorganic and organic components in field measurements, whereas the effect of this mixing state on the hygroscopicity of aerosol particles has remained unknown. In this study, the hygroscopic behavior of mixtures of C2-C4 dicarboxylic acids and NaCl was investigated. For both externally and internally mixed malonic acid-NaCl and succinic acid-NaCl particles, correlation between water content and chemical composition was observed and the water content of these mixtures at relative humidity (RH) above 80% can be well predicted by the Zdanovskii-Stokes-Robinson (ZSR) method. In contrast, a nonlinear relation between the total water content of the mixtures and the water content of each chemical composition separately was found for oxalic acid-NaCl mixtures. Compared to the values predicted by the ZSR method, the dissolution of oxalic acid in external mixtures resulted in an increase in the total water content, whereas the formation of less hygroscopic disodium oxalate in internal mixtures led to a significant decrease in the total water content. Furthermore, we found that the hygroscopicity of the sodium dicarboxylate plays a critical role in determining the aqueous chemistry of dicarboxylic acid-NaCl mixtures during the humidifying and dehumidifying process. It was also found that the hydration of oxalic acid and the deliquescence of NaCl did not change in external oxalic acid-NaCl mixtures. The deliquescence relative humidity (DRHs) for both malonic acid and NaCl decreased in both external and internal mixtures. These results could help in understanding the conversion processes of dicarboxylic acids to dicarboxylate salts, as well as the substitution of Cl by oxalate in the atmosphere. It was demonstrated that the effect of coexisting components on the hygroscopic behavior of mixed aerosols should not be neglected. PMID- 23941510 TI - Comprehensive study of DNA binding on iron (II,III) oxide nanoparticles with a positively charged polyamine three-dimensional coating. AB - Iron (II,III) oxide Fe3O4 nanoparticles (25 and 50 nm NPs) are grafted with amine groups through silanization in order to generate a positively charged coating for binding negatively charged species including DNA molecules. The spatial nature of the coating changes from a 2-D-functionalized surface (monoamines) through a layer of amine oligomers (diethylenetriamine or DETA, about 1 nm in length) to a 3-D layer of polyamine (polyethyleneimine or PEI, thickness >=3.5 nm). These Fe3O4-PEI NPs were prepared by binding short-chain PEI polymers to the iodopropyl groups grafted on the NP surface. In this work, the surface charge density, or zeta potential, of the nanoparticles is found not to be the only factor influencing the DNA binding capacity, which also seems not to be affected by their buffering capacity profile in the range of pH 4-10. This study also allows the investigation of this 3-D effect on the surface of a nanoparticle as opposed to conventional 2-D amine functionalization. The flexibility of the PEI coating, which consists of only 1, 2, and 3 degrees amines, on the nanoparticle surface has a significant influence on the overall DNA binding capacity and the binding efficiency (or N/P ratio). These polyamine-functionalized nanoparticles can be used in the purification of biomolecules and the delivery of drugs and large biomolecules. PMID- 23941509 TI - DNA vaccines targeting the encoded antigens to dendritic cells induce potent antitumor immunity in mice. AB - BACKGROUND: Although DNA vaccine holds a great potential for cancer immunotherapy, effective long-lasting antitumoral immunity sufficient to induce durable responses in cancer patients remains to be achieved. Considering the pivotal role of dendritic cells (DC) in the antigen processing and presentation, we prepared DC-targeting DNA vaccines by fusing tumor-associated antigen HER2/neu ectodomain to single chain antibody fragment (scFv) from NLDC-145 antibody specific for DC-restricted surface molecule DEC-205 (scFvNLDC-145), and explored its antitumoral efficacy and underlying mechanisms in mouse breast cancer models. RESULTS: In vivo targeting assay demonstrated that scFvNLDC-145 specifically delivered DNA vaccine-encoded antigen to DC. Compared with untargeted HER2/neu DNA vaccines, vaccination with scFvNLDC-145-HER2/neu markedly promoted the HER2/neu-specific cellular and humoral immune responses with long-lasting immune memory, resulting in effective protection against challenge of HER2/neu-positive D2F2/E2 breast tumor while ineffective in parental HER2/neu-negative D2F2 breast tumor. More importantly, in combination with temporary depletion of regulatory T cells (Treg) by low-dose cyclophosphamide, vaccination with scFvNLDC-145-HER2/neu induced the regression of established D2F2/E2 breast tumor and significantly retarded the development of spontaneous mammary carcinomas in transgenic BALB neuT mice. CONCLUSION: Our findings demonstrate that DC-targeted DNA vaccines for in vivo direct delivery of tumor antigens to DC could induce potent antigen specific cellular and humoral immune responses and, if additional combination with systemic Treg depletion, was able to elicit an impressively therapeutic antitumoral activity, providing a rationale for further development of this approach for cancer treatment. PMID- 23941512 TI - A modified Maquet technique for management of cranial cruciate avulsion in a cat. AB - This case report describes the management of cranial cruciate ligament avulsion from the femur of a four-year-old Norwegian Forest cat that presented with a history of lameness which had not improved with conservative treatment. During medial arthrotomy, avulsion of the cranial cruciate ligament from the caudomedial aspect of the lateral femoral condyle was suspected and the torn portion resected. A modified Maquet technique was performed on the left tibia resulting in a rapid improvement in lameness postoperatively. Histopathology of the resected cranial cruciate ligament confirmed avulsion. To the authors' knowledge this is the first reported use of this technique in the cat, and the first of stifle instability due to cranial cruciate ligament avulsion from the femur in the cat. PMID- 23941511 TI - The annual costs of cardiovascular diseases and mental disorders attributable to job strain in France. AB - BACKGROUND: Work stress has become a major occupational risk factor in industrialized countries and an important economic issue. The objective was to estimate the annual costs of coronary heart diseases (CHD) and mental disorders (MD) attributable to job strain exposure according to Karasek's model in France for the year 2003 from a societal perspective. METHODS: We produced attributable fraction estimates which were applied to the number of cases (morbidity and mortality) and the costs of CHD and MD. Relative risk estimates came from a systematic literature review of prospective studies. We conducted meta-analyses based on this selection of studies. Prevalence of exposure to job strain came from the national SUMER survey conducted in France in 2003. Costs included direct medical costs and indirect costs: production losses due to sick leaves and premature deaths. RESULTS: Between 8.8 and 10.2% of CHD morbidity was attributable to job strain, and between 9.4 and 11.2% of CHD mortality was attributable to this exposure for men. Between 15.2 and 19.8% of MD was attributable to job strain for men, and between 14.3 and 27.1% for women. As a whole, between 450 000 and 590 000 cases of diseases and 910-1130 deaths were attributable to job strain for men. From 730 000 to 1 380 000 cases of diseases and from 150 to 280 deaths were attributable to job strain for women. The total number of sick leave days amounted from 5 to 6.6 million days for men, and from 8.5 to 16 million days for women. The total costs of CHD and MD attributable to job strain exposure ranged from 1.8 to 3 billion euros for the year 2003 (0.12 0.19% GDP). Medical costs accounted for 11% of the total costs, value of life costs accounted for 13-15% and sick leave costs for 74-77%. The cost of CHD was estimated at 113-133 million euros and the cost of MD was between 1.7 - 2.8 billion euros in 2003. CONCLUSION: This study on the economic burden of diseases attributable to job strain in France provides relevant insights for policy-makers when defining public health priorities for prevention policies. PMID- 23941513 TI - The identification of novel targets of miR-16 and characterization of their biological functions in cancer cells. AB - BACKGROUND: In eukaryotes, miR-16 is an important microRNA (miRNA) that is involved in numerous biological processes. However, it is not fully understood how miR-16 executes its physiological functions. In the present study, we aimed to identify novel miR-16 targets and study their biological functions. METHODS: Candidate target genes of miR-16 were screened by microarray analysis of mRNA levels in several cancer cell lines with enhanced miR-16. Three bioinformatics algorithms, including TargetScan, PicTar, and miRanda, were used in combination to calculate the miR-16 targets. The expression levels of miR-16 and target mRNA were examined by relative quantification RT-PCR, and the expression levels of target protein were detected by Western blot. Luciferase reporter plasmids were constructed to confirm direct targeting. The effect of miR-16 and target gene on cell viability was evaluated using MTT assays. The effects of miR-16 and target gene on apoptosis and cell cycle distribution were evaluated by flow cytometry analysis. RESULTS: By overexpressing miR-16 in several cancer cell lines and measuring global mRNA levels using microarray analysis, we identified 27 genes that may be regulated by miR-16. After the bioinformatics filtering process, 18 genes were selected as candidate miR-16 targets. Furthermore, we experimentally validated three of these candidates, MAP7 (microtubule-associated protein 7), PRDM4 (PR domain containing 4) and CDS2 (CDP-diacylglycerol synthase 2), as direct targets of miR-16. Finally, we demonstrated that miR-16 targeting MAP7 played a critical role in regulating proliferation but not apoptosis and cell cycle progression in cancer cells. CONCLUSION: In summary, the present study identifies several novel miR-16 targets and illustrates a novel function of miR 16 targeting MAP7 in modulating proliferation in cancer cells. PMID- 23941514 TI - The phosphodiesterase 8B gene rs4704397 is associated with thyroid function, risk of myocardial infarction, and body height: the Tromso study. AB - OBJECTIVE: High serum thyrotropin (TSH) levels predict cardiovascular disease (CVD). Recently several single nucleotide polymorphisms (SNPs) associated with TSH levels have been identified, one of them being the rs4704397 SNP in the phosphodiesterase 8B (PDE8B) gene. If the relation between thyroid function and CVD is causal, one could also expect rs4704397 genotypes to predict CVD and possibly health in general. METHODS: DNA was prepared and genotyping performed for rs4704397 in subjects who participated in the fourth survey of the Tromso Study in 1994-1995 and who were registered with the endpoints myocardial infarction (MI), type 2 diabetes (T2DM), cancer, or death, as well as a randomly selected control group. Similarly, genotyping was performed in subjects who had participated in clinical trials where serum TSH, free T4 (fT4), and free T3 (fT3) were measured. RESULTS: From the Tromso Study, 8938 subjects without thyroid disease or thyroid medication were successfully genotyped for rs4704397. Among these, 2098 were registered with MI, 1025 with T2DM, 2748 with cancer, and 3592 had died. The minor homozygote genotype (A:A) had a median serum TSH level that was 0.29 mIU/L higher than in the major homozygote genotype (G:G). The A:A genotype had a significantly increased risk of MI as compared to the G:G genotype (1.14 [1.00-1.29], hazard ratio [confidence interval], Cox regression with adjustment for age, sex, and body mass index). No significant associations were seen with the other endpoints or CVD risk factors. Furthermore, subjects with the G:G genotype were significantly taller than subjects with the A:A genotype (mean difference 1.5 cm). In 584 subjects with serum TSH, fT4, and fT3 measurements, the subjects with the A:A genotype had significantly higher serum TSH and nonsignificantly lower serum fT3 (mean difference 0.15 pmol/L) levels than subjects with the G:G genotype. CONCLUSION: rs4704397 is associated with thyroid function, risk of MI, and body height. However, confirmation in other cohorts is needed before firm conclusions can be drawn. PMID- 23941515 TI - Treatment of chronic myeloid leukemia elderly patients in the tyrosine kinase inhibitor era. AB - The prevalence of chronic myeloid leukemia (CML) is expected to double in the next 15 years. The introduction of imatinib significantly changed the prognosis of CML, challenging the concept of a fatal disease. Nowdays, imatinib, nilotinib and dasatinib are registered for first-line treatment of CML patients in chronic phase (CP). Considering elderly patients, the most extensively studied TKI is imatinib, that induces a rate of cytogenetic and molecular responses comparable between the younger and the elderly patients. Once a CCgR with imatinib is achieved, the probability to be alive and disease free at 8 years is more than 80%. These results confirm that imatinib has to be considered the first-line treatment for the elderly and that the CCgR is the guide parameter for treatment modulation and the most solid marker of long term outcome. Nevertheless, older patients tolerate imatinib worse in comparison to the younger, and this causes a higher rate of therapy discontinuation and less adherence to chronic treatment. Thus, the toxic profile of each TKI is one of the most important factors driving the choice of the best drug. Another important factor is the potency of the TKI. Since nilotinib and dasatinib are more potent than imatinib in inducing cytogenetic and molecular responses, they could be preferred for increasing the proportion of patients who can achieve deeper molecular responses, allowing treatment discontinuation. This approach is intriguing, but it is still experimental. Another therapeutic strategy could be the identification of the minimal effective dose of TKI in order to maintain the CCgR, but also this approach is under clinical investigation. PMID- 23941517 TI - Autophagy in chronic myeloid leukaemia: stem cell survival and implication in therapy. AB - The insensitivity of Chronic Myeloid Leukaemia (CML) stem cells to Tyrosine Kinase Inhibitor (TKI) treatment is now believed to be the main reason for disease persistence experienced in patients. It has been shown that autophagy, an evolutionarily conserved catabolic process that involves degradation of unnecessary or harmful cellular components via lysosomes, is induced following TKI treatment in CML cells. Of clinical importance, autophagy inhibition, using the anti-malarial drug hydroxychloroquine (HCQ), sensitised CML cells, including primitive CML stem cells, to TKI treatment. In this review we discuss the role of autophagy in the maintenance and survival of stem cells in more detail, with a focus on its role in survival of CML stem cells and the possibility to inhibit this pathway as a way to eliminate persistent CML stem cells in vitro and in patients. PMID- 23941518 TI - Optimization of antimicrobial combined effect of organic acids and temperature on foodborne Salmonella and Escherichia coli in cattle feed by response surface methodology. AB - Despite the importance of feedstuffs and feed ingredients in the food chain, few studies have analyzed the effectiveness of usual methods for the microbial decontamination of feeds. This work aimed to study the combined effect of temperature and organic acids (formic or lactic) on the inactivation of 10 isolates of Salmonella enterica and Escherichia coli obtained from vegetable feed ingredients, including cereals and other processed materials, in cattle feed. A central composite design was used with acid concentrations ranging from 0 to 0.2% (vol/wt) and temperatures from 50 degrees C to 70 degrees C. Second-order models were obtained to predict the survival inhibitions. The results reported in the present study indicate that temperature affects the survivability more significantly than acid concentration, whose effect was isolate dependent. However, after 2 min of treatment, optimal microbial inhibitions were generally achieved at temperatures above 65 degrees C, using 0.1% formic acid or 0.2% lactic acid for Salmonella isolates and around 0.1% lactic acid or 0.2% formic acid for E. coli isolates, respectively. This work provides a set of guidelines helpful to reduce microbial contamination of feeds and highlights the importance of feed-ingredient monitoring to reduce pathogen contamination risk during feed processing. PMID- 23941519 TI - Attachment of bacterial pathogens to a bacterial cellulose-derived plant cell wall model: a proof of concept. AB - This study aimed to establish, as a proof of concept, whether bacterial cellulose (BC)-derived plant cell wall models could be used to investigate foodborne bacterial pathogen attachment. Attachment of two strains each of Salmonella enterica and Listeria monocytogenes to four BC-derived plant cell wall models (namely, BC, BC-pectin [BCP], BC-xyloglucan [BCX], and BC-pectin-xyloglucan [BCPX]) was investigated. Chemical analysis indicated that the BCPX composite (31% cellulose, 45.6% pectin, 23.4% xyloglucan) had a composition typical of plant cell walls. The Salmonella strains attached in significantly (p<0.05) higher numbers (~6 log colony-forming units [CFU]/cm(2)) to the composites than the Listeria strains (~5 log CFU/cm(2)). Strain-specific differences were also apparent with one Salmonella strain, for example, attaching in significantly (p<0.05) higher numbers to the BCX composite than to the other composites. This study highlights the potential usefulness of these composites to understand attachment of foodborne bacteria to fresh produce. PMID- 23941516 TI - Use of single nucleotide polymorphism array technology to improve the identification of chromosomal lesions in leukemia. AB - Acute leukemias are characterized by recurring chromosomal and genetic abnormalities that disrupt normal development and drive aberrant cell proliferation and survival. Identification of these abnormalities plays important role in diagnosis, risk assessment and patient classification. Until the last decade methods to detect these aberrations have included genome wide approaches, such as conventional cytogenetics, but with a low sensitivity (5-10%), or gene candidate approaches, such as fluorescent in situ hybridization, having a greater sensitivity but being limited to only known regions of the genome. Single nucleotide polymorphism (SNP) technology is a screening method that has revolutionized our way to find genetic alterations, enabling linkage and association studies between SNP genotype and disease as well as the identification of alterations in DNA content on a whole genome scale. The adoption of this approach for the study of lymphoid and myeloid leukemias contributed to the identification of novel genetic alterations, such as losses/gains/uniparental disomy not visible by cytogenetics and implicated in pathogenesis, improving risk assessment and patient classification and in some cases working as targets for tailored therapies. In this review, we reported recent advances obtained in the knowledge of the genomic complexity of chronic myeloid leukemia and acute leukemias thanks to the use of high-throughput technologies, such as SNP array. PMID- 23941520 TI - Outcomes of cataract surgery in ocular cicatricial pemphigoid. AB - PURPOSE: To report the outcomes of cataract surgery in ocular cicatricial pemphigoid (OCP). SETTING: L. V. Prasad Eye Institute, Hyderabad, India. DESIGN: Retrospective, interventional case series. METHODS: Patients diagnosed with OCP who had undergone cataract surgery were included. Staging of disease, type of surgery, pre- and postoperative best-corrected visual acuity (BCVA), and number and duration of topical and systemic medications were recorded. Complications and any exacerbation or worsening of disease were noted. RESULTS: Nine eyes of 7 patients (3 male, 4 female) were included in the study, with mean age of 60.44 +/ 2.6 years (range 56-64 years). Follow-up ranged from 6 months to 10 years (mean 52.9 +/- 46.25 months). Surgery performed was extracapsular cataract extraction with posterior chamber intraocular lens implantation (n = 5) or phacoemulsification with posterior chamber intraocular lens implantation (n = 4). Best-corrected visual acuity improved by more than 2 lines in 6 of 9 (66.67%) eyes, which remained stable till the last follow-up. Three eyes had no visual improvement due to corneal scar in 2 patients and preexisting posterior staphyloma in 1 eye. Disease progression was noted in 2 of 9 operated eyes by one stage at the end of 1 year. CONCLUSION: In this series, cataract surgery could be safely performed with no major intra- or postoperative complications. While the surgical intervention itself was not associated with acute exacerbations of inflammation, progression of disease was noted in some cases over time. In spite of ongoing disease, cataract surgery in OCP was associated with stable visual outcomes. PMID- 23941521 TI - Identification of compounds inhibiting the C-S lyase activity of a cell extract from a Staphylococcus sp. isolated from human skin. AB - The C-S lyase activity of bacteria in the human armpit releases highly malodorous, volatile sulfur compounds from nonvolatile precursor molecules. Such compounds significantly contribute to human body odour. Hence, C-S lyase represents an attractive target for anti-body-odour cosmetic products. Here, aiming at a final use in an ethanol-based deodorant formulation, 267 compounds and compound mixtures were screened for their ability to inhibit the C-S lyase activity of a Stapyhlococcus sp. crude extract. Staphylococcus sp. Isolate 128, closely related to Staphylococcus hominis, was chosen as the test bacterium, as it showed a reproducibly high specific C-S lyase activity on three different culturing media. Using a photometric assay and benzylcysteine as substrate, six rather complex, plant-derived compound mixtures and five well defined chemical compounds or compound mixtures were identified as inhibitors, leading to an inhibition of >=70% at concentrations of <=0.5% in the assay. The inhibition data have demonstrated that compounds with two vicinal hydroxyl groups or one hydroxyl and one keto group bound to an aryl residue are characteristic for the inhibition. The substances identified as C-S lyase inhibitors have the potential to improve the performance of anti-body-odour cosmetic products, for example, ethanol-based deodorants. SIGNIFICANCE AND IMPACT OF THE STUDY: Bacterial C-S lyase represents one of the key enzymes involved in human body odour formation. The aim of this study was to identify compounds inhibiting the C-S lyase activity of a Staphylococcus sp. isolate from the human skin. The compounds identified as the best inhibitors are characterized by the following features: two vicinal hydroxyl groups or one hydroxyl and one keto group bound to an aryl residue. They might be used to improve the performance of cosmetic products aiming to prevent the formation of microbially caused human body odour, for example, ethanol-based deodorants. PMID- 23941522 TI - Nanolithography by plasmonic heating and optical manipulation of gold nanoparticles. AB - Noble-metal particles feature intriguing optical properties, which can be utilized to manipulate them by means of light. Light absorbed by gold nanoparticles, for example, is very efficiently converted into heat, and single particles can thus be used as a fine tool to apply heat to a nanoscopic area. At the same time, gold nanoparticles are subject to optical forces when they are irradiated with a focused laser beam, which renders it possible to print, manipulate, and optically trap them in two and three dimensions. Here, we demonstrate how these properties can be used to control the polymerization reaction and thermal curing of polydimethylsiloxane (PDMS) at the nanoscale and how these findings can be applied to synthesize polymer nanostructures such as particles and nanowires with subdiffraction limited resolution. PMID- 23941523 TI - Characterization of the bacterioplankton community and its antibiotic resistance genes in the Baltic Sea. AB - The residues from human environments often contain antibiotics and antibiotic resistance genes (ARGs) that can contaminate natural environments; the clearest consequence of that is the selection of antibiotic-resistant bacteria. The Baltic Sea is the second largest isolated brackish water reservoir on Earth, serving as a drainage area for people in 14 countries, which differ from one another in antibiotic use and sewage treatment policies. The aim of this study was to characterize the bacterioplankton structure and quantify ARGs (tetA, tetB, tetM, ermB, sul1, blaSHV, and ampC) within the bacterioplankton community of the Baltic Sea. Quantitative polymerase chain reaction was applied to quantify ARGs from four different sampling sites of the Baltic Sea over 2 years, and the bacterial communities were profiled sequencing the V6 region of the 16S rRNA gene on Illumina HiSeq2000. The results revealed that all the resistance genes targeted in the study were detectable from the Baltic Sea bacterioplankton. The percentage of tetA, tetB, tetM, ermB, and sul1 genes in the sea bacterial community varied between 0.0077% and 0.1089%, 0.0003% and 0.0019%, 0.0001% and 0.0105%, 0% and 0.0136%, and 0.0001% and 0.0438%, respectively. The most numerous ARG detected was the tetA gene and this gene also had the highest proportion in the whole microbial community. A strong association between bacterioplankton ARGs' abundance data and community phylogenetic composition was found, implying that the abundance of most of the studied ARGs in the Baltic Sea is determined by fluctuations in its bacterial community structure. PMID- 23941524 TI - Hybrid polypeptide micelles loading indocyanine green for tumor imaging and photothermal effect study. AB - Indocyanine green (ICG) is a near-infrared (NIR) fluorescence dye for extensive applications; however, it is limited for further biological application due to its poor aqueous stability in vitro, concentration-dependent aggregation, rapid elimination from the body, and lack of target specificity. To overcome its limitations, ICG was encapsulated in the core of a polymeric micelle, which self assembled from amphiphilic PEG-polypeptide hybrid triblock copolymers of poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu), with PLLeu as the hydrophobic core and PEG as the hydrophilic shell. The ICG was associated with the hydrophobic core via hydrophobic interaction and also the hydrophilic heads through electrostatic attractive interaction. Compared with free ICG, PEG-PLL-PLLeu-ICG micelles significantly improved quantum yield and fluorescent stability. The cellular uptake experiments showed that PEG-PLL-PLLeu ICG micelles have a high cellular uptake rate. And the in vivo experiments revealed the excellent passive tumor targeting ability and long circulation time of PEG-PLL-PLLeu-ICG. The above results indicated the broad prospects of PEG-PLL PLLeu-ICG application in the fields of tumor diagnosis and imaging. In addition, temperature measurements under NIR laser irradiation and in vitro photothermal ablation studies proved the potential application of PEG-PLL-PLLeu-ICG in tumor photothermal therapy. PMID- 23941525 TI - Left-sided scimitar vein causing cyanosis after Fontan operation: successful transcatheter device occlusion using magnetic resonance imaging X-ray fusion. AB - We present the case of a 3-year-old boy with asplenia-type heterotaxy syndrome and functionally single ventricle congenital heart disease who developed cyanosis early after the Fontan operation. Combined cardiac magnetic resonance imaging (MRI) and catheterization identified a large hepatic vein to pulmonary vein connection as the source of right to left shunt. The anatomy was quite unusual, suggesting an underlying diagnosis of mixed total anomalous pulmonary venous connection with left-sided scimitar vein. This pattern of pulmonary venous return has not been previously reported in a patient with asplenia. MRI x-ray fusion was used to guide transcatheter device occlusion of the scimitar vein, resulting in marked clinical improvement. PMID- 23941526 TI - Maternal uterine vascular remodeling during pregnancy. AB - Remodeling of the maternal uterine vasculature during pregnancy is a unique cardiovascular process that occurs in the adult and results in significant structural and functional changes in large and small arteries and veins, and in the creation of the placenta--a new fetomaternal vascular organ. This expansive, hypertrophic process results in increases in both lumen circumference and length, and is effected through a combination of tissue and cellular hypertrophy, endothelial and vascular smooth muscle hyperplasia, and matrix remodeling. This review summarizes what is currently known about the time course and extent of the remodeling process, and how local vs. systemic factors influence its genesis. The main focus is on upstream maternal vessels rather than spiral artery changes, although the latter are considered from the overall hemodynamic perspective. We also consider some of the underlying mechanisms and provide a hypothetical scenario that integrates our current knowledge. Abrogation of this adaptive vascular process is associated with several human gestational pathologies such as preeclampsia and intrauterine growth restriction (IUGR), which not only raise the risk of infant mortality and morbidity but are also a significant source of maternal mortality and susceptibility to cardiovascular and other diseases for both mother and neonate later in life. PMID- 23941527 TI - No role for initial severity on the efficacy of antidepressants: results of a multi-meta-analysis. AB - INTRODUCTION: During the last decade, a number of meta-analyses questioned the clinically relevant efficacy of antidepressants. Part of the debate concerned the method used in each of these meta-analyses as well as the quality of the data set. MATERIALS AND METHODS: The Kirsch data set was analysed with a number of different methods, and eight key questions were tackled. We fit random effects models in both Bayesian and frequentist statistical frameworks using raw mean difference and standardised mean difference scales. We also compare between-study heterogeneity estimates and produce treatment rank probabilities for all antidepressants. The role of the initial severity is further examined using meta regression methods. RESULTS: The results suggest that antidepressants have a standardised effect size equal to 0.34 which is lower but comparable to the effect of antipsychotics in schizophrenia and acute mania. The raw HDRS difference from placebo is 2.82 with the value of 3 included in the confidence interval (2.21-3.44). No role of initial severity was found after partially controlling for the effect of structural (mathematical) coupling. Although data are not definite, even after controlling for baseline severity, there is a strong possibility that venlafaxine is superior to fluoxetine, with the other two agents positioned in the middle. The decrease in the difference between the agent and placebo in more recent studies in comparison to older ones is attributed to baseline severity alone. DISCUSSION: The results reported here conclude the debate on the efficacy of antidepressants and suggest that antidepressants are clearly superior to placebo. They also suggest that baseline severity cannot be utilized to dictate whether the treatment should include medication or not. Suggestions like this, proposed by guidelines or institutions (e.g. the NICE), should be considered mistaken. PMID- 23941529 TI - Didehydroroflamycoin pentaene macrolide family from Streptomyces durmitorensis MS405(T) : production optimization and antimicrobial activity. AB - AIMS: The aim of this study was to improve production of pentaene 32,33 didehydroroflamycoin (DDHR) in Streptomyces durmitorensis MS405 strain to obtain quantities sufficient for in depth analysis of antimicrobial properties. METHODS AND RESULTS: Through classical medium optimization conditions for stable growth, DDHR production within 7 days of incubation was established. Yields of 215 mg l( 1) were achieved in shake flask experiments in complex medium with mannitol as the primary carbon source. DDHR had poor antibacterial activity with minimal inhibitory concentrations (MIC) of 400 MUg ml(-1) for Staphylococcus aureus and Bacillus subtilis, while MIC of 70 MUg ml(-1) was determined for Candida albicans. Using flow cytometry and fluorescent microscopy, it was demonstrated that DDHR induced membrane damage in C. albicans followed by cell death. Combination studies with known antifungal nystatin showed that DDHR is a promising agent for the development of novel antimycotic treatments potentially less toxic for human cells. CONCLUSIONS: Pentaene didehydroroflamycoin has no antibacterial activity but can be further developed for the application in antifungal therapy. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first report on the stable and production in high yields of a novel pentaene family that acts on Candida cell membranes and can be used in combination with known antifungals. Polyenes are still antifungal antibiotics of choice, and therefore, isolation and production of new lead structures are highly significant. PMID- 23941528 TI - SIRT1 but not its increased expression is essential for lifespan extension in caloric-restricted mice. AB - The SIRT1 deacetylase is one of the best-studied putative mediators of some of the anti-aging effects of calorie restriction (CR), but its role in CR-dependent lifespan extension has not been demonstrated. We previously found that mice lacking both copies of SIRT1 displayed a shorter median lifespan than wild-type mice on an ad libitum diet. Here, we report that median lifespan extension in CR heterozygote SIRT1(+/-) mice was identical (51%) to that observed in wild-type mice, but SIRT1(+/-) mice displayed a higher frequency of certain pathologies. Although larger studies in additional genetic backgrounds are needed, these results provide strong initial evidence for the requirement of SIRT1 for the lifespan extension effects of CR, but suggest that its high expression is not required for CR-induced lifespan extension. PMID- 23941531 TI - Improving the capacity of polypropylene to be used in antioxidant active films: incorporation of plasticizer and natural antioxidants. AB - Two types of active antioxidant food packages with improved release properties, based on polypropylene (PP) as one of the most common polymers used in food packaging applications, were developed. Incorporation of catechin and green tea as antioxidant provided PP with 6 times higher stabilization against thermal oxidation. Release of natural antioxidants (catechins, gallic acid, caffeine, and quercetin) into various food simulants from that nonpolar matrix were improved by blending poly(propylene glycol)-block-poly(ethylene glycol)-block-poly(propylene glycol) (PPG-PEG-PPG) as plasticizer into the polymer formulation. Increasing release levels between 10- and 40-fold into simulant A and between 6 and 20-fold into simulant D1 resulted from the incorporation of catechin and green tea as antioxidants and PPG-PEG-PPG as plasticizer into the film formulation. The efficiency of the antioxidants in the food simulants after the release process was also corroborated through antioxidant activity tests. Therefore, the developed PPG-PEG-PPG-modified polypropylene resulted in a potential system to be used in active packaging. PMID- 23941530 TI - Identification of a single amino acid in GluN1 that is critical for glycine primed internalization of NMDA receptors. AB - BACKGROUND: NMDA receptors are ligand-gated ion channels with essential roles in glutamatergic synaptic transmission and plasticity in the CNS. As co-receptors for glutamate and glycine, gating of the NMDA receptor/channel pore requires agonist binding to the glycine sites, as well as to the glutamate sites, on the ligand-binding domains of the receptor. In addition to channel gating, glycine has been found to prime NMDA receptors for internalization upon subsequent stimulation of glutamate and glycine sites. RESULTS: Here we address the key issue of identifying molecular determinants in the glycine-binding subunit, GluN1, that are essential for priming of NMDA receptors. We found that glycine treatment of wild-type NMDA receptors led to recruitment of the adaptor protein 2 (AP-2), and subsequent internalization after activating the receptors by NMDA plus glycine. However, with a glycine-binding mutant of GluN1 - N710R/Y711R/E712A/A714L - we found that treating with glycine did not promote recruitment of AP-2 nor were glycine-treated receptors internalized when subsequently activated with NMDA plus glycine. Likewise, GluN1 carrying a single point mutation - A714L - did not prime upon glycine treatment. Importantly, both of the mutant receptors were functional, as stimulating with NMDA plus glycine evoked inward currents. CONCLUSIONS: Thus, we have identified a single amino acid in GluN1 that is critical for priming of NMDA receptors by glycine. Moreover, we have demonstrated the principle that while NMDA receptor gating and priming share a common requirement for glycine binding, the molecular constraints in GluN1 for gating are distinct from those for priming. PMID- 23941532 TI - Molecular characteristics and differences of effluent organic matter from parallel activated sludge and integrated fixed-film activated sludge (IFAS) processes. AB - A direct comparison between parallel activated sludge and integrated fixed-film activated sludge (IFAS) processes was performed in this study because both treatments received the same primary effluent, although differences may still remain due to different return flow rates. Modern ultrahigh resolution electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry was applied to characterize the complexity of effluent organic matter (EfOM) and to evaluate both processes in their abilities to change the EfOM molecular composition. At different stages during the two processes a direct comparison of the performance and changes in molecular composition of the IFAS with those of the activated sludge was undertaken. Large differences in the molecular composition between both processes were only apparent in the early stage of the aeration cells and the first cell of the IFAS possibly due to the higher flow rate and a delay in aerobic bacterial degradation. Despite the double flow rate (0.263 m(3) s(-1)) in the IFAS reactors compared to the activated sludge, by the end of the treatment the EfOM composition of both processes were undistinguishable from each other. However, a much more complex EfOM was generated in both processes, suggesting that bacteria are responsible for an increase in molecular diversity in the effluent. PMID- 23941534 TI - Polyradicals of polycyclic aromatic hydrocarbons as finite size models of graphene: highly open-shell nature, symmetry breaking, and enhanced-edge electron density. AB - Properties of polyradicals (all CH bonds dissociated) of benzene and certain polycyclic aromatic hydrocarbons (PAHs) were studied. The occurrence of symmetry breaking is revealed in going from benzene and the PAHs to their polyradicals. Polyradicals would serve as finite size models of graphene with unpassivated edges in a more realistic way than the PAHs. Monoradicals (one CH bond dissociated) of benzene and all of the PAHs and higher radicals of benzene and one PAH (two to all CH bonds successively dissociated) were also investigated. Reliability of the methodology employed was ascertained by a comparison of our calculated single CH bond dissociation energy of benzene with the available previous experimental and theoretical results. Besides ground-state geometries, the aspects studied include single and successive CH bond dissociation energies, and electron density, molecular electrostatic potential (MEP), and spin density distributions. All of the monoradicals studied were found to have doublet spin multiplicity, while polyradicals with 4 to 16 rings and zigzag or mixed-type edges were found to have spin multiplicities varying from triplet to 11et. Bond lengths and bond angles of rings located at the edges are appreciably modified in going from PAHs to polyradicals. Electron density and spin density are found to be enhanced at the edges of monoradicals and polyradicals of PAHs, as found previously for PAHs. However, MEP maps of polyradicals have significantly different features from those of monoradicals and PAHs, which has a significant implication. PMID- 23941533 TI - Feasibility study demonstrating that enzymatic template generation and amplification can be employed as a novel method for molecular antimicrobial susceptibility testing. AB - BACKGROUND: Antimicrobial Susceptibility Testing (AST) is a methodology in which the sensitivity of a microorganism is determined via its inability to proliferate in the presence of an antimicrobial agent. Results are reported as minimum inhibitory concentrations (MICs). The present study demonstrates that measurement of DNA polymerase activity via Enzymatic Template Generation and Amplification (ETGA) can be used as a novel means of determining the MIC of a microbe to an antibiotic agent much sooner than the current standardized method. METHODS: Time course analysis of ETGA is presented from bacterial cultures containing antibiotic agents and compared to the end-point results of standard macrobroth method AST. RESULTS: MIC determinations from ETGA results at 4, 6, and 22 hours are compared to the MICs from the standard method and the results are shown to be in agreement. Additionally, reliable AST analysis using ETGA can be performed on bacteria harvested directly from spiked blood cultures. CONCLUSIONS: AST analysis with ETGA is shown to be equivalent to AST analysis using gene-specific qPCR assays against the measured microbe. Future development of this novel method for performing AST in a clinical setting is discussed. PMID- 23941535 TI - Synthesis of raspberry-like poly(styrene-glycidyl methacrylate) particles via a one-step soap-free emulsion polymerization process accompanied by phase separation. AB - We herein report a facile method to prepare raspberry-like poly(styrene-glycidyl methacrylate) [P(S-GMA)] particles with controllable structure via a one-step soap-free emulsion polymerization process accompanied by phase separation. In this method, corona particles with a size of 10-20 nm were produced in situ in the later polymerization stage by the migrating of S-enriched polymers from GMA enriched core particles. The size of the corona particles and the roughness of the raspberry-like particles can be easily controlled by adjusting the amount of styrene (S), glycidyl methacrylate (GMA), and divinylbenzene (DVB). The structure of raspberry-like P(S-GMA) particles was confirmed by transmission electron microscopy, scanning electron microscopy, and atomic force microscopy. A possible mechanism of the formation of raspberry-like particles was proposed. PMID- 23941537 TI - Conservative management of fractures of the third metatarsal bone in the racing greyhound. AB - OBJECTIVE: To assess (2006 to 2012) conservative management for treatment of fractures of the third metatarsal bone (MT3) in racing greyhounds. METHODS: All racing greyhounds with MT3 fractures seen prospectively between 2006 and 2012 were included. Fracture morphology, type of conservative management, outcome and the time to a return to racing were recorded. Outcome was assessed either by communication with the trainer or by accessing the website of the Greyhound Board of Great Britain to find the complete racing history of the dog. RESULTS: Eighteen cases were evaluated. Six had a support dressing and 12 had no external dressings, treatment consisting of kennel rest alone. Two dogs were retired from racing at the time of injury, two dogs sustained other injuries and the remainder (n=14) returned to successful racing with no loss of form. CLINICAL SIGNIFICANCE: Conservative management for MT3 fractures consisting of a programme of exercise restriction carries an excellent prognosis for a return to previous racing form. External support dressings do not appear to be necessary either for the welfare of the dog or for fracture management. PMID- 23941538 TI - Calix[2]thia[4]phyrin: an expanded calixphyrin with aggregation-induced enhanced emission and anion receptor properties. AB - The synthesis of calix[2]thia[4]phyrin 3, a core-modified expanded calixphyrin, by an efficient synthetic route is reported. 3 exhibits an aggregation-induced enhanced emission (AIEE) phenomenon upon addition of increasing amounts of water. This is attributed to the restricted intramolecular rotation of the meso-aryl rings present on the sp(3) bridging carbons. SEM studies revealed the formation of aggregation in an acetonitrile/water mixture with an average diameter of the aggregate in the range 0.38-2.08 MUm. The photoluminescence quantum yield of 3 in 9:1 water/acetonitrile is 5-fold higher than the quantum yield in acetonitrile alone. Single-crystal X-ray analysis of 3 revealed a chairlike conformation stabilized by N-H...N and C-H...pi intramolecular hydrogen-bonding interactions. Fluorine atoms on the meso-pentafluorophenyl groups are involved in C-H...F intermolecular hydrogen-bonding interactions to generate a two-dimensional supramolecular assembly in the solid state. In the diprotonated state, 3 has affinity for anions and forms 1:1 complexes with SO4(2-), NO3(-), Cl(-), and ClO4(-) in solution. The tetrahedral anions bind more strongly than the other anions. Single-crystal X-ray structure studies of the ClO4(-) anion complex with 3 revealed the formation of both 1:1 and 1:2 complexes in the solid state, with the host and the guest being held together by N-H...O hydrogen-bonding interactions. PMID- 23941536 TI - Listening to diverse community voices: the tensions of responding to community expectations in developing a male circumcision program for HIV prevention in Papua New Guinea. AB - BACKGROUND: The success of health programs is influenced not only by their acceptability but also their ability to meet and respond to community expectations of service delivery. The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have recommended medical male circumcision (MC) as an essential component of comprehensive HIV prevention programs in high burden settings. This study investigated community-level perceptions of MC for HIV prevention in Papua New Guinea (PNG), a setting where diverse traditional and contemporary forms of penile foreskin cutting practices have been described. METHODS: A multi-method qualitative study was undertaken in four provinces in two stages from 2009 to 2011. A total of 82 in-depth interviews, and 45 focus group discussions were completed during Stage 1. Stage 2 incorporated eight participatory workshops that were an integral part of the research dissemination process to communities. The workshops also provided opportunity to review key themes and consolidate earlier findings as part of the research process. Qualitative data analysis used a grounded theory approach and was facilitated using qualitative data management software. RESULTS: A number of diverse considerations for the delivery of MC for HIV prevention in PNG were described, with conflicting views both between and within communities. Key issues included: location of the service, service provider, age eligibility, type of cut, community awareness and potential shame amongst youth. Key to developing appropriate health service delivery models was an appreciation of the differences in expectations and traditions of unique cultural groups in PNG. Establishing strong community coalitions, raising awareness and building trust were seen as integral to success. CONCLUSIONS: Difficulties exist in the implementation of new programs in a pluralistic society such as PNG, particularly if tensions arise between biomedical knowledge and medico-legal requirements, compared to existing socio-cultural interests. Community participatory approaches offer important opportunities to explore and design culturally safe, specific and accessible programs. PMID- 23941539 TI - Ethanolic extract of propolis inhibits atherosclerosis in ApoE-knockout mice. AB - BACKGROUND: The present study was undertaken to investigate the effects and underlying mechanism of ethanolic extract of propolis (EEP) on the development of atherosclerotic lesions in ApoE-/- mice. METHODS: Eight-week-old male ApoE-/- mice fed a high-fat diet were treated with EEP (160 mg/kg/d) or vehicle (the same dose) respectively for 14 weeks. The serum levels of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were determined by enzymatic methods. Non-HDL-C was calculated as TC minus HDL-C. Serum interleukin 6 (IL-6), interleukin-17 (IL-17), endothelin (ET), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) were determined with enzyme-linked immunosorbent assay methods. Nitric oxide (NO) content was measured with an enzymatic nitrate reductase assay. Analyses of atherosclerotic lesions in whole aorta and aortic root sections were performed with plaque staining using Oil Red O. RESULTS: Compared with the vehicle-treated group, serum contents of total cholesterol (TC), triglycerides (TG) and non-HDL-C reduced significantly by 31.88%, 21.01%, and 27.11% respectively in the EEP-treated group. Administration of EEP decreased the level of IL-6 and increased the level of IL-17 in ApoE-/- mice with a high-fat diet. Compared with the vehicle-treated group,EEP significantly reduced the levels of ET and VEGF,and showed a trend to increase NO and inhibit iNOS. In the ApoE-/- mice fed a high-fat diet, EEP significantly reduced atherosclerotic lesion development in the aortic root and whole aorta. CONCLUSION: EEP can inhibit atherosclerotic lesion formation in ApoE /- mice fed a high-fat diet possibly through modulating cholesterol, regulating inflammatory reaction,inhibiting ET and VEGF, and protecting vascular endothelial cells. PMID- 23941540 TI - Subclinical thyroid dysfunction and functional capacity among elderly. AB - BACKGROUND: Subclinical thyroid dysfunction is common among older people and has been associated with decreased functional capacity but with conflicting data. The aim of this study was to assess the association between subclinical thyroid dysfunction and functional capacity in an elderly population. METHODS: We included 5182 participants with a mean age of 75.2 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Self-reported functional capacity was assessed using the Barthel Index (BI) and the Instrumental Activities of Daily Living (IADL) scores at baseline and during follow-up. Participants with subclinical hyperthyroidism (n=65) and subclinical hypothyroidism (n=173) were compared to euthyroid participants (n=4944). The association between persistent subclinical thyroid dysfunction and functional capacity and decline was also investigated. RESULTS: At baseline, compared to euthyroid participants (BI 19.73+/-SE 0.06; IADL 13.52+/-0.02), there was no difference in functional capacity for participants with subclinical hyperthyroidism (BI 19.60+/-0.09; IADL 13.51+/-0.12, p>0.05) or subclinical hypothyroidism (BI 19.82+/-0.06; IADL 13.55+/-0.08, p>0.05). Over a mean 3.2-year follow-up period, there was no association between thyroid function and annual decline of either BI or IADL (p>0.05). No association was found between persistent subclinical thyroid dysfunction and functional capacity at baseline or during follow-up (p>0.05). Results were similar after excluding participants with a maximum BI and/or IADL score at baseline. CONCLUSION: Among well-functioning community-dwelling elderly, we found no evidence that subclinical thyroid dysfunction contributes to decreased functional capacity. PMID- 23941541 TI - Identification and characterization of an archaeal ketopantoate reductase and its involvement in regulation of coenzyme A biosynthesis. AB - Coenzyme A (CoA) biosynthesis in bacteria and eukaryotes is regulated primarily by feedback inhibition towards pantothenate kinase (PanK). As most archaea utilize a modified route for CoA biosynthesis and do not harbour PanK, the mechanisms governing regulation of CoA biosynthesis are unknown. Here we performed genetic and biochemical studies on the ketopantoate reductase (KPR) from the hyperthermophilic archaeon Thermococcus kodakarensis. KPR catalyses the second step in CoA biosynthesis, the reduction of 2-oxopantoate to pantoate. Gene disruption of TK1968, whose product was 20-29% identical to previously characterized KPRs from bacteria/eukaryotes, resulted in a strain with growth defects that were complemented by addition of pantoate. The TK1968 protein (Tk KPR) displayed reductase activity specific for 2-oxopantoate and preferred NADH as the electron donor, distinct to the bacterial/eukaryotic NADPH-dependent enzymes. Tk-KPR activity decreased dramatically in the presence of CoA and KPR activity in cell-free extracts was also inhibited by CoA. Kinetic studies indicated that CoA inhibits KPR by competing with NADH. Inhibition of ketopantoate hydroxymethyltransferase, the first enzyme of the pathway, by CoA was not observed. Our results suggest that CoA biosynthesis in T. kodakarensis is regulated by feedback inhibition of KPR, providing a feasible regulation mechanism of CoA biosynthesis in archaea. PMID- 23941542 TI - Intraoperative dexamethasone implant in uveitis patients with cataract undergoing phacoemulsification. AB - PURPOSE: To study the role of intraoperative intravitreal dexamethasone implant in patients of uveitis with cataract undergoing phacoemulsification. METHODS: This prospective study included 20 patients with uveitis and cataract who underwent phacoemulsification with intraocular lens implantation. Ten patients (10 eyes) received an intravitreal dexamethasone implant intraoperatively (implant group), and 10 patients (10 eyes) received oral steroids (steroid group). Outcome measures were best-corrected visual acuity (BCVA), intraocular pressure (IOP), and central macular thickness (CMT). RESULTS: The logMar BCVA improved from 0.93 +/- 0.49 to 0.23 +/- 0.23 and from 1.29 +/- 0.47 to 0.22 +/- 0.16 in the implant and steroid groups, respectively. Postoperative IOP and CMT showed no statistically significant differences between the two groups. None of the patients in either group had significant IOP rise requiring any surgical intervention. CONCLUSIONS: A single intraoperative intravitreal dexamethasone implant during phacoemulsification in patients of uveitis with cataract seems to be an effective alternative for postoperative oral steroids. PMID- 23941543 TI - The development of an integrated care model for patients with severe or very severe chronic obstructive pulmonary disease (COPD): the COPD-Home model. AB - BACKGROUND: Adherence to guidelines for managing stable chronic obstructive pulmonary disease (COPD) and its exacerbations is inadequate among healthcare workers and patients. An appropriate care model would meet patient needs, enhance their coping with COPD and improve their quality of life (QOL). AIM: This study aims to present the 'COPD-Home' as an integrated care model for patients with severe or very severe COPD. MODEL: One principle of the COPD-Home model is that hospital treatment should lead to follow up in the patient's home. The model also includes education, improved coordination of levels of care, improved accessibility and a management plan. One of the main elements of the COPD-Home model is the clear role of the home-care nurse. Model development is based on earlier research and clinical experience. It comprises: (i) education provided through an education programme for patients and involved nurses, (ii) joint visits and telephone checks, (iii) a call centre for support and communication with a general practitioner and (iv) an individualised self-management plan including home monitoring and a plan for pharmacological and nonpharmacological interventions. CONCLUSION: The COPD-Home model attempts to cultivate competences and behaviours of patients and community nurses that better accord with guidelines for interventions. The next step in its development will be to evaluate its ability to assist both healthcare workers and planners to improve the management of COPD, reduce exacerbations and improve QOL and coping among patients with COPD. PMID- 23941544 TI - Molecular layer deposition on carbon nanotubes. AB - Molecular layer deposition (MLD) techniques were used to deposit conformal coatings on bulk quantities of carbon nanotubes (CNTs). Several metalcone MLD chemistries were employed, including alucone (trimethylaluminum/glycerol and trimethylaluminum/ethylene glycol), titanicone (TiCl4/glycerol), and zincone (diethyl zinc/glycerol). The metalcone MLD films grew directly on the CNTs and MLD initiation did not require atomic layer deposition (ALD) of an adhesion layer. Transmission electron microscopy revealed that MLD formed three dimensional conformal deposits throughout a CNT scaffold. Mechanical testing was also performed on sheets of CNT networks coated by MLD. Young's Modulus values improved from an initial value of 510 MPa for uncoated CNT sheet to values that ranged from 2.2 GPa, for 10 nm of glycerol alucone (AlGL), to 8.7 GPa for a composite 5 nm AlGL + 5 nm Al2O3 coating. PMID- 23941545 TI - Polymerization-induced self-assembly of galactose-functionalized biocompatible diblock copolymers for intracellular delivery. AB - Recent advances in polymer science are enabling substantial progress in nanobiotechnology, particularly in the design of new tools for enhanced understanding of cell biology and for smart drug delivery formulations. Herein, a range of novel galactosylated diblock copolymer nano-objects is prepared directly in concentrated aqueous solution via reversible addition-fragmentation chain transfer polymerization using polymerization-induced self-assembly. The resulting nanospheres, worm-like micelles, or vesicles interact in vitro with galectins as judged by a turbidity assay. In addition, galactosylated vesicles are highly biocompatible and allow intracellular delivery of an encapsulated molecular cargo. PMID- 23941546 TI - Adaptation of Dekkera bruxellensis to lignocellulose-based substrate. AB - Adaptation of Dekkera bruxellensis to lignocellulose hydrolysate was investigated. Cells of D. bruxellensis were grown for 72 and 192 H in batch and continuous culture, respectively (adapted cells). Cultivations in semisynthetic medium were run as controls (nonadapted cells). To test the adaptation, cells from these cultures were reinoculated in the lignocellulose medium, and growth and ethanol production characteristics were monitored. Cells adapted to lignocellulose hydrolysate had a shorter lag phase, grew faster, and produced a higher ethanol concentration as compared with nonadapted cells. A stability test showed that after cultivation in rich medium, cells partially lost the adapted phenotype but still showed faster growth and higher ethanol production as compared with nonadapted cells. Because alcohol dehydrogenase genes have been described to be involved in the adaptation to furfural in Saccharomyces cerevisiae, an analogous mechanism of adaptation to lignocelluloses hydrolysate of D. bruxellensis was hypothesized. However, gene expression analysis showed that genes homologous to S. cerevisiae ADH1 were not involved in the adaptation to lignocelluloses hydrolysate in D. bruxellensis. PMID- 23941547 TI - Sparse evidence for equine or avian influenza virus infections among Mongolian adults with animal exposures. AB - In recent years, Mongolia has experienced recurrent epizootics of equine influenza virus (EIV) among its 2.1 million horses and multiple incursions of highly pathogenic avian influenza (HPAI) virus via migrating birds. No human EIV or HPAI infections have been reported. In 2009, 439 adults in Mongolia were enrolled in a population-based study of zoonotic influenza transmission. Enrollment sera were examined for serological evidence of infection with nine avian, three human, and one equine influenza virus strains. Seroreactivity was sparse among participants suggesting little human risk of zoonotic influenza infection. PMID- 23941548 TI - Alpha-1 acid glycoprotein reduces hepatic leukocyte recruitment in murine models of either early endotoxemia or early sepsis. AB - OBJECTIVE: To characterize the effect of systemically administered AGP on early leukocyte recruitment in the livers of endotoxemic or septic mice and to determine whether this is influenced by LPS sequestration. METHODS: Endotoxemia was induced in C57Bl/6 mice via intraperitoneal injection of LPS. Sepsis was induced in mice by cecal ligation and perforation. AGP (165 mg/kg) or saline (20 mL/kg) or HAS (200 mg/kg) was administered immediately after surgery or LPS injection and the hepatic microcirculation was examined by intravital microscopy at four hour. RESULTS: Leukocyte adhesion in the PSV was reduced by treatment with AGP in mice subjected to either LPS or CLP protocols compared to either saline or HAS treatment. AGP-treated mice also had significantly higher sinusoidal flow in both models. Pre-incubation of LPS with AGP reduced the ability of LPS to recruit leukocytes to the liver microcirculation. CONCLUSIONS: AGP was more effective in limiting hepatic inflammation and maintaining perfusion than saline or HAS, in both endotoxemic and septic mice. AGP sequestration of LPS may contribute to its anti-inflammatory effects. PMID- 23941550 TI - There are some big changes in Health Expectations. PMID- 23941549 TI - Use of dexmedetomidine for prophylactic analgesia and sedation in delayed extubation patients after craniotomy: a study protocol and statistical analysis plan for a randomized controlled trial. AB - BACKGROUND: Pain and agitation are common in patients after craniotomy. They can result in tachycardia, hypertension, immunosuppression, increased catecholamine production and increased oxygen consumption. Dexmedetomidine, an alpha-2 agonist, provides adequate sedation without respiratory depression, while facilitating frequent neurological evaluation. METHODS/DESIGN: The study is a prospective, randomized, double-blind, controlled, parallel-group design. Consecutive patients are randomly assigned to one of the two treatment study groups, labeled 'Dex group' or 'Saline group.' Dexmedetomidine group patients receive a continuous infusion of 0.6 MUg/kg/h (10 ug/ml). Placebo group patients receive a maintenance infusion of 0.9% sodium chloride for injection at a volume and rate equal to that of dexmedetomidine. The mean percentages of time in optimal sedation, vital signs, various and adverse events, the percentage of patients requiring propofol for rescue to achieve/maintain targeted sedation (Sedation-Agitation Scale, SAS 3 to 4) and total dose of propofol required throughout the study drug infusion are collected. The percentage of patients requiring fentanyl for additional rescue to analgesia and total dose of fentanyl required are recorded. The effects of dexmedetomidine on hemodynamic and recovery responses during extubation are measured. Intensive care unit and hospital length of stay also are collected. Plasma levels of epinephrine, norepinephrine, dopamine, cortisol, neuron-specific enolase and S100-B are measured before infusion (T1), at two hours (T2), four hours (T3) and eight hours (T4) after infusion and at the end of infusion (T5) in 20 patients in each group. DISCUSSION: The study has been initiated as planned in July 2012. One interim analysis advised continuation of the trial. The study will be completed in July 2013. TRIAL REGISTRATION: ClinicalTrials (NCT): ChiCTR-PRC 12002903. PMID- 23941553 TI - Type III hypersensitivity reaction with immune complex deposition in 2 critically ill dogs administered human serum albumin. AB - OBJECTIVE: To describe 2 cases of vasculitis that were attributed to a type III hypersensitivity reaction in critically ill dogs occurring 8-16 days postadministration of human serum albumin (HSA). CASE OR SERIES SUMMARY: Skin biopsies were obtained from 3 different sites in 2 critically ill dogs that developed vasculitis 8-16 days following treatment with HSA. Histopathological findings from both dogs indicated epidermal pallor, widespread edema and hemorrhage, degenerative neutrophilic perivascular infiltrates, and multifocal areas of neutrophilic or leukocytoclastic vasculitis. Immunohistochemical staining using an anti-human serum albumin rabbit antibody suggested that the antigen-antibody complexes seen in the dermis were associated with the administration of HSA. NEW OR UNIQUE INFORMATION PROVIDED: In this case series, we documented a leukocytoclastic vasculitis and probable antigen-antibody complexes to human albumin in the dermis of 2 critically ill dogs after administration of HSA. Previously, type III hypersensitivity reactions had only been reported in healthy dogs that had received HSA. This report also describes the potential use of immunohistochemical staining to detect the HSA antigen in tissue sections through the use of specifically labeled antibodies. PMID- 23941552 TI - Vascular endothelial cells facilitated HCC invasion and metastasis through the Akt and NF-kappaB pathways induced by paracrine cytokines. AB - BACKGROUND: It is well documented that cancer cells secrete angiogenic factors to recruit and sustain tumor vascular networks. However, little is known about the effects of endothelial cells on the behavior of tumor cells. The study here was to determine the roles of endothelial cells in HCC cell growth, migration and invasion. METHODS: A mixture of highly metastatic MHCC97H cells and HUVEC cells, as well as MHCC97H cells alone were subcutaneously injected into nude mice to observe the effects of HUVECs on HCC growth. The biological characteristics of MHCC97H cells respectively treated with conditioned medium (CM) derived from HUVECs and endothelial cell basal medium (EBM) in vitro, such as proliferation, migration and invasion, invasion/metastasis associated gene expression, were comparatively analyzed. Differential cytokines between CM and EBM were screened and identified using human cytokine array. Effects of the interested differential cytokine CCL2, IL-8 and CXCL16 and its related signaling pathways were further investigated in HCC cells. RESULTS: Subcutaneous tumorigenicity of MHCC97H cells in nude mice was promoted by HUVECs and its invasion/metastasis associated genes were significantly upregulated. The in vitro, proliferation, migration and invasion of HCC cells treated with CM were all significantly enhanced as compared to those with EBM stimulation. Simultaneously, PI3K/Akt and ERK1/2 pathway in HCC cells were activated by CM. Total of 25 differential cytokines were identified between CM and EBM such as angiopoietin-2, CCL2 (MCP-1), uPA, endostatin, CXCL16, IL-8, pentraxin 3 etc. The selected differential cytokines CCL2, IL-8 and CXCL16 all modulated the expressions of HCC invasion/metastasis genes, especially MMP2 and MMP9. In exposure to CCL2 or CXCL16 alone, upregulation in AKT phosphorylation but no change in ERK phosphorylation were found in MHCC97H cells, moreover the contents of nuclear transcription factor NF-kappaB were increased as compared to the control. However, no effects on the activation of Akt and ERK pathway in MHCC97H were found in exposure to IL-8. CONCLUSION: This study expands the contribution of endothelial cells to the progression of HCC. It unveils a new paradigm in which endothelial cells function as initiators of molecular crosstalks that enhance survival, migration and invasion of HCC cells. PMID- 23941554 TI - Detection of biological contaminants on foods and food surfaces using laser induced breakdown spectroscopy (LIBS). AB - The rapid detection of biological contaminants, such as Escherichia coli O157:H7 and Salmonella enterica , on foods and food-processing surfaces is important to ensure food safety and streamline the food-monitoring process. Laser-induced breakdown spectroscopy (LIBS) is an ideal candidate technology for this application because sample preparation is minimal and results are available rapidly (seconds to minutes). Here, multivariate regression analysis of LIBS data is used to differentiate the live bacterial pathogens E. coli O157:H7 and S. enterica on various foods (eggshell, milk, bologna, ground beef, chicken, and lettuce) and surfaces (metal drain strainer and cutting board). The type (E. coli or S. enterica) of bacteria could be differentiated in all cases studied along with the metabolic state (viable or heat killed). This study provides data showing the potential of LIBS for the rapid identification of biological contaminants using spectra collected directly from foods and surfaces. PMID- 23941556 TI - Food losses and waste in China and their implication for water and land. AB - Conventional approaches to food security are questionable due to their emphasis on food production and corresponding neglect of the huge amount of food losses and waste. We provide a comprehensive review on available information concerning China's food losses and waste. The results show that the food loss rate (FLR) of grains in the entire supply chain is 19.0% +/- 5.8% in China, with the consumer segment having the single largest portion of food waste of 7.3% +/- 4.8%. The total water footprint (WF) related to food losses and waste in China in 2010 was estimated to be 135 +/- 60 billion m(3), equivalent to the WF of Canada. Such losses also imply that 26 +/- 11 million hectares of land were used in vain, equivalent to the total arable land of Mexico. There is an urgent need for dialogue between actors in the supply chain, from farmer to the consumer, on strategies to reduce the high rates of food losses and waste and thereby make a more worthwhile use of scarce natural resources. PMID- 23941555 TI - AtCTF7 is required for establishment of sister chromatid cohesion and association of cohesin with chromatin during meiosis in Arabidopsis. AB - BACKGROUND: The establishment of sister chromatid cohesion followed by its controlled release at the metaphase to anaphase transition is necessary for faithful segregation of chromosomes in mitosis and meiosis. Cohesion is established by the action of Ctf7/Eco1 on the cohesin complex during DNA replication following loading of cohesin onto chromatin by the Scc2-Scc4 complex. Ctf7 is also required for sister chromatid cohesion during repair of DNA double strand breaks. Ctf7 contains an acetyltransferase domain and a zinc finger motif and acetylates conserved lysine residues in the Smc3 subunit of cohesin. In Arabidopsis CTF7 is encoded by a single gene and mutations in AtCTF7 cause embryo lethality indicating that the gene is essential. RESULTS: To study the function of Ctf7 in plants and to determine its role in sister chromatid cohesion, we constructed a conditional allele of AtCTF7 in Arabidopsis using an inducible RNA interference (RNAi) strategy, so as to avoid the embryo lethality caused by mutations in AtCTF7. We found that induction of RNAi against AtCTF7 caused severe inhibition and defects in growth during vegetative and reproductive stages as well as sterility. AtCTF7-RNAi plants displayed chromosome fragmentation and loss of sister chromatid cohesion during meiosis. Immunostaining for the cohesion subunit AtSCC3 showed a marked reduction in association of cohesin with chromatin during meiosis in AtCTF7-RNAi plants. CONCLUSIONS: We find that AtCTF7 is essential for sister chromatid cohesion during meiosis in Arabidopsis and is required for association of cohesin with chromatin in prophase of meiosis. PMID- 23941557 TI - Hydrated polyamide membrane and its interaction with alginate: a molecular dynamics study. AB - The properties of the hydrated amorphous polyamide (PA) membrane and its binding with alginate are investigated through molecular dynamics simulations. The density of the hydrated membrane, surface morphology, and water diffusion near and inside the membrane are compared to other studies. Particular focus is given to the steered molecular dynamics (SMD) simulation of the binding between the PA membrane and an alginate model. The PA surface composition is determined on the basis of experimental measurements of the oxygen/nitrogen (O/N) ratio. The surface model is built using a configurational-bias Monte Carlo technique. The consistent valence force field (CVFF) is used to describe the atomic interactions in the membrane-foulant system. Simulation results show that the carboxylate groups in both the PA surface and alginate exhibit strong binding with metal ions. This binding mechanism plays a major role in the PA-alginate fouling through the formation of an ionic binding bridge. Specifically, Ca(2+) ions have stronger binding with the carboxylate group than Na(+) ions, while the binding breakdown time is shorter for Ca(2+) than Na(+) because of the comparably higher hydration free energy of Ca(2+) ions with water molecules. PMID- 23941558 TI - Vitamin D modulates prostaglandin E2 synthesis and degradation in human lung fibroblasts. AB - Vitamin D insufficiency has been increasingly recognized in the general population worldwide and has been associated with several lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), and respiratory tract infections. Fibroblasts play a critical role in tissue repair and remodeling, which is a key feature of COPD and asthma. Fibroblasts modulate tissue repair by producing and modifying extracellular matrix components and by releasing mediators that act as autocrine or paracrine modulators of tissue remodeling. The current study was designed to investigate if vitamin D alters fibroblast release of key autocrine/paracrine repair factors. First, we demonstrated that human fetal lung (HFL)-1 cells express the vitamin D receptor (VDR) and that vitamin D, 25-hydroxyvitamin D [25(OH)D], or 1,25-dihydroxyvitamin D [1,25(OH)2D] induce VDR nuclear translocation and increase VDR-DNA binding activity. We next demonstrated that vitamin D, 25(OH)D, and 1,25(OH)2D significantly reduced prostaglandin (PG)E2 production by human lung fibroblasts (HFL-1) but had no effect on transforming growth factor beta1, vascular endothelial growth factor, or fibronectin production. Vitamin D, 25(OH)D, and 1,25(OH)2D significantly inhibited IL-1beta-induced microsomal PGE synthase (mPGES)-1 expression; in contrast, all three forms of vitamin D stimulated 15 hydroxy PG dehydrogenase, an enzyme that degrades PGE2. Cyclooxygenase-1 and -2 and the other two PGE2 synthases (mPGES-2 and cytosolic PGE synthase) were not altered by vitamin D, 25(OH)D, or 1,25(OH)2D. Finally, the effect of PGE2 inhibition by 25(OH)D was observed in adult lung fibroblasts. These findings suggest that vitamin D can regulate PGE2 synthesis and degradation and by this mechanism can modulate fibroblast-mediated tissue repair function. PMID- 23941559 TI - Microwave spectrum and molecular structure of vinyl chloride-acetylene, a side binding complex. AB - The structure of the gas-phase bimolecular complex formed between vinyl chloride and acetylene is determined using a combination of broad-band, chirped-pulse, and narrow-band, Balle-Flygare Fourier transform microwave spectroscopy from 5.8 to 20.7 GHz. Although all previous examples of complexes formed between protic acids and haloethylenes are observed to have similar modes of binding regardless of the specific identity of the acid, HF, HCl, or HCCH, the vinyl chloride-HCCH complex has HCCH located at one end of the vinyl chloride with the secondary interaction occurring with the geminal hydrogen atom as opposed to the "top" binding configuration found for vinyl chloride-HF. Nevertheless, the details of the structure, such as hydrogen bond length (3.01 A) and amount of deviation from linearity (58.5 degrees ), do reflect the strength of the interaction and show clear correlations with the gas-phase acidity. Comparison with analogous complexes allows the determination of the relative importance of electrostatic interactions and steric requirements in leading to the observed structures. PMID- 23941560 TI - Theoretical Study of Fluorescence Spectra Utilizing the pKa Values of Acids in Their Excited States. AB - Assignment of the fluorescence spectrum of firefly luciferin in aqueous solutions was achieved by utilizing not only emission energies but also theoretical absorption spectra and relative concentrations as estimated by pKa values. Calculated Gibbs free energies were utilized to estimate pKa values. These pKa values were then corrected by employing the experimental results. It was previously thought that the main peak near 550 nm observed in the experimental fluorescence spectra at all pH values corresponds to emission from the first excited state of the luciferin dianion [Ando et al. (2010) Jpn. J. Appl. Phys. 49, 117002-117008]. However, we found that the peak near 550 nm at low pH corresponds to emission from the first excited state of the phenolate monoanion of luciferin. Furthermore, we found that the causes of the red fluorescence at pH 1-2 are not only the emission from phenol monoanion but also the emission from the protonated species at nitrogen atom in the thiazoline ring of dianion. PMID- 23941561 TI - Experimental mechanistic studies of the tail-to-tail dimerization of methyl methacrylate catalyzed by N-heterocyclic carbene. AB - We and others have previously reported the intermolecular umpolung reactions of Michael acceptors catalyzed by an N-heterocyclic carbene (NHC). The representative tail-to-tail dimerization of methyl methacrylate (MMA) has now been intensively investigated, leading to the following conclusions: (1) The catalysis involves the deoxy-Breslow intermediate, which is quite stable and remains active after the catalysis. (2) Addition of the intermediate to MMA and the final catalyst elimination are the rate-limiting steps. Addition of the NHC to MMA and the proton transfers are relatively very rapid. (3) The two alkenyl protons of the first MMA undergo an intermolecular transfer to C3 and C5 of the dimer. (4) The initial proton transfer is intermolecular. (5) Compared with the benzoin condensation, noticeable differences in the kinetics, reversibility, and stability of the intermediates are observed. PMID- 23941562 TI - Comparative measurement of aortic root by transthoracic echocardiography in normal Korean population based on two different guidelines. AB - BACKGROUND: Aortic root size is an important parameter in vascular diseases and can be easily assessed by transthoracic echocardiography. However, measurements values may vary according to cardiac cycle and the definition used for edge. This study aimed to define normal values according to the measurement method specified by two different guidelines to determine the influence of the different methods on echocardiographic measurements. METHODS: Healthy Korean adults were enrolled. The aortic root diameters were measured twice at four levels (aortic annulus, sinuses of Valsalva, sinotubular junction, and ascending aorta) by the 2005 American Society of Echocardiography (ASE) guidelines (measured from leading edge to leading edge during diastole) and the 2010 ASE pediatric guidelines (measured from inner edge to inner edge during systole). RESULTS: One hundred twelve subjects aged 20-69 years were enrolled. The aortic diameters (cm) determine by the aforementioned two guidelines showed significant difference. Measurements were larger in 2005 ASE guideline at aortic annuls, sinuses of Valsalva, and sinotubular junction level, but smaller at ascending aortic level with 2-3mm of differences. Intraobserver variability was similarly good, but interobserver variability was slightly higher than intraobserver variability in both measurement methods. BSA and age was most important determinant for aortic root size. CONCLUSIONS: The measurement method of aortic root can affect the echocardiographic result. The measurement method should be noted when assessing clinical significance of aortic root measurement. PMID- 23941563 TI - Implementation of the participatory approach to increase supervisors' self efficacy in supporting employees at risk for sick leave; design of a randomised controlled trial. AB - BACKGROUND: The burden of sick leave for society and organisations underlines the urgent need to prevent sick leave. An effective workplace intervention for organisations to shorten sick leave episodes is the Participatory Approach (PA). In this study, we hypothesize that implementation of the PA for supervisors within organisations may prevent sick leave as well. However, implementation of the PA within an organisation is difficult, and barriers at different levels (employee, supervisor and organisational) exist. Therefore, the primary aim of this study is to evaluate the effectiveness of a multifaceted implementation strategy of the PA. METHODS: In a cluster randomised controlled trial (RCT) a multifaceted implementation of the PA will be compared with a minimal implementation strategy of the PA. Participating organisations are a university medical centre, a university and a steel factory. Randomisation will take place at department level. Intervention departments will receive a multifaceted implementation strategy of the PA, which incorporates a working group, supervisor training, and supervisor coaching. Control departments will receive the minimal implementation strategy of the PA, consisting of written information only. The primary outcome measure is self-efficacy of supervisors in joint problem solving to improve work functioning of employees with health complaints and to prevent sick leave. A secondary outcome measure at supervisor level is self-efficacy in communicating with employees about situations of reduced work functioning or being at risk for sick leave. Secondary outcome measures at employee level are attitude, self-efficacy, and social influence, with regard to addressing situations of reduced work functioning or being at risk for sick leave, as well as work functioning, psychological well being, and sick leave. Measurements will take place at baseline, and after six and twelve months follow-up. A process evaluation will be performed as well. DISCUSSION: This study will be relevant for all organisations with employees at risk for sick leave in health care, education, and industry. Study results will give an insight into the effectiveness of the multifaceted implementation strategy of the PA for supervisors to improve work functioning of employees with health complaints, and to prevent sick leave. PMID- 23941564 TI - Personal dignity in the terminally ill from the perspective of caregivers: a survey among trained volunteers and physicians. AB - BACKGROUND: Although dignity is increasingly considered a goal of palliative care, little research has evaluated the understanding of dignity at the end of life from a caregiver's perspective. OBJECTIVE: The study objective was to investigate and compare the views of trained volunteers and SCEN physicians on maintaining dignity for patients reaching the end of life. DESIGN: The study is a survey questionnaire study. SUBJECTS: Subjects were two groups of caregivers involved in care for dying patients: trained volunteers (n=236) and end-of-life consultants (SCEN physicians; n=427). MEASUREMENTS: Measurement was done via the Dutch version of the 22-item Patient Dignity Inventory on symptoms and experiences that have been shown to influence the sense of dignity in terminally ill patients. Respondents were asked to rate on a five-point scale the extent to which they considered the items as influential on dignity in terminally ill patients, and as problematic in practice in maintaining dignity for patients in the last phase of life. RESULTS: Overall, volunteers indicated items more frequently as influential to dignity and as problematic in maintaining dignity at the end of life, compared to SCEN physicians. Volunteers gave significantly higher ratings than SCEN physicians to most of the social items, and to half of the psychological and existential items. CONCLUSIONS: It seems that SCEN physicians consider the physical aspects of suffering to be most influential and problematic in practice in preserving dignity, while volunteers think psychosocial aspects are most important in preserving dignity at the end of life. These findings suggest that the role and responsibilities of caregivers involved in care for terminally ill patients affect the factors that they think influence dignity. PMID- 23941565 TI - Evaluation of the English version of the End-of-Life Nursing Education Questionnaire. AB - BACKGROUND: End-of-Life Nursing Education Consortium (ELNEC) train-the-trainer workshops prepare participants to teach ELNEC content to others. In 2010, researchers in Japan developed and validated the End-of-Life Nursing Education Questionnaire (ELNEQ) to measure the impact of ELNEC workshops on participants' readiness to teach the content. OBJECTIVE: The study's objective was to evaluate the psychometric properties of the English version of the ELNEQ. DESIGN AND SUBJECTS: The study was a pre-test/posttest cross-sectional survey design with 113 participants. MEASUREMENTS: The English version of the ELNEQ is composed of 20 items measuring five domains related to teaching end-of-life (EOL) content: confidence in teaching; motivation for teaching; preparedness to teach; preparedness to lead initiatives; and expected influence on participants. RESULTS: Reliability was established for all domains (Cronbach's alpha+/-range 0.83-0.99) and the scale as a whole (Cronbach's alpha+/-= 0.92), as was content validity at the item level. Confirmatory factor analysis showed excellent fit for both the first order and second order factor models. Sensitivity was confirmed as comparisons between pre- and posttest results on all scales and overall were significant. CONCLUSIONS: The English version of the ELNEQ is a psychometrically sound instrument for measuring the impact of ELNEC train-the-trainer workshops. PMID- 23941566 TI - Effects of diphenyl diselenide and diphenyl ditellurite on chicken embryo development. AB - Studies of our group has demonstrated that (PhSe)2 plays some pharmacologic activities. In addition, it is possible that this compound would be an alternative source of organic selenium in animal foods. However, previous works showed that diphenyl diselenide (PhSe)2 and diphenyl ditelluride (PhTe)2 are toxic for mammals, but their undesirable effects were never tested in avian models. Then, the present study was carried to examine the possible teratogenic effects of (PhSe)2 and (PhTe)2 on chicken embryo development. The eggs were injected with (PhSe)2 at 0, 1 and 10 nmol or with (PhTe)2 at 4 nmol. The control was injected with 10 ul of soya bean oil (vehicle). In order to determine the possible toxic effect of these chemicals, we measure the embryo dimensions, the encephalon, heart and liver weight, thiobarturic acid reactive species (TBARS) level and the delta-aminonevulinate dehydratase (ALA-D) activity. (PhSe)2 and (PhTe)2 did not affect the embryo dimensions. Treatment with (PhSe)2 at 10 nmol per egg caused a increase on TBARS level and on ALA-D activity of the liver tissue, whereas (PhTe)2 decreased encephalon weight, had a tendency to increase to increase TBARS level but did not affect ALA-D activity. Taken together, these results indicate that (PhSe)2 and (PhTe)2 are slightly toxic for chicken embryos. Furthermore, (PhTe)2 caused a decrease in encephalon, which indicates its neurotoxicity. Finally, these results indicate that (PhTe)2 seems not be promissory for therapeutic applications, whereas (PhSe)2 could be of clinical and/or nutritional concern, which will be target for further researches. PMID- 23941567 TI - Cooperative and allosterically controlled nucleotide binding regulates the DNA binding activity of NrdR. AB - Ribonucleotide reductases (RNRs) are required for the synthesis of deoxyribonucleoside triphosphates (dNTPs) from ribonucleotides. In Escherichia coli, regulation of RNR expression is co-ordinated with the cell cycle, and involves several regulatory proteins. One of these, NrdR, has recently been shown to regulate all three nrd operons that encode RNR isoenzymes. Repression by NrdR is believed to be stimulated by elevated dNTPs, although there is no direct evidence for this model. Here, we sought to elucidate the mechanism by which NrdR regulates nrd expression according to the abundance of (d)NTPs. We determined that ATP and dATP bind to NrdR in a negatively cooperative fashion, such that neither can fully occupy the protein. Both nucleotides also appear to act as positive heterotropic effectors, since the binding of one stimulates binding of the other. Nucleotide binding stimulates self-association of NrdR, with tri- and diphosphates stimulating oligomerization more effectively than monophosphates. As prepared NrdR contains (deoxy)nucleoside monophosphates, diphosphates and triphosphates, and its DNA binding activity is inhibited by triphosphates and diphosphates but not by monophosphates. We propose a model in which NrdR selectively binds (deoxy)nucleoside triphosphates, which are hydrolysed to their monophosphate counterparts in order to regulate DNA binding. PMID- 23941569 TI - Endogenous endophthalmitis caused by diphtheroid bacillus. AB - Diphtheroids were generally regarded as nonpathogenic contaminants, but recent clinical studies have emphasized that they may cause serious systemic and ocular disease mostly in patients with underlying medical conditions. In this study we present a case report of acute onset endogenous endophthalmitis associated with heavy growth of diphtheroids on the culture of anterior chamber fluid sample in a 46-year-old man with uncontrolled diabetes mellitus. He did well after appropriate treatment and a functional vision was restored. This case highlights the importance of proper management for the outcomes of patients with endogenous endophthalmitis. It is also significant to be cautious about a life-threatening medical status in a patient with such presentation. PMID- 23941570 TI - Headache and pituitary disease: a systematic review. AB - Headache is very common in pituitary disease and is reported to be present in more than a third of all patients with pituitary adenomas. Tumour size, cavernous sinus invasion, traction or displacement of intracranial pain-sensitive structures such as blood vessels, cranial nerves and dura mater, and hormonal hypersecretion are implicated causes. The present review attempts to systematically review the literature for any combination of headache and pituitary or hormone overproduction or deficiency. Most data available are retrospective and/or not based on the International Headache Society (IHS) classification. Whereas in pituitary apoplexy a mechanical component explains the almost universal association of the condition with headaches, this correlation is less clear in other forms of pituitary disease and a positive impact of surgery on headaches is not guaranteed. Similarly, invasion into the cavernous sinus or local inflammatory changes have been linked to headaches without convincing evidence. Some studies suggest that oversecretion of GH and prolactin may be important for the development of headaches, and treatment, particularly with somatostatin analogues, has been shown to improve symptoms in these patients. Otherwise, treatment rests on general treatment options for headaches based on an accurate clinical history and a precise classification which includes assessment of the patient's psychosocial risk factors. PMID- 23941571 TI - Detection of dihydrofolate reductase conformational change by FRET using two fluorescent amino acids. AB - Two fluorescent amino acids, including the novel fluorescent species 4-biphenyl-l phenylalanine (1), have been incorporated at positions 17 and 115 of dihydrofolate reductase (DHFR) to enable a study of conformational changes associated with inhibitor binding. Unlike most studies involving fluorescently labeled proteins, the fluorophores were incorporated into the amino acid side chains, and both probes [1 and L-(7-hydroxycoumarin-4-yl)ethylglycine (2)] were smaller than fluorophores typically used for such studies. The DHFR positions were chosen as potentially useful for Forster resonance energy transfer (FRET) measurements on the basis of their estimated separation (17-18 A) and the expected change in distance along the reaction coordinate. Also of interest was the steric accessibility of the two sites: Glu17 is on the surface of DHFR, while Ile115 is within a folded region of the protein. Modified DHFR I (1 at position 17; 2 at position 115) and DHFR II (2 at position 17; 1 at position 115) were both catalytically competent. However, DHFR II containing the potentially rotatable biphenylphenylalanine moiety at sterically encumbered position 115 was significantly more active than DHFR I. Irradiation of the modified DHFRs at 280 nm effected excitation of 1, energy transfer to 2, and emission by 2 at 450 nm. However, the energy transfer was substantially more efficient in DHFR II. The effect of inhibitor binding was also measured. Trimethoprim mediated concentration-dependent diminution of the emission observed at 450 nm for DHFR II but not for DHFR I. These findings demonstrate that amino acids containing small fluorophores can be introduced into DHFR with minimal disruption of function and in a fashion that enables sensitive monitoring of changes in DHFR conformation. PMID- 23941572 TI - Effect of small molecule osmolytes on the self-assembly and functionality of globular protein-polymer diblock copolymers. AB - Blending the small molecule osmolytes glycerol and trehalose with the model globular protein-polymer block copolymer mCherry-b-poly(N-isopropyl acrylamide) (mCherry-b-PNIPAM) is demonstrated to improve protein functionality in self assembled nanostructures. The incorporation of either additive into block copolymers results in functionality retention in the solid state of 80 and 100% for PNIPAM volume fractions of 40 and 55%, respectively. This represents a large improvement over the 50-60% functionality observed in the absence of any additive. Furthermore, glycerol decreases the thermal stability of block copolymer films by 15-20 degrees C, while trehalose results in an improvement in the thermal stability by 15-20 degrees C. These results suggest that hydrogen bond replacement is responsible for the retention of protein function but suppression or enhancement of thermal motion based on the glass transition of the osmolyte primarily determines thermal stability. While both osmolytes are observed to have a disordering effect on the nanostructure morphology with increasing concentration, this effect is less pronounced in materials with a larger polymer volume fraction. Glycerol preferentially localizes in the protein domains and swells the nanostructures, inducing disordering or a change in morphology depending on the PNIPAM coil fraction. In contrast, trehalose is observed to macrophase separate from the block copolymer, which results in nanodomains becoming more disordered without changing significantly in size. PMID- 23941573 TI - Expression of codon optimized human bone morphogenetic protein 4 in Pichia pastoris. AB - Bone morphogenetic proteins (BMPs) are TGF-beta family member proteins that have therapeutic potential. The amount of BMPs from natural resources is limited, and the production of biologically active BMPs in heterologous protein expression systems remains an obstacle for their clinical application. In this study, the DNA sequence of human BMP4 mature domain (hBMP4) was optimized according to the codon relative synonymous codon usage values in Pichia pastoris, and the A+T content in the sequence after optimization was within the range of 30% to 55%. In Pichia pastoris cultured in shake-flask, the expression level of hBMP4 protein from the optimized sequence (48 mg/L) increased fourfold in comparison with that from the native sequence (12 mg/L). Recombinant hBMP4 protein was purified by SP Sepharose and heparin affinity chromatography. The biological activities of recombinant hBMP4 were examined by measuring proliferation stimulation in cells and induction of ectopic cartilage formation in mouse models. Our results demonstrated that the optimized DNA sequence could significantly enhance hBMP4 protein expression in Pichia pastoris compared with the native sequence and produce biologically active recombinant hBMP4; this indicates the potential of this optimized sequence for bulk production of hBMP4 protein in future clinical applications. PMID- 23941574 TI - Empty iron stores in children and young adults--the diagnostic accuracy of MCV, MCH, and MCHC. AB - INTRODUCTION: Erythrocyte mean cell volume (MCV) is used clinically to classify anemia, and normal values may be used to exclude iron deficiency. We have studied the diagnostic accuracy of MCV and the related measures mean cell hemoglobin (MCH) and mean cell hemoglobin concentration (MCHC) in diagnosing empty iron stores in children and young adults. METHODS: Diagnostic accuracy of MCV, MCH, and MCHC was studied by ROC curve analysis in 6443 ambulant patients aged 0.5-25 years, of which 476 were anemic. In all patients, blood hemoglobin, MCV, MCH, and serum ferritin were measured in specimens sampled at the same time. MCHC was calculated as MCH divided by MCV. The gold standard of empty iron stores was s ferritin <10, 15, or 20 MUg/L. The cutoff limit of MCV giving 90% sensitivity in diagnosing serum ferritin <15 MUg/L was constructed using quantile regression. RESULTS: Generally, MCH was slightly more accurate than MCV and MCHC. In the whole study population, the area under the ROC curve was 0.68-0.93 for MCV, 0.73 0.96 for MCH, and 0.68-0.87 for MCHC; and 0.70-0.86, 0.71-0.89, and 0.68-0.88, respectively, in the anemic subpopulation. At the cutoff limits of MCV giving a sensitivity of 90% at all ages in anemic patients, the specificity was about 50%. CONCLUSION: Mean cell hemoglobin, MCH, and MCHC are only moderately accurate in diagnosing empty iron stores in children and young adults, and normal values of these tests do not exclude empty iron stores in anemic patients. PMID- 23941575 TI - RABEX-5 plays an oncogenic role in breast cancer by activating MMP-9 pathway. AB - BACKGROUND: RABEX-5, a guanine nucleotide exchange factor (GEF) for RAB-5, plays an important role in cell mobility and altered expression associated with tumor metastasis. This study aimed to investigate the role of RABEX-5 in proliferation and metastasis of breast cancer in vitro and ex vivo. METHODS: RABEX-5 expression was examined in breast cancer, benign tumor and normal breast tissues by immunohistochemistry and western blot. Two stable cell lines were established, the MCF-7/NC negative control cell line and the MCF-7/KD cell line, which stably expressed an RNA interference (RNAi) construct that induced downregulation of RABEX-5 expression. These cell lines were utilized to evaluate the role of RABEX 5 in cell proliferation and migration in vitro and tumorigenicity in vivo. The possible role of RABEX-5 in the regulation of matrix metallopeptidase 9 (MMP-9) was evaluated using western blot and real-time PCR. RESULTS: RABEX-5 expression was found to be significantly higher in breast cancer tissues compared with benign tumor and normal breast tissues. High levels of RABEX-5 expression were associated with axillary lymph node metastasis. In addition, RABEX-5 silencing significantly reduced cancer cell proliferation, colony formation and migration ability in vitro and inhibited tumor growth in vivo. RABEX -5 knockdown also attenuated the migration of breast cancer cells via modulation of MMP-9 transcriptional activity. CONCLUSIONS: Our results indicate that RABEX-5 plays an oncogenic role in breast cancer by modulating the proliferation and metastasis potential of breast cancer cells. Thus, RABEX-5 is a promising prognostic indicator for patients with breast cancer. PMID- 23941577 TI - Adjuvant aromatase inhibitor options in overweight and obese postmenopausal women with breast cancer. PMID- 23941576 TI - Reversal of the neurological deficit in acute stroke with the signal of efficacy trial of auto-BPAP to limit damage from suspected sleep apnea (Reverse-STEAL): study protocol for a randomized controlled trial. AB - BACKGROUND: Although the negative impact of sleep apnea on the clinical course of acute ischemic stroke (AIS) is well known, data regarding non-invasive ventilation in acute patients are scarce. Several studies have shown its tolerability and safety, yet no controlled randomized sequential phase studies exist that aim to establish the efficacy of early non-invasive ventilation in AIS patients. METHODS/DESIGN: We decided to examine our hypothesis that early non invasive ventilation with auto-titrating bilevel positive airway pressure (auto BPAP) positively affects short-term clinical outcomes in AIS patients. We perform a multicenter, prospective, randomized, controlled, third rater- blinded, parallel-group trial. Patients with AIS with proximal arterial obstruction and clinically suspected sleep apnea will be randomized to standard stroke care alone or standard stroke care plus auto-BPAP. Auto-BPAP will be initiated within 24 hours of stroke onset and performed for a maximum of 48 hours during diurnal and nocturnal sleep. Patients will undergo unattended cardiorespiratory polygraphy between days three and five to assess sleep apnea. Our primary endpoint will be any early neurological improvement on the NIHSS at 72 hours from randomization. Safety, tolerability, short-term and three-months functional outcomes will be assessed as secondary endpoints by un-blinded and blinded observers respectively. DISCUSSION: We expect that this study will advance our understanding of how early treatment with non-invasive ventilation can counterbalance, or possibly reverse, the deleterious effects of sleep apnea in the acute phase of ischemic stroke. The study will provide preliminary data to power a subsequent phase III study. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01812993. PMID- 23941578 TI - Potential role of catalase in mice with lipopolysaccharide/D-galactosamine induced fulminant liver injury. AB - AIM: Lipopolysaccharide (LPS)-induced liver injury in D-galactosamine (D-Gal) sensitized mice is a well-established animal model widely used in exploring the pathogenesis of fulminant hepatitis. Increasing evidence has indicated that reactive oxygen species (ROS)-induced oxidative injury may be involved in LPS/D Gal-induced hepatitis. Catalase (CAT) is a major antioxidant enzyme while aminotriazole (ATZ) is commonly used as a CAT inhibitor. In the present study, the effects of ATZ on LPS/D-Gal-induced liver injury were investigated. METHODS: Fuliminant liver injury was induced by intraperitoneal injection of LPS combined with D-Gal, ATZ was administrated 0.5 h prior to LPS/D-Gal challenge. The degree of liver injury, the level of hepatic oxidative stress, the grade of hepatic apoptosis and the survival of experimental animals were determined. RESULTS: Our experimental data showed that treatment with ATZ significantly enhanced LPS/D-Gal induced elevation of serum aspartate transaminase (AST) and alanine transaminase (ALT), exacerbated the hepatic histopathological abnormality and decreased the survival rate of experimental animals. ATZ inhibited the activity of CAT, increased the content of H2 O2 and the levels of malondialdehyde (MDA) in liver tissues. In addition, treatment with ATZ also enhanced LPS/D-Gal-induced hepatic apoptosis as evidenced by increased caspases activities in liver tissues and increased number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells in liver sections. CONCLUSION: These findings suggested that CAT might be involved in the progression of LPS/D-Gal-induced fulminant liver injury. PMID- 23941579 TI - Creation of arteriovenous fistulae for hemodialysis in octogenarians. AB - Elderly patients, defined as octogenarians and nonagenarians, are an increasing population entering renal replacement therapy. Advanced age appears as an exclusive factor negatively influencing dialysis practice. Elderly patients are referred late for the initiation of hemodialysis and more likely are offered catheters rather than arteriovenous fistulae (AVF), which increase mortality and negatively affect quality of life. We present our approach to the creation of vascular access for hemodialysis in this demanding population. In 2006-2012, 39 patients aged 85.9 +/- 2.05 with end-stage renal disease, mainly resulting from ischemic nephropathy, were admitted to the Department of Nephrology to establish permanent vascular access for hemodialysis: preferably AVF. Temporary dialysis catheters were implanted in uremic emergency to bridge the time to fistula creation/maturation. AVF was attempted in 87.2% of the patients. Primary AVF function was achieved in 54% of the patients. Cumulative proportional survival of AVF at months 12 and 24 was 81.5%. Ninety-four percent of AVF were localized on the forearm: 74% in the distal and 20% in the proximal part. Mean duration of hemodialysis therapy was 20.80 +/- 19.45 months. The mean time of AVF use was 15.9 +/- 20.2 months. Until present, 38% have been dialyzed using AVF for 31.0 +/ 18.8 months. Five patients died with functioning fistula. Eight patients initiated hemodialysis therapy with fistula. During further observation, the use of AVF increased to 62%. Elderly patients should not be denied creation of AVF as a rule. The outcome of AVF benefits more from acknowledging individual vascular conditions rather than age of the patient. PMID- 23941580 TI - Is a large scale community programme as effective as a community rehabilitation programme delivered in the setting of a clinical trial? AB - BACKGROUND: The rationale for commissioning community pulmonary rehabilitation programmes is based on evidence from randomised clinical trials. However, there are a number of reasons why similar programmes might be less effective outside the environment of a clinical trial. These include a less highly selected patient group and less control over the fidelity of intervention delivery. The main objective of this study was therefore to test the hypothesis that the real-world programme would have similar outcomes to an intervention delivered in the context of a clinical trial. METHODS: As part of the evaluation of an innovative community-based pulmonary rehabilitation programme ("BreathingSpace"), clinical and quality of life measures were collected before and after delivery of a rehabilitation programme. Baseline characteristics of participants and the change in symptoms and quality of life after the BreathingSpace programme were compared to measures collected in the community-based arm of a separate randomised trial of pulmonary rehabilitation. RESULTS: Despite differences between the BreathingSpace participants and research participants in clinical status at baseline, patient reported symptoms and quality of life measures were similar. Improvements in both symptoms and quality of life were of the same order of magnitude despite the different contexts, setting and scale of the two intervention programmes. Whilst 73% (326/448) of those considered suitable for community rehabilitation in the trial and 80% (393/491) assessed as suitable for the BreathingSpace programme agreed to participate, less than half of participants completed rehabilitation, whether in a research or "real world" setting (47% and 45% respectively). CONCLUSION: The before-after changes in outcomes seen in a "real world" community rehabilitation programme are similar in magnitude to those seen in the intervention arm of a clinical trial. However suboptimal uptake and high dropout rates from rehabilitation amongst eligible participants occurs in both clinical trials and community based programmes and must be addressed if the benefits of rehabilitation for people with chronic lung disease are to be maximised. PMID- 23941581 TI - Influence of soil geochemical and physical properties on chromium(VI) sorption and bioaccessibility. AB - The Department of Defense (DoD) is faced with the daunting task of possible remediation of numerous soil-Cr(VI) contaminated sites throughout the continental U.S. The primary risk driver at these sites is hand-to-mouth ingestion of contaminated soil by children. In the following study we investigate the impact of soil geochemical and physical properties on the sorption and bioaccessibility of Cr(VI) in a vast array of soils relevant to neighboring DoD sites. For the 35 soils used in this study, A-horizon soils typically sorbed significantly more Cr(VI) relative to B-horizon soils. Multiple linear regression analysis suggested that Cr(VI) sorption increased with increasing soil total organic C (TOC) and decreasing soil pH. The bioaccessibility of total Cr (CrT) and Cr(VI) on the soils decreased with increasing soil TOC content. As the soil TOC content approached 0.4%, the bioaccessibility of soil bound Cr systematically decreased from approximately 65 to 10%. As the soil TOC content increased from 0.4 to 4%, the bioaccessibility of Cr(VI) and CrT remained relatively constant at approximately 4% and 10%, respectively. X-ray absorption near edge structure (XANES) spectroscopy suggested that Cr(VI) reduction to Cr(III) was prevalent and that the redox transformation of Cr(VI) increased with increasing soil TOC. XANES confirmed that nearly all bioaccessible soil Cr was the Cr(VI) moiety. Multiple linear regression analysis suggested that the bioaccessibility of Cr(VI) and its reduced counterpart Cr(III), decreased with increasing soil TOC and increasing soil pH. This is consistent with the observation that the reduction reaction and formation of Cr(III) increased with increasing soil TOC and that Cr(III) was significantly less bioaccessible relative to Cr(VI). The model was found to adequately describe CrT bioaccessibility in soils from DoD facilities where Cr(VI) contaminated sites were present. The results of this study illustrate the importance of soil properties on Cr(VI) sorption and bioassessability and help define what soil types have the greatest risk associated with Cr(VI) exposure. PMID- 23941582 TI - Nile-Red-nanoclay hybrids: red emissive optical probes for use in aqueous dispersion. AB - Water-dispersible and (bio)functionalizable nanoclays have a considerable potential as inexpensive carriers for organic molecules like drugs and fluorophores. Aiming at simple design strategies for red-emissive optical probes for the life sciences from commercial precursors with minimum synthetic effort, we systematically studied the dye loading behavior and stability of differently functionalized laponites. Here, we present a comprehensive study of the absorption and emission properties of the red emissive hydrophobic and neutral dye Nile Red, a well-known polarity probe, which is almost insoluble and nonemissive in water. Adsorption of this probe onto disk-shaped nanoclays was studied in aqueous dispersion as function of dye concentration, in the absence and presence of the cationic surfactant cetyltrimethylammonium bromide (CTAB) assisting dye loading, and as a function of pH. This laponite loading strategy yields strongly fluorescent nanoclay suspensions with a fluorescence quantum yield of 0.34 at low dye loading concentration. The dye concentration-, CTAB-, and pH-dependent absorption, fluorescence emission, and fluorescence excitation spectra of the Nile-Red-nanoclay suspensions suggest the formation of several Nile Red species including emissive Nile Red monomers facing a polar environment, nonemissive H-type dimers, and protonated Nile Red molecules that are also nonfluorescent. Formation of all nonemissive Nile Red species could be suppressed by modification of the laponite with CTAB. This underlines the great potential of properly modified and functionalized laponite nanodisks as platform for optical probes with drug delivery capacities, for example, for tumor and therapy imaging. Moreover, comparison of the Nile Red dimer absorption spectra with absorption spectra of previously studied Nile Red aggregates in dendrimer systems and micelles and other literature systems reveals a considerable dependence of the dimer absorption band on microenvironment polarity which has not yet been reported so far for H-type dye aggregates. PMID- 23941584 TI - Collisional activation of N2O decomposition and CO oxidation reactions on isolated rhodium clusters. AB - The reactions of nitrous oxide decorated rhodium clusters, RhnN2O(+) (n = 5, 6), have been studied by Fourier transform ion cyclotron resonance mass spectrometry. Collision induced dissociation with Ar is shown to lead to one of two processes; desorption of the intact N2O moiety (indicating molecular adsorption in the parent cluster) or N2O decomposition liberating molecular nitrogen with the latter becoming increasingly dominant at higher collision energies. Consistent with the results of earlier studies, which employed infrared excitation [Hermes, A. C.; et al. J. Phys. Chem. Lett. 2011, 2, 3053], Rh5ON2O(+) is observed to behave qualitatively differently to Rh5N2O(+) with decomposition of the nitrous oxide dominating the chemistry of the former. In other experiments, the reactivity of RhnN2O(+) clusters with CO has been studied. Chemisorption of (13)CO is calculated to deposit ca. 2 eV into the parent cluster, initiating a range of chemical processes on the cluster surface, which are fit to a simple reaction mechanism. Clear differences are again observed in the reaction branching ratios for Rh5N2O(+) and Rh6N2O(+) parent cluster ions. For the n = 5 cluster, the combined N2O reduction/CO oxidation is the most significant reaction channel, while the n = 6 cluster preferentially is oxidized to Rh6O(+) with loss of N2 and CO. Even larger differences are observed in the reactions of the N2O decorated cluster oxides, RhnON2O(+), for which more reaction possibilities arise. The results of all studies are discussed in relation to infrared driven processes on the same parent cluster species [Hamilton, S. M.; et al. J. Am. Chem. Soc. 2010, 132, 1448; J. Phys. Chem. A, 2011, 115, 2489]. PMID- 23941585 TI - Evidence of man-vector contact in torn long-lasting insecticide-treated nets. AB - BACKGROUND: Studies indicate that physical damage to long-lasting insecticide treated nets (LLINs) occurs at a surprisingly rapid rate following net distribution. To what extent does such damage affect the impact of LLINs? Can vectors pass a compromised LLIN barrier to bite? Do more resistant vectors enter the insecticide-treated nets (ITNs) through holes? METHODS: The study was carried out in three geo-locations. Two types of LLINs (polyester and polyethylene) with 'standardized' physical damage were compared with similarly damaged, but non insecticidal (control) nets. The proportionate Holes Index (pHI) of each net was 276. Mosquitoes were captured inside the nets, identified taxonomically, and subjected to molecular analysis to estimate Knock-down resistance (Kdr) frequency. RESULTS: The most commonly observed species was Anopheles gambiae, accounting for approximately 70% (1,076/1,550) of the total mosquitoes collected both in LLINs and non-insecticidal nets. When compared with controls, number of vectors captured in torn LLINs was significantly reduced. Nonetheless in a night, an average of 5 An. gambiae s.l could enter the damaged LLINs to bite. Similar numbers of resistant mosquitoes were collected in both LLINs and non-insecticidal (control) nets (p > 0.05). CONCLUSIONS: At a pHI of 276, man-vector contact was observed in torn LLINs. The insecticide at the surface of LLINs could only reduce the number of vectors. Resistant mosquitoes have opportunity to enter both non insecticidal (control) nets and LLINs to bite. PMID- 23941583 TI - Circadian redox signaling in plant immunity and abiotic stress. AB - SIGNIFICANCE: Plant crops are critically important to provide quality food and bio-energy to sustain a growing human population. Circadian clocks have been shown to deliver an adaptive advantage to plants, vastly increasing biomass production by efficient anticipation to the solar cycle. Plant stress, on the other hand, whether biotic or abiotic, prevents crops from reaching maximum productivity. RECENT ADVANCES: Stress is associated with fluctuations in cellular redox and increased phytohormone signaling. Recently, direct links between circadian timekeeping, redox fluctuations, and hormone signaling have been identified. A direct implication is that circadian control of cellular redox homeostasis influences how plants negate stress to ensure growth and reproduction. CRITICAL ISSUES: Complex cellular biochemistry leads from perception of stress via hormone signals and formation of reactive oxygen intermediates to a physiological response. Circadian clocks and metabolic pathways intertwine to form a confusing biochemical labyrinth. Here, we aim to find order in this complex matter by reviewing current advances in our understanding of the interface between these networks. FUTURE DIRECTIONS: Although the link is now clearly defined, at present a key question remains as to what extent the circadian clock modulates redox, and vice versa. Furthermore, the mechanistic basis by which the circadian clock gates redox- and hormone-mediated stress responses remains largely elusive. PMID- 23941586 TI - Threading the needle in health-risk communication: increasing vulnerability salience while promoting self-worth. AB - Health interventions often draw attention to the risks associated with unhealthy choice but in the process produce a boomerang effect such that those targeted become more committed to risky behavior. In 2 studies designed to promote condom use among sexually active college students, the authors document strategies for highlighting risk while promoting healthy choices. Study 1 demonstrated that optimistic perceptions regarding the likelihood of contracting sexually transmitted diseases (STDs) can be counteracted by drawing attention to the emotional consequences of contracting STDs, instead of its likelihood. Rather than promoting condom use, however, this procedure generated a boomerang effect: It decreased commitment to using condoms, especially among high self-esteem individuals. Study 2 showed that this unwanted effect could be reversed when emotional vulnerability was paired with a self-affirmation. This finding suggests that there can be benefits to adding threatening content to health interventions, provided that the message also contains elements designed to protect feelings of self-worth. PMID- 23941587 TI - Two decades of experience with laparoscopic nissen fundoplication in infants and children: a critical evaluation of indications, technique, and results. AB - BACKGROUND: Laparoscopic fundoplication for gastroesophageal reflux disease has become a common procedure performed in infants and children over the last 20 years. This report describes a 20-year experience with nearly 2000 consecutive laparoscopic Nissen fundoplications. SUBJECTS AND METHODS: With Institutional Review Board approval, the data of all patients undergoing fundoplication from 1992 to 2011 were reviewed. Data were kept prospectively from the time of first encounter with each patient. Ages ranged from 5 days to 18 years, and weight ranged from 1.2 to 120 kg. The 2008 fundoplications were performed by or under the direct supervision of a single surgeon. Patients were divided into groups based on age: <6 months, 6-12 months, 1-6 years, and >6 years. Data on indications, surgical demographics, postoperative course including any complications, and long-term follow-up were kept prospectively on each patient. RESULTS: Average operative time dropped dramatically from 109 minutes for the first 30 cases compared with 35 minutes for the last 30. Of the 283 procedures that were redo fundoplications, 85 patients had had previous open surgery, and 198 cases had had previous laparoscopic surgery. Intraoperative and postoperative complication rates were 0.13% and 4.0%, respectively, in the primary group but were 2.2% and 4.2%, respectively, in the redo group. Average time to discharge post-fundoplication for the primary group was 1.1 days. The overall wrap failure rate for primary fundoplications was 4.6% and was highest in the <6-month age group. The failure rate in the redo group was 6.8%. The most common causes of wrap failure were hiatal hernia (46%) and slipped Nissen (34%). CONCLUSIONS: This study shows in a large operative experience over 20 years that laparoscopic fundoplication is safe and effective in the pediatric population. Technical considerations are paramount to improved outcomes, and key points include adequate creation of intraabdominal esophagus, limited hiatal dissection, creation of a tension-free and appropriate orientation, and positioning of the wrap. Clinical results are favorable to the traditional open fundoplication but with a significant decrease in morbidity and hospitalization. Laparoscopic Nissen fundoplication should be considered the gold standard for antireflux procedures. PMID- 23941588 TI - Radiofrequency volumetric thermal ablation of fibroids: a prospective, clinical analysis of two years' outcome from the Halt trial. AB - BACKGROUND: Although most myomas are asymptomatic, quality of life is compromised for many women with uterine fibroid disease. Twelve-month outcomes from the Halt Trial have been reported in the literature. Here we analyze the clinical success of radiofrequency volumetric thermal ablation (RFVTA) of symptomatic uterine fibroids at two years of follow up. METHODS: Prospective, multicenter, outpatient interventional clinical trial of fibroid treatment by RFVTA in 124 premenopausal women (mean age, 42.4 +/- 4.4 years) with symptomatic uterine fibroids and objectively confirmed heavy menstrual bleeding (>=160 to <=500 mL).Outcome measures included: subject responses to validated questionnaires, treatment emergent adverse events, and surgical re-intervention for fibroids at 24 months postprocedure. Continuous and categorical variables were summarized using descriptive statistics and means and percentages. Comparisons between visits were based on t-tests using repeated measures models. P-values < 0.05, adjusted for multiplicity, were statistically significant. RESULTS: One hundred twelve subjects were followed through 24 months. Change in symptom severity from baseline was -35.7 (95% CI, -40.1 to -31.4; p<.001). Change in health-related quality of life (HRQL) was 40.9 (95% CI, 36.2 to 45.6; p < .001). HRQL subscores also improved significantly from baseline to 24 months in all categories (concern, activities, energy/mood, control, self-consciousness, and sexual function) [p<.001]. Six patients underwent surgical re-intervention for fibroid related bleeding between 12 and 24 months providing a re-intervention rate of 4.8% (6/124). CONCLUSION: Radiofrequency volumetric thermal ablation of myomas significantly reduces symptom severity and improves quality of life with low surgical re-intervention through 24 months of follow up. PMID- 23941589 TI - Dicationic ring-opening reactions of trans-2-phenylcyclopropylamine.HCl: electrophilic cleavage of the distal (C2-C3) bond of cyclopropanes. AB - Electrophilic ring opening of trans-2-phenylcyclopropylamine.HCl occurs at the distal (C2-C3) bond. This is consistent with weakening of the distal bond by the sigma-withdrawing ammonium group and charge-charge repulsive effects in the transition state. PMID- 23941591 TI - Impaired slow axonal transport in diabetic peripheral nerve is independent of RAGE. AB - Diabetic peripheral nerve dysfunction is a common complication occurring in 30 50% of long-term diabetic patients. The pathogenesis of this dysfunction remains unclear but growing evidence suggests that it might be attributed, in part, to alteration in axonal transport. Our previous studies demonstrated that RAGE (Receptor for Advanced Glycation Endproducts) contributes to the pathogenesis of diabetic peripheral neuropathy and impairs nerve regeneration consequent to sciatic nerve crush, particularly in diabetes. We hypothesize that RAGE plays a role in axonal transport impairment via the interaction of its cytoplasmic domain with mammalian Diaphanous 1 (mDia1) - actin interacting molecule. Studies showed that mDia1-RAGE interaction is necessary for RAGE-ligand-dependent cellular migration, AKT phosphorylation, macrophage inflammatory response and smooth muscle migration. Here, we studied RAGE, mDia1 and markers of axonal transport rates in the peripheral nerves of wild-type C57BL/6 and RAGE null control and streptozotocin-injected diabetic mice at 1, 3 and 6 h after sciatic nerve crush. The results show that in both control and diabetic nerves, the amount of RAGE accumulated at the proximal and distal side of the crush area is similar, indicating that the recycling rate for RAGE is very high and that it is evenly transported from and towards the neuronal cell body. Furthermore, we show that slow axonal transport of proteins such as Neurofilament is affected by diabetes in a RAGE-independent manner. Finally, our study demonstrates that mDia1 axonal transport is impaired in diabetes, suggesting that diabetes-related changes affecting actin binding proteins occur early in the course of the disease. PMID- 23941592 TI - Combined blue nevus-smooth muscle hamartoma: a series of 12 cases. AB - BACKGROUND: One of the most common types of combined melanocytic nevus is that of a blue nevus with ordinary melanocytic nevus. Blue nevi have also been described in association with non-melanocytic cell types, such as those of neural or mesenchymal derivation. Although there are rare descriptions in the literature of blue nevi with myomatous structures, the specific association of combined blue nevi with smooth muscle hyperplasia has not been reported METHODS: We review the clinicopathological features of 12 cases of combined blue nevi with smooth muscle hyperplasia. RESULTS: The majority of these lesions occurred on the back of middle-aged patients and were clinically interpreted as melanocytic nevi or melanoma. Histopathologic examination revealed a combined population of 'common' and blue nevus melanocytes with accompanying smooth muscle hyperplasia. In addition to a lentiginous proliferation of melanocytes at the dermal-epidermal junction with variable basilar hyperpigmentation, there were varying degrees of epidermal acanthosis and follicular induction (three cases). CONCLUSION: We present an unusual hamartoma with features of combined blue nevus and smooth muscle hyperplasia, which has not been previously described. PMID- 23941593 TI - Use of bone anchoring device in electromagnetic computer-assisted navigation in lateral skull base surgery. AB - CONCLUSION: The use of the bone anchoring device associated with a fiducial marker, both fixed close to the operating field, improves the reproducibility and effectiveness of the computer-assisted navigation in lateral skull base surgery. OBJECTIVES: Computer-assisted navigation in lateral skull base surgery using the electromagnetic system Digipointeur((r)) needs an external fiducial marker (titanium screw) close to the operating field to increase position accuracy (PA) to about 1 mm. Displacement of the emitter placed in the mouth (Buccostat((r))) induces a drift of the system, leading to at least 20% of unsuccessful procedures. The aim of this study was to evaluate the PA, stability, and reproducibility of computer-assisted navigation in lateral skull base surgery using a bone anchoring device to provide a fixed registration system near the operating field. METHODS: Forty patients undergoing a lateral skull base procedure with the Digipointeur((r)) system performed with both the titanium screw and bone anchoring device were included in this prospective study. They were divided in two groups. In the first one (n = 9), the PA was measured before and after screw registration for five intratemporal landmarks, during a translabyrinthine approach. In the second group (n = 31), all lateral skull base procedures were included and the PA was evaluated visually by the surgeon on different landmarks of the approaches as well as the stability of the system. RESULTS: In the first group, the PA was 7.08 +/- 0.59 mm and 0.77 +/- 0.17 mm (mean +/- SEM, p < 0.0001) before and after screw registration, respectively. In the second group, the PA was considered as accurate by the surgeon in all cases and no drift of the system was observed. Computer-assisted surgery was never abandoned due to increased stability of the bone-anchored emitter. PMID- 23941594 TI - Bimodal intramolecular excitation energy transfer in a multichromophore photosynthetic model system: hybrid fusion proteins comprising natural phycobilin and artificial chlorophyll-binding domains. AB - The phycobilisomes of cyanobacteria and red-algae are highly efficient peripheral light-harvesting complexes that capture and transfer light energy in a cascade of excitation energy transfer steps through multiple phycobilin chromophores to the chlorophylls of core photosystems. In this work, we focus on the last step of this process by constructing simple functional analogs of natural phycobilisome photosystem complexes that are based on bichromophoric protein complexes comprising a phycobilin- and a chlorophyll- or porphyrin-binding domain. The former is based on ApcE(1-240), the N-terminal chromophore-binding domain of the phycobilisome's L(CM) core-membrane linker, and the latter on HP7, a de novo designed four-helix bundle protein that was originally planned as a high-affinity heme-binding protein, analogous to b-type cytochromes. We fused a modified HP7 protein sequence to ApcEDelta, a water-soluble fragment of ApcE(1-240) obtained by excising a putative hydrophobic loop sequence of residues 77-153. HP7 was fused either to the N- or the C-terminus of ApcEDelta or inserted between residues 76 and 78, thereby replacing the native hydrophobic loop domain. We describe the assembly, spectral characteristics, and intramolecular excitation energy transfer of two unique systems: in the first, the short-wavelength absorbing zinc-mesoporphyrin is bound to the HP7 domain and serves as an excitation-energy donor to the long-wavelength absorbing phycocyanobilin bound to the ApcE domain; in the second, the short-wavelength absorbing phycoerythrobilin is bound to the ApcE domain and serves as an excitation energy donor to the long wavelength absorbing zinc-bacteriochlorophyllide bound to the HP7 domain. All the systems that were constructed and tested exhibited significant intramolecular fluorescence resonance energy transfer with yields ranging from 21% to 50%. This confirms that our modular, covalent approach for studying EET between the cyclic and open chain tetrapyrroles is reasonable, and may be extended to larger structures mimicking light-harvesting in cyanobacteria. The design, construction, and characterization process demonstrated many of the advances in constructing such model systems, particularly in our ability to control the fold and aggregation state of protein-based systems. At the same time, it underlines the potential of exploiting the versatility and flexibility of protein-based systems in assembling multiple pigments into effective light-harvesting arrays and tuning the spectral properties of multichromophore systems. PMID- 23941596 TI - Polydopamine-assisted osteoinductive peptide immobilization of polymer scaffolds for enhanced bone regeneration by human adipose-derived stem cells. AB - Immobilization of osteoinductive molecules, including growth factors or peptides, on polymer scaffolds is critical for improving stem cell-mediated bone tissue engineering. Such molecules provide osteogenesis-stimulating signals for stem cells. Typical methods used for polymeric scaffold modification (e.g., chemical conjugation or physical adsorption), however, have limitations (e.g., multistep, complicated procedures, material denaturation, batch-to-batch inconsistency, and inadequate conjugation) that diminish the overall efficiency of the process. Therefore, in this study, we report a biologically inspired strategy to prepare functional polymer scaffolds that efficiently regulate the osteogenic differentiation of human adipose-derived stem cells (hADSCs). Polymerization of dopamine (DA), a repeated motif observed in mussel adhesive protein, under alkaline pH conditions, allows for coating of a polydopamine (pDA) layer onto polymer scaffolds. Our study demonstrates that predeposition of a pDA layer facilitates highly efficient, simple immobilization of peptides derived from osteogenic growth factor (bone morphogenetic protein-2; BMP-2) on poly(lactic-co glycolic acid) (PLGA) scaffolds via catechol chemistry. The BMP-2 peptide immobilized PLGA scaffolds greatly enhanced in vitro osteogenic differentiation and calcium mineralization of hADSCs using either osteogenic medium or nonosteogenic medium. Furthermore, transplantation of hADSCs using pDA-BMP-2-PLGA scaffolds significantly promoted in vivo bone formation in critical-sized calvarial bone defects. Therefore, pDA-mediated catechol functionalization would be a simple and effective method for developing tissue engineering scaffolds exhibiting enhanced osteoinductivity. To the best of our knowledge, this is the first study demonstrating that pDA-mediated surface modification of polymer scaffolds potentiates the regenerative capacity of human stem cells for healing tissue defect in vivo. PMID- 23941597 TI - Monica Gallivan, good-bye to a friend. PMID- 23941598 TI - Social aspects of HIV/AIDS and aging: a thematic review. AB - Little research can be found describing social aspects of aging with human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) in Canada specifically, despite an overall increase in an aging population and increased numbers of those aging with HIV/AIDS. A systematic literature review was conducted with a selective focus on social aspects related to older adults who are living with or at risk for contracting HIV/AIDS. The primary themes that emerged in the literature are ageism and stigma, gender, mental health, and social supports. Recommendations for future research regarding prevention and education of risks for older adults and programming suitable for a wide range of audiences are presented. PMID- 23941599 TI - Sternal wound infection caused by Mycobacterium chelonae. AB - INTRODUCTION: Sternal wound infection caused by Mycobacterium chelonae, a member of the rapidly growing nontuberculous mycobacteria (NTM), is rare and may present without signs and symptoms of systemic infection. METHODS: We present a patient who had a M. chelonae infection of the sternum following excision of a left atrial myxoma and conducted a review of the literature from 1976 to 2013. RESULTS: Seventy cases of NTM sternal wound infection after cardiac surgery were identified, including six outbreaks and ten sporadic cases including the present case. Thirty-four cases were isolated coronary artery bypass grafting (CABG) surgery, 16 cases were isolated valve replacement, and two cases were valve replacement with CABG. The age range of the patients was between 6 and 78 years. The average time from the surgery was 49 +/- 58 days which was longer than the usual bacterial mediastinitis. The overall mortality rate was 29%. CONCLUSION: NTM sternal wound infection is rare but may be fatal if not properly treated. The toxic signs are often subtle and it will take longer to isolate compared to typical bacterial mediastinitis. Early recognition, the use of appropriate antibiotics based on susceptibility tests, and aggressive surgical debridement are required for full recovery. PMID- 23941601 TI - Comparison of poliglecaprone-25 and polyglactin-910 in cutaneous surgery. AB - BACKGROUND: Few clinical studies have compared deep absorbable sutures. Poliglecaprone-25 and polyglactin-910 are two of the most commonly used absorbable sutures in cutaneous surgery. OBJECTIVES: To compare the rate of suture extrusion, degree of lumpiness, and appearance of scars from wounds closed with poliglecaprone-25 and polyglactin-910. METHODS: Poliglecaprone-25 or polyglactin-910 was used for closure of the deep part of Mohs defects. The number of extruded sutures and the number of lumps were recorded at each follow-up visit. Photographs of 1-week and 3-month postoperative scars were rated on a visual analogue scale. RESULTS: One hundred forty patients completed the study. There was a statistically significant difference in the percentage of extruded sutures between poliglecaprone-25 (3.1%) and polyglactin-910 (11.4%) (p < .01). There was not a statistically significant difference in the percentage of lumps (both 22%) or overall appearance of scars at 1 week or 3 months. CONCLUSION: Poliglecaprone-25 resulted in significantly less extruded sutures than did polyglactin-910, although both resulted in the same degree of lumpiness and similar-appearing scars at 1 week and 3 months. PMID- 23941600 TI - Striking life events associated with primary breast cancer susceptibility in women: a meta-analysis study. AB - PURPOSE: The association between striking life events, an important stress and acute anxiety disorder, and the occurrence of primary breast cancer is unclear. The current meta-analysis was designed to assess the relationship between striking life events and primary breast cancer incidence in women. METHODS: Systematic computerized searching of the PubMed, ScienceDirect, Embase, and BMJ databases with the combinations of controlled descriptors from Mesh, including breast cancer, breast tumor, cancer of breast, mammary carcinoma, life events, life change events, case-control studies, case-base studies, cohort study, and cohort analysis and identified a total of 307 papers published from January 1995 to April 2012. Following evaluation of methodological quality with the Downs & Black criteria, seven case-control or cohort studies were selected and the association between striking life events and primary breast cancer incidence in women was measured using random effect or fixed-effect odds ratios combined with 95% confidence interval. RESULTS: The seven studies included in the final meta analysis included 99,807 women. A meta-analysis showed that the pooled OR for striking life events and breast cancer was 1.51 (95% CI 1.15 - 1.97, P = 0.003), indicating that women with striking life events were at 1.5-fold greater risk of developing breast cancer. The pooled OR for severe striking life events and breast cancer was 2.07 (95% CI 1.06 - 4.03), indicating that women with severe striking life events were at 2-fold greater risk of developing breast cancer. CONCLUSIONS: The current meta-analysis showed significant evidence for a positive association between striking life events and primary breast cancer incidence in women. PMID- 23941602 TI - Computational profiling of bioactive compounds using a target-dependent composite workflow. AB - Computational target fishing is a chemoinformatic method aimed at determining main and secondary targets of bioactive compounds in order to explain their mechanism of action, anticipate potential side effects, or repurpose existing drugs for novel therapeutic indications. Many existing successes in this area have been based on a use of a single computational method to estimate potentially new target-ligand associations. We herewith present an automated workflow using several methods to optimally browse target-ligand space according to existing knowledge on either ligand and target space under investigation. The protocol uses four ligand-based (SVM classification, SVR affinity prediction, nearest neighbors interpolation, shape similarity) and two structure-based approaches (docking, protein-ligand pharmacophore match) in series, according to well defined ligand and target property checks. The workflow was remarkably accurate (72%) in identifying the main target of 189 clinical candidates and proposed two novel off-targets which could be experimentally validated. Rolofylline, an adenosine A1 receptor antagonist, was confirmed to inhibit phosphodiesterase 5 with a moderate affinity (IC50 = 13.8 MUM). More interestingly, we describe a strong binding (IC50 = 142 nM) of a claimed selective phosphodiesterase 10 A inhibitor (PF-2545920) with the cysteinyl leukotriene type 1 G protein-coupled receptor. PMID- 23941604 TI - Discrimination of fibrotic staging of chronic hepatitis C using multiple fibrotic markers. AB - AIM: In order to evaluate and judge a fibrotic stage of patients with chronic hepatitis C, multivariate regression analysis was performed using multiple fibrotic markers. METHODS: A total of 581 patients from eight hepatology units and institutes were diagnosed by needle biopsy as having chronic liver disease caused by hepatitis C virus. Twenty-three variables and their natural logarithmic transformation were employed in the multivariate analysis. RESULTS: Multivariate regression analysis finally obtained the following function: z = 2.89 * ln (type IV collagen 7S) (ng/mL) - 0.011 * (platelet count) (*10(3) /mm(3) ) + 0.79 * ln (total bilirubin) (mg/dL) + 0.39 * ln (hyaluronic acid) (MUg/L) - 1.87. Median values of the fibrotic score of F1 (n = 172), F2 (n = 80), F3 (n = 37) and F4 (n = 16) were calculated as 1.00, 1.45, 2.82 and 3.83, respectively. Multiple regression coefficient and coefficient of determination were 0.56 and 0.320, respectively. Validation with patient data from other institutions demonstrated good reproducibility of the fibrotic score for hepatitis C (FSC), showing 1.10 in F1 (n = 156), 2.35 in F2 (n = 73), 3.16 in F3 (n = 36) and 3.58 in F4 (n = 11). CONCLUSION: A concise multiple regression function using four laboratory parameters successfully predicted pathological fibrotic stage of patients with hepatitis C virus infection. PMID- 23941603 TI - Comparative value of clinical, cytological, and histopathological features in feline mammary gland tumors; an experimental model for the study of human breast cancer. AB - BACKGROUND: The diagnosis of breast lesions is usually confirmed by fine-needle aspiration cytology (FNAC) or histological biopsy. Although there is increasing literature regarding the advantages and limitations of both modalities, there is no literature regarding the accuracy of these modalities for diagnosing breast lesions in high-risk patients, who usually have lesions detected by screening. Moreover, few studies have been published regarding the cytopathology of mammary tumors in cats despite widespread use of the animal model for breast cancer formation and inhibition. The objective of the present study was to evaluate the diagnostic interest of cytological and histopathological analysis in feline mammary tumours (FMTs), in order to evaluate its possible value as an animal model. METHODS: The study was performed in 3 female cats submitted to surgical resections of mammary tumours. The mammary tumours were excised by simple mastectomy or regional mastectomy, with or without the superficial inguinal lymph nodes. Female cats were of different breeds (1 siamese and 2 persians). Before surgical excision of the tumour, FNA cytology was performed using a 0.4 mm diameter needle attached to a 8 ml syringe held in a standard metal syringe holder. The cytological sample was smeared onto a glass slide and either air dried for May-Grunwald-stain and masses were surgically removed, the tumours were grossly examined and tissue samples were fixed in 10%-buffered-formalin and embedded in paraffin. Sections 4 MUm thick were obtained from each sample and H&E stained. RESULTS: Cytologically, atypical epithelial cells coupled to giant nucleus, chromatin anomalies, mitotic figures, spindle shape cells, anisocytosis with anisokaryosis and hyperchromasia were found. Histologically, these tumors are characterized by pleomorphic and polygonal cell population together with mitotic figures, necrotic foci and various numbers inflammatory foci. Also, spindle shaped cells, haemorrhage localized in the different regions, local invasiveness and enlarged nuclei were observed. The samples included 3 tumors of mammary glands mammary tumors were complex carcinomas (n = 2) and adenocarcinoma (n = 1). The histological grades of the 3 cases were as follows: grade II, (1/3); grade III, (2/3) with high mitotic index. The preferential localization of mammary neoplasms was in the inguinal lobe (1/3 case) and abdominal lobes (2/3 cases). Furthermore, 1case of the inguinal mass affected the left caudo-inguinal lobe and 2cases right cranio and caudo abdominal lobes. CONCLUSION: The study concluded that cytology could be used as a quick, rapid, field diagnostic technique in combination with histopathology for the diagnosis of feline mammary tumors (FMTs). Our findings in feline MTs indicate that FMTs could be useful as an animal model of human breast cancer. Moreover, because of the similarity of the cytohistopathological findings in the human and feline mammary gland tumours, it is possible to use the same cytopathological criteria applied in human pathology for the diagnosis of feline mammary gland tumours. VIRTUAL SLIDE: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2047361423103295. PMID- 23941605 TI - Relationship between Geriatric Nutritional Risk Index and total lymphocyte count and mortality of hemodialysis patients. AB - We examined the relationships between Geriatric Nutritional Risk Index (GNRI), total lymphocyte count (TLC), and mortality in hemodialysis (HD) patients. We examined GNRI and TLC in 120 maintenance HD patients and followed these patients for 120 months. Predictors of all-cause death were examined using life table analysis and the Cox proportional hazards model. TLC marginally correlated with GNRI (r = 0.176; p = 0.090) and significantly with phosphorus levels (r = 0.206; p = 0.026). Life table analysis revealed that subjects with a GNRI < 90 (n = 19) had lower survival rates than did those with a GNRI >= 90 (n = 101; Wilcoxon's test, p = 0.048), but subjects with a TLC < 1500/mm(3) (n = 76) had similar survival rates compared with subjects with a TLC >= 1500/mm(3) (n = 44; Wilcoxon's test, p = 0.500). Multivariate Cox proportional hazards analyses demonstrated that GNRI is a significant predictor of mortality (hazard ratio 9.315, 95% confidence interval 1.161-74.753, p = 0.036), after adjusting for age, sex, presence of type 2 diabetes mellitus, Kt/V, normalized protein catabolic rate, hematocrit, phosphorus, systolic blood pressure and TLC. Our findings suggest the TLC may be used as a simple nutritional tool, but may not be a predictor of mortality in HD patients. These findings require confirmation by further studies. PMID- 23941607 TI - Molecular dynamics simulation of SDS and CTAB micellization and prediction of partition equilibria with COSMOmic. AB - Molecular dynamics (MD) simulations of the self-assembly of different ionic surfactants have been performed in order to obtain representative micellar structures. Subsequently, these structures were used to predict the partition behavior of various solutes in these micelles with COSMOmic, an extension of COSMO-RS. This paper includes multiple self-assembled micelles of SDS (sodium dodecyl sulfate, anionic surfactant) and CTAB (cetyltrimethylammoniumbromide, cationic surfactant) at different concentrations. Micellar size, density profiles, and shape (eccentricity) have been investigated. However, the size strongly depends on the functional definition of a micelle. For this reason, we present a method based on the free monomer concentration in aqueous solution as an optimization criterion for the micelle definition. The combination of MD with COSMOmic has the benefit of combining detailed atomistic information from MD with fast calculations of COSMOmic. For the first time the influence of micelle structure on pratition equilibria, predicted with COSMOmic, were investigated. In case of SDS more than 4600 and for CTAB more than 800 single micelles have been studied. The predictions of the partition coefficients with COSMOmic are in good agreement with experimental data. Additionally, the most favorable locations of selected molecules in the micelles as well as probable energy barriers are determined even for complex solutes such as toluene, propanolol, ephedrine, acetone, phenol, lidocaine, syringic acid, coumarin, isovanillin, ferulic acid, and vanillic acid. This method can therefore be applied as a potential screening tool for solutes (e.g., drugs) to find the optimal solute-surfactant combination. PMID- 23941606 TI - Preferences, predictions and patient enablement: a preliminary study. AB - BACKGROUND: The widely used patient enablement instrument (PEI) is sometimes contrasted against measures of patient satisfaction as being a more objective measure of consultation quality, in that it is less likely to be positively influenced by fulfilling pre-existing expectations for specific consultation outcomes (such as prescriptions or referrals). However the relationship between expectation and enablement is underexplored, as is the relationship between 'expectation' understood as a patient preference for outcome, and patient prediction of outcome. The aims of the study are to 1) assess the feasibility of measuring the relationship between expectation fulfilment and patient enablement, and 2) measure the difference (if any) between expectation understood as preference, and expectation understood as prediction. METHODS: A questionnaire study was carried out on 67 patients attending three General Practices in the Australian Capital Territory. Patient preferences and predictions for a range of possible outcomes were recorded prior to the consultation. PEI and the actual outcomes of the consultation were recorded at the conclusion of the consultation. Data analysis compared expectation fulfilment as concordance between the preferred, predicted, and actual outcomes, with the PEI as a dependant variable. RESULTS: No statistically significant relationship was found between either preference-outcome concordance and PEI, or prediction-outcome concordance. Statistically insignificant trends in both cases ran counter to expectations; i.e. with PEI (weakly) positively correlated with greater discordance. The degree of concordance between preferred outcomes and predicted outcomes was less than the concordance between either preferred outcomes and actual outcomes, or predicted outcomes and actual outcomes. CONCLUSIONS: The relationship between expectation fulfilment and enablement remains uncertain, whether expectation is measured as stated preferences for specific outcomes, or the predictions made regarding receiving such outcomes. However the lack of agreement between these two senses of 'patient expectation' suggests that explicitly demarcating these concepts during study design is strongly advisable. PMID- 23941608 TI - Diffusive gradients in thin films technique equipped with a mixed binding gel for simultaneous measurements of dissolved reactive phosphorus and dissolved iron. AB - Developing a technique to track the release of phosphorus (P) and iron (Fe) simultaneously in sediments would be very useful in deepening our understanding of the internal loading process of P coupled with Fe cycling in aquatic systems. In this study, a new technique was established to measure simultaneously the dissolved reactive P (DRP) and dissolved Fe primarily released from sediment solids based on the diffusive gradients in thin films (DGT) theory. A mixed binding gel (ZrO-Chelex gel) used for assembling DGT was developed for simultaneous uptake of DRP and dissolved Fe(II) using amorphous zirconium hydroxide (Zr-oxide) and Chelex-100 resin as binding agents. Simultaneous measurements of DRP and dissolved Fe(II) with the ZrO-Chelex DGT were validated in solution and were independent of solution pH and ionic strength in normal environments. The capacities of the ZrO-Chelex DGT for measurements of DRP and dissolved Fe(II) were 90 MUg P cm(-2) and 75 MUg Fe cm(-2), with the latter being greater than that (45 MUg Fe cm(-2)) observed with the Chelex-100 resin DGT commonly used in DGT measurements of metals. Microcosm experiments further confirmed the feasibility of the ZrO-Chelex DGT for simultaneous measurement of P and Fe in sediments, with a higher concentration of Fe being measured due to this method's higher capacity compared with the Chelex-100 resin DGT. PMID- 23941609 TI - A meta-analysis and systematic review of HIV risk behavior among fishermen. AB - With HIV prevalence levels up to 30%, fishermen as a group have a comparable prevalence to at-risk populations such as female sex workers (FSWs), truck drivers, military personnel, and prisoners. This study examines sexual risk behavior among fishermen, primarily in Africa and Asia. A meta-analysis embedded within a systematic review is utilized for this study. This study included 44 peer-reviewed articles and gray literature from 1992 to 2012. The study found that 42% of fishermen engaged in transactional sex, 48% of whom reported not using a condom with FSWs. Ninety percent of the fishermen reported having partners outside of their regular partner, but only 7% reported using a condom with their regular partner. Mobility, peer norms, and alcohol were found to be contextual risks for HIV infection. The findings have important implications for HIV prevention, targeting fishermen, and their sexual networks. Prevention strategies are needed to address HIV risk among this population. PMID- 23941610 TI - Employing virtual advisors in preventive care for underserved communities: results from the COMPASS study. AB - Electronically delivered health promotion programs that are aimed primarily at educated, health-literate individuals have proliferated, raising concerns that such trends could exacerbate health disparities in the United States and elsewhere. The efficacy of a culturally and linguistically adapted virtual advisor that provides tailored physical activity advice and support was tested in low-income older adults. Forty inactive adults (92.5% Latino) 55 years of age and older were randomized to a 4-month virtual advisor walking intervention or a waitlist control. Four-month increases in reported minutes of walking/week were greater in the virtual advisor arm (mean increase = 253.5 +/- 248.7 minutes/week) relative to the control (mean increase = 26.8 +/- 67.0 minutes/week; p = .0008). Walking increases in the virtual advisor arm were substantiated via objectively measured daily steps (slope analysis p = .002). All but one intervention participant continued some interaction with the virtual advisor in the 20-week poststudy period (mean number of poststudy sessions = 14.0 +/- 20.5). The results indicate that a virtual advisor delivering culturally and linguistically adapted physical activity advice led to meaningful 4-month increases in walking relative to control among underserved older adults. This interactive technology, which requires minimal language and computer literacy, may help reduce health disparities by ensuring that all groups benefit from e-health opportunities. PMID- 23941611 TI - Influence of integrated services on postpartum family planning use: a cross sectional survey from urban Senegal. AB - BACKGROUND: Although the majority of postpartum women indicate a desire to delay a next birth, family planning (FP) methods are often not offered to, or taken up by, women in the first year postpartum. This study uses data from urban Senegal to examine exposure to FP information and services at the time of delivery and at child immunization appointments and to determine if these points of integration are associated with greater use of postpartum FP. METHODS: A representative, household sample of women, ages 15-49, was surveyed from six cities in Senegal in 2011. This study focuses on women who were within two years postpartum (n = 1879). We also include women who were surveyed through exit interviews after a visit to a high volume health facility in the same six cities; clients included were visiting the health facility for delivery, post-abortion care, postnatal care, and child immunization services (n = 794). Descriptive analyses are presented to examine exposure to FP services among postpartum women and women visiting the health facility. Logistic regression models are used to estimate the effect of integrated services on postpartum FP use in the household sample of women. Analyses were conducted using Stata version 12. RESULTS: Among exit interview clients, knowledge of integrated services is high but only a few reported receiving FP services. A majority of the women who did not receive FP services indicated an interest in receiving such information and services.Among the household sample of women up to two-years postpartum, those who received FP information at the time of delivery are more likely to be using modern FP postpartum than their counterparts who also delivered in a facility but did not receive such information. Exposure to FP services at an immunization visit was not significantly related to postpartum FP use. Another key finding is that women with greater self-efficacy are more likely to use a modern FP method. CONCLUSION: This study's findings lend strong support for the need to improve integration of FP services into maternal, newborn, and child health services with the goal of increasing postpartum women's use of FP methods in urban Senegal. PMID- 23941612 TI - Oxidative Heck reaction of glycals and aryl hydrazines: a palladium-catalyzed C glycosylation. AB - An efficient Heck-type C-glycosylation of glycals via the C-N bond cleavage of aryl hydrazines has been developed. The flexibility of the reaction was tested by the substrate scope, consisting of glycals from different carbohydrate origins as well as aryl hydrazines with various substituents. Pure alpha-C-glycosides were obtained when (3R)-glycals were employed, whereas alpha,beta mixtures were observed with (3S)-glycals. PMID- 23941613 TI - Applying quality by design (QbD) concept for fabrication of chitosan coated nanoliposomes. AB - In the present investigation, a quality by design (QbD) strategy was successfully applied to the fabrication of chitosan-coated nanoliposomes (CH-NLPs) encapsulating a hydrophilic drug. The effects of the processing variables on the particle size, encapsulation efficiency (%EE) and coating efficiency (%CE) of CH NLPs (prepared using a modified ethanol injection method) were investigated. The concentrations of lipid, cholesterol, drug and chitosan; stirring speed, sonication time; organic:aqueous phase ratio; and temperature were identified as the key factors after risk analysis for conducting a screening design study. A separate study was designed to investigate the robustness of the predicted design space. The particle size, %EE and %CE of the optimized CH-NLPs were 111.3 nm, 33.4% and 35.2%, respectively. The observed responses were in accordance with the predicted response, which confirms the suitability and robustness of the design space for CH-NLP formulation. In conclusion, optimization of the selected key variables will help minimize the problems related to size, %EE and %CE that are generally encountered when scaling up processes for NLP formulations. The robustness of the design space will help minimize both intra-batch and inter batch variations, which are quite common in the pharmaceutical industry. PMID- 23941614 TI - Radiofrequency ablation versus hepatic resection for the treatment of early-stage hepatocellular carcinoma meeting Milan criteria: a systematic review and meta analysis. AB - Current options for the treatment of the early-stage HCC conforming to the Milan criteria consist of liver transplantation, hepatic resection (HR), transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) .Whether HR or RFA is the better treatment for early HCC has long been debated. The aim of our paper is to compare the therapeutic effects of radiofrequency ablation (RFA) and hepatic resection (HR) in the treatment of early-stage hepatocellular carcinoma (HCC). Controlled trials evaluating the efficacy between RFA and HR for the treatment of early-stage HCC published before June 2013 were searched electronically using MEDLINE, PubMed, Cochrane Library, and EMBASE databases. Using inclusion and exclusion criteria, two randomized controlled trials and 10 nonrandomized controlled trials were included in the meta- analysis. The results showed that the 3,5-year overall survival rates and 1,3,5 disease-free survival rates were significantly lower after RFA than after HR. However, complications after treatment were less common and the length of hospital stay was significantly shorter after RFA. Additionally, there was no significant difference in the 1-year overall survival rate between RFA and HR. The conclusions of the results show that the difference in the short-term effectiveness of RFA and HR in the treatment of small HCC is not notable, but the long-term efficacy of HR is better than that of RFA. However, HR is associated with more complications and a longer hospital stay. PMID- 23941615 TI - New natural compounds from Rhododendron lepidotum. AB - Phytochemical investigation of the aerial parts of Rhododendron lepidotum yielded 8-[2',6'-dimethoxy-4'-(1",2",3"-trihydroxy-propyl)-phenyl]-7-hydroxy benzopyranone (1), 3-O-beta-d-glycopyranosyl betulinic amide (2) and 8-hydroxy 7,7'-oxydicoumarin (4) and five known compounds. Among the known molecules, betulinic amide (3) was earlier reported as a semi-synthetic product. The structures of new molecules 1, 2 and 4 were elucidated on the basis of extensive spectroscopic investigations (1D NMR, 2D NMR and mass spectrometry). PMID- 23941616 TI - Network mechanisms of responsiveness to continuous theta-burst stimulation. AB - Continuous theta-burst stimulation (cTBS) can modify behavior, but effects are inconsistent and their mechanisms insufficiently understood. As coherence in resting-state networks influences human behavior, we hypothesized that cTBS may act via modulation of neural oscillation coherence. This study used electroencephalography (EEG) to investigate whether behavioral effects of cTBS on visuospatial attention are associated with coherence changes in the attention network. In healthy human subjects, cTBS of the right posterior parietal cortex (PPC) and the right frontal eye field was compared with sham stimulation. Effects on visuospatial attention were quantified with a visual exploration task, and network effects were assessed from surface EEG with inverse solutions and source coherence analyses. Before stimulation, left visual exploration was linearly correlated with alpha-band coherence between the right temporo-parietal cortex and the rest of the brain. Posterior parietal cortex stimulation induced neglect like visual exploration behavior in the majority, but not all, subjects. It reduced alpha-band coherence between the stimulation site and the rest of the brain but also enhanced it between the contralateral left parietal cortex and the rest of the brain. The contralateral increase correlated with the induced reduction in left visual attention. The behavioral response of individual participants to cTBS could be predicted by coherence in the right temporo parietal junction before stimulation. Behavioral effects of cTBS therefore depend on network states before stimulation and are linearly associated with changes in network interactions. In particular, cTBS modulates an interhemispheric competition in alpha-band coherence. EEG network imaging might help to optimize therapeutic cTBS in the future. PMID- 23941617 TI - Histopathology of acneiform eruptions in patients treated with epidermal growth factor receptor inhibitors. AB - BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) are anticancer agents that have been approved for use in a variety of solid tumors. EGFR inhibiting agents produce a variety of cutaneous adverse events: most commonly a follicular papulopustular (acneiform) eruption on the face, scalp, chest and upper back. OBJECTIVE: The goal of this manuscript is to elucidate the histopathologic findings associated with this most common adverse event. METHODS: The histopathological findings of 10 patients with papulopustular eruptions induced by EGFRIs are described and compared to the four prior published case series of acneiform rashes attributed to EGFRIs. RESULTS: All 10 patients in our case series showed a superficial, predominantly neutrophilic suppurative folliculitis with ectatic follicular infundibula and rupture of the epithelial lining. Similar pathology was found in the four other case series discussing this phenomenon. CONCLUSION: While the characteristic clinical appearance of this rash precludes the need for a biopsy in most cases, this knowledge promotes our understanding of the pathophysiologic process. As the use of EGFRIs expands, dermatopathologists will see these reactions more commonly and will need to recognize this pattern. PMID- 23941618 TI - Differences in microthrix form between stomach and spiral intestine stages of the cestode, Trilocularia: interspecific variation or development? AB - Tetraphyllidean cestodes of the genus Trilocularia have been reported from Squalus acanthias throughout this shark's global distribution, occupying both the stomach and spiral intestine. This study investigated whether variation seen in microthrix form among specimens within this host species is indicative of interspecific variation or is attributable to developmental transformation of a single cestode species. Sequence data for the 2 nuclear genes 28S rDNA (D1-D3) and ITS1, and the mitochondrial gene 16S rDNA, were generated for 22 specimens of Trilocularia; 3 from the stomach and 19 from the spiral intestine, including individuals exhibiting each of the 3 spinithrix forms found. Sequence data for 22 specimens were identical for the 2 nuclear genes. Some variation was seen in the mitochondrial gene but maximum likelihood analysis revealed no pattern with either site or microthrix type, suggesting microthrix variation may be developmental. To explore the developmental hypothesis further, a total of 118 juvenile worms from the stomach and 124 from the spiral intestine were collected from S. acanthias off the coast of Rhode Island and examined with either scanning electron microscopy (SEM) or light microscopy. SEM revealed differences in microthrix form between worms from the 2 sites. Of the stomach and spiral intestine worms examined, respectively, 98% versus 30% were scolopate, 2% versus 47% were aristate gladiate, and 0% versus 15% were lingulate in microthrix form. In addition, 3 of the 77 specimens from the spiral intestine examined with SEM exhibited mixtures of spinitriches. ANOVAs showed significant differences in the morphometrics of stomach worms, when compared to spiral intestine worms, as well as significat differences in the scolex width:below scolex width ratio of worms with scolopate spinitriches when compared to those with aristate gladiate or lingulate spinitriches. In combination, these data suggest that microthrix form may change over the course of development, indicating that caution should be exercised when interpreting microthrix patterns in the context of species designations. PMID- 23941619 TI - Stress-responsive polymers containing cyclobutane core mechanophores: reactivity and mechanistic insights. AB - A primary goal of covalent mechanochemistry is to develop polymer bound mechanophores that undergo constructive transformations in response to otherwise destructive forces. The [2 + 2] cycloreversion of cyclobutane mechanophores has emerged as a versatile framework to develop a wide range of stress-activated functionality. Herein, we report the development of a class of cyclobutane bearing bicyclo[4.2.0]octane mechanophores. Using carbodiimide polyesterification, these stress-responsive units were incorporated into high molecular weight polymers containing up to 700 mechanophores per polymer chain. Under exposure to the otherwise destructive elongational forces of pulsed ultrasound, these mechanophores unravel by ~7 A per monomer unit to form alpha,beta-unsaturated esters that react constructively via thiol-ene conjugate addition to form sulfide functionalized copolymers and cross-linked polymer networks. To probe the dynamics of the mechanochemical ring opening, a series of bicyclo[4.2.0]octane derivatives that varied in stereochemistry, substitution, and symmetry were synthesized and activated. Reactivity and product stereochemistry was analyzed by (1)H NMR, which allowed us to interrogate the mechanism of the mechanochemical [2 + 2] cycloreversion. These results support that the ring opening is not concerted but proceeds via a 1,4 diradical intermediate. The bicyclo[4.2.0]octanes hold promise as active functional groups in new classes of stress-responsive polymeric materials. PMID- 23941621 TI - Acute intramural hematoma of the aorta complicated by spinal cord ischemia. AB - We present an unusual case of spinal cord ischemia from an acute type B intramural hematoma that was successfully treated with blood pressure elevation and drainage of cerebral spinal fluid. PMID- 23941622 TI - MTA1 promotes nasopharyngeal carcinoma growth in vitro and in vivo. AB - BACKGROUND: The prognostic value of metastasis-associated gene 1 (MTA1) in nasopharyngeal carcinoma (NPC) has been suggested. However, there is still no direct evidence that MTA1 promotes NPC growth in vivo. In this study, we aimed to investigate the function of MTA1 in the regulation of NPC cell proliferation and tumorigenesis in vitro and in vivo. METHODS: Stable MTA1 knockdown or overexpression NPC cell lines were employed. The effects of MTA1 depletion or overexpression on cell proliferation, colony formation, cell cycle progression were examined by MTT, colony formation and flow cytometry assay. The effects of MTA1 depletion on tumor growth in vivo were examined in mouse xenograft model. RESULTS: MTA1 knockdown or overexpression drastically changed the proliferation, colony formation and cell cycle of NPC cells in vitro. MTA1 depletion significantly suppressed NPC tumorigenesis in vivo. CONCLUSION: MTA1 promotes NPC cell proliferation via enhancing G1 to S phase transition, leading to increased tumor growth. Targeting MTA1 is a promising approach to reduce tumor burden of NPC. PMID- 23941623 TI - Inheritance of Cry1F resistance, cross-resistance and frequency of resistant alleles in Spodoptera frugiperda (Lepidoptera: Noctuidae). AB - Transgenic maize, Zea maize L., expressing the Cry1F protein from Bacillus thuringiensis has been registered for Spodoptera frugiperda (J. E. Smith) control since 2003. Unexpected damage to Cry1F maize was reported in 2006 in Puerto Rico and Cry1F resistance in S. frugiperda was documented. The inheritance of Cry1F resistance was characterized in a S. frugiperda resistant strain originating from Puerto Rico, which displayed >289-fold resistance to purified Cry1F. Concentration-response bioassays of reciprocal crosses of resistant and susceptible parental populations indicated that resistance is recessive and autosomal. Bioassays of the backcross of the F1 generation crossed with the resistant parental strain suggest that a single locus is responsible for resistance. In addition, cross-resistance to Cry1Aa, Cry1Ab, Cry1Ac, Cry1Ba, Cry2Aa and Vip3Aa was assessed in the Cry1F-resistant strain. There was no significant cross-resistance to Cry1Aa, Cry1Ba and Cry2Aa, although only limited effects were observed in the susceptible strain. Vip3Aa was highly effective against susceptible and resistant insects indicating no cross-resistance with Cry1F. In contrast, low levels of cross-resistance were observed for both Cry1Ab and Cry1Ac. Because the resistance is recessive and conferred by a single locus, an F1 screening assay was used to measure the frequency of Cry1F-resistant alleles from populations of Florida and Texas in 2010 and 2011. A total frequency of resistant alleles of 0.13 and 0.02 was found for Florida and Texas populations, respectively, indicating resistant alleles could be found in US populations, although there have been no reports of reduced efficacy of Cry1F expressing plants. PMID- 23941624 TI - A review of the metabolism of 1,4-butanediol diglycidyl ether-crosslinked hyaluronic acid dermal fillers. AB - BACKGROUND: Cosmetic procedures are growing ever more common, and the use of soft tissue fillers is increasing. Practicing physicians need to be aware of the biological behavior of these products in tissue to enable them to respond to any safety concerns that their patients raise. OBJECTIVES: To provide an overview of the metabolism of 1,4-butanediol diglycidyl ether (BDDE)-crosslinked hyaluronic acid (HA) dermal fillers and to examine the safety of the resulting byproducts. METHODS: A review of available evidence was conducted. RESULTS: After reaction with HA, the epoxide groups of BDDE are neutralized, and only trace amounts of unreacted BDDE remain in the product (<2 parts per million). When crosslinked HA, uncrosslinked HA, and unreacted BDDE degrade, they break down into harmless byproducts or into byproducts that are identical to substances already found in the skin. CONCLUSION: Clinical and biocompatibility data from longer than 15 years support the favorable clinical safety profile of BDDE-crosslinked HA and its degradation products. Given the strength of the empirical evidence, physicians should be confident in offering these products to their patients. PMID- 23941625 TI - Relative risk of irritable bowel syndrome following acute gastroenteritis and associated risk factors. AB - SUMMARY: A prospective cohort study using electronic medical records was undertaken to estimate the relative risk (RR) of irritable bowel syndrome (IBS) following acute gastroenteritis (GE) in primary-care patients in The Netherlands and explore risk factors. Patients aged 18-70 years who consulted for GE symptoms from 1998 to 2009, met inclusion/exclusion criteria and had at least 1 year of follow-up data were included. Patients with non-GE consultations, matched by age, gender, consulting practice and time of visit, served as the reference group. At 1 year, 1.2% of GE patients (N = 2428) had been diagnosed with IBS compared to 0.3% of the reference group (N = 2354). GE patients had increased risk of IBS [RR 4.85, 95% confidence interval (CI) 2.02-11.63]. For GE patients, concomitant cramps and history of psycho-social consultations were significantly associated with increased risk. GE patients had increased risk of IBS up to 5 years post exposure (RR 5.40, 95% CI 2.60-11.24), suggesting there may be other contributing factors. PMID- 23941620 TI - Role of RNA polymerase and transcription in the organization of the bacterial nucleoid. PMID- 23941626 TI - Apical root resorption during orthodontic treatment with aligners? A retrospective radiometric study. AB - INTRODUCTION: Objective of this study was to investigate the incidence and severity of apical root resorptions (ARR) during orthodontic treatment with aligners. MATERIALS AND METHODS: The sample comprised 100 patients (17-75 years of age) with a class I occlusion and anterior crowding before treatment, treated exclusively with aligners (Invisalign(r), Align Technologies, Santa Clara, CA, USA). The following teeth were assessed: upper and lower anterior teeth and first molars. Root and crown lengths of a total of 1600 teeth were measured twice in pre- and post-treatment panoramic radiographs. Afterwards, relative changes of the root length during treatment were calculated by a root-crown-ratio taking pre and post-treatment root and crown lengths into consideration. A reduction of this ratio was considered as a shortening of the initial root length. Additionally, tooth movements of the front teeth were assessed by lateral cephalograms and the 3-dimensonal set up of each patient. RESULTS: All patients had a reduction of the pre-treatment root length with a minimum of two teeth. On average 7.36 teeth per patient were affected. 54% of 1600 measured teeth showed no measurable root reduction. A reduction of >0%-10% of the pre-treatment root length was found in 27.75%, a distinct reduction of >10%-20% in 11.94%. 6.31% of all teeth were affected with a considerable reduction of >20%. We found no statistically significant correlation between relative root length changes and the individual tooth, gender, age or sagittal and vertical orthodontic tooth movement; except for extrusion of upper front teeth, which was considered as not clinical relevant due to the small amount of mean 4% ARR. CONCLUSIONS: The present study is the first analyzing ARR in patients with a fully implemented orthodontic treatment with aligners (i.e. resolving anterior crowding). The variety was high and no clinical relevant influence factor could be detected. A minimum of two teeth with a root length reduction was found in every patient. On average, 7.36 teeth per patient were affected. PMID- 23941627 TI - Concurrent partial splenic embolization with transcatheter arterial chemoembolization for hepatocellular carcinoma can maintain hepatic functional reserve. AB - AIM: Hepatocellular carcinoma (HCC) is frequently complicated with cirrhosis, and it is not unusual for treatment options to be limited as a result of pancytopenia due to hypersplenism. Partial splenic embolization (PSE) has been performed for thrombocytopenia resulting from hypersplenism. We studied the efficacy in terms of hepatic functional reserve and safety in patients who underwent concurrent transcatheter arterial chemoembolization (TACE) with PSE for HCC. METHODS: The study population consisted of 101 HCC patients with thrombocytopenia. Fifty-three patients were treated with concurrent TACE/PSE (PSE group), and the remaining 48 TACE patients without PSE (non-PSE group) were investigated hepatic functional reserve. RESULTS: Platelet counts were significantly higher in the PSE group after 2 weeks, 2 months and 6 months after TACE than the non-PSE group. Child Pugh score significantly deteriorated from 7.13 +/- 1.16 to 7.60 +/- 1.20 at 2 weeks, to 7.71 +/- 1.25 at 2 months, and 7.71 +/- 1.35 at 6 weeks after TACE in the non-PSE group. Hence, it worsened from 7.04 +/- 1.05 to 7.21 +/- 0.99 at 2 weeks temporally, but improved to 7.00 +/- 1.17 after 2 months and 6.70 +/- 1.16 at 6 weeks after TACE in the PSE group. CONCLUSION: Thrombocytopenia has been improved and treatment continued using concurrent PSE. In addition, hepatic functional reserve could be maintained even after treatment for HCC. Concurrent TACE and PSE for HCC with thrombocytopenia can be expected to help maintain hepatic reserve, and may contribute to improving the prognosis of HCC. PMID- 23941629 TI - Fumaric acid microenvironment tablet formulation and process development for crystalline cenicriviroc mesylate, a BCS IV compound. AB - Cenicriviroc mesylate (CVC) is a potent dual antagonist of C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) in phase 2b development as an entry inhibitor for HIV-1 infection treatment.1,2 CVC is a weak base exhibiting BCS IV characteristics with a highly pH dependent solubility profile (>100 mg/mL for pH < 2 and <0.2 MUg/mL for pH > 4) and low Caco-2 cell line permeability. Previous tablet formulations of CVC, including spray-dried dispersion and a wet granulation with citric acid, had been found unacceptable for commercial use due to chemical and physical instability or unacceptably high excipient loading precluding fixed-dose combinability. A high drug loading, 26% (w/w), acidic microenvironment tablet formulation with fumaric acid solubilizer (1:1 CVC/fumaric acid) and a dry granulation process was developed iteratively through a sequence of prototypes characterized by beagle dog absorption studies, focused beam reflectance measurement (FBRM), dynamic vapor sorption (DVS), and accelerated stability testing. The fumaric acid based dry granulated product demonstrated a mean bioavailability comparable to an oral solution dose in a dog model. Stability and moisture sensitivity of the formulation were improved via the dry granulation process technique and the use of fumaric acid. It is hypothesized that the observed slow dissolution kinetics of fumaric acid prolongs an acidic microenvironment around the agglomerated CVC crystals and excipients leading to increased CVC dissolution and thereby absorption. The fumaric acid formulation also demonstrated absorption resilience to gastric pH extremes in a dog model. This optimized formulation and process enables CVC to be a viable candidate for current HIV treatment paradigms of single once daily fixed-dose combination products. PMID- 23941630 TI - Uptake mechanism for iodine species to black carbon. AB - Natural organic matter (NOM) plays an important role in determining the fate and transport of iodine species such as iodide (I(-)) and iodate (IO3(-)) in groundwater system. Although NOM exists as diverse forms in environments, prior iodine studies have mainly focused on uptake processes of iodide and iodate to humic materials. This study was conducted to determine the iodide and iodate uptake potential for a particulate NOM (i.e., black carbon [BC]). A laboratory produced BC and commercial humic acid were used for batch experiments to compare their iodine uptake properties. The BC exhibited >100 times greater uptake capability for iodide than iodate at low pH of ~3, while iodide uptake was negligible for the humic acid. The uptake properties of both solids strongly depend on the initial iodine aqueous concentrations. After uptake reaction of iodide to the BC, X-ray absorption fine structure spectroscopy results indicated that the iodide was converted to electrophilic species, and iodine was covalently bound to carbon atom in polycyclic aromatic hydrocarbons present in the BC. The computed distribution coefficients (i.e., Kd values) suggest that the BC materials retard significantly the transport of iodide at low pH in environmental systems containing even a small amount of BC. PMID- 23941628 TI - Nonsteroidal anti-inflammatory drugs, gastroprotection, and benefit-risk. AB - BACKGROUND: Gastroprotective agents (GPA) substantially reduce morbidity and mortality with long-term nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin. OBJECTIVE: To evaluate efficacy of NSAIDs, protection against NSAID induced gastrointestinal harm, and balance of benefit and risk. METHODS: Free text searches of PubMed (December 2012) supplemented with "related citation" and "cited by" facilities on PubMed and Google Scholar for patient requirements, NSAID effectiveness, pain relief benefits, gastroprotective strategies, adherence to gastroprotection prescribing, and serious harm with NSAIDs and GPA. RESULTS: Patients want 50% reduction in pain intensity and improved fatigue, distress, and quality of life. Meta-analyses of NSAID trials in musculoskeletal conditions had bimodal responses with good pain relief or little. Number needed to treat (NNTs) for good pain relief were 3 to 9. Proton pump inhibitors (PPI) and high-dose histamine-2 receptor antagonists (H2 RA) provided similar gastroprotection, with no conclusive evidence of greater PPI efficacy compared with high-dose H2 RA. Prescriber adherence to guidance on use of GPA with NSAIDS was 49% in studies published since 2005; patient adherence was less than 100%. PPI use at higher doses over longer periods is associated with increased risk of serious adverse events, including fracture; no such evidence was found for H2 RA. Patients with chronic conditions are more willing to accept risk of harm for successful treatment than their physicians. CONCLUSION: Guidance on NSAIDs use should ensure that patients have a good level of pain relief and that gastroprotection is guaranteed for the NSAID delivering good pain relief. Fixed-dose combinations of NSAID plus GPA offer one solution. PMID- 23941631 TI - Efficacy of early treatment with toltrazuril in prevention of coccidiosis and necrotic enteritis in chickens. AB - In the present study, efficacy of the toltrazuril treatment for prevention of coccidiosis and necrotic enteritis was tested. Ninety-six 14-day-old commercial broiler chickens were caged and divided into eight groups (n=12), designated groups 1 to 8. Chickens of groups 1 to 6 were inoculated orally at 18 days of age with 25,000 oocysts of Eimeria tenella and 75,000 oocysts of Eimeria brunetti. At 22 days of age, chickens of groups 1 to 6 were infected with 10(9) colony-forming unit Clostridium perfringens. Chickens of group 1 were treated with 75 parts/10(6) toltrazuril in drinking water for 8 h on two consecutive days up to 12 h before Eimeria infection, while chickens of groups 2 to 5 were treated with the same dose of toltrazuril at 12 h, 36 h, 60 h and 84 h after Eimeria infection, respectively. The non-treated group 6 served as a positive control. Chickens in group 7 were treated with toltrazuril at 17 and 18 days of age, and those of group 8 remained uninfected and non-treated as a negative control. The feed conversion ratio was higher in the positive control compared with other groups. The mortality rates were 16.8% and 41.7% in the late toltrazuril-treated (at 84 h) and infected non-treated chickens, respectively. Lesions scores of necrotic enteritis or coccidiosis in infected, non-treated chickens were significantly more severe compared with negative controls (P<0.01) and late toltrazuril-treated (at 84 h) chickens (P<0.05). In conclusion, application of toltrazuril before Eimeria challenge protected chickens from coccidiosis and indirectly from successive necrotic enteritis caused by C. perfringens infection. PMID- 23941632 TI - Percutaneous transhepatic biliary drainage assisted by real-time virtual sonography: a retrospective study. AB - BACKGROUND: Real-time virtual sonography (RVS) is a diagnostic imaging support system that can synchronize with ultrasound images in conjunction with computed tomography or magnetic resonance images using magnetic navigation system. RVS has been applied in clinical practice to perform such procedures as radiofrequency ablation and biopsy; however, the application of RVS for percutaneous transhepatic biliary drainage (PTBD) is rare. METHODS: Between 2007 and 2012, RVS assisted PTBD was performed for 30 patients (19 males and 11 females; age range, 41 to 89 years; mean age, 66.9 years) with obstructive jaundice. The targeted bile duct was determined using the RVS system before the procedure. The intervention was considered to be successful when the targeted bile duct was punctured and the drainage catheter was placed in the bile duct. Complications were evaluated according to the Society of Interventional Radiology Clinical Practice Guidelines. RESULTS: A total of 37 interventions were performed for 30 patients. The interventions were successful in 35 (95%) of 37 interventions. The targeted bile ducts were: B3 (n = 24), B5 (n = 7), B8 (n = 3), B6 (n = 1), and the anterior (n = 1) and posterior (n = 1) branches of the right bile duct. The mean targeted bile duct diameter was 4.9 mm (1.9 to 8.2 mm). PTBD was able to be accomplished in all patients because the non-targeted bile ducts were successfully punctured alternatively. No major complications were observed in relation to the interventional procedure. CONCLUSIONS: RVS-assisted PTBD is a feasible and safe procedure. Accurate puncture of targeted bile ducts can be achieved using this method. PMID- 23941634 TI - Perfluorooctanoic acid induced-developmental cardiotoxicity: are peroxisome proliferator activated receptor alpha (PPARalpha) and bone morphorgenic protein 2 (BMP2) pathways involved? AB - Perfluorooctanoic acid (PFOA) is an environmental contaminant known to induce developmental toxicity in animal models through activation of the peroxisome proliferator-activated receptor alpha (PPARalpha). Previously, it was demonstrated that in ovo exposure to PFOA induced cardiotoxicity in chicken embryos and hatchlings. To investigate potential PPARalpha-mediated mechanisms, fertile chicken eggs were injected prior to incubation with WY 14,643, a PPARalpha agonist. Cardiac morphology and function were evaluated in late-stage embryos and hatchlings. Histologically, unlike PFOA, WY 14,643 did not induce thinning of the right ventricular wall. Via echocardiography, however, WY 14,643 induced effects similar to those of PFOA, including increased left ventricular wall thickness and mass, elevated heart rate, ejection fraction, fractional shortening, and decreased stroke volume. Additionally, to investigate mechanisms associated with early heart development, a separate group of fertile chicken eggs was injected prior to incubation with PFOA or WY 14,643 and in early-stage embryos, gene expression and protein concentration associated with the bone morphogenic protein (BMP2) pathway were determined. Although changes were not statistically consistent among doses, expression of BMP2, Nkx2.5, and GATA4 mRNA in early embryos was altered by PFOA exposure; however, protein concentrations of these targets were not markedly altered by either PFOA or WY 14,643. Protein levels of pSMAD1/5, a transcriptional regulator stimulated by BMPs, were altered by both PFOA and WY 14,643, but in different directions; PFOA reduced cytoplasmic pSMAD1/5, whereas WY 14,643 decreased nuclear pSMAD1/5. Taken together, these data suggest that developmental cardiotoxicity induced by PFOA likely involves both PPARalpha and BMP2 pathways. PMID- 23941635 TI - Pulmonary and cardiovascular responses of rats to inhalation of silver nanoparticles. AB - Exposure to wet aerosols generated during use of spray products containing silver (Ag) has not been evaluated. The goal was to assess the potential for cardiopulmonary toxicity following an acute inhalation of wet silver colloid. Rats were exposed by inhalation to a low concentration (100 MUg/m(3) ) using an undiluted commercial antimicrobial product (20 mg/L total silver; approximately 33 nm mean aerodynamic diameter [MAD]) or to a higher concentration (1000 MUg/m(3)) using a suspension (200 mg/L total silver; approximately 39 nm MAD) synthesized to possess a similar size distribution of Ag nanoparticles for 5 h. Estimated lung burdens from deposition models were 0, 1.4, or 14 MUg Ag/rat after exposure to control aerosol, low, and high doses, respectively. At 1 and 7 d postexposure, the following parameters were monitored: pulmonary inflammation, lung cell toxicity, alveolar air/blood barrier damage, alveolar macrophage activity, blood cell differentials, responsiveness of tail artery to vasoconstrictor or vasodilatory agents, and heart rate and blood pressure in response to isoproterenol or norepinephrine, respectively. Changes in pulmonary or cardiovascular parameters were absent or nonsignificant at 1 or 7 d postexposure with the exceptions of increased blood monocytes 1 d after high-dose Ag exposure and decreased dilation of tail artery after stimulation, as well as elevated heart rate in response to isoproterenol 1 d after low-dose Ag exposure, possibly due to bioavailable ionic Ag in the commercial product. In summary, short-term inhalation of nano-Ag did not produce apparent marked acute toxicity in this animal model. PMID- 23941633 TI - A goal management intervention for polyarthritis patients: rationale and design of a randomized controlled trial. AB - BACKGROUND: A health promotion intervention was developed for inflammatory arthritis patients, based on goal management. Elevated levels of depression and anxiety symptoms, which indicate maladjustment, are found in such patients. Other indicators of adaptation to chronic disease are positive affect, purpose in life and social participation. The new intervention focuses on to improving adaptation by increasing psychological and social well-being and decreasing symptoms of affective disorders. Content includes how patients can cope with activities and life goals that are threatened or have become impossible to attain due to arthritis. The four goal management strategies used are: goal maintenance, goal adjustment, goal disengagement and reengagement. Ability to use various goal management strategies, coping versatility and self-efficacy are hypothesized to mediate the intervention's effect on primary and secondary outcomes. The primary outcome is depressive symptoms. Secondary outcomes are anxiety symptoms, positive affect, purpose in life, social participation, pain, fatigue and physical functioning. A cost-effectiveness analysis and stakeholders' analysis are planned. METHODS/DESIGN: The protocol-based psycho-educational program consists of six group-based meetings and homework assignments, led by a trained nurse. Participants are introduced to goal management strategies and learn to use these strategies to cope with threatened personal goals. Four general hospitals participate in a randomized controlled trial with one intervention group and a waiting list control condition. DISCUSSION: The purpose of this study is to evaluate the effectiveness of a goal management intervention. The study has a holistic focus as both the absence of psychological distress and presence of well being are assessed. In the intervention, applicable goal management competencies are learned that assist people in their choice of behaviors to sustain and enhance their quality of life. TRIAL REGISTRATION: Nederlands Trial Register = NTR3606, registration date 11-09-2012. PMID- 23941637 TI - Methodology for national risk analysis and prioritization of toxic industrial chemicals. AB - The identification of chemicals that pose the greatest threat to human health from incidental releases is a cornerstone in public health preparedness for chemical threats. The present study developed and applied a methodology for the risk analysis and prioritization of industrial chemicals to identify the most significant chemicals that pose a threat to public health in Finland. The prioritization criteria included acute and chronic health hazards, physicochemical and environmental hazards, national production and use quantities, the physicochemical properties of the substances, and the history of substance-related incidents. The presented methodology enabled a systematic review and prioritization of industrial chemicals for the purpose of national public health preparedness for chemical incidents. PMID- 23941638 TI - Electrophysiological responses to visuospatial regularity. AB - Humans are quicker to detect reflectional than rotational or translational symmetry, despite the fact that these patterns are equally regular. We were interested in the neural correlates of these perceptual effects. Participants viewed random, reflection, rotation, and translation patterns while we recorded EEG from the scalp. Half the participants classified the pattern regularity overtly, the other half did not explicitly attend to pattern regularity but reported rare oddball trials, where two squares were embedded among the dots. The amplitude of a symmetry-related ERP known as the sustained posterior negativity was most pronounced for reflection, then rotation and translation. We suggest that reflectional symmetry, despite its biological significance, may not be processed by unique visual mechanisms, but instead it could be a preferred stimulus for a more general regularity-sensitive network in the extrastriate visual cortex. PMID- 23941636 TI - Popcorn flavoring effects on reactivity of rat airways in vivo and in vitro. AB - "Popcorn workers' lung" is an obstructive pulmonary disease produced by inhalation of volatile artificial butter flavorings. In rats, inhalation of diacetyl, a major component of butter flavoring, and inhalation of a diacetyl substitute, 2,3-pentanedione, produce similar damage to airway epithelium. The effects of diacetyl and 2,3-pentanedione and mixtures of diacetyl, acetic acid, and acetoin, all components of butter flavoring, on pulmonary function and airway reactivity to methacholine (MCh) were investigated. Lung resistance (RL) and dynamic compliance (Cdyn) were negligibly changed 18 h after a 6-h inhalation exposure to diacetyl or 2,3-pentanedione (100-360 ppm). Reactivity to MCh was not markedly changed after diacetyl, but was modestly decreased after 2,3 pentanedione inhalation. Inhaled diacetyl exerted essentially no effect on reactivity to mucosally applied MCh, but 2,3-pentanedione (320 and 360 ppm) increased reactivity to MCh in the isolated, perfused trachea preparation (IPT). In IPT, diacetyl and 2,3-pentanedione (>=3 mM) applied to the serosal and mucosal surfaces of intact and epithelium-denuded tracheas initiated transient contractions followed by relaxations. Inhaled acetoin (150 ppm) exerted no effect on pulmonary function and airway reactivity in vivo; acetic acid (27 ppm) produced hyperreactivity to MCh; and exposure to diacetyl + acetoin + acetic acid (250 + 150 + 27 ppm) led to a diacetyl-like reduction in reactivity. Data suggest that the effects of 2,3-pentanedione on airway reactivity are greater than those of diacetyl, and that flavorings are airway smooth muscle relaxants and constrictors, thus indicating a complex mechanism. PMID- 23941639 TI - Impact of extended-spectrum beta-lactamase on acute pyelonephritis treated with empirical ceftriaxone. AB - BACKGROUND: Ceftriaxone is frequently administered empirically for hospitalized patients with acute pyelonephritis (APN) due to prevalent quinolone resistance in our hospital; however, its use is inappropriate for extended-spectrum beta lactamase (ESBL)-producing Escherichia coli, an increasing problem. METHODS: A retrospective, 1:2 matched cohort study was performed to evaluate the impact of ESBL on APN treated with empirical ceftriaxone. Each patient in ESBL group was matched with two patients in the non-ESBL group, using a 16-point scoring system, which included age, sex, bacteremia, simplified acute physiology score 2, Charlson comorbidity index and APN severity score. RESULTS: From 2009 to 2011, among 1,322 community-onset cases of the E. coli bacteriuria with 212 (16%) ESBL producers, 261 patients with APN were treated empirically with ceftriaxone in a secondary care hospital. Among these 261 cases, twenty-six patients in the ESBL group and 52 matched patients in the non-ESBL group (1:2) were included. Mean time to defervescence was 4.6+/-2.2 days in the ESBL group and 2.6+/-1.3 days in the non-ESBL group (p<0.01). Rate of microbiological resolution within 5 days after antibiotic treatment was 77% (17/22) in the ESBL group and 100% (45/45) in the non-ESBL group (p=0.01). The duration of hospitalization was 13.3+/-8.2 days in the ESBL group and 7.3+/-3.5 days in the non-ESBL group (p<0.01). No patient died in either group. CONCLUSION: Empirical ceftriaxone therapy for APN caused by ESBL-producing E. coli is inappropriate, and consequently can delay recovery and result in longer hospitalization. PMID- 23941640 TI - Structural refinement of ladder-type perylenediimide dimers: a classical tale of conformational dynamics. AB - We have synthesized and thoroughly characterized two representative ladder-type acetylene-bridged perylenediimide dimers bearing long alkyl chain solubilizing groups, bis[1-ethynyl-N,N'-bis(1-hexylheptyl)-perylene-3,4:9,10-tetracarboxylic diimide] ([PDICC]2, 1) and 1,1'-ethynyl-bis[N,N'-bis(1-hexylheptyl)-perylene 3,4:9,10-tetracarboxylic diimide] ([PDI]2CC, 2). In these dimeric PDI molecules, NMR-based structural characterization became nontrivial because severe (1)H spectral broadening and greater than expected numbers of observed (13)C resonances substantially complicated the interpretation of traditional 1-D spectra. However, rational two-dimensional NMR approaches based on both homo- and heteronuclear couplings ((1)H-(1)H COSY; (1)H-(13)C HSQC), in conjunction with high-level structural DFT calculations (GIAO/B3LYP/6-31G(d,p)/PCM, chloroform), were readily applied to these structures, producing well-defined analytical characterization, and the associated methodology is described in detail. Furthermore, on the basis of dynamic NMR experiments, both 1 and 2 were found to exist in a perylene-centered conformational dynamic equilibrium (DeltaG? = 13-17 kcal/mol), which primarily caused the observed ambiguities in conventional 1-D spectra. PMID- 23941641 TI - Molecular modelling on small molecular CDK2 inhibitors: an integrated approach using a combination of molecular docking, 3D-QSAR and pharmacophore modelling. AB - Cyclin-dependent kinase 2 (CDK2) has been identified as an important target for developing novel anticancer agents. Molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR) and pharmacophore modelling were combined with the ultimate goal of studying the structure-activity relationship of CDK2 inhibitors. The comparative molecular similarity indices analysis (CoMSIA) model constructed based on a set of 3-aminopyrazole derivatives as CDK2 inhibitors gave statistically significant results (q (2) = 0.700; r (2) = 0.982). A HypoGen pharmacophore model, constructed using diverse CDK2 inhibitors, also showed significant statistics ([Formula: see text]Cost = 61.483; RMSD = 0.53; Correlation coefficient = 0.98). The small residues and error values between the estimated and experimental activities of the training and test set compounds proved their strong capability of activity prediction. The structural insights obtained from these two models were consistent with each other. The pharmacophore model summarized the important pharmacophoric features required for protein-ligand binding. The 3D contour maps in combination with the comprehensive pharmacophoric features helped to better interpret the structure-activity relationship. The results will be beneficial for the discovery and design of novel CDK2 inhibitors. The simplicity of this approach provides expansion to its applicability in optimizing other classes of small molecular CDK2 inhibitors. PMID- 23941642 TI - Role, Function and Therapeutic Potential of microRNAs in Vascular Aging. AB - Due to increased life expectancy in a growing world population, the impact of ageing on the pathophysiology of cardiovascular diseases will increase. Therefore, a better understanding of age-related biological changes is important and necessary to combat cardiovascular diseases in the future. microRNAs (miRs) are small non coding RNAs emerging as key regulator in several vascular pathologies such as atherosclerosis or hypertension, which show a clear association with increasing age. This review discusses the involvement of miRs in several age-associated pathologies such as oxidative stress, vascular inflammation, vascular tension, endothelial cell senescence and impaired angiogenesis. PMID- 23941643 TI - Energy-efficient encoding by shifting spikes in neocortical neurons. AB - The speed of computations in neocortical networks critically depends on the ability of populations of spiking neurons to rapidly detect subtle changes in the input and translate them into firing rate changes. However, high sensitivity to perturbations may lead to explosion of noise and increased energy consumption. Can neuronal networks reconcile the requirements for high sensitivity, operation in a low-noise regime, and constrained energy consumption? Using intracellular recordings in slices from the rat visual cortex, we show that layer 2/3 pyramidal neurons are highly sensitive to minor input perturbations. They can change their population firing rate in response to small artificial excitatory postsynaptic currents (aEPSCs) immersed in fluctuating noise very quickly, within 2-2.5 ms. These quick responses were mediated by the generation of new, additional action potentials (APs), but also by shifting spikes into the response peak. In that latter case, the spike count increase during the peak and the decrease after the peak cancelled each other, thus producing quick responses without increases in total spike count and associated energy costs. The contribution of spikes from one or the other source depended on the aEPSCs timing relative to the waves of depolarization produced by ongoing activity. Neurons responded by shifting spikes to aEPSCs arriving at the beginning of a depolarization wave, but generated additional spikes in response to aEPSCs arriving towards the end of a wave. We conclude that neuronal networks can combine high sensitivity to perturbations and operation in a low-noise regime. Moreover, certain patterns of ongoing activity favor this combination and energy-efficient computations. PMID- 23941644 TI - Dislodgement of port-A catheters in pediatric oncology patients: 11 years of experience. AB - BACKGROUND: Port-A catheters are frequently used in pediatric cancer patients. Their dislodgement is potentially seriously risky although the incidence is not high. We analyzed our 11 years of data to address this important problem. METHODS: From January 2001 to December 2011, 330 port-A catheters of different brands were implanted in pediatric cancer patients. In total, eight children suffered a dislodgement of their catheter. Their ages ranged from four to thirteen years, with a median age of ten. Five patients presented with catheter dysfunction, two presented with a cough and one was identified incidentally during surgery to remove his port. RESULTS: The downstream ends of the dislodged catheters were located in the right atrium (three patients), left pulmonary artery (three) and inferior vena cava (two). Six of the eight catheters were broken at the site of anastomosis to the port and the other two were broken halfway in between. All episodes of dislodgement happened after the chemotherapy regimen was completed. The dislodged catheters were successfully retrieved without complications by transcatheter retrieval using a gooseneck snare. CONCLUSIONS: The dislodgment rate of port-A catheter in our series was 2.4%. Chest X-rays can rapidly detect the problem. Most of the catheters were broken at the site of anastomosis. Earlier explantation of port-A catheters after completing chemotherapy may be considered to avoid the dislodgement of catheters, but this needs to be weighed against the possibility of underlying disease recurrence. However, we should re-examine how long port-A catheters need to be retained after chemotherapy considering the improved cure rate of pediatric cancer. PMID- 23941645 TI - The impact of roller compaction and tablet compression on physicomechanical properties of pharmaceutical excipients. AB - Material properties play a significant role in pharmaceutical processing. The impact of roller compaction (RC) and tablet compression on solid fraction (SF), tensile strength (TS) and flexural modulus (FM) of Avicel DG [co-processed excipient with 75% microcrystalline cellulose (MCC) and 25% anhydrous dibasic calcium phosphate (DCPA)], lactose and 1:1 Mixture of the two was studied. Materials were roller compacted at different force and roller type and compressed into tablets over a range of compression pressures (CP). SF, TS and FM were determined for ribbons and tablets. Roller force was a significant variable affecting SF while roller type was not. Both SF and TS of tablets increased with CP with Avicel DG exhibiting greater TS than that of 1:1 Mixture while tablets of lactose had the lowest TS. The TS of tablets decreased exponentially with tablet porosity. Ribbon of Avicel DG had higher TS and lower SF than lactose and greater reworkability. This is attributed to plastic deformation of MCC resulting in high degree of bonding and fragmentation of DCPA that fills the void spaces during tablet compression. The lack of significant increase in SF and low tablet TS for lactose upon compression is likely due to its brittle fragmentation and some elastic recovery as shown by the high FM. PMID- 23941646 TI - Primary cutaneous follicular helper T-cell lymphoma: diagnostic pitfalls of this new lymphoma subtype. AB - The recently proposed entity of cutaneous follicular helper T (T(FH)) cell lymphoma (CT(FH)CL) harbors distinct clinical and histopathologic features. Here, diagnostic pitfalls are exemplified in a case report and by review of the literature. A 45-year-old patient developed rapidly growing nodules and plaques on upper arms and buttocks, which were initially misdiagnosed as primary cutaneous follicle center B-cell lymphoma (CFCL). Consequently, systemic therapy with rituximab failed and consecutive skin biopsies revealed CT(FH)CL (CD3+CD4+CD10+PD-1+bcl6+ICOS+CXCL13+). Interestingly, the prima vista PD-1 positive and CD10-positive tumor cells lost PD-1 expression in follow-up biopsies while retaining CD10, ICOS and CXCL13 expression. All biopsy specimens displayed an identical clonal T-cell population. Initially, nodules were controlled by local radiotherapy and oral psoralen combined with ultraviolet A (PUVA) therapy. However, disease recurred and progressed rapidly with disseminated nodules. Treatment with bexarotene, methotrexate and polychemotherapy failed to stop disease progression. Finally, modified total skin electron beam radiation resulted in complete remission. Disease stabilized on maintenance therapy with bexarotene in combination with ultraviolet A (UVA) therapy. The case highlights that because of concomitant B-cell stimulation, CT(FH)CL clinicopathologically is prone to be mistaken for CFCL. Importantly, CT(FH)CL might lose PD-1 while retaining CD10 expression in later stages, which may lead to confusion in distinguishing CT(FH)CL from CFCL. PMID- 23941647 TI - Bilayer molecular electronics: all-carbon electronic junctions containing molecular bilayers made with "click" chemistry. AB - Bilayer molecular junctions were fabricated by using the alkyne/azide "click" reaction on a carbon substrate, followed by deposition of a carbon top contact in a crossbar configuration. The click reaction on an alkyne layer formed by diazonium reduction permitted incorporation of a range of molecules into the resulting bilayer, including alkane, aromatic, and redox-active molecules, with high yield (>90%) and good reproducibility. Detailed characterization of the current-voltage behavior of bilayer molecular junctions indicated that charge transport is consistent with tunneling, but that the effective barrier does not strongly vary with molecular structure for the series of molecules studied. PMID- 23941648 TI - Role of organolithium aggregates and mixed aggregates in organolithium mechanisms. PMID- 23941650 TI - Is postdilatation with a noncompliant balloon necessary after coronary stent deployment during primary angioplasty? AB - BACKGROUND: Postdilatation (PD) with noncompliant balloon during elective percutaneous coronary intervention (PCI) is performed usually in clinical practice in order to optimize stent expansion. However, current knowledge about its use in patients undergoing primary PCI is controversial. This study aims to evaluate the angiographical and clinical results of PD in patients who underwent primary PCI with drug eluting stents (DESs). METHODS: A total of 405 consecutive patients (mean age 56.9 +/- 12.3 years; 302 male) with ST elevation myocardial infarction were evaluated retrospectively. Patients received DES with or without predilatation according to physician's discretion. Eligible patients were divided into 2 groups based on PD procedure. The clinical end-points were death, target vessel revascularization (TVR) and stent thrombosis at 6 months after PCI. The angiographic end-points were postprocedural correct Thrombolysis in Myocardial Infarction (TIMI) frame count (cTFC), final TIMI flow, and myocardial blush grade (MBG). RESULTS: PD was performed in 214 patients (52.8%). Angiographical parameters such as TIMI flow, cTFC, and MBG did not differ after PD (P>0.05). During 6-month follow-up, TVR and stent thrombosis rates were lower in the PD group (6 vs. 16, P=0.03; and 3 vs. 10, P=0.04, respectively). PD and diabetes were detected as independent predictors of MACE (beta=0.52, P=0.01, and beta= 0.47, P=0.02; respectively). CONCLUSION: Our study revealed that PD does not yield adverse effects on final angiographic parameters when performed during primary PCI. Besides PD seems to decrease probability of stent thrombosis and TVR. PMID- 23941649 TI - Synthesis of omega-hydroxy dodecanoic acid based on an engineered CYP153A fusion construct. AB - A bacterial P450 monooxygenase-based whole cell biocatalyst using Escherichia coli has been applied in the production of omega-hydroxy dodecanoic acid from dodecanoic acid (C12-FA) or the corresponding methyl ester. We have constructed and purified a chimeric protein where the fusion of the monooxygenase CYP153A from Marinobacter aquaeloei to the reductase domain of P450 BM3 from Bacillus megaterium ensures optimal protein expression and efficient electron coupling. The chimera was demonstrated to be functional and three times more efficient than other sets of redox components evaluated. The established fusion protein (CYP153AM. aq. -CPR) was used for the hydroxylation of C12-FA in in vivo studies. These experiments yielded 1.2 g l(-1) omega-hydroxy dodecanoic from 10 g l(-1) C12-FA with high regioselectivity (> 95%) for the terminal position. As a second strategy, we utilized C12-FA methyl ester as substrate in a two-phase system (5:1 aqueous/organic phase) configuration to overcome low substrate solubility and product toxicity by continuous extraction. The biocatalytic system was further improved with the coexpression of an additional outer membrane transport system (AlkL) to increase the substrate transfer into the cell, resulting in the production of 4 g l(-1) omega-hydroxy dodecanoic acid. We further summarized the most important aspects of the whole-cell process and thereupon discuss the limits of the applied oxygenation reactions referring to hydrogen peroxide, acetate and P450 concentrations that impact the efficiency of the production host negatively. PMID- 23941651 TI - Glycoprotein IIb/III inhibition during acute percutaneous coronary intervention: tool or talisman? PMID- 23941652 TI - GuideLiner mother-and-child guide catheter extension: a simple adjunctive tool in PCI for balloon uncrossable chronic total occlusions. AB - OBJECTIVES: To investigate the use of the GuideLiner "mother-and-child" guide catheter extension system as a simple solution to facilitate initial device delivery in balloon uncrossable chronic total occlusions (CTOs) undergoing percutaneous coronary intervention (PCI). BACKGROUND: During PCIs for CTO lesions, an important reason for procedural failure is the inability to deliver a balloon or microcatheter across the lesion. METHODS: We retrospectively accessed our interventional registry for 07/01/2010 to 03/21/2012 and extracted data on all CTO lesions involving GuideLiner catheter use. Cine review was performed to identify cases where a guidewire had crossed the CTO and the use of a GuideLiner catheter facilitated initial device delivery. RESULTS: We identified 28 patients that underwent PCI for CTO with a GuideLiner catheter used to assist initial balloon or microcatheter advancement across the culprit lesion. Mean overall CTO length was 26.3 +/- 18.1 mm. The GuideLiner catheter was successful in delivering a small balloon to the CTO lesion in 85.7% of cases (24/28). A single CTO PCI resulted in a distal guidewire perforation, but there was no hemodynamic compromise or pericardial effusion and the patient was discharged the next day. Overall procedural success in these selected cases (where a guidewire had already crossed the CTO) was 89.3% (25/28). CONCLUSIONS: The GuideLiner mother-and-child catheter is a simple, safe and efficacious adjunctive device for difficult CTO PCIs where despite standard measures it is not possible to deliver an initial balloon or microcatheter across the occluded segment. PMID- 23941653 TI - Simvastatin decreases stent-induced in-stent restenosis rate via downregulating the expression of PCNA and upregulating that of p27kip1. AB - BACKGROUND: The inhibition of the proliferation and migration of vascular smooth muscle cells (VSMC) is one cholesterol-independent effect of statins that could lower the rate of in-stent restenosis (ISR), even if the exact mechanism remains unclear. The aim of this study was to explore the exact inhibitory mechanisms of simvastatin on ISR in vivo. METHODS: Forty-five rabbits were randomized into 3 feeding groups of equal size (n=15): normal rabbit chow (normal group), a high cholesterol diet (control group), and a simvastatin-enriched high-cholesterol diet (simvastatin group). Balloon de-endothelialization was first performed in the control and simvastatin groups after 3 days, followed by stent deployment at week 14. All rabbits were killed at week 18, and the histological changes of the ISR segments were observed. The expressions of cyclin-dependent kinase inhibitor p27 (p27kip1), proliferating cell nuclear antigen (PCNA), and alpha-smooth muscle (alpha-SM) actin were measured. RESULTS: In the simvastatin group compared to the control group, the neointimal thickness, neointimal area, and degree of stenosis decreased, while the residual lumen area increased significantly (P<0.05). Moreover, the expression of alpha-SM actin in the control group decreased by 55.4% compared to the normal group, while it increased by 29.7% with respect to the simvastatin group (P<0.05). Finally, the expression of p27kip1 increased, while that of PCNA decreased significantly in the simvastatin group compared to the control group (P<0.05). CONCLUSIONS: Simvastatin may inhibit VSMC phenotype modulation and proliferation by downregulating the expression of PCNA and upregulating that of p27kip1. PMID- 23941654 TI - Impact of interatrial septum anatomic features on short- and long-term outcomes after transcatheter closure of patent foramen ovale: single device type versus anatomic-driven device selection strategy. AB - BACKGROUNDS: We reported the short- and long-term results of our institutional single center registry Interatrial Septum Interventions Study (ISIS) about the impact of different anatomic characteristics and related device selection in patent foramen ovale (PFO) closure. METHODS: Over a 9 year period (September 2003 September 2012) we prospectively enrolled 340 consecutive patients (mean age 44 +/- 15. 5 years, 198 females) who had been referred to our center for PFO catheter-based closure. The first 105 patients received a single type of device independently from the anatomy (single device strategy). The remaining 235 patients received a different device based on intracardiac echocardiographic study of interatrial septum anatomy (anatomic strategy). RESULTS: Immediate success rate was 100% in both groups, whereas the rate of immediate complications was 10.4% and 2.5% (P<0.01) in the single strategy group and anatomic strategy group, respectively. During a mean follow-up of 59.3 +/- 28.9 months, the occlusion rate was 86.6% and 94%, whereas the incidence of recurrences was 1.8% and 0% in the single device strategy group and anatomic strategy group, respectively. CONCLUSION: The results from ISIS registry showed that anatomy of interatrial septum associated with PFO is quite complex leading to an increased rate of complications and a slightly lower closure rate if treated with a single device strategy. PMID- 23941655 TI - Experience with the Atrium Advanta covered stent for aortic obstruction. AB - INTRODUCTION: We sought to assess the efficacy, safety and clinical outcomes of the Advanta V12TM covered stent in management of coarctation of the aorta (CoA). MATERIALS AND METHODS: Stent functionality was assessed by review of angiographic imaging, clinical data at admission, discharge and at the last clinic visit, stent configuration on chest roentgenogram, radiation exposure, and complications. RESULTS: Between October 2009 and February 2012, 17 patients underwent stent implantation. There were 9-12, 2-14, and 6-16 mm diameter stents deployed. Balloon angioplasty after implantation was required in 2 patients. Mean percent recoil in the middle of the stent for the 12, 14, and 16 mm implants was 14%, 24%, and 24%, respectively. There was improvement in CoA diameter from 6.6 +/- 3.2 to 11.5 +/- 1.7 mm (P<0.0001) and a reduction in the peak pressure gradient from 23.1 +/- 10.1 to 0.8 +/- 3.3 mmHg (P<0.0001). No patient had a symptomatic complication. Left arm cuff blood pressure fell 24 hours after implantation and left arm to leg blood pressure gradient fell to <20 mmHg in all (P<0.0001). Follow-up was a median 242 days and at the last clinic visit there were no statistically different findings from discharge. Five children (33%) required antihypertensive medications but 3 were off medication at latest follow up. Three patients (18%) required reintervention. CONCLUSION: The implantation of the AdvantaTM V12 stent for the treatment of CoA is safe and effective in the early term. However, further study is required to determine longer-term stent efficacy. PMID- 23941656 TI - First clinical experience with Celt ACD((r)) : a femoral arterial puncture closure device. AB - INTRODUCTION: This prospective nonrandomized study compared the safety and efficacy of a novel arterial closure device (ACD) in common femoral artery procedures to that of the FDA submitted historical manual pressure control group, who underwent either a diagnostic angiogram (DA) or a percutaneous coronary intervention (PCI) procedure. METHODS AND RESULTS: A total of 55 patients were enrolled in this study of the novel ACD. Of the 55 patients, 39 were enrolled in the DA group and 16 were enrolled in the PCI group. Six patients were excluded. A device was deployed in 49 patients. Time to hemostasis (TTH), time to ambulation (TTA), device function, and device-related vascular complications were measured. In the device group, the TTH for the combined DA and PCI patients was 32 seconds (0.54 +/- 0.93 minutes), significantly lower when compared with 16.0 +/- 12.2 minutes (P<0.0001) for the control group. Overall major vascular complication rate did not differ significantly, device group (1/49) and the historical control group (1/217). TTA in the combined PCI and DA device group was 226.4 +/- 231.9 at the German site (site ambulation policy). In the Irish site, the average TTA in the PCI group was 187 minutes (n=8) and 85 minutes (n=14) in the DA group. CONCLUSION: The Celt ACD(r) device is safe, effective, and significantly decreases the TTH compared to manual pressure and has a low vascular complications rate. The device may be effective in early ambulation and discharge of patients postcoronary intervention procedures. PMID- 23941658 TI - Tonsillectomy ameliorates histological damage of recurrent immunoglobulin A nephropathy after kidney transplantation. AB - AIM: Recurrence of immunoglobulin A (IgA) nephropathy (IgAN) after renal transplantation is important as a cause of graft failure under improving rejection control. However, no specific therapy for recurrent IgAN is currently available. In this study, we evaluated the histological efficacy of tonsillectomy for allograft IgAN. METHODS: Fifteen kidney recipients (male 9, female 6, mean age 40.9 +/- 9.3 years), who received a diagnosis of IgA nephropathy by allograft biopsy, were enrolled in this study. Tonsillectomy was performed 44.1 +/- 27.1 months after the kidney transplantation. All patients underwent a repeat graft biopsy at 23.8 +/- 15.8 months after tonsillectomy. RESULTS: Six patients had microhematuria before tonsillectomy. At 12 months after treatment, the microhematuria disappeared in five of these patients and one patient had mild hematuria. Three patients had severe proteinuria (more than 1.0 g/gCr) before tonsillectomy and improved after treatment. On histological analysis, four patients had acute lesions including cellular or fibrocellular crescents. The acute lesions disappeared after these treatments in all patients. Eleven patients had chronic lesions including global sclerosis, segmental sclerosis and fibrous crescents. The chronic lesion was ameliorated in six patients, unchanged in three and deteriorated in two patients. CONCLUSIONS: Tonsillectomy improves not only clinical findings but also ameliorates histological damage caused by recurrent IgAN after kidney transplantation. Tonsillectomy is a novel and effective treatment for recurrent IgAN. PMID- 23941657 TI - Commensal Clostridia: leading players in the maintenance of gut homeostasis. AB - The gastrointestinal tract is a complex and dynamic network where an intricate and mutualistic symbiosis modulates the relationship between the host and the microbiota in order to establish and ensure gut homeostasis. Commensal Clostridia consist of gram-positive, rod-shaped bacteria in the phylum Firmicutes and make up a substantial part of the total bacteria in the gut microbiota. They start to colonize the intestine of breastfed infants during the first month of life and populate a specific region in the intestinal mucosa in close relationship with intestinal cells. This position allows them to participate as crucial factors in modulating physiologic, metabolic and immune processes in the gut during the entire lifespan, by interacting with the other resident microbe populations, but also by providing specific and essential functions. This review focus on what is currently known regarding the role of commensal Clostridia in the maintenance of overall gut function, as well as touch on their potential contribution in the unfavorable alteration of microbiota composition (dysbiosis) that has been implicated in several gastrointestinal disorders. Commensal Clostridia are strongly involved in the maintenance of overall gut function. This leads to important translational implications in regard to the prevention and treatment of dysbiosis, to drug efficacy and toxicity, and to the development of therapies that may modulate the composition of the microflora, capitalizing on the key role of commensal Clostridia, with the end goal of promoting gut health. PMID- 23941659 TI - Competition between honeydew producers in an ant-hemipteran interaction may enhance biological control of an invasive pest. AB - Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Liviidae), is an invasive citrus pest in southern California, which secretes honeydew and has the potential to spread a lethal bacterial disease, huanglongbing, of citrus. In urban citrus, Argentine ant, Linepithema humile (Mayr) (Hymenoptera: Formicidae), also an invasive pest, tends honeydew-producing hemipterans. We used field data to determine whether the mutualistic relationship between L. humile and six established species of honeydew producers may hinder or favor the establishment of D. citri and its biological control with Tamarixia radiata (Waterston) (Hymenoptera: Eulophidae) in citrus via competition or mutualism for ants, respectively. In the field, L. humile and D. citri are engaged in a mutualistic relationship. Ants harvest solid honeydew secreted by psyllid nymphs and tended more than 55% of observed D. citri colonies. Linepithema humile displayed a preference hierarchy when tending honeydew producers infesting citrus. It responded equally or less intensively to D. citri than to other honeydew producing species. Consequently, the mutualism between L. humile and D. citri was affected by the presence of other honeydew-producing species, and the percentage of D. citri colonies tended by L. humile. The number of ants per D. citri colony also decreased as the number of other honeydew producers increased. Diaphorina citri density was also affected by the presence of other honeydew producers. Both colony size and the number of D. citri nymphs counted per tree decreased as the number of other honeydew producers increased. Our results indicate that competition between honeydew producers for the mutualist ant L. humile may hinder the establishment of D. citri by possibly facilitating increased biological control. PMID- 23941661 TI - KLIFS: a knowledge-based structural database to navigate kinase-ligand interaction space. AB - Protein kinases regulate the majority of signal transduction pathways in cells and have become important targets for the development of designer drugs. We present a systematic analysis of kinase-ligand interactions in all regions of the catalytic cleft of all 1252 human kinase-ligand cocrystal structures present in the Protein Data Bank (PDB). The kinase-ligand interaction fingerprints and structure database (KLIFS) contains a consistent alignment of 85 kinase ligand binding site residues that enables the identification of family specific interaction features and classification of ligands according to their binding modes. We illustrate how systematic mining of kinase-ligand interaction space gives new insights into how conserved and selective kinase interaction hot spots can accommodate the large diversity of chemical scaffolds in kinase ligands. These analyses lead to an improved understanding of the structural requirements of kinase binding that will be useful in ligand discovery and design studies. PMID- 23941662 TI - Zirconium complexes supported by an N-perfluoro-arylated diamidopyridyl ligand: synthesis of hydrazinediido complexes. AB - The N-perfluoro-phenylated pyridyldiamine H2N2(PFP)N(py) (1) has been prepared by a palladium-catalyzed coupling of hexafluorobenzene and the diamine (H2NCH2)2C(CH3)(2-C5H4N) using the palladacycle trans-di(MU-acetato)bis[o-(di-o tolylphosphino)benzyl]palladium(II) as catalyst. Reactions of H2N2(PFP)N(py) and Zr(NMe2)4 at room temperature or 90 degrees C led to the complexes [(N(PFP)N2(TFAP)N(py))ZrF(NMe2)] (2) and [(N2(TFAP)N(py))ZrF2] (3) in which one or two dimethylamido groups replaced one or two ortho fluorine atoms of the pentafluorophenyl groups in the ligand. Reaction of Me3SiX (X = Cl, I) with [(N2(TFAP)N(py))ZrF2] (3) resulted in the formation of mixed halogenated complexes [(N2(TFAP)N(py))ZrFI] (4) and [(N2(TFAP)N(py))ZrFCl] (5) in which the axially bound fluorido ligand is substituted. Reaction of [(N2(TFAP)N(py))ZrF2] (3) with LiNHNPh2 afforded the monohydrazido(1-) complex [(N2(TFAP)N(py))ZrF(NHNPh2)] (6) which was converted to the dimeric fluoro potassium bridged hydrazinediido complex [Zr(N2(TFAP)N(py))FNNPh2K]2 (7) using KHMDS. The corresponding reaction with LiHMDS yielded the monomeric, donor free complex [Zr(N2(TFAP)N(py))NNPh2] (8). PMID- 23941660 TI - Family history of psychosis moderates early auditory cortical response abnormalities in non-psychotic bipolar disorder. AB - OBJECTIVES: Bipolar I disorder is a disabling illness affecting 1% of people worldwide. Family and twin studies suggest that psychotic bipolar disorder (BDP) represents a homogeneous subgroup with an etiology distinct from non-psychotic bipolar disorder (BDNP) and partially shared with schizophrenia. Studies of auditory electrophysiology [e.g., paired-stimulus and oddball measured with electroencephalography (EEG)] consistently report deviations in psychotic groups (schizophrenia, BDP), yet such studies comparing BDP and BDNP are sparse and, in some cases, conflicting. Auditory EEG responses are significantly reduced in unaffected relatives of psychosis patients, suggesting that they may relate to both psychosis liability and expression. METHODS: While 64-sensor EEGs were recorded, age- and gender-matched samples of 70 BDP, 35 BDNP {20 with a family history of psychosis [BDNP(+)]}, and 70 psychiatrically healthy subjects were presented with typical auditory paired-stimuli and auditory oddball paradigms. RESULTS: Oddball P3b reductions were present and indistinguishable across all patient groups. P2s to paired stimuli were abnormal only in BDP and BDNP(+). Conversely, N1 reductions to stimuli in both paradigms and P3a reductions were present in both BDP and BDNP(-) groups but were absent in BDNP(+). CONCLUSIONS: Although nearly all auditory neural response components studied were abnormal in BDP, BDNP abnormalities at early- and mid-latencies were moderated by family psychosis history. The relationship between psychosis expression, heritable psychosis risk, and neurophysiology within bipolar disorder, therefore, may be complex. Consideration of such clinical disease heterogeneity may be important for future investigations of the pathophysiology of major psychiatric disturbance. PMID- 23941663 TI - Epiduroscopy for patients with lumbosacral radicular pain. AB - Lumbosacral radicular pain is a pain in the distribution area of one of the nerves of the lumbosacral plexus, with or without sensory and/or motor impairment. A major source of lumbosacral radicular pain is failed back surgery, which is defined as persistent or recurrent pain, mainly in the region of the lower back and legs even after technically, anatomically successful spine surgeries. If lumbosacral radicular neuropathic pain fails to respond to conservative or interventional treatments, epiduroscopy can be performed as part of a multidisciplinary approach. Epiduroscopy aids in identifying painful structures in the epidural space, establishing a diagnosis and administering therapy. The novelty consists in the use of an epiduroscope to deliver therapies such as adhesiolysis and targeted administration of epidural medications. Clinical trials report favorable treatment outcomes in 30% to 50% of patients. Complications are rare and related to the rate or volume of epidural fluid infusion or inadvertent dural puncture. In patients with lumbosacral radicular pain, especially after back surgery, epiduroscopy with adhesiolysis may be considered (evidence rating 2 B+). PMID- 23941664 TI - Processing of the S-cone signals in the early visual cortex of primates. AB - The short-wavelength-sensitive (S) cones play an important role in color vision of primates, and may also contribute to the coding of other visual features, such as luminance and motion. The color signals carried by the S cones and other cone types are largely separated in the subcortical visual pathway. Studies on nonhuman primates or humans have suggested that these signals are combined in the striate cortex (V1) following a substantial amplification of the S-cone signals in the same area. In addition to reviewing these studies, this review describes the circuitry in V1 that may underlie the processing of the S-cone signals and the dynamics of this processing. It also relates the interaction between various cone signals in V1 to the results of some psychophysical and physiological studies on color perception, which leads to a discussion of a previous model, in which color perception is produced by a multistage processing of the cone signals. Finally, I discuss the processing of the S-cone signals in the extrastriate area V2. PMID- 23941665 TI - Adsorption of drugs on nanodiamond: toward development of a drug delivery platform. AB - Nanodiamond particles produced by detonation synthesis and having ~5 nm diameter possess unique properties, including low cell toxicity, biocompatibility, stable structure, and highly tailorable surface chemistry, which render them an attractive material for developing drug delivery systems. Although the potential for nanodiamonds in delivery and sustained release of anticancer drugs has been recently demonstrated, very little is known about the details of adsorption/desorption equilibria of these and other drugs on/from nanodiamonds with different purity, surface chemistry, and agglomeration state. Since adsorption is the basic mechanism most commonly used for the loading of drugs onto nanodiamond, the fundamental studies into the details of adsorption and desorption on nanodiamond are critically important for the rational design of the nanodiamond drug delivery systems capable of targeted delivery and triggered release, while minimizing potential leaks of dangerous drugs. In this paper we report on a physical-chemical study of the adsorption of doxorubicin and polymyxin B on nanodiamonds, analyzing the role of purification and surface chemistry of the adsorbent. PMID- 23941666 TI - Johan Turi's animal, mineral, vegetable cures and healing practices: an in-depth analysis of Sami (Saami) folk healing one hundred years ago. AB - BACKGROUND: The healing knowledge of a Sami (Saami) hunter and reindeer herder was surveyed as a window into the concepts of health, healing, and disease in early twentieth-century Sapmi (Northern Sweden). The two books of Johan Turi (1854-1936)--An Account of the Sami (1910) and Lappish Texts (1918-19) were examined to determine the varieties of recorded zootherapeutic, mineral, chemical, and ethnobotanical lore, as well as the therapeutic acts, identified conditions, and veterinary knowledge included. METHODS: Tabulation of the materials and species mentioned in Turi's descriptions (n = 137) permitted analysis of the relative frequency of differing types of healing in Turi's overall therapeutic repertoire, his relative attention to chronic vs. acute ailments, and the frequency of magic as a component of healing. A qualitative appraisal was made of the degree to which outside influences affected Sami healing of the period. A further assessment of the possible clinical efficacy of the recorded remedies was undertaken. RESULTS: Turi's remedies consist most often of zootherapeutics (31%), followed by physical acts such as massage, moxibustion, or manipulation (22%). Ethnobotanical cures make up a significantly smaller portion of his repertoire (17%), followed by mineral and chemical cures (12%). Magic rituals (including incantations and ritual acts) make up a significant portion of Turi's repertoire, and could be used alone (17%) or in conjunction with other types of healing (38%). Turi's healing aimed primarily at acute ailments (65%), with chronic conditions addressed less often (35%). A literature review revealed that Turi's remedies held a marked frequency of likely efficacy, at least in cases in which it was possible to ascertain the precise species, conditions, or substances described. Although it is possible at times to recognize foreign sources in Turi's repertoire, it is clear that Turi understood all his healing methods as distinctively Sami. CONCLUSION: The research illustrates the variety and depth of a single informant's healing knowledge, and demonstrates the value of both historical sources and in-depth data collection with single experts as useful means of assessing and characterizing an indigenous population's healing traditions. PMID- 23941667 TI - Dual sensory loss: development of a dual sensory loss protocol and design of a randomized controlled trial. AB - BACKGROUND: Dual sensory loss (DSL) has a negative impact on health and wellbeing and its prevalence is expected to increase due to demographic aging. However, specialized care or rehabilitation programs for DSL are scarce. Until now, low vision rehabilitation does not sufficiently target concurrent impairments in vision and hearing. This study aims to 1) develop a DSL protocol (for occupational therapists working in low vision rehabilitation) which focuses on optimal use of the senses and teaches DSL patients and their communication partners to use effective communication strategies, and 2) describe the multicenter parallel randomized controlled trial (RCT) designed to test the effectiveness and cost-effectiveness of the DSL protocol. METHODS/DESIGN: To develop a DSL protocol, literature was reviewed and content was discussed with professionals in eye/ear care (interviews/focus groups) and DSL patients (interviews). A pilot study was conducted to test and confirm the DSL protocol. In addition, a two-armed international multi-center RCT will evaluate the effectiveness and cost-effectiveness of the DSL protocol compared to waiting list controls, in 124 patients in low vision rehabilitation centers in the Netherlands and Belgium. DISCUSSION: This study provides a treatment protocol for rehabilitation of DSL within low vision rehabilitation, which aims to be a valuable addition to the general low vision rehabilitation care. TRIAL REGISTRATION: Netherlands Trial Register (NTR) identifier: NTR2843. PMID- 23941668 TI - Adiposity has unique influence on the renin-aldosterone axis and blood pressure in black children. AB - OBJECTIVE: To comparatively examine the effects of adiposity on the levels of plasma renin activity (PRA), plasma aldosterone concentration (PAC), and aldosterone-renin ratio (ARR) in young black and white children. STUDY DESIGN: We prospectively assessed 248 black and 345 white children and adolescents. A novel analytical technique was used to assess the concurrent influences of age and body mass index (BMI) on PRA, PAC, and ARR. The estimated effects were depicted by colored contour plots. RESULTS: In contrast to whites, blacks had lower PRA (2.76 vs 3.36 ng/mL/h; P < .001) and lower PAC (9.01 vs 14.59 ng/dL; P < .001). In blacks, BMI was negatively associated with PRA (P = .001), consistent with an association with a more expanded plasma volume; there was no association with PAC. In whites, BMI was positively associated with PAC (P = .005); we did not detect a BMI-PRA association. The effects of BMI on ARR were directionally similar in the two race groups but more pronounced in blacks. Mean systolic blood pressure was greater in blacks with lower PRA (P < .01), higher PAC (P = .015), and higher ARR (P = .49). CONCLUSIONS: An increase in adiposity was associated with a suppressed PRA in blacks and an increase in PAC in whites. The unique relationship between adiposity and renin-aldosterone axis in blacks suggests the possible existence of a population-specific mechanism characterized by volume expansion, which could in turn enhance the influences of adiposity on blood pressure in black children and adolescents. PMID- 23941669 TI - Neurocognitive test performance and symptom reporting in cheerleaders with concussions. AB - OBJECTIVE: To evaluate neurocognitive test results and symptom reporting after sports-related concussion in a group of female cheerleaders. STUDY DESIGN: Junior and senior high school female cheerleaders (n = 138) underwent preparticipation baseline testing and repeated the ImPACT (Immediate Postconcussion Assessment and Cognitive Testing) evaluation within 7 days of concussive injury (range, 0-7 days; mean, 3.9 days). Postinjury neurocognitive and symptom scores were compared with preinjury (baseline) scores. "Abnormal" test performance was determined statistically using Reliable Change Index scores and self-reported symptoms. Main outcome variables included the composite scores indices from the ImPACT test, as well as symptoms reported by participants. Preinjury baseline and postinjury test results were compared using MANOVA. RESULTS: As a group, cheerleaders with concussion evaluated within 7 days of injury performed poorly on the ImPACT test battery relative to their own baseline (F = 6.5; P = .00). In addition, 61% of the cheerleaders with concussions reported an increase in symptoms compared with baseline. The groups did not differ significantly by position on the squad (F = 0.37; P = .96). Of the group of cheerleaders who did not report increased symptoms at the time of postinjury evaluation, 37% had at least 1 abnormal ImPACT composite score result, suggesting some residual cognitive decline compared with baseline. CONCLUSION: The diagnosis and management of concussion in cheerleaders should not consist solely of self-reported symptoms. Neurocognitive test results represent an important component of the evaluation process and may identify athletes with residual neurocognitive deficits who report being clinically asymptomatic. PMID- 23941670 TI - Targeting 2.5 versus 4 g/kg/day of amino acids for extremely low birth weight infants: a randomized clinical trial. AB - OBJECTIVE: To compare the effect of 2.5 vs 4 g/kg/d of amino acid (AA) in parenteral nutrition of extremely low birth weight infants on metabolic tolerance, short-term growth, and neurodevelopment. STUDY DESIGN: One hundred thirty-one infants with birth weight between 500 and 1249 g were randomized to 2.5 (standard AA [SAA] group) or 4 (high AA [HAA] group) g/kg/d AA intake, with equal nonprotein energy. The primary outcome was body size at 36 weeks. RESULTS: One hundred thirty-one patients were randomized and 114 analyzed (58 SAA group and 56 HAA group). Study groups had similar demographics and clinical characteristics. Elevated blood urea (BU >70 mg/dL = BU nitrogen >32.6 mg/dL) occurred in 24% vs 59% (P = .000) and hyperglycemia (>175 mg/dL) in 34% vs 11% (P = .003) of the SAA and HAA patients, respectively. Body weight, length, and head circumference at 36 weeks and 2 years were similar between groups. Bayley Scales of Infant and Toddler Development, Third Edition score was 94 +/- 13 in the SAA group and 97 +/- 15 in the HAA group (P = .35). CONCLUSIONS: The HAA group had higher BU levels and better glucose control. An extra 8 g/kg of AA over the first 10 days of life did not improve growth and neurodevelopment. PMID- 23941671 TI - Risk factors for the introduction of avian influenza virus in breeder duck flocks during the first 24 weeks of laying. AB - A study was carried out in French breeder duck flocks in 2008 and 2009 to identify practices and events related to the introduction of avian influenza viruses (AIVs). The status of flocks was assessed using serological methods for all subtypes of AIV without typing. Flocks managed with both natural mating and artificial insemination were investigated every 4 weeks from the beginning of the laying period up to seroconversion or for a maximum of 6 months. A questionnaire was completed with the farmer during each visit and 20 female ducks were randomly sampled for blood testing. Only flocks that tested seronegative at the first visit were included in the study (n =151 flocks managed with natural mating or artificial insemination). Data were analysed using survival analysis to identify factors influencing the time to seroconversion. Three separate models were constructed: one for the whole sample, one for natural mating flocks, and one for artificial insemination flocks. Factors related to the time to introduction of AIV included the type of production system linked to artificial insemination practices, the neighbourhood, poor disinfection practices, liquid manure management, presence of wildlife, and vehicles entering the building. No clear relationship could be observed in the serological status of male and female ducks in farms keeping male ducks separately from female ducks for artificial insemination. By respecting carefully biosecurity measures, it should be possible to decrease AIV infection of breeder duck flocks. PMID- 23941673 TI - Serotype-specific anti-Dengue virus NS1 mouse antibodies cross-react with prM and are potentially involved in virus production. AB - Dengue virus (DENV) infection induces a strong B-cell immune response against the viral nonstructural protein 1 (NS1). Anti-NS1 antibodies (Abs) may affect virus production because they coexist with the virus in the patients' blood. The present study examined whether ten mouse monoclonal antibodies (MAbs) raised against NS1 affected production of the DENV-2. Three MAbs, 4C2, 4G11, and 4E5, showed weak neutralizing activity in a focus reduction assay. In addition, two serotype-specific MAbs, 4C2 and 4G11, protected suckling mice from lethal infection with DENV-2. An immunoprecipitation assay with DENV-2 showed that these MAbs, which were specific for the NS1 of DENV-4 and DENV-1, cross-reacted with the DENV-2 pre-membrane (prM) protein, but not with DENV-2 NS1. Interestingly, high concentrations of MAb 4G11 showed antibody-dependent enhancement of DENV-2 infection in human monocyte THP-1 cells. Taken together, these observations suggest that serotype-specific anti-NS1 MAbs are potentially involved in virus production. PMID- 23941674 TI - The isolation of novel phage display-derived human recombinant antibodies against CCR5, the major co-receptor of HIV. AB - Selecting for antibodies against specific cell-surface proteins is a difficult task due to many unrelated proteins that are expressed on the cell surface. Here, we describe a method to screen antibody-presenting phage libraries against native cell-surface proteins. We applied this method to isolate antibodies that selectively recognize CCR5, which is the major co-receptor for HIV entry (consequently, playing a pivotal role in HIV transmission and pathogenesis). We employed a phage screening strategy by using cells that co-express GFP and CCR5, along with an excess of control cells that do not express these proteins (and are otherwise identical to the CCR5-expressing cells). These control cells are intended to remove most of the phages that bind the cells nonspecifically; thus leading to an enrichment of the phages presenting anti-CCR5-specific antibodies. Subsequently, the CCR5-presenting cells were quantitatively sorted by flow cytometry, and the bound phages were eluted, amplified, and used for further successive selection rounds. Several different clones of human single-chain Fv antibodies that interact with CCR5-expressing cells were identified. The most specific monoclonal antibody was converted to a full-length IgG and bound the second extracellular loop of CCR5. The experimental approach presented herein for screening for CCR5-specific antibodies can be applicable to screen antibody presenting phage libraries against any cell-surface expressed protein of interest. PMID- 23941675 TI - Influenza virus M2e with additional cysteine residues shows enhanced immunogenicity and protection against lethal virus challenge. AB - The amino acid sequence of the extracellular domain of matrix protein 2 (M2e) is conserved among all subtypes of influenza A viruses. Therefore, the M2e peptide can be considered as a target antigen for the development of a universal influenza vaccine. We evaluated the effects of adding cysteine residues to a peptide of amino acids 2-24 of M2e. Mice immunized with some of these peptides containing one, two, three, four, or five extra cysteines displayed enhanced antibody titers to M2e. In addition, immunization with a peptide containing three extra cysteines, along with an aluminum adjuvant, protected mice more effectively against a lethal influenza virus challenge than the original M2e peptide. These results indicated that an M2e peptide containing additional cysteine residues could be a universal influenza vaccine candidate even without the addition of strong adjuvants. PMID- 23941676 TI - Towards improving the retrospective diagnosis of congenital cytomegalovirus infection in dried blood spots. PMID- 23941677 TI - An unusual case of orbito-frontal rod fence stab injury with a good outcome. AB - BACKGROUND: High-energy non-missile penetrating injuries (stab injuries) account for a small percentage of penetrating head injuries and they present a series of special features. CASE PRESENTATION: A 35-year-old man suffered orbito-frontal? and trans-cranial injuries after falling five meters from a terrace onto a rod iron fence. The removal of the metal rod was performed outside the operating room. The orbital roof was exposed and repaired through a bifrontal craniotomy and the frontal sinuses were cranialised. The orbital floor and zygoma were plated with micro-screws. CONCLUSION: The patient recovered without significant complications, apart from a slight paresis of the right superior rectus; the ocular globe remained intact.The positive outcome obtained in this very challenging case is attributable to the competency of the Neurotrauma Unit and to the use of a synergistic approach which involved the contribution of neurosurgeons, maxillo-facial surgeons, radiologists and anaesthesiologists. PMID- 23941679 TI - A study of multiple deliveries in Portugal: indications of an Iberian Peninsula pattern. AB - Information on multiple deliveries with regard to Portugal is scarce. Based on data provided by the Portuguese Institute of Statistics (INE), the rates for double and triple deliveries were calculated since 1930. The results obtained show for twins a uniform temporal pattern up to the 1970s. At this time rates decreased, but later they gradually recovered, reaching their maximum level in 2010. For triplets, the highest rates occurred between 1999 and 2002. For the period 1988-2011, the rates of multiple deliveries were related to a set of variables recorded in the INE database on live births. Significant differences (p < .001) between simple and multiple deliveries were obtained for maternal age, parity and marital status. Considering the year when the delivery occurred, significant differences (p < .001) persisted for maternal age regardless of the year. For the type of mating, significance was consistently found since the year 2002 (either by using the marital or the cohabitation criteria), and for parity since 2003. With regard to territorial variation, throughout seven periods between 1930 and 2011, the rates among the 20 administrative Portuguese territories, including the two insular districts of Acores and Madeira, were mostly stable for twinning rates, with a minimum level in 1970-1989. Regarding triplets, the greatest inter-district variation was found after 1980. The results of the Portuguese study on multiple deliveries are interpreted in the context of the Iberian Peninsula based on findings reported for Spain. PMID- 23941678 TI - Simulation in healthcare education: a best evidence practical guide. AMEE Guide No. 82. AB - Over the past two decades, there has been an exponential and enthusiastic adoption of simulation in healthcare education internationally. Medicine has learned much from professions that have established programs in simulation for training, such as aviation, the military and space exploration. Increased demands on training hours, limited patient encounters, and a focus on patient safety have led to a new paradigm of education in healthcare that increasingly involves technology and innovative ways to provide a standardized curriculum. A robust body of literature is growing, seeking to answer the question of how best to use simulation in healthcare education. Building on the groundwork of the Best Evidence in Medical Education (BEME) Guide on the features of simulators that lead to effective learning, this current Guide provides practical guidance to aid educators in effectively using simulation for training. It is a selective review to describe best practices and illustrative case studies. This Guide is the second part of a two-part AMEE Guide on simulation in healthcare education. The first Guide focuses on building a simulation program, and discusses more operational topics such as types of simulators, simulation center structure and set-up, fidelity management, and scenario engineering, as well as faculty preparation. This Guide will focus on the educational principles that lead to effective learning, and include topics such as feedback and debriefing, deliberate practice, and curriculum integration - all central to simulation efficacy. The important subjects of mastery learning, range of difficulty, capturing clinical variation, and individualized learning are also examined. Finally, we discuss approaches to team training and suggest future directions. Each section follows a framework of background and definition, its importance to effective use of simulation, practical points with examples, and challenges generally encountered. Simulation-based healthcare education has great potential for use throughout the healthcare education continuum, from undergraduate to continuing education. It can also be used to train a variety of healthcare providers in different disciplines from novices to experts. This Guide aims to equip healthcare educators with the tools to use this learning modality to its full capability. PMID- 23941680 TI - Two-stage hepatectomy after autologous CD133+ stem cells administration: a case report. AB - Liver resection is the mainstay of treatment for patients with primary and metastatic liver tumors. However, a large majority of patients present for initial medical evaluation with primary and metastatic liver tumors when their cancer is unresectable. Several trials have been undertaken to identify alternative treatments and complementary therapies. In the near future, the field of liver surgery will aim to increase the number of patients that can benefit from resection, since radical removal of the tumor currently provides the sole chance of cure. This paper reports the case of a patient with an advanced colonic cancer in the era of stem cell therapy. In 2011, a 57 years old white Caucasian man with a previous history of non-Hodgkin lymphoma (NHL) was diagnosed with colon cancer and bilobar liver metastases. Following neoadjuvant therapy, the patient was enrolled in a protocol of stem cell administration for liver regeneration. Surgery was initially performed on the primary cancer and left liver lobe. An extended right lobectomy to S1 was then performed after a portal vein embolization (PVE) and stem cell stimulation of the remaining liver. The postoperative course was uneventful and the patient was free of disease after 12 months. Extreme liver resection can provide a safer option and a chance of cure to otherwise unresectable patients when liver regeneration is boosted by PVE and stem cell administration. PMID- 23941681 TI - Levels of infection of intestinal helminth species in the golden jackal Canis aureus from Serbia. AB - During the past decade, golden jackal populations have substantially increased, yet little is known of their potential for transmitting parasites within animal and human hosts. In the present study, between 2005 and 2010, 447 jackals from six localities in Serbia were examined for intestinal parasites. Two species of trematodes (Alaria alata, Pseudamphistomum truncatum), three nematodes (Toxocara canis, Ancylostoma caninum, Gongylonema sp.), and seven cestodes (Taenia pisiformis, Taenia hydatigena, Multiceps multiceps, Multiceps serialis, Mesocestoides lineatus, Mesocestoides litteratus, Dipylidium caninum) were identified. Pseudamphistomum truncatum and M. serialis species were recorded for the first time. The overall prevalence of parasitic infection was 10.3%. No significant differences were found in the prevalence of infection between males and females (P>0.817), between localities (P>0.502), or with regard to annual cycles (P>0.502). In the infected jackal population, 65% harboured multiple infections and one individual was a host to five different types of parasite species, the highest number of parasites we recorded in a single host. These findings indicate that although the prevalence of gastrointestinal helminths in the jackal population in Serbia is significantly lower than expected from earlier studies, further monitoring is required given the jackal's rapid population increase. PMID- 23941682 TI - A single-center analysis of abdominal imaging in the evaluation of kidney transplant recipients. AB - Many transplantation programs utilize noninvasive abdominal and pelvic imaging in the pre-operative evaluation of recipient candidates. Practice patterns vary, and consensus guidelines addressing the risks and benefits of computed tomography (CT) and magnetic resonance imaging (MRI) in the pre-transplant evaluation process do not currently exist. In this single-center study, we examined the frequency, clinical significance, and associated costs of CT and MRI findings during the pre-transplant evaluation of renal transplant recipients. A retrospective chart review of 3041 adult patients who underwent a CT/CTA or MRI/MRA of the abdomen and pelvis for pre-transplant evaluation between 2005 and 2010 was performed. Pre-transplant imaging with MRI offered a more sensitive evaluation in comparison with CT, with the notable exception of abnormalities in which calcium was detected. Patients imaged with CT had a significantly greater proportion of subsequent clinical actions arising from imaging findings. The total financial cost of MRI was greater than that of CT. No cases of nephrogenic systemic fibrosis (NSF) in patients who received MultiHance gadolinium contrast were reported. In conclusion, the risks, benefits, and costs of CT/CTA and MRI/MRA must be carefully considered to optimize the pre-operative evaluation of renal transplant recipients. PMID- 23941683 TI - Development of QSAR-based two-stage prediction model for estimating mixture toxicity. AB - Conventionally, concentration addition (CA) and independent action (IA) models based on additive toxicity are often used to estimate the mixture toxicity of similarly- and dissimilarly-acting chemicals, respectively. A two-stage prediction (TSP) model has been developed as an integrated addition model that can perform the CA and IA calculations stage by stage. However, the use of the conventional TSP model is limited if the mode of toxic action (MoA) for every mixture component is not readily known. The aim of this study was to develop and evaluate a quantitative structure-activity relationship-based TSP (QSAR-TSP) model for estimating mixture toxicity in the absence of knowledge on the MoAs of the constituents. For this purpose, different clustering methods of mixture constituents using computerized analysis based on the structural similarity between chemicals were applied as a part of the predictions of mixture toxicity. The relative importance of molecular descriptors was additionally determined by Random Forest analysis. This study highlights the prediction power of the QSAR TSP model and its potential to overcome the limitations of the conventional TSP model, and how clustering methods of mixture components that employ chemical structural information to categorize might be applied to predict mixture toxicity effectively. PMID- 23941684 TI - Review: Could neurotransmitters influence neurogenesis and neurorepair after stroke? AB - Brain ischaemia and reperfusion produce alterations in the microenvironment of the parenchyma, including ATP depletion, ionic homeostasis alterations, inflammation, release of multiple cytokines and abnormal release of neurotransmitters. As a consequence, the induction of proliferation and migration of neural stem cells is redirected towards the peri-infarct region. The success of new neurorestorative treatments for damaged brain implies the need to describe with greater accuracy the mechanisms in charge of regulating adult neurogenesis, under both physiological and pathological conditions. Recent evidence demonstrates that many neurotransmitters, glutamate in particular, control the subventricular zone (SVZ), thus being part of the complex signal network that exerts a remarkable influence on the production of new neurones. Neurotransmitters provide a link between brain activity and SVZ neurogenesis. Therefore, a deeper knowledge of the role of neurotransmitters systems, such as glutamate and its transporters, in adult neurogenesis, may prove a valuable tool to be utilized as a neurorestorative therapy in this pathology. PMID- 23941685 TI - Excited-state interaction of red and green perylene diimides with luminescent Ru(II) polypyridine complex. AB - Three new perylene diimide (PDI)-based ligands have been synthesized by the covalent attachment of dipyrido[a,c]phenazine moiety to one of the bay-positions of PDI, while the second position has been substituted with either a 4-tert butylphenoxy or a pyrrolidinyl group to obtain two types of chromophores, Ph-PDI and Py-PDI, respectively, with distinct properties. In the case of Py-PDI, the resultant 1,7- and 1,6-regioisomers have been successfully separated by column chromatography and characterized by (1)H NMR spectroscopy. The ligands have been employed to prepare donor-acceptor-based ensembles incorporating the covalently linked PDI and Ru(II) polypyridine complex as the acting chromophores. A comprehensive study of the excited-state photodynamics of the ensembles has been performed by means of electrochemical and steady state and time-resolved spectroscopic methods. Although, in all the three ensembles, the photoexcitation of either chromophore resulted in a long-lived triplet excited state of PDI ((3)PDI) as the final excited state, the photochemical reactions leading to the triplet states were found to be essentially different for the two types of the ensembles. In the case of the Ph-PDI-based ensemble, the excitation of either chromophore leads to the electron transfer from the Ru(II) complex to Ph-PDI, whereas for the Py-PDI-based ensembles, the electron transfer is observed in the opposite direction and only when the Ru(II) complex is excited. The difference in the behavior was rationalized based on electrochemical study of the compounds, which has shown that the Ph-PDI chromophore is a better electron acceptor and the Py-PDI chromophores are relatively better electron donors. This study shows a chemical approach to control the photoreactions in PDI-based dichromophoric ensembles including the possibility to switch the direction of the photoinduced electron transfer. PMID- 23941686 TI - Update on the discovery and development of cholesteryl ester transfer protein inhibitors for reducing residual cardiovascular risk. AB - Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester and triglycerides between plasma lipoprotein particles HDL and LDL/VLDL, resulting in equilibration between these lipoprotein fractions. Therapy that modulates HDL metabolism to increase HDL-c levels could be an effective strategy to reduce residual cardiovascular risk since it is estimated that for each mg/dL increase in plasma HDL cholesterol, there could be a 2-3% decrease in cardiovascular risk. Modification of the lipoprotein profile by CETP inhibitors is promising, but the beneficial effect of reducing coronary heart disease risk has not yet been proven. To date, four CETP inhibitors have advanced to phase 3 cardiovascular outcome clinical trials, and two have been terminated for off target adverse effects and lack of efficacy. This perspective will summarize recent events, new research developments, and the discovery of new classes of CETP inhibitors. PMID- 23941687 TI - Anionic phenolic compounds bind stronger with transthyretin than their neutral forms: nonnegligible mechanisms in virtual screening of endocrine disrupting chemicals. AB - The molecular structures of many endocrine-disrupting chemicals (EDCs) contain groups that ionize under physiological pH conditions. It is unclear whether the neutral and ionic forms have different binding mechanisms with the macromolecular targets. We selected phenolic compounds and human transthyretin (hTTR) as a model system and employed molecular docking with quantum mechanics/molecular mechanics optimizations to probe the mechanisms. The binding patterns of ionizable ligands in hTTR crystal structures were also analyzed. We found that the anionic forms of the phenolic compounds bind stronger than the corresponding neutral forms with hTTR. Electrostatic and van de Waals interactions are the dominant forces for most of the anionic and neutral forms, respectively. Because of the dominant and orientational electrostatic interactions, the -O(-) groups point toward the entry port of the binding site. The aromatic rings of the compounds also form cation-pi interactions with the -NH3(+) group of Lys 15 residues in hTTR. Molecular descriptors were selected to characterize the interactions and construct a quantitative structure-activity relationship model on the relative competing potency of chemicals with T4 binding to hTTR. It is concluded that the effects of ionization should not be neglected when constructing in silico models for screening of potential EDCs. PMID- 23941688 TI - Fine tuning of the pH-dependent drug release rate from polyHPMA-ellipticinium conjugates. AB - Polymer conjugates of anticancer drugs have shown high potential for assisting in cancer treatments. The pH-labile spacers allow site-specific triggered release of the drugs. We synthesized and characterized model drug conjugates with hydrazide bond-containing poly[N-(2-hydroxypropyl)methacrylamide] differing in the chemical surrounding of the hydrazone bond-containing spacer to find structure-drug release rate relationships. The conjugate selected for further studies shows negligible drug release in a pH 7.4 buffer but released 50% of the ellipticinium drug within 24h in a pH 5.0 phosphate saline buffer. The ellipticinium drug retained the antiproliferative activity of the ellipticine. PMID- 23941689 TI - Activin-A promotes the development of goat isolated secondary follicles in vitro. AB - The role of activin-A in follicular development and on the mRNA expression levels of different genes in goat secondary follicles was evaluated. Goat secondary follicles (>= 150 MUm) were cultured for 18 days under control conditions or with the addition of either 50 or 100 ng/ml activin-A (Experiment 1). The mRNA levels for the genes that code for activin-A, ActR-IA, ActR-IB, ActR-IIA, ActR-IIB, follicle stimulating hormone receptor (FSH-R) and P450 aromatase were measured in each condition (Experiment 2). We observed that after 6 days of culture, the antrum formation rate was higher in cultures with added activin-A than in the cultured control (P < 0.05). The addition of 50 ng/ml activin-A increased the follicular growth rate in the final third of the culture (days 12-18), resulting in a higher percentage of meiosis resumption (P < 0.05). On day 6, the addition of activin-A (50 ng/ml) increased the levels of ActR-IA mRNA compared with the cultured control (P < 0.05). After 18 days, the addition of 50 ng/ml activin-A significantly increased the levels of its own mRNA compared with the non-cultured control. Moreover, this treatment reduced the mRNA levels of P450 aromatase in comparison with the cultured control (P < 0.05). Higher levels of P450 aromatase mRNA were found for both activin-A treatments compared with the non-cultured control (P < 0.05). No difference in estradiol levels was detected among any of the tested treatments. In conclusion, the addition of activin-A to culture medium stimulated early antrum formation as well as an increase in the daily follicular growth rate and the percentage of meiosis resumption. PMID- 23941690 TI - Allergic fungal sinusitis and eosinophilic mucin rhinosinusitis: diagnostic criteria. AB - BACKGROUND: Chronic sinusitis is one of the most common otolaryngological diagnoses. Allergic fungal sinusitis and eosinophilic mucin rhinosinusitis can easily be misdiagnosed and treated as chronic sinusitis, causing continuing harm. AIM: To better identify and characterise these two subgroups of patients, who may suffer from a systemic disease requiring multidisciplinary treatment and prolonged follow up. METHODS: A retrospective, longitudinal study of all patients diagnosed with allergic fungal sinusitis or eosinophilic mucin rhinosinusitis within one otolaryngology department over a 15-year period. RESULTS: Thirty-four patients were identified, 26 with eosinophilic mucin rhinosinusitis and 8 with allergic fungal sinusitis. Orbital involvement at diagnosis was commoner in allergic fungal sinusitis patients (50 per cent) than eosinophilic mucin rhinosinusitis patients (7.7 per cent; p < 0.05). Asthma was diagnosed in 73 per cent of eosinophilic mucin rhinosinusitis patients and 37 per cent of allergic fungal sinusitis patients. CONCLUSION: Allergic fungal sinusitis and eosinophilic mucin rhinosinusitis have the same clinical presentation but different clinical courses. The role of fungus and the ability to confirm its presence are still problematic issues, and additional studies are required. PMID- 23941691 TI - A platelet dense-granule secretion defect may lead to a muted inflammatory cell mobilization response in cystic fibrosis patients. PMID- 23941692 TI - Plants used for making recreational tea in Europe: a review based on specific research sites. AB - This paper is a review of local plants used in water infusions as aromatic and refreshing hot beverages (recreational tea) consumed in food-related settings in Europe, and not for specific medicinal purposes. The reviewed 29 areas are located across Europe, covering the post-Soviet countries, eastern and Mediterranean Europe. Altogether, 142 taxa belonging to 99 genera and 40 families were reported. The most important families for making herbal tea in all research areas were Lamiaceae and Asteraceae, while Rosaceae was popular only in eastern and central Europe. With regards to botanical genera, the dominant taxa included Mentha, Tilia, Thymus, Origanum, Rubus and Matricaria. The clear favorite was Origanum vulgare L., mentioned in 61% of the regions. Regionally, other important taxa included Rubus idaeus L. in eastern Europe, Chamaemelum nobile (L.) All. in southern Europe and Rosa canina L. in central Europe. Future research on the pharmacological, nutritional and chemical properties of the plants most frequently used in the tea-making process is essential to ensure their safety and appropriateness for daily consumption. Moreover, regional studies dedicated to the study of local plants used for making recreational tea are important to improve our understanding of their selection criteria, cultural importance and perceived properties in Europe and abroad. PMID- 23941693 TI - Basal cell carcinoma of the prostate: clinicopathologic analysis of three cases and a review of the literature. AB - BACKGROUND: Although conventional adenocarcinoma accounts for the majority of prostatic carcinomas, it is important to recognize rare variants, like basal cell carcinoma (BCC), which has distinctive histopathological and biological features. CASE REPORT: We analyzed three cases of prostatic BCC and all of them complained of acute urinary retention and digital rectal examination disclosed a stony hard prostate. However, all of them presented with low prostate-specific antigen. The diagnosis relied on transrectal ultrasound-guided needle biopsies or transurethral resection of the prostate (TURP). The microscopic findings suggested basaloid cells with large pleomorphic nuclei and scant cytoplasm, showing peripheral palisading and forming solid nests, and immunohistochemical markers like 34betaE12, p63 and Ki67 staining, were positive. After active treatment, two of the patients are alive with tumor and one died five months after discharge from our hospital. PMID- 23941694 TI - Novel open-source electronic medical records system for palliative care in low resource settings. AB - BACKGROUND: The need for palliative care in sub-Saharan Africa is staggering: this region shoulders over 67% of the global burden of HIV/AIDS and cancer. However, provisions for these essential services remain limited and poorly integrated with national health systems in most nations. Moreover, the evidence base for palliative care in the region remains scarce. This study chronicles the development and evaluation of DataPall, an open-source electronic medical records system that can be used to track patients, manage data, and generate reports for palliative care providers in these settings.DataPall was developed using design criteria encompassing both functional and technical objectives articulated by hospital leaders and palliative care staff at a leading palliative care center in Malawi. The database can be used with computers that run Windows XP SP 2 or newer, and does not require an internet connection for use. Subsequent to its development and implementation in two hospitals, DataPall was tested among both trained and untrained hospital staff populations on the basis of its usability with comparison to existing paper records systems as well as on the speed at which users could perform basic database functions. Additionally, all participants evaluated this program on a standard system usability scale. RESULTS: In a study of health professionals in a Malawian hospital, DataPall enabled palliative care providers to find patients' appointments, on average, in less than half the time required to locate the same record in current paper records. Moreover, participants generated customizable reports documenting patient records and comprehensive reports on providers' activities with little training necessary. Participants affirmed this ease of use on the system usability scale. CONCLUSIONS: DataPall is a simple, effective electronic medical records system that can assist in developing an evidence base of clinical data for palliative care in low resource settings. The system is available at no cost, is specifically designed to chronicle care in the region, and is catered to meet the technical needs and user specifications of such facilities. PMID- 23941695 TI - Origins of the helical wrapping of phenyleneethynylene polymers about single walled carbon nanotubes. AB - The highly charged, conjugated polymer poly[p-{2,5-bis(3 propoxysulfonicacidsodiumsalt)}phenylene]ethynylene (PPES) has been shown to wrap single-wall carbon nanotubes (SWNTs), adopting a robust helical superstructure. Surprisingly, PPES adopts a helical rather than a linear conformation when adhered to SWNTs. The complexes formed by PPES and related polymers upon helical wrapping of a SWNT are investigated using atomistic molecular dynamics (MD) simulations in the presence and absence of aqueous solvent. In simulations of the PPES/SWNT system in an aqueous environment, PPES spontaneously takes on a helical conformation. A potential of mean force, DeltaA(xi), is calculated as a function of xi, the component of the end-to-end vector of the polymer chain projected on the SWNT axis; xi is a monotonic function of the polymer's helical pitch. DeltaA(xi) provides a means to quantify the relative free energies of helical conformations of the polymer when wrapped about the SWNT. The aqueous system possesses a global minimum in DeltaA(xi) at the experimentally observed value of the helical pitch. The presence of this minimum is associated with preferred side chain conformations, where the side chains adopt conformations that provide van der Waals contact between the tubes and the aliphatic components of the side chains, while exposing the anionic sulfonates for aqueous solvation. The simulations provide a free energy estimate of a 0.2 kcal/mol/monomer preference for the helical over the linear conformation of the PPES/SWNT system in an aqueous environment. PMID- 23941696 TI - Identification of a specific one amino acid change in recombinant human transglutaminase 2 that regulates its activity and calcium sensitivity. AB - TG2 (transglutaminase 2) is a calcium-dependent protein cross-linking enzyme which is involved in a variety of cellular processes. The threshold level of calcium needed for endogenous and recombinant TG2 activity has been controversial, the former being more sensitive to calcium than the latter. In the present study we address this question by identifying a single amino acid change from conserved valine to glycine at position 224 in recombinant TG2 compared with the endogenous sequence present in the available genomic databases. Substituting a valine residue for Gly224 in the recombinant TG2 increased its calcium-binding affinity and transamidation activity 10-fold and isopeptidase activity severalfold, explaining the inactivity of widely used recombinant TG2 at physiological calcium concentrations. ITC (isothermal titration calorimetry) measurements showed 7-fold higher calcium-binding affinities for TG2 valine residues which could be activated inside cells. The two forms had comparable substrate- and GTP-binding affinities and also bound fibronectin similarly, but coeliac antibodies had a higher affinity for TG2 valine residues. Structural analysis indicated a higher stability for TG2 valine residues and a decrease in flexibility of the calcium-binding loop resulting in improved metal-binding affinity. The results of the present study suggest that Val224 increases TG2 activity by modulating its calcium-binding affinity enabling transamidation reactions inside cells. PMID- 23941697 TI - The health foundation. PMID- 23941698 TI - How to develop a patient and carer advisory group in a quality improvement study. AB - BACKGROUND: This paper explores how a group of people with renal or other vascular conditions collaborated with renal practitioners in undertaking a quality improvement project, the aim of which was to reduce variation in care for people with Stages 3-4 chronic kidney disease. DEVELOPMENT AND ROLE OF THE GROUP: The patient advisory group supporting the project took a decisive and leading role in the creation of self-management materials and subsequent training for healthcare professionals and patients. The role of the patient advisory group was evaluated informally throughout the project. Confidence amongst the patient advisory group members grew as the project developed. CONCLUSION: Clinicians are often unclear on how to involve patients and carers in quality improvement projects, yet it is increasingly recognised as important. In practice, patients with experience of long-term conditions can co-lead quality improvement projects. It is recommended that further evaluation of the role of advisory groups is warranted. PMID- 23941699 TI - Training nurses to support greater patient engagement in haemodialysis. AB - BACKGROUND: Evidence supports the view that people with long term conditions who are encouraged to take a greater interest in their treatment can experience a range of health benefits. Traditionally centre-based haemodialysis patients have been passive recipients whilst nurses have been deliverers of care. The Shared Haemodialysis Care (SHC) programme changes this relationship. OBJECTIVE: Our aim was to initiate a programme of education in SHC across Yorkshire and Humber in North England, with its objective to support centre-based patients to take on aspects of their own treatment. DESIGN & PARTICIPANTS: A three tiered training model was designed to educate all grades of nursing staff. Central to this approach was the development of a four day competency based course aimed at training 25% of junior sisters/charge nurses, staff nurses and Level 3 health care assistants (unqualified nurses). MEASUREMENTS/APPROACH: We measured the number of staff trained and assessed staff knowledge using a pre and post course questionnaire. Individual course day evaluations and 'Light bulb moment 'sessions captured qualitative data and a census form relating to interest in and uptake of SHC captured patient engagement data. RESULTS: The pre and post delegate questionnaires from every cohort have demonstrated significant positive shifts in all the objectives of the training programme. The target of 25% of staff trained has been reached in all but one group of units. A third of all patients across Yorkshire and Humber are significantly engaged in their haemodialysis care. CONCLUSION: A nurse-led education programme can provide nurse participants with the tools to encourage and support patients to become more engaged in their haemodialysis treatment. PMID- 23941700 TI - The safer clinical systems project in renal care. AB - BACKGROUND: Current systems in place in healthcare are designed to detect harm after it has happened (e.g critical incident reports) and make recommendations based on an assessment of that event. Safer Clinical Systems, a Health Foundation funded project, is designed to proactively search for risk within systems, rather than being reactive to harm. OBJECTIVES: The aim of the Safer Clinical Systems project in Renal Care was to reduce the risks associated with shared care for patients who are undergoing surgery but are looked after peri-operatively by nephrology teams on nephrology wards. This report details our findings of the diagnostic phase of Safer Clinical Systems: the proactive search for risk. METHODS: We have evaluated the current system of care using a set of risk evaluation and process mapping tools (Failure Modes and Effects Analysis (FMEA) and Hierarchical Task Analysis HTA). RESULTS: We have engaged staff with the process mapping and risk assessment tools. We now understand our system and understand where the highest risk tasks are undertaken during a renal in-patient stay during which a patient has an operation. These key tasks occur across the perioperaive period and are not confined to one aspect of care. A measurement strategy and intervention plan have been designed around these tasks. CONCLUSION: Safer Clinical Systems has identified high risk, low reliability tasks in our system. We look forward to fully reporting these data in 2014. PMID- 23941701 TI - Laboratory database population surveillance to improve detection of progressive chronic kidney disease. AB - BACKGROUND: Some patients with chronic kidney disease are still referred late for specialist care despite the evidence that earlier detection and intervention can halt or delay progression to end-stage kidney disease (ESKD). OBJECTIVES: To develop a population surveillance system using existing laboratory data to enable early detection of patients at high risk of ESKD by reviewing cumulative graphs of estimated glomerular filtration rate (eGFR). METHODS: A database was developed, updated daily with data from the laboratory computer. Cumulative eGFR graphs containing up to five years of data are reviewed by clinical scientists for all primary care patients or out-patients with a low eGFR for their age. For those with a declining trend, a report containing the eGFR graph is sent to the requesting doctor. A retrospective audit was performed using historical data to assess the predictive value of the graphs. RESULTS: In nine months, we reported 370,000 eGFR results, reviewing 12,000 eGFR graphs. On average 60 graphs per week were flagged as 'high' or 'intermediate' risk. Patients with graphs flagged as high risk had a significantly higher mortality after 3.5 years and a significantly greater chance of requiring renal replacement therapy after 4.5 years of follow-up. Five patients (7%) with graphs flagged as high risk had a sustained >25% fall in eGFR without evidence of secondary care referral. Feedback about the service from requesting clinicians was 73% positive. CONCLUSIONS: We have developed a system for laboratory staff to review cumulative eGFR graphs for a large population and identify patients at highest risk of developing ESKD. Further research is needed to measure the impact of this service on patient outcomes. PMID- 23941702 TI - Overcoming challenges in improvement work. AB - The Health Foundation is an independent charity working to improve healthcare in the UK, so that we have a system of the highest possible quality-safe, effective, person-centred, timely, efficient and equitable. We believe that in order to achieve this, health services need to continually improve the way they work. The Foundation conducts research and evaluation, puts ideas into practice through improvement programmes, develops leaders and shares evidence to drive wider change. The work is a focused around two priority areas: patient safety and person-centred care. The Foundation has supported work to improve services for patients with kidney disease and, in common with other quality improvement projects, there have been challenges to overcome. Awareness of these common challenges can help others to be more prepared when planning service improvements. PMID- 23941703 TI - Impact of interlead distance on immediate and mid-term response to cardiac resynchronization therapy. AB - OBJECTIVES: It is currently recommended that the left ventricular (LV) lead be placed at the posterolateral or lateral wall of heart during cardiac resynchronization therapy (CRT). The aim of our study is to evaluate the influence of interlead distance on immediate and mid-term response to CRT with altered right ventricular (RV) pacing site. DESIGN: A total of 35 consecutive patients underwent CRT for standard indications. RV pacing site was altered from RV outflow tract (RVOT) to RV apex (RVA) in the course of implantation, permitting assessment of a "poorer response" and a "better response" site based on intraprocedural aortic velocity time integral (aVTI). LV-RV interlead distances were compared between these sites during operation. We also made a comparison of the interlead distances between responders and non-responders 6 months after CRT. RESULTS: In the process of CRT implantation, the better response site showed significantly larger interlead distance (16.5 +/- 4.4 cm vs.12.4 +/- 5.6 cm, p = 0.001) as well as its vertical component (9.8 +/- 4.8 cm vs. 4.3 +/- 2.8 mm, p = 0.001) on lateral fluoroscopy view as compared with the poorer response site. Furthermore, RVA proved more likely to be the "better response" site than RVOT (91% vs. 9%, p = 0.001). At 6-month -up, responders demonstrated larger direct interlead distance (18.1 +/- 4.5 cm vs. 14.8 +/- 3.5 cm, p = 0.011) and horizontal interlead distance (14.1 +/- 6.6 cm vs. 8.3 +/- 6.1 cm, p = 0.004) on the lateral radiograph in comparison with non-responders with great significance. CONCLUSIONS: Larger interlead distance on lateral fluoroscopy view is associated with more favorable immediate and mid-term response to CRT. Use of these findings may help to maximize the benefit derived from CRT. PMID- 23941704 TI - Major influences on buying decision processes by international university students. Differences by continent of origin. AB - To analyze how food values and other variables related to dietary acculturation affect international university students' food buying decisions, this article provides an in-depth review of relevant literature related to the food buying decisions of groups of sojourners, which suggest several research hypotheses. The data collection targeted international university students in Spain and used factorial analysis of the main components together with linear parametric regressions. The resulting findings offer distinct insights, according to sojourners' continent of origin. Specifically, whereas European students exhibit a higher propensity to value sustainable production practices in the food choices, American students emphasize flavor and exhibit a greater degree of adaptation. These findings in turn suggest some key managerial recommendations and research guidelines for both private and public operators in related fields. PMID- 23941705 TI - Performance and microbial community analysis of the anaerobic reactor with coke oven gas biomethanation and in situ biogas upgrading. AB - A new method for simultaneous coke oven gas (COG) biomethanation and in situ biogas upgrading in anaerobic reactor was developed in this study. The simulated coke oven gas (SCOG) (92% H2 and 8% CO) was injected directly into the anaerobic reactor treating sewage sludge through hollow fiber membrane (HFM). With pH control at 8.0, the added H2 and CO were fully consumed and no negative effects on the anaerobic degradation of sewage sludge were observed. The maximum CH4 content in the biogas was 99%. The addition of SCOG resulted in enrichment and dominance of homoacetogenetic genus Treponema and hydrogenotrophic genus Methanoculleus in the liquid, which indicated that H2 were converted to methane by both direct (hydrogenotrophic methanogenesis) and indirect (homoacetogenesis+aceticlastic methanogenesis) pathways in the liquid. However, the aceticlasitic genus Methanosaeta was dominant for archaea in the biofilm on the HFM, which indicated indirect (homoacetogenesis+aceticlastic methanogenesis) H2 conversion pathway on the biofilm. PMID- 23941706 TI - A full scale anaerobic-anoxic-aerobic process coupled with low-dose ozonation for performance improvement. AB - The effectiveness of RAS degradation under low dose ozone and effect of ozonated sludge on a full scale anaerobic-anoxic-aerobic (A/A/O) process were examined. The ratios of chemical oxygen demand (COD) to nitrogen and COD to phosphorus of ozonated sludge were 23 and 91 respectively on average, much higher than in influent. Compared with the performance of A/A/O process alone, COD removal efficiency slightly decreased after insertion of the ozonation system. Ammonia removal became more stable, but total nitrogen and total phosphorus removal efficiency was not improved. Sludge volume index (SVI) of activated sludge reached to an optimal value of 80-120 mL/g quickly due to ozonation combined with A/A/O process which reduced the danger of sludge bulking. Overall, the combination of biological process with ozonation at a low dose rate shows promise. Compared with higher dose ozonation, low-dose ozonation can improve the performance of A/A/O effectively at a smaller cost. PMID- 23941707 TI - Parameter estimation and characterization of a single-chamber microbial fuel cell for dairy wastewater treatment. AB - In this study, for the first time, the conduction-based model is extended, and then combined with Genetic Algorithm to estimate the design parameters of a MFC treating dairy wastewater. The optimized parameters are, then, validated. The estimated half-saturation potential of -0.13 V (vs. SHE) is in good agreement while the biofilm conductivity of 8.76*10(-4) mS cm(-1) is three orders of magnitude lower than that previously-reported for pure-culture biofilm. Simulations show that the ohmic and concentration overpotentials contribute almost equally in dropping cell voltage in which the concentration film and biofilm conductivity comprise the main resistances, respectively. Thus, polarization analysis and determining the controlling steps will be possible through that developed extension. This study introduces a reliable method to estimate the design parameters of a particular MFC and to characterize it. PMID- 23941708 TI - Influence of different demineralization treatments on physicochemical structure and thermal degradation of biomass. AB - To study the catalytic role of alkali and alkaline earth metallic species and eliminate their negative impact during biomass thermal utilization, different leaching methods have been applied in numerous experiments. Thus it is necessary to investigate the potential influence on biomass physicochemical structure using different agents. Rice straw was selected to study the demineralization impact on physicochemical structure and pyrolysis characteristics. It is shown that strong acid leaching exhibited higher removal efficiency of minerals, but it introduced more notable impact on physicochemical structure of biomass comparing to water and weak acid leaching. Different leaching methods give chance to study catalysis characteristics of intrinsic metals on biomass thermal reaction. Contrast to alkaline earth metals especially Ca hindering thermal decomposition, alkali metals promoted this reaction obviously. In addition, comparing to physicochemical structure changes created by leaching process, the influence of removal of minerals played the dominant role in biomass thermal behavior. PMID- 23941709 TI - Ethanol production from macauba (Acrocomia aculeata) presscake hemicellulosic hydrolysate by Candida boidinii UFMG14. AB - Yeasts capable of growth on xylose were isolated from macauba (Acrocomia aculeata) fruit, a Brazilian palm tree with great potential for use as biodiesel feedstock production. Candida boidinii UFMG14 strain achieved the highest ethanol production (5 g/L) and was chosen to ferment macauba presscake hemicellulosic hydrolysate (MPHH). The MPHH was produced by the first time in this work and the resultant fivefold concentrate showed considerable sugar content (52.3 and 34.2 g/L xylose and glucose, respectively) and low furfural (0.01 g/L) and hydroxymethylfurfural (0.15 g/L) concentrations. C. boidinii UFMG14 fermentation was evaluated in supplemented and non-supplemented MPHH containing either 10 or 25 g/L of xylose. The maximum ethanol production (12 g/L) was observed after 48 h of fermentation. The ethanol yield was significantly affected by supplementation and concentration of MPHH while ethanol productivity was affected only by MPHH concentration. This is the first study demonstrating theC. boidinii potential for ethanol production from hemicellulose byproducts. PMID- 23941710 TI - Simultaneous saccharification and fermentation of Agave tequilana fructans by Kluyveromyces marxianus yeasts for bioethanol and tequila production. AB - Agave tequilana fructans (ATF) constitute a substrate for bioethanol and tequila industries. As Kluyveromyces marxianus produces specific fructanases for ATF hydrolysis, as well as ethanol, it can perform simultaneous saccharification and fermentation. In this work, fifteen K. marxianus yeasts were evaluated to develop inoculums with fructanase activity on ATF. These inoculums were added to an ATF medium for simultaneous saccharification and fermentation. All the yeasts, showed exo-fructanhydrolase activity with different substrate specificities. The yeast with highest fructanase activity in the inoculums showed the lowest ethanol production level (20 g/l). Five K. marxianus strains were the most suitable for the simultaneous saccharification and fermentation of ATF. The volatile compounds composition was evaluated at the end of fermentation, and a high diversity was observed between yeasts, nevertheless all of them produced high levels of isobutyl alcohol. The simultaneous saccharification and fermentation of ATF with K. marxianus strains has potential for industrial application. PMID- 23941711 TI - Production of 2,3-butanediol by engineered Saccharomyces cerevisiae. AB - In order to produce 2,3-butanediol (2,3-BD) with a high titer, it is necessary to engineer Saccharomyces cerevisiae by deleting the competing pathway and overexpressing the 2,3-BD biosynthetic pathway. A pyruvate decarboxylase (Pdc) deficient mutant was constructed and evolved for rapid glucose consumption without ethanol production. Genome re-sequencing of the evolved strain (SOS4) revealed a point mutation (A81P) in MTH1 coding for a transcriptional regulator involved in glucose sensing, unlike the previously reported Pdc-deficient mutant which had internal deletion in MTH1. When alsS and alsD genes from Bacillus subtilis, and endogenous BDH1 gene were overexpressed in SOS4, the resulting strain (BD4) not only produced 2,3-BD efficiently, but also consumed glucose faster than the parental strain. In fed-batch fermentation with optimum aeration, 2,3-BD concentration increased up to 96.2 g/L. These results suggest that S. cerevisiae might be a promising host for producing 2,3-BD for industrial applications. PMID- 23941712 TI - Prediction of biogas yield and its kinetics in reed canary grass using near infrared reflectance spectroscopy and chemometrics. AB - A rapid method is needed to assess biogas and methane yield potential of various kinds of substrate prior to anaerobic digestion. This study reports near infrared reflectance spectroscopy (NIRS) as a rapid alternative method to the conventional batch methods for prediction of specific biogas yield (SBY), specific methane yield (SMY) and kinetics of biogas yield (k-SBY) of reed canary grass (RCG) biomass. Dried and powdered RCG biomass with different level of maturity was used for biochemical composition analysis, batch assays and NIRS analysis. Calibration models were developed using partial least square (PLS) regression from NIRS spectra. The calibration models for SBY (R(2)=0.68, RPD=1.83) and k-SBY (R(2)=0.71, RPD=1.75) were better than the model for SMY (R(2)=0.53, RPD=1.49). Although the PLS model for SMY was less successful, the model performance was better compared to the models based on chemical composition. PMID- 23941723 TI - Clinical outcomes of older depressed patients with and without comorbid neuroticism. AB - BACKGROUND: Neuroticism is a psychological construct that includes tendency to exhibit negative affect (NA), having poor stress tolerance and being at risk for depression and anxiety disorders. The consequences of neuroticism in the elderly adults are understudied. We hypothesized that older depressed patients with comorbid neuroticism at baseline would have worse mood and cognitive outcomes compared with older depressed patients without neuroticism. METHODS: One hundred and ten older depressed adults completed baseline self-reports of depression and the NEO-Personality Inventory as a measure of neuroticism, were administered a battery of cognitive tests annually and were seen by a study psychiatrist who assessed patients using the Montgomery Asberg Depression Rating Scale (MADRS) and treated patients with antidepressants using an established treatment guideline. Patients were followed as clinically indicated for up to three years. We measured remission (defined as MADRS score <= 6) rates at one year as a categorical outcome. In addition, we used Cox proportional hazard models to examine the relationship between neuroticism and change in MADRS and cognitive score over time. RESULTS: Non-remitters (30%) at one year had higher scores in total neuroticism (TN), vulnerability to stress (VS), and NA. Over three years, time to achieve remission was associated with higher TN, higher VS, and greater NA. In analyses controlling for baseline cognitive score, age, sex, and education, VS was associated with baseline to two-year change in cognition. CONCLUSIONS: Presence of neuroticism in older depressed patients treated with medication is associated with poor mood outcomes and may indicate increased risk of cognitive decline. PMID- 23941724 TI - Cardiovascular burden associated with uremic toxins in patients with chronic kidney disease. AB - BACKGROUND: Retention of uremic toxins in patients with chronic kidney disease (CKD) negatively affects multiple organ systems, including the cardiovascular system, resulting in significant morbidity and mortality. Alleviation of the adverse effects of uremic toxins is an important priority in the management of CKD. SCOPE: This review focuses on the evidence for the influence of uremic toxins on cardiovascular morbidity and mortality among patients with CKD and slowly developing uremia. The cardiovascular effects of acute kidney injury and rapidly developing azotemia are beyond the scope of this review and will not be discussed. Data on potential treatment options aimed at ameliorating the toxic effects of uremic toxins are summarized. FINDINGS: Uremic toxins are associated with significant cardiovascular morbidity and mortality in patients with CKD. While a number of preclinical studies have detailed these effects, clinical studies directly evaluating cardiovascular outcomes consequent to the presence of uremic toxins have only recently become available. CONCLUSION: Uremic toxins play an important role in the progression of cardiovascular disease in patients with CKD. Further studies are needed to better characterize the impact of these compounds on cardiovascular outcomes. Beneficial treatments are currently available that, in preliminary studies, appear to neutralize some of the adverse effects of uremic toxins. Large randomized clinical trials are needed to further determine the utility of these varied therapeutic agents. PMID- 23941725 TI - Broadening the scope of epidemiology in conflict-affected settings: opportunities for mental health prevention and promotion. AB - This editorial proposes a shift in emphasis in the field of mental health epidemiology in conflict-affected settings. After a brief summary of the nature of contemporary armed conflicts, we consider the current and potential roles that epidemiology can play with regard to: (1) establishing the burden of mental disorders; (2) identifying risk and protective factors; and (3) intervention research. We advocate for improved methodological rigor; more attention to mixed methods approaches and multi-level longitudinal research; inclusion of the determinants of mental health beyond conflict-related violence; and consideration of a wider array of mental health outcomes. We particularly highlight the importance of expanding interest to epidemiological research that advances prevention and promotion interventions (e.g., in the early childhood period), in order to fill the gap between epidemiology and mental health practice in conflict affected settings. PMID- 23941726 TI - Melting of chiral order in terbium manganate (TbMnO3) observed with resonant x ray Bragg diffraction. AB - Resonant Bragg diffraction of soft, circularly polarized x-rays has been used to observe directly the temperature dependence of chiral-order melting in a motif of Mn ions in terbium manganate. The underlying mechanism uses the b-axis component of a cycloid, which vanishes outside the polar phase. Melting is witnessed by the first and second harmonics of a cycloid, and we explain why the observed temperature dependence differs in the two harmonics. Conclusions follow from an exact treatment of diffraction by using atomic multipoles in a circular cycloid, since a standard treatment of the diffraction, based on a single material-vector identified with the magnetic dipole, does not reproduce correctly observations at the second harmonic. PMID- 23941727 TI - Novel laryngoscopic strategies to improve evaluation of the site and extent of primary hypopharyngeal tumours. AB - OBJECTIVE: To investigate different strategies for displaying the hypopharynx and oesophageal entrance during laryngoscopy for hypopharyngeal cancer. PATIENTS AND METHODS: A total of 113 patients with hypopharyngeal cancer underwent laryngoscopy prior to surgery. The hypopharynx was displayed by: (1) pulling the anterior cervical skin; (2) having the patient perform the Valsalva balloon blowing manoeuvre; and (3) injecting oxygen through the biopsy channel to expose the oesophageal entrance. The effect of these methods on visualisation of primary tumour size and extent was assessed. RESULTS: During pronunciation of the letter 'e', the hypopharynx was displayed in only 33 patients (29.2 per cent); with anterior cervical skin traction plus the balloon-blowing manoeuvre, the hypopharynx was displayed in 106 patients (93.8 per cent; p < 0.001). The combined strategy was superior especially when judging the extent of posterior pharyngeal wall and postcricoid invasion. Oesophageal entrance involvement was visible in 33 patients upon injecting oxygen through the laryngoscopic biopsy channel, and in 25 patients during radiological examination; laryngoscopy was superior to radiological examination in determining the extent of oesophageal entrance invasion (p = 0.003). CONCLUSION: Adequate laryngoscopic display of the hypopharynx could increase the accuracy of pre-treatment hypopharyngeal cancer staging. PMID- 23941729 TI - Vitamin D3 insufficiency and colorectal cancer. AB - Traditionally the main recognized function of vitamin D has been calcium and phosphate homeostasis. Nevertheless, recent evidences have highlighted the importance of vitamin D3 as a protective agent against various cancers. The association between CRC and vitamin D3 was first suggested in ecologic studies, but further was confirmed by observational studies in humans and experimental studies in both animal models and cellular lines. The protective role of vitamin D3 against cancer has been attributed to its influence of on cell proliferation, differentiation, apoptosis, DNA repair mechanisms, inflammation and immune function. In its active (calcitriol) form (1,25-dihydroxyvitamin D3[1alpha,25 (OH)2D3]) vitamin D3 and the nuclear vitamin D receptor (VDR) regulate hundreds of genes including those coding for proteins involved in cell differentiation and cell proliferation. The current review addresses some of the key mechanisms that influence the biological actions of vitamin D and its metabolites. The insights derived from these mechanisms may aid in designing new uses for this hormone and its non-hypercalcemic derivatives in the treatment and/or prevention of CRC. PMID- 23941730 TI - Chylous ascites as a complication of laparoscopic colorectal surgery. AB - INTRODUCTION: Until now, no data have been available on the incidence of chylous ascites after laparoscopic colorectal surgery. METHODS: From January 2007 to December 2011, 137 patients with colorectal cancer underwent laparoscopic surgery at our institution. The clinical data of the patients with postoperative chylous ascites were compared with those of the patients without chylous ascites. RESULTS: Chylous ascites developed in 9 of the 137 patients (6.5%). Blood loss, operative time, tumor location, and extent of lymph node dissection were not associated with postoperative chylous ascites. Mean postoperative hospital stay for patients with chylous ascites was significantly longer than that for patients without any complications (14 days vs 10 days; P < 0.001). Recurrence was observed in two of the nine patients with chylous ascites; it developed locally and in the liver in one patient, and peritoneal dissemination was seen in the other. The recurrence rate in the chylous ascites group (22.2%) was significantly higher than that in the non-chylous ascites group (3.9%; P = 0.016). The 3-year disease-free survival in the chylous ascites group (76.2%) was significantly lower than that in the non-chylous ascites group (93.4%; P = 0.020); however, the 3-year overall survival rates did not differ between the groups (87.5% vs 94.4%, respectively; P = 0.332). CONCLUSION: Chylous ascites are not a rare complication of laparoscopic colorectal surgery. It was managed conservatively in all cases but was associated with longer hospital stays. We recommend careful tissue dissection at a suitable plane and meticulous clipping during lymphadenectomy to prevent chyle leakage when lymphatic invasion is suspected. PMID- 23941728 TI - Targeting inflammatory pathways in chronic lymphocytic leukemia. AB - Despite recent major advances in leukemia research, the pathobiology of chronic lymphocytic leukemia (CLL) remains poorly understood. Herein we review the role chronic inflammation plays in the initiation and progression of CLL. The robust production of inflammatory cytokines and chemokines accompanied by activation of intra-cellular pro-inflammatory pathways, and the presence of somatic mutations that activate pro-inflammatory signaling pathways, suggest that chronic inflammation plays a pathophysiological role in this disease. Indeed, glucocorticoids and non-steroidal anti-inflammatory possess anti-tumor activity, and glucocorticoids have been broadly used to treat CLL and its complications. Recent clinical trials demonstrated that tyrosine kinase inhibitors, such as ibrutinib and the immune-modulatory agent lenalidomide, induced impressive clinical responses in CLL patients with relapsed or refractory disease. As those pro-inflammatory pathway inhibitors and immune modulating drugs proved to be effective in CLL, other agents with similar activities are currently investigated in clinical trials. New insights into the pathobiology of CLL and the development of novel classes of drugs will undoubtedly provide us with effective tools to treat and perhaps cure CLL. PMID- 23941731 TI - Association between diagonal earlobe crease and cardio-ankle vascular index in asymptomatic hypertensive patients. AB - OBJECTIVE: The aim of this study was to investigate the association between earlobe crease (ELC) and cardio-ankle vascular index (CAVI) in asymptomatic hypertensive subjects. MATERIALS AND METHODS: A total of 75 subjects with ELC and 75 age- and gender-matched patients without ELC were prospectively selected from subjects admitted to the Outpatient Cardiology Clinic. ELC was assigned to a person with a crease stretching obliquely from the outer ear canal towards the border of the earlobe of at least one ear. CAVI was assessed by a VaSera VS-1000 instrument. RESULTS: There were statistically significant higher CAVI values in ELC subjects (9.8 +/- 2.1 vs. 8.6 +/- 1.6, p < 0.001). There was a significant and positive association between CAVI and age (r = 0.42, p < 0.001), ELC (r = 0.31, p < 0.001), BMI (0.20, p < 0.001) and male gender (r = 0.21, p = 0.04). Linear regression analysis demonstrated ELC (95% confidence interval, CI, 0.61 1.74, p = 0.009), age (95% CI 0.03-0.09, p < 0.001) and male gender (95% CI 0.48 1.55, p = 0.03) as independent determinants of CAVI. Also, there was a higher prevalence of ELC in subjects with subclinical atherosclerosis (CAVI >=9) than in normal subjects (CAVI <9). CONCLUSION: Patients with ELC had higher CAVI than normal subjects. This observation of ELC is simple, adds no cost and can be easily made by most physicians, and it may provide important predictive information of arterial stiffness and subclinical atherosclerosis in asymptomatic hypertensive subjects. (c) 2013 S. Karger AG, Basel. PMID- 23941732 TI - The 2011 outcome from the Swedish Health Care Registry on Heart Disease (SWEDEHEART). AB - OBJECTIVES: The Swedish Web-system for Enhancement and Development of Evidence based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) collects data to support the improvement of care for heart disease. DESIGN: SWEDEHEART collects on-line data from consecutive patients treated at any coronary care unit n = (74), followed for secondary prevention, undergoing any coronary angiography, percutaneous coronary intervention, percutaneous valve or cardiac surgery. The registry is governed by an independent steering committee, the software is developed by Uppsala Clinical Research Center and it is funded by The Swedish national health care provider independent of industry support. Approximately 80,000 patients per year enter the database which consists of more than 3 million patients. RESULTS: Base-line, procedural, complications and discharge data consists of several hundred variables. The data quality is secured by monitoring. Outcomes are validated by linkage to other registries such as the National Cause of Death Register, the National Patient Registry, and the National Registry of Drug prescriptions. Thanks to the unique social security number provided to all citizens follow-up is complete. The 2011 outcomes with special emphasis on patients more than 80 years of age are presented. CONCLUSION: SWEDEHEART is a unique complete national registry for heart disease. PMID- 23941733 TI - RIKS-HIA Annual Report 2011. PMID- 23941734 TI - SEPHIA Annual Report 2011. PMID- 23941736 TI - Swedish Heart Surgery Registry Annual Report 2011. PMID- 23941735 TI - SCAAR Annual Report 2011. PMID- 23941737 TI - TAVI Annual Report 2011. PMID- 23941739 TI - Three-month treatment with adaptive servoventilation improves cardiac function and physical activity in patients with chronic heart failure and cheyne-stokes respiration: a prospective randomized controlled trial. AB - BACKGROUND: Cheyne-Stokes respiration frequently occurs in patients with congestive heart failure (CHF). Adaptive servoventilation (ASV) is a novel therapy with potential benefits. This prospective randomized trial investigated the effects of ASV on myocardial function and physical capacity. METHODS: Patients with severe CHF, despite optimal cardiac medication and/or left ventricular ejection fraction (LVEF) <=40% and Cheyne-Stokes breathing for >25% of sleeping time were included. Fifty-one patients, age 57-81 years (4 were women), were randomized to either an ASV or a control group; 30 patients completed the study (15 from each group). The primary end point was any change in LVEF. The secondary end points were alterations in physical capacity according to the 6-min walk test or the New York Heart Association (NYHA) class. RESULTS: In the ASV-treatment group, LVEF improved from baseline (32 +/- 11%) to study end (36 +/- 13%), p = 0.013. The 6-min walk test improved from 377 +/- 115 to 430 +/- 123 m (p = 0.014) and the NYHA class from 3.2 (3.0-3.0) to 2.0 (2.0-3.0) (p < 0.001). No changes occurred in the control group. CONCLUSION: Three months of ASV treatment improved LVEF and physical capacity in CHF patients with Cheyne-Stokes respiration. These results suggest that ASV may be a beneficial supplement to standard medication in these patients. PMID- 23941740 TI - Nurse-to-patient ratios and neonatal outcomes: a brief systematic review. AB - BACKGROUND: Higher patient-to-nurse ratios and nursing workload are associated with increased mortality in the adult intensive care unit (ICU). Most neonatal ICUs (NICUs) in the United Kingdom do not meet national staffing recommendations. The impact of staffing on outcomes in the NICU is unknown. OBJECTIVE: To determine how nurse-to-patient ratios or nursing workload affects outcomes in the NICU. METHODS: Two authors (M.S., S.S.) searched PubMed, Medline, and EMBASE for eligible studies. Included studies reported on both the outcomes of infants admitted to a NICU and nurse-to-patient ratios or workload, and were published between 1/1990 and 4/2010 in any language. The primary outcome was mortality before discharge, relative to nurse-to-patient ratios. Secondary outcomes were intraventricular hemorrhage, daily weight gain, days on assisted ventilation, days on oxygen and nosocomial infection. Study quality was assessed with the STROBE checklist. RESULTS: Seven studies met the inclusion criteria. Three reported on the same group of patients. Only four studies reported death before discharge from the NICU relative to nurse-to-patient ratios. Three reported an association between lower nurse-to-patient ratios and higher mortality, and one reported just the opposite. Because each study used a different definition of nurse staffing, a meta-analysis could not be performed. CONCLUSIONS: Nurse-to patient ratios appear to affect outcomes of neonatal intensive care, but limitations of the existing literature prevent clear conclusions about optimal staffing strategies. Evidence-based standards for staffing could impact public policy and lead to improvements in patient safety and decreased rates of adverse outcomes. More research on this subject, including a standard and valid measure of nursing workload, is urgently needed. PMID- 23941741 TI - Reduced expression of SP1 and SP4 transcription factors in peripheral blood mononuclear cells in first-episode psychosis. AB - Alterations of transcription factor specificity protein 4 (SP4) and 1 (SP1) have been linked to different neuropsychiatric diseases. Reduced SP4 and SP1 protein levels in the prefrontal cortex have been associated with bipolar disorder and schizophrenia, respectively, suggesting that both factors could be involved in the pathogenesis of disorders with psychotic features. The aim of this study was to investigate whether the reduction of SP1, SP4 and SP3 protein and mRNA expression in peripheral blood mononuclear cells in the early stages of psychosis may act as a potential biomarker of these disorders. A cross-sectional study of first-episode psychosis patients (n = 14) compared to gender- and age-matched healthy controls (n = 14) was designed. Patients were recruited through the adult mental health services of Parc Sanitari Sant Joan de Deu. Protein and gene expression levels of SP1, SP4 and SP3 were assessed in peripheral blood mononuclear cells of patients with first-episode psychosis and healthy control subjects. We report that protein levels of SP1 and SP4, but not SP3, are significantly reduced in patients compared to controls. In contrast, we did not observe any differences in expression levels for SP1, SP4 or SP3 genes between patient and control groups. In patients, SP4 protein levels were significantly associated with SP1 protein levels. No association was found, however, between protein and gene expression levels for each factor. Our study shows reduced SP1 and SP4 protein levels in first-episode psychosis in lymphocytes, suggesting that these transcription factors are potential peripheral biomarkers of psychotic spectrum disorders in the early stages. PMID- 23941742 TI - Psychiatric history of women who have had an abortion. AB - Prior research has focused primarily on the mental health consequences of abortion; little is known about mental health before abortion. In this study, the psychiatric history of women who have had an abortion is investigated. 325 Women who recently had an abortion were compared with 1902 women from the population based Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). Lifetime prevalence estimates of various mental disorders were measured using the Composite International Diagnostic Interview 3.0. Compared to the reference sample, women in the abortion sample were three times more likely to report a history of any mental disorder (OR = 3.06, 95% CI = 2.36-3.98). The highest odds were found for conduct disorder (OR = 6.97, 95% CI = 4.41-11.01) and drug dependence (OR = 4.96, 95% CI = 2.55-9.66). Similar results were found for lifetime-minus-last-year prevalence estimates and for women who had first-time abortions only. The results support the notion that psychiatric history may explain associations that have been found between abortion and mental health. Psychiatric history should therefore be taken into account when investigating the mental health consequences of abortion. PMID- 23941743 TI - Differences between younger and older patients with childhood hodgkin lymphoma. AB - From 1979 to 2006, 74 children with Hodgkin's lymphoma were treated at our center. Among them, 15 (14 boys and 1 girl) and 59 (33 boys and 26 girls) patients were younger and older than 8 years, respectively. Six (40%) children among younger patients and 26 (44%) among older patients had advanced stage disease. We detected 3 (20%) relapses among younger patients and 5 (8.5%) among the older patients. All of younger patients are alive whereas three of the older patients have died. Second malignancy developed in one and three children among younger and older patients, respectively. The only difference that was detected concerning the age was a male predominance among the younger patients. PMID- 23941744 TI - Intraocular pressure and steep Trendelenburg during minimally invasive gynecologic surgery: is there a risk? AB - STUDY OBJECTIVE: Steep Trendelenburg position is frequently used during gynecologic minimally invasive surgery (MIS). However, little attention has been given to the potential impact of this nonphysiologic positioning on patients, specifically intraocular pressure (IOP). The purpose of our study was to evaluate IOP changes during laparoscopic or robotic hysterectomy conducted in the steep Trendelenburg position. DESIGN: Prospective cohort study (Canadian Task Force classification II-2). SETTING: John Sealy Hospital at the University of Texas Medical Branch, Galveston, TX. PATIENTS: Female patients with no history of ocular pathology who underwent elective robotic or laparoscopic hysterectomy. INTERVENTIONS: The anesthesia protocol was standardized for all study patients. IOP and mean arterial pressure (MAP) were obtained before anesthesia, after general anesthesia and intubation were achieved, after 1 hour of steep Trendelenburg positioning, after 2 hours of steep Trendelenburg positioning, and after the patient was returned to the supine position. Ocular perfusion pressure (OPP) was calculated using the following equation: OPP = MAP - IOP. MAIN RESULTS: A total of 10 patients were included in this prospective study. A significant increase in IOP from baseline was observed after 1 hour and 2 hours of steep Trendelenburg positioning (p = .005 and .002, respectively). There was a statistically significant trend of increasing the IOP from baseline to the second hour of steep Trendelenburg positioning (p < .001). The IOP remained significantly elevated once the patient was returned to the supine position when compared with the baseline IOP (p = .006). OPP significantly decreased from baseline after 2 hours of steep Trendelenburg positioning (p = .03). CONCLUSIONS: IOP increases significantly when patients are placed in the steep Trendelenburg position. Although further studies are needed to better characterize this process, given the aging population of our MIS patients in whom risk for glaucoma is significant, preoperative ocular health assessment should be considered in certain cases. PMID- 23941745 TI - Interactive short-term effects of equivalent temperature and air pollution on human mortality in Berlin and Lisbon. AB - There is substantial evidence that both temperature and air pollution are predictors of mortality. Thus far, few studies have focused on the potential interactive effects between the thermal environment and different measures of air pollution. Such interactions, however, are biologically plausible, as (extreme) temperature or increased air pollution might make individuals more susceptible to the effects of each respective predictor. This study investigated the interactive effects between equivalent temperature and air pollution (ozone and particulate matter) in Berlin (Germany) and Lisbon (Portugal) using different types of Poisson regression models. The findings suggest that interactive effects exist between air pollutants and equivalent temperature. Bivariate response surface models and generalised additive models (GAMs) including interaction terms showed an increased risk of mortality during periods of elevated equivalent temperatures and air pollution. Cold effects were mostly unaffected by air pollution. The study underscores the importance of air pollution control in mitigating heat effects. PMID- 23941747 TI - The effect of cannabichromene on adult neural stem/progenitor cells. AB - Apart from the psychotropic compound Delta(9)-tetrahydrocannabinol (THC), evidence suggests that other non-psychotropic phytocannabinoids are also of potential clinical use. This study aimed at elucidating the effect of major non THC phytocannabinoids on the fate of adult neural stem progenitor cells (NSPCs), which are an essential component of brain function in health as well as in pathology. We tested three compounds: cannabidiol, cannabigerol, and cannabichromene (CBC), and found that CBC has a positive effect on the viability of mouse NSPCs during differentiation in vitro. The expression of NSPC and astrocyte markers nestin and Glial fibrillary acidic protein (GFAP), respectively, was up- and down-regulated, respectively. CBC stimulated ERK1/2 phosphorylation; however, this effect had a slower onset in comparison to typical MAPK stimulation. A MEK inhibitor, U0126, antagonized the up-regulation of nestin but not the down-regulation of GFAP. Based on a previous report, we studied the potential involvement of the adenosine A1 receptor in the effect of CBC on these cells and found that the selective adenosine A1 receptor antagonist, DPCPX, counteracted both ERK1/2 phosphorylation and up-regulation of nestin by CBC, indicating that also adenosine is involved in these effects of CBC, but possibly not in CBC inhibitory effect on GFAP expression. Next, we measured ATP levels as an equilibrium marker of adenosine and found higher ATP levels during differentiation of NSPCs in the presence of CBC. Taken together, our results suggest that CBC raises the viability of NSPCs while inhibiting their differentiation into astroglia, possibly through up-regulation of ATP and adenosine signalling. PMID- 23941746 TI - Replication stress-induced alternative mRNA splicing alters properties of the histone RNA-binding protein HBP/SLBP: a key factor in the control of histone gene expression. AB - Animal replication-dependent histone genes produce histone proteins for the packaging of newly replicated genomic DNA. The expression of these histone genes occurs during S phase and is linked to DNA replication via S-phase checkpoints. The histone RNA-binding protein HBP/SLBP (hairpin-binding protein/stem-loop binding protein), an essential regulator of histone gene expression, binds to the conserved hairpin structure located in the 3'UTR (untranslated region) of histone mRNA and participates in histone pre-mRNA processing, translation and histone mRNA degradation. Here, we report the accumulation of alternatively spliced HBP/SLBP transcripts lacking exons 2 and/or 3 in HeLa cells exposed to replication stress. We also detected a shorter HBP/SLBP protein isoform under these conditions that can be accounted for by alternative splicing of HBP/SLBP mRNA. HBP/SLBP mRNA alternative splicing returned to low levels again upon removal of replication stress and was abrogated by caffeine, suggesting the involvement of checkpoint kinases. Analysis of HBP/SLBP cellular localization using GFP (green fluorescent protein) fusion proteins revealed that HBP/SLBP protein and isoforms lacking the domains encoded by exon 2 and exons 2 and 3 were found in the nucleus and cytoplasm, whereas HBP/SLBP lacking the domain encoded by exon 3 was predominantly localised to the nucleus. This isoform lacks the conserved region important for protein-protein interaction with the CTIF [CBP80/20 (cap-binding protein 80/20)]-dependent initiation translation factor and the eIF4E (eukaryotic initiation factor 4E)-dependent translation factor SLIP1/MIF4GD (SLBP-interacting protein 1/MIF4G domain). Consistent with this, we have previously demonstrated that this region is required for the function of HBP/SLBP in cap-dependent translation. In conclusion, alternative splicing allows the synthesis of HBP/SLBP isoforms with different properties that may be important for regulating HBP/SLBP functions during replication stress. PMID- 23941748 TI - Easy upgrade of the TRACERLab FX C Pro for [11C]carboxylation reactions: application to the routine production of [1-11C]acetate. AB - Carbon-11-labeled acetate ([1-(11)C]acetate) is a radiopharmaceutical of importance in clinical practice as well as in preclinical research in cardiology and oncology. Its preparation is based on the [(11)C]carboxylation reaction of a Grignard reagent with [(11)C]CO2. Most of the commercially available synthesizers are only dedicated to the preparation of [(11)C]methyl iodide (or [(11)C]methyl triflate) for the radiomethylation of an appropriate precursor but not for the direct use of cyclotron-produced [(11)C]CO2. Based on the classical [(11)C]carboxylation reaction and SPE purification, we propose in this technical note a detailed, simple, easy-to-handle and fully reversible modification of the TRACERLab FX C Pro to operate, on demand, [(11)C]carboxylation reactions, exemplified herein by the production of [1-(11)C]acetate, or [(11)C]radiomethylation reactions. This also opens new prospects to other type of radiochemical reactions involving [(11)C]CO2. PMID- 23941749 TI - PENELOPE-2008 Monte Carlo simulation of gamma exposure induced by 60Co and NORM radionuclides in closed geometries. AB - We present Monte Carlo simulations of the gamma exposure in closed rooms made of steel or concrete and contaminated by 60Co or NORM radionuclides. The computer code PENELOPE-2008 (Salvat et al., 2009) was used. Our simulations for 60Co suggest considering detailed Monte Carlo simulations in future recommendations on clearance and exemption of materials with low radioactivity. For NORM nuclides our calculations suggest that Monte Carlo simulations are a possible alternative in case a material fails the dose rate criteria by using the RP 112 screening method. PMID- 23941750 TI - The humanity of it all: exposing love, life, work and stupidity. PMID- 23941751 TI - A concept paper: using the outcomes of common surgical conditions as quality metrics to benchmark district surgical services in South Africa as part of a systematic quality improvement programme. AB - The fourth, fifth and sixth Millennium Development Goals relate directly to improving global healthcare and health outcomes. The focus is to improve global health outcomes by reducing maternal and childhood mortality and the burden of infectious diseases such as HIV/AIDS, tuberculosis and malaria. Specific targets and time frames have been set for these diseases. There is, however, no specific mention of surgically treated diseases in these goals, reflecting a bias that is slowly changing with emerging consensus that surgical care is an integral part of primary healthcare systems in the developing world. The disparities between the developed and developing world in terms of wealth and social indicators are reflected in disparities in access to surgical care. Health administrators must develop plans and strategies to reduce these disparities. However, any strategic plan that addresses deficits in healthcare must have a system of metrics, which benchmark the current quality of care so that specific improvement targets may be set.This concept paper outlines the role of surgical services in a primary healthcare system, highlights the ongoing disparities in access to surgical care and outcomes of surgical care, discusses the importance of a systems-based approach to healthcare and quality improvement, and reviews the current state of surgical care at district hospitals in South Africa. Finally, it proposes that the results from a recently published study on acute appendicitis, as well as data from a number of other common surgical conditions, can provide measurable outcomes across a healthcare system and so act as an indicator for judging improvements in surgical care. This would provide a framework for the introduction of collection of these outcomes as a routine epidemiological health policy tool. PMID- 23941752 TI - Base deficit as an early marker of coagulopathy in trauma. AB - BACKGROUND: The acute coagulopathy of trauma is associated with hypoperfusion, metabolic acidosis and an increased mortality rate. Biochemical markers of hypoperfusion, namely base deficit (BD) and lactate, are commonly used to assess the degree of hypoperfusion. Early identification of hypoperfusion and acidosis using BD and lactate may help predict the development of coagulopathy in trauma patients and direct therapy. OBJECTIVES: To identify whether a correlation exists between BD, lactate, injury severity, early-onset coagulopathy and mortality. METHODS: A retrospective chart analysis was undertaken of patients transferred directly from scene to the level I trauma unit at Inkosi Albert Luthuli Central Hospital, Durban, South Africa, from 2007 to 2008. Patients with evidence of hypoperfusion were selected. Hypoperfusion was defined as a base deficit >-2 and coagulopathy as an International Normalized Ratio (INR) of >1.2. BD, lactate, chloride, temperature, Injury Severity Score (ISS), INR and mortality were recorded in this cohort. Student's t-test and Fisher's exact test were used for continuous and categorical variables, respectively. Correlation curves were used to determine the degree of association between the variables BD, lactate and ISS with respect to the INR. A p-value of <0.05 was considered statistically significant. RESULTS: Of the 28 patients, males (n=18) accounted for 64.3% of admissions. The mean age was 31 years (range 1 - 75 years, median 30 years). The mechanism of injury was penetrating trauma in 5 cases (17.9%) and blunt trauma in 23 (82.1%). The median ISS was 24 (range 4 - 59). In 16 patients (57.1%) the INR was within normal limits, but in 12 (42.9%) it was over 1.2. There was a significant correlation between BD, ISS and INR (r=0.393; p=0.019 and r=0.565, respectively; p<0.001). Lactate showed a weak and non-significant association with the INR (r=0.232; p=0.18). There were a total of 12 deaths (42.8%) in this cohort of patients with biochemical evidence of hypoperfusion. There was a significant increase in mortality in patients with evidence of hypoperfusion and an elevated INR (75.0% v. 18.7%; p=0.006). CONCLUSION: BD but not lactate correlates with the development of the coagulopathy of trauma. The ISS showed a significant correlation with coagulation disturbances, and the combination of hypoperfusion and coagulopathy was associated with a significant increase in mortality. PMID- 23941753 TI - Firearm injuries to children in Cape Town, South Africa: impact of the 2004 Firearms Control Act. AB - BACKGROUND: Before the introduction of the Firearms Control Act in 2004, the epidemiology of childhood firearm injuries from 1991 to 2001 in Cape Town, South Africa, was reported. This study analyses current data as a comparator to assess the impact of the Act. METHODS: Firearm injuries seen at Red Cross War Memorial Children's Hospital, Cape Town, from 2001 to 2010 were respectively reviewed. Data recorded included the patients' folder numbers, gender, date of birth, age, date of presentation, date discharged and inpatient stay, firearm type, number of shots, circumstances, injury sites, injury type, treatment, resulting morbidities and survival. These data were compared with the 1991 - 2001 data. RESULTS: One hundred and sixty-three children presented with firearm injuries during this period. The results showed a decrease in incidence from 2001 to 2010. Older children and males had a higher incidence than younger children and females. Most injuries were to an extremity and were unintentional. Mortality had reduced significantly from the previous study (6% to 2.6%), as did the total number of inpatient days (1 063 to 617). CONCLUSIONS: Compared with the earlier study, this study showed a significant reduction in the number of children presenting with a firearm-related injury. Mortality and inpatient stay were also significantly reduced. The study shows the impact that the Firearms Control Act has had in terms of paediatric firearm-related injury and provides evidence that the medical profession can play an important role in reducing violence. PMID- 23941754 TI - Open globe injuries in patients seen at Groote Schuur Hospital, Cape Town, South Africa. AB - BACKGROUND: Ocular trauma accounts for a significant proportion of admissions to the eye ward at Groote Schuur Hospital (GSH), Cape Town, South Africa. There are few published studies on ocular trauma in South Africa. Some studies elsewhere have shown an association between open globe injuries and recent alcohol use, but no such study has been conducted in this country. OBJECTIVES: To identify causes of and outcomes after open globe injuries at GSH, with emphasis on the association between assault and alcohol use as well as the relationship, if any, between victim and assailant. METHODS: This was a prospective case series of all adult patients admitted to GSH with open globe injuries over a 2-year period. Ocular findings were recorded with a minimum 3-month follow-up period. RESULTS: There were 249 open globe injuries. Assault had occurred in 183 (73.5%), and 66 (26.5%) were accidental. In the assault-related cases, 95 (51.9%) of the assailants were reported to have used alcohol and 121 (66.1%) of the victims admitted to alcohol use prior to the assault. There was a statistically significant relationship between ethanol use and type of injury, 71.4% of assault cases overall being associated with ethanol use. In assault-related cases, the assailant was known to the victim in 113 cases (61.7%). Of the patients, 78.7% had a final acuity of <3/60 in the traumatised eye. CONCLUSION: A significant number of open globe injuries due to assault are related to ethanol abuse and occur when the victim and assailant are known to each other. Such injuries are likely to have a poor prognosis. PMID- 23941755 TI - The use of diverting colostomies in paediatric peri-anal burns: experience in 45 patients. AB - BACKGROUND: Peri-anal burns are common in children. Continual exposure to enteric organisms may lead to a contaminated burn wound, invasive sepsis, graft loss, scar contracture, anal and urinary malfunction, and delayed discharge from hospital. Use of a temporary diverting colostomy has been advocated to reduce complications. OBJECTIVES: To review the incidence, indications, methods, bacteriology, therapeutic effects and outcomes of colostomy for perianal burns. METHODS: A prospective study of children with peri-anal burns and stomas over a 17-year period. Prophylactic or therapeutic faecal diversion was achieved by temporary, divided sigmoid end-colostomy with Hartmann's closure of the distal end. RESULTS: Between 1995 and 2012, 45 children with peri-anal burns received a colostomy. The mean total body surface area burned was 35% (range 3 - 80%). There were 28 flame burns, 16 fluid burns and 1 contact burn. Prophylactic colostomies were performed in 29 children, on average on day 6 after admission, and therapeutic colostomies to counteract deep wound infection and septicaemia in 16 patients, on average on day 24. In all but 2 cases there was a marked improvement in clinical appearance, graft take and healing. The bacterial profile changed from gut-derived organisms to Pseudomonas aeruginosa or no pathogens. Complications occurred in 5 patients (11.1%). Three stomas required manual reduction. Two children died of established septic shock, compounded by stomal dehiscence in 1 case. Reversal of the colostomy was performed on average at 4 months. CONCLUSION: Diverting colostomy has therapeutic advantages in a select group of paediatric burns patients in whom continual faecal soiling poses a threat to both graft and life. PMID- 23941756 TI - The scope of plastic surgery. AB - OBJECTIVE: To ascertain junior doctors' awareness of the scope of public-sector plastic surgery practice. METHOD: A 12-part questionnaire asked the respondents to name, from a list, the specialty they felt was best equipped to manage patients with specific conditions. RESULTS: The data demonstrate that perception of the scope of plastic and reconstructive surgery is grossly limited. Although plastic surgeons were associated with reconstructive procedures, they were not necessarily identified as primary surgeons for procedures that they commonly perform. A significant number of respondents believed that plastic surgeons are seldom the first line of referral, and are more involved in cases with aesthetic rather than functional sequelae. DISCUSSION: These findings should be regarded with concern, particularly in light of the fact that these doctors will be responsible for carrying the burden of primary care delivery in South Africa and for referrals to secondary and tertiary levels of care. The study motivates for increased exposure to plastic surgery during undergraduate and postgraduate medical training. PMID- 23941757 TI - A paediatric case of AAST grade IV duodenal injury with application of damage control surgery. AB - Isolated severe blunt duodenal injuries are rare. We present an American Association for the Surgery of Trauma grade IV duodenal injury in a paediatric patient. The strategic use of damage control surgical principles, involving an initial abbreviated laparotomy followed by a delayed reconstruction, resulted in a successful outcome. PMID- 23941758 TI - A new deconvolution approach to robust fluence for intensity modulation under geometrical uncertainty. AB - This work addresses random geometrical uncertainties that are intrinsically observed in radiation therapy by means of a new deconvolution method combining a series expansion and a Butterworth filter. The method efficiently suppresses high frequency components by discarding the higher order terms of the series expansion and then filtering out deviations on the field edges. An additional approximation is made in order to set the fluence values outside the field to zero in the robust profiles. This method is compared to the deconvolution kernel method for a regular 2D fluence map, a real intensity-modulated radiation therapy field, and a prostate case. The results show that accuracy is improved while fulfilling clinical planning requirements. PMID- 23941759 TI - Oral administration of LPS and lipoteichoic acid prepartum modulated reactants of innate and humoral immunity in periparturient dairy cows. AB - The study evaluated the effects of repeated oral exposure to LPS and lipoteichoic acid (LTA) on immune responses of dairy cows. Thirty pregnant Holstein cows were randomly assigned to two treatment groups. Cows received orally either 2 ml of 0.85% sterile saline solution (control group), or 2 ml of sterile saline solution containing three doses of LPS from Escherichia coli 0111 : B4 along with a flat dose of LTA from Bacillus subtilis. Blood and saliva samples were collected and analyzed for serum amyloid A (SAA); LPS-binding protein (LBP); anti-LPS plasma IgA, IgG and IgM; TNF-alpha; and IL-1. Results showed greater concentrations of IgA in the saliva of treated cows compared with the controls (P < 0.01). Treated cows had lower plasma concentrations of anti-LPS IgA, IgG and IgM Abs, and TNF alpha than the controls (P < 0.05). There was a tendency for the concentrations of plasma LBP (P = 0.06) and haptoglobin (P = 0.10) to be lesser in the treatment group, although no differences were found in the concentration of plasma SAA and IL-1 (P > 0.10). Overall, the results of this study indicate that repeated oral administration with LPS and LTA stimulates innate and humoral immune responses in periparturient dairy cows. PMID- 23941760 TI - TLR4-mediated pro-inflammatory dendritic cell differentiation in humans requires the combined action of MyD88 and TRIF. AB - TLR4 ligation can activate both the MyD88 and the Toll-IL-1 receptor domain containing adaptor inducing IFN-beta (TRIF) signaling route. Whereas MyD88 is generally recognized as a universal adaptor for pro-inflammatory responses, TRIF is mainly thought to contribute to specific type I IFN responses. Here, we investigated the contribution of both MyD88 and TRIF to TLR4-mediated pro inflammatory dendritic cell (DC) differentiation in human. Pro-inflammatory cytokine induction was strongly decreased in monophosphoryl lipid A- and LPS matured monocyte-derived DCs when either MyD88 or TRIF were down-regulated by small interfering RNA electroporation. Induction of co-stimulatory molecule expression was entirely dependent on the TRIF pathway. Our results demonstrate that in human DCs the TRIF pathway is important for overall pro-inflammatory DC differentiation via TLR4 by mediating co-stimulation and playing a non-redundant role in pro-inflammatory cytokine induction. PMID- 23941762 TI - Pharmacological treatment of dementia: a scoping review of systematic reviews. AB - BACKGROUND: Until now, multiple reviews on the pharmacological treatment of dementia have been published. METHODS: We performed a scoping review to summarize research findings and to identify gaps in the existing literature. We searched the literature and assessed the risk of bias of the included reviews. A team of clinical experts assessed the fields in which more research is necessary. Fifty five reviews with a low risk of bias were included, most of them concerning the treatment of cognitive decline (n = 16) and behavioral symptoms (n = 10) in Alzheimer's disease (AD). For cognitive impairment, cholinesterase inhibitors (n = 13) and memantine (n = 7) were described most frequently. Little information was found about the treatment of depression in dementia. CONCLUSIONS: For many current treatments, there is sufficient evidence. New research should focus on the symptomatic treatment of the earliest and most salient complaints in AD as well as on disease-modifying interventions acting at the level of the amyloid cascade. PMID- 23941763 TI - Parental panic treatment reduces children's long-term psychopathology: a prospective longitudinal study. PMID- 23941761 TI - Effects of phosphate binder therapy on vascular stiffness in early-stage chronic kidney disease. AB - BACKGROUND/AIMS: Cardiovascular disease (CVD) is increased in chronic kidney disease (CKD), and contributed to by the CKD-mineral bone disorder (CKD-MBD). CKD MBD begins in early CKD and its vascular manifestations begin with vascular stiffness proceeding to increased carotid artery intima-media thickness (cIMT) and vascular calcification (VC). Phosphorus is associated with this progression and is considered a CVD risk factor in CKD. We hypothesized that modifying phosphorus balance with lanthanum carbonate (LaCO3) in early CKD would not produce hypophosphatemia and may affect vascular manifestations of CKD-MBD. METHODS: We randomized 38 subjects with normophosphatemic stage 3 CKD to a fixed dose of LaCO3 or matching placebo without adjusting dietary phosphorus in a 12 month randomized, double-blind, pilot and feasibility study. The primary outcome was the change in serum phosphorus. Secondary outcomes were changes in measures of phosphate homeostasis and vascular stiffness assessed by carotid-femoral pulse wave velocity (PWV), cIMT and VC over 12 months. RESULTS: There were no statistically significant differences between LaCO3 and placebo with respect to the change in serum phosphorus, urinary phosphorus, tubular reabsorption of phosphorus, PWV, cIMT, or VC. Biomarkers of the early CKD-MBD such as plasma fibroblast growth factor-23, Dickkopf-related protein 1 (DKK1), and sclerostin were increased 2- to 3-fold at baseline, but were not affected by LaCO3. CONCLUSION: Twelve months of LaCO3 had no effect on serum phosphorus and did not alter phosphate homeostasis, PWV, cIMT, VC, or biomarkers of CKD-MBD. PMID- 23941764 TI - Anomalous piezoelectric response due to stabilization of two ferroelectric phases in Zr-modified BaTiO3. AB - The lead-free Ba(Ti1-xZrx)O3 ceramic has shown enhanced piezo-response (d33) in a narrow composition interval (0.01 <= x <= 0.03) exhibiting the coexistence of two ferroelectric phases. The system presents two electric-field-dependent-property regimes: (i) a low field regime (E < 1.7 kV mm(-1)) where d33 is nearly independent of the poling field, and (ii) E > 1.7 kV mm(-1) for which d33 drops sharply. X-ray diffraction studies revealed that the later phenomenon is related to field driven irreversible structural transformation, which tends to drive the system away from an equilibrium two phase state to a nearly single phase metastable state. PMID- 23941765 TI - Long-term ventilation tubes: for how long should they be used? PMID- 23941766 TI - Is fluorine-18 fluorodeoxyglucose positron emission tomography useful for detecting bladder lesions? A meta-analysis of the literature. AB - OBJECTIVE: To evaluate the diagnostic accuracy of fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) in the detection of bladder lesions. METHODS: We conducted a systematic PubMed/MEDLINE and Embase database search of articles published before November 2012. Sensitivity, specificity, likelihood ratio and diagnostic odds ratio were pooled. A summary receiver operating characteristic curve was also used to summarize overall test performance. All meta-analyses were performed using the Meta-DiSc software (version 1.4). RESULTS: Six studies met the inclusion criteria. The pooled sensitivity and specificity of PET or PET/CT for the detection of bladder cancer was 80.0% (95% CI: 71.0-87.0%) and 84.0% (95% CI: 69.0-93.0%), respectively. The overall positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 3.47 (95% CI: 1.03-11.65), 0.31 (95% CI: 0.13-0.70) and 13.86 (95% CI: 2.84-67.74), respectively. Besides, the area (+/- standard error) under the symmetrical summary receiver operating characteristic curve was 0.8574 +/- 0.0704. CONCLUSION: When compared with results of MRI and CT published by other studies, (18)F-FDG PET or PET/CT showed no superiority in detecting local bladder lesions. As a whole body imaging, it is suggested that PET is more appropriate for the detection of metastasis. PMID- 23941767 TI - Mechanical evaluation of three access devices for laparoendoscopic single-site surgery. AB - BACKGROUND: Many access devices have been developed for laparoendoscopic single site surgery (LESS) during recent years. However, investigations are needed to determine which port is most suitable for this relatively new technique. The aim of this study was to evaluate commonly used ports using mechanical approaches in a training simulator. Any port that required less force and shorter surgery times had superior maneuverability. METHODS: The following three commercially available access devices were evaluated: Multi-ports, TriPort, and single-incision laparoscopic surgery (SILS) Port. A LESS mechanical evaluation platform was developed to investigate the forces that acted on the instruments in the ports while moving along horizontal and vertical axes. In addition, a strain-force measurement system was used to compare the average load on the ports when performing standard maneuvers. Additionally, the task completion time was recorded when the maneuvers in these ports were completed. RESULTS: During the horizontal displacement of the instrument, the traction forces of the Multi-ports were lower than those of the SILS Port, which were lower than those of the TriPort. The average traction forces were significantly different in pairwise multiple comparisons (P < 0.05). When the instrument was inserted into the ports, the vertical friction forces of the Multi-ports were the lowest and those of the TriPort were the highest. On extraction of the instrument, the friction forces of the Multi-ports remained the lowest, followed by those of the TriPort and SILS Port. There were statistically significant results among all the devices (P < 0.05). The average load required to perform the task was less for the SILS Port than that for the TriPort (P < 0.05). Similarly, the average load for the Multi ports was significantly less than that for the TriPort (P < 0.001). The participants who used the Multi-ports had significantly faster task times than those who used the SILS Port or TriPort (P < 0.005). CONCLUSIONS: Compared with the TriPort and SILS Port, the Multi-ports was associated with the least average load and the shortest task performance times in a training simulator. This study demonstrates that the Multi-ports may offer superior maneuverability for LESS. PMID- 23941768 TI - WITHDRAWN: Neutrophil activation in Behcet's Disease. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.intimp.2013.07.017. The duplicate article has therefore been withdrawn. PMID- 23941769 TI - Negatively-regulated necroptosis by autophagy required caspase-6 activation in TNFalpha-treated murine fibrosarcoma L929 cells. AB - Autophagy and necroptosis have been known to be interconnected, while the relationship between autophagy and necroptosis remains unclear. Here, we demonstrated that pan-caspase inhibitor z-VAD-fmk (zVAD) exacerbated TNFalpha induced necroptosis and autophagy in murine fibrosarcoma L929 cells. And the RIP 1 inhibitor necrostatin-1 inhibited TNFalpha+zVAD-induced necroptosis and autophagy. Inhibition of autophagy by 3-methyladenine (3MA) or small interfering RNA (siRNA) against Beclin 1 augmented TNFalpha-induced necroptosis, while, autophagy inhibition did not influence TNFalpha+zVAD-induced necroptosis. These results suggested that autophagy was a downstream consequence of necroptosis, and had a negative-feedback function to necroptosis in TNFalpha-treated L929 cells, but not in the presence of zVAD. Subsequently, TNFalpha administration was accompanied with caspase-6 activation. Inhibition of caspase-6 activity by z-V E(OMe)-I-D(OMe)-fmk (zVEID) or caspase-6 (p20) siRNA had no effect on necroptosis but promoted TNFalpha-induced autophagy. Meanwhile, autophagy inhibition further increased caspase-6 activation. Caspase-6 (p20) siRNA sequestered the increased necroptotic ratio by 3MA pretreatment in TNFalpha-treated L929 cells. In addition, caspase-6 activation induced by TNFalpha administration was inhibited by zVAD. Further, autophagy induced by higher concentration of zVAD did not negatively regulate necroptosis because caspase-6 was not activated. Collectively, our data indicated that autophagy was a downstream consequence of necroptosis, and negatively regulated necroptosis when caspase-6 was activated in TNFalpha-treated L929 cells. PMID- 23941770 TI - Extracellular ATP inhibits IL-1-induced MMP-1 expression through the action of CD39/nucleotidase triphosphate dephosphorylase-1 on human gingival fibroblasts. AB - Extracellular adenosine triphosphate (ATP) is sequentially dephosphorylated by two ectoenzymes: CD39/nucleotidase triphosphate dephosphorylase (ENTPD) and CD73/5'-ectonucleotidase (5'-NT). Adenosine, its notable metabolite, may elicit potent anti-inflammatory responses. We examined whether the CD39-adenosinergic axis may exist in gingival fibroblasts and have an effect on the expression of matrix metalloproteinase (MMP)-1, the excess production of which leads to pathological matrix degradation. We showed that transcripts of CD39, CD73, and adenosine receptors A1, A2a, and A2b, but not A3, were expressed by human gingival fibroblasts by RT-PCR. We also identified the expression of CD39 in fibroblastic cells in rat gingiva by immunohistochemistry. ATP inhibited the expression of MMP-1 triggered by interleukin-1 at gene and protein levels. However, ATP-gammaS, a stable ATP analog, did not. The ATP-mediated MMP-1 inhibition was restored in the presence of POM-1, a specific ENTPD inhibitor, suggesting that CD39/ENTPD was involved in the MMP-1 inhibition. ATP metabolites including adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP), and adenosine inhibited MMP-1 expression, but ADP-betaS, a stable ADP, did not, suggesting that adenosine converted from ATP by the action of CD39/ENTPD and CD73/5'-NT may contribute to MMP-1 inhibition. Adenosine-mediated MMP-1 inhibition was restored in the presence of H89, a protein kinase A (PKA) inhibitor. Conversely, forskolin, an enhancer of intracellular cAMP, mimicked the effect of adenosine, suggesting that the cAMP/PKA signaling pathway is involved in adenosine-mediated MMP-1 inhibition. The present findings suggest the existence of an endogenous anti-tissue destructive mechanism in gingival tissue via the CD39-adenosinergic axis. PMID- 23941771 TI - Aplotaxene blocks T cell activation by modulation of protein kinase C-theta dependent pathway. AB - Aplotaxene, (8Z, 11Z, 14Z)-heptadeca-1, 8, 11, 14-tetraene, is one of the major components of essential oil obtained from Inula helenium root, which is used in Oriental medicine. However, the effects of aplotaxene on immunity have not been investigated. Here, we show that aplotaxene inhibits T cell activation in terms of IL-2 and CD69 expression. Aplotaxene, at a concentration that optimally inhibits IL-2 production, has little effect on apoptotic or necrotic cell death, suggesting that apoptosis is not a mechanism for aplotaxene-mediated inhibition of T cell activation. Aplotaxene affects neither superantigeninduced conjugate formation between Jurkat T cells and Raji B cells nor clustering of CD3 and LFA-1 at the immunological synapse. Aplotaxene significantly inhibits PKC-theta phosphorylation and translocation to the immunological synapse, and blocks PMA induced T-cell receptor internalization. Furthermore, aplotaxene leads to inhibition of mitogen-activated protein kinases (JNK, ERK and p38) phosphorylation and NF-kappaB, NF-AT, and AP-1 promoter activities in Jurkat T cells. Taken together, our findings provide evidence for the immunosuppressive effect of aplotaxene on activated T cells through the modulation of the PKC-theta and MAPK pathways, suggesting that aplotaxene may be a novel immunotherapeutic agent for immunological diseases related to the overactivation of T cells. PMID- 23941772 TI - Gamma tocotrienol, a potent radioprotector, preferentially upregulates expression of anti-apoptotic genes to promote intestinal cell survival. AB - Gamma tocotrienol (GT3) has been reported as a potent ameliorator of radiation induced gastrointestinal (GI) toxicity when administered prophylactically. This study aimed to evaluate the role of GT3 mediated pro- and anti-apoptotic gene regulation in protecting mice from radiation-induced GI damage. Male 10- to 12 weeks-old CD2F1 mice were administered with a single dose of 200 mg/kg of GT3 or equal volume of vehicle (5% Tween-80) 24 h before exposure to 11 Gy of whole-body gamma-radiation. Mouse jejunum was surgically removed 4 and 24h after radiation exposure, and was used for PCR array, histology, immunohistochemistry, and immunoblot analysis. Results were compared among vehicle pre-treated no radiation, vehicle pre-treated irradiated, and GT3 pre-treated irradiated groups. GT3 pretreated irradiated groups, both 4h and 24h after radiation, showed greater upregulation of anti-apoptotic gene expression than vehicle pretreated irradiated groups. TUNEL staining and intestinal crypt analysis showed protection of jejunum after GT3 pre-treatment and immunoblot results were supportive of PCR data. Our study demonstrated that GT3-mediated protection of intestinal cells from a GI toxic dose of radiation occurred via upregulation of antiapoptotic and downregulation of pro-apoptotic factors, both at the transcript as well as at the protein levels. PMID- 23941773 TI - Anti-cancer effect and apoptosis induction of cordycepin through DR3 pathway in the human colonic cancer cell HT-29. AB - Cordycepin is known to have many pharmacological effects such as anti tumorigenic, anti-inflammatory and anti-angiogenic activity. However, cordycepin induced apoptosis through the DR3 pathway in human colon cancer cells has not been studied. The effect of cordycepin on anti-proliferation was investigated in this study. Cordycepin significantly inhibited cell viability in a dose and time dependent manner. Cordycepin increased sub G1 and G2/M phase arrest on HT-29 cells at the concentration of 100 MUM, whereas cordycepin at 200 MUM and 400 MUM increased G1 phase arrest. Cordycepin induced apoptosis in HT-29 cells in a dose dependent manner as detected by Hoechst and Annexin V-FITC staining. Intracellular ROS levels were higher in cordycepin treated cells as compared to control cells. The protein related to apoptosis was determined by antibody array. p53 and Bax expression increased treatment with cordycepin for 18 h. DR3, caspase 8, caspase-1, cleaved caspase-3 and cleaved PARP expression increased. These finding suggest that the cordycepin induces apoptosis through the DR3 pathway in human colon cancer HT-29. These findings suggest that cordycepin should be evaluated further as a therapeutic agent in human colon cancer. PMID- 23941774 TI - Influence of the matrix in bioavailability of flufenoxuron, lufenuron, pyriproxyfen and fenoxycarb residues in grapes and wine. AB - The aim of this study is to ascertain the in vitro bioavailablity of pesticides that regulate and inhibit the growth of insects--flufenoxuron, lufenuron, pyriproxyfen and fenoxycarb--in grapes grown under good agricultural practice (GAP), while respecting the pre-harvest intervals (PHI) for critical conditions (CAP), in the most unfavorable conditions. The bioavailability of wines obtained from grapes in each assay and in standard solutions is also studied in order to establish matrix-related differences. Human gastric digestion, intestinal digestion and absorption were imitated. Porcine pepsin, porcine pancreatin, bile salts and semipermeable cellulose dialysis tubing were used. The analysis of the residues of the insecticides studied was performed by extraction with the QuEChERS method, and determination was with HPLC-MS. In all cases it was observed that the pesticides can be ordered according to their dialyzation capacity: fenoxycarb>pyriproxyfen>lufenuron>flufenoxuron. The different matrices can also be ordered according to the matrix effect they impose on the dialysis: grape>wine>standards. The highest percentages of dialyzation for grape and wine matrices are achieved for fenoxycarb (3.27%) and pyriproxifen (2.04%) in wine. PMID- 23941775 TI - Control of konzo by detoxification of cassava flour in three villages in the Democratic Republic of Congo. AB - Three villages in Boko Health Zone, Bandundu Province, Democratic Republic of Congo (DRC), had 61 konzo cases and konzo prevalences of 2.5%, 4.1% and 7.5% respectively. Konzo cases occurred every year for 10 years and every month, peaking in July. The high mean cyanide content of cassava flour of 50 ppm was due to short soaking of cassava roots for 1-2 days instead of 3-4 days. Konzo cases were examined and village women taught the wetting method that removes cyanogens from flour. The villages were visited every month for 1 year following previous methodology. No new konzo cases occurred during the intervention, mean flour cyanide levels reduced from 50 to 14 ppm and mean urinary thiocyanate levels of school children reduced from 930 to 150 MUmole/L. The percentage of children with urinary thiocyanate levels of >350 MUmole/L was reduced from a maximum of 80 in Ikialala before the intervention to 0 in Ikusama, Ikialala and 3 in Imboso Mwanga 1 year later. This is the second time that konzo has been controlled and success depends on regular use of the wetting method by village women. The methodology is now being used in other villages in DRC with financial support of AusAID. PMID- 23941776 TI - Role of tumor necrosis factor-alpha, interferon-gamma and Fas-ligand on in vitro nitric oxide activity in the corpus luteum. AB - Normal reproductive function involves the expression of inflammatory mediators. Regarding the corpus luteum (CL), cytokines promote the cross-talk between immune, vascular and steroidogenic cells, among others. Moreover, TNF, IFNG and FASL were shown to regulate equine CL establishment and regression. We hypothesized that cytokines action on equine CL may be mediated by nitric oxide (NO), through the regulation of endothelial NO synthase (eNOS) expression. TNF increased eNOS mRNA level and NO metabolite (nitrite) production during CL growth. Cytokines combined action (TNF+IFNG+FASL) promoted eNOS protein upregulation in mid-CL and nitrite production in mid and late-CL. However, in late-CL, TNF alone decreased nitrite secretion. These results indicate that in equine CL, cytokines TNF, IFNG and FASL regulate NO activity, via eNOS expression modulation. PMID- 23941777 TI - Assessment of serum IGF-1 and adipokines related to metabolic dysfunction in HIV infected adults. AB - PURPOSE: HIV/HAART associated metabolic syndrome (HAMS) seems to result from direct influence of HIV, adverse effects of combined antiretroviral therapy (cART) and individual genetic predisposition. This study aimed to assess the influence of HIV infection and cART on serum concentration of insulin-like growth factor-1 (IGF-1) and adipokines related to metabolic abnormalities. METHODS: Seventy-two HIV infected patients including 48 HIV/HCV coinfected were enrolled in this study. Insulin resistance was evaluated by Homeostatic Model Assessment (HOMA) indexes. Serum concentrations of IGF-1, adiponectin, chemerin and visfatin were measured by ELISA. RESULTS: Significant correlation between serum IGF-1 level and CD4 lymphocytes count was demonstrated and the lowest values were observed in subjects with CD4<200 cells/MUL. Serum concentration of IGF-1 was significantly higher in patients treated with protease inhibitors based regimen compared to non-nucleoside reverse transcriptase inhibitors and healthy subjects. A significant negative correlation between serum concentration of adiponectin and waist-hip ratio as an indicator of central obesity, was found. There were significant positive correlations between serum concentration of chemerin and HOMA1-IR and serum IGF-1 concentration. Serum chemerin was increased in patients with insulin resistance vs. those with preserved insulin sensitivity. CONCLUSIONS: According to these results HAMS is associated with insulin resistance and imbalance of adipokines serum concentration, therefore identification of pathways related to HAMS development might be helpful in management of the syndrome. Serum IGF-1 largely depends on level of immunodeficiency in HIV-infection and may provide a link between immune dysfunction and development of HIV-associated lipodystrophy, AIDS wasting syndrome, diabetes and/or cardiovascular diseases in HIV-infected patients. PMID- 23941778 TI - Post-acute serum eosinophil and neutrophil-associated cytokine/chemokine profile can distinguish between patients with neuromyelitis optica and multiple sclerosis; and identifies potential pathophysiological mechanisms - a pilot study. AB - Neuromelitis optica (NMO) is an inflammatory, demyelinating disease of the central nervous system. It is distinguished from multiple sclerosis (MS) by clinical and radiological features and the presence of aquaporin 4 antibodies in approximately 70%. Despite the discovery of these antibodies and the evidence of neutrophils and eosinophils in the CNS parenchyma, the immunopathogenesis of NMO remains poorly understood. Previous studies attempting to assess the role cytokines and chemokines in NMO have primarily been conducted in acute cerebrospinal fluid from East Asian cohorts, have assessed small numbers of mediators in isolation and have not accounted for important confounding factors including antibody status and disease severity. Therefore we conducted a study of a more extensive range of cytokines and associated mediators in post-acute serum from a UK cohort using unsupervised and multivariate analytical techniques to assess the relative concentration of mediators in concert. Our study of 29 patients (aquaporin 4 antibody positive NMO n=19, MS n=10), matched where possible, including for disease severity, has identified and confirmed some key cytokine/chemokine markers in NMO distinct from MS. Our findings shed further light on the importance of specific inflammatory mediators with predominant function in the differentiation, chemotaxis and activity of neutrophils and eosinophils, particularly CCL4, CCL11, granulocyte-colony stimulating factor and myeloperoxidase, and these may represent potential immunomodulatory targets. PMID- 23941779 TI - Similarities and differences in physiological responses to 'Candidatus Liberibacter solanacearum' infection among different potato cultivars. AB - Zebra chip disease (ZC), putatively caused by the fastidious bacterium 'Candidatus Liberibacter solanacearum', is a threat to potato growers worldwide. However, little is known about biochemical shifts in different potato genotypes in response to 'Ca. L. solanacearum' infection. To address this, 'Red La Soda', 'Russet Norkotah', and 'FL 1867' potato were infected with 'Ca. L. solanacearum' 4, 3, 2, and 1 weeks before harvest to observe variability in cultivar responses to 'Ca. L. solanacearum' infection. ZC symptoms, 'Ca. L. solanacearum' titers, and tuber biochemistry were assessed. Red La Soda tubers exhibited greater symptoms when infected for 4 weeks than Russet Norkotah or FL 1867 tubers. 'Ca. L. solanacearum' titers did not vary among cultivars. Tuber levels of amino acids, carbohydrates, and phenolics varied among cultivars but no consistent trends were observed. Individual amino acids and phenolics were greater in FL 1867 than Red La Soda, whereas others were greater in Red La Soda or Russet Norkotah than FL 1867. Most amino acids, carbohydrates, and phenolics were positively associated with infection duration and symptoms regardless of cultivar. Associations between most of the evaluated compounds and 'Ca. L. solanacearum' titer were positive in Red La Soda. However, no associations between 'Ca. L. solanacearum' quantity and compounds were observed in FL 1867 and Russet Norkotah. PMID- 23941780 TI - White pine blister rust resistance in limber pine: evidence for a major gene. AB - Limber pine (Pinus flexilis) is being threatened by the lethal disease white pine blister rust caused by the non-native pathogen Cronartium ribicola. The types and frequencies of genetic resistance to the rust will likely determine the potential success of restoration or proactive measures. These first extensive inoculation trials using individual tree seed collections from >100 limber pine trees confirm that genetic segregation of a stem symptom-free trait to blister rust is consistent with inheritance by a single dominant resistance (R) gene, and the resistance allele appears to be distinct from the R allele in western white pine. Following previous conventions, we are naming the R gene for limber pine "Cr4." The frequency of the Cr4 allele across healthy and recently invaded populations in the Southern Rocky Mountains was unexpectedly high (5.0%, ranging from 0 to 13.9%). Cr4 is in equilibrium, suggesting that it is not a product of a recent mutation and may have other adaptive significance within the species, possibly related to other abiotic or biotic stress factors. The identification of Cr4 in native populations of limber pine early in the invasion progress in this region provides useful information for predicting near-term impacts and structuring long term management strategies. PMID- 23941781 TI - Cognitive therapy for social anxiety disorder: the impact of the "self-focused attention and safety behaviours experiment" on the course of treatment. AB - BACKGROUND AND AIMS: Several studies have shown that cognitive therapy is an effective treatment for social anxiety disorder (SAD). However, it remains unclear which of the complex interventions are associated with an anxiety reduction during the course of treatment. The aim of this study was to examine the impact of the intervention referred to as the "self-focused attention and safety behaviours experiment" on treatment outcome. METHOD: This study was part of a randomized controlled trial including 16 sessions of either individual cognitive therapy (CT) or interpersonal therapy (IPT) for SAD. Of particular importance, a concomitant time-series analysis was used to investigate the impact of the self-focused attention and safety behaviours experiment on subsequent social anxiety (1, 2, 3, and 4 weeks after the intervention) in 32 patients with SAD, who are receiving cognitive treatment. RESULTS: The results revealed a significant reduction of social anxiety after the self-focused attention and safety behaviours experiment during the subsequent month of treatment. CONCLUSION: The findings of the current study confirm current cognitive theories of SAD and demonstrate the importance of interventions that target self-focused attention and safety behaviour in cognitive therapy for SAD. PMID- 23941782 TI - Cadmium modifies the cell cycle and apoptotic profiles of human breast cancer cells treated with 5-fluorouracil. AB - Industrialisation, the proximity of factories to cities, and human work activities have led to a disproportionate use of substances containing heavy metals, such as cadmium (Cd), which may have deleterious effects on human health. Carcinogenic effects of Cd and its relationship with breast cancer, among other tumours, have been reported. 5-Fluorouracil (5-FU) is a fluoropyrimidine anticancer drug used to treat solid tumours of the colon, breast, stomach, liver, and pancreas. The purpose of this work was to study the effects of Cd on cell cycle, apoptosis, and gene and protein expression in MCF-7 breast cancer cells treated with 5-FU. Cd altered the cell cycle profile, and its effects were greater when used either alone or in combination with 5-FU compared with 5-FU alone. Cd significantly suppressed apoptosis of MCF-7 cells pre-treated with 5 FU. Regarding gene and protein expression, bcl2 expression was mainly upregulated by all treatments involving Cd. The expression of caspase 8 and caspase 9 was decreased by most of the treatments and at all times evaluated. C-myc expression was increased by all treatments involving Cd, especially 5-FU plus Cd at the half time of treatment. Cd plus 5-FU decreased cyclin D1 and increased cyclin A1 expression. In conclusion, our results indicate that exposure to Cd blocks the anticancer effects of 5-FU in MCF-7 cells. These results could have important clinical implications in patients treated with 5-FU-based therapies and who are exposed to high levels of Cd. PMID- 23941783 TI - Glycogen synthase kinase 3beta inhibition as a therapeutic approach in the treatment of endometrial cancer. AB - Alternative strategies beyond current chemotherapy and radiation therapy regimens are needed in the treatment of advanced stage and recurrent endometrial cancers. There is considerable promise for biologic agents targeting the extracellular signal-regulated kinase (ERK) pathway for treatment of these cancers. Many downstream substrates of the ERK signaling pathway, such as glycogen synthase kinase 3beta (GSK3beta), and their roles in endometrial carcinogenesis have not yet been investigated. In this study, we tested the importance of GSK3beta inhibition in endometrial cancer cell lines and in vivo models. Inhibition of GSK3beta by either lithium chloride (LiCl) or specific GSK3beta inhibitor VIII showed cytostatic and cytotoxic effects on multiple endometrial cancer cell lines, with little effect on the immortalized normal endometrial cell line. Flow cytometry and immunofluorescence revealed a G2/M cell cycle arrest in both type I (AN3CA, KLE, and RL952) and type II (ARK1) endometrial cancer cell lines. In addition, LiCl pre-treatment sensitized AN3CA cells to the chemotherapy agent paclitaxel. Administration of LiCl to AN3CA tumor-bearing mice resulted in partial or complete regression of some tumors. Thus, GSK3beta activity is associated with endometrial cancer tumorigenesis and its pharmacologic inhibition reduces cell proliferation and tumor growth. PMID- 23941789 TI - Impact of annual urodynamic evaluations on guiding bladder management in individuals with spinal cord injuries. AB - STUDY DESIGN: A single-center institutional review board-approved prospective cross-sectional observational study. CONTEXT: Urodynamic studies are essential to accurately direct bladder management following spinal cord injury (SCI). There is no consensus on how often testing should be performed. OBJECTIVE: To determine the impact of annual urodynamic studies on guiding bladder management following SCI. METHODS: Individuals with traumatic SCI undergoing annual urological evaluations were enrolled in this study. They had to be injured for at least 2 years so that urodynamic changes could be compared with their previous annual urodynamic evaluation. Changes in the urodynamic parameters and autonomic dysreflexia were determined by comparing this study with the previous year's study. All studies were done with the same physician and nursing staff. Demographic data, bladder management, urodynamic parameters, and the need and type of interventions based on the urodynamic study were obtained. The main outcome measure was whether or not there was a need for an intervention based on the urodynamics. Interventions were classified as urological intervention, non urological intervention, or a combination of urological and non-urological intervention. The impact of the type of bladder management, length of injury, and level of injury was also evaluated. RESULTS: Ninety-six consecutive individuals with SCI undergoing annual urodynamic evaluations were enrolled over a 5-month period. Overall, 47.9% of individuals required at least one type of intervention based on urodynamic studies: 82.6% were urological interventions (medication changes were most common, comprising 54.3% of urological interventions); 13.0% were non-urological interventions; and 4.3% were a combination of non-urological and urological interventions. The need for interventions did not appear to be influenced by the type of bladder management, the length of time post-injury or level of injury. CONCLUSION: Annual urodynamic evaluation plays an important role in guiding bladder management following SCI. PMID- 23941788 TI - Use of botulinum toxin in individuals with neurogenic detrusor overactivity: state of the art review. AB - BACKGROUND: Botulinum neurotoxin (BoNT) injection into the bladder wall has been shown to be an effective alternative to anticholinergic (antimuscarinic) medications and more invasive surgery in those with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity (NDO) and urinary incontinence who are not tolerating anticholinergic medications. In August 2011, Botox((r)) (onabotulinumtoxinA) received Food and Drug Administration (FDA) approval for this use. Clinically, intradetrusor injection of BoNT has been found to decrease urinary incontinence and improve quality of life. Its impact on urodynamic parameters is an increase in the maximum cystometric (bladder) capacity and decrease in the maximum detrusor pressures. The most common side effects are urinary tract infections and urinary retention. There have been rare reports and a black box warning of distant spread of BoNT. BoNT has gained popularity because of its effectiveness and long duration of action, relative ease of administration, easy learning curve, reproducibility of results on repeated administration, and low incidence of complications. OBJECTIVE: To discuss the structure and function, mechanisms of action, clinical and urodynamic studies, injection technique, potential beneficial and adverse effects, and potential areas of research of BoNT. METHODS: Literature search focused on botulinum toxin in MEDLINE/PubMed. Search terms included botulinum toxin, neurogenic bladder, NDO, botox bladder, botox spinal cord injury, botox, FDA, botox side effects. All papers identified were English language, full-text papers. In addition, English abstracts of non-English papers were noted. The reference list of identified articles was also searched for further papers. CONCLUSION: Botulinum toxin is an alternative treatment for individuals with NDO who fail to tolerate anticholinergic medications. Its popularity has increased because of the literature, which has supported its effectiveness, safety, easy use and learning curve, reproducibility of results on repeated use, and recent FDA approval of Botox((r)) (onabotulinumtoxinA). PMID- 23941784 TI - High lysophosphatidylcholine acyltransferase 1 expression independently predicts high risk for biochemical recurrence in prostate cancers. AB - Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been suggested to play a role in cancer. To assess its role in prostate cancer, LPCAT1 expression was analyzed on a tissue microarray containing samples from 11,152 prostate cancer patients. In benign prostate glands, LPCAT1 immunostaining was absent or weak. In prostate cancer, LPCAT1 positivity was found in 73.8% of 8786 interpretable tumors including 29.2% with strong expression. Increased LPCAT1 expression was associated with advanced tumor stage (pT3b/T4) (p < 0.0001), high Gleason score (>=4 + 4) (p < 0.0001), positive nodal involvement (p = 0.0002), positive surgical margin (p = 0.0005), and early PSA recurrence (p < 0.0001). High LPCAT1 expression was strongly linked to ERG-fusion type prostate cancer. Strong LPCAT1 staining was detected in 45.3% of ERG positive but in only 16.7% of ERG negative tumors (p < 0.0001). Within ERG negative cancers, LPCAT1 staining was strongly increased within the subgroup of PTEN deleted cancers (p < 0.0001). Further subgroup analyses revealed that associations of high LPCAT1 expression with PSA recurrence and unfavorable tumor phenotype were largely driven by ERG negative cancers (p < 0.0001) while these effects were substantially mitigated in ERG positive cancers (p = 0.0073). The prognostic impact of LPCAT1 expression was independent of histological and clinical parameters. It is concluded, that LPCAT1 measurement, either alone or in combination, may be utilized for better clinical decision-making. These data also highlight the potentially important role of lipid metabolism in prostate cancer biology. PMID- 23941790 TI - Heavy reliance on carbohydrate across a wide range of exercise intensities during voluntary arm ergometry in persons with paraplegia. AB - CONTEXT/OBJECTIVE: To describe and compare substrate oxidation and partitioning during voluntary arm ergometry in individuals with paraplegia and non-disabled individuals over a wide range of exercise intensities. DESIGN: Cross-sectional study. SETTING: Clinical research facility. PARTICIPANTS: Ten apparently healthy, sedentary men with paraplegia and seven healthy, non-disabled subjects. INTERVENTIONS: Rest and continuous progressive voluntary arm ergometry between 30 and 80% of peak aerobic capacity (VO2peak). OUTCOME MEASURES: Total energy expenditure and whole body rates of fat and carbohydrate oxidation. RESULTS: A maximal whole body fat oxidation (WBFO) rate of 0.13 +/- 0.07 g/minute was reached at 41 +/- 9% VO2peak for subjects with paraplegia, although carbohydrate became the predominant fuel source during exercise exceeding an intensity of 30 40% VO2peak. Both the maximal WBFO rate (0.06 +/- 0.04 g/minute) and the intensity at which it occurred (13 +/- 3% VO2peak) were significantly lower for the non-disabled subjects than those with paraplegia. CONCLUSION: Sedentary individuals with paraplegia are more capable of oxidizing fat during voluntary arm ergometry than non-disabled individuals perhaps due to local adaptations of upper body skeletal muscle used for daily locomotion. However, carbohydrate is the predominant fuel source oxidized across a wide range of intensities during voluntary arm ergometry in those with paraplegia, while WBFO is limited and maximally achieved at low exercise intensities compared to that achieved by able bodied individuals during leg ergometry. These findings may partially explain the diminished rates of fat loss imposed by acute bouts of physical activity in those with paraplegia. PMID- 23941791 TI - Colonoscopy is high yield in spinal cord injury. AB - OBJECTIVES/BACKGROUND: Colorectal cancer (CRC) can be prevented by routine colonoscopy. CRC screening in special populations, e.g. spinal cord injury and disorders, presents unique barriers and, potentially, a higher risk of complications. We were concerned about potentially higher risks of complications and sought to determine the safety of colonoscopy. METHODS: Retrospective observational design using medical record review for 311 patients who underwent 368 colonoscopies from two large VA SCI centers from 1997-2008. Patient demographics and peri-procedural characteristics, including indication, bowel prep quality, and pathological findings are presented. Descriptive statistics are presented. RESULTS: The population was predominantly male and Caucasian, and 199 (64%) had high-level injuries (T6 or above). Median age at colonoscopy was 61 years (interquartile range 53-69). Just <1/2 of the colonoscopies were diagnostic, usually for evidence of rectal bleeding. Although a majority of colonoscopies were reported as poorly prepped, the proportion that were adequately prepped increased over time (from 3.7 to 61.3%, P = <0.0001). Of the 146 polyps removed, 101 (69%) were adenomas or carcinomas. Ten subjects had 11 complications, none of which required surgical intervention. CONCLUSIONS: Although providing quality colonoscopic care in this population is labor intensive, the data suggests that it appears safe and therapeutically beneficial. The results indicate that the risk of screening is outweighed by the likelihood of finding polyps. Recognition of the benefit of colonoscopy in this population may have improved bowel prep and reporting over time. Spinal cord injury providers should continue to offer screening or diagnostic colonoscopy to their patients when indicated, while being aware of the special challenges that they face. PMID- 23941792 TI - Prediction of limb lean tissue mass from bioimpedance spectroscopy in persons with chronic spinal cord injury. AB - BACKGROUND: Bioimpedance spectroscopy (BIS) is a non-invasive, simple, and inexpensive modality that uses 256 frequencies to determine the extracellular volume impedance (ECVRe) and intracellular volume impedance (ICVRi) in the total body and regional compartments. As such, it may have utility as a surrogate measure to assess lean tissue mass (LTM). OBJECTIVE: To compare the relationship between LTM from dual-energy X-ray absorptiometry (DXA) and BIS impedance values in spinal cord injury (SCI) and able-bodied (AB) control subjects using a cross sectional research design. METHODS: In 60 subjects (30 AB and 30 SCI), a total body DXA scan was used to obtain total body and leg LTM. BIS was performed to measure the impedance quotient of the ECVRe and ICVRi in the total body and limbs. RESULTS: BIS-derived ECVRe yielded a model for LTM in paraplegia, tetraplegia, and control for the right leg (RL) (R(2) = 0.75, standard errors of estimation (SEE) = 1.02 kg, P < 0.0001; R(2) = 0.65, SEE = 0.91 kg, P = 0.0006; and R(2) = 0.54, SEE = 1.31 kg, P < 0.0001, respectively) and left leg (LL) (R(2) = 0.76, SEE = 1.06 kg, P < 0.0001; R(2) = 0.64, SEE = 0.83 kg, P = 0.0006; and R(2) = 0.54, SEE = 1.34 kg, P < 0.0001, respectively). The ICVRi was similarly predictive of LTM in paraplegia, tetraplegia, and AB controls for the RL (R(2) = 0.85, SEE = 1.31 kg, P < 0.0001; R(2) = 0.52, SEE = 0.95 kg, P = 0.003; and R(2) = 0.398, SEE = 1.46 kg, P = 0.0003, respectively) and LL (R(2) = 0.62, SEE = 1.32 kg, P = 0.0003; R(2) = 0.57, SEE = 0.91 kg, P = 0.002; and R(2) = 0.42, SEE = 1.31 kg, P = 0.0001, respectively). CONCLUSION: Findings demonstrate that the BIS derived impedance quotients for ECVRe and ICVRi may be used as surrogate markers to track changes in leg LTM in persons with SCI. PMID- 23941793 TI - A prospective report on the prevalence of heart rate and blood pressure abnormalities in veterans with spinal cord injuries. AB - OBJECTIVE: Decentralized autonomic cardiovascular regulation may lead to increased prevalence of heart rate (HR) and blood pressure (BP) abnormalities in veterans with SCI. In addition, comorbid medical conditions and prescription medication use may increase HR and BP abnormalities. These abnormalities include bradycardia, and tachycardia, hypotension, hypertension as well as autonomic dysreflexia and orthostatic hypotension; the prevalence of which is unknown. DESIGN: HR and BP data were measured during a routine annual physical examination in 64 veterans with SCI. Measurements of HR and BP were recorded in the seated and supine positions to document the influence of body position and to document intra-subject variability in these assessments. RESULTS: All subjects were chronically injured (20 +/- 14 years), 33 subjects were tetraplegic (T: C3-C8), nine had high paraplegia (HP: T1-T6), and 22 had low paraplegia (LP: T7-L2). Regardless of position, the prevalence of bradycardia was increased in the T group, whereas prevalence of tachycardia was increased in the HP and LP groups. Systolic hypotension was more common in the T and HP groups than the LP group and positional effects were most evident in the T group. Systolic hypertension was comparable in the T and HP groups but was twice as prevalent in the LP group. Increased prevalence of individuals with three or more medical conditions and prescribed three or more medications which might influence HR and BP was observed. CONCLUSION: Decentralized autonomic regulation, comorbid medical conditions, and prescription medication use in veterans with SCI result in HR and BP abnormalities; our data suggest that these abnormalities vary depending on the level of injury and orthostatic positioning. PMID- 23941794 TI - A retrospective chart review of heart rate and blood pressure abnormalities in veterans with spinal cord injury. AB - OBJECTIVE: Autonomic impairment may lead to increased prevalence of heart rate (HR) and blood pressure (BP) abnormalities in veterans with spinal cord injury (SCI). In addition, comorbid medical conditions and prescription medication use may influence these abnormalities, including bradycardia, and tachycardia, hypotension, hypertension as well as autonomic dysreflexia (AD), and orthostatic hypotension (OH). DESIGN: A retrospective review of clinical and administrative datasets in veterans with SCI and compared the prevalence rates between clinical values and ICD-9 diagnostic codes in individuals with tetraplegia (T: C1-C8), high paraplegia (HP: T1-T6), and low paraplegia (LP: T7 and below). RESULTS: The prevalence of clinical values indicative of a HR >= 80 beats per minute was higher in the HP compared to the LP and T groups. A systolic BP (SBP) <= 110 mmHg was more common in the T compared to the HP and LP groups, whereas the prevalence of a SBP >= 140 mmHg was increased in the LP compared to the HP and T groups. Diagnosis of hypertension was 39-60% whereas the diagnosis of hypotension was less than 1%. Diagnosis of AD and OH was highest in the T group, but remained below 10%, regardless of categorical lesion level. Antihypertensive medications were commonly prescribed (55%), and patients on these medications were less likely to have high BP. The odds ratio of higher SBP and DBP increased with age and body mass index (BMI). CONCLUSION: In veterans with SCI, the prevalence of HR and BP abnormalities varied depending on level of lesion, age, BMI, and prescription medication use. PMID- 23941795 TI - Low-dose baclofen therapy raised plasma insulin-like growth factor-1 concentrations, but not into the normal range in a predictable and sustained manner in men with chronic spinal cord injury. AB - OBJECTIVE: To evaluate, whether once-daily oral baclofen administration increases and/or sustains plasma insulin-like growth factor-1 (IGF-1) concentration in 11 men with chronic spinal cord injury (SCI) and IGF-1 deficiency (i.e. <250 ng/ml). DESIGN: Prospective, open-label, dose titration study. Baclofen was administered at 20 mg/day for 8 weeks; then increased to 40 mg/day for another 8 weeks. Plasma IGF-1 and self-reported side effects were measured at baseline and every other week for the duration of the study. RESULTS: The subjects were 43 +/- 12 years old, had duration of injury of 20 +/- 12 years; eight subjects had a complete motor injury, and eight had paraplegia. Nine of 11 subjects completed the 20 mg/day treatment and 5 subjects completed the 40 mg/day treatment. Plasma IGF-1 levels improved with each baclofen dose; however, only one subject increased from baseline and remained above the targeted physiological range of 250 ng/ml throughout treatment. A significant increase in IGF-1concentration was observed between baseline and week 2 (154 +/- 63 vs. 217 +/- 69 ng/ml; P < 0.05), weeks 8 and 10 (188 +/- 95 vs. 228 +/- 93 ng/ml; P < 0.05), and weeks 8 and 16 (188 +/- 95 vs. 259 +/- 92 ng/ml; P < 0.05). No serious side effects were observed at 20 mg/day; the 40 mg/day dose was less well tolerated. CONCLUSION: Baclofen was not effective at sustaining plasma IGF-1 concentrations in the physiological range in men with chronic SCI. PMID- 23941796 TI - The association of age, pain, and fatigue with physical functioning and depressive symptoms in persons with spinal cord injury. AB - CONTEXT/OBJECTIVE: To describe the relationship of pain and fatigue with physical and psychological functioning in adults with spinal cord injury (SCI). DESIGN: Cross-sectional survey. SETTING: Community-based survey. PARTICIPANTS: Convenience sample of individuals with SCI. INTERVENTION: Not applicable. OUTCOME MEASURES: Physical functioning (Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Functioning item bank items), depression (Patient Health Questionnaire-9 (PHQ-9)), pain severity (0-10 Numerical Rating Scale (NRS)), and fatigue (0-10 NRS). RESULTS: Pain and fatigue were independently associated with depression, but only pain was associated with physical functioning. Additionally, depression was more severe among middle-aged participants relative to younger or older participants. Physical functioning declined with increasing age, as well as with higher level of injury. CONCLUSIONS: The findings support the need for continued development of effective treatments for both pain and fatigue in order to prevent and mitigate the negative effects these symptoms can have on functioning. PMID- 23941797 TI - Antibiotic prescribing trends in the emergency department for veterans with spinal cord injury and disorder 2002-2007. AB - OBJECTIVE: Clinical guidelines exist to promote antibiotic stewardship, particularly in ambulatory care settings such as the emergency department (ED). However, there is limited evidence on prescribing practice for persons with spinal cord injury and disorder (SCI/D). The goal of this study was to assess trends in antibiotic prescribing in the ED setting for persons with SCI/D. DESIGN: A retrospective dynamic cohort study design. SETTING: ED visits that did not result in same day hospitalization over 6 years (fiscal year (FY) 2002 FY2007) in Department of Veterans Affairs (VA) facilities Participants Veterans with SCI/D. OUTCOME MEASURES: VA clinical and administrative databases were used to identify the cohort and to obtain demographics, diagnoses, and medications. The rate of antibiotic prescribing for ED visits was defined as the number of antibiotics/total ED visits. RESULTS: Veterans with SCI/D had 21 934 ED visits and 5887 antibiotics prescribed over the study period (rate of 268.4 prescriptions/1000 visits). The antibiotic prescribing rate increased from 238.8/1000 visits in FY2002 to 310.8/1000 visits in FY2007 (P < 0.0001). This increase in the rate of prescribing was seen across all patient demographics and factors assessed. CONCLUSION: Although clinical guidelines for judicious use of antibiotics in persons with SCI/D have been disseminated to providers, antibiotic prescribing in an ED setting is high and continuing to rise in this population. PMID- 23941799 TI - Spinal cord injury facts and figures at a glance. PMID- 23941798 TI - Marfan syndrome and symptomatic sacral cyst: report of two cases. AB - CONTEXT: Meningeal abnormalities such as dural ectasia are seen in Marfan syndrome, but spinal meningeal cysts are rarely seen. These cysts usually asymptomatic and often found incidentally on magnetic resonance imaging, large cysts may cause neurological deficits and pain secondary to nerve root compression. DESIGN: Case reports. FINDINGS: Two patients with Marfan syndrome presented with urinary symptoms secondary to dural ectasia and sacral cysts. Patient 1 had a history of low back pain, erectile dysfunction, and occasional urinary incontinence and groin pain with recent symptom worsening. He underwent L5 partial laminectomy and S1-S2 laminectomy with sacral cyst decompression. Nine weeks later, he underwent drainage of a sacral pseudomeningocele. Pain and urinary symptoms resolved, and he remains neurologically normal 2 years after surgery. Patient 2 presented after a fall on his tailbone, complaining of low back pain and difficulty urinating. Physical therapy was implemented, but after 4 weeks, urinary retention had not improved. He then underwent resection of the sacral cyst and S1-S3 laminectomy. Pain and paresthesias resolved and bowel function returned to normal. Other than needing intermittent self catheterization, all other neurologic findings were normal 30 months after surgery. CONCLUSION/CLINICAL RELEVANCE: Surgical goals for sacral cysts include resection as well as closure of the dura, which can be challenging due to thinning from ectasia. Neurosurgical intervention in Marfan syndrome is associated with a high risk of dural tears and osseous complications, and should be performed only when symptoms are severe. PMID- 23941800 TI - Computational fluid dynamics modelling of perfusion measurements in dynamic contrast-enhanced computed tomography: development, validation and clinical applications. AB - Dynamic contrast-enhanced computed tomography (DCE-CT) is an imaging tool that aids in evaluating functional characteristics of tissue at different stages of disease management: diagnostic, radiation treatment planning, treatment effectiveness, and monitoring. Clinical validation of DCE-derived perfusion parameters remains an outstanding problem to address prior to perfusion imaging becoming a widespread standard as a non-invasive quantitative measurement tool. One approach to this validation process has been the development of quality assurance phantoms in order to facilitate controlled perfusion ex vivo. However, most of these systems fail to establish and accurately replicate physiologically relevant capillary permeability and exchange performance. The current work presents the first step in the development of a prospective suite of physics based perfusion simulations based on coupled fluid flow and particle transport phenomena with the goal of enhancing the understanding of clinical contrast agent kinetics. Existing knowledge about a controllable, two-compartmental fluid exchange phantom was used to validate the computational fluid dynamics (CFD) simulation model presented herein. The sensitivity of CFD-derived contrast uptake curves to contrast injection parameters, including injection duration and flow rate, were quantified and found to be within 10% accuracy. The CFD model was employed to evaluate two commonly used clinical kinetic algorithms used to derive perfusion parameters: Fick's principle and the modified Tofts model. Neither kinetic model was able to capture the true transport phenomena it aimed to represent but if the overall contrast concentration after injection remained identical, then successive DCE-CT evaluations could be compared and could indeed reflect differences in regional tissue flow. This study sets the groundwork for future explorations in phantom development and pharmaco-kinetic modelling, as well as the development of novel contrast agents for DCE imaging. PMID- 23941802 TI - Bibliotherapy on coping with illness improves health literacy but not heart related anxiety of patients in cardiological rehabilitation. PMID- 23941801 TI - Effect of early stage kidney disease on cardiac mass: comparison to post-donation renal function. AB - BACKGROUND/AIM: In chronic renal failure the increase in cardiovascular risk is in part related to the high prevalence of left ventricular hypertrophy. The aim of the present monocentric retrospective study was to evaluate the influence of the presence of parenchymal kidney disease on left ventricular geometry in normotensive (arterial pressure <140/90 mm Hg) patients (KD+, n = 50, mean age 39 +/- 19 years) with mild to moderate renal failure (stage 2-3 chronic kidney disease). METHODS: Left ventricular geometry was estimated by echocardiography and compared to a group of healthy subjects with similarly reduced renal function as a consequence of renal donation (KD-, n = 63, mean age 52 +/- 12 years). RESULTS: Subjects with and without kidney disease had similar blood pressure, body mass index and isotopic glomerular filtration rate. Left ventricular mass (LVM) indexed to body surface area was greater in KD+ as compared to KD- subjects and the difference was more pronounced in women than in men. The increase in LVM in KD+ patients was associated with lower albuminemia and hematocrit, and a higher plasma renin activity and aldosterone as compared to KD- subjects. In multivariate analysis, kidney disease emerged as an important determinant of LVM index independently of age, gender and blood pressure. CONCLUSION: This observation suggests that the presence of kidney disease has an independent amplifying effect on LVM which could be related to volume overload and/or prohypertrophic factors such as aldosterone. PMID- 23941803 TI - An existential understanding of psychotherapy and psychiatric practice. AB - In this paper Karl Jaspers' writings on psychotherapy and the psychiatric practice will be profoundly investigated and a meticulous reconstruction of the development of his understandings in the course of his oeuvre will be presented. This reconstruction allows for arguing that Jaspers displays a methodologically critical attitude towards medicine as a 'science of actions' and that he did refrain from developing an existential psychotherapy for methodological and existential reasons. Nonetheless and aside from Jaspers' abstention, some of his concepts from existential philosophy, like 'Grenzsituation' (border-situation, limit-situation) or 'Gehause' (shell, housings), can be extraordinarily fruitful in psychotherapy and in the psychiatric practice because it requires a change of attitude in order to bring these concepts into play. This different attitude could be called the attitude of the fellow sufferer, or, more neutral, the attitude of the fellow human being. PMID- 23941804 TI - Clinical impact of endoscopic devices for colorectal endoscopic submucosal dissection. AB - BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) allows the en bloc resection of large colorectal tumors. This requires a safe and effective ESD instrument. We compared colorectal ESD outcome using a bipolar or monopolar knife. METHODS: We retrospectively studied 122 patients and 125 lesions in consecutive cases treated at our hospital. Patients were divided into a bipolar knife group (BKG; n = 45) and a monopolar knife group (MKG; n = 80). Comparisons were based on age and gender, tumor morphology, size and location, specimen size, procedure time, complications, and en bloc resection and curative resection rates. RESULTS: There were no significant differences in age and gender, tumor morphology, size and location, or specimen size between the 2 groups. The procedure time was significantly shorter in the MKG than in the BKG (p < 0.05). The number of patients for whom the procedure time exceeded 120 min was significantly lower in the MKG than in the BKG (p < 0.05). CONCLUSIONS: In this study, the monopolar knife was shown to be effective for colorectal ESD with a shorter procedure time. PMID- 23941805 TI - Levels, composition profiles and sources of polycyclic aromatic hydrocarbons in surface sediments from Nan'ao Island, a representative mariculture base in South China. AB - Levels, composition profiles and sources of 16 polycyclic aromatic hydrocarbons (PAHs) in surface sediments from Nan'ao Island, one of the largest mariculture bases in South China were investigated. The total PAHs concentrations ranged from 265.49 to 951.27 ng/g (dry weight) with a mean of 515.90 ng/g, and seven possible carcinogenic PAHs accounted for 76.94% of total PAHs. Among various mariculture sections, the highest PAHs level was found in the large seaweed culture; while the lowest concentration was detected in the abandoned culture. The composition of PAHs was characterized by low molecular weight PAHs, and Phe Ant and Pyr were the dominant constituent. PAHs may be mainly originated from petroleum and combustion of biomass and coal. Risk assessments suggested that the probability of adverse effect was lower than 25% and PAHs exposure was moderately carcinogenic. PMID- 23941806 TI - Marine spatial planning and oil spill risk analysis: finding common grounds. AB - A flow of key information links marine spatial planning (MSP) and oil spill risk analysis (OSRA), two distinct processes needed to achieve true sustainable management of coastal and marine areas. OSRA informs MSP on areas of high risk to oil spills allowing a redefinition of planning objectives and the relocation of activities to increase the ecosystem's overall utility and resilience. Concomitantly, MSP continuously generates a large amount of data that is vital to OSRA. The Environmental Sensitivity Index (ESI) mapping system emerges as an operational tool to implement the MSP-OSRA link. Given the high level of commonalities between ESI and MSP data (both in biophysical and human dimensions), ESI tools (both paper maps and dynamic GIS-based product) are easily developed to further inform MSP and oil spill risk management. Finally, several other benefits from implementing the MSP-OSRA link are highlighted. PMID- 23941807 TI - Musical ear syndrome in adult cochlear implant patients. AB - OBJECTIVE: Except for a single case report, musical ear syndrome in cochlear implantees has not been studied. We aimed to study the prevalence and nature of musical ear syndrome among adult cochlear implant patients, as well as the effect on their emotional well-being. STUDY DESIGN, PATIENTS AND INTERVENTION: A cross sectional survey of patients aged 18 years and above who had received cochlear implants for profound hearing loss between 1997 and 2010. RESULTS: Of the 82 patients studied, 18 (22 per cent) were found to have experienced musical ear syndrome. Seven and 11 patients had musical ear syndrome prior to and after cochlear implantation, respectively. The character of musical ear syndrome symptoms was described as instrumental music (n = 2), singing (6) or both (10). Fourteen patients reported an adverse emotional effect, with three expressing 'intolerance'. CONCLUSIONS: In this study, 22 per cent of cochlear implantees experienced musical ear syndrome. These symptoms affected patients' emotional state, but most coped well. Musical ear syndrome can occur prior to and after cochlear implantation. PMID- 23941808 TI - Designer thermal switches: the effect of the contact material on instantaneous thermoelectric transport through a strongly interacting quantum dot. AB - We investigate the effect of contact material on the instantaneous thermoelectric response of a quantum dot pushed suddenly into the Kondo regime via a gate voltage using time dependent non-crossing approximation and linear response Onsager relations. We utilize graphene and metal contacts for this purpose. Instantaneous thermopower displays sinusoidal oscillations whose frequency is proportional to the energy separation between the van Hove singularity in the contact density of states and the Fermi level for both cases, regardless of the asymmetry factor at the onset of the Kondo timescale. The amplitude of the oscillations increases with decreasing temperature, saturating around the Kondo temperature. We also calculate the instantaneous figure of merit and show that the oscillations taking place at temperatures above the Kondo temperature are enhanced more than the ones occurring at lower temperatures due to the violation of the Wiedemann-Franz law. Graphene emerges as a more promising electrode candidate than ordinary metals in single electron devices since it can minimize these oscillations. PMID- 23941809 TI - The thymulin-lactotropic axis in rodents: thymectomy, immunoneutralization and gene transfer studies. AB - OBJECTIVES: There is clear evidence on the existence of a thymus-pituitary axis which seems to be particularly important during perinatal life. In particular, the thymic peptide thymulin has been shown to be a relevant player in thymus pituitary communication. Our goal was to explore the effect of thymulin on circulating prolactin (PRL) levels in different animal models. To this end we undertook a series of experiments in rats and mice, implementing adult thymectomy, thymulin immunoneutralization in normal C57BL/6 mice and neonatal thymulin gene therapy in nude mice. METHODS: We assessed the impact of the above manipulations on PRL secretion and lactotrope morphology by measuring serum PRL by radioimmunoassay and by performing morphometric analysis of the lactotropic cell population in the anterior pituitary gland. RESULTS: Adult thymectomy in female rats slightly increased serum PRL, an effect that was partially reversed by thymulin gene therapy. In mice, thymulin immunoneutralization from birth to age 32 days reduced serum PRL both in males and females. Thymulin immunoneutralization induced a significant (p < 0.01) decrease in lactotrope cell density (CD) and volume density (VD) without changes in cell size (CS). Neonatal thymulin gene therapy markedly increased serum thymulin (p < 0.01) and lactotrope CD, CS and VD in nude mice of both sexes. CONCLUSIONS: Our findings suggest a modulatory effect of thymulin on the lactotrope cell population and on serum PRL, particularly during early life. PMID- 23941811 TI - Exploring the effect of case formulation driven CBT for children with anxiety disorders: a feasibility study. AB - BACKGROUND: Little is known about the effect of case-formulation based cognitive behaviour therapy (CBT) for anxious children. AIM: The present study explores the feasibility of case-formulation driven CBT for anxious children. Parents were involved in treatment as either co-facilitators (involved only as the child's assistants, treatment being primarily directed at the child), or as co-clients (parents received therapy targeting theoretically established maintaining mechanisms; children received half of the sessions, parents the other half). METHOD: Feasibility of the case-formulation driven CBT was established by comparing the completion rate and the percentage of children free of anxiety after treatment, with manualized treatments reported in existing meta-analyses. Children aged 7-12 years and their parents participated (n = 54). Families were assessed at pre- and posttreatment and at 6-month follow-up. RESULTS: All families completed treatment and the percentage of recovery in the case formulation driven approach was comparable to results obtained in manualized treatments. CONCLUSION: The findings from this stage I study supports the notion that a case-formulation driven approach to CBT may be a feasible option when selecting treatment for anxious children; however, further studies must be conducted before firm conclusions can be drawn. PMID- 23941810 TI - Excessive hydrogen peroxide enhances the attachment of amyloid beta1-42 in the lens epithelium of UPL rats, a hereditary model for cataracts. AB - Several studies have reported that hydrogen peroxide (H2O2) is related to the toxicity of amyloid beta (Abeta), and that the accumulation of Abeta in the lenses of humans causes lens opacification. In this study, we investigate the accumulation of Abeta1-42 in the lenses of UPL rats, which then leads to lens opacification. In addition, we demonstrate the effect of disulfiram eye drops (DSF), a potent radical scavenger, on Abeta1-42 accumulation in the lenses of UPL rats. The H2O2 levels in 46- to 60-day-old UPL rat lenses are significantly higher than in normal rats, and the Abeta1-42 levels in 53- and 60-day-old UPL rats are also increased only in lens epithelium containing capsules (capsule epithelium), not in the lens cortex and nucleus. However, no increases in amyloid precursor protein (APP), beta- or gamma-secretase mRNA were observed in lenses of the corresponding ages. It has been thought that Abeta1-42 that accumulates in the lenses of UPL rats is actually produced in another tissue containing neuronal cells, such as brain or retina. Abeta1-42 levels in the brain and retina rise with aging, and the levels of APP, beta- and gamma-secretase mRNA in the retinas of 53-day-old UPL rats with opaque lenses are significantly higher than in 25-day old UPL rats with transparent lenses. In contrast to the results in retinas, the levels of APP, beta- and gamma-secretase mRNA in the brains of 25- and 53-day-old UPL rats are similar. On the other hand, in an in vitro study, Abeta1-42 attachment in the lens capsule-epithelium of UPL rats was found to increase in H2O2. In addition, in an in vivo study, the inhibition of H2O2 by DSF was found to attenuate the increase in Abeta1-42 in the lens capsule-epithelium of 60-day old UPL rats. Taken together, we hypothesize that excessive H2O2 in the lens enhances the attachment of Abeta1-42 in the lens capsule-epithelium of UPL rats, and that the instillation of DSF has the ability to attenuate the attachment of Abeta1-42 by inhibiting H2O2 production in lens. These findings provide significant information that can be used to design further studies aimed at developing anti-cataract drugs. PMID- 23941812 TI - Intracellular tracking of single-plasmid DNA particles after delivery by electroporation. AB - Electroporation is a physical method of transferring molecules into cells and tissues. It takes advantage of the transient permeabilization of the cell membrane induced by electric field pulses, which gives hydrophilic molecules access to the cytoplasm. This method offers high transfer efficiency for small molecules that freely diffuse through electrically permeabilized membranes. Larger molecules, such as plasmid DNA, face several barriers (plasma membrane, cytoplasmic crowding, and nuclear envelope), which reduce transfection efficiency and engender a complex mechanism of transfer. Our work provides insight into the way electrotransferred DNA crosses the cytoplasm to reach the nucleus. For this purpose, single-particle tracking experiments of fluorescently labeled DNA were performed. Investigations were focused on the involvement of the cytoskeleton using drugs disrupting or stabilizing actin and tubulin filaments as the two relevant cellular networks for particle transport. The analysis of 315 movies (~4,000 trajectories) reveals that DNA is actively transported through the cytoskeleton. The large number of events allows a statistical quantification of the DNA motion kinetics inside the cell. Disruption of both filament types reduces occurrence and velocities of active transport and displacements of DNA particles. Interestingly, stabilization of both networks does not enhance DNA transport. PMID- 23941814 TI - Simvastatin enhances the chemotherapeutic efficacy of S-1 against bile duct cancer: E2F-1/TS downregulation might be the mechanism. AB - Simvastatin has inhibitory effects on cancers. The present study aimed to investigate the interactive effects between simvastatin and S-1 against bile duct cancer and its mechanisms. The effects of simvastatin and 5-fluorouracil (5-FU) alone or in combination on the growth and apoptosis of the human cholangiocarcinoma cell line EGI-1 and the gallbladder carcinoma cell line Mz-ChA 1 cells were evaluated in vitro. Real-time PCR and western blot were used to determine E2F-1 and thymidylate synthase (TS) expressions in the treated cells. Tumoricidal efficacy of simvastatin and S-1 was further investigated in a subcutaneous bile duct cancer model in NOD/SCID mice. Simvastatin enhanced the cytotoxicity of 5-FU on bile duct cancer cells in vitro. IC50 of 5-FU alone was 4.34 MUmol/l for EGI-1 and 13.9 MUmol/l for MZ-ChA-1, whereas it decreased markedly to 0.90 and 2.95 MUmol/l, respectively, when combined with simvastatin. The Chou and Talalay combination index of 5-FU and simvastatin was 0.41 and 0.40 at IC50 for EGI-1 and MZ-ChA-1, respectively. Simvastatin alone or plus 5-FU significantly suppressed E2F-1 and TS expressions in EGI-1 and MZ-ChA-1. Simvastatin plus 5-FU induced greater proportion of apoptotic cells on both EGI-1 and MZ-ChA-1, with an increase in cleaved caspase-3 levels, compared with simvastatin or 5-FU alone (all P < 0.05). Simvastatin plus S-1 induced greater tumor inhibition than simvastatin or S-1 alone with E2F-1/TS downregulation in vivo (all P < 0.05). Simvastatin and S-1 exerted synergistic effects against bile duct cancer, which might be mediated by E2F-1/TS downregulation. The combination could be a reasonable regimen in the management of bile duct cancer. PMID- 23941813 TI - Integration-deficient lentiviral vectors expressing codon-optimized R338L human FIX restore normal hemostasis in Hemophilia B mice. AB - Integration-deficient lentiviral vectors (IDLVs) have been shown to transduce a wide spectrum of target cells and organs in vitro and in vivo and to maintain long-term transgene expression in nondividing cells. However, epigenetic silencing of episomal vector genomes reduces IDLV transgene expression levels and renders these safe vectors less efficient. In this article, we describe for the first time a complete correction of factor IX (FIX) deficiency in hemophilia B mice by IDLVs carrying a novel, highly potent human FIX cDNA. A 50-fold increase in human FIX cDNA potency was achieved by combining two mechanistically independent yet synergistic strategies: (i) optimization of the human FIX cDNA codon usage to increase human FIX protein production per vector genome and (ii) generation of a highly catalytic mutant human FIX protein in which the arginine residue at position 338 was substituted with leucine. The enhanced human FIX activity was not associated with liver damage or with the formation of human FIX directed inhibitory antibodies and rendered IDLV-treated FIX-knockout mice resistant to a challenging tail-clipping assay. A novel S1 nuclease-based B1 quantitative polymerase chain reaction assay showed low levels of IDLV integration in mouse liver. Overall, this study demonstrates that IDLVs carrying an improved human FIX cDNA safely and efficiently cure hemophilia B in a mouse model. PMID- 23941815 TI - Modelling the lattice dynamics in Si(x)Ge(1-x) alloys. AB - The development of simplified models for the simulation of thermodynamic and thermal transport properties in random alloys is of great importance. In this paper we show how a simple second nearest neighbour model can reliably capture the lattice dynamics of Si(x)Ge(1-x) alloys. The model parameters are extracted from DFT-calculated force constant matrices for pure Si, pure Ge and the Si0.5Ge0.5 ordered alloy. We extract the nearest neighbour contributions directly from density functional theory, whereas effective interactions are obtained for the second nearest neighbour contributions. We demonstrate how the thermal properties, including the expansion coefficient, can be reliably reproduced and that the model is transferable to random Si(x)Ge(1-x) alloys. PMID- 23941816 TI - Approximate truncation robust computed tomography--ATRACT. AB - We present an approximate truncation robust algorithm to compute tomographic images (ATRACT). This algorithm targets at reconstructing volumetric images from cone-beam projections in scenarios where these projections are highly truncated in each dimension. It thus facilitates reconstructions of small subvolumes of interest, without involving prior knowledge about the object. Our method is readily applicable to medical C-arm imaging, where it may contribute to new clinical workflows together with a considerable reduction of x-ray dose. We give a detailed derivation of ATRACT that starts from the conventional Feldkamp filtered-backprojection algorithm and that involves, as one component, a novel original formula for the inversion of the two-dimensional Radon transform. Discretization and numerical implementation are discussed and reconstruction results from both, simulated projections and first clinical data sets are presented. PMID- 23941817 TI - High-resolution MRI velocimetry compared with numerical simulations. AB - Alterations of the blood flow are associated with various cardiovascular diseases. Precise knowledge of the velocity distribution is therefore important for understanding these diseases and predicting the effect of different medical intervention schemes. The goal of this work is to estimate the precision with which the velocity field can be measured and predicted by studying two simple model geometries with NMR micro imaging and computational fluid dynamics. For these initial experiments, we use water as an ideal test medium. The phantoms consist of tubes simulating a straight blood vessel and a step between two tubes of different diameters, which can be seen as a minimal model of the situation behind a stenosis. For both models, we compare the experimental data with the numerical prediction, using the experimental boundary conditions. For the simpler model, we also compare the data to the analytical solution. As an additional validation, we determine the divergence of the velocity field and verify that it vanishes within the experimental uncertainties. We discuss the resulting precision of the simulation and the outlook for extending this approach to the analysis of specific cases of arteriovascular problems. PMID- 23941818 TI - Temperature dependence of relaxation times and temperature mapping in ultra-low field MRI. AB - Ultra-low-field MRI is an emerging technology that allows MRI and NMR measurements in microtesla-range fields. In this work, the possibilities of relaxation-based temperature measurements with ultra-low-field MRI were investigated by measuring T1 and T2 relaxation times of agarose gel at 50 MUT-52 mT and at temperatures 5-45 degrees C. Measurements with a 3T scanner were made for comparison. The Bloembergen-Purcell-Pound relaxation theory was combined with a two-state model to explain the field-strength and temperature dependence of the data. The results show that the temperature dependencies of agarose gel T1 and T2 in the microtesla range differ drastically from those at 3T; the effect of temperature on T1 is reversed at approximately 5 mT. The obtained results were used to reconstruct temperature maps from ultra-low-field scans. These time dependent temperature maps measured from an agarose gel phantom at 50 MUT reproduced the temperature gradient with good contrast. PMID- 23941819 TI - Sinonasal blue naevus: case report and clinicopathological review. AB - OBJECTIVE: To highlight the important clinical and histological features of sinonasal blue naevi. METHODS: A case of blue naevus of the nasal cavity is described (including endoscopic and histological pictures) and the existing literature is reviewed. RESULTS: There have been five reported cases (including the presented case). Clinically, sinonasal blue naevi are heavily pigmented lesions that are small and asymptomatic. Histopathologically, blue naevi exhibit heavily pigmented dendritic melanocytes that are never abnormal in form. CONCLUSION: Blue naevus should be a differential diagnosis for pigmented lesions within the sinonasal cavity, despite its rarity. It may be initially suspected by its small size and asymptomatic nature. However, histological examination is required for definitive diagnosis, looking for the key microscopic features described above. PMID- 23941820 TI - Current status of healthy human skin models: can histone deacetylase inhibitors potentially improve the present replacement models? AB - Histone deacetylase inhibitors (HDACi), a relatively new group of epigenetic agents, are being investigated as powerful chemotherapeutics because of their antiproliferative and prodifferentiation effects both in vitro and in vivo, in various tumor cell lines. Only little is known with respect to their effects on normal cells. Yet, to understand tissue pathology and evaluate potential effects of new chemical entities in tissue homeostasis, insight into the physiology of healthy tissue is necessary. Therefore, this review addresses the effects of HDACi on healthy human primary skin cell cultures and three-dimensional epidermal models. In general, HDACi exert an effect on both the epidermal morphology and differentiation process of human skin. The latter is manifested through cell cycle arrest, disorganization of the basal layer, thinning of the stratum spinosum and thickening of the stratum corneum, reorganization of the cytoskeleton and increased formation of cornified envelopes. This overview shows that, although only a limited number of reports exist, these molecules might be an interesting tool for the development and study of new human skin models. PMID- 23941821 TI - Association of gastric mucosal injury severity with platelet function and gastric pH during low-dose aspirin treatment. AB - INTRODUCTION: The antiplatelet effects of low-dose aspirin (LDA) vary between individuals. Here, we investigated the relationship between the incidence of LDA induced mucosal injury, antiplatelet effects of LDA, and intragastric pH. METHODS: We evaluated gastric injury severity and platelet function using the VerifyNow(r) System before and after administration of 100 mg aspirin for 7 days to 18 young healthy subjects (study 1). We investigated whether injury was correlated with platelet function and gastric juice pH in 45 patients with cardiovascular disease administered LDA daily (study 2). RESULTS: In study 1, platelet aggregation was attenuated by LDA to different degrees. Although 55.6% of subjects (10/18) developed gastric injury of modified Lanza score (MLS) >= 3, no significant difference in platelet function was detected between the mild (n = 8, MLS: 0-2) and severe injury groups (n = 10, MLS: 3-5). In study 2, the severity of LDA-induced injury was associated with gastric juice pH, but not with antiplatelet effects of LDA. DISCUSSION: In contrast to gastric juice pH, the antiplatelet effect had no correlation with the severity of gastric mucosal injury. Monitoring gastric acidity, rather than platelet function, may be useful for predicting the risk of gastric injury during LDA treatment. PMID- 23941822 TI - Antineutrophil cytoplasmic antibody vasculitis associated with influenza vaccination. AB - BACKGROUND: Administration of influenza vaccines has been associated with the development of autoantibodies and autoimmune rheumatic disease. PATIENTS: We discuss 2 patients who developed antineutrophil cytoplasmic antibody-associated vasculitis (AAV) in temporal association with influenza immunization. AAV was diagnosed 2 and 4 weeks after immunization in these patients. Both patients had renal involvement with one requiring dialysis. Both patients were treated with cyclophosphamide and corticosteroids, and plasmapheresis was added to the immunosuppressive regimen in one patient with dialysis-dependent renal failure. Both patients achieved disease remission. The patient with initial dialysis dependent renal failure reached end-stage renal disease. There are 6 previous cases of AAV in the literature described in temporal association with administration of influenza vaccines. CONCLUSION: A causal role of vaccines in AAV cannot be confirmed with these case reports. The temporality suggests that the influenza vaccine may be a triggering factor for induction of vasculitis in predisposed individuals. We review the literature on reported cases of AAV following influenza vaccine administration and discuss possible mechanisms for influenza vaccine-associated AAV. PMID- 23941828 TI - Inflammation and cancer stem cells. AB - Cancer stem cells are becoming recognised as being responsible for metastasis and treatment resistance. The complex cellular and molecular network that regulates cancer stem cells and the role that inflammation plays in cancer progression are slowly being elucidated. Cytokines, secreted by tumour associated immune cells, activate the necessary pathways required by cancer stem cells to facilitate cancer stem cells progressing through the epithelial-mesenchymal transition and migrating to distant sites. Once in situ, these cancer stem cells can secrete their own attractants, thus providing an environment whereby these cells can continue to propagate the tumour in a secondary niche. PMID- 23941825 TI - Virus induced inflammation and cancer development. AB - Chronic inflammation as a result of viral infection significantly increases the likelihood of cancer development. A handful of diverse viruses have confirmed roles in cancer development and progression, but the list of suspected oncogenic viruses is continually growing. Viruses induce cancer directly and indirectly, by activating inflammatory signalling pathways and cytokines, stimulating growth of infected cells and inhibiting apoptosis. Although oncogenic viruses induce inflammation by various mechanisms, it is generally mediated by the MAPK, NFkappaB and STAT3 signalling pathways. This review will explore the unique mechanisms by which different oncogenic viruses induce inflammation to promote cancer initiation and progression. PMID- 23941826 TI - A semisynthetic taxane Yg-3-46a effectively evades P-glycoprotein and beta-III tubulin mediated tumor drug resistance in vitro. AB - Tumor resistance, especially that mediated by P-glycoprotein (P-gp) and beta-III tubulin, is a major obstacle to the efficacy of most microtubule-targeting anticancer drugs in clinics. A novel semisynthetic taxane, 2-debenzoyl-2-(3 azidobenzyl)-10-propionyldocetaxel (Yg-3-46a) was shown to be highly cytotoxic to breast cancer cell lines MCF-7 and MCF/ADR which overexpressed P-gp via long term culture with doxorubicin, and cervical cancer cell lines Hela and Hela/betaIII which overexpressed betaIII-tubulin via stable transfection with TUBB3 gene. siRNA transfection experiments also confirmed that Yg-3-46a can circumvent P-gp and beta-III tubulin mediated drug resistance. In addition, its cytotoxicity was lower than that of paclitaxel in the human mammary cell line HBL-100 and the human telomerase-immortalized retinal pigment epithelium cell line (hTERT-RPE1), suggesting a better safety margin for this compound in vivo. It exhibited more potent microtubule polymerization ability than paclitaxel in vitro, and also induced G2/M phase arrest in MCF-7/ADR cells. Moreover, it was found to induce apoptosis in MCF-7/ADR cells through the caspase-dependent death-receptor pathway by enhancing levels of Fas and FasL, and activating caspase-8 and 3. Yg-3-46a was found to be a poorer substrate of P-gp compared to paclitaxel, in both binding and ATPase experiments, which is likely responsible for its ability to circumvent P-gp mediated multidrug resistance (MDR). All of these results indicate that Yg-3 46a is a novel microtubule-stabilizing agent that has the potential to evade drug resistance mediated by P-gp and beta-III tubulin overexpression. PMID- 23941827 TI - Carboxypeptidase E promotes cancer cell survival, but inhibits migration and invasion. AB - Carboxypeptidase E (CPE), a prohormone processing enzyme is highly expressed and secreted from (neuro)endocrine tumors and gliomas, and has been implicated in cancer progression by promoting tumor growth. Our study demonstrates that secreted or exogenously applied CPE promotes survival of pheochromocytoma (PC12) and hepatocellular carcinoma (MHCC97H) cells under nutrient starvation and hypoxic conditions, but had no effect on their proliferation. CPE also reduced migration and invasion of fibrosarcoma (HT1080) cells. We show that CPE treatment mediates survival of MHCC97H cells during metabolic stress by up-regulating the expression of anti-apoptotic protein BCL-2, and other pro-survival genes, via activation of the ERK1/2 pathway. PMID- 23941824 TI - Production of human parvovirus 4 VP2 virus-like particles in yeast and their evaluation as an antigen for detection of virus-specific antibodies in human serum. AB - BACKGROUND: Human parvovirus 4 (PARV4) is a recently discovered member of the Parvoviridae family, which is not closely related to any previously discovered human parvoviruses. PARV4 has been isolated from the plasma of individuals with symptoms of acute viral infection; however, until recently PARV4 had not been associated with any disease, and its prevalence in the human population is yet to be established. METHODS: The major capsid protein VP2 of PARV4 was generated in the yeast Saccharomyces cerevisiae and used for serological detection of virus specific IgG and IgM in the sera of low-risk individuals. RESULTS: One hundred and seventy serum specimens obtained from patients with acute respiratory diseases were tested for PARV4-specific IgG and IgM antibodies. Sixteen individuals (9.4%) were diagnosed as seropositive, including 6 IgM and IgG positive, 6 IgM positive/IgG negative and 4 IgG positive/IgM negative. Seven of the 16 seropositive individuals were between the ages of 3 and 11 with no evidence of parenteral exposure to PARV4 infection. CONCLUSION: Our data demonstrate that recombinant yeast-derived VP2 protein, self-assembled to virus like particles, can represent a useful tool when studying the seroprevalence of PARV4 infection. The presence of PARV4-specific antibodies in a low-risk group may indicate the possibility of alternative routes of virus transmission. PMID- 23941829 TI - NAFLD leads to liver cancer: do we have sufficient evidence? AB - Primary liver cancer has several well-recognized risk factors, such as HBV and HCV infection, alcohol abuse and aflatoxin. Recent studies show that nonalcoholic fatty liver disease (NAFLD), especially its aggressive form nonalcoholic steatohepatitis (NASH) is associated with an increased risk of liver cancer, mainly hepatocellular carcinoma (HCC). On the other hand, clinical and epidemiological data have showed that HCC has rarely been found in a "pure" fatty liver in human. Thus, the question we need to ask is do we have sufficient evidence to support a causative role of NAFLD in liver cancer? Furthermore, if NAFLD is indeed a causative factor for liver cancer, what is the mechanism? Perhaps at this stage, fatty liver and NASH can be regarded as a definite risk factor for liver cancer, but to conclude that NAFLD induces HCC requires more robust in vitro and in vivo data. PMID- 23941830 TI - Omics-based nanomedicine: the future of personalized oncology. AB - The traditional "one treatment fits all" paradigm disregards the heterogeneity between cancer patients, and within a particular tumor, thus limit the success of common treatments. Moreover, current treatment lacks specificity and therefore most of the anticancer drugs induce severe adverse effects. Personalized medicine aims to individualize therapeutic interventions, based on the growing knowledge of the human multiple '-oms' (e.g. genome, epigenome, transcriptome, proteome and metabolome), which has led to the discovery of various biomarkers that can be used to detect early stage cancers and predict tumor progression, drug response, and clinical outcome. Nanomedicine, the application of nanotechnology to healthcare, holds great promise for revolutionizing disease management such as drug delivery, molecular imaging, reduced adverse effects and the ability to contain both therapeutic and diagnostic modalities simultaneously termed theranostics. Personalizednanomedicine has the power of combining nanomedicine with clinical and molecular biomarkers ("OMICS" data) achieving improve prognosis and disease management as well as individualized drug selection and dosage profiling to ensure maximal efficacy and safety. Tumor's heterogeneity sets a countless challenge for future personalized therapy in cancer, however the use of multi-parameter 'omic's data for specific molecular biomarkers recognition together with versatile drug delivery nanocarriers, which could target concomitantly and specifically tumor cells subpopulations, might heralds a brighter future for personalized cancer management. In this review, we present the current leading technologies available for personalized oncology. We discusses the immense potential of combining the best of these two worlds, nanomedicine and high throughput OMICS technologies to pave the way towards cancer personalized medicine. PMID- 23941823 TI - Diversity of secondary metabolites from marine Bacillus species: chemistry and biological activity. AB - Marine Bacillus species produce versatile secondary metabolites including lipopeptides, polypeptides, macrolactones, fatty acids, polyketides, and isocoumarins. These structurally diverse compounds exhibit a wide range of biological activities, such as antimicrobial, anticancer, and antialgal activities. Some marine Bacillus strains can detoxify heavy metals through reduction processes and have the ability to produce carotenoids. The present article reviews the chemistry and biological activities of secondary metabolites from marine isolates. Side by side, the potential for application of these novel natural products from marine Bacillus strains as drugs, pesticides, carotenoids, and tools for the bioremediation of heavy metal toxicity are also discussed. PMID- 23941831 TI - Chronic ulcerative colitis and colorectal cancer. AB - One of the most important consequences of chronically active ulcerative colitis (UC) or Crohn's disease (CD) - the two major forms of inflammatory bowel disease (IBD) - is the development of colorectal cancer (CRC). An increased risk for the occurrence of CRC in up to 30% of affected patients after 35years of UC has been reported. Recent evidence from population based studies indicates a lower risk. Nevertheless the incidence is still significantly increased as compared to individuals without chronic colitis. Colitis-associated CRC (CAC) does not display the adenoma-carcinoma sequence which is typical for sporadic CRC and the pathophysiology appears to be different. Chronic inflammation and the increased turnover of epithelial cells contribute to the development of low- and high-grade dysplasia which may further transform into CAC. Reactive oxygen species (ROS) generated by the inflammatory infiltrate are thought to contribute to the generation of dysplastic lesions. In sporadic CRC the sequence of mutations that finally lead to malignancy involves early activation of Wnt/beta-catenin pathway (in 90% of cases) including mutations in adenomatous polyposis coli (APC) tumor suppressor gene, its regulating kinase GSK3beta and beta-catenin itself. beta catenin mutations are rarer in CAC and mutations in APC occur rather late during the disease progression, whereas there are earlier mutations in p53 and K-ras. Recent data indicate that the intestinal microbiome and its interaction with a functionally impaired mucosal barrier may also play a role in CAC development. CACs frequently show aggressive growth and early metastases. The treatment of CAC in patients with colitis always includes proctocolectomy with ileoanal anastomosis as meta- or synchronic lesions are frequent. PMID- 23941835 TI - [Strategy of prevention and treatment on neonatal necrotizing enterocolitis]. PMID- 23941832 TI - Tumoricidal effects of the JAK inhibitor Ruxolitinib (INC424) on hepatocellular carcinoma in vitro. AB - Hepatocellular carcinoma (HCC) is an aggressive tumour with limited treatment options. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signalling pathway plays a key role in promoting tumorigenesis in HCC. Recently a new JAK inhibitor Ruxolitinib (INC424) has been developed by Novartis Pharmaceuticals and it shows high affinity for JAK signalling with very low affinity for non-JAK targets. Clinical trials have demonstrated that Ruxolitinib has good therapeutic efficacy for the treatment of myelofibrosis and is currently FDA approved for the treatment of advanced stages of this disease. Our study tested the effects of Ruxolitinib on HCC tumorigenesis in vitro. Ruxolitinib effectively inhibited JAK/STAT signalling in HCC cells with a significant reduction in the expression of JAK downstream targets pSTAT1 and pSTAT3. Ruxolitinib also caused a marked reduction in the proliferation and colony formation of HCC cells. The antiproliferative effect of Ruxolitinib on HCC cells is unlikely due to off-target effects with no inhibition of key regulators of other cell proliferative pathways. To our knowledge this study is the first to report on the effect of Ruxolitinib on liver cancer cells. PMID- 23941836 TI - [Predicting outcome in necrotizing enterocolitis with the score for neonatal acute physiology: a retrospective study of 62 cases]. AB - OBJECTIVE: To explore the value of the score for neonatal acute physiology (score for neonatal acute physiology, SNAP) in predicting outcome and risk of surgery of necrotizing enterocolitis (NEC). METHOD: A total of 62 NEC patients in neonatal intensive care unit (NICU) of Zhejiang University Children's Hospital were reviewed from October 2001 to October 2011. All the patients were classified into surgery group and non-surgery group according to whether the patient had the surgical intervention. Also the patients were divided into death group and alive group according to the outcome. Data on gestational age at birth, gender, birth weight, early clinical manifestations, treatment and prognosis of all patients were collected. SNAP-II and score for neonatal acute physiology and perinatal extension II (SNAPPE-II) were calculated on the day of diagnosis. RESULT: Abdominal distension, which was seen in 91.9% of the cases, was the commonest early clinical manifestation. The next was residual and bloody stool. SNAP-II and SNAPPE-II score in surgery group (26.5,26.5) were higher than that of the non surgery group (13.0, 13.0,P = 0.002, 0.006). And the same scores in death group (29.0,32.0) were higher than those in the alive group (8.0, 8.0) (P = 0.000, 0.000). Measuring the scores as a predictor of surgery, the area under ROC curve for SNAP-II was 0.745, and was 0.714 for SNAPPE-II. The area under ROC curve for SNAP-II was 0.916, and was 0.929 for SNAPPE-II.The best positive point of SNAP-II and SNAPPE-II for predicting surgery was 22 and 28. The best positive point of SNAP-II and SNAPPE-II for predicting death was 18.5 and 22. CONCLUSION: The SNAP II and SNAPPE-II score may be used to predict the prognosis and the risk of surgery in the NEC patients. The scores are also good predictors of mortality in the early period when NEC occurs. PMID- 23941837 TI - [Imaging assessment of neonatal necrotizing enterocolitis]. AB - OBJECTIVE: To improve the understanding of recognizing and diagnosis of neonatal necrotizing enterocolitis (NEC), imaging assessment of neonates with NEC was analyzed retrospectively. METHOD: Data of 211 cases of NEC were retrospectively collected from the Department of Neonatology, Children's Hospital of Chongqing Medical University between Jan.1(st) 2006-Dec.31(st) 2011. RESULT: Analysis of abdominal X-ray of 211 cases showed that there were 40 cases (19.0%) who had no changes on each X-ray, 47 cases (22.3%) had improvement and 23 cases (10.9%) became worse. In the group of no changes, positive rate with good prognosis was 97.5% and with poor prognosis, it was 2.5%. In the group of improvement, positive rate with good prognosis was 97.9%, and the contrary was 2.1%. Positive rate with good prognosis was 56.5%, and the contrary was 43.5% in worse group. Chi-square analysis of the three groups showed chi(2) = 31.742, P < 0.01. Comparison of detection rate of pneumoperitoneum on abdominal X-ray (16.0%, 12/75) and Doppler US (1.3%, 1/75), chi(2) = 10.191, P < 0.05, portal pneumatosis on abdominal X ray(1.3%, 1/75) versus Doppler US (12.0%,9/75), chi(2) = 6.857, P < 0.05. Surgical timing mostly corresponded to pneumoperitoneum (OR = 19.543) and intestinal obstruction (OR = 19.527) of abdominal X-ray. The logistic regression equation is y = -2.915-1.588x1+2.972x4+2.973x7 + 1.711x9 (chi(2) = 101.705, P < 0.01). CONCLUSION: Abdominal X-ray is the most important method of diagnosis of NEC, the group of deterioration of abdominal X-ray has obvious bad prognosis differ from no change group and better group. Comparison with abdominal X-ray and Doppler US, the former in pneumoperitoneum positive rate was higher than the latter, at the same time, portal pneumatosis on Doppler US is more sensitive to abdominal X-ray, the value of two imaging assessments both supplement each other. Surgical timing mostly corresponds to pneumoperitoneum and intestinal obstruction. PMID- 23941834 TI - Prevalence and prognosis of schizophrenia in Jinuo people in China: a prospective 30-year follow-up study. AB - BACKGROUND: There are few studies investigating the influence of the development on mental health of minorities in China. AIMS: To follow up the prevalence, natural course and prognosis of schizophrenia in Jinuo people, the last group to be recognized as a 'national minority' in China, every 10 years since 1979. METHODS: From 1979 to 2009, 15%-19% of Jinuo residents were evaluated by random cluster sampling and followed up every 10 years using the Chinese version of the Composite International Diagnostic Interview (CIDI) as the screening tool and the International Classification of Diseases (ICD) as diagnostic criteria tool. RESULTS: There were no significant differences for the lifetime prevalence and current prevalence of schizophrenia across the three decades. Neither were there any significant differences for the prognosis of schizophrenia; however, at least half the patients had deteriorated or had residual symptoms in the follow-up. PANSS symptoms were significantly different according to different illness duration. CONCLUSIONS: During the three decades, there was no increasing trend for schizophrenia prevalence in Jinuo society; however, the prognosis of schizophrenia was not optimistic. In the natural, untreated status, schizophrenia patients with an illness duration of more than 20 years had more serious symptoms. PMID- 23941838 TI - [Meta-analysis of post-transfusion necrotizing enterocolitis in neonates]. AB - OBJECTIVE: To quantitatively assess the association between transfusions and the risk of necrotizing enterocolitis (NEC) in neonates. METHOD: Both Chinese and English literature published from Jan. 1985 to Nov. 2011 about the case-control study of the association between transfusions and neonatal NEC were retrieved by searching the electronic resource databases. A meta-analysis was then performed on the comparison and synthesis of findings from included studies. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using RevMan 5.0 software. Sensitivity analysis was conducted and possible publication bias was tested as well. RESULT: A total of 7 case-control studies (480 blood transfusion cases, 2845 control cases) were included. The meta-analysis with a random-effects model found a pooled OR of 3.35 (95% CI: 1.54-7.27). Sensitivity analysis showed that OR for post-transfusion NEC within 48 h was 4.21 (95% CI: 2.17-8.16). The OR was 4.29 (95% CI: 1.39-13.24) after factors such as gestational age and birth weight were de-confounded. The fail-safe number was 263. CONCLUSION: Blood transfusion can increase the risk of NEC in neonates. The clinical application of this conclusion should be cautious due to limited reports. High-quality randomized control trials are still needed for the further proof of the association between blood transfusion and neonatal NEC. PMID- 23941839 TI - [Advances in studies on etiology and risk factors of neonatal necrotizing enterocolitis]. PMID- 23941840 TI - [Progresses in studies on allogeneic hematopoietic stem cell transplantation in children with acquired severe aplastic anemia]. PMID- 23941842 TI - [Clinical characteristics and molecular epidemiology of the novel influenza A (H1N1) infection in children in Shanghai]. AB - OBJECTIVE: To investigate the epidemiological features, genetic drift in the epitopes of hemagglutinin (HA) of the novel influenza A (H1N1) virus and oseltamivir-resistant variants characterized by H275Y and N295S mutations in children in Shanghai since the outbreak. METHOD: Between June 2009 and May 2012, a prospective surveillance study was carried out in Shanghainese children who attended the outpatient clinic of Children's Hospital of Fudan University for influenza-like illness. One-step real-time fluorescence quantitative RT-PCR was performed to detect seasonal influenza A and influenza B virus and the novel influenza A (H1N1) virus in the respiratory samples. Genetic drift from the vaccine strain in HA epitopes of the novel influenza H1N1 virus and the molecular markers associated with oseltamivir resistance in neuraminidase (NA) were analyzed. RESULT: Out of 3475 enrolled cases, the novel influenza A (H1N1) virus was confirmed virologically in 222 (6.4%) otherwise healthy children with 133 (59.9%) being boys and 89 (40.1%) girls. The median ages of children with the novel influenza A (H1N1) virus infection during the first wave from August 2009 to February 2010 and the second wave from December 2010 to February 2011 were 53.5 months and 32.0 months, respectively (Z = -4.601, P = 0.000); 119 (46.9%) had the close contact with persons suffering from fever or respiratory infection, of whom, 68 (57.1%) contacts were family members and 47 (39.5%) contacts were classmates. During the outbreak in 2009-2010 season, 66 (40.9%) were exposed to primary index cases, school students were the major exposure subjects, accounting for 50.0%. The nucleotide sequences of HA1 gene were highly homologous between the vaccine strain A/California/07/2009 and Shanghai circulating novel influenza A (H1N1) strains and only S83P mutation in epitope E of HA was detected inclusively in the circulating strains. The H275Y and N295S amino acid mutations associated with oseltamivir resistance were not found in the circulating novel influenza (H1N1) strains. CONCLUSION: Two major waves of the novel influenza A (H1N1) outbreaks occurred in Shanghainese children during 2009-2011. Institutional children were the major affected individuals during the 2009 pandemic wave. Households and schools were the main sites of transmission among children during influenza pandemic. Influenza vaccination should be enhanced in children and their close family contacts. The novel influenza A (H1N1) virus in Shanghai has not undergone significant genetic changes. Oseltamivir is effective for the treatment of the novel influenza A (H1N1) virus. PMID- 23941833 TI - Molecular imaging in pancreatic cancer--a roadmap for therapeutic decisions. AB - Pancreatic ductaladeno carcinoma (PDAC) is a deadly cancer characterized by multiple molecular alterations, the presence of an intense stroma, poor perfusion, and resistance to therapy. In addition to standard imaging techniques, experimental imaging strategies, such as those utilizing molecular probes, nanoparticle-based agents, and tagged antibodies are actively being explored experimentally. It is hoped that advances in these technologies will allow for detecting PDAC at an early stage, and could serve to validate experimental therapies, rapidly identify non-responders, and assist in the design of novel therapeutic strategies tailored to the patient's molecular profile. PMID- 23941847 TI - [Recommendations for diagnosis and treatment of primary immune thrombocytopenia in children]. PMID- 23941841 TI - [The status of protein intake and energy supply in the early life of very/extremely low birth weight infants]. AB - OBJECTIVE: To study the relationship of protein intake and energy supply with the physical growth in very/extremely low birth weight infant at their early life. METHOD: Retrospective survey was performed in Neonatal Intensive Care Unit (NICU) in Peking University First Hospital. Inclusion criteria were preterm infant, birth weight < 1500 g, hospitalization for longer than 2 weeks, discharge with body weight greater than 1800 g. The infants were divided into two groups according to gestational age (GA). GA < 32 weeks and >= 32 weeks. Physical growth and its relation with the protein intake and energy supply were analyzed. The predictive value of serum blood urea nitrogen (BUN) on protein intake was studied. RESULT: Ninety-three very/extremely low birth weight infants were involved, 69 in GA < 32 weeks group and 24 in GA >= 32 weeks group.Compared with GA >= 32 group, GA < 32 weeks preterm infants had more weight loss, (9.2 +/- 4.4)% vs. (5.0 +/- 3.1)%, P = 0.000; slower birth weight recovery (10.6 +/- 3.8) d vs. (7.1 +/- 2.6) d, P = 0.000; poorer weight gain at 1, 4, 5 weeks of life, ( 4.5 +/- 9.3) g/ (kg.d) vs. (3.4 +/- 6.9) g/ (kg.d), P = 0.000 , (13.5 +/- 7.3) g/ (kg.d) vs. (19.2 +/- 4.9) g/ (kg.d), P = 0.001, (14.6 +/- 5.6) g/ (kg.d) vs. (18.2 +/- 4.5) g/ (kg.d), P = 0.031; less energy supply at 1 to 5 weeks (P value was 0.000,0.000,0.025,0.001,0.008 respectively) and less protein intake at 1, 4, 5 weeks of life (P value was 0.009,0.006,0.032). Extrauterine growth retardation (EUGR) was still predominant in our subjects, 47.8% in GA < 32 weeks group, and 95.8% in GA >= 32 weeks group, P = 0.000. The incidence increased greater in GA < 32 weeks infants, 43.5% vs. 20.8%, P = 0.000.The duration of weight loss and mechanical ventilation correlated negatively with weight gain rate, respectively beta = -0.591, P = 0.000 and beta = -0.281, P = 0.005; the average energy supply and time taken to reach full enteral feeding were factors improving weight gain, respectively beta = 0.202, P = 0.021 and beta = 0.354, P = 0.000. After birth, serum BUN declined gradually. Positive relation showed between average protein intake at 3(rd) week and BUN level at the end of 3 weeks, r = 0.420, P = 0.000. Serum BUN 1.44, 1.49 mmol/L at the end of 3(rd) and 4(th) week were cut-off predictors for protein intake less than 3 g/(kg.d) at related period, sensitivity and specificity were 65.3%, 83.3% and 60%, 80% respectively. CONCLUSION: No enough protein intake and energy supply, poor weight gain are critical problems in the management of very/extremely low birth weight infants. Prevention from NEC, appropriate parenteral/enteral nutrition transforming will benefit their physical growth. Low serum BUN after 3 weeks of life is a valuable predictor of low protein intake. PMID- 23941848 TI - [Recommendation for the diagnosis of inherited metabolic etiologies in pediatric cardiomyopathy]. PMID- 23941843 TI - [Influence of ketogenic diet on the clinical effects and electroencephalogram features in 31 children with pharmacoresistant epileptic encephalopathy]. AB - OBJECTIVE: To investigate the effect of ketogenic diet (KD) on the clinical and electroencephalogram features in children with pharmacoresistant epileptic encephalopathy. METHOD: Thirty-one children (19 boys, 12 girls) aged 7 months to 7 years (mean 2 years 5 month) with epilepsy refractory to conventional antiepileptic drugs (AEDs) were included in this study. In addition to their original AED treatment, the children were assigned to different ketogenic diets based on their age. The prospective electro-clinical assessment was performed prior to the KD and then one week, one month and again 3 months after the initiation of therapy, respectively. RESULT: The reduction of seizure frequency in 52%, 68% and 71% of all patients exceeded 50% one week, one month and three months after KD treatment respectively. KD is particularly effective in myoclonic astatic epilepsy (MAE; Doose Syndrome) and West syndrome with 100% and 81.25% of the patients having a greater than 50% seizure reduction, respectively. After 3 months of KD treatment, more than 2/3 patients experienced a reduction in interictal epileptiform discharges (IEDs) and improvement in EEG background. CONCLUSION: The clinical and electroencephalographic improvement confirms that KD is beneficial in children with refractory epilepsy. PMID- 23941845 TI - [Evaluation of coronary artery diameter in normal children by echocardiography and its clinical significance]. AB - OBJECTIVE: To obtain normal range of coronary artery diameter with body surface area (BSA) dynamic changes in normal children at different age. METHOD: The left main coronary artery (LCA), left anterior descending artery (LAD), left circumflex artery (LCX) and the right coronary artery (RCA) diameter were measured in 400 normal subjects from Chinese population aged 0 d to 18 years [(6.43 +/- 4.45) years], using HP Sonos 5500 color Doppler ultrasonic system, according to the standard method of measuring the coronary artery diameter. RESULT: (1) The diameters of LCA, LAD, LCX and RCA in different age groups (0 d 12 months, -3 years, -6 years, -9 years, -12 years, -18 years) had significant differences (F = 61.688, 51.343, 46.375, 50.192, P < 0.01,all groups mean differences had significant differences, there was significant difference between every two groups, P < 0.05), there were no significant differences between male and female subjects (P > 0.05). (2) The correlation analyses showed that the diameter of LCA, LAD, LCX and RCA had significant linear correlations with age, height, weight and BSA (r ranged from 0.71 to 0.85, P < 0.01 ). (3) The regression analyses were respectively performed on the diameters of LCA, LAD, LCX and RCA with BSA to establish seven regression models. The coefficients were compared for each model, the best model was chosen to create a Z score calculator, tracing out the Z value curve, through clinical practice,we chose Z score within +/- 2 as the coronary artery diameter's normal range for Chinese children. CONCLUSION: Coronary artery diameter's Z score curve is effective and reliable, it provide objective basis for clinicians and sonographers to accurately and quickly diagnose the anomalies in diameter of coronary artery. PMID- 23941844 TI - [Analysis of clinical application of endoscopic retrograde cholangiopancreatography for the pancreatic diseases in children]. AB - OBJECTIVE: To study the feasibility and risk of endoscopic retrograde cholangiopancreatography (ERCP) for children in clinic, and to evaluate the effects of ERCP in diagnosis and treatment of the pancreatic diseases in children. METHOD: Totally 98 patients under 14 years of age who underwent ERCP from 1994 to 2011 were enrolled in the study. The data of diagnosis, anesthesia type, treatments, and postoperative complications were collected. RESULT: The 98 patients were 4 to 14 years old, of whom 32 cases suffered from acute pancreatitis (30 cases with biliary disease and 2 with hyperlipidemia); 42 cases had chronic pancreatitis, of whom 36 had calculus of pancreatic duct, pancreatic pseudocyst was seen in 6 cases. Pancreas divisum was found in 20 cases, choledochopancreatic junction anomaly in 6 cases,and annular pancreas in 1 case. The operations of dissection of pancreatic duct and biliary duct, calculus removal, insertion of endoprosthesis and draining tube in pancreatic duct or biliary duct were performed. No patients died from ERCP complications. In observation of postoperative complications, acute pancreatitis after ERCP occurred in 1 case, with the incidence rate of 1%, 1 case had bleeding (1%), and 5 cases had hyperamylasemia (5%). All the complications were cured within 1 week. The average hospital stay was 5.51 d. CONCLUSION: ERCP is useful and safe in children under suitable condition of doctors and equipments, and no high rates of complications were observed. PMID- 23941846 TI - [Infantile polycystic kidney disease: a case report and literature review]. AB - OBJECTIVE: To summarize the clinical characteristics, diagnosis, treatments and outcomes of perinatal autosomal recessive polycystic kidney disease. METHODS: The clinical data of one case with infantile polycystic kidney disease diagnosed in perinatal stage and the reports of 11 cases seen in the past 15 years searched in Pubmed, OVID and Elsevier and CNKI, Wanfang database by using the polycystic kidney disease, infant, perinatal, autosomal recessive and case report as keyword were reviewed and analyzed. RESULTS: The infant was characterized by huge kidneys, severe respiratory and renal compromise. The kidneys were symmetrically enlarged and highly echogenic by ultrasonographic examination and showed high signal intensity on T2-weighted images by MRI. Histologic analysis showed pulmonary hypoplasia, numerous dilated and elongated tubular structures in the kidney and dilated intrahepatic biliary ducts. Among the 12 cases, 8 cases' presumptive diagnosis was made by prenatal ultrasound revealed enlarged kidneys and oligohydramnios. All cases suffered respiratory distress after birth, and 5 cases complicated pneumothorax. 6 cases died in neonatal stage because of respiratory failure.1 case died 2 m after birth because of renal failure. Five cases are alive and underwent dialysis, nephrectomy or renal transplant. CONCLUSION: Newborn infants with perinatal autosomal recessive polycystic kidney disease often have poor outcome and died from respiratory and renal failure. Aggressive respiratory support and renal replacement therapy (including nephrectomy, dialysis and transplantation) may give these infants a favorable outcome. PMID- 23941854 TI - [The minutes of the 12th national conference on pediatric critical care of Chinese Medical Association]. PMID- 23941851 TI - [Experts' comment]. PMID- 23941852 TI - [Neonatal clown-like discoloration in a case]. PMID- 23941850 TI - [Fully automated peripheral vein synchronous exchange transfusion treatment of neonatal clozapine poisoning: report of one case]. PMID- 23941855 TI - [Summary of the 17th national conference on pediatric cardiovascular diseases]. PMID- 23941849 TI - [Intensive reading of Recommendations for Diagnosis and Treatment of Primary Immune Thrombocytopenia in Children]. PMID- 23941856 TI - Global maternal and child health goals will not be achieved without addressing HIV-related stigma. PMID- 23941853 TI - [Septo-optic dysplasia complex in a case]. PMID- 23941857 TI - Triple antithrombotic therapy is the independent predictor for the occurrence of major bleeding complications: analysis of percent time in therapeutic range. AB - BACKGROUND: Triple antithrombotic therapy increases the risk of bleeding events in patients undergoing percutaneous coronary intervention. However, it remains unclear whether good control of percent time in therapeutic range is associated with reduced occurrence of bleeding complications in patients undergoing triple antithrombotic therapy. METHODS AND RESULTS: This study included 2648 patients (70 +/- 11 years; 2037 men) who underwent percutaneous coronary intervention with stent in the Ibaraki Cardiovascular Assessment Study registry and received dual antiplatelet therapy with or without warfarin. Clinical end points were defined as the occurrence of major bleeding complications (MBC), major adverse cardiac and cerebrovascular event, and all-cause death. Among these 2648 patients, 182 (7%) patients received warfarin. After a median follow-up period of 25 months (interquartile range, 15-35 months), MBC had occurred in 48 (2%) patients, major adverse cardiac and cerebrovascular event in 484 (18%) patients, and all-cause death in 206 (8%) patients. Multivariable Cox regression analysis revealed that triple antithrombotic therapy was the independent predictor for the occurrence of MBC (hazard ratio, 7.25; 95% confidence interval, 3.05-17.21; P<0.001). The time in therapeutic range value did not differ between the patients with and without MBC occurrence (83% [interquartile range, 50%-90%] versus 75% [interquartile range, 58%-87%]; P=0.7). However, the mean international normalized ratio of prothrombin time at the time of MBC occurrence was 3.3 +/- 2.1. Triple antithrombotic therapy did not have a predictive value for the occurrence of all cause death (P=0.1) and stroke (P=0.2). CONCLUSIONS: Triple antithrombotic therapy predisposes patients to an increased risk of MBC regardless of the time in therapeutic range. PMID- 23941859 TI - Outcomes after primary transcatheter therapy in infants and young children with severe bilateral peripheral pulmonary artery stenosis. AB - BACKGROUND: Angioplasty and stent implantation have become accepted therapies for isolated peripheral pulmonary stenosis, and have been shown to increase vessel diameter and reduce right ventricular (RV) pressure acutely in patients with pulmonary artery (PA) stenosis. The purpose of this study was to assess long-term outcomes after primary transcatheter therapy for peripheral pulmonary stenosis. METHODS AND RESULTS: We studied 69 patients who underwent primary transcatheter intervention for severe isolated peripheral pulmonary stenosis at <= 5 years of age. Genetic/syndromic diagnoses included Williams syndrome (n=23), non-Williams familial arteriopathy (n=12), and Alagille syndrome (n=3). At the initial PA intervention, median RV:aortic pressure ratio decreased from 1.00 to 0.88 (median decrease, 0.18; P<0.001). Patients with a higher preintervention RV:aortic pressure ratio had a greater reduction (P<0.001). During follow-up (median, 8.5 years), 10 patients died, 5 from complications of PA catheterization (all before 1998). Thirteen patients underwent surgical PA intervention, most within 1 year and along with repair of supravalvar aortic stenosis. Freedom from any PA reintervention was 38 +/- 6% at 1 year and 22 +/- 6% at 5 years. The median RV:aortic pressure ratio decreased from 1.0 at baseline to 0.53 at the most recent catheterization (P<0.001), and 82% of patients with available clinical follow-up were asymptomatic. CONCLUSIONS: Transcatheter therapy for infants with severe peripheral pulmonary stenosis has become safer, regardless of genetic condition. Coupled with reintervention and surgical relief in selected cases, RV:aortic pressure ratios decrease substantially and most patients are asymptomatic at late follow-up. PMID- 23941858 TI - Aortic regurgitation and left ventricular remodeling after transcatheter aortic valve implantation: a serial cardiac magnetic resonance imaging study. AB - BACKGROUND: Aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) has been associated with poor outcomes, but little is known about how it evolves over time. We evaluated left ventricular (LV) function, remodeling, and the occurrence and evolution of AR after TAVI by using cardiac MRI. METHODS AND RESULTS: Forty-three patients treated with transfemoral TAVI underwent cardiac MRI 1 week and 6 months after TAVI. LV volumes and function were assessed by using standard cine MRI sequences. Phase-contrast imaging was performed to quantify the degree of AR. The mean age of the evaluated patients was 80 years, and 65% of patients were women. At baseline MRI, the median LV ejection fraction was 58.1%, which improved significantly at follow-up to 63.4% (P<0.0001). A significant reduction of LV end-diastolic volume (149.7 +/- 41.4 140.1 +/- 43.9 mL; P=0.014) and of LV mass (156.3 +/- 32.8-142.7 +/- 39.3 g; P<0.001) was observed. Over time, aortic regurgitant fraction increased slightly but significantly from 5.2% to 7.8% (P=0.04). Subgroup analysis revealed that significant changes of LV ejection fraction, volumes, and mass only occurred in patients with no or mild AR at baseline MRI, whereas those parameters remained unchanged in patients with AR more than or equal to grade II. CONCLUSIONS: By using cardiac MRI in patients with TAVI, a significant improvement of LV function, volume, and mass can be documented. Mild-to-moderate AR is commonly seen, and AR shows a small increase over time. More-than-mild AR seems to prevent LV functional and structural recovery after TAVI. PMID- 23941861 TI - Timing of mortality after severe bleeding and recurrent myocardial infarction in patients with ST-segment-elevation myocardial infarction. AB - BACKGROUND: The prognosis of initial survivors of ST-segment-elevation myocardial infarction (STEMI) is affected by both recurrent myocardial infarction (MI) and severe bleeding. The aim of the current study was to investigate how mortality is affected in time after bleeding and recurrent MI. METHODS AND RESULTS: From January 1, 2003, to July 31, 2008, a total of 2002 patients were treated with primary percutaneous coronary intervention for ST-segment-elevation MI and followed up for the occurrence of recurrent MI and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) severe bleeding. Primary outcome was all-cause mortality within 4 years of follow up. In a time-dependent, covariate-adjusted Cox regression model, both bleeding and recurrent MI were associated with an increase in mortality shortly after the adverse event: hazard ratio, 14.37 (95% confidence interval [CI], 7.69-26.84) for the first day after recurrent MI and 5.42 (95% CI, 2.88-10.22) for the first day after bleeding. Thereafter the risk of subsequent mortality gradually decreased but remained elevated long after a recurrent MI (hazard ratio, 4.95 [95% CI, 3.27 7.48] between 1 day and 1 year after recurrent MI and hazard ratio, 2.56 [95% CI, 1.56-4.21] beyond 1 year after recurrent MI), but decreased to nonsignificant level beyond 1 month after the bleeding (hazard ratio, 0.56 [95% CI, 0.27-1.14]). CONCLUSIONS: The occurrence of both recurrent MI and bleeding in the first year after ST-segment-elevation MI is associated with subsequent mortality. The risk implication of recurrent MI, however, was greater and more sustained over time than that of severe bleeding. PMID- 23941863 TI - Rho kinase inhibitor fasudil regulates microglia polarization and function. AB - Macrophages/microglia exhibit phenotypic and functional heterogeneity under physiological and pathological conditions. Owing to this heterogeneity, the polarization of macrophages/microglia is capable of effecting both detrimental and beneficial outcomes in various disease processes. In this study, murine microglial cell line BV-2 and primary microglia were used as cell models to elucidate the polarization of microglia. Using flow cytometry, Western blot, chemical/enzymatic determination, and immunohistochemistry, treatment with LPS primed microglia into the M1 phenotype in both BV-2 cells and primary microglia, while fasudil skewed LPS-stimulated M1 toward M2 microglia, which showed lower NF kappaB activity and inflammatory cytokines IL-1beta, IL-6, and TNF-alpha, and increased anti-inflammatory cytokine IL-10. To examine whether the regulatory role of LPS and fasudil on microglia can occur in vivo, mice were administered LPS (25 MUg/10 MUl) via nasal instillation every other day for 1 month. The results demonstrated that LPS also triggered iNOS(+)/CD11b(+) M1 microglia in the brain, while fasudil increased Arg-1(+)/CD11b(+) M2 microglia, although the difference did not reach statistical significance. Fasudil-conditioned microglia medium promoted a neuroprotective effect against PC12 neurons, suggesting that fasudil-induced M2 microglia contribute to the survival of neurons. These results indicate a new treatment option whereby fasudil inhibits the inflammatory response by controlling a helpful polarization in microglia/macrophages. PMID- 23941860 TI - Adoption of transradial percutaneous coronary intervention and outcomes according to center radial volume in the Veterans Affairs Healthcare system: insights from the Veterans Affairs clinical assessment, reporting, and tracking (CART) program. AB - BACKGROUND: Studies examining the association between radial approach and post percutaneous coronary intervention (PCI) bleeding and mortality have reached conflicting conclusions. There are no current data about the use and outcomes of transradial PCI (r-PCI) in the Veterans Affairs system. METHODS AND RESULTS: Consecutive veterans (n=24143 patients) undergoing PCI in the Veterans Affairs between 2007 and 2010 were examined. On the basis of propensity to undergo r-PCI, 3 cohorts matched with veterans undergoing transfemoral access were constructed among sites performing >= 1 r-PCI, >= 50 r-PCI (high volume), and <50 r-PCI (low volume). Cox proportional hazard models were used to determine the association between PCI access site, blood transfusion, and mortality. The prevalence of r PCI increased over time (2007=2.1%; 2010=8.8%). Overall, there was no difference in procedure success between matched groups (r-PCI 97.3% versus transfemoral PCI 96.6%; P=0.182), or in the risk of postprocedure transfusion or mortality. Among matched patients treated at high r-PCI volume sites, radial access was associated with a decreased risk of post-PCI blood transfusion (hazard ratio, 0.4; 95% confidence interval, 0.3-0.7; P<0.001), and no significant difference in the risk of mortality (hazard ratio, 0.7; 95% confidence interval, 0.4-1.3; P=0.279). CONCLUSIONS: Within the Veterans Affairs, the use of r-PCI increased over time. r PCI may be associated with a significant decreased risk of post-PCI blood transfusion among higher volume r-PCI sites. These data demonstrate that potential benefits of r-PCI in terms of reduced post-PCI blood transfusions may be more pronounced at sites that routinely use radial access. PMID- 23941862 TI - Designing and developing a literature-derived, population-based dietary inflammatory index. AB - OBJECTIVE: To design and develop a literature-derived, population-based dietary inflammatory index (DII) to compare diverse populations on the inflammatory potential of their diets. DESIGN: Peer-reviewed primary research articles published through December 2010 on the effect of diet on inflammation were screened for possible inclusion in the DII scoring algorithm. Qualifying articles were scored according to whether each dietary parameter increased (+1), decreased (-1) or had no (0) effect on six inflammatory biomarkers: IL-1beta, IL-4, IL-6, IL-10, TNF-alpha and C-reactive protein. SETTING: The Dietary Inflammatory Index Development Study was conducted in the Cancer Prevention and Control Program of the University of South Carolina in Columbia, SC, USA from 2011 to 2012. RESULTS: A total of ~6500 articles published through December 2010 on the effect of dietary parameters on the six inflammatory markers were screened for inclusion in the DII scoring algorithm. Eleven food consumption data sets from countries around the world were identified that allowed individuals' intakes to be expressed relative to the range of intakes of the forty-five food parameters observed across these diverse populations. Qualifying articles (n 1943) were read and scored based on the forty-five pro- and anti-inflammatory food parameters identified in the search. When fit to this composite global database, the DII score of the maximally pro-inflammatory diet was +7.98, the maximally anti inflammatory DII score was -8.87 and the median was +0.23. CONCLUSIONS: The DII reflects both a robust literature base and standardization of individual intakes to global referent values. The success of this first-of-a-kind attempt at relating intakes of inflammation-modulating foods relative to global norms sets the stage for use of the DII in a wide variety of epidemiological and clinical studies. PMID- 23941864 TI - Lipid rescue reverses the bupivacaine-induced block of the fast Na+ current (INa) in cardiomyocytes of the rat left ventricle. AB - BACKGROUND: Cardiovascular resuscitation upon intoxication with lipophilic ion channel-blocking agents has proven most difficult. Recently, favorable results have been reported when lipid rescue therapy is performed, i.e., the infusion of a triglyceride-rich lipid emulsion during resuscitation. However, the mechanism of action is poorly understood. METHODS: The authors investigate the effects of a clinically used lipid emulsion (Lipovenos(r) MCT 20%; Fresenius Kabi AG, Bad Homburg, Germany) on the block of the fast Na current (INa) induced by the lipophilic local anesthetic bupivacaine in adult rat left ventricular myocytes by using the whole cell patch clamp technique. RESULTS: Bupivacaine at 10 um decreased INa by 54% (-19.3 +/- 1.9 pApF vs. -42.3 +/- 4.3 pApF; n = 17; P < 0.001; VPip = -40 mV, 1 Hz). Addition of 10% lipid emulsion in the presence of bupivacaine produced a 37% increase in INa (-26.4 +/- 2.8 pApF; n = 17; P < 0.001 vs. bupivacaine alone). To test whether these results could be explained by a reduction in the free bupivacaine concentration by the lipid (lipid-sink effect), the authors removed the lipid phase from the bupivacaine-lipid mixture by ultracentrifugation. Also, the resulting water phase led to an increase in INa (+19%; n = 17; P < 0.001 vs. bupivacaine), demonstrating that part of the bupivacaine had been removed during ultracentrifugation. The substantially less lipophilic mepivacaine (40 um) reduced INa by 27% (n = 24; P < 0.001). The mepivacaine-lipid mixture caused a significant increase in INa (+17%; n = 24; P < 0.001). For mepivacaine, only a small lipid-sink effect could be demonstrated (+8%; n = 23; P < 0.01), reflecting its poor lipid solubility. CONCLUSION: The authors demonstrate lipid rescue on the single-cell level and provide evidence for a lipid-sink mechanism. PMID- 23941870 TI - Interlayer magnetoresistance in multilayer Dirac electron systems: motion and merging of Dirac cones. AB - We theoretically study the effect of the motion and the merging of Dirac cones on the interlayer magnetoresistance in multilayer graphene-like systems. This merging, which can be induced by a uniaxial strain, gives rise in a monolayer Dirac electron system to a topological transition from a semi-metallic phase to an insulating phase whereby Dirac points disappear. Based on a universal Hamiltonian, proposed to describe the motion and the merging of Dirac points in two-dimensional Dirac electron crystals, we calculate the interlayer conductivity of a stack of deformed graphene-like layers using the Kubo formula in the quantum limit where only the contribution of the n = 0 Landau level is relevant. A crossover from a negative to a positive interlayer magnetoresistance is found to take place as the merging is approached. This sign change of the magnetoresistance can also result from a coupling between the Dirac valleys, which is enhanced as the magnetic field amplitude increases. Our results describe the behavior of the magnetotransport in the organic conductor alpha-(BEDT)2I3 and in a stack of deformed graphene-like systems. The latter can be simulated by optical lattices or microwave experiments in which the merging of Dirac cones can be observed. PMID- 23941867 TI - Genetic modification of dividing cells using episomally maintained S/MAR DNA vectors. AB - The development of episomally maintained DNA vectors to genetically modify dividing cells efficiently and stably, without the risk of integration-mediated genotoxicity, should prove to be a valuable tool in genetic research. In this study, we demonstrate the utility of Scaffold/Matrix Attachment Region (S/MAR) DNA vectors to model the restoration of a functional wild-type copy of the gene folliculin (FLCN) implicated in the renal cancer Birt-Hogg-Dube (BHD). Inactivation of FLCN has been shown to be involved in the development of sporadic renal neoplasia in BHD. S/MAR-modified BHD tumor cells (named UOK257-FS) show restored stable FLCN expression and have normalized downstream TGFbeta signals. We demonstrate that UOK257-FS cells show a reduced growth rate in vitro and suppression of xenograft tumor development in vivo, compared with the original FLCN-null UOK257 cell line. In addition, we demonstrate that mTOR signaling in serum-starved FLCN-restored cells is differentially regulated compared with the FLCN-deficient cell. The novel UOK257-FS cell line will be useful for studying the signaling pathways affected in BHD pathogenesis. Significantly, this study demonstrates the suitability of S/MAR vectors to successfully model the functional expression of a therapeutic gene in a cancer cell line and will aid the identification of novel cancer markers for diagnosis and therapy.Molecular Therapy-Nucleic Acids (2013) 2, e115; doi:10.1038/mtna.2013.40; published online 13 August 2013. PMID- 23941866 TI - A practical approach to immunotherapy of hepatocellular carcinoma using T cells redirected against hepatitis B virus. AB - Hepatocellular carcinoma (HCC) cells often have hepatitis B virus (HBV)-DNA integration and can be targeted by HBV-specific T cells. The use of viral vectors to introduce exogenous HBV-specific T-cell receptors (TCR) on T cells to redirect their specificity is complex and expensive to implement in clinical trials. Moreover, it raises safety concerns related to insertional mutagenesis and potential toxicity of long-lived HBV-specific T cells in patients with persistent infection. To develop a more practical and safer approach to cell therapy of HCC, we used electroporation of mRNA encoding anti-HBV TCR. Approximately 80% of CD8(+) T cells expressed functional HBV TCR 24 hours postelectroporation, an expression efficiency much higher than that obtained by retroviral transduction (~18%). Antigen-specific cytokine production of electroporated T cells was efficient within 72-hour period, after which the redirected T cells lost their HBV-specific function. Despite this transient functionality, the TCR electroporated T cells efficiently prevented tumor seeding and suppressed the growth of established tumors in a xenograft model of HCC. Finally, we established a method for large-scale TCR mRNA electroporation that yielded large numbers of highly functional clinical-grade anti-HBV T cells. This method represents a practical approach to cell therapy of HCC and its inherently self-limiting toxicity suggests potential for application in other HBV-related pathologies.Molecular Therapy-Nucleic Acids (2013) 2, e114; doi:10.1038/mtna.2013.43; published online 13 August 2013. PMID- 23941865 TI - Acute uterine irritation provokes colonic motility via transient receptor potential A(1)-dependent spinal NR2B phosphorylation in rats. AB - BACKGROUND: Patients with inflammatory gynecological/obstetrical problems often complain of irritable bowel syndrome. The authors examined whether acute uterus irritation reflexively provokes colonic motility in rat preparations. METHODS: A modified colon manometry and striated abdominal muscle electromyogram activity in response to mustard oil (MO) instillation into the uterine horn were continuously recorded in anesthetized rats. The lumbosacral (L6-S1) dorsal horn was dissected to assess the level and the cellular location of phosphorylated NR2B subunit using Western blotting and immunofluorescence analysis, respectively. Finally, the uterine transient receptor potential A1 or spinal NR2B subunit was pharmacologically blocked to elucidate its roles. RESULTS: MO (0.1%, 0.2 ml) injected into the lower uterine horn dramatically provoked colonic hypermotility characterized by rhythmic colonic contractions (about 3-4 contractions per 10 min, n = 7) accompanied by synchronized electromyogram firing in the abdominal muscle (about 4-5 folds of control, n = 7). In addition to provoking colonic hypermotility, MO administration also up-regulated phosphorylated (about 2-3 folds of control, n = 7), but not total, NR2B expression in the dorsal horn neurons. Both intrathecal Ro 25-6981 (a selective NR2B subunit antagonist; 10 MUM, 10 MUl) and intrauterine HC-030031 (a selective transient receptor potential A1 receptor antagonist; 30 mg/kg, 0.2 ml) injected before the MO instillation attenuated the MO-induced colonic hypermotility and spinal NR2B phosphorylation. CONCLUSION: The comorbidity of gynecological/obstetrical and gastrointestinal problems is not coincidental but rather causal in nature, and clinicians should investigate for gynecological/urological diseases in the setting of bowel problems with no known pathological etiology. PMID- 23941871 TI - A form of mitofusin 2 (Mfn2) lacking the transmembrane domains and the COOH terminal end stimulates metabolism in muscle and liver cells. AB - Mitofusin 2 (Mfn2), a protein that participates in mitochondrial fusion, is required to maintain normal mitochondrial metabolism in skeletal muscle and liver. Given that muscle Mfn2 is repressed in obese or type 2 diabetic subjects, this protein may have a potential pathophysiological role in these conditions. To evaluate whether the metabolic effects of Mfn2 can be dissociated from its function in mitochondrial dynamics, we studied a form of human Mfn2, lacking the two transmembrane domains and the COOH-terminal coiled coil (DeltaMfn2). This form localized in mitochondria but did not alter mitochondrial morphology in cells or in skeletal muscle fibers. The expression of DeltaMfn2 in mouse skeletal muscle stimulated glucose oxidation and enhanced respiratory control ratio, which occurred in the absence of changes in mitochondrial mass. DeltaMfn2 did not stimulate mitochondrial respiration in Mfn2-deficient muscle cells. The expression of DeltaMfn2 in mouse liver or in hepatoma cells stimulated gluconeogenesis. In addition, DeltaMfn2 activated basal and maximal respiration both in muscle and liver cells. In all, we show that a form of Mfn2 lacking mitochondrial fusion activity stimulates mitochondrial function and enhances glucose metabolism in muscle and liver tissues. This study suggests that Mfn2 regulates metabolism independently of changes in mitochondrial morphology. PMID- 23941869 TI - Delineating anatomical boundaries using the boundary fragment model. AB - In this paper we present a method to automatically isolate relevant anatomical boundary positions in an image using only the structure of edges. The purpose of this method is to facilitate model-based segmentation algorithms which rely on accurate initialisation and assume that the correct anatomical boundary positions are close to the current model surface. The method is built around a weak parts based shape model - the Boundary Fragment Model (BFM) - which represents an object by sections of its boundary. Following previous literature, we use the BFM in a boosted classifier framework to first automatically detect the object of interest. Extending previous work, we use the BFM to drive a classifier which isolates boundary candidates from spurious and irrelevant edge responses. The application of our algorithm leads to a labelled edge map which encodes the positions of (multiple) object boundaries. By way of illustrating what is a general solution, the task of identifying the endocardium and epicardium in three dimensional ultrasound images is completely examined, including a detailed analysis of the parameters which impact on the model construction, the structure of the learned edge response classifier, and implementation concerns. For completeness, we also demonstrate how the output boundary positions can be used in a full model-based segmentation framework. PMID- 23941875 TI - Role of stearoyl-CoA desaturase-1 in skeletal muscle function and metabolism. AB - Stearoyl-CoA desaturase-1 (SCD1) converts saturated fatty acids (SFA) into monounsaturated fatty acids and is necessary for proper liver, adipose tissue, and skeletal muscle lipid metabolism. While there is a wealth of information regarding SCD1 expression in the liver, research on its effect in skeletal muscle is scarce. Furthermore, the majority of information about its role is derived from global knockout mice, which are known to be hypermetabolic and fail to accumulate SCD1's substrate, SFA. We now know that SCD1 expression is important in regulating lipid bilayer fluidity, increasing triglyceride formation, and enabling lipogenesis and may protect against SFA-induced lipotoxicity. Exercise has been shown to increase SCD1 expression, which may contribute to an increase in intramyocellular triglyceride at the expense of free fatty acids and diacylglycerol. This review is intended to define the role of SCD1 in skeletal muscle and discuss the potential benefits of its activity in the context of lipid metabolism, insulin sensitivity, exercise training, and obesity. PMID- 23941874 TI - Caveolin-1/PTRF upregulation constitutes a mechanism for mediating p53-induced cellular senescence: implications for evidence-based therapy of delayed wound healing in diabetes. AB - A heightened state of oxidative stress and senescence of fibroblasts constitute potential therapeutic targets in nonhealing diabetic wounds. Here, we studied the underlying mechanism mediating diabetes-induced cellular senescence using in vitro cultured dermal fibroblasts and in vivo circular wounds. Our results demonstrated that the total antioxidant capacity and mRNA levels of thioredoxinreductase and glucose-6-phosphate dehydrogenase as well as the ratio of NADPH/NADP were decreased markedly in fibroblasts from patients with type 2 diabetes (DFs). Consistent with this shift in favor of excessive reactive oxygen species, DFs also displayed a significant increase in senescence-associated beta galactosidase activity and phospho-gamma-histone H2AX (pH2AX) level. Moreover, the ability of PDGF to promote cell proliferation/migration and regulate the phosphorylation-dependent activation of Akt and ERK1/2 appears to be attenuated as a function of diabetes. Mechanistically, we found that diabetes-induced oxidative stress upregulated caveolin-1 (Cav-1) and PTRF expression, which in turn sequestered Mdm2 away from p53. This process resulted in the activation of a p53/p21-dependent pathway and the induction of premature senescence in DFs. Most of the aforementioned oxidative stress and senescence-based features observed in DFs were recapitulated in a 10-day-old diabetic wound. Intriguingly, we confirmed that the targeted depletion of Cav-1 or PTRF using siRNA- or Vivo-Morpholino antisense-based gene therapy markedly inhibited diabetes/oxidative stress-induced premature senescence and also accelerated tissue repair in this disease state. Overall, our data illuminate Cav-1/PTRF-1 as a key player of a novel signaling pathway that may link a heightened state of oxidative stress to cellular senescence and impaired wound healing in diabetes. PMID- 23941873 TI - Direct and indirect effects of growth hormone receptor ablation on liver expression of xenobiotic metabolizing genes. AB - Detoxification of ingested xenobiotic chemicals, and of potentially toxic endogenous metabolites, is carried out largely through a series of enzymes synthesized in the liver, sometimes called "xenobiotic metabolizing enzymes" (XME). Expression of these XME is sexually dimorphic in rodents and humans, with many of the XME expressed at higher levels in females. This expression pattern is thought to be regulated, in part, by the sex differences in circadian growth hormone (GH) pulsatility. We have evaluated mRNA, in the liver, for 52 XME genes in male and female mice of four mutant stocks, with diminished levels of GH receptor (GHR) either globally (GKO), or in liver (LKO), fat (FKO), or muscle (MKO) tissue specifically. The data show complex, sex-specific changes. For some XME, the expression pattern is consistent with direct control of hepatic mRNA by GHR in the liver. In contrast, other XME show evidence for indirect pathways in which hepatic XME expression is altered by GH signals in fat or skeletal muscle. The effects of GHR-null mutations on glucose control, responses to dietary interventions, steroid metabolism, detoxification pathways, and lifespan may depend on a mixture of direct hepatic effects and cross talk between different GH responsive tissues. PMID- 23941877 TI - Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of Ser727 on STAT3 in prostate cancer cells. AB - Cyclin-dependent kinase 5 (Cdk5) is known to regulate prostate cancer metastasis. Our previous results indicated that Cdk5 activates androgen receptor (AR) and supports prostate cancer growth. We also found that STAT3 is a target of Cdk5 in promoting thyroid cancer cell growth, whereas STAT3 may play a role as a regulator to AR activation under cytokine control. In this study, we investigated the regulation of Cdk5 and its activator p35 on STAT3/AR signaling in prostate cancer cells. Our results show that Cdk5 biochemically interacts with STAT3 and that this interaction depends on Cdk5 activation in prostate cancer cells. The phosphorylation of STAT3 at Ser727 (p-Ser727-STAT3) is regulated by Cdk5 in cells and xenograft tumors. The mutant of STAT3 S727A reduces its interaction with Cdk5. We further show that the nuclear distribution of p-Ser727-STAT3 and the expression of STAT3-regulated genes (junB, c-fos, c-myc, and survivin) are regulated by Cdk5 activation. STAT3 mutant does not further decrease cell proliferation upon Cdk5 inhibition, which implies that the role of STAT3 regulated by Cdk5 correlates to cell proliferation control. Interestingly, Cdk5 may regulate the interaction between STAT3 and AR through phosphorylation of Ser727-STAT3 and therefore upregulate AR protein stability and transactivation. Correspondingly, clinical evidence shows that the level of p-Ser727-STAT3 is significantly correlated with Gleason score and the levels of upstream regulators (Cdk5 and p35) as well as downstream protein (AR). In conclusion, this study demonstrates that Cdk5 regulates STAT3 activation through Ser727 phosphorylation and further promotes AR activation by protein-protein interaction in prostate cancer cells. PMID- 23941880 TI - A facile fabrication of alginate microbubbles using a gas foaming reaction. AB - Microbubble particles have been extensively utilized as temporal templates for various biomedical applications. This study proposes a facile strategy to obtain microbubble-containing alginate particles (i.e., microbubbles inside alginate gel particles, called alginate microbubbles). The chemical reaction of sodium bicarbonate and hydrogen peroxide to produce gaseous carbon dioxide and oxygen was utilized to form microbubbles within alginate particles. Uniform alginate particles were obtained by a stable needle-based droplet formation process. Kinetic reaction of gas formation was monitored for 2% alginate particles. The gas formation increased with the concentrations of sodium bicarbonate (1-5 wt%) and hydrogen peroxide (0-36.5 wt%). PMID- 23941868 TI - Post-translational intracellular trafficking determines the type of immune response elicited by DNA vaccines expressing Gag antigen of Human Immunodeficiency Virus Type 1 (HIV-1). AB - In the current study, immune responses induced by Gag DNA vaccines with different designs were evaluated in Balb/C mice. The results demonstrated that the DNA vaccine with the full length wild type gag gene (Wt-Gag) mainly produced Gag antigens intracellularly and induced a higher level of cell-mediated immune (CMI) responses, as measured by IFN-gamma ELISPOT, intracellular cytokine staining (ICS), and cytotoxic T lymphocytes (CTL) assays against a dominant CD8(+) T cell epitope (AMQMLKETI). In contrast, the addition of a tissue plasminogen activator (tPA) leader sequence significantly improved overall Gag protein expression/secretion and Gag-specific antibody responses; however, Gag-specific CMI responses were decreased. The mutation of zinc-finger motif changed Gag protein expression patterns and reduced the ability to generate both CMI and antibody responses against Gag. These findings indicate that the structure and post-translational processing of antigens expressed by DNA vaccines play a critical role in eliciting optimal antibody or CMI responses. PMID- 23941879 TI - Skeletal muscle denervation causes skeletal muscle atrophy through a pathway that involves both Gadd45a and HDAC4. AB - Skeletal muscle denervation causes muscle atrophy via complex molecular mechanisms that are not well understood. To better understand these mechanisms, we investigated how muscle denervation increases growth arrest and DNA damage inducible 45alpha (Gadd45a) mRNA in skeletal muscle. Previous studies established that muscle denervation strongly induces Gadd45a mRNA, which increases Gadd45a, a small myonuclear protein that is required for denervation-induced muscle fiber atrophy. However, the mechanism by which denervation increases Gadd45a mRNA remained unknown. Here, we demonstrate that histone deacetylase 4 (HDAC4) mediates induction of Gadd45a mRNA in denervated muscle. Using mouse models, we show that HDAC4 is required for induction of Gadd45a mRNA during muscle denervation. Conversely, forced expression of HDAC4 is sufficient to increase skeletal muscle Gadd45a mRNA in the absence of muscle denervation. Moreover, Gadd45a mediates several downstream effects of HDAC4, including induction of myogenin mRNA, induction of mRNAs encoding the embryonic nicotinic acetylcholine receptor, and, most importantly, skeletal muscle fiber atrophy. Because Gadd45a induction is also a key event in fasting-induced muscle atrophy, we tested whether HDAC4 might also contribute to Gadd45a induction during fasting. Interestingly, however, HDAC4 is not required for fasting-induced Gadd45a expression or muscle atrophy. Furthermore, activating transcription factor 4 (ATF4), which contributes to fasting-induced Gadd45a expression, is not required for denervation-induced Gadd45a expression or muscle atrophy. Collectively, these results identify HDAC4 as an important regulator of Gadd45a in denervation induced muscle atrophy and elucidate Gadd45a as a convergence point for distinct upstream regulators during muscle denervation and fasting. PMID- 23941881 TI - Synthesis of photoresponsive dual NIR two-photon absorptive [60]fullerene triads and tetrads. AB - Broadband nonlinear optical (NLO) organic nanostructures exhibiting both ultrafast photoresponse and a large cross-section of two-photon absorption throughout a wide NIR spectrum may make them suitable for use as nonlinear biophotonic materials. We report here the synthesis and characterization of two C60-(antenna)(x) analogous compounds as branched triad C60(>DPAF-C18)(>CPAF C(2M)) and tetrad C60(>DPAF-C18)(>CPAF-C(2M))2 nanostructures. These compounds showed approximately equal extinction coefficients of optical absorption over 400 550 nm that corresponds to near-IR two-photon based excitation wavelengths at 780 1,100 nm. Accordingly, they may be utilized as potential precursor candidates to the active-core structures of photosensitizing nanodrugs for 2gamma-PDT in the biological optical window of 800-1,050 nm. PMID- 23941878 TI - Effects of recovery sleep after one work week of mild sleep restriction on interleukin-6 and cortisol secretion and daytime sleepiness and performance. AB - One workweek of mild sleep restriction adversely impacts sleepiness, performance, and proinflammatory cytokines. Many individuals try to overcome these adverse effects by extending their sleep on weekends. To assess whether extended recovery sleep reverses the effects of mild sleep restriction on sleepiness/alertness, inflammation, and stress hormones, 30 healthy young men and women (mean age +/- SD, 24.7 +/- 3.5 yr; mean body mass index +/- SD, 23.6 +/- 2.4 kg/m(2)) participated in a sleep laboratory experiment of 13 nights [4 baseline nights (8 h/night), followed by 6 sleep restriction nights (6 h/night) and 3 recovery nights (10 h/night)]. Twenty-four-hour profiles of circulating IL-6 and cortisol, objective and subjective daytime sleepiness (Multiple Sleep Latency Test and Stanford Sleepiness Scale), and performance (Psychomotor Vigilance Task) were assessed on days 4 (baseline), 10 (after 1 wk of sleep restriction), and 13 (after 2 nights of recovery sleep). Serial 24-h IL-6 plasma levels increased significantly during sleep restriction and returned to baseline after recovery sleep. Serial 24-h cortisol levels during restriction did not change compared with baseline, but after recovery they were significantly lower. Subjective and objective sleepiness increased significantly after restriction and returned to baseline after recovery. In contrast, performance deteriorated significantly after restriction and did not improve after recovery. Extended recovery sleep over the weekend reverses the impact of one work week of mild sleep restriction on daytime sleepiness, fatigue, and IL-6 levels, reduces cortisol levels, but does not correct performance deficits. The long-term effects of a repeated sleep restriction/sleep recovery weekly cycle in humans remain unknown. PMID- 23941876 TI - Loss of CCR5 results in glucose intolerance in diet-induced obese mice. AB - Macrophage and T cell infiltration into metabolic tissues contributes to obesity associated inflammation and insulin resistance (IR). C-C chemokine receptor 5 (CCR5), expressed on macrophages and T cells, plays a critical role in the recruitment and activation of proinflammatory M1 and TH1 immune cells to tissues and is elevated in adipose tissue (AT) and liver of obese humans and mice. Thus, we hypothesized that deficiency of CCR5 would protect against diet-induced inflammation and IR. CCR5-deficient (CCR5(-/-)) mice and C57BL/6 (WT) controls were fed 10% low-fat (LF) or 60% high-fat (HF) diets for 16 wk. HF feeding increased adiposity, blood glucose, and plasma insulin levels equally in both genotypes. Opposing our hypothesis, HF-fed CCR5(-/-) mice were significantly more glucose intolerant than WT mice. In AT, there was a significant reduction in the M1-associated gene CD11c, whereas M2 associated genes were not different between genotypes. In addition, HF feeding caused a twofold increase in CD4(+) T cells in the AT of CCR5(-/-) compared with WT mice. In liver and muscle, no differences in immune cell infiltration or inflammatory cytokine expression were detected. However, in AT and muscle, there was a mild reduction in insulin-induced phosphorylation of AKT and IRbeta in CCR5(-/-) compared with WT mice. These findings suggest that whereas CCR5 plays a minor role in regulating immune cell infiltration and inflammation in metabolic tissues, deficiency of CCR5 impairs systemic glucose tolerance as well as AT and muscle insulin signaling. PMID- 23941884 TI - Ring expansion of vinylaziridines through the strain-release pericyclic reaction: recent developments and applications. AB - Recent syntheses of azetidines, pyrrolidines, piperidines and azepines through cycloaddition or sigmatropic rearrangements of vinylaziridines are described. Applications to natural product synthesis and mechanistic investigations are also summarized. PMID- 23941882 TI - Susceptibility of Staphylococcus aureus clinical isolates to propolis extract alone or in combination with antimicrobial drugs. AB - The objective of this study was to assess in vitro the antimicrobial activity of ethanolic extract of Polish propolis (EEPP) against methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates. The combined effect of EEPP and 10 selected antistaphylococcal drugs on S. aureus clinical cultures was also investigated. EEPP composition was analyzed by a High Performance Liquid Chromatography (HPLC) method. The flavonoid compounds identified in Polish Propolis included flavones, flavonones, flavonolols, flavonols and phenolic acids. EEPP displayed varying effectiveness against twelve S. aureus strains, with minimal inhibitory concentration (MIC) within the range from 0.39 to 0.78 mg/mL, determined by broth microdilution method. The average MIC was 0.54 +/- 0.22 mg/mL, while calculated MIC50 and MIC90 were 0.39 mg/mL and 0.78 mg/mL, respectively. The minimum bactericidal concentration (MBC) of the EEPP ranged from 0.78 to 3.13 mg/mL. The in vitro combined effect of EEPP and 10 antibacterial drugs was investigated using disk diffusion method-based assay. Addition of EEPP to cefoxitin (FOX), clindamycin (DA), tetracycline (TE), tobramycin (TOB), linezolid (LIN), trimethoprim+sulfamethoxazole (SXT), penicillin (P), erythromycin (E) regimen, yielded stronger, cumulative antimicrobial effect, against all tested S. aureus strains than EEPP and chemotherapeutics alone. In the case of ciprofloxacin (CIP) and chloramphenicol (C) no synergism with EEPP was observed. PMID- 23941883 TI - Phenylpropanoid, sapnol A, lignan and neolignan sophorosides, saposides A and B, isolated from Canadian sugar maple sap. AB - One new phenolic compound, sapnol A (1), and two new aromatic sophorosides, named saposides A (2) and B (3) were isolated from sugar maple sap. In addition, seven known phenolic compounds 4-10 were isolated. These structures were determined on the basis of NMR experiments as well as chemical evidence. Furthermore, all the isolated compounds 1-10 were tested for antioxidative activity by the superoxide dismutase (SOD)-like assay. PMID- 23941885 TI - Monte Carlo calculated microdosimetric spread for cell nucleus-sized targets exposed to brachytherapy 125I and 192Ir sources and 60Co cell irradiation. AB - The stochastic nature of ionizing radiation interactions causes a microdosimetric spread in energy depositions for cell or cell nucleus-sized volumes. The magnitude of the spread may be a confounding factor in dose response analysis. The aim of this work is to give values for the microdosimetric spread for a range of doses imparted by (125)I and (192)Ir brachytherapy radionuclides, and for a (60)Co source. An upgraded version of the Monte Carlo code PENELOPE was used to obtain frequency distributions of specific energy for each of these radiation qualities and for four different cell nucleus-sized volumes. The results demonstrate that the magnitude of the microdosimetric spread increases when the target size decreases or when the energy of the radiation quality is reduced. Frequency distributions calculated according to the formalism of Kellerer and Chmelevsky using full convolution of the Monte Carlo calculated single track frequency distributions confirm that at doses exceeding 0.08 Gy for (125)I, 0.1 Gy for (192)Ir, and 0.2 Gy for (60)Co, the resulting distribution can be accurately approximated with a normal distribution. A parameterization of the width of the distribution as a function of dose and target volume of interest is presented as a convenient form for the use in response modelling or similar contexts. PMID- 23941887 TI - Clinical usefulness of endoscopic palliation in patients with biliary obstruction caused by hepatocellular carcinoma. AB - BACKGROUND/AIMS: To evaluate the clinical usefulness of endoscopic biliary drainage (EBD) in patients with hepatocellular carcinoma (HCC). METHODS: A total of 111 jaundiced patients underwent attempted EBD for relief of HCC-related biliary stricture at our hospital over a 5-year period and all were included in the intention-to-treat (ITT) analysis. RESULTS: After an endoscopic attempt at drainage, 46 (41.4%) of the 111 patients achieved a favorable response. Biliary cannulation failed in 5 patients. Child-Pugh class C, portal vein thrombosis and severe hyperbilirubinemia were negatively correlated with a favorable EBD response. In the ITT population, 40 (87.0%) of the favorable responders received further treatment for HCC, >2 (3.1%) of the unfavorable responders (p < 0.001). The median survival time for ITT patients with and without a favorable response to EBD was 8.7 and 1.3 months, respectively (p < 0.001). Cox's model showed that a favorable EBD response was an independent predictor of longer survival (hazard ratio 0.20, p < 0.001). CONCLUSIONS: For HCC patients with tumor-related biliary obstruction, predictors of effective endoscopic palliation of cholestasis were relatively mild hyperbilirubinemia and preserved liver function and intact portal vein flow. A favorable EBD response was associated with longer survival outcomes. PMID- 23941888 TI - Voltage gated sodium and calcium channel blockers for the treatment of chronic inflammatory pain. AB - The inflammatory response is a natural response of the body that occurs immediately following tissue damage, which may be due to injury, infection or disease. The acute inflammatory response is an essential mechanism that promotes healing and a key aspect is the ensuing pain, which warns the subject to protect the site of injury. Thus, it is common to see a zone of primary sensitization as well as consequential central sensitization that generally, is maintained by a peripheral drive from the zone of tissue injury. Inflammation associated with chronic pain states, such as rheumatoid and osteoarthritis, cancer and migraine etc. is deleterious to health and often debilitating for the patient. Thus there is a large unmet clinical need. The mechanisms underlying both acute and chronic inflammatory pain are extensive and complex, involving a diversity of cell types, receptors and proteins. Among these the contribution of voltage gated sodium and calcium channels on peripheral nociceptors is critical for nociceptive transmission beyond the peripheral transducers and changes in their distribution, accumulation, clustering and functional activities have been linked to both inflammatory and neuropathic pain. The latter has been the main area for trials and use of drugs that modulate ion channels such as carbamazepine and gabapentin, but given the large peripheral drive that follows tissue damage, there is a clear rationale for blocking voltage gated sodium and calcium channels in these pain states. It has been hypothesized that pain of inflammatory origin may evolve into a condition that resembles neuropathic pain, but mixed pains such as low back pain and cancer pain often include elements of both pain states. This review considers the therapeutic potential for sodium and calcium channel blockers for the treatment of chronic inflammatory pain states. PMID- 23941893 TI - Adherence junction proteins in angiogenesis: modulation by aspirin and salicylic acid. PMID- 23941872 TI - Arterio-venous balance studies of skeletal muscle fatty acid metabolism: What can we believe? AB - The arterio-venous balance (A-V balance/difference) technique has been used by a number of groups, including ours, to study skeletal muscle fatty acid metabolism. Several lines of evidence indicate that, like glycogen, intramyocellular triglycerides (imcTG) are an energy source for local use. As such, the report that increased release of free fatty acids (FFA) via lipolysis from skeletal muscle, but not from adipose tissue, is responsible for the increased systemic lipolysis during IL-6 infusion in healthy humans is somewhat unexpected (26). It appears that given the complex anatomy of human limbs, as to be discussed in this review, it is virtually impossible to determine whether any fatty acids being released into the venous circulation of an arm or leg derive from the lipolysis of intermuscular fat residing between muscle groups, intramuscular fat residing within muscle groups (between epimysium and perimysium, or bundles), or the intramyocellular triglyceride droplets (imcTG). In many cases, it may even be difficult to be confident that there is no contribution of FFA from subcutaneous adipose tissue. This question is fundamentally important as one attempts to interpret the results of skeletal muscle fatty acid metabolism studies using the A-V balance technique. In this Perspectives article, we examine the reported results of fatty acid kinetics obtained using the techniques to evaluate the degree of and how to minimize contamination when attempting to sample skeletal muscle-specific fatty acids. PMID- 23941886 TI - Indolent mucormycosis of the paranasal sinus in immunocompetent patients: are antifungal drugs needed? AB - OBJECTIVE: To report the clinical characteristics and treatment outcomes of indolent paranasal mucormycosis in immunocompetent individuals. MATERIALS AND METHODS: A retrospective review of four immunocompetent patients with indolent mucormycosis of the paranasal sinus managed by endoscopic sinus surgery only was performed. One year of regular follow up comprised angled endoscopy and repeated paranasal sinus computed tomography three months after surgery. RESULTS: Clinical symptoms were non-specific. Pre-operative paranasal sinus computed tomography showed opacification of the unilateral maxillary sinus with focal calcification but without bony destruction or extension to the orbit or cranium. All patients underwent endoscopic sinus surgery without administration of antifungal agents. There was no recurrence on regular clinical and radiological follow up. CONCLUSION: For indolent paranasal mucormycosis in immunocompetent patients, endoscopic sinus surgery can be the treatment of choice, and the administration of antifungal drugs may not be necessary. PMID- 23941895 TI - Transport equations of energy for ferromagnetic insulators in contact with electrodes. AB - A phenomenological derivation of the transport equations for ferromagnetic moments and associated energy and heat is proposed. The model describes the transfer of energy through an interface composed of a ferromagnetic insulator in contact with normal electrodes. A reduction method applied to the ferromagnetic degrees of freedom allows a two-channel model to be defined for the transport of magnetic moments. It is shown that a heat current flowing into the insulating ferromagnet-produced e.g. by electromagnetic resonance, thermal gradient, magneto mechanical or magneto-optical excitations-can generate a magneto-voltaic potential and a pure spin-current in the non-ferromagnetic electrode. PMID- 23941896 TI - Clindamycin-induced acute kidney injury: large biopsy case series. AB - BACKGROUND: While clindamycin-induced acute kidney injury (AKI) is uncommon, it has occurred more frequently in recent years. SUMMARY: We investigated 24 patients diagnosed with clindamycin-induced AKI retrospectively. The dosage of clindamycin was 1.0-1.5 g/day. Fifteen patients had episodes of gross hematuria, but fever, skin rash and eosinophilia were rare. Urine analysis revealed mild proteinuria and severe tubular dysfunction. Twenty-three patients were diagnosed with AKI stage 3 upon admission. The clindamycin lymphocyte transformation assay was positive for 63.2% of the patients. Acute interstitial nephritis (AIN) and acute tubular necrosis (ATN) were proven by renal biopsy, and renal insufficiency appeared to result from tubular toxicity and drug crystals. In the majority (87.5%) of the patients, AKI was severe and required renal replacement therapy, but all of their renal function recovered significantly 2 months after discharge. Clindamycin-induced AKI is largely reversible and has episodes of gross hematuria. Renal biopsies confirmed AIN or ATN in these patients. PMID- 23941894 TI - Carbon nanotube membranes with ultrahigh specific adsorption capacity for water desalination and purification. AB - Development of technologies for water desalination and purification is critical to meet the global challenges of insufficient water supply and inadequate sanitation, especially for point-of-use applications. Conventional desalination methods are energy and operationally intensive, whereas adsorption-based techniques are simple and easy to use for point-of-use water purification, yet their capacity to remove salts is limited. Here we report that plasma-modified ultralong carbon nanotubes exhibit ultrahigh specific adsorption capacity for salt (exceeding 400% by weight) that is two orders of magnitude higher than that found in the current state-of-the-art activated carbon-based water treatment systems. We exploit this adsorption capacity in ultralong carbon nanotube-based membranes that can remove salt, as well as organic and metal contaminants. These ultralong carbon nanotube-based membranes may lead to next-generation rechargeable, point-of-use potable water purification appliances with superior desalination, disinfection and filtration properties. PMID- 23941897 TI - Mediterranean diet adherence rates in Sicily, southern Italy. AB - OBJECTIVE: To assess adherence to the Mediterranean diet and nutrient intakes in a population of Sicily, southern Italy and to evaluate possible determinants, particularly socio-cultural and lifestyle factors. DESIGN: Cross-sectional. SETTING: Urban and rural areas of eastern Sicily. SUBJECTS: Between May 2009 and December 2010, 3090 adults were randomly recruited through the collaboration of fourteen general practitioners. Adherence to the Mediterranean diet was measured by the MedDietScore. Nutrient intakes were assessed through the 24 h recall of the previous day's dietary intake. RESULTS: Rural participants were barely more adherent to the Mediterranean diet than their urban counterparts (mean scores were 27.8 and 27.2, respectively, P = 0.037). The MedDietScore was correlated with intakes of MUFA, fibre and vitamin C, as well as with consumption of non refined cereals, vegetables, fruit, meat, dairy products, alcohol and nuts. Regression analysis revealed that older and more educated people were more likely to be in the highest tertile of MedDietScore (OR = 1.90; 95 % CI 1.39, 2.59 and OR = 1.29; 95 % CI 1.05, 1.58, respectively). A significant difference in quantity (moderate) and quality (red wine and beer) of alcohol was found according to adherence to the Mediterranean diet. Finally, more active participants were 1.5 times more likely to form part of the high-adherence group. CONCLUSIONS: A slow but concrete moving away from traditional patterns has been observed in younger people and low educated people. Public health interventions should focus on these target populations in order to improve the quality of their diet. PMID- 23941892 TI - Care of acute myocardial infarction in the coronary care units of Piedmont in 2007: results from the 'PRIMA_sweet' region-wide survey. AB - BACKGROUND: The treatment of acute myocardial infarction (AMI), both with ST segment elevation [ST-elevation myocardial infarction (STEMI)] and non-ST-segment elevation [non-ST-elevation myocardial infarction (NSTEMI)], is evolving in Piedmont, with an increase in interventional procedures and hub-and-spoke networks. This new region-wide survey provides updated assessment of the management of STEMI and unprecedented data on NSTEMI. METHODS: In 30 coronary care units in Piedmont, all patients with AMI symptoms of duration less than 48 h, between January and March 2007, were included. RESULTS: Of 921 patients, 447 had STEMI and 474 NSTEMI. Diabetes was present in 35% and chronic kidney disease in 38%. Hospital mortality was 4.7% [95% confidence interval (CI) 3.3-6.1]: age 75 years or older, Killip class higher than 1 and known diabetes or abnormal blood glucose on admission were multivariate predictors. Thrombolysis and primary percutaneous transluminal coronary angioplasty (pPTCA) were performed in 17.6 and 53.1% of 391 patients, respectively, with STEMI of 12 h or less, and 29.3% had no reperfusion therapy, notably 52% of patients aged 75 years or older and 51% of those reaching non-24/24 h interventional centres. Mortality after pPTCA was 2.5% and onsite door-to-balloon time was less than 90 min in 67.5%. Overall mortality after STEMI was 5.4% (95% CI 3.2-7.6). In NSTEMI, use of antithrombotic treatments was extensive, but invasive treatment within 72 h was limited to 8% of patients in centres without interventional facilities and independent of patient's risk profile. Mortality after NSTEMI was 4.0% (95% CI 2.2-5.8) and was predicted by both the Global Registry of Acute Coronary Events risk score and diabetes. CONCLUSION: There is room for improvement in the treatment of AMI in our region, with more extensive use of reperfusion therapy in STEMI, especially in the elderly, and early revascularization and optimal medical treatment in higher-risk NSTEMI. PMID- 23941890 TI - Direct fetal intravenous immunoglobulin infusion as an adjunct to intrauterine fetal blood transfusion in rhesus-allommunized pregnancies: a pilot study. AB - OBJECTIVES: To study the usefulness of direct fetal intravenous immunoglobulin (IVIG) infusion along with intrauterine transfusion (IUT) in the management of severe fetal anemia in rhesus (Rh) alloimmunized pregnancies. METHODS: Thirty four consecutive Rh-isoimmunized pregnant women who required serial IUTs received either blood alone (control group, n = 16) or IVIG and blood (study group, n = 18). Pregnancies were followed up to delivery, and fetal outcome was recorded. The rate of fall of hematocrit was measured and compared between the two groups. RESULTS: There was a slower rate of fall of hematocrit in the study group (IUT and IVIG) compared to the control group (only IUT). The mean rate of fall was 0.72 +/- 0.54% per day in the study group while it was 1.29 +/- 0.95% per day in the control group (p = 0.005). CONCLUSION: Fall of fetal hematocrit was reduced in the study group. The results of this pilot study can be used to time the next transfusion in patients receiving IVIG along with IUT (taking the rate of fall as 0.70%). This may eventually result in decreasing the number of transfusions per fetus. PMID- 23941900 TI - Factors that drive variation among gut microbial communities. AB - Surveys of humans from around the world have revealed differences in gut microbiota composition among geographically separated populations. But because humans from the same regions often share common ancestry as well as dietary and cultural habits, most studies have not been able to differentiate among the effects of heritable factors and external factors on the composition of the gut microbiota. Here we discuss how the analysis of gut microbial communities of chimpanzees residing in Gombe Stream National Park has provided an unprecedented opportunity to measure the effects of external factors while controlling for heritable factors. The differences in gut microbiota composition between separated host populations of chimpanzees are due almost entirely to external factors, with the contribution of heritable factors to intraspecific variation in gut microbiota composition being too small to detect. The dominant influence of external factors in generating differences among the gut microbiota of our closest relatives lends promise to the possibility of manipulating the composition of the gut microbiome within human hosts. These results highlight the need for controlled studies that isolate the roles of specific external factors, such as diet, cultural practices and geography, in generating differences in the gut microbiota composition. PMID- 23941891 TI - Interleukin-22 as a molecular adjuvant facilitates IL-17-producing CD8+ T cell responses against a HBV DNA vaccine in mice. AB - Interleukin-22 (IL-22) is mainly produced by activated Th1 cells, Th17 cells and NK cells and promotes anti-microbial defense, pro-inflammatory and tissue remodeling responses. However, its potential use as a vaccine adjuvant has not been tested. In this study, we tested if a DNA construct expressing IL-22 (pVAX IL-22) could be used as a molecular adjuvant to enhance host immune responses induced by HBV DNA vaccination (pcD-S2). After immunizing mice with pcD-S2 combined with pVAX-IL-22, we didn't find enhancement of HBsAg-specific antibody responses in comparison to mice immunized with pcD-S2 alone. However, there was an enhancement of the level of IL-17 expression in antigen specific CD8(+) cytotoxic T lymphocytes (Tc17). By using CD8 T-cell knockout (KO) and IL-17 KO mice, Tc17 cells were found to be a dominant population driving cytotoxicity. Importantly, there was a correlation between pVAX-IL-22 enhancement of T lymphocytes and a reduction of HBsAg-positive hepatocytes in HBsAg transgenic mice. These results demonstrate that IL-22 might be used as an effective adjuvant to enhance cellular immune responses during HBsAg DNA vaccination since it can induce Tc17 cells to break tolerance in HBsAg transgenic mice. PMID- 23941899 TI - Steroidal glycoalkaloid profiling and structures of glycoalkaloids in wild tomato fruit. AB - Steroidal glycoalkaloids (SGAs) constitute one of the main groups of secondary metabolites in tomato fruit. However, the detailed composition of SGAs other than alpha-tomatine, dehydrotomatine and esculeoside A, remains unclear. Comparative SGA profiling was performed in eight tomato accessions, including wild tomato species by HPLC-Fourier transform ion cyclotron resonance mass spectrometry (HPLC FTICR/MS). On the basis of molecular formulae obtained from accurate m/z and fragmentation patterns by multistage MS/ MS (MS(n)), 123 glycoalkaloids in total were screened. Detailed MS(n) analysis showed that the observed structural diversity was derived from various chemical modifications, such as glycosylation, acetylation, hydroxylation and isomerization. Total SGA content in each tomato accession was in the range of 121-1986 nmol/gfr.wt. Furthermore, the compositional variety of SGA structures was distinctive in some tomato accessions. While most tomato accessions were basically categorized as alpha tomatine-rich or esculeoside A-rich group, other specific SGAs also accumulated at high levels in wild tomato. Here, five such SGAs were isolated and their structures were determined by NMR spectroscopic analysis, indicating three of them were presumably synthesized during alpha-tomatine metabolism. PMID- 23941901 TI - Neuromuscular onset succession of high level gymnasts during dynamic leg acceleration phases on high bar. AB - In several athletic disciplines there is evidence that for generating the most effective acceleration of a specific body part the transfer of momentum should run in a "whip-like" consecutive succession of body parts towards the segment which shall be accelerated most effectively (e.g. the arm in throwing disciplines). This study investigated the question how this relates to the succession of neuromuscular activation to induce such "whip like" leg acceleration in sports like gymnastics with changed conditions concerning the body position and momentary rotational axis of movements (e.g. performing giant swings on high bar). The study demonstrates that during different long hang elements, performed by 12 high level gymnasts, the succession of the neuromuscular activation runs primarily from the bar (punctum fixum) towards the legs (punctum mobile). This demonstrates that the frequently used teaching instruction, first to accelerate the legs for a successful realization of such movements, according to a high level kinematic output, is contradictory to the neuromuscular input patterns, being used in high level athletes, realizing these skills with high efficiency. Based on these findings new approaches could be developed for more direct and more adequate teaching methods regarding to an earlier optimization and facilitation of fundamental movement requirements. PMID- 23941907 TI - Indications for pediatric external ventricular drain placement and risk factors for conversion to a ventriculoperitoneal shunt. AB - BACKGROUND/AIMS: The external ventricular drain (EVD) is commonly used for the treatment of hydrocephalus and intracranial pressure (ICP) monitoring. In this study, we retrospectively reviewed indications for EVD placement over the last 20 years in pediatric patients at our institution. Additionally, we evaluated the rate that an EVD needed to be converted to a ventriculoperitoneal shunt (VPS) and ascertained how hydrocephalus etiology impacted long-term drainage requirements. METHODS: Patients that received an EVD between 1990 and 2010 at our institution were identified using billing codes. Demographics, etiology of hydrocephalus, length of stay (LOS) and EVD duration were recorded. Only patients receiving their first EVD were included; those with any prior ventricular catheter (including prior shunts) were excluded from this study. RESULTS: A total of 180 patients underwent first-time placement of an EVD over the 20-year period. Of these, 78.9% were placed on the right side and 81.7% were performed through a frontal burr hole site. The average age of all patients at their initial procedure was 9.3 years (median 9.8; range 0-18), hospital LOS was 22.5 days (median 16; range 1-174) and EVD duration was 7.8 days (median 7; range 1-37). Trauma (43.3%) and neoplasms (32.2%) were the most common indications. Approximately, one quarter of the patients were unable to become EVD independent and, therefore, required a VPS. Only patients receiving an EVD for traumatic brain injury were significantly less likely to be converted to a shunt than other causes of hydrocephalus (relative risk, RR = 0.18, 95% confidence interval, CI = 0.07-0.46). Conversely, patients with neoplasms (RR = 3.56, 95% CI = 1.74-7.31), obstructive hydrocephalus (RR = 5.48, 95% CI = 1.37-22.0) and intraventricular hemorrhage (RR = 9.86, 95% CI = 1.05-92.3) were more likely to need a shunt. CONCLUSION: Traumatic brain injuries and neoplasms represent the most common indications for EVD placement in the pediatric population. While patients with neoplasm were much more likely to need conversion to a VPS for long-term cerebrospinal fluid diversion, the majority of EVDs in patients with head injuries were successfully weaned. PMID- 23941889 TI - Deep brain stimulation improves movement amplitude but not hastening of repetitive finger movements. AB - External pacing cues, dopaminergic medication, and bilateral subthalamic nucleus deep brain stimulation (STN-DBS) improve repetitive movements performed at low rates. When the pacing rate is increased to frequencies near 2 Hz and above, both external pacing cues and Parkinson's medication were shown to be ineffective at improving repetitive finger movement performance. It remains unclear if STN-DBS improves the performance of repetitive finger movements at high pacing rates. This study examined the effects of STN-DBS on the amplitude and rate of repetitive finger movement across a range of external pacing rates. Nine participants with STN-DBS (OFF and ON stimulation) and nine matched healthy adults performed repetitive index finger flexion movements paced by an acoustic tone that increased from 1.0 to 3.0 Hz. OFF stimulation, most subjects moved at rates that were substantially higher (hastening pattern) or lower (bradykinesia pattern) than the tone rate, particularly at high pacing rates. ON stimulation, movement rate improved in subjects with the bradykinesia pattern, but not in those with the hastening pattern. Overall, STN-DBS did not significantly affect movement rate. In contrast, STN-DBS significantly (p<0.05) improved movement amplitude across all pacing rates. These findings demonstrate that STN-DBS improves movement amplitude, but had no effect on the rate of movement in participants with a hastening pattern. Separately testing movement amplitude and movement rate using both high and low rate externally paced cues in the clinical environment may aid in the diagnosis and treatment of people with Parkinson's disease. PMID- 23941905 TI - Irisinemia: a novel concept to coin in clinical medicine? AB - Skeletal muscle can express and release substances such as cytokines or other peptides capable of modulating metabolic processes. These cytokines, named 'myokines', function as hormones either locally within the muscle or by targeting distant organs. A novel peptidic myokine named 'irisin' has been recently identified. It has been noted that circulating irisin levels are lower in type 2 diabetes (T2D) compared with nondiabetic controls as well as in patients with chronic kidney disease. In addition, a negative correlation between the hemoglobin A1c (HbA1c) and circulating levels of irisin has been also observed. Thus, the blood concentration of irisin may reflect the metabolic status of patients suffering from metabolism disorders. In addition to glycemia or HbA1c, 'irisinemia' may also become a new promising concept employed to monitor metabolic disorders such as T2D or obesity, representing a novel and useful tool in the management of metabolic diseases in the near future. PMID- 23941898 TI - Parviflorals A-F, trinorcadalenes and bis-trinorcadalenes from the roots of Decaschistia parviflora. AB - Trinorcadalenes, parviflorals A and B (1 and 2), and four bis-trinorcadalenes, parviflorals C-F (3-6), together with the known trinorcadalenes, syriacusins A (7) and C (8), scopoletin (9) and stigmasterol were isolated from roots of Decaschistia parviflora. Their structures were established by spectroscopic techniques. The CD spectra of the bis-trinorcadalenes (3-6) established their absolute configurations at the binaphthyl axis. Further, structure 6 was confirmed by a single-crystal X-ray crystallographic analysis. Compounds 2 and 6 showed antimalarial activity against Plasmodium falciparum with IC50 values of 11.45 and 6.85 MUM, respectively. Compounds 1, 5, 7 and 8 also exhibited weak antifungal activity against Candida albicans, with IC50 values in the range of 37.03-197.68 MUM. Compounds 1-3 and 5-8 showed weak antimycobacterial activity against Mycobacterium tuberculosis with MIC values in the range of 54.30-192.13 MUM. In addition, several of these compounds possessed cytotoxicity towards the cancer cell lines, KB, MCF7 and NCI-H187 with IC50 values in the range of 2.20 90.09 MUM. PMID- 23941908 TI - 3D finite element model for writing long-period fiber gratings by CO2 laser radiation. AB - In the last years, mid-infrared radiation emitted by CO2 lasers has become increasing popular as a tool in the development of long-period fiber gratings. However, although the development and characterization of the resulting sensing devices have progressed quickly, further research is still necessary to consolidate functional models, especially regarding the interaction between laser radiation and the fiber's material. In this paper, a 3D finite element model is presented to simulate the interaction between laser radiation and an optical fiber and to determine the resulting refractive index change. Dependence with temperature of the main parameters of the optical fiber materials (with special focus on the absorption of incident laser radiation) is considered, as well as convection and radiation losses. Thermal and residual stress analyses are made for a standard single mode fiber, and experimental results are presented. PMID- 23941903 TI - Comparison of morphological and molecular genetic sex-typing on mediaeval human skeletal remains. AB - Archaeological excavations conducted at an early mediaeval cemetery in Volders (Tyrol, Austria) produced 141 complete skeletal remains dated between the 5th/6th and 12th/13th centuries. These skeletons represent one of the largest historical series of human remains ever discovered in the East Alpine region. Little historical information is available for this region and time period. The good state of preservation of these bioarchaeological finds offered the opportunity of performing molecular genetic investigations. Adequate DNA extraction methods were tested in the attempt to obtain as high DNA yields as possible for further analyses. Molecular genetic sex-typing using a dedicated PCR multiplex ("Genderplex") gave interpretable results in 88 remains, 78 of which had previously been sexed based on morphological features. We observed a discrepancy in sex determination between the two methods in 21 cases. An unbiased follow-up morphological examination of these finds showed congruence with the DNA results in all but five samples. PMID- 23941902 TI - Hope language in patients undergoing epilepsy surgery. AB - Candidates for epilepsy surgery often use the word "hope" to express their attitudes and beliefs about surgery. However, studies suggest that hope has a multiplicity of meanings that are not well understood. The goal of this analysis was to evaluate whether Candidates for epilepsy surgery use hope language to express a traditional, expected optimism during presurgery interviews. We examined patients' uses of the word "hope" and its derivatives (hoping, hopeful, hopefully) through a secondary analysis of 37 interviews of adult patients prior to epilepsy surgery. Approximately 1/3 of all hope statements were coded as expressions of optimism, while 1/3 were not optimistic, and 1/3 had unclear meanings. In addition to traditionally optimistic uses of the term, other themes surrounding use of this word included ideas of dread, worry, uncertainty, and temporizing language. This information may help clinicians communicate more effectively with patients, enhancing the informed consent process for epilepsy surgery. PMID- 23941906 TI - Candida albicans and Enterococcus faecalis in the gut: synergy in commensalism? AB - The fungus Candida albicans and the gram-positive bacterium Enterococcus faecalis are both normal residents of the human gut microbiome and cause opportunistic disseminated infections in immunocompromised individuals. Using a nematode infection model, we recently showed that co-infection resulted in less pathology and less mortality than infection with either species alone and this was partly explained by an interkingdom signaling event in which a bacterial-derived product inhibits hyphal morphogenesis of C. albicans. In this addendum we discuss these findings in the contest of other described bacterial-fungal interactions and recent data suggesting a potentially synergistic relationship between these two species in the mouse gut as well. We suggest that E. faecalis and C. albicans promote a mutually beneficial association with the host, in effect choosing a commensal lifestyle over a pathogenic one. PMID- 23941904 TI - The different impact of BRCA mutations on the survival of epithelial ovarian cancer patients: a retrospective single-center experience. AB - OBJECTIVES: The objective of this study was to examine whether the oncologic outcomes of BRCA1-associated and BRCA2-associated ovarian cancers correlate differently. METHODS: Genetic data and clinical characteristics were correlated with progression-free survival (PFS) and overall survival (OS). RESULTS: Data from 147 BRCA-mutated patients (119 BRCA1-positive and 28 BRCA2-positive) were analyzed. At a median follow-up of 69 months, the median PFS was 27.2 and 45.46 months for BRCA1 and BRCA2 patients, respectively (p = 0.03). Median OS was 77.23 and 111.47 months for BRCA1 and BRCA2 patients, respectively (p = 0.08). CONCLUSION: BRCA2 mutations confer PFS and a trend to OS advantage compared with the BRCA1 mutation in BRCA-mutated epithelial ovarian cancer patients. PMID- 23941914 TI - Modified use of Kocher's dissector in ligation of the superior thyroid pedicle. AB - BACKGROUND: More than a century has passed since Emil Theodor Kocher first described the use of 'Kocher's thyroid dissector' to secure the superior thyroid pedicle. METHOD: Despite the technological advances in thyroid surgery, the dissector remains an extremely useful instrument. This paper describes a modified use of the dissector, and reports on how this facilitates safer and easier surgery. RESULTS AND CONCLUSION: Application of this simple, modified technique can improve the safety and efficiency of thyroid surgery, with negligible financial outlay. PMID- 23941909 TI - The capability of fiber Bragg grating sensors to measure amputees' trans-tibial stump/socket interface pressures. AB - This study presents the first investigation into the capability of fiber Bragg grating (FBG) sensors to measure interface pressure between the stump and the prosthetic sockets of a trans-tibial amputee. FBG element(s) were recoated with and embedded in a thin layer of epoxy material to form a sensing pad, which was in turn embedded in a silicone polymer material to form a pressure sensor. The sensor was tested in real time by inserting a heavy-duty balloon into the socket and inflating it by using an air compressor. This test was conducted to examine the sensitivity and repeatability of the sensor when subjected to pressure from the stump of the trans-tibial amputee and to mimic the actual environment of the amputee's Patellar Tendon (PT) bar. The sensor exhibited a sensitivity of 127 pm/N and a maximum FSO hysteresis of around ~0.09 in real-time operation. Very good reliability was achieved when the sensor was utilized for in situ measurements. This study may lead to smart FBG-based amputee stump/socket structures for pressure monitoring in amputee socket systems, which will result in better-designed prosthetic sockets that ensure improved patient satisfaction. PMID- 23941912 TI - Sensor networks for optimal target localization with bearings-only measurements in constrained three-dimensional scenarios. AB - In this paper, we address the problem of determining the optimal geometric configuration of an acoustic sensor network that will maximize the angle-related information available for underwater target positioning. In the set-up adopted, a set of autonomous vehicles carries a network of acoustic units that measure the elevation and azimuth angles between a target and each of the receivers on board the vehicles. It is assumed that the angle measurements are corrupted by white Gaussian noise, the variance of which is distance-dependent. Using tools from estimation theory, the problem is converted into that of minimizing, by proper choice of the sensor positions, the trace of the inverse of the Fisher Information Matrix (also called the Cramer-Rao Bound matrix) to determine the sensor configuration that yields the minimum possible covariance of any unbiased target estimator. It is shown that the optimal configuration of the sensors depends explicitly on the intensity of the measurement noise, the constraints imposed on the sensor configuration, the target depth and the probabilistic distribution that defines the prior uncertainty in the target position. Simulation examples illustrate the key results derived. PMID- 23941911 TI - A novel angular acceleration sensor based on the electromagnetic induction principle and investigation of its calibration tests. AB - An angular acceleration sensor can be used for the dynamic analysis of human and joint motions. In this paper, an angular acceleration sensor with novel structure based on the principle of electromagnetic induction is designed. The method involves the construction of a constant magnetic field by the excitation windings of sensor, and the cup-shaped rotor that cut the magnetic field. The output windings of the sensor generate an electromotive force, which is directly proportional to the angular acceleration through the electromagnetic coupling when the rotor has rotational angular acceleration. The mechanical structure and the magnetic working circuit of the sensor are described. The output properties and the mathematical model including the transfer function and state-space model of the sensor are established. The asymptotical stability of the sensor when it is working is verified by the Lyapunov Theorem. An angular acceleration calibration device based on the torsional pendulum principle is designed. The method involves the coaxial connection of the angular acceleration sensor, torsion pendulum and a high-precision angle sensor, and then an initial external force is applied to the torsion pendulum to produce a periodic damping angle oscillation. The angular acceleration sensor and the angle sensor will generate two corresponding electrical signals. The sensitivity coefficient of the angular acceleration sensor can be obtained after processing these two-channel signals. The experiment results show that the sensitivity coefficient of the sensor is about 17.29 mv/Krad.s2. Finally, the errors existing in the practical applications of the sensor are discussed and the corresponding improvement measures are proposed to provide effective technical support for the practical promotion of the novel sensor. PMID- 23941910 TI - Synthesis of bimetallic platinum nanoparticles for biosensors. AB - The use of magnetic nanomaterials in biosensing applications is growing as a consequence of their remarkable properties; but controlling the composition and shape of metallic nanoalloys is problematic when more than one precursor is required for wet chemistry synthesis. We have developed a successful simultaneous reduction method for preparation of near-spherical platinum-based nanoalloys containing magnetic solutes. We avoided particular difficulties in preparing platinum nanoalloys containing Ni, Co and Fe by the identification of appropriate synthesis temperatures and chemistry. We used transmission electron microscopy (TEM) to show that our particles have a narrow size distribution, uniform size and morphology, and good crystallinity in the as-synthesized condition. Energy dispersive spectroscopy (EDS) and X-ray diffraction (XRD) confirms the coexistence of Pt with the magnetic solute in a face-centered cubic (FCC) solid solution. PMID- 23941913 TI - Immunogenicity of a reduced-dose whole killed rabies vaccine is significantly enhanced by ISCOMATRIXTM adjuvant, Merck amorphous aluminum hydroxylphosphate sulfate (MAA) or a synthetic TLR9 agonist in rhesus macaques. AB - There is a need for novel rabies vaccines suitable for short course, pre- and post-exposure prophylactic regimens which require reduced doses of antigen to address the current worldwide supply issue. We evaluated in rhesus macaques the immunogenicity of a quarter-dose of a standard rabies vaccine formulated with Merck's amorphous aluminum hydroxylphosphate sulfate adjuvant, the saponin-based ISCOMATRIXTM adjuvant, or a synthetic TLR9 agonist. All adjuvants significantly increased the magnitude and durability of the humoral immune response as measured by rapid fluorescent focus inhibition test (RFFIT). Several three-dose vaccine regimens resulted in adequate neutralizing antibody of >= 0.5 IU/ml earlier than the critical day seven post the first dose. Rabies vaccine with ISCOMATRIXTM adjuvant given at days 0 and 3 resulted in neutralizing antibody titers which developed faster and were up to one log10 higher compared to WHO-recommended intramuscular and intradermal regimens and furthermore, passive administration of human rabies immunoglobulin did not interfere with immunogenicity of this reduced dose, short course vaccine regimen. Adjuvantation of whole-killed rabies vaccine for intramuscular injection may therefore be a viable alternative to intradermal application of non-adjuvanted vaccine for both pre- and post-exposure regimens. PMID- 23941915 TI - Muscle hyperalgesia is widespread in patients with complex regional pain syndrome. AB - Patients with complex regional pain syndrome (CRPS) frequently show prominent sensory abnormalities in their affected limb, which may extend proximally and even to unaffected body regions. This study examines whether sensory dysfunction is observed in unaffected body parts of CRPS patients, and investigates whether the extent of dysfunction is similar for the various sensory modalities. Quantitative sensory testing was performed in the unaffected extremities and cheeks of 48 patients with CRPS of the arm (31 with dystonia), and the results were compared with values obtained among healthy controls. The most prominent abnormality was the pressure pain threshold, which showed a consistent pattern of higher sensitivity in unaffected contralateral arms and unaffected legs, as well as the cheek, and demonstrated the largest effect sizes. The cheeks of CRPS patients showed thermal hypoesthesia and hyperalgesia as well as a loss of vibration detection. Except for a lower vibration threshold in the contralateral leg of CRPS patients with dystonia, no differences in sensory modalities were found between CRPS patients with and without dystonia. These results point to a general disturbance in central pain processing in patients with CRPS, which may be attributed to impaired endogenous pain control. Since pressure pain is the most deviant sensory abnormality in both unaffected and affected body regions of CRPS patients, this test may serve as an important outcome parameter in future studies and may be used as a tool to monitor the course of the disease. PMID- 23941919 TI - Isolated increases in in-office pressure account for a significant proportion of nurse-derived blood pressure-target organ relations. AB - AIMS: We determined the extent to which relationships between nurse-derived blood pressures (BPs) and cardiovascular damage may be attributed to isolated increases in in-office SBP independent of ambulatory BP. METHODS: In 750 participants from a community sample, nurse-derived office BP, ambulatory BP, carotid-femoral pulse wave velocity (PWV; applanation tonometry and SphygmoCor software; n=662), and left ventricular mass indexed to height (LVMI; echocardiography; n=463) were determined. RESULTS: Nurse-derived office BP was associated with organ changes independent of 24-h BP (LVMI; partial r=0.15, P<0.005, PWV; partial r=0.21, P<0.0001) and day BP. However, in both unadjusted (P<0.0001 for both) and multivariate adjusted models (including adjustments for 24-h BP; LVMI; partial r=0.14, P<0.01, PWV; partial r=0.21, P<0.0001), nurse office-day SBP (an index of isolated increases in in-office BP) was associated with target organ changes independent of ambulatory BP and additional confounders, with the highest quartile (>=15 mmHg) showing the most marked increases in LVMI (P<0.0005) and PWV (P<0.0001) as compared to the lowest quartile (<-5 mmHg). These relationships were reproduced in those with normotensive day BP values and the quantitative effect of nurse office-day BP on target organ changes was at least equivalent to that of ambulatory BP. CONCLUSION: Nurse-elicited isolated increases in in-office BP account for a significant proportion of the relationship between nurse-derived BP and target organ changes independent of ambulatory BP. Therefore, high quality nurse-derived BP measurements do not approximate the impact of BP effects per se on cardiovascular damage. PMID- 23941923 TI - Stasis and adaptation. AB - Many of our most pressing societal challenges arise from our inability to move on from present practices and structures and do what is needed. Healthcare struggles to improve safety and quality. It resists adoption of best practices and persists in high levels of unwarranted variation in care delivery, and clings to financially unsustainable models of care. One explanation for this state of affairs is not a lack of will, but that we are experiencing system inertia--a consequence of the increasing complexity of our human systems. In this paper I explore three possible system level interventions that may help design systems that are less likely to approach inertia, as well as help change our current systems so that they again become adaptive, and move to the outcomes we desire. Firstly, I question our religious belief in the power of standards, an intervention designed to minimise adaptation and almost from first principles designed to lead to inertia. Next I explore the power of apoptosis, a process that sees existing structures and practices programmatically removed to free up resource for adaptation. Finally I explore a flexible but controversial approach to system management called market-based control. Whether any of these, together or in tandem, are a way out of inertia is an open question. However, it is time for us to engage with the challenge of system inertia, and find a way out. PMID- 23941918 TI - Progress in improving the lives of patients with albinism in sub-Saharan Africa. PMID- 23941927 TI - Sociotechnical systems as innovation systems in the medical and health domain. AB - It is argued that a development of healthcare systems should emerge within a healthcare providing organization and as part of daily practice instead of something implemented by a third party, in order to become successful. This sociotechnical view on system development is shared with new methods developed in the end-user development field. However, is it possible to realize this in practice? This paper explores the obstacles and potentials in the realization, leading to a discussion about sociotechnical systems as innovation systems. We describe two examples of sociotechnical innovation systems, and discuss the results from an end user driven innovation process perspective. PMID- 23941917 TI - Melanoma and rituximab: an incidental association? AB - Rituximab is an anti-CD20 monoclonal antibody increasingly used in haematology and rheumatology, but also in internal medicine and dermatology. It has a good tolerance profile without known increased risk of cancer. We report a case of nodular melanoma with a 4.8 mm Breslow thickness that appeared after 2 years of rituximab in a 45-year-old patient with non-Hodgkin lymphoma. Fifteen additional rituximab-associated melanoma cases in 13 patients have been identified in the literature and in the EudraVigilance database. These patients were treated for various indications and had melanomas, often aggressive, initially diagnosed at a metastatic stage in 31% of cases. Our work raises the question of rituximab accountability in melanoma onset in these immunosuppressed patients. A dermatological monitoring seems necessary in patients treated with rituximab, especially in case of risk factors for melanoma. In case of individual melanoma history, the benefit/risk ratio of initiating rituximab therapy should be carefully assessed. PMID- 23941926 TI - How standards will degrade the concepts of the art of medicine. AB - The paper is dealing with the problematic positioning of the whole health care system towards the concept of standard. There is a constant quest for standards, and a prediction of how everyday language gradually will disappear. It is the assumption and conjecture of this paper that as we outdo everyday language from our communication in the system we lose major part of meaning-construction concerning health and life of the patient/citizen. It is the normative and ethical aim of the discussion to frame how human factors are terminated as standards and bodies as machines replaces everyday language and bodies as carrier of health. Hans Georg Gadamer has led me on the way through inspiring essays on the Enigma of Health. PMID- 23941921 TI - Context sensitive health informatics: concepts, methods and tools. AB - Context is a key consideration when designing and evaluating health information technology (HIT) and cannot be overstated. Unintended consequences are common post HIT implementation and even well designed technology may not achieve desired outcomes because of contextual issues. While context should be considered in the design and evaluation of health information systems (HISs) there is a shortcoming of empirical research on contextual aspects of HIT. This conference integrates the sociotechnical and Human-Centered-Design (HCD) approaches and showcases current research on context sensitive health informatics. The papers and presentations outlines theories and models for studying contextual issues and insights on how we can better design HIT to accommodate different healthcare contexts. PMID- 23941924 TI - Technology-induced errors: where do they come from and what can we do about them? AB - The introduction of health information technology (HIT) has been associated with a decrease in medical error and this has been one of the main reasons for international efforts at increasing adoption of systems such as electronic health records, computerized physician order entry and clinical decision support systems. However, in recent years there is growing evidence that if not designed and tested properly such HIT can also lead to new categories of errors that were previously unseen in healthcare. These errors are known as technology-induced errors and they typically manifest themselves in the complex interaction between healthcare providers and HIT during real clinical use. In this paper the author explores the concept of technology-induced error in healthcare and discusses a range of strategies for detecting and mitigating such errors. Strategies include creating new organizations whose focus is to reduce technology-induced errors, develop and deploy new ways to detect such errors before systems are released, as well as approaches to reporting such errors after they occur. Other strategies include the development of regulation and policy to reduce such errors. It is argued that a multi-faceted approach to dealing with technology-induced error is needed. PMID- 23941928 TI - Contextualisation of clinical information from fragmented health records. AB - Traditionally health records have a source-oriented structure, as opposed to a clinically logical structure. The aim of the current study is to record and depict the clinically logical information structure built by doctors as part of their contextualisation of clinical information, to compare this structure to that of a given health record, and to assess whether a structural difference may have negative consequences. Eight doctors in a medical department were observed during contextualisation of clinical information. The method of observation included simultaneous interviews and with the technique used it was possible to depict the clinically logical information structure and compare it to the structure of the health record. The doctors' information structure was found to differ widely from the structure of the health record, causing split-attention and stress. It is concluded that the present health record is suboptimal. Further research in information support based on clinically logical structure is recommended. PMID- 23941929 TI - Clinical handover improvement in context: exploring tensions between user-centred approaches and standardisation. AB - User-centred approaches in the development and evaluation of health information systems promote the importance of involving users and understanding their social contexts to optimise the quality and safety of these systems for patient care. Simultaneously, the standardisation of clinical practices has also been advocated to improve the quality and safety of patient care. In the context of clinical handover improvement within three different departments in one tertiary teaching hospital, this paper highlights the potential for tensions between these two approaches and explores their implications. Based on a user-centred approach, the paper reports on the unique requirements identified within each of the three departments for an information system to support improved clinical handover. Each department had clinical practices, work cultures and user requirements that needed to be considered and accommodated. This led to the project developing distinct minimum data sets for each of the three departments that posed challenges for efforts to standardise handover practices across the hospital and for building an integrated information system. While on the one hand accommodating unique departmental user requirements was valuable, they revealed the potential for the introduction of quality and safety risks at the organisational level. To resolve these tensions, the project team developed an approach called flexible standardisation that has now been embedded in Australia' s national guidelines on clinical handover improvement. PMID- 23941916 TI - Human-relevant levels of added sugar consumption increase female mortality and lower male fitness in mice. AB - Consumption of added sugar has increased over recent decades and is correlated with numerous diseases. Rodent models have elucidated mechanisms of toxicity, but only at concentrations beyond typical human exposure. Here we show that comparatively low levels of added sugar consumption have substantial negative effects on mouse survival, competitive ability, and reproduction. Using Organismal Performance Assays--in which mice fed human-relevant concentrations of added sugar (25% kcal from a mixture of fructose and glucose, modeling high fructose corn syrup) and control mice compete in seminatural enclosures for territories, resources and mates--we demonstrate that fructose/glucose-fed females experience a twofold increase in mortality while fructose/glucose-fed males control 26% fewer territories and produce 25% less offspring. These findings represent the lowest level of sugar consumption shown to adversely affect mammalian health. Clinical defects of fructose/glucose-fed mice were decreased glucose clearance and increased fasting cholesterol. Our data highlight that physiological adversity can exist when clinical disruptions are minor, and suggest that Organismal Performance Assays represent a promising technique for unmasking negative effects of toxicants. PMID- 23941932 TI - Using patient-reported experiences for pharmacovigilance? AB - Recent international guidelines encourage more prominent placement of patient generated information about medications on the pharmacovigilance information landscape. Online platforms where patients share medication experiences with one another and with healthcare professionals are one possible avenue to accomplishing this goal. Public reports of medication-related events posted on the web, however, are under-utilized in the pharmacovigilance community. Moreover, little is known about who writes such reviews, what information is shared and how this information can be used by authorities. This paper reports the first results of a study of user and comment characteristics on a European based platform. PMID- 23941930 TI - A framework for reporting on human factor/usability studies of health information technologies. AB - Increasingly, studies are being published on the potential negative effect of introducing poor designed Health Information Technology (HIT) into clinical settings, relating to technology-induced errors and adverse events. Academic research on HIT design and evaluation is an extremely important source of information in providing new insights into factors contributing to successful system (re)design efforts, system user-friendliness and usability issues and safety critical aspects of HIT design. However, these studies have been inconsistent and incomprehensive in their reporting, complicating the appraisal of outcomes, generalizability of study findings, meta-analysis and harmonization of the available evidence. To improve identification of type of use errors and safety related issues regarding design and implementation of HIT, consensus on issues to be reported on in scientific publications is a necessary step forward. This study presents the first approach to a framework providing a set of principles to follow for comprehensive and unambiguous reporting of HIT design and usability evaluation studies with the objective to reduce variation, improve on the publication reporting quality and proper indexation of these studies. This framework may be helpful in expanding the knowledge base not only concerning the application of Human Factors (HF)/Usability studies of HIT but also improve the knowledge base of how to (re)design and implement effective, efficient and safe HIT. PMID- 23941920 TI - Crying in infants: on the possible role of intestinal microbiota in the development of colic. AB - Up to around a quarter of all infants cry excessively and unsoothably during their first months of life. This phenomenon has been termed "infant colic." In most cases, physicians are unable to determine the cause of the colicky behavior. In a recent study, and by means of comprehensive and deep analyses of more than 1000 intestinal phylotypes, we found that infants with colic showed lower microbiota diversity and stability than control infants in the first weeks of life. Colic-control differences in the abundance of certain bacteria were also found at 2 weeks. These microbial signatures possibly explain the colic phenotype. In this addendum we discuss other recent publications on the subject and present previously unpublished analyses of our own. We address possible mechanisms behind the links between microbiota and crying, and present future directions that could further help elucidate the hypothesized relations between intestinal microbiota and infant colic. PMID- 23941933 TI - The temporal landscape of residential aged care facilities--implications for context-sensitive health technology. AB - Health information technology (IT) can have a profound effect on the temporal flow and organisation of work. Yet research into the context, meaning and significance of temporal factors remains limited, most likely because of its complexity. This study outlines the role of communications in the context of the temporal and organizational landscape of seven Australian residential aged care facilities displaying a range of information exchange practices and health IT capacity. The study used qualitative and observational methods to identify temporal factors associated with internal and external modes of communication across the facilities and to explore the use of artifacts. The study concludes with a depiction of the temporal landscape of residential aged care particularly in regards to the way that work is allocated, prioritized, sequenced and coordinated. We argue that the temporal landscape involves key context-sensitive factors that are critical to understanding the way that humans accommodate to, and deal with health technologies, and which are therefore important for the delivery of safe and effective care. PMID- 23941935 TI - A design to empower patients in long term wellbeing monitoring and chronic disease management in mHealth. AB - With the growing population with chronic disease in most developed countries, the amount and variety of interactive medical devices adopted in healthcare and wellbeing management is on the rise. Studies show that people with chronic conditions are facing many barriers to effective self-management, which leads to significant economic losses in many countries. The question as to how we can design personal medical devices that are able to facilitate an effective self management by tackling these barriers presents a challenging research topic. We offer an overview of a controlled-experiment designed to evaluate an innovative tagging feature and a confidence of measurement feature in chronic disease management. This is a work-in-progress, which will finish by the end of June 2013. PMID- 23941934 TI - Contextual constraints for the design of patient-centered health IT tools. AB - Technologists are constantly working to improve clinical practice by developing new health information technology (Health IT) tools, yet may not always consider the context of how these tools may be used. Patient preferences can vary widely as a result of demographics, health conditions, physical limitations, and personal inclinations, with healthcare providers having to adapt clinical encounters to better suit patient needs. Health IT tools, too, need to be agile across different healthcare contexts, with each stakeholder's specific needs in mind. In this paper, we discuss the challenges and limitations associated with the design and automation of contextually sensitive devices in the healthcare environment. We target the various contexts in which health information is presented in patient-provider encounters, and discuss contextual constraints that may apply to the aforementioned situations. In addition, we present a number of suggestions for informational constraints and the design of informational tools in these settings so that patient and provider informational needs can be better met in clinical communication contexts. PMID- 23941937 TI - The usability-error ontology. AB - Clinical Systems have become standard partners with clinicians in the care of patients. As these systems become integral parts of the clinical workflow, they have the potential to help improve patient outcomes, however they have also in some cases have led to adverse events and has resulted in patients coming to harm. Often the root cause analysis of these adverse events can be traced back to Usability Errors in the Health Information Technology (HIT) or its interaction with users. Interoperability of the documentation of HIT related Usability Errors in a consistent fashion can improve our ability to do systematic reviews and meta analyses. In an effort to support improved and more interoperable data capture regarding Usability Errors, we have created the Usability Error Ontology (UEO) as a classification method for representing knowledge regarding Usability Errors. We expect the UEO will grow over time to support an increasing number of HIT system types. In this manuscript, we present this Ontology of Usability Error Types and specifically address Computerized Physician Order Entry (CPOE), Electronic Health Records (EHR) and Revenue Cycle HIT systems. PMID- 23941939 TI - Safety-oriented usability test of a semi-automated unit dose system: role of task allocation between human and machine. AB - The distribution of tasks between humans and machines in the design of healthcare systems is an important issue for patient safety. This paper presents a usability test performed to compare a semi-automated unit dose system (UDS) with the usual/manual preparation procedure for preparing and administering drugs. The results show that the UDS prevents the frequent administration errors encountered with the usual cabinets and produces a better performance in terms of time for filling the pill dispensers (6.52 sec +/- 1.1 vs. 8.5 sec +/- 1.5 (t(9, 16) = 3.12, p <.007)). But the results also stress that the UDS takes entire control of the preparation and administration tasks, thus leading to a loss of control of the process by nurses (difficulties experienced by them in resuming their actions, difficulties in memorizing drugs, lack of confidence in the UDS while they "blindly" rely on it). The distribution of tasks between the nurses and the UDS should be modified to give back control to the nurses. Design suggestions were provided in this way. For instance, the UDS may guide the nurses for the drugs localization in the cabinet but leaves the validation of the drugs to the nurses. PMID- 23941938 TI - The role of human factors when evaluating information accountability for eHealth systems. AB - The availability of health information is rapidly increasing; its expansion and proliferation is inevitable. At the same time, breeding of health information silos is an unstoppable and relentless exercise. Information security and privacy concerns are therefore major barriers in the eHealth socio-eco system. We proposed Information Accountability as a measurable human factor that should eliminate and mitigate security concerns. Information accountability measures would be practicable and feasible if legislative requirements are also embedded. In this context, information accountability constitutes a key component for the development of effective information technology requirements for health information system. Our conceptual approach to measuring human factors related to information accountability in eHealth is presented in this paper. Measuring the human factors associated with information accountability can benefit from extant theories from information systems research and business management. However, the application of such theories must clearly address the specialised nature of the application context coupled with the role of the users within the context. PMID- 23941941 TI - Information gaps in reporting patient falls: the challenges and technical solutions. AB - The emerging computerized system for patient safety event reporting eases the course of learning from medical errors and adverse events for a safer healthcare environment. To a medical event like patient falls, the course usually involves pre, during and post stages for the prediction, reporting and solution of the event. However, the reporting stage often separates from the other two stages for risk assessment and cause analysis. As this iterative flow of actions falls apart and becomes unintelligible or intangible due to information gaps, it is dubious for users to join and complete the task at all three stages in a high quality. Therefore, in this paper, by referencing studies in aspects of Norman' s task action theory and fall management programs, we proposed a gap-bridging model to describe the process of assisting users in proceeding along the stages by user centered design approaches. Based upon the model, we also developed a series of interface artifacts served as gap-bridging features, which hold promise in improving the quality of reporting and reporter engagement of the system. PMID- 23941942 TI - Extended communication possibilities for nurses: taking context into consideration. AB - Due to the versatile nature of nurses' work, whether contact requests can be initiated or received depends on the situation the nurses find themselves in. Through a qualitative study influenced by the participatory design methodology, we uncover issues with a communication system at a hospital when nurses are situated in different contexts. Based on the findings, we suggest a new system design where nurses can initiate and receive contact requests on a heterogeneous set of devices. Further, we argue that the new system should allow communication of context information to aid nurses to assert whether to engage in a communication request or not. PMID- 23941943 TI - How to co-develop services, work, and information systems in healthcare: the daisy approach. AB - Information systems in healthcare need to be designed and developed in a collaborative way. However, existing collaborative methodologies for the parallel development of healthcare work and information systems are vague and fragmented. Furthermore, they neither address people-centred healthcare nor limited-resource contexts. In this paper we introduce an emerging holistic approach, based on a unifying theoretical basis, for co-developing the services, work and information systems in healthcare. The approach intends to (a) be collaborative in nature; (b) address the domains of both healthcare professionals and ordinary people / communities; (c) span the main analysis and design tasks of socio-technical information systems development from needs assessment through requirements setting to functional-architectural solutions; (d) be contextually sensitive; and (e) be practicable in "real life" beyond research settings. PMID- 23941944 TI - Coordination considerations of healthcare information technology. AB - While health information technology (HIT) may be designed to support specific tasks the integrated nature of healthcare delivery often requires HIT to play various coordination roles. While studies have shown that coordination issues with HIT can cause adverse impacts there is little research that has looked at the specific types of coordination that HIT need to support. This paper uses a longitudinal study of a perioperative information system to identify and discuss different categories of HIT coordination. The findings can help the design and evaluation of HIT to support the coordination needs of healthcare delivery. PMID- 23941945 TI - Impact of the context of use analysis for the extension of an existing medical device: an analgesia monitor case study. AB - The EU revised Medical Device Directive introduces a major change in the CE marking of medical devices (MD) aiming at improving their safety. Manufacturers must now comply with an "ergonomics" essential requirement to prevent risks of use errors. This requirement is characterized by the integration of a usability engineering process in the MD design cycle to be documented in a usability engineering file. This study focuses on the first step of the usability engineering process, i.e. the analysis of the intended context of use of the MD, and shows the benefits of this analysis when performed early in the MD design cycle. Usability experts have conducted an analysis of the intended contexts of use for the extension of an existing device (analgesia monitor) in order to support manufacturer's design choices. Observations and interviews were carried out in two neonatology units (Maternity and Neonatology Intensive Care units) with a particular focus on pain management activities performed by physicians and nursery nurses. The results highlight irreducible differences between the two environments which led to identify different risks of use errors and specific ergonomics requirements. The results provided the manufacturer enough information to make informed decision about the extension of the device. PMID- 23941947 TI - Fidelity in clinical simulation: how low can you go? AB - Clinical simulation may be used to identify user needs for context sensitive functionalities in e-Health. The objective with this paper is to describe how user requirements and use cases in a large EHR-platform procurement may be validated by clinical simulation using a very low-fidelity prototype without any existing test data. Instead of using test scenarios and use cases, the healthcare professionals who are participating in the clinical simulation are generating both scenario and patient data themselves. We found that this approach allows for an imaginative discussion, not restricted by known functionalities and limitations, of the ideal EHR-platform. Subsequently, we discuss benefits and challenges of using an extremely low fidelity environment and discuss the degree of fidelity necessary for conducting clinical simulation. PMID- 23941949 TI - Digital communication to support clinical supervision: considering the human factors. AB - During the last three years the School of Nursing and Midwifery at the University of Tasmania has used a needs assessment survey to explore the needs of organizations and nursing professionals that facilitate and clinically supervise Bachelor of Nursing students in the workplace. Findings from the survey indicated that staff at healthcare organizations wanted a communication strategy that was easily accessible by clinicians who supervised students during work integrated learning placements. In particular they wanted to receive timely information related to the role and function of supervisors in practice. The development of the digital strategy to strengthen the development of a community of practice between the University, organizations, facilities and clinical supervisors was identified as the key method of improving communication. Blogging and micro blogging were selected as methods of choice for the implementation of the digital strategy because they were easy to set up, use and enable equity of access to geographically dispersed practitioners in urban and rural areas. Change champions were identified to disseminate information about the strategy within their workplaces. Although clinicians indicated electronic communication as their preferred method, there were a number of human factors at a systems and individual level identified to be challenges when communicating with clinical supervisors who were based off-campus. Information communication technology policies and embedded culture towards social presence were impediments to using this approach in some organizations. Additionally, it was found that it is necessary for this group of clinicians to be educated about using digital methods to undertake their role as clinical supervisors in their varied clinical practice environments. PMID- 23941948 TI - Using clinical and computer simulations to reason about the impact of context on system safety and technology-induced error. AB - This paper describes how simulations can be used to reason about the impact of user interface design features in exploring the effect of different contexts of use on the occurrence of technology-induced errors. The paper describes our approach in several phases, using an example from the analysis of technology induced errors in medication administration. In the initial phase a clinical simulation is conducted to gather baseline data on the occurrence of technology induced error using the technology under study. In this phase of the study, data arising from the clinical simulation are collected and then analyzed using qualitative and quantitative approaches to assess the relationship between aspects of interface design (i.e. usability problems) and rates of technology induced error. In the next phase, the base rates for error associated with specific types of usability problems (from the initial phase) form the input into computer-based mathematical simulations. This approach links clinical simulations with computer-based simulations and demonstrates the potential impact of aspects of interface design and contextual factors upon medical error along with the implications for correcting interface design issues. PMID- 23941950 TI - Exploring the contextual and human factors of electronic medication reconciliation research: a scoping review. AB - Medication reconciliation (MedRec) is an important task that occurs in a variety of different contexts. Similar to other healthcare practices, MedRec is transitioning from being a paper-based process to one that is performed electronically. This paper will provide a scoping review of the prevalent research topics from both contextual and human factors perspectives. METHODS: PubMed and CINAHL were searched for all articles including the term "medication reconciliation". The 139 articles that met inclusion criteria were reviewed for themes and findings. RESULTS: Three primary themes surfaced through this analysis: a) The contextual factors of MedRec, b) information technology (IT) in MedRec, and c) obstacles and opportunities for improving MedRec. DISCUSSION: MedRec is performed in a variety of settings. The transition to electronic MedRec (eMedRec) has the potential to mitigate errors associated with a paper-based system but also creates opportunities for new technology-induced errors to occur. Interoperability with other health information systems is ideal. Additionally, Process standardization and workflow are important considerations when transitioning to eMedRec. CONCLUSION: As the process of medication reconciliation transitions from a paper-based to an electronic task, it is imperative to minimize the opportunity for human error and maximize the effectiveness of the system as a whole. Further, it is important for research to continue to explore original strategies for IT to enhance medication reconciliation. PMID- 23941951 TI - Clinical simulation as a boundary object in design of health IT-systems. AB - Healthcare organizations are very complex, holding numerous stakeholders with various approaches and goals towards the design of health IT-systems. Some of these differences may be approached by applying the concept of boundary objects in a participatory IT-design process. Traditionally clinical simulation provides the opportunity to evaluate the design and the usage of clinical IT-systems without endangering the patients and interrupting clinical work. In this paper we present how clinical simulation additionally holds the potential to function as a boundary object in the design process. The case points out that clinical simulation provides an opportunity for discussions and mutual learning among the various stakeholders involved in design of standardized electronic clinical documentation templates. The paper presents and discusses the use of clinical simulation in the translation, transfer and transformation of knowledge between various stakeholders in a large healthcare organization. PMID- 23941953 TI - Essential questions: accuracy, errors and user perceptions in a drag/drop user composable electronic health record. AB - In previous work we have described the creation and user testing of a drag/drop user-composable electronic health record, MedWISE. Any new design poses new potential problems; here we discuss the accuracy, potential for new types of errors, and user reactions to the approach, including their perceptions of ease of use and usefulness. Our results come from a mixed methods laboratory study with 18 clinicians at a large academic medical center. 12 used MedWISE and 6 used the conventional system. MedWISE users had comparable assessment accuracy to use of the conventional system, low (1/10) risk of diagnosis momentum error, and overall favorable and even enthusiastic user perception. 10/12 said the system eased their cognitive process, Ease of use and usefulness were rated 3.79 and 4.00 on a 5-point Likert scale. Users were unconcerned about the possibility of increased errors due to their trust in colleagues and system similarities to current practice. After first describing the issues, we suggest a method to elucidate risks in innovative and current systems. PMID- 23941954 TI - Understanding the information dynamics of medication administration in residential aged care facilities (RACFs): a prerequisite for design of effective ICT systems. AB - Medication information is a critical part of the information required to ensure residents' safety in the highly collaborative care context of RACFs. Studies report poor medication information as a barrier to improve medication management in RACFs. Research exploring medication work practices in aged care settings remains limited. This study aimed to identify contextual and work practice factors contributing to breakdowns in medication information exchange in RACFs in relation to the medication administration process. We employed non-participant observations and semi-structured interviews to explore information practices in three Australian RACFs. Findings identified inefficiencies due to lack of information timeliness, manual stock management, multiple data transcriptions, inadequate design of essential documents such as administration sheets and a reliance on manual auditing procedures. Technological solutions such as electronic medication administration records offer opportunities to overcome some of the identified problems. However these interventions need to be designed to align with the collaborative team based processes they intend to support. PMID- 23941955 TI - Using personas as an intermediate construct in the development of tailored messages: a case study. AB - Tailoring health education messages to patients' preferences for message style is believed to increase patients' susceptibility to the given advice. This paper presents a persona-centered approach towards creating tailored health messages for chronically ill patients. A case study of tailoring messages to the preferences of patients with coronary heart disease illustrates the approach and shows the need for patient-centered data collection so that personas reflect patients' preferences. Based on these personas, a manageable set of tailored messages can be created in a step-by-step approach. PMID- 23941956 TI - Collecting data in real time with postcards. AB - The success of information technology (IT) in transforming healthcare is often limited by the lack of clear understanding of the context at which the technology is used. Various methods have been proposed to understand healthcare context better in designing and implementing Health Information Systems. These methods often involve cross-sectional, retrospective data collection. This paper describes the postcard method for prospective real-time data collection, both in paper format and electronic format. This paper then describes the results obtained using postcard techniques in Denmark and Australia. The benefits of this technique are illustrated. There are limitations in using postcard techniques and this paper provides a detail discussion about these limitations. Postcard techniques provide unique advantages in understanding real time healthcare context and it is an important technique to consider in IT design and implementation in healthcare. PMID- 23941960 TI - Co-administration of flagellin augments immune responses to inactivated foot-and mouth disease virus (FMDV) antigen. AB - Foot-and-mouth disease virus (FMDV) is one of the most contagious animal virus known that affects livestock health and production. This study aimed to investigate the effect of flagellin, a toll-like receptor 5 agonist, on the immune responses to inactivated FMDV antigen in guinea pig model. Our results showed that the co-administration of flagellin with FMDV antigen through intradermal route induces earlier and higher anti-FMDV neutralizing antibody responses as compared to FMDV antigen alone. Both IgG1 and IgG2 antibody-isotype responses were enhanced, but the IgG1/IgG2 ratios were relatively low, indicative of TH1 type of immune activation. On live viral challenge, flagellin+FMDV immunized guinea pigs showed 70% (7 out of 10) protection rate as compared to 40% (4 out of 10) in FMDV alone immunized guinea pigs. The results demonstrate that the co-administration of flagellin augments immune responses (preferably TH1 type) and protective efficacy against FMDV in guinea pigs. PMID- 23941961 TI - Mutant prevention concentration and PK-PD relationships of enrofloxacin for Pasteurella multocida in buffalo calves. AB - This study validated the use of mutant prevention concentration (MPC) and pharmacokinetic and pharmacodynamic (PK-PD) modeling approach for optimization of dose regimen of enrofloxacin to contain the emergence of Pasteurella multocida resistance. The PK and PD characteristics of enrofloxacin were investigated in buffalo calves after intramuscular administration at a dose rate of 12 mg/kg. The concentration of enrofloxacin and ciprofloxacin in serum were determined by high performance liquid chromatography. The serum peak concentration (Cmax), terminal half-life (t1/2K10), volume of distribution (Vd(area)/F) and mean residence time (MRT) of enrofloxacin were 1.89 +/- 0.35 MUg/ml, 5.14 +/- 0.66 h, 5.59 +/- 0.99 l/kg/h and 8.52 +/- 1.29 h, respectively. The percent metabolite conversion ratio of ciprofloxacin to enrofloxacin was 79. The binding of enrofloxacin to plasma proteins was 11%. The MIC, MBC and MPC for enrofloxacin against P. multocida were 0.05, 0.06 MUg/ml and 1.50 MUg/ml.In vitro and ex-vivo bactericidal activity of enrofloxacin was concentration dependent. Modeling of ex-vivo growth inhibition data to the sigmoid Emax equation provided AUC24h/MIC values to produce bacteriostatic (19 h), bactericidal (43 h) and bacterial eradication (64 h). PK PD data in conjunction with MPC and MIC90 data predicted dosage schedules for enrofloxacin that may achieve optimum efficacy in respect of bacteriological and clinical cure and minimize the risk of emergence of resistance. PMID- 23941962 TI - Expression of beta2 adrenoceptors within enteric neurons of the horse ileum. AB - The activity of the gastrointestinal tract is regulated through the activation of adrenergic receptors (ARs). Since data concerning the distribution of ARs in the horse intestine is virtually absent, we investigated the distribution of beta2-AR in the horse ileum using double-immunofluorescence. The beta2-AR-immunoreactivity (IR) was observed in most (95%) neurons located in submucosal plexus (SMP) and in few (8%) neurons of the myenteric plexus (MP). Tyrosine hydroxylase (TH)-IR fibers were observed close to neurons expressing beta2-AR-IR. Since beta2-AR is virtually expressed in most neurons located in the horse SMP and in a lower percentage of neurons in the MP, it is reasonable to retain that this adrenergic receptor could regulate the activity of both secretomotor neurons and motor neurons innervating muscle layers and blood vessels. The high density of TH-IR fibers near beta2-AR-IR enteric neurons indicates that the excitability of these cells could be directly modulated by the sympathetic system. PMID- 23941963 TI - Karyotypically abnormal human ESCs are sensitive to HDAC inhibitors and show altered regulation of genes linked to cancers and neurological diseases. AB - Genomic abnormalities may accumulate in human embryonic stem cells (hESCs) during in vitro maintenance. Characterization of the mechanisms enabling survival and expansion of abnormal hESCs is important due to consequences of genetic changes for the therapeutic utilization of stem cells. Furthermore, these cells provide an excellent model to study transformation in vitro. We report here that the histone deacetylase proteins, HDAC1 and HDAC2, are increased in karyotypically abnormal hESCs when compared to their normal counterparts. Importantly, similar to many cancer cell lines, we found that HDAC inhibitors repress proliferation of the karyotypically abnormal hESCs, whereas normal cells are more resistant to the treatment. The decreased proliferation correlates with downregulation of HDAC1 and HDAC2 proteins, induction of the proliferation inhibitor, cyclin-dependent kinase inhibitor 1A (CDKN1A), and altered regulation of tumor suppressor protein Retinoblastoma 1 (RB1). Through genome-wide transcriptome analysis we have identified genes with altered expression and responsiveness to HDAC inhibition in abnormal cells. Most of these genes are linked to severe developmental and neurological diseases and cancers. Our results highlight the importance of epigenetic mechanisms in the regulation of genomic stability of hESCs, and provide valuable candidates for targeted and selective growth inhibition of karyotypically abnormal cells. PMID- 23941964 TI - Modelling amyloid fibril formation kinetics: mechanisms of nucleation and growth. AB - Amyloid and amyloid-like fibrils are self-assembling protein nanostructures, of interest for their robust material properties and inherent biological compatibility as well as their putative role in a number of debilitating mammalian disorders. Understanding fibril formation is essential to the development of strategies to control, manipulate or prevent fibril growth. As such, this area of research has attracted significant attention over the last half century. This review describes a number of different models that have been formulated to describe the kinetics of fibril assembly. We describe the macroscopic implications of mechanisms in which secondary processes such as secondary nucleation, fragmentation or branching dominate the assembly pathway, compared to mechanisms dominated by the influence of primary nucleation. We further describe how experimental data can be analysed with respect to the predictions of kinetic models. PMID- 23941965 TI - Canine visceral leishmaniasis: incidence and risk factors for infection in a cohort study in Brazil. AB - Zoonotic visceral leishmaniasis in Brazil is caused by Leishmania infantum parasites and is transmitted by sand flies of the Phlebotominae family. Dogs are the main urban reservoirs and represent the major source of contagion for the vectors. Studies have shown that most infected dogs are polymerase chain reaction positive months before seroconversion. Herein, we describe a cohort study designed to identify the incidence of and risk factors for L. infantum infection as detected by polymerase chain reaction-restriction fragment length polymorphism. To determine the risk factors for infection, we conducted a baseline canine survey (n=1443) from which dogs were selected for the cohort study (n=282) involving three evaluations over the course of a 26-month follow-up period. Serology, molecular tests, and a structured questionnaire were used. The risk factors for infection were identified by means of the Cox regression model. The overall infection incidence was 5.8 per 100 dog-months (95% confidence interval 5.1-6.5). Increased risk of infection was associated with the presence of previous cases of canine visceral leishmaniasis in the domiciles (hazard ratio [HR] 1.4; 95% confidence interval [CI] 1.1-1.8) and unplastered house walls (HR 3.6; 95% CI 1.6-8.1). These risk factors suggest that insecticide spraying in cracks and crevices in unplastered walls can reduce biting rates within and around homes. Furthermore, our results demonstrate that the Visceral Leishmaniasis Control and Surveillance Program should adopt environmental management measures in homes with previous cases of canine visceral leishmaniasis, because these homes are more likely to maintain the transmission cycle. PMID- 23941966 TI - Spontaneous neonatal arterial thromboembolism: infants at risk, diagnosis, treatment, and outcomes. AB - Neonatal spontaneous arterial thromboembolism is a rare phenomenon with a high risk of morbidity and mortality. Currently, there is little information regarding common risk factors, diagnostic strategies, therapeutic interventions, and outcomes of this condition. The objective was to nucleate the best evidence regarding the disorder in order to facilitate early detection and treatment recommendations and document adverse outcomes. Web of Science, PubMed, Medline, CINAHL, Cochrane Databases, DARE, and OVID databases were searched using the following keywords: 'arterial' AND 'thrombus' OR 'thrombosis' OR 'thromboembolism' OR 'embolism' AND 'spontaneous' AND 'at birth' OR 'newborn' OR 'neonatal' OR 'fetal' AND 'umbilical cord' OR 'umbilical wall necrosis' AND 'coagulation abnormality' OR 'placenta bits' OR 'ischemic limbs'. The search yielded 172 articles, all of which were case series or single case descriptions. Twenty-seven met inclusion criteria, with a total of 53 newborns and 30 newborn pathology reports. Ultrasound was the preferred method of diagnosis and thromboembolic locations varied with the most common site being umbilical, resulting in embolism and vascular compromise. Treatment interventions and drug dosages were not standardized and ranged from use of anticoagulants to surgery and hyperbaric oxygen. The reported mortality rate was 32.8%. Recurring etiological features facilitated identification of possible sequences of events contributing to the disorder. The literature lacks empirical evidence to affirm causes and predisposing risk factors for timely diagnosis and effective treatment of spontaneous neonatal arterial thromboembolism. Further research is needed to clearly establish the causes and the efficacy of specific treatment options. PMID- 23941967 TI - Relationships of glycoproteins IIb-IIIa and Ib content with mean platelet volume and their genetic polymorphisms. AB - Quantity of platelet adhesion molecules significantly varies in normal donors and cardiovascular patients and might be affected by platelet size and genetic variations. In this study, we assessed relationships of the content of glycoprotein (GP) IIb-IIIa and GPIb with mean platelet volume (MPV) and their genetic polymorphisms. MPV and GPIIb-IIIa and GPIb numbers were measured in 116 patients with acute coronary syndrome (ACS) at days 1, 3-5 and 8-12 after disease onset and in 32 healthy volunteers. GPIIb-IIIa and GPIb allelic variants were determined in ACS patients. Strong interactions of GPIIb-IIIa and GPIb numbers and MPV were observed in ACS patients and healthy volunteers. In patients, coefficients of correlation (r) were 0.642 and 0.510 (analysis of individual mean values) and in volunteers - 0.594 and 0.508 for GPIIb-IIIa and GPIb, respectively (everywhere P < 0.005). In ACS patients, correlations were highly significant at each tested time point. GPIIb-IIIa and GPIb genetic polymorphisms [GPIIIa Leu33Pro, GPIbalpha Thr145Met and GPIbalpha (-5)T/C (Kozak)] determined in ACS patients had no significant impact on their expression. Modest correlation was revealed between MPV and plasma thrombopoietin (TPO) measured at the first day of ACS (r = 0.279, P = 0.005). The data obtained indicated that GPIIb-IIIa and GPIb levels are mainly affected by platelet size (MPV) but not by their genetic variations. In some ACS patients, production of large platelets with high GPIIb IIIa and GPIb contents might be stimulated by elevated TPO. PMID- 23941968 TI - Budd-Chiari syndrome in very young adult patients with polycythemia vera: report of case series with good outcome with direct thrombin inhibitor treatment. AB - Polycythemia vera is a Philadelphia chromosome-negative myeloproliferative disorder with incidence of 1% under the age of 25. The Budd-Chiari syndrome (BCS) is a well known complication of polycythemia vera even in children, and characterized by occlusion of hepatic outflow. A computerized archive search of medical records at Sheba Medical Center of the past three decades of patients with polycythemia vera and BCS under the age of 25 years was performed. A work-up for JAK2 V617F mutation and thrombophilia was done. Medical charts and imaging tests were carefully reviewed. Three patients under the age of 22 were finally recruited. Two of those were found in life-threatening condition and improved clinically following treatment with bivalirudin, a direct thrombin inhibitor. It is conceivable that bivalirudin contributed to a favorable outcome of those patients in comparison to historical outcome previously reported. In conclusion, polycythemia vera in the young is not a mild disease since BCS, which is one of its complication, can be fatal even in those age group unrelated to the presence of hereditary thrombophilia. Once BCS occurs, we would suggest giving a trial with bivalirudin before an invasive procedure is planned. PMID- 23941970 TI - Ascending transaqueductal cystoventriculoperitoneal shunting in Dandy-Walker malformation: technical note. AB - The optimal treatment for Dandy-Walker malformation is still controversial. Ventriculoperitoneal shunting, cystoperitoneal shunting or combinations are the most common surgical options in the management of this clinical entity. Endoscopic procedures like ventriculocystostomy, 3rd ventriculostomy or endoscopy assisted shunt surgeries have become the focus of recent publications. We describe a new transcystic endoscopic technique, with the usage of a single ascending transaqueductal shunt catheter with additional holes, whereby both the posterior fossa cyst and supratentorial ventricular compartments are drained effectively. By using this new technique complications associated with combined shunting can be avoided. In addition, by equalizing the pressure within the supra and infratentorial compartments, the upward or downward herniations associated with single-catheter shunting can be prevented. PMID- 23941969 TI - Eating disorder pathology in adolescents participating in a lifestyle intervention for obesity: associations with weight change, general psychopathology and health-related quality of life. AB - OBJECTIVE: The aim of this study was to identify the prevalence of eating disorder symptoms in obese adolescents participating in a lifestyle intervention for weight loss and to investigate possible relationships with weight change, general psychopathology, and health-related quality of life (HRQOL). METHOD: At the beginning and after completion of a 6-month lifestyle intervention, 41 participants (20 females; age: 13.7 +/- 1.4 years) reported on core symptoms of eating disorders (SCOFF), self-esteem (Rosenberg Self-Esteem Scale, RSES), and HRQOL (Questionnaire for Measuring Health-Related Quality of Life in Children and Adolescents, KINDL), while parents filled in a questionnaire assessing their children's internalizing and externalizing behavioral problems (Child Behavior Checklist, CBCL). RESULTS: Compared to age-matched normative samples, patients showed increased behavior problems and an impaired HRQOL. 43% of the patients were screened positive for an eating disorder pathology, and this subgroup showed an increased psychopathological burden compared to patients that were screened negative. The lifestyle intervention resulted in a significant weight loss which was unaffected by the presence of an eating disorder pathology. The screening rate for eating disorders remained stable after the intervention. CONCLUSION: The large overlap, mutual interaction, and high burden of eating and weight problems in children and adolescents underpin the need for an integrated view in both prevention and treatment approaches in pediatric obesity. PMID- 23941971 TI - Scanning electron microscopy studies of neoformations on stony materials of modern building works. AB - The built environment is subjected to several pollutants under variable environmental conditions defined by diverse geochemical systems. These geochemical systems promote the occurrence of neoformations that can have a detrimental effect on surfaces of the building materials. Hence, the study of neoformations helps in the understanding of weathering processes that affect built structures. In the present paper we present a scanning electron microscopy study of macroscopic manifestations of neoformations detected during an extensive visual survey of several modern architectural works in urban areas of northern and central Portugal. The studies performed suggest that cementitious materials play an important role as a source of pollutants for the most common neoformations such as carbonate rich stains and coatings, as well as salt efflorescences of alkaline sulphates and carbonates. There are also indications of contributions from organic sources for alkaline nitrates and atmospheric pollution for gypsum-rich black crusts. Other less common neoformations include phosphate aggregates and silica stains that represent interesting indicators of the geochemical systems in built environments. In the case of carbonate-rich coatings, indications of recurrence related to the circulation of carbonate forming solutions relevant to the maintenance of built surfaces were detected. PMID- 23941972 TI - Cognitive reserve: implications for assessment and intervention. AB - The concept of reserve is used to explain the observation that some individuals function better than others in the presence of brain pathology. This article reviews the concept of reserve from its theoretical basis to the implication of reserve for clinical practice. A distinction between brain reserve, referring to individual differences in the anatomic substrate, and cognitive reserve, referring to differences in the flexibility or adaptivity of cognitive networks, is useful. Epidemiologic evidence indicates that a set of life exposures including higher educational and occupational attainment, and engaging in leisure activities is associated with a lower risk of incident dementia, suggesting that these life exposures may enhance cognitive reserve. This provides a basis for controlled clinical studies that can test specific exposures that may enhance reserve. The concept of cognitive reserve also has important implications for clinical practice in terms of diagnosis and prognosis. PMID- 23941974 TI - Screening for Cronobacter species in powdered and reconstituted infant formulas and from equipment used in formula preparation in maternity hospitals. AB - BACKGROUND/AIMS: Cronobacter spp. have been identified as being of considerable risk to neonates. The occurrence of organisms in infant formulas is therefore of considerable interest. METHODS: The occurrence of Cronobacter spp. in infant feeds (formulas and fortified cow's milk) was determined using most probable number (MPN) analysis, and from formula preparation utensils. Ninety-nine samples were analyzed, of which 42 were unopened cans of powdered infant formula (PIF), 25 reconstituted infant formulas in feeding bottles, 27 utensils used in the preparation of infant formula and 5 samples of fortified cow's milk. Presumptive Cronobacter spp. isolates were identified using the 7 allele multilocus sequence typing (MLST) scheme. RESULTS: C. sakazakii, C. malonaticus and C. muytjensii were recovered from PIF. Although the incidence of Cronobacter in PIF was 29% (12/42), the level was low with an average of 0.54 MPN/100 g. According to MLST profiling, C. sakazakii was the most frequently isolated Cronobacter species, and C. sakazakii ST4 (associated with neonatal meningitis) was recovered from 2/42 PIF samples at 0.51 and 0.92 MPN/100 g. CONCLUSIONS: Cronobacter spp. can be isolated from PIF and therefore strict hygienic practices during PIF preparation are important to minimize neonate exposure and reduce the risk of severe infections. PMID- 23941973 TI - Forecasting flowering phenology under climate warming by modelling the regulatory dynamics of flowering-time genes. AB - Understanding how climate warming has an impact on the life cycle schedule of terrestrial organisms is critical to evaluate ecosystem vulnerability to environmental change. Despite recent advances identifying the molecular basis of temperature responses, few studies have incorporated this knowledge into predictive models. Here we develop a method to forecast flowering phenology by modelling regulatory dynamics of key flowering-time genes in perennial life cycles. The model, parameterized by controlled laboratory experiments, accurately reproduces the seasonal changes in gene expression, the corresponding timing of floral initiation and return to vegetative growth after a period of flowering in complex natural environments. A striking scenario forecast by the model under climate warming is that the shift in the return time to vegetative growth is greater than that in floral initiation, which results in a significant reduction of the flowering period. Our study demonstrates the usefulness of gene expression assessment to predict unexplored risks of climate change. PMID- 23941975 TI - Food and water deprivation disrupts latent inhibition with an auditory fear conditioning procedure. AB - Latent inhibition (LI), operationally defined as the reduced conditioned response to a stimulus that has been preexposed before conditioning, seems to be determined by the interaction of different processes that includes attentional, associative, memory, motivational, and emotional factors. In this paper we focused on the role of deprivation level on LI intensity using an auditory fear conditioning procedure with rats. LI was observed when the animals were non deprived, but it was disrupted when the rats were water- or food-deprived. We propose that deprivation induced an increase in attention to the to-be-CS, and, as a result, LI was disrupted in deprived animals. The implications of the results for the current interpretations of LI are also discussed. PMID- 23941976 TI - Seasonal variations in behaviour of thermoregulation in juveniles and adults Liolaemus lutzae (Squamata, Liolaemidae) in a remnant of Brazilian restinga. AB - Adaptations of lizards inhabiting hot arid environments should include mechanisms of behavioural thermoregulation. In contrast, in environments with lower temperatures lizards tend to behave as thermoconformers. Herein we aim to infer thermoregulatory behaviours exhibited by Liolaemus lutzae (a lizard species endemic to restingas in the coast of the state of Rio de Janeiro, Brazil) in two different seasonal thermal environments. In the dry season, the body temperatures (Tb) of the lizards were higher than air temperature (Ta) and similar to substrate temperature (Ts), suggesting thermoconformer thermoregulatory behaviour using Ts. During the rainy season, the higher percentage of negative values of DeltaTs (=Tb-Ts) and DeltaTa (=Tb-Ta) and the tendency for lower Tb compared to Ts suggest a more active behavioural thermoregulation in that season. The DeltaTs was higher for juveniles in the rainy season, suggesting that youngest lizards tended to thermoregulate more actively regarding to Ts than adults. L. lutzae probably survives under high Ts due to the behaviour of the individuals sheltering inside burrows or under detritus and burying themselves into the sand. This behavioural flexibility may potentially reduce variations in Tb of active lizards in changing thermal environments both during the daily cycle and between seasons. PMID- 23941977 TI - Efficient liver gene transfer with foamy virus vectors. AB - BACKGROUND: Liver gene transfer offers hope for the correction of genetic and acquired disorders. Efficient gene transfer in large animals can be obtained with hydrodynamic gene transfer (HGT), a method that can achieve sufficient levels of gene delivery. MATERIAL AND METHODS: To test the relative efficiency between plasmid versus foamy virus (FV) vector-based liver gene transfer efficiency, we applied HGT in 4 juvenile pigs, using the same plasmid backbone, either naked or coated as a FV vector particle. Gene transfer efficiency and persistence of expression was assayed by PCR and real-time PCR, respectively, at 1 week and at 1 month after the infusions. RESULTS: HGT was tolerated well and no adverse reactions were observed. Plasmid injections resulted in no detectable DNA sequences at 1 week. At the 1 month time point, 2/15 liver sections analyzed were positive for the presence of plasmid DNA. When FV vectors were infused under identical conditions, 18/28 (64.3%) of the liver samples were positive for the presence of vector sequences, and the expression levels reached 29.7 and 15.6% of the endogenous GAPDH levels in the injected and the adjacent liver lobes. CONCLUSIONS: Our results indicate that medium-term therapeutic levels of gene expression can be obtained with FV vectors, an effect that can be attributed to the potential of the HGT procedure and to the natural affinity of FV vectors for hepatocytes. PMID- 23941978 TI - A novel adjuvant-free H fusion system for the production of recombinant immunogens in Escherichia coli: Its application to a 12 kDa antigen from Cryptosporidium parvum. AB - The production of recombinant antigens in Escherichia coli and specific polyclonal antibodies for diagnosis and therapy is still a challenge for world wide researchers. Several different strategies have been explored to improve both antigen and antibody production, all of them depending on a successful expression and immunogenicity of the antigen. Gene fusion technology attempted to address these challenges: fusion partners have been applied to optimize recombinant antigen production in E. coli, and to increase protein immunogenicity. Taking a 12-kDa surface adhesion antigen from Cryptosporidium parvum (CP12) by example, the novel H fusion partner was presented in this work as an attractive option for the development of recombinant immunogens and its adjuvant-free immunization. The H tag (of only 1 kDa) efficiently triggered a CP12-specific immune response, and it also improved the immunization procedure without requiring co-administration of adjuvants. Moreover, polyclonal antibodies raised against the HCP12 fusion antigen detected native antigen structures displayed on the surface of C. parvum oocysts. The H tag proved to be an advanced strategy and promising technology for the diagnosis and therapy of C. parvum infections in animals and humans, allowing a rapid and simple recombinant production of the CP12 antigen. PMID- 23941980 TI - Association of Asef and Cdc42 expression to tubular injury in diseased human kidney. AB - BACKGROUND: Cdc42 is a small guanosine-5'-triphosphatase of the Rho family and plays essential roles in the establishment of cellular polarity and tight junctions in epithelial cells. Adenomatous polyposis coli-associated exchange factor (Asef) is a canonical guanine nucleotide exchange factor of Cdc42 and renders Cdc42 to be guanosine-5'-triphosphate bound and activated. The expression patterns and their significance in human renal diseases are unknown. METHODS: We examined the expression of Cdc42 and Asef in kidney biopsy specimens of 15 patients and in normal kidney tissue using immunofluorescence and correlated the expression patterns with the clinical characteristics. We also analyzed the coexpression pattern of Ki-67, a marker indicating cell division, and Asef in selected patients. RESULTS: Expression of Asef and Cdc42 together was associated with tubular injury with 100% specificity. Expression of Asef, regardless of Cdc42, also showed a significant diagnostic odds ratio for the presence of the injury. Expression of Asef was associated with lower estimated glomerular filtration rate at the time of biopsy and larger area of interstitial fibrosis. All Ki-67-expressing tubular cells expressed Asef. CONCLUSIONS: Induction of Asef and Cdc42 in the renal tubules is a cellular response to injury. Asef induction seems a necessary step for injured tubular cells to enter cell cycle. PMID- 23941979 TI - Association of genetic polymorphisms with histological grading of necroinflammation, staging of fibrosis, and liver function in Mexicans with chronic hepatitis C virus infection. AB - BACKGROUND/AIM: The aim of this work was to establish an association between the single-nucleotide polymorphisms (SNPs) of TGFB1 (rs1800471), AT (rs3789679), MMP 1 (rs17886084), MMP-3 (rs35068180), and PAI-1 (rs1799889) and the histological grading of necroinflammation, staging of hepatic fibrosis, and liver function in Mexican patients with advanced liver fibrosis due to chronic hepatitis C virus infection. METHODS: AT, MMP-1, MMP-3, and PAI-1 gene polymorphisms were analyzed by polymerase chain reaction in real time, whereas TGFB1 polymorphism was detected by polymerase chain reaction-based restriction fragment length polymorphism in 38 patients with established advanced liver fibrosis and 50 subjects from the general population. Grading of necroinflammation and staging of liver fibrosis were assessed by liver biopsy and graded according to modified histological activity index Ishak score. RESULTS: Regarding TGFB1 SNP, significant differences were found between G/G and G/C genotypes of patients with hepatic necroinflammation (P = 0.05) and hepatic fibrosis (P = 0.002). There were also significant differences among genotypes of patients with the AT SNP in hepatic necroinflammation (P = 0.01). The albumin-globulin ratio between genotypes of patients with the MMP-3 SNP gene showed significant differences (P = 0.02). CONCLUSION: Our findings demonstrate that a specific combination of genotypes associated with biochemical values and a histological high score determine more severe liver disease. The presence of the G/G genotype of TGFB1 SNP in patients was significantly associated with severity of liver necroinflammation and fibrosis. Patients with the G/G genotype of AT SNP were associated with severe necroinflammation. The albumin-globulin ratio was increased in patients with the 6A allele of MMP-3 SNP. These results might contribute to diagnosis and further establishment of liver disease treatment. PMID- 23941981 TI - Association of a novel polymorphism of the beta2-chimaerin gene (CHN2) with smoking. AB - OBJECTIVE: The CHN2 gene encodes the beta2-chimaerin, a Rac-specific guanosine-5' triphosphatase activating protein with an important role in the establishment of functional brain circuitry by controlling axon pruning. Genetic studies suggest that the CHN2 gene harbors variants that contribute to addiction vulnerability and smoking behavior. To further evaluate the role of beta2-chimaerin in nicotine addiction, we investigated the association of 3 individual polymorphisms of the CHN2 gene with smoking dependence. METHODS: Three hundred sixty-one healthy volunteers, 173 smokers (mean +/- SD age, 60.4 +/- 1.4 years) and 188 control subjects (mean +/- SD age, 45.9 +/- 1.4 years) were genotyped for 3 single nucleotide polymorphisms in the CHN2 gene (rs3750103, rs12112301, and rs186911567). The association of these polymorphisms with smoking habits was analyzed. RESULTS: There was no significant association of polymorphisms rs12112301 and rs3750103 with smoking. However, there was a significant difference in the frequency of the rs186911567 polymorphism between the smokers and the controls (P = 0.003). CONCLUSIONS: We report for the first time a significant association of the novel rs186911567 polymorphism of the CHN2 gene with smoking. PMID- 23941982 TI - Fatty acids production from hydrogen and carbon dioxide by mixed culture in the membrane biofilm reactor. AB - Gasification of waste to syngas (H2/CO2) is seen as a promising route to a circular economy. Biological conversion of the gaseous compounds into a liquid fuel or chemical, preferably medium chain fatty acids (caproate and caprylate) is an attractive concept. This study for the first time demonstrated in-situ production of medium chain fatty acids from H2 and CO2 in a hollow-fiber membrane biofilm reactor by mixed microbial culture. The hydrogen was for 100% utilized within the biofilms attached on the outer surface of the hollow-fiber membrane. The obtained concentrations of acetate, butyrate, caproate and caprylate were 7.4, 1.8, 0.98 and 0.42 g/L, respectively. The biomass specific production rate of caproate (31.4 mmol-C/(L day g-biomass)) was similar to literature reports for suspended cell cultures while for caprylate the rate (19.1 mmol-C/(L day g biomass)) was more than 6 times higher. Microbial community analysis showed the biofilms were dominated by Clostridium spp., such as Clostridium ljungdahlii and Clostridium kluyveri. This study demonstrates a potential technology for syngas fermentation in the hollow-fiber membrane biofilm reactors. PMID- 23941983 TI - The potential for self-sanitisation of faecal sludge by intrinsic ammonia. AB - Faecal sludge has the potential to be used as a sustainable fertiliser in agriculture, but the sludge must be sanitised due to its content of pathogenic microorganisms. The intrinsic ammonia from the urine may be sufficient for sanitisation of the sludge if it is not too diluted by flush water or lost by ventilation. To evaluate the potential for this sanitisation method, inactivation of Enterococcus faecalis, Salmonella typhimurium and Ascaris suum eggs during treatment were assessed. The inactivation was studied at different storage temperatures (10-28 degrees C) and in several sludge mixes with different contents of urine, faeces and flush water, and with ammonia concentrations from 40 to 400 mM. All pathogens were inactivated by the ammonia, and ascaris eggs were the most persistent. Lower flush water volume and higher urine content favoured inactivation, mainly due to increased uncharged ammonia (NH3) concentration. The lag phase in ascaris inactivation was shortened by increasing temperature and NH3 concentration, while post-lag phase inactivation was not influenced by NH3 concentration. Faecal sludge can be sanitised by airtight storage without the use of additives when flush water volumes are sufficiently low. For temperatures of 23-28 degrees C, a 3 log reduction of ascaris egg viability can be achieved within 1-6 months depending on ammonia concentration and temperature. PMID- 23941984 TI - Physiological challenges for intracortical electrodes. AB - The clinical use of chronic electrode implants for measurement or stimulation of neuronal activity has increased over the past decade with the advent of deep brain stimulation and the use of brain-computer interfaces. However, despite the wide-spread application of electrode implants, their chronic use is still limited by technical difficulties. Many of the reported issues, ranging from short circuits to loss of signal due to increased electrical impedance, may be traced back to the reaction of the cortical tissue to the implanted devices: the foreign body response (FBR). This response consists of several phases that ultimately result in neuronal loss and the formation of a dense glial sheath that encapsulates the implant. Empirical evidence suggests that reducing the FBR has a positive effect on the electrical properties of implants, which can potentially expand their clinical use by improving their chronic usability. The primary focus of this work is to review the consequences of the FBR and recent developments that can be considered to control and limit its development. We will discuss how the choice of device material and electrode-architecture influences the tissue reaction, as well as modifications that allow for less stiff implants, increase electrode conductivity, or improve the implant-tissue integration. Several promising biological solutions include the local release of anti-inflammatory compounds to weaken the initial inflammatory phase of the FBR, as well as methods to diminish the negative effects of the glial sheath on neuronal regrowth. PMID- 23941985 TI - Left cathodal trans-cranial direct current stimulation of the parietal cortex leads to an asymmetrical modulation of the vestibular-ocular reflex. AB - Multi-sensory visuo-vestibular cortical areas within the parietal lobe are important for spatial orientation and possibly for descending modulation of the vestibular-ocular reflex (VOR). Functional imaging and lesion studies suggest that vestibular cortical processing is localized primarily in the non-dominant parietal lobe. However, the role of inter-hemispheric parietal balance in vestibular processing is poorly understood. Therefore, we tested whether experimentally induced asymmetries in right versus left parietal excitability would modulate vestibular function. VOR function was assessed in right-handed normal subjects during caloric ear irrigation (30 degrees C), before and after trans-cranial direct current stimulation (tDCS) was applied bilaterally over the parietal cortex. Bilateral tDCS with the anode over the right and the cathode over the left parietal region resulted in significant asymmetrical modulation of the VOR, with highly suppressed responses during the right caloric irrigation (i.e. rightward slow phase nystagmus). In contrast, we observed no VOR modulation during either cathodal stimulation of the right parietal cortex or SHAM tDCS conditions. Application of unilateral tDCS revealed that the left cathodal stimulation was critical in inducing the observed modulation of the VOR. We show that disruption of parietal inter-hemispheric balance can induce asymmetries in vestibular function. This is the first report using neuromodulation to show right hemisphere dominance for vestibular cortical processing. PMID- 23941986 TI - Effects of repetitive transcranial magnetic stimulation (rTMS) on specific symptom clusters in depersonalization disorder (DPD). PMID- 23941987 TI - Teaching billing and coding to medical students: a pilot study. AB - Complex billing practices cost the US healthcare system billions of dollars annually. Coding for outpatient office visits [known as Evaluation & Management (E&M) services] is commonly particularly fraught with errors. The best way to insure proper billing and coding by practicing physicians is to teach this as part of the medical school curriculum. Here, in a pilot study, we show that medical students can learn well the basic principles from lectures. This approach is easy to implement into a medical school curriculum. PMID- 23941988 TI - Human collagen produced in plants: more than just another molecule. AB - Consequential to its essential role as a mechanical support and affinity regulator in extracellular matrices, collagen constitutes a highly sought after scaffolding material for regeneration and healing applications. However, substantiated concerns have been raised with regard to quality and safety of animal tissue-extracted collagen, particularly in relation to its immunogenicity, risk of disease transmission and overall quality and consistency. In parallel, contamination with undesirable cellular factors can significantly impair its bioactivity, vis-a-vis its impact on cell recruitment, proliferation and differentiation. High-scale production of recombinant human collagen Type I (rhCOL1) in the tobacco plant provides a source of an homogenic, heterotrimeric, thermally stable "virgin" collagen which self assembles to fine homogenous fibrils displaying intact binding sites and has been applied to form numerous functional scaffolds for tissue engineering and regenerative medicine. In addition, rhCOL1 can form liquid crystal structures, yielding a well-organized and mechanically strong membrane, two properties indispensable to extracellular matrix (ECM) mimicry. Overall, the shortcomings of animal- and cadaver-derived collagens arising from their source diversity and recycled nature are fully overcome in the plant setting, constituting a collagen source ideal for tissue engineering and regenerative medicine applications. PMID- 23941989 TI - Recombinant baculovirus displayed vaccine: a novel tool for the development of a cross-protective influenza H5N1 vaccine. AB - The rapid evolution of new sublineages of H5N1 influenza in Asia poses the greatest challenge in vaccine development for pre-pandemic preparedness. To overcome the antigenic diversity of H5N1 strains, multiple vaccine strains can be designed based on the distribution of neutralizing epitopes in the globular head of H5 hemagglutinin (HA). Recently, we selected two different HAs of H5N1 strains based on the neutralizing epitopes and reactivity with different neutralizing antibodies. The HAs of selected vaccine strains were individually expressed on the baculovirus envelope (bivalent-BacHA) with its native antigenic configuration. Further, oral delivery of live bivalent-BacHA elicited broadly reactive humoral, mucosal and cell-mediated immune responses and showed complete protection against antigenically distinct H5N1 strains in mice. The strategy for the vaccine strain selection, vaccine design and route of administration will provide an idea for development of a widely protective vaccine against highly pathogenic H5N1 for pre-pandemic preparedness. PMID- 23941990 TI - Effect of erythropoietin on healing of corneal epithelial defects in rabbits. AB - BACKGROUND/AIM: Corneal epithelial defects may heal slowly in patients with diabetes, limbal stem cell deficiency, extensive chemical burns or anesthetized corneas. Studies have shown that erythropoietin, a glycoprotein hormone that promotes red blood cell proliferation and inhibits apoptosis of erythroid progenitors, may also exert a cytoprotective, antiapoptotic effect on nonhematopoietic cells. The aim of the study was to examine the effect of erythropoietin on the healing process of corneal epithelial erosions in rabbit eyes. METHODS: Fifteen New Zealand albino rabbits were divided into 3 groups following induction of unilateral uniform corneal epithelial erosions. The first group received local treatment with erythropoietin-containing cellulose-based gel 4 times daily; the second group received treatment with cellulose-based gel without erythropoietin 4 times daily, and the third group received no treatment. The healing process was monitored twice daily using cobalt-blue-filtered slit lamp photography and digital images of fluorescein-stained corneas until complete re-epithelization was achieved. Following re-epithelization, corneas were removed for histologic processing. One-way analysis of variance and Mann-Whitney tests were used for statistical analysis. RESULTS: Mean +/- SD time to complete re epithelization was 55 +/- 2.19 h in the group treated with erythropoietin containing cellulose-based gel, 66.5 +/- 14.25 h in the group treated with gel only and 62.2 +/- 9.09 h in the untreated group (p = 0.16, not significant). There was no significant difference among the groups in the time to complete re epithelization or the rate of epithelial healing. Histologic corneal evaluation revealed stromal vascularization in 2 of the 6 erythropoietin-treated rabbits and in neither of the control groups. CONCLUSION: Erythropoietin has no beneficial effect on the rate of healing of corneal epithelial erosions in rabbit eyes, and corneal stroma neovascularization seems to be a significant adverse effect. PMID- 23941991 TI - New engineered antibodies against prions. AB - A number of recently developed and approved therapeutic agents based on highly specific and potent antibodies have shown the potential of antibody therapy. As the next step, antibody-based therapeutics will be bioengineered in a way that they not only bind pathogenic targets but also address other issues, including drug targeting and delivery. For antibodies that are expected to act within brain tissue, like those that are directed against the pathogenic prion protein isoform, one of the major obstacles is the blood-brain barrier which prevents efficient transfer of the antibody, even of the engineered single-chain variants. We recently demonstrated that a specific prion-specific antibody construct which was injected into the murine tail vein can be efficiently transported into brain tissue. The novelty of the work was in that the cell penetrating peptide was used as a linker connecting both specificity-determining domains of the antibody peptide, thus eliminating the need for the standard flexible linker, composed of an arrangement of three consecutive (Gly 4Ser) repeats. This paves the road toward improved bioengineered antibody variants that target brain antigens. PMID- 23941992 TI - N-Myc knockdown and apigenin treatment controlled growth of malignant neuroblastoma cells having N-Myc amplification. AB - Malignant neuroblastomas mostly occur in children and are frequently associated with N-Myc amplification. Oncogene amplification, which is selective increase in copy number of the oncogene, provides survival advantages in solid tumors including malignant neuroblastoma. We have decreased expression of N-Myc oncogene using short hairpin RNA (shRNA) plasmid to increase anti-tumor efficacy of the isoflavonoid apigenin (APG) in human malignant neuroblastoma SK-N-DZ and SK-N-BE2 cell lines that harbor N-Myc amplification. N-Myc knockdown induced morphological and biochemical features of neuronal differentiation. Combination of N-Myc knockdown and APG most effectively induced morphological and biochemical features of apoptotic death. This combination therapy also prevented cell migration and decreased N-Myc driven survival, angiogenic, and invasive factors. Collectively, N-Myc knockdown and APG treatment is a promising strategy for controlling the growth of human malignant neuroblastoma cell lines that harbor N-Myc amplification. PMID- 23941993 TI - Evaluating the antioxidative activity of diselenide containing compounds in human blood. AB - This study was designed to determine and compare the antioxidant effects of synthetic organoselenium compounds. In experimental trials three different diselenides were used: bis(2-hydroxyphenyl) diselenide, bis{[2-(4 hydroxybenzyl)imino]phenyl} diselenide and bis[2-(4 methylphenylsulfonylamino)phenyl] diselenide. The compounds were screened for antioxidant activities in human blood under oxidation stress conditions. Oxidative stress was induced in vitro in human blood platelet samples and in plasma by 0.1 mM peroxynitrite (ONOO(-)) or by Fe(2+). In experimental trials the levels of chosen oxidative stress markers (TBARS, O2(-), and protein carbonyl groups) were significantly decreased by the action of the tested compounds. The antioxidative properties and the changes in proteins and lipids in the presence of new synthesized selenoorganic compounds were studied in vitro and compared with activity of ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one)--a classical antioxidant, well known as the most important glutathione peroxidase mimetic agent. Our results indicate that the tested diselenides have distinctly protective effects against oxidative alterations of biomolecules caused by ONOO( ) and Fe(2+) in blood platelets and in plasma. Therefore it seems that not only ebselen with a wide spectrum of therapeutic actions but also other organoselenium compounds can be considered in the future as active pharmacological agents. PMID- 23941994 TI - Nondestructive characterization and enzyme cleaning of painted surfaces: assessment from the macro to nano level. AB - This work establishes a multiscale and multitechnique nondestructive approach as valid methodology for monitoring surface properties and evaluating the effectiveness of enzymatic removal of varnishes from paintings/polychrome artefacts. Mock-up samples (documented reconstructions of oil, tempera, and gilded layers on canvas and wooden supports) were covered with different proteinaceous varnishes (egg white, animal and fish glue, casein) and then characterized before and after the removal of these coatings with enzyme-based solutions. The varnish was cleaned in several steps (two dry swabs and two wet swabs) with a clearance step for removing the residues from proteinaceous varnish or from enzyme solution. Microscopy [stereomicroscopy (SM), optical microscopy (OM), atomic force microscopy (AFM), and scanning electron microscopy (SEM)] and colorimetric (CIE L*a*b* system) techniques were used for characterization of the reconstruction surfaces at different scales (macro-scale by SM and OM; micro scale by SEM and nano-scale by AFM). These techniques were also used to monitor the cleaning treatment. Although results presented in this work were obtained for the specific treatment of enzyme removal, the methodology could be extended to other types of materials and cleaning. Further experiments on real works of art are needed for a complete validation of the methodology. PMID- 23941996 TI - Gene therapy approaches to prevent corneal graft rejection: where do we stand? AB - Cornea transplantation (penetrating keratoplasty) is the most frequently performed transplant procedure in humans. Despite advances in microsurgery and immunosuppressive treatment protocols, a significant number of corneal grafts still undergo immune-mediated allograft rejection. Topical treatment with corticosteroids is currently the gold standard and while this treatment is effective in many corneal transplant patients, it is much less effective in 'high risk' patients with previous episodes of neovascularisation or graft rejection. Therefore, alternative approaches such as genetic modification of donor corneas are needed to prevent corneal transplant rejection. Cornea transplantation holds the unique advantage in that gene therapy can be used to modify allografts ex vivo prior to transplantation. Many preclinical studies using local (and systemic) gene transfer have been performed to date and many different gene transfer vehicles (gene therapy vectors) and therapeutic strategies (immunomodulatory or graft-protective) have been investigated to prevent corneal allograft rejection. The most recent gene therapy applications to prevent corneal allograft rejection will be reviewed in this article. Moreover, it will be discussed why the development of clinical trials for the genetic modification of corneal grafts prior to transplantation is lagging behind of those for the treatment of inherited retinal diseases. PMID- 23941995 TI - Beyond the histone tail: acetylation at the nucleosome dyad commands transcription. AB - Post-translational modifications (PTMs) of histones have been implicated in cellular processes such as transcription, replication and DNA repair. These processes normally involve dynamic changes in chromatin structure and DNA accessibility. Most of the PTMs reported so far map on the histone tails and essentially affect chromatin structure indirectly by recruiting effector proteins. A recent study by Schneider and colleagues published in Cell (1) has uncovered the function of H3K122 acetylation found within the histone globular domain and specifically positioned on the DNA-bound surface of the nucleosome. Their findings demonstrate a direct effect of histone PTMs on chromatin dynamics, and propose that modifications located in different parts of the nucleosome employ distinct regulatory mechanisms. PMID- 23941997 TI - Peroral endoscopic myotomy for the treatment of achalasia in children. AB - Peroral endoscopic myotomy (POEM) is a new endoscopic technique for the treatment of esophageal achalasia, with excellent results in adults. Three children with classic-type achalasia (mean age 9.6 years) underwent POEM in a single center. Mean basal lower esophageal sphincter pressure and Eckard score were 34.6 mmHg and 5.3, respectively. Mean length of myotomy was 10 cm. On average, POEM was completed in 60.6 minutes. No patients experienced postoperative complications or gastroesophageal reflux disease. In the 2 patients who completed a 12-month follow-up, complete symptoms relief was documented (Eckard score 0), as well as a significant drop of the basal lower esophageal sphincter pressure. PMID- 23942000 TI - Recurrent acalculous cholecystitis in a child with chronic granulomatous disease. PMID- 23941999 TI - Ultrasonographic predictors of esophageal varices. AB - OBJECTIVE: The aim of this study was to identify ultrasonographic predictors of esophageal varices (EVs) in children and adolescents with chronic liver disease (CLD) and extrahepatic portal venous obstruction (EHPVO). METHODS: This study evaluates 53 patients younger than 20 years with CLD or EHPVO and no history of bleeding or prophylactic EVs treatment. They were divided into 2 groups: group I (35 with CLD) and group II (18 with EHPVO). Splenorenal shunt (SS), gallbladder wall varices, gallbladder wall thickening (GT), and lesser omental thickness (LOT) were compared with the presence of EVs, gastric varices, and portal hypertensive gastropathy (PHG). Univariate (chi2 test, Fisher exact test, and Wilcoxon signed rank test) and multivariate (logistic regression) analyses were performed. The area under the receiver operating curve was calculated. RESULTS: EVs were observed in 48.5% of patients with CLD and in 83.3% of patients with EHPVO. SS (P = 0.0329) and LOT (P = 0.0151) predicted EV among patients with CLD. A median of 5.3 mm of LOT was considered a predictor of EVs among these patients. Multivariate analysis showed SS as an independent predictor of EVs in patients with EHPVO (odds ratio 15). Gallbladder varices (P = 0.0245) and GT (P = 0.0289) predicted EVs among patients with EHPVO. PHG occurred more often among patients with CLD who had SS (P = 0.0384) and greater LOT (P = 0.0226). CONCLUSIONS: SS and a greater LOT were indicative of EV among children and adolescents with CLD. Gallbladder varices and GT were indicative of EVs among patients with EHPVO. SS and a greater LOT were indicative of PHG among patients with CLD. PMID- 23942002 TI - Portal vein thrombosis and stroke in a patient with tetralogy of Fallot. PMID- 23942001 TI - Efficacy of pegylated interferon alpha-2b and ribavirin in chronic hepatitis C virus (genotypes 1 and 4) infection. AB - BACKGROUND AND OBJECTIVE: The course of chronic hepatitis C in children is often mild or asymptomatic, but may lead to liver cirrhosis and neoplasm. The aim of our study was retrospective evaluation of treatment efficacy using pegylated interferon (IFN)-alpha2b with ribavirin in children and adolescents with chronic hepatitis C, both treatment naive and re-treated. METHODS: The study comprised 79 patients with chronic hepatitis C ages 8 to 18 years (43 patients re-treated; 54 infected with genotype 1 hepatitis C virus and 25 with genotype 4), treated with pegylated IFN-alpha2b (1.5 MUg . kg-1 . week-1) plus ribavirin (15 mg . kg-1 . day-1) for 48 weeks. The primary endpoint was sustained virologic response (SVR). RESULTS: Early viral response (EVR) was observed in 43.1% and end-of-treatment response in 47.9% of patients. In 44.3% of patients, SVR was achieved, which was maintained for at least the next 6 months. Patients not treated before significantly more frequently attained EVR, end-of-treatment response, and SVR (64%, 65.6%, and 63.9%, respectively) as compared with re-treated patients (30%, 33.3%, and 27.9%, respectively). Among 28 patients who attained EVR, 23 achieved SVR. In 2 patients, despite lack of EVR, SVR was observed. There were numerous adverse effects. They were not so severe as to discontinue therapy. CONCLUSIONS: Combined therapy with pegylated IFN-alpha2b and ribavirin in patients with chronic hepatitis C, infected with hepatitis C virus genotypes 1 and 4, was more effective in treatment-naive patients (63.9%) as compared with re-therapy cases (27.9%). SVR was maintained for at least the next 6 months in all of the patients. The applied treatment has limited efficacy and evokes numerous adverse effects; thus, search for new methods of treatment is mandatory. PMID- 23942003 TI - Effects of surgical correction of neuromuscular scoliosis on gastric myoelectrical activity, emptying, and upper gastrointestinal symptoms. AB - OBJECTIVES: Gastrointestinal complications are frequent after surgical correction of neuromuscular scoliosis, but the effects of scoliosis surgery on gastric function and upper gastrointestinal symptoms over the long term are unknown. METHODS: Thirty-one children (16 spastic, 15 flaccid patients) who underwent surgical correction of neuromuscular scoliosis were included in a prospective follow-up study. Median (range) age at surgery was 14.9 (5-20) years and follow up time 4.3 (2-8) years. Electrogastrography (n=28), gastric emptying scintigraphy (n=17), and structured upper gastrointestinal symptoms questionnaire (n=26) were evaluated before and after surgery. The results were related to patients' clinical state, type and extent of corrective spinal surgery, and gastrointestinal complications. RESULTS: The median main scoliosis curve of 81 degrees (51-129 degrees) was corrected to 25 degrees (1.0-85 degrees) after surgery. In electrogastrogram, power ratio increased from preoperative 1.4 (0.30 11) to postoperative 6.2 (1.2-26) in the spastic group (P=0.008), whereas in the flaccid group, power ratio remained unchanged at 2.2 (0.1-17). Patients with prolonged postoperative paralytic ileus had the most substantial increase in gastric power ratio (P=0.038). Correction of sagittal spinal balance correlated with increased postprandial normogastric activity after surgery (R=0.459; P=0.004). The gastric emptying results, upper gastrointestinal symptoms, and body mass index were not significantly altered after scoliosis surgery. CONCLUSIONS: Gastric myoelectrical power increased after surgical correction of spastic neuromuscular scoliosis and was associated with prolonged postoperative paralytic ileus. Correction of poor, stooped spinal balance improved gastric myoelectrical activity. The net effect of scoliosis surgery on gastric emptying, upper gastrointestinal symptoms, and clinical nutritional state was minimal. PMID- 23942004 TI - Effects of boric acid and 2-aminoethoxydiphenyl borate on necrotizing enterocolitis. AB - OBJECTIVE: The aim was to study the effects of boric acid (BA) and 2 aminoethoxydiphenyl borate (2-APB) on oxidative stress and inflammation in an experimental necrotizing enterocolitis (NEC) rat model. METHODS: Experimental NEC was induced in 40 newborn Sprague-Dawley rats by asphyxia and hypothermia applied in 3 consecutive days. Rats were subdivided into 4 subgroups as NEC, NEC+BA, NEC+2-APB, and controls. BA and 2-APB were applied daily before the procedure. Serum total antioxidant status, superoxide dismutase (SOD), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and erythrocyte glutathione (GSH) levels were measured. Pathological changes for NEC in intestinal architecture were evaluated by a grading system. RESULTS: Pretreatment with BA and 2-APB resulted in a decrease in NEC incidence. In all of the NEC groups, decreased serum levels of GSH and SOD were measured. Boron limited GSH consumption but had no effect on SOD levels. Total antioxidant status levels were not statistically different among groups. In our experimental NEC model, BA, but not 2-APB, prevented the increase of TNF-alpha. Pretreatment with BA and 2-APB downregulated the activity levels of IL-6 in NEC. CONCLUSIONS: In the experimental NEC model, BA and 2-APB partly prevent NEC formation, modulate the oxidative stress parameters, bring a significant decrease in GSH consumption, and enhance the antioxidant defense mechanism, but have no effect on total antioxidant status. BA inhibits the hypoxia and hypothermia-induced increase in both IL-6 and TNF-a, but 2-APB only in IL-6. Boron may be beneficial in preventing NEC. PMID- 23942005 TI - Overexpression of LDOC1 in human biliary epithelial cells inhibits apoptosis through NF-kappaB signaling. AB - OBJECTIVES: Biliary atresia (BA) is a devastating pediatric cholestatic liver disease. Increasing evidence indicates that nuclear factor (NF)-kappaB signaling plays a key role in the pathogenesis of BA. Leucine zipper downregulated in cancer 1 (LDOC1) may control the expression of NF-kappaB. The aim of this study was to evaluate the relation between LDOC1 and inflammation/apoptosis mediated by NF-kappaB in the human intrahepatic biliary epithelial cells (HIBECs). METHODS: HIBECs were divided into 3 treatment groups: control, mock transfection group, and LDOC1 transfection. Immunofluorescence, reverse transcription polymerase chain reaction, Western blot, and flow cytometry analysis were used to investigate the effectiveness of LDOC1-transfected HIBECs and the expression of NF-kappaB. Apoptosis was detected by Hochest/ propidium iodide staining. Interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha levels were evaluated by enzyme-linked immunosorbent assay. RESULTS: The expression of NF-kappaB was higher in the LDOC1-transfected group when compared with the control and mock transfected groups as evaluated by immunofluorescence, reverese transcription polymerase chain reaction, and Western blot analysis. The rate of apoptosis was significantly lower in the LDOC1-transfected group when compared with the control and mock-transfected groups. The levels of IL-2 and TNF-alpha were significantly higher in the LDOC1-transfected group when compared with the control and mock transfected groups. CONCLUSIONS: Upregulation of LDOC1 in HIBEC increases the expression of NF-kappaB, which may promote the activation of IL-2 and TNF-alpha secretion and inhibit cell apoptosis. PMID- 23942006 TI - Intraesophageal pressure recording improves the detection of cough during multichannel intraluminal impedance testing in children. AB - BACKGROUND: One of the primary reasons for referral for reflux testing is to correlate reflux events with symptoms such as cough. Adult studies have suggested that symptom recording is flawed and pediatricians feel this is an even more significant problem because there may be errors in both parental and patient reports. We hypothesize that intraesophageal pressure recording (IEPR) provides an objective method to identify coughs during reflux testing in children. METHODS: We recruited 20 children undergoing multichannel intraluminal impedance with pH (pH-MII) testing for the evaluation of cough. We placed simultaneous intraesophageal pressure and pH-MII catheters. Tracings were blindly scored by 2 observers without knowledge of patient/parent symptom report. After the blinded scoring, patient/parent report of symptoms was recorded. RESULTS: Ninety-four percent of all coughs were detected by IEPR and only 48% of all coughs were reported by patients/parents. The mean time from the IEPR cough to the patient/parent cough was 11+/-16 seconds. Using IEPR as the criterion standard for the detection of cough, the sensitivity of patient report for the detection of cough is 46%. Using varying symptom windows because of the increased precision of IEPR, the number of patients with a positive symptom index could be reduced from 30% to 0%, preventing children from being falsely categorized as having reflux-related lung disease. CONCLUSIONS: Parental and patient symptom recording in children is inadequate for making the diagnosis of reflux-related lung disease. If patients undergo pH-MII testing for reflux-related cough, IEPR should become the new standard by which to correlate reflux with cough. PMID- 23942007 TI - Improved outcomes in liver transplantation in children with acute liver failure. AB - OBJECTIVE: The aim of our study was to review the experiences of a living donor dominant transplantation program for children with acute liver failure (ALF). METHODS: Data were derived from the retrospective chart review of 50 children with ALF in a major liver center in the Republic of Korea. RESULTS: A total of 50 children with ALF underwent 47 (94%) primary living donor liver transplantations and 3 (6%) cadaveric liver transplantations. The cumulative survival rates of the grafts at 1 and 5 years were 81.9% and 79.2%, respectively. The overall retransplantation rate was 12%. The cumulative survival rates of these patients at 1 and 5 years were all 87.9%. Most incidents of mortality followed the failure of the preceding graft. We observed no mortalities among donors. Based on multivariate analysis, children who had pretransplant thrombocytopenia or had to use the molecular adsorbent recycling system preoperatively were related to the graft loss. Age younger than 2 years and a hyperacute onset (within 7 days) of hepatic encephalopathy were associated with pretransplant thrombocytopenia. CONCLUSIONS: Living donor-dominant transplantation program in the present study demonstrates tolerable achievements in terms of clinical outcomes of recipients and donors; however, putative factors, such as pretransplant thrombocytopenia, seem to play unclear roles in a poor prognosis following transplantation. PMID- 23942008 TI - Mutarotation in biologically important pure L-fucose and its enantiomer. AB - The sugar specific mutarotation reaction in biologically important L-fucose and its enantiomer in the pure, anhydrous, supercooled liquid state has been studied. Kinetics measurements in the temperature range 313-328 K at ambient pressure have been performed by means of dielectric spectroscopy, a method widely used for studying the molecular dynamics of glass-forming liquids. The kinetic curves have been obtained by tracking the equilibration process in sugar melted and quenched to the desired temperature. Thereafter, an activation energy equal to Ea = 140 kJ mol(-1) for D-fucose and Ea = 123 kJ mol(-1) for L-fucose has been derived from the Arrhenius fit of temperature dependent rate constants. It was also shown that the kinetics curves at the lowest temperatures studied have sigmoidal shape, which was connected to the high concentration of furanosidic forms. PMID- 23942009 TI - Deep sequencing-based identification of pathogen-specific microRNAs in the plasma of rabbits infected with Schistosoma japonicum. AB - Circulating microRNAs (miRNAs) have received considerable attention as a novel class of biomarkers for the diagnosis of cancer and as signalling molecules in mediating intercellular communication. Schistosomes, the causative agents of schistosomiasis, live in the blood vessels of a mammalian host in the adult stage. In the present study, we characterized schistosome-specific small RNA populations in the plasma of rabbits infected with Schistosoma japonicum (S. japonicum) using a deep sequencing method and then identified five schistosome specific miRNAs, including four known miRNAs (Bantam, miR-3479, miR-10 and miR 3096), and one novel miRNA (miR-0001, miRBase ID: sja-miR-8185). Four of the five schistosome-specific miRNAs were also detected by real-time RT-PCR in the plasma of S. japonicum-infected mice. In addition, our study indicated that schistosome Argonaute 2/3 may be an excretory-secretory (ES) protein. In summary, our findings are expected to provide useful information for further development of novel biomarkers for the diagnosis of schistosomiasis and also for deeper understanding of the mechanism of host-parasite interaction. PMID- 23942010 TI - Long-term clinical outcomes, motion, strength, and function after total claviculectomy. AB - BACKGROUND: Total excision of the clavicle is rarely performed. No previous study has documented long-term outcomes with objective measurements of strength, motion, and patient-centered outcomes. We present the long-term consequences of total claviculectomy on shoulder girdle function, global upper extremity function, and overall general health. METHODS: Five total claviculectomy patients were evaluated at 2 time points (2005 and 2010, mean 4.8 and 9.4 years postoperatively) by use of the DASH, SF-36, Simple Shoulder Test, ASES, UCLA, HSS, and Constant shoulder scores. Isokinetic strength, clinical range of motion, and kinematic analysis were performed on each limb pair. RESULTS: All clinical scores allowing side-to-side comparison were poorer for the aclaviculate side, with significance reached for 2005 ASES scores and 2010 ASES, UCLA, HSS, and Constant scores. DASH scores and SF-36 scores were not significantly inferior to age- and sex-matched population norms. Deficits in strength were present in the aclaviculate limbs, with significance reached for adduction in 2005 and for forward flexion and external rotation in 2010. Kinematic and clinical range of motion analysis revealed scapular dyskinesis and significant deficits in external rotation in the aclaviculate limb. CONCLUSIONS: We found that the clavicle contributes to the strength, coordinated scapulohumeral rhythm, and overall range of motion of the shoulder girdle. Patients compensate for loss of the clavicle with minimal functional deficit. With time, patients gradually lose some compensatory ability as evidenced by deteriorating limb-specific, patient centered outcome measures, diminished strength in certain planes of shoulder motion, and scapular dyskinesis at long-term follow-up. Despite objective deficits, these patients continue to have normal self-perceptions of overall health and global upper extremity function. PMID- 23942011 TI - Long-term programming of enhanced aggression by peripuberty stress in female rats. AB - Human literature has linked adverse early life experiences with an increased risk to develop violent behaviors in both boys and girls. We have previously shown that male rats submitted to stress during the peripuberty period display as adults abnormal aggressive behavior against both male intruders and female partners. In the present study, we examined whether the same stress protocol would affect the development of aggressive behaviors in female rats. We evaluated the behavior of these peripuberty stressed female rats when confronted, at adulthood, with either female or male intruders, and during their cohabitation with male partners. Given that estrus cycle influences mood and aggressive behaviors, female aggressive behavior was assessed at different estrus cycle phases: estrus and diestrus, and during pregnancy and lactancy. Additionally, we evaluated postpartum plasma levels of vasopressin, oxytocin and corticosterone, hormones associated with aggression and the regulation of social behavior. Compared to control females, females submitted to stressful events during puberty exhibited higher and more sustained rates of aggression during adulthood independently on the estrus cycle or the sex of the intruder, and they had higher levels of plasma vasopressin. Significant correlations between plasma levels of vasopressin and corticosterone and aggressive behavior were also found. Strikingly, our results showed opposite intragroup correlations suggesting a different role of these hormones on aggression depending on life experiences. We provide here an animal model, devoid of cultural influences strongly supporting a role for biological factors in the development of aggressive behaviors following exposure to stressful events at puberty in females. PMID- 23942012 TI - Bipolar Disorder is associated with the rs6971 polymorphism in the gene encoding 18 kDa Translocator Protein (TSPO). AB - TSPO mediated transport of cholesterol into the mitochondrion is a necessary step in steroid synthesis. The rs6971 polymorphism in the TSPO gene causes an amino acid substitution (Ala147Thr) within the transmembrane domain where the cholesterol-binding pocket is located, and has been shown to affect the steroidogenic pathway. We report a nominal association between this TSPO polymorphism and the diagnosis of Bipolar Disorder in both the genome-wide dataset of the Wellcome Trust Case-Control Consortium and the Psychiatric Genome Wide Association Study Consortium Bipolar Disorder group (OR=1.11, p=0.007; OR=1.10, p=0.011, respectively). We propose that the amino acid substitution affects hypothalamic-pituitary-adrenal (HPA) regulation, and hence may predispose to Bipolar Disorder. This supports the hypothesis that HPA dysregulation has a causal role in Bipolar Disorder, and is not just a consequence of the disease. PMID- 23942013 TI - Neuromotor speech impairment: it's all in the talking. AB - The aim of this article is to explicate the uniqueness of the motor activity implied in spoken language production and to emphasize how important it is, from a theoretical and a clinical perspective, to consider the motor events associated with speaking as domain-specific, i.e., as pertaining to the domain of linguistic expression. First, phylogenetic data are reviewed demonstrating the specificity of the human vocal tract motor network regarding (i) the entrenchment of laryngeal motor skills within the organization of vocal tract movements, (ii) the evolution of a neural basis for skill acquisition within this system, and (iii) the integration of this system into an auditory-motor network. Second, ontogenetic evidence and existing knowledge about the experience-dependent plasticity of the brain are reported to explicate that during speech acquisition the vocal tract motor system is constrained by universal properties of speech production and by the specific phonological properties of the speaker's ambient language. Third, clinical data from dysarthria and apraxia of speech provide the background for a discussion about the theoretical underpinnings of domain-general versus domain-specific views of speech motor control. The article ends with a brief sketch of a holistic neurophonetic approach in experimental inquiries, assessment, and treatment of neuromotor speech impairment. PMID- 23942014 TI - Does low birth weight predict hypertension and obesity in schoolchildren? AB - BACKGROUND: Birth weight appears to play a role in determining high blood pressure (BP) and obesity during childhood. The purpose of this study is to investigate the association between birth weight and later obesity and hypertension among 10- to 13-year-old schoolchildren. METHODS: A total of 1,184 primary school students were selected from 20 randomized schools between 2011 and 2012 in Iran. Height, weight, waist circumference and BP were measured using standard instruments. Data were analyzed using stepwise regression and logistic regression models. RESULTS: 13.5% of children had a history of low birth weight. First-degree family history of obesity, excessive gestational weight gain and birth weight were significantly correlated with overweight/obesity and abdominal obesity (p = 0.001), whereas only birth weight was associated with high BP (p = 0.001). An inverse correlation was found between waist circumference and systolic/diastolic BP. The duration of breastfeeding in children with low birth weight was inversely correlated with obesity/overweight, abdominal obesity and hypertension. CONCLUSION: The results suggests that birth weight is inversely associated with BP and more so with obesity and abdominal obesity. The duration of having been breastfed could have an influence on later hypertension, obesity and abdominal obesity. Further results are needed to test these correlations as well as diagnosing early life factors to prevent young adult overweight/obesity or hypertension. PMID- 23942015 TI - Bridging studies in support of oral pediatric formulation development. AB - Adequate pediatric formulations are a must to ensure compliance to treatment, and safe delivery of the intended dose. Adult formulations may not be suitable for children, and new pediatric formulation(s) must be developed for the pediatric studies, and for market. As the development of pediatric formulations with optimized properties for market might be challenging, preliminary "enabling" formulations might be envisaged for early pediatric studies, prior to the introduction of more elegant market formulations in the confirmatory study. Supportive clinical studies, such as relative bioavailability (RBA) studies may be necessary to establish the bridge from adult and/or enabling formulations to the final pediatric formulation. Late changes to the pediatric formulation will necessitate establishment of bioequivalence (BE) between the two drug products. As failure to demonstrate BE can delay approval, it is strongly advised that the final pediatric formulation(s) be introduced no later than in the pivotal program. RBA studies assessing performance of pediatric formulations are typically performed in adult healthy volunteers, however a possible interplay between age/disease and formulation effects must be taken into account. Formulation bridging based on in vitro approaches might be envisaged under certain circumstances, such as minor formulation changes, development of new dosage strengths, or BCS class-supported biowaivers. PMID- 23942016 TI - Fate of bulk and trace organics during a simulated aquifer recharge and recovery (ARR)-ozone hybrid process. AB - The attenuation of bulk organic matter and trace organic contaminants (TOrCs) was evaluated for various aquifer recharge and recovery (ARR)-ozone (O3) hybrid treatment process combinations using soil-batch reactor and bench-scale ozonation experiments as a proof of concept prior to pilot and/or field studies. In water reclamation and especially potable reuse, refractory bulk organic matter and TOrCs are of potential health concern in recycled waters. In this study, the role of biotransformation of bulk organic matter and TOrCs was investigated considering different simulated treatment combinations, including soil passage (ARR) alone, ARR after ozonation (O3-ARR), and ARR prior to ozonation (ARR-O3). During oxic (aerobic) ARR simulations, soluble microbial-like substances (e.g., higher molecular weight polysaccharides and proteins) were easily removed while (lower molecular weight) humic substances and aromatic organic matter were not efficiently removed. During ARR-ozone treatment simulations, removals of bulk organic matter and TOrCs were rapid and effective compared to ARR alone. A higher reduction of effluent-derived organic matter, including aromatic organic matter and humic substances, was observed in the ARR-O3 hybrid followed by the O3-ARR hybrid. An enhanced attenuation of recalcitrant TOrCs was observed while increasing the ozone dose slightly (O3: DOC=1). TOrC removal efficiency also increased during the post-ozone treatment combination (i.e., ARR-O3). In addition, the carcinogenic wastewater disinfection byproduct N nitrosodimethylamine (NDMA) was eliminated below the method reporting limit (<5 ng L(-1)) both during ARR treatment alone and the ARR-ozone hybrid. PMID- 23942017 TI - Heavy metal removal in an UASB-CW system treating municipal wastewater. AB - The objective of the present study was to investigate for the first time the long term removal of heavy metals (HMs) in a combined UASB-CW system treating municipal wastewater. The research was carried out in a field pilot plant constituted for an up-flow anaerobic sludge bed (UASB) digester as a pretreatment, followed by a surface flow constructed wetland (CW) and finally by a subsurface flow CW. While the UASB showed (pseudo) steady state operational conditions and generated a periodical purge of sludge, CWs were characterised by the progressive accumulation and mineralisation of retained solids. This paper analyses the evolution of HM removal from the water stream over time (over a period of 4.7 year of operation) and the accumulation of HMs in UASB sludge and CW sediments at two horizons of 2.7 and 4.0 year of operation. High removal efficiencies were found for some metals in the following order: Sn > Cr > Cu > Pb > Zn > Fe (63-94%). Medium removal efficiencies were registered for Ni (49%), Hg (42%), and Ag (40%), and finally Mn and As showed negative percentage removals. Removal efficiencies of total HMs were higher in UASB and SF units and lower in the last SSF unit. PMID- 23942018 TI - Synergistic effects of perfluoroalkyl acids mixtures with J-shaped concentration responses on viability of a human liver cell line. AB - Some perfluoroalkyl acids (PFAAs) are highly persistent and bioaccumulative, resulting in their broad coexisting distribution in humans and the environment. Our aim was to investigate the individual and joint effects of PFAAs on cellular viability of a human liver cell line (HL-7702) using the MTT assay. Equipartition ray design and equivalent-effect concentration ratio (EECR) mixtures were used to investigate the binary and multiple effects of PFAAs, respectively. All tested PFAAs mixtures and the individuals (except perfluorododecanoic acid (PFDoDA) and perfluorotetradecanoic acid (PFTeDA)) showed obvious non-monotonic J-shaped concentration-response curves (CRC) on HL-7702. The inhibitory effect of individual PFAAs increased with the elongation of the carbon chain and was dominated by their molecular volume. The three binary mixtures (PFOA/S, PFHxA/S and PFBA/S) showed that synergistic effects occurred under effective inhibitory concentrations (IC) of IC0, IC10, and IC50 in mixtures, while for IC-20 the synergistic effect only occurred under higher PFSA proportion in mixtures. Furthermore, EECR mixtures of the nine individual PFAAs with J-shaped CRC also showed synergistic effects. However, mixtures of the eleven individual PFAAs including those with S-shaped CRC resulted in partial addition effects on HL 7702. Our results indicated that the individual stimulatory responses of HL-7702 to PFAA may produce adverse effects in mixtures at relevant dose levels. PMID- 23942019 TI - Hydroxylation of bisphenol A by hyper lignin-degrading fungus Phanerochaete sordida YK-624 under non-ligninolytic condition. AB - Bisphenol A (BPA) is one of the representative compounds of the endocrine disrupting compounds group and the highest volume chemicals produced worldwide. As a result, BPA is often detected in many soil and water environments. In this study, we demonstrated the transformation of BPA from liquid cultures inoculated with hyper lignin-degrading fungus Phanerochaete sordida YK-624. Under non ligninolytic condition, approximately 80% of BPA was eliminated after 7d of incubation. High-resolution electrospray ionization mass spectra and nuclear magnetic resonance analyses of a metabolite isolated from the culture supernatant suggested that BPA was metabolized to hydroxy-BPA, 4-(2-(4-hydroxyphenyl)propan-2 yl)benzene-1,2-diol, which has a much lower estrogenic activity than BPA. In addition, we investigated the effect of the cytochrome P450 inhibitor piperonyl butoxide (PB) on the hydroxylation of BPA, markedly lower transformation activity of BPA was observed in cultures containing PB. These results suggest that cytochrome P450 plays an important role in the hydroxylation of BPA by P. sordida YK-624 under non-ligninolytic condition. PMID- 23942020 TI - Influence of seasonal climate differences on the pharmaceutical, hormone and personal care product removal efficiency of a drinking water treatment plant. AB - The potential presence of pharmaceuticals, hormones and personal care products in drinking water supplies has raised concerned over the efficiency with which these substances are removed by water treatment processes. In this work, we analyzed samples of raw, unprocessed water collected in different periods and found them to contain higher levels of these contaminants in the colder periods (viz. 12-314 ng L(-1) in autumn and winter as compared to 8-127 ng L(-1) in spring and summer) as a result of their biodegradation being favoured by high temperatures and solar irradiance. We also assessed the efficiency with which these contaminants are removed from drinking water by a water treatment plant operating in south-eastern Spain. Preoxidation with potassium permanganate and chloramination with sodium hypochlorite in the presence of highly concentrated ammonia were found to be the treatment steps most markedly contributing to the removal of pharmaceuticals, hormones and personal care products from drinking water (especially in the warmer periods, where these contaminants were completely removed from the water). By contrast, water treated in the colder periods (autumn and winter) still contained small amounts of ibuprofen and carbamazepine (0.09-0.5 ng L(-1)) which, however, accounted for less than 0.2% of their original concentrations in the water prior to treatment. PMID- 23942021 TI - Aerobic biotransformation of decabromodiphenyl ether (PBDE-209) by Pseudomonas aeruginosa. AB - Aerobic biodegradation of decabromodiphenyl ether (PBDE-209) by Pseudomonas aeruginosa under the influence of co-metabolic substrates and heavy metal cadmium ion was studied, The results showed that certain amount of co-metabolic substrates, such as glucose, sucrose, lactose, starch, and beef extract, would promote the biodegradation of PBDE-209, among which glucose most favorably accelerated PBDE-209 degradation by about 36% within 5d. The highest degradation efficiency was reached at the ratio of PBDE-209 and glucose 1:5 while excessive carbon source would actually hamper the degradation efficiency. Exploration of influences of cadmium ion on PBDE-209 biodegradation indicated that degradation efficiency was stimulated at low concentrations of Cd(2+) (0.5-2 mg L(-1)) while inhibited at higher levels (5-10 mg L(-1)), inferring that the heavy metals of different concentrations possessed mixed reactions on PBDE-209 bioremoval. Bromine ion was produced during the biotransformation process and its concentration had a good negative correlation with the residues of PBDE-209. Two nonabromodiphenyl ethers (PBDE-208, PBDE-207), four octabromodiphenyl ethers (PBDE-203, PBDE-202, PBDE-197, PBDE-196) and one heptabromodiphenyl ethers (PBDE 183) were formed with the decomposition of PBDE-209, demonstrating that the main aerobic transformation mechanism of PBDE-209 was debromination. PMID- 23942022 TI - [Prevalence of HIV and sexually transmitted infections and characteristics of men who have sex with men at a community-based center in Yokohama, Japan]. AB - OBJECTIVES: To investigate the characteristics of men who have sex with men (MSM) in a sample of men who sought voluntary testing and counseling (VCT) for human immunodeficiency virus (HIV) and sexually transmitted infections (STIs) in a community-based center in Yokohama, Japan. The prevalence of HIV/STIs and the incidence rate of HIV were also assessed. METHODS: We investigated VCT records of 449 clients who received free anonymous night VCT services between 2008 and 2011. The tests included rapid HIV antibody, Treponema pallidum antibody (TP Ab), and hepatitis B surface antigen (HBs Ag) tests. We also analyzed VCT records of 82 clients who had at least two tests at our center to estimate the HIV incidence rate. RESULTS: The number of MSM who visited the community center for the first time was 423. Those who resided in Kanagawa Prefecture accounted for 78.5% of the sample, and 30.5% had never been tested for HIV previously. The rate of consistent condom use in the past six months was 44.9%. The results revealed that 3.1%, 10.2%, and 1.7% of MSM tested positive for HIV, TP Ab, and HBs Ag respectively. There was no significant difference in age, residence, previous HIV testing rates, and the rate of consistent condom use in the past six months between subjects who underwent multiple HIV tests at the community center and those who did not undergo any test after the first visit. HIV-positive individuals were all referred to hospitals nearby. Of 82 repeat HIV testers, one was a seroconverter, indicating an incidence rate of 1.00 per 100 person-years (95% confidence interval, 0.00-5.58). CONCLUSION: Our VCT services were accepted by MSM with a high risk of HIV/STIs infection. HIV prevalence was higher than that at local health centers. The HIV incidence rate was equivalent to the previous study that estimated HIV incidence rate from national and sentinel surveillance data. Creating and sustaining alternative VCT venues targeting MSM with high risk of HIV/STIs infection should be considered in other prefectures in Japan to facilitate the early detection and treatment of HIV/STIs. PMID- 23942023 TI - [Validity of the "Kaigo-Yobo Check-List" as a frailty index]. AB - OBJECTIVES: A frailty index for Japanese older people is not yet available. This study examined the validity of "Kaigo-Yobo Check-List" (CL) as a frailty index. METHODS: The study site was Kusatsu town, Gunma prefecture. Out of 612 older persons aged 65 years and over who undertook a comprehensive geriatric assessment in 2007, results from 526 who had no missing data were used to examine the cross sectional relationship between frailty as defined by Fried's criteria (= external criteria) and CL scores in order to evaluate concurrent and construct validity. Further, 916 older individuals aged 70 years and over who responded to the baseline survey in 2001 were followed for the subsequent 4 years and 4 months regarding the onset of ADL disability, service use under the Long Term Care Insurance program, and mortality. We examined the predictive validity of the CL for such adverse outcomes after adjustment for gender, age, and comorbidity. RESULTS: The CL (cut-off point = 3/4) discriminated frailty from non-frailty at the sensitivity of 70.0% and specificity of 89.3%. The higher the CL score, the higher the prevalence of frailty; the trend was highly significant (P < 0.001). The Multitrail Multimethod Model showed that there were significant associations among three components of CL (homeboundness, falling, and lower nutrition) and four out of five components of Fried's frailty criteria (shrinking, exhaustion, low activity, and slowness), whereas those components of the CL did not have an association with the weakness component of Fried's frailty criteria. As compared with older persons who had CL scores of 3 points or below, those who had CL scores of 4 or more points had a significantly higher risk for developing adverse outcomes. Multivariate-adjusted odds ratios for ADL disability at 2 and 4 years after baseline were 5.25 (95% confidence interval, 2.79-9.89) and 3.42 (1.79 6.54), respectively. Likewise, multivariate-adjusted hazard ratios for the onset of service use under the Long Term Care Insurance program and mortality during the follow-up period of 4 years and 4 months were 3.50 (2.41-5.07) and 2.43 (1.70 3.47), respectively. Although the construct validity remained inconclusive, the "Kaigo-Yobo Check-List" showed CONCLUSION: good concurrent and predictive validity as a frailty index. Since it comprises 15 easy-to-answer questions, it could be widely used for research on frailty and its preventive intervention. PMID- 23942024 TI - [Development of the role scale for municipal supervising public health nurses]. AB - OBJECTIVES: As public health nurses are becoming increasingly decentralized in municipalities, recommendations for allocating supervising public health nurses are being made. This study aimed to develop a scale for measuring the implementation of role of municipal supervising public health nurses and to test its reliability and validity. METHODS: Scale items were developed using results of a qualitative inductive analysis of interview data, and the items were then revised following an examination of content validity by experts, resulting in a provisional scale of 17 items. A self-administered, written questionnaire was then completed by supervising public health nurses or public health nurses holding the most senior positions in all municipalities nationwide, with the exception of three prefectures in the Tohoku region (total 1,621 locations). RESULTS: In total, 1,036 responses were received, and 931 were used for analysis (valid response rate = 57.4%). Of these, 406 were completed by supervising public health nurses. After deleting one item as a result of item analysis and conducting principal component analysis, factor analysis was conducted using the major factor method and Promax rotation. One item with high loading on multiple factors was deleted, resulting in a scale comprising 15 items and 3 factors. The cumulative contribution ratio was 56.10%. The three factors were labeled "Promotion of health activities across the whole locality," "Coordination as a PHN role leader," and "Development of the skills of public health nurses". The reliability coefficient of the RMSP (Role Scale for Municipal Supervising Public Health Nurses) as a whole was 0.84 using the split-half method (Spearman-Brown formula) and 0.91 using Cronbach's alpha, confirming internal consistency. In terms of validity, an examination was conducted of the correlation of two RMSP scale scores (strength of awareness of role as a supervising public health nurse and confidence as a supervising public health nurse) and scores on existing scales assessing management abilities, and a significant correlation (P < 0.01) was obtained. Additionally, a comparison of the RMSP scores of decentralized local public health nurses according to rank and years of service in areas where there were no supervising public health nurses with the RMSP scores of supervising public health nurses showed that the scores of supervising public health nurses were higher. CONCLUSION: The developed scale was found to be reliable and valid for measuring the implementation of supervising public health nurses' role. PMID- 23942025 TI - [Usage conditions and intentions to use monitoring services for the elderly living alone]. AB - OBJECTIVES: To examine the usage conditions and intentions to use monitoring services for independent living by the elderly living alone. METHODS: A cross sectional survey was conducted using a mail-in, self-administered questionnaire in September 2011. The target population comprised 2,569 elderly people living in Ota Ward, Tokyo. The data of individuals living alone were extracted from the data of all respondents. The response rate was 67.8%. The sample consisted of 1,095 elderly people living alone. Logistic regression analyses were conducted with the usage conditions and intention to use monitoring services set as dependent variables. The factors related to the usage conditions and the intention to use monitoring services were examined. Gender, age, medical histories, existence of children living in the neighborhood, advanced activities of daily living, frequency of going outdoors, social relations, economic status, education, and mental factors were set as independent variables. RESULTS: The monitoring services used to facilitate independent living included the following: emergency communication service = 124 (11.3%), information registration service = 197 (18.0%), monitoring by people = 113 (10.3%), and monitoring by sensor = 51 (4.7%). The number of respondents who indicated their intention to use monitoring services included the following: emergency communication service = 525 (47.9% of the entire sample, 81.4% of non-users), information registration service = 396 (36.2% of the entire sample, 75.1% of non-users), monitoring by people = 357 (32.6% of the entire sample, 60.0% of non-users), monitoring by sensor = 335 (30.6% of the entire sample, 53.1% of non-users). The respondents' ages and medical histories were related to the usage of monitoring services. Their level of anxiety was related to the intention to use monitoring services. CONCLUSION: Usage and intention to use services was greater in conditions in which the elderly needed help to cope with emergent situations than usage and intention to use services that monitored daily life. The elderly who were aware of their need tended to use monitoring services. A future challenge is to expand the use of monitoring services to foster independent living of the elderly living alone. PMID- 23942026 TI - [Reliability and validity of the simplified Japanese version of the WHO-Five Well being Index (S-WHO-5-J)]. AB - OBJECTIVES: To examine the reliability and validity of the simplified Japanese version of the WHO-Five Well-Being Index (S-WHO-5-J), which reduces the original 6-point scale to a 4-point scale. METHODS: Subjects were selected from 4,439 community-dwelling elderly living in Tokyo. Their mean age +/- SD was 74.2 +/- 6.6 years, and 2,475 (55.8%) were female. We mailed a questionnaire to all potential subjects, and collected 3,068 (69.1%). We analyzed the data from 1,356 questionnaires that had no missing values for the following items: S-WHO-5-J, Geriatric Depression Scale short version (GDS-15), age, gender, persons living together, need of care, subjective rating of health, physical pain, subjective memory impairment, activities of daily living (TMIG Index of Competence), social support, housebound, and subjective feeling of economic affluence. The mean age +/- SD of the sample was 73.2 +/- 5.9 years, and the proportion of females was 51.1%. An additional analysis compared the number of missing values between a simplified version and an original version using the data of 2,034 subjects from another study. RESULTS: A factor analysis identified only one factor and showed high correlation coefficients between total score and items (0.79-0.87) and between all items (0.52-0.82) and a high Cronbach's alpha (0.889). The S-WHO-5-J was correlated to the GDS-15, to the item on mental health and to factors that affected mental health, physical health (subjective rating of health, physical pain, illness), physical function (walking, falling, nutritional status, oral health care), memory impairment, activities of daily living, and social function (housebound, interaction with others, social support). Additional analysis showed that there were fewer missing values for the S-WHO-5-J than for the WHO-5-J. CONCLUSION: The S-WHO-5-J is a reliable, valid, and convenient measure of mental health for large samples of community-dwelling elderly persons. PMID- 23942027 TI - beta-Amyloid precursor protein: function in stem cell development and Alzheimer's disease brain. AB - Stem cell therapy may be a suitable approach for the treatment of many neurodegenerative diseases. However, one major impediment to the development of successful cell-based therapies is our limited understanding of the mechanisms that instruct neural stem cell behaviour, such as proliferation and cell fate specification. The beta-amyloid precursor protein (APP) of Alzheimer's disease (AD) may play an important role in neural stem cell proliferation and differentiation. Our recent work shows that in vitro, APP stimulates neural stem or progenitor cell proliferation and neuronal differentiation. The effect on proliferation is mediated by an autocrine factor that we have identified as cystatin C. As cystatin C expression is also reported to inhibit the development of amyloid pathology in APP transgenic mice, our finding has implications for the possible use of cystatin C for the therapy of AD. PMID- 23942029 TI - Filtering lymphocytes may decrease the need for immunosuppression in solid organ transplantation. AB - Organ transplantation has become very important for patients with irreversible organ diseases. The transplanted organ is foreign to the host and, therefore, it induces a complex immune response of the patient. Therefore, Immunosuppressive agents are usually required to suppress both specific and nonspecific immunity and prevent allograft rejection in recipients who undergo organ transplantation. Of the late years, newer immunosuppressive agents with non-overlapping toxicities have been used in combinations in order to provide better patient and graft survival. However, these medications are associated with significant adverse effects that impact quality of life and sometimes long-term survival of the patient. Adverse effects can differ between the immunosuppressants, but many result from the overall state of immunosuppression. Strategies to manage immunosuppressant adverse effects often involve minimizing exposure to the drugs while balancing the risk for rejection. However, to prevent rejection of the transplanted organ, there may be unproven approaches other than immunosuppressive drugs. Filtering lymphocytes by a specific filter with respect to their size can be an alternative way. Our hypothesis was concerning of if such a filter could manage this and take the place of these drugs. PMID- 23942030 TI - Three-dimensional kinematic stress magnetic resonance image analysis shows promise for detecting altered anatomical relationships of tissues in the cervical spine associated with painful radiculopathy. AB - For some patients with radiculopathy a source of nerve root compression cannot be identified despite positive electromyography (EMG) evidence. This discrepancy hampers the effective clinical management for these individuals. Although it has been well-established that tissues in the cervical spine move in a three dimensional (3D) manner, the 3D motions of the neural elements and their relationship to the bones surrounding them are largely unknown even for asymptomatic normal subjects. We hypothesize that abnormal mechanical loading of cervical nerve roots during pain-provoking head positioning may be responsible for radicular pain in those cases in which there is no evidence of nerve root compression on conventional cervical magnetic resonance imaging (MRI) with the neck in the neutral position. This biomechanical imaging proof-of-concept study focused on quantitatively defining the architectural relationships between the neural and bony structures in the cervical spine using measurements derived from 3D MR images acquired in neutral and pain-provoking neck positions for subjects: (1) with radicular symptoms and evidence of root compression by conventional MRI and positive EMG, (2) with radicular symptoms and no evidence of root compression by MRI but positive EMG, and (3) asymptomatic age-matched controls. Function and pain scores were measured, along with neck range of motion, for all subjects. MR imaging was performed in both a neutral position and a pain-provoking position. Anatomical architectural data derived from analysis of the 3D MR images were compared between symptomatic and asymptomatic groups, and the symptomatic groups with and without imaging evidence of root compression. Several differences in the architectural relationships between the bone and neural tissues were identified between the asymptomatic and symptomatic groups. In addition, changes in architectural relationships were also detected between the symptomatic groups with and without imaging evidence of nerve root compression. As demonstrated in the data and a case study the 3D stress MR imaging approach provides utility to identify biomechanical relationships between hard and soft tissues that are otherwise undetected by standard clinical imaging methods. This technique offers a promising approach to detect the source of radiculopathy to inform clinical management for this pathology. PMID- 23942031 TI - Why does serotonergic activity drastically decrease during REM sleep? AB - Here, I postulate two hypotheses that can explain the missing link between sleep and the serotonergic system in terms of spine homeostasis and memory consolidation. As dendritic spines contain many kinds of serotonin receptors, and the activation of serotonin receptors generally increases the number of spines in the cortex and hippocampus, I postulate that serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level. Furthermore, since synaptic consolidation during REM sleep needs long-term potentiation (LTP), and serotonin is reported to inhibit LTP in the cortex, I postulate that serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation. Until now, why serotonergic neurons show these dramatic changes in the sleep-wake cycle remains unexplained; however, making these hypotheses, I can confer physiological meanings on these dramatic changes of serotonergic neurons in terms of spine homeostasis and memory consolidation. PMID- 23942032 TI - Possible chemical initiators of cognitive dysfunction in phenylketonuria, Parkinson's disease and Alzheimer's disease. AB - Though a great deal is known of the pathophysiology of phenylketonuria (PKU), Parkinson's disease (PD) and Alzheimer's disease (AD) very little is known regarding possible chemical species responsible for initiating the cascade of events that ultimately cause cognitive dysfunction. Can these be viewed as inborn errors in metabolism, occurring at various stages in the life cycle, analogous to adult onset diabetes? One major deficiency in understanding such conditions is the paucity of information regarding the total metabolic pathway for various amino acids that may be implicated in their causation. For example in PKU, its etiology was reported in 1934 and dietary restriction of phenylalanine proved effective for individuals with unsatisfactory metabolism of phenylalanine. Yet, current phenylalanine metabolism does not take into account fully the multiple biochemical pathways operating whose role is preventing burdensome accumulations of intermediates that can contribute to morbidity and toxicity. The same may apply for metabolism of tyrosine in PD and methionine in AD. Especially important, are the presence of labile and reactive chemical species which may be causative agents in protein alteration, misfolding and the creation of prions in neurodegenerative diseases, thereby preventing normal protein catabolism and excretion. Though genetic or epigenetic factors must be responsible, the question remains how are these translated into the chemical structures responsible for disease initiation? The purpose of this presentation is to explore potential labile metabolites in those biochemical pathways, which may be contributing factors. Finally it is worth noting, that drug development has been increasingly designed based upon targeting genetic deficiencies. The effectiveness of this approach for the treatment of these neurodegenerative illnesses will be determined in the future. PMID- 23942033 TI - The evolution of ACh and GABA as neurotransmitters: a hypothesis. AB - The development of a signaling system requires the evolution of a mechanism for producing signals, receptors and adaptive reactions to the signal. It is reasonable to assume that the evolution of such a system cannot be the consequence of a coordinated set of mutations resulting in a complete signaling system. It is more likely that each component evolved due to an advantage that was independent of its role in the signaling system. We hypothesize how the neurotransmitters acetylcholine (ACh) and gamma-aminobutyric acid (GABA) evolved gradually, from an initial stage in which the efflux of these molecules from the cell was an inevitable consequence of specific metabolic activities of the cell. The efflux later served as a cue that reflects the activity of the cell that released the molecules. These cues can later evolve into paracrine signals. We further suggest that the signals used in paracrine signaling were adopted by the central nervous system, as peripheral cells were already attentive to these signals. Signaling molecules released by the target cells of neurons, as an inevitable consequence of the activities of the target cells, could function as retrograde signals of the activity of the target cell. We hypothesize that ACh released by innervated myocytes functions as a retrograde signal of myocyte response to neuronal stimulation. PMID- 23942028 TI - Serotonergic hallucinogens as translational models relevant to schizophrenia. AB - One of the oldest models of schizophrenia is based on the effects of serotonergic hallucinogens such as mescaline, psilocybin, and (+)-lysergic acid diethylamide (LSD), which act through the serotonin 5-HT(2A) receptor. These compounds produce a 'model psychosis' in normal individuals that resembles at least some of the positive symptoms of schizophrenia. Based on these similarities, and because evidence has emerged that the serotonergic system plays a role in the pathogenesis of schizophrenia in some patients, animal models relevant to schizophrenia have been developed based on hallucinogen effects. Here we review the behavioural effects of hallucinogens in four of those models, the receptor and neurochemical mechanisms for the effects and their translational relevance. Despite the difficulty of modelling hallucinogen effects in nonverbal species, animal models of schizophrenia based on hallucinogens have yielded important insights into the linkage between 5-HT and schizophrenia and have helped to identify receptor targets and interactions that could be exploited in the development of new therapeutic agents. PMID- 23942034 TI - Dyslipidemia in pediatric systemic lupus erythematosus: the relationship with disease activity and plasma homocysteine and cysteine concentrations. AB - OBJECTIVE: To evaluate the presence of dyslipidemia and plasma concentrations of homocysteine (Hcy) and cysteine (Cys) in adolescents with juvenile systemic lupus erythematosus (SLE) and relate these findings to disease activity (Systemic Lupus Erythematosus Disease Activity Index, SLEDAI) and cardiovascular risk factors. METHODS: A cross-sectional controlled study including 26 female adolescents with SLE and 26 healthy controls was conducted. We evaluated SLEDAI, medications, anthropometric data, dietary intake, lipid profile, proteinuria, Hcy, Cys, folic acid, vitamin B12, and high-sensitivity C-reactive protein levels. RESULTS: Dyslipidemia was observed in 46.2% of the patients and in 19.2% of the controls. The SLE group had a higher Cys concentration and a lower high-density lipoprotein cholesterol concentration compared with the controls. In the multivariate analysis only Hcy was significantly and independently associated with the presence of dyslipidemia in the juvenile SLE group; an increase of 1 MUmol/l in the Hcy concentration doubled the chance of dyslipidemia (OR: 2.1; 95% CI: 1.1 4.9; p = 0.030). The Cys concentration was correlated with Hcy, total cholesterol, low-density lipoprotein cholesterol, and triglyceride concentrations. CONCLUSION: We observed the presence of cardiovascular risk factors in adolescents with juvenile SLE. The early identification of biochemical alterations allows the development of intervention strategies that may lower the risk of cardiovascular disease. PMID- 23942035 TI - Doping of polycrystalline CdTe for high-efficiency solar cells on flexible metal foil. AB - Roll-to-roll manufacturing of CdTe solar cells on flexible metal foil substrates is one of the most attractive options for low-cost photovoltaic module production. However, various efforts to grow CdTe solar cells on metal foil have resulted in low efficiencies. This is caused by the fact that the conventional device structure must be inverted, which imposes severe restrictions on device processing and consequently limits the electronic quality of the CdTe layer. Here we introduce an innovative concept for the controlled doping of the CdTe layer in the inverted device structure by means of evaporation of sub-monolayer amounts of Cu and subsequent annealing, which enables breakthrough efficiencies up to 13.6%. For the first time, CdTe solar cells on metal foil exceed the 10% efficiency threshold for industrialization. The controlled doping of CdTe with Cu leads to increased hole density, enhanced carrier lifetime and improved carrier collection in the solar cell. Our results offer new research directions for solving persistent challenges of CdTe photovoltaics. PMID- 23942036 TI - Clarifying the causal relationship in women between childhood sexual abuse and lifetime major depression. AB - BACKGROUND: Childhood sexual abuse (CSA) is strongly associated with risk for major depression (MD) but the degree to which this association is causal remains uncertain. METHOD: We applied structural equation modeling using the Mplus program to 1493 longitudinally assessed female twins from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. RESULTS: Our model included (i) retrospective self- and co-twin reports on CSA, (ii) major potentially confounding covariates, (iii) assessment of lifetime history of MD at two separate interviews, and (iv) mood-congruent recall (implemented by allowing current depressive symptoms to predict reporting of CSA). In a model with only measurement error, CSA explained 9.6% of MD. Including four key covariates reduced the variance explained to 5.3%, with the largest effects found for parental loss and low parental warmth. Adding the effect of mood-congruent recall to a final well-fitting model reduced the percentage of variance explained in lifetime MD (LTMD) by CSA to 4.4%. In this model, current depressive symptoms significantly predicted recall of CSA. CONCLUSIONS: In a model correcting for measurement error, confounding and the impact of mood-congruent recall, CSA remains substantially associated with the risk for LTMD in women. These findings strongly suggest, but do not prove, that this association is causal, and are consistent with previous results in this sample using a co-twin control design, but also indicate that more than half of the uncorrected CSA-MD association is probably not causal. Traumatic life experiences contribute substantially to the risk for LTMD. PMID- 23942037 TI - Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells. AB - The nuclear factor erythroid derived 2-related factor 2 (Nrf2) and the antioxidant protein heme oxygenase-1 (HO-1) are crucial components of the cellular stress response. These two systems work together to combat oxidative stress and inflammation and are attractive drug targets for counteracting different pathologies, including neuroinflammation. We aimed to identify the most effective Nrf2/HO-1 activators that modulate the inflammatory response in microglia cells. In the present study, we searched the literature and selected 56 compounds reported to activate Nrf2 or HO-1 and analyzed them for HO-1 induction at 6 and 24h and cytotoxicity in BV2 microglial cells in vitro. Approximately 20 compounds up-regulated HO-1 at the concentrations tested (5-20 MUM) with carnosol, supercurcumin, cobalt protoporphyrin-IX and dimethyl fumarate exhibiting the best induction/low cytotoxicity profile. Up-regulation of HO-1 by some compounds resulted in increased cellular bilirubin levels but did not augment the expression of proteins involved in heme synthesis (ALAS 1) or biliverdin reductase. Bilirubin production by HO-1 inducers correlated with their potency in inhibiting nitrite production after challenge with interferon-gamma (INF-gamma) or lipopolysaccharide (LPS). The compounds down-regulated the inflammatory response (TNF-alpha, PGE2 and nitrite) more strongly in cells challenged with INF-gamma than LPS, and silencing HO-1 or Nrf2 with shRNA differentially affected the levels of inflammatory markers. These findings indicate that some small activators of Nrf2/HO-1 are effective modulators of microglia inflammation and highlight the chemical scaffolds that can serve for the synthesis of potent new derivatives to counteract neuroinflammation and neurodegeneration. PMID- 23942038 TI - A double dose of levocetirizine leads to better control of histamine-induced flare, wheal and itch in healthy donors. AB - Levocetirizine is classified as a nonsedating second-generation antihistamine. This drug is used to treat allergic disorders such as urticaria and pruritus. Thus far, studies have demonstrated an increase in efficacy for refractory urticaria by increasing doses of antihistamines; however, more lines of supportive evidence for these guidelines are required to justify this management strategy. In this study, we found that a double dose of levocetirizine suppressed histamine-induced flare formation more rapidly and sustainably, and wheal and itch more extensively, compared with the conventional dose using both visual and laser Doppler imaging scales in a noninvasive manner. These results suggest that double-dosed levocetirizine treatment suppresses histamine-induced skin symptoms more rapidly, profoundly and sustainably than conventionally dosed levocetirizine treatment. PMID- 23942039 TI - Impact of a multivariate index assay on referral patterns for surgical management of an adnexal mass. AB - OBJECTIVE: To determine the impact on referral patterns of using a Multivariate Index Assay, CA125, modified-American College of Obstetricians and Gynecologists referral guidelines, and clinical assessment among patients undergoing surgery for an adnexal mass after initial evaluation by nongynecologic oncologists. STUDY DESIGN: Overall, 770 patients were enrolled by nongynecologic oncologists from 2 related, multiinstitutional, prospective trials and analyzed retrospectively. All patients had preoperative imaging and biomarker analysis. The subset of patients enrolled by nongynecologic oncologists was analyzed to determine the projected referral patterns and sensitivity for malignancy based on multivariate index assay (MIA), CA125, modified-American College of Obstetricians and Gynecologists (ACOG) guidelines, and clinical assessment compared with actual practice. RESULTS: The prevalence of malignancy was 21.3% (n = 164). In clinical practice, 462/770 patients (60.0%) were referred to a gynecologic oncologist for surgery. Triage based on CA125 predicted referral of 157/770 patients (20.4%) with sensitivity of 68.3% (95% confidence interval [CI], 60.8-74.9). Triage based on modified-ACOG guidelines would have resulted in referral of 256/770 patients (33.2%) with a sensitivity of 79.3% (95% CI, 72.4-84.8). Clinical assessment predicted referral of 184/763 patients (24.1%) with a sensitivity of 73.2% (95% CI, 65.9-79.4). Risk stratification using multivariate index assay would have resulted in referral of 429/770 (55.7%) patients, with sensitivity of 90.2% (95% CI, 84.7-93.9). MIA demonstrated statistically significant higher sensitivity (P < .0001) and lower specificity (P < .0001) for detecting malignancy compared with clinical assessment, CA125, and modified-ACOG guidelines. CONCLUSION: In this study population, use of MIA as a risk stratification test was associated with referral patterns by nongynecologic oncologists comparable to actual clinical practice and higher sensitivity for malignancy than other adnexal mass triage algorithms. PMID- 23942040 TI - The health disparities of uterine fibroid tumors for African American women: a public health issue. AB - Uterine fibroid tumors (leiomyomas) are the most common benign pelvic tumors in women and are the major indication for hysterectomy. Fibroid tumors are more common and more severe among African American women. Although this disease disproportionately affects the African American population, we understand little about what causes the disparity. Fibroid tumors should be considered a public health issue, given the magnitude of the problem and the costs of health care for this disease. In this review, we examine the burden of disease from fibroid tumors in the African American population and review the natural history, diagnosis, and treatment of uterine fibroid tumors, with emphasis on how these can differ, depending on race. We also focus on the socioeconomic burden caused by the disease and describe the anticipated influence of new health care reforms and funding mechanisms for fibroid tumor research. PMID- 23942041 TI - Language Delay in 3-Year-Old Children With ADHD Symptoms. AB - OBJECTIVE: Little is known about cognition in preschoolers with ADHD and language delay (LD). The objective was to investigate cognitive functions in preschoolers with ADHD symptoms and LD compared with children with ADHD symptoms only and to estimate the frequency of children with ADHD symptoms, co-occurring language delay, and delays on cognitive measures. METHOD: Participants were recruited from the Norwegian Mother and Child Cohort Study. The teacher report of expressive language and the cognitive tests from 119 3-year-old children with parent reported ADHD symptoms and LD were compared with those of 258 children with ADHD symptoms only. RESULTS: The ADHD + LD group performed significantly worse than the ADHD group on most language-related measures. There were no differences between the groups on most nonverbal measures. Single measures had a limited potential of differentiating between the groups. CONCLUSION: ADHD symptoms and co occurring LD in preschoolers were characterized by cognitive deficits associated with both disorders, not with global neurodevelopmental delay. PMID- 23942042 TI - Prevalence and smoking behavior characteristics of nonselected smokers with childhood and/or adult self-reported ADHD symptoms in a smoking-cessation program: a cross-sectional study. AB - BACKGROUND: ADHD involves impairing core symptoms of inattention and hyperactivity/impulsivity in children (childhood ADHD = CH) that may persist in adulthood (adult ADHD = AD). Conflicting findings have been found regarding AD prevalences among adult smokers, and it is unclear whether AD is associated with a more severe smoking behavior in adulthood. OBJECTIVE: The aim of this article is (a) to determine CH and AD prevalences in a nonselected sample of adult smokers, (b) to describe the characteristics of smokers with ADHD symptoms versus those without, and (c) to determine whether CH and/or AD symptoms are risk factors for more severe smoking in adulthood. METHOD: Three hundred and seventy three participants aged 18 years and over were prospectively recruited in a smoking-cessation unit. Participants were classified as "no ADHD symptoms," "CH symptoms," or "AD symptoms" according to their baseline score on the Wender Utah Rating Scale (WURS) alone (for CH symptoms) and WURS combined to the Adult Self Report Scale (ASRS) for AD symptoms. Other clinical variables were reported at first consultation. RESULTS: (a) CH symptoms were reported in 15.3% (57/373) of the total sample, 42.1% (24/57) of whom also had persistent ADHD symptoms in adulthood (prevalence of AD was 24/373 = 6.4%). (b) In comparison with participants without ADHD symptoms, smokers with ADHD symptoms consume significantly more tobacco, but ADHD symptoms were no longer significantly associated with the daily number of smoked cigarettes after adjustment for sociodemographic variables. No significant association was found between the two groups and age at the first cigarette, age at onset daily smoking, and nicotine dependence. (c) Participants were categorized into three groups: Group 1 without ADHD symptoms lifetime (NH; n = 316), Group 2 with childhood history of ADHD symptoms (CH; n = 33), and Group 3 with Adult ADHD symptoms (AD; n = 24). The association with tobacco consumption (>20 cigarettes/day) was significant for CH only (p = .02). After adjustment for gender, age, professional status, and educational level, this association was not longer significant. CONCLUSION: Childhood and adult ADHD symptoms are both highly prevalent among nonselected smokers but our study failed to show more severe smoking characteristics among these participants after adjustment with sociodemographic variables. PMID- 23942043 TI - Influence of deep sternal wound infection on long-term survival after cardiac surgery. AB - BACKGROUND: This study aimed to investigate the influence of deep sternal wound infection on long-term survival following cardiac surgery. MATERIAL AND METHODS: In our institutional database we retrospectively evaluated medical records of 4732 adult patients who received open-heart surgery from January 1995 through December 2005. The predictive factors for DSWI were determined using logistic regression analysis. Then, each patient with deep sternal wound infection (DSWI) was matched with 2 controls without DSWI, according to the risk factors identified previously. After checking balance resulting from matching, short-term mortality was compared between groups using a paired test, and long-term survival was compared using Kaplan-Meier analysis and a Cox proportional hazard model. RESULTS: Overall, 4732 records were analyzed. The mean age of the investigated population was 69.3+/-12.8 years. DSWI occurred in 74 (1.56%) patients. Significant independent predictive factors for deep sternal infections were active smoking (OR 2.19, CI95 1.35-3.53, p=0.001), obesity (OR 1.96, CI95 1.20 3.21, p=0.007), and insulin-dependent diabetes mellitus (OR 2.09, CI95 1.05 10.06, p=0.016). Mean follow-up in the matched set was 125 months, IQR 99-162. After matching, in-hospital mortality was higher in the DSWI group (8.1% vs. 2.7% p=0.03), but DSWI was not an independent predictor of long-term survival (adjusted HR 1.5, CI95 0.7-3.2, p=0.33). CONCLUSIONS: The results presented in this report clearly show that post-sternotomy deep wound infection does not influence long-term survival in an adult general cardio-surgical patient population. PMID- 23942045 TI - The results of preoperative halo-gravity traction in children with severe spinal deformity. AB - Halo-gravity traction has been used preoperatively for patients with severe spinal deformity but there are limited data in the literature on the results and complications. We studied the outcomes of perioperative halo-gravity traction in children with severe spinal deformity. A retrospective study was carried out on patients who were treated at our center. Twenty-one patients were included in the study. Radiographic and pulmonary function parameters showed significant improvement during the course of traction and at the final follow-up. The overall complication rate was 19%, including two patients with pin loosening and two patients with superficial pin-site infections treated with oral antibiotics. PMID- 23942044 TI - Developmental language disorders: challenges and implications of cross-group comparisons. AB - Historically, specific language impairment (SLI) and language deficits associated with autism spectrum disorders (ASD) have been viewed as distinct developmental language disorders. However, over the last decade or so, a considerable amount of research has explored general similarities or specific areas of overlap between children with SLI and ASD based on language and cognitive profiles, neuroimaging findings, and genetic research. The clinical classification schemes that are used to identify the children necessarily influence the extent to which SLI and ASD are viewed as overlapping or distinct conditions. Yet, the criteria used to diagnose these two populations vary across countries and even across investigators within a given country. This necessarily impacts the findings from comparative investigations of these groups. With these challenges in mind, clinical implications of evidence for similarities and distinctions between children with SLI and ASD will be discussed with respect to differential diagnosis and treatment. PMID- 23942046 TI - Visual speech form influences the speed of auditory speech processing. AB - An important property of visual speech (movements of the lips and mouth) is that it generally begins before auditory speech. Research using brain-based paradigms has demonstrated that seeing visual speech speeds up the activation of the listener's auditory cortex but it is not clear whether these observed neural processes link to behaviour. It was hypothesized that the very early portion of visual speech (occurring before auditory speech) will allow listeners to predict the following auditory event and so facilitate the speed of speech perception. This was tested in the current behavioural experiments. Further, we tested whether the salience of the visual speech played a role in this speech facilitation effect (Experiment 1). We also determined the relative contributions that visual form (what) and temporal (when) cues made (Experiment 2). The results showed that visual speech cues facilitated response times and that this was based on form rather than temporal cues. PMID- 23942047 TI - District nurses' knowledge development in wound management: ongoing learning without organizational support. AB - AIM: The aim of this study was to describe district nurses' (DNs') experiences of their knowledge development in wound management when treating patients with different types of wounds at healthcare centers. BACKGROUND: In primary healthcare, DNs are mainly responsible for wound management. Previous research has focused on DNs' level of expertise regarding wound management, mostly based on quantitative studies. An unanswered question concerns DNs' knowledge development in wound management. The present study therefore intends to broaden understanding and to provide deeper knowledge in regard to the DNs' experiences of their knowledge development when treating patients with wounds. METHODS: A qualitative descriptive design was used. Subjects were a purposeful sample of 16 DNs from eight healthcare centers in a metropolitan area in Stockholm, Sweden. The study was conducted with qualitative interviews and qualitative content analysis was used to analyze the data. RESULTS: The content analysis resulted in three categories and 11 sub-categories. The first category, 'ongoing learning by experience,' was based on experiences of learning alongside clinical practice. The second category 'searching for information,' consisted of various channels for obtaining information. The third category, 'lacking organizational support,' consisted of experiences related to the DNs' work organization, which hindered their development in wound care knowledge. CONCLUSIONS: The DNs experienced that they were in a constant state of learning and obtained their wound care knowledge to a great extent through practical work, from their colleagues as well as from various companies. A lack of organizational structures and support from staff management made it difficult for DNs to develop their knowledge and skills in wound management, which can lead to inadequate wound management. PMID- 23942048 TI - Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells. AB - Heart disease is the leading cause of death in the world. Heart tissue engineering holds a great promise for future heart disease therapy by building personalized heart tissues. Here we create heart constructs by repopulating decellularized mouse hearts with human induced pluripotent stem cell-derived multipotential cardiovascular progenitor cells. We show that the seeded multipotential cardiovascular progenitor cells migrate, proliferate and differentiate in situ into cardiomyocytes, smooth muscle cells and endothelial cells to reconstruct the decellularized hearts. After 20 days of perfusion, the engineered heart tissues exhibit spontaneous contractions, generate mechanical force and are responsive to drugs. In addition, we observe that heart extracellular matrix promoted cardiomyocyte proliferation, differentiation and myofilament formation from the repopulated human multipotential cardiovascular progenitor cells. Our novel strategy to engineer personalized heart constructs could benefit the study of early heart formation or may find application in preclinical testing. PMID- 23942049 TI - Effect of tibial plateau leveling osteotomy on patellofemoral alignment: a study using canine cadavers. AB - Tibial plateau leveling osteotomy (TPLO) has been shown to alter the biomechanics of the femorotibial joint; however, the effect of TPLO on patellofemoral (PF) joint alignment remains unknown. The purpose of this study was to evaluate PF joint kinematics before and after cranial cruciate ligament (CrCL) transection and following TPLO in a cadaveric stifle model with set patellar tendon load, tested in passive range of motion at 90 degrees , 105 degrees , 120 degrees , 135 degrees and 150 degrees of flexion. The PF joint poses were measured on mediolateral projection radiographs using a two-dimensional computer digitization technique. In the subluxated CrCL-deficient stifle, the PF joint had an increase in patellar tilt angle. In the reduced CrCL-deficient stifle treated by TPLO, there was distal and caudal displacement of the patella relative to the femur and a decreased patellar tilt angle. The estimated patellar moment arm following TPLO was not different from the control stifle. On the basis of these results, TPLO alters PF joint kinematics. The changes in PF joint alignment induced by TPLO may be a biomechanical factor predisposing to patellar tendonitis following TPLO. PMID- 23942050 TI - Beneficial effect of rutin on oxonate-induced hyperuricemia and renal dysfunction in mice. AB - AIMS: The aim of the present study was to investigate the effects of rutin on potassium oxonate-induced hyperuricemia and renal dysfunction in mice. METHODS: Rutin was administered orally 1 h after oxonate at doses of 25, 50 and 100 mg.kg( 1). Serum uric acid levels and kidney function parameters were assayed. Mouse uromodulin levels in serum, urine and kidney were determined by the ELISA method. Simultaneously, the expression levels of renal organic ion transporters were detected. RESULTS: Rutin significantly decreased serum urate, creatinine and blood urea nitrogen, serum and kidney uromodulin levels, and increased urine uromodulin, urate and creatinine excretion in hyperuricemic mice. Rutin at 50 and 100 mg.kg(-1) significantly downregulated mRNA and protein levels of mouse glucose transporter 9 and urate transporter 1, and upregulated mRNA and protein levels of organic anion transporter 1 and organic cation/carnitine transporters in the kidney of hyperuricemic mice. CONCLUSIONS: Rutin exerted its hypouricemic action and renal function improvement by the regulation of renal organic ion transporters. PMID- 23942051 TI - Lysine221 is the general base residue of the isochorismate synthase from Pseudomonas aeruginosa (PchA) in a reaction that is diffusion limited. AB - The isochorismate synthase from Pseudomonas aeruginosa (PchA) catalyzes the conversion of chorismate to isochorismate, which is subsequently converted by a second enzyme (PchB) to salicylate for incorporation into the salicylate-capped siderophore pyochelin. PchA is a member of the MST family of enzymes, which includes the structurally homologous isochorismate synthases from Escherichia coli (EntC and MenF) and salicylate synthases from Yersinia enterocolitica (Irp9) and Mycobacterium tuberculosis (MbtI). The latter enzymes generate isochorismate as an intermediate before generating salicylate and pyruvate. General acid general base catalysis has been proposed for isochorismate synthesis in all five enzymes, but the residues required for the isomerization are a matter of debate, with both lysine221 and glutamate313 proposed as the general base (PchA numbering). This work includes a classical characterization of PchA with steady state kinetic analysis, solvent kinetic isotope effect analysis and by measuring the effect of viscosogens on catalysis. The results suggest that isochorismate production from chorismate by the MST enzymes is the result of general acid general base catalysis with a lysine as the base and a glutamic acid as the acid, in reverse protonation states. Chemistry is determined to not be rate limiting, favoring the hypothesis of a conformational or binding step as the slow step. PMID- 23942053 TI - Characterization of cysteine string protein in rat parotid acinar cells. AB - Cysteine string proteins (CSPs) are secretory vesicle chaperone proteins that contain: (i) a heavily palmitoylated cysteine string (comprised of 14 cysteine residues, responsible for the localization of CSP to secretory vesicle membranes), (ii) an N-terminal J-domain (DnaJ domain of Hsc70, 70kDa heat-shock cognate protein family of co-chaperones), and (iii) a linker domain (important in mediating CSP effects on secretion). In this study, we investigated the localization of CSP1 in rat parotid acinar cells and evaluated the role of CSP1 in parotid secretion. RT-PCR and western blotting revealed that CSP1 was expressed and associated with Hsc70 in rat parotid acinar cells. Further, CSP1 associated with syntaxin 4, but not with syntaxin 3, on the apical plasma membrane. Introduction of anti-CSP1 antibody into SLO-permeabilized acinar cells enhanced isoproterenol (IPR)-induced amylase release. Introduction of GST-CSP11 112, containing both the J-domain and the adjacent linker region, enhanced IPR induced amylase release, whereas neither GST-CSP11-82, containing the J-domain only, nor GST-CSP183-112, containing the linker region only, did produce detectable enhancement. These results indicated that both the J-domain and the linker domain of CSP1 are necessary to function an important role in acinar cell exocytosis. PMID- 23942052 TI - Human heart failure is accompanied by altered protein kinase A subunit expression and post-translational state. AB - beta-Adrenergic receptor blockade reduces total mortality and all-cause hospitalizations in patients with heart failure (HF). Nonetheless, beta-blockade does not halt disease progression, suggesting that cAMP-dependent protein kinase (PKA) signaling downstream of beta-adrenergic receptor activation may persist through unique post-translational states. In this study, human myocardial tissue was used to examine the state of PKA subunits. As expected, total myosin binding protein-C phosphorylation and Ser23/24 troponin I phosphorylation significantly decreased in HF. Examination of PKA subunits demonstrated no change in type II regulatory (RIIalpha) or catalytic (Calpha) subunit expression, although site specific RIIalpha (Ser96) and Calpha (Thr197) phosphorylation were increased in HF. Further, the expression of type I regulatory subunit (RI) was increased in HF. Isoelectric focusing of RIalpha demonstrated up to three variants, consistent with reports that Ser77 and Ser83 are in vivo phosphorylation sites. Western blots with site-specific monoclonal antibodies showed increased Ser83 phosphorylation in HF. 8-fluo-cAMP binding by wild type and phosphomimic Ser77 and Ser83 mutant RIalpha proteins demonstrated reduced Kd for the double mutant as compared to WT RIalpha. Therefore, failing myocardium displays altered expression and post-translational modification of PKA subunits that may impact downstream signaling. PMID- 23942055 TI - A longitudinal examination of psychosocial impairment across the anxiety disorders. AB - BACKGROUND: Anxiety disorders are highly prevalent disorders associated with substantial psychosocial impairment, but few studies have examined impairment within specific anxiety disorders. Furthermore, it is unclear how change in different types of anxiety has an impact on change in impairment, particularly given high rates of co-morbidity. The current study assessed the temporal associations of impairment and symptoms of three common anxiety disorders in a large, diagnostically heterogeneous clinical sample. METHOD: Data were collected from 606 treatment-seeking individuals at an anxiety clinic, most of whom subsequently enrolled in cognitive-behavioral therapy. Symptoms of panic, social anxiety and generalized anxiety disorder (GAD), as well as levels of impairment, were assessed three times over 2 years. In addition to examining levels of impairment across diagnostic groups, latent growth modeling was used to evaluate the longitudinal associations of anxiety symptoms and impairment. RESULTS: Those with a principal diagnosis of GAD reported higher levels of impairment in some domains at baseline; however, at follow-up assessments individuals with social anxiety disorder reported greater impairment than those with panic disorder. Anxiety symptoms and impairment both declined over time. Change in all three anxiety symptoms was closely associated with change in impairment, but only GAD remained a significant (positive) predictor of change in impairment after accounting for co-morbidity. CONCLUSIONS: Impairment and all three anxiety disorders were closely associated, both cross-sectionally and longitudinally. Because change in GAD was most specifically related to change in impairment, treatment for those with multiple anxiety disorders could focus on treating GAD symptoms first or treating transdiagnostic processes. PMID- 23942054 TI - Transient knockdown of presenilin-1 provokes endoplasmic reticulum stress related formation of autophagosomes in HepG2 cells. AB - The involvement of presenilins in the endoplasmic reticulum (ER) related autophagy was investigated by their transient knockdown in HepG2 cells. The silencing of PSEN1 but not of PSEN2 led to cell growth impairment and decreased viability. PSEN1 silencing resulted in ER stress response as evidenced by the elevated levels of glucose regulated protein 78 (Grp78), protein disulfide isomerase (PDI), and CCAAT/enhancer-binding protein homologous protein (CHOP) and by the activation of activating transcription factor 6 (ATF6). The activation of autophagy was indicated by the increased procession of microtubule-associated light chain 3 protein isoform B (LC3B) and by decreased phosphorylation of mammalian target of rapamycin (mTOR) and 70kDa ribosomal protein S6 kinase (p70S6K). Formation of ER-related cytoplasmic vacuolization colocalizing with the autophagic marker LC3B was also observed. The morphological effects and LC3B activation in presenilin-1 knockdown cells could be prevented by using the phosphoinositide 3-kinase (PI3K) inhibitor wortmannin or by calcium chelation. The results show that presenilin-1 hampers the ER stress dependent initiation of macroautophagy. PMID- 23942056 TI - Phenotypic and metabolic aspects of prostatic epithelial cells in aged gerbils after antisteroidal therapy: turnover in the state of chromatin condensation and androgen-independent cell replacement. AB - The gerbil is a rodent considered a good model for studies of prostatic morphophysiology under different experimental conditions. Studies involving castration and steroidal blockers of aged gerbils showed that the glandular epithelium persists after long-term therapy, preventing the organ atrophy. Thus, the objective of this study was to evaluate the phenotypic characteristics and behavior of prostatic epithelial cells that remained after different periods of hormone ablation in aged gerbils. The identification of elements that influenced the survival of this cell type was performed by morphometric, nuclear phenotypes, ultrastructural and immune histochemical analysis. The most significant responses to treatment, by analyzing morphometric features, were observed during the first three time points (day 1, day 3, and day 7), after which there appeared to be an adjustment of the gland to the hormone ablation. All treatments led to changes in the state of chromatin condensation, DNA methylation pattern and phenotypic changes indicated cell senescence. Additionally, an increase in the basal cells seemed to guarantee self-renewal properties to the epithelium. These data indicate that changes occur at many levels, including gene expression and nuclear architecture in the epithelial cells, when aging and steroidal blockade are associated. These aspects are important when considering castration-resistant prostate cancer, a malignant tumor posing difficult therapeutic intervention. PMID- 23942057 TI - HLA correlates in a cohort of slow progressors from China: effects on HIV-1 disease progression. AB - We looked at our HIV + slow progressors cohort to determine if there were any human leukocyte antigen (HLA) correlates for protection. No statistically significant allelic differences were found between the HIV + and control cohorts using regression analysis, though trends were noted. Data for Elite Controllers showed an increased frequency of B*57. Likewise, no correlation was inferred with the clinical data of the HIV + cohort. We hypothesize that the protective effect of HLA alleles may have been lost over time. PMID- 23942058 TI - Disparities in HIV transmission risk among HIV-infected black and white men who have sex with men, United States, 2009. AB - OBJECTIVE: To better understand why HIV incidence is substantially higher among black than white men who have sex with men (MSM), we present the first nationally representative estimates of factors that contribute to transmission - sexual behavior, antiretroviral therapy (ART) use, and viral suppression - among HIV infected black and white MSM in the United States. DESIGN: The Medical Monitoring Project (MMP) is a complex sample survey of HIV-infected adults receiving medical care in the United States. METHODS: We used weighted interview and medical record data collected during June 2009 to May 2010 to estimate the prevalence of sexual behaviors, ART use, and viral suppression among sexually active HIV-infected black and white MSM. We used chi tests to assess significant differences between races and logistic regression models to identify factors that mediated the racial differences. RESULTS: Sexual risk behaviors among black and white MSM were similar. Black MSM were significantly less likely than white MSM to take ART (80 vs. 91%) and be durably virally suppressed (48 vs. 69%). Accounting for mediators (e.g. age, insurance, poverty, education, time since diagnosis, and disease stage) reduced, but did not eliminate, disparities in ART use and rendered differences in viral suppression among those on ART insignificant. CONCLUSION: Lower levels of ART use and viral suppression among HIV-infected black MSM may increase the likelihood of HIV transmission. Addressing the patient-level factors and structural inequalities that contribute to lower levels of ART use and viral suppression among this group will improve clinical outcomes and might reduce racial disparities in HIV incidence. PMID- 23942060 TI - In-vitro phenotypic susceptibility of HIV-1 'non-B' integrase inhibitors naive clinical isolates to dolutegravir and raltegravir. AB - In this study, we assessed phenotypic susceptibility to dolutegravir and raltegravir in a large variety of HIV-1 'non-B' subtypes (n = 72) issued from integrase inhibitor-naive clinical isolates. All samples were susceptible to both dolutegravir and raltegravir with median IC50 values of 1.22 nmol/l and 1.53 nmol/l, respectively; similar to that observed for the B subtype. Thus, despite the high prevalence of polymorphic substitutions in integrase in 'non-B' clinical isolates, phenotypic susceptibility to dolutegravir remained unchanged. PMID- 23942061 TI - Imaging and cognitive reserve studies predict dementia in presymptomatic Alzheimer's disease subjects. AB - There is strong evidence that Alzheimer's disease (AD) pathology starts decades before clinical onset. Cognitive reserve (CR) and brain reserve can be a good predictive model for AD development. Neuroimaging can help in describing cerebral reserves, as well as in detecting AD brain pathology before the onset of clinical dementia. Education and occupation act as proxies for CR and are associated with a lower risk of AD and delayed onset of symptoms. The apolipoprotein E (ApoE) epsilon4 allele is a strong risk factor for AD and is associated with lower hippocampal volume even in normal aging. A fluorodeoxyglucose positron emission tomography study of brain metabolism shows different metabolic phenotypes among subjects with different educational levels and ApoE genotypes. More highly educated subjects reach a clinical level when the cerebral areas involved in coping with network disruption are seriously impaired, and the AD-epsilon4 carriers show more global metabolic brain impairment compared with non-epsilon4 carriers. Thus, CR can counteract a genetically unfavorable background, suggesting a possible preventive strategy. AD research findings have already produced results, since recent epidemiological studies report a decreasing incidence of AD in the last years. PMID- 23942059 TI - Home visits during pregnancy enhance male partner HIV counselling and testing in Kenya: a randomized clinical trial. AB - BACKGROUND: HIV testing male partners of pregnant women may decrease HIV transmission to women and promote uptake of prevention of mother-to-child HIV transmission (PMTCT) interventions. However, it has been difficult to access male partners in antenatal care (ANC) clinics. We hypothesized that home visits to offer HIV testing to partners of women attending ANC would increase partner HIV testing. METHODS: Women attending their first ANC were enrolled, interviewed using smartphone audio-computer-assisted self-interviews and randomized to home visits or written invitations for male partners to come to clinic, if they were married or cohabiting, unaccompanied by partners and had no prior couple HIV counselling and testing (CHCT). Enrolled men were offered CHCT (HIV testing and mutual disclosure). Prevalence of CHCT, male HIV seropositivity, couple serodiscordance and intimate partner violence, reported as physical threat from partner, were compared at 6 weeks. RESULTS: Among 495 women screened, 312 were eligible, and 300 randomized to clinic-based or home-based CHCT. Median age was 22 years (interquartile range 20-26 years), and 87% were monogamous. CHCT was significantly higher in home-visit than in clinic-invitation arm (n = 128, 85% vs. n = 54, 36%; P < 0.001). Home-arm identified more HIV-seropositive men (12.0 vs. 8.0%; P = 0.248) and more HIV-discordant couples (14.7 vs. 4.7%; P = 0.003). There was no difference in intimate partner violence. CONCLUSION: Home visits of pregnant women were safe and resulted in more male partner testing and mutual disclosure of HIV status. This strategy could facilitate prevention of maternal HIV acquisition, improve PMTCT uptake and increase male HIV diagnosis. PMID- 23942062 TI - Association between aspartic acid repeat polymorphism of the asporin gene and susceptibility to knee osteoarthritis: a genetic meta-analysis. AB - OBJECTIVE: Knee osteoarthritis (KOA) is a common disease that is characterized by the degeneration of joint cartilage in the knee. Genetic factors have been implicated in KOA. Recently, several genetic studies have suggested that susceptibility to KOA is affected by the number of aspartic acid (D) residues in the amino-terminal of the asporin protein, but evidence remains conflicting. Therefore, the objective of the present meta-analysis was to investigate whether or not the D-repeat polymorphism is associated with susceptibility to KOA. METHODS: A systematic search of all relevant studies published through Dec 2012 was conducted using the MEDLINE, EMBASE, OVID, and ScienceDirect. Allelic counts were evaluated for the D14 and D13 alleles respectively. The included studies were only assessed in the analysis of the following allele model: D14 allele vs others alleles combined, D13 allele vs others alleles combined, and D14 allele vs D13 allele. RESULTS: Seven studies (eight comparisons) with 5515 total participants (2334 KOA patients and 3181 controls), which involved four Caucasian and four Asian populations, were eligible for inclusion. Meta-analysis was conducted for genotype D14 vs others combined, D13 vs others combined, and D14 vs D13. In the stratification based on ethnicity, studies were divided into Caucasian and Asian populations. We did not detect positive association between KOA and the D14 allele in Asian populations (OR = 1.527, 95% CI: 0.879-2.653) and in Caucasian populations (OR = 1.053, 95% CI: 0.905-1.225). There was also no positive association between susceptibility to KOA and D13 allele in Asian populations (OR = 0.950, 95% CI: 0.732-1.233) and in Caucasian populations (OR = 0.866, 95% CI: 0.723-1.037). CONCLUSION: The present results suggest that the D repeat of asporin gene (ASPN) may not be a major susceptibility locus in the Caucasian and Asian populations with KOA. Because of the limitations of the present meta-analysis, accurate conclusions could not be drawn based on the current evidence, and further studies with large sample size are required. PMID- 23942063 TI - Synovial fluid levels of bradykinin correlate with biochemical markers for cartilage degradation and inflammation in knee osteoarthritis. AB - OBJECTIVE: To determine the content of bradykinin (BK) and markers of cartilage degradation and inflammation in the synovial fluid (SF) of patients with knee osteoarthritis (OA), and to evaluate correlations with biomarkers or clinical parameters. METHODS: SFs were obtained from 30 patients with knee OA. Levels of basal and generated BK, cartilage oligomeric matrix protein (COMP), interleukin (IL) 1, IL-6, IL-8 and matrix metalloprotease (MMP) 1, MMP-3, MMP-13 and sulfated glycosaminoglycans (GAGs) were measured by enzyme-linked immunosorbent assay (ELISA) or colorimetric assays. RESULTS: The mean concentration of basal BK (in the presence of peptidase and protease inhibitors to avoid degradation and de novo formation of BK) was 422 pg/ml (95% confidence interval, CI, 281-563) whereas that of in vitro generated BK (in the presence of peptidase inhibitors SFs were incubated 60 min at 37 degrees C to measure the potential capability to generate BK) was 3427 pg/ml (2591-4264). The content of MMP-13, IL-1alpha, and IL 1beta was under assay sensitivity. Basal BK levels positively correlated (Spearman's rank correlation) with GAGs (40 MUg/ml, 26-54, r = 0.4834, P = 0.0308) and IL-6 (553 pg/ml, 171-935, r = 0.3946, P = 0.0377) similarly to the generated BK (GAGs, r = 0.4563, P = 0.0431; IL-6, r = 0.5605, P = 0.0019). Statistical analysis of basal BK and biomarkers was significant (P = 0.0483). When applying a stepwise logistic regression analysis considering biomarkers together with clinical parameters, results indicated that K/L radiographic OA grade and COMP improved the model (P = 0.0032). CONCLUSION: The presence of BK in the knee OA SF and its correlations with cartilage degradation and inflammation markers of OA support its participation in OA pathology. PMID- 23942065 TI - Comment on 'Fertility preservation in cancer survivors: a national survey of oncologists' current knowledge, practice and attitudes'--oncologists must not allow personal attitudes to influence discussions on fertility preservation for cancer survivors. PMID- 23942064 TI - Osteoarthritis year in review: outcome of rehabilitation. AB - PURPOSE: This review highlights seminal publications of rehabilitation interventions for osteoarthritis (OA) since April 2012. METHODS: Medline in process, Embase, CINAHL and Cochrane databases were searched from April 2012 through February 2013 for English language publications using key words osteoarthritis, rehabilitation, physiotherapy, physical therapy, and exercise. Rehabilitation intervention studies included randomized trials or systematic reviews/meta-analyses or pre-post studies. Pilot randomized trials, feasibility studies and studies of surgical interventions unless they included evaluation of a rehabilitation intervention were excluded. RESULTS: Twenty-five studies were identified for inclusion and grouped thematically. The short-term benefits (i.e., to 3 months) of variable types and dosages of exercise were demonstrated for a number of outcomes including pain, stiffness, function, balance, biomarkers, and executive function and dual task performance (related to falling) in people with knee OA. Modalities such as 890-nm radiation, interferential current, short wave diathermy, ultrasound and neuromuscular functional electrical stimulation did not demonstrate benefit over sham controls in those with knee OA. Spa therapy improved pain over the period of treatment in those with knee and hand OA. Supervised self-management based on cognitive therapy principles resulted in improved outcomes for people with knee OA. Shock absorbing insoles compared to normal footwear minimally improved knee pain and but not function and did not decrease knee load. Neuromuscular and motor training improved function in those with total hip replacement. Accelerated weight-bearing and rehabilitation (8 versus 11 weeks) was demonstrated to be safe and effective at 5 years following matrix autologous chondrocyte implantation for cartilage defects in the knee. CONCLUSIONS: Exercise remains a mainstay of conservative management although most studies report only short-term outcomes. Self-management strategies also are beneficial in knee OA. There seems to be a placebo effect with most trials of physical modalities although spa therapy demonstrated very short-term effects. PMID- 23942066 TI - Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI. AB - BACKGROUND: Non-invasive imaging biomarkers underpin the development of molecularly targeted anti-cancer drugs. This study evaluates tumour apparent diffusion coefficient (ADC), measured by diffusion-weighted magnetic resonance imaging (DW-MRI), as a biomarker of response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in human tumour xenografts. METHODS: Nude mice bearing human BRAF(V600D) WM266.4 melanoma or BRAF(V600E) Colo205 colon carcinoma xenografts were treated for 4 days with vehicle or selumetinib. DW-MRI was performed before and 2 h after the last dose and excised tumours analysed for levels of phospho-ERK1/2, cleaved caspase 3 (CC3) and necrosis. RESULTS: Selumetinib treatment induced tumour stasis and reduced ERK1/2 phosphorylation in both WM266.4 and Colo205 tumour xenografts. Relative to day 0, mean tumour ADC was unchanged in the control groups but was significantly increased by up to 1.6 fold in selumetinib-treated WM266.4 and Colo205 tumours. Histological analysis revealed a significant increase in necrosis in selumetinib-treated WM266.4 and Colo205 xenografts and CC3 staining in selumetinib-treated Colo205 tumours relative to controls. CONCLUSION: Changes in ADC following treatment with the MEK1/2 inhibitor selumetinib in responsive human tumour xenografts were concomitant with induction of tumour cell death. ADC may provide a useful non invasive pharmacodynamic biomarker for early clinical assessment of response to selumetinib and other MEK-ERK1/2 signalling-targeted therapies. PMID- 23942067 TI - Clinical significance of disseminated tumour cells in non-small cell lung cancer. AB - BACKGROUND: Early-stage non-small cell lung cancer (NSCLC) patients have a high risk of disease relapse despite curatively intended surgical resection, and the detection of tumour cells in the bone marrow could be one method of determining the presence of the disseminated disease in its early stages. METHODS: Bone marrow aspirates were collected from 296 patients at the time of surgery, and the presence of disseminated tumour cells was determined with the help of immunomagnetic selection (IMS) using the MOC31-antibody recognising EpCAM and with the help of standard immunocytochemistry (ICC) using the anti-cytokeratin (CK) antibodies AE1/AE3. RESULTS: Disseminated tumour cells were found in 152 of 252 (59%) bone marrow samples using IMS and in 25 of 234 (11%) samples using ICC. No association between the two detection methods was observed. The presence of EpCAM+ cells was not associated with any clinicopathological parameters, whereas a higher frequency of CK+ cells was found in patients with an advanced pT status. Disseminated tumour cells, as detected using IMS, had no prognostic impact. Patients with CK+ cells in the bone marrow had a reduced relapse-free survival, but the difference was not statistically significant. CONCLUSION: Our findings do not support the further development of DTC detection for clinical use in early stage NSCLC. Future studies should include the molecular characterisation of DTCs, along with an attempt to identify subpopulations of cells with biological and clinical significance. PMID- 23942068 TI - Formation and repair kinetics of Pt-(GpG) DNA adducts in extracted circulating tumour cells and response to platinum treatment. AB - BACKGROUND: Pt-(GpG) intrastrand crosslinks are the major DNA adducts induced by platinum-based anticancer drugs. In the cell lines and mouse models, the persistence of these lesions correlates significantly with cell damage. Here we studied Pt-(GpG) DNA adducts in circulating tumour cells (CTC) treated with cisplatin in medium upfront to systemic therapy from patients with advanced non small-cell lung cancer (NSCLC). METHODS: Blood was drawn before systemic treatment and the CD45/CD15-depleted fraction of mononuclear cells was exposed to cisplatin, verified for the presence of CTC by pan-cytokeratin (pCK) staining and immunoanalysed for the level of Pt-(GpG) in DNA. RESULTS: Immunostaining for pCK, CD45 and subsequently for Pt-(GpG) adducts in the cisplatin-exposed cells (ex vivo) at different time points depicted distinct differences for adduct persistence in CTC between responders vs non-responders. CONCLUSION: Pt-(GpG) adducts can be detected in CTC from NSCLC patients and assessing their kinetics may constitute a clinically feasible biomarker for response prediction and dose individualisation of platinum-based chemotherapy. This functional pre-therapeutic test might represent a more biological approach than measuring protein factors or other molecular markers. PMID- 23942069 TI - Support vector machine-based nomogram predicts postoperative distant metastasis for patients with oesophageal squamous cell carcinoma. AB - BACKGROUND: We aim to develop effective models for predicting postoperative distant metastasis for oesophageal squamous cell carcinoma (OSCC) for the purpose of guiding tailored therapy. METHODS: We used data from two centres to establish training (n=319) and validation (n=164) cohorts. All patients underwent curative surgical treatment. The clinicopathological features and 23 immunomarkers detected by immunohistochemistry were involved for variable selection. We constructed eight support vector machine (SVM)-based nomograms (SVM1-SVM4 and SVM1'-SVM4'). The nomogram constructed with the training cohort was tested further with the validation cohort. RESULTS: The outcome of the SVM1 model in predicting postoperative distant metastasis was as follows: sensitivity, 44.7%; specificity, 90.9%; positive predictive value, 81.0%; negative predictive value, 65.6%; and overall accuracy, 69.5%. The corresponding outcome of the SVM2 model was as follows: 44.7%, 92.1%, 82.9%, 65.9%, and 70.1%, respectively. The corresponding outcome of the SVM3 model was as follows: 55.3%, 93.2%, 87.5%, 70.7%, and 75.6%, respectively. The SVM4 model was the most effective nomogram in prediction, and the corresponding outcome was as follows: 56.6%, 97.7%, 95.6%, 72.3%, and 78.7%, respectively.Similar results were observed in SVM1', SVM2', SVM3', and SVM4', respectively. CONCLUSION: The SVM-based models integrating clinicopathological features and molecular markers as variables are helpful in selecting the patients of OSCC with high risk of postoperative distant metastasis. PMID- 23942070 TI - Cetuximab and platinum-based chemoradio- or chemotherapy of patients with epidermal growth factor receptor expressing adenoid cystic carcinoma: a phase II trial. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) is highly expressed in adenoid cystic carcinoma (ACC). The efficacy and toxicity of cetuximab with concomitant platinum-based chemoradio- or chemotherapy in patients with locally advanced or metastatic ACC, respectively, was evaluated. METHODS: Eligible patients (9 with locally advanced tumour and 12 with metastases) had positive tumour EGFR expression. The cetuximab loading dose (400 mg m-2) was followed by 250 mg m-2 per week. Locally advanced tumours were irradiated (mean dose 65 Gy) and treated with concomitant cisplatin (75 mg m-2, intravenously). Patients with metastases received concomitant cisplatin and 5-fluorouracil (4 * 1000 mg m-2). RESULTS: For patients with locally advanced disease (median follow-up: 52 months), the median progression-free survival (PFS) was 64 months and the 2-year overall survival (OS) rate was 100%. For patients with metastases (median follow up: 72 months), the median PFS and OS were 13 and 24 months, respectively. In both groups the objective response rate was >40%. Skin rash, in-field dermatitis, mucositis and vomiting were the most frequent grade 3/4 adverse events. CONCLUSION: In this single-arm study, the efficacy of cetuximab plus chemoradio- or chemotherapy appeared favourable as compared with historical controls. All side effects were manageable and did not hamper the treatment. PMID- 23942071 TI - Microtubule-associated protein tau facilitates the targeted killing of proliferating cancer cells in vitro and in a xenograft mouse tumour model in vivo. AB - BACKGROUND: Antibody drug conjugates (ADCs) and immunotoxins (ITs) are promising anticancer immunotherapeutics. Despite their encouraging performance in clinical trials, both ADCs and ITs often suffer from disadvantages such as stoichiometrically undefined chemical linkage of the cytotoxic payload (ADCs) and the potential immunogenicity of toxins derived from bacteria and plants (ITs). METHODS: Human microtubule-associated protein tau (MAP) was cloned in-frame with human EGF, expressed in E. coli and purified by standard chromatographic methods. The in vitro activity was confirmed by flow cytometry, cell viability assays and tubulin polymerisation assay. The in vivo efficacy was demonstrated using noninvasive far-red in vivo imaging. RESULTS: The EGF-MAP selectively induced apoptosis in EGFR-overexpressing proliferating cancer cells through stabilisation of microtubules. Nonproliferating cells were not affected, demonstrating superior selectivity of EGF-MAP for cancer cells. The EGF-MAP was well tolerated at high doses in mice compared with the ETA'-based control. The in vivo efficacy of EGF MAP was demonstrated in a tumour xenograft mouse model. CONCLUSION: Our data indicate the general mechanism of action for a new class of human immunotherapeutic reagents suitable for the treatment of cancer. This approach combines the binding specificity of targeting ligands with the selective cytotoxicity of MAP towards proliferating cells. PMID- 23942072 TI - Prospective validation of the breast cancer risk prediction model BOADICEA and a batch-mode version BOADICEACentre. AB - BACKGROUND: Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction algorithm that can be used to compute estimates of age-specific risk of breast cancer. It is uncertain whether BOADICEA performs adequately for populations outside the United Kingdom. METHODS: Using a batch mode version of BOADICEA that we developed (BOADICEACentre), we calculated the cumulative 10-year invasive breast cancer risk for 4176 Australian women of European ancestry unaffected at baseline from 1601 case and control families in the Australian Breast Cancer Family Registry. Based on 115 incident breast cancers, we investigated calibration, discrimination (using receiver-operating characteristic (ROC) curves) and accuracy at the individual level. RESULTS: The ratio of expected to observed number of breast cancers was 0.92 (95% confidence interval (CI) 0.76-1.10). The E/O ratios by subgroups of the participant's relationship to the index case and by the reported number of affected relatives ranged between 0.83 and 0.98 and all 95% CIs included 1.00. The area under the ROC curve was 0.70 (95% CI 0.66-0.75) and there was no evidence of systematic under- or over-dispersion (P=0.2). CONCLUSION: BOADICEA is well calibrated for Australian women, and had good discrimination and accuracy at the individual level. PMID- 23942073 TI - Clinical relevance of lymph node ratio in breast cancer patients with one to three positive lymph nodes. AB - BACKGROUND: To test the hypotheses that breast cancer patients with one to three positive lymph nodes (pN1) consist of heterogeneous prognostic subsets and that the ratio of positive nodes to total nodes dissected (lymph node ratio, LNR) might discriminate patients with a higher risk as candidates for post-mastectomy radiation therapy (PMRT). METHODS: Using information from 7741 node-positive patients, we first identified cutoff values of the LNR using the nonparametric bootstrap method. Focusing on 3477 patients with pN1 disease, we then evaluated the clinical relevance of the LNR categorised by the estimated cutoff values (categorised LNR, cLNR). RESULTS: Among 3477 patients with pN1 disease, 3059 and 418 patients were assigned into the low and intermediate cLNR groups, respectively, based on a cutoff value of 0.18. The prognostic factors associated with poor overall survival (OS) included younger age, T2 stage, negative oestrogen/progesterone receptors, high histologic grade, and intermediate cLNR. Post-mastectomy radiation therapy significantly increased OS in patients assigned to the intermediate cLNR (hazard ratio, 0.39; 95% confidence interval, 0.17-0.89; P=0.0248), whereas patients in the low cLNR group derived no additional survival benefit from PMRT. CONCLUSION: This study suggests that PMRT should be recommended for patients with pN1 disease and an intermediate cLNR. PMID- 23942074 TI - Baseline tumour measurements predict survival in advanced non-small cell lung cancer. AB - BACKGROUND: The association between tumour measurements and survival has been studied extensively in early-stage and locally advanced non-small cell lung cancer (NSCLC). We analysed these factors in patients with advanced NSCLC. METHODS: Data were derived from the E4599 trial of paclitaxel-carboplatin+/ bevacizumab. Associations between the Response Evaluation Criteria in Solid Tumors (RECIST) baseline sum longest diameter (BSLD), response rate, progression free survival (PFS) and overall survival (OS) were evaluated using univariate and multivariable Cox regression models. RESULTS: A total of 759 of the 850 patients (89%) in the E4599 trial had measurable diseases and were included in this analysis. The median BSLD was 7.5 cm. BSLD predicted OS (hazard ratio (HR) 1.41; P<0.001) and had a trend towards association with PFS (HR 1.14; P=0.08). The median OS was 12.6 months for patients with BSLD <7.5 cm compared with 9.5 months for BSLD >= 7.5 cm. This association persisted in a multivariable model controlling multiple prognostic factors, including the presence and sites of extrathoracic disease (HR 1.24; P=0.01). There was no association between BSLD and response rate. CONCLUSION: Tumour measurements are associated with survival in the E4599 trial. If validated in other populations, this parameter may provide important prognostic information to patients and clinicians. PMID- 23942075 TI - HER2-overexpressing breast cancer: FDG uptake after two cycles of chemotherapy predicts the outcome of neoadjuvant treatment. AB - BACKGROUND: Pathologic complete response (pCR) to neoadjuvant treatment (NAT) is associated with improved survival of patients with HER2+ breast cancer. We investigated the ability of interim positron emission tomography (PET) regarding early prediction of pathology outcomes. METHODS: During 61 months, consecutive patients with locally advanced or large HER2+ breast cancer patients without distant metastases were included. All patients received NAT with four cycles of epirubicin+cyclophosphamide, followed by four cycles of docetaxel+trastuzumab. 18F-fluorodeoxyglucose (18F-FDG)-PET/computed tomography (CT) was performed at baseline (PET1) and after two cycles of chemotherapy (PET2). Maximum standardised uptake values were measured in the primary tumour as well as in the axillary lymph nodes. The correlation between pathologic response and SUV parameters (SUVmax at PET1, PET2 and DeltaSUVmax) was examined with the t-test. The predictive performance regarding the identification of non-responders was evaluated using receiver operating characteristics (ROC) analysis. RESULTS: Thirty women were prospectively included and 60 PET/CT examination performed. At baseline, 22 patients had PET+ axilla and in nine of them 18F-FDG uptake was higher than in the primary tumour. At surgery, 14 patients (47%) showed residual tumour (non-pCR), whereas 16 (53%) reached pCR. Best prediction was obtained when considering the absolute residual SUVmax value at PET2 (AUC=0.91) vs 0.67 for SUVmax at PET1 and 0.86 for DeltaSUVmax. The risk of non-pCR was 92.3% in patients with any site of residual uptake >3 at PET2, no matter whether in breast or axilla, vs 11.8% in patients with uptake <=3 (P=0.0001). The sensitivity, specificity, PPV, NPV and overall accuracy of this cutoff were, respectively: 85.7%, 93.8%, 92.3%, 88.2% and 90%. CONCLUSION: The level of residual 18F-FDG uptake after two cycles of chemotherapy predicts residual disease at completion of NAT with chemotherapy+trastuzumab with high accuracy. Because many innovative therapeutic strategies are now available (e.g., addition of a second HER2 directed therapy or an antiangiogenic), early prediction of poor response is critical. PMID- 23942077 TI - Reply: Comment on 'Fertility preservation in cancer survivors: a national survey of oncologists' current knowledge, practice and attitudes'--oncologists must not allow personal attitudes to influence discussions on fertility preservation for cancer survivors. PMID- 23942076 TI - Which breast cancer decisions remain non-compliant with guidelines despite the use of computerised decision support? AB - BACKGROUND: Despite multidisciplinary tumour boards (MTBs), non-compliance with clinical practice guidelines is still observed for breast cancer patients. Computerised clinical decision support systems (CDSSs) may improve the implementation of guidelines, but cases of non-compliance persist. METHODS: OncoDoc2, a guideline-based decision support system, has been routinely used to remind MTB physicians of patient-specific recommended care plans. Non-compliant MTB decisions were analysed using a multivariate adjusted logistic regression model. RESULTS: Between 2007 and 2009, 1624 decisions for invasive breast cancers with a global non-compliance rate of 8.3% were analysed. Patient factors associated with non-compliance were age>80 years (odds ratio (OR): 7.7; 95% confidence interval (CI): 3.7-15.7) in pre-surgical decisions; microinvasive tumour (OR: 5.2; 95% CI: 1.5-17.5), surgical discovery of microinvasion in addition to a unique invasive tumour (OR: 4.2; 95% CI: 1.4-12.5), and prior neoadjuvant treatment (OR: 4.2; 95% CI: 1.1-15.1) in decisions with recommendation of re-excision; age<35 years (OR: 4.7; 95% CI: 1.9-11.4), positive hormonal receptors with human epidermal growth factor receptor 2 overexpression (OR: 15.7; 95% CI: 3.1-78.7), and the absence of prior axillary surgery (OR: 17.2; 95% CI: 5.1-58.1) in adjuvant decisions. CONCLUSION: Residual non compliance despite the use of OncoDoc2 illustrates the need to question the clinical profiles where evidence is missing. These findings challenge the weaknesses of guideline content rather than the use of CDSSs. PMID- 23942078 TI - Ribosomal s6 protein kinase 4: a prognostic factor for renal cell carcinoma. AB - BACKGROUND: The expression and function of ribosomal s6 protein kinase 4 (RSK4) in renal cell carcinoma (RCC) are unknown. METHODS: Immunohistochemistry was used to detect the expression of RSK4 in RCC, and the relationship between RSK4 expression and clinicopathological features as well as prognosis of RCC patients was statistically analysed. Ectopic RSK4 expression in RCC cell lines was performed to determine its effect on cell cycle regulation, tumour invasiveness, and metastatic capability. RESULTS: RSK4 was overexpressed in RCCs (P=0.003), compared with normal tissues, and the expression varied in different RCC subtypes (P=0.021), especially in two subtypes of papillary RCCs (P=0.001). RSK4 expression was positively correlated with high pT stage (P<0.001), high Fuhrman grade (P<0.001), lymph node involvement (P<0.001), and presence of distant metastasis (P=0.039), and could predict poor outcome in RCC patients. Molecular studies showed that overexpression of RSK4 could promote cell cycle progression and enhance the invasive and metastatic capability of RCC cell lines and vice versa. CONCLUSION: The expression pattern and molecular mechanisms of RSK4 in RCCs indicate that it could be a potential independent prognostic factor and serve as a new potential therapeutic target for RCC patients. PMID- 23942079 TI - Mutational analysis of Polycomb genes in solid tumours identifies PHC3 amplification as a possible cancer-driving genetic alteration. AB - BACKGROUND: Polycomb group genes (PcGs) are epigenetic effectors implicated in most cancer hallmarks. The mutational status of all PcGs has never been systematically assessed in solid tumours. METHODS: We conducted a multi-step analysis on publically available databases and patient samples to identify somatic aberrations of PcGs. RESULTS: Data from more than 1000 cancer patients show for the first time that the PcG member PHC3 is amplified in three epithelial neoplasms (rate: 8-35%). This aberration predicts poorer prognosis in lung and uterine carcinomas (P<0.01). Gene amplification correlates with mRNA overexpression (P<0.01), suggesting a functional role of this aberration. CONCLUSION: PHC3 amplification may emerge as a biomarker and potential therapeutic target in a relevant fraction of epithelial tumours. PMID- 23942081 TI - Differential relationships between set-shifting abilities and dimensions of insight in schizophrenia. AB - BACKGROUND: To assess insight in a large sample of patients with schizophrenia and to study its relationship with set shifting as an executive function. METHODS: The insight of a sample of 161 clinically stable, community-dwelling patients with schizophrenia was evaluated by means of the Scale to Assess Unawareness of Mental Disorder (SUMD). Set shifting was measured using the Trail Making Test time required to complete part B minus the time required to complete part A (TMT B-A). Linear regression analyses were performed to investigate the relationships of TMT B-A with different dimensions of general insight. RESULTS: Regression analyses revealed a significant association between TMT B-A and two of the SUMD general components: 'awareness of mental disorder' and 'awareness of the efficacy of treatment'. The 'awareness of social consequences' component was not significantly associated with set shifting. CONCLUSIONS: Our results show a significant relation between set shifting and insight, but not in the same manner for the different components of the SUMD general score. PMID- 23942082 TI - Gold nanoisland arrays by repeated deposition and post-deposition annealing for surface-enhanced Raman spectroscopy. AB - Gold nanoisland arrays with well controlled growth were achieved by repeated sputtering deposition and post-deposition annealing processes. When each deposition was set at 5 nm (nominal thickness based on gold mass), the single deposition and annealing process (single process) yielded gold nanoisland arrays with an average diameter of ~16 nm based on top view scanning electron microscopy (SEM). When the deposition and annealing process was repeated two more times (triple process), top view SEM showed the nanoisland arrays grew to ~38 nm in average diameter. The surface-enhanced Raman spectroscopy (SERS) measurement indicated that triple processed nanoisland arrays led to the highest SERS enhancement, suggesting the necessity of pursuing nanoislands with larger sizes. The gold nanoisland arrays after the triple process were further sputtered with a final layer of gold thin film at different nominal thicknesses. An optimal nominal thickness for SERS was determined experimentally at ~40 nm, as a result of the competition between the positive and negative effects of the final gold deposition. Last, the uniformity of the optimized SERS substrate was investigated on a 5 cm x 5 cm platform. SERS measurements demonstrated a relative standard deviation of ~7% in terms of spectral variation over the entire substrate, rendering the process in the present study a promising fabrication approach for large-scale production of SERS substrates. PMID- 23942080 TI - A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours. AB - BACKGROUND: This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics, and antitumour activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with docetaxel in patients with incurable solid tumours. METHODS: PX-866 was administered at escalating doses (4-8 mg daily) with docetaxel 75 mg m-2 intravenously every 21 days. Archived tumour tissue was assessed for potential predictive biomarkers. RESULTS: Forty-three patients were enrolled. Most adverse events (AEs) were grade 1 or 2. The most frequent study drug-related AE was diarrhoea (76.7%), with gastrointestinal disorders occurring in 79.1% (docetaxel related) and 83.7% (PX-866-related). No dose-limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent MTD. Co-administration of PX-866 and docetaxel did not affect either drug's PKs. Best responses in 35 evaluable patients were: 2 partial responses (6%), 22 stable disease (63%), and 11 disease progression (31%). Eleven patients remained on study for >180 days, including 8 who maintained disease control on single-agent PX-866. Overall median progression free survival (PFS) was 73.5 days (range: 1-569). A non-significant association between longer PFS for PIK3CA-MUT/KRAS-WT vs PIK3CA-WT/KRAS-WT was observed. CONCLUSION: Treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity. Further investigation with this combination is justified. PMID- 23942083 TI - Seed-mediated connectivity among fragmented populations of Quercus castanea (Fagaceae) in a Mexican landscape. AB - PREMISE OF STUDY: Anthropogenic fragmentation is an ongoing process in many forested areas that may create loss of connectivity among tree populations and constitutes a serious threat to ecological and genetic processes. We tested the central hypothesis that seed dispersal mitigates the impact of fragmentation by comparing connectivity and genetic diversity of adult vs. seedling populations in recently fragmented populations of the Mexican red oak Quercus castanea. METHODS: Adult individuals, established before fragmentation, and seedlings, established after fragmentation, were sampled at 33 forest fragments of variable size (0.2 to 294 ha) within the Cuitzeo basin, Michoacan state, and genotyped using seven highly polymorphic chloroplast microsatellite markers (cpSSRs). To test whether seed dispersal retains connectivity among fragmented populations, we compared genetic diversity and connectivity networks between adults and progeny and determined the effect of fragment size on these values. KEY RESULTS: Seventy haplotypes were identified, 63 in the adults and 60 in the seedlings, with average within-population diversity (hS) values of 0.624 in the adults and 0.630 in the seedlings. A positive correlation of genetic diversity values with fragment size was found in the seedling populations but not in the adult populations. The network connectivity analysis revealed lower connectivity among seedling populations than among adults. The number of connections (edges) as well as other network properties, such as betweenness centrality, node degree and closeness, were significantly lower in the seedlings network. CONCLUSIONS: Habitat fragmentation in this landscape is disrupting seed-dispersal-mediated genetic connectivity among extant populations. PMID- 23942084 TI - Anatomical and physical changes in leaves during the production of tamales. AB - PREMISE OF THE STUDY: Tamale preparation has a long tradition in Mexico. To understand which material properties have been considered important for this purpose throughout the years, a study was conducted of the anatomical, chemical, and mechanical properties of the leaves of four plant species used in tamale preparation in Veracruz, Mexico: Calathea misantlensis, Canna indica, Musa paradisiaca, and Oreopanax capitatus. METHODS: Four cooking treatments were considered: fresh (F), roasted (soasado, R), steamed (S), and roasted plus steamed (R/S). Chemical, anatomical, and mechanical analyses were conducted before and after each treatment. Leaf samples were tested for tensile strength at both parallel and perpendicular orientation relative to the fibers. KEY RESULTS: Musa paradisiaca had the highest proportion of cellulose, while the remaining species shared similar lower proportions. Leaves were stronger and stiffer in the longitudinal direction of the fibers. Musa paradisiaca leaves had higher values of mechanical strength than the other species. The cooking process that most affected the mechanical properties was steaming. CONCLUSIONS: The chemical constituents of the leaves are closely correlated with their physical properties. The treatment that caused the greatest decrease in leaf physical integrity was steaming, while the combination of roasting and steaming showed similar results to those of steaming alone. No evident anatomical changes are produced by any of the treatments. This is one of the few studies comparing physical, chemical, and anatomical characteristics of leaves used for human consumption, before and after cooking. PMID- 23942085 TI - Intraspecies variation in cotton border cell production: rhizosphere microbiome implications. AB - PREMISE OF THE STUDY: Border cells, which separate from the root cap, can comprise >90% of carbon-based exudates released into the rhizosphere, but may not provide a general source of nutrients for soil microorganisms. Instead, this population of specialized cells appears to function in defense of the root tip by an extracellular trapping process similar to that of mammalian white blood cells. Border cell production is tightly regulated, and direct tests of their impact on crop production have been hindered by lack of intraspecies variation. * METHODS: Border cell number, viability, and clumping were compared among 22 cotton cultivars. Slime layer "extracellular trap" production by border cells in response to copper chloride, an elicitor of plant defenses, was compared in two cultivars with divergent border cell production. Trapping of bacteria by border cells in these lines also was measured. * KEY RESULTS: Emerging roots of some cultivars produced more than 20000 border cells per root, a 100% increase over previously reported values for this species. No differences in border cell morphology, viability, or clumping were found. Copper chloride-induced extracellular trap formation by border cells from a cultivar that produced 27921 +/- 2111 cells per root was similar to that of cells from a cultivar with 10002 +/- 614 cells, but bacterial trapping was reduced. * CONCLUSIONS: Intraspecific variation in border cell production provides a tool to measure their impact on plant development in the laboratory, greenhouse, and field. Further research is needed to determine the basis for this variation, and its impact on rhizosphere community structure. PMID- 23942086 TI - Temperature regulates positively photoblastic seed germination in four ficus (moraceae) tree species from contrasting habitats in a seasonal tropical rainforest. AB - PREMISE OF THE STUDY: Differences in seed germination responses of trees in tropical forests to temperature and light quality may contribute to their coexistence. We investigated the effects of temperature and red:far-red light (R:FR ratio) on seed germination of two gap-demanding species (Ficus hispida and F. racemosa) and two shade-tolerant species (F. altissima and F. auriculata) in a tropical seasonal rainforest in southwest China. METHODS: A R:FR ratio gradient was created by filtering fluorescent light through polyester filters. Four temperature treatments were used to test the effect of temperature on seed germination of the four Ficus tree species across the R:FR gradient. KEY RESULTS: Seeds of the four Ficus species were positively photoblastic. Seed germination of F. hispida and F. racemosa was not affected across the R:FR ratio gradient (0.25 1.19) at 25/35 degrees C, but it was inhibited under low R:FR at 22/23 degrees C. By contrast, germination percentages of F. altissima and F. auriculata were not inhibited along the entire light gradient in all temperature treatments. CONCLUSIONS: Differences in germination responses of Ficus species might contribute to differences in their habitat preferences. The inhibitory effect of understory temperatures in the forest might be a new mechanism that prevents positively photoblastic seeds of the gap-demanding species such as F. hispida and F. racemosa from germinating in the understory and in small canopy gaps. PMID- 23942087 TI - Fruit structure in Magnoliaceae s.l. and Archaeanthus and their relationships. AB - PREMISE OF THE STUDY: The family Magnoliaceae s.l. is a basal angiosperm family with two subfamilies-Magnolioideae and Liriodendroideae, which differ by the types and structure of their fruits and seeds. The late Albian genus Archaeanthus shares many features of its reproductive organs with Magnoliaceae s.l., but its pericarp anatomy was never studied in detail. A broad-scale carpological investigation of Archaeanthus and Magnoliaceae s.l. was undertaken to reveal the nature of the similarities in fruit structure and to reconstruct Archaeanthus pericarp anatomy. These data are important to determine the early stages of fruit morphogenesis and thus to clarify relationships of Archaeanthus to the taxa of Magnoliaceae s.l. METHODS: The pericarp anatomy was studied with light microscopy, SEM, and polarizing microscopy. KEY RESULTS: The dehiscent, polyspermous follicles shed from the receptacle of Archaeanthus share similarities with dehiscent follicles of Magnoliaceae s.s. and shedding nutlets of Liriodendron. The seeds of Archaeanthus are dorsiventrally flattened, ovoid, and encircled with a single circular wing. The pericarps of all the taxa studied are differentiated into exocarp (epidermis), multilayered mesocarp, and endocarp (fiber-like sclereids). The mesocarp consists of parenchyma with scattered secretory cells and sclereid clusters (Magnoliaceae s.s., Archaeanthus) or composed by sclerenchyma (Liriodendron). CONCLUSIONS: The specializations of dehiscent multifollicles of unknown Cretaceous ancestors for different modes of seed and fruitlet dispersal formed the basis for the differentiation of two evolutionary lines with their divergence occurring more than 100 million years ago: Magnoliaceae s.s. and the Archaeanthus-Liriodendroidea-Liriodendron line (Liriodendraceae s.l.) within the order Magnoliales. PMID- 23942088 TI - Effect of DHA and coenzymeQ10 against Abeta- and zinc-induced mitochondrial dysfunction in human neuronal cells. AB - BACKGROUND: Beta-amyloid (Abeta) protein is a key factor in the pathogenesis of Alzheimer's disease (AD) and it has been reported that mitochondria is involved in the biochemical pathway by which Abeta can lead to neuronal dysfunction. Coenzyme Q10 (CoQ10) is an essential cofactor involved in the mitochondrial electron transport chain and has been suggested as a potential therapeutic agent in AD. Zinc toxicity also affects cellular energy production by decreasing oxygen consumption rate (OCR) and ATP turnover in human neuronal cells, which can be restored by the neuroprotective effect of docosahexaenoic acid (DHA). METHOD: In the present study, using Seahorse XF-24 Metabolic Flux Analysis we investigated the effect of DHA and CoQ10 alone and in combination against Abeta- and zinc mediated changes in the mitochondrial function of M17 neuroblastoma cell line. RESULTS: Here, we observed that DHA is specifically neuroprotective against zinc triggered mitochondrial dysfunction, but does not directly affect Abeta neurotoxicity. CoQ10 has shown to be protective against both Abeta- and zinc induced alterations in mitochondrial function. CONCLUSION: Our results indicate that DHA and CoQ10 may be useful for the prevention, treatment and management of neurodegenerative diseases such as AD. PMID- 23942089 TI - The influence of early drinking contexts on current drinking among adult lesbian and bisexual women. AB - BACKGROUND: Differences exist in alcohol-related outcomes across subgroups of sexual minority women. Likewise, stressors associated with coming out and living as lesbian or bisexual are hypothesized to be highly variable. Lesbians' and bisexual women's risks for hazardous drinking are explored in a 2006 NIAAA-funded interview study of women living in the Northeastern United States. OBJECTIVES: The primary objective of the present study is to replicate and extend an earlier analysis of the relationship between early drinking contexts and current drinking outcomes of adult lesbians with a convenience sample that includes a subgroup of self-identified bisexual women. Potential differences in the early drinking contexts of these two groups of self-identified lesbian and bisexual women are also explored. DESIGN: Bivariate and multiple regression analyses are used to examine relationships between early drinking contexts and current drinking of a racially and age-diverse convenience sample of 145 adult lesbian (N = 94) and bisexually identified (N = 51) women. RESULTS AND CONCLUSIONS: Consistent with previous research, patterns established while coming out have an enduring effect on drinking outcomes of lesbians; findings for bisexual women are inconclusive. Implications for research and practice are discussed. PMID- 23942091 TI - Pertuzumab: optimizing HER2 blockade. AB - Pertuzumab has been approved by the U.S. Food and Drug Administration for use in combination with trastuzumab and docetaxel for the first-line treatment of patients with advanced HER2-positive (HER2(+)) breast cancer. Pertuzumab is a recombinant humanized monoclonal antibody that binds to the extracellular dimerization domain II of HER2 and inhibits heterodimerization of HER2 with other HER family members, including EGF receptor (EGFR), HER3, and HER4. The HER2-HER3 heterodimer is a robust activator of phosphoinositide 3-kinase (PI3K) pathway signaling and functions as the most transforming and mitogenic of the receptor complexes formed by the HER family of proteins; thus, blockade of HER2-HER3 likely represents the most relevant action of pertuzumab. In the seminal phase III study, patients with HER2(+) metastatic breast cancer were randomized to receive trastuzumab and docetaxel, with or without pertuzumab: Addition of pertuzumab significantly prolonged progression-free survival with an increase of 6.1 months (12.4 vs. 18.5 months, respectively). In a subsequent analysis with 30 months of median follow-up, pertuzumab conferred a 34% reduction in the risk of mortality. Here, we review the mechanism of action of pertuzumab, the rationale for combining it with trastuzumab/pertuzumab, clinical data, and future directions for this work. PMID- 23942090 TI - Predicting outcomes among adolescents with disruptive disorders being treated in a system of care program. AB - BACKGROUND: "Systems of care" are strengths-based approaches to treating adolescents and others with disruptive disorders. However, little is known about why some adolescents improve and others do not. OBJECTIVE: To examine changes in personal strengths and family functioning as predictors of behavioral and social functioning among adolescents with disruptive disorders who participated in a system of care program. DESIGN: Secondary analyses of data from 114 adolescents (12-17 years of age) with disruptive disorders and their caregivers who participated in the Dawn Project Evaluation Study. Caregivers completed in-depth interviews conducted by trained data collectors using standardized questionnaires. Baseline and 12- month data are reported here. RESULTS: Improvement in personal strengths was a significant predictor of improvement in adolescent behavioral and social functioning, controlling for demographics (p < .001). CONCLUSION: In adolescents with disruptive disorders, psychiatric nurses should focus on enhancing adolescents' personal strengths to improve behavioral and social functioning. PMID- 23942092 TI - Identification of lethal microRNAs specific for head and neck cancer. AB - PURPOSE: The prognosis of head and neck squamous cell carcinomas (HNSCC) remains disappointing and the development of novel anti-cancer agents is urgently awaited. We identified by a functional genetic screen microRNAs that are selectively lethal for head and neck cancer cells but not for normal cells. We further investigated the genes targeted by these microRNAs. EXPERIMENTAL DESIGN: A retroviral expression library of human microRNAs was introduced in HNSCC cell lines and normal oropharyngeal keratinocytes to identify tumor-selective lethal microRNAs. Potential downstream gene targets of these microRNAs were identified by gene expression profiling and validated by functional assays. RESULTS: We identified six microRNAs that selectively inhibit proliferation of head and neck cancer cells. By gene expression profiling and 3'-untranslated region (UTR) luciferase reporter assays, we showed that the ataxia telangiectasia mutated (ATM) gene is a common target for at least two and likely three of these microRNAs. Specific inhibition of ATM resulted in a similar tumor-specific lethal effect, whereas the phenotype was reverted in rescue experiments. CONCLUSIONS: These six microRNAs might be developed as novel anti-cancer agents and highlight ATM as an interesting novel therapeutic target for head and neck cancer. PMID- 23942094 TI - Novel clinically relevant genes in gastrointestinal stromal tumors identified by exome sequencing. AB - PURPOSE: Chromosomal gains and losses resulting in altered gene dosage are known to be recurrent in gastrointestinal stromal tumors (GIST). The aim of our study was the identification of clinical relevant genes in these candidate regions. MATERIAL AND METHODS: A cohort of 174 GIST was investigated using DNA array (n = 29), FISH (n = 125), exome sequencing (n = 13), and immunohistochemistry (n = 145). RESULTS: Array analysis revealed recurrent copy number variations (CNVs) of chromosomal arms 1p, 1q, 3p, 4q, 5q, 7p, 11q, 12p, 13q, 14q, 15q, and 22q. FISH studies of these CNVs showed that relative loss of 1p was associated with shorter disease-free survival (DFS). Analysis of exome sequencing concentrating on target regions showing recurrent CNVs revealed a median number of 3,404 (range 1,641 13,602) variants (SNPs, insertions, deletions) in each tumor minus paired blood sample; variants in at least three samples were observed in 37 genes. After further analysis, target genes were reduced to 10 in addition to KIT and PDGFRA. Immunohistochemical investigation showed that expression of SYNE2 and DIAPH1 was associated with shorter DFS, expression of RAD54L2 with shorter and expression of KIT with longer overall survival. CONCLUSION: Using a novel approach combining DNA arrays, exome sequencing, and immunohistochemistry, we were able to identify 10 target genes in GIST, of which three showed hithero unknown clinical relevance. Because the identified target genes SYNE2, MAPK8IP2, and DIAPH1 have been shown to be involved in MAP kinase signaling, our data further indicate the important role of this pathway in GIST. PMID- 23942093 TI - Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. AB - PURPOSE: The AMP-activated protein kinase (AMPK) serves as an energy sensor in eukaryotic cells and occupies a central role in linking metabolism and cancer development. However, the phosphorylation status of AMPK and its therapeutic value in human hepatocellular carcinoma (HCC) remain unclear. EXPERIMENTAL DESIGN: The phosphorylation status of AMPK (Thr172) was determined by immunoblotting and immunostaining in specimens from 273 patients with HCC (including 253 patients with hepatitis B virus -related HCC). Kaplan-Meier survival analysis was used to determine the correlation with prognosis. The effects of therapeutic metformin/AMPK activation were assessed in cultured human HCC cell lines and primary HCC cells in vitro and in xenograft tumors model in vivo. To define the mechanisms of anticancer effects of metformin, we examined its influence on AMPK activation and NF-kappaB pathway. RESULTS: AMPK is dysfunctional in patients with HCC, and low p-AMPK staining is correlated with aggressive clinicopathologic features and poor prognosis. Activation of AMPK by metformin not only inhibited HCC cells growth in vitro and in vivo, but also augmented cisplatin-induced growth inhibition in HCC cells. Knockdown of AMPKalpha expression can greatly decrease the inhibitory effect of metformin, indicating that AMPK activation is required for the anticancer action of metformin. Mechanistically, metformin/AMPK activation inhibited NF-kappaB signaling through upregulation of IkappaBalpha. Activation of NF-kappaB signaling by ectopic expression of P65 or overexpression of an undegradable mutant form of IkappaBalpha attenuated the anticancer effects of metformin. CONCLUSIONS: These results present novel insight into a critical role of AMPK in HCC progression. Anticancer effects of therapeutic metformin/AMPK activation unravel metformin's potential in treatment of HCC. PMID- 23942097 TI - Reading outside the box. PMID- 23942095 TI - Pharmacologic inhibition of Jak2-Stat5 signaling By Jak2 inhibitor AZD1480 potently suppresses growth of both primary and castrate-resistant prostate cancer. AB - PURPOSE: Progression of prostate cancer to the lethal castrate-resistant stage coincides with loss of responsiveness to androgen deprivation and requires development of novel therapies. We previously provided proof-of-concept that Stat5a/b is a therapeutic target protein for prostate cancer. Here, we show that pharmacologic targeting of Jak2-dependent Stat5a/b signaling by the Jak2 inhibitor AZD1480 blocks castrate-resistant growth of prostate cancer. EXPERIMENTAL DESIGN: Efficacy of AZD1480 in disrupting Jak2-Stat5a/b signaling and decreasing prostate cancer cell viability was evaluated in prostate cancer cells. A unique prostate cancer xenograft mouse model (CWR22Pc), which mimics prostate cancer clinical progression in patients, was used to assess in vivo responsiveness of primary and castrate-resistant prostate cancer (CRPC) to AZD1480. Patient-derived clinical prostate cancers, grown ex vivo in organ explant cultures, were tested for responsiveness to AZD1480. RESULTS: AZD1480 robustly inhibited Stat5a/b phosphorylation, dimerization, nuclear translocation, DNA binding, and transcriptional activity in prostate cancer cells. AZD1480 reduced prostate cancer cell viability sustained by Jak2-Stat5a/b signaling through induction of apoptosis, which was rescued by constitutively active Stat5a/b. In mice, pharmacologic targeting of Stat5a/b by AZD1480 potently blocked growth of primary androgen-dependent as well as recurrent castrate resistant CWR22Pc xenograft tumors, and prolonged survival of tumor-bearing mice versus vehicle or docetaxel-treated mice. Finally, nine of 12 clinical prostate cancers responded to AZD1480 by extensive apoptotic epithelial cell loss, concurrent with reduced levels of nuclear Stat5a/b. CONCLUSIONS: We report the first evidence for efficacy of pharmacologic targeting of Stat5a/b as a strategy to inhibit castrate-resistant growth of prostate cancer, supporting further clinical development of Stat5a/b inhibitors as therapy for advanced prostate cancer. PMID- 23942099 TI - Understanding the fundamentals of measurement instruments. PMID- 23942098 TI - Using the patient engagement framework to develop an institutional mobile health strategy. AB - An increasing number of patients with chronic conditions present a challenge to the health care system in the United States and around the globe. The numbers of chronically ill patients who have mobile phones are also on the rise. Mobile phones present an opportunity for the clinical nurse specialist to reach large numbers of patients with chronic conditions as well as their caregivers, including minorities and those of lower socioeconomic status. Although the latest research evidence does not yet support the widespread adoption of mobile technologies for care provision, health care institutions can start forming a step-by-step plan to engage with patients and their families through mobile technologies. The modified Patient Engagement Framework offers steps to adoption of mobile health applications. PMID- 23942100 TI - Medication adherence and patient outcomes: part 1: why patients fail to take prescribed medications. PMID- 23942101 TI - Unfractionated heparin versus low-molecular-weight heparin for avoiding heparin induced thrombocytopenia in postoperative patients. PMID- 23942102 TI - A pilot study to test the feasibility of a nonpharmacologic intervention for the prevention of delirium in the medical intensive care unit. AB - PURPOSE/OBJECTIVES: The aims of this study were to determine the feasibility of and test a multicomponent, nonpharmacologic, nurse-driven intervention for prevention of delirium. DESIGN: This was a prospective, cohort pilot study. SETTING: This study was carried out in a 12-bed medical intensive care unit in a Magnet-designated community hospital in a major metropolitan city in the Southwest United States. SAMPLE: A convenience sample of consented patients meeting inclusion criteria was included in this study. METHODS: A multicomponent prevention protocol consisting of sedation cessation, sleep-wake cycles, sensory stimulation, mobility, and music was tested. FINDINGS: Capturing data for the interventions was problematic. Insufficient documentation systems and inadequate multidisciplinary participation in carrying out the protocol, especially mobility, were barriers. CONCLUSIONS: There was little difference in the proportion of delirium before and after intervention. Success in the identification and prevention of delirium requires a multidisciplinary approach. IMPLICATIONS: Further research is needed using a larger sample size. Refinement of a mobility program is needed. PMID- 23942103 TI - Changes in provider perceptions of family presence during resuscitation. AB - PURPOSE/OBJECTIVES: The purpose of this study was to measure changes in perceptions of healthcare providers (HCPs) in the cardiac intensive care unit (CICU) before and after an implementation of an educational program that included approval of a unit-based guideline for family presence (FP) during resuscitation and invasive procedures. DESIGN: A descriptive pretest and posttest design was used to measure changes in perception for FP during resuscitation and invasive procedures. SETTING: The setting for this study was a CICU of a large academic medical center. SAMPLE: A convenient sample of HCPs who work in a CICU was included in this study. METHODS: Healthcare providers completed the FP scales for confidence and risk-benefit for resuscitation and invasive procedure before and after the implementation of an FP educational program. The program included presentations, discussions, and collaborative guideline development approval with CICU HCPs. FINDINGS: There were 43 HCPs before and 40 HCPs after the FP educational program who completed the FP Confidence and Risk-Benefit Scales. There was improvement in FP Risk Benefit Scale for resuscitation (P < .01), although there was no change in the invasive procedure scale. There was no significant change in confidence for FP for resuscitation or invasive procedures, although there was a trend toward improved scores. There was a significant increase in the number of family members present during resuscitation after the educational program (P < .02). IMPLICATIONS: The conduct of FP educational program and the approval of a unit-based guideline improved HCPs' perception of risk and benefit of FP during resuscitation and the actual presence of family during resuscitation. This effort provided the infrastructure for FP in the CICU and support for further FP efforts. PMID- 23942104 TI - Skills and attributes required by clinical nurse specialists to promote evidence based practice. AB - PURPOSE/OBJECTIVES: The purposes of this article were to describe the challenges that clinical nurse specialists (CNS) face in their role and to examine how CNSs describe the skills and attributes that are needed to promote the use of evidence based practice (EBP) in their workplaces. This article is based on findings from a dissertation regarding how CNSs promote EBP in a western Canadian province. DESIGN: A sequential explanatory participant selection mixed-methods design was used for this study. SETTING: The study took place in a western Canadian province that has a population of 1 million people, with 42.7% of the population residing in the 2 largest cities. SAMPLE: The sample was drawn from a provincial registered nurse database. The sample for the survey was 23, and for the interviews, there were 11 participants. METHODS: The telephone survey contained 113 questions grouped into several subcategories. SPSS 18 was used to analyze the survey data. The semistructured interviews were conducted face to face, transcribed, and reviewed for recurrent themes. Interpretive description was used to analyze the themes. FINDINGS: The major challenges faced by CNSs are role strain, lack of support and resources, and role ambiguity. The skills and attributes required to be a CNS are graduate preparation, clinical expertise, and people/communication skills. CONCLUSIONS: Clinical nurse specialists can improve patient outcomes by promoting EBP; to do so, they need to work in supportive contexts that give those in the CNS role a set of clear role expectations. IMPLICATIONS: There are challenges faced by CNSs in Canada, and there is a need to strengthen the CNS's role by standardizing the regulatory requirements at a national level. PMID- 23942105 TI - Assessment and prediction of pruritus in sickle cell disease patients: a preliminary study. AB - PURPOSE/OBJECTIVES: The purpose of this study was to better predict and assess pruritus in inpatients and outpatients with sickle cell disease. The aims were to describe the incidence and severity of pruritus using the visual analog scale (VAS) and the National Cancer Institute Common Toxicity Criteria (CTC) scale and to predict pruritus from common complications. DESIGN: This study was a prospective, cross-sectional design. SETTING: The study was conducted at a Midwestern National Cancer Institute hospital. SAMPLE: This prospective, cross sectional design included patients with a diagnosis of sickle cell disease who were older than 18 years. METHODS: A demographic data form was used to collect biographical characteristics, and the CTC scale and VAS were used to evaluate pruritus. RESULTS: The participants (n = 56) were mostly women (62%) and outpatients (58%) and the mean number of complications was 1.9. The mean VAS score was 3.75, and the CTC score was 1.55. For inpatients, the mean VAS score was 5.17, and the CTC score was 1.65. For outpatients, the mean VAS score was 2.76, and CTC score was 1.56. The sensitivity and specificity for the VAS were 75% and 93%, respectively. The CTC scale was 56.2% and 100%, respectively. The difference in the area under the curve between the VAS and the CTC scale was 11.4% in favor of the VAS. Among complications (pulmonary hypertension, liver insufficiency, acute chest syndrome, renal insufficiency, iron overload, and chronic pain medication), chronic pain medication was the only significant predictor. CONCLUSIONS: Pruritus is common particularly in inpatients as well as outpatients. The VAS is a more sensitive and specific tool to measure pruritus. Chronic pain medication use is a predictor of pruritus. IMPLICATIONS: Clinicians must make patients aware that pruritus exists especially when pain medication is administered or prescribed. PMID- 23942106 TI - Knowledge, attitudes, and practices of Turkish intern nurses regarding physical restraints. AB - OBJECTIVE: This study was carried out to determine knowledge, attitudes, and practices of intern nurses who completed the nursing internship program on the use of physical restraints. DESIGN: This research was conducted using descriptive and cross-sectional research design. METHODS: The study sample comprises 91 fourth-grade students who took an integrated curriculum and completed the nursing internship program. The data were collected with the Demographic Characteristics Questionnaire and the Levels of Knowledge, Attitudes and Practices of Staff Regarding Physical Restraints Questionnaire. For the assessment of the data, percentages, the arithmetic mean, and t test were used. RESULTS: The findings indicated that, of the intern nurses, 95.6% observed the use of physical restraints during their education, and 69.2% applied physical restraints. The mean knowledge, attitude, and practice scores of the nurses for physical restraint were 9.38 +/- 1.19 (0-11 points), 34.70 +/- 5.62 (12-48 points), and 37.95 +/- 2.32 (14-42 points), respectively. CONCLUSIONS: Intern nurses' knowledge about how to use physical restraints was at a very good level; they displayed positive attitudes, and they used their knowledge and attitudes in their practices to a great extent. IMPLICATIONS: Although there are studies on the knowledge, attitudes, and practices of nurses working in the fields of elderly care, rehabilitation, and psychiatry in acute care units, there are no studies investigating intern nurses and other nursing students. However, intern nurses about to begin their careers should make accurate decisions regarding the use of physical restrains if they are to ensure patient safety and to fulfill this application effectively in their professional lives. PMID- 23942108 TI - Profile. Interview by Jo Ellen Rust. PMID- 23942109 TI - Revisiting the Mark Morris dance group Dance for Parkinson's Disease program. PMID- 23942110 TI - LRRFIP2 negatively regulates NLRP3 inflammasome activation in macrophages by promoting Flightless-I-mediated caspase-1 inhibition. AB - The NLRP3 inflammasome is the most characterized inflammasome activated by cellular infection or stress, which is responsible for the maturation of proinflammatory cytokines IL-1beta and IL-18. The precise molecular mechanism for negative regulation of NLRP3 inflammasome activation needs to be further defined. Here we identify leucine-rich repeat Fli-I-interacting protein 2 (LRRFIP2) as an NLRP3-associated protein and an inhibitor for NLRP3 inflammasome activation. LRRFIP2 binds to NLRP3 via its N terminus upon NLRP3 inflammasome activation, and also interacts with Flightless-I, a pseudosubstrate of caspase-1, via its Coil motif. Knockdown of Flightless-I significantly promotes NLRP3 inflammasome activation. LRRFIP2 enhances the interaction between Flightless-I and caspase-1, facilitating the inhibitory effect of Flightless-I on caspase-1 activation. Furthermore, silencing of Flightless-I abrogates the inhibitory effect of LRRFIP2 on NLRP3 inflammasome. These data demonstrate that LRRFIP2 inhibits NLRP3 inflammasome activation by recruiting the caspase-1 inhibitor Flightless-I, thus outlining a new mechanism for negative regulation of NLRP3 inflammasome. PMID- 23942111 TI - Bilateral asymmetry of humeral torsion and length in African apes and humans. AB - Few studies have directly compared human and African ape upper limb skeletal asymmetries despite the potential such comparisons have for understanding the origins of functional lateralization in humans and non-human primates. Here, we report the magnitude and direction of asymmetries in humeral torsion and humeral length in paired humeri of 40 Gorilla gorilla, 40 Pan troglodytes and 40 Homo sapiens. We test whether absolute and directional asymmetries differ between measurements, species and sexes. Our results show that humans are unique in being lateralized to the right for both measurements, consistent with human population level handedness patterns, while apes show no significant directionality at the species level in either measurement. However, absolute torsion asymmetries in apes occur in the same magnitude as in humans, suggesting the existence of functional lateralization at the individual level. PMID- 23942112 TI - Final decisions: how hospice enrollment prompts meaningful choices about life closure. AB - OBJECTIVE: The purpose of this study was to explore and describe decisions that faced newly enrolled hospice patients and their caregivers after hospice enrollment. METHOD: An exploratory, descriptive, cross-sectional design was employed using qualitative methods. In-depth in-person interviews were conducted with current hospice patients (n = 35) and caregivers (n = 45) from 53 families. RESULTS: The decision to enroll in hospice was a critical juncture on the trajectory of a terminal illness that allowed patients and their families an opportunity to consider subsequent tasks that were important for life closure. A typology of five decisions is presented: (1) operationalized advance care planning (ACP): a renewed focus on decisions about care at life's end; (2) surrogate decision-making: caregivers begin making both informal and formal decisions for the dying person; (3) meaning-making: the foreshortened time brings into focus decisions about seeing special people, attending events, and creating memories; (4) Location of death: decisions about whether the person wants to and can remain at home to die; and (5) final acts: decisions about funeral arrangements, wills, and leaving a legacy become central. ACP was found to exist on a continuum that ranged from absent ACP, dormant ACP, simplified ACP to activated ACP. Hospice enrollment became a catalyst for reactivating discussion of end-of-life choices. SIGNIFICANCE OF RESULTS: Hospice enrollment prompts the need to consider subsequent important choices that contribute to meaningful life closure, are central to the completion of a family relationship, and may influence adaptation in bereaved caregivers. It is important for clinicians to recognize that well-timed encouragement to consider and explore the use of hospice services, although it may indeed diminish hope for cure or recovery, simultaneously offers an opportunity to engage with important and time-sensitive developmental tasks. PMID- 23942113 TI - Transcriptional regulation of the legumain gene by p53 in HCT116 cells. AB - Legumain (EC 3.4.22.34) is an asparaginyl endopeptidase. Strong legumain activity was observed in the mouse kidney, and legumain was found to be highly expressed in tumors. We previously reported that bovine kidney annexin A2 was co-purified with legumain and that legumain cleaved the N-terminal region of annexin A2 at an Asn residue in vitro and in vivo. In this study, we found a p53-binding site in intron 1 of the human legumain gene using computational analysis. To determine whether transcription of the legumain gene is regulated by p53, HCT116 cells were transfected with p53 siRNA and the effect of knockdown of p53 expression on legumain expression was examined. The results showed that expression levels of both legumain mRNA and protein were decreased in the siRNA-treated cells. Furthermore, enzyme activity of legumain was also increased by doxorubicin and its activity was reduced by knockdown of p53 in HCT116 cells. These results suggest that legumain expression and its enzyme activity are regulated by p53. PMID- 23942114 TI - Induction of human breast cell carcinogenesis by triclocarban and intervention by curcumin. AB - More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens and co-carcinogens. To identify co carcinogens with abilities to induce cellular pre-malignancy, we studied the activity of triclocarban (TCC), an antimicrobial agent commonly used in household and personal care products. Here, we demonstrated, for the first time, that chronic exposure to TCC at physiologically-achievable nanomolar concentrations resulted in progressive carcinogenesis of human breast cells from non-cancerous to pre-malignant. Pre-malignant carcinogenesis was measured by increasingly acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth and increased cell proliferation, without acquisition of cellular tumorigenicity. Long-term TCC exposure also induced constitutive activation of the Erk-Nox pathway and increases of reactive oxygen species (ROS) in cells. A single TCC exposure induced transient induction of the Erk-Nox pathway, ROS elevation, increased cell proliferation, and DNA damage in not only non-cancerous breast cells but also breast cancer cells. Using these constitutively- and transiently-induced changes as endpoints, we revealed that non-cytotoxic curcumin was effective in intervention of TCC-induced cellular pre malignancy. Our results lead us to suggest that the co-carcinogenic potential of TCC should be seriously considered in epidemiological studies to reveal the significance of TCC in the development of sporadic breast cancer. Using TCC induced transient and constitutive endpoints as targets will likely help identify non-cytotoxic preventive agents, such as curcumin, effective in suppressing TCC induced cellular pre-malignancy. PMID- 23942115 TI - A derivative of ascorbic acid modulates cAMP production. AB - We reported, in previous experiments, that AA is a global regulator of cAMP pools. In this study, we demonstrate that K873, an analog of AA we synthesized and presenting antiproliferative properties, has also an impact on cAMP production. However, K873 has no antioxidant activity, at the contrary of AA. It definitively demonstrates that action of AA on the cAMP production is not linked to antioxidant activity. These data suggest that AA, and derivatives of this molecule, could be promising drug acting on biological processes that are under the control of cAMP dependent pathway. PMID- 23942116 TI - Efficient isolation of specific genomic regions and identification of associated proteins by engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) using CRISPR. AB - Isolation of specific genomic regions retaining molecular interactions is necessary for their biochemical analysis. Here, we established a novel method, engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP), for purification of specific genomic regions retaining molecular interactions. We showed that enChIP using the CRISPR system efficiently isolates specific genomic regions. In this form of enChIP, specific genomic regions are immunoprecipitated with antibody against a tag(s), which is fused to a catalytically inactive form of Cas9 (dCas9), which is co-expressed with a guide RNA (gRNA) and recognizes endogenous DNA sequence in the genomic regions of interest. enChIP-mass spectrometry (enChIP-MS) targeting endogenous loci identified associated proteins. enChIP using the CRISPR system would be a convenient and useful tool for dissecting chromatin structure of genomic regions of interest. PMID- 23942117 TI - Arsenic-induced cutaneous hyperplastic lesions are associated with the dysregulation of Yap, a Hippo signaling-related protein. AB - Arsenic exposure in humans causes a number of toxic manifestations in the skin including cutaneous neoplasm. However, the mechanism of these alterations remains elusive. Here, we provide novel observations that arsenic induced Hippo signaling pathway in the murine skin. This pathway plays crucial roles in determining organ size during the embryonic development and if aberrantly activated in adults, contributes to the pathogenesis of epithelial neoplasm. Arsenic treatment enhanced phosphorylation-dependent activation of LATS1 kinase and other Hippo signaling regulatory proteins Sav1 and MOB1. Phospho-LATS kinase is known to catalyze the inactivation of a transcriptional co-activator, Yap. However, in arsenic-treated epidermis, we did not observed its inactivation. Thus, as expected, unphosphorylated-Yap was translocated to the nucleus in arsenic-treated epidermis. Yap by binding to the transcription factors TEADs induces transcription of its target genes. Consistently, an up-regulation of Yap dependent target genes Cyr61, Gli2, Ankrd1 and Ctgf was observed in the skin of arsenic-treated mice. Phosphorylated Yap is important in regulating tight and adherens junctions through its binding to alphaCatenin. We found disruption of these junctions in the arsenic-treated mouse skin despite an increase in alphaCatenin. These data provide evidence that arsenic-induced canonical Hippo signaling pathway and Yap-mediated disruption of tight and adherens junctions are independently regulated. These effects together may contribute to the carcinogenic effects of arsenic in the skin. PMID- 23942118 TI - Maintenance of cellular ATP level by caloric restriction correlates chronological survival of budding yeast. AB - The free radical theory of aging emphasizes cumulative oxidative damage in the genome and intracellular proteins due to reactive oxygen species (ROS), which is a major cause for aging. Caloric restriction (CR) has been known as a representative treatment that prevents aging; however, its mechanism of action remains elusive. Here, we show that CR extends the chronological lifespan (CLS) of budding yeast by maintaining cellular energy levels. CR reduced the generation of total ROS and mitochondrial superoxide; however, CR did not reduce the oxidative damage in proteins and DNA. Subsequently, calorie-restricted yeast had higher mitochondrial membrane potential (MMP), and it sustained consistent ATP levels during the process of chronological aging. Our results suggest that CR extends the survival of the chronologically aged cells by improving the efficiency of energy metabolism for the maintenance of the ATP level rather than reducing the global oxidative damage of proteins and DNA. PMID- 23942120 TI - R-spondin3 prevents mesenteric ischemia/reperfusion-induced tissue damage by tightening endothelium and preventing vascular leakage. AB - Inflammation and vascular injury triggered by ischemia/reperfusion (I/R) represent a leading cause of morbidity and mortality in a number of clinical settings. Wnt and its homolog partners R-spondins, in addition to regulating embryonic development have recently been demonstrated to serve as wound-healing agents in inflammation-associated conditions. Here we ask whether R-spondins could prevent inflammation-associated tissue damage in ischemic disorders and thus investigate the role of R-spondin3 (R-spo3) in a mouse model of mesenteric I/R. We demonstrate that R-spo3 ameliorates mesenteric I/R-induced local intestinal as well as remote lung damage by suppressing local and systemic cytokine response and deposition of IgM and complement in intestinal tissues. We also show that decreased inflammatory response is accompanied by tightening of endothelial cell junctions and reduction in vascular leakage. We conclude that R spo3 stabilizes endothelial junctions and inhibits vascular leakage during I/R and thereby mitigates the inflammatory events and associated tissue damage. Our findings uniquely demonstrate a protective effect of R-spo3 in I/R-related tissue injury and suggest a mechanism by which it may have these effects. PMID- 23942122 TI - Assessing what to address in science communication. AB - As members of a democratic society, individuals face complex decisions about whether to support climate change mitigation, vaccinations, genetically modified food, nanotechnology, geoengineering, and so on. To inform people's decisions and public debate, scientific experts at government agencies, nongovernmental organizations, and other organizations aim to provide understandable and scientifically accurate communication materials. Such communications aim to improve people's understanding of the decision-relevant issues, and if needed, promote behavior change. Unfortunately, existing communications sometimes fail when scientific experts lack information about what people need to know to make more informed decisions or what wording people use to describe relevant concepts. We provide an introduction for scientific experts about how to use mental models research with intended audience members to inform their communication efforts. Specifically, we describe how to conduct interviews to characterize people's decision-relevant beliefs or mental models of the topic under consideration, identify gaps and misconceptions in their knowledge, and reveal their preferred wording. We also describe methods for designing follow-up surveys with larger samples to examine the prevalence of beliefs as well as the relationships of beliefs with behaviors. Finally, we discuss how findings from these interviews and surveys can be used to design communications that effectively address gaps and misconceptions in people's mental models in wording that they understand. We present applications to different scientific domains, showing that this approach leads to communications that improve recipients' understanding and ability to make informed decisions. PMID- 23942123 TI - Cytosolic flagellin-induced lysosomal pathway regulates inflammasome-dependent and -independent macrophage responses. AB - NAIP5/NLRC4 (neuronal apoptosis inhibitory protein 5/nucleotide oligomerization domain-like receptor family, caspase activation recruitment domain domain containing 4) inflammasome activation by cytosolic flagellin results in caspase-1 mediated processing and secretion of IL-1beta/IL-18 and pyroptosis, an inflammatory cell death pathway. Here, we found that although NLRC4, ASC, and caspase-1 are required for IL-1beta secretion in response to cytosolic flagellin, cell death, nevertheless, occurs in the absence of these molecules. Cytosolic flagellin-induced inflammasome-independent cell death is accompanied by IL-1alpha secretion and is temporally correlated with the restriction of Salmonella Typhimurium infection. Despite displaying some apoptotic features, this peculiar form of cell death do not require caspase activation but is regulated by a lysosomal pathway, in which cathepsin B and cathepsin D play redundant roles. Moreover, cathepsin B contributes to NAIP5/NLRC4 inflammasome-induced pyroptosis and IL-1alpha and IL-1beta production in response to cytosolic flagellin. Together, our data describe a pathway induced by cytosolic flagellin that induces a peculiar form of cell death and regulates inflammasome-mediated effector mechanisms of macrophages. PMID- 23942124 TI - Nucleic acid determinants for selective deamination of DNA over RNA by activation induced deaminase. AB - Activation-induced deaminase (AID), a member of the larger AID/APOBEC family, is the key catalyst in initiating antibody somatic hypermutation and class-switch recombination. The DNA deamination model accounting for AID's functional role posits that AID deaminates genomic deoxycytosine bases within the immunoglobulin locus, activating downstream repair pathways that result in antibody maturation. Although this model is well supported, the molecular basis for AID's selectivity for DNA over RNA remains an open and pressing question, reflecting a broader need to elucidate how AID/APOBEC enzymes engage their substrates. To address these questions, we have synthesized a series of chimeric nucleic acid substrates and characterized their reactivity with AID. These chimeric substrates feature targeted variations at the 2'-position of nucleotide sugars, allowing us to interrogate the steric and conformational basis for nucleic acid selectivity. We demonstrate that modifications to the target nucleotide can significantly alter AID's reactivity. Strikingly, within a substrate that is otherwise DNA, a single RNA-like 2'-hydroxyl substitution at the target cytosine is sufficient to compromise deamination. Alternatively, modifications that favor a DNA-like conformation (or sugar pucker) are compatible with deamination. AID's closely related homolog APOBEC1 is similarly sensitive to RNA-like substitutions at the target cytosine. Inversely, with unreactive 2'-fluoro-RNA substrates, AID's deaminase activity was rescued by introducing a trinucleotide DNA patch spanning the target cytosine and two nucleotides upstream. These data suggest a role for nucleotide sugar pucker in explaining the molecular basis for AID's DNA selectivity and, more generally, suggest how other nucleic acid-modifying enzymes may distinguish DNA from RNA. PMID- 23942125 TI - The sciences of science communication. AB - The May 2012 Sackler Colloquium on "The Science of Science Communication" brought together scientists with research to communicate and scientists whose research could facilitate that communication. The latter include decision scientists who can identify the scientific results that an audience needs to know, from among all of the scientific results that it would be nice to know; behavioral scientists who can design ways to convey those results and then evaluate the success of those attempts; and social scientists who can create the channels needed for trustworthy communications. This overview offers an introduction to these communication sciences and their roles in science-based communication programs. PMID- 23942126 TI - Differential transformation capacity of neuro-glial progenitors during development. AB - Gliomas represent the most common type of brain tumor, but show considerable variability in histologic appearance and clinical outcome. The phenotypic differences between types and grades of gliomas have not been explained solely on the grounds of differing oncogenic stimuli. Several studies have demonstrated that some phenotypic differences may be attributed to regional differences in the neural stem cells from which tumors arise. We hypothesized that temporal differences may also play a role, with tumor phenotypic variability reflecting intrinsic differences in neural stem cells at distinct developmental stages. To determine how the tumorigenic potential of lineally related stem cells changes over time, we used a conditional transgenic system that integrates Cre-Lox mediated and Tet-regulated expression to drive K-ras(G12D) expression in neuro glial progenitor populations at different developmental time points. Using this model, we demonstrate that K-ras(G12D)-induced transformation is dependent on the developmental stage at which it is introduced. Diffuse malignant brain tumors develop during early embryogenesis but not when K-ras(G12D) expression is induced during late embryogenesis or early postnatal life. We show that differential expression of cell-cycle regulators during development may be responsible for this differing susceptibility to malignant transformation and that loss of p53 can overcome the transformation resistance seen at later developmental stages. These results highlight the interplay between genetic alterations and the molecular changes that accompany specific developmental stages; early progenitors may lack the regulatory mechanisms present at later, more lineage-restrictive, developmental time points, making them more susceptible to transformation. PMID- 23942127 TI - The science of science communication. Introduction. PMID- 23942129 TI - Brain mechanisms for simple perception and bistable perception. AB - When faced with ambiguous sensory inputs, subjective perception alternates between the different interpretations in a stochastic manner. Such multistable perception phenomena have intrigued scientists and laymen alike for over a century. Despite rigorous investigations, the underlying mechanisms of multistable perception remain elusive. Recent studies using multivariate pattern analysis revealed that activity patterns in posterior visual areas correlate with fluctuating percepts. However, increasing evidence suggests that vision--and perception at large--is an active inferential process involving hierarchical brain systems. We applied searchlight multivariate pattern analysis to functional magnetic resonance imaging signals across the human brain to decode perceptual content during bistable perception and simple unambiguous perception. Although perceptually reflective activity patterns during simple perception localized predominantly to posterior visual regions, bistable perception involved additionally many higher-order frontoparietal and temporal regions. Moreover, compared with simple perception, both top-down and bottom-up influences were dramatically enhanced during bistable perception. We further studied the intermittent presentation of ambiguous images--a condition that is known to elicit perceptual memory. Compared with continuous presentation, intermittent presentation recruited even more higher-order regions and was accompanied by further strengthened top-down influences but relatively weakened bottom-up influences. Taken together, these results strongly support an active top-down inferential process in perception. PMID- 23942130 TI - The Drug Facts Box: Improving the communication of prescription drug information. AB - Communication about prescription drugs ought to be a paragon of public science communication. Unfortunately, it is not. Consumers see $4 billion of direct-to consumer advertising annually, which typically fails to present data about how well drugs work. The professional label--the Food and Drug Administration's (FDA) mechanism to get physicians information needed for appropriate prescribing--may also fail to present benefit data. FDA labeling guidance, in fact, suggests that industry omit benefit data for new drugs in an existing class and for drugs approved on the basis of unfamiliar outcomes (such as depression rating scales). The medical literature is also problematic: there is selective reporting of favorable trials, favorable outcomes within trials, and "spinning" unfavorable results to maximize benefit and minimize harm. In contrast, publicly available FDA reviews always include the phase 3 trial data on benefit and harm, which are the basis of drug approval. However, these reviews are practically inaccessible: lengthy, poorly organized, and weakly summarized. To improve accessibility, we developed the Drug Facts Box: a one-page summary of benefit and harm data for each indication of a drug. A series of studies--including national randomized trials--demonstrates that most consumers understand the Drug Facts Box and that it improves decision-making. Despite calls from their own Risk Communication Advisory Committee and Congress (in the Affordable Care Act) to consider implementing boxes, the FDA announced it needs at least 3-5 y more to make a decision. Given its potential public health impact, physicians and the public should not have to wait that long for better drug information. PMID- 23942132 TI - Rapid prototyping of carbon-based chemiresistive gas sensors on paper. AB - Chemically functionalized carbon nanotubes (CNTs) are promising materials for sensing of gases and volatile organic compounds. However, the poor solubility of carbon nanotubes hinders their chemical functionalization and the subsequent integration of these materials into devices. This manuscript describes a solvent free procedure for rapid prototyping of selective chemiresistors from CNTs and graphite on the surface of paper. This procedure enables fabrication of functional gas sensors from commercially available starting materials in less than 15 min. The first step of this procedure involves the generation of solid composites of CNTs or graphite with small molecule selectors--designed to interact with specific classes of gaseous analytes--by solvent-free mechanical mixing in a ball mill and subsequent compression. The second step involves deposition of chemiresistive sensors by mechanical abrasion of these solid composites onto the surface of paper. Parallel fabrication of multiple chemiresistors from diverse composites rapidly generates cross-reactive arrays capable of sensing and differentiating gases and volatile organic compounds at part-per-million and part-per-thousand concentrations. PMID- 23942131 TI - Long-lasting transition toward sustainable elimination of desert malaria under irrigation development. AB - In arid areas, people living in the proximity of irrigation infrastructure are potentially exposed to a higher risk of malaria due to changes in ecohydrological conditions that lead to increased vector abundance. However, irrigation provides a pathway to economic prosperity that over longer time scales is expected to counteract these negative effects. A better understanding of this transition between increased malaria risk and regional elimination, in particular whether it is slow or abrupt, is relevant to sustainable development and disease management. By relying on space as a surrogate for stages of time, we investigate this transition in a semidesert region of India where a megairrigation project is underway and expected to cover more than 1,900 million hectares and benefit around 1 million farmers. Based on spatio-temporal epidemiological cases of Plasmodium vivax malaria and land-use irrigation from remote sensing sources, we show that this transition is characterized by an enhanced risk in areas adjacent to the trunk of the irrigation network, despite a forceful and costly insecticide based control. Moreover, this transition between climate-driven epidemics and sustained low risk has already lasted a decade. Given the magnitude of these projects, these results suggest that increased health costs have to be planned for over a long time horizon. They further highlight the need to integrate assessments of both health and environmental impacts to guide adaptive mitigation strategies. Our results should help to define and track these transitions in other arid parts of the world subjected to similar tradeoffs. PMID- 23942133 TI - Effect of oral clonidine, etoricoxib, and gabapentin as premedication on sensory and motor blocks and post operative analgesia in surgeries under subarachnoid block using bupivacaine. AB - Oral premedicant has better patient compliance since it avoids a potential needle prick, and hence can be considered closest to an ideal premedicant. This was a randomized prospective observational study on 120 patients after obtaining ethical committee approval and valid informed consent from patients to be part of the study. We assessed the onset and duration of both sensory and motor blocks along with postoperative analgesic requirement by the patient in terms of first dose and total dose required over the period of 24 hours. It is recommended that clonidine, etoricoxib, and gabapentin be considered as good premedicants for patients undergoing surgery under spinal anesthesia. However, more research using these drugs needs to be carried out in the field of premedication. PMID- 23942134 TI - Immunoresponsive postinfectious autonomic neuropathy. AB - A 36-year-old healthy woman developed a postinfectious autonomic neuropathy with adrenergic failure and symptoms of orthostatic intolerance. Treatment with immunomodulating therapy, including corticosteroids and immunoglobulin, resulted in marked improvement in clinical symptoms and findings on autonomic testing. PMID- 23942135 TI - Interventions of weight reduction and prevention in children and adolescents: update. AB - There is currently a plethora of information regarding the assessment and treatment of obesity in adults, adolescents, and children available to individuals working in health care-related fields. However, summarizing this information, especially for the pediatric population, is a daunting task. The purpose of this study is to simplify, summarize, and alert pharmacists, pharmacy technicians, and health care providers/workers to the main nonpharmacologic and pharmacologic treatment options concerning pediatric obesity and weight loss. PMID- 23942136 TI - Gastrointestinal Stromal Tumors: A Review. AB - The understanding of aberrant molecular pathways that result in gastrointestinal stromal tumors (GISTs) and the rapid development of molecular therapies that target these pathways represent one of the great milestones in translational oncology. The story of GIST is unique in that targeted molecular therapy was successfully applied in clinical therapeutics, with dramatic results redefining the management of these traditionally chemotherapy-resistant tumors. We briefly review the molecular biology and clinical presentation of GIST and then discuss the adjuvant and neoadjuvant use of tyrosine kinase inhibitors in early-stage GIST and their use in metastatic disease. Newer therapeutic advances in the rapidly changing field of GIST management are also discussed. PMID- 23942137 TI - The effect of SV 293, a D2 dopamine receptor-selective antagonist, on D2 receptor mediated GIRK channel activation and adenylyl cyclase inhibition. AB - SV 293 [1-([5-methoxy-1H-indol-3-yl]methyl)-4-(4-[methylthio]phenyl)piperidin-4 ol] binds with 100-fold higher affinity to human D2 receptors compared to the human D3 and D4 dopamine receptor subtypes. We investigated the intrinsic efficacy of this compound at the D2 dopamine receptor subtype using both: (1) a forskolin-dependent adenylyl cyclase inhibition assay and (2) an electrophysiological assay for evaluating coupling to G-protein-coupled inwardly rectifying potassium channels. In both assays SV 293 was found to be a neutral antagonist capable of blocking the effects of the full D2-like receptor agonist quinpirole. Based upon these results we propose that SV 293 is a useful pharmacological tool that can be used for both in vitro and in vivo studies to investigate the role of D2-like dopamine receptor subtypes in neurological, neuropsychiatric and movement disorders where dopaminergic pathways have been implicated. PMID- 23942138 TI - SLCO1B1 genetic variant associated with statin-induced myopathy: a proof-of concept study using the clinical practice research datalink. AB - This study aimed to determine whether patients with statin-induced myopathy could be identified using the United Kingdom Clinical Practice Research Datalink, whether DNA could be obtained, and whether previously reported associations of statin myopathy with the SLCO1B1 c.521T>C and COQ2 rs4693075 polymorphisms could be replicated. Seventy-seven statin-induced myopathy patients (serum creatine phosphokinase (CPK) > 4* upper limit of normal (ULN)) and 372 statin-tolerant controls were identified and recruited. Multiple logistic regression analysis showed the SLCO1B1 c.521T>C single-nucleotide polymorphism to be a significant risk factor (P = 0.009), with an odds ratio (OR) per variant allele of 2.06 (1.32 3.15) for all myopathy and 4.09 (2.06-8.16) for severe myopathy (CPK > 10* ULN, and/or rhabdomyolysis; n = 23). COQ2 rs4693075 was not associated with myopathy. Meta-analysis showed an association between c.521C>T and simvastatin-induced myopathy, although power for other statins was limited. Our data replicate the association of SLCO1B1 variants with statin-induced myopathy. Furthermore, we demonstrate how electronic medical records provide a time- and cost-efficient means of recruiting patients with severe adverse drug reactions for pharmacogenetic studies. PMID- 23942139 TI - Association between oral health and the risk of lacunar infarction in Japanese adults. AB - BACKGROUND: Poor oral health is associated with an increased risk of dementia in the elderly. One possible pathway linking these two phenomena is lacunar infarction, a potential cause of dementia. An association between poor oral health and an increased risk of ischaemic stroke has been recognised through the oral infection-inflammation pathway. However, little is known about whether poor oral health is associated with the progression of lacunar infarction. OBJECTIVE: We examined the association between variables related to oral health and lacunar infarction, as detected by magnetic resonance imaging (MRI). METHODS: A total of 110 subjects (52 men, 58 women), aged 27-76 years, who visited our periodontology clinic participated in this study. The subjects underwent dental radiography, periodontal examinations and brain MRI. One experienced specialist in cardiovascular disease and one experienced neurosurgeon determined the number of lacunar infarctions on brain MRI. Periodontologists performed clinical periodontal examinations. Variables related to oral health were determined from the radiographs by an oral radiologist. Information on the subjects' lifestyles and disease histories were obtained using a structured questionnaire and confirmed by clinical records. Adjacent categories logit regression analysis with backward elimination was used to determine variables associated with three groups based on the number of lacunar infarctions. RESULTS: Of the 110 subjects, 61 had lacunar infarctions. Nineteen had multiple (>=7) lesions. Aging (p = 0.0004), increased time spent in physical activity per day (p = 0.042), the presence of hypertension (p = 0.006), the absence of hyperlipidaemia (p = 0.045), the presence of diabetes mellitus (p = 0.025) and low alveolar bone height (p = 0.026) were significantly associated with an increased number of lacunar infarctions in the final regression model. The significance of hyperlipidaemia and alveolar bone height disappeared in an unadjusted model. An increased pocket depth, which indicates current periodontal disease progression, tended to be associated with an increased number of lacunar infarctions (p = 0.058). This tendency did not disappear in an unadjusted model. CONCLUSION: Our results suggest that lacunar infarction may be associated with current periodontal disease in Japanese adults. PMID- 23942140 TI - The dynamic nature of depression: a new micro-level perspective of mental disorder that meets current challenges. AB - The examination of moment-to-moment, 'micro-level' patterns of experience and behaviour using experience sampling methodology has contributed to our understanding of the 'macro-level' development of full-blown symptoms and disorders. This paper argues that the micro-level perspective can be used to identify the smallest building blocks underlying the onset and course of mental ill-health. Psychopathology may be the result of the continuous dynamic interplay between micro-level moment-to-moment experiences and behavioural patterns over time. Reinforcing loops between momentary states may alter the course of mental health towards either a more or less healthy state. An example with observed data, from a population of individuals with depressive symptoms, supports the validity of a dynamic network model of psychopathology and shows that together and over time, this continuous interplay between momentary states may result in the cluster of symptoms we call major depressive disorder. This approach may help conceptualize the nature of mental disorders, and generate individualized insights useful for diagnosis and treatment in psychiatry. PMID- 23942141 TI - Grid-free powder averages: on the applications of the Fokker-Planck equation to solid state NMR. AB - We demonstrate that Fokker-Planck equations in which spatial coordinates are treated on the same conceptual level as spin coordinates yield a convenient formalism for treating magic angle spinning NMR experiments. In particular, time dependence disappears from the background Hamiltonian (sample spinning is treated as an interaction), spherical quadrature grids are avoided completely (coordinate distributions are a part of the formalism) and relaxation theory with any linear diffusion operator is easily adopted from the Stochastic Liouville Equation theory. The proposed formalism contains Floquet theory as a special case. The elimination of the spherical averaging grid comes at the cost of increased matrix dimensions, but we show that this can be mitigated by the use of state space restriction and tensor train techniques. It is also demonstrated that low correlation order basis sets apparently give accurate answers in powder-averaged MAS simulations, meaning that polynomially scaling simulation algorithms do exist for a large class of solid state NMR experiments. PMID- 23942143 TI - Human papillomavirus 16/18 infections in lung cancer patients in Mexico. AB - BACKGROUND/AIMS: Human papillomavirus (HPV) is an epitheliotropic, double stranded DNA virus, and its high-risk genotypes are associated with human cancer. HPV genome has been detected in lung carcinomas in certain places around the world, including Mexico; however, the prevalence of this is unclear. In this study, we examine the frequency of high-risk HPV 16/18 in lung cancer tissues from a Mexican population. METHODS: 39 lung cancer specimens were analyzed by polymerase chain reaction (PCR) using HPV GP5+/GP6+ primers and then were genotyped using specific primers to HPV 16/18. Additionally, in situ hybridization (ISH) was performed using BIO-labeled oligonucleotide probes. RESULTS: Our results identified 15 positive cases (38.46%) for HPV 16 and 1 positive case (2.56%) for HPV 18 by PCR. ISH showed the presence of HPV DNA in 13 of 16 (81%) samples, in agreement with the PCR results. CONCLUSIONS: In this study, we detected HPV 16/18 gene sequences in lung cancer samples obtained from Mexican patients by PCR and ISH. We found the highest prevalence of HPV 16 infection in lung adenocarcinomas, suggesting that HPV infection may be associated with lung cancer. However, further studies are needed to elucidate the role of HPV in lung carcinogenesis. PMID- 23942144 TI - The effect of dimethyl sulfoxide (DMSO) on dentin bonding and nanoleakage of etch and-rinse adhesives. AB - OBJECTIVE: The objective was to examine the effect of a solvent dimethyl sulfoxide (DMSO) on resin-dentin bond durability, as well as potential functional mechanisms behind the effect. METHODS: Microtensile bond strength (MUTBS) was evaluated in extracted human teeth in two separate experiments. Dentin specimens were acid-etched and assigned to pre-treatment with 0.5mM (0.004%) DMSO as additional primer for 30s and to controls with water pre-treatment. Two-step etch and-rinse adhesive (Scotchbond 1XT, 3M ESPE) was applied and resin composite build-ups were created. Specimens were immediately tested for MUTBS or stored in artificial saliva for 6 and 12 months prior to testing. Additional immediate and 6-month specimens were examined for interfacial nanoleakage analysis under SEM. Matrix metalloproteinase (MMP) inhibition by DMSO was examined with gelatin zymography. Demineralized dentin disks were incubated in 100% DMSO to observe the optical clearing effect. RESULTS: The use of 0.5mM DMSO had no effect on immediate bond strength or nanoleakage. In controls, MUTBS decreased significantly after storage, but increased significantly in DMSO-treated group. The control group had significantly lower MUTBS than DMSO-group after 6 and 12 months. DMSO also eliminated the increase in nanoleakage seen in controls. 5% and higher DMSO concentrations significantly inhibited the gelatinases. DMSO induced optical clearing effect demonstrating collagen dissociation. SIGNIFICANCE: DMSO as a solvent may be useful in improving the preservation of long-term dentin adhesive bond strength. The effect may relate to dentinal enzyme inhibition or improved wetting of collagen by adhesives. The collagen dissociation required much higher DMSO concentrations than the 0.5mM DMSO used for bonding. PMID- 23942145 TI - In vitro evaluation of plant-derived agents to preserve dentin collagen. AB - OBJECTIVE: Biomodification of dentin by a natural crosslinker has been recommended to improve a mechanical property of demineralized dentin. This study investigated the effect of various plant-derived agents (hesperidin, proanthocyanidin, epigallocatechin gallate and genipin) on the stability of dentin collagen matrix to resist collagenase degradation. METHODS: The dentin specimens were treated with glutaraldehyde (0.5% and 5.0%) and each plant-derived test solution (0.5%). They were subjected to ultimate tensile strength (UTS) and swelling ratio measurements. Demineralized human dentin powder was incubated with 0.02%, 0.1% and 0.5% of each test agent and followed by bacterial collagenase digestion. The extent of collagen degradation was investigated using hydroxyproline assay. RESULTS: The UTS and swelling ratio measurements revealed that the mechanical property of dentin was improved by the use of these natural agents. The greatest reduction in collagen degradation was shown following the use of hesperidin, proanthocyanidin, and epigallocatechin gallate at 0.5%. SIGNIFICANCE: The use of hesperidin, proanthocyanidin, and epigallocatechin gallate could improve the mechanical properties of collagen and resist enzymatic degradation, leading to functional repair of pathological dentin lesion. PMID- 23942147 TI - Yeast petites and small colony variants: for everything there is a season. AB - The yeast petite mutant was first found in the yeast Saccharomyces cerevisiae. The colony is small because of a block in the aerobic respiratory chain pathway, which generates ATP. The petite yeasts are thus unable to grow on nonfermentable carbon sources (such as glycerol or ethanol), and form small anaerobic-sized colonies when grown in the presence of fermentable carbon sources (such as glucose). The petite phenotype results from mutations in the mitochondrial genome, loss of mitochondria, or mutations in the host cell genome. The latter mutations affect nuclear-encoded genes involved in oxidative phosphorylation and these mutants are termed neutral petites. They all produce wild-type progeny when crossed with a wild-type strain. The staphylococcal small colony variant (SCV) is a slow-growing mutant that typically exhibits the loss of many phenotypic characteristics and pathogenic traits. SCVs are mostly small, nonpigmented, and nonhaemolytic. Their small size is often due to an inability to synthesize electron transport chain components and so cannot generate ATP by oxidative phosphorylation. Evidence suggests that they are responsible for persistent and/or recurrent infections. This chapter compares the physiological and genetic basis of the petite mutants and SCVs. The review focuses principally on two representatives, the eukaryote S. cerevisiae and the prokaryote Staphylococcus aureus. There is, clearly, commonality in the physiological response. Interestingly, the similarity, based on their physiological states, has not been commented on previously. The finding of an overlapping physiological response that occurs across a taxonomic divide is novel. PMID- 23942146 TI - A low cytotoxic and ratiometric fluorescent nanosensor based on carbon-dots for intracellular pH sensing and mapping. AB - Intracellular pH plays a critical role in the function of cells, and its regulation is essential for most cellular processes. In this study, we demonstrate a fluorescence resonance energy transfer (FRET)-based ratiometric pH nanosensor with carbon-dot (CD) as the carrier. The sensor was prepared by covalently linking a pH-sensitive fluorescent dye (fluorescein isothiocyanate, FITC) onto carbon-dot. As the FRET donor, the carbon-dot exhibits bright fluorescence emission as well as lambdaex-dependent photoluminescence emission, and a suitable excitation wavelength for the donor (CD) can be chosen to match the energy acceptor (fluorescein moiety). The fluorescein moieties on a CD undergo structural and spectral conversion as the pH changes, affording the nanoplatform a FRET-based pH sensor. The CD-based system exhibits a significant change in fluorescence intensity ratio between pH 4 and 8 with a pKa value of 5.69. It also displays excellent water dispersibility, good spectral reversibility, satisfactory cell permeability and low cytotoxicity. Following the living cell uptake, this nanoplatform with dual-chromatic emissions can facilitate real-time visualization of the pH evolution involved in the endocytic pathway of the nanosensor. This reversible and low cytotoxic fluorescent nanoplatform may be highly valuable in a variety of biological studies, such as endocytic trafficking, endosome/lysosome maturation, and pH regulation in subcellular organelles. PMID- 23942148 TI - Fungal spores for dispersion in space and time. AB - Spores are an integral part of the life cycle of the gross majority of fungi. Their morphology and the mode of formation are both highly variable among the fungi, as is their resistance to stressors. The main aim for spores is to be dispersed, both in space, by various mechanisms or in time, by an extended period of dormancy. Some fungal ascospores belong to the most stress-resistant eukaryotic cells described to date. Stabilization is a process in which biomolecules and complexes thereof are protected by different types of molecules against heat, drought, or other molecules. This review discusses the most important compounds that are known to protect fungal spores and also addresses the biophysics of cell protection. It further covers the phenomena of dormancy, breaking of dormancy, and early germination. Germination is the transition from a dormant cell toward a vegetative cell and includes a number of specific changes. Finally, the applied aspects of spore biology are discussed. PMID- 23942142 TI - Intercellular adhesion molecule 1: recent findings and new concepts involved in mammalian spermatogenesis. AB - Spermatogenesis, the process of spermatozoa production, is regulated by several endocrine factors, including testosterone, follicle stimulating hormone, luteinizing hormone and estradiol 17beta. For spermatogenesis to reach completion, developing germ cells must traverse the seminiferous epithelium while remaining transiently attached to Sertoli cells. If germ cell adhesion were to be compromised for a period of time longer than usual, germ cells would slough from the seminiferous epithelium and infertility would result. Presently, Sertoli-germ cell adhesion is known to be mediated largely by classical and desmosomal cadherins. More recent studies, however, have begun to expand long-standing concepts and to examine the roles of other proteins such as intercellular adhesion molecules. In this review, we focus on the biology of intercellular adhesion molecules in the mammalian testis, hoping that this information is useful in the design of future studies. PMID- 23942150 TI - Chromera velia: The Missing Link in the Evolution of Parasitism. AB - Since the pivotal publication announcing the discovery of Chromera velia in 2008, there has been a flurry of interest and research into this novel alga. Found by chance while studying the symbionts of corals in Australian reefs, C. velia has turned out to be a very important organism. It holds a unique position as the evolutionary intermediate between photosynthetic dinoflagellate algae and parasitic apicomplexans. Biological characterization has revealed similarities to both dinoflagellates and apicomplexans. Of particular interest is the photosynthetic plastid that is closely related to the apicomplexan apicoplast. This plastid in C. velia has a highly effective photosynthetic system with photoprotective properties such as nonphotochemical quenching. The apicoplast is essential for cell health and is therefore a potential drug target for the apicomplexans that cause malaria and other diseases. The tetrapyrrole, sterol, and galactolipid pathways have been explored in C. velia to find parallels with apicomplexans that could lead to new insights to fight these parasites. Ecologically, C. velia is very similar to dinoflagellates, reflecting their common ancestry and revealing how the ancestors of apicomplexans may have lived before they evolved to become parasitic. PMID- 23942151 TI - TAZ mediates lysophosphatidic acid-induced migration and proliferation of epithelial ovarian cancer cells. AB - BACKGROUND: Transcriptional co-activator with PDZ-binding motif (TAZ), a downstream effector of the Hippo pathway, has been reported to regulate organ size, tissue homeostasis, and tumorigenesis by acting as a transcriptional co activator. Lysophosphatidic acid (LPA) is a bioactive lipid implicated in tumorigenesis and metastasis of ovarian cancer through activation of G protein coupled receptors. However, the involvement of TAZ in LPA-induced tumorigenesis of ovarian cancer has not been elucidated. METHODS: In order to demonstrate the role of TAZ in LPA-stimulated tumorigenesis, the effects of LPA on TAZ expression and cell migration were determined by Western blotting and chemotaxis analyses in R182 human epithelial ovarian cancer cells. RESULTS AND CONCLUSION: Treatment of R182 cells with the LPA receptor inhibitor Ki16425 blocked LPA-induced cell migration. In addition, transfection of R182 cells with small interfering RNA specific for LPA receptor 1 resulted in abrogation of LPA-stimulated cell migration. LPA induced phosphorylation of ERK and p38 MAP kinase in R182 cells and pretreatment of cells with the MEK-ERK pathway inhibitor U0126, but not the p38 MAPK inhibitor SB202190, resulted in abrogation of LPA-induced cell migration. Pretreatment of R182 cells with U0126 attenuated LPA-induced mRNA levels of TAZ and its transcriptional target genes, such as CTGF and CYR61, without affecting phosphorylation level of YAP. These results suggest that MEK ERK pathway plays a key role in LPA-induced cell migration and mRNA expression of TAZ in R182 cells, without affecting stability of TAZ protein. In addition, small interfering RNA-mediated silencing of TAZ expression attenuated LPA-stimulated migration of R182 cells. These results suggest that TAZ plays a key role in LPA stimulated migration of epithelial ovarian cancer cells. PMID- 23942152 TI - Reciprocal learning with task cards for teaching Basic Life Support (BLS): investigating effectiveness and the effect of instructor expertise on learning outcomes. A randomized controlled trial. AB - BACKGROUND: Basic Life Support (BLS) education in secondary schools and universities is often neglected or outsourced because teachers indicate not feeling competent to teach this content. OBJECTIVE: Investigate reciprocal learning with task cards as instructional model for teaching BLS and the effect of instructor expertise in BLS on learning outcomes. METHODS: There were 175 students (mean age = 18.9 years) randomized across a reciprocal/BLS instructor (RBI) group, a reciprocal/non-BLS instructor (RNI) group, and a traditional/BLS instructor group (TBI). In the RBI and RNI group, students were taught BLS through reciprocal learning with task cards. The instructor in the RBI group was certified in BLS by the European Resuscitation Council. In the TBI, students were taught BLS by a certified instructor according to the Belgian Red Cross instructional model. Student performance was assessed 1 day (intervention) and 3 weeks after intervention (retention). RESULTS: At retention, significantly higher BLS performances were found in the RBI group (M = 78%), p = 0.007, ES = 0.25, and the RNI group (M = 80%), p < 0.001, Effect Size (ES) = .36, compared to the TBI (M = 73%). Significantly more students remembered and performed all BLS skills in the experimental groups at intervention and retention. No differences in BLS performance were found between the reciprocal groups. Ventilation volumes and flow rates were significantly better in the TBI at intervention and retention. CONCLUSION: Reciprocal learning with task cards is a valuable model for teaching BLS when instructors are not experienced or skilled in BLS. PMID- 23942149 TI - Regulation of bacterial pathogenesis by intestinal short-chain Fatty acids. AB - The human gut microbiota is inextricably linked to health and disease. One important function of the commensal organisms living in the intestine is to provide colonization resistance against invading enteric pathogens. Because of the complex nature of the interaction between the microbiota and its host, multiple mechanisms likely contribute to resistance. In this review, we dissect the biological role of short-chain fatty acids (SCFA), which are fermentation end products of the intestinal microbiota, in host-pathogen interactions. SCFA exert an extensive influence on host physiology through nutritional, regulatory, and immunomodulatory functions and can also affect bacterial fitness as a form of acid stress. Moreover, SCFA act as a signal for virulence gene regulation in common enteric pathogens. Taken together, these studies highlight the importance of the chemical environment where the biology of the host, the microbiota, and the pathogen intersects, which provides a basis for designing effective infection prevention and control. PMID- 23942153 TI - Bedside ultrasound maximizes patient satisfaction. AB - BACKGROUND: Bedside ultrasound (US) is associated with improved patient satisfaction, perhaps as a consequence of improved time to diagnosis and decreased length of stay (LOS). OBJECTIVES: Our study aimed to quantify the association between beside US and patient satisfaction and to assess patient attitudes toward US and perception of their interaction with the clinician performing the examination. METHODS: We enrolled a convenience sample of adult patients who received a bedside US. The control group had similar LOS and presenting complaints but did not have a bedside US. Both groups answered survey questions during their emergency department (ED) visit and again by telephone 1 week later. The questionnaire assessed patient perceptions and satisfaction on a 5-point Likert scale. RESULTS: Seventy patients were enrolled over 10 months. The intervention group had significantly higher scores on overall ED satisfaction (4.69 vs. 4.23; mean difference 0.46; 95% confidence interval [CI] 0.17-0.75), diagnostic testing (4.54 vs. 4.09; mean difference 0.46; 95% CI 0.16-0.76), and skills/abilities of the emergency physician (4.77 vs. 4.14; mean difference 0.63; 95% CI 0.29-0.96). A trend to higher scores for the intervention group persisted on follow-up survey. CONCLUSIONS: Patients who had a bedside US had statistically significant higher satisfaction scores with overall ED care, diagnostic testing, and with their perception of the emergency physician. Bedside US has the potential not only to expedite care and diagnosis, but also to maximize satisfaction scores and improve the patient-physician relationship, which has increasing relevance to health care organizations and hospitals that rely on satisfaction surveys. PMID- 23942154 TI - Effective teaching and feedback skills for international emergency medicine "train the trainers" programs. AB - BACKGROUND: As the specialty of Emergency Medicine (EM) develops around the world, it has become common for practitioners from countries with mature EM systems to assist those in regions with developing systems. One effective and frequently used model is "train the trainers," in which a group of consultant teachers instructs a cadre of clinicians in the host region to then become the future teachers of EM in that area. This model has the advantage of overcoming cultural barriers to instruction and can lead to providing a lasting training infrastructure in the region. A key to a successful program is the use of effective and culturally appropriate teaching and feedback skills. OBJECTIVES: The goal of this article is to bring together experts in adult education with experts in training in the international setting to present teaching and feedback skills and how they can be applied in different settings and cultures. DISCUSSION: Cutting edge instruction and evaluation techniques that can be employed in intercultural "train the trainers" programs will be presented. The characteristics of successful programs, using specifics from actual programs, will also be shared. CONCLUSION: Applying the described teaching and evaluation skills with modifications based on local culture will help empower newly trained teachers who will contribute in turn to the longevity of EM in the region and set a high teaching standard that will benefit generations of future colleagues. PMID- 23942156 TI - The power of now: brief mindfulness induction led to increased randomness of clicking sequence. AB - The capacity for random movement production is known to be limited in humans (e.g., Newell, Deutsch, & Morrison, 2000). We examined the effects of a brief mindfulness induction on random movement production because there are useful implications for variability in solving movement-related problems. The main task involved randomly clicking the 9 boxes in a 3 * 3 grid presented on a computer screen for five minutes. We characterized the sequence of clicking in terms of degrees of randomness, or periodicity, based on the fit, or probability, of the experimental data with its best fitting Bayesian network (4-click memory nodes) using the Markov chain Monte Carlo (MCMC) approach. Sixty-three participants were randomly assigned to either the experimental or the control condition. Mixed design repeated-measures ANOVA results show that the short mindfulness induction had a positive effect on the randomness of the sequence subsequently produced. This finding suggests that mindfulness may be a suitable strategy for increasing random movement behavior. PMID- 23942157 TI - Orofacial muscular activity and related skin movement during the preparatory and sustained phases of tone production on the French horn. AB - This study investigated activity of the embouchure-related orofacial muscles during pre- and postattack phases of sound production by 10 trained French-horn players. Surface electromyogram (EMG) from five selected facial muscles, and related facial skin kinematics were examined in relation to pitch and intensity of a tone produced. No difference in EMGs and facial kinematics between the two phases was found, indicating importance of appropriate formation of preattack embouchure. EMGs in all muscles during the postattack phase increased linearly with an increase in pitch, and they also increased with tone intensity without interacting with the pitch effect. Orofacial skin movement remained constant across all pitches and intensities except for lateral retraction of the lips during high-pitch tone production. Contraction of the orofacial muscles is fundamentally isometric by which tension on the lips and the cheeks is regulated for flexible sound parameter control. PMID- 23942162 TI - Organometallic ruthenium anticancer complexes inhibit human glutathione-S transferase pi. AB - The organometallic ruthenium(II) anticancer complexes [(eta(6)-arene)Ru(en)Cl](+) (arene = p-cymene (1), biphenyl (2) or 9,10-dihydrophenanthrene (3); en = ethylenediamine), exhibit in vitro and in vivo anticancer activities. In the present work, we show that they inhibit human glutathione-S-transferase pi (GSTpi) with IC50 values of 59.4 +/- 1.3, 63.2 +/- 0.4 and 37.2 +/- 1.1 MUM, respectively. Mass spectrometry revealed that complex 1 binds to the S-donors of Cys15, Cys48 within the G-site and Cys102 at the interface of the GSTpi dimer, while complex 2 binds to Cys48 and Met92 at the dimer interface and complex 3 to Cys15, Cys48 and Met92. Moreover, the binding of complex 1 to Cys15 and Cys102, complex 2 to Cys48 and complex 3 to Cys15 induces the irreversible oxidation of the coordinated thiolates to sulfenates. Molecular modeling studies indicate that the coordination of the {(arene)Ru(en)}(2+) fragment to Cys48 blocks the hydrophilic G-site sterically, perhaps preventing substrate from proper positioning and accounting for the reduction in enzymatic activity of ruthenated GSTpi. The binding of the ruthenium arene complexes to Cys102 or Met92 disrupts the dimer interface which is an essential structural feature for the proper functioning of GSTpi, perhaps also contributing to the inhibition of GSTpi. PMID- 23942163 TI - rhEGF-containing thermosensitive and mucoadhesive polymeric sol-gel for endoscopic treatment of gastric ulcer and bleeding. AB - Gastrointestinal endoscopy is a standard diagnostic tool for gastrointestinal ulcers and cancer. In this study, we have developed recombinant human epidermal growth factor-containing ulcer-coating polymeric sol-gel for endoscopic application. Chitosan and pluronic F127 were employed for their thermoresponsive and bioadhesive properties. At temperatures below 21, polymeric sol-gel remains liquid during endoscopic application and transforms to gel at body temperature after application on ulcers. In an in vitro cellular wounding assay, recombinant human epidermal growth factor sol-gel significantly enhanced the cell migration and decreased the wounding area (68%) compared to nontreated, recombinant human epidermal growth factor solution, and sol-gel without recombinant human epidermal growth factor (42, 49, and 32 % decreased at day 1). The in vivo ulcer-healing study was performed in an acetic acid-induced gastric ulcer rat model and proved that our recombinant human epidermal growth factor endoscopic sol-gel facilitated the ulcer-healing process more efficiently than the other treatments. Ulcer sizes in the recombinant human epidermal growth factor sol-gel group were decreased 2.9 and 2.1-fold compared with those in the nontreated group on days 1 and 3 after ulceration, respectively. The mucosal thickness in the recombinant human epidermal growth factor sol-gel group was significantly increased compared to that in the nontreated group (3.2- and 6.9-fold on days 1 and 3 after ulceration, respectively). In a gastric retention study, recombinant human epidermal growth factor sol-gel stayed on the gastric mucosa more than 2 h after application. The present study suggests that recombinant human epidermal growth factor sol-gel is a prospective candidate for treating gastric ulcers via endoscopic application. PMID- 23942164 TI - Anthropometric and physical characteristics of english academy rugby league players. AB - The purpose of the present study was to evaluate the anthropometric and physical characteristics of English academy rugby league players by annual-age category (under 16s-under 20s) and between backs and forwards. Data were collected on 133 academy players over a 6-year period (resulting in a total of 257 assessments). Player assessments comprised of anthropometric (height, body mass, sum of 4 skinfolds) and physical (vertical jump, 10- and 20-m sprint, estimated V[Combining Dot Above]O2max via the yo-yo intermittent recovery test level 1, absolute 1 repetition maximum [1RM], and relative squat, bench press, and prone row) measures. Univariate analysis of variance demonstrated significant (p <= 0.05) increases in height, body mass, vertical jump, absolute, and relative strength measures across the 5 annual-age categories (e.g., body mass: under 16s = 75.2 +/- 11.1, under 20s = 88.9 +/- 8.5 kg; vertical jump: under 16s = 45.7 +/- 5.2, under 20s = 52.8 +/- 5.4 cm; 1RM bench press: under 16s = 73.9 +/- 13.2, under 20s = 114.3 +/- 15.3 kg). Independent t-tests identified significant (p <= 0.05) differences between backs and forwards for anthropometric (e.g., under 16s body mass: backs = 68.4 +/- 8.6, forwards = 80.9 +/- 9.7 kg) and physical (e.g., under 19s 20-m sprint: backs = 3.04 +/- 0.08, forwards = 3.14 +/- 0.12s; under 18s relative squat: backs = 1.65 +/- 0.18, forwards = 1.51 +/- 0.17 kg.kg) characteristics that were dependent on the age category and measure assessed. Findings highlight that anthropometric and physical characteristics develop across annual-age categories and between backs and forwards in academy rugby league players. These findings provide comparative data for such populations and support the need to monitor player development in junior rugby league players. PMID- 23942165 TI - Snatch technique of United States national level weightlifters. AB - This study analyzed the top 3 successful snatch attempts by individual lifters in each weight class at a U.S. National Championship weightlifting meet. Two dimensional (2-D) body position and characteristics of the lifts were compared via 2D video analysis in groups of lifters who displaced forward, showed no displacement, or displaced backward to receive the bar. No significant group differences (p > 0.05) were noted for body mass, bar mass, or hip angle. The rearward displacement group had a significantly greater horizontal distance between the shoulder and heel at the end of the pull (determined as the point where the bar ceases to accelerate vertically). Hip angles for the no displacement group had a small-to-moderate effect size (0.50) in comparison to the forward displacement group, but they only showed a small effect size (0.17) when compared with the rearward displacement group. The forward displacement group showed a small-to-moderate effect size compared with both the no displacement group (0.51) and the rearward displacement group (0.55) concerning the horizontal distance from the shoulder to the heel. These data seem to suggest that rearward displacement in the drop-under phase in the snatch is not detrimental to performance and actually seems to be a preferred technique in U.S. national level lifters. In addition to evidence that rearward displacement is exhibited in elite lifters and is coached globally, it seems this is the preferred technique in international competitions. This technique may be considered a viable variation of the snatch by coaches and athletes of all levels. PMID- 23942166 TI - A time-saving method to assess power output at lactate threshold in well-trained and elite cyclists. AB - The purpose of this study was to examine the relationship between lactate threshold (LT) as a percentage of maximal oxygen consumption (V[Combining Dot Above]O2max) and power output at LT (LTW) and also to investigate to what extent V[Combining Dot Above]O2max, oxygen cost of cycling (CC), and maximal aerobic power (MAP) determine LTW in cycling to develop a new time-saving model for testing LTW. To do this, 108 male competitive cyclists with an average V[Combining Dot Above]O2max of 65.2 +/- 7.4 ml.kg.min and an average LTW of 274 +/- 43 W were tested for V[Combining Dot Above]O2max, LT %V[Combining Dot Above]O2max, LTW, MAP, and CC on a test ergometer cycle. The product of MAP and individual LT in %V[Combining Dot Above]O2max was found to be a good determinant of LTW (R = 0.98, p < 0.0001). However, LT in %V[Combining Dot Above]O2max was found to be a poor determinant of LTW (R = 0.39, p < 0.0001). Based on these findings, we have suggested a new time-saving method for calculating LTW in well trained cyclists. The benefits from this model come both from tracking LTW during training interventions and from regularly assessing training status in competitive cyclists. Briefly, this method is based on the present findings that LTW depends on LT in %V[Combining Dot Above]O2max, V[Combining Dot Above]O2max, and CC and may after an initial test session reduce the time for the subsequent testing of LTW by as much as 50% without the need for blood samples. PMID- 23942167 TI - Optimizing Interval Training at Power Output Associated With Peak Oxygen Uptake in Well-Trained Cyclists. AB - The purpose of this study was to investigate the acute physiological responses of interval protocols using the minimal power output (MAP) that elicits peak oxygen uptake (V[Combining Dot Above]O2peak) as exercise intensity and different durations of work intervals during intermittent cycling. In randomized order, 13 well-trained male cyclists (V[Combining Dot Above]O2peak = 67 +/- 6 ml.kg.min) performed 3 different interval protocols to exhaustion. Time to exhaustion and time >= 90% of V[Combining Dot Above]O2peak were measured with MAP as exercise intensity, and work duration of the intervals equals either 80% of Tmax, 50% of Tmax, or 30 seconds with recovery period being 50% of the work duration at intensity equal to 50% of MAP. The major findings were that the interval protocol using 30-second work periods induced longer time >=90% of V[Combining Dot Above]O2peak and longer work duration at MAP intensity than the interval protocols using work periods of 50% of Tmax or 80% of Tmax (p <= 0.05). There was no difference between the protocols using work periods of 50% of Tmax or 80% of Tmax. In conclusion, the present study suggests that the 30-second work interval protocol acutely induces a larger exercise stimulus in well-trained cyclists than the protocols using work periods of 50% of Tmax or 80% of Tmax. The practical application of the present findings is that fixed 30-second work intervals can be used to optimize training time at MAP and time >=90% of V[Combining Dot Above]O2peak in well-trained cyclists using MAP exercise intensity and a 2:1 work:recovery ratio. PMID- 23942169 TI - Comparison of the physiological responses and time-motion characteristics of young soccer players in small-sided games: the effect of goalkeeper. AB - The purpose of this study was to investigate the effect of "with goalkeeper" (SSGwith) and "without goalkeeper" (SSGwithout) conditions on players' physiological responses and time-motion characteristics in small-sided games. Sixteen young soccer players (age: 16.5 +/- 1.5 years; height: 175.5 +/- 5.2 cm; body mass: 63.0 +/- 6.9 kg; training experience: 6.3 +/- 1.3 years) participated in 2 different 2-a-side, 3-a-side, and 4-a-side games: SSGwith and SSGwithout. The players underwent anthropometric measurements (height and body mass) followed by the Yo-Yo intermittent recovery test (level 1). Then they played 2-a-side, 3-a side, and 4-a-side SSGwith and SSGwithout soccer-specific SSGs in random order at 2-day intervals. Heart rate (HR) responses and distance covered in different speed zones (walking [WLK, 0-6.9 km.h(-1)], low-intensity running [LIR, 7.0-12.9 km.h(-1)], moderate-intensity running [MIR, 13.0-17.9 km.h(-1)], and high intensity running [HIR, >18 km.h(-1)]) were measured during the SSGs, whereas the rating of perceived exertion (RPE) and blood lactate (La) were determined at the end of the last bout of each SSG. During the SSGwithout players showed higher %HR, La, and RPE (p <= 0.05), greater distance covered in LIR, MIR, HIR, and total distance (p <= 0.05) compared with the SSGwith during the 2-a-side, 3-a side, and 4-a-side games. The results of this study suggest that both SSGwith and SSGwithout could be used for the physiological adaptations required for soccer specific aerobic endurance. However, if coaches want both higher physiological responses and greater distance covered in the intensity running zone from their teams, SSGwithout should be organized. In addition, this study also suggests that smaller format games (i.e., 2-a-side) may promote some anaerobic adaptations for youth soccer players. PMID- 23942172 TI - A pan-Canadian web-based education program to support screening for distress: evaluation of outcomes. AB - OBJECTIVE: Cancer-related distress has been endorsed as the sixth vital sign by many international cancer organizations, and some countries such as Canada have implemented national screening for distress programs. The completion of a screening tool is an important first step in improving responsiveness to cancer related distress, but screening must be followed with skilled supportive care to make a difference in patient-reported outcomes. Our objective was to create a web based education program to support nurses and other frontline staff in providing an initial response to screening results. METHOD: To address screening and supportive care learning needs, the Canadian Association of Psychosocial Oncology (CAPO), with support from the Canadian Partnership Against Cancer, created a web based education program as one component of the national screening for distress agenda. The program provides clinically grounded and interactive learning through the use of PowerPoint presentations, video clips of clinical interactions with patients and family members, and test questions. Presentation topics include, for example, strategies for dealing with screening results, managing referrals, and supportive counseling. We employed a matched pairs, pre-post survey design to assess the effect of the education program on confidence in screening and in providing initial supportive care. RESULTS: Our analysis of the first 147 matched pairs to complete the course suggests that satisfaction with the course was high. Statistically significant increases in confidence in relation to screening for distress and assessing distress, and in providing initial supportive care, were evident. SIGNIFICANCE OF RESULTS: Our ongoing experience with CAPO's Interprofessional Psychosocial Oncology Distance Education (IPODE) project (www.ipode.ca) project suggests that healthcare professionals value web-based learning for its accessibility and convenience. Such programs appear to offer excellent opportunities for cost-effective education that supports practice change. PMID- 23942170 TI - The Relationship Between Dynamic Stability and Multidirectional Speed. AB - Lockie, RG, Schultz, AB, Callaghan, SJ, and Jeffriess, MD. The relationship between dynamic stability and multidirectional speed. J Strength Cond Res 30(11): 3033-3043, 2016-Dynamic stability is said to contribute to multidirectional (linear and change-of-direction) speed, although little research confirms this. This study analyzed the relationship between dynamic stability as measured by lower-limb functional reaching in 6 directions (anterolateral, lateral, posterolateral, posteromedial, medial, and anteromedial) within a modified star excursion balance test and multidirectional speed (40-m sprint: 0-10, 0-20, and 0 40 m intervals; T-test; change-of-direction and acceleration test [CODAT]). Sixteen male field sport athletes (age, 23.31 +/- 5.34 years; height, 1.78 +/- 0.07 m; mass, 80.60 +/- 9.89 kg) completed testing. A 1-way analysis of variance determined significant (p <= 0.05) differences in excursions between faster and slower subjects. All data were pooled for a Spearman's correlation analysis (p <= 0.05). Faster subjects had greater left leg medial reach (76.24 +/- 5.33 vs. 65.94 +/- 10.75%), right leg posteromedial reach (85.20 +/- 8.07 vs. 73.59 +/- 12.64%), and a smaller between-leg difference in lateral reach (2.26 +/- 1.85 vs. 6.46 +/- 4.29%). Longer reach distances (greater dynamic stability) correlated with faster speed test times (rho = -0.499 to 0.664). Dynamic stability relationships were pronounced for the change-of-direction speed tests. For example, smaller between-leg excursion differences in anterolateral, lateral, posterolateral, and posteromedial reaches related to faster T-test and CODAT times (rho = 0.502-0.804). There is a relationship between dynamic stability as measured by functional reaching and multidirectional speed in field sport athletes, possibly because of similarities in movement demands and muscle recruitment. Dynamic stability training could strengthen muscles for multidirectional sprinting and develop functional joint motion. PMID- 23942173 TI - How can we improve transfer of outcomes from randomized clinical trials to clinical practice with disease-modifying drugs in Alzheimer's disease? AB - BACKGROUND: Randomized clinical trials (RCTs) for putative disease-modifying drugs in Alzheimer's disease (AD) are using cognitive outcomes, such as the Alzheimer's Disease Assessment Scale--cognitive subscale, activities of daily living scales, such as the Alzheimer's Disease Cooperative Study Activities of Daily Living, and time from mild cognitive impairment to AD dementia. OBJECTIVE: It was the aim of this study to build clinically relevant outcomes for future use in clinical practice into RCT designs and help third-party payers to measure benefit. METHODS: We used a literature review for analysis. RESULTS: The Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) appears to be the most reliable primary outcome for RCT at different stages of AD, with the Relevant Outcome Scale for Alzheimer's Disease (ROSA) as a suitable alternative. The importance of current AD biomarkers vis-a- vis determination of efficacy of disease-modifying drugs has yet to be established; however, it is likely that at least one amyloid specific test will be required prior to treatment with a drug acting predominantly on beta-amyloid (Abeta42). Furthermore, serial MRI may be required to monitor adverse side effects associated with such drugs. CONCLUSIONS: Global clinical scales such as CDR-SB and ROSA should be considered for use with treatments aiming at slowing disease progression. PMID- 23942174 TI - Financial crises: impact on mental health and suggested responses. PMID- 23942175 TI - Low vitamin D status is associated with reduced muscle mass and impaired physical performance in frail elderly people. AB - BACKGROUND/OBJECTIVES: Serum 25-hydroxyvitamin D (25(OH)D) status has been associated with muscle mass, strength and physical performance in healthy elderly people. Yet, in pre-frail and frail elderly people this association has not been studied. The objective of this study was to explore the association between vitamin D intake and serum 25(OH)D status with muscle mass, strength and physical performance in a pre-frail and frail elderly population. SUBJECTS/METHODS: This cross-sectional study included 127 pre-frail and frail elderly people in The Netherlands. Whole body and appendicular lean mass (ALM) (dual energy X-ray absorptiometry), leg strength (one repetition maximum), handgrip strength and physical performance (short physical performance battery) were measured, and blood samples were collected for the assessment of serum 25(OH)D status (liquid chromatography-tandem mass spectrometry). In addition, habitual dietary intake (3 day food records) and physical activity data (accelerometers) were collected. RESULTS: In total, 53% of the participants had a serum 25(OH)D level below 50 nmol/l. After adjustment for confounding factors, 25(OH)D status was associated with ALM (beta=0.012, P=0.05) and with physical performance (beta=0.020, P<0.05). Vitamin D intake was associated with physical performance (beta=0.18, P<0.05) but not with ALM (P>0.05). CONCLUSION: In this frail elderly population, 25(OH)D status is low and suggests a modest association with reduced ALM and impaired physical performance. In addition, vitamin D intake tended to be associated with impaired physical performance. Our findings highlight the need for well-designed intervention trials to assess the impact of vitamin D supplementation on 25(OH)D status, muscle mass and physical performance in pre-frail and frail elderly people. PMID- 23942176 TI - A narrative review of recent progress in understanding the relationship between tuberculosis and protein energy malnutrition. AB - Protein energy malnutrition (PEM) and tuberculosis (TB) are the major public health issues, particularly in the developing country setting. Malnutrition is an underlying cause of many deaths and when left untreated devastates normal physical and cognitive development. TB continues to gather momentum as a serious infectious killer. They have both rightly been highlighted as important global health issues by their inclusion in the Millennium Development Goals. But what is known of their relationship with one another? It is historically accepted that PEM and TB have a synergistic relationship adversely having an impact on one another. However, researchers have sought to apply this understanding in an examination of the relationship between TB and PEM with often inconclusive results. This narrative review of recently published research and current knowledge may help delineate the association between PEM and TB mortality. Such results will assist future research in this important area of health--an area lacking evidence-based guidance. PMID- 23942177 TI - Nutrient intake in the GEICO multicenter trial: the effects of a multicomponent worksite intervention. AB - BACKGROUND/OBJECTIVES: To assess the effects on macro- and micronutrient intake of a nutrition intervention program in corporate settings across the United States. SUBJECTS/METHODS: Two hundred and ninety-two individuals who were overweight or had type 2 diabetes were recruited from 10 sites of a US insurance company. Two hundred and seventy-one participants completed baseline diet recalls, and 183 participants completed dietary recalls at 18 weeks. Sites were randomly assigned to an intervention group (five sites) or to a control group (five sites) for 18 weeks. At intervention sites, participants were asked to follow a low-fat vegan diet and attend weekly group meetings. At control sites, participants continued their usual diets. At baseline and 18 weeks, participants completed 2-day diet recalls. Between-group differences in changes in nutrient intake were assessed using an analysis of covariance. RESULTS: Compared with those in the control group, intervention-group participants significantly reduced the reported intake of total fat (P=0.02), saturated (P=0.006) and monounsaturated fats (P=0.01), cholesterol (P=0.009), protein (P=0.03) and calcium (P=0.02), and increased the intake of carbohydrate (P=0.006), fiber (P=0.002), beta-carotene (P=0.01), vitamin C (P=0.003), magnesium (P=0.04) and potassium (P=0.002). CONCLUSIONS: An 18-week intervention program in a corporate setting reduces intake of total fat, saturated fat and cholesterol and increases the intake of protective nutrients, particularly fiber, beta-carotene, vitamin C, magnesium and potassium. The reduction in calcium intake indicates the need for planning for this nutrient. PMID- 23942178 TI - Assessing body composition in taller or broader individuals using dual-energy X ray absorptiometry: a systematic review. AB - BACKGROUND/OBJECTIVES: Dual-energy X-ray absorptiometry (DXA) is an accurate and reliable method for determining body composition, but a limiting feature is the restricted scanning areas (~190 * 60 cm(2)). This shortcoming is relevant not only to athletes involved in sports where height is a major performance determinant but also to obese individuals with a large trunk mass and breadth in whom body dimensions frequently exceed the scan area. This study reviews solutions for DXA length and/or width limitations and its accuracy for body composition assessment using the PRISMA statement guidelines. SUBJECTS/METHODS: Reviewed studies included English language articles from MEDLINE and Thomson Reuters Web of Knowledge platform (1990-2013), and were selected if procedures to overcome the scan area limitations and its validity in assessing the body composition of healthy participants were addressed. Search terms included: DXA, scan, height, width, length, wide, large, tall and obese. RESULTS: A total of seven studies met the criteria and were selected. The sum of two DXA scans and adopting a knee-bent position are alternative procedures proposed for evaluating individuals using pencil and fan-beam Hologic instruments, who are taller than the scan area, whereas a half-body scan is recommended for overcoming the limitations of whole-body measurements in subjects who are wider than the scan area width of Lunar densitometers. CONCLUSIONS: Overall, the proposed procedures are useful and valid, in particular the half-body scan alternative, which avoids unnecessary radiation exposure and scanning time. However, these alternatives were developed for specific densitometers, models and scan mode, and applicability to other instruments requires further research. PMID- 23942179 TI - Variation of serum metabolites related to habitual diet: a targeted metabolomic approach in EPIC-Potsdam. AB - BACKGROUND/OBJECTIVE: Serum metabolites have been linked to higher risk of chronic diseases but determinants of serum metabolites are not clear. We aimed to investigate the association between habitual diet as a modifiable risk factor and relevant serum metabolites. SUBJECTS/METHODS: This cross-sectional study comprised 2380 EPIC-Potsdam participants. Intake of 45 food groups was assessed by food frequency questionnaire and concentrations of 127 serum metabolites were measured by targeted metabolomics. Reduced rank regression was used to find dietary patterns that explain the maximum variation of metabolites. RESULTS: In the multivariable-adjusted model, the proportion of explained variation by habitual diet was ranked as follows: acyl-alkyl-phosphatidylcholines (5.7%), sphingomyelins (5.1%), diacyl-phosphatidylcholines (4.4%), lyso phosphatidylcholines (4.1%), acylcarnitines (3.5%), amino acids (2.2%) and hexose (1.6%). A pattern with high intake of butter and low intake of margarine was related to acylcarnitines, acyl-alkyl-phosphatidylcholines, lyso phosphatidylcholines and hydroxy-sphingomyelins, particularly with saturated and monounsaturated fatty acid side chains. A pattern with high intake of red meat and fish and low intake of whole-grain bread and tea was related to hexose and phosphatidylcholines. A pattern consisting of high intake of potatoes, dairy products and cornflakes particularly explained methionine and branched chain amino acids. Dietary patterns related to type 2 diabetes-relevant metabolites included high intake of red meat and low intake of whole-grain bread, tea, coffee, cake and cookies, canned fruits and fish. CONCLUSIONS: Dietary patterns characterized by intakes of red meat, whole-grain bread, tea and coffee were linked to relevant metabolites and could be potential targets for chronic disease prevention. PMID- 23942180 TI - Dietary patterns and longitudinal change in body mass in European children: a follow-up study on the IDEFICS multicenter cohort. AB - BACKGROUND/OBJECTIVES: Longitudinal studies investigating dietary patterns (DPs) and their association with childhood overweight/obesity are lacking in Europe. We identified DPs and investigated their association with overweight/obesity and changes in body mass index (BMI) in a cohort of European children. SUBJECTS/METHODS: Children aged 2-10 from eight European countries were recruited in 2007-2008. Food frequency questionnaires were collected from 14 989 children. BMI and BMI z-scores were derived from height and weight and were used to identify overweight/obese children. After 2 years (mean), anthropometric measurements were repeated in 9427 children. Principal component analysis was used to identify DPs. Simplified DPs (SDPs) were derived from DPs. Adjusted odds ratios (ORs) for overweight/obesity with increasing DP intake were estimated using multilevel logistic regression. Associations of BMI change with DP and SDP were assessed by multilevel mixed regression. Models were adjusted for baseline BMI, age, sex, physical activity and family income. RESULTS: Four DPs were identified that explained 25% of food intake variance: snacking, sweet and fat, vegetables and wholemeal, and protein and water. After 2 years, 849(9%) children became overweight/obese. Children in the highest vegetables and wholemeal tertile had lower risk of becoming overweight/obese (OR: 0.69, 95% confidence intervals (CIs): 0.54-0.88). Children in the highest SDP tertile of vegetables and wholemeal had similarly lower risk of becoming overweight/obese (OR: 0.64, 95% CIs: 0.51-0.82), and their BMI increased by 0.7 kg/m(2) over the study period significantly less than the increase in the lowest tertile (0.84 kg/m(2)). CONCLUSIONS: Our findings suggest that promoting a diet rich in vegetables and wholemeal cereals may counteract overweight/obesity in children. PMID- 23942181 TI - Umbilical cord mesenchymal stem cell transplantation significantly improves neurological function in patients with sequelae of traumatic brain injury. AB - The aim of this study was to investigate the effects of transplantation with umbilical cord mesenchymal stem cells in patients with sequelae of traumatic brain injury (TBI). The study hypothesis was that umbilical cord mesenchymal stem cell transplantation could safely and effectively improve neurological function in patients with sequelae of traumatic brain injury. Forty patients with sequelae of TBI were randomly assigned to the stem cell treatment group or the control group. The patients in the stem cell treatment group underwent 4 stem cell transplantations via lumbar puncture. All patients of the group were also evaluated using Fugl-Meyer Assessments (FMA) and Functional Independence Measures (FIM) before and at 6 months after the stem cell transplantation. The patients in the control group did not receive any medical treatment (i.e., neither surgery nor medical intervention), and their FMA and FIM scores were determined on the day of the visit to the clinic and at 6 months after that clinical observation. The FMA results demonstrated an improvement in upper extremity motor sub-score, lower extremity motor sub-score, sensation sub-score and balance sub-score in the stem cell transplantation group at 6 months after the transplantation (P<0.05). The FIM results also exhibited significant improvement (P<0.05) in the patient self-care sub-score, sphincter control sub-score, mobility sub-score, locomotion sub-score, communication sub-score and social cognition sub-score. The control group exhibited no improvements after 6 months (P>0.05). All in all, the study results confirmed that the umbilical cord mesenchymal stem cell transplantation improved the neurological function and self-care in patients with TBI sequels. Umbilical cord mesenchymal stem cell transplantation may be a potential treatment for patients with sequelae of TBI. Further research, including a multicenter and large sample size prospective randomized clinical trial, will be required to define definitively the role of umbilical cord mesenchymal stem cell transplantation on sequelae of TBI. PMID- 23942183 TI - Oxidative pathways of chemical toxicity and oxidative stress biomarkers in marine organisms. AB - The antioxidant system of marine organisms consists of low molecular weight scavengers and antioxidant enzymes which interact in a sophisticated network. Environmental pollutants can unbalance this system through closely related mechanisms, indirect relationships and cascade effects acting from pre transcriptional to catalytic levels. Chemically-mediated pathways have the potential to greatly enhance intracellular formation of reactive oxygen species (ROS); at the same time, excessive levels of oxyradicals down-regulate xenobiotics metabolism, with important environmental implications for organisms exposed to chemical mixtures. Interactions between different classes of chemicals, generation of ROS and onset of oxidative stress conditions are partly modulated by changes in levels and functions of redox-sensitive signaling proteins and transcription factors. The Nrf2-Keap1 pathway still remains largely unexplored in marine organisms, despite the elevated degree of identity and similarity with homolog transcripts and proteins from different species. Recent evidences on transcriptional up-regulation of this system are consistent with the capability to provide a prolonged expression of ARE-regulated cytoprotective genes, and to efficiently switch off this mechanism when oxidative pressure decreases. Although gene expression and catalytic activities of antioxidants are often measured as alternative biomarkers in monitoring biological effects of contaminants, conflicting results between molecular and biochemical responses are quite frequent. The links between effects occurring at various intracellular levels can be masked by non-genomic processes affecting mRNA stability and protein turnover, different timing for transcriptional and translational mechanisms, metabolic capability of tissues, post-transcriptional modifications of proteins, bi-phasic responses of antioxidant enzymes and interactions occurring in chemical mixtures. In this respect, caution should be taken in monitoring studies where mRNA levels of antioxidants could represent a snapshot of cell activity at a given time, not an effective endpoint of environmental pollutants. PMID- 23942182 TI - Advancing the research agenda for diagnostic error reduction. AB - Diagnostic errors remain an underemphasised and understudied area of patient safety research. We briefly summarise the methods that have been used to conduct research on epidemiology, contributing factors and interventions related to diagnostic error and outline directions for future research. Research methods that have studied epidemiology of diagnostic error provide some estimate on diagnostic error rates. However, there appears to be a large variability in the reported rates due to the heterogeneity of definitions and study methods used. Thus, future methods should focus on obtaining more precise estimates in different settings of care. This would lay the foundation for measuring error rates over time to evaluate improvements. Research methods have studied contributing factors for diagnostic error in both naturalistic and experimental settings. Both approaches have revealed important and complementary information. Newer conceptual models from outside healthcare are needed to advance the depth and rigour of analysis of systems and cognitive insights of causes of error. While the literature has suggested many potentially fruitful interventions for reducing diagnostic errors, most have not been systematically evaluated and/or widely implemented in practice. Research is needed to study promising intervention areas such as enhanced patient involvement in diagnosis, improving diagnosis through the use of electronic tools and identification and reduction of specific diagnostic process 'pitfalls' (eg, failure to conduct appropriate diagnostic evaluation of a breast lump after a 'normal' mammogram). The last decade of research on diagnostic error has made promising steps and laid a foundation for more rigorous methods to advance the field. PMID- 23942184 TI - Vascular galectins: regulators of tumor progression and targets for cancer therapy. AB - Galectins are a family of carbohydrate binding proteins with a broad range of cytokine and growth factor-like functions in multiple steps of cancer progression. They contribute to tumor cell transformation, promote tumor angiogenesis, hamper the anti-tumor immune response, and facilitate tumor metastasis. Consequently, galectins are considered as multifunctional targets for cancer therapy. Interestingly, many of the functions related to tumor progression can be linked to galectins expressed by endothelial cells in the tumor vascular bed. Since the tumor vasculature is an easily accessible target for cancer therapy, understanding how galectins in the tumor endothelium influence cancer progression is important for the translational development of galectin-targeting therapies. PMID- 23942185 TI - Nanoscale biomemory composed of recombinant azurin on a nanogap electrode. AB - We fabricate a nanoscale biomemory device composed of recombinant azurin on nanogap electrodes. For this, size-controllable nanogap electrodes are fabricated by photolithography, electron beam lithography, and surface catalyzed chemical deposition. Moreover, we investigate the effect of gap distance to optimize the size of electrodes for a biomemory device and explore the mechanism of electron transfer from immobilized protein to a nanogap counter-electrode. As the distance of the nanogap electrode is decreased in the nanoscale, the absolute current intensity decreases according to the distance decrement between the electrodes due to direct electron transfer, in contrast with the diffusion phenomenon of a micro-electrode. The biomemory function is achieved on the optimized nanogap electrode. These results demonstrate that the fabricated nanodevice composed of a nanogap electrode and biomaterials provides various advantages such as quantitative control of signals and exclusion of environmental effects such as noise. The proposed bioelectronics device, which could be mass-produced easily, could be applied to construct a nanoscale bioelectronics system composed of a single biomolecule. PMID- 23942186 TI - Functional and molecular characterization of novel Hansenula polymorpha genes, HpPMT5 and HpPMT6, encoding protein O-mannosyltransferases. AB - The genome of the thermotolerant methylotrophic yeast Hansenula polymorpha reveals the presence of five PMT homologues (HpPMT1, HpPMT2, HpPMT4, HpPMT5, and HpPMT6) encoding protein O-mannosyltransferases. Here, we report on the systematic characterization of HpPMT5 and HpPMT6, encoding novel PMT1 and PMT2 subfamily members, respectively. Although no apparent growth defects were detected in the Hppmt5Delta and Hppmt6Delta single mutants, the single mutants showed dramatic sensitivity to the Pmt1p inhibitor, and the Hppmt1pmt5Delta and Hppmt1pmt6Delta double mutants displayed increased susceptibility to cell wall disturbing reagents. Activation of the cell wall integrity signaling pathway in the double mutant strains was further indicated by the markedly induced phosphorylation of MAP kinases, such as HpMpk1p and HpHog1p. Noticeably, O mannosylation of the surface glycoproteins HpWsc1p and HpMid2p became severely defective only in the double mutants, supporting the involvement of HpPmt5p and HpPmt6p in O-mannosylation of these sensor proteins. On the other hand, co immunoprecipitation experiments revealed only marginal interaction between HpPmt5p and HpPmt2p, even in the absence of HpPmt1p. Taken together, our results suggest that the functions of HpPmt5p and HpPmt6p are minor but become crucial upon the loss of HpPmt1p for protein O-mannosylation, which is essential for cell growth, cell wall integrity, and stress resistance in H. polymorpha. PMID- 23942187 TI - Genes involved in protein glycosylation determine the activity and cell internalization of the antifungal peptide PAF26 in Saccharomyces cerevisiae. AB - We have previously characterized the synthetic hexapeptide PAF26 as a cell penetrating and non-lytic antifungal peptide that is active against Saccharomyces cerevisiae and filamentous fungi. Numerous cell wall (CW) proteins are glycosylated in fungi and many of these play important roles in fungal pathogenesis. In this study, we screened a collection of S. cerevisiae deletion mutants for protein glycosylation genes whose deletion altered the sensitivity to PAF26. Increased tolerance to PAF26 was observed in mutants with the following disrupted genes: PMT1-6, EOS1, ALG5, MNN1, MNN4 and MNN5. Significantly, genes coding for protein O-mannosyltransferase 2 (Pmt2p), which is responsible for the addition of the first mannosyl residue of O-linked carbohydrates, and for Eos1p, an enzyme involved in N-linked glycosylation of proteins, showed resistance to PAF26 and defects in CW integrity. Microscopic studies on the S. cerevisiae Deltaeos1 deletion mutant demonstrated a blockage of peptide internalization by cells. Protoplasts lacking CWs interacted with the peptide, but were more resistant to peptide killing than cells possessing CWs due to a blockage in PAF26 internalization. Interestingly, protoplasts obtained from Deltaeos1 behaved similarly to those of the parental strain. Collectively, these observations demonstrate that the CW is a positive factor that determines the internalization of the PAF26, and that Eos1p exerts its activity through the glycosylation of specific protein(s) involved in peptide internalization. PMID- 23942188 TI - G protein-cAMP signaling pathway mediated by PGA3 plays different roles in regulating the expressions of amylases and cellulases in Penicillium decumbens. AB - Heterotrimeric G proteins (G proteins) have been extensively investigated for their regulatory functions in morphogenesis and development in filamentous fungi. In addition, G proteins were also shown to be involved in the regulation of cellulase expression in some fungi. Here, we report the different regulatory effects of PGA3, a group III G protein alpha subunit, on the expressions of amylases and cellulases in Penicillium decumbens. Deletion of pga3 resulted in impaired amylase production and significantly decreased transcription of the major amylase gene amy15A. Supplementation of exogenous cAMP or its analog dibutyryl-cAMP restored amylase production in Deltapga3 strain, suggesting an essential role of PGA3 in amylase synthesis via controlling cAMP level. On the other hand, the transcription of major cellulase gene cel7A-2 increased, nevertheless cellulase activity in the medium was not affected, in Deltapga3. The above regulatory effects of PGA3 are carbon source-independent, and are achieved, at least, by cAMP-mediated regulation of the expression level of transcription factor AmyR. The functions of PGA3 revealed by gene deletion were partially supported by the analysis of the mutant carrying dominantly-activated PGA3. The results provided new insights into the understanding of the physiological functions of G protein-cAMP pathway in filamentous fungi. PMID- 23942189 TI - A new infant case of Nakajo-Nishimura syndrome with a genetic mutation in the immunoproteasome subunit: an overlapping entity with JMP and CANDLE syndrome related to PSMB8 mutations. AB - Nakajo-Nishimura syndrome (NNS) is a very rare hereditary autoinflammatory disorder that generally has its onset in infancy with pernio-like rashes and gradually develops into partial lipodystrophy. A distinct homozygous PSMB8 mutation encoding an immunoproteasome subunit has recently been identified as its genetic cause. Here, we report a new case of a patient with NNS who developed exudative erythemas on his face and extremities at 2 months of age, along with high fever, elevated serum hepatic aminotransferase levels and hepatosplenomegaly. Massive infiltration of inflammatory cells was observed histologically in the dermis and subcutis without apparent leukocytoclastic vasculitis. These symptoms improved with oral corticosteroids but recurred periodically, and a thin angular face with long clubbed fingers gradually developed. Identification of the PSMB8 mutation finalized the diagnosis of NNS at 5 years of age. Understanding a variety of clinicopathological features at the developmental stages is necessary to make an early diagnosis of NNS. PMID- 23942190 TI - PhyloPhlAn is a new method for improved phylogenetic and taxonomic placement of microbes. AB - New microbial genomes are constantly being sequenced, and it is crucial to accurately determine their taxonomic identities and evolutionary relationships. Here we report PhyloPhlAn, a new method to assign microbial phylogeny and putative taxonomy using >400 proteins optimized from among 3,737 genomes. This method measures the sequence diversity of all clades, classifies genomes from deep-branching candidate divisions through closely related subspecies and improves consistency between phylogenetic and taxonomic groupings. PhyloPhlAn improved taxonomic accuracy for existing and newly sequenced genomes, detecting 157 erroneous labels, correcting 46 and placing or refining 130 new genomes. We provide examples of accurate classifications from subspecies (Sulfolobus spp.) to phyla, and of preliminary rooting of deep-branching candidate divisions, including consistent statistical support for Caldiserica (formerly candidate division OP5). PhyloPhlAn will thus be useful for both phylogenetic assessment and taxonomic quality control of newly sequenced genomes. The final phylogenies, conserved protein sequences and open-source implementation are available online. PMID- 23942191 TI - BMP15 prevents cumulus cell apoptosis through CCL2 and FBN1 in porcine ovaries. AB - BACKGROUND: Bone morphogenetic protein-15 (BMP15) is a maternal gene necessary for mammalian reproduction. BMP15 expression increased in oocytes accompanied by follicle growth and development. The function and regulation mechanism of BMP15 in porcine cumulus cell apoptosis process is still unclear now. METHODS: In this study, flow cytometry (FCM) was used to analyze the effects of BMP15 with different concentrations to cumulus cell apoptosis. High-throughput sequencing technology was carried out to screen regulatory genes linked closely with BMP15. In order to confirm the function of (MCP-1)/CCL2 and FBN1 in cumulus cell apoptosis, RNA interference (RNAi) method was used to inhibit the expression of (MCP-1)/CCL2 and FBN1. Apoptosis and proliferation of cumulus cell treated with siRNA transfection technology were measured by FCM, 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide, quantitative real time-PCR (RT-qPCR) and western blotting. RESULTS: The results showed that the apoptosis levels of cumulus cell treated by BMP15 decreased significantly in a dose-dependent manner. The expression of related genes protein 1 (MCP-1)/CCL2 and fibrillin1 (FBN1) were both regulated by BMP15. After transfection, the proliferation of porcine cumulus cells increased significantly and apoptosis of cumulus cells was prevented while FBN1 was silenced after BMP15 treatment. The proliferation of cumulus cells decreased significantly and apoptosis rate of cumulus cells increased significantly while CCL2 was silenced. CONCLUSION: The results obtained in this study firstly demonstrated that CCL2 and FBN1 are important regulatory factors of BMP15 in preventing cumulus cell apoptosis in porcine ovaries. PMID- 23942192 TI - Factors that affect the efficacy of fluoroscopically guided selective spinal nerve root block in the treatment of radicular pain: a prospective cohort study. AB - AIM: The fluoroscopically guided selective nerve root block (SNRB) is being used increasingly as a therapy for radicular pain as well as a diagnostic tool. However, studies and the literature reviews have yet to reach a definite conclusion on the efficacy in this setting. Our aim was to prospectively investigate factors that may affect the success of this procedure. MATERIALS AND METHODS: A total of 301 treatment episodes with 283 patients were assessed over 25 months by patient questionnaire over a 7-day period. Changes in analgesic benefit over time, by operating consultant, referring specialty, spinal level, and the presence of periprocedural symptom provocation were evaluated. Statistical analysis was performed by using the chi(2) test, Wilcoxon test, and Kruskal-Wallis rank sum test, and the asymptotic marginal-homogeneity test. P < .05 was considered significant. RESULTS: There was a statistically significant increase in pain relief over the 7 days after the procedure. Pain provocation during the procedure did not improve analgesic success. Cervical, lumbar, and sacral level procedures were equally efficacious. The specialist who referred the patient and the use of contrast to verify needle position during the procedure also did not affect the analgesic outcome. Overall, 69.1% of patients experienced some pain relief by day 7. CONCLUSION: Analgesic success rates of selective nerve root blocks did not vary with spinal level, or use of contrast or periprocedural replication of symptoms, when using fluoroscopic guidance. Patients may expect a continued significant improvement in their symptoms for at least a week after the procedure. PMID- 23942193 TI - Pulmonary ablation: a primer. AB - Percutaneous image-guided thermal ablation is safe and efficacious in achieving local control and improving outcome in the treatment of both early stage non small-cell lung cancer and pulmonary metastatic disease, in which surgical treatment is precluded by comorbidity, poor cardiorespiratory reserve, or unfavorable disease distribution. Radiofrequency ablation is the most established technology, but new thermal ablation technologies such as microwave ablation and cryoablation may offer some advantages. The use of advanced techniques, such as induced pneumothorax and the popsicle stick technique, or combining thermal ablation with radiotherapy, widens the treatment options available to the multidisciplinary team. The intent of this article is to provide the reader with a practical knowledge base of pulmonary ablation by concentrating on indications, techniques, and follow-up. PMID- 23942194 TI - Language and mathematical problems as precursors of psychotic-like experiences and juvenile mania symptoms. AB - BACKGROUND: Psychotic-like experiences (PLEs) and juvenile mania in adolescence index risk for severe psychopathology in adulthood. The importance of childhood problems with communication, reading, speech and mathematics for the development of PLEs and juvenile mania is not well understood. METHOD: Through the Child and Adolescent Twin Study in Sweden, we identified 5812 children. The parents were interviewed about their children's development at age 9 or 12 years. At age 15 or 18 years, children and parents completed questionnaires targeting current PLEs and juvenile mania symptoms. Logistic regressions were used to assess associations between problems with communication, reading, speech and mathematics and PLEs/juvenile mania symptoms. To evaluate the relative importance of genes and environment in these associations, we used bivariate twin analyses based on structural equation models. RESULTS: Children with parent-endorsed childhood problems with communication, reading and mathematics had an increased risk of developing auditory hallucinations and parental-reported juvenile mania symptoms in adolescence. The most consistent finding was that children with childhood problems with communication, reading and mathematics had an increased risk of developing auditory hallucinations [for example, the risk for self-reported auditory hallucinations at age 15 was increased by 96% for children with communication problems: OR (odds ratio) 1.96, 95% confidence interval (CI) 1.33 2.88]. The twin analyses showed that genetic effects accounted for the increased risk of PLEs and juvenile mania symptoms among children with communication problems. CONCLUSIONS: Childhood problems with communication, reading and mathematics predict PLEs and juvenile mania symptoms in adolescence. Similar to the case for schizophrenia and bipolar disorder, PLEs and juvenile mania may share genetic aetiological factors. PMID- 23942195 TI - Inhibition of amyloid precursor protein processing leads to downregulation of apoptotic genes in Alzheimer's disease animal models. AB - BACKGROUND AND METHODS: We previously reported the development of site-directed monoclonal antibodies able to inhibit the initiation of the amyloid precursor protein (APP) processing site, named 'blocking beta site 1' (BBS1). The beneficial effect of intracerebroventricular administration of these antibodies in the triple transgenic mouse model of Alzheimer's disease (AD) showed improvement in cognitive functions and reduction in tau and amyloid pathology. Amyloid-beta may not be the only active component of AD neurotoxicity and may involve other proteolytic APP fragments such as the APP intracellular domain, proposed to work as a transcription factor involved in the regulation of p53 and glycogen synthase kinase 3beta (GSK3beta) as well as affecting several physiological processes contributing to AD pathology. RESULTS: We show that inhibition of the beta-secretase cleavage site via site-directed antibodies resulted in a major reduction in phosphorylated GSK3beta levels, which is the active form of GSK3beta, as well as in p53 levels. CONCLUSION: A therapy that is capable of reducing not only the direct hallmarks of AD but also the components that lead to neuronal apoptosis might have neuroprotective potential in AD treatment. PMID- 23942196 TI - Upregulation of aquaporin expression in the salivary glands of heat-acclimated rats. AB - It is known that aquaporin (AQP) 5 expression in the apical membrane of acinar cells in salivary glands is important for the secretion of saliva in rodents and humans. Although heat acclimation enhances saliva secretion in rodents, the molecular mechanism of how heat induces saliva secretion has not been determined. Here, we found that heat acclimation enhanced the expression of AQP5 and AQP1 in rat submandibular glands concomitant with the promotion of the HIF-1alpha pathway, leading to VEGF induction and CD31-positive angiogenesis. The apical membrane distribution of AQP5 in serous acinar cells enhanced after heat acclimation, while AQP1 expression was restricted to the endothelial cells in the submandibular glands. A network of AQPs may be involved in heat-acclimated regulation in saliva secretion. Because AQPs probably plays a crucial role in saliva secretion in humans, these findings may lead to a novel strategy for treating saliva hyposecretion. PMID- 23942197 TI - Healing stories: narrative characteristics in cancer survivorship narratives and psychological health among hematopoietic stem cell transplant survivors. AB - OBJECTIVES: Survivors of hematopoietic stem cell transplant (HSCT) have experienced a life threatening and potentially traumatic illness and treatment that make them vulnerable to long lasting negative psychological outcomes, including anxiety and depression. Nevertheless, studies show that overcoming cancer and its treatment can present an opportunity for personal growth and psychological health (reduced symptoms of anxiety and depression and high levels of emotional well-being) through resilience. However, research has not yet clarified what differentiates HSCT survivors who experience psychological growth from those who do not. By analyzing recovery narratives, we examined whether HSCT survivors' interpretation of their experiences helps explain differences in their post-treatment psychological health. METHODS: Guided by narrative psychology theory, we analyzed the narratives of 23 HSCT survivors writing about their experience of cancer treatment. Psychological health was measured by: (1) emotional well-being subscale part of the Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT), (2) depression, and (3) anxiety subscales of the Brief Symptom Inventory. RESULTS: Findings revealed a positive relation between psychological health and a greater number of redemption episodes (going from an emotionally negative life event to an emotionally positive one) as well as fewer negative emotional expressions. SIGNIFICANCE OF THE RESULTS: Theoretical and practical implications of these findings are discussed, showing how narratives can inform interventions to assist cancer survivors with their psychological recovery. PMID- 23942198 TI - Accurate molecular diagnosis of phenylketonuria and tetrahydrobiopterin-deficient hyperphenylalaninemias using high-throughput targeted sequencing. AB - Genetic diagnostics of phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficient hyperphenylalaninemia (BH4DH) rely on methods that scan for known mutations or on laborious molecular tools that use Sanger sequencing. We have implemented a novel and much more efficient strategy based on high-throughput multiplex-targeted resequencing of four genes (PAH, GCH1, PTS, and QDPR) that, when affected by loss-of-function mutations, cause PKU and BH4DH. We have validated this approach in a cohort of 95 samples with the previously known PAH, GCH1, PTS, and QDPR mutations and one control sample. Pooled barcoded DNA libraries were enriched using a custom NimbleGen SeqCap EZ Choice array and sequenced using a HiSeq2000 sequencer. The combination of several robust bioinformatics tools allowed us to detect all known pathogenic mutations (point mutations, short insertions/deletions, and large genomic rearrangements) in the 95 samples, without detecting spurious calls in these genes in the control sample. We then used the same capture assay in a discovery cohort of 11 uncharacterized HPA patients using a MiSeq sequencer. In addition, we report the precise characterization of the breakpoints of four genomic rearrangements in PAH, including a novel deletion of 899 bp in intron 3. Our study is a proof-of principle that high-throughput-targeted resequencing is ready to substitute classical molecular methods to perform differential genetic diagnosis of hyperphenylalaninemias, allowing the establishment of specifically tailored treatments a few days after birth. PMID- 23942199 TI - New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia. AB - Despite recent progress in our understanding of renal magnesium (Mg(2+)) handling, the molecular mechanisms accounting for transepithelial Mg(2+) transport are still poorly understood. Mutations in the TRPM6 gene, encoding the epithelial Mg(2+) channel TRPM6 (transient receptor potential melastatin 6), have been proven to be the molecular cause of hypomagnesemia with secondary hypocalcemia (HSH; OMIM 602014). HSH manifests in the newborn period being characterized by very low serum Mg(2+) levels (<0.4 mmol/l) accompanied by low serum calcium (Ca(2+)) concentrations. A proportion of previously described TRPM6 mutations lead to a truncated TRPM6 protein resulting in a complete loss-of function of the ion channel. In addition, five-point mutations have been previously described. The aim of this study was to complement the current clinical picture by adding the molecular data from five new missense mutations found in five patients with HSH. To this end, patch-clamp analysis and cell surface measurements were performed to assess the effect of the various mutations on TRPM6 channel function. All mutant channels, expressed in HEK293 cells, showed loss-of-function, whereas no severe trafficking impairment to the plasma membrane surface was observed. We conclude that the new TRPM6 missense mutations lead to dysregulated intestinal/renal Mg(2+) (re)absorption as a consequence of loss of TRPM6 channel function. PMID- 23942200 TI - Sustained effects of online genetics education: a randomized controlled trial on oncogenetics. AB - Medical professionals are increasingly expected to deliver genetic services in daily patient care. However, genetics education is considered to be suboptimal and in urgent need of revision and innovation. We designed a Genetics e-learning Continuing Professional Development (CPD) module aimed at improving general practitioners' (GPs') knowledge about oncogenetics, and we conducted a randomized controlled trial to evaluate the outcomes at the first two levels of the Kirkpatrick framework (satisfaction, learning and behavior). Between September 2011 and March 2012, a parallel-group, pre- and post-retention (6-month follow up) controlled group intervention trial was conducted, with repeated measurements using validated questionnaires. Eighty Dutch GP volunteers were randomly assigned to the intervention or the control group. Satisfaction with the module was high, with the three item's scores in the range 4.1-4.3 (5-point scale) and a global score of 7.9 (10-point scale). Knowledge gains post test and at retention test were 0.055 (P<0.05) and 0.079 (P<0.01), respectively, with moderate effect sizes (0.27 and 0.31, respectively). The participants appreciated applicability in daily practice of knowledge aspects (item scores 3.3-3.8, five-point scale), but scores on self-reported identification of disease, referral to a specialist and knowledge about the possibilities/limitations of genetic testing were near neutral (2.7-2.8, five-point scale). The Genetics e-learning CPD module proved to be a feasible, satisfactory and clinically applicable method to improve oncogenetics knowledge. The educational effects can inform further development of online genetics modules aimed at improving physicians' genetics knowledge and could potentially be relevant internationally and across a wider range of potential audiences. PMID- 23942201 TI - Recommendations for reporting results of diagnostic genetic testing (biochemical, cytogenetic and molecular genetic). AB - Genetic test results can have considerable importance for patients, their parents and more remote family members. Clinical therapy and surveillance, reproductive decisions and genetic diagnostics in family members, including prenatal diagnosis, are based on these results. The genetic test report should therefore provide a clear, concise, accurate, fully interpretative and authoritative answer to the clinical question. The need for harmonizing reporting practice of genetic tests has been recognised by the External Quality Assessment (EQA), providers and laboratories. The ESHG Genetic Services Quality Committee has produced reporting guidelines for the genetic disciplines (biochemical, cytogenetic and molecular genetic). These guidelines give assistance on report content, including the interpretation of results. Selected examples of genetic test reports for all three disciplines are provided in an annexe. PMID- 23942203 TI - Streamlined ion torrent PGM-based diagnostics: BRCA1 and BRCA2 genes as a model. AB - To meet challenges in terms of throughput and turnaround time, many diagnostic laboratories are shifting from Sanger sequencing to higher throughput next generation sequencing (NGS) platforms. Bearing in mind that the performance and quality criteria expected from NGS in diagnostic or research settings are strikingly different, we have developed an Ion Torrent's PGM-based routine diagnostic procedure for BRCA1/2 sequencing. The procedure was first tested on a training set of 62 control samples, and then blindly validated on 77 samples in parallel with our routine technique. The training set was composed of difficult cases, for example, insertions and/or deletions of various sizes, large-scale rearrangements and, obviously, mutations occurring in homopolymer regions. We also compared two bioinformatic solutions in this diagnostic context, an in-house academic pipeline and the commercially available NextGene software (Softgenetics). NextGene analysis provided higher sensitivity, as four previously undetected single-nucleotide variations were found. Regarding specificity, an average of 1.5 confirmatory Sanger sequencings per patient was needed for complete BRCA1/2 screening. Large-scale rearrangements were identified by two distinct analyses, that is, bioinformatics and fragment analysis with electrophoresis profile comparison. Turnaround time was enhanced, as a series of 30 patients were sequenced by one technician, making the results available for the clinician in 10 working days following blood sampling. BRCA1/2 genes are a good model, representative of the difficulties commonly encountered in diagnostic settings, which is why we believe our findings are of interest for the whole community, and the pipeline described can be adapted by any user of PGM for diagnostic purposes. PMID- 23942202 TI - Genetic analysis of the role of Alx4 in the coordination of lower body and external genitalia formation. AB - Although several syndromes include abnormalities of both the ventral body wall and external genitalia, the developmental bases of this correlation are largely unknown. Naturally occurring mutations in Aristaless-like 4 (Alx4, Strong's luxoid: Alx4Lst) have ventral body wall and pelvic girdle abnormalities. We sought to determine whether the development of the genital tubercle (GT) and its derivatives, the external genitalia, is affected by this mutation. We thus performed genetic and tissue labeling analyses in mutant mice. Alx4Lst/Lst mutants displayed hypoplasia of the dorsal GT and reduced expression of Fibronectin. We analyzed cell migration during GT formation by tissue labeling experiments and discovered that the cells located in the proximal segment of the umbilical cord (infra-umbilical mesenchyme) migrate toward the dorsal part of the GT. The Alx4Lst/Lst mutants also displayed augmented expression of Hh signal related genes. Hence, we analyzed a series of combinatorial mutants for Alx4, Sonic hedgehog (Shh) and GLI-Kruppel family member 3 (Gli3). These phenotype genotype analyses suggested a genetic interaction between Alx4 and Hh signaling during GT formation. Moreover, Hh gain-of-function mutants phenocopied some of these phenotypes. These observations reveal novel information regarding the pathogenic mechanisms of syndromic lower ventral body malformations, which are largely unknown. PMID- 23942205 TI - Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB. AB - Mutations in the SQSTM1 gene have been reported to be associated with amyotrophic lateral sclerosis (ALS). We sought to determine the frequency of these mutations in a UK familial ALS (FALS) cohort. Sequences of all eight exons of the SQSTM1 gene were analysed in index cases from 61 different FALS kindred lacking known FALS mutations. Six exonic variants c.463G>A, p.(Glu155Lys), c.822G>C, p.(Glu274Asp), c.888G>T, p.(=), c.954C>T, p.(=), c.1038G>A, p.(=) and c.1175C>T, p.(Pro392Leu) were identified in five FALS index cases, three of which were non synonymous and three were synonymous. One index case harboured three variants (c.822G>C, c.888G>T and c.954C>T), and a second index case harboured two variants (c.822G>C and c.954C>T). Only the p.(Pro392Leu) and p.(Glu155Lys) mutations were predicted to be pathogenic. In one p.(Pro392Leu) kindred, the carrier developed both ALS and Paget's disease of bone (PDB), and, in the p.(Glu155Lys) kindred, the father of the proband developed PDB. All p.(Pro392Leu) carriers were heterozygous for a previously reported founder haplotype for PDB, where this mutation has an established causal effect. The frequency of the p.(Pro392Leu) mutation in this UK FALS cohort was 2.3% and 0.97% overall including three previously screened FALS cohorts. Our results confirm the presence of the p.(Pro392Leu) SQSTM1 mutation in FALS. This mutation is the most common SQSTM1 mutation found in ALS to date, and a likely pathogenicity is supported by having an established causal role in PDB. The occurrence of the same mutation in ALS and PDB is indicative of a common pathogenic pathway that converges on protein homeostasis. PMID- 23942206 TI - Is depression the wrong treatment target for improving outcome in coronary artery disease? PMID- 23942207 TI - Evaluation of resistless Ga+ beam lithography for UV NIL stamp fabrication. AB - This paper presents an alternative rapid prototyping approach for the fabrication of stamps for UV nanoimprint lithography. In this process, areas implanted with gallium serve as an etch mask for the dry etching of quartz. The implantation is performed using a focused ion beam system. To avoid charging of the quartz substrate the use of thin layers of chromium or carbon on the quartz substrate has been evaluated. The resulting quartz structures exhibit very smooth surfaces after dry etching, if the implantation dose is high enough to form a stable etch mask. Furthermore, anisotropic etching could be realized by optimization of a quartz etching process involving C4F8 and O2 after the use of resistless Ga(+) beam lithography. Finally, imprints into a UV curing resist are performed successfully with the manufactured stamps, proving that the presence of Ga rich areas on the stamp is not detrimental to the curing of the resist or the functionality of the anti-sticking layer. PMID- 23942204 TI - Autosomal-dominant nystagmus, foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation. AB - Autosomal-dominant idiopathic infantile nystagmus has been linked to 6p12 (OMIM 164100), 7p11.2 (OMIM 608345) and 13q31-q33 (OMIM 193003). PAX6 (11p13, OMIM 607108) mutations can also cause autosomal-dominant nystagmus, typically in association with aniridia or iris hypoplasia. We studied a large multigenerational white British family with autosomal-dominant nystagmus, normal irides and presenile cataracts. An SNP-based genome-wide analysis revealed a linkage to a 13.4-MB region on chromosome 11p13 with a maximum lod score of 2.93. A mutation analysis of the entire coding region and splice junctions of the PAX6 gene revealed a novel heterozygous missense mutation (c.227C>G) that segregated with the phenotype and is predicted to result in the amino-acid substitution of proline by arginine at codon 76 p.(P76R). The amino-acid variation p.(P76R) within the paired box domain is likely to destabilise the protein due to steric hindrance as a result of the introduction of a polar and larger amino acid. Eye movement recordings showed a significant intrafamilial variability of horizontal, vertical and torsional nystagmus. High-resolution in vivo imaging of the retina using optical coherence tomography (OCT) revealed features of foveal hypoplasia, including rudimentary foveal pit, incursion of inner retinal layers, short photoreceptor outer segments and optic nerve hypoplasia. Thus, this study presents a family that segregates a PAX6 mutation with nystagmus and foveal hypoplasia in the absence of iris abnormalities. Moreover, it is the first study showing detailed characteristics using eye movement recordings of autosomal dominant nystagmus in a multigenerational family with a novel PAX6 mutation. PMID- 23942208 TI - Modified phosphatidylethanolamines induce different levels of cytokine expression in monocytes and dendritic cells. AB - Glycation of phosphatidylethanolamine (PE) is a reaction that is known to occur under the chronic hyperglycemic conditions found in diabetes. Glycated phosphatidylethanolamines were found in plasma and atherosclerotic plaques of diabetic patients, and its presence was correlated with increased oxidative stress. Moreover, upregulation of cytokines and other inflammatory mediators can be observed not only in diabetes, but also under oxidized phosphatidylcholine stimulation. In this study, we evaluate the effect of dipalmitoyl phosphatidylethanolamine (DPPE) and linoleoyl-palmitoyl-phosphatidylethanolamine (PLPE) structural oxidation, glycation and glycoxidation, on monocyte and myeloid dendritic cell stimulation. Expression of cytokines, IL-1beta, IL-6, IL-8, MIP 1beta and TNF-alpha, were determined using flow cytometry after cell stimulations with native PEs, oxidized, glycated and glycoxidized PEs. Native PE, PLPE and DPPE, and all modified PEs were able to increase the stimulation levels of monocytes and mDCs. Generally, in monocytes and mDCs stimulation, GluOxPLPE and GluDPPE were the PLPE/DPPE modifications that induced the most pronounced rise in cytokine production. However, GluOxDPPE was the DPPE modification that produced the lowest stimulation levels of mDCs and monocytes. Our results indicate that glycated PE and glycoxidized PE may have an important contribution to the low grade systemic inflammation associated with diabetes and to the development of diabetic complications. PMID- 23942209 TI - Targeted delivery of neurogenin-2 protein in the treatment for cerebral ischemia reperfusion injury. AB - Neurogenin-2 (Ngn2), as a proneural gene that promotes the survival and differentiation of neural precursor cells, is an attractive candidate for therapy against cerebral ischemia-reperfusion injury. However, the delivery approach limits its clinical application. To deliver Ngn2 protein into the cerebral ischemic region and exert a therapeutic effect on injured neurons after ischemia, we here reported that the fusion protein TAT-LBD-Ngn2 was constructed by fusing a transactivator of transcription (TAT) domain and a laminin-binding domain (LBD) to Ngn2. TAT-LBD-Ngn2 promoted the outgrowth of neuronal neurite, increased the survival rate and alleviated apoptosis of hippocampal neurons exposed to oxygen glucose deprivation in vitro. Furthermore, a focal cerebral ischemia model in C57BL/6 mice showed that TAT-LBD-Ngn2 efficiently crossed the blood brain barrier, aggregated in the ischemic zone and was consistently incorporated into neurons. Moreover, TAT-LBD-Ngn2 transduced into brains attenuated neuronal degeneration and apoptosis in the ischemic zone. TAT-LBD-Ngn2 treatment resulted in a reduction of infarct volume that was associated with a parallel improvement in neurological functional outcomes after reperfusion. In conclusion, the targeted delivery of TAT-LBD-Ngn2 into the ischemic zone attenuated cerebral ischemia-reperfusion injury through the inhibition of neuronal degeneration and apoptosis, suggesting that TAT-LBD-Ngn2 is a promising target candidate for the treatment of ischemic stroke. PMID- 23942210 TI - Effect of engineered anisotropy on the susceptibility of human pluripotent stem cell-derived ventricular cardiomyocytes to arrhythmias. AB - Human (h) pluripotent stem cells (PSC) such as embryonic stem cells (ESC) can be directed into cardiomyocytes (CMs), representing a potential unlimited cell source for disease modeling, cardiotoxicity screening and myocardial repair. Although the electrophysiology of single hESC-CMs is now better defined, their multi-cellular arrhythmogenicity has not been thoroughly assessed due to the lack of a suitable experimental platform. Indeed, the generation of ventricular (V) fibrillation requires single-cell triggers as well as sustained multi-cellular reentrant events. Although native VCMs are aligned in a highly organized fashion such that electrical conduction is anisotropic for coordinated contractions, hESC derived CM (hESC-CM) clusters are heterogenous and randomly organized, and therefore not representative of native conditions. Here, we reported that engineered alignment of hESC-VCMs on biomimetic grooves uniquely led to physiologically relevant responses. Aligned but not isotropic control preparations showed distinct longitudinal (L) and transverse (T) conduction velocities (CV), resembling the native human V anisotropic ratio (AR = LCV/TCV = 1.8-2.0). Importantly, the total incidence of spontaneous and inducible arrhythmias significantly reduced from 57% in controls to 17-23% of aligned preparations, thereby providing a physiological baseline for assessing arrhythmogenicity. As such, promotion of pro-arrhythmic effect (e.g., spatial dispersion by beta adrenergic stimulation) could be better predicted. Mechanistically, such anisotropy-induced electrical stability was not due to maturation of the cellular properties of hESC-VCMs but their physical arrangement. In conclusion, not only do functional anisotropic hESC-VCMs engineered by multi-scale topography represent a more accurate model for efficacious drug discovery and development as well as arrhythmogenicity screening (of pharmacological and genetic factors), but our approach may also lead to future transplantable prototypes with improved efficacy and safety against arrhythmias. PMID- 23942211 TI - Anti-angiogenic activity of heparin functionalised cerium oxide nanoparticles. AB - Cerium oxide nanoparticles (nanoceria) are widely reported to be non-cytotoxic and modulate intracellular reactive oxygen species (ROS). In this study, nanoceria (dxRD = 12 nm) were functionalised with either 130 or 880 molecules of unfractionated heparin using the organosilane linker, 3 aminopropyltriethoxysilane. Nanoceria with a low level of heparin functionalisation were found to scavenge intracellular ROS to the same extent as unfunctionalised nanoceria and significantly more than cells exposed to medium only. In contrast, nanoceria with the highest level of heparin functionalisation were not as effective at scavenging intracellular ROS. Nanoceria were localised predominantly in the cytoplasm, while heparin-nanoceria were localised in both the cytoplasm and lysosomes. Together these data demonstrated that the level of nanoceria surface functionalisation with heparin determined the intracellular localisation and ROS scavenging ability of these particles. Additionally, heparin nanoceria were effective in reducing endothelial cell proliferation indicating that they may find application in the control of angiogenesis in cancer in the future. PMID- 23942213 TI - Short-term effects of escitalopram on regional brain function in first-episode drug-naive patients with major depressive disorder assessed by resting-state functional magnetic resonance imaging. AB - BACKGROUND: Most knowledge regarding the effects of antidepressant drugs is at the receptor level, distal from the nervous system effects that mediate their clinical efficacy. Using functional magnetic resonance imaging (fMRI), this study investigated the effects of escitalopram, a selective serotonin reuptake inhibitor (SSRI), on resting-state brain function in patients with major depressive disorder (MDD). METHOD: Fourteen first-episode drug-naive MDD patients completed two fMRI scans before and after 8 weeks of escitalopram therapy. Scans were also acquired in 14 matched healthy subjects. Data were analyzed using the regional homogeneity (ReHo) approach. RESULTS: Compared to controls, MDD patients before treatment demonstrated decreased ReHo in the frontal (right superior frontal gyrus), temporal (left middle and right inferior temporal gyri), parietal (right precuneus) and occipital (left superior occipital gyrus and right cuneus) cortices, and increased ReHo in the left dorsal medial prefrontal gyrus and left anterior lobe of the cerebellum. Compared to the unmedicated state, ReHo in the patients after treatment was decreased in the left dorsal medial prefrontal gyrus, the right insula and the bilateral thalamus, and increased in the right superior frontal gyrus. Compared to controls, patients after treatment displayed a ReHo decrease in the right precuneus and a ReHo increase in the left anterior lobe of the cerebellum. CONCLUSIONS: Successful treatment with escitalopram may be associated with modulation of resting-state brain activity in regions within the fronto-limbic circuit. This study provides new insight into the effects of antidepressants on functional brain systems in MDD. PMID- 23942212 TI - Anti-CD30 antibody conjugated liposomal doxorubicin with significantly improved therapeutic efficacy against anaplastic large cell lymphoma. AB - The use of nano-carriers has been shown to improve the delivery and efficacy of chemotherapeutic agents in cancer patients. Recent studies suggest that decoration of the surface of nano-carriers with various targeting moieties may further improve the overall therapeutic efficacy. In this study, we compared the therapeutic efficacy of Doxil((r)) (commercial doxorubicin-loaded liposomes) and that of Doxil((r)) conjugated with anti-CD30 antibodies (CD30-targeted Doxil((r))) in treating anaplastic large cell lymphoma (ALCL), a type of T-cell lymphoma characterized by a high CD30 expression. Compared to Doxil((r)), the CD30-targeted Doxil((r)) showed a significantly higher binding affinity to ALCL cells (5.3% versus 27%, p = 0.005) and a lower inhibitory concentration at 50% (IC50) in-vitro (32.6 MUg/mL versus 12.6 MUg/mL, p = 0.006). In a SCID mouse xenograft model, CD30-targeted Doxil((r)) inhibited tumor growth more significantly than the unconjugated formulation; specifically, tumors in mice treated with CD30-targeted Doxil((r)) were significantly smaller than those in mice treated with Doxil((r)) (average, 117 mm(3) versus 270 mm(3), p = 0.001) at 18 days after the tumors were inoculated. Our findings have provided the proof-of principle of using CD30-targeted nano-carriers to treat cancers that are characterized by a high level of CD30 expression, such as ALCL. PMID- 23942214 TI - Re: "the association between complement component 2/complement factor B polymorphisms and age-related macular degeneration: a huge review and meta analysis". PMID- 23942215 TI - Understanding the independent and joint associations of the home and workplace built environments on cardiorespiratory fitness and body mass index. AB - This observational study examined the associations of built environment features around the home and workplace with cardiorespiratory fitness (CRF) based on a treadmill test and body mass index (BMI) (weight (kg)/height (m)(2)). The study included 8,857 adults aged 20-88 years who completed a preventive medical examination in 2000-2007 while living in 12 Texas counties. Analyses examining workplace neighborhood characteristics included a subset of 4,734 participants. Built environment variables were derived around addresses by using geographic information systems. Models were adjusted for individual-level and census block group-level demographics and socioeconomic status, smoking, BMI (in CRF models), and all other home or workplace built environment variables. CRF was associated with higher intersection density, higher number of private exercise facilities around the home and workplace, larger area of vegetation around the home, and shorter distance to the closest city center. Aside from vegetation, these same built environment features around the home were also associated with BMI. Participants who lived and worked in neighborhoods in the lowest tertiles for intersection density and the number of private exercise facilities had lower CRF and higher BMI values than participants who lived and worked in higher tertiles for these variables. This study contributes new evidence to suggest that built environment features around homes and workplaces may affect health. PMID- 23942217 TI - Big data meets the electronic medical record: a commentary on "identifying patients at increased risk for unplanned readmission". PMID- 23942216 TI - Early-onset alopecia and amyotrophic lateral sclerosis: a cohort study. AB - A recent meta-analysis of 7 genome-wide association studies on early balding (alopecia) revealed single nucleotide polymorphism variants in the region of the amyotrophic lateral sclerosis (ALS) gene TAR DNA-binding protein 43 (TARDBP/TDP 43). We therefore explored the association of early-onset alopecia and ALS in the Health Professionals Follow-up Study, a large cohort of 51,529 US men. In 1992, the participants (then aged 46-81 years) were asked to report their hair line pattern at age 45 years. During the follow-up period (1992-2008), 42 men were diagnosed with ALS. Of those, 13 had reported no alopecia, 18 had reported moderate alopecia, and 11 had reported extensive alopecia at age 45 years. Those who reported extensive alopecia had an almost 3-fold increased risk of ALS compared with those who reported no alopecia (relative risk = 2.74, 95% confidence interval: 1.23, 6.13). Furthermore, we observed a linear trend of increased risk of ALS with increasing level of balding at age 45 years (Ptrend = 0.02). In conclusion, men with early-onset alopecia seem to have a higher risk of ALS. The mechanisms underlying this association deserve further investigation. PMID- 23942218 TI - Identifying patients at increased risk for unplanned readmission. AB - BACKGROUND: Reducing readmissions is a national priority, but many hospitals lack practical tools to identify patients at increased risk of unplanned readmission. OBJECTIVE: To estimate the association between a composite measure of patient condition at discharge, the Rothman Index (RI), and unplanned readmission within 30 days of discharge. SUBJECTS: Adult medical and surgical patients in a major teaching hospital in 2011. MEASURES: The RI is a composite measure updated regularly from the electronic medical record based on changes in vital signs, nursing assessments, Braden score, cardiac rhythms, and laboratory test results. We developed 4 categories of RI and tested its association with readmission within 30 days, using logistic regression, adjusted for patient age, sex, insurance status, service assignment (medical or surgical), and primary discharge diagnosis. RESULTS: Sixteen percent of the sample patients (N=2730) had an unplanned readmission within 30 days of discharge. The risk of readmission for a patient in the highest risk category (RI<70) was >1 in 5 while the risk of readmission for patients in the lowest risk category was about 1 in 10. In multivariable analysis, patients with an RI<70 (the highest risk category) or 70 79 (medium risk category) had 2.65 (95% confidence interval, 1.72-4.07) and 2.40 (95% confidence interval, 1.57-3.67) times higher odds of unplanned readmission, respectively, compared with patients in the lowest risk category. CONCLUSION: Clinicians can use the RI to help target hospital programs and supports to patients at highest risk of readmission. PMID- 23942219 TI - The association of hospital volume with mortality and costs of care for stroke in Japan. AB - BACKGROUND: The association between hospital volume and patient outcomes remains unclear for stroke. Little is known about whether these relationships differ by stroke subtypes. OBJECTIVES: To examine the association of hospital volume with in-hospital mortality and costs of care for stroke. RESEARCH DESIGN: Secondary data analysis of national hospital database. SUBJECTS: A total of 66,406 patients admitted between July 1 and December 31, 2010 with primary diagnosis of stroke at 796 acute care hospitals in Japan were included. MEASURES: We used a locally weighted scatter-plot smoothing method to test the relationship between hospital volume and outcomes. On the basis of these results, we categorized patient volume into 3 groups (10-50, 51-100, and >100 discharges/6 mo). We tested the volume outcome relationship using multivariable regression models adjusting for patient and hospital characteristics. Subgroup analysis was conducted by stratifying on stroke subtype. RESULTS: Compared with those treated at high-volume hospitals (>100 discharges), patients admitted to low-volume hospitals (10-50 discharges) had higher in-hospital mortality (adjusted odds ratio, 1.45; 95% CI, 1.23-1.71, P<0.0001). In the lowest volume hospitals, adjusted costs of care per discharge were 8.0% lower (95% CI, -14.1% to -1.8%, P=0.01) compared with the highest volume hospitals. The volume-mortality association was significant across all stroke subtypes. Highest volume hospitals had higher costs than lowest volume hospitals for subarachnoid hemorrhage, but this association was nonsignificant for ischemic and hemorrhagic stroke. CONCLUSIONS: Highest volume hospitals had lower mortality than the lowest volume hospitals for stroke in Japan. Highest volume hospitals had higher costs for subarachnoid hemorrhage, but not for ischemic and hemorrhagic stroke. PMID- 23942220 TI - Validity of the AHRQ patient safety indicator for postoperative physiologic and metabolic derangement based on a national sample of medical records. AB - OBJECTIVE: The Agency for Healthcare Research and Quality Patient Safety Indicator (PSI) 10, "Postoperative Physiologic and Metabolic Derangement" (PPMD), uses administrative data to detect postoperative acute kidney injury (AKI) requiring dialysis and diabetes-related complications. We sought to evaluate the indicator's criterion validity. RESEARCH DESIGN: We conducted a retrospective cross-sectional study of hospitalization records flagged positive and negative by PSI 10 from a diverse set of 35 hospitals between February 1, 2006 and June 30, 2009. Trained nurse abstractors reviewed medical records. We determined the indicator's sensitivity, specificity, and positive and negative predictive values. RESULTS: Of 94 records flagged by PSI 10 (87 for AKI, 7 for diabetic complications, 1 for both), 69 (73%) involved an accurately coded event; 60 (64%; 95% CI, 46%-79%) represented true PPMD from a clinical perspective. Two of 8 records flagged for diabetic complications were true events. Nineteen false positives involved preoperative renal failure. Three of 230 records flagged negative (enriched with questionably negative records) represented true PPMD. The indicator's sensitivity was 66% (20%-94%), specificity 99.9% (99.5%-100%), and negative predictive value 99.9% (99.4%-100%). Considering dialysis access procedures tantamount to dialysis and excluding records with lower urinary tract obstruction might increase the sensitivity and positive predictive value to 98% (87%-100%) and 72% (50%-87%), respectively. CONCLUSIONS: PSI 10 mostly concerns AKI and currently has moderate criterion validity, which might improve with increased use of "present on admission" coding, abandonment of the diabetes criteria, and adjustments to the indicator specifications regarding dialysis access and urinary tract obstruction. PMID- 23942221 TI - Differential receipt of sentinel lymph node biopsy within practice-based research networks. AB - BACKGROUND: Practice-based research networks (PBRNs) are promising for accelerating not only research, but also dissemination of research-based evidence into broader community practice. Sentinel lymph node biopsy (SLNB) is an innovation in breast cancer care associated with equivalent survival and lower morbidity, as compared with standard axillary lymph node dissection. We examined the diffusion of SLNB into practice and whether affiliation with the Community Clinical Oncology Program (CCOP), a cancer-focused PBRN, was associated with more rapid uptake of SLNB. RESEARCH DESIGN: Surveillance Epidemiology and End Results Medicare data were used to study women diagnosed with stage I or II breast cancer in the years 2000-2005 and undergoing breast-conserving surgery with axillary staging (n=6226). The primary outcome was undergoing SLNB. CCOP affiliation of the surgical physician was ascertained from NCI records. Multivariable generalized linear modeling with generalized estimating equations was used to measure association between CCOP exposure and undergoing SLNB, controlling for potential confounders. RESULTS: Women treated by a CCOP physician had significantly higher odds of receiving SLNB compared with women treated by a non CCOP physician (OR 2.68; 95% CI, 1.35-5.34). The magnitude of this association was larger than that observed among patients treated by physicians operating in medical school-affiliated hospitals (OR 1.76; 95% CI, 1.30-2.39). CONCLUSIONS: Women treated by CCOP-affiliated physicians were more likely to undergo SLNB irrespective of the hospital's medical school affiliation, suggesting that the CCOP PBRN may play a role in the rapid adoption of research-based innovation in community practice. PMID- 23942222 TI - Composite quality measures for common inpatient medical conditions. AB - BACKGROUND: Public reporting on quality aims to help patients select better hospitals. However, individual quality measures are suboptimal in identifying superior and inferior hospitals based on outcome performance. OBJECTIVE: To combine structure, process, and outcome measures into an empirically derived composite quality measure for heart failure (HF), acute myocardial infarction (AMI), and pneumonia (PNA). To assess how well the composite measure predicts future high and low performers, and explains variance in future hospital mortality. RESEARCH DESIGN: Using national Medicare data, we created a cohort of older patients treated at an acute care hospital for HF (n=1,203,595), AMI (n=625,595), or PNA (n=1,234,299). We ranked hospitals on the basis of their July 2005 to June 2008 performance on the composite. We then estimated the odds of future (July to December 2009) 30-day, risk-adjusted mortality at the worst versus best quintile of hospitals. We repeated this analysis using 2005-2008 performance on existing quality indicators, including mortality. RESULTS: The composite (vs. Hospital Compare) explained 68% (vs. 39%) of variation in future AMI mortality rates. In 2009, if an AMI patient had chosen a hospital in the worst versus best quintile of performance using 2005-2008 composite (vs. Hospital Compare) rankings, he or she would have had 1.61 (vs. 1.39) times the odds of dying in 30 days (P-value for difference <0.001). Results were similar for HF and PNA. CONCLUSIONS: Composite measures of quality for HF, AMI, and PNA performed better than existing measures at explaining variation in future mortality and predicting future high and low performers. PMID- 23942223 TI - Obesity and prostate cancer incidence and mortality: a systematic review of prospective cohort studies. AB - BACKGROUND: There has been a large body of research on obesity and the risk of prostate cancer (PCa) that has been published recently. However, the epidemiological evidence for such an association has not been consistent. This may be attributed to the nature of case-control and retrospective studies, which generally are more prone to biases. Therefore, we conducted a systematic review of prospective cohort studies to assess the association between obesity and the risk of PCa incidence and death. METHODS: A search of the PubMed database and references of published studies (from inception until March 2013) was conducted. Twenty-three eligible studies were identified and included in the systematic review. RESULTS: The evidence from the prospective cohort studies linking obesity with PCa incidence has not been consistent. However, cumulative data is compelling for a strong positive association between obesity and fatal PCa. CONCLUSIONS: Obesity is a significant diet-related risk factor for fatal PCa. Further well-constructed, large cohort studies on the potential association between obesity and PCa, as well as on underlying mechanisms, are needed. PMID- 23942225 TI - Reactive oxygen species play a central role in hexavalent chromium-induced apoptosis in Hep3B cells without the functional roles of p53 and caspase-3. AB - BACKGROUND/AIMS: Hexavalent chromium [Cr(VI)] and its compounds, which have the extensive application in diverse industries including metallurgy, textile and electroplating, are known to be genotoxic and mutagenic to humans. Although it is supported by a large body of literatures that p53 and caspase-3 played key roles in Cr(VI)-induced cytotoxicity, it is clear that Cr(VI) could induce apoptosis either without activating caspase, or in a p53- independent manner. METHODS: In the present study, by using Z-VAD-fmk to inhibit caspase-3 in p53-deficient Hep3B cells, we explored the effect of Cr(VI) on apoptosis induction and the related mechanisms when the functions of p53 and caspase were simultaneously blocked. RESULTS: We found that Cr(VI) still induced DNA damage, mitochondrial injury, oxidative stress and apoptosis in Hep3B cells without the functional roles of p53 and caspase-3, and the mechanism study revealed that this was in a ROS-dependent manner since NAC co-treatment showed the protective effect against Cr(VI)-induced apoptosis. CONCLUSION: Our research has disclosed the mechanism involved in Cr(VI)-induced cytotoxicity following the loss of p53 and caspase-3 functions and shed light on the importance of using antioxidants for primary and secondary prevention in Cr(VI) occupational exposure populations. PMID- 23942224 TI - Hemorrhagic and ischemic stroke in children with cancer. AB - BACKGROUND: Adult survivors of childhood cancer have an increased risk of cerebrovascular disease; little is known about early stroke risk in childhood cancer. Our objectives were to assess stroke prevalence in children with cancer, to establish cancer and stroke type, and to determine if modifiable risk factors for stroke were present. METHODS: Children with stroke and cancer were compared with all children seen for cancer at a single institution between 2000 and 2009. An International Classification of Disease, 9th version, code search and search of existing pediatric oncology and stroke databases identified children <18 years with ischemic stroke, intracerebral hemorrhage, and cerebral sinovenous thrombosis. RESULTS: Of 1411 children with cancer, 15 had a stroke (1.1%, 95% CI: 0.6-1.7%). Stroke classifications were seven intracerebral hemorrhages, five ischemic strokes (one of which was followed by intracerebral hemorrhage), and three sinovenous thromboses. Stroke occurred at a median of 5 months after cancer diagnosis. Ten children with strokes had hematologic malignancies and five had brain tumors. Thirteen patients died poststroke, eight because of withdrawal of care. White blood cell count >=48,000/mm3 was found in four children, all with intracerebral hemorrhage. Five of seven children with intracerebral hemorrhage had platelets <50,000/mm3. CONCLUSIONS: Stroke has a prevalence of approximately 1% in children with cancer. Hemorrhagic stroke and ischemic stroke occur with approximately equal frequency; children with leukemia and brain tumors are at greatest risk. PMID- 23942226 TI - Semantic relations differentially impact associative recognition memory: electrophysiological evidence. AB - Though associative recognition memory is thought to rely primarily on recollection, recent research indicates that familiarity might also make a substantial contribution when to-be-learned items are integrated into a coherent structure by means of an existing semantic relation. It remains unclear how different types of semantic relations, such as categorical (e.g., dancer-singer) and thematic (e.g., dancer-stage) relations might affect associative recognition, however. Using event-related potentials (ERPs), we addressed this question by manipulating the type of semantic link between paired words in an associative recognition memory experiment. An early midfrontal old/new effect, typically linked to familiarity, was observed across the relation types. In contrast, a robust left parietal old/new effect was found in the categorical condition only, suggesting a clear contribution of recollection to associative recognition for this kind of pairs. One interpretation of this pattern is that familiarity was sufficiently diagnostic for associative recognition of thematic relations, which could result from the integrative nature of the thematic relatedness compared to the similarity-based nature of categorical pairs. The present study suggests that the extent to which recollection and familiarity are involved in associative recognition is at least in part determined by the properties of semantic relations between the paired associates. PMID- 23942228 TI - Adipogenic potential in human mesenchymal stem cells strictly depends on adult or foetal tissue harvest. AB - Cell-based therapies promise important developments for regenerative medicine purposes. Adipose tissue and the adipogenic process has become central to an increasing number of translational efforts in addition to plastic and reconstructive surgical applications. In recent experimental clinical trials, human mesenchymal stem cells (MSC) have been proven to be well tolerated because of their low immunoreactivity. MSC are multipotent cells found among mature cells in different tissues and organs with the potentiality to differentiate in many cell types, including osteocytes, chondrocytes and adipocytes, thus being a suitable cell source for tissue engineering strategies. We compared the adipogenic potential of MSC originated from two adult sources as fat pads and bone marrow, and from four foetal sources as umbilical cord blood, Wharton's jelly, amniotic fluid and preterm umbilical cord perivascular cells. Surprisingly, adult MSC displayed higher differentiation capacities confirmed by gene expression analysis on a selected panel of adipogenesis-related genes. Further, an in-depth molecular analysis highlighted the early and vigorous activation of the PPARgamma transcription factor-cascade in adipose-derived MSC that resulted to be both delayed and reduced in foetal MSC accounting for their lack of adipogenic potential. Thus, MSC show a different degree of phenotypic plasticity depending on the source tissue, that should be taken into consideration for the selection of the most appropriate MSC type for specific tissue regeneration purposes. PMID- 23942229 TI - The relationship between body image, age, and distress in women facing breast cancer surgery. AB - OBJECTIVES: Research suggests that the strength of the relationship between body image and emotional distress decreases with age. Past research has focused on expected aging-related body changes, and has not yet examined unexpected body changes (e.g., breast cancer surgery). The present post-hoc study assessed relationships between age, body image, and emotional distress in women facing breast cancer surgery. METHODS: Older (>= 65 years, n = 40) and younger (<65 years, n = 40) women were matched on race/ethnicity, marital status, and surgery type. Within one week prior to surgery, participants completed measures of demographics, aspects of body image, and emotional distress (general and surgery specific). RESULTS: Results indicated that: (1) body image did not differ by age (p > 0.999); (2) older women reported less pre-surgical emotional distress than younger women (p's < 0.01); and, (3) age moderated the relationship between body image and emotional distress (p's < 0.06). SIGNIFICANCE OF RESULTS: The results suggest that younger women, particularly those with poor body image, are at an increased risk for pre-surgical emotional distress. These women may benefit from pre-surgical interventions designed to improve body image or to reduce pre surgical emotional distress. PMID- 23942230 TI - MRI for iron mapping in Alzheimer's disease. AB - BACKGROUND: Monitoring iron deposition became possible with new dedicated quantitative MRI sequences. These sequences hold promise to determine the role of iron in Alzheimer's disease (AD). It is currently unclear as to whether iron accumulation is pathogenically involved in AD or solely represents an epiphenomenon of the neurodegenerative process. OBJECTIVE: We discuss currently available MR methods for quantitative iron mapping in the brain and provide an overview of results in animal models as well as in AD patients. METHODS: A short literature review was used for analysis. RESULTS: R2*-based imaging is the best validated technique for iron detection. Current research applications include amyloid plaque detection in postmortem brains and in transgenic animal models and quantitative iron mapping in gray matter. AD patients have increased iron levels in the putamen, pulvinar thalamus, red nucleus, hippocampus, and temporal cortex. The clinical consequences of this finding and the dynamics of iron accumulation in AD are widely unknown. CONCLUSIONS: MRI allows to quantitatively map iron accumulation in the brain. The clinical significance of increased iron levels in AD needs to be determined in both cross-sectional and longitudinal studies. The advent of ultra-high field imaging in clinical applications will increase image resolution and will allow in vivo iron detection in neocortical structures in AD patients both cross-sectionally and longitudinally. PMID- 23942231 TI - Polarity index of psychological interventions in maintenance treatment of bipolar disorder. AB - BACKGROUND: Although several adjunctive psychological interventions are effective in the maintenance of bipolar disorders (BD), no attempt has been made to classify them according to their ability to prevent manic versus depressive episodes. Our study aims to rank the adjunctive psychotherapies for the prophylaxis of BD by means of their polarity index (PI). METHODS: Randomized controlled trials comparing the efficacy of a psychological intervention with a comparator in BD maintenance treatment in patients aged over 18 were systematically reviewed. Exclusion criteria were a small sample size, a study sample not exclusively composed of bipolar patients and the absence of a control group. PI is a novel metric indicating the relative antimanic versus antidepressive preventive efficacy of treatments. PI was retrieved by calculating the ratio of the number needed to treat (NNT) for prevention of depression and the NNT for prevention of mania. PI >1.0 indicates a relatively higher antimanic prophylactic efficacy and PI <1.0 a greater antidepressive efficacy. RESULTS: A total of 9 studies were included. PI was 0.33, 0.63 and 0.89 for cognitive behavioral therapy, 0.42 for family-focused therapy, 0.73 and 0.78 for psychoeducation, 1 for enhanced relapse prevention, 1.78 for caregiver group psychoeducation and 3.36 for brief technique-driven interventions. With regard to the PI for 1 cognitive-behavioral study, enhanced relapse prevention and brief technique-driven interventions may not be reliable since those trials were negative. CONCLUSIONS: The PI provides a measure of how much depression preventive or (hypo) mania-preventive an intervention is and may guide the choice of adjunctive psychotherapy in the context of individualized long-term treatment of BD. PMID- 23942233 TI - Identification of the missing pluripotency mediator downstream of leukaemia inhibitory factor. AB - Self-renewal of pluripotent mouse embryonic stem (ES) cells is sustained by the cytokine leukaemia inhibitory factor (LIF) acting through the transcription factor Stat3. Several targets of Stat3 have previously been identified, most notably the reprogramming factor Klf4. However, such factors are neither required nor sufficient for the potent effect of LIF. We took advantage of Stat3 null ES cells to confirm that Stat3 mediates the self-renewal response to LIF. Through comparative transcriptome analysis intersected with genome location data, we arrived at a set of candidate transcription factor effectors. Among these, Tfcp2l1 (also known as Crtr-1) was most abundant. Constitutive expression of Tfcp2l1 at levels similar to those induced by LIF effectively substituted for LIF or Stat3 in sustaining clonal self-renewal and pluripotency. Conversely, knockdown of Tfcp2l1 profoundly compromised responsiveness to LIF. We further found that Tfcp2l1 is both necessary and sufficient to direct molecular reprogramming of post-implantation epiblast stem cells to naive pluripotency. These results establish Tfcp2l1 as the principal bridge between LIF/Stat3 input and the transcription factor core of naive pluripotency. PMID- 23942232 TI - Toll-like receptor-mediated IRE1alpha activation as a therapeutic target for inflammatory arthritis. AB - In rheumatoid arthritis (RA), macrophage is one of the major sources of inflammatory mediators. Macrophages produce inflammatory cytokines through toll like receptor (TLR)-mediated signalling during RA. Herein, we studied macrophages from the synovial fluid of RA patients and observed a significant increase in activation of inositol-requiring enzyme 1alpha (IRE1alpha), a primary unfolded protein response (UPR) transducer. Myeloid-specific deletion of the IRE1alpha gene protected mice from inflammatory arthritis, and treatment with the IRE1alpha specific inhibitor 4U8C attenuated joint inflammation in mice. IRE1alpha was required for optimal production of pro-inflammatory cytokines as evidenced by impaired TLR-induced cytokine production in IRE1alpha-null macrophages and neutrophils. Further analyses demonstrated that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6) plays a key role in TLR-mediated IRE1alpha activation by catalysing IRE1alpha ubiquitination and blocking the recruitment of protein phosphatase 2A (PP2A), a phosphatase that inhibits IRE1alpha phosphorylation. In summary, we discovered a novel regulatory axis through TRAF6 mediated IRE1alpha ubiquitination in regulating TLR-induced IRE1alpha activation in pro-inflammatory cytokine production, and demonstrated that IRE1alpha is a potential therapeutic target for inflammatory arthritis. PMID- 23942234 TI - Genome-wide survey by ChIP-seq reveals YY1 regulation of lincRNAs in skeletal myogenesis. AB - Skeletal muscle differentiation is orchestrated by a network of transcription factors, epigenetic regulators, and non-coding RNAs. The transcription factor Yin Yang 1 (YY1) silences multiple target genes in myoblasts (MBs) by recruiting Ezh2 (Enhancer of Zeste Homologue2). To elucidate genome-wide YY1 binding in MBs, we performed chromatin immunoprecipitation (ChIP)-seq and found 1820 specific binding sites in MBs with a large portion residing in intergenic regions. Detailed analysis demonstrated that YY1 acts as an activator for many loci in addition to its known repressor function. No significant co-occupancy was found between YY1 and Ezh2, suggesting an additional Ezh2-independent function for YY1 in MBs. Further analysis of intergenic binding sites showed that YY1 potentially regulates dozens of large intergenic non-coding RNAs (lincRNAs), whose function in myogenesis is underexplored. We characterized a novel muscle-associated lincRNA (Yam-1) that is positively regulated by YY1. Yam-1 is downregulated upon differentiation and acts as an inhibitor of myogenesis. We demonstrated that Yam 1 functions through in cis regulation of miR-715, which in turn targets Wnt7b. Our findings not only provide the first genome-wide picture of YY1 association in muscle cells, but also uncover the functional role of lincRNA Yam-1. PMID- 23942235 TI - Allosteric regulation of E2:E3 interactions promote a processive ubiquitination machine. AB - RING finger proteins constitute the large majority of ubiquitin ligases (E3s) and function by interacting with ubiquitin-conjugating enzymes (E2s) charged with ubiquitin. How low-affinity RING-E2 interactions result in highly processive substrate ubiquitination is largely unknown. The RING E3, gp78, represents an excellent model to study this process. gp78 includes a high-affinity secondary binding region for its cognate E2, Ube2g2, the G2BR. The G2BR allosterically enhances RING:Ube2g2 binding and ubiquitination. Structural analysis of the RING:Ube2g2:G2BR complex reveals that a G2BR-induced conformational effect at the RING:Ube2g2 interface is necessary for enhanced binding of RING to Ube2g2 or Ube2g2 conjugated to Ub. This conformational effect and a key ternary interaction with conjugated ubiquitin are required for ubiquitin transfer. Moreover, RING:Ube2g2 binding induces a second allosteric effect, disrupting Ube2g2:G2BR contacts, decreasing affinity and facilitating E2 exchange. Thus, gp78 is a ubiquitination machine where multiple E2-binding sites coordinately facilitate processive ubiquitination. PMID- 23942236 TI - The Yin and Yang of enhancer-like RNAs. PMID- 23942237 TI - Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells. AB - The linear ubiquitin chain assembly complex (LUBAC) plays a crucial role in activating the canonical NF-kappaB pathway, which is important for B-cell development and function. Here, we describe a mouse model (B-HOIP(Deltalinear)) in which the linear polyubiquitination activity of LUBAC is specifically ablated in B cells. Canonical NF-kappaB and ERK activation, mediated by the tumour necrosis factor (TNF) receptor superfamily receptors CD40 and TACI, was impaired in B cells from B-HOIP(Deltalinear) mice due to defective activation of the IKK complex; however, B-cell receptor (BCR)-mediated activation of the NF-kappaB and ERK pathways was unaffected. B-HOIP(Deltalinear) mice show impaired B1-cell development and defective antibody responses to thymus-dependent and thymus independent II antigens. Taken together, these data suggest that LUBAC-mediated linear polyubiquitination is essential for B-cell development and activation, possibly via canonical NF-kappaB and ERK activation induced by the TNF receptor superfamily, but not by the BCR. PMID- 23942239 TI - One step hydrothermal synthesis of a carbon nanotube/cerium oxide nanocomposite and its electrochemical properties. AB - A carbon nanotube (CNT)/cerium oxide composite was prepared by a one-pot hydrothermal reaction in the presence of KOH and capping agent polyvinylpyrrolidone. The nanocomposite displayed pronounced capacitive behaviour with very small diffusion resistance. The electrochemical performance of the composite electrode in a symmetric supercapacitor displayed a high energy density of 35.9 Wh kg(-1) corresponding to a specific capacitance of 289 F g(-1). These composite electrodes also demonstrated a long cycle life with better capacity retention. PMID- 23942238 TI - Embryonic stem cell self-renewal pathways converge on the transcription factor Tfcp2l1. AB - Mouse embryonic stem cell (mESC) self-renewal can be maintained by activation of the leukaemia inhibitory factor (LIF)/signal transducer and activator of transcription 3 (Stat3) signalling pathway or dual inhibition (2i) of glycogen synthase kinase 3 (Gsk3) and mitogen-activated protein kinase kinase (MEK). Several downstream targets of the pathways involved have been identified that when individually overexpressed can partially support self-renewal. However, none of these targets is shared among the involved pathways. Here, we show that the CP2 family transcription factor Tfcp2l1 is a common target in LIF/Stat3- and 2i mediated self-renewal, and forced expression of Tfcp2l1 can recapitulate the self renewal-promoting effect of LIF or either of the 2i components. In addition, Tfcp2l1 can reprogram post-implantation epiblast stem cells to naive pluripotent ESCs. Tfcp2l1 upregulates Nanog expression and promotes self-renewal in a Nanog dependent manner. We conclude that Tfcp2l1 is at the intersection of LIF- and 2i mediated self-renewal pathways and plays a critical role in maintaining ESC identity. Our study provides an expanded understanding of the current model of ground-state pluripotency. PMID- 23942240 TI - Bioefficacy of essential oil from Polygonum hydropiper L. against mosquitoes, Anopheles stephensi and Culex quinquefasciatus. AB - The biological activity of essential oil extracted from the leaves of Polygonum hydropiper and a compound, confertifolin, isolated from this plant was bioassayed against larva of mosquitoes, Anopheles stephensi and Culex quinquefasciatus. The essential oil showed the LC50 values of 189 and 243ppm; 217 and 242ppm, confertifolin (6,6,9a-trimethyl-4,5,5a,6,7,8,9,9a-octahydronaphtho[1,2-c]furan 3(1H)-one) showed the LC50 values of 2.40 and 3.09ppm; 4.07 and 4.18ppm against the second and fourth instar larvae of An. stephensi and Cx. quinquefasciatus, respectively. At 10ppm confertifolin showed ovicidal activity of 100, 98.6 and 86.4% against An. stephensi and 100, 100 and 75.2% against Cx. quinquefasciatus on 0-6, 6-12 and 12-18h old eggs; the repellent activity persisted for 314.6 and 319.0min; oviposition deterrent activity was 97.2 and 99% and adulticidal activity was 100 and 100% against An. stephensi and Cx. quinquefasciatus, respectively. The results were statistically significant. Confertifolin could be considered for use in the control of human vector mosquitoes. PMID- 23942242 TI - Endothelial dysfunction is associated with a greater depressive symptom score in a general elderly population: the Hoorn Study. AB - BACKGROUND: Endothelial dysfunction (ED), low-grade inflammation (LGI) and oxidative stress (OxS) may be involved in the pathobiology of depression. Previous studies on the association of these processes in depression have yielded contradictory results. We therefore investigated comprehensively, in a population based cohort study, the association between ED, LGI and OxS on the one hand and depressive symptoms on the other. METHOD: We used data from the Hoorn Study and determined biomarkers of ED [flow-mediated dilatation (FMD), von Willebrand factor, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1, soluble thrombomodulin and soluble endothelial selectin], LGI [C-reactive protein, tumour necrosis factor-alpha, interleukin 6, interleukin 8, serum amyloid A, myeloperoxidase (MPO) and sICAM-1] and OxS (oxidized low density lipoprotein and MPO). Depressive symptoms were quantified by the Center for Epidemiologic Studies Depression Scale (CES-D) questionnaire (n = 493; age 68 years; 49.9% female). Regression analyses were performed with the use of biomarker Z scores. Adjustments were made for age, sex and glucose metabolism status (cohort stratification variables) and prior cardiovascular disease, hypertension, waist-to-hip ratio, cholesterol levels, education level, physical activity, dietary habits, and the use of antihypertensive and/or lipid lowering medication and/or metformin (potential confounders). RESULTS: After adjustment for age, sex and glucose metabolism status, one standard deviation increase in the ED Z score was associated with a 1.9 [95% confidence interval (CI) 0.7-3.1] higher CES-D score. Additional adjustments did not materially change this result. LGI and OxS were not associated with the CES-D score. CONCLUSIONS: ED, as quantified by an array of circulating biomarkers and FMD, was independently associated with depressive symptoms. This study supports the hypothesis that ED plays an important role in the pathobiology of depression. PMID- 23942241 TI - Complement anaphylatoxin C3a is a potent inducer of embryonic chick retina regeneration. AB - Identifying the initiation signals for tissue regeneration in vertebrates is one of the major challenges in regenerative biology. Much of the research thus far has indicated that certain growth factors have key roles. Here we show that complement fragment C3a is sufficient to induce complete regeneration of the embryonic chick retina from stem/progenitor cells present in the eye, independent of fibroblast growth factor receptor signaling. Instead, C3a induces retina regeneration via STAT3 activation, which in turn activates the injury- and inflammation-responsive factors, IL-6, IL-8 and TNF-alpha. This activation sets forth regulation of Wnt2b, Six3 and Sox2, genes associated with retina stem and progenitor cells. Thus, our results establish a mechanism for retina regeneration based on injury and inflammation signals. Furthermore, our results indicate a unique function for complement anaphylatoxins that implicate these molecules in the induction and complete regeneration of the retina, opening new avenues of experimentation in the field. PMID- 23942244 TI - Oral estrogen therapy may mitigate the effects of aerobic training on cardiorespiratory fitness in postmenopausal women: a double-blind, randomized clinical pilot study. AB - OBJECTIVE: The aim of this study was to evaluate the isolated and associated effects of oral estrogen therapy and aerobic training on cardiorespiratory fitness in postmenopausal women. METHODS: Forty-two hysterectomized healthy postmenopausal women were randomly divided (in a double-blind manner) into four groups: placebo-control (n = 9), estrogen therapy-control (n = 12), placebo aerobic training (PLA-AT; n = 11), and estrogen therapy-aerobic training (ET-AT; n = 10). The estrogen therapy groups received estradiol valerate (1 mg/day) and the aerobic training groups trained on a cycle ergometer three times per week at moderate intensity. Before and 6 months after the interventions, all women underwent a maximal cardiopulmonary exercise test on a cycle ergometer. RESULTS: Regardless of hormone therapy, aerobic training increased oxygen uptake at anaerobic threshold (P = 0.001), oxygen uptake at respiratory compensation point (P = 0.043), and oxygen uptake at peak exercise (P = 0.020). The increases at respiratory compensation point and peak exercise were significantly greater in the groups receiving placebo than in the groups receiving estrogen (oxygen uptake at respiratory compensation point: PLA-AT +5.3 [2.8] vs ET-AT +3.0 [2.5] mL kg( 1) min(-1), P = 0.04; oxygen uptake at peak exercise: PLA-AT +5.8 [3.4] vs ET-AT +2.8 [1.4] mL kg(-1) min(-1), P = 0.02). CONCLUSIONS: Oral estrogen therapy may mitigate the cardiorespiratory fitness increase induced by aerobic training in hysterectomized healthy postmenopausal women. PMID- 23942245 TI - Sleep parameters and health-related quality of life with bazedoxifene/conjugated estrogens: a randomized trial. AB - OBJECTIVE: The effects of bazedoxifene (BZA)/conjugated estrogens (CE) on sleep and health-related quality of life (HRQoL) were evaluated in nonhysterectomized postmenopausal women who were enrolled in a randomized, double-blind, placebo- and active-controlled phase 3 trial. METHODS: The sleep/HRQoL substudy enrolled 459 women with bothersome moderate to severe vasomotor symptoms who were randomized to BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, BZA 20 mg, CE 0.45 mg/medroxyprogesterone acetate (MPA) 1.5 mg, or placebo for 1 year. On months 3 and 12, sleep parameters were evaluated using the Medical Outcomes Study sleep scale, and HRQoL was assessed using the Menopause-Specific Quality of Life (MENQOL) questionnaire. RESULTS: BZA/CE and CE/MPA significantly improved sleep and HRQoL compared with placebo. On month 3, most Medical Outcomes Study sleep parameter improvements with BZA/CE and CE/MPA versus placebo were not significant. On month 12, both BZA/CE doses and CE/MPA significantly improved time to fall asleep and sleep disturbance (P < 0.05 vs. placebo); BZA 20 mg/CE 0.625 mg and CE/MPA also showed significant improvements in sleep adequacy and sleep problem indices I and II (P < 0.01 vs placebo). Both BZA/CE doses and CE/MPA significantly improved MENQOL vasomotor function score versus placebo at 3 and 12 months (P < 0.001). At 3 months, total MENQOL score was significantly improved with BZA 20 mg/CE 0.625 mg and CE/MPA versus placebo (P < 0.05); at 12 months, both BZA/CE doses and CE/MPA showed significant improvements (P < 0.001). CONCLUSIONS: Symptomatic postmenopausal women who are treated with BZA/CE for 1 year demonstrate significant improvements in sleep and HRQoL, similar to women treated with CE/MPA. PMID- 23942246 TI - Hot flashes and sleep: pieces of the puzzle. PMID- 23942247 TI - Reproductive history and postmenopausal rheumatoid arthritis among women 60 years or older: Third National Health and Nutrition Examination Survey. AB - OBJECTIVE: Rheumatoid arthritis, a condition of unknown etiology, has been associated with considerable costs to society. The purpose of this study is to determine whether selected reproductive history characteristics are associated with postmenopausal rheumatoid arthritis diagnosis. METHODS: Secondary analyses were performed using cross-sectional data from the Third National Health and Nutrition Examination Survey. Of 1,892 eligible participants, 182 fulfilled the criteria for postmenopausal rheumatoid arthritis, based on self-report and the 1987 American College of Rheumatology criteria. Logistic regression models were constructed, and odds ratios (ORs) with their 95% CIs were calculated for selected reproductive history characteristics as predictors of postmenopausal rheumatoid arthritis, after adjustment for potential confounders. RESULTS: Multivariate logistic models suggested that age at menopause was the only reproductive characteristic that was significantly associated with the outcome of interest (OR, 0.96; 95% CI, 0.93-0.99). Compared with women experiencing menopause at 50 years of age or later, those who experienced menopause before 40 years of age (OR, 2.53; 95% CI, 1.41-4.53) had increased odds of postmenopausal rheumatoid arthritis. CONCLUSIONS: Women who experience menopause before 40 years of age seem to be at increased risk for postmenopausal rheumatoid arthritis. Conversely, age at menarche and pregnancy history may not predict rheumatoid arthritis after menopause. Further research is needed to confirm and elucidate these epidemiological findings. PMID- 23942248 TI - Lifetime hormone exposure and cognition in postmenopausal women with breast cancer. PMID- 23942249 TI - Association between low bone mineral density and increased alpha-defensin in salivary fluid among postmenopausal women. AB - OBJECTIVE: This study aims to evaluate the concentration of alpha-defensin human neutrophil peptide-1 (HNP-1; a peptide released by neutrophils) in salivary fluid among postmenopausal women and to compare bone mineral density among postmenopausal women with different concentrations of this peptide. METHODS: We consecutively enrolled 61 postmenopausal women. Bone density was measured by dual energy x-ray absorptiometry, and alpha-defensin HNP-1 was identified by proteomic analysis of salivary fluid specimen. RESULTS: We found a significant difference in bone mineral density among postmenopausal women with different concentrations of alpha-defensin HNP-1 in salivary fluid. In particular, women with higher alpha defensin concentrations had the lowest bone density in comparison with those with a lower concentration of defensin (P = 0.03 between groups). Univariate and multivariate linear regression analyses showed a significative inverse relationship between bone mineral density and age (r = -0.58, beta = -0.56) and peak of alpha-defensin (r = -0.26, beta = -0.21). CONCLUSIONS: Low bone mineral density is found in postmenopausal women with high alpha-defensin HNP-1 concentrations. Therefore, alpha-defensin HNP-1 could be a novel biomarker for osteoporosis. PMID- 23942250 TI - Obstetrician-gynecologists' opinions on elective bilateral oophorectomy at the time of hysterectomy in the United States: a nationwide survey. AB - OBJECTIVE: This study aims to assess obstetrician-gynecologists' opinions on elective bilateral oophorectomy (BO) at the time of hysterectomy in the United States and to describe factors that influence their views. METHODS: In April 2012, an anonymous survey was mailed twice to practicing obstetrician gynecologists, randomly selected from a list produced by the American Medical Association, in an effort to assess their opinions regarding elective BO at the time of hysterectomy. The effects of gynecologists' various characteristics on their opinions were also evaluated. RESULTS: Of 1,002 mailed surveys, 443 (44%) were returned completed. Of the respondents, 59% were male and 79% were white. The largest age group was 51 to 55 years (20%), and the mean time since completion of residency was 23 years. In women with an average risk of ovarian cancer, the proportions of physicians who favored elective BO were as follows: women younger than 51 years, 32%; women aged 51 to 65 years, 62%; women older than 65 years, 6%. These recommendations were not influenced by the physicians' age, sex, training, or geographic region. If a hysterectomy candidate was younger than 51 years and had a personal history of breast or ovarian cancer and a family history of ovarian cancer, these proportions were increased to 77% and 64%, respectively. Other factors that influenced the respondents' recommendations were the women's personal history of cardiovascular disease (21%), osteoporosis (23%), and sexual dysfunction (23%). CONCLUSIONS: One third of obstetrician gynecologists continue to recommend elective BO for hysterectomy candidates younger than 51 years. The majority recommend elective BO for women aged 51 to 65 years. Their demographic characteristics do not influence their opinions. PMID- 23942252 TI - Patulin-induced suicidal erythrocyte death. AB - BACKGROUND: Patulin, the most common mycotoxin in apples and apple-derived products, triggers apoptosis and has thus been considered for the treatment of cancer. Similar to apoptosis of nucleated cells, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and by cell membrane scrambling leading to phosphatidylserine-exposure at the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca(2+)-activity ([Ca(2+)]i). The present study explored, whether exposure of human erythrocytes to patulin is followed by eryptosis. METHODS: Forward scatter was measured to estimate cell volume, annexin V binding to detect phosphatidylserine-exposure, hemoglobin release to quantify hemolysis, and Fluo3-fuorescence to determine [Ca(2+)]i. RESULTS: A 48 h exposure to patulin significantly increased [Ca(2+)]I (5 uM), significantly decreased forward scatter (5 uM) and significantly increased annexin-V-binding (2.5 uM). Patulin (10 uM) induced annexin-V-binding was virtually abrogated by removal of extracellular Ca(2+). CONCLUSION: Patulin stimulates Ca(2+) entry into erythrocytes, an effect triggering suicidal erythrocyte death or eryptosis. PMID- 23942251 TI - Does hormone therapy affect blood pressure changes in the Diabetes Prevention Program? AB - OBJECTIVE: This study aims to examine whether blood pressure reductions differ by estrogen use among overweight glucose-intolerant women. METHODS: We conducted a secondary analysis of Diabetes Prevention Program postmenopausal participants who used oral estrogen with or without progestogen at baseline and 1-year follow-up (n = 324) versus those who did not use oral estrogen with or without progestogen at either time point (n = 382). Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were examined by randomization arm (intensive lifestyle change [ILS], metformin 850 mg twice daily, or placebo). Associations between changes in blood pressure and changes in sex hormone-binding globulin, estradiol, testosterone, and dehydroepiandrosterone were also examined. RESULTS: Estrogen users and nonusers had similar prevalences of baseline hypertension (33% vs 34%, P = 0.82) and use of blood pressure medications at baseline (P = 0.25) and on follow-up (P = 0.10). Estrogen users and nonusers randomized to ILS had similar decreases in SBP (-3.3 vs -4.7 mm Hg, P = 0.45) and DBP (-3.1 vs -4.7 mm Hg, P = 0.16). Among estrogen users, women randomized to ILS had significant declines in SBP (P = 0.016) and DBP (P = 0.009) versus placebo. Among nonusers, women randomized to ILS had significant declines in DBP (P = 0.001) versus placebo, but declines in SBP were not significant (P = 0.11). Metformin was not associated with blood pressure reductions versus placebo regardless of estrogen therapy. Blood pressure changes were not associated with changes in sex hormones regardless of estrogen therapy. CONCLUSIONS: Among overweight women with dysglycemia, the magnitude of blood pressure reductions after ILS is unrelated to postmenopausal estrogen use. PMID- 23942254 TI - Family-centered assessment and function for children with chronic mechanical respiratory support. AB - INTRODUCTION: The purpose of this study was to assess health-related quality of life (HRQL) when managing severe, chronic respiratory insufficiency (CRI) at home. METHODS: Families enrolled in a comprehensive program for CRI completed the Child Health Ratings Inventories with (a) parent-proxy ratings of the child's HRQL and (b) the parent's own HRQL. Psychometrics and known groups comparisons were reported. Linear regressions models assessed the effect of the parent's HRQL on proxy ratings. RESULTS: Eighty-six parents (67%) completed the measures. The child global HRQL score was low (63.1, SD = 24.9), although ratings of "family life" were higher (73.8, SD = 26.5). The parent global HRQL and emotional functioning (EF) scores were low, despite preserved physical and role function. Having a child with a congenital versus an acquired disability was associated with higher parental EF (p = .004). Higher parental EF correlated with a higher global child HRQL (p < .001). DISCUSSION: Families of children with CRI experience reduced HRQL. The Child Health Ratings Inventories is a valid tool for this assessment, identifying emotional distress and potential gaps in support. PMID- 23942253 TI - ABA-insensitive (ABI) 4 and ABI5 synergistically regulate DGAT1 expression in Arabidopsis seedlings under stress. AB - Triacylglycerol (TAG) accumulation is essential for seed maturation in plants. Diacylglycerol acyltransferase 1 (DGAT1) is the rate-limiting enzyme in TAG biosynthesis. In this study, we show that TAG accumulation in Arabidopsis seedlings is correlated with environmental stress, and both ABI4 and ABI5 play important roles in regulating DGAT1 expression. Tobacco transient assays revealed the synergistic effect of ABI4 with ABI5 in regulating DGAT1 expression. Taken together, our findings indicate ABI5 is an important accessory factor with ABI4 in the activation of DGAT1 in Arabidopsis seedlings under stress. PMID- 23942255 TI - Internet informs parents about growth hormone. AB - BACKGROUND: Parents' knowledge influences decisions regarding medical care for their children. METHODS: Parents of pediatric primary care patients aged 9-14 years, irrespective of height, participated in open focus groups (OFGs). Moderators asked the question, 'How do people find out about growth hormone (GH)?' Because many parents cited the Internet, the top 10 results from the Google searches of 'growth hormone children' and 'parents of children who take growth hormone' were examined. Three investigators independently performed content analysis and then reached a consensus. The results were tabulated via summary statistics. RESULTS: Eighteen websites were reviewed, most with the purpose of education (56%) and many funded by commercial sources (44%). GH treatment information varied, with 33% of the sites containing content only about US FDA-approved indications. Fifty-six percent of the sites included information about psychosocial benefits from treatment, with 44% acknowledging them as controversial. Although important to OFG participants, risks and costs were each omitted from 39% of the websites. CONCLUSION: Parents often turn to the Internet for GH-related information for their children, although its content may be incomplete and/or biased. Clinicians may want to provide parents with tools for critically evaluating Internet-based information, a list of prereviewed websites, or their own educational materials. PMID- 23942256 TI - Controlled growth of platinum nanowire arrays on sulfur doped graphene as high performance electrocatalyst. AB - Graphene supported Pt nanostructures have great potential to be used as catalysts in electrochemical energy conversion and storage technologies; however the simultaneous control of Pt morphology and dispersion, along with ideally tailoring the physical properties of the catalyst support properties has proven very challenging. Using sulfur doped graphene (SG) as a support material, the heterogeneous dopant atoms could serve as nucleation sites allowing for the preparation of SG supported Pt nanowire arrays with ultra-thin diameters (2-5 nm) and dense surface coverage. Detailed investigation of the preparation technique reveals that the structure of the resulting composite could be readily controlled by fine tuning the Pt nanowire nucleation and growth reaction kinetics and the Pt support interactions, whereby a mechanistic platinum nanowire array growth model is proposed. Electrochemical characterization demonstrates that the composite materials have 2-3 times higher catalytic activities toward the oxygen reduction and methanol oxidation reaction compared with commercial Pt/C catalyst. PMID- 23942257 TI - Treatment of posttraumatic stress disorder at the end-of-life: application of the Stepwise Psychosocial Palliative Care model. AB - OBJECTIVES: Feldman (2011) has proposed a new approach to the treatment of posttraumatic stress disorder (PTSD) in individuals at the end-of-life known as Stepwise Psychosocial Palliative Care (SPPC). This approach helps to compensate for the disadvantages of existing PTSD interventions with regard to treating patients with life-limiting and terminal illnesses by employing a palliative care philosophy. The model relies on cognitive and behavioral techniques drawn from evidence-based approaches to PTSD, deploying them in a stage-wise manner designed to allow for interventions to track with patents' needs and prognoses. Because this model is relatively new, we seek to explore issues related to its implementation in the complex settings in which providers encounter patients at the end-of-life. We also seek to provide concrete guidance to providers regarding the management of PTSD at the end-of-life in diverse palliative care settings. METHODS: We examine three specific cases in which the SPPC model was utilized, highlighting particular treatment challenges and strategies. These case studies provide information regarding the SPPC model's application to patients in two distinct palliative care settings-a palliative care consult team and an inpatient palliative care unit. RESULTS: The SPPC model's stage-wise approach allows for its flexible use given a variety of constraints related to setting and patient issues. SIGNIFICANCE OF RESULTS: The SPPC model provides an alternative to existing psychosocial treatments for PTSD that may be more appropriate for patients at the end of life. PMID- 23942258 TI - Tuning the thermal diffusivity of silver based nanofluids by controlling nanoparticle aggregation. AB - With the aim of preparing stable nanofluids for heat exchange applications and to study the effect of surfactant on the aggregation of nanoparticles and thermal diffusivity, stable silver colloids were synthesized in water by a green method, reducing AgNO3 with fructose in the presence of poly-vinylpyrollidone (PVP) of various molecular weights. A silver nanopowder was precipitated from the colloids and re-dispersed at 4 vol% in deionized water. The Ag colloids were characterized by UV-visible spectroscopy, combined dynamic light scattering and zeta-potential measurements, and laser flash thermal diffusivity. The Ag nanopowders were characterized by scanning electron microscopy and thermal gravimetric analysis. It was found that the molecular weight of PVP strongly affects the zeta-potential and the aggregation of nanoparticles, thereby affecting the thermal diffusivity of the obtained colloids. In particular, it was observed that on increasing the molecular weight of PVP the absolute value of the zeta-potential is reduced, leading to increased aggregation of nanoparticles. A clear relation was identified between thermal diffusivity and aggregation, showing higher thermal diffusivity for nanofluids having higher aggregation. A maximum improvement of thermal diffusivity by about 12% was found for nanofluids prepared with PVP having higher molecular weight. PMID- 23942259 TI - Mindfulness-based cognitive therapy for patients with medically unexplained symptoms: a randomized controlled trial. AB - BACKGROUND: Patients with medically unexplained symptoms make heavy demands on the health care system. An offer for psychological treatment is often declined. There is a need for acceptable and effective treatments. We assessed the acceptability and effectiveness of mindfulness-based cognitive therapy (MBCT) for patients with persistent medically unexplained symptoms. METHOD: A randomized controlled trial comparing MBCT (n = 64) to enhanced usual care (EUC; n = 61). Participants were the 10% most frequently attending patients in primary care. The primary outcome measure was general health status at the end of treatment. Secondary outcome measures were mental and physical functioning. Assessments took place at the end of treatment and at the 9-month follow-up. RESULTS: Health status and physical functioning did not significantly differ between groups. However, participants in the MBCT group reported a significantly greater improvement in mental functioning at the end of treatment (adjusted mean difference, 3.9; 95% CI, 0.24-7.6), in particular with regard to vitality and social functioning. In addition, at 9 months of follow-up, the mindfulness skills 'observing' and 'describing' were significantly higher in the MBCT group. Within the MBCT group, almost half of the outcome measures had significantly improved at the end of treatment, whereas in the EUC group none had. CONCLUSIONS: MBCT was feasible for frequently attending patients with persistent medically unexplained symptoms in primary care. Although MBCT did not lead to a significant difference in general health status between the two groups, it did result in a significant improvement in mental functioning. PMID- 23942260 TI - Current challenges and opportunities in nonclinical safety testing of biologics. AB - Nonclinical safety testing of new biotherapeutic entities represents its own challenges and opportunities in drug development. Hot topics in this field have been discussed recently at the 2nd Annual BioSafe European General Membership Meeting. In this feature article, discussions on the challenges surrounding the use of PEGylated therapeutic proteins, selection of cynomolgus monkey as preclinical species, unexpected pharmacokinetics of biologics and the safety implications thereof are summarized. In addition, new developments in immunosafety testing of biologics, the use of transgenic mouse models and PK and safety implications of multispecific targeting approaches are discussed. Overall, the increasing complexity of new biologic modalities and formats warrants tailor made nonclinical development strategies and experimental testing. PMID- 23942261 TI - Association between cytosolic glycerol 3-phosphate dehydrogenase gene expression in human subcutaneous adipose tissue and BMI. AB - BACKGROUND/AIMS: Cytosolic glycerol 3-phosphate dehydrogenase (cGPDH) is a key enzyme providing glycerol 3-phosphate for triacylglycerol synthesis in adipose tissue and is regarded as a marker for adipocyte differentiation. The aim of this study was to test the hypothesis that an increase in cGPDH gene expression in subcutaneous adipose tissue is associated with obesity. METHODS: mRNA levels in human subcutaneous adipose tissue were analysed by Real-Time PCR. RESULTS: We found that human subcutaneous adipose tissue cGPDH activity and cGPDH mRNA level were greater in obese patients than in lean subjects and were positively correlated with BMI and fat mass. Moreover, a strong positive correlation between subcutaneous adipose tissue cGPDH mRNA level and cGPDH activity was found. The data presented here indicates also that PPARgamma mRNA level is positively correlated with body mass index and fat mass as well as with adipose tissue cGPDH mRNA level. Moreover, the association between subcutaneous adipose tissue cGPDH mRNA level and fatty acid translocase (FAT/CD36) mRNA level was also observed. CONCLUSION: The obtained results suggest that in comparison to lean subjects the increase in subcutaneous adipose tissue cGPDH gene expression in the obese, is probably the result of adipose tissue expansion during obesity. PMID- 23942263 TI - Stable right ventricular size and function during short-term follow-up in patients with pulmonary regurgitation after tetralogy of Fallot repair. AB - AIM: To assess changes in ventricular size and function over time in conservatively treated adult patients with repaired tetralogy of Fallot (TOF) and significant pulmonary regurgitation (PR). MATERIALS AND METHODS: Patients with repaired TOF who had undergone more than one cardiac magnetic resonance study were identified. To confine the cause of ventricular size and function deviation to PR, patients with residual ventricular septal defect, more than mild regurgitation at a valve other than the pulmonary valve, and known coronary artery disease were excluded. RESULTS: The final analysis included 27 adults with PR fraction >20%. During a follow-up of mean 2.1 +/- 0.8 years, there was no change in right ventricular (RV) end-diastolic volume (EDV; 162.1 +/- 27.6 versus 164 +/- 29.6 ml/m(2), p = 0.5). Left ventricular (LV) EDV showed a small decrease (85.1 +/- 16.2 versus 81.5 +/- 14.1 ml/m(2), p = 0.02). The mean PR fraction, PR volume, and peak RV outflow tract gradient did not change. Additionally, both RV ejection fraction (EF) and LVEF remained stable over the follow-up period (48.1 +/- 6.5 versus 48.4 +/- 6.7%, p = 0.83, and 57.3 +/- 5.4 versus 57.2 +/- 5.1 %, p = 0.91, respectively). Only two asymptomatic patients (7.4% of the study group) developed symptoms and the remaining did not deteriorate. CONCLUSION: The RVEDV, RVEF, and LVEF remained stable over a mean follow-up of approximately 2 years in the majority of adult patients after TOF repair with significant PR and a wide range of RVEDV. PMID- 23942262 TI - Feline serum amyloid A protein as an endogenous Toll-like receptor 4 agonist. AB - Serum amyloid A (SAA) is one of the major acute phase proteins and a biomarker of infection or inflammation in humans and cats. In humans, cytokine-like functions of SAA protein have been determined, and SAA is considered to be an important factor in immune responses. However, there are no reports about the functions of SAA protein in cats. In the present study, the functions of feline SAA protein on peripheral monocytes were investigated by using TNF-alpha production as an indicator. In feline peripheral blood monocytes, SAA protein stimulated the transcription of TNF-alpha within 2h and induced TNF-alpha secretion in time- and dose-dependent manners. The production of TNF-alpha by SAA stimulation in feline monocytes was found to be mediated by the activation of nuclear factor-kappa B (NF-kappaB). Moreover, SAA-stimulated TNF-alpha production was prevented by a Toll-like receptor 4 (TLR4) antagonist. On the basis of these results, feline SAA was demonstrated to be an endogenous agonist of TLR4 for the stimulation of TNF alpha production and secretion by peripheral monocytes. These results suggest that feline SAA can play an important role in the regulation of inflammation and immune responses as it does in humans. PMID- 23942264 TI - Disc-retained tubes for radiologically inserted gastrostomy (RIG): not up to the job? AB - AIM: To assess the insertion procedure and performance of disc-retained gastrostomy tubes, recording complications and accidental displacements by prospective audit, and to determine whether primary placement of the tube off licence was feasible. MATERIALS AND METHODS: Disc-retained 12 F single-lumen Monarch gastrostomy tubes (Enteral UK, Selby, UK) were inserted by three gastrointestinal interventional radiologists in a supra-regional cancer centre. The 12 F tubes required a 20 F peel-away sheath with four-point gastropexy fixation and were placed under conscious sedation, using electrocardiogram (EEG) bispectral index monitoring. Follow-up was performed in an in-house gastrostomy drop-in clinic at 1 week and 1 month, supplemented with weekly telephone follow up. Patients also had open access to the gastrostomy drop-in clinic for immediate advice and complication management. RESULTS: Eighteen patients underwent primary insertion of a Monarch gastrostomy tube over 5 months. A total of 6/18 (33%) tubes displaced; 4/18 (22%) completely, 2/18 (11%) occult into the peritoneum. Four of 18 (22%) patients developed infection at the stoma site. Due to the unexpectedly poor performance of the tube, the study was terminated early. CONCLUSION: Initial experience with the Monarch disc-retained gastrostomy tube demonstrates it unsuitable for primary placement with current protocols. In view of the potentially serious complications, the Medicines and Healthcare Products Regulatory Agency (MHRA) has been informed. A request has been made to the distributer to reassess the tube design and/or review the procedure promoted for primary placement. PMID- 23942265 TI - Decomposition of forest products buried in landfills. AB - The objective of this study was to investigate the decomposition of selected wood and paper products in landfills. The decomposition of these products under anaerobic landfill conditions results in the generation of biogenic carbon dioxide and methane, while the un-decomposed portion represents a biogenic carbon sink. Information on the decomposition of these municipal waste components is used to estimate national methane emissions inventories, for attribution of carbon storage credits, and to assess the life-cycle greenhouse gas impacts of wood and paper products. Hardwood (HW), softwood (SW), plywood (PW), oriented strand board (OSB), particleboard (PB), medium-density fiberboard (MDF), newsprint (NP), corrugated container (CC) and copy paper (CP) were buried in landfills operated with leachate recirculation, and were excavated after approximately 1.5 and 2.5yr. Samples were analyzed for cellulose (C), hemicellulose (H), lignin (L), volatile solids (VS), and organic carbon (OC). A holocellulose decomposition index (HOD) and carbon storage factor (CSF) were calculated to evaluate the extent of solids decomposition and carbon storage. Samples of OSB made from HW exhibited cellulose plus hemicellulose (C+H) loss of up to 38%, while loss for the other wood types was 0-10% in most samples. The C+H loss was up to 81%, 95% and 96% for NP, CP and CC, respectively. The CSFs for wood and paper samples ranged from 0.34 to 0.47 and 0.02 to 0.27gOCg(-1) dry material, respectively. These results, in general, correlated well with an earlier laboratory-scale study, though NP and CC decomposition measured in this study were higher than previously reported. PMID- 23942266 TI - [An ecological perspective on the determinants of the cognitive vitality of seniors]. AB - Cognitive aging is a heterogeneous reality among the senior population. Studies have recently identified certain factors that may contribute to maintaining the cognitive health of seniors. To date, these research studies have primarily focused on individual determinants, namely: health conditions and lifestyle habits. A review of the literature was conducted in order to explore the socio environmental factors that may influence the cognitive vitality of seniors. This review demonstrates that studies that have examined this potential link are very rare. Only the type and socioeconomic level of the neighbourhood of the residence, as well as the size of the social network, were identified as influential factors. However, studies have shown that the environment could modulate certain lifestyle habits which, in turn, can influence cognition. This article uses an ecological approach to illustrate individual and socio environmental targets for the promotion of the cognitive health of seniors. PMID- 23942267 TI - Sodium butyrate inhibits interferon-gamma induced indoleamine 2,3-dioxygenase expression via STAT1 in nasopharyngeal carcinoma cells. AB - AIMS: Indoleamine 2,3-dioxygenase (IDO) inhibits T-cell proliferation by catalyzing the conversion of l-tryptophan to l-kynurenine. IDO-induced immune tolerance weakens the clinical outcomes of immunotherapies. Sodium butyrate (NaB), one of the histone deacetylase inhibitors (HDACIs), has potential anti tumor effects. Our previous studies revealed that NaB could inhibit IFN-gamma induced IDO expression in nasopharyngeal carcinoma cells, CNE2. In the present study, we aim to investigate to the mechanism of NaB interfering with the interferon-gamma (IFN-gamma)-mediated IDO expression signaling transduction. MAIN METHODS: IDO expression and STAT1 phosphorylation in CNE2 cells were analyzed by western blotting and STAT1 acetylation was evaluated by immunoprecipitation. STAT1 nuclear translocation and NF-kappaB activity were detected by transient transfection and reporter gene assay. KEY FINDINGS: We found that NaB inhibited IFN-gamma-induced IDO expression in CNE2 cells via decreasing phosphorylation and nuclear translocation of STAT1, but not via down-regulation of IFN-gamma-receptor (IFNGR). Immunoprecipitation assays revealed that NaB increased STAT1 acetylation. Furthermore, NaB elevated the activity of NF-kappaB in CNE2 cells, and blocking the NF-kappaB activity had no effect on the IFN-gamma-induced IDO expression. SIGNIFICANCE: These results suggest that NaB inhibited IFN-gamma induced IDO expression via STAT1 increased acetylation, decreased phosphorylation, and reduced nuclear translocation. These provided new evidence for the anti-tumor action of NaB and potential drug targets to reduce the IDO induced immune tolerance. PMID- 23942268 TI - Chronic ketamine administration impairs mitochondrial complex I in the rat liver. AB - AIM: Ketamine can induce hepatotoxicity which has been suggested to be dependent on mitochondrial impairment. This study investigated the long-term effects of chronic low-dose ketamine on liver mitochondrial function, oxidative stress parameters, liver histology and glycogen content. MAIN METHODS: Adult rats were administered with saline or ketamine (5 or 10mg/kg) twice a day for a fourteen day period in order to mimic chronic treatments. Effects between groups were compared ten days after the treatment had ended. Liver mitochondrial function was monitored in isolated mitochondrial extracts through evaluation of respiration parameters and activity of respiratory complexes, as well as oxidative stress, through lipid peroxidation, protein oxidation and superoxide dismutase activity. The hepatic histology and liver glycogen content were also evaluated. KEY FINDINGS: Ketamine groups showed a decreased evolution in body weight gains during the treatment period. Ketamine had no effect either on serum liver enzymes or on the oxidative stress parameters of liver mitochondria. Ketamine decreased the hepatic glycogen content, inhibited mitochondrial complex I and oxygen consumption when glutamate-malate substrate was used. SIGNIFICANCE: These findings reflect a long-term mitochondrial bioenergetic deterioration induced by ketamine, which may explain the increased susceptibility of some patients to its prolonged or repeated use. PMID- 23942269 TI - Mouse models of plaque rupture. AB - PURPOSE OF REVIEW: Atherosclerotic plaque destabilization and rupture is an important pathological condition that may account for approximately 70% of acute myocardial infarction cases. To analyse the mechanisms by which an atherosclerotic plaque destabilizes and ruptures and examine the effects of novel therapeutic approaches, several groups have developed mouse models of plaque rupture. RECENT FINDINGS: Findings from intracoronary imaging modalities support the role of rupture-prone 'vulnerable plaques' characterized by pathological studies as precursors of plaque rupture and acute myocardial infarction. Atherosclerotic plaques in the brachiocephalic arteries of apolipoprotein E (ApoE)-deficient mice fed a high-fat diet demonstrate several key histological features of ruptured human plaques. Angiotensin II infusion accelerates plaque destabilization and rupture, which has enabled researchers to analyse the role of pathophysiological and genetic factors that accelerate plaque destabilization and rupture and qualitatively examine the effects of experimental therapies. The plaque rupture model in the brachiocephalic arteries of ApoE-deficient mice is disputed due to dissimilarities from human plaques regarding the incidence of thrombotic occlusion and computer-simulated mechanical stress in the plaque. SUMMARY: Although no mouse model examined completely simulates the entire process of plaque rupture, the brachiocephalic artery in ApoE-deficient mice fed a high fat diet, with or without angiotensin II infusion, is a practically feasible model for plaque rupture. PMID- 23942270 TI - Hypoxia in atherosclerosis and inflammation. AB - PURPOSE OF REVIEW: Hypoxia triggers various cellular processes, both in physiological and pathological conditions, and has recently also been implicated in atherosclerosis. This review summarizes the recent evidence for the presence and the role of hypoxia in atherosclerosis. Additionally, it will elucidate on hypoxic signaling, which is interlinked with inflammatory signaling, and discuss recent advances in imaging of hypoxia in atherosclerosis. RECENT FINDINGS: Hypoxia is present in atherosclerotic plaques in humans and animal models, and systemic hypoxia promotes atherosclerosis. Hypoxia stimulates proatherosclerotic processes, like deficient lipid efflux, inflammation, interference with macrophage polarization and glucose metabolism. However, the molecular mechanism of hypoxia-mediated atherogenesis remains unclear. Noninvasive imaging directly targeting plaque hypoxia has been applied in animal models of atherosclerosis, but remains to be validated in humans. Meanwhile, the metabolic marker 18F fluorodeoxyglucose, used to detect human atherosclerosis in vivo, may serve as an indirect marker of plaque hypoxia due to enhanced glucose uptake in anaerobic metabolism. SUMMARY: Recent studies underscore the proatherogenic role of hypoxia in macrophage lipid and glucose metabolism, inflammation and polarization. These studies provide new insights into the pathogenesis of atherosclerosis and unravel novel therapeutic targets and new options for noninvasive imaging of human atherosclerotic plaques. PMID- 23942271 TI - Karyotype-phenotype correlation in partial trisomies of the short arm of chromosome 6: a family case report and review of the literature. AB - The first child (proband) of nonconsanguineous Caucasian parents underwent genetic investigation because she was affected with congenital choanal atresia, heart defects and kidney hyposplasia with mild transient renal insufficiency. The direct DNA sequencing after PCR of the CHD7 gene, which is thought to be responsible for approximately 60-70% of the cases of CHARGE syndrome/association, found no mutations. The cytogenetic analysis (standard GTG banding karyotype) revealed the presence of extrachromosomal material on 10q. The chromosome analysis was completed with array CGH (30 kb resolution), MLPA and FISH, which allowed the identification of three 6p regions (6p.25.3p23 * 3): 2 of these regions are normally located on chromosome 6, and the third region is translocated to the long arm of chromosome 10. The same chromosomal rearrangement was subsequently found in the father, who was affected with congenital ptosis and progressive hearing loss, and in the proband's sister, the second child, who presented at birth with choanal atresia and congenital heart defects. The mutated karyotypes, which were directly inherited, are thought to be responsible for a variable phenotype, including craniofacial dysmorphisms, choanal atresia, congenital ptosis, sensorineural hearing loss, heart defects, developmental delay, and renal dysfunction. Nevertheless, to achieve a complete audiological assessment of the father, he underwent further investigation that revealed an increased level of the coagulation factor XIII (300% increased activity), fluctuating levels of fibrin D-dimer degradation products (from 296 to 1,587 ng/ml) and a homoplasmic mitochondrial DNA mutation: T961G in the MTRNR1 (12S rRNA) gene. He was made a candidate for cochlear implantation. Preoperative high resolution computed tomography and magnetic resonance imaging of the temporal bone revealed the presence of an Arnold-Chiari malformation type I. To the best of our knowledge, this study is the second report on partial 6p trisomy that involves the 10q terminal region. Furthermore, we report the first case of documented Arnold-Chiari malformation type I and increased factor XIII activity associated with 6p trisomy. We present a comprehensive report of the familial cases and an exhaustive literature review. PMID- 23942272 TI - Assessing clinician's subjective experience during interaction with patients. AB - BACKGROUND: While psychiatric literature has shown renewed interest in fine psychopathological investigation, little study has been devoted to the clinician's subjective experience with the patient, which is highly valued by the phenomenological and psychodynamic traditions. We aimed at developing a valid and reliable instrument to measure such experience. SAMPLING AND METHODS: First, 104 self-report items were developed, based on daily clinical practice and references from the literature on clinician's subjective experience. Of these, 46 were retained after pilot testing and exclusion of items with poor psychometric properties. Thirteen psychiatrists and 527 first-contact patients participated in the validation study. Psychiatrists completed the 'Assessment of Clinician's Subjective Experience' (ACSE) instrument and the Brief Psychiatric Rating Scale (BPRS) after the visit and the Profile of Mood State (POMS) before and after it. The ACSE was completed again for 60 patients with stable BPRS scores over a short retest interval. Principal component analysis with orthogonal rotation was performed. The internal consistency and test-retest stability of ACSE factorially derived scales were calculated. Convergent validity was tested by examining the correlations between ACSE scores and change in POMS scores during the visit. RESULTS: Five factors (interpreted as tension, difficulty of attunement, engagement, disconfirmation, impotence) accounting for 57% of total variance were extracted. All ACSE scales showed high internal consistency and stability, and correlated with conceptually related POMS scales. CONCLUSIONS: The pattern of subjective experience identified by the ACSE is consistent with classical psychopathological descriptions and previous related studies. Despite limitations such as the relatively small number of psychiatrists studied and the exclusively self-report nature of the instrument, this study supports the validity and reliability of the ACSE and suggests that it may be a valuable tool for training, research and possibly diagnostic purposes. PMID- 23942274 TI - Cancer distress screening data: translating knowledge into clinical action for a quality response. AB - OBJECTIVES: The purpose of this paper is to summarize the use of the knowledge to action framework for adapting guidelines for practice and the evidence for effective implementation interventions to promote a quality response to cancer distress screening data. METHODS: We summarize progress in screening implementation in Ontario, Canada and the application of a systematic approach for adapting knowledge to practice and use of evidence-based knowledge translation interventions to ensure the uptake of best practices to manage distress. RESULTS: While significant progress has been made in the uptake of distress screening it is less clear if this has resulted in improvements in patient outcomes, i.e., reduced distress. The use of evidence-based knowledge translation strategies tailored to barriers at many levels of care delivery is critical to facilitate the uptake of distress screening data by the primary oncology team. SIGNIFICANCE OF RESULTS: There is a wealth of knowledge about the approaches that can be applied to translate knowledge into practice to improve psychosocial care and promote evidence-based distress management by the primary care oncology team. However, further implementation research is needed to advance knowledge about the most effective strategies in the context of cancer care. PMID- 23942273 TI - Prenatal exposure to environmental phenols: concentrations in amniotic fluid and variability in urinary concentrations during pregnancy. AB - BACKGROUND: Maternal urinary biomarkers are often used to assess fetal exposure to phenols and their precursors. Their effectiveness as a measure of exposure in epidemiological studies depends on their variability during pregnancy and their ability to accurately predict fetal exposure. OBJECTIVES: We assessed the relationship between urinary and amniotic fluid concentrations of nine environmental phenols, and the reproducibility of urinary concentrations, among pregnant women. METHODS: Seventy-one women referred for amniocentesis were included. Maternal urine was collected at the time of the amniocentesis appointment and on two subsequent occasions. Urine and amniotic fluid were analyzed for 2,4- and 2,5-dichlorophenols, bisphenol A, benzophenone-3, triclosan, and methyl-, ethyl-, propyl-, and butylparabens using online solid phase extraction-high performance liquid chromatography-isotope dilution tandem mass spectrometry. RESULTS: Only benzophenone-3 and propylparaben were detectable in more than half of the amniotic fluid samples; for these phenols, concentrations in amniotic fluid and maternal urine collected on the same day were positively correlated (rho = 0.53 and 0.32, respectively). Other phenols were detected infrequently in amniotic fluid (e.g., bisphenol A was detected in only two samples). The intraclass correlation coefficients (ICCs) of urinary concentrations in samples from individual women ranged from 0.48 and 0.62 for all phenols except bisphenol A (ICC = 0.11). CONCLUSION: Amniotic fluid detection frequencies for most phenols were low. The reproducibility of urine measures was poor for bisphenol A, but good for the other phenols. Although a single sample may provide a reasonable estimate of exposure for some phenols, collecting multiple urine samples during pregnancy is an option to reduce exposure measurement error in studies regarding the effects of phenol prenatal exposure on health. PMID- 23942275 TI - The HUMNxl scoring criteria for different cell types and nuclear anomalies in the buccal micronucleus cytome assay - an update and expanded photogallery. AB - The buccal micronucleus cytome assay is a minimally invasive cytological and interphase cytogenetic technique for measuring DNA damage and cell death biomarkers in the oral epithelium. In this report we provide an updated and more comprehensive version of the cellular and nuclear scoring criteria used in the assay accompanied with a photogallery of the various cell types and nuclear anomalies. These detailed scoring criteria complement previous published protocols of this assay and form the basis for guiding intra- and inter laboratory slide scoring comparisons. The scoring criteria update described in this paper is the outcome of ongoing efforts of the HUMN and HUMNxl projects (www.humn.org) to standardize the application of micronucleus assay for use in human biomonitoring and to update procedures as knowledge on mechanisms and technical capability improvements. PMID- 23942276 TI - Mindfulness-oriented recovery enhancement reduces pain attentional bias in chronic pain patients. AB - BACKGROUND: Chronic pain involves hypervigilance for pain-related stimuli. Selective attention to pain-related stimuli, known as pain attentional bias (AB), can exacerbate chronic pain, prolong suffering, and undermine quality of life. The aim of this study was to determine if a multimodal mindfulness-oriented intervention could significantly reduce pain AB among chronic pain patients receiving opioid analgesics. METHODS: A total of 67 chronic pain patients were randomized to an 8-week Mindfulness-Oriented Recovery Enhancement (MORE) intervention or a social support group intervention and began treatment. A dot probe task was used to measure pain AB. Primary outcomes were pain AB scores for cues presented for 2,000 and 200 ms. RESULTS: Prior to intervention, participants exhibited a significant bias towards pain-related cues presented for 2,000 ms, but no bias for cues presented for 200 ms. A statistically significant time * intervention condition interaction was observed for 2,000 ms pain AB, such that participants in MORE evidenced significantly reduced posttreatment pain AB relative to pretreatment levels, whereas no significant pre-post treatment changes in pain AB were observed for support group participants. Decreases in pain AB were associated with increased perceived control over pain and attenuated reactivity to distressing thoughts and emotions. CONCLUSION: Study findings provide the first indication that a mindfulness-oriented intervention may reduce pain AB among adults suffering from chronic pain. Given the magnitude of chronic pain in postindustrial societies, coupled with the dramatic escalation in prescription opioid misuse, future studies should evaluate MORE as a nonpharmacological means of addressing factors linked with chronic pain. PMID- 23942278 TI - The effect of copper pre-cleaning on graphene synthesis. AB - Copper foil is the most common substrate to synthesize monolayer graphene by chemical vapor deposition (CVD). The surface morphology and conditions of the copper foil can be very different depending on the various suppliers or different batches. These surface properties of copper strongly affect the growth behavior of graphene, thus rendering the growth conditions irreproducible when different batches of Cu foil are used. Furthermore, the quality of the graphene is severely affected as well. In this work, we report a facile method of copper pre-cleaning to improve the graphene quality and the reproducibility of the growth process. We found that the commercial Ni etchant (based on nitric acid) or nitric acid is the most effective cleaning agent among various acidic or basic solutions. The graphene grown on thus-treated copper surfaces is very clean and mostly monolayer when observed under scanning electron microscopy (SEM) and optical imaging, as compared to the graphene grown on untreated copper foil. Different batches (but with the same catalog number) of copper foil from Alfa Aesar Company were examined to explore the effect of copper pre-cleaning; consistent growth results were obtained when pre-cleaning was used. This method overcomes a commonly encountered problem in graphene growth and could become one of the standard protocols for preparing the copper foil substrate for growing graphene or other 2D materials. PMID- 23942279 TI - Microfluidic isolation of highly pure embryonic stem cells using feeder-separated co-culture system. AB - Engineered artificial tissues from stem cells show great potential in regenerative medicine, disease therapies and organ transplantation. To date, stem cells are typically co-cultured with inactivated feeder layers to maintain their undifferentiated state, and to ensure reliable cell purity. Herein, we propose a novel microfabricated approach for feeder-separated coculture of mouse embryonic stem (mES) cells on polydimethylsiloxane (PDMS) porous membrane-assembled 3D microdevice. Normal mouse embryonic fibroblasts (mEFs) without inactivation were specifically co-cultured with mES cells, resulting in the formation of mES cell colonies on spatially controlled co-culture with feeder layers. An excellent undifferentiated state was confirmed by the expressions of Nanog, octamer binding protein 4 (Oct-4) and alkaline phosphatase (ALP) after 5 days culture. As a result, with the significant advantages of efficiency and simplicity, pure mES cell populations (a purity of 89.2%) from mEFs co-cultures were easily collected without any further purification or separation. PMID- 23942280 TI - Formation of nitrogen-doped graphene nanoscrolls by adsorption of magnetic gamma Fe2O3 nanoparticles. AB - Graphene nanoscrolls are Archimedean-type spirals formed by rolling single-layer graphene sheets. Their unique structure makes them conceptually interesting and understanding their formation gives important information on the manipulation and characteristics of various carbon nanostructures. Here we report a 100% efficient process to transform nitrogen-doped reduced graphene oxide sheets into homogeneous nanoscrolls by decoration with magnetic gamma-Fe2O3 nanoparticles. Through a large number of control experiments, magnetic characterization of the decorated nanoparticles, and ab initio calculations, we conclude that the rolling is initiated by the strong adsorption of maghemite nanoparticles at nitrogen defects in the graphene lattice and their mutual magnetic interaction. The nanoscroll formation is fully reversible and upon removal of the maghemite nanoparticles, the nanoscrolls return to open sheets. Besides supplying information on the rolling mechanism of graphene nanoscrolls, our results also provide important information on the stabilization of iron oxide nanoparticles. PMID- 23942281 TI - Genetic architecture of survival and fitness-related traits in two populations of Atlantic salmon. AB - The additive genetic effects of traits can be used to predict evolutionary trajectories, such as responses to selection. Non-additive genetic and maternal environmental effects can also change evolutionary trajectories and influence phenotypes, but these effects have received less attention by researchers. We partitioned the phenotypic variance of survival and fitness-related traits into additive genetic, non-additive genetic and maternal environmental effects using a full-factorial breeding design within two allopatric populations of Atlantic salmon (Salmo salar). Maternal environmental effects were large at early life stages, but decreased during development, with non-additive genetic effects being most significant at later juvenile stages (alevin and fry). Non-additive genetic effects were also, on average, larger than additive genetic effects. The populations, generally, did not differ in the trait values or inferred genetic architecture of the traits. Any differences between the populations for trait values could be explained by maternal environmental effects. We discuss whether the similarities in architectures of these populations is the result of natural selection across a common juvenile environment. PMID- 23942282 TI - Moderate exercise restores pancreatic beta-cell function and autonomic nervous system activity in obese rats induced by high-fat diet. AB - BACKGROUND/AIMS: Metabolic syndrome has been identified as one of the most significant threats to human health in the 21(st) century. Exercise training has been shown to counteract obesity and metabolic syndrome. The present study aimed to investigate the effects of moderate exercise training on pancreatic beta-cell function and autonomic nervous system (ANS) activity in rats fed a high-fat diet (HFD). METHODS: Weaning rats were divided into four groups: rats fed a standard chow or HFD (sedentary, Control-SED and HFD-SED; or exercised, Control-EXE and HFD-EXE, respectively). Exercised rats ran (from 21- to 91-days-old) for 60 minutes (3 times/week) over a 10-week period. Glucose and insulin tolerance tests were performed. Pancreatic islets were isolated to study glucose-induced insulin secretion (GIIS). Parasympathetic and sympathetic nerve electrical signals were measured, and liver samples were processed and histologically analyzed. RESULTS: Exercise prevented obesity, insulin resistance, and liver steatosis as well as improved total cholesterol, ALT, and AST levels. Islets from HFD rats showed insulin hypersecretion which was ameliorated by exercise. Exercise decreased vagal nerve activity in the HFD-EXE group and increased the activity of the sympathetic nervous system in both exercised groups. CONCLUSION: Exercise prevents obesity and liver steatosis and restores pancreatic beta-cell function and ANS activity in HFD-obese rats. PMID- 23942283 TI - Incidence, mechanisms, and severity of match-related collegiate women's soccer injuries on FieldTurf and natural grass surfaces: a 5-year prospective study. AB - BACKGROUND: Numerous injuries have been attributed to playing on artificial turf. Over the past 2 decades, however, newer generations of synthetic turf have been developed to duplicate the playing characteristics of natural grass. Although synthetic turf has been determined to be safer than natural grass in some studies, few long-term studies have been conducted comparing match-related collegiate soccer injuries between the 2 playing surfaces. HYPOTHESIS: Collegiate female soccer athletes do not experience any difference in the incidence, mechanisms, and severity of match-related injuries on FieldTurf and on natural grass. STUDY DESIGN: Cohort study: Level of evidence, 2. METHODS: Female soccer athletes from 13 universities were evaluated over 5 competitive seasons for injury incidence, injury category, time of injury, injury time loss, player position, injury mechanism and situation, primary type of injury, injury grade and anatomic location, field location at the time of injury, injury severity, head and lower extremity trauma, cleat design, turf age, and environmental factors. In sum, 797 collegiate games were evaluated for match-related soccer injuries sustained on FieldTurf or natural grass during 5 seasons. RESULTS: Overall, 355 team games (44.5%) were played on FieldTurf versus 442 team games (55.5%) on natural grass. A total of 693 injuries were documented, with 272 (39.2%) occurring during play on FieldTurf and 421 (60.8%) on natural grass. Multivariate analysis per 10 team games indicated a significant playing surface effect: F2,690 = 6.435, P = .002, n-beta = .904. A significantly lower total injury incidence rate (IIR) of 7.7 (95% confidence interval [CI], 7.2-8.1) versus 9.5 (95% CI, 9.3-9.7) (P = .0001) and lower rate of substantial injuries, 0.7 (95% CI, 0.5-1.0) versus 1.5 (95% CI, 1.2-1.9) (P = .001), were documented on FieldTurf versus natural grass, respectively. Analyses also indicated significantly less trauma on FieldTurf when comparing injury time loss, player position, injury grade, injuries under various field conditions and temperatures, cleat design, and turf age. CONCLUSION: Although similarities existed between FieldTurf and natural grass during competitive match play, FieldTurf is a practical alternative when comparing injuries in collegiate women's soccer. It must be reiterated that the findings of this study may be generalizable to only collegiate competition and this specific artificial surface. PMID- 23942284 TI - Multiple channeling improves the structural integrity of rotator cuff repair. AB - BACKGROUND: Multiple channeling is a straightforward additional procedure for rotator cuff repair that creates multiple channels in the greater tuberosity, through which bone marrow of the proximal humerus communicates with the repair site. PURPOSE: To investigate the effect of multiple channeling on clinical and structural outcomes of arthroscopic rotator cuff repair. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 124 patients with a full thickness rotator cuff tear were included in the study. Fifty-seven patients underwent arthroscopic rotator cuff repair with multiple channeling (the multiple channeling group) and 67 without it (the conventional group). Analysis of surface markers was performed to characterize the cells recruited by multiple channeling using flow cytometry. Clinical outcomes were evaluated preoperatively and at a minimum of 2 years after surgery (average, 36.79 +/- 13.69 months) with respect to pain, range of motion, muscle strength, overall satisfaction, and commonly used functional scores. At a minimum of 9 months after surgery, structural integrity was assessed by magnetic resonance imaging or computed tomography arthrography. RESULTS: Mesenchymal stem cells (MSCs) positive for CD73, CD90, and CD105 and negative for CD45 could be isolated and cultured from bone marrow mononuclear cells of the proximal humerus. Clinical outcomes, including pain, range of motion, strength, overall satisfaction, and functional scores, showed no statistical difference between the 2 groups (all P > .05). The retear rate of the multiple channeling group (22.2%) was significantly lower than that of the conventional group (45.2%) (P = .023). CONCLUSION: The findings of the study showed that multiple channeling significantly decreased the retear rate after arthroscopic rotator cuff repair, probably via the recruitment of endogenous MSCs from the proximal humerus. Although the results did not show significant differences in the clinical outcomes between the 2 groups, better clinical outcomes might be anticipated in the multiple channeling group via improved structural integrity in a long-term follow-up. PMID- 23942285 TI - Treatment outcomes of single- versus double-row repair for larger than medium sized rotator cuff tears: the effect of preoperative remnant tendon length. AB - BACKGROUND: In rotator cuff repair, no practical guidelines exist for deciding which technique is the most beneficial to outcomes. PURPOSE: To determine which of 2 repair techniques, the single-row (SR) and double-row suture bridge (DR-SB) methods, leads to better therapeutic outcomes in terms of remnant tendon length in patients with larger than medium-sized cuff tears. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Remnant tendon length, muscle atrophy, and fatty degeneration were measured on preoperative magnetic resonance imaging (MRI) in 78 patients with larger than medium-sized rotator cuff tears who were available for follow-up MRI. There were 30 patients with remnant tendons <10 mm in length (group 1) and 48 with remnant tendons >=10 mm in length (group 2). In group 1, the SR technique was performed on 17 patients and the DR-SB technique on 13 patients. In group 2, the SR technique was performed on 16 patients and the DR-SB technique on 32 patients. The mean follow-up period for all patients was 26.6 months (range, 24-42 months). Clinical outcomes were evaluated using the University of California, Los Angeles (UCLA), Constant, and American Shoulder and Elbow Surgeons (ASES) scores. RESULTS: In group 1, there was 1 retear (6%) with the SR repair and 6 (46%) with the DR-SB repair. In group 2, there were 3 retears (19%) with the SR repair and 2 (6%) with the DR-SB repair. The retear rate was significantly higher in patients with the DR-SB repair in group 1 (P = .025), while there was no significant difference between the 2 techniques in group 2 (P = .316). The UCLA and Constant scores were significantly higher in patients with the SR repair in group 1 (P = .02 and P = .029, respectively), and the UCLA and ASES scores were significantly higher in patients with the DR-SB repair in group 2 (P < .001 and P = .001, respectively). CONCLUSION: Remnant tendon length should be considered to improve repair integrity. The SR technique may provide superior rotator cuff integrity when remnant tendons are <10 mm in length. PMID- 23942286 TI - Effect of postoperative repair integrity on health-related quality of life after rotator cuff repair: healed versus retear group. AB - BACKGROUND: Although rotator cuff repair is performed to improve health-related quality of life (HRQL) by reducing pain and improving shoulder function, it has not been clearly demonstrated that HRQL is improved in retear cases. PURPOSE: To compare HRQL outcomes after rotator cuff repair between patients with healed cuffs and those with retears using the Short Form-36 Health Survey (SF-36). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 81 patients who underwent rotator cuff repair were enrolled in this study. There were 56 patients in the healed group and 25 patients in the retear group. The mean age at the time of surgery was 56 years (range, 35-73 years) in the healed group and 59.7 years (range, 45-74 years) in the retear group. The mean follow-up period was 29.7 months (range, 14-95 months) and 26.4 months (range, 13-101 months) in the healed and retear groups, respectively. RESULTS: At final follow-up, the SF-36 scores for physical and mental component summaries (PCS and MCS, respectively) revealed significant improvement, from 36.6 to 51.2 (PCS) and 34.4 to 51.6 (MCS) in the healed group (P < .0001 in both cases) and from 34.2 to 49.4 (PCS) and 33.4 to 53.2 (MCS) in the retear group (P < .0001 in both cases). Mean scores on the SF 36 subscale for role limitations because of physical health problems (RP) were 52.3 in the healed group and 50.6 in the retear group. The RP and PCS scores were significantly higher in the healed group (P = .007 and P = .025, respectively). All domains and component summaries also had a fair to moderate correlation (range, 0.296-0.496) with the SF-36 score. CONCLUSION: Although clinical shoulder outcome measures (University of California, Los Angeles [UCLA] and American Shoulder and Elbow Surgeons [ASES] scores) and all dimensions of the SF-36 showed significant improvement in both groups after rotator cuff repair, scores were significantly higher in the healed group on RP and PCS of the SF-36 as well as on the UCLA and ASES. There was no significant difference in MCS scores between the 2 groups. Despite similar improvements in the MCS scores, there were apparent objective differences between the groups. The values were statistically significant but clinically not significant for some of these measures. PMID- 23942288 TI - A direct comparison of visual discrimination of shape and size on a large range of aspect ratios. AB - Participants viewed pairs of ellipses differing in size and aspect ratio (short axis divided by long axis length). In separate experiments with identical stimuli participants were asked to indicate the larger or the more circular ellipse of the pair. First, the size discrimination thresholds decreased with an increase in the circularity of the ellipses. Second, size discrimination thresholds were lower than aspect ratio thresholds, except for the circle and more elongated ellipses where both were similar. Third, there was also an effect of size on aspect ratio discrimination such that larger stimuli appeared more circular. PMID- 23942287 TI - Epicutaneous patch test--a new diagnostic option to prevent the rejection of silicone-covered cochlear implants in children. AB - OBJECTIVES: Cochlear implantation (CI) is a revolutionary method for hearing rehabilitation in patients with severe or profound sensorineural hearing loss. One of the surgical complications may be the necrosis of the skin flap above the receiver-stimulator coil, resulting in device extrusion. Our aim was to find the plausible causes of the silicone covered implant rejection. PATIENTS AND METHODS: Authors present four cases of cochlear implant rejection, briefly describe their dermato-surgical solutions and analyse their innovative method - the epicutanoeus patch testing with silicone samples. RESULTS: They observed positive skin reaction in three of the four cases. CONCLUSION: Authors analyse the applicability and results of their surgical solutions and the epicutaneous testing in connection with the prevention of skin flap necrosis and rejection of silicone-covered cochlear implants. PMID- 23942289 TI - Texture sparseness, but not local phase structure, impairs second-order segmentation. AB - Texture boundary segmentation is typically thought to reflect a comparison of differences in Fourier energy (i.e. low-order texture statistics) on either side of a boundary. However in a previous study (Arsenault, Yoonessi, & Baker, 2011) we showed that the distribution of energy within a natural texture (i.e. its higher-order statistical structure) also influences segmentation of contrast boundaries. Here we examine the influence of specific higher-order texture statistics on segmentation of contrast- and orientation-defined boundaries. Using naturalistic synthetic textures to manipulate the sparseness, global phase structure, and local phase alignments of carrier textures, we measure segmentation thresholds based on forced-choice judgments of boundary orientation. We find a similar pattern of results for both contrast and orientation boundaries: (1) randomizing all structure by globally phase scrambling the texture reduces segmentation thresholds substantially, (2) decreasing sparseness also reduces thresholds, and (3) removing local phase alignments has little or no effect on segmentation thresholds. We show that a two-stage filter model with an intermediate compressive nonlinearity and expansive output nonlinearity can account for these data using synthetic textures. Furthermore, the model parameter fits obtained using synthetic textures also predict the segmentation thresholds presented in Arsenault, Yoonessi, and Baker (2011) for natural and phase scrambled natural texture carriers. PMID- 23942290 TI - Refractory coeliac disease. AB - PURPOSE OF REVIEW: Concept of refractory coeliac disease (RCD) emerged in the past decade and refers to persistence of malnutrition and intestinal villous atrophy for more than 1 year strict gluten-free diet in coeliac patients. Diagnosis of this condition remains difficult and conditions treatment and follow up. RECENT FINDINGS: RCD has been subdivided into two subgroups according to the normal [type I RCD (RCDI)] or abnormal phenotype of intraepithelial lymphocytes [type II RCD (RCDII)]. RCDII is considered as a low-grade intraepithelial lymphoma and has a very poor prognosis, leading to intractable ulcerative jejunitis, gastrointestinal and extra-intestinal dissemination of the abnormal intraepithelial lymphocytes, and to their frequent transformation into a high grade invasive lymphoma. SUMMARY: Herein, we review here the distinctive diagnostic features of RCDI and RCDII, the risk of developing overt lymphoma and different therapeutic approaches. PMID- 23942291 TI - Refractory Hodgkin lymphoma. AB - PURPOSE OF REVIEW: Despite the advances in the treatment of Hodgkin Lymphoma, patients with refractory disease still have a poor prognosis. Hodgkin Lymphoma can be refractory at first diagnosis or might become refractory later in the course of treatment. Both situations represent a therapeutic challenge. RECENT FINDINGS: Intensified chemotherapy with BEACOPP escalated has been evaluated in early unfavourable and advanced Hodgkin Lymphoma and led to an improved tumour control and reduced rates of refractory disease. Furthermore, there is growing evidence for the role of tandem autologous transplant in breaking refractory disease. For patients relapsing after autologous transplant, more recent analyses have reported outcome and defined risk factors. The antibody drug conjugate brentuximab vedotin is a new, highly effective therapeutic option for these patients. Dose-reduced allogeneic transplant is a therapeutic alternative for patients relapsing after autologous transplant, but induction of a remission is the prerequisite for a successful allogeneic transplant. Brentuximab vedotin has been evaluated as a bridge to allogeneic transplant for patients refractory to conventional treatment. SUMMARY: Recent therapeutic advances have improved the prognosis of Hodgkin Lymphoma by prevention or successful treatment of refractory disease. The use of new drugs such as brentuximab vedotin will hopefully further increase the cure rates. PMID- 23942292 TI - The role of Helicobacter pylori eradication in the treatment of diffuse large B cell and marginal zone lymphomas of the stomach. AB - PURPOSE OF REVIEW: This review is focused on the effect of Helicobacter pylori eradication with antibiotics in patients with primary gastric lymphomas of indolent and aggressive nature. RECENT FINDINGS: Gastrointestinal lymphoma is the most common form of extranodal lymphoma, involving primarily the stomach in 60 75% of cases. The most common histological subtypes are diffuse large B-cell lymphoma (DLBCL) and marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)-type. H. pylori infection has been implicated in the pathogenesis of gastric MALT lymphoma; its role in gastric DLBCL remains controversial. Recently, international guidelines established that patients with gastric MALT lymphoma should be treated with upfront H. pylori-eradicating antibiotic therapy and that residual microscopic or molecular disease does not need for additional antiblastic treatment. The excellent prognosis of patients with gastric DLBCL managed with conservative chemo-radiotherapy led some investigators to test H. pylori eradication as exclusive treatment in prospective trials, keeping chemo-radiotherapy for unresponsive patients. This conservative strategy was well tolerated and active in patients with limited-stage DLBCL (+/ MALT areas) of the stomach. SUMMARY: H. pylori eradication is a suitable strategy as exclusive upfront treatment for both patients with MALT-type lymphomas or with DLBCL of the stomach. Additional trials are needed to elucidate related controversial issues. PMID- 23942293 TI - Pathology of lymphoma in HIV. AB - PURPOSE OF REVIEW: HIV-infected individuals have a greatly increased risk of developing malignancies, even when HIV infection is successfully controlled with antiretrovirals. Non-Hodgkin's lymphoma is considered an AIDS-defining entity, and this disease is currently the most common type of cancer in HIV-infected individuals in the USA and Europe. Here, we describe the different types of lymphomas occurring in individuals with AIDS, and the most relevant pathologic features helpful for histologic and immunohistochemical diagnosis. RECENT FINDINGS: The incidence of some AIDS-related lymphoma subtypes has changed since the introduction of combined antiretroviral therapy, and some of the diagnostic methodologies have evolved. New biomarkers of disease have been identified, which may be useful for diagnosis. SUMMARY: Better pathological classification strategies and deeper molecular understanding of the different lymphoma subtypes that occur in people with AIDS will begin to allow the transition to more precise diagnosis and targeted treatments. PMID- 23942294 TI - Current questions in HIV-associated lung cancer. AB - PURPOSE OF REVIEW: In this review, we explore current questions regarding risk factors contributing to frequent and early onset of lung cancer among populations with HIV infection, treatment, and outcomes of lung cancer in HIV-infected patients as well as challenges in a newly evolving era of lung cancer screening. RECENT FINDINGS: Lung cancer, seen in three-fold excess in HIV-infected populations, has become the most common non-AIDS defining malignancy in the highly active antiretroviral therapy era. HIV-associated lung cancer appears to be associated with young age at diagnosis, cigarette smoking, advanced stage at presentation, and a more aggressive clinical course. There is no unified explanation for these observations, and aside from traditional risk factors, HIV related immunosuppression and biological differences might play a role. In addition to smoking cessation interventions, screening and early cancer detection in HIV-infected populations are of high clinical importance, although evidence supporting lung cancer screening in this particularly high-risk subset is currently lacking, as are prospective studies of lung cancer therapy. SUMMARY: There is an urgent need for prospective clinical trials in HIV-associated lung cancer to improve understanding of lung cancer pathogenesis and to optimize patient care. Several clinical trials are in progress to address questions in cancer biology, screening, and treatment for this significant cause of mortality in persons with HIV infection. PMID- 23942295 TI - Screening guidelines for non-AIDS defining cancers in HIV-infected individuals. AB - PURPOSE OF REVIEW: The growing burden of non-AIDS defining malignancies (non ADMs) among people living with HIV/AIDS (PLWHA) highlights the need for cancer prevention and early detection. In this article, we propose screening guidelines for non-ADMs in PLWHA. RECENT FINDINGS: A number of recent findings may help direct cancer screening guidelines in PLWHA. Screening for lung cancer with low dose helical chest computerized tomography (LDCT) in the National Lung Screening Trial data demonstrated a decrease in lung cancer and all-cause mortality. Recent studies have demonstrated a favorable experience among PLWHA with liver transplantation. Overdiagnosis is common with breast and prostate cancer screening. Anal cancer rates were substantially higher for HIV-infected MSM, other men and women than for HIV-uninfected individuals. SUMMARY: Screening recommendations for the general population can be applied to PLWHA patients for breast, colon and prostate cancer. Screening for lung cancer with LDCT could be considered in PLWHA at risk. American Association for the Study of Liver Diseases screening recommendations with biennial ultrasonography may be applied to at-risk PLWHA for hepatocellular carcinoma. All HIV-infected adults should be offered anal cancer screening as part of clinical care at specialized centres. PMID- 23942296 TI - Psychological consequences of cancer screening in HIV. AB - PURPOSE OF REVIEW: There is a growing awareness of the increase in non-AIDS defining cancers (NADC) in the HIV-infected population. Cancer screening is one means of reducing morbidity and mortality, but such screening may have psychological consequences across those with high and low-risk results, such as increased anxiety, worry and potential behavior change like increased self examination or medical follow-up. This review examines the literature on psychological consequences of screening for NADC in HIV-infected populations. RECENT FINDINGS: Anal cancer is the only cancer type in which the psychological consequence of screening has been investigated in HIV-infected populations. Screening increases worry about anal cancer, particularly in those who are younger, have higher baseline anxiety or more symptoms. Participants with low risk results show unrealistic optimism; this is a potential concern as it may lead to unrealistic beliefs about future risk, the need for healthy behaviors or follow-up screening. The lack of standardized screening protocols and programs makes assessing psychological consequences difficult. SUMMARY: More research is needed to determine if HIV populations differ from general population studies. Increased health promotion or symptom awareness is important for NADC with no standardized screening. Screening programs need to be aware of the potential for increased anxiety and worry and provide support as needed. PMID- 23942297 TI - Role of stereotactic radiosurgery in gynecologic cancer. AB - PURPOSE OF REVIEW: This current work offers an opinion on the evidence accumulated in humans regarding stereotactic ablative radiation (SABR) therapy, a favorable option for the treatment of persistent or recurrent metastatic gynecologic cancers. RECENT FINDINGS: SABR precisely and accurately kills cancer cells, making durable disease control possible. This article evaluates SABR's clinical performance and the variations in the main components of SABR technology, such as target localization and radiation beam collimation coupled with respiratory motion tracking, in the context of their contribution to the banked clinical successes in gynecologic radiation oncology. SUMMARY: In an era of patient requests for short radiotherapy courses, SABR now provides well tolerated and efficacious treatment for women with gynecologic cancers. PMID- 23942298 TI - Current controversies in the management of germ cell ovarian tumours. AB - PURPOSE OF REVIEW: Fewer than 70 new cases of malignant ovarian germ cell tumours (MOGCTs) are seen each year in the UK. Because of their rarity, no randomized trials have been reported and many of the advances in management have arisen from adopting practices developed for managing male germ cell tumours (GCTs). Not surprisingly, there have been few important publications related to ovarian germ cell tumuors over the past 2 years. We have therefore included some relevant male germ cell publications. The area in which there is greatest variability in practice globally is in the proportion of patients with stage 1a disease who go on surveillance rather than receiving adjuvant chemotherapy. Although there is increasing agreement about the best management of ovarian GCTs amongst those who treat more than five per year, many patients are still treated by doctors who usually manage epithelial ovarian cancer but rarely see these patients. RECENT FINDINGS: Novel biomarkers including microRNA profiles and DICER1 mutations, identify potential diagnostic and therapeutic targets in this group of tumours. The role of KIT mutation and amplification in the development of ovarian dysgerminoma and the use of Sunitinib, a receptor tyrosine kinase inhibitor with an effect on vascular endothelial growth factor, platelet-derived growth factor and KIT receptors in patients with platinum-resistant GCT, are novel promising approaches. SUMMARY: We will therefore highlight some key differences in management of epithelial and germ cell ovarian tumours. PMID- 23942299 TI - Management of sarcomas of the uterus. AB - PURPOSE OF REVIEW: Uterine sarcomas are rare malignancies accounting for 8-10% of all uterine malignancies, but are significantly more aggressive and have worse prognosis. Management of uterine sarcomas including leiomyosarcoma (LMS), endometrial stromal sarcoma, high-grade undifferentiated sarcoma and adenosarcoma is reviewed. RECENT FINDINGS: Uterine carcinosarcomas are staged and treated similarly to high-grade epithelial endometrial carcinomas and are no longer considered uterine sarcomas. Gemcitabine/docetaxel with doxorubicin holds promise for the treatment of LMS. A recently developed nomogram was demonstrated to predict disease recurrence in patients with LMS which may allow us to identify a subset of patients who are likely to recur and target this population for adjuvant systemic therapy. Cytogenetic abnormalities have been identified that allow differentiation of endometrial stromal sarcomas from high-grade undifferentiated uterine sarcomas which may be useful in pathologically difficult cases. SUMMARY: Uterine sarcomas are a heterogeneous group of tumors. To date, limited advancements have been made in discovering targeted therapies to these tumors. Chemotherapy with gemcitabine/docetaxel followed by doxorubicin holds promise in the treatment of LMS. Given the rarity of these tumors and the lack of clinical trials to guide management, patients with uterine sarcomas should be encouraged to enroll on clinical trials. PMID- 23942300 TI - Clear cell cancer of the ovary. AB - PURPOSE OF REVIEW: Recent discoveries have demonstrated that ovarian cancer is actually composed of multiple separate diseases. Clear cell cancer is an important example. This review will describe the unique biology of clear cell carcinoma, its novel molecular features, and the recent translation of this into new therapeutic approaches. RECENT FINDINGS: Clear cell cancer of the ovary is now recognized as a unique disease. Recent work has shown that a subset of clear cell cancers evolve from endometriosis. The oxidative stress conditions found within endometriotic lesions are likely to contribute to the transformation process. Molecular alterations within clear cell cancers include unique cytokine expression patterns and c-met amplification. Clear cell-specific clinical trials based upon these biologic discoveries have been designed and are presently active. SUMMARY: These studies provide substantive support for a unique clinical management of clear cell cancer of the ovary. Future research will exploit the molecular pathways identified in these tumors in an effort to provide more effective therapies. Presently, agents that target angiogenesis or cellular metabolism would be reasonable therapeutic approaches to these tumors. PMID- 23942301 TI - Angiogenesis as a target for the treatment of ovarian cancer. AB - PURPOSE OF REVIEW: Angiogenesis has been validated as a target in ovarian cancer through four randomized trials that have reported improved progression-free survival (PFS) in patients with ovarian cancer whose conventional treatment was supplemented with concurrent and maintenance administration of the antivascular endothelial growth factor (VEGF) antibody, bevacizumab. These trials [the International Collaborative Ovarian Neoplasm Group trial (ICON7), the Gynecologic Oncology Group trial (GOG218), OCEANS and AURELIA] have shown that the tumour vasculature is a valid target throughout the lifetime of patients with ovarian cancer. This review seeks to address some of the remaining questions surrounding the optimal strategy for the use of bevacizumab in ovarian cancer. RECENT FINDINGS: The first-line trials, ICON7 and GOG218, showed improvements in PFS and in the case of ICON7, an early analysis reported increased overall survival in a predefined group of patients at high risk of disease progression. Trials in recurrent disease, OCEANS and AURELIA, also showed improvements in PFS, raising questions about whether VEGF-inhibiting agents should be confined to first-line therapy, second-line therapy or both. SUMMARY: Both the first-line trials stopped maintenance bevacizumab after 12 and 15 months, respectively; yet, current data suggest that maintenance therapy should continue at least until progression. In addition, current research is focussing on the identification of predictive biomarkers for VEGF inhibitors and candidates have been identified. Thus, the true clinical benefit from VEGF pathway inhibitors in the first-line treatment of ovarian cancer is likely to increase over the next few years. PMID- 23942302 TI - Management of the late effects of treatments for gynecological cancer. AB - PURPOSE OF REVIEW: As the number of gynecologic cancer survivors grows, there is an increased awareness and need for effective therapy for late side-effects caused by cancer treatments. Several treatment modalities are used to treat gynecologic malignancies, including surgery, radiotherapy, and chemotherapy. Each modality can be responsible for causing late-term side-effects. RECENT FINDINGS: There has been an increased awareness of the late detrimental side-effects of cancer treatment, mostly by the use of patient-generated surveys. Effective ways to treat and ameliorate the late side-effects have lagged behind the ability to describe and categorize these effects on patient's quality of life. SUMMARY: This review will highlight the recent studies to help the clinician caring for gynecologic cancer survivors in recognizing and treating the late effects of cancer therapy. PMID- 23942303 TI - WHO Classification of Soft Tissue and Bone, fourth edition: summary and commentary. PMID- 23942304 TI - Current world literature. Lymphoma; cancer in AIDS; gynecologic cancer. PMID- 23942306 TI - Sixty-four-slice multidetector computerized tomography in the evaluation of transmesenteric internal hernias following Roux-en-Y bariatric surgery. AB - OBJECTIVE: To evaluate the accuracy of 64-slice multidetector computerized tomography (MDCT) in the detection of transmesenteric internal hernias in patients following Roux-en-Y gastric bypass (RYGB) for bariatric surgery patients. SUBJECTS AND METHODS: This retrospective study was performed on post bariatric RYGB patients presenting with signs and symptoms suggestive of internal hernias at our institution from the period of April 2010 until March 2012. The patients who had symptoms suggestive of internal hernia had undergone 64-slice MDCT. All the patients who on CT examination were found to have features suggestive of internal hernia were subjected to laparoscopic exploration. RESULTS: Of the 102 patients who had undergone laparoscopic RYGB, 42 (41.2%) were suspected of having internal hernia. Of these, 23 (55%) had CT findings of hernia while the remaining 19 (45%) were considered normal. Of the 23, 21 (91%) patients were confirmed for internal hernia at laparoscopy. The 19 (45%) patients that did not reveal any signs for internal hernia on CT and the 2 patients that were considered normal on laparoscopy were treated conservatively. The sensitivity, specificity and positive and negative predictive values for MDCT in the diagnosis of internal hernias were 100, 90.5, 91 and 91.3% respectively. CONCLUSION: The 64 slice MDCT was accurate in the diagnosis of transmesenteric internal hernias in post-RYGB for bariatric surgery patients. The presence of clustered loops with mesenteric swirl is a reliable indicator of transmesenteric internal hernia. PMID- 23942307 TI - Vaccinia virus outperforms a panel of other poxviruses as a potent oncolytic agent for the control of head and neck squamous cell carcinoma cell lines. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide. Existing therapies for advanced tumors have high failure rates and can have severe consequences in terms of pain, disfigurement, and poor speech and swallowing function. New treatment strategies are needed to improve outcomes for patients suffering with this disease and oncolytic viruses represent a promising approach. METHODS: We infected six well-characterized HNSCC cell lines (Cal27, Detroit562, FaDu, SCC4, SCC15, SCC25), with increasing doses of a panel of poxviruses (including myxoma, vaccinia, raccoonpox and tanapox viruses) modified to express green fluorescence protein to determine which virus was the most effective oncolytic agent in cell-based assays. RESULTS: While myxoma, raccoonpox and tanapox displayed differing efficacy in the panel of cell lines, vaccinia virus was the most potent of the tested poxviruses and was highly effective in controlling cell growth in all cell lines. CONCLUSION: Oncolytic poxviruses, particularly vaccinia virus, were effective in killing HNSCC in vitro and hold promise as potential treatments for patients with HNSCC. PMID- 23942309 TI - Transformers: changing the face of nursing and midwifery in the media. AB - AIM: This paper reports an educational strategy designed to sensitise and empower students about the impact of media representations of nursing and midwifery on their public image. BACKGROUND: Numerous studies continue to reveal that stories about nursing and midwifery presented in the mainstream media are often superficial, stereotypical and demeaning. Inaccurate portrayals of nursing damage our professional reputation with the public and potential consumers. It also sends the wrong message to future nursing students. Images are a powerful conductor of misinformation, suggesting to others that nurses are not important agents for social change. METHODS: In 2012, a small team of academics designed a photography competition and judging process for undergraduate and postgraduate students of nursing and midwifery enrolled at a regional Australian university. RESULTS: The winning entries were photographs of high quality and conveyed rich meaning. They provide an interesting and positive counterpoint to derogatory images often propagated by mainstream media. CONCLUSION: There is benefit in extending this project so that it: appeals to more students, builds leadership skills, leads to wider social change and benefits society. The intention is to develop the process of student engagement as an educational intervention, and explore experiences and outcomes with stakeholders. PMID- 23942308 TI - Heterogeneity and matching of ventilation and perfusion within anatomical lung units in rats. AB - Prior studies exploring the spatial distributions of ventilation and perfusion have partitioned the lung into discrete regions not constrained by anatomical boundaries and may blur regional differences in perfusion and ventilation. To characterize the anatomical heterogeneity of regional ventilation and perfusion, we administered fluorescent microspheres to mark regional ventilation and perfusion in five Sprague-Dawley rats and then using highly automated computer algorithms, partitioned the lungs into regions defined by anatomical structures identified in the images. The anatomical regions ranged in size from the near acinar to the lobar level. Ventilation and perfusion were well correlated at the smallest anatomical level. Perfusion and ventilation heterogeneity were relatively less in rats compared to data previously published in larger animals. The more uniform distributions may be due to a smaller gravitational gradient and/or the fewer number of generations in the distribution trees before reaching the level of gas exchange, making regional matching of ventilation and perfusion less extensive in small animals. PMID- 23942310 TI - Size-fractionated particle number concentrations and daily mortality in a Chinese city. AB - BACKGROUND: Associations between airborne particles and health outcomes have been documented worldwide; however, there is limited information regarding health effects associated with different particle sizes. OBJECTIVES: We explored the association between size-fractionated particle number concentrations (PNCs) and daily mortality in Shenyang, China. METHODS: We collected daily data on cause specific mortality and PNCs for particles measuring 0.25-10 MUm in diameter between 1 December 2006 and 30 November 2008. We used quasi-Poisson regression generalized additive models to estimate associations between PNCs and mortality, and we used natural spline smoothing functions to adjust for time-varying covariates and long-term and seasonal trends. RESULTS: Mean numbers of daily deaths were 67, 32, and 7 for all natural causes, cardiovascular diseases, and respiratory diseases, respectively. Interquartile range (IQR) increases in PNCs for particles measuring 0.25-0.50 MUm were significantly associated with total and cardiovascular mortality, but not respiratory mortality. Effect estimates were larger for PNCs during the warm season than the cool season, and increased with decreasing particle size. IQR increases in PNCs of 0.25-0.28 MUm, 0.35-0.40 MUm, and 0.45-0.50 MUm particles were associated with 2.41% (95% CI: 1.23, 3.58%), 1.31% (95% CI: 0.52, 2.09%), and 0.45% (95% CI: 0.04, 0.87%) higher total mortality, respectively. Associations were generally stable after adjustment for mass concentrations of ambient particles and gaseous pollutants. CONCLUSIONS: Our findings suggest that particles < 0.5 MUm in diameter may be most responsible for adverse health effects of particulate air pollution and that adverse health effects may increase with decreasing particle size. PMID- 23942311 TI - Strain mapping in selected area electron diffraction method combining a Cs corrected TEM with a stage scanning system. AB - A novel strain mapping method with high spatial resolution is proposed on the basis of the selected area electron diffraction. It consists of a Cs-corrected transmission electron microscope (TEM) and a stage scanning system. The Cs corrected TEM sufficiently narrows a selected area aperture without image selection error and enables us to obtain diffraction patterns from selected nanometer-scale regions with a parallel beam. The diffraction spots are very sharp due to the parallel beam, thus facilitating the strain measurement. The stage scanning system for controlling the sample stage with piezoelectric actuators can scan an electron beam over an area without changing the electron beam optics. I critically examined the validity and flexibility of this method by using a current strain-induced semiconductor device. PMID- 23942312 TI - Sensitivity of flexural vibration mode of the rectangular atomic force microscope micro cantilevers in liquid to the surface stiffness variations. AB - In this paper, the resonance frequencies and modal sensitivity of flexural vibration modes of a rectangular atomic force microscope (AFM) cantilever immersed in a liquid to surface stiffness variations have been analyzed and a closed-form expression is derived. For this purpose, the Euler-Bernoulli beam theory is used to develop the AFM cantilever model in liquid. Then, an expression for the resonance frequencies of AFM cantilever in liquid is derived and the results of the derived expression are compared with the experimental measurements. Based on this expression, the effect of the surface contact stiffness on flexural mode of a rectangular AFM cantilever in a fluid is investigated and compared with the case that AFM cantilever operates in the air. The results show that in the low surface stiffness, the first mode is the most sensitive mode and the best image contrast is obtained by excitation this mode, but by increasing the sample surface stiffness the higher modes have better image contrast. In addition, comparison between modal sensitivities in air and liquid shows that the resonance frequency shifts in the air are greater than the shifts in the fluid, which means that for the similar surface stiffness the image contrast in air, is better than liquid. PMID- 23942313 TI - Transfer-free synthesis of multilayer graphene using a single-step process in an evaporator and formation confirmation by laser mode-locking. AB - Multilayer graphene is synthesized by a simplified process employing an evaporator in which a target substrate is deposited with a Ni catalyst layer before being heated to grow graphene directly. Carbon atoms adsorbed onto the surface of the Ni source as impurities from the atmosphere are incorporated into the catalyst layer during the deposition, and diffuse toward the catalyst/substrate interface, where they crystallize as graphene with a thickness of less than 2 nm. The need for a transfer process and external carbon supply is eliminated. The graphene is characterized by conventional analysis approaches, including nano-scale visualization and Raman spectroscopy, and utilizing photonics, graphene-functionalized passive laser mode-locking is demonstrated to confirm the successful synthesis of the graphene layer, resulting in an operating center wavelength of 1569.4 nm, a pulse duration of 1.35 ps, and a repetition rate of 31.6 MHz. PMID- 23942314 TI - Towards an understanding of the regulatory mechanisms of totipotency. AB - The 21st century started with an important discovery that a pluripotent stem cell can be induced from differentiated cells by 'simply' introducing a few transcription factors. Because pluripotent embryonic stem cells can be stably maintained in culture and also induced, the mechanisms as to how cells maintain and acquire pluripotency have been extensively interrogated. In contrast, how cells maintain or acquire totipotency and the cell potency that exists in the zygote are still poorly understood. To address this question, it is necessary to capture the features that reside in totipotent cells. Here, we review recent results, which shed light on the unique epigenetic state in totipotent cells, and discuss how totipotency is regulated before finding its way towards pluripotency. PMID- 23942315 TI - Proteomic analysis of cell fate decision. AB - The field of proteomics is progressing at a rapid pace, developing from primarily a specialist technology to a valuable tool in biological research. Importantly, the establishment of mass spectrometry as a quantitative method, miniaturisation of liquid chromatography techniques, and improved sensitivity of mass spectrometric instrumentation now enable near-complete monitoring of cellular proteome dynamics. An increasing number of studies are therefore now applying quantitative proteomics to study proteins and posttranslational modifications in stem cells, to reveal molecular mechanisms and pathways underlying pluripotency, differentiation and reprogramming. PMID- 23942316 TI - General route to ZnO nanorod arrays on conducting substrates via galvanic-cell based approach. AB - Wurtzite ZnO nanorod exhibits many unique properties, which make it promising for various optoelectronic applications. To grow well-aligned ZnO nanorod arrays on various substrates, a seed layer is usually required to improve the density and vertical alignment. The reported works about seedless hydrothermal synthesis either require special substrates, or require external electrical field to enhance the ZnO nucleation. Here, we report a general method for the one-pot synthesis of homogenous and well-aligned ZnO nanorods on common conducting substrates without a seed layer. This method, based on the galvanic-cell structure, makes use of the contact potential between different materials as the driving force for ZnO growth. It is applicable to different conducting substrates at low temperature. More importantly, the as-grown ZnO nanorods show enhanced photoelectric response. This unique large scale low-temperature processing method could be of great importance for the application of ZnO nanostructures. PMID- 23942318 TI - Individual music therapy for mental health care clients with low therapy motivation: multicentre randomised controlled trial. AB - BACKGROUND: Music therapy (MT) has been shown to be efficacious for mental health care clients with various disorders such as schizophrenia, depression and substance abuse. Referral to MT in clinical practice is often based on other factors than diagnosis. We aimed to examine the effectiveness of resource oriented MT for mental health care clients with low motivation for other therapies. METHOD: This was a pragmatic parallel trial. In specialised centres in Norway, Austria and Australia, 144 adults with non-organic mental disorders and low therapy motivation were randomised to 3 months of biweekly individual, resource-oriented MT plus treatment as usual (TAU) or TAU alone. TAU was typically intensive (71% were inpatients) and included the best combination of therapies available for each participant, excluding MT. Blinded assessments of the Scale for the Assessment of Negative Symptoms (SANS) and 15 secondary outcomes were collected before randomisation and after 1, 3 and 9 months. Changes were analysed on an intention-to-treat basis using generalised estimating equations in longitudinal linear models, controlling for diagnosis, site and time point. RESULTS: MT was superior to TAU for total negative symptoms (SANS, d = 0.54, p < 0.001) as well as functioning, clinical global impressions, social avoidance through music, and vitality (all p < 0.01). CONCLUSION: Individual MT as conducted in routine practice is an effective addition to usual care for mental health care clients with low motivation. PMID- 23942321 TI - Staphylococcal protein A, Panton-Valentine leukocidin and coagulase aggravate the bone loss and bone destruction in osteomyelitis. AB - BACKGROUND/AIMS: Osteomyelitis is a debilitating infectious disease of the bone which is predominantly caused by Staphylococcus aureus (S. aureus). The purpose of this study was to investigate the role of the S. aureus virulence factors, i.e. protein A (SpA), Panton-Valentine leukocidin (PVL) and coagulase (Coa) on osteomyelitis. METHODS: The effect of SpA, PVL and Coa on osteoblasts was studied through the following aspects including osteoblast proliferation, apoptosis, bone formation, bone mineralization and RANK-L expression. S. aureus overexpressing PVL, SpA or Coa was constructed and used to study the role of PVL, SpA and Coa, respectively. S. aureus silencing PVL, SpA or Coa was also constructed and used for reversing verification. Osteoblast proliferation was detected by MTT tetrazolium dye reduction assay. Apoptosis was determined by Annexin V-FITC staining. The levels of pro-caspase 3, cleaved-caspase 3, pro-caspase 9 and cleaved-caspase 9 were detected by western blot. Bone formation markers including collagen I, osteopontin and osteocalcin were detected by real time RT-PCR. Alkaline phosphatase activity was measured by adding p-nitrophenyl phosphate as a phosphatase substrate. Von kossa stain and alizarin red stain were applied for determining phosphate and calcium deposition, respectively. The RANK-L expression was tested by ELISA. RESULTS: PVL, SpA and Coa inhibited osteoblast proliferation, induced osteoblast apotosis, prohibited bone formation and mineralization and upregulated RANK-L expression. CONCLUSIONS: PVL, SpA and Coa play a critical role on bone loss and bone destruction of osteomyelitis. PMID- 23942319 TI - Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults. AB - BACKGROUND: Liraglutide 3.0 mg, with diet and exercise, produced substantial weight loss over 1 year that was sustained over 2 years in obese non-diabetic adults. Nausea was the most frequent side effect. OBJECTIVE: To evaluate routinely collected data on nausea and vomiting among individuals on liraglutide and their influence on tolerability and body weight. DESIGN: A randomized, placebo-controlled, double-blind 20-week study with an 84-week extension (sponsor unblinded at 20 weeks, open-label after 1 year) in eight European countries (Clinicaltrials.gov: NCT00422058). SUBJECTS: After commencing a 500-kcal/day deficit diet plus exercise, 564 participants (18-65 years, body mass index (BMI) 30-40 kg m(-2)) were randomly assigned (after a 2-week run-in period) to once daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg), placebo or open-label orlistat (120 mg * 3 per day). After 1 year, participants on liraglutide/placebo switched to liraglutide 2.4 mg, and subsequently, to liraglutide 3.0 mg (based on 20-week and 1-year results, respectively). RESULTS: The intention-to-treat population comprised 561 participants (n=90-98 per arm, age 45.9+/-10.3 years, BMI 34.8+/-2.7 kg m(-2) (mean+/-s.d.)). In year 1, more participants reported ?1 episode of nausea/vomiting on treatment with liraglutide 1.2-3.0 mg (17-38%) than with placebo or orlistat (both 4%, P?0.001). Most episodes occurred during dose escalation (weeks 1-6), with 'mild' or 'moderate' symptoms. Among participants on liraglutide 3.0 mg, 48% reported some nausea and 13% some vomiting, with considerable variation between countries, but only 4 out of 93 (4%) reported withdrawals. The mean 1-year weight loss on treatment with liraglutide 3.0 mg from randomization was 9.2 kg for participants reporting nausea/vomiting episodes, versus 6.3 kg for those with none (a treatment difference of 2.9 kg (95% confidence interval 0.5-5.3); P=0.02). Both weight losses were significantly greater than the respective weight losses for participants on placebo (P<0.001) or orlistat (P<0.05). Quality-of-life scores at 20 weeks improved similarly with or without nausea/vomiting on treatment with liraglutide 3.0 mg. CONCLUSION: Transient nausea and vomiting on treatment with liraglutide 3.0 mg was associated with greater weight loss, although symptoms appeared tolerable and did not attenuate quality-of-life improvements. Improved data collection methods on nausea are warranted. PMID- 23942320 TI - The Capsaspora genome reveals a complex unicellular prehistory of animals. AB - To reconstruct the evolutionary origin of multicellular animals from their unicellular ancestors, the genome sequences of diverse unicellular relatives are essential. However, only the genome of the choanoflagellate Monosiga brevicollis has been reported to date. Here we completely sequence the genome of the filasterean Capsaspora owczarzaki, the closest known unicellular relative of metazoans besides choanoflagellates. Analyses of this genome alter our understanding of the molecular complexity of metazoans' unicellular ancestors showing that they had a richer repertoire of proteins involved in cell adhesion and transcriptional regulation than previously inferred only with the choanoflagellate genome. Some of these proteins were secondarily lost in choanoflagellates. In contrast, most intercellular signalling systems controlling development evolved later concomitant with the emergence of the first metazoans. We propose that the acquisition of these metazoan-specific developmental systems and the co-option of pre-existing genes drove the evolutionary transition from unicellular protists to metazoans. PMID- 23942322 TI - Simplified protocol for isolation of multipotential NG2 cells from postnatal mouse. AB - BACKGROUND: The functions of NG2 cells have attracted much attention since they were identified. At present, our understanding of their properties and functions is still limited due to the lack of an easy protocol for isolating them from mice. NEW METHOD: In the present study, in postnatal mouse cortical tissue cultures, cell confluence was achieved at DIV 6-8 by frequently changing the medium in the absence of viable neurons, and abundant NG2 cells grew on top of the astrocyte layer before microglia started to thrive. Thus, we developed a simple protocol to separate mouse NG2 cells by shaking the cultures on an orbital shaker at 37 degrees C for only 3-4h. RESULTS: The yield and purity of NG2 cells were sufficiently high, and the cells displayed immunological and electrophysiological phenotypes typical of NG2 cells. They expressed a large delayed-rectifier K+ current (ID) and a transient A-type K+ current (IA) that were electrophysiologically different from astrocytes and neurons. They showed significantly enhanced chemo-attractive migration after application of GABA. They also showed properties of multipotential neuronal precursor cells and were capable of generating oligodendrocytes (54.2+/-8.1%), neurons (up to 13.3+/ 6.8%), and astrocytes (93.9+/-4.3%) under defined conditions. Comparison with Existing Method(s): When compared to other methods available for the isolation of mouse NG2 cells, the procedure we present is simple, relatively fast, and economical. CONCLUSIONS: Overall, we present evidence that this new method for isolating NG2 cells from postnatal mice is simple, economical, and effective. PMID- 23942323 TI - Disease activity only moderately correlates with quality of life impairment in patients with chronic spontaneous urticaria. AB - BACKGROUND: The impact of chronic spontaneous urticaria (CSU) on health-related quality of life (HRQoL) is widely held to be mainly influenced by disease activity and comorbidities. OBJECTIVE: To assess the correlation between disease activity and HRQoL impairment by using validated disease-specific instruments. METHODS: The Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) was translated into Greek and subsequently applied to 110 CSU patients along with the Dermatology Life Quality Index and the Urticaria Activity Score. After the validity and reliability of the Greek CU-Q2oL had been determined, we assessed the relation between disease activity and HRQoL impairment by computing correlations as well as by performing multiple regression analysis. RESULTS: Exploratory factor analysis revealed a six-scale structure of the Greek CU-Q2oL that explained 67.9% of its total variance. The internal consistency was satisfactory with Cronbach's alpha >0.7. Disease activity was the only predictor of quality of life impairment, but it only moderately correlated with the CU-Q2oL total score (r = 0.40, p < 0.0001). CONCLUSION: Our results suggest that there are additional factors to disease activity that are responsible for the pronounced reduction of HRQoL in CSU, and this supports the recommendation to assess and monitor both disease activity and quality of life in CSU patients. PMID- 23942324 TI - 90Y microsphere therapy: does 90Y PET/CT imaging obviate the need for 90Y Bremsstrahlung SPECT/CT imaging? AB - BACKGROUND: Transarterial radioembolization using Y microspheres is a novel therapeutic option for inoperable hepatic malignancies. As these spheres are radiolucent, real-time assessment of their distribution during the infusion process under fluoroscopic guidance is not possible. Bremsstrahlung radiations arising from 90Y have conventionally been used for imaging its biodistribution. Recent studies have proved that sources of 90Y also emit positrons, which can further be used for PET/computed tomography (CT) imaging. This study aimed to assess the feasibility of 90Y PET/CT imaging in evaluating microsphere distributions and to compare its findings with those of Bremsstrahlung imaging. MATERIALS AND METHODS: Thirty-five sessions of 90Y microsphere transarterial radioembolization were performed on 30 patients with hepatic malignancies. 90Y PET/CT imaging was performed within 3 h of therapy. Bremsstrahlung imaging was also performed for each patient. The imaging findings were compared for concordance in the distribution of microspheres. RESULTS: Exact one-to-one correspondence between 90Y PET/CT imaging and 90Y Bremsstrahlung imaging was observed in 97.14% of cases (i.e. in 34/35 cases). Discordance was observed only in one case in which 90Y PET/CT imaging resolved the microsphere uptake in the inferior vena cava tumor thrombus, which was, however, not visualized on Bremsstrahlung imaging. CONCLUSION: There is good concordance in the imaging findings of 90Y PET/CT and 90Y Bremsstrahlung imaging. 90Y PET/CT imaging scores over the conventionally used Bremsstrahlung imaging in terms of better resolution, ease of technique, and comparable image acquisition time. This makes it a preferred imaging modality for assessment of the distribution of 90Y microspheres. PMID- 23942325 TI - 99mTc-MDP SPECT/CT of the spine and sacrum at a multispecialty institution: clinical use, findings, and impact on patient management. AB - OBJECTIVE: The use of technetium-99m methylene diphosphonate single-photon emission tomography/computed tomography (99mTc-MDP SPECT/CT) of the spine and sacrum has increased over the past years; however, there is little information about the optimal clinical role and true clinical impact of this modality. METHODS: All 99mTc-MDP SPECT/CT examinations of the spine and sacrum performed at our large multispecialty institution between 1 January 2008 and 12 April 2012 were identified. The indications, findings, clinical context, and impact on patient management were identified through a retrospective chart review. RESULTS: Of the 212 99mTc-MDP SPECT/CT examinations of the spine and sacrum identified, 191 (90%) were for pain evaluation, 14 (7%) were to assess infection, and seven (3%) were to evaluate a potential malignancy. The most common specific indication was evaluation of facet joint pain in 70/191 (37%) patients, and the most common finding was facet joint activity in 106/212 (50%) patients. Several findings were reported, although facet joint activity was the most frequent. The other findings included costovertebral joint activity, pars interarticularis defects, an osteoid osteoma, a lumbosacral pseudoarticulation, and a postoperative pseudoarthrosis. A resultant change in clinical management was documented in 168/212 (79%) patients. Ninety-two of the 212 (44%) patients had undergone an MRI of the same region for any indication within +/-6 months. CONCLUSION: 99mTc-MDP SPECT/CT of the spine and sacrum is most frequently used for the diagnosis and management of pain. It helps identify several potential pain generators, is often used in patients who have a near-contemporaneous MRI, and has an impact on the procedural and/or conservative management in most patients. In addition, several areas in need of future research to establish the optimal clinical role of this modality were identified. PMID- 23942327 TI - Current considerations in the management of facial nerve palsy. AB - PURPOSE OF REVIEW: Facial nerve palsy is a potentially devastating condition that can arise from many different causes. Appropriate management is complicated by the wide spectrum of clinical presentation and disease severity that characterizes this condition. As such, recent studies have focused on augmenting our understanding of the underlying anatomy and pathophysiology of facial nerve palsy, while also exploring different treatment options. RECENT FINDINGS: There have been a multitude of radiologic investigations that have delineated anatomical considerations pertinent to facial neuropathy, whereas various grading schemes and software programs have been developed to facilitate the clinical assessment of patients. Furthermore, a wide variety of medical and surgical treatment options have been proposed - whereas some are variants of previously described methods, others represent novel approaches. SUMMARY: Appropriate management of facial nerve palsy is dependent on a multitude of factors and must be tailored to patients on an individual basis. The studies summarized in this article highlight the recent advancements geared toward refining the assessment and treatment of patients with facial neuropathy. PMID- 23942328 TI - Acta Biomaterialia Special Issue: 4th Biometal 2012, Maratea, Italy: August 27 September 1, 2012. PMID- 23942326 TI - Domestic radon exposure and risk of childhood cancer: a prospective census-based cohort study. AB - BACKGROUND: In contrast with established evidence linking high doses of ionizing radiation with childhood cancer, research on low-dose ionizing radiation and childhood cancer has produced inconsistent results. OBJECTIVE: We investigated the association between domestic radon exposure and childhood cancers, particularly leukemia and central nervous system (CNS) tumors. METHODS: We conducted a nationwide census-based cohort study including all children < 16 years of age living in Switzerland on 5 December 2000, the date of the 2000 census. Follow-up lasted until the date of diagnosis, death, emigration, a child's 16th birthday, or 31 December 2008. Domestic radon levels were estimated for each individual home address using a model developed and validated based on approximately 45,000 measurements taken throughout Switzerland. Data were analyzed with Cox proportional hazard models adjusted for child age, child sex, birth order, parents' socioeconomic status, environmental gamma radiation, and period effects. RESULTS: In total, 997 childhood cancer cases were included in the study. Compared with children exposed to a radon concentration below the median (< 77.7 Bq/m3), adjusted hazard ratios for children with exposure >= the 90th percentile (>= 139.9 Bq/m3) were 0.93 (95% CI: 0.74, 1.16) for all cancers, 0.95 (95% CI: 0.63, 1.43) for all leukemias, 0.90 (95% CI: 0.56, 1.43) for acute lymphoblastic leukemia, and 1.05 (95% CI: 0.68, 1.61) for CNS tumors. CONCLUSIONS: We did not find evidence that domestic radon exposure is associated with childhood cancer, despite relatively high radon levels in Switzerland. PMID- 23942329 TI - Tissue microarray in a subset of South African patients with DLBCL. AB - Tissue samples from 93 de novo diffuse large B-cell lymphoma patients seen between 1995 and 2009 randomly receiving either standard combination chemotherapy (CHOP, n=48) or the identical program with rituximab (n=45) were subtyped using an investigational immunohistochemical (IHC) based tissue microarray (TMA) and contrasted to the approximately corresponding categories as defined either by Hans and associates using a three marker panel into germinal or non-germinal centre subtypes or by Choi and colleagues with two additional antibodies into germinal centre (GCB) or activated B-cells (ABC). Each of these primary subdivisions was further evaluated for expression of BCL2 and LMO2 both of which are recognised to predicate response. The addition of rituximab to the uniform drug regimen did not show any significant improvement in 5 years overall (63% versus 59%, p 0.68) or event-free survival (42% versus 39%, p 0.94), for CHOP versus R-CHOP comparisons. Similarly no differences were evident in subtype analysis. Interestingly however, when segregated on the Choi criteria, cytotoxic drugs alone showed a non-significant trend in improved survival (74% versus 55%, p 0.32) as well as event-free survival (44% versus 40%, p 0.42) for the germinal centre as opposed to the activated B-cell subtype. Nevertheless not even a small difference could be demonstrated in the presence of the anti CD 20 monoclonal antibody. According to Choi, both regimens (chemotherapy or immunotherapy antibody) revealed similar results to the Hans algorithm on 5 years OS as well as 3 year EFS when comparing GCB versus ABC or non-GCB subgroups. BCL2 and LMO2 marker expression of the respective immunohistochemical (IHC) subtype, despite small sample size, revealed the following. Analysis by Choi criteria on survival for BCL2, no matter for which subsets (GCB or ABC) or treatment modality (chemotherapy with or without the addition of rituximab) showed no difference in 5 years OS or EFS. In contrast, a significant difference for better EFS (p=0.0015) in the BCL2 positive group of the ABC subgroups subtypes treated with rituximab containing chemotherapy. For LMO2 similar results on survival outcome were seen thus showing no difference in 5 years OS or EFS - regardless of subtype or treatment modality. Also here, this was contrasted by better EFS (p=0.039) in the LMO2 positive group of ABC subtypes when treated with the rituximab containing regimen. The use of the IHC based TMA methodology has shown to be a simple, cost effective and a robust alternative to gene expression profiling (GEP) which is currently regarded as the gold standard for the classification in lymphomas. It provides a useful prognostic tool in stratifying DLBCL or other entities in future, even when frozen tissue samples are not available for GEP analysis. With the current budgetary limitations in South African public hospitals chemotherapy protocols for lymphoproliferative disorders exclude agents such as rituximab. Local therapeutic drug committees consider the approximately 15% overall survival benefit seen at 5 years for DLBCL when rituximab is added to combination chemotherapy as too marginal for justifying the arising additional expenses. Accordingly, demonstration that a specific molecular subtype accounts for superior outcome, when using these regimens, is needed. Such an option would provide convincing evidence for the use of immunochemotherapy in a resource constrained setting. PMID- 23942330 TI - Is sentinel lymph node dissection an appropriate standard of care for low-stage endometrial cancers? A review of the literature. AB - BACKGROUND/AIMS: To review the literature and compare detection rates, false negative (FN) rates, and negative predictive values (NPVs) of sentinel lymph node (SLN) biopsy in endometrial cancer to those in breast and vulvar cancer. Secondary objectives were to evaluate techniques of SLN biopsy in endometrial cancer. METHODS: The PubMed database was searched for applicable scientific articles. Detection rates, FN rates, and NPVs were calculated for all studies. Studies were stratified by techniques and compared. RESULTS: Nineteen articles met criteria for this review. The overall detection rates ranged from 62 to 100%, the FN rate ranged from 0 to 50%, and the NPVs ranged from 95 to 100%. There is no technique that is definitively superior to any other with regard to surgical modality, injectant used, injection site, or pathologic techniques. CONCLUSIONS: Studies on SLN biopsy in endometrial cancer have a large range of detection rates and FN rates, and larger studies including more patients with metastatic disease are needed for comparison with breast and vulvar cancers. While no techniques are definitively superior to others, minimally invasive surgery, cervical injection, and pathologic analysis utilizing HE staining, immunohistochemistry, and ultrastaging may be clinically advantageous. PMID- 23942331 TI - Supporting a distributed execution of clinical guidelines. AB - Clinical guidelines (GL) play an important role in medical practice: the one of optimizing the quality of patient care on the basis of evidence based medicine. In order to achieve this goal, the interaction between different agents, who cooperate in the execution of the same GL, is a crucial issue. As a matter of fact, in many cases (e.g. in chronic disorders) the GL execution requires that patient treatment is not performed/completed in the hospital, but is continued in different contexts (e.g. at home, or in the general practitioner's ambulatory), under the responsibility of different agents. In this situation, the correct interaction and communication between the agents themselves is critical for the quality of care, and human resources coordination is a key issue to be addressed by the managers of the involved healthcare services. In this paper we describe how GLARE (Guideline Acquisition, Representation, and Execution), a computerized GL management system, has been extended in order to support such a need. In particular, we have provided: (i) an extension to GL actions representation languages, (ii) proper scheduling and (iii) querying services. By means of these enhancements we aimed at guaranteeing (1) treatment continuity and (2) responsibility assignment support in the various steps of a coordinated and distributed patient care process. We illustrate our approach by means of a practical case study. PMID- 23942332 TI - Noninvasive fetal ECG estimation using adaptive comb filter. AB - This paper describes a robust and simple algorithm for fetal electrocardiogram (FECG) estimation from abdominal signal using adaptive comb filter (ACF). The ACF can adjust itself to the temporal variations in fundamental frequency, which makes it qualified for the estimation of quasi-periodic component from physiologic signal, such as ECG. The validity and performance of the described method are confirmed through experiments on real fetal ECG data. A comparison with the well-known independent component analysis (ICA) method has also been presented. PMID- 23942333 TI - Subsurface-AFM: sensitivity to the heterodyne signal. AB - Applying heterodyne force microscopy (HFM), it has been impressively demonstrated that it is possible to obtain subsurface information: 20 nm large gold nanoparticles that were buried 500 nm deep have been imaged. It is the heterodyne signal that contains the subsurface information. We elucidate, both theoretically and experimentally, the sensitivity to the heterodyne signal as a function of the tip-sample distance. This is crucial information for experiments as the distance, and therefore the sensitivity, is tunable. We show that the amplitude of the heterodyne signal has a local maximum in the attractive part of the tip-sample interaction, before it surprisingly reaches an even higher plateau, when the tip sample interaction is repulsive. This can only be explained by a non-decreasing amplitude of the ultrasonic motion of the tip, although it is in full contact with the surface. We confirm this counterintuitive tip behavior experimentally even on a hard surface like silicon. PMID- 23942334 TI - European accreditation of endometriosis centers of expertise? PMID- 23942335 TI - beta-Blocker use and all-cause mortality of melanoma patients: results from a population-based Dutch cohort study. AB - BACKGROUND: Results from preclinical and observational studies suggest that beta adrenoreceptor inhibition might influence disease progression of melanoma. PATIENTS AND METHODS: Patients ?18years with cutaneous melanoma (Breslow thickness >1mm) registered in the Eindhoven Cancer Registry between January 1, 1998 and December 31, 2010, who were also registered with PHARMO record linkage system (RLS), were eligible. Randomly selected patients using beta-blockers from PHARMO record linkage system (RLS) matched on age and gender served as a control cohort. Adjusted time-dependent and time-fixed Cox proportional hazard models were employed to estimate the hazard ratio of all-cause mortality. Five-year relative survival rates for all-cause mortality were calculated to estimate disease specific survival. RESULTS: 203 of 709 eligible patients used beta blockers after melanoma diagnosis. The use of beta-blockers was not associated with the risk of dying (adjusted hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.55-1.24). Neither duration of exposure nor beta-blocker dosage showed significant influence on survival. Five-year relative survival for beta-blocker users was lower than in non-users amongst melanoma patients (80.9% and 83.7%, respectively) but higher among the beta-blocker control group compared to the general population (101.4%). CONCLUSION: Our results do not show a statistically significant impact of beta-blocker exposure on overall survival of melanoma patients, regardless of the timing, duration or dosage of beta-blocker use. PMID- 23942336 TI - Bcl-wav and the mitochondrial calcium uniporter drive gastrula morphogenesis in zebrafish. AB - Bcl-2 proteins are acknowledged as key regulators of programmed cell death. However, increasing data suggest additional roles, including regulation of the cell cycle, metabolism and cytoskeletal dynamics. Here we report the discovery and characterization of a new Bcl-2-related multidomain apoptosis accelerator, Bcl-wav, found in fish and frogs. Genetic and molecular studies in zebrafish indicate that Bcl-wav and the recently identified mitochondrial calcium uniporter (MCU) contribute to the formation of the notochord axis by controlling blastomere convergence and extension movements during gastrulation. Furthermore, we found that Bcl-wav controls intracellular Ca(2+) trafficking by acting on the mitochondrial voltage-dependent anion channel, and possibly on MCU, with direct consequences on actin microfilament dynamics and blastomere migration guidance. Thus, from an evolutionary point of view, the original function of Bcl-2 proteins might have been to contribute in controlling the global positioning system of blastomeres during gastrulation, a critical step in metazoan development. PMID- 23942338 TI - Cystacyclin, a novel microbial metabolite with NGF mimetic activity. PMID- 23942339 TI - Upregulation of Na+,Cl(-)-coupled betaine/gamma-amino-butyric acid transporter BGT1 by Tau tubulin kinase 2. AB - BACKGROUND/AIMS: The serine/threonine kinase Tau-tubulin-kinase 2 (TTBK2) is expressed in various tissues including kidney, liver and brain. Loss of function mutations of TTBK2 lead to autosomal dominant spinocerebellar ataxia type 11 (SCA11). Cell survival is fostered by cellular accumulation of organic osmolytes. Carriers accomplishing cellular accumulation of organic osmolytes include the Na(+), Cl(-)-coupled betaine/gamma-amino-butyric acid transporter BGT1. The present study explored whether TTBK2 participates in the regulation of BGT1 activity. METHODS: Electrogenic transport of GABA was determined in Xenopus oocytes expressing BGT1 with or without wild-type TTBK2, truncated TTBK2[1-450] or kinase inactive mutants TTBK2- KD and TTBK2[1-450]-KD. RESULTS: Coexpression of wild-type TTBK2, but not of TTBK2[1-450], TTBK2-KD or TTBK2[1-450]-KD, increased electrogenic GABA transport. Wildtype TTBK2 increased the maximal transport rate without significantly modifying affinity of the carrier. Coexpression of wild-type TTBK2 significantly delayed the decline of transport following inhibition of carrier insertion with brefeldin A, indicating that wild type TTBK2 increased carrier stability in the cell membrane. CONCLUSION: Tau tubulin-kinase 2 TTBK2 is a powerful stimulator of the osmolyte and GABA transporter BGT1. PMID- 23942337 TI - Structural basis for the modulation of the neuronal voltage-gated sodium channel NaV1.6 by calmodulin. AB - The neuronal-voltage gated sodium channel (VGSC), Na(V)1.6, plays an important role in propagating action potentials along myelinated axons. Calmodulin (CaM) is known to modulate the inactivation kinetics of Na(V)1.6 by interacting with its IQ motif. Here we report the crystal structure of apo-CaM:Na(V)1.6IQ motif, along with functional studies. The IQ motif of Na(V)1.6 adopts an alpha-helical conformation in its interaction with the C-lobe of CaM. CaM uses different residues to interact with Na(V)1.6IQ motif depending on the presence or absence of Ca2+. Three residues from Na(V)1.6, Arg1902, Tyr1904 and Arg1905 were identified as the key common interacting residues in both the presence and absence of Ca2+. Substitution of Arg1902 and Tyr1904 with alanine showed a reduced rate of Na(V)1.6 inactivation in electrophysiological experiments in vivo. Compared with other CaM:Na(V) complexes, our results reveal a different mode of interaction for CaM:Na(V)1.6 and provides structural insight into the isoform-specific modulation of VGSCs. PMID- 23942340 TI - Serodiagnosis of grass carp reovirus infection in grass carp Ctenopharyngodon idella by a novel Western blot technique. AB - Frequent outbreaks of grass carp hemorrhagic disease, caused by grass carp reovirus (GCRV) infection, pose as serious threats to the production of grass carp Ctenopharyngodon idella. Although various nucleic acids-based diagnostic methods have been shown effective, lack of commercial monoclonal antibody against grass carp IgM has impeded the development of any reliable immunoassays in detection of GCRV infection. The present study describes the preparation and screening of monoclonal antibodies against the constant region of grass carp IgM protein, and the development of a Western blot (WB) protocol for the specific detection of antibodies against outer capsid VP7 protein of GCRV that serves as antibody-capture antigen in the immunoassay. In comparison to a conventional RT PCR method, validity of the WB is further demonstrated by testing on clinical fish serum samples collected from a grass carp farm in Jiangxi Province during disease pandemic in 2011. In conclusion, the WB technique established in this study could be employed for specific serodiagnosis of GCRV infection. PMID- 23942341 TI - Detection and differentiation of field and vaccine strains of canine distemper virus using reverse transcription followed by nested real time PCR (RT-nqPCR) and RFLP analysis. AB - Canine distemper virus (CDV) is the cause of a severe and highly contagious disease in dogs. Practical diagnosis of canine distemper based on clinical signs and laboratory tests are required to confirm CDV infection. The present study aimed to develop a molecular assay to detect and differentiate field and vaccine CDV strains. Reverse transcription followed by nested real time polymerase chain reaction (RT-nqPCR) was developed, which exhibited analytical specificity (all the samples from healthy dogs and other canine infectious agents were not incorrectly detected) and sensitivity (all replicates of a vaccine strain were positive up to the 3125-fold dilution - 10(0.7) TCID50). RT-nqPCR was validated for CDV detection on different clinical samples (blood, urine, rectal and conjunctival swabs) of 103 animals suspected to have distemper. A total of 53 animals were found to be positive based on RT-nqPCR in at least one clinical sample. Blood resulted in more positive samples (50 out of 53, 94.3%), followed by urine (44/53, 83.0%), rectal (38/53, 71%) and conjunctival (27/53, 50.9%) swabs. A commercial immunochromatography (IC) assay had detected CDV in only 30 conjunctival samples of these positive dogs. Nucleoprotein (NC) gene sequencing of 25 samples demonstrated that 23 of them were closer to other Brazilian field strains and the remaining two to vaccine strains. A single nucleotide sequences difference, which creates an Msp I restriction enzyme digestion, was used to differentiate between field and vaccine CDV strains by restriction fragment length polymorphism (RFLP) analysis. The complete assay was more sensitive than was IC for the detection of CDV. Blood was the more frequently positive specimen and the addition of a restriction enzyme step allowed the differentiation of vaccine and Brazilian field strains. PMID- 23942343 TI - Improved adhesion of dense silica coatings on polymers by atmospheric plasma pretreatment. AB - Oxygen atmospheric plasma was used to pretreat polycarbonate (PC) and stretched poly(methyl methacrylate) (PMMA) surfaces in order to enhance the adhesion of the dense silica coatings deposited by atmospheric plasma on the polymer substrates. The treatment time and chemical structure of the polymers were found to be important factors. For PC, a short treatment increased the adhesion energy, while longer treatment times decreased the adhesion. In contrast, plasma pretreatment monotonically decreased the adhesion of PMMA, and pristine PMMA exhibited much higher adhesion than the PC counterpart. We found that adhesion enhancement was achieved through improved chemical bonding, chain interdiffusion, and mechanical interlocking at the coating/substrate interface, after a short atmospheric plasma treatment. Decreased adhesion resulted from overoxidation and low-molecular weight weak layer formation on the polymer surface by prolonged atmospheric plasma treatment. The dramatic differences in the behavior of PC and PMMA in relation to the plasma treatment time were due to their dissimilar resistance to atmospheric plasma exposure. PMID- 23942342 TI - A biopsychosocial model of interferon-alpha-induced depression in patients with chronic hepatitis C infection. AB - BACKGROUND: The aim of this prospective study was to gain a more comprehensive picture of the biopsychosocial effects of interferon-alpha (IFN-alpha) treatment of patients with chronic hepatitis C (HCV). The predictors of depressive development and changes in health-related quality of life, life satisfaction and cognitive ability were measured with the inclusion of the social context. Furthermore, the effects of IFN-alpha treatment on indoleamine 2,3-dioxygenase, the level of tryptophan supply in the brain, the development of neurotoxic kynurenine metabolites and the thyroid glands were investigated. Therefore, for the first time the conditions for the development of depressive episodes in HCV patients treated with IFN-alpha were examined over the entire period of treatment as well as 3 months later, applying a holistic biopsychosocial model. METHOD: Psychiatric and biological assessments were carried out at 6 different times: before, during (at 1, 3, 6 and 9 months) and after the end of IFN-alpha treatment. RESULTS: During IFN-alpha treatment 22 (53.7%) of 41 patients fulfilled the criteria for a treatment-related depressive disorder at least once during treatment. Contributing factors are tryptophan depletion (tryptophan to competing amino acids quotient), increased neurotoxic challenge (kynurenine to kynurenic acid quotient), less social support, female gender, preexisting psychiatric vulnerability, means of transmission, low financial security, impaired sexual satisfaction, small circle of friends, impaired physical role, strong body pain, low general health and vitality, reduced social functioning, impaired mental health and impaired emotional role. CONCLUSIONS: The awareness of relevant risk factors of IFN-alpha treatment-induced depression is essential to develop preventative treatment strategies. PMID- 23942344 TI - Papillary renal cell cancer is strongly associated with simple renal cysts. AB - INTRODUCTION: The purpose of this study was to evaluate the prevalence of simple renal cysts (SRCs) in patients with renal neoplasia. PATIENTS AND METHODS: The study population consisted of 482 patients who underwent partial or radical nephrectomy for kidney tumour between 2006 and 2010. Prevalence of cysts was evaluated retrospectively on a preoperative CT or MRI scan. RESULTS: SRCs are more prevalent in patients with papillary renal cell cancer (RCC) than patients with clear cell RCC. All obese (BMI >=30) patients in our study population had SRCs. CONCLUSIONS: This is the first study to show an association between SRCs and papillary RCC. PMID- 23942345 TI - Predictions for sex of first born child reflect masculine and feminine characteristics in male and female undergraduates. AB - Previous research has identified physical and behavioral differences between parents who produce sons and those who produce daughters. However, the possibility that men and women have predictions about the sexes of their offspring based on these differences, or any other interoceptive cues, has not been investigated. We compared the dominance, sociosexual orientation, estradiol, testosterone, and 2D:4D ratios of men and women who predicted they would conceive a boy as their first child with those who predicted a girl. Women who predicted they would have a boy were more dominant and less sociosexually restricted than those who predicted they would have a girl. Men who predicted they would have a girl had higher salivary estradiol and higher (more feminine) 2D:4D ratios than those who predicted they would have a boy. Possible implications of these results are discussed in the context of evolutionary theory. PMID- 23942346 TI - The effect of statistical learning on internal stimulus representations: predictable items are enhanced even when not predicted. AB - Statistical learning is the automatic and unconscious learning of environmental regularities and is a basic mechanism of learning in a variety of human perceptual and cognitive domains. Previous studies have mainly focused on the associative mechanisms of statistical learning. However, an unexplored question is whether the internal representations of individual stimuli are altered as their associations are learned. Using a temporal statistical learning paradigm, we examine this question across three experiments and find clear evidence that the internal representations of individual stimuli are differentially altered according to their degree of temporal predictability. These findings complement previous accounts of statistical learning and reveal an enriched mechanism of human learning, such that learning to associate items also enhances the representations of certain items relative to others. PMID- 23942347 TI - Grammatical aspect, lexical aspect, and event duration constrain the availability of events in narratives. AB - The present study investigates how readers' representations of narratives are constrained by three sources of temporal information; grammatical aspect, lexical aspect, and the duration of intervening events. Participants read short stories in which a target event with an intrinsic endpoint or not (lexical aspect: accomplishments/activities) was described as ongoing or completed (grammatical aspect: imperfective/perfective). An intervening sentence described either a long or short duration event before the target situation was reintroduced later in the story. The electroencephalogram time-locked to the reintroduction of the target event elicited a larger N400 for perfective versus imperfective accomplishments, and this effect occurred only after short intervening events. Alternatively, the N400 to targets in the activity condition did not vary as a function of grammatical aspect or duration of intervening events. These results provide novel insight into how the temporal properties of events interact to constrain the availability of concepts in situation models. PMID- 23942348 TI - Object-centered representations support flexible exogenous visual attention across translation and reflection. AB - Visual attention can be deployed to stimuli based on our willful, top-down goal (endogenous attention) or on their intrinsic saliency against the background (exogenous attention). Flexibility is thought to be a hallmark of endogenous attention, whereas decades of research show that exogenous attention is attracted to the retinotopic locations of the salient stimuli. However, to the extent that salient stimuli in the natural environment usually form specific spatial relations with the surrounding context and are dynamic, exogenous attention, to be adaptive, should embrace these structural regularities. Here we test a non retinotopic, object-centered mechanism in exogenous attention, in which exogenous attention is dynamically attracted to a relative, object-centered location. Using a moving frame configuration, we presented two frames in succession, forming either apparent translational motion or in mirror reflection, with a completely uninformative, transient cue presented at one of the item locations in the first frame. Despite that the cue is presented in a spatially separate frame, in both translation and mirror reflection, behavioralperformance in visual search is enhanced when the target in the second frame appears at the same relative location as the cue location than at other locations. These results provide unambiguous evidence for non-retinotopic exogenous attention and further reveal an object-centered mechanism supporting flexible exogenous attention. Moreover, attentional generalization across mirror reflection may constitute an attentional correlate of perceptual generalization across lateral mirror images, supporting an adaptive, functional account of mirror images confusion. PMID- 23942349 TI - Do infants bind mental states to agents? AB - Recent findings suggest that infants understand others' preferential choice and can use the perspectives and beliefs of others to interpret their actions. The standard interpretation in the field is that infants understand preferential choice as a dispositional state of the agent. It is possible, however, that these social situations trigger the acquisition of more general, not person-specific knowledge. In a looking-time study we showed an Agent A demonstrating a choice, that only could have been interpreted as preferential based on the perspective (and thus the belief) of the agent, not the observer. Then we introduced a new agent (Agent B), who chose consistently or inconsistently with Agent A; also varying whether Agent B was an adult or a child. Results show that infants expected Agent B (both the adult and the child) to choose as Agent A, but only in the condition where according to Agent A's knowledge two objects were present in familiarization(confirming previous evidence on the importance of contrastive choice). We interpret these results in the following way: (1) infants do not encode the perspectives of other agents as person-specific sources of knowledge and (2) they learn about the object, rather than the agent's disposition towards that object. We propose that early theory of mind processes lack the binding of belief content to the belief holder. However, such limitation may in fact serve an important function, allowing infants to acquire information through the perspectives of others in the form of universal access to general information. PMID- 23942351 TI - Population & health services research. Editorial. PMID- 23942350 TI - Event segmentation ability uniquely predicts event memory. AB - Memory for everyday events plays a central role in tasks of daily living, autobiographical memory, and planning. Event memory depends in part on segmenting ongoing activity into meaningful units. This study examined the relationship between event segmentation and memory in a lifespan sample to answer the following question: Is the ability to segment activity into meaningful events a unique predictor of subsequent memory, or is the relationship between event perception and memory accounted for by general cognitive abilities? Two hundred and eight adults ranging from 20 to 79years old segmented movies of everyday events and attempted to remember the events afterwards. They also completed psychometric ability tests and tests measuring script knowledge for everyday events. Event segmentation and script knowledge both explained unique variance in event memory above and beyond the psychometric measures, and did so as strongly in older as in younger adults. These results suggest that event segmentation is a basic cognitive mechanism, important for memory across the lifespan. PMID- 23942352 TI - A new possible mechanism of hearing loss after microvascular decompression for hemifacial spasm. AB - OBJECTIVE: Hearing loss is a well-known complication that may occur during microvascular decompression (MVD) for hemifacial spasm (HFS). Cause and risk factors are highly variable. We present cases of hearing loss induced by saline overinfusion after MVD. STUDY DESIGN: Retrospective review in a tertiary referral center. INTERVENTION: Three hundred thirty-one patients with HFS underwent MVD from March 2009 to October 2010. MAIN OUTCOME MEASURES: Brain stem auditory evoked potential (BAEP) was monitored during the surgery. Before completion of the dural closure, the surgical field was routinely filled with warm saline to avoid postoperative pneumocephalus and epidural hematoma. RESULTS: Seven patients experienced a change in wave V amplitude and latency after the dural closure. In 2 patients, the amplitudes decreased by less than 50%, and latencies were delayed by less than 1.0 ms, ipsilaterally in 1 patient and contralaterally in the other. In 1 patient, decreased amplitude and delayed latency appeared bilaterally with more severity on the operated side, accompanied by delayed ipsilateral permanent hearing loss. In 4 of the 7 patients, an ipsilateral response of BAEP was completely absent. Of these 4 patients, 2 experienced permanent hearing loss, and another 2 patients who underwent dural reopening and saline drainage had restoration of their normal hearing. CONCLUSION: Intradural compression due to overinfusion of saline may lead to postoperative hearing loss, although the incidence is low, and immediate decompression by drainage may be required. PMID- 23942353 TI - Pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis--a review. AB - Among the various types of interstitial lung diseases, idiopathic pulmonary fibrosis (IPF) is the most common disorder and has a poor prognosis and a limited response to pharmacological treatment. In patients with IPF, functional exercise tolerance and quality of life have been shown to be significantly decreased. Current IPF guidelines suggest only a weak recommendation for pulmonary rehabilitation (PR). However, PR is regarded as a reasonable choice for the majority of patients with IPF. This review will summarize all of the available studies that have investigated the effects of PR in patients with IPF so far. Although only a small number of studies have been published to date, most studies have found significant short-term improvements in functional exercise capacity, quality of life, and level of perceived dyspnea. Long-term improvements or maintenance strategies of PR in IPF patients have not been adequately investigated yet. Up to now there is still no sufficient evidence for the recommendation of PR in IPF. However, physical training seems to be the major component of all PR programs. The current review will discuss potential exercise training regimens for patients with IPF and suggest additional useful modalities of a specific multidisciplinary PR program for IPF patients. Based on the current literature and our own experience, this article will try to highlight the importance of PR as an additional, beneficial therapeutic option for patients with IPF. PMID- 23942354 TI - Identifying clusters in genomics data by recursive partitioning. AB - Genomics studies frequently involve clustering of molecular data to identify groups, but common clustering methods such as K-means clustering and hierarchical clustering do not determine the number of clusters. Methods for estimating the number of clusters typically focus on identifying the global structure in the data, however the discovery of substructures within clusters may also be of great biological interest. We propose a novel method, Partitioning Algorithm based on Recursive Thresholding (PART), that recursively uncovers distinct subgroups in the groups already identified. Outliers are common in high-dimensional genomics data and may mask the presence of substructure within a cluster. A crucial feature of the algorithm is the introduction of tentative splits of clusters to isolate outliers that might otherwise halt the recursion prematurely. The method is demonstrated on simulated as well as a wide range of real data sets from gene expression microarrays, where the correct clusters were known in advance. When subclusters are present and the variance is large or varies between the clusters, the proposed method performs better than two established global methods on simulated data. On the real data sets the overall performance of PART is superior to the global methods when used in combination with hierarchical clustering. The method is implemented in the R package clusterGenomics and is freely available from CRAN (The Comprehensive R Archive Network). PMID- 23942355 TI - Enhanced reactivity and related optical changes of Ag nanoparticles on amorphous Al2O3 supports. AB - Pairs of samples containing Ag nanoparticles (NPs) of different dimensions have been produced under the same conditions but on different substrates, namely standard glass slides and a thin layer of amorphous aluminum oxide (a-Al2O3) on glass. Upon storage in ambient conditions (air and room temperature) the color of samples changed and a blue-shift and damping of the surface plasmon resonance was observed. The changes are weaker for the samples on-glass and tend to saturate after 12 months. In contrast, the changes for the samples on a-Al2O3 appear to be still progressing after 25 months. While x-ray photoelectron spectroscopy shows a slight sulfurization and negligible oxidation of the Ag for the on-glass samples upon 25 months aging, it shows that Ag is strongly oxidized for the on a-Al2O3 samples and sulfurization is negligible. Both optical and chemical results are consistent with the production of a shell at the expense of a reduction of the metal core dimensions, the latter being responsible for the blue-shift and related to the small (<10 nm initial diameter) of the NPs. The enhanced reactivity of the Ag NPs on the a-Al2O3 supports goes along with specific morphological changes of the Ag NPs and the observation of nitrogen. PMID- 23942356 TI - Short term signaling responses in roots of young soybean seedlings exposed to cadmium stress. AB - In the present study, the expression of fourteen genes involved in various signal transduction pathways was examined in young soybean (Glycine max) seedlings exposed to cadmium at two concentrations (10 mg L(-1) and 25 mg L(-1)) for short time periods (3, 6 and 24 h). The results show that cadmium causes induction of genes encoding proteins involved in ethylene and polyamines metabolism, nitric oxide generation, MAPK cascades and regulation of other genes' expression. The bioinformatic analysis of promoter sequences of Cd-inducible genes revealed that their promoters possess several regulative motifs associated with the plant response to stress factors and abscisic acid and ethylene signaling. The involvement of ethylene in the response of soybean seedlings to cadmium stress was further confirmed by the real-time analysis of ethylene production during 24 h of CdCl2 treatment. The role of the described signaling elements in transduction of the cadmium signal in young soybean seedlings is discussed. PMID- 23942357 TI - Pyoverdine secreted by Pseudomonas aeruginosa as a biological recognition element for the fluorescent detection of furazolidone. AB - Methods for the rapid and sensitive detection of furazolidone, a pesticide used for the treatment of infections of animals and human beings, have been urgently recommended for its large residual, strong carcinogenicity and genotoxicity in the environment. In this study, a method for the detection of furazolidone based on the rapid fluorescence quenching of pyoverdine by furazolidone was developed. Pyoverdine secreted by a Pseudomonas aeruginosa strain PA1 was purified through affinity chromatography and its fluorescent property was characterized. The fluorescence of pyoverdine could be quenched by furazolidone with specificity, and based on this phenomenon a fluorescent method for furazolidone detection was established. Fluorescence of pyoverdine was quenched by furazolidone probably due to the electron transfer from pyoverdine to furazolidone. The optimal pH for the detection was 7.2 in 50 mM 3-(N-Morpholino) propanesulfonic acid solution, and the whole detection process could be completed within a few seconds. The linear range of the detection was 2-160 uM and the limit of detection (LOD) was 0.5 uM. This study developed a novel fluorescent method for furazolidone detection, and the rapid and specific fluorescent biosensor can be potentially applied for furazolidone detection in the aquatic samples. PMID- 23942358 TI - Microfluidic chip integrated with flexible PDMS-based electrochemical cytosensor for dynamic analysis of drug-induced apoptosis on HeLa cells. AB - A novel microfluidic platform integrated with a flexible PDMS-based electrochemical cytosensor was developed for real-time monitoring of the proliferation and apoptosis of HeLa cells. The PDMS-gold film, which had a conductive smooth surface and was semi-transparent, facilitated electrochemical measurements and optical microscope observations. We observed distinct increases and decreases in peak current intensity, corresponding to cell proliferation in culture medium and apoptosis in the presence of an anticancer drug, respectively. This electrochemical analysis method permitted real-time, label-free monitoring of cell behavior, and the electrochemical results were confirmed with optical microscopy. The flexible microfluidic electrochemical platform presented here is suitable for on-site monitoring of cell behavior in microenvironments. PMID- 23942360 TI - Pretreatment of macroalgae for volatile fatty acid production. AB - In this study, a novel method was proposed for the biological pretreatment of macroalgae (Laminaria japonica, Pachymeniopsis elliptica, and Enteromorpha crinita) for production of volatile fatty acid (VFA) by anaerobic fermentation. The amount of VFA produced from 40 g/L of L. japonica increased from 8.3 g/L (control) to 15.6 g/L when it was biologically pretreated with Vibrio harveyi. The biological treatment of L. japonica with Vibrio spp. was most effective likely due to the alginate lyase activity of Vibrio spp. However, a considerable effect was also observed after biological pretreatment of P. elliptica and E. crinita, which are red and green algae, respectively. Alkaline pretreatment of 40 g/L of L. japonica with 0.5 N NaOH resulted in an increase of VFA production to 12.2 g/L. These results indicate that VFA production from macroalgae can be significantly enhanced using the proposed biological pretreatments. PMID- 23942359 TI - A combined metabonomic and proteomic approach identifies frontal cortex changes in a chronic phencyclidine rat model in relation to human schizophrenia brain pathology. AB - Current schizophrenia (SCZ) treatments fail to treat the broad range of manifestations associated with this devastating disorder. Thus, new translational models that reproduce the core pathological features are urgently needed to facilitate novel drug discovery efforts. Here, we report findings from the first comprehensive label-free liquid-mass spectrometry proteomic- and proton nuclear magnetic resonance-based metabonomic profiling of the rat frontal cortex after chronic phencyclidine (PCP) intervention, which induces SCZ-like symptoms. The findings were compared with results from a proteomic profiling of post-mortem prefrontal cortex from SCZ patients and with relevant findings in the literature. Through this approach, we identified proteomic alterations in glutamate-mediated Ca(2+) signaling (Ca(2+)/calmodulin-dependent protein kinase II, PPP3CA, and VISL1), mitochondrial function (GOT2 and PKLR), and cytoskeletal remodeling (ARP3). Metabonomic profiling revealed changes in the levels of glutamate, glutamine, glycine, pyruvate, and the Ca(2+) regulator taurine. Effects on similar pathways were also identified in the prefrontal cortex tissue from human SCZ subjects. The discovery of similar but not identical proteomic and metabonomic alterations in the chronic PCP rat model and human brain indicates that this model recapitulates only some of the molecular alterations of the disease. This knowledge may be helpful in understanding mechanisms underlying psychosis, which, in turn, can facilitate improved therapy and drug discovery for SCZ and other psychiatric diseases. Most importantly, these molecular findings suggest that the combined use of multiple models may be required for more effective translation to studies of human SCZ. PMID- 23942361 TI - Akt isoforms differentially protect against stroke-induced neuronal injury by regulating mTOR activities. AB - Protein kinases Akt1 and Akt3 are considered to be more crucial to brain function than Akt2. We investigated the roles of Akt1 and Akt3 in stroke-induced brain injury and examined their interactions with the Akt/mTOR pathways. Focal ischemia was induced in rats. Lentiviral vectors expressing constitutively active Akt1 and Akt3 (cAkt1 and cAkt3) were injected into the ischemic cortex. Infarct sizes and gene and protein expressions in the Akt/mTOR pathways were evaluated. The results show that Akt1 and Akt3 proteins were degraded as early as 1 hour after stroke, whereas Akt2 proteins remained unchanged until 24 hours after stroke. Lentiviral mediated overexpression of cAkt1 or cAkt3 reduced neuronal death after in vitro and in vivo ischemia. Interestingly, cAkt3 overexpression resulted in stronger protection than cAkt1 overexpression. Western blot analyses further showed that cAkt3 promoted significantly higher levels of phosphorylated Akt and phosphorylated mTOR than cAkt1. The mTOR inhibitor rapamycin blocked the protective effects of both cAkt1 and cAkt3. In conclusion, Akt isoforms are differentially regulated after stroke and Akt3 offers stronger protection than cAkt1 by maintaining Akt levels and promoting mTOR activity. PMID- 23942362 TI - Blood flow distribution during heat stress: cerebral and systemic blood flow. AB - The purpose of the present study was to assess the effect of heat stress-induced changes in systemic circulation on intra- and extracranial blood flows and its distribution. Twelve healthy subjects with a mean age of 22+/-2 (s.d.) years dressed in a tube-lined suit and rested in a supine position. Cardiac output (Q), internal carotid artery (ICA), external carotid artery (ECA), and vertebral artery (VA) blood flows were measured by ultrasonography before and during whole body heating. Esophageal temperature increased from 37.0+/-0.2 degrees C to 38.4+/-0.2 degrees C during whole body heating. Despite an increase in Q (59+/ 31%, P<0.001), ICA and VA decreased to 83+/-15% (P=0.001) and 87+/-8% (P=0.002), respectively, whereas ECA blood flow gradually increased from 188+/-72 to 422+/ 189 mL/minute (+135%, P<0.001). These findings indicate that heat stress modified the effect of Q on blood flows at each artery; the increased Q due to heat stress was redistributed to extracranial vascular beds. PMID- 23942363 TI - Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. AB - Hypertension in the elderly substantially contributes to cerebromicrovascular damage and promotes the development of vascular cognitive impairment. Despite the importance of the myogenic mechanism in cerebromicrovascular protection, it is not well understood how aging affects the functional adaptation of cerebral arteries to high blood pressure. Hypertension was induced in young (3 months) and aged (24 months) C57/BL6 mice by chronic infusion of angiotensin II (AngII). In young hypertensive mice, the range of cerebral blood flow autoregulation was extended to higher pressure values, and the pressure-induced tone of middle cerebral artery (MCA) was increased. In aged hypertensive mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In young mice, the mechanism of adaptation to hypertension involved upregulation of the 20-HETE (20-hydroxy-5,8,11,14-eicosatetraenoic acid)/transient receptor potential cation channel, subfamily C (TRPC6) pathway and this mechanism was impaired in aged hypertensive mice. Downstream consequences of cerebrovascular autoregulatory dysfunction in aged AngII-induced hypertensive mice included exacerbated disruption of the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal dependent cognitive function. Collectively, aging impairs autoregulatory protection in the brain of mice with AngII-induced hypertension, potentially exacerbating cerebromicrovascular injury and neuroinflammation. PMID- 23942364 TI - Neuroprotective effects of geranylgeranylacetone in experimental traumatic brain injury. AB - Geranylgeranylacetone (GGA) is an inducer of heat-shock protein 70 (HSP70) that has been used clinically for many years as an antiulcer treatment. It is centrally active after oral administration and is neuroprotective in experimental brain ischemia/stroke models. We examined the effects of single oral GGA before treatment (800 mg/kg, 48 hours before trauma) or after treatment (800 mg/kg, 3 hours after trauma) on long-term functional recovery and histologic outcomes after moderate-level controlled cortical impact, an experimental traumatic brain injury (TBI) model in mice. The GGA pretreatment increased the number of HSP70(+) cells and attenuated posttraumatic alpha-fodrin cleavage, a marker of apoptotic cell death. It also improved sensorimotor performance on a beam walk task; enhanced recovery of cognitive/affective function in the Morris water maze, novel object recognition, and tail-suspension tests; and improved outcomes using a composite neuroscore. Furthermore, GGA pretreatment reduced the lesion size and neuronal loss in the hippocampus, cortex, and thalamus, and decreased microglial activation in the cortex when compared with vehicle-treated TBI controls. Notably, GGA was also effective in a posttreatment paradigm, showing significant improvements in sensorimotor function, and reducing cortical neuronal loss. Given these neuroprotective actions and considering its longstanding clinical use, GGA should be considered for the clinical treatment of TBI. PMID- 23942365 TI - The influence of noise on BOLD-mediated vessel size imaging analysis methods. AB - Vessel size imaging (VSI) is a magnetic resonance imaging (MRI) technique that aims to provide quantitative measurements of tissue microvasculature. An emerging variation of this technique uses the blood oxygenation level-dependent (BOLD) effect as the source of the imaging contrast. Gas challenges have the advantage over contrast injection techniques in that they are noninvasive and easily repeatable because of the fast washout of the contrast. However, initial results from BOLD-VSI studies are somewhat contradictory, with substantially different estimates of the mean vessel radius. Owing to BOLD-VSI being an emerging technique, there is not yet a standard processing methodology, and different techniques have been used to calculate the mean vessel radius and reject uncertain estimates. In addition, the acquisition methodology and signal modeling vary from group to group. Owing to these differences, it is difficult to determine the source of this variation. Here we use computer modeling to assess the impact of noise on the accuracy and precision of different BOLD-VSI calculations. Our results show both potential overestimates and underestimates of the mean vessel radius, which is confirmed with a validation study at 3T. PMID- 23942366 TI - Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. AB - Mononuclear phagocytes are a population of multi-phenotypic cells and have dual roles in brain destruction/reconstruction. The phenotype-specific roles of microglia/macrophages in traumatic brain injury (TBI) are, however, poorly characterized. In the present study, TBI was induced in mice by a controlled cortical impact (CCI) and animals were killed at 1 to 14 days post injury. Real time polymerase chain reaction (RT-PCR) and immunofluorescence staining for M1 and M2 markers were performed to characterize phenotypic changes of microglia/macrophages in both gray and white matter. We found that the number of M1-like phagocytes increased in cortex, striatum and corpus callosum (CC) during the first week and remained elevated until at least 14 days after TBI. In contrast, M2-like microglia/macrophages peaked at 5 days, but decreased rapidly thereafter. Notably, the severity of white matter injury (WMI), manifested by immunohistochemical staining for neurofilament SMI-32, was strongly correlated with the number of M1-like phagocytes. In vitro experiments using a conditioned medium transfer system confirmed that M1 microglia-conditioned media exacerbated oxygen glucose deprivation-induced oligodendrocyte death. Our results indicate that microglia/macrophages respond dynamically to TBI, experiencing a transient M2 phenotype followed by a shift to the M1 phenotype. The M1 phenotypic shift may propel WMI progression and represents a rational target for TBI treatment. PMID- 23942367 TI - Measuring alpha4beta2* nicotinic acetylcholine receptor density in vivo with [(18)F]nifene PET in the nonhuman primate. AB - [(18)F]Nifene is an agonist PET radioligand developed to image alpha4beta2* nicotinic acetylcholine receptors (nAChRs). This work aims to quantify the receptor density (Bmax) of alpha4beta2* nAChRs and the in vivo (apparent) dissociation constant (KDapp) of [(18)F]nifene. Multiple-injection [(18)F]nifene experiments with varying cold nifene masses were conducted on four rhesus monkeys with a microPET P4 scanner. Compartment modeling techniques were used to estimate regional Bmax values and a global value of KDapp. The fast kinetic properties of [(18)F]nifene also permitted alternative estimates of Bmax and KDapp at transient equilibrium with the same experimental data using Scatchard-like methodologies. Averaged across subjects, the compartment modeling analysis yielded Bmax values of 4.8+/-1.4, 4.3+/-1.0, 1.2+/-0.4, and 1.2+/-0.3 pmol/mL in the regions of antereoventral thalamus, lateral geniculate, frontal cortex, and subiculum, respectively. The KDapp of nifene was 2.4+/-0.3 pmol/mL. The Scatchard analysis based on graphical evaluation of the data after transient equilibrium yielded Bmax estimations comparable to the modeling results with a positive bias of 28%. These findings show the utility of [(18)F]nifene for measuring alpha4beta2* nAChR Bmax in vivo in the rhesus monkey with a single PET experiment. PMID- 23942372 TI - Genetically encoded system to track histone modification in vivo. AB - Post-translational histone modifications play key roles in gene regulation, development, and differentiation, but their dynamics in living organisms remain almost completely unknown. To address this problem, we developed a genetically encoded system for tracking histone modifications by generating fluorescent modification-specific intracellular antibodies (mintbodies) that can be expressed in vivo. To demonstrate, an H3 lysine 9 acetylation specific mintbody (H3K9ac mintbody) was engineered and stably expressed in human cells. In good agreement with the localization of its target acetylation, H3K9ac-mintbody was enriched in euchromatin, and its kinetics measurably changed upon treatment with a histone deacetylase inhibitor. We also generated transgenic fruit fly and zebrafish stably expressing H3K9ac-mintbody for in vivo tracking. Dramatic changes in H3K9ac-mintbody localization during Drosophila embryogenesis could highlight enhanced acetylation at the start of zygotic transcription around mitotic cycle 7. Together, this work demonstrates the broad potential of mintbody and lays the foundation for epigenetic analysis in vivo. PMID- 23942373 TI - Education and psychological support meet the supportive care needs of Taiwanese women three months after surgery for newly diagnosed breast cancer: a non randomised quasi-experimental study. AB - BACKGROUND: Few studies have comprehensively examined the effectiveness of information and psychosocial support on all dimensions of cancer patients' supportive care needs. OBJECTIVES: To investigate the effects of education and psychological support on anxiety, symptom distress, social support, and unmet supportive care needs of Taiwanese women newly diagnosed with breast cancer over 3 months after surgery. DESIGN: Two-group, non-randomised quasi-experimental design. SETTING: The general surgical outpatient department of the largest teaching medical centre in northern Taiwan. PARTICIPANTS: Women newly diagnosed with breast cancer (N=80) were divided into experimental (n=40) and control (n=40) groups. METHODS: The experimental group received education and psychological support in the form of individual face-to-face and telephone follow up sessions; the control group received routine care. Data were collected during the patients' first postoperative visit (baseline), 1 month after surgery, and 3 months after surgery. RESULTS: After adjusting for covariates, the levels of symptom distress and unmet needs for participants in the experimental group were lower at 1 and 3 months after surgery than for those in the control group, with the results at 3 months achieving significance. However, the sexuality needs for both groups were not significantly different at 1 and 3 months. Furthermore, levels of state anxiety were significantly lower for the experimental group at 1 and 3 months than for the control group. CONCLUSION: The education and psychological support components of our intervention programme effectively improved the unmet supportive care needs of patients newly diagnosed with breast cancer 3 months after surgery. Following prolonged treatment, women with breast cancer still have physical, psychological, and information care needs. Thus, clinical healthcare personnel should continually and actively provide culturally sensitive, individualised, and accessible information and psychological support to these patients. PMID- 23942374 TI - Floppy mitral valve (FMV)/mitral valve prolapse (MVP) and the FMV/MVP syndrome: pathophysiologic mechanisms and pathogenesis of symptoms. AB - Mitral valve prolapse (MVP) results from the systolic movement of a portion or segments of the mitral valve leaflets into the left atrium during left ventricular systole. It is well appreciated today that floppy mitral valve (FMV) is the central issue in the MVP and mitral valve regurgitation (MVR) story. The term FMV refers to the expansion of the area of the mitral valve leaflets with elongated chordae tendineae, chordae rupture and mitral annular dilation. FMV/MVP occurs in a heterogeneous group of patients with a wide spectrum of mitral valve involvement from mild to severe. Two types of symptoms can be defined in FMV/MVP patients. In one group of patients, symptoms are directly related to progressive MVR. In the other group, symptoms cannot be explained by the degree of MVR alone; activation of the autonomic nervous system has been implicated for the explanation of symptoms in this group of patients which is referred to as the FMV/MVP syndrome. In this brief review, the natural history, pathophysiologic mechanisms and management of patients with FMV/MVP/MVR and FMV/MVP syndrome are discussed. PMID- 23942375 TI - Coupling an universal primer to SBE combined spectral codification strategy for single nucleotide polymorphism analysis. AB - We previously reported a strategy that combines Forster resonance energy transfer (FRET) based spectral codification with a single base extension (SBE) reaction for single nucleotide sequence discrimination in solution. This strategy is capable of unequivocally detect the allele variants present in solution. To extend the use of this tool to any locus of interest, it would be required the development of an universal approach capable of combining a sequence specific SBE primer to an universal sequence labeled and optimized for spectral codification. Here, we extend this concept to a general strategy by means of a labeled universal oligonucleotide primer (donor), a sequence specific primer that allows for incorporation of the complementary acceptor labeled ddNTP, which allows discrimination the allele variant in the sample via the unambiguous FRET signature of the donor/acceptor pair. PMID- 23942376 TI - Direct ethanol production from glucose, xylose and sugarcane bagasse by the corn endophytic fungi Fusarium verticillioides and Acremonium zeae. AB - Production of ethanol with two corn endophytic fungi, Fusarium verticillioides and Acremonium zeae, was studied. The yield of ethanol from glucose, xylose and a mixture of both sugars were 0.47, 0.46 and 0.50g/g ethanol/sugar for F. verticillioides and 0.37, 0.39 and 0.48g/g ethanol/sugar for A. zeae. Both fungi were able to co-ferment glucose and xylose. Ethanol production from 40g/L of pre treated sugarcane bagasse was 4.6 and 3.9g/L for F. verticillioides and A. zeae, respectively, yielding 0.31g/g of ethanol per consumed sugar. Both fungi studied were capable of co-fermenting glucose and xylose at high yields. Moreover, they were able to produce ethanol directly from lignocellulosic biomass, demonstrating to be suitable microorganisms for consolidated bioprocessing. PMID- 23942377 TI - Engineering Escherichia coli for improved ethanol production from gluconate. AB - We report on engineering Escherichia coli to produce ethanol at high yield from gluconic acid (gluconate). Knocking out genes encoding for the competing pathways (l-lactate dehydrogenase and pyruvate formate lyase A) in E. coli KO11 eliminated lactate production, lowered the carbon flow toward acetate production, and improved the ethanol yield from 87.5% to 97.5% of the theoretical maximum, while the growth rate of the mutant strain was about 70% of the wild type. The corresponding genetic modifications led to a small improvement of ethanol yield from 101.5% to 106.0% on glucose. Deletion of the pyruvate dehydrogenase gene (pdh) alone improved the ethanol yield from 87.5% to 90.4% when gluconate was a substrate. The growth rate of the mutant strain was identical to that of the wild type. The corresponding genetic modification led to no improvements on ethanol yield on glucose. PMID- 23942378 TI - Nucleic acid aptamers for capture and detection of Listeria spp. AB - The purpose of this study was to identify biotinylated single-stranded (ss) DNA aptamers with binding specificity to Listeria and use these for capture and subsequent qPCR detection of the organism. For aptamer selection, SELEX (systematic evolution of ligands by exponential enrichment) was applied to a biotin-labeled ssDNA combinatorial library. After multiple rounds of selection and counter-selection, aptamers separated, sequenced, and characterized by flow cytometry showed binding affinities to L. monocytogenes of 18-23%. Although selected for using L. monocytogenes, these aptamers showed similar binding affinity for other members of the Listeria genus and low binding affinity for non Listeria species. One aptamer, Lbi-17, was chosen for development of a prototype capture and detection assay. When Lbi-17 was conjugated to magnetic beads and used in a combined aptamer magnetic capture (AMC)-qPCR assay, the pathogen could be detected at concentrations <60 CFU/500 MUl buffer in the presence of a heterogeneous cocktail of non-Listeria bacterial cells, with a capture efficiency of 26-77%. Parallel experiments using immunomagnetic separation (IMS)-qPCR produced the same detection limit but lower capture efficiency (16-21%). Increasing assay volume to 10 and 50 ml resulted in reduced capture efficiency and higher limits of detection, at 2.7 and 4.8 log10 CFU L. monocytogenes per sample, respectively, for the AMC-qPCR assay. Biotinylated ssDNA aptamers are promising ligands for food-borne pathogen concentration prior to detection using molecular methods. PMID- 23942379 TI - Horizontal transfer of antibiotic resistance genes in a membrane bioreactor. AB - Growing attention has been paid to the dissemination of antibiotic resistance genes (ARGs) in wastewater microbial communities. The application of membrane bioreactors (MBRs) in wastewater treatment is becoming increasingly widespread. We hypothesized that the transfer of ARGs among bacteria could occur in MBRs, which combine a high density of bacterial cells, biofilms, and antibiotic resistance bacteria or ARGs. In this study, the transfer discipline and dissemination of the RP4 plasmid in MBRs were investigated by the counting plate method, the MIDI microorganism identification system, and quantitative polymerase chain reaction (qPCR) techniques. The results showed that the average transfer frequency of the RP4 plasmid from the donor strain to cultivable bacteria in activated sludge was 2.76*10-5 per recipient, which was greater than the transfer frequency in wastewater and bacterial sludge reported previously. In addition, many bacterial species in the activated sludge had received RP4 by horizontal transfer, while the genera of Shewanella spp., Photobacterium spp., Pseudomonas spp., Proteus spp., and Vibrio spp. were more likely to acquire this plasmid. Interestingly, the abundance of the RP4 plasmid in total DNA remained at high levels and relatively stable at 104 copies/mg of biosolids, suggesting that ARGs were transferred from donor strains to activated sludge bacteria in our study. Thus, the presence of ARGs in sewage sludge poses a potential health threat. PMID- 23942380 TI - Direct oligonucleotide synthesis onto super-paramagnetic beads. AB - Super-paramagnetic beads (SPMB)s used for a variety of molecular diagnostic assays are prepared by attaching pre-synthesized oligonucleotides to the surface via a cumbersome and low efficient method of carbodiimide-mediated amide bond formation. To mainstream the process, we describe a novel procedure of direct oligonucleotide synthesis onto the surface of SPMBs (e.g. MyOne Dynabeads). With the many challenges surrounding containment of paramagnetic beads (<=1 MUm) during automated oligonucleotide synthesis, we show that by applying a magnetic force directly to the SPMBs we prevent their loss caused by high-pressure drain steps during synthesis. To date we have synthesized 40 mers using a Spacer 9 phosphoramidite (triethylene glycol) coupled to the surface of hydroxylated SPMBs. HPLC analysis shows successful product generation with an average yield of 200 pmol per sample. Furthermore, because of the versatility of this powerful research tool, we envision its use in any laboratory working with conventional synthesis automation, as employed for single columns and for multi-well titer plates. In addition to direct synthesis of oligodeoxynucleotides (DNA) onto SPMBs, this platform also has the potential for RNA and peptide nucleic acid synthesis. PMID- 23942381 TI - A highly efficient site-specific integration strategy using combination of homologous recombination and the PhiC31 integrase. AB - The introduction of double-strand breaks (DSBs) at target sites could greatly enhance homologous recombination, and engineered nucleases, such as zinc finger and transcription activator-like effector nucleases, have been successfully developed for making such breaks. In this study, we present a highly efficient site-specific integration strategy based on homologous recombination and PhiC31 integrase. An attB sequence was introduced at the homologous arm of an insertion targeting vector. DSBs at the target locus and donor were then simultaneously generated by the PhiC31 integrase when co-transfected with the donor vector, consequently stimulating homologous recombination. The results demonstrated that our strategy is feasible and the efficiency at the BF4 target site, which we previously identified in the bovine genome, was as high as 93%. The frequency at another site (BF10) was almost two-fold greater in comparison to the vector without homologous arms. This technology requires no sophisticated nuclease design efforts, and the off-target effect is reduced by PhiC31 integrase compared to the use of engineered nucleases, thereby offering a simple and safe way to effectively express a donor gene at a desired locus. This development has great potential value, especially in transgenesis or gene therapy applications. PMID- 23942382 TI - History of suicidal behaviour and analgesic use in community-dwelling elderly. PMID- 23942383 TI - Evolution of lateral structures during the functional stack build-up of P3HT:PCBM based bulk heterojunction solar cells. AB - Bulk heterojunction (BHJ) solar cells from 1,2-dichlorobenzene solution processed regioregular poly(3-hexylthiophene-2,5-diyl) (P3HT): phenyl-C61-butyric acid methyl ester (PCBM) are prepared and investigated at different steps of the multilayer stack build-up of the device. The inner structure is probed from the molecular to the mesoscale with grazing incidence small/wide-angle X-ray scattering (GISAXS/GIWAXS) and X-ray reflectivity (XRR). The surface morphology is detected with atomic force microscopy (AFM). Therefore, an in-depth knowledge of the three-dimensional morphology of the bulk heterojunction solar cell, starting from the cleaned ITO substrate up to the final post-treated solar cell, is generated. The active layer structure is influenced by the annealing as well as by the top contact deposition. Structures coarsen during the evaporation of the metal contacts. The P3HT crystal structure strongly depends on the device processing as well. These morphological changes together with the diffusion of aluminum atoms to the active layer are of importance for the device efficiency. PMID- 23942384 TI - Reasons to love life. Effects of a suicide-awareness campaign on the utilization of a telephone emergency line in Austria. AB - BACKGROUND: A suicide awareness campaign was initiated in the Austrian federal state of Styria to increase help-seeking behavior in the population. Billboards were shown throughout Styria depicting joyful everyday-life situations with a focus on social and family connectedness, and promoting the Telephone Emergency Service, a crisis hotline. AIMS: The present study investigated the impact of this campaign on the utilization of the crisis hotline and on suicide rates. METHOD: Phone calls and suicide rates in the study region 3 months before the campaign were compared with rates 3 months after the campaign. The changes were contrasted with the characteristics of phone calls and the suicide rate in a comparable control region. RESULTS: There were significantly more phone calls in the study region after the awareness campaign compared to the control region, which was similar to seasonal trends in nonintervention years, and there was no increase of suicide-related phone calls. The proportion of suicide-related phone calls referring to family problems decreased after the initiation of the campaign. Suicide rates did not change. CONCLUSION: The campaign may have had some minor immediate impact on the utilization of the Telephone Emergency Service, but it did not seem to motivate suicidal individuals, especially those with family problems, to call. PMID- 23942385 TI - The interaction effect between low income and severe illness on the risk of death by suicide after self-harm. AB - BACKGROUND: Previous Western studies have reported that the prevalence of death by suicide within 1 year after self-harm was 0.5-2%; however, no studies have focused on the Far East. AIMS: To calculate the prevalence of death by suicide after self-harm over different lengths of follow-up time and to determine the predictors of death by suicide after self-harm. METHOD: Our study was based on 3,388 inpatients hospitalized between 2000 and 2007 in any of the 1,230 hospitals in Taiwan. Death by suicide after self-harm among the members of this cohort was tracked after 3 months, 6 months, and 1-8 years. The tracking continued until December 31, 2008. We analyzed the prevalence and risk factors of death by suicide after self-harm using Cox's regression model. RESULTS: Of the 3,388 individuals with a history of self-harm included in the study, 48 (1.4%) died by suicide after self-harm within 3 months and 97 (2.9%) within 1 year. In all, 144 (4.3%) died by suicide after self-harm within 8 years. The predictors of death by suicide were violent methods (such as hanging, drowning, firearms, and jumping), low income, and severe illness. Moreover, an interaction effect was noted between low income and severe illness on the outcome (death by suicide). CONCLUSION: It seems that effective healthcare for individuals who engage in self-harming behavior would benefit from supplementing medical care with social assistance, such as the support of a social worker. PMID- 23942386 TI - Association between psychopathology and suicidal behavior in schizophrenia. A cross-sectional study of 509 participants. AB - BACKGROUND: Suicide in schizophrenia is a serious problem--ideation rates go up to 40%, and approximately one half of patients attempt suicide at least once. The distinction between attempters and ideators is vital in everyday clinical practice. AIM: To explore the association between psychopathology and suicidal behavior in a comparative study of three groups of patients with schizophrenia: suicide ideators, suicide attempters, and subjects without suicide ideation and behavior. METHOD: The study included 509 patients: suicide attempters (n = 159), ideators (n = 180), and a comparative group (n = 170). The clinical assessment consisted of a structured psychiatric interview and an evaluation of sociodemographics, suicidality (SIBQ), psychopathology (PANSS), and depression (CDSS). RESULTS: Suicide attempters were more depressed than ideators, and both groups had higher CDSS scores than the comparative group. The overall contribution of positive, negative, and general PANSS symptoms was not statistically significant enough to differentiate ideators from attempters. A principal component analysis of the PANSS items revealed five components: disinhibition, withdrawal, anxiety and guilt, reality distortion, and disorganization. Two logistic regression analyses showed that suicide ideation or attempt was significantly related to depression, anxiety, guilt, gender, age, and number of previous hospitalizations. Compared to suicide ideators, attempters were more depressed, had a higher number of previous hospitalizations, and lower education. CONCLUSION: The results indicate that clinicians should look for depression, anxiety, and guilt feelings, while positive and negative symptoms seem to be less relevant for suicide assessment in schizophrenia. PMID- 23942387 TI - Cost effectiveness of a community-based crisis intervention program for people bereaved by suicide. AB - BACKGROUND: Postvention services aim to ameliorate distress and reduce future incidences of suicide. The StandBy Response Service is one such service operating in Australia for those bereaved through suicide. Few previous studies have reported estimates or evaluations of the economic impact and outcomes associated with the implementation of bereavement/grief interventions. AIMS: To estimate the cost-effectiveness of a postvention service from a societal perspective. METHOD: A Markov model was constructed to estimate the health outcomes, quality-adjusted life years, and associated costs such as medical costs and time off work. Data were obtained from a prospective cross-sectional study comparing previous clients of the StandBy service with a control group of people bereaved by suicide who had not had contact with StandBy. Costs and outcomes were measured at 1 year after suicide bereavement and an incremental cost-effectiveness ratio was calculated. RESULTS: The base case found that the StandBy service dominated usual care with a cost saving from providing the StandBy service of AUS $803 and an increase in quality-adjusted life years of 0.02. Probabilistic sensitivity analysis indicates there is an 81% chance the service would be cost-effective given a range of possible scenarios. CONCLUSION: Postvention services are a cost-effective strategy and may even be cost-saving if all costs to society from suicide are taken into account. PMID- 23942388 TI - Lithotrites and postoperative fever: does lithotrite type matter? Results from the Clinical Research Office of the Endourological Society Percutaneous Nephrolithotomy Global Study. AB - OBJECTIVE: To compare the risks of fever from different lithotrites after percutaneous nephrolithotomy (PNL). MATERIALS AND METHODS: The Clinical Research Office of the Endourological Society (CROES) PNL database is a prospective, multi institutional, international PNL registry. Of 5,803 total patients, 4,968 received preoperative antibiotics, were supplied with complete information and included in this analysis. The lithotrites assessed included no fragmentation, ultrasonic, laser, pneumatic and combination ultrasonic/pneumatic. Risk of fever was estimated using multivariate logistic regression with adjustment for diabetes, steroid use, a history of positive urine culture, the presence of staghorn calculi or preoperative nephrostomy, stone burden and lithotrite. RESULTS: The overall fever rate was 10%. Pneumatic lithotrites were used in 43% of the cohort, followed by ultrasonic (24%), combination ultrasonic/pneumatic (17.3%), no fragmentation (8.4%) and laser (7.3%). Fever rates were no different between patients who underwent no or any fragmentation (p = 0.117), nor among patients when stratified by lithotrite (p = 0.429). On multivariate analysis, fragmentation was not significantly associated with fever [Odds Ratio (OR) 1.17, p = 0.413], while diabetes (OR 1.32, p = 0.048), positive urine culture (OR 2.08, p < 0.001), staghorn calculi (OR 1.80, p < 0.001) and nephrostomy (OR 1.65, p < 0.001) increased fever risk. Fever risk among lithotrites did not differ (p >= 0.128). CONCLUSIONS: Risk of post-PNL fever was not significantly different among the various lithotrites used in the CROES PNL study. PMID- 23942389 TI - Trends and characteristics among HIV-infected and diabetic travelers seeking pre travel advice. AB - The number of individuals with a chronic disease increases. Better treatment options have improved chronic patients' quality of life, likely increasing their motivation for travel. This may have resulted in a change in the number of HIV infected travelers and/or travelers with Diabetes Mellitus (DM) visiting our travel clinic. We retrospectively analyzed the database of the travel clinic of the Public Health Service Amsterdam, between January 2001 and December 2011 and examined the records for patients with these conditions. Of the 25,000 travelers who consult our clinic annually, the proportion of travelers with HIV or DM has increased significantly. A total of 564 HIV-infected travelers visited our clinic. The mean age was 41 years, 86% were male, 43% visited a yellow fever endemic country and 46.5% had a CD4 count <500 cells/mm(3). Travelers with low CD4 counts traveled significantly more often to visit friends or relatives. A total of 3704 diabetics visited our clinic. The mean age was 55 years, 52% were male, 27% visited a yellow fever endemic country and 36% were insulin-dependent. Insulin-dependent diabetics traveled more often for work than non-insulin dependent diabetics. Adequately trained and qualified travel health professionals and up-to-date guidelines for travelers with chronic diseases are of increasing importance. PMID- 23942390 TI - A single-molecule stretching method for lateral and normal AFM lever calibration. AB - A novel method for quantitative lateral force measurement (LFM) calibration has been developed. Using a single-molecule spectroscopy approach it is possible to calibrate the AFM levers for both lateral and normal spring constants with a single image scan. Moreover, our method does not involve tip modifications. Dextran molecules were chosen for testing our calibration procedure due to their characteristic plateau feature in the force-elongation curve which enables an easy identification of single-molecule stretching events. Using a non-standard (tilted) geometry of AFM scanning, it is possible to observe different components of the stretching force on both normal and lateral force signals. These signals can be further compared to the values obtained by standard (normal) spectroscopic measurements. The values of the normal spring constant obtained with our method are in good agreement with the results obtained from the method exploiting the energy equipartition theorem. The statistical analysis shows that the approach proposed in our paper gives reproducible results of the lateral sensitivity with a relative standard deviation less than 15%. PMID- 23942391 TI - Breastfeeding practices among the Old Order Mennonites in Ontario, Canada: a multiple methods study. AB - BACKGROUND: The Old Order Mennonites (OOM) of rural Ontario have a lifestyle that is very distinct from the rest of Canada. Breastfeeding practices among this community have not been described previously. OBJECTIVES: This study aimed to estimate the prevalence of exclusive breastfeeding (EBF) at 2, 4, and 6 months; to compare the prevalence of EBF among OOM and Canadian women; to investigate factors associated with EBF at 6 months; and to gain qualitative insight into the breastfeeding practices of OOM women. METHODS: Data on maternal characteristics, delivery factors, and infant feeding methods at birth and at 2, 4, and 6 months were obtained from medical records at the Elmira Medical Centre for all births to OOM women between January 2006 and December 2011. Semi-structured interviews were carried out with 2 lactation consultants working at the Elmira Medical Centre. RESULTS: Complete breastfeeding data were available for 195 of 225 OOM women (77.4%). The majority of OOM women initiated breastfeeding (87.9%); 81.4% continued to breastfeed exclusively at 2 months, 74.0% to 4 months, and 36.8% to 6 months. Women who had a homebirth (12.3%) had 2.6-fold higher odds of EBF at 6 months (odds ratio, 2.59; 95% confidence interval, 1.03-6.53) compared with women who delivered in a hospital. Cultural and religious influences and community support were suggested as reasons for the relatively high prevalence of EBF. CONCLUSION: Breastfeeding rates among OOM women are consistently higher in the first 6 months of life compared to the general Canadian population. Homebirth independently predicted increased odds of EBF at 6 months. PMID- 23942392 TI - Age-related functional reorganization, structural changes, and preserved cognition. AB - Although healthy aging is associated with general cognitive decline, there is considerable variability in the extent to which cognitive functions decline or are preserved. Preserved cognitive function in the context of age-related neuroanatomical and functional changes, has been attributed to compensatory mechanisms. However, the existing sparse evidence is largely focused on functions associated with the frontal cortex, leaving open the question of how wider age related brain changes relate to compensation. We evaluated relationships between age-related neural and functional changes in the context of preserved cognitive function by combining measures of structure, function, and cognitive performance during spoken language comprehension using a paradigm that does not involve an explicit task. We used a graph theoretical approach to derive cognitive activation-related functional magnetic resonance imaging networks. Correlating network properties with age, neuroanatomical variations, and behavioral data, we found that decreased gray matter integrity was associated with decreased connectivity within key language regions but increased overall functional connectivity. However, this network reorganization was less efficient, suggesting that engagement of a more distributed network in aging might be triggered by reduced connectivity within specialized networks. PMID- 23942393 TI - Comparing exposure metrics for the effects of fine particulate matter on emergency hospital admissions. AB - A crucial step in an epidemiological study of the effects of air pollution is to accurately quantify exposure of the population. In this paper, we investigate the sensitivity of the health effects estimates associated with short-term exposure to fine particulate matter with respect to three potential metrics for daily exposure: ambient monitor data, estimated values from a deterministic atmospheric chemistry model, and stochastic daily average human exposure simulation output. Each of these metrics has strengths and weaknesses when estimating the association between daily changes in ambient exposure to fine particulate matter and daily emergency hospital admissions. Monitor data is readily available, but is incomplete over space and time. The atmospheric chemistry model output is spatially and temporally complete but may be less accurate than monitor data. The stochastic human exposure estimates account for human activity patterns and variability in pollutant concentration across microenvironments, but requires extensive input information and computation time. To compare these metrics, we consider a case study of the association between fine particulate matter and emergency hospital admissions for respiratory cases for the Medicare population across three counties in New York. Of particular interest is to quantify the impact and/or benefit to using the stochastic human exposure output to measure ambient exposure to fine particulate matter. Results indicate that the stochastic human exposure simulation output indicates approximately the same increase in the relative risk associated with emergency admissions as using a chemistry model or monitoring data as exposure metrics. However, the stochastic human exposure simulation output and the atmospheric chemistry model both bring additional information, which helps to reduce the uncertainly in our estimated risk. PMID- 23942395 TI - Ensuring neurologically intact survival in low birth weight newborns. PMID- 23942394 TI - Electromagnetic field exposure assessment in Europe radiofrequency fields (10 MHz 6 GHz). AB - Average levels of exposure to radiofrequency (RF) electromagnetic fields (EMFs) of the general public in Europe are difficult to summarize, as exposure levels have been reported differently in those studies in which they have been measured, and a large proportion of reported measurements were very low, sometimes falling below detection limits of the equipment used. The goal of this paper is to present an overview of the scientific literature on RF EMF exposure in Europe and to characterize exposure within the European population. A comparative analysis of the results of spot or long-term RF EMF measurements in the EU indicated that mean electric field strengths were between 0.08 V/m and 1.8 V/m. The overwhelming majority of measured mean electric field strengths were <1 V/m. It is estimated that <1% were above 6 V/m and <0.1% were above 20 V/m. No exposure levels exceeding European Council recommendations were identified in these surveys. Most population exposures from signals of radio and television broadcast towers were observed to be weak because these transmitters are usually far away from exposed individuals and are spatially sparsely distributed. On the other hand, the contribution made to RF exposure from wireless telecommunications technology is continuously increasing and its contribution was above 60% of the total exposure. According to the European exposure assessment studies identified, three population exposure categories (intermittent variable partial body exposure, intermittent variable low-level whole-body (WB) exposure and continuous low-level WB exposure) were recognized by the authors as informative for possible future risk assessment. PMID- 23942396 TI - Changing gears and child health policy: the journal during the editorship of SK Bhargava (1980-1984). PMID- 23942397 TI - Workplace based assessment: a step to promote competency based postgraduate training. AB - There has been an increasing emphasis on defining outcomes of medical education in terms of performance of trainees. This is a step beyond the description of outcomes in terms of competence that encompasses mostly potential abilities rather than the actual performance. The contextual adaptations and behavior judgments of the trainees are best assessed by a program of in-training assessment. Workplace based assessment (WPBA) is one of the modalities, which assesses the trainee in authentic settings. Though Postgraduate (PG) medical training in India is said to be competency-based, most institutions do not have any formative or in-training assessment program for the same. The two cardinal elements of WPBA are direct observation and conducted in work place in addition to provision of feedback to the trainee. The WPBA conforms to the highest (Level 4: Does) of Millers pyramid and also has the potential to assess at all four levels. Some of the tools used for WPBA are: Logbooks, Clinical Encounter Cards (CEC), mini-Clinical Evaluation Exercise (mini-CEX), Case based discussions, Direct Observation of Procedural Skills (DOPS), Multisource feedback (peers, co workers, seniors, patients) etc. These can be documented in the form of a portfolio that provides a longitudinal view of experiences and progress of the trainee. The WPBA scores high on validity and educational impact by virtue of being based on direct observation in real situation and contextual feedback. The feasibility and acceptability is enhanced by making appropriate choices of tools, advance planning, building of mutual trust, and training of assessors. Given the established benefits of WPBA in shaping clinical learning, there is an imminent need for including this mode of assessment in our clinical training programs especially PG training. PMID- 23942398 TI - Measles control strategies in India: position paper of Indian Academy of Pediatrics. AB - Measles continues to be a major cause of childhood morbidity and mortality in India. Recent studies estimate that 80,000 Indian children die each year due to measles and its complications, amounting to 4% of under-5 deaths. Immunization against measles directly contributes to the reduction of under five child mortality and hence to the achievement of Millennium Development Goal 4 (MDG 4). The live attenuated measles vaccines are safe, effective and provide long lasting protection. The key strategies being followed globally for measles mortality reduction are high coverage of measles first dose, sensitive laboratory supported surveillance, appropriate case management, and providing second dose of measles vaccine. Prior to 2010, India was the only country in the world that had not introduced a second dose of measles vaccine in its National immunization program. We herein discuss the current status of measles vaccination along with the rationale and challenges of providing a second opportunity for measles vaccination, and the principles of measles catch-up campaigns. PMID- 23942399 TI - Immunological and hematological effects of perinatal exposure to antiretroviral drugs in HIV exposed, non infected children. PMID- 23942400 TI - Diagnostic approach to primary immunodeficiency disorders. AB - Primary immunodeficiency disorders (PIDs) are a heterogeneous group of inherited disorders that affect different components of the immune system. There are more than 150 different disorders which have been described till date. Despite major advances in the molecular characterization of PIDs over the last 20 years, many patients remain undiagnosed or are diagnosed too late with severe consequences. Recognizing different clinical manifestations of PID is the first most important step. It should be followed by use of appropriate diagnostic tools from a vast number of investigations available. This review will focus on important presenting features of PID and laboratory approach for diagnosis of suspected cases of PID. PMID- 23942401 TI - Influenza-B associated rhabdomyolysis and acute renal failure. AB - We present a 15 year old boy who developed severe rhabdomyolysis and acute renal failure following influenza B infection. His renal function was restored after appropriate therapy for rhabdomyolysis. Although rapidly progressive pneumonia, respiratory failure, and acute respiratory distress syndrome are the most common severe complications of influenza B infection, clinicians should be aware that influenza B may be complicated with rhabdomyolysis and acute renal failure in children. PMID- 23942402 TI - Naxos disease and Carvajal variant. AB - An 11-yr-old girl, born out of a consanguineous marriage presented with recurrent exertional syncope due to ventricular tachycardia. She had woolly hair, palmoplantar hyperkeratosis and mild cardiomegaly. Echocardiogram revealed mild left ventricular dysfunction. Features were consistent with Carvajal variant of Naxos disease, an arrhythmogenic cardiomyopathy with autosomal recessive inheritance. PMID- 23942403 TI - Bardet-Biedl syndrome a rare cause of cardiomyopathy. AB - Bardet Biedl syndrome (BBS) is a rare autosomal recessive condition characterized by retinitis pigmentosa, polydactyly, obesity, learning disabilities, hypogonadism and renal anomalies. Cardiomyopathy in association with BBS has previously being reported only twice in literature. We report a case of a patient presenting with features of cardiomyopathy, who was subsequently diagnosed to have BBS. PMID- 23942404 TI - Meningitis due to Neisseria meningitidis serogroup B in India. AB - Invasive meningococcal disease has a fulminant course and high mortality. Neisseria meningitidis serogroup A is predominantly responsible for meningococcal disease in India and the developing countries. Group B meningococcus, which is prevalent in the developing world is uncommon in India. We herein report the second case of group B meningococcal infection from the country, two decades after the reporting of the first case. Ineffective vaccines against serogroup B warrant the need for close surveillance of this disease. PMID- 23942405 TI - Myxoid lipoblastoma. AB - A rapidly growing soft tissue mass in the axilla of an infant raises the suspicion of a lipoblastoma or a liposarcoma. Excisional/incisional biopsy is vital in confirming the diagnosis and hence avoiding aggressive extirpation. This case report highlights the role of histopathology and immunohistochemistry as the gold standard in differentiating a lipoblastoma from a liposarcoma. In some cases where the histopathology is inconclusive, genetic rearrangement of the PLAG1 (pleomorphic adenoma gene 1) oncogene on chromosome 8q12 helps in confirming the diagnosis of lipoblastoma. PMID- 23942406 TI - Rhizomelic chondrodysplasia punctata with maternal systemic lupus erythromatosus. AB - We report Rhizomelic Chondrodysplasia Punctata (RDCP), a rare, autosomal recessive disorder with rhizomelic shortening of limbs, congenital cataracts and seizures but without any biochemical abnormality. The mother of the baby developed Systemic Lupus Erythromatosus (SLE) with Ro/SSA antibodies 11 months after delivery. Ro/SSA antibodies may generate calreticulin antibodies causing characteristic skeletal changes. PMID- 23942407 TI - Very low-dose intravenous immunoglobulin for treatment of immune thrombocytopenic purpura. PMID- 23942408 TI - Ventricular ectopic beats in a child receiving carbamazepine. PMID- 23942409 TI - Management of severe scorpion sting at a rural hospital. PMID- 23942410 TI - Childhood catatonia. PMID- 23942411 TI - Further considerations on the so-called Rowell syndrome. PMID- 23942412 TI - Effect of infliximab top-down therapy on weight gain in pediatric Crohn's disease. PMID- 23942413 TI - Chronic bullous disease of childhood. PMID- 23942414 TI - Bronze baby syndrome. PMID- 23942415 TI - Effects of alpha-tocopherol supplementation on liver of rats chronically exposed to ethanol. AB - BACKGROUND/AIMS: Chronic alcoholism is characterized by hepatotoxicity associated with antioxidant and redox status imbalance. Continuous ethanol intake induces free radical synthesis, resulting in the depletion of antioxidants, especially alpha-tocopherol, which has an important role in lipid peroxidation. This study aimed to evaluate if alpha-tocopherol supplementation can restore liver phenotype in rats chronically exposed to ethanol. METHODS: alpha-Tocopherol levels were determined and histologic analysis of liver was performed. Hepatic gene expression was analyzed through oligonucleotide microarray and real-time PCR. RESULTS: Alcohol exposure for 6 weeks did not decrease hepatic alpha-tocopherol levels; however, both groups exposed to ethanol (supplemented or not with alpha tocopherol) displayed fatty liver. The antioxidant supplementation prevented Mallory bodies and inflammatory infiltration, but not apoptosis, in liver of the rats exposed to ethanol. Gene expression analysis showed evidence of adaptive response to chronic alcohol consumption, where antioxidant components were not regulated. Nevertheless, differentially expressed genes reflected the change in cellular homeostasis. CONCLUSION: The hepatic alpha-tocopherol content was coherent with the antioxidant gene expression in this study. Cells are likely to have adapted and restored their antioxidant status after long-term ethanol exposure, which might be the reason for such conflicting reports concerning alpha tocopherol status in chronic alcoholism. PMID- 23942416 TI - Deep subwavelength fourfold rotationally symmetric split-ring-resonator metamaterials for highly sensitive and robust biosensing platform. AB - Metamaterials provide a good platform for biochemical sensing due to its strong field localization at nanoscale. In this work, we show that electric and magnetic resonant modes in split-ring-resonator (SRR) can be efficiently excited under unpolarized light illumination when the SRRs are arranged in fourfold rotationally symmetric lattice configuration. The fabrication and characterization of deep subwavelength (~lambda/15) gold-based SRR structures with resonator size as small as ~ 60 nm are reported with magnetic resonances in Vis-NIR spectrum range. The feasibility for sensing is demonstrated with refractive index sensitivity as high as ~ 636 nm/RIU. PMID- 23942417 TI - Systematic investigation of organic photovoltaic cell charge injection/performance modulation by dipolar organosilane interfacial layers. AB - With the goal of investigating and enhancing anode performance in bulk heterojunction (BHJ) organic photovoltaic (OPV) cells, the glass/tin-doped indium oxide (ITO) anodes are modified with a series of robust silane-tethered bis(fluoroaryl)amines to form self-assembled interfacial layers (IFLs). The modified ITO anodes are characterized by contact angle measurements, X-ray reflectivity, ultraviolet photoelectron spectroscopy, X-ray photoelectron spectroscopy, grazing incidence X-ray diffraction, atomic force microscopy, and cyclic voltammetry. These techniques reveal the presence of hydrophobic amorphous monolayers of 6.68 to 9.76 A thickness, and modified anode work functions ranging from 4.66 to 5.27 eV. Two series of glass/ITO/IFL/active layer/LiF/Al BHJ OPVs are fabricated with the active layer = poly(3-hexylthiophene):phenyl-C71-butyric acid methyl ester (P3HT:PC71BM) or poly[[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2 b:4,5-b']dithiophene-2,6-diyl][3-fluoro-2-[(2-ethylhexyl)-carbonyl]thi-eno[3,4 b]thiophenediyl]]:phenyl-C71-butyric acid methyl ester (PTB7:PC71BM). OPV analysis under AM 1.5G conditions reveals significant performance enhancement versus unmodified glass/ITO anodes. Strong positive correlations between the electrochemically derived heterogeneous electron transport rate constants (ks) and the device open circuit voltage (Voc), short circuit current (Jsc), hence OPV power conversion efficiency (PCE), are observed for these modified anodes. Furthermore, the strong functional dependence of the device response on ks increases as greater densities of charge carriers are generated in the BHJ OPV active layer, and is attributable to enhanced anode carrier extraction in the case of high-ks IFLs. PMID- 23942419 TI - A highly permeable mixed matrix membrane containing CAU-1-NH2 for H2 and CO2 separation. AB - A thin and compact mixed matrix membrane containing CAU-1-NH2 and the poly(methyl methacrylate) polymer has been originally synthesized. The as-prepared membrane exhibits high permeability of H2 and excellent H2/CO2 selectivity. PMID- 23942418 TI - Incentive learning for morphine-associated stimuli during protracted abstinence increases conditioned drug preference. AB - Previous studies from our laboratory found that rats express increased preference for drug-paired stimuli following 2 or 5 weeks of protracted abstinence from chronic drug exposure as compared with naive animals. Here, we show that this increased morphine place preference depends upon experiencing drug-stimulus pairings specifically in the abstinent state, indicating a critical role for incentive learning. Male Sprague Dawley rats were initially conditioned for morphine place preference (8 mg/kg) and then made dependent on morphine (by subcutaneous morphine pellets) and subjected to forced abstinence. Place preference was tested every 1-2 weeks with no additional drug-cue conditioning. In this paradigm, there was no difference between morphine-pelleted (dependent) and placebo-pelleted (non-dependent) rats in place preference at any time during abstinence (up to 6 weeks). However, these same morphine-pelleted rats expressed significantly increased preference when they were subsequently re-conditioned for morphine place preference during protracted abstinence. Placebo-pelleted rats did not show enhanced preference after re-conditioning. These findings reveal that incentive learning has a key role in increased morphine place preference when drug is experienced during protracted abstinence. This indicates that incentive learning is involved not only in instrumental responding (as previously reported), but also in updating Pavlovian-conditioned responses to morphine associated stimuli. Therefore, enhanced morphine preference is not a direct consequence of the negative affective state of abstinence, but instead reflects increased acquisition of morphine-stimulus associations during abstinence. These results indicate that, during the development of addiction in humans, drug associated stimuli acquire increasingly stronger incentive properties each time they are re-experienced. PMID- 23942420 TI - Design and synthesis of positional isomers of 5 and 6-bromo-1-[(phenyl)sulfonyl] 2-[(4-nitrophenoxy)methyl]-1H-benzimidazoles as possible antimicrobial and antitubercular agents. AB - In this Letter, we report the structure-activity relationship (SAR) studies on series of positional isomers of 5(6)-bromo-1-[(phenyl)sulfonyl]-2-[(4 nitrophenoxy)methyl]-1H-benzimidazoles derivatives 7(a-j) and 8(a-j) synthesized in good yields and characterized by (1)H NMR, (13)C NMR and mass spectral analyses. The crystal structure of 7a was evidenced by X-ray diffraction study. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, (Gram-positive), Escherichia coli and Klebsiella pneumoniae (Gram-negative), antifungal activity against Candida albicans, Aspergillus flavus and Rhizopus sp. and antitubercular activity against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis, Mycobacterium fortuitum and MDR-TB strains. The synthesized compounds displayed interesting antimicrobial activity. The compounds 7b, 7e and 7h displayed significant activity against Mycobacterium tuberculosis H37Rv strain. PMID- 23942421 TI - The first synthesis of natural disulfide bruguiesulfurol and biological evaluation of its derivatives as a novel scaffold for PTP1B inhibitors. AB - Bruguiesulfurol (1), a cyclic 4-hydroxy-dithiosulfonate isolated from mangrove plant Bruguiera gymnorrhiza, was concisely synthesized for the first time in four steps, and a series of its synthetic derivatives were evaluated for in vitro inhibitory effects on PTP1B and related PTPs. Some derivatives were found to have improved pharmacological profile compared with hit 1. Among them, 5a showed the potent selectivity towards PTP1B over other PTPs, including TCPTP, and 7j exhibited the strongest PTP1B inhibitory activity with an IC50 value of 4.54 MUM. PMID- 23942423 TI - Another option in reducing hospital readmissions from skilled nursing facilities: Project RED (ReEngineered Discharge). PMID- 23942424 TI - Experimental evidence of tunable space-charge-layer-induced electrical properties of nanocrystalline ceria thin films. AB - Fully dense nanocrystalline ceria films were successfully deposited on a MgO single crystal by pulsed laser deposition (PLD). The electrical conductivity of the nanocrystalline thin film was 20 times higher than that of the bulk sample. The activation energy of bulk ceria was 2.3 eV, whereas the activation energy of the nanocrystalline sample was only 1.2 eV. After post-annealing at 1273 K in which the grain size of the nanocrystalline thin film increased to ~400 nm, the electrical conductivity and activation energy of the film were changed similar to those of bulk. These unique electrical properties of the nano-crystalline thin film can be attributed to the grain size effect, or more specifically, to the space charge layer (SCL) effect. Furthermore, the electrical conductivity of the nanocrystalline thin film became similar to that of the bulk in an extremely reducing atmosphere because of the unusual dependence of the SCL effect on the oxygen partial pressure. PMID- 23942422 TI - Fallers in postacute rehabilitation have worse functional recovery and increased health services use. AB - OBJECTIVES: To determine characteristics associated with single and multiple fallers during postacute rehabilitation and to investigate the relationship among falls, rehabilitation outcomes, and health services use. DESIGN: Retrospective cohort study. SETTING: Geriatric postacute rehabilitation hospital. PARTICIPANTS: Patients (n = 4026) consecutively admitted over a 5-year period (2003-2007). MEASUREMENTS: All falls during hospitalization were prospectively recorded. Collected patients' characteristics included health, functional, cognitive, and affective status data. Length of stay and discharge destination were retrieved from the administrative database. RESULTS: During rehabilitation stay, 11.4% (458/4026) of patients fell once and an additional 6.3% (253/4026) fell several times. Compared with nonfallers, fallers were older and more frequently men. They were globally frailer, with lower Barthel score and more comorbidities, cognitive impairment, and depressive symptoms. In multivariate analyses, compared with 1 time fallers, multiple fallers were more likely to have lower Barthel score (adjOR: 2.45, 95% CI: 1.48-4.07; P = .001), cognitive impairment (adjOR: 1.43, 95% CI: 1.04-1.96; P = .026), and to have been admitted from a medicine ward (adjOR: 1.55, 95% CI: 1.03-2.32; P = .035). Odds of poor functional recovery and institutionalization at discharge, as well as length of stay, increased incrementally from nonfallers to 1-time and to multiple fallers. CONCLUSION: In these patients admitted to postacute rehabilitation, the proportion of fallers and multiple fallers was high. Multiple fallers were particularly at risk of poor functional recovery and increased health services use. Specific fall prevention programs targeting high-risk patients with cognitive impairment and low functional status should be developed in further studies. PMID- 23942425 TI - Psychiatric comorbidity and personality structure in patients with polyvalent addiction. AB - BACKGROUND: This study focuses on the systematic psychiatric evaluation of polydrug-using opiate-dependent patients, using the standard DSM-IV diagnostic interviews and a new psychodynamic instrument operationalizing personality organization (Structured Interview of Personality Organization, STIPO). SAMPLING AND METHOD: 50 patients were interviewed with the Structured Clinical Interview for DSM-IV Disorders (SCID) I and II and the STIPO by two independent researchers at a detoxification treatment unit. RESULTS: According to the SCID I and II, all patients had at least one axis I disorder, 90% at least one axis II disorder. A correspondence was found between STIPO and SCID results, in that more pathology in the SCID coincided with more severity in the STIPO. According to the STIPO, 100% of the patients were located at the level of borderline personality organization, indicating identity pathology according to Kernberg's model. CONCLUSION: Given the fact that comorbid psychiatric disorders compromise the outcome of detoxification and dehabituation treatments, it is highly relevant to diagnose these disorders and to assess underlying personality pathology. While the evidence of psychosocial treatments in addiction therapy is still weak, the integration of syndrome-tailored treatment modules may help improve the treatment of patients with this chronically relapsing condition. LIMITATION: small sample size. PMID- 23942427 TI - Ifenprodil for the treatment of flashbacks in adolescent female posttraumatic stress disorder patients with a history of abuse. PMID- 23942429 TI - Kick-starting mission Uday district coordinators meeting. PMID- 23942431 TI - Leading the journal to Silver Jubilee and beyond Dr R N Srivastava as the editor from1985 to 1990. PMID- 23942430 TI - National newborn screening program still a hype or a hope now? AB - The year 2013 marks 50 years of both newborn screening and the Indian Academy of Pediatrics. India has seen a lot of change in terms of motivation, evolution and implementation of newborn screening as pilot projects for few disorders. Facilities for implementing screening using tandem mass spectrometry or what is termed as expanded newborn screening have also become available. We attempt to discuss the evolution of newborn screening and the way to carry it forward in the country. The current strengths, the major obstacles and gritty challenges are enlisted. No moment could be so opportune than this year to discuss the rainbow of hope with all its colors with respect to newborn screening in our country. PMID- 23942428 TI - Kinetic and mechanistic investigation of the substitution reactions of four and five co-ordinated rhodium stibine complexes with a bulky phosphite. AB - The substitution reaction of trans-[Rh(Cl)(CO)(SbPh3)2] (1) with tris(2,4-di-tert butylphenyl)phosphite (2,4-TBPP) to form trans-[Rh(Cl)(CO)(2,4-TBPP)2] (4) in two consecutive steps has been investigated by UV-vis stopped-flow spectrophotometry. The experiments were performed in dichloromethane and in ethyl acetate, at 298 K and 268 K respectively for the first reaction step, and for the second reaction step over a temperature range from 278 to 313 K in both solvents. The first step is very fast (up to 1630 s(-1)) and on the limit of what is observable with the stopped-flow technique. Introduction of the five-coordinate complex trans [Rh(Cl)(CO)(SbPh3)3] (2) in equilibrium with (1), by adding an excess SbPh3, led to a significant decrease in overall reaction rate for the formation of the intermediate trans-[Rh(Cl)(CO)(SbPh3)2(2,4-TBPP)] (3). Activation parameters for the second substitution reaction, in which 3 is converted to 4, has been determined as DeltaH? = 22.85 +/- 0.17 and 28.38 +/- 0.10 kJ mol(-1) and DeltaS? = -144.7 +/- 0.6 and -100.9 +/- 0.4 J mol(-1) K(-1) for CH2Cl2 and EtOAc respectively, supporting an associative pathway. A strongly coordinating solvent promotes both reactions. In all reaction steps a strong tendency for stibines to promote 5-coordinated, fairly stable intermediates is manifested. PMID- 23942435 TI - Thrombotic microangiopathic syndrome: a novel complication of diabetic ketoacidosis. AB - Thrombotic microangiopathic syndrome secondary to diabetic ketoacidosis is an under reported entity in children. We describe 2 girls who developed thrombotic thrombocytopenic purpura (TTP) and thrombocytopenia associated multi organ failure (TAMOF) in new onset diabetes. Both patients presented with classical findings of DKA and were intubated due to low GCS, admitted in PICU and managed according to DKA guidelines. Later on, both patients developed thrombocytopenia, acute kidney injury, and low hemoglobin along with evidence of microangiopathy on peripheral smear. One patient developed paraparesis while other patient had high LDH levels. The clinical diagnosis of TTP and TAMOF was made respectively. Both patients were treated with plasmapharesis and renal replacement therapy. Both gradually improved and were discharged. PMID- 23942432 TI - Vitamin D deficiency in childhood-a review of current guidelines on diagnosis and management. AB - Vitamin D deficiency has emerged as a significant public health problem throughout the world. Even in the Indian context,it has been reported to be present in majority of children in spite of wide availability of sunlight. Recent guidelines have defined vitamin D status as severe deficiency, deficiency, sufficiency and risk for toxicity as 25(OH)D levels <5, <15, >20 and >50ng/mL, respectively.The manifestations of deficiency may vary from hypocalcemic seizures, tetany in infancy and adolescence to florid rickets in toddlers. Treatment is necessary for all individuals with deficiency whether symptomatic or not and consists of vitamin D supplementation as Stoss therapy or daily or weekly oral regimens with equal efficacy and safety, combined with calcium supplements. Routine supplementation starting from newborn period is being increasingly endorsed by various international organizations. Prevention by sensible sunlight exposure, food fortification and routine supplementation are the currently available options for tackling this nutritional deficiency. PMID- 23942436 TI - Neonatal zygomycosis with gastric perforation. AB - Zygomycosis is a rare infection in neonates. The clinical presentation is non specific and diagnosis most often is made at autopsy. Surgical debridement performed early improves survival. We report a case of neonatal zygomycosis with gastric perforation. PMID- 23942434 TI - Locked-in syndrome as a presentation of snakebite. AB - Snake bite is a common condition in tropical countries. Neurotoxic features of snake bite vary from early morning neuroparalytic syndrome to various cranial nerve palsies. Locked in syndrome (LIS) is a rare presentation. We present four children that had LIS; three patients had total and one had incomplete LIS. All patients made successful recovery with polyvalent anti-snake venom and supportive management. This case series highlights the importance of early diagnosis of LIS in snake bite. PMID- 23942433 TI - Distal renal tubular acidosis with hereditary spherocytosis. AB - Hereditary spherocytosis (HS) and distal renal tubular acidosis (dRTA), although distinct entities, share the same protein i.e. the anion exchanger1 (AE1) protein. Despite this, their coexistence has been rarely reported. We hereby describe the largest family to date with co-existence of dRTA and HS and discuss the molecular basis for the co-inheritance of these conditions. PMID- 23942439 TI - Latency intervals of Moro response: a valuable neuro-screening tool. AB - Moro response in healthy term newborns were studied to determine latency interval, time taken for optimal response (embracing movement of arms), and total duration of reflex response. Latency interval for onset of response was 0.41 0.49. Time taken for optimal response was 0.910-1.041s. Total duration of Moro response was 2.34 -2.59 s. Values were similar for males and females. Optimal response in babies born by cesarean section were significantly delayed than vaginal babies. PMID- 23942437 TI - Inferior vena caval and right atrial thrombosis: complicating pyogenic liver abscess. AB - Vascular complication of liver abscess are rare but life-threatening. We herein report a 2 year 9 month boy with pyogenic hepatic abscess complicated by inferior vena cava thrombus extending to right atrium. Early clinical suspicion aided by ultrasonography and echocardiography confirmed the diagnosis. The child was treated successfully with timely medical and surgical intervention. PMID- 23942440 TI - Bone metabolism in cow milk allergic children. AB - Children with cow milk allergy are suspected to develop calcium metabolism disturbances. We observed increased markers of bone turnover in these children. Children with cow milk allergy are more prone to develop the disturbances of the bone mineralization even in the first year of life. PMID- 23942438 TI - Hematidrosis. AB - Hematidrosis is an extremely rare clinical entity characterized by recurrent episodes of skin bleeding mixed with sweat. We report a case of hematidrosis in a 10 year old girl where detailed laboratory and histopathological investigation revealed no abnormality. The girl was successfully treated with propranolol with no recurrence of bleeding over a follow-up of 3 months. PMID- 23942441 TI - Bacteriology and antibiotic resistance pattern in community acquired urinary tract infection. AB - Extensive use of antibiotics have resulted in development of resistance among most commonly used drugs in community acquired urinary tract infection (UTI). This study was conducted to identify the resistance pattern in community acquired UTI .We collected urine for routine examination and culture from suprapubic urine in all the cases to avoid any contamination. E. Coli was the most common organism identified. Among oral antibiotics, there was high degree of resistance to penicillin group and cephalosporin groups. Among parentral antibiotics, all the cephalosporins were variably resistant except cephaperazone-salbactum. PMID- 23942442 TI - Delayed presentation of traumatic diaphragmatic hernia. PMID- 23942443 TI - Synthetic apple juice masquerading as low-osmolar ORS. PMID- 23942444 TI - Prevention of mother to child transmission of hepatitis B infection-need for holistic approach. PMID- 23942445 TI - Behcet disease presenting as deep vein thrombosis and epididymoorchitis. PMID- 23942446 TI - Febrile rash and convalescent rash of dengue fever. PMID- 23942447 TI - Darier-white disease. PMID- 23942448 TI - V-SRC informs integrin signalling. PMID- 23942449 TI - Morphogenesis: fuelling vessel sprouting. PMID- 23942450 TI - Mechanisms and mechanics of cell competition in epithelia. AB - When fast-growing cells are confronted with slow-growing cells in a mosaic tissue, the slow-growing cells are often progressively eliminated by apoptosis through a process known as cell competition. The underlying signalling pathways remain unknown, but recent findings have shown that cell crowding within an epithelium leads to the eviction of cells from the epithelial sheet. This suggests that mechanical forces could contribute to cell elimination during cell competition. PMID- 23942452 TI - Cell cycle: Getting to the centre. PMID- 23942451 TI - Protein adaptation: mitotic functions for membrane trafficking proteins. AB - Membrane trafficking and mitosis are two essential processes in eukaryotic cells. Surprisingly, many proteins best known for their role in membrane trafficking have additional 'moonlighting' functions in mitosis. Despite having proteins in common, there is insufficient evidence for a specific connection between these two processes. Instead, these phenomena demonstrate the adaptability of the membrane trafficking machinery that allows its repurposing for different cellular functions. PMID- 23942456 TI - Effects of bursty protein production on the noisy oscillatory properties of downstream pathways. AB - Experiments show that proteins are translated in sharp bursts; similar bursty phenomena have been observed for protein import into compartments. Here we investigate the effect of burstiness in protein expression and import on the stochastic properties of downstream pathways. We consider two identical pathways with equal mean input rates, except in one pathway proteins are input one at a time and in the other proteins are input in bursts. Deterministically the dynamics of these two pathways are indistinguishable. However the stochastic behavior falls in three categories: (i) both pathways display or do not display noise-induced oscillations; (ii) the non-bursty input pathway displays noise induced oscillations whereas the bursty one does not; (iii) the reverse of (ii). We derive necessary conditions for these three cases to classify systems involving autocatalysis, trimerization and genetic feedback loops. Our results suggest that single cell rhythms can be controlled by regulation of burstiness in protein production. PMID- 23942453 TI - Restarting life: fertilization and the transition from meiosis to mitosis. AB - Fertilization triggers a complex cellular programme that transforms two highly specialized meiotic germ cells, the oocyte and the sperm, into a totipotent mitotic embryo. Linkages between sister chromatids are remodelled to support the switch from reductional meiotic to equational mitotic divisions; the centrosome, which is absent from the egg, is reintroduced; cell division shifts from being extremely asymmetric to symmetric; genomic imprinting is selectively erased and re-established; and protein expression shifts from translational control to transcriptional control. Recent work has started to reveal how this remarkable transition from meiosis to mitosis is achieved. PMID- 23942458 TI - Security analysis and improvements to the PsychoPass method. AB - BACKGROUND: In a recent paper, Pietro Cipresso et al proposed the PsychoPass method, a simple way to create strong passwords that are easy to remember. However, the method has some security issues that need to be addressed. OBJECTIVE: To perform a security analysis on the PsychoPass method and outline the limitations of and possible improvements to the method. METHODS: We used the brute force analysis and dictionary attack analysis of the PsychoPass method to outline its weaknesses. RESULTS: The first issue with the Psychopass method is that it requires the password reproduction on the same keyboard layout as was used to generate the password. The second issue is a security weakness: although the produced password is 24 characters long, the password is still weak. We elaborate on the weakness and propose a solution that produces strong passwords. The proposed version first requires the use of the SHIFT and ALT-GR keys in combination with other keys, and second, the keys need to be 1-2 distances apart. CONCLUSIONS: The proposed improved PsychoPass method yields passwords that can be broken only in hundreds of years based on current computing powers. The proposed PsychoPass method requires 10 keys, as opposed to 20 keys in the original method, for comparable password strength. PMID- 23942457 TI - Characterizing HIV manifestations and treatment outcomes of perinatally infected adolescents in Asia. AB - BACKGROUND: More perinatally HIV-infected children in Asia are reaching adolescence. METHODS: We analyzed data from July 1991 to March 2011 reported by 18 clinics in 6 countries of children age >12 years. RESULTS: Of 1254 adolescents, 33 (2.6%) died, and 52 (4.1%) were lost to follow-up within 2.4-year (3566 person-years) median follow-up period. Of 1061 adolescents under active follow-up, 485 (46%) were male, median (interquartile range) age was 14.7 (13.3 16.4) years, 73% had lost a parent(s), 93% attended school and 62% were aware of their HIV status. At the most recent evaluation, 93% were receiving highly active antiretroviral therapy, 71% (N = 737/1035) had CD4 >= 500 cells/mm(3) and 87% (N = 718/830) had viral load (VL) <400 copies/mL. Current CD4 >= 200 cells/mm(3), no previous World Health Organization stage 3 or 4 and being on a first-line regimen were independently associated with recent VL <400 copies/mL. Current age <15 years, VL <400 copies/mL, CD4 15-24% (vs. <10%) at antiretroviral therapy initiation, no previous World Health Organization stage 3 or 4 and antiretroviral therapy duration of >= 1 year were associated with recent CD4 >= 500 cells/mm(3). Primary causes of death after age 12 were opportunistic infections (N = 15/33) and other AIDS- or treatment-related conditions (N = 9/33). Those at age 12 with CD4 <200 versus >= 500 cells/mm and those with VL >= 10,000 versus <10,000 copies/mL were 17.4 and 4.76 times more likely to die in adolescence, respectively. CONCLUSION: Adolescents in this cohort have been successfully maintained in HIV care. Initiating treatment at earlier stages of disease was associated with immune recovery and virologic suppression during adolescence. PMID- 23942459 TI - Involvement of heat shock proteins in Candida albicans biofilm formation. AB - Biofilm growth represents one of the most challenging problems associated with Candida infections, largely due to the natural resistance of biofilm to the common antifungal drugs. As elevated expression of heat shock proteins (HSP) promotes Candida yeast-hyphae switch, which is an essential step in biofilm formation, we investigated the expression of hsp genes during Candida albicans biofilm development. By measuring mRNA levels using qRT-PCR, we found that all three hsp genes that we monitored are overexpressed in the initial stage of C. albicans biofilm formation. To corroborate this finding, we examined the effect of 17-DMAG, a specific Hsp90 inhibitor, on the formation of C. albicans biofilm. Our results indicate the requirement of HSP during the early phase of Candida biofilm development. PMID- 23942460 TI - Self-running Ga droplets on GaAs (111)A and (111)B surfaces. AB - Thermal decomposition of GaAs (111)A and (111)B surfaces in ultrahigh vacuum results in self-running Ga droplets. Although Ga droplets on the (111)B surface run in one main direction, those on the (111)A surface run in multiple directions, frequently taking sharp turns and swerving around pyramidal etch pits, leaving behind mixed smooth-triangular trails as a result of simultaneous in-plane driving and out-of-plane crystallographic etching. The droplet motion is partially guided by dislocation strain fields. The results hint at the possibilities of using subsurface dislocation network and prepatterned, etched surfaces to control metallic droplet motion on single-crystal semiconductor surfaces. PMID- 23942463 TI - A decatungstate-type polyoxoniobate with centered manganese: [H2Mn(IV)Nb10O32]8- as a soluble tetramethylammonium salt. AB - A highly symmetric Mn(IV)-centered polyoxoniobate [H2Mn(IV)Nb10O32](8-) was synthesized via hydrothermal methods as a soluble tetramethylammonium salt. The structure is similar to decatungstate structure [W10O32](4-), except for the central heteroatom. The cluster is stable between 4 < pH < 10, as was characterized with ESI-MS and UV-Vis spectroscopy. PMID- 23942461 TI - Freedom and mystery: an intellectual history of Jaspers' General Psychopathology. AB - The Kantian idea of freedom was introduced to psychiatry methodologically by Karl Jaspers. It influenced the genesis and design of his doctrine of understanding, General Psychopathology, even more decisively than Nietzsche's topos of resentment did. This article places Jaspers' work in the framework of a history of ideas. It begins by pursuing Nietzsche's perspective in the context of Darwinism, then focuses on the role concealed resentment played for Jaspers' genealogical concept of understanding in the first (1913) edition of General Psychopathology, which is primarily oriented towards Max Weber, before examining the idea of Kantian freedom, which was to become crucial for Jaspers' later work. The antinomy of freedom already shapes the suicidology contained in Jaspers' Philosophy of 1931. The idea gains prominence in the final, philosophically grounded revision of GeneralPsychopathology published in 1941/1942. Jaspers' reception of Kantian idealism leads him to develop a concept of critical understanding that clearly distinguishes itself from speculative understanding, whose hazards Jaspers illustrates on the basis of Viktor von Weizsacker's theory of medicine. This goes far beyond Kant, embracing Schelling and Hegel philosophically. As it were, Jaspers and von Weizsacker represent critical and postcritical thought in psychopathology and psychosomatics. The epilogue sums up by placing the inquiry in the context of Jaspers' life and work. PMID- 23942465 TI - Expression of the lymphoid enhancer factor 1 is required for normal hematopoietic stem and progenitor cell function. PMID- 23942466 TI - Development: Branched for function. PMID- 23942467 TI - The neuroscience of memory: implications for the courtroom. AB - Although memory can be hazy at times, it is often assumed that memories of violent or otherwise stressful events are so well encoded that they are effectively indelible and that confidently retrieved memories are almost certainly accurate. However, findings from basic psychological research and neuroscience studies indicate that memory is a reconstructive process that is susceptible to distortion. In the courtroom, even minor memory distortions can have severe consequences that are partly driven by common misunderstandings about memory--for example, that memory is more veridical than it may actually be. PMID- 23942468 TI - Techniques: Optogenetics takes more control. PMID- 23942472 TI - Current concepts and new trends in the diagnosis and management of recurrent miscarriage. AB - Pregnancy is a proinflammatory and hypercoagulable state. Miscarriage concerns approximately 15% of pregnancies. Recurrent miscarriage is a rather rare condition with an estimated incidence of 1% to 3%. However, despite years of investigation, the etiology is not established in up to 50% of cases. A multidisciplinary approach in the evaluation of miscarriage is essential to understand the cause and risk of recurrence. Although genetic factors are the major cause of spontaneous miscarriages, their relationship with recurrent miscarriage is less frequent. Recently, many kinds of genetic polymorphisms have also been found to be associated. Endocrine disorders such as poorly controlled diabetes, polycystic ovary syndrome, and hypothyroidism are linked with recurrent miscarriage. The relationship between recurrent miscarriage and subclinical thyroid disorders and thyroid autoimmunity is disputed, especially in early miscarriages. Uterine malformations should be considered as a cause of recurrent miscarriage. Although autoimmune-based recurrent miscarriage has been described, mainly antiphospholipid antibodies, the role of alloimmune mechanisms remains poorly understood. The influence of congenital thrombophilia is controversial. Antiphospholipid syndrome or antiphospholipid antibody-related recurrent miscarriage, and some endocrinologic disorders, have a specific and effective treatment. Still, the effectiveness of some common treatments needs to be demonstrated. PMID- 23942471 TI - Exploring electronic structure of one-atom thick polycrystalline graphene films: a nano angle resolved photoemission study. AB - The ability to produce large, continuous and defect free films of graphene is presently a major challenge for multiple applications. Even though the scalability of graphene films is closely associated to a manifest polycrystalline character, only a few numbers of experiments have explored so far the electronic structure down to single graphene grains. Here we report a high resolution angle and lateral resolved photoelectron spectroscopy (nano-ARPES) study of one-atom thick graphene films on thin copper foils synthesized by chemical vapor deposition. Our results show the robustness of the Dirac relativistic-like electronic spectrum as a function of the size, shape and orientation of the single-crystal pristine grains in the graphene films investigated. Moreover, by mapping grain by grain the electronic dynamics of this unique Dirac system, we show that the single-grain gap-size is 80% smaller than the multi-grain gap recently reported by classical ARPES. PMID- 23942473 TI - Update on raloxifene: mechanism of action, clinical efficacy, adverse effects, and contraindications. AB - Raloxifene is the only selective estrogen receptor modulator approved for long term treatment in the prevention of osteoporotic fractures and for the reduction of invasive breast cancer risk in post-menopausal women. The demonstrated beneficial effects on bone and mammalian tissue led clinical and molecular research to focus mainly on these organs, giving less attention to all other systemic effects. The aim of this review was to evaluate all described systemic effects of raloxifene, investigating its molecular and tissutal mechanism of action. A literature research was carried out in electronic databases MEDLINE, EMBASE, ScienceDirect, and the Cochrane Library in interval time between 2000 and 2012. Outcomes were considered in relation to positive/adverse effects concerning bone metabolism, lipid metabolism, coagulation pattern, menopausal symptoms, breast cancer onset, and endometrial cancer onset. Raloxifene acts as an estrogen agonist or antagonist depending on the tissue. This feature is related to specific actions on at least 2 distinct estrogen receptors, whose proportions vary according to tissue type. Raloxifene is a drug for the treatment of osteoporosis and for the prevention of estrogen receptor-positive breast cancer because it guarantees a safety profile on the endometrium. Raloxifene is furthermore an effective therapy in women with increased levels of plasma cholesterol. Raloxifene treatment shifts the coagulation pattern toward prothrombosis, and the patients should be exhaustively informed about the risks associated with therapy. Raloxifene does not show to affect memory and cognition. Finally, it is noteworthy that quality-of-life studies demonstrated some favorable effects of raloxifene. PMID- 23942470 TI - The brain reward circuitry in mood disorders. AB - Mood disorders are common and debilitating conditions characterized in part by profound deficits in reward-related behavioural domains. A recent literature has identified important structural and functional alterations within the brain's reward circuitry--particularly in the ventral tegmental area-nucleus accumbens pathway--that are associated with symptoms such as anhedonia and aberrant reward associated perception and memory. This Review synthesizes recent data from human and rodent studies from which emerges a circuit-level framework for understanding reward deficits in depression. We also discuss some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms. PMID- 23942474 TI - Infiltrative neurosarcoidosis presenting as secondary amenorrhea: case report and review of the literature. AB - In this report, we describe abrupt onset of secondary amenorrhea in a woman with history of chronic systemic sarcoidosis. Endocrinologic evaluation of her hypothalamic-pituitary axis revealed abnormally low levels of follicle stimulating hormone, luteinizing hormone, and insulinlike growth factor 1 and elevated prolactin. Urine osmolality was low, and serum osmolality was high. Magnetic resonance imaging revealed diffuse extensive leptomeningeal enhancement, with involvement of the hypothalamus, pituitary stalk, and the optic chiasm. Clinical diagnosis was consistent with neurosarcoidosis with hypothalamic pituitary infiltration resulting in clinical hypogonadotropic hypogonadism, hyper prolactinemia, and diabetes insipidus. In our report, we provide an overview of basic reproductive neuroendocrinology and discuss salient concepts of the pathogenesis, clinical manifestations, evaluation, and management of hypogonadotropic hypogonadism. The current literature on neurosarcoidosis with involvement of the hypothalamic-pituitary axis is summarized. The possibility of infiltrative process should be considered in patients with new diagnosis of hypogonadotropic hypogonadal amenorrhea. PMID- 23942475 TI - Crown-linked dipyridylamino-triazine ligands and their spin-crossover iron(II) derivatives: magnetism, photomagnetism and cooperativity. AB - The syntheses, crystallography and magnetic properties of a series of compounds of formula trans-[Fe(II)(L(1))2(NCX)2] (X = S, Se, BH3 (1-3)), cis [Fe(II)(L(2))(NCX)2].CH2Cl2 (X = S, Se, BH3 (4-6)) and trans [Fe(II)(L(3))(NCX)2]n (X = S, Se (7-8)) are described (L(1) = 6-chloro-N(2),N(2) diethyl-N(4),N(4)-di(pyridin-2-yl)-1,3,5-triazine-2,4-diamine, L(2) = 6,6' (1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(N(2),N(2)-diethyl N(4),N(4)-di(pyridin-2-yl)-1,3,5-triazine-2,4-diamine, L(3) = 6,6'-(1,4,10,13 tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(N(2),N(2),N(4),N(4) tetra(pyridin-2-yl)-1,3,5-triazine-2,4-diamine)). The magnetostructural properties of 1-8 have been probed in detail by variable temperature magnetic measurements and crystallographic methods. 1-6 display mononuclear structures while 7 and 8 form 1-D chain structures. Complexes 4-6 have the potential to form 1D-chains via L(2) bridging, but instead form mononuclear complexes. Magnetic studies show that complexes 1, 2, and 4 remain in the high-spin (HS) state at all temperatures. An aged, dry, powdered sample of 3 gives an abrupt HS to LS transition (T1/2 = 200 K), while a freshly prepared, powdered sample of 3.1.5H2O displays thermal hysteresis (Delta = 7 K). Complexes 5, 6 and 7 undergo a gradual spin transition with T1/2 values of 100 K, 150 K and 130 K, respectively. Cooperativity parameters are compared, with 3 showing cooperativity (positive C) and 5 and 6 showing anticooperativity. Photomagnetic LIESST (light induced excited spin state trapping) studies were performed on complexes 5 and 6 and reveal T(LIESST) values lower than 60 K. An attempt has been made to understand the electronic structure of complex 3 and its cooperativity behaviour using density functional methods, the calculations reproducing the sign and, in part, the magnitude of the cooperativity. PMID- 23942469 TI - Nuclear calcium signalling in the regulation of brain function. AB - Synaptic activity initiates biochemical processes that have various outcomes, including the formation of memories, increases in neuronal survival and the development of chronic pain and addiction. Virtually all activity-induced, long lasting adaptations of brain functions require a dialogue between synapses and the nucleus that results in changes in gene expression. Calcium signals that are induced by synaptic activity and propagate into the nucleus are a major route for synapse-to-nucleus communication. Recent findings indicate that diverse forms of neuroadaptation require calcium transients in the nucleus to switch on the necessary genomic programme. Deficits in nuclear calcium signalling as a result of a reduction in synaptic activity or increased extrasynaptic NMDA receptor signalling may underlie the aetiologies of various diseases, including neurodegeneration and cognitive dysfunction. PMID- 23942476 TI - Predictive power of quantitative and qualitative fecal immunochemical tests for hemoglobin in population screening for colorectal neoplasm. AB - The aim of this study was to evaluate the performance of qualitative and quantitative fecal immunochemical tests (FITs) in population screening for colorectal neoplasm. A total of 9000 participants aged between 40 and 74 years were enrolled in this study. Each participant received two stool sampling tubes and was asked to simultaneously submit two stool samples from the same bowel movement. The stool samples of each participant were tested using an immunogold labeling FIT dipstick (qualitative FIT) and an automated fecal blood analyzer (quantitative FIT). Colonoscopy was performed for those who test positive in either FIT. The positive predictive values and population detection rates of the FITs for predicting colorectal neoplasm were compared. A total of 6494 (72.16%) participants simultaneously submitted two stool samples. The diagnostic consistency for a positive result between quantitative and qualitative FITs was poor (kappa=0.278, 95% confidence interval=0.223-0.333). The positive predictive values of the quantitative FIT were significantly higher than those of the qualitative FIT for predicting large (>=1 cm) adenomas (23 cases, 14.29% and 16 cases, 6.72%, P=0.013) and colorectal cancer (10 cases, 6.21% and 5 cases, 2.10%, P=0.034); however, the population detection rate for advanced neoplasm of the quantitative FIT was not significantly different from that of the qualitative FIT. Quantitative FIT is superior to qualitative FIT in predicting advanced colorectal neoplasm during colorectal cancer screening. Further studies are needed to elucidate the causes of the predictive superiority. PMID- 23942477 TI - Complementary iTRAQ proteomics and RNA-seq transcriptomics reveal multiple levels of regulation in response to nitrogen starvation in Synechocystis sp. PCC 6803. AB - Sequential adaptation to environmental stress needs complex regulation at different cellular levels in cyanobacteria. To uncover the regulatory mechanism in response to nitrogen starvation, we investigated the genome-wide correlation between protein abundance and gene expression in a model cyanobacterium Synechocystis sp. PCC 6803 using complementary quantitative iTRAQ proteomics and RNA-seq transcriptomics. Consistent with the cell growth inhibition, proteomic analysis indicated phase-dependent down-regulation of proteins related to nitrogen metabolism, ribosome complexes, glycolysis pathway and tricarboxylic acid (TCA) cycles by nitrogen starvation. Transcriptomic analysis also showed that genes related to "Photosynthesis", "Protein synthesis" and "Energy metabolism" were significantly down-regulated by nitrogen starvation. Interestingly, the concordance between protein abundances and their corresponding mRNAs exhibited a functional categories-dependent pattern, with some categories, such as "Protein synthesis" and "Energy metabolism", having a relatively high correlation, while others even with numerous discordant changes in protein-mRNA pairs, indicated divergent regulation of transcriptional and post-transcriptional processes. In particular, an increased abundance of proteins related to "Photosynthesis" upon nitrogen starvation was found to be reversely correlated with the down-regulation of their corresponding mRNAs. In addition, two metabolic modules highly correlated with nitrogen starvation were identified by a co expression network analysis, and were found to contain mostly photosynthetic proteins and hypothetical proteins, respectively. We further confirmed the involvement of the photosynthetic genes in nitrogen starvation tolerance by constructing and analyzing the psbV gene deletion mutant. PMID- 23942478 TI - Determination of polycyclic aromatic hydrocarbons in solid matrices using automated cold fiber headspace solid phase microextraction technique. AB - The extraction efficiency of analytes in a cold fiber headspace solid-phase microextraction (CF-HS-SPME) system was investigated both theoretically and experimentally. The system was applied for quantitative extraction of polycyclic aromatic hydrocarbons (PAHs) from solid matrices. In order to achieve better extraction efficiency for PAHs, a method with programmed coating temperature was considered and optimized, leading to higher extraction efficiency for most studied analytes when compared with traditional methods. After optimization of extraction with the programmed coating temperature method, the recoveries were above 90% for the majority of tested compounds from the sand matrix, resulting in exhaustive extraction. Certified reference soil was used to evaluate the cold fiber SPME system. Several organic solvents were used to improve the extraction efficiency. Diethylamine was used successfully to realize the exhaustive extraction for volatile compounds and enhance the recoveries of 60-75% for semi volatile PAHs. Obtained results indicate that the automated cold fiber extraction is a convenient approach to facilitate high throughput, solventless sample preparation. PMID- 23942479 TI - The preferred conformation of dipeptides in the context of biosynthesis. AB - Globular proteins are folded polypeptide structures comprising stretches of secondary structures (helical (alpha- or 310 helix type), polyproline helix or beta-strands) interspersed by regions of less well-ordered structure ("random coil"). Protein fold prediction is a very active field impacting inte alia on protein engineering and misfolding studies. Apart from the many studies of protein refolding from the denatured state, there has been considerable interest in studying the initial formation of peptides during biosynthesis, when there are at the outset only a few residues in the emerging polypeptide. Although there have been many studies employing quantum chemical methods of the conformation of dipeptides, these have mostly been carried out in the gas phase or simulated water. None of these conditions really apply in the interior confines of the ribosome. In the present work, we are concerned with the conformation of dipeptides in this low dielectric environment. Furthermore, only the residue types glycine and alanine have been studied by previous authors, but we extend this repertoire to include leucine and isoleucine, position isomers which have very different structural propensities. PMID- 23942481 TI - Mixing and non-stoichiometry in Fe-Ni-Cr-Zn-O spinel compounds: density functional theory calculations. AB - Density functional theory (DFT) calculations have been performed on A(2+)B2(3+)O4(2-) (where A(2+) = Fe, Ni or Zn, and B(3+) = Fe or Cr) spinel oxides in order to determine some of their thermodynamic properties. Mixing energies were calculated for Fe3O4-NiFe2O4, Fe3O4-ZnFe2O4, Fe3O4-FeCr2O4, NiFe2O4 ZnFe2O4, NiFe2O4-NiCr2O4, FeCr2O4-NiCr2O4, FeCr2O4-ZnCr2O4 and ZnCr2O4-ZnFe2O4 pseudo-binaries based on special quasi random (SQS) structures to account for cationic disorder. The results generally agree with available experimental data and the rule that two normal or two inverse spinel compounds easily form solid solutions, while inverse-normal spinel mixtures exhibit positive deviation from solid solution behavior (i.e. immiscibility). Even though the NiFe2O4-NiCr2O4 and Fe3O4-FeCr2O4 systems obey this rule, they exhibit additional features with implications for the corresponding phase diagrams. In addition to mixing enthalpies, non-stoichiometry was also considered by calculating the energies of the relevant defect reactions resulting in A, B and O excess (or deficiency). The DFT calculations predict close to zero or slightly exothermic reactions for both A and B excess in a number of spinel compounds. PMID- 23942480 TI - Internet-based early intervention to prevent posttraumatic stress disorder in injury patients: randomized controlled trial. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) develops in 10-20% of injury patients. We developed a novel, self-guided Internet-based intervention (called Trauma TIPS) based on techniques from cognitive behavioral therapy (CBT) to prevent the onset of PTSD symptoms. OBJECTIVE: To determine whether Trauma TIPS is effective in preventing the onset of PTSD symptoms in injury patients. METHODS: Adult, level 1 trauma center patients were randomly assigned to receive the fully automated Trauma TIPS Internet intervention (n=151) or to receive no early intervention (n=149). Trauma TIPS consisted of psychoeducation, in vivo exposure, and stress management techniques. Both groups were free to use care as usual (nonprotocolized talks with hospital staff). PTSD symptom severity was assessed at 1, 3, 6, and 12 months post injury with a clinical interview (Clinician-Administered PTSD Scale) by blinded trained interviewers and self report instrument (Impact of Event Scale-Revised). Secondary outcomes were acute anxiety and arousal (assessed online), self-reported depressive and anxiety symptoms (Hospital Anxiety and Depression Scale), and mental health care utilization. Intervention usage was documented. RESULTS: The mean number of intervention logins was 1.7, SD 2.5, median 1, interquartile range (IQR) 1-2. Thirty-four patients in the intervention group did not log in (22.5%), 63 (41.7%) logged in once, and 54 (35.8%) logged in multiple times (mean 3.6, SD 3.5, median 3, IQR 2-4). On clinician-assessed and self-reported PTSD symptoms, both the intervention and control group showed a significant decrease over time (P<.001) without significant differences in trend. PTSD at 12 months was diagnosed in 4.7% of controls and 4.4% of intervention group patients. There were no group differences on anxiety or depressive symptoms over time. Post hoc analyses using latent growth mixture modeling showed a significant decrease in PTSD symptoms in a subgroup of patients with severe initial symptoms (n=20) (P<.001). CONCLUSIONS: Our results do not support the efficacy of the Trauma TIPS Internet-based early intervention in the prevention of PTSD symptoms for an unselected population of injury patients. Moreover, uptake was relatively low since one-fifth of individuals did not log in to the intervention. Future research should therefore focus on innovative strategies to increase intervention usage, for example, adding gameplay, embedding it in a blended care context, and targeting high-risk individuals who are more likely to benefit from the intervention. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 57754429; http://www.controlled-trials.com/ISRCTN57754429 (Archived by WebCite at http://webcitation.org/6FeJtJJyD). PMID- 23942482 TI - Introduction to the ASCO Quality Care Symposium. PMID- 23942483 TI - Valuing cancer care: challenges and opportunities. PMID- 23942485 TI - Tying payment incentives to quality measurement. PMID- 23942484 TI - Does value mean quality? The payer's perspective. PMID- 23942486 TI - Accountable care organizations and the practice of oncology. PMID- 23942487 TI - Identifying tools and strategies to provide quality oncology care. PMID- 23942488 TI - It's not the model that matters--still lost in transition. PMID- 23942489 TI - Data-driven transformation to an oncology patient-centered medical home. PMID- 23942490 TI - Partnership between a cancer center and payer: opportunities for improved quality of care and cost reduction. PMID- 23942491 TI - Models that work: incorporating quality principles in different clinical settings. PMID- 23942492 TI - Measuring and improving quality of care in an academic medical center. AB - The Donabedian definition of quality-structure, process, and outcome-provides a useful framework. A relentless focus on measuring process adherence and outcome is critical. Systemic improvements usually require teams to plan and to implement them. The lean or Toyota production system for process improvement is one useful method of organizing work, although different approaches are often necessary at the physician, practice unit, and statewide level. Challenges include scalability of the change (ie, rolling them out across the institution or system), tailoring the information technology tools, and building systems for sustainability. PMID- 23942493 TI - Information technology interventions to improve cancer care quality: a report from the American Society of Clinical Oncology Quality Care Symposium. PMID- 23942494 TI - ASCO's approach to a learning health care system in oncology. AB - The promise of emerging science and the challenges confronting today's health care system can both be addressed by fully embracing the IoM's vision of a learning health care system. ASCO's initial foray into realizing this vision for oncology shows great promise. PMID- 23942495 TI - Using the American College of Surgeons cancer registry to drive quality. PMID- 23942497 TI - Envisioning Watson as a rapid-learning system for oncology. PMID- 23942496 TI - From the first visit on: information technology and communication. PMID- 23942498 TI - Summary of oral abstract session B: innovating to improve care quality. PMID- 23942499 TI - American Society of Clinical Oncology Quality Care Symposium 2012: re-engineering your practice to deliver quality and value. PMID- 23942500 TI - From craft to profession: the path to highly predictable cancer care. PMID- 23942501 TI - Quality assessment across a national cancer network. AB - The approaches outlined in this report, coupled with a spirit of internal and external collaboration, enable complete translation of the MD Anderson multidisciplinary care model as well as extension of our organizational research mission. Quality management with the ability to benchmark quality metrics against our main Houston campus remains a cornerstone of our overarching strategy to maintain consistent high-quality care throughout our national network. PMID- 23942502 TI - Re-engineering a small oncology practice for quality using the ASCO Quality Oncology Practice Initiative. PMID- 23942503 TI - Development and implementation of oncology care pathways in an integrated care network: the Via Oncology Pathways experience. AB - Physician involvement is integral to a successful clinical pathways program. The Via Pathways model used at the UPMC CancerCenter, in which the oncologists developing the clinical content are ultimately the oncologists who use the Pathways Portal, has proven to be successful in ensuring physician participation. In addition, an agile user interface and pragmatic layout of the tool are essential for incorporating pathways into the daily workflow of physicians. When appropriately developed and implemented, clinical pathways are an effective tool for standardizing care and ensuring quality. PMID- 23942504 TI - Conformance with supportive care quality measures is associated with better quality of life in patients with cancer receiving palliative care. AB - PURPOSE: As palliative care further integrates into cancer care, descriptions of how supportive care quality measures improve patient outcomes are necessary to establish best practices. METHODS: We assessed the relationship between conformance to 18 palliative care quality measures and quality of life from data obtained using our novel point-of-care, electronic quality monitoring system, the Quality Data Collection Tool for Palliative Care (QDACT-PC). All patients with cancer from January 2008 through March 2011 seen in the Carolinas Palliative Care Consortium were evaluated for demographic, disease, prognostic, performance status, and measure conformance variables. Using univariate and multivariate regression, we examined the relationship between these variable and high quality of life at the initial specialty palliative care consultation. RESULTS: Our cohort included 459 patients, the majority of whom were over age 65 years (66%) and white (84%). Lung (29.1%) and GI (24.7%) cancers were most common. In univariate analyses, conformance to assessment of comprehensive symptoms, fatigue and constipation assessment, timely management of pain and constipation, and timely emotional well-being assessment were associated with highest levels of quality of life (all Ps < .05). In a multivariate model (C-stat = 0.66), performance status (odds ratio [OR], 5.21; P = .003), estimated life expectancy (OR, 22.6; P = .003), conformance to the measure related to emotional well-being assessment (OR, 1.60; P = .026), and comprehensive screening of symptoms (OR, 1.74, P = .008) remained significant. CONCLUSION: Oncology care pathways that routinely incorporate supportive care principles, such as comprehensive symptom and emotional well-being assessments, may improve patient outcomes. PMID- 23942505 TI - Development of a virtual multidisciplinary lung cancer tumor board in a community setting. AB - PURPOSE: Creating an effective platform for multidisciplinary tumor conferences can be challenging in the rural community setting. The Duke Cancer Network created an Internet-based platform for a multidisciplinary conference to enhance the care of patients with lung cancer. This conference incorporates providers from different physical locations within a rural community and affiliated providers from a university-based cancer center 2 hours away. An electronic Web conferencing tool connects providers aurally and visually. METHODS: Conferences were set up using a commercially available Web conferencing platform. The video platform provides a secure Web site coupled with a secure teleconference platform to ensure patient confidentiality. Multiple disciplines are invited to participate, including radiology, radiation oncology, thoracic surgery, pathology, and medical oncology. Participants only need telephone access and Internet connection to participate. RESULTS: Patient histories and physicals are presented, and the Web conferencing platform allows radiologic and histologic images to be reviewed. Treatment plans for patients are discussed, allowing providers to coordinate care among the different subspecialties. Patients who need referral to the affiliated university-based cancer center for specialized services are identified. Pertinent treatment guidelines and journal articles are reviewed. On average, there are 10 participants with one to two cases presented per session. CONCLUSION: The use of a Web conferencing platform allows subspecialty providers throughout the community and hours away to discuss lung cancer patient cases. This platform increases convenience for providers, eliminating travel to a central location. Coordination of care for patients requiring multidisciplinary care is facilitated, shortening evaluation time before definitive treatment plan. PMID- 23942506 TI - New accountability, new challenges: improving treatment reporting to a tumor registry. AB - BACKGROUND: As adjuvant treatment moves to outpatient settings, required reporting is problematic. We undertook a solutions-focused exercise to identify reporting barriers and devise a pilot improvement intervention. METHODS: We convened a multidisciplinary group of community-based oncologists, tumor registry (TR) staff, and hospital leadership. The group identified three key barriers to reporting: (1) inability to identify correct managing physician, (2) poor communication, and (3) manual reporting burden. Our intervention addressed the first two barriers and involved correcting physician contact information, simplifying contact forms, ascertaining cases in real time, and priming physician office staff to respond to TR requests. RESULTS: Preintervention, the TR did not identify any pilot patients' managing medical oncologists and little adjuvant treatment. During the April-May 2012 intervention, 22 patients with breast cancer listed our volunteer surgeon as managing physician. The TR sent 22 treatment letters to the surgeon's office and received 19 (86%) responses identifying the managing medical oncologist. Nine of the 19 cases (47%) were closed. To close a case required an average of 5.9 contacts and 28 minutes for electronic medical record-based cases and 38.9 minutes for community oncology cases. Sixty-four percent of required treatment was reported. Surgical staff spent ~0.5 hours per case to identify the oncologist prescribing adjuvant treatment. CONCLUSION: The solutions-focused exercise improved identification of managing oncologists from 0% to 86% for patients treated by community oncologists. Treatment reporting increased from 2.6% to 64%. The pilot did not address the burden of reporting, which remains great. Electronic records can reduce this burden, but this approach is not currently feasible for many oncologists. PMID- 23942507 TI - Evolution of the Quality Oncology Practice Initiative supportive care quality measures portfolio and conformance at a Veterans Affairs medical center. AB - PURPOSE: A growing set of quality measures is being implemented to evaluate all components of cancer care, from diagnosis through the end of life. We investigated the Quality Oncology Practice Initiative (QOPI) quality measures portfolio. Additionally, we explored the effect of quality measure type on conformance. METHODS: We performed QOPI data collections twice per year from fall 2007 through fall 2010 and spring 2012, using chart review of the Durham Veterans Administration outpatient oncology clinic. We categorized QOPI measures as nontreatment-related supportive care (NTSC), treatment-related supportive care (TSC), diagnostic, or therapeutic. Descriptive statistics and chi(2) were used to compare longitudinal conformance. RESULTS: The majority of QOPI measures in spring 2012 assess processes of chemotherapy treatment (therapeutic, 54.3%; TSC, 8.7%) or diagnostic modalities (19.6%). Measures targeting NTSC are few (17.4%) but increased from three measures in fall 2007 to eight measures in spring 2012. During those 5 years, average conformance to NTSC, TSC, diagnostic, and therapeutic measures was 71.4%, 86.1%, 89.3%, and 75.4%, respectively (P < .001). Within the NTSC measures, emotional well-being and constipation assessment were least documented (41.0% and 46.3%, respectively). In spring 2012, NTSC measure conformance (75.8%) remained significantly lower than diagnostic measure conformance (91.5%; P < .001). CONCLUSION: Most QOPI quality measures assess diagnosis or treatment processes of care and not supportive care. Aggregate conformance to the NTSC measures was lower than that of other categories. The differential conformance demonstrates the necessity of standardized documentation methods and quality improvement efforts that remain commensurate with the increasing portfolio of supportive care measures. PMID- 23942509 TI - Physician inter-annotator agreement in the Quality Oncology Practice Initiative manual abstraction task. AB - PURPOSE: The Quality Oncology Practice Initiative (QOPI) relies on the accuracy of manual abstraction of clinical data from paper-based and electronic medical records (EMRs). Although there is no "gold standard" to measure manual abstraction accuracy, measurement of inter-annotator agreement (IAA) is a commonly agreed-on surrogate. We quantified the IAA of QOPI abstractions on a cohort of cancer patients treated at Beth Israel Deaconess Medical Center. METHODS: The EMR charts of 49 patients (20 colorectal cancer; 18 breast cancer; 11 non-Hodgkin lymphoma) were abstracted by separate physician abstractors in the fall 2010 and fall 2011 QOPI abstraction rounds. Cohen's kappa (kappa) was calculated for encoded data; raw levels of agreement and magnitude of discrepancies were calculated for numeric and dated data. RESULTS: One hundred two data elements with 2,035 paired entries were analyzed. Overall IAA for the 1,496 coded entries was kappa = 0.75; median IAA for n = 85 individual coded elements was kappa = 0.84 (interquartile range, 0.30 to 1.00). Overall IAA for the 421 dated entries was 73%; median IAA for n = 17 individual dated elements was 67% (interquartile range, 61% to 86%). CONCLUSION: This study establishes a baseline level of IAA for a complex medical abstraction task with clear relevance for the oncology community. Given that the observed kappa is considered only fair IAA, and that the rate of date discrepancy is high, caution is necessary in interpreting the results of QOPI and other manual abstractions of clinical oncology data. The accuracy of automated data extraction efforts, possibly including a future evolution of QOPI, will also need to be carefully evaluated. PMID- 23942510 TI - Hydrophobic plasma polymer coated silica particles for petroleum hydrocarbon removal. AB - In recent years, functionalized hydrophobic materials have attracted considerable interest as oil removal agents. This investigation has applied plasma polymerization as a novel method to develop hydrophobic and oleophilic particles for water purification. 1,7-Octadiene was plasma polymerized onto silica particles using a radio frequency inductively coupled reactor fitted with a rotating chamber. Plasma polymerized 1,7-octadiene (ppOD) films were deposited using plasma power of 40 W and monomer flow rate of 2 sccm, while polymerization time was varied from 5 to 60 min. The surface chemistry of ppOD coated particles was investigated via X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectroscopy, while Washburn capillary rise measurements were applied to evaluate the hydrophobicity and oleophilicity of the particles. The effectiveness of ppOD coated particles for the removal of hydrophobic matter from water was demonstrated by adsorption of motor oil, kerosene, and crude oil. Petroleum hydrocarbon removal was examined by varying removal time and particle mass. The morphology of oil-loaded ppOD coated particles was examined via environmental scanning electron microscopy observations. Increasing the polymerization time increased the concentration of hydrocarbon functionalities on the surface, thus also increasing the hydrophobicity and oil removal efficiency (ORE). The ppOD coated particles have shown to have excellent ORE. These particles were capable of removing 99.0-99.5% of high viscosity motor oil in 10 min, while more than 99.5% of low viscosity crude oil and kerosene was adsorbed in less than 30 s. Plasma polymerization has shown to be a promising approach to produce a new class of materials for a fast, facile, and efficient oil removal. PMID- 23942508 TI - Practice-based evidence to evidence-based practice: building the National Radiation Oncology Registry. AB - The National Radiation Oncology Registry (NROR), sponsored by the Radiation Oncology Institute and the American Society for Radiation Oncology, is designed to collect standardized information on cancer care delivery among patients treated with radiotherapy in the United States and will focus on patients with prostate cancer. Stakeholders were engaged through a forum that emphasized the need for patient-centered outcomes, minimal data burden, and maximal connectivity to existing registries and databases. An electronic infrastructure is under development to provide connectivity across radiation oncology and hospital information systems. The NROR Gateway features automatic abstraction as well as aggregation of treatment and outcome data. The prostate cancer data dictionary provides standardized elements in four domains: facility, physician, patient, and treatment. The pilot phase will consist of clinical centers chosen to provide a representative mix of radiation treatment modalities, facility types, population based settings, and regional locations. The initial set of radiation practice metrics includes physician board certification and maintenance, ordering of staging scans, active surveillance discussion, dose prescriptions for low risk/high-risk disease, radiation fields for low-risk/high-risk disease, image guided radiation therapy use, androgen deprivation therapy use, post brachytherapy implant computed tomography dosimetry, collection of toxicity assessments, and longitudinal patient follow-up. The NROR pilot study will provide the framework for expansion to a nationwide electronic registry for radiation oncology. PMID- 23942511 TI - Multifunctional carbon nanoelectrodes fabricated by focused ion beam milling. AB - We report a strategy for fabrication of sub-micron, multifunctional carbon electrodes and application of these electrodes as probes for scanning electrochemical microscopy (SECM) and scanning ion conductance microscopy (SICM). The fabrication process utilized chemical vapor deposition of parylene, followed by thermal pyrolysis to form conductive carbon and then further deposition of parylene to form an insulation layer. To achieve well-defined electrode geometries, two methods of electrode exposure were utilized. In the first method, carbon probes were masked in polydimethylsiloxane (PDMS) to obtain a cone-shaped electrode. In the second method, the electrode area was exposed via milling with a focused ion beam (FIB) to reveal a carbon ring electrode, carbon ring/platinum disk electrode, or carbon ring/nanopore electrode. Carbon electrodes were batch fabricated (~35/batch) through the vapor deposition process and were characterized with scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM), and cyclic voltammetry (CV) measurements. Additionally, Raman spectroscopy was utilized to examine the effects of Ga(+) ion implantation, a result of FIB milling. Constant-height, feedback mode SECM was performed with conical carbon electrodes and carbon ring electrodes. We demonstrate the utility of carbon ring/nanopore electrodes with SECM-SICM to simultaneously collect topography, ion current and electrochemical current images. In addition, carbon ring/nanopore electrodes were utilized in substrate generation/tip collection (SG/TC) SECM. In SG/TC SECM, localized delivery of redox molecules affords a higher resolution, than when the redox molecules are present in the bath solution. Multifunctional geometries of carbon electrode probes will find utility in electroanalytical applications, in general, and more specifically with electrochemical microscopy as discussed herein. PMID- 23942512 TI - An interview with Francois Guillemot. Interview by Catarina Vicente. AB - Francois Guillemot heads the Division of Molecular Neurobiology at the MRC National Institute of Medical Research (NIMR) in London. His research focuses on the transcriptional control of neurogenesis, adult neurogenesis and the epigenetic regulation of gene expression in neural development. Francois recently became an editor for Development, and we asked him about his research and career, as well as his lab's future move to the Crick Institute. PMID- 23942513 TI - A molecular basis for developmental plasticity in early mammalian embryos. AB - Early mammalian embryos exhibit remarkable plasticity, as highlighted by the ability of separated early blastomeres to produce a whole organism. Recent work in the mouse implicates a network of transcription factors in governing the establishment of the primary embryonic lineages. A combination of genetics and embryology has uncovered the organisation and function of the components of this network, revealing a gradual resolution from ubiquitous to lineage-specific expression through a combination of defined regulatory relationships, spatially organised signalling, and biases from mechanical inputs. Here, we summarise this information, link it to classical embryology and propose a molecular framework for the establishment and regulation of developmental plasticity. PMID- 23942514 TI - The Osa-containing SWI/SNF chromatin-remodeling complex regulates stem cell commitment in the adult Drosophila intestine. AB - The proportion of stem cells versus differentiated progeny is well balanced to maintain tissue homeostasis, which in turn depends on the balance of the different signaling pathways involved in stem cell self-renewal versus lineage specific differentiation. In a screen for genes that regulate cell lineage determination in the posterior midgut, we identified that the Osa-containing SWI/SNF (Brahma) chromatin-remodeling complex regulates Drosophila midgut homeostasis. Mutations in subunits of the Osa-containing complex result in intestinal stem cell (ISC) expansion as well as enteroendocrine (EE) cell reduction. We further demonstrated that Osa regulates ISC self-renewal and differentiation into enterocytes by elaborating Notch signaling, and ISC commitment to differentiation into EE cells by regulating the expression of Asense, an EE cell fate determinant. Our data uncover a unique mechanism whereby the commitment of stem cells to discrete lineages is coordinately regulated by chromatin-remodeling factors. PMID- 23942515 TI - Cranial neural crest cells form corridors prefiguring sensory neuroblast migration. AB - The majority of cranial sensory neurons originate in placodes in the surface ectoderm, migrating to form ganglia that connect to the central nervous system (CNS). Interactions between inward-migrating sensory neuroblasts and emigrant cranial neural crest cells (NCCs) play a role in coordinating this process, but how the relationship between these two cell populations is established is not clear. Here, we demonstrate that NCCs generate corridors delineating the path of migratory neuroblasts between the placode and CNS in both chick and mouse. In vitro analysis shows that NCCs are not essential for neuroblast migration, yet act as a superior substrate to mesoderm, suggesting provision of a corridor through a less-permissive mesodermal territory. Early organisation of NCC corridors occurs prior to sensory neurogenesis and can be recapitulated in vitro; however, NCC extension to the placode requires placodal neurogenesis, demonstrating reciprocal interactions. Together, our data indicate that NCC corridors impose physical organisation for precise ganglion formation and connection to the CNS, providing a local environment to enclose migrating neuroblasts and axonal processes as they migrate through a non-neural territory. PMID- 23942516 TI - CAF-1 promotes Notch signaling through epigenetic control of target gene expression during Drosophila development. AB - The histone chaperone CAF-1 is known for its role in DNA replication-coupled histone deposition. However, loss of function causes lethality only in higher multicellular organisms such as mice and flies, but not in unicellular organisms such as yeasts, suggesting that CAF-1 has other important functions than histone deposition during animal development. Emerging evidence indicates that CAF-1 also has a role in higher order chromatin organization and heterochromatin-mediated gene expression; it remains unclear whether CAF-1 has a role in specific signaling cascades to promote gene expression during development. Here, we report that knockdown of one of the subunits of Drosophila CAF-1, dCAF-1-p105 (Caf1 105), results in phenotypes that resemble those of, and are augmented synergistically by, mutations of Notch positive regulatory pathway components. Depletion of dCAF-1-p105 leads to abrogation of cut expression and to downregulation of other Notch target genes in wing imaginal discs. dCAF-1-p105 is associated with Suppressor of Hairless [Su(H)] and regulates its binding to the enhancer region of E(spl)mbeta. The association of dCAF-1-p105 with Su(H) on chromatin establishes an active local chromatin status for transcription by maintaining a high level of histone H4 acetylation. In response to induced Notch activation, dCAF-1 associates with the Notch intracellular domain to activate the expression of Notch target genes in cultured S2 cells, manifesting the role of dCAF-1 in Notch signaling. Together, our results reveal a novel epigenetic function of dCAF-1 in promoting Notch pathway activity that regulates normal Drosophila development. PMID- 23942517 TI - Post-transcriptional regulation of myotube elongation and myogenesis by Hoi Polloi. AB - Striated muscle development requires the coordinated expression of genes involved in sarcomere formation and contractility, as well as genes that determine muscle morphology. However, relatively little is known about the molecular mechanisms that control the early stages of muscle morphogenesis. To explore this facet of myogenesis, we performed a genetic screen for regulators of somatic muscle morphology in Drosophila, and identified the putative RNA-binding protein (RBP) Hoi Polloi (Hoip). Hoip is expressed in striated muscle precursors within the muscle lineage and controls two genetically separable events: myotube elongation and sarcomeric protein expression. Myotubes fail to elongate in hoip mutant embryos, even though the known regulators of somatic muscle elongation, target recognition and muscle attachment are expressed normally. In addition, a majority of sarcomeric proteins, including Myosin Heavy Chain (MHC) and Tropomyosin, require Hoip for their expression. A transgenic MHC construct that contains the endogenous MHC promoter and a spliced open reading frame rescues MHC protein expression in hoip embryos, demonstrating the involvement of Hoip in pre-mRNA splicing, but not in transcription, of muscle structural genes. In addition, the human Hoip ortholog NHP2L1 rescues muscle defects in hoip embryos, and knockdown of endogenous nhp2l1 in zebrafish disrupts skeletal muscle development. We conclude that Hoip is a conserved, post-transcriptional regulator of muscle morphogenesis and structural gene expression. PMID- 23942520 TI - Appropriate amino acid mixtures for tryptophan depletion and tyrosine/phenylalanine depletion and the safety of long-term amino acid depletion in humans. PMID- 23942521 TI - Synthesis of non-siliceous mesoporous oxides. AB - Mesoporous non-siliceous oxides have attracted great interest due to their unique properties and potential applications. Since the discovery of mesoporous silicates in 1990s, organic-inorganic assembly processes by using surfactants or block copolymers as soft templates have been considered as a feasible path for creating mesopores in metal oxides. However, the harsh sol-gel conditions and low thermal stabilities have limited the expansion of this method to various metal oxide species. Nanocasting, using ordered mesoporous silica or carbon as a hard template, has provided possibilities for preparing novel mesoporous materials with new structures, compositions and high thermal stabilities. This review concerns the synthesis, composition, and parameter control of mesoporous non siliceous oxides. Four synthesis routes, i.e. soft-templating (surfactants or block copolymers as templates), hard-templating (mesoporous silicas or carbons as sacrificial templates), colloidal crystal templating (3-D ordered colloidal particles as a template), and super lattice routes, are summarized in this review. Mesoporous metal oxides with different compositions have different properties. Non-siliceous mesoporous oxides are comprehensively described, including a discussion of constituting elements, synthesis, and structures. General aspects concerning pore size control, atomic scale crystallinity, and phase control are also reviewed. PMID- 23942518 TI - Pax7 is regulated by cMyb during early neural crest development through a novel enhancer. AB - The neural crest (NC) is a migratory population of cells unique to vertebrates that generates many diverse derivatives. NC cells arise during gastrulation at the neural plate border (NPB), which is later elevated as the neural folds (NFs) form and fuse in the dorsal region of the closed neural tube, from where NC cells emigrate. In chick embryos, Pax7 is an early marker, and necessary component of NC development. Unlike other early NPB markers, which are co-expressed in lateral ectoderm, medial neural plate or posterior-lateral mesoderm, Pax7 early expression seems more restricted to the NPB. However, the molecular mechanisms controlling early Pax7 expression remain poorly understood. Here, we identify a novel enhancer of Pax7 in avian embryos that replicates the expression of Pax7 associated with early NC development. Expression from this enhancer is found in early NPB, NFs and early emigrating NC, but unlike Pax7, which is also expressed in mesodermal derivatives, this enhancer is not active in somites. Further analysis demonstrates that cMyb is able to interact with this enhancer and modulates reporter and endogenous early Pax7 expression; thus, cMyb is identified as a novel regulator of Pax7 in early NC development. PMID- 23942522 TI - Characterization of VIP1 activity as a transcriptional regulator in vitro and in planta. AB - VIP1 (VirE2 interacting protein 1), initially discovered as a host protein involved in Agrobacterium-plant cell DNA transfer, is a transcription factor of the basic leucine-zipper (bZIP) domain family that regulates several defence related genes in Arabidopsis. We have developed assays to assess VIP1 binding to its DNA target in vitro and transcriptional activation efficiency in planta. Several point mutations in the VIP1 response element VRE affected the VIP1 activity, and a strong correlation between VIP1-VRE binding and transcriptional activation levels was observed. Promoter activation by VIP1 was influenced by bacterial and plant proteins known to interact with VIP1 during Agrobacterium infection, i.e., VirE2, VirF and VIP2. VirF, an F-box protein, strongly decreased VIP1 transcriptional activation ability, but not its binding to VRE in vitro, most likely by triggering proteasomal degradation of VIP1. Finally, activation of a VRE-containing promoter was observed in dividing cells, probably resulting from activation of endogenous VIP1. PMID- 23942523 TI - An internet intervention to improve asthma management: rationale and protocol of a randomized controlled trial. AB - BACKGROUND: Many studies have shown the effectiveness of self-management for patients with asthma. In particular, possession and use of a written asthma action plan provided by a doctor has shown to significantly improve patients' asthma control. Yet, uptake of a written asthma action plan and preventative asthma management is low in the community, especially amongst adults. OBJECTIVE: A Web-based personally controlled health management system (PCHMS) called Healthy.me will be evaluated in a 2010 CONSORT-compliant 2-group (static websites verse PCHMS) parallel randomized controlled trial (RCT) (allocation ratio 1:1). METHODS: The PCHMS integrates an untethered personal health record with consumer care pathways and social forums. After eligibility assessment, a sample of 300 adult patients with moderate persistent asthma will be randomly assigned to one of these arms. After 12 months of using either Healthy.me or information websites (usual care arm), a post-study assessment will be conducted. RESULTS: The primary outcome measure is possession of or revision of an asthma action plan during the study. Secondary outcome measures include: (1) adherence to the asthma action plan, (2) rate of planned and unplanned visits to healthcare providers for asthma issues, (3) usage patterns of Healthy.me and attrition rates, (4) asthma control and asthma exacerbation scores, and (5) impact of asthma on life and competing demands, and days lost from work. CONCLUSIONS: This RCT will provide insights into whether access to an online PCHMS will improve uptake of a written asthma action plan and preventative asthma actions. TRIAL REGISTRATION: Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12612000716864; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362714 (Archived by WebCite at http://www.webcitation.org/6IYBJGRnW). PMID- 23942525 TI - Signalling pathway database usability: lessons learned. AB - BACKGROUND: issues and limitations related to accessibility, understandability and ease of use of signalling pathway databases may hamper or divert research workflow, leading, in the worst case, to the generation of confusing reference frameworks and misinterpretation of experimental results. In an attempt to retrieve signalling pathway data related to a specific set of test genes, we queried and analysed the results from six of the major curated signalling pathway databases: Reactome, PathwayCommons, KEGG, InnateDB, PID, and Wikipathways. FINDINGS: although we expected differences - often a desirable feature for the integration of each individual query, we observed variations of exceptional magnitude, with disproportionate quality and quantity of the results. Some of the more remarkable differences can be explained by the diverse conceptual designs and purposes of the databases, the types of data stored and the structure of the query, as well as by missing or erroneous descriptions of the search procedure. To go beyond the mere enumeration of these problems, we identified a number of operational features, in particular inner and cross coherence, which, once quantified, offer objective criteria to choose the best source of information. CONCLUSIONS: in silico biology heavily relies on the information stored in databases. To ensure that computational biology mirrors biological reality and offers focused hypotheses to be experimentally validated, coherence of data codification is crucial and yet highly underestimated. We make practical recommendations for the end-user to cope with the current state of the databases as well as for the maintainers of those databases to contribute to the goal of the full enactment of the open data paradigm. PMID- 23942526 TI - Influence of graphene synthesizing techniques on the photocatalytic performance of graphene-TiO2 nanocomposites. AB - Model photocatalysts composed of TiO2-graphene nanocomposites are prepared to address the effect of graphene quality on their photocatalytic performance. Graphene is synthesized by catalyst-assisted chemical vapor deposition (CVD), catalyst-free CVD and solution processing methods. TiO2 is prepared by reactive magnetron sputtering and subsequent annealing. Fabricated model photocatalysts have different morphology and physical properties, as revealed using spectrophotometry, atomic force microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, photoluminescence, and four-probe electrical measurements. All graphene-containing composites have significantly higher photocatalytic activity compared to bare TiO2 films in the gas phase methanol photooxidation tests. Their activity is proportional to the electrical conductivity and surface roughness of the respective carbon structure, which in turn depends on the preparation methods. The mechanisms of enhancement are further assessed by comparison with the performance of reference TiO2-graphitic-carbon and TiO2-Au thin films. PMID- 23942524 TI - Critical role of interleukin-5 in the development of a mite antigen-induced chronic bronchial asthma model. AB - OBJECTIVE AND DESIGN: Asthma is associated with eosinophilic airway inflammation and characterized by enhanced airway sensitivity. Interleukin (IL)-5 plays an important role in the pathogenesis of asthma. The involvement of IL-5 receptor mediated cellular signals in the pathogenesis of a mite antigen-induced chronic asthma model was investigated. SUBJECTS: In this study, 48 female C57BL/6J (WT) mice and IL-5 receptor-deficient (IL-5RKO) mice were used. TREATMENT: Mite antigen (50 MUl) was intranasally administered 13 times to WT and IL-5RKO mice. METHODS: Airway hypersensitivity (Mch PC200) and specific antigen exposure tests were performed, and lung tissue, bronchoalveolar lavage fluid (BALF), and blood were collected to investigate the asthma pathology and differences in the local pulmonary levels of cytokines and chemokines. RESULTS: Airway sensitivity was enhanced and antigen-specific airway resistance was increased in WT mice. In addition, the number of eosinophils and Th2 cytokine levels in the BALF were increased. In contrast, IL-5RKO mice did not acquire the asthma pathology, such as antigen-specific airway resistance and eosinophilic airway inflammation. Mch PC200 was significantly correlated with cysteinyl leukotriene levels in WT mice. CONCLUSION: These findings suggested that both IL-5 induced eosinophils and cysteinyl leukotrienes are involved in the pathology of this mite antigen-induced chronic asthma model. PMID- 23942527 TI - Prospective randomized trial of hybrid NOTES colectomy versus conventional laparoscopic colectomy for left-sided colonic tumors. AB - BACKGROUND: We conducted a randomized study of a laparoscopic technique for removing left-sided colon tumors that can reduce postoperative pain and other wound-related complications compared to the conventional technique. It is a novel technique of hybrid natural orifice translumenal endoscopic surgery (NOTES) colectomy (HNC) whereby laparoscopic colonic mobilization, transection, and anastomosis are performed intracorporeally. The specimen is then delivered through the anus using the transanal endoscopic operation (TEO) device, precluding the need for mini-laparotomy. We compared the short-term outcomes of patients who underwent HNC with those who underwent conventional laparoscopic colectomy (CL). METHODS: Patients suffering left-sided colonic tumor were recruited and were randomized into two groups: HNC and CL. Operative data and complications were prospectively recorded and analyzed. RESULTS: During a 3-year period, we recruited 70 patients (35 per group). No significant difference was observed between the two groups with respect to operating time (105 vs. 100 min, p = 0.851), blood loss (30 vs. 30 ml, p = 0.954), or length of hospital stay (5 vs. 5 days, p = 0.990). The maximum pain score during the first week was significantly lower in the HNC group (1 vs. 2, p = 0.017). No patients in the HNC group developed wound infection, whereas four patients in the CL group did so (p = 0.005). CONCLUSIONS: With this hybrid NOTES technique, selected patients with left-sided colonic tumors can enjoy the full benefits of minimally invasive surgery with significantly less wound pain and a lower wound infection rate than are observed with CL. PMID- 23942528 TI - Heavy and trace metals in carcinoma of the gallbladder. AB - BACKGROUND: Carcinoma of the gallbladder is the commonest malignancy of the biliary tract in northern India The etiologic relation of specific metals (heavy and trace) and their compounds to neoplasia has been a topic of investigation for some time but not adequately described for carcinoma of the gallbladder. The aim of the present study was to evaluate the relation of heavy and trace metals to this malignancy. METHODS: The levels of selenium, zinc, copper, manganese, cadmium, chromium, lead, and nickel were estimated in serum, bile, gallstones, and gallbladder tissue using atomic absorption spectrophotometry. The tests were carried out in 30 patients with gallbladder cancer and 30 sex-matched patients with cholelithiasis. RESULTS: Selenium and zinc levels were significantly reduced (p < 0.001) and copper concentration was found to be significantly higher (p < 0.001) in serum, bile, and gallbladder tissue from patients with carcinoma of the gallbladder. Lead, cadmium, chromium, and nickel levels were elevated in serum and bile in patients with carcinoma of the gallbladder. CONCLUSIONS: The present study demonstrated a significant decrease in serum, biliary, and tissue levels of selenium and zinc but increased copper, lead, cadmium, chromium, and nickel levels in patients with carcinoma of the gallbladder, indicating a strong relation between the concentrations of these metals and gallbladder cancer. PMID- 23942529 TI - Single-port cholecystectomy and quality of life. PMID- 23942530 TI - Hospital management practices and availability of surgery in sub-Saharan Africa: a pilot study of three hospitals. AB - BACKGROUND: Sub-Saharan Africa has a high surgical burden of disease but performs a disproportionately low volume of surgery. Closing this surgical gap will require increased surgical productivity of existing systems. We examined specific hospital management practices in three sub-Saharan African hospitals that are associated with surgical productivity and quality. METHODS: We conducted 54 face to-face, structured interviews with administrators, clinicians, and technicians at a teaching hospital, district hospital, and religious mission hospital across two countries in sub-Saharan Africa. Questions focused on recommended general management practices within five domains: goal setting, operations management, talent management, quality monitoring, and financial oversight. Records from each interview were analyzed in a qualitative fashion. Each hospital's management practices were scored according to the degree of implementation of the management practices (1 = none; 3 = some; 5 = systematic). RESULTS: The mission hospital had the highest number of employees per 100 beds (226), surgeons per operating room (3), and annual number of operations per operating room (1,800). None of the three hospitals had achieved systematic implementation of management practices in all 14 measures. The mission hospital had the highest total management score (44/70 points; average = 3.1 for each of the 14 measures). The teaching and district hospitals had statistically significantly lower management scores (average 1.3 and 1.1, respectively; p < .001). CONCLUSIONS: It is possible to meaningfully assess hospital management practices in low resource settings. We observed substantial variation in implementation of basic management practices at the three hospitals. Future research should focus on whether enhancing management practices can improve surgical capacity and outcomes. PMID- 23942531 TI - Outcome of surgical resection as a first line therapy in T3 non-small cell lung cancer patients. AB - BACKGROUND: The T3 category of the 7th Edition of the TNM classification of non small cell lung cancer (NSCLC) has added two factors that do not appear in the 6th Edition, large tumor size (>7 cm) and pulmonary metastasis of the same lobe. These factors are considered to have different biological and clinical features. In the present study we assessed the outcome of surgical resection as a first line therapy for T3 NSCLC. METHODS: A total of 145 patients who were diagnosed according to the TNM 7th Edition with pathologic T3 NSCLC received surgical resection in our institution as a first line treatment. The outcomes of their treatment were analyzed. RESULTS: The 5-year survival rate was 46.9 %. On the basis of the 6th TNM Edition, the 5-year survival rate was 63.1 % for patients diagnosed with T2 disease (large tumor size), 44.3 % for patients diagnosed with T3 disease, and 33.1 % for patients diagnosed with T4 disease (pulmonary metastasis of the same lobe). There were no significant correlations between these categories and overall survival (OS). Nevertheless, 6th Edition T factors were found to be significantly correlated with lymph node status (p < 0.01). The univariate analyses showed that age, lymph node metastasis, and curative resection had significant effects on OS. In addition, the multivariate analysis identified age and N factor as independent prognostic factors in this cohort. CONCLUSIONS: Indications for surgical resection as a first line therapy in T3 NSCLC should be based on N factors and patient age. Lymph node metastasis, especially N2 disease, was increasingly frequent in patients with 6th Edition T classifications. PMID- 23942532 TI - Access to a simulator is not enough: the benefits of virtual reality training based on peer-group-derived benchmarks--a randomized controlled trial. AB - BACKGROUND: Virtual reality (VR) simulators are widely used to familiarize surgical novices with laparoscopy, but VR training methods differ in efficacy. In the present trial, self-controlled basic VR training (SC-training) was tested against training based on peer-group-derived benchmarks (PGD-training). METHODS: First, novice laparoscopic residents were randomized into a SC group (n = 34), and a group using PGD-benchmarks (n = 34) for basic laparoscopic training. After completing basic training, both groups performed 60 VR laparoscopic cholecystectomies for performance analysis. Primary endpoints were simulator metrics; secondary endpoints were program adherence, trainee motivation, and training efficacy. RESULTS: Altogether, 66 residents completed basic training, and 3,837 of 3,960 (96.8 %) cholecystectomies were available for analysis. Course adherence was good, with only two dropouts, both in the SC-group. The PGD-group spent more time and repetitions in basic training until the benchmarks were reached and subsequently showed better performance in the readout cholecystectomies: Median time (gallbladder extraction) showed significant differences of 520 s (IQR 354-738 s) in SC-training versus 390 s (IQR 278-536 s) in the PGD-group (p < 0.001) and 215 s (IQR 175-276 s) in experts, respectively. Path length of the right instrument also showed significant differences, again with the PGD-training group being more efficient. CONCLUSIONS: Basic VR laparoscopic training based on PGD benchmarks with external assessment is superior to SC training, resulting in higher trainee motivation and better performance in simulated laparoscopic cholecystectomies. We recommend such a basic course based on PGD benchmarks before advancing to more elaborate VR training. PMID- 23942533 TI - One-stage urethroplasty for urethral strictures at the Ladoke Akintola University of Technology Teaching Hospital, Osogbo, south western Nigeria. AB - BACKGROUND: Urethral stricture, a common urologic condition, is probably the most common cause of urinary retention in tropical Africa and a frequent cause of lower urinary tract symptoms worldwide. This study aimed at presenting our experience with one-stage urethroplasty at the Ladoke Akintola University of Technology Teaching Hospital Osogbo, Nigeria. METHODS: All male patients who underwent one-stage urethroplasty between December 2005 and December 2011 were studied retrospectively. Details of their presentation and management were reviewed. RESULTS: A total of 50 patients aged 2-75 years (mean +/- SD 44.2 +/- 21.53 years) with a urethral stricture underwent one-stage urethroplasty. The modal age group was 61-75 years (26 %). In all, 27 (54 %) patients were >40 years. Strictures following previous urethritis were more common (29, 58 %) than those seen after trauma (21, 42 %). Strictures following trauma were more common in men <= 40 years (52.2 %), and 69 % of strictures in men >40 years were infective in origin. Altogether, 88 % of strictures were exclusively found in the anterior urethra. In all, 32 (64 %) patients had bacteriuria at presentation. Strictures >= 2 cm with extensive fibrosis were noted in 21 (42 %). Excision of scar tissue was done, followed by end-to-end anastomosis in 32 (64 %), penile pedicle flap in 16 (32 %), and buccal mucosal graft in 2 (4 %) of the patients. Wound infection was the most common complication. Overall, 76 % of patients achieved a urine flow rate of 15 ml/s and postvoid residual urine of <= 50 ml. CONCLUSIONS: One-stage urethroplasty offered satisfactory results in the study group. It is recommended for urethral reconstruction in men with urethral stricture. PMID- 23942534 TI - Impact of day 2 C-reactive protein on day 3 and 4 thresholds associated with infective complications following curative surgery for colorectal cancer. AB - BACKGROUND: The postoperative systemic inflammatory response, as evidenced by C reactive protein (CRP) on days 3 and 4, has been reported to be associated with the development of infective complications following surgery for colorectal cancer. However, patients in enhanced recovery after surgery require earlier assessment at day 2, the peak CRP response to surgery. The aim of the present study was to assess the impact of day 2 CRP on the CRP concentrations on days 3 and 4. METHODS: Patients with colorectal cancer undergoing elective resection were recorded in a prospective database (n = 357). CRP was measured preoperatively and on days 1-4 postoperatively. Correlations between day 2 CRP and day 3 and day 4 CRP concentrations were examined. RESULTS: The majority of patients were >= 65 (72 %), male (53 %), underwent right or left hemicolectomy (63 %), and had node-negative disease (61 %). Day 2 CRP was not significantly associated with age, sex, operation type, or tumor stage. Day 2 CRP was directly associated with day 3 (r (2) = 0.601, p < 0.001) and day 4 (r (2) = 0.270, p < 0.001) CRP. The median day 2 CRP that corresponded with the previously described thresholds for predicting infective complications was ~190 mg/L, and for predicting an anastomotic leak 200 mg/L. CONCLUSIONS: A day 2 CRP concentration >190 mg/L was associated with day 3 and 4 CRP concentrations above established CRP thresholds for the development of infective complications. PMID- 23942535 TI - Completely removing solitary intraductal papillomas using the Mammotome system guided by ultrasonography is feasible and safe. AB - BACKGROUND: Because of the potential for an intraductal papilloma to progress to malignancy and the likelihood of detecting unexpected coexisting malignant disease, complete removal of the intraductal papilloma is safer than merely sampling it. The purpose of this study was to estimate the feasibility and safety of excising a solitary intraductal papilloma using the Mammotome system guided by ultrasonography (US). METHODS: We retrospectively reviewed the clinical information of 136 patients who underwent excision of solitary intraductal papillomas using the 8-gauge probe with the US-guided Mammotome system between December 2005 and December 2011 at our institution. Their lesions had been suspected preoperatively or were occasionally diagnosed postoperatively. RESULTS: There were no local recurrences during the follow-up period. Of the patients who showed atypia and underwent re-excision, only 2 (6.1 %) had local ductal atypia. The patients with atypia were significantly older than the patients without atypia (p < 0.05). CONCLUSIONS: Using the US-guided 8-gauge probe Mammotome system to completely remove a solitary intraductal papilloma is feasible and safe. Close follow-up may be considered for those whose lesions exhibit atypia. PMID- 23942536 TI - Re: lower reoperation rate for recurrence after mesh versus sutured elective repair in small umbilical and epigastric hernias: a nationwide register study. PMID- 23942537 TI - Recurrence rate of pulmonary hydatidosis after surgery: reply. PMID- 23942538 TI - A simple isotope dilution electrospray ionization tandem mass spectrometry method for the determination of free phenytoin. AB - BACKGROUND: Phenytoin (diphenylhydantoin) is an anticonvulsant drug frequently prescribed for the treatment of many types of seizures. Because the drug is highly protein bound (90%-95%) and many conditions can displace the drug from proteins, the measurement of free phenytoin is warranted. Due to the unavailability of free phenytoin assays in many chemistry analyzers or limitations of immunoassays, chromatographic methods such as liquid chromatography-tandem mass spectrometry (LC-MS-MS) are preferred for the assay of free phenytoin. METHODS: The sample preparation involved ultrafiltration of serum or plasma to separate free phenytoin. Acetonitrile containing internal standard, phenytoin-d10, was added to the ultrafiltrate. The samples were centrifuged, and supernatants were injected into an LC-MS-MS involving reverse phase Ultra BiPh 5 MUm * 50 * 2.1-mm analytical column, and mobile phases, water and methanol containing 0.1% formic acid. The mass/charge (m/z) transitions were as follows: phenytoin -253.0 > 182.2 and 253.0 > 104.00; phenytoin-d10 -263.2 > 192.12. RESULTS: Linearity of the method ranged from 0.1 to 4.0 MUg/mL. Within-run and between-run imprecision values were <5% and <10%, respectively. The samples were stable for 2 weeks at 4 degrees C and 4 weeks at -20 degrees C. The method compared well with the laborious liquid-liquid extraction method and did not show any significant ion suppression or enhancement. CONCLUSIONS: A simple LC-MS-MS method was developed for the assay of free phenytoin. The method does not require laborious liquid-liquid or solid-phase extraction. The method has high analytical sensitivity, low imprecision, and a wide analytical measurement range. PMID- 23942539 TI - Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5 fluorouracil therapy among colorectal cancer patients. AB - BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is a pyrimidine catabolic enzyme involved in the initial and rate-limiting step of the catabolic pathway of toxic metabolites of 5-fluorouracil (5-FU). Several studies have reported that deficiency of DPD and polymorphisms of its gene are related to 5-FU toxicities and death. Association between serum concentration of 5-FU and its related toxicity has also been previously demonstrated. Hence, this study aims to understand the role of DPYD variants in serum level of 5-FU and the risk of developing toxicity to prevent adverse reactions and maximize therapy outcome for personalized medicine. METHODS: A total of 26 patients comprising 3 different ethnic groups (Malay, Chinese, and Indian) diagnosed with colorectal cancer and treated with 5-FU chemotherapy regimen from local hospital were recruited. Polymerase chain reaction and denaturing high-performance liquid chromatography methods were developed to screen polymorphisms of DPYD gene. High-performance liquid chromatography-based quantification assay was developed to measure the serum concentration of 5-FU among these patients. RESULTS: Patients with DPYD genotypes of deficient enzyme activity had higher median serum levels of 5-FU compared with normal DPD group (median, 11.51 mcg/mL; 95% confidence interval, 10.18-16.11 versus median, 0.83 mcg/mL; 95% confidence interval, 0.55-5.90, Mann Whitney U test; P = 0.010). Patients with neutropenia (n = 11) had significantly higher serum concentrations of 5-FU as compared with those with normal white blood cell count (n = 15) (Mann-Whitney U test, P = 0.031). Combined regression analysis showed that the predictive power of DPYD*5 (rs1801159) and 1896 T>C (rs17376848) for serum concentrations of 5-FU in the studied group was 36.6% (P = 0.04). Similarly, DPYD*5 and 1896 T>C accounted for 29.9% of the occurrences of neutropenia (analysis of variance, P = 0.017). CONCLUSIONS: This study revealed that DPYD*5 (rs1801159) and 1896 T>C (rs17376848) are potentially useful predictive markers of patients' responses to 5-FU chemotherapy. Pharmacogenotyping is therefore recommended to guide dosing of 5-FU and prevent neutropenia. PMID- 23942540 TI - Lacosamide therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs. AB - BACKGROUND: Lacosamide (LCM) is one of the newer antiepileptic drugs (AEDs) licensed as add-on treatment for partial epilepsy. Data on LCM pharmacokinetics and interactions are limited and partly contradictory. The purpose of this study was to assess the effect of concomitant AED therapy on steady state plasma concentrations of LCM in a population of patients with epilepsy. METHODS: Steady state plasma concentrations of LCM were assessed in a cohort of 75 consecutive patients with epilepsy referred to the Laboratory of Clinical Neuropharmacology for AED therapeutic monitoring over 16 months. Plasma LCM concentrations were measured by high-performance liquid chromatography with spectrophotometric detection. RESULTS: Median morning trough plasma concentration-to-weight-adjusted dose ratio of LCM [(mg/L)/(mg/kg/d)] was significantly reduced (0.94 versus 1.35, P < 0.001) in patients treated with LCM plus AED strong inducers of cytochrome P450 metabolism, namely, carbamazepine, phenobarbital, and phenytoin (group A, n = 33), compared with a pool of patients not comedicated with AED strong inducers, predominantly including oxcarbazepine, levetiracetam, lamotrigine, and valproic acid (group B, n = 42). The 2 groups were comparable for age, gender, weight, LCM daily dose, and dosing frequency. LCM plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 75 to 600 mg/d, although, at a given drug dose, a large interpatient variability was observed in matched, plasma drug concentration. CONCLUSIONS: Our findings confirm, in a real-patient clinical setting, preliminary evidence from randomized, clinical trials showing that carbamazepine, phenobarbital, or phenytoin significantly reduces the overall systemic exposure to LCM. From a practical point of view, patients on concomitant AED strong inducers may require a 30% higher dose of LCM compared with patients not receiving strongly inducing AED cotherapy, to achieve the same plasma drug concentration. PMID- 23942541 TI - Neurodevelopment of children assessed after prenatal exposure to polybrominated diethyl ethers from collapse of world trade center. PMID- 23942542 TI - Pharmacokinetics of ciprofloxacin in hospitalized geriatric patients: comparison between nasogastric tube and oral administration. AB - OBJECTIVES: Drug administration to debilitated elderly patients on enteral feeding through a nasogastric tube (NGT) can modify the pharmacokinetic characteristics of the drug and influence its therapeutic blood concentration. The aim of this study was to evaluate the pharmacokinetics of ciprofloxacin administered through an NGT and to compare it with those of a group of patients receiving the drug orally. METHODS: Twenty patients in stable clinical and hemodynamic condition from the long-term care ward of a geriatric multilevel hospital were studied. Patients in group 1 (n = 10) had oropharyngeal dysphagia and received food and medications, including ciprofloxacin, by NGT. Group 2 (n = 10) included age- and disease-matched orally fed patients from the same department receiving ciprofloxacin orally. Blood samples for ciprofloxacin concentration were taken at steady state, before drug administration, time 0, and at 1, 2, 3, 4, 6, 8, and 10 hours after drug administration. Ciprofloxacin was measured using liquid chromatography with tandem mass spectrometric detection. The mean daily dose was the same in both the groups: 1000 mg (500 mg twice daily). RESULTS: Pharmacokinetic parameters of ciprofloxacin were not significantly different between the 2 groups: trough concentrations were 1.24 +/- 0.95 MUg/mL (0.25-3.67 MUg/mL) versus 1.30 +/- 0.61 MUg/mL (0.21-2.36 MUg/mL) (P = 0.76); Cmax 3.30 +/- 2.16 MUg/mL (1.54-8.62 MUg/mL) versus 4.24 +/- 1.99 MUg/mL (2.24-9.02 MUg/mL) (P = 0.356); tmax 2.8 +/- 1.5 versus 3.1 +/- 2.8 hours (P = 0.799); and AUC0-10 20.2 +/- 12.1 MUg.h.mL (9-51.07 MUg.h.mL) versus 24.4 +/- 13.0 MUg.h.mL (5.57-52.48 MUg.h.mL) (P = 0.493), in the oral fed versus NGT, respectively. CONCLUSIONS: Ciprofloxacin pharmacokinetic parameters are not significantly different between patients receiving the drug through NGT compared with those who received it orally, and therefore, in frail elderly patients, this route of administration can be considered. PMID- 23942543 TI - Diagnostic value of concentration profiles of glucocorticosteroids and endocannabinoids in hair. AB - BACKGROUND: Endogenous corticosteroids and endocannabinoids are both known to be involved in stress adaption and anti-inflammatory and immuneregulatory effects. The application of hair as retrospective specimen for long-term recording of corticosteroids and its association with stress-induced biochemical alterations was intensively examined. METHODS: To evaluate the stability and correlation of various parameters of the endocannabinoid and corticosteroid systems, a prospective study was carried out. Hair samples were collected monthly over a pregnancy cycle (sixth week of pregnancy to 9 weeks postpartum). By comparison of hair concentrations in particular segments (ie, grown in the same time span but collected at different times), an examination of analyte stability in hair was achieved. Additionally, the comparison of proximal segments provided on biochemical information that is independent of alteration due to physical instability. The detection limits of a validated procedure using solid-phase extraction cleanup and liquid chromatography-mass spectrometry proved to be suitable to identify the endogenous levels of cortisol (limits of detection = 1.6 pg/mg), cortisone (2.1 pg/mg), anandamide (AEA, 0.3 pg/mg), and 2 arachidonoylglycerol (15 pg/mg). RESULTS: Corticosteroid concentrations in corresponding hair segments were found to be reduced with increasing hair age; an average decline of cortisol and cortisone by 50% in 4 months was estimated. Independently, an increase of cortisol and cortisone in proximal segments collected during pregnancy was confirmed, which is assumed to be stress related. Endocannabinoids proved to be by far more stable, as demonstrated by subsequent monthly collection of corresponding segments and there was hardly any washout of AEA detectable. Elevated hair concentrations of AEA and 2-arachidonoylglycerol were detected in the first-second trimester of pregnancy, which corresponds to negative correlations between AEA, cortisol, and cortisone. PMID- 23942544 TI - Development and validation of a high-performance liquid chromatography ultraviolet method for lapatinib quantification in human plasma. AB - A selective and precise high-performance liquid chromatography ultraviolet method was developed and validated for the determination of lapatinib in human plasma. After protein precipitation with acetonitrile, lapatinib and sorafenib were separated using isocratic elution (on a C18 Ultrabase column using a mobile phase of acetonitrile/20 mM ammonium acetate in a proportion 53:47 (v/v) pumped at a constant flow rate of 1.2 mL/min). Quantification was performed at 260 nm. Calibration curves were linear over the range 0.2-10 ug/mL. Inter- and intraday coefficients of variation were less than 7%. The limit of detection and the lower limit of quantification were 0.1 and 0.2 ug/mL, respectively. Recoveries of lapatinib from plasma were higher than 86.7% in all cases. The assay was applied to the determination of the drug in the plasma of 2 cancer patients receiving lapatinib, 1000 and 1250 mg orally, and could be useful for therapeutic drug monitoring of lapatinib in routine clinical practice. PMID- 23942545 TI - Monitoring antigen-specific biologics: current knowledge and future prospects. AB - An increasing number of antigen-specific biologics have been introduced into clinical practice, and the ones that arrived first have already reached the end of their patented life span. Despite the use of these agents for over a decade, individualized dosing is not standard practice. Most patients are treated according to treatment protocols, with a fixed dose administered at fixed time intervals. Although the between-subject variability in the volume of distribution is small, there is a moderate to high between-subject variability in the clearance of these biologics. The formation of neutralizing antidrug antibodies (ADAs) further contributes to the variability in the pharmacokinetics and pharmacodynamics. After the development of assays to detect biologic drug serum concentrations and ADA titers, the first clinical studies in immune-mediated diseases such as rheumatology, gastroenterology, and dermatology have now shown clear concentration-effect relationships. By monitoring the serum trough concentrations of biologics, patients with high drug exposure could be identified and dose reductions in those patients may lead to improved safety and substantial cost savings. Low biologic drug serum concentrations may be due to the development of ADAs, and if these are detected, a switch to an alternative treatment is indicated. We envision a vast expansion of therapeutic drug monitoring to support the use of biologics, and we urge the International Association of Therapeutic Drug Monitoring and Clinical Toxicology to embark on initiatives to investigate the contribution of therapeutic drug monitoring to this field. PMID- 23942546 TI - The end-of-treatment ribavirin concentration predicts hepatitis C virus relapse. AB - BACKGROUND: The optimization of combination therapy with ribavirin (RBV) and pegylated interferon alpha has substantially improved sustained virologic response (SVR) rates and lowered virologic relapse rates in patients infected with hepatitis C virus (HCV). In this study, we performed an analysis of the relationship between the end-of-treatment plasma RBV concentration and virologic relapse. METHODS: Thirty-four patients with HCV treated with pegylated interferon/RBV and with an end-of-treatment response were assayed for plasma RBV concentration using liquid chromatography assay coupled to tandem mass spectrometric detection on the last day of the treatment. Clinical data and the concentration of RBV were compared between patients classified as either relapsers or nonrelapsers. RESULTS: Eleven patients (32.4%) relapsed and 23 patients (67.6%) achieved an SVR. The mean plasma RBV concentration on the last day of treatment was 1380 +/- 312 ng/mL for relapsers and 2278 +/- 569 ng/mL for SVR patients (P < 0.0001). A receiver operating characteristic analysis showed that a threshold of 1960 ng/mL was associated with the greatest sensitivity and specificity (100% and 83%, respectively, with an area under the curve of 0.94; P < 0.0001) for discriminating between patients who relapsed and those who did not. A univariate logistic regression analysis indicated that a plasma RBV concentration of <1960 ng/mL at the end of the treatment was strongly associated with relapse (odds ratio, 55; 95% confidence interval, 7.24-infinity; P = 0.0001) independently of age, body weight, RBV dose, baseline viral load, the interleukin 28B genotype, and response to previous courses of treatment. CONCLUSIONS: Our study results highlight the relevance of measuring plasma RBV concentrations during and at the end of HCV treatment, with a view to avoiding virologic relapse. PMID- 23942547 TI - Water-based layer-by-layer surface chemical modification of biomimetic materials: oil repellency. AB - Biomimetic materials possessing hierarchical surface roughness thrive when complementary terminal chemical functionality is introduced. However, incorporating terminal functionality on the biomimetic material is the challenge, especially, when its roughness needs to be preserved. Hence, we report surface chemical modification of biomimetic materials through water-based layer-by-layer deposition. The amine terminated biomimetic replica PDMS-replica(Silica/NH2) was prepared by treating silica-modified replica (i.e., PDMS-replica(Silica)) with the aqueous solution of branched ethoxylated polyethylenimine (EPEI). Next, -CF3 terminal PDMS-replica(Silica/NH2/CF3) was obtained by treating PDMS replica(Silica/NH2) with the aqueous solution of phosphate ester fluorosurfactant. PDMS-replica(Silica/NH2/CF3) showed superhydrophobicity (advancing thetawater ~ 140 degrees ) and high oil repellency (advancing thetaoil ~ 110 degrees ). X-ray photoelectron spectroscopy (XPS) revealed well-organized terminal -CF3 groups present on the PDMS-replica(Silica/NH2/CF3) surface. During the process of layer-by-layer deposition, the surface topography was monitored using scanning electron microscopy (SEM). This method could be extended to get desired terminal chemical functionality on the biomimetic materials which would furnish interesting surface properties in air or under water. PMID- 23942548 TI - Acylsilanes: valuable organosilicon reagents in organic synthesis. AB - Acylsilanes are a fascinating class of compounds that display a number of distinctive chemical and physical properties. The unique reactivity pattern of the acylsilane functional group [R-C(O)Si] makes them an increasingly attractive moiety in modern organic synthesis, and as such, they have been utilised in a diverse range of transformations. This review provides an overview of the recent advances in the synthesis and application of acylsilanes in organic chemistry, with a particular focus on the progress made in the last two decades. PMID- 23942549 TI - Systemic administration of follistatin288 increases muscle mass and reduces fat accumulation in mice. AB - The present study describes the physiological response associated with daily subcutaneous injection of mice with recombinant follistatin288. This systemic administration of follistatin288 increases the follistatin levels in serum, indicating that the protein enters the circulation. The data suggest that a dose dependent increase in body lean mass also occurs, together with an increase in muscle mass, possibly as a result of an increase in the size of the muscle fibers. After thirteen weeks of treatment, metabolic changes were observed; additionally, the switching of muscle fiber types was also apparent through myosin heavy chain remodeling, implying that changes are occurring at the molecular level. Furthermore, an increase in the muscle mass was associated with a significant decrease in the body fat mass. Overall, this study raises the possibility for the use of follistatin288 as an agent to treat muscle wasting diseases and/or to restrict fat accumulation by systemic administration of the protein. PMID- 23942550 TI - Climate change is predicted to negatively influence Moroccan endemic reptile richness. Implications for conservation in protected areas. AB - The identification of species-rich areas and their prognosticated turnover under climate change are crucial for the conservation of endemic taxa. This study aims to identify areas of reptile endemicity richness in a global biodiversity hot spot (Morocco) under current and future climatic conditions and to investigate the role of protected areas in biodiversity conservation under climate change. Species distribution models (SDM) were performed over the distribution of 21 endemic reptiles, combined to estimate current species richness at 1 * 1 km resolution and projected to years 2050 and 2080 according to distinct story lines and ensemble global circulation models, assuming unlimited and null dispersion ability. Generalized additive models were performed between species richness and geographic characteristics of 43 protected areas. SDM found precipitation as the most important factor related to current species distributions. Important reductions in future suitable areas were predicted for 50 % of species, and four species were identified as highly vulnerable to extinction. Drastic reductions in species-rich areas were predicted for the future, with considerable variability between years and dispersal scenarios. High turnover rates of species composition were predicted for eastern Morocco, whereas low values were forecasted for the Northern Atlantic coast and mountains. Species richness for current and future conditions was significantly related to the altitude and latitude of protected areas. Protected areas located in mountains and/or in the Northern Atlantic coast were identified as refugia, where population monitoring and conservation management is needed. PMID- 23942553 TI - The role of fibroblast growth factor-23 in cardiorenal syndrome. AB - Abnormalities in chronic kidney disease-related bone and mineral metabolism (CKD MBD) have emerged as novel risk factors in excess cardiovascular mortality in patients with CKD and end-stage renal disease (ESRD). The pathophysiological links between CKD-MBD and adverse cardiovascular events in this patient population are unclear. Hyperphosphatemia through induction of vascular calcifications and decreased active vitamin D production leading to activation of the renin angiotensin system (RAS) along with defects in innate immunity are purported to be the proximate cause of CKD-MBD-associated mortality in CKD. Recently, this view has been challenged by the observation that fibroblast growth factor-23 (FGF23), a newly discovered hormone produced in the bone that regulates phosphate and vitamin D metabolism by the kidney, is a strong predictor of adverse cardiovascular outcomes in patients with CKD and ESRD. Whether these associations between elevated circulating FGF23 levels and cardiovascular outcomes are causative, and if so, the mechanisms mediating the effects of FGF23 on the cardiovascular system are not clear. The principal physiological functions of FGF23 are mediated by activation of FGF receptor/alpha-klotho coreceptor complexes in target tissues. Elevated FGF23 has been associated with left ventricular hypertrophy (LVH), and it has been suggested that FGF23 may induce myocardial hypertrophy through a direct effect on cardiac myocytes. A direct 'off target' effect of FGF23 on LVH is controversial, however, since alpha-klotho (which is believed to be indispensable for the physiologic actions of FGF23) is not expressed in the myocardium. Another possibility is that FGF23's effect on the heart is mediated indirectly, via 'on target' regulation of hormonal pathways in the kidney, which include suppression of angiotensin-converting enzyme 2, Cyp27b1and alpha-klotho, which would be predicted to act on circulating factors known to regulate RAS, 1,25(OH)2D production and ion transport in the myocardium. Understanding of FGF23's pathophysiology and mechanisms of action responsible for its negative effects will be necessary to develop therapeutic strategies to treat CKD-MBD. PMID- 23942551 TI - Inhibition of Src kinase blocks high glucose-induced EGFR transactivation and collagen synthesis in mesangial cells and prevents diabetic nephropathy in mice. AB - Chronic exposure to high glucose leads to diabetic nephropathy characterized by increased mesangial matrix protein (e.g., collagen) accumulation. Altered cell signaling and gene expression accompanied by oxidative stress have been documented. The contribution of the tyrosine kinase, c-Src (Src), which is sensitive to oxidative stress, was examined. Cultured rat mesangial cells were exposed to high glucose (25 mmol/L) in the presence and absence of Src inhibitors (PP2, SU6656), Src small interfering RNA (siRNA), and the tumor necrosis factor alpha-converting enzyme (TACE) inhibitor, TAPI-2. Src was investigated in vivo by administration of PP2 to streptozotocin (STZ)-induced diabetic DBA2/J mice. High glucose stimulated Src, TACE, epidermal growth factor receptor (EGFR), mitogen activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2, p38), and collagen IV accumulation in mesangial cells. PP2 and SU6656 blocked high glucose-stimulated phosphorylation of Src Tyr-416, EGFR, and MAPKs. These inhibitors and Src knockdown by siRNA, as well as TAPI-2, also abrogated high glucose-induced phosphorylation of these targets and collagen IV accumulation. In STZ-diabetic mice, albuminuria, increased Src pTyr-416, TACE activation, ERK and EGFR phosphorylation, glomerular collagen accumulation, and podocyte loss were inhibited by PP2. These data indicate a role for Src in a high glucose-Src-TACE heparin-binding epidermal growth factor-EGFR-MAPK-signaling pathway to collagen accumulation. Thus, Src may provide a novel therapeutic target for diabetic nephropathy. PMID- 23942554 TI - Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants. AB - BACKGROUND: To evaluate the relationships between postnatal change in circulatory insulin-like growth factor-I (IGF-I) concentrations, brain volumes, and developmental outcome at 2 y of age in very preterm infants. METHODS: IGF-I was measured weekly, and nutritional intake was calculated daily from birth until a postmenstrual age (PMA) of 35 wk. Individual beta coefficients for IGF-I, IGF I(B), representing the rate of increase in IGF-I from birth until a PMA of 35 wk were calculated. Brain magnetic resonance imaging was performed at term age, with segmentation into total brain, cerebellar, gray matter, and unmyelinated white matter volume (UWMV). Developmental outcome was evaluated using Bayley Scales of Infant Development-II. RESULTS: Forty-nine infants, with mean gestational age (GA) of 26.0 wk, were evaluated at mean 24.6 mo corrected age. Higher IGF-I(B), UWMV, and cerebellar volume were associated with a decreased risk for a Mental Developmental Index (MDI) < 85 (odds ratio (95% confidence interval): 0.6 (0.4 0.9), 0.96 (0.94-0.99), and 0.78 (0.6-0.96), respectively). In multivariate analysis, higher IGF-I(B) and higher UWMV combined with female gender constituted the two models with the highest predictive value for MDI > 85. CONCLUSION: A higher rate of increase in circulating IGF-I is associated with a decreased risk for subnormal MDI at 2 y of corrected age. This relationship is in part dependent on brain volume at term age. PMID- 23942555 TI - Cerebrovascular autoregulation and neurologic injury in neonatal hypoxic-ischemic encephalopathy. AB - BACKGROUND: Neonates with hypoxic-ischemic encephalopathy (HIE) are at risk of cerebral blood flow dysregulation. Our objective was to describe the relationship between autoregulation and neurologic injury in HIE. METHODS: Neonates with HIE had autoregulation monitoring with the hemoglobin volume index (HVx) during therapeutic hypothermia, rewarming, and the first 6 h of normothermia. The 5-mm Hg range of mean arterial blood pressure (MAP) with best vasoreactivity (MAPOPT) was identified. The percentage of time spent with MAP below MAPOPT and deviation in MAP from MAPOPT were measured. Neonates received brain magnetic resonance imaging (MRI) 3-7 d after treatment. MRIs were coded as no, mild, or moderate/severe injury in five regions. RESULTS: HVx identified MAPOPT in 79% (19/24), 77% (17/22), and 86% (18/21) of the neonates during hypothermia, rewarming, and normothermia, respectively. Neonates with moderate/severe injury in paracentral gyri, white matter, basal ganglia, and thalamus spent a greater proportion of time with MAP below MAPOPT during rewarming than neonates with no or mild injury. Neonates with moderate/severe injury in paracentral gyri, basal ganglia, and thalamus had greater MAP deviation below MAPOPT during rewarming than neonates without injury. CONCLUSION: Maintaining MAP within or above MAPOPT may reduce the risk of neurologic injuries in neonatal HIE. PMID- 23942556 TI - Exploratory study of the relationship of fat-free mass to speed of brain processing in preterm infants. AB - BACKGROUND: Preterm infants are at risk for long-term neurodevelopmental impairment as a function of postnatal nutritional status. Despite adequate neonatal weight gain, preterm infants have altered body composition, with lower fat-free mass (FFM) and higher adiposity at term corrected gestational age (CGA) than their term counterparts. The relationship between postnatal body composition and speed of brain processing in preterm infants is unknown. METHODS: Anthropometric measurements and body composition testing via air displacement plethysmography were performed on 16 appropriate-for-gestational age (GA) preterm (mean GA: 30.4 +/- 2.8 wk) infants at term and 4 mo CGA. Infant visual pathway development was assessed at 4 mo CGA using pattern-reversal visual evoked potential (VEP); P100 (positive peak) latency was used to index neuronal speed of processing. RESULTS: Increased FFM at discharge (P = 0.02) and 4 mo CGA (P = 0.006) was associated with shorter latencies to the P100 peak. P100 latency was not related to total body weight, fat mass, or body fat percentage. CONCLUSION: FFM reflects protein accretion and indexes growth of organs, including the brain. The association of shorter VEP latency (i.e., faster neuronal processing) with higher FFM (i.e., better protein status) may be attributed to the positive effects of protein status on neuronal growth and differentiation. PMID- 23942557 TI - Specific biochemical amniotic fluid pattern of fetal isolated esophageal atresia. AB - BACKGROUND: Perinatal care of esophageal atresia (EA) may be improved by prenatal diagnosis. Ultrasound findings (polyhydramnios and/or nonvisualization of fetal stomach) lead to a detection rate of ~50%. An amniotic fluid (AF) biochemical pattern characterized by high total protein, gamma-glutamyl transpeptidase (GGTP), and normal l-leucine-aminopeptidase (AMP) leads to a 100% detection rate. The aim of this study was to explain this specific pattern. METHODS: On the basis of enzyme activities assay, the following four objectives were sought: (i) comparing AF markers between EA and other digestive tract atresias, (ii) determining local GGTP synthesis in the esophagus (immunohistobiochemistry), (iii) determining the presence of a specific AF-AMP activity inhibitor, and (iv) comparing AF-AMP and AF-GGTP half-lives. RESULTS: The AF-EA pattern was similar to that observed in upper duodenal atresia (above the Oddi sphincter). No local synthesis of GGTP was observed in the esophagus. No AF-AMP activity inhibitor was found. AF-GGTP had a longer half-life than AF-AMP. CONCLUSION: Due to the swallowing anomaly observed in EA, GGTP and AMP values physiologically observed at 18 wk will decrease on the basis of the half-lives of markers, with a flat slope for GGTP and a sharp slope for AMP, therefore explaining the differences observed in the AF-EA pattern. PMID- 23942558 TI - Septicemia mortality reduction in neonates in a heart rate characteristics monitoring trial. AB - BACKGROUND: Abnormal heart rate characteristics (HRC) wax and wane in early stages of culture-positive, late-onset septicemia (LOS) in patients in the neonatal intensive care unit (NICU). Continuously monitoring an HRC index leads to a reduction in mortality among very low birth weight (VLBW) infants. We hypothesized that the reduction in mortality was due to a decrease in septicemia associated mortality. METHODS: This is a secondary analysis of clinical and HRC data from 2,989 VLBW infants enrolled in a randomized clinical trial of HRC monitoring in nine NICUs from 2004 to 2010. RESULTS: LOS was diagnosed 974 times in 700 patients, and the incidence and distribution of organisms were similar in HRC display and nondisplay groups. Mortality within 30 d of LOS was lower in the HRC display as compared with the nondisplay group (11.8 vs. 19.6%; relative risk: 0.61; 95% confidence interval: 0.43, 0.87; P < 0.01), but mortality reduction was not statistically significant for patients without LOS. There were fewer large, abrupt increases in the HRC index in the days leading up to LOS diagnosis in infants whose HRC index was displayed. CONCLUSION: Continuous HRC monitoring is associated with a lower septicemia-associated mortality in VLBW infants, possibly due to diagnosis earlier in the course of illness. PMID- 23942559 TI - TARC/CCL17 gene polymorphisms and expression associated with susceptibility and coronary artery aneurysm formation in Kawasaki disease. AB - BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. Thymus and activation-regulated chemokine/chemokine ligand 17 (TARC/CCL17) is one of the Th2 chemokines and has been suggested as a candidate gene for conferring susceptibility to Th2 associated with allergy diseases. This study examined the correlation between gene polymorphisms and plasma levels of TARC/CCL17 in patients with KD and the outcomes of KD. METHODS: A total of 381 KD patients and 564 controls were subjected to determination of five tagging single-nucleotide polymorphisms of TARC/CCL17. In addition, plasma TARC/CCL17 levels were measured by enzyme-linked immunosorbent assay. RESULTS: Polymorphisms of TARC/CCL17 were significantly different between normal children and patients with KD. A allele of rs4784805 has better intravenous immunoglobulin (IVIG) treatment response to KD. Furthermore, plasma TARC/CCL17 levels were higher in KD patients than that in controls before IVIG treatment. After IVIG treatment, plasma TARC/CCL17 levels decreased significantly. CONCLUSION: This study provides the first evidence supporting the association between TARC/CCL17 polymorphisms, susceptibility of KD, and IVIG responses in KD patients. PMID- 23942560 TI - Comparing near-infrared spectroscopy devices and their sensors for monitoring regional cerebral oxygen saturation in the neonate. AB - BACKGROUND: Near-infrared spectroscopy (NIRS) is an upcoming clinical method for monitoring regional cerebral oxygen saturation (rScO2) in neonates. There is a growing market offering different devices and sensors. Even though this technique is increasingly clinically applied, little is known about the similarities and/or differences in rScO2 values between the different devices and sensors. The aim of this study was to compare the rScO2 values obtained in (preterm) neonates with all available sensors of three frequently used NIRS devices. METHODS: Fifty-five neonates admitted to our neonatal intensive care unit (NICU) were included in this study. rScO2 was simultaneously monitored bilaterally with two different NIRS sensors (left and right frontoparietal) for at least 1 h. Then, the sensors were switched, and measurements were collected for at least another hour. RESULTS: We detected a rather close correlation between all investigated sensors from the three different NIRS devices, but absolute rScO2 values showed substantial differences: Bland-Altman analysis showed average differences from 10 to 15%. CONCLUSION: Although the rScO2 values correlated well between different NIRS sensors, sometimes there were substantial differences between the absolute rScO2 values, which may complicate clinical application. PMID- 23942561 TI - [Secondary immunodeficiency in rheumatological diseases]. AB - Immunosuppressive treatment plays a crucial role in the management of autoimmune and autoinflammatory diseases. Knowledge about the ensuing immune deficits resulting from these therapies as well as common infections in immunocompromised patients should be familiar to all doctors involved in the prescription and administration of immunosuppressive drugs. Comprehensive pretreatment screening, regular monitoring both during and following treatment as well common sense preventive measures, such as vaccination can help further minimise the risk of infection. PMID- 23942562 TI - [Are the recommendations on tuberculosis screening still valid? Interferon gamma release assay (IGRA) and/or tuberculin skin test for diagnosis of latent tuberculosis infection (LTBI)]. PMID- 23942563 TI - The extra burden of infliximab infusions in inflammatory bowel disease. AB - BACKGROUND: Infliximab (IFX) infusions require repeated hospitalizations. The median duration of each hospitalization stay, including time for infusion and the cost for the health care system, are unknown. We assessed the extra burden of IFX infusions in inflammatory bowel disease (IBD). METHODS: This was a prospective cross-sectional study enrolling all consecutive patients with IBD treated with IFX at the Nancy IBD Unit (January to March 2012). Four parameters were assessed: median travel duration, median time that patients stayed at the IBD unit, reimbursement for transport by the health care system, and impact of IFX infusions on their work. RESULTS: Among 137 IBD patients, 48.9% were women, 74.5% had Crohn's disease, and the median age was 35 (range, 18-65) years. The median travel duration backward and forward from home to the Nancy IBD unit was 2 (range, 0.5-4) hours. The patients stayed at the IBD unit for a median period of 4.5 (range, 2.8-6.7) hours. For 63.5% of the patients (87/137), transport was reimbursed by the health care system. Of the patients receiving IFX infusions, 10.9% (15/137) were unemployed, 24.8% (34/137) had the agreement of their employer to spend 1 day at the hospital for their IFX infusion, 27.0% (36/137) asked specifically a vacation for the IFX infusion, and 13.9% (19/137) were in sick leave. CONCLUSIONS: The patients spend a median of 6.5 hours outside their home for each IFX infusion, and they often take a day of vacation or rest. This represents an extra burden for IFX-treated patients and for the health care system. PMID- 23942564 TI - Short-term stress, but not mucosal healing nor depression was predictive for the risk of relapse in patients with ulcerative colitis: a prospective 12-month follow-up study. AB - BACKGROUND: Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease. Psychological factors such as depression and stress are under debate to contribute to the risk of relapse. The impact of mucosal healing to reduce the risk of relapse had not been studied prospectively. The aim of this study was to identify whether depression and stress increase and mucosal healing reduces the risk of clinical relapse in patients with UC in clinical remission. METHODS: Patients in clinical remission were followed prospectively for 1 year, or less if they relapsed. Endoscopy and histology score and long-term perceived stress (Perceived Stress Questionnaire) were measured at baseline. Mucosal healing was defined by a Mayo Endoscopy score of 0-1. Depression (Hospital Anxiety and Depression Scale) and acute perceived stress (Cohen Perceived Stress Scale) were measured at baseline and after 1, 3, 6, 9, and 12 months. A time-dependent multivariate Cox regression model determined the predictors of time to relapse. RESULTS: Seventy-five patients were included into final analysis, of which 28 (37.3%) relapsed. Short-term stress at the last visit before relapse (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 1.01-1.10) and male gender (HR = 2.38, 95% CI = 1.01-5.61), but not baseline mucosal healing (HR = 0.86, 95% CI = 0.35-2.11), baseline long-term stress (HR = 0.20, 95% CI = 0.01-3.31), and depression at the last visit before relapse (HR = 1.08, 95% CI = 0.95-1.22) were predictive for a relapse. CONCLUSIONS: Short-term stress but not depression nor mucosal healing was predictive for the risk of relapse in patients with UC in clinical remission. Larger multicentre studies are necessary to confirm our findings. PMID- 23942565 TI - MALDI-ToF mass spectrometry coupled with multivariate pattern recognition analysis for the rapid biomarker profiling of Escherichia coli in different growth phases. AB - Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-ToF MS) has been exploited extensively in the field of microbiology for the characterisation of bacterial species, the detection of biomarkers for early disease diagnosis and bacterial identification. Here, the multivariate data analysis technique of partial least squares-discriminant analysis (PLS-DA) was applied to 'intact cell' MALDI-ToF MS data obtained from Escherichia coli cell samples to determine if such an approach could be used to distinguish between, and characterise, different growth phases. PLS-DA is a technique that has the potential to extract systematic variation from large and noisy data sets by identifying a lower-dimensional subspace that contains latent information. The application of PLS-DA to the MALDI-ToF data obtained from cells at different stages of growth resulted in the successful classification of the samples according to the growth phase of the bacteria cultures. A further outcome of the analysis was that it was possible to identify the mass-to-charge (m/z) ratio peaks or ion signals that contributed to the classification of the samples. The Swiss-Prot/TrEMBL database and primary literature were then used to provisionally assign a small number of these m/z ion signals to proteins, and these tentative assignments revealed that the major contributors from the exponential phase were ribosomal proteins. Additional assignments were possible for the stationary phase and the decline phase cultures where the proteins identified were consistent with previously observed biological interpretation. In summary, the results show that MALDI-ToF MS, PLS-DA and a protein database search can be used in combination to discriminate between 'intact cell' E. coli cell samples in different growth phases and thus could potentially be used as a tool in process development in the bioprocessing industry to enhance cell growth and cell engineering strategies. PMID- 23942566 TI - Multi-walled carbon nanotubes as sorptive material for solventless in-tube microextraction (ITEX2)--a factorial design study. AB - Multi-walled carbon nanotubes were evaluated as sorptive packing material for in tube microextraction (ITEX2) in combination with GC-MS for the analysis of benzene, toluene, ethylbenzene, xylenes, and naphthalene in aqueous samples. For method development, a three-level full factorial design of experiment (DoE) was performed incorporating extraction temperature, number of extraction strokes, and extraction flow. The statistical analysis of method development showed that all considered extraction parameters significantly affected the extraction yield. Furthermore, it was shown that some factors significantly interacted with each other, which indicates the advantage of using DoE for method development. The thereby optimized ITEX2 protocol was validated regarding its linear dynamic range, method detection limit (MDL), and precision. The MDLs of investigated analytes ranged between 2 ng L(-1) for naphthalene and 11 ng L(-1) for p-xylene. The relatively low MDL obtained for naphthalene, despite its comparably low air water partitioning, can be explained by its strong interaction with carbon nanotubes. All obtained MDLs are at least comparable to previous reports on microextraction techniques, emphasizing both the quality of ITEX2 and the highly promising sorbent characteristics of carbon nanotubes. Furthermore, the method was applied to three real samples, which demonstrated good recoveries of analytes from tap water, a bank filtrate, and an effluent from a wastewater treatment plant. PMID- 23942567 TI - Hemoglobin as a major binding protein for methylmercury in white-sided dolphin liver. AB - As methylmercury (MeHg) can be bioaccumulated and biomagnified in the trophic web, its toxicity for marine mammals is of major concern. Mercury speciation in marine biota has been widely studied, mainly focused on the discrimination and quantification of inorganic Hg and MeHg. Less attention has been paid to the interactions of Hg with biomolecules and the characterization of its specific binding, which play a key role in metabolic pathways controlling its uptake, transformation, and toxicity. In the studied white-sided dolphin (Lagenorhynchus acutus) liver homogenate (QC04LH4) sample, approximately 60% of the total MeHg was found in the water soluble fraction, specifically associated with high molecular weight biomolecules. The identity of the involved proteins was investigated (after tryptic digestion of the fraction) by MURPLC with parallel detection by ICP-MS and ESI-MS/MS. Molecular mass spectrometry experiments were carried out at high resolution (100000) to ensure accurate protein identification and determination of the MeHg binding sites. Cysteine residue on the dolphin hemoglobin beta chain was found to be the main MeHg binding site, suggesting that hemoglobin is a major MeHg binding protein in this marine mammal and could be a potential carrier of this MeHg from blood to liver prior to its degradation in this organ. In parallel, a significant proportion of selenium was found to be present as selenoneine and a potential role for this compound in Hg detoxification is discussed. PMID- 23942568 TI - A new restricted access molecularly imprinted polymer capped with albumin for direct extraction of drugs from biological matrices: the case of chlorpromazine in human plasma. AB - A new restricted access molecularly imprinted polymer coated with bovine serum albumin (RAMIP-BSA) was developed, characterized, and used for direct analysis of chlorpromazine in human plasma samples. The RAMIP-BSA was synthesized using chlorpromazine, methacrylic acid, and ethylene glycol dimethacrylate as template, functional monomer, and cross-linker, respectively. Glycerol dimethacrylate and hydroxy methyl methacrylate were used to promote a hydrophilic surface (high density of hydroxyl groups). Afterward, the polymer was coated with BSA using glutaraldehyde as cross-linker, resulting in a protein chemical shield around it. The material was able to eliminate ca. 99% of protein when a 44-mg mL(-1) BSA aqueous solution was passed through it. The RAMIP-BSA was packed in a column and used for direct analysis of chlorpromazine in human plasma samples in an online column switching high-performance liquid chromatography system. The analytical calibration curve was prepared in a pool of human plasma samples with chlorpromazine concentrations ranging from 30 to 350 MUg L(-1). The correlation coefficient obtained was 0.995 and the limit of quantification was 30 MUg L(-1). Intra-day and inter-day precision and accuracy presented variation coefficients and relative errors lower than 15% and within -15 and 15%, respectively. The sample throughput was 3 h(-1) (sample preparation and chromatographic analysis steps) and the same RAMIP-BSA column was efficiently used for about 90 cycles. PMID- 23942569 TI - Rapid analysis of aflatoxin M1 in milk using dispersive liquid-liquid microextraction coupled with ultrahigh pressure liquid chromatography tandem mass spectrometry. AB - A simple, rapid, and sensitive method based on simultaneous protein precipitation and extraction of aflatoxin M1 (AFM1) followed by dispersive liquid-liquid microextraction (DLLME) and ultrahigh pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) analysis was developed for the determination of AFM1 in milk samples. In order to precipitate the proteins and extract AFM1 from milk, a sample pretreatment using acetonitrile and NaCl as the extraction/denaturant solvent and salting-out agent, respectively, was optimised. Subsequently, the acetonitrile (upper) phase, containing AFM1, was used as the disperser solvent in DLLME, and extractant (chloroform) and water were added in turn to the extract to perform the DLLME process. The main parameters affecting the extraction efficiency of the whole analytical procedure, such as acetonitrile volume, amount of salt, type and volume of extractant and water volume, were carefully optimised by experimental design. Under optimum conditions, the developed method provides an enrichment factor of 33 and detection and quantification limits (0.6 and 2.0 ng kg(-1), respectively) below the maximum levels imposed by current regulations for AFM1 in milk and infant milk formulae. Recoveries (61.3-75.3%) and repeatability (RSD < 10, n = 3), tested in different types of milk at four AFM1 levels, met the performance criteria required by EC Regulation No. 401/2006. Moreover, the matrix effect on the signal intensity of the analyte was negligible. The proposed method provides a rapid extraction and an accurate determination of AFM1 in milk and formula milk using a simple and inexpensive sample preparation procedure. PMID- 23942570 TI - BH3 helix-derived biophotonic nanoswitches regulate cytochrome c release in permeabilised cells. AB - Dynamic physical interactions between proteins underpin all key cellular processes and are a highly attractive area for the development of research tools and medicines. Protein-protein interactions frequently involve alpha-helical structures, but peptides matching the sequences of these structures usually do not fold correctly in isolation. Therefore, much research has focused on the creation of small peptides that adopt stable alpha-helical structures even in the absence of their intended protein targets. We show that short peptides alkylated with azobenzene crosslinkers can be used to photo-stimulate mitochondrial membrane depolarization and cytochrome c release in permeabilised cells, the initial events of the intrinsic apoptosis pathway. PMID- 23942571 TI - Why PEO as a binder or polymer coating increases capacity in the Li-S system. AB - PEO, used either as a binder or a polymer coating, and PEGDME, used as an electrolyte additive, are shown to increase the reversible capacity of Li-S cells. The effect, in all three cases, is the same: an improved solvent system for the electrochemistry of sulfur species and suppression of cathode passivation on discharge. This constitutes a novel interpretation of the mechanistic behaviour of polyethers in the Li-S system, and sheds new light upon several previous studies. PMID- 23942572 TI - IFIT5 potentiates anti-viral response through enhancing innate immune signaling pathways. AB - Humans have a distinct combination of IFIT (IFN-induced protein with tetratricopeptide repeats) family orthologs, including IFIT1 (ISG56), IFIT2 (ISG54), IFIT3 (ISG60), and IFIT5 (ISG58). The function of IFIT1/IFIT2/IFIT3 has been intensively investigated. However, little is known about the role of IFIT5 in any cellular processes. In this study, we reported that both the mRNA and protein levels of IFIT5 are up-regulated in response to RNA virus infection or polyinosinic-cytidylic acid stimulation. Ectopic expression of IFIT5 could synergize IRF3- and NF-kappaB-mediated gene expression, whereas knockdown of IFIT5 impairs the transcription of these genes. Consistently, anti-viral responses of host cells are significantly increased or decreased in the presence or absence of IFIT5. Mechanistically, IFIT5 co-localizes partly with mitochondria and interacts with RIG-I and MAVS. Our study identified that IFIT5 is an important enhancer in innate immune response. PMID- 23942573 TI - Molecular mechanisms of the cartilage-specific microRNA-140 in osteoarthritis. AB - Osteoarthritis (OA) is the most widespread chronic degenerative joint disorder, characterized by progressive destruction of articular cartilage, subchondral bone alterations, formation of osteophytes and synovitis. MicroRNAs (miRNAs) are a class of endogenous and non-coding single-strand RNAs with a length of about 22 nucleotides, and many of them are evolutionarily conserved. miRNAs have been implicated in the process of development and pathogenesis of diseases, and tissue specific miRNA functional studies in mice have revealed both pathogenic and protective functions. miRNA-140 (miR-140) was shown to be specifically expressed in cartilage tissues in developing zebrafish and mouse embryos during the development of both long and flat bones. Recently, miR-140 has been reported in many studies to play significant roles in OA pathogenesis. Although the previous results were not always consistent, the molecular mechanisms of the regulation and dual function of miR-140 in cartilage homeostasis and development have been established in previous studies. Further elucidation of the molecular basis of miR-140 will uncover synergistic inhibitory effects of miR-140 and other factors on OA pathogenesis, and provide a novel means of treating OA disease. PMID- 23942574 TI - Precision phenotyping of biomass accumulation in triticale reveals temporal genetic patterns of regulation. AB - To extend agricultural productivity by knowledge-based breeding and tailor varieties adapted to specific environmental conditions, it is imperative to improve our ability to assess the dynamic changes of the phenome of crops under field conditions. To this end, we have developed a precision phenotyping platform that combines various sensors for a non-invasive, high-throughput and high dimensional phenotyping of small grain cereals. This platform yielded high prediction accuracies and heritabilities for biomass of triticale. Genetic variation for biomass accumulation was dissected with 647 doubled haploid lines derived from four families. Employing a genome-wide association mapping approach, two major quantitative trait loci (QTL) for biomass were identified and the genetic architecture of biomass accumulation was found to be characterized by dynamic temporal patterns. Our findings highlight the potential of precision phenotyping to assess the dynamic genetics of complex traits, especially those not amenable to traditional phenotyping. PMID- 23942576 TI - Cu3MCh3 (M = Sb, Bi; Ch = S, Se) as candidate solar cell absorbers: insights from theory. AB - As the thin film photovoltaic sector continues to expand, there is an emerging need to base these technologies on abundant, low cost materials in place of the expensive, rare, or toxic elements such as Te, In, or Cd that currently constitute the industry standards. To this end, the geometric and electronic structure of four materials comprising low cost, earth abundant elements (Cu3SbS3, Cu3SbSe3, Cu3BiS3, and Cu3BiSe3) are investigated with the screened hybrid exchange-correlation functional HSE06 and their candidacy for use as absorber materials assessed. The materials are shown to exhibit low VBM effective masses, due partially to the presence of lone pairs that originate from the Sb and Bi states. Although all four materials possess indirect fundamental band gaps, calculated optical absorbance shows direct transitions close in energy. Optical band gaps within the visible-light spectrum are also predicted for three of the systems, (Cu3SbSe3, Cu3BiS3 and Cu3BiSe3) making them promising candidates for PV applications. PMID- 23942575 TI - Fluorescent sensing of cocaine based on a structure switching aptamer, gold nanoparticles and graphene oxide. AB - This study demonstrates a cocaine sensing method employing graphene oxide (GO), gold nanoparticles and a structure switching aptamer, which can fold into a three way junction in the presence of cocaine. On the observation of gold nanoparticles (Au NPs) induced graphene oxide fluorescence quenching, a structure switching aptamer of cocaine was introduced as the linker between the two parts. Firstly, two fragments of a cocaine aptamer were immobilized covalently onto GO and Au NPs, respectively. Then when the three-way junction formed, the Au NPs were drawn near to the GO surface and induced a fluorescence intensity decrease. The limit of detection was 0.1 MUM for cocaine in purified water, and well defined results were also obtained in biological fluids and the specificity experiment, which expands the feasibility of the as-prepared sensor for practical applications. PMID- 23942577 TI - The effect of a preoperative spiritual/religious intervention on anxiety in Shia Muslim patients undergoing coronary artery bypass graft surgery: a randomized controlled trial. AB - BACKGROUND: Coronary artery bypass grafting (CABG) is associated with anxiety. Preoperative anxiety is considered a predictor for a range of suboptimal postsurgical outcomes. OBJECTIVE: To evaluate the effect of a spiritual/religious training intervention on anxiety in Shia Muslim individuals scheduled for CABG. METHODS: A randomized controlled trial of a preoperative spiritual/religious training intervention, congruent with Islamic supplication (Zikr), was administered in five sessions of 45 minutes duration to test the impact on anxiety in comparison with standard care. Seventy participants were selected based on inclusion criteria and randomly allocated to treatment and control groups. Baseline levels of anxiety and the impact of the intervention were assessed using the Persian version of the Hamilton Anxiety Scale. RESULTS: Baseline characteristics were comparable between the intervention and control groups. Following the intervention, there was a statistically significant difference in anxiety mean scores between intervention (19.48 +/- 2.03) and control groups (43.27 +/- 5.49), p < .001. CONCLUSIONS: This study demonstrates that preoperative spiritual/religious training can reduce anxiety in Muslim patients undergoing CABG. Further evaluation of this intervention in other population groups is warranted and the study underscores the importance of culturally appropriate and interventions. PMID- 23942579 TI - A trial-based approach to statin guidelines. PMID- 23942580 TI - [Werner Leibbrand as psychiatric opponent of National Socialism]. AB - The psychiatrist and medical historian Werner Leibbrand resigned from the Berlin Medical Association after the seizure of power in protest against the exclusion of Jewish colleagues and lost both the license to practice as well as his professional position in the public health service. After the end of the war the American military authorities appointed him as expert witness for the prosecution in the Nurnberg Doctors Trial. In addition to a biographical review, Leibbrand's resolute although still undisputed attitude as ethical expert in the trials will be roughly outlined. PMID- 23942581 TI - [In truth could nothing on earth help? Kleist's suicide from a psychiatric perspective]. AB - Heinrich von Kleist (1777-1811) was a German poet and dramatist. During the celebrations marking the 200th anniversary of his death in November 2011, his double suicide with Henriette Vogel on the shores of the Kleine Wannsee near Berlin was extensively and publicly debated in Germany. The meticulous reconstruction of his suicidal condition demonstrates that often only a few aspects of this condition are highlighted in German-speaking feuilleton or biographies. Contrasting the popular stylization of Kleist's suicide as a "well defended deliberate self-killing" or a "romantic double suicide" it is argued that: (a) retrospective psychiatric diagnosis or psychological models of explanation are necessarily questionable (so-called pitfall of pathography), (b) Kleist's mental narrowness regarding suicide as a behavioral option was multifactorially motivated and (c) his sentence "The truth is that on earth no help was possible for me" clearly expresses his desperation but delivers no justification for his suicide. On the contrary, from a clinical ethical point of view suicide can only be justified if no improvement of the condition is objectively possible. Even if this would have been the case in Kleist's time, nowadays modern psychotherapeutic and pharmacological means are reliably and easily able to help people in comparable situations. With a discussion and meticulous reconstruction this paper increases the understanding of Kleist's suicide and opens a clear view on his life and works. PMID- 23942582 TI - [The Kleine-Levin syndrome: new aspects of a rare disease]. AB - The Kleine-Levin syndrome (KLS) is a rare disease which can occur one to several times per year. The KLS belongs to the group of hypersomnia of central origin occurring mainly during the second decade of life after infections, sleep deprivation, alcohol consumption or minor trauma. Early manifestation combined with hypersexuality during symptomatic phases can be a predictor for a long course of the disease, which lasts a mean of 1-27 years. Due to the lack of biological markers diagnosis at first manifestation is difficult. The classical trias of hypersomnia, hyperphagia and hypersexuality can only be found in 45 % of patients. The dominant clinical symptoms are hypersomnia with changes in perception and behavior. Subtraction of perfusion studies performed during symptomatic and asymptomatic phases showed decreased perfusion of the left hypothalamus, thalamus, basal ganglia, medial and dorsolateral frontal and temporal regions. In the few patients who had lumbar punctures in both symptomatic and asymptomatic phases hypocretin-1 was moderately to slightly lowered during symptomatic phases. Meta-analyses showed good therapeutic effects of stimulants on the symptom sleepiness. Lithium reduces the frequency and duration of symptomatic phases. Assuming that KLS is underdiagnosed it should be considered as a differential diagnosis in young patients with recurrent hypersomnia. PMID- 23942583 TI - Systematic review of the epidemiology of urinary incontinence and detrusor overactivity among patients with neurogenic overactive bladder. AB - BACKGROUND: The prevalence and incidence of neurogenic overactive bladder (nOAB) are poorly defined. This systematic literature review identified nOAB epidemiological data and estimated the incidence and prevalence of urinary incontinence (UI) and detrusor overactivity (DO) in patients with multiple sclerosis (MS), spinal cord injury (SCI), Parkinson's disease (PD), stroke and spina bifida. An initial search of MEDLINE, Embase, PubMed, and the Cochrane library was supplemented by an internet search for grey literature and manual searching of the bibliographies of retrieved articles. Additional study selection identified comparable studies for statistical analysis. A descriptive statistical analysis, single-arm meta-analysis and stratified analysis were conducted using predefined criteria. SUMMARY: Initial selection identified 189 articles containing prevalence data. Secondary selection for statistical analysis identified 39 and 52 articles with prevalence of UI and DO, respectively. Random effect meta-analysis found the prevalence of UI was 50.9% in patients with MS, 52.3% with SCI, 33.1% with PD and 23.6% with stroke. Spina bifida was excluded due to insufficient data. The prevalence of DO may be biased and artificially elevated because it can only be measured with urodynamic investigations. KEY MESSAGES: A substantial proportion of patients with neurological conditions develop UI that may be attributable to nOAB. PMID- 23942584 TI - How to switch a fluorophore: from undesired blinking to controlled photoswitching. AB - Molecular optical photoswitches based on fluorescent proteins and organic dyes are fundamental for super-resolution fluorescence imaging and tracking methods. Precise control of switching, bio-labeling compatibility, and high brightness make photoswitches broadly applicable. This review emphasizes the design and development of photoswitches and the requirements they need to fulfill for their successful application in single-molecule localization microscopy. Furthermore, we discuss recent developments in improving the photoswitching performance with a special focus on organic dyes. PMID- 23942585 TI - Dietary walnut oil modulates liver steatosis in the obese Zucker rat. AB - PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. We aimed to clarify the impact of dietary walnut oil versus animal fat on hepatic steatosis, representing the initial step of multistage pathogenesis of NAFLD, in Zucker obese rats. METHODS: Zucker lean ad libitum (a.l.), Zucker obese a.l. or Zucker obese pair fed (p.f.) to the lean received isocaloric diets containing 8% walnut oil (W8), W14 or 14% lard (L14) (n = 10/group). Body weight, clinical serology, liver weight, lipid content and fatty acid composition and hepatic lipid metabolism-related transcripts were evaluated. RESULTS: Compared to lean, Zucker obese a.l. and p.f. showed hepatic triacylglyceride (TAG) accumulation. In Zucker obese p.f., W14 compared to W8 and L14 reduced liver lipids, TAG as well as hepatic omega-6 (n-6)/n-3 ratio and SCD activity index [(C18:0 + C18:1)/C18:0 ratio] paralleled by decreased lipoprotein lipase mRNA in obese p.f. and elevated microsomal triglyceride transfer protein mRNA in lean and obese. Further, W14 elevated the fasting blood TAG and reduced cholesterol levels in obese. CONCLUSIONS: In our model, consumption of W14 inhibited hepatic lipid accumulation along with modulated hepatic gene expression implicated in hepatic fatty acid influx or lipoprotein assembly. These results provide first indication that dietary lipids from walnut oil are modulators of hepatic steatosis as the initial step of progressive NAFLD pathogenesis. PMID- 23942587 TI - Use of water activity characteristics enables a simplified approach for defining the reference moisture condition for FDA cocoa powder in-house reference material. AB - The Food and Drug Administration uses water activity behavior characteristics when adjusting test portion mass to correct for the moisture condition of its cocoa powder in-house reference material. The cocoa powder's moisture condition, and therefore weight, equilibrates according to the relative humidity (RH) of its surroundings. This process is predictable and defined by an isotherm. The reference values in the certificate of analysis are relative to the material's condition at 30% RH, which is assumed to be mid-range for typical laboratory settings. Since mass variations are relatively small within a 15-50% RH range, the mass may be measured immediately after removing a test portion from a storage bottle and used without correction if a standard uncertainty of 0.7% is acceptable for the mass. If greater accuracy is needed and the laboratory RH is known, a very simple and quick procedure can be used whereby the test portion is left open and exposed to the laboratory air overnight before weighing. After applying a correction, the standard uncertainty for mass measurement drops to 0.3%. PMID- 23942588 TI - Optimised protocols for the metabolic profiling of S. cerevisiae by 1H-NMR and HRMAS spectroscopy. AB - An optimised extraction protocol for the analysis of Saccharomyces cerevisiae aqueous and organic metabolites by nuclear magnetic resonance spectroscopy that allows the identification and quantification of up to 50 different compounds is presented. The method was compared with other metabolic profiling protocols for S. cerevisiae, where generally different analytical techniques are applied for metabolite quantification. In addition, the analysis of intact S. cerevisiae cells by HRMAS was implemented for the first time as a complementary method. The optimised protocols were applied to study the metabolic effect of glucose and galactose on S. cerevisiae growth. Furthermore, the metabolic reaction of S. cerevisiae to osmotic stress has been studied. PMID- 23942586 TI - Mediterranean diet reduces the adverse effect of the TCF7L2-rs7903146 polymorphism on cardiovascular risk factors and stroke incidence: a randomized controlled trial in a high-cardiovascular-risk population. AB - OBJECTIVE: Transcription factor 7-like 2 (TCF7L2) polymorphisms are strongly associated with type 2 diabetes, but controversially with plasma lipids and cardiovascular disease. Interactions of the Mediterranean diet (MedDiet) on these associations are unknown. We investigated whether the TCF7L2-rs7903146 (C>T) polymorphism associations with type 2 diabetes, glucose, lipids, and cardiovascular disease incidence were modulated by MedDiet. RESEARCH DESIGN AND METHODS: A randomized trial (two MedDiet intervention groups and a control group) with 7,018 participants in the PREvencion con DIetaMEDiterranea study was undertaken and major cardiovascular events assessed. Data were analyzed at baseline and after a median follow-up of 4.8 years. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for cardiovascular events. RESULTS: The TCF7L2-rs7903146 polymorphism was associated with type 2 diabetes (odds ratio 1.87 [95% CI 1.62-2.17] for TT compared with CC). MedDiet interacted significantly with rs7903146 on fasting glucose at baseline (P interaction = 0.004). When adherence to the MedDiet was low, TT had higher fasting glucose concentrations (132.3 +/- 3.5 mg/dL) than CC+CT (127.3 +/- 3.2 mg/dL) individuals (P = 0.001). Nevertheless, when adherence was high, this increase was not observed (P = 0.605). This modulation was also detected for total cholesterol, LDL cholesterol, and triglycerides (P interaction < 0.05 for all). Likewise, in the randomized trial, TT subjects had a higher stroke incidence in the control group (adjusted HR 2.91 [95% CI 1.36-6.19]; P = 0.006 compared with CC), whereas dietary intervention with MedDiet reduced stroke incidence in TT homozygotes (adjusted HR 0.96 [95% CI 0.49-1.87]; P = 0.892 for TT compared with CC). CONCLUSIONS: Our novel results suggest that MedDiet may not only reduce increased fasting glucose and lipids in TT individuals, but also stroke incidence. PMID- 23942589 TI - Carprofen-imprinted monolith prepared by reversible addition-fragmentation chain transfer polymerization in room temperature ionic liquids. AB - To obtain fast separation, ionic liquids were used as porogens first in combination with reversible addition-fragmentation chain transfer (RAFT) polymerization to prepare a new type of molecularly imprinted polymer (MIP) monolith. The imprinted monolithic column was synthesized using a mixture of carprofen (template), 4-vinylpyridine, ethylene glycol dimethacrylate, [BMIM]BF4, and chain transfer agent (CTA). Some polymerization factors, such as template monomer molar ratio, the degree of crosslinking, the composition of the porogen, and the content of CTA, on the column efficiency and imprinting effect of the resulting MIP monolith were systematically investigated. Affinity screening of structurally similar compounds with the template can be achieved in 200 s on the MIP monolith due to high column efficiency (up to 12,070 plates/m) and good column permeability. Recognition mechanism of the imprinted monolith was also investigated. PMID- 23942590 TI - Polydimethylsiloxane-based wide-range mass calibration for direct analysis in real-time mass spectrometry. AB - Direct analysis in real-time mass spectrometry (DART-MS) is normally applied for small-molecule analysis up to about m/z 1,000. Here, for the analysis of polydimethylsiloxanes, high-mass capabilities expanding beyond m/z 3,000 are demonstrated. In addition, polydimethylsiloxanes provide an ideal mass calibration standard for positive-ion DART-MS. A mass reference list has been compiled to cover ions from m/z 200 up to m/z 2,600. Species with more than 20 silicon atoms exhibit increasingly broader isotopic patterns with decreasing abundances of the monoisotopic ions. The use of the first isotopic peaks for analyte ions above m/z 2,000 serves as a work-around and ensures easy and reproducible recognition of the reference peaks by the instrument data system. Here, the positive-ion DART mass spectra of polydimethylsiloxanes and the corresponding experimental procedures are described, and the mass reference list is provided. PMID- 23942591 TI - Synthesis of cyclic peptide hemicryptophanes: enantioselective recognition of a chiral zwitterionic guest. AB - The synthesis of the first members of a new class of cyclic peptide-containing hemicryptophanes is described. Synthesis was achieved through attachment of veratryl groups to the L-tyrosine side chains of a cyclic hexapeptide, c(YG)3, followed by intramolecular cyclodehydration to generate the CTV unit. The diastereomeric P- and M-hemicryptophanes were generated in a 2 : 1 ratio and were separated by chromatography. The enantioselective binding properties of the hemicryptophanes were investigated by complexation with carnitine. Both isomers were found to have significant selectivity for binding (R)-carnitine. PMID- 23942592 TI - Pulse-dose radiofrequency for knee osteoartrithis. AB - PURPOSE: Knee osteoarthritis (OA) is a leading cause of disability in the elderly. The purpose of this study was to investigate the effectiveness of pulse dose radiofrequency (PDRF) in patients with chronic pain refractory to conservative therapies. MATERIAL AND METHODS: Between January 2011 and November 2012, PDRF was performed on 40 patients. A 20-gauge cannula, 10 cm in length, was introduced in the antero-lateral region of the interested knee, and its tip was placed in the joint space under fluoroscopic guidance. After the spindle was removed, an RF needle with a 10-mm "active tip" was introduced. PDRF was performed with 1,200 pulses at high voltage (45 V) with 20-ms duration followed by a 480-ms silent phase. RESULTS: Mean VAS scores before the procedures was 6.8 +/- 0.8. A great decrease of pain intensity was achieved 1 week after PDRF (mean VAS scores 1.8 +/- 0.4 [p < 0.05]) with stabilization of painful symptomatology in the following months and excellent results 1 year after treatment (mean VAS scores 2.3 +/- 0.6 after 12 months [p < 0.05]). Western Ontario and McMaster Universities Index of Osteoarthritis scores showed improved quality of life in all patients at 6 months (p < 0.05) and at 1 year (p < 0.05) after PDRF. No patients developed complications. CONCLUSION: This study successfully investigated the effectiveness of PDRF in patients with chronic pain unresponsive to conservative therapies. PDRF seems to be an effective and reliable technique for palliative management of chronic pain in patients with knee OA. PMID- 23942594 TI - Diterpenoids of terrestrial origin. AB - Covering January to December 2012. Previous review, Nat.Prod.Rep., 2012, 29, 890 898. This review covers the isolation and chemistry of diterpenoids from terrestrial as opposed to marine sources and includes labdanes, clerodanes, abietanes, pimaranes, kauranes, cembranes and their cyclization products. There are 169 references. PMID- 23942593 TI - The effects of metallic implants on electroporation therapies: feasibility of irreversible electroporation for brachytherapy salvage. AB - PURPOSE: Electroporation-based therapies deliver brief electric pulses into a targeted volume to destabilize cellular membranes. Nonthermal irreversible electroporation (IRE) provides focal ablation with effects dependent on the electric field distribution, which changes in heterogeneous environments. It should be determined if highly conductive metallic implants in targeted regions, such as radiotherapy brachytherapy seeds in prostate tissue, will alter treatment outcomes. Theoretical and experimental models determine the impact of prostate brachytherapy seeds on IRE treatments. MATERIALS AND METHODS: This study delivered IRE pulses in nonanimal, as well as in ex vivo and in vivo tissue, with and in the absence of expired radiotherapy seeds. Electrical current was measured and lesion dimensions were examined macroscopically and with magnetic resonance imaging. Finite-element treatment simulations predicted the effects of brachytherapy seeds in the targeted region on electrical current, electric field, and temperature distributions. RESULTS: There was no significant difference in electrical behavior in tissue containing a grid of expired radiotherapy seeds relative to those without seeds for nonanimal, ex vivo, and in vivo experiments (all p > 0.1). Numerical simulations predict no significant alteration of electric field or thermal effects (all p > 0.1). Histology showed cellular necrosis in the region near the electrodes and seeds within the ablation region; however, there were no seeds beyond the ablation margins. CONCLUSION: This study suggests that electroporation therapies can be implemented in regions containing small metallic implants without significant changes to electrical and thermal effects relative to use in tissue without the implants. This supports the ability to use IRE as a salvage therapy option for brachytherapy. PMID- 23942597 TI - The MASCC/ISOO mucositis guidelines: dissemination and clinical impact. PMID- 23942596 TI - Does it matter what you call it? A randomized trial of language used to describe palliative care services. AB - INTRODUCTION: Integration of palliative care into oncology practice remains suboptimal. Misperceptions about the meaning of palliative care may negatively impact utilization. PURPOSE: We assessed whether the term and/or description of palliative care services affected patient views. METHODS: 2x2 between-subject randomized factorial telephone survey of 169 patients with advanced cancer. Patients were randomized into one of four groups that differed by name (supportive care vs. palliative care) and description (patient-centered vs. traditional). Main outcomes (0-10 Likert scale) were patient understanding, impressions, perceived need, and intended use of services. RESULTS: When compared to palliative care, the term supportive care was associated with better understanding (7.7 vs. 6.8; p = 0.021), more favorable impressions (8.4 vs. 7.3; p = 0.002), and higher future perceived need (8.6 vs. 7.7; p = 0.017). There was no difference in outcomes between traditional and patient-centered descriptions. In adjusted linear regression models, the term supportive care remained associated with more favorable impressions (p = 0.003) and higher future perceived need (p = 0.022) when compared to palliative care. CONCLUSIONS: Patients with advanced cancer view the name supportive care more favorably than palliative care. Future efforts to integrate principles of palliative medicine into oncology may require changing impressions of palliative care or substituting the term supportive care. PMID- 23942599 TI - The dynamic motion of a M (M = Ca, Yb) atom inside the C74 (D3h) cage: a relativistic DFT study. AB - The interaction between M (M = Ca, Yb) atom and C74 (D 3h) has been investigated by all electron relativistic density function theory. With the aid of the representative patch of C74 (D 3h), we studied the interaction between C74 (D 3h) and M (M = Ca, Yb) atom and obtained the interaction potential. Optimized structures show that there are three equivalent stable isomers and there is one transition state between every two stable isomers. According to the minimum energy pathway, the possible movement trajectory of M (M = Ca, Yb) atom in the C74 (D 3h) cage is explored. The calculated energy barrier for Yb atoms moving from the stable isomer to the transition state is 10.4 kcal mol(-1) and the energy barrier for Ca atoms is 6.1 kcal mol(-1). The calculated NMR spectra of M@C74 (M = Ca, Yb) are in good agreement with the experimental data. There are nine lines in the spectra: one 1/6 intensity signal, four half intensity signals and four full intensity signals. PMID- 23942595 TI - Clinical practice guidelines for the prevention and treatment of acute and late radiation reactions from the MASCC Skin Toxicity Study Group. AB - Radiation dermatitis (RD) results from radiotherapy and often occurs within the first 4 weeks of treatment, although late effects also occur. While RD may resolve over time, it can have a profound effect on patients' quality of life and lead to dose modifications. A study group of international, interdisciplinary experts convened to develop RD prevention and treatment guidelines based on evidence from randomized, controlled trials. Evidence-based recommendations were developed after an extensive literature review. Randomized, controlled trials with standardized measurement of outcomes were considered the best evidence, and a majority of the recommendations were formulated from this literature. The adoption of washing with water, with or without a mild soap, and allowing the use of antiperspirants is supported by randomized trials. Use of topical prophylactic corticosteroids (mometasone) is recommended to reduce discomfort and itching. There is some evidence that silver sulfadiazine cream can reduce dermatitis score. There is insufficient evidence to support, and therefore the panel recommends against the use of trolamine, topical sulcrate, hyaluronic acid, ascorbic acid, silver leaf dressing, light-emitting diode lasers, Theta cream, dexpanthenol, calendula, proteolytic enzymes, sulcralfate, oral zinc, and pentoxifylline. Moreover, there is no evidence to support the superiority for any specific intervention in a reactive fashion. For patients with established radiation-induced telangiectasia and fibrosis, the panel suggests the use of pulse dye laser for visual appearance, and the use of pentoxifylline and vitamin E for the reduction of fibrosis. PMID- 23942600 TI - Direct dynamics simulations of the hydrogen abstraction reaction Cl + CF3CF2CH2OH. AB - The mechanism and kinetics of 2,2,3,3,3-pentafluoropropanol (CF3CF2CH2OH) reaction with Chlorine atom (Cl) is investigated in this work. Two hydrogen abstraction channels of the title reaction are identified. The geometries of all the stationary points in the potential energy surface are obtained at the BHandHLYP/6-311G level, and the energies of the selected points along the minimum energy path (MEP) are improved by the CCSD(T) method. A dual-level direct dynamics method is employed to study the kinetic nature of the hydrogen abstraction reaction channels. The calculated rate coefficients show that the hydrogen abstraction from the CH2 group is the primary channel. The calculated total rate coefficients are in best agreement with the experimental values. The four-parameter rate coefficients expression of the title reaction between the temperatures 200 K and 1000 K is provided. PMID- 23942601 TI - Single crystal architecture and absorption spectra of octathio[8]circulene and sym-tetraselenatetrathio[8]circulene: QTAIM and TD-DFT approach. AB - The single crystal architecture of the high-symmetry octathio[8]circulene and sym tetraselenatetrathio[8]circulene is studied at the density functional theory (DFT) level with the quantum theory of atoms in molecules (QTAIMs) approach to the electron density distribution analysis. The presence of stabilizing intermolecular C---C, C---S and C---Se contacts in the longitudinal and transversal projections of the single crystals is postulated on the grounds of the previous high-resolution X-ray data for octathio[8]circulene; it is supported by the present QTAIM calculations and also predicted in some new details for both circulenes. We suggest that the appearance of the observed red color for the monocrystalline octathio[8]circulene is caused by strong intermolecular interactions between the molecules in the single crystal. However, the intermolecular interactions for the sym-tetraselenatetrathio[8]circulene crystal fragment are weaker and molecular layers are more friable in comparison to octathio[8]circulene crystal structure. These lead to the absence of visible absorption for the sym-tetraselenatetrathio[8]circulene crystal. PMID- 23942603 TI - [Screening for everyone?]. PMID- 23942604 TI - [Limits of mammography screening: current controversies and perspectives]. AB - In recent years overdiagnosis has been claimed to be a major disadvantage of breast cancer screening. Studies estimating overdiagnosis have shown substantial discrepancies due to differences in the underlying epidemiological methods. Valid estimates based on studies with sufficient follow-up have shown a proportion of overdiagnosis of much less than 10 % of cancer detected by screening. Special attention should be given to intraductal carcinoma in situ as it is a precursor lesion of invasive cancer but the progression potential is poorly understood and it is currently treated similarly to invasive cancer. This highlights the urgent need for better stratification of the disease in research and clinical practice allowing individual risk-adapted appropriate therapy. In this respect new molecular and genetic biomarkers seem to be the most promising approach for predicting disease behavior.Interval carcinoma represents a limitation of breast cancer screening and the impact on screening effectiveness is still unknown. Recent studies have emphasized that interval carcinoma is more aggressive than cancer detected by screening. Hence the occurrence and distribution of interval cancer should be recorded accurately by national cancer registries and evaluated by the screening services. Quality assurance measures may help to reduce the rate of false negative cases to a minimum. Further research focusing on subgroups of screening participants with a higher risk for interval cancer occurrence seems to be a prerequisite for developing future prevention strategies. PMID- 23942605 TI - Theoretical study on the effect of N-substitution on the electronic structures and photophysical properties of phosphorescent Ir(III) complexes. AB - DFT/TDDFT calculations were carried out to investigate the electronic structures, absorption and emission spectra, and phosphorescence efficiency of recent synthesized Ir(III) complexes [Ir(tfmppy)2(tpip)] (1), [Ir(dfppy)2(tpip)] (2) (tfmppy = 4-trifluoromethylphenylpyridine; dfppy = 4,6-difluorophenylpyridine; tpip = tetraphenylimidodiphosphinate). The calculated absorption and emission wavelengths are in agreement with experimental data. The electron transition properties have been analyzed. Compared with 2, the higher quantum yield of experimental observation for 1 was explained by its larger separation between 3MLCT/pi->pi* and 3MC d-d states. Based on these experimental structures, a series of cyclometalated Ir(III) complexes have been designed by substituting "CH" groups with the N atom at 1-, 2-, 3-, and 4-positions on the pyridine moiety in C^N ligands of 1 and 2, respectively. The calculated results reveal that the N substitution not only tunes the emitting color of 1 and 2 but also enhances photoluminescence quantum efficiency. It is hoped that the designed 1a, 2a and 2c could be potential candidates as blue-emitting materials with high quantum efficiency. Moreover, the effects of different functionals on emission properties were also investigated. PMID- 23942606 TI - Liver failure after major liver resection: risk assessment by using preoperative Gadoxetic acid-enhanced 3-T MR imaging. AB - PURPOSE: To determine if gadoxetic acid-enhanced magnetic resonance (MR) imaging with measurement of relative liver enhancement (RLE) on hepatobiliary phase images can allow preoperative assessment of the risk of liver failure after major liver resection. MATERIALS AND METHODS: The local institutional review committee approved this retrospective analysis and waived written informed consent. The study included 73 patients (39 men; median age, 64.4 years) who underwent gadoxetic acid-enhanced 3-T MR imaging before resection of three or more liver segments. RLE was calculated as the ratio of signal intensity measurements of the liver parenchyma before and 20 minutes after intravenous administration of gadoxetic acid. RLE was assessed in each liver segment and the mean value of all segments was used for analysis. Posthepatectomy liver failure was defined according to the "50-50 criteria" (ie, prothrombin time <50% and serum bilirubin >50 umol/L on postoperative day 5) and the International Study Group of Liver Surgery (ISGLS) classification. The association of RLE and liver failure was tested with univariate and multivariate logistic regression analysis. In addition to RLE, the latter also included demographic, clinical, operative, and histologic variables. RESULTS: Patients with liver failure according to the 50-50 criteria (n = 3) had significantly lower RLE (54.5%) than those without (125.6%) (P = .009). According to ISGLS criteria, RLE was 112.5% in patients with grade A liver failure (n = 20), 88.4% in patients with grade B (n = 7), 41.7% (n = 2) in patients with grade C, and 136.5% (P < .001) in those without liver failure. In a logistic regression analysis, RLE was inversely related to the probability of liver failure according to the 50-50 (P = .02) and ISGLS (P < .001) criteria. In a multivariate analysis, RLE was independently associated with a higher probability of liver failure according to ISGLS classification (P = .003). CONCLUSION: Gadoxetic acid-enhanced MR imaging can help with the assessment of the risk for liver failure after major liver resection. PMID- 23942607 TI - Is diffusion anisotropy a biomarker for disease severity and surgical prognosis of cervical spondylotic myelopathy? AB - PURPOSE: To explore the value of diffusion-tensor (DT) imaging in addressing the severity of cervical spondylotic myelopathy (CSM) and predicting the outcome of surgical treatment. MATERIALS AND METHODS: From July 2009 to May 2012, 65 volunteers were recruited for this institutional review board-approved study, and all gave informed consent; 20 volunteers were healthy subjects (age range, 41-62 years), and 45 were patients with CSM (age range, 43-86 years). Anatomic and DT 3.0-T magnetic resonance images were obtained. Surgical decompression was performed in 22 patients with CSM, and patients were followed up for 6 months to 2 years. The clinical severity of myelopathy and postoperative recovery were assessed by using the modified Japanese Orthopaedic Association (mJOA) score. A recovery ratio (comparison of postoperative with preoperative mJOA score) of more than 50% indicated a good clinical outcome of surgery. DT findings, patient age, T2 high signal intensity (HSI), and somatosensory evoked potential (SEP) were analyzed by using a logistic regression model to predict the surgical outcome of patients with CSM. RESULTS: A significant difference in cervical cord mean fractional anisotropy (FA) was found between healthy subjects and patients with CSM (0.65 +/- 0.05 [standard deviation] vs 0.52 +/- 0.13, P < .001). FA values were significantly correlated with the severity of neurologic dysfunction indicated by mJOA score (r(2) = 0.327, P = .016). Logistic regression analysis showed that mean FA (P = .030) and FA at the C2 vertebra (P = .035) enabled prediction of good surgical outcome; however, preoperative mJOA (P = .927), T2 HSI (P = .176), SEP amplitude (P = .154), and latency (P = .260) did not. CONCLUSION: FA is a biomarker for the severity of myelopathy and for subsequent surgical outcome. PMID- 23942608 TI - Mayer-Rokitansky-Kuster-Hauser syndrome: diagnosis with MR imaging. AB - PURPOSE: To evaluate the diverse magnetic resonance (MR) imaging findings of the pelvis in women with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. MATERIALS AND METHODS: This retrospective review had institutional review board approval with waiver of informed consent. Between 2001 and 2011, 215 female patients with MRKH syndrome attended clinics, and 66 underwent pelvic MR imaging (age range, 14 40 years; median age, 19 years). One reviewer reviewed MR images for presence, site, volumes, and differentiation into layers (myometrium, junctional zone, and endometrium) of uterine remnants. Ovarian volumes and positions were assessed. Vaginal length was measured. RESULTS: Rudimentary uteri were found in 61 patients (92%); 54 were bilateral, and seven were unilateral. All uterine buds were located laterally in the pelvis and had a constant caudal relationship with their paired ovary. Mean uterine volume was 6.4 mL (range, 0.4-80.2 mL), and 18 uteri had a volume greater than 10 mL. Twenty-four uterine buds (21%) showed differentiation into more than one layer. Two uteri contained intraluminal blood, and two showed signs of adenomyosis, indicating functioning endometrial tissue; these patients had cyclical pain. Bilateral ovaries were present in 54 patients; ovaries were ectopic in 27 patients. Twenty-two patients had no discernible vagina (dimple or less). Of the 44 patients with a vagina, the mean length was 2.0 cm (range, 1.0-6.5 cm). CONCLUSION: Rudimentary uteri are common in patients with MRKH syndrome. They can be relatively large and have functioning endometrium, which can be associated with pain. Uteri have a constant caudal relationship to ovaries. Ovaries are commonly ectopic, and this must be recognized in patients undergoing fertility treatment. Online supplemental material is available for this article. PMID- 23942609 TI - Effect of specimen-specific anisotropic material properties in quantitative computed tomography-based finite element analysis of the vertebra. AB - Intra- and inter-specimen variations in trabecular anisotropy are often ignored in quantitative computed tomography (QCT)-based finite element (FE) models of the vertebra. The material properties are typically estimated solely from local variations in bone mineral density (BMD), and a fixed representation of elastic anisotropy ("generic anisotropy") is assumed. This study evaluated the effect of incorporating specimen-specific, trabecular anisotropy on QCT-based FE predictions of vertebral stiffness and deformation patterns. Orthotropic material properties estimated from microcomputed tomography data ("specimen-specific anisotropy"), were assigned to a large, columnar region of the L1 centrum (n = 12), and generic-anisotropic material properties were assigned to the remainder of the vertebral body. Results were compared to FE analyses in which generic anisotropic properties were used throughout. FE analyses were also performed on only the columnar regions. For the columnar regions, the axial stiffnesses obtained from the two categories of material properties were uncorrelated with each other (p = 0.604), and the distributions of minimum principal strain were distinctly different (p <= 0.022). In contrast, for the whole vertebral bodies in both axial and flexural loading, the stiffnesses obtained using the two categories of material properties were highly correlated (R2 > 0.82, p < 0.001) with, and were no different (p > 0.359) from, each other. Only moderate variations in strain distributions were observed between the two categories of material properties. The contrasting results for the columns versus vertebrae indicate a large contribution of the peripheral regions of the vertebral body to the mechanical behavior of this bone. In companion analyses on the effect of the degree of anisotropy (DA), the axial stiffnesses of the trabecular column (p < 0.001) and vertebra (p = 0.007) increased with increasing DA. These findings demonstrate the need for accurate modeling of the peripheral regions of the vertebral body in analyses of the mechanical behavior of the vertebra. PMID- 23942610 TI - Association of Asian ethnicity with disease activity in SLE: an observational study from the Monash Lupus Clinic. AB - OBJECTIVE: Systemic lupus erythematosus (SLE), an autoimmune condition with diverse clinical manifestations, is reported to have different expression in populations of different ancestry. Most previous studies compared patients of different ethnic groups from geographically distinct cohorts. In our study, we aimed to characterize disease manifestations in patients of different ethnic groups from a single centre, and studied patterns of disease activity over time. METHODS: Demographics, baseline disease characteristics and autoantibody profiles, and disease activity (SLEDAI) measured at each visit, were captured from all consenting patients prospectively followed between 2007 and 2011 in an urban teaching hospital lupus clinic. Ethnicity was self-reported. RESULTS: Asian ethnicity was significantly associated with more clinically severe SLE. Time adjusted mean SLEDAI (p = 0.01) and maximum SLEDAI (p = 0.0018) were significantly higher in Asian patients. Asians were more likely to have renal disease (OR 2.9, 95% CI 1.4-5.98; p = 0.004) and persistently active disease (PAD) (OR 2.14, 95% CI 1.05-4.38, p = 0.04). Asian lupus patients also had a significantly higher proportion of autoantibody positivity to anti-dsDNA, anti RNP, anti-Sm, anti-Ro and anti-La, as well as increased likelihood of hypocomplementaemia and immunosuppressant use. CONCLUSION: In this single-cohort study, Asian ethnicity was found to be associated with increased SLE disease activity. This suggests significant inter-ethnic genetic contributions to the regulation of autoimmune responses and disease severity in SLE. PMID- 23942611 TI - ELECTRa (European Lead Extraction ConTRolled) Registry--shedding light on transvenous lead extraction real-world practice in Europe. AB - With the growing recognition of the clinical need and wider indications for cardiovascular implantable electronic devices (CIED), the number of implant procedures has increased considerably. Consequently, the rate of complications related to these devices has also increased. Transvenous lead extraction (TLE) is the gold standard in the treatment of CIED-related infective complications and is often required in the management of lead malfunction. An increasing number of centers currently perform TLE procedures. The ELECTRa (European Lead Extraction ConTRolled) Registry is the first large prospective multicenter registry of consecutive patients undergoing TLE in Europe, conducted by the European Heart Rhythm Association (EHRA) and managed by the European Society of Cardiology (ESC) EURObservational Research Department. The primary objective of the registry is to evaluate the acute and long-term safety of TLE; the secondary objective is to describe the characteristics of the patients, the leads, the indications for TLE, and the tools and techniques currently used for TLE. About 100 centers will be enrolled on a voluntary basis from European countries; they are anonymous and stratified on the basis of their volume of activity into high-volume centers (>30 patients/year) and low-volume centers: (<=30 patients/year). Each participating center will have to enroll and follow up for 1 year consecutively assessed patients undergoing TLE from November 2012 to January 2014. The target is to achieve a sample size of at least 3,500 patients for statistical analysis. Data will be collected using a Web-based system and will be audited at randomly selected centers. The official start was on 6 November. Eighty-nine centers have joined so far, 65 centers are currently active, those who have already obtained the approval of their own ethics committee, and 1,099 patients were enrolled at the end of June 2013. The independence of the registry, the consecutiveness of the patient enrolment, and the monitoring of the study are characteristics of this registry that will contribute to the scientific validity of the objectives to be achieved. PMID- 23942612 TI - Medial calcar of proximal humeral fracture as landmark in restoration of humeral length in case of hemiarthroplasty. AB - PURPOSE: Several methods to restore the appropriate length of the humerus in the case of proximal humeral fractures treated by hemiarthroplasty have been previously published. Our study evaluates the possibility of using the medial calcar of humerus for humeral length reconstruction not based on preoperative planning. METHODS: Preparations of 320 dry humeral bones were used for the purpose of the study. Points of interest were marked on each bone: the most proximal point of the humeral head, the crest of greater tuberosity, diameters of the head, the anatomical and surgical necks. Proximal parts of bones were then scanned from two angles with a digital camera and all measurements were performed on calibrated photographs. We compared accuracy in humeral length reconstruction using insertion of the pectoralis major and the area of medial calcar where usually a fracture develops. RESULTS: The distance between the top part of the humeral head and the insertion of pectoralis major was 54.1 +/- 6.0 mm. The distance between the lateral margin of the anatomical neck and the medial calcar was 51.4 +/- 4.3 mm. We compared these data with diameters of the humeral head. CONCLUSIONS: The site of the fracture can be used for the reconstruction of the humeral length with greater accuracy than area of the pectoralis major insertion. We suggest that to obtain the final distance between the lateral margin of the artificial head and medial calcar of the fracture 2-3 mm should be added to the diameter of the head. PMID- 23942613 TI - 16S-rRNA-based analysis of bacterial diversity in the gut of fungus-cultivating termites (Microtermes and Odontotermes species). AB - The interaction between termites and their gut symbionts has continued to attract the curiosity of researchers over time. The aim of this study was to characterize and compare the bacterial diversity and community structure in the guts of three termites (Odontotermes somaliensis, Odontotermes sp. and Microtermes sp.) using 16S rRNA gene sequencing of clone libraries. Clone libraries were screened by restriction fragment length polymorphism and representative clones from O. somaliensis (100 out of 330 clones), Odontotermes sp. (100 out of 359 clones) and Microtermes sp. (96 out 336 clones) were sequenced. Phylogenetic analysis indicated seven bacterial phyla were represented: Bacteroidetes, Spirochaetes, Firmicutes, Proteobacteria, Synergistetes, Planctomycetes and Actinobacteria. Sequences representing the phylum Bacteroidetes (>60 %) were the most abundant group in Odontotermes while those of Spirochaetes (29 %) and Firmicutes (23 %) were the abundant groups in Microtermes. The gut bacterial community structure within the two Odontotermes species investigated here was almost identical at the phylum level, but the Microtermes sp. had a unique bacterial community structure. Bacterial diversity was higher in Odontotermes than in Microtermes. The affiliation and clustering of the sequences, often with those from other termites' guts, indicate a majority of the gut bacteria are autochthonous having mutualistic relationships with their hosts. The findings underscore the presence of termite-specific bacterial lineages, the majority of which are still uncultured. PMID- 23942614 TI - Gracilibacillus marinus sp. nov., isolated from the northern South China Sea. AB - Two gram-positive, aerobic, spore-forming, rod-shaped bacteria, designated HB09003(T) and HB12160, were isolated from seawater and sediment in the northern South China Sea, respectively. Cells were found to be motile by means of peritrichous flagella. The strains were found to grow with 0-15 % (w/v) NaCl, at 10-45 degrees C and pH 5.0-10.7, with an optimum of 3 % NaCl, 28 degrees C and pH 8.5, respectively. The predominant isoprenoid quinone of strain HB09003(T), selected as the representative strain, was identified as MK-7. This strain was found to possess anteiso-C15:0, iso-C15:0, anteiso-C17:0 and C16:0 as the major fatty acids. The G+C contents of strain HB09003(T) and HB12160 were determined to be 34.1 and 34.3 mol%, respectively. Analysis of the 16S rRNA gene sequences of the two strains showed an affiliation with the genus Gracilibacillus, with Gracilibacillus kekensis CGMCC 1.10681(T) (similarity of 97.4, 98.0 %, respectively) and Gracilibacillus ureilyticus CGMCC 1.7727(T) (similarity of 97.1, 97.8 %, respectively) as their closest relatives. The DNA-DNA hybridization values between strain HB09003(T) and the two type strains were 42.2 and 54.1 %, respectively. On the basis of phenotypic and genotypic data, strain HB09003(T) and HB12160 are proposed to represent a novel species of the genus Gracilibacillus, for which the name Gracilibacillus marinus sp. nov. is proposed. The type strain is HB09003(T) (=CGMCC 1.10343(T) = DSM 23372(T)). PMID- 23942615 TI - Crescent and star shapes of members of the Chlamydiales order: impact of fixative methods. AB - Members of the Chlamydiales order all share a biphasic lifecycle alternating between small infectious particles, the elementary bodies (EBs) and larger intracellular forms able to replicate, the reticulate bodies. Whereas the classical Chlamydia usually harbours round-shaped EBs, some members of the Chlamydia-related families display crescent and star-shaped morphologies by electron microscopy. To determine the impact of fixative methods on the shape of the bacterial cells, different buffer and fixative combinations were tested on purified EBs of Criblamydia sequanensis, Estrella lausannensis, Parachlamydia acanthamoebae, and Waddlia chondrophila. A linear discriminant analysis was performed on particle metrics extracted from electron microscopy images to recognize crescent, round, star and intermediary forms. Depending on the buffer and fixatives used, a mixture of alternative shapes were observed in varying proportions with stars and crescents being more frequent in C. sequanensis and P. acanthamoebae, respectively. No tested buffer and chemical fixative preserved ideally the round shape of a majority of bacteria and other methods such as deep freezing and cryofixation should be applied. Although crescent and star shapes could represent a fixation artifact, they certainly point towards a diverse composition and organization of membrane proteins or intracellular structures rather than being a distinct developmental stage. PMID- 23942616 TI - Effects of Parkinson's disease on optimization and structure of variance in multi finger tasks. AB - We explored the role of the basal ganglia in two components of multi-finger synergies by testing a group of patients with early-stage Parkinson's disease and a group of healthy controls. Synergies were defined as co-varied adjustments of commands to individual fingers that reduced variance of the total force and moment of force. The framework of the uncontrolled manifold hypothesis was used to quantify such co-variation patterns, while average performance across repetitive trials (sharing patterns) was analyzed using the analytical inverse optimization (ANIO) approach. The subjects performed four-finger pressing tasks that involved the accurate production of combinations of the total force and total moment of force and also repetitive trials at two selected combinations of the total force and moment. The ANIO approach revealed significantly larger deviations of the experimental data planes from an optimal plane for the patients compared to the control subjects. The synergy indices computed for total force stabilization were significantly higher in the control subjects compared to the patients; this was not true for synergy indices computed for moment of force stabilization. The differences in the synergy indices were due to the larger amount of variance that affected total force in the patients, while the amount of variance that did not affect total force was comparable between the groups. We conclude that the basal ganglia play an important role in both components of synergies reflecting optimization of the sharing patterns and stability of performance with respect to functionally important variables. PMID- 23942617 TI - Thrombospondin-4 expression is activated during the stromal response to invasive breast cancer. AB - The thromobospondins are a family of extracellular glycoproteins that are activated during tissue remodeling processes such as embryogenesis, wound healing and cancer. Thrombospondin-4 (THBS4) is known to have roles in cellular migration, adhesion and attachment, as well as proliferation in different contexts. Data to support a role in cancer biology is increasing, including for gastrointestinal and prostate tumours. Here, using a combination of immunohistochemistry, immunofluorescence and analysis of publicly available genomic and expression data, we present the first study describing the pattern of expression of THBS4 in normal breast and breast cancer. THBS4 was located to the basement membrane of large ducts and vessels in normal breast tissue, but was absent from epithelium and extracellular matrix. There was a significant induction in expression in cancer-associated stroma relative to normal stroma (P = 0.0033), neoplastic epithelium (P < 0.0001) and normal epithelium (P < 0.0001). There was no difference in stromal expression of THBS4 between invasive ductal carcinomas (IDC) and invasive lobular carcinomas (ILC). The THBS4 mRNA levels were variable yet were generally highest in tumours typically rich in stromal content (ILC, ER positive low grade IDC; luminal A and normal-like subtypes). Genomic alterations of the THBS4 gene (somatic mutations and gene copy number) are rare suggesting this dramatic activation in expression is most likely dynamically regulated through the interaction between invading tumour cells and stromal fibroblasts in the local microenvironment. In summary, THBS4 expression in breast cancer-associated extracellular matrix contributes to the activated stromal response exhibited during tumour progression and this may facilitate invasion of tumour cells. PMID- 23942618 TI - Activation of the NF-kB pathway downregulates TFF-1 in gastric carcinogenesis. AB - Trefoil factor 1 (TFF1) is expressed in the normal superficial epithelium of the stomach and is implicated in the maintenance of gastric epithelial structure and function. During gastric carcinogenesis, in which pro-inflammatory cytokines play a crucial role, its expression level decreases suggesting a role as tumor suppressor factor. We have compared expression of TFF1 in gastric mucosa from cancer patients, in which several degrees of inflammatory infiltrate are present, with that in normal mucosa from non-cancer patients without infiltrating inflammatory cells. TFF1 is less expressed in the superficial gastric epithelium from cancer patients than in that from normal individuals in which the nuclear factor (NF)-kappaB pathway is not activated. We analyzed TFF1 expression in ex vivo samples of gastric mucosa from cancer patients, and in MKN45 gastric cancer cell line after exposure to proinflammatory cytokines interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha, that activate the NF-kappaB pathway. We found that IL-1beta and TNF-alpha activate the NF-kappaB pathway, as reflected in the nuclear expression of p65 and the activation of p-IkappaBalpha, and downregulate TFF1 expression after 1 or 2 h of exposure. Moreover, cells in the superficial gastric epithelium in ex vivo samples co-expressed TFF1/p65 at cellular level, whereas tumor cells did not. In summary, downregulation of TFF1 expression during gastric neoplastic transformation is associated with activation of the NF-kappaB pathway through IL-1beta or TNF-alpha, but other regulatory mechanisms might also be involved. PMID- 23942619 TI - Aberrant methylation of microRNA-34b/c is a predictive marker of metachronous gastric cancer risk. AB - BACKGROUND: Metachronous gastric cancer (GC) can develop after endoscopic resection of GC and cannot be predicted based on clinical signature. Aberrant DNA methylation in noncancerous gastric mucosa is strongly implicated in gastric carcinogenesis and could be a useful biomarker of GC risk. We evaluated the clinical utility of DNA methylation as a biomarker of metachronous GC risk. METHOD: We carried out scheduled follow-up endoscopy in 129 patients after curative endoscopic resection of GC. Biopsy specimens were collected from noncancerous mucosa in the gastric antrum and body, after which quantitative methylation analysis of miR-34b/c, SFRP1, SFRP2, SFRP5, DKK2 and DKK3 was carried out using bisulfite pyrosequencing. The utility of the methylation for predicting the risk of metachronous GC development was assessed using Kaplan-Meier and Cox proportional hazards model analyses. RESULTS: During the follow-up period, 17 patients (13%) developed metachronous GCs. The cumulative incidence of metachronous GC was significantly higher among patients with elevated miR-34b/c, SFRP2 and DKK2 methylation in their gastric body. MiR-34b/c showed the strongest association with the risk of metachronous GC, and the cumulative incidence of metachronous GC was much higher in the high-miR-34b/c-methylation group than the low-methylation group. Multivariate analysis adjusted for age, sex, H. pylori status and pathological findings showed miR-34b/c methylation in gastric body to be an independent predictor of metachronous GC risk. CONCLUSION: Our results suggest that methylation of miR-34b/c in the mucosa of the noncancerous gastric body may be a useful biomarker for predicting the risk of metachronous GC. PMID- 23942620 TI - Characteristics of Japanese inflammatory bowel disease susceptibility loci. AB - BACKGROUND: There are substantial differences in inflammatory bowel disease (IBD) genetics depending on the populations examined. We aimed to identify Japanese population-specific or true culprit susceptibility genes through a meta-analysis of past genetic studies of Japanese IBD. METHODS: For this study, we reviewed 2,703 articles. The review process consisted of three screening stages: we initially searched for relevant studies and then relevant single nucleotide polymorphisms (SNPs). Finally, we adjusted them for the meta-analysis. To maximize our chances of analysis, we introduced proxy SNPs during the first stage. To minimize publication bias, no significant SNPs and solitary SNPs without pairs were combined to be reconsidered during the third stage. Additionally, two SNPs were newly genotyped. Finally, we conducted a meta analysis of 37 published studies in 50 SNPs located at 22 loci corresponding to the total number of 4,853 Crohn's disease (CD), 5,612 ulcerative colitis (UC) patients, and 14,239 healthy controls. RESULTS: We confirmed that the NKX2-3 polymorphism is associated with common susceptibility to IBD and that HLA DRB1*0450 alleles increase susceptibility to CD but reduce risk for UC while HLA DRB1*1502 alleles increase susceptibility to UC but reduce CD risk. Moreover, we found individual disease risk loci: TNFSF15 and TNFalpha to CD and HLA-B*5201, and NFKBIL1 to UC. The genetic risk of HLA was substantially high (odds ratios ranged from 1.54 to 2.69) while that of common susceptibility loci to IBD was modest (odds ratio ranged from 1.13 to 1.24). CONCLUSIONS: Results indicate that Japanese IBD susceptibility loci identified by the meta-analysis are closely associated with the HLA regions. PMID- 23942623 TI - Evaluation of nanoparticles as endocytic tracers in cellular microbiology. AB - The study of pathogen interactions with eukaryotic host cells requires the introduction of fluorescent probes to visualize processes such as endocytosis, intracellular transport or host cell manipulation by the pathogen. Here, three types of fluorescent nanoparticles (NPs), i.e. Rhodamine-labeled polymethacrylate (PMA) NPs, silica NPs and gold NPs, were employed to label the host cellular endolysosomal system and monitor manipulations by the pathogen Salmonella enterica. Using live cell imaging, we investigated the performance of NPs in cellular uptake, labeling of endocytic vesicles and lysosomes, as well as interaction with the pathogen. We show that fluorescent gold and silica, but not PMA NPs appropriately label host cell structures and efficiently track rearrangements of the host endosomal system by the activities of intracellular Salmonella. Silica NPs slightly aggregated and located in Salmonella-induced compartments as isolated dots, while gold NPs distributed uniformly inside such structures. Both silica and gold NPs exhibited no adverse impact on either host cells or pathogens, and are versatile tools for infection biology. PMID- 23942621 TI - Interaction between polygenic risk for cigarette use and environmental exposures in the Detroit Neighborhood Health Study. AB - Cigarette smoking is influenced both by genetic and environmental factors. Until this year, all large-scale gene identification studies on smoking were conducted in populations of European ancestry. Consequently, the genetic architecture of smoking is not well described in other populations. Further, despite a rich epidemiologic literature focused on the social determinants of smoking, few studies have examined the moderation of genetic influences (for example, gene environment interactions) on smoking in African Americans. In the Detroit Neighborhood Health Study (DNHS), a sample of randomly selected majority African American residents of Detroit, we constructed a genetic risk score (GRS), in which we combined top (P-value <5 * 10(-7)) genetic variants from a recent meta analysis conducted in a large sample of African Americans. Using regression (effective n=399), we first tested for association between the GRS and cigarettes per day, attempting to replicate the findings from the meta-analysis. Second, we examined interactions with three social contexts that may moderate the genetic association with smoking: traumatic events, neighborhood social cohesion and neighborhood physical disorder. Among individuals who had ever smoked cigarettes, the GRS significantly predicted the number of cigarettes smoked per day and accounted for ~3% of the overall variance in the trait. Significant interactions were observed between the GRS and number of traumatic events experienced, as well as between the GRS and average neighborhood social cohesion; the association between genetic risk and smoking was greater among individuals who had experienced an increased number of traumatic events in their lifetimes, and diminished among individuals who lived in a neighborhood characterized by greater social cohesion. This study provides support for the utility of the GRS as an alternative approach to replication of common polygenic variation, and in gene environment interaction, for smoking behaviors. In addition, this study indicates that environmental determinants have the potential to both exacerbate (traumatic events) and diminish (neighborhood social cohesion) genetic influences on smoking behaviors. PMID- 23942622 TI - The effects of congenital brain serotonin deficiency on responses to chronic fluoxetine. AB - The importance of reversing brain serotonin (5-HT) deficiency and promoting hippocampal neurogenesis in the mechanisms of action for antidepressants remain highly controversial. Here we examined the behavioral, neurochemical and neurogenic effects of chronic fluoxetine (FLX) in a mouse model of congenital 5 HT deficiency, the tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mouse. Our results demonstrate that congenital 5-HT deficiency prevents a subset of the signature molecular, cellular and behavioral effects of FLX, despite the fact that FLX restores the 5-HT levels of Tph2KI mice to essentially the levels observed in wild-type mice at baseline. These results suggest that inducing supra physiological levels of 5-HT, not merely reversing 5-HT deficiency, is required for many of the antidepressant-like effects of FLX. We also demonstrate that co administration of the 5-HT precursor, 5-hydroxytryptophan (5-HTP), along with FLX rescues the novelty suppressed feeding (NSF) anxiolytic-like effect of FLX in Tph2KI mice, despite still failing to induce neurogenesis. Thus, our results indicate that brain 5-HT deficiency reduces the efficacy of FLX and that supplementation with 5-HTP can restore some antidepressant-like responses in the context of 5-HT deficiency. Our findings also suggest that feeding latency reductions in the NSF induced by chronic 5-HT elevation are not mediated by drug induced increments in neurogenesis in 5-HT-deficient animals. Overall, these findings shed new light on the impact of 5-HT deficiency on responses to FLX and may have important implications for treatment selection in depression and anxiety disorders. PMID- 23942624 TI - On the mechanism of iodine oxide particle formation. AB - The formation of atmospherically relevant iodine oxides IxOy (x = 1,...,3, y = 1,...,7) has been studied experimentally using time-of-flight mass spectrometry combined with a soft ionisation source, complemented with ab initio electronic structure calculations of ionisation potentials and bond energies at a high level of theory presented in detail in the accompanying paper (Galvez et al., 2013). For the first time, direct experimental evidence of the I2Oy (y = 1,...,5) molecules in the gas phase has been obtained. These chemical species are observed alongside their precursors (IO and OIO) in experiments where large amounts of aerosol are also generated. The measured relative concentrations of the IxOy molecules and their dependence on ozone concentration have been investigated by using chemical modelling and rate theory calculations. It is concluded that I2O4 is the most plausible candidate to initiate nucleation, while the contribution of I2O5 in the initial steps is likely to be marginal. The absence of large I3Oy (y = 3,...,6) peaks in the mass spectra and the high stability of the I2O4-I2O4 dimer indicate that dimerisation of I2O4 is the key step in iodine oxide particle nucleation. PMID- 23942628 TI - Erratum to: Folds and Buckles at the Nanoscale: Experimental and Theoretical Investigation of the Bending Properties of Graphene Membranes. PMID- 23942626 TI - [Controlling instruments in radiology]. AB - Due to the rising costs and competitive pressures radiological clinics and practices are now facing, controlling instruments are gaining importance in the optimization of structures and processes of the various diagnostic examinations and interventional procedures. It will be shown how the use of selected controlling instruments can secure and improve the performance of radiological facilities. A definition of the concept of controlling will be provided. It will be shown which controlling instruments can be applied in radiological departments and practices. As an example, two of the controlling instruments, material cost analysis and benchmarking, will be illustrated. PMID- 23942627 TI - Early surfactant guided by lamellar body counts on gastric aspirate in very preterm infants. AB - BACKGROUND: We have developed a rapid method, based on lamellar body counts (LBC) on gastric aspirate, for identifying newborns who will develop respiratory distress syndrome with a need for surfactant supplementation. OBJECTIVE: We set out to test whether it was possible to improve the outcome when used in a clinical trial. METHODS: We randomly assigned 380 infants born at 24-29 weeks' gestation and supported with nasal continuous positive airway pressure (nCPAP) to receive surfactant guided either by LBC (intervention group) or increasing need for oxygen (control group). The primary outcome was mechanical ventilation or death within 5 days. Secondary outcomes included need for oxygen expressed by arterial to alveolar oxygen tension ratio (a/APO2) at the age of 6 h and need for oxygen at day 28. RESULTS: The primary outcomes were equal (25%) in the two groups. The intervention group had higher a/APO2 than the control group at 6 h, median 0.64 versus 0.52 (p < 0.01), and the subgroup with gestational age 26-29 weeks needed fewer days of oxygen supplementation than the controls, median 2 vs. 9 days (p = 0.01), and fewer infants needed oxygen at day 28 (p = 0.04). Furthermore, there was a tendency in the intervention group towards a shorter duration of nCPAP. Too little or viscose aspirate in 23% of the cases was a limitation of the method. CONCLUSION: Using LBC test as indicator of lung maturity and early surfactant therapy in very preterm newborns, it is possible to reduce the need for oxygen supplementation. PMID- 23942629 TI - Ultimate size control of encapsulated gold nanoparticles. AB - We report an original and scalable synthesis pathway to produce encapsulated gold nanoparticles. Precise control of the gold particles is achieved in the range of 1-10 nm through the impregnation of silicalite-1 with a controlled concentration of gold solution, followed by dissolution-recrystallization of the zeolite. PMID- 23942625 TI - A creature with a hundred waggly tails: intrinsically disordered proteins in the ribosome. AB - Intrinsic disorder (i.e., lack of a unique 3-D structure) is a common phenomenon, and many biologically active proteins are disordered as a whole, or contain long disordered regions. These intrinsically disordered proteins/regions constitute a significant part of all proteomes, and their functional repertoire is complementary to functions of ordered proteins. In fact, intrinsic disorder represents an important driving force for many specific functions. An illustrative example of such disorder-centric functional class is RNA-binding proteins. In this study, we present the results of comprehensive bioinformatics analyses of the abundance and roles of intrinsic disorder in 3,411 ribosomal proteins from 32 species. We show that many ribosomal proteins are intrinsically disordered or hybrid proteins that contain ordered and disordered domains. Predicted globular domains of many ribosomal proteins contain noticeable regions of intrinsic disorder. We also show that disorder in ribosomal proteins has different characteristics compared to other proteins that interact with RNA and DNA including overall abundance, evolutionary conservation, and involvement in protein-protein interactions. Furthermore, intrinsic disorder is not only abundant in the ribosomal proteins, but we demonstrate that it is absolutely necessary for their various functions. PMID- 23942630 TI - Endoscopic swept-source optical coherence tomography based on a two-axis microelectromechanical system mirror. AB - A microelectromechanical system (MEMS) mirror based endoscopic swept-source optical coherence tomography (SS-OCT) system that can perform three-dimensional (3-D) imaging at high speed is reported. The key component enabling 3-D endoscopic imaging is a two-axis MEMS scanning mirror which has a 0.8*0.8 mm2 mirror plate and a 1.6*1.4 mm2 device footprint. The diameter of the endoscopic probe is only 3.5 mm. The imaging rate of the SS-OCT system is 50 frames/s. OCT images of both human suspicious oral leukoplakia tissue and normal buccal mucosa were taken in vivo and compared. The OCT imaging result agrees well with the histopathological analysis. PMID- 23942631 TI - Blind unmixing of spectrally resolved lifetime images. AB - A method, is presented for blind unmixing spectrally resolved fluorescence lifetime images. The method is based on the combined analysis of spectral and lifetime phasors and allows unmixing of up to three components without any prior knowledge. Fractional intensities, spectra and decay curves of the individual components can be extracted with this new technique. The reliability and sensitivity are investigated and the possibility of extending the method to unmix more components is discussed. The method is evaluated on mixtures of fluorescent dyes and labeled cells. PMID- 23942633 TI - Wavelet-based data and solution compression for efficient image reconstruction in fluorescence diffuse optical tomography. AB - Current fluorescence diffuse optical tomography (fDOT) systems can provide large data sets and, in addition, the unknown parameters to be estimated are so numerous that the sensitivity matrix is too large to store. Alternatively, iterative methods can be used, but they can be extremely slow at converging when dealing with large matrices. A few approaches suitable for the reconstruction of images from very large data sets have been developed. However, they either require explicit construction of the sensitivity matrix, suffer from slow computation times, or can only be applied to restricted geometries. We introduce a method for fast reconstruction in fDOT with large data and solution spaces, which preserves the resolution of the forward operator whilst compressing its representation. The method does not require construction of the full matrix, and thus allows storage and direct inversion of the explicitly constructed compressed system matrix. The method is tested using simulated and experimental data. Results show that the fDOT image reconstruction problem can be effectively compressed without significant loss of information and with the added advantage of reducing image noise. PMID- 23942632 TI - Fast segmentation and high-quality three-dimensional volume mesh creation from medical images for diffuse optical tomography. AB - Multimodal approaches that combine near-infrared (NIR) and conventional imaging modalities have been shown to improve optical parameter estimation dramatically and thus represent a prevailing trend in NIR imaging. These approaches typically involve applying anatomical templates from magnetic resonance imaging/computed tomography/ultrasound images to guide the recovery of optical parameters. However, merging these data sets using current technology requires multiple software packages, substantial expertise, significant time-commitment, and often results in unacceptably poor mesh quality for optical image reconstruction, a reality that represents a significant roadblock for translational research of multimodal NIR imaging. This work addresses these challenges directly by introducing automated digital imaging and communications in medicine image stack segmentation and a new one-click three-dimensional mesh generator optimized for multimodal NIR imaging, and combining these capabilities into a single software package (available for free download) with a streamlined workflow. Image processing time and mesh quality benchmarks were examined for four common multimodal NIR use-cases (breast, brain, pancreas, and small animal) and were compared to a commercial image processing package. Applying these tools resulted in a fivefold decrease in image processing time and 62% improvement in minimum mesh quality, in the absence of extra mesh postprocessing. These capabilities represent a significant step toward enabling translational multimodal NIR research for both expert and nonexpert users in an open-source platform. PMID- 23942634 TI - High-contrast multilayer imaging of biological organisms through dark-field digital refocusing. AB - We have developed an imaging system to extract high contrast images from different layers of biological organisms. Utilizing a digital holographic approach, the system works without scanning through layers of the specimen. In dark-field illumination, scattered light has the main contribution in image formation, but in the case of coherent illumination, this creates a strong speckle noise that reduces the image quality. To remove this restriction, the specimen has been illuminated with various speckle-fields and a hologram has been recorded for each speckle-field. Each hologram has been analyzed separately and the corresponding intensity image has been reconstructed. The final image has been derived by averaging over the reconstructed images. A correlation approach has been utilized to determine the number of speckle-fields required to achieve a desired contrast and image quality. The reconstructed intensity images in different object layers are shown for different sea urchin larvae. Two multimedia files are attached to illustrate the process of digital focusing. PMID- 23942635 TI - Intestinal perfusion monitoring using photoplethysmography. AB - In abdominal trauma patients, monitoring intestinal perfusion and oxygen consumption is essential during the resuscitation period. Photoplethysmography is an optical technique potentially capable of monitoring these changes in real time to provide the medical staff with a timely and quantitative measure of the adequacy of resuscitation. The challenges for using optical techniques in monitoring hemodynamics in intestinal tissue are discussed, and the solutions to these challenges are presented using a combination of Monte Carlo modeling and theoretical analysis of light propagation in tissue. In particular, it is shown that by using visible wavelengths (i.e., 470 and 525 nm), the perfusion signal is enhanced and the background contribution is decreased compared with using traditional near-infrared wavelengths leading to an order of magnitude enhancement in the signal-to-background ratio. It was further shown that, using the visible wavelengths, similar sensitivity to oxygenation changes could be obtained (over 50% compared with that of near-infrared wavelengths). This is mainly due to the increased contrast between tissue and blood in that spectral region and the confinement of the photons to the thickness of the small intestine. Moreover, the modeling results show that the source to detector separation should be limited to roughly 6 mm while using traditional near infrared light, with a few centimeters source to detector separation leads to poor signal-to-background ratio. Finally, a visible wavelength system is tested in an in vivo porcine study, and the possibility of monitoring intestinal perfusion changes is showed. PMID- 23942636 TI - Monoclonal gammopathy of undetermined significance and fatal polyarteritis nodosa. PMID- 23942637 TI - Unusual hepatic involvement with significant fibrosis in adult T cell leukemia. PMID- 23942638 TI - Sensing extremely limited H2 contents by Pd nanogap connected to an amorphous InGaZnO thin-film transistor. AB - A palladium (Pd) nanogap-based thin-film has been connected to an electrically stable amorphous InGaZnO thin-film transistor, to form a hydrogen sensor demonstrating a dramatic sensing capability. As a result of the Pd connection to the transistor source, our sensor circuit greatly enhances the hydrogen-induced signal and sensing speed in the sense of output voltage, clearly resolving a minimum hydrogen content of 0.05%. When the nanogap-based Pd thin-film was connected to the transistor gate, an extremely limited hydrogen content of even less than 0.05% was visibly detected through gate voltage shifts. Our results exhibit the most promising and practical ways to sense extremely limited hydrogen contents, originating from two methods: transistor-to-Pd nanogap resistor and transistor-to-Pd nanogap capacitor coupling. PMID- 23942639 TI - Peripheral T-cell lymphoma emerging in a patient with aggressive polymyositis: molecular evidence for neoplastic transformation of an oligoclonal T-cell infiltrate. AB - We report a rare case of peripheral T-cell lymphoma arising in a 52-year-old man with biopsy-proven aggressive polymyositis, who had cardiac involvement, progressive bulbar symptoms, and died 11 months post diagnosis due to multiorgan failure. Using a multimodality approach including immunohistochemistry, genome wide single nucleotide polymorphism (SNP)-array analysis, and high-throughput sequencing of the complementary determining region 3 (CDR3) of T-cell receptor beta (TCRbeta) genes, our study demonstrates a molecular link between polymyositis and T-cell lymphoma, and provides evidence of the rapid and possibly late occurrence of genomic instability during neoplastic transformation of an oligoclonal T-cell population. Immunohistochemical analysis revealed loss of CD5, CD7, and CD8 antigen expression in autopsy tissue samples, as well as the occurrence of aberrant CD56 expression, not seen in pre-mortem biopsies, supporting the emergence of a neoplastic T-cell population. Multiplex polymerase chain reaction and next-generation sequencing of the TCRbeta CDR3 region displayed two unique T-cell clones in both the diagnostic biopsy confirming polymyositis and the autopsy muscle tissue exhibiting T-cell lymphoma, linking the two pathological processes. SNP-array analysis revealed complex genomic abnormalities at autopsy but not in the pre-mortem muscle biopsies displaying polymyositis, confirming malignant transformation of the oligoclonal T-cell infiltrate. Our findings raise the possibility that clinically aggressive polymyositis might represent a preneoplastic condition in some instances, similar to certain other autoimmune and inflammatory disorders. PMID- 23942641 TI - Attention to endogenous and exogenous cues affects auditory localization. AB - Three experiments examine attentional differences in auditory localization using either endogenous or exogenous visual cues. Participants were presented with visual cues on a computer screen and asked to localize auditory targets presented through headphones. In conditions in which the auditory and visual stimuli traveled in the same direction, participants showed illusory directional hearing (Hari in Neurosci Lett 189:29-30, 1995) in that the targets were perceived to travel through the head. In conditions in which the directions of the auditory and visual stimuli were conflicting, participants localized the auditory targets as traveling in the direction of the visual cues. These data suggest that visual capture plays a predominate role in the processes of auditory localization that occurs within the head. Additionally, endogenous response times were significantly greater than exogenous response times. We propose this is the result of additional time required to shift one's attentional window in the endogenous condition. PMID- 23942640 TI - Past rewards capture spatial attention and action choices. AB - The desire to increase rewards and minimize punishing events is a powerful driver in behaviour. Here, we assess how the value of a location affects subsequent deployment of goal-directed attention as well as involuntary capture of attention on a trial-to-trial basis. By tracking eye position, we investigated whether the ability of an irrelevant, salient visual stimulus to capture gaze (stimulus driven attention) is modulated by that location's previous value. We found that distractors draw attention to them significantly more if they appear at a location previously associated with a reward, even when gazing towards them now leads to punishments. Within the same experiment, it was possible to demonstrate that a location associated with a reward can also bias subsequent goal-directed attention (indexed by action choices) towards it. Moreover, individuals who were vulnerable to being distracted by previous reward history, as indexed by oculomotor capture, were also more likely to direct their actions to those locations when they had a free choice. Even when the number of initial responses was made to be rewarded and punished stimuli were equalized, the effects of previous reward history on both distractibility and action choices remained. Finally, a covert attention task requiring button-press responses rather than overt gaze shifts demonstrated the same pattern of findings. Thus, past rewards can act to modulate both subsequent stimulus-driven as well as goal-directed attention. These findings reveal that there can be surprising short-term costs of using reward cues to regulate behaviour. They show that current valence information, if maintained inappropriately, can have negative subsequent effects, with attention and action choices being vulnerable to capture and bias, mechanisms that are of potential importance in understanding distractibility and abnormal action choices. PMID- 23942642 TI - Pause time alters the preparation of two-component movements. AB - Targeted reciprocal aiming movements are pervasive in everyday life, but it is unclear how the timing parameters between task elements affect the preparation of these movements. This study used a loud (124 dB) startling acoustic stimulus (SAS) to probe how changes in the pause time between the outward and return components of a reciprocal aiming task affected the preparatory state of the motor system. Participants performed a visually guided wrist extension-flexion task to a target located at 20 degrees from the start position and were instructed to pause the movement within the wrist extension target zone for either 50, 200, or 500 ms. A SAS was presented during 25 % of trials before either the onset of the wrist extension (out) or flexion (return) components of the task to determine how motor preparation was affected by task requirements. Results showed that the presentation of a SAS prior to the initial outward movement led to significantly earlier onsets of both the outward and return components (p < .05), indicating that the pause time in the planned action was pre-planned. For the longer (200, 500 ms) pause-time conditions, a SAS delivered prior to returning from the target region triggered the return portion of the movement early. These findings suggest that the shortest pause-time movement (50 ms) was preplanned as a single action, whereas for reciprocal movements with longer pause times at least the initial part of the movement and the timing of the pause were preplanned and integrated, while the return portion was more independent. PMID- 23942643 TI - Protonation-triggered conformational modulation of an N,N'-dialkylbispidine: first observation of the elusive boat-boat conformer. AB - Modulation of the solution conformations of N,N'-bis(benzhydryl)bispidine has been achieved by protonation. Conformers have been characterized by NMR spectroscopy using nuclear Overhauser effects and residual dipolar couplings. In contrast to the preference for the chair-chair conformation for the free base and the monoprotonated species, the diprotonated bispidine is revealed to exist as a mixture of chair-boat and boat-boat conformers. While boat-boat conformers of bispidines have previously not been detected, they are here observed to constitute up to 70% of the bispidine population. PMID- 23942644 TI - A theoretical study on the formation of iodine oxide aggregates and monohydrates. AB - Biotic and abiotic emissions of molecular iodine and iodocarbons from the sea or the ice surface and the intertidal zone to the coastal/polar marine boundary layer lead to the formation of iodine oxides, which subsequently nucleate forming iodine oxide particles (IOPs). Although the link between coastal iodine emissions and ultrafine aerosol bursts is well established, the details of the nucleation mechanism have not yet been elucidated. In this paper, results of a theoretical study of a range of potentially relevant aggregation reactions of different iodine oxides, as well as complexation with water molecules, are reported. Thermochemical properties of these reactions are obtained from high level ab initio correlated calculations including spin-orbit corrections. The results show that the nucleation path most likely proceeds through dimerisation of I2O4. It is also shown that water can hinder gas-to-particle conversion to some extent, although complexation with key iodine oxides does not remove enough of these to stop IOP formation. A consistent picture of this process emerges from the theoretical study presented here and the findings of a new laboratory study reported in the accompanying paper (Gomez Martin et al., 2013). PMID- 23942645 TI - Primary visual cortex projections to extrastriate cortices in enucleated and anophthalmic mice. AB - In the mouse, visual extrastriate areas are located within distinct acallosal zones. It has been proposed that the striate-extrastriate and callosal projections are interdependent. In visually deprived mice, the normal patterns of callosal and striate-extrastriate projections are disrupted. It remains unknown whether visual deprivation affects the topography of V1-extrastriate projections and their relationship with callosal projections. Two anterograde tracers were injected in V1 and multiple retrograde tracer injections were performed in the contralateral hemisphere of intact and enucleated C57BL/6 mice and in ZRDCT/An mice to determine the effects of prenatal and postnatal afferent sensory activity on the topography of V1-extrastriate and callosal projections. Greater topographic anomalies were found in striate-extrastriate projections of anophthalmic than enucleated mice. In enucleated mice, the relationship between striate-extrastriate projections and callosal zones was highly variable. In anophthalmic mice, there was also a greater overlap between these projections. These results suggest that the prenatal afferent sensory activity regulates some aspects of the distribution of V1-extrastriate and callosal projections, in addition to the development of a normal topographic representation in extrastriate areas. PMID- 23942646 TI - Interactions between benthic predators and zooplanktonic prey are affected by turbulent waves. AB - Predators capture prey in complex and variable environments. In the ocean, bottom dwelling (benthic) organisms are subjected to water currents, waves, and turbulent eddies. For benthic predators that feed on small animals carried in the water (zooplankton), flow not only delivers prey, but can also shape predator prey interactions. Benthic passive suspension feeders collect prey delivered by movement of ambient water onto capture-surfaces, whereas motile benthic predators, such as burrow-dwelling fish, dart out to catch passing zooplankton. How does the flow of ambient water affect these contrasting modes of predation by benthic zooplanktivores? We studied the effects of turbulent, wavy flow on the encounter, capture, and retention of motile zooplanktonic prey (copepods, Acartia spp.) by passive benthic suspension feeders (sea anemones, Anthopleura elegantissima). Predator-prey interactions were video-recorded in a wave generating flume under two regimes of oscillating flow with different peak wave velocities and levels of turbulent kinetic energy ("weak" and "strong" waves). Rates of encounter (number of prey passing through a sea anemone's capture zone per time), capture (prey contacting and sticking to tentacles per time), and retention (prey retained on tentacles, without struggling free or washing off, per time) were measured at both strengths of waves. Strong waves enhanced encounter rates both for dead copepods and for actively swimming copepods, but there was so much variability in the behavior of the live prey that the effect of wave strength on encounter rates was not significant. Trapping efficiency (number of prey retained per number encountered) was the same in both flow regimes because, although fewer prey executed maneuvers to escape capture in strong waves, more of the captured prey was washed off the predators' tentacles. Although peak water velocities and turbulence of waves did not affect feeding rates of passive suspension-feeding sea anemones, increases in these aspects of flow have been shown to enhance feeding rates and efficiency of motile benthic fish that lunge out of their burrows to catch zooplankton. Faster, more turbulent flow interferes with the ability of prey to detect predators and execute escape maneuvers, and thus enhances capture rates both for passive suspension-feeding predators and for actively swimming predators. However, prey captured in the mouths of fish are not washed away by ambient flow, whereas prey captured on the tentacles of suspension feeders can be swept off before they are ingested. Therefore, the effects of flowing water on predation on zooplankton by benthic animals depend on the feeding mode of the predator. PMID- 23942647 TI - Unpacking the black box of implementation: the next generation for policy, research and practice. PMID- 23942648 TI - Epidural analgesia confusing the diagnosis of spontaneous acute thoracic epidural hematoma after cesarean section. PMID- 23942649 TI - Lipid resuscitation: development in basic research and application to clinical practice. PMID- 23942650 TI - Experience of atypical chest pain that can be overlooked and neglected in youths. PMID- 23942651 TI - Infant feeding tube as rescue endotracheal tube in an infant with an aerodigestive foreign body. PMID- 23942652 TI - Iridium catalysis: application of asymmetric reductive hydrogenation. AB - Iridium, despite being one of the least abundant transition metals, has found several uses. N,P-ligated iridium catalysts are used to perform many highly selective reactions. These methodologies have been developed extensively over the past 15 years. More recently, the application of iridium N,P catalysts in asymmetric hydrogenation has been a focus of research to find novel applications and to expand on their current synthetic utility. The aim of this perspective is to highlight the advances made by the Andersson group. PMID- 23942653 TI - Hot flashes and blood pressure in middle-aged Japanese women. AB - BACKGROUND: Some Western studies have reported that hot flashes are risk factors of cardiovascular diseases. We aimed to investigate the association between hot flashes and blood pressure in middle-aged Japanese women. METHODS: Annual medical checkup data from 1,058 healthy middle-aged Japanese women were analyzed. Nonstandardized coefficients (B), which were calculated by multiple linear regression analysis, were used to evaluate differences in blood pressure resulting from hot flashes. RESULTS: The prevalence of current hot flashes was 20.2%, and the experience of hot flashes was significantly more frequent according to age (P < 0.01). Systolic blood pressure was significantly higher in women currently experiencing hot flashes and in those experiencing them within the previous month than in those without such experience (B = 6.0, P < 0.01; B = 3.7, P < 0.05, respectively). Diastolic blood pressure was significantly higher in women currently experiencing hot flashes than in those without such experience (B = 3.9; P < 0.01). Among current smokers, systolic blood pressure was 16.4mm Hg higher in those currently experiencing hot flashes (P < 0.01), but this difference was less among nonsmokers (P < 0.05). In addition, pulse pressure was 10.5mm Hg higher in current smokers currently experiencing hot flashes than in other current smokers (P < 0.01), but not among nonsmokers. CONCLUSIONS: In middle-aged Japanese women, hot flashes were associated with higher pulse pressure among smokers but not among nonsmokers. PMID- 23942656 TI - Concentration dependence of graphene oxide-nanoneedle manganese oxide composites reduced by hydrazine hydrate for an electrochemical supercapacitor. AB - Graphene-MnO2 composites are reduced from GO-MnO2 using various concentrations of hydrazine hydrate with a fixed reduction time to optimize the hydrazine concentration to obtain excellent electrochemical performance. Changes in the oxygen-containing functional groups are observed as the concentration of hydrazine is varied. These changes affect the electrical conductivity and density of MnO2 nanoneedles, which impact the surface area and can significantly affect the supercapacitive performance. The characterization of morphology and microstructure of the as-prepared composites demonstrates that MnO2 is successfully formed on the GO surface and GO is successfully reduced by using hydrazine hydrate as a reducing agent. The capacitive properties of the graphene MnO2 electrodes which reduced 50 mM of hydrazine (RGO-MnO2(50)) show a low sheet resistance value as well as a high surface area, resulting in excellent electrochemical performance (383.82 F g(-1) at a scan rate of 10 mV s(-1)). It is anticipated that the formation of nanoneedle structures of MnO2 on graphene oxide surfaces utilizing the 50 mM hydrazine reduction procedure is a promising fabrication method for supercapacitor electrodes. PMID- 23942655 TI - Influence of the AGTR1 A1166C genotype on the progression of arterial stiffness: A 16-year longitudinal study. AB - BACKGROUND: We examined the influence of the AGTR1 A1166C genotype on the 16-year evolution of pulse wave velocity (PWV) in a middle-aged population. In a cross sectional study, we reported that the presence of the AGTR1 1166C allele was associated with higher aortic stiffness compared with the AGTR1 1166AA genotype. METHODS: The study was conducted in 259 subjects who underwent 3 health check-ups over 16 years at the Centre IPC-Paris: an initial visit in 1992-1993, an intermediate visit in 1998-1999, and a final visit in 2007-2008. Aortic stiffness was assessed during the 3 visits by measuring carotid-femoral PWV. AGTR1 A1166C polymorphism was assayed by allele-specific oligonucleotide hybridization. RESULTS: AGTR1 1166C allele carriers (AC + CC genotypes) had a 35% more pronounced increase in PWV over this 16-year period when compared with the AGTR1 1166AA subjects (3.01 +/- 0.32 vs. 1.92 +/- 0.23 m/s; P < 0.001). This increase remained significant after adjustment for age, sex, initial PWV values, and changes in blood pressure (+37%; P < 0.05). The genotype-related differences in PWV were only observed at the last visit (i.e., later in life, after the age of 55 years). The effects of this genotype on PWV were not related to the presence of antihypertensive treatment. CONCLUSIONS: This is the first long-term longitudinal study indicating that AT1 1166C carriers are at increased risk of pronounced arterial stiffening during aging especially after the age of 55. PMID- 23942654 TI - Plasma bicarbonate and odds of incident hypertension. AB - BACKGROUND: Several biomarkers of metabolic acidosis, including lower plasma bicarbonate, have been associated with prevalent hypertension in cross-sectional studies. We sought to examine prospectively whether lower plasma bicarbonate is associated with incident hypertension. METHODS: We conducted a prospective case control study nested within the Nurses' Health Study II. Plasma bicarbonate was measured in 695 nonobese women without hypertension at time of blood draw who subsequently developed hypertension during 6 years of follow-up. Control subjects were matched to case subjects according to age, race, time and day of blood draw, and day of menstrual cycle. We used unconditional logistic regression to generate odds ratios (ORs) for development of hypertension by quintile of baseline plasma bicarbonate. RESULTS: After adjusting for matching factors, body mass index, family history of hypertension, plasma creatinine, and dietary and lifestyle factors, higher plasma bicarbonate was associated with lower odds of developing hypertension across quintiles (P for linear trend = 0.04). Those in the highest compared with the lowest quintile of plasma bicarbonate had 31% lower odds of developing hypertension (OR = 0.69; 95% confidence interval = 0.48-0.99). Further adjustment for diet-estimated net endogenous acid production, plasma insulin, 25 hydroxyvitamin D, and uric acid did not alter these findings. CONCLUSIONS: Our case-control study is consistent with a modest association between higher plasma bicarbonate and reduced odds of developing hypertension among nonobese women, although our findings are of borderline statistical significance. Further research is required to confirm this finding as part of a larger prospective cohort study and to elucidate the mechanism for this relation. PMID- 23942657 TI - Providing Informal Care in Terminal Illness: An Analysis of Preferences for Support Using a Discrete Choice Experiment. AB - BACKGROUND: The trend for terminally ill patients to receive much of their end-of life care at home necessitates the design of services to facilitate this. Care at home also requires that informal care be provided by family members and friends. This study investigated informal carers' preferences for support services to aid the development of end-of-life health care services. METHODS: This cross sectional study used 2 discrete choice experiments to ascertain the preferences of carers supporting patients with different levels of care need, determined by the assistance needed with personal care and labeled High Care (HC) and Low Care (LC). The sample included 168 informal carers of people receiving palliative care at home from 2 palliative care services in Sydney, Australia. Data were collected in face-to-face interviews; carers chose between 2 hypothetical plans of support services and their current services. Data were analyzed with generalized multinomial logit models that were used to calculate the impact of each attribute on the probability of a carer choosing a service plan. RESULTS: Preferred support included nursing services; the probability of choosing a plan increased significantly if it included nurse home visits and phone advice (P < 0.001). HC carers also wanted doctor home visits, home respite, and help with personal care (P < 0.05), and LC carers wanted help with household tasks, transport, and a case coordinator (P < 0.001). On average, both groups of carers preferred their current services, but this varied with characteristics of the carer and the caregiving situation. CONCLUSIONS: The most valued services are those that support carers in their caregiving role; however, supportive care preferences vary with the different circumstances of patients and carers. PMID- 23942658 TI - Nanocrystalline cellulose-porphyrin hybrids: synthesis, supramolecular properties, and singlet-oxygen production. AB - An amino-trisulfonate tetraphenylporphyrin was conjugated to carboxylate cellulose nanocrystals giving rise to a new nanomaterial with interesting binding properties. PMID- 23942662 TI - Chicken in sunrise: Georgia O'Keeffe. PMID- 23942663 TI - Blood pressure, cholesterol guidelines face more delays. PMID- 23942664 TI - Deadly MERS coronavirus not yet a global concern. PMID- 23942665 TI - Preventing suicide's ripple effects takes coordinated effort. PMID- 23942674 TI - The evolution of the master diagnostician. PMID- 23942675 TI - Social media and physicians' online identity crisis. PMID- 23942676 TI - A piece of my mind. Scared of worms. PMID- 23942677 TI - Surgery for mitral regurgitation: sooner or later? PMID- 23942678 TI - Research letters in JAMA: small but mighty. PMID- 23942679 TI - Association between early surgical intervention vs watchful waiting and outcomes for mitral regurgitation due to flail mitral valve leaflets. AB - IMPORTANCE: The optimal management of severe mitral valve regurgitation in patients without class I triggers (heart failure symptoms or left ventricular dysfunction) remains controversial in part due to the poorly defined long-term consequences of current management strategies. In the absence of clinical trial data, analysis of large multicenter registries is critical. OBJECTIVE: To ascertain the comparative effectiveness of initial medical management (nonsurgical observation) vs early mitral valve surgery following the diagnosis of mitral regurgitation due to flail leaflets. DESIGN, SETTING, AND PARTICIPANTS: The Mitral Regurgitation International Database (MIDA) registry includes 2097 consecutive patients with flail mitral valve regurgitation (1980-2004) receiving routine cardiac care from 6 tertiary centers (France, Italy, Belgium, and the United States). Mean follow-up was 10.3 years and was 98% complete. Of 1021 patients with mitral regurgitation without the American College of Cardiology (ACC) and the American Heart Association (AHA) guideline class I triggers, 575 patients were initially medically managed and 446 underwent mitral valve surgery within 3 months following detection. MAIN OUTCOMES AND MEASURES: Association between treatment strategy and survival, heart failure, and new-onset atrial fibrillation. RESULTS: There was no significant difference in early mortality (1.1% for early surgery vs 0.5% for medical management, P=.28) and new-onset heart failure rates (0.9% for early surgery vs 0.9% for medical management, P=.96) between treatment strategies at 3 months. In contrast, long-term survival rates were higher for patients with early surgery (86% vs 69% at 10 years, P < .001), which was confirmed in adjusted models (hazard ratio [HR], 0.55 [95% CI, 0.41-0.72], P < .001), a propensity-matched cohort (32 variables; HR, 0.52 [95% CI, 0.35-0.79], P = .002), and an inverse probability-weighted analysis (HR, 0.66 [95% CI, 0.52-0.83], P < .001), associated with a 5-year reduction in mortality of 52.6% (P < .001). Similar results were observed in relative reduction in mortality following early surgery in the subset with class II triggers (59.3 after 5 years, P = .002). Long-term heart failure risk was also lower with early surgery (7% vs 23% at 10 years, P < .001), which was confirmed in risk-adjusted models (HR, 0.29 [95% CI, 0.19-0.43], P < .001), a propensity-matched cohort (HR, 0.44 [95% CI, 0.26-0.76], P = .003), and in the inverse probability-weighted analysis (HR, 0.51 [95% CI, 0.36-0.72], P < .001). Reduction in late-onset atrial fibrillation was not observed (HR, 0.85 [95% CI, 0.64-1.13], P = .26). CONCLUSION AND RELEVANCE: Among registry patients with mitral valve regurgitation due to flail mitral leaflets, performance of early mitral surgery compared with initial medical management was associated with greater long-term survival and a lower risk of heart failure, with no difference in new-onset atrial fibrillation. PMID- 23942680 TI - QRS duration, bundle-branch block morphology, and outcomes among older patients with heart failure receiving cardiac resynchronization therapy. AB - IMPORTANCE: The benefits of cardiac resynchronization therapy (CRT) in clinical trials were greater among patients with left bundle-branch block (LBBB) or longer QRS duration. OBJECTIVE: To measure associations between QRS duration and morphology and outcomes among patients receiving a CRT defibrillator (CRT-D) in clinical practice. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of Medicare beneficiaries in the National Cardiovascular Data Registry's ICD Registry between 2006 and 2009 who underwent CRT-D implantation. Patients were stratified according to whether they were admitted for CRT-D implantation or for another reason, then categorized as having either LBBB or no LBBB and QRS duration of either 150 ms or greater or 120 to 149 ms. MAIN OUTCOMES AND MEASURES: All-cause mortality; all-cause, cardiovascular, and heart failure readmission; and complications. Patients underwent follow-up for up to 3 years, with follow-up through December 2011. RESULTS: Among 24 169 patients admitted for CRT-D implantation, 1-year and 3-year mortality rates were 9.2% and 25.9%, respectively. All-cause readmission rates were 10.2% at 30 days and 43.3% at 1 year. Both the unadjusted rate and adjusted risk of 3-year mortality were lowest among patients with LBBB and QRS duration of 150 ms or greater (20.9%), compared with LBBB and QRS duration of 120 to 149 ms (26.5%; adjusted hazard ratio [HR], 1.30 [99% CI, 1.18-1.42]), no LBBB and QRS duration of 150 ms or greater (30.7%; HR, 1.34 [99% CI, 1.20-1.49]), and no LBBB and QRS duration of 120 to 149 ms (32.3%; HR, 1.52 [99% CI, 1.38-1.67]). The unadjusted rate and adjusted risk of 1 year all-cause readmission were also lowest among patients with LBBB and QRS duration of 150 ms or greater (38.6%), compared with LBBB and QRS duration of 120 to 149 ms (44.8%; adjusted HR, 1.18 [99% CI, 1.10-1.26]), no LBBB and QRS duration of 150 ms or greater (45.7%; HR, 1.16 [99% CI, 1.08-1.26]), and no LBBB and QRS duration of 120 to 149 ms (49.6%; HR, 1.31 [99% CI, 1.23-1.40]). There were no observed associations with complications. CONCLUSIONS AND RELEVANCE: Among fee-for-service Medicare beneficiaries undergoing CRT-D implantation in clinical practice, LBBB and QRS duration of 150 ms or greater, compared with LBBB and QRS duration less than 150 ms or no LBBB regardless of QRS duration, was associated with lower risk of all-cause mortality and of all-cause, cardiovascular, and heart failure readmissions. PMID- 23942681 TI - Barrett esophagus and risk of esophageal cancer: a clinical review. AB - IMPORTANCE: Barrett esophagus, a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma, a tumor that has increased in incidence more than 7-fold over the past several decades. Controversy exists regarding the issues of endoscopic screening and surveillance for Barrett esophagus, treatment for the underlying GERD, and the role of endoscopic eradication therapy. OBJECTIVES: To review current concepts on the pathogenesis, diagnosis, and treatment of Barrett esophagus; to discuss the importance of dysplasia and the role of endoscopic eradication therapy for its treatment; and to review current management guidelines. EVIDENCE REVIEW: MEDLINE and the Cochrane Library were searched from 1984 to April 2013. Additional citations were obtained by reviewing references from selected research and review articles. FINDINGS: Risk factors for cancer in Barrett esophagus include chronic GERD, hiatal hernia, advanced age, male sex, white race, cigarette smoking, and obesity with an intra-abdominal body fat distribution. The annual risk of esophageal cancer is approximately 0.25% for patients without dysplasia and 6% for patients with high-grade dysplasia. High-quality studies have found no significant differences in cancer incidence for patients with Barrett esophagus whose GERD is treated medically or surgically. Endoscopic eradication therapy with radiofrequency ablation significantly reduces the frequency of progression to cancer for patients with high-grade dysplasia. CONCLUSIONS AND RELEVANCE: Endoscopic screening is recommended for patients with multiple risk factors for cancer in Barrett esophagus. For patients with Barrett esophagus without dysplasia, endoscopic surveillance at intervals of 3 to 5 years is recommended, and GERD is treated much as it is for patients without Barrett esophagus. Endoscopic eradication therapy is the treatment of choice for high-grade dysplasia and is an option for low-grade dysplasia. Endoscopic eradication therapy is not recommended for the general population of patients with nondysplastic Barrett esophagus. PMID- 23942682 TI - Zonisamide for weight reduction in obese adults. PMID- 23942683 TI - A painful bulge in the left flank. PMID- 23942684 TI - Incidence of sports-related sudden death in France by specific sports and sex. PMID- 23942685 TI - Efficacy of sublingual immunotherapy. PMID- 23942686 TI - Efficacy of sublingual immunotherapy. PMID- 23942687 TI - Efficacy of sublingual immunotherapy-reply. PMID- 23942688 TI - Mortality after perioperative beta-blocker use in noncardiac surgery. PMID- 23942689 TI - The role of persuasion. PMID- 23942690 TI - Mortality after perioperative beta-blocker use in noncardiac surgery-reply. PMID- 23942693 TI - The role of persuasion-reply. PMID- 23942695 TI - Mushroom fallacies. PMID- 23942696 TI - JAMA Patient Page. Options for colorectal cancer screening. PMID- 23942697 TI - Pesticide residues in sediments and aquatic species in Lake Nokoue and Cotonou Lagoon in the Republic of Benin. AB - Lake Nokoue and Cotonou Lagoon are the most important and most productive continental freshwaters in Benin, with an estimated fish production of over 2 tonnes per hectare in Lake Nokoue. Organochlorine pesticides are used in agriculture and to repel tsetse flies, malaria mosquitoes and other diseases raised. Sediment, fish, shrimp and oyster species were collected in Lake Nokoue and Cotonou Lagoon for pesticide residues analysis. The main pesticides identified in sediment were pp'-DDT and its metabolites pp-DDE and pp'-DDD, with residue levels between the detection limit and 24.4 MUg/kg dry weight. Fish species commonly consumed such as Elops lacerta, Podamasys jubelini, Gobbienellus occidentalis, Ethmalosa fimbriata, Mugil cephalus and Hemichromis fasciatus were contaminated with residues of seven to nine pesticides, including pp-DDE, op' DDD, pp'-DDD, op'-DDT, pp'-DDT, alpha-endosulfan, aldrin, dieldrin and gamma hexachlorocyclohexane. The levels ranged from detection limit to 289 ng/g lipid. The same pesticides were also detected in other aquatic species, such as shrimp and oysters. A summed risk assessment, comparing pesticide intake levels through fish consumption with tolerable daily intake levels proposed by the World Health Organization, showed in all cases a low risk for human health. PMID- 23942699 TI - IJPH goes environmental: does it? PMID- 23942698 TI - Assessment of self-medication in population buying antibiotics in pharmacies: a pilot study from Beirut and its suburbs. AB - OBJECTIVES: This study was performed to assess self-medication with antibiotics (ATB) in the general population and its associated factors. METHODS: Face to face interviews using a structured questionnaire were conducted to collect data from ATB buyers in pharmacies in Beirut area. Data were analyzed using descriptive statistics and Chi-square test. A multivariate logistic regression was performed to predict self-medication. RESULTS: 42 % of 319 participants were buying ATB without prescription and the pharmacists were the main helpers (18.8 %). Saving time was the most common cited reason for self-medication with ATB (39.7 %). The logistic regression showed that self-medication with ATB was significantly increased among men [OR = 3.03; IC 95 % (2-5)]; it was associated with sore throat symptoms [OR = 2.38; IC 95 % (1.40-4.03)] and the ignorance of ATB use dangers [OR = 3.33; IC 95 % (1.96-5.55)]. In addition, it was prominent with amoxicillin [OR = 1.93; IC 95 % (0.17-1.34)], and inversely related to quinolone [OR = 0.44; IC 95 % (0.18-1.03)] and cephalosporin families [OR = 0.28; IC 95 % (0.11-1.68)] or other ATB classes [OR = 0.96; IC 95 % (0.41-2.22)]. CONCLUSIONS: Self-medication with antibiotics is a relatively frequent problem in Beirut area. Interventions are required to reduce antibiotic misuse. PMID- 23942700 TI - High-throughput analysis of drugs in biological fluids by desorption electrospray ionization mass spectrometry coupled with thin liquid membrane extraction. AB - Biological fluids such as urine, saliva and whole blood were analyzed for contents of drugs by a new combination of desorption electrospray ionization mass spectrometry (DESI-MS) and thin liquid membrane extraction (TLME). Analytes from the sample were extracted into a thin liquid membrane of hexadecane deposited on a porous Teflon membrane, from which they were subsequently analyzed directly by DESI. The total analysis time was 15 minutes for analysis of several samples with a potential analysis time of less than a minute per sample. Thanks to the pre concentration and sample clean-up built into the method, methadone was detected in urine in full-scan mode with an LOD of 4 ng mL(-1), while amitriptyline, nortriptyline and pethidine showed LODs of 17 ng mL(-1). Quantification was possible for several basic drugs using one common internal standard, providing relative accuracies in the range of 10-30%. A reliability test was performed on 20 samples with methadone, amitriptyline, nortriptyline and pethidine in urine, showing that none of the samples having concentrations above the LOD were missed and no false positives were found. Diphenhydramine and one of its metabolites were detected in authentic samples of urine and saliva, and methadone was detected from a whole-blood sample spiked to a concentration of 100 ng mL(-1). The method has several advantages, such as extremely low price in consumables, the possibility of fast analysis of very crude biofluids such as whole blood and the potential for a very high sample throughput. PMID- 23942701 TI - Effects of pain mitigation and method of castration on behavior and feedlot performance in cull beef bulls. AB - The objectives of this study were to evaluate the effects of castration method (banding vs. surgical) and use of analgesia on behavior and feedlot performance in cull bulls. Angus, Hereford, and Angus-crossbred bulls (n = 20; initial BW = 384 +/- 59.3 kg; 336 +/- 20.1 d old) were housed in feedlot pens equipped with the ability to measure individual daily feed intake. A balanced randomized block design using a 2 * 2 factorial arrangement of treatments was used. A multimodal analgesia (MMA) protocol was used and consisted of sutcutaneous ketamine stun containing butorphanol (0.01 mg/kg BW), xylazine (0.02 mg/kg BW), ketamine (0.04 mg/kg BW), and a local 2% lidocaine hydrochloride anesthetic block of the spermatic cords (10 mL/cord) and scrotum (10 mL) on d 0. Flunixin meglumine (1.2 mg/kg) was administered intravenously on d 0, 1, 2, and 3 to MMA cattle. Cattle were stratified to treatments based on breed, BW, age, and a temperament score. Treatments included 1) band castration without analgesia (BND), 2) band castration with analgesia (BND-MMA), 3) surgical castration without analgesia (SURG), and 4) surgical castration with analgesia (SURG-MMA). All castrations were performed on d 0. Chute exit velocity (EV) and time in chute (TIC) were collected on d -9, 0, 1, 2, and 13. Willingness-to-enter-chute (WTE) score, rectal temperature (TEMP), heart rate (HR), and respiration (RESP) were collected on d 0, 1, 2, 3, and 13. Cattle were weighed on d -9 and 13 while feeding behaviors were collected continuously for 57 d precastration and 28 d postcastration. There was a tendency (P < 0.09) for ADG to be greater in cattle receiving analgesia. Both SURG treatments exhibited elevated TEMP on d 1 (P < 0.001) and 2 (P < 0.05) compared to BND treatments. Postcastration DMI was greater (P = 0.02) in MMA treatments compared with nonmedicated treatments throughout the trial. Meal duration was greater (P < 0.05) in BND than SURG castrates during the first week postcastration. Results suggest that pain mitigation reduces the impact of castration on ADG and DMI. PMID- 23942702 TI - Genome-wide association of meat quality traits and tenderness in swine. AB - Pork quality has a large impact on consumer preference and perception of eating quality. A genome-wide association was performed for pork quality traits [intramuscular fat (IMF)], slice shear force (SSF), color attributes, purge, cooking loss, and pH] from 531 to 1,237 records on barrows and gilts of a Landrace-Duroc-Yorkshire population using the Illumina PorcineSNP60 BeadChip. Associations were detected using MTDFREML for all traits. Intramuscular fat had the greatest number of SNP associations, followed by pH, purge, cooking loss, shear force, and color. Two regions contained associations for multiple traits; one on SSC1 at 255 Mb near calcineurin subunit B (PPP3R2) was associated with SSF, moisture loss, and pH, and one on SSC6 from 28 to 29.5 Mb for purge and IMF containing the candidate genes glucose-6-phosphate isomerase (GPI) and KCTD15. Some of the other compelling candidate genes in regions associated with meat quality include CEBPA, SNAI1, and FAM132A for IMF, CAPN1 for SSF, GLUL for pH, and PRKAG3 and ITGB1 with cooking loss. PMID- 23942703 TI - Realimentation of nutrient restricted pregnant beef cows supports compensatory fetal muscle growth. AB - Drought and other weather-related disasters impact the amount and quality of grains and forages available to beef cattle. The impact of nutrient restriction at specific gestational timeframes on fetal skeletal muscle growth was examined. Crossbred beef cows were fed to NRC recommendations (CCC) or restricted to 60% of said levels for the first 85 or 140 d of pregnancy followed by realimentation to recommended protein and energy levels (RCC and RRC, respectively). Fetal infraspinatus (INF) morphometrics and gene expression analyses were performed at d 85, 140, and 254 of gestation. Results demonstrate that fetal primary myofibers are larger (P < 0.05) after 85 d of maternal caloric restriction by comparison to controls. Realimentation of pregnant dams at d 85 causes an increase (P < 0.05) in RCC INF cross-sectional area (CSA) by comparison to RRC at d 140 but the fibers remain smaller (P < 0.05) than CCC muscle cells. Returning nutrient load to recommended levels at d 140 of pregnancy increases RRC CSA equivalent to CCC fibers at d 254 (343.4 +/- 5.2 and 345.2 +/- 5.3 MUm(2), respectively). Fetal RRC and CCC muscle fibers are smaller (P < 0.05) than RCC fibers at d 254 suggesting the later experienced compensatory growth. Numbers of Paired box 7 (Pax7) immunopositive cells were fewer (P < 0.05) in the nutrient restricted fetuses at d 85 suggesting a loss of muscle progenitor cells. Moreover, mRNA content for the collagen crosslinking enzymes, lysyl oxidase and bone morphogenetic protein 1, were greater (P < 0.05) in the d 85 nutrient restricted fetal INF than CCC suggesting increased connective tissue cell numbers and/or activity. Because myogenesis is acutely regulated by the IGF, mRNA content of these growth factors and their receptors was examined. Fetal IGF1 mRNA content was lower in the d 85 nutrient restriction fetuses (P < 0.05) by comparison to CCC. Levels of INF IGF2 mRNA were greater (P < 0.05) in d 85 NR fetuses than CCC. Continued nutrient restriction through d 140 resulted in a reduction (P < 0.05) in IGF2 expression by comparison to CCC. No treatment effect on IGF1R or IGF2R mRNA content was noted. In summary, NR for 85 d causes an increase in primary INF fiber size that may be a result of increased IGF2 transcription and Pax7-immunopositive cell fusion. Realimentation of NR beef cows supports compensatory growth of the fetal musculature such that normal muscle fiber size and muscle progenitor numbers are achieved before birth. PMID- 23942704 TI - Feasibility of selection for male contribution to embryo survival as a way of improving male reproductive performance and semen quality in rabbits. AB - The objective of this research was assess the male contribution to the number of implanted embryos (IE) and embryo survival (ES) estimated as the rate of variance due to male genetic and permanent environmental effects regarding total variance. In prolific species, the number of embryos and ES at early stages of gestation could be considered as fertility measurements because it indicates the number and rate of fertilized ova which are able to initiate the embryo development. Analyzed traits were ovulation rate (OR) estimated as the number of corpora lutea in both ovaries, IE estimated as the number of implantation sites, and ES calculated as IE/OR. A total of 1477 records from 900 females were used to analyze OR, whereas 1081 records from 855 females and 201 males were used to analyze IE and ES. The number of animals in the pedigree was 1107. The model included the systematic effects of year-season, parity order, lactation, and the random effects of additive genetics and permanent environmental effects due to the female (for OR) or both sexes (for IE and ES). Gibbs sampling was used to estimate posterior distributions of model parameters. The heritabilities of the male contribution to IE and ES were low (0.05 [0.01, 0.10] and 0.07 [0.02, 0.12]) but these estimates are probably biased downward since laparoscopy was only performed on those does that were pregnant at d 12 of gestation, instead of on all mated does. The genetic correlations between all analyzed traits and also between male and female genetic components of IE and ES were inaccurate, and it was not possible to draw any conclusion about them. The proportion of variation due to the male nonadditive genetic plus permanent environmental effects for IE and ES was almost negligible (0.027 [0.001, 0.058] and 0.031 [0.002, 0.068] for IE and ES, respectively), being the repeatability for male contribution on IE and ES around 8 and 10%, respectively. PMID- 23942705 TI - Backtest and novelty behavior of female and castrated male piglets, with diverging social breeding values for growth. AB - Pigs housed together in a group influence each other's growth. Part of this effect is genetic and can be represented in a social breeding value. It is unknown, however, which traits are associated with social breeding values. The aim of this study was, therefore, to investigate whether personality and response to novelty could be associated with social breeding values for growth in piglets. Female and castrated male piglets from 80 litters, with either an estimated relative positive or negative social breeding value (+SBV or -SBV) for growth, were individually tested in a backtest and novel environment test, and group-wise in a novel object (i.e., a feeder with feed) test and human approach test. All tests were performed during the suckling period. No differences between +SBV and SBV piglets were found for the frequency and latency of struggling and vocalizing in the backtest (at least, P > 0.30). In the novel object test, piglets with a +SBV for growth touched the feeder faster than piglets with -SBV for growth (P = 0.01) and were more frequently present near the person in the human approach test (P < 0.01). No behavioral differences between +SBV and -SBV piglets were found in the novel environment test (at least, P > 0.40), but piglets that struggled more in the backtest walked more in this test (P = 0.02). Behavior was affected by gender in each test. Female piglets were faster than castrated male piglets to start struggling in the backtest (P = 0.047). In the novel object test, females were faster than males to touch the feeder and sample the feed. In the human approach test, they were also faster than male piglets to touch a person (all, P < 0.001). Females were also more frequently present near the feeder (P < 0.001) and person (P = 0.03). In the novel environment test, female piglets explored the floor more (P = 0.046), produced less low- (P = 0.04) and high-pitched vocalizations (P = 0.02), and defecated (P = 0.08) and urinated less than male piglets (P < 0.01). It was concluded that +SBV and -SBV piglets do not differ in their response to the backtest, and only subtle differences were found in their response to novelty. More research is warranted to identify the traits underlying SBV for growth in pigs. Moreover, castrated male piglets seemed to react more fearfully to each test than female piglets. PMID- 23942706 TI - A simple amino acid dose-response method to quantify amino acid requirements of individual meal-fed pigs. AB - Two experiments were conducted to develop a simplified dose-response technique to estimate the Lys requirement of individual, meal-fed growing pigs. In Exp. 1, we studied adaptation processes that occur during such a dose-response study in meal fed pigs, and in Exp. 2, we studied the accuracy of this simplified technique to estimate changes in Lys requirement estimates of pigs following changes in energy intake. In Exp. 1, the effect of the Lys supply strategy on the Lys requirement was assessed in 14 barrows fed an increasing [low to high (LH)] or decreasing [high to low (HL)] total Lys supply, with total Lys levels varying from 0.36 to 1.06 g/MJ DE in 7 equidistant steps of 4 d each. Urinary urea and ammonia excretion and whole body N turnover were measured. In Exp. 2, the accuracy of the dose-response technique to determine a shift in Lys requirement was assessed in 20 barrows fed at either 2.2 [low energy (LE)] or 2.7 [high energy (HE)] times the energy requirements for maintenance, with total Lys supply decreasing from 1.10 to 0.37 g Lys/MJ DE in 9 equidistant steps of 3 d each. In Exp. 1, a lower increment in protein synthesis, breakdown, and whole body N turnover with increasing dietary Lys supply was observed in LH pigs than HL pigs (P < 0.01) and the estimated Lys requirement was 0.06 g/MJ DE greater (P = 0.01) in LH pigs than HL pigs. These results indicated that pigs at a decreasing Lys supply strategy require less time for metabolic adaptation to a change in Lys supply than those at an increasing Lys supply. In Exp. 2, the estimated Lys requirement was 2.6 g/d greater (P < 0.001) in HE pigs than LE pigs. The variation in AA requirement estimates between individual pigs was low (4.9% in LH pigs and 3.0% in HL pigs in Exp. 1 and 8.1% in LE pigs and 6.0% in HE pigs in Exp. 2). The present studies indicated that a dose-response technique with a decreasing Lys supply in time and a step length of 3 d with urinary N excretion as response criteria provides a simple, accurate technique to quantitatively estimate a change in AA requirements of individual meal-fed pigs. PMID- 23942707 TI - Alteration of digestive tract microbiome in neonatal Holstein bull calves by bacitracin methylene disalicylate treatment and scours. AB - The effects of bacitracin methylene disalicylate (BMD) and scours on the fecal microbiome, animal performance, and health were studied in Holstein bull calves. Holstein bull calves (n = 150) were obtained from a single source at 12 to 24 h of age. Bull calves were randomly assigned to 1 of 2 treatments including CON (no BMD; n = 75 calves) and BMD (n = 75 calves). Starting 3 d after arrival, BMD was added into milk replacer (0.5 g/feeding; twice daily) and fed to the calves for 10 consecutive d. No differences (P > 0.10) were observed in ADG for d 0 to 28 and d 0 to 56, DMI for d 0 to 28, d 29 to 56, and d 0 to 56, or G:F for d 0 to 28, d 29 to 56, and d 0 to 56; ADG for d 29 to 56 tended to increase (P < 0.10) for BMD-treated calves compared with controls. Fecal samples were collected from 15 scouring calves and 10 cohorts (nonscouring calves received on the same day and administered the same treatment as the scouring calves). Animal morbidity and fecal score did not vary between the 2 treatments. Mortality was not influenced by the treatments in the BMD administration period or throughout the experiment. Fecal samples were subjected to pyrotagged 454 FLX pyrosequencing of 16S rRNA gene amplicon to examine compositional dynamics of fecal microbes. Escherichia, Enterococcus, and Shigella had greater (P < 0.05) populations in the BMD group whereas Dorea, Roseburia, Fecalibacterium, Papillibacter, Collinsella, Eubacterium, Peptostreptococcus, and Prevotella were decreased (P < 0.05) by BMD treatment. Genus populations were also compared between scouring and nonscouring calves. Streptococcus was the only genus that had notable increase (P < 0.05) in fecal samples from scouring calves whereas populations of Bacteroides, Roseburia, and Eubacterium were markedly (P < 0.05) greater in nonscouring calves. These results show that BMD has the ability to alter the composition of the fecal microbiome but failed to improve performance in Holstein bull calves. Discrepancy of microorganism profiles between scouring and nonscouring calves might be associated with the occurrence of scours and bacterial genera identified might be potential target of treating diarrhea. PMID- 23942708 TI - Impact of a leptin single nucleotide polymorphism and zilpaterol hydrochloride on growth and carcass characteristics in finishing steers. AB - A total of 4,178 steers (mean initial BW = 403.9 +/- 16.04 kg) were used to test the interactive effects, if any, of leptin R25C genotypes (CC, CT, or TT) and zilpaterol hydrochloride (ZH) feeding duration on growth performance and carcass traits. Steers were blocked by arrival at the feed yard, genotyped for the leptin SNP, allotted to genotype-specific pens (90 steers/pen), and assigned randomly within genotype and block to 0 or 21 d of dietary ZH. All pens within a block were slaughtered on the same day (132.1 +/- 10.9 d on feed). Final BW of steers fed ZH was 6.0 kg heavier (P = 0.008), and ZH-fed steers had greater (P = 0.003) ADG than steers not fed ZH. Feeding ZH decreased DMI in steers with increased frequency of the T allele (9.67, 9.53, and 9.28 kg/d for CC, CT, and TT, respectively), but DMI increased with the frequency of the T allele (9.68, 9.90, and 10.1 kg for CC, CT, and TT, respectively) when ZH was not fed (leptin genotype * ZH, P = 0.011). At the conclusion of the study, ultrasonic fat was greatest for TT steers (11.4 +/- 0.28 mm) and least (P = 0.003) for CC steers (11.0 +/- 0.25 mm). Regardless of ZH-feeding duration, TT steers produced a greater (P = 0.006) percentage of USDA yield grade (YG) 4 or higher carcasses (5.4 vs. 2.7%) and a lesser (P = 0.006) percentage of YG 1 carcasses (17.7 vs. 26.8%) than CC steers. In addition, ZH-fed steers produced a greater (P < 0.001) percentage of USDA YG 1 carcasses (25.9 vs. 16.2%) and a lesser (P < 0.001) percentage of YG 4 or higher carcasses (1.6 vs. 6.0%) than steers fed the control diet. Marbling scores and the percentage of carcasses grading USDA Choice and Prime were greater in TT than CC steers when fed diets devoid of ZH, but both marbling and quality grades did not differ among leptin genotypes when fed ZH for 21 d (leptin genotype * ZH, P <= 0.03). The amount of HCW gain tended to be less (P = 0.095) for steers of the TT genotype (12.7 kg) than either CC (16.3 kg) or CT (17.0 kg) genotypes. Results indicated that leptin R25C genotype impacted most traits associated with fatness whereas feeding ZH for 21 d affected HCW and ADG positively but impacted feed intake, marbling, and USDA quality grades negatively. PMID- 23942709 TI - Effect of age, weight, and sire on embryo and fetal survival in sheep. AB - The goal was to estimate the heritabilities and genetic variances for embryo and fetal survival (ES) in sheep along with the effect of premating ewe weight, age, and bilateral or unilateral ovulation on ES. The data consisted of 11,369 records on ovulation rate and litter size. Statistical models for ES included year and ovulation rate as fixed effects, premating ewe weight, and age as covariates, and sire of embryo, maternal grandsire (MGS), and permanent maternal environmental effects of the ewe as random effects. The variance components were estimated using REML. In ewes that survived to yr 6, the mean litter size was 1.87, 2.05, 2.01, 2.07, and 1.91 +/- 0.04 in ewes of age 2, 3, 4, 5, and 6 yr, respectively. Litter size was less in ewes of age 2 and 6 yr compared to ewes of age 3, 4, and 5 yr (P < 0.01). Ovulation rate was lower at age 2 yr and increased from age 2 to 6 yr (P < 0.05). Two-year-old ewes had lower ES than 3-yr-old ewes (P < 0.01) and the probability of ES decreased after age 3 yr (P < 0.01). Thus, ES contributes significantly to lower fertility in 2-yr-old ewes. In ewes with high ovulation rates (i.e., 5 corpora lutea, CL), more balanced ovulations (i.e., 2 or 3 CL on each ovary) tended (P = 0.06) to be associated with increased ES. A quadratic relationship was observed between ewe weight and litter size (P < 0.01) and a positive linear relationship between premating ewe weight and ovulation rate (P < 0.01). A quadratic effect of ewe weight on ES was observed, with decreased ES for low and high ewe weights (P < 0.01). The optimal ewe weight for ES increased with ovulation rate, which is consistent with the requirement of greater body reserves for maintaining a larger number of fetuses during gestation. A quadratic relationship between ewe weight and the probability that a ewe is able to maintain a pregnancy was also observed (P < 0.05). Pregnancy loss is due to failure of the embryo or fetus or failure of the dam to maintain the pregnancy. The sire of the embryo only influences the embryo, whereas the MGS influences both the ewe and the embryo. The heritability for the direct additive effect on ES in ewes that lambed was 0.0081 +/- 0.0139, and the heritability for the maternal additive effect was 0.0447 +/- 0.0242. The permanent maternal environmental variance component was significant and explained 8.5% of the phenotypic variance. Thus, genetically, the dam's ability to maintain a pregnancy has 5.5 times the effect on pregnancy loss than the embryo's ability to survive, and this, in turn, was only half the size of the permanent environmental effect. Therefore, selection among dams based on the mean embryonic survival of their embryos will provide an effective way to improve embryonic survival. PMID- 23942710 TI - Mice do not accumulate muscle lipid in response to dietary conjugated linoleic acid. AB - Dietary CLA decreases body fat in several species and in pigs this is accompanied by increased muscle lipid. Our objective was to determine if mice could be used as a model for CLA-induced increased marbling in pigs. We used our model of enhanced CLA response, where mice fed coconut oil (CO) lose more body fat than mice fed soy oil (SO). Mice (21 d old; Imprinting Control Region [ICR]) were fed SO or CO diets for 6 wk followed by 12 d of 0 or 0.5% mixed isomer CLA. Ether extraction determined that thigh muscle lipid content was reduced by both CLA and CO (P = 0.007 and P = 0.006, respectively). Conjugated linoleic acid also caused a reduction (P = 0.016) in carnitine palmitoyltransferase (CPT) enzyme activity, so less fatty acid oxidation appeared to be occurring. Lumbar muscle, which is more similar to the longissimus dorsi tested in pigs, did not differ in lipid content between mice (56 d old; ICR) fed SO or SO+CLA for 14 d. Therefore, CLA fed mice do not appear to be accumulating excess lipid in their muscle. However, CLA addition to CO diets increased (P = 0.007) the mRNA expression of PPAR-gamma in the thigh muscle to the level of SO-fed mice, indicating that intramuscular adipocyte differentiation may be increasing. On the other hand, liver lipid was increased (P < 0.0001) by CO and tended to be increased (P = 0.099) by CLA. Liver CPT activity was decreased (P = 0.018) in SO+CLA-fed mice but not CO+CLA. It appears that mice may accumulate lipid in their livers preferentially over muscle when fed CLA and therefore are not a good model for CLA-induced muscle lipid accumulation. PMID- 23942711 TI - Enteric methane emission, diet digestibility, and nitrogen excretion from beef heifers fed sainfoin or alfalfa. AB - Effects of plant-bound condensed tannin (CT)-containing sainfoin vs. CT-free alfalfa (or low-CT alfalfa-sainfoin mixture), plant stage of maturity, and their interaction on enteric methane (CH4) emissions, diet digestibility, and N excretion were studied, using 8 ruminally cannulated beef heifers in 2 sequential short-term experiments (Exp. 1 and 2). In Exp. 1, first growth legumes were harvested daily and offered fresh to heifers. Heifers were assigned to 100% sainfoin or 80% alfalfa:20% sainfoin (as-fed basis). Responses were measured at early (late vegetative to early bud; stage 2 to 3) and late (early flower; stage 5) stage of maturity. In Exp. 2, the same legumes were harvested from second growth (late bud; stage 4) and offered to heifers as hay; 100% sainfoin or 100% alfalfa. In both experiments, heifers were fed once daily at 1* maintenance. When fed as fresh forage (Exp. 1), sainfoin, compared with the alfalfa-sainfoin blend, had greater digestibility of OM (74.7 vs. 70.9%; P = 0.02), yet tended to have lower CP digestibility (73.2 vs. 77.1%; P = 0.059). There was no difference between fresh legumes for CH4 emissions [25.9 g/kg DMI +/- 4.02 SE; 8.5% of gross energy intake (GEI) +/- 1.26 SE; or 36.8 g/kg digested OM +/- 1.75 SE]. The fresh legumes were more digestible at early, rather than at late, maturity and, consequently, enteric CH4 (27.4 vs. 24.4 g/kg DMI; P < 0.004; 8.9 vs. 8.1% GEI; P < 0.008) was greater at early, rather than at later, growth. When fed as hay (Exp. 2), sainfoin, compared with alfalfa, had greater digestibility of OM (60.5 vs. 50.3%; P = 0.007), lower digestibility of CP (64.2 vs. 68.8%; P = 0.004), yet there was no difference between the legume hays for CH4 emissions (22.4 g/kg DMI +/- 1.29 SD and 7.1% GEI +/- 0.40 SD). However, on the basis of OM digested, CH4 emissions were lower for sainfoin than alfalfa hay (44.3 vs. 59.0 g/kg; P = 0.008). Percentage of total N excretion in urine was less for sainfoin compared with alfalfa, both for fresh legumes in Exp. 1 (74 vs. 78%; P = 0.017) or hay in Exp. 2 (64 vs. 72%; P < 0.001), and increasing maturity lowered urinary N excretion. In conclusion, feeding CT-containing sainfoin partially shifted N excretion from urine to feces, but it had little impact on enteric CH4 emissions from beef cattle fed at maintenance as compared with feeding either 80% alfalfa:20% sainfoin (fresh forages) or 100% alfalfa (hay). Feeding fresh legumes harvested between the late vegetative to early bud stage, compared with harvested at the early flower stage, increased N excreted in urine as well as enteric CH4 emissions from beef cattle fed at maintenance. PMID- 23942712 TI - Moderate decreases in the forage-to-concentrate ratio before feed restriction and increases thereafter independently improve the recovery from a feed restriction insult in beef cattle. AB - The objective of this study was to determine if the forage-to-concentrate ratio (F:C) of diets fed prior to and during (PRE) feed restriction (FR) and diets fed post-FR (POST) affect the recovery for DMI, ruminal fermentation, and short-chain fatty acid (SCFA) absorption following FR. Twenty ovariectomized and ruminally cannulated Angus * Hereford heifers were used in this study and were fed (ad libitum) either a high forage (HF; F:C = 92:8) or a moderate forage (MF; F:C = 60:40) diet for 19 d. Heifers were then exposed to a 5-d FR period where feed was restricted to 25% of ad libitum intake relative to that measured during the previous 5 d. After FR, heifers were provided feed ad libitum with one half of the HF and MF heifers receiving the HF or MF diet during the 3-wk recovery period (REC1, REC2, and REC3). This resulted in 4 treatment combinations separated over time (PRE-POST): HF-HF, HF-MF, MF-HF, and MF-MF. The PRE * POST interaction was not significant for any of the measured variables, and the PRE * POST * period interaction was only significant for the molar proportion of ruminal butyrate. For heifers fed HF PRE, DMI increased from REC1 to REC3 whereas DMI did not differ among periods for heifers fed MF PRE (PRE * period, P = 0.045). The duration that pH < 5.5 (PRE * POST; P = 0.003) was numerically greater during REC1 for heifers fed HF than MF PRE (191 vs. 98 min/d), with duration decreasing from REC1 to REC2 for heifers fed HF PRE. Total ruminal SCFA concentration and absorption rate were not affected by the diet fed PRE (P > 0.05) or period (P > 0.05). For heifers fed MF POST, DMI increased from REC1 to REC3 whereas DMI did not differ among POST periods for heifers fed HF POST (POST * period, P = 0.033). The duration that ruminal pH was <5.5 was greater for heifers fed MF than HF POST (274.9 vs. 14.1 min/d; POST * period, P < 0.001) with MF heifers decreasing duration from REC1 to REC2 whereas duration did not differ among periods for HF. Ruminal SCFA concentration and rate of absorption were not affected (P > 0.05) by diet fed POST. It is concluded that feeding a MF diet prior to and during FR improves the recovery response for DMI. Irrespective of the prefeeding, however, a HF diet is beneficial in the POST-restriction period because it most effectively alleviated ruminal pH reduction and hastened DMI recovery. PMID- 23942713 TI - Endogenous intestinal losses of calcium and true total tract digestibility of calcium in canola meal fed to growing pigs. AB - An experiment was conducted to test the hypothesis that values for apparent total tract digestibility (ATTD) of Ca in pigs are influenced by endogenous Ca lost from the gastrointestinal tract. The objective was to determine the endogenous loss of Ca, the ATTD of Ca, and the true total tract digestibility (TTTD) of Ca in canola meal without and with microbial phytase. The second objective was to determine the balance of Ca in pigs fed diets based on canola meal without or with microbial phytase. Forty-eight growing barrows (initial BW: 16.72 +/- 2.52 kg) were allotted to 8 dietary treatments in a randomized complete block design with 6 pigs per treatment. Diets were based on sucrose, cornstarch, potato protein isolate, corn gluten meal, and canola meal. Diets were formulated to contain 0.08, 0.16, 0.24, or 0.32% Ca from canola meal. All diets were formulated with 0 or 1,500 units/kg of microbial phytase and contained 0.32% digestible P. Feces and urine samples were collected from d 6 to 11. Total endogenous losses of Ca were determined using the regression procedure. Results indicated that ATTD of Ca and Ca retention increased (P < 0.05) if dietary Ca increased and also increased (P < 0.01) when phytase was added to the diets. The estimated total endogenous loss of Ca was 0.160 and 0.189 g/kg DMI for canola meal without and with microbial phytase, respectively, and these values were not different. The TTTD of Ca increased (P < 0.01) if phytase was used but was not affected by the level of dietary Ca. As dietary Ca increased, the amount of Ca absorbed and retained increased (P < 0.01) to a greater extent if phytase was used than when no phytase was included in the diet (interaction, P < 0.05). Fecal P excretion increased (P < 0.01) as dietary Ca increased but was reduced (P < 0.01) by the use of phytase. The ATTD of P decreased (P < 0.01) with increasing dietary Ca to a lesser extent if phytase was used than when no phytase was used (interaction, P < 0.01). In conclusion, endogenous Ca is lost from the gastrointestinal tract of growing pigs, and values for TTTD of Ca are, therefore, different from values for ATTD of Ca. Values for ATTD of Ca are influenced by level of dietary Ca, but that is not the case for values for TTTD of Ca. The ATTD of P decreases as dietary Ca increases, but microbial phytase increases Ca and P digestibility and Ca retention in pigs fed diets based on canola meal whereas it does not influence endogenous losses of Ca. PMID- 23942714 TI - Genetic parameters for male fertility and its relationship to skatole and androstenone in Danish Landrace boars. AB - Concerns have been raised regarding selection against the boar taint compounds, androstenone and skatole, due to potential unfavorable genetic correlations with important male fertility traits (i.e., selection of boars with low levels of these boar taint compounds might also reduce male fertility). Hence, the objective of this investigation was to study the genetic association between direct measures of male fertility and the boar taint compounds in Danish Landrace pigs. Concentrations of skatole and androstenone in the back fat were available for approximately 6,000 and 1,000 Landrace boars, respectively. The litter size traits, such as total number born, live piglets at d 5, and piglet survival until d 5 on relatives of the slaughter boars, were extracted from the Danish Landrace breeding program, yielding 35,715 records. Semen volume, sperm concentration, subjective sperm quality score, and total number of sperm were available from 95,267 ejaculates. These ejaculates were collected between 2005 and 2012 and originated from 3,145 Landrace boars from 12 AI stations in Denmark. The traits were analyzed using single and multitrait animal models including univariate random regression models. Skatole and androstenone concentrations were moderate to highly heritable (i.e., 0.33 and 0.59, respectively). The genetic correlation between the two compounds was moderate (0.40). Genetic variance of sperm production per ejaculate increased during the productive life of the boar, resulting in heritability estimates increasing from 0.18 to 0.31. Genetic correlations between sperm production per ejaculate at different ages were high and generally larger than 0.8, indicating that later genetic merit can be predicted from records at an early age. The heritability (based on service-sire genetic component) of both total number of piglets born and survival to d 5 were 0.02, and the correlation between these effects and the additive genetic effect on boar taint ranged from 0.05 to -0.40 (none of these correlations were significantly different from zero). Most importantly, the genetic correlations between skatole and androstenone and the different semen traits tended to be more favorable with increase in age of the boars. In conclusion, these data suggest that concentrations of skatole and androstenone can be reduced through genetic selection without negatively affecting important male fertility traits in Danish Landrace pigs. PMID- 23942715 TI - Effect of mannan oligosaccharides (Bio-Mos) and outdoor access housing on pig growth, feed efficiency and carcass composition. AB - The present study was conducted as a 3 * 2 factorial experiment in 7 pen replications conducted using progeny (n = 360) of successive farrowings of 1 Landrace breeding female population. Grower-finisher dietary treatments included the addition of Bio-Mos (BM; at 0.2, 0.1 and 0.05% inclusion rates for phase 1 (30.2 to 63.5 kg), 2 (63.5 to 90.5 kg), and 3 (90.5 to 113.6 kg), respectively), the inclusion of a subtherapeutic antibiotic (AB; tetracycline; at 0.0055% inclusion rate in all dietary phases) and a no additive control (CON) diet. Housing systems were a conventional, indoor (IN) facility providing 1.0 m(2)/pig solid concrete and 0.3 m(2)/pig slatted floor with 12 pigs per pen and an outdoor access (OUT) system providing 1.1 m(2)/pig indoor, bedded concrete, and 1.9 m(2)/pig outdoor solid concrete with 6 pigs per pen. Housing systems analyses acknowledge confounding of space with number of pigs per pen. Daily growth rate (ADG), feed intake (ADFI), feed conversion (G:F), ultrasonic carcass composition, blood hematocrit (1 group), and observed illnesses were measured. Dietary * housing treatment interactions were not observed. Pigs reared in OUT had greater ADFI (0.1 kg/d; P = 0.01) resulting in greater ADG (0.04 kg/d; P < 0.0005) and required fewer days to reach a standard 113.6 kg endpoint (4.0 d; P < 0.0005) but had reduced (poorer) G:F (0.01 kg gain/kg feed; P = 0.05) when compared to IN. Pigs fed BM and CON diets had greater ADG (0.02 kg/d; P < 0.05) and required 3 fewer days to 113.6 kg (P < 0.05) when compared with pigs fed AB. Carcass composition measures were not different across dietary or housing treatments. Hematocrit was 2 units greater (P < 0.05) at the end of the trial (d 84) for OUT housed pigs but not different at the start, d 28, or d 56 of the trial. In the present study, the addition of a subtherapeutic antibiotic in swine finisher diets did not improve pig growth, efficiency, or health whereas the addition of BM did not increase growth performance compared to the CON diet in both housing systems, a finding suggesting the potential for improved gut health and or improved appetite in pigs not fed an antibiotic. Whereas pigs reared OUT had greater growth rate and a more desirable hematocrit level, the observed differences may be attributed to stocking density, number of pigs per pen, or outdoor access, effects that are not able to be fully described under the experimental design. PMID- 23942717 TI - Feed restriction reduces short-chain fatty acid absorption across the reticulorumen of beef cattle independent of diet. AB - The objective of this study was to evaluate the effects of the forage-to concentrate ratio (F:C) of diets fed before and during short-term feed restriction (FR) on rumen fermentation, absorptive capacity of the reticulorumen, and apparent total tract digestibility. Twenty ovariectomized and ruminally cannulated Angus * Hereford heifers were blocked by BW and individually penned in box stalls (9 m(2)), having free access to water throughout the study. Heifers were randomly assigned to 1 of 2 dietary treatments, receiving either a high forage diet (HF; F:C of 92:8) or a moderate forage diet (MF; F:C of 60:40). Diets were fed ad libitum for 14 d before 5 d of baseline measurements (BASE) followed by 5 d of FR where heifers were restricted to 25% of ad libitum DMI relative to BASE. Dry matter intake was measured daily and ruminal pH was recorded every 2 min throughout the study. Ruminal fluid and blood samples were collected on d 3 of BASE and FR whereas short-chain fatty acid (SCFA) absorption was assessed in vivo using the isolated washed reticulorumen technique on d 5 of BASE and FR. Indigestible NDF was used as a marker to estimate apparent total tract digestibility. Diet * period interactions (P = 0.030 and 0.025) were detected for DMI and ruminal SCFA concentration, respectively. The interaction was the result of greater DMI and numerically greater SCFA concentration for MF than HF during BASE, with a reduction observed for both during FR, although treatment effects were no longer present. Period effects (BASE vs. FR) but not treatment effects (P > 0.05) were detected for mean ruminal pH (P < 0.001) and the total SCFA absorption rate (mmol/h; P = 0.038). During BASE, mean pH was reduced (6.4 vs. 6.9) and the SCFA absorption rate was greater relative to FR (674.5 vs. 554.8 mmol/h). Diet (P < 0.001) and period (P < 0.001) effects were detected for DM and OM digestibility with greater digestibility occurring for heifers fed MF than HF (70.5 vs. 63.3% for DM and 73.0 vs. 66% for OM) and greater digestibility during FR than BASE (69.5 vs. 64.3% for DM and 71.7 vs. 67.2% for OM). During FR, NDF digestibility was also greater than during BASE (P < 0.001; 62.4 vs. 55.8%). The effect of FR on serum NEFA differed by diet (diet * period, P < 0.001) with NEFA being greater for heifers fed HF than MF during FR (474.4 vs. 377.7 MUEq/mL, respectively) with no differences observed between HF and MF during BASE. It can be concluded that severe short-term FR had a negative impact on ruminal SCFA absorption and energy balance and that altering the F:C of the diet does not mitigate these effects. PMID- 23942716 TI - Invited review: the preterm pig as a model in pediatric gastroenterology. AB - At birth, the newborn mammal undergoes a transition from a sterile uterine environment with a constant nutrient supply, to a microbe-rich environment with intermittent oral intake of complex milk nutrients via the gastrointestinal tract (GIT). These functional challenges partly explain the relatively high morbidity and mortality of neonates. Preterm birth interrupts prenatal organ maturation, including that of the GIT, and increases disease risk. Exemplary is necrotizing enterocolitis (NEC), which is associated closely with GIT immaturity, enteral feeding, and bacterial colonization. Infants with NEC may require resection of the necrotic parts of the intestine, leading to short bowel syndrome (SBS), characterized by reduced digestive capacity, fluid loss, and dependency on parenteral nutrition. This review presents the preterm pig as a translational model in pediatric gastroenterology that has provided new insights into important pediatric diseases such as NEC and SBS. We describe protocols for delivery, care, and handling of preterm pigs, and show how the immature GIT responds to delivery method and different nutritional and therapeutic interventions. The preterm pig may also provide a sensitive model for postnatal adaptation of weak term piglets showing high mortality. Attributes of the preterm pig model include close similarities with preterm infants in body size, organ development, and many clinical features, thereby providing a translational advantage relative to rodent models of GIT immaturity. On the other hand, the need for a sow surgical facility, a piglet intensive care unit, and clinically trained personnel may limit widespread use of preterm pigs. Studies on organ adaptation in preterm pigs help to identify the physiological basis of neonatal survival for hypersensitive newborns and aid in defining the optimal diet and rearing conditions during the critical neonatal period. PMID- 23942718 TI - Survey of transportation procedures, management practices, and health assessment related to quality, quantity, and value for market beef and dairy cows and bulls. AB - This survey consisted of data collected from 23 beef harvest plants to document transportation procedures, management practices, and health assessments of market beef and dairy cows and bulls (about n ? 7,000 animals). Gooseneck/bumper-pulled trailers were used more often to transport dairy cattle than beef cattle to market whereas tractor-trailers were used more often to transport beef cattle than dairy cattle. All loads (n = 103) met the American Meat Institute Foundation guidelines for spacing. Loads where more than 3% of the cattle slipped during unloading were observed in 27.3% of beef loads and 29.0% of the dairy loads. Beef loads had numerically greater usage of electrical prods (32.4%) versus dairy loads (15.4%) during unloading and were more likely to have a variety of driving aids used more aggressively on them. Fewer cattle had horns, brands, and mud/manure contamination on hides than in the previous survey in 1999. The predominant hide color for beef cows was black (44.2%) whereas the predominant color for dairy cows was the Holstein pattern (92.9%). Fewer cattle displayed evidence of bovine ocular neoplasia (2.9%) than in previous surveys in 1994 (8.5%) and 1999 (4.3%). Knots on live cattle were found less in the round (0.5%) and more in the shoulder region (4.6%) than in 1999 (1.4% and 0.4%, respectively). Dairy cows were more frequently lame in 2007 (48.7%) than 1999 (39.2%) whereas beef cows had numerically less lameness (16.3% vs. 26.6%, respectively). Most beef cows (62.3%) and dairy cows (68.9%) received midpoint body condition scores (3, 4, and 5 for beef; 2 and 3 for dairy). Beef cows had higher numerical percentages of no defects present (72.0%) versus dairy cows (63.0%) when evaluated for a variety of reproductive, health, or management conditions. Continued improvements in several key factors related to transportation, management, and health were observed in this survey, which could result in increased value in market beef and dairy cows and bulls. PMID- 23942719 TI - Selection criteria for sexual precocity in Guzerat bulls raised under grazing conditions. AB - The objectives of the present study were to obtain posterior densities of genetic parameters for scrotal circumference (SC), testicular volume (TV), BW, and age at puberty, to determine their correlations, and to evaluate the inclusion of these traits as selection criteria for sexual precocity in Guzerat bulls. Two-trait analyses were performed including records of SC, TV, and BW at 365, 450, 550, 650, 730, 850, and 970 d of age with age at puberty of 1,783 Guzerat bulls born between 2000 and 2011. The (co)variance components were estimated using Bayesian methods. Posterior means of heritability ranged from 0.45 to 0.60 for SC, from 0.35 to 0.55 for TV, and from 0.39 to 0.60 for BW. Posterior means of heritabilities for age at puberty using the two-trait analysis with SC ranged from 0.46 to 0.55, those with TV ranged from 0.49 to 0.57, and those with BW ranged from 0.49 to 0.62. The genetic correlation between age at puberty and SC ranged from -0.52 to -0.85, those between age at puberty and TV ranged from -0.33 to -0.66, and those between age at puberty and BW ranged from -0.38 to -0.72. In general, the same trend was observed for the phenotypic correlation between age at puberty and SC, TV, and BW. The selection of the top 10% of young males for SC, TV, or BW caused a decrease in age at puberty, with the most favorable expected correlated response in age at puberty at 650 d of age (-119.95 +/- 15.1 d per generation), 730 d of age (-82.20 +/- 20.9), and 850 d of age (-93.68 +/- 21.5), respectively. In conclusion, SC, TV, and BW can be used as selection criteria to improve early sexual development in Guzerat bulls, and SC measured at 650 d of age is the most advantageous indicative selection criterion for improvement of age at puberty in Guzerat young bulls. PMID- 23942721 TI - Synthesis of novel pyrazole-based heterocycles via a copper(II)-catalysed domino annulation. AB - Pyrazole-based beta-aminonitriles and beta-amino-carbaldehydes as bifunctional building blocks are introduced in a facile copper(II)-catalysed one-pot domino generation of multiple N-containing heterobi- and tricycles. This streamlined synthetic approach permits easy access to novel pyrazole-fused imidazo- and pyrimido[1,2-c]pyrimidinones and to pyrazolo[3,4-d]pyrimidinone species with isolated yields up to 90%. The present study also reveals a unique amine isocyanate coupling promotion via copper(II)-based catalytic activation. PMID- 23942720 TI - The role of the aryl hydrocarbon receptor in normal and malignant B cell development. AB - The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically studied for its role in environmental chemical-mediated toxicity and carcinogenicity. In the last 5 years, however, it has become clear that the AhR, presumably activated by endogenous ligand(s), plays an important role in immune system development and function. Other articles in this edition summarize AhR function during T cell and antigen-presenting cell development and function, including the effects of AhR activation on dendritic cell function, T cell skewing, inflammation, and autoimmune disease. Here, we focus on AhR expression and function during B cell differentiation. Studies exploiting immunosuppressive environmental chemicals to probe the role of the AhR in humoral immunity are also reviewed to illustrate the multiple levels at which a "nominally activated" AhR could control B cell differentiation from the hematopoietic stem cell through the pro-B cell, mature B cell, and antibody-secreting plasma cell stages. Finally, a putative role for the AhR in the basic biology of B cell malignancies, many of which have been associated with exposure to environmental AhR ligands, is discussed. PMID- 23942723 TI - [HPV in urology. Basic principles and controversies]. AB - The information presented in this article summarizes some of the basic knowledge on human papillomavirus (HPV) infections and the consequences particularly in men. According to current understanding most HPV infections are latent and transient in immunocompetent patients but some will persist. Predominantly due to the different oncogenic potential of various HPV types, persisting infections can give rise to benign or malignant neoplasms in both genders. Current controversies, such as the need for HPV testing in men or routine male HPV vaccination will be discussed. High-risk male populations, e.g. men who have sex with men (MSM) and HIV positive men, merit special attention from urologists in the future. The groups of HIV positive MSMs are at an extremely high risk of developing anal cancer that currently even exceeds the highest reported incidence of cervical cancer. PMID- 23942722 TI - Effects of pH on the production of phosphate and pyrophosphate by matrix vesicles' biomimetics. AB - During endochondral bone formation, chondrocytes and osteoblasts synthesize and mineralize the extracellular matrix through a process that initiates within matrix vesicles (MVs) and ends with bone mineral propagation onto the collagenous scaffold. pH gradients have been identified in the growth plate of long bones, but how pH changes affect the initiation of skeletal mineralization is not known. Tissue-nonspecific alkaline phosphatase (TNAP) degrades extracellular inorganic pyrophosphate (PPi), a mineralization inhibitor produced by ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1), while contributing Pi from ATP to initiate mineralization. TNAP and NPP1, alone or combined, were reconstituted in dipalmitoylphosphatidylcholine liposomes to mimic the microenvironment of MVs. The hydrolysis of ATP, ADP, AMP, and PPi was studied at pH 8 and 9 and compared to the data determined at pH 7.4. While catalytic efficiencies in general were higher at alkaline pH, PPi hydrolysis was maximal at pH 8 and indicated a preferential utilization of PPi over ATP at pH 8 versus 9. In addition, all proteoliposomes induced mineral formation when incubated in a synthetic cartilage lymph containing 1 mM ATP as substrate and amorphous calcium phosphate or calcium phosphate-phosphatidylserine complexes as nucleators. Propagation of mineralization was significantly more efficient at pH 7.5 and 8 than at pH 9. Since a slight pH elevation from 7.4 to 8 promotes considerably more hydrolysis of ATP, ADP, and AMP primarily by TNAP, this small pH change facilitates mineralization, especially via upregulated PPi hydrolysis by both NPP1 and TNAP, further elevating the Pi/PPi ratio, thus enhancing bone mineralization. PMID- 23942724 TI - [Use of hydrogel as spacer in Denovier's space: optimization of IMRT radiotherapy of localized prostate cancer]. AB - BACKGROUND: Radiotherapy is an appropriate primary therapy for localized prostate cancer in accordance with urological guidelines. Especially in tumors of higher grade malignancy, dose escalation up to 80,0 Gy seems to be an advantage; however rectum toxicity can be a problem. By injecting a synthetic hydrogel (SpaceOAR(r)) as a spacer between the prostate and rectum, rectal toxicity can be reduced. We report on our experiences with 47 patients and an average follow-up of 241 days. METHODS: From February 2012 to November 2012, 47 patients were included in the study series. Before external radiotherapy the hydrogel was injected between prostate and rectum in the so-called Denovier space. This interdisciplinary procedure was carried out with the patient under general anesthesia using transrectal ultrasound guidance and video documentation. The patients were hospitalized for 1 day. The exact position of the gel was assessed by means of magnetic resonance imaging (MRI). Radiotherapy was initiated 7-14 days after gel application in a dose escalation manner by means of intensity modulated radiation therapy (IMRT) up to a dose of 80,0 Gy. Average follow-up was 241 (100-386, SD 91) days. RESULTS: No early side effects specific for the application were observed. The achieved distance between rectum and the mid-plane of the prostate gland was on average 13.8 (6-24, SD=3.8) mm. Calculated V70 (rectal volume irradiated with 70.0 Gy or more) could be reduced to an average of 1.5 (0-8, SD=1.7) %. One patient showed an asymptomatic lesion of the rectal mucosa after irradiation with 38,0 Gy. This lesion was closely controlled and gel penetration was found. As a result radiotherapy was discontinued. Without further treatment the necrosis had completely healed 3 months later. CONCLUSIONS: Hydrogel application between prostate and rectum allows dose escalation up to 80,0 Gy and seems to reduce morbidity in patients with localized prostate cancer receiving radiotherapy. However, before final judgement of the new technique further studies must follow. PMID- 23942725 TI - Fluorescent colour modulation in Zn(II)-based metallo-supramolecular polymer films by electronic-state control of the ligand. AB - A series of Zn(II)-based metallo-supramolecular polymers were prepared by 1 : 1 complexation of Zn(ClO4)2 and bis(terpyridine)s with electron-donating (alkoxy) or electron-withdrawing (cyano) groups at the 6-position of the peripheral pyridine moiety. The Zn(II)-based polymers displayed relatively high quantum yields (PhiPL = 0.68-0.76) in solution at room temperature. More importantly, they showed different luminescent colours of blue, cyan, and green in the film state, because of the large Stokes shift caused by the substituent effect of the ligand. PMID- 23942726 TI - Managing voids of Si anodes in lithium ion batteries. AB - The implementation of silicon (Si) in practical lithium ion battery electrodes has been hindered due to its large volume change and consequent structural and interfacial instabilities. Coating nanostructured Si with a second phase (e.g., carbon (C)) represents a very promising strategy for dealing with these critical issues facing Si-based electrodes. In this review article, we will outline recent advances in coating Si with engineered C matrices. By exemplifying hollow core shell, core-hollow shell, and core-shell structured Si-C hybrid nanomaterials, we aim to highlight the importance of managing voids in designing such Si-C hybrid electrodes, and provide some scientific insights into the development of advanced Si-based anodes for next-generation lithium ion batteries. PMID- 23942727 TI - Extracorporeal membrane oxygenation in the acute treatment of cardiovascular collapse immediately post-partum. AB - We describe the use of extracorporeal membrane oxygenation (ECMO) in a 30-year old woman at 37 weeks' gestation, following cardiac arrest from pulmonary embolism immediately post-partum from an emergent Caesarean section. In this case, ECMO was initiated though modified techniques with only the equipment available in a delivery room as a last resort to save a new mother after a significant downtime of 83 min. The patient received tissue plasminogen activator during the resuscitation resulting in significant blood loss. However, the patient was stabilized on ECMO and after 5 weeks in the intensive care unit achieved complete physical and neurologic recovery. To our knowledge, this is the first reported case where ECMO has been used in a resuscitation from massive pulmonary embolism immediately post-partum, after thombolytics were administered. Here, we discuss our strategies for emergent cannulation in a suboptimal environment, management of profound bleeding and oxygenation strategies in this hostile setting. Given the potential for success and the significant life-years gained, aggressive measures, such as ECMO, should be considered in such extreme life-threatening cases. PMID- 23942728 TI - Accuracy in detecting knee effusion with clinical examination and the effect of effusion, the patient's body mass index, and the clinician's experience. AB - The purpose of this study was to determine the accuracy of detecting knee effusion with clinical examination and to evaluate whether the amount of effusion, patient obesity, and the clinicians' experience affect the clinicians' decisions in patients with knee osteoarthritis. Patients presenting with knee pain were examined by two residents with different levels of experience and underwent ultrasonographic examination, including measurement of effusion in the medial, mid, and lateral aspects of the suprapatellar bursa. One hundred seventy two knees of 86 patients were examined. Of the knees investigated, 127 (73.8 %) had effusion. The consistency between ultrasonographic and resident examination were weak (kappa = 0.193, p = 0.007 and kappa = 0.349, p < 0.001), although the more experienced senior resident had a stronger agreement. The overall inter rater agreement between the two residents was low (kappa = 0.254). The senior resident had a significantly higher accuracy ratio (p = 0.036). In the knees without effusion, the two examiners had no agreement (kappa = -0.028, p = 0.856); however, the ratios of the true decisions were similar (p = 1.0). The accuracy of the less experienced resident's decisions was affected by effusion depth (p = 0.005). Clinicians' decisions and their accuracy in detecting knee effusion during clinical examination were different, especially in the absence of effusion. The consistency between ultrasonography and residents was low. The accuracy of clinical examination was affected by effusion depth and experience, but not by patient obesity. PMID- 23942729 TI - What the phlebologist should know about local anesthetics. AB - An increasing number of phlebological interventions are performed under local and tumescent anesthesia. Although the modern local anesthetic agents are generally perceived as being effective and safe drugs, the administration of these drugs may be associated with a number of adverse events. It is therefore mandatory that everyone who uses these compounds has insight into the pharmacological actions of these drugs and is capable of recognizing and adequately treating potential adverse events. The present narrative review summarizes the current knowledge on mechanisms of action of the most important local anesthetic drugs and reviews the potential adverse effects as well as their treatment. PMID- 23942730 TI - Why spin contamination is a major problem in the calculation of spin-spin coupling in triplet biradicals. AB - In organic triplet biradicals, zero field splitting is dominated by the spin dipolar interaction. While it has been observed before that spin-unrestricted density functional calculations give huge errors for systems with small D values, a consistent explanation was still missing. Using model systems, this work demonstrates how spin contamination creates unphysical one-center terms in the two-particle density matrix that spoil the calculated results. PMID- 23942732 TI - Cobalt-doped ZnO nanocrystals: quantum confinement and surface effects from ab initio methods. AB - Cobalt-doped ZnO nanocrystals were studied through ab initio methods based on the Density Functional Theory. Both quantum confinement and surface effects were explicitly taken into account. When only quantum confinement effects are considered, Co atoms interact through a superexchange mechanism, stabilizing an antiferromagnetic ground state. Usually, this is the case for high quality nanoparticles with perfect surface saturation. When the surfaces were considered, a strong hybridization between the Co atoms and surfaces was observed, strongly changing their electronic and magnetic properties. Our results indicated that the surfaces might qualitatively change the properties of impurities in semiconductor nanocrystals. PMID- 23942731 TI - Investigations on beta1,4-galactosyltransferase I using 6-sulfo-GlcNAc as an acceptor sugar substrate. AB - 6-sulfate modified N-acetylglucosamine (6-sulfo-GlcNAc) is often found as part of many biologically important carbohydrate epitopes such as 6-sulfo-Le(X). In these epitopes, the 6-sulfo-GlcNAc moiety is extended by a galactose sugar in a beta1-4 linkage. The beta4GalT1 enzyme transfers galactose (Gal) from UDP-Gal to N acetylglucosamine (GlcNAc) in the presence of manganese. Here we report that the beta4GalT1 enzyme transfers Gal to the 6-sulfo-GlcNAc and 4-methylumbelliferyl-6 sulfo-N-acetyl-beta-D-glucosaminide (6-sulfo-betaGlcNAc-MU) acceptor substrates, although with very low efficiency. To understand the effect that the 6-sulfate group on the GlcNAc acceptor has on the catalytic activity of the beta4GalT1 molecule, we have determined the crystal structure of the catalytic domain of bovine beta4GalT1 mutant enzyme M344H-beta4GalT1 complex with the 6-sulfo-GlcNAc molecule. In the crystal structure, the 6-sulfo-GlcNAc is bound to the protein in a way that is similar to the GlcNAc molecule. However, the 6-sulfate group engages in additional interactions with the hydrophobic region, residues 276-285, of the protein molecule, and this group is found wedged between the aromatic side chains of Phe-280 and Trp314 residues. Since the side chain of the Trp314 residue undergoes conformational changes during the catalytic cycle of the enzyme, molecular interaction between Trp314 and the 6-sulfate group might hinder this conformational change. Therefore, the lack of a favorable binding environment, together with hindrance to the conformational changes, might be responsible for the poor catalytic activity. PMID- 23942733 TI - Efficacy and safety evaluation of intensive statin therapy in older patients with coronary heart disease: a systematic review and meta-analysis. AB - PURPOSE: To reveal and evaluate the efficacy and safety of intensive statin therapy in older patients (age >= 65 years) with coronary heart disease (CHD). METHODS: Electronic databases were searched for randomized controlled trials (RCTs) that involved intensive statin therapy use in older patients with CHD. Data was extracted and used to calculate risk ratios (RR) by software Revman 5.1. RESULTS: Five RCTs and 11,132 patients were included in. Compared with non intensive statin therapy, intensive statin therapy had significant effect on reducing low density lipoprotein cholesterol (LDL-C) levels (55.4 %) and total cholesterol (TC) and triglyceride (Tg). Although the results showed that intensive statin therapy had no superior effect on reduction of mortality (both all-cause mortality [RR = 0.97, p = 0.65] and cardiac death [RR = 0.95, p = 0.57]) and cardiac arrest (RR = 1.09, p = 0.81), it possessed significant effects on prevention of nonfatal myocardial infarction (MI) (RR = 0.78, p = 0.008), stroke (RR = 0.72, p = 0.02) and coronary revascularization (RR = 0.69, p = 0.007). In terms of side effects, intensive statin therapy was associated with small absolute increase in incidence of drug discontinuation, due to adverse events (3.9 %) and liver enzymes abnormalities (1.7 %). And the occurrence rates of myopathy, rhabdomyolysis and creatine kinase (CK) elevation were very low. CONCLUSIONS: This results show that intensive statin therapy has excellent effects on reduction of serum lipid level including LDL-C, TC, Tg, and also on prevention of nonfatal MI, stroke and coronary revascularization with small absolute increased risk of side effects. Our analysis supports the use of intensive statin therapy in patients >= 65 years old with CHD. PMID- 23942735 TI - [Adults with congenital heart disease: treatment and medical problems]. AB - By improvement of the medical care, children with congenital heart disease survive in much greater numbers: the figure of ACHD-patients in Germany is estimated up to 203,000 to 301,000. The need for a specialized care of these patients is accepted by the scientific societies, who introduced a certification for doctors and centers and created guidelines. The medical problems include imaging, treatment of arrhythmia, congestive heart failure and cyanosis, prophylaxis of infectious endocarditis, exercise and pregnancy. For the most frequent defects, indication for treatment and postoperative care is summarized. PMID- 23942736 TI - [Extracardial influences on the heart and on heart failure]. PMID- 23942737 TI - Bayesian advice for gaydar-based picking up: commentary on Lyons, Lynch, Brewer, and Bruno (2013). PMID- 23942734 TI - [Assessment of systolic function in patients with poor echogenicity: echocardiographic methods]. AB - The visual echocardiographic evaluation of left ventricular (LV) systolic function can be cumbersome, especially in patients with poor image quality. This review describes several alternative echocardiographic methods to determine LV systolic function: endocardial border delineation by contrast agents, mitral annular plane systolic excursion, mitral annular velocity derived from tissue Doppler, myocardial performance index, mitral regurgitation derived LV dP/dtMax and estimation of cardiac output by Doppler echocardiography. The review introduces the respective methods along with the presentation of suitable measurements, clinical implications and methodological limitations. PMID- 23942740 TI - [Abstracts at congresses of the German Society of Urology. Trends and quality]. AB - BACKGROUND: The congress of the German Society of Urology is the third biggest urology congress worldwide and reflects the scientific landscape of urology in Germany. In the congress abstracts, detailed data regarding study design, current trends in urologic research and the cooperation of authors are lacking. We wanted to identify factors contributing to the likelihood of an abstract being followed by a publication in a peer-reviewed journal. MATERIAL AND METHODS: The two congresses of the years 2002 and 2009 were exemplarily analyzed. Various aspects regarding study design and cooperations were retrieved from the abstracts and trends were determined. Subsequent publications in peer-reviewed journals were searched for in MEDLINE and potential factors influencing publication success were identified. Significance was tested for using the chi (2) and Mann-Whitney-U statistical tests. RESULTS: A total of 732 abstracts (2002: 352, 2009: 380) were analyzed, one third of which contained prospective, retrospective or preclinical/experimental studies. Internal (28.7 %) and national (27.6 %) cooperations were most frequent. Significant trends towards more retrospective studies (p=0.008) and national cooperations (p=0.019) were found. Of the abstracts 49.2 % (2002) and 56.3% (2009) were followed by publication in peer reviewed journals (median 15.1 months) with a significantly higher mean impact factor in 2009 (3.4 vs. 2.1, respectively p>0.0001). Therapeutic studies and those including statistics or national cooperations were significantly more likely to be published. CONCLUSION: In the future urologic research should focus on prospective studies. Many abstracts are not followed by a publication in a peer-reviewed journal. This is especially true for abstracts containing no statistics. As national collaborations are correlated with successful publication, an early national networking of young researching urologists should be promoted. PMID- 23942738 TI - [Surgery of inferior vena cava-associated urological tumor lesions]. AB - BACKGROUND: Tumor lesions of the inferior vena cava are extremely challenging with regard to adequate therapeutic management also in advanced malignant urological tumor lesions which can be caused by malignant adhesion, impression and tumor infiltration from the surrounding tissue. This can be the case with metastases from a seminoma or testicular carcinoma (differential diagnosis: primary vena cava leiomyosarcoma), tumor-associated growth into and within the inferior vena cava originating from renal cell carcinoma or carcinoma of the pararenal gland. The aim of this overview was to summarize current clinical and operative experiences in the treatment of inferior vena cava-associated urological tumor lesions, perioperative management, individual-specific and finding-adapted surgical technique and possible outcome, including prognostic considerations from clinical daily practice and representative data found in the literature. BASIC STATEMENTS: The primary aim of the surgical approach is to achieve R0 resection with reconstruction of the inferior vena cava lumen providing a reasonable risk-benefit ratio, which comprises i) complete resection and substitution of the inferior vena cava by a prosthesis along the previous extent of tumor growth, ii) partial resection of the vena cava wall with subsequent patch-plasty or tangential resection with primary suture or iii) removal of the vena cava thrombus after cavotomy. Particular attention should be paid to tumor thrombi reaching the right atrium which need to be extracted after sternotomy and atriotomy using an extracorporeal circulation (cardiac surgeon). For surgical planning, subdivision of the inferior vena cava into three segments, infracardiac, infrahepatic and infrarenal third, has been proven and tested. CONCLUSIONS: The current development status and advances in surgical approaches as well as advances in medical technology allow the successful approach to such advanced stage urological tumor manifestations. A deciding factor is the abdominal and cardiovascular surgical expertise of each surgeon after formation of a team of surgical specialists (including urologists) and only then prognostic advantages can be achieved. PMID- 23942741 TI - [Novel preclinical models and biomarkers for prostate cancer]. AB - The ultimate goal of a personalized approach to prostate cancer patient management relies on two prerequisites: the development of preclinical but clinically relevant model systems and robust prognostic and predictive biomarkers. The past several years have shown significant progress towards these two prerequisites which will be highlighted in this review using some notable examples. PMID- 23942742 TI - [Urology in the concept of comprehensive cancer centers]. AB - BACKGROUND: Urologic cancers comprise one quarter of all newly diagnosed cancers per year in Germany. In addition to the increasing incidence treatment of solid and hematological tumors has become more differentiated, complex and potentially more effective as well as more expensive. Following the example of the USA multidisciplinary translational comprehensive cancer centers (CCCs) have been established in Germany. The financial support from the government and nonprofit organizations, such as the German Cancer Aid aims to ensure and to optimize treatment of tumor patients now and in the future. Coupled with this development new funding opportunities for translational research are opening up for the participating clinical and scientific partners. DISCUSSION: Just as attractive and coherent integration of urology into the structures of a CCC where available appears to be, just as controversial is the professional modus operandi. Using the example of the National Center for Tumor Diseases in Heidelberg (NCT), the current manuscript discusses the risks and opportunities of this new centralized form of oncological care in urology. Detailed knowledge of organizational structures, clinical operations and funding is a prerequisite for any partner of a CCC to succeed in such a highly demanding environment as a specialty instead of becoming mere surgical proceduralists. PMID- 23942743 TI - Persistent multifocal atrial tachycardia in infant with encephalocraniocutaneous lipomatosis: a case report. AB - Encephalocraniocutaneous lipomatosis (ECCL, Haberland syndrome, Fishman syndrome) is a very rare congenital disorder, involving skin, eye, bone and central nervous system malformations. In this paper we present a case of a 2-month-old boy with encephalocraniocutaneous lipomatosis diagnosed on the basis of characteristic clinical manifestations and neuroimaging findings. Neurologically, the child presented only with mild physical and mental retardation. 24-h Holter monitoring revealed asymptomatic multifocal atrial tachycardia. Initial therapy with digoxin and metoprolol was not effective. Introduction of propafenone resulted in supression of supraventricular arrhythmia. During the 3- years follow-up, sinus rhythm persisted, but neurological status deteriorated. CONCLUSION: Supraventricular arrhythmia may be associated with Haberland syndrome. It seems that propafenone is most effective in this condition. PMID- 23942744 TI - Heated humidified high-flow nasal cannula versus low-flow nasal cannula as weaning mode from nasal CPAP in infants <=28 weeks of gestation. AB - Despite the paucity of evidence, the practice of weaning nasal continuous positive airway pressure (NCPAP) is widespread. However, the most clinically effective non-invasive ventilatory support strategy remains to be determined. We compared the outcome of very premature infants with respiratory distress syndrome treated with a combination of NCPAP and heated humidified high-flow nasal cannula (HHFNC) versus NCPAP and low-flow nasal cannula (LFNC). Between 2004 and 2008, patients <=28 weeks of gestation and <1,250 g of birth weight were treated with NCPAP + HHFNC or NCPAP + LFNC. Their respiratory and non-respiratory outcome including cost-effectiveness was compared after matching for antenatal steroid doses, mode of delivery, birth plurality, gestational age, birth weight, gender, surfactant doses, length of mechanical ventilation and clinical risk index for babies-II (CRIB-II) score. Thirty-nine infants received HHFNC + NCPAP, and 40 received NCPAP + LFNC. Median gestational age and birth weight were 27 weeks and 930 g and 27 weeks and 980 g, respectively. The total number of NCPAP days was significantly reduced by 50 % in the HHFNC group. Thirteen percent of the patients on NCPAP suffered from nasal bridge lesions compared to none on HHFNC. Respiratory and non-respiratory outcome was not significantly different otherwise. Combination of NCPAP and HHFNC reduced costs by 33 %. CONCLUSIONS: HHFNC shortens NCPAP time without increasing overall length of non-invasive respiratory support in very preterm infants. Unlike NCPAP, HHFNC does not seem to increase the risk of nasal trauma and appears to improve cost-effectiveness whilst producing otherwise equal respiratory and non-respiratory outcomes. PMID- 23942745 TI - Extracorporeal life support for a 5-week-old infant with idiopathic pulmonary hemosiderosis. AB - Idiopathic pulmonary hemosiderosis is a rare disease defined by the triad of iron deficiency anemia, hemoptysis, and diffuse pulmonary infiltrates on chest radiograph. Idiopathic pulmonary hemosiderosis is known to cause dyspnea and, in some cases, acute onset of massive pulmonary hemorrhage which is traditionally treated with conventional mechanical ventilation or high-frequency oscillation in conjunction with immunosuppressive therapy. In this case report, we describe a 5 week-old infant presenting with hemoptysis, massive pulmonary hemorrhage, and significant hypercapnic respiratory failure. The patient failed conventional ventilation but responded well to extracorporeal life support that was initiated early in his course. Idiopathic pulmonary hemosiderosis was suspected in light of his response to high-dose steroids and was confirmed by subsequent lung biopsies. CONCLUSION: Patients with severe pulmonary hemorrhage secondary to idiopathic pulmonary hemosiderosis can be safely supported with extracorporeal life support when conventional therapies have been exhausted. PMID- 23942746 TI - Isolated hepatobiliary cryptococcosis manifesting as obstructive jaundice in an immunocompetent child: case report and review of the literature. AB - The majority of patients with symptomatic cryptococcosis have an underlying immunocompromising condition. In the absence of coexisting immunocompromising condition, Cryptococcus neoformans is rarely considered in the differential diagnosis of obstructive jaundice that occurs in children with hilar masslike lesion. Here, we report a 5-year-old boy without immunoglobulin or lymphocyte abnormalities who developed a hepatobiliary infection with C. neoformans. Ultrasonography and computed tomography showed dilatation of the bilateral intrahepatic bile ducts and a low-attenuated mass in the hepatic hilum. Microscopic examination of tissue samples revealed abundant numbers of encapsulated yeast cell suggestive of C. neoformans. After 4 months of antifungal therapy (liposomal amphotericin B for 2 weeks and oral fluconazole for 3 months), the disease was effectively controlled. Unnecessary operation could be avoided by an early and accurate diagnosis. By sharing our experience, we suggest hepatobiliary surgeons and gastroenterologists should have a suspicion of this unusual entity to make earlier diagnosis and treatment. PMID- 23942747 TI - Impact of prenatal care utilization on infant care practices in Nepal: a national representative cross-sectional survey. AB - This study aimed to examine the utilization of prenatal care and its association with infant care practices using a nationally representative sample of Nepalese mothers and children. The study data was based on the 2006 Nepal Demographic and Health Survey which comprised of women age 15-49 years old who had delivered within three years prior to the survey (N = 4,136). A multilevel logistic regression model was fitted to assess the influence of prenatal care utilization on several indicators of infant care. Neonatal mortality is still high in Nepal (46 per 1,000 live births). After taking into account several maternal and child characteristics, children of mothers with no prenatal care were at increased risk of neonatal death (OR = 2.03, 95 % CI = 1.28-3.23). Compared to women with no prenatal care, those with more than three visits were more likely to immunize their children (OR = 2.66, 95 % CI = 2.10-3.36) and more likely to initiate breastfeeding within 1 h after birth (OR = 1.25, 95 % CI = 1.02-1.54). Having skilled attendants at prenatal care and at birth was also associated with better infant care practices. CONCLUSION: Neonatal mortality is still high in Nepal. Adequate prenatal care utilization may represent a key preventative strategy, which, in the present study, was associated with improvement in neonatal mortality, higher likelihood of having immunization, and initiation of breastfeeding within 1 h after birth. Public health awareness programs and interventions are needed in Nepal to increase the utilization of prenatal care as well as delivery assisted by skilled attendants. PMID- 23942748 TI - Ligand-interchange reactions between M(IV) (M = Ti, V) oxide bis-acetylacetonates and halides of high-valent group 4 and 5 metals. A synthetic and electrochemical study. AB - The reactions of M'O(acac)2 [M' = Ti, V; acac = acetylacetonato anion] with equimolar amounts of MF5 (M = Nb, Ta) in CH2Cl2 afforded Ti(acac)2F2, 1a, and [V(acac)3][MF6] (M = Nb, 4a; M = Ta, 4b), respectively. MOF3 (M = Nb, 2a; M = Ta, 2b) were co-produced from MF5/TiO(acac)2. The intermediate species [TaF4{OTi(acac)2}2][TaF6], 3, was intercepted in the course of the formation of 1a from TiO(acac)2/TaF5. NbCl5 reacted with TiO(acac)2 yielding selectively the previously reported [NbO(acac)Cl2]x, 5, and Ti2(acac)2(MU-Cl)2Cl4, 6. Complex 6 was alternatively obtained from the addition of a two-fold excess of TiCl4 to VO(acac)2. The 1:1 reactions of TiX4 (X = F, Cl) with TiO(acac)2 in dichloromethane gave Ti(acac)2X2 (X = F, 1a; X = Cl, 1b) and TiOX2 (X = F, 7a; X = Cl, 7b). The 1:1 combination of TiX4 (X = F, Cl) with VO(acac)2 led to 1a,b and VOX2 (X = F, 8a; X = Cl, 8b). The MU-oxido compounds (C6F5)3B-O-M'(acac)2 (M' = Ti, V) underwent fragmentation by [PF6]- in chlorinated solvent, yielding POF3, 9, and [B(C6F5)3F]-, 10, according to NMR studies; 1a and V(acac)3(+), respectively, were detected as the metal-containing species. Electrochemical studies were carried out aiming at the full characterization of the products and the observation of possible degradation pathways. PMID- 23942749 TI - Relationship between genetic variability in Rhizophagus irregularis and tolerance to saline conditions. AB - Reclamation of saline soils produced by extraction of bitumen from oil sands is challenging. The main objective of this study was to select a salt-tolerant arbuscular mycorrhizal (AM) fungal isolate that could, in the future, be used to pre-inoculate plants used in reclamation of saline substrates produced by oil sand industry. To achieve this, the effects of NaCl, Na(2)SO(4), and saline release water from composite tailings (CT) on hyphal growth of two AM fungal isolates from non-saline (Rhizophagus irregularis DAOM 181602, Rhizophagus sp. DAOM 227023) and three isolates of R. irregularis isolated from saline or sodic soils (DAOM 234181, DAOM241558, and DAOM241559) were tested in vitro. Pre symbiotic hyphal growth of the five isolates, in absence of a host plant, decreased with increasing salt stress and no spores germinated in CT. The symbiotic extraradical phase of the four isolates of R. irregularis developed well in saline media compared to the Rhizophagus sp. Nevertheless, fungal development of the four R. irregularis isolates differed in saline media indicating phenotypic variations between isolates. PMID- 23942750 TI - Prediction of pneumonia 30-day readmissions: a single-center attempt to increase model performance. AB - BACKGROUND: Existing models developed to predict 30 days readmissions for pneumonia lack discriminative ability. We attempted to increase model performance with the addition of variables found to be of benefit in other studies. METHODS: From 133,368 admissions to a tertiary-care hospital from January 2009 to March 2012, the study cohort consisted of 956 index admissions for pneumonia, using the Centers for Medicare and Medicaid Services definition. We collected variables previously reported to be associated with 30-day all-cause readmission, including vital signs, comorbidities, laboratory values, demographics, socioeconomic indicators, and indicators of hospital utilization. Separate logistic regression models were developed to identify the predictors of all-cause hospital readmission 30 days after discharge from the index pneumonia admission for pneumonia-related readmissions, and for pneumonia-unrelated readmissions. RESULTS: Of the 965 index admissions for pneumonia, 148 (15.5%) subjects were readmitted within 30 days. The variables in the multivariate-model that were significantly associated with 30-day all-cause readmission were male sex (odds ratio 1.59, 95% CI 1.03-2.45), 3 or more previous admissions (odds ratio 1.84, 95% CI 1.22-2.78), chronic lung disease (odds ratio 1.63, 95% CI 1.07-2.48), cancer (odds ratio 2.18, 95% CI 1.24-3.84), median income < $43,000 (odds ratio 1.82, 95% CI 1.18-2.81), history of anxiety or depression (odds ratio 1.62, 95% CI 1.04-2.52), and hematocrit < 30% (odds ratio 1.86, 95% CI 1.07-3.22). The model performance, as measured by the C statistic, was 0.71 (0.66-0.75), with minimal optimism according to bootstrap re-sampling (optimism corrected C statistic 0.67). CONCLUSIONS: The addition of socioeconomic status and healthcare utilization variables significantly improved model performance, compared to the model using only the Centers for Medicare and Medicaid Services variables. PMID- 23942751 TI - Influence of FIO2 on PaCO2 during noninvasive ventilation in patients with COPD. AB - BACKGROUND: The administration of a high FIO2 to COPD patients breathing spontaneously may result in hypercapnia, due to reversal of preexisting regional hypoxic pulmonary vasoconstriction, resulting in a greater dead space. Arterial blood gas trends have not been reported in these patients. In a 31-bed medical ICU in a teaching hospital we prospectively investigated the response of 17 CO2 retaining COPD patients, after acute respiratory crisis stabilization with noninvasive ventilation, to an FIO2 of 1.0 for 40 min, after having been noninvasively ventilated with an FIO2 of <= 0.50 for 40 min. RESULTS: The mean +/ SD baseline findings were: PaO2 101.4 +/- 21.7 mm Hg, PaCO2 52.6 +/- 10.4 mm Hg, breathing frequency 17.8 +/- 3.7 breaths/min, tidal volume 601 +/- 8 mL, and Glasgow coma score of 14.8 +/- 0.3. PaO2 significantly increased (P < .001) when FIO2 was increased to 1.0, but there was no significant change in PaCO2, breathing frequency, tidal volume, or Glasgow coma score. CONCLUSIONS: During noninvasive ventilation with an FIO2 sufficient to maintain a normal PaO2, a further increase in FIO2 did not increase PaCO2 in our CO2-retaining COPD patients. PMID- 23942752 TI - Kinetics of changes in oxyhemoglobin saturation during walking and cycling tests in COPD. AB - BACKGROUND: The patterns and kinetics of changes in SpO2 in the 6-min walk test (6MWT) and cycling test have not been addressed in patients with COPD. METHODS: We studied 60 COPD subjects, with a mean +/- SD FEV1 of 54 +/- 18% of predicted. We compared the changes in SpO2 (DeltaSpO2) within and between the 2 tests, and the differences between the desaturators and non-desaturators. RESULTS: In the 6MWT there were 4 patterns of SpO2. Desaturation then resaturation was the most common (46%). DeltaSpO2 >= 3% occurred at approximately 1.2 min, and the nadir was at 3.5 min where resaturation occurred thereafter. The DeltaSpO2 between the start and the nadir (start-vs-nadir DeltaSpO2) was greater than the start-vs-end DeltaSpO2 (P < .001). The desaturators had less inspiratory muscle strength, worse dyspnea, and shorter 6-min walk distance, whereas the resaturators had greater FEV1/FVC and less functional residual capacity (all P < .05). In the cycling test there were 3 patterns of SpO2. Desaturation was the most common (57%). The DeltaSpO2 >= 3% and nadir SpO2 occurred at 4.6 min and 6.6 min, respectively, of the 6.8-min cycling exercise duration. The desaturators had lower body mass index, lower oxygen-cost diagram score, less post-exercise inspiratory muscle strength, lower diffusing capacity, lower SpO2, lower work during 6MWT, and lower peak exercise performance (all P < .05). In both tests, the start-vs-nadir DeltaSpO2 during the 6MWT was greater (P = .02) but the start vs-end DeltaSpO2 was similar (P = .79). The desaturators in both tests had lower oxygen-cost-diagram scores (P < .01) and poorer peak exercise performance. CONCLUSIONS: Measurement of start-vs-nadir DeltaSpO2 rather than start-vs-end DeltaSpO2 during the 6MWT is recommended, because start-vs-nadir DeltaSpO2 is greater, and the nadir SpO2 is earlier. In both the 6MWT and the cycling exercise test, desaturation can be predicted with the oxygen-cost-diagram score, which has more capability to predict peak exercise performance than the 6MWT. PMID- 23942753 TI - Data downloads for effective noninvasive ventilation in patients with neuromuscular respiratory failure. PMID- 23942754 TI - The use of extubation readiness parameters: a survey of pediatric critical care physicians. AB - BACKGROUND: The pediatric literature addressing extubation readiness parameters and strategies to wean from mechanical ventilation is limited. METHODS: We designed a survey to assess the use of extubation readiness parameters among pediatric critical care physicians at academic centers in the United States. RESULTS: The overall response rate was 44.1% (417/945). The majority of respondents check for air leak and the amount of tracheal secretions. Fewer respondents use sedation score, the rapid shallow breathing index, or the airway occlusion pressure 0.1 s after the start of inspiratory flow prior to extubation. The majority perform a spontaneous breathing trial with pressure support. The majority consider 30 cm H2O as the upper limit of an air leak test, and the need for endotracheal suctioning once every 2-4 hours as acceptable for extubation. In preparation for termination of mechanical ventilation the majority daily wean the ventilator rate and/or the pressure support instead of conducting a spontaneous breathing trial. CONCLUSIONS: Most pediatric critical care physicians reported assessing extubation readiness by checking air leak and suctioning need, and less often consider or perform sedation score or the rapid shallow breathing index. PMID- 23942755 TI - Expression of GLTSCR2/Pict-1 in squamous cell carcinomas of the skin. AB - The most important cause of cutaneous squamous cell carcinomas (SCC) is DNA damage induced by exposure to solar UV irradiation. DNA damage induced by UV irradiation is sensed by early DNA damage response (DDR) proteins. Recently, GLTSCR2 has been suggested to play a role in UV light-induced DDR. To explore the role of GLTSCR2 in the development of cutaneous SCC, we investigated the molecular mechanism underlying GLTSCR2 inactivation in response to UV irradiation. We analyzed cutaneous SCC (n=42), basal cell carcinomas (BCC; n=26), and normal skin tissue samples (n=36) and compared GLTSCR2 expression between tumor and normal tissues, using immunohistochemistry. Next, to investigate the effects of UV irradiation on GLTSCR2, we performed immunocytochemistry, RT-PCR, immunoblotting, half-life assay for GLTSCR2, and comet assay after UV irradiation in primary keratinocytes. GLTSCR2 expression in SCC was significantly lower than that of normal skin tissue (p<0.05), but not different between BCC and normal skin. In cultured primary keratinocytes, GLTSCR2 expression was decreased and translocated after UV irradiation. UV irradiation accelerated degradation of GLTSCR2 through proteasomal pathway. Knockdown of GLTSCR2 resulted in marked decrease in gammaH2AX foci after UV exposure. Furthermore, comet assay showed that DNA damage after UV exposure persists longer in GLTSCR2 knocked-down cells. Our data show that GLTSCR2 is downregulated in SCC of the skin and that UV light exposure decreases the stability of GLTSCR2 and sensitizes keratinocytes to DNA damage. Therefore, our data suggest that GLTSCR2 might be involved in the development and/or progression of SCC of the skin. PMID- 23942757 TI - Evanescent field excited plasmonic nano-antenna for improving SERS signal. AB - The purpose of this work is to develop a high-performance surface-enhanced Raman scattering (SERS) substrate with high light harvesting and SERS emitting efficiencies based on the principle of a plasmonic nano-antenna. A prism/Ag nanowell array was designed and constructed based on the Kretschmann configuration. Almost 100% of the incident light can be absorbed at the resonance angle. A strong electromagnetic (EM) field is generated in the near field along the rim and at the center of the nanowells by means of the localized energy of surface plasmons (SPs), resulting in the electric field being enhanced 300 times at the Ag surface. The co-enhancement of localized SPs and propagating SPs was achieved in this substrate. The plasmonic nano-antenna structure can also redirect the SERS, which benefits the SERS collection. The SERS sensitivity on this configuration was improved by about 40 times compared with that on a conventional Kretschmann configuration with a flat Ag film. This SERS substrate design with full consideration on the tuning of the EM field in the near field and SERS space distribution in the far field could give insight into the design of a new generation of SERS substrates. PMID- 23942756 TI - Ultraviolet light exposure stimulates HMGB1 release by keratinocytes. AB - The primary cause of non-melanoma skin cancer is ultraviolet (UV) light from the sun. Many studies have demonstrated that cutaneous inflammation resulting from UV exposure is important for the development of skin cancer. In fact, anti inflammatory drugs have been shown to be effective in preventing skin cancer in animal models and in clinical trials. One new class of inflammatory mediators that could regulate UV-induced inflammation and skin carcinogenesis is alarmins. Alarmins are endogenous molecules that act as potent pro-inflammatory mediators when they are released by cells or accumulate extracellularly. The purpose of the current studies was to examine the expression and release of the alarmin high mobility group box 1 (HMGB1) after acute and chronic UV irradiation. Acute UV exposure stimulated the release of HMGB1 in cultured human keratinocytes and epidermal keratinocytes in murine skin. HMGB1 release correlated with pro inflammatory cytokine production in vitro and inflammatory cell infiltration in vivo. HMGB1 was also examined in tumors arising in chronically irradiated murine skin. HMGB1 protein expression in low grade, benign papillomas was similar to adjacent skin. However, HMGB1 staining was more widespread with a higher number of HMGB1-positive cells observed in high grade papillomas and malignant tumors. Overall, the data suggest that HMGB1 may be an important regulator of UV-induced cutaneous inflammation and tumor formation. Additional studies are needed to assess whether targeting HMGB1 would be a useful strategy to prevent tumors from developing in response to chronic UV exposure. PMID- 23942758 TI - A scoping literature review of the provision of orthoses and prostheses in resource-limited environments 2000-2010. Part two: research and outcomes. AB - BACKGROUND: Despite the activities of many orthotic and prosthetic provision organizations in resource-limited environments, there is still a great need and there are several areas for improvement, as identified in Part One of this series. OBJECTIVES: Our goal was to examine outcomes and conclusions of research studies to produce an evidence base for determining factors that may lead to successful provision of orthoses and prostheses in resource-limited environments. STUDY DESIGN: Literature review. METHODS: We conducted a scoping literature review of all information related to orthotic and prosthetic provision in resource-limited environments published from 2000 to 2010. We extracted measured outcomes reported in all types of articles and analyzed conclusions from research studies. RESULTS: Reported outcomes included durability, cost, satisfaction, use/nonuse of device, amount of utilization, walking speed, discomfort, pain, fit, misalignment, capacity for service provision, number of devices produced or delivered, and number of graduates from training programs. CONCLUSIONS: There are many gaps in the evidence base, notably in measuring inclusion, participation, and quality of life for orthosis and prosthesis users in resource-limited environments. There is a paucity of reported outcomes for orthotics. Valid, reliable, and standard methods of data collection and reporting are needed to advance the field and enhance the evidence base. PMID- 23942759 TI - Patients with rare diseases using pharmacists for medication information. AB - OBJECTIVES: To determine whether patients with a rare illness (1) use pharmacists for medication information more or less frequently than physicians and the Internet, (2) perceive pharmacists as a more or less credible medical information resource than physicians and the Internet, and (3) obtain different types of medication information from pharmacists, physicians, and the Internet. DESIGN: Cross-sectional survey. SETTING: Online data collected between 2008 and 2009. PATIENTS: Adult, English-proficient vasculitis patients (n = 232) who were taking at least one medication to treat their vasculitis. INTERVENTION: Administration of online survey. MAIN OUTCOME MEASURES: Patient use of pharmacists, physicians, and the Internet for medication information; perceived credibility of pharmacists, physicians, and the Internet as sources of medication information; and types of medication information obtained from pharmacists, physicians, and the Internet. RESULTS: Participants consulted physicians and the Internet more than pharmacists for medication information; only 96 participants (41.4%) ever used pharmacists for vasculitis medication information. Females and participants who used community pharmacies were significantly more likely to consult pharmacists for medication information as compared with males and patients who did not use community pharmacies. Participants perceived pharmacists were a less credible source of medication information than physicians and the Internet. Participants used physicians and/or the Internet more than pharmacists for five of eight types of medication information, including adverse effects and drug effectiveness. CONCLUSION: Vasculitis patients consulted sources other than pharmacists for medication information. Several factors, including perceived pharmacist credibility and a noncommunity-based pharmacy, may contribute to infrequent patient use of pharmacists as a medication information source. Future qualitative research should document how patients with rare disease perceive and interact with pharmacists to understand why many view pharmacists as only moderately credible sources of medication information. PMID- 23942760 TI - Synthesis, spectroscopic and biological studies of a fluorescent Pt(II) (terpy) based 1,8-naphthalimide conjugate as a DNA targeting agent. AB - The bi-functional complex [Pt(II)(terpy)(py-naphth)](NO3)2(), incorporating both 2,2':6',2''-terpyridine and 4-N,N'-dimethylamino-1,8-naphthalimide moieties, displays a high binding affinity for DNA as well as displaying cytotoxicity towards and inducing apoptosis in malignant cell lines. PMID- 23942761 TI - Efficient bubble propulsion of polymer-based microengines in real-life environments. AB - Template-electrodeposited polymer/Pt microtube engines display efficient propulsion in a wide range of real-life samples ranging from seawater to human serum. Remarkably high speeds are observed in fuel-enhanced raw serum, apple juice, seawater, lake and river water samples. Our results indicate that polymer based microengines hold considerable promise for diverse practical applications and that real samples exert different effects upon propulsion of different bubble propelled microtube engines. PMID- 23942762 TI - Estimation of the efficiency of Japanese hospitals using a dynamic and network data envelopment analysis model. AB - The purpose of this study was to perform an interim evaluation of the policy effect of the current reform of Japan's municipal hospitals. We focused on efficiency improvements both within hospitals and within two separate internal hospital organizations. Hospitals have two heterogeneous internal organizations: the medical examination division and administration division. The administration division carries out business management and the medical-examination division provides medical care services. We employed a dynamic-network data envelopment analysis model (DN model) to perform the evaluation. The model makes it possible to simultaneously estimate both the efficiencies of separate organizations and the dynamic changes of the efficiencies. This study is the first empirical application of the DN model in the healthcare field. Results showed that the average overall efficiency obtained with the DN model was 0.854 for 2007. The dynamic change in efficiency scores from 2007 to 2009 was slightly lower. The average efficiency score was 0.862 for 2007 and 0.860 for 2009. The average estimated efficiency of the administration division decreased from 0.867 for 2007 to 0.8508 for 2009. In contrast, the average efficiency of the medical examination division increased from 0.858 for 2007 to 0.870 for 2009. We were unable to find any significant improvement in efficiency despite the reform policy. Thus, there are no positive policy effects despite the increased financial support from the central government. PMID- 23942763 TI - A simple non-empirical procedure for spin-component-scaled MP2 methods applied to the calculation of the dissociation energy curve of noncovalently-interacting systems. AB - We present a simple and non-empirical method to determine optimal scaling coefficients, within the (spin-component)-scaled MP2 approach, for calculating intermolecular potential energies of noncovalently-interacting systems. The method is based on an observed proportionality between (spin-component) MP2 and CCSD(T) energies for a wide range of intermolecular distances and allows us to compute with high accuracy a large portion of the dissociation curve at the cost of a single CCSD(T) calculation. The accuracy of the present procedure is assessed for a series of noncovalently-interacting test systems: the obtained results reproduce CCSD(T) quality in all cases and definitely outperform conventional MP2, CCSD and SCS-MP2 results. The difficult case of the beryllium dimer is also considered. PMID- 23942765 TI - Diffusion magnetic resonance imaging in preterm brain injury. AB - INTRODUCTION: White matter injury and abnormal maturation are thought to be major contributors to the neurodevelopmental disabilities observed in children and adolescents who were born preterm. Early detection of abnormal white matter maturation is important in the design of preventive, protective, and rehabilitative strategies for the management of the preterm infant. Diffusion weighted magnetic resonance imaging (d-MRI) has become a valuable tool in assessing white matter maturation and injury in survivors of preterm birth. In this review, we aim to (1) describe the basic concepts of d-MRI; (2) evaluate the methods that are currently used to analyse d-MRI; (3) discuss neuroimaging correlates of preterm brain injury observed at term corrected age; during infancy, adolescence and in early adulthood; and (4) explore the relationship between d-MRI measures and subsequent neurodevelopmental performance. METHODS: References for this review were identified through searches of PubMed and Google Scholar before March 2013. RESULTS: The impact of premature birth on cerebral white matter can be observed from term-equivalent age through to adulthood. Disruptions to white matter development, identified by d-MRI, are related to diminished performance in functional domains including motor performance, cognition and behaviour in early childhood and in later life. CONCLUSION: d-MRI is an effective tool for investigating preterm white matter injury. With advances in image acquisition and analysis approaches, d-MRI has the potential to be a biomarker of subsequent outcome and to evaluate efficacy of clinical interventions in this population. PMID- 23942764 TI - Parental history of type 2 diabetes, TCF7L2 variant and lower insulin secretion are associated with incident hypertension. Data from the DESIR and RISC cohorts. AB - AIMS/HYPOTHESIS: The relationship between insulin secretion and the incidence of hypertension has not been well characterised. We hypothesised that both a parental history of diabetes and TCF7L2 rs7903146 polymorphism, which increases susceptibility to diabetes because of impaired beta cell function, are associated with incident hypertension. In a separate cohort, we assessed whether low insulin secretion is related to incident hypertension. METHODS: Nine year incident hypertension was studied in 2,391 normotensive participants from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. The relationship between insulin secretion and 3 year incident hypertension was investigated in 1,047 non-diabetic, normotensive individuals from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort. Insulin secretion during OGTT was expressed in relation to the degree of insulin resistance, as assessed by a hyperinsulinaemic-euglycaemic clamp. RESULTS: In the DESIR cohort, a parental history of diabetes and the TCF7L2 at risk variant were both associated with hypertension incidence at year 9, independently of waist circumference, BP, fasting glucose, insulin levels and HOMA-IR at inclusion (p = 0.02 for parental history, p = 0.006 for TCF7L2). In the RISC cohort, a lower insulin secretion rate during the OGTT at baseline was associated with both higher BP and a greater risk of hypertension at year 3. This inverse correlation between the insulin secretion rate and incident hypertension persisted after controlling for baseline insulin resistance, glycaemia and BP (p = 0.007). CONCLUSIONS/INTERPRETATION: Parental history of diabetes, TCF7L2 rs7903146 polymorphism and a reduced insulin secretion rate were consistently associated with incident hypertension. A low insulin secretion rate might be a new risk factor for incident hypertension, beyond insulin resistance. PMID- 23942766 TI - Serum endothelin-1 and NT-proBNP, but not ADMA, endoglin and TIMP-1 levels, reflect impaired right ventricular function in patients with systemic sclerosis. AB - BACKGROUND: Heart and pulmonary involvement is a leading cause of systemic sclerosis (SSc)-related deaths. OBJECTIVES: The aim of our study was to assess if biochemical markers of right ventricular (RV) overload, endothelial function and collagen metabolism can predict RV dysfunction assessed by Doppler echocardiography in SSc patients. METHODS: We prospectively studied 111 consecutive patients (101 F, 10 M, age 54.2 +/- 13.8 years) with diagnosed SSc (mean disease duration 9.4 +/- 11.4 years) and a group of 21 age-matched subjects (18 F, 3 M, age 49.3 + 10.5 years). We performed transthoracic echocardiography (Phillips iE 33) and measured serum endothelin-1 (ET-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), asymmetric dimethylarginine (ADMA), endoglin and human tissue inhibitor of matrix metalloproteinase (TIMP-1) concentration. RESULTS: Median serum NT-proBNP level in SSc patients was 133.5 (range 21.86 17,670 pg/ml) and was significantly higher than in controls (p = 0.0002). Moreover, the median serum ET-1 level of 1.49 (range 0.26-8.75 pg/ml) was higher in SSc patients (p = 0.002). However, no significant differences in ADMA, TIMP-1 and endoglin serum concentration between SSc patients and controls were observed. Serum NT-proBNP concentration correlated positively with echocardiographic signs of RV overload: tricuspid regurgitation pressure gradient (r = 0.38, p = 0.0004) and RV Tei index (r = 0.25, p = 0.01). ET-1 serum level correlated negatively with tricuspid annular plane systolic excursion (r = -0.4, p = 0.01) and positively with inferior vena cava diameter measured at expiration (r = 0.38, p = 0.0002). The echocardiographic signs of RV overload were significantly more pronounced in the highest NT-proBNP tertile (>195 pg/ml) group than in the lowest one (<88 pg/ml). CONCLUSIONS: Serum ET-1 and NT-proBNP, but not endoglin, ADMA and TIMP-1 levels correlating with the echocardiographic parameters of RV overload, can be considered as noninvasive indicators of RV dysfunction in SSc patients. PMID- 23942767 TI - Impact of cardiac involvement on the risk of mortality among patients with systemic sclerosis: a 5-year follow-up of a single-center cohort. AB - Cardiac involvement is among the leading causes of mortality in patients with systemic sclerosis (SSc). Previously, we demonstrated in a single-center, cross sectional study the frequent coexistence of different forms of cardiac involvement in systemic sclerosis including pulmonary arterial hypertension (PAH), coronary artery disease (CAD), and microvascular dysfunction (MVD). The aim of the present study was to investigate the prognostic significance of cardiac involvement. One hundred twenty patients with SSc were enrolled. All cases underwent a non-invasive cardiovascular protocol. In 30 patients with suspected cardiac involvement, right heart catheterization and intra-coronary pressure-wire-supplemented coronary angiography were performed. Clinical follow up was 5 years. Patients with CAD at the baseline showed a trend for higher cardiovascular mortality while in patients with MVD this difference was significant (26.7 % versus 9.5 %, p = 0.077 and 30 % versus 10.1 %, p < 0.05, respectively). Cardiovascular mortality of PAH cases was higher but, however, did not reach statistical significance 21.4 % versus 10.4 %, p = 0.261. Cardiovascular event-free survival was significantly lower among patients with combinations of two or three disorders (p < 0.05). Multivariate analysis of organ involvements and comorbidities showed that the diffuse cutaneous subset, the presence of kidney involvement, the velocity of the tricuspid regurgitation, as well as diabetes mellitus were independent predictors of overall mortality. MVD and CAD alone or in combination with PAH significantly affected the 5-year cardiovascular mortality. These findings highlight the prognostic importance of coronary disease in patients with SSc [ www.clinicaltrials.gov (Reg. Nr.: NCT00843102)]. PMID- 23942769 TI - Synthesis and characterization of poly-L-leucine initialized and immobilized by rehydrated hydrotalcite: understanding stability and the nature of interaction. AB - PLLs were synthesized by the ring-opening polycondensation (ROP) method using alpha-L-leucine N-carboxyanhydride (NCA) and initialized by triethylamine (Et3N), water or rehydrated hydrotalcite (HTrus). The role of temperature, different initiators and water in ROP was further investigated. In general, the initiators used in the polymerization reaction lead to PLL alpha-helical chains containing 5 40 monomers with NCA endgroups via a monomer-activated mechanism. However, the water has a twofold effect on ROP, as both a nucleophile and a base, which involves competition between two different types of initiating mechanisms (nucleophilic attack or deprotonation of the NCA monomer) in the polymerization reaction. This competition provides as a main product NCA endgroups with an alpha helical structure and leads to the formation of the PLL cyclic-chains and beta sheet structures which reduce the polymer Mw and the PD of the polypeptide. Furthermore, the water can hydrolyze the NCA endgroups resulting in PLL alpha helical chains that contain living groups as the main product. On the other hand, the HTrus presents a double role: as both an initiator and a support. The polymers synthesized in the presence of HTrus presented a HT-carboxylate endgroup. The PLLs immobilized in HTrus through an anion-exchange method performed for just 30 minutes presented the PLL immobilized in the interlayer space of the HTrus. The PLL chains of the immobilized counterpart are stabilized by H-bonding with the M-OH of the HT structure. All the polypeptides and biohybrid materials synthesized have been characterized using different techniques (EA, ICP, XRD, Raman, MALDI-TOF, ESI-TOF, FT-IR at increasing temperatures, TG/DT analyses and TEM). PMID- 23942768 TI - Cytomegalovirus disease of the upper gastrointestinal tract in patients with rheumatic diseases: a case series and literature review. AB - Cytomegalovirus disease of the upper gastrointestinal tract (CMV-UGT) is a rare but significant complication in patients with rheumatic diseases. We reviewed records for January 2004 to December 2012 and investigated the occurrence of CMV UGT in patients with rheumatic diseases to evaluate clinical characteristics, the value of the CMV antigenemia assay, and the association between immunosuppressive therapy and CMV-UGT. Ten CMV-UGT events (six gastric ulcer, two esophagitis, one gastritis, and one duodenal ulcer) in nine patients (three rheumatoid arthritis, three systemic lupus erythematosus, one dermatomyositis, one systemic sclerosis, and one overlap syndrome) were identified based on pathology. Mean age was 66.5 (range, 53-76) years. The CMV antigenemia assay was negative in five cases (50 %). All ten cases received glucocorticoids and six (60 %) received pulsed glucocorticoids. Mean prednisolone dose was 31.3 (range, 7.5-40) mg/day at diagnosis. Concomitant immunosuppressive agents were used in eight cases (80 %). Considering other published cases, the most common immunosuppressive drug was cyclophosphamide (ten cases; 45 %). Notably, two of our patients who were treated with low-dose glucocorticoids plus other milder immunosuppressive drugs (methotrexate and cyclosporine) also developed CMV-UGT. Life-threatening complications such as massive bleeding or perforated ulcer occurred in two patients. These results suggest that patients receiving intensive immunosuppressive therapy such as high-dose glucocorticoids and cyclophosphamide are at higher risk for developing CMV-UGT. Moreover, CMV-UGT can occur even with low-dose glucocorticoid therapy and relatively mild immunosuppressive agents. The value of the CMV antigenemia assay for predicting CMV-UGT appears to be limited. PMID- 23942770 TI - Case report: glioblastoma multiforme complicating familial cavernous malformations. PMID- 23942771 TI - A luminescent metal-organic framework for sensing methanol in ethanol solution. AB - A new luminescent Zn-MOF has been synthesized under hydrothermal condition using a semi-rigid ligand H3pcoip (4-(2-carboxyphenoxy)isophthalic acid) is reported. The luminescence properties of 1 in methanol, ethanol, and water have been investigated. Interestingly, compound 1 has a unique response to methanol compared to ethanol and water. Moreover, 1 displays a turn-on switching property triggered by methanol solvent molecules and a high sensitivity towards methanol concentration as low as 2 * 10(-7) (V(MeOH)/V(total)) in ethanol solution. The results indicate that the Zn-MOF has potential application as a sensor for detecting methanol in ethanol solution with excellent selectivity and high sensitivity. PMID- 23942772 TI - Maternal passive smoking during pregnancy and neural tube defects in offspring: a meta-analysis. AB - PURPOSE: This study aims to examine the association between maternal passive smoking during pregnancy and the occurrence of neural tube defects (NTDs) in offspring. METHODS: We retrieved studies published on the association between maternal passive smoking during pregnancy and the occurrence of NTDs in offspring. Meta-analysis was applied to calculate the pooled effect estimates and their 95% confidence intervals (CIs) using data from 10 case-control studies. The publication bias was assessed by the Egger's regression asymmetry test and Begg's rank correlation test with Begg's funnel plot. RESULTS: The pooled effect estimate of maternal passive smoking was 1.82 (95% CI 1.46-2.27) for total NTDs; the effect estimates were 1.72 (95% CI 1.44-2.06), 1.52 (95% CI 1.29-1.79), and 2.32 (95% CI 1.34-4.01) for NTDs subtypes of anencephaly, spina bifida and encephalocele, respectively. Stratified by geographic region of the studies, the pooled effect estimates were 2.11 (95% CI 1.46-3.06), 1.65 (95% CI 1.16-2.34), 1.25 (95% CI 0.41-3.80) in China, USA and Iran, respectively. CONCLUSIONS: This meta-analysis suggested that maternal passive smoking during pregnancy was associated with an increased risk of total NTDs and three NTDs subtypes in offspring. Specifically, the associations were also found to be significantly positive both in China and USA. PMID- 23942773 TI - Different cytotoxicities and cellular localizations of novel quindoline derivatives with or without boronic acid modifications in cancer cells. AB - The synthesis of a 4 * 4 series of novel quindoline derivatives with or without boronic acid modifications and their cytotoxicities, cellular localizations, and implications on cancer cells are presented and discussed. PMID- 23942774 TI - Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). AB - BACKGROUND: In a phase III trial (ClinicalTrials.gov registration ID: NCT00094653), ipilimumab significantly improved survival versus a vaccine control in pretreated patients with metastatic melanoma. Here, we characterize outcomes of those patients who survived >= 2 years. METHODS: Patients were randomized (3 : 1 : 1) to receive ipilimumab 3 mg/kg + gp100 vaccine, ipilimumab 3 mg/kg + placebo, or gp100 vaccine alone. Baseline demographic data, duration of survival, responses, and safety among patients with >= 2 years' survival were analyzed. RESULTS: Among 676 randomized patients, 474 and 259 patients had at least 2 or 3 years of potential follow-up, respectively, and were eligible for analysis. Among these, 94 (20%) and 42 (16%) survived >= 2 and >= 3 years, respectively. Survival rates at 2 and 3 years were 25% (24 of 95) and 25% (13 of 53) with ipilimumab alone and 19% (54 of 284) and 15% (24 of 156) with ipilimumab plus gp100. Safety among patients with >= 2 years' survival was comparable with the overall study population, with the onset of new ipilimumab-related toxic effect (all grades) reported in 6 of 78 (8%) patients. CONCLUSIONS: Ipilimumab results in survival of >= 2 years in one-fifth of pretreated patients with 2 years potential follow-up in a phase III trial. New onset, low-grade events starting after administration of the last dose were infrequent. TRIAL REGISTRATION ID: NCT00094653. PMID- 23942775 TI - Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis. AB - BACKGROUND: Many patients with refractory or relapsed gastric cancer after first line chemotherapy have received salvage chemotherapy in routine clinical practice. However, there was no evidence to support this treatment until recent phase III trials demonstrated substantial prolongation of overall survival. Therefore, we conducted a meta-analysis of these trials and investigated whether second-line chemotherapy was more effective than best supportive care. PATIENTS AND METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2013), MEDLINE (1950 to March week 4, 2013) and EMBASE (1980 2013, week 13). In addition, we searched all abstracts and virtual meeting presentations from the American Society of Clinical Oncology (ASCO) conferences held between 2004 and 2013. RESULTS: The search process yielded 578 studies, two of which were randomized phase III trials that compared chemotherapy with supportive care. From the abstracts and virtual meeting presentations of ASCO held between 2004 and 2013, 127 abstracts were identified that evaluated second line chemotherapy; only one relevant abstract was included in the meta-analysis. A total of 410 patients were eligible for analysis, of whom 150 received docetaxel chemotherapy, and 81 received irinotecan chemotherapy. A significant reduction in the risk of death [HR = 0.64, 95% confidence interval (CI) 0.52 0.79, P < 0.0001] was observed with salvage chemotherapy. When the analysis was restricted to irinotecan or docetaxel, there was still significant reduction in the risk of death with each chemotherapeutic agent. The HR was 0.55 (95% CI 0.40 0.77, P = 0.0004) for irinotecan and 0.71 (95% CI 0.56-0.90, P = 0.004) for docetaxel. CONCLUSION: This meta-analysis demonstrated evidence to support second line chemotherapy in advanced gastric cancer. PMID- 23942776 TI - Attitude of employees of a university clinic to complementary and alternative medicine in oncology. AB - BACKGROUND: Cancer patients often use complementary and alternative medicine (CAM), yet discussion with the oncologist is often missing and oncologists lack knowledge in CAM. PATIENTS AND METHODS: In order to learn more about the attitude of professionals in oncology toward CAM, a survey was conducted on employees of a German university clinic using a structured questionnaire. RESULTS: In total, 547 employees took part in the survey. One-third would definitely use CAM on cancer patients. Female employees are more interested in CAM than males (80% versus 20%; P = 0.001); physicians are less interested than nurses (57% versus 72%; P = 0.008). 2.5% of physicians and 9% of nurses are convinced that CAM is as effective as conventional therapy in cancer. Fifty-two percent of physicians and 12% of nurses agree that adverse effects due to CAM may be possible. Seventy three percent did not consider themselves adequately informed on CAM for their professional work. CONCLUSIONS: As a substantial part of participants would use CAM on cancer patients and most are interested in but not trained on this topic, there is a need for training of professionals from different professions working in oncology. PMID- 23942777 TI - Assessment of the axial rotation of the pelvis with the EOS(r) imaging system: intra- and inter-observer reproducibility and accuracy study. AB - PURPOSE: A source of radiological bias occurs when the axial rotation of the pelvis is disregarded in hip and spine biomechanics analyses. The EOS imaging system (EOS Imaging, France) offers the possibility of detecting and measuring the axial rotation of bones. Reproducibility and accuracy have not been documented in the case of the pelvis. METHODS: A dry pelvis has been X-rayed with the EOS system every 5 degrees from 30 degrees left to 30 degrees right according to a laser line reference goniometer. Three observers have measured the rotation. One observer did it 3 times. The intra- and inter-observer reproducibility and the accuracy have been calculated using the root mean square standard deviation calculation. The relationship between the axial rotation and the offset between the left and right acetabulae on the lateral view was investigated. RESULTS: The 95 % CI was +/-0.23 degrees for the intra-observer and +/-0.33 degrees for the inter-observer reliability. The mean of signed differences between the software calculation and the actual axial rotation of the pelvis was -0.39 degrees (SD 0.77 degrees ). The lateral acetabular offset was proportional to the sin of the rotation. Approximately, 30 mm offset corresponded to about 10 degrees rotation. CONCLUSIONS: The 3D slot scanning imaging system demonstrated significant reproducibility and accuracy for the assessment of the axial rotation of the pelvis. PMID- 23942778 TI - Carbon nanotubes as electronic interconnects in solid acid fuel cell electrodes. AB - Carbon nanotubes have been explored as interconnects in solid acid fuel cells to improve the link between nanoscale Pt catalyst particles and macroscale current collectors. The nanotubes were grown by chemical vapor deposition on carbon paper substrates, using nickel nanoparticles as the catalyst, and were characterized using scanning electron microscopy and Raman spectroscopy. The composite electrode material, consisting of CsH2PO4, platinum nanoparticles, and platinum on carbon-black nanoparticles, was deposited onto the nanotube-overgrown carbon paper by electrospraying, forming a highly porous, fractal structure. AC impedance spectroscopy in a symmetric cell configuration revealed a significant reduction of the electrode impedance as compared to similarly prepared electrodes without carbon nanotubes. PMID- 23942779 TI - A genome-wide association study of behavioral disinhibition. AB - We report results from a genome wide association study (GWAS) of five quantitative indicators of behavioral disinhibition: nicotine, alcohol consumption, alcohol dependence, illicit drugs, and non-substance related behavioral disinhibition. The sample, consisting of 7,188 Caucasian individuals clustered in 2,300 nuclear families, was genotyped on over 520,000 SNP markers from Illumina's Human 660W-Quad Array. Analysis of individual SNP associations revealed only one marker-component phenotype association, between rs1868152 and illicit drugs, with a p value below the standard genome-wide threshold of 5 * 10( 8). Because we had analyzed five separate phenotypes, we do not consider this single association to be significant. However, we report 13 SNPs that were associated at p < 10(-5) for one phenotype and p < 10(-3) for at least two other phenotypes, which are potential candidates for future investigations of variants associated with general behavioral disinhibition. Biometric analysis of the twin and family data yielded estimates of additive heritability for the component phenotypes ranging from 49 to 70%, GCTA estimates of heritability for the same phenotypes ranged from 8 to 37%. Consequently, even though the common variants genotyped on the GWAS array appear in aggregate to account for a sizable proportion of heritable effects in multiple indicators of behavioral disinhibition, our data suggest that most of the additive heritability remains "missing". PMID- 23942780 TI - High glucose activates the alternative ACE2/Ang-(1-7)/Mas and APN/Ang IV/IRAP RAS axes in pancreatic beta-cells. AB - The activation of the classical angiotensin (Ang)-converting enzyme (ACE)/Ang II/Ang II type 1 receptor (AT1R) axis of the renin-angiotensin system (RAS) has been associated with islet dysfunction and insulin resistance. Hyperglycaemia, hypertension and obesity, major components of metabolic syndrome, are all associated with increased systemic and tissue levels of Ang II. Whereas it is well established that Ang II, by binding to AT1R, impairs glucose-stimulated insulin secretion and insulin signaling, the contribution of alternative RAS axes to beta-cell function remains to be fully elucidated. In this study, using the BRIN-BD11 rat insulinoma cell line, we i) examined the basal expression levels of components of classical and alternative RAS axes and ii) investigated the effects of normal (5.5 mM) and elevated (11, 15, 25 mM) glucose concentrations on their expression and/or enzymatic activity by means of reverse transcription quantitative PCR (RT-qPCR), immunoblot analysis and enzymatic activity assays. The results correlated with the insulin production and release. Essential components of all RAS axes were found to be expressed in the BRIN-BD11 cells. Components of the alternative RAS axes, ACE2, neutral endopeptidase 24.11, Mas receptor (Mas), aminopeptidases A (APA) and N (APN) and insulin-regulated aminopeptidase (IRAP) showed an increased expression/activity in response to high glucose. These alterations were paralleled by the glucose-dependent increase in insulin production and release. By contrast, components of the classical RAS axis, ACE, AT1R and Ang II type 2 receptor (AT2R), remained largely unaffected under these conditions. Glucose induced the activation of the alternative ACE2/Ang-(1-7)/Mas and APN/Ang IV/IRAP RAS axes simultaneously with the stimulation of insulin production/release. Our data suggest the existence of a functional link between the local RAS axis and pancreatic beta-cell function; however, further studies are required to confirm this hypothesis. PMID- 23942781 TI - A defense of compulsory vaccination. AB - Vaccine refusal harms and risks harming innocent bystanders. People are not entitled to harm innocents or to impose deadly risks on others, so in these cases there is nothing to be said for the right to refuse vaccination. Compulsory vaccination is therefore justified because non-vaccination can rightly be prohibited, just as other kinds of harmful and risky conduct are rightly prohibited. I develop an analogy to random gunfire to illustrate this point. Vaccine refusal, I argue, is morally similar to firing a weapon into the air and endangering innocent bystanders. By re-framing vaccine refusal as harmful and reckless conduct my aim is to shift the focus of the vaccine debate from non vaccinators' religious and refusal rights to everyone else's rights against being infected with contagious illnesses. Religious freedom and rights of informed consent do not entitle non-vaccinators to harm innocent bystanders, and so coercive vaccination requirements are permissible for the sake of the potential victims of the anti-vaccine movement. PMID- 23942782 TI - Effect of Fenton reagent shock and recovery periods on anaerobic microbial community structure and degradation of chlorinated aliphatics. AB - This study investigates the effect of Fenton reagent on the structure and function of a microbial consortium during the anaerobic degradation of hexachloroethane (HCA) and tetrachloroethene (PCE). Anaerobic biodegradation tests of HCA and PCE were performed in batch reactors using an anaerobic microbial consortium that had been exposed to Fenton reagent for durations of 0, 0.04, and 2 days and then allowed to recover for periods of 0, 3, and 7 days. The bacterial community structure was determined using culture-independent methods of 16S rRNA gene sequencing and automated ribosomal intergenic spacer analysis. Larger recovery periods partially restored the microbial community structure; however, the recovery periods did not restore the loss of ability to degrade HCA and PCE in cultures shocked for 0.04 days, and PCE in cultures shocked for 2 days. Overall the exposure to Fenton reagent had an impact on bacterial community structure with downstream effects on HCA and PCE degradation. This study highlights that the impacts of short- and long-term shocks on microbial community structure and function can be correlated using a combination of biodegradation tests and community structure analysis tools. PMID- 23942783 TI - Paracetamol therapy for patent ductus arteriosus in premature infants: a chance before surgical ligation. AB - Patent ductus arteriosus (PDA) remains a common problem in premature infants. Treatment options include pharmacologic therapy and surgical ligation, but these are associated with potentially significant adverse effects. This report describes the effect of administering oral paracetamol to premature neonates with PDA. The study enrolled seven premature neonates followed up with the diagnosis of hemodynamically significant PDA (hsPDA) between February and December 2012 and treated with oral paracetamol. Patients with hsPDA were given at least two or more courses of ibuprofen treatment. If this therapy failed to promote ductal closure, the patients with clinical symptoms who had hsPDA defined by echocardiography were treated with oral paracetamol (15 mg/kg every 6 h). If these patients did not respond to paracetamol therapy, the PDA was closed by surgical ligation. The mean gestational age of the seven patients in this study was 26.1 weeks, and their mean birth weight was 936 g. Paracetamol treatment was started at 36.2 +/- 11.6 days. The mean internal ductal diameter was 2.0 +/- 0.2 mm, and the left atrium-to-aorta ratio was 1.5 +/- 0.2. All the patients were administered oral paracetamol because of no response to ibuprofen treatment. The hsPDA was successfully closed with oral paracetamol in five (71.4 %) of the seven patients. The remaining two patients had surgical ligation performed, but one of them died. No side effects related to paracetamol were observed. Oral paracetamol may be used as an alternative drug for the management of hsPDA in premature neonates when ibuprofen treatment is unsuccessful and the only other therapeutic option is surgery. PMID- 23942785 TI - Increased serum levels of S100A8/A9 and S100A12 are associated with cardiovascular disease in patients with inactive systemic lupus erythematosus. AB - OBJECTIVES: Patients with SLE have an increased morbidity and mortality from cardiovascular disease (CVD). The reason for this is not entirely understood, but is believed to be partly related to the long-lasting inflammatory process seen in SLE. The aim of the present study was to investigate whether there is an association between CVD and serum levels of the proinflammatory proteins S100A8/A9 and S100A12 in SLE. METHODS: Serum levels of S100A8/A9 and S100A12 were measured with ELISA in 237 SLE patients with clinically inactive disease and without infections, as well as in 100 healthy individuals. Cardiovascular manifestations were defined according to the SLICC/ACR Damage Index (SLICC/ACR DI). RESULTS: Serum levels of S100A8/A9 were elevated in our inactive SLE patients as compared with healthy individuals (P < 0.0001), which was not seen for S100A12 (P = 0.12). SLE patients with a history of CVD had increased serum levels of both S100A8/A9 and S100A12 compared with patients with no CVD or venous thromboembolism (P = 0.003 and P = 0.006, respectively). The presence of organ damage according to SLICC/ACR-DI was associated with an increase in both S100A8/A9 and S100A12 serum levels (P = 0.001 and P = 0.006, respectively). CONCLUSION: Elevated serum levels of S100A8/A9 and S100A12 may be used as an indicator of severe disease and CVD in SLE, suggesting that SLE patients with elevated serum S100A8/A9 and S100A12 concentrations may benefit from more intense cardiovascular primary preventive strategies and possibly also from more intense and early immunosuppressive treatment. PMID- 23942784 TI - Effect of antiepilepsy drug therapy on ventricular function in children with epilepsy: a tissue Doppler imaging study. AB - Impaired cardiac myocardial function may contribute to the risk for sudden unexpected death of a patient with epilepsy. This study aimed to investigate the effect of antiepilepsy drugs (AEDs) on cardiac function in pediatric epileptic patients using standard and tissue Doppler imaging (TDI) echocardiography. This hospital-based, prospective cross-sectional study investigated 52 epileptic children (mean age 9.3 +/- 3.1 years) treated with AEDs (duration 2.4-10.0 years) and 36 healthy children (mean age 9.5 +/- 4.0 years). In the epilepsy group, standard echocardiography showed increased left ventricular (LV) end-diastolic and end-systolic diameters, an increased LV mass index, and preserved ejection fraction. The patients also exhibited increased mitral peak A-wave velocity and mitral E-wave deceleration time as well as a decreased mitral E/A ratio. The E/Em ratio was significantly higher in the epilepsy group (5.6 +/- 1.2) than in the control group (5.2 +/- 1.1) (p = 0.016). In the epilepsy group, TDI showed an increased isovolumetric relaxation time and myocardial performance index (MPI). It also exhibited decreased early diastolic velocity (Em) and a decreased mitral annular displacement index in these patients. There were positive correlations between the LV lateral wall MPI (r = 0.231), septal MPI (r = 0.223), and LV mass index (p < 0.05) but no correlation with the duration of AED treatment. The authors detected subclinical ventricular dysfunction associated with AEDs at a preclinical stage. They suggest that TDI can be useful for determining the short- and long-term cardiac effects of AEDs. PMID- 23942786 TI - [Initial diagnosis and treatment for poisoning]. AB - Intoxication is a common source of morbidity and mortality in adults as well as children. It accounts for 5-10 % of all emergency calls and emergency department visits. The screening of patients with altered consciousness for signs of intoxication is therefore mandatory. The diagnostics and treatment of intoxicated patients have not changed significantly over the past few years. Supportive care continues to be the most important aspect of treatment and should precede specific antitoxin treatments. PMID- 23942787 TI - Safety and efficacy of recombinant activated factor VII for refractory hemorrhage in pediatric patients on extracorporeal membrane oxygenation: a single center review. AB - BACKGROUND: Medically refractory hemorrhage in patients on ECMO (extracorporeal membrane oxygenation) support can have catastrophic complications. Recombinant Activated Factor VII (rFVIIa; NovoSeven(r)) may provide lifesaving hemostasis; however, there are reports of catastrophic thrombosis related to its administration. OBJECTIVE: This review attempts to add safety and efficacy data to existing literature regarding the use of rFVIIa for refractory hemorrhage in pediatric patients on ECMO support. Design/ METHODS: A retrospective chart review was performed for all pediatric patients on ECMO who received rFVIIa for refractory hemorrhage from 2004 to 2009. Data was extracted for each refractory bleeding event, including patient blood loss and transfused blood products in the 6 hours before the first dose, between rFVIIa doses and in the 6 hours after the final dose. For purposes of data collection, a hemorrhagic event was defined as new onset hemorrhage or a hemorrhage occurring at least 12 hours after the most recent dose of rFVIIa. RESULTS: In total, seven patients aged 1 month to 15 years received rFVIIa for 14 different hemorrhagic events. There was no significant difference in blood loss or blood product transfusion associated with rFVIIa administration. There was one patient-related and one ECMO-related complication temporally associated with rFVIIa administration: decreased ECMO circuit oxygenator efficiency and the development of an intra-gastric clot requiring surgical evacuation. CONCLUSION: These data suggest limited efficacy for rFVIIa use for refractory hemorrhage in pediatric patients on ECMO support. There were two non-catastrophic complications temporally associated with its administration. PMID- 23942788 TI - Transient autoimmune hyperthyroidism following the withdrawal of Natalizumab in patients with multiple sclerosis. PMID- 23942789 TI - Adsorption and detection of Escherichia coli using an Au substrate modified with a catecholate-type artificial siderophore-Fe3+ complex. AB - A catecholate-type artificial siderophore with a terminal-NH2 group (1) and its Fe(3+) complex (2) were prepared. Siderophore 1 was characterized by (1)H NMR, FT IR, and ESI-TOF MS spectroscopy. The corresponding Fe(3+) complex 2 was obtained by reaction of 1 with Fe(acac)3. The absorption band at 500 nm (epsilon = 4670 M( 1) cm(-1) at pH 7.0) of the electronic absorption spectrum of 2 is assignable as the LMCT (O(catecholate) -> Fe(3+)) absorption band. This band indicates the formation of the Fe(3+) complex of 1. The biological activity of 2 with respect to Escherichia coli was clearly confirmed by observing that it permeates into the cell membrane. The self-assembled monolayer of 2 on an Au substrate, 2/Au, was prepared and its preparation was confirmed by FT-IR reflection-absorption spectroscopy (IR-RAS) and cyclic voltammetry (CV). Furthermore, a quartz crystal microbalance (QCM) chip modified with 2 effectively adsorbed E. coli. M. flavescens, an organism which is incapable of synthesizing siderophores and must therefore use exogenous hydroxamate-type siderophores for growth, did not adsorb on 2/Au. In contrast, E. coli did not adsorb on the hydroxamate-type artificial siderophore-Fe(3+) complex (3)-modified Au substrate, 3/Au. These results provide preliminary evidence that microbes recognized Fe(3+) ion-bound siderophores on the surface. The detection limit of 2/Au was ~10(4) CFU mL(-1). PMID- 23942790 TI - Predicted values of exercise capacity in heart failure: where we are, where to go. AB - Cardiopulmonary exercise testing (CPET) is a procedure widely used in daily clinical activity to investigate cardiac and pulmonary disorders. Peak oxygen consumption (VO2 peak) is the most validated and clinically accepted parameter used to report aerobic capacity in healthy individuals and in different clinical settings. However, peak VO2 is influenced by several factors, whose variability is nowadays particularly evident due to the extensive use of CPET even in very young and very old subgroups of patients. Thus, its diagnostic and prognostic significance may be improved by the use of % of predicted VO2. At present, many sets of normal values are available, making the identification of the most proper max VO2 predicted value a challenging problem. In fact, normal value sets have been obtained from studies whose accuracy was reduced by important limitations, such as small sample size, low grade of heterogeneity of the population enrolled, poor rigorousness of methods, or difficulty in interpreting results. Accordingly, the aim of the present review is threefold: (A) to report some illustrative cases to show how the choice of the normal value set can influence the report of CPET; (B) to describe the most known and used reference value sets, highlighting the main characteristics of sample population, the most important methodological aspects, and the major limitations of the studies; (C) to suggest which equation should be used, if any, and to underline its weakness. PMID- 23942791 TI - Modelling under-reporting in epidemics. AB - Under-reporting of infected cases is crucial for many diseases because of the bias it can introduce when making inference for the model parameters. The objective of this paper is to study the effect of under-reporting in epidemics by considering the stochastic Markovian SIR epidemic in which various reporting processes are incorporated. In particular, we first investigate the effect on the estimation process of ignoring under-reporting when it is present in an epidemic outbreak. We show that such an approach leads to under-estimation of the infection rate and the reproduction number. Secondly, by allowing for the fact that under-reporting is occurring, we develop suitable models for estimation of the epidemic parameters and explore how well the reporting rate and other model parameters can be estimated. We consider the case of a constant reporting probability and also more realistic assumptions which involve the reporting probability depending on time or the source of infection for each infected individual. Due to the incomplete nature of the data and reporting process, the Bayesian approach provides a natural modelling framework and we perform inference using data augmentation and reversible jump Markov chain Monte Carlo techniques. PMID- 23942792 TI - Interaction of gold nanoparticles with thermoresponsive microgels: influence of the cross-linker density on optical properties. AB - The interaction of spherical gold nanoparticles (Au-NPs) with microgels composed of chemically cross-linked poly-(N-isopropylacrylamide) is reported. Simple mixing of the two components leads to adsorption of the gold particles onto the microgels. Different loading densities can be achieved by varying the ratio of gold particles to microgel particles. The adsorption of gold nanoparticles is analysed by TEM, UV-Vis absorption spectroscopy and SAXS. The influence of the microgel mesh size on the adsorption of gold nanoparticles is investigated by using microgels with three different cross-linker densities. The results suggest a strong relationship between the nanoparticle penetration depth and the cross linker density. This, in turn, directly influences the optical properties of the colloids due to plasmon resonance coupling. In addition, information about the mesh size distribution of the microgels is obtained. For the first time the change in optical properties by varying cross-linker density and temperature is directly related to the formation of dimers of gold particles, proven by SAXS. PMID- 23942793 TI - Racial and ethnic disparities in the use of antipsychotic medication: a systematic review and meta-analysis. AB - OBJECTIVE: To conduct a systematic review and meta-analysis of published evidence on ethnic or racial disparities in the outpatient use versus non-use of antipsychotics and in the outpatient use of newer versus older antipsychotics. METHOD: Electronic databases were searched for potentially relevant studies. Two independent reviewers conducted the review in three stages: title review, abstract review and full-text review. Included studies were those that: (a) report measures of disparity in the outpatient use of antipsychotic drugs in clearly defined racial or ethnic groups (b) have a primary focus on ethnic or racial disparities, and (c) have adjusted for factors known to influence medicine use. Odds ratios were pooled following the inverse-variance method of weighting effect sizes. I (2) statistics were calculated to quantify the amount of variation that is likely due to heterogeneity between studies. Funnel plots were produced and Egger's statistic was calculated to assess potential publication bias. RESULTS: No significant differences were found in the odds of using any antipsychotics among African Americans (OR = 1.01, CI = 0.99-1.02) compared with non-African Americans and among Latinos (OR = 0.98, CI = 0.86-1.13) compared with non-Latinos. Small to moderate but statistically non-significant disparities were also noted in other ethnic groups: Asians (OR = 1.10, CI = 0.88-1.36), Maoris (OR = 0.78, CI = 0.53-1.13) and Pacific Islanders (OR = 0.97, CI = 0.84-1.11). Among those who received antipsychotic medication, African Americans (OR = 0.62, CI = 0.50-0.78) and Latinos (OR = 0.77, CI = 0.73-0.81) appeared to have lower odds of receiving newer antipsychotics compared with non-African Americans and non Latinos. CONCLUSION: No significant ethnic disparities in the use versus non-use of any antipsychotics were observed, but, among those who received antipsychotic treatment, ethnic minorities were consistently less likely than non-ethnic minorities to be treated with newer antipsychotics. PMID- 23942794 TI - Abundance and novel lineages of thraustochytrids in Hawaiian waters. AB - Thraustochydrids has been known for their ubiquitous distribution in the ocean. However, a few efforts have been made to investigate their ecology. In this study, we have applied molecular method, acriflavine direct detection, and classical oceanographic methods to investigate the abundance and diversity of thraustochytrids in the North Pacific subtropical gyre. Our results revealed interesting temporal and spatial variations of their population. Out of three seasons (spring, summer, and fall), cruise Hawaii Ocean Time-series (HOT)-216 during November 2009 obtained the highest abundance of thraustochytrids ranging from 1,890 (Station S1C1, 45 m) to 630,000 (Station S2C12, 100 m) cells L(-1) of seawater, which accounted for a 0.79 to 281.0 % biomass ratio to that of bacteria in terms of gram carbon per liter. A patchy distribution of these organisms was widely observed in the water column and they were somehow related to the maximum chlorophyll layers. A total of 25 operational taxonomic units (OTUs) from cruise HOT-216 formed four phylogroups in the specific labyrinthulomycetes 18S rRNA based phylogenetic tree, with the largest group of 20 OTUs fell into the Aplanochytrium cluster and the others aligned with uncultured clones or none, thus appeared to be undescribed. This study indicates the presence of new thraustochytrids lineages and their quantitative importance in the marine water column. PMID- 23942796 TI - The prognostic significance of Jun transcription factors in ovarian cancer. AB - PURPOSE: The Jun proteins (c-Jun, JunD and JunB) play an important role in the regulation of cell proliferation, apoptosis and angiogenesis. It is well established that these proteins participate in the carcinogenesis and progression in several tumour types. However, little is known about the prognostic significance of Jun proteins in patients with invasive epithelial ovarian carcinoma. METHODS: We analysed fresh-frozen tissues of 161 ovarian cancer patients by using Western blot analysis to investigate protein levels of JunB, JunD, c-Jun and phosphorylated c-Jun (pc-Jun Ser63). The results were correlated with clinicopathologic prognostic parameters and survival data. RESULTS: A high pc-Jun expression was significantly associated with shorter progression-free survival (14 vs. 16 months, p = 0.017) and overall survival (25 vs. 41 months, p = 0.038). In case of JunD, moderate protein levels were associated with a better prognosis, leading to longer progression-free and overall survival compared to weak or strong JunD expression (PFS in cases with weak/moderate/strong JunD expression: 14 vs. 19.5 vs. 16 months, p = 0.011; OAS: 32 vs. 42 vs. 35.5 months, p = 0.009). Multivariate Cox regression analysis confirmed an independent and significant impact of pc-Jun and JunD on the patient's prognosis. CONCLUSIONS: Our results show that Jun proteins (pc-Jun and JunD) influence carcinogenesis and tumour progression, suggesting a significant role as prognostic predictors in human ovarian carcinoma. PMID- 23942795 TI - The development of dasatinib as a treatment for chronic myeloid leukemia (CML): from initial studies to application in newly diagnosed patients. AB - PURPOSE: Dasatinib is a dual Abl/Src tyrosine kinase inhibitor (TKI) designed as a prototypic short-acting BCR-ABL-targeted TKI that inhibits BCR-ABL with greater potency compared with imatinib, nilotinib, bosutinib, and ponatinib and has been shown to have potential immunomodulatory effects. Dasatinib is approved for the treatment of all phases of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to prior imatinib treatment and first-line treatment for CML in chronic phase. In this article, the development of dasatinib as a treatment for patients with CML is reviewed. METHODS: This is a review of the relevant literature regarding dasatinib development in CML (2003-2013). RESULTS: Dasatinib demonstrates efficacy against most BCR-ABL mutations arising during imatinib therapy and is effective in treating patients with imatinib resistance due to other mechanisms. Randomized trial data show that first-line dasatinib provides superior responses compared with imatinib and enables patients to achieve early, deep responses correlated with improved longer-term outcomes. Dasatinib has a generally acceptable safety profile, with most adverse events (AEs) proving manageable and reversible. Cytopenias are commonly observed with dasatinib, and some nonhematologic AEs including pleural effusion have been consistently reported. CONCLUSION: Dasatinib is an effective treatment option for patients with CML. PMID- 23942797 TI - Brief original scientific report: a new surgical approach for the treatment of left pulmonary and hepatic hydatid disease. AB - BACKGROUND: The combination of pulmonary and hepatic hydatid cysts is frequently encountered, and poses a challenge in terms of surgical accessibility. The surgical treatment of the two locations by the same incision (thoracotomy with phrenotomy) has been proposed, but always from the right side. However, applying this technique to the left side seems to be more difficult and unusual. We herein describe a new left-sided technique that was used to treat two patients with pulmonary and hepatic hydatid cysts. METHODS: The first patient was 14-year-old; he had bilateral pulmonary hydatid cysts and one type I cyst of the left lobe of the liver. The second patient was a 10-year-old female who had a hydatid cyst of the upper left lobe with one type III cyst of hepatic segments 2 and 3. RESULTS: Both patients were operated on via a left lateral thoracotomy through the sixth intercostal space. They underwent cystectomy for the left pulmonary hydatid cysts, followed by padding, and then the hepatic cyst was treated by Lagrot's method via a radial phrenotomy. The postoperative course was uneventful in both cases, with postoperative hospital stays of 3 and 5 days, respectively. CONCLUSION: This combined treatment of pulmonary and hepatic hydatid cysts by the left-sided thoracic approach is feasible and provides a good outcome. It should be indicated under the same conditions of accessibility and feasibility applied for the right thoracic side. PMID- 23942798 TI - Single-port versus multiport laparoscopic resection for gastric gastrointestinal stromal tumors: a case-matched comparison. AB - PURPOSE: The aim of this study was to compare the outcomes of single-port laparoscopic gastric resection (SPLGR) with multiport laparoscopic gastric resection (MPLGR) for gastric gastrointestinal stromal tumors (GISTs). METHODS: Between April 2009 and December 2012, 16 consecutive patients with gastric GISTs underwent SPLGR. The patients undergoing the SPLGR were case-matched for age, sex, body mass index and tumor location with those undergoing MPLGR. The demographic and surgical outcomes were analyzed and compared from the review of a prospectively collected database of 16 patients who underwent MPLGR. RESULTS: All 16 patients underwent complete SPLGR without any intraoperative complications. No significant differences were observed in the mean length of the operation (91.4 vs. 94.1 min), blood loss (6.3 vs. 10.1 ml) and length of postoperative hospital stay (4.7 vs. 5.4 days) between the SPLGR and MPLGR groups. The tumor size was similar (37.8 vs. 32.1 mm) and negative surgical margins were achieved in all patients. At a mean follow-up of 27 months, all 16 SPLGR patients were disease free. CONCLUSIONS: Our initial comparison demonstrated that SPLGR, when performed by experienced surgeons, is a safe and feasible procedure for patients with gastric GISTs, resulting in good surgical and oncological outcomes. PMID- 23942800 TI - [Transfer of the flexor digitorum superficialis tendons of the middle and ring fingers to restore extension of fingers and thumb (Boyes' transfer)]. AB - OBJECTIVES: Restoration of extension in the metacarpophalangeal joints of the fingers as well as in the interphalangeal joint of the thumb by transfer of the superficial flexor tendons of the long and ring fingers (flexor digitorum superficialis III and IV). INDICATIONS: The indications for surgery are substantial loss and palsy of muscles innervated by the radial nerve and its roots. CONTRAINDICATIONS: The procedure is contraindicated by reversible radial palsy, palsy or substantial loss of flexors, limited passive mobility due to contracture, ankylosis or instability of the affected joints, instability of the wrist joint, palsy of the wrist flexors, ankylosis of the wrist joint in an unfavorable position, adhesions of flexor or extensor tendons, insufficient soft tissue coverage or soft tissue defects and passage of transposed tendons through scarred tissue. SURGICAL TECHNIQUE: The surgical technique involves division of the superficialis tendons of the long and ring fingers proximal to Camper's chiasm and routing of the tendons to the dorsum of the hand through separate fenestrations of the interosseus membrane. The flexor digitorum superficialis tendon III is interwoven into the tendons of the extensor pollicis longus und extensor indicis and the flexor digitorum superficialis IV is interwoven into the extensor digitorum tendons. POSTOPERATIVE MANAGEMENT: Forearm splinting in 20 degrees wrist extension including the metacarpophalangeal joints of the fingers in extension and the thumb in the automatic stop position for 4 weeks leaving the proximal and distal interphalangeal joints free. RESULTS: From March 1999 to January 2010 a Boyes' transfer was performed in 13 patients (8 female and 5 male) and the right side was affected in 8, the left side in 5 and the dominant hand in 7 cases. The patient age at the time of surgery was an average of 47 +/- 17 (13 73) years. The interval between radial palsy and tendon transfer was an average of 79 +/- 144 (4-543) months. The final follow-up was performed at an average of 82 +/- 35 (32-165) months. According to the Haas scoring system finger extension was excellent in 5, good in 5, fair in 3 and unfavorable in 4 cases and thumb extension was excellent in 5, good in 3, fair in 1 and unfavorable in 5 patients. The mean disabilities of the arm, shoulder and hand (DASH) score was 36 +/- 24 (11-85) points. Although disability of varying degrees persisted in all patients, Boyes' transfer is considered to be a safe procedure to restore finger and thumb extension with excellent and good functional results, a high degree of patient satisfaction and few complications. PMID- 23942801 TI - [Enlargement plasty of the first dorsal compartment for the surgical treatment of de Quervain's tenosynovitis]. AB - OBJECTIVE: Reliable reduction of pain, observance of anatomical variations, avoidance of complications. INDICATIONS: Failure of conservative treatment, clinically obvious diagnosis, positive Finkelstein test (pathognomonic). CONTRAINDICATIONS: Previous splitting of the retinaculum of the first dorsal compartment, uncertainty of diagnosis. SURGICAL TECHNIQUE: Skin incision with protection of the branches of the superficial radial nerve, exposure of the first dorsal compartment, w-shaped incision and preparation of the retinaculum lobes, exposure of all tendons, inspection of the whole compartment and possible anatomic variations. Loose adaptation of the lobes, irrigation, hemostasis, skin closing. POSTOPERATIVE MANAGEMENT: Consequent immobilization in a thumb cast for a total of 3 weeks (+ 3 weeks optional depending on load/profession). Sutures removed after 2 weeks, then the patient can start mobilization exercises (without the splint) after 3 weeks. RESULTS: Between August 2005 and July 2007, 38 patients (40 wrists) were operated without complications. No tendon subluxation/dislocation, one wrist with persistent slightly positive Finkelstein test, in all other cases complete relief of the symptoms. All patients would elect to repeat the surgery. PMID- 23942802 TI - [Operative treatment of claw deformity by lassoplasty]. AB - OBJECTIVES: The aim is correction of claw deformity of the fingers by intrinsic paralysis. INDICATIONS: Indications are claw deformity of fingers caused by palsy or functional loss of the interosseus or lumbrical muscles as far as the function of the superficial and deep flexors of the finger is intact. CONTRAINDICATIONS: Contraindications are loss or paralysis of finger flexors supplied by the median nerve, fixed extension or flexion contracture of the finger joints, osteoarthritis and other malfunctions of the finger joints, no active flexion and extension of the interphalangeal joints due to compromised tendon gliding. Relative: Upper ulnar nerve palsy with functional loss of the deep flexor of the small and ring finger and possibly of the middle finger. SURGICAL TECHNIQUE: The operation technique involves detachment of the flexor digitorum superficialis IV tendon (FDS IV) distal to Camper's chiasm, division of the tendon into separate strips, interweaving of each tendon strip into the proximal part of the A2 pulley of the affected fingers. In cases of claw deformity of all fingers it may be advantageous to apply the superficial flexor tendon of the long finger in addition to the FDS IV tendon as otherwise the FDS IV tendon has to be divided into four strips resulting in relatively thin tendon strips. If the FDS III and IV tendons are applied, the two strips of the FDS IV tendon are used for lassoplasty of the small and ring fingers and the FDS III tendon for lassoplasty of the middle and index fingers. POSTOPERATIVE MANAGEMENT: Postoperative management includes immobilization of the operated fingers by a dorsoulnar forearm plaster cast including the metacarpophalangeal joints which are flexed to 70 degrees . After 2 weeks replacement of the cast by a thermoplastic splint for another 4 weeks. During the whole period exercises for the finger and thumb should be carried out. RESULTS: From April 2003 to June 2012 a total of 17 patients, 8 female and 9 male were surgically treated for claw deformity. The dominant hand was affected in seven patients. The average age was 46 +/- 15 (22 80) years, the average interval from onset of ulnar palsy to lassoplasty was 61 +/- 91 (3-288) months. The final follow-up was performed after an average of 42 +/- 32 (2-112) months. Claw deformity was resolved in 14 out of the 17 patients. The grip strength was on average 58 +/- 28 % (11-96 %) of the unaffected hand, the mean disabilities of the arm, shoulder and hand (DASH) score was 32 +/- 18 (5 68) points and the degree of patient satisfaction 7 +/- 2 (0-10). According to own results and those in the literature lassoplasty can be recommended for the treatment of claw deformity. PMID- 23942803 TI - [Tendon transfers of the upper extremities]. PMID- 23942805 TI - Delightful contradictions! PMID- 23942804 TI - Human papilloma virus lesions of the oral cavity: healing and relapse after treatment with 810-980 nm diode laser. AB - This study evaluated the therapeutic efficacy of laser therapy in treating oral human papilloma virus (HPV) lesions. In particular, mode of action, healing, postoperative patient compliance, visual numeric scale (VNS) pain index, and recurrence were analyzed. During 2001-2012, in 170 patients (80 women and 90 men), 174 intraoral and lip HPV lesions were detected and excised by diode laser of different wavelengths (810-980 nm), with an average power of 2.1 W, in continuous wave mode, using 300 to 320 MUm optical fibers. In most cases (95.4%), complete healing occurred in the first 30 days. There were no adverse effects and all patients were carefully followed up until complete healing occurred, documenting any complications. There was only one recurrence, which was later treated successfully; the mean VNS pain score was below one. In treating HPV lesions, the diode laser is not only a valuable tool for their eradication but especially it reduces relapses, thanks to the characteristics of the laser light. PMID- 23942807 TI - Interview with Chris Moody. PMID- 23942806 TI - Assessing remedies for missing weekly individual exposure in sport injury studies. AB - BACKGROUND: In sport injury epidemiology research, the injury incidence rate (IR) is defined as the number of injuries over a given length of participation time (exposure, eg, game hours). However, it is common that individual weekly exposure is missing due to requirements of personnel at every game to record exposure information. Ignoring this issue will lead to an inflated injury rate because the total exposure serves as the denominator of IR, where the number of injury cases were captured accurately. PURPOSE: This paper used data collected from a large community cohort study in youth ice hockey as an example, and compared six methods to handle missing weekly exposure of individual players. METHODS: The six methods to handle missing weekly exposures include available case analysis, last observation carried forward, mean imputation, multiple imputation, bootstrapping and best/worst case analysis. To estimate injury rate ratios (IRRs) between Alberta and Quebec, as in the original study, three statistical models were applied to the imputed datasets: Poisson, zero-inflated Poisson and negative binomial regression models. RESULTS: The final sample for imputation included 2098 players for whom 12.5% of weekly game hours were missing. Estimated IRs and IRRs with CIs from different imputation methods were similar when the proportion of missing was small. Simulations showed that mean and multiple imputations provide the least biased estimates of IRR when the proportion of missing was large. CONCLUSIONS: Complicated methods, like multiple imputation or bootstrap, are not superior over the mean imputation, a much simpler method, in handling missing weekly exposure of injury data where exposures were missing at random. PMID- 23942808 TI - Syntheses of Pd(II)/Pt(II) complexes with non-chelating 4-pyridylselenolate ligand ranging from mononuclear to macrocyclic structures and their utility as catalysts in Suzuki C-C coupling reaction. AB - Treatment of Na2PdCl4 or [MCl2(PhCN)2] with bis(4-pyridyl)diselenide yielded an insoluble product of composition [MCl2(4,4'-(C5H4N)2Se2)]n (1). The reactions of Na2PdCl4 with one and two eq. of Na(4-SeC5H4N) afforded insoluble products [PdCl(4-SeC5H4N)]n (2) and [Pd(4-SeC5H4N)2]n (3), respectively. On treatment with PPh3, 2 and 3 gave trans-[PdCl(4-SeC5H4N)(PPh3)2] (4a) and trans-[Pd(4 SeC5H4N)2(PPh3)2] (5a), respectively. The oxidative addition of bis(4 pyridyl)diselenide to Pt(PPh3)4 exclusively yielded trans-[Pt(4-SeC5H4N)2(PPh3)2] (5b). The treatment of two eq. of Na(4-SeC5H4N) with cis-[PtX2(PR3)2] afforded 5b (X = Cl) and trans-[Pt(4-SeC5H4N)2(PEt3)2] (5c) (X = Cl or CF3SO3). The reactions of cis-[MCl2(P?P)] and [M2Cl2(MU-Cl)2(PR3)2] with two eq. of Na(4-SeC5H4N) exclusively yielded cis-[M(4-SeC5H4N)2(P?P)] (M/P?P = Pd/dppe (6a), Pt/dppm (6b) and Pt/dppp (6c)) and [MCl(4-SeC5H4N)(PR3)]n (7), respectively. The complex trans [PtCl(4-SeC5H4N)(PEt3)2] (4b) was isolated from the redistribution reaction between 5c and cis-[PtCl2(PEt3)2]. The complex [PdCl(4-SeC5H4N)(PPh3)]n (7b) exists in bi- and tri-nuclear forms, whereas [MCl(4-SeC5H4N)(PEt3)]n (7a, 7c) and [PtCl(4-SeC5H4N)(PMe2Ph)]n (7d) retain their trinuclear structure in solution. Molecular structures of 4a, 4b, 5a, 5c, 6a, 6c, 7a, 7b and 7c were established by single crystal X-ray diffraction analyses. The complexes trans-[PdCl(4 SeC5H4N)(PPh3)2] and [PdCl(4-SeC5H4N)(PPh3)]n can act as catalysts for Suzuki C-C cross coupling reaction. PMID- 23942809 TI - Synthesis, biological evaluation and molecular docking of novel 5-phenyl-1H pyrazol derivatives as potential BRAF(V600E) inhibitors. AB - The RAF-MEK-ERK cascade appears to be intimately involved in the regulation of cell cycle progression and apoptosis. The BRAF(V600E) mutant results in constitutive activation of the ERK pathway, which can lead to cellular growth dysregulation. A series of 5-phenyl-1H-pyrazol derivatives (3a-5e) have been designed and synthesized, and their biological activities were evaluated as potential BRAF(V600E) inhibitors. All the compounds were reported for the first time except 3e, and compound 1-(4-bromo-2-hydroxybenzyl)-3-phenyl-1-(5-phenyl-1H pyrazol-3-yl)urea (5c) displayed the most potent inhibitory activity (BRAF(V600E) IC50 = 0.19 MUM). Antiproliferative assay results indicated that compound 5c possessed high antiproliferative activity against cell lines WM266.4 and A375 in vitro, with IC50 values of 1.50 and 1.32 MUM, respectively, which were comparable with the positive control vemurafenib. Docking simulations showed that compound 5c binds tightly to the BRAF(V600E) active site and acts as BRAF(V600E) inhibitor. A 3D-QSAR model was also built to provide more pharmacophore understanding towards designing new agents with more potent BRAF(V600E) inhibitory activity. PMID- 23942810 TI - Outcomes of same-site re-operation with minimal use of mitomycin in failed trabeculectomy. AB - To evaluate efficacy and safety of same site re-operation in eyes with failed trabeculectomy. A retrospective, noncomparative, interventional case series. We reviewed the medical records of 35 eyes of 35 patients who underwent same-site re operation for failed trabeculectomy. The surgery involved a fornix-based peritomy at the same site as the previous trabeculectomy with application of 0.2 mg/mL mitomycin for 1 min. Primary outcome measures were intraocular pressure (IOP) control and number of antiglaucoma medications at last follow-up. Success rates were defined according to criteria (A) IOP <= 21 mmHg or (B) IOP <= 18 mmHg, with or without antiglaucoma medication. The mean age of the patients was 43.3 +/- 18.0 years and 62.9 % were male. The mean follow-up was 13.6 +/- 12.0 months (range 6-49 months). At final follow-up, mean baseline IOP was reduced from 27.2 +/- 8.0 to 16.6 +/- 7.5 mmHg (p < 0001). The mean number of antiglaucoma medications was reduced from 2.8 +/- 0.8 to 1.0 +/- 1.3 (p < 0001). This study supports the efficacy and safety of same-site re-operation with minimal use of mitomycin C for management of failed filtering blebs following trabeculectomy. PMID- 23942812 TI - Temporary removal of the posterior bony canal wall with reconstruction using microplate osteosynthesis in cholesteatoma surgery: a case series and description of the technique. AB - We describe the surgical technique of temporary removal of the posterior auditory canal wall with reconstruction and report the outcome of using this technique as a treatment method for cholesteatoma in a case series. In 32 cases of cholesteatoma surgery a technique of temporary removal of the posterior bony wall was applied. During primary surgery the posterior auditory canal wall was removed using an oscillating saw. For the purpose of reconstruction, the canal wall was repositioned and fixed using two titanium microplates (n = 26). In case the canal wall could not be reconstructed with osteosynthesis, either glass-ionomeric cement (BioCemTM) was used for fixation (n = 4) or fibrin glue (TissucolTM) (n = 2) to support the posterior wall. The outcome includes the healing process in the first postoperative month, the absence of residual or recurrent disease and the successful reconstruction of the posterior auditory canal wall as evaluated during second-look surgery. When microplates where used, we saw healing problems of the canal skin in about 4% of patients. Recurrent cholesteatoma was found in 4 cases (14%), residual cholesteatoma in 8 ears (25%). In the osteosynthesis group, successful reconstruction was achieved in 25 patients (96%). In 3 out of 4 patients of the glass-ionomeric cement group (75%) excessive granulation tissue developed with extensive bony lysis. Temporary removal of the posterior auditory canal wall offers potential for the control of cholesteatoma. Our first results suggest that osteosynthesis allows for a good anatomical and functional reconstruction. PMID- 23942815 TI - Correlation between antibodies and histology in celiac disease: incidence of celiac disease is higher than expected in the pediatric population. AB - The present study aims to report on the correlation between the degree of negativity of anti-endomysial antibodies and anti-tissue transglutaminase antibodies in the IgA and IgG classes with regard to histological grade, in 44 newly diagnosed children with celiac disease (CD). Samples with negative antibodies, but a positive histology from a 5-year program searching for CD in the pediatric population were collected. A total of 4247 biopsy samples were used in this study. We documented that certain pediatric patients are seronegative, while the disease is active and the incidence of CD is higher than expected in the pediatric population. This is an important finding, which demonstrates the lack of association between autoantibodies and lesions, and justifies the use of biopsies for an accurate CD diagnosis and the importance of revising the diagnostic criteria in a clinical, endoscopic and serological context. We recommend a more active search for incidences of the disease in the pediatric population. Serological markers are not the main method for the diagnosis of CD as they are considered to only have a supporting role clinically. Biopsies of the small intestine are always necessary for the diagnosis of CD in these patients. PMID- 23942816 TI - Geno- and cyto-toxicity in free-living rodent Mus spretus exposed to simulated onshore oil spill. AB - This study investigated geno- and cyto-toxic damage in the free-living rodent, Mus spretus after exposure to a simulated spill of crude oil on soil. The results revealed increased mutagenicity and cytotoxicity in bone marrow cells and increased DNA damage in blood cells. Exposure to crude oil increased sperm abnormalities, with lasso-like folds being the most common. These results point to the value of this rodent in serving as a sentinel species for the monitoring and prediction of environmental hazards. PMID- 23942813 TI - Risks and medico-legal aspects of endoscopic sinus surgery: a review. AB - The aim of this study was to perform a systematic literature review of risks and medico-legal aspects of endoscopic sinus surgery. The development of sophisticated technologies and instruments for endoscopic sinus surgery (ESS) has caused a dramatic increase in the number of otolaryngologists performing sinus surgery and the number of cases performed. This expansion was accompanied by an increase in malpractice lawsuits. Over the past 20 years, rhinology claims represented 70 % of the total indemnity compensation for otolaryngology claims and ESS was the surgical procedure most often involved. Only then will a careful analysis and assessment of the possible and potential risk factors of ESS, which may mislead the surgeon, allow a correct clinical risk management, with activities and procedures aimed at reducing the possibility of complications that may expose the physician to a malpractice suit. PMID- 23942817 TI - [Restoration of thumb flexion at the interphalangeal joint by transposition of the flexor digitorum superficialis tendon from the ring finger]. AB - OBJECTIVE: Restoration of active thumb flexion at the distal joint. INDICATIONS: Loss of active flexion of the interphalangeal (IP) joint of the thumb if there is a transection of the flexor pollicis longus (FPL) tendon at the tendon channel of the thumb or thenar and direct suture is not possible but the tendon channel is intact, as alternative procedure to a free tendon graft if the transection is proximal to the tendon channel and the muscle of the FPL is contracted/injured or the FPL tendon is unharmed but the FPL muscle is partially or complete paralyzed. CONTRAINDICATIONS: Insufficiency of the FPL tendon channel, impairment of the superficial or deep flexor tendon of the ring finger, limited passive motion of the proximal and distal thumb joints, acute local general infection and non compliance or incapacity of the patient. SURGICAL TECHNIQUE: The surgical technique depends on the necessity of transosseous refixation of the FDS IV at the base of the distal phalanx of the thumb or the possibility of woven sutures through the FPL proximal to the tendon channel. If the tendon channel is intact the distal part of the FPL tendon is shortened to 1 cm, the FDS IV tendon is cut distal to the chiasma of Camper, pulled through the carpal tunnel and moved into the channel of the FPL tendon and fixed transosseously through the base of the distal phalanx of the thumb. If the transection of the FPL tendon is located proximal to the tendon channel and muscle of the FPL is injured, FDS IV tendon will be woven using the Pulvertaft technique through the FPL tendon at the distal forearm. POSTOPERATIVE MANAGEMENT: Postoperative 6 weeks motion of thumb flexion without resistance in relieved position of the thumb through a thermoplast splint and 6 weeks of functional use of the hand with increasing weight bearing. RESULTS: In this study 10 patients with FDS IV transposition to reconstruct an isolated rupture of the FPL tendon could be followed for an average of 4.1 years postoperatively. The active range of motion of the IP joint of the thumb averaged 65 degrees (10-100 degrees ), 8/10 patients achieved an equal active and passive range of motion of the IP joint of the thumb, in 2 patients some flexion insufficiency remained, 9 patients could reach the fingertip of the small finger with the thumb and 1 patient lacked 3 mm. Contracture of the proximal thumb joint developed in two patients. After removal of the FDS IV tendon two patients developed contracture of the PIP joint of the ring finger. The grip force was reduced to 81 %, lateral grip to 83 % and pinch grip to 77 %. The DASH score averaged 18 (0-31) and 8/10 patients would choose to undergo this surgery again. PMID- 23942818 TI - Endovenous laser ablation of the great saphenous vein versus high ligation: long term results. AB - Endovenous laser therapy (EVLT) for greater saphenous vein (GSV) insufficiency is a relatively new method of treatment only recently made available in Iran. This is the first long-term randomized trial comparing EVLT with high ligation of saphenous vein (HLS) in the Iranian population. Sixty-five patients met the inclusion criteria and were divided into homogenous treatment groups of EVLT (n = 30) or HLS (n = 35). Clinical severity, etiology, anatomy, pathophysiology (CEAP) classification and Aberdeen Varicose Vein Symptom Severity Scores (AVSS) were used to determine disease severity and symptoms before and after the procedure in both groups. Outcome was measured by the rate of recurrence as shown in Doppler ultrasonography evaluation. Follow-up was conducted 1 week and 3, 6, 12, and 18 months after the intervention. The occlusion rate of GSV was similar in both groups (93.6% for EVLT, 88.3 for HLS) at 18 months of follow-up. The median CEAP score showed a dramatic decrease in both groups after 1 week which was sustained for the rest of the study. The Aberdeen Varicose Vein Symptom Severity score was significantly lower in the EVLT group at 12 and 18 months of follow-up. There was no significant difference in patient satisfaction in both groups. Our findings show that EVLT may offer a better long-term relief of symptoms. This, alongside its better cosmetic outcome, and less invasive anesthesia requirements may make it the favorable choice for treatment of GSV insufficiency. PMID- 23942819 TI - Postoperative complications following neoadjuvant bevacizumab treatment for advanced colorectal cancer. AB - PURPOSES: Attempts have been made to use bevacizumab (BEV) in an adjuvant or neoadjuvant setting. However, BEV is known to cause various adverse events, and the safety of neoadjuvant BEV has not yet been fully evaluated. This study assessed the postoperative complications in patients receiving neoadjuvant BEV for colorectal cancer. METHODS: The data for 78 patients with resectable advanced or metastatic colorectal cancer who received neoadjuvant BEV followed by surgical resection were retrospectively analyzed. RESULTS: The median interval between the last BEV dose and surgery was 9 weeks. The most common postoperative complication was pelvic sepsis, which occurred in 11 patients (14 %). A biliary fistula developed in four of 23 patients who underwent liver resection. Anastomotic leakage occurred in six of 24 patients with a colorectal anastomosis, four of whom required re-laparotomy. In a univariate analysis, male gender and a greater intraoperative blood loss were associated with postoperative complications of any grade. Colorectal anastomosis was a risk factor for major complications. In a multivariate analysis, intraoperative blood loss was an independent risk factor for postoperative complications of any grade (HR 6.338; P = 0.003). With regard to major postoperative complications, colorectal primary anastomosis was the only independent predictive risk factor (HR 8.285; P = 0.013). CONCLUSIONS: In patients with colorectal cancer who underwent elective surgery after BEV treatment, the interval between BEV and surgery was not a risk factor for postoperative complications (based on a median interval of 9 weeks). Colorectal primary anastomosis was the only independent risk factor for major postoperative complications. PMID- 23942821 TI - TCNQ-embedded heptacene and nonacene: synthesis, characterization and physical properties. AB - Incorporation of 7,7,8,8-tetracyanoquinodimethane (TCNQ) moieties into the acene backbone has been successfully achieved and two heptacene-TCNQ derivatives and one nonacene-TCNQ derivative have been synthesized and well characterized. Two TCNQ moieties have been embedded into heptacene and nonacene backbones for the first time. All the three compounds have good stability and solubility due to the presence of TCNQ moieties. Single crystal analysis revealed a bent butterfly-like conformation of these molecules. Their charge transport properties have been characterized using organic field effect transistors (OFETs). PMID- 23942822 TI - Highlights from the 48th EUCHEM conference on stereochemistry, Burgenstock, Switzerland, May 2013. PMID- 23942820 TI - Positive peritoneal washing cytology is a potential risk factor for the recurrence of curatively resected colorectal cancer. AB - PURPOSES: Whether free peritoneal cancer cells should be considered peritoneal dissemination in colorectal cancer patients remains controversial. The aim of this study was to investigate the clinical significance of positive peritoneal washing cytology (PWC) in patients with colorectal cancer. METHODS: We retrospectively analyzed the records of 771 sequential patients diagnosed with stage 0-III colorectal cancer who underwent R0 resection and had no distant metastases or peritoneal dissemination. RESULTS: PWC was performed on all 771 patients. Sixty-eight patients experienced metastasis recurrence, 10 of whom experienced peritoneal recurrence. Of the 10 patients with peritoneal recurrence, 6 had positive PWC. Out of the 771 patients, 21 had positive PWC. Of these 21 patients, 6 had peritoneal recurrence, while 4 had distant metastasis and no peritoneal recurrence during the observation period. The 5-year disease-free survival was 89.0 % in the patients with negative PWC vs. 46.8 % in the patients with positive PWC (p < 0.0001, log-rank test). A Cox proportional hazards model revealed that positive PWC was the strongest independent risk factor for cancer specific recurrence. CONCLUSIONS: Our study highlights PWC as a useful prognostic tool in patients undergoing curative surgery for colorectal cancer, since positive PWC was shown to be a potential risk factor for recurrence. PMID- 23942823 TI - Highly uniform and monodisperse GdOF:Ln3+ (Ln = Eu, Tb, Tm, Dy, Ho, Sm) microspheres: hydrothermal synthesis and tunable-luminescence properties. AB - GdOF:Ln(3+) (Ln = Eu, Tb, Tm, Dy, Ho and Sm) microspheres (1.5 MUm) with high uniformity and monodispersity have been synthesized via a facile hydrothermal method followed by heat treatment (600 degrees C). X-Ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), as well as photoluminescence (PL) and cathodoluminescence (CL) spectra are used to characterize the resulting samples. A series of controlled experiments indicate that sodium citrate (Cit(3 )) as a shape modifier introduced into the reaction system plays a critical role in the shape evolution of the final products. Furthermore, the shape and size of the products can be further manipulated by adjusting the dosage of Cit(3-) and pH values in the initial solution. The possible formation mechanism for these microspheres has been presented. Under UV light and low-voltage electron beam excitation, GdOF:Ln(3+) microspheres show the characteristic f-f transitions of Ln(3+) (Eu, Tb/Ho, Tm, Dy and Sm) ions and give bright red, green, blue, yellow and yellowish-orange emission, respectively. In addition, multicolored luminescence containing white emission have been successfully confected for co doped GdOF:Ln(3+) phosphors by changing the doped Ln(3+) ions and adjusting their doping concentrations due to the simultaneous luminescence of Ln(3+) in the GdOF host, making these materials have potential applications in field-emission display devices. PMID- 23942825 TI - Health services accreditation: what is the evidence that the benefits justify the costs? AB - PURPOSE: To identify and analyse research on the use of economic evaluation in health services accreditation. DATA SOURCES: Seven online health and economic databases, and key accreditation agency and health department websites were searched between June and December 2011. STUDY SELECTION: The selection criteria were English language and published empirical research studies on the topic of economic evaluation of health service accreditation. No formal economic evaluation of health services accreditation has been carried out to date. Empirical data on costs and benefits were analysed in 6 and 15 studies, respectively. Data extraction Meta-analysis was unsuitable due to output variability. Attributes relating to STUDY DESIGN: scalability and independence of outcome data were collected. For the benefit studies, we also assessed the strength of claim that accreditation improved patient safety and quality, and sources of potential bias. RESULTS OF DATA SYNTHESIS: The incremental costs ranged from 0.2 to 1.7% of total costs averaged over the accreditation cycle. The benefit studies were inconclusive in terms of showing clear evidence that accreditation improves patient safety and quality of care. CONCLUSION: The lack of formal economic appraisal makes it difficult to evaluate accreditation in comparison to other methods to improve patient safety and quality of care. The lack of a clear relationship between accreditation and the outcomes measured in the benefit studies makes it difficult to design and conduct such appraisals without a more robust and explicit understanding of the costs and benefits involved. PMID- 23942826 TI - Parental emotion socialization in clinically depressed adolescents: enhancing and dampening positive affect. AB - This study compared parental socialization of adolescent positive affect in families of depressed and healthy adolescents. Participants were 107 adolescents (42 boys) aged 14 - 18 years and their parents. Half of the participants met criteria for major depressive disorder and the others were demographically matched adolescents without emotional or behavioral disorders. Results based on multi-source questionnaire and interview data indicated that mothers and fathers of depressed adolescents were less accepting of adolescents' positive affect and more likely to use strategies that dampen adolescents' positive affect than were parents of healthy adolescents. Additionally, fathers of depressed adolescents exhibited fewer responses likely to enhance the adolescents' positive affect than were fathers of healthy adolescents. These findings build on those of previous work in examining parental responses to adolescent emotions, focusing on positive emotions and including both mothers and fathers. PMID- 23942824 TI - Physical comorbidity and its relevance on mortality in schizophrenia: a naturalistic 12-year follow-up in general hospital admissions. AB - Schizophrenia is a major psychotic disorder with significant comorbidity and mortality. Patients with schizophrenia are said to suffer more type-2 diabetes mellitus (T2DM) and diabetogenic complications. However, there is little consistent evidence that comorbidity with physical diseases leads to excess mortality in schizophrenic patients. Consequently, we investigated whether the burden of physical comorbidity and its relevance on hospital mortality differed between patients with and without schizophrenia in a 12-year follow-up in general hospital admissions. During 1 January 2000 and 31 June 2012, 1418 adult patients with schizophrenia were admitted to three General Manchester NHS Hospitals. All comorbid diseases with a prevalemce >=1% were compared with those of 14,180 age- and gender-matched hospital controls. Risk factors, i.e. comorbid diseases that were predictors for general hospital mortality were identified using multivariate logistic regression analyses. Compared with controls, schizophrenic patients had a higher proportion of emergency admissions (69.8 vs. 43.0%), an extended average length of stay at index hospitalization (8.1 vs. 3.4 days), a higher number of hospital admissions (11.5 vs. 6.3), a shorter length of survival (1895 vs. 2161 days), and a nearly twofold increased mortality rate (18.0 vs. 9.7%). Schizophrenic patients suffered more depression, T2DM, alcohol abuse, asthma, COPD, and twenty-three more diseases, many of them diabetic-related complications or other environmentally influenced conditions. In contrast, hypertension, cataract, angina, and hyperlipidaemia were less prevalent in the schizophrenia population compared to the control population. In deceased schizophrenic patients, T2DM was the most frequently recorded comorbidity, contributing to 31.4% of hospital deaths (only 14.4% of schizophrenic patients with comorbid T2DM survived the study period). Further predictors of general hospital mortality in schizophrenia were found to be alcoholic liver disease (OR = 10.3), parkinsonism (OR = 5.0), T1DM (OR = 3.8), non-specific renal failure (OR = 3.5), ischaemic stroke (OR = 3.3), pneumonia (OR = 3.0), iron-deficiency anaemia (OR = 2.8), COPD (OR = 2.8), and bronchitis (OR = 2.6). There were no significant differences in their impact on hospital mortality compared to control subjects with the same diseases except parkinsonism which was associated with higher mortality in the schizophrenia population compared with the control population. The prevalence of parkinsonism was significantly elevated in the 255 deceased schizophrenic patients (5.5 %) than in those 1,163 surviving the study period (0.8 %, OR = 5.0) and deceased schizophrenic patients had significantly more suffered extrapyramidal symptoms than deceased control subjects (5.5 vs. 1.5 %). Therefore patients with schizophrenia have a higher burden of physical comorbidity that is associated with a worse outcome in a 12-year follow-up of mortality in general hospitals compared with hospital controls. However, schizophrenic patients die of the same physical diseases as their peers without schizophrenia. The most relevant physical risk factors of general hospital mortality are T2DM, COPD and infectious respiratory complications, iron-deficiency anaemia, T1DM, unspecific renal failure, ischaemic stroke, and alcoholic liver disease. Additionally, parkinsonism is a major risk factor for general hospital mortality in schizophrenia. Thus, optimal monitoring and management of acute T2DM and COPD with its infectious respiratory complications, as well as the accurate detection and management of iron-deficiency anaemia, of diabetic-related long-term micro- and macrovascular complications, of alcoholic liver disease, and of extrapyramidal symptoms are of utmost relevance in schizophrenia. PMID- 23942827 TI - The factor structure of anxiety and depressive disorders in a sample of clinic referred adolescents. AB - The current study used confirmatory factor analysis (CFA) to examine the factor structure of anxiety and depressive disorders in a sample of clinic-referred adolescents, aged between 12 and 18 years, for diagnoses based on parent (N = 655; male = 441) and adolescent (N = 626; male = 417) interviews. Three models were examined: a 1-factor model, with all anxiety and depressive disorders in a single factor; a DSM-based 2-factor model, with anxiety disorders in one factor, and depressive disorders in another factor; and an alternate 2-factor model, with fear related anxiety disorders in one factor, and other anxiety and depressive disorders in another factor. The findings indicated support for all three models. Also, ADHD and ODD/CD were associated with only the shared variances between the latent factors in the 2-factor models, and not their unique variance. The implications of the findings for taxonomy, comorbidity, and clinical practice are discussed. PMID- 23942829 TI - Muslim teachers' conceptions of evolution in several countries. AB - Using a questionnaire validated by the project Biohead-Citizen, where 15 questions are dedicated to evolution, we analyse Muslim teachers' conceptions of evolution in several countries. The first part compares nine francophone countries, with varying degrees of Muslim or Christian culture: France, Morocco, Algeria, Tunisia, Lebanon, Senegal, Burkina Faso, Cameroon and Gabon, and shows a strong contrast between France and the eight other countries. The second part compares Muslim and Christian teachers in the countries where the comparison is possible, finding no difference, or a few differences in Lebanon. The third part analyses the data related to the 2130 Muslim teachers sampled to identify the controlled parameters that can be correlated to their variations. The discussion is structured by three questions: Are Muslim countries, and Muslim teachers, more creationist than other ones? Is the teachers' knowledge related to their more or less creationist conceptions? Are Muslim teachers more creationist in European countries? PMID- 23942828 TI - German guidelines for the sequential medical treatment of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs. AB - The German Society of Rheumatology approved new German guidelines for the sequential medical treatment of rheumatoid arthritis (RA) based on the European League Against Rheumatism (EULAR) recommendations for the management of RA published in 2010. An update of the EULAR systematic literature research was performed in Medline, Embase, and Cochrane databases. Meta-analyses, controlled trials, cohort studies, and registry data addressing traditional and biologic disease-modifying antirheumatic drugs, glucocorticoids, and treatment strategies published between January 2009 and August 2011 were included. Two reviewers independently evaluated and compared the additional data that had been published after the time limit set by the EULAR recommendations. A national guideline working group developed an adapted set of recommendations. The new German guidelines were accepted by vote using an informal Delphi approach. Twelve recommendations and the resulting updated treatment algorithm were developed and approved as a practical orientation for rheumatologists. These recommendations are based on a successive treatment with traditional and biologic disease modifying drugs depending on the individual progress of the disease and distinct patient characteristics. The German guidelines have been developed on the basis of the internationally well-recognized EULAR recommendations. In addition, more recent evidence from a systematic literature research was considered. They have been developed and approved by a group of national experts aiming at guidance for rheumatologists to reach best medical practice. PMID- 23942830 TI - Public media communications about H1N1, risk perceptions and immunization behaviours: A Quebec-France comparison. AB - During the H1N1 pandemic, governments tailored their communications plans in order to influence risk perception and promote public compliance with the public health plan measures. Considering the volume and the content of calls to flu information centres as indicators of the public risk perception, this mixed method study compares the relation between public communications, risk perception and immunization behaviour in Quebec and France. Results suggest that advocating for clear information and coordination between health authorities and the media promotes adherence to preventive behaviour. However, over-exaggerating the risks and minimizing the population's agency may undermine health authority credibility. PMID- 23942831 TI - Fracking in the UK press: threat dynamics in an unfolding debate. AB - Shale gas is a novel source of fossil fuel which is extracted by induced hydraulic fracturing, or "fracking". This article examines the socio-political dimension of fracking as manifested in the UK press at three key temporal points in the debate on the practice. Three newspaper corpora were analysed qualitatively using Thematic Analysis and Social Representations Theory. Three overarching themes are discussed: "April-May 2011: from Optimism to Scepticism"; "November 2011: (De-) Constructing and Re-Constructing Risk and Danger"; "April 2012: consolidating Social Representations of Fracking". In this article, we examine the emergence of and inter-relations between competing social representations, discuss the dynamics of threat positioning and show how threat can be re-construed in order to serve particular socio-political ends in the debate on fracking. PMID- 23942832 TI - Exploring the limits of nucleobase expansion: computational design of naphthohomologated (xx-) purines and comparison to the natural and xDNA purines. AB - The properties of doubly-expanded (xx-) purine analogues are compared to the natural and singly-expanded (x-) purines using quantum chemical (B3LYP, MP2) methods. Purine expansion upon incorporation of a benzene or naphthalene spacer affects the preferred orientation of the base about the glycosidic bond in the corresponding nucleoside to a similar extent. Although the natural purines preferentially adopt the anti orientation with respect to the 2'-deoxyribose moiety, the syn and anti conformations are almost isoenergetic in the case of the expanded analogues. However, the anti/syn rotational barrier either remains similar to or is slightly elevated upon purine expansion, and therefore the expanded analogues will likely display similar rigidity with respect to rotation about the glycosidic bond as the natural purines. The A:T Watson-Crick hydrogen bond strength is slightly enhanced, while the G:C interaction energy decreases slightly, upon incorporation of either expanded purine. As expected, the largest effect of base expansion occurs on the stacking energies. Specifically, the maximum (most negative) stacking energies in isolated purine dimers formed by aligning the nucleobase centers of mass can be increased by up to 34% by including a single x-purine and by up to 51% by including an xx-purine. Although increases in the purinepurine intrastrand stacking interactions are found even when a simplified duplex model composed of two stacked (hydrogen-bonded) base pairs is considered, the purinepyrimidine stacking energies decrease upon purine expansion. However, the total stability (sum of all hydrogen-bonding and stacking interactions) of natural duplex models is up to 10% and 22% greater for duplexes containing expanded x- and xx-purines respectively, which is mainly due to enhanced inter and intrastrand stacking interactions. Thus, unidirectional expansion in the size of the nucleobase spacer can continuously enhance the stability of expanded duplexes. PMID- 23942834 TI - Recent developments in manufacturing oligosaccharides with prebiotic functions. AB - The market for prebiotics is steadily growing. To satisfy this increasing worldwide demand, the introduction of effective bioprocessing methods and implementation strategies is required. In this chapter, we review recent developments in the manufacture of galactooligosaccharides (GOS) and fructooligosaccharides (FOS). These well-established oligosaccharides (OS) provide several health benefits and have excellent technological properties that make their use as food ingredients especially attractive. The biosyntheses of lactose-based GOS and sucrose-based FOS show similarities in terms of reaction mechanisms and product formation. Both GOS and FOS can be synthesized using whole cells or (partially) purified enzymes in immobilized or free forms. The biocatalysis results in a final product that consists of OS, unreacted disaccharides, and monosaccharides. This incomplete conversion poses a challenge to manufacturers because an enrichment of OS in this mixture adds value to the product. For removing digestible carbohydrates from OS, a variety of bioengineering techniques have been investigated, including downstream separation technologies, additional bioconversion steps applying enzymes, and selective fermentation strategies. This chapter summarizes the state-of-the-art manufacturing strategies and recent advances in bioprocessing technologies that can lead to new possibilities for manufacturing and purifying sucrose-based FOS and lactose-based GOS. PMID- 23942835 TI - Reductive electropolymerization of bis-tridentate ruthenium complexes with 5,5'' divinyl-4'-tolyl-2,2':6',2''-terpyridine. AB - Four bis-tridentate ruthenium complexes with 5,5''-divinyl-4'-tolyl-2,2':6',2'' terpyridine (dvtpy) have been synthesized. Among them, 3(PF6) ([(dvtpy)Ru(Mebib)](PF6)) and 4(PF6) ([(dvtpy)Ru(dpb)](PF6)) are cyclometalated, and 5(PF6)2 ([(dvtpy)Ru(Mebip)](PF6)2) and 6(PF6)2 ([(dvtpy)Ru(tpy)](PF6)2) are noncyclometalated, where Mebib is 2-deprotonated-1,3-bis(N methylbenzimidazolyl)benzene, dpb is 2-deprotonated-1,3-di(2-pyridyl)benzene, Mebip is 2,6-bis(N-methylbenzimidazolyl)pyridine, and tpy is 2,2':6',2'' terpyridine, respectively. Reductive electropolymerization of these complexes and copolymerization of 4(PF6) and 5(PF6)2 proceeded smoothly, both on glassy carbon and ITO glass electrodes, to afford stable metallopolymeric films with well defined redox processes. On the basis of the monomer structures, electrochemical properties, and polymerization mechanism, the polymer chains of these materials are supposed to be composed of organic frameworks with the metal ions laterally chelated to the main backbones. The polymeric films on ITO surfaces display promising electrochromism in the visible region with good reversibility and moderate contrast ratio. Besides, the apparent diffusion constants of films of 3(PF6)-6(PF6)2 were measured by potential step chronoamperometry and the typical surface morphology of poly-5(PF6)2/ITO film was studied using SEM. PMID- 23942836 TI - Postdural puncture headache: a neglected complication after lumbar puncture and intrathecal chemotherapy in children with acute lymphoblastic leukemia. PMID- 23942837 TI - Neuroprotective effect of brain-derived neurotrophic factor mediated by autophagy through the PI3K/Akt/mTOR pathway. AB - Brain-derived neurotrophic factor (BDNF) has been demonstrated to be a potent growth factor that is beneficial in neuronal functions following hypoxia-ischemia (HI). Mature BDNF triggers three enzymes, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and phosphoinositide phospholipase C gamma (PLCgamma), which are its predominant downstream regulators. The PI3K-Akt signaling pathway is upstream of the mammalian target of rapamycin (mTOR), which is important in the induction of autophagy. However, whether the neuroprotective effect of BDNF is mediated by autophagy through the PI3K/Akt/mTOR pathway remains to be elucidated. Cortical neurons were cultured following isolation from pregnant rats (gestational days 16-18). The induction of autophagy following BDNF treatment was analyzed by microtubule-associated protein light chain 3 (LC3) conversion and autophagosome formation. The phosphorylation of Akt, mTOR and ribosomal protein S6 kinase (p70S6K) was analyzed in cultured cells with or without BDNF treatment. Cell viability was determined by a Cell Counting Kit-8 for estimating the protective effect of BDNF. Results demonstrated that autophagy was induced in cells with oxygen deprivation. BDNF promoted cell viability via the upregulation of autophagy. Moreover, LC3 upregulation was related to Akt/mTOR/p70S6K inhibition by BDNF. In conclusion, the results suggested that the neuroprotective effect of BDNF was mediated by autophagy through the PI3K/Akt/mTOR pathway. PMID- 23942838 TI - [Benign and semimalignant spinal tumors. Characteristics in children and adults]. AB - Diagnostic radiology and magnetic resonance imaging (MRI) are the most important imaging tools in the evaluation of benign bone tumors. Computed tomography (CT) is an additional tool for bony lesions, such as in cases of confirmation of the diagnosis of osteoid osteomas. For benign bony lesions three-stage skeletal scintigraphy is an optional additional diagnostic tool. The identification of benign or semimalignant bone tumors is not always clear; therefore percutaneous biopsy is necessary in most cases. In benign spinal tumors an intralesional curettage with reconstruction and stabilization is sufficient. In cases of semimalignant tumors, e.g. giant cell tumors localized in the spine, an en bloc resection is necessary because of the high recurrence rate. PMID- 23942839 TI - [Significance and importance of physical medicine in the context of conservative therapy for rheumatic patients]. AB - Rheumatic diseases usually progress to morphological and functional deficits and thus cause impairment of physical health and function. Based on this fact physiotherapeutic options are elementary and indispensable in clinical rheumatology and orthopedic surgery. This article focuses on the significance and importance of physical medicine in the context of conservative therapy in rheumatic patients. Furthermore, an overview is presented about the basic principles and therapeutic options, the consequences of rheumatic diseases, the reality of health care and the evidence for individual physiotherapeutic measure. PMID- 23942840 TI - Integration of genomic and functional approaches reveals enhancers at LMX1A and LMX1B. AB - LMX1A and LMX1B encode two closely related members of the LIM homeobox family of transcription factors. These genes play significant, and frequently overlapping, roles in the development of many structures in the nervous system, including the cerebellum, hindbrain, spinal cord roof plate, sensory systems and dopaminergic midbrain neurons. Little is known about the cis-acting regulatory elements (REs) that dictate their temporal and spatial expression or about the regulatory landscape surrounding them. The availability of comparative sequence data and the advent of genomic technologies such as ChIP-seq have revolutionized our capacity to identify regulatory sequences like enhancers. Despite this wealth of data, the vast majority of loci lack any significant in vivo functional exploration of their non-coding regions. We have completed a significant functional screen of conserved non-coding sequences (putative REs) scattered across these critical human loci, assaying the temporal and spatial control using zebrafish transgenesis. We first identify and describe the LMX1A paralogs lmx1a and lmx1a like, comparing their expression during embryogenesis with that in mammals, along with lmx1ba and lmx1bb genes. Consistent with their prominent neuronal expression, 47/71 sequences selected within and flanking LMX1A and LMX1B exert spatial control of reporter expression in the central nervous system (CNS) of mosaic zebrafish embryos. Upon germline transmission, we identify CNS reporter expression in multiple independent founders for 22 constructs (LMX1A, n = 17; LMX1B, n = 5). The identified enhancers display significant overlap in their spatial control and represent only a fraction of the conserved non-coding sequences at these critical genes. Our data reveal the abundance of regulatory instruction located near these developmentally important genes. PMID- 23942841 TI - Silencing of TaBTF3 gene impairs tolerance to freezing and drought stresses in wheat. AB - Basic transcription factor 3 (BTF3), the beta-subunit of the nascent polypeptide associated complex, is responsible for the transcriptional initiation of RNA polymerase II and is also involved in cell apoptosis, translation initiation regulation, growth, development, and other functions. Here, we report the impact of BTF3 on abiotic tolerance in higher plants. The transcription levels of the TaBTF3 gene, first isolated from wheat seedlings in our lab, were differentially regulated by diverse abiotic stresses and hormone treatments, including PEG induced stress (20 % polyethylene glycol 6000), cold (4 degrees C), salt (100 mM NaCl), abscisic acid (100 MUM), methyl jasmonate (50 MUM), and salicylic acid (50 MUM). Southern blot analysis indicated that, in the wheat genome, TaBTF3 is a multi-copy gene. Compared to BSMV-GFP-infected wheat plants (control), under freezing (-8 degrees C for 48 h) or drought stress (withholding water for 15 days) conditions, TaBTF3-silenced wheat plants showed lower survival rates, free proline content, and relative water content and higher relative electrical conductivity and water loss rate. These results suggest that silencing of the TaBTF3 gene may impair tolerance to freezing and drought stresses in wheat and that it may be involved in the response to abiotic stresses in higher plants. PMID- 23942843 TI - A novel phase-mixed MgTiO3-MgTi2O5 heterogeneous nanorod for high efficiency photocatalytic hydrogen production. AB - A phase-mixed MgTiO3-MgTi2O5 heterogeneous nanorod is fabricated via an ethylene glycol-mediated route to promote the photocatalytic hydrogen production activity significantly. The excellent charge separation and fast electron transport are the main reasons for the high efficiency due to the formation of phase-mixed heterogeneous junctions. PMID- 23942842 TI - Assessment of pathologically diagnosed patients with Castleman's disease associated with diffuse parenchymal lung involvement using the diagnostic criteria for IgG4-related disease. AB - BACKGROUND: IgG4-related disease (IgG4RD) is a recently recognized disease entity. Differentiating IgG4RD from plasma cell type Castleman's disease (PCD) is important but also difficult using only pathological findings. In addition, little is known about the association between these two diseases with diffuse parenchymal lung involvement. METHODS: We analyzed the serum IgG4 levels and the ratio of IgG4/IgG-positive plasmacytes in the lung and lymph node specimens of eight patients previously pathologically diagnosed of PCD with diffuse parenchymal lung involvement (DL-PCD). We also compared the clinical and laboratory findings observed in these patients. RESULTS: Six of the eight patients exhibited abundant IgG4-positive plasmacytes in the lung and lymph node tissues and elevated serum IgG4 levels, thereby fulfilling the diagnostic criteria of IgG4RD with DL (DL-IgG4RD) in addition to having obstructive phlebitis and massive lymphoplasmacytic infiltration with fibrosis. However, three of these six patients exhibited higher levels of serum interleukin-6 and were still diagnosed with DL-PCD. Accordingly, three of these eight patients were considered as IgG4RD with DL (DL-IgG4RD), and the other five patients were ultimately given a diagnosis of DL-PCD. These two diseases have different characteristics in terms of age, symptoms, serum levels of C-reactive protein, and IgA, complicating allergic disorders, response to corticosteroids, and prognosis. CONCLUSIONS: This is the first report to show a high prevalence of DL IgG4RD in DL-PCD patients, although additional large investigations are necessary. Clinical and laboratory findings are important for distinguishing between these two diseases in other organs, as previously described. PMID- 23942844 TI - Molecular and functional characterization of mulberry EST encoding remorin (MiREM) involved in abiotic stress. AB - KEY MESSAGE: Group1 remorins may help the plants to optimize their growth under adverse conditions by their involvement in mediating osmotic stress responses in plants. ABSTRACT: Mulberry (Morus indica), a deciduous woody tree, serves as the cardinal component of the sericulture industry. Genomic endeavors in sequencing of mulberry ESTs provided clues to stress-specific clones, but their functional relevance remains fragmentary. Therefore in this study, we assessed the functional significance of a remorin gene family member that was identified in leaf ESTs. Remorins represent a large, plant-specific multigene family gaining importance in recent times with respect to their role in plant-microbe interactions, although their role in response to environmental stresses remains speculative as in vivo functions of remorin genes are limited. Mulberry remorin (MiREM) localizes to plasma membrane and is ubiquitously present in all plant organs. Expression analysis of MiREM by northern analysis reveals that its transcript increases under different abiotic stress conditions especially during dehydration and salt stress, implicating it in regulation of stress signaling pathways. Concomitantly, transgenic Arabidopsis plants overexpressing heterologous remorin show tolerance to dehydration and salinity at the germination and seedling stages as revealed by percentage germination, root inhibition assays, fresh weight and activity of photosystem II. This study predicts the possible function of group 1 remorin gene in mediating osmotic stress thus bringing novel perspectives in understanding the function of remorins in plant abiotic stress responses. PMID- 23942846 TI - Is there a motivation for a universal behaviour in molecular populations undergoing chemical reactions? AB - Many chemical reactions demonstrate a very similar evolution of reagent concentrations in time, although their species are quite different. This can be linked with a universal stochastic behavior of reagents. In this paper we show what role in understanding chemical kinetics stochastic models play. To support this concept, we consider two interesting cases known in the literature as first- and second-order reactions. The former has a stretched exponential decay in time for its reagent concentration, and the latter evolves hyperbolically. We have established that the behavior can be explained by limit theorems of probability theory. The reaction evolution is directly connected with different behavior motivations in reagent populations. The reason for the universal kinetics is found in the indices of the corresponding probability distribution functions. They are macroscopic parameters measured in chemical experiments. Such an approach allows ones to discover what happens with molecular populations in microscopic dynamics. PMID- 23942845 TI - Expression of an apoplast-directed, T-phylloplanin-GFP fusion gene confers resistance against Peronospora tabacina disease in a susceptible tobacco. AB - KEY MESSAGE: Phylloplanins are plant-derived, antifungal glycoproteins produced by leaf trichomes. Expression of phylloplanin-GFP fusion gene to the apoplast of a blue mold susceptible tobacco resulted in increased resistance to this pathogen. ABSTRACT: Tobaccos and certain other plants secrete phylloplanin glycoproteins to aerial surfaces where they appear to provide first-point-of contact resistance against fungi/fungi-like pathogens. These proteins can be collected by water washing of aerial plant surfaces, and as shown for tobacco and a sunflower phylloplanins, spraying concentrated washes onto, e.g., turf grass aerial surfaces can provide resistance against various fungi/fungi-like pathogens, in the laboratory. These results suggest that natural-product, phylloplanins may be useful as broad-selectivity fungicides. An obvious question now is can a tobacco phylloplanin gene be introduced into a disease-susceptible plant to confer endogenous resistance. Here we demonstrate that introduction of a tobacco phylloplanin gene--as a fusion with the GFP gene--targeted to the apoplasm can increase resistance to blue mold disease in a susceptible host tobacco. PMID- 23942850 TI - Electrochemical reduction induced self-doping of Ti3+ for efficient water splitting performance on TiO2 based photoelectrodes. AB - Hetero-element doping (e.g., N, F, C) of TiO2 is inevitably accompanied by significantly increased structural defects due to the dopants' nature being foreign impurities. Very recently, in situ self-doping with homo-species (e.g., Ti(3+)) has been emerging as a rational solution to enhance TiO2 photoactivity within both UV and visible light regions. Herein we demonstrate that conventional electrochemical reduction is indeed a facile and effective strategy to induce in situ self-doping of Ti(3+) into TiO2 and the self-doped TiO2 photoelectrodes showed remarkably improved and very stable water splitting performance. In this study, hierarchical TiO2 nanotube arrays (TiO2 NTs) were chosen as TiO2 substrates and then electrochemically reduced under varying conditions to produce Ti(3+) self-doped TiO2 NTs (ECR-TiO2 NTs). The optimized saturation photocurrent density and photoconversion efficiency on the ECR-TiO2 NTs under simulated AM 1.5G illumination were identified to be 2.8 mA cm(-2) at 1.23 V vs. RHE and 1.27% respectively, which are the highest values ever reported for TiO2 based photoelectrodes. The electrochemical impedance spectra measurement confirms that the electrochemical induced Ti(3+) self-doping improved the electrical conductivity of the ECR-TiO2 NTs. The versatility and effectiveness of the electrochemical reduction method for Ti(3+) self-doping in P25 based TiO2 was also examined and confirmed. PMID- 23942848 TI - Effect of adjuvant trastuzumab treatment in conventional clinical setting: an observational retrospective multicenter Italian study. AB - Clinical trials have shown the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancers, but routine clinical use awaits evaluation of compliance, safety, and effectiveness. Adjuvant trastuzumab-based therapy in routine clinical use was evaluated in the retrospective study GHEA, recording 1,002 patients treated according to the HERA protocol between March 2005 and December 2009 in 42 Italian oncology departments; 874 (87.23 %) patients completed 1-year trastuzumab treatment. In 128 patients (12.77 %), trastuzumab was withdrawn due to cardiac or non-cardiac toxicity (28 and 29 patients, respectively), disease progression (5 patients) or the clinician's decision (66 patients). In addition, 156 patients experienced minor non-cardiac toxicities; 10 and 44 patients showed CHF and decreased LVEF, respectively, at the end of treatment. Compliance and safety of adjuvant trastuzumab-based therapy in Italian hospitals were high and close to those reported in the HERA trial. With a median follow-up of 32 months, 107 breast cancer relapses were recorded (overall frequency, 10.67 %), and lymph node involvement, estrogen receptor negativity, lymphoid infiltration, and vascular invasion were identified as independent prognostic factors for tumor recurrence, indicating that relapses were associated with advanced tumor stage. Analysis of site and frequency of distant metastases showed that bone metastases were significantly more frequent during or immediately after trastuzumab (<18 months from the start of treatment) compared to recurrences in bone after the end of treatment and wash-out of the drug (>18 months from the start of treatment) (35.89 vs. 14.28 %, p = 0.0240); no significant differences were observed in recurrences in the other recorded body sites, raising the possibility that the protection exerted by trastuzumab is lower in bone metastases. PMID- 23942847 TI - Eyeblink conditioning: a non-invasive biomarker for neurodevelopmental disorders. AB - Eyeblink conditioning (EBC) is a classical conditioning paradigm typically used to study the underlying neural processes of learning and memory. EBC has a well defined neural circuitry, is non-invasive, and can be employed in human infants shortly after birth making it an ideal tool to use in both developing and special populations. In addition, abnormalities in the cerebellum, a region of the brain highly involved in EBC, have been implicated in a number of neurodevelopmental disorders including autism spectrum disorders (ASDs). In the current paper, we review studies that have employed EBC as a biomarker for several neurodevelopmental disorders including fetal alcohol syndrome, Down syndrome, fragile X syndrome, attention deficit/hyperactivity disorder, dyslexia, specific language impairment, and schizophrenia. In addition, we discuss the benefits of using such a tool in individuals with ASD. PMID- 23942851 TI - High concentrations of pyridoxal stimulate the expression of IGFBP1 in HepG2 cells through upregulation of the ERK/c-Jun pathway. AB - Increasing evidence suggests that dietary vitamin B6 is linked to the prevention of cancer and cardiovascular disease. However, the molecular mechanisms involved in this process are not yet understood. Preliminary results in the current study indicated, following DNA microarray analysis and quantitative PCR, that insulin like growth factor-binding protein 1 (IGFBP1) mRNA is upregulated in HT29 colon carcinoma cells exposed to pyridoxal (PL, 500 uM). IGFBP1 is secreted from the liver and is hypothesized to exert a protective role in the development of cancer and cardiovascular disease. Thus, further experiments were performed to investigate the effect of PL on the expression of IGFBP1 in HepG2 hepatocellular carcinoma cells. The addition of PL (500 uM) markedly increased the expression of IGFBP1 mRNA in HepG2 cells at 6, 12 and 24 h (P<0.01), whereas other vitamers (500 uM), including pyridoxal 5'-phosphate (PLP), pyridoxine (PN) and pyridoxamine (PM), caused no such effect. The expression of the IGFBP1 protein in the cell lysate and culture medium was elevated in the presence of PL. PL elevated expression of the active form of ERK1 protein, p-ERK1, and the p-c-Jun protein, a downstream factor of ERK. Furthermore, IGFBP1 expression, elevated by PL, was suppressed by PD98059, an ERK inhibitor. Higher expression of IGFBP1 protein by PL was suppressed by cycloheximide. These results suggest that PL may induce the expression of IGFBP1 in hepatoma cells via a mechanism involving the ERK/c-Jun pathway. PMID- 23942852 TI - Observation of a large magnetocaloric effect in a 2D Gd(III)-based coordination polymer. AB - A new 2D Gd(III)-based coordination polymer has close to the highest cryogenic magnetocaloric effect of any MOF reported so far. The experimental results reveal its structural features and magnetic properties. PMID- 23942854 TI - [Palliative medicine : everywhere, for everybody, by everyone]. PMID- 23942855 TI - Fatal short-coupled torsade de pointes in a patient with primary oxalosis. PMID- 23942856 TI - Intensive care unit mortality after cardiac arrest: the relative contribution of shock and brain injury in a large cohort. AB - OBJECTIVE: Brain injury is well established as a cause of early mortality after out-of-hospital cardiac arrest (OHCA), but postresuscitation shock also contributes to these deaths. This study aims to describe the respective incidence, risk factors, and relation to mortality of post-cardiac arrest (CA) shock and brain injury. DESIGN: Retrospective analysis of an observational cohort. SETTING: 24-bed medical intensive care unit (ICU) in a French university hospital. PATIENTS: All consecutive patients admitted following OHCA were considered for analysis. Post-CA shock was defined as a need for infusion of vasoactive drugs after resuscitation. Death related to brain injury included brain death and care withdrawal for poor neurological evolution. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Between 2000 and 2009, 1,152 patients were admitted after OHCA. Post-CA shock occurred in 789 (68%) patients. Independent factors associated with its onset were high blood lactate and creatinine levels at ICU admission. During the ICU stay, 269 (34.8%) patients died from post-CA shock and 499 (65.2%) from neurological injury. Age, raised blood lactate and creatinine values, and time from collapse to restoration of spontaneous circulation increased the risk of ICU mortality from both shock and brain injury, whereas a shockable rhythm was associated with reduced risk of death from these causes. Finally, bystander cardiopulmonary resuscitation (CPR) decreased the risk of death from neurological injury. CONCLUSIONS: Brain injury accounts for the majority of deaths, but post-CA shock affects more than two-thirds of OHCA patients. Mortality from post-CA shock and brain injury share similar risk factors, which are related to the quality of the rescue process. PMID- 23942858 TI - Looking beyond survival rates: neurological outcomes after extracorporeal life support. PMID- 23942857 TI - Risk factors and impact of major bleeding in critically ill patients receiving heparin thromboprophylaxis. AB - PURPOSE: Bleeding frequently complicates critical illness and may have serious consequences. Our objectives are to describe the predictors of major bleeding and the association between bleeding and mortality in medical-surgical critically ill patients receiving heparin thromboprophylaxis. METHODS: We prospectively studied patients from 67 intensive care units and six countries enrolled in a thromboprophylaxis trial (NCT00182143) comparing dalteparin with unfractionated heparin. Patients with trauma, orthopedic surgery or neurosurgery were excluded. Trained research coordinators used a validated tool to document bleeding, which underwent duplicate independent blinded adjudication. Major bleeding was defined as hypovolemic shock, bleeding into critical sites, requiring an invasive intervention or transfusion of at least two units of red blood cells, or associated with hypotension or tachycardia in the absence of other causes. Adjusted Cox proportional hazard regression analysis was used to identify major bleeding predictors and the association between bleeding and mortality. RESULTS: Among 3,746 patients, bleeding occurred in 208 [5.6 %, 95 % confidence interval (CI) 4.9-6.3 %]. Time-dependent predictors were prolonged activated partial thromboplastin time [hazard ratio (HR) 1.10, 1.05-1.14 per 10 s increase], lower platelet count (HR 1.16, 1.09-1.24 per 50 * 10(9)/L decrease), therapeutic heparin (HR 3.26, 1.72-6.17), antiplatelet agents (HR 1.38, 1.02-1.88), renal replacement therapy (HR 1.75, 1.20-2.56), and recent surgery (HR 1.64, 1.01 2.65). Type of pharmacologic thromboprophylaxis was not associated with bleeding. Patients with bleeding had a higher risk of in-hospital death (HR 2.09, 1.69 2.57). CONCLUSIONS: As major bleeding has modifiable risk factors and is associated with in-hospital mortality, strategies to mitigate these factors should be evaluated in critically ill patients. PMID- 23942859 TI - Invasive candidiasis in pediatric intensive care in Greece: a nationwide study. AB - PURPOSE: To record the practices for prevention and management of invasive candidiasis in the PICU and investigate the epidemiology of candidiasis and its outcome nationwide. METHODS: A multicenter national study among PICUs throughout Greece. A questionnaire referring to local practices of prevention and management of candidemia was filled in, and a retrospective study of episodes that occurred during 5 years was conducted in all seven Greek PICUs. RESULTS: Clinical practices regarding surveillance cultures, catheter replacement protocols and antibiotic use were similar, although the case mix differed. In all PICUs prophylactic antifungal treatment was administered in transplant and neutropenic oncology patients. Discrepancy existed between PICUs concerning the first-line antifungal agents and treatment duration of candidemia. Twenty-two candidemias were nationally recorded between 2005 and 2009 with a median incidence of 6.4 cases/1,000 admissions. Median age was 8.2 (0.3-16.6) years. Candida albicans was isolated in 45.4 % of episodes followed by Candida parapsilosis (22.7 %). Common findings were presence of central venous and urinary catheters as well as mechanical ventilation and administration of antibiotics with anti-anaerobic activity in almost all patients with candidemia. Total parenteral nutrition was administered to five (22.7 %) patients. Most of the patients had a chronic underlying disease; five were oncology patients, and two-thirds of those with candidemia were colonized with Candida spp. Lipid amphotericin B formulations were the predominant therapeutic choice (54.5 %). Thirty-day mortality was 18.2 %. CONCLUSION: This first national study adds information to the epidemiology of candidemia in critically ill children. In these special patients, candidemia has a relatively low incidence and tends toward non-albicans Candida preponderance. PMID- 23942860 TI - Reply to Megarbane: Is early implementation of extracorporeal life support in severely colchicine-poisoned patients lifesaving? Definitive evidence is still lacking. PMID- 23942861 TI - The monitoring of acute cor pulmonale is still necessary in "Berlin" ARDS patients. PMID- 23942862 TI - I wished she had meningoencephalitis. PMID- 23942863 TI - Ganglion cyst of the cruciate ligament with atlantoaxial subluxation. AB - BACKGROUND: Ganglion cysts of the cruciate ligament are rare and sometimes asymptomatic. The authors present three cases of ganglion cysts of the cruciate ligament with atlantoaxial subluxation, which has rarely been reported previously. METHODS: Generally, ganglion cysts of the cruciate ligament are reported as case reports. Several theories regarding the process of cyst formation and the development of treatment options have been described. However, trans-oral decompression with total removal of the cyst may be one of the options for treatment of this kind of disease. RESULTS: A retrospective review of three patients, two female and one male patient, with a mean age of 68 years was conducted. The operation performed was a trans-oral decompression with cyst removal for all patients. Clinical outcomes were evaluated after the operation. All patients underwent trans-oral decompression with total removal of the cyst, followed by posterior fusion and pathologic examination of the cyst, revealing myxoid stroma with an absence of synovial linings. CONCLUSION: The ganglion cysts and synovial cysts of the cruciate ligament are two different diseases with different presentation, pathogenesis, pathophysiology, and pathologic findings. PMID- 23942864 TI - Facile synthesis of Au-Ag core-shell nanoparticles with uniform sub-2.5 nm interior nanogaps. AB - A facile method was established to fabricate uniform nanogaps between a Au core and a Au-Ag alloy shell. The size of nanogaps is controllable due to fast dissolution of AgCl and AgBr in CTAB and the crystal growth of the shell on a designed template. These Au-Ag core-shell nanoparticles with uniform sub-2.5 nm interior nanogaps can be potentially used for various applications. PMID- 23942865 TI - Microbeam irradiation of C. elegans nematode in microfluidic channels. AB - To perform high-throughput studies on the biological effects of ionizing radiation in vivo, we have implemented a microfluidic tool for microbeam irradiation of Caenorhabditis elegans. The device allows the immobilization of worms with minimal stress for a rapid and controlled microbeam irradiation of multiple samples in parallel. Adapted from an established design, our microfluidic clamp consists of 16 tapered channels with 10-MUm-thin bottoms to ensure charged particle traversal. Worms are introduced into the microfluidic device through liquid flow between an inlet and an outlet, and the size of each microchannel guarantees that young adult worms are immobilized within minutes without the use of anesthesia. After site-specific irradiation with the microbeam, the worms can be released by reversing the flow direction in the clamp and collected for analysis of biological endpoints such as repair of radiation induced DNA damage. For such studies, minimal sample manipulation and reduced use of drugs such as anesthetics that might interfere with normal physiological processes are preferable. By using our microfluidic device that allows simultaneous immobilization and imaging for irradiation of several whole living samples on a single clamp, here we show that 4.5-MeV proton microbeam irradiation induced DNA damage in wild-type C. elegans, as assessed by the formation of Rad51 foci that are essential for homologous repair of radiation-induced DNA damage. PMID- 23942866 TI - Attenuated second-order Moller-Plesset perturbation theory: performance within the aug-cc-pVTZ basis. AB - Attenuated second-order Moller-Plesset perturbation theory (MP2) within the finite aug-cc-pVTZ (aTZ) basis set is developed for inter- and intra-molecular non-bonded interactions. A single attenuation parameter is optimized on the S66 database of 66 intermolecular interactions, leading to a very large RMS error reduction by a factor of greater than 5 relative to standard MP2/aTZ. Attenuation introduces an error of opposite sign to basis set superposition error (BSSE) and overestimation of dispersion interactions in finite basis MP2. A variety of tests including the S22 set, conformer energies of peptides, alkanes, sugars, sulfate water clusters, and the coronene dimer establish the transferability of the MP2(terfc, aTZ) model to other inter and intra-molecular interactions. Direct comparisons against attenuation in the smaller aug-cc-pVDZ basis shows that MP2(terfc, aTZ) often significantly outperforms MP2(terfc, aDZ), although at higher computational cost. MP2(terfc, aDZ) and MP2(terfc, aTZ) often out-perform MP2 at the complete basis set limit. Comparison of the two attenuated MP2 models against each other and against attenuation using non-augmented basis sets gives insight into the error cancellation responsible for their remarkable success. PMID- 23942867 TI - Are steroids required for induction therapy and relapses in lupus nephritis? PMID- 23942868 TI - Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind randomised placebo controlled study (RAPID-PsA). AB - OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-PsA (NCT01087788), an ongoing Phase 3 trial in patients with psoriatic arthritis (PsA). METHODS: Patients were randomised 1:1:1 to placebo, 200 mg CZP every 2 weeks (Q2W) or 400 mg CZP every 4 weeks (Q4W). Patients could have had exposure to one previous tumour necrosis factor (TNF) inhibitor therapy. Primary endpoints were American College of Rheumatology 20% (ACR20) response at week 12 and modified Total Sharp Score change from baseline at week 24. Secondary endpoints included; Psoriatic Arthritis Response Criteria (PsARC) score, Health Assessment Questionnaire Disability Index (HAQ-DI), Psoriasis Area and Severity Index, Leeds Enthesitis Index, Leeds Dactylitis Index, and Modified Nail Psoriasis Severity Index. RESULTS: Of 409 patients randomised, 368 completed 24 weeks of treatment. ACR20 response was significantly greater in CZP 200 mg Q2W and 400 mg Q4W-treated patients than placebo (58.0% and 51.9% vs 24.3% (p<0.001)) at week 12, with improvements observed by week 1. There was a statistically significant improvement in physical function from baseline, measured by HAQ-DI in CZP patients compared with placebo (-0.50 vs -0.19, p<0.001) and more patients treated with CZP 200 mg Q2W and CZP 400 mg achieved an improvement in PsARC at week 24 than placebo (78.3% and 77.0% vs 33.1% (p<0.001)). Sustained improvements were observed in psoriatic skin involvement, enthesitis, dactylitis and nail disease. Higher ACR20 response with CZP was independent of prior TNF inhibitor exposure. No new safety signals were observed. CONCLUSIONS: Rapid improvements in the signs and symptoms of PsA, including joints, skin, enthesitis, dactylitis and nail disease were observed across both CZP dosing regimens. PMID- 23942870 TI - Probing adsorption sites for CO on ceria. AB - Ceria based catalysts show remarkable activity for CO conversion reactions such as CO oxidation and the water-gas shift reaction. The identification of adsorption sites on the catalyst surfaces is essential to understand the reaction mechanisms of these reactions, but the complexity of heterogeneous powder catalysts and the propensity of ceria to easily change oxidation states in the presence of small concentrations of either oxidizing or reducing agents make the process difficult. In this study, the adsorption of CO on CuOx/Cu(111) and CeOx/Cu(111) systems has been studied using infrared reflection absorption spectroscopy (IRRAS), X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) calculations. IR peaks for the adsorbed CO on O/Cu(111) with only chemisorbed oxygen, well-ordered Cu2O/Cu(111) and disordered copper oxide [CuOx/Cu(111)] were observed at 2070-2072, 2097-2098 and 2101-2111 cm(-1), respectively. On CeOx/Cu(111) systems CO chemisorbs at 90 K only on Cu sites under ultra-high vacuum (UHV) conditions, whereas at elevated CO pressures and low temperatures adsorption of CO on Ce(3+) is observed, with a corresponding IR peak at 2162 cm(-1). These experimental results are further supported by DFT calculations, and help to unequivocally distinguish the presence of Ce(3+) cations on catalyst samples by using CO as a probe molecule. PMID- 23942869 TI - Effect of different imputation approaches on the evaluation of radiographic progression in patients with psoriatic arthritis: results of the RAPID-PsA 24 week phase III double-blind randomised placebo-controlled study of certolizumab pegol. AB - OBJECTIVES: To report the effect of different imputation methodologies on the assessment of radiographic progression in clinical trials. METHODS: The 216-week RAPID-psoriatic arthritis (PsA) (NCT01087788) trial of certolizumab pegol (CZP) in patients with active PsA was double-blind and placebo-controlled until week 24. A primary end point was change from baseline in modified Total Sharp Score(s) (mTSS). Prespecified imputation methodology in patients with fewer than two analysable mTSS used minimum observed baseline score for missing baseline values and maximum observed week 24 score for missing week 24 values. Post hoc analyses used alternative methods of imputation in patients with fewer than two analysable mTSS. mTSS non-progressors were defined as patients with <=0 (predefined) or <=0.5 (post hoc) change in mTSS from baseline to week 24. Baseline mTSS and C reactive protein levels as predictors of radiographic progression were investigated. RESULTS: 409 patients were randomised. Baseline demographics were similar between groups. Prespecified imputation analysis inappropriately overestimated radiographic progression (least squares mean placebo, 28.9; CZP, 18.3; p>=0.05). Multiple post hoc analyses demonstrated that CZP inhibited radiographic progression compared with placebo, particularly in patients with high baseline mTSS and C-reactive protein levels. mTSS non-progression rate was higher in CZP than placebo groups in all analyses. CONCLUSIONS: Inappropriate prespecified imputation methodology resulted in an unrealistic assessment of progression in all arms. Methodologies for imputing missing radiographic data can greatly affect assessment and reporting of mTSS progression. PMID- 23942871 TI - The effect of alendronate on the expression of important cell factors in osteoclasts. AB - This study investigated the effects of alendronate (ALN) on critical cell factors in osteoclasts. RAW 264.7 cells were induced by sRANKL to change to mature osteoclasts. On the sixth day of incubation, the osteoclasts were treated with ALN at various concentrations and for different incubation times. The concentration groups included 10-5 M, 10-6 M and 10-7 M ALN, respectively. The cells were incubated for 0 (control group), 2, 4, 6 and 8 h for each dose group. The mRNA and protein expression of tartrate-resistant acid phosphatase, carbonic anhydrase II, osteoclast-associated receptor and FAS/FASL genes in osteoclasts was analyzed. A concentration- and time-dependent decrease in the mRNA and protein expression levels of the five genes was observed, and no significant difference between the two control groups was observed (P>0.05). Notably, significant differences between any two experimental groups were observed (P<0.05). Thus, ALN significantly decreased the expression of critical factors involved in osteoclast function. PMID- 23942872 TI - Trends and clinical implications of preoperative breast MRI in Medicare beneficiaries with breast cancer. AB - While there has been increasing interest in the use of preoperative breast magnetic resonance imaging (MRI) for women with breast cancer, little is known about trends in MRI use, or the association of MRI with surgical approach among older women. Using the Surveillance, Epidemiology and End Results-Medicare database, we identified a cohort of women diagnosed with breast cancer from 2000 to 2009 who underwent surgery. We used Medicare claims to identify preoperative breast MRI and surgical approach. We evaluated temporal trends in MRI use according to age and type of surgery, and identified factors associated with MRI. We assessed the association between MRI and surgical approach: breast-conserving surgery (BCS) versus mastectomy, bilateral versus unilateral mastectomy, and use of contralateral prophylactic mastectomy. Among the 72,461 women in our cohort, 10.1 % underwent breast MRI. Preoperative MRI use increased from 0.8 % in 2000 2001 to 25.2 % in 2008-2009 (p < 0.001). Overall, 43.3 % received mastectomy and 56.7 % received BCS. After adjustment for clinical and demographic factors, MRI was associated with an increased likelihood of having a mastectomy compared to BCS (adjusted odds ratio = 1.21, 95 % CI 1.14-1.28). Among women who underwent mastectomy, MRI was significantly associated with an increased likelihood of having bilateral cancer diagnosed (9.7 %) and undergoing bilateral mastectomy (12.5 %) compared to women without MRI (3.7 and 4.1 %, respectively, p < 0.001 for both). In conclusion, the use of preoperative breast MRI has increased substantially among older women with breast cancer and is associated with an increased likelihood of being diagnosed with bilateral cancer, and more invasive surgery. PMID- 23942873 TI - The impact of endocrine therapy on sexual dysfunction in postmenopausal women with early stage breast cancer: encouraging results from a prospective study. AB - The goal of this project was to investigate the contentious issue of a possible effect of endocrine therapy (ET) on sexual dysfunction (SD) in postmenopausal early stage breast cancer survivors. To date, few studies have assessed sexual functioning prior to initiating ET and none have taken sexual distress into account when reporting the prevalence of ET-induced SD. We report the findings of a study on the change in SD (defined as experiencing sexual problems causing distress) during the first 6 months of ET usage. Between January 2009 and May 2011, 118 patients entered the study and 66 completed questionnaires prior to initiation of ET and after 6 months of use. Sexual functioning (SF) was evaluated with the female sexual function index while sexual distress was assessed with the female sexual distress scale (FSDS-R). Gynecological symptoms were measured with the FACT-B ES subscale. Over time, the level of gynecological symptoms increased (p < 0.001), whereas no decline in SF was observed. The percentage of women who reported experiencing at least one sexual problem (85 %) and the percentage who were sexually distressed (30 %) remained the same across time. Importantly, the change in the prevalence of SD between baseline (24 %) and 6 months (29 %) was not statistically significant. Women experiencing SD at baseline were more likely to experience SD after 6 months of ET usage (OR = 7.4, 95 % CI = 1.5-36.9) than women who had no SD prior to initiating ET. The observation that SF remained stable across time is encouraging news. However, longer follow-up and the inclusion of women who were premenopausal at diagnosis are needed to determine the potential influence of extended duration of ET (e.g., at least 5 years) on SD. Further studies, including assessing the impact of early identification of patients at risk of developing SD and timely intervention, are warranted. PMID- 23942874 TI - High body mass index is associated with worse quality of life in breast cancer patients receiving radiotherapy. AB - The purpose of this study was to examine the impact of body mass index (BMI) on breast cancer patients' self-reported health-related quality of life among patients treated with radiation therapy (RT). Women with breast cancer undergoing RT were prospectively enrolled in an Institutional Review Board-approved clinical trial between 2009 and 2012. Quality of life (QOL) assessments were collected pre RT, during RT, and within 3 months post-RT using Euroqol (EQ-5D), MD Anderson Symptom Inventory, and functional assessment of cancer therapy-general (FACT-G). 183 breast cancer patients were enrolled, of whom 140 completed assessments at one or more time-point. After adjusting for age, chemotherapy, prior RT, type of breast surgery, and comorbidities, higher BMI remained significantly associated with worse QOL pre-RT, during RT, and post-RT in breast cancer patients. Higher BMI was strongly associated with worse overall FACT-G score on treatment and greater decline in physical well-being on treatment, which persisted after treatment. While effects on QOL of patients in the underweight and normal weight group peaked during treatment, rapidly improving by follow-up, obese patients had worse functional well-being that was more persistent at follow-up. Higher BMI was associated with worse QOL for breast cancer patients before, during, and after RT, and also was associated with reduced return to baseline QOL 3 months post-RT. PMID- 23942875 TI - Novel synthesis of various orthogonally protected Calpha-methyllysine analogues and biological evaluation of a vapreotide analogue containing (S)-alpha methyllysine. AB - Prochiral malonic diesters containing a quaternary carbon center have been successfully transformed into a diverse set of (t)Boc-Fmoc-alpha(2,2) methyllysine-OH analogues through chiral malonic half-ester intermediates obtained via enzymatic (Pig Liver Esterase, PLE) hydrolysis. The variety of chiral half-ester intermediates, which vary from 1 to 6 methylene units in the side chain, are achieved in moderate to high optical purity and in good yields. The PLE hydrolysis of malonic diesters with various side chain lengths appears to obey the Jones's PLE model according to the stereochemical configurations of the resulting chiral half-esters. The established synthetic strategy allows the construction of both enantiomers of alpha(2,2)-methyllysine analogues, and a (S) beta(2,2)-methyllysine analogue from a common synthon by straightforward manipulation of protecting groups. Two different straightforward and cost effective synthetic strategies are described for the synthesis of alpha(2,2) methyllysine analogues. The described strategies should find significant usefulness in preparing novel peptide libraries with unnatural lysine analogues. A Vapreotide analogue incorporating (S)-alpha(2,2)-methyllysine was prepared. However, the Vapreotide analogue with (S)-alpha-methyl-alpha-lysine is found to lose its specific binding to somatostatin receptor subtype 2 (SSTR2). PMID- 23942876 TI - Synthesis of the building block 2-hydroxyisobutyrate from fructose and butyrate by Cupriavidus necator H16. AB - 2-Hydroxyisobutyryl-coenzyme A mutase, originally discovered in the context of methyl tert-butyl ether degradation in Aquincola tertiaricarbonis L108, catalyzes the isomerization of 3-hydroxybutyryl-coenzyme A (3-HB-CoA) to 2 hydroxyisobutyryl-CoA. It thus constitutes the basis for a biotechnological route from practically any renewable carbon to 2-hydroxyisobutyrate (2-HIB) via the common metabolite 3-hydroxybutyrate. At first sight, recombinant Cupriavidus necator H16 expressing the mutase seems to be well suited for such a synthesis process, as a strong overflow metabolism via (R)-3-HB-CoA is easily induced in this bacterium possessing the poly-3-hydroxybutyrate metabolism. However, the recently established stereospecificity of the mutase, dominantly preferring the (S)-enantiomer of 3-HB-CoA, calls for a closer investigation of C. necator as potential 2-HIB production strain and raised the question about the strain's potential to yield 2-HIB from substrates directly providing (S)-3-HB-CoA. We compared two mutase-expressing C. necator H16 strains for their capability to synthesize 2-HIB from fructose and butyrate, delivering either (R)- or (S)-3-HB CoA. Our results indicate that due to the enantiospecificity of the mutase, fructose is a weaker substrate for 2-HIB synthesis than butyrate. Production rates achieved with the PHB-negative strain H16 PHB(-)4 on butyrate were higher than on fructose. Using the wild-type did not significantly improve the production rates as the latter showed a 34-fold and a 5-fold lower 2-HIB synthesis rate compared to H16 PHB(-)4 on fructose and butyrate, respectively. Moreover, both strains showed concomitant excretion of undesired side products, such as pyruvate and 3-hydroxybutyrate, significantly decreasing the 2-HIB yield. PMID- 23942877 TI - Cloning, expression, and characterization of the beta-glucosidase hydrolyzing secoisolariciresinol diglucoside to secoisolariciresinol from Bacteroides uniformis ZL1. AB - Previously, from the human intestinal flora we isolated the bacterial strain Bacteroides uniformis ZL1, which could convert secoisolariciresinol diglucoside (SDG) to its aglycone secoisolariciresinol (SECO) in vivo. In this study, 24 putative beta-glucosidase genes were screened from the genome of B. uniformis ATCC 8492, which were used as templates to design PCR primers for the target genes in B. uniformis ZL1. Fifteen genes (bgl1-bgl15) were amplified from strain ZL1, and among them we identified bgl8 as the gene encoding the SDG-hydrolyzing beta-glucosidase. We sequenced the bgl8 gene, cloned it into the expression vector and then transformed Escherichia coli to construct the recombinant bacteria that could synthesize the target beta-glucosidase (BuBGL8). We purified and characterized BuBGL8, which showed maximal activity and stability under the culture conditions of pH 6.0 and 30 degrees C. SDG (2.0 mg/ml) was converted to SECO by both the purified BuBGL8 (0.035 mg/ml) and crude enzyme extract (0.23 mg crude protein/ml) with the efficiency of more than 90 % after 90 min at the reaction conditions. This is, to our knowledge, the first report of using recombinant bacteria to synthesize the SDG-hydrolyzing beta-glucosidase, which could be used to produce SECO from SDG conveniently and highly efficiently. PMID- 23942878 TI - Expression and delivery of an endolysin to combat Clostridium perfringens. AB - Clostridium perfringens is a cause for increasing concern due to its responsibility for severe infections both in humans and animals, especially poultry. To find new control strategies to treat C. perfringens infection, we investigated the activity and delivery of a bacteriophage endolysin. We identified a new endolysin, designated CP25L, which shows similarity to an N acetylmuramoyl-L-alanine amidase domain and is distinct from other C. perfringens endolysins whose activity has been demonstrated in vitro. The cp25l gene was cloned and expressed in Escherichia coli, and the gene product demonstrated lytic activity against all 25 C. perfringens strains tested. The probiotic strain Lactobacillus johnsonii FI9785 was engineered to deliver the endolysin to the gastrointestinal tract. The integration of the nisRK two-component regulatory system from the Lactococcus lactis nisin A biosynthesis operon into the chromosome of L. johnsonii allowed constitutive expression of the endolysin under the control of the nisA promoter (P nisA ), while the use of a signal peptide (SLPmod) led to successful secretion of the active endolysin to the surrounding media. The high specificity and activity of the endolysin suggest that it may be developed as an effective tool to enhance the control of C. perfringens by L. johnsonii in the gastrointestinal tract. PMID- 23942879 TI - Analysis of factors affecting the performance of partial nitrification in a sequencing batch reactor. AB - The objective of this study was to analyze the factors affecting the performance of partial nitrification in a sequencing batch reactor. During a 140-day long term operation, influent pH value, dissolved oxygen (DO), and chemical oxygen demand/nitrogen (COD/N) ratio were selected as operating factors to evaluate the maintenance and recovery of nitrite accumulation. Results showed that high DO concentration (2-4 mg/L) could damage nitrite accumulation immediately. However, nitrite accumulation ratio (NAR) could be increased from 1.68 +/- 1.51 to 35.46 +/- 7.86% when increasing the pH values from 7.5 to 8.3 due to the increased free ammonia concentration. Afterwards, stable partial nitrification and high NAR could be recovered when the reactor operated under low DO concentration (0.5-1.0 mg/L). However, it required a long time to recover the partial nitrification of the reactor when the influent COD/N ratios were altered. Fluorescence in situ hybridization analysis implied that ammonium oxidizing bacteria were completely recovered to the dominant nitrifying bacteria in the system. Meanwhile, sludge volumetric index of the reactor gradually decreased from 115.6 to 56.6 mL/g, while the mean diameter of sludge improved from 74.57 to 428.8 MUm by using the strategy of reducing settling time. The obtained results could provide useful information between the operational conditions and the performance of partial nitrification when treating nitrogen-rich industrial wastewater. PMID- 23942880 TI - Characterization of alpha-galacto-oligosaccharides formed via heterologous expression of alpha-galactosidases from Lactobacillus reuteri in Lactococcus lactis. AB - alpha-Galacto-oligosaccharides (alpha-GOS) are produced by transgalactosylation reactions of alpha-galactosidase (alpha-Gal) or by conversion of raffinose family oligosaccharides by levansucrase. Similarly to beta-GOS, alpha-GOS have the potential to mimic glycan receptors on eukaryotic cells and act as molecular decoys to prevent bacterial infection; however, data on transgalactosylation reactions of alpha-Gal remain scarce. The alpha-Gal gene sequence from Lactobacillus reuteri was cloned into an alpha-Gal negative strain of Lactococcus lactis. Transgalactosylation reactions were achieved using crude cell extracts with melibiose or raffinose as galactosyl donor and fucose, N-acetylglucosamine or lactose as galactosyl acceptor. The composition, sequence and most linkage types of alpha-GOS formed with acceptors saccharides were determined by liquid chromatography-tandem mass spectrometry. alpha-Gal of Lactobacillus reuteri formed (1 -> 3)-, (1 -> 4)- or (1 -> 6)-linked alpha-GOS but exhibited a preference for formation of (1 -> 6)-linkages. Fucose, N-acetylglucosamine and lactose were suitable galactosyl acceptors for alpha-Gal of L. reuteri, resulting in formation of (1 -> 3)-, (1 -> 4)- or (1 -> 6)-linked hetero-oligosaccharides. By determining the structural specificity of alpha-Gal and increasing the variation of oligosaccharides produced by introducing alternative acceptor sugars, this work supports further studies to assess alpha-GOS pathogen adhesion prevention in mammalian hosts. PMID- 23942881 TI - Patient-specific total knee arthroplasty: the importance of planning by the surgeon. AB - PURPOSE: The purpose of the study was to evaluate the accuracy of the planning of the patient-specific pin guides in total knee arthroplasty (TKA). This planning was performed primarily by a technician of the company and offered to the surgeon. All parameters of the implantation can either be modified or accepted by the surgeon. The hypothesis was that the plan needs preoperative intervention by the surgeon. METHODS: A prospective study in 50 patients was carried out. All patients received the same posterior-stabilised implant with patient-specific instrumentation. All surgical parameters (coronal, sagittal, rotational alignment, femoral and tibial resection levels and implant sizes) were checked by the orthopaedic surgeon and changed if necessary. RESULTS: Preoperatively, the femoral size was changed in 8 patients (16 %), the femoral flexion in 23 patients (46 %), the femoral shift in 34 patients (68 %), the tibial size in 24 patients (48 %) and the tibial rotation in all patients. The epicondylar axis was accepted in 47 patients (94 %) in the technician plan. Mean planning time was 8 +/- 4 min. Intraoperatively, the femoral anterior-posterior size was in 50 patients (100 %) the same as in the surgeon and in 42 patients (84 %) the same as in the technician plan (p = 0.003). The tibial component implanted was in 42 patients (84 %) the same as in the surgeon and in 19 patients (38 %) the same as in the technician plan (p < 0.0001). A femoral distal recut was necessary in 31 patients (62 %) and a change of the tibial proximal cut in 17 patients (34 %) during surgery. Intraoperatively, no changes of the femoral and tibial alignment, the femoral anterior-posterior size, the femoral flexion, the femoral shift, the femoral and tibial rotation were necessary. Postoperatively, the coronal mechanical overall axis was within +/-3 degrees in 47 patients (94 %) with a maximum deviation of 5.6 degrees . CONCLUSIONS: Significant changes of the technician plan were necessary to get an accurate preoperative plan. Intraoperative changes were significant less compared to the surgeon than to the technician plan. No major changes (alignment, femoral anterior-posterior size and rotation) of the surgeon plan were necessary. Surgeons using patient-specific pin guides in TKA may verify the default plan provided by the technician. A blind reply on the technician plan may be not recommended. LEVEL OF EVIDENCE: Therapeutic study, Level III. PMID- 23942882 TI - Radiographic accuracy in TKA with a CT-based patient-specific cutting block technique. AB - PURPOSE: Patient-specific instrumentation (PSI) technology for the implantation of total knee arthroplasty (TKA) has a rising interest in the orthopaedic community. Data of PSI are controversially discussed. The hypothesis of this paper is that the radiological accuracy of CT-based PSI is similar to the one of navigated TKA published in the literature. METHODS: Since 2010, all 301 consecutively performed PSI TKAs (GMK MyKnee(c)) were included in this study. The radiological assessment consisted in a preoperative and postoperative standard X ray and long-standing X-ray. Changes from the planned to the definitively implanted component size were documented. Postoperative analysis included limb alignment and position of femoral and tibial components (for varus/valgus and flexion or tibial slope). RESULTS: The postoperative average hip-knee-ankle angle was 180.1 degrees +/- 2.0 degrees . In the frontal plane a total of 12.4 % of outliers >3 degrees , for the tibial components 4.1 % of outliers >3 degrees and for the femoral components 4.8 % of outliers >3 degrees were measured. A total of 12.3 % of outliers for posterior tibial slope and 9 % of outliers >3 degrees for the femoral flexion were noted. 10.8 % of the 602 planned size components were adapted intraoperatively. CONCLUSION: Although it is still unknown which limb axis is the correct one for the best clinical result, a technology providing the aimed axis in a most precise way should be chosen. Comparing the outcome of the current study with the data from the literature, there does not seem to be any difference compared to computer-assisted surgery. LEVEL OF EVIDENCE: IV. PMID- 23942883 TI - Colloidal particles in a drying suspension: a phase field crystal approach. AB - Using a phase field crystal model we study the structure and dynamics of a drop of colloidal suspension during evaporation of the solvent. We model an experimental system where contact line pinning of the drop on the substrate is non-existent. Under such carefully controlled conditions, evaporation of the drop produces an ordered or disordered arrangement of the colloidal residue depending only on the initial average density of solute and the drying rate. We obtain a non-equilibrium phase boundary showing amorphous and crystalline phases of single component and binary mixtures of colloidal particles in the density-drying rate plane. While single-component colloids order in the two-dimensional triangular lattice, a symmetric binary mixture of mutually repulsive particles can be ordered into three triangular sub-lattices in two dimensions. Two of them are occupied by the two species of particles with the third sub-lattice vacant. PMID- 23942885 TI - Population genetic data of the AmpFlSTR(r) Identifiler(r) Plus and PowerPlex(r) 16 HS STR loci in four Canadian populations. AB - Allele frequencies and forensically relevant population statistics were estimated for the short tandem repeat (STR) loci of the AmpFlSTR(r) Identifiler(r) Plus and PowerPlex(r) 16 HS amplification kits, including D2S1338, D19S433, Penta D, and Penta E, for three First Nations Aboriginal populations and for Caucasians in Canada. The cumulative power of discrimination was >= 0.999999999999984 and the cumulative power of exclusion was >= 0.999929363 for both amplification systems in all populations. No significant departure from Hardy-Weinberg equilibrium was detected for D2S1338, D19S433, Penta D, and Penta E or the 13 Combined DNA Index System core STR loci after correction for multiple testing. Significant genetic diversity was observed between these four populations. Comparison with published frequency data for other populations is also presented. PMID- 23942884 TI - Epidemiological gender-specific aspects in urolithiasis. AB - PURPOSE: The incidence of urolithiasis is worldwide increasing and contributes to a rising economic and health care burden. The objective of this review is to identify gender differences in urolithiasis epidemiology in Europe and the USA as well as gender-specific risk factors for urolithiasis. EVIDENCE ACQUISITION: A systematic review of the present literature was performed including English journals without a time limit. The MeSH terms used were as follows: ("Sex Characteristics"[Mesh]) AND "Urolithiasis"[Mesh] or ("Epidemiology"[Mesh]) AND "Urolithiasis"[Mesh]. Additionally, reference search of retrieved papers identified additional references. The MEDLINE database was searched. EVIDENCE SYNTHESIS: The prevalence of urolithiasis is rising worldwide including both genders in different age groups. Especially women face an increase in prevalence in the USA. Overweight seems to be an important cause for this development. Additionally insulin resistance and hypertonia, conditions present in the metabolic syndrome complex, contribute to this phenomenon. CONCLUSION: Stone prevalence across all age groups and both genders is increasing. Lifestyle changes along with increasing prevalence of obesity are key factors for this development. Female gender did significantly differ in the risk ratio of stone development in different variables including body mass index, hyperinsulinemia, and hypertension. It is important to inform the public on measures how to change lifestyle and dietary measures for preventing or lowering events of stone disease. PMID- 23942886 TI - Plasticity at axon initial segment of hippocampal CA3 neurons in rat after status epilepticus induced by lithium-pilocarpine. AB - BACKGROUND: The axon initial segment (AIS) is a specialized membrane region in the axon of neurons wherein numerous specific voltage-gated sodium channels (VGSCs) are clustered and action potentials are initiated. The AIS is currently considered as a new plastic hotspot. METHODS: We investigated the alterations in Nav1.6 (SCN8A) and its adapter protein ankyrin G in the AIS of the hippocampal cornu ammonis 3 (CA3) pyramidal cells of rat after status epilepticus induced by lithium-pilocarpine (PISE). RESULTS: Nav1.6 and ankyrin G were colocalized in the AIS of hippocampal CA3 pyramidal neurons. Compared with the control group, the protein and mRNA expression of Nav1.6 increased within 24 h and 60 days after PISE. By contrast, ankyrin G protein expression decreased slightly within 24 h but increased within 60 days, whereas ankyrin G mRNA increased within 24 h and 60 days after PISE. However, the protein and mRNA expression levels of Nav1.6 and ankyrin G within 7 days after PISE did not differ significantly with those of the control. CONCLUSIONS: Nav1.6 and ankyrin G may participate in the plastic changes in the AIS of hippocampus CA3 neurons after PISE and play potential roles in epileptogenesis by regulating neuronal excitability. PMID- 23942887 TI - Ternary 3D architectures of CdS QDs/graphene/ZnIn2S4 heterostructures for efficient photocatalytic H2 production. AB - Highly efficient hydrogen production can be achieved by three-dimensional (3D) architectures of CdS quantum dots (QDs) incorporated in the porous assembly of marigold-like ZnIn2S4 heterostructures coupled with graphene, leading to an efficient electron transfer between them and the enhancement of the ZnIn2S4 photostability. The as-prepared samples were characterized by X-ray diffraction, electron microscopy, Brunauer-Emmett-Teller analysis, X-ray photoelectron spectroscopy, UV-vis diffuse reflectance absorption spectra, and photoluminescence spectra. Especially, 3 wt% CdS QDs decorated ZnIn2S4 heteroarchitectures showed a high rate of H2-production at 1.9 mmol h(-1), more 2.7 times than that of ZnIn2S4. The rate was further increased to 2.7 mmol h(-1) with a high quantum efficiency of 56% using the 3 wt% CdS QDs decorated ZnIn2S4 composites coupled with 1 wt% graphene (about 4 times higher than that of the pure ZnIn2S4). Moreover, the CdS QDs/graphene/ZnIn2S4 exhibited strong durability due to the high hydrothermal stability of the flower-like structure and the inhibition of CdS leaching owing to its strong interaction with ZnIn2S4. The excellent photocatalytic performance is ascribed to the enhanced light absorption and the improved separation of photogenerated carriers. This finding highlights the validity of 3D semiconductor heterostructures as effective building blocks for exploring efficient visible-light-active photocatalysts. PMID- 23942888 TI - [Preclinical treatment of multiple trauma : what is important?]. AB - Multiple trauma is still the most common cause of death in the age group below 40 years but rarely occurs in prehospital emergencies in Germany. Therefore, personal experience of emergency physicians in prehospital treatment of multiple trauma is often limited. Priority-based therapy according to standardized algorithms and advances in clinical and intensive care have reduced hospital mortality down to 13 %. Time factors, treatment and transport by Helicopter Emergency Medical Services seem to have had a significant impact on the outcome. The current German multiple trauma S3 guidelines provide algorithms for preclinical treatment. The underlying scientific evidence in this respect is, however, low. PMID- 23942889 TI - [Pathophysiology of multiple trauma : intensive care medicine and timing of treatment]. AB - After severe multiple injuries (first hit) a two-phase immunological response with early hyperinflammation followed by immunosuppression can be observed. This process involves a variety of humoral and cellular factors. Depending on the individual predisposition, overall injury severity and injury pattern, both reactions can lead to sepsis and multiorgan failure. Various clinical and intensive care parameters indicate stabilization of specific organ functions. The clinical course can be positively influenced by adequate intensive care therapy, avoiding iatrogenic second hits by non-emergency surgical interventions during a phase of immunological dysregulation. Important decision parameters besides time to initial trauma include adequate oxygenation, no coagulopathy, declining inflammatory mediators and normalized serum lactate. PMID- 23942890 TI - [Genetic investigations of pheochromocytoma and paraganglioma]. PMID- 23942891 TI - Cyclotrimerization of terminal alkynes catalyzed by the system of NiCl2/Zn and (benzimidazolyl)-6-(1-(arylimino)ethyl)pyridines. AB - An effective regioselective cyclotrimerization of terminal alkynes is achieved by the direct utilization of NiCl2.6H2O, Zn, and 2-(benzimidazolyl)-6-(1 (arylimino)ethyl)pyridine in one step under ambient temperature. PMID- 23942892 TI - Experiences in fertility preservation: lessons learned to ensure that fertility and reproductive autonomy remain options for cancer survivors. AB - PURPOSE: Assess fertility preservation (FP) measures chosen by patients newly diagnosed with malignancy and their outcomes. METHODS: Reproductive-age patients referred for FP underwent counseling and elected cryopreservation vs. no treatment. Outcome measures included ovarian stimulation, FP choice, oocytes/zygotes retrieved/cryopreserved and pregnancy outcome. RESULTS: From 2005 to 2012, 136 patients were counseled with 124 electing treatment: 83 oocyte-only, 21 oocyte + zygote and 20 zygote-only cryopreservation. Age, partnership and financial status factored into FP choice. Treatment was completed in 12 +/- 2 days with 14 +/- 11 metaphase-II oocytes harvested and cryopreserved/cycle. Eight patients returned to attempt pregnancy; three succeeded. CONCLUSIONS: Our data demonstrate that oocyte and/or zygote banking are feasible FP options for women with malignancy; given the choice, the majority elected oocyte cryopreservation, highlighting desire for reproductive autonomy. Continued growth and research, combined with interdisciplinary communication, will ensure that appropriate candidates are offered FP and the potential for future parenthood, an important quality-of-life marker for survivors. PMID- 23942893 TI - Stabilizing effect of electrostatic vs. aromatic interactions in diproline nucleated peptide beta-hairpins. AB - The contribution of Tyr-His vs. Cys-His interacting pairs to the scaffold stability of (D)Pro-(L)Pro nucleated peptide beta-hairpins has been examined. We present direct evidence for the superiority of the Cys-His pairs, mediated by sulphur-imidazole interactions, as added stabilizing agents of the beta-hairpin scaffold. PMID- 23942894 TI - Self-assembled dextran sulphate nanoparticles for targeting rheumatoid arthritis. AB - The amphiphilic block copolymer, composed of hydrophilic dextran sulfate as the targeting ligand and hydrophobic polycaprolactone as the hydrophobic segment, was prepared via click chemistry to develop self-assembled nanoparticles for targeting rheumatoid arthritis. PMID- 23942895 TI - Synergistic vasculogenic effects of AMD3100 and stromal-cell-derived factor 1alpha in vasa nervorum of the sciatic nerve of mice with diabetic peripheral neuropathy. AB - Autologous endothelial progenitor cell (EPC) transplantation has been suggested as a potential therapeutic approach in diabetic neuropathy (DN). However, such treatment might be limited by safety concerns regarding possible unwanted proliferation or differentiation of the transplanted stem cells. An alternative approach is the stimulation of endogenous bone-marrow-derived EPC (BM-EPC) recruitment into ischemic lesions by the administration of stem cell mobilization agents or chemokines. We first tested the EPC mobilization effect of vascular endothelial growth factor (VEGF) and AMD3100 in a mouse model of diabetes and found that AMD3100 was effective as an EPC mobilization agent, whereas VEGF did not increase circulating EPCs in these animals. Because recent studies have suggested that deceased local expression of stromal-cell-derived factor (SDF) 1alpha in diabetes is the main cause of defective EPC migration, AMD3100 was administrated systemically to stimulate EPC mobilization and SDF-1alpha was injected locally to enhance its migration into the streptozotocin-induced DN mice model. This combined therapy increased local expression levels of vasculogenesis associated factors and newly formed endothelial cells in the sciatic nerve, resulting in the restoration of the sciatic vasa nervorum. The treatment also improved the impaired conduction velocity of the sciatic nerve in DN mice. Thus, AMD3100 might be an effective EPC mobilization agent in diabetes, with local SDF 1alpha injection synergistically increasing vascularity in diabetic nerves. This represents a novel potential therapeutic option for DN patients. PMID- 23942896 TI - Immunolocalization and distribution of functional temperature-sensitive TRP channels in salivary glands. AB - Transient receptor potential (TRP) cation channels are unique cellular sensors involved in multiple cellular functions. Their role in salivary secretion remains to be elucidated. The expression and localization of temperature-sensitive TRP channels in salivary (submandibular, sublingual and parotid) glands were analyzed by immunohistochemistry and quantitative real-time reverse transcription plus the polymerase chain reaction (RT-PCR). The effects of various TRP channel agonists on carbachol (CCh)-induced salivary secretion in the submandibular gland and on the intracellular Ca(2+) concentration ([Ca(2+)]i) in a submandibular epithelial cell line were also investigated. Immunohistochemistry revealed the expression of TRP-melastatin subfamily member 8 (TRPM8) and TRP-ankyrin subfamily member 1 (TRPA1) in myoepithelial, acinar and ductal cells in the sublingual, submandibular and parotid glands. In addition, TRP-vanilloid subfamily member 1 (TRPV1), TRPV3 and TRPV4 were also expressed in myoepithelial, acinar and ductal cells in all three types of gland. Quantitative real-time RT-PCR results demonstrated the mRNA expression of TRPV1, TRPV3, TRPV4, TRPM8 and TRPA1 in acinar and ductal cells in these salivary glands. Perfusion of the entire submandibular gland with the TRPV1 agonist capsaicin (1 MUM) via the submandibular artery significantly increased CCh-induced salivation, whereas perfusion with TRPM8 and TRPA1 agonists (0.5 MUM WS12 and 100 MUM allyl isothiocyanate) decreased it. Application of agonists for each of the thermosensitive TRP channels increased [Ca(2+)]i in a submandibular epithelial cell line. These results indicate that temperature-sensitive TRP channels are localized and distributed in acinar, ductal and myoepithelial cells in salivary glands and that they play a functional role in the regulation and/or modulation of salivary secretion. PMID- 23942897 TI - Leading compounds for the validation of animal models of psychopathology. AB - Modelling of complex psychiatric disorders, e.g., depression and schizophrenia, in animals is a major challenge, since they are characterized by certain disturbances in functions that are absolutely unique to humans. Furthermore, we still have not identified the genetic and neurobiological mechanisms, nor do we know precisely the circuits in the brain that function abnormally in mood and psychotic disorders. Consequently, the pharmacological treatments used are mostly variations on a theme that was started more than 50 years ago. Thus, progress in novel drug development with improved therapeutic efficacy would benefit greatly from improved animal models. Here, we review the available animal models of depression and schizophrenia and focus on the way that they respond to various types of potential candidate molecules, such as novel antidepressant or antipsychotic drugs, as an index of predictive validity. We conclude that the generation of convincing and useful animal models of mental illnesses could be a bridge to success in drug discovery. PMID- 23942899 TI - Meningothelial meningioma in a Malayan sun bear (Helarctos malayanus). AB - A 24-year-old, spayed female Malayan sun bear (Helarctos malayanus) in the Taipei Zoo (Taipei, Taiwan) showed clinical signs of slowly progressive anorexia, dullness, compulsive pacing, and circling. The animal subsequently developed acute severe stupor and persistent recumbency. Postcontrast study of computed tomography revealed a spheroid, extra-axial mass with strong but heterogeneous hyperattenuation in the left temporal lobe of the cerebrum. At necropsy, a solitary, well-circumscribed intracranial mass measuring 3 cm * 2.5 cm * 2 cm was attached to the left pyriform lobe with compression of the adjacent neuroparenchyma. Cytological examination obtained from the mass revealed large clumps and sheets of cohesive polyhedral cells with round nuclei, wispy cytoplasm, and indistinct cell borders. Microscopically, the mass was composed of densely packed round to polygonal cells arranged in lobules and small nests. Psammoma bodies, xanthomatous change, and cholesterol deposition were also noted. Immunohistochemical staining of the tumor was positive for vimentin, pancytokeratin, cytokeratin (CK)34BE12, neuron-specific enolase, and epithelial membrane antigen, but negative for glial fibrillary acidic protein and S100 protein. The cytological, histological, and immunohistochemical features were compatible with a meningothelial meningioma. PMID- 23942900 TI - Simultaneous detection of Chlamydia spp., Coxiella burnetii, and Neospora caninum in abortion material of ruminants by multiplex real-time polymerase chain reaction. AB - Chlamydia spp., Coxiella burnetii, and Neospora caninum are responsible for reproductive diseases and are closely linked with high abortion rates in ruminants. Furthermore, C. burnetii and Chlamydia spp. have zoonotic potential. A real-time polymerase chain reaction (PCR) assay was developed for the simultaneous detection of Chlamydia spp., C. burnetii, and N. caninum. The detection of beta-actin as internal control in the same PCR reaction provides additional information about sample quality by detecting the presence of PCR inhibitors. The multiplex real-time PCR developed in the current study shows a greater sensitivity compared to previously used single-target PCR reactions with a reproducible detection limit of 0.13 plasmid copies per PCR for each target. Additional parallel amplification of all detectable pathogens did not adversely impact sensitivity. This new multiplex PCR allows the highly sensitive, cost effective, and rapid detection of 3 important pathogens and has the potential to be a useful time-saving tool in the routine diagnosis of abortion cases in ruminants. PMID- 23942901 TI - Abortion and premature birth in cattle following vaccination with Brucella abortus strain RB51. AB - Brucella abortus RB51 is the vaccine strain currently licensed for immunizing cattle against brucellosis in the United States. Most cattle are vaccinated as heifer calves at 4-12 months of age. Adult cattle may be vaccinated in selected high-risk situations. Two herds of pregnant adult cattle in the brucellosis endemic area of Wyoming were vaccinated with a standard label dose (1.0-3.4 * 10(10) organisms) of RB51. Reproductive losses in the vaccinated herds were 5.3% (herd A) and 0.6% (herd B) and included abortions, stillbirths, premature calves, and unbred cows (presumed early abortion). Brucella abortus was cultured from multiple tissues of aborted and premature calves (7/9), and from placenta. Isolates were identified as B. abortus strain RB51 by standard strain typing procedures and a species-specific polymerase chain reaction. Bronchopneumonia with intralesional bacteria and placentitis were observed microscopically. There was no evidence of involvement of other infectious or toxic causes of abortion. Producers, veterinarians, and laboratory staff should be alert to the risk of abortion when pregnant cattle are vaccinated with RB51, to potential human exposure, and to the importance of distinguishing field from vaccinal strains of B. abortus. PMID- 23942902 TI - Evaluation of two commercial enzyme-linked immunosorbent assay kits for the detection of serum antibodies against Akabane virus in cattle. AB - In New Zealand, an arbovirus surveillance program has been operating for more than 20 years, which includes testing of cattle with the Akabane virus neutralization test. With the aim to replace this laborious test by an easier-to perform enzyme-linked immunosorbent assay (ELISA), 2 commercial ELISA kits, ELISA 1 from France (originally from Australia) and ELISA-2 from Japan, were compared, using 334 serum samples from noninfected New Zealand cattle, and 548 serum samples from naturally infected cattle herds in Australia. Diagnostic specificities for the test methods were high, ranging from 99.4% to 100%. The diagnostic sensitivities varied considerably between the test methods and differed from the values reported by the manufacturers (94% for each ELISA). The diagnostic sensitivities relative to the virus neutralization test (n = 378) were 96.0% for ELISA-1 or 98.9% when suspect samples were included, and 78.0% for ELISA-2. Differences in the commercial ELISA kits may be explained by the presence of other Simbu serogroup viruses in Australian cattle herds, causing cross-reactions in ELISA-1. Both commercial ELISA kits would be fit for purpose and could replace the virus neutralization test for Akabane virus surveillance in New Zealand. ELISA-1 may be able to detect other Simbu serogroup viruses, should they be present. The current study shows that despite comparable ELISA test characteristics given by the manufacturers, evaluation on the target population revealed marked differences in the ELISA kits test methods' characteristics. PMID- 23942903 TI - Assemble the puzzle: bizarre-looking lesions. PMID- 23942904 TI - Effects of sterigmatocystin on esophageal epithelium and experimental reflux esophagitis in rats. AB - Patients with reflux esophagitis experience an increased incidence of esophageal cancer. In China, this may be the result of contamination of the food supply by Aspergillus fungi, which is known to harbor sterigmatocystin, a carcinogenic mycotoxin. To delineate the potential link between sterigmatocystin and esophageal cancer, an experimental model of reflux esophagitis was developed in rats that had undergone a cardiectomy and partial pylorus ligation. The rats were treated with sterigmatocystin or saline, and esophageal squamous cell hyperplasia was assessed based on the pathological evaluation. The expression of proliferating cell nuclear antigen (PCNA), transporter associated with antigen processing 1 (TAP1) and low molecular weight protein 2 (LMP2) was determined by immunohistochemistry. Intraperitoneal administration of sterigmatocystin promoted the proliferation of squamous epithelium. In addition, it also increased the expression of PCNA in esophageal epithelial cells in rats with reflux esophagitis and was correlated with the increased severity of epithelial hyperplasia. The expression levels of TAP1 and LMP2, which are located in the cytoplasm of esophageal epithelial cells, were reduced in rats with reflux esophagitis, and sterigmatocystin exposure further decreased the expression. Thus, the downregulation of TAP1 and LMP2 proteins by sterigmatocystin may directly affect tumor immunity by allowing transformed cells to escape the host immune surveillance, thereby promoting esophageal cancer. PMID- 23942905 TI - Modulation of the stability of amyloidogenic precursors by anion binding strongly influences the rate of amyloid nucleation. AB - A deep understanding of the physicochemical factors modulating amyloid aggregation of proteins is crucial to develop therapeutic and preventive approaches for amyloid-related diseases. The earliest molecular events of the aggregation cascade represent some of the main targets as indicated by the toxic nature of certain early oligomers. Here, we study how different types of salt ions influence the kinetics of amyloid assembly of the N47A mutant alpha-spectrin SH3 domain using a battery of techniques. The salts influenced aggregation rates to different extents without altering the overall mechanism and the high apparent order of the experimental kinetics. A quantitative analysis of the initial aggregation rates measured by thioflavine-T fluorescence using a simple nucleation model allowed us to estimate the kinetic and thermodynamic magnitudes of crucial aggregation precursors, as well as to evaluate the impact of each type of ion on the earliest amyloid nucleation stages. Whilst cations did not have any noticeable effect under our experimental conditions, anions stabilized an amyloidogenic intermediate state and also increased the rate of the conformational conversion from dynamic oligomers to amyloid nuclei, resulting in a strong acceleration of the nucleation process. Anions appear to act by preferential binding to the amyloidogenic intermediate state, thus enhancing its population and subsequent oligomerization. Overall, our results contribute to the rationalization of the effect of ions on the amyloid nucleation stage and give insight into the properties of the crucial intermediate precursors of amyloid aggregation. PMID- 23942906 TI - Pathology-based validation of FDG PET segmentation tools for volume assessment of lymph node metastases from head and neck cancer. AB - PURPOSE: FDG PET is increasingly incorporated into radiation treatment planning of head and neck cancer. However, there are only limited data on the accuracy of radiotherapy target volume delineation by FDG PET. The purpose of this study was to validate FDG PET segmentation tools for volume assessment of lymph node metastases from head and neck cancer against the pathological method as the standard. METHODS: Twelve patients with head and neck cancer and 28 metastatic lymph nodes eligible for therapeutic neck dissection underwent preoperative FDG PET/CT. The metastatic lymph nodes were delineated on CT (NodeCT) and ten PET segmentation tools were used to assess FDG PET-based nodal volumes: interpreting FDG PET visually (PETVIS), applying an isocontour at a standardized uptake value (SUV) of 2.5 (PETSUV), two segmentation tools with a fixed threshold of 40% and 50%, and two adaptive threshold based methods. The latter four tools were applied with the primary tumour as reference and also with the lymph node itself as reference. Nodal volumes were compared with the true volume as determined by pathological examination. RESULTS: Both NodeCT and PETVIS showed good correlations with the pathological volume. PET segmentation tools using the metastatic node as reference all performed well but not better than PETVIS. The tools using the primary tumour as reference correlated poorly with pathology. PETSUV was unsatisfactory in 35% of the patients due to merging of the contours of adjacent nodes. CONCLUSION: FDG PET accurately estimates metastatic lymph node volume, but beyond the detection of lymph node metastases (staging), it has no added value over CT alone for the delineation of routine radiotherapy target volumes. If FDG PET is used in radiotherapy planning, treatment adaptation or response assessment, we recommend an automated segmentation method for purposes of reproducibility and interinstitutional comparison. PMID- 23942907 TI - Areas of normal pulmonary parenchyma on HRCT exhibit increased FDG PET signal in IPF patients. AB - PURPOSE: Patients with idiopathic pulmonary fibrosis (IPF) show increased PET signal at sites of morphological abnormality on high-resolution computed tomography (HRCT). The purpose of this investigation was to investigate the PET signal at sites of normal-appearing lung on HRCT in IPF. METHODS: Consecutive IPF patients (22 men, 3 women) were prospectively recruited. The patients underwent (18)F-FDG PET/HRCT. The pulmonary imaging findings in the IPF patients were compared to the findings in a control population. Pulmonary uptake of (18)F-FDG (mean SUV) was quantified at sites of morphologically normal parenchyma on HRCT. SUVs were also corrected for tissue fraction (TF). The mean SUV in IPF patients was compared with that in 25 controls (patients with lymphoma in remission or suspected paraneoplastic syndrome with normal PET/CT appearances). RESULTS: The pulmonary SUV (mean +/- SD) uncorrected for TF in the controls was 0.48 +/- 0.14 and 0.78 +/- 0.24 taken from normal lung regions in IPF patients (p < 0.001). The TF-corrected mean SUV in the controls was 2.24 +/- 0.29 and 3.24 +/- 0.84 in IPF patients (p < 0.001). CONCLUSION: IPF patients have increased pulmonary uptake of (18)F-FDG on PET in areas of lung with a normal morphological appearance on HRCT. This may have implications for determining disease mechanisms and treatment monitoring. PMID- 23942908 TI - The complementary roles of dynamic contrast-enhanced MRI and 18F fluorodeoxyglucose PET/CT for imaging of carotid atherosclerosis. AB - PURPOSE: Inflammation and neovascularization in vulnerable atherosclerotic plaques are key features for severe clinical events. Dynamic contrast-enhanced (DCE) MRI and FDG PET are two noninvasive imaging techniques capable of quantifying plaque neovascularization and inflammatory infiltrate, respectively. However, their mutual role in defining plaque vulnerability and their possible overlap has not been thoroughly investigated. We studied the relationship between DCE-MRI and (18)F-FDG PET data from the carotid arteries of 40 subjects with coronary heart disease (CHD) or CHD risk equivalent, as a substudy of the dal PLAQUE trial (NCT00655473). METHODS: The dal-PLAQUE trial was a multicenter study that evaluated dalcetrapib, a cholesteryl ester transfer protein modulator. Subjects underwent anatomical MRI, DCE-MRI and (18)F-FDG PET. Only baseline imaging and biomarker data (before randomization) from dal-PLAQUE were used as part of this substudy. Our primary goal was to evaluate the relationship between DCE-MRI and (18)F-FDG PET data. As secondary endpoints, we evaluated the relationship between (a) PET data and whole-vessel anatomical MRI data, and (b) DCE-MRI and matching anatomical MRI data. All correlations were estimated using a mixed linear model. RESULTS: We found a significant inverse relationship between several perfusion indices by DCE-MRI and (18)F-FDG uptake by PET. Regarding our secondary endpoints, there was a significant relationship between plaque burden measured by anatomical MRI with several perfusion indices by DCE-MRI and (18)F FDG uptake by PET. No relationship was found between plaque composition by anatomical MRI and DCE-MRI or (18)F-FDG PET metrics. CONCLUSION: In this study we observed a significant, weak inverse relationship between inflammation measured as (18)F-FDG uptake by PET and plaque perfusion by DCE-MRI. Our findings suggest that there may be a complex relationship between plaque inflammation and microvascularization during the different stages of plaque development. (18)F-FDG PET and DCE-MRI may have complementary roles in future clinical practice in identifying subjects at high risk of cardiovascular events. PMID- 23942911 TI - Copper(II)-catalyzed trifluoromethylation of N-aryl imines. AB - Methods for imine trifluoromethylation are of great importance because amines with trifluoromethylated stereogenic centers are useful building blocks for synthetic chemistry and drug discovery. Herein, we describe a new copper(II) catalyzed imine trifluoromethylation method without the use of Lewis base activators, presumably through cooperative activation. PMID- 23942910 TI - Vascular deposition patterns for nanoparticles in an inflamed patient-specific arterial tree. AB - Inflammation, a precursor to many diseases including cancer and atherosclerosis, induces differential surface expression of specific vascular molecules. Blood borne nanoparticles (NPs), loaded with therapeutic and imaging agents, can recognize and use these molecules as vascular docking sites. Here, a computational model is developed within the isogeometric analysis framework to understand and predict the vascular deposition of NPs within an inflamed arterial tree. The NPs have a diameter ranging from 0.1 to 2.0 MUm and are decorated with antibodies directed toward three endothelial adhesion molecules, namely intravascular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin, whose surface density depends on the local wall shear stress. Results indicate VCAM-1 targeted NPs adhere more, with ICAM-1 directed NPs adhering least efficiently, resulting in approximately an order-of-magnitude lower average particle surface density. ICAM-1 and E-selectin directed 0.5 MUm NPs are distributed more uniformly (heterogeneity index ~ 0.9 and 1.0, respectively) over the bifurcating vascular branches compared to their VCAM-1 counterparts (heterogeneity index ~ 1.4). When the NPs are coated with antibodies for VCAM-1 and E-selectin in equal proportions, a more uniform vascular distribution is achieved compared with VCAM-1-only targeted particles, thus demonstrating the advantage of NP multivalency in vascular targeting. Furthermore, the larger NPs (2 MUm) adhere more (~ 200%) in the lower branches compared to the upper branch. This computational framework provides insights into how size, ligand type, density, and multivalency can be manipulated to enhance NP vascular adhesion in an individual patient. PMID- 23942912 TI - Comprehensive transcriptome profiling and functional analysis of the frog (Bombina maxima) immune system. AB - Amphibians occupy a key phylogenetic position in vertebrates and evolution of the immune system. But, the resources of its transcriptome or genome are still little now. Bombina maxima possess strong ability to survival in very harsh environment with a more mature immune system. We obtained a comprehensive transcriptome by RNA-sequencing technology. 14.3% of transcripts were identified to be skin specific genes, most of which were not isolated from skin secretion in previous works or novel non-coding RNAs. 27.9% of transcripts were mapped into 242 predicted KEGG pathways and 6.16% of transcripts related to human disease and cancer. Of 39 448 transcripts with the coding sequence, at least 1501 transcripts (570 genes) related to the immune system process. The molecules of immune signalling pathway were almost presented, several transcripts with high expression in skin and stomach. Experiments showed that lipopolysaccharide or bacteria challenge stimulated pro-inflammatory cytokine production and activation of pro-inflammatory caspase-1. These frog's data can remarkably expand the existing genome or transcriptome resources of amphibians, especially immunity data. The entity of the data provides a valuable platform for further investigation on more detailed immune response in B. maxima and a comparative study with other amphibians. PMID- 23942914 TI - [Treatment of the severely injured at the highest level : the Trauma Register DGU(r) becomes "twenty"]. PMID- 23942913 TI - Biomarkers of cognitive dysfunction in traumatic brain injury. AB - Acetylcholine, glutamate, dopamine, serotonin (5-HT), gamma-aminobutyric acid, substance P (SP), amyloid-beta (Abeta) and neurotrophic protein S100B are arguably the most important cognition-related biomarkers in the brain. Among this list are five neurotransmitters that signal through postsynaptic receptors. Our knowledge of cognition-related biomarkers has been advanced through translational experiments and clinical case-study data. Although these biomarkers are widespread in the brain and pronounced individual variations exist, these biomarkers can be used to identify both acute and chronic abnormalities following traumatic brain injury. Changes in these biomarkers likely indicate damage to brain networks or to key brain cell types that support cognitive functions. Identification of such biomarker abnormalities could result in earlier diagnoses, improved prognoses and therapies that enable neurotransmitters to return to normal levels. PMID- 23942915 TI - [Surgical treatment of short bowel syndrome]. PMID- 23942916 TI - Impact of age cutoffs on a lynch syndrome screening program. AB - PURPOSE: To determine the impact of applying an age cutoff to tumor-based Lynch syndrome (LS) screening, specifically focusing on changes in relative effectiveness, efficiency, and cost. The project was undertaken to answer questions about implementation of the LS screening program in an integrated health care delivery system. PATIENTS AND METHODS: Clinical data extracted from an internal cancer registry, previous modeling efforts, published literature, and gray data were used to populate decision models designed to answer questions about the impact of age cutoffs in LS screening. Patients with colorectal cancer (CRC) were stratified at 10-year intervals from ages 50 to 80 years and compared with no age cutoff. Outcomes are reported for a cohort of 325 patients screened and includes total cost to screen, LS cases present in the cutoff category, number of LS cases expected to be identified by screening, cost per LS case detected, and total number and percentage of LS cases missed. CONCLUSION: Applying an age cutoff to an LS screening program has considerable potential for decreasing total screening costs and increasing efficiency, but at a loss of effectiveness. Imposing an age cutoff of 50 years reduces the cost of the screening program to 16% of a program with no age cutoff, but at the expense of missing more than half of the cases. Failure to identify LS cases is magnified by a cascade effect in family members. The results of this analysis influenced the final policy in our system. PMID- 23942917 TI - Tumor-based screening for hereditary nonpolyposis colorectal cancer: does age based selection optimize yield? PMID- 23942918 TI - Evaluating use characteristics for the oncotype dx 21-gene recurrence score and concordance with chemotherapy use in early-stage breast cancer. AB - PURPOSE: Oncotype Dx 21-gene assay recurrence score (RS) predicts recurrence of early-stage breast cancer (ESBC). We investigated whether patient, tumor, or practice characteristics drive its use and explored Oncotype DX RS and chemotherapy use in subgroups. METHODS: Patients with ESBC with documented estrogen receptor-positive, lymph node-negative, human epidermal growth factor receptor 2-negative tumors registered within McKesson Specialty Health's iKnowMed electronic health record were included. Patient and practice characteristics by region and size were analyzed. The association between Oncotype DX RS value and use of chemotherapy were assessed. RESULTS: The study included 6,229 patients. Of these, 1,822 (29%) had an Oncotype DX RS result. Test use was 36%, 38%, 34%, 25%, and 6%, respectively, in patients age <= 45, 46-55, 56-65, 66-75, and >= 76 years; 33%, 25%, and 9% in patients with Eastern Cooperative Oncology Group performance status of 0, 1, and >= 2; 7%, 9%, 25%, 38%, 27%, and 10% in T1mic, T1a, T1b, T1c, T2, and T3 tumors; and 26%, 32%, and 33% for grades 1, 2, and 3 tumors. Of the 1,822 patients with available Oncotype DX RS, adjuvant chemotherapy use was 6%, 42%, and 84% in the low-, intermediate-, and high-risk groups. CONCLUSION: Patients who were younger, had better ECOG performance status, or had higher grade tumors were more likely to undergo RS testing. It appears that the RS test may have influenced the decision about whether to administer adjuvant chemotherapy: a low RS score was associated with lower chemotherapy use and a high RS score was associated with higher chemotherapy use. PMID- 23942919 TI - Overcoming obstacles in accessing unfunded oral chemotherapy: physician experience and challenges. AB - PURPOSE: Previous studies have shown hematologists and medical oncologists may not accept the financial limits set by governing agencies on patient access to oral chemotherapy. The purpose of this study was to capture the methods physicians used to overcome barriers to accessing chemotherapeutic regimens for their patients. METHODS: A total of 640 medical oncologists and hematologists across Canada were surveyed using a 13-item Web-based survey tool. The survey was delivered by e-mail with three follow-up reminders. After a response period of 3 months, results were collated and analyzed with descriptive statistics. RESULTS: Of the 640 invitations, 568 were successfully delivered, and 183 responses were received (response rate, 32.0%). Among respondents, 101 treated solid malignancies (55.2%), 49 treated nonsolid malignancies (26.8%), and 33 treated both (18.0%). To overcome funding barriers, participating oncologists enrolled patients onto clinical trials (90.5%), used compassionate access programs (96.1%), and made special requests to government (91.8%). Other methods included writing false claims on forms to fit funding criteria for drugs (31.1%) and using leftover drug supplies (31.0%). Physicians felt their inability to obtain unfunded medications had a negative impact on their patients' clinical outcomes (56.0%) and psychosocial quality of life (73.0%). Only 28.5% of physicians contacted their governing body with concerns about oral chemotherapy funding. CONCLUSION: Canadian physicians use numerous methods to obtain unfunded oral chemotherapies, including falsifying claims on access forms and submitting special requests to government agencies. Further study is warranted to explore the disconnection between policymakers and physicians with regard to funding of oral chemotherapies. PMID- 23942920 TI - Protecting patient access to oral cancer drugs in the United States. PMID- 23942921 TI - Physical, psychosocial, relationship, and economic burden of caring for people with cancer: a review. AB - The aim of this article is to provide an overview of the issues faced by caregivers of people diagnosed with cancer, with a particular emphasis on the physical, psychosocial, and economic impact of caring. A review of the literature identified cancer as one of the most common health conditions in receipt of informal caregiving, with the majority of caregivers reporting taking on the role of caring because of family responsibility and there being little choice or no one else to provide the care. For some, caregiving can extend for several years and become equivalent to a full-time job, with significant consequent health, psychosocial, and financial burdens. Having a better understanding of the critical and broad roles that caregivers play in the oncology setting and the impact of these on their health and well-being may assist health care professionals in supporting caregivers with these tasks and targeting services and interventions toward those most in need. PMID- 23942922 TI - Comparison of pegfilgrastim prescribing practice to national guidelines at a university hospital outpatient oncology clinic. AB - PURPOSE: Pegfilgrastim reduces the risk of febrile neutropenia (FN) and is indicated as primary prophylaxis when the risk of FN approaches 20% in each chemotherapy cycle. There have been few reports evaluating the appropriate use of pegfilgrastim in comparison with published guidelines. We sought to determine possible over-prescribing as a way to maintain quality and reduce cost. METHODS: A retrospective medical record review was performed to determine whether pegfilgrastim was used appropriately in the primary prophylaxis of FN in chemotherapy regimens with less than 20% risk of FN. Patients were identified by means of administrative records, and data were collected from the electronic medical record at an academic cancer center outpatient clinic serving approximately 13,000 patients per year. RESULTS: Two hundred ninety-two patients were identified, of whom 124 were initially evaluated and 88 were included. Thirty-three patients (37%) had no risk factors, and 20 (22%) had one risk factor that would justify pegfilgrastim use with low- or intermediate-risk regimens. The most common cancer diagnosis of patients with zero or one risk factor was lymphoma, and the most common regimens with overuse of pegfilgrastim were doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) and ritux-imab cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP). One hundred eighty four pegfilgrastim doses (46%) were classified as avoidable. The cost to the health system for unnecessary drug use was $712,264 in 1 year. CONCLUSION: At one institution, approximately one half of all primary prophylaxis pegfilgrastim was not indicated per published guidelines. This represents an excellent opportunity to change prescribing practices to reduce costs without harming patients. PMID- 23942923 TI - Communicating safe outpatient management of fever and neutropenia. PMID- 23942924 TI - Measuring clinical trial-associated workload in a community clinical oncology program. AB - PURPOSE: The ability to quantify clinical trial-associated workload can have a significant impact on the efficiency and success of a research organization. However, methods to effectively estimate the number of research staff needed for clinical trial recruitment, maintenance, compliance, and follow-up are lacking. To address this need, the Wichita Community Clinical Oncology Program (WCCOP) developed and implemented an acuity-based workload assessment tool to facilitate assessment and balancing of workload among its research nursing staff. METHODS: An acuity-based measurement tool was developed, assigning acuity scores for individual clinical trials using six trial-related determinants. Using trial acuity scores and numbers of patients per trial, acuity scores for individual research nursing staff were then calculated and compared on a monthly basis. RESULTS: During the 11 years that data were collected, acuity scores increased from 65% to 181%. However, during this same period, WCCOP was able to decrease individual research nurse staff full-time equivalent (FTE) acuity scores and number of patients per FTE. These trends reflect the use of the acuity-based measurement tool to determine actual workload and use of the acuity data to direct hiring decisions. CONCLUSION: Clinical trial workload has been successfully measured and used to guide staffing by one community clinical oncology program. Further research is needed regarding its applicability to other research programs. PMID- 23942925 TI - Overview of accountable care organizations for oncology specialists. AB - Accountable care organizations (ACOs) are poised to become major components of health care delivery in the United States. The practice of oncology, often laden with high charges, is likely to undergo major shifts as ACOs become widespread. In this article, we review the economic factors leading to the growth of ACOs and discuss some elements of the current ACO model proposed in the Affordable Care Act. Oncology specialists-in medicine, surgery, and radiation oncology-will have important roles in determining the place of specialty care in an ACO framework and will have to take the lead in educating patients, primary care physicians, and administrators on the value propositions related to their activities. We also describe how oncology specialists may participate in the model to ensure success for physicians and patients. PMID- 23942926 TI - Computerized prescriber order entry implementation in a physician assistant managed hematology and oncology inpatient service: effects on workflow and task switching. AB - PURPOSE: Little is known about the impact of computerized prescriber order entry (CPOE) systems on inpatient hematology/oncology services. The objective of this study was to quantify the impact of an inpatient CPOE implementation on workflow, with an emphasis on ordering and direct patient care time. METHODS: We conducted a direct-observation time-and-motion study of the provider team of a hematology/oncology inpatient service both before and after CPOE implementation, characterizing workflow into 60 distinct activity categories. The provider team comprised physician assistants supervised by attending physicians. Results were adjusted to account for variations in the census. We also conducted an analysis of computer logs to assess CPOE system usage. RESULTS: Study participants were observed for 228.0 hours over 53 observation sessions. There was little change in the proportion of census-adjusted time spent on ordering (10.2% before v 11.4% after) and on direct patient care (50.7% before v 47.8% after). Workflow fragmentation decreased, with providers spending an average of 131.2 seconds on a continuous task before implementation and 218.3 seconds after (P < .01). An eight fold decrease in the number of pages was observed during the course of the study. CONCLUSION: CPOE implementation did not negatively affect time available for direct patient care. Workflow fragmentation decreased, which is likely beneficial. PMID- 23942927 TI - Developing a performance data suite to facilitate lean improvement in a chemotherapy day unit. AB - PURPOSE: A multidisciplinary team from the Peter MacCallum Cancer Centre in Melbourne, Australia, developed a performance data suite to support a service improvement project based on lean manufacturing principles in its 19-chair chemotherapy day unit (CDU) and cytosuite chemotherapy production facility. The aims of the project were to reduce patient wait time and improve equity of access to the CDU. METHODS: A project team consisting of a pharmacist and CDU nurse supported the management team for 10 months in engaging staff and customers to identify waste in processes, analyze root causes, eliminate non-value-adding steps, reduce variation, and level workloads to improve quality and flow. Process mapping, staff and patient tracking and opinion surveys, medical record audits, and interrogation of electronic treatment records were undertaken. RESULTS: This project delivered a 38% reduction in median wait time on the day (from 32 to 20 minutes; P < .01), 7-day reduction in time to commencement of treatment for patients receiving combined chemoradiotherapy regimens (from 25 to 18 days; P < .01), and 22% reduction in wastage associated with expired drug and pharmacy rework (from 29% to 7%; P < .01). Improvements in efficiency enabled the cytosuite to increase the percentage of product manufactured within 10 minutes of appointment times by 29% (from 47% to 76%; P < .01). CONCLUSION: A lean improvement methodology provided a robust framework for improved understanding and management of complex system constraints within a CDU, resulting in improved access to treatment and reduced waiting times on the day. PMID- 23942928 TI - Impact of oncology drug shortages on patient therapy: unplanned treatment changes. AB - PURPOSE: Cancer drug shortages have increased considerably over the past 5 years, but quantitative analyses of the scope and effects are limited. We assessed the effects of drug shortages on outpatient medication use in a single New York City university hospital. METHODS: We examined pharmacy records for drug shortages, as defined by the American Society of Health-System Pharmacists. We assessed outpatient records for all patients with cancer treated with infusional antineoplastic medications from April 2010 to September 2010 and April 2011 to September 2011. RESULTS: Twelve medications were in shortage in 2010 and 22 in 2011. Drugs in shortage were used for 170 patients (50.8%) in 2010 and 241 patients (63.6%) in 2011 (P < .001). Of 235 patients treated in August-September 2011, there were 23(9.8%) documented therapy changes due to shortages, compared with zero changes in August-September 2010 (P < .001). Among patients treated in August-September 2010, 24 (11.4%) received paclitaxel and 19 (9.0%) received docetaxel. Among patients treated in August-September 2011, 11 (4.7%) received paclitaxel and 38 (16.2%) received docetaxel, a 69% decrease for paclitaxel and 80% increase for docetaxel from 1 year prior (P = .009, and P = .024, respectively). The estimated cost of a single treatment with paclitaxel for one patient with body-surface area 1.75 was $47.59 versus $858.39 for docetaxel, a 1,704% increase. Surveyed physicians frequently reported lower level evidence (30.4%) and increased risk of toxicity (34.8%) with alternative therapy in drug shortage cases. CONCLUSION: Oncology drug shortages affected the majority of patients in our center and increased at an alarming rate. Drug shortages have substantial economic costs and mandate treatment changes that may affect efficacy and toxicity. PMID- 23942929 TI - Oncologists' strategies and barriers to effective communication about the end of life. AB - PURPOSE: Communicating about the end of life with patients has been reported as one of the most difficult and stressful part of the work of oncologists. Despite this fact, oncologists receive little training in this area, and many do not communicate effectively with patients. The purpose of this analysis, part of a larger study examining oncologists' experiences of patient loss, was to explore oncologists' communication strategies and communication barriers when discussing end-of-life issues with patients. METHODS: Twenty oncologists were interviewed at three hospitals about their communication strategies on end-of-life issues with patients. The data were analyzed using the grounded theory method. RESULTS: The findings revealed the strategies to effective communication about the end of life included: being open and honest; having ongoing, early conversations; communicating about modifying treatment goals; and balancing hope and reality. Barriers to implementing these strategies fell broadly into three domains, including physician factors, patient factors, and institutional factors. Physician factors included difficulty with treatment and palliation, personal discomfort with death and dying, diffusion of responsibility among colleagues, using the "death-defying mode," lack of experience, and lack of mentorship. Patient factors included, patients and/or families being reluctant to talk about the end of life, language barriers, and younger age. Institutional factors included stigma around palliative care, lack of protocol about end-of-life issues; and lack of training for oncologists on how to talk with patients about end-of-life issues. CONCLUSION: We conclude by drawing implications from our study and suggest that further research and intervention are necessary to aid oncologists in achieving effective communication about end-of-life issues. PMID- 23942930 TI - Use of the word "cure" in oncology. AB - PURPOSE: Use of the word "cure" in cancer care reflects a balance of physician and patient optimism, realism, medico-legal concerns, and even superstition. This study surveyed a group of oncology specialists regarding the frequency and determinants of using the word cure. METHODS: Oncology clinicians at the Dana Farber Cancer Institute (n = 180) were invited to complete a survey regarding the word cure in cancer care. Participants completed a 19-question survey regarding how commonly their patients are cured, how often they use the word cure in their practice, and details about its use. Three case scenarios were presented to elicit participants' views. RESULTS: Of the 117 participants (65%) who provided responses, 81% were hesitant to tell a patient that they are cured, and 63% would never tell a patient that they are cured. Only 7% felt that greater than 75% of their patients are, or will be, cured. The participating clinicians reported that only 34% of patients ask if they are cured. For 20-year survivors of testicular cancer, large-cell lymphoma, and estrogen receptor-positive breast cancer, 84%, 76%, and 48% of clinicians, respectively, believed that the patients were cured, and 35%, 43%, and 56% recommended annual oncology follow-up of the patients. Twenty-three percent of oncology clinicians believed that patients should never be discharged from the cancer center. CONCLUSION: Oncology clinicians report that patients are hesitant to ask whether they are cured, and the clinicians are hesitant to tell patients they are cured. Annual oncology follow-up was frequently endorsed, even after 20 years in remission. PMID- 23942931 TI - Practicing western oncology in Shanghai, China: one group's experience. PMID- 23942932 TI - Ethics in oncology: an annotated bibliography of important literature. AB - The aim of this annotated bibliography about important articles in the field of ethics and oncology is to provide the practicing hematologist/oncologist with a brief overview of some of the important literature in this crucial area. PMID- 23942933 TI - Efficiency of colorectal cancer care among veterans: analysis of treatment wait times at Veterans Affairs Medical Centers. AB - PURPOSE: Timeliness of cancer treatment is an important aspect of health care quality. Veterans Affairs Medical Centers (VAMCs) are expected to treat a growing number of patients with cancer. Our objectives were to examine treatment times from diagnosis to first-course therapy for patients with colon and rectal cancers and assess factors associated with prolonged wait times. METHODS: From the VA Central Cancer Registry, patients who underwent colon or rectal resection for cancer from 1998 to 2008 were identified. Time from diagnosis to definitive cancer-directed therapy was measured, and multivariable regression methods were used to determine predictors of prolonged wait times for colon (>= 45 days) and rectal (>= 60 days) cancers. RESULTS: From 124 VAMCs, 14,097 patients underwent colectomy, and 3,390 underwent rectal resection for cancer. For colon cancer, the median time to treatment increased by 68% over time (P < .001). From 2007 to 2008, the median time to colectomy was 32 days. Predictors of prolonged wait times included age >= 55 years (v < 55 years), time period (2007 to 2008 v 1998 to 2000), black race (v white), marriage status (married v unmarried), high volume center status (v low volume), and treatment at a different hospital (v same hospital as initial diagnosis; all P < .05). For rectal cancer, the overall median time to first-course treatment increased by 74% (P < .001). From 2007 to 2008, the median time to proctectomy was 47 days. Similar predictors of prolonged wait times were identified for rectal cancer. CONCLUSION: Time to first treatment has increased for patients with colon and rectal cancers at VAMCs. Patient, tumor, and hospital factors are associated with prolonged time to treatment. PMID- 23942935 TI - Ensuring that guidelines help reduce patient harm. PMID- 23942934 TI - Lymph node evaluation for colon cancer in an era of quality guidelines: who improves? AB - INTRODUCTION: In the 1990s, several organizations began recommending evaluation of > 12 lymph nodes during colon resection because of its association with improved survival. We examined practice implications of multispecialty quality guidelines over the past 20 years recommending evaluation of >= 12 lymph nodes during colon resection for adequate staging. MATERIALS AND METHODS: We used the 1988 to 2009 Surveillance, Epidemiology, and End Results program to conduct a retrospective observational cohort study of 90,203 surgically treated patients with colon cancer. We used Cochran-Armitage tests to examine trends in lymph node examination over time and multivariate logistic regression to identify patient characteristics associated with guideline-recommended lymph node evaluation. RESULTS: The introduction of practice guidelines was associated with gradual increases in guideline-recommended lymph node evaluation. From 1988 to 1990, 34% of patients had > 12 lymph nodes evaluated, increasing to 38% in 1994 to 1996 and to > 75% from 2006 to 2009. Younger, white patients and those with more-extensive bowel penetration (T3/4 nonmetastatic) and high tumor grade saw more-rapid increases in lymph node evaluation (P < .001). Multivariate analyses demonstrated a significant interaction between year of diagnosis and both T stage and grade, indicating that those with higher T stage and higher grade were more likely to receive guideline-recommended care earlier. CONCLUSION: The implementation of lymph node evaluation guidelines was accepted gradually into practice but adopted more quickly among higher risk patients. By identifying patients who are least likely to receive guideline-recommended care, these findings present a starting point for promoting targeted improvements in cancer care and further understanding underlying contributors to these disparities. PMID- 23942937 TI - The risk stratification based on the CHA2DS2-VASc may predict the response to intravenous thrombolysis after stroke. AB - CHA2DS2-VASc score influences the outcome in stroke patients with or without atrial fibrillation (AF). We assessed whether the risk stratification based on the prestroke CHA2DS2-VASc score may predict the response to intravenous (IV) thrombolysis in stroke patients. We conducted an analysis on prospectively collected data of 516 consecutive AF and non-AF patients treated with IV thrombolysis. Outcome measures were major improvement (NIH Stroke Scale [NIHSS] <=8 points from baseline or NIHSS score 0) and deterioration (death or NIHSS >=1 points from baseline) or no improvement (NIHSS score equivalent to baseline) at 24 h; excellent (modified Rankin Scale [mRS] score <=1) and unfavorable outcome (mRS score >2) at 3 months. Multivariate analysis showed that ORs for major improvement and excellent outcome were lower in patients with intermediate risk (CHA2DS2-VASc = 1) (OR 0.39, 95 % CI 0.16-0.92, p = 0.032; OR 0.10, 95 % CI 0.02 0.56, p = 0.009), moderately high risk (CHA2DS2-VASc = 2) (OR 0.43, 95 % CI 0.19 0.96, p = 0.040; OR 0.16, 95 % CI 0.03-0.76, p = 0.022), and very high risk (CHA2DS2-VASc > 3) (OR 0.31, 95 % CI 0.15-0.65, p = 0.002; OR 0.17, 95 % CI 0.04 0.81, p = 0.026), whereas ORs for deterioration or no improvement and unfavorable outcome were higher only in patients with very high risk (OR 4.26, 95 % CI 1.24 14.65, p = 0.021; OR 9.26, 95 % CI 1.15-74.65, p = 0.037), compared with low risk (CHA2DS2-VASc = 0). Low-risk level based on the prestroke CHA2DS2-VASc score was predictor of effective response to IV thrombolysis. Very high-risk level was predictor of failed response, compared with low-risk level. PMID- 23942936 TI - Screening intervention to identify eligible patients and improve accrual to phase II-IV oncology clinical trials. AB - PURPOSE: Low enrolment rates in clinical trials present a barrier to the development of novel cancer therapies. Currently, only 3% of patients with cancer participate, and many studies fail to achieve necessary enrolment. The objective of this study was to evaluate whether a screening intervention to identify potentially eligible patients (PEPs) would increase accrual rates. PATIENTS AND METHODS: Over a 4-month intervention period, PEPs for 21 phase II-IV breast, gastrointestinal, genitourinary, gynecology, and lung cancer trials were identified by a screening coordinator. This individual reviewed the electronic medical records of patients attending outpatient clinics and flagged PEPs for 10 medical oncologists at the BC Cancer Agency. Patients who were already documented to be trial eligible by physicians were not flagged. Oncologists were surveyed regarding the helpfulness and accuracy of the intervention. RESULTS: During the intervention period, 73 patients were enrolled, compared with 61 patients enrolled in the 4 months prior and 51 patients in the 4 months after. A total of 2,098 charts were reviewed, and 120 PEPs were identified during the intervention period, resulting in 19 PEPs who enrolled and four PEPs who declined a clinical trial. Relative accrual rates adjusted for oncologist appointments were 0.85 (P = .15) before and 0.70 (P < .005) after, relative to the intervention period. Oncologist-returned surveys indicated that 67% of flags were helpful, and 70% were accurate. CONCLUSIONS: In this study, manually screening patient records increased enrolment to specific clinical trials. A screening intervention process, involving a dedicated screening coordinator, should be considered to improve clinical trial accrual. PMID- 23942938 TI - Rotation in total knee arthroplasty: no difference between patient-specific and conventional instrumentation. AB - PURPOSE: It was our hypothesis that patient-specific instrumentation (PSI) can improve the accuracy of the rotational alignment in TKA based on the concept of the system and on the potential to clearly identify pre-operatively during planning the classical anatomical landmarks that serve as references to set-up the rotation both for the femur and tibia. MATERIALS AND METHODS: In this prospective comparative randomized study, 40 patients (20 in each group) operated in our institution between September 2012 and January 2013 by the 2 senior authors were included. Randomization of patients into one of the two groups was done by the Hospital Informatics Department with the use of a systematic sampling method. All patients received the same cemented high-flex mobile bearing TKA. In the PSI group, implant position was compared to the planed position using previously validated dedicated software. The position of the implants (frontal and sagittal) was compared in the 2 groups on standard X-rays, and the rotational position was analysed on post-operative CT-scan. RESULTS: 90 % of the patients add <2 degrees or mm of difference between the planned position of the implants and the obtained position, except for the tibial rotation where the variations were much higher. Mean HKA was 179 degrees (171-185) in the PSI group with 4 outliers (2 varus: 171 degrees and 172 degrees :184 degrees and 185 degrees ) and 178.3 degrees with 2 outliers (171 degrees and 176 degrees ) in the control group. No difference was observed between the two groups concerning the frontal and sagittal position of the implants on the ML and AP X-rays. No significant difference of femoral rotation was observed between the two groups with a mean of 0.4 degrees in the PSI group and 0.2 degrees in the control group (p: n.s). Mean tibial rotation was 8 degrees of internal rotation in the PSI group and 15 degrees of internal rotation in the standard group (p: n.s). CONCLUSION: Based on our results, we were unable to confirm our hypothesis as PSI cannot improve rotation in TKA. More work needs to be done to more clearly define the place of PSI in TKA, to keep on improving the accuracy of the system and to better define the individual targets in TKA in terms of frontal, sagittal and rotational positioning of the implant for each patient. LEVEL OF EVIDENCE: Prospective comparative randomized study, Level II. PMID- 23942940 TI - Electron transfer with azurin at Au-SAM junctions in contact with a protic ionic melt: impact of glassy dynamics. AB - Gold electrodes were coated with alkanethiol SAM-azurin (Az, blue cupredoxin) assemblies and placed in contact with a water-doped and buffered protic ionic melt as the electrolyte, choline dihydrogen phosphate ([ch][dhp]). Fast-scan protein-film voltammetry was applied to explore interfacial biological electron transfer (ET) under conditions approaching the glass-transition border. The ET rate was studied as a function of the water amount, temperature (273-353 K), and pressure (0.1-150 MPa). Exposure of the Az films to the semi-solid electrolyte greatly affected the protein's conformational dynamics, hence the ET rate, via the mechanism occurring in the extra complicated dynamically-controlled regime, is compared to the earlier studies on the reference system with a conventional electrolyte (D. E. Khoshtariya et al., Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 2757-2762), allowing for the disclosure of even more uncommon mechanistic motifs. For samples with low water content (ca. 3 or less waters per [ch][dhp]), at moderately low temperatures (below ca. 298 K) and/or high pressure (150 MPa), the voltammetric profiles systematically deviated from the standard Marcus current-overvoltage pattern, deemed as attributable to a breakdown of the linear response approximation through the essential steepening of the Gibbs energy wells near the glass-forming threshold. Electrolytes with a higher water content (6 to 15 waters per [ch][dhp]) display anomalous temperature and pressure performances, suggesting that the system crosses a broad nonergodic zone which arises from the interplay of ET-coupled large-scale conformational (highly cooperative) modes of the Az protein, inherently linked to the electrolyte's (water-doped [ch][dhp]) slowest collective relaxation(s). PMID- 23942939 TI - Patient-specific instruments: industry's innovation with a surgeon's interest. AB - PURPOSE: The aim of this study was (1) to survey the orthopaedic companies about the volume of patient-specific instruments (PSI) used in Europe and worldwide; (2) to survey a group of knee arthroplasty surgeons on their acceptance of PSI and finally; (3) to survey a medico-legal expert on PSI-related issues. METHODS: Seven orthopaedic implant manufacturers were contacted to obtain their sales figures (in volume) of PSI in Europe and worldwide for the 2011 and 2012 period. During the Open Meeting of the Belgian Knee Society, a survey by a direct voting system was submitted to a selection of knee surgeons. Finally, a number of medico legal 'PSI-related' questions were submitted to an adult reconstruction surgeon/legal expert. RESULTS: The total volume, for all contacted companies, of PSI in Europe for 2012 was 17,515 total knee arthroplasty (TKA) and 82,556 TKA worldwide. Biomet (Warsaw, USA) was the number one in volume, both in Europe as worldwide with their Signature system. Biomet represented 27 % of the market share in PSI worldwide. Stryker preferred not to reply to the survey because of the FDA class 1 recall on ShapeMatch cutting guides. Eighty per cent of the Belgian knee surgeons expressed a great interest in PSI and especially, for 58 % of them, if it would increase their surgical accuracy. They valued it even more in unicompartmental arthroplasty, and 55 % was ready to use single-use instruments. Surprisingly, 47 % of surgeons thought it was the company's responsibility if something goes wrong with a PSI-assisted case. The medico-legal expert concluded that PSI is a complex process that exposes surgeons to new risks in case of failure and stated that companies should not produce surgical guides without validation of the planning by the surgeon. CONCLUSION: Patient-specific instruments is of great interest if it can proof to increase the surgical accuracy in knee arthroplasty to the level surgeons are expecting and if in the same time it would make the surgical process more efficient. LEVEL OF EVIDENCE: V. PMID- 23942941 TI - Relative anion binding affinity in a series of interpenetrated coordination cages. AB - Previously, we have reported on the quantitative self-assembly of a series of interpenetrated double-cages [Pd4Ligand8] with ligands based on various organic backbones. For dibenzosuberone-based cages it was shown that anion binding in the outer two pockets follows an allosteric mechanism. Herein we wish to report the anion binding capabilities of three related phenothiazine cages. We present a systematic comparison of the relative halide (Cl(-) and Br(-)) binding affinities and the structural rearrangements of four double-cages based on NMR titrations, NOESY experiments and electronic structure calculations. PMID- 23942943 TI - Quantized friction across ionic liquid thin films. AB - Ionic liquids - salts in the liquid state under ambient conditions - are of great interest as precision lubricants. Ionic liquids form layered structures at surfaces, yet it is not clear how this nano-structure relates to their lubrication properties. We measured the friction force between atomically smooth solid surfaces across ionic liquid films of controlled thickness in terms of the number of ion layers. Multiple friction-load regimes emerge, each corresponding to a different number of ion layers in the film. In contrast to molecular liquids, the friction coefficients differ for each layer due to their varying composition. PMID- 23942944 TI - Visceral obesity predicts adverse pathological features in urothelial bladder cancer patients undergoing radical cystectomy: a retrospective cohort study. AB - PURPOSE: To evaluate the pathological characteristics of patients with metabolic syndrome (MetS) undergoing radical cystectomy (RC) for urothelial bladder cancer (BCa). METHODS: We retrospectively analyzed 262 consecutive patients with muscle invasive urothelial BCa or non-muscle-invasive urothelial BCa bacillus Calmette Guerin refractory undergoing RC with standard pelvic lymphadenectomy. The patients were stratified into those with or without MetS, and a bivariate logistic regression analysis was done to assess MetS and, separately, each single MetS component as independent predictors of higher pathological stage as well as of the presence of lymph vascular invasion (LVI) and lymph node metastasis (LM). RESULTS: Metabolic syndrome was found in 36.3 % of patients. At logistic regression analysis, the presence of MetS did not predict the risk of both higher pathological stage and LVI and LM. Investigating the single components of MetS after adjusting for age, gender, and smoking, the risk of higher pathological stage increased with body mass index [BMI (OR 1.307, 95 % CI 1.098-1.555)], waist circumference (OR 1.414, 95 % CI 1.364-1.668), and blood hypertension (OR 2.326, 95 % CI 1.147-4.717). Higher BMI also predicted the presence of LVI (OR 1.432, 95 % CI 1.173-1.748) and LM (OR 1.202, 95 % CI 0.951-1.519), whereas HDL cholesterol was inversely associated with the risk of LVI and LM. CONCLUSIONS: Metabolic syndrome does not represent an independent risk factor for worse pathological findings in BCa. Conversely, individual components of MetS could increase the risk of higher stage as well as LM. PMID- 23942945 TI - Fueling the public health workforce pipeline through student surge capacity response teams. AB - In January 2003, the University of North Carolina Center for Public Health Preparedness established Team Epi-Aid to match graduate student volunteers with state and local health departments to assist with outbreaks and other applied public health projects. This study assessed whether Team Epi-Aid participation by full-time graduate students impacted post-graduation employment, particularly by influencing students to work in governmental public health upon graduation. In September 2010, 223 program alumni were contacted for an online survey and 10 selected for follow-up interviews. Eighty-three Team Epi-Aid alumni answered the survey (response rate = 37 %). Forty-one (49 %) reported participating in at least one activity, with 12/41 (29 %) indicating participation in Team Epi-Aid influenced their job choice following graduation. In 6 months prior to enrolling at UNC, 30 (36 %) reported employment in public health, with 16/30 (53 %) employed in governmental public health. In 6 months following graduation, 34 (41 %) reported employment in public health, with 27 (80 %) employed in governmental public health. Eight alumni completed telephone interviews (response rate = 80 %). Five credited Team Epi-Aid with influencing their post-graduation career. Experience in applied public health through a group such as Team Epi-Aid may influence job choice for public health graduates. PMID- 23942946 TI - Determination of the effects of lactoferrin in a preclinical mouse model of experimental colitis. AB - The aim of this study was to determine the therapeutic efficacy of lactoferrin (Lf) on dextran sulphate sodium (DSS)-induced experimental colitis in BALB/c mice. Eighty BALB/c mice were randomly divided into 4 groups; the normal, model, apo-Lf and holo-Lf groups. Fecal character, fecal occult blood, hematochezia and disease activity index (DAI) were recorded daily. The length of the colon was measured and histological scores were evaluated 28 days post-treatment. Myeloperoxidase (MPO) activity was also determined and the expression of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were measured by quantitative (q)PCR. Lf relieved the inflammatory condition of DSS induced experimental colitis in mice. The DAI and histological scores of Lf treated mice were lower compared with those of mice in the control group. The length of the colon of Lf-treated mice was longer compared with that of mice in the control group. Treatment with Lf decreased MPO activity and the expression levels of IL-1beta and TNF-alpha. In addition, Lf was found to promote beneficial effects in a mouse model of experimental colitis. Treatment with apo-Lf was superior to that of holo-Lf in the mouse model of DSS-induced experimental colitis. Supplemental therapy with apo-Lf may provide an important new tool in the clinical management of ulcerative colitis. PMID- 23942947 TI - In search of the everyday life of older people in Japan: reflections based on scholarly literature. AB - The main objective of this paper is to critically examine discourses about old age in Japan, a country with perspectives that are culturally different from the European and American perspectives that tend to dominate the scholarly discourse on ageing. We focus our inquiry on the scientific discourse as representative of a system of knowledge that has a crucial role in determining ways of thinking and perceiving old age. Our literature review is based on a study of academic articles, within the field of gerontology, about the everyday life of older people in Japan that were published in the 10-year period between 1999 and 2009. We apply a Foucauldian gerontology perspective as our analytical tool. The results of our study indicate that there is insufficient knowledge about the everyday life of older people in Japan in gerontological research. We identify a number of discursive practices applied in various research projects that present a one-sided story of old age in Japan. In the conclusion of this paper, we identify a need for interdisciplinary and qualitative studies of old age in Japan that would include voices of older people. PMID- 23942948 TI - Eight years experience in the management of median arcuate ligament syndrome by decompression, celiac ganglion sympathectomy, and selective revascularization. AB - We aim to review an 8-year experience of median arcuate ligament syndrome (MALS) with chronic gastrointestinal ischemia (CGI) and evaluate clinical outcomes of arcuate ligament decompression, celiac sympathectomy, and selective revascularization. Between December 2002 and March 2012, of 25 patients referred with symptoms of CGI, 11 patients (10 women and 1 man) had clinical signs of abdominal angina and radiological evidence of MALS. Mean age was 50 +/- 20.4 years. Median symptom duration was 34 months. All patients had median arcuate decompression and celiac sympathectomy. In all, 8 did not require revascularization, 2 had retrograde celiac and/or superior mesenteric artery (SMA) stenting, and 1 had SMA bypass. There was no mortality. The 30-day morbidity was 9%. Mean follow-up was 60 months. Eight patients noted complete relief of abdominal pain, and 1 reported some improvement. The MALS is not solely a vascular compression syndrome. The neurological component requires careful celiac plexus sympathectomy in addition to arcuate ligament decompression. PMID- 23942949 TI - Trade-offs between light interception and leaf water shedding: a comparison of shade- and sun-adapted species in a subtropical rainforest. AB - Species in high-rainfall regions have two major alternative approaches to quickly drain off water, i.e., increasing leaf inclination angles relative to the horizontal plane, or developing long leaf drip tips. We hypothesized that shade adapted species will have more pronounced leaf drip tips but not greater inclination angles (which can reduce the ability to intercept light) compared to sun-adapted species and that length of leaf drip tips will be negatively correlated with photosynthetic capacity [characterized by light-saturated net photosynthetic rates (Amax), associated light compensation points (LCP), and light saturation points (LSP)]. We tested this hypothesis by measuring morphological and physiological traits that are associated with light interception and water shedding for seven shade-adapted shrub species, ten sun adapted understory shrub species, and 15 sun-adapted tree species in a subtropical Chinese rainforest, where mean annual precipitation is around 1,600 mm. Shade-adapted understory species had lower LMA, Amax, LSP, and LCP compared to understory or canopy sun-adapted species; their leaf and twig inclination angles were significantly smaller and leaf drip tips were significantly longer than those in sun-adapted species. This suggests that shade-adapted understory species tend to develop pronounced leaf drip tips but not large leaf inclination angles to shed water. The length of leaf drip tips was negatively correlated with leaf inclination angles and photosynthetic capacity. These relationships were consistent between ordinary regression and phylogenetic generalized least squares analyses. Our study illustrates the trade-offs between light interception and leaf water shedding and indicates that length of leaf drip tips can be used as an indicator of adaptation to shady conditions and overall photosynthetic performance of shrub species in subtropical rainforests. PMID- 23942950 TI - Pro-inflammatory role of platelets in hypertension-mediated end-organ damage : Editorial to: "Inhibition of Platelet activation by clopidogrel prevents hypertension-induced cardiac inflammation and fibrosis" by L.-X. Jia et al. PMID- 23942951 TI - Primary hepatic neuroendocrine carcinoma: MR imaging findings including preliminary observation on diffusion-weighted imaging. AB - PURPOSE: To investigate MR imaging findings of primary hepatic neuroendocrine carcinoma (PHNEC) including preliminary observations on diffusion-weighted imaging (DWI). MATERIALS AND METHODS: MR images of eight patients with pathologically confirmed PHNEC were retrospectively analyzed. The morphological characteristics and dynamic enhancement patterns were evaluated. RESULTS: One case showed a well-defined solitary nodule with homogenous hypointensity on T1 weighted imaging (T1WI) and hyperintensity on T2-weighted imaging (T2WI) and DWI. The remaining seven cases appeared as well-defined dominant masses with multiple satellite nodules. The dominant masses demonstrated heterogeneous hypointensity on T1WI and hyperintensity on T2WI, which all appeared as a marked enhancement at arterial phase and rapid washout at portal venous phase. Six cases demonstrated rim-like enhancement at equilibrium phase. The satellite lesions showed heterogeneous hypointensity on T1WI and marked hyperintensity on T2WI with variable enhancements, such as homogeneous, rim-like enhancement. All the dominant masses and satellite nodules appeared as markedly hyperintensity and reduced apparent coefficient (ADCs) values on DWI. The mean ADC value of the tumors was significantly lower than that of surrounding liver parenchyma (1.02 +/ 0.57 vs. 2.24 * 10(-3) mm(2)/s, p = 0.000). CONCLUSION: PHNECs typically appear as a large dominant hypervascular mass accompanied by satellite nodules, with rapid washout and capsular enhancement on dynamic MR imaging and restricted diffusion on DWI. PMID- 23942953 TI - Detection of RHDVa on the Iberian Peninsula: isolation of an RHDVa strain from a Spanish rabbitry. AB - Rabbit haemorrhagic disease virus (RHDV), genus Lagovirus, family Caliciviridae, causes a large number of deaths in wild and domestic adult European rabbits (Oryctolagus cuniculus). The first documented outbreak dates from 1984 in China, but the virus rapidly dispersed worldwide. In 1997, an antigenic variant was detected in Italy and designated RHDVa. Despite causing symptoms similar to those caused by classic RHDV strains, marked antigenic and genetic differences exist. In some parts of Europe, RHDVa is replacing classic strains. Here, we report the presence of RHDVa on the Iberian Peninsula, where this variant was thought not to contribute to viral diversity. PMID- 23942952 TI - Physicochemical analysis of rotavirus segment 11 supports a 'modified panhandle' structure and not the predicted alternative tRNA-like structure (TRLS). AB - Rotaviruses are a major cause of acute gastroenteritis, which is often fatal in infants. The viral genome consists of 11 double-stranded RNA segments, but little is known about their cis-acting sequences and structural elements. Covariation studies and phylogenetic analysis exploring the potential structure of RNA11 of rotaviruses suggested that, besides the previously predicted "modified panhandle" structure, the 5' and 3' termini of one of the isoforms of the bovine rotavirus UKtc strain may interact to form a tRNA-like structure (TRLS). Such TRLSs have been identified in RNAs of plant viruses, where they are important for enhancing replication and packaging. However, using tRNA mimicry assays (in vitro aminoacylation and 3'- adenylation), we found no biochemical evidence for tRNA like functions of RNA11. Capping, synthetic 3' adenylation and manipulation of divalent cation concentrations did not change this finding. NMR studies on a 5'- and 3'-deletion construct of RNA11 containing the putative intra-strand complementary sequences supported a predominant panhandle structure and did not conform to a cloverleaf fold despite the strong evidence for a predicted structure in this conserved region of the viral RNA. Additional viral or cellular factors may be needed to stabilise it into a form with tRNA-like properties. PMID- 23942955 TI - Innovation opportunities in critical results communication: practical solutions. PMID- 23942954 TI - Genomic and evolutionary characterization of a novel influenza-C-like virus from swine. AB - We recently described the isolation of a novel influenza virus from swine exhibiting respiratory disease in the United States that is distantly related to human influenza C virus. Based on genetic, biochemical and morphological analysis, the virus was provisionally classified as C/swine/Oklahoma/1334/2011 (C/OK). To further understand the genetics and evolution of this novel pathogen, we performed a comprehensive analysis of its sequence and phylogeny. The results demonstrated that C/OK and human influenza C viruses share a conserved array of predicted functional domains in the viral RNA genome replication and viral entry machinery but vary at key functional sites. Furthermore, our evolutionary analysis showed that homologous genes of C/OK and human influenza C viruses diverged from each other an estimated several hundred to several thousand years ago. Taken together, the findings described in this study support and extend our previous observations that C/OK is a genetically and evolutionarily distinct influenza virus in the family Orthomyxoviridae. PMID- 23942956 TI - Ensuring appropriate use of cardiac imaging. PMID- 23942957 TI - Effects of post-reactor functionalization on the phase behaviour of an ethylene-1 octene copolymer studied using solid-state high resolution 13C NMR spectroscopy. AB - The effects of post-reactor functionalization with naphthoate-TEMPO on the structure and morphology of an ethylene-1-octene copolymer were investigated by means of solid-state NMR techniques and DSC measurements. Selective (13)C MAS experiments allowed the orthorhombic and the monoclinic crystalline phases and two amorphous phases with different degree of mobility to be detected and quantified. (13)C and (1)H relaxation time measurements and spin diffusion experiments gave insight into the polymer dynamics within the different phases, the crystalline domain dimensions, and the rate of chain diffusion between amorphous and crystalline phases. Comparison of the results obtained for the pristine copolymer and the functionalized samples clearly indicated that the functionalization procedure causes redistribution within the crystalline and the amorphous phases with no relevant change in the degree of crystallinity or in the crystalline domain average size, and slows down chain diffusion. PMID- 23942958 TI - [Robotics: innovation in minimally invasive surgery]. PMID- 23942959 TI - [Robotic colorectal surgery: current status and future developments]. AB - Robotic assistance has the potential to compensate for the limitations inherent in standard laparoscopic surgery. The daVinci(r) surgical system remains the only currently available commercial robotic system. It has found popularity in rectal cancer surgery where its application has consistently been shown to reduce the need to convert to open surgery. With this exception, the technological advances of the robotic system have not so far translated into any reproducible patient benefit. The first part of this manuscript presents an overview of the current daVinci(r) platform, its applications, the evidence base and future developments in colorectal surgery. The second part of the manuscript looks at other robot systems in development and the different innovations and strategies taken to advance minimally invasive surgery.The English full-text version of this article is available at SpringerLink (under supplemental). PMID- 23942960 TI - [Application of the da Vinci robotic system in thoracic surgery]. AB - INTRODUCTION: The latest technical developments of minimally invasive thoracic surgery are characterized by robotic-assisted operative procedures. Robotic assisted thymectomy is the most advanced method in this field. METHODS: A systematic literature search (PubMed, Medline) was carried out and the databank system of Intuitive Surgical (Sunnyvale, CA) was analysed. Target criteria were the analysis of the quantitative data over time, technical advantages and limiting factors of robotic-assisted thoracic surgery. RESULTS: The da Vinci robotic system has been used in thoracic surgery since 2001, and up to 2012 a total of 10,895 robotic-assisted lobotomies have been carried out worldwide. A total of 12 ectopic parathyroid glands in the mediastinum were resected and published. Furthermore, more than 3,500 cases of robotic-assisted thymectomy were performed. A rapid increase in the number of operations has occurred particularly for thymectomy and lung resections. DISCUSSION: Acceptance of robotic-assisted thymectomy for myasthenia and/or thymoma and mediastinal tumors is growing rapidly. For anatomic lung resection in lung cancer, robotic-assisted hilar and lymph node dissection due to this new quality are also comparable to open surgical techniques. The principles form the intrinsic technical advantages of the da Vinci robotic system. PMID- 23942962 TI - [Robotics-assisted laparoscopic colorectal resection]. AB - The value of laparoscopic surgery for rectal cancer is still controversially discussed. Robotics offers the opportunity to leave the limitations of conventional laparoscopy behind us. The three-dimensional visualization and the superior dexterity by wristed instruments should be particularly helpful in complex laparoscopic procedures in confined spaces such as the small pelvis. Colorectal resections using the Da Vinci(r) system are well established and becoming increasingly more standard procedures. Nerve-sparing total mesorectal excision in patients with rectal cancer, total mesocolic excision in patients with right-sided colon cancer and rectopexy in patients with pelvic floor insufficiency are the most promising indications. The prospective randomized ROLARR study has been evaluating the application of the Da Vinci(r) system in laparoscopic rectal cancer surgery since 2011. Besides the currently available clinical data the perioperative and intraoperative logistics and strategy will be presented in detail. PMID- 23942964 TI - [Recruiting for multicenter surgical studies in Germany]. PMID- 23942963 TI - [Altering the therapeutic paradigm towards a distal bowel margin of < 1 cm in patients with low-lying rectal cancer: a systematic review and commentary]. PMID- 23942961 TI - [Robotic hepatobiliary and gastric surgery]. AB - Hepatobiliary surgery is a challenging surgical subspecialty that requires highly specialized training and an adequate level of experience in order to be performed safely. As a result, minimally invasive hepatobiliary surgery has been met with slower acceptance as compared to other subspecialties, with many surgeons in the field still reluctant about the approach. On the other hand, gastric surgery is a very popular field of surgery with an extensive amount of literature especially regarding open and laparoscopic surgery but not much about the robotic approach especially for oncological disease. Recent development of the robotic platform has provided a tool able to overcome many of the limitations of conventional laparoscopic hepatobiliary surgery. Augmented dexterity enabled by the endowristed movements, software filtration of the surgeon's movements, and high definition three-dimensional vision provided by the stereoscopic camera, allow for steady and careful dissection of the liver hilum structures, as well as prompt and precise endosuturing in cases of intraoperative bleeding. These advantages have fostered many centers to widen the indications for minimally invasive hepatobiliary and gastric surgery, with encouraging initial results. As one of the surgical groups that has performed the largest number of robot assisted procedures worldwide, we provide a review of the state of the art in minimally invasive robot-assisted hepatobiliary and gastric surgery.The English full-text version of this article is available at SpringerLink (under supplemental). PMID- 23942966 TI - Towards a highly efficient simulated sunlight driven photocatalyst: a case of heterostructured ZnO/ZnS hybrid structure. AB - Large scale ZnO/ZnS heterostructured microflowers are fabricated through a rapid and facile strategy via microwave-assisted in situ surface sulfidation route. The as-obtained product possesses an average diameter of about 2 MUm and is composed of many thin nanowires. Through a careful inspection under various growth conditions, the morphologies of the as-prepared hybrid structures could be controlled by tailoring the concentration of thioacetamide (TAA) solution during the microwave irradiation, and a possible growth mechanism was proposed. The photocatalytic experiment results for the photodegradation of eosin B under simulated sunlight irradiation revealed that the hybrid nanostructures possess significantly higher photocatalytic activity which is about triple that of the original ZnO precursors, indicating their potential applications in organically polluted water treatment. The optimal sulfidation concentration to realize the maximum photocatalytic activity in the ZnO/ZnS hybrid structures is also proposed and discussed. Meanwhile, this facile, rapid microwave-assisted strategy is scalable and can be extended to synthesize other oxide/sulfide (MOx/MSy) heterostructures. PMID- 23942967 TI - Neuroprotectin D1 reduces the severity of herpes simplex virus-induced corneal immunopathology. AB - PURPOSE: Neuroprotectin D1 (NPD1) is an anti-inflammatory and proresolving lipid mediator biosynthesized from the omega-3-polyunsaturated fatty acid docosahexaenoic acid (DHA). The purpose of this study is to test the therapeutic potential of NPD1 for the treatment of herpes simplex virus (HSV)-induced stromal keratitis (SK) using a mouse model. METHODS: C57BL/6 mice were infected ocularly with HSV-1 strain RE. Infected animals were treated topically with methyl ester prodrug NPD1 (300 ng/eye, 5-MUL drop). Development of SK lesions, infiltration of inflammatory cells into the cornea, and production of proinflammatory cytokines, chemokines, and angiogenic factors were compared to untreated animals using slit lamp biomicroscopy, flow cytometry, ELISA, and quantitative PCR (qPCR). RESULTS: Topical administration of NPD1 resulted in a significant reduction in the severity and incidence of SK, as well as the extent of corneal neovascularization in the NPD1-treated animals compared to their untreated counterparts. Infiltration of fewer neutrophils and pathogenic CD4+ T cells into the cornea, along with a lower number of cells that could be induced ex vivo to produce IFN gamma and IL-17, occurred with NPD1 treatment. Additionally, treatment with NPD1 diminished the production of proinflammatory cytokines, chemokines, and angiogenic factors, such as IL-6, CXCL1, CXCL-10, CCL-20, VEGF-A, MMP-2, and MMP 9 in the corneas of infected animals. Importantly, treatment with NPD1 increased the production of the anti-inflammatory cytokine, IL-10. CONCLUSIONS: Our novel findings demonstrate that NPD1 treatment could represent a valuable therapeutic approach to control SK lesions. PMID- 23942968 TI - Novel quinic acid derivative KZ-41 prevents retinal endothelial cell apoptosis without inhibiting retinoblastoma cell death through p38 signaling. AB - PURPOSE: To determine whether a novel NF-kappaB inhibitor, KZ-41, can inhibit melphalan's actions on retinal endothelial cell (REC) inflammation and apoptosis, without eliminating the chemotherapeutic efficacy of melphalan on cell death of retinoblastoma cells (Y79). METHODS: RECs were cultured in M131 medium supplemented with growth factors and antibiotics. Once cells reached confluence, they were treated with or without 10 MUM KZ-41, following treatment with 4 MUg/mL melphalan. Cell proteins were extracted and analyzed for intracellular adhesion molecule 1 (ICAM-1) levels and Cell Death ELISA. RECs were also transfected with or without NF-kappaB siRNA or treated with SB202190 (p38 [mitogen activated protein kinase] MAPK inhibitor) before melphalan treatment to determine the involvement of NF-kappaB and p38 MAPK in REC apoptosis and ICAM-1 levels. We also cultured retinoblastoma cells (Y79) in RMPI-1640 medium supplemented with 20% fetal bovine serum and performed a Cell Death ELISA after melphalan + KZ-41 treatment to determine if the treatments altered melphalan's ability to promote cell death of Y79 cells. RESULTS: KZ-41 inhibited melphalan-stimulation of ICAM-1 levels and REC apoptosis, whereas KZ-41 did not alter melphalan's effects on Y79 cells. KZ-41's protective effects on REC were mediated through p38 MAPK activation. Although KZ-41 blocked both NF-kappaB- and p38 MAPK-dependent ICAM-1 stimulation; the p38 MAPK/ICAM-1 pathway appears to be the primary pathway involved in melphalan-induced REC apoptosis. CONCLUSIONS: KZ-41 protects REC against melphalan-induced upregulation of ICAM-1 and apoptosis through p38 MAPK dependent pathways. PMID- 23942969 TI - Pilot study of Doppler optical coherence tomography of retinal blood flow following laser photocoagulation in poorly controlled diabetic patients. AB - PURPOSE: To investigate the effect of panretinal photocoagulation (PRP) on retinal blood flow and shear rate using Doppler Fourier-domain optical coherence tomography (FD-OCT) in poorly controlled diabetics with proliferative diabetic retinopathy (PDR). METHODS: This was a prospective interventional pilot study in patients with a new clinical diagnosis of PDR. Retinal blood flow and vessel diameter were measured using Doppler FD-OCT according to a previously described method, immediately before PRP treatment and 7 to 8 weeks after the last PRP session. RESULTS: Ten patients with poorly controlled PDR (mean hemoglobin A1C = 9.2 +/- 2.0%) and 10 control subjects were included in the study. PDR patients had significantly lower blood flow (~25%) than control subjects both at baseline (P = 0.01) and after PRP (P = 0.003). Compared to controls, venous and arterial velocities were significantly decreased in diabetics at baseline (~27%; P < 0.001 and 0.017, respectively) as well as after PRP (P < 0.001 and 0.006, respectively). Compared to controls, venous and arterial shear rates were significantly reduced in diabetics at baseline (~27%; P = 0.002, 0.03) and after PRP (P = 0.002, 0.03). PRP in this group of PDR patients did not have a statistically significant effect on retinal blood flow or vessel parameters, though there was a trend for decreased arterial diameter (P = 0.09). CONCLUSIONS: This is the first study to use Doppler FD-OCT to quantify functional changes in retinal vascular parameters in poorly controlled PDR patients. Compared to controls, blood flow parameters in these patients were decreased at baseline, but did not decrease further following PRP, with important implications related to diabetes control, endothelial function, and therapeutic response. PMID- 23942972 TI - Mice with a targeted disruption of Slc4a11 model the progressive corneal changes of congenital hereditary endothelial dystrophy. AB - PURPOSE: To establish an animal model of congenital hereditary endothelial dystrophy (CHED) using Slc4a11 knockout (KO) mice and evaluate the abnormalities in the cornea and kidney. METHODS: The Slc4a11 KO mouse model was generated by gene deletion. Corneal abnormalities were evaluated using slit-lamp photography, anterior segment optical coherence tomography (AS-OCT), immunohistochemistry, RT PCR, corneal endothelial cell staining, and electron microscopy. The temporal corneal changes were also monitored. Histological and functional changes of the kidney were also evaluated. RESULTS: Successful knockout of the Slc4a11 gene was confirmed by immunohistochemistry and RT-PCR. Slit-lamp photography and AS-OCT showed progressive corneal edema. Increased corneal endothelial cell size with decreased corneal endothelial cell density was observed with increased age. Scanning electron microscopy also revealed progressive cell swelling and distortion of the hexagonal cell morphology with time. Transmission electron microscopy showed characteristic ultrastructural findings of CHED, including endothelial vacuolization, thickening of the Descemet membrane, disorganization of collagen fibril, deposition of amorphous material, and progression of these changes with age. Decreased urine osmolarity and electrolyte concentrations suggesting abnormality in water resorption were also detected. CONCLUSIONS: Our Slc4a11 KO mouse model successfully represents clinical manifestations of human CHED. We were able to show chronological corneal progression for the first time in a knockout mouse model as well as renal abnormalities. PMID- 23942970 TI - CD11b+GR1+ myeloid cells secrete NGF and promote trigeminal ganglion neurite growth: implications for corneal nerve regeneration. AB - PURPOSE: We characterized fluorescent bone marrow cells (YFP(+) BMCs) in the thy1 YFP mouse and determine if they promote trigeminal ganglion (TG) cell neurite growth. METHODS: Excimer laser annular keratectomy was performed in thy1-YFP mice, and corneas were imaged. BMCs were harvested from femur and tibia, and the expression of surface markers on YFP(+) BMCs was analyzed by flow cytometry. The immunosuppressive action of BMCs (YFP(+) and YFP(-)) was evaluated in an allogenic mixed lymphocyte reaction (MLR). Neurotrophic action of BMCs (YFP(+) and YFP(-)) was determined in compartmental and transwell cultures of dissociated TG cells. RESULTS: Following annular keratectomy, YFP(+) BMCs infiltrated the cornea. YFP(+) BMCs shared surface markers (CD11b+Gr1+Ly6C+Ly6G-F4/80(low)) with monocytic myeloid-derived suppressor cells (MDSCs), had similar morphology, and suppressed T-cell proliferation in allogenic MLR in a dose-dependent manner. YFP(+) BMCs, but not YFP(-) BMCs, significantly increased growth of TG neurites in vitro. When cultured in a transwell with TG neurites, YFP(+) BMCs expressed neurotrophins and secreted nerve growth factor (NGF) in conditioned medium. YFP(+) BMCs that infiltrated the cornea maintained their phenotype and actions (neuronal and immune). CONCLUSIONS: YFP(+) BMCs in thy1-YFP mice have immunophenotypic features of MDSCs. They secrete NGF and promote neuroregeneration. Their immunosuppressive and neurotrophic actions are preserved after corneal infiltration. These findings increase our understanding of the beneficial roles played by leukocyte trafficking in the cornea and may lead to therapeutic strategies that use NGF-secreting myeloid cells to repair diseased or injured neurons. PMID- 23942971 TI - Comparison of two methods for composite score generation in dry eye syndrome. AB - PURPOSE: To compare two methods of composite score generation in dry eye syndrome (DES). METHODS: Male patients seen in the Miami Veterans Affairs eye clinic with normal eyelid, corneal, and conjunctival anatomy were recruited to participate in the study. Patients filled out the Dry Eye Questionnaire 5 (DEQ5) and underwent measurement of tear film parameters. DES severity scores were generated by independent component analysis (ICA) and latent class analysis (LCA). RESULTS: A total of 247 men were included in the study. Mean age was 69 years (SD 9). Using ICA analysis, osmolarity was found to carry the largest weight, followed by eyelid vascularity and meibomian orifice plugging. Conjunctival injection and tear breakup time (TBUT) carried the lowest weights. Using LCA analysis, TBUT was found to be best at discriminating healthy from diseased eyes, followed closely by Schirmer's test. DEQ5, eyelid vascularity, and conjunctival injection were the poorest at discrimination. The adjusted correlation coefficient between the two generated composite scores was 0.63, indicating that the shared variance was less than 40%. CONCLUSIONS: Both ICA and LCA produced composite scores for dry eye severity, with weak to moderate agreement; however, agreement for the relative importance of single diagnostic tests was poor between the two methods. PMID- 23942973 TI - AMD-associated variants at the chromosome 10q26 locus and the stability of ARMS2 transcripts. AB - PURPOSE: To analyze the effect of variants including age-related macular degeneration (AMD)-associated combinative insertion/deletion polymorphism (indel) at 3'UTR of ARMS2 and possibly associated R38X on the stability of ARMS2 transcripts. METHODS: ARMS2 transcription from minigene vectors carrying different alleles at variants R38X and the indel were assessed in mouse embryonic fibroblasts (MEFs). Dual luciferase assays were applied to evaluate the effect of the indel on gene expression. RT-PCR and quantitative RT-PCR (qRT-PCR) were used to measure the two ARMS2 transcripts (isoform A and isoform B) in MEFs and human retina-RPE-choroid samples (n = 83). RESULTS: Allele X at variant R38X decreased exogenous ARMS2 transcripts in MEFs compared to allele R. In contrast, the indel did not change the level of exogenous ARMS2 transcripts. After blocking transcription by actinomycin D, R38X appeared to accelerate the degradation of ARMS2 transcripts, while the indel did not obviously affect the stability of ARMS2 transcripts compared to the wild-type (WT) allele. Dual luciferase assays further indicated that the indel did not influence gene expression. Quantitative RT-PCR results showed that there was no significant difference in two ARMS2 transcript splice isoforms among retina-RPE-choroid samples carrying different genotypes at variants R38X and the indel. CONCLUSIONS: Variant R38X, not the indel, decreases the stability of ARMS2 transcripts in vitro. However, genotypes at R38X and the indel do not obviously affect the level of ARMS2 transcripts in retina-RPE-choroid samples. These results suggest that variants R38X and the indel are less likely to play a pathogenic role in AMD by changing the level of ARMS2 transcripts. PMID- 23942974 TI - Modulation of angiogenesis by genetic manipulation of ATF4 in mouse model of oxygen-induced retinopathy [corrected]. AB - PURPOSE: The activation of the unfolded protein response (UPR) and an increase in activating transcription factor 4 (ATF4) has been previously reported in the diabetic retina. Despite this, a direct link between ATF4 and the degree of proliferative retinopathy has not been demonstrated to date. Therefore, the objective of this study was to determine whether ATF4 deficiency could reduce neovascularization in mice with oxygen-induced retinopathy (OIR). METHODS: We induced OIR in C57BL/6, ATF4(+/-), and endoplasmic reticulum stress-activated indicator (ERAI) mice and used quantitative RT-PCR and Western blot analysis to evaluate relative gene and protein expression. Histology and microscopy were used to calculate the extent of neovascularization in flat-mounted retinas. RESULTS: Experimental data revealed Xbp1 splicing in the retinal ganglia cells, outer plexiform layer, inner nuclear layer, and outer nuclear layer and in pericytes of postdevelopment day 17 ERAI OIR mice, confirming the activation of IRE1 UPR signaling. In naive ATF4-deficient mice, we also observed an elevation in UPR associated and vascular-associated gene expression (Bip, Atf6, Hif1a, Pik3/Akt, Flt1/Vegfa, and Tgfb1), which may have contributed to the alleviation of hypoxia driven neovascularization in experimental ATF4(+/-) retinas. The OIR ATF4(+/-) retinas demonstrated reprogramming of the UPR seen at both the mRNA (Atf6 and Bip) and protein (pATF6 and peIf2alpha) levels, as well as a reduction in vascularization-associated gene expression (Flt1, Vegf1, Hif1, and Tgb1). These changes corresponded to the decline in the rate of neovascularization. CONCLUSIONS: Our study validates ATF4 as a prospective therapeutic target to inhibit neovascularization in proliferative retinopathy. PMID- 23942976 TI - Tissue engineering: creation of an autogenic collagenous neoligament to cure urinary stress incontinence. PMID- 23942975 TI - Impact of soft contact lens edge design and midperipheral lens shape on the epithelium and its indentation with lens mobility. AB - PURPOSE: To evaluate the influence of soft contact lens midperipheral shape profile and edge design on the apparent epithelial thickness and indentation of the ocular surface with lens movement. METHODS: Four soft contact lens designs comprising of two different plano midperipheral shape profiles and two edge designs (chiseled and knife edge) of silicone-hydrogel material were examined in 26 subjects aged 24.7 +/- 4.6 years, each worn bilaterally in randomized order. Lens movement was imaged enface on insertion, at 2 and 4 hours with a high-speed, high-resolution camera simultaneous to the cross-section of the edge of the contact lens interaction with the ocular surface captured using optical coherence tomography (OCT) nasally, temporally, and inferiorly. Optical imaging distortions were individually corrected for by imaging the apparent distortion of a glass slide surface by the removed lens. RESULTS: Apparent epithelial thickness varied with edge position (P < 0.001). When distortion was corrected for, epithelial indentation decreased with time after insertion (P = 0.010), changed after a blink (P < 0.001), and varied with position on the lens edge (P < 0.001), with the latter being affected by midperipheral lens shape profile and edge design. Horizontal and vertical lens movement did not change with time postinsertion. Vertical motion was affected by midperipheral lens shape profile (P < 0.001) and edge design (P < 0.001). Lens movement was associated with physiologic epithelium thickness for lens midperipheral shape profile and edge designs. CONCLUSIONS: Dynamic OCT coupled with high-resolution video demonstrated that soft contact lens movement and image-corrected ocular surface indentation were influenced by both lens edge design and midperipheral lens shape profiles. PMID- 23942977 TI - A late complication of transobturator tape procedure: vaginocutaneous fistula formation with vaginal mesh erosion. AB - Transobturator tape procedures are a common treatment modality in patients with stress urinary incontinence (SUI). Various complications have been reported related to this procedure. We present a rare case of vaginocutaneous fistula formation 5 years after transobturator tape surgery. A 56-year-old woman presented with complaints of increased vaginal discharge, difficulty in coitus, and serosanguineous discharge from the left groin 5 years after transobturator tape surgery for SUI. Pelvic examination revealed 2-3 cm of extruded mesh at the anterior vaginal wall. The vaginocutaneous fistula was detected at surgery. The suburethral tape was removed, and the fistula tract was excised and repaired primarily. Postoperative period was uneventful, and the patient was still continent 6 weeks postoperatively. With widespread use of mesh for treating SUI, we will likely see a variety of complications in the long term. PMID- 23942978 TI - Tissue engineering: creation of an autogenic collagenous neoligament for cure of urinary stress incontinence. Reply to Petros. PMID- 23942980 TI - Sacrificial polymer thin-film template with tunability to construct high-density Au nanoparticle arrays and their refractive index sensing. AB - Great challenges still remain to assemble metal nanoparticles on a substrate with tunability, high density, robust stability, good dispersion and well-retained properties for various applications. Herein a new concept using a polymer thin film as a sacrificial template is investigated to fabricate highly dense and well dispersed nanoparticle arrays. In contrast to a conventional "hard" template, the polymer template is a porous multilayered film allowing in situ growth of Au nanoparticles with a restricted ripening mode, and tuning the nanoparticle size and density of the arrays is possible by simply adjusting the loading conditions. The prepared substrate-attached nanoparticle arrays demonstrate good thermal and chemical stability, while offering highly sensitive and tunable localized surface plasmon resonance (LSPR) refractive index sensing with a broad linear dynamic range. This method could be extended to controllably fabricate other robust and "clean" nanoparticle arrays on various substrates for various applications including sensing, catalysis and optoelectronics. PMID- 23942979 TI - Long-term outcomes of synthetic transobturator nonabsorbable anterior mesh versus anterior colporrhaphy in symptomatic, advanced pelvic organ prolapse surgery. AB - INTRODUCTION AND HYPOTHESIS: Anterior vaginal mesh (AVM) combined with sacrospinous ligament fixation (SSF) yields better long-term success rates over anterior colporrhaphy (AC) in advanced pelvic organ prolapse (POP) surgery, with a low rate of mesh-related complications. METHODS: Medical records of 198 patients who underwent surgery for POP between January 2006 and March 2010 were reviewed retrospectively. Patients' assessment at baseline and third-year postoperative follow-up were analyzed. SSF plus AC or AVM was performed for apical and anterior compartment repair. Primary outcome was objective cure [Pelvic Organ Prolapse Quantification (POP-Q) stage <= 1)], and subjective cure defined as negative response to questions 2 and 3 on the POPDI-6. Secondary outcomes were complications, symptoms severity and quality of life as measured with validated questionnaires. RESULTS: Post-operative data were available for 186 patients, 72 in AC group and 114 in AVM group were analyzed. The mean age, parity and operating time in AVM group were significantly higher as compared to AC group. The overall objective and subjective cure rate in AVM group was significantly higher than AC group (90.3 % and 88.6 % versus 73.6 % and 70.8 %, with P value = 0.003 and 0.002 respectively). Mesh exposure rate was 3.5 %. Improvement in both POPDI-6 and PISQ-12 in AVM group was statistically significant compared to AC group. CONCLUSION: Transobturator synthetic nonabsorbable AVM combined with SSF yielded a favorable and sustainable result over 5 years as compared to traditional AC, both in anatomical and subjective success rate. Mesh related morbidities were low and acceptable. PMID- 23942981 TI - Polygraphy vs. polysomnography: missing osas in symptomatic snorers--a reminder for clinicians. AB - PURPOSES: The purposes of this study are to investigate the usefulness of polygraphy (PG) in diagnosing obstructive sleep apnea (OSA) in sleepy/tired snorers compared to polysomnography (PSG) and, further, to search for suspected respiratory arousals in the PG. METHODS: One hundred eighty-seven adults suffering from sleepiness/tiredness and snoring had undergone ambulant PG and were considered to be normal, using American Academy of Sleep Medicine's 2007 hypopnea criteria A. After approximately 7 months, in-lab PSG was performed using hypopnea criteria B, where arousals are also recognized. Validated questionnaires (Hospital Anxiety and Depression Scale, self-rated general health) were answered. In a subgroup, the sensitivity and specificity were calculated for flow limitation index (FLI) and flattening index (FlatI) in PG compared with the respiratory distress index (RDI) in PSG. RESULTS: Despite the normal PG, at PSG, the median RDI was 11.0 (range, 0-89.1). One hundred sixty-eight out of one hundred seventy-eight (90%) were found to have at least mild OSA and 119/187 (64%) with moderate-severe OSA according to the RDI values. The sensitivity and specificity were low (<70%) for FLI and FlatI. Forty-nine percent of the patients rated anxiety at borderline or pathological levels, 35% rated corresponding depression levels, and 45% rated poor or fair general health. CONCLUSIONS: PG was insufficient to rule out OSA when the respiratory events were mainly associated with arousals. Almost half of these patients experience low general health and psychiatric problems. We recommend a full-night PSG when PG is "normal", and patients have symptoms of snoring and sleepiness/tiredness. PMID- 23942982 TI - Baseline serum glucose concentration and symptomatic haemorrhagic transformation in non-diabetic stroke patients treated by intravenous thrombolysis. AB - Intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) improves outcome in ischaemic stroke, despite an increased risk of symptomatic haemorrhagic transformation (sHT). A higher baseline serum glucose concentration is associated with an increased risk of sHT. However, as most studies did not exclude diabetic patients, this effect may be partially due to diabetic micro angiopathy. Our objective was to test the hypothesis that baseline serum glucose concentration is associated with sHT in non-diabetic patients treated by i.v. rt PA. We analysed the influence of baseline serum glucose concentrations on sHT (ECASS2 definition) in consecutive non-diabetic patients treated by i.v. rt-PA for ischaemic stroke. Secondary end-points were death (<7 days, 8 days to 3 months, all deaths <3 months), and unfavourable outcome at 3 months (modified Rankin scale 2-6 if different from the pre-stroke value). Five hundred and five consecutive patients met inclusion criteria [242 men (47.9 %); median age 71 years (interquartile range, IQR) 57-81; median baseline national institutes of health stroke scale score 12 (IQR 6-17)]. Thirty-seven had sHT (7.3 %). After adjustment, baseline serum glucose concentrations were independently associated with sHT (adjOR: 1.176 for 1 mmol/l increase; 95 % CI: 1.020-1.357: p = 0.025). Increased admission serum glucose concentrations in non-diabetic patients treated by i.v. rt-PA for cerebral ischaemia are associated with sHT. Whether lowering serum glucose lowers the risk of sHT needs to be evaluated. PMID- 23942983 TI - Chemical diversity among populations of Mikania micrantha: geographic mosaic structure and herbivory. AB - Populations of the same species vary in their secondary metabolite content. This variation has been attributed to biotic and abiotic environmental conditions as well as to historical factors. Some studies have focused on the geographic variation of chemical diversity in plant populations, but whether this structure conforms to a central-marginal model or a mosaic pattern remains unclear. Furthermore, assessing the chemical diversity of invasive plants in their native distribution facilitates the understanding of their relationships with natural enemies. We examined the geographic variation of chemical diversity in Mexican populations of the bittervine weed Mikania micrantha and its relationship to herbivore damage. The foliar volatile terpenoid blend was analyzed in 165 individuals of 14 populations in the Pacific and Gulf of Mexico tropical watersheds. A cluster analysis grouped individuals with similar terpenoid blends into 56 compositional types. Chemical diversity was measured using the number of compounds and their concentration within the blends for individuals, and the number and frequency of compositional types for populations. A stepwise multiple regression analysis performed with geographic, climatic, and chemical diversity variables explained herbivore damage. However, population-level chemical diversity was the only variable found to be significant (beta = -0.79, P = 0.042) in the model (R(2) = 0.89). A Mantel test using Euclidean distances did not indicate any separation by geographic origin; however, four barriers were identified using Monmonier's algorithm. We conclude that variation in population level chemical diversity follows a mosaic pattern in which geographic factors (i.e., natural barriers) have some effect and that variation is also associated with the local intensity of herbivore attack. PMID- 23942984 TI - Effects of electroacupuncture on spinal alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionic acid receptor in rats injected with complete Freund's adjuvant. AB - The effects of electroacupuncture (EA) on spinal alpha-amino-3-hydroxy-5-methyl-4 isoxazole-propionic acid (AMPA) receptor subunits in male rats injected with complete Freund's adjuvant (CFA) were investigated. Bilateral EA stimulation (2 Hz, 1 mA) was administered by needle insertion for 30 min once daily at acupoints corresponding to Zusanli and Sanyinjiao, and the thermal thresholds were measured. To examine the changes in the AMPA receptor subunits, the L4-5 segments of the spinal cord were analyzed by qPCR, western blot analysis and immunohistochemistry. The CFA-induced thermal sensitivity of the rat hind paw was significantly inhibited by EA stimulation from day 3 following CFA injection. On day 5 following CFA injection, there were no significant changes in the expression of the AMPA receptor GluR1 subunit in the CFA-injected rats with or without EA stimulation, compared with the control rats. However, the expression of the GluR2 subunit was significantly decreased by CFA treatment. Western blot analysis revealed that the expression of the phosphorylated GluR1 subunit in the control rats was not significantly different compared with that in the CFA injected rats with and without EA stimulation. However, phosphorylation of the ipsilateral GluR2 subunit was significantly increased in the CFA-injected rats, and this activation was prevented by EA stimulation. Immunohistochemical analysis revealed a greater expression of phospho-GluR2 following CFA injection, which was inhibited by EA stimulation. These results suggested that phosphorylation of the AMPA receptor, particularly the GluR2 subunit, may be important in EA analgesia of CFA-induced inflammation. PMID- 23942985 TI - The role of multiple chemotactic mechanisms in a model of chemotaxis in C. elegans: different mechanisms are specialised for different environments. AB - Unlike simpler organisms, C. elegans possesses several distinct chemosensory pathways and chemotactic mechanisms. These mechanisms and pathways are individually capable of driving chemotaxis in a chemical concentration gradient. However, it is not understood if they are redundant or co-operate in more sophisticated ways. Here we examine the specialisation of different chemotactic mechanisms in a model of chemotaxis to NaCl. We explore the performance of different chemotactic mechanisms in a range of chemical gradients and show that, in the model, far from being redundant, the mechanisms are specialised both for different environments and for distinct features within those environments. We also show that the chemotactic drive mediated by the ASE pathway is not robust to the presence of noise in the chemical gradient. This problem cannot be solved along the ASE pathway without destroying its ability to drive chemotaxis. Instead, we show that robustness to noise can be achieved by introducing a second, much slower NaCl-sensing pathway. This secondary pathway is simpler than the ASE pathway, in the sense that it can respond to either up-steps or down steps in NaCl but not both, and could correspond to one of several candidates in the literature which we identify and evaluate. This work provides one possible explanation of why there are multiple NaCl sensing pathways and chemotactic mechanisms in C. elegans: rather than being redundant the different pathways and mechanism are specialised both for the characteristics of different environments and for distinct features within a single environment. PMID- 23942986 TI - Use of narcotic analgesics associated with increased falls and fractures in elderly patients with osteoarthritis. PMID- 23942987 TI - Evaluation of a pilot study to influence medication adherence of patients with diabetes mellitus type-2 by the pharmacy. AB - BACKGROUND: Interventions aimed to increase adherence to drug treatment usually are not tailored to the needs of individual patients. A modular pharmacy intervention, named 'Support for Diabetes', was developed to improve adherence to type 2 diabetes treatment. OBJECTIVE: To evaluate the implementation of a new care intervention by using focus groups including pharmacy teams, and assess patient satisfaction. SETTING: Community pharmacies in The Netherlands. METHOD: The intervention comprises a structured patient interview, an intervention guide and modular interventions tailored to the underlying cause of non-adherence. Feasibility was studied in non-adherent type 2 diabetes mellitus patients, and evaluated by means of focus group interviews with pharmacists and pharmacy technicians. Topics included practicability of the patient selection procedure, patient interviews, materials developed for the intervention and general practitioner (GP) co-operation. Patients' experiences (n = 36) were assessed by means of a questionnaire. MAIN OUTCOME MEASURE: Feasibility of the intervention and patients' satisfaction. RESULTS: Pharmacists and pharmacy technicians considered the intervention feasible and appreciated its pro-active approach. Involvement of pharmacy technicians proved a stimulating factor. Poor co operation with GPs and lack of time as well as financial compensation were interfering factors. Patients appreciated the intervention and reported to follow the advice of pharmacists. CONCLUSION: The 'Support for Diabetes' intervention is feasible to implement in pharmacy practice. Poor co-operation between pharmacists and GPs and lack of re-imbursement are obstructions for implementation on a wider scale. These issues should receive attention of pharmacists, policymakers and researchers. PMID- 23942988 TI - Comment on Chen et al.: Patellar resurfacing versus nonresurfacing in total knee arthroplasty: a meta-analysis of randomised controlled trials. PMID- 23942989 TI - Lateral ankle instability in high-demand athletes: reconstruction with fibular periosteal flap. AB - PURPOSE: Fibular periosteal flaps have been used to address chronic lateral ankle instability, but there are no studies in the literature reporting functional outcomes after this particular procedure in high-demand athletes. We postulated that for chronic instability, nonanatomical reconstruction of the lateral ankle ligament with a fibular periosteal flap will return high-demand athletes to their previous levels of activity. METHODS: Forty patients who had grade III ankle sprain and experienced no success after a course of supervised conservative management lasting at least six months and who had a preinjury Tegner score of >= 6 underwent a lateral compartment reconstruction with a fibular periosteal flap. Each patient was given the Tegner and Karlsson questionnaire and was evaluated by the Zwipp method, Foot and Ankle Outcome Score (FAOS) and the American Orthopaedic Foot and Ankle Society (AOFAS) score at the six-month, one, two and three-year time points. Range of motion (ROM) of the affected ankle was assessed, and stress X-rays were performed. Mean patient age was 24.5 (range17-30) years, and no patient was lost to follow-up. RESULTS: Mean follow-up was 36 (minimum 18) months, mean Tegner scores at the one, two and three-year time points were 8.8, 8.9 and 8.9, respectively, and mean Karlsson scores were 93 +/- 5.2, 95 +/- 3.1 and 94.9, respectively. AOFAS and FAOS scores improved from a mean of 69.4 and 71.4, respectively, in the preoperative group to a mean of 97.2 and 94.4, respectively, at the last follow-up. The ROM was equal to the contralateral ankle in all but two patients at the two-year follow-up. No major complications were found. CONCLUSION: Nonanatomical ligament reconstruction with a fibular periosteal flap for chronic lateral ankle instability was effective in returning high-demand athletes to their preinjury functional levels. PMID- 23942991 TI - Images in vascular medicine. Endovascular treatment of chronic occluded renal artery. PMID- 23942992 TI - Energy-transfer from Gd(III) to Tb(III) in (Gd,Yb,Tb)PO4 nanocrystals. AB - The photoluminescence properties of (Gd,Yb,Tb)PO4 nanocrystals synthesized via a hydrothermal route at 150 degrees C are reported. Energy-transfer from Gd(3+) to Tb(3+) is witnessed by the detailed analyses of excited-state lifetimes, emission quantum yields, and emission and excitation spectra at room temperature, for Tb(3+) concentrations ranging from 0.5 to 5.0 mol%. Absolute-emission quantum yields up to 42% are obtained by exciting within the (6)I7/2-17/2 (Gd(3+)) manifold at 272 nm. The room temperature emission spectrum is dominated by the (5)D4 -> (7)F5 (Tb(3+)) transition at 543 nm, with a long decay-time (3.95-6.25 ms) and exhibiting a rise-time component. The (5)D3 -> (7)F6 (Tb(3+)) rise-time (0.078 ms) and the (6)P7/2 -> (8)S7/2 (Gd(3+)) decay-time (0.103 ms) are of the same order, supporting the Gd(3+) to Tb(3+) energy-transfer process. A remarkably longer lifetime of 2.29 ms was measured at 11 K for the (6)P7/2 -> (8)S7/2 (Gd(3+)) emission upon excitation at 272 nm, while the emission spectrum at 11 K is dominated by the (6)P7/2 -> (8)S7/2 transition line, showing that the Gd(3+) to Tb(3+) energy-transfer process is mainly phonon-assisted with an efficiency of ~95% at room temperature. The Gd(3+) to Tb(3+) energy transfer is governed by the exchange mechanism with rates between 10(2) and 10(3) s(-1), depending on the energy mismatch conditions between the (6)I7/2 and (6)P7/2 levels of Gd(3+) and the Tb(3+ 5)I7, (5)F2,3 and (5)H5,6,7 manifolds and the radial overlap integral values. PMID- 23942990 TI - Acculturation-related predictors of very light smoking among Latinos in California and nationwide. AB - The prevalence of light smoking has increased among Latinos. The purpose of this study was to identify demographic and acculturation-related factors associated with very light smoking, defined as smoking 1-5 cigarettes per day (CPD), among Latinos in California and nationwide. Latino smokers in the 2007-2008 National Health and Nutrition Examination Survey (NHANES) or the 2009 California Health Interview Survey (CHIS) were analyzed. Logistic regression assessed factors associated with very light smoking. Among NHANES smokers, those born in Mexico or who lived fewer years in the US were more likely to be very light smokers than 6+ CPD smokers. Among CHIS smokers, those born in Mexico, in another Spanish speaking country, or who spent smaller percentages of their life in the US were more likely to be very light smokers. Findings from this study can be used to design tobacco control media campaigns that include very light smokers. PMID- 23942993 TI - Models of anxiety, depression, somatization, and coping as predictors of abdominal pain in a community sample of school-age children. AB - OBJECTIVE: To examine whether somatization mediates the relationship of coping styles and internalizing problems with abdominal pain. METHODS: 230 school children (M age = 11.80 years; 43.8% male; 21.3% White) completed measures of coping style, anxiety, and depression early in the school year, and subsequently reported abdominal pain symptoms weekly. RESULTS: The results showed (a) the association of anxiety and depression with abdominal pain may be mediated by somatization; (b) there are similarities and differences in the association of coping styles with pain for models including anxiety versus depression. Significant indirect effects showed higher levels of passive coping were associated with more pain via somatization and either anxiety or depression. For active coping, results differed for models including anxiety versus depression. Accommodative coping showed no independent relationship with abdominal pain. CONCLUSIONS: Somatization may mediate the relationship of internalizing symptoms and coping styles with pain. Treatment implications are discussed. PMID- 23942994 TI - A multilevel analysis of the role of parental and community variables on young children's health. AB - OBJECTIVE: The purpose of this study was to examine the associations among community characteristics, family economic adversity, parents' health beliefs, and parents' and children's health using cross-level mediation analyses. METHODS: Survey data were collected from a nationally representative sample of 1,337 families with children between 3 and 6 years nested within 45 Trinidad and Tobago community clusters. RESULTS: At the individual level, parents' health belief of internality was a significant mediator between family economic adversity, adult health, and children's health. In the cross-level mediation analyses, health belief of internality was a significant mediator between community health problems and children's health. There were between-community variations in the relationship between adult health, health belief of powerful others, and children's health. CONCLUSIONS: There is strong evidence of the role of community and family influences on children's health. Findings indicate the need to use a multilevel analytical approach in studies of children's health. PMID- 23942996 TI - S6K1 inhibition enhances tamoxifen-induced cell death in MCF-7 cells through translational inhibition of Mcl-1 and survivin. AB - S6 kinase 1 (S6K1) was suggested to be a marker for endocrine therapy resistance in breast cancer. We examined whether tamoxifen's effect can be modulated by S6K1 inhibition. S6K1 inhibition by PF4708671, a selective inhibitor of S6K1, acts synergistically with tamoxifen in S6K1-high MCF-7 cells. Similarly, the knockdown of S6K1 with small interfering RNA (siRNA) significantly sensitized MCF-7 cells to tamoxifen. Inhibition of S6K1 by PF4708671 led to a marked decrease in the expression levels of the anti-apoptotic proteins Mcl-1 and survivin, which was not related to mRNA levels. In addition, suppression of Mcl-1 or survivin, using specific siRNA, further enhanced cell sensitivity to tamoxifen. These results showed that inhibition of S6K1 acts synergistically with tamoxifen, via translational modulation of Mcl-1 and survivin. Based on these findings, we propose that targeting S6K1 may be an effective strategy to overcome tamoxifen resistance in breast cancer. PMID- 23942995 TI - Myopia and diabetes mellitus as modificatory factors of glaucomatous optic neuropathy. AB - Myopic deformation of the eye and metabolic alterations of the nerve tissue of patients with diabetes may modify glaucomatous optic neuropathy (GON). Blockage of axonal transport of neurotrophic factors (NTFs) is the event crucial to understanding the factors that affect GON. The primary, but not sole, blockage site is at the lamina cribrosa (LC). Other than this primary site of damage at the LC, 7 other factors may explain atypical nerve fiber layer (NFL) defects and the vulnerability of the nerve fibers in eyes with high myopia and glaucoma: a second point of blockage at the edge of the posterior scleral foramen; ectatic strain on the NFL; ectasia and distortion of the LC; association of a hypoplastic optic disc; thin and weak collagen fibers; peripapillary chorioretinal atrophy; and myopic neuropathy. Among diabetic patients, diabetic neuropathy in the retinal NFL is present initially, and increased resistance to aqueous outflow leads to ocular hypertension. Superimposition of GON on diabetic neuropathy and ocular hypertension in patients with diabetes may enhance their susceptibility to nerve damage. Results of a meta-analysis study suggested a positive association between diabetes mellitus and glaucoma whereas other reports suggested that leakage of vascular endothelial growth factor, a survival mechanism of ischemic neural tissue, and enhanced stiffness of the LC as a result of diabetic glycation may protect neurons from apoptosis. Thus, modification of GON as a result of diabetes remains controversial. PMID- 23942997 TI - Single-step syntheses of no-carrier-added functionalized [18F]fluoroarenes as labeling synthons from diaryliodonium salts. AB - Radiotracers labelled with short-lived fluorine-18 (t(1/2) = 109.7 min) are keenly sought for biomedical imaging with positron emission tomography (PET). The radiotracers are mostly required at high specific radioactivities, necessitating their radiosyntheses from cyclotron-produced no-carrier-added [(18)F]fluoride ion. PET radiotracers encompass wide structural diversity and molecular weight. Hence, diverse (18)F-labeling methodology is needed to accomplish the required radiosyntheses in a simple and rapid manner. A useful strategy is to introduce nucleophilic [(18)F]fluoride ion first into a labeling synthon that may then be applied to label the target radiotracer. Here, we show that various functionalized [(18)F]fluoroarenes may be rapidly synthesized as labeling synthons through single-step reactions of appropriate diaryliodonium salts with [(18)F]fluoride ion. Decay-corrected radiochemical yields (RCYs) varied with position of functional group, choice of electron-rich aryl ring in the diaryliodonium salt, and choice of anion. Under best conditions, (18)F-labeled fluorobenzaldehydes, fluorobenzyl halides, fluorobenzoic acid esters and fluorophenyl ketones were obtained selectively in 40-73%, 20-55%, 46-89% and 81 98% RCYs, respectively. This versatile straightforward methodology will enhance the scope for producing structurally complex, yet useful, PET radiotracers. PMID- 23942998 TI - Uranyl-water-containing complexes: solid-state UV-MALDI mass spectrometric and IR spectroscopic approach for selective quantitation. AB - Since primary environmental concept for long storage of nuclear waste involved assessment of water in uranium complexes depending on migration processes, the paper emphasized solid-state matrix-assisted laser desorption/ionization (MALDI) mass spectrometric (MS) and IR spectroscopic determination of UO2(NO3)2.6H2O; UO2(NO3)2.3H2O, alpha-, beta-, and gamma-UO3 modifications; UO3.xH2O (x = 1 or 2); UO3.H2O, described chemically as UO2(OH)2, beta- and gamma-UO2(OH)2 modifications; and UO4.2H2O, respectively. Advantages and limitation of vibrational spectroscopic approach are discussed, comparing optical spectroscopic data and crystallographic ones. Structural similarities occurred in alpha-gamma modifications of UO3, and UO2(OH)2 compositions are analyzed. Selective speciation achieved by solid-state mass spectrometry is discussed both in terms of its analytical contribution for environmental quality assurance and assessment of radionuclides, and fundamental methodological interest related the mechanistic complex water exchange of UO3.H2O forms in the gas phase. In addition to high selectivity and precision, UV-MALDI-MS, employing an Orbitrap analyzer, was a method that provided fast steps that limited sample pretreatment techniques for direct analysis including imaging. Therefore, random and systematic errors altering metrology and originating from the sample pretreatment stages in the widely implemented analytical protocols for environmental sampling determination of actinides are significantly reduced involving the UV-MALDI-Orbitrap-MS method. The method of quantum chemistry is utilized as well to predict reliably the thermodynamics and nature of U-O bonds in uranium species in gas and condensed phases. PMID- 23942999 TI - Contamination levels of polychlorinated biphenyls in wild versus cultivated samples of female and male mussels (Mytilus sp.) from the Northwest Coast of Iberian Peninsula--new application for QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) methodology. AB - A newly analytical method based on QuEChERS extraction followed by gas chromatography with mass spectrometry (GC-MS) analysis was developed and validated for the quantification of 18 PCBs in wild (from Matosinhos Beach, Portugal) and cultivated (from Ria de Arousa, Spain) mussel samples, pooled by sex. Wild animals showed higher PCB levels than cultivated mussels, with males from both origins, presenting an upper contamination profile comparing with females. This fact seems to be correlated with few biometric parameters, but other interdependencies, not addressed herein, such as distinct lipid contents between sexes, as a consequence of the gametogenic stage, may also explain this data. Overall, data reiterate the importance of investigating the presence of PCBs in marine biological samples, which can act both as bioindicators of environmental contamination, either as food quality controls for human health. PMID- 23943000 TI - Degradation pathways of low-ethoxylated nonylphenols by isolated bacteria using an improved method. AB - Nonylphenol ethoxylates (NPEOs) with low ethoxylation degree (NPav2EO; containing two ethoxy units on average) and estrogenic properties are the intermediate products of nonionic surfactant NPEOs. To better understand the environmental fate of low-ethoxylated NPEOs, phylogenetically diverse low-ethoxylated NPEO degrading bacteria were isolated from activated sludge using gellan gum as the gelling reagent. Four isolates belonging to four genera, i.e., Pseudomonas sp. NP522b in gamma-Proteobacteria, Variovorax sp. NP427b and Ralstonia sp. NP47a in beta-Proteobacteria, and Sphingomonas sp. NP42a in alpha-Proteobacteria were acquired. Ralstonia sp. NP47a or Sphingomonas sp. NP42a, have not been reported for the degradation of low-ethoxylated NPEOs previously. The biotransformation pathways of these isolates were investigated. The first three strains (NP522b, NP427b, and NP47a) exhibited high NPav2EO oxidation ability by oxidizing the polyethoxy (EO) chain to form low-ethoxylated nonylphenoxy carboxylates, and then further oxidizing the alkyl chain to form carboxyalkylphenol polyethoxycarboxylates. Furthermore, Sphingomonas sp. NP42a degraded NPav2EO through a nonoxidative pathway with nonylphenol monoethoxylate as the dominant product. PMID- 23943001 TI - Deriving sorption indices for the prediction of potential phosphorus loss from calcareous soils. AB - The aim of this study was to develop techniques to evaluate soil phosphorus (P) sorption capacity (PSC) and determine critical soil P levels to predict P loss potential for calcareous soils. Seventy-five soils mostly from Northern China were analyzed for soil P using four extraction methods (water, Pw; carbonate, POls; ammonium oxalate, Pox; and Mehlich 3, PM3) as well as PSC derived from single-point (PSC150) and multipoint sorption (S t) isotherms. Strong correlation was found between PSC150 and S t (r (2)=0.89, p<0.001). The sum of alphaCaM3 and betaMgM3 as an index of PSC (PSC(CaM3 + MgM3)) was most closely related to the maximum amount of P sorbed (S max) as given by the sum of S t and soil initial P setting alpha=0.039 and beta=0.462 (r (2)=0.80, p<0.001). The degree of P saturation (DPS) was thereafter calculated from PSC(CaM3 + MgM3) (DPS(CaM3 + MgM3)), to which Olsen P (POls) was significantly correlated (r (2)=0.82, p<0.001). In a split-line regression from Pw against DPS(CaM3 + MgM3) (r (2)=0.87, p<0.05), a change point was identified at 28.1% DPS(CaM3 + MgM3), which was equivalent to 49.2 mg kg(-1) POls and corresponded to a Pw concentration of 8.8 mg kg(-1). After the change point, a sharp increase in Pw was observed. Our results reveal a new approach to approximating DPS from CaM3 and MgM3 for calcareous soils without the need to generate a S max. We conclude that in the absence of an environmental soil test criteria for P, the DPS(CaM3 + MgM3) and POls could be used to predict P loss potential from calcareous soils. PMID- 23943002 TI - Field controlled experiments on the physiological responses of maize (Zea mays L.) leaves to low-level air and soil mercury exposures. AB - Thousands of tons of mercury (Hg) are released from anthropogenic and natural sources to the atmosphere in a gaseous elemental form per year, yet little is known regarding the influence of airborne Hg on the physiological activities of plant leaves. In the present study, the effects of low-level air and soil Hg exposures on the gas exchange parameters of maize (Zea mays L.) leaves and their accumulation of Hg, proline, and malondialdehyde (MDA) were examined via field open-top chamber and Hg-enriched soil experiments, respectively. Low-level air Hg exposures (<50 ng m(-3)) had little effects on the gas exchange parameters of maize leaves during most of the daytime (p > 0.05). However, both the net photosynthesis rate and carboxylation efficiency of maize leaves exposed to 50 ng m(-3) air Hg were significantly lower than those exposed to 2 ng m(-3) air Hg in late morning (p < 0.05). Additionally, the Hg, proline, and MDA concentrations in maize leaves exposed to 20 and 50 ng m(-3) air Hg were significantly higher than those exposed to 2 ng m(-3) air Hg (p < 0.05). These results indicated that the increase in airborne Hg potentially damaged functional photosynthetic apparatus in plant leaves, inducing free proline accumulation and membrane lipid peroxidation. Due to minor translocation of soil Hg to the leaves, low-level soil Hg exposures (<1,000 ng g(-1)) had no significant influences on the gas exchange parameters, or the Hg, proline, and MDA concentrations in maize leaves (p > 0.05). Compared to soil Hg, airborne Hg easily caused physiological stress to plant leaves. The effects of increasing atmospheric Hg concentration on plant physiology should be of concern. PMID- 23943003 TI - A protocol for assessing the effectiveness of oil spill dispersants in stimulating the biodegradation of oil. AB - Dispersants are important tools in oil spill response. Taking advantage of the energy in even small waves, they disperse floating oil slicks into tiny droplets (<70 MUm) that entrain in the water column and drift apart so that they do not re agglomerate to re-form a floating slick. The dramatically increased surface area allows microbial access to much more of the oil, and diffusion and dilution lead to oil concentrations where natural background levels of biologically available oxygen, nitrogen, and phosphorus are sufficient for microbial growth and oil consumption. Dispersants are only used on substantial spills in relatively deep water (usually >10 m), conditions that are impossible to replicate in the laboratory. To date, laboratory experiments aimed at following the biodegradation of dispersed oil usually show only minimal stimulation of the rate of biodegradation, but principally because the oil in these experiments disperses fairly effectively without dispersant. What is needed is a test protocol that allows comparison between an untreated slick that remains on the water surface during the entire biodegradation study and dispersant-treated oil that remains in the water column as small dispersed oil droplets. We show here that when this is accomplished, the rate of biodegradation is dramatically stimulated by an effective dispersant, Corexit 9500. Further development of this approach might result in a useful tool for comparing the full benefits of different dispersants. PMID- 23943005 TI - Antidyslipidemic and antioxidant effects of novel Lupeol-derived chalcones. AB - A series of Lupeol-based chalcones have been synthesized aiming to enhance the therapeutic efficacy of parent compound, the novel compounds were evaluated for their antidyslipidemic activity in triton-WR 1339 induced hyperlipidemic rats. Among the ten synthesized chalcones, the most active K4, K8, and K9 reversed the plasma levels of TC by (24, 25, 27 %), phospholipid by (25, 26, 25 %) and triacylglycerol by (27, 24, 24 %) respectively. In addition, the compounds showed significant in vitro antioxidant activity. The lipid lowering activity of these compounds were mediated through lipoprotein lipase activation (12-21 %) and enhanced post-heparin lipolytic activity (15-16 %). The compounds also displayed noteworthy inhibitory effect on 3-hydroxy-3-methyl-glutaryl reductase activity (in vitro). The in vitro effect of the most active compounds on MDI-induced adipogenesis using 3T3-L1 preadipocytes at 10 and 20 MUM concentrations showed significant inhibition (20-32 %) of adipogenesis. PMID- 23943006 TI - Release of single cells from the colonial oil-producing alga Botryococcus braunii by chemical treatments. AB - We tested for chemical reagents that would be useful in preparing a large number of vital single cells from colonial Botryococcus braunii B-race, variety Showa. Among the 18 reagents assayed, glycerol and erythritol showed the highest potency for releasing single cells. Incubation in medium containing these reagents released 40-50 % single cells in 15 min. Fluorescent staining with Nile red revealed that except for the cap-like structures the released single cells were free of hydrocarbon oils that accumulated in the extracellular matrix where the single cells were embedded. However, to maintain the prepared single cells in vital condition, they must be maintained at a high concentration (>2 * 10(7) cells/ml); at low concentrations, they rapidly lost chlorophyll and get disrupted. In contrast to the above results obtained using B-race, Showa, single cells prepared from A-race varieties survived even at low cell concentrations. PMID- 23943004 TI - The potential environmental risks of pharmaceuticals in Vietnamese aquatic systems: case study of antibiotics and synthetic hormones. AB - Presently, many pharmaceuticals are listed as emerging contaminants since they are considered to be great potential threats to environmental ecosystems. These contaminants, thus, present significant research interest due to their extensive use and their physicochemical and toxicological properties. This review discusses a whole range of findings that address various aspects of the usage, occurrence, and potentially environmental risks of pharmaceuticals released from various anthropogenic sources, with emphasis on the aquatic systems in Vietnam. The published information and collected data on the usage and occurrence of antibiotics and synthetic hormone in effluents and aquatic systems of Vietnam is reported. This is followed by a potential ecological risk assessment of these pollutants. The extensive use of antibiotics and synthetic hormones in Vietnam could cause the discharge and accumulation of these contaminants in the aquatic systems and potentially poses serious risks for ecosystems. Vietnam is known to have extensively used antibiotics and synthetic hormones, so these contaminants are inevitably detected in aquatic systems. Thus, an appropriate monitoring program of these contaminants is urgently needed in order to mitigate their negative effects and protect the ecosystems. PMID- 23943007 TI - Ranking the significance of fermentation conditions on the volatile organic compounds of Tuber melanosporum fermentation system by combination of head-space solid phase microextraction and chromatographic fingerprint similarity analysis. AB - Tuber melanosporum is highly appreciated in culinary contexts due to its unique and characteristic aroma. T. melanosporum fermentation has been established as a promising alternative for fruiting bodies to produce volatile organic compounds (VOCs). In this work, a technique using a combination of chromatographic fingerprint similarity analysis, head-space solid phase microextraction and gas chromatography was developed to rank the significance of fermentation conditions on the VOCs profile during T. melanosporum fermentation. Omission tests indicated that the absence of major carbon source (i.e., sucrose) in the fermentation media had the most significant effect on the profile of VOCs, followed by the absence of yeast extract or peptone. Consideration of the culture conditions revealed that VOCs produced was the most significantly affected by temperature. These results indicated that it is possible to adjust the aroma of truffles via fermentation process control. PMID- 23943008 TI - [Leukostasis and tumor lysis: important complications of hyperleukocytosis]. AB - The occurrence of hyperleukocytosis (leukocytes > 100.000/MUl) is associated with complications such as leukostasis, tumor lysis and consumption coagulopathy in patients with acute leukemia much more often than in patients with chronic malignant hematological diseases. To manage these situations may be complex as organ failure is often imminent or manifest, infectious complications arise and indications for induction chemotherapy are usually urgent. Prophylaxis and therapy of the tumor lysis syndrome consists of hydration, lowering of uric acid and the management of electrolyte disturbances. Leukostasis requires immediate reduction of the leukocyte count by leukapheresis, administration of hydroxycarbamide and, ultimately, by causative and specific treatment of the underlying disease itself. In patients with curable diseases or favorable long term prognosis, transfer to the intensive care unit must be evaluated early in the course of impending organ dysfunction, especially in cases of acute respiratory failure. PMID- 23943010 TI - Effective preconditioning for ab initio ground state energy minimization with non orthogonal localized molecular orbitals. AB - The non-orthogonal localized molecular orbital (NOLMO) is the most localized representation of electronic degrees of freedom. As such, NOLMOs are thus potentially the most efficient for linear-scaling calculations of electronic structures for large systems. However, direct ab initio calculations with NOLMO have not been fully implemented and widely used, partly because of the slow convergence issue in the optimization of NOLMO. Towards realizing the potential of NOLMO for large systems, we applied an energy minimum variational principle for carrying out ab initio self-consistent-field (SCF) calculations with NOLMOs. We developed an effective preconditioning approach using the diagonal part of the second order derivatives and show that the convergence of the energy optimization is significantly improved. The speed of convergence of the energy and density are comparable with that of the conventional SCF approach, thus paving the way for the optimization of NOLMO in linear scaling calculations for large systems. PMID- 23943009 TI - Extended treatment of Cushing's disease with pasireotide: results from a 2-year, Phase II study. AB - In a previous 15-day, Phase II study of patients with de novo or persistent/recurrent Cushing's disease (core study), treatment with pasireotide 600 MUg sc bid reduced urinary free cortisol (UFC) levels in 76% of patients and normalized UFC in 17%. The objective of this study was to evaluate the efficacy and safety of extended treatment with pasireotide. This was a planned, open ended, single-arm, multicenter extension study (primary endpoint: 6 months). Patients aged >=18 years with Cushing's disease who completed the core study could enter the extension if they achieved UFC normalization at core study end and/or obtained significant clinical benefit. Of the 38 patients who completed the core study, 19 entered the extension and 18 were included in the efficacy analyses (three responders, 11 reducers, four non-reducers in the core study). At data cut-off, median treatment duration in the extension was 9.7 months (range: 2 months to 4.8 years). At extension month 6, 56% of the 18 patients had lower UFC than at core baseline and 22% had normalized UFC. Of the four patients who remained on study drug at month 24, one had normalized UFC. Reductions in serum cortisol, plasma adrenocorticotropic hormone, body weight and diastolic blood pressure were observed. The most common adverse events were mild-to-moderate gastrointestinal disorders and hyperglycemia. Pasireotide offers a tumor-directed medical therapy that may be effective for the extended treatment of some patients with Cushing's disease. PMID- 23943011 TI - Effect of enhanced UV-B radiation and low-energy N+ ion beam radiation on the response of photosynthesis, antioxidant enzymes, and lipid peroxidation in rice (Oryza sativa) seedlings. AB - To understand the effect of enhanced UV-B radiation and low-energy N(+) ion beam radiation on the response of photosynthesis, antioxidant enzymes, and lipid peroxidation in rice seedlings, Oryza sativa was exposed to three different doses of low-energy N(+) ion beam and enhanced UV-B alone and in combination. Enhanced UV-B caused a marked decline in some photosynthetic parameters (net photosynthetic rate, transpiration rate, and stomatal conductance) and photosynthetic pigments, whereas it induced an increase in hydrogen peroxide (H2O2) accumulation, the rate of superoxide radical production, and the content of malondialdehyde (MDA). Enhanced UV-B also induced an increase in the activity of antioxidant enzymes (superoxide dismutase [SOD], peroxidase (POD), and catalase [CAT]) and some nonenzymatic antioxidants such as proline. Under the combined treatment of enhanced UV-B and low-energy N(+) ion beam at the dose of 3.0 * 10(17) N(+) cm(-2), the activity of antioxidant compounds (SOD, POD, CAT, proline, and glutathione), photosynthetic pigments, and some photosynthetic parameters (net photosynthetic rate, transpiration rate, and stomatal conductance) increased significantly; however, the MDA content, H2O2 accumulation, and rate of superoxide radical production showed a remarkable decrease compared with the enhanced UV-B treatment alone. These results implied that the appropriate dose of low-energy N(+) ion beam treatment may alleviate the damage caused by the enhanced UV-B radiation on rice. PMID- 23943012 TI - Apoptosis of human gastric carcinoma SGC-7901 induced by deoxycholic acid via the mitochondrial-dependent pathway. AB - The study aimed to evaluate the effects of deoxycholic acid (DCA) on human gastric carcinoma cell lines and to explore its mechanisms. In the present study, effects of DCA on SGC-7901 cell growth, cell cycle, and apoptosis were investigated by MTT assay, inverted microscopy, fluorescence microscopy, PI single- and FITC/PI double-staining flow cytometry, and western blotting. The study have revealed that DCA significantly inhibited the growth of SGC-7901 cells in a dose- and time-dependent manner and arrested cell cycle at G0/G1 phase. SGC 7901 cells showed typical apoptotic morphological changes after treated with DCA for 48 h. The intensity of typical apoptosis pattern- "ladders" formed by DNA in fragments of multiples of 200 base pairs was also observed. Apoptosis of SGC-7901 cells induced by DCA were associated with collapse of the mitochondrial membrane potential. DCA treatment could also increase the ratio of Bax to Bcl-2 in SGC 7901 cells. Meanwhile, the expression of p53, cyclinD1, and c-Myc were changed after DCA treatment. These results suggest that DCA induces apoptosis of gastric carcinoma cells through an intrinsic mitochondrial-dependent pathway, and the increase in the Bax/Bcl-2 ratio and collapse of the mitochondrial membrane potential may play important roles in DCA-induced apoptosis of gastric carcinoma cells. PMID- 23943013 TI - Treatment of xanthelasma palpebrarum by upper eyelid skin flap incorporating blepharoplasty. AB - BACKGROUND: Wound repair after xanthelasma palpebrarum excision in the upper eyelid is a challenge for the plastic surgeon due to the difficulty obtaining tissue of the appropriate color and texture. The authors present their treatment of xanthelasma palpebrarum by an upper eyelid skin flap incorporating blepharoplasty with satisfactory results for 16 patients. METHODS: From September 2004 to August 2012, 32 xanthelasma lesions in the upper eyelids of 16 patients were surgically excised, after which an orbicularis oculi muscle myocutaneous flap was formed in blepharoplasty. The flap was used to repair the defect resulting from excision of the lesion. The xanthelasma palpebrarum treatment and blepharoplasty were performed simultaneously. RESULTS: No flap necrosis complications occurred after the operation. During a 3- to 12-months follow-up period, no lesion recurrence, lagophthalmos, hypertrophic scar, or bulky appearance was noted in any of the 16 patients. Aesthetic results in the upper eyelid were obtained for all the patients. CONCLUSION: By the reported method, the "waste" skin in blepharoplasty can become "treasure" material for covering the defect resulting from lesion excision. No new donor area is required. The dual effects are excision of the xanthelasma lesion and a satisfactory cosmetic result in the upper eyelid. This procedure could be the preferred option for xanthelasma palpebrarum in the upper eyelid. PMID- 23943014 TI - Optically pure heterobimetallic helicates from self-assembly and click strategies. AB - Single diastereomer, diamagnetic, octahedral Fe(II) tris chelate complexes are synthesised that contain three pendant pyridine proligands pre-organised for coordination to a second metal. They bind Cu(I) and Ag(I) with coordination geometry depending on the identity of the metal and the detail of the ligand structure, but for example homohelical (DeltaFe,DeltaCu) configured systems with unusual trigonal planar Cu cations are formed exclusively in solution as shown by VT-NMR and supported by DFT calculations. Similar heterobimetallic tris(triazole) complexes are synthesised via clean CuAAC reactions at a tris(alkynyl) complex, although here the configurations of the two metals differ (DeltaFe,LambdaCu), leading to the first optically pure heterohelicates. A second series of Fe complexes perform less well in either strategy as a result of lack of preorganisation. PMID- 23943015 TI - Late presentation and loss to follow-up of immigrants newly diagnosed with HIV in the HAART era. AB - To compare clinical characteristics and therapeutic management of newly HIV diagnosed immigrants to natives. Patients with a first HIV diagnosis from 1996 to 2010 were included. Of 716 new diagnoses, 85 (12 %) were immigrants. Migrants were younger, more frequently females and sexually infected, less likely to voluntarily request testing, and less HCV-coinfected. Late presenters (CD4 <350 or AIDS) were 76 % among migrants versus 56 % in natives (p = 0.006) with an increasing trend over time. HAART was initiated in 76.5 % of natives and 72.4 % of immigrants; the number/type of adverse events and treatment discontinuation were similar. Immigrants received more NNRTIs-based regimens. A similar proportion of patients reached virological suppression at month 1-3-6 after HAART initiation, but 43 % of immigrants versus 27 % of natives resulted lost to follow up (p < 0.001). Diagnosis of HIV was often delayed among migrants, who also presented a higher rate of lost to follow-up. PMID- 23943017 TI - Multi-layer haemocompatible diamond-like carbon coatings obtained by combined radio frequency plasma enhanced chemical vapor deposition and magnetron sputtering. AB - Radio-frequency Plasma Enhanced Chemical Vapour Deposition (in different methane dilutions) was used to synthesize adherent and haemocompatible diamond-like carbon (DLC) films on medical grade titanium substrates. The improvement of the adherence has been achieved by interposing a functional buffer layer with graded composition TixTiC1-x (x = 0-1) synthesized by magnetron co-sputtering. Bonding strength values of up to ~67 MPa have been measured by pull-out tests. Films with different sp(3)/sp(2) ratio have been obtained by changing the methane concentration in the deposition chamber. Raman spectroscopy, X-ray photoelectron spectroscopy and X-ray diffraction were employed for the physical-chemical characterization of the samples. The highest concentration of sp(3)-C (~87 %), corresponding to a lower DLC surface energy (28.7 mJ/m(2) ), was deposited in a pure methane atmosphere. The biological response of the DLC films was assayed by a state-of-the-art biological analysis method (surface enhanced laser desorption/ionization-time of flight mass spectroscopy), in conjunction with other dedicated testing techniques: Western blot and partial thromboplastin time. The data support a cause-effect relationship between sp(3)-C content, surface energy and coagulation time, as well as between platelet-surface adherence properties and protein adsorption profiles. PMID- 23943016 TI - Cultural beliefs and clinical breast examination in Hmong American women: the crucial role of modesty. AB - Despite grave cancer disparities in Hmong American women, investigation of the group's breast cancer screening behavior is sparse. This study examined how cultural factors are associated with breast cancer screening utilization, specifically clinical breast exam (CBE), in this population. One hundred and sixty-four Hmong American women between ages 18 and 67 were recruited from a large Midwestern metropolitan area with a median age of 28.0 years. Logistic regression was used to assess the association of cultural variables with receipt of CBE. Roughly 73% of Hmong American women reported ever having had a CBE. Logistic regression revealed that endorsing more modest views was the greatest barrier to ever having had a CBE. Age and language preference were also found to be significant predictors of past CBE use. Cultural factors should be considered in developing interventions aimed at promoting breast cancer screening in this population. In particular, Hmong American women who have less English proficiency and are relatively younger should be targeted in breast cancer screening efforts. PMID- 23943018 TI - Solid-state NMR sequential assignments of the amyloid core of full-length Sup35p. AB - Sup35p is a yeast prion and is responsible for the [PSI(+)] trait in Saccharomyces cerevisiae. With 685 amino acids, full-length soluble and fibrillar Sup35p are challenging targets for structural biology as they cannot be investigated by X-ray crystallography or NMR in solution. We present solid-state NMR studies of fibrils formed by the full-length Sup35 protein. We detect an ordered and rigid core of the protein that gives rise to narrow and strong peaks, while large parts of the protein show either static disorder or dynamics on time scales which interfere with dipolar polarization transfer or shorten the coherence lifetime. Thus, only a small subset of resonances is observed in 3D spectra. Here we describe in detail the sequential assignments of the 22 residues for which resonances are observed in 3D spectra: their chemical shifts mostly corresponding to beta-sheet secondary structure. We suspect that these residues form the amyloid core of the fibril. PMID- 23943019 TI - Peer-led and professional-led group interventions for people with co-occurring disorders: a qualitative study. AB - This pilot study evaluated the experience of people with co-occurring disorders (mental illness and addiction) in relation to peer-led and professional-led group interventions. The study used a qualitative (phenomenological) approach to evaluate the experience of a convenience sample of 6 individuals with co occurring disorders who participated in up to 8 sessions each of both peer-led and professional-led group interventions (with a similar rate of attendance in both groups). The semi-structured interview data were coded and thematically analyzed. We found 5 themes within and across the 2 interventions. In both groups, participants experienced a positive environment and personal growth, and learned, albeit different things. They were more comfortable in the peer-led group and acquired more knowledge and skills in the professional-led group. Offering both peer-led and professional-led group interventions to people with co occurring disorders may be better than offering either alone. PMID- 23943021 TI - Resolution of new-onset diabetes after radical pancreatic resection predicts long term survival in patients with pancreatic ductal cell adenocarcinoma. AB - PURPOSE: To demonstrate the effect of diabetes mellitus (DM) (stratified by long term/new-onset presurgical diabetes, resolved/unresolved postsurgical diabetes) on prognosis for pancreatic ductal cell adenocarcinoma (PDAC) after radical resection. METHODS: One hundred ninety-nine patients who underwent radical resection for PDAC between 2007 and 2011 at Ruijin Hospital (Shanghai, China) were retrospectively analyzed. Clinical and pathologic characteristics, surgical and adjuvant chemotherapy related outcomes, disease-free survival (DFS), and postoperative survival were compared among patients with long-term (>=2 years)/new-onset (<2 years) presurgical diabetes and resolved/unresolved postsurgical diabetes. Univariate and multivariable analysis was performed to determine factors associated with DFS and overall survival (OS). RESULTS: Of 199 patients, 90 (44.7%) had DM, 64 of which were new onset and 26 of which were long standing. Resolution of DM after radical pancreatic resection was observed in 65% (42 of 64) in the new-onset group, but in none of the long-standing group. Resolved new-onset DM patients had larger, well-differentiated tumors compared to patients with unresolved new-onset DM. Patients with long-standing DM had shorter postoperative DFS and OS than nondiabetic/new-onset DM, whereas postoperative resolved new-onset DM is associated with longer DFS and OS than unresolved DM. Morbidity was higher and postoperative hospital stay was longer in patients with new-onset DM compared with patients with long-standing DM and patients without DM. There was no difference in the adjuvant chemotherapy toxicity rate among patients with long-standing or new-onset DM and those without DM. CONCLUSIONS: Different status of DM has different effects on outcome after resection for PDAC. Long-standing DM is related to progression of disease, whereas postsurgical resolved new-onset DM is a favorable prognostic factor. PMID- 23943020 TI - Priority of lymph node dissection for Siewert type II/III adenocarcinoma of the esophagogastric junction. AB - OBJECTIVE: The purpose of this study was to clarify the priority of nodal dissection in Siewert types II and III adenocarcinoma of the esophagogastric junction (AEG). METHODS: The priority of nodal dissection was evaluated based on the therapeutic value index calculated by multiplying of the frequency of metastasis to each station and the 5-year survival rate of patients with metastasis to that station. RESULTS: A total of 176 patients (95 type II and 81 type III) were examined. Among the lymph nodes that had a metastatic incidence exceeding 10 %, the stations showing the first to fourth highest index were the paracardial and lesser curvature nodes (Nos. 1, 2, and 3) and the node at the root of the left gastric artery (No. 7) in the total cohort, as well as in each type. The next station was the lower thoracic paraesophageal lymph node (No. 110), followed by the nodes along the proximal splenic artery (No. 11p) in type II, whereas it was the nodes along the proximal splenic artery (No. 11p) followed by the para-aortic nodes (No. 16a2), the nodes at the celiac artery (No. 9), and the nodes around the splenic hilum (No. 10) in type III. CONCLUSIONS: These results suggest that the highest priority nodal stations to be dissected were the paracardial and lesser curvature nodes (Nos. 1, 2, and 3) and the nodes at the root of the left gastric artery (No. 7), regardless of the Siewert subtype, but the subsequent priority was different depending on the subtype. PMID- 23943022 TI - Impact of tumor grade on pancreatic cancer prognosis: validation of a novel TNMG staging system. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) patients demonstrate highly variable survival within each stage of the American Joint Committee on Cancer (AJCC) staging system. We hypothesize that tumor grade is partly responsible for this variation. Recently our group developed a novel tumor, node, metastasis, grade (TNMG) classification system utilizing Surveillance Epidemiology and End Results (SEER) data in which the presence of high tumor grade results in advancement to the next higher AJCC stage. This study's objective was to validate this TNMG staging system utilizing single-institution data. METHODS: All patients with PDAC who underwent resection at UCLA between 1990 and 2009 were identified. Clinicopathologic data reviewed included age, sex, node status, tumor size, grade, and stage. Grade was redefined as a dichotomous variable. The impact of grade on survival was assessed by Cox regression analysis. Disease was restaged into the TNMG system and compared to the AJCC staging system. RESULTS: We identified 256 patients who underwent resection for PDAC. Patients with low-grade tumors experienced a 13-month improvement in median survival compared to those with high-grade tumors. On multivariate analysis, tumor grade was the strongest predictor of survival with a hazard ratio of 2.02 (p = 0.0005). Restaging disease according to the novel TNMG staging system resulted in improved survival discrimination between stages compared to the current AJCC system. CONCLUSIONS: We were able to demonstrate that grade is one of the strongest independent prognostic factors in PDAC. Restaging with our novel TNMG system demonstrated improved prognostication. This system offers an effective and convenient way of adding grade to the current AJCC staging system. PMID- 23943023 TI - Rational study endpoint(s) for preoperative trials in pancreatic cancer: pathologic response rate, margin negative resection, overall survival or 'all of the above'? PMID- 23943025 TI - Small cell carcinoma of the esophagus: a SEER database analysis. AB - BACKGROUND: Small cell cancer (SCC) of the esophagus is an uncommon malignancy with perceived poor prognosis, but there are few data to guide therapeutic decisions. We examined the Surveillance, Epidemiology, and End Results (SEER) database to identify prognostic factors for survival. METHODS: All patients with esophageal cancer in the SEER database between 1973 and 2009 were included. Univariate and multivariate analyses were performed in patients with and without SCC, examining the relationship of small cell histology, surgery, and other potential prognostic factors with overall survival (censored at 72 months). RESULTS: Of 64,799 esophageal cancer patients identified in the SEER database, 387 (0.6 %) had small cell histology. As compared with non-small cell histology, patients with small cell histology were similar in age and race but had a higher proportion of women (p < 0.001), had a higher stage at diagnosis (p < 0.001), and were less likely to undergo surgical resection (p < 0.01). Multivariate predictors associated with poor survival in the overall cohort included age, female gender, black race, and stage. In patients treated with surgery, multivariate predictors associated with poor survival included age, male gender, race, and stage but not small cell histology. In patients with small cell histology, both age and stage were associated with poor survival, but surgery and preoperative radiotherapy were associated with improved survival. CONCLUSIONS: SCC of the esophagus presents at an advanced stage and confers a poor prognosis. The survival benefit of surgery and radiotherapy suggests that all esophageal SCC patients should be considered for preoperative radiotherapy and surgery in a stage-appropriate fashion. PMID- 23943024 TI - Radioactive seed localization compared to wire localization in breast-conserving surgery: initial 6-month experience. AB - BACKGROUND: Wire localization (WL) of nonpalpable breast cancers on the day of surgery is uncomfortable for patients and impacts operating room efficiency. Radioactive seed localization (RSL) before the day of surgery avoids these disadvantages. In this study we compare outcomes of our initial 6-month experience with RSL to those with WL in the preceding 6 months. METHODS: Lumpectomies for invasive or intraductal cancers localized with a single (125)iodine seed (January-June 2012) were compared with those using 1 wire (July December 2011). Surgeons and radiologists did not change. Positive and close margins were defined as tumor on ink and tumor <=1 mm from ink, respectively. Demographic and clinical characteristics and outcomes were compared between RSL and WL patients. RESULTS: There were 431 RSL and 256 WL lumpectomies performed. Clinicopathologic characteristics did not differ between groups. Most seeds (90 %) were placed before the day of surgery. Positive margins were present in 7.7 % of RSL versus 5.5 % of WL patients, and 16.9 % of RSL versus 19.9 % of WL had close margins (p = 0.38). The median operative time was longer for lumpectomy and sentinel lymph node biopsy (SLNB) in the RSL group (55 vs. 48 min, p < 0.0001). There was no significant difference in the volume of tissue excised between groups. CONCLUSIONS: In the first 6 months of RSL, operative scheduling was simplified, while rates of positive and close margins were similar to those seen after many years of experience with WL. Operative time was slightly longer for RSL lumpectomy and SLNB; we anticipate this will decrease with experience. PMID- 23943026 TI - Prognostic value of mucinous histology depends on microsatellite instability status in patients with stage III colon cancer treated with adjuvant FOLFOX chemotherapy: a retrospective cohort study. AB - BACKGROUND: The close association between mucinous histology and microsatellite instability (MSI) may have hindered the evaluation of prognostic significance of mucinous histology. The aim of this retrospective study was to investigate whether mucinous histology was associated with a worse prognosis, independent of MSI status, compared to nonmucinous histology in patients with stage III colon cancer. METHODS: This study enrolled 394 consecutive patients with stage III colorectal cancer treated with adjuvant FOLFOX after curative resection (R0). Clinicopathological information was retrospectively reviewed. Tumors were analyzed for MSI by polymerase chain reaction to determine MSI status. Kaplan Meier method, log-rank test, and Cox proportional hazard regression models were used. RESULTS: The estimated rate of 3-year disease-free survival (DFS) in patients with nonmucinous adenocarcinoma (NMA 79.2 %) was significantly greater than that in patients with mucinous adenocarcinoma (MA) and adenocarcinoma with mucinous component (MC) (56.9 %; log-rank, P = 0.002). In univariate analysis, histology (NMA vs. MA/MC), American Joint Committee on Cancer stage (IIIA, IIIB, and IIIC), and lymphovascular invasion (present vs. absent) were significantly associated with DFS. In multivariate analysis, mucinous histology (MA/MC) was associated with decreased DFS in all patients (hazard ratio 1.82, 95 % confidence interval 1.03-3.23, P = 0.0403). In patients with MA/MC, no difference in DFS was observed between MSI and microsatellite stability (log-rank, P = 0.732). CONCLUSIONS: Mucinous histology is an independent poor prognostic factor for DFS in patients with stage III colon cancer after adjuvant FOLFOX chemotherapy. PMID- 23943027 TI - Patient demographic and tumor characteristics influencing oncologist follow-up frequency in older breast cancer survivors. AB - BACKGROUND: Although recommendations for breast cancer follow-up frequency exist, current follow-up guidelines are standardized, without consideration of individual patient characteristics. Some studies suggest oncologists are using these characteristics to tailor follow-up recommendations, but it is unclear how this is translating into practice. The objective of this study was to examine current patterns of oncologist breast cancer follow-up and determine the association between patient and tumor characteristics and follow-up frequency. METHODS: The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify stage I-III breast cancer patients diagnosed 2000-2007 (n = 39,241). Oncologist follow-up visits were defined using Medicare specialty provider codes and the linked AMA Masterfile. Multinomial logistic regression determined the association between patient and tumor characteristics and oncologist follow-up visit frequency. RESULTS: Younger age (p < 0.001), positive nodes (p < 0.001), estrogen receptor/progesterone receptor positivity (p < 0.001), and increasing treatment intensity (p < 0.001) were most strongly associated with more frequent follow-up. However, after accounting for these characteristics, significant variation in follow-up frequency was observed. In addition to patient factors, the number and types of oncologists involved in follow-up were associated with follow-up frequency (p < 0.001). Types of oncologists providing follow-up varied, with medical oncologists the sole providers of follow-up for 19-51 % of breast cancer survivors. Overall, 58 % of patients received surgical oncology, and 51 % undergoing radiation received radiation oncology follow-up, usually in combination with medical oncology. CONCLUSIONS: Significant variation in breast cancer follow-up frequency exists. Developing follow-up guidelines tailored for patient, tumor, and treatment characteristics while also providing guidance on who should provide follow-up has the potential to increase clinical efficiency. PMID- 23943028 TI - Chromobox homolog 4 is correlated with prognosis and tumor cell growth in hepatocellular carcinoma. AB - BACKGROUND: Chromobox homolog 4 (CBX4) is a member of the chromobox family of Polycomb group proteins involved in the chromatin remodeling and transcriptional regulation. However, its clinical relevance in hepatocellular carcinoma (HCC) has not yet been explored. METHODS: Immunohistochemistry was used to analyze cytoplasmic expression of CBX4 in 246 HCC specimens. The expression of CBX4 in HCC cell lines and LO2 was detected by Western blot test. Cell cycle and MTT assays were used to determine the changes of cell growth capacity. The expression of downstream genes related to proliferation was detected by Western blot test. RESULTS: The expression of CBX4 was up-regulated in multiple HCC cell lines and clinical samples. Although the CBX4 protein was detectable in both nucleus and cytoplasm in HCC tumor tissues, the high expression of CBX4 in cytoplasm was correlated with the alpha-fetoprotein level in serum (P = 0.036), tumor size (P = 0.029), pathologic differentiation (P = 0.033), and tumor, node, metastasis classification system stages (P = 0.032). Moreover, HCC patients who had a high level of CBX4 in cytoplasm had a shorter overall survival (P = 0.003) and recurrence-free survival (P = 0.012). Indeed, using HCC cell line, knockdown of CBX4 led to down-regulating proliferating cell nuclear antigen and cyclin E2 as well as up-regulating p16, followed by decreased cell proliferation and impaired cell cycle progression. CONCLUSIONS: The cytoplasmic CBX4 protein may be a useful prognostic biomarker and a potential therapeutic target for HCC. PMID- 23943029 TI - In vivo fluorescence imaging of gastrointestinal stromal tumors using fluorophore conjugated anti-KIT antibody. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are frequently characterized by KIT overexpression. Tumor-free margins and complete cytoreduction of disease are mainstays of treatment. We hypothesized that fluorescently labeled anti-KIT antibodies can label GIST in vivo. METHODS: KIT K641E(+/-) transgenic mice that spontaneously develop cecal GISTs were used in this study, with C57BL/6 mice serving as controls. Alexa 488 fluorophore-conjugated anti-KIT antibodies were delivered via the tail vein 24 h prior to fluorescence imaging. Following fluorescence laparoscopy, mice were sacrificed. The gastrointestinal tracts were grossly examined for tumors followed by fluorescence imaging. Tumors were harvested for histologic confirmation. RESULTS: KIT K641E(+/-) mice and C57BL/6 control mice received anti-KIT antibody or isotope control antibody. Fluorescence laparoscopy had a high tumor signal-to-background noise ratio. Upon blinded review of intravital fluorescence and bright light images, there were 2 false positive and 0 false-negative results. The accuracy was 92 %. The sensitivity, specificity, positive and negative predictive values were 100, 87, 85, and 100 %, respectively, for the combined modalities. CONCLUSIONS: In this study, we present a method for in vivo fluorescence labeling of GIST in a murine model. Several translatable applications include: laparoscopic staging; visualization of peritoneal metastases; assessment of margin status; endoscopic differentiation of GISTs from other benign submucosal tumors; and longitudinal surveillance of disease response. This novel approach has clear clinical applications that warrant further research and development. PMID- 23943030 TI - Epitrochlear lymph node dissection and axillary lymph node biopsy. An unusual clinical presentation in a patient with forearm melanoma. PMID- 23943031 TI - Presentation, management, and outcomes of hyperparathyroidism in octogenarians and nonagenarians. AB - BACKGROUND: Various elective surgical procedures are routinely performed on patients >=80 years of age. With primary hyperparathyroidism (PHPT), surgical management is the only treatment. The goal of this study was to compare presentation and outcome of patients >=80 to that of those <80 years of age. METHODS: Retrospective review of a prospectively collected database of all parathyroidectomies for PHPT performed at a university hospital. Patients >=80 years at the time of surgery compared with patients <80 years. RESULTS: Over 13 years, 1,826 patients underwent parathyroidectomy for PHPT. A total of 154 patients were >=80 years at the time of surgery (8.4 %), ranging from 80 to 91 years. Patients >=80 years had higher serum PTH, creatinine and vitamin D levels and lower T scores. Calcium levels were similar. Patients >=80 years had a greater history of hypertension, coronary artery disease, congestive heart failure, and stroke. Psychiatric disease was less common. Patients >=80 years had the procedure under local anesthesia only more often. Use of a unilateral approach was equivalent. Rates of adenoma, double adenoma, and hyperplasia were comparable. Patients >=80 years were observed overnight more frequently. Stays >24 h and disease recurrence and persistence, as well as morbidity rates, were all equivalent. CONCLUSION: Disease presentation of PHPT in patients >=80 is similar to <80. Despite increased comorbidities, parathyroidectomy is a safe procedure in this patient population with a noted equivalent complication rate to younger patients. Operative management remains the only treatment. Patient age should not be a deterrent to offer curative surgical intervention. PMID- 23943032 TI - Minimal benefit to subsequent intraoperative parathyroid hormone testing after all four glands have been identified. AB - BACKGROUND: Modern tools, such as intraoperative parathyroid hormone (IoPTH) assay, reduce operative time and extent of parathyroidectomy. However, the utility of a subsequent final set of IoPTH after all four glands are visualized remains questionable. This study was designed to determine the added value of IoPTH assay following parathyroidectomy with four-gland visualization in patients with primary hyperparathyroidism (PHPT). METHODS: A retrospective review of patients who underwent parathyroidectomy for PHPT between July 2001 and February 2012 by two experienced endocrine surgeons was performed. Included were patients with operative reports indicating that all four parathyroid glands were identified. Following four-gland visualization a subsequent final set of IoPTH was measured to confirm cure. Cure was defined as at least 50 % fall by 5, 10, or 15 min postexcision compared with preincision levels. RESULTS: Of 1,838 patients that underwent parathyroidectomy, four glands were visualized in 238 cases (13 %). Of those patients meeting inclusion criteria with four glands visualized, the final set of IoPTH fell to cure criteria in 235 patients (98 %). An inadequate drop was documented in three (2 %) patients all of which were found to have multigland disease. Only in one patient (0.4 %) was a fifth parathyroid gland identified and resected. In all three cases, the subsequent final IoPTH did not affect the ultimate outcome or cure rate. CONCLUSIONS: When experienced surgeons visualize all four parathyroid glands, drawing a subsequent final set of IoPTH rarely changes the operative course and therefore serves a limited role. PMID- 23943033 TI - Technical factors that affect anastomotic integrity following esophagectomy: systematic review and meta-analysis. AB - BACKGROUND: Due to the significant contribution of anastomotic leak, with its disastrous consequences to patient morbidity and mortality, multiple parameters have been proposed and individually meta-analyzed for the formation of the ideal esophagogastric anastomosis following cancer resection. The purpose of this pooled analysis was to examine the main technical parameters that impact on anastomotic integrity. METHODS: Medline, Embase, trial registries, and conference proceedings were searched. Technical factors evaluated included hand-sewn versus stapled esophagogastric anastomosis (EGA), cervical versus thoracic EGA, minimally invasive versus open esophagectomy, anterior versus posterior route of reconstruction and ischemic conditioning of the gastric conduit. The outcome of interest was the incidence of anastomotic leak, for which pooled odds ratios were calculated for each technical factor. RESULTS: No significant difference in the incidence of anastomotic leak was demonstrated for the following technical factors: hand-sewn versus stapled EGA, minimally invasive versus open esophagectomy, anterior versus posterior route of reconstruction and ischemic conditioning of the gastric conduit. Four randomized, controlled trials comprising 298 patients were included that compared cervical and thoracic EGA. Anastomotic leak was seen more commonly in the cervical group (13.64 %) than in the thoracic group (2.96 %). Pooled analysis demonstrated a significantly increased incidence of anastomotic leak in the cervical group (pooled odds ratio = 4.73; 95 % CI 1.61-13.9; P = 0.005). CONCLUSIONS: A tailored surgical approach to the patient's physiology and esophageal cancer stage is the most important factor that influences anastomotic integrity after esophagectomy. PMID- 23943034 TI - Multigland disease and slower decline in intraoperative PTH characterize mild primary hyperparathyroidism. AB - BACKGROUND: Many patients with primary hyperparathyroidism (PHPT) present with less severe biochemical parameters. The purpose of this study was to compare the presentation, operative findings, and outcomes of these patients with "mild" PHPT to patients with "overt" disease. METHODS: A retrospective review of a prospectively collected parathyroid database was performed to identify cases of PHPT undergoing an initial neck operation. Patients were classified as mild when either the preoperative calcium or PTH was within the normal limits. Comparisons were made with the Student's t test, Chi-squared test, or Wilcoxon rank-sum test where appropriate. Kaplan-Meier estimates were plotted for disease-free survival and compared by the log-rank test. RESULTS: Of the 1,429 patients who met inclusion criteria, 1,049 were classified as overt and 388 (27.1 %) were mild. Within the mild group, 122 (31.4 %) presented with normocalcemic PHPT and 266 (68.6 %) had a normal PTH. The two groups had similar demographics and renal function. Interestingly, the mild group had more than double the rate of kidney stones (3.1 vs. 1.3 %, p = 0.02). The mild group was less likely to localize on sestamibi scan (62.4 vs. 78.7 %, p < 0.01). Intraoperatively, more mild patients exhibited multigland disease (34.3 vs. 14.1 %, p < 0.01). When examining intraoperative PTH (IoPTH) kinetics where single adenomas were excised, the IoPTH fell at a rate of 6.9 pg/min in mild patients compared with 11.5 pg/min in the overt group (p < 0.01). Accordingly, 62.2 % of patients in the overt group and 53.3 % in the mild group were cured at 5 min postexcision (p < 0.01). There was no difference in the rates of persistence or recurrence between the groups, and disease-free survival estimates were identical (p = 0.27). CONCLUSIONS: Patients with mild PHPT were more likely to have multigland disease and a slower decline in IoPTH, but these patients can be successfully treated with surgery. PMID- 23943035 TI - Management of papillary lesions of the breast: can larger core needle biopsy samples identify patients who may avoid surgical excision? AB - BACKGROUND: The ability to distinguish benign from atypical/malignant papillary lesions on core needle biopsy is limited by the representative nature of the biopsy method, thus follow-up excision is usually recommended. We aimed to determine if larger samples of tissue obtained by core needle biopsy can more reliably predict the true benign nature of a papilloma. METHODS: We reviewed the pathology slides and medical records of 51 patients who were diagnosed with benign papillomas on core needle biopsy from 2000 to 2010, who subsequently underwent surgical excision. The characteristics of the core needle biopsy that were associated with retention of benign histology on excision were determined and analyzed. RESULTS: Atypical ductal hyperplasia and carcinoma were identified in 5.8 % (3/51) and 5.8 % (3/51) of papillary lesions, respectively, when excised. Patients whose lesions were diagnosed as benign on excision were significantly distinguished by the area (mm(2)) of tissue sampled by core needle biopsy (mean +/- standard deviation (SD): 101.5 +/- 106.5) compared with those with atypia or carcinoma on excision (mean +/- SD: 41.7 +/- 24.0, P = 0.003). All biopsies performed with 12-gauge or larger needles retained benign features on excision. Core needle biopsy tissue samples consisting of >=7 cores, or measuring >96 mm(2) in aggregate, had a negative predictive value for atypia/malignancy of 100 %. CONCLUSIONS: Larger tissue samples significantly improved the predictive value of benign histology on core needle biopsy. A papilloma sampled by a 12 gauge or larger needle, >=7 cores, or >96 mm(2) retained its benign features upon excision. PMID- 23943036 TI - Multimodal treatment strategy for clinical T3 thoracic esophageal cancer. AB - PURPOSE: Our goal was to create a multimodal treatment strategy for patients with locally advanced esophageal cancer (EC). METHODS: A retrospective review identified a total of 193 patients with clinical T3 thoracic EC were categorized into 3 groups: 81 who had surgery only (group I); 102 who had planned neoadjuvant chemoradiotherapy (NACRT; group II); and 10 who had salvage esophagectomy after definitive chemoradiotherapy (dCRT; group III). RESULTS: Postoperative complications developed in 27, 45, and 80 % of patients in group I, group II, and group III, respectively. NACRT and dCRT were independent risk factors associated with postoperative complications; the odds ratios for group II and group III, compared with group I, were 2.1 and 8.8, respectively. The respective mortality rates were 4, 2, and 20 % (group I vs. group III, p < 0.05; group II vs. group III, p < 0.01). The 5-year survival rate was 25.2 % in group I and 41.6 % in group II. The 5-year survival rate in group II patients with markedly effective NACRT (89.2 %) was significantly better than in patients with ineffective/slightly effective (11.8 %; p < 0.0001) and moderately effective treatment (51 %; p < 0.05). Four patients who had noncurative surgery died within 4 months after salvage esophagectomy, whereas four of six patients were still alive after curative surgery. CONCLUSIONS: A pathological complete response to NACRT is critical for improving survival in patients with clinical T3 thoracic EC. Salvage surgery should be considered only in carefully selected patients with locally advanced EC. PMID- 23943037 TI - A technique for laparoendoscopic resection of posterior fundic gastric GISTs without need for a gastrotomy. AB - BACKGROUND: The majority of gastrointestinal stromal tumors (GISTs) are located in the stomach. With greater experience in minimally invasive oncologic surgery, gastric GISTs are being increasingly approached laparoscopically. Posterior proximally located endophytic gastric GISTs can be challenging to approach laparoscopically and excise with an adequate margin without an anterior or posterior gastrotomy, or intragastric ports. METHODS: The gastrocolic and gastrosplenic ligaments are divided up to the gastroesophageal junction. The left lateral segment of the liver is mobilized to allow anterior reflection of the gastric fundus. Intraoperative ultrasound confirms the location and extent of the tumor base. Upper endoscopy is performed to trans-illuminate, confirm tumor location, and search for multifocality. Traction sutures are placed around the tumor to distract endophytic lesions. With organo-axial rotation of the stomach using the stay sutures, an endoGIA stapler approximates the posterior fundic wall under the base of the lesion ensuring an adequate margin and eliminating the risk of gastric spillage. Appropriate stapler placement and margins are assisted real time endoscopically with picture-in-picture. The stapleline is tested for leaks and inspected for hemostasis laparoendoscopically. RESULTS: Complete resection of GISTs with adequate margins is performed with sound oncologic principles and demonstrated in tumors of varying sizes and locations in the proximal posterior stomach, including near the GE junction. CONCLUSIONS: This video demonstrates a simple laparoendoscopic technique to quickly localize even small tumors, visually confirm adequate margins, and excise gastric GISTs without spillage or gastrotomy that are located in a typically difficult area of the stomach to approach laparoscopically. PMID- 23943038 TI - Visible-light activatable organic CO-releasing molecules (PhotoCORMs) that simultaneously generate fluorophores. AB - Novel organic photoCORMs based on micelle-encapsulated unsaturated cyclic alpha diketones were designed and synthesized. These photoCORMs can be activated by visible light, have potentially low toxicity, allow the delivery of carbon monoxide to be monitored by fluorescence imaging techniques, and thus are useful tools for the study of the biological function of CO. PMID- 23943039 TI - Laparoendoscopic single-site surgery in gynecology: a review of the literature, tools, and techniques. AB - Recent decades have witnessed a tremendous shift from laparotomy to laparoscopy as the surgical approach of choice in gynecology. Completion of increasingly complicated procedures has been facilitated by technical advances in instrumentation. Lately, increasing attention has been paid to reducing both the number and size of laparoscopic incisions, with the ultimate goal being the absence of any visible scar. Laparoendoscopic single-site surgery (LESS), or single-incision laparoscopy, describes the use of 1 small skin incision to complete laparoscopic surgical procedures where traditionally multiple incisions were created. In addition to examining the developing literature related to LESS in gynecology, the aims of this review were to describe the technical challenges encountered during performance of LESS and to provide practical solutions for instrumentation and surgical techniques that allow them to be overcome. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to identify potential benefits of LESS, and implement practical solutions for instrumentation and surgical techniques to overcome technical challenges faced during LESS. PMID- 23943040 TI - Role of complementary and alternative medicine to achieve fertility in uninsured patients. AB - Among those facing infertility in the United States, underinsured and uninsured women are at the greatest disadvantage. Women who receive medical care under Medicaid are rarely covered for infertility testing; only 4 states will cover infertility treatment as an element of family planning and preconception care. Studies exploring the use of complementary and alternative medicine (CAM) in infertility patients have focused on patients who have insurance. We conducted a review of the literature via MEDLINE. Articles were limited to English-language, human studies published between 1990 and 2011. Significant disparities exist in access to infertility treatment based on race and ethnicity, household income, and level of education, even in states with mandated insurance coverage. Given the steep costs of assisted reproductive technologies, many infertility patients augment traditional medical treatment with CAM. Acupuncture and herbal supplements are the most studied therapies. Although dietary supplementsmay enhance fertility, the use of othermore expensive forms of CAM such as acupuncture has had mixed results. Complementary and alternative medicine may be a viable option for infertility care for uninsured patients who cannot otherwise afford treatment. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to analyze the effects that health care disparities have on fertility treatments for uninsured and underinsured women and evaluate the literature to determine which complementary and alternative treatments for infertility can improve fertility. PMID- 23943041 TI - Eating disorders during pregnancy. AB - Eating disorders during pregnancy, once thought to be rare, occur in a significant number of women. The incidences of the major eating disorders anorexia nervosa and bulimia nervosa-are increasing because of cultural pressures on the drive for thinness. Because the age range for these major eating disorders overlaps with the age range for reproductive function, it is not unusual for a clinician to encounter a pregnant patient with a major eating disorder. Eating disorders attributable to the pregnant state include pregnancy sickness, pica, and ptyalism. The diagnostic criteria, etiology, nutritional behavioral influences, evolutionary psychological considerations where elucidated, and treatment of these disorders will be presented. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to review how the major eating disorders impact pregnancy, to diagnose eating disorders during pregnancy using the diagnostic criteria, and to treat eating disorders during pregnancy. PMID- 23943044 TI - Chemical profiling of deoxyhypusine hydroxylase inhibitors for antimalarial therapy. AB - A first approach to discover new antimalarials has been recently performed in a combined approach with data from GlaxoSmithKline Tres Cantos Antimalarial Set, Novartis-GNF Malaria Box Data set and St. Jude Children's Research Hospital. These data are assembled in the Malaria Box. In a first phenotypic forward chemical genetic approach, 400 chemicals were employed to eradicate the parasite in the erythrocytic stages. The advantage of phenotypic screens for the identification of novel chemotypes is that no a priori assumptions are made concerning a fixed target and that active compounds inherently have cellular bioavailability. In a first screen 40 mostly heterocyclic, highly active compounds (in nmol range of growth inhibition) were identified with EC50 values <=2 MUM against chloroquine-resistant Plasmodium falciparum strains and a therapeutic window >=10 against two mammalian cell lines. 78 % of the compounds had no violations with the Lipinski Rule of 5 and only 1 % of the compounds showed cytotoxicity when applied at concentrations of 10 MUM. This pre-selective step of parasitic eradication will be used further for a test of the Malaria Box with a potential in iron chelating capacity to inhibit deoxyhypusine hydroxylase (DOHH) from P. falciparum and vivax. DOHH, a metalloprotein which consists of ferrous iron and catalyzes the second step of the posttranslational modification at a specific lysine in eukaryotic initiation factor 5A (EIF-5A) to hypusine. Hypusine is a novel, non-proteinogenic amino acid, which is essential in eukaryotes and for parasitic proliferation. DOHH seems to be a "druggable" target, since it has only 26 % amino acid identity to its human orthologue. For a High-throughput Screening (HTS) of DOOH inhibitors, rapid and robust analytical tools are a prerequisite. A proteomic platform for the detection of hypusine metabolites is currently established. Ultra performance Liquid Chromatography enables the detection of hypusine metabolites with retention times of 7.4 min for deoxyhypusine and 7.3 min for hypusine. Alternatively, the analytes can be detected by their masses with gas chromatography/mass spectrometry or one dimensional chromatography coupled to mass spectrometry. Moreover, the identified hits will be tracked further to test their efficacy in novel "in vitro assays". Subsequently in vivo inhibition in a humanized mouse model will be tested. PMID- 23943042 TI - Elephant trunk technique for hybrid aortic arch repair. AB - The original elephant trunk technique was developed by Borst in 1983 for the treatment of aortic arch aneurysms. This technique reduced operative risks, but was associated with cumulative mortality rates of 6.9 % for the first stage and 7.5 % for the second stage. Patients also waited a long time between two major surgical procedures. Only 50.4 % of patients underwent the second-stage surgery, and there was a significant interval mortality rate of 10.7 %. With the advent of stent-graft techniques, two different hybrid elephant trunk techniques were developed. One technique is first-stage elephant trunk graft placement followed by second-stage endovascular completion. The conventional elephant trunk graft provides a good landing zone for the stent-graft, and endovascular completion is a useful alternative to conventional second-stage surgery. This method has few major complications, and a postoperative paraplegia rate of 1.1 %. The other technique is the frozen elephant trunk technique. This technique eliminates the need for subsequent endovascular completion, and is particularly useful for the treatment of acute type A dissection because it can achieve a secure seal. However, it is associated with a higher rate of spinal cord ischemia than other methods such as the original elephant trunk technique. The left subclavian artery (LSA) is often lost when performing a hybrid elephant trunk procedure. Revascularization of the LSA should be performed to prevent arm ischemia and neurological complications such as paraplegia or stroke, although the level of evidence for this recommendation is low. PMID- 23943045 TI - Squaring the cube: a family of octametallic lanthanide complexes including a Dy8 single-molecule magnet. AB - A series of isostructural octanuclear lanthanide complexes of general formula [Ln8(sao)4(MU3-OH)4(NO3)12(DMF)12] (Ln = Nd (), Sm (), Eu (), Gd (), Tb (), Dy (), Ho (), Er (); DMF = dimethylformamide) have been prepared via reactions of salicylaldoxime (saoH2), tetramethylammonium hydroxide (Me4NOH) with the appropriate lanthanide nitrate salt (Ln(NO3)3.6H2O). The metallic skeletons of the complexes describe [Ln4] tetrahedra encapsulated inside a [Ln4] square with the inner core stabilised through MU3-OH(-) ions and the periphery by MU4-sao(2-) ligands. The magnetic properties of compounds were investigated by dc and ac magnetometry. Temperature dependent ac magnetic susceptibility data reveal that the dysprosium analogue () displays an out-of-phase signal in the absence of an applied magnetic field indicative of slow relaxation of the magnetization typical of a Single-Molecule Magnet (SMM). Micro-SQUID measurements reveal temperature and sweep rate dependent hysteresis below 1.0 K. PMID- 23943043 TI - Oral administration of MSG increases expression of glutamate receptors and transporters in the gastrointestinal tract of young piglets. AB - Glutamate receptors and transporters, including T1R1 and T1R3 (taste receptor 1, subtypes 1 and 3), mGluRs (metabotropic glutamate receptors), EAAC-1 (excitatory amino acid carrier-1), GLAST-1 (glutamate-aspartate transporter-1), and GLT-1 (glutamate transporter-1), are expressed in the gastrointestinal tract. This study determined effects of oral administration of monosodium glutamate [MSG; 0, 0.06, 0.5, or 1 g/kg body weight (BW)/day] for 21 days on expression of glutamate receptors and transporters in the stomach and jejunum of sow-reared piglets. Both mRNA and protein levels for gastric T1R1, T1R3, mGluR1, mGluR4, EAAT1, EAAT2, EAAT3, and EAAT4 and mRNA levels for jejunal T1R1, T1R3, EAAT1, EAAT2, EAAT3 and EAAT4 were increased (P < 0.05) by MSG supplementation. Among all groups, mRNA levels for gastric EAAT1, EAAT2, EAAT3, and EAAT4 were highest (P < 0.05) in piglets receiving 1 g MSG/kg BW/day. EAAT1 and EAAT2 mRNA levels in the stomach and jejunum of piglets receiving 0.5 g MSG/kg BW/day, as well as jejunal EAAT3 and EAAT4 mRNA levels in piglets receiving 1 g MSG/kg BW/day, were higher (P < 0.05) than those in the control and in piglets receiving 0.06 g MSG/kg BW/day. Furthermore, protein levels for jejunal T1R1 and EAAT3 were higher (P < 0.05) in piglets receiving 1 g MSG/kg BW/day than those in the control and in piglets receiving 0.06 g MSG/kg BW/day. Collectively, these findings indicate that dietary MSG may beneficially stimulate glutamate signaling and sensing in the stomach and jejunum of young pigs, as well as their gastrointestinal function. PMID- 23943046 TI - Effect of surfactants and identification of metabolites on the biodegradation of fluoranthene by basidiomycetes fungal isolate Armillaria sp. F022. AB - The effects of structure and concentration of surfactants on the biodegradation of fluoranthene, a three rings polycyclic aromatic hydrocarbon in the aqueous phase, as well as their effects on the biodegradation and enzyme activity were investigated. The toxicity ranking of studied surfactants is: non-ionic Tween 80 4,500 mg/L) was showed by Tween 80 (10 mg/L) culture, manifesting that the non-ionic surfactant present in the culture were beneficial to the fungal growth. Laccase showed the highest enzymes activity in all surfactants culture. Non-ionic Tween 80 showed a significant result for laccase activity (1,902 U/L) in the Armillaria sp. F022 culture. The increased enzymes cumulative activity may stem directly from the rising fluoranthene biodegradability as addition of appropriate surfactants. The biotransformation of fluoranthene was greatly improved by Tween 80, and totally fluoranthene degradation was obtained as Tween 80 was 10 mg/L. Two fluoranthene metabolites were isolated from the culture medium and analyzed by a thin layer chromatography, UV visible spectrometer and gas chromatography-mass spectrometry (GC-MS). The oxidation of fluoranthene is initiated by oxygenation at the C-2,3 positions resulting 9-fluorenone. At the end of experiment, one metabolite was detected in the culture extract and identified as phthalic acid. Evidently, Armillaria sp. F022 seems efficient, high effective and deserves further application on the enhanced bioremediation technologies for the treatment of fluoranthene-contaminated soil. PMID- 23943047 TI - Screening of phytase producers and optimization of culture conditions for submerged fermentation. AB - Phytase (myo-inositol-hexakisphosphate phosphohydrolase) is an enzyme, which breaks down phytate to inositol and orthophosphoric acid. Phytase has been used as feed additive, and in some medical applications for years. To date, phytase production has been usually performed as a solid-state fermentation with small production volumes. Therefore, the aim of this study was to increase the phytase activity in submerged fermentations by screening several microorganism strains based on the literature to select the most productive phytase producer and optimizing growth parameters such as temperature, pH, and aeration level using response surface methodology (RSM). As a result, among the four different microorganisms evaluated, Aspergillus ficuum (NRRL 3135) was selected as the most productive strain. Optimum temperature, pH, and aeration values were determined as 33 degrees C, 4.5, and 0.9 vvm, respectively, for A. ficuum in 2-l batch submerged phytase productions. Under these conditions, phytase activity was measured as 2.27 U/ml. Therefore, this is a unique study showing the production of phytase with A. ficuum successfully in submerged fermentation as opposed to the traditional solid-state fermentation. PMID- 23943048 TI - Elicitation and in situ adsorption enhanced secondary metabolites production of Tripterygium wilfordii Hook. f. adventitious root fragment liquid cultures in shake flask and a modified bubble column bioreactor. AB - The experiments of elicitation and in situ adsorption were conducted in shake flasks and then tested in a modified bubble column bioreactor for enhancing the productions of three active metabolites in Tripterygium wilfordii Hook. f., triptolide, wilforgine and wilforine. Methyl jasmonate was screened out as the elicitor and the non-ionic polymeric ion-exchange resin of Amberlite((r)) XAD-7 was used for in situ product removal and protecting the alkaloids from degradation in the medium. In shake flask experiments, 3.55-fold, 49.11-fold, and 10.40-fold of triptolide, wilforgine, and wilforine, respectively, could be recovered from the medium and XAD-7 resin by elicitation and in situ product removal, compared with the control. The modified 10 L bubble column bioreactor had similar productions of the three active metabolites but needed a further optimization of parameters for better growth of adventitious roots. PMID- 23943049 TI - Pre- and/or postsurgical administration of estradiol benzoate increases rates of skin flap viability in female rats. PMID- 23943050 TI - The "PIP problem": clinical and histologic characteristics. AB - Implants from Poly Implant Prothese (PIP), the French manufacturer, showed increased risk of implant rupture and silicone leakage through the shell. Concerns also exist about the potential irritant behavior of silicone gel filler in these implants. This report presents the clinical, histologic, and microbiologic characteristics of a capsule and a siliconoma from a patient with a ruptured PIP implant. A 41-year-old woman submitted to breast augmentation in 2005 with PIP silicone gel implants presented with a recent history of progressive asymmetric breast enlargement and an enlarged lymph node on her right axilla. No capsular contracture was observed. A breast ultrasonography showed intra- and extracapsular ruptures of the right implant. The woman underwent explantation. Histologic analysis of the breast capsules showed a thin capsule with a chronic, mild inflammatory response. Microbiologic analysis showed no bacterial agent. The irritant behavior of the PIP silicone gel previously described was not able to produce capsular contracture or an exuberant inflammatory reaction. Studies to evaluate the potential risks of the silicone gel and to define the hazards for women implanted with those prostheses are urgently needed. PMID- 23943051 TI - Stiffness, compliance, resilience, and creep deformation: understanding implant soft tissue dynamics in the augmented breast: fundamentals based on materials science. AB - BACKGROUND: Postoperative tissue stretch deformities are among the possible complications in breast augmentation. These deformities are responsible for many potential risks such as bottoming-out deformity, breakdown of the inframammary fold, permanent tissue atrophy, sensory loss, and breast distortion (visible implant edges and traction rippling), among others. Although the elastic properties of the breast are a major concern for plastic surgeons, concepts such as stiffness, compliance, elasticity, and resilience have not been sufficiently defined or explored in the plastic surgery literature. METHODS: Similar to any other material, living tissues are subject to the fundamentals of the mechanics of materials. Based on their experience with more than 5,000 breast augmentations, the authors explored the basic fundamentals of the mechanics of materials in search of a rational explanation for long-term results in breast augmentation and augmentation-mastopexy. RESULTS: A basic law of the mechanics of materials determines that when a material (e.g., breast) is loaded with a force (e.g., implant), it produces a stress that causes the material to deform (e.g., breast augmentation), and this behavior might be graphed in a theoretical material's stress-stress curve. This deformation will increase with time although the load (implant) remains constant, a concept termed "creep deformation." Because the breast, like all human tissues, is a viscoelastic material, the application of concepts such as elastic and plastic deformation, stiffness, compliance, resilience, and creep deformation can and should be applied to breast augmentation surgery. CONCLUSIONS: The authors have found that the principles of the mechanics of materials can provide plastic surgeons with some clues for a predictable, long-lasting good result in breast augmentation and augmentation mastopexy. Future studies are needed to develop these concepts and evaluate how they might individually determine the mid- and long-term outcomes of augmented breasts. PMID- 23943052 TI - PXS-4681A, a potent and selective mechanism-based inhibitor of SSAO/VAP-1 with anti-inflammatory effects in vivo. AB - Semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1), is a member of the copper-dependent amine oxidase family that is associated with various forms of inflammation and fibrosis. To investigate the therapeutic potential of SSAO/VAP-1 inhibition, potent and selective inhibitors with drug-like properties are required. PXS-4681A [(Z)-4-(2-(aminomethyl)-3 fluoroallyloxy)benzenesulfonamide hydrochloride] is a mechanism-based inhibitor of enzyme function with a pharmacokinetic and pharmacodynamic profile that ensures complete, long-lasting inhibition of the enzyme after a single low dose in vivo. PXS-4681A irreversibly inhibits the enzyme with an apparent Ki of 37 nM and a kinact of 0.26 min(-1) with no observed turnover in vitro. It is highly selective for SSAO/VAP-1 when profiled against related amine oxidases, ion channels, and seven-transmembrane domain receptors, and is superior to previously reported inhibitors. In mouse models of lung inflammation and localized inflammation, dosing of this molecule at 2 mg/kg attenuates neutrophil migration, tumor necrosis factor-alpha, and interleukin-6 levels. These results demonstrate the drug-like properties of PXS-4681A and its potential use in the treatment of inflammation. PMID- 23943053 TI - Is there a sphingomyelin-based hydrogen bond barrier at the mammalian host schistosome parasite interface? AB - Schistosomes develop, mature, copulate, lay eggs, and live for years in the mammalian host bloodstream, importing nutrients across the tegument, but entirely impervious to the surrounding elements of the immune system. We have hypothesized that sphingomyelin (SM) in the parasite apical lipid bilayer is responsible for these sieving properties via formation of a tight hydrogen bond network with the surrounding water. Here we have used quasi-elastic neutron scattering for characterizing the diffusion of larval and adult Schistosoma mansoni and adult Schistosoma haematobium in the surrounding medium, under various environmental conditions. The results documented the presence of a hydrogen bond barrier around larvae and adult schistosomes. The hydrogen bond network readily collapses if worms are subjected to hypoxic conditions, likely via activation of the parasite tegument-associated neutral sphingomyelinase, and consequent excessive SM hydrolysis. The slower dynamics of lung-stage larvae as compared to adult worms has been related to the existence of hydrogen-bonded networks of different strength and then to their differential resistance to immune attacks. PMID- 23943054 TI - Oxidized low-density lipoprotein and C-reactive protein have combined utility for better predicting prognosis after acute coronary syndrome. AB - It has been shown that the elevated concentrations of oxidized low-density lipoprotein (Ox-LDL) or high-sensitivity C-reactive protein (hs-CRP) are predictive of future cardiovascular events for acute coronary syndrome (ACS) patients. But, the combined value of Ox-LDL and hs-CRP for predicting cardiovascular events is still unknown. Serum concentrations of Ox-LDL, hs-CRP, and cTnT were measured in a prospective cohort of 425 selective ACS patients followed 3-5 years for the occurrence of acute myocardial infarction (AMI) or death (AMI/death). Among 425 enrolled patients, 124 patients demonstrated AMI/death. Baseline levels of Ox-LDL, hs-CRP, and cTnT were significantly higher in AMI/death group than the event-free survival group. Kaplan-Meier survival analyses supported that elevations in Ox-LDL or hs-CRP predicted increased cardiovascular events risks. However, the strongest risk prediction was achieved by assessing Ox-LDL and hs-CRP together. Patients with high levels of Ox-LDL and hs-CRP were more likely to experience AMI or death than those with either Ox-LDL or hs-CRP elevated. Receiver-operating characteristic curves showed that Ox-LDL and hs-CRP have higher sensitivity and specificity than those of cTnT for predicting AMI or death. This was reflected by the AUC values for Ox-LDL, hs-CRP, and cTnT, which were 0.891, 0.834, and 0.626, respectively. The combined use of Ox-LDL and hs-CRP may improve prognosis after ACS with high-sensitivity and specificity. PMID- 23943055 TI - Delphinidin activates NFAT and induces IL-2 production through SOCE in T cells. AB - Delphinidin is an anthocyanidin that possesses antioxidant and anti-inflammatory effects; however, some reports suggest that delphinidin has pro-inflammatory properties. For this reason, we assessed the effect of delphinidin on cytokine production in T cells. We demonstrated that delphinidin increased the cytosolic free Ca(2+) concentration by releasing Ca(2+) from intracellular stores and increasing Ca(2+) entry. The putative Ca(2+) release activated Ca(2+) (CRAC) channel inhibitors BTP2 and gadolinium reduced the calcium entry stimulated by the anthocyanidin. Delphinidin induced nuclear factor of activated T cells (NFAT) translocation and NFAT-Luc activity in Jurkat cells and was dependent on the CRAC channel and calcineurin pathway. Delphinidin increased the mRNA expression and production of IL-2 in Jurkat cells and was inhibited by BTP2 and cyclosporine A. Using peripheral blood lymphocytes, we demonstrated that delphinidin increased the production of IL-2 and IFN-gamma and was inhibited by BTP2. Taken together, our results suggest that delphinidin exerts immunostimulatory effects on T cells by increasing cytokine production through CRAC channel and NFAT activation. PMID- 23943056 TI - The transcription factor SlSHINE3 modulates defense responses in tomato plants. AB - The cuticle plays an important role in plant interactions with pathogens and with their surroundings. The cuticle acts as both a physical barrier against physical stresses and pathogens and a chemical deterrent and activator of the plant defense response. Cuticle production in tomato plants is regulated by several transcription factors, including SlSHINE3, an ortholog of the Arabidopsis WIN/SHN3. Here we used a SlSHINE3-overexpressing (SlSHN3-OE) and silenced (Slshn3 RNAi) lines and a mutant in SlCYP86A69 (Slcyp86A69)--a direct target of SlSHN3- to analyze the roles of the leaf cuticle and cutin content and composition in the tomato plant's defense response to the necrotrophic foliar pathogen Botrytis cinerea and the biotrophic bacterial pathogen Xanthomonas campestris pv. vesicatoria. We showed that SlSHN3, which is predominantly expressed in tomato fruit epidermis, also affects tomato leaf cuticle, as morphological alterations in the SlSHN3-OE leaf tissue resulted in shiny, stunted and permeable leaves. SlSHN3-OE leaves accumulated 38% more cutin monomers than wild-type leaves, while Slshn3-RNAi and Slcyp86A69 plants showed a 40 and 70% decrease in leaf cutin monomers, respectively. Overexpression of SlSHN3 resulted in resistance to B. cinerea infection and to X. campestris pv. vesicatoria, correlated with cuticle permeability and elevated expression of pathogenesis-related genes PR1a and AOS. Further analysis revealed that B. cinerea-infected Slshn3-RNAi plants are more sensitive to B. cinerea and produce more hydrogen peroxide than wild-type plants. Cutin monomer content and composition differed between SlSHN3-OE, Slcyp86A69, Slshn3-RNAi and wild-type plants, and cutin monomer extracted from SlSHN3-OE plants altered the expression of pathogenesis-related genes in wild-type plants. PMID- 23943057 TI - Adding intelligence to mobile asset management in hospitals: the true value of RFID. AB - RFID (Radio Frequency Identification) technology is expected to play a vital role in the healthcare arena, especially in times when cost containments are at the top of the priorities of healthcare management authorities. Medical equipment represents a significant share of yearly healthcare operational costs; hence, ensuring an effective and efficient management of such key assets is critical to promptly and reliably deliver a diversity of clinical services at the patient bedside. Empirical evidence from a phased-out RFID implementation in one European hospital demonstrates that RFID has the potential to transform asset management by improving inventory management, enhancing asset utilization, increasing staff productivity, improving care services, enhancing maintenance compliance, and increasing information visibility. Most importantly, RFID allows the emergence of intelligent asset management processes, which is, undoubtedly, the most important benefit that could be derived from the RFID system. Results show that the added intelligence can be rather basic (auto-status change) or a bit more advanced (personalized automatic triggers). More importantly, adding intelligence improves planning and decision-making processes. PMID- 23943058 TI - [Lateral ligament injuries of the ankle joint]. AB - Lateral ligament injuries are the most common sports injury and have a high incidence even in non-sportive activities. Although lateral ligament injuries are very common there is still a controversial debate on the best management. The diagnosis is based on clinical examination and X-ray images help to rule out fractures. Further imaging, especially magnetic resonance imaging (MRI) is used to diagnose associated injuries. According to the recommendations of the various scientific societies the primary therapy of lateral ligament injuries is conservative. Chronic ankle instability develops in 10-20 % of patients and the instability can be a result of sensomotoric deficits or insufficient healing of the lateral ligament complex. If the patient does not respond to an intensive rehabilitation program an operative reconstruction of the lateral ligaments has to be considered. Most of the procedures currently performed are anatomical reconstructions due to better long-term results compared to tenodesis procedures. PMID- 23943059 TI - [The posterior malleolus or Volkmann's triangle: coming to terms with the past]. AB - Having observed Nelsons and Jensen's rule for the fixation of the posterior malleolus in ankle fractures for over 70 years recent studies have shown that this dogma might have its limitations. Today no one can determine with absolute conviction what to do with this controversial fragment. To fix it operatively means to follow some strict surgical procedures (e.g. anatomy, approach and placement of implants). These guidelines are presented, the indications for fixation are discussed and the prognosis for these difficult fractures is outlined. PMID- 23943061 TI - Impact of stress hormone on adipogenesis in the 3T3-L1 adipocytes. AB - Stress hormone is known to play a vital role in lipolysis and adipogenesis in fat cells. The present study was carried out to evaluate the effect of epinephrine on adipogenesis in the 3T3-L1 cells. The investigation on adipogenesis was done in both mono and co-cultured 3T3-L1 cells. 3T3-L1 preadipocytes and C2C12 cells were grown independently on transwell plates and transferred to differentiation medium. Following differentiation, C2C12 cells transferred to 3T3-L1 plate and treated with medium containing 10 MUg/ml of epinephrine. Adipogenic markers such as fatty acid binding protein 4, peroxisome proliferator activating receptor, CCAAT/enhancer-binding protein, adiponectin, lipoprotein lipase and fatty acid synthase mRNA expressions were evaluated in the 3T3-L1 cells. Epinephrine treatment reduced adipogenesis, evidenced by reducing adipogenic marker mRNA expression in the 3T3-L1 cells. In addition, glycerol accumulation and oil red-O staining supported the reduced rate of adipogenesis. Taking all together, it is concluded that the stress hormone, epinephrine reduces the rate of adipogenesis in the mono and co-cultured 3T3-L1 cells. In addition, the rate of adipogenesis is much reduced in the co-cultured 3T3-L1 cells compared monocultured 3T3-L1 cells. PMID- 23943062 TI - Mineralized collagen coatings formed by electrochemical deposition. AB - Understanding and controlling the process of electrochemical deposition (ECD) of a mineralized collagen coating on metallic orthopedic implants is important for engineering highly bioactive coatings. In this work, the influence of different ECD parameters was investigated. The results showed that the mineralization degree of the coatings increased with deposition time, voltage potential and H2O2 addition, while chitosan addition led to weakening of mineralization, heavy mineralization resulted in a porous coating morphology. Furthermore, two typical coatings, dense and porous, were analyzed to investigate their microstructure and evaluated for their cytocompatibility; the dense coating showed better osteoblast adhesion and proliferation. Based on our understanding of how the different coating parameters influenced the coating, we proposed an ECD process in which the pH gradient near the cathode and the collagen isoelectric point were suggested to play crucial roles in controlling the mineralization and morphology of the coatings. The proposed ECD process may offer a guide for controlled deposition of a desired bioactive coating. PMID- 23943063 TI - Cost implications of the physiotherapy management of complex tibial fractures treated with circular frames. AB - Seventy-three consecutive patients with complex tibial fractures treated with an Ilizarov frame or Taylor Spatial Frame received physiotherapy between April 2008 and April 2010. Data were collected prospectively, and physiotherapy input was recorded (in minutes) for the patients identified. This included treatment received as an inpatient as well as an outpatient. The data were categorized for proximal, middle and distal third tibial fractures for analysis. The average cost of physiotherapy for an inpatient with an Ilizarov frame is L121.82 per case, whereas that for an outpatient receiving treatment for trauma was calculated as L404.60. The combined average cost of physiotherapy to support treatment of a complex tibial fracture with a fine wire fixator is L546.27. Treatment involving circular frames is complex and expensive, and the high physiotherapy cost is not reflected in Healthcare Resource Group codes. This cost calculation will help service units, and NHS Trusts develop realistic costing plans to support treatment. Cost implications of the physiotherapy management of complex tibial fractures using the Ilizarov technique. PMID- 23943064 TI - Occurrence of Human Cosavirus in Wastewater and River Water in Japan. AB - Human cosavirus was detected using reverse transcription-quantitative polymerase chain reaction in 71 % of raw sewage and 29 % each of secondary-treated sewage and river water samples in the Kofu Basin, Japan. The highest concentration was 2.80 * 10(6) copies/l. Nucleotide sequence analysis revealed multiple genotypes of the virus in wastewater. PMID- 23943065 TI - GIV Noroviruses in Wastewaters and in Stool Specimens from Hospitalized Patients. AB - Noroviruses (NoVs) are important human pathogens associated with foodborne and waterborne gastroenteritis. These viruses are genetically highly heterogeneous, with more than forty genotypes within three genogroups (GI, GII, and GIV) identified in humans. However, the vast majority of human infections are associated with variants of a unique genotype, GII.4. Aside from these NoV strains of epidemiological relevance, NoV strains of genogroup GIV (Alphatron like) are reported in a sporadic fashion and their overall prevalence in the community is unknown and this likely reflects the lack of specific diagnostic tools. We analyzed raw sewages collected from 32 wastewater treatment plants distributed throughout Italy (307 samples) and stool specimens collected from hospitalized patients with clinical signs of diarrhea of unknown etiology (285 samples). By using specific qualitative and quantitative RT-PCR assays, 21.8 % of the sewage samples and 3.2 % of the stool specimens tested positive for GIV NoVs. The number of genome copies in fecal samples ranged from 5.08 * 104 to 1.73* 106/g of feces. Sequence analysis showed limited genetic variability in human GIV viruses. The presence of GIV NoV both in sewage and in clinical samples confirms that not only GI and GII NoVs but also GIV strains are circulating in humans. Monitoring of GIV NoV is recommended in order to understand the dynamics of circulation in human populations, environmental contamination, and potential health risks. PMID- 23943067 TI - Unicystic ameloblastoma presenting in Gardner's syndrome. PMID- 23943066 TI - Primary paraganglioma of thyroid gland: a clinicopathologic and immunohistochemical analysis of three cases with a review of the literature. AB - Thyroid paraganglioma is an extremely rare tumor and frequently mistaken for other thyroid neoplasms. Increased awareness of its potential presentation in thyroid and its characteristic features is essential for avoiding diagnostic and therapeutic pitfalls. We describe here three additional cases of primary thyroid paraganglioma and analyze their clinical findings and pathological characteristics. Patients included two women and one man presenting with asymptomatic thyroid nodules. Radiological examinations were nonspecific and none had been diagnosed correctly before surgery. On intraoperative frozen section consultation they were all misdiagnosed as carcinomas, either primary or metastatic. However, the permanent sections showed features consistent with paraganglioma. Of note, two cases displayed extension into adjacent thyroid tissues, one of which exhibited increased mitotic activity, confluent tumor necrosis and vascular invasion. Immunohistochemically, the neoplastic chief cells expressed chromogranin, synaptophysin, neuron-specific enolase and CD56, whereas the sustentacular cells were highlighted by S100 protein. All three patients were well with normal hormone secretion, without local recurrence or distant metastasis at last follow-up (range 10-47 months). We further reviewed the literature to summarize the characteristics of this distinctive entity. Albeit being very rare, paraganglioma should be included in the differential diagnosis of hypervascular thyroidal neoplasms. Accurate diagnosis relies on the histopathogical findings and adjunctive immunohistochemcial studies. To date, all the reported cases have pursued a benign course. Although atypical features seem to have no association with clinical behavior, long time postoperative surveillance with biochemical screening of hormone secretion, cervical ultrasonography and whole-body CT scan is recommended. PMID- 23943068 TI - A new model for graduate education and innovation in medical technology. AB - We describe a new model of graduate education in bioengineering innovation and design- a year long Master's degree program that educates engineers in the process of healthcare technology innovation for both advanced and low-resource global markets. Students are trained in an iterative "Spiral Innovation" approach that ensures early, staged, and repeated examination of all key elements of a successful medical device. This includes clinical immersion based problem identification and assessment (at Johns Hopkins Medicine and abroad), team based concept and business model development, and project planning based on iterative technical and business plan de-risking. The experiential, project based learning process is closely supported by several core courses in business, design, and engineering. Students in the program work on two team based projects, one focused on addressing healthcare needs in advanced markets and a second focused on low resource settings. The program recently completed its fourth year of existence, and has graduated 61 students, who have continued on to industry or startups (one half), additional graduate education, or medical school (one third), or our own Global Health Innovation Fellowships. Over the 4 years, the program has sponsored 10 global health teams and 14 domestic/advanced market medtech teams, and launched 5 startups, of which 4 are still active. Projects have attracted over US$2.5M in follow-on awards and grants, that are supporting the continued development of over a dozen projects. PMID- 23943069 TI - Chemical tools for temporally and spatially resolved mass spectrometry-based proteomics. AB - Accurate measurements of the abundances, synthesis rates and degradation rates of cellular proteins are critical for understanding how cells and organisms respond to changes in their environments. Over the past two decades, there has been increasing interest in the use of mass spectrometry for proteomic analysis. In many systems, however, protein diversity as well as cell and tissue heterogeneity limit the usefulness of mass spectrometry-based proteomics. As a result, researchers have had difficulty in systematically identifying proteins expressed within specified time intervals, or low abundance proteins expressed in specific tissues or in a few cells in complex microbial systems. In this review, we present recently-developed tools and strategies that probe these two subsets of the proteome: proteins synthesized during well-defined time intervals--temporally resolved proteomics--and proteins expressed in predetermined cell types, cells or cellular compartments--spatially resolved proteomics--with a focus on chemical and biological mass spectrometry-based methodologies. PMID- 23943070 TI - Cellularized microcarriers as adhesive building blocks for fabrication of tubular tissue constructs. AB - To meet demands of vascular reconstruction, there is a need for prosthetic alternatives to natural blood vessels. Here we explored a new conduit fabrication approach. Macroporous, gelatin microcarriers laden with human umbilical vein endothelial cells and aortic smooth muscle cells were dispensed into tubular agarose molds and found to adhere to form living tubular tissues. The ability of cellularized microcarriers to adhere to one another involved cellular and extracellular matrix bridging that included the formation of epithelium-like cell layers lining the lumenal and ablumenal surfaces of the constructs and the deposition of collagen and elastin fibers. The tubular tissues behaved as elastic solids, with a uniaxial mechanical response that is qualitatively similar to that of native vascular tissues and consistent with their elastin and collagen composition. Linearized measures of the mechanical response of the fabricated tubular tissues at both low and high strains were observed to increase with duration of static culture, with no significant loss of stiffness following decellularization. The findings highlight the utility of cellularized macroporous gelatin microcarriers as self-adhering building blocks for the fabrication of living tubular structures. PMID- 23943072 TI - Dysphagia, short-term outcomes, and cost of care after anterior cervical disc surgery. AB - Dysphonia and dysphagia are common complications of anterior cervical discectomy (ACD). We sought to determine the relationship between dysphagia and in-hospital mortality, complications, speech therapy/dysphagia training, length of hospitalization, and costs associated with ACD. Discharge data from the Nationwide Inpatient Sample for 1,649,871 patients who underwent ACD of fewer than four vertebrae for benign acquired disease between 2001 and 2010 were analyzed using cross-tabulations and multivariate regression modeling. Dysphagia was reported in 32,922 cases (2.0 %). Speech therapy/dysphagia training was reported in less than 0.1 % of all cases and in only 0.2 % of patients with dysphagia. Dysphagia was significantly associated with age >=65 years (OR = 1.5 [95 % CI 1.4-1.7], P < 0.001), advanced comorbidity (OR = 2.3 [2.0-2.6], P < 0.001), revision surgery (OR = 2.7 [2.3-3.1], P < 0.001), disc prosthesis placement (OR = 1.5 [1.0-2.0], P = 0.029), and vocal cord paralysis (OR = 11.6 [8.3-16.1], P < 0.001). Dysphagia was a significant predictor of aspiration pneumonia (OR = 8.6 [6.7-10.9], P < 0.001), tracheostomy (OR = 2.3 [1.6-3.3], P < 0.001), gastrostomy (OR = 30.9 [25.3-37.8], P < 0.001), and speech therapy/dysphagia training (OR = 32.0 [15.4-66.4], P < 0.001). Aspiration pneumonia was significantly associated with in-hospital mortality (OR = 15.9 [11.0-23.1], P < 0.001). Dysphagia, vocal cord paralysis, and aspiration pneumonia were significant predictors of increased length of hospitalization and hospital-related costs, with aspiration pneumonia having the single largest impact on length of hospitalization and costs. Dysphagia is significantly associated with increased morbidity, length of hospitalization, and hospital related costs in ACD patients. Despite the known risk of dysphagia in ACD patients and an established role for the speech-language pathologist in dysphagia management, speech-language pathology intervention appears underutilized in this population. PMID- 23943071 TI - A mechatronic system for quantitative application and assessment of massage-like actions in small animals. AB - Massage therapy has a long history and has been widely believed effective in restoring tissue function, relieving pain and stress, and promoting overall well being. However, the application of massage-like actions and the efficacy of massage are largely based on anecdotal experiences that are difficult to define and measure. This leads to a somewhat limited evidence-based interface of massage therapy with modern medicine. In this study, we introduce a mechatronic device that delivers highly reproducible massage-like mechanical loads to the hind limbs of small animals (rats and rabbits), where various massage-like actions are quantified by the loading parameters (magnitude, frequency and duration) of the compressive and transverse forces on the subject tissues. The effect of massage is measured by the difference in passive viscoelastic properties of the subject tissues before and after mechanical loading, both obtained by the same device. Results show that this device is useful in identifying the loading parameters that are most conducive to a change in tissue mechanical properties, and can determine the range of loading parameters that result in sustained changes in tissue mechanical properties and function. This device presents the first step in our effort for quantifying the application of massage-like actions used clinically and measurement of their efficacy that can readily be combined with various quantitative measures (e.g., active mechanical properties and physiological assays) for determining the therapeutic and mechanistic effects of massage therapies. PMID- 23943075 TI - Effect of nutrient management planning on crop yield, nitrate leaching and sediment loading in Thomas Brook watershed. AB - Government priorities on provincial Nutrient Management Planning (NMP) programs include improving the program effectiveness for environmental quality protection, and promoting more widespread adoption. Understanding the effect of NMP on both crop yield and key water-quality parameters in agricultural watersheds requires a comprehensive evaluation that takes into consideration important NMP attributes and location-specific farming conditions. This study applied the Soil and Water Assessment Tool (SWAT) to investigate the effects of crop and rotation sequence, tillage type, and nutrient N application rate on crop yield and the associated groundwater [Formula: see text] leaching and sediment loss. The SWAT model was applied to the Thomas Brook Watershed, located in the most intensively managed agricultural region of Nova Scotia, Canada. Cropping systems evaluated included seven fertilizer application rates and two tillage systems (i.e., conventional tillage and no-till). The analysis reflected cropping systems commonly managed by farmers in the Annapolis Valley region, including grain corn-based and potato based cropping systems, and a vegetable-horticulture system. ANOVA models were developed and used to assess the effects of crop management choices on crop yield and two water-quality parameters (i.e., [Formula: see text] leaching and sediment loading). Results suggest that existing recommended N-fertilizer rate can be reduced by 10-25 %, for grain crop production, to significantly lower [Formula: see text] leaching (P > 0.05) while optimizing the crop yield. The analysis identified the nutrient N rates in combination with specific crops and rotation systems that can be used to manage [Formula: see text] leaching while balancing impacts on crop yields within the watershed. PMID- 23943076 TI - Understanding triangulation in research. PMID- 23943073 TI - Risk factors for false-negative results of T-SPOT.TB and tuberculin skin test in extrapulmonary tuberculosis. AB - PURPOSE: T-SPOT.TB, a recently developed T cell-based assay, has shown promise in diagnosing extrapulmonary tuberculosis (EPTB). However, a limited number of reports have compared the risk factors for false-negative results of tuberculin skin tests (TSTs) and T-SPOT.TB assays in patients with EPTB. We, thus, conducted a prospective, blinded, observational study to evaluate the risk factors for false-negative T-SPOT.TB and TST results in patients with EPTB. METHODS: Between April 2008 and November 2011, all adult patients with suspected EPTB were prospectively enrolled at Asan Medical Center, Seoul, South Korea (an intermediate TB-burden country). Only patients with confirmed and probable EPTB who underwent TST and T-SPOT.TB were included in the final analysis. RESULTS: Of the 324 patients who underwent both TST and T-SPOT.TB testing, 128 patients with 96 (75 %) culture- or polymerase chain reaction (PCR)-confirmed and 32 (25 %) probable EPTB were finally analyzed. T-SPOT.TB assays were less likely to yield false-negative results than TSTs [17 % (22/128) vs. 54 % (69/128), p < 0.001]. In a multivariate analysis, miliary TB was associated with false-negative TSTs [odds ratio (OR) = 5.3; 95 % confidence interval (CI) 1.7-16.1], while immunosuppression showed a trend toward false-negative TSTs (OR = 2.5; 95 % CI 0.9-6.8). Conversely, lymph node TB (OR = 0.2; 95 % CI 0.1-0.5) and skeletal TB (OR = 0.2; 95 % CI 0.1-0.5) were associated with true-positive TST results. The only risk factor for false-negative T-SPOT.TB results was TB meningitis (OR = 2.6; 95 % CI 1.0-6.6). CONCLUSIONS: Our findings suggest that T-SPOT.TB has a better sensitivity to diagnose EPTB than TST, especially in patients with immunosuppression or miliary TB. PMID- 23943077 TI - [Changes of the psychogeriatric inpatient care at the University Psychiatric Hospitals in Basel following the constitution of an outpatient care service for the elderly]. AB - OBJECTIVE: 10-year follow-up of the psychogeriatric inpatient care at the University Psychiatric Hospitals Basel following the establishment of an outpatient care service for the elderly (ADA). METHOD: Standardized chart review of a random sample of psychogeriatric cases (>= 65 y) of the years 1997 and 2007 (n = 100 each) in terms of socio-demographic, diagnostic, therapeutic und administrative data. RESULTS: The number of patients with contact to both inpatient and outpatient services prior to admission increased. There was no change regarding the amount of unvoluntary admissions. As expected more complex cases were treated. The case management showed changes towards greater guideline conformity. CONCLUSION: The 10-year follow-up shows a better outpatient treatment and the provision of inpatient facilities for complex multimorbid and emergency patients. PMID- 23943078 TI - [Experience of loss and complicated grief in depressive inpatients]. AB - OBJECTIVE: Inpatients diagnosed with major depression that had lost a loved person were asked about loss-related variables and symptoms of complicated grief (CG). METHODS AND RESULTS: CG was assessed by the Inventory of Complicated Grief (ICG-R). 14.2% of n = 127 individuals with unipolar depression met the criteria for CG. Depressive patients with CG compared to those without CG had a lower educational level; reported a higher loss-related burden at the time of loss, during the survey and the year after the loss; had significant different closeness within the relationships to the deceased; and time of loss was more recently. CONCLUSIONS: An adequate differential diagnostic is essential for the treatment of major depression. Therefore loss-related factors and symptoms of complicated grief must be investigated regularly. PMID- 23943079 TI - Spatial patterns in wet and dry deposition of atmospheric mercury and trace elements in central Illinois, USA. AB - An intensive 1-month atmospheric sampling campaign was conducted concurrently at eight monitoring sites in central Illinois, USA, from June 9 to July 3, 2011 to assess spatial patterns in wet and dry deposition of mercury and other trace elements. Summed wet deposition of mercury ranged from 3.1 to 5.4 MUg/m(2) across sites for the total study period, while summed dry deposition of reactive mercury (gaseous oxidized mercury plus particulate bound mercury) ranged from 0.7 to 1.6 MUg/m(2), with no statistically significant differences found spatially between northern and southern sites. Ratios of summed wet to summed dry mercury deposition across sites ranged from 2.2 to 4.9 indicating that wet deposition of mercury was dominant during the study period. Volume-weighted mean mercury concentrations in precipitation were found to be significantly higher at northern sites, while precipitation depth was significantly higher at southern sites. These results showed that substantial amounts of mercury deposition, especially wet deposition, occurred during the study period relative to typical annual wet deposition levels. Summed wet deposition of anthropogenic trace elements was much higher, compared to summed dry deposition, for sulfur, selenium, and copper, while at some sites summed dry deposition dominated summed wet deposition for lead and zinc. This study highlights that while wet deposition of Hg was dominant during this spring/summer-season study, Hg dry deposition also contributed an important fraction and should be considered for implementation in future Hg deposition monitoring studies. PMID- 23943081 TI - Benefits to rare plants and highway safety from annual population reductions of a "native invader," white-tailed deer, in a Chicago-area woodland. AB - Overabundant white-tailed deer are one of the most serious threats to woodland plant communities in the Chicago area. Moreover, the abundant deer in a highly populated area causes economic harm and poses hazards to human safety through collisions with vehicles. The artificial conditions causing the overabundance and resulting consequences qualify the white-tailed deer in the Chicago area to be considered as "native invaders". We examined the benefits of culling deer at a Chicago-area woodland preserve by comparing browse rates on four endangered plant species from years before culling began with years with culling. We also examined deer-vehicle collision and traffic flow rates on area roads from years before culling began and years with culling to assess whether population reductions may have benefited road safety in the area. All four endangered plant species (three orchid species and sweet fern) had lower browse rates in years with culls, although the decreased browsing rates were statistically distinguishable for only two of the species (grass pink orchid and sweet fern). After first verifying that traffic flow rates did not decrease from pre-cull years to years with culls, we analyzed the Illinois Department of Transportation data from area roads based on deer-vehicle collisions causing >US$500 in damage and showed a one-third reduction in deer-vehicle collisions. An economic analysis showed a cost savings during the cull years of US$0.6 million for reducing browsing to just these four monitored plant species and the reduction in deer-vehicle collisions. PMID- 23943080 TI - Metal translocation patterns in Solanum melongena grown in close proximity to traffic. AB - The purpose of this study is to examine tissue patterns of metal (Cr, Ni, Cu, Cd, and Pb) concentrations in Solanum melongena cultivated in close proximity to traffic to help elucidate associated elemental deposition and soil-to-root and root-to-shoot transfers. Plants were cultivated in a commercial soil mix at three sites in Toronto, Canada. Metal concentrations were determined on microwave digested bulk and rhizosphere soil and tissue samples per ICP-MS, along with two standard reference materials (NIST #1570a and #2709a). Unwashed and washed S. melongena samples were also analyzed, along with Origanum vulgare plants from the same sites, to assess the effectiveness of washing in reducing metal concentrations. The tissue distribution of Cr, Ni, Cu, and Pb demonstrated variability as a function of traffic proximity. Copper was found to easily translocate to roots in soils susceptible to waterlogging, while Cd had the highest soil-to-root and root-to-shoot translocation. The translocation of Cd was highest at the roadside site, due to a greater relative enrichment of this metal in the rhizosphere of S. melongena plants. Washing O. vulgare leaves was more effective in removing metal-associated particles compared to S. melongena samples. Cadmium uptake is of greatest concern given its toxicity and translocation potential. PMID- 23943082 TI - Photocatalytic discoloration of Methyl Orange by anatase/schorl composite: optimization using response surface method. AB - The anatase/schorl composites were prepared and employed for the photocatalytic discoloration of an azo dye, Methyl Orange (MO). X-ray diffraction results indicated that TiO2 existed in the form of anatase phase and no diffraction peaks of schorl could be observed for all the composite samples. Scanning electron micrographs showed that the particles of anatase were well deposited and dispersed on the surface of schorl. Photocatalytic experiments revealed that the anatase/schorl composites exhibited higher photocatalytic activity for MO discoloration than pure TiO2 and more than 90% discoloration ratio could be obtained within 60 min UV irradiation when the sample containing 3 wt.% of schorl as TiO2 support was used. Then, the central composite design (CCD) under the response surface methodology (RSM) was employed for the experiment design and process optimization. The significance of a second-order polynomial model for predicting the optimal values of MO discoloration was evaluated by the analysis of variance (ANOVA) and 3D response surface plots for the interactions between two variables were constructed. Based on the model prediction, the optimum conditions for the photocatalytic discoloration of MO by TiO2/schorl composite were determined to be 15 * 10(-3) mM MO initial concentration, 2.7 g/l photocatalyst dosage, solution pH 6.6 and 43 min reaction time, with a maximum MO discoloration ratio of 98.6%. Finally, a discoloration ratio of 94.3% was achieved for the real sample under the optimum conditions, which was very close to the predicted value, implying that RSM is a powerful and satisfactory strategy for the process optimization. PMID- 23943083 TI - Differentiation of rabbit bone mesenchymal stem cells into endothelial cells in vitro and promotion of defective bone regeneration in vivo. AB - Tissue engineering strategies often fail to regenerate bones because of inadequate vascularization, especially in the reconstruction of large segmental bone defects. Large volumes of vascular endothelial cells (ECs) that functionally interact with osteoblasts during osteogenesis are difficult to obtain. In this study, we simulated bone healing by co-culturing differentiated ECs and mesenchymal stem cells (MSCs) either on a culture plate or on a polylactide glycolic acid (PLGA) scaffold in vitro. We also evaluated the effect of osteogenesis in repairing rabbit mandible defects in vivo. In this study, MSCs were separated from rabbit as the seed cells. After passage, the MSCs were cultured in an EC-conditioned medium to differentiate into ECs. Immunohistochemical staining analysis with CD34 showed that the induced cells had the characteristics of ECs and MSC. The induced ECs were co-cultured in vitro, and the induction of MSCs to osteoblast served as the control. Alkaline phosphatase (ALP) and alizarin red (AZR) staining experiments were performed, and the Coomassie brilliant blue total protein and ALP activity were measured. The MSCs proliferated and differentiated into osteoblast-like cells through direct contact between the derived ECs and MSCs. The co-cultured cells were seeded on PLGA scaffold to repair 1 cm mandible defects in the rabbit. The effectiveness of the repairs was assessed through soft X-ray and histological analyses. The main findings indicated that MSCs survived well on the scaffold and that the scaffold is biocompatible and noncytotoxic. The results demonstrated that the co-cultured MSC-derived ECs improved MSC osteogenesis and promoted new bone formation. This study may serve as a basis for the use of in vitro co-culturing techniques as an improvisation to bone tissue engineering for the repair of large bone defects. PMID- 23943084 TI - Resonance assignment for a particularly challenging protein based on systematic unlabeling of amino acids to complement incomplete NMR data sets. AB - NMR-based structure determination of a protein requires the assignment of resonances as indispensable first step. Even though heteronuclear through-bond correlation methods are available for that purpose, challenging situations arise in cases where the protein in question only yields samples of limited concentration and/or stability. Here we present a strategy based upon specific individual unlabeling of all 20 standard amino acids to complement standard NMR experiments and to achieve unambiguous backbone assignments for the fast precipitating 23 kDa catalytic domain of human aprataxin of which only incomplete standard NMR data sets could be obtained. Together with the validation of this approach utilizing the protein GB1 as a model, a comprehensive insight into metabolic interconversion ("scrambling") of NH and CO groups in a standard Escherichia coli expression host is provided. PMID- 23943085 TI - Identification of interleukin-1 beta, but no other inflammatory proteins, as an early onset pre-eclampsia biomarker in first trimester serum by bead-based multiplexed immunoassays. AB - OBJECTIVE: This study aimed to determine the predictive value of growth factors, cardiovascular, and immunological markers for first trimester identification of early onset pre-eclampsia (PE). METHODS: In a retrospective case-control study, maternal serum samples of 35 early onset PE cases and 35 controls were analysed by multiplexed immunoassays, to determine serum concentrations of 41 proteins whose functionality can be associated with PE pathogenesis. All levels were converted into multiples of the gestation-specific normal median. For prediction modelling, proteins that were found to be significant were combined with previously obtained values of three established PE markers, that is, placental growth factor, placental protein 13, and pregnancy-associated plasma protein A. Prediction modelling was used to determine predicted detection rates for 5% and 10% false-positive rates. RESULTS: Three of the proteins examined in this study, interleukin-1 beta (IL-1beta), fibrinogen, and carcinoembryonic antigen, showed significantly different serum levels at p < 0.05. In prediction modelling, only IL-1beta added predictive value to the three previously established biomarkers, by increasing detection from 38.2% to 44.1% at a 5% false-positive rate. CONCLUSIONS: This study indicates that IL-1beta has potential to improve first trimester prediction of pre-eclampsia. Studies on larger cohorts will be needed to validate these findings. PMID- 23943086 TI - Abstracts of the 61st Annual and Scientific Meeting of the Irish Gerontological Society. September 20-21, 2013. Dublin, Ireland. PMID- 23943087 TI - Enhancement of monoclonal antibody production in CHO cells by exposure to He-Ne laser radiation. AB - This study tested the effectiveness of laser biostimulation in small-scale cultures in vitro. We investigated the response of recombinant CHO cells, which are used for the production of monoclonal antibody, to low level laser radiation. The cells were irradiated using a 632.8 nm He-Ne laser in a continuous wave mode at different energy doses. We incubated the irradiated cells in small batch cultures and assessed their proliferation and productivity at various time intervals. Compared to untreated cells, the irradiated cells showed a significant increase in antibody production. Moreover, the results showed that laser irradiation did not affect viability and slightly enhanced proliferation rate. PMID- 23943088 TI - Simultaneous optimal experimental design for in vitro binding parameter estimation. AB - Simultaneous optimization of in vitro ligand binding studies using an optimal design software package that can incorporate multiple design variables through non-linear mixed effect models and provide a general optimized design regardless of the binding site capacity and relative binding rates for a two binding system. Experimental design optimization was employed with D- and ED-optimality using PopED 2.8 including commonly encountered factors during experimentation (residual error, between experiment variability and non-specific binding) for in vitro ligand binding experiments: association, dissociation, equilibrium and non specific binding experiments. Moreover, a method for optimizing several design parameters (ligand concentrations, measurement times and total number of samples) was examined. With changes in relative binding site density and relative binding rates, different measurement times and ligand concentrations were needed to provide precise estimation of binding parameters. However, using optimized design variables, significant reductions in number of samples provided as good or better precision of the parameter estimates compared to the original extensive sampling design. Employing ED-optimality led to a general experimental design regardless of the relative binding site density and relative binding rates. Precision of the parameter estimates were as good as the extensive sampling design for most parameters and better for the poorly estimated parameters. Optimized designs for in vitro ligand binding studies provided robust parameter estimation while allowing more efficient and cost effective experimentation by reducing the measurement times and separate ligand concentrations required and in some cases, the total number of samples. PMID- 23943090 TI - Numerical simulations of carotid MRI quantify the accuracy in measuring atherosclerotic plaque components in vivo. AB - PURPOSE: Atherosclerotic carotid plaques can be quantified in vivo by MRI. However, the accuracy in segmentation and quantification of components such as the thin fibrous cap (FC) and lipid-rich necrotic core (LRNC) remains unknown due to the lack of a submillimeter scale ground truth. METHODS: A novel approach was taken by numerically simulating in vivo carotid MRI providing a ground truth comparison. Upon evaluation of a simulated clinical protocol, MR readers segmented simulated images of cross-sectional plaque geometries derived from histological data of 12 patients. RESULTS: MR readers showed high correlation (R) and intraclass correlation (ICC) in measuring the luminal area (R = 0.996, ICC = 0.99), vessel wall area (R = 0.96, ICC = 0.94) and LRNC area (R = 0.95, ICC = 0.94). LRNC area was underestimated (mean error, -24%). Minimum FC thickness showed a mediocre correlation and intraclass correlation (R = 0.71, ICC = 0.69). CONCLUSION: Current clinical MRI can quantify carotid plaques but shows limitations for thin FC thickness quantification. These limitations could influence the reliability of carotid MRI for assessing plaque rupture risk associated with FC thickness. Overall, MRI simulations provide a feasible methodology for assessing segmentation and quantification accuracy, as well as for improving scan protocol design. PMID- 23943092 TI - Coexistence of habitat specialists and generalists in metapopulation models of multiple-habitat landscapes. AB - In coarse-grained environments specialists are generally predicted to dominate. Empirically, however, coexistence with generalists is often observed. We present a simple, but previously unrecognized, mechanism for coexistence of a habitat generalist and a number of habitat specialist species. In our model all species have a metapopulation structure in a landscape consisting of patches of different habitat types, governed by local extinction and colonization. Each specialist is limited to its specific type of habitat. The generalist can use more types of habitat, has a lower local competitive ability but can exploit patches left open by the specialists. Our modeling shows that coexistence is easily possible. The mechanism amounts to a colonization/competition trade-off at the landscape level, where the colonization advantage of the inferior competitor does not arise from a higher colonization rate but from its ability to use more types of habitat. Habitat availability has to be intermediate: when there are few patches of each habitat, only the generalist is able to maintain itself and when there are many patches, high propagule pressure of the specialists excludes the generalist. Habitat selection or temporal variations in relative habitat quality are not necessary for coexistence. Increased niche-width, colonization rate or local competitive ability of the generalist enhances its performance compared to the specialists. Various types of habitat degradation favour generalism. When able to use a broad range of habitats, generalists can generate so much propagule pressure that only a low level of local competitive ability is needed to globally exclude the specialists. Hence, in a reversal of the original problem, the question is why there are so many specialist metapopulations? PMID- 23943091 TI - Calmodulin-like protein AtCML3 mediates dimerization of peroxisomal processing protease AtDEG15 and contributes to normal peroxisome metabolism. AB - Matrix enzymes are imported into peroxisomes and glyoxysomes, a subclass of peroxisomes involved in lipid mobilization. Two peroxisomal targeting signals (PTS), the C-terminal PTS1 and the N-terminal PTS2, mediate the translocation of proteins into the organelle. PTS2 processing upon import is conserved in higher eukaryotes, and in watermelon the glyoxysomal processing protease (GPP) was shown to catalyse PTS2 processing. GPP and its ortholog, the peroxisomal DEG protease from Arabidopsis thaliana (AtDEG15), belong to the Deg/HtrA family of ATP independent serine proteases with Escherichia coli DegP as their prototype. GPP existes in monomeric and dimeric forms. Their equilibrium is shifted towards the monomer upon Ca(2+)-removal and towards the dimer upon Ca(2+)-addition, which is accompanied by a change in substrate specificity from a general protease (monomer) to the specific cleavage of the PTS2 (dimer). We describe the Ca(2+)/calmodulin (CaM) mediated dimerization of AtDEG15. Dimerization is mediated by the CaM-like protein AtCML3 as shown by yeast two and three hybrid analyses. The binding of AtCML3 occurs within the first 25 N-terminal amino acids of AtDEG15, a domain containing a predicted CaM-binding motif. Biochemical analysis of AtDEG15 deletion constructs in planta support the requirement of the CaM-binding domain for PTS2 processing. Phylogenetic analyses indicate that the CaM-binding site is conserved in peroxisomal processing proteases of higher plants (dicots, monocots) but not present in orthologs of animals or cellular slime molds. Despite normal PTS2 processing activity, an atcml3 mutant exhibited reduced 2,4-DB sensitivity, a phenotype previously reported for the atdeg15 mutant, indicating similarly impaired peroxisome metabolism. PMID- 23943093 TI - Taking a geometric look at the socio-political functioning schemes of the living. Catastrophe theory and theoretical sociology. AB - The aim of this communication is to consider morphological processes in sociology, mainly through the study of the stability of forms of sociality. At the same time, it aims to study the regulation of constraints, related to an increasingly conflictual environment, through political organization. We use a specific theoretical framework: the catastrophe theory developed by Rene Thom in topology, further developed by Claude Bruter from a physics point of view, and reworked by Jacques Viret in biology. The idea is to show the existence of archetypal processes organizing social forms. PMID- 23943094 TI - Factors associated with undertreatment of atrial fibrillation in geriatric outpatients with Alzheimer disease. AB - BACKGROUND: According to international recommendations [from the American College of Cardiology/American Heart Association/European Society of Cardiology] and those of the Haute Autorite de Sante (HAS) in France, treatment with a vitamin K antagonist is recommended in patients with atrial fibrillation (AF) in the presence of a high thromboembolic risk factor [history of stroke, transient ischemic attack, systemic embolism, or valvular heart disease, or presence of a mechanical heart valve prosthesis] or at least two moderate risk factors (age >=75 years, hypertension, congestive heart failure, or diabetes). In patients with a major contraindication, the vitamin K antagonist can be replaced by an antiplatelet agent (APA). These recommendations are not systematically observed in patients with Alzheimer disease (AD). The aim of our study was to determine the factors associated with undertreatment of AF in geriatric outpatients with AD. METHODS: Use of oral anticoagulants or APAs was studied in 66 patients with AF who were included in the French Network on Alzheimer Disease (REAL.FR) cohort, consisting of 686 outpatients living at home, supported by an informal caregiver, and suffering from Alzheimer-type dementia, with a Mini Mental Status Examination (MMSE) score between 10 and 26. First, demographic characteristics (age, sex, body mass index [BMI], living arrangements, educational level), medical conditions (comorbidity, number of medications), disability (activities of daily living [ADL], instrumental activities of daily living [IADL]), risk of falls (one leg balance test), cognitive status (according to MMSE, Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog], and Clinical Dementia Rating [CDR] scores), risk factors for stroke (hypertension, history of stroke, congestive heart failure, diabetes, or age >=75 years) and potential contraindications to oral anticoagulants (OACs) or APAs (polypharmacy, risk of falls, renal failure, gastrointestinal diseases) of patients receiving OACs were compared with those of patients receiving APAs and those of patients receiving no treatment for AF. Then the same characteristics were compared between patients receiving no treatment for AF and those receiving OACs or APAs. RESULTS: Only 56 % (n = 37) of patients with AF were receiving OACs or APAs at the baseline visit, of whom 18 (49 %) were receiving OACs and 19 (51 %) were receiving APAs. Bivariate analysis showed that patients receiving OACs or APAs were significantly more likely to have a history of cardiovascular disease (p = 0.005)-in particular, hypertension (p = 0.037)-less likely to be living alone and unaided (p = 0.038), and less likely to be taking nonsteroidal anti-inflammatory drugs [NSAIDs] (p = 0.001). CONCLUSION: Despite the national and international recommendations, nearly half of AD patients with AF do not receive OACs or APAs. A history of cardiovascular disease-in particular, hypertension-improves access to treatment, but use of NSAIDs and living alone without home care seem to be the main factors associated with non-prescription of OACs or APAs. PMID- 23943095 TI - Trajectories of experience of real life events. A semiotic approach to the dynamics of positioning. AB - This paper is devoted to the study of experience as a semiotic process of constructing the personal meaning of the situation lived. Its main purpose is to devise a semiotic methodology capable of describing and explaining the dynamics of positioning when facing personal lived experiences in real life contexts. Twenty four young adults were exposed to a simulated conflict and then asked to write a narrative of their understanding of the incident and a self-report of their personal experiences. Results show how narratives and trajectories of experience present different forms in each participant, which could be related to: a) the understanding of the situation lived and the position taken regarding the conflict; and b) the position each participant takes regarding the reports they had to produce for the researchers. The incorporation of reflexivity into the applied method allows identification of how the dynamics of double positioning leave traces in the records produced. PMID- 23943096 TI - Adapting to climate variability and change: experiences from cereal-based farming in the central rift and Kobo Valleys, Ethiopia. AB - Small-holder farmers in Ethiopia are facing several climate related hazards, in particular highly variable rainfall with severe droughts which can have devastating effects on their livelihoods. Projected changes in climate are expected to aggravate the existing challenges. This study examines farmer perceptions on current climate variability and long-term changes, current adaptive strategies, and potential barriers for successful further adaptation in two case study regions-the Central Rift Valley (CRV) and Kobo Valley. The study was based on a household questionnaire, interviews with key stakeholders, and focus group discussions. The result revealed that about 99 % of the respondents at the CRV and 96 % at the Kobo Valley perceived an increase in temperature and 94 % at CRV and 91 % at the Kobo Valley perceived a decrease in rainfall over the last 20-30 years. Inter-annual and intraseasonal rainfall variability also has increased according to the farmers. The observed climate data (1977-2009) also showed an increasing trend in temperature and high inter-annual and intra seasonal rainfall variability. In contrast to farmers' perceptions of a decrease in rainfall totals, observed rainfall data showed no statistically significant decline. The interaction among various bio-physical and socio-economic factors, changes in rainfall intensity and reduced water available to crops due to increased hot spells, may have influenced the perception of farmers with respect to rainfall trends. In recent decades, farmers in both the CRV and Kobo have changed farming practices to adapt to perceived climate change and variability, for example, through crop and variety choice, adjustment of cropping calendar, and in situ moisture conservation. These relatively low-cost changes in farm practices were within the limited adaptation capacity of farmers, which may be insufficient to deal with the impacts of future climate change. Anticipated climate change is expected to impose new risks outside the range of current experiences. To enable farmers to adapt to these impacts critical technological, institutional, and market-access constraints need to be removed. Inconsistencies between farmers' perceptions and observed climate trends (e.g., decrease in annual rainfall) could lead to sub-optimal or counterproductive adaptations, and therefore must be removed by better communication and capacity building, for example through Climate Field Schools. Enabling strategies, which are among others targeted at agricultural inputs, credit supply, market access, and strengthening of local knowledge and information services need to become integral part of government policies to assist farmers to adapt to the impacts of current and future climate change. PMID- 23943097 TI - Orthogonal functionalisation of upconverting NaYF4 nanocrystals. AB - A simple and straightforward method for the orthogonal functionalisation of upconverting NaYF4 nanocrystals (UCNCs)-doped withYb(3+) and Er(3+)-based on N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide/N-hydroxysuccinimide (EDC/NHS) selective reactions between two dyes and two different reactive groups present at the periphery of the upconverting nanocrystals is reported. Organic-soluble UCNCs of 10 and 50 nm in size are encapsulated efficiently in a 1:1 mixture of two commercial 3000 Da poly(ethylene glycol) derivatives with two different reactive groups (amino and carboxylic groups). The water-dispersible UCNCs are non cytotoxic, stable in the physiological environment, and present free amine and carboxylic reactive groups on their periphery, allowing rapid, selective, and modular covalent conjugation to payloads through EDC/NHS reactions. PEG encapsulated UCNCs with and without covalent conjugation to payloads are characterised in vitro through spectroscopic, dynamic light scattering, and electron microscopy measurements. Living cell analyses coupled with TEM measurements confirm the uptake and low cytotoxicity of the coated UCNCs. They are linked covalently to two different dyes, internalised by living cells, and analysed by confocal microscopy. The related colocalisation measurements prove the reactivity of both amines and carboxylic acids on the periphery of the nanocrystals. This approach demonstrates that it is possible to produce water dispersible and cyto-compatible dual-functional UCNCs. PMID- 23943099 TI - International perspectives on advanced liver surgery. PMID- 23943098 TI - X-ray fluorescence imaging of single human cancer cells reveals that the N heterocyclic ligands of iodinated analogues of ruthenium anticancer drugs remain coordinated after cellular uptake. AB - Analogues of KP1019 containing iodinated indazole ligands were prepared to investigate the biological fate of the Ru-N-heterocycle bond in this class of anticancer agents. The new complexes, 5-iodoindazolium trans-tetrachloridobis(5 iodoindazole)ruthen(III)ate (1) and 5-iodoindazolium trans-tetrachlorido(dimethyl sulfoxide)(5-iodoindazole)ruthen(III)ate (3), were characterized by elemental analysis, mass spectrometry and UV-vis spectrophotometry. Tetramethylammonium salts of these complexes (2 and 4) were synthesized and characterized in a similar manner. Half-maximum inhibitory concentrations of 2 and 4 with regard to A549 cells at 24 h were determined on the basis of the dose-response curves derived from real-time cell adhesion impedance measurements and were shown to be in the same range as those determined for KP1019 and NAMI-A using the same method. X-ray fluorescence imaging of single cultured A549 cells treated with 2 or 4 showed that, in both cases, the distribution of ruthenium and iodine was identical, indicating that the Ru-N bonds in the anionic complexes remained intact after incubation in culture medium and subsequent cellular uptake and processing. PMID- 23943100 TI - Precision in liver surgery. AB - Continuous theoretical and technological progress in the face of increasing expectations for quality health care has transformed the surgical paradigm. The authors systematically review these historical trends and propose the novel paradigm of "precision surgery," featuring certainty-based practice to ensure the best result for each patient with multiobjective optimization of therapeutic effectiveness, surgical safety, and minimal invasiveness. The main characteristics of precision surgery may be summarized as determinacy, predictability, controllability, integration, standardization, and individualization. The strategy of precision in liver surgery is to seek a balance of maximizing the removal of the target lesion, while maximizing the functional liver remnant and minimizing surgical invasiveness. In this article, the authors demonstrate the application of precision approaches in specific settings in complex liver surgery. They propose that the concept of precision surgery should be considered for wider application in liver surgery and other fields as a step toward the ultimate goal of perfect surgery. PMID- 23943101 TI - Assessment of hepatic function, operative candidacy, and medical management after liver resection in the patient with underlying liver disease. AB - Liver resection in patients with underlying liver disease remains a formidable challenge. It requires adequate patient selection, a precise surgical plan, and avoidance of additional ischemic insults during surgery. Precise estimation of the residual liver volume using computed tomography or magnetic resonance imaging and computer-assisted volumetry allows the calculation of residual to total liver volume (RLV/TLV) ratios. Although RLV/TLV ratios over 20 to 25% are considered sufficient in healthy livers, patients with cirrhosis may only tolerate resections that result in RLV/TLV ratios over 40% and higher. Conventional laboratory tests may not be able to sufficiently predict liver reserve after resection. Dynamic tests such as indocyanine green clearance have been used to assess residual liver function and assist in deciding about operability of patients with underlying liver disease undergoing extensive resections. Intraoperative management should focus on avoiding blood loss and ischemic injury to the liver. Low central venous pressure may reduce blood loss and is recommended if tolerated without impeding renal perfusion. Portal vein and hepatic artery occlusion during resection can reduce blood loss, but will cause ischemic insult to the liver that may jeopardize residual liver function and induce postoperative hepatic failure. When feasible, vascular occlusion should be avoided in patients with underlying liver disease. The postoperative recovery is usually fast if sufficient liver remains. However, vigilance is required to detect liver dysfunction and treat its complications. PMID- 23943102 TI - Interventional radiology in the multidisciplinary management of liver lesions: pre- and postoperative roles. AB - The management algorithm for patents with liver lesions, most often hepatocellular carcinoma (HCC) or colorectal cancer metastasis, are complex, ever changing, and involve multiple treatment modalities including chemotherapy, external-beam radiation, surgery, and locoregional therapies (LRTs). This complexity necessitates a multidisciplinary approach including hepatologists, oncologists, hepatobiliary surgeons, radiation oncologists, and interventional radiologists to coordinate and deliver the complex care that these patients need in a timely manner. The interventional radiologist and hepatobiliary surgeon work closely together in both the pre- and postoperative setting. Preoperative roles include delivering LRTs to patients with HCC and interventions aimed at hepatic optimization prior to resection or transplantation. LRT in this setting is performed either to bridge the patient to transplant or to downstage the initially nontransplant candidate so appropriate transplant criteria are met. Postoperative roles include the management of biliary and vascular complications that may occur after resection or transplantation. PMID- 23943103 TI - Laparoscopic liver resection: lessons at the end of the second decade. AB - Laparoscopic liver surgery has evolved over the last two decades. Advancements in surgical technology, surgical technique, and postoperative care have aided in lifting barriers to laparoscopic liver resection (LLR). In this review, the authors highlight the modern indications, benefits, safety, and feasibility of laparoscopic liver resections. Moreover, they analyze various studies comparing laparoscopic major hepatectomies to open surgery. Morbidity and mortality rates are at an all-time low in this era of laparoscopic liver surgery. The role of laparoscopy for oncologic resections is compared with open liver resections. Attention is given to oncologic margins and survival rates. In addition, the authors examine the safety and efficacy of LLR for nontraditional laparoscopic segments and tumors abutting major hepatic vasculature. Various resection techniques are reviewed including the use of the hanging-maneuver and modern stapling devices. Finally, they examine several novel techniques for laparoscopic liver resections including the hybrid technique, as is used in laparoscopic living donor hepatectomies, the use of hand-assistance to avoid conversion to open surgery, and the use of the robotic platform to aid in complex biliary or vascular reconstructions. Current barriers to laparoscopic liver surgery will continue to fall over the next decade. PMID- 23943104 TI - Diagnosis and management of benign liver tumors. AB - The widespread use of imaging modalities and the continuous improvement in their sensitivity have lead to an increasing number of incidental findings of focal liver masses, either solitary or multiple. Most of these so-called incidentalomas are benign and are discovered in healthy, asymptomatic patients. The main issue is to ensure the proper diagnosis, so that clear management recommendations can be provided. Surgery is rarely indicated in these circumstances. Infrequently, benign liver tumors are diagnosed because of symptoms or complications, and require urgent management including surgery as a major role in the cure. Due to better understanding of the clinical and pathological features of benign liver tumors, the increased accuracy of imaging tools, and improvement in surgical techniques (including laparoscopy), the management of these lesions has evolved. Here the clinical and biological features of the most common solid and cystic benign liver tumors are reviewed, and the key points of management focusing on the role of surgery, preventive or diagnostic, are addressed. PMID- 23943105 TI - Operative management of cholangiocarcinoma. AB - Cholangiocarcinomas (CCAs) are rare malignancies that originate from the epithelial cells of the bile ducts. It is the second most-common primary liver cancer after hepatocellular carcinoma. Recent epidemiologic studies have shown that the overall incidence and mortality rates of CCAs are increasing. Diagnosis is often challenging due to the difficulty in getting tissue/cytology for confirmation, and it comprises a combination of cross-imaging, tumor markers, histology, and cholangiography. Surgery involving major resections of liver, bile duct, pancreas, and at times adjacent vessels is the only chance for cure. Evaluation should be focused on the assessment of tumor resectability, hepatic reserve, and patient physiological fitness for major surgery. In patients not fit for major surgery, biliary drainage for jaundice is an appropriate intervention and if there is histologic confirmation of a CCA, palliative therapies focused on local and systemic disease control should be considered. The endeavor to expand the indications for liver transplantation reflects the efforts to provide an effective form of therapy for a previously untreatable disease. A multidisciplinary specialized approach should be the platform for providing the best comprehensive care for these patients. PMID- 23943107 TI - Resection strategies for hepatocellular carcinoma. AB - Liver resection is the treatment of choice and standard of care in patients with hepatocellular carcinoma (HCC). The ultimate goal of liver resection in HCC patients is to resect primary tumor with an adequate margin while preserving as much functional liver parenchyma as possible. Tremendous improvements in perioperative outcomes after liver resection have been achieved in the past three decades. The overall and disease-free survival rates have also improved. Liver resection is feasible and safe even in cirrhotic patients. This is a result of more accurate preoperative evaluation of liver function, the ability to manipulate future liver remnant volume, the use of anatomical resection and an anterior approach, meticulous surgical techniques to achieve bloodless liver resection, and better perioperative care. The purpose of this review is to highlight the importance of different resection strategies for HCC that in turn have contributed to the safety and improvement in long-term outcomes after liver resection. PMID- 23943106 TI - Operative management of colorectal liver metastases. AB - In this review, the authors describe the management of patients with colorectal liver metastases in the era of effective chemotherapies and advanced interventional radiology. They give special attention to the surgical procedures that decrease the operative mortality and morbidity and produce clear margins. They discuss the best timing for chemotherapy, resection of the primary tumor, and resection of the liver metastases in an effort to improve long-term survival. The use of preoperative portal vein embolization, two-stage hepatectomy for bilobar synchronous liver metastases, and the liver-first strategy have allowed for treatment of patients with advanced disease with a curative intent, and to obtain 5-year overall survival of 30 to 60% despite poor prognostic factors and a cure (no recurrence at 10 years) in more than 20% of patients. These rates would have been unimaginable only two decades ago. PMID- 23943108 TI - Hepatocellular carcinoma: resection versus transplantation. AB - Hepatic resection and transplantation remain the standard curative therapies for hepatocellular carcinoma. These treatments are limited to either patients with early-stage tumors in the case of transplantation or patients with preserved liver function in the case of resection. Currently, patients with early-stage tumors and advanced liver disease are best served by transplant evaluation; however, the best treatment strategy for patients with well-preserved liver function, absence of portal hypertension, and early-stage HCC is debated. Numerous retrospective studies have documented better disease-free survival with transplantation, although the benefit on overall survival is less clear. This effect is likely due to the availability of effective liver-directed therapies for recurrence postresection and the effect of immunosuppression on tumor progression following posttransplant recurrence. Survival studies based on intention-to-treat principle incorporating patients listed for transplantation, but did not undergo the procedure due to waitlist dropoff have also suggested that overall survival rates may not be different despite high recurrence rates following resection. Transplantation has been shown to offer a survival advantage beyond 5-years; however, improvements in adjuvant therapies may narrow this gap. Determining optimal therapy for an individual patient requires consideration of numerous factors including tumor stage, severity of liver disease, and comorbidities as well as geographic and logistical factors that may affect transplant availability. PMID- 23943109 TI - A two-step right hepatic lobectomy with portal vein ligation for large hepatocellular carcinoma: rapid induction of left-lobe regeneration and clinicopathologic correlation. AB - The patient is a 56-year-old man with a long history of chronic hepatitis B, who developed multiple hepatocellular carcinomas in the right lobe with invasion of the right anterior portal vein. There was no evidence of tumor involvement in the left lobe or in extrahepatic organs. Given that the patient had advanced hepatocellular carcinoma associated with gross vascular invasion, a two-step liver resection procedure was performed with right portal vein ligation during the first operation and a subsequent right lobectomy of the liver. The stage I portal vein ligation induced a rapid growth of the left and caudate lobes of the liver with a volume increase from 201 to 405.2 mL in 9 days associated with a slight shrinkage of the tumor nodules. The subsequent right lobectomy was successfully done with a complete removal of tumor nodules and a well-compensated liver function. Postoperatively the patient was complicated with Staphylococcus aureus peritonitis, which was controlled eventually. Biopsy of the left lobe of liver revealed severe small- and medium- droplet steatosis, in addition to regenerative changes. In summary, right portal vein ligation with in situ splitting of the liver allows the surgeon to proceed with hepatic resection in cases where portal vein embolization is technically not possible. The increased risk of morbidity and mortality certainly must be weighed when contemplating this approach and is discussed in this report. PMID- 23943111 TI - Performance variance on walking while talking tasks: theory, findings, and clinical implications. AB - Dual tasks that involve walking and cognitive interference tests are commonly used in mobility assessments and interventions. However, factors that explain variance in dual-task performance costs are poorly understood. We, therefore, examined the moderating effects of two putative constructs, postural reserve and hazard estimate, on performance on a walking while talking paradigm. Participants were 285 non-demented older adults (mean age = 76.9 years; %female = 54.4). Postural reserve was operationalized as the presence or absence of clinical gait abnormalities. An empirical factor, based on measures of executive functions, served as a marker for hazard estimate. The moderation effects of postural reserve and hazard estimate on dual-task costs were examined via two-way interactions in a joint linear mixed effect model. Significant dual-task costs were observed for gait speed (95% CI = 30.814 to 39.121) and cognitive accuracy (95% CI = 6.568 to 13.607). High hazard estimate had a protective effect against decline in gait speed (95% CI = -8.372 to -0.151) and cognitive accuracy (95% CI = -8.372 to -0.680). Poor postural reserve was associated with reduced decline in gait speed (95% CI = -9.611 to -0.702) but did not moderate the decline in cognitive accuracy (95% CI = -3.016 to 4.559). Assessing postural reserve and hazard estimate can help improve mobility risk assessment procedures and interventions for individuals with cognitive and movement disorders. PMID- 23943113 TI - Fundamental use of surgical energy (FUSE). PMID- 23943112 TI - Cortical inhibition is reduced following short-term training in young and older adults. AB - The purpose of this study was to investigate age-related differences in short term training adaptations in cortical excitability and inhibition. Thirty young (21.9 +/- 3.1 years) and 30 older (72.9 +/- 4.6 years) individuals participated in the study. Each participant was randomly assigned to a control (n = 30) or a resistance training (n = 30) group, with equal numbers of young and older subjects in each group. Participants completed 2 days of testing, separated by 2 weeks during which time the training group participated in resistance training of the ankle dorsiflexor muscles three times per week. During each testing session, transcranial magnetic stimulation was used to generate motor evoked potentials (MEPs) and silent periods in the tibialis anterior. Hoffmann reflexes (H reflexes) and compound muscle action potentials (M-waves) were also evoked via electrical stimulation of the peroneal nerve. At baseline, young subjects had higher maximum voluntary contraction (MVC) force (p = 0.002), larger M-wave amplitude (p < 0.001), and longer duration silent periods (p = 0.01) than older individuals, with no differences in the maximal amplitude of the MEP (p = 0.23) or H-reflex (p = 0.57). In the trained group, MVC increased in both young (17.4 %) and older (19.8 %) participants (p < 0.001), and the duration of the silent period decreased by ~15 and 12 ms, respectively (p < 0.001). Training did not significantly impact MEP (p = 0.69) or H-reflex amplitudes (p = 0.38). There were no significant changes in any measures in the control group (p >= 0.19) across the two testing sessions. These results indicate that a reduction in cortical inhibition may be an important neural adaptation in response to training in both young and older adults. PMID- 23943114 TI - Patient-centered outcomes after laparoscopic cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is the second most common general surgical operation performed in the United States, yet little has been reported on patient-centered outcomes. METHODS: We prospectively followed 100 patients for 2 years as part of an institutional review board-approved study. The Surgical Outcomes Measurement System (SOMS) was used to quantify quality-of-life (QoL) values at various time points postoperatively. RESULTS: Maximum pain was reported at 24 h (5.5 +/- 2.2), and decreased to preoperative levels at 7 days (1.2 +/- 2.3 vs. 2.0 +/- 1.6, P = 0.096). Bowel function improved from before the operation to 3 weeks after surgery (10.7 +/- 3.8 vs. 12.0 +/- 3.2, P < 0.05), but then regressed to preoperative levels. Physical function worsened from before surgery (31.7 +/- 6.2) to 1 week (27.5 +/- 5.9, P < 0.0001), but surpassed preoperative levels at 3 weeks (33.5 +/- 3.4, P < 0.01). Return to the activities of daily living occurred at 6.3 +/- 4.7 days and work at 11.1 +/- 9.0 days. Fatigue increased from before surgery (15.8 +/- 6.2) to week 1 (20.7 +/- 6.6, P < 0.0001) before improving at week 3 (14.0 +/- 5.8, P < 0.01). Forty-four patients contacted the health care team 61 times before their 3 weeks appointment, most commonly for wound issues (26.2%), pain (24.6%), and gastrointestinal issues (24.6%). Seventy-two percent reported that the procedure had no negative effect on cosmesis at 6 months. Satisfaction with the procedure was high, averaging 9.52 out of 11. CONCLUSIONS: QoL is significantly affected in the 24 h after LC but returns to baseline at week 3. Cosmesis and overall satisfaction are high, and QoL improvements are maintained in the long term except for bowel function, which regresses to preoperative levels of impairment. Analysis of patient-initiated contacts after LC may provide feedback on discharge counseling to increase patient satisfaction. PMID- 23943115 TI - Endoscopic submucosal dissection for early gastric cancer with undifferentiated histology: could we extend the criteria beyond? AB - BACKGROUND: Endoscopic submucosal desection (ESD) is an effective treatment for selected patients with early gastric cancer (EGC). The purpose of this study was to examine the short-term and long-term outcomes of ESD of undifferentiated early gastric cancer. METHODS: Data for 1,241 patients who underwent ESD for treatment of EGC between February 2003 and May 2010 were collected. We performed a retrospective analysis of the medical records of 74 patients diagnosed with undifferentiated EGC. We divided the enrolled cases into two groups: the expanded criteria group (EC group) versus the non-EC group, according to lesion size, presence of ulceration, and pathologic review. RESULTS: Of a total of 74 lesions with undifferentiated EGC, as a result of pathologic examination the EC group included 29 cases and the non-EC group included 45 cases. The mean diameter of lesions was 19.86 +/- 12.5 mm. The overall rates of en bloc resection and complete resection were 90.5% (67/74) and 73% (54/74), respectively. The curative resection rate was low at 31.1%. If limited to the pathologically diagnosed EC group, the curative resection rate was 79.3% (23/29). During median follow-up periods of 34 months (range 7-81), local recurrences were observed in 5.5% (4/74) of patients. All of these were in the non-EC group and all underwent noncurative resection. There was no mortality related to ESD for treatment of EGC during follow-up. CONCLUSIONS: ESD may be a feasible treatment for selected patients with undifferentiated EGC; this should be validated by development of new criteria for ESD for treatment of EGC. PMID- 23943116 TI - Cost analysis of open and laparoscopic pancreaticoduodenectomy: a single institution comparison. AB - INTRODUCTION: The laparoscopic approach to pancreaticoduodenectomy has been recently more frequently reported and is now being performed at multiple centers across the US. While laparoscopic pancreaticoduodenectomy (LPD) has been shown to be safe and feasible, comparing its cost in relation to open pancreaticoduodenectomy (OPD) has not been examined. The aim of this study is to examine the cost of LPD compared with OPD at a single institution over a 3-year time period. METHODS: An institutional database was analyzed to compare patients who underwent OPD and LPD (including Whipple resections and total pancreatectomy) between May 2009 and June 2012. A cost analysis was performed, which included the use the hospital billing database to assess surgical costs, hospital admission costs, and overall cost of the patient's care during the index admission. The operative costs were further analyzed with respect to OR time and surgical supplies. Standard statistical analysis was performed to assess for significance. RESULTS: In the study time period, 123 patients underwent pancreaticoduodenectomy, including 48 OPD (39%) and 75 LPD (61%). The groups were similar with respect to age, gender, ASA, vein resection, and indication for surgery. In the LPD group, the use of hand assist or conversion to OPD occurred in 3 (4%) and 10 (13%) patients, respectively. Additionally, 10% of the OPD group underwent total pancreatectomy (n = 5), compared to 21% of the LPD (n = 16). Mean operative time for OPD and LPD was 355 min (range 199-681) and 551 min (range 390 819) respectively (p < 0.0001). Median hospital stay for OPD and LPD was 8 days (range 5-63), and 7 days (range 4-68) respectively (p = 0.5). Morbidity rates were equal at 31% for the two groups. The LPD group was associated with significantly higher surgical cost due to both increased time and supply cost. However, mean hospital admission cost associated with OPD was greater in comparison to the LPD group, though not significant. The overall total cost of care was similar between the two groups. CONCLUSIONS: LPD is associated with equivalent overall cost compared with OPD. While operating time and supply costs were higher for LPD, this was balanced by decreased cost of the postoperative admission. PMID- 23943117 TI - Long-term outcome after laparoscopic fenestration of simple liver cysts. AB - BACKGROUND: Simple liver cysts (LCs) represent the most common benign liver disease, with a prevalence of 3-5%. Laparoscopic fenestration is considered the best treatment for symptomatic LCs, but few studies have analyzed the rate or type of recurrence during a long-term follow-up period (>5 years). METHODS: Between January 2000 and December 2010, 47 patients underwent laparoscopic fenestration for simple LCs. The indications were symptoms for 42 patients and an uncertain diagnosis for five patients. The follow-up assessment consisted of regular patient evaluations, with results of laboratory data and liver ultrasound. RESULTS: Conversion to laparotomy was not necessary in any case. The postoperative mortality and morbidity rates were nil. The mean follow-up period was 67 months (range 12-142 months), and 26 patients (55.3%) had a follow-up period longer than 5 years. During the follow-up period, 40 patients (85.1%) did not present with any type of recurrence. The overall recurrence rate was 14.9% (seven patients) based on five patients (10.6%) with radiologic asymptomatic recurrences detected by ultrasound or computed tomography (CT) scan and two patients (4.3%) with clinicoradiologic symptomatic recurrences. Both symptomatic recurrences involved LCs located in the right posterior segments. CONCLUSIONS: Laparoscopic fenestration provided complete relief of symptoms for about 95% of patients with simple LCs. Recurrence after surgery was experienced by 14.9% of the patients, but only in 4.3% (two patients) was this recurrence symptomatic requiring a second treatment. The site of recurrence was more frequently in the right posterior segments. Laparoscopic fenestration of symptomatic LCs can be considered a safe and effective procedure that can yield good long-term results. PMID- 23943119 TI - Vaginal cuff closure during robotic single-port hysterectomy: is the vaginal route always the best one? AB - The recent development of single-port robotic surgery in gynecologic surgery has added the benefits of minimally invasive surgery and greater aesthetic patient satisfaction to the other benefits that robotic surgery offers. However, single port robotic hysterectomy has raised the question about a better approach to closure of the vaginal cuff. This report describes the technical feasibility of using robotic intracorporeal needles and extracorporeal knots to perform the vaginal cuff closure for selected patients. PMID- 23943118 TI - Single-incision cholecystectomy: a comparative study of standard laparoscopic, robotic, and SPIDER platforms. AB - BACKGROUND: Many series have shown the feasibility and safety of single-incision laparoscopic cholecystectomy (SILC), but this technique still has limitations such as instrument collisions and lack of triangulation. Recently, two single incision platforms, robotic and SPIDER, have attempted to ameliorate such problems. This study aimed to compare three different techniques of single incision cholecystectomy: standard laparoscopic, robotic, and SPIDER approaches. METHODS: The authors retrospectively collected data from their first 166 single incision robotic cholecystectomies (SIRCs) and compared the findings with the data from their first 166 SILCs and the first 166 s-generation SPIDER procedures. All the SILCs were performed with three trocars placed in one umbilical incision and with gallbladder retraction using a Prolene stitch on the right upper quadrant. All the robotic cases were managed using the da Vinci Single-Site Surgical System, and all the SPIDER procedures were performed using the SPIDER Surgical System. RESULTS: The SILC, SIRC, and SPIDER groups consisted respectively of 129 (76.3%), 131 (78.9%), and 136 (81.9%) women with the respective mean ages of 44.5 +/- 14.3, 51.6 +/- 15.9, and 46.4 +/- 15.2 years. The mean body mass indexes (BMIs) were respectively 29.1 +/- 5.6, 29.4 +/- 6.2, and 27.5 +/- 4.8 kg/m(2), and the mean surgical times were 37.1 +/- 13.3, 63.0 +/ 25.2, and 52.8 +/- 18.7 min. The total hospital stays were respectively 1.3 +/- 5.3, 1.2 +/- 2.2, and 1.5 +/- 2.6 days, and complications were seen respectively in three SILC cases (1.8%), three SIRC cases (1.8%), and two SPIDER cases (1.2%). CONCLUSIONS: The results of this study demonstrate similar results among the three platforms for most of the parameters measured. The SILC procedure appears to be superior to SIRC and SPIDER in terms of surgical time, but selection bias could be the cause. The SILS, SIRC, and SPIDER procedures all are similar in terms of complication profile. It can be concluded that SILC, SIRC, and SPIDER all are feasible and safe alternatives when used for single-incision cholecystectomy. PMID- 23943120 TI - Influence of conversion on the perioperative and oncologic outcomes of laparoscopic resection for rectal cancer compared with primarily open resection. AB - BACKGROUND: This study aimed to evaluate the influence of conversion on perioperative and short- and long-term oncologic outcomes in laparoscopic resection for rectal cancer and to compare these with those for an open control group. METHODS: The data of 276 consecutive patients who underwent surgery for rectal cancer between 2006 and 2010 at a single institution were prospectively collected. Of the 276 patients, 114 underwent primarily open surgery, and 162 underwent laparoscopic surgery (on an intention-to-treat basis). Of the 162 laparoscopic patients, 38 (23.5%) underwent conversion to open surgery. The three groups of patients were compared: the conversion surgery group, the open surgery group, and the completed laparoscopy surgery group. RESULTS: The converted patients had more wound infections (18.4 vs 4.8%, p = 0.009), but the wound infection rate in the primarily open group also was significantly higher than in the laparoscopic resection group (p = 0.007). No further differences in perioperative morbidity, including anastomotic leakage, were found. The perioperative 30-day mortality rate was comparable between all the groups (0.6 vs 2.6 vs 2.6%, nonsignificant difference). The oncologic parameters such as number of harvested lymph nodes and rate of R0 resection were equal in all the groups. The completed laparoscopy group had a shorter hospital stay [12 vs 16 days in the primarily open group (p = 0.02) vs 15 days in the converted group (p = 0.03)]. The rates for survival, local recurrence (4.5 vs 3 vs 3%), and metachronous metastasis (10.1 vs 9.3 vs 9%) did not differ significantly between the three groups after a period of 3 years. CONCLUSION: Conversion to open surgery in laparoscopic rectal resection has no negative effect on perioperative or long term oncologic outcome. PMID- 23943122 TI - Ultrasound-guided percutaneous drainage of infected pancreatic necrosis. PMID- 23943121 TI - Volume and outcome relationship in bariatric surgery in the laparoscopic era. AB - BACKGROUND: The relationship between volume and outcomes in bariatric surgery is well established in the literature. However, the analyses were performed primarily in the open surgery era and in the absence of national accreditation. The recent Metabolic Bariatric Surgery Accreditation and Quality Improvement Program proposed an annual threshold volume of 50 stapling cases. This study aimed to examine the effect of volume and accreditation on surgical outcomes for bariatric surgery in this laparoscopic era. METHODS: The Nationwide Inpatient Sample was used for analysis of the outcomes experienced by morbidly obese patients who underwent an elective laparoscopic stapling bariatric surgical procedure between 2006 and 2010. In this analysis, low-volume centers (LVC < 50 stapling cases/year) were compared with high-volume centers (HVC >= 50 stapling cases/year). Multivariate analysis was performed to examine risk-adjusted serious morbidity and in-hospital mortality between the LVCs and HVCs. Additionally, within the HVC group, risk-adjusted outcomes of accredited versus nonaccredited centers were examined. RESULTS: Between 2006 and 2010, 277,760 laparoscopic stapling bariatric procedures were performed, with 85% of the cases managed at HVCs. The mean number of laparoscopic stapling cases managed per year was 17 +/- 14 at LVCs and 144 +/- 117 at HVCs. The in-hospital mortality was higher at LVCs (0.17%) than at HVCs (0.07%). Multivariate analysis showed that laparoscopic stapling procedures performed at LVCs had higher rates of mortality than those performed at HVCs [odds ratio (OR) 2.5; 95% confidence interval (CI) 1.3-4.8; p < 0.01] as well as higher rates of serious morbidity (OR 1.2; 95% CI 1.1-1.4; p < 0.01). The in-hospital mortality rate at nonaccredited HVCs was 0.22% compared with 0.06% at accredited HVCs. Multivariate analysis showed that nonaccredited centers had higher rates of mortality than accredited centers (OR 3.6; 95% CI 1.5 8.3; p < 0.01) but lower rates of serious morbidity (OR 0.8; 95% CI 0.7-0.9; p < 0.01). CONCLUSION: In this era of laparoscopy, hospitals managing more than 50 laparoscopic stapling cases per year have improved outcomes. However, nonaccredited HVCs have outcomes similar to those of LVCs. Therefore, the impact of accreditation on outcomes may be greater than that of volume. PMID- 23943123 TI - Ectopic F0F 1 ATP synthase contains both nuclear and mitochondrially-encoded subunits. AB - Over the past few years, several reports have described the presence of F0F1 ATP synthase subunits at the surface of hepatocytes, where the hydrolytic activity of F1 sector faces outside and triggers HDL endocytosis. An intriguing question is whether the ectopic enzyme has same subunit composition and molecular mass as that of the mitochondrial ATP synthase. Also due to the polar nature of hepatocytes, the enzyme may be localized to a particular cell boundary. Using different methods to prepare rat liver plasma membranes, which have been subjected to digitonin extraction, hr CN PAGE, immunoblotting, and mass spectrometry analysis, we demonstrate the presence of ecto-F0F1 complexes which have a similar molecular weight to the monomeric form of the mitochondrial complexes, containing both nuclear and mitochondrially-encoded subunits. This finding makes it unlikely that the enzyme assembles on the plasma membranes, but suggest it to be transported whole after being assembled in mitochondria by still unknown pathways. Moreover, the plasma membrane preparation enriched in basolateral proteins contains much higher amounts of complete and active F0F1 complexes, consistent with their specific function to modulate the HDL uptake on hepatocyte surface. PMID- 23943125 TI - Quantifying coronary artery calcification from a contrast-enhanced cardiac computed tomography angiography study. AB - AIMS: We sought to quantify coronary artery calcium (CAC) using a single contrast enhanced cardiac computed tomography angiography (CCTA) study. CCTA has been successfully used for the assessment of coronary artery stenoses, whereas non contrast ECG-gated computed tomography (Standard-CAC) is commonly performed to quantify CAC. Thus each scan individually contributes to the total radiation dose. METHODS RESULTS: Patients who underwent both Standard-CAC and CCTA scans were identified. Standard-CAC images were scored using the Agatston method. CCTA scans were scored for CAC (CCTA-CAC), whereby CAC was defined as plaque with attenuation 2 SD above the mean attenuation value of the ascending aorta (HU(aorta)). The correlation between Standard-CAC and CCTA-CAC was determined with the slope used to derive a correction factor for the conversion of CCTA-CAC results to a Standard-CAC Agatston score (AS). To test applicability, the correction factor was assessed in a separate validation cohort of similar demographics. From April 2011 to June 2012, a derivation cohort of 92 patients was identified and analysed. An additional 47 patients were identified for the validation cohort. Correlation between Standard-CAC and CCTA-CAC was excellent (r = 0.96). The slope (y = 2.74 * CCTA-CAC score) derived correction factor from the derivation cohort was used to adjust CCTA-CAC derived scores to an AS (CCTA CAC(corrected) = 2.74 * CCTA-CAC). The correction factor was applied to the validation cohort CCTA-CAC results with excellent agreement between CCTA CAC(corrected) and Standard-CAC (kappa = 0.93). CONCLUSIONS: Quantification of CAC from a single contrast-enhanced CCTA scan is feasible and correlates well with Standard-CAC. Larger, multicentre studies are needed to validate the universal applicability of CAC quantified using CCTA. PMID- 23943124 TI - Vitamin E modulates oxidative stress and protein kinase C activator (PMA)-induced TRPM2 channel gate in dorsal root ganglion of rats. AB - It is well known that Ca(2+) influx through cation channels induces peripheral pain in dorsal root ganglion (DRG) neurons. Melastatin-like transient receptor potential 2 (TRPM2) channel is a oxidative redox sensitive Ca(2+)-permeable cation channel. There is scarce report on block of the channels. Since the mechanisms that lead to TRPM2 inhibition in response to oxidative stress and protein kinase C (PKC) activation are not understood, we investigated effects of the antioxidants on the inhibition of TRPM2 channel currents in the DRG neurons of rats. The DRG peripheral neurons were freshly isolated from rats and the neurons were incubated by phorbol 12-myristate 13-acetate (PMA) which leads to activation of PKC and cause oxidative stress. In whole-cell patch clamp experiments, TRPM2 currents in the DRG incubated with PMA were stimulated by H2O2. In addition, the PMA-induced activation of TRPM2 channels were blocked by nonspecific TRPM2 channels inhibitors [2-aminoethyl diphenylborinate (2-APB) and N-(p-amylcinnamoyl)anthranilic acid (ACA)]. The currents in the neurons are also totally blocked by vitamin E incubation. However, administration of catalase and vitamin C with/without the vitamin E incubation did not block the currents. In conclusion, we indicated that vitamin E modulated oxidative stress-induced TRPM2 channel activation in the DRG neurons. The results may be useful modulation of oxidative stress-induced peripheral pain in sensory neurons. PMID- 23943126 TI - Establishing a public umbilical cord blood stem cell bank for South Africa: an enquiry into public acceptability. AB - South Africa (SA) faces a large unmet need for bone marrow (BM) transplantation, which could be alleviated in part by establishing a public umbilical cord blood stem cell bank (UCB SCB). Umbilical cord blood is an increasingly utilised source of hematopoietic stem cells for BM transplantation in addition to BM or mobilized peripheral blood stem cells. Establishing a public UCB SCB would therefore be a positive step towards improving the quality of health care in SA by providing for an important unmet need. This study takes the form of an enquiry into the acceptability of establishing a public bank through an interview with and questionnaire completed by mothers-to-be in the antenatal clinic of a large public hospital in SA. Initial results are positive, with 85 % of the participants in favour of establishing a public UCB SCB in SA. This initial probe will serve as a model for a more comprehensive national enquiry into public support and acceptability in different clinics, hospitals and provinces in SA. PMID- 23943131 TI - The Nozoe Autograph Books: segment 6. PMID- 23943127 TI - Highly enantioselective gamma-amination by N-heterocyclic carbene catalyzed [4+2] annulation of oxidized enals and azodicarboxylates. AB - gamma-Amination: The title reaction was developed to give the corresponding dihydropyridazinones in good yields with excellent enantioselectivities (see scheme; Mes=2,4,6-trimethylphenyl). The annulation reaction worked well for gamma aryl, gamma-alkyl, or gamma-alkenyl oxidized enals. Highly enantiopure tetrahydropyridazinones and gamma-amino acid derivatives could be easily prepared by chemical transformations of the resulting dihydropyridazinones. PMID- 23943132 TI - Single-session photodynamic therapy combined with intravitreal ranibizumab for neovascular age-related macular degeneration: a comprehensive functional retinal assessment. AB - PURPOSE: To explore functional retinal changes in neovascular AMD patients (nAMD) treated with ranibizumab 0.5 mg combined with photodynamic therapy (PDT) 3 days after the first injection in the long term. METHODS: Patients with no prior treatment for nAMD were treated with 3 injections of ranibizumab 0.5 mg 1 month apart and a single session of standard PDT 3 days after the first injection. Best corrected visual acuity and time-domain OCT at baseline and every 28 +/- 2 days were performed; microperimetry at 3, 6, and 12 months and multifocal electroretinogramm (mfERG) at 3 and 12 months were repeated. Fluorescein angiography and vision-related quality-of-life questionnaire were performed at baseline and 12 months. RESULTS: 12/15 nAMD patients completed the 12 months study and received an average of 3.4 +/- 0.7 injections. Mean VA changed from 54.67 +/- 15.72 to 59.0 +/- 24.77 letters (p = 0.371), while mean retinal sensitivity from 5.5 +/- 4.8 to 6.6 +/- 6.0 dB (p = 0.216). MfERG N1-P1 response amplitude densities (RADs) were significantly different from baseline (p < 0.01) in the central 0 degrees -2.5 degrees , whereas in the peripheral retinal areas (2.5 degrees -20 degrees ), not significant (p > 0.01) changes in N1-P1 RADs were detected. The "general vision" VFQ-25 subscale showed a statistically significant improvement at 3 and 12 months. CONCLUSIONS: Ranibizumab 0.5 mg combined with standard PDT 3 days after the first injection determines an improvement of mfERG values in the retinal central area in nAMD patients in long-term follow-up. PMID- 23943134 TI - Evaluation of a primary prevention program for anxiety disorders using story books with children aged 9-12 years. AB - This article reports the results of a study evaluating a book-supported primary prevention program "Dominique's Handy Tricks" for anxiety disorders in children aged 9-12 years. This cognitive-behavioural program is delivered using a combination of storybooks and workshop sessions. The originality of the program comes from the use of storybooks that were not developed specifically for anxiety management. Every session is based on a story describing characters facing common stressors and how they manage to cope with their daily problems. In our randomized control trial with 46 children, participation in the program led to a significant improvement in coping skills, perceived self-efficacy, anxiety sensitivity, as well as in symptoms of anxiety and fear. The theoretical and practical elements underlying the delivery of this primary prevention program are described. CONCLUSION: It is suggested that such an approach, without any labelling specific to anxiety disorders, can be useful in primary prevention programs. PMID- 23943133 TI - Ulysses: the effectiveness of a multidisciplinary cognitive behavioural pain management programme-an 8-year review. AB - OBJECTIVES: To characterise a cohort of patients with chronic pain registered to the Ulysses cognitive behavioural pain management programme (CBT-PMP) and to evaluate the effectiveness of the CBT-PMP 6 months post-discharge. METHODS: A review of patients referred to the Ulysses CBT-PMP from 2002 to 2010 was undertaken. The profile of patients was established. Domains measured included pain, physical and psychological function. Relationships between these factors were explored. Clinically significant changes in outcome measures were established at the 6-month follow-up. RESULTS: In total 553 patients registered to the CBT-PMP, pre-post data were available for 91 % of patients and 52 % at 6 months. The majority of patients were female and aged between 40 and 50 years. Most patients had significant psychological morbidity (76 % depression, 84.5 % anxiety), moderate reports of pain [numerical rating scale, mean (SD) 6.0 (2.2)], and low levels of functional activity. At 6 months follow-up, statistically significant positive findings for physical and psychological outcome measures are supplemented by results showing their clinical significance. With regard to psychological function, a clinically significant change (depending on outcome measure) was shown between 1 in 2 and 1 in 10 patients. Improvements in physical function were lower with rates of 1 in 4 to 1 in 14 reporting significant gains. CONCLUSION: The effectiveness of the Ulysses CBT-PMP is established with measures of clinically significant change for physical and psychological outcomes contributing to the evidence for this novel approach of analysis. Future research determining benchmarks for CBT-PMP outcomes will assist clinicians in monitoring and enhancing patient's progress in clinical practice. PMID- 23943135 TI - Piloting Lead with Love: a film-based intervention to improve parents' responses to their lesbian, gay, and bisexual children. AB - Lesbian, gay, and bisexual youth are at increased risk for a variety of poor health outcomes, relative to their heterosexual counterparts, and recent research implicates family responses to a child's sexual orientation as an important predictor of these health difficulties. Lead with Love is a 35-min documentary style preventive intervention created to improve parents' behaviors toward their lesbian, gay, and bisexual (LGB) children, by providing parents with support, information, and concrete behavioral guidance. The film was made available free online, and was promoted widely with a multi-media marketing campaign. In this paper we describe the theoretical and empirical rationale for the intervention, and report findings from pilot data collected in the first year after the film's release. Specifically, we gathered data to examine the feasibility of reaching parents of LGB youth with this intervention, to determine whether it was acceptable, and to provide preliminary indicators of its potential efficacy. In the first 12 months after launch, 10,949 individuals viewed the film online. The film successfully reached parents of LGB youth (n=1,865), including the hardest to reach parents: 21% had only learned about their child's sexual orientation in the past month, 36% reported having an LGB child was "very" or "extremely" hard for them, and 86% had never obtained any other formal support for having an LGB child. Parents who completed a follow-up assessment immediately after the film reported significant pre- to post-film increases in self-efficacy for parenting an LGB child. PMID- 23943136 TI - Neighbourhood perceptions and sense of coherence in adolescence. AB - The neighbourhood has traditionally been neglected in studies about adolescents' sense of coherence (SOC). The current study represents the first attempt to analyse the associations between neighbourhood assets, neighbourhood risks, and SOC during adolescence. The sample consisted of 7,580 Spanish adolescents aged 13 18 who were selected for the 2009/10 edition of the Health Behaviour in School aged Children (HBSC) survey in Spain. The adolescents completed self-report questionnaires that included the SOC-29 scale and separate HBSC scales measuring neighbourhood risks and assets. The results showed that neighbourhood risks were negatively associated with the adolescents' SOC. In contrast, neighbourhood assets, especially relationships with significant adults, were positively associated with the adolescents' SOC. Assets explained 6.5% of the variability in SOC scores after controlling for risks, suggesting that assets may play a significant role, even in neighbourhoods where risks are present. We discuss implications and future research directions. PMID- 23943137 TI - Sex differences and effects of estrogenic compounds on the expression of inflammatory molecules by astrocytes exposed to the insecticide dimethoate. AB - A low dose of the organophosphorus insecticide dimethoate (DMT) produces oxidation of lipids and proteins and impairs mitochondrial function in the brain of male rats, together with a reduction of gonadal hormones in plasma. Here, we have assessed whether DMT affected the expression of inflammatory molecules, the production of reactive oxygen species (ROS), and the expression of steroidogenic proteins and estrogen receptors in cortical astrocyte-enriched cultures obtained separately from male and female CD1 mice pups. Furthermore, we have analyzed whether estradiol may counteract the effects of DMT. A dose of DMT (2 MUg/mL) did not affect cell viability, increased interleukin (IL) 6, IL1beta, tumor necrosis factor (TNF)alpha, interferon-gamma-inducible protein 10 (IP10), ERbeta, steroidogenic acute regulatory protein, and aromatase mRNA levels and ERalpha protein levels in male but not in female cultures. Estradiol decreased the mRNA levels of IL6, IP10, TNFalpha, and IL1beta in male but not in female cultures treated with DMT. The effect of estradiol was prevented by the ER antagonist ICI 182,780, fully imitated by an ERbeta agonist and partially imitated by an ERalpha agonist. Furthermore, DMT increased the production of ROS in male astrocytes while estradiol reduced ROS production to control levels. These findings indicate that a sublethal dose of DMT alters astrocyte function. The selective action of estradiol on male astrocytes and the sexually dimorphic action of DMT suggest that the pesticide may have different neurological outcomes in males and females. PMID- 23943138 TI - Characterization of photosystem I in rice (Oryza sativa L.) seedlings upon exposure to random positioning machine. AB - To gain a better understanding of how photosynthesis is adapted under altered gravity forces, photosynthetic apparatus and its functioning were investigated in rice (Oryza sativa L.) seedlings grown in a random positioning machine (RPM). A decrease in fresh weight and dry weight was observed in rice seedlings grown under RPM condition. No significant changes were found in the chloroplast ultrastructure and total chlorophyll content between the RPM and control samples. Analyses of chlorophyll fluorescence and thermoluminescence demonstrate that PSII activity was unchanged under RPM condition. However, PSI activity decreased significantly under RPM condition. 77 K fluorescence emission spectra show a blue shift and reduction of PSI fluorescence emission peak in the RPM seedlings. In addition, RPM caused a significant decrease in the amplitude of absorbance changes of P700 at 820 nm (A 820) induced by saturated far-red light. Moreover, the PSI efficiency (Phi I) decreased significantly under RPM condition. Immunoblot and blue native gel analyses further illustrate that accumulation of PSI proteins was greatly decreased in the RPM seedlings. Our results suggest that PSI, but not PSII, is down-regulated under RPM condition. PMID- 23943139 TI - Executive control resources and snack food consumption in the presence of restraining versus facilitating cues. AB - Prior studies have documented a negative relationship between strength of executive control resources (ECRs) and frequency of snack food consumption. However, little is known about what effect environmental cues (restraining versus facilitating) have on the engagement of such control resources. We presented 88 healthy adults with standardized tests of ECRs followed by a bogus taste test for three appetitive snack foods. Participants were randomly assigned to receive instructions to eat the bare minimum to make their ratings ("restraint condition"), eat as much as they like ("facilitation condition") or no special instructions. We surreptitiously measured the weight of food consumed during the taste test. Findings revealed a main effect of treatment condition, such that those in the restraint condition ate significantly less than those in either of the other conditions; however, this main effect was qualified by an ECR by treatment condition interaction. Specifically, those in the facilitation condition showed a strong negative association between ECR strength and amount of food consumed, whereas those in the restraint and control conditions did not. Findings suggest that the effect of ECR strength on consumption of snack food varies substantially by the characteristics of contextual cues. PMID- 23943140 TI - Associations among pain, pain attitudes, and pain behaviors in patients with metastatic breast cancer. AB - Metastatic breast cancer (MBC) patients often experience pain which can trigger pain behaviors, such as distorted ambulation. Psychological variables, such as individuals' attitudes toward pain, play a role in pain intervention. In this study, we used the cognitive-behavioral model of pain to examine the influence of patients' attitudes toward pain (as measured by the survey of pain attitudes or SOPA) on their pain behaviors (as measured by the pain behaviors checklist). Two hundred-one MBC patients completed surveys at treatment initiation and again 3 and 6 months later. Linear Mixed Model with repeated measures analyses showed that SOPA-solicitude, SOPA-emotions, SOPA-cure, SOPA-disability, and SOPA medication pain attitudes were consistently significantly associated with pain behaviors at each assessment time point. Additionally, the belief that a medical cure for pain exists buffered the positive association between pain severity and pain behaviors. Our findings support and extend the cognitive-behavioral model of pain and suggest that it may be useful to target pain attitudes in pain management interventions for MBC patients. PMID- 23943141 TI - Safety and tolerability of an intra-seasonal initiation of the SQ-standardised grass allergy immunotherapy tablet: a non-interventional observational study investigating the feasibility during routine administration. AB - BACKGROUND AND OBJECTIVE: For specific immunotherapy to pollen allergy, a pre seasonal start of treatment is recommended by international guidelines. In a placebo-controlled clinical trial with adults, an intra-seasonal start of therapy with the SQ-standardised grass allergy immunotherapy tablet (AIT) was well tolerated. The objective of our study was to investigate the feasibility of an intra-seasonal start of grass AIT administered during routine treatment by practising allergists. METHODS: In a multicentre, prospective, open-label, uncontrolled, non-interventional observational study, data on routine treatment with grass AIT were recorded in patients who started administration of tablets within the 2010 grass pollen season in Germany. Adverse events (AEs) were recorded by the physician at visits for the first administration in the clinic and at the end of the 1- to 3-month observation period. AEs and daily administration of the tablet were recorded by the patients in diaries for the first 14 days. Treatment satisfaction, global tolerability and perceived effect of treatment were assessed by the patient and physician at the end of the study. RESULTS: A total of 662 patients were treated with 1 tablet daily by 286 physicians. Grass AIT was started intra-seasonally in 620 patients and post season in 42. The average treatment period was 51.6 days. AEs were recorded in 52.1 % of all patients and in 35.6 % at first administration, with throat irritation (21.3 %), paraesthesia oral (19.9 %), oral pruritus (14.0 %) and ear pruritus (10.3 %) being the most frequent AEs related to grass AIT. The intensity of the AEs was assessed as mild or moderate in 42.1 % of patients and severe in 8.0 %; AEs related to grass AIT were classified as serious in two patients. Grass AIT was discontinued due to AEs in 7.7 % of patients. Diaries were evaluable for 77.0 % of patients; the average rate of patients with AEs decreased continuously from 44.7 % (day 1) to 26.9 % (day 14) and the average daily rate of patients who forgot to take their tablet was about 5 %. Overall tolerability was assessed by 87.2 % of patients and 91.4 % physicians as "very good" or "good" and effectiveness of treatment was assessed as "very good" or "good" in 81.4 % of patients and 85.8 % of physicians. More than 90 % of patients and physicians were satisfied with the treatment. CONCLUSION: The tolerability data for an intra seasonal start of grass AIT during routine treatment confirm the safety profile from the previous controlled trial. Tolerability was assessed as good in combination with high satisfaction with the treatment and compliance. PMID- 23943142 TI - The comparison of 24-hour urinary sodium, albumin, and protein excretion in chronic kidney disease patients with type 2 diabetes mellitus using insulin detemir or insulin glargine. AB - BACKGROUND AND OBJECTIVE: Insulin detemir induces bodyweight loss or less weight gain in patients with type 2 diabetes mellitus. However, in contrast to insulin detemir, insulin glargine has no weight loss effect. Increased sodium excretion has been speculated to be one of the mechanisms of weight loss by insulin detemir. However, there are no studies in the literature comparing sodium excretion between patients using insulin detemir and those using insulin glargine. There are also no studies comparing the excretion of urinary albumin and urinary protein in chronic kidney disease (CKD) patients using insulin detemir or insulin glargine. Thus, the aim of the current study was to compare the effects of insulin detemir and insulin glargine on sodium, albumin, and protein excretion in patients with various stages of CKD and concomitant type 2 diabetes. METHODS: Demographic, clinical, and laboratory data were evaluated for all patients. Hypoglycemic attacks, appetite score, 24-h urinary sodium, albumin, and protein excretion were also measured. RESULTS: A total of 47 patients (23 taking insulin detemir, 24 taking insulin glargine) were included in the study. There were no differences with respect to 24-h sodium (p = 0.694), albumin (p = 0.297), or protein excretion (p = 0.202) between patient groups. Appetite and hypoglycemic attacks also did not differ between groups. Use of insulin detemir or insulin glargine was not related to sodium, albumin, and protein excretion in stepwise regression analysis. CONCLUSION: There was no difference between insulin detemir and insulin glargine with respect to sodium, albumin, and protein excretion in type 2 diabetic CKD patients. Studies are needed both in CKD patients and those with normal renal function to highlight mechanisms regarding the weight loss effect unique to insulin detemir. PMID- 23943143 TI - Mechanistic insight into the nickel-catalyzed cross-coupling of aryl phosphates with arylboronic acids: potassium phosphate is not a spectator base but is involved in the transmetalation step in the Suzuki-Miyaura reaction. PMID- 23943144 TI - Revisional bariatric surgery: perioperative morbidity is determined by type of procedure. AB - BACKGROUND: Revisional bariatric procedures are on the rise. The higher complexity of these procedures has been reported to lead to increased risk of complications. The objective of our study was to compare the perioperative risk profile of revisional bariatric surgery with primary bariatric surgery in our experience. METHODS: A prospectively maintained database of all patients undergoing bariatric surgery by three fellowship-trained bariatric surgeons from June 2005 to January 2013 at a center of excellence was reviewed. Patient demographics, type of initial and revisional operation, number of prior gastric surgeries, indications for revision, postoperative morbidity and mortality, length of stay, 30-day readmissions, and reoperations were recorded. These outcomes were compared between revisional and primary procedures by the Mann Whitney or Chi square tests. RESULTS: Of 1,556 patients undergoing bariatric surgery, 102 patients (6.5%) underwent revisional procedures during the study period. Indications for revisions included inadequate weight loss in 67, failed fundoplications with recurrent gastroesophageal reflux disease in 29, and other in 6 cases. Revisional bariatric procedures belonged into four categories: band to sleeve gastrectomy (n = 23), band to Roux-en-Y gastric bypass (n = 25), fundoplication to bypass (n = 29), and other (n = 25). Revisional procedures were associated with higher rates of readmissions and overall morbidity but no differences in leak rates and mortality compared with primary procedures. Band revisions had similar length of stay with primary procedures and had fewer complications compared with other revisions. Patients undergoing fundoplication to bypass revisions were older, had a higher number of prior gastric procedures, and the highest morbidity (40%) and reoperation (20%) rates. CONCLUSIONS: In experienced hands, many revisional bariatric procedures can be accomplished safely, with excellent perioperative outcomes that are similar to primary procedures. As the complexity of the revisional procedure and number of prior surgeries increases, however, so does the perioperative morbidity, with fundoplication revisions to gastric bypass representing the highest risk group. PMID- 23943145 TI - Is the routine use of intraoperative cholangiography during laparoscopic cholecystectomy really the key to lowering bile duct injuries? PMID- 23943146 TI - Sequentiality of daily life physiology: an automatized segmentation approach. AB - Based on the hypotheses that (1) a physiological organization exists inside each activity of daily life and (2) the pattern of evolution of physiological variables is characteristic of each activity, pattern changes should be detected on daily life physiological recordings. The present study aims at investigating whether a simple segmentation method can be set up to detect pattern changes on physiological recordings carried out during daily life. Heart and breathing rates and skin temperature have been non-invasively recorded in volunteers following scenarios made of "daily life" steps (13 records). An observer, undergoing the scenario, wrote down annotations during the recording time. Two segmentation procedures have been compared to the annotations, a visual inspection of the signals and an automatic program based on a trends detection algorithm applied to one physiological signal (skin temperature). The annotations resulted in a total number of 213 segments defined on the 13 records, the best visual inspection detected less segments (120) than the automatic program (194). If evaluated in terms of the number of correspondences between the times marks given by annotations and those resulting from both physiologically based segmentations, the automatic program was better than the visual inspection. The mean time lags between annotation and program time marks remain <60 s (the precision of annotation times marks). We conclude that physiological variables time series recorded in common life conditions exhibit different successive patterns that can be detected by a simple trends detection algorithm. Theses sequences are coherent with the corresponding annotated activity. PMID- 23943147 TI - Global stability of enzymatic chains of full reversible Michaelis-Menten reactions. AB - We consider a chain of metabolic reactions catalyzed by enzymes, of reversible Michaelis-Menten type with full dynamics, i.e. not reduced with any quasi-steady state approximations. We study the corresponding dynamical system and show its global stability if the equilibrium exists. If the system is open, the equilibrium may not exist. The main tool is monotone systems theory. Finally we study the implications of these results for the study of coupled genetic metabolic systems. PMID- 23943148 TI - Evaluating the implementation fidelity of a multicomponent intervention for oral health promotion in preschool children. AB - This study evaluates the process of implementation of a longitudinal intervention program to promote oral health in preschool children in Flanders, Belgium. As the program was implemented in an existing preventive health care organization, the study also evaluates this setting as the context for implementation. Qualitative and quantitative methods were used to evaluate implementation fidelity, based on Carroll's theoretical framework of implementation fidelity (Carroll et al., Implementation Science 2:40, 2007). Questionnaire data from participants and health workers were analyzed, and document analyses were performed to compare registrations of the actions with the planning manual. Results were mixed. Whereas more than 88 % of all parents attended all home visits, only 57 % received at least 9 of the 11 planned consultations. Fifty-two percent of the families received all supporting materials, and on average, 73 % of all attending families received all information at a contact as described in the manual. Moderating factors such as the adequate use of facilitators and high participant responsiveness had a positive impact on implementation fidelity, whereas the quality of delivery differed to a great extent between the nurses who were involved during the entire intervention period and those who gave only a few sessions. Implementing an intervention in an existing well-baby program has many advantages, although lack of time presents a challenge to implementation fidelity. The results of this process evaluation allow a better understanding of the contribution of implementation fidelity to the effectiveness of health promotion programs. PMID- 23943149 TI - Cross-national comparison of prenatal methamphetamine exposure on infant and early child physical growth: a natural experiment. AB - The current study seeks to compare the effects of prenatal methamphetamine exposure (PME) on infant and child physical growth between the USA and New Zealand (NZ). This cross-national comparison provides a unique opportunity to examine the potential impact of services provided to drug using mothers on child health. The longitudinal Infant Development, Environment and Lifestyle study of PME from birth to 36 months was conducted in the USA and NZ. The US cohort included 204 children with PME and 212 non-PME matched comparisons (NPME); the NZ cohort included 108 children with PME and 115 NPME matched comparisons. Latent growth curve models were used to examine effects of PME, country of origin, and the country * PME interaction on growth in length/height and weight. In regard to length/height, PME and country of origin were associated with initial length and growth over time. There was also a significant interaction effect, such that children with PME in the USA were shorter at birth than children with PME in NZ after controlling for other prenatal exposures, infant set, socioeconomic status, and maternal height. In regard to weight, there was only an effect of country of origin. Effects of PME on infant and child growth were shown to differ across countries, with exposed children in NZ faring better than exposed children in the USA. Implications for prevention programs and public policy are discussed. PMID- 23943150 TI - Religious involvement and readiness to confirm reported physical disability. AB - This investigation examines the influence of religious involvement on likelihood of verifying previously reported disability, net of current activity difficulty and self-rated health. It compares African American and white community-dwelling adults confirming (N = 348) and not confirming (N = 164) activity limitations. Logistic regressions show service attendance negatively associated with disability perception only among African Americans. For whites, use of beliefs in coping mitigates against confirmation of disability. Observed associations are conditioned by socioeconomic status and gender. These results underscore the importance of social context, as well as multidimensional religiosity, in understanding the health and disability implications of religiousness. PMID- 23943152 TI - Positive changes in the medical educational environment following introduction of a new systems-based curriculum: DREEM or reality? Curricular change and the Environment. AB - BACKGROUND: Evaluation of a new systems-based curriculum in an undergraduate Irish Medical School was carried out with the validated Dundee Ready Educational Environment (DREEM) inventory. Comparison was made with the results from a previous DREEM study in the old curriculum. METHODS: DREEM was administered to 225 medical students enrolled in the new curriculum. Data analysis was carried out using SPSS 17.0 and the Student unpaired t test. RESULTS: Increased mean scores supported greater satisfaction with the educational environment in the new curriculum. Students perceived better opportunities to develop interpersonal skills, ask questions and learn about empathy. Areas of concern included timetabling, support for stressed students and provision of feedback. Clinical students perceived their overall environment more positively. Pre-clinical students were more confident about passing exams and felt better prepared for clinical practice. Male students were more positive about the environment and found the teaching more stimulating. Female students perceived greater development of their problem-solving skills. Non-Irish students no longer perceived the atmosphere and their social self-perceptions more negative than Irish students, as was the case in the old curriculum. CONCLUSIONS: DREEM is a valuable tool in evaluating the educational environment and monitoring the impact of curricular change. PMID- 23943153 TI - Metastasis of intracranial meningeal hemangiopericytoma to thoracic spine 17 years after surgical excision: a case report. PMID- 23943154 TI - Digalloylresveratrol, a novel resveratrol analog inhibits the growth of human pancreatic cancer cells. AB - Digalloylresveratrol (DIG) is a recently synthesized substance aimed to combine the effects of the natural polyphenolic compounds gallic acid and resveratrol, which both are excellent free radical scavengers with anticancer activity. In this study, we investigated the effects of DIG in the human AsPC-1 and BxPC-3 pancreatic adenocarcinoma cell lines. Treatment with DIG dose-dependently attenuated cells in the S phase of the cell cycle and led to a significant depletion of the dATP pool in AsPC-1 cells. The incorporation of (14)C-cytidine into nascent DNA of tumor cells was significantly inhibited at all DIG concentrations due to inhibition of ribonucleotide reductase, a key enzyme of DNA synthesis in tumor cells. Furthermore, Erk1/2 became inactivated and moderated p38 phosphorylation reflecting increased replication stress. DIG also activated ATM and Chk2, and induced the phosphorylation and proteasomal degradation of the proto-oncogene Cdc25A, which contributed to cell cycle attenuation. Taken together, DIG is an excellent free radical scavenger, strongly inhibits RR in situ activity, cell cycle progression, and colony formation in AsPC-1 and BxPC-3 cells thus warranting further investigations. PMID- 23943155 TI - Combined de-novo mutation and non-random X-chromosome inactivation causing Wiskott-Aldrich syndrome in a female with thrombocytopenia. AB - OBJECTIVE: Disorders linked to mutations in the X chromosomes typically affect males. The aim of the study is to decipher the mechanism of disease expression in a female patient with a heterozygous mutation on the X-chromosome. PATIENTS AND METHODS: Clinical data was extracted from the Canadian Inherited Marrow Failure Registry. Genomic ribonucleic acid (DNA) and complementary DNA (cDNA) underwent Sanger sequencing. Protein analysis was performed by flow cytometry. X inactivation patterns were analyzed by evaluating the DNA methylation status and cDNA clonal expression of several genes on the X-chromosome. SNP array was used for molecular karyotyping of the X-chromosome. RESULTS: A female with thrombocytopenia, eczema and mild T-lymphocyte abnormalities with extensive negative diagnostic testing, was suspected to have Wiskott-Aldrich syndrome (WAS)/X-linked thrombocytopenia. Although the girl had a mutation (c.397G > A, p.E133K) in only one allele, she was found to have an extremely skewed X inactivation pattern and no expression of the WAS protein. Family studies using DNA methylation analysis and cDNA clonal expression of several genes on the X chromosome demonstrated that the patient developed de-novo non-random inactivation of the X-chromosome that does not carry the mutation. Genome-wide high-density molecular karyotyping excluded deletions and amplifications as a cause for the non-random inactivation of one X-chromosome. CONCLUSIONS: Our study emphasizes the need to test selected female patients with complete or incomplete disease expression for X-linked disorders even in the absence of a family history. PMID- 23943159 TI - Small molecule hormone or hormone-like ligands of integrin alphaVbeta3: implications for cancer cell behavior. AB - Integrins are heterodimeric structural components of the plasma membrane whose ligands include a large number of extracellular matrix (ECM) proteins. The ligands contain Arg-Gly-Asp (RGD) sequences that enable recognition of ECM proteins by as many as eight integrins, but other distinguishing features of the proteins permit the integrins to generate intracellular signals specific to the ECM molecules. Recently, integrin alphavbeta3 has been shown to have a panel of previously unappreciated small molecule receptor sites for thyroid hormone and hormone analogues, for dihydrotestosterone, and for resveratrol, a polyphenol that has certain estrogen-like features. These binding sites are close to the RGD recognition site of alphavbeta3. The thyroid hormone receptor site on the extracellular domain of alphavbeta3 contains two domains with discrete functions in terms of intracellular protein trafficking and gene expression. Occupancy of the receptor by a deaminated thyroid hormone analogue, tetraiodothyroacetic acid (tetrac), prevents cell responses to agonist thyroid hormones (L-thyroxine; 3, 5, 3'-triiodo-L-thyronine) and modulates expression of a number of cancer cell survival pathway genes in an up- or downregulation pattern coherent to induction of cell death. The small molecule thyroid hormone receptor on the integrin also regulates activity of five vascular growth factor receptors and/or their ligands, providing control of angiogenesis via specific pharmacologic regulation of this thyroid hormone receptor. The resveratrol receptor induces programmed cancer cell death via p53, even when the latter has undergone specific mutations. There is also evidence for the presence of several receptors on integrin alphavbeta3 for authentic steroids, including a dihydrotestosterone site that supports proliferation of breast cancer cells that lack nuclear androgen and estrogen receptors. The existence of these small molecule hormone receptors on an integrin with a remarkably complex functional profile defines novel pharmacologic options via individual small molecule receptor manipulation for control of cancer cell behavior. This refinement of up-down control at the level of discrete receptors is not a function of the use of alphavbeta3 antibody or RGD peptides that occlude regions of the integrin. PMID- 23943160 TI - Ligand-activated peroxisome proliferator-activated receptor beta/delta modulates human endometrial cancer cell survival. AB - Endometrial cancer is the fourth most common malignancy among women and is a major cause of morbidity contributing to approximately 8,200 annual deaths in the USA. Despite advances to the understanding of endometrial cancer, novel interventions for the disease are necessary given that many tumors become refractory to therapy. As a strategy to identify novel therapies for endometrial carcinoma, in this study, we examined the contribution of the peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) to endometrial cancer cell proliferation and apoptosis. We found that when activated with the highly selective PPARbeta/delta agonists, GW0742 and GW501516, PPARbeta/delta inhibited the proliferation and markedly induced the apoptosis of three endometrial cancer cell lines. The specificity of the PPARbeta/delta-induced effects on cell proliferation and apoptosis was demonstrated using PPARbeta/delta-selective antagonists and PPARbeta/delta small interfering RNA in combination with PPARbeta/delta-selective agonists. Furthermore, we showed that PPARbeta/delta activation increased phosphatase and tensin homolog expression, which led to protein kinase B (AKT) and glycogen synthase kinase-3beta (GSK3beta) dephosphorylation, and increased beta-catenin phosphorylation associated with its degradation. Overall, our data suggest that the antitumorigenic effect of PPARbeta/delta activation in endometrial cancer is mediated through the negative regulation of the AKT/GSK3beta/beta-catenin pathway. These findings warrant further investigation of PPARbeta/delta as a therapeutic target in endometrial cancer. PMID- 23943161 TI - Preventive effects of conservative treatment with short-term teriparatide on the progression of vertebral body collapse after osteoporotic vertebral compression fracture. AB - The progression of fractured vertebral collapse is not rare after a conservative treatment of vertebral compression fracture (VCF). Teriparatide has been shown to directly stimulate bone formation and improve bone density, but there is a lack of evidence regarding its use in fracture management. Conservative treatment with short-term teriparatide is effective for decreasing the progression of fractured vertebral body collapse. INTRODUCTION: Few studies have reported on the prevention of collapsed vertebral body progression after osteoporotic VCF. Teriparatide rapidly enhances bone formation and increases bone strength. This study evaluated preventive effects of short-term teriparatide on the progression of vertebral body collapse after osteoporotic VCF. METHODS: Radiographs of 68 women with single-level osteoporotic VCF at thoracolumbar junction (T11-L2) were reviewed. Among them, 32 patients were treated conservatively with teriparatide (minimum 3 months) (group I), and 36 were treated with antiresorptive (group II). We measured kyphosis and wedge angle of the fractured vertebral body, and ratios of anterior, middle, and posterior heights of the collapsed body to posterior height of a normal upper vertebra were determined. The degree of collapse progression was compared between two groups. RESULTS: The progression of fractured vertebral body collapse was shown in both groups, but the degree of progression was significantly lower in group I than in group II. At the last follow-up, mean increments of kyphosis and wedge angle were significantly lower in group I (4.0 degrees +/- 4.2 degrees and 3.6 degrees +/- 3.6 degrees ) than in group II (6.8 degrees +/- 4.1 degrees and 5.8 degrees +/- 3.5 degrees ) (p = 0.032 and p = 0.037). Decrement percentages of anterior and middle border height were significantly lower in group I (9.6 +/- 10.3 and 7.4 +/- 7.5 %) than in group II (18.1 +/- 9.7 and 13.8 +/- 12.2 %) (p = 0.001 and p = 0.025), but not in posterior height (p = 0.086). CONCLUSIONS: In female patients with single level osteoporotic VCF at the thoracolumbar junction, short-term teriparatide treatment did not prevent but did decrease the progression of fractured vertebral body collapse. PMID- 23943162 TI - The impact of recombinant parathyroid hormone on malignancies and mortality: 7 years of experience based on nationwide Danish registers. AB - We used Danish registers to identify patients with osteoporosis, who had been treated with parathyroid hormone and evaluated the probability of developing cancer. We did not find an increased risk of cancer among the patients treated with parathyroid hormone. INTRODUCTION: We evaluated the incidences of malignancies and mortality in osteoporotic patients treated with rPTH. METHODS: Using Danish nationwide registers, we identified patients diagnosed with osteoporosis in the period 1995 through 2010. Each patient treated with rPTH ("case") was compared with 10 gender- and age-matched patients who did also have osteoporosis but did not receive rPTH ("control"). RESULTS: A total of 4,104 cases (80.3 % females) were identified. The mean age at the beginning of rPTH treatment was 70.9 (SD 9.7) years. During a follow-up time of 10,118 person-years for the cases and 88,005 person-years for the controls, a total of 255 cases (6.2 %) compared with 2,103 controls (5.1 %) experienced a cancer (Chi square, p = 0.003). We found an adjusted cancer related HR of 1.1 (95 %CI 0.9-1.4) among the cases. Lung cancer was the only cancer type with a significantly increased rate among patients receiving rPTH (HR 1.7; 95 % CI 1.3-2.3). No cases developed osteosarcomas and nine controls developed osteosarcoma. During follow-up, 627 (15.3 %) cases died and 4,175 (10.2 %) controls died, which yielded an excess mortality risk of 26 % (95 % CI 16-37 %). This could be due to differences in the prevalence of vertebral fractures between the rPTH-treated and non-treated patients. CONCLUSION: This study did not support the hypothesis describing a possible link between rPTH treatment and the development of cancer. We also conclude that osteosarcoma has not been diagnosed in any Danish patient receiving rPTH since the year 2003 when it was introduced on the market. PMID- 23943163 TI - Comparison of vertebral bone marrow fat assessed by 1H MRS and inphase and out-of phase MRI among family members. AB - Inphase and out-of-phase magnetic resonance imaging is a robust and fast method which can provide similar vertebral bone marrow fat estimation as (1)H proton magnetic resonance spectroscopy, indicating that this technique is a potentially useful tool in both research and clinical practice. INTRODUCTION: The importance of evaluating bone marrow fat lies in the fact that osteoporosis and obesity, two disorders of body composition, are growing in prevalence. Bone fat mass can be reliably assessed using proton magnetic resonance spectroscopy ((1)H MRS), but this method is technically demanding and needs advanced post-processing unlike inphase and out-of-phase magnetic resonance imaging (MRI), which is a robust and fast method. METHODS: We compared vertebral bone marrow fat (BMF) content assessed by inphase and out-of-phase MRI and (1)H MRS using a 1.5-T MRI scanner in mothers (n = 34, aged 49.4 years), fathers (n = 31, aged 53.1 years) and their daughters (n = 40, aged 20.3 years) who participated in the CALEX family study. Signal intensity on the inphase and out-of-phase MRI was analyzed from the same location and size of the single-voxel (1)H MRS measurement. RESULTS: Positive correlations were found between (1)H MRS and inphase and out-of-phase MRI in the axial plane (r = 0.746, p < 0.001) and sagittal plane (r = 0.804, p < 0.001). The mean differences between (1)H MRS and inphase and out-of-phase MRI in the axial and sagittal planes were relatively small, at 4.13 and 2.67 %, and the agreement between techniques was 89.4 and 93.2 %, respectively. Girls had a significantly lower vertebral BMF than mothers and fathers with both methods (for all, p < 0.001). CONCLUSIONS: We conclude that inphase and out-of-phase MRI can provide similar vertebral BMF estimation as (1)H MRS, indicating that this technique is a potentially useful tool in both research and clinical practice. PMID- 23943164 TI - Menopause may be the common link that resulted in the association between higher serum ferritin level and lower bone mineral density in women >= 45 years of age. PMID- 23943165 TI - Menopause may be the common link that resulted in the association between a higher serum ferritin level and lower bone mineral density in women >= 45 years of age: response to Lee and Kim. PMID- 23943166 TI - Fracture patterns and bone mass in South African adolescent-mother pairs: the Birth to Twenty cohort. AB - The associations of fracture prevalence and bone mass in adolescents with maternal fracture history and bone mass have not been investigated previously in South Africa. Maternal bone mass has a significant inverse association with their adolescents' fracture rates and bone mass across all ethnic groups. INTRODUCTION: Differences in fracture rates and bone mass between families and individuals of different ethnic origins may be due to differing lifestyles and/or genetic backgrounds. This study aimed to assess associations of fracture prevalence and bone mass in adolescents with maternal fracture history and bone mass, and sibling fracture history. METHODS: Data from 1,389 adolescent-biological mother pairs from the Birth to Twenty longitudinal study were obtained. Questionnaires were completed on adolescent fractures until 17/18 years of age and on sibling fractures. Biological mothers completed questionnaires on their own fractures prior to the age of 18 years. Anthropometric and bone mass data on adolescent biological mother pairs were collected. RESULTS: An adolescent's risk of lifetime fracture decreased with increasing maternal lumbar spine (LS) bone mineral content (BMC; 24 % reduction in fracture risk for every unit increase in maternal LS BMC Z-score) and increased if they were white, male, or had a sibling with a history of fracture. Adolescent height, weight, male gender, maternal bone area and BMC, and white ethnicity were positive predictors of adolescent bone mass. White adolescents and their mothers had a higher fracture prevalence (adolescents 42 %, mothers 31 %) compared to the black (adolescents 20 %, mothers 6 %) and mixed ancestry (adolescents 20 %, mothers 16 %) groups. CONCLUSION: Maternal bone mass has a significant inverse association with their adolescent off-springs' fracture risk and bone mass. Furthermore, there is a strong familial component in fracture patterns among South African adolescents and their siblings. PMID- 23943167 TI - Alendronate and risk of lower limb ischemic vascular events: a population-based cohort study. AB - While alendronate inhibits atherosclerosis experimentally, its effect on lower limb ischemia risk is unknown. Our results suggest that alendronate reduces the risk of lower limb ischemic vascular events requiring surgical interventions, including amputation. Our results are relevant for patients at risk of lower limb ischemia undergoing fragility fracture treatment. INTRODUCTION: This study aimed to determine the association between alendronate therapy and the risk of lower limb ischemic vascular events (i.e., bypass surgery, endovascular stenting, and major lower limb amputation for lower limb ischemia). METHODS: We used a nationwide population-based cohort of patients aged over 50 years diagnosed with a vertebral or hip fracture between January 1999 and June 2010. We compared the risk of lower limb ischemic vascular events between patients undergoing treatment with alendronate (n = 3,731) and an age- and sex-matched comparison group (n = 7,462) over 5 years of follow-up. Hazard ratios (HR) were estimated using Cox proportional regression analysis with adjustment for treatment status, comorbidities, and other variables. RESULTS: Ten patients (0.3 %) in the alendronate treatment group had a lower limb ischemic vascular event compared with 51 patients (0.7 %) in the comparison group. The incidence of lower limb ischemic vascular events was 8.4 (95 % CI, 4.0-15.5) per 10,000 person-years in the alendronate group and 21.8 (95 % CI, 16.2-28.7) per 10,000 person-years in the comparison group. The risk of a lower limb ischemic vascular event in the alendronate treatment group was lower (adjusted HR, 0.41; 95 % CI, 0.21-0.82). CONCLUSION: Alendronate treatment was associated with a reduced risk of lower limb ischemic vascular events among hip or vertebral fragility fracture patients. PMID- 23943169 TI - Ferric carboxymaltose approved for iron deficiency anemia. PMID- 23943168 TI - An experimental therapy to improve skeletal growth and prevent bone loss in a mouse model overexpressing IL-6. AB - Premature osteoporosis and stunted growth are common complications of childhood chronic inflammatory disease. Presently, no treatment regimens are available for these defects in juvenile diseases. We identified the sequential Fc-OPG/hPTH treatment as an experimental therapy that improves the skeletal growth and prevents the bone loss in a mouse model overexpressing IL-6. INTRODUCTION: Premature osteoporosis and stunted growth are common complications of childhood chronic inflammatory diseases and have a significant impact on patients' quality of life. Presently, no treatment regimens are available for these defects in juvenile diseases. To test a new therapeutic approach, we used growing mice overexpressing the pro-inflammatory cytokine IL-6 (TG), which show a generalized bone loss and stunted growth. METHODS: Since TG mice present increased bone resorption and impaired bone formation, we tested a combined therapy with the antiresorptive modified osteoprotegerin, Fc-OPG, and the anabolic PTH. We injected TG mice with Fc-OPG once at the 4th day of life and with hPTH(1-34) everyday from the 16th to the 30th day of age. RESULTS: A complete prevention of growth and bone defects was observed in treated mice due to normalization of osteoclast and osteoblast parameters. Re-establishment of normal bone turnover was confirmed by RT-PCR analysis and by in vitro experiments that revealed the full rescue of osteoclast and osteoblast functions. The phenotypic recovery of TG mice was due to the sequential treatment, because TG mice treated with Fc-OPG or hPTH alone showed an increase of body weight, tibia length, and bone volume to intermediate levels between those observed in vehicle-treated WT and TG mice. CONCLUSIONS: Our results identified the sequential Fc-OPG/hPTH treatment as an experimental therapy that improves the skeletal growth and prevents the bone loss in IL-6 overexpressing mice, thus providing the proof of principle for a therapeutic approach to correct these defects in juvenile inflammatory diseases. PMID- 23943170 TI - Health care providers want electronic, standardized REMS programs. PMID- 23943171 TI - Quadrivalent influenza vaccines get buy-in from pharmacists. PMID- 23943172 TI - Poor quantitative skills of newly insured may affect ability to manage medications. PMID- 23943175 TI - Using lean methodology to improve operational and clinical efficiency. PMID- 23943176 TI - Physical and chemical stability of ceftazidime and cefazolin in peritoneal dialysis solutions packaged in dual-chamber infusion bags. PMID- 23943177 TI - Role for a resident representative on a regional conference steering committee. PMID- 23943178 TI - Implementation of inpatient blood glucose monitoring by clinical pharmacists. PMID- 23943179 TI - Sulfonamide cross-reactivity: is there evidence to support broad cross allergenicity? AB - PURPOSE: Published and manufacturer-provided data regarding potential cross reactivity between antibacterial and nonantibacterial sulfonamide agents are reviewed. SUMMARY: An estimated 3-6% of the general population is allergic to sulfonamides and thus at risk for type I and other hypersensitivity reactions to sulfamethoxazole and other sulfonamide antibacterial agents. Concerns have been raised that a history of sulfa allergy may be associated with an increased risk of adverse reactions to a wide range of nonantibacterial sulfonamides, including certain antivirals, carbonic anhydrase inhibitors, cyclooxygenase-2- selective nonsteroidal antiinflammatory drugs, loop and thiazide diuretics, and sulfonylureas; concerns have also been raised that patients who have experienced an allergic reaction to one nonantibacterial sulfonamide may be at risk for an adverse reaction to others. Structurally, none of the nonantibiotic sulfonamides exhibit both of the features shown to be responsible for sulfonamide reactions (i.e., an N-containing ring attached to the N1 nitrogen of the sulfonamide group and an arylamine group at the N4 position), and only two agents (amprenavir and fosamprenavir) have the latter characteristic. A comprehensive literature search (1966-December 2011) identified nine case reports indicating possible cross reactivity to sulfonamide medications; however, in most cases, adequate patient testing was not conducted to firmly establish either sulfa allergy or sulfonamide cross-sensitivity. The weight of evidence suggests that withholding nonantibacterial sulfonamides from patients with prior reactions to antibacterial sulfonamides or other nonantibacterial sulfonamides is not clinically justified. CONCLUSION: A review of the professional literature and manufacturer-provided data did not find convincing evidence of broad cross-reactivity between antibacterial and nonantibacterial sulfonamide agents. PMID- 23943180 TI - Intravenous acetylcysteine for indications other than acetaminophen overdose. AB - PURPOSE: The use of intravenous acetylcysteine for off-label indications, specifically non-acetaminophen-induced acute liver failure (NAI-ALF), severe alcoholic hepatitis, and contrast-induced nephropathy (CIN), is reviewed. SUMMARY: I.V. acetylcysteine is most often used as an antidote for acetaminophen overdose due to its ability to increase levels of glutathione; however, it is also used to treat NAI-ALF and severe alcoholic hepatitis and to prevent CIN. Although the i.v. and oral formulations of acetylcysteine have been evaluated for these indications, most studies have examined the i.v. form. I.V. acetylcysteine is used in the treatment of NAI-ALF to improve oxygenation to the liver. One large randomized trial of 173 adults with NAI-ALF from any etiology and of any grade encephalopathy demonstrated overall improvement in transplant-free survival, particularly for patients with low-grade encephalopathy, though overall survival was not improved. When used to treat severe alcoholic hepatitis, i.v. acetylcysteine serves as an antioxidant and glutathione source. A trial of 174 patients with severe alcoholic hepatitis revealed that patients had 28-day survival benefit when treated with acetylcysteine; improvement in patients with hepatorenal syndrome was also noted. When used for the prevention of CIN, i.v. acetylcysteine provides antioxidants and vasodilation. The benefit for this indication is limited to surrogate markers such as serum creatinine and in patients with multiple risk factors for the development of CIN. CONCLUSION: Data regarding the use of i.v. acetylcysteine for the treatment of NAI-ALF and severe alcoholic hepatitis and in the prevention of CIN are inconclusive, though some evidence supports its use in certain populations. PMID- 23943181 TI - Reversible ageusia associated with romidepsin therapy. AB - PURPOSE: The case of a patient who reported the complete loss of his sense of taste after about 3.5 months of romidepsin therapy is presented. SUMMARY: A man with a 12-year history of treatment-refractory cutaneous T-cell lymphoma (CTCL) developed taste disturbances progressing to ageusia (the absence of taste perception) while receiving romidepsin therapy. He reported a metallic taste during the first round of romidepsin therapy (14 mg/m2 given as a four-hour infusion on days 1, 8, and 15 of each four-week cycle); during the ninth infusion, he reported the complete loss of taste sensations. The patient chose to continue romidepsin therapy because of a favorable overall response but requested a reduced frequency of infusions due to unabated ageusia. After implementation of a revised administration schedule (infusions only on days 1 and 8 of each cycle), the man gradually regained his sense of taste, with complete reversal of ageusia once romidepsin use was discontinued after two more cycles. The application of the algorithm of Naranjo et al. to this case yielded a score of 6, indicating a probable association between the taste disturbances and romidepsin use. A literature search identified no other reports of romidepsin-associated ageusia. CONCLUSION: A 67-year-old man reported ageusia during the third cycle of romidepsin therapy for CTCL. Taste sensation began to slowly recover following a reduction in the frequency of romidepsin administration, but therapy was ultimately discontinued partly due to the impact of this adverse reaction on the patient's quality of life. PMID- 23943182 TI - Clinical outcomes associated with conversion from brand-name to generic tacrolimus in hospitalized kidney transplant recipients. AB - PURPOSE: The safety of converting kidney transplant recipients on brand-name tacrolimus to generic tacrolimus during hospitalization was evaluated. METHODS: A single-center observational study compared tacrolimus dosages and trough tacrolimus levels in kidney transplant recipients who had a kidney transplant more than 90 days before hospital admission. Patients in the "brand" group were maintained on brand-name tacrolimus throughout the entire study period. Patients in the generic group were maintained on brand-name tacrolimus before hospital admission, converted to the generic formulation during hospitalization, and returned to the brand-name product at discharge. Tacrolimus dosages were converted on a milligram-per-milligram basis and adjusted, if needed. Outcomes evaluated included the percentage of patients requiring a dosage change, absolute change in average tacrolimus trough level, and frequency of biopsy-proven acute rejection within six months of discharge. RESULTS: A total of 100 patients were evaluated for inclusion in the brand group, with 42 meeting study criteria; 98 patients were evaluated in the generic group, with 36 qualifying for the study. There were no significant differences between the brand and generic groups with respect to dosage adjustments required or trough tacrolimus levels at any point in the transition of care. Mean trough concentrations were similar between groups during all periods of care. The only occurrence of new-onset acute rejection within six months after admission occurred in the brand group. CONCLUSION: Substitution of a generic formulation of tacrolimus for the innovator product during hospitalization of kidney transplant recipients was safely implemented. Tacrolimus dosage adjustments were common throughout the transitions of care, regardless of the formulation used. PMID- 23943183 TI - Effect of a pharmacist on timing of postintubation sedative and analgesic use in trauma resuscitations. AB - PURPOSE: Pharmacists' impact in reducing the time interval from intubation to sedative and analgesic use during trauma patient resuscitations is investigated. METHODS: A retrospective cohort study was conducted at a level 1 trauma center to compare medication-use outcomes in consecutive cases in which trauma patients underwent rocuronium-assisted rapid-sequence intubation (RSI) and subsequent sedation and analgesia with or without a pharmacist's participation on the resuscitation team. The primary and secondary outcomes were, respectively, the time to sedative provision and the time to analgesic provision after intubation. RESULTS: Relative to resuscitation cases not involving a pharmacist, the presence of the pharmacist during RSI was associated with decreased mean times to provision of postintubation sedation (9 minutes versus 28 minutes, p = 0.007) and analgesia (21 minutes versus 44 minutes, p = 0.057). The cumulative proportions of patients receiving appropriate sedation 5, 10, and 15 minutes after intubation were 11%, 26%, and 41% in the pharmacist-absent group and 33%, 53%, and 63% in the pharmacist-present group (p = 0.009, 0.008, and 0.045, respectively); for postintubation analgesic use, the corresponding figures were 9%, 14%, and 23% in the pharmacist-absent group and 17%, 30%, and 43% in the pharmacist-present group (p = 0.236, 0.066, and 0.039, respectively). CONCLUSION: The presence of a pharmacist during RSI procedures was associated with decreased times to postintubation sedative and analgesic use, indicating that pharmacist participation in trauma-resuscitation responses can facilitate appropriate drug therapy. PMID- 23943185 TI - Usefulness of laboratory values in predicting effectiveness of recombinant factor VIIa in surgical patients with bleeding. AB - PURPOSE: The results of a study to determine whether certain laboratory values can predict the effectiveness of recombinant factor VIIa (rFVIIa) therapy to control postoperative bleeding in surgical patients are presented. METHODS: In a retrospective observational study at a large university hospital, the records of all adult patients on the cardiothoracic surgery (CTS) and general or trauma surgery (GTS) units who received rFVIIa for treatment-refractory nonsurgical bleeding episodes (an off-label use) during a 17-month period were reviewed. Collected data included blood product requirements before and after administration of rFVIIa, selected periadministration laboratory values (e.g., International Normalized Ratio, platelet count, arterial pH, fibrinogen concentration), 24-hour and 30-day mortality, and documented adverse thrombotic events. RESULTS: Among the 18 GTS and 32 CTS patients who received rFVIIa during the study period, hemostasis (as defined according to 12- and 24-hour transfusion requirements) was achieved in 50% of patients in both groups. Two of the evaluated laboratory values were found to be predictive of reduced rFVIIa effectiveness. Hemostasis was not achieved in any patient with an arterial pH of <=7.1 or a fibrinogen concentration of <100 mg/dL. The study results did not support the hypothesis that a platelet count of <50,000 cells/L is associated with reduced effectiveness of rFVIIa therapy for the studied indication. Adverse thrombotic events occurred in 14 patients (28%) after rFVIIa administration. CONCLUSION: CTS and GTS patients with bleeding episodes and an arterial pH of <=7.1 or a fibrinogen concentration of <100 mg/dL were not likely to achieve hemostasis after rFVIIa therapy. PMID- 23943184 TI - Comparative cost-effectiveness analysis of voriconazole and fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants. AB - PURPOSE: The cost-effectiveness of voriconazole versus fluconazole prophylaxis against fungal infections in hematopoietic cell transplant (HCT) recipients is investigated. METHODS: A decision-analytic model was developed to estimate the drug costs associated with planned or supplemental prophylaxis and empirical therapy and the costs of treating suspected or documented invasive fungal infections (IFIs) in HCT recipients. Published clinical trial data on 599 patients who received 100-180 days of prophylactic therapy with voriconazole or fluconazole were used to model specified IFI-prevention and mortality outcomes; 6 month, 12-month, and lifetime incremental cost-effectiveness ratios (ICERs) were estimated, with a bootstrap analysis performed to reffect the uncertainty of the clinical trial data. RESULTS: Estimated mean total prophylaxis and IFI-related costs associated with voriconazole versus fluconazole prophylaxis over 12 months were higher in the entire study population and among patients receiving HCT for diagnoses other than acute myeloid leukemia (AML) but were not significantly different for patients with AML. The cost per IFI avoided ($66,919) and the cost per life-year gained ($5,453) were lower among patients with AML who received voriconazole relative to the full study population. ICERs were more favorable for voriconazole over a 6-month time frame and when modeling was conducted using generic price data. Assuming a threshold value of $50,000 for one year of life gained, the calculated probability of voriconazole being cost-effective was 33% for the full study population and 85% for the AML subgroup. CONCLUSION: The decision model indicated that voriconazole prophylaxis was cost-effective for patients undergoing allogeneic HCT for AML. PMID- 23943186 TI - Drug shortages as an impetus to improve parenteral nutrition practices. AB - PURPOSE: A medical center's implementation of adult and pediatric parenteral nutrition (PN) algorithms and other strategies for managing PN ingredient shortages are described. SUMMARY: In response to nationwide shortages of amino acids and other PN ingredients in 2010, a large Massachusetts teaching hospital undertook a quality-improvement initiative to ensure appropriate patient selection for PN therapy. A clinical pharmacist was designated as a nutrition support leader with responsibility for the management of PN practices. Clinical pharmacists collaborated with clinical dietitians to establish PN eligibility criteria based on established practice guidelines and developed evidence-based adult and pediatric nutrition support algorithms. In addition, (1) physicians were required to obtain a nutrition service consultation before initial prescribing of PN therapy, (2) the initial ordering of PN therapy through the computerized prescriber-order-entry (CPOE) system was restricted to clinical dietitians and clinical pharmacists, (3) the use of premixed PN solutions at the discretion of dietitians was increased, and (4) the practice of adding i.v. multivitamins and trace elements to PN solutions was restricted. During the first year after implementation of the PN algorithms, CPOE restrictions, and other process changes, PN orders were reduced by an average of five orders per day relative to the preceding 11-month period, helping to ensure continued patient access to PN therapy. CONCLUSION: PN ingredient shortages prompted changes in the decision-making process for the prescription of PN. Guidelines for ordering PN were successfully implemented and allowed for the appropriate selection of qualified patients and the management of PN ingredient shortages. PMID- 23943187 TI - Discretion of the Food and Drug Administration to enforce compounding rules. PMID- 23943188 TI - Actions of the ASHP Board of Directors--meeting of June 1 and 4, 2013. PMID- 23943189 TI - Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preterm infants. AB - BACKGROUND: Intraventricular haemorrhage (IVH) is a major complication of preterm birth. Large haemorrhages are associated with a high risk of disability and hydrocephalus. Instability of blood pressure and cerebral blood flow are postulated as causative factors. Another mechanism may involve reperfusion damage from oxygen free radicals. Phenobarbital has been suggested as a safe treatment that stabilises blood pressure and may protect against free radicals. OBJECTIVES: To determine the effect of postnatal administration of phenobarbital on the risk of IVH, neurodevelopmental impairment or death in preterm infants. SEARCH METHODS: We used the search strategy of the Neonatal Collaborative Review Group. The original review author (A Whitelaw) was an active trialist in this area and had personal contact with many groups in this field. He handsearched journals from 1976 (when cranial computed tomography (CT) scanning started) to October 2000; these included: Pediatrics, Journal of Pediatrics, Archives of Disease in Childhood, Pediatric Research, Developmental Medicine and Child Neurology, Acta Paediatrica, European Journal of Pediatrics, Neuropediatrics, New England Journal of Medicine, Lancet and British Medical Journal. We searched the National Library of Medicine (USA) database (via PubMed) and the Cochrane Central Register of Controlled Trials (CENTRAL, 2012, Issue 10) through to 31 October 2012. We did not limit the searches to the English language, as long as the article included an English abstract. We read identified articles in the original language or translated. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials in which phenobarbital was given to preterm infants identified as being at risk of IVH because of gestational age below 34 weeks, birthweight below 1500 g or respiratory failure. Adequate determination of IVH by ultrasound or CT was also required. DATA COLLECTION AND ANALYSIS: In addition to details of patient selection and control of bias, we extracted the details of the administration of phenobarbital. We searched for the following endpoints: IVH (with grading), posthaemorrhagic ventricular dilation or hydrocephalus, neurodevelopmental impairment and death. In addition, we searched for possible adverse effects of phenobarbitone, for example hypotension, mechanical ventilation, pneumothorax, hypercapnia and acidosis. MAIN RESULTS: We included 12 controlled trials that recruited 982 infants. There was heterogeneity between trials for the outcome IVH, with three trials finding a significant decrease in IVH and one trial finding an increase in IVH in the group receiving phenobarbital. Meta-analysis showed no difference between the phenobarbital treated group and the control group in either all IVH (typical risk ratio (RR) 0.91; 95% CI 0.77 to 1.08), severe IVH (typical RR 0.77; 95% CI 0.58 to 1.04), posthaemorrhagic ventricular dilation (typical RR 0.89; 95% CI 0.38 to 2.08), severe neurodevelopmental impairment (typical RR 1.44; 95% CI 0.41 to 5.04) or death before hospital discharge (typical RR 0.88; 95% CI 0.64 to 1.21). There was a consistent trend in the trials towards increased use of mechanical ventilation in the phenobarbital-treated group, which was supported by the meta-analysis (typical RR 1.18; 95% CI 1.06 to 1.32; typical risk difference 0.129; 95% CI 0.04 to 0.21), but there was no significant difference in pneumothorax, acidosis or hypercapnia. AUTHORS' CONCLUSIONS: Postnatal administration of phenobarbital cannot be recommended as prophylaxis to prevent IVH in preterm infants and is associated with an increased need for mechanical ventilation. PMID- 23943190 TI - Electroencephalography in pediatric moyamoya disease: reappraisal of clinical value. AB - PURPOSE: The clinical value of electroencephalography (EEG) in pediatric moyamoya disease has been underestimated, though the characteristic patterns are well known. We undertook this study to evaluate the clinical value of EEG as a diagnostic and postoperative follow-up modality in pediatric moyamoya disease. METHODS: We retrospectively reviewed the pre and postoperative EEG with effective hyperventilation in 127 pediatric moyamoya patients and compared their patterns with hemodynamic images. RESULTS: One hundred and two patients (80.3 %) among 127 showed abnormal EEG findings before revascularization surgery. The typical rebuild-up phenomenon was observed in 82 (64.6 %) and localized build-up in 32 (25.2 %) without any significant clinical ischemic events during and after hyperventilation. The rebuild-up was observed more frequently in younger age groups (less than 13 years) and Suzuki stages III. The location of the rebuild-up distribution and asymmetric build-up was consistent with the area showing hemodynamic abnormalities on single photon emission computed tomography and/or perfusion magnetic resonance imaging. Postoperative follow-up EEGs were performed in 41 patients. Six patients with remaining rebuild-up in postoperative follow-up EEG showed poorer postoperative clinical outcomes. CONCLUSIONS: This study may reappraise EEG as an easy, safe, and adjunctive diagnostic and postoperative follow-up modality for evaluation of hemodynamic status and clinical outcome, especially in children with moyamoya disease. PMID- 23943191 TI - Giant cell reparative granuloma of the pediatric cranium: case report and review of the literature. AB - PURPOSE: Giant cell reparative granulomas are rare bone tumors. Although benign, these tumors are locally destructive and can be highly vascular. They seldom occur in the cranial vault. We describe a multidisciplinary approach to a case of giant cell reparative granuloma of the cranium in a 3-year-old patient. CASE REPORT: A 3-year-old girl female referred to the pediatric neurosurgery department for evaluation of a retro-auricular mass. She had a history of recurrent otitis media with two subsequent courses of antibiotics without resolution. CT imaging revealed an expansive lesion located in the right mastoid region. Open surgical biopsy revealed a hemorrhagic tumor consistent with a giant cell reparative granuloma. Angiography identified a hypervascular tumor blush that was supplied by the occipital artery. Preoperative transcatheter embolization was performed followed by a multidisciplinary surgical resection and reconstruction. Blood loss was minimal, and the patient recovered well after surgery. CONCLUSION: Preoperative endovascular embolization and a multidisciplinary intraoperative approach with primary resection and cranial vault reconstruction is an effective approach to hypervascular giant cell reparative granulomas. PMID- 23943192 TI - Epigenetic modifications in cell lines of human astrocytoma differentially regulate expression of apoptotic genes. AB - OBJECTS: Epigenetic alterations, known as epimutations, act by deregulating gene expression. These epimutations are reversible through the action of chromatin modifiers such as DNA methylation (DNA-met) and histone deacetylases (HDAC) inhibitors. The present study evaluated the effect of 5-azacitidine (5-aza) and sodium butyrate (NaBu) as inhibitors of DNA-met and HDAC, respectively, in the expression of genes involved in apoptosis. METHODS: D54-MG, U373-MG, and T98G cell lines were exposed to 8 mM of NaBu and 12 MUM of 5-aza, as well as a combination of both, for 24 h. The expression of the Bcl-2, Bak-1, Bax, Caspase 3, and Caspase-9 genes was assessed by RT-PCR. RESULTS: They show that the Bcl-2, Caspase-3, and Caspase-9 genes were not expressed by the U373-MG and T98G lines, and that the D54-MG line did not express Bak-1. After treatment, however, these cell lines expressed all of the genes due to the effect of 5-aza on Bak-1 in D54 MG and Caspase-9 in T98G, which suggests repression by DNA-met. Meanwhile, Bcl-2, Caspase-3, and Caspase-9 were in the U373-MG and T98G lines expressed after NaBu treatment. The effect of 5-aza induced an increase in the expression of Bax and Bcl-2, while NaBu produced a similar effect on the Bak-1 and Bax genes. CONCLUSIONS: Results reveal that histone deacetylation is the principle mechanism for repressing these genes and that their basal expression is regulated primarily by this form of histone modification. PMID- 23943193 TI - Backbone-directed perylene dye self-assembly into oligomer stacks. AB - Arm wrestling: Backbone-directed "arm-to-arm" aggregation of a newly designed perylene bisimide (PBI) dyad with a defined intramolecular space leads to the growth of kinetically stable extended PBI pi-stacks. This PBI dyad was shown to assemble into oligomers up to 21 units in length. PMID- 23943195 TI - Custom-fit ruthenium(II) metallopeptides: a new twist to DNA binding with coordination compounds. AB - A new bipyridine building block has been used for the solid-phase synthesis of dinuclear DNA-binding ruthenium(II) metallopeptides. Detailed spectroscopic studies suggest that these compounds bind to the DNA by insertion into the DNA minor groove. Moreover, the potential of the solid-phase peptide synthesis approach is demonstrated by the straightforward synthesis of an octaarginine derivative that shows effective cellular internalization and cytotoxicity linked with strong DNA interaction, as evidenced by steady-state fluorescence spectroscopy and AFM studies. PMID- 23943196 TI - Hydrothermal realization of a hierarchical, flowerlike MnWO4@MWCNTs nanocomposite with enhanced reversible Li storage as a new anode material. AB - A phase-pure MnWO4-based nanocomposite, MnWO4@MWCNTs (MWCNTs=multiwalled carbon nanotubes), was successfully synthesized through a simple hydrothermal reaction at 180 degrees C by adjusting the pH of the precursor medium. The resulting nanocomposite maintains the original flowerlike morphology of MnWO4 with hierarchical structures composed of numerous single-crystalline nanorods that drive growth preferentially along the [001] direction. The growth mechanism for the flowerlike formations is also discussed. In addition, the Li electroactivity of pure MnWO4 and MnWO4@MWCNTs electrodes was investigated. As an anode for Li ion batteries, the MnWO4@MWCNTs nanocomposite showed enhanced electrochemical performance in reversible Li storage relative to that shown by bare MnWO4 electrodes, including a high capacity of 425 mAh g(-1) and superior rate performance. This performance can be attributed to the synergistic effect of the nanocomposite combined with the MWCNTs, which provide efficient electron transport in their role as a conductor. PMID- 23943194 TI - The change in the amount of immunoglobulins as a response to stress experienced by soldiers on a peacekeeping mission. AB - PURPOSE: Recent studies have demonstrated various changes in systemic and mucosal immunity in people undergoing psychological stress. This study was designated for an assay of associations between the stress experienced by Lithuanian soldiers as a response to changed job conditions (deployment to Afghanistan) and level of immunoglobulins. Salivary and sera immunoglobulin concentrations were assessed and compared before and after the military mission; the associations between the deployment-related stress and the immunoglobulin level were examined. METHODS: Special questionnaires covering state of health and strain experienced were used. Quantitative detection of immunoglobulins was performed by sandwich ELISA. RESULTS: Comparison of the medians at three time points (before, after the deployment and 1 year after the mission) showed an increased level of salivary secretory immunoglobulin A (S-IgA) in association with deployment. Chi-square test of independence indicated statistically significant relationship between the stress and S-IgA amount. Correlation analysis using different health control methods revealed masked fear of soldiers to be expelled from the military service. CONCLUSIONS: The results indicated that salivary S-IgA is the most sensitive representative of mucosal immunity system to psychological stress related to changed job conditions in military service. PMID- 23943198 TI - This issue is the first with a special focus: articles to one subject are co occurring in one volume. Introduction. PMID- 23943197 TI - The promise and limits of PET texture analysis. AB - Metabolic heterogeneity is a recognized characteristic of malignant tumors. Positron emission tomography (PET) texture analysis evaluated intratumoral heterogeneity in the uptake of (18)F-fluorodeoxyglucose. There were recent evidences that PET textural features were of prognostic significance in patients with different solid tumors. Unfortunately, there are still crucial standardization challenges to transform PET texture parameters from their current use as research tools into the arena of validated technologies for use in oncology practice. Testing its generalizability, robustness, consistency, and limitations is necessary before implementing it in daily patient care. PMID- 23943201 TI - Complexation of rhodium(II) tetracarboxylates with aliphatic diamines in solution: 1H and 13C NMR and DFT investigations. AB - The complexation of rhodium(II) tetraacetate, tetrakistrifluoroaceate and tetrakisoctanoate with a set of diamines (ethane-1,diamine, propane-1,3-diamine and nonane-1,9-diamine) and their N,N'-dimethyl and N,N,N',N'-tetramethyl derivatives in chloroform solution has been investigated by (1) H and (13) C NMR spectroscopy and density functional theory (DFT) modelling. A combination of two bifunctional reagents, diamines and rhodium(II) tetracarboxylates, yielded insoluble coordination polymers as main products of complexation and various adducts in the solution, being in equilibrium with insoluble material. All diamines initially formed the 2 : 1 (blue), (1 : 1)n oligomeric (red) and 1 : 2 (red) axial adducts in solution, depending on the reagents' molar ratio. Adducts of primary and secondary diamines decomposed in the presence of ligand excess, the former via unstable equatorial complexes. The complexation of secondary diamines slowed down the inversion at nitrogen atoms in NH(CH3 ) functional groups and resulted in the formation of nitrogenous stereogenic centres, detectable by NMR. Axial adducts of tertiary diamines appeared to be relatively stable. The presence of long aliphatic chains in molecules (adducts of nonane-1,9 diamines or rhodium(II) tetrakisoctanoate) increased adduct solubility. Hypothetical structures of the equatorial adduct of rhodium(II) tetraacetate with ethane-1,2-diamine and their NMR parameters were explored by means of DFT calculations. PMID- 23943202 TI - The acceptability of parenting strategies for grandparents providing care to their grandchildren. AB - Despite the evidence supporting parenting programmes as a pathway to reduce and prevent childhood emotional and behavioural problems, these programmes still have low rates of uptake by families in the community. One way of increasing the participation rates of families in parenting programmes is to adopt a consumer's perspective to programme design and development. This study sought to examine whether grandparents providing regular care to their grandchildren viewed the strategies advocated in a parenting programme developed specifically for them as being acceptable and useful, and whether there were barriers to programme use. Forty-five grandparents, with an average age of 61.4 years (SD = 5.0), participated in the study. Grandparents provided between 11 and 20 h of care per week to their grandchildren, who were on average 4.5 years old (SD = 2.4), with the majority being boys (60%). Results revealed that grandparents found the strategies promoted in the parenting programme highly acceptable and useful and were likely to use the strategies. Barriers to using specific strategies included time demands and belief that a specific strategy would not work. The implications of these findings are discussed within the context of consumer involvement in programme design and development. PMID- 23943204 TI - Ground and remote sensing-based measurements of leaf area index in a transitional forest and seasonal flooded forest in Brazil. AB - Leaf area index (LAI) is a key driver of forest productivity and evapotranspiration; however, it is a difficult and labor-intensive variable to measure, making its measurement impractical for large-scale and long-term studies of tropical forest structure and function. In contrast, satellite estimates of LAI have shown promise for large-scale and long-term studies, but their performance has been equivocal and the biases are not well known. We measured total, overstory, and understory LAI of an Amazon-savanna transitional forest (ASTF) over 3 years and a seasonal flooded forest (SFF) during 4 years using a light extinction method and two remote sensing methods (LAI MODIS product and the Landsat-METRIC method), with the objectives of (1) evaluating the performance of the remote sensing methods, and (2) understanding how total, overstory and understory LAI interact with micrometeorological variables. Total, overstory and understory LAI differed between both sites, with ASTF having higher LAI values than SFF, but neither site exhibited year-to-year variation in LAI despite large differences in meteorological variables. LAI values at the two sites have different patterns of correlation with micrometeorological variables. ASTF exhibited smaller seasonal variations in LAI than SFF. In contrast, SFF exhibited small changes in total LAI; however, dry season declines in overstory LAI were counteracted by understory increases in LAI. MODIS LAI correlated weakly to total LAI for SFF but not for ASTF, while METRIC LAI had no correlation to total LAI. However, MODIS LAI correlated strongly with overstory LAI for both sites, but had no correlation with understory LAI. Furthermore, LAI estimates based on canopy light extinction were correlated positively with seasonal variations in rainfall and soil water content and negatively with vapor pressure deficit and solar radiation; however, in some cases satellite-derived estimates of LAI exhibited no correlation with climate variables (METRIC LAI or MODIS LAI for ASTF). These data indicate that the satellite-derived estimates of LAI are insensitive to the understory variations in LAI that occur in many seasonal tropical forests and the micrometeorological variables that control seasonal variations in leaf phenology. While more ground-based measurements are needed to adequately quantify the performance of these satellite-based LAI products, our data indicate that their output must be interpreted with caution in seasonal tropical forests. PMID- 23943203 TI - Rationale for and review of neoadjuvant therapy prior to radical prostatectomy for patients with high-risk prostate cancer. AB - Despite state of the art local therapy, a significant portion of men with high risk prostate cancer develop progressive disease. Neoadjuvant systemic therapy prior to radical prostatectomy (RP) is an approach that can potentially maximize survival outcomes in patients with localized disease. This approach is under investigation with a wide array of agents and provides an opportunity to assess pathologic and biologic activity of novel treatments. The aim of this review is to explore the past and present role of neoadjuvant therapy prior to definitive therapy with RP in patients with high-risk localized or locally advanced disease. The results of neoadjuvant androgen-deprivation therapy (ADT), including use of newer agents such as abiraterone, are promising. Neoadjuvant chemotherapy, primarily with docetaxel, with or without ADT has also demonstrated efficacy in men with high-risk disease. Other novel agents targeting the vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR), clusterin, and the immune system are currently under investigation and have led to variable results in early clinical trials. Despite optimistic data, approval of neoadjuvant therapy prior to RP in patients with high-risk prostate cancer will depend on positive results from well designed phase III trials. PMID- 23943205 TI - Satureja khuzestanica prevents the development of morphine analgesic tolerance through suppression of spinal glial cell activation in rats. AB - Glial cell activation and oxidative stress are important factors in the induction of opioid side effects such as tolerance and dependence. It has been demonstrated that Satureja khuzistanica extract (SKE) has antioxidative, antinociceptive and anti-inflammatory properties; however, its influences on opioid analgesic tolerance have not yet been clarified. Adult male Wistar rats were rendered analgesic-tolerant by injection of 10 mg/kg morphine twice daily for 8 days. To determine the effect of SKE on the development of morphine tolerance, different doses of SKE (25, 50 and 100 mg/kg i.p.) were injected simultaneously with morphine. The tail-flick test was used to assess the nociceptive threshold. The lumbar spinal cord was assayed to determine glial fibrillary acidic protein (GFAP) and tumor necrosis factor alpha (TNFalpha) levels by the Western blotting method. Our results showed that chronic morphine produced tolerance to the antinociceptive effect of morphine. However, SKE could prevent, in a dose dependent manner, morphine tolerance development. In tolerant animals, a significant increase in GFAP and TNFalpha levels was observed in the lumbar spinal cord, and was reversed to control levels by 100 mg/kg SKE. Our data revealed that Satureja khuzistanica had beneficial effects in preventing opioid tolerance and the underlying mechanisms of those effects may be due, at least in part, to reduce spinal glial cell activation. PMID- 23943206 TI - Novel FOXF1 deep intronic deletion causes lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins. AB - Haploinsufficiency of FOXF1 causes an autosomal dominant neonatally lethal lung disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). We identified novel 0.8-kb deletion within the 1.4-kb intron of FOXF1 in a deceased newborn diagnosed with ACDMPV. The deletion arose de novo on the maternal copy of the chromosome 16, and did not affect FOXF1 minigene splicing tested in lung fibroblasts. However, FOXF1 transcript level in the ACDMPV peripheral lung tissue was reduced by almost 40%. We found that, in an in vitro reporter assay, the FOXF1 intron exhibited moderate transcriptional enhancer activity, correlating with the presence of binding sites for expression regulators CTCF and CEBPB, whereas its truncated copy, which lost major CTCF and CEBPB-binding sites, inhibited the FOXF1 promoter. Our data further emphasize the importance of testing the non-protein coding regions of the genome currently not covered by diagnostic chromosomal microarray analyses or whole-exome sequencing. PMID- 23943208 TI - Unraveling DNA damage response-signaling networks through systems approaches. AB - Genotoxic perturbation holds a central place in cancer formation and aging, but also is key to cancer therapy by irradiation or chemotherapeutic drugs. Sensing of DNA lesions initiates a highly complex DNA damage response (DDR). This response involves signaling cascades that activate appropriate damage repair pathways, arrest the cell cycle, and ultimately determine cell survival or death. The DDR must be integrated with ongoing signaling and housekeeping processes. With the emergence of high-throughput omics technologies, it has become clear that DNA damage-mediated responses penetrate far deeper than previously appreciated into virtually all cellular signaling pathways. Advances in the last decade have revealed a plethora of early DNA damage-induced changes in posttranslational modifications and subsequent alterations in gene expression profiles, and have provided a glimpse into the assorted rewiring of signal transduction cascades providing biomarkers for chemo- or radiosensitivity. At the same time, genome-wide RNAi screening has provided mechanistic insights into DDR signaling cascades and identified genes involved in mechanisms of cancer resistance to genotoxic therapies. Most recently, distinct omics datasets have been integrated, and sophisticated mathematical models have been applied to the DDR. Here, we review such recent advances that have widened and, in some cases, deepened our knowledge of DDR signaling. PMID- 23943207 TI - Immune monitoring of islet and pancreas transplant recipients. AB - Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing beta-cells are destroyed. Islet or pancreas transplantation can restore insulin secretion and are established therapies for subgroups of T1D patients. Long-term insulin-independence is, however, hampered by recurrent autoimmunity and rejection. Accurate monitoring of these immune events is therefore of critical relevance for the timely detection of deleterious immune responses. The identification of relevant immune biomarkers of allo- and autoreactivity has allowed a more accurate monitoring of disease progression and responses to therapy at early stages, allowing proper therapeutic intervention, and possibly improvements in the success rate of islet and pancreas transplantation. This review describes the tools established and validated to monitor immune correlates of auto- and alloreactivity that associate with clinical outcome and identifies challenges that current immunosuppression strategies trying to preserve islet graft function face. PMID- 23943209 TI - Monocrotophos in Gandaman village: India school lunch deaths and need for improved toxicity testing. PMID- 23943210 TI - Probabilistic ecological risk assessment of polycyclic aromatic hydrocarbons in southwestern catchments of the Bohai Sea, China. AB - A probability risk assessment was undertaken to study the individual and combined ecological risks induced by six polycyclic aromatic hydrocarbons (PAHs) both in surface water and sediment from southwestern catchments of the Bohai Sea, China. The actual measured PAH concentrations in water and sediment were compared with toxicity effect data (the 10th percentile of predicted no effect concentration) to calculate the risk quotients (RQs) for an individual PAH. The equilibrium partitioning method was applied to estimate toxicity data in sediment. A method based on the equivalent concentration concept was proposed and applied to assess the combined ecological risk of multiple PAHs. Monte Carlo simulation and bootstrap technique were utilized to calculate the distribution of RQs and associated uncertainties. The ecological safety level was defined by RQ <= 1. Results indicated that both in water and sediment, fluoranthene and pyrene posed the highest risks, whereas acenaphthene and fluorene posed negligible risks. Naphthalene and phenanthrene did not pose risks to the ecological community in surface water but had relatively higher risks in sediment. The median RQs of combined risk in surface water and sediment were 0.934 and 2.42, and the probabilities of RQ > 1 were up to 0.473 and 0.599, respectively, which were much higher than the individual compound acting alone. The risk level in sediment was quite higher than in surface water probably owing to the non-equilibrium distribution between two phases, which suggested that local authorities should focus more on sediment quality management. PMID- 23943211 TI - Antioxidant response and histopathological changes in brain tissue of pigeon exposed to avermectin. AB - Avermectins (AVMs) are the active components of some insecticidal and nematicidal products used in agriculture and veterinary medicine for the prevention of parasitic diseases. Residues of AVM drugs or their metabolites in livestock feces have toxic effects on non-target aquatic and terrestrial organisms. In this study, oxidative stress responses and pathological changes on pigeon brain tissues and serum after subchronic exposure to AVM for 30, 60 and 90 days were investigated. The decrease in antioxidant enzyme (superoxide dismutase, SOD and glutathione peroxidase, GSH-Px) activities and increase in methane dicarboxylic aldehyde content in a dose-time-dependent manner in the brain and serum of pigeon were observed. The protein carbonyl content, an indicator of protein oxidation, and DNA-protein crosslink coefficient were significantly augmented with dose-time dependent properties. The microscopic structures of the cerebrum, cerebellum and optic lobe altered obviously, the severity of which increased with the concentration of AVM and exposure time. The results imply that AVM could induce oxidative damage to the brain tissue and serum of pigeon. The information presented in this study is helpful to understand the mechanism of AVM-induced oxidative stress in birds. PMID- 23943213 TI - Dynamic cerebral autoregulation in acute intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Cerebral autoregulation (CA) is not universally impaired in acute intracerebral hemorrhage (ICH); however, the dynamic components of CA are probably more vulnerable. This study, therefore, evaluates the time course of dynamic CA in acute ICH and its relationship to clinical outcome. METHODS: Twenty six patients with ICH were studied on days 1, 3, and 5 after ictus. Dynamic CA was measured from spontaneous fluctuations in blood pressure and middle cerebral artery flow velocity by transfer function phase (reflecting rapidity of CA) and gain (reflecting damping characteristics of CA) in the low frequency range. Results were compared with those from 55 controls and related with clinical factors and 90-day outcome (modified Rankin scale). RESULTS: Phase did not fluctuate significantly over time, nor did it differ between sides or differ from controls. Gain was always higher in patients than in controls but showed no significant association with outcome or other clinical factors. At day 1, poorer ipsilateral phase was associated with lower blood pressure and higher ICH volume. Poorer phase always coincided with lower Glasgow Coma Scale values. Poorer ipsilateral phase on day 5 was related with poorer clinical outcome according to multivariate analysis (P=0.013). CONCLUSIONS: Dynamic temporal characteristics of CA (phase) are not generally altered in acute ICH. Poorer individual phase values are, however, associated with larger ICH volume, lower blood pressure, and worsened outcome. Dampening characteristics of CA (gain) are generally impaired in acute ICH but not related to clinical factors or outcome. PMID- 23943214 TI - Response to letter regarding article, "CYP2C19 polymorphisms and antiplatelet effects of clopidogrel in acute ischemic stroke in China". PMID- 23943215 TI - Aggressive medical therapy alone is adequate in certain patients with severe symptomatic carotid stenosis. PMID- 23943216 TI - Letter by Dong et al regarding article, "CYP2C19 polymorphisms and antiplatelet effects of clopidogrel in acute ischemic stroke in China". PMID- 23943217 TI - Cost-effectiveness of surgical decompression for space-occupying hemispheric infarction. AB - BACKGROUND AND PURPOSE: Surgical decompression reduces mortality and increases the probability of a favorable functional outcome after space-occupying hemispheric infarction. Its cost-effectiveness is uncertain. METHODS: We assessed clinical outcomes, costs, and cost-effectiveness for the first 3 years in patients who were randomized to surgical decompression or best medical treatment within 48 hours after symptom onset in the Hemicraniectomy After Middle Cerebral Artery Infarction With Life-Threatening Edema Trial (HAMLET). Data on medical consumption were derived from case record files, hospital charts, and general practitioners. We calculated costs per quality-adjusted life year (QALY). Uncertainty was assessed with bootstrapping. A Markov model was constructed to estimate costs and health outcomes after 3 years. RESULTS: Of 39 patients enrolled within 48 hours, 21 were randomized to surgical decompression. After 3 years, 5 surgical (24%) and 14 medical patients (78%) had died. In the first 3 years after enrollment, operated patients had more QALYs than medically treated patients (mean difference, 1.0 QALY [95% confidence interval, 0.6-1.4]), but at higher costs (mean difference, ?127,000 [95% confidence interval, 73,100 181,000]), indicating incremental costs of ?127,000 per QALY gained. Ninety-eight percent of incremental cost-effectiveness ratios replicated by bootstrapping were >?80,000 per QALY gained. Markov modeling suggested costs of ~?60,000 per QALY gained for a patient's lifetime. CONCLUSIONS: Surgical decompression for space occupying infarction results in an increase in QALYs, but at very high costs. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN94237756. PMID- 23943218 TI - Thrombolysis for ischemic stroke associated with infective endocarditis: results from the nationwide inpatient sample. AB - BACKGROUND AND PURPOSE: Cerebral ischemic events are highly prevalent and associated with high rates of death and disability in patients with infective endocarditis (IE). However, the role of thrombolysis in these patients remains unclear. We sought to determine the rates and outcomes of acute ischemic stroke patients with IE treated with intravenous thrombolysis (IVT). METHODS: We determined the rates of post-thrombolytic intracerebral hemorrhage and favorable outcome among acute ischemic stroke patients with IE treated with IVT. Patients were identified using Nationwide Inpatient Sample data from 2002 to 2010. We compared the rates of various outcomes with ischemic stroke patients without IE treated with IVT. RESULTS: There were 222 patients (mean age 59+/-18 years; 46% women) who were treated with IVT for acute ischemic stroke associated with IE and 134,048 patients (mean age 69+/-15 years; 49% women) who were treated for stroke without IE. The rate of post-thrombolytic intracerebral hemorrhage was significantly higher in patients with IE compared with those without IE (20% versus 6.5%; P=0.006). There was a significantly lower rate of favorable outcome in the IE group (10% versus 37%; P=0.01). CONCLUSIONS: High rates of post thrombolytic intracerebral hemorrhage and low rates of favorable outcome mandate caution in using IVT in acute ischemic stroke patients with IE. PMID- 23943219 TI - Letter by Aries et al regarding article, "autoregulation of cerebral blood flow is preserved in primary intracerebral hemorrhage". PMID- 23943220 TI - Letter by Wachter et al regarding article, "occult atrial fibrillation in cryptogenic stroke: detection by 7-day electrocardiogram versus implantable cardiac monitors". PMID- 23943222 TI - Pleasure of discovery: why we love research. PMID- 23943221 TI - Role of histone lysine methyltransferases SUV39H1 and SETDB1 in gliomagenesis: modulation of cell proliferation, migration, and colony formation. AB - Posttranslational modifications of histones are considered as critical regulators of gene expression, playing significant role in the pathogenesis and progression of tumors. Trimethylation of histone 3 lysine 9 (H3K9me3), a repressed transcription mark, is mainly regulated by the histone lysine N methyltransferases (HKMTs), SUV39H1 and SETDB1. The present study investigated the implication of these HKMTs in glioma progression. SUV39H1 and SETDB1 expression was upregulated in glioma cell lines (GOS-3, 1321N1, T98G, U87MG) and in glioma tissues compared to normal brain being positively correlated with grade and histological malignancy. Suppression by siRNA of the two HKMTs for 24 and 48 h resulted in significantly reduced proliferation of GOS-3 and T98G glioma cells with siSUV39H1 effects been most prominent. Furthermore, HKMTs knockdown-induced apoptosis with a high rate of apoptotic cells have been observed after siSUV39H1 and siSETDB1 for both cell lines. Additionally, suppression of the two HKMTs reduced cell migration and clonogenic ability of both glioma cell lines. Our results indicate overexpression of SETDB1 and SUV39H1 in gliomas. Treatments that alter HKMT expression affect the proliferative and apoptotic rates in glioma cells as well as their migratory and colony formation capacity. These data suggest that both HKMTs and especially SUV39H1 may serve as novel biomarkers for future therapeutic targeting of these tumors. PMID- 23943223 TI - The influence of surgical hoods and togas on airborne particle concentration at the surgical site: an experimental study. AB - BACKGROUND: Arthroplasty surgeons are increasingly using personal protection systems with helmets. It is theoretically possible for the fans in these helmets to blow squames, sweat droplets and orobronchial fomites onto the surgical site. A controlled experiment was set up to investigate the effect of different surgical gowns on counts of airborne particles measuring >=0.3 MUm, using a hand held particle counter. METHODS: The clothing that was sequentially tested included the following: 1. Barrier((r)) surgical gown (single use) made from nonwoven polypropylene (Molnlycke Health Care Ltd, Dunstable, UK) 2. Stryker((r)) T5 Helmet (reusable) covered with a disposable Stryker((r)) T4/T5 urethane hood worn separate to and enclosed by the Barrier((r)) surgical gown both at the front and back 3. Stryker((r)) T5 Helmet (reusable) worn within a disposable Stryker((r)) T4/T5 urethane zippered toga (Stryker Corporation, Kalamazoo, MI, USA) Six readings were taken for each of the following three setups in a randomised order: 1. Gown: surgeon with surgical gown and face mask 2. Hood: surgeon with surgical gown and hood, maximum fan speed 3. Toga: surgeon with toga, maximum fan speed Wilcoxon rank sum tests were applied to assess equality of means between the three occlusive measures (gown, hood, toga). P values were computed based upon one-sided tests and adjusted for multiple comparisons using the Bonferroni correction. RESULTS: The mean particle counts (over more than 5 L of air) for the three set-ups were: gown: 1178 (least protective), hood: 328, toga: 42 (most protective). There was a significant reduction in particle counts for the toga versus gown (p = 0.007) and toga versus hood (p = 0.037); differences in particle counts were not significant between the hood and gown (p = 0.140). CONCLUSIONS: The fans in the helmets do not increase contaminants by blowing particles from the head area. A significant reduction in surgeon originated contaminants was seen with the toga compared to both the hood/gown separate ensemble and gowns alone. PMID- 23943224 TI - Normal sequential changes in neutrophil CD64 expression after total joint arthroplasty. AB - BACKGROUND: Neutrophil CD64 has been reported to be a sensitive and specific infection marker. Its measurement is thus considered to be useful in early diagnosis of post-operative periprosthetic infection. However, even its normal sequential changes after non-infectious total joint arthroplasty have remained ambiguous. Accordingly, we analyzed 2-week sequential neutrophil CD64 expression changes after total joint arthroplasty in order to clarify its normal postoperative kinetics. PATIENTS AND METHOD: From 41 patients who underwent primary total joint arthroplasties, peripheral blood samples were obtained at 1 day before (baseline) and 1, 3, 5, 7, and 14 days after surgery, and CD64 expression per cell was quantitatively measured. C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR) and white blood cell count (WBC) were simultaneously measured. RESULTS: No cases of postoperative local infection were observed. Levels of CD64 significantly elevated from day 1, peaked at day 3, and decreased significantly following day 5. Statistical analysis confirmed that significant differences existed between the baseline level and the levels at days 1 and 3, while no significant differences existed between the baseline level and those at days 5, 7 or 14. In 17 patients, CD64 peaked at over 2,000 molecules/cell, the level reported to be a cutoff value for distinguishing infection. Multiple regression analysis showed that the sole parameter of baseline CD64 level significantly explained the peak CD64 level. Postoperative CD64 peaks ranged from 1.6 to 2.7 times (median 1.9) the baseline levels. CRP, ESR and WBC also showed rapid elevations and all but WBC remained significantly higher than baseline at day 14. CONCLUSION: CD64 levels rise significantly, peaking within about 3 days following normal total joint arthroplasty, but decrease rapidly to near baseline within about 5 days. The data obtained can be expected to form a possible basis for early diagnosis of postoperative periprosthetic infection. PMID- 23943225 TI - Surgical correction of severe kyphoscoliosis resulting in a neurological complication in Marshall-Smith syndrome. PMID- 23943226 TI - The relationship between pretreatment anaemia and survival in patients with adult soft tissue sarcoma. AB - INTRODUCTION: Anaemia is present in more than 30 % of patients with various cancers at the time of initial presentation. Anaemia or a lower level of haemoglobin (Hb) is an indicator of poorer prognosis in many cancers. Several studies have also demonstrated that high levels of proinflammatory cytokines contribute to the development of anaemia. However, no studies have assessed the correlation between anaemia and survival in patients with soft tissue sarcoma. The aim of this study was to elucidate the relationship between anaemia and clinical outcome and to determine whether pretreatment anaemia predicted disease specific survival in patients with adult soft tissue sarcoma. METHODS: A total of 376 patients between 2003 and 2010 were retrospectively reviewed. Patients who presented with metastases or/and local recurrence at diagnosis were excluded from this study. RESULTS: Hb levels varied from 8.0 to 17.3 g/dl in all patients. Pretreatment anaemia was seen in 114 patients. Hb levels were significantly correlated to C-reactive protein levels (Spearman rho = -0.54, p < 0.0001). The tumour histological grade, age and tumour size were also significantly correlated to Hb levels. Patients with anaemia had a worse disease-specific survival (52.6 % at 5 years) than those without anaemia (79.7 % at 5 years) (p < 0.0001). Patients with anaemia also had a worse event-free rate (44 % at 5 years) than those without anaemia (66.3 % at 5 years) (p < 0.0001). Multivariate analysis showed that anaemia remained an independent predictor of survival (p = 0.002) and events (p = 0.0003). CONCLUSION: Pretreatment anaemia may be indicative of an aggressive characteristic in patients with soft tissue sarcoma. We recommend the routine measurement of Hb level to identify patients who are at greater risk of death or an event. PMID- 23943227 TI - Childhood central nervous system tumors at MAHAK's Pediatric Cancer Treatment and Research Center (MPCTRC), Tehran, Iran. AB - PURPOSE: As central nervous system (CNS) tumors account for second most common childhood malignancies and the first cause of mortality in children with cancer, improving treatment modalities can lead to increase the health care of patients. In this study, we examined the prevalence of childhood brain tumors in patients who referred to MAHAK's Pediatric Cancer Treatment and Research Center (MPCTRC) for treatment. METHODS: A retrospective review of all children less than 15 years old with a CNS histologically proven tumor, who presented to MPCTRC from April 2007 to April 2010, was performed. Data was analyzed by SPSS version 19 with Kolmogorov-Smirnov and Chi-square tests. RESULTS: There were 198 (124 boys) children eligible for the study. The majority of the tumors were infratentorial (n = 134), and the rest were supratentorial (n = 60) and spinal (n = 4) cases. The median age was 6.11 +/- 3.65 years old. Medulloblastoma (n = 66), low-grade glioma (n = 52), and high-grade glioma (n = 40) were the most common tumors. The mean duration of follow-up was 21 months. At the time of this analysis, there were 105 (53 %) children alive, 82 (41.4 %) deaths, and 11 (5.6 %) lost for follow-up. The survival rate was 51.68 +/- 5.22 %. CONCLUSIONS: In contrast of high rate of death in this study, other general characteristics can serve as benchmark for improving our care for children with brain tumors in Iran. PMID- 23943229 TI - Polymeric micelles for multidrug delivery and combination therapy. AB - The use of conventional therapy based on a single therapeutic agent is not optimal to treat human diseases. The concept called "combination therapy", based on simultaneous administration of multiple therapeutics is recognized as a more efficient solution. Interestingly, this concept has been in use since ancient times in traditional herbal remedies with drug combinations, despite mechanisms of these therapeutics not fully comprehended by scientists. This idea has been recently re-enacted in modern scenarios with the introduction of polymeric micelles loaded with several drugs as multidrug nanocarriers. This Concept article presents current research and developments on the application of polymeric micelles for multidrug delivery and combination therapy. The principles of micelle formation, their structure, and the developments and concept of multidrug delivery are introduced, followed by discussion on recent advances of multidrug delivery concepts directed towards targeted drug delivery and cancer, gene, and RNA therapies. The advantages of various polymeric micelles designed for different applications, and new developments combined with diagnostics and imaging are elucidated. A compilation work from our group based on multidrug loaded micelles as carriers in drug-releasing implants for local delivery systems based on titania nanotubes is summarized. Finally, an overview of recent developments and prospective outlook for future trends in this field is given. PMID- 23943230 TI - Continuous glucose monitoring: current use and future directions. AB - Continuous glucose monitoring (CGM) is an emerging technology that provides a continuous measure of interstitial glucose levels. In addition to providing a more complete pattern of glucose excursions, CGMs utilize real-time alarms for thresholds and predictions of hypo- and hyperglycemia, as well as rate of change alarms for rapid glycemic excursions. CGM users have been able to improve glycemic control without increasing their risk of hypoglycemia. Sensor accuracy, reliability, and wearability are important challenges to CGM success and are critical to the development of an artificial pancreas (or closed-loop system). PMID- 23943231 TI - A chronic oral reference dose for hexavalent chromium-induced intestinal cancer. AB - High concentrations of hexavalent chromium [Cr(VI)] in drinking water induce villous cytotoxicity and compensatory crypt hyperplasia in the small intestines of mice (but not rats). Lifetime exposure to such cytotoxic concentrations increases intestinal neoplasms in mice, suggesting that the mode of action for Cr(VI)-induced intestinal tumors involves chronic wounding and compensatory cell proliferation of the intestine. Therefore, we developed a chronic oral reference dose (RfD) designed to be protective of intestinal damage and thus intestinal cancer. A physiologically based pharmacokinetic model for chromium in mice was used to estimate the amount of Cr(VI) entering each intestinal tissue section (duodenum, jejunum and ileum) from the lumen per day (normalized to intestinal tissue weight). These internal dose metrics, together with corresponding incidences for diffuse hyperplasia, were used to derive points of departure using benchmark dose modeling and constrained nonlinear regression. Both modeling techniques resulted in similar points of departure, which were subsequently converted to human equivalent doses using a human physiologically based pharmacokinetic model. Applying appropriate uncertainty factors, an RfD of 0.006 mg kg(-1) day(-1) was derived for diffuse hyperplasia-an effect that precedes tumor formation. This RfD is protective of both noncancer and cancer effects in the small intestine and corresponds to a safe drinking water equivalent level of 210 ug l(-1). This concentration is higher than the current federal maximum contaminant level for total Cr (100 ug l(-1)) and well above levels of Cr(VI) in US drinking water supplies (typically <= 5 ug l(-1)). PMID- 23943232 TI - Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility. AB - BACKGROUND: The use of assisted reproductive techniques is increasing, but the possible link between fertility drugs and ovarian cancer remains controversial. OBJECTIVES: To evaluate the risk of ovarian cancer in women treated with ovulation stimulating drugs for subfertility. SEARCH METHODS: We searched for published and unpublished observational studies from 1990 to February 2013. The following databases were used: the Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 1, MEDLINE (to February week 4 2013), EMBASE (to 2013 week 09) and databases of conference abstracts. We also scanned reference lists of retrieved articles. The search was not restricted by language of publication. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) and non randomised studies, and case series including more than 30 participants, reporting on women with exposure to ovarian stimulating drugs for treatment of subfertility and histologically confirmed borderline or invasive ovarian cancer. DATA COLLECTION AND ANALYSIS: At least two review authors independently conducted eligibility and 'Risk of bias' assessment, and extracted data. We grouped studies based on the fertility drug used for two outcomes: borderline ovarian tumours and invasive ovarian cancer. We expressed findings as adjusted odds ratio (OR), risk ratio (RR), hazard ratio (HR) or crude OR if adjusted values were not reported and standardised incidence ratio (SIR) where reported. We conducted no meta analyses due to expected methodological and clinical heterogeneity. MAIN RESULTS: We included 11 case-control studies and 14 cohort studies, which included a total of 182,972 women.Seven cohort studies showed no evidence of an increased risk of invasive ovarian cancer in subfertile women treated with any drug compared with untreated subfertile women. Seven case-control studies showed no evidence of an increased risk, compared with control women of a similar age. Two cohort studies reported an increased incidence of invasive ovarian cancer in subfertile women treated with any fertility drug compared with the general population. One of these reported a SIR of 5.0 (95% confidence interval (CI) 1.0 to 15), based on three cancer cases, and a decreased risk when cancer cases diagnosed within one year of treatment were excluded from the analysis(SIR 1.67, 95% CI 0.02 to 9.27). The other cohort study reported an OR of 2.09 (95% CI 1.39 to 3.12), based on 26 cases.For borderline ovarian tumours, exposure to any fertility drug was associated with a two to three-fold increased risk in two case-control studies. One case-control study reported an OR of 28 (95% CI 1.5 to 516), which was based on only four cases. In one cohort study, there was more than a two-fold increase in the incidence of borderline tumours compared with the general population (SIR 2.6, 95% CI 1.4 to 4.6) and in another the risk of a borderline ovarian tumour was HR 4.23 (95% CI 1.25 to 14.33) for subfertile women treated with in vitro fertilisation (IVF) compared with a non-IVF treated group with more than one year of follow-up.There was no evidence of an increased risk in women exposed to clomiphene alone or clomiphene plus gonadotrophin, compared with unexposed women. One case-control study reported an increased risk in users of human menopausal gonadotrophin (HMG)(OR 9.4, 95% CI 1.7 to 52). However, this estimate is based on only six cases with a history of HMG use. AUTHORS' CONCLUSIONS: We found no convincing evidence of an increase in the risk of invasive ovarian tumours with fertility drug treatment. There may be an increased risk of borderline ovarian tumours in subfertile women treated with IVF. Studies showing an increase in the risk of ovarian cancer had a high overall risk of bias, due to retrospective study design, lack of accounting for potential confounding and estimates based on a small number of cases. More studies at low risk of bias are needed. PMID- 23943234 TI - Total phenolic and phytosterol compounds and the radical scavenging activity of germinated Australian sweet lupin flour. AB - In addition to their favourable nutritional profile, legumes also contain a range of bioactive compounds such as phenolic compounds and phytosterols which may protect against chronic diseases including cancer and cardiovascular disease. Germination of some legume seeds has been previously reported to increase the concentration of the bioactive compounds. In this study, the effect of germination of Australian Sweet Lupin (ASL) seeds for 9 days on the concentration of some bioactive compounds and the radical scavenging activity in the resulting flour was determined. The concentration of total phenolic compounds in methanolic extracts of germinated ASL flour was determined using Folin Ciocalteu reagent and phytosterols in oil extracts were analyzed by gas-liquid chromatography. The methanolic and oil extracts were also used to determine radical scavenging activity toward 2,2-diphenyl-1-picrylhydrazyl. In the methanolic extracts of germinated ASL flour, phenolic contents and the antioxidant activity were significantly increased following germination (700 and 1400 %, respectively). Analysis of the oil extracts of germinated ASL flour revealed that the concentration of phytosterols and the antioxidant activity were also increased significantly compared to ungerminated ASL flour (300 and 800 %, respectively). The relative proportion of phytosterols in germinated ASL flour was: beta sitosterol (60 %), stigmasterol (30 %) and campesterol (10 %). Germination increases the concentration of bioactive compounds and the radical scavenging activity in the germinated ASL flour. PMID- 23943235 TI - Cytologic subtyping of lung adenocarcinoma by using the proposed International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) adenocarcinoma classification. AB - BACKGROUND: The significance of histologic subtyping of surgically resected lung adenocarcinoma (ADC) was recently proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification. Approximately 70% of lung cancer patients present with advanced disease, and small biopsies or cytology specimens are frequently the only available diagnostic material. It is uncertain whether proposed morphologic subtyping of ADC can be applied to small specimens. The objective of this study was to assess the applicability of morphologic subtyping of ADC on cytologic specimens. METHODS: Consecutive, newly diagnosed primary lung ADC specimens from patients with matched surgical resection and cytology specimens (n = 66) were selected for the study. The dominant morphologic pattern was determined according to the IASLC/ATS/ERS classification. The number and percentage of malignant cells in cytology specimens were also evaluated. RESULTS: Concordant subtyping of ADC between the dominant pattern on resection and cytology specimens was observed in 26 cases (40%), and was discordant in 32 cases (48%). Concordance increased in specimens that had >200 cells and when correlating with the primary or secondary histologic pattern. The acinar pattern was the most common in concordant cases, whereas discordant cases had a predominantly solid pattern. CONCLUSIONS: Application of the IASLC/ATS/ERS ADC classification to cytologic specimens is challenging and depends on the sufficient cellularity of cytologic preparations. The identification of solid and micropapillary patterns is prognostically important but may be unreliable and difficult on cytology specimens. Future studies are needed to establish reproducible cytologic criteria for the precise subtyping of lung ADC on small specimens. PMID- 23943236 TI - Optimization of the C11-BODIPY(581/591) dye for the determination of lipid oxidation in Chlamydomonas reinhardtii by flow cytometry. AB - Lipid oxidation is a recognized end point for the study of oxidative stress and is an important parameter to describe the mode of micropollutant action on aquatic microorganisms. Therefore, the development of quick and reliable methodologies probing the oxidative stress and damage in living cells is highly sought. In the present proof-of-concept work, we examined the potential of the fluorescent dye C11-BODIPY(591/581) to probe lipid oxidation in the green microalga Chlamydomonas reinhardtii. C11-BODIPY(591/581) staining was combined with flow cytometry measurements to obtain multiparameter information on cellular features and oxidative stress damage within single cells. First, staining conditions were optimized by exploring the capability of the dye to stain algal cells under increasing cell and dye concentrations and different staining procedures. Then lipid oxidation in algae induced by short- and long-term exposures to the three metallic micropollutants, copper, mercury, and nanoparticulate copper oxide, and the two organic contaminants, diethyldithiocarbamate (DDC) and diuron was determined. In this work we pointed out C11-BODIPY(591/581) applicability in a wide range of exposure conditions, including studies of oxidation as a function of time and that it is suitable for in vivo measurements of lipid oxidation due to its high permeation and stability in cells and its low interference with algal autofluorescence. (c) 2013 International Society for Advancement of Cytometry. PMID- 23943238 TI - [The Austrian Palliative Society]. PMID- 23943237 TI - Ferroportin diseases: functional studies, a link between genetic and clinical phenotype. AB - Ferroportin (FPN) mediates iron export from cells and this function is modulated by serum hepcidin. Mutations in the FPN gene (SLC40A1) lead to autosomal dominant iron overload diseases related either to loss or to gain of function, and usually characterized by normal or low transferrin saturation versus elevated transferrin saturation, respectively. However, for the same mutation, the phenotypic expression may vary from one patient to another. Using in vitro overexpression of wild-type or mutant FPN proteins, we characterized the functional impact of five recently identified FPN gene mutations regarding FPN localization, cell iron status, and hepcidin sensitivity. Our aim was to integrate functional results and biological findings in probands and relatives. We show that while the p.Arg371Gln (R371Q) mutation had no impact on studied parameters, the p.Trp158Leu (W158L), p.Arg88Gly (R88G), and p.Asn185Asp (N185D) mutations caused an iron export defect and were classified as loss-of-function mutations. The p.Gly204Ser (G204S) mutation induced a gain of FPN function. Functional studies are useful to determine whether or not a FPN gene mutation found in an iron overloaded patient is deleterious and to characterize its biological impact, especially when family studies are not fully informative and/or additional confounding factors may affect bio-clinical expression. PMID- 23943239 TI - Automatic control of the NMB level in general anaesthesia with a switching total system mass control strategy. AB - This paper presents a model based switching control strategy to drive the neuromuscular blockade (NMB) level of patients undergoing general anesthesia to a predefined reference. A single-input single-output Wiener system with only two parameters is used to model the effect of two different muscle relaxants, atracurium and rocuronium, and a switching controller is designed based on a bank of total system mass control laws. Each of such laws is tuned for an individual model from a bank chosen to represent the behavior of the whole population. The control law to be applied at each instant corresponds to the model whose NMB response is closer to the patient's response. Moreover a scheme to improve the reference tracking quality based on the analysis of the patient's response, as well as, a comparison between the switching strategy and the Extended Kalman Kilter (EKF) technique are presented. The results are illustrated by means of several simulations, where switching shows to provide good results, both in theory and in practice, with a desirable reference tracking. The reference tracking improvement technique is able to produce a better reference tracking. Also, this technique showed a better performance than the (EKF). Based on these results, the switching control strategy with a bank of total system mass control laws proved to be robust enough to be used as an automatic control system for the NMB level. PMID- 23943241 TI - Soil water, salt, and groundwater characteristics in shelterbelts with no irrigation for several years in an extremely arid area. AB - This paper is based on long-term monitoring data for soil water, salt content, and groundwater characteristics taken from shelterbelts where there has been no irrigation for at least 5 years. This study investigated the distribution characteristics of soil water and salt content in soils with different textures. The relationships between soil moisture, soil salinity, and groundwater level were analyzed using 3 years of monitoring data from a typical oasis located in an extremely arid area in northwest China. The results showed that (1) the variation trend in soil moisture with soil depth in the shelterbelts varied depending on soil texture. The soil moisture was lower in sandy and loamy shelterbelts and higher in clay shelterbelts. (2) Salinity was higher (about 3.0 mS cm(-1)) in clay shelterbelts and lower (about 0.8 mS cm(-1)) in sandy shelterbelts. (3) There was a negative correlation between soil moisture in the shelterbelts and groundwater level. Soil moisture decreased gradually as the depth of groundwater table declined. (4) There was a positive correlation between soil salinity in the shelterbelts and the depth of groundwater table. Salinity increased gradually as groundwater levels declined. PMID- 23943240 TI - Combining in vitro embryotoxicity data with physiologically based kinetic (PBK) modelling to define in vivo dose-response curves for developmental toxicity of phenol in rat and human. AB - In vitro assays are often used for the hazard characterisation of compounds, but their application for quantitative risk assessment purposes is limited. This is because in vitro assays cannot provide a complete in vivo dose-response curve from which a point of departure (PoD) for risk assessment can be derived, like the no observed adverse effect level (NOAEL) or the 95 % lower confidence limit of the benchmark dose (BMDL). To overcome this constraint, the present study combined in vitro data with a physiologically based kinetic (PBK) model applying reverse dosimetry. To this end, embryotoxicity of phenol was evaluated in vitro using the embryonic stem cell test (EST), revealing a concentration-dependent inhibition of differentiation into beating cardiomyocytes. In addition, a PBK model was developed on the basis of in vitro and in silico data and data available from the literature only. After evaluating the PBK model performance, effective concentrations (ECx) obtained with the EST served as an input for in vivo plasma concentrations in the PBK model. Applying PBK-based reverse dosimetry provided in vivo external effective dose levels (EDx) from which an in vivo dose response curve and a PoD for risk assessment were derived. The predicted PoD lies within the variation of the NOAELs obtained from in vivo developmental toxicity data from the literature. In conclusion, the present study showed that it was possible to accurately predict a PoD for the risk assessment of phenol using in vitro toxicity data combined with reverse PBK modelling. PMID- 23943242 TI - Trace element concentration and speciation in selected urban soils in New York City. AB - A long history of urbanization and industrialization has affected trace elements in New York City (NYC) soils. Selected NYC pedons were analyzed by aqua regia microwave digestion and sequential chemical extraction as follows: water soluble (WS); exchangeable (EX); specifically sorbed/carbonate bound (SS/CAR); oxide bound (OX); organic/sulfide bound (OM/S). Soils showed a range in properties (e.g., pH 3.9 to 7.4). Sum of total extractable (SUMTE) trace elements was higher in NYC parks compared to Bronx River watershed sites. NYC surface horizons showed higher total extractable (TE) levels compared to US non-anthropogenic soils. TE levels increased over 10 year in some of the relatively undisturbed and mostly wooded park sites. Surface horizons of park sites with long-term anthropogenic inputs showed elevated TE levels vs. subsurface horizons. Conversely, some Bronx River watershed soils showed increased concentrations with depth, reflective of their formation in a thick mantle of construction debris increasing with depth and intermingled with anthrotransported soil materials. Short-range variability was evident in primary pedons and satellite samples (e.g., Pb 253 +/- 143 mg/kg). Long-range variability was indicated by PbTE (348 versus 156 mg/kg) and HgTE (1 versus 0.3 mg/kg) concentrations varying several-fold in the same soil but in different geographic locations. Relative predominance of fractions: RES (37 %) > SS/CAR (22 %) > OX (20 %) > OM/S (10 %) > EX (7 %) > WS (4 %). WS and EX fractions were greatest for Hg (7 %) and Cd (14 %), respectively. RES was predominant fraction for Co, Cr, Ni, and Zn (41 to 51 %); SS/CAR for Cd and Pb (40 and 63 %); OM/S for Cu and Hg (36 and 37 %); and OX for As (59 %). PMID- 23943243 TI - Atmospheric depositional fluxes and sources apportionment of organochlorine pesticides in the Pearl River Delta region, South China. AB - Organochlorine pesticides (OCPs) have variously been phased out in agricultural activities, but they are still widely detected in air, water, and soil systems due to their recalcitrant nature in the environment. The purposes of this study were to assess potential OCP pollution via dry and wet deposition over the fast developing Pearl River Delta area with 41,700 km(2), where the main effort has been focused on emerging pollutants such as petroleum hydrocarbons and PM2.5. We quantified both the dry and wet deposition fluxes of 19 OCPs including dichlorodiphenyltrichloroethanes (DDTs), endosulfans (Endos), and hexachlorocyclohexanes (HCHs). The results showed that each year about 67.4, 42.0, 15.0, and 8.07 kg of total OCPs, DDTs, Endos, and HCHs were returned to the ground, among which 11.7, 10.4, 0.84, and 0.16 kg were in the dry deposition forms. The large spatial variations in OCP deposition fluxes indicated that OCP pollution in the air is mainly influenced on local scales because evaporation from local soil is likely the major source of the phased out OCPs. Source analysis indicated that DDTs may be still in use as antifouling agent and/or dicofol, but Endos and HCHs were mainly derived from the residual of historical usage. The study suggests that the historical OCP pollutants are persistent at high levels in this area and should not be overlooked, while we tackle emerging pollutants. PMID- 23943244 TI - Flow injection analysis of trace chromium (VI) in drinking water with a liquid waveguide capillary cell and spectrophotometric detection. AB - Hexavalent chromium (Cr(VI)) is an acknowledged hazardous material in drinking waters. As such, effective monitoring and assessment of the risks posed by Cr(VI) are important analytical objectives for both human health and environmental science. However, because of the lack of highly sensitive, rapid, and simple procedures, a relatively limited number of studies have been carried out in this field. Here we report a simple and sensitive analytical procedure of flow injection analysis (FIA) for sub-nanomolar Cr(VI) in drinking water samples with a liquid core waveguide capillary cell (LWCC). The procedure is based on a highly selective reaction between 1, 5-diphenylcarbazide and Cr(VI) under acidic conditions. The optimized experimental parameters included reagent concentrations, injection volume, length of mixing coil, and flow rate. Measurements at 540 nm, and a 650-nm reference wavelength, produced a 0.12-nM detection limit. Relative standard deviations for 1, 2, and 10 nM samples were 5.6, 3.6, and 0.72 % (n = 9), and the analysis time was <2 min sample(-1). The effects of salinity and interfering ions, especially Fe(III), were evaluated. Using the FIA-LWCC method, different sources of bottled waters and tap waters were examined. The Cr(VI) concentrations of the bottled waters ranged from the detection limit to ~20 nM, and tap waters collected from the same community supply had Cr(VI) concentration around 14 nM. PMID- 23943245 TI - Effect of air-drying and oven-drying treatment on Cr(VI) content and Cr bond forms in soil. AB - Air-drying and oven-drying are pretreatment processes often used before testing and analyzing various soil characteristics in the laboratory. This study selected three kinds of soil, including red soil, entisol, and alluvial soil, and examined the variation of the Cr(VI) content and Cr bond forms in these soils during air drying and oven-drying. The results show that when the soil is air-dried in natural environment, the Cr(VI) content decreases with air-drying time. On day 10 of air-drying, the Cr(VI) content in these soils is 22.8~47.9 % of the initial value. When the soil is oven-dried, the Cr(VI) concentration decays faster; on day 8, the Cr(VI) is no longer detected in these soil samples. When the Cr(VI) contaminated soil is treated by air-drying and oven-drying, the Cr bond form converts into a more stable form. After oven-drying, the Cr mainly exists in Fe Mn oxide form, organic bond form, and residual form. The air-drying and oven drying pretreatment processes of soil reduce the Cr(VI) content and stabilize the Cr bond form. If the laboratory analytic results are applied to risk analysis or remediation strategy planning for chromium-contaminated soil, the toxicity, bioavailability, and mobility of Cr in soil may be underrated. PMID- 23943246 TI - Small RNA biology: from fundamental studies to applications. PMID- 23943247 TI - Successes and failures for drugs in late-stage development for Alzheimer's disease. AB - To date, symptomatic medications prevail as the mainstay of treatment options for Alzheimer's disease (AD). There have been tremendous investments made to increase the numbers of drugs approved and the targets engaged, in an effort to alter the disease course or pathophysiology of AD. Unfortunately, almost all studies have not met expectations and no new drug (beyond medical foods) has been approved for the treatment of AD in the last decade. This review is a comparison of novel AD therapies in the late phases of clinical testing, including recent high-profile clinical failures, and agents in development with relatively unexplored mechanisms of action, with a focus on their potential as therapeutic agents and their proposed advantages over the treatments currently in use. PMID- 23943248 TI - Prevention of inappropriate prescribing in hospitalized older patients using a computerized prescription support system (INTERcheck((r))). AB - BACKGROUND: Polypharmacy is very common among older adults and can lead to inappropriate prescribing, poor adherence to treatment, adverse drug events and the prevalence of potential drug-drug interactions (DDIs). Electronic prescription database software may help to prevent inappropriate prescribing and minimize the occurrence of adverse drug reactions. INTERcheck((r)) is a Computerized Prescription Support System (CPSS) developed in order to optimize drug prescription for elderly people with multimorbidity. OBJECTIVES: The objectives of this study were (i) to evaluate the applicability of INTERcheck((r)) as a means of reviewing the pharmacological profiles of elderly patients hospitalized in an acute geriatric ward in Northern Italy; and (ii) to evaluate the effectiveness of INTERcheck((r)) in reducing potentially inappropriate medications (PIMs), potentially severe DDIs and the anticholinergic burden in daily practice. METHODS: Two samples of elderly patients (aged 65+ years) hospitalized in a geriatric ward in Italy were enrolled throughout 2012. During the first (observation) phase, medications prescribed to 74 patients at admission and discharge were analyzed with INTERCheck((r)) without any kind of interference based on information obtained from the software. During the second (intervention) phase, the treatment of 60 patients was reviewed and changed at discharge according to INTERCheck((r)) suggestions. RESULTS: In the observational period, the number of patients exposed to at least one PIM remained unchanged on both admission (n = 29; 39.1 %) and discharge (n = 28; 37.8 %). In the intervention phase, 25 patients (41.7 %) were exposed to at least one PIM at admission and 7 (11.6 %) at discharge (p < 0.001). The number of patients exposed to at least one potentially severe DDI decreased from 27 (45.0 %) to 20 (33.3 %), although the difference was not statistically significant (p = 0.703), while the number of new-onset potentially severe DDIs decreased from 37 (59.0 %) to 9 (33.0 %) [p < 0.001]. CONCLUSIONS: The use of INTERCheck((r)) was associated with a significant reduction in PIMs and new-onset potentially severe DDIs. CPSSs combining different prescribing quality measures should be considered as an important strategy for optimizing medication prescription for elderly patients. PMID- 23943249 TI - Mechanical thrombectomy in proximal subclavian artery in-stent occlusion. AB - PURPOSE: Mechanical thrombectomy is an established tool for endovascular therapy of acute/chronic in-stent occlusions of the lower extremities, especially for the superficial femoral artery. The authors report the use of the Rotarex catheter system for an in-stent proximal subclavian occlusion. CASE PRESENTATION: A 51 year-old female patient with previous multiple attempts at left subclavian revascularization; primary endovascular stenting at the origin of the subclavian artery occluded at 3 months, and a carotid-subclavian bypass was placed distally to the stent. After 6 months from the first treatment, the patient was readmitted with an acute left arm ischemia and full occlusion of the bypass was confirmed at computed tomography angiography. An anterograde thrombectomy for in-stent restenosis, together with PTA with a drug-eluting balloon was performed in the subclavian artery with confirmed patency at 6 months. CONCLUSION: Mechanical thrombectomy together with drug-eluting balloon PTA for in-stent occlusion or restenosis of the subclavian artery could be a promising procedure with a lower invasivity and risk with respect to surgical options. PMID- 23943251 TI - Hirschsprung's disease associated with Down syndrome: a meta-analysis of incidence, functional outcomes and mortality. AB - PURPOSE: Down syndrome (DS) is the most frequent chromosomal abnormality associated with Hirschsprung's disease (HD). It has often been suggested that this association results in poorer outcomes with regard to postoperative complications, continence and mortality. On the other hand, the results after surgical treatment of HD in patients with DS are reportedly similar to those in cases with HD alone. The objective of this study was to determine the incidence of DS in cohorts with HD, and to compare pre-/postoperative complications, functional outcome and mortality between cohorts with and without coexisting DS. METHODS: A systematic literature-based search for relevant cohorts was conducted using multiple online databases. The number of DS cases in HD cohorts was recorded and data on pre-/postoperative complications, functional outcome and mortality were extracted. Pooled odds ratios with 95% confidence intervals were calculated using meta-analysis methodology. RESULTS: Sixty-one articles met defined inclusion criteria, comprising data from 16,497 patients with HD. The overall incidence of DS among them was 7.32%. Vice versa, the incidence of HD in 29,418 patients with DS was 2.62%. There were no significant differences regarding the male-to-female ratio between cohorts with and without coexisting DS (4:1 vs. 3:1 respectively; P = 0.5376). The rate of additional comorbidities was significantly higher in HD associated with DS (P < 0.0001). Recto-sigmoid HD was in both cohorts the most common type of HD (P = 0.8231). Long-segment HD was significantly more frequent in HD with coexisting DS (P = 0.0267), while total colonic aganglionosis occurred significantly more often in HD without DS (P = 0.0003). There were no significant differences in preoperative constipation/obstruction (P = 0.5967), but the rate of preoperative enterocolitis was significantly higher in HD associated with DS (P = 0.0486). Postoperative complications such as recurrent enterocolitis (P = 0.0112) and soiling (P = 0.0002) were significantly more frequent in HD with coexisting DS. Although not statistically significant, fecal incontinence (P = 0.1014) and persistent constipation (P = 0.1670) occurred more often after surgical treatment of HD with DS. The mortality rate was significantly higher in HD associated with DS (P < 0.0001). CONCLUSIONS: The association of HD with DS is well-recognized with an incidence of 7.32%. A large number of patients with DS continue to have persistent bowel dysfunction after surgical treatment of HD. Our data provide strong evidence that the coexistence of HD and DS is associated with higher rates of pre-/postoperative enterocolitis, poorer functional outcomes and increased mortality. PMID- 23943250 TI - Classification and diagnostic criteria of variants of Hirschsprung's disease. AB - "Variants of Hirschsprung's disease" are conditions that clinically resemble Hirschsprung's disease (HD), despite the presence of ganglion cells in rectal suction biopsies. The diagnosis and management of these patients can be challenging. Specific histological, immunohistochemical and electron microscopic investigations are required to characterize this heterogeneous group of functional bowel disorders. Variants of HD include intestinal neuronal dysplasia, intestinal ganglioneuromatosis, isolated hypoganglionosis, immature ganglia, absence of the argyrophil plexus, internal anal sphincter achalasia and congenital smooth muscle cell disorders such as megacystis microcolon intestinal hypoperistalsis syndrome. This review article systematically classifies variants of HD based on current diagnostic criteria with an additional focus on pathogenesis, epidemiology, clinical presentation, management and outcome. PMID- 23943252 TI - NT-proBNP, a useful tool in hypertensive patients undergoing a diagnostic evaluation for primary aldosteronism. AB - Primary aldosteronism (PA) is the most frequent form of secondary hypertension, but diagnostic tools for this disease still lack optimal accuracy. The heart is one important target tissue for damage due to excess aldosterone, and the role of natriuretic peptides is well recognized in diagnosing heart failure. We hypothesized that measuring the NT-proBNP could improve the diagnostic evaluation of PA. We enrolled 132 hypertensive patients, who underwent aldosterone to renin ratio (ARR) screening, and 81 underwent an intravenous saline loading test (ivSLT) because of a high ARR. The NT-proBNP level positively correlated with the ARR and inversely correlated with the renin level. The NT-proBNP level was higher in patients with a high ARR than in those with a low ARR and higher in patients with a positive ivSLT than in those with a negative ivSLT. After logistic regression analysis, an NT-proBNP value above the median and male gender were predictors of a positive ivSLT. The proportion of patients with a positive ivSLT ranged from only 23 % in females with a low NT-proBNP to 93 % in males with a high NT-proBNP. NT-proBNP and gender are predictors of a positive PA confirmatory test. These findings highlight the possibility of using NT-proBNP to identify which patients with a high ARR should receive a complete PA diagnostic evaluation. PMID- 23943253 TI - Authors reply to Dr. Kawada's comments. PMID- 23943254 TI - Urinary Smad1 is a new biomarker for diagnosis and evaluating the severity of diabetic nephropathy. AB - The aim of this study was to analyze urinary Smad1 level in patients with type 2 diabetes, explore the possibility of Smad1 being a biomarker for early diagnosis and evaluation of severity of diabetic nephropathy, and explore the impact factors affecting urinary Smad1 concentration. In this study, 132 subjects with type 2 diabetes and 50 healthy volunteers were enrolled. Subjects were grouped according to urine albumin to creatinine ratio (ACR) into: normal albumin in urine (NAU), low albumin in urine (LAU), high albumin in urine (HAU), and very high albumin in urine (VHAU). Among those, LAU, HAU, and VHAU were regarded as the diabetic nephropathy group (DN group), NAU was regarded as nondiabetic nephropathy (non-DN group), and the healthy volunteers were the controls. Enzyme linked immunosorbent assay was used to detect the urinary Smad1 concentration, urinary Smad1 to creatinine ratio (SCR) was used as the standard reference. Compared with non-DN group, SCR of DN group was higher (P < 0.05), while there was no difference between the non-DN group and controls (P > 0.05). There was no significant difference for SCR between LAU and NAU groups (P > 0.05). The SCR was higher in VHAU group than those in HAU and LAU groups, and higher in HAU than that in LAU group (P < 0.05). Pearson correlation analysis showed that SCR measures were positively correlated to ACR, duration and diabetic retinopathy of the disease (r = 0.285, 0.230, 0.202; P = 0.001, 0.008, 0.019, respectively). Multiple linear regression analysis showed that ACR and duration were independent impact factors for SCR (P < 0.05). This is the first known study examining the correlation of Smad1 and DN in clinical practice. It suggested that the urinary Smad1 may be a potential diagnostic parameter for DN and may be used to evaluate the severity of DN. However, it cannot predict those in patients with the earliest DN and low urine albumin concentration. Furthermore, ACR and duration may be independent impact factors for urinary Smad1. PMID- 23943255 TI - Effects of water soluble PM2.5 extracts exposure on human lung epithelial cells (A549): A proteomic study. AB - Exposure to airborne particulate matter (PM)2.5, a PM with aerodynamic diameter of less than 2.5 um, is known to be associated with a variety of adverse health effects. However, the molecular mechanisms involved in fine PM toxicity are still not well characterized. The present study aims to provide new insights into the cytotoxicity of PM2.5 on human lung epithelial cells (A549) at the proteomic level. Two-dimensional difference gel electrophoresis revealed a total of 27 protein spots, whose abundance were significantly altered in A549 cells exposed to water-soluble PM2.5 extracts (WSPE). Among these, 12 spots were upregulated while 15 were downregulated. Twenty-two proteins were further identified by matrix-assisted laser desorption/ionization time-of-flight tandem mass/mass spectrometry and database search. The results revealed that oxidative stress, metabolic disturbance, dysregulation of signal transduction, aberrant protein synthesis and degradation, as well as cytoskeleton disorganization are major factors contributing to WSPE-mediated toxicity in human lung cells. It is further proposed that induction of apoptosis through p53, c-Myc and p21 pathways may be one of the key toxicological events occurred in A549 cells under WSPE stress. The data obtained here will aid our understanding of the toxic mechanisms related to PM2.5, and develop useful biomarkers indicative of inhalable PM2.5 exposure. PMID- 23943256 TI - The 3.5-year survival rates of primary molars treated according to three treatment protocols: a controlled clinical trial. AB - OBJECTIVES: This study aimed to test the hypothesis that there is no difference in the survival rates of molars treated according to the conventional restorative treatment (CRT) using amalgam, atraumatic restorative treatment (ART) using high viscosity glass ionomer, and ultraconservative treatment (UCT) protocol after 3.5 years. MATERIALS AND METHODS: Cavitated primary molars were treated according to CRT, ART, and UCT (small cavities were restored with ART and medium/large cavities were daily cleaned with toothpaste/toothbrush under supervision). Molar extractions resulting from toothache, sepsis, or pulp exposure were failures. The Kaplan-Meier method was used to estimate the survival curves. RESULTS: The numbers of treated teeth, among the 302 6-7-year-old children, were 341 (CRT), 244 (ART), and 281 (for UCT group: 109 small ART, 166 open cavities, and 6 combinations). Protocol groups were similar at baseline regarding gender and mean decayed missing filled tooth score, but not regarding age and type of surface. The numbers of molars extracted were 22 (CRT), 16 (ART), and 26 (UCT). Fistulae were most often recorded. After 3.5 years, the cumulative survival rate +/- standard error for all molars treated was 90.9 +/- 2.0 % with CRT, 90.4 +/- 2.4 % with ART, and 89.0 [corrected] +/- 1.9 % with UCT (p = 0.13). Only a type of surface effect was observed over the 3.5-year period: survival rates for molars were higher for single- than for multiple-surface cavities. CONCLUSION: There was no difference in the cumulative survival rates of primary molars treated according to the CRT, ART, and UCT protocols over a 3.5-year period. CLINICAL RELEVANCE: Keeping cavities in primary molars biofilm-free might be another treatment option alongside restoring such cavities through conventional and ART protocols. PMID- 23943257 TI - Vomer flap for hard palate repair is related to favorable maxillary growth in unilateral cleft lip and palate. AB - OBJECTIVE: Vomer flap repair is assumed to improve maxillary growth because of reduced scarring in growth-sensitive areas of the palate. Our aim was to evaluate whether facial growth in patients with unilateral cleft lip and palate was significantly affected by the technique of hard palate repair (vomer flap versus two-flap). MATERIALS AND METHODS: For this retrospective longitudinal study, we analyzed 334 cephalometric radiographs from 95 patients with nonsyndromic complete unilateral cleft lip and palate who underwent hard palate repair by two different techniques (vomer flap versus two-flap). Clinical notes were reviewed to record treatment histories. Cephalometry was used to determine facial morphology and growth rate. The associations among facial morphology at age 20, facial growth rate, and technique of hard palate repair were assessed using generalized estimating equation analysis. RESULTS: The hard palate repair technique significantly influenced protrusion of the maxilla (SNA: beta = -3.5 degrees , 95 % CI = -5.2-1.7; p = 0.001) and the anteroposterior jaw relation (ANB: beta = -4.2 degrees , 95 % CI = -6.4-1.9; p = 0.001; Wits: beta = -5.7 mm, 95 % CI = -9.6-1.2; p = 0.01) at age 20, and their growth rates (SNA p = 0.001, ANB p < 0.01, and Wits p = 0.02). CONCLUSIONS: The results suggest that in patients with unilateral cleft lip and palate, vomer flap repair has a smaller adverse effect than two-flap on growth of the maxilla. This effect on maxillary growth is on the anteroposterior development of the alveolar maxilla and is progressive with age. We now perform hard palate closure with vomer flap followed by soft palate closure using Furlow palatoplasty. CLINICAL RELEVANCE: These findings may improve treatment outcome by modifying the treatment protocol for patients with unilateral cleft lip and palate. PMID- 23943258 TI - Measurement equivalence using a mixed-mode approach to administer health-related quality of life instruments. AB - PURPOSE: To evaluate the effects of mode, order of administration, and the interaction of mode and order on health-related quality of life scales when self administered by mixed mode (paper-mode and web-mode) for measurement equivalence. METHODS: Health-related quality of life data was analyzed from the Cancer of the Prostate Strategic Urologic Research Endeavor using the Medical Outcomes Study (MOS) Short Form-36 (SF-36) and the University of California Los Angeles Prostate Cancer Index (UCLA-PCI). A randomized crossover design assigned participants to two groups with a preferred 2-5-day washout period. Cognitive debriefing evaluated participants' mode preference. RESULTS: Of the 245 men enrolled, 85 % completed both modes. The majority were White (97 %), college educated (66 %), reported an annual income >$75,000 (46 %), and a median age of 69 years. Intraclass correlation coefficients were high for each item on both instruments (r = .54-.97). Exact percentage agreement for yes/no items was high (>=.88). For the SF-36, significant differences were observed for order of administration (physical component and physical function scores) and for the interaction between mode and order (mental component, role emotional, social function, vitality, and mental health scores). For the UCLA-PCI, the largest difference was 12.8 points lower for sexual bother for order of administration by web-mode first (p = .03). Seventy percent preferred the web-mode, 21 % had no preference, and 9 % preferred the paper-mode. CONCLUSION: Web-mode and paper-mode administrations of the SF-36 and UCLA-PCI are equivalent in men with prostate cancer, implying that mixed-mode survey administration is warranted. PMID- 23943259 TI - Mapping scores from the Strengths and Difficulties Questionnaire (SDQ) to preference-based utility values. AB - PURPOSE: Quality of life mapping methods such as "Transfer to Utility" can be used to translate scores on disease-specific measures to utility values, when traditional utility measurement methods (e.g. standard gamble, time trade-off, preference-based multi-attribute instruments) have not been used. The aim of this study was to generate preliminary ordinary least squares (OLS) regression-based algorithms to transform scores from the Strengths and Difficulties Questionnaires (SDQ), a widely used measure of mental health in children and adolescents, to utility values obtained using the preference-based Child Health Utility (CHU9D) instrument. METHODS: Two hundred caregivers of children receiving community mental health services completed the SDQ and CHU9D during a telephone interview. Two OLS regressions were run with the CHU9D utility value as the dependent variable and SDQ subscales as predictors. Resulting algorithms were validated by comparing predicted and observed group mean utility values in randomly selected subsamples. RESULTS: Preliminary validation was obtained for two algorithms, utilising five and three subscales of the SDQ, respectively. Root mean square error values (.124) for both models suggested poor fit at an individual level, but both algorithms performed well in predicting mean group observed utility values. CONCLUSION: This research generated algorithms for translating SDQ scores to utility values and providing researchers with an additional tool for conducting health economic evaluations with child and adolescent mental health data. PMID- 23943260 TI - Determinants of quality of life in Spanish transsexuals attending a gender unit before genital sex reassignment surgery. AB - PURPOSE: To evaluate the self-reported perceived quality of life (QoL) in transsexuals attending a Spanish gender identity unit before genital sex reassignment surgery, and to identify possible determinants that likely contribute to their QoL. METHODS: A sample of 119 male-to-female (MF) and 74 female-to-male (FM) transsexuals were included in the study. The WHOQOL-BREF scale was used to evaluate self-reported QoL. Possible determinants included age, sex, education, employment, partnership status, undergoing cross-sex hormonal therapy, receiving at least one non-genital sex reassignment surgery, and family support (assessed with the family APGAR questionnaire). RESULTS: Mean scores of all QoL domains ranged from 55.44 to 63.51. Linear regression analyses revealed that undergoing cross-sex hormonal treatment, having family support, and having an occupation were associated with a better QoL for all transsexuals. FM transsexuals have higher social domain QoL scores than MF transsexuals. The model accounts for 20.6 % of the variance in the physical, 32.5 % in the psychological, 21.9 % in the social, and 20.1 % in the environment domains, and 22.9 % in the global QoL factor. CONCLUSIONS: Cross-sex hormonal treatment, family support, and working or studying are linked to a better self-reported QoL in transsexuals. Healthcare providers should consider these factors when planning interventions to promote the health-related QoL of transsexuals. PMID- 23943261 TI - How do clinical and psychological variables relate to quality of life in end stage renal disease? Validating a proximal-distal model. AB - PURPOSE: The aims of this study were to: (1) validate the proximal-distal (PD) model in predialysis and early dialysis and (2) examine the role of hemoglobin on quality of life (QoL) in these patient groups. METHODS: Cross-sectional observational studies of 475 participants recruited from four major university teaching hospitals were conducted. The multi-sample structural equation modeling with latent composite techniques was employed to test the PD model. Seven factors were measured, including QoL, positive affect, depression, physical functioning, kidney disease symptoms, comorbidity and hemoglobin. RESULTS: The results showed that both the equality-constrained and equality-unconstrained PD models were supported by fit statistics. The chi square difference test of the two models was non-significant, indicating that the PD model was consistent across groups. The alternative models were rejected by fit statistics, suggesting that hemoglobin does not impact on psychological states but QoL. CONCLUSIONS: This study validates the PD model across the end-stage renal disease (ESRD) patient groups and shows a hierarchical causal relationship between clinical factors, physical functioning, psychological states and QoL, with hemoglobin as an exception. This model provides an empirical framework for integrating and studying a range of clinical factors and health outcomes in ESRD. PMID- 23943263 TI - Antibiotics for preventing complications in children with measles. AB - BACKGROUND: Measles is the leading killer among vaccine-preventable diseases; it is responsible for an estimated 44% of the 1.7 million vaccine-preventable deaths among children annually. OBJECTIVES: To assess the effects of antibiotics given to children with measles to prevent complications and reduce pneumonia, other morbidities and mortality. SEARCH METHODS: We searched CENTRAL 2013, Issue 4, MEDLINE (1966 to May week 4, 2013) and EMBASE (1980 to May 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing antibiotics with placebo or no treatment, to prevent complications in children with measles. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. MAIN RESULTS: Seven trials with 1263 children were included. The methodological quality of most studies was poor. Only two studies were randomized, double-blind trials. There was variation in antibiotics used, their doses, schedule and evaluation of outcome. Pooled study data showed that the incidence of pneumonia was lower in the treatment group compared to the control group. However, the difference was not statistically significant. Of the 654 children who received antibiotics, 27 (4.1%) developed pneumonia; while out of 609 children in the control group, 59 (9.6%) developed pneumonia (odds ratio (OR) 0.35; 95% confidence interval (0.12 to 1.01). The one trial that showed an increase in the rate of pneumonia with antibiotics was conducted in 1942 and compared oral sulfathiazole with symptomatic treatment. If the results of this trial are removed from the meta-analysis, there is a statistically significant reduction in the incidence of pneumonia in children receiving antibiotics (OR 0.26; 95% CI 0.12 to 0.60). The incidence of other complications was significantly lower in children receiving antibiotics: purulent otitis media (OR 0.34; 95% CI 0.16 to 0.73) and tonsillitis (OR 0.08; 95% CI 0.01 to 0.72). There was no difference in the incidence of conjunctivitis (OR 0.39; 95% CI 0.15 to 1.0), diarrhea (OR 0.53; 95% CI 0.23 to 1.22) or croup (OR 0.16; 95% CI 0.01 to 4.06). No major adverse effects attributable to antibiotics were reported. AUTHORS' CONCLUSIONS: The studies reviewed were of poor quality and used older antibiotics. This review suggests a beneficial effect of antibiotics in preventing complications such as pneumonia, purulent otitis media and tonsillitis in children with measles. On the basis of this review, it is not possible to recommend definitive guidelines on the type of antibiotic, duration or the day of initiation. There is a need for more evidence from high-quality RCTs to answer these questions. PMID- 23943262 TI - EPR characterisation of the ferrous nitrosyl complex formed within the oxygenase domain of NO synthase. AB - Nitric oxide is produced in mammals by a class of enzymes called NO synthases (NOSs). It plays a central role in cellular signalling but also has deleterious effects, as it leads to the production of reactive oxygen and nitrogen species. NO forms a relatively stable adduct with ferrous haem proteins, which, in the case of NOS, is also a key catalytic intermediate. Despite extensive studies on the ferrous nitrosyl complex of other haem proteins (in particular myoglobin), little characterisation has been performed in the case of NOS. We report here a temperature-dependent EPR study of the ferrous nitrosyl complex of the inducible mammalian NOS and the bacterial NOS-like protein from Bacillus subtilis. The results show that the overall behaviours are similar to those observed for other haem proteins, but with distinct ratios between axial and rhombic forms in the case of the two NOS proteins. The distal environment appears to control the existence of the axial form and the evolution of the rhombic form. PMID- 23943264 TI - Progress in lithium-sulfur batteries: the effective role of a polysulfide-added electrolyte as buffer to prevent cathode dissolution. AB - Paving the road for sulfur: A unique electrolyte composition designed for the development of stable lithium-sulfur batteries with high energy. A battery with a high and stable capacity is prepared by using an electrolyte containing a dissolved catholyte-type compound, that is, Li2 S8 polysulfide. The cell is characterized by a capacity approaching the theoretical value at a working voltage of 2.1 V, which is remarkable compared to conventional lithium ion batteries. PMID- 23943266 TI - The Merkel cell carcinoma challenge: a review from the fine needle aspiration service. PMID- 23943267 TI - Detection of silver nanoparticles in cells by flow cytometry using light scatter and far-red fluorescence. AB - The cellular uptake of different sized silver nanoparticles (AgNP) (10, 50, and 75 nm) coated with polyvinylpyrrolidone (PVP) or citrate on a human derived retinal pigment epithelial cell line (ARPE-19) was detected by flow cytometry following 24-h incubation of the cells with AgNP. A dose dependent increase of side scatter and far red fluorescence was observed with both PVP and citrate coated 50 nm or 75 nm silver particles. Using five different flow cytometers, a far red fluorescence signal in the 700-800 nm range increased as much as 100 times background as a ratio comparing the intensity measurements of treated sample and controls. The citrate-coated silver nanoparticles (AgNP) revealed slightly more side scatter and far red fluorescence than did the PVP coated silver nanoparticles. This increased far red fluorescence signal was observed with 50 and 75 nm particles, but not with 10 nm particles. Morphological evaluation by dark field microscopy showed silver particles (50 and 75 nm) clumped and concentrated around the nucleus. One possible hypothesis to explain the emission of far red fluorescence from cells incubated with silver nanoparticles is that the silver nanoparticles inside cells agglomerate into small nano clusters that form surface plasmon resonance which interacts with laser light to emit a strong far red fluorescence signal. The results demonstrate that two different parameters (side scatter and far red fluorescence) on standard flow cytometers can be used to detect and observe metallic nanoparticles inside cells. The strength of the far red fluorescence suggests that it may be particularly useful for applications that require high sensitivity. (c) Published 2013 Wiley-Periodicals, Inc. PMID- 23943265 TI - Body mass maximizes power output in human jumping: a strength-independent optimum loading behavior. AB - It is well known that in vitro muscles maximize their power output when acting against a moderate resistance regarding their maximum strength. Similar behavior has been observed from in vivo muscular systems in both single-joint and most of the multi-joint maximum performance tasks. We refer to that phenomenon as a strength-dependent behavior, since the optimum external load that maximizes the mechanical power output of particular muscle(s) or neuro-musculoskeletal system corresponds to a certain percent of maximum strength. In this review paper, we present evidence that the optimum load in maximum vertical jumps is one's own body mass, regardless of the strength of the lower limb muscles (i.e., the strength-independent behavior). Although the discussed phenomenon is still underexplored, we believe that several neuro-mechanical mechanisms are involved. Among these are a long-term adaptation of the muscular force-velocity relationship to the body weight and inertia, alteration of the jumping technique, load-specific muscle activation and jumping skills. Further exploration of the discussed strength-independent behavior of the lower limb muscles is of importance for refining various training and rehabilitation procedures, as well as for understanding the design and function of lower limb muscles. PMID- 23943268 TI - Walking in the footprints of giants. PMID- 23943269 TI - Plus ca ne change pas: evolution may be a race, but to where? PMID- 23943270 TI - The end of higher taxa: a reply to Tattersall. PMID- 23943271 TI - Understanding primate communities: recent developments and future directions. AB - In 1999, the edited volume Primate Communities presented several studies that examined broad-scale patterns of primate diversity. Similar studies were being conducted on nonprimate taxa; advances in data availability and statistical approaches were allowing scientists to investigate a variety of new questions and to reexamine classical questions in novel ways. While such studies on nonprimate taxa have continued at a steady pace, they have only crept forward for primate species (Fig. 1). In the intervening time, the field of macroecology (Box 1) rapidly developed and has resulted in several books and the establishment of new research institutes. We suggest that examining primate communities, especially in a macroecological context, is an important line of research for our field to embrace and an area where biological anthropologists can provide major contributions. We review the current state of research, describe new datasets and research tools, and suggest future research directions. PMID- 23943272 TI - Natural cooperators: food sharing in humans and other primates. AB - The study of cooperation is rich with theoretical models and laboratory experiments that have greatly advanced our knowledge of human uniqueness, but have sometimes lacked ecological validity. We therefore emphasize the need to tie discussions of human cooperation to the natural history of our species and its closest relatives, focusing on behavioral contexts best suited to reveal underlying selection pressures and evolved decision rules. Food sharing is a fundamental form of cooperation that is well-studied across primates and is particularly noteworthy because of its central role in shaping evolved human life history, social organization, and cooperative psychology. Here we synthesize available evidence on food sharing in humans and other primates, tracing the origins of offspring provisioning, mutualism, trade, and reciprocity throughout the primate order. While primates may gain some benefits from sharing, humans, faced with more collective action problems in a risky foraging niche, expanded on primate patterns to buffer risk and recruit mates and allies through reciprocity and signaling, and established co-evolving social norms of production and sharing. Differences in the necessity for sharing are reflected in differences in sharing psychology across species, thus helping to explain unique aspects of our evolved cooperative psychology. PMID- 23943274 TI - Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity. AB - Over 35 years research on PAKs, RAC/CDC42(p21)-activated kinases, comes of age, and in particular PAK1 has been well known to be responsible for a variety of diseases such as cancer (mainly solid tumors), Alzheimer's disease, acquired immune deficiency syndrome and other viral/bacterial infections, inflammatory diseases (asthma and arthritis), diabetes (type 2), neurofibromatosis, tuberous sclerosis, epilepsy, depression, schizophrenia, learning disability, autism, etc. Although several distinct synthetic PAK1-blockers have been recently developed, no FDA-approved PAK1 blockers are available on the market as yet. Thus, patients suffering from these PAK1-dependent diseases have to rely on solely a variety of herbal therapeutics such as propolis and curcumin that block PAK1 without affecting normal cell growth. Furthermore, several recent studies revealed that some of these herbal therapeutics significantly extend the lifespan of nematodes (C. elegans) and fruit flies (Drosophila), and PAK1-deficient worm lives longer than the wild type. Here, I outline mainly pathological phenotypes of hyper activated PAK1 and a list of herbal therapeutics that block PAK1, but cause no side (harmful) effect on healthy people or animals. PMID- 23943273 TI - Syndesmosis injuries of the ankle. AB - Ankle syndesmosis injuries are relatively frequent in sports, especially skiing, ice hockey, and soccer, accounting for 1 %-18 % of all ankle sprains. The evolution is unpredictable: When missed, repeated episodes of ankle instability may predispose to early degenerative changes, and frank osteoarthritis may ensue. Diagnosis is clinical and radiological, but arthroscopy may provide a definitive response, allowing one to address secondary injuries to bone and cartilage. Obvious diastasis needs to be reduced and fixed operatively, whereas less severe injuries are controversial. Nonoperative treatment may be beneficial, but it entails long rehabilitation. In professional athletes, more aggressive surgical treatment is warranted. PMID- 23943275 TI - Time until nursing home admission in people with mild dementia: comparison of dementia with Lewy bodies and Alzheimer's dementia. AB - OBJECTIVE: We studied time until nursing home admission (NHA) in mild dementia and predictors for NHA in people with Dementia with Lewy bodies (DLB) and how it compares to Alzheimer's dementia (AD). METHODS: Kaplan-Meier survival analysis and Cox proportional hazards were applied. RESULTS: Median time until NHA was 1114 days (95% confidence interval [CI] [932, 1296]). In DLB median time until NHA was 663 days [472, 998]) as compared with 1336 days (1068, 1606) in AD, p < 0.0005. Predictors of shorter time to NHA in the DLB and AD groups in unadjusted analyses were a DLB diagnosis, the use of antipsychotic medication, more advanced age, longer duration of dementia symptoms prior to diagnosis, living alone, higher reported caregiver distress, and more neuropsychiatric symptoms. The use of cholinesterase inhibitors was associated with halved risk of NHA in the combined DLB/AD group in the unadjusted Cox regression. In adjusted Cox regression in the DLB group, we found the use of cholinesterase inhibitors to be associated with reduced risk of NHA (HR = 0.24) and the use of antipsychotic medication to be associated with increased risk of NHA (HR = 37) during the study period. CONCLUSION: Patients diagnosed with DLB had nearly 2 years shorter time to NHA than those diagnosed with AD. In the DLB group, the use of cholinesterase inhibitors was associated with reduced and the use of antipsychotics with increased risk of NHA. Future studies should explore whether better identification and management of the variety of clinical problems in patients diagnosed with DLB can delay NHA. PMID- 23943276 TI - A novel colorectal and cervical cancer education program: findings from the community network for cancer prevention Forum Theater program. AB - Medically underserved populations continue to be disproportionately burdened by cancer. The exact reason for this disparity has not been fully elucidated, but likely involves multiple factors. We explored the potential utility of a novel community-based cancer education program called Forum Theater (FT), aimed at raising awareness about colorectal (CRC) and cervical cancer (CxC) screening among African-American, Hispanic, and Vietnamese populations. We also determined audience likelihood of obtaining CRC and CxC screening in the 6 months following performances. Thirty FT performances were held between September 2011 and July 2012. A brief survey was administered at each performance, eliciting responses on key CRC and CxC screening questions. A total of 662 community residents (316 Hispanic, 165 African-American, and 181 Vietnamese; overall mean age 50.3 +/- 16.4) participated in performances. The survey response rate was 71.1 %. After seeing FT performances, the majority responded correctly (>70 %) on CRC and CxC screening questions. In comparison to Hispanic and Vietnamese participants, African-Americans were less likely to report that CRC and CxC are preventable (p < 0.05), that timely and regular screening saves lives (p = 0.05), and that CxC screening should begin at age 21 for most women (p < 0.05). Our findings suggest that FT may be an effective strategy to disseminate cancer screening information. Lack of awareness that CRC/CxC screening saves lives and that CRC/CxC is preventable, as reported by African-Americans, may not stem from lack of knowledge or misconceptions alone, but may be influenced by a sense of fatalism regarding cancer outcomes in this population. PMID- 23943277 TI - Making it work: health care provider perspectives on strategies to increase colorectal cancer screening in federally qualified health centers. AB - Colorectal cancer screening (CRCS) rates are low among men and women who seek health care at federally qualified health centers (FQHCs). This study explores health care providers' perspectives about their patient's motivators and impediments to CRCS and receptivity to preparatory education. A mixed methods design consisting of in-depth interviews, focus groups, and a short survey is used in this study. The participants of this study are 17 health care providers practicing in FQHCs in the Tampa Bay area. Test-specific patient impediments and motivations were identified including fear of abnormal findings, importance of offering less invasive fecal occult blood tests, and need for patient-centered test-specific educational materials in clinics. Opportunities to improve provider practices were identified including providers' reliance on patients' report of symptoms as a cue to recommend CRCS and overemphasis of clinic-based guaiac stool tests. This study adds to the literature on CRCS test-specific motivators and impediments. Providers offered unique approaches for motivating patients to follow through with recommended CRCS and were receptive to in-clinic patient education. Findings readily inform the design of educational materials and interventions to increase CRCS in FQHCs. PMID- 23943278 TI - Factors affecting African American men's use of online colorectal cancer education. AB - Colorectal cancer (CRC) incidence rates have decreased due to the increased use of CRC screenings that permit the detection and removal of polyps. However, CRC is still the second most common cause of cancer death among men ages 40 to 79 years; incidence and mortality rates for CRC are higher among African American (AA) men than among white men and AA women. CRC screening rates for AA men are comparable to their counterparts of other racial groups, but adherence to the screening guidelines is less, contributing to disparities in CRC mortality. Internet use is widespread and could be a channel to reach and disseminate health information to AA men; however, there are disparities in Internet use, and limited literature exists on how to best address this divide. This pilot project sought to understand African American male attitudes on colorectal cancer screening (CRCS), receipt of CRCS information, and the best strategy to provide African American men online CRCS education. Three focus groups and a feasibility trial were completed with African American men, ages of 45 to 75. Data suggest that disseminating information online is not a very effective way to reach older African American men with limited education. Although we do not recommend using websites among this population, email was more effective in getting participants to the website even though participants expressed a preference for phone messages. Recommendations for future research are provided. PMID- 23943279 TI - Identification of (Z)-4- and 1-tridecene in the metathoracic gland secretions of stink bugs employing the GC/FT-IR technique. AB - The composition of stink bug allomones is similar for most species and includes hydrocarbons, as well as saturated and unsaturated aldehydes and esters. Analysis of extracts of the metathoracic glands of seven pentatomid species from different genera by gas chromatography/Fourier transform-infrared (GC/FT-IR) showed that the compound previously thought to be 1-tridecene actually showed characteristic bands of an internal as well as terminal double bond, the former compound having (Z)-configuration. The mass spectrum of an epoxy-derivative of the natural material demonstrated that the internal double bound was located at C4. GC/FT-IR and co-injections with synthetic standards on different capillary columns proved that all these stink bugs had 1-tridecene and (Z)-4-tridecene in their defensive secretions. PMID- 23943281 TI - 3D brain atlas reconstructor service--online repository of three-dimensional models of brain structures. AB - Brain atlases are important tools of neuroscience. Traditionally prepared in paper book format, more and more commonly they take digital form which extends their utility. To simplify work with different atlases, to lay the ground for developing universal tools which could abstract from the origin of the atlas, efforts are being made to provide common interfaces to these atlases. 3D Brain Atlas Reconstructor service (3dBARs) described here is a repository of digital representations of different brain atlases in CAF format which we recently proposed and a repository of 3D models of brain structures. A graphical front-end is provided for creating and viewing the reconstructed models as well as the underlying 2D atlas data. An application programming interface (API) facilitates programmatic access to the service contents from other websites. From a typical user's point of view, 3dBARs offers an accessible way to mine publicly available atlasing data with a convenient browser based interface, without the need to install extra software. For a developer of services related to brain atlases, 3dBARs supplies mechanisms for enhancing functionality of other software. The policy of the service is to accept new datasets as delivered by interested parties and we work with the researchers who obtain original data to make them available to the neuroscience community at large. The functionality offered by the 3dBARs situates it at the core of present and future general atlasing services tying it strongly to the global atlasing neuroinformatics infrastructure. PMID- 23943280 TI - Approach to cerebrospinal fluid (CSF) biomarker discovery and evaluation in HIV infection. AB - Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previously-defined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers. PMID- 23943282 TI - Role of 0.4 % glyceryl trinitrate ointment after stapled trans-anal rectal resection for obstructed defecation syndrome: a prospective, randomized trial. AB - PURPOSE: The anal fissure and spasm represent possible complications and causes of postoperative anal pain in patients that have undergone stapled trans-anal rectal resection (STARR). The etiology of these complications is still questioned such as the treatment modality. This study was designed to evaluate the effectiveness of topical glyceryl trinitrate (GTN) 0.4 % in determining decrease of incidence of postoperative anal spams and fissure and reduction of early postoperative pain. METHODS: From a total of 243 patients referred for obstructed defecation syndrome (ODS) 104 (42.7 %) underwent STARR and were randomized to receive (Group 1) or not (Group 2) topical 0.4 % GTN ointment every 12 h for four postoperative weeks. Postoperative evaluation was made at 1, 6, and 12 months. RESULTS: At 1 month follow-up, the incidence of anal spasm in Groups 1 and 2 was, respectively, 0 and 14.6 % (6/41) (p = 0.010; Fisher's exact test). The incidence of anal fissure was 4/41 (9.7 %) in Group 2 and 0/44 (0 %) in Group 1 (p = 0.05; Fisher's exact test). Significant differences in median visual analogue scale score between groups were found at 1 week and 1 month follow-up (1; 0-5 vs. 2; 0 7: p = 0.0104; Mann-Whitney U test). CONCLUSION: Anal spasm and fissure may represent a cause of early postoperative anal pain in patients that have undergone STARR procedure for ODS. The use of topical GTN 0.4 % ointment in the early postoperative course seems to reduce the incidence of anal spasm and fissure and to improve the associated early postoperative pain. PMID- 23943283 TI - Clinical implication of additional selective lateral lymph node excision in patients with locally advanced rectal cancer who underwent preoperative chemoradiotherapy. AB - PURPOSE: To identify the indication and prognostic significance of lateral lymph node (LLN) excision in locally advanced rectal cancer patients underwent preoperative chemoradiotherapy. METHODS: Included were 67 consecutive patients with suspicious LLN metastasis who underwent chemoradiotherapy and surgery including selective LLN excision (82 excisions). The excisions were grouped according to the presence of LLN metastasis and compared in terms of the clinicopathological findings and oncological results. The correlation between the largest short-axis diameter of LLN measured by imaging and metastasis rates was explored. RESULTS: LLN metastases were identified in 32 excisions (40.0 %). The calculated short-axis LLN diameter predicting metastasis was 11.7 mm (before chemoradiotherapy) and 11.4 mm (before surgery). LLN metastasis was observed more frequently in the low rectum (p = 0.031) and associated with higher CEA levels (p = 0.048). The 3-year overall survival rates for patients with and without LLN metastasis were 60.3 % and 90.3 % (p = 0.048), while the 3-year disease-free survival rates were 31.4 % and 70.5 % (p = 0.009). The hazard ratio of LLN metastasis for recurrence was 2.938 (95 % CI = 1.258-6.863). CONCLUSIONS: LLN metastasis in rectal cancer patients underwent chemoradiotherapy was a distinct poor prognostic factor. Selective LLN excision based on imaging studies may have a role for such patients. PMID- 23943284 TI - Oxidative phosphorylation and ion transport in the mitochondria of two strains of rats varying in their resistance to stress and hypoxia. AB - The role of mitochondria in the inherited or ontogenetically acquired reactions of organism to stress is not studied enough. In the present work, we examined the functional state of the coupled respiratory chain, potassium and calcium transport and rate of hydrogen peroxide production on two rat lines: August and Wistar-which possess different resistance to emotional stress and hypoxia. It was established that the respiration rate and efficiency of oxidative phosphorylation were higher in August rats than in Wistar ones. In August rats, the rate of potassium transport and ATP-dependent mitochondrial swelling as well as the concentration of the ion in the mitochondrial matrix were almost twice as higher comparatively to those parameters in Wistar rats. The rate of H2O2 production was found to be decreased in the mitochondria of August rats. It was also demonstrated that the two rat lines differed by their resistance to the opening of the palmitate/Ca(2+)-induced pore and by their ability to retain calcium within mitochondria. The paper discusses the involvement of the mitochondrial ATP dependent potassium channel in the adaptation of animals to adverse effects. PMID- 23943285 TI - Identification of miR-1293 potential target gene: TIMP-1. AB - Tissue inhibitor of metalloproteinases 1 (TIMP-1) is a glycosylated protein with multiple activities in the regulation of biological processes, such as cell growth and apoptosis as well as tumor invasion and metastasis. Bioinformatics analysis using TargetScan and miRanda suggested tissue inhibitors of TIMP-1 are among the targets of miR-1293. To confirm this, we cloned both wild-type and mutant TIMP-1 3'UTR fragments by overlap extension PCR, constructed the recombinant plasmids pGL3-TIMP-1-wt, -mut, and pcDNA 3.1(+)/TIMP-1-CDS and, respectively, co-transfected them into 293T cells with the miR-1293 inhibitor, mimics or the miR inhibitor-NC using a BTX ECM 2001 square-wave electroporator. We used a luciferase assay to investigate binding of miR-1293 to the 3'UTR of TIMP-1. Effects on the levels of the TIMP-1 protein were analyzed by Western blot experiments. The luciferase reporter assay showed a statistically significant (P < 0.05) upregulation of activity. Western blot analysis showed a significant increase of expression of the TIMP-1 gene co-transfected with the miR-1293 inhibitor, and demonstrated direct binding of miR-1293 to the 3'UTR of TIMP-1. In this study, we identified TIMP-1 as a novel direct target for miR-1293, which provides the basis for further study of the multifunctional mechanisms of miR 1293 and TIMP-1 in the regulation of a variety of diseases. PMID- 23943286 TI - What to do about "higher" and "lower" organisms? Some suggestions. PMID- 23943287 TI - Dr. Kathleen Drew-Baker, "Mother of the Sea", a Manchester scientist celebrated each year for half a century in Japan. AB - 2013 marks the 50th annual Drew festival in Uto City, Japan, celebrating the work of University of Manchester botanist, Dr. Kathleen Drew-Baker. Her insight into the reproductive biology of algae was the key to efficient farming of the seaweed "nori" which is a familiar component of Japanese food. PMID- 23943292 TI - Reply to the Merkel cell carcinoma challenge: a review from the fine needle aspiration service. PMID- 23943291 TI - Thirty down, only ten to go?! Awareness and influence of a 10-year time frame in TTO. AB - BACKGROUND: Time trade-off (TTO) exercises typically present respondents with a limited time horizon, for example 10 years, thus implicitly considerably reducing remaining life expectancy for the average respondent. It is unclear how this affects health state valuations. AIM: The aim of the study is to investigate how awareness of the reduced life span implied by a 10-year TTO affects health state valuations, using an experimental design. METHODS: Two Web-based questionnaires (Q1 and Q2) were administered in a sample representative of the Dutch population. Both questionnaires contained three 10-year TTO exercises valuing three distinct health states, specified using the EQ-5D. Q1 used a TTO instruction not explicitly emphasizing the fact that remaining life expectancy was reduced to 10 years, while in Q2 respondents were explicitly made aware of this fact by emphasizing their implied age of death. Respondents answering Q1 were asked retrospectively whether they had been aware of their reduced life span due to the 10-year TTO. RESULTS: In total, 656 respondents completed the questionnaires (Q1: 339 and Q2: 317). The average age of the respondents was 43 years and 51 % of respondents were male. The average numbers of years traded off for the respondents of Q1 were for TTO1 0.443, TTO2 0.552, and TTO3 2.083 years. For the respondents of Q2, these averages were lower, i.e., TTO1 0.401 (p = 0.085 vs. Q1), TTO2: 0.546 (p = 0.036 vs. Q1), and TTO3: 1.467 years (p = 0.000 vs. Q1). Fifty-seven percent of respondents in Q1 confirmed that they were aware of the reduced life span. This spontaneous awareness had a limited and mixed influence on results. The generalized negative binomial regression analysis, explaining the time traded off showed that age, subjective life expectancy, and questionnaire Q2 (vs. Q1) were negatively associated with the years traded off, whereas education and worse health states in the TTO exercise had a significant positive impact on the years traded off. The probit model investigating the impact on the willingness to trade showed that age (-), education (+), subjective life expectancy (-), questionnaire Q2 versus Q1 (-), the interaction between Q2 and male gender (+), and worse health states in the TTO exercise (+) had a significant impact on the willingness to trade. CONCLUSION: These findings emphasize the importance of expected and implied life expectancy in TTOs. PMID- 23943293 TI - From "Click" to "Fenton" chemistry for 5-bromo-2'-deoxyuridine determination. AB - Ascorbic acid (AA) and copper have been increasingly employed in flow cytometry (FCM) and high content analysis (HCA) since the introduction of "click chemistry" as a non-destructive alternative to classical 5-bromo-2'-deoxyuridine (BrdU) immunodetection for DNA synthesis and proliferation assays. Mixtures of ascorbate and catalytic copper, under certain experimental conditions, act as oxidizing agent, catalyzing the formation of reactive hydroxyl radicals through hydrogen peroxides decomposition via Fenton reaction. We developed a procedure for BrdU incorporation detection based on the use of AA and cupric ions as DNA damaging agents. Optimal DNA damaging conditions were identified and found to provide results comparable with "click" 5-ethynyl-deoxyuridine (EdU) cycloaddition approach and classical BrdU immunodetection. Scavenger agents were found to prevent hydroxyl-induced DNA damages, providing the proof-of-concept for the use of this procedure for DNA denaturation prior to BrdU detection. We demonstrated hydroxyl radicals' reaction to be readily applicable to HCA and FCM assays, for both classical BrdU immunostaining and EdU cycloaddition procedure. This technique was successfully employed for BrdU pulse-chase experiments and in multiparametric immunofluorescence assays for the simultaneous detection of labile phosphoproteins in intact cells. The use of AA/Cu prior to immunodetection for BrdU incorporation assays is a viable alternative to chemical/physical DNA denaturing agents (acids or heat), since it allows preservation of labile epitopes such as phosphoproteins, and over enzymatic agents (digestion with DNases) for its lower cost. PMID- 23943294 TI - The mechanism of glucose isomerization to fructose over Sn-BEA zeolite: a periodic density functional theory study. AB - The isomerization of glucose to fructose in the presence of Sn-containing zeolite BEA (beta polymorph A) was studied by periodic DFT calculations. Focus was placed on the nature of the active site and the reaction mechanism. The reactivities of the perfect lattice Sn(IV) site and the hydroxylated SnOH species are predicted to be similar. The isomerization activity of the latter can be enhanced by creating an extended silanol nest in its vicinity. Besides the increased Lewis acidity and coordination flexibility of the Sn center, the enhanced reactivity in this case is ascribed to the reaction environment that promotes activation of the confined sugar intermediates through hydrogen bonding. The resulting multidentate activation of the substrate favors the rate-determining hydrogen-shift reaction. These findings suggest the important role of defect lattice sites in Sn-BEA for catalytic glucose isomerization. PMID- 23943296 TI - Acute pesticide poisoning among children in South Korea: findings from National Health Insurance claims data, 2006-2009. AB - OBJECTIVES: The aim of this study was to estimate the incidence of acute pesticide poisoning among children in South Korea and describe the related epidemiologic characteristics. METHODS: We evaluated the age-standardized rates of incidence of pesticide poisoning among children in South Korea from 2006 through 2009 using National Health Insurance claims data. RESULTS: A total of 1232 children aged 0-14 years were identified from the acute pesticide poisoning cases reported across South Korea during the study period. The annual average age standardized rate of incidence from acute pesticide poisoning was 3.6 per 100 000. The majority of the cases were identified in the categories of the 1-4-year old age-group (56.5%), outpatients (80.0%), single-day visit to a hospital (70.4%) and summer occurrence (43.3%). CONCLUSIONS: Acute pesticide poisoning is prevalent among children in South Korea; therefore, intervention efforts are needed to reduce the cases of pesticide poisoning among children. PMID- 23943295 TI - Effects of FlAsH/tetracysteine (TC) Tag on PrP proteolysis and PrPres formation by TC-scanning. AB - Protein-protein interactions associated with proteolytic processing and aggregation are integral to normal and pathological aspects of prion protein (PrP) biology. Characterization of these interactions requires the identification of amino acid residues involved. The FlAsH/tetracysteine (FlAsH/TC) tag is a small fluorescent tag amenable to insertion at internal sites in proteins. In this study, we used serial FlAsH/TC insertions (TC-scanning) as a probe to characterize sites of protein-protein interaction between PrP and other molecules. To explore this application in the context of substrate-protease interactions, we analyzed the effect of FlAsH/TC insertions on proteolysis of cellular prion protein (PrPsen) in in vitro reactions and generation of the C1 metabolic fragment of PrPsen in live neuroblastoma cells. The influence of FlAsH/TC insertion was evaluated by TC-scanning across the cleavage sites of each protease. The results showed that FlAsH/TC inhibited protease cleavage only within limited ranges of the cleavage sites, which varied from about one to six residues in width, depending on the protease, providing an estimate of the PrP residues interacting with each protease. TC-scanning was also used to probe a different type of protein-protein interaction: the conformational conversion of FlAsH-PrPsen to the prion disease-associated isoform, PrPres. PrP constructs with FlAsH/TC insertions at residues 90-96 but not 97-101 were converted to FlAsH PrPres, identifying a boundary separating loosely versus compactly folded regions of PrPres. Our observations demonstrate that TC-scanning with the FlAsH/TC tag can be a versatile method for probing protein-protein interactions and folding processes. PMID- 23943297 TI - The rheumatoid forefoot. AB - Rheumatoid arthritis (RA) manifests itself in a variety of ways, with its effect being seen in around 90 % of sufferers' feet. The foot has been found to be the most common reason for incapacity in patients with RA, with the forefoot the most common area. The foot is second, behind only the hand, as the most common place for manifestation of RA. Pain in the foot is commonly the most debilitating condition, which causes the patient to seek specialist help. As well as pain, foot deformities such as hallux valgus and claw toes are common complaints. These symptoms often arise as a result of continued walking on an unstable foot, leading to painful callosities and dislocation of the metatarsophalangeal joints. Other conditions, such as pannus formation and Morton's neuroma, can be related to RA. This review sets out what we believe to be a successful approach to the rheumatoid forefoot, which aims at the relief of pain and the preservation of ambulation. Key to a successful outcome is appropriate medical control with a multidisciplinary approach that enables close liaison between orthopaedic surgeons, orthotists, and rheumatologists. Combined clinics provide this multidisciplinary care. Those treating RA need to be aware of the high incidence of foot involvement and how early intervention may benefit the patient. The aim of this article is to present current evidence to enable people to develop a treatment algorithm for this condition. PMID- 23943298 TI - Coadministration of erlotinib and curcumin augmentatively reduces cell viability in lung cancer cells. AB - Resistance to erlotinib in lung cancer cases includes T790M mutant epidermal growth factor receptor and c-Met gene amplification, but other unknown mechanisms account for about 30% of the resistance. Activation of the nuclear factor kappa B (NFkappaB)-related pathways in association with the reduction in ikappaB level may be one of such potential mechanisms. It is known that curcumin inhibits the inducible activation of NFkappaB at least in part by sustaining ikappaB expression level. Therefore, we evaluated the effects of coadministration of erlotinib and curcumin on lung cancer cells. We found that erlotinib and curcumin augmentatively reduced cell viability. Studies in PC9 cells showed that induction of apoptosis was involved. Expression of ikappaB was elevated in PC9 cells by curcumin administration, and pretreatment with siRNAs for ikappaB significantly attenuated the reduction in cell viability after coadministration of erlotinib and curcumin. Furthermore, coadministration of erlotinib and/or curcumin augmentatively attenuated the growth of PC9 tumors in mice. These results suggested the existence of an augmentative tumor growth inhibitory effect between erlotinib and curcumin, and this effect was at least in part mediated by the increase in the expression of ikappaB induced by curcumin. PMID- 23943299 TI - Adjuvant leuprolide with or without docetaxel in patients with high-risk prostate cancer after radical prostatectomy (TAX-3501): important lessons for future trials. AB - BACKGROUND: The current trial evaluated 2 common therapies for patients with advanced prostate cancer, docetaxel and hormonal therapy (HT), in the surgical adjuvant setting. METHODS: TAX-3501 was a randomized, phase 3, adjuvant study post-radical prostatectomy (RP) in high-risk patients with prostate cancer (n=228) comparing 18 months of HT with (CHT) without docetaxel chemotherapy either immediately (I) or deferred (D). High-risk disease was defined as a 5-year freedom-from-disease-progression rate of <= 60% as predicted by a post-RP nomogram. Progression-free survival (PFS), including prostate-specific antigen disease recurrence, was the primary endpoint. The authors also assessed the accuracy of the nomogram and analyzed testosterone recovery in 108 patients treated with HT who had at least 1 posttreatment testosterone value. RESULTS: Between December 2005 and September 2007, 228 patients were randomized between the treatment cohorts. TAX-3501 was terminated prematurely because of enrollment challenges, leaving it underpowered to detect differences in PFS. After a median follow-up of 3.4 years (interquartile range, 2.3-3.8 years), 39 of 228 patients (17%) demonstrated PSA disease progression, and metastatic disease progression occurred in 1 patient. The median time to baseline testosterone recovery after the completion of treatment was prolonged at 487 days (95% confidence interval, 457-546 days). The nomogram's predicted versus observed freedom from disease progression was significantly different for the combination D(HT) and D(CHT) group (P<.00001). CONCLUSIONS: TAX-3501 illustrated several difficulties involved in conducting postoperative adjuvant systemic trials in men with high-risk prostate cancer: the lack of consensus regarding patient selection and treatment, the need for long follow-up time, nonvalidated intermediate endpoints, evolving standard approaches, and the need for long-term research support. Except for selected patients at very high-risk of disease recurrence and death, surgical adjuvant trials in patients with prostate cancer may not be feasible. PMID- 23943300 TI - Human stick balancing: an intermittent control explanation. AB - There are two issues in balancing a stick pivoting on a finger tip (or mechanically on a moving cart): maintaining the stick angle near to vertical and maintaining the horizontal position within the bounds of reach or cart track. The (linearised) dynamics of the angle are second order (although driven by pivot acceleration), and so, as in human standing, control of the angle is not, by itself very difficult. However, once the angle is under control, the position dynamics are, in general, fourth order. This makes control quite difficult for humans (and even an engineering control system requires careful design). Recently, three of the authors have experimentally demonstrated that humans control the stick angle in a special way: the closed-loop inverted pendulum behaves as a non-inverted pendulum with a virtual pivot somewhere between the stick centre and tip and with increased gravity. Moreover, they suggest that the virtual pivot lies at the radius of gyration (about the mass centre) above the mass centre. This paper gives a continuous-time control-theoretical interpretation of the virtual-pendulum approach. In particular, by using a novel cascade control structure, it is shown that the horizontal control of the virtual pivot becomes a second-order problem which is much easier to solve than the generic fourth-order problem. Hence, the use of the virtual pivot approach allows the control problem to be perceived by the subject as two separate second-order problems rather than a single fourth-order problem, and the control problem is therefore simplified. The theoretical predictions are verified using the data previously presented by three of the authors and analysed using a standard parameter estimation method. The experimental data indicate that although all subjects adopt the virtual pivot approach, the less expert subjects exhibit larger amplitude angular motion and poorly controlled translational motion. It is known that human control systems are delayed and intermittent, and therefore, the continuous-time strategy cannot be correct. However, the model of intermittent control used in this paper is based on the virtual pivot continuous-time control scheme, handles time delays and moreover masquerades as the underlying continuous time controller. In addition, the event-driven properties of intermittent control can explain experimentally observed variability. PMID- 23943301 TI - Novel registration-based framework for CT angiography in lower legs. AB - Proper subtraction and visualization of contrast-enhanced blood vessels in lower extremities using computed tomography angiography (CTA) is based on precise masking of all non-contrasted structures in the area, and it is the main prerequisite for correct diagnosis and decision on treatment for peripheral arterial occlusive disease (PAOD). Because of possible motion of patients during the CTA examination, precise elimination of non-contrasted tissues, including bones, calcifications, and soft tissue, is still very challenging for lower legs, that is, from knees to toes. We propose novel registration-based framework for detection and correction of the motion in lower legs, which typically occurs between and during CTA pre-contrast and post-contrast acquisitions. Within the framework, two registration cores are proposed as alternatives, and resulting CTA subtraction images are compared with Advanced Vessel Analysis considered one of the reference commercial tools among clinical applications for CTA of lower extremities. The CTA subtraction images of 55 patients examined for PAOD are evaluated visually by four expert observers on the Philips Extended Brilliance Workspace using four criteria assessing the overall robustness of tested methods. According to the complex evaluation, the proposed framework enabled valuable improvements of CTA examination of lower legs. PMID- 23943302 TI - Mortality disparities among groups participating in an East Africa surveying expedition: the Herbert Henry Austin expedition of 1900-1901. AB - In the late nineteenth and early twentieth centuries, a number of European expeditions traveled to the region of Lake Rudolf, now largely in northern Kenya. Although diverse in intent, many of these were undertaken in the interests of furthering colonial territorial claims. In 1900-1901, Major Herbert Henry Austin led a British expedition down to the lake from Khartoum in the north. Of the 62 African, Arab, and European members of this expedition, only 18 (29 %) arrived at its final destination at Lake Baringo in Kenya. Because of a confluence of adverse climatic, social, and political conditions, the expedition ran short of food supplies when it arrived at the northern end of the lake in April 1901. For the next 4 months, the members of the expedition struggled down the west side of the lake and beyond. The greatest mortality (91 %) occurred among the 32 African transport drivers who were the most marginally nourished at the outset of the trip. The lowest mortality among the Africans on the expedition (15 %) occurred among the members of the Tenth Sudanese Rifles Battalion, who had an excellent nutritional status at the start of the expedition. Major Austin himself suffered from severe scurvy with retinal hemorrhages which left him partially blind in his right eye. An analysis of the mortality rates among the groups that participated in this expedition was undertaken. This revealed that poor nutritional status at the start of the trip was predictive of death from starvation. PMID- 23943303 TI - Mitochondrial fission-fusion as an emerging key regulator of cell proliferation and differentiation. AB - Mitochondrial shape change, brought about by molecules that promote either fission or fusion between individual mitochondria, has been documented in several model systems. However, the deeper significance of mitochondrial shape change has only recently begun to emerge: among others, it appears to play a role in the regulation of cell proliferation. Here, I review the emerging interplay between mitochondrial fission-fusion components with cell cycle regulatory machineries and how that may impact cell differentiation. Regulation of mitochondrial shape may modulate mitochondrial metabolism and/or energetics to promote crosstalk between signaling components and the cell cycle machinery. Focused research in this area will reveal the exact role of mitochondria in development and disease, specifically in stem cell regulation and tumorigenesis. Such research may also reveal whether and how the endosymbiotic event that gave rise to the mitochondrion was crucial for the evolution of cell cycle regulatory mechanisms in eukaryotes that are absent in prokaryotes. PMID- 23943304 TI - Pathological changes in the thyroid gland in crush asphyxia. AB - To determine whether crush asphyxia may be associated with macro- and microscopic changes in the thyroid gland, four cases of death due to crush asphyxia were evaluated where the decedents (males aged 36, 37, 45, and 65 years respectively) suffered lethal chest compressions. The diagnosis of crush asphyxia in each case was suggested by the death scene description and confirmed by the finding of injuries to the torso, with marked congestion of the face, neck, and upper body associated with petechial and subconjunctival hemorrhages. In addition to other pathological findings, each decedent had intense congestion of their thyroid gland resulting in a dark/black appearance. Microscopically, stromal capillaries were engorged, with bulging of capillaries into the follicles. Rupture of these small vessels had created focal intrafollicular aggregates of erythrocytes within the colloid. As intense suffusion of the thyroid gland with blood in cases of crush asphyxia may impart an appearance of "black thyroid" this may be another feature of this condition to look for at autopsy, in addition to intrafollicular blood lakes on histology. PMID- 23943305 TI - Usefulness of IGH/TCR PCR studies in lymphoproliferative disorders with inconclusive clonality by flow cytometry. AB - In up to 5-15% of studies of lymphoproliferative disorders (LPD), flow cytometry (FCM) or immunomorphologic methods cannot discriminate malignant from reactive processes. The aim of this work was to determine the usefulness of PCR for solving these diagnostic uncertainties. We analyzed IGH and TCRgamma genes by PCR in 106 samples with inconclusive FCM results. A clonal result was registered in 36/106 studies, with a LPD being confirmed in 27 (75%) of these cases. Specifically, 9/9 IGH clonal and 16/25 TCRgamma clonal results were finally diagnosed with LPD. Additionally, two clonal TCRgamma samples with suspicion of undefined LPD were finally diagnosed with T LPD. Although polyclonal results were obtained in 47 of the cases studied (38 IGH and nine TCRgamma), hematologic neoplasms were diagnosed in 4/38 IGH polyclonal and in 1/9 TCRgamma polyclonal studies. There were also 14 PCR polyclonal results (four IGH, 10 TCRgamma), albeit nonconclusive. Of these, 2/4 were eventually diagnosed with B-cell lymphoma and 3/10 with T-cell LPD. In eight IGH samples, the results of PCR techniques were noninformative but in 3/8 cases a B lymphoma was finally confirmed. We concluded that PCR is a useful technique to identify LPD when FCM is inconclusive. A PCR clonal B result is indicative of malignancy but IGH polyclonal and nonconclusive results do not exclude lymphoid neoplasms. Interpretation of T-cell clonality should be based on all the available clinical and analytical data. PMID- 23943306 TI - Pronounced transcriptional regulation of apoptotic and TNF-NF-kappa-B signaling genes during the course of thymoquinone mediated apoptosis in HeLa cells. AB - Thymoquinone (TQ) is the active ingredient extracted from the essential oil of Nigella sativa. A number of studies implicated TQ as an antitumor agent. In this study, cytotoxic effects of the oil of N. sativa and TQ were evaluated on human cervical cancer cell line, HeLa cells. IC50 value was ~0.125 MUl/ml for N. sativa oil preparations and 12.5 MUM for TQ. TQ strongly inhibited wound healing at all concentrations ranging from 12.5 to 100 MUM in a scratch wound healing assay. Additionally, induction of apoptosis by TQ was assessed by Giemsa staining and TQ was found to induce apoptosis in cancer cells especially at concentrations of 50 and 100 MUM. TQ-mediated transcriptional regulation of 84 genes involved in apoptosis was studied using a PCR array. At low dose (12.5 MUM), TQ was found to induce expression of four pro-apoptotic genes: BIK (~22.7-fold), FASL (~2.9 fold), BCL2L10 (~2.1-fold), and CASP1 (~2-fold). TQ was also found to reduce the expression of an anti-apoptotic gene implicated in NF-kappa-B signaling and cancer: RELA (~8-fold). At high dose (100 MUM), TQ mediated the expression of 21 genes implicated directly in apoptosis (6 genes), TNF signaling (10 genes), and NF-kappa-B signaling (3 genes) such as BIK, BID, TNFRSF10A, TNFRSF10B, TNF, TRAF3, RELA, and RELB. In conclusion, this study implicates the role of TQ in the inhibition of cancer cell proliferation and migration. At the same time, our results strongly suggest that TQ intervenes with TNF and NF-kappa-B signaling during TQ-mediated induction of apoptosis in cancer cells. PMID- 23943307 TI - Underestimation of rat serum vancomycin concentrations measured by an enzyme multiplied immunoassay technique and the strategy for its avoidance. AB - An enzyme-multiplied immunoassay technique (EMIT) has been widely adopted for the measurement of serum concentrations of vancomycin (VCM) in clinical practice. Because of the growing demand for its application to fundamental pharmacokinetic studies, we examined whether VCM concentrations in rat serum were accurately measured by EMIT. It was found that measured values of known amounts of VCM spiked to rat serum were markedly underestimated with a large analytical variance. When ultrafiltrated rat serum was used as the sample matrix, interference was significantly improved, and the degree of underestimation was attenuated also by diluting samples with physiological saline. These results suggest that endogenous substances of a high molecular weight in rat serum interfere with the analysis of VCM concentrations by EMIT. However, measured values of rat serum VCM concentrations by EMIT were restored to theoretical levels by exposing samples to 70 degrees C for 3-7 min. A likely explanation for the avoidance of interference is that an appropriate thermal force eliminated the immunological function of endogenous substances falsely recognizing VCM without affecting the VCM molecule itself. Regarding serum samples collected from rats that were administered VCM, values measured by EMIT following the heat-treatment agreed well with those by the high performance liquid chromatography (HPLC) method. This is the first report showing interference by endogenous high molecular substances in the measurement of drug concentrations in rat serum using EMIT. Our findings will contribute to the appropriate use of VCM based on evidence provided by clinical-oriented rat experiments requiring the measurement of serum VCM concentrations by EMIT. PMID- 23943308 TI - ERCP in the patient with surgically altered anatomy. AB - Endoscopic retrogade cholangiopancreatography (ERCP) is a standard of care endoscopic technique using a conventional side-viewing duodenoscope to treat a wide variety of biliopancreatic pathologies. However, surgically altered gastric and/or small bowel anatomy renders ERCP more challenging because of several reasons. Depending on the type of surgical reconstruction, different endoscopic approaches have been developed in order to perform therapeutic ERCP. The current review highlights the latest ERCP developments to deal with biliopancreatic problems in patients with surgically altered anatomy, and discusses future directions of improvement. PMID- 23943310 TI - Number density of liquid inclusions formed in frozen aqueous electrolyte. AB - Frozen aqueous chlorides (<=50 mM) are characterized by using confocal fluorescence microscopy and small angel X-ray scattering (SAXS). The former method allows us to determine the size of a liquid inclusion formed in the ice matrix at temperatures above the eutectic point of the system (t(eu)). Isolated liquid inclusions of a uniform size are formed when the temperature of a frozen electrolyte increases past t(eu). The size of the liquid inclusions depends on the observation temperature as well as on the concentration (c(salt)) and type of salt dissolved in the original unfrozen solution. However, the number density of liquid inclusions is almost constant and independent of these experimental parameters, particularly when an electrolyte is frozen in liquid nitrogen. Salt accumulation can then occur at the imperfections of the ice crystals. The occurrence probability of the imperfections is independent of the nature of an incorporated salt. The amount of a salt confined in each inclusion ranges from 7 to 240 fmol, depending on c(salt). SAXS measurements provide information on the size of individual salt crystals formed at temperatures below t(eu). The radius of gyration of a salt crystal ranges from 2 to 2.8 nm, and does not depend significantly on c(salt). Thus, each inclusion is formed from 10(6)-10(9) nanocrystals, which can act as seeds. When doped ice is prepared at higher temperatures, for example -16 degrees C, the isolation of liquid inclusions is not sufficient and coalescence occurs more easily upon an increase in temperature or cs(alt). However, when c(salt) is lower than 10 mM, the number density of liquid inclusions is almost constant, irrespective of the freezing temperature. PMID- 23943309 TI - Dietary strategies to reduce metabolic syndrome. AB - Metabolic syndrome (MetS) is a cluster of metabolic abnormalities characterized by central obesity, dyslipidemias, hypertension, high fasting glucose, chronic low-grade inflammation and oxidative stress. This condition has become an increasing problem in our society where about 34 % of adults are diagnosed with MetS. In parallel with the adult situation, a significant number of children present lipid abnormalities and insulin resistance, which can be used as markers of MetS in the pediatric population. Changes in lifestyle including healthy dietary regimens and increased physical activity should be the first lines of therapy to decrease MetS. In this article, we present the most recent information on successful dietary modifications that can reduce the parameters associated with MetS. Successful dietary strategies include energy restriction and weight loss, manipulation of dietary macronutrients--either through restriction of carbohydrates, fat, or enrichment in beneficial fatty acids, incorporation of functional foods and bioactive nutrients, and adherence to dietary and lifestyle patterns such the Mediterranean diet and diet/exercise regimens. Together, the recent findings presented in this review serve as evidence to support the therapeutic treatment of MetS through diet. PMID- 23943311 TI - Anastomotic leakage after low anterior resection for rectal cancer: comparison of stapled versus compression anastomosis. AB - PURPOSE: Surgical technique and perioperative management in rectal cancer surgery have been substantially improved and standardized during the last decades. However, anastomotic leakage following low anterior resection still is a significant problem. Based on animal experimental data of improved healing of compression anastomosis, we hypothesized that a compression anastomotic device might improve healing rates of the highest-risk anastomoses. METHODS: All low anterior resections for rectal cancer performed or directly supervised by the senior author between January 2004 and June 2012 were analyzed. Only patients with a stapled or compression anastomosis located within 6 cm from the anal verge were included. Until December 2008, circular staplers were employed, while since January 2009, a novel compression anastomotic device was used for rectal reconstruction exclusively. RESULTS: Out of 197 patients operated for rectal cancer, a total of 96 (34 females, 35.4 %) fulfilled inclusion criteria. Fifty eight (60.4 %) were reconstructed with circular staplers and 38 (39.6 %) using a compression anastomotic device. Significantly, more laparoscopic procedures were recorded in the compression anastomosis group, but distribution of gender, age, body mass index, American Society of Anaesthesiologists score, rate of preoperative radiotherapy, tumor staging, or stoma diversion rate were similar. Anastomotic leakage was observed in seven cases (7/58, 12.1 %) in the stapled and twice (2/38, 5.3 %) in the compression anastomosis group (p = 0.26). CONCLUSIONS: In this series, rectal reconstruction following low anterior resection using a novel compression anastomotic device was safe and (at least) equally effective compared to traditional circular staplers concerning leak rate. PMID- 23943312 TI - Reduced-intensity conditioning followed by cord blood transplantation in a patient with refractory folliculotropic mycosis fungoides. AB - Advanced-stage mycosis fungoides (MF) has a generally poor prognosis. Allogeneic hematopoietic stem cell transplantation improves the outcome of advanced-stage MF. Recently, cord blood has been used as an alternative stem cell source; however, there are few reports of MF patients treated using cord blood transplantation. Here, we report a rare case of refractory folliculotropic MF, which was treated with reduced-intensity conditioning followed by cord blood transplantation. PMID- 23943313 TI - Anti-Sp17 monoclonal antibody-doxorubicin conjugates as molecularly targeted chemotherapy for ovarian carcinoma. AB - Sperm protein 17 (Sp17) is selectively overexpressed in several human malignancies including ovarian carcinoma, but is absent or expressed at low levels in most normal tissues. Previous work from our group characterized an anti Sp17 monoclonal antibody (clone 3C12) and showed that it specifically targeted tumor cells. In this report, we investigated whether a novel immunoconjugate containing 3C12 linked to the chemotherapeutic agent doxorubicin [(DOX) Adriamycin] had antitumor activity against ovarian cancer cell lines and tumor models. DOX was conjugated to 3C12 using a linker, and the specificity of 3C12 DOX was examined in Sp17-positive SKOV3 and Sp17-negative COC2 ovarian cancer cells using cell-based ELISA and internalization assays. The cytotoxicity of 3C12 DOX was assessed with the MTT assay, and its therapeutic effectiveness was evaluated in immunodeficient mice bearing SKOV3 cells. In vitro, the 3C12-DOX immunoconjugate specifically bound to and was internalized by Sp17-positive SKOV3 cells but did not bind to Sp17-negative cells. Treatment with 3C12-DOX (0.001 to 10 MUg/mL) decreased the viability of SKOV3 cells in a Sp17-specific manner. In vivo, 3C12-DOX (3 mg/kg) induced the regression of established SKOV3 xenograft tumors in BALB/c mice compared with control treatment. The antitumor effects of 3C12-DOX were significantly associated with the induction of apoptosis in tumor cells. In addition, 3C12-DOX showed no observable adverse effects or toxicity when compared with DOX alone in mice bearing ovarian tumor xenografts. Our findings suggest that 3C12-DOX may be a potential antibody-drug conjugate for clinical development. PMID- 23943314 TI - Z-2-(beta-D-glucopyranosyloxy)-3-phenylpropenoic acid, an alpha-hydroxy acid from rooibos (Aspalathus linearis) with hypoglycemic activity. AB - SCOPE: The rare enolic phenylpyruvic acid-2-O-glucoside, (PPAG:Z-2-(beta-D glucopyranosyloxy)-3-phenylpropenoic acid), is one of the major constituents of fermented rooibos infusions. 3-Phenylpyruvic acid (2-oxo-3-phenylpropanoic acid), without the sugar moiety and with a keto form instead of an enolic arrangement, has been shown to enhance insulin release and glucose uptake in muscle cells. The purpose of this study was to assess if PPAG has similar activity on glucose metabolism. METHODS AND RESULTS: Preliminary in vitro studies confirmed that PPAG, isolated from rooibos, enhanced glucose uptake. A dose-response study in Chang cells showed that PPAG enhanced glucose uptake in the concentration range 1.0-31.6 MUM (EC50 = 3.6 MUM). In obese insulin-resistant rats, oral administration of PPAG lowered fasting glucose concentrations and improved oral glucose tolerance values; messenger RNA expression of glucokinase, glucose transporter 1 and 2, insulin receptor, peroxisome proliferator-activated receptor alpha, and suppressor of cytokine signaling 3, were increased in the liver. This suggests that the liver is mainly responsible for PPAG bioactivity. CONCLUSION: This study describes for the first time that PPAG increases in vitro glucose uptake and improves glucose tolerance in an obese insulin-resistant rat model, suggesting that it has potential as a new class of antidiabetic therapeutics that would contribute to the antidiabetic effect of rooibos. PMID- 23943315 TI - Similarities and differences in patient characteristics between heart failure registries versus clinical trials. AB - Acute and chronic heart failure results in significant morbidity and mortality to patients and is a major concern for the healthcare systems. Various randomized controlled trials have demonstrated an improvement in morbidity and mortality for patients with heart failure. However, the findings of these trials are often applicable to a limited population. Several large-scale registries are now shedding insight as to the treatment, outcomes, and follow-up of patients in a real-life clinical setting. The objective of this review is to examine some of the heart failure therapies, such as cardiac resynchronization therapy, implantable cardioverter defibrillators and medications, in the context of randomized trials versus clinical registries. This review will also identify how registries are improving patient outcomes and how they are uncovering differences and gaps in treatment in non-randomized trial settings. PMID- 23943316 TI - High dose deferoxamine in intracerebral hemorrhage (HI-DEF) trial: rationale, design, and methods. AB - BACKGROUND: Hemoglobin degradation products, in particular iron, have been implicated in secondary neuronal injury following intracerebral hemorrhage (ICH). The iron chelator Deferoxamine Mesylate (DFO) exerts diverse neuroprotective effects, reduces perihematoma edema (PHE) and neuronal damage, and improves functional recovery after experimental ICH. We hypothesize that treatment with DFO could minimize neuronal injury and improve outcome in ICH patients. As a prelude to test this hypothesis, we conducted a Phase I, open-label study to determine the tolerability, safety, and maximum tolerated dose (MTD) of DFO in patients with ICH. Intravenous infusions of DFO in doses up to 62 mg/kg/day (up to a maximum of 6000 mg/day) were well-tolerated and did not seem to increase serious adverse events (SAEs) or mortality. We have initiated a multi-center, double-blind, randomized, placebo-controlled, Phase II clinical trial (High Dose Deferoxamine [HI-DEF] in Intracerebral Hemorrhage) to determine if it is futile to move DFO forward to Phase III efficacy evaluation. METHODS: We will randomize 324 subjects with spontaneous ICH to either DFO at 62 mg/kg/day (up to a maximum daily dose of 6000 mg/day) or saline placebo, given by intravenous infusion for 5 consecutive days. Treatment will be initiated within 24 hours after ICH symptom onset. All subjects will be followed for 3 months and will receive standard of care therapy while participating in the study. At 3 months, the proportion of DFO treated subjects with a good clinical outcome, assessed by modified Rankin Scale, will be compared to the placebo proportion in a futility analysis. CONCLUSIONS: The Hi-Def trial is expected to advance our understanding of the pathopgysiology of secondary neuronal injury in ICH and will provide a crucial "Go/No Go" signal as to whether a Phase III trial to investigate the efficacy of DFO is warranted. PMID- 23943318 TI - Intermittent versus continuous cerebrospinal fluid drainage management in adult severe traumatic brain injury: assessment of intracranial pressure burden. AB - INTRODUCTION: There is clinical equipoise regarding whether neurointensive care unit management of external ventricular drains (EVD) in severe traumatic brain injury (TBI) should involve an open EVD, with continuous drainage of cerebrospinal fluid (CSF), versus a closed EVD, with intermittent opening as necessary to drain CSF. In a matched cohort design, we assessed the relative impact of continuous versus intermittent CSF drainage on intracranial pressure in the management of adult severe TBI. METHODS: Sixty-two severe TBI patients were assessed. Thirty-one patients managed by open EVD drainage were matched by age, sex, and injury severity (initial Glasgow Coma Scale (GCS) score) to 31 patients treated with a closed EVD drainage. Patients in the open EVD group also had a parenchymal intracranial pressure (ICP) monitor placed through an adjacent burr hole, allowing real-time recording of ICP. Hourly ICP and other pertinent data, such as length of stay in intensive care unit (LOS-ICU), Injury Severity Score, and survival status, were extracted from our prospective database. RESULTS: With age, injury severity (initial GCS score), and neurosurgical intervention adjusted for, there was a statistically significant difference of 5.66 mmHg in mean ICP (p < 0.0001) between the open and the closed EVD groups, with the closed EVD group exhibiting greater mean ICP. ICP burden (ICP >= 20 mmHg) was shown to be significantly higher in the intermittent EVD group (p = 0.0002) in comparison with the continuous EVD group. CONCLUSION: Continuous CSF drainage via an open EVD seemed to be associated with more effective ICP control in the management of adult severe TBI. PMID- 23943317 TI - Brain injury biomarkers as outcome predictors in pediatric severe traumatic brain injury. AB - BACKGROUND: To systematically review the literature on brain injury biomarkers, defined as any injury biomarker detected in cerebrospinal fluid (CSF) or blood injury biomarkers primarily expressed in the brain parenchyma, to determine outcome prediction in pediatric severe traumatic brain injury (sTBI). METHODS: A search of MEDLINE((r)), EMBASE((r)), PsycINFO((r)), Pubmed((r)), and the Cochrane Database, as well as grey literature sources, personal contacts, hand searches, and reference lists. The search terms used were traumatic brain injury, biomarkers, prognosis, and children. No language, publication type, or publication date restrictions were imposed. All articles were critically reviewed by two clinicians independently. RESULTS: A total of 7,150 articles were identified initially with 16 studies identified for review. Eighteen different biomarkers were examined; 11 in CSF and 7 in blood. Outcomes assessed included either in-hospital mortality or functional state (hospital discharge, 3-months or 6-months; Glasgow Outcome Scale or Pediatric Cerebral Performance Category). Significant correlations were established between sTBI outcomes and various biomarkers in CSF (IL-6, IL-8, IL-1beta, S100beta, NGF, NSE, DCX, ET-1, HMGB-1, cytochrome C) and blood (GFAP, NF-H, UCH-L1, SBDP-145, leptin). Mixed results were obtained for blood S100beta. Outcome did not correlate with several biomarkers in either CSF (BDNF, GDNF, alpha-Syn) or blood (NSE, MBP). The Class of Evidence was considered II in 1 study and III in the remaining 15 studies. CONCLUSIONS: Based on the status of current sTBI biomarker research, we recommend that future research should be directed at both novel biomarker discovery and validation of biomarker panels in large, well-designed longitudinal studies. PMID- 23943319 TI - Reduced EGFR level potentially mediates the Abeta42-induced neuronal loss in transgenic fruit fly and mouse. PMID- 23943321 TI - siRNA-mediated DNA methylation and H3K9 dimethylation in plants. AB - Heterochromatic siRNAs regulate transcriptional gene silencing by inducing DNA methylation and histone H3K9 dimethylation. Recent advances have revealed the distinct phases involved in siRNA mediated silencing pathway, although the precise functions of a number of factors remain undesignated, putative mechanisms for the connection between DNA and histone methylation have been investigated, and much effort has been invested to understand the biological functions of siRNA mediated epigenetic modification. In this review, we summarize the mechanism of siRNA-mediated epigenetic modification, which involves the production of siRNA and the recruitments of DNA and histone methytransferases to the target sequences assisted by complementary pairing between 24-nt siRNAs and nascent scaffold RNAs, the roles of siRNA-mediated epigenetic modification in maintaining genome stability and regulating gene expression have been discussed, newly identified players of the siRNA mediated silencing pathway have also been introduced. PMID- 23943322 TI - A new molecular explanation for age-related neurodegeneration: the Tyr682 residue of amyloid precursor protein. AB - Emerging evidence supports the role for the intracellular domains of amyloid precursor protein (APP) in the physiology and function of APP. In this short report, I discuss the hypothesis that mutation of Tyr682 on the Y682 ENPTY687 C terminal motif of APP may be directly or indirectly associated with alterations in APP functioning and activity, leading to neuronal defects and deficits. Mutation of Tyr682 induces an early and progressive age-dependent cognitive and locomotor decline that is associated with a loss of synaptic connections, a decrease in cholinergic tone, and defects in NGF signaling. These findings support a model in which APP-C-terminal domain exerts a pathogenic function in neuronal development and decline, and suggest that Tyr682 potentially could modulate the properties of APP metabolites in humans. PMID- 23943323 TI - Changes in the availability of screening mammography, 2000-2010. AB - BACKGROUND: Rates of screening mammography have plateaued, and the number of mammography facilities has declined in the past decade. The objective of this study was to assess changes over time and geographic disparities in the availability of mammography services. METHODS: Using information from the US Food and Drug Administration and the US Census, county-level mammography capacity was defined as the number of mammography machines per 10,000 women aged >= 40 years. Cross-sectional variation and longitudinal changes in capacity were examined in relation to county characteristics. RESULTS: Between 2000 and 2010, the number of mammography facilities declined 10% from 9434 to 8469, the number of mammography machines declined 10% from 13,100 to 11,762, and the median county mammography capacity decreased nearly 20% from 1.77 to 1.42 machines per 10,000 women aged >= 40 years. In cross-sectional analysis, counties with greater percentages of uninsured residents, less educated residents, greater population density, and higher managed care penetration had lower mammography capacity. Conversely, counties with more hospital beds per 100,000 population had higher capacity. High initial mammography capacity, growth in both the percentage of the population aged >= 65 years and the percentage living in poverty, and increased managed care penetration were all associated with a decrease in mammography capacity between 2000 and 2010. Only the percentage of rural residents was associated with an increase in capacity. CONCLUSIONS: Geographic variation in mammography capacity and declines in capacity over time are associated with demographic, socioeconomic, and health care market characteristics. Maldistribution of mammography resources may explain geographic disparities in breast cancer screening rates. PMID- 23943325 TI - Improved radiocarbon dating for contaminated archaeological bone collagen, silk, wool and hair samples via cross-flow nanofiltrated amino acids. AB - RATIONALE: Radiocarbon dating and stable isotope analyses of bone collagen, wool, hair and silk contaminated with extraneous carbon (e.g. humic substances) does not yield reliable results if these materials are pre-treated using conventional methods. METHODS: A cross-flow nanofiltration method was developed that can be applied to various protein materials like collagen, hair, silk, wool and leather, and should be able to remove low-molecular and high-molecular weight contaminants. To avoid extraneous carbon contamination via the filter a ceramic filter (molecular weight cut-off of 200 Da) was used. The amino acids, released by hot acid hydrolysis of the protein material, were collected in the permeate and contaminants in the retentate (>200 Da). RESULTS: (14)C-dating results for various contaminated archaeological samples were compared for bulk material (pre treated with the conventional methods) and for cross-flow nanofiltrated amino acids (permeate) originating from the same samples. Contamination and quality control of (14)C dates of bulk and permeate samples were obtained by measuring C:N ratios, fluorescence spectra, and delta(13)C and delta(15)N values of the samples. Cross-flow nanofiltration decreases the C:N ratio which means that contaminants have been removed. CONCLUSIONS: Cross-flow nanofiltration clearly improved sample quality and (14)C results. It is a quick and non-labor-intensive technique and can easily be implemented in any (14)C and stable isotope laboratory for routine sample pre-treatment analyses. PMID- 23943324 TI - Piperine potentiates the antidepressant-like effect of trans-resveratrol: involvement of monoaminergic system. AB - Major depression is characterized by dysfunction of neuroendocrine and immune networks. Trans-resveratrol, a phenolic compound presented in polygonum cuspidatum, was demonstrated previously to exert antidepressant-like effects through regulating monoaminergic system, oxidative/antioxidant defense and inflammatory response. The present study investigated the synergistic antidepressant-like effect of trans-resveratrol and piperine, a bioavailability enhancer, in mice and explored the possible mechanism. Trans-resveratrol was shown to reduce the immobility time both in the tail suspension and forced swimming tests (TST and FST). But the maximal inhibition was nearly 60% even if the doses were increased by 160 mg/kg; while piperine produced weak antidepressant-like effects in these two models. The interaction between trans resveratrol and piperine was shown a clear-cut synergistic effect as evidenced by an isobolographic analysis. The further study suggested that the anti-immobility response from the subthreshold dose of piperine (2.5 mg/kg) and low doses of trans-resveratrol (10 and 20 mg/kg) was abolished by pretreatment with para chlorophenylalanine (PCPA, 300 mg/kg, i.p.) in TST and FST, indicating the involvement of serotonergic system. Moreover, treatment with the subthreshold dose of piperine and low doses of trans-resveratrol attenuated reserpine-induced hypothermia and ptosis arguing for the relevance of noradrenaline. Additional evidence from neurochemical (monoamines in the frontal cortex, hippocampus, and hypothalamus) and biochemical (monoamine oxidase, MAO activity) assays corroborated the synergistically elevated monoaminergic system after co-treatment with trans-resveratrol and piperine. The present results indicate the effect of trans-resveratrol combined with piperine on depressive-like behaviors may be partly due to the potentiated activation of monoaminergic system in the brain. Further studies are necessary to elucidate the involvement of the oxidative/nitrosative stress, inflammatory and neuroprotective pathway in the antidepressant-like effect of this combination. The synergistic effect obtained from the combination may provide innovative clues for designing novel antidepressants with high efficacy and low side effects. PMID- 23943326 TI - Effects of distilled water rinsing on stable isotope ratios of acid-treated marine invertebrate (Paguridae) samples. AB - RATIONALE: Stable isotope ratios are widely used to infer trophic relationships, although a growing number of studies show that sample pre-treatments (such as acidification to remove carbonates) can cause changes in isotope ratios. Samples are often rinsed in distilled water after acidification, and we examine the effects of this step in particular on the isotope ratios of marine invertebrate samples. METHODS: Samples of whole hermit crabs (Paguridae) were subjected to one of three treatments: acidification using dilute hydrochloric acid without subsequent distilled water rinsing; acidification with rinsing; and rinsing with no acidification. Continuous-flow isotope ratio mass spectrometry was used to compare the mean carbon and nitrogen stable isotope ratios of treated and untreated material. RESULTS: Acidification (both with and without subsequent distilled water rinsing) resulted in reductions in mean delta(13)C values (1.939 and 3.1460/00, respectively), while rinsing without prior acidification led to a smaller (but still significant) increase. Nitrogen isotope ratios were not affected by acidification, but subsequent rinsing with distilled water caused a decrease of approximately 10/00. CONCLUSIONS: Acidification of samples is clearly necessary in the presence of carbonates to obtain useful carbon isotope ratio data. However, post-acidification rinsing can result in further (potentially undesirable) changes to both carbon and nitrogen isotope ratios. Ideally, rinsing should be avoided, but the impacts are small enough to be of little concern in many studies. Rinsing (or not) should be considered carefully on the basis of the aims of a study. PMID- 23943327 TI - Capabilities and limitations of direct analysis in real time orbitrap mass spectrometry and tandem mass spectrometry for the analysis of synthetic and natural polymers. AB - RATIONALE: Despite the widespread use of direct analysis in real time mass spectrometry (DART-MS), its capabilities in terms of accessible mass range and the types of polymers that can be analysed are not well known. The goal of this work was to evaluate the capabilities and limitations of this ionization technique combined with orbitrap mass spectrometry and tandem mass spectrometry, for the characterization (structural and polydispersity metrics) of various synthetic and natural polymers. METHODS: The capabilities and limitations of DART MS (and -MS(2)), using an orbitrap mass spectrometer, for polymer analysis were evaluated using various industrial synthetic polymers and biopolymers. Stainless steel mesh screens secured on a movable rail were used as the sampling surface, onto which 5 MUL of various polymers dissolved in tetrahydrofuran were added. Assignment of spectral features and calculation of molecular weight and polydispersity metrics were performed using PolymerixTM software and the results were compared with those obtained by gel-permeation chromatography (GPC). RESULTS: Protonated oligomers and ammonium adducts were instantaneously detected as the major ionisation products in positive ion mode. Only perfluoropolyethers (PFPEs) were ionised in negative mode and detected as [M](-.) ions. Only singly charged molecular species were observed for all oligomers under study, allowing for a rapid determination of the molecular weight and polydispersity metrics of polymers. At elevated DART gas temperatures (400-500 degrees C) the molecular weight and polydispersity metrics compared fairly well with those obtained by GPC, with polymers whose masses ranged from 200 g x mol(-1) to 4000 g x mol(-1). CONCLUSIONS: DART-MS allowed the direct and rapid analysis (mass spectra and tandem mass spectra of all the polymers were acquired in seconds) based on the exact masses of their [M+H](+) and [M+NH4](+) ions (in the positive mode) or [M]( .) ions (for polymers having a high sensitivity toward electron-capture ionisation such as PFPEs), as well as the exact masses of their product ions, for both synthetic and natural polymers under ambient conditions without any sample pre-treatment. PMID- 23943328 TI - Plasma metabolome analysis by integrated ionization rapid-resolution liquid chromatography/tandem mass spectrometry. AB - RATIONALE: Acquiring global information on plasma-endogenous metabolites challenges metabolomics. This study has been designed to investigate the suitability of integrated ionization rapid-resolution liquid chromatography/tandem mass spectrometry (RRLC/MS/MS) for different kinds of metabolites in complex plasma, and provides an approach for plasma metabolomics in acquiring more comprehensive data of metabolites. METHODS: Integrated ionization of electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and atmospheric pressure photoionization (APPI) combined with RRLC/MS/MS has been carried out to perform analysis on the global plasma metabolome of healthy volunteers. The contributions to the total numbers of ion features by RRLC/MS with ESI, APCI, and APPI in positive and negative ion modes were calculated. Representative unique and identical ions were identified. The intensities of identical ions were compared. RESULTS: Each of ESI, APCI, and APPI coupled with RRLC/MS has its own advantage over the other two techniques for certain types of metabolites in plasma. LC/ESI-MS is very sensitive for detecting glycerophosphocholines, glycerophosphoethanolamines, acyl carnitines, bile acids, sulfate, etc. LC/APCI-MS is suitable for analyzing cyclic alcohols, fatty acids, and linoleic acids. LC/APPI-MS proves to be appropriate in detecting steroids, sphingolipids, some amino acids, nucleosides, and purines in plasma. CONCLUSIONS: It is suggested that the integrated ionization LC/MS approach should be applied for global plasma metabolomics. Moreover, the results obtained demonstrate that it is preferable to choose certain techniques from LC/ESI-MS, LC/APCI-MS, and LC/APPI-MS for metabolite target analysis. PMID- 23943329 TI - Structural elucidation and identification of a new derivative of phenethylamine using quadrupole time-of-flight mass spectrometry. AB - RATIONALE: In recent years, the phenomenon of uncontrolled distribution of new psychoactive substances that were marketed without prior toxicological studies has been observed. Because many designer drugs are related in chemical structure, the potential for misidentifying them is an important problem. It is therefore essential to develop an analytical procedure for unequivocal elucidation of the structures of these compounds. The issue has been discussed in the context of 25I NBMD [2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2,3 methylenedioxyphenyl)methyl]ethanamine], a psychoactive substance first discovered on the drug market in 2012. METHODS: The substance was extracted from blotter papers with methanol. Separation was achieved via liquid chromatography. Analysis was conducted by electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-QTOFMS). Identification of the psychoactive component was supported by electron impact gas chromatography/mass spectrometry (GC/EI-MS). RESULTS: The high accuracy of the LC/ESI-QTOFMS method allowed the molecular mass of the investigated substance (M(exp) = 441.0438 Da; mass error, ?m = 0.2 ppm) and the formulae of ions formed during fragmentation to be determined. The main ions were recorded at m/z = 135.0440, 290.9876 and 305.9981. Structures of the obtained ions were elucidated in the tandem mass spectrometry (MS/MS) experiments by comparing them to mass spectra of previously detected derivatives of phenethylamine. CONCLUSIONS: The performed study indicated the potential for using LC/QTOFMS method to identify new designer drugs. This technique can be used supplementary to standard GC/MS. Prior knowledge of the fragmentation mechanisms of phenethylamines allowed to predict the mass spectra of the novel substance- 25I-NBMD. PMID- 23943330 TI - Liquid chromatography/mass spectrometry methods for measuring dipeptide abundance in non-small-cell lung cancer. AB - RATIONALE: Metabolomic profiling is a promising methodology of identifying candidate biomarkers for disease detection and monitoring. Although lung cancer is among the leading causes of cancer-related mortality worldwide, the lung tumor metabolome has not been fully characterized. METHODS: We utilized a targeted metabolomic approach to analyze discrete groups of related metabolites. We adopted a dansyl [5-(dimethylamino)-1-naphthalene sulfonamide] derivatization with liquid chromatography/mass spectrometry (LC/MS) to analyze changes of metabolites from paired tumor and normal lung tissues. Identification of dansylated dipeptides was confirmed with synthetic standards. A systematic analysis of retention times was required to reliably identify isobaric dipeptides. We validated our findings in a separate sample cohort. RESULTS: We produced a database of the LC retention times and MS/MS spectra of 361 dansyl dipeptides. Interpretation of the spectra is presented. Using this standard data, we identified a total of 279 dipeptides in lung tumor tissue. The abundance of 90 dipeptides was selectively increased in lung tumor tissue compared to normal tissue. In a second set of validation tissues, 12 dipeptides were selectively increased. CONCLUSIONS: A systematic evaluation of certain metabolite classes in lung tumors may identify promising disease-specific metabolites. Our database of all possible dipeptides will facilitate ongoing translational applications of metabolomic profiling as it relates to lung cancer. PMID- 23943331 TI - Stable carbon isotope analysis of dissolved inorganic carbon (DIC) and dissolved organic carbon (DOC) in natural waters--results from a worldwide proficiency test. AB - RATIONALE: Stable carbon isotope ratios of dissolved inorganic (DIC) and organic carbon (DOC) are of particular interest in aquatic geochemistry. The precision for this type of analysis is typically reported in the range of 0.10/00 to 0.50/00. However, there is no published attempt that compares delta(13)C measurements of DIC and DOC among different laboratories for natural water samples. METHODS: Five natural water samples (lake water, seawater, two geothermal waters, and petroleum well water) were analyzed for delta(13)CDIC and delta(13)CDOC values by five laboratories with isotope ratio mass spectrometry (IRMS) in an international proficiency test. RESULTS: The reported delta(13)CDIC values for lake water and seawater showed fairly good agreement within a range of about 10/00, whereas geothermal and petroleum waters were characterized by much larger differences (up to 6.60/00 between laboratories). delta(13)CDOC values were only comparable for seawater and showed differences of 10 to 210/00 for other samples. CONCLUSIONS: This study indicates that scatter in delta(13)CDIC isotope data can be in the range of several per mil for samples from extreme environments (geothermal waters) and may not yield reliable information with respect to dissolved carbon (petroleum wells). The analyses of lake water and seawater also revealed a larger than expected difference and researchers from various disciplines should be aware of this. Evaluation of analytical procedures of the participating laboratories indicated that the differences cannot be explained by analytical errors or different data normalization procedures and must be related to specific sample characteristics or secondary effects during sample storage and handling. Our results reveal the need for further research on sources of error and on method standardization. PMID- 23943332 TI - Chemically facilitating the generation of diagnostic ions from SUMO(2/3) remnant isopeptides. AB - RATIONALE: Mapping sites of wild-type SUMO modification is a challenging endeavour. Here we postulate that a combination of chemical derivatistation and collision-induced dissociation (CID) could be used to generate SUMO remnant diagnostic ions to aid both detection of these isopeptides and increase the analytical value of the product ion spectra required to characterize the nature and position of modification. METHODS: SUMO(2/3)ylated proteins were digested with trypsin to generate isopeptides bearing TGG and QTGG isotags. The resulting digests were then dimethyl labelled followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) utilising CID in a data-dependent acquisition on a QSTAR XL. Product ion spectra were interrogated for the presence of iso-N-terminal fragment ions in addition to backbone sequence ions. The ability to diagnostically detect these isopeptides was tested by generation of co-XICs of the iso-N-terminal fragments in a semi-complex background. RESULTS: Dimethyl labelling facilitated the robust detection of a1', b2' & b3' (TGG isotag) and a1', b2' & b4' (QTGG isotag) ions. The abundance of both N-terminal and iso-N terminal fragment ions, supported by dimethyl labelling, facilitated the generation of information-rich product ion spectra of these isopeptides to aid confident site assignment. Moreover, the diagnostic nature of the combined XICs of the iso-N-terminal fragments supported detection of the isopeptide signals from a semi-complex background. CONCLUSIONS: A combination of dimethyl labelling and CID does indeed lead to the generation of SUMO remnant isopeptide product ion spectra which are more analytically rich. This enables an improvement in characterization of both the isotag and backbone sequences and the site of modification. The diagnostic value of iso-N-terminal fragment ions allows for post-acquisition XIC interrogation to detect putative isopeptides of interest. PMID- 23943333 TI - In vivo and in vitro metabolism of the synthetic cannabinoid JWH-200. AB - RATIONALE: The synthetic cannabinoid JWH-200 (1-[2-(4-morpholinyl)ethyl]-3-(1 naphthoyl)-indole) appeared on the market around 2009. In order to identify markers for misuse of this compound and allow for the development of adequate routine methods, the metabolism of this compound was investigated using two models. METHODS: In vitro and in vivo (both with and without enzymatic hydrolysis) samples were purified by solid-phase extraction and analyzed using liquid chromatography. Electrospray ionization high-resolution Orbitrap mass spectrometry was used for the identification of the metabolites. To confirm the results in vivo, triple-quadrupole mass spectrometry was employed RESULTS: In the in vitro model, using human liver microsomes, 22 metabolites were detected which could be divided into 11 metabolite classes. By using the chimeric mouse model with humanized liver, most of these metabolites were confirmed in vivo. It was found that all metabolites are excreted in urine as conjugates, mostly as glucuronides with varying conjugation rates. CONCLUSIONS: The metabolite formed by consecutive morpholine cleavage and oxidation of the remaining side chain to a carboxylic group was detected in the highest amounts with the longest detection time. Therefore, it is the best candidate metabolite to detect JWH-200 abuse in urine. PMID- 23943334 TI - Triangular core-shell ZnO@SiO2 nanoparticles. AB - Well packed! Core-shell nanostructures composed of ZnO particles encapsulated in an equilateral triangular SiO2 shell are reported for the first time. The quantum confinement effects within the nanostructures can be used to tune their properties for optoelectronic applications. PMID- 23943335 TI - Simultaneous determination of pharmaceutical components in dietary supplements for weight loss by capillary electrophoresis tandem mass spectrometry. AB - A simple capillary electrophoresis tandem mass spectrometry method was developed for the simultaneous determination of 20 pharmaceutical components such as cathartics and appetite suppressants in dietary supplements for weight loss. This method allowed multidrug target screening and confirmation in differing radically in chemical structure. The separation was achieved on an uncoated fused-silica capillary using 20 mM ammonium formate in 20 % v/v acetonitrile-water (pH 8.0) as the electrolyte, followed by detection mixed with a sheath liquid that consisted of a mixture of 5 mM ammonium formate and 0.1 % v/v formic acid in 50 % v/v methanol-water. Samples were hydrodynamically injected and separated at 30 kV within 25 min. The limits of detection were 1.0-750 ug/g for the target analytes. The method was successfully applied to 12 dietary supplements for weight loss and 3 non-prescription drugs. The proposed method was suitable as the determination and identification of pharmaceutical components in dietary supplements for weight loss. PMID- 23943336 TI - The ultrasound contrast imaging properties of lipid microbubbles loaded with urokinase in dog livers and their thrombolytic effects when combined with low frequency ultrasound in vitro. AB - A new microbubble loaded with urokinase (uPA-MB) was explored in a previous study. However, its zeta potential and ultrasound contrast imaging properties and its thrombolytic effects when combined with low-frequency ultrasound (LFUS) were unclear. The zeta potential and ultrasound contrast imaging property of 5 uPA-MBs loading with 50,000 IU uPA was respectively detected using a Malvern laser particle analyzer and a Logiq 9 digital premium ultrasound system. Its ultrasound contrast imaging property was performed on the livers of two healthy dogs to compare with SonoVue. And the clot mass loss rate, D-dimer concentration and surface morphology of the clot residues were measured to evaluate the thrombolytic effect after treatment with three doses of 5 uPA-MBs combined with LFUS in vitro. The zeta potential of 5 uPA-MBs (-27.0 +/- 2.40 mV) was higher than that of normal microbubbles (-36.95 +/- 1.77 mV). Contrast-enhanced imaging of the hepatic vessels using 5 uPA-MBs was similar to SonoVue, while the imaging duration of 5 uPA-MBs (10 min) was longer than SonoVue (6 min). The thrombolytic effect of three doses of uPA-MBs combined with LFUS was significantly better than that of the control group and showed dose dependence. The 5 uPA-MBs have a negative charge on their surface and good echogenicity as ultrasound contrast agents. The 5 uPA-MBs combined with LFUS can promote thrombolysis in a dose dependent manner. PMID- 23943337 TI - Pharmacodynamic effects of EV-077 in patients with diabetes mellitus and coronary artery disease on aspirin or clopidogrel monotherapy: results of an in vitro pilot investigation. AB - Patients with diabetes mellitus (DM) have increased propensity to generate thromboxane A2 (TXA2) and other eicosanoids which can contribute to their heightened platelet reactivity. EV-077 is a potent thromboxane receptor antagonist and thromboxane synthase inhibitor and thus represents an attractive therapy in patients with DM. However, the effects of EV-077 on pharmacodynamic (PD) profiles in patients with DM and coronary artery disease (CAD) while on antiplatelet therapy is poorly explored and represented the aim of this in vitro pilot investigation. Patients with DM and stable CAD (n = 10) on low-dose aspirin (81 mg/day) were enrolled and then switched to clopidogrel (75 mg/day) monotherapy for 7-10 days. PD assessments were conducted while on aspirin and on clopidogrel using light transmittance aggregometry following stimuli with U-46619 [TXA2 stable analogue (7 MUM)], arachidonic acid [AA (1 mM)], collagen (3 MUg/mL) and adenosine diphosphate [ADP (5 MUM and 20 MUM)] with and without in vitro EV 077. EV-077 completely inhibited U-46619-stimulated platelet aggregation (p = 0.005 for both aspirin and clopidogrel) and also showed a significant reduction of collagen-induced aggregation (aspirin p = 0.008; clopidogrel p = 0.005). EV 077 significantly reduced AA-induced platelet aggregation in clopidogrel (p = 0.009), but not aspirin (p = 0.667) treated patients. Ultimately, EV-077 significantly reduced ADP-mediated platelet aggregation in both aspirin (ADP 5 MUM p = 0.012; ADP 20 MUM p = 0.032) and clopidogrel (ADP 5 MUM p = 0.007; ADP 20 MUM p = 0.008) treated patients. In conclusion, in DM patients with CAD on aspirin or clopidogrel monotherapy, in vitro EV-077 exerts potent platelet inhibitory effects on multiple platelet signaling pathways. These data support that EV-077 has only additive platelet inhibiting effects on top of standard antiplatelet therapies. These findings warrant further investigation in ex vivo settings. PMID- 23943338 TI - Off-label thrombolysis versus full adherence to the current European Alteplase license: impact on early clinical outcomes after acute ischemic stroke. AB - According to current European Alteplase license, therapeutic-window for intravenous (IV) thrombolysis in acute ischemic stroke has recently been extended to 4.5 h after symptoms onset. However, due to numerous contraindications, the portion of patients eligible for treatment still remains limited. Early neurological status after thrombolysis could identify more faithfully the impact of off-label Alteplase use that long-term functional outcome. We aimed to identify the impact of off-label thrombolysis and each off-label criterion on early clinical outcomes compared with the current European Alteplase license. We conducted an analysis on prospectively collected data of 500 consecutive thrombolysed patients. The primary outcome measures included major neurological improvement (NIHSS score decrease of <=8 points from baseline or NIHSS score of 0) and neurological deterioration (NIHSS score increase of >=4 points from baseline or death) at 24 h. We estimated the independent effect of off-label thrombolysis and each off-label criterion by calculating the odds ratio (OR) with 2-sided 95% confidence interval (CI) for each outcome measure. As the reference, we used patients fully adhering to the current European Alteplase license. 237 (47.4%) patients were treated with IV thrombolysis beyond the current European Alteplase license. We did not find significant differences between off- and on label thrombolysis on early clinical outcomes. No off-label criteria were associated with decreased rate of major neurological improvement compared with on label thrombolysis. History of stroke and concomitant diabetes was the only off label criterion associated with increased rate of neurological deterioration (OR 5.84, 95% CI 1.61-21.19; p = 0.024). Off-label thrombolysis may be less effective at 24 h than on-label Alteplase use in patients with previous stroke and concomitant diabetes. Instead, the impact of other off-label criteria on early clinical outcomes was not different compared with current European Alteplase license. PMID- 23943340 TI - CHA(2)DS(2)-VASc versus CHADS(2) for stroke risk assessment in low-risk patients with atrial fibrillation: a pilot study from a single center of the NCDR-PINNACLE registry. AB - The CHADS(2) score is widely used to assess the risk of stroke in patients with atrial fibrillation (AF). Patients with score of 0 and 1 are considered 'low risk' and are often treated with aspirin. In a Danish Study, the CHA(2)DS(2)- VASc score was shown to identify low and high-risk subgroups among patients with CHADS(2) score of 0 and 1, with annual risk ranging from 0.84 to 8.18%. This study seeks to assess whether using CHA(2)DS(2)--VASc score will identify high risk subset of patients with low CHADS(2) scores in an American population. This pilot study examined data from our cardiology fellowship ambulatory clinics from January 2009 to May 2012 using the NCDR-PINNACLE registry. Each cardiology fellow entered patients' data using on-line software developed by the American College of Cardiology. Among 2,048 patients followed at our clinics, 478 had AF. Of those, 161 patients had CHADS(2) score of 0 (44 patients) or 1 (117 patients). Calculating the CHA(2)DS(2)--VASc score in these patients, 12 (7.4%) had score of 0, 50 (31.1%) had score of 1, 66(41%) had score of 2, 31 (19.3%) had score of 3 and 2 (1.2%) had score of 4. Using original CHADS(2) recommendation, warfarin would not be strongly recommended in any of these patients. Utilizing the CHA(2)DS(2)--VASc score, 61.5% of the 161 patients would have a score of 2 or more signifying increased risk where anticoagulation may be indicated. Compared to CHADS(2), CHA(2)DS(2)--VASc may more precisely predict the risk of stroke and anticoagulation strategy in low-risk patients with non-valvular AF. PMID- 23943339 TI - Periprocedural coagulability in patients undergoing ablation of atrial fibrillation: lessons from a periablation anticoagulation strategy of a brief withdrawal of warfarin without heparin bridging. AB - We aimed to examine what becomes of the coagulable state when warfarin is interrupted in patients undergoing ablation of atrial fibrillation (AF). We studied 62 patients with a CHADS2 score of 0 or 1 who underwent ablation for paroxysmal AF. Warfarin was discontinued the day before the ablation without heparin-bridging, and intravenous heparin was administered during the procedure in a conventional manner, and warfarin was then resumed after achieving hemostasis of the access site. The international normalized ratio (INR) values or D-dimer levels were measured at five different time points during the periprocedural period, and the periprocedural hemorrhagic and thromboembolic complications were assessed. The INR value constantly decreased after withdrawal of warfarin, and did not recover to the level before its discontinuation at the time of hospital discharge despite a short interruption of warfarin (mean +/- SD, 1.75 +/- 0.52 to 1.41 +/- 0.27, p < 0.0001). However, the D-dimer level continued to increase over a period of 48 h after the ablation in spite of the administration of a sufficient amount of heparin during the procedure and a quick resumption of warfarin (mean +/- SD, 0.57 +/- 0.19 to 0.85 +/- 0.36 MUg/mL, p < 0.0001). The INR value measured just before the ablation had a significant inverse correlation to the D-dimer levels assessed just before (r = -0.304), immediately after (r = -0.440), 24 h after (r = -0.442) and 48 h after the ablation (r = -0.463). In conclusion, the risk of hyper-coagulability may increase during the early postprocedural period of AF ablation in patients who were inappropriately anticoagulated with warfarin. PMID- 23943341 TI - Intravenous thrombolysis in stroke patients under 55 years of age: is there a different effect according to etiology and severity? AB - The effect of intravenous thrombolysis (IVT) according to etiology and stroke severity in young patients with ischemic stroke (IS) has not been described previously. To analyze the effect of IVT in young patients with IS according to etiological subtype and stroke severity. Observational study with inclusion of IS patients under 55 years of age (2007-2012). Two groups were compared according to IVT treatment. Favorable outcomes were defined as 3 months modified Rankin Scale <=2. Multivariate analyses were performed to determine those factors independently associated with favorable outcomes, and subgroup analyses were conducted to assess the effect of IVT according to etiological stroke subtype and severity on admission, adjusted for other prognostic variables. We evaluated 262 patients. 63 (24%) received IVT. The mean age and the sex distribution were similar in the IVT treated and the non-treated groups. Multivariate analyses showed that IVT was associated with a higher probability of favorable outcome (OR, 95% CI: 4.652, 1.294-16.722) whereas artery dissection (OR, 95% CI: 0.191, 0.056-0.654) and NIHSS (OR, 95% CI: 0.727, 0.664-0.797) were associated with a lower probability of a favorable outcome. The subgroup analysis showed that the beneficial effect of IVT on outcomes was significant in moderate-severe strokes (NIHSS >=8) (OR, 95% CI: 3.782, 1.095-13.069) and in cardioembolism (OR, 95% CI: 41.887, 1.001-1751.596). In IS patients under 55 years of age, those with moderate-severe strokes benefit more from IVT than those with mild strokes. Cardioembolic infarctions may benefit more from IV tPA than other etiologies. PMID- 23943342 TI - Clinical management of coronary heart disease in hypertension : practical recommendations from the Italian Society of Hypertension (SIIA). PMID- 23943343 TI - Heat shock, with recovery, promotes protection of Nicotiana tabacum during subsequent exposure to Ralstonia solanacearum. AB - Host-pathogen interactions in plants are complex and potentially influenced by heat shock/stress (HS). Host HS proteins (HSPs) induced prior to bacterial exposure may facilitate the folding of newly synthesized defense proteins and promote incompatible host-pathogen interactions. We hypothesized that a non lethal HS, with recovery, promotes protection of Nicotiana tabacum during subsequent exposure to avirulent soilborne necrotrophic pathogen Ralstonia solanacearum. The objective of this study included investigating the effects of HS with or without recovery on the outcome of bacterial exposure to a virulent and avirulent biovar of R. solanacearum in N. tabacum cell suspensions. This was assessed by quantifying host Hsp70/Hsc70 levels, mitochondrial electron (e (-)) transport activity as a marker of viability, and phosphatidylserine externalization and DNA fragmentation as markers of apoptosis. Our findings support the hypothesis that HS, with recovery, promotes protection of N. tabacum during subsequent exposure to R. solanacearum, suggesting a role for Hsp70/Hsc70 in the observed protection of e (-) transport, increased apoptosis, and DNA fragmentation. PMID- 23943345 TI - Adaptive release of natural enemies in a pest-natural enemy system with pesticide resistance. AB - Integrated pest management options such as combining chemical and biological control are optimal for combating pesticide resistance, but pose questions if a pest is to be controlled to extinction. These questions include (i) what is the relationship between the evolution of pesticide resistance and the number of natural enemies released? (ii) How does the cumulative number of natural enemies dying affect the number of natural enemies to be released? To address these questions, we developed two novel pest-natural enemy interaction models incorporating the evolution of pesticide resistance. We investigated the number of natural enemies to be released when threshold conditions for the extinction of the pest population in two different control tactics are reached. Our results show that the number of natural enemies to be released to ensure pest eradication in the presence of increasing pesticide resistance can be determined analytically and depends on the cumulative number of dead natural enemies before the next scheduled release time. PMID- 23943344 TI - Regulation of electrical bursting in a spatiotemporal model of a GnRH neuron. AB - Gonadotropin-releasing hormone (GnRH) neurons are hypothalamic neurons that control the pulsatile release of GnRH that governs fertility and reproduction in mammals. The mechanisms underlying the pulsatile release of GnRH are not well understood. Some mathematical models have been developed previously to explain different aspects of these activities, such as the properties of burst action potential firing and their associated Ca(2+) transients. These previous studies were based on experimental recordings taken from the soma of GnRH neurons. However, some research groups have shown that the dendrites of GnRH neurons play very important roles. In particular, it is now known that the site of action potential initiation in these neurons is often in the dendrite, over 100 MUm from the soma. This raises an important question. Since some of the mechanisms for controlling the burst length and interburst interval are located in the soma, how can electrical bursting be controlled when initiated at a site located some distance from these controlling mechanisms? In order to answer this question, we construct a spatio-temporal mathematical model that includes both the soma and the dendrite. Our model shows that the diffusion coefficient for the spread of electrical potentials in the dendrite is large enough to coordinate burst firing of action potentials when the initiation site is located at some distance from the soma. PMID- 23943346 TI - The effects of seasonal forcing on invertebrate-disease interactions with immune priming. AB - There is increasing experimental evidence that exposure to low doses of infection may 'prime' the immune response of invertebrate hosts, giving them greater protection against future infection. This form of immune memory is not compatible with the 'acquired immunity' modelled by the classic Susceptible-Infected Recovered (SIR) epidemiological model, but instead requires the development of an alternative Susceptible-Primed-Infected (SPI) framework. Some initial theoretical work has explored the epidemiological and evolutionary dynamics of the SPI model, but these have assumed hosts exist in a constant environment. In reality, natural invertebrate-disease systems will be subject to significant environmental variation. Here, I use bifurcation analysis using numerical continuation software, complemented with numerical simulations, to investigate the effects of seasonal forcing on the already complex epidemiological dynamics of the SPI model. I show that multi-year cycles, quasi-periodicity, chaos, and multiple stability may all result, and highlight the importance not just of the forcing amplitude, but also the ecological and epidemiological background, for complex dynamics to emerge. PMID- 23943347 TI - Probiotic VSL#3-induced TGF-beta ameliorates food allergy inflammation in a mouse model of peanut sensitization through the induction of regulatory T cells in the gut mucosa. AB - SCOPE: Among food allergies, peanut allergy is frequently associated with severe anaphylactic reactions. In the need for safe and effective therapeutic strategies, probiotics may be considered on the basis of their immunomodulatory properties. The aim of the present study was to investigate the immunological mediators involved in the effects of probiotic VSL#3 oral supplementation on Th2 inflammation and anaphylaxis in a mouse model of peanut allergy. METHODS AND RESULTS: VSL#3 supplementation to peanut-sensitized mice was effective in ameliorating anaphylaxis and Th2-mediated inflammation, by promoting regulatory responses in the jejunum mucosa and in the mesenteric lymph node, as evaluated by ELISA, real-time PCR, histologic, and immunohistochemical analysis. Probiotic induced TGF-beta mediates its protective effects through the induction of regulatory T cells expressing FOXP3 and/or latency-associated peptide, as proven by in vivo blockade of TGF-beta in VSL#3-treated mice with a neutralizing monoclonal antibody one day before challenge. CONCLUSION: TGF-beta, induced in the gut by VSL#3 supplementation, is capable of reducing the Th2 inflammation associated with food anaphylaxis in a mouse model of peanut sensitization. TGF beta acts through the induction/maintenance of regulatory T cells expressing FOXP3 and/or latency-associated peptide. Probiotics supplementation may represent an effective and safe strategy for treating food allergies in adult population. PMID- 23943348 TI - Intimate partner violence and HIV: a review. AB - Intimate partner violence (IPV) is a common and negative social determinant of health. IPV also increases vulnerability to risks associated with HIV transmission and contributes to HIV transmission. IPV is therefore predictably common among people living with HIV. It is increasingly being recognized as an important predictor of poor outcomes for those living with HIV by affecting retention to care, mental health, adherence to therapy, frequency of follow-up; all of which lead to more hospitalizations and progression to AIDS. HIV care providers can safely and effectively screen all HIV patients for IPV. Screening offers the opportunity to identify those at risk for poor outcomes and mitigate its effects. Further research is required in further defining the risk factors and outcomes of IPV and optimizing interventions. We review the association between HIV infection and IPV and make recommendations for IPV screening of HIV positive individuals and those at high risk for HIV. PMID- 23943349 TI - Acute hemorrhagic leukoencephalopathy associated with influenza A (H1N1) virus. AB - BACKGROUND: Acute hemorrhagic leukoencephalopathy (AHLE) is a rare condition associated with H1N1. In this condition the infection triggers an autoimmune response which results in perivascular demyelination and hemorrhage in the brain parenchyma. METHODS: We report a case of a patient who developed brain edema and herniation as a result of AHLE. RESULTS: A 27-year-old presented to a community hospital with fever, dyspnea, and malaise and was found to have H1N1-associated pneumonia. Despite treatment he progressed to acute respiratory distress syndrome and required mechanical ventilation. Due to failure on conventional ventilation, he was transferred to our hospital and was placed on high-frequency oscillatory ventilation. He was showing improvement until day 6 of transfer to our hospital when he was suddenly noted to have a rise in his blood pressure followed by hypotension. The following morning he was noted to have non-reactive pupils and was declared brain dead. Autopsy of the brain was consistent with AHLE. CONCLUSIONS: This case emphasizes the importance of awareness of this disease. The non-specific signs and symptoms, and the use of sedatives, make diagnosis challenging in the early stages of this disease. If suspected early, appropriate imaging can aid in the diagnosis. Treatment with immunosuppressive agents and plasmapheresis may prevent rapid progression and death. This is the first published case of AHLE in association with H1N1 that has been confirmed pathologically. PMID- 23943350 TI - Preclinical studies of noncharged oxime reactivators for organophosphate exposure. AB - A countermeasure that protects the brain from organophosphate toxicity is an unmet need. Few small molecule reactivators that can cross the blood brain barrier and reactivate brain acetyl cholinesterases have been reported. Herein, we describe preclinical investigations of a new class of amidine-oxime reactivator of cholinesterases with improved potency and blood brain barrier permeability. (Z)-N-((E)-1-(Dimethylamino)-2-(hydroxyimino)ethylidene)butan-1 aminium chloride, 1, is zwitterionic at physiological pH but possesses increased oxime nucleophilicity because of the adjacent amidine functionality. The amidine oximes reported herein were observed to be nontoxic (up to 200 mg/kg in vivo) and are chemically and metabolically stable. The results presented herein show that uncharged amidine-oxime reactivators such as 1 can penetrate the blood brain barrier in animals and protect from the toxicity of nerve agent model compounds. PMID- 23943352 TI - Comparison of force fields on the basis of various model approaches--how to design the best model for the [CnMIM][NTf2] family of ionic liquids. AB - In this contribution, we present two new united-atom force fields (UA-FFs) for 1 alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [C(n)MIM][NTf(2)] (n=1, 2, 4, 6, 8) ionic liquids (ILs). One is parametrized manually, and the other is developed with the gradient-based optimization workflow (GROW). By doing so, we wanted to perform a hard test to determine how researchers could benefit from semiautomated optimization procedures. As with our already published all atom force field (AA-FF) for [C(n)MIM][NTf(2)] (T. Koddermann, D. Paschek, R. Ludwig, ChemPhysChem- 2007, 8, 2464), the new force fields were derived to fit experimental densities, self-diffusion coefficients, and NMR rotational correlation times for the IL cation and for water molecules dissolved in [C(2)MIM][NTf(2)]. In the manual force field, the alkyl chains of the cation and the CF3 groups of the anion were treated as united atoms. In the GROW force field, only the alkyl chains of the cation were united. All other parts of the structures of the ions remained unchanged to prevent any loss of physical information. Structural, dynamic, and thermodynamic properties such as viscosity, cation rotational correlation times, and heats of vaporization calculated with the new force fields were compared with values simulated with the previous AA-FF and the experimental data. All simulated properties were in excellent agreement with the experimental values. Altogether, the UA-FFs are slightly superior for speed-up reasons. The UA-FF speeds up the simulation by about 100 % and reduces the demanded disk space by about 78 %. More importantly, real time and efforts to generate force fields could be significantly reduced by utilizing GROW. The real time for the GROW parametrization in this work was 2 months. Manual parametrization, in contrast, may take up to 12 months, and this is, therefore, a significant increase in speed, though it is difficult to estimate the duration of manual parametrization. PMID- 23943353 TI - The discovery of 3-(1-aminoethylidene)quinoline-2, 4(1H,3H)-dione derivatives as novel PSII electron transport inhibitors. AB - Based on the structures of the 4-hydroxyphenylpyruvate dioxygenase inhibitor mesotrione and natural product fischerellin A, a series of imine derivatives of (E)-3-acyl-quinoline-2,4(1H,3H)-dione (6, 12 and 16) were designed, synthesized and systematically evaluated for their herbicidal activity. The bioassay results indicated that most of the synthesized compounds displayed good to excellent herbicidal activity, of which 6e, 6g, 6h, 6q and 6t exhibited more than 50 % inhibition against Brassica napus L., Amaranthus retroflexu or Digitaria adscendens at a dosage of 94 g ha-1 or lower. The symptom of injured leaves in vivo, the high Hill reaction inhibitory activity of 6h in vitro(IC50 0.1MUgmL-1) and the computer-based binding model of compound 6h with D1 protein in photosystem II (PSII) reaction centre suggest this novel structure to likely be a new type of PSII electron transport inhibitor. Thus, we have found a novel type of diketone enamine structure targeted at the PSII reaction centre. PMID- 23943354 TI - Ph3P/CCl4 as a highly efficient reagent for one-pot N-alkylation of sulfonamides from alcohols: a rapid route to N-alkyl sulfonamides synthesis. AB - A mild, efficient, and selective protocol for the one-pot N-alkylation of sulfonamides with alcohols using triphenylphosphine and carbon tetrachloride is described. In this method, treatment of alcohols with a mixture of triphenylphosphine, carbon tetrachloride, and potassium sulfonylamide salts in refluxing anhydrous DMF furnishes the corresponding N-alkyl sulfonamides in good to excellent yields. This protocol is highly efficient for various structurally diverse alcohols and potassium sulfonylamide salts. In this paper the influence of solvents and various reagents as sources for electrophilic-halogen instead of carbon tetrachloride in combination with triphenylphosphine have been examined. This protocol demonstrates the selectivity between primary and secondary alcohols. A plausible mechanism for this protocol has been described. PMID- 23943355 TI - Udder health in relation to udder and teat morphometry in Holstein Friesian * Sahiwal crossbred dairy cows. AB - The present investigation involved 261 Holstein Friesian (HF) * Sahiwal cows to study the udder health as well as the udder and teat morphometry. The udder health was defined on the basis of bacteriology and California mastitis test of quarter foremilk. The morphometry parameters included udder fore depth (UFD, distance from the point where the fore udder merges within the abdomen to a point in front of the fore teats at the level of the udder base), udder rear depth (URD, distance from the bottom of the vulva to the base of the rear udder), udder depth (UD, level of the udder base with respect to hock joint), height of the udder from the floor, teat length, teat diameter (at mid of the teat barrel), teat-tip to floor distance and distance between the teats. The URD, UD and height of udder from the floor showed a significant (P < 0.05) relation to the udder health with mastitic cows having larger URD, smaller udder distance from the floor and the udder base placed below the hock joint. The cows with teat length larger than 4.5 cm and teat diameter 3.0 cm or larger had significantly more quarters affected with mastitis. Further, cows with teats placed nearer to the floor were more susceptible to mastitis (P < 0.01). No significant differences were found between healthy and mastitic udders with respect to UFD and distance between teats. It can be concluded that selection for optimum udder and teat morphometry in breeding programmes may help to reduce susceptibility to intramammary infections in HF * Sahiwal cows. PMID- 23943356 TI - Cell death proteins: an evolutionary role in cellular adaptation before the advent of apoptosis. AB - Programmed cell death (PCD) or apoptosis is a broadly conserved phenomenon in metazoans, whereby activation of canonical signal pathways induces an ordered dismantling and death of a cell. Paradoxically, the constituent proteins and pathways of PCD (most notably the metacaspase/caspase protease mediated signal pathways) have been demonstrated to retain non-death functions across all phyla including yeast, nematodes, drosophila, and mammals. The ancient conservation of both death and non-death functions of PCD proteins raises an interesting evolutionary conundrum: was the primordial intent of these factors to induce cell death or to regulate other cellular adaptations? Here, we propose the hypothesis that apoptotic behavior of PCD proteins evolved or were co-opted from core non death functions. PMID- 23943358 TI - Simultaneous ESI-APCI+ ionization and fragmentation pathways for nine benzodiazepines and zolpidem using single quadrupole LC-MS. AB - Nine important 1,4-benzodiazepines and zolpidem were characterized by liquid chromatography-mass spectrometry using a multimode ionization source able to generate ions using both electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI), and a single quadrupole mass analyzer. An optimum chromatographic separation was applied for all target compounds in less than 8 minutes using a Zorbax Eclipse Plus column (100 * 4.6 mm, 3.5 um) kept at 35 degrees C and a 0.3% HCOOH/ACN/IPA (61:34:5) mobile phase pumped at 1 ml/min. Optimization of LC-MS method generated low limit of quantitation (LOQ) values situated in the range 0.3-20.5 ng/ml. Comparison between differences in method sensitivity, under specified chromatographic conditions, when using ESI-only, APCI-only, and simultaneous ESI-APCI ionization with such a multimode source was discussed. Mixed ESI-APCI(+) mode proved to be the most sensitive ionization generating an average 35% detector response increase compared to ESI-only ionization and 350% detector response increase with respect to APCI-only ionization. Characterization of the nine benzodiazepines and zolpidem concerning their MS fragmentation pathway following 'in-source' collision-induced dissociation is discussed in detail and some general trends regarding these fragmentations are set. PMID- 23943357 TI - Myelosuppression after frontline fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: analysis of persistent and new-onset cytopenia. AB - BACKGROUND: The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced improved response rates and a prolonged survival in patients with chronic lymphocytic leukemia (CLL). However, its therapeutic power is counterbalanced by significant hematologic toxicity. Persistent and new-onset cytopenia after the completion of FCR raise concern about disease recurrence, the development of therapy-related myeloid malignancies (TRMM), and infections. METHODS: A total of 207 patients with CLL who achieved complete response, complete response with incomplete bone marrow recovery, or nodular partial remission were analyzed after frontline FCR therapy. RESULTS: Three months after the completion of therapy, 35% of patients had developed grade 2 to 4 cytopenia (according to Common Terminology Criteria for Adverse Events [version 4.0]). Factors found to be associated with cytopenia at 3 months after therapy were older age, advanced Rai stage disease, and lower baseline blood counts. Moreover, patients with cytopenia were less likely to have completed 6 courses of therapy with FCR. At 6 months and 9 months after therapy, the prevalence of grade 2 to 4 cytopenia was 24% and 12%, respectively. No differences in progression-free survival and overall survival were noted between cytopenic and noncytopenic patients or between patients with persistent and new-onset cytopenia. The prevalence of TRMM was 2.3% and did not differ significantly between cytopenic and noncytopenic patients or between those with persistent and new-onset disease. Late infections were more common in patients who were cytopenic at 9 months (38%) and were mostly bacterial (67%). CONCLUSIONS: Cytopenia after the completion of therapy is a common complication of frontline FCR that improves over time, particularly for new-onset cases. The presence of persistent cytopenia (lasting up to 9 months after the completion of therapy) should not raise concern about CLL recurrence of the development of TRMM, but should encourage surveillance for bacterial infections for an additional 9 months. PMID- 23943359 TI - Anaerobic respiration and antioxidant responses of Corythucha ciliata (Say) adults to heat-induced oxidative stress under laboratory and field conditions. AB - High temperature often induces oxidative stress and antioxidant response in insects. This phenomenon has been well documented under controlled laboratory conditions, but whether it happens under fluctuating field conditions is largely unknown. In this study, we used an invasive lace bug (Corythucha ciliata) as a model species to compare the effects of controlled thermal treatments (2 h at 33 43 degrees C with 2 degrees C intervals in the laboratory) and naturally fluctuating thermal conditions (08:00-14:00 at 2-h intervals (29.7-37.2 degrees C) on a hot summer day in a field in Shanghai, China) on lipid peroxidation (malondialdehyde (MDA) was the marker) and anaerobic respiration (lactate dehydrogenase (LDH) was the marker), as well as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione reductase (GR). The results show that MDA concentration increased significantly in response to heat stresses with similar trend in the laboratory and field. LDH activities did not significantly vary across temperatures in the laboratory-exposed individuals, but they significantly increased by rising temperature in the field. The activities or concentrations of SOD, CAT, GSH, and GR all significantly increased with increasing temperature in the two populations. These findings indicate that high temperature induces oxidative stress, resulting in high anaerobic respiration and antioxidant defenses in C. ciliata under both the laboratory and field conditions, which likely provide a defense mechanism against oxidative damage due to the accumulation of ROS. PMID- 23943361 TI - Diagnostic dental radiographs not allowed! A child with ataxia telangiectasia. AB - BACKGROUND: Ataxia telangiectasia (AT) is a rare neurodegenerative condition which has not previously been reported in the dental literature. It is a life threatening and debilitating disorder of progressive cerebellar ataxia and choreoathetosis, progressive oculocutaneous telangiectasias, immunodeficiency with susceptibility to sinopulmonary infections, impaired organ maturation, X-ray hypersensitivity, and a high incidence of malignancies. Of importance in dentistry is the contra-indication for taking diagnostic radiographs. CASE REPORT: A 5-year-old girl with AT was referred by her paediatrician for dental care as she had never been seen by a dentist. She presented with caries affecting a number of primary teeth. Diagnostic radiographs could not be taken due to her X ray hypersensitivity. TREATMENT: She was given antibiotic prophylaxis for dental treatment under general anaesthetic. She had composite restorations, stainless steel crowns and extractions completed. FOLLOW-UP: She has been reviewed for over 2 years with ongoing enhanced prevention. CONCLUSION: This case reports a rare condition in which diagnostic dental radiographs are contra-indicated. PMID- 23943360 TI - Barriers to dental care for children with autism spectrum disorder. AB - AIMS: This study examined the problems encountered by children with autism spectrum disorder (ASD), when accessing dental care. STUDY DESIGN: This was a cross-sectional, case-control questionnaire study. METHODS: A piloted questionnaire was developed to identify the main barriers to dental care experienced by patients with ASD in Hull and East Riding. The study group was comprised of parents/carers of children with ASD, and the control group was comprised of parents/carers of age matched healthy, neurotypical children. STATISTICS: Results were analysed using Chi-square and Fisher's exact tests where appropriate. Significance was deemed at p < 0.05. Ordinal data was presented using medians and 25th and 75th centiles and compared using Mann-Whitney U test. METHODS: A piloted questionnaire was developed to identify the main barriers to dental care experienced by patients with ASD in Hull and East Riding. The study group was comprised of parents/carers of children with ASD, and the control group was comprised of parents/carers of age matched healthy, neurotypical children. RESULTS: 112 subjects completed the questionnaire. There was no significant difference in accessing dental care between study and control groups (p = 0.051), although access was perceived as more difficult in the ASD group (p < 0.001). There was a significantly greater perceived difficulty in travelling to the dental surgery in the ASD group. Predicted negative behaviours were more frequent in the ASD group. All suggested interventions were predicted to be helpful in a significantly greater proportion of the ASD group. CONCLUSION: Difficulties exist for children with ASD in accessing dental care in the Hull and East Riding area. PMID- 23943362 TI - Flavonoid apigenin modified gene expression associated with inflammation and cancer and induced apoptosis in human pancreatic cancer cells through inhibition of GSK-3beta/NF-kappaB signaling cascade. AB - SCOPE: The objective was to examine the inhibitory effects of citrus fruit bioactive compounds on BxPC-3 and PANC-1 human pancreatic cancer cells, focusing on the antiproliferative mechanism of action of the flavonoid apigenin related to the glycogen synthase kinase-3beta/nuclear factor kappa B signaling pathway. METHODS AND RESULTS: Flavonoids, limonoids, phenolic acids, and ascorbic acid were tested for cytotoxic effects on BxPC-3 and PANC-1 cells; apigenin was the most potent (IC50 = 23 and 12 MUM for 24 and 48 h for BxPC-3 and IC50 = 71 and 41 MUM for 24 and 48 h for PANC-1). Apigenin induced pancreatic cell death through inhibition of the glycogen synthase kinase-3beta/nuclear factor kappa B signaling pathway. Apigenin arrested cell cycle at G2 /M phase (36 and 32% at 50 MUM for BxPC-3 and PANC-1, respectively) with concomitant decrease in the expression of cyclin B1. Apigenin activated the mitochondrial pathway of apoptosis (44 and 14% at 50 MUM for BxPC-3 and PANC-1, respectively) and modified the expression of apoptotic proteins. Apigenin highly upregulated the expression of cytokine genes IL17F (114.2-fold), LTA (33.1-fold), IL17C (23.2-fold), IL17A (11.3-fold), and IFNB1 (8.9-fold) in BxPC-3 cells, which potentially contributed to the anticancer properties. CONCLUSION: Flavonoids have a protective role in pancreatic cancer tumorigenesis. PMID- 23943363 TI - Equilibria of an epidemic game with piecewise linear social distancing cost. AB - Around the world, infectious disease epidemics continue to threaten people's health. When epidemics strike, we often respond by changing our behaviors to reduce our risk of infection. This response is sometimes called "social distancing." Since behavior changes can be costly, we would like to know the optimal social distancing behavior. But the benefits of changes in behavior depend on the course of the epidemic, which itself depends on our behaviors. Differential population game theory provides a method for resolving this circular dependence. Here, I present the analysis of a special case of the differential SIR epidemic population game with social distancing when the relative infection rate is linear, but bounded below by zero. Equilibrium solutions are constructed in closed-form for an open-ended epidemic. Constructions are also provided for epidemics that are stopped by the deployment of a vaccination that becomes available a fixed-time after the start of the epidemic. This can be used to anticipate a window of opportunity during which mass vaccination can significantly reduce the cost of an epidemic. PMID- 23943364 TI - The influence of immunity loss on persistence and recurrence of endemic infections. AB - Conditions for persistence of endemic infections with immunity loss are derived and shown to agree with conditions for recurrence recently established by Chaffee and Kuske (Bull. Math. Biol. 73(11):2552-2574, 2011). PMID- 23943365 TI - Trophic structure, stability, and parasite persistence threshold in food webs. AB - Food web structure of free-living species is an important determinant of parasite species richness. Downwardly asymmetric predator-prey interactions (where there are more prey than predator species) have been shown, both theoretically and empirically, to harbour more trophically transmitted parasite species than expected due to chance. Here, we demonstrate that this could be due to the increase in the basic reproductive ratio that the addition of non-host prey species to a system creates. However, we note that the basic reproductive ratio is only increased by those prey that stabilise oscillations in a predator-prey system, and is decreased by those that do not. PMID- 23943366 TI - Neural interconnections between portio minor and portio major at the porus trigeminus: application to failed surgical treatment of trigeminal neuralgia. AB - Recalcitrant trigeminal neuralgia following surgical treatment can be a life altering condition. To explore alternative anatomic reasons for such a complication, the authors examined the potential for nerve connections between the sensory and motor roots of the trigeminal nerve at the opening of Meckel's cave (porus trigeminus). In 15 embalmed adult cadavers (30 sides), the authors performed microdissection of the skull base and specifically at the opening of Meckel's cave. Two sides (6.67%) were found to have interneural connections between the sensory and motor roots at Meckel's cave. These occurred in one male and one female cadaver, both on right sides. Both connections were histologically verified to be neural and were 0.5 mm in diameter and 2.2 and 3.2 mm in length, respectively. Both connections traveled in an oblique fashion from the portio major to the portio minor. On the basis of authors' findings, the sensory and motor components of the trigeminal nerve at the opening of Meckel's cave may be interconnected with a neural anastomosis. Such findings may be of use during the surgical treatment of trigeminal neuralgia or other surgery of the posterior fossa so that inadvertent transection or traction does not occur. PMID- 23943368 TI - Assessment of natural radioactivity levels and associated dose rates in soil samples from Northern Rajasthan, India. AB - The analysis of naturally occurring radionuclides ((226)Ra, (232)Th and (40)K) has been carried out in 40 soil samples collected from four districts of the Northern Rajasthan, India using gamma-ray spectrometry with an NaI(Tl) detector. The activity concentrations of the samples range from 38+/-9 to 65+/-11 Bq kg(-1) with a mean value of 52 Bq kg(-1) for (226)Ra, from 8+/-8 to 32+/-9 Bq kg(-1) with a mean value of 19 Bq kg(-1) for (232)Th and from 929+/-185 to 1894+/-249 Bq kg(-1) with a mean value of 1627 Bq kg(-1) for (40)K. The measured activity concentration of (226)Ra and (40)K in soil was higher and for (232)Th was lower than the worldwide range. Radium equivalent activities were calculated for the soil samples to assess the radiation hazards arising due to the use of these soils in the construction of buildings. The calculated average radium equivalent activity was 205+/-20 Bq kg(-1), which is less than the recommended limit of 370 Bq kg(-1) by the Organization for Economic Cooperation and Development. The total absorbed dose rate calculated from the activity concentration of (226)Ra, (232)Th and (40)K ranges from 77 to 123 nGy h(-1) with an average value of 103 nGy h(-1). The mean external (Hex) and internal hazard indices (Hin) for the area under study were determined to be 0.55 and 0.69, respectively. The corresponding average annual effective dose was found to be 0.63 mSv. PMID- 23943367 TI - Cholinergic dysfunction in Parkinson's disease. AB - There is increasing interest in the clinical effects of cholinergic basal forebrain and tegmental pedunculopontine complex (PPN) projection degeneration in Parkinson's disease (PD). Recent evidence supports an expanded role beyond cognitive impairment, including effects on olfaction, mood, REM sleep behavior disorder, and motor functions. Cholinergic denervation is variable in PD without dementia and may contribute to clinical symptom heterogeneity. Early in vivo imaging evidence that impaired cholinergic integrity of the PPN associates with frequent falling in PD is now confirmed by human post-mortem evidence. Brainstem cholinergic lesioning studies in primates confirm the role of the PPN in mobility impairment. Degeneration of basal forebrain cholinergic projections correlates with decreased walking speed. Cumulatively, these findings provide evidence for a new paradigm to explain dopamine-resistant features of mobility impairments in PD. Recognition of the increased clinical role of cholinergic system degeneration may motivate new research to expand indications for cholinergic therapy in PD. PMID- 23943369 TI - Comprehensive assessment of the association between tumor necrosis factor alpha G238A polymorphism and liver cancer risk. AB - Tumor necrosis factor alpha (TNF-alpha) has been suggested to play an important role in the development and liver cancer. TNF-alpha 238 G/A polymorphism was hypothesized to increase the risk of liver cancer, but findings from previous studies were controversial. To explore a more precise estimation of the relationship between TNF-alpha 238 G/A polymorphism and liver cancer, we performed a meta-analysis. PubMed, Embase, and China Biology Medicine databases were searched for all publications on this association through March 12, 2013. Odds ratios (ORs) with its 95% confidence intervals (CIs) were used to assess the strength of this association. Eleven studies with 1,406 liver cancer cases and 2,386 noncancer controls were included into this meta-analysis. Overall, there was a significant association between TNF-alpha 238 G/A polymorphism and increased risk of liver cancer under all three genetic models (A vs. G, OR 1.51, 95% CI 1.20-1.89, P < 0.001, I(2) = 37.7%; AG vs. GG, OR 1.49, 95% CI 1.01-2.21, P = 0.045, I(2) = 53.2%; AA/AG vs. GG, OR 1.76, 95% CI 1.35-2.30, P < 0.001, I(2) = 36.5%). The sensitivity analysis further strengthened the validity of the positive association. Subgroup analysis of nine studies from Asian countries showed that there was a significant association between TNF-alpha 238 G/A polymorphism and increased risk of liver cancer in Asians (A vs. G, OR 1.35, 95% CI 1.03-1.76, P = 0.027, I(2) = 40.2%; AA/AG vs. GG, OR 1.56, 95% CI 1.14-2.15, P = 0.006, I(2) = 41.9%). In conclusion, TNF-alpha 238 G/A polymorphism is significantly associated with increased risk of liver cancer, especially in Asians. PMID- 23943370 TI - The role of beclin-1 expression in patients with gastric cancer: a meta-analysis. AB - Beclin-1 has been identified as a reliable biomarker in monitoring the prognosis for tumors. We carried out a meta-analysis focusing on the relationship between beclin-1 and the clinical characteristics of patients with gastric cancer. We identified articles in MEDLINE, PubMed, Embase, ISI Web of Science, and Chinese National Knowledge Infrastructure databases by using the following strategy: ("beclin 1" or "beclin-1" or "ATG6") and ("gastric cancer" or "stomach cancer"). We conducted a final analysis of 1,254 patients from seven studies. The pooled odds ratio (OR) indicated a significant association between beclin-1 expression and the differentiation of gastric cancer (pooled OR = 0.23; 95 % confidence interval (CI) = 0.07-0.73) or tumor-node-metastasis staging of gastric cancer (pooled OR = 0.62; 95 % CI = 0.48-0.79). Beclin-1 expression was different in intestinal- and diffuse-type gastric cancer (pooled OR = 0.55; 95 % CI = 0.39 0.77). No association between beclin-1 and tumor size (pooled OR = 0.73; 95 % CI = 0.45-1.17) or lymph node metastasis (pooled OR = 0.59; 95 % CI = 0.17-1.99) was observed. PMID- 23943371 TI - X-ray repair cross-complementing group 1 codon 399 polymorphism and lung cancer risk: an updated meta-analysis. AB - Many epidemiologic studies have investigated the association between x-ray repair cross-complementing group 1 gene (XRCC1) codon 399 polymorphism and lung cancer risk, but the results were inconsistent. We performed a meta-analysis of 46 studies on XRCC1 codon 399 polymorphism and lung cancer risk published before June 2013. In general population, the M allele and MM genotype were associated with increased risk of lung cancer compared with C allele and CC genotype, and the ORs were 1.06 (95% CI 1.01-1.12) and 1.19 (95% CI 1.05-1.34), respectively. When it was stratified according to Asian population, the association between XRCC1 codon 399 polymorphism and lung cancer risk was further strengthened. The ORs of comparison between M vs. C, MM vs. CC, and MM vs. CM + CC were 1.14 (95% CI 1.03-1.26), 1.41 (95% CI 1.11-1.78), and 1.38 (95% CI 1.12-1.71), respectively. The association between codon 399 polymorphism and lung cancer risk in nonsmoking Chinese women was stronger than any other subgroups. However, no associations were found in the Caucasian and African population. This meta analysis has demonstrated that codon 399 polymorphism of XRCC1 gene might contribute to individual's susceptibility to lung cancer in Asian population, and especially in nonsmoking Chinese women. Future studies focused on interactions between combined genes and environmental risk factors are warranted. PMID- 23943373 TI - Antimuscarinic use among individuals with urinary incontinence who reside in long term care facilities. AB - PURPOSE: To assess appropriateness of antimuscarinic use in long-term care facilities (LTCFs) among treated and untreated urinary incontinence (UI) residents from 2007 to 2009. METHODS: We conducted a retrospective analysis using the AnalytiCare(SM) database consisting of minimum data sets (MDS) assessments and prescription records of 90,660 residents from 2007 to 2009. UI (MDS H1b >= 1) residents with >= 14-day LTCF stay were identified and categorized as treated if they had >= 1 antimuscarinic prescription and untreated if they had no antimuscarinics. A random sample of untreated residents was matched based on treated residents' type of MDS assessment. We defined appropriate antimuscarinic use if residents had adequate cognitive function [<= 4 on the cognitive performance scale (0 = intact to 6 = very severe impairment)] and mobility [scoring <4 on mobility for toileting scale (MDS item G1iA 0 = independent to 4 = total dependent)]. Chi-square tests were used to detect statistical difference between cohorts. RESULTS: A total of 5,327 residents (2,840 treated; 2,487 untreated) were selected [mean age (standard deviation) 80 (8), 81 (8) years; female (76, 65 %), respectively]. On study-defined MDS assessment, 63 % of treated and 69 % of untreated residents had UI (P < 0.01). Approximately 84 % of treated and 74 % of untreated residents may have had cognitive function and mobility sufficient for appropriate antimuscarinic use (P < 0.01). CONCLUSIONS: Our study identified a high percentage of LTCF residents with UI who may have been candidates for antimuscarinics. However, due to the MDS limitation, we were unable to identify overactive bladder patients among these untreated residents with UI. It is possible that untreated control residents had UI due to other factors not amenable to treatment with antimuscarinic agents. Therefore, choice of treatment for each resident needs to be individualized and carefully monitored for efficacy and adverse effects. This retrospective analysis requires prospective confirmation. Proper patient selection for antimuscarinic treatment requires careful assessment of underlying physical status including cognitive function, mobility, and comorbidities. PMID- 23943374 TI - Key pathways and genes controlling the development and progression of clear cell renal cell carcinoma (ccRCC) based on gene set enrichment analysis. AB - BACKGROUND: Clear-cell renal cell carcinoma (ccRCC) is one of the most common types of kidney cancer in adults; however, its causes are not completely understood. The study was designed to filter the key pathways and genes associated with the occurrence or development of ccRCC, acquaint its pathogenesis at gene and pathway level, to provide more theory evidence and targeted therapy for ccRCC. METHODS: Gene set enrichment analysis (GSEA) and meta-analysis (Meta) were used to screen the critical pathways and genes which may affect the occurrence and progression of ccRCC on the transcription level. Corresponding pathways of significant genes were obtained with the online website DAVID ( http://david.abcc.ncifcrf.gov/ ). RESULTS: Thirty seven consistent pathways and key genes in these pathways related to ccRCC were obtained with combined GSEA and meta-analysis. These pathways were mainly involved in metabolism, organismal systems, cellular processes and environmental information processing. CONCLUSION: The gene pathways that we identified could provide insight concerning the development of ccRCC. Further studies are needed to determine the biological function for the positive genes. PMID- 23943375 TI - Geraniol ameliorates the motor behavior and neurotrophic factors inadequacy in MPTP-induced mice model of Parkinson's disease. AB - Many experiments affirm the notion that augmentation of neurotrophic factors (NTFs) activity, especially brain-derived neurotrophic factors and glial cell derived neurotrophic factors, could prevent or halt the progress of neurodegeneration in Parkinson's disease (PD). In this study, we investigated the therapeutic accomplishment of geraniol (GE 100 mg/kg) on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mice model of PD. Current investigation proved that pretreatment with GE ameliorates the MPTP-induced alterations in behavioral, biochemical, immunohistochemical, and immunoblotting manifestations in mice. Systematically, the loss of dopaminergic neurons and reduced NTFs mRNA expressions induced by MPTP was ameliorated to a significant extent by pretreatment with GE. We found that GE confers a potent neuroprotective agent against MPTP-induced dopaminergic denervation and may become a potential therapeutic agent for PD and/or its progression. PMID- 23943376 TI - Coralline algal structure is more sensitive to rate, rather than the magnitude, of ocean acidification. AB - Marine pCO2 enrichment via ocean acidification (OA), upwelling and release from carbon capture and storage (CCS) facilities is projected to have devastating impacts on marine biomineralisers and the services they provide. However, empirical studies using stable endpoint pCO2 concentrations find species exhibit variable biological and geochemical responses rather than the expected negative patterns. In addition, the carbonate chemistry of many marine systems is now being observed to be more variable than previously thought. To underpin more robust projections of future OA impacts on marine biomineralisers and their role in ecosystem service provision, we investigate coralline algal responses to realistically variable scenarios of marine pCO2 enrichment. Coralline algae are important in ecosystem function; providing habitats and nursery areas, hosting high biodiversity, stabilizing reef structures and contributing to the carbon cycle. Red coralline marine algae were exposed for 80 days to one of three pH treatments: (i) current pH (control); (ii) low pH (7.7) representing OA change; and (iii) an abrupt drop to low pH (7.7) representing the higher rates of pH change observed at natural vent systems, in areas of upwelling and during CCS releases. We demonstrate that red coralline algae respond differently to the rate and the magnitude of pH change induced by pCO2 enrichment. At low pH, coralline algae survived by increasing their calcification rates. However, when the change to low pH occurred at a fast rate we detected, using Raman spectroscopy, weaknesses in the calcite skeleton, with evidence of dissolution and molecular positional disorder. This suggests that, while coralline algae will continue to calcify, they may be structurally weakened, putting at risk the ecosystem services they provide. Notwithstanding evolutionary adaptation, the ability of coralline algae to cope with OA may thus be determined primarily by the rate, rather than magnitude, at which pCO2 enrichment occurs. PMID- 23943378 TI - Vertically oriented graphene bridging active-layer/current-collector interface for ultrahigh rate supercapacitors. AB - Dense networks of graphene nanosheets standing vertically on a current collector can work as numerous electrically conductive bridges to facilitate charge transport and mitigate the constriction/spreading resistance at the interface between the active material and the current collector. The vertically oriented graphene-bridged supercapacitors present excellent rate and power capabilities. PMID- 23943377 TI - Exosomes carrying mycobacterial antigens can protect mice against Mycobacterium tuberculosis infection. AB - Approximately 2 billion people are infected with Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), and an estimated 1.5 million individuals die annually from TB. Presently, Mycobacterium bovis BCG remains the only licensed TB vaccine; however, previous studies suggest its protective efficacy wanes over time and fails in preventing pulmonary TB. Therefore, a safe and effective vaccine is urgently required to replace BCG or boost BCG immunizations. Our previous studies revealed that mycobacterial proteins are released via exosomes from macrophages infected with M. tuberculosis or pulsed with M. tuberculosis culture filtrate proteins (CFP). In the present study, exosomes purified from macrophages treated with M. tuberculosis CFP were found to induce antigen-specific IFN-gamma and IL-2-expressing CD4(+) and CD8(+) T cells. In exosome-vaccinated mice, there was a similar TH1 immune response but a more limited TH2 response compared to BCG-vaccinated mice. Using a low-dose M. tuberculosis mouse aerosol infection model, exosomes from CFP-treated macrophages were found to both prime a protective immune response as well as boost prior BCG immunization. The protection was equal to or superior to BCG. In conclusion, our findings suggest that exosomes might serve as a novel cell-free vaccine against an M. tuberculosis infection. PMID- 23943379 TI - Individual and relational risk factors for the development of eating disorders in adolescent aesthetic athletes and general adolescents. AB - This study compared potential risk and protective factors, levels of disordered eating (DE), and their relationship among young aesthetic athletes (elite and non elite) and controls (N = 725; 62.5 % females; mean age = 15.3, SD = 2.1). The participants completed self-report measures (McKnight Risk Factor Survey-IV, Contour Drawing Rating Scale and Eating Disorder Examination-Questionnaire). Female elite athletes showed a greater risk of developing eating disorders than non-elite athletes and controls, with no difference between the three groups of males. Multiple group analyses revealed important differences in DE predictors. Although social pressure is the strongest DE predictor in non-elite athletes and controls, in elite athletes, the strongest DE predictor is body image dissatisfaction. Parental influences, rather than self-esteem, are predictors of DE in elite athletes, unlike the other two groups. These results show that the risk and protective factors involved in the development of DE are not universally valid. The results highlight the importance of studying specific characteristics associated with DE in aesthetic athletes. Some implications for ED risk assessment and prevention are discussed. PMID- 23943381 TI - Smarter neuronal signaling complexes from existing components: how regulatory modifications were acquired during animal evolution: evolution of palmitoylation dependent regulation of AMPA-type ionotropic glutamate receptors. AB - Neurons of organisms with complex and flexible behavior, especially humans, must precisely control protein localization and activity to support higher brain functions such as learning and memory. In contrast, simpler organisms generally have simpler individual neurons, less complex nervous systems and display more limited behaviors. Strikingly, however, many key neuronal proteins are conserved between organisms that have very different degrees of behavioral complexity. Here we discuss a possible mechanism by which conserved neuronal proteins acquired new attributes that were crucial in the evolution of complexity of nervous system structure and function. Specifically, we hypothesize that vertebrate-specific post-translational palmitoylation sites and PDZ-binding protein-protein interaction motifs act as gain-of-function mutations, increasing the regulatory potential of conserved proteins without affecting their core functions. We further hypothesize that the additional regulation of neurotransmitter receptors and other membrane proteins made possible by these sites and motifs is critical for the function of complex nervous systems. PMID- 23943380 TI - Inhibiting UHRF1 expression enhances radiosensitivity in human esophageal squamous cell carcinoma. AB - Radiotherapy is an effective treatment for some esophageal cancers, but the molecular mechanisms of radiosensitivity remain unknown. Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) is a novel nuclear protein which is overexpressed in various cancers but not yet examined in esophageal squamous cell carcinoma (ESCC). The correlation between UHRF1 and the radioresistance in ESCC is still unclear. In the present study, the expression of UHRF1 was examined by immunohistochemistry in specimens of ESCC patients treated with radiotherapy. The results showed that UHRF1 was significantly overexpressed in ESCC specimens. Overexpression of UHRF1 correlated significantly with advanced T-stage, positive lymph node metastasis and poor differentiation. In addition, UHRF1 was associated with radiotherapy response, in which overexpression of UHRF1 was observed more frequently in the radioresistant group than in the effective group. At the molecular level, inhibition of UHRF1 by lentivirus-mediated shRNA targeting UHRF1 increased the radiosensitivity and apoptosis, while decreased radiation-induced G2/M phase arrest in TE-1 cells. Moreover, inhibition of UHRF1 resulted in higher residual gammaH2AX expression after irradiation, but not initial gammaH2AX. Further study showed that inhibition of UHRF1 down-regulated the endogenous expressions of DNA repair protein Ku70 and Ku80 in TE-1 cells, and significantly inhibited the increase of these proteins after irradiation. Above all, our data suggested that UHRF1 might play an important role in radioresistance of ESCC, and inhibition of UHRF1 can increase the radiosensitivity of TE-1 cells by altering cell cycle progression, enhancing apoptosis, and decreasing DNA damage repair capacity. PMID- 23943382 TI - Incorporation of physiologically based pharmacokinetic modeling in the evaluation of solubility requirements for the salt selection process: a case study using phenytoin. AB - In the pharmaceutical industry, salt is commonly used to improve the oral bioavailability of poorly soluble compounds. Currently, there is a limited understanding on the solubility requirement for salts that will translate to improvement in oral exposure. Despite the obvious need, there is very little research reported in this area mainly due to the complexity of such a system. To our knowledge, no report has been published to guide this important process and salt solubility requirement still remains unanswered. Physiologically based pharmacokinetic (PBPK) modeling offers a means to dynamically integrate the complex interplay of the processes determining oral absorption. A sensitivity analysis was performed using a PBPK model describing phenytoin to determine a solubility requirement for phenytoin salts needed to achieve optimal oral bioavailability for a given dose. Based on the analysis, it is predicted that phenytoin salts with solubility greater than 0.3 mg/mL would show no further increases in oral bioavailability. A salt screen was performed using a variety of phenytoin salts. The piperazine and sodium salts showed the lowest and highest aqueous solubility and were tested in vivo. Consistent with our analysis, we observed no significant differences in oral bioavailability for these two salts despite an approximate 60 fold difference in solubility. Our study illustrates that higher solubility salts sometimes provide no additional improvements in oral bioavailability and PBPK modeling can be utilized as an important tool to provide guidance to the salt selection and define a salt solubility requirement. PMID- 23943383 TI - Overview of food products and dietary constituents with antidiabetic properties and their putative mechanisms of action: a natural approach to complement pharmacotherapy in the management of diabetes. AB - Diabetes is one of the fastest growing chronic, noncommunicable diseases worldwide. Currently, 11 major classes of pharmacotherapy are available for the management of this metabolic disorder. However, the usage of these drugs is often associated with undesirable side effects, including weight gain and hypoglycemia. There is thus a need for new, safe and effective treatment strategies. Diet is known to play a major role in the prevention and management of diabetes. Numerous studies have reported the putative association of the consumption of specific food products, or their constituents, with the incidence of diabetes, and mounting evidence now suggests that some dietary factors can improve glycemic regulation. Foods and dietary constituents, similar to synthetic drugs, have been shown to modulate hormones, enzymes, and organ systems involved in carbohydrate metabolism. The present article reviews the major classes and modes of action of antidiabetic drugs, and examines the evidence on food products and dietary factors with antidiabetic properties as well as their plausible mechanisms of action. The findings suggest potential use of dietary constituents as a complementary approach to pharmacotherapy in the prevention and/or management of diabetes, but further research is necessary to identify the active components and evaluate their efficacy and safety. PMID- 23943384 TI - Therapeutic options for adult T-cell leukemia/lymphoma. AB - Adult T-cell leukemia/lymphoma (ATL) is the first human malignancy associated with a retroviral infection and occurs in approximately 5 % of the 15 million to 20 million people infected by human T-cell lymphotropic virus 1. In general, ATL is resistant to chemotherapy, and while awaiting new therapeutics, patients commonly face a detrimental progress of the disease and death. The viral oncoprotein Tax is a key player in the cause of ATL and acts by interfering with DNA repair, cell cycle, apoptosis, and proliferative cellular programs. The Shimoyama classification describes four different subtypes (acute, lymphoma, chronic, and smoldering) associated with different outcomes, and that require different treatment strategies tailored to the clinical presentation. In aggressive ATL (acute and lymphoma subtypes), clinical trials, mostly from Japan, have demonstrated that combinations of chemotherapy can induce acceptable response rates, especially in the lymphoma subtype. However, the overall outcome remains extremely poor owing to a high rate of relapse. Similarly, the so-called indolent forms (smoldering and chronic subtypes) have a poor outcome whether they are managed with watching and waiting or treated with chemotherapy. We recently realized a worldwide meta-analysis and showed that the combination of zidovudine and interferon alpha is highly effective in the leukemic subtypes of ATL and should be considered as standard first-line therapy in that setting. This combination has changed the natural history of the disease through achievement of significantly improved long-term survival in patients with smoldering and chronic ATL as well as a subset of patients with acute ATL. Patients with lymphoma-type ATL still benefit from chemotherapy induction with concurrent or sequential antiretroviral therapy with zidovudine and interferon alpha. Allogeneic stem cell transplantation is a promising option but has several barriers. New drugs such as the new antibody anti-CXCR4 show promising results. Prospective trials testing maintenance therapy in order to avoid relapse are warranted when the patient cannot undergo allogeneic stem cell transplantation. PMID- 23943385 TI - Surgical management of gastroparesis: gastrostomy/jejunostomy tubes, gastrectomy, pyloroplasty, gastric electrical stimulation. PMID- 23943386 TI - Changes in gastrosplenic circulation and splenic function after distal pancreatectomy with spleen preservation and splenic vessel excision. AB - INTRODUCTION: Distal pancreatectomy with spleen preservation and splenic vessel excision is a commonly used technique. However, it produces significant gastrosplenic circulation and splenic function changes. PURPOSE: The aim of this work was to determine the immediate consequences on gastrosplenic circulation, late consequences on splenic function, and development of varicose veins. METHODS: Thirty-five patients with pancreatic tumors and anatomical feasibility were included. Preoperative splenic circulation was evaluated by dynamic contrast enhanced computed tomography (CT) scans. Early splenic perfusion was assessed by CT 7 days after surgery and late changes in gastrosplenic circulation 6 months after surgery. Varicose veins were evaluated by CT and endoscopy 6 months after surgery. Pitted cells and Howell-Jolly bodies were used as markers of splenic function. Postoperatory findings included changes in splenic perfusion 7 days and 6 months after surgery, development of varicose veins on CT scans and endoscopy, and detection of markers of splenic hypofunction on blood smears. RESULTS AND CONCLUSION: Seven days after surgery, 63% of patients had some degree of splenic hypoperfusion, and 6 months after surgery, 83% of patients had normal perfusion. CT scans showed varices in 26 patients, and endoscopy revealed varicose veins in 11. Two patients experienced bleeding; markers of splenic hypofunction were found in 59% of cases. PMID- 23943387 TI - Trends and patterns of utilization in post-treatment surveillance imaging among patients treated for hepatocellular carcinoma. AB - BACKGROUND: Little is known about the patterns of utilization of surveillance imaging after treatment of hepatocellular carcinoma (HCC). We sought to define population-based patterns of surveillance and investigate if intensity of surveillance impacted outcome following HCC treatment. METHODS: The Surveillance, Epidemiology, and End Results-Medicare database was used to identify patients with HCC diagnosed between 1998 and 2007 who underwent resection, ablation, or intra-arterial therapy (IAT). The association between imaging frequency and long term survival was analyzed. RESULTS: Of the 1,467 patients, most underwent ablation only (41.5%), while fewer underwent liver resection only (29.6 %) or IAT only (18.3%). Most patients had at least one CT scan (92.7%) during follow-up, while fewer had an MRI (34.1%). A temporal trend was noted with more frequent surveillance imaging obtained in post-treatment year 1 (2.5 scans/year) vs. year 5 (0.9 scans/year; P = 0.01); 34.5% of alive patients had no imaging after 2 years. Frequency of surveillance imaging correlated with procedure type (total number of scans/5 years, resection, 4.7; ablation, 4.9; IAT, 3.7; P < 0.001). Frequency of surveillance imaging was not associated with a survival benefit (three to four scans/year, 49.5 months vs. two scans/year, 71.7 months vs. one scan/year, 67.6 months; P = 0.01) CONCLUSION: Marked heterogeneity exists in how often surveillance imaging is obtained following treatment of HCC. Higher intensity imaging does not confer a survival benefit. PMID- 23943388 TI - Complete versus partial fundoplication in children with gastroesophageal reflux disease: results of a systematic review and meta-analysis. AB - Complete fundoplication (Nissen) has long been accepted as the gold standard surgical procedure in children with therapy-resistant gastroesophageal reflux disease (GERD); however, increasingly more evidence has become available for partial fundoplication as an alternative. The aim of this study was to perform a systematic review and meta-analysis comparing complete versus partial fundoplication in children with therapy-resistant GERD. PubMed (1960 to 2011), EMBASE (from 1980 to 2011), and the Cochrane Library (issue 3, 2011) were systematically searched according to the PRISMA statement. Results were pooled in meta-analyses and expressed as risk ratios (RRs). In total, eight original trials comparing complete to partial fundoplication were identified. Seven of these studies had a retrospective study design. Short-term (RR 0.64; p = 0.28) and long term (RR 0.85; p = 0.42) postoperative reflux control was similar for complete and partial fundoplication. Complete fundoplication required significantly more endoscopic dilatations for severe dysphagia (RR 7.26; p = 0.007) than partial fundoplication. This systematic review and meta-analysis showed that reflux control is similar after both complete and partial fundoplication, while partial fundoplication significantly reduces the number of dilatations to treat severe dysphagia. However, because of the lack of a well-designed study, we have to be cautious in making definitive conclusions. To decide which type of fundoplication is the best practice in pediatric GERD patients, more randomized controlled trials comparing complete to partial fundoplication in children with GERD are warranted. PMID- 23943389 TI - Augmented reality-guided artery-first pancreatico-duodenectomy. AB - BACKGROUND: Augmented Reality (AR) in surgery consists in the fusion of synthetic computer-generated images (3D virtual model) obtained from medical imaging preoperative work-up and real-time patient images with the aim to visualize unapparent anatomical details. The potential of AR navigation as a tool to improve safety of the surgical dissection is presented in a case of pancreatico duodenectomy (PD). METHODS: A 77-year-old male patient underwent an AR-assisted PD. The 3D virtual anatomical model was obtained from thoraco-abdominal CT scan using customary software (VR-RENDER(r), IRCAD). The virtual model was superimposed to the operative field using an Exoscope (VITOM(r), Karl Storz, Tuttlingen, Germany) as well as different visible landmarks (inferior vena cava, left renal vein, aorta, superior mesenteric vein, inferior margin of the pancreas). A computer scientist manually registered virtual and real images using a video mixer (MX 70; Panasonic, Secaucus, NJ) in real time. Dissection of the superior mesenteric artery and the hanging maneuver were performed under AR guidance along the hanging plane. RESULTS: AR allowed for precise and safe recognition of all the important vascular structures. Operative time was 360 min. AR display and fine registration was performed within 6 min. The postoperative course was uneventful. The pathology was positive for ampullary adenocarcinoma; the final stage was pT1N0 (0/43 retrieved lymph nodes) with clear surgical margins. CONCLUSIONS: AR is a valuable navigation tool that can enhance the ability to achieve a safe surgical resection during PD. PMID- 23943390 TI - Quantitative MRI and ultrastructural examination of the cuprizone mouse model of demyelination. AB - The cuprizone mouse model of demyelination was used to investigate the influence that white matter changes have on different magnetic resonance imaging results. In vivo T2 -weighted and magnetization transfer images (MTIs) were acquired weekly in control (n = 5) and cuprizone-fed (n = 5) mice, with significant increases in signal intensity in T2 -weighted images (p < 0.001) and lower magnetization transfer ratio (p < 0.001) in the corpus callosum of the cuprizone fed mice starting at 3 weeks and peaking at 4 and 5 weeks, respectively. Diffusion tensor imaging (DTI), quantitative MTI (qMTI), and T1/T2 measurements were used to analyze freshly excised tissue after 6 weeks of cuprizone administration. In multicomponent T2 analysis with 10 ms echo spacing, there was no visible myelin water component associated with the short T2 value. Quantitative MTI metrics showed significant differences in the corpus callosum and external capsule of the cuprizone-fed mice, similar to previous studies of multiple sclerosis in humans and animal models of demyelination. Fractional anisotropy was significantly lower and mean, axial, and radial diffusivity were significantly higher in the cuprizone-fed mice. Cellular distributions measured in electron micrographs of the corpus callosum correlated strongly to several different quantitative MRI metrics. The largest Spearman correlation coefficient varied depending on cellular type: T1 versus the myelinated axon fraction (rho = 0.90), the bound pool fraction (f) versus the myelin sheath fraction (rho = 0.93), and axial diffusivity versus the non-myelinated cell fraction (rho = 0.92). Using Pearson's correlation coefficient, f was strongly correlated to the myelin sheath fraction (r = 0.98) with a linear equation predicting myelin content (5.37f - 0.25). Of the calculated MRI metrics, f was the strongest indicator of myelin content, while longitudinal relaxation rates and diffusivity measurements were the strongest indicators of changes in tissue structure. PMID- 23943391 TI - Isolates of beta-lactamase-negative ampicillin-resistant Haemophilus influenzae causing invasive infections in Spain remain susceptible to cefotaxime and imipenem. AB - OBJECTIVES: The epidemiology of invasive Haemophilus influenzae has changed in recent years. beta-Lactamase-negative ampicillin-resistant (BLNAR) invasive isolates have recently been described in Europe but their clinical significance is unclear. Our main goal was to determine whether invasive H. influenzae remains susceptible to beta-lactam antibiotics indicated in the treatment of invasive infections. METHODS: The antibiotic susceptibility of 307 invasive H. influenzae isolates to seven beta-lactam antibiotics was determined by microdilution and interpreted by EUCAST and CLSI breakpoints. We also identified the bla genes, the amino acid substitutions in the transpeptidase domain of penicillin-binding protein 3 (PBP3), the molecular epidemiology of invasive BLNAR isolates by PFGE and MLST, and the time-kill curves of two isolates with PBP3 mutations conferring reduced susceptibility to aminopenicillins and cephalosporins. RESULTS: Of the invasive isolates, 86.6% were non-typeable and 62% were isolated from adults. Decreased susceptibility to beta-lactams was due to the BLNAR genotype (gBLNAR; 19.2%) and to beta-lactamase production (16.9%). Susceptibility rates to amoxicillin/clavulanic acid, cefotaxime, cefixime and imipenem were greater than 98%. Of 18 gBLNAR non-typeable isolates studied by MLST, 15 different STs were obtained. Amoxicillin and cefotaxime were bactericidal after 2 and 4 h of incubation, respectively. CONCLUSIONS: Invasive H. influenzae disease was mainly due to non-typeable isolates infecting adults, and the most common mechanism of beta-lactam resistance was mutations in the transpeptidase domain of PBP3. The gBLNAR non-typeable isolates were genetically diverse. The majority of invasive H. influenzae remained susceptible to third-generation cephalosporins; amoxicillin and cefotaxime were bactericidal in two gBLNAR isolates. PMID- 23943392 TI - Association between myeloperoxidase G-463A polymorphism and lung cancer risk. AB - Many epidemiologic studies have investigated the association between myeloperoxidase (MPO) G-463A polymorphism and lung cancer risk, but the results were controversial. We performed a meta-analysis of 25 studies on MPO polymorphism and lung cancer risk published before July 2013. The allele of A was found to be associated with decreased risk of lung cancer compared with G allele (OR, 0.90; 95% CI, 0.82-0.98) in the general population. The significant association remained in the comparison between AA + AG and GG (OR, 0.92; 95% CI, 0.87-0.98). When it was stratified according to Asian population, the association between MPO polymorphism and lung cancer risk was further strengthened. However, no associations were found in the Caucasian population. This meta-analysis has demonstrated that MPO polymorphism might contribute to individual's susceptibility to lung cancer in Asian population. Caucasian authors could re investigate the association between MPO polymorphism and lung cancer risk with more specific participants. Future studies focusing on interactions between combined genes and environmental risk factors are warranted. PMID- 23943394 TI - Association between MPO 463G>A polymorphism and risk of lung cancer: a meta analysis. AB - There is a possible association between myeloperoxidase (MPO) 463G>A polymorphism and risk of lung cancer, but previous studies report conflicting results. We performed a meta-analysis of available molecular epidemiologic studies to comprehensively assess the association between MPO 463G>A polymorphism and risk of lung cancer. A systemic literature search was performed in Pubmed, Embase, and Wanfang databases for molecular epidemiologic studies on the association MPO 463G>A polymorphism and risk of lung cancer on March 16, 2013. The pooled odds ratios (ORs) with their 95% confidence interval (95% CI) were calculated to assess the strength of the association. Twenty-six individual case-control studies with a total of 18,433 subjects (7,752 cases and 10,681 controls) were finally included into the meta-analysis. Overall, MPO 463G>A polymorphism was significantly associated with decreased risk of lung cancer under two main genetic comparison models (for A versus G, OR = 0.91, 95 % CI 0.83-0.99, P = 0.035; for AG/AA versus GG, OR = 0.90, 95% CI 0.81-0.99, P = 0.029). Meta analysis of studies with high quality also showed that MPO 463G>A polymorphism was significantly associated with decreased risk of lung cancer under two main genetic comparison models (for A versus G, OR = 0.91, 95% CI 0.83-0.99, P = 0.035; for AG/AA versus GG, OR = 0.90, 95% CI 0.80-0.99, P = 0.048). Subgroup analysis by ethnicity further showed that there was a significant association between MPO 463G>A polymorphism and decreased risk of lung cancer in Caucasians but not in Asians. The meta-analysis suggests that MPO 463G>A polymorphism is associated with decreased risk of lung cancer, especially in Caucasians. PMID- 23943393 TI - The circadian clock and the hypoxic response pathway in kidney cancer. AB - The most frequent malignant tumor of the kidney in adults is represented by renal cell carcinoma characterized by high lethality related to presence of metastatic disease at the time of diagnosis. The main characteristic molecular feature of most sporadic renal cell carcinomas is the mutation of the tumor suppressor gene encoding the von Hippel-Lindau protein, with alteration of regulated pathways and activation of hypoxia-inducible transcription factors. Hypoxia-inducible transcription factors are transcriptional regulators of genes controlling mammalian oxygen homeostasis, energy metabolism, neovascularisation, internal pH, cell survival, and migration and are considered powerful promoters of tumor growth. Tight interrelationships have been evidenced between hypoxic response pathway and circadian pathway. Severe deregulation of genes involved in the circadian clock circuitry and response to hypoxia has been found in patients affected by kidney cancer, influencing the process of carcinogenesis, as well as disease progression and outcome. The study of alterations of clock gene expression and hypoxia correlated pathway in kidney cancer may promote the comprehension of pathophysiological mechanisms involved in renal cell carcinoma onset and evolution and may help to exploit more effective therapeutic approaches. PMID- 23943395 TI - Concurrent schedules: discriminating reinforcer-ratio reversals at a fixed time after the previous reinforcer. AB - Six pigeons worked on concurrent exponential variable-interval schedules in which the relative frequency of food deliveries for responding on the two alternatives reversed at a fixed time after each food delivery. Across conditions, the point of food-ratio reversal was varied from 10 s to 30 s, and the overall reinforcer rate was varied from 1.33 to 4 per minute. The effect of rate of food delivery and food-ratio-reversal time on choice and response rates was small. In all conditions, postfood choice was toward the locally richer key, regardless of the last-food location. Unlike the local food ratio which changed in a stepwise fashion, local choice changed according to a decelerating monotonic function, becoming substantially less extreme than the local food ratio soon after food delivery. This deviation in choice appeared to result from the birds' inaccurate discrimination of the time of food deliveries; local choice was described well by a model that assumed that log response ratios matched food ratios that were redistributed across surrounding time bins with mean time t and a constant coefficient of variation. We suggest that local choice is controlled by the likely availability of food in time, and that choice matches the discriminated log of the ratio of food rates across time since the last food delivery. PMID- 23943396 TI - The expression pattern and histological distribution of sialyltransferases ST3Gal III in yellow chicken. AB - In chicken, ST3 beta-galactoside alpha-2, 3-sialyltransferase III (ST3GAL III) is one of the key enzymes participating in the biosynthesis of avian influenza virus receptors. Knowledge about ST3Gal III could increase our understanding of its function in the occurrence and development of avian influenza. To date, no detailed data have been published about the expression pattern and histological distribution of ST3Gal III in chicken. This paper presents data on the nucleotide sequence, mRNA expression pattern and histological distribution of ST3Gal III protein in yellow chicken for the first time. The results show that the nucleotide homology of ST3Gal III among yellow chicken and turkey, chicken, cattle, humans, swine, mouse, rat and chimpanzee was 98%, 92%, 75%, 59%, 70%, 76% and 75%. The relative expression level of ST3Gal III in the heart, kidney and brain of yellow chicken was significantly higher than in other tissues examined for mRNA level (P < 0.05). The histological distribution of ST3Gal III in the heart, liver, spleen, lung, thymus and bursa of Fabricius was determined by immunohistochemical staining using rabbit anti-chicken ST3Gal III IgG prepared by us. Interestingly, the epithelial reticular cells in the immune organs proved to be positive, which may suggest that these cells are important immune cells playing a role in influenza virus infection. The results of this study provide basic data for further research on the functions of ST3Gal III in chicken. PMID- 23943398 TI - Seasonality of North Atlantic phytoplankton from space: impact of environmental forcing on a changing phenology (1998-2012). AB - Seasonal pulses of phytoplankton drive seasonal cycles of carbon fixation and particle sedimentation, and might condition recruitment success in many exploited species. Taking advantage of long-term series of remotely sensed chlorophyll a (1998-2012), we analyzed changes in phytoplankton seasonality in the North Atlantic Ocean. Phytoplankton phenology was analyzed based on a probabilistic characterization of bloom incidence. This approach allowed us to detect changes in the prevalence of different seasonal cycles and, at the same time, to estimate bloom timing and magnitude taking into account uncertainty in bloom detection. Deviations between different sensors stressed the importance of a prolonged overlap between successive missions to ensure a correct assessment of phenological changes, as well as the advantage of semi-analytical chlorophyll algorithms over empirical ones to reduce biases. Earlier and more intense blooms were detected in the subpolar Atlantic, while advanced blooms of less magnitude were common in the Subtropical gyre. In the temperate North Atlantic, spring blooms advanced their timing and decreased in magnitude, whereas fall blooms delayed and increased their intensity. At the same time, the prevalence of locations with a single autumn/winter bloom or with a bimodal seasonal cycle increased, in consonance with a poleward expansion of subtropical conditions. Changes in bloom timing and magnitude presented a clear signature of environmental factors, especially wind forcing, although changes on incident photosynthetically active radiation and sea surface temperature were also important depending on latitude. Trends in bloom magnitude matched changes in mean chlorophyll a during the study period, suggesting that seasonal peaks drive long-term trends in chlorophyll a concentration. Our results link changes in North Atlantic climate with recent trends in the phenology of phytoplankton, suggesting an intensification of these impacts in the near future. PMID- 23943397 TI - The protective effect of salvianolic acid B on blood-spinal cord barrier after compression spinal cord injury in rats. AB - Salvianolic acid B (Sal B), a bioactive compound isolated from the Chinese medicinal herb danshen, is commonly used for the prevention and treatment of cardiovascular disease. The present study was performed to investigate the effect of Sal B on the blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) in a rat model. Sal B (1, 10, and 50 mg/kg i.v.) was administered to rats immediately following SCI. The permeability of the BSCB and spinal cord tissue water content were evaluated. Additionally, the expression levels of tight junction proteins and heme oxygenase-1 (HO-1) were monitored by Western blot analysis. Enzyme-linked immunosorbent assay analysis of spinal cord tissue homogenates was performed 24 h post-SCI to evaluate the expression of inflammation-related cytokines. In addition, the motor recovery of SCI rats was assessed using the Basso, Beattie, and Bresnahan scoring system. Compared to the SCI group, rats treated with Sal B (10, 50 mg/kg) exhibited significantly reduced spinal cord tissue water content and BSCB permeability. Further, the motor function of rats was also greatly improved by Sal B administration. The expression of pro-inflammatory factors TNF-alpha and NF-kappaB was found to be greatly increased 24 h post-SCI, and this upregulation was significantly attenuated by Sal B treatment. The expression of ZO-1 and occludin was upregulated by Sal B (10 mg/kg) treatment after SCI, and this effect was blocked by the HO-1 inhibitor ZnPP. Taken together, our results clearly indicate that Sal B attenuates SCI by promoting the repair of the damaged BSCB, demonstrating that this molecule is a novel and promising therapeutic agent for human SCI. PMID- 23943399 TI - Restoration of superhydrophobicity in crushed polymer films by treatment with water: self-healing and recovery of damaged topographic features aided by an unlikely source. AB - The crushing of superhydrophobic polymer multilayers destroys micro/nanoscale topographic features critical for the maintenance of superhydrophobicity. We demonstrate that these surface features can be recovered, and that superhydrophobicity can be fully restored, by treatment of damaged films with liquid water. These polymer-based films can also sustain other forms of severe abuse without loss of superhydrophobicity. This combination of features addresses several important practical issues associated with the durability of artificial superhydrophobic surfaces. PMID- 23943400 TI - Characteristics of individuals who report present and past weight loss behaviours: results from a Canadian university community. AB - PURPOSE: To characterise individuals who reported present and past weight loss behaviours on psycho-behavioural factors known to influence body weight, e.g. overeating, dietary restriction. METHODS: An online questionnaire was distributed to a university community. Questions pertaining to present weight loss, previous weight loss, eating behaviour tendencies, perceived stress and sleep quality were answered by 3,069 individuals. Body weight and height were self-reported. RESULTS: Present and past weight loss behaviours were prevalent in the sample, with 33.3 % of the participants who reported trying to lose weight, 33.1 % who reported having previously lost weight (>10 lbs), and 18.8 % who reported repeated weight loss behaviour (i.e. present and past weight loss behaviours). Trying to lose weight and previous weight loss were both independently associated with increased risk for psycho-behavioural characteristics known to be associated with obesity, e.g. overeating tendencies, perceived stress, short sleep duration. This risk was particularly elevated among the underweight/normal-weight individuals who reported repeated weight loss behaviours. Indeed, adjusted odds ratios for reporting restrictive and overeating tendencies, perceived stress and short sleep for these individuals were significantly higher compared to their underweight/normal-weight peers who did not report repeated weight loss behaviours (adjusted odds ratios 4.7, 2.7, 1.8, and 1.8, respectively, p < 0.01 to <0.0001). CONCLUSIONS: Normal-weight individuals reporting weight loss behaviours are characterised by a psycho-behaviour profile which may further increase their risk of weight gain. PMID- 23943401 TI - In vitro-in vivo correlation of efavirenz tablets using GastroPlus(r). AB - The aim of the present work was to use GastroPlusTM software for the prediction of pharmacokinetic profiles and in vitro-in vivo correlation (IVIVC) as tools to optimize the development of new generic medications. GastroPlusTM was used to simulate the gastrointestinal compartment and was based on the advanced compartmental absorption and transit model. Powder dissolution and efavirenz tablet dissolution studies were carried out to generate data from which correlation was established. The simulated plasma profile, based on the physicochemical properties of efavirenz, was almost identical to that observed in vivo for biobatches A and B. A level A IVIVC was established for the dissolution method obtained for the generic candidate using the Wagner-Nelson (r (2) = 0.85) and for Loo-Riegelman models (r(2) = 0.92). The percentage of fraction absorbed indicated that 0.5% sodium lauryl sulfate may be considered a biorelevant dissolution medium for efavirenz tablets. The simulation of gastrointestinal bioavailability and IVIVC obtained from immediate-release tablet formulations suggests that GastroPlusTM is a valuable in silico method for IVIVC and for studies directed at developing formulations of class II drugs. PMID- 23943402 TI - Separation of dietary omega-3 and omega-6 fatty acids in food by capillary electrophoresis. AB - A lower dietary omega-6/omega-3 (n-6/n-3) fatty acid ratio (<4) has been shown to be beneficial in preventing a number of chronic illnesses. Interest exists in developing more rapid and sensitive analytical methods for profiling fatty acid levels in foods. An aqueous CE method was developed for the simultaneous determination of 15 n-3 and n-6 relevant fatty acids. The effect of pH and concentration of buffer, type and concentration of organic modifier, and additive on the separation was investigated in order to determine the best conditions for the analysis. Baseline separations of the 15 fatty acids were achieved using 40 mM borate buffer at pH 9.50 containing 50 mM SDS, 10 mM beta-cyclodextrin, and 10% acetonitrile. The developed CE method has LODs of <5 mg/L and good linearity (R(2) > 0.980) for all fatty acids studied. The proposed method was successfully applied to the determination of n-3 and n-6 fatty acids in flax seed, Udo(r) oils and a selection of grass-fed and grain-fed beef muscle samples. PMID- 23943403 TI - Reproducibility of positive results for the detection of serum galactomannan by PlateliaTM aspergillus EIA. AB - Galactomannan (GM) was recently included in consensus guidelines as an indirect mycological criterion for the diagnosis of invasive aspergillosis. Currently, there is an enzyme immunoassay available to detect GM in biological samples, the PlateliaTM Aspergillus EIA. In this study, the reproducibility of positive results obtained using this assay was evaluated using serum samples from neutropenic patients. A trend toward lower values was observed, and 55 %(27/49) of positive results were negative after retesting. A low reproducibility of positive results for the detection of GM in serum was observed. PMID- 23943404 TI - Feline nasal granuloma due to Cryptoccocus gattii type VGII. AB - The aims of this study are to make a more precise identification of the etiologic agent of a nasal granuloma in a cat, to verify the susceptibility to the antifungal drugs: ketoconazole, itraconazole, fluconazole, posaconazole, voriconazole, amphotericin B and the proper treatment. Part of the granuloma's fragment was removed, added to a saline solution and sent to the Laboratory of Mycology. The solution was then seeded in Sabouraud dextrose agar, and the yeast was primarily identified by the traditional methods. The confirmation of the specie Cryptococcus gattii and its molecular type were performed using the PCR RFLP molecular techniques. The antifungal susceptibility was verified by using the E-test method, and the cat was treated with itraconazole associated with 5 flucytosine. The isolated strain was identified as C. gattii type VGII and was susceptible to all antifungal drugs tested. The treatment with itraconazole associated with 5-flucytosine led to the cure of granulomatous lesions in the feline after 6 months. The characterization and molecular investigation of this microorganism are relevant because they could help us better understand the epidemiology of the infection and to guide us to treat properly the disease. PMID- 23943405 TI - Murine model of disseminated fusariosis: evaluation of the fungal burden by traditional CFU and quantitative PCR. AB - Systemic disease is the most severe clinical form of fusariosis, and the treatment involves a challenge due to the refractory response to antifungals. Treatment for murine Fusarium solani infection has been described in models that employ CFU quantitation in organs as a parameter of therapeutic efficacy. However, CFU counts do not precisely reproduce the amount of cells for filamentous fungi such as F. solani. In this study, we developed a murine model of disseminated fusariosis and compared the fungal burden with two methods: CFU and quantitative PCR. ICR and BALB/c mice received an intravenous injection of 1 * 10(7) conidia of F. solani per mouse. On days 2, 5, 7, and 9, mice from each mice strain were killed. The spleen and kidneys of each animal were removed and evaluated by qPCR and CFU determinations. Results from CFU assay indicated that the spleen and kidneys had almost the same fungal burden in both BALB/c and ICR mice during the days of the evaluation. In the qPCR assay, the spleen and kidney of each mouse strain had increased fungal burden in each determination throughout the entire experiment. The fungal load determined by the qPCR assay was significantly greater than that determined from CFU measurements of tissue. qPCR could be considered as a tool for quantitative evaluation of fungal burden in experimental disseminated F. solani infection. PMID- 23943406 TI - Quinary protein structure and the consequences of crowding in living cells: leaving the test-tube behind. AB - Although the importance of weak protein-protein interactions has been understood since the 1980s, scant attention has been paid to this "quinary structure". The transient nature of quinary structure facilitates dynamic sub-cellular organization through loose grouping of proteins with multiple binding partners. Despite our growing appreciation of the quinary structure paradigm in cell biology, we do not yet understand how the many forces inside the cell--the excluded volume effect, the "stickiness" of the cytoplasm, and hydrodynamic interactions--perturb the weakest functional protein interactions. We discuss the unresolved problem of how the forces in the cell modulate quinary structure, and to what extent the cell has evolved to exert control over the weakest biomolecular interactions. We conclude by highlighting the new experimental and computational tools coming on-line for in vivo studies, which are a critical next step if we are to understand quinary structure in its native environment. PMID- 23943408 TI - Prenatal identification of invasive placentation using ultrasound: systematic review and meta-analysis. AB - OBJECTIVE: The accuracy of prospective sonographic prenatal detection of invasive placentation is unclear. The objective of this study was to conduct a systematic review and meta-analysis to assess the performance of ultrasound in at-risk women for prenatal identification of invasive placentation. METHODS: MEDLINE, EMBASE, The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE) and The Cochrane Central Register of Controlled Trials (CENTRAL) were searched using the search terms 'placenta accreta', 'placenta increta', 'placenta percreta', 'ultrasound', 'magnetic resonance imaging (MRI)', 'invasive placenta' and 'infiltrative placenta'. Two authors independently abstracted data from the articles. Sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), the diagnostic odds ratio (DOR) and their 95% CIs for each study were calculated. Forest plots and summary receiver-operating characteristics curves were produced. Between-study heterogeneity was explored both graphically and statistically. The MOOSE (meta-analysis of observational studies in epidemiology) guidelines were followed. RESULTS: Twenty-three studies involving 3707 pregnancies at risk for invasive placentation were included. The overall performance of ultrasound for the antenatal detection of invasive placentation was as follows: sensitivity, 90.72 (95% CI, 87.2-93.6)%; specificity, 96.94 (95% CI, 96.3-97.5)%; LR+, 11.01 (95% CI, 6.1-20.0); LR-, 0.16 (95% CI, 0.11-0.23); and DOR, 98.59 (95% CI, 48.8-199.0). Among the different ultrasound signs, color Doppler had the best predictive accuracy (sensitivity, 90.74 (95% CI, 85.2-94.7)%; specificity, 87.68 (95% CI, 84.6-90.4)%; LR+, 7.77 (95% CI, 3.3-18.4); LR-, 0.17 (95% CI, 0.10-0.29); and DOR, 69.02 (95% CI, 22.8 208.9)). CONCLUSIONS: Ultrasound has a high accuracy for prenatal diagnosis of disorders of invasive placentation in high-risk women. The use of color Doppler improves the test performance. PMID- 23943407 TI - Conditioned pain modulation: a predictor for development and treatment of neuropathic pain. AB - Psychophysical evaluation of endogenous pain inhibition via conditioned pain modulation (CPM) represents a new generation of laboratory tests for pain assessment. In this review we discuss recent findings on CPM in neuropathic pain and refer to psychophysical, neurophysiological, and methodological aspects of its clinical implications. Typically, chronic neuropathic pain patients express less efficient CPM, to the extent that incidence of acquiring neuropathic pain (e.g. post-surgery) and its intensity can be predicted by a pre-surgery CPM assessment. Moreover, pre-treatment CPM evaluation may assist in the correct choice of serotonin-noradrenalin reuptake inhibitor analgesic agents for individual patients. Evaluation of pain modulation capabilities can serve as a step forward in individualizing pain medicine. PMID- 23943409 TI - Volume and outcomes after esophageal cancer surgery: the experience of the Region of Lombardy-Italy. AB - Surgical procedures for cancer of the esophagus are complex operations, with considerable perioperative morbidity and mortality that require high use of resources. Recent reports indicate better results with centralization of these procedures, referring patients to high-volume dedicated hospitals. The aim of this study was to analyze the results of resective surgery for cancer of the esophagus and cardia performed in hospitals of the Region of Lombardy over the period 2005-2011, in terms of volume of operations, 30-day postoperative mortality, and length of hospitalization. The results showed a significant relation between reduction of mortality rate and number of resections performed in intermediate- and high-volume centers. In the Region of Lombardy there is an inverse relation between volume of esophagectomies in the single hospital, length of postoperative hospital stay, and postoperative 30-day mortality. Centralization of care on a regional level and standardized clinical pathways of diagnosis and care at single healthcare organizations and professionals should be implemented to improve clinical results in patients affected by esophageal and cardia cancer. PMID- 23943411 TI - Acceptance. PMID- 23943410 TI - Mortality in schizophrenia: clinical and serological predictors. AB - Persons with schizophrenia have a reduced life expectancy largely due to death from natural causes. Factors that have been previously associated with excess mortality include cigarette smoking and antipsychotic medication. The role of other environmental factors such as exposure to infectious agents has been the subject of only limited investigation. We prospectively assessed a cohort of persons with schizophrenia with a clinical evaluation and a blood sample from which antibodies to human herpes viruses and Toxoplasma gondii were measured. Mortality was determined with data from the National Death Index following a period of up to 11 years. We examined the role of demographic, serological, and clinical factors on mortality. A total of 25 (5%) of 517 persons died of natural causes. The standardized mortality ratio was 2.80 (95% CI 0.89, 6.38). After adjusting for age and gender, mortality from natural causes was predicted in separate models by cigarette smoking (relative risk [RR] = 4.66, P = .0029); lower cognitive score (RR = 0.96, P = .013); level of antibodies to Epstein-Barr virus (RR = 1.22, P = .0041) and to Herpes Simplex virus type 1 (RR = 1.19, P = .030); immunologic disease (RR = 3.14, P = .044); and genitourinary disease (RR = 2.70; P = .035). Because cigarette smoking confers an almost 5-fold risk of mortality, smoking cessation is an urgent priority. Having an elevated level of antibodies to Epstein-Barr virus and to Herpes Simplex virus type 1 are also significant predictors of death from natural causes. PMID- 23943412 TI - Depression and impulsivity as pathways to violence: implications for antiaggressive treatment. AB - BACKGROUND: Difficulties with affect regulation and impulse control have a strong influence on violence. The objective of this study was to determine whether baseline depression and impulsivity predict aggression and whether they predict differential response to antiaggressive treatment. This is important, as we lack knowledge as to the selection of antipsychotics for the treatment of aggression. METHODS: Physically aggressive inpatients with schizophrenia who received an evaluation of depression and impulsivity at baseline were randomly assigned in a double-blind, parallel group, 12-week trial to clozapine, olanzapine, or haloperidol. Trait impulsivity was measured by the Barratt Impulsiveness Scale; depression by the Positive and Negative Syndrome Scale Depression factor. The number and severity of aggressive events, as measured by the Modified Overt Aggression Scale (MOAS), were the outcome measures. RESULTS: Baseline depression and impulsivity predicted higher levels of aggression, as measured by the MOAS total score, over the 12-week treatment period across all 3 medication groups. In addition, there was a strong interaction effect between baseline depression/impulsivity and medication grouping in predicting MOAS score. In particular, when higher depression and impulsivity were present at baseline, patients on haloperidol presented with more aggression than patients on the other 3 medications. CONCLUSIONS: Depression and impulsivity are important predictors of aggression and of differential response to antiaggressive treatment. This is most likely due to the medications' dissimilar neurotransmitter profiles. By identifying patients who will respond better to a given medication, we will be able to develop individualized strategies for the treatment of violent behavior. PMID- 23943413 TI - Molecular cloning and prokaryotic expression of vp5 gene of grass carp reovirus strain GCRV096. AB - VP5 is an outer capsid protein of grass carp reovirus (GCRV). It is predicted to involve in helping GCRV enter the host cells. In this study, the full-length vp5 gene (accession number in GenBank: JN206664.1) was cloned from GCRV strain GCRV096, which was isolated from diseased grass carp (Ctenopharyngodon idella) in southern China by RT-PCR technique using the primers designed from the known vp5 gene sequences of other strains of GCRV published in GenBank. The ORF sequence of vp5 is composed of 1,947 nucleotides encoding a 648-residues protein with a calculated molecular mass of 68.6 kDa and an estimated isoelectric point of 6.1. Sequence analysis results showed that VP5 might serve as a penetration protein and play an important role in GCRV penetration into the host cells. A full length of vp5 gene was subcloned into the prokaryotic expression vector pET-28a (+) and the recombinant plasmid (pET/GCRV-VP5) was then transduced into Escherichia coli BL21 (DE3) cells to express VP5 in vitro. SDS-PAGE and western blotting analysis indicated that the protein expressed successfully. Results also showed that the fusion protein expressed in the form of inclusion body, and it expressed in the highest level when induced with 0.2-mM IPTG at 28 degrees C for 4 h. These results are important for the future study on the molecular structure, function, and immunogenicity of GCRV capsid protein. PMID- 23943414 TI - Rosavirus: the prototype of a proposed new genus of the Picornaviridae family. AB - We describe a 8,724-nucleotide-long picornavirus genome encoding a single 2,470 aa polyprotein obtained from the feces of a wild mouse. Rosavirus is genetically closest to the double ORF Dicipivirus found in canine feces that is currently the only picornavirus with a second internal ribosome entry site (IRES). Of note, a section of rosavirus' 5'UTR showed strong sequence and structural conservation with the type II IRES from the Parechovirus and Hungarovirus genera possibly reflecting exchange of genetic modules between genera. Based on genetic distance criteria rosavirus qualifies as prototype of a new genus of the Picornaviridae family. PMID- 23943415 TI - Ultrasonography is not more reliable than anthropometry for assessing visceral fat in obese children. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Visceral fat accumulation is a risk factor for obesity-related complications. Waist circumference is used in clinical practice to assess visceral adiposity. WHAT THIS STUDY ADDS: Ultrasound is not superior to waist circumference for assessing visceral obesity in obese children. The optimal site for measuring waist circumference in obese children is at the smallest body circumference between xiphisternum and umbilicus. OBJECTIVE: Visceral fat accumulation is a well-established risk factor for obesity-related complications. In children, it has not been determined whether ultrasonography is superior to waist measurement for assessing visceral fat. Moreover, the optimal site for waist measurement has not been determined. DESIGN: In a prospective cohort of 92 severely obese children and adolescents (age 13.9 +/- 2.2 years, body mass index z-score 3.29 +/- 0.33), we evaluated the performance of ultrasonography and two different methods of waist circumference measurement, using magnetic resonance imaging as the reference standard. RESULTS: Waist circumference, defined as the smallest body circumference between xiphisternum and umbilicus had the strongest correlation with visceral fat quantity (r = 0.69 all, r = 0.68 girls, r = 0.64 boys). It was not outperformed by ultrasonography (r = 0.60 all, r = 0.62 girls, r = 0.50 boys) and correlated significantly better than the World Health Organization standard for waist measurement, midway between lower margin of the last rib and the crest of the ilium, (r = 0.51 all, r = 0.39 girls, r = 0.46 boys). CONCLUSIONS: Waist circumference measurement, defined as the smallest body circumference between xiphisternum and umbilicus, is the preferred non-invasive technique for daily clinical practice to assess visceral fat accumulation in severely obese children and adolescents. There is no place for ultrasonography for the quantification of visceral fat in this group. PMID- 23943417 TI - The TV in your pocket: development of liquid-crystal materials for the new millennium. AB - New liquid crystals with very low viscosity, good mesophase behavior, and high reliability are necessary to achieve the breakthrough from flat computer monitors to large displays for television. Fluorine plays a decisive role not only because of the polarity it induces in organic molecules but also because of its low polarizability and weak propensity for ion solvation. In addition, subtle stereoelectronic effects in fluorine-containing liquid crystals influence material properties and allow these to be tuned to some extent to achieve the desired outcome. Some fairly sophisticated chemistry is required that is normally ruled out in the specialty chemicals industry because of cost. The television display market is now entering a phase of saturation. The broad availability of the internet has led to an ever increasing tendency for mobile products. Tablet PCs and smartphones require touch-panel functionality and low power consumption. New LCD modes with high-performance liquid crystals and additional components, such as polymerizable materials, can be used in such products. PMID- 23943418 TI - Self-assembled supramolecular nanotube yarn. AB - Metric length supramolecular nanotube yarns are fabricated though a spinning process from the diluted aqueous solution of self-assembled nanotubes, with bolaamphiphiles working as molecular building blocks. These non-covalent bonding based nanotube yarns show outstanding mechanical strength compared with some conventional polymers and could be operated under the macro conditions. PMID- 23943419 TI - Warfarin-induced skin necrosis. PMID- 23943420 TI - Calcinosis in adult-onset dermatomyositis: metastatic or dystrophic? PMID- 23943421 TI - Guideline-inconsistent breast cancer screening for women over 50: a vignette based survey. AB - BACKGROUND: Professional organizations have issued guidelines recommending breast cancer screening for women 50 years of age. OBJECTIVE: This study examines the percent of U.S. primary care physicians who report breast cancer screening practices that are not consistent with guidelines, and the characteristics of physicians who reported offering extra test modalities. DESIGN: We analyzed a subset of a 2008 cross-sectional Women's Health Care survey sent to primary care physicians randomly selected from the national American Medical Association (AMA) Physician Masterfile. A subset of physicians received a survey that presented a vignette of a health maintenance visit for an asymptomatic 51-year-old woman who was not at high risk for breast cancer. Responses were weighted to represent physicians nationally. PARTICIPANTS: 1,654 U.S. family physicians, general internists, and obstetrician-gynecologists under age 65, who practiced in office or hospital based settings (62.8 % response rate). After exclusions, 553 study physicians remained for analysis. MAIN MEASURE: Physician self-report of breast cancer screening practices that are not consistent with the recommendations of the U.S. Preventive Services Task Force (USPSTF), the American College of Obstetrics and Gynecology (ACOG), and the American Cancer Society (ACS), defined as almost always offering mammography. KEY RESULTS: 36.0 % (95 % CI: 31.8 %-40.5 %) of physicians reported offering breast cancer screening tests inconsistent with national guidelines, with most offering extra tests (magnetic resonance imaging [MRI] and/or ultrasound) (33.2 %, 95 % CI 29.1 %-37.6 %). In adjusted analysis, risk-averse physicians and those who believed in the clinical effectiveness of MRI were more likely to offer extra breast cancer screening tests. CONCLUSIONS: Physicians often report offering breast cancer screening test modalities beyond those recommended for a 51-year-old woman. Strategies, such as academic detailing regarding appropriate use of technology and provision of clinical decision support for breast cancer screening, could decrease overuse of resources. PMID- 23943422 TI - Non-traditional risk factors are important contributors to the racial disparity in diabetes risk: the atherosclerosis risk in communities study. AB - BACKGROUND: Traditional risk factors, particularly obesity, do not completely explain the excess risk of diabetes among African Americans compared to whites. OBJECTIVE: We sought to quantify the impact of recently identified, non traditional risk factors on the racial disparity in diabetes risk. DESIGN: Prospective cohort study. PARTICIPANTS: We analyzed data from 2,322 African American and 8,840 white participants without diabetes at baseline from the Atherosclerosis Risk in Communities (ARIC) Study. MAIN MEASURES: We used Cox regression to quantify the association of incident diabetes by race over 9 years of in-person and 17 years of telephone follow-up, adjusting for traditional and non-traditional risk factors based on literature search. We calculated the mediation effect of a covariate as the percent change in the coefficient of race in multivariate models without and with the covariate of interest; 95 % confidence intervals (95 % CI) were calculated using boot-strapping. KEY RESULTS: African American race was independently associated with incident diabetes. Body mass index (BMI), forced vital capacity (FVC), systolic blood pressure, and serum potassium had the greatest explanatory effects for the difference in diabetes risk between races, with mediation effects (95 % CI) of 22.0 % (11.7 %, 42.2 %), 21.7 %(9.5 %, 43.1 %), 17.9 % (10.2 %, 37.4 %) and 17.7 % (8.2 %, 39.4 %), respectively, during 9 years of in-person follow-up, with continued effect over 17 years of telephone follow-up. CONCLUSIONS: Non-traditional risk factors, particularly FVC and serum potassium, are potential mediators of the association between race and diabetes risk. They should be studied further to verify their importance and to determine if they mark causal relationships that can be addressed to reduce the racial disparity in diabetes risk. PMID- 23943423 TI - Pattern of clinically relevant mutations in consecutive series of Russian colorectal cancer patients. AB - One hundred and ninety-five consecutive surgically treated Russian colorectal cancer (CRC) patients were retrospectively analyzed for the presence of mutations in KRAS, NRAS, BRAF and PIK3CA genes as well as for the microsatellite instability status. Comparison between high-resolution melting analysis, co amplification at lower denaturation temperature PCR, DNA sequencing and allele specific PCR for the detection of KRAS codon 12/13 mutations revealed that none of these methods alone provided satisfactory results in 100 % of the analyzed cases; this experience supports the use of more than one mutation-detecting technique at least in some circumstances. KRAS codon 12/13 substitutions were detected in 70 (35.9 %) CRC cases. Other mutations in the RAS/RAF genes occurred in 22 (11.3 %) cases and included rare KRAS (n = 6), NRAS (n = 8) and BRAF (n = 8) alterations. 5 BRAF mutations affected codon 600, while the remaining 3 potentially functional substitutions were located in the position 594. Twenty four (12.3 %) CRC cases carried mutations in the PIK3CA, and 18 of these tumors also contained activating alteration in the RAS/RAF genes (p = 0.007). Only 3 (1.5 %) CRC cases showed high-level microsatellite instability (MSI-H) as determined by a panel of mononucleotide markers. Overall, the distribution of potentially predictive mutations in Russian CRC cases is similar to the one observed in other patient series of European descent. Noticeable occurrence of D594G mutation in BRAF oncogene and low frequency of MSI-H may deserve specific attention. PMID- 23943425 TI - Rapid determination of catecholamines in urine samples by nonaqueous microchip electrophoresis with LIF detection. AB - A method was developed for the rapid separation of catecholamines by nonaqueous microchip electrophoresis with LIF detection, A homemade pump-free negative pressure sampling device was used for rapid bias-free sampling in nonaqueous microchip electrophoresis, the injection time was 0.5 s and the electrophoresis separation conditions were optimized. Under the optimized conditions, the samples were separated completely in less than 1 min. The average migration times of the epinephrine, dopamine, and norepinephrine were 34.26, 43.81, and 50.07 s, with a relative standard deviation of 1.05, 1.26 and 0.89% (n = 7), respectively. The linearity of the method ranged from 0.0125 to 2.0 mg/L for epinephrine and 0.025~4.0 mg/L for dopamine, and norepinephrine, with correlation coefficients ranging between 0.9978 and 0.9986. The detection limits of epinephrine, dopamine, and norepinephrine were 2.5, 5.0 and 5.0 MUg/L, respectively. The recoveries of epinephrine, dopamine, and norepinephrine in spiked urine samples were between 86 and 103%, with relative standard deviations of 4.5~6.8% (n = 5). The proposed nonaqueous microchip electrophoresis with laser induced fluorescence detection system combined with a pump-free negative pressure sampling device was a simple, inexpensive, energy efficient, miniaturized system that can be successfully applied for the determination of catecholamines in urine samples. This article is protected by copyright. All rights reserved. PMID- 23943424 TI - Multi-modality imaging of the aortic valve in the era of transcatheter aortic valve replacement: a guide for patient selection, valve selection, and valve delivery. AB - Aortic stenosis is a common condition traditionally treated surgically. Transcatheter aortic valve replacement (TAVR) is an exciting and new method allowing treatment of high risk and inoperable patients. Multimodality imaging is extremely important in the preprocedural evaluation, the performance of the procedure, and the post-procedural assessment and includes transthoracic echocardiography, transesophageal echocardiography, conventional angiography, multi-detector computed tomography, and cardiac magnetic resonance. This paper will review the role of various imaging modalities during the phases of the TAVR procedure with an emphasis on the advantages and limitations of each approach. PMID- 23943426 TI - Surveillance of dermatophytosis in northeast of Iran (Mashhad) and review of published studies. AB - Dermatophytoses are considered to be one of the major public health problems in the world and are among the most commonly diagnosed skin diseases in Iran. In spite of improved personal hygiene and living environment, dermatophytosis continues to spread and persist. To determine the prevalence of dermatophytosis and their etiologic agents in Mashhad (Iran), five hundred and sixty patients suspected to have fungal infection were studied. Subjects who participated in this study were 330 males and 230 females ranged in age from 4 months to 70 years with a mean age of about 25.5 years. Clinical materials including skin scraping, hair and scalp sample, nail clipping and subungual debris were collected. All of the specimens were assessed by direct examination and culture. Of 560 patients, 166 (29.6 %) had dermatophytosis. The types of tinea according to anatomical areas were as follows: tinea corporis (33.1 %), tinea capitis (32.5 %), tinea manuum (17.5 %), tinea cruris (10.2 %), tinea pedis (5.4 %), tinea unguium (0.6 %) and tinea barbae (0.6 %). Trichophyton verrucosum was the most prevalent species followed by Trichophyton violaceum and Trichophyton mentagrophytes. The prevalence of dermatophytosis in males was higher than in females. Based on a review of published studies from different parts of Iran, there are regional differences in the incidence of dermatophytosis. Epidermophyton floccosum has been the most prevalent species, and Microsporum canis has been isolated less than from the other countries. PMID- 23943427 TI - Differential sensitivity of the species of Candida parapsilosis sensu lato complex against statins. AB - Candida parapsilosis sensu stricto, Candida orthopsilosis and Candida metapsilosis are human fungal pathogens with clinical importance. The recently reclassified three closely related species have significant variation in virulence, clinical prevalence and susceptibility characteristics to different antifungal compounds. The aim of this study was to investigate the in vitro activity of atorvastatin and fluvastatin against C. metapsilosis, C. orthopsilosis and C. parapsilosis. Susceptibility tests showed that C. parapsilosis was the most sensitive while C. orthopsilosis was the least susceptible species to both drugs. On the basis of the differential sensitivity, we developed a simple, reliable and highly cost-effective plate assay to distinguish these closely related species. Applying this method, 54 isolates belonging to the C. parapsilosis sensu lato complex deposited in Szeged Microbial Collection could be sorted into the three species with 100 % probability. PMID- 23943428 TI - Sialoglycoproteins in morphological distinct stages of Mucor polymorphosporus and their influence on phagocytosis by human blood phagocytes. AB - The possible role of sialic acids in host cells-fungi interaction and their association with glycoproteins were evaluated using a clinical isolate of the dimorphic fungus Mucor polymorphosporus. Lectin-binding assays with spores and yeast cells denoted the presence of surface sialoglycoconjugates containing 2,3- and 2,6-linked sialylglycosyl groups. Western blotting with peroxidase-labeled Limulus polyphemus agglutinin revealed the occurrence of different sialoglycoprotein types in both cell lysates and cell wall protein extracts of mycelia, spores, and yeasts of M. polymorphosporus. Sialic acids contributed to the surface negative charge of spores and yeast forms as evaluated by adherence to a cationic substrate. Sialidase-treated spores were less resistant to phagocytosis by human neutrophils and monocytes from healthy individuals than control (untreated) fungal suspensions. The results suggest that sialic acids are terminal units of various glycoproteins of M. polymorphosporus, contributing to negative charge of yeasts and spore cells and protecting infectious propagules from destruction by host cells. PMID- 23943429 TI - HIV-1 genotypic diversity and prevalence of drug resistance among treatment naive HIV-infected individuals in Chengdu of China. AB - AIDS is becoming one of leading cause of death among infectious diseases in China. There has been rapidly increasing epidemic of HIV/AIDS in Chengdu since 2003. In order to investigate HIV-1 subtype distribution, drug resistance associated mutations as well as drug resistance prevalence among treatment naive HIV-infected individuals in Chengdu of China, 244 HIV confirmed-reactive serum samples were collected from 2007 to 2010, including 165 obtained from blood centers and 79 obtained from hospitals. HIV-1 pol including whole protease, and partial reverse transcriptase genes was amplified, sequenced, and analyzed for subtype determination and drug resistance profile description. A total of 159 amplified sequences which were acquired from 98 sample obtained at blood centers and 61 samples obtained at hospitals had the following genotype distribution: G (0.6%), F1 (0.6%), A1 (0.6%), B (1.9%), circulating recombinant form (CRF) 01_AE (42.8%), CRF07_BC (49.1%), and CRF08_BC (4.4%). There were 12.2 and 24.6 % samples obtained from blood centers and hospitals, respectively, that harbored drug resistance-associated mutations, and the prevalence of drug resistance among all cases was 1.3%. This was the first report of HIV molecular surveillance among treatment naive HIV-infected individuals in Chengdu. Our findings were believed to be helpful on contribution to comprehensive HIV control program in China. PMID- 23943430 TI - Color matters--material ejection and ion yields in UV-MALDI mass spectrometry as a function of laser wavelength and laser fluence. AB - The success of matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) as a widely employed analytical tool in the biomolecular sciences builds strongly on an effective laser-material interaction that is resulting in a soft co-desorption and ionization of matrix and imbedded biomolecules. To obtain a maximized ion yield for the analyte(s) of interest, in general both wavelength and fluence need to be tuned to match the specific optical absorption profile of the used matrix. However, commonly only lasers with fixed emission wavelengths of either 337 or 355 nm are used for MALDI-MS. Here, we employed a wavelength tunable dye laser and recorded both the neutral material ejection and the MS ion data in a wide wavelength and fluence range between 280 and 377.5 nm. alpha-Cyano 4-hydroxycinnamic acid (HCCA), 4-chloro-alpha-cyanocinnamic acid (ClCCA), alpha cyano-2,4-difluorocinnamic acid (DiFCCA), and 2,5-dihydroxybenzoic acid (DHB) were investigated as matrices, and several peptides as analytes. Recording of the material ejection was achieved by adopting a photoacoustic approach. Relative ion yields were derived by division of photoacoustic and ion signals. In this way, distinct wavelength/fluence regions can be identified for which maximum ion yields were obtained. For the tested matrices, optimal results were achieved for wavelengths corresponding to areas of high optical absorption of the respective matrix and at fluences about a factor of 2-3 above the matrix- and wavelength dependent ion detection threshold fluences. The material ejection as probed by the photoacoustic method is excellently fitted by the quasithermal model, while a sigmoidal function allows for an empirical description of the ion signal-fluence relationship. PMID- 23943431 TI - Fragmentation reactions of methionine-containing protonated octapeptides and fragment ions therefrom: an energy-resolved study. AB - The fragmentation reactions of the MH(+) ions as well as the b7, a7, and a7* ions derived therefrom have been studied in detail for the octapeptides MAAAAAAA, AAMAAAAA, AAAAMAAA, and AAAAAAMA. Ionization was by electrospray using a QqToF mass spectrometer, which allowed a study of the evolution of the fragmentation channels as a function of the collision energy. Not surprisingly, the product ion mass spectra for the b7 ions are independent of the original precursor sequence, indicating macrocyclization and reopening to the same mixture of protonated oxazolones prior to fragmentation. The results show that this sequence scrambling results in a distinct preference to place the Met residue in the C-terminal position of the protonated oxazolones. The a7 and a7* ions also produce product ion mass spectra independent of the original peptide sequence. The results for the a7 ions indicate that fragmentation occurs primarily from an amide structure analogous to that observed for a4 ions (Bythell et al. in J Am Chem Soc 132:14766 14779, 2010). Clearly, the rearrangement reaction they have proposed applies equally well to an ions as large as a7. The major fragmentation modes of the MH(+) ions at low collision energies produce b7, b6, and b5 ions. As the collision energy is increased further fragmentation of these primary products produces, in part, non-direct sequence ions, which become prominent at lower m/z values, particularly for the peptides with the Met residue near the N-terminus. PMID- 23943433 TI - Work-function-tuned reduced graphene oxide via direct surface functionalization as source/drain electrodes in bottom-contact organic transistors. AB - RGO electrodes with work functions that can be widely tuned using direct surface functionalization are demonstrated by self-assembled monolayers anchored onto the surfaces of the RGO electrodes, which can remarkably enhance the device performance of organic field-effect transistors. PMID- 23943434 TI - Error and discovery: why repeating can be new. PMID- 23943432 TI - Dissociation of multisubunit protein-ligand complexes in the gas phase. Evidence for ligand migration. AB - The results of collision-induced dissociation (CID) experiments performed on gaseous protonated and deprotonated ions of complexes of cholera toxin B subunit homopentamer (CTB5) with the pentasaccharide (beta-D-Galp-(1->3)-beta-D-GalpNAc (1->4)[alpha-D-Neu5Ac-(2->3)]-beta-D-Galp-(1->4)-beta-D-Glcp (GM1)) and corresponding glycosphingolipid (beta-D-Galp-(1->3)-beta-D-GalpNAc-(1->4)[alpha-D Neu5Ac-(2->3)]-beta-D-Galp-(1->4)-beta-D-Glcp-Cer (GM1-Cer)) ligands, and the homotetramer streptavidin (S4) with biotin (B) and 1,2-dipalmitoyl-sn-glycero-3 phosphoethanolamine-N-(biotinyl) (Btl), are reported. The protonated (CTB5 + 5GM1)(n+) ions dissociated predominantly by the loss of a single subunit, with the concomitant migration of ligand to another subunit. The simultaneous loss of ligand and subunit was observed as a minor pathway. In contrast, the deprotonated (CTB5 + 5GM1)(n-) ions dissociated preferentially by the loss of deprotonated ligand; the loss of ligand-bound and ligand-free subunit were minor pathways. The presence of ceramide (Cer) promoted ligand migration and the loss of subunit. The main dissociation pathway for the protonated and deprotonated (S4 + 4B)(n+/-) ions, as well as for deprotonated (S4 + 4Btl)(n-) ions, was loss of the ligand. However, subunit loss from the (S4 + 4B)(n+) ions was observed as a minor pathway. The (S4 + 4Btl)(n+) ions dissociated predominantly by the loss of free and ligand-bound subunit. The charge state of the complex and the collision energy were found to have little effect on the relative contribution of the different dissociation channels. Thermally-driven ligand migration between subunits was captured in the results of molecular dynamics simulations performed on protonated (CTB5 + 5GM1)(15+) ions (with a range of charge configurations) at 800 K. Notably, the migration pathway was found to be highly dependent on the charge configuration of the ion. The main conclusion of this study is that the dissociation pathways of multisubunit protein-ligand complexes in the gas phase depend, not only on the native topology of the complex, but also on structural changes that occur upon collisional activation. PMID- 23943435 TI - Temporal divergence of percent body fat and body mass index in pre-teenage children: the LOOK longitudinal study. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The index of body mass related to stature, (body mass index, BMI, kgm(-2) ), is widely used as a proxy for percent body fat (%BF) in cross-sectional and longitudinal investigations. BMI does not distinguish between lean and fat mass and in children, the cross-sectional relationship between %BF and BMI changes with age and sex. WHAT THIS STUDY ADDS: While BMI increases linearly with age from age 8 to 12 years in both boys and girls, %BF plateaus off between 10 and 12 years. Repeated measures in children show a systematic decrease in %BF for any given BMI from age 8 to 10 to 12 years. Because changes in BMI misrepresent changes in %BF, its use as a proxy of %BF should be avoided in longitudinal studies in this age group. BACKGROUND: Body mass index (BMI, kgm(-2) ) is commonly used as an indicator of pediatric adiposity, but with its inability to distinguish changes in lean and fat mass, its use in longitudinal studies of children requires careful consideration. OBJECTIVE: To investigate the suitability of BMI as a surrogate of percent body fat (%BF) in pediatric longitudinal investigations. METHODS: In this longitudinal study, healthy Australian children (256 girls and 278 boys) were measured at ages 8.0 (standard deviation 0.3), 10.0 and 12.0 years for height, weight and percent body fat (%BF) by dual-energy X-ray absorptiometry. RESULTS: The patterns of change in the means of %BF and BMI were different (P < 0.001). While mean BMI increased linearly from 8 to 12 years of age, %BF did not change between 10 and 12 years. Relationships between %BF and BMI in boys and girls were curvilinear and varied with age (P < 0.001) and gender (P < 0.001); any given BMI corresponding with a lower %BF as a child became older. CONCLUSION: Considering the divergence of temporal patterns of %BF and BMI between 10 and 12 years of age, employment of BMI as a proxy for %BF in absolute or age and sex standardized forms in pediatric longitudinal investigations is problematical. PMID- 23943436 TI - Comparison of immunoassay screening tests and LC-MS-MS for urine detection of benzodiazepines and their metabolites: results of a national proficiency test. AB - For most diverse purposes, different immunoassay (IA) screening methods are usually used to detect benzodiazepines and their metabolites in urine. In this study, we compared the main IAs used in forensic toxicology (Cloned Enzyme Donor Immunoassay, CEDIA(r); Enzyme-Multiplied Immunoassay Technique, EMIT(r); Fluorescent Polarization ImmunoAssay, FPIA(r); Kinetic Interaction of Microparticles in Solution, KIMS(r) and Immunochromatographic Techniques, IMC) with liquid chromatography-tandem mass spectrometry (LC-MS-MS). Twelve urine specimens were analyzed by 178 laboratories in Italy that participated in a National Proficiency Test, providing both qualitative and semi-quantitative results. Each IA was evaluated by the parameters: true positive, true negative, false positive (FP), false negative (FN), sensitivity (SENS), specificity (SPEC), positive predictive value, negative predictive value (NPV) and accuracy. SPEC was affected by a high FP rate for all IAs. The lowest SENS and NPV were provided by FPIA due to a high number of FN cases. Comparing IA semi-quantitative data with LC-MS-MS results, an overestimation of benzodiazepine amount is noted. This paper draws attention to the problem of the careless use of IA tests for forensic purposes as they may provide FP and/or FN results that can lead to errors of great severity. PMID- 23943437 TI - Recommendations for toxicological investigation of drug-impaired driving and motor vehicle fatalities. AB - This report describes the review and update of a set of minimum recommendations for the toxicological investigation of suspected alcohol and drug-impaired driving cases and motor vehicle fatalities involving drugs or alcohol. The recommendations have the goal of ensuring that a consistent set of data regarding the most frequently encountered drugs linked to driving impairment is collected for practical application in the investigation of these cases and to allow epidemiological monitoring and the development of evidence-based public policy on this important public safety issue. The recommendations are based on a survey of practices in US laboratories performing this kind of analysis, consideration of existing epidemiological crash and arrest data and practical considerations of widely available technology platforms in laboratories performing this work. The final recommendations were derived from a consensus meeting of experts recruited from survey respondents and the membership of the National Safety Council's Alcohol, Drug and Impairment Division (formerly known as the Committee on Alcohol and Other Drugs, CAOD). PMID- 23943439 TI - Design, synthesis and biological evaluation of B-region modified diarylalkyl amide analogues as novel TRPV1 antagonists. AB - Design, synthesis and biological evaluation of B-region, known to be a dipolar interacting pharmacophore, modified diarylalkyl amide analogues for novel TRPV1 (transient receptor potential channel, vanilloid subfamily member 1) antagonists was described. A variety of moieties including guanidines, heterocyclic rings, cinnamides, and alpha-substituted acetamides were introduced at the B-region. TRPV1 antagonistic activities of these analogues were evaluated by (45)Ca(2+) uptake assay in rat DRG neuron. In particular, alpha,alpha-difluoroamide 53 exhibited 3-fold more potent TRPV1 antagonistic activity (IC50 = 0.058 MUM) than the parent amide analogue 6. PMID- 23943438 TI - Significant role of MU-calpain (CANP1) in proliferation/survival of bovine skeletal muscle satellite cells. AB - Calpains are a family of Ca(2+)-dependent intracellular cysteine proteases, including the ubiquitously expressed MU-calpain (CANP1) and m-calpain (CANP2). The CANP1 has been found to play a central role in postmortem proteolysis and meat tenderization. However, the physiological roles of CANP1 in cattle skeletal satellite cells remain unclear. In this study, three small interference RNA sequences (siRNAs) targeting CANP1 gene were designed and ligated into pSilencer plasmid vector to construct shRNA expression constructs. Suppression of CANP1 in satellite cells was evaluated using these shRNA expressing constructs. Our results revealed that all three siRNAs could downregulate the expression of CANP1. Suppression of CANP1 significantly reduced cell viability in cell proliferation when compared with control cells. We found a crosstalk between CANP1 and caspase systems, particularly suppression of CANP1 resulted in an increase in the expressions of apoptotic caspases such as caspase-3, caspase-6, caspase-7, caspase-8, and caspase-9, as well as heat-shock protein (HSP) systems. Additionally, suppression of CANP1 led to the upregulation of other apoptosis and DNA damage-regulating genes whilst at the same time downregulating proliferation, migration, and differentiation-regulating genes. The results of our findings report for the first time that suppression of CANP1 resulted in the activation of caspase and HSP systems which might in turn regulate apoptosis through the caspase-dependent cell death pathway. This clearly demonstrates the key roles of CANP1 in regulation of cell proliferation and survival. PMID- 23943440 TI - Transgenic mouse models. AB - The generation of transgenic mouse models has been a powerful technique for several decades and is still widely used. There have been many manuals and general reviews of this technology. This chapter is designed to be a "how-to" resource with detailed specifics. PMID- 23943441 TI - Pulmonary antigen presenting cells: isolation, purification, and culture. AB - Antigen presenting cells (APCs) such as dendritic cells (DCs) and macrophages comprise a relatively small fraction of leukocytes residing in lymphoid and non lymphoid tissues. Accordingly, functional analyses of these cells have been hampered by low cell yields. Also, alveolar macrophages share several physical properties with DCs, and this has complicated efforts to prepare pure populations of lung APCs. To overcome these difficulties, we have developed improved flow cytometry-based methods to analyze and purify APCs from the lung and its draining lymph nodes (LNs). In this chapter, we describe these methods in detail, as well as methods for culturing APCs and characterizing their interactions with T cells. PMID- 23943442 TI - Evaluation of T cell function in allergic disease. AB - T lymphocytes play positive and negative roles in the pathogenesis of allergic disease. Isolation and functional characterization of T lymphocyte subpopulations is an important aspect of understanding allergy models and allergy therapies. Measurement of the T cell surface proteins and T cell proliferation can provide insight into T cell activation. T cell function and the identities of T cell subsets can be determined by measuring cytokine production, either via intracellular cytokine staining or ELISPOT. This chapter outlines protocols for T cell isolation as well as the evaluation of surface protein expression, proliferation, intracellular cytokine staining, and ELISPOT. PMID- 23943443 TI - Evaluating B-cells: from bone marrow precursors to antibody-producing cells. AB - Lymphocyte characterization is primarily based on the differential expression of surface markers. In this context, flow-cytometry analysis (FACS) is an exceptional technique that not only allows the identification of B-cell subsets, but can also be used to evaluate cell function, activation, and division. Here, we will combine the use of FACS analysis and ELISA techniques to identify murine bone marrow and peripheral B-cell subsets. The main function of B cells, derived through a multistage differentiation process from precursor cells, is to produce antibodies. This task is performed by terminally differentiated B cells called antibody-secreting cells (ASC) present at mucosal sites, in the bone marrow and in the spleen. The number and specificity of ASC can be measured by Enzyme-linked immunosorbent spot (ELISPOT) assay, a variation of the enzyme-linked immunosorbent assay (ELISA) used to quantify serum immunoglobulins. PMID- 23943444 TI - Protocols for identifying, enumerating, and assessing mouse eosinophils. AB - Eosinophils are prominent in allergic diseases, and their effector functions are studied in numerous gene-deleted and transgenic mouse models. However, mouse eosinophils and human eosinophils are not structurally or functionally equivalent, and assays designed to evaluate the properties of human eosinophils may or may not be reliable or effective in experiments targeting their murine counterparts. In this chapter, we emphasize methods focused on detection, isolation, and functional assessment of eosinophils from mouse tissue and present a protocol that promotes the growth and differentiation of eosinophils from unselected mouse bone marrow progenitors. Overall, these protocols provide a scaffold on which the relative contributions of mouse eosinophils can be evaluated. PMID- 23943445 TI - Evaluation of classical, alternative, and regulatory functions of bone marrow derived macrophages. AB - The role of macrophage subsets in allergic diseases in vivo is under current investigation. These cells perform sentinel functions in the lung, the skin, and the gastrointestinal mucosa. Their interface with environmental cues influences the initiation, progression, development, and resolution of allergic diseases. Researchers often culture bone marrow-derived macrophages to study macrophage biology. The in vitro maturation of bone marrow precursor cells into mature macrophages is a powerful technique used to study macrophage biology. The polarization or differential activation of macrophages into functionally distinct subsets can provide insight into allergic disease pathologies. Classically activated, alternatively activated, and regulatory macrophages have different effector functions that can affect allergic responses. Understanding macrophage biology during allergen exposure, host sensitization, and disease progression/resolution may lead to improved therapeutic interventions. The purpose of this chapter is to outline protocols used for the culture and polarization of classically activated, alternatively activated, and regulatory macrophages. In addition, the techniques to measure macrophage-specific effector molecules by ELISA, RT-PCR, and immunoblotting are reviewed. PMID- 23943446 TI - Applications of mouse airway epithelial cell culture for asthma research. AB - Primary airway epithelial cell culture provides a valuable tool for studying cell differentiation, cell-cell interactions, and the role of immune system factors in asthma pathogenesis. In this chapter, we discuss the application of mouse tracheal epithelial cell cultures for the study of asthma biology. A major advantage of this system is the ability to use airway epithelial cells from mice with defined genetic backgrounds. The in vitro proliferation and differentiation of mouse airway epithelial cells uses the air-liquid interface condition to generate well-differentiated epithelia with characteristics of native airways. Protocols are provided for manipulation of differentiation, induction of mucous cell metaplasia, genetic modification, and cell and pathogen coculture. Assays for the assessment of gene expression, responses of cells, and analysis of specific cell subpopulations within the airway epithelium are included. PMID- 23943447 TI - Isolation and characterization of mast cells in mouse models of allergic diseases. AB - After their activation, mast cells release a variety of bioactive mediators that contribute to characteristic symptoms of allergic reactions. Ex vivo analysis of mast cells derived from their progenitors or isolated from mice is an indispensable tool for the development of newer and more effective therapies of allergic syndromes. Here, we describe the differentiation and isolation of mouse mast cells from different sources including differentiation from bone marrow, differentiation from fetal liver, and isolation of residential connective tissue type mast cells from the peritoneum. These techniques are valuable tools for the study of mast cell function and their contribution to allergic reactions. PMID- 23943448 TI - Purifying and measuring immunoglobulin E (IgE) and anti-IgE. AB - Immunoglobulins (Igs) are a critical component of the adaptive immune system of both man and mouse. The ability to detect and characterize Igs is an invaluable technique for immunology in either a research or a clinical setting. The advent of enzyme-linked immunosorbent assays (ELISAs) and monoclonal antibody technology has proven instrumental for advancing the science of Ig biology. IgE is of interest as it is the primary Ig responsible for allergic reactions ranging from allergic rhinitis to anaphylaxis. Here, we describe the history behind the IgE discovery and the protocol for purifying IgE and anti-IgE in the mouse. This is followed by our ELISA protocol for mouse IgE detection. PMID- 23943449 TI - Protocols for the induction and evaluation of systemic anaphylaxis in mice. AB - Mouse models of systemic anaphylaxis are important tools for the study of mast cell function, for the elucidation of the pathomechanisms of anaphylaxis, and for identifying and characterizing potential therapies for anaphylaxis. Here, we describe two murine models of systemic anaphylaxis that have been a key part of research in these areas. In a passive model, mice are sensitized with antigen specific IgE antibody 24 h prior to antigen challenge. In an active model, mice are instead sensitized with antigen 18-21 days prior to challenge. Hypothermia serves as the primary quantifiable indicator of anaphylaxis in these models. PMID- 23943450 TI - Contact hypersensitivity models in mice. AB - The contact hypersensitivity (CHS) reaction is commonly utilized to study cell mediated host immune responses to epicutaneously applied allergens. This reaction is divided into two distinct phases, the afferent phase and the efferent phase. During the afferent phase of this model, mice are exposed to a contact allergen, which is typically a hapten that is applied to a location distal to the site of elicitation. Following a brief intermission, mice are reexposed to the contact allergen during the elicitation phase at a site proximal to the location of sensitization. In mice, the pinna of the ear is typically utilized to evaluate the elicitation phase. While the CHS reaction is typically utilized to study Th1 mediated immune responses, it is now evident that Th2 and Th17 cells also contribute during the elicitation phase of the model. Likewise, in humans, elevated immune responses to contact allergens are associated with a variety of atopic diseases. Here, we describe a common protocol for the induction and assessment of the CHS reaction in mice. PMID- 23943451 TI - Induction of allergic rhinitis in mice. AB - We describe a method for allergic rhinitis (AR) induction in mice. Methodology involves nasal infusions of small volumes of ovalbumin for both initial sensitization and challenges. The latter are frequent and carried out over several weeks. This methodology more closely resembles natural AR induction than does the common use of systemic sensitization, often with adjuvants, followed by nasal challenges with relatively large allergen volumes. Also described are methodologies for collection of cardiac blood and perfusion for preparation of histological samples, both essential in verifying AR induction in individual animals. PMID- 23943452 TI - Induction of allergic airway disease using house dust mite allergen. AB - Mouse models of allergic airway inflammation have proven essential in understanding the mechanisms and pathophysiology underling human asthma. There is a diverse range of mouse models described in the literature that typically vary slightly by allergen, duration of exposure, and route of sensitization. In general, each of these models has proven to be acceptable surrogates for studying specific aspects of the human disease, including airway inflammation, airway hyperresponsiveness (AHR), and airway remodeling. Here, we describe a highly versatile model based on nasal sensitization with house dust mite antigen (DMA). Mice receive multiple intranasal inoculations with DMA each week for a period of 4-16 weeks, which results in increased Th2-mediated airway inflammation and AHR. However, an added feature of the long--term exposures described here is the ability to more accurately evaluate the impact of chronic inflammation on airway remodeling and lung pathophysiology in response to a clinically relevant allergen. PMID- 23943453 TI - An inhalation model of allergic fungal asthma: Aspergillus fumigatus-induced inflammation and remodeling in allergic airway disease. AB - The ability to accurately mimic normal processes for sensitization and allergen challenge in an experimental animal model are useful in that they allow researchers to critically manipulate the complex interactions of multiple cell types. In the context of the allergic lung, multiple cell types form complex cellular networks and function to regulate a variety of temporal and spatial changes. Mouse models of allergic airway disease have proven to be highly useful for dissecting these complex interactions, particularly in addressing remodeling of the allergic airway in chronic asthma. Until we can better represent the normal processes that initiate and perpetuate asthma, our understanding of the mechanisms of tissue injury leading to chronic remodeling of the airways and effective therapeutic strategies to treat this disease will remain limited. It was with this goal in mind that we set about devising an inhalational model of Aspergillus fumigatus-induced fungal asthma in a murine experimental system. PMID- 23943454 TI - PAMPs and DAMPs in allergy exacerbation models. AB - Sensitization of mice to real-life allergens or harmless antigen with the use of adjuvants will lead to the induction of DAMPs in the immune system. We have shown that the Th2-inducing adjuvant aluminum hydroxide or exposure of the airways to house dust mite leads to the release of DAMPs: uric acid, ATP, and IL-1. Exposure to DAMPs or PAMPs present in allergens or added to harmless allergens, such as the experimental allergen ovalbumin, induces several immune responses, including cellular influx and activation. Cellular influx can be analyzed by flow cytometry. Likewise, cellular activation can be assessed by measuring increased expression and release of chemokines and cytokines. These inflammatory mediators can be analyzed by ELISA or confocal microscopy. Here, we describe the protocols for these assessments and a protocol that takes advantage of bone marrow chimeric mice to further elucidate mechanism. PMID- 23943455 TI - Assessment of airway hyperresponsiveness in mouse models of allergic lung disease using detailed measurements of respiratory mechanics. AB - This chapter provides an outline of the procedures necessary to measure airway hyperresponsiveness to inhaled methacholine in mouse models of allergic lung disease. We present a method for acquiring detailed measurements of respiratory mechanics using broadband low-frequency oscillatory waveforms applied at the subject's airway opening and analyzed using the constant phase model of the lung. We acknowledge that there are other methods of measuring airway responsiveness in allergic rodent models. However, a discussion of the merits and or detriments of these various methods have been vigorously debated in the primary literature and are beyond the scope of this chapter. The goal of this chapter is to provide a guide in how to begin these types of assays in laboratories which have little to no experience with these particular types of assessments. PMID- 23943456 TI - Bilateral vagotomy as a tool for determining autonomic involvement in airway responses in mouse models of asthma. AB - This chapter describes the use of bilateral vagotomy as a tool for determining autonomic regulation of airway responses to the exogenous bronchoconstrictor thromboxane mimetic U46619 in an acute model of asthma in the mouse. Mice receive a sensitization of ovalbumin (OVA) and adjuvant followed by 3 days of OVA aerosol to induce allergic airway disease characterized by bronchoalveolar lavage (BAL) eosinophilia, increased mucus production, and elevated IgE and IL-13. Using a small animal ventilator (Flexi-vent) and the forced oscillatory technique fit to the constant phase model of the lung, a variety of features associated with human asthma can be evaluated in mouse models. For example, this protocol describes the methods to evaluate central and peripheral airway mechanics, airway resistance (R aw) and tissue damping (G), and tissue elastance (H) in response to U46619. The contribution of autonomic nerves in this response is determined by severing both the left and right vagus nerves prior to aerosol challenge. PMID- 23943457 TI - Clara epithelial cell depletion in the lung. AB - The bronchial epithelium has been increasingly recognized as an important immunomodulatory compartment in asthma and other lung diseases. Clara cells, which comprise the nonciliated secretory epithelial cells, are an important epithelial cell type with functions in the regulation of lung homeostasis and inflammation. Using naphthalene, Clara cells can be depleted within 24 h and regenerate by 1 month, hence, providing an easy method to study the impact of Clara cells on lung inflammation. PMID- 23943458 TI - A mouse model for evaluating the contribution of fibrocytes and myofibroblasts to airway remodeling in allergic asthma. AB - Airway remodeling is a term used to collectively indicate bronchial structural changes that may lead to irreversible airflow obstruction and progressive decline in lung function in asthmatic patients. Bronchial myofibroblasts contribute to airway remodeling by producing collagenous proteins in the subepithelial zone and by increasing the density of contractile cells in the bronchial wall. A substantial proportion of bronchial myofibroblasts in asthma differentiate from circulating mesenchymal progenitor cells known as fibrocytes. Here, we describe a mouse model of allergic asthma for evaluating the functional role of fibrocytes and myofibroblasts in this disease and the inhibitory effects of novel therapeutic candidates. PMID- 23943459 TI - Assessment of airway hyperresponsiveness in murine tracheal rings. AB - Isolated tracheal rings have often been used to directly measure the contractile output of airway smooth muscle (ASM). Here, we describe the method for excising murine tracheas, mounting tracheal rings in organ baths, and measuring the isometric forces generated by the ASM when stimulated by drug additions or electric field stimulation. The apparatus for the setup and the pathways responsible for stimulation are detailed. Examples of the responses and analyses of two types of ASM stimulation are illustrated: (1) the carbachol concentration response curve and (2) the frequency-response curve elicited by electric field stimulation. PMID- 23943461 TI - Expression profiling to identify candidate genes associated with allergic phenotypes. AB - Transcript profiling reveals valuable insights to molecular and cellular activity related to disease. Gene expression profiles provide clues as to how tissues or cells in a particular environment may respond to stimuli. Gene-targeted examination of transcript changes is accomplished by employing a quantitative PCR approach using cDNA prepared from isolated RNA. PMID- 23943462 TI - Flow cytometric methods for the assessment of allergic disease. AB - Multiparametric flow cytometry is a powerful technique that allows the quantification and characterization of heterogeneous populations of cells. Advances in flow cytometric instrumentation, software, and reagents are occurring at a rapid pace, and flow cytometric methods are increasingly being applied to better understand cellular responses associated with a diverse array of disease conditions. This chapter provides an overview of some common applications of flow cytometry in characterizing mouse models of allergic airway disease. PMID- 23943460 TI - Use of the cockroach antigen model of acute asthma to determine the immunomodulatory role of early exposure to gastrointestinal infection. AB - The increased incidence of asthma over the last 50 years in developed countries has been associated with a decrease in infections acquired early in childhood. These early infections are thought to shape subsequent immune responses. Although there have been multiple clinical associations between gastrointestinal infections and decreased asthma incidence, it has been difficult to move beyond a simple correlation when studying human patients. This section describes an acute asthma model in C57BL/6 mice designed to specifically evaluate the effect of prior gastric Helicobacter colonization and inflammation in a murine model of cockroach allergen-induced asthma. PMID- 23943463 TI - Generation of bone marrow and fetal liver chimeric mice. AB - The creation of bone marrow and fetal liver chimeric mice has proven to be a valuable tool in the field of immunology. Chimeric mice are used to study the contribution of various cell types of hematopoietic versus non-hematopoietic origin in the course of an immune response. In this chapter, we describe a detailed method to obtain bone marrow or fetal liver chimeric mice and assess the efficiency of donor cells to repopulate the hematopoietic compartment of recipient mice. PMID- 23943464 TI - Statistical screening of medium components for recombinant production of Pseudomonas aeruginosa ATCC 9027 rhamnolipids by nonpathogenic cell factory Pseudomonas putida KT2440. AB - Rhamnolipids (RLs) produced by the opportunistic human pathogen Pseudomonas aeruginosa are considered as potential candidates for the next generation of surfactants. Large-scale production of RLs depends on progress in strain engineering, medium design, operating strategies, and purification procedures. In this work, the rhlAB genes extracted from a mono_RLs_producing strain of P. aeruginosa (ATCC 9027) were introduced to an appropriate safety host Pseudomonas putida KT2440. The capability of the recombinant strain was evaluated in various media. As a prerequisite for optimal medium design, a set of 32 experiments was performed in two steps for screening a number of macro-nutritional compounds. In the experiments, a two-level fractional factorial design resolution IV was followed by a two-level full factorial one. By means of this approach, it was observed that glycerol, yeast extract, and peptone have significant positive influence on recombinant RLs production while the yeast extract/peptone two factor and glycerol/yeast extract/peptone three-factor interactions have considerable negative effects. A wide range of variation from 0 to 570 mg/l was obtained for RLs production during the screening experiments indicating the importance of medium optimization. The results point out the opportunity for possible higher yields of RLs through further screening, mixture/combined mixture designs, and high-cell-density cultivations. PMID- 23943465 TI - Androgen activity and markers of inflammation among men in NHANES III. AB - OBJECTIVES: Inflammation contributes to chronic diseases. Lower serum testosterone among men is associated with less inflammation, yet immune defense is thought to trade-off against reproduction with androgens adversely affecting immune function. Anti-androgens are effective at castrate levels of serum testosterone, suggesting serum testosterone may not capture all androgen activity. The association of two androgen biomarkers with key markers of inflammation was examined. METHODS: The adjusted association of serum testosterone and androstanediol glucuronide with C-reactive protein, white blood cell, granulocyte and lymphocyte count, fibrinogen, and hemoglobin, as a control outcome because testosterone administration raises hemoglobin, were examined in a nationally representative sample of 1,490 US men from the National Health and Nutrition Examination Survey III phase 1 (1988-1991) using multivariable linear regression. RESULTS: Serum testosterone and androstanediol glucuronide were weakly correlated (0.13). Serum testosterone was associated with lower white blood cell count [-0.26 * 10(-9) per standard deviation, 95% confidence interval (CI) -0.37 to -0.14] and granulocyte count (-0.21 * 10(-9) , 95% CI -0.29 to 0.13) but not with hemoglobin (0.02 g/l, 95% CI -0.89 to 0.92), adjusted for age, education, race/ethnicity, smoking, and alcohol. Similarly adjusted, androstanediol glucuronide was not associated with white blood cell count (0.10 * 10(-9) , 95% CI -0.05 to -0.25), granulocyte count (0.12 * 10(-9) , 95% CI -0.02 to 0.25), or fibrinogen (0.05 g/l, 95% CI -0.004 to 0.11), but was with hemoglobin (0.70 g/l, 95% CI 0.07 to 1.32). CONCLUSIONS: Different androgen biomarkers had different associations with inflammatory markers, highlighting the need to consider several androgen biomarkers. The possibility remains that androgens may generate inflammatory processes with implications for chronic diseases. PMID- 23943466 TI - Effect of morphine and SIV on dendritic cell trafficking into the central nervous system of rhesus macaques. AB - Recruitment of immune cells such as monocytes/macrophages and dendritic cells (DCs) across the blood-brain barrier (BBB) has been documented in diseases involving neuroinflammation. Neuroinvasion by HIV leads to neurocognitive diseases and alters the permeability of the BBB. Likewise, many HIV patients use drugs of abuse such as morphine, which can further compromise the BBB. While the role of monocytes and macrophages in neuroAIDS is well established, research demonstrating the presence and role of DCs in the CNS during HIV infection has not been developed yet. In this respect, this study explored the presence of DCs in the brain parenchyma of rhesus macaques infected with a neurovirulent form of SIV (SIV mac239 R71/17E) and administered with morphine. Cells positive for DC markers including CD11c (integrin), macDC-SIGN (dendritic cell-specific ICAM-3 grabbing nonintegrin), CD83 (a maturation factor), and HLA-DR (MHC class II) were consistently found in the brain parenchyma of SIV-infected macaques as well as infected macaques on morphine. Control animals did not exhibit any DC presence in their brains. These results provide first evidence of DCs' relevance in NeuroAIDS vis-a-vis drugs of abuse and open new avenues of understanding and investigative HIV-CNS inflictions. PMID- 23943468 TI - Improved neurocognitive test performance in both arms of the SMART study: impact of practice effect. AB - We evaluated factors associated with improvement in neurocognitive performance in 258 HIV-infected adults with baseline CD4 lymphocyte counts above 350 cells/mm3 randomized to intermittent, CD4-guided antiretroviral therapy (ART) (128 participants) versus continuous therapy (130) in the Neurology substudy of the Strategies for Management of Antiretroviral Therapy trial. Participants were enrolled in Australia, North America, Brazil, and Thailand, and neurocognitive performance was assessed by a five-test battery at baseline and month 6. The primary outcome was change in the quantitative neurocognitive performance z score (QNPZ-5), the average of the z scores of the five tests. Associations of the 6 month change in test scores with ART use, CD4 cell counts, HIV RNA levels, and other factors were determined using multiple regression models. At baseline, median age was 40 years, median CD4 cell count was 513 cells/mm3, 88 % had plasma HIV RNA <= 400 copies/mL, and mean QNPZ-5 was -0.68. Neurocognitive performance improved in both treatment groups by 6 months; QNPZ-5 scores increased by 0.20 and 0.13 in the intermittent and continuous ART groups, respectively (both P < 0.001 for increase and P = 0.26 for difference). ART was used on average for 3.6 and 5.9 out of the 6 months in the intermittent and continuous ART groups, respectively, but the increase in neurocognitive test scores could not be explained by ART use, changes in CD4, or plasma HIV RNA, which suggests a practice effect. The impact of a practice effect after 6 months emphasizes the need for a control group in HIV studies that measure intervention effects using neurocognitive tests similar to ours. PMID- 23943467 TI - Immunological control of herpes simplex virus infections. AB - Herpes simplex virus type 1 (HSV-1) is capable of causing a latent infection in sensory neurons that lasts for the lifetime of the host. The primary infection is resolved following the induction of the innate immune response that controls replication of the virus until the adaptive immune response can clear the active infection. HSV-1-specific CD8(+) T cells survey the ganglionic regions containing latently infected neurons and participate in preventing reactivation of HSV from latency. The long-term residence and migration dynamics of the T cells in the trigeminal ganglia appear to distinguish them from the traditional memory T cell subsets. Recently described tissue resident memory (TRM) T cells establish residence and survive for long periods in peripheral tissue compartments following antigen exposure. This review focuses on the immune system response to HSV-1 infection. Particular emphasis is placed on the evidence pointing to the HSV-1-specific CD8(+) T cells in the trigeminal belonging to the TRM class of memory T cells and the role of TRM cells in virus infection, pathogenesis, latency, and disease. PMID- 23943470 TI - Is depression simply a nonspecific response to brain injury? AB - Depressive disorders are among the most common ailments affecting humankind and some of the world's leading causes of medical disability. Despite being common, disabling and a major public health problem, the etiology of depression is unknown. Indeed, investigators have suggested that the causes of depression are multiple and multi-factorial. With these considerations in mind, in this article we examine the hypothesis that our inability to identify the causes of depressive disorders is because depression is a nonspecific epiphenomenon of brain injury or insult arising through multiple pathways. PMID- 23943469 TI - Neuroimmunological aspects of human T cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis. AB - Human T cell leukemia virus type 1 (HTLV-1) is a human retrovirus etiologically associated with adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Only approximately 0.25-4 % of infected individuals develop HAM/TSP; the majority of infected individuals remain lifelong asymptomatic carriers. Recent data suggest that immunological aspects of host-virus interactions might play an important role in the development and pathogenesis of HAM/TSP. This review outlines and discusses the current understanding, ongoing developments, and future perspectives of HAM/TSP research. PMID- 23943473 TI - Advanced photoassisted atomic switches produced using ITO nanowire electrodes and molten photoconductive organic semiconductors. AB - Photoassisted atomic switches (PASs) are those produced using photoconductive organic materials. However, the use of solid photoconductive materials and the formation of a large Ag conductive bridge lead to the formation of large voids during the shrinking of Ag conductive bridges; this may degrade the performance of PASs. A low-melting-point organic semiconductor is used as a molten photoconductive material, and self-assembled ITO nanowires are used as transparent electrodes. Stable atomic switching is observed only under light irradiation. PMID- 23943472 TI - Presence of diadenosine polyphosphates in microdialysis samples from rat cerebellum in vivo: effect of mild hyperammonemia on their receptors. AB - Diadenosine triphosphate (Ap(3)A), diadenosine tetraphosphate (Ap(4)A), and diadenosine pentaphosphate (Ap(5)A) have been identified in microdialysis samples from the cerebellum of conscious freely moving rats, under basal conditions, by means of a high-performance liquid chromatography method. The occurrence of Ap(3)A in the cerebellar microdyalisates is noteworthy, as the presence of this compound in the interstitial medium in neural tissues has not been previously described. The concentrations measured for the diadenosine polyphosphates in the cerebellar dialysate were (in nanomolar) 10.5 +/- 2.9, 5.4 +/- 1.2, and 5.8 +/- 1.3 for Ap(3)A, Ap(4)A, and Ap(5)A, respectively. These concentrations are in the range that allows the activation of the presynaptic dinucleotide receptor in nerve terminals. However, a possible interaction of these dinucleotides with other purinergic receptors cannot be ruled out, as rat cerebellum expresses a variety of P2X or P2Y receptors susceptible to be activated by diadenosine polyphosphates, such as the P2X1-4, P2Y(1), P2Y(2), P2Y(4), and P2Y(12) receptors, as demonstrated by quantitative real-time PCR. Also, the ecto nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP3, able to hydrolyze the diadenosine polyphosphates and terminate their extracellular actions, are expressed in the rat cerebellum. All these evidences contribute to reinforce the role of diadenosine polyphosphates as signaling molecules in the central nervous system. Finally, we have analyzed the possible differences in the concentration of diadenosine polyphosphates in the cerebellar extracellular medium and changes in the expression levels of their receptors and hydrolyzing enzymes in an animal model of moderate hyperammonemia. PMID- 23943471 TI - Integrative medicine for treating depression: an update on the latest evidence. AB - Integrative medicine (IntM) is a growing medical trend combining conventional medical approaches with evidence-based complementary therapies to promote well being. Over half of individuals with depression use some form of IntM for symptom management. The purpose of the current study was to critically review the scientific evidence for IntM techniques in treating adult unipolar depression. We examined randomized controlled trials, systematic reviews, and meta-analyses published in the last one to three years using PsychINFO, PubMed, and Cochrane Library databases. The strongest evidence currently exists for mindfulness-based interventions and St. John's Wort (SJW) as monotherapies, and there is relatively strong evidence to support the use of omega-3 fatty acids and exercise as adjunct therapies. However, there remains an overall lack of methodologically rigorous research to support the efficacy of many other IntM techniques. Providers should be aware that many patients use IntM techniques for depression treatment and inquire regularly about such use. PMID- 23943475 TI - Solid-phase peptide synthesis: an introduction. AB - This chapter provides an introduction to and overview of peptide chemistry with a focus on solid-phase peptide synthesis. The background, the most common reagents, and some mechanisms are presented. This chapter also points to the different chapters and puts them into perspective. PMID- 23943474 TI - Improving peptide relative quantification in MALDI-TOF MS for biomarker assessment. AB - Proteomic profiling by MALDI-TOF MS presents various advantages (speed of analysis, ease of use, relatively low cost, sensitivity, tolerance against detergents and contaminants, and possibility of automation) and is being currently used in many applications (e.g. peptide/protein identification and quantification, biomarker discovery, and imaging MS). Earlier studies by many groups indicated that moderate reproducibility in relative peptide quantification is a major limitation of MALDI-TOF MS. In the present work, we examined and demonstrate a clear effect, in cases apparently random, of sample dilution in complex samples (urine) on the relative quantification of peptides by MALDI-TOF MS. Results indicate that in urine relative abundance of peptides cannot be assessed with confidence based on a single MALDI-TOF MS spectrum. To account for this issue, we developed and propose a novel method of determining the relative abundance of peptides, taking into account that peptides have individual linear quantification ranges in relation to sample dilution. We developed an algorithm that calculates the range of dilutions at which each peptide responds in a linear manner and normalizes the received peptide intensity values accordingly. This concept was successfully applied to a set of urine samples from patients diagnosed with diabetes presenting normoalbuminuria (controls) and macroalbuminuria (cases). PMID- 23943476 TI - Linkers, resins, and general procedures for solid-phase peptide synthesis. AB - This chapter describes the basic protocols for solid-phase peptide synthesis using the Fmoc group as the N (alpha)-protecting group (Fmoc-SPPS). The chapter introduces resins and their handling, choice of linkers, and the most common methods for peptide chain assembly. The proper choice of resins and linkers for solid-phase synthesis is a key parameter for successful peptide synthesis. This chapter provides an overview of the most common and useful resins and linkers for the synthesis of peptides with C-terminal amides, carboxylic acids, and more. The chapter finishes with robust protocols for general solid-phase peptide synthesis, i.e., the standard operations. PMID- 23943477 TI - Peptide release, side-chain deprotection, work-up, and isolation. AB - After having successfully synthesized a peptide, it has to be released from the solid support, unless it is being used for on-resin display. The linker and, in some cases, the cleavage mixture determine the C-terminal functionality of the released peptide. In most cases, the peptide is released with concomitant removal of side-chain protecting groups. However, some combinations of linkers and side chain protecting groups enable a two-stage procedure, either using orthogonal chemistry or graduated labilities. Herein, we describe protocols for the release of peptides from the most commonly used linker types providing a variety of different C-terminal functionalities, including acids, amides, amines, and aldehydes. Moreover, suggestions for determination of peptide purity and for storage conditions are provided. PMID- 23943478 TI - Synthesis of peptides using tert-butyloxycarbonyl (Boc) as the alpha-amino protection group. AB - The use of the tert-butyloxycarbonyl (Boc) as the Nalpha-amino protecting group in peptide synthesis can be advantageous in several cases, such as synthesis of hydrophobic peptides and peptides containing ester and thioester moieties. The primary challenge of using Boc SPPS is the need for treatment of the resin-bound peptide with hazardous hydrogen fluoride (HF), which requires special equipment. PMID- 23943479 TI - Sequential formation of regioselective disulfide bonds in synthetic peptides with multiple disulfide bonds. AB - Numerous methods have been developed for the formation of disulfide bonds in recombinant DNA-derived and chemically synthesized peptides and proteins, but only a few have found widespread acceptance. The choice of method(s) for formation of disulfide in synthetic peptides and proteins needs to be tailored for each individual polypeptide in such a way so that the reaction conditions are selective, efficient, and safe and give the maximum yield. Here we describe the sequential formation of three disulfide bonds regioselectively which has been optimized for the synthesis of two-chained, heterodimeric polypeptide members of the insulin-relaxin superfamily. PMID- 23943480 TI - Synthesis of cyclic disulfide-rich peptides. AB - In this chapter we describe two SPPS approaches for producing cyclic disulfide rich peptides in our laboratory, including cyclotides from plants, cyclic conotoxins from cone snail venoms, chlorotoxin from scorpion venom, and the sunflower trypsin inhibitor peptide, SFTI-1. PMID- 23943481 TI - Preparation of C-terminally modified chemokines by expressed protein ligation. AB - In order to link structural features on a molecular level to the function of chemokines, site-specific modification strategies are strongly required. These can be used to incorporate fluorescent dyes and/or physical probes to allow investigations in a wide range of biological and physical techniques, e.g., nuclear magnetic resonance (NMR) spectroscopy, fluorescence microscopy, fluorescence resonance energy transfer (FRET), or fluorescence correlation spectroscopy (FCS). Only a limited number of functional groups within the 20 canonical amino acids allow ligation strategies that can be helpful to introduce novel functionalities, which in turn expand the scope of chemoselective and orthogonal reactivity of (semi)synthetic chemokines. In the present chapter we mainly focus on the fabulous history of native chemical ligation (NCL) and provide a general protocol for the preparation of C-terminally modified SDF 1alpha including tips and tricks for practical work. We believe that this protocol can be easily adapted to other chemokines and many proteins in general. PMID- 23943482 TI - Synthesis of C-terminal peptide thioesters using Fmoc-based solid-phase peptide chemistry. AB - This chapter provides two protocols for the solid-phase synthesis of peptide thioesters using N (alpha) -Fmoc-protected amino acids. The first protocol is based on a so-called safety-catch linker, while the second relies on a backbone amide linker. PMID- 23943483 TI - Backbone amide linker strategy: protocols for the synthesis of C-terminal peptide aldehydes. AB - In the backbone amide linker (BAL) strategy, the peptide is anchored not at the C terminus but through a backbone amide, which leaves the C-terminal available for various modifications. This is thus a very general strategy for the introduction of C-terminal modifications. The BAL strategy was originally developed using a trisalkoxybenzyl linker, but since then range linkers (handles) with different properties have also been developed. The BAL anchoring is established by anchoring an aromatic aldehyde, typically a trisalkoxybenzaldehyde, to the solid support, followed by attachment of the first amino acid residue by reductive amination. This can be used as a general approach for the introduction of other C terminal modifications as well as functionalities, such as fluorophors. The second step is an acylation of a secondary amine, followed by standard Fmoc-based solid-phase synthesis to assemble the final peptide. One useful application of this strategy is in the synthesis of C-terminal peptide aldehydes. The C-terminal aldehyde is masked as an acetal during synthesis and then conveniently demasked in the final cleavage step to generate the free aldehyde. Another application is in the synthesis of peptide thioesters with a C-terminal glycine. PMID- 23943484 TI - Synthesis of N-methylated peptides: on-resin methylation and microwave-assisted couplings. AB - N-methylation may positively influence the pharmacokinetic properties of peptides by improving oral availability and in vivo half-life. Additionally, target affinity and specificity may be improved. Here, we describe the solid-phase N methylation of peptides using direct alkylation. This method allows a rapid N methyl scan of synthetic, bioactive peptides. Additionally, a microwave-enhanced method for the difficult coupling onto the methylated N terminus is provided. PMID- 23943485 TI - Synthesis of antimicrobial peptoids. AB - Peptoids (N-substituted glycines) are mimics of alpha-peptides in which the side chains are attached to the backbone N (alpha) -amide nitrogen instead of the C (alpha) -atom. Peptoids hold promise as therapeutics since they often retain the biological activity of the parent peptide and are stable to proteases. In recent years, peptoids have attracted attention as new potential antibiotics against multiresistant bacteria. Here we describe the submonomer solid-phase synthesis of an antimicrobial peptoid, H-Nmbn-Nlys-Nlys-Nnap-Nbut-Nmbn-Nlys-NH2. PMID- 23943486 TI - Synthesis of lipidated peptides. AB - One of the main reasons of the high diversity and complexity of the human proteome compared to the human genome is the extensive work performed by the posttranslational machinery to incorporate numerous different functionalities on proteins. The covalent attachment of chemical moieties in proteins after translation is known as posttranslational modification (PTM) and has a crucial role in controlling protein localization and activity. Relevant modifications include phosphorylation, carboxymethylation, glycosylation, acetylation, or lipidation. Despite their essential role on protein function, the synthesis of fully posttranslationally modified proteins has been challenging. However, important advances on chemical biology have enabled the synthesis of fully posttranslationally modified peptides and proteins. As a result of this, peptides bearing, i.e., phosphorylated amino acids, C-terminal methylations, lipid modifications, or nonnatural tags have become accessible. These peptides, as well as the corresponding proteins obtained using ligation techniques, have been invaluable tools in biochemical and biophysical studies. As an example of these advances, this chapter describes the methods developed for the synthesis of lipidated peptides from the Ras and Rab families. PMID- 23943487 TI - Solid-phase synthesis of phosphopeptides. AB - Phosphopeptides are generally prepared by incorporation of suitable, protected phosphoamino acid derivatives during peptide synthesis using routine coupling protocols. The feasibility of chemical synthesis of phosphorylated peptides by Fmoc-SPPS was greatly enhanced by the introduction of the monobenzyl protecting group for the phosphate group. This minimized beta-elimination of the phosphate group and made Fmoc-based synthesis of phosphopeptides the preferred synthesis strategy. Described here is our strategy for the synthesis of phosphopeptides attached to the solid support PEGA via a backbone amide linker type. This linker allows removal of side-chain protection groups without releasing the phosphopeptide from the solid support, thus enabling solid-phase-based pull-down reactions and peptide-protein interaction studies. PMID- 23943488 TI - Synthesis of O-glycopeptides and construction of glycopeptide microarrays. AB - O-glycosylation of proteins is an important modification which affects biological function and immunity. In this chapter, we provide protocols for efficient solid phase O-glycopeptide synthesis (SPGPS) and protocols for the construction of glycopeptide microarray chips for screening applications. This will be exemplified for mucin-type glycopeptides and the construction of glycopeptide microarrays. To this end, the protocols provided are particularly suited for small-scale robotic parallel synthesis. N-Terminal amine capping of deletion peptides during synthesis stands out as vital to this strategy. It allows for direct on-slide enrichment of the full-length target product and thereby bypasses tedious isolation and purification procedures. PMID- 23943489 TI - Instruments for automated peptide synthesis. AB - This chapter provides an introduction to and an overview of current instrumentation for solid-phase peptide synthesis (SPPS). Presently, the two most common designs differ in their mode of liquid handling: the first relies on valves and valve blocks for distribution of reagents, while the second uses a robotic platform. They also differ in their mode of mixing the reactants in the reaction vessel, where the former can utilize sparging, 180 degrees rotational shaking, or vortexing, while the latter typically uses vortexing. Valve-based instruments are often single channel (one peptide at a time), but can also be expanded to allow parallel synthesis of up to 12 and even 24 peptides, however, at the price of added complexity. Valve systems often use inert gas for their operation. The X-Y robotic platforms are ideal for parallel synthesis of large numbers of peptides up to 192 and even peptide libraries. However, although less common, the robotic platform is also very suitable for single-channel operation and can also be used for operations under inert gas. Some single-channeled synthesizers are available with UV feedback monitoring of the Fmoc removal which can be useful for some applications. Importantly, single-channel synthesizers can be equipped with fast and precise microwave heating to accelerate the synthesis and to overcome synthetic difficulties. A whole range of synthesizers with different designs are commercially available. The choice of peptide synthesizer will depend on intended application, for example on the type of chemistry, scale, and the number of peptides that are required and so on. PMID- 23943490 TI - Microwave-assisted solid-phase peptide synthesis using the biotage Syro WaveTM. AB - Fast and precise heating by microwave irradiation during solid-phase peptide synthesis (SPPS) can reduce reaction times as well as provide better purities and greater yields for the synthesis of difficult peptides. Microwave- assisted SPPS has proven to be a useful and reliable tool for the synthesis of peptides as well as small proteins. It is particularly well suited for sequences with a high propensity to form beta-sheet-type structures and for sterically difficult couplings. In this protocol, conditions and detailed procedures are described for performing microwave-assisted SPPS using the Syro WaveTM. Here we describe the synthesis of two difficult peptide sequences: the first is derived from the C terminus of the MuLV CTL epitope, the second is a de novo designed peptide with a C-terminal alkyne. PMID- 23943491 TI - Microwave-assisted solid-phase peptide synthesis based on the Fmoc protecting group strategy (CEM). AB - Microwave-assisted peptide synthesis has become one of the most widely used tools by peptide chemists for the synthesis of both routine and difficult peptide sequences. Microwave technology significantly reduces the synthesis time while also improving the quality of the peptides produced. Microwave energy allows most amino acid couplings to be completed in just 5 min. The Fmoc removal can also be accelerated in the microwave decreasing the reaction time from at least 15 min to only 3 min in most cases. Common side reactions such as racemization and aspartimide formation are easily controllable with optimized methods that can be applied routinely. This protocol outlines the detailed procedure for performing both manual and automated microwave-assisted peptide synthesis of two difficult peptide sequences, ACP (65-74) and beta-amyloid, in high purity and yield. PMID- 23943492 TI - A 2-yr service report of cell line authentication. PMID- 23943495 TI - A resol-assisted co-assembly approach to crystalline mesoporous niobia spheres for electrochemical biosensing. AB - Templated pores: A resol-assisted solvent-evaporation-induced self-assembly (RA EISA) gives unique ordered mesoporous niobia spheres by using the amphiphilic diblock copolymer PEO-b-PS as a template. The mesoporous Nb2O5 spheres have ordered hexagonal structures, large pore size and high surface area, and a nanocrystalline framework. They show excellent electrochemical sensing of hydrogen peroxide. PMID- 23943496 TI - The cost-effectiveness of using financial incentives to improve provider quality: a framework and application. AB - Despite growing adoption of pay-for-performance (P4P) programmes in health care, there is remarkably little evidence on the cost-effectiveness of such schemes. We review the limited number of previous studies and critique the frameworks adopted and the narrow range of costs and outcomes considered, before proposing a new more comprehensive framework, which we apply to the first P4P scheme introduced for hospitals in England. We emphasise that evaluations of cost-effectiveness need to consider who the residual claimant is on any cost savings, the possibility of positive and negative spillovers, and whether performance improvement is a transitory or investment activity. Our application to the Advancing Quality initiative demonstrates that the incentive payments represented less than half of the L 13 m total programme costs. By generating approximately 5200 quality-adjusted life years and L 4.4 m of savings in reduced length of stay, we find that the programme was a cost-effective use of resources in its first 18 months. PMID- 23943497 TI - Textures shape the attentional focus: evidence from exogenous and endogenous cueing. AB - The spatial cueing paradigm (Posner Quarterly Journal of Experimental Psychology 32:3-25, 1980) has often been used to investigate the time course of the deployment of visual attention in space. In a series of eight experiments we investigated whether spatial cues would not only enhance processing of stimuli presented at cued locations, but also enhance processing of the entire texture in which the stimuli were presented. Results showed highest accuracy for responses to stimuli presented at cued locations, a replication of the traditional cueing effect (Posner 1980). Additionally, stimuli presented at uncued locations were responded to with higher accuracy when they were presented inside the same texture as the cued location, as compared with stimuli presented outside the texture with the cued location. To investigate this texture advantage for both automatic and voluntary attention deployment, exogenous and endogenous cues were used. The texture advantage was observed for short interstimulus intervals (ISIs) of 50 and 100 ms for exogenous cues and for a longer ISI of 200 ms for endogenous cues. These findings indicate that the arrangement of task-irrelevant visual stimuli also can have a large impact on the cueing effect. This suggests that visual spatial attention spreads texture-wise across the visual field. Control experiments revealed that the homogeneity within texture elements contributes most to the effect but that the texture advantage is a function of both orientation contrast at the texture border and homogeneity within texture elements. PMID- 23943494 TI - Genetics and epigenetics of systemic lupus erythematosus. AB - Genetics unquestionably contributes to systemic lupus erythematosus (SLE) predisposition, progression and outcome. Nevertheless, single-gene defects causing lupus-like phenotypes have been infrequently documented. The majority of the identified genetic SLE risk factors are, therefore, common variants, responsible for a small effect on the global risk. Recently, genome wide association studies led to the identification of a growing number of gene variants associated with SLE susceptibility, particular disease phenotypes, and antibody profiles. Further studies addressed the biological effects of these variants. In addition, the role of epigenetics has recently been revealed. These combined efforts contributed to a better understanding of SLE pathogenesis and to the characterization of clinically relevant pathways. In this review, we describe SLE-associated single-gene defects, common variants, and epigenetic changes. We also discuss the limitations of current methods and the challenges that we still have to face in order to incorporate genomic and epigenomic data into clinical practice. PMID- 23943498 TI - The time course of temporal attention effects on nonconscious prime processing. AB - We presented a masked prime at various prime-target intervals (PTIs) before a target that required a speeded motor response and investigated the impact of temporal attention on the nonconscious prime processing. The allocation of temporal attention to the target was manipulated by presenting an accessory tone and comparing that condition with a no-tone condition. The results showed that, independently of the visibility of the prime, temporal attention led to an enhanced effect of prime-target congruency on the reaction times, and that the amount of the enhancement increased with increasing PTIs. This effect pattern is consistent with the assumption of increasing influences of temporal attention and of the increasing PTI on nonconscious prime processing; it argues against the hypothesis that temporal attention narrows the time period in which the prime may affect target processing. An accumulator model is proposed assuming that target related temporal attention increases the accumulation rate for masked primes and, thus, enhances the impact of the prime on the speed of choice decisions. PMID- 23943499 TI - Colavita dominance effect revisited: the effect of semantic congruity. AB - To investigate the effect of semantic congruity on audiovisual target responses, participants detected a semantic concept that was embedded in a series of rapidly presented stimuli. The target concept appeared as a picture, an environmental sound, or both; and in bimodal trials, the audiovisual events were either consistent or inconsistent in their representation of a semantic concept. The results showed faster detection latencies to bimodal than to unimodal targets and a higher rate of missed targets when visual distractors were presented together with auditory targets, in comparison to auditory targets presented alone. The findings of Experiment 2 showed a cross-modal asymmetry, such that visual distractors were found to interfere with the accuracy of auditory target detection, but auditory distractors had no effect on either the speed or the accuracy of visual target detection. The biased-competition theory of attention (Desimone & Duncan Annual Review of Neuroscience 18: 1995; Duncan, Humphreys, & Ward Current Opinion in Neurobiology 7: 255-261 1997) was used to explain the findings because, when the saliency of the visual stimuli was reduced by the addition of a noise filter in Experiment 4, visual interference on auditory target detection was diminished. Additionally, the results showed faster and more accurate target detection when semantic concepts were represented in a visual rather than an auditory format. PMID- 23943500 TI - Apparent causality affects perceived simultaneity. AB - The present research addresses the question of how visual predictive information and implied causality affect audio-visual synchrony perception. Previous research has shown a systematic shift in the likelihood of observers to accept audio leading stimulus pairs as being apparently simultaneous in variants of audio visual stimulus pairs that differ in (1) the amount of visual predictive information available and (2) the apparent causal relation between the auditory and visual components. An experiment was designed to separate the predictability and causality explanations, and the results indicated that shifts in subjective simultaneity were explained completely by changes in the implied causal relations in the stimuli and that predictability had no added value. Together with earlier findings, these results further indicate that the observed shifts in subjective simultaneity due to causal relations among auditory and visual events do not reflect a mere change in response strategy, but rather result from early multimodal integration processes in event perception. PMID- 23943493 TI - Purinergic signalling in the musculoskeletal system. AB - It is now widely recognised that extracellular nucleotides, signalling via purinergic receptors, participate in numerous biological processes in most tissues. It has become evident that extracellular nucleotides have significant regulatory effects in the musculoskeletal system. In early development, ATP released from motor nerves along with acetylcholine acts as a cotransmitter in neuromuscular transmission; in mature animals, ATP functions as a neuromodulator. Purinergic receptors expressed by skeletal muscle and satellite cells play important pathophysiological roles in their development or repair. In many cell types, expression of purinergic receptors is often dependent on differentiation. For example, sequential expression of P2X5, P2Y1 and P2X2 receptors occurs during muscle regeneration in the mdx model of muscular dystrophy. In bone and cartilage cells, the functional effects of purinergic signalling appear to be largely negative. ATP stimulates the formation and activation of osteoclasts, the bone destroying cells. Another role appears to be as a potent local inhibitor of mineralisation. In osteoblasts, the bone-forming cells, ATP acts via P2 receptors to limit bone mineralisation by inhibiting alkaline phosphatase expression and activity. Extracellular ATP additionally exerts significant effects on mineralisation via its hydrolysis product, pyrophosphate. Evidence now suggests that purinergic signalling is potentially important in several bone and joint disorders including osteoporosis, rheumatoid arthritis and cancers. Strategies for future musculoskeletal therapies might involve modulation of purinergic receptor function or of the ecto-nucleotidases responsible for ATP breakdown or ATP transport inhibitors. PMID- 23943501 TI - The Cdk inhibitor flavopiridol enhances temozolomide-induced cytotoxicity in human glioma cells. AB - The recent progress in chemotherapy for malignant gliomas is attributable to the introduction of the DNA-methylating agent temozolomide (TMZ); however, drug resistance remains a major issue. Previous studies have shown that TMZ induces prolonged arrest of human glioma cells in the G2/M phase of the cell cycle followed by a senescence-like phenomenon or mitotic catastrophe. These findings suggest that the G2 checkpoint is linked to DNA repair mechanisms. We investigated the effect of a cyclin-dependent kinase (Cdk) inhibitor flavopiridol (FP) that inhibits the action of Cdc2, a key protein in the G2 checkpoint pathway, on TMZ-treated glioma cells. Colony formation efficiency revealed that FP potentiated the cytotoxicity of TMZ in glioma cells in a p53-independent manner. This effect was clearly associated with the suppression of key proteins at the G2-M transition, accumulation of the cells exclusively at the G2 phase, and increase in a double-stranded DNA break marker (seen on performing immunoblotting). TMZ-resistant clones showed activation of the G2 checkpoint in response to TMZ, while FP treatment resensitized these clones to TMZ. FP also enhanced the cytotoxicity of TMZ in U87MG-AktER cells. Moreover, administration of TMZ and/or FP to nude mice with xenografted U87MG cells revealed that FP sensitized xenografted U87MG cells to TMZ in these mice. Our findings suggest that TMZ resistance could be promoted by enhanced DNA repair activity in the G2-M transition and that a Cdk inhibitor could suppress this activity, leading to potentiation of TMZ action on glioma cells. PMID- 23943502 TI - MiR-29c inhibits glioma cell proliferation, migration, invasion and angiogenesis. AB - Previous studies reported that miR-29c is significantly downregulated in several tumors. However, little is known about the effect and molecular mechanisms of action of miR-29c in human glioma. Using quantitative RT-PCR, we demonstrated that miR-29c was significantly downregulated in glioma cell lines and human primary glioma tissues, compared to normal human astrocytes and matched non-tumor associated tissues (P < 0.05, chi(2) test). Overexpression of miR-29c dramatically reduced the proliferation and caused cessation of cell cycle. The reduced cell proliferation is due to G1 phase arrest as cyclin D1 and cyclin E are diminished whereas p27 and p21 are upregulated. We further demonstrated that miR-29c overexpression suppressed the glioma cell migration and invasion abilities by targeting MMP-2. In addition, we also found that overexpression of miR-29c sharply inhibited angiogenesis, which correlated with down-regulation of VEGF. The data indicate that miR-29c may be a tumor suppressor involved in the progression of glioma. PMID- 23943503 TI - Magnolol induces apoptosis via caspase-independent pathways in non-small cell lung cancer cells. AB - Magnolol, a hydroxylated biphenyl agent isolated from herbal planet Magnolia officinalis, is a component of traditional Asian herbal teas. It has been reported to have anti-microbial, anti-inflammatory, and anti-cancer activity. Non small cell lung cancer (NSCLC) cell lines (A549, H441 and H520) and normal human bronchial epithelial cells (HBECs) were used to evaluate the cytotoxic effect of magnolol. We show that magnolol inhibited cellular proliferation, increased DNA fragmentation, and decreased mitochondrial membrane potential in all NSCLC cells, but had no cytotoxic effect on HBECs. Magnolol triggered the release of pro apoptotic proteins: Bid, Bax and cytochrome c from mitochondria, but did not activate the caspase-3, -8, and -9, suggesting that magnolol induces apoptosis of NSCLC cell lines via a caspase-independent pathway. The caspase-independent pathway is mediated through the activation of nuclear translocation of apoptosis inducing factor, endonuclease G and cleaved poly(ADP-ribose) polymerase, which played important roles in mediating cell death. Furthermore, magnolol inhibited PI3K/AKT and ERK1/2 activity, but up-regulated p38 and JNK activity in A549 cell lines. The results of this study provided a basis for understanding and developing magnolol as a novel treatment of NSCLC. PMID- 23943505 TI - In-depth proteomic analysis of mouse microglia using a combination of FASP and StageTip-based, high pH, reversed-phase fractionation. AB - Microglia are major immune cells in the central nervous system. A characterization of microglia proteome would facilitate on the study of microglial functions in association with various neurodegenerative diseases. To build a reference proteome, we established a BV-2 microglial proteome to a depth of 5494 unique protein groups using a novel strategy that combined FASP, StageTip based high pH fractionation, and high-resolution MS quickly and cost efficiently. By bioinformatics analysis, the BV-2 proteome is a valuable resource for studies of microglial function, such as in the immune response, inflammatory response, and phagocytosis. All MS data have been deposited in the ProteomeXchange with identifier PXD000168. PMID- 23943504 TI - A new model for developmental neuronal death and excitatory/inhibitory balance in hippocampus. AB - The nervous system develops through a program that produces neurons in excess and then eliminates approximately half during a period of naturally occurring death. Neuronal activity has been shown to promote the survival of neurons during this period by stimulating the production and release of neurotrophins. In the peripheral nervous system (PNS), neurons depends on neurotrophins that activate survival pathways, which explains how the size of target cells influences number of neurons that innervate them (neurotrophin hypothesis). However, in the central nervous system (CNS), the role of neurotrophins has not been clear. Contrary to the neurotrophin hypothesis, a recent study shows that, in neonatal hippocampus, neurotrophins cannot promote survival without spontaneous network activity: Neurotrophins recruit neurons into spontaneously active networks, and this activity determines which neurons survive. By placing neurotrophin upstream of activity in the survival signaling pathway, these new results change our understanding of how neurotrophins promote survival. Spontaneous, synchronized network activity begins to spread through both principle neurons and interneurons in the hippocampus as they enter the death period. At this stage, neurotransmission mediated by gamma-aminobutyric acid (GABA) is excitatory and drives the spontaneous activity. An important recent observation is that neurotrophins preferentially recruit GABAergic neurons into spontaneously active networks; thus, neurotrophins select for survival only those neurons joined to active networks with strong GABAergic inputs, which would later become inhibitory. A proper excitatory/inhibitory (E/I) balance is critical for normal adult brain function. This balance may be especially important in the hippocampus where impairments in E/I balance are associated with pathologies including epilepsy. Here, I discuss the molecular mechanisms for survival in neonatal neurons, how these mechanisms change during development, and how they may be linked to degenerative diseases. PMID- 23943506 TI - The ethanol extract isolated from Weiqi Decoction induces G2/M arrest and apoptosis in AGS cells. AB - OBJECTIVE: To evaluate the effects of the ethanol extract isolated from Weiqi Decoction (WQD-EE) on AGS cell proliferation and apoptosis. METHODS: By using high-performance liquid chromatography with ultraviolet detectors (HPLC-UV) assay and MTT method, the main compounds in WQD-EE and cell viability were detected. And cell cycle distributions were determined by flow cytometry with propidium iodine (PI) staining while apoptosis was detected by flow cytometry with annexin V/PI double staining. Finally, caspase-3 activities were measured by colorimetric method and protein expression was determined by Western blotting. RESULTS: HPLC analysis showed that naringin (35.92 MUg/mg), nobiletin (21.98 MUg/mg), neohesperidin (17.98 MUg/mg) and tangeretin (0.756 MUg/mg) may be the main compounds in WQD-EE. WQD-EE not only inhibited AGS and MCF 7 cell proliferation in a dose-dependent manner, but also blocked cell cycle progression at G2/M stage as well as inducing cell apoptosis at concentrations triggering significant inhibition of proliferation and cell cycle arrest in AGS cells. While at 0.5 mg/mL, WQD-EE significantly increased caspase-3 activity by 2.75 and 7.47 times at 24 h and 48 h, respectively. Moreover, WQD-EE in one hand reduced protein expressions of p53 and cyclin B1, and in other hand enhanced protein expressions of cytochrome c and Bax. Protein levels of Bcl-2, Fas L and Fas were not significantly affected by WQD-EE. CONCLUSIONS: WQD-EE inhibits AGS cell proliferation through G2/M arrest due to down-regulation of cyclin B1 protein expression, and promotes apoptosis by caspase-3 and mitochondria-dependent pathways, but not by p53-dependent pathway. PMID- 23943507 TI - Quality assessment of clinical research on liver cancer treated by intra-arterial infusion of Chinese medicine. AB - OBJECTIVE: To assess the methodological quality of clinical research on Chinese medicine (CM) applied by intra-arterial infusion in treating primary liver cancer (PLC). METHODS: Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and three Chinese databases, including Chinese BioMedical Database (CBM), China National Knowledge Infrastructure (CNKI) and China Academic Journal (VIP) were searched. Chinese articles were also searched manually in 16 journals. Two reviewers independently selected studies, the quality of literatures were assessed according to the Cochrane Collaboration method of quality assessment. RESULTS: A total of 14 articles met the inclusion criteria for this review. Only three of these articles described the randomization method used. None of the studies was blinded. All of the articles didn't report the calculation of the sample size. Only six studies mentioned adverse reactions. All of the studies were of grade C according to the Cochrane Collaboration method. Six studies reported results of survival, and only two of these reported better efficacy in the treatment groups. CONCLUSIONS: The quality of studies concerned intra arterial infusion of CM in treating with PLC was poor and the exact effect of these medicines still need evaluation. Well designed RCTs with large sample sizes, adequate follow-up data and reliable methods of assessment are needed to better appraise the real effect of CMs in the treatment of PLC patients. PMID- 23943508 TI - Semiconducting polymer nanoprobe for in vivo imaging of reactive oxygen and nitrogen species. PMID- 23943509 TI - Myofascial trigger points of the pelvic floor: associations with urological pain syndromes and treatment strategies including injection therapy. AB - Myofascial trigger points (MTrP), or muscle "contraction knots," of the pelvic floor may be identified in as many as 85 % of patients suffering from urological, colorectal and gynecological pelvic pain syndromes; and can be responsible for some, if not all, symptoms related to these syndromes. Identification and conservative treatment of MTrPs in these populations has often been associated with impressive clinical improvements. In refractory cases, more "aggressive" therapy with varied trigger point needling techniques, including dry needling, anesthetic injections, or onabotulinumtoxinA injections, may be used, in combination with conservative therapies. PMID- 23943510 TI - Reduced DHPRalpha1S and RyR1 expression levels are associated with diaphragm contractile dysfunction during sepsis. AB - INTRODUCTION: Sepsis often causes diaphragm contractile dysfunction. Dihydropyridine receptors (DHPRalpha1s and DHPRalpha1c) and ryanodine receptors (RyR1, RyR2, and RyR3) are essential for excitation-contraction coupling in striated muscles. However, their expression in diaphragm during sepsis have not been explored. METHODS: Eight rats received endotoxin, and 8 more rats received placebo. After 24 hours, 3) diaphragm isometric contractile force was measured. The mRNA and protein levels of DHPRs and RyRs in diaphragm muscles were determined. RESULTS: Sepsis weakened diaphragm contractile function. The expression levels of DHPRalpha1s and RyR1 were significantly lower in septic rats than in control rats. The expression levels of DHPRalpha1c and RyR3 were unaffected by sepsis. RyR2 was undetectable at both mRNA and protein levels in the control and sepsis groups. CONCLUSIONS: Weakened diaphragm contraction in the septic rats was associated with reduced mRNA and protein expression of DHPRalpha1s and RyR1, the isoforms of skeletal muscles. PMID- 23943511 TI - Defect-rich MoS2 ultrathin nanosheets with additional active edge sites for enhanced electrocatalytic hydrogen evolution. AB - Defect-rich MoS2 ultrathin nanosheets are synthesized on a gram scale for electrocatalytic hydrogen evolution. The novel defect-rich structure introduces additional active edge sites into the MoS2 ultrathin nanosheets, which significantly improves their electrocatalytic performance. Low onset overpotential and small Tafel slope, along with large cathodic current density and excellent durability, are all achieved for the novel hydrogen-evolution reaction electrocatalyst. PMID- 23943512 TI - Computational heterogeneity in the human mesencephalic dopamine system. AB - Recent evidence in animals has indicated that the mesencephalic dopamine system is heterogeneous anatomically, molecularly, and functionally, and it has been suggested that the dopamine system comprises distinct functional systems. Identifying and characterizing these systems in humans will have widespread ramifications for understanding drug addiction and mental health disorders. Model based studies in humans have suggested an analogous computational heterogeneity, in which dopaminergic targets in striatum encode both experience-based learning signals and counterfactual learning signals that are based on hypothetical information. We used brainstem-tailored fMRI to identify mesencephalic sources of experiential and counterfactual learning signals. Participants completed a decision-making task based on investing in markets. This sequential investment task generated experience-based learning signals, in the form of temporal difference (TD) reward prediction errors, and counterfactual learning signals, in the form of "fictive errors." Fictive errors are reinforcement learning signals based on hypothetical information about "what could have been." An additional learning signal was constructed to be relatable to a motivational salience signal. Blood oxygenation level dependent responses in regions of substantia nigra (SN) and ventral tegmental area (VTA), where dopamine neurons are located, coded for TD and fictive errors, and additionally were related to the motivational salience signal. These results are highly consistent with animal electrophysiology and provide direct evidence that human SN and VTA heterogeneously handle important reward-harvesting computations. PMID- 23943513 TI - The role of kinematics in cortical regions for continuous human motion perception. AB - It has been proposed that we make sense of the movements of others by observing fluctuations in the kinematic properties of their actions. At the neural level, activity in the human motion complex (hMT+) and posterior superior temporal sulcus (pSTS) has been implicated in this relationship. However, previous neuroimaging studies have largely utilized brief, diminished stimuli, and the role of relevant kinematic parameters for the processing of human action remains unclear. We addressed this issue by showing extended-duration natural displays of an actor engaged in two common activities, to 12 participants in an fMRI study under passive viewing conditions. Our region-of-interest analysis focused on three neural areas (hMT+, pSTS, and fusiform face area) and was accompanied by a whole-brain analysis. The kinematic properties of the actor, particularly the speed of body part motion and the distance between body parts, were related to activity in hMT+ and pSTS. Whole-brain exploratory analyses revealed additional areas in posterior cortex, frontal cortex, and the cerebellum whose activity was related to these features. These results indicate that the kinematic properties of peoples' movements are continually monitored during everyday activity as a step to determining actions and intent. PMID- 23943514 TI - Dynamics of alpha oscillations elucidate facial affect recognition in schizophrenia. AB - Impaired facial affect recognition is characteristic of schizophrenia and has been related to impaired social function, but the relevant neural mechanisms have not been fully identified. The present study sought to identify the role of oscillatory alpha activity in that deficit during the process of facial emotion recognition. Neuromagnetic brain activity was monitored while 44 schizophrenia patients and 44 healthy controls viewed 5-s videos showing human faces gradually changing from neutral to fearful or happy expressions or from the neutral face of one poser to the neutral face of another. Recognition performance was determined separately by self-report. Relative to prestimulus baseline, controls exhibited a 10- to 15-Hz power increase prior to full recognition and a 10- to 15-Hz power decrease during the postrecognition phase. These results support recent proposals about the function of alpha-band oscillations in normal stimulus evaluation. The patients failed to show this sequence of alpha power increase and decrease and also showed low 10- to 15-Hz power and high 10- to 15-Hz connectivity during the prestimulus baseline. In light of the proposal that a combination of alpha power increase and functional disconnection facilitates information intake and processing, the finding of an abnormal association of low baseline alpha power and high connectivity in schizophrenia suggests a state of impaired readiness that fosters abnormal dynamics during facial affect recognition. PMID- 23943515 TI - Attention biases and habituation of attention biases are associated with 5-HTTLPR and COMTval158met. AB - Fundamental biases in affective information processing are modulated by individual differences in the emotional response to environmental stimuli that may be partly based on the individual's genetic make-up. To extend prior dot probe studies on attention genetics, we used a visual-search paradigm (VSP) with pictures of angry and happy faces of both sexes as targets, neutral faces as distractors, and a varying set size. Participants were selected a priori depending on their 5-HTTLPR (s/s, s/l, l/l; on a constant rs25531 A-allele background) and COMTval158met (val/val, valmet, met/met) genotypes and were matched for sex and age. We demonstrate a bias towards angry male faces (as opposed to happy male faces) irrespective of 5-HTTLPR genotype in the first experimental block that was maintained during the second experimental block only in carriers of the s-allele, which implies differential habituation processes. While a bias towards angry male faces was observed irrespective of COMTval158met genotype, only individuals with the val/val genotype exhibited a bias towards a happy female face (as opposed to an angry female face). In sum, our results both replicate and extend prior findings in the field of attention genetics and add important pieces of information to the research on attentional biases in emotion processing. PMID- 23943516 TI - Isolation rearing effects on probabilistic learning and cognitive flexibility in rats. AB - Isolation rearing is a neurodevelopmental manipulation that produces neurochemical, structural, and behavioral alterations in rodents that in many ways are consistent with schizophrenia. Symptoms induced by isolation rearing that mirror clinically relevant aspects of schizophrenia, such as cognitive deficits, open up the possibility of testing putative therapeutics in isolation reared animals prior to clinical development. We investigated what effect isolation rearing would have on cognitive flexibility, a cognitive function characteristically disrupted in schizophrenia. For this purpose, we assessed cognitive flexibility using between- and within-session probabilistic reversal learning tasks based on clinical tests. Isolation-reared rats required more sessions, though not more task trials, to acquire criterion performance in the reversal phase of the task, and were slower to adjust their task strategy after reward contingencies were switched. Isolation-reared rats also completed fewer trials and exhibited lower levels of overall activity in the probabilistic reversal-learning task than did the socially reared rats. This finding contrasted with the elevated levels of unconditioned investigatory activity and reduced levels of locomotor habituation that isolation-reared rats displayed in the behavioral pattern monitor. Finally, isolation-reared rats also exhibited sensorimotor gating deficits, reflected by decreased prepulse inhibition of the startle response, consistent with previous studies. We concluded that isolation rearing constitutes a valuable, noninvasive manipulation for modeling schizophrenia-like cognitive deficits and assessing putative therapeutics. PMID- 23943517 TI - The impact of technological intensity of service provision on physician expenditures: an exploratory investigation. AB - Advances in technology and subsequent changes in clinical practice can lead to increases in healthcare costs. Our objective is to assess the impact that changes in the technological intensity of physician-provided health services have had on the age pattern of both the volume of services provided and the average expenditures associated with them. We based our analysis on age-sex-specific patient-level administrative records of diagnoses and treatments. These records include virtually all physician services provided in the province of Ontario, Canada in a 10-year span ending in 2004 and their associated costs. An algorithm is developed to classify services and their costs into three levels of technological intensity. We find that while the overall age-standardized level and cost of services per capita have decreased, the volume and cost of high technologically intensive treatments have increased, especially among older patients. PMID- 23943519 TI - A tribute to Hans Kummer (1930-2013). PMID- 23943518 TI - Glycogen synthase kinase-3beta is involved in electroacupuncture pretreatment via the cannabinoid CB1 receptor in ischemic stroke. AB - We have previously shown that electroacupuncture (EA) pretreatment produces neuroprotective effects, which were mediated through an endocannabinoid signal transduction mechanism. Herein, we have studied the possible contribution of the phosphorylated form of glycogen synthase kinase-3beta (GSK-3beta) in EA pretreatment-induced neuroprotection via the cannabinoid CB1 receptor (CB1R). Focal transient cerebral ischemia was induced by middle cerebral artery occlusion in rats. Phosphorylation of GSK-3beta at Ser-9 [p-GSK-3beta (Ser-9)] was evaluated in the penumbra tissue following reperfusion. Infarct size and neurological score were assessed in the presence of either PI3K inhibitors or a GSK-3beta inhibitor 72 h after reperfusion. Cellular apoptosis was evidenced by TUNEL staining and determination of the Bax/Bcl-2 ratio 24 h after reperfusion. The present study showed that EA pretreatment increased p-GSK-3beta(Ser-9) 2 h after reperfusion in the ipsilateral penumbra. Augmented phosphorylation of GSK 3beta induced similar neuroprotective effects as did EA pretreatment. By contrast, inhibition of PI3K dampened the levels of p-GSK-3beta(Ser-9), and reversed not only the neuroprotective effect but also the anti-apoptotic effect following EA pretreatment. Regulation of GSK-3beta by EA pretreatment was abolished following treatment with a CB1R antagonist and CB1R knockdown, whereas two CB1R agonists enhanced the phosphorylation of GSK-3beta. Therefore we conclude that EA pretreatment protects against cerebral ischemia/reperfusion injury through CB1R-mediated phosphorylation of GSK-3beta. PMID- 23943520 TI - Spinocerebellar ataxias in Brazil--frequencies and modulating effects of related genes. AB - This study describes the frequency of spinocerebellar ataxias and of CAG repeats range in different geographical regions of Brazil, and explores the hypothetical role of normal CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 genes on age at onset and on neurological findings. Patients with symptoms and family history compatible with a SCA were recruited in 11 cities of the country; clinical data and DNA samples were collected. Capillary electrophoresis was performed to detect CAG lengths at SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA12, SCA17, and DRPLA associated genes, and a repeat primed PCR was used to detect ATTCT expansions at SCA10 gene. Five hundred forty-four patients (359 families) were included. There were 214 SCA3/MJD families (59.6 %), 28 SCA2 (7.8 %), 20 SCA7 (5.6 %), 15 SCA1 (4.2 %), 12 SCA10 (3.3 %), 5 SCA6 (1.4 %), and 65 families without a molecular diagnosis (18.1 %). Divergent rates of SCA3/MJD, SCA2, and SCA7 were seen in regions with different ethnic backgrounds. 64.7 % of our SCA10 patients presented seizures. Among SCA2 patients, longer ATXN3 CAG alleles were associated with earlier ages at onset (p < 0.036, linear regression). A portrait of SCAs in Brazil was obtained, where variation in frequencies seemed to parallel ethnic differences. New potential interactions between some SCA-related genes were presented. PMID- 23943522 TI - Decreased succinate dehydrogenase activity of gamma and alpha motoneurons in mouse spinal cords following 13 weeks of exposure to microgravity. AB - Cell body size and succinate dehydrogenase activity of motoneurons in the dorsolateral region of the ventral horn in the lumbar and cervical segments of the mouse spinal cord were assessed after long-term exposure to microgravity and compared with those of ground-based controls. Mice were housed in a mouse drawer system on the International Space Station for 13 weeks. The mice were transported to the International Space Station by the Space Shuttle Discovery and returned to Earth by the Space Shuttle Atlantis. No changes in the cell body size of motoneurons were observed in either segment after exposure to microgravity, but succinate dehydrogenase activity of small-sized (<300 MUm(2)) gamma and medium sized (300-700 MUm(2)) alpha motoneurons, which have higher succinate dehydrogenase activity than large-sized (>700 MUm(2)) alpha motoneurons, in both segments was lower than that of ground-based controls. We concluded that exposure to microgravity for longer than 3 months induced decreased succinate dehydrogenase activity of both gamma and slow-type alpha motoneurons. In particular, the decreased succinate dehydrogenase activity of gamma motoneurons was observed only after long-term exposure to microgravity. PMID- 23943521 TI - Non-invasive cerebellar stimulation--a consensus paper. AB - The field of neurostimulation of the cerebellum either with transcranial magnetic stimulation (TMS; single pulse or repetitive (rTMS)) or transcranial direct current stimulation (tDCS; anodal or cathodal) is gaining popularity in the scientific community, in particular because these stimulation techniques are non invasive and provide novel information on cerebellar functions. There is a consensus amongst the panel of experts that both TMS and tDCS can effectively influence cerebellar functions, not only in the motor domain, with effects on visually guided tracking tasks, motor surround inhibition, motor adaptation and learning, but also for the cognitive and affective operations handled by the cerebro-cerebellar circuits. Verbal working memory, semantic associations and predictive language processing are amongst these operations. Both TMS and tDCS modulate the connectivity between the cerebellum and the primary motor cortex, tuning cerebellar excitability. Cerebellar TMS is an effective and valuable method to evaluate the cerebello-thalamo-cortical loop functions and for the study of the pathophysiology of ataxia. In most circumstances, DCS induces a polarity-dependent site-specific modulation of cerebellar activity. Paired associative stimulation of the cerebello-dentato-thalamo-M1 pathway can induce bidirectional long-term spike-timing-dependent plasticity-like changes of corticospinal excitability. However, the panel of experts considers that several important issues still remain unresolved and require further research. In particular, the role of TMS in promoting cerebellar plasticity is not established. Moreover, the exact positioning of electrode stimulation and the duration of the after effects of tDCS remain unclear. Future studies are required to better define how DCS over particular regions of the cerebellum affects individual cerebellar symptoms, given the topographical organization of cerebellar symptoms. The long-term neural consequences of non-invasive cerebellar modulation are also unclear. Although there is an agreement that the clinical applications in cerebellar disorders are likely numerous, it is emphasized that rigorous large-scale clinical trials are missing. Further studies should be encouraged to better clarify the role of using non-invasive neurostimulation techniques over the cerebellum in motor, cognitive and psychiatric rehabilitation strategies. PMID- 23943524 TI - A high-throughput sample preparation method for cellular proteomics using 96-well filter plates. AB - A high-throughput sample preparation protocol based on the use of 96-well molecular weight cutoff (MWCO) filter plates was developed for shotgun proteomics of cell lysates. All sample preparation steps, including cell lysis, buffer exchange, protein denaturation, reduction, alkylation and proteolytic digestion are performed in a 96-well plate format, making the platform extremely well suited for processing large numbers of samples and directly compatible with functional assays for cellular proteomics. In addition, the usage of a single plate for all sample preparation steps following cell lysis reduces potential samples losses and allows for automation. The MWCO filter also enables sample concentration, thereby increasing the overall sensitivity, and implementation of washing steps involving organic solvents, for example, to remove cell membranes constituents. The optimized protocol allowed for higher throughput with improved sensitivity in terms of the number of identified cellular proteins when compared to an established protocol employing gel-filtration columns. PMID- 23943523 TI - The expression and release of Hsp60 in 6-OHDA induced in vivo and in vitro models of Parkinson's disease. AB - In Parkinson's disease, dopaminergic neuron damage/death causes the release of soluble substances that are selectively toxic to neighboring/additional dopaminergic neurons through the activation of microglia. Hsp60 can be released from injured cells of central nervous system to activate microglia. However, its expression and role in Parkinson's disease has not been well understood. Here, we performed a 6-OHDA treated Parkinson's disease model in adult rats. Western blot analysis showed a time-course expression of Hsp60, which decreased gradually and then rose back. Immunofluorescence staining showed that Hsp60 was decreased in dopaminergic neuron, and most Hsp60 located on the surface of activated microglia. Furthermore, in cellular Parkinson's disease model, Hsp60 was obviously detected in the culture supernatants after 6-OHDA treatment, and a concomitant decrease in cell extracts. Taken together, our results suggested that Hsp60 could be released extracellularly to activate microglia in Parkinson's disease model. PMID- 23943525 TI - Advancing the concept of moral distress. PMID- 23943526 TI - Photochemical double 5-exo cyclization of alkenyl-substituted dithienylacetylenes: efficient synthesis of diarylated dithienofulvalenes. AB - Smooth and selective: Upon photoirradiation, bis(3-alkenyl-2-thienyl)acetylenes smoothly and selectively undergo double 5-exo-dig cyclization to produce a series of thiophene-fused pentafulvalenes with various aryl substituents. In this fused pi-conjugated skeleton, the fused thiophene rings and the aryl substituents significantly modulate the electronic structure of the pentafulvalene skeleton. PMID- 23943530 TI - Composite electrospun nanofibers for influencing stem cell fate. AB - The design of new bioactive materials, provided with "instructive properties" and able to regulate stem cell behavior, is the goal for several research groups involved in tissue engineering. This new function, commonly reserved for growth factors, can lead to the development of a new class of implantable scaffolds, useful for accelerating tissue regeneration in a controlled manner. In this scenario, the likely most versatile and effective tools for the realization of such scaffolds are based on nano- and microtechnology. Here, we show how exploiting the electrostatic spinning (ES) technique for producing a nanofibrillar composite structure, by mimicking topographically the extracellular matrix environment, can influence the fate of human bone marrow mesenchymal stem cells, inducing osteogenic differentiation in the absence of chemical treatments or cellular reprogramming. Basic cues on the choice of the materials and useful experimental instructions for realizing composite nanofibrous scaffolds will be given as well as fundamental tips. PMID- 23943527 TI - Hip dysplasia is more severe in Charcot-Marie-Tooth disease than in developmental dysplasia of the hip. AB - BACKGROUND: Patients with Charcot-Marie-Tooth disease may develop hip dysplasia. Hip geometry in these patients has not been well described in the literature. QUESTIONS/PURPOSES: We compared the hip morphometry in Charcot-Marie-Tooth hip dysplasia (CMTHD) and developmental dysplasia of the hip (DDH) in terms of extent of (1) acetabular dysplasia and subluxation, (2) acetabular anteversion and osseous support, (3) coxa valga and femoral version, and (4) osteoarthritis. METHODS: Fourteen patients with CMTHD (19 hips; mean age, 23 years) presenting for periacetabular osteotomy were matched to 45 patients with DDH (45 hips; mean age, 21 years) based on age, sex, and BMI. We assessed acetabular dysplasia and subluxation using lateral center-edge angle (LCEA), anterior center-edge angle (ACEA), and acetabular roof angle of Tonnis (TA) on plain pelvic radiographs and acetabular volume, area of femoral head covered by acetabulum, and percentage of femoral head covered by acetabulum on three-dimensional CT reconstruction models. Acetabular version and bony support, femoral version, and neck-shaft angle were measured on two-dimensional axial CT scans. Hip osteoarthritis was graded radiographically according to Tonnis criteria. RESULTS: Acetabular dysplasia was more severe in CMTHD, as measured by smaller LCEA (p < 0.001), ACEA (p < 0.001), and acetabular volume (p = 0.0178) and larger TA (p = 0.025). Hip subluxation was more pronounced in CMTHD, as demonstrated by lower area of femoral head covered by acetabulum (p = 0.034) and percentage of femoral head covered by acetabulum (p = 0.007). CMTHD was associated with higher acetabular anteversion (p < 0.001), lower anterior (p < 0.001) and posterior (p = 0.072) osseous support, and more severe coxa valga (p < 0.001). More (p = 0.006) arthritic hips were found in CMTHD. CONCLUSIONS: The extent of acetabular dysplasia, hip subluxation, acetabular anteversion, coxa valga, and hip osteoarthritis was more severe in CMTHD. These findings are important in choosing the appropriate surgical strategy for patients affected by CMTHD. PMID- 23943531 TI - Mesenchymal stem cells and nano-structured surfaces. AB - Mesenchymal stem cells (MSCs) represent multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage cells), and adipocytes (fat cells). Their multi-potency provides a great promise as a cell source for tissue engineering and cell-based therapy for many diseases, particularly bone diseases and bone formation. To be able to direct and modulate the differentiation of MSCs into the desired cell types in situ in the tissue, nanotechnology is introduced and used to facilitate or promote cell growth and differentiation. These nano-materials can provide a fine structure and tuneable surface in nanoscales to help the cell adhesion and promote the cell growth and differentiation of MSCs. This could be a dominant direction in future for stem cells based therapy or tissue engineering for various diseases. Therefore, the isolation, manipulation, and differentiation of MSCs are very important steps to make meaningful use of MSCs for disease treatments. In this chapter, we have described a method of isolating MSC from human bone marrow, and how to culture and differentiate them in vitro. We have also provided research methods on how to use MSCs in an in vitro model and how to observe MSC biological response on the surface of nano-scaled materials. PMID- 23943529 TI - Treatment of femoral head osteonecrosis in the United States: 16-year analysis of the Nationwide Inpatient Sample. AB - BACKGROUND: Many surgical interventions are used to treat osteonecrosis of the femoral head. The instance and distribution of these various procedures may give some insight into the practicing community's understanding of the efficacy of these treatments. We therefore sought to determine trends in the types and numbers of procedures performed for atraumatic osteonecrosis from 1992 through 2008 in the United States. QUESTIONS/PURPOSES: (1) How has the overall incidence of surgical treatment for atraumatic osteonecrosis changed over this time period; and (2) how has the percentage of THA performed for osteonecrosis (compared with joint-preserving procedures) changed over this time period? METHODS: The Nationwide Inpatient Sample database was used to collect information for all patients who had an International Classification of Diseases, 9(th) Revision diagnosis of hip osteonecrosis between 1992 and 2008. Procedures were collated according to frequency, and trends were analyzed for joint-preserving and joint replacing procedures. RESULTS: The total number of procedures performed over this time period for osteonecrosis of the hip increased from 3570 procedures to 6400 procedures per year. In 1992, 75% (n = 2678) of the procedures performed to treat osteonecrosis of the hip were THA, which increased to 88% (n = 5632) in 2008. The percentage of joint-preserving procedures consequently decreased from 25% to 12% over this period. CONCLUSIONS: Previously, THA was believed to have poor survivorship and clinical results for the treatment of osteonecrosis of the hip, but reports since 1993 have suggested improved survivorship of these reconstructions. Our study suggests that surgeons have incorporated this into their practice patterns, in that an increasing percentage of patients with this diagnosis are treated with THA. Additionally, the total number of procedures performed for osteonecrosis has increased, which may reflect an improved awareness of this disease and more aggressive approaches to diagnosis and treatment. PMID- 23943532 TI - Analytical glycomics. PMID- 23943533 TI - Norberto Guzman, PH.D., M.SC. - happy 65th birthday. PMID- 23943539 TI - The January effect: medication reinitiation among Medicare Part D beneficiaries. AB - The Medicare prescription drug program (Part D) standard benefit includes deductible, initial coverage, coverage gap and catastrophic coverage phases. As beneficiaries enter each phase, their out-of-pocket medication costs change discontinuously. The benefit cycle restarts on 1 January of the next year. Taking advantage of variation in drug coverage, we study how individuals reinitiate discontinued medications in response to the non-linear price schedule. Because some beneficiaries who receive low-income subsidies (LIS) have zero or fixed small copayments throughout the year, we perform a difference-in-difference analysis by using the LIS group as a comparison. We find that individuals delay reinitiating important medications in December and are significantly more likely to reinitiate in January than in other months. Although we find some evidence that reinitiation is lower in the final months of the year, it is mostly driven by those who face higher prices due to the coverage gap. Our study suggests that individuals respond more to the current price of medications and do not anticipate future prices as well as theory would suggest. PMID- 23943540 TI - Fabrication of red-blood-cell-like polyelectrolyte microcapsules and their deformation and recovery behavior through a microcapillary. AB - Multilayer microcapsules with a biconcave discoidal shape mimicking red blood cells (RBCs) are fabricated. The structure of the RBC-like microcapsules is verified by scanning electron and confocal laser scanning microscopies. The capsules show elastic deformation after being forced through a microcapillary with a smaller diameter, exhibiting a high recovery ratio of ~90%. When the capsules are coated with hemoglobin (Hb),they are able to reversibly bind and release oxygen. PMID- 23943541 TI - A history of morphine-induced taste aversion learning fails to affect morphine induced place preference conditioning in rats. AB - Drugs of abuse have both rewarding and aversive effects, as indexed by the fact that they support place preferences and taste aversions, respectively. In the present study, we explored whether having a history with the aversive effects of morphine (via taste aversion conditioning) impacted the subsequent rewarding effects of morphine, as measured in the place preference design. In Experiment 1, rats were exposed to a taste aversion procedure in which saccharin was followed by morphine. Place preference conditioning was then initiated in which animals were injected with morphine and placed on one side of a two-chambered apparatus. Animals with a taste aversion history acquired place preferences to the same degree as controls without such a history, suggesting that morphine's affective properties condition multiple effects, dependent on the specific stimuli present during conditioning. To determine whether these results were a reflection of processes operating in traditional associative conditioning, in a modified blocking procedure, place preference conditioning was attempted in the presence of a taste previously associated with morphine (Exp. 2). Under these conditions, animals still acquired morphine-induced place preferences comparable to those of animals without a morphine or conditioning history. These results are consistent with the position that drugs of abuse have multiple stimulus effects (positive and negative) that are differentially associated with specific stimuli (environmental and taste) that drive different behavioral responses (approach and avoidance). PMID- 23943542 TI - Nanobubble ultrasound contrast agents for enhanced delivery of thermal sensitizer to tumors undergoing radiofrequency ablation. AB - PURPOSE: Pluronic has been shown to sensitize various tumor cell lines to chemotherapy and hyperthermia by altering the membrane fluidity, depleting ATP, and modulating the heat shock protein 70 expression. In our prior work, Pluronic was also used to formulate nanosized ultrasound contrast agents. In the current study we evaluate the use of these contrast agents as vehicles for image-guided delivery of Pluronic to improve outcomes of tumor radiofrequency (RF) ablation. METHODS: Lipid-shelled Pluronic nanobubbles were prepared and examined for size distribution, zeta potential, stability, biodistribution, accumulation of nanobubbles in the tumor, and treatment efficacy. LS174-T xenograft tumor-bearing mice were used to evaluate tumor growth suppression and measure treatment efficacy after RF ablation. RESULTS: The average diameter of Pluronic bubbles was 230 nm, and initial bubble echogenicity was 16 dB. In vitro, cells exposed to Pluronic nanobubbles exhibited low cytotoxicity in the absence of ultrasound, even if heat (43 oC) was applied. When the cells were exposed to Pluronic nanobubbles, heat, and ultrasound; viability was significantly reduced. In vivo, tumors treated with ultrasound-modulated nanobubbles prior to RF ablation showed a significant reduction in growth compared to the RF alone (P<0.05). CONCLUSION: Lipid and Pluronic-shelled, echogenic nanobubbles combined with ultrasound modulation can serve as an effective theranostic method for sensitization of tumors to RF ablation. PMID- 23943543 TI - Optimization of naltrexone diclofenac codrugs for sustained drug delivery across microneedle-treated skin. AB - PURPOSE: The purpose of this work was to optimize the structure of codrugs for extended delivery across microneedle treated skin. Naltrexone, the model compound was linked with diclofenac, a nonspecific cyclooxygenase inhibitor to enhance the pore lifetime following microneedle treatment and develop a 7 day transdermal system for naltrexone. METHODS: Four different codrugs of naltrexone and diclofenac were compared in terms of stability and solubility. Transdermal flux, permeability and skin concentration of both parent drugs and codrugs were quantified to form a structure permeability relationship. RESULTS: The results indicated that all codrugs bioconverted in the skin. The degree of conversion was dependent on the structure, phenol linked codrugs were less stable compared to the secondary alcohol linked structures. The flux of naltrexone across microneedle treated skin and the skin concentration of diclofenac were higher for the phenol linked codrugs. The polyethylene glycol link enhanced solubility of the codrugs, which translated into flux enhancement. CONCLUSION: The current studies indicated that formulation stability of codrugs and the flux of naltrexone can be enhanced via structure design optimization. The polyethylene glycol linked naltrexone diclofenac codrug is better suited for a 7 day drug delivery system both in terms of stability and drug delivery. PMID- 23943544 TI - Molecular basis of crystal morphology-dependent adhesion behavior of mefenamic acid during tableting. AB - PURPOSE: The molecular basis of crystal surface adhesion leading to sticking was investigated by exploring the correlation of crystal adhesion to oxidized iron coated atomic force microscope (AFM) tips and bulk powder sticking behavior during tableting of two morphologically different crystals of a model drug, mefenamic acid (MA), to differences in their surface functional group orientation and energy. METHODS: MA was recrystallized into two morphologies (plates and needles) of the same crystalline form. Crystal adhesion to oxidized iron coated AFM tips and bulk powder sticking to tablet punches was assessed using a direct compression formulation. Surface functional group orientation and energies on crystal faces were modeled using Accelrys Material Studio software. RESULTS: Needle-shaped morphology showed higher sticking tendency than plates despite similar particle size. This correlated with higher crystal surface adhesion of needle-shaped morphology to oxidized iron coated AFM probe tips, and greater surface energy and exposure of polar functional groups. CONCLUSIONS: Higher surface exposure of polar functional groups correlates with higher tendency to stick to metal surfaces and AFM tips, indicating involvement of specific polar interactions in the adhesion behavior. In addition, an AFM method is identified to prospectively assess the risk of sticking during the early stages of drug development. PMID- 23943545 TI - In vitro-in vivo correlation in skin permeation. AB - PURPOSE: In vitro skin permeation studies have been used extensively in the development and optimisation of delivery of actives in vivo. However, there are few reported correlations of such in vitro studies with in vivo data. The aim of this study was to investigate the skin permeation of a model active, niacinamide, both in vitro and in vivo. METHODS: Conventional diffusion cell studies were conducted in human skin to determine niacinamide permeation from a range of vehicles which included dimethyl isosorbide (DMI), propylene glycol (PG), propylene glycol monolaurate (PGML), N-methyl 2-pyrrolidone (NMP), Miglyol 812N(r) (MG), and mineral oil (MO). Single, binary or ternary systems were examined. The same vehicles were subsequently examined to investigate niacinamide delivery in vivo. For this proof-of-concept study one donor was used for the in vitro studies and one volunteer for the in vivo investigations to minimise biovariability. Analysis of in vitro samples was conducted using HPLC and in vivo uptake of niacinamide was evaluated using Confocal Raman spectroscopy (CRS). RESULTS: The amount of niacinamide permeated through skin in vitro was linearly proportional to the intensity of the niacinamide signal determined in the stratum corneum in vivo. A good correlation was observed between the signal intensities of selected vehicles and niacinamide signal intensity. CONCLUSIONS: The findings provide further support for the use of CRS to monitor drug delivery into and across the skin. In addition, the results highlight the critical role of the vehicle and its disposition in skin for effective dermal delivery. PMID- 23943546 TI - Tofacitinib for treatment of rheumatoid arthritis. AB - The management of rheumatoid arthritis has seen a dramatic improvement with the introduction of a range of biological disease modifying anti-rheumatic drugs (DMARDs) in recent years. Nonetheless, a proportion of patients remain resistant or intolerant to multiple conventional and biological DMARDs, so innovative strategies are needed to offer patients new therapeutic options. Tofacitinib is the first of a new class of orally active DMARDs, with immunomodulating effects through inhibition of intracellular Janus kinase (JAK) pathways. It has been recently licensed for treatment of adults with moderate to severe RA in the US, Japan, and Russia. In this review the authors evaluate the efficacy and safety of tofacitinib in RA, focusing predominantly on the phase 3 study data. PMID- 23943548 TI - The X-ray crystal structure of a cuprate-carbonyl pi-complex. PMID- 23943547 TI - Vitamin D deficiency in pregnancy after bariatric surgery. AB - The objective of this study was to describe the main factors related to the installation and/or aggravation of vitamin D deficiency (VDD) and its clinical consequences in pregnant women after bariatric surgery. An electronic search on VDD in pregnancy and after bariatric surgery was conducted in publications from 1998 until 2012 that presented studies performed in humans. We provided an overview of VDD after bariatric surgery, in pregnancy, and in pregnancy in women who underwent bariatric surgery. In view of the high percentage of VDD postoperatively and the role of this vitamin in pregnancy, we recommend the investigation of vitamin D nutritional status in prenatal care. PMID- 23943549 TI - Comments on 'An information criterion for marginal structural models' by R. W. Platt, M. A. Brookhart, S. R. Cole, D. Westreich, and E. F. Schisterman. PMID- 23943550 TI - Reply to taguri and matsuyama. PMID- 23943552 TI - The effect of sex ratios on suicide. AB - Whereas sex ratios are likely to affect the likelihood of marriage, how sex ratios affect health and survival is underexplored. This study uses suicide as a measure of mental health and examines how suicides are affected by sex ratios. As women tend to marry men older than themselves, shrinking populations will lead to higher sex ratios (i.e., higher proportions of men) in the marriage market. Using data from Japan, I find that high sex ratios, both early-life and current, are correlated with higher male suicide rates, whereas female suicide rates are generally not affected. The results of this study have important implications for public health in countries where imbalanced sex ratios are a concern. PMID- 23943551 TI - The emergence of cognitive control abilities in childhood. AB - Cognitive control, otherwise known as executive function, refers to our ability to flexibly adjust or regulate habitual actions or behaviors. As a cluster of separable components, it depends heavily on the prefrontal cortex, one of the last brain regions to reach adult maturity. Cognitive control processes are thought to be among the key factors for scholastic success, and thus, underdeveloped cognitive control abilities might contribute to an achievement gap. In this chapter, we first discuss the prolonged maturation of the prefrontal cortex that leads to delayed emergence of cognitive control abilities in children. We briefly describe some of the functional effects of prolonged maturation of the prefrontal cortex. We then discuss how experience and environmental factors such as education and socioeconomic status may affect the development of cognitive control abilities, before turning to cognitive training interventions as a promising avenue for reducing this cognitive "gap" in both healthy children and those with developmental disabilities. Taken together, our hope is that by understanding the interaction of brain development, environmental factors, and the promise of cognitive interventions in children, this knowledge can help to both guide educational achievement and inform educational policy. PMID- 23943553 TI - An exceptional artificial photocatalyst, Nih -CdSe/CdS core/shell hybrid, made in situ from CdSe quantum dots and nickel salts for efficient hydrogen evolution. AB - A novel hybrid Nih -CdSe/CdS core/shell quantum dot is a simple and exceptional artificial photocatalyst for H2 production from 2-propanol aqueous solution. Studies on the nature of the artificial photocatalyst and mechanism for H2 production demonstrate that the synthetic strategy is general and the artificial photocatalyst holds promise for light capture, electron transfer, and catalysis at the surface of the Nih -CdSe/CdS core/shell quantum dots, leading to a self healing system for H2 evolution in harmony. PMID- 23943554 TI - Absolute pitch memory: its prevalence among musicians and dependence on the testing context. AB - Absolute pitch (AP) is widely believed to be a rare ability possessed by only a small group of gifted and special individuals (AP possessors). While AP has fascinated psychologists, neuroscientists, and musicians for more than a century, no theory can satisfactorily explain why this ability is so rare and difficult to learn. Here, we show that AP ability appears rare because of the methodological issues of the standard pitch-naming test. Specifically, the standard test unnecessarily poses a high decisional demand on AP judgments and uses a testing context that is highly inconsistent with one's musical training. These extra cognitive challenges are not central to AP memory per se and have thus led to consistent underestimation of AP ability in the population. Using the standard test, we replicated the typical findings that the accuracy for general violinists was low (12.38 %; chance level = 0 %). With identical stimuli, scoring criteria, and participants, violinists attained 25 % accuracy in a pitch verification test in which the decisional demand of AP judgment was reduced. When the testing context was increasingly similar to their musical experience, verification accuracy improved further and reached 39 %, three times higher than that for the standard test. Results were replicated with a separate group of pianists. Our findings challenge current theories about AP and suggest that the prevalence of AP among musicians has been highly underestimated in prior work. A multimodal framework is proposed to better explain AP memory. PMID- 23943556 TI - Revisiting absolute and relative judgments in the WITNESS model. AB - The WITNESS model (Clark in Applied Cognitive Psychology 17:629-654, 2003) provides a theoretical framework with which to investigate the factors that contribute to eyewitness identification decisions. One key factor involves the contributions of absolute versus relative judgments. An absolute contribution is determined by the degree of match between an individual lineup member and memory for the perpetrator; a relative contribution involves the degree to which the best-matching lineup member is a better match to memory than the remaining lineup members. In WITNESS, the proportional contributions of relative versus absolute judgments are governed by the values of the decision weight parameters. We conducted an exploration of the WITNESS model's parameter space to determine the identifiability of these relative/absolute decision weight parameters, and compared the results to a restricted version of the model that does not vary the decision weight parameters. This exploration revealed that the decision weights in WITNESS are difficult to identify: Data often can be fit equally well by setting the decision weights to nearly any value and compensating with a criterion adjustment. Clark, Erickson, and Breneman (Law and Human Behavior 35:364-380, 2011) claimed to demonstrate a theoretical basis for the superiority of lineup decisions that are based on absolute contributions, but the relationship between the decision weights and the criterion weakens this claim. These findings necessitate reconsidering the role of the relative/absolute judgment distinction in eyewitness decision making. PMID- 23943555 TI - Crossing the arms confuses the clocks: sensory feedback and the bimanual advantage. AB - The bimanual advantage refers to the finding that tapping with two fingers on opposite hands exhibits reduced timing variability, as compared with tapping with only one finger. Two leading theories propose that the bimanual advantage results from the addition of either sensory (i.e., enhanced feedback) or cognitive (i.e., multiple timekeeper) processes involved in timing. Given that crossing the arms impairs perception of tactile stimuli and modulates cortical activation following tactile stimulation, we investigated the role of crossing the arms in the bimanual advantage. Participants tapped unimanually or bimanually with their arms crossed or uncrossed on a tabletop or in the air. With arms crossed, we expected increased interval timing variance. Similarly, for air tapping, we expected reduced bimanual advantage, due to reduced sensory feedback. A significant bimanual advantage was observed for the uncrossed, but not the crossed posture in tabletop tapping. Furthermore, removing tactile feedback from taps eliminated the bimanual advantage for both postures. Together, these findings suggest that crossing the arms likely impairs integration of internal (i.e., effector specific) and external (i.e., environment-specific) information and that this multisensory integration is crucial to reducing timing variability during repetitive coordinated bimanual tasks. PMID- 23943557 TI - The dud-alternative effect in memory for associations: putting confidence into local context. AB - When participants are asked to provide confidence judgments for each provided alternative in a multiple-choice memory task, such judgments are inflated if the assessed alternatives are accompanied by an implausible (dud) alternative. This finding, termed the dud-alternative effect, has been recently documented in a memory setting with a lineup procedure (Charman, Wells, & Joy, Law & Human Behavior 35:479-500 2011). In the present study, we developed a novel paradigm to investigate the dud-alternative effect in memory. The paradigm utilizes a multiple-choice associative recognition task in which dud alternatives can be rejected on the basis of their unfamiliarity. In two experiments, we demonstrated a reliable dud-alternative effect with our novel procedure. The results demonstrated that the dud-alternative effect in episodic memory is not limited to tasks based on perceptual factors, but is a general phenomenon concerning confidence judgments. PMID- 23943558 TI - [Development and validation of the Informant Assessment of Geriatric Delirium Scale (I-AGeD). Recognition of delirium in geriatric patients]. AB - OBJECTIVES: Delirium is common in older patients admitted to hospital. Information obtained from patient's relatives or caregivers may contribute to improved detection. Our aim was to develop a caregiver based questionnaire, the Informant Assessment of Geriatric Delirium (I-AGeD), to assist in better recognition of delirium in elderly patients. METHODS: A cross-sectional observational study using a scale construction patient cohort and two validation cohorts was conducted at geriatric departments of two teaching hospitals in The Netherlands. Delirium status, based on DSM-IV criteria, was assessed directly on admission by a geriatric resident and evaluated within the first 48 h of admission. Caregivers filled out a 37-item questionnaire of which 10 items were selected reflecting delirium symptoms, based on their discriminatory abilities, internal consistency and inter-item correlations. RESULTS: A total of 88 patients with complete study protocols in the construction cohort were included. Average age was 86.4 (SD 8.5), and 31/88 patients had delirium on admission. Internal consistency of the 10-item I-AGeD was high (Cronbach's alpha = 0.85). At a cut off score of >4 sensitivity was 77.4% and specificity 63.2%. In patients without dementia, sensitivity was 100% and specificity 65.2%. Validation occurred by means of two validation cohorts, one consisted of 59 patients and the other of 33 patients. Sensitivity and specificity in these samples ranged from 70.0% to 88.9% and 66.7% to 100%, respectively. CONCLUSION: The newly constructed caregiver based I-AGeD questionnaire is a valid screening instrument for delirium on admission to hospital in geriatric patients. PMID- 23943560 TI - Comparison of the reactivity of 2-Li-C6H4CH2NMe2 with MCl4 (M=Th, U): isolation of a thorium aryl complex or a uranium benzyne complex. AB - Why do U react like that? Reaction of 2-Li-C6H4CH2NMe2 with [MCl4(DME)n] (M=Th, n=2; M=U, n=0) results in the formation of a thorium aryl complex, [Th(2 C6H4CH2NMe2)4] or a uranium benzyne complex, [Li][U(2,3-C6H3CH2NMe2)(2 C6H4CH2NMe2)3]. A DFT analysis suggests that the formation of a benzyne complex with U but not with Th is a kinetic and not thermodynamic effect. PMID- 23943559 TI - A prospective study on survival in cancer patients with and without venous thromboembolism. AB - Retrospective population-based studies showed that in cancer patients venous thromboembolism (VTE) is associated with reduced survival. Master Oncology is a multicenter study in patients with solid advanced cancer aimed at assessing (1) risk factors for VTE using a case-control design, and (2) survival in cases (patients with VTE) and controls (patients without VTE). Survival data were prospectively collected for at least 10 months. Overall, 237 cases and 339 controls were included in the analysis. The following factors were found to be associated with an increased risk of VTE: body mass index (BMI; OR 2.02; 95% CI 1.31-3.12 for >=26 vs. <23 kg/m(2)), ECOG score (OR 2.14; 95% CI 1.47-3.11 for grade 1, and 3.32; 95% CI 1.64-6.00 for grade 2-3, compared to grade 0) and recent diagnosis of cancer (OR 1.90; 95% CI 1.33-2.71 for <12 vs. >=12 months). After an average prospective observation of 8.3 months, 136 cases (57.4%) and 127 controls (37.5%) died with a median survival of 8.7 (95% CI 7.5-10.9) and 14.3 months (95% CI 12.2-18.7), respectively, (Wilcoxon = 27.72, p < 0.001; multivariate hazard ratio 1.55; 95% CI 1.21-2.00). Median survival time was reduced for both patients with symptomatic (Wilcoxon = 35.22, p < 0.001) and asymptomatic VTE (Wilcoxon = 4.63, p = 0.031). Patients with advanced solid cancer, high BMI, high ECOG score, and recent diagnosis of cancer are associated with an increased risk for VTE. Patients with both symptomatic and asymptomatic VTE have a reduced survival compared to those without VTE. PMID- 23943561 TI - Cost analysis of skeletal-related events in Spanish patients with bone metastases from solid tumours. AB - PURPOSE: To estimate the cost per skeletal-related event (SRE) in patients with bone metastases secondary to solid tumours in the Spanish healthcare setting. METHODS: Patients diagnosed with bone metastases secondary to breast, prostate or lung cancer were included in this multicentre, observational study. SREs are defined as pathologic fracture (vertebral and non-vertebral fracture), radiation to bone, spinal cord compression or surgery to bone. Health resource utilisation associated with these events (inpatient stays, outpatient, emergency room and home health visits, nursing home stays and procedures) were collected retrospectively for all SREs that occurred in the 97 days prior to enrolment and prospectively during follow-up. Unit costs were obtained from the 2010 eSalud healthcare costs database. RESULTS: A total of 93 Spanish patients with solid tumours were included (31 had breast cancer, 21 prostate cancer and 41 lung cancer), contributing a total of 143 SREs to this cost analysis. Inpatient stays (between 9.0 and 29.9 days of mean length of stay per inpatient stay by SRE type) and outpatient visits (between 1.7 and 6.4 mean visits per SRE type) were the most frequently reported types of health resources utilised. The mean cost per SRE was between 2,377.79 (radiation to bone) and 7,902.62 (spinal cord compression). CONCLUSION: SREs are associated with a significant consumption of healthcare resources that generate a substantial economic burden for the Spanish healthcare system. PMID- 23943563 TI - Structural characterization of alumina-supported Rh catalysts: effects of ceriation and zirconiation by using metal-organic precursors. AB - The effects of the addition of ceria and zirconia on the structural properties of supported rhodium catalysts (1.6 and 4 wt % Rh/gamma-Al2O3) are studied. Ceria and zirconia are deposited by using two preparation methods. Method I involves the deposition of ceria on gamma-Al2O3 from Ce(acac)3, and the rhodium metal is subsequently added, whereas method II is based on a controlled surface reaction technique, that is, the decomposition of metal-organic M(acac)x (in which M=Ce, x=3 and M=Zr, x=4) on Rh/gamma-Al2O3. The structures of the prepared catalyst materials are characterized ex situ by using N2 physisorption, transmission electron microscopy, high-angle annular dark-field scanning transmission election microscopy, energy-dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy (XPS), and X-ray absorption fine structure spectroscopy (XAFS). All supported rhodium systems readily oxidize in air at room temperature. By using ceriated and zirconiated precursors, a larger rhodium-based metallic core fraction is obtained in comparison to the undoped rhodium catalysts, suggesting that ceria and zirconia protect the rhodium particles against extensive oxidation. XPS results indicate that after the calcination and reduction treatments, a small amount of chlorine is retained on the support of all rhodium catalysts. EXAFS analysis shows significant Rh-Cl interactions for Rh/Al2O3 and Rh/CeOx /Al2O3 (method I) catalysts. After reaction with H2/He in situ, for series of samples with 1.6 wt % Rh, the EXAFS first shell analysis affords a mean size of approximately 30 atoms. A broader spread is evident with a 4 wt % rhodium loading (ca. 30-110 atoms), with the incorporation of zirconium providing the largest particle sizes. PMID- 23943564 TI - Connectivity. AB - The connectivity of neuronal systems is their most fundamental characteristic. Here, we focus on recent developments in understanding structural and functional connectivity at the macroscale, which is accessible with current imaging technology. Structural connectivity is examined via diffusion weighted imaging methods, of which diffusion tensor imaging is the most frequently used. Many cross-sectional and an increasing number of longitudinal studies using diffusion tensor imaging have been recently conducted over the period of development starting with newborns. Functional connectivity has been studied through task based functional magnetic resonance imaging, and increasingly through studies on task-free functional imaging, also known as resting state functional imaging. The study of intrinsic functional connectivity beginning during fetal life reveals the developmental organization of intrinsic connectivity networks such as the default mode network, the dorsal attention network, the frontal-parietal executive control network, as well as primary cortical networks. As methods of examining both structural and functional connectivity mature, they increasingly inform our understanding of the development of connectivity in service of the long-term goal of delineating the substrates of much of developmental psychopathology. PMID- 23943562 TI - H19 DMR methylation correlates to the progression of esophageal squamous cell carcinoma through IGF2 imprinting pathway. AB - BACKGROUND: H19 gene has been proved to be essential for human tumor growth which contains CpG rich regions. Imprinted gene expression in many cancers is usually associated with the function of methylation. We performed this study to better understand wether H19 DMR methylation correlates to the progression of esophageal squamous cell carcinoma through IGF2 imprinting pathway. METHODS: LOI of IGF2 was detected in 276 samples, which were determined as heterozygote with ApaI polymorphism in exon 9 of IGF2 by PCR-RFLP and RT-PCR-RFLP. Methylation status of H19 DMR in informative samples was analyzed by bisulfite sequencing PCR. IGF2 expression was examined by real-time PCR and IHC. RESULTS: 208 ESCC patients were informative for ApaI polymorphism. 92 tumor and 30 normal tissues showed IGF2 LOI. Methylation status of H19 CBS6 was higher in patients with IGF2 LOI compared to patients with IGF2 MOI (p < 0.05). IGF2 expression in patients with IGF2 LOI was higher than patients with IGF2 MOI (p < 0.05) which was correlated with lymph node involvement, neoplastic grade and metastasis (p < 0.05). CONCLUSIONS: Our results suggested that H19 CBS6 hypermethylation is related to the LOI of IGF2 which usually leads to an overexpression of IGF2, playing important roles in the occurrence, development as well as metastasis of ESCC. Therefore, H19 CBS6 methylation potentially represents a novel clinically relevant epigenetic marker to identify individuals at increased risk for the occurrence, progression and prognosis of ESCC. PMID- 23943565 TI - Variable presentation between a mother and a fetus with Goltz syndrome. PMID- 23943567 TI - From theory to the bedside of the patient: it's a long and devious way to go. PMID- 23943566 TI - Impact factor 2012 for cardiovascular journals: true impact? PMID- 23943569 TI - Synthesis of symmetrical and nonsymmetrical bisthienylcyclopentenes. AB - Diarylethenes possess unique structural properties, which enabled them to find widespread applications in the field of photochromism. Nowadays, bisthienylcyclopentenes (BTCs) present the most popular subfamily of these compounds, which are widely used as P-type chromophores. This minireview summarises the main strategies for the synthesis of symmetrical and nonsymmetrical BTCs. In addition, attention is drawn to desymmetrisations achieved by monosubstitutions, which is not frequently utilised, although it can be highly advantageous. This is supported with some of the authors' latest results. PMID- 23943571 TI - Chronic constipation. AB - The lack of information about management of chronic constipation in children amidst general physicians has necessitated this review. A literature search in PubMed was conducted with regard to epidemiology, clinical features, investigation and management of chronic constipation in children. English language studies published over the last 20 y were considered and relevant information was extracted. Constipation is a common problem among children; the commonest cause is functional (95 %). An elaborate history and thorough physical examination are only essential things required to make a diagnosis of functional constipation. Management consists of disimpaction, followed by maintenance therapy with oral laxative, dietary modification and toilet training. A regular follow-up with slow tapering of laxative is the must for effective treatment. Early withdrawal of laxative is the commonest cause of recurrence. PMID- 23943570 TI - DNA modification under mild conditions by Suzuki-Miyaura cross-coupling for the generation of functional probes. AB - Quick and clean: A method for Pd-catalyzed Suzuki-Miyaura cross-coupling to iododeoxyuridine (IdU) in DNA is described. Key to the reactivity is the choice of the ligand and the buffer. A covalent [Pd]-DNA intermediate was isolated and characterized. Photocrosslinking probes were generated to trap proteins that bind to epigenetic DNA modifications. PMID- 23943572 TI - Editorial: Advances in diagnosis of hematological disorders. PMID- 23943573 TI - Flow cytometry in hematological disorders. AB - Flow cytometry with its rapidly increasing applications is being used essentially in all fields of diagnostic medicine. In hematological disorders it is most commonly used in diagnosis, characterization, prognostication and even selecting target therapy of acute leukemia and to some extent lymphomas. It is increasingly finding place in other fields of hematology i.e., non-malignant disorders of all blood cell types including RBCs and platelets along with leukocytes. In this review the authors have discussed some of these applications with an emphasis on disorders specific to pediatric patients. PMID- 23943574 TI - Factors influencing the television viewing practices of Indian children. AB - OBJECTIVES: To study the effect of socio-demographic factors, parental regulations and maternal television usage on the television viewing practices of Indian schoolchildren. METHODS: Mothers of 6-12 y old children were interviewed using a pre-tested questionnaire at the pediatric outpatient. The television viewing practices of 405 schoolchildren with maternal television viewing and parental television rules were analyzed. Specific television viewing practices considered harmful in the present study were- viewing television >2 h, viewing television just prior to sleep (at bedtime), predominantly viewing general adult channels and using television as an aid to sleep. RESULTS: 35.8 % (n = 145) of the children viewed television for >2 h on schooldays. 20 % (n = 81) used television as sleep-aid. 28.1 % (n = 114) children had televisions in the room they slept. The frequency of parental television rules were with respect to: duration of viewing- 77.5 % (n = 314), timing of viewing- 63.7 % (n = 258), content- 35.6 % (n = 144). The children of families with the rule needing of parental permission to switch on the television [present in 34.8 % (n = 141) children] had lower harmful television viewing practices: duration of television viewing on schooldays >2 h (23.4 %, n = 33, P < 0.001); television viewed just before sleep (39 %, n = 55, P < 0.001); use of television as sleep-aid (12.1 %, n = 17, P = 0.003). 26.7 % (n = 108) of the mothers viewed television for >2 h. Linear regression analysis showed association between average television duration of children and average maternal television duration on schooldays (Beta = 0.246, t = 5.09, P < 0.001). Binary logistic regression analysis showed that harmful television viewing practices were significantly more in children with television in bedroom [OR = 7.49(4.19-13.38), P < 0.001]. It was reduced significantly by the parental rules on content viewed [OR = 0.41(0.23-0.72), P = 0.002]; need of permission to switch on television [OR = 0.31(0.18-0.53), P < 0.001] and a higher maternal education [OR = 0.29 (0.14-0.59), P = 0.001]. CONCLUSIONS: Lower maternal education, increased maternal television usage, presence of television in bedroom resulted in harmful television viewing practices among Indian children. The parental rules that were effective in countering these were the rule on content viewed and needing parental permission to switch on television. PMID- 23943575 TI - Surgical placement of totally implantable venous access device-an institutional experience. AB - OBJECTIVES: To investigate the advantages and disadvantages of Totally implantable venous access devices (TIVAD) catheter in pediatric age group and also to review this subject in the recent literature and compare the results with the present results. METHODS: A total of 61 cases, 2 mo to 14 y old, were included in the index study. TIVADs were implanted in these patients for chemotherapy. The device was inserted under general anesthesia (GA) by open technique. All the children were followed up for a mean period of 7.2 mo. RESULTS: Out of 61 cases, 9 cases had complications; 3 requiring removal of the port due to infection and in one case the device had to be reinserted due to malpositioning, one had late wound dehiscence with exposed port chamber which needed operative correction and four had minor wound infections. There was no mortality. Complications like hemo or pneumothorax, arterial puncture, hematoma formation were very less with open technique of insertion of the port. Most patients and their parents were satisfied with TIVAD. CONCLUSIONS: Thus, TIVAD can be a useful device for many chronic patients who need an IV access for multiple injections especially in pediatric age group. PMID- 23943576 TI - 'Double midbrain' sign in extensive optic pathway glioma in neurofibromatosis-1. PMID- 23943577 TI - Isolation and enrichment of pathogens with a surface-modified aluminium chip for Raman spectroscopic applications. AB - We developed a Raman-compatible chip for isolating microorganisms from complex media. The isolation of bacteria is achieved by using antibodies as capture molecules. Due to the very specific interaction with the targets, this approach is promising for isolation of bacteria even from complex matrices such as body fluids. Our choice of capture molecules also enabled the investigation of samples containing yet unidentified bacteria, as the antibodies can capture a large variety of bacteria based on their analogue cell wall surface structures. The capability of our system is demonstrated for a broad range of different Gram positive and Gram-negative germs. Subsequent identification is done by recording Raman spectra of the bacteria. Further, it is shown that classification with chemometric methods is possible. PMID- 23943578 TI - [Resection or interventional treatment of hepatocellular carcinoma: which method for which patient?]. PMID- 23943579 TI - Association of gestational maternal hypothyroxinemia and increased autism risk. AB - OBJECTIVE: Transient gestational hypothyroxinemia in rodents induces cortical neuronal migration brain lesions resembling those of autism. We investigated the association between maternal hypothyroxinemia (gestational weeks 6-18) and autistic symptoms in children. METHODS: The mother-and-child cohort of the Generation R Study (Rotterdam, the Netherlands) began prenatal enrollment between 2002 and 2006. At a mean gestational age of 13.4 weeks (standard deviation=1.9, range=5.9-17.9), maternal thyroid function tests (serum thyrotropin [TSH], free thyroxine [fT4], and thyroid peroxidase [TPO] antibodies) were assessed in 5,100 women. We defined severe maternal hypothyroxinemia as fT4<5th percentile with normal TSH. Six years later, parents reported behavioral and emotional symptoms in 4,039 children (79%) using the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist and/or the Social Responsiveness Scale (SRS). We defined a probable autistic child by a PDP score>98th percentile and SRS score in the top 5% of the sample (n=81, 2.0%). RESULTS: Severe maternal hypothyroxinemia (n=136) was associated with an almost 4-fold increase in the odds of having a probable autistic child (adjusted odds ratio=3.89, 95% confidence interval [CI]=1.83-8.20, p<0.001). Using PDP scores, children of mothers with severe hypothyroxinemia had higher scores of autistic symptoms by age 6 years (adjusted B=0.23, 95% CI=0.03-0.37); SRS results were similar. No risk was found for children of TPO-antibody-positive mothers (n=308). INTERPRETATION: We found a consistent association between severe, early gestation maternal hypothyroxinemia and autistic symptoms in offspring. Findings are concordant with epidemiological, biological, and experimental data on autism. Although these findings cannot establish causality, they open the possibility of preventive interventions. PMID- 23943580 TI - Combining EEG, MIDI, and motion capture techniques for investigating musical performance. AB - This article describes a setup for the simultaneous recording of electrophysiological data (EEG), musical data (MIDI), and three-dimensional movement data. Previously, each of these three different kinds of measurements, conducted sequentially, has been proven to provide important information about different aspects of music performance as an example of a demanding multisensory motor skill. With the method described here, it is possible to record brain related activity and movement data simultaneously, with accurate timing resolution and at relatively low costs. EEG and MIDI data were synchronized with a modified version of the FTAP software, sending synchronization signals to the EEG recording device simultaneously with keypress events. Similarly, a motion capture system sent synchronization signals simultaneously with each recorded frame. The setup can be used for studies investigating cognitive and motor processes during music performance and music-like tasks--for example, in the domains of motor control, learning, music therapy, or musical emotions. Thus, this setup offers a promising possibility of a more behaviorally driven analysis of brain activity. PMID- 23943581 TI - Subjective frequency ratings for 432 ASL signs. AB - Given the importance of lexical frequency for psycholinguistic research and the lack of comprehensive frequency data for sign languages, we collected subjective estimates of lexical frequency for 432 signs in American Sign Language (ASL). Our participants were 59 deaf signers who first began to acquire ASL at ages ranging from birth to 14 years old and who had a minimum of 10 years of experience. Subjective frequency estimates were made on a scale ranging from 1 = rarely see the sign to 7 = always see the sign. The mean subjective frequency ratings for individual signs did not vary in relation to age of sign language exposure (AoLE), chronological age, or length of ASL experience. Nor did AoLE show significant effects on the response times (RTs) for making the ratings. However, RTs were highly correlated with mean frequency ratings. These results suggest that the distributions of subjective lexical frequencies are consistent across signers with varying AoLEs. The implications for research practice are that subjective frequency ratings from random samples of highly experienced deaf signers can provide a reasonable measure of lexical control in sign language experiments. The Appendix gives the mean and median subjective frequency ratings and the mean and median log(RT) of the ASL signs for the entire sample; the supplemental material gives these measures for the three AoLE groups: native, early, and late. PMID- 23943582 TI - A measure for assessing the effects of audiovisual speech integration. AB - We propose a measure of audiovisual speech integration that takes into account accuracy and response times. This measure should prove beneficial for researchers investigating multisensory speech recognition, since it relates to normal-hearing and aging populations. As an example, age-related sensory decline influences both the rate at which one processes information and the ability to utilize cues from different sensory modalities. Our function assesses integration when both auditory and visual information are available, by comparing performance on these audiovisual trials with theoretical predictions for performance under the assumptions of parallel, independent self-terminating processing of single modality inputs. We provide example data from an audiovisual identification experiment and discuss applications for measuring audiovisual integration skills across the life span. PMID- 23943583 TI - A standardized set of 260 pictures for Turkish: norms of name and image agreement, age of acquisition, visual complexity, and conceptual familiarity. AB - In the present study, normative data in Turkish are presented for the 260 color versions of the original Snodgrass and Vanderwart (1980) picture set for the first time. Norms are reported for name and image agreement, age of acquisition (AoA), visual complexity, and conceptual familiarity, together with written word frequency, and numbers of letters and syllables. We collected data from 277 native Turkish adults in a variety of tasks. The results indicated that, whilst several measures displayed language-specific variation, we also reported what seem to be language-independent-that is, universal-measures that show a systematic relationship across several languages. The implications of the reported measures in the domain of psycholinguistic research in Turkish and for wider cross-linguistic comparisons are discussed. PMID- 23943584 TI - The transitional impact scale: assessing the material and psychological impact of life transitions. AB - The Transitional Impact Scale (TIS) advances the measurement of event cognition into the real world. The TIS was created to provide a measure of change for important life transitions, including an index of their transitional properties and magnitude. Pilot work prior to Study 1 led to the creation of a 95-item version (TIS-95). A principal components analysis of TIS-95 (n = 215) resulted in two dimensions that we rotated to a Varimax criterion and interpreted as (1) material change (e.g., "This event changed where I live") and (2) psychological change (e.g., "This event changed the way I think about things"). TIS-95 was reduced to 25 items. In Study 2, the structure of TIS-25 was replicated (n = 531) using the same method. The best 12 items were retained. TIS-12 was evaluated in two random split-half samples (n = 557 and n = 553). These samples produced essentially identical results, as assessed through factor comparison. The cumulative scales formed from items constituting each factor demonstrated good internal consistency (Cronbach's alpha ranged from .79 to .86). PMID- 23943585 TI - Outcome following prenatal diagnosis of severe bilateral renal hypoplasia. AB - OBJECTIVE: The aim of this research was to evaluate the outcome and prognostic value of fetal serum beta2-microglobulin in case of prenatal diagnosis of severe bilateral renal hypoplasia. METHODS: Cases of hypoplastic kidneys were detected on ultrasound and referred to our laboratory for determination of fetal blood beta2-microglobulin, over a 12-year period. Prenatal prognostic assessment was based upon amniotic fluid volume and fetal serum beta2-microglobulin (cut-off: 5 mg/L). Outcome measures were postnatal renal function or renal pathological features when termination of pregnancy (TOP) and genetic studies were performed. RESULTS: A total of 34 cases were identified; 13 (38%) were liveborn and 21 (62%) underwent TOP. Renal hypoplasia was confirmed postnatally in all cases. Oligohydramnios/anhydramnios was observed in 30/34 (88%) cases. Associated genetic or anatomical anomalies were found in 8/34 (24%) cases. Renal function of liveborn infants was normal in 4/13 cases. Renal lesions were observed in all TOPs (21/21 cases). Overall, 30/34 (88.2%) cases had a poor outcome. beta2 microglobulin accurately predicts poor renal outcome in 27/31 (87.1%) cases. beta2-microglobulin was not interpretable in three cases due to amniotic fluid contamination. The prognostic value of beta2-microglobulin was similar to that of amniotic fluid volume assessment. CONCLUSION: Hypoplastic kidneys complicated by oligohydramnios/anhydramnios are associated with poor outcome. Fetal serum beta2 microglobulin and oligohydramnios both predicted poor outcome. PMID- 23943587 TI - Soft scorpionate anions as platforms for novel heterocycles. AB - Soft scorpionates have thus far been seen mainly as a family of ligands. Their chemistry is extended here to the production of novel cationic macrocycles using dihaloalkanes. By replacing the dihaloalkanes with mild oxidising agents (NO(+), I2) we obtain two unique polycyclic heterocycles. The mechanism which leads to the formation of these polycyclic heterocycles is investigated using ab initio DFT calculations. PMID- 23943586 TI - Increased proteome coverage by combining PAGE and peptide isoelectric focusing: comparative study of gel-based separation approaches. AB - The in-depth analysis of complex proteome samples requires fractionation of the sample into subsamples prior to LC-MS/MS in shotgun proteomics experiments. We have established a 3D workflow for shotgun proteomics that relies on protein separation by 1D PAGE, gel fractionation, trypsin digestion, and peptide separation by in-gel IEF, prior to RP-HPLC-MS/MS. Our results show that applying peptide IEF can significantly increase the number of proteins identified from PAGE subfractionation. This method delivers deeper proteome coverage and provides a large degree of flexibility in experimentally approaching highly complex mixtures by still relying on protein separation according to molecular weight in the first dimension. PMID- 23943588 TI - Pacifier cleaning practices and risk of allergy development. PMID- 23943589 TI - Effect of provision of micronutrient supplementation on growth and morbidity among young children in Pakistan. PMID- 23943590 TI - Goodbye to needles. PMID- 23943592 TI - Synthesis of the natural product building block 5-(3-bromophenyl)-4-hydroxy-5 methylhexan-2-one and its chiral characterization by using chiroptical spectroscopy. AB - The absolute configuration of 5-(3-bromophenyl)-4-hydroxy-5-methylhexan-2-one, an intermediate in the synthesis of various natural products, is assigned by using vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and optical rotatory dispersion (ORD). Experimental spectra were compared to density functional theory (DFT) calculations of the molecule with known configuration. These three techniques independently confirm that the absolute configuration is (S)-5-(3-bromophenyl)-4-hydroxy-5-methylhexan-2-one, thus enabling us to assign the absolute configuration with high reliability. The reliability of the VCD analysis was assessed quantitatively by using the CompareVOA program. We found that, in cases in which the agreement between theory and experiment was very good, a value of 10 cm(-1) for the triangular weighting function gave a more realistic discriminative power between enantiomers than the default value of 20 cm(-1). PMID- 23943593 TI - Type VI collagen turnover-related peptides-novel serological biomarkers of muscle mass and anabolic response to loading in young men. AB - BACKGROUND: Immobilization-induced loss of muscle mass is a complex phenomenon with several parallels to sarcopenic and cachectic muscle loss. Muscle is a large organ with a protein turnover that is orders of magnitude larger than most other tissues. Thus, we hypothesize that muscle loss and regain is reflected by peptide biomarkers derived from type VI collagen processing released in the circulation. METHODS: In order to test this hypothesis, we set out to develop an ELISA assay against an type VI collagen N-terminal globular domain epitope (IC6) and measured the levels of IC6 and an MMP-generated degradation fragment of collagen 6, (C6M) in a human immobilization-remobilization study setup with young (n = 11) and old (n = 9) men. They were subjected to 2 weeks of unilateral lower limb immobilization followed by 4 weeks of remobilization including thrice weekly resistance training, using the contralateral leg as internal controls. Subjects were sampled for strength, quadriceps muscle volume and blood at baseline (PRE), post-immobilization (2W), and post-remobilization (4W). Blood were subsequently analyzed for levels of the C6M and IC6 biomarkers. We subsequently tested if there was any correlation between C6M, IC6, or the C6M/IC6 ratio and muscle mass or strength at baseline. We also tested whether there was any relation between these biomarkers and changes in muscle mass or strength with immobilization or remobilization. RESULTS: The model produced significant loss of muscle mass and strength in the immobilized leg. This loss was bigger in young subjects than in elderly, but whereas the young recovered almost fully, the elderly had limited regrowth of muscle. We found a significant correlation between IC6 and muscle mass at baseline in young subjects (R (2) = 0.6563, p = 0.0045), but none in the elderly. We also found a significant correlation between C6M measured at the 4W time point and the change in muscle mass during remobilization, again only manifesting in the young men(R (2) = 0.6523, p = 0.0085). This discrepancy between the young and the elderly may be caused in part by much smaller changes in muscle mass in the elderly and partly by the relative small sample size. CONCLUSION: While we cannot rule out the possibility that these biomarkers in part stem from other tissues, our results strongly indicate that these markers represent novel biomarkers of muscle mass or change in muscle mass in young men. PMID- 23943596 TI - Synthesis and drug release of star-shaped poly(benzyl L-aspartate)-block poly(ethylene glycol) copolymers with POSS cores. AB - Star-shaped amphiphilic block copolymers with polyhedral oligomeric silsesquioxanes (POSS) as cores are synthesized using the "arm-first" strategy. First, the block copolymer poly(benzyl L-aspartate)-block-poly(ethylene glycol) (PBLA-b-PEG) is synthesized via ring-opening polymerization of beta-benzyl L aspartate-N-carboxyanhydride (BLA-NCA) with alpha-methoxy-omega aminopoly(ethylene glycol) (mPEG-NH2 ) as a macroinitiator. The copolymers are then immobilized on the eight groups of the polyhedral oligomeric silsesquioxanes (POSS-COOH). The star-shaped copolymers (POSS-g-(PBLA-b-PEG)) are characterized by (1) H NMR and FT-IR spectroscopy and gel permeation chromatography. The star shaped block copolymers self-assemble into micelles in aqueous medium. Quercetin is used as a model drug and the drug loading content and encapsulation efficiency increases with increasing chain length of the PBLA blocks. The drug release behaviors of drug loaded micelles are investigated and the cytotoxicity assay demonstrates that the POSS-g-(PBLA-b-PEG) copolymers are non-toxic. The star shaped block copolymers are potential carriers for anticancer drug delivery. PMID- 23943595 TI - Glucocorticoids antagonize RUNX2 during osteoblast differentiation in cultures of ST2 pluripotent mesenchymal cells. AB - The efficacy of glucocorticoids (GCs) in treating a wide range of autoimmune and inflammatory conditions is blemished by severe side effects, including osteoporosis. The chief mechanism leading to GC-induced osteoporosis is inhibition of bone formation, but the role of RUNX2, a master regulator of osteoblast differentiation and bone formation, has not been well studied. We assessed effects of the synthetic GC dexamethasone (dex) on transcription of RUNX2-stimulated genes during the differentiation of mesenchymal pluripotent cells into osteoblasts. Dex inhibited a RUNX2 reporter gene and attenuated locus dependently RUNX2-driven expression of several endogenous target genes. The anti RUNX2 activity of dex was not attributable to decreased RUNX2 expression, but rather to physical interaction between RUNX2 and the GC receptor (GR), demonstrated by co-immunoprecipitation assays and co-immunofluorescence imaging. Investigation of the RUNX2/GR interaction may lead to the development of bone sparing GC treatment modalities for the management of autoimmune and inflammatory diseases. PMID- 23943597 TI - Perinatal grief following a termination of pregnancy for foetal abnormality: the impact of coping strategies. AB - OBJECTIVE: Pregnancy termination for foetal abnormality (TFA) can have significant psychological repercussions, but little is known about the coping strategies involved in dealing with TFA. This study examined the relationships between women's coping strategies and perinatal grief. METHOD: A total of 166 women completed a survey online. Coping and perinatal grief were measured using the Brief COPE and Short Perinatal Grief Scales. Data were analysed through multiple regression analyses. RESULTS: Despite using mostly adaptive coping strategies, women's levels of grief were high and varied according to obstetric and termination variables. Grief was predicted by behavioural disengagement, venting, planning, religion, self-blame, being recently bereaved, being childless at the time of TFA, not having had children/being pregnant since TFA and uncertainty about the decision to terminate the pregnancy. Acceptance and positive reframing negatively predicted grief. CONCLUSION: Identifying women vulnerable to poor psychological adjustment and promoting coping strategies associated with lower levels of grief may be beneficial. This could be addressed through information provision and interventions such as Cognitive Behavioural Therapy or Acceptance and Commitment Therapy. PMID- 23943599 TI - Exclusive synthesis of Au11(PPh3)8Br3 against the Cl analogue and the electronic interaction between cluster metal core and surface ligands. AB - To goldly go...: Exclusive Au11(PPh3)8Br3 (see illustration) formation was obtained by a novel two-phase method, although the molar ratio of Br(-)/Cl(-) was 1:4, as identified by ESI-MS. Interestingly, the interaction of Au11 core electrons with the benzene pi electrons of the phosphine ligands was revealed by NMR spectroscopy and optical absorption spectroscopic analyses. PMID- 23943598 TI - Sugar-modified foldamers as conformationally defined and biologically distinct glycopeptide mimics. PMID- 23943600 TI - Subtyping of pulmonary adenocarcinoma in cytologic specimens: the next challenge. PMID- 23943601 TI - Anomalous property of Ag(BO2)2 hyperhalogen: does spin-orbit coupling matter? AB - Hyperhalogens were recently identified as a new class of highly electronagative species which are composed of metals and superhalogens. In this work, high-level theoretical calculations and photoelectron spectroscopy experiments are systematically conducted to investigate a series of coinage-metal-containing hyperhalogen anions, Cu(BO(2))(2)(-), Ag(BO(2))(2)(-), and Au(BO(2))(2)(-). The vertical electron detachment energy (VDE) of Ag(BO(2))(2)(-) is anomalously higher than those of Au(BO(2))(2)(-) and Cu(BO(2))(2)(-). In quantitative agreement with the experiment, high-level ab initio calculations reveal that spin orbit coupling (SOC) lowers the VDE of Au(BO(2))(2)(-) significantly. The sizable magnitude of about 0.5 eV of SOC effect on the VDE of Au(BO(2))(2)(-) demonstrates that SOC plays an important role in the electronic structure of gold hyperhalogens. This study represents a new paradigm for relativistic electronic structure calculations for the one-electron-removal process of ionic Au(I)L(2) complexes, which is characterized by a substantial SOC effect. PMID- 23943602 TI - Design of k-space channel combination kernels and integration with parallel imaging. AB - PURPOSE: In this work, a new method is described for producing local k-space channel combination kernels using a small amount of low-resolution multichannel calibration data. Additionally, this work describes how these channel combination kernels can be combined with local k-space unaliasing kernels produced by the calibration phase of parallel imaging methods such as GRAPPA, PARS and ARC. METHODS: Experiments were conducted to evaluate both the image quality and computational efficiency of the proposed method compared to a channel-by-channel parallel imaging approach with image-space sum-of-squares channel combination. RESULTS: Results indicate comparable image quality overall, with some very minor differences seen in reduced field-of-view imaging. It was demonstrated that this method enables a speed up in computation time on the order of 3-16X for 32 channel data sets. CONCLUSION: The proposed method enables high quality channel combination to occur earlier in the reconstruction pipeline, reducing computational and memory requirements for image reconstruction. PMID- 23943604 TI - Interactions of the multidrug resistance modulators tariquidar and elacridar and their analogues with P-glycoprotein. AB - Tariquidar and elacridar are among the most potent inhibitors of the multidrug resistance transporter P-glycoprotein (P-gp), but how they interact with the protein is yet unknown. In this work, we describe a possible way in which these inhibitors interact with P-gp. We rely on structure-activity relationship analysis of a small group of tariquidar and elacridar analogues that was purposefully selected, designed, and tested. Structural modifications of the compounds relate to the presence or absence of functional groups in the tariquidar and elacridar scaffolds. The activity of the compounds was evaluated by their effects on the accumulation of P-gp substrates rhodamine 123 and Hoechst 33342 in resistant tumor cells. The data allow estimation of the ability of the compounds to interact with the experimentally proposed R- and H-sites to which rhodamine 123 and Hoechst 33342 bind, respectively. Using an inward-facing homology model of human P-gp based on the crystallographic structure of mouse P gp, we demonstrate that these binding sites may overlap with the binding sites of the QZ59 ligands co-crystallized with mouse P-gp. Based on this SAR analysis, and using flexible alignment and docking, we propose possible binding modes for tariquidar and elacridar. Our results suggest the possibility for the studied compounds to bind to sites that coincide or overlap with the binding sites of rhodamine 123 and Hoechst 33342. These results contribute to further understanding of structure-function relationships of P-gp and can help in the design of selective and potent P-gp inhibitors with potential clinical use. PMID- 23943603 TI - The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges. AB - Inflammation is a fundamental response of the immune system whose successful termination involves the elimination of the invading pathogens, the resolution of inflammation and the repair of the local damaged tissue. In this context, the interleukin 10 (IL-10)-mediated anti-inflammatory response (AIR) represents an essential homeostatic mechanism that controls the degree and duration of inflammation. Here, we review recent work on the mechanistic characterization of the IL-10-mediated AIR on multiple levels: from the cataloguing of the in vivo genomic targets of STAT3 (the transcription factor downstream of IL-10) to the identification of specific co-factors that endow STAT3 with genomic-binding specificity, and how genomic and computational methods are being used to elucidate the regulatory mechanisms of this essential physiological response in macrophages. PMID- 23943605 TI - Singlet-oxygen-sensitizing near-infrared-fluorescent multimodal nanoparticles. AB - Nanoprobes based on quantum clusters (QC) with near-infrared fluorescence, magnetic-resonance-imaging contrast, and singlet-oxygen-sensitized intracellular fluorescence are studied. The generation of singlet oxygen and singlet-oxygen sensitized fluorescence uncaging by magnetic and NIR-emitting nanoparticles are exploited for multimodal bioimaging in vitro. PMID- 23943606 TI - Electrochemically informed synthesis: oxidation versus coordination of 5,6 bis(phenylchalcogeno)acenaphthenes. AB - Chalcogen dications: Facile synthesis of E--E bonded dications can be readily achieved. Radical cations are identified as the intermediates. PMID- 23943607 TI - Resolving molecular events in the regulation of meiosis in male and female germ cells. AB - In mammalian species, the process of meiosis, in which genes are randomly assorted between parental chromosomes during formation of egg and sperm cells, occurs prenatally in females but postnatally in males. To understand sex-specific differences in signaling mechanisms that underlie fertility, many studies have focused on identifying factors that control meiotic induction. Studies in mice using genetic knockout of the transcriptional regulator Polycomb repressive complex-1 (PRC1) and pharmacological inhibition of retinoic acid (RA) signaling suggest that PRC1 prevents female meiotic induction until release of PRC1 repression by increased RA signaling in the ovary. However, genetic studies with mice lacking RA synthesis in reproductive tissues indicate that RA is required for male but not female meiosis, suggesting that RA functions as a male-specific inducer of meiosis and that another factor releases PRC1 repression to initiate female meiosis. Correct resolution of the molecular events governing female and male meiosis is important for treating infertility and devising improved birth control strategies. PMID- 23943608 TI - Computational modeling of ERBB2-amplified breast cancer identifies combined ErbB2/3 blockade as superior to the combination of MEK and AKT inhibitors. AB - Crosstalk and compensatory circuits within cancer signaling networks limit the activity of most targeted therapies. For example, altered signaling in the networks activated by the ErbB family of receptors, particularly in ERBB2 amplified cancers, contributes to drug resistance. We developed a multiscale systems model of signaling networks in ERBB2-amplified breast cancer to quantitatively investigate relationships between biomarkers (markers of network activity) and combination drug efficacy. This model linked ErbB receptor family signaling to breast tumor growth through two kinase cascades: the PI3K/AKT survival pathway and the Ras/MEK/ERK growth and proliferation pathway. The model predicted molecular mechanisms of resistance to individual therapeutics. In particular, ERBB2-amplified breast cancer cells stimulated with the ErbB3 ligand heregulin were resistant to growth arrest induced by inhibitors of AKT and MEK or coapplication of two inhibitors of the receptor ErbB2 [Herceptin (trastuzumab) and Tykerb (lapatinib)]. We used model simulations to predict the response of ErbB2-positive breast cancer xenografts to combination therapies and verified these predictions in mice. Treatment with trastuzumab, lapatinib, and the ErbB3 inhibitor MM-111 was more effective in inhibiting tumor growth than the combination of AKT and MEK inhibitors and even induced tumor regression, indicating that targeting both ErbB3 and ErbB2 may be an improved therapeutic approach for ErbB2-positive breast cancer patients. PMID- 23943609 TI - A computational model predicts that Gbetagamma acts at a cleft between channel subunits to activate GIRK1 channels. AB - The atrial G protein (heterotrimeric guanine nucleotide-binding protein) regulated inwardly rectifying K(+) (GIRK1 and GIRK4) heterotetrameric channels underlie the acetylcholine-induced K(+) current responsible for vagal inhibition of heart rate and are activated by the G protein betagamma subunits (Gbetagamma). We used a multistage protein-protein docking approach with data from published structures of GIRK1 and Gbetagamma to generate an experimentally testable interaction model of Gbetagamma docked onto the cytosolic domains of the GIRK1 homotetramer. The model suggested a mechanism by which Gbetagamma promotes the open state of a specific cytosolic gate in the channel, the G loop gate. The predicted structure showed that the Gbeta subunit interacts with the channel near the site of action for ethanol and stabilizes an intersubunit cleft formed by two loops (LM and DE) of adjacent channel subunits. Using a heterologous expression system, we disrupted the predicted GIRK1- and Gbetagamma-interacting residues by mutation of one protein and then rescued the regulatory activity by mutating reciprocal residues in the other protein. Disulfide cross-linking of channels and Gbetagamma with cysteine mutations at the predicted interacting residues yielded activated channels. The mechanism of Gbetagamma-induced activation of GIRK4 was distinct from GIRK1 homotetramers. However, GIRK1-GIRK4 heterotetrameric channels activated by Gbetagamma displayed responses indicating that the GIRK1 subunit dominated the response pattern. This work demonstrated that combining computational with experimental approaches is an effective method for elucidating interactions within protein complexes that otherwise might be challenging to decipher. PMID- 23943610 TI - Simultaneous T(1) and B(1) (+) mapping using reference region variable flip angle imaging. AB - PURPOSE: To present a new method that can simultaneously and efficiently measure T1 and B1 (+) maps using reference region variable flip angle (RR-VFA) imaging. METHODS: Assuming T1 relaxation time in a reference region such as fat is well characterized, and the reference region sufficiently covers smoothly varying B1 (+) field inhomogeneity, B1 (+) maps can be measured from VFA images, conventionally used for T1 measurements. Fat-only images from two-point Dixon acquisitions were used to compute B1 (+) maps, and the B1 (+) maps were compared with ones using the double-angle method (DAM) in 22 breast MRI patients at 3T. Additionally, high spatial resolution VFA images were acquired to show T1 measurements with and without the RR-VFA B1 (+) correction in six patients. RESULTS: RR-VFA is able to generate reliable B1 (+) maps, similar to those using the conventional DAM. This simultaneous T1 and B1 (+) mapping can also be used to reduce T1 estimation errors, where T1 maps have more uniform fibroglandular tissue T1 and better depiction of heterogeneous T1 of breast masses. CONCLUSION: A new method that can measure both T1 and B1 (+) maps based on Dixon VFA images is described, offering improved T1 quantification with no scan time penalty. PMID- 23943611 TI - {Mo24Fe12} macrocycles: anion templation with large polyoxometalate guests. AB - POM and circumstance: Nanometer-sized polyoxometalates (POMs) bring a new direction to anion-templated supramolecular chemistry. The Keggin (left) and Dawson-type (right) polyoxoanions direct the assembly of giant metallomacrocycles through an array of weak hydrogen-bonding interactions. The concerted action of multiple hydrogen bonds keeps the templating guests embedded within the hosts, even in the solution state. PMID- 23943612 TI - A conformational mimetic approach for the synthesis of carbocyclic nucleosides as anti-HCV leads. AB - Computer-aided approaches coupled with medicinal chemistry were used to explore novel carbocyclic nucleosides as potential anti-hepatitis C virus (HCV) agents. Conformational analyses were carried out on 6-amino-1H-pyrazolo[3,4-d]pyrimidine (6-APP)-based carbocyclic nucleoside analogues, which were considered as nucleoside mimetics to act as HCV RNA-dependent RNA polymerase (RdRp) inhibitors. Structural insight gained from the modeling studies revealed the molecular basis behind these nucleoside mimetics. The rationally chosen 6-APP analogues were prepared and evaluated for anti-HCV activity. RdRp SiteMap analysis revealed the presence of a hydrophobic cavity near C7 of the nucleosides; introduction of bulkier substituents at this position enhanced their activity. Herein we report the identification of an iodinated compound with an EC50 value of 6.6 MUM as a preliminary anti-HCV lead. PMID- 23943613 TI - From natural product-inspired pyrrolidine scaffolds to the development of new human Golgi alpha-mannosidase II inhibitors. PMID- 23943614 TI - Comparison of the inhibition mechanisms of adalimumab and infliximab in treating tumor necrosis factor alpha-associated diseases from a molecular view. AB - TNFalpha-targeting therapy with the use of the drugs Etanercept, Infliximab, and Adalimumab is used in the clinical treatment of various inflammatory and immune diseases. Although all of these reagents function to disrupt the interaction between TNFalpha and its receptors, clinical investigations showed the advantages of Adalimumab treatment compared with Etanercept and Infliximab. However, the underlying molecular mechanism of action of Adalimumab remains unclear. In our previous work, we presented structural data on how Infliximab binds with the E-F loop of TNFalpha and functions as a TNFalpha receptor-binding blocker. To further elucidate the variations between TNFalpha inhibitors, we solved the crystal structure of TNFalpha in complex with Adalimumab Fab. The structural observation and the mutagenesis analysis provided direct evidence for identifying the Adalimumab epitope on TNFalpha and revealed the mechanism of Adalimumab inhibition of TNFalpha by occupying the TNFalpha receptor-binding site. The larger antigen-antibody interface in TNFalpha Adalimumab also provided information at a molecular level for further understanding the clinical advantages of Adalimumab therapy compared with Infliximab. PMID- 23943615 TI - Fas signal promotes the immunosuppressive function of regulatory dendritic cells via the ERK/beta-catenin pathway. AB - Dendritic cells (DCs) play important roles in the initiation of immune response and also in the maintenance of immune tolerance. Now, many kinds of regulatory DCs with different phenotypes have been identified to suppress immune response and contribute to the control of autoimmune diseases. However, the mechanisms by which regulatory DCs can be regulated to exert the immunosuppressive function in the immune microenvironment remain to be fully investigated. In addition, how T cells, once activated, can feedback affect the function of regulatory DCs during immune response needs to be further identified. We previously identified a unique subset of CD11b(hi)Ia(low) regulatory DCs, differentiated from mature DCs or hematopoietic stem cells under a stromal microenvironment in spleen and liver, which can negatively regulate immune response in a feedback way. Here, we show that CD11b(hi)Ia(low) regulatory DCs expressed high level of Fas, and endothelial stromal cell-derived TGF-beta could induce high expression of Fas on regulatory DCs via ERK activation. Fas ligation could promote regulatory DCs to inhibit CD4(+) T cell proliferation more significantly. Furthermore, Fas ligation preferentially induced regulatory DCs to produce IL-10 and IP-10 via ERK-mediated inactivation of GSK-3 and subsequent up-regulation of beta-catenin. Interestingly, activated T cells could promote regulatory DCs to secrete more IL 10 and IP-10 partially through FasL. Therefore, our results demonstrate that Fas signal, at least from the activated T cells, can promote the immunosuppressive function of Fas-expressing regulatory DCs, providing a new manner for the regulatory DCs to regulate adaptive immunity. PMID- 23943616 TI - Identification of biochemically distinct properties of the small ubiquitin related modifier (SUMO) conjugation pathway in Plasmodium falciparum. AB - Small ubiquitin-related modifiers (SUMOs) are post-translationally conjugated to other proteins and are thereby essential regulators of a wide range of cellular processes. Sumoylation, and enzymes of the sumoylation pathway, are conserved in the malaria causing parasite, Plasmodium falciparum. However, the specific functions of sumoylation in P. falciparum, and the degree of functional conservation between enzymes of the human and P. falciparum sumoylation pathways, have not been characterized. Here, we demonstrate that sumoylation levels peak during midstages of the intra-erythrocyte developmental cycle, concomitant with hemoglobin consumption and elevated oxidative stress. In vitro studies revealed that P. falciparum E1- and E2-conjugating enzymes interact effectively to recognize and modify RanGAP1, a model mammalian SUMO substrate. However, in heterologous reactions, P. falciparum E1 and E2 enzymes failed to interact with cognate human E2 and E1 partners, respectively, to modify RanGAP1. Structural analysis, binding studies, and functional assays revealed divergent amino acid residues within the E1-E2 binding interface that define organism-specific enzyme interactions. Our studies identify sumoylation as a potentially important regulator of oxidative stress response during the P. falciparum intra-erythrocyte developmental cycle, and define E1 and E2 interactions as a promising target for development of parasite-specific inhibitors of sumoylation and parasite replication. PMID- 23943617 TI - Discovery of beta-1,4-D-mannosyl-N-acetyl-D-glucosamine phosphorylase involved in the metabolism of N-glycans. AB - A gene cluster involved in N-glycan metabolism was identified in the genome of Bacteroides thetaiotaomicron VPI-5482. This gene cluster encodes a major facilitator superfamily transporter, a starch utilization system-like transporter consisting of a TonB-dependent oligosaccharide transporter and an outer membrane lipoprotein, four glycoside hydrolases (alpha-mannosidase, beta-N acetylhexosaminidase, exo-alpha-sialidase, and endo-beta-N acetylglucosaminidase), and a phosphorylase (BT1033) with unknown function. It was demonstrated that BT1033 catalyzed the reversible phosphorolysis of beta-1,4 D-mannosyl-N-acetyl-D-glucosamine in a typical sequential Bi Bi mechanism. These results indicate that BT1033 plays a crucial role as a key enzyme in the N-glycan catabolism where beta-1,4-D-mannosyl-N-acetyl-D-glucosamine is liberated from N glycans by sequential glycoside hydrolase-catalyzed reactions, transported into the cell, and intracellularly converted into alpha-D-mannose 1-phosphate and N acetyl-D-glucosamine. In addition, intestinal anaerobic bacteria such as Bacteroides fragilis, Bacteroides helcogenes, Bacteroides salanitronis, Bacteroides vulgatus, Prevotella denticola, Prevotella dentalis, Prevotella melaninogenica, Parabacteroides distasonis, and Alistipes finegoldii were also suggested to possess the similar metabolic pathway for N-glycans. A notable feature of the new metabolic pathway for N-glycans is the more efficient use of ATP-stored energy, in comparison with the conventional pathway where beta mannosidase and ATP-dependent hexokinase participate, because it is possible to directly phosphorylate the D-mannose residue of beta-1,4-D-mannosyl-N-acetyl-D glucosamine to enter glycolysis. This is the first report of a metabolic pathway for N-glycans that includes a phosphorylase. We propose 4-O-beta-D-mannopyranosyl N-acetyl-D-glucosamine:phosphate alpha-D-mannosyltransferase as the systematic name and beta-1,4-D-mannosyl-N-acetyl-D-glucosamine phosphorylase as the short name for BT1033. PMID- 23943618 TI - Leucine carboxyl methyltransferase 1 (LCMT1)-dependent methylation regulates the association of protein phosphatase 2A and Tau protein with plasma membrane microdomains in neuroblastoma cells. AB - Down-regulation of protein phosphatase 2A (PP2A) methylation occurs in Alzheimer disease (AD). However, the regulation of PP2A methylation remains poorly understood. We have reported that altered leucine carboxyl methyltransferase (LCMT1)-dependent PP2A methylation is associated with down-regulation of PP2A holoenzymes containing the Balpha subunit (PP2A/Balpha) and subsequent accumulation of phosphorylated Tau in N2a cells, in vivo and in AD. Here, we show that pools of LCMT1, methylated PP2A, and PP2A/Balpha are co-enriched in cholesterol-rich plasma membrane microdomains/rafts purified from N2a cells. In contrast, demethylated PP2A is preferentially distributed in non-rafts wherein small amounts of the PP2A methylesterase PME-1 are exclusively present. A methylation-incompetent PP2A mutant is excluded from rafts. Enhanced methylation of PP2A promotes the association of PP2A and Tau with the plasma membrane. Altered PP2A methylation following expression of a catalytically inactive LCMT1 mutant, knockdown of LCMT1, or alterations in one-carbon metabolism all result in a loss of plasma membrane-associated PP2A and Tau in N2a cells. This correlates with accumulation of soluble phosphorylated Tau, a hallmark of AD and other tauopathies. Thus, our findings reveal a distinct compartmentalization of PP2A and PP2A regulatory enzymes in plasma membrane microdomains and identify a novel methylation-dependent mechanism involved in modulating the targeting of PP2A, and its substrate Tau, to the plasma membrane. We propose that alterations in the membrane localization of PP2A and Tau following down-regulation of LCMT1 may lead to PP2A and Tau dysfunction in AD. PMID- 23943619 TI - The extended transmembrane Orai1 N-terminal (ETON) region combines binding interface and gate for Orai1 activation by STIM1. AB - STIM1 and Orai1 represent the two molecular key components of the Ca(2+) release activated Ca(2+) channels. Their activation involves STIM1 C terminus coupling to both the N terminus and the C terminus of Orai. Here we focused on the extended transmembrane Orai1 N-terminal (ETON, aa73-90) region, conserved among the Orai family forming an elongated helix of TM1 as recently shown by x-ray crystallography. To identify "hot spot" residues in the ETON binding interface for STIM1 interaction, numerous Orai1 constructs with N-terminal truncations or point mutations within the ETON region were generated. N-terminal truncations of the first four residues of the ETON region or beyond completely abolished STIM1 dependent Orai1 function. Loss of Orai1 function resulted from neither an impairment of plasma membrane targeting nor pore damage, but from a disruption of STIM1 interaction. In a complementary approach, we monitored STIM1-Orai interaction via Orai1 V102A by determining restored Ca(2+) selectivity as a consequence of STIM1 coupling. Orai1 N-terminal truncations that led to a loss of function consistently failed to restore Ca(2+) selectivity of Orai1 V102A in the presence of STIM1, demonstrating impairment of STIM1 binding. Hence, the major portion of the ETON region (aa76-90) is essential for STIM1 binding and Orai1 activation. Mutagenesis within the ETON region revealed several hydrophobic and basic hot spot residues that appear to control STIM1 coupling to Orai1 in a concerted manner. Moreover, we identified two basic residues, which protrude into the elongated pore to redound to Orai1 gating. We suggest that several hot spot residues in the ETON region contribute in aggregate to the binding of STIM1, which in turn is coupled to a conformational reorientation of the gate. PMID- 23943620 TI - Activation of protein kinase C-mitogen-activated protein kinase signaling in response to inositol starvation triggers Sir2p-dependent telomeric silencing in yeast. AB - Depriving wild type yeast of inositol, a soluble precursor for phospholipid, phosphoinositide, and complex sphingolipid synthesis, activates the protein kinase C (PKC)-MAPK signaling pathway, which plays a key role in the activation of NAD(+)-dependent telomeric silencing. We now report that triggering PKC-MAPK signaling by inositol deprivation or by blocking inositol-containing sphingolipid synthesis with aureobasidin A results in increased telomeric silencing regulated by the MAPK, Slt2p, and the NAD(+)-dependent deacetylase, Sir2p. Consistent with the dependence on NAD(+) in Sir2p-regulated silencing, we found that inositol depletion induces the expression of BNA2, which is required for the de novo synthesis of NAD(+). Moreover, telomeric silencing is greatly reduced in bna2Delta and npt1Delta mutants, which are defective in de novo and salvage pathways for NAD(+) synthesis, respectively. Surprisingly, however, omitting nicotinic acid from the growth medium, which reduces cellular NAD(+) levels, leads to increased telomeric silencing in the absence of inositol and/or at high temperature. This increase in telomeric silencing in response to inositol starvation is correlated to chronological life span extension but is Sir2p independent. We conclude that activation of the PKC-MAPK signaling by interruption of inositol sphingolipid synthesis leads to increased Sir2p dependent silencing and is dependent upon the de novo and salvage pathways for NAD(+) synthesis but is not correlated with cellular NAD(+) levels. PMID- 23943621 TI - Coordinate functional regulation between microsomal prostaglandin E synthase-1 (mPGES-1) and peroxisome proliferator-activated receptor gamma (PPARgamma) in the conversion of white-to-brown adipocytes. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated nuclear receptor and a master regulator of adipogenesis. Microsomal prostaglandin E (PGE) synthase-1 (mPGES-1) is an inducible enzyme that couples with cyclooxygenase-2 for the biosynthesis of PGE2. In this study we demonstrate the existence of a coordinate functional interaction between PPARgamma and mPGES 1 in controlling the process of pre-adipocyte differentiation in white adipose tissue (WAT). Adipocyte-specific PPARgamma knock-out mice carrying an aP2 promoter-driven Cre recombinase transgene showed a blunted response to the adipogenic effects of a high fat diet. Pre-adipocytes from these knock-out mice showed loss of PPARgamma and were resistant to rosiglitazone-induced WAT differentiation. In parallel, WAT from these mice showed increased expression of uncoupling protein 1, a mitochondrial enzyme that dissipates chemical energy as heat. Adipose tissue from mice lacking PPARgamma also showed mPGES-1 up regulation and increased PGE2 levels. In turn, PGE2 suppressed PPARgamma expression and blocked rosiglitazone-induced pre-adipocyte differentiation toward white adipocytes while directly elevating uncoupling protein 1 expression and pre adipocyte differentiation into mature beige/brite adipocytes. Consistently, pharmacological mPGES-1 inhibition directed pre-adipocyte differentiation toward white adipocytes while suppressing differentiation into beige/brite adipocytes. This browning effect was reproduced in knockdown experiments using a siRNA directed against mPGES-1. The effects of PGE2 on pre-adipocyte differentiation were not seen in mice lacking PPARgamma in adipose tissue and were not mirrored by other eicosanoids (i.e. leukotriene B4). Taken together, these findings identify PGE2 as a key regulator of white-to-brown adipogenesis and suggest the existence of a coordinate regulation of adipogenesis between PPARgamma and mPGES 1. PMID- 23943622 TI - Phospholipase B is activated in response to sterol removal and stimulates acrosome exocytosis in murine sperm. AB - Despite a strict requirement for sterol removal for sperm to undergo acrosome exocytosis (AE), the mechanisms by which changes in membrane sterols are transduced into changes in sperm fertilization competence are poorly understood. We have previously shown in live murine sperm that the plasma membrane overlying the acrosome (APM) contains several types of microdomains known as membrane rafts. When characterizing the membrane raft-associated proteomes, we identified phospholipase B (PLB), a calcium-independent enzyme exhibiting multiple activities. Here, we show that sperm surface PLB is activated in response to sterol removal. Both biochemical activity assays and immunoblots of subcellular fractions of sperm incubated with the sterol acceptor 2-hydroxypropyl-beta cyclodextrin (2-OHCD) confirmed the release of an active PLB fragment. Specific protease inhibitors prevented PLB activation, revealing a mechanistic requirement for proteolytic cleavage. Competitive inhibitors of PLB reduced the ability of sperm both to undergo AE and to fertilize oocytes in vitro, suggesting an important role in fertilization. This was reinforced by our finding that incubation either with protein concentrate released from 2-OHCD-treated sperm or with recombinant PLB peptide corresponding to the catalytic domain was able to induce AE in the absence of other stimuli. Together, these results lead us to propose a novel mechanism by which sterol removal promotes membrane fusogenicity and AE, helping confer fertilization competence. Importantly, this mechanism provides a basis for the newly emerging model of AE in which membrane fusions occur during capacitation/transit through the cumulus, prior to any physical contact between the sperm and the oocyte's zona pellucida. PMID- 23943623 TI - Adipocyte fetuin-A contributes to macrophage migration into adipose tissue and polarization of macrophages. AB - Macrophage infiltration into adipose tissue during obesity and their phenotypic conversion from anti-inflammatory M2 to proinflammatory M1 subtype significantly contributes to develop a link between inflammation and insulin resistance; signaling molecule(s) for these events, however, remains poorly understood. We demonstrate here that excess lipid in the adipose tissue environment may trigger one such signal. Adipose tissue from obese diabetic db/db mice, high fat diet-fed mice, and obese diabetic patients showed significantly elevated fetuin-A (FetA) levels in respect to their controls; partially hepatectomized high fat diet mice did not show noticeable alteration, indicating adipose tissue to be the source of this alteration. In adipocytes, fatty acid induces FetA gene and protein expressions, resulting in its copious release. We found that FetA could act as a chemoattractant for macrophages. To simulate lipid-induced inflammatory conditions when proinflammatory adipose tissue and macrophages create a niche of an altered microenvironment, we set up a transculture system of macrophages and adipocytes; the addition of fatty acid to adipocytes released FetA into the medium, which polarized M2 macrophages to M1. This was further confirmed by direct FetA addition to macrophages. Taken together, lipid-induced FetA from adipocytes is an efficient chemokine for macrophage migration and polarization. These findings open a new dimension for understanding obesity-induced inflammation. PMID- 23943625 TI - Electrical penetration graph studies to investigate the effects of cyantraniliprole on feeding behavior of Myzus persicae (Hemiptera: Aphididae) on Capsicum annuum. AB - BACKGROUND: The anthranilic diamide insecticide cyantraniliprole has been shown to suppress aphid and whitefly populations as well as reduce transmission of plant viruses by thrips and whiteflies when taken up systemically by the plant. In this study, electrical penetration graphing (EPG) was used to compare effects of cyantraniliprole on feeding behavior of Myzus persicae with those of the neonicotinoid insecticide imidacloprid applied as a soil drench to pepper plants two-, six-, and ten-days post-treatment. RESULTS: Significant reductions in the total amount of time spent probing, mean number of phloem feeding events, and mean number of intracellular punctures were observed on both cyantraniliprole- and imidacloprid-treated plants, compared to aphids that fed on plants treated only with water. Imidacloprid treatment also caused a significant reduction in the total number of probes relative to the water treated control. The effects of cyantraniliprole were statistically significant only in assays conducted at ten days post-treatment, whereas the effects of imidacloprid on aphid feeding were significant in assays conducted at two-, six-, and ten-days post-treatment. CONCLUSION: These findings document significant effects of cyantraniliprole on feeding by Myzus persicae. PMID- 23943627 TI - Uterine artery embolization in single symptomatic leiomyoma: do anatomical imaging criteria predict clinical presentation and long-term outcome? AB - BACKGROUND: Uterine artery embolization (UAE) has proven to be an effective treatment alternative for women suffering from symptomatic uterine leiomyomas. However, long-term clinical evaluation reveals treatment failure in approximately 25% of patients. To cope with the great variability in the extent of leiomyoma disease former studies are based on the simplifying assumption that the largest leiomyoma mainly causes the symptoms. PURPOSE: To evaluate whether anatomical characteristics in women with a single symptomatic leiomyoma influence clinical presentation and outcome after UAE. MATERIAL AND METHODS: Ninety-one patients with a single leiomyoma underwent UAE. Age, uterine and fibroid volume, fibroid location, and clinical symptoms (bleeding- and/or bulk-related symptoms) were documented. The need for reinterventions (i.e. repeat UAE, hysterectomy, myomectomy) and unchanged or worsened symptoms after UAE were classified as treatment failure (TF). Contrast-enhanced magnetic resonance imaging (MRI) 48-72 h after UAE was available in 38 women. The rate of fibroid infarction was determined and patients were assigned to one of three groups: complete (100%), almost complete (90-99%), or partial infarction (<90%). Cox regression analysis (CRA) was used to determine the influence of morphological and clinical parameters on outcome. RESULTS: Follow-up was available in 79/91 (87%) women (median age, 42 years; range, 33-56 years) at a median of 5 years (range, 3.1-9.2 years) after UAE. Anatomical leiomyoma criteria neither connected to specific clinical presentation nor influenced clinical outcome. Younger women showed a higher risk for TF with every year older lowering the risk by the factor of 0.86 (P = 0.024). Subgroup analysis showed predictive value of fibroid infarction with a cumulative survival free from TF of 91% for complete vs. 0% for partial infarction (P < 0.001). CONCLUSION: Even in women with single leiomyomas, anatomical criteria do not specify clinical presentation or predict clinical outcome. Younger patient age and incomplete fibroid infarction relate to higher rates of TF. PMID- 23943626 TI - Innovative developments for long-term mammalian pest control. AB - BACKGROUND: Invasive mammalian pests have inflicted substantial environmental and economic damage on a worldwide scale. RESULTS: Over the last 30 years there has been minimal innovation in the development of new control tools. The development of new vertebrate pesticides, for example, has been largely restricted due to the costly and time-consuming processes associated with testing and registration. CONCLUSION: In this article we discuss recent progress and trends in a number of areas of research aimed to achieve long-term population suppression or eradication of mammalian pest species. The examples discussed here are emerging from research being conducted in New Zealand, where invasive mammalian pests are one of the greatest threats facing the national environment and economy. PMID- 23943624 TI - The Med1 subunit of the mediator complex induces liver cell proliferation and is phosphorylated by AMP kinase. AB - Mediator, a large multisubunit protein complex, plays a pivotal role in gene transcription by linking gene-specific transcription factors with the preinitiation complex and RNA polymerase II. In the liver, the key subunit of the Mediator complex, Med1, interacts with several nuclear receptors and transcription factors to direct gene-specific transcription. Conditional knock out of Med1 in the liver showed that hepatocytes lacking Med1 did not regenerate following either partial hepatectomy or treatment with certain nuclear receptor activators and failed to give rise to tumors when challenged with carcinogens. We now report that the adenovirally driven overexpression of Med1 in mouse liver stimulates hepatocyte DNA synthesis with enhanced expression of DNA replication, cell cycle control, and liver-specific genes, indicating that Med1 alone is necessary and sufficient for liver cell proliferation. Importantly, we demonstrate that AMP-activated protein kinase (AMPK), an important cellular energy sensor, interacts with, and directly phosphorylates, Med1 in vitro at serine 656, serine 756, and serine 796. AMPK also phosphorylates Med1 in vivo in mouse liver and in cultured primary hepatocytes and HEK293 and HeLa cells. In addition, we demonstrate that PPARalpha activators increase AMPK-mediated Med1 phosphorylation in vivo. Inhibition of AMPK by compound C decreased hepatocyte proliferation induced by Med1 and also by the PPARalpha activators fenofibrate and Wy-14,643. Co-treatment with compound C attenuated PPARalpha activator inducible fatty acid beta-oxidation in liver. Our results suggest that Med1 phosphorylation by its association with AMPK regulates liver cell proliferation and fatty acid oxidation, most likely as a downstream effector of PPARalpha and AMPK. PMID- 23943628 TI - MR imaging of articular cartilage at 1.5T and 3.0T: comparison of IDEAL 2D FSE and 3D SPGR with fat-saturated 2D FSE and 3D SPGR in a porcine model. AB - BACKGROUND: IDEAL technique is a robust fat-water separation method which is potentially useful in cartilage imaging with significant improvement in the cartilage signal-to-noise ratio (SNR). PURPOSE: To identify whether iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) improved diagnostic performance for IDEAL 2D fast spin echo (FSE) and 3D spoiled gradient-recalled echo (SPGR) versus fat-saturated (FS) protocols at 1.5 and 3.0 T in the evaluation of patella-femoral cartilage lesions. MATERIAL AND METHODS: Forty-six artificial cartilage lesions were created in femoro-patellar articular cartilages of 11 porcine knees. All knees underwent MR examination at 1.5 and 3.0 T with MR protocol consisting of sagittal FS 2D FSE and 3D SPGR and IDEAL 2D FSE and IDEAL 3D SPGR, respectively. Qualitative assessment was performed to compare the diagnostic performance between 1.5- and 3.0-T protocols and between IDEAL and FS protocols. RESULTS: IDEAL 3D SPGR had a significantly higher accuracy for detecting partial thickness cartilage lesions (P < 0.01) than FS SPGR protocols, whereas there was no significant difference in diagnostic performance between IDEAL and FS 2D FSE except for one cartilage lesion. For all imaging sequences, no significant difference was observed in the diagnostic performance between 1.5- and 3.0-T imaging protocols (P = 0.42-0.91). CONCLUSION: Compared with conventional FS SPGR imaging, IDEAL 3D SPGR provided a better diagnostic performance for evaluation of porcine knee articular cartilage lesions in the knee joints at 1.5 and 3.0 T. IDEAL 3D SPGR may therefore be useful for detecting partial-thickness cartilage lesions in patients with degenerative osteoarthritis. PMID- 23943629 TI - An FP-CIT PET comparison of the difference in dopaminergic neuronal loss in subtypes of early Parkinson's disease. AB - BACKGROUND: Patients with tremor-dominant Parkinson's disease (PD) have slower disease progression, show less cognitive decline, and have more favorable outcomes than patients with non-tremor PD. However, the pathophysiology of PD tremor remains unclear. Whether there are differences in nigrostriatal dopaminergic dysfunction between the two PD subtypes is unknown. PURPOSE: To evaluate the differences in regional dopamine transporter (DAT) density in the brain between different subtypes of early PD using FP-CIT PET/CT. MATERIAL AND METHODS: We recruited 43 patients with PD (21 tremor-dominant PD [TP] and 22 non tremor-dominant PD [NTP]) and 18 age-matched healthy controls. All patients with PD underwent FP-CIT PET/CT imaging and evaluated Parkinsonian motor severity by using the Hoehn and Yahr stage and Part III of the Unified Parkinson's Disease Rating Scale (UPDRS). We also compared tremor and non-tremor symptoms with motor phenotype scores between two subtypes of PD. RESULTS: All patients with PD demonstrated a significantly decreased FP-CIT uptake in the putamen compared to healthy controls. Differences in putamen FP-CIT uptake versus caudate nucleus FP CIT uptake in PD showed putamen uptake was significantly more impaired than that in the caudate nucleus. However, there was no significant difference in FP-CIT uptake in the striatum between both PD groups at the same early stage of disease. CONCLUSION: We suggest that differential of DAT uptake in the striatum did not allow for a reliable separation of subtypes into tremor-dominant and non-tremor dominant, especially in the early stages of PD. Therefore, we assumed that many systems besides the nigrostriatal dopaminergic system are involved in the generation of tremors in PD. PMID- 23943630 TI - Improving the biocontrol potential of Steinernema feltiae against Delia radicum through dosage, application technique and timing. AB - BACKGROUND: The potential of the entomopathogenic nematode (EPN) Steinernema feltiae Filipjev as a biocontrol agent against the cabbage maggot Delia radicum (L.), was assessed in three field tests, focusing on EPN dosage, application technique and timing. RESULTS: Spraying cabbage plant trays with different doses of infective juveniles (IJs) (50,000, 100,000 and 200,000 per plant) generated a similar reduction of plant mortality. Spraying plant trays with 200,000 IJs of Steinernema feltiae per plant temporarily reduced the number of maggots around the plants' roots, while neither spraying a lower dose (50,000 IJs/plant) nor soil drenching with 200,000 or 50,000 IJs/plant) reduced maggot numbers. When applied as a plant tray spray, IJs of S. feltiae took 1-2 weeks to spread through the soil surrounding the roots. The pathogenicity of the EPNs, as evaluated by a Galleria mellonella bait test, was highest (up to 100% mortality) until up to five weeks after application, and declined to control levels after 4-7 weeks. Follow-up drench applications with EPNs, applied one and/or two weeks after the first EPN application, did not influence control of Delia radicum. CONCLUSION: Plant tray spraying provides better placement of Steinernema feltiae than soil drench treatments for control of Delia radicum. Plant mortality was not dose dependent in the presented trials, unlike the reduction of maggot numbers. Further research into timing and application technique of follow-up treatments with S. feltiae is required to increase efficacy to commercial standards. PMID- 23943631 TI - A survey of the use of complementary and alternative medicine in Illinois hospice and palliative care organizations. AB - This research assesses complementary and alternative medicine (CAM) use and administration for patients and family caregivers in Illinois hospice and palliative care organizations. An online survey was administered to a sample of 108 contacts of Illinois organizations listed in the National Hospice and Palliative Care Organization website, and 90.3% of the responding organizations offered some type of CAM. The top 5 most frequently offered CAM modalities to patients were pet therapy (64.5%), music therapy (61.3%), massage therapy (54.8%), art therapy (29.0%), and energy therapies (25.8%); these were the same top 5 offered to families but with different frequencies. Findings regarding utilization, administration, financing, and spiritual/cultural competency are discussed with policy recommendations for data collection, administrative improvements, and integration of CAM providers into service delivery. PMID- 23943632 TI - The final breath. PMID- 23943633 TI - Stigmatising attitudes towards people with mental disorders: a comparison of Australian health professionals with the general community. AB - OBJECTIVE: The aim of this paper was to explore attitudes towards people with mental disorders among Australian health professionals (psychiatrists, psychologists and general practitioners (GPs)) and to compare their attitudes with members of the general community. METHODS: The study involved a postal survey of 518 GPs, 506 psychiatrists and 498 clinical psychologists and a telephone survey of 6019 members of the general community. Participants were given a case vignette describing a person with either depression, depression with suicidal thoughts, early schizophrenia, chronic schizophrenia, post-traumatic stress disorder (PTSD) or social phobia and two questionnaires to assess stigmatising attitudes (the Depression Stigma Scale and the Social Distance Scale). Exploratory structural equation modelling was used to elucidate the structure of stigma as measured by the two scales, to establish dimensions of stigma and to compare patterns of association according to gender, age, vignette and professional grouping. RESULTS: The measurement characteristics of stigmatising attitudes in health professionals were found to be comparable to those in members of the general community in social distance and also in personal and perceived attitude stigma, with each forming distinct dimensions and each comprising 'Weak-not-sick' and 'Dangerous/unpredictable' components. Among health professionals, female gender, age and being a GP were associated with higher scores on the personal stigma scales. Mental health professionals had lower scores on the personal 'Weak-not-sick' and 'Dangerous/unpredictable' scales than members of the general community, while there were no significant differences in the desire for social distance between health professionals and the general community. CONCLUSIONS: While mental health professionals have less stigmatising attitudes than the general public, the greater beliefs in dangerousness and personal weakness by GPs should be addressed. PMID- 23943634 TI - Relationship Between Red Cell Distribution Width and the GRACE Risk Score With In Hospital Death in Patients With Acute Coronary Syndrome. AB - The aim of this study was to evaluate the relationship between red cell distribution width (RDW) and Global Registry of Acute Coronary Events (GRACE) risk score in patients with unstable angina pectoris (UAP) and non-ST elevation myocardial infarction (NSTEMI). We retrospectively enrolled 193 patients with UAP/NSTEMI (mean age 63.6 +/- 12.6 years; men 57%) in this study. Higher RDW values were associated with increased in-hospital mortality (P = .001). There is a significant correlation between RDW and GRACE score (P < .001). In multivariate logistic regression analysis, RDW was found to be an independent predictor of high GRACE score (odds ratio: 1.513, 95% confidence interval: 1.116-2.051, P = .008). A cutoff value of >15.74 for RDW predicted high GRACE score, with a 64% sensitivity and 65% specificity. Our study results demonstrated that high RDW was an independent predictor of high GRACE score, and it is associated with in hospital mortality in UAP/NSTEMI. PMID- 23943635 TI - BLAD: a comprehensive database of widely circulated beta-lactamases. AB - MOTIVATION: Beta-lactamases confer resistance to a broad range of antibiotics and inhibitors by accumulating mutations. The number of beta-lactamases and their variants is steadily increasing. The horizontal gene transfer likely plays a major role in dissemination of these markers to new environments and hosts. Moreover, information about the beta-lactamase classes and their variants was scattered. Categorizing all these classes and their associated variants along with their epidemiology and resistance pattern information on one platform could be helpful to the researcher working on multidrug-resistant bacteria. Thus, the beta-lactamase database (BLAD) has been developed to provide comprehensive information (epidemiology and resistance pattern) on beta-lactamases. Beta lactamase gene sequences in BLAD are linked with structural data, phenotypic data (i.e. antibiotic resistance) and literature references to experimental studies. In summary, BLAD integrates information that may provide insight into the epidemiology of multidrug resistance and enable the designing of novel drug candidates. AVAILABILITY: The database can be accessed from the website www.blad.co.in. PMID- 23943636 TI - DRAW+SneakPeek: analysis workflow and quality metric management for DNA-seq experiments. AB - SUMMARY: We report our new DRAW+SneakPeek software for DNA-seq analysis. DNA resequencing analysis workflow (DRAW) automates the workflow of processing raw sequence reads including quality control, read alignment and variant calling on high-performance computing facilities such as Amazon elastic compute cloud. SneakPeek provides an effective interface for reviewing dozens of quality metrics reported by DRAW, so users can assess the quality of data and diagnose problems in their sequencing procedures. Both DRAW and SneakPeek are freely available under the MIT license, and are available as Amazon machine images to be used directly on Amazon cloud with minimal installation. AVAILABILITY: DRAW+SneakPeek is released under the MIT license and is available for academic and nonprofit use for free. The information about source code, Amazon machine images and instructions on how to install and run DRAW+SneakPeek locally and on Amazon elastic compute cloud is available at the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (http://www.niagads.org/) and Wang lab Web site (http://wanglab.pcbi.upenn.edu/). PMID- 23943637 TI - Joint haplotype phasing and genotype calling of multiple individuals using haplotype informative reads. AB - MOTIVATION: Hidden Markov model, based on Li and Stephens model that takes into account chromosome sharing of multiple individuals, results in mainstream haplotype phasing algorithms for genotyping arrays and next-generation sequencing (NGS) data. However, existing methods based on this model assume that the allele count data are independently observed at individual sites and do not consider haplotype informative reads, i.e. reads that cover multiple heterozygous sites, which carry useful haplotype information. In our previous work, we developed a new hidden Markov model to incorporate a two-site joint emission term that captures the haplotype information across two adjacent sites. Although our model improves the accuracy of genotype calling and haplotype phasing, haplotype information in reads covering non-adjacent sites and/or more than two adjacent sites is not used because of the severe computational burden. RESULTS: We develop a new probabilistic model for genotype calling and haplotype phasing from NGS data that incorporates haplotype information of multiple adjacent and/or non adjacent sites covered by a read over an arbitrary distance. We develop a new hybrid Markov Chain Monte Carlo algorithm that combines the Gibbs sampling algorithm of HapSeq and Metropolis-Hastings algorithm and is computationally feasible. We show by simulation and real data from the 1000 Genomes Project that our model offers superior performance for haplotype phasing and genotype calling for population NGS data over existing methods. AVAILABILITY: HapSeq2 is available at www.ssg.uab.edu/hapseq/. PMID- 23943638 TI - BMS-927711 for the acute treatment of migraine. PMID- 23943639 TI - Clearing up the mess. PMID- 23943640 TI - Best BETs from the Manchester Royal Infirmary. BET 1: intranasal lorazepam is an acceptable alternative to intravenous lorazepam in the control of acute seizures in children. AB - A short-cut review was carried out to determine whether intranasal lorazepam was as effective as intravenous lorazepam in the control of seizures in children. Eighteen papers were found using the reported search, of which one was directly relevant and another compared intranasal lorazepam with intramuscular paraldehyde. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses are shown in table 1. It is concluded that intranasal lorazepam appears to be a safe and effective treatment for this condition. PMID- 23943643 TI - Best BETs from the Manchester Royal Infirmary. BET 3: does hydrotherapy help improve post ankle fracture symptoms? AB - A short-cut review was carried out to determine whether hydrotherapy is an effective treatment to reduce pain and improve function in patients recovering from an ankle fracture. Although 12 papers were found using the reported search, no studies were relevant to this three-part question. No evidence was found to support this treatment. PMID- 23943642 TI - Best BETs from the Manchester Royal Infirmary. BET 2: should intranasal lidocaine be used in patients with acute cluster headache? AB - A short-cut review was carried out to determine whether intranasal lidocaine was an effective treatment for patients with acute cluster headaches. Two hundred and seventy-two papers were found using the reported search, of which four were considered relevant to the three-part question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses are shown in table 2. Although the included studies all found some degree of symptomatic relief with this treatment, the methodological weaknesses of the studies compromised the validity of this finding, and the authors concluded that there was insufficient evidence to support this treatment in clinical practice. PMID- 23943644 TI - Best BETs from the Manchester Royal Infirmary. BET 4: does leg position alter cerebrospinal fluid opening pressure during lumbar puncture? AB - A short-cut review was carried out to determine whether cerebrospinal fluid (CSF) opening pressure is significantly affected by the patient's leg position during the procedure. A total of 1410 papers was found using the reported search, of which five were considered relevant to the three-part question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses are shown in table 3. It is concluded that alternative leg positions may affect the opening pressure by a small margin but this is unlikely to be of clinical significance. PMID- 23943645 TI - Short answer question case series: abdominal swelling, bruising and pain after fall. PMID- 23943647 TI - Silk glove or just a pig's ear? PMID- 23943648 TI - Thrombomodulin functions as a plasminogen receptor to modulate angiogenesis. AB - Urokinase-type plasminogen activator (uPA) activates plasminogen (Plg) through a major pericellular proteolytic system involved in cell migration and angiogenesis; however, the Plg receptor that participates in uPA-mediated Plg activation has not yet been identified. In this study, we demonstrated that thrombomodulin (TM), a type I transmembrane glycoprotein, is a novel Plg receptor that plays a role in pericellular proteolysis and cell migration. Plg activation at the cell surface and the extent of its cell migration- and invasion-promoting effect are cellular TM expression dependent. Direct binding of Plg and the recombinant TM extracellular domain, with a KD of 0.1-0.3 MUM, was determined through surface plasmon resonance analysis. Colocalization of TM, Plg, and the uPA receptor within plasma membrane lipid rafts, at the leading edge of migrating endothelial cells, was demonstrated and was also shown to overlap with areas of major pericellular proteolysis. Moreover, the roles of TM and Plg in neoangiogenesis were demonstrated in vivo through the skin wound-healing model. In conclusion, we propose that TM is a novel Plg receptor that regulates uPA/uPA receptor-mediated Plg activation and pericellular proteolysis within lipid rafts at the leading edge of migrating cells during angiogenesis. PMID- 23943649 TI - Alternative models of cardiac rehabilitation: a systematic review. AB - The traditional hospital-based model of cardiac rehabilitation faces substantial challenges, such as cost and accessibility. These challenges have led to the development of alternative models of cardiac rehabilitation in recent years. The aim of this study was to identify and critique evidence for the effectiveness of these alternative models. A total of 22 databases were searched to identify quantitative studies or systematic reviews of quantitative studies regarding the effectiveness of alternative models of cardiac rehabilitation. Included studies were appraised using a Critical Appraisal Skills Programme tool and the National Health and Medical Research Council's designations for Level of Evidence. The 83 included articles described interventions in the following broad categories of alternative models of care: multifactorial individualized telehealth, internet based, telehealth focused on exercise, telehealth focused on recovery, community- or home-based, and complementary therapies. Multifactorial individualized telehealth and community- or home-based cardiac rehabilitation are effective alternative models of cardiac rehabilitation, as they have produced similar reductions in cardiovascular disease risk factors compared with hospital-based programmes. While further research is required to address the paucity of data available regarding the effectiveness of alternative models of cardiac rehabilitation in rural, remote, and culturally and linguistically diverse populations, our review indicates there is no need to rely on hospital-based strategies alone to deliver effective cardiac rehabilitation. Local healthcare systems should strive to integrate alternative models of cardiac rehabilitation, such as brief telehealth interventions tailored to individual's risk factor profiles as well as community- or home-based programmes, in order to ensure there are choices available for patients that best fit their needs, risk factor profile, and preferences. PMID- 23943650 TI - Diminutive somatic deletions in the 5q region lead to a phenotype atypical of classical 5q- syndrome. AB - Classical 5q- syndrome is an acquired macrocytic anemia of the elderly. Similar to Diamond Blackfan anemia (DBA), an inherited red cell aplasia, the bone marrow is characterized by a paucity of erythroid precursors. RPS14 deletions in combination with other deletions in the region have been implicated as causative of the 5q- syndrome phenotype. We asked whether smaller, less easily detectable deletions could account for a syndrome with a modified phenotype. We employed single-nucleotide polymorphism array genotyping to identify small deletions in patients diagnosed with DBA and other anemias lacking molecular diagnoses. Diminutive mosaic deletions involving RPS14 were identified in a 5-year-old patient with nonclassical DBA and in a 17-year-old patient with myelodysplastic syndrome. Patients with nonclassical DBA and other hypoproliferative anemias may have somatically acquired 5q deletions with RPS14 haploinsufficiency not identified by fluorescence in situ hybridization or cytogenetic testing, thus refining the spectrum of disorders with 5q- deletions. PMID- 23943651 TI - Blockade of invariant TCR-CD1d interaction specifically inhibits antibody production against blood group A carbohydrates. AB - Previously, we detected B cells expressing receptors for blood group A carbohydrates in the CD11b(+)CD5(+) B-1a subpopulation in mice, similar to that in blood group O or B in humans. In the present study, we demonstrate that CD1d restricted natural killer T (NKT) cells are required to produce anti-A antibodies (Abs), probably through collaboration with B-1a cells. After immunization of wild type (WT) mice with human blood group A red blood cells (A-RBCs), interleukin (IL)-5 exclusively and transiently increased and the anti-A Abs were elevated in sera. However, these reactions were not observed in CD1d(-/-) mice, which lack NKT cells. Administration of anti-mouse CD1d blocking monoclonal Abs (mAb) prior to immunization abolished IL-5 production by NKT cells and anti-A Ab production in WT mice. Administration of anti-IL-5 neutralizing mAb also diminished anti-A Ab production in WT mice, suggesting that IL-5 secreted from NKT cells critically regulates anti-A Ab production by B-1a cells. In nonobese diabetic/severe combined immunodeficient (NOD/SCID/gammac(null)) mice, into which peripheral blood mononuclear cells from type O human volunteers were engrafted, administration of anti-human CD1d mAb prior to A-RBC immunization completely inhibited anti-A Ab production. Thus, anti-CD1d treatment might constitute a novel approach that could help in evading Ab-mediated rejection in ABO incompatible transplant recipients. PMID- 23943654 TI - Influence of common associated forefoot disorders on preoperative quality of life in patients with hallux valgus. AB - BACKGROUND: Hallux valgus (HV) is frequently associated with other forefoot disorders, but its influence on preoperative quality of life (QOL) has not been well characterized. The main purpose of this study was to assess the influence of common associated forefoot disorders (metatarsalgia and lesser toe deformities) on preoperative QOL in patients with HV. METHODS: Preoperative QOL assessed through the Short Form-36 (SF-36, version 2) was obtained from 94 patients with HV from a database. Patients were classified according to their condition: HV alone, HV and metatarsalgia, HV and lesser toe deformities, and HV and both metatarsalgia and lesser toe deformities. Values of each domain were compared among groups. In addition, a correlational study between SF-36 and radiographic severity of HV was performed. The mean age of the 94 patients was 62.6 +/- 12.3 years. There were 42.6% patients with HV alone, 30.8% with HV and metatarsalgia, 16% with HV and lesser toe deformities, and 10.6% with HV and both metatarsalgia and lesser toe deformities. RESULTS: Patients with HV and associated metatarsalgia and lesser toe deformities had significantly worse physical function (P = .029), role-physical (P = .017), bodily pain (P = .045), role emotional (P = .016), mental health (P = .001), and mental component summary (P = .003) compared to patients with HV alone. There were no significant correlations between radiographic HV and intermetatarsal angles and any of the domains or summaries of the SF-36. CONCLUSION: Patients with HV and both metatarsalgia and lesser toe deformities have significantly worse QOL compared to patients with HV alone. The presence of associated forefoot deformities may be a discriminating factor for the prioritization of surgical treatment of HV. LEVEL OF EVIDENCE: Level III, cross-sectional study. PMID- 23943653 TI - Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies. AB - PU-H71 is a purine-scaffold Hsp90 inhibitor that, in contrast to other Hsp90 inhibitors, displays unique selectivity for binding the fraction of Hsp90 that is preferentially associated with oncogenic client proteins and enriched in tumor cells (teHsp90). This property allows PU-H71 to potently suppress teHsp90 without inducing toxicity in normal cells. We found that lymphoma cells infected by Epstein-Barr virus or Kaposi sarcoma-associated herpes virus (KSHV) are exquisitely sensitive to this compound. Using PU-H71 affinity capture and proteomics, an unbiased approach to reveal oncogenic networks, we identified the teHsp90 interactome in KSHV(+) primary effusion lymphoma cells. Viral and cellular proteins were identified, including many involved in nuclear factor (NF) kappaB signaling, apoptosis, and autophagy. KSHV vFLIP is a viral oncoprotein homologous to cFLIPs, with NF-kappaB-activating and antiapoptotic activities. We show that teHsp90 binds vFLIP but not cFLIPs. Treatment with PU-H71 induced degradation of vFLIP and IKKgamma, NF-kappaB downregulation, apoptosis and autophagy in vitro, and more importantly, tumor responses in mice. Analysis of the interactome revealed apoptosis as a central pathway; therefore, we tested a BCL2 family inhibitor in primary effusion lymphoma cells. We found strong activity and synergy with PU-H71. Our findings demonstrate PU-H71 affinity capture identifies actionable networks that may help design rational combinations of effective therapies. PMID- 23943652 TI - BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells. AB - Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow (BM) blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with cells from treated mice compared with cells from untreated mice, with a reduction of BM blasts, Lin /Sca-1(+)/c-Kit(+), and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by technicium-labeled annexin V single photon emission computed tomography and ex vivo by annexin V/7 amino actinomycin D flow cytometry, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, caspase 3 cleavage, and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type (WT) AKT or protein kinase B, extracellular signal regulated kinase 1/2 and mitogen-activated protein kinase patterns in spleen cells after treatment, which showed reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation, and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells. PMID- 23943655 TI - Markers that can Reflect Asthmatic Activity before and after Reduction of Inhaled Corticosteroids: A Pilot Study. AB - Evaluation of airway inflammation is important in achieving adequate dosing of inhaled corticosteroids (ICS) for treating bronchial asthma. However, there is no evaluation tool that can be used in clinical settings. We examined biomarkers that can precisely reflect airway inflammation when ICS are decreased in stable asthmatic patients. This was a 12-week, single-arm, open-label clinical study performed at a single university hospital. Twenty-five patients (6 male and 19 female) with stable asthma were included in this study. We investigated whether the levels of nitrite and nitrate in exhaled breath condensate (EBC) increase after ICS reduction. We also investigated whether blood eosinophils, serum immunoglobulin E (IgE), high-sensitivity C reactive protein (hs-CRP), interleukin (IL)-13, IL-17, and periostin are different before and after ICS reduction. Peak expiratory flow (PEF), pulmonary function tests, asthma control test (ACT), and asthma quality of life questionnaire (AQLQ) were also examined. We considered an unscheduled hospital visit due to asthmatic symptoms and decline in average PEF over one week by more than 10% to indicate disease instability, and compared patients with stable and unstable disease for analysis. Unstable status was detected in 5 patients. Age, sex, asthma duration, ACT and AQLQ scores, and the level of serum IgE did not differ between stable and unstable groups. In the unstable group, the total concentration of nitrite and nitrate at the last visit was 9.84 (6.65-11.24) MUM. Surprisingly, this was similar to the concentration at the first visit (5.58 (2.94-17.29) MUM). Serum periostin before ICS reduction (141.9 [107.7-147.7] pg/mL) was higher in the unstable group than in the stable group (91.5 [78.75-103.5] pg/mL). The unstable group had a higher peripheral blood eosinophil count and wider diurnal variation of PEF at the first visit compared to the stable group. Higher eosinophils in peripheral blood and wider diurnal variation of PEF were predictive markers for unstable disease after ICS reduction. Serum periostin is another candidate for the predictive marker. PMID- 23943657 TI - Comment on: C57BL/6 neuromuscular healthspan scoring system. PMID- 23943656 TI - Bioinformatics analysis of transcriptome dynamics during growth in angus cattle longissimus muscle. AB - Transcriptome dynamics in the longissimus muscle (LM) of young Angus cattle were evaluated at 0, 60, 120, and 220 days from early-weaning. Bioinformatic analysis was performed using the dynamic impact approach (DIA) by means of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Database for Annotation, Visualization and Integrated Discovery (DAVID) databases. Between 0 to 120 days (growing phase) most of the highly-impacted pathways (eg, ascorbate and aldarate metabolism, drug metabolism, cytochrome P450 and Retinol metabolism) were inhibited. The phase between 120 to 220 days (finishing phase) was characterized by the most striking differences with 3,784 differentially expressed genes (DEGs). Analysis of those DEGs revealed that the most impacted KEGG canonical pathway was glycosylphosphatidylinositol (GPI)-anchor biosynthesis, which was inhibited. Furthermore, inhibition of calpastatin and activation of tyrosine aminotransferase ubiquitination at 220 days promotes proteasomal degradation, while the concurrent activation of ribosomal proteins promotes protein synthesis. Therefore, the balance of these processes likely results in a steady-state of protein turnover during the finishing phase. Results underscore the importance of transcriptome dynamics in LM during growth. PMID- 23943658 TI - Using conversation topics for predicting therapy outcomes in schizophrenia. AB - Previous research shows that aspects of doctor-patient communication in therapy can predict patient symptoms, satisfaction and future adherence to treatment (a significant problem with conditions such as schizophrenia). However, automatic prediction has so far shown success only when based on low-level lexical features, and it is unclear how well these can generalize to new data, or whether their effectiveness is due to their capturing aspects of style, structure or content. Here, we examine the use of topic as a higher-level measure of content, more likely to generalize and to have more explanatory power. Investigations show that while topics predict some important factors such as patient satisfaction and ratings of therapy quality, they lack the full predictive power of lower-level features. For some factors, unsupervised methods produce models comparable to manual annotation. PMID- 23943659 TI - Antiretroviral therapy, pregnancy, and birth defects: a discussion on the updated data. AB - An increasing number of HIV-infected women of childbearing age are initiating antiretroviral therapy (ART) worldwide. This review aims to discuss updated data of the eligible ART regimens and their role in inducing birth defects in utero. Zidovudine and lamivudine plus a non-nucleoside reverse-transcriptase inhibitor or protease inhibitor (PI) is the first-line regimen applied. The role of zidovudine exposition monotherapy or associated with other ART in inducing birth defects remains inconclusive. The main organ systems involved are genitourinary and cardiovascular. For HIV-infected pregnant women, World Health Organization (WHO) guidelines up to 2010 recommend the same group of drugs that are prescribed to nonpregnant women. The exception is efavirenz, which has been associated with an increase in the risk of teratogenicity. Increased rates of birth defects were found in large cohorts and computational studies conducted recently in infants exposed to efavirenz-containing regimens. The combination of zidovudine and lamivudine and lopinavir/ritonavir is one of the most used ART regimens for prevention of mother-to-child-transmission. Conflicting data about the role of PI exposure in utero and birth defects have been reported. However, a reduced number of studies evaluating the role of PI in inducing birth defects in women are available. An association between prematurity and PI exposure in pregnancy was extensively described. Some questions arise due to the tendency of initiating ART early in the life of HIV-infected individuals or those at risk of infection. Longtime exposure to different ART regimens and the potential effect of birth defect induction in pregnancy are not completely understood. Developing regions harbor the highest numbers of women of reproductive age exposed to ART. Most of the largest and expressive data come from developed countries, and could not be sufficiently representative of pregnant women living in developing countries. PMID- 23943660 TI - Assessing the HIV rapid test in the fight against the HIV/AIDS epidemic in Trinidad. AB - OBJECTIVE: To evaluate the human immunodeficiency virus (HIV) rapid test as an effective tool in the response to the HIV/acquired immunodeficiency syndrome (AIDS) epidemic in Trinidad. DESIGN AND METHODS: The study is comprised of a retrospective analysis of data collected from May 2008 to July 15, 2011 and a prospective arm of those tested during July 18, 2011 - August 30, 2011. During the prospective phase, blood samples were tested using rapid tests manufactured by Inverness Medical Innovation and Trinity Biotech followed by an enzyme-linked immunosorbent assay test, irrespective of the results of the rapid test. A structured questionnaire was administered to collect demographic data and risk behaviors. The study was conducted in one randomly selected primary health care facility of the eight that offered same-day HIV testing in Trinidad. RESULTS: A total of 297 persons participated in the prospective arm of the study and the rapid test was found to have a sensitivity of 100% and a specificity of 99.6%. Females and those aged 20-29 years were most likely to participate. Over the study period, the number of persons who received rapid tests increased but the prevalence of positive HIV test results decreased from 4.4% in 2008 to 2.1% in 2011. The main reasons for being tested were curiosity (38%), results being obtainable the same day (27%), and confidentiality (13%). Approximately 50% of respondents reported more than one sex partner in the previous year while 14% used condoms regularly. CONCLUSION: People need to know their own HIV status and that of their partners to make healthy decisions about sexual behavior. At the health facility studied, 2.6% of people who took the HIV rapid test were HIV positive. PMID- 23943662 TI - Letter from the editor. PMID- 23943661 TI - Cervical squamous cell lymph node metastases from an unknown primary site: survival and patterns of recurrence after radiotherapy. AB - INTRODUCTION: The purpose of the present retrospective study was to review outcome and patterns of failure of patients who were treated with radiotherapy for cervical lymph node metastases from an unknown primary site (CUP). PATIENTS AND METHODS: Between 2000 and 2009, 34 patients diagnosed with squamous cell CUP were admitted to radiotherapy in curative intent. In 26 of 34 patients (76%) neck dissection was performed prior to radiotherapy, extracapsular extension (ECE) was seen in 20 of 34 patients (59%). Target volumes included the bilateral neck and panpharyngeal mucosa. Concomitant chemotherapy was applied in 14 of 34 patients (41%). RESULTS: After a median follow-up of 45 months for the entire group, 2 of 34 patients (6%) presented with an isolated regional recurrence, another 2 of 34 patients (6%) developed both local and distant recurrence, and 6 of 34 patients (18%) had distant failure only. Estimated overall survival after 2- and 5 -years was 78% and 63%. All patients with N1 or N2a disease (n=6) were disease free after 5 years. ECE, concomitant chemotherapy and involvement of neck levels 4 and 5 were associated with worse overall survival on univariate analysis. CONCLUSION: Radiotherapy of the panpharynx and bilateral neck leads to excellent local control while distant metastases are the most frequent site of failure and prognostically limiting. Therefore intensified concomitant or sequential systemic therapies should be evaluated in future trials. PMID- 23943663 TI - Quality improvement in inflammatory bowel disease. AB - Chronic illnesses such as inflammatory bowel disease (IBD) present a unique opportunity to define and improve the quality of care. Processes of care can be complex, and outcomes of care may vary across different healthcare delivery settings. Patients with IBD are managed over long periods of time and often by the same physician within a single care delivery system. Both patients with Crohn's disease and ulcerative colitis have variable courses of disease progression that require changes in therapy over time. These factors necessitate multiple areas of potential assessment and improvement of processes and outcomes of care. A current initiative is the development of quality measures. The American Gastroenterological Association has developed accountability measures for the Physician Quality Reporting System, and the Crohn's and Colitis Foundation of America has developed a set of top 10 recommended processes and outcomes of measurement for high-quality care of patients with IBD. In addition, the pediatric ImproveCareNow collaborative network has collected improvement data from dozens of pediatric centers over the past 5 years and has demonstrated improvement in overall disease activity in their cohort through iterative quality improvement processes. Future directions for quality indicators for adults with IBD will involve implementation of quality-measure reporting, both for purposes of reimbursement as well as improvement of care. These strategies will need to be closely monitored to evaluate the effect of improvement programs on outcomes. PMID- 23943664 TI - Screening for hepatitis B virus and hepatitis C virus at a community fair: a single-center experience. AB - Despite recommendations for screening for hepatitis B virus (HBV) and hepatitis C virus (HCV), most individuals are still unaware of their infection status. The disparities in screening for HBV and HCV can be attributed to lack of awareness, language barriers, and difficulty in accessing healthcare. To address these issues, an exhibit booth was set up at an annual cultural festival to promote awareness about HBV and HCV and also provide free screening for a local Floridian community. Recruitment was conducted in various languages by physicians and nurses who specialize in hepatology. All materials associated with the screening process were sponsored by the Schiff Center for Liver Diseases, which is located at the University of Miami Miller School of Medicine in Florida. In the first year of the screening initiative, 173 of 11,000 fair attendees were screened for HBV. Twenty-nine (17%) of those screened tested positive for antibodies to hepatitis B core antigen (anti-HBc), and only 1 individual tested positive for chronic HBV, with positive hepatitis B surface antigen (HBsAg). Screening for HCV and an extended patient questionnaire were added to the screening program in the second year of the initiative. A total 231 of 9,000 fair attendees volunteered to be screened for both HBV and HCV. Twenty-nine (13%) of these people tested positive for anti-HBc, and 3 tested positive for HBsAg. Only 1 person tested positive for anti-HCV, but this individual had undetectable HCV RNA levels. Our single-center experience illustrates that, despite efforts to improve access to screening, only 2-3% of attendees at a cultural fair embraced the screening efforts. Other strategies will be required to enhance participation in screening programs for viral hepatitis. PMID- 23943665 TI - Measuring Disability in IBD: The IBD Disability Index. PMID- 23943666 TI - The Resect-and-Discard Strategy for Management of Small and Diminutive Colonic Polyps. PMID- 23943667 TI - Management of GERD-Related Chronic Cough. PMID- 23943668 TI - Management of anemia in patients receiving triple therapy for hepatitis C. PMID- 23943669 TI - Adalimumab in the Treatment of Moderate-to-Severe Ulcerative Colitis: ULTRA 2 Trial Results. PMID- 23943670 TI - Adalimumab: Another Treatment Option for Moderate-to-Severe UC. PMID- 23943671 TI - A large prolapsed inflammatory fibroid polyp of the esophagus: an unusual presentation. PMID- 23943672 TI - Clinical pearls on the diagnosis and management of a rare subepithelial tumor. PMID- 23943673 TI - GASTRO-HEP News. PMID- 23943674 TI - Acute depletion of plasma membrane phospholipids-dissecting the roles of PtdIns(4)P and PtdIns(4,5)P2. PMID- 23943675 TI - The nuclear membrane as a lipid 'sink'-linking cell cycle progression to lipid synthesis. PMID- 23943676 TI - Developed lower-positioned transverse ligament restricts eyelid opening and folding and determines Japanese as being with or without visible superior palpebral crease. AB - INTRODUCTION: We have reported that a developed lower-positioned transverse ligament between the superior-medial orbital rim and the lateral orbital rim on the lateral horn in the lower orbital fat space antagonizes eyelid opening and folding in certain Japanese to produce narrow eye, no visible superior palpebral crease, and full eyelid. In this study, we confirmed relationship between development of the lower-positioned transverse ligament and presence of the superior palpebral crease. METHODS: We evaluated whether (1) digital immobilization of eyebrow movement during eyelid opening and (2) a developed lower-positioned transverse ligament could classify Japanese subjects as being with or without visible superior palpebral crease. RESULTS: Digital immobilization of eyebrow movement restricted eyelid opening in all subjects without visible superior palpebral crease but did not restrict in any subject with visible superior palpebral crease. Macroscopic and microscopic evidence revealed that the lower-positioned transverse ligament behind the lower orbital septum in subjects without visible superior palpebral crease was significantly more developed than that in subjects with visible superior palpebral crease. CONCLUSIONS: Since a developed lower-positioned transverse ligament antagonizes opening and folding of the anterior lamella of the upper eyelid in subjects without visible superior palpebral crease, these individuals open their eyelids by lifting the eyebrow with the anterior lamella and the lower-positioned transverse ligament owing to increased tonic contraction of the frontalis muscle, in addition to the retractile force of the levator aponeurotic expansions. In subjects with visible superior palpebral crease, the undeveloped lower-positioned transverse ligament does not antagonize opening and folding of the anterior lamella, and so they open their eyelids by folding the anterior lamella on the superior palpebral crease via the retractile force of the levator aponeurotic expansions. PMID- 23943677 TI - Upper extremity composite tissue allotransplantation imaging. AB - OBJECTIVE: Upper extremity (UE) transplantation is the most commonly performed composite tissue allotransplantation worldwide. However, there is a lack of imaging standards for pre- and posttransplant evaluation. This study highlights the protocols and findings of UE allotransplantation toward standardization and implementation for clinical trials. METHODS: Multimodality imaging protocols for a unilateral hand transplant candidate and a bilateral mid-forearm level UE transplant recipient include radiography, computed tomography (CT), magnetic resonance (MR) imaging, catheter angiography, and vascular ultrasonography. Pre- and posttransplant findings, including dynamic CT and MR performed for assessment of motor activity of transplanted hands, are assessed, and image quality of vessels and bones on CT and MR evaluated. RESULTS: Preoperative imaging demonstrates extensive skeletal deformity and variation in vascular anatomy and vessel patency. Posttransplant images confirm bony union in anatomical alignment and patency of vascular anastomoses. Mild differences in rate of vascular enhancement and extent of vascular networks are noted between the 2 transplanted limbs. Dynamic CT and MR demonstrate a 15 degrees to 30 degrees range of motion at metacarpophalangeal joints and 90 degrees to 110 degrees at proximal interphalangeal joints of both transplanted hands at 8 months posttransplant. Image quality was slightly better for CT than for MR in the first subject, while MR was slightly better in the second subject. CONCLUSION: Advanced vascular and musculoskeletal imaging play an important role in surgical planning and can provide novel posttransplantation data to monitor the success of the procedure. Implementation of more standardized protocols should enable a more comprehensive assessment to evaluate the efficacy in clinical trials. PMID- 23943678 TI - The Supraorbital Margin of Japanese Who Have No Visible Superior Palpebral Crease and Persistently Lift the Eyebrow in Primary Gaze is Higher and More Obtuse Than Those Who Do Not. AB - OBJECTIVE: Anthropological studies divided the Japanese into the Yayoi migrants, who had narrow eye, no visible superior palpebral crease, and high-positioned round supraorbital margins for cold tolerance, and the Jomon natives, who had wide eye, visible superior palpebral crease, and low-positioned straight supraorbital margins, thus suggesting an anatomical discrepancy between the vertical palpebral fissure and the height of the supraorbital margin. Because Japanese subjects without visible superior palpebral crease open their eyelids by lifting the eyebrows with the anterior lamella owing to increased tonic contraction of the frontalis muscle, we hypothesized that persistently lifting the eyebrows in primary gaze mechanically remodels the supraorbital margin to be high positioned and round. METHOD: We evaluated whether subjects without visible superior palpebral crease persistently lifted their eyelids more than subjects with visible superior palpebral crease, whether the presence of persistently lifted eyebrow in primary gaze affected the relative height of the supraorbital margin in coronal view 3-dimensional computed tomography imaging, and whether the shape of the supraorbital margin in the coronal view affected that in the sagittal view 3-dimensional computed tomography imaging. RESULTS: Eyebrow height in subjects without visible superior palpebral crease was significantly larger than that in subjects with visible superior palpebral crease. The supraorbital margin of subjects without visible superior palpebral crease who persistently lifted the eyebrows in primary gaze was higher (rounder) and more obtuse than that of Japanese subjects with visible superior palpebral crease who did not. CONCLUSIONS: The mechanical pressure applied to the supraorbital margin by persistently lifting the eyebrows appears to functionally, rather than genetically, create the high (round) and obtuse supraorbital margin. PMID- 23943679 TI - De Quervain's Disease. PMID- 23943680 TI - Scalp reconstruction with free latissimus dorsi muscle. PMID- 23943681 TI - The influences of immigration on health information seeking behaviors among Korean Americans and Native Koreans. AB - Korean Americans (KAs) have low screening rates for cancer and are often not well informed about their chronic diseases. Reduced access to health-related information is one reason for gaps in knowledge and the widening health disparities among minority populations. However, little research exists about KAs' health information seeking behaviors. Guided by the Structural Influence Model, this study examines the influence of immigration status on KAs' trust in health information sources and health information seeking behaviors. Cross sectional surveys were conducted in the Washington, D.C., metropolitan area as well as in the Gwangju metropolitan city in South Korea during 2006-2007. Two hundred and fifty-four KAs and 208 native Koreans who were 40 years of age or older completed the surveys. When comparing native Koreans to KAs, we found KAs were 3 times more likely to trust health information from newspapers or magazines (odds ratio [OR] = 3.13; 95% confidence interval [CI] = 1.49-6.54) and 11 times more likely to read the health sections of newspapers or magazines (OR = 11.35; 95% CI = 3.92-32.91) in multivariate adjusted models. However, they were less likely to look for health information from TV (OR = 0.29; 95% CI = 0.12-0.72) than native Koreans. Our results indicate that immigration status has profound influences on KAs' health information seeking behaviors. Increasing the availability of reliable and valid health information from printed Korean language magazines or newspapers could have a positive influence on increasing awareness and promoting screening behaviors among KAs. PMID- 23943682 TI - Macular edema: drying is not repairing. PMID- 23943683 TI - Intravitreal Bevacizumab with or without Triamcinolone for Refractory Diabetic Macular Edema: Long-term Results of a Clinical Trial. AB - PURPOSE: To report the long-term results of intravitreal bevacizumab (IVB) injection alone or combined, at the time of first IVB injection, with intravitreal triamcinolone acetonide (IVT) for treatment of refractory diabetic macular edema (DME). METHODS: In this randomized clinical trial, 115 eyes of 101 patients with refractory DME were enrolled and randomly assigned to one of the three study arms: the IVB group (41 eyes) received three consecutive injections of 1.25 mg IVB at 6-week intervals; the IVB/IVT group (37 eyes) additionally received 2 mg of IVT at the time of first IVB injection; and the control (sham injection) group. Patients in the IVB and IVB/IVT groups were followed for a mean of 13.3 months and received retreatment with IVB alone whenever indicated. Main outcome measures were best corrected visual acuity (BCVA) and central macular thickness (CMT). RESULTS: At the last follow up, CMT decreased significantly in the IVB group (p=0.013) but it was not significant (p=0.13) in the IVB/IVT group. Mean CMT improvement was 91 (95% CI, 20 to 161) microns and 57 (95% CI, -18 to 133) microns in the IVB and IVB/IVT groups, respectively. Mean BCVA improvement from baseline was 0.28 (95% CI, 0.18 to 0.38) logMAR (P=0.017) in the IVB group and 0.19 (95% CI, 0.08 to 0.30) logMAR (P=0.001) in the IVB/IVT group. There was no difference between the two groups in terms of visual improvment (p=0.42). In generalized linear mixed model, only the time interval between the last injection and CMT measurement was statistically significant (P=0.04). The same results were repeated for visual acuity (P=0.03). CONCLUSION: Three loading doses of IVB (added doses if required) have long-term beneficial effects for treatment of refractory DME. Adding triamcinolone to this regimen provides no additional long term benefit. PMID- 23943684 TI - Limbal Stem Cell Transplantation for Gelatinous Drop-like Corneal Dystrophy. AB - PURPOSE: To report the outcomes of allograft limbal stem cell transplantation for recurrent gelatinous drop-like corneal dystrophy (GDLD). METHODS: In this non comparative interventional case series, 4 eyes of 3 consecutive patients with recurrent GDLD underwent allograft limbal stem cell transplantation. Two eyes underwent concomitant penetrating keratoplasty while the other two underwent simultaneous superficial keratectomy. Main outcome measures were best spectacle corrected visual acuity, intraocular pressure and corneal clarity. RESULTS: Patient age ranged from 28 to 63 years. Mean follow-up after surgery was 23+/-10 (median, 22; range, 12-36) months. Mean visual acuity improved from 2.70+/-0.61 logMAR preoperatively to 1.05+/-0.06 logMAR at final postoperative visit (P=0.066). Intraocular pressure was normal in all eyes at baseline and remained within normal limits at all postoperative visits. All corneas remained smooth and clear during the follow-up period with no episode of rejection or recurrence. All patients maintained ambulatory vision until final follow-up. CONCLUSION: The present study provides further evidence that limbal stem cell transplantation may be an effective therapeutic alternative in patients with GDLD. PMID- 23943685 TI - Correlation between Corneal Topographic Indices and Higher-Order Aberrations in Keratoconus. AB - PURPOSE: To compare corneal higher-order aberrations (HOAs) between normal and keratoconic eyes, and to investigate the association between elevation-based corneal topographic indices and corneal wavefront data in the latter group. METHODS: In this cross-sectional comparative study, 77 normal right eyes of 77 control subjects and 66 eyes of 36 keratoconic patients were included. In each eye, elevation- based corneal topographic indices including mean keratometry readings, best-fit sphere, maximum elevation, and 3-mm and 5-mm zone irregularity indices were measured using Orbscan II. The Galilei Scheimpflug analyzer was used to measure HOAs of the corneal surface. The independent student t-test was used to compare HOAs between the study groups. Spearman correlation was used to investigate possible associations between Orbscan and Galilei data in the keratoconus group. RESULTS: All Zernike coefficients up to the 4th order except for horizontal trefoil, and vertical and horizontal tetrafoil were significantly greater in the keratoconus group than normal eyes (P<0.05). Root mean square (RMS) of HOAs up to the 6th order and total HOAs were significantly higher in the keratoconus group (P<0.05). In the keratoconus group, the strongest association was observed between vertical coma (r=-0.71, P<0.01) and total RMS of HOAs (r=0.94, P<0.01) with irregularity in the 3-mm zone. Spherical and vertical coma aberrations were significantly correlated with mean keratometry (P<0.05 for both comparisons). CONCLUSION: Centrally located corneal HOAs are significantly greater in keratoconic eyes than normal controls. Anterior and inferior displacement of the cornea causes the majority of higher-order aberrations observed in keratoconus. PMID- 23943686 TI - Oxygen Tension in the Aqueous Humor of Human Eyes under Different Oxygenation Conditions. AB - PURPOSE: To measure oxygen tension in the aqueous humor of human eyes under different oxygenation conditions. METHODS: This prospective comparative interventional case series consisted of two parts. In the first part, 120 consecutive patients scheduled for cataract surgery were randomized into group I (control group) in which surgery was performed under local anesthesia inhaling 21% oxygen; group II in whom general anesthesia using 50% oxygen was employed; and group III receiving general anesthesia with 100% oxygen. After aspirating 0.2 ml aqueous humor under sterile conditions, the aqueous sample and a simultaneously drawn arterial blood sample were immediately analyzed using a blood gas analyzer. In part II the same procedures were performed in 10 patients after fitting a contact lens and patching the eye for 20 minutes (group IV) and in 10 patients after transcorneal delivery of oxygen at a flow rate of 5 L/min (group V). RESULTS: Mean aqueous PO2 in groups I, II and III was 112.3+/-6.2, 141.1+/-20.4, and 170.1+/-27 mmHg, respectively (P values <0.001) and mean arterial PO2 was 85.7+/-7.9, 184.6+/-46, and379.1+/-75.9 mmHg, respectively (P values <0.001). Aqueous PO2 was 77.2+/-9.2 mmHg in group IV and 152.3+/-10.9 mmHg in group V (P values <0.001). There was a significant correlation between aqueous and blood PO2 (r=0.537, P<0.001). The contribution of atmospheric oxygen to aqueous PO2 was 23.7%. CONCLUSION: Aqueous oxygen tension is mostly dependent on the systemic circulation and in part on the atmosphere. Increasing inspiratory oxygen and transcorneal oxygen delivery both increase aqueous PO2 levels. PMID- 23943687 TI - Outcomes of trabeculectomy with 5-Fluorouracil at a nigerian tertiary hospital. AB - PURPOSE: To report the outcomes of trabeculectomy with adjunctive 5-Fluorouracil (5- FU) at a Nigerian tertiary hospital. METHODS: In this prospective study, all patients with glaucoma undergoing trabeculectomy with 5-FU at the University College Hospital, Ibadan, Nigeria, from June 2009 to May2010 were enrolled. Each patient had a complete ophthalmic evaluation. Intraocular pressure (IOP), visual acuity (VA) and complications post-trabeculectomy were assessed at one year. Success of the procedure was defined as complete when no additional medications were required to achieve an IOP of <=18mmHg, or qualified when additional medications were required to achieve the same goal. RESULTS: A total of 47 eyes of 31 patients with mean age of 48.9+/-19.6 (range 14-77; median 52) years including 21 (67.7%) male subjects underwent trabeculectomy with 5-FU. Mean presenting IOP was 31.8+/-12.2 mmHg. Mean deviation (MD) on Humphrey visual fields was -15.9+/-9.7dB with the majority of the patients (18 subjects 58.1%) presenting with advanced glaucoma based on MD worse than -12dB and severe glaucomatous optic neuropathy (cup to disc ratio of 0.9-1.0). At 1 year postoperatively, 95.1% achieved qualified success while 83% had complete success. CONCLUSION: This prospective study adds to the existing knowledge that trabeculectomy with 5-FU is effective at controlling IOP in Nigerian patients. PMID- 23943688 TI - Modified frontalis sling procedure with lid crease formation. AB - PURPOSE: To report the results of a modified frontalis sling procedure using Mersilene mesh for correction of upper lid ptosis associated with poor levator muscle function. METHODS: This interventional case series included 10 patients (15 eyelids) with congenital ptosis and poor levator function. All subjects underwent the upper lid sling procedure with modifications. Main outcomes were lid crease height and position. RESULTS: Overall, 15 eyelids from ten patients including 7 male and 3 female subjects underwent surgery. After a mean period of 10.2+/-2.8 months, all cases had symmetrical lid crease and contour; upper lid margin to corneal reflex distance and lid fissure were both increased significantly. CONCLUSION: This modified frontalis sling procedure may be considered as an alternative to conventional surgery; this method provides good cosmesis and is associated with a low rate of reoperations. PMID- 23943689 TI - Intelligence Quotient (IQ) in Congenital Strabismus. AB - PURPOSE: To evaluate intelligence quotient (IQ) in patients with congenital strabismus. METHODS: All patients with congenital strabismus scheduled for surgery were enrolled consecutively over a one year period in a cross-sectional study and were evaluated for verbal, performance and total IQ scores, and compared to the mean normal IQ of 100+/-15. RESULTS: During the study period, 109 patients with mean age of 18.4+/-10.5 (range, 4-63) years were included. Educational status in most patients (80%) was less than high-school. Most patients (80%) lived in urban areas and 46 patients (42.2%) had some degrees of unilateral or bilateral amblyopia. Mean verbal IQ was 87.2+/-19.6 (range, 45 127), performance IQ was 81+/-15.5 (range, 44-111) and total IQ was 83.5+/-18.3 (range, 40-120). Total IQ was significantly lower in comparison to the normal population (P<0.01) and significantly higher in urban as compared to rural residents (85.1+/-19.5 versus 77.3+/-10.8 respectively, P=0.02). Patients with coexisting amblyopia and alternate deviation had lower IQ levels. Verbal IQ was insignificantly higher in myopes than emmetropes and hyperopes. IQ was better with vertical deviations and was higher in esotropes than exotropes; however, these differences were not statistically significant (P>0.05 for all comparisons). CONCLUSION: Patients with congenital strabismus in this study had lower mean IQ scores than the normal population which may be due to genetic background or acquired causes secondary to strabismus. PMID- 23943690 TI - Advances in retinal stem cell biology. AB - Tremendous progress has been made in recent years to generate retinal cells from pluripotent cell sources. These advances provide hope for those suffering from blindness due to lost retinal cells. Understanding the intrinsic genetic network in model organisms, like fly and frog, has led to a better understanding of the extrinsic signaling pathways necessary for retinal progenitor cell formation in mouse and human cell cultures. This review focuses on the culture methods used by different groups, which has culminated in the generation of laminated retinal tissue from both embryonic and induced pluripotent cells. The review also briefly describes advances made in transplantation studies using donor retinal progenitor and cultured retinal cells. PMID- 23943691 TI - The six syndromes of the sixth cranial nerve. AB - The sixth cranial nerve runs a long course from the brainstem to the lateral rectus muscle. Based on the location of an abnormality, other neurologic structures may be involved with the pathology related to this nerve. Sixth nerve palsy is frequently due to a benign process with full recovery within weeks, yet caution is warranted as it may portend a serious neurologic process. Hence, early diagnosis is often critical for some conditions that present with sixth nerve palsy. This article outlines a simple clinical approach to sixth nerve palsy based on its anatomy. PMID- 23943692 TI - Acute Corneal Hydrops following Post-keratoplasty Suture Removal in Pellucid Marginal Degeneration. AB - PURPOSE: To report acute corneal hydrops following suture removal after penetrating keratoplasty (PK) in a case of pellucid marginal degeneration (PMD). CASE REPORT: A young female underwent PK for corneal scarring in her left eye due to PMD; 8 months later the last sutures were removed. A few days following suture removal, the patient developed acute hydrops in the inferior aspect of the host graft interface mostly in the recipient portion in the presence of a positive Seidel test. Review of the patient's records revealed suture tract leakage in the early postoperative period at the same location which had been significantly thin. The patient received conservative therapy leading to complete resolution of the condition. CONCLUSION: Through and through suture bites in a mismatched host graft interface can predispose the patient to acute hydrops in PMD when the sutures are removed during routine postoperative care. PMID- 23943693 TI - Management of bilateral congenital upper eyelid eversion with severe chemosis. AB - PURPOSE: To report a case of complete bilateral congenital upper eyelid eversion associated with severe chemosis in a newborn, and to describe a semi-invasive technique for its management. CASE REPORT: The patient was a four-hour-old Nigerian neonate with bilateral congenital upper eyelid eversion with severe and progressive chemosis. Conservative management failed to resolve the condition. However, compression eyelid sutures resulted in prompt and satisfactory resolution. CONCLUSION: Compression eyelid suturing is a semi-invasive technique for management of severe chemosis due to congenital upper lid eversion resulting in rapid and satisfactory resolution of the condition. PMID- 23943694 TI - Retinal Hemorrhages in a Neonate following Vacuum Extraction. PMID- 23943695 TI - Anti-VEGF Agents and Glaucoma Filtering Surgery. PMID- 23943696 TI - A smouldering fire in the eye: vuurtje. PMID- 23943698 TI - Maternal obesity and heart disease in the offspring. PMID- 23943697 TI - Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years. AB - OBJECTIVES: To determine whether maternal obesity during pregnancy is associated with increased mortality from cardiovascular events in adult offspring. DESIGN: Record linkage cohort analysis. SETTING: Birth records from the Aberdeen Maternity and Neonatal databank linked to the General Register of Deaths, Scotland, and the Scottish Morbidity Record systems. POPULATION: 37 709 people with birth records from 1950 to present day. MAIN OUTCOME MEASURES: Death and hospital admissions for cardiovascular events up to 1 January 2012 in offspring aged 34-61. Maternal body mass index (BMI) was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on outcomes in offspring was tested with time to event analysis with Cox proportional hazard regression to compare outcomes in offspring of mothers in underweight, overweight, or obese categories of BMI compared with offspring of women with normal BMI. RESULTS: All cause mortality was increased in offspring of obese mothers (BMI >30) compared with mothers with normal BMI after adjustment for maternal age at delivery, socioeconomic status, sex of offspring, current age, birth weight, gestation at delivery, and gestation at measurement of BMI (hazard ratio 1.35, 95% confidence interval 1.17 to 1.55). In adjusted models, offspring of obese mothers also had an increased risk of hospital admission for a cardiovascular event (1.29, 1.06 to 1.57) compared with offspring of mothers with normal BMI. The offspring of overweight mothers also had a higher risk of adverse outcomes. CONCLUSIONS: Maternal obesity is associated with an increased risk of premature death in adult offspring. As one in five women in the United Kingdom is obese at antenatal booking, strategies to optimise weight before pregnancy are urgently required. PMID- 23943699 TI - Emergency cerclage placement in multifetal pregnancies with a dilated cervix and exposed membranes: case series. AB - Pregnancies complicated by midtrimester painless cervical dilation are known to have associations with preterm birth. In situations where fetal amniotic membranes are exposed, the risk of perinatal morbidity and mortality increases dramatically in this particularly high-risk population. Multifetal gestations further increase the risk of preterm birth, yet there remains a paucity of data supporting therapeutic intervention for these patients. We report a case series of 12 multifetal gestations with painless cervical dilation and exposed fetal membranes that underwent emergency cerclage placement. Pregnancy prolongation was achieved on average 60.25 days with 76.9% neonatal survival. These findings are suggestive that emergency cerclage may be a beneficial treatment in this unique patient population. PMID- 23943700 TI - Glucose-6-phosphate dehydrogenase deficiency and adrenal hemorrhage in a filipino neonate with hyperbilirubinemia. AB - We report on a Filipino neonate with early onset and prolonged hyperbilirubinemia who was delivered by a vacuum extraction due to a prolonged labor. Subsequent studies revealed adrenal hemorrhage and glucose-6-phosphate dehydrogenase (G6PD) deficiency. It is likely that asphyxia and resultant hypoxia underlie the occurrence of adrenal hemorrhage and the clinical manifestation of G6PD deficiency and that the presence of the two events explains the early onset and prolonged hyperbilirubinemia of this neonate. Our results represent the importance of examining possible underlying factors for the development of severe, early onset, or prolonged hyperbilirubinemia. PMID- 23943701 TI - Congenital acinar dysplasia: report of a case and review of literature. AB - Objective Describe a case of congenital acinar dysplasia and review the literature. Study Design Retrospective chart review and literature search. Results Congenital acinar dysplasia is a rare malformation of growth arrest of the lower respiratory tract resulting in critical respiratory insufficiency at birth. It is a form of pulmonary hypoplasia that is characterized by diffuse maldevelopment and derangement of the acinar and alveolar architecture of the lungs, resulting in the complete absence of gas exchanging units. The growth arrested lung tissue resembles the pseudoglandular phase of 16 weeks' gestation. The etiology is unknown. It is diagnosed by exclusion of all other causes of pulmonary hypoplasia and a summation of clinical, imaging, and histopathologic findings. Conclusion There is no cure and clinical treatment is supportive until death of the infant. We present a case of congenital acinar dysplasia in a male infant who lived 20 days with intensive support. PMID- 23943702 TI - Does preeclampsia predict the risk of late postpartum eclampsia? AB - Objective To investigate potential predictive symptoms of late postpartum eclampsia (LPE). Study Design Retrospective review of patients delivered at a single academic medical center and diagnosed with eclampsia greater than 48 hours postdelivery. Results Among 19 patients with eclampsia, 5 (26%) patients with confirmed eclampsia seized greater than 48 hours after delivery. None of these patients showed evidence of preeclampsia intrapartum or immediately postpartum and none received intrapartum magnesium sulfate. Prior to seizure activity, 4 of 5 (80%) patients had increased blood pressure and 2 of 5 (40%) had central nervous system symptoms (headache and visual changes). Conclusion Gestational hypertension (GHTN) may be a risk factor for LPE. Consideration of seizure prophylaxis for patients with GHTN may facilitate the prevention of LPE. PMID- 23943703 TI - A tailgut cyst-cystic mass diagnosed by prenatal ultrasonography. AB - Tailgut cysts are congenital lesions found in the presacral space. These have been mainly identified in adults and are rare in children, especially neonates. Here, we present the case of a neonate with a presacral cystic mass detected by prenatal ultrasonography that was diagnosed as a tailgut cyst after postnatal surgical removal. When a presacral cyst is encountered, tailgut cyst should be considered in the differential diagnosis. PMID- 23943704 TI - Nephrocalcinosis and placental findings in neonatal bartter syndrome. AB - Neonatal Bartter syndrome (NBS) is an inherited renal tubular disorder associated with hypokalemic alkalosis. Here we report a case of genetically diagnosed NBS. Polyhydramnios was noted at 26 weeks. A boy was born at 31 weeks and 1 day, weighed 1344 g, and had an Apgar score of 8/8. We initiated indomethacin (IND) at a dose of 0.2 mg/kg/d on day 31, and increased it to approximately 3 mg/kg/d. However, his urinary calcium (Ca) levels remained unchanged. At 4 months of age, nephrocalcinosis was detected by ultrasound. The placenta weighed 700 g (+2.7 standard deviations). Although the proportion of terminal villi was consistent with the gestational age, many of them exhibited poorly dilated capillaries. Hemosiderin pigment was seen throughout the amniochorionic connective tissue and along about 50% of the trophoblast basement membrane (TBM). Von Kossa stain revealed the corresponding area of mineralization along the TBM. In our opinion, urinary Ca levels were high and did not change after IND initiation, indicating that nephrocalcinosis may be inevitable. Enhanced inflow of maternal plasma through the basement membrane would cause Ca deposition, given that the same finding was obtained in the case with polyhydramnios. The same mechanism would also explain the hemosiderin pigment distribution. PMID- 23943705 TI - Utility of maternal 6-thioguanine nucleotide levels in predicting neonatal pancytopenia. AB - An infant with pancytopenia was born to a mother who used the common immunosuppressant azathioprine (AZA). Maternal and neonatal blood levels of 6 thioguanine nucleotides (6TGN; metabolite of AZA) were 1890 and 1480 pmol/8 * 10(8) red blood cells, respectively. Maternal 6TGN levels could be useful in predicting neonatal pancytopenia. PMID- 23943706 TI - Management of pregnancy in a patient with severe hemophilia type a. AB - Hemophilia type A is a rare inherited bleeding disorder with a diversity of clinical manifestations ranging from persistent bleeding after minor trauma, spontaneous deep muscle or joint hemorrhage, to intracranial hemorrhage. As an X linked disorder, hemophilia is rare in females and therefore there is little experience with pregnancy and no standardized guidelines to prevent bleeding antepartum, at delivery, and postpartum. We report the clinical course and management of a woman with severe hemophilia A who on two occasions had uncomplicated pregnancies and vaginal deliveries at term utilizing bolus recombinant factor VIII concentrate. PMID- 23943707 TI - Confined blood chimerism in monochorionic dizygotic twins conceived spontaneously. AB - Traditionally, monochorionicity has been regarded as synonymous with monozygosity. However, several recent cases of monochorionic dizygotic twins have shown that monochorionic twins can be dizygous. We report a rare case of monochorionic diamnionic, gender-discordant twins who were conceived spontaneously. Initially, a monochorionic placenta was diagnosed by ultrasonography at 8 weeks of gestation and then confirmed by pathology after delivery. The twins had different genders. A comparison of cytogenetic analyses using peripheral blood lymphocytes and skin fibroblasts revealed that chimerism was confined to blood cells. We have experienced two cases of monochorionic dizygotic twins since 2003. These cases suggest that monochorionic dizygotic twins are not as rare as previously thought. PMID- 23943708 TI - Second-trimester diagnosis of triploidy: a series of four cases. AB - Triploidy occurs in 2 to 3% of conceptuses and accounts for approximately 20% of chromosomally abnormal first-trimester miscarriages. As such, triploidy is estimated to occur in 1 of 3,500 pregnancies at 12 weeks', 1 in 30,000 at 16 weeks', and 1 in 250,000 at 20 weeks' gestation. We present a series of four cases of second-trimester triploidy diagnosed at our center within a 1-year timeframe. This is remarkable, as the delivery volume at our institution is roughly 2,500/y. All patients were at least 19 weeks' gestation, with multiple abnormalities identified on prenatal ultrasound at 18 to 20 weeks' gestation; all fetuses had lethal anomalies, but anomalies were not consistent between cases. All patients elected for induction of labor before 24 weeks' gestational age. Two of the four cases had amniocentesis and chromosome analysis prior to delivery, and two cases had chromosome analysis performed on fetal tissue after delivery. All fetuses were examined following delivery. This case series demonstrates that the diagnosis of triploidy may not be obvious based on ultrasound and physical examination findings and highlights the importance of routine chromosome analysis on all prenatal diagnoses of multiple congenital anomalies prior to consideration of more complex genetic testing. PMID- 23943709 TI - A case of alloimmune thrombocytopenia, hemorrhagic anemia-induced fetal hydrops, maternal mirror syndrome, and human chorionic gonadotropin-induced thyrotoxicosis. AB - Fetal/neonatal alloimmune thrombocytopenia (FNAIT) can be a cause of severe fetal thrombocytopenia, with the common presentation being intracranial hemorrhage in the fetus, usually in the third trimester. A very unusual case of fetal anemia progressed to hydrops. This was further complicated by maternal Mirror syndrome and human chorionic gonadotropin-induced thyrotoxicosis. Without knowledge of etiology, and possibly due to associated cardiac dysfunction, fetal transfusion resulted in fetal demise. Subsequent testing revealed FNAIT as the cause of severe hemorrhagic anemia. In cases with fetal anemia without presence of red blood cell antibodies, FNAIT must be ruled out as a cause prior to performing fetal transfusion. Fetal heart may adapt differently to acute hemorrhagic anemia compared with a more subacute hemolytic anemia. PMID- 23943710 TI - Management of pregnancy-associated thrombotic thrombocytopenia purpura. AB - Thrombotic thrombocytopenia purpura (TTP) is an infrequent but serious disease. Pregnancy is a known risk factor for presentation or relapse of TTP. Difficulties in differentiating TTP from preeclampsia/HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, and current treatment recommendations are discussed in this case report. A woman with previously treated and stable TTP had a relapse at 36 weeks' gestation. Careful surveillance led to an early diagnosis. Severe disease in the peripartum period was treated successfully with cryosupernatant plasma-based plasmapheresis and platelet transfusion, with good maternal and neonatal outcomes. Cryosupernatant plasma is a viable alternative to fresh frozen plasma for plasmapheresis for TTP and may offer some therapeutic and logistical advantages. Platelet transfusion can be undertaken safely if needed to prevent or treat significant hemorrhage. PMID- 23943711 TI - Pregnancy and Perinatal Outcomes Associated with Acinetobacter baumannii Infection. AB - Objective To determine perinatal and pregnancy outcomes of Acinetobacter baumannii infection using clinicopathologic material from pregnant women, neonates, and perinatal postmortem examinations with positive cultures. Study Design This is a retrospective record review with placental and postmortem examination. Results During a 5-year period, 40 positive cultures were found. Three pregnancies with positive cultures close in the peripartum period were all associated with adverse outcomes including spontaneous abortion, preterm labor, and one full-term birth with histological chorioamnionitis. Two positive cultures were found in preterm neonates in the neonatal intensive care unit. Two of three cases of perinatal death grew pure cultures from blood and/or fetal tissue with placental or fetal examination demonstrating evidence of infection/inflammation with fetal inflammatory response. Conclusion This is the first case series report of A. baumannii-positive cultures in maternal, fetal, and neonatal specimen, with histopathologic evidence of infection. The results suggest a significant role of A. baumannii infection in adverse pregnancy and perinatal outcomes. PMID- 23943712 TI - Clitoral epidermoid cyst presenting as pseudoclitoromegaly of pregnancy. AB - Objective Acquired clitoromegaly is rare and may result from hormonal and nonhormonal causes, and evaluation of the pregnant patient with clitoromegaly invokes a specific set of differential diagnoses. Methods Case report. Results We describe the case of a young woman with pregnancy-associated clitoral enlargement whose hormonal evaluation proved negative. Further investigation concluded that an epidermoid cyst was the culprit of her pseudoclitoromegaly. The patient underwent successful surgical resection and has had no recurrence at her subsequent pregnancy. Conclusion We review the differential diagnosis of clitoromegaly, including hormonal and nonhormonal causes, with focus on the evaluation of pregnancy-associated clitoromegaly. PMID- 23943713 TI - The efficacy and safety of preoperative lumbar drain placement in anterior skull base surgery. AB - This study assesses the efficacy of preoperative lumbar drain (LD) placement prior to elective open cranial and endoscopic anterior skull base (ASB) surgery in reducing postoperative cerebrospinal fluid (CSF) leak. A retrospective review of 93 patients who underwent LD placement at our institution between 2006 and 2011 was performed. Of these patients, 43 underwent elective LD placement prior to ASB surgery; 2 patients had evidence of CSF rhinorrhea prior to surgery, and 41 had no evidence of a preoperative CSF leak. Of those 41 patients, 2 developed CSF rhinorrhea (2/41= 4.9%) as a result of surgery-all in our endoscopic patient population (N = 21; 2/21= 9.5%). No postoperative CSF leaks were noted in our open ASB surgery cohort (N = 20). Other complications were rare, but we encountered two instances of delayed malignant cerebral edema in the open ASB cohort that are discussed in detail. Overall, preoperative LD placement was found to be an effective means of preventing postoperative CSF leaks after ASB approaches, but potential and significant intracranial complications may occur in select patients that merit careful consideration prior to LD placement. PMID- 23943714 TI - Delayed cavernous carotid artery pseudoaneurysm caused by absorbable plate following transsphenoidal surgery: case report and review of the literature. AB - Background Bioabsorbable plates are frequently utilized in the repair of skull base defects following transsphenoidal operations. Traumatic intracranial pseudoaneurysms are a rare complication of transsphenoidal surgery. To date, iatrogenic carotid pseudoaneurysm associated with the use of an absorbable plate has been reported once. Results A 57-year-old man with a large nonfunctional pituitary macroadenoma underwent an endoscopic transsphenoidal operation with gross total resection. An absorbable plate was placed extradurally to reconstruct the sellar floor. He experienced delayed repeated epistaxis, followed by a right middle cerebral artery distribution embolic stroke. Computed tomorgraphy (CT) angiogram 6 weeks postoperatively revealed a 6 * 4 mm pseudoaneurysm located on the medial wall of the right cavernous internal carotid artery. Stent coiling was used to successfully obliterate the pseudoaneurysm, and the patient fully recovered. Conclusion Delayed erosion of the carotid artery wall caused by a plate used to reconstruct the sellar floor may manifest with epistaxis or embolic stroke. The authors' preference is to avoid insertion of a rigid plate for sellar floor reconstruction in the absence of intraoperative cerebrospinal fluid (CSF) leaks, unless it is required to buttress a large skull base defect. Short-segment embolization with stent coiling is the preferred treatment option for carotid pseudoaneurysms following transsphenoidal operations. PMID- 23943715 TI - Primary intraosseous cavernous hemangioma of the clivus: case report and review of the literature. AB - Primary intraosseous hemangiomas are benign, vascular malformations that account for approximately 1% of all primary bone neoplasms. These tumors are mostly found in vertebral bodies and are rarely seen in the calvarium, where they represent 0.2% of bony neoplasms. When found in the skull, they tend to present with vague symptoms and do not have the typical radiological findings suggestive of hemangiomas. Because of this, these tumors can be missed in many cases or may be misinterpreted as more ominous lesions like multiple myeloma or osteosarcoma. Involvement of the skull base is exceedingly rare, and presentation with cranial nerve unilateral polyneuropathies has not been reported. We report a patient case with review of recent pertinent literature. PMID- 23943716 TI - Injury to the Temporal Lobe via Medial Transorbital Entry of a Toothbrush. AB - Objectives Intracranial penetration by foreign bodies entering via the orbit represent an unusual form of traumatic brain injury. Nevertheless, much is at stake with high risk for cranial nerve and neurovascular injury. We present a case where the bristled end of a toothbrush entered the brain as a projectile via the superior orbital fissure and discuss considerations for surgical management. Setting A 35-year-old woman suffered a periorbital injury after her husband threw an electric toothbrush at a wall and the head of the toothbrush became a missile that projected through her superior orbital fissure and into her right temporal lobe. She complained of headache and incomplete vision loss in the affected eye. Intervention After obtaining a cerebrovascular angiogram, we proceeded with emergent orbital decompression and anterograde extraction of the foreign body via a modified frontotemporal orbitozygomatic approach with drilling of the skull base allowing for en bloc removal of the toothbrush. Conclusions The patient recovered well with improvement in her vision and partial third and sixth nerve palsies. This report illustrates a unique mechanism of injury with a novel intracranial foreign body. We review the neurosurgeon's need for prompt management with an approach customized to the structure of the offending object, the damaged elements, and the surrounding cranial nerves and vascular anatomy. PMID- 23943717 TI - Xanthoma of the occipital bone and with preserved inner and outer bone cortex: case report. AB - Objective We present a unique case of a midline xanthoma of the occipital bone exhibiting atypical imaging characteristics with preserved bone cortex that has not previously been described. Participant This man presented with refractory headaches and suboccipital pain and a mass within the diploe of the occipital bone but with preserved inner and outer cortex of the bone. Magnetic resonance imaging showed a midline, enhancing, and marrow-replacing process in the occipital bone measuring 1.5 cm in anteroposterior (AP) diameter, resulting in mild indentation of the dorsal aspect of the cerebellar vermis. Results The patient underwent a suboccipital craniectomy. Tumor resection was from the foramen magnum to the inion and laterally until normal bone was encountered. The xanthoma was yellowish and bled a moderate amount upon resection. Conclusion An isolated cranial xanthoma with preserved inner and outer bone cortex involving the occipital bone and of midline location has yet to be described. The differential diagnosis of osteoexpansile skull lesion with preserved bone cortex should now include xanthoma. Given the broad spectrum of imaging characteristics exhibited by this unusual diagnosis, surgical intervention is indicated from a diagnostic as well as a therapeutic standpoint. PMID- 23943718 TI - Positron emission tomography-computed tomography coregistration for diagnosis and intraoperative localization in recurrent nelson syndrome. AB - Recurrent pituitary disease presents unique challenges, including in some cases difficulty localizing a tumor radiographically. Here, we present the case of a patient with recurrent Nelson syndrome whose radiographic work-up was complicated by a significant parasellar metallic artifact. Positron emission tomography ultimately localized the lesion, and coregistration with computed tomography allowed for accurate intraoperative navigation. Additionally, we review a range of imaging techniques available in the evaluation of pituitary disease. PMID- 23943719 TI - Osteoblastoma of the lateral skull base: work-up, surgical management, and a review of the literature". AB - Objectives To describe the work-up and surgical management of an osteoblastoma involving the lateral skull base. Typically occurring in the spine or long bones, osteoblastomas of the craniofacial skeleton are exceedingly rare and infrequently reported. A review of the current literature regarding temporal bone osteoblastoma, diagnosis, and treatment is described. Methods This case report describes the clinical presentation, radiographic studies, surgical management, histology, and postoperative follow-up of a young man presenting to a tertiary care neurotology practice with osteoblastoma involving the lateral skull base. A review of the current literature regarding osteoblastoma of the skull base, work up, and treatment is described. Results A 15-year-old adolescent boy with a greater than 1-year history of right-sided retroauricular pain, a palpable postauricular mass, and chronic headaches presented for evaluation/management. Microscope examination of the ears, hearing, and cranial nerve function were normal. High-resolution temporal bone computed tomography and magnetic resonance imaging scans were obtained, which revealed an expansile mass involving the junction of the temporal and occipital bones. The patient underwent a combined retrosigmoid/retrolabyrinthine resection of this extradural tumor. Histology revealed a benign bone neoplasm consistent with osteoblastoma. Complete surgical resection was achieved, and the patient's symptoms fully resolved. Follow-up imaging studies found no evidence of recurrence. The scientific literature relevant to work-up and management of osteoblastoma is reviewed. Discussion Osteoblastomas of the lateral skull base are rare, histologically benign tumors that can present with radiographic features suggestive of malignancy. An en bloc resection is important for both diagnosis and definitive treatment of these neoplasms. The differential diagnosis on imaging and histology is discussed. PMID- 23943721 TI - Vascular leiomyoma and geniculate ganglion. AB - Objectives Discussion of a rare case of angioleiomyoma involving the geniculate ganglion and the intratemporal facial nerve segment and its surgical treatment. Design Case report. Setting Presence of an expansive lesion englobing the geniculate ganglion without any lesion to the cerebellopontine angle. Participants A 45-year-old man with a grade III facial paralysis according to the House-Brackmann scale of evaluation. Main Outcomes Measure Surgical pathology, radiologic appearance, histological features, and postoperative facial function. Results Removal of the entire lesion was achieved, preserving the anatomic integrity of the nerve; no nerve graft was necessary. Postoperative histology and immunohistochemical studies revealed features indicative of solid vascular leiomyoma. Conclusion Angioleiomyoma should be considered in the differential diagnosis of geniculate ganglion lesions. Optimal postoperative facial function is possible only by preserving the anatomical and functional integrity of the facial nerve. PMID- 23943720 TI - Value of Free-Run Electromyographic Monitoring of Extraocular Cranial Nerves during Expanded Endonasal Surgery (EES) of the Skull Base. AB - Objective To evaluate the value of free-run electromyography (f-EMG) monitoring of extraocular cranial nerves (EOCN) III, IV, and VI during expanded endonasal surgery (EES) of the skull base in reducing iatrogenic cranial nerve (CN) deficits. Design We retrospectively identified 200 patients out of 990 who had at least one EOCN monitored during EES. We further separated patients into groups according to the specific CN monitored. In each CN group, we classified patients who had significant (SG) f-EMG activity as Group I and those who did not as Group II. Results A total of 696 EOCNs were monitored. The number of muscles supplied by EOCNs that had SG f-EMG activity was 88, including CN III = 46, CN IV = 21, and CN VI = 21. There were two deficits involving CN VI in patients who had SG f EMG activity during surgery. There were 14 deficits observed, including CN III = 3, CN IV = 2, and CN VI = 9 in patients who did not have SG f-EMG activity during surgery. Conclusions f-EMG monitoring of EOCN during EES can be useful in identifying the location of the nerve. It seems to have limited value in predicting postoperative neurological deficits. Future studies to evaluate the EMG of EOCN during EES need to be done with both f-EMG and triggered EMG. PMID- 23943722 TI - A case of orbital emphysema associated with frontal sinus pneumocele. AB - Orbital emphysema is usually caused by trauma and fracture of an orbital bone, allowing air to pass from the sinuses into the orbit. Orbital emphysema without any significant trauma is rare. We present a case of a 67-year-old-woman who complained of left exophthalmos without any history of trauma, sneezing, or sinus surgery. Computed tomography scanning showed left orbital emphysema protruding the eyeball forward. The left frontal sinus was remarkably enlarged associated with a partial defect of the orbital roof, allowing air entry into the orbit. In addition, the frontal sinus ostium was occluded with the mucocele that served as a one-way valve between the frontal and the ethmoidal sinuses. We performed frontal craniotomy and removed the mucocele and the inner table of frontal bone to communicate the frontal sinus with the nasal cavity. After operation, her exophthalmos was improved. PMID- 23943723 TI - Diagnosis and surgical management of traumatic cerebrospinal fluid oculorrhea: case report and systematic review of the literature. AB - Background Oculorrhea, or cerebrospinal fluid leakage developing from a cranio orbital fistula, is a rare development following traumatic injury. Case Report A 22-year-old man involved in a motor vehicle accident developed a blowout fracture of the left orbital roof penetrating the frontal lobe, inducing oculorrhea. He underwent a supraorbital craniotomy for removal of the bony fragment and skull base reconstruction using a pericranial flap. Methods A systematic review of the database was performed to identify all prior cases of traumatic oculorrhea. Results Twenty-two reported cases met inclusion criteria for subsequent analysis. Oculorrhea developed due to blunt and penetrating head injury in 14 (64%) and 8 patients (36%), respectively. The most common mechanisms were car accidents, stab wounds, falls, and gunshot wounds. Ocular signs and symptoms-including visual loss, ophthalmoplegia, and pupillary dysfunction-were commonly associated findings. Initial conservative management was successful in four patients. Thirteen patients underwent initial surgical intervention, and three additional patients required operative intervention following failed conservative treatment. Conclusion Although oculorrhea rarely develops following severe orbital trauma, suspicion should nevertheless be maintained to facilitate more prompt diagnosis and management. The decision for conservative versus surgical management often depends on the severity of the fracture and dural injury. PMID- 23943724 TI - Patient-centered treatment goals. PMID- 23943725 TI - Aspirin and salicylate in respiratory disease. AB - This article describes the natural history, pathogenesis and diagnosis of Aspirin Exacerbated Respiratory Disease. The evidence base for the role of oral aspirin and nasal L-Lysine-aspirin desensitisation is reviewed. Evidence for the role of dietary salicylic acid and its avoidance is also reviewed. PMID- 23943726 TI - Olfactory loss after head and neck cancer radiation therapy. AB - BACKGROUND: A reduced sense of smell may be one explanation for why patients with cancer in the ear, nose and throat (ENT) region who are treated with radiation therapy lose weight. The purpose of this study was to investigate whether radiation therapy has a negative effect on olfactory function and, if so, whether this effect is dose-related. METHODOLOGY: Seventy-one patients were tested using odour-detection sensitivity and olfactory identification tests before radiation therapy and 20 months after it. RESULTS: Patients who received radiation close to the olfactory organ showed a reduced sense of smell, in both tests. A multiple regression analysis showed that the radiation dose was related to decline in the olfactory function, while age, sex, chemotherapy and interactions between these variables were not. CONCLUSION: Radiation therapy can damage olfactory cells. PMID- 23943727 TI - Clinical usefulness and feasibility of time-frequency analysis of chemosensory event-related potentials. AB - BACKGROUND: The clinical usefulness of olfactory event-related brain potentials (OERPs) to assess olfactory function is limited by the relatively low signal-to noise ratio of the responses identified using conventional time-domain averaging. Recently, it was shown that time-frequency analysis of the obtained EEG signals can markedly improve the signal-to-noise ratio of OERPs in healthy controls, because it enhances both phase-locked and non phase-locked EEG responses. The aim of the present study was to investigate the clinical usefulness of this approach and evaluate its feasibility in a clinical setting. METHODOLOGY: We retrospectively analysed EEG recordings obtained from 45 patients (15 anosmic, 15 hyposmic and 15 normos- mic). The responses to olfactory stimulation were analysed using conventional time-domain analysis and joint time-frequency analysis. The ability of the two methods to discriminate between anosmic, hyposmic and normosmic patients was assessed using a Receiver Operating Characteristic analysis. RESULTS: The discrimination performance of OERPs identified using conventional time-domain averaging was poor. In contrast, the discrimination performance of the EEG response identified in the time-frequency domain was relatively high. Furthermore, we found a significant correlation between the magnitude of this response and the psychophysical olfactory score. CONCLUSION: Time-frequency analysis of the EEG responses to olfactory stimulation could be used as an effective and reliable diagnostic tool for the objective clinical evaluation of olfactory function in patients. PMID- 23943728 TI - Clinical effects of sinus surgery and adjuvant therapy in cystic fibrosis patients - can chronic lung infections be postponed? AB - BACKGROUND: The paranasal sinuses can be a bacterial reservoir for pulmonary infections in patients with cystic fibrosis (CF) METHODOLOGY: In this prospective, non-randomised, uncontrolled, intervention cohort study, the clinical effect of sinus surgery followed by two weeks' intravenous antibiotics, 6 months' antibiotic nasal irrigations was assessed in 106 CF patients. RESULTS: One year after sinus surgery, the prevalence of intermittently colonised patients had decreased by 38%, while the prevalence of non-colonised patients had increased by 150%. The frequency of pulmonary samples with CF pathogens was reduced after surgery. Specific IgG against P. aeruginosa decreased after six months. Additionally, the self reported symptoms of chronic rhinosinusitis and quality of life improved. CONCLUSION: Combined sinus surgery and postoperative systemic and topical antibiotic treatment significantly reduced the frequency of pulmonary samples positive for CF pathogens in the first year after sinus surgery. PMID- 23943729 TI - Do patients with chronic rhinosinusitis with nasal polyps suffer with facial pain? AB - BACKGROUND: Many patients attribute their symptoms of facial pain or headache to sinus problems. Facial pain is one of the symptoms of rhinosinusitis according to European and American consensus documents. This symptom, however, has been insufficiently studied in the group of patients with chronic rhinosinusitis with nasal polyps (CRSwNP). The aim of this work is to study the symptom of facial pain in patients with CRSwNP. METHODS: Patients with CRSwNP were prospectively asked to score their facial pain according to the scoring system used in the Sino Nasal Outcome Test 22 (SNOT 22). RESULTS: Fifty patients fulfilled the inclusion criteria. Thirty-one patients had grade II polyps and 19 patients had grade III polyps. Of these patients, 76% had absent or very mild facial pain. Only 16% of patients had moderate or severe facial pain. All patients with severe facial pain had viscid secretions within their sinuses. CONCLUSION: Significant facial pain is uncommon in patients with CRSwNP. It is important to consider this when counselling patients before surgery. PMID- 23943730 TI - Serial blood serotonin levels in a randomized controlled trial comparing the efficacy of low-dose amitriptyline, amitriptyline with pindolol and surrogate placebo in patients with chronic tension-type facial pain. AB - BACKGROUND: Patients often present with chronic facial pain despite normal nasal endoscopy and sinus computerized tomography. Such pain has increasingly been recognized as being of neurological origin with one of the commonest underlying causes being mid-facial segmental tension-type pain (MFP) which is a version of tension headache in the face. Descending serotonergic neuronal projections are known to modulate pain and intra-platelet serotonin levels are an accepted model reflecting central intra-neuronal serotonin. OBJECTIVES: 1.To determine whether low-dose amitriptyline significantly changes whole blood serotonin compared to a surrogate placebo in patients with chronic MFP 2. To determine whether the addition of pindolol, a beta blocker with serotonin receptor blocking properties further alters blood serotonin. METHODOLOGY: Sixty-two patients were randomized to three treatment groups a) amitriptyline , b) amitriptyline with pindolol, and c) loratadine as surrogate placebo. Whole blood serotonin was taken before and after 8 weeks of treatment. Serotonin was also measured in 40 age-matched healthy controls. RESULTS: There was a significant reduction in blood serotonin levels in the amitriptyline with pindolol group. A non-significant reduction was seen in the amitriptyline group, with no change in serotonin levels in the surrogate placebo group. A comparison of change in serotonin with change in pain frequency and intensity scores is presented. Women in the control group had significantly higher serotonin levels than men. Women with tension-type facial pain who failed to respond to treatment had significantly lower blood serotonin than women in the control group. CONCLUSION: When linked to the clinical response this study provides evidence that the serotonergic system is involved in the modulation of chronic MFP. Serotonin levels are sex-dependent and related to treatment response. PMID- 23943731 TI - Does airway integrated nasal packing after septal surgery improve body oxygenation? AB - BACKGROUND: Airway integrated nasal packing reportedly improves body oxygenation after septal surgery. This randomized controlled study examined the effect of airway integrated nasal packing on oxygen saturation. METHODS: Eighty patients with septal deviation and hypertrophic turbinate were randomly divided into two groups: Group 1 patients were postoperatively packed with airway integrated Nasopore, and Group 2 patients were postoperatively packed with Nasopore without airway integration. The haemodynamic parameters and SpO2 (oxyhemoglobin saturation levels when measured using pulse oximetry) were sequentially checked. Nasal pain sensations were recorded using a visual analog scale. RESULTS: SpO2 was not significantly different between Groups 1 and 2. Nasal pain levels were significantly higher in Group 1 than in Group 2 at both 4 (p = 0.034) and 6 (p = 0.001) hours postoperatively. There were no significant differences between the two groups in the incidences of septal haematoma, perforation, or bleeding, or in sequentially checked heart rate, mean blood pressure, or respiration rate. CONCLUSION: It was not evident that integrated airways improved the reduction of SpO2. However, Group 1 patients, with integrated airways, had more pain than did Group 2 patients, without integrated airways. EVIDENCE LEVEL: 1b. PMID- 23943732 TI - Evaluating the relationship between nasal obstruction and mean platelet volume by using acoustic rhinometry in patients with septum deviation. AB - BACKGROUND: Nasal airway obstruction is a common cause of upper airway obstruction. It is associated strongly with obstructive and hypoxic manifestations. Mean platelet volume (MPV) levels increase in hypoxic conditions. MPV is one of the platelet activation indices which re!ects the platelet production rate. We aimed to evaluate the relationship between MPV levels and nasal septal deviation (NSD) by using acoustics rhinometry in patients with septum deviation. METHODS: We performed a retrospective study of 51 patients with NSD and 58 healthy age matched subjects as control group. The diagnosis of patients with NSD was based on anterior rhinoscopy, endoscopic nasal examination and acoustics rhinometry. All the patients underwent Cottle- or Killian-type septoplasty under general anesthesia. Blood samples were collected before nasal septoplasty. RESULTS: MPV and platelet distribution width (PDW) levels were significantly higher and mean platelet count was lower in patients with NSD than the control group. A negative correlation was found between MPV, NDVol2 (volume2 of non-deviated side of the nose) and TNDVol (total volume of non-deviated side of the nose) values. CONCLUSION: MPV values increase in patients with NSD. Moreover, this increase was found in relation with the severity of obstruction. PMID- 23943733 TI - Influence of exposure to tobacco cigarette smoke on the eosinophil count in the nasal mucosa of young patients with perennial allergic rhinitis. AB - BACKGROUND: To assess the influence of exposure to tobacco cigarette smoke on the eosinophil count and the frequency of apoptosis of eosinophils in the nasal mucosa of teenagers with perennial allergic rhinitis. METHODS: Fifty patients were evaluated (aged 10 to 19 years old): 25 patients with and 25 patients with no recent exposure to tobacco cigarette smoke, by means of The Global Youth Tobacco Survey and cotinine/creatinine ratio. After a clinical evaluation, all the patients replied to a validated questionnaire of the severity of nasal symptoms; then, a nasal sample was processed to identify the eosinophil count and the frequency of apoptosis of eosinophils. RESULTS: Patients with active exposure to tobacco cigarette smoke had higher eosinophil counts than patients with no exposure to the smoke. In the two groups, apoptosis of eosinophils in the nasal mucosa was scarce and no significant correlation was observed between the frequency/severity of the nasal symptoms and the eosinophil count. CONCLUSION: Teenagers with perennial allergic rhinitis and active exposure to tobacco cigarette smoke may show increased eosinophil counts in the nasal mucosa, which might not be related to apoptosis of eosinophils or to the frequency/severity of nasal symptoms. PMID- 23943734 TI - Premedication with clonidine before TIVA optimizes surgical field visualization and shortens duration of endoscopic sinus surgery - results of a clinical trial. AB - BACKGROUND: During functional endoscopic sinus surgery (FESS), intraoperative bleeding can significantly compromise visualization of the surgical field. Clonidine constricts peripheral blood vessels and reduces systemic blood pressure, which in combination decrease nasal mucosa blood flow. This dual effect can potentially reduce bleeding during FESS and stabilize the intraoperative hemodynamic profile of the patient. AIM: The aim of this prospective study was to assess if the quality of the surgical field visualization during FESS was improved when clonidine was used as a premedication agent. METHODOLOGY: A group of 44 patients undergoing FESS for chronic sinusitis and polyp removal were enrolled and randomly assigned to receive either oral clonidine or midazolam as preoperative premedication. During the operation, the quality of the surgical field was assessed and graded by the operating surgeon using the scale proposed by Boezaart. The evaluations were done during surgery at 15 minutes (K1), 30 minutes (K2), 60 minutes (K3) and 120 minutes (K4) after incision. RESULTS: The duration of the surgical procedure was significantly shorter in the clonidine group: mean time of surgery: 80 vs. 96 min in the clonidine and midazolam groups, respectively. Also better quality of surgical field was observed at all time points in the clonidine group. CONCLUSION: Premedication with clonidine before FESS results in shortening of the surgical time and a better quality of the surgical field. PMID- 23943735 TI - Nasal and paranasal involvement in primary Sjogren's syndrome. AB - BACKGROUND: The aim of this study is to investigate nasal and paranasal signs and symptoms of the primary Sjogren's syndrome patients and compare them with healthy controls. METHODOLOGY: Seventy-seven (7 M, 70 F) primary Sjogren's syndrome patients and 77 healthy controls were included in the study. Anterior rhinoscopy, nasal endoscopy, 5 component smell discrimination test, nasal clearance analysis with saccharin test and electrorhinomanometer were performed. RESULTS: Nasal crusting was present in 31 and 24 individuals in patient and control groups, respectively. Sinusitis was present in 2 and 1 individuals in patient and control groups, respectively. Nasal polyposis was present in 7 and 1 individuals in patient and control groups, respectively. These differences were not statistically different. CONCLUSION: Although there were some findings in a few patients, nasal findings were insignificant and mild even in patients with severe oral or ocular findings. Rhinomanometry, nasal clearance determination or smell discrimination tests have very little value in the diagnosis or management of primary Sjogren's syndrome. Nasal polyposis was higher in the patient group, though it did not reach a significant level. Nasal glandular involvement is mild and insignificant in primary Sjogren's syndrome. PMID- 23943736 TI - Optimising outcomes in the management of spontaneous cerebrospinal fluid rhinorrhoea. AB - BACKGROUND: To describe our experience of the management of spontaneous cerebrospinal fluid (CSF) rhinorrhoea in a large case series focusing on surgical approach, peri-operative management and outcomes; to evaluate the efficacy of endoscopic CSF leak repairs. METHODOLOGY: Retrospective chart review was performed for all patients with spontaneous CSF rhinorrhoea managed from 2003 to 2011 at a tertiary referral centre. Data regarding demographics, presentation, site of leak, peri-operative management, surgical approach, body mass index (BMI), follow up and success rates was collated. RESULTS: Thirty-six patients were identified: 9 male and 27 female with a mean age of 50.4 years. Eight patients had previous failed repairs in other units. Success rate after first surgery was 89 % and after second surgery was 100 %. Four patients had recurrences, 3 underwent successful revisions and the fourth had complete cessation of the leak after gastric bypass surgery and weight reduction. All failures were before 2004 prior to instigation of an anatomic three-layered repair with no further failures in the following 7 years. Mean follow up was 21.5 months. Mean body mass index was 34.0 kg/m2. Fifty percent of spontaneous leaks were from the cribriform plate, 22 % sphenoid, 14 % ethmoid and 14 % frontal sinus. CONCLUSION: Endoscopic CSF fistula closure has become the gold standard of care. In order to optimise the outcome, we recommend a multidisciplinary approach to manage the associated idiopathic intracranial hypertension and an anatomic three-layered closure technique for recalcitrant cases. PMID- 23943737 TI - Evaluation of inferior turbinate outfracture outcomes using computed tomography. AB - BACKGROUND: Outfracture of the inferior turbinate (IT) presents numerous advantages, but it is generally believed that the lateralized IT will resume its original position. The purpose of this study was to evaluate the outcome of IT outfracture objectively using computed tomography (CT). METHODOLOGY: Fifteen patients who underwent bilateral IT outfracture for the removal of pituitary adenomas by the endonasal approach were enrolled. The angles between the lateral wall of the nasal cavity (NC) and IT on both sides were measured from CT scans before and at least 6 months after operation. In addition, we evaluated the effects of variables including age, thickness of IT attachment site and width of the nasal floor, on the angles. RESULTS: Regardless of the side where a Hardy retractor was placed, the angle between the lateral wall of the NC and IT decreased significantly within 6 months after the outfracture compared to preoperative values on both sides. Other variables showed no significant correlations with the angle between the IT and the lateral wall of the NC. CONCLUSION: The outfracture procedure effectively lateralized the IT and it maintained that position for at least 6 months after the operation. PMID- 23943738 TI - A retrospective analysis of 29 isolated sphenoid fungus ball cases from a medical centre in Korea (1999-2012). AB - BACKGROUND: Isolated sphenoid sinus disease (ISSD) is rare. Fungus ball (FB) is the third most common ISSD. We analysed the characteristics of isolated sphenoid FB based on demographic data, presenting symptoms, preoperative computed tomography (CT), magnetic resonance imaging (MRI), and treatment outcomes. METHODOLOGY: From 1999 to 2012, 29 patients were identified with isolated sphenoid FB. Demographic data; clinical characteristics; endoscopic, CT, and MRI findings and treatment outcomes were retrospectively analysed. RESULTS: The most common symptom was headaches, which were localized in various regions of the brain. Other symptoms were uncommon. The most common CT findings were sclerosis, calcification, enlarged sinus and total opacification. On T2-weighted MRI images, we most commonly observed signal void. Endoscopic transnasal paraseptal sphenoidotomy was performed in all patients, and for most, this was performed under local anaesthesia. No recurrence was observed in any patient. CONCLUSION: Isolated sphenoid FB is predominantly observed in older women, and it is characterised by headaches and sclerosis of the sinus wall observed on CT scans. In cases of isolated sphenoid FB, endoscopic transnasal paraseptal sphenoidotomy can be successfully performed under local anaesthesia, which may facilitate rapid recovery and a low morbidity rate. PMID- 23943739 TI - Coadaptive stability of interfering particles with HIV-1 when there is an evolutionary conflict. PMID- 23943740 TI - Reply to "Coadaptive stability of interfering particles with HIV-1 when there is an evolutionary conflict". PMID- 23943742 TI - Study results show it's time to rethink systematic review methods. PMID- 23943743 TI - Drug approval packages and briefing documents are already freely available. PMID- 23943744 TI - Healthy pregnant women still don't need routine iron supplementation. PMID- 23943745 TI - Author's reply to Steer. PMID- 23943746 TI - Consent forms for clinical trials are too aggressive. PMID- 23943747 TI - Social care should be free for everyone in last weeks of life. PMID- 23943748 TI - The law should be changed to allow assisted dying. PMID- 23943749 TI - The Swiss experience of assisted suicide is positive. PMID- 23943750 TI - What do families and professional organisations really think about assisted dying? PMID- 23943751 TI - GPs could start by listening to dying patients and thus improve care. PMID- 23943752 TI - Abnormal vaginal discharge. PMID- 23943753 TI - Ban routine use of critically important antibiotics in food animals. PMID- 23943754 TI - Giving dying people what they want. PMID- 23943755 TI - Bringing chemistry out of the kitchen. PMID- 23943756 TI - Making the medical notes of hunger strikers at Guantanamo Bay available to trusted doctors. PMID- 23943757 TI - Livestock origin for a human pandemic clone of community-associated methicillin resistant Staphylococcus aureus. AB - The importance of livestock as a source of bacterial pathogens with the potential for epidemic spread in human populations is unclear. In recent years, there has been a global increase in community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections of healthy humans, but an understanding of the different evolutionary origins of CA-MRSA clones and the basis for their recent expansion is lacking. Here, using a high-resolution phylogenetic approach, we report the discovery of two emergent clones of human epidemic CA-MRSA which resulted from independent livestock-to-human host jumps by the major bovine S. aureus complex, CC97. Of note, one of the new clones was isolated from human infections on four continents, demonstrating its global dissemination since the host jump occurred over 40 years ago. The emergence of both human S. aureus clones coincided with the independent acquisition of mobile genetic elements encoding antimicrobial resistance and human-specific mediators of immune evasion, consistent with an important role for these genetic events in the capacity to survive and transmit among human populations. In conclusion, we provide evidence that livestock represent a reservoir for the emergence of new human-pathogenic S. aureus clones with the capacity for pandemic spread. These findings have major public health implications highlighting the importance of surveillance for early identification of emergent clones and improved transmission control measures at the human-livestock interface. IMPORTANCE: Animals are the major source of new pathogens affecting humans. However, the potential for pathogenic bacteria that originally were found in animals to switch hosts and become widely established in human populations is not clear. Here, we report the discovery of emergent clones of methicillin-resistant Staphylococcus aureus (MRSA) that originated in livestock and switched to humans, followed by host-adaptive evolution and epidemic spread in global human populations. Our findings demonstrate that livestock can act as a reservoir for the emergence of new human bacterial clones with potential for pandemic spread, highlighting the potential role of surveillance and biosecurity measures in the agricultural setting for preventing the emergence of new human pathogens. PMID- 23943758 TI - Canine distemper virus: an emerging disease in wild endangered Amur tigers (Panthera tigris altaica). AB - Fewer than 500 Amur tigers (Panthera tigris altaica) remain in the wild. Due to low numbers and their solitary and reclusive nature, tiger sightings across their range in the Russian Far East and China are rare; sightings of sick tigers are rarer still. Serious neurologic disease observed in several wild tigers since 2001 suggested disease emergence in this endangered species. To investigate this possibility, histology, immunohistochemistry (IHC), in situ hybridization (ISH), and reverse transcription-PCR (RT-PCR) were performed on tissues from 5 affected tigers that died or were destroyed in 2001, 2004, or 2010. Our results reveal canine distemper virus (CDV) infection as the cause of neurologic disease in two tigers and definitively establish infection in a third. Nonsuppurative encephalitis with demyelination, eosinophilic nuclear viral inclusions, and positive immunolabeling for CDV by IHC and ISH were present in the two tigers with available brain tissue. CDV phosphoprotein (P) and hemagglutinin (H) gene products were obtained from brains of these two tigers by RT-PCR, and a short fragment of CDV P gene sequence was detected in lymph node tissue of a third tiger. Phylogenetically, Amur tiger CDV groups with an Arctic-like strain in Baikal seals (Phoca siberica). Our results, which include mapping the location of positive tigers and recognition of a cluster of cases in 2010, coupled with a lack of reported CDV antibodies in Amur tigers prior to 2000 suggest wide geographic distribution of CDV across the tiger range and recent emergence of CDV as a significant infectious disease threat to endangered Amur tigers in the Russian Far East. IMPORTANCE: Recognition of disease emergence in wildlife is a rare occurrence. Here, for the first time, we identify and characterize a canine distemper virus (CDV), the second most common cause of infectious disease death in domestic dogs and a viral disease of global importance in common and endangered carnivores, as the etiology of neurologic disease and fatal encephalitis in wild, endangered Amur tigers. We establish that in 2010 CDV directly or indirectly killed -1% of Amur tigers. Location of positive cases over an expansive geographic area suggests that CDV is widely distributed across the tiger range. Interspecies interactions are increasing as human populations grow and expand into wildlife habitats. Identifying animal reservoirs for CDV and identifying the CDV strains that are transmissible to and among wildlife species, including Amur tigers and sympatric critically endangered Amur leopards (Panthera pardus orientalis), is essential for guiding conservation and mitigation efforts. PMID- 23943759 TI - Genomic insights to control the emergence of vancomycin-resistant enterococci. AB - Nosocomial outbreaks of vancomycin-resistant Enterococcus faecium (VREfm) are thought to occur by transmission of VREfm between patients, predicting that infection control interventions will limit cross-transmission. Despite implementation of such strategies, the incidence of VREfm infections continues to rise. We aimed to use genomics to better understand the epidemiology of E. faecium within a large hospital and investigate the reasons for failure of infection control strategies. Whole-genome sequencing was performed on 61 E. faecium (36 VREfm) isolates, predominately from blood cultures collected at a single hospital between 1998 and 2009, and on five vanB-positive anaerobic commensal bacteria isolated from human feces. Phylogenomic analysis and precise mapping of the vanB gene, which contains the Tn1549 transposon, showed that at least 18 of the 36 VREfm isolates had acquired the transposon via independent insertion events, indicating de novo generation of VREfm rather than cross transmission. Furthermore, Tn1549 sequences found in 15 of the 36 VREfm isolates were the same as the Tn1549 sequence from one of the gut anaerobes. National and international comparator E. faecium isolates were phylogenetically interspersed with isolates from our hospital, suggesting that our findings might be globally representative. These data demonstrate that VREfm generation within a patient is common, presumably occurring in the human bowel during antibiotic therapy, and help explain our inability to reduce VREfm infections. A recommendation from our findings is that infection control practices should include screening patients for specific hospital clones of vancomycin-susceptible E. faecium rather than just VREfm. IMPORTANCE: Enterococcus faecium is an increasingly important human pathogen causing predominantly antibiotic-resistant infections in hospitalized patients. Large amounts of health care funding are spent trying to control antibiotic-resistant bacteria in hospitals globally, yet in many institutions around the world, vancomycin-resistant E. faecium (VREfm) infections continue to rise. The new findings from this study help explain the failures of our current approaches to controlling vanB VREfm in health care institutions. Given the importance of this bacterium as a cause of hospital-acquired infections and the difficulties faced by infection control units in trying to prevent colonization in their institutions, the novel findings from this study provide evidence that a new approach to controlling VREfm in hospitals is required. In particular, more attention should be given to understanding the epidemiology of hospital-adapted vancomycin-susceptible E. faecium, and patients at higher risk for de novo generation of VREfm need to be identified and optimally managed. PMID- 23943760 TI - Occurrence of cyclic di-GMP-modulating output domains in cyanobacteria: an illuminating perspective. AB - Microorganisms use a variety of metabolites to respond to external stimuli, including second messengers that amplify primary signals and elicit biochemical changes in a cell. Levels of the second messenger cyclic dimeric GMP (c-di-GMP) are regulated by a variety of environmental stimuli and play a critical role in regulating cellular processes such as biofilm formation and cellular motility. Cyclic di-GMP signaling systems have been largely characterized in pathogenic bacteria; however, proteins that can impact the synthesis or degradation of c-di GMP are prominent in cyanobacterial species and yet remain largely underexplored. In cyanobacteria, many putative c-di-GMP synthesis or degradation domains are found in genes that also harbor light-responsive signal input domains, suggesting that light is an important signal for altering c-di-GMP homeostasis. Indeed, c-di GMP-associated domains are often the second most common output domain in photoreceptors-outnumbered only by a histidine kinase output domain. Cyanobacteria differ from other bacteria regarding the number and types of photoreceptor domains associated with c-di-GMP domains. Due to the widespread distribution of c-di-GMP domains in cyanobacteria, we investigated the evolutionary origin of a subset of genes. Phylogenetic analyses showed that c-di GMP signaling systems were present early in cyanobacteria and c-di-GMP genes were both vertically and horizontally inherited during their evolution. Finally, we compared intracellular levels of c-di-GMP in two cyanobacterial species under different light qualities, confirming that light is an important factor for regulating this second messenger in vivo. IMPORTANCE: This study shows that many proteins containing cyclic dimeric GMP (c-di-GMP)-regulatory domains in cyanobacteria are associated with photoreceptor domains. Although the functional roles of c-di-GMP domain-containing proteins in cyanobacteria are only beginning to emerge, the abundance of these multidomain proteins in cyanobacteria that occupy diverse habitats ranging from freshwater to marine to soil environments suggests an important role for the regulation of c-di-GMP in these organisms. Indeed, we showed that light distinctly regulates c-di-GMP levels in Fremyella diplosiphon and Synechocystis sp. strain PCC6803. Our findings are consistent with the occurrence of c-di-GMP domains based on evolutionary origin and as an adaptation to specific habitat characteristics. Phylogenetic analyses of these domains clearly separate two distinctive clades, one composed of domains belonging predominantly to cyanobacteria and the other belonging to a mix of cyanobacteria and other bacteria. We further demonstrate that in cyanobacteria the acquisition of c-di-GMP signaling domains occurred both vertically and horizontally. PMID- 23943761 TI - Old Cryptococcus neoformans cells contribute to virulence in chronic cryptococcosis. AB - Does cell age matter in virulence? The emergence of persister cells during chronic infections is critical for persistence of infection, but little is known how this occurs. Here, we demonstrate for the first time that the replicative age of the fungal pathogen Cryptococcus neoformans contributes to persistence during chronic meningoencephalitis. Generationally older C. neoformans cells are more resistant to hydrogen peroxide stress, macrophage intracellular killing, and antifungal agents. Older cells accumulate in both experimental rat infection and in human cryptococcosis. Mathematical modeling supports the concept that the presence of older C. neoformans cells emerges from in vivo selection pressures. We propose that advanced replicative aging is a new unanticipated virulence trait that emerges during chronic fungal infection and facilitates persistence. Therapeutic interventions that target old cells could help in the clearance of chronic infections. IMPORTANCE: Our findings that the generational age of Cryptococcus neoformans cells matters in pathogenesis introduces a novel concept to eukaryotic pathogenesis research. We propose that emerging properties of aging C. neoformans cells and possibly also other fungal pathogens contribute to persistence and virulence. Whereas the replicative life span of strains may not matter for virulence per se, age-related resilience and thus the generational age of individual C. neoformans cells within a pathogen population could greatly affect persistence of the pathogen population and therefore impact outcome. PMID- 23943762 TI - CspA from Borrelia burgdorferi inhibits the terminal complement pathway. AB - In order to survive and persist in an immunocompetent human host, Borrelia burgdorferi controls the human immune attack and blocks the damaging effects of the activated complement system. These Gram-negative spirochetes use CspA (CRASP 1) and four additional immune evasion proteins to bind combinations of human plasma regulators, including factor H, factor H-like protein 1 (FHL-1), complement factor H-related protein 1 (CFHR1), CFHR2, CFHR5, and plasminogen. As many microbial immune evasion proteins have multiple functions, we hypothesized that CspA has additional roles in complement or immune control. Here, we identify CspA as a terminal complement inhibitor. Borrelial CspA binds the human terminal complement components C7 and C9 and blocks assembly and membrane insertion of the terminal complement complex (TCC). CspA inhibits TCC assembly at the level of C7, as revealed by hemolytic assays, and inhibits polymerization of C9. CspA, when ectopically expressed on the surface of serum-sensitive Borrelia garinii, blocks TCC assembly on the level of C7 and induces serum resistance in the transformed bacteria. This CspA-mediated serum resistance and terminal complement pathway inhibition allow B. burgdorferi to survive in the hostile environment of human plasma. IMPORTANCE: The present study defines a new mechanism by which the pathogenic bacterium Borrelia burgdorferi controls the terminal complement pathway of the human host to survive in human serum. The borrelial CspA binds to terminal pathway proteins C7 and C9 and inhibits the terminal complement pathway at the step of C7 and thereby inhibits terminal complement complex (TCC) assembly and membrane insertion. CspA blocks TCC assembly and insertion when expressed at the bacterial surface. CspA is the first TCC inhibitor cloned and functionally characterized from a Gram-negative bacterium. This identification of a bacterial TCC inhibitor of pathogen origin expands our knowledge of complement evasion of pathogenic bacteria and shows that pathogenic bacteria target the terminal pathway of complement. Thus, CspA as a central microbial virulence factor can represent an interesting biomarker and a target to develop new therapeutics and vaccines against borreliae. PMID- 23943763 TI - Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles. AB - Coronaviruses (CoV), like other positive-stranded RNA viruses, redirect and rearrange host cell membranes for use as part of the viral genome replication and transcription machinery. Specifically, coronaviruses induce the formation of double-membrane vesicles in infected cells. Although these double-membrane vesicles have been well characterized, the mechanism behind their formation remains unclear, including which viral proteins are responsible. Here, we use transfection of plasmid constructs encoding full-length versions of the three transmembrane-containing nonstructural proteins (nsps) of the severe acute respiratory syndrome (SARS) coronavirus to examine the ability of each to induce double-membrane vesicles in tissue culture. nsp3 has membrane disordering and proliferation ability, both in its full-length form and in a C-terminal-truncated form. nsp3 and nsp4 working together have the ability to pair membranes. nsp6 has membrane proliferation ability as well, inducing perinuclear vesicles localized around the microtubule organizing center. Together, nsp3, nsp4, and nsp6 have the ability to induce double-membrane vesicles that are similar to those observed in SARS coronavirus-infected cells. This activity appears to require the full-length form of nsp3 for action, as double-membrane vesicles were not seen in cells coexpressing the C-terminal truncation nsp3 with nsp4 and nsp6. IMPORTANCE: Although the majority of infections caused by coronaviruses in humans are relatively mild, the SARS outbreak of 2002 to 2003 and the emergence of the human coronavirus Middle Eastern respiratory syndrome (MERS-CoV) in 2012 highlight the ability of these viruses to cause severe pathology and fatality. Insight into the molecular biology of how coronaviruses take over the host cell is critical for a full understanding of any known and possible future outbreaks caused by these viruses. Additionally, since membrane rearrangement is a tactic used by all known positive-sense single-stranded RNA viruses, this work adds to that body of knowledge and may prove beneficial in the development of future therapies not only for human coronavirus infections but for other pathogens as well. PMID- 23943764 TI - The activity and specificity of the outer membrane protein chaperone SurA are modulated by a proline isomerase domain. AB - SurA is a component of the periplasmic chaperone network that plays a central role in biogenesis of integral outer membrane beta-barrel proteins (OMPs) in Escherichia coli. Although SurA contains two well-conserved proline isomerase (PPIase) domains, the contribution of these domains to SurA function is unclear. In the present work, we show that defects in OMP assembly caused by mutation of the beta-barrel assembly factors BamA or BamB can be corrected by gain-of function mutations in SurA that map to the first PPIase domain. These mutations apparently bypass the requirement for a stable interaction between SurA and the Bam complex and enhance SurA chaperone activity in vivo despite destabilization of the protein in vitro. Our findings suggest an autoinhibitory mechanism for regulation of SurA chaperone activity through interdomain interactions involving a PPIase domain. We propose a model in which SurA activity is modulated by an interaction between SurA and the Bam complex that alters the substrate specificity of the chaperone. IMPORTANCE: The dominant surA mutations described here alter amino acid residues that are highly conserved in eukaryotic homologs of SurA, including Pin 1, the human proline isomerase (PPIase) implicated in Alzheimer's disease and certain cancers. Consequently, a mechanistic description of SurA function may enhance our understanding of clinically important PPIases and their role(s) in disease. In addition, the virulence of Gram-negative bacterial pathogens, such as Salmonella, Shigella, and Escherichia coli O157:H7, is largely dependent on SurA, making this PPIase/chaperone an attractive antibiotic target. Investigating the function of SurA in outer membrane (OM) biogenesis will be useful in the development of novel therapeutic strategies for the disruption of the OM or the processes that are essential for its assembly. PMID- 23943771 TI - Adherence to a Mediterranean diet is associated with a better health-related quality of life: a possible role of high dietary antioxidant content. AB - OBJECTIVES: Mediterranean diet (MD) is associated with a reduced risk of major chronic disease. Health-related quality of life (HRQL) is a valid predictor of mortality. The aim of this study is to investigate the association between MD and HRQL and to examine the possible role of dietary antioxidants, fibre content and/or fatty acid components. DESIGN: Cross-sectional study on a sample of Italian participants enrolled in the Moli-sani Project, a population-based cohort study. Food intake was recorded by the Italian European prospective investigation into cancer and nutrition study food frequency questionnaire. Adherence to MD was appraised by a Greek Mediterranean diet score (MDS), an Italian Mediterranean diet index (IMI) and by principal component analysis (PCA). HRQL was assessed by the 36-Item Short Form Health Survey. SETTING: Molise region, Italy. PARTICIPANTS: 16 937 participants of 24 325 Italian citizens (age>=35). MAIN OUTCOMES: Dietary patterns and HRQL. RESULTS: Mental health was associated consistently and positively with MDS, IMI and an 'Olive oil and vegetable' pattern (PCA1), but negatively with an 'Eggs and sweets' pattern (PCA3). Physical health was associated positively with MDS and PCA1, but negatively with a 'Meat and pasta' pattern. Subjects with the highest MD adherence had 42% (MDS), 34% (IMI) or 59% (PCA1) statistically significant multivariable odds of being in the uppermost level of mental health, as compared with subjects in the lowest category. The associations disappeared after further adjustment for either total food antioxidant content or dietary fibre, while they were not modified by the inclusion of either monounsaturated or polyunsaturated fatty acids. Individuals in the highest PCA1 or PCA3 had significantly higher odds of being in the top level of physical health. CONCLUSIONS: Adherence to an MD pattern is associated with better HRQL. The association is stronger with mental health than with physical health. Dietary total antioxidant and fibre content independently explain this relationship. PMID- 23943772 TI - Does access to neighbourhood green space promote a healthy duration of sleep? Novel findings from a cross-sectional study of 259 319 Australians. AB - OBJECTIVES: Experiments demonstrate that exposure to parks and other 'green spaces' promote favourable psychological and physiological outcomes. As a consequence, people who reside in greener neighbourhoods may also have a lower risk of short sleep duration (<6 h). This is potentially important as short sleep duration is a correlate of obesity, chronic disease and mortality, but so far this hypothesis has not been previously investigated. DESIGN: Cross-sectional data analysis. SETTING: New South Wales, Australia. PARTICIPANTS: This study investigated whether neighbourhood green space was associated with a healthier duration of sleep (to the nearest hour) among 259 319 Australians who completed the 45 and Up Study baseline questionnaire between 2006 and 2009 inclusive. PRIMARY AND SECONDARY OUTCOME MEASURES: Multinomial logit regression was used to investigate the influence of an objective measure of green space on categories of sleep duration: 8 h (normal); between 9 and 10 h (mid-long sleep); over 10 h (long sleep); between 6 and 7 h (mid-short sleep); and less than 6 h (short sleep). Models were adjusted for psychological distress, physical activity and a range of demographic and socioeconomic characteristics. RESULTS: People living in greener neighbourhoods reported a lower risk of short sleep. For example, compared with participants living in areas with 20% green space land-use, the relative risk ratios for participants with 80%+ green space was 0.86 (95% CI 0.81 to 0.92) for durations between 6 and 7 h, and 0.68 (95% CI 0.57 to 0.80) for less than 6 h sleep. Unexpectedly, the benefit of more green space for achieving 8 h of sleep was not explained by controls for psychological distress, physical activity or other socioeconomic factors. CONCLUSIONS: Green space planning policies may have wider public health benefits than previously recognised. Further research in the role of green spaces in promoting healthier sleep durations and patterns is warranted. PMID- 23943773 TI - What attributes of patients affect their involvement in safety? A key opinion leaders' perspective. AB - OBJECTIVE: Little is known about which attributes the patients need when they wish to maximise their capability to partner safely in healthcare. We aimed to identify these attributes from the perspective of key opinion leaders. DESIGN: Delphi study involving indirect group interaction through a structured two-round survey. SETTING: International electronic survey. PARTICIPANTS: 11 (65%) of the 17 invited internationally recognised experts on patient safety completed the study. OUTCOME MEASURES: 50 patient attributes were rated by the Delphi panel for their ability to contribute maximally to safe health care. RESULTS: The panellists agreed that 13 attributes are important for patients who want to maximise the role of safe partners. These domains relate to: autonomy, awareness, conscientiousness, knowledge, rationality, responsiveness and vigilance; for example, important attributes of autonomy include the ability to speak up, freedom to act and ability to act independently. Spanning seven domains, the attributes emphasise intellectual attributes and, to a lesser extent, moral attributes. CONCLUSIONS: Whereas current safety discourses emphasise attributes of professionals, this study identified the patient attributes which key opinion leaders believe can maximise the capability of patients to partner safely in healthcare. Further research is needed that asks patients about the attributes they believe are most important. PMID- 23943774 TI - Endogenous testosterone level and testosterone supplementation therapy in chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis. AB - OBJECTIVE: Low testosterone level may be a reversible risk factor for functional disability and deterioration in patients with chronic obstructive pulmonary disease (COPD). We sought to systematically assess the endogenous testosterone levels and effect of testosterone therapy on exercise capacity and health-related quality of life (HRQoL) outcomes in COPD patients, as well as to inform guidelines and practice. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched PubMed, Scopus, Cochrane Library, CINAHL, Health Source Nursing and PsychINFO and the reference lists of retrieved articles published before May 2012. INCLUSION CRITERIA: Observational studies on endogenous testosterone levels in people with chronic lung disease compared with controls, or randomised controlled trials (RCTs) on testosterone therapy for exercise capacity and/or HRQoL outcomes in COPD patients were eligible. DATA EXTRACTION AND ANALYSIS: Data on the mean difference in endogenous total testosterone (TT) values, and the mean difference in exercise capacity and HRQoL values were extracted and pooled using random effects meta-analysis. RESULTS: Nine observational studies in 2918 men with COPD reported consistently lower levels of TT compared with controls (weighted mean difference was -3.21 nmol/L (95% CI 5.18 to -1.23)). Six RCTs in 287 participants yielded five studies on peak muscle strength and peak cardiorespiratory fitness outcomes (peak oxygen uptake (VO2) and workload) and three studies on HRQoL outcomes. Testosterone therapies significantly improved peak muscle strength (standardised mean difference (SMD) was 0.31 (95% CI 0.05 to 0.56)) and peak workload (SMD was 0.27 (95% CI 0.01 to 0.52)) compared with control conditions (all but one used placebo), but not peak VO2 (SMD was 0.21 (95% CI -0.15 to 0.56)) or HRQoL (SMD was -0.03 (95% CI -0.32 to 0.25)). CONCLUSIONS: Men with COPD have clinically relevant lower than normal TT levels. Insufficient evidence from short-term studies in predominately male COPD patients suggests that testosterone therapy improves exercise capacity outcomes, namely peak muscle strength and peak workload. PMID- 23943775 TI - A generalised model for individualising a treatment recommendation based on group level evidence from randomised clinical trials. AB - OBJECTIVES: Randomised controlled trials report group-level treatment effects. However, an individual patient confronting a treatment decision needs to know whether that person's expected treatment benefit will exceed the expected treatment harm. We describe a flexible model for individualising a treatment decision. It individualises group-level results from randomised trials using clinical prediction guides. METHODS: We constructed models that estimate the size of individualised absolute risk reduction (ARR) for the target outcome that is required to offset individualised absolute risk increase (ARI) for the treatment harm. Inputs to the model include estimates for the individualised predicted absolute treatment benefit and harm, and the relative value assigned by the patient to harm/benefit. A decision rule recommends treatment when the predicted benefit exceeds the predicted harm, value-adjusted. We also derived expressions for the maximum treatment harm, or the maximum relative value for harm/benefit, above which treatment would not be recommended. RESULTS: For the simpler model, including one kind of benefit and one kind of harm, the individualised ARR required to justify treatment was expressed as required ARRtarget(i)=ARIharm(i) * RVharm/target(i). A complex model was also developed, applicable to treatments causing multiple kinds of benefits and/or harms. We demonstrated the applicability of the models to treatments tested in superiority trials (either placebo or active control, either fixed harm or variable harm) and non inferiority trials. CONCLUSIONS: Individualised treatment recommendations can be derived using a model that applies clinical prediction guides to the results of randomised trials in order to identify which individual patients are likely to derive a clinically important benefit from the treatment. The resulting individualised prediction-based recommendations require validation by comparison with strategies of treat all or treat none. PMID- 23943776 TI - Cost-effectiveness of HCV case-finding for people who inject drugs via dried blood spot testing in specialist addiction services and prisons. AB - OBJECTIVES: People who inject drugs (PWID) are at high risk for acquiring hepatitis C virus (HCV), but many are unaware of their infection. HCV dried blood spot (DBS) testing increases case-finding in addiction services and prisons. We determine the cost-effectiveness of increasing HCV case-finding among PWID by offering DBS testing in specialist addiction services or prisons as compared to using venepuncture. DESIGN: Cost-utility analysis using a dynamic HCV transmission model among PWID, including: disease progression, diagnosis, treatment, injecting status, incarceration and addition services contact. SETTING UK INTERVENTION: DBS testing in specialist addiction services or prisons. Intervention impact was determined by a meta-analysis of primary data. PRIMARY AND SECONDARY OUTCOME MEASURES: Costs (in UK L, L1=US$1.60) and utilities (quality-adjusted life years, QALYs) were attached to each state and the incremental cost effectiveness ratio (ICER) determined. Multivariate uncertainty and one-way sensitivity analyses were performed. RESULTS: For a L20 000 per QALY gained willingness-to-pay threshold, DBS testing in addiction services is cost effective (ICER of L14 600 per QALY gained). Under the base-case assumption of no continuity of treatment/care when exiting/entering prison, DBS testing in prisons is not cost-effective (ICER of L59 400 per QALY gained). Results are robust to changes in HCV prevalence; increasing PWID treatment rates to those for ex-PWID considerably reduces ICER (L4500 and L30 000 per QALY gained for addiction services and prison, respectively). If continuity of care is >40%, the prison DBS ICER falls below L20 000 per QALY gained. CONCLUSIONS: Despite low PWID treatment rates, increasing case-finding can be cost-effective in specialist addiction services, and in prisons if continuity of treatment/care is ensured. PMID- 23943777 TI - Urinary albumin excretion as a marker of endothelial dysfunction in migraine sufferers: the HUNT study, Norway. AB - OBJECTIVE: To investigate urine albumin leakage as a marker of endothelial dysfunction in migraine patients. DESIGN: A population-based health study. PARTICIPANTS: 303 patients with migraine, 1009 patients with non-migraine headache and 5287 headache-free controls. OUTCOMES: The association between urine albumin- to-creatine ratio (ACR) and headache status was investigated in the Nord Trondelag Health Study (HUNT-2). Patients were selected in two strata, based on either (1) self-reported hypertension/diabetes (morbid sample) or (2) a random sample. Analyses were performed using analysis of covariance. RESULTS: There was no association between headache status and ACR in the study population (p=0.23, mean ACR for migraine 1.66, 95% CI 1.31 to 2.01, for non-migraine headache 1.90, 95% CI 1.71 to 2.09 and for no headache 1.73, 95% CI 1.64 to 1.81) after relevant adjustments. Similarly, no association between headache status and ACR was seen when the analysis was stratified for morbid and random samples, or for migraine with and without aura. CONCLUSIONS: We found no evidence of increased urine albumin leakage in migraine sufferers when compared with headache-free controls. This could indicate that systemic endothelial dysfunction is not a prominent feature of migraine. PMID- 23943778 TI - Statin use and asthma control in patients with severe asthma. AB - OBJECTIVES: We hypothesised that severe asthmatics taking a statin drug, in addition to inhaled corticosteroids/long-acting beta-agonist inhaler therapy, would have better asthma symptom control and improved lung function compared to their controls. STUDY DESIGN: A retrospective, cross-sectional study of 165 patients with severe asthma seen from 2001-2008. Hierarchical linear and logistic regression models were used for modelling fitting. SETTING: University of California, Davis Medical Center (Sacramento, California, USA). Academic, single centre, severe asthma subspecialty clinic. PARTICIPANTS: 612 screened, 223 eligible and 165 adult patients were included in the final study (N=165; 31 statin users and 134 non-users). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was asthma control as measured by the Asthma Control Test (ACT). The secondary endpoints included lung function, symptoms and the need for corticosteroid burst and peripheral eosinophil count. RESULTS: At baseline, statin users compared to non-users were older, had lower lung function (FEV1% predicted, FEV1, forced vital capacity and FEF25-75%) and had a higher prevalence of comorbid conditions. Statin use was associated with more aspirin and ipratropium inhaler use than in non-users. Patients in both groups were obese (body mass index >= 30). Statin users had better asthma symptom control compared to non-users (higher adjusted mean ACT score by 2.2+/-0.94 points, p<0.02). Median statin use was for 1 year. There were no statistically significant differences in lung function, corticosteroid or rescue bronchodilator use or peripheral eosinophilia between the two groups. CONCLUSIONS: In our severe asthma referral population, statin users already taking inhaled controller therapy achieved better asthma control compared to non-users. The implications of this study is that patients with severe asthma could potentially benefit from added statin treatment. Because our study population was on average obese, the obese severe asthmatic may be a viable asthma subphenotype for further studies. Prospective randomised clinical trials evaluating the safety and efficacy of statins in severe asthma are warranted. PMID- 23943779 TI - Application of an improved proteomics method for abundant protein cleanup: molecular and genomic mechanisms study in plant defense. AB - High abundance proteins like ribulose-1,5-bisphosphate carboxylase oxygenase (Rubisco) impose a consistent challenge for the whole proteome characterization using shot-gun proteomics. To address this challenge, we developed and evaluated Polyethyleneimine Assisted Rubisco Cleanup (PARC) as a new method by combining both abundant protein removal and fractionation. The new approach was applied to a plant insect interaction study to validate the platform and investigate mechanisms for plant defense against herbivorous insects. Our results indicated that PARC can effectively remove Rubisco, improve the protein identification, and discover almost three times more differentially regulated proteins. The significantly enhanced shot-gun proteomics performance was translated into in depth proteomic and molecular mechanisms for plant insect interaction, where carbon re-distribution was used to play an essential role. Moreover, the transcriptomic validation also confirmed the reliability of PARC analysis. Finally, functional studies were carried out for two differentially regulated genes as revealed by PARC analysis. Insect resistance was induced by over expressing either jacalin-like or cupin-like genes in rice. The results further highlighted that PARC can serve as an effective strategy for proteomics analysis and gene discovery. PMID- 23943780 TI - Shanghai fever: a distinct Pseudomonas aeruginosa enteric disease. AB - BACKGROUND: Shanghai fever, a community-acquired enteric illness associated with sepsis caused by Pseudomonas aeruginosa, was first described in 1918. The understanding of Shanghai fever is incomplete. OBJECTIVE: To delineate the clinical features and to examine the host and microbial factors associated with Shanghai fever. METHODS: We prospectively enrolled 27 consecutive previously healthy children with community-acquired P aeruginosa enteritis and sepsis between July 2003 and June 2012. An immunological investigation, including measurement of serum immunoglobulin levels and lymphocyte subpopulations, was performed. The clonal relationship of bacterial isolates was determined by multilocus sequence typing (MLST) and the virulence of isolates was measured using cellular and animal models. RESULTS: The median age of the patients was 7 months; 24 (89%) were aged <1 year. The most common clinical manifestations were fever (100%), diarrhoea (96%) and shock (81%). Leucopenia, thrombocytopenia, high C-reactive protein levels, coagulopathy and hypoalbuminaemia were the key laboratory findings. Necrotising enteritis with or without bowel perforation, ecthyma gangrenosum and seizures were main complications. The death rate was 15%. No common primary immune deficiency was identified. MLST genotypes indicated that isolates from Shanghai fever were non-clonal, but they shared similar phenotypes which were invariably cytotoxic, invasive and adhesive in cellular experiments and caused prolonged gut colonisation and more death than respiratory and laboratory control strains in mice. CONCLUSIONS: Shanghai fever is a sporadic community-acquired disease of previously healthy infants that manifests as sepsis associated with P aeruginosa enteric disease. Both host and microbial factors play a role in pathogenesis. PMID- 23943781 TI - Inflammatory components in human Alzheimer's disease and after active amyloid beta42 immunization. AB - Inflammatory processes are important in the pathogenesis of Alzheimer's disease and in response to amyloid-beta immunotherapy. We investigated the expression of multiple inflammatory markers in the brains of 28 non-immunized patients with Alzheimer's disease and 11 patients with Alzheimer's disease immunized against amyloid-beta42 (AN1792): microglial ionized calcium-binding adaptor Iba-1, lysosome marker CD68, macrophage scavenger receptor A, Fcgamma receptors I (CD64) and II (CD32); and also immunoglobulin IgG, complement C1q and the T lymphocyte marker CD3 using immunohistochemistry. The data were analysed with regard to amyloid-beta and phospho-tau pathology, severity of cerebral amyloid angiopathy and cortical microhaemorrhages. In non-immunized Alzheimer's disease cases, amyloid-beta42 correlated inversely with CD32 and Iba-1, whereas phospho-tau correlated directly with all microglial markers, IgG, C1q and the number of T cells. In immunized Alzheimer's disease cases, amyloid-beta42 load correlated directly with macrophage scavenger receptor A-positive clusters and inversely with C1q. The severity of cerebral amyloid angiopathy and microhaemorrhages did not relate to any of the analysed markers. Overall, the levels of CD68, macrophage scavenger receptor A, CD64, CD32 and the number of macrophage scavenger receptor A-positive plaque-related clusters were significantly lower in immunized than non-immunized cases, although there was no significant difference in Iba-1 load, number of Iba-1-positive cells, IgG load, C1q load or number of T cells. Our findings indicate that different microglial populations co-exist in the Alzheimer's disease brain, and that the local inflammatory status within the grey matter is importantly linked with tau pathology. After amyloid-beta immunization, the microglial functional state is altered in association with reduced amyloid-beta and tau pathology. The results suggest that, in the long term, amyloid-beta immunotherapy results in downregulation of microglial activation and potentially reduces the inflammation-mediated component of the neurodegeneration of Alzheimer's disease. PMID- 23943782 TI - Donating blood and organs: using an extended theory of planned behavior perspective to identify similarities and differences in individual motivations to donate. AB - Due to the critical shortage and continued need of blood and organ donations (ODs), research exploring similarities and differences in the motivational determinants of these behaviors is needed. In a sample of 258 university students, we used a cross-sectional design to test the utility of an extended theory of planned behavior (TPB) including moral norm, self-identity and in-group altruism (family/close friends and ethnic group), to predict people's blood and OD intentions. Overall, the extended TPB explained 77.0% and 74.6% of variance in blood and OD intentions, respectively. In regression analyses, common contributors to intentions across donation contexts were attitude, self-efficacy and self-identity. Normative influences varied with subjective norm as a significant predictor related to OD intentions but not blood donation intentions at the final step of regression analyses. Moral norm did not contribute significantly to blood or OD intentions. In-group altruism (family/close friends) was significantly related to OD intentions only in regressions. Future donation strategies should increase confidence to donate, foster a perception of self as the type of person who donates blood and/or organs, and address preferences to donate organs to in-group members only. PMID- 23943783 TI - High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model. AB - There is epidemiologic evidence that obesity increases the risk of cancers. Several underlying mechanisms, including inflammation and insulin resistance, are proposed. However, the driving mechanisms in pancreatic cancer are poorly understood. The goal of the present study was to develop a model of diet-induced obesity and pancreatic cancer development in a state-of-the-art mouse model, which resembles important clinical features of human obesity, for example, weight gain and metabolic disturbances. Offspring of Pdx-1-Cre and LSL-KrasG12D mice were allocated to either a high-fat, high-calorie diet (HFCD; ~4,535 kcal/kg; 40% of calories from fats) or control diet (~3,725 kcal/kg; 12% of calories from fats) for 3 months. Compared with control animals, mice fed with the HFCD significantly gained more weight and developed hyperinsulinemia, hyperglycemia, hyperleptinemia, and elevated levels of insulin-like growth factor I (IGF-I). The pancreas of HFCD-fed animals showed robust signs of inflammation with increased numbers of infiltrating inflammatory cells (macrophages and T cells), elevated levels of several cytokines and chemokines, increased stromal fibrosis, and more advanced PanIN lesions. Our results show that a diet high in fats and calories leads to obesity and metabolic disturbances similar to humans and accelerates early pancreatic neoplasia in the conditional KrasG12D mouse model. This model and findings will provide the basis for more robust studies attempting to unravel the mechanisms underlying the cancer-promoting properties of obesity, as well as to evaluate dietary- and chemopreventive strategies targeting obesity-associated pancreatic cancer development. PMID- 23943784 TI - Examination of whole blood DNA methylation as a potential risk marker for gastric cancer. AB - Whole blood DNA methylation analysis has been proposed to be a risk marker for cancer that can be used to target patients for preventive interventions. To test this, we examined whole blood DNA methylation of 16 CpG island promoters and LINE1 repetitive element in patients with gastric cancer and control subjects. Bisulfite pyrosequencing was used to quantify the methylation of 14 CpG island promoters (MINT25, RORA, GDNF, CDH1, RARAB2, ER, CDH13, MYOD1, SFRP1, P2RX7, SLC16A12, IGF2, DPYS, and N33) and LINE1 from 72 patients with gastric cancer, 67 control, and 52 healthy young individuals. Quantitative methylation-specific real time PCR was also conducted for 3 CpG island promoters (MINT25, MYO3A, and SOX11). Among all sites tested, only a marginal increase in the methylation of the SFRP1 promoter was observed in the blood of patients with gastric cancer when compared with the control group (11.3 % vs 10.5%; age-adjusted P value: P = 0.009), and this association was also seen in a validation set of 91 patients with gastric cancer (11.5% vs 10.5%; age-adjusted P value: P = 0.001). The methylation of 9 sites (GDNF, CDH1, RARAB2, CDH13, MYOD1, SFRP1, SLC16A12, DPYS, N33, and LINE1) and their mean Z score was correlated with higher age (R = 0.41, P < 0.0001) and marginally with telomere shortening (R = -0.18, P = 0.01) but not with gastric cancer risk (other than SFRP1 methylation). Variability in whole blood DNA methylation of cancer markers is primarily associated with aging, reflecting turnover of white blood cells, and has no direct link to gastric cancer predisposition. SFRP1 methylation in whole blood may be associated with gastric cancer risk. PMID- 23943786 TI - Human in vitro eugenics: close, yet far away. PMID- 23943785 TI - Acacetin inhibits in vitro and in vivo angiogenesis and downregulates Stat signaling and VEGF expression. AB - Angiogenesis is an effective target in cancer control. The antiangiogenic efficacy and associated mechanisms of acacetin, a plant flavone, are poorly known. In the present study, acacetin inhibited growth and survival (up to 92%; P < 0.001), and capillary-like tube formation on Matrigel (up to 98%; P < 0.001) by human umbilical vein endothelial cells (HUVEC) in regular condition, as well as VEGF-induced and tumor cells conditioned medium-stimulated growth conditions. It caused retraction and disintegration of preformed capillary networks (up to 91%; P < 0.001). HUVEC migration and invasion were suppressed by 68% to 100% (P < 0.001). Acacetin inhibited Stat-1 (Tyr701) and Stat-3 (Tyr705) phosphorylation, and downregulated proangiogenic factors including VEGF, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), matrix metalloproteinase 2 (MMP-2), and basic fibroblast growth factor (bFGF) in HUVEC. It also suppressed nuclear localization of pStat-3 (Tyr705). Acacetin strongly inhibited capillary sprouting and networking from rat aortic rings and fertilized chicken egg chorioallantoic membrane (CAM; ~71%; P < 0.001). Furthermore, it suppressed angiogenesis in Matrigel plugs implanted in Swiss albino mice. Acacetin also inhibited tyrosine phosphorylation of Stat-1 and -3, and expression of VEGF in cancer cells. Overall, acacetin inhibits Stat signaling and suppresses angiogenesis in vitro, ex vivo, and in vivo, and therefore, it could be a potential agent to inhibit tumor angiogenesis and growth. PMID- 23943787 TI - Sortase A promotes virulence in experimental Staphylococcus lugdunensis endocarditis. AB - Staphylococcus lugdunensis is a commensal of humans and an opportunistic pathogen. It can cause an aggressive form of infective endocarditis in healthy humans akin to Staphylococcus aureus. Here we compared the virulence of the genome-sequenced S. lugdunensis strain N920143 to S. aureus in an experimental rat endocarditis model. N920143 caused a milder course of disease with lower levels of bacteraemia and smaller endocardial vegetations than S. aureus strain Newman. However, vegetations were comparable to those produced by S. aureus MRSA strain COL. Little is known about virulence factors of S. lugdunensis as systems to manipulate the bacterium genetically are currently limited. Here, we report a method for electroporation of S. lugdunensis with plasmid DNA and demonstrate that the low efficiency of transformation is due to the activity of a conserved type I restriction-modification system. To streamline the transformation process, we constructed SL01B, an E. coli strain expressing the hsdM/hsdS genes of N920143. Modified plasmid DNA isolated from SL01B transformed S. lugdunensis strains from clonal complexes 1 and 2 efficiently. A deletion mutant of N920143 lacking sortase A was significantly less virulent than the wild-type in the endocarditis model. Mutants defective in single surface proteins Fbl or vWbl were not significantly different from the wild-type but showed trends towards reduced virulence. PMID- 23943788 TI - BBS mutations modify phenotypic expression of CEP290-related ciliopathies. AB - Ciliopathies are a group of heterogeneous disorders associated with ciliary dysfunction. Diseases in this group display considerable phenotypic variation within individual syndromes and overlapping phenotypes among clinically distinct disorders. Particularly, mutations in CEP290 cause phenotypically diverse ciliopathies ranging from isolated retinal degeneration, nephronophthisis and Joubert syndrome, to the neonatal lethal Meckel-Gruber syndrome. However, the underlying mechanisms of the variable expressivity in ciliopathies are not well understood. Here, we show that components of the BBSome, a protein complex composed of seven Bardet-Biedl syndrome (BBS) proteins, physically and genetically interact with CEP290 and modulate the expression of disease phenotypes caused by CEP290 mutations. The BBSome binds to the N-terminal region of CEP290 through BBS4 and co-localizes with CEP290 to the transition zone (TZ) of primary cilia and centriolar satellites in ciliated cells, as well as to the connecting cilium in photoreceptor cells. Although CEP290 still localizes to the TZ and connecting cilium in BBSome-depleted cells, its localization to centriolar satellites is disrupted and CEP290 appears to disperse throughout the cytoplasm in BBSome-depleted cells. Genetic interactions were tested using Cep290(rd16)- and Bbs4-null mutant mouse lines. Additional loss of Bbs4 alleles in Cep290(rd16/rd16) mice results in increased body weight and accelerated photoreceptor degeneration compared with mice without Bbs4 mutations. Furthermore, double-heterozygous mice (Cep290(+/rd16);Bbs4(+/-)) have increased body weight compared with single-heterozygous animals. Our data indicate that genetic interactions between BBSome components and CEP290 could underlie the variable expression and overlapping phenotypes of ciliopathies caused by CEP290 mutations. PMID- 23943790 TI - Selective inhibition of caspases in skeletal muscle reverses the apoptotic synaptic degeneration in slow-channel myasthenic syndrome. AB - Slow-channel syndrome (SCS) is a congenital myasthenic disorder caused by point mutations in subunits of skeletal muscle acetylcholine receptor leading to Ca(2+) overload and degeneration of the postsynaptic membrane, nuclei and mitochondria of the neuromuscular junction (NMJ). In both SCS muscle biopsies and transgenic mouse models for SCS (mSCS), the endplate regions are shrunken, and there is evidence of DNA damage in the subsynaptic region. Activated caspase-9, -3 and -7 are intensely co-localized at the NMJ, and the Ca(2+)-activated protease, calpain, and the atypical cyclin-dependent kinase (Cdk5) are overactivated in mSCS. Thus, the true mediator(s) of the disease process is not clear. Here, we demonstrate that selective inhibition of effector caspases, caspase-3 and -7, or initiator caspase, caspase-9, in limb muscle in vivo by localized expression of recombinant inhibitor proteins dramatically decreases subsynaptic DNA damage, increases endplate area and improves ultrastructural abnormalities in SCS transgenic mice. Calpain and Cdk5 are not affected by this treatment. On the other hand, inhibition of Cdk5 by expression of a dominant-negative form of Cdk5 has no effect on the degeneration. Together with previous studies, these results indicate that focal activation of caspase activity at the NMJ is the principal pathological process responsible for the synaptic apoptosis in SCS. Thus, treatments that reduce muscle caspase activity are likely to be of benefit for SCS patients. PMID- 23943789 TI - Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited macular degeneration. AB - Macular degenerations, inherited and age related, are important causes of vision loss. Human genetic studies have suggested perturbation of the complement system is important in the pathogenesis of age-related macular degeneration. The mechanisms underlying the involvement of the complement system are not understood, although complement and inflammation have been implicated in drusen formation. Drusen are an early clinical hallmark of inherited and age-related forms of macular degeneration. We studied one of the earliest stages of macular degeneration which precedes and leads to the formation of drusen, i.e. the formation of basal deposits. The studies were done using a mouse model of the inherited macular dystrophy Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML) which is caused by a p.Arg345Trp mutation in EFEMP1. The hallmark of DHRD/ML is the formation of drusen at an early age, and gene targeted Efemp1(R345W/R345W) mice develop extensive basal deposits. Proteomic analyses of Bruch's membrane/choroid and Bruch's membrane in the Efemp1(R345W/R345W) mice indicate that the basal deposits comprise normal extracellular matrix (ECM) components present in abnormal amounts. The proteomic analyses also identified significant changes in proteins with immune-related function, including complement components, in the diseased tissue samples. Genetic ablation of the complement response via generation of Efemp1(R345W/R345W):C3(-/-) double-mutant mice inhibited the formation of basal deposits. The results demonstrate a critical role for the complement system in basal deposit formation, and suggest that complement-mediated recognition of abnormal ECM may participate in basal deposit formation in DHRD/ML and perhaps other macular degenerations. PMID- 23943791 TI - A GAA repeat expansion reporter model of Friedreich's ataxia recapitulates the genomic context and allows rapid screening of therapeutic compounds. AB - Friedreich's ataxia (FRDA) is caused by large GAA expansions in intron 1 of the frataxin gene (FXN), which lead to reduced FXN expression through a mechanism not fully understood. Understanding such mechanism is essential for the identification of novel therapies for FRDA and this can be accelerated by the development of cell models which recapitulate the genomic context of the FXN locus and allow direct comparison of normal and expanded FXN loci with rapid detection of frataxin levels. Here we describe the development of the first GAA expanded FXN genomic DNA reporter model of FRDA. We modified BAC vectors carrying the whole FXN genomic DNA locus by inserting the luciferase gene in exon 5a of the FXN gene (pBAC-FXN-Luc) and replacing the six GAA repeats present in the vector with an ~310 GAA repeat expansion (pBAC-FXN-GAA-Luc). We generated human clonal cell lines carrying the two vectors using site-specific integration to allow direct comparison of normal and expanded FXN loci. We demonstrate that the presence of expanded GAA repeats recapitulates the epigenetic modifications and repression of gene expression seen in FRDA. We applied the GAA-expanded reporter model to the screening of a library of novel small molecules and identified one molecule which up-regulates FXN expression in FRDA patient primary cells and restores normal histone acetylation around the GAA repeats. These results suggest the potential use of genomic reporter cell models for the study of FRDA and the identification of novel therapies, combining physiologically relevant expression with the advantages of quantitative reporter gene expression. PMID- 23943792 TI - Sequencing the human microbiome in health and disease. AB - Molecular techniques have revolutionized the practice of standard microbiology. In particular, 16S rRNA sequencing, whole microbial genome sequencing and metagenomics are revealing the extraordinary diversity of microorganisms on Earth and their vast genetic and metabolic repertoire. The increase in length, accuracy and number of reads generated by high-throughput sequencing has coincided with a surge of interest in the human microbiota, the totality of bacteria associated with the human body, in both health and disease. Traditional views of host/pathogen interactions are being challenged as the human microbiota are being revealed to be important in normal immune system function, to diseases not previously thought to have a microbial component and to infectious diseases with unknown aetiology. In this review, we introduce the nature of the human microbiota and application of these three key sequencing techniques for its study, highlighting both advances and challenges in the field. We go on to discuss how further adoption of additional techniques, also originally developed in environmental microbiology, will allow the establishment of disease causality against a background of numerous, complex and interacting microorganisms within the human host. PMID- 23943793 TI - Elevated FGF21 secretion, PGC-1alpha and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle. AB - Iron-sulfur (Fe-S) clusters are ancient enzyme cofactors found in virtually all life forms. We evaluated the physiological effects of chronic Fe-S cluster deficiency in human skeletal muscle, a tissue that relies heavily on Fe-S cluster mediated aerobic energy metabolism. Despite greatly decreased oxidative capacity, muscle tissue from patients deficient in the Fe-S cluster scaffold protein ISCU showed a predominance of type I oxidative muscle fibers and higher capillary density, enhanced expression of transcriptional co-activator PGC-1alpha and increased mitochondrial fatty acid oxidation genes. These Fe-S cluster-deficient muscles showed a dramatic up-regulation of the ketogenic enzyme HMGCS2 and the secreted protein FGF21 (fibroblast growth factor 21). Enhanced muscle FGF21 expression was reflected by elevated circulating FGF21 levels in the patients, and robust FGF21 secretion could be recapitulated by respiratory chain inhibition in cultured myotubes. Our findings reveal that mitochondrial energy starvation elicits a coordinated response in Fe-S-deficient skeletal muscle that is reflected systemically by increased plasma FGF21 levels. PMID- 23943795 TI - Fertility drugs and endometrial cancer risk: results from an extended follow-up of a large infertility cohort. AB - STUDY QUESTION: Do fertility drugs influence the subsequent risk of endometrial cancer in a manner that is independent of other risk predictors, such as parity? SUMMARY ANSWER: In this follow-up of a large cohort of women evaluated for infertility and for whom information was captured on fertility drugs, indications for usage and other risk factors that might influence cancer risk, we found no evidence for a substantial relationship between fertility drug use and endometrial cancer risk. WHAT IS ALREADY KNOWN: Although the hormonal etiology of endometrial cancer has been well established, it remains unclear whether the use of fertility drugs has an influence on risk. Results regarding the effects of fertility drugs on endometrial cancer risk have been inconsistent, although several studies have shown some evidence for possible increases in risk. The relationship is of particular interest given that clomiphene, a commonly prescribed drug, is a selective estrogen receptor modulator, with chemical properties similar to tamoxifen, another drug linked to an increase in endometrial cancer risk. STUDY DESIGN, SIZE, DURATION: In a retrospective cohort of 12 193 women evaluated for infertility between 1965 and 1988 at five US sites, follow-up was pursued through 2010 via both passive as well as active (questionnaire) means. PARTICIPANTS, SETTING, METHODS: Among the 9832 subjects for whom follow-up was allowed and achieved, 259 346 at-risk person-years (i.e. prior to hysterectomy) were accrued, and 118 invasive endometrial cancers identified. Cox regression determined hazard ratios (HRs) and 95% confidence intervals (CIs) for fertility treatments adjusted for endometrial cancer risk factors and causes of infertility. MAIN RESULTS AND THE ROLE OF CHANCE: Although we observed slight increases in endometrial cancer risk associated with clomiphene (HR = 1.39, 95% CI: 0.96-2.01) and the less commonly prescribed gonadotrophins (1.34, 0.76-2.37), there were no convincing relationships of risk with either cycles of use or cumulative exposures for either drug. A statistically significant risk associated with the use of clomiphene among women who began use at younger ages (<30) (1.93, 1.24-3.00) may have reflected indications for drug usage rather than the effect of the drug itself. Women who received clomiphene followed by gonadotrophins were at a non-significantly elevated risk (1.77, 0.98-3.19). LIMITATIONS, REASONS FOR CAUTION: Like most studies of endometrial cancer, we were limited by sample sizes, particularly for evaluating subgroup associations. We were also unable to follow all women and were not able to obtain complete risk factor information (including hysterectomy status) for the entire cohort. WIDER IMPLICATIONS OF THE FINDINGS: Although we found no support for a relationship between fertility drugs and endometrial cancer risk, the association should continue to be monitored given that our study population was still young and had not yet reached the age of peak endometrial cancer incidence. STUDY FUNDING/COMPETING INTEREST(S): This project was supported in part by funds from the intramural research program of the National Cancer Institute, National Institutes of Health. None of the authors has any conflicting interests to declare. PMID- 23943794 TI - Epigenetic regulation of the RHOX homeobox gene cluster and its association with human male infertility. AB - The X-linked RHOX cluster encodes a set of homeobox genes that are selectively expressed in the reproductive tract. Members of the RHOX cluster regulate target genes important for spermatogenesis promote male fertility in mice. Studies show that demethylating agents strongly upregulate the expression of mouse Rhox genes, suggesting that they are regulated by DNA methylation. However, whether this extends to human RHOX genes, whether DNA methylation directly regulates RHOX gene transcription and how this relates to human male infertility are unknown. To address these issues, we first defined the promoter regions of human RHOX genes and performed gain- and loss-of-function experiments to determine whether human RHOX gene transcription is regulated by DNA methylation. Our results indicated that DNA methylation is necessary and sufficient to silence human RHOX gene expression. To determine whether RHOX cluster methylation associates with male infertility, we evaluated the methylation status of RHOX genes in sperm from a large cohort of infertility patients. Linear regression analysis revealed a strong association between RHOX gene cluster hypermethylation and three independent types of semen abnormalities. Hypermethylation was restricted specifically to the RHOX cluster; we did not observe it in genes immediately adjacent to it on the X chromosome. Our results strongly suggest that human RHOX homeobox genes are under an epigenetic control mechanism that is aberrantly regulated in infertility patients. We propose that hypermethylation of the RHOX gene cluster serves as a marker for idiopathic infertility and that it is a candidate to exert a causal role in male infertility. PMID- 23943796 TI - Cross-border reproductive care among French patients: experiences in Greece, Spain and Belgium. AB - STUDY QUESTION: What are the characteristics, motivation and experience of French patients seeking cross-border reproductive care (CBRC)? SUMMARY ANSWER: French patients seeking CBRC are same-sex couples, single women who are not eligible for assisted reproduction technologies (ARTs) in France and heterosexual couples seeking oocyte donation due to extremely limited access to this technique in France, while their choice of Greece as a destination is influenced by financial issues. WHAT IS KNOWN ALREADY: CBRC is a new, increasing, complex and poorly understood phenomenon. A few studies have investigated UK, German or Italian CBRC patients, but none have specifically investigated French patients although France is one of the top four countries of origin of CBRC patients in Europe. STUDY DESIGN, SIZE, DURATION: A cross-sectional study was carried out in 2010-2012 in three ART centres in Greece, Belgium and Spain in order to investigate French patients treated in these centres. Recruitment was prospective in Greece and Belgium and retrospective in Spain. The overall response rate was 68%, with 128 French patients participating. PARTICIPANTS/MATERIALS, SETTING, METHODS: French patients filled in a questionnaire. Information was collected on their socio economic characteristics and their search for ART treatment in France and in other countries. MAIN RESULTS AND THE ROLE OF CHANCE: In the Belgian centre, 89% of French patients used sperm donation whereas oocyte donation was used by 100% of patients in the Greek centre and 74% of patients in the Spanish centre. The majority (94%) of French patients using sperm donation in Belgium were not legally eligible for access to ART in France as they were same-sex couples or single women, and the main criterion of choice of centre was its geographical proximity (71%). Most of the French patients using oocyte donation in Greece and Spain fulfilled criteria for fully reimbursed oocyte donation treatment in France as they were heterosexual couples (99%) with the woman aged <43 years (65%). For these couples, CBRC was motivated by the extremely limited access to oocyte donation in France. Half of French CBRC patients using oocyte donation in Spain had a low/intermediate occupational level (such as primary school teachers, nurses, administrative officers or sales agents, workers and employees) and this proportion was much higher in Greece (82%, P < 0.01). LIMITATIONS, REASONS FOR CAUTION: Larger and more wide-ranging studies are needed as this study included only 128 patients who may not be representative of all French CBRC patients, especially because the study was carried out only in three ART centres and these too may not be representative. WIDER IMPLICATIONS OF THE FINDINGS: CBRC among French patients had been thought to reflect mainly law evasion. This study showed that the reality is much more complex and that CBRC among French patients reflects both law evasion and limited access to oocyte donation in France. It also brings new insight into the characteristics of the patients by suggesting a certain degree of 'democratization' in access to such care. However, the choice of centre seemed related to socio-economic characteristics, in that the Greek centre treated a less advantaged population than the Spanish centre. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by French public research funds, the Institute Emilie du Chatelet from the Ile-de-France Region, the Biomedicine Agency and the Research Institute of Public Health (IReSP). There are no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 23943797 TI - Epithelial-mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and Grainyhead-like-2. AB - Epithelial-mesenchymal transition (EMT) in carcinoma cells enhances malignant progression by promoting invasion and survival. EMT is induced by microenvironmental factors, including TGF-beta and Wnt agonists, and by the E-box binding transcription factors Twist, Snail, and ZEB. Grainyhead-like-2 (GRHL2), a member of the mammalian Grainyhead family of wound-healing regulatory transcription factors, suppresses EMT and restores sensitivity to anoikis by repressing ZEB1 expression and inhibiting TGF-beta signaling. In this study, we elucidate the functional relationship between GRHL2 and ZEB1 in EMT/MET and tumor biology. At least three homeodomain proteins, Six1, LBX1, and HoxA5, transactivated the ZEB1 promoter, in the case of Six1, through direct protein promoter interaction. GRHL2 altered the Six1-DNA complex, inhibiting this transactivation. Correspondingly, GRHL2 expression prevented tumor initiation in xenograft assays, sensitized breast cancer cells to paclitaxel, and suppressed the emergence of CD44(high)CD24(low) cells (defining the cancer stem cell phenotype in the cell type studied). GRHL2 was downregulated in recurrent mouse tumors that had evolved to an oncogene-independent, EMT-like state, supporting a role for GRHL2 downregulation in this phenotypic transition, modeling disease recurrence. The combination of TGF-beta and Wnt activation repressed GRHL2 expression by direct interaction of ZEB1 with the GRHL2 promoter, inducing EMT. Together, our observations indicate that a reciprocal feedback loop between GRHL2 and ZEB1 controls epithelial versus mesenchymal phenotypes and EMT-driven tumor progression. PMID- 23943798 TI - Histone acetyltransferase PCAF is required for Hedgehog-Gli-dependent transcription and cancer cell proliferation. AB - The Hedgehog (Hh) signaling pathway plays an important role in embryonic patterning and development of many tissues and organs as well as in maintaining and repairing mature tissues in adults. Uncontrolled activation of the Hh-Gli pathway has been implicated in developmental abnormalities as well as in several cancers, including brain tumors like medulloblastoma and glioblastoma. Inhibition of aberrant Hh-Gli signaling has, thus, emerged as an attractive approach for anticancer therapy; however, the mechanisms that mediate Hh-Gli signaling in vertebrates remain poorly understood. Here, we show that the histone acetyltransferase PCAF/KAT2B is an important factor of the Hh pathway. Specifically, we show that PCAF depletion impairs Hh activity and reduces expression of Hh target genes. Consequently, PCAF downregulation in medulloblastoma and glioblastoma cells leads to decreased proliferation and increased apoptosis. In addition, we found that PCAF interacts with GLI1, the downstream effector in the Hh-Gli pathway, and that PCAF or GLI1 loss reduces the levels of H3K9 acetylation on Hh target gene promoters. Finally, we observed that PCAF silencing reduces the tumor-forming potential of neural stem cells in vivo. In summary, our study identified the acetyltransferase PCAF as a positive cofactor of the Hh-Gli signaling pathway, leading us to propose PCAF as a candidate therapeutic target for the treatment of patients with medulloblastoma and glioblastoma. PMID- 23943800 TI - Carboxyl-terminal modulator protein positively regulates Akt phosphorylation and acts as an oncogenic driver in breast cancer. AB - Akt activation has been implicated broadly in tumorigenesis, but the basis for its dysregulation in cancer cells is incompletely understood. In this study, we sought to clarify a regulatory role for the Akt-binding carboxy-terminal modulator protein (CTMP), which has been controversial. In evaluating CTMP expression in paired normal-tumor specimens of 198 patients with breast cancer, we found that CTMP was upregulated in breast tumors, where it was associated with poor patient survival. Notably, CTMP expression also correlated positively with Akt phosphorylation in breast cancer clinical specimens and cell lines. Furthermore, ectopic expression of CTMP promoted cell proliferation and enhanced the tumorigenic properties of estrogen-dependent breast cancer cells. This effect was correlated with increased sensitivity to insulin-induced Akt phosphorylation, which is mediated primarily by the phosphoinositide 3-kinase-Akt pathway. In contrast, short hairpin RNA-mediated silencing of endogenous CTMP decreased the proliferation of estrogen-dependent or estrogen-independent breast cancer cells. Mechanistic investigations defined the N-terminal domain of CTMP at amino acids 1 to 64 as responsible for Akt binding. Taken together, our results firmly corroborate the concept that CTMP promotes Akt phosphorylation and functions as an oncogenic molecule in breast cancer. PMID- 23943799 TI - Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53. AB - The Notch pathway has been implicated in a number of malignancies with different roles that are cell- and tissue-type dependent. Notch1 is a putative oncogene in non-small cell lung cancer (NSCLC) and activation of the pathway represents a negative prognostic factor. To establish the role of Notch1 in lung adenocarcinoma, we directly assessed its requirement in Kras-induced tumorigenesis in vivo using an autochthonous model of lung adenocarcinoma with concomitant expression of oncogenic Kras and deletion of Notch1. We found that Notch1 function is required for tumor initiation via suppression of p53-mediated apoptosis through the regulation of p53 stability. These findings implicate Notch1 as a critical effector in Kras-driven lung adenocarcinoma and as a regulator of p53 at a posttranslational level. Moreover, our study provides new insights to explain, at a molecular level, the correlation between Notch1 activity and poor prognosis in patients with NSCLC carrying wild-type p53. This information is critical for design and implementation of new therapeutic strategies in this cohort of patients representing 50% of NSCLC cases. PMID- 23943801 TI - FGFR4 promotes stroma-induced epithelial-to-mesenchymal transition in colorectal cancer. AB - Tumor cells evolve by interacting with the local microenvironment; however, the tumor-stroma interactions that govern tumor metastasis are poorly understood. In this study, proteomic analyses reveal that coculture with tumor-associated fibroblasts (TAF) induces significant overexpression of FGFR4, but not other FGFRs, in colorectal cancer cell lines. Mechanistic study shows that FGFR4 plays crucial roles in TAF-induced epithelial-to-mesenchymal transition (EMT) in colorectal cancer cell lines. Accumulated FGFR4 in cell membrane phosphorylates beta-catenin, leading to translocation of beta-catenin into the nucleus. Further, TAF-derived CCL2 and its downstream transcription factor, Ets-1, are prerequisites for TAF-induced FGFR4 upregulation. Furthermore, FGFR4-associated pathways are shown to be preferentially activated in colorectal tumor samples, and direct tumor metastasis in a mouse metastasis model. Our study shows a pivotal role of FGFR4 in tumor-stroma interactions during colorectal cancer metastasis, and suggests novel therapeutic opportunities for the treatment of colorectal cancer. PMID- 23943803 TI - What can plants do for cell biology? AB - Historically, cell biologists studied organisms that represented a reasonable sampling of life's diversity, whereas recently research has narrowed into a few model systems. As a result, the cells of plants have been relatively neglected. Here I choose three examples to illustrate how plants have been informative and could be even more so. Owing to their ease of imaging and genetic tractability, multicellular plant model systems provide a unique opportunity to address long standing questions in cell biology. PMID- 23943805 TI - Developing lipid nanoparticle-based siRNA therapeutics for hepatocellular carcinoma using an integrated approach. AB - Successful siRNA therapeutics requires the optimal integration of multiple components, including an efficient delivery system, a disease indication that is appropriate for siRNA-based therapy, and a potent and nontoxic siRNA against a robust therapeutic target. Although all currently available delivery systems have limitations, it is important to recognize that a careful selection of the disease indication, therapeutic target, and siRNA molecule could partially compensate for deficiencies associated with the delivery system and makes it possible to advance a therapeutic siRNA regimen. In this study, we present the development of siRNA therapeutics for hepatocellular carcinoma using an integrated approach, including the development of an efficient lipid nanoparticle delivery system, the identification of a robust therapeutic target that does not trigger liver toxicity upon target knockdown, and the selection of potent and nonimmunogenic siRNA molecules against the target. The resulting siRNA-containing lipid nanoparticles produced significant antitumor efficacy in orthotopic hepatocellular carcinoma models, and, thus, represent a promising starting point for the development of siRNA therapeutics for hepatocellular carcinoma. PMID- 23943804 TI - Histone deacetylase inhibition overcomes drug resistance through a miRNA dependent mechanism. AB - The treatment of specific tumor cell lines with poly- and oligoamine analogs results in a superinduction of polyamine catabolism that is associated with cytotoxicity; however, other tumor cells show resistance to analog treatment. Recent data indicate that some of these analogs also have direct epigenetic effects. We, therefore, sought to determine the effects of combining specific analogs with an epigenetic targeting agent in phenotypically resistant human lung cancer cell lines. We show that the histone deacetylase inhibitor MS-275, when combined with (N(1), N(11))-bisethylnorspermine (BENSpm) or (N(1), N(12)) bis(ethyl)-cis-6,7-dehydrospermine tetrahydrochloride (PG-11047), synergistically induces the polyamine catabolic enzyme spermidine/spermine N(1)-acetyltransferase (SSAT), a major determinant of sensitivity to the antitumor analogs. Evidence indicates that the mechanism of this synergy includes reactivation of miR-200a, which targets and destabilizes kelch-like ECH-associated protein 1 (KEAP1) mRNA, resulting in the translocation and binding of nuclear factor (erythroid-derived 2)-like 2 (NRF2) to the polyamine-responsive element of the SSAT promoter. This transcriptional stimulation, combined with positive regulation of SSAT mRNA and protein by the analogs, results in decreased intracellular concentrations of natural polyamines and growth inhibition. The finding that an epigenetic targeting agent is capable of inducing a rate-limiting step in polyamine catabolism to overcome resistance to the antitumor analogs represents a completely novel chemotherapeutic approach. In addition, this is the first demonstration of miRNA-mediated regulation of the polyamine catabolic pathway. Furthermore, the individual agents used in this study have been investigated clinically; therefore, translation of these combinations into the clinical setting holds promise. PMID- 23943806 TI - Bilateral medial medullary syndrome secondary to Takayasu arteritis. AB - Medial medullary syndrome (MMS) is a rare type of stroke which results due to occlusion of the anterior spinal artery or vertebral artery or its branches. In this case report we present a patient who developed MMS secondary to Takayasu arteritis (TA). TA is a chronic inflammatory arteritis primarily involving the arch of aorta and its branches, which in our patient resulted in occlusion of subclavian arteries as well as infarction of the medial medulla bilaterally. To our knowledge this is the first time that MMS has been found to occur secondary to TA. PMID- 23943807 TI - Haemophagocytic lymphohistiocytosis presenting as liver failure following Epstein Barr and prior hepatitis A infections. AB - Haemophagocytic lymphohistiocytosis (HLH) is associated with high mortality even after prompt diagnosis. We present a young man with HLH triggered by two common viral diseases, infectious mononucleosis and hepatitis A. This patient presented with fever, rapidly progressive liver failure, anasarca and cholestasis, followed by anaemia and neutropenia. His carbohydrate antigen 19-9 reached over 9000 U/mL. Initial bone marrow and liver biopsies did not show histological features of malignancy or HLH. The patient was finally diagnosed and treated almost 1 year after the initial symptoms started, and had an excellent response with etoposide and dexamethasone. This case is unusual because it was triggered following mononucleosis in a patient with positive total antibodies against hepatitis A, with rapidly developing liver failure, and also because the patient's response was excellent despite the delay in treatment. It underscores the importance of suspecting HLH when severe systemic illness develops after a viral infection, even in the absence of clear histological features. PMID- 23943808 TI - Idiopathic intracranial hypertension as an initial presentation of systemic lupus erythematosus. AB - A 14-year-old girl with no known illness presented with a several week history of headaches and vomiting. The patient also reported having joint pain and swelling to the wrists and knees. She had no prior history of headaches, use of hormonal contraception or other medications, recent weight changes or family history of autoimmune disease. Blood pressure temperature, height and weight were normal. She was alert, there was alopecia, cervical lympadenopathy, symmetrical synovitis to the wrists, bilateral papilloedema and cranial nerve VI palsy. Laboratory investigations revealed a normochromic normocytic anaemia, leucopenia and lymphopenia. Serum chemistries were normal. CT of the brain was normal. Lumbar puncture revealed an opening pressure of greater than 300 mm H2O; cerebrospinal fluid (CSF) analysis was normal. HIV antibodies were non-reactive. Despite treatment with acetazolamide she developed somnolence. Hence MR venography was performed which showed no evidence of cerebral vein thrombosis. Further investigations revealed a positive direct coombs test, positive antinuclear antibodies (ANA) positive antidouble-stranded DNA (dsDNA) and false positive VDRL. Complement levels were reduced. Anti-Smith, anticardiolipin antibodies and lupus anticoagulant were negative. PMID- 23943809 TI - Inadequate testosterone suppression after medical and subsequent surgical castration in a patient with prostate cancer. AB - Androgen deprivation is a cornerstone in prostate cancer management. We present a 69-year-old man, with a poorly differentiated prostate cancer with skeletal and lymph node metastases. After medical and subsequent surgical castration serum testosterone concentrations remained inappropriately high (4.9 and 4.5 nmol/L; castration range < 0.5). For cancer staging a CT was performed which showed bilateral adrenal enlargement. Endocrine workup revealed elevated levels of adrenal androgens and adrenal precursors. Mutation analysis confirmed a non classical 21-hydroxylase deficiency, that is, a mild form of congenital adrenal hyperplasia (CAH). To suppress adrenocorticotrophic hormone and the excess adrenal androgen secretion, treatment with hydrocortisone and prednisolone was started with success. Inadequate testosterone suppression after castration due to previously undiagnosed CAH has not previously been reported. Considering the estimated prevalence of 1% in selected populations, non-classical CAH should be considered when testosterone is not adequately suppressed after castration in men with prostate cancer. PMID- 23943810 TI - The first case report of McLeod syndrome in a Chinese patient. AB - We report the first case of McLeod syndrome (MLS) in a 47-year-old Chinese man who presented with progressive limb weakness, chorea of feet, red blood cell acanthocytosis, absence of Kx red blood cell antigen and weak expression of Kell antigens. The diagnosis of MLS was confirmed by genetic testing showing a hemizygous mutation of XK gene. We review literature on neuroacanthocytosis in the Chinese population. PMID- 23943811 TI - Eggshell calcification. PMID- 23943812 TI - Basal ganglia calcification. PMID- 23943813 TI - Evidence for different mechanisms of action behind the mutagenic effects of 4 NOPD and OPD: the role of DNA damage, oxidative stress and an imbalanced nucleotide pool. AB - The mutagenicity of 4-nitro-o-phenylenediamine (4-NOPD) and o-phenylenediamine (OPD) was compared using the Mouse Lymphoma Assay (MLA) with or without metabolic activation (S9). As expected, OPD was found to be a more potent mutagen than 4 NOPD. To evaluate possible mechanisms behind their mutagenic effects, the following end points were also monitored in cells that had been exposed to similar concentrations of the compounds as in the MLA: general DNA damage (using a standard protocol for the Comet assay); oxidative DNA damage (using a modified procedure for the Comet assay in combination with the enzyme hOGG1); reactive oxygen species (ROS; using the CM-H2DCFDA assay); and the balance of the nucleotide pool (measured after conversion to the corresponding nucleosides dC, dT, dG and dA using high-performance liquid chromatography). Both compounds increased the level of general DNA damage. Again, OPD was found to be more potent than 4-NOPD (which only increased the level of general DNA damage in the presence of S9). Although less obvious for OPD, both compounds increased the level of oxidative DNA damage. However, an increase in intracellular ROS was only observed in cells exposed to 4-NOPD, both with and without S9 (which in itself induced oxidative stress). Both compounds decreased the concentrations of dA, dT and dC. A striking effect of OPD was the sharp reduction of dA observed already at very low concentration, both with and without S9 (which in itself affected the precursor pool). Taken together, our results indicate that indirect effects on DNA, possibly related to an unbalanced nucleotide pool, mediate the mutagenicity and DNA-damaging effects of 4-NOPD and OPD to a large extent. Although induction of intracellular oxidative stress seems to be a possible mechanism behind the genotoxicity of 4-NOPD, this pathway seems to be of less importance for the more potent mutagen OPD. PMID- 23943814 TI - Entrapment of a micro-guidewire during stenting of basilar stenosis. AB - Entrapment of a microwire related to intracranial endovascular therapy is an uncommon complication. A 64-year-old man with symptomatic basilar artery stenosis was treated with stenting. A 300 cm Synchro microwire became trapped in the P1 segment of the left posterior cerebral artery during the procedure. The decision was made to leave the microwire in place, considering that aggressive retrieval procedures could cause injury to the cerebral vasculature. The entrapped microwire was later inadvertently dislocated and removed while pulling the microwire back into the femoral artery with a looped catheter from the left femoral access. This demonstrates that, although entrapment of a microwire during endovascular therapy is a rare event, an optimal salvage technique needs to be explored further. PMID- 23943815 TI - Onyx is associated with poor venous penetration in the treatment of spinal dural arteriovenous fistulas. AB - BACKGROUND AND PURPOSE: The use of Onyx has become the mainstream for the treatment of cranial dural arteriovenous fistulas (AVFs) and arteriovenous malformations, but the reported success for type I spinal dural arteriovenous fistulas (sDAVFs) remains limited. We review our experience with Onyx and report its limitations in the treatment of spinal AVFs. MATERIALS AND METHODS: We retrospectively reviewed the Interventional Neuroradiology Procedure database at Washington University for cases of sDAVF embolization. Radiology reports were reviewed for fistula classification, treatment technique, and initial and follow up results. Angiographic images were reviewed to confirm diagnosis, treatment, and penetration of embolisate into the draining vein. RESULTS: With the use of Onyx, sDAVFs were obliterated in six of seven patients at the time of treatment. Follow-up angiography confirmed sDAVF obliteration in two patients, and recurrence in two cases. Two patients had no follow-up. One patient not cured at the time of treatment was treated surgically. Of the nine total treatments, Onyx successfully crossed the nidus into the draining vein in only four cases. Successful venous embolization was facilitated with positioning of the microcatheter to less than 5 mm from the nidus in three of the four cases. The use of n-butyl cyanoacrylate (NBCA) resulted in venous penetration in eight of 10 cases, and short term follow-up cure in seven of 10 patients. CONCLUSIONS: Our experience with Onyx for type I sDAVF embolization has been tempered by difficulty in achieving venous penetration and, consequently, a high rate of recurrence. For management of these fistulas, we favor NBCA or surgical treatment. PMID- 23943816 TI - Modified murine intracranial aneurysm model: aneurysm formation and rupture by elastase and hypertension. AB - INTRODUCTION: Cerebral aneurysms occur in up to 5% of the population. There are several murine models of aneurysms; however, all have limitations and none reproducibly model aneurysm rupture. To fulfill this need, we modified two current rodent aneurysm models to create a murine model which reproducibly produces intracranial aneurysms and rupture. METHODS: The left common carotid arteries and the right renal arteries were ligated in C57BL/6 female mice with a hypertensive diet. One week later, small burr holes were created with a stereotactic frame using the following stereotactic measurements: 1.2 mm rostral and 0.7 mm lateral to the right of the bregma. A 26 G needle was gradually advanced via the burr hole until contact with the skull base, upon which the needle was pulled back 0.3 mm. Five, 10 and 20 MUL of 10 U/mL elastase solution and 10 MUL of 1 U/mL elastase solution were stereotactically injected into the basal cisterns. Angiotensin II was then continually infused at a dose of 1000 ng/kg/min via an osmotic pump placed subcutaneously. In the control mice, 20 MUL bromophenol blue solution was injected. Three weeks later, or earlier if mice expired prior to 3 weeks, the circle of Willis was inspected by microscopy for aneurysm formation and/or signs of rupture. Histological analyses were then performed to evaluate elastic lamina destruction, inflammatory cell and macrophage infiltration, absence of intimal endothelial cells and thickening of the smooth muscle layer within the aneurysm wall. To compare with human aneurysms, human aneurysm specimens (n=35; 34 unruptured and 1 ruptured) and normal control superficial temporal arteries (STAs) (n=9) were examined. RESULTS: All mice given 5, 10 and 20 MUL of 10 U/mL elastase solution developed intracranial aneurysms within the circle of Willis; 40%, 60% and 50% of mice had ruptured aneurysms, respectively. In mice given 10 MUL of 1.0 U/mL elastase solution, 90% developed intracranial aneurysms and 20% had ruptured aneurysms. Aneurysms were confirmed by examining the destruction of the elastic lamina. Aneurysms consistently demonstrated CD45 positive inflammatory cell and F4/80 positive macrophage infiltration within the aneurysm wall which was not present in the circle of Willis of normal sham-operated mice. These results were similar to those in human aneurysms and STA control arteries. CONCLUSIONS: We modified two current rodent aneurysm models to create a murine model that produces consistent aneurysms and rupture and can be used for studying cerebral aneurysm formation, rupture and treatment. PMID- 23943817 TI - A prospective, multicenter pilot study investigating the utility of flat detector derived parenchymal blood volume maps to estimate cerebral blood volume in stroke patients. AB - PURPOSE: Newer flat panel angiographic detector (FD) systems have the capability to generate parenchymal blood volume (PBV) maps. The ability to generate these maps in the angiographic suite has the potential to markedly expedite the triage and treatment of patients with acute ischemic stroke. The present study compares FP-PBV maps with cerebral blood volume (CBV) maps derived using standard dynamic CT perfusion (CTP) in a population of patients with stroke. METHODS: 56 patients with cerebrovascular ischemic disease at two participating institutions prospectively underwent both standard dynamic CTP imaging followed by FD-PBV imaging (syngo Neuro PBV IR; Siemens, Erlangen, Germany) under a protocol approved by both institutional review boards. The feasibility of the FD system to generate PBV maps was assessed. The radiation doses for both studies were compared. The sensitivity and specificity of the PBV technique to detect (1) any blood volume deficit and (2) a blood volume deficit greater than one-third of a vascular territory, were defined using standard dynamic CTP CBV maps as the gold standard. RESULTS: Of the 56 patients imaged, PBV maps were technically adequate in 42 (75%). The 14 inadequate studies were not interpretable secondary to patient motion/positioning (n=4), an injection issue (n=2), or another reason (n=8). The average dose for FD-PBV was 219 mGy (median 208) versus 204 mGy (median 201) for CT-CBV. On CT-CBV maps 26 of 42 had a CBV deficit (61.9%) and 15 (35.7%) had a deficit that accounted for greater than one-third of a vascular territory. FD-PBV maps were 100% sensitive and 81.3% specific to detect any CBV deficit and 100% sensitive and 62.9% specific to detect any CBV deficit of greater than one-third of a territory. CONCLUSIONS: PBV maps can be generated using FP systems. The average radiation dose is similar to a standard CTP examination. PBV maps have a high sensitivity for detecting CBV deficits defined by conventional CTP. PBV maps often overestimate the size of CBV deficits. We hypothesize that the FP protocol initiates PBV imaging prior to complete saturation of the blood volume in areas perfused via indirect pathways (ie, leptomeningeal collaterals), resulting in an overestimation of CBV deficits, particularly in the setting of large vessel occlusion. PMID- 23943818 TI - Intermittent balloon occlusion to favor nidal penetration during embolization of arteriovenous malformations: a technique modification. AB - Endovascular embolization of brain arteriovenous malformations (AVMs) has improved with liquid occlusive agents, but flow-related and anatomic restrictions limit endovascular capabilities. AVM compartments supplied by leptomeningeal networks and feeding arteries too small and/or tortuous for safe catheterization are rarely penetrated by liquid occlusive agents. A case with both impediments prompted a novel solution. A balloon was inflated across the supply to a lenticulostriate feeder, thereby favoring penetration of the liquid occlusive agent, injected from a different feeding territory, back into the AVM compartment supplied by the temporarily occluded feeder. This technique may reduce the number of embolization stages in large high-flow AVMs and increase the likelihood of achieving complete occlusion. This technique is highly complex and requires meticulous monitoring of multiple events. PMID- 23943819 TI - Multilocus parasite gene polymorphism and/or parasite-selected mutations in host genome may discriminate between relapse and reinfection in the failure of miltefosine treatment in visceral leishmaniasis. PMID- 23943821 TI - Impact of colonization pressure and strain type on methicillin-resistant Staphylococcus aureus transmission in children. AB - We studied the transmissibility of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and healthcare-associated methicillin-resistant S. aureus (HA-MRSA) strains and the association of MRSA colonization pressure and MRSA transmission in critically ill children. Importantly, we found that in hospitalized children MRSA colonization pressure above 10% increases the risk of MRSA transmission 3-fold, and CA-MRSA and HA-MRSA strains have similar transmission dynamics. PMID- 23943820 TI - Clinical manifestations and management of left ventricular assist device associated infections. AB - BACKGROUND: Infection is a serious complication of left ventricular assist device (LVAD) therapy. Published data regarding LVAD-associated infections (LVADIs) are limited by single-center experiences and use of nonstandardized definitions. METHODS: We retrospectively reviewed 247 patients who underwent continuous-flow LVAD implantation from January 2005 to December 2011 at Mayo Clinic campuses in Minnesota, Arizona, and Florida. LVADIs were defined using the International Society for Heart and Lung Transplantation criteria. RESULTS: We identified 101 episodes of LVADI in 78 patients (32%) from this cohort. Mean age (+/- standard deviation [SD]) was 57+/-15 years. The majority (94%) underwent Heartmate II implantation, with 62% LVADs placed as destination therapy. The most common type of LVADIs were driveline infections (47%), followed by bloodstream infections (24% VAD related, and 22% non-VAD related). The most common causative pathogens included gram-positive cocci (45%), predominantly staphylococci, and nosocomial gram-negative bacilli (27%). Almost half (42%) of the patients were managed by chronic suppressive antimicrobial therapy. While 14% of the patients had intraoperative debridement, only 3 underwent complete LVAD removal. The average duration (+/-SD) of LVAD support was 1.5+/-1.0 years. At year 2 of follow-up, the cumulative incidence of all-cause mortality was estimated to be 43%. CONCLUSION: Clinical manifestations of LVADI vary on the basis of the type of infection and the causative pathogen. Mortality remained high despite combined medical and surgical intervention and chronic suppressive antimicrobial therapy. Based on clinical experiences, a management algorithm for LVADI is proposed to assist in the decision-making process. PMID- 23943822 TI - Clinical, virological, and histopathological manifestations of fatal human infections by avian influenza A(H7N9) virus. AB - BACKGROUND: Systematic analysis of histopathological and serial virological changes of fatal influenza A(H7N9) cases is lacking. METHODS: Patients with A(H7N9) infection admitted to our intensive care unit during 10-23 April 2013 were included. Viral loads in the respiratory tract, as inferred from the cycle threshold (Ct) value of reverse transcription polymerase chain reaction (RT-PCR), and the serum hemagglutination inhibition (HAI) antibody titer, were analyzed. Postmortem biopsies of the lung, liver, kidney, spleen, bone marrow, and heart were examined. RESULTS: Twelve patients (6 deaths, 6 survivors) were included. Median viral load was higher in sputa than the nasopharyngeal swabs for fatal cases (median Ct, 23 vs 30.5; P = .08). RT-PCR for A(H7N9) was positive in stool samples (4/6 [67%]) of fatal cases and (2/6 [33%]) of survivors, but was negative in the cerebrospinal fluid, urine, or blood of all patients. Nosocomial bacterial infections were more common in patients who died than in survivors (83% vs 50%). HAI titers increased by >=4-fold in those with convalescent sera. Postmortem biopsy for 3 patients showed acute diffuse alveolar damage. Patient 1, who died 8 days after symptom onset, had intra-alveolar hemorrhage. Patients 2 and 3, who died 11 days after symptom onset, had pulmonary fibroproliferative changes. Reactive hemophagocytosis in the bone marrow and lymphoid atrophy in splenic tissues were compatible with laboratory findings of leukopenia, lymphopenia, and thrombocytopenia. Hypoxic and fatty changes of kidney and liver tissues are compatible with impaired renal or liver function. CONCLUSIONS: Fatal A(H7N9) infection was characterized by viral and secondary bacterial pneumonia with 67% having positive RT-PCR in stool. PMID- 23943823 TI - Reply to Das. PMID- 23943824 TI - One-year follow-up of immunocompetent male patients treated with miltefosine for primary visceral leishmaniasis in Bihar, India. PMID- 23943826 TI - The globalization of healthcare: implications of medical tourism for the infectious disease clinician. AB - Travel abroad for healthcare has increased rapidly; interventions include organ transplant; cardiac surgery; reproductive care; and joint, cosmetic, and dental procedures. Individuals who receive medical care abroad are a vulnerable, sentinel population, who sample the local environment and can carry home unusual and resistant infections, documented in many reports. Medical tourists are at risk for hospital-associated and procedure-related infections as well as for locally endemic infections. Patients may not volunteer details about care abroad, so clinicians must inquire about medical procedures abroad as well as recent travel. Special infection control measures may be warranted. Healthcare abroad is associated with diverse financial, legal, ethical, and health-related issues. We focus on problems the infectious disease clinician may encounter and provide a framework for evaluating returned medical tourists with suspected infections. A better system is needed to ensure broad access to high-quality health services, continuity of care, and surveillance for complications. PMID- 23943827 TI - Reply to P. Borchmann et al. PMID- 23943825 TI - Low baseline CD4+ count is associated with greater bone mineral density loss after antiretroviral therapy initiation. AB - BACKGROUND: Bone mineral density (BMD) decreases 2%-6% in the 2 years after antiretroviral therapy (ART) initiation. Pre-ART immune deficiency and early immune recovery may contribute to this loss. METHODS: We pooled data from 3 studies of ART initiation in treatment-naive patients in which serial whole-body dual-energy X-ray absorptiometry scans were performed. We used linear regression to evaluate effects of baseline CD4(+) and 16-week CD4(+) change (both absolute and relative) on 96-week total BMD change from baseline. We performed multivariable linear regression to assess associations between baseline variables of age, sex, race/ethnicity, body mass index (BMI), hepatitis C status, parent study, human immunodeficiency virus type 1 (HIV-1) RNA level, and assignment to a protease inhibitor (PI)- or tenofovir-containing regimen on 96-week total BMD change. RESULTS: The included 796 subjects had mean 96-week total BMD loss of 2.0%. In multivariable analysis, baseline CD4(+) cell count was significantly associated with 96-week BMD loss; individuals with baseline CD4(+) <50 cells/uL lost significantly more BMD compared to those with CD4(+) >=500 cells/uL. A greater relative, but not absolute, 16-week increase in CD4(+) count was significantly associated with greater declines in BMD, but not after controlling for baseline CD4(+) count. In multivariable analysis, older age, female sex, lower BMI, higher HIV-1 RNA levels, and PI and tenofovir assignment were also associated with greater BMD decline. CONCLUSIONS: Low pretreatment CD4(+) count, but not greater CD4(+) count increase, is a strong and independent risk factor for bone loss after ART initiation. ART initiation at higher CD4(+) counts may reduce the burden of osteoporosis and fragility fractures. PMID- 23943828 TI - Reply to e.g. Russi et Al and R. Haddad. PMID- 23943829 TI - Reply to v.R. Bhatt et Al and m.C. Chamberlain. PMID- 23943830 TI - Reply to A.H. Kamal. PMID- 23943831 TI - Reply to F. Gelsomino et al. PMID- 23943832 TI - Reply to C.s. Tam et Al. PMID- 23943833 TI - Reply to O.R. Colegio et al. PMID- 23943834 TI - Reply to e. Esin et al. PMID- 23943835 TI - Reply to A. Azad et al. PMID- 23943836 TI - Reply to K. Zaman et al. PMID- 23943837 TI - Reply to C.M. Booth et al. PMID- 23943838 TI - Effect of neuronal nicotinic acetylcholine receptor genes (CHRN) on longitudinal cigarettes per day in adolescents and young adults. AB - INTRODUCTION: Few studies have sought to identify specific genetic markers associated with cigarettes per day (CPD) during adolescence and young adulthood, the period of greatest vulnerability for the development of nicotine dependence. METHODS: We used a longitudinal design to investigate the effect of neuronal nicotinic acetylcholine receptor (CHRN) subunit genes on CPD from 15 to 21 years of age in young smokers of European descent (N = 439, 59% female). The number of CPD typically smoked during the previous 30 days was self-reported. Single nucleotide polymorphisms (SNPs) from CHRN genes were genotyped using DNA extracted from saliva samples collected at the 5-year assessment. Mixed-model analyses of SNP effects were computed across age at the time of assessment using log-transformed CPD as the phenotype. Data from the 1000 Genomes Project were used to clarify the architecture of CHRN genes to inform SNP selection and interpretation of results. RESULTS: CPD was associated with a CHRNB3A6 region tagged by rs2304297, with CHRNA5A3B4 haplotype C (tagged by rs569207), and with the CHRNA2 SNP rs2271920, ps < .004. The reliability of single-SNP associations was supported by the correspondence between a more extensive set of SNP signals and the underlying genetic architecture. The 3 signals identified in this study appear to make independent contributions to CPD, and their combined effect accounts for 5.5% of the variance in log-transformed CPD. CONCLUSIONS: Level of CPD during adolescence and young adulthood is associated with CHRNB3A6, CHRNA5A3B4, and CHRNA2. PMID- 23943840 TI - Beliefs associated with intention to ban smoking in households with smokers. AB - INTRODUCTION: Smoking in homes exposes family members to secondhand smoke, an exposure that is harmful to children and adults. This study identifies barriers to instituting household smoking bans and beliefs that are positively and negatively related to smoking bans in households with smokers. METHODS: A telephone survey of parents living in Philadelphia with at least 1 smoker and a child under the age of 13 years in the household was conducted in 2012. Using the reasoned action model, the survey assessed beliefs regarding attitudes, norms, and self-efficacy/control predictors of intention to ban household smoking. RESULTS: Forty-seven percent of households reported high intention to not allow smoking in the home. Regression analysis to identify the reasoned action predictors associated with intention to restrict smoking in the home showed that all 3 of the predictors of intention (attitude, normative pressure, and control) were significantly related to intention. Important underlying beliefs related to intention included beliefs about the health effects of secondhand smoke on children's health, norms regarding those restrictions, and barriers to enforcing such restrictions. CONCLUSIONS: Messages that increase concern about the health effects of secondhand smoke on children, that contrast the rights of smokers with negative health effects, and that suggest alternative locations to smoke are promising strategies to motivate smokers to implement indoor smoking bans. PMID- 23943839 TI - Nicotine dependence and biochemical exposure measures in the second trimester of pregnancy. AB - INTRODUCTION: The Heaviness of Smoking Index (HSI) is validated to measure nicotine dependence in nonpregnant smokers, and in these smokers, mean salivary and serum cotinine levels are related by a ratio of 1.25. However, as nicotine metabolism increases during gestation, these findings may differ in pregnancy. We investigated the validity of HSI in pregnancy by comparing this with 3 biochemical measures; in a search for a less-invasive cotinine measure in pregnancy, we also explored the relationship between mean blood and salivary cotinine levels. METHODS: Cross-sectional analyses using baseline data from the Smoking, Nicotine, and Pregnancy Trial. Participants were 16-46 years old, 12-24 weeks gestation, smoked more than 5 cigarettes per day, and had exhaled carbon monoxide (CO) readings of at least 8 ppm. Linear regression was used to examine correlations between HSI and blood cotinine and salivary cotinine and exhaled CO. Correlation between blood and salivary cotinine was investigated using linear regression through the origin. RESULTS: HSI scores were associated with blood cotinine (R2 = 0.20, n = 662, p < .001), salivary cotinine (R2 = 0.11, n = 967, p < .001), and exhaled CO (R2 = 0.13, n = 1,050, p < .001). Salivary and blood cotinine levels, taken simultaneously, were highly correlated (R2 = 0.91, n = 628, p < .001) and the saliva:blood level ratio was 1.01 (95% CI 0.99-1.04). CONCLUSIONS: Correlations between HSI and biochemical measures in pregnancy were comparable with those obtained outside pregnancy, suggesting that HSI has similar validity in pregnant smokers. Salivary and blood cotinine levels are roughly equivalent in pregnant smokers. PMID- 23943841 TI - Influence of snuff and smoking habits in early pregnancy on risks for stillbirth and early neonatal mortality. AB - INTRODUCTION: Prenatal exposure to Swedish snuff (including nicotine and other components in grinded tobacco) is reported to increase stillbirth risk, but the effect of snuff on early neonatal mortality is unknown. Prenatal smoking exposure is associated with risks for both stillbirth and early neonatal mortality. We aimed to study if women who quit using snuff or quit smoking before first antenatal visit reduce their risks. METHODS: In a nationwide study of 851,371 singleton births in Sweden from 1999 to 2010, we used multiple logistic regression models to examine associations between cessation or continuation of snuff use or smoking and risks for stillbirth (at 28 weeks or later) and early neonatal mortality (death during the first week of life). RESULTS: Compared with nontobacco users, snuff users and smokers in early pregnancy had increased risks for stillbirths, and adjusted odds ratios (ORs), with 95% confidence intervals (CI), were 1.43 (1.02-1.99) and 1.59 (1.40-1.80), respectively. Women who stopped using snuff or stopped smoking before first visit to antenatal care had no increased risks. Compared with nontobacco users, smokers had an increased risk for early neonatal mortality (adjusted OR = 1.37 [95% CI 1.11-1.71]). Women who stopped smoking and snuff users in early pregnancy had no increased risks of early neonatal mortality. CONCLUSIONS: Both snuff and smoking influence risk for stillbirth, and women who stop using snuff or smoking have a similar stillbirth risk as nontobacco users. Smoking but not snuff use influences risk for early neonatal mortality. PMID- 23943842 TI - An observational study of group waterpipe use in a natural environment. AB - INTRODUCTION: To date research on tobacco smoking with a waterpipe (hookah, narghile, and shisha) has focused primarily on the individual user in a laboratory setting. Yet, waterpipe tobacco smoking is often a social practice that occurs in cafes, homes, and other natural settings. This observational study examined the behavior of waterpipe tobacco smokers and the social and contextual features of waterpipe use among groups in their natural environment. METHODS: Trained observers visited urban waterpipe cafes on multiple occasions during an 8 month period. Observations of 241 individual users in naturally formed groups were made on smoking topography (puff frequency, duration, and interpuff interval [IPI]) and engagement in other activities (e.g., food and drink consumption, other tobacco use, and media viewing). RESULTS: Most users were male in group sizes of 3-4 persons, on average, and each table had 1 waterpipe, on average. The predominant social features during observational periods were conversation and nonalcoholic drinking. Greater puff number was associated with smaller group sizes and more waterpipes per group, while longer IPIs were associated with larger group sizes and fewer waterpipes per group. Additionally, greater puff frequency was observed during media viewing and in the absence of other tobacco use. CONCLUSIONS: Overall, the results suggest that waterpipe smoking behavior is affected by group size and by certain social activities. Discussion focuses on how these findings enhance our understanding of factors that may influence exposure to waterpipe tobacco smoke toxicants in naturalistic environments. PMID- 23943843 TI - Methodology for developing and evaluating the PROMIS smoking item banks. AB - INTRODUCTION: This article describes the procedures used in the PROMIS Smoking Initiative for the development and evaluation of item banks, short forms (SFs), and computerized adaptive tests (CATs) for the assessment of 6 constructs related to cigarette smoking: nicotine dependence, coping expectancies, emotional and sensory expectancies, health expectancies, psychosocial expectancies, and social motivations for smoking. METHODS: Analyses were conducted using response data from a large national sample of smokers. Items related to each construct were subjected to extensive item factor analyses and evaluation of differential item functioning (DIF). Final item banks were calibrated, and SF assessments were developed for each construct. The performance of the SFs and the potential use of the item banks for CAT administration were examined through simulation study. RESULTS: Item selection based on dimensionality assessment and DIF analyses produced item banks that were essentially unidimensional in structure and free of bias. Simulation studies demonstrated that the constructs could be accurately measured with a relatively small number of carefully selected items, either through fixed SFs or CAT-based assessment. Illustrative results are presented, and subsequent articles provide detailed discussion of each item bank in turn. CONCLUSIONS: The development of the PROMIS smoking item banks provides researchers with new tools for measuring smoking-related constructs. The use of the calibrated item banks and suggested SF assessments will enhance the quality of score estimates, thus advancing smoking research. Moreover, the methods used in the current study, including innovative approaches to item selection and SF construction, may have general relevance to item bank development and evaluation. PMID- 23943844 TI - Intergenerational transfer of smoking across three generations and forty-five years. AB - OBJECTIVES: Although many have examined the linkages between smoking behaviors across 2 generations, few have examined these linkages among 3 generations. METHODS: U.S. population representative data for 3 generations are drawn from the Panel Study of Income Dynamics (PSID) in order to examine whether smoking behaviors are passed down from generation to generation and the magnitude of the influence of smoking behaviors across generations (N = 830). RESULTS: Results indicate direct linkages between both grandparent (G1) and parent (G2) smoking (OR = 4.53; 95% CI = 2.57-7.97) and parent (G2) and young adult offspring (G3) smoking (OR = 2.91; 95% CI = 1.60-5.31). Although the direct link between grandparent (G1) and grandchildren (G3) was not significant (OR = 2.25; 95% CI = 0.96-5.23, p < .10), mediation analyses reveal that the link between G3 and G1 smoking is significantly mediated by G2 smoking. CONCLUSIONS: Regardless of generation, parent smoking behavior has a direct influence on offspring smoking behavior. The link between grandparent (G1) and grandchild (G3) smoking is mediated by parent (G2) smoking, suggesting that smoking behavior is passed from one generation to the next generation and in turn to the next generation. PMID- 23943845 TI - Pharmacists' smoking cessation counseling practices: a comparison between 2005 and 2010. AB - INTRODUCTION: To determine if smoking cessation counseling practices and related psychosocial characteristics improved among pharmacists between 2005 and 2010. METHODS: Data were collected in 2005 and 2010 from randomly selected pharmacists in Quebec, Canada. Participants completed mailed self-report questionnaires on cessation counseling practices and psychosocial characteristics (i.e., belief that counseling is the role of pharmacists, self-efficacy, barriers, and knowledge of community resources). The association between each of year and training (either during or after undergraduate studies) and each outcome was investigated in each sex separately with multiple linear regression models using pooled data across 2005 and 2010. RESULTS: Among female pharmacists, cessation counseling for patients ready to quit improved over time. Training during and after undergraduate studies was significantly associated with higher self efficacy, better knowledge of community resources, and improved counseling for patients ready and not ready to quit. Also, training after studies was significantly associated with more advantageous beliefs about counseling. Among male pharmacists, knowledge of community resources and perceived barriers to counseling improved over time, but there were no significant differences in cessation counseling. Training during and after undergraduate studies was significantly associated with higher self-efficacy. Training during undergraduate studies was also associated with higher counseling score in patients ready to quit, and training after studies was associated with better knowledge of community resources. CONCLUSION: Smoking cessation counseling for patients ready to quit improved from 2005 to 2010 among female pharmacists but not among male pharmacists. Training is generally associated with improved counseling and improved cessation-related psychosocial characteristics. PMID- 23943846 TI - Reactions to framing of cessation messages: insights from dual-smoker couples. AB - INTRODUCTION: Couples in which both members smoke (dual-smoker couples) have not been the explicit target of cessation interventions. Quit rates are lower and relapse rates are higher among individuals in dual-smoker couples. A potentially effective strategy to motivate dual-smoker couples to quit is to convey messages that highlight how the positive outcomes of quitting (gain frame) or the negative outcomes of continued smoking (loss frame) affect the couple rather than the individual smoker. We explored whether dual-smoker couples' smoking behaviors (e.g., amount smoked) and desire to quit would differ as a function of message frame (gain vs. loss) or outcome focus (individual vs. couple). METHODS: Dual smoker couples (N = 40) completed a baseline survey and were then randomized to review gain- or loss-framed messages that varied whether the outcomes influenced the individual or the couple. Main outcomes were desire to quit after reading messages and smoking behaviors at a 1-month follow-up. RESULTS: Couple-focused messages produced the strongest desire to quit and decreased amount of cigarettes smoked at follow-up. The latter effect was mediated by desire to quit. Loss framed messages produced inconsistent effects on desire to quit. There were no significant interactions between outcome focus and message framing. CONCLUSIONS: Findings suggest that messages emphasizing how smoking affects both partners can motivate cessation among dual-smoker couples. Contrary to findings showing that gain-framed messages motivate cessation targeting individual smokers, results suggest that loss-framed messages may be more persuasive than gain-framed messages when the target of the outcome involves significant others. PMID- 23943847 TI - Relationship of cigarette-related perceptions to cigarette design features: findings from the 2009 ITC U.S. Survey. AB - INTRODUCTION: Many governments around the world have banned the use of misleading cigarette descriptors such as "light" and "mild" because the cigarettes so labeled were found not to reduce smokers' health risks. However, underlying cigarette design features, which are retained in many brands, likely contribute to ongoing belief that these cigarettes are less harmful by producing perceptions of lightness/smoothness through lighter taste and reduced harshness and irritation. METHODS: Participants (N = 320) were recruited from the International Tobacco Control U.S. Survey conducted in 2009 and 2010, when they answered questions about smoking behavior, attitudes and beliefs about tobacco products, and key mediators and moderators of tobacco use behaviors. Participants also submitted an unopened pack of their usual brand of cigarettes for analysis using established methods. RESULTS: Own-brand filter ventilation level (M 29%, range 0% 71%) was consistently associated with perceived lightness (p < .001) and smoothness (p = .005) of own brand. Those whose brand bore a light/mild label (55% of participants) were more likely to report their cigarettes were lighter [71.9% vs. 41.9%; chi(2)(2) = 38.1, p < .001] and smoother than other brands [75.5% vs. 68.7%; chi(2)(2) = 7.8, p = .020]. CONCLUSION: Product design features, particularly filter ventilation, influence smokers' beliefs about product attributes such as lightness and smoothness, independent of package labels. Regulation of cigarette design features such as filter ventilation should be considered as a complement to removal of misleading terms in order to reduce smokers' misperceptions regarding product risks. PMID- 23943848 TI - A type III ACC synthase, ACS7, is involved in root gravitropism in Arabidopsis thaliana. AB - Ethylene is an important plant hormone that regulates developmental processes in plants. The ethylene biosynthesis pathway is a highly regulated process at both the transcriptional and post-translational level. The transcriptional regulation of these ethylene biosynthesis genes is well known. However, post-translational modifications of the key ethylene biosynthesis enzyme 1-aminocyclopropane-1 carboxylate (ACC) synthase (ACS) are little understood. In vitro kinase assays were conducted on the type III ACS, AtACS7, fusion protein and peptides to determine whether the AtACS7 protein can be phosphorylated by calcium-dependent protein kinase (CDPK). AtACS7 was phosphorylated at Ser216, Thr296, and Ser299 by AtCDPK16 in vitro. To investigate further the function of the ACS7 gene in Arabidopsis, an acs7-1 loss-of-function mutant was isolated. The acs7-1 mutant exhibited less sensitivity to the inhibition of root gravitropism by treatment with the calcium chelator ethylene glycol tetraacetic acid (EGTA). Seedlings were treated with gradient concentrations of ACC. The results showed that a certain concentration of ethylene enhanced the gravity response. Moreover, the acs7-1 mutant was less sensitive to inhibition of the gravity response by treatment with the auxin polar transport inhibitor 1-naphthylphthalamic acid, but exogenous ACC application recovered root gravitropism. Altogether, the results indicate that AtACS7 is involved in root gravitropism in a calcium-dependent manner in Arabidopsis. PMID- 23943850 TI - Randomized controlled trial of levamisole hydrochloride as adjunctive therapy in severe falciparum malaria with high parasitemia. AB - BACKGROUND: Cytoadherence and sequestration of erythrocytes containing mature stages of Plasmodium falciparum are central to the pathogenesis of severe malaria. The oral anthelminthic drug levamisole inhibits cytoadherence in vitro and reduces sequestration of late-stage parasites in uncomplicated falciparum malaria treated with quinine. METHODS: Fifty-six adult patients with severe malaria and high parasitemia admitted to a referral hospital in Bangladesh were randomized to receive a single dose of levamisole hydrochloride (150 mg) or no adjuvant to antimalarial treatment with intravenous artesunate. RESULTS: Circulating late-stage parasites measured as the median area under the parasite clearance curves were 2150 (interquartile range [IQR], 0-28 025) parasites/uL * hour in patients treated with levamisole and 5489 (IQR, 192-25 848) parasites/uL * hour in controls (P = .25). The "sequestration ratios" at 6 and 12 hours for all parasite stages and changes in microvascular blood flow did not differ between treatment groups (all P > .40). The median time to normalization of plasma lactate (<2 mmol/L) was 24 (IQR, 12-30) hours with levamisole vs 28 (IQR, 12-36) hours without levamisole (P = .15). CONCLUSIONS: There was no benefit of a single-dose of levamisole hydrochloride as adjuvant to intravenous artesunate in the treatment of adults with severe falciparum malaria. Rapid parasite killing by intravenous artesunate might obscure the effects of levamisole. PMID- 23943851 TI - Viral suppression following switch to second-line antiretroviral therapy: associations with nucleoside reverse transcriptase inhibitor resistance and subtherapeutic drug concentrations prior to switch. AB - BACKGROUND: High rates of second-line antiretroviral treatment (ART) failure are reported. The association with resistance and nonadherence on switching to second line ART requires clarification. METHODS: Using prospectively collected data from patients in South Africa, we constructed a cohort of patients switched to second line ART (1 January 2003 through 31 December 2008). Genotyping and drug concentrations (lamivudine, nevirapine, and efavirenz) were measured on stored samples preswitch. Their association with viral load (VL) <400 copies/mL by 15 months was assessed using modified Poisson regression. RESULTS: One hundred twenty-two of 417 patients (49% male; median age, 36 years) had genotyping (n = 115) and/or drug concentrations (n = 80) measured. Median CD4 count and VL at switch were 177 cells/uL (interquartile range [IQR], 77-263) and 4.3 log10 copies/mL (IQR, 3.8-4.7), respectively. Fifty-five percent (n = 44/80) had subtherapeutic drug concentrations preswitch. More patients with therapeutic vs subtherapeutic ART had resistance (n = 73): no major mutations (3% vs 51%), nonnucleoside reverse transcriptase inhibitor (94% vs 44%), M184V/I (94% vs 26%), and >= 1 thymidine analogue mutations (47% vs 18%), all P = .01; and nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance mutations (26% vs 13%, P = .23). Following switch, 68% (n = 83/122) achieved VL <400 copies/mL. Absence of NRTI mutations and subtherapeutic ART preswitch were associated with failure to achieve VL <400 copies/mL. CONCLUSIONS: Nonadherence, suggested by subtherapeutic ART with/without major resistance mutations, significantly contributed to failure when switching regimen. Unresolved nonadherence, not NRTI resistance, drives early second-line failure. PMID- 23943852 TI - Gene expression signatures but not cell cycle checkpoint functions distinguish AT carriers from normal individuals. AB - Ataxia telangiectasia (AT) is a rare autosomal recessive disease caused by mutations in the ataxia telangiectasia-mutated gene (ATM). AT carriers with one mutant ATM allele are usually not severely affected although they carry an increased risk of developing cancer. There has not been an easy and reliable diagnostic method to identify AT carriers. Cell cycle checkpoint functions upon ionizing radiation (IR)-induced DNA damage and gene expression signatures were analyzed in the current study to test for differential responses in human lymphoblastoid cell lines with different ATM genotypes. While both dose- and time dependent G1 and G2 checkpoint functions were highly attenuated in ATM-/- cell lines, these functions were preserved in ATM+/- cell lines equivalent to ATM+/+ cell lines. However, gene expression signatures at both baseline (consisting of 203 probes) and post-IR treatment (consisting of 126 probes) were able to distinguish ATM+/- cell lines from ATM+/+ and ATM-/- cell lines. Gene ontology (GO) and pathway analysis of the genes in the baseline signature indicate that ATM function-related categories, DNA metabolism, cell cycle, cell death control, and the p53 signaling pathway, were overrepresented. The same analyses of the genes in the IR-responsive signature revealed that biological categories including response to DNA damage stimulus, p53 signaling, and cell cycle pathways were overrepresented, which again confirmed involvement of ATM functions. The results indicate that AT carriers who have unaffected G1 and G2 checkpoint functions can be distinguished from normal individuals and AT patients by expression signatures of genes related to ATM functions. PMID- 23943849 TI - Therapeutic targeting of autophagy in disease: biology and pharmacology. AB - Autophagy, a process of self-digestion of the cytoplasm and organelles through which cellular components are recycled for reuse or energy production, is an evolutionarily conserved response to metabolic stress found in eukaryotes from yeast to mammals. It is noteworthy that autophagy is also associated with various pathophysiologic conditions in which this cellular process plays either a cytoprotective or cytopathic role in response to a variety of stresses such as metabolic, inflammatory, neurodegenerative, and therapeutic stress. It is now generally believed that modulating the activity of autophagy through targeting specific regulatory molecules in the autophagy machinery may impact disease processes, thus autophagy may represent a new pharmacologic target for drug development and therapeutic intervention of various human disorders. Induction or inhibition of autophagy using small molecule compounds has shown promise in the treatment of diseases such as cancer. Depending on context, induction or suppression of autophagy may exert therapeutic effects via promoting either cell survival or death, two major events targeted by therapies for various disorders. A better understanding of the biology of autophagy and the pharmacology of autophagy modulators has the potential for facilitating the development of autophagy-based therapeutic interventions for several human diseases. PMID- 23943853 TI - Human angiotensinogen +11525 C/A polymorphism modulates its gene expression through microRNA binding. AB - Hypertension is a serious risk factor for cardiovascular disease. Like other complex disease, hypertension is caused by a combination of genetic and environmental factors. The renin-angiotensin system plays an important role in the regulation of blood pressure. Angiotensinogen (AGT) gene is associated with essential hypertension in Caucasians, Japanese, and Asian-Indian subjects. AGT gene may also be associated with cardiac hypertrophy, coronary atherosclerosis, and microangiopathy related cerebral damage. Human AGT gene has a C/A polymorphism at nucleoside 11525 (rs7079) that is located in the 3'-untranslated region (3'-UTR) and is modestly associated with increased blood pressure. We show here that miR-31 and miR-584 bind strongly to the hAGT 3'-UTR containing 11525C allele compared with 11525A allele. We also show that transfection of miR-31 and miR-584 downregulates the hAGT mRNA and protein levels in human liver cells. These studies may provide new therapeutic approach to reduce hypertension. PMID- 23943854 TI - Systems genetics of hepatocellular damage in vivo and in vitro: identification of a critical network on chromosome 11 in mouse. AB - Quantitative trait locus (QTL) mapping is a powerful method to find modifier loci that influence disease risk and progression without prior knowledge of underlying genetic mechanisms. The aim of this study is to identify gene loci that contribute to individual differences in liver fibrosis following chronic liver damage. For this purpose, we carried out a mapping study across a panel of 21 BXD recombinant inbred strains using primary hepatocytes challenged with transforming growth factor (TGF)-beta for 48 h. We identified a 6 Mb interval on chromosome 11 that is a major modifier of TGF-beta-induced hepatocyte injury. Corresponding in vivo genetic analysis of fibrosis after chronic hepatotoxic injury by carbon tetrachloride (CCl4 ip for 6 wk) highlighted the same locus. Expression QTL (eQTL) analysis in liver tissues in the BXD family identified six polymorphisms in this region that are associated with strong cis eQTLs and that correlate well with gene expression in liver after both 6 wk CCl4 treatment and acute ethanol damage of the liver. Within this interval we rank two genes containing coding sequence variants as strong candidates that may modulate the severity of liver fibrosis: 1) the extracellular proteinase inhibitor gene Expi (also known as Wdnm1 or Wfdc18) and 2) musashi RNA-binding protein 2 (Msi2). The powerful combination of experimental, genetics, and bioinformatics methods, as well as combined in vitro and in vivo approaches can be used to define QTLs, genes, and even candidate sequence variants linked to hepatotoxicity and fibrosis. PMID- 23943855 TI - Haploinsufficiency of osterix in chondrocytes impairs skeletal growth in mice. AB - Osterix (Osx) is essential for both intramembranous or endochondral bone formation. Osteoblast-specific ablation of Osx using Col1alpha1-Cre resulted in osteopenia, because of impaired osteoblast differentiation in adult mice. Since Osx is also known to be expressed in chondrocytes, we evaluated the role of Osx expressed in chondrocytes by examining the skeletal phenotype of mice with conditional disruption of Osx in Col2alpha1-expressing chondrocytes. Surprisingly, Cre-positive mice that were homozygous for Osx floxed alleles died after birth. Alcian blue and alizarin red staining revealed that the lengths of skeleton, femur, and vertebrae were reduced by 21, 26, and 14% (P < 0.01), respectively, in the knockout (KO) compared with wild-type mice. To determine if haploid insufficiency of Osx in chondrocytes influenced postnatal skeletal growth, we compared skeletal phenotype of floxed heterozygous mice that were Cre positive or Cre-negative. Body length was reduced by 8% (P < 0.001), and areal BMD of total body, femur, and tibia was reduced by 5, 7, and 8% (P < 0.05), respectively, in mice with conditional disruption of one allele of Osx in chondrocytes. Micro-CT showed reduced cortical volumetric bone mineral density and trabecular bone volume to total volume in the femurs of Osx(flox/+);col2alpha1-Cre mice. Histological analysis revealed that the impairment of longitudinal growth was associated with disrupted growth plates in the Osx(flox/+);col2alpha1-Cre mice. Primary chondrocytes isolated from KO embryos showed reduced expression of chondral ossification markers but elevated expression of chondrogenesis markers. Our findings indicate that Osx expressed in chondrocytes regulates bone growth in part by regulating chondrocyte hypertrophy. PMID- 23943856 TI - Primary extramedullary plasmacytoma of the penis: a case report. AB - Extramedullary plasmacytoma involving the penis is extremely rare. Here, we describe a case of primary extramedullary plasmacytoma of the penis in a 64-year old man who presented with a palpable penile mass. Nuclear magnetic resonance imaging revealed the presence of a large, round non-encapsulated mass in the perineum. A contrast-enhanced computed tomography scan of the pelvis showed that the mass was located in the tunica albuginea and corpora cavernosa at the base of the penis. The mass encased the urethra and demonstrated no marked enhancement during the arterial phase. The patient underwent successful surgical resection of the tumor. Histologically, the tumor was composed primarily of neoplastic plasma cells that were positive for CD38, vimentin and Ki 67. Postoperatively, the patient recovered well and exhibited no evidence of development of multiple myeloma, local recurrence or distant metastasis at 2 months post-surgery. To the best of our knowledge, our case represents the first documented case of human primary extramedullary plasmacytoma of the penis. PMID- 23943858 TI - Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk. AB - Obesity is associated with significantly increased cardiovascular (CV) risk and mortality. Several molecular mechanisms underlying this association have been implied, among which the intestinal barrier has gained a growing interest. In experimental models of obesity, significant alterations in the intestinal barrier lead to increased intestinal permeability, favoring translocation of microbiome derived lipopolysaccharide to the bloodstream. This has been shown to result in a two- to threefold increase in its serum concentrations, a threshold named 'metabolic endotoxemia' (ME). ME may trigger toll-like receptor 4-mediated inflammatory activation, eliciting a chronic low-grade proinflammatory and pro oxidative stress status, which may result in high CV risk and target-organ damage. In this review, we discuss the potential molecular implications of ME on several CV risk factors, such as obesity, insulin resistance, dyslipidemia, and oxidative stress, as well as its potential impact on the development of CV target organ disease. PMID- 23943857 TI - Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib. AB - The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Among different structurally related COX-2 inhibitors, only celecoxib was found to cause apoptosis and cell death of human lung cancer cells (IC50 values of 19.96 uM [A549], 12.48 uM [H460], and 41.39 uM [H358]) that was paralleled by a time- and concentration-dependent upregulation of COX-2 and peroxisome proliferator-activated receptor gamma (PPARgamma) at mRNA and protein levels. Apoptotic death of celecoxib-treated cancer cells was suppressed by the PPARgamma antagonist GW9662 and by siRNA targeting PPARgamma and, surprisingly, also by the selective COX-2 inhibitor NS-398 and siRNA targeting COX-2. NS-398 (1 uM) was shown to suppress celecoxib-induced COX-2 activity. Among the COX-2-dependent prostaglandins (PG) induced upon celecoxib treatment, PGD2 and 15-deoxy-Delta12,14-PGJ2 were found to induce a cytosol-to nucleus translocation of PPARgamma as well as a PPARgamma-dependent apoptosis. Celecoxib-elicited PPARgamma translocation was inhibited by NS-398. Finally, a COX-2- and PPARgamma-dependent cytotoxic action of celecoxib was proven for primary human lung tumor cells. Together, our data demonstrate a proapoptotic mechanism of celecoxib involving initial upregulation of COX-2 and PPARgamma and a subsequent nuclear translocation of PPARgamma by COX-2-dependent PGs. PMID- 23943859 TI - Arabidopsis histone methylase CAU1/PRMT5/SKB1 acts as an epigenetic suppressor of the calcium signaling gene CAS to mediate stomatal closure in response to extracellular calcium. AB - Elevations in extracellular calcium ([Ca(2+)]o) are known to stimulate cytosolic calcium ([Ca(2+)]cyt) oscillations to close stomata. However, the underlying mechanisms regulating this process remain largely to be determined. Here, through the functional characterization of the calcium underaccumulation mutant cau1, we report that the epigenetic regulation of CAS, a putative Ca(2+) binding protein proposed to be an external Ca(2+) sensor, is involved in this process. cau1 mutant plants display increased drought tolerance and stomatal closure. A mutation in CAU1 significantly increased the expression level of the calcium signaling gene CAS, and functional disruption of CAS abolished the enhanced drought tolerance and stomatal [Ca(2+)]o signaling in cau1. Map-based cloning revealed that CAU1 encodes the H4R3sme2 (for histone H4 Arg 3 with symmetric dimethylation)-type histone methylase protein arginine methytransferase5/Shk1 binding protein1. Chromatin immunoprecipitation assays showed that CAU1 binds to the CAS promoter and modulates the H4R3sme2-type histone methylation of the CAS chromatin. When exposed to elevated [Ca(2+)]o, the protein levels of CAU1 decreased and less CAU1 bound to the CAS promoter. In addition, the methylation level of H4R3sme2 decreased in the CAS chromatin. Together, these data suggest that in response to increases in [Ca(2+)]o, fewer CAU1 protein molecules bind to the CAS promoter, leading to decreased H4R3sme2 methylation and consequent derepression of the expression of CAS to mediate stomatal closure and drought tolerance. PMID- 23943860 TI - Central region component1, a novel synaptonemal complex component, is essential for meiotic recombination initiation in rice. AB - In meiosis, homologous recombination entails programmed DNA double-strand break (DSB) formation and synaptonemal complex (SC) assembly coupled with the DSB repair. Although SCs display extensive structural conservation among species, their components identified are poorly conserved at the sequence level. Here, we identified a novel SC component, designated central region component1 (CRC1), in rice (Oryza sativa). CRC1 colocalizes with ZEP1, the rice SC transverse filament protein, to the central region of SCs in a mutually dependent fashion. Consistent with this colocalization, CRC1 interacts with ZEP1 in yeast two-hybrid assays. CRC1 is orthologous to Saccharomyces cerevisiae pachytene checkpoint2 (Pch2) and Mus musculus THYROID receptor-interacting protein13 (TRIP13) and may be a conserved SC component. Additionally, we provide evidence that CRC1 is essential for meiotic DSB formation. CRC1 interacts with homologous pairing aberration in rice meiosis1 (PAIR1) in vitro, suggesting that these proteins act as a complex to promote DSB formation. PAIR2, the rice ortholog of budding yeast homolog pairing1, is required for homologous chromosome pairing. We found that CRC1 is also essential for the recruitment of PAIR2 onto meiotic chromosomes. The roles of CRC1 identified here have not been reported for Pch2 or TRIP13. PMID- 23943861 TI - Predicting gene function from uncontrolled expression variation among individual wild-type Arabidopsis plants. AB - Gene expression profiling studies are usually performed on pooled samples grown under tightly controlled experimental conditions to suppress variability among individuals and increase experimental reproducibility. In addition, to mask unwanted residual effects, the samples are often subjected to relatively harsh treatments that are unrealistic in a natural context. Here, we show that expression variations among individual wild-type Arabidopsis thaliana plants grown under the same macroscopic growth conditions contain as much information on the underlying gene network structure as expression profiles of pooled plant samples under controlled experimental perturbations. We advocate the use of subtle uncontrolled variations in gene expression between individuals to uncover functional links between genes and unravel regulatory influences. As a case study, we use this approach to identify ILL6 as a new regulatory component of the jasmonate response pathway. PMID- 23943863 TI - Our shifting understanding of factors influencing prostate-specific antigen. PMID- 23943862 TI - Arabidopsis basic helix-loop-helix transcription factors MYC2, MYC3, and MYC4 regulate glucosinolate biosynthesis, insect performance, and feeding behavior. AB - Arabidopsis thaliana plants fend off insect attack by constitutive and inducible production of toxic metabolites, such as glucosinolates (GSs). A triple mutant lacking MYC2, MYC3, and MYC4, three basic helix-loop-helix transcription factors that are known to additively control jasmonate-related defense responses, was shown to have a highly reduced expression of GS biosynthesis genes. The myc2 myc3 myc4 (myc234) triple mutant was almost completely devoid of GS and was extremely susceptible to the generalist herbivore Spodoptera littoralis. On the contrary, the specialist Pieris brassicae was unaffected by the presence of GS and preferred to feed on wild-type plants. In addition, lack of GS in myc234 drastically modified S. littoralis feeding behavior. Surprisingly, the expression of MYB factors known to regulate GS biosynthesis genes was not altered in myc234, suggesting that MYC2/MYC3/MYC4 are necessary for direct transcriptional activation of GS biosynthesis genes. To support this, chromatin immunoprecipitation analysis showed that MYC2 binds directly to the promoter of several GS biosynthesis genes in vivo. Furthermore, yeast two-hybrid and pull down experiments indicated that MYC2/MYC3/MYC4 interact directly with GS-related MYBs. This specific MYC-MYB interaction plays a crucial role in the regulation of defense secondary metabolite production and underlines the importance of GS in shaping plant interactions with adapted and nonadapted herbivores. PMID- 23943864 TI - Shiftwork and prostate-specific antigen in the National Health and Nutrition Examination Survey. AB - BACKGROUND: Shiftwork has been implicated as a risk factor for prostate cancer. Results from prior studies have been mixed but generally support an association between circadian disruption and prostate cancer. Our aim was to investigate the relationship between shiftwork and prostate-specific antigen (PSA) test obtained as part of the National Health and Nutrition Examination Survey (NHANES) study. METHODS: We combined three NHANES surveys (2005-2010) to obtain current work schedule among employed men aged 40 to 65 years with no prior history of cancer (except nonmelanoma skin cancer). Men who reported working regular night shifts or rotating shifts were considered shiftworkers. We obtained the total and percentage free PSA test results for these men and dichotomized total PSA into less than 4.0 ng/mL or 4.0 ng/mL or greater and total PSA of 4.0 ng/mL or greater combined with percentage free PSA less than or equal to 25%. Using multivariable logistic regression models, we compared PSA level among current shiftworkers and nonshiftworkers. All statistical tests were two-sided. RESULTS: We found a statistically significant, age-adjusted association between current shiftwork and elevated PSA at the 4.0 ng/mL or greater level (odds ratio = 2.48, 95% confidence interval [CI] = 1.08 to 5.70; P = .03). The confounder-adjusted odds ratio was 2.62 (95% CI = 1.16 to 5.95; P = .02). The confounder-adjusted odds ratio for those with total PSA of 4.0 ng/mL or greater and free PSA less than or equal to 25% was 3.13 (95% CI = 1.38 to 7.09; P = .01). CONCLUSIONS: We observed a strong positive association with shiftwork and elevated PSA level. Our data support the notion that sleep or circadian disruption is associated with elevated PSA, indicating that shiftworking men likely have an increased risk of developing prostate cancer. PMID- 23943866 TI - Phosphorylation of the Smo tail is controlled by membrane localisation and is dispensable for clustering. AB - The Hedgehog (Hh) signalling cascade is highly conserved and involved in development and disease throughout evolution. Nevertheless, in comparison with other pathways, our mechanistic understanding of Hh signal transduction is remarkably incomplete. In the absence of ligand, the Hh receptor Patched (Ptc) represses the key signal transducer Smoothened (Smo) through an unknown mechanism. Hh binding to Ptc alleviates this repression, causing Smo redistribution to the plasma membrane, phosphorylation and opening of the Smo cytoplasmic tail, and Smo oligomerisation. However, the order and interdependence of these events is as yet poorly understood. We have mathematically modelled and simulated Smo activation for two alternative modes of pathway activation, with Ptc primarily affecting either Smo localisation or phosphorylation. Visualising Smo activation through a novel, fluorescence-based reporter allowed us to test these competing models. Here, we show that Smo localisation to the plasma membrane is sufficient for phosphorylation of the cytoplasmic tail in the presence of Ptc. Using fluorescence cross-correlation spectroscopy (FCCS), we also demonstrate that inactivation of Ptc by Hh induces Smo clustering irrespective of Smo phosphorylation. Our observations therefore support a model of Hh signal transduction whereby Smo subcellular localisation and not phosphorylation is the primary target of Ptc function. PMID- 23943865 TI - Strigolactones stimulate internode elongation independently of gibberellins. AB - Strigolactone (SL) mutants in diverse species show reduced stature in addition to their extensive branching. Here, we show that this dwarfism in pea (Pisum sativum) is not attributable to the strong branching of the mutants. The continuous supply of the synthetic SL GR24 via the root system using hydroponics can restore internode length of the SL-deficient rms1 mutant but not of the SL response rms4 mutant, indicating that SLs stimulate internode elongation via RMS4. Cytological analysis of internode epidermal cells indicates that SLs control cell number but not cell length, suggesting that SL may affect stem elongation by stimulating cell division. Consequently, SLs can repress (in axillary buds) or promote (in the stem) cell division in a tissue-dependent manner. Because gibberellins (GAs) increase internode length by affecting both cell division and cell length, we tested if SLs stimulate internode elongation by affecting GA metabolism or signaling. Genetic analyses using SL-deficient and GA deficient or DELLA-deficient double mutants, together with molecular and physiological approaches, suggest that SLs act independently from GAs to stimulate internode elongation. PMID- 23943867 TI - Invadolysin, a conserved lipid-droplet-associated metalloproteinase, is required for mitochondrial function in Drosophila. AB - Mitochondria are the main producers of ATP, the principal energy source of the cell, and reactive oxygen species (ROS), important signaling molecules. Mitochondrial morphogenesis and function depend on a hierarchical network of mechanisms in which proteases appear to be center stage. The invadolysin gene encodes an essential conserved metalloproteinase of the M8 family that is necessary for mitosis and cell migration during Drosophila development. We previously demonstrated that invadolysin is found associated with lipid droplets in cells. Here, we present data demonstrating that invadolysin interacts physically with three mitochondrial ATP synthase subunits. Our studies have focused on the genetic phenotypes of invadolysin and bellwether, the Drosophila homolog of ATP synthase alpha, mutants. The invadolysin mutation presents defects in mitochondrial physiology similar to those observed in bellwether mutants. The invadolysin and bellwether mutants have parallel phenotypes that affect lipid storage and mitochondrial electron transport chain activity, which result in a reduction in ATP production and an accumulation of ROS. As a consequence, invadolysin mutant larvae show lower energetic status and higher oxidative stress. Our data demonstrate an essential role for invadolysin in mitochondrial function that is crucial for normal development and survival. PMID- 23943868 TI - Dynein light chain interaction with the peroxisomal import docking complex modulates peroxisome biogenesis in yeast. AB - Dynein is a large macromolecular motor complex that moves cargo along microtubules. A motor-independent role for the light chain of dynein, Dyn2p, in peroxisome biology in Saccharomyces cerevisiae was suggested from its interaction with Pex14p, a component of the peroxisomal matrix protein import docking complex. Here we show that cells of the yeast Yarrowia lipolytica deleted for the gene encoding the homologue of Dyn2p are impaired in peroxisome function and biogenesis. These cells exhibit compromised growth on medium containing oleic acid as the carbon source, the metabolism of which requires functional peroxisomes. Their peroxisomes have abnormal morphology, atypical matrix protein localization, and an absence of proteolytic processing of the matrix enzyme thiolase, which normally occurs upon its import into the peroxisome. We also show physical and genetic interactions between Dyn2p and members of the docking complex, particularly Pex17p. Together, our results demonstrate a role for Dyn2p in the assembly of functional peroxisomes and provide evidence that Dyn2p acts in cooperation with the peroxisomal matrix protein import docking complex to effect optimal matrix protein import. PMID- 23943869 TI - Oncogenic K-ras segregates at spatially distinct plasma membrane signaling platforms according to its phosphorylation status. AB - Activating mutations in the K-Ras small GTPase are extensively found in human tumors. Although these mutations induce the generation of a constitutively GTP loaded, active form of K-Ras, phosphorylation at Ser181 within the C-terminal hypervariable region can modulate oncogenic K-Ras function without affecting the in vitro affinity for its effector Raf-1. In striking contrast, K-Ras phosphorylated at Ser181 shows increased interaction in cells with the active form of Raf-1 and with p110alpha, the catalytic subunit of PI 3-kinase. Because the majority of phosphorylated K-Ras is located at the plasma membrane, different localization within this membrane according to the phosphorylation status was explored. Density-gradient fractionation of the plasma membrane in the absence of detergents showed segregation of K-Ras mutants that carry a phosphomimetic or unphosphorylatable serine residue (S181D or S181A, respectively). Moreover, statistical analysis of immunoelectron microscopy showed that both phosphorylation mutants form distinct nanoclusters that do not overlap. Finally, induction of oncogenic K-Ras phosphorylation - by activation of protein kinase C (PKC) - increased its co-clustering with the phosphomimetic K-Ras mutant, whereas (when PKC is inhibited) non-phosphorylated oncogenic K-Ras clusters with the non phosphorylatable K-Ras mutant. Most interestingly, PI 3-kinase (p110alpha) was found in phosphorylated K-Ras nanoclusters but not in non-phosphorylated K-Ras nanoclusters. In conclusion, our data provide - for the first time - evidence that PKC-dependent phosphorylation of oncogenic K-Ras induced its segregation in spatially distinct nanoclusters at the plasma membrane that, in turn, favor activation of Raf-1 and PI 3-kinase. PMID- 23943870 TI - Complex modulation of the cold receptor TRPM8 by volatile anaesthetics and its role in complications of general anaesthesia. AB - The mechanisms by which volatile general anaesthetics (VAs) produce a depression of central nervous system are beginning to be better understood, but little is known about a number of side effects. Here, we show that the cold receptor transient receptor potential melastatin 8 (TRPM8) undergoes a complex modulation by clinical concentrations of VAs in dorsal root ganglion neurons and HEK-293 cells heterologously expressing TRPM8. VAs produced a transient enhancement of TRPM8 through a depolarizing shift of its activation towards physiological membrane potentials, followed by a sustained TRPM8 inhibition. The stimulatory action of VAs engaged molecular determinants distinct from those used by the TRPM8 agonist. Transient TRPM8 activation by VAs could explain side effects such as inhibition of respiratory drive, shivering and the cooling sensation during the beginning of anaesthesia, whereas the second phase of VA action, that associated with sustained TRPM8 inhibition, might be responsible for hypothermia. Consistent with this, both hypothermia and the inhibition of respiratory drive induced by VAs are partially abolished in Trpm8-knockout animals. Thus, we propose TRPM8 as a new clinical target for diminishing common and serious complications of general anaesthesia. PMID- 23943871 TI - Protein 4.1R binds to CLASP2 and regulates dynamics, organization and attachment of microtubules to the cell cortex. AB - The microtubule (MT) cytoskeleton is essential for many cellular processes, including cell polarity and migration. Cortical platforms, formed by a subset of MT plus-end-tracking proteins, such as CLASP2, and non-MT binding proteins such as LL5beta, attach distal ends of MTs to the cell cortex. However, the mechanisms involved in organizing these platforms have not yet been described in detail. Here we show that 4.1R, a FERM-domain-containing protein, interacts and colocalizes with cortical CLASP2 and is required for the correct number and dynamics of CLASP2 cortical platforms. Protein 4.1R also controls binding of CLASP2 to MTs at the cell edge by locally altering GSK3 activity. Furthermore, in 4.1R-knockdown cells MT plus-ends were maintained for longer in the vicinity of cell edges, but instead of being tethered to the cell cortex, MTs continued to grow, bending at cell margins and losing their radial distribution. Our results suggest a previously unidentified role for the scaffolding protein 4.1R in locally controlling CLASP2 behavior, CLASP2 cortical platform turnover and GSK3 activity, enabling correct MT organization and dynamics essential for cell polarity. PMID- 23943872 TI - Targeting of the Arf-GEF GBF1 to lipid droplets and Golgi membranes. AB - Lipid droplet metabolism and secretory pathway trafficking both require activation of the Arf1 small G protein. The spatiotemporal regulation of Arf1 activation is mediated by guanine nucleotide exchange factors (GEFs) of the GBF and BIG families, but the mechanisms of their localization to multiple sites within cells are poorly understood. Here we show that GBF1 has a lipid-binding domain (HDS1) immediately downstream of the catalytic Sec7 domain, which mediates association with both lipid droplets and Golgi membranes in cells, and with bilayer liposomes and artificial droplets in vitro. An amphipathic helix within HDS1 is necessary and sufficient for lipid binding, both in vitro and in cells. The HDS1 domain of GBF1 is stably associated with lipid droplets in cells, and the catalytic Sec7 domain inhibits this potent lipid-droplet-binding capacity. Additional sequences upstream of the Sec7 domain-HDS1 tandem are required for localization to Golgi membranes. This mechanism provides insight into crosstalk between lipid droplet function and secretory trafficking. PMID- 23943874 TI - Features of Ras activation by a mislocalized oncogenic tyrosine kinase: FLT3 ITD signals through K-Ras at the plasma membrane of acute myeloid leukemia cells. AB - FMS-like tyrosine kinase 3 with internal tandem duplication (FLT3 ITD) is an important oncoprotein in acute myeloid leukemia (AML). Owing to its constitutive kinase activity FLT3 ITD partially accumulates at endomembranes, a feature shared with other disease-associated, mutated receptor tyrosine kinases. Because Ras proteins also transit through endomembranes we have investigated the possible existence of an intracellular FLT3-ITD/Ras signaling pathway by comparing Ras signaling of FLT3 ITD with that of wild-type FLT3. Ligand stimulation activated both K- and N-Ras in cells expressing wild-type FLT3. Live-cell Ras-GTP imaging revealed ligand-induced Ras activation at the plasma membrane (PM). FLT3-ITD dependent constitutive activation of K-Ras and N-Ras was also observed primarily at the PM, supporting the view that the PM-resident pool of FLT3 ITD engaged the Ras/Erk pathway in AML cells. Accordingly, specific interference with FLT3 ITD/Ras signaling at the PM using PM-restricted dominant negative K-RasS17N potently inhibited cell proliferation and promoted apoptosis. In conclusion, Ras signaling is crucial for FLT3-ITD-dependent cell transformation and FLT3 ITD addresses PM-bound Ras despite its pronounced mislocalization to endomembranes. PMID- 23943873 TI - Epidermal keratinocyte polarity and motility require Ca2+ influx through TRPV1. AB - Ca(2+) has long been known to play an important role in cellular polarity and guidance. We studied the role of Ca(2+) signaling during random and directed cell migration to better understand whether Ca(2+) directs cell motility from the leading edge and which ion channels are involved in this function by using primary zebrafish keratinocytes. Rapid line-scan and time-lapse imaging of intracellular Ca(2+) (Ca(2+)i) during migration and automated image alignment enabled us to characterize and map the spatiotemporal changes in Ca(2+)i. We show that asymmetric distributions of lamellipodial Ca(2+) sparks are encoded in frequency, not amplitude, and that they correlate with cellular rotation during migration. Directed migration during galvanotaxis increases the frequency of Ca(2+) sparks over the entire lamellipod; however, these events do not give rise to asymmetric Ca(2+)i signals that correlate with turning. We demonstrate that Ca(2+)-permeable channels within these cells are mechanically activated and include several transient receptor potential family members, including TRPV1. Last, we demonstrate that cell motility and Ca(2+)i activity are affected by pharmacological agents that target TRPV1, indicating a novel role for this channel during cell migration. PMID- 23943875 TI - Ca2+ and calpain control membrane expansion during the rapid cell spreading of neutrophils. AB - Following adherence of neutrophils to the endothelium, neutrophils undergo a major morphological change that is a necessary prelude to their extravasation. We show here that this shape change is triggered by an elevation of cytosolic inositol (1,4,5)-trisphosphate (IP3), to provoke physiological Ca(2+) influx through a store-operated mechanism. This transition from a spherical to 'flattened' neutrophil morphology is rapid (~100 seconds) and is accompanied by an apparent rapid expansion of the area of the plasma membrane. However, no new membrane is added into the plasma membrane. Pharmacological inhibition of calpain activation, which is triggered by Ca(2+) influx during neutrophil spreading, prevents normal cell flattening. In calpain-suppressed cells, an aberrant form of cell spreading can occur where an uncoordinated and localised expansion of the plasma membrane is evident. These data show that rapid neutrophil spreading is triggered by Ca(2+) influx, which causes activation of calpain and release of furled plasma membrane to allow its apparent 'expansion'. PMID- 23943877 TI - Distinct modes of centromere protein dynamics during cell cycle progression in Drosophila S2R+ cells. AB - Centromeres are specified epigenetically in animal cells. Therefore, faithful chromosome inheritance requires accurate maintenance of epigenetic centromere marks during progression through the cell cycle. Clarification of the mechanisms that control centromere protein behavior during the cell cycle should profit from the relatively simple protein composition of Drosophila centromeres. Thus we have analyzed the dynamics of the three key players Cid/Cenp-A, Cenp-C and Cal1 in S2R+ cells using quantitative microscopy and fluorescence recovery after photobleaching, in combination with novel fluorescent cell cycle markers. As revealed by the observed protein abundances and mobilities, centromeres proceed through at least five distinct states during the cell cycle, distinguished in part by unexpected Cid behavior. In addition to the predominant Cid loading onto centromeres during G1, a considerable but transient increase was detected during early mitosis. A low level of Cid loading was detected in late S and G2, starting at the reported time of centromere DNA replication. Our results reveal the complexities of Drosophila centromere protein dynamics and its intricate coordination with cell cycle progression. PMID- 23943876 TI - Bem3, a Cdc42 GTPase-activating protein, traffics to an intracellular compartment and recruits the secretory Rab GTPase Sec4 to endomembranes. AB - Cell polarity is essential for many cellular functions including division and cell-fate determination. Although RhoGTPase signaling and vesicle trafficking are both required for the establishment of cell polarity, the mechanisms by which they are coordinated are unclear. Here, we demonstrate that the yeast RhoGAP (GTPase activating protein), Bem3, is targeted to sites of polarized growth by the endocytic and recycling pathways. Specifically, deletion of SLA2 or RCY1 led to mislocalization of Bem3 to depolarized puncta and accumulation in intracellular compartments, respectively. Bem3 partitioned between the plasma membrane and an intracellular membrane-bound compartment. These Bem3-positive structures were polarized towards sites of bud emergence and were mostly observed during the pre-mitotic phase of apical growth. Cell biological and biochemical approaches demonstrated that this intracellular Bem3 compartment contained markers for both the endocytic and secretory pathways, which were reminiscent of the Spitzenkorper present in the hyphal tips of growing fungi. Importantly, Bem3 was not a passive cargo, but recruited the secretory Rab protein, Sec4, to the Bem3-containing compartments. Moreover, Bem3 deletion resulted in less efficient localization of Sec4 to bud tips during early stages of bud emergence. Surprisingly, these effects of Bem3 on Sec4 were independent of its GAP activity, but depended on its ability to efficiently bind endomembranes. This work unveils unsuspected and important details of the relationship between vesicle traffic and elements of the cell polarity machinery: (1) Bem3, a cell polarity and peripherally associated membrane protein, relies on vesicle trafficking to maintain its proper localization; and (2) in turn, Bem3 influences secretory vesicle trafficking. PMID- 23943879 TI - Probing cellular processes by long-term live imaging--historic problems and current solutions. AB - Living organisms, tissues, cells and molecules are highly dynamic. The importance of their continuous and long-term observation has been recognized for over a century but has been limited by technological hurdles. Improvements in imaging technologies, genetics, protein engineering and data analysis have more recently allowed us to answer long-standing questions in biology using quantitative continuous long-term imaging. This requires a multidisciplinary collaboration between scientists of various backgrounds: biologists asking relevant questions, imaging specialists and engineers developing hardware, and informaticians and mathematicians developing software for data acquisition, analysis and computational modeling. Despite recent improvements, there are still obstacles to be addressed before this technology can achieve its full potential. This Commentary aims at providing an overview of currently available technologies for quantitative continuous long-term single-cell imaging, their limitations and what is required to bring this field to the next level. We provide an historical perspective on the development of this technology and discuss key issues in time lapse imaging: keeping cells alive, using labels, reporters and biosensors, and hardware and software requirements. We highlight crucial and often non-obvious problems for researchers venturing into the field and hope to inspire experts in the field and from related disciplines to contribute to future solutions. PMID- 23943878 TI - Myosin X and its motorless isoform differentially modulate dendritic spine development by regulating trafficking and retention of vasodilator-stimulated phosphoprotein. AB - Myosin X (Myo10) is an unconventional myosin with two known isoforms: full-length (FL)-Myo10 that has motor activity, and a recently identified brain-expressed isoform, headless (Hdl)-Myo10, which lacks most of the motor domain. FL-Myo10 is involved in the regulation of filopodia formation in non-neuronal cells; however, the biological function of Hdl-Myo10 remains largely unknown. Here, we show that FL- and Hdl-Myo10 have important, but distinct, roles in the development of dendritic spines and synapses in hippocampal neurons. FL-Myo10 induces formation of dendritic filopodia and modulates filopodia dynamics by trafficking the actin binding protein vasodilator-stimulated phosphoprotein (VASP) to the tips of filopodia. By contrast, Hdl-Myo10 acts on dendritic spines to enhance spine and synaptic density as well as spine head expansion by increasing the retention of VASP in spines. Thus, this study demonstrates a novel biological function for Hdl Myo10 and an important new role for both Myo10 isoforms in the development of dendritic spines and synapses. PMID- 23943880 TI - N-terminus oligomerization regulates the function of cardiac ryanodine receptors. AB - The ryanodine receptor (RyR) is an ion channel composed of four identical subunits mediating calcium efflux from the endo/sarcoplasmic reticulum of excitable and non-excitable cells. We present several lines of evidence indicating that the RyR2 N-terminus is capable of self-association. A combination of yeast two-hybrid screens, co-immunoprecipitation analysis, chemical crosslinking and gel filtration assays collectively demonstrate that a RyR2 N terminal fragment possesses the intrinsic ability to oligomerize, enabling apparent tetramer formation. Interestingly, N-terminus tetramerization mediated by endogenous disulfide bond formation occurs in native RyR2, but notably not in RyR1. Disruption of N-terminal inter-subunit interactions within RyR2 results in dysregulation of channel activation at diastolic Ca(2+) concentrations from ryanodine binding and single channel measurements. Our findings suggest that the N-terminus interactions mediating tetramer assembly are involved in RyR channel closure, identifying a crucial role for this structural association in the dynamic regulation of intracellular Ca(2+) release. PMID- 23943881 TI - Endocytosis of EGFR requires its kinase activity and N-terminal transmembrane dimerization motif. AB - EGFR signaling is attenuated by endocytosis and degradation of receptor-ligand complexes in lysosomes. Endocytosis of EGFR is known to be regulated by multiple post-translational modifications. The observation that prevention of these modifications does not block endocytosis completely, suggests the involvement of other mechanism(s). Recently, receptor clustering has been suggested to induce internalization of multiple types of membrane receptors. However, the mechanism of clustering-induced internalization remains unknown. We have used biparatopic antibody fragments from llama (VHHs) to induce EGFR clustering without stimulating tyrosine kinase activity. Using this approach, we have found an essential role for the N-terminal GG4-like dimerization motif in the transmembrane domain (TMD) for clustering-induced internalization. Moreover, conventional EGF-induced receptor internalization depends exclusively on this TMD dimerization and kinase activity. Mutations in this dimerization motif eventually lead to reduced EGFR degradation and sustained signaling. We propose a novel role for the TMD dimerization motif in the negative-feedback control of EGFR. The widely conserved nature of GG4-like dimerization motifs in transmembrane proteins suggests a general role for these motifs in clustering-induced internalization. PMID- 23943882 TI - The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis. AB - The apelin receptor (APJ; gene symbol APLNR) is a member of the G protein-coupled receptor gene family. Neural gene expression patterns of APJ, and its cognate ligand apelin, in the brain implicate the apelinergic system in the regulation of a number of physiological processes. APJ and apelin are highly expressed in the hypothalamo-neurohypophysial system, which regulates fluid homeostasis, in the hypothalamic-pituitary-adrenal axis, which controls the neuroendocrine response to stress, and in the forebrain and lower brainstem regions, which are involved in cardiovascular function. Recently, apelin, synthesised and secreted by adipocytes, has been described as a beneficial adipokine related to obesity, and there is growing awareness of a potential role for apelin and APJ in glucose and energy metabolism. In this review we provide a comprehensive overview of the structure, expression pattern and regulation of apelin and its receptor, as well as the main second messengers and signalling proteins activated by apelin. We also highlight the physiological and pathological roles that support this system as a novel therapeutic target for pharmacological intervention in treating conditions related to altered water balance, stress-induced disorders such as anxiety and depression, and cardiovascular and metabolic disorders. PMID- 23943883 TI - Blunted HPA axis response in lactating, vasopressin-deficient Brattleboro rats. AB - Adaptation to stress is a basic phenomenon in mammalian life that is mandatorily associated with the activity of the hypothalamic-pituitary-adrenal (HPA) axis. An increased resting activity of the HPA axis can be measured during pregnancy and lactation, suggesting that these reproductive states lead to chronic load in females. In this study, we examined the consequences of the congenital lack of vasopressin on the activity of the HPA axis during lactation using vasopressin deficient Brattleboro rats. Virgin and lactating, homozygous vasopressin deficient rats were compared with control, heterozygous rats. In control dams compared with virgins, physiological changes similar to those observed in a chronic stress state (thymus involution, adrenal gland hyperplasia, elevation of proopiomelanocortin mRNA levels in the adenohypophysis, and resting plasma corticosterone levels) were observed. In vasopressin-deficient dams, adrenal gland hyperplasia and resting corticosterone level elevations were not observed. Corticotropin-releasing hormone (Crh) mRNA levels in the hypothalamic paraventricular nucleus were elevated in only the control dams, while oxytocin (OT) mRNA levels were higher in vasopressin-deficient virgins and lactation induced a further increase in both the genotypes. Suckling-induced ACTH and corticosterone level elevations were blunted in vasopressin-deficient dams. Anaphylactoid reaction (i.v. egg white) and insulin-induced hypoglycemia stimulated the HPA axis, which were blunted in lactating rats compared with the virgins and in vasopressin-deficient rats compared with the controls without interaction of the two factors. Vasopressin seems to contribute to the physiological changes observed during lactation mimicking a chronic stress state, but its role in acute HPA axis regulation during lactation seems to be similar to that observed in virgins. If vasopressin is congenitally absent, OT, but not the CRH, compensates for the missing vasopressin; however, the functional restitution remains incomplete. PMID- 23943884 TI - Assessing patient-centered communication in cancer care: stakeholder perspectives. AB - PURPOSE: Patient-centered communication is critical to quality cancer care. Effective communication can help patients and family members cope with cancer, make informed decisions, and effectively manage their care; suboptimal communication can contribute to care breakdowns and undermine clinician-patient relationships. The study purpose was to explore stakeholders' views on the feasibility and acceptability of collecting self-reported patient and family perceptions of communication experiences while receiving cancer care. The results were intended to inform the design, development, and implementation of a structured and generalizable patient-level reporting system. METHODS: This was a formative, qualitative study that used semistructured interviews with cancer patients, family members, clinicians, and leaders of health care organizations. The constant comparative method was used to identify major themes in the interview transcripts. RESULTS: A total of 106 stakeholders were interviewed. Thematic saturation was achieved. All stakeholders recognized the importance of communication and endorsed efforts to improve communication during cancer care. Patients, clinicians, and leaders expressed concerns about the potential consequences of reports of suboptimal communication experiences, such as damage to the clinician-patient relationship, and the need for effective improvement strategies. Patients and family members would report good communication experiences in order to encourage such practices. Practical and logistic issues were identified. CONCLUSION: Patient reports of their communication experiences during cancer care could increase understanding of the communication process, stimulate improvements, inform interventions, and provide a basis for evaluating changes in communication practices. This qualitative study provides a foundation for the design and pilot testing of such a patient reporting system. PMID- 23943886 TI - Improving the relative dose intensity of systemic chemotherapy in a community based outpatient cancer center. AB - PURPOSE: This three-phase study was performed to improve the mean relative dose intensity (RDI) of chemotherapy administered to patients in a community-based outpatient cancer center. METHODS: Medical records were reviewed for patients who began receiving systemic chemotherapy for lymphoma or cancer of the breast, lung, endometrium, ovary, or colon. During phase 1, records were reviewed and the mean RDI was determined through collection of demographic, diagnostic, chemotherapy, and laboratory data. Phase 2 involved implementation of quality improvement initiatives to improve the RDI: development of a febrile neutropenia risk assessment tool, revision of our dose cancellation policy, and interdisciplinary education. Finally, after implementation of these initiatives, the mean RDI was prospectively determined in phase 3, similar to phase 1. RESULTS: The mean RDI was determined to be 83% during phase 1 compared with 91% during phase 3 (P=.0087). For adjuvant chemotherapy, the mean RDI was 85% and 95% for phases 1 and 3, respectively (P=.0035). Likewise, for metastatic disease, the mean RDI was 76% and 82% for phases 1 and 3, respectively (P=.3935). The proportion of regimens that met or exceeded the recommended minimum goal RDI of 85% was 54% for phase 1 and 80% for phase 3. Granulocyte colony-stimulating factor use increased from 69% preintervention to 81% postintervention. CONCLUSION: The mean overall RDI improved above the threshold goal of 85%, with the RDI for adjuvant chemotherapy reaching 95%, after implementation of three quality-improvement initiatives. With continued education and following policies already in place, further improvements in RDI could be demonstrated. PMID- 23943887 TI - Hospital management of outpatient oncology treatment decisions: a survey to identify strategies and concerns. AB - PURPOSE: Historically, hospitals did not actively restrict or manage outpatient oncology drug use, because treatment options were few, and reimbursement was generous. Recent growth of novel agents coupled with reimbursement challenges may require a strategy change. The extent of hospital engagement in controlling outpatient oncology drug use is currently unknown. Our objective was to describe the extent of hospital outpatient oncology drug management, management strategies employed, and specific drugs/tumor types of most concern for inappropriate use and cost. METHODS: A multiple choice-question survey assessed management strategies and the drugs/tumors of greatest concern in US hospitals that dispense outpatient chemotherapy. From June to July 2011, the survey was distributed electronically to members of the Hematology-Oncology Pharmacy Association, representing 281 institutions. RESULTS: The survey was completed by 93 respondents (33% institutional response rate). Most institutions (99%) use at least one form of control to manage outpatient oncology drug therapy; 89% establish preferred therapies, and most use a multidisciplinary management team consisting of oncologists, pharmacists, nurses, and other practitioners. Tumor types of most concern for inappropriate drug use and cost were: prostate, breast, non-small-cell lung, melanoma, and colorectal. Fifty-five percent were concerned about drugs used in supportive care management. Drugs most restricted were: cetuximab, bevacizumab, eribulin, panitumumab, and trastuzumab. CONCLUSION: There is active control, management, and restriction of outpatient oncology drugs by hospitals. A majority of these institutions use a multidisciplinary team with active involvement by an oncologist. Future evaluations of hospital programs should consider monitoring the evolution of how institutions manage outpatient oncology services. PMID- 23943885 TI - Advanced diagnostic breast cancer imaging: variation and patterns of care in Washington state. AB - INTRODUCTION: Because receipt of breast imaging likely occurs in nonrandom patterns, selection bias is an important issue in studies that attempt to elucidate associations between imaging and breast cancer outcomes. The purpose of this study was to analyze use of advanced diagnostic imaging in a cohort of patients with breast cancer insured by commercial, managed care, and public health plans by demographic, health insurance, and clinical variables from 2002 to 2009. METHODS: We identified women with breast cancer diagnoses from a Surveillance Epidemiology and End Results (SEER) registry whose data could be linked to claims from participating health plans. We examined imaging that occurred between cancer diagnosis and initiation of treatment and classified patients according to receipt of (1) mammography or ultrasound only; (2) breast magnetic resonance imaging (MRI); and (3) other advanced imaging (computed tomography [CT] of the chest, abdoment, and pelvis; positron emission tomography [PET]; or PET-CT). We used logistic regression to identify factors associated with receipt of breast MRI as well as other advanced imaging. RESULTS: Commercial health plan, younger age, and later year of diagnosis were strongly associated with receipt of breast MRI and other advanced imaging. Women with prescription drug plans and those who had less comorbidities were more likely to have received breast MRI. CONCLUSION: Use of breast MRI and other advanced imaging is increasing among patients newly diagnosed with breast cancer; individual patient and insurance-related factors are associated with receipt of these imaging tests. Whether use of diagnostic advanced imaging affects outcomes such as re-excision, cancer recurrence, mortality rates, and costs of breast cancer treatment remains to be determined. PMID- 23943888 TI - Closing the quality loop: facilitating improvement in oncology practice through timely access to clinical performance indicators. AB - PURPOSE: Health care organizations and professionals are being called on to develop clear and transparent measures of quality and to demonstrate the application of the data to performance improvement at the system and provider levels. MATERIALS AND METHODS: Cancer Care Ontario (CCO) initiated a pathology reporting project aimed at improving the quality of cancer pathology by standardizing the content, format, and transmission of reports to a central registry and enabling the information to be available for planning, quality measurement, and quality improvement. This population-based quality-improvement project involved more than 400 Ontario pathologists and more than 100 hospitals. Clinically relevant quality indicators that used the newly available data were developed and shared. Synoptic pathology data were electronically captured at the point of report development and used to automate the timely generation of clinical performance indicators that support quality improvement in surgical oncology. These reports provided comparison data at the organizational, regional, and population levels. RESULTS: Monthly quality indicator reports are generated and distributed to each cancer center and are used to generate dialogue at the professional, organizational, and regional levels regarding evidence-informed quality-improvement opportunities. Since the launch of the project, colorectal lymph node retrieval rates have increased from 76% to 87%, and pT2 prostatectomy margin positivity rates have decreased from 37% to 21%. CONCLUSION: High-quality, complete cancer pathology reports are important not only for contemporary oncological practice, but also for secondary users of pathology information including tumor registries, health planners, epidemiologists, and others involved in quality-improvement activities and research. PMID- 23943889 TI - Study of imatinib treatment patterns and outcomes among US veteran patients with Philadelphia chromosome-positive chronic myeloid leukemia. AB - PURPOSE: This study investigated the treatment patterns and outcomes for US veteran patients with chronic myeloid leukemia-chronic phase (CML-CP) initiated on imatinib (IM). PATIENTS AND METHODS: Patients (age>=18 years) with at least one CML diagnosis (International Classification of Diseases, Ninth Edition Clinical Modification: 205.1x) during the period January 1, 2000, to June 30, 2011, and initiated on IM as first-line therapy were identified in the VISN 16 data warehouse (N=137). Accelerated and blastic phases (AP/BP) were identified on the basis of WHO classification using complete blood count (CBC) data. Rates of IM dose adjustment, discontinuation, and switching to another drug therapy were estimated. Time to discontinuation, progression to AP/BP, and survival were assessed using Kaplan-Meier analysis (KM). RESULTS: During follow-up, 19.0% of patients had at least one dose increase; of these, 19.2% switched to another therapy. Dose reductions occurred in 25.6% of patients. Among patients who discontinued IM (n=74; 54.0%), whereas 16.2% switched to other therapies, 27.0% neither restarted IM nor switched to other therapies. KM showed that 25.6% and 42.4% of patients discontinued IM treatment by year 1 and 2, and 8.1% and 16.0% demonstrated disease progression by year 1 and 2, respectively. Among patients who experienced disease progression (n=28), 32.1% continued IM postprogression, 32.1% discontinued IM before progression, 28.6% discontinued IM postprogression without switching, and 7.1% switched to other therapies postprogression. The mortality rates were 3.0% and 9.5% after IM initiation, and 21.7% and 42.7% after disease progression by year 1 and 2, respectively. CONCLUSION: In this veteran population, a substantial number of IM-treated patients, including those with disease progression, either discontinued or interrupted IM use without switching to other therapies. PMID- 23943890 TI - Qualitative analysis of practicing oncologists' attitudes and experiences regarding collection of patient-reported outcomes. AB - PURPOSE: There is growing interest in incorporating routine collection of patient reported outcomes (PROs) into cancer care. Practicing oncologists are a stakeholder group whose views are not well characterized. METHODS: We developed an interview guide after literature review and in-depth interviews with leaders in the field. We conducted 45-minute semistructured interviews with a diverse sample of medical oncologists identified through affiliation with the Quality Oncology Practice Initiative or a minority-based Community Clinical Oncology Program until thematic saturation. Multiple analysts independently reviewed and thematically coded verbatim transcripts. RESULTS: Seventeen interviews were conducted with oncologists from 15 states. Emergent themes included variable understanding and experience with PROs. There was enthusiasm for the potential of PROs to improve the efficiency and thoroughness of the patient encounter. Fundamental concerns included information overload, possibility of identifying problems without access to intervention, depersonalization of the physician patient encounter, cost, and inefficiency. Barriers identified included the need for buy-in from other stakeholders in the practice, lack of appropriate referral resources, staffing needs, and technology concerns. Few identified patient compliance, data sharing/privacy, or medical liability as a major barrier to implementation. CONCLUSION: Practicing oncologists had variable understanding of the details of PROs but, when introduced to the concept, recognized utility in improving the efficiency and thoroughness of the patient encounter if implemented properly. The time is right to begin pilot testing such measures with community oncologists so they can lend their expertise to national discussions on which measures to use and how best to use them. PMID- 23943891 TI - An automated system for detecting nonadherence in laboratory testing and monitoring for myelosuppression in patients receiving self-administered oral chemotherapy. AB - INTRODUCTION: Patient compliance with routine monitoring for self-administered chemotherapy is problematic. We sought to assess monitoring lapses and incidents of myelosuppression in patients undergoing self-administered chemotherapy for glioblastoma, as well as test software designed to detect and alert clinicians to lapses in monitoring. PATIENTS AND METHODS: A retrospective analysis was conducted to identify patients (N=117) who received standard oral temozolomide for glioblastoma at our institution from 2003 to 2010. Gaps in monitoring were classified as minor (10 to 12 days) or major (13 to 28 days), and adverse events were graded using standard criteria. During the prospective portion of the study, we tested a software-based system that alerted clinicians of monitoring lapses and adverse events among patients receiving self-administered temozolomide for glioblastoma (n=37). RESULTS: Our retrospective review found that 34 of 117 patients experienced monitoring gaps during treatment. No association between gaps and risk of myelosuppression were found. Patients with gaps were more likely to be male (P=.04). Patients monitored prospectively with the software experienced no major gaps in monitoring (P=.007 compared with retrospective patients). CONCLUSION: Our retrospective review demonstrated that monitoring nonadherence was occurring at a substantial rate. Our computerized system eliminated major gaps in monitoring in the prospective portion of our study. Although there is no association between monitoring gaps and the occurrence of adverse events, when they do coincide, continuing oral chemotherapy during an unrecognized adverse event may worsen the patient's condition. Automated systems are justified and serve a function not currently being addressed. PMID- 23943892 TI - Patterns of care in palliative radiotherapy: a population-based study. AB - PURPOSE: Approximately one half of the radiotherapy (RT) prescribed in the United States is delivered with palliative intent. The purpose of this study was to investigate the patterns of delivery of palliative RT across the United States. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare linked database, 51,610 patients were identified with incident stage IV breast, prostate, lung, or colorectal cancer diagnosed between 2000 and 2007 and observed through 2009. Multivariate logistic regression determined predictors of palliative RT. RESULTS: Forty-one percent of the study population received palliative RT, including 53% of patients with lung cancer, followed by those with breast (42%), prostate (40%), and colorectal cancers (12%). Multivariate analysis revealed that older patients (P<.001) and those with higher Charlson comorbidity scores (P<.001) were less likely to receive palliative RT. Black patients with prostate cancer were 20% less likely (P<.001), and black patients with colorectal cancer were 28% less likely (P<.001), than white patients to receive palliative RT. Among those treated with RT, 23% of patients with lung cancer died within 2 weeks of completing treatment, followed by those with colorectal (12%), breast (11%), and prostate cancers (8%). In addition to tumor site, significant predictors (P<.05) of death within 2 weeks of receiving RT included increased age, increased comorbidity, and male sex. CONCLUSION: Inequality in the receipt of palliative RT exists among the elderly and patients with comorbid conditions and varies with race. In addition, a significant number of patients die shortly after receiving RT. Understanding these patterns of care, along with further research into the underlying causes, will improve access and quality of palliative RT. PMID- 23943893 TI - Impact of physician assistants on the outcomes of patients with acute myelogenous leukemia receiving chemotherapy in an academic medical center. AB - PURPOSE: Inpatient academic medical center care historically has been delivered by faculty physicians in conjunction with physicians in training (house officers [HOs]). Alternative staffing models have emerged secondary to American Counsel for Graduate Medical Education work-hour restrictions. The purpose of this study was to assess the quality of acute myelogenous leukemia (AML) care provided by a physician assistant (PA) service compared with a traditional model. PATIENTS AND METHODS: Data were retrospectively collected on patients admitted with AML for reinduction chemotherapy from 2008 to 2012. Primary outcome measures were inpatient mortality and length of stay (LOS). Secondary measures included readmissions, intensive care unit (ICU) transfers, consults requested, and radiologic studies ordered. RESULTS: Ninety-five patients with AML were reviewed. Forty-seven patients (49.5%) were admitted to the HO service, and 48 patients (50.5%) were admitted to the PA service. Demographic data were similar between services. LOS was significantly different between the services, with a mean of 36.8 days with the HO model compared with 30.9 days with the PA service (P=.03). The 14-day readmission rate also differed significantly; it was 10.6% (five of 47 patients) and zero for the HO and PA models, respectively (P=.03). The mean number of consults with the HO model was 2.11 (range, zero to five) versus 1.47 (range, zero to four) with the PA service (P=.03). Mortality and ICU transfers were not significantly different. CONCLUSION: The data demonstrate equivalent mortality and ICU transfers, with a decrease in LOS, readmission rates, and consults for patients cared for in the PA service. This suggests that the PA service is associated with increased operational efficiency and decreased health service use without compromising health care outcomes. PMID- 23943894 TI - Impact of chemotherapy-induced peripheral neuropathy on treatment delivery in nonmetastatic breast cancer. AB - PURPOSE: To determine the incidence of dose-limiting (DL) chemotherapy-induced peripheral neuropathy (CIPN) events in clinical practice. PATIENTS AND METHODS: This retrospective cohort study included 488 women who received docetaxel or paclitaxel. The primary outcome was a DL event (dose delay, dose reduction, or treatment discontinuation) attributed to CIPN (DL CIPN). The paired t test was used to test the difference in received cumulative dose and planned cumulative dose by dose reduction and treatment discontinuation status. RESULTS: A total of 150 unique DL events occurred in 120 women (24.6%). More than one third (37.3%; n=56) of the events were attributed to CIPN. The 56 DL CIPN events occurred in 50 women (10.2%). DL CIPN incidence differed significantly by agent (docetaxel, 2.4%; n=five of 209; paclitaxel, 16.1%; n=45 of 279; P<.001). DL CIPN occurred in 24.5% and 14.4% of women who received paclitaxel 80 mg/m2 weekly for 12 cycles and 175 mg/m2 biweekly for four cycles, respectively (adjusted odds ratio, 2.11; 95% CI, 0.97 to 4.60; P=.06). The cumulative dose actually received was significantly lower than the planned cumulative dose among women who had a dose reduction or treatment termination attributed to CIPN (9.4% less; P<.001 and 28.4% less; P<.001, respectively). CONCLUSION: Oncologists limited the dosing of chemotherapy because of CIPN in a significant proportion of paclitaxel recipients, most frequently in those who received a weekly regimen. Patients who had their dose reduced or discontinued received significantly less cumulative chemotherapy than planned. The implications of these DL CIPN events on treatment outcomes must be investigated. PMID- 23943895 TI - Using the Delphi technique to improve clinical outcomes through the development of quality indicators in renal cell carcinoma. AB - PURPOSE: Optimal quality of care is needed for ideal outcomes. In renal cell carcinoma (RCC), there is a lack of information defining optimal care. This is particularly important in RCC, with increased complexity of care and a need for coordination among providers. The goal of this study was to identify quality indicators (QIs) and measures of quality care across the RCC disease spectrum. MATERIALS AND METHODS: A modified Delphi technique was used to select QIs that are relevant and practical to RCC care. This technique involved an expert panel of 13 urologic and medical oncologists who participated in two e-mail questionnaires and an in-person meeting to review and prioritize potential QIs. These potential QIs were identified from a systematic literature review or were suggested by panel members. RESULTS: From 233 literature citations, 34 possible QIs were identified; 24 additional potential QIs were suggested. A final set of 23 QIs was established. These are distributed across the RCC disease spectrum as follows (number of QIs in parentheses): screening (n=1), diagnosis/prognosis (n=3), surgical for localized disease (n=6), surgery for advanced disease (n=3), systemic therapy (n=6), and follow-up (n=2). In addition, two QIs related to survival outcomes (overall and progression-free survival) were selected. CONCLUSION: A systematic, consensus-based approach was used to determine relevant QIs in RCC care. These 23 QIs will provide a means of evaluating the quality of RCC care in an effort to improve outcomes in patients. The next step will be to establish a means of measuring each QI based on defined or yet-to-be-defined benchmarks. PMID- 23943896 TI - Documenting the benefits and cost savings of a large multistate cancer pathway program from a payer's perspective. AB - PURPOSE: Clinical pathways are viewed as valuable practice tools leading to presumed cost savings. CareFirst BlueCross BlueShield partnering with P4 Pathways implemented a multistate oncology clinical pathways program in 2008. This is the first comprehensive evaluation to our knowledge of a pathways program implemented on a broad scale. METHODS: This study used a retrospective single-group, pretest post-test design. Data representing preclinical pathways (year -1) and 2 years after program initiation (years +1 and +2) were obtained from claims data. Participating sites with >=one claim for breast, lung, or colorectal cancer treatment from each year were included in the evaluation. Compliance was defined as site attainment of prespecified annual thresholds for the use of chemotherapy and supportive care. Savings were determined by comparing per-patient changes in drug and hospital costs through year +2 with the projected annual expenditure increases of 12% and 7%, respectively. RESULTS: Forty-six sites representing 4,713 patients met inclusion criteria. The unadjusted site compliance rate for chemotherapy was 83% and 54% for years +1 and +2, respectively; supportive care site compliance was 74% for both years. Per-patient drug costs increased from $16,494 in year -1 to $16,906 in year +2 (P=.587), whereas hospitalization costs decreased from $2,502 to $1,064 (P=.004). Compared with projected cost increases, pathways resulted in $10.3 million in savings by participant sites ($7.0 million from drugs and $3.3 million from hospitalizations) or $30.9 million when extrapolated to the entire health plan. CONCLUSION: Broadly implemented clinical pathways can achieve reasonable physician compliance, resulting in substantial cost savings. PMID- 23943898 TI - "Stop smoking!" Do we say it enough? AB - PURPOSE: Patients who continue to smoke after the diagnosis of bronchogenic carcinoma (BC) experience increased rates of morbidity and mortality. Evidence suggests that smokers are more likely to quit if they are counseled by their physicians. However, there may be a prevailing belief among physicians that treating tobacco dependence is futile in this population. The purpose of this study was to investigate whether physicians addressed smoking cessation with patients who were diagnosed with BC. METHODS: A retrospective medical record review of patients who were diagnosed with BC between 2008 and 2010 was conducted at a community medical center using the hospital cancer registry. Demographic information including age, race, sex, stage, and smoking status at the time of diagnosis was collected. Evidence of tobacco cessation counseling was sought through billing codes, physician notes, and orders surrounding the time of diagnosis. RESULTS: A total of 948 patients were diagnosed with lung cancer between 2008 and 2010; 438 were current smokers at diagnosis, and only 36% were counseled on smoking cessation. On average, each patient encountered three different physicians in both the inpatient and outpatient settings. Of note, patients with stage I disease were 1.7* more likely to be counseled than those with stage IV disease (P=.017). CONCLUSION: Despite evidence that smoking cessation is beneficial even after the diagnosis of BC, physicians are not counseling their patients sufficiently. With the implementation of quality improvement programs, we expect smoking cessation counseling for patients with BC will improve. PMID- 23943897 TI - Prevalence of pain and analgesic use in men with metastatic prostate cancer using a patient-reported outcome measure. AB - PURPOSE: Contemporary tumor-directed therapies for metastatic castration resistant prostate cancer (mCRPC) are approved to prolong life, but their effects on symptoms such as pain are less well understood as a result of the lack of analytically valid assessments of pain prevalence and severity, clinically meaningful definitions of therapeutic benefit, and methodologic standards of trial conduct. This study establishes pain characteristics in the mCRPC population using a PRO measure. MATERIALS AND METHODS: Patients with prostate cancer participated in an anonymous survey at five US comprehensive cancer centers in the Prostate Cancer Clinical Trials Consortium that incorporated the Brief Pain Inventory (BPI), analgesic use, and interference with daily activities. Prevalence and severity of cancer-related pain and analgesic use were tabulated according to castration-resistant status and exposure to docetaxel chemotherapy. RESULTS: Four hundred sixty-one patients with prostate cancer participated, of whom 147 had mCRPC involving bone (61% [89 of 147] docetaxel exposed, 39% [58 of 147] docetaxel naive). Pain of any level was more common among docetaxel-exposed versus docetaxel-naive patients with mCRPC (70% [62 of 89] v 38% [22 of 58], respectively; P<.001). BPI score>=4 was reported by 38% (34 of 89) of docetaxel-pretreated and 24% (14 of 58) of docetaxel-naive patients with mCRPC; 40% of these patients with pain intensity>=4 reported no current narcotic analgesic. CONCLUSION: Pain prevalence and severity were higher in patients with prior docetaxel exposure. Analgesics were underutilized. These results provide a method for estimating accruals along the disease continuum, and for enabling design of trials appropriately powered to assess pain. PMID- 23943899 TI - Clinical ethics consultation in oncology. AB - PURPOSE: There is limited empirical research exploring the nature of clinical ethical consultations within the oncology population. Our objective was to review and describe clinical ethics consultations at two National Cancer Institute designated comprehensive cancer centers to identify opportunities for systems improvement in clinical care and opportunities for staff education. METHODS: This case series is derived from two institutional prospectively maintained clinical ethics consultation databases. All ethics consultations from 2007 through 2011 that related to adult patients with cancer were included. RESULTS: A total of 208 eligible patient cases were identified. The most common primary issues leading to ethics consultation were code status and advance directives (25%), surrogate decision making (17%), and medical futility (13%). Communication lapses were identified in 45% of patient cases, and interpersonal conflict arose in 51%. Before ethics consultation, 26% of patients had do-not-resuscitate orders, which increased to 60% after ethics consultation. Palliative care consultation occurred in 41% of patient cases. CONCLUSION: Ethics consultations among patients with cancer reflect the complexities inherent to their clinical management. Appropriately honoring patients' wishes within the context of overall goals of care is crucial. Thoughtful consideration of the role of and relationship with palliative care experts, communication barriers, sources of interpersonal conflict, symptom control, and end-of-life care is paramount to optimal management strategies in this patient population. PMID- 23943900 TI - Childhood cancer survivors' familiarity with and opinions of the Patient Protection and Affordable Care Act. AB - PURPOSE: The Patient Protection and Affordable Care Act (ACA) offers avenues to increase insurance options and access to care; however, it is unknown whether populations with pre-existing conditions, such as cancer survivors, will benefit from the expanded coverage options. We explored childhood cancer survivors' familiarity with and opinion of the ACA to understand how survivors' insurance coverage may be affected. MATERIALS AND METHODS: From April to July 2012 we conducted in-depth, semistructured telephone interviews with 53 adult survivors recruited from the Utah Cancer SEER Registry. Participants were randomly selected from sex, age, and rural/urban strata and were younger than 21 years at time of diagnosis. Interviews were recorded, transcribed, and analyzed with NVivo 9 by two coders (kappa=0.94). We report on the 49 participants who had heard of the ACA. RESULTS: Most survivors were unaware of ACA provisions beyond the insurance mandate. Few knew about coverage for children up to age 26 or pre-existing insurance options. Although one third believed the ACA could potentially benefit them via expanded insurance coverage, many were concerned that the ACA would lead to rising health care costs and decreasing quality of care. Survivors had concerns specific to their cancer history, including fears of future health care rationing if they developed subsequent health problems. CONCLUSION: Childhood cancer survivors have a low level of familiarity with the ACA and are unaware of how it may affect them given their cancer history. These survivors require targeted education to increase knowledge about the ACA. PMID- 23943901 TI - Cost concerns of patients with cancer. AB - PURPOSE: Health care providers are accustomed to identifying populations for whom cost-related concerns may be a significant barrier, such as the poor, but few empiric data have been collected to substantiate such assumptions, particularly among insured patients. METHODS: Patients with cancer from academic and community hospitals completed a questionnaire that included closed-ended items concerning demographic variables, optimism, numeracy, and concerns about present and future medical costs. In addition, they answered open-ended questions regarding cost concerns and medical expenses. RESULTS: Nearly all (99%) participants were insured. In response to the closed-ended questions, 30.3% of patients reported concern about paying for their cancer treatment, 22.3% reported that their family had made sacrifices to pay for their care, and 8.3% stated that their insurance adequately covered their current health care costs, and 17.3% reported concerns about coverage for their costs in the future. On open-ended questions, 35.3% reported additional expenses, and 47.5% reported concerns about health care costs. None of the assessed patient characteristics proved to be a robust predictor across all cost-related concerns. There was a strong association between the identification of concerns or expenses on the open-ended questions and concerns on closed-ended questions. CONCLUSION: Cost concerns are common among patients with cancer who have health insurance. Health care providers may alleviate concerns by discussing cost-related concerns with all patients, not only those of lower socioeconomic status or those without insurance. A closed ended screening question may help to initiate these conversations. This may identify potential resources, lower distress, and enable patients to make optimal treatment decisions. PMID- 23943902 TI - Improving quality of cancer care at community hospitals: impact of the National Cancer Institute Community Cancer Centers Program pilot. AB - PURPOSE: Patients with cancer treated at community hospitals may experience decreased quality of care compared with patients treated at higher-volume cancer hospitals. The National Cancer Institute Community Cancer Centers Program (NCCCP) pilot is designed to enhance research and improve cancer care at community hospitals. We assessed changes in quality of care among the 16 initial NCCCP sites versus 25 similar hospitals that did not participate in the NCCCP. METHODS: We compared changes in concordance with five National Quality Forum-approved quality of care measures (three for breast cancer, two for colon cancer) for patients diagnosed from 2006 to 2007 (pre-NCCCP initiation) versus 2008 to 2010 (post-NCCCP initiation) at NCCCP and comparison-group hospitals. Data were collected using the Commission on Cancer Rapid Quality Reporting System. Analyses were performed using multivariate logistic regression. RESULTS: Analyses included 18,608 patients with breast cancer and 7,031 patients with colon cancer. After NCCCP initiation, patient-level concordance rates for all five quality-of-care measures increased significantly among NCCCP and comparison-group hospitals. Increased quality of care among NCCCP sites was significantly greater than that among comparison-group hospitals for radiation therapy after breast-conserving surgery and hormonal therapy for women with hormone receptor-positive breast cancer. In multivariate regressions, increases in hormonal therapy among NCCCP site patients were significantly greater than those among comparison-group hospitals. CONCLUSION: Both NCCCP and comparison-group hospitals showed improved quality of care; however, NCCCP sites had significantly greater improvements for a subset of measures. This greater increase may reflect the multidisciplinary focus of the NCCCP. Because many individuals receive cancer treatment at community hospitals, facilitating high-quality care in these environments must be a priority. PMID- 23943903 TI - End-of-life care in oncology inpatients: who, where, how? PMID- 23943905 TI - Helping patients quit tobacco: ASCO's efforts to help oncology care specialists. PMID- 23943906 TI - Pretreatment patient comorbidity and tobacco use increase cost and risk of postoperative complications after esophagectomy at a high-volume cancer center. AB - PURPOSE: Understanding the mechanisms and drivers of cost is a key component of improving the value of cancer care at both the system and patient level. Previous research on the cost of esophagectomy has established important postoperative drivers of cost; however, no study has linked pretreatment patient characteristics with cost. We sought to identify pretreatment patient characteristics that increase inpatient cost, length of stay, and risk of anastomotic leak and major pulmonary event (MPE) after esophagectomy for locally advanced esophageal adenocarcinoma. METHODS: We identified 191 patients with locally advanced esophageal adenocarcinoma treated with trimodality therapy at our institution between January 2002 and December 2008. All patients underwent espophagectomy 6 to 8 weeks after completion of neoadjuvant therapy. Multiple linear regression models were used to identify pretreatment predictors of total cost and length of stay. Multivariable logistic regression was used to identify pretreatment factors associated with leak and MPE. RESULTS: Pretreatment comorbidity (beta=0.1215, P=.039) and history of tobacco use (beta=0.0022, P=.028) significantly increased cost of esophagectomy. A comorbid condition increased total cost by 12.9%. Comorbidity (beta=0.2597, P=.001) and poor performance status (beta=0.1514, P=.021) were also significantly associated with prolonged length of stay. Patients with a higher comorbidity score had an increased risk of anastomotic leak (odds ratio, 6.564; 95% CI, 1.676 to 25.716) and MPE (odds ratio, 2.732; 95% CI, 1.317 to 5.666). CONCLUSION: Pretreatment patient comorbidity and tobacco use increases cost and risk of postoperative complications after esophagectomy. Other institutions must examine the relationship between their own costs and outcomes as cancer care delivery and payment systems become integrated at a national level. PMID- 23943904 TI - Addressing tobacco use in patients with cancer: a survey of American Society of Clinical Oncology members. AB - PURPOSE: Assessing tobacco use and providing cessation support is recommended by the American Society for Clinical Oncology (ASCO). The purpose of this study was to evaluate practice patterns and perceptions of tobacco use and barriers to providing cessation support for patients with cancer. METHODS: In 2012, an online survey was sent to 18,502 full ASCO members asking about their practice patterns regarding tobacco assessment, cessation support, perceptions of tobacco use, and barriers to providing cessation support for patients with cancer. Responses from 1,197 ASCO members are reported. RESULTS: At initial visit, most respondents routinely ask patients about tobacco use (90%), ask patients to quit (80%), and advise patients to stop using tobacco (84%). However, only 44% routinely discuss medication options with patients, and only 39% provide cessation support. Tobacco assessments decrease at follow-up assessments. Most respondents (87%) agree or strongly agree that smoking affects cancer outcomes, and 86% believe cessation should be a standard part of clinical cancer care. However, only 29% report adequate training in tobacco cessation interventions. Inability to get patients to quit (72%) and patient resistance to treatment (74%) are dominant barriers to cessation intervention, but only 8% describe cessation as a waste of time. CONCLUSION: Among ASCO members who responded to an online survey about their practice patterns regarding tobacco, most believe that tobacco cessation is important and frequently assess tobacco at initial visit, but few provide cessation support. Interventions are needed to increase access to tobacco cessation support for patients with cancer. PMID- 23943907 TI - Improving communication between oncologists and reproductive specialists to promote timely referral of patients with cancer. PMID- 23943908 TI - Reply to A. Azad et al. PMID- 23943909 TI - Reply to A. Azad et al. PMID- 23943910 TI - Spherical nucleic acids: a whole new ball game. PMID- 23943912 TI - Elisabeth Kirstin Beahm: a remarkable woman, a remarkable life. PMID- 23943913 TI - Response. PMID- 23943915 TI - A global future - a regional focus. PMID- 23943914 TI - Ecosystem-level controls on root-rhizosphere respiration. AB - Recent advances in the partitioning of autotrophic from heterotrophic respiration processes in soils in conjunction with new high temporal resolution soil respiration data sets offer insights into biotic and environmental controls of respiration. Besides temperature, many emerging controlling factors have not yet been incorporated into ecosystem-scale models. We synthesize recent research that has partitioned soil respiration into its process components to evaluate effects of nitrogen, temperature and photosynthesis on autotrophic flux from soils at the ecosystem level. Despite the widely used temperature dependence of root respiration, gross primary productivity (GPP) can explain most patterns of ecosystem root respiration (and to some extent heterotrophic respiration) at within-season time-scales. Specifically, heterotrophi crespiration is influenced by a seasonally variable supply of recent photosynthetic products in the rhizosphere. The contribution of stored root carbon (C) to root respiratory fluxes also varied seasonally, partially decoupling the proportion of photosynthetic C driving root respiration. In order to reflect recent insights, new hierarchical models, which incorporate root respiration as a primary function of GPP and which respond to environmental variables by modifying Callocation belowground, are needed for better prediction of future ecosystem C sequestration. PMID- 23943916 TI - 5 by 5 - what's next in AVA advocacy? PMID- 23943917 TI - High rates of suicide among vets is concerning. PMID- 23943918 TI - Thinking like an animal. PMID- 23943919 TI - Tick paralysis bad news for horses. PMID- 23943920 TI - Pet sheep - man's new best friend? PMID- 23943921 TI - Vets nuke pets. PMID- 23943922 TI - Casual or permanent? What's the difference? PMID- 23943923 TI - The future of veterinary vaccines. PMID- 23943924 TI - Re: economics of the veterinary profession in Australia - pricing and charging for veterinary services. PMID- 23943925 TI - Re: hand disinfection. PMID- 23943926 TI - Radial head fractures. PMID- 23943927 TI - Can science relate to our emotions? PMID- 23943928 TI - Vertebrate versus invertebrate neural circuits. PMID- 23943929 TI - Denis Pelli. PMID- 23943930 TI - Dear Readers. PMID- 23943931 TI - 2013 Rho Chi Lecture: writing the headlines of tomorrow. PMID- 23943932 TI - NTDB(r) data points: How complicated is it? PMID- 23943933 TI - ACS releases 2002 NTDBTM annual report. PMID- 23943934 TI - The author responds. PMID- 23943935 TI - Long road to a bright future. PMID- 23943936 TI - Blazing her own trail. PMID- 23943937 TI - Putting in the time and effort. PMID- 23943938 TI - Ready to lead: Clark Fobian anticipates role as AVMA president. Interview by R. Scott Nolen. PMID- 23943939 TI - House to deliberate on education council, alternative medicine. PMID- 23943940 TI - Vital funding for lab network added to Farm Bill. PMID- 23943941 TI - The accidental epidemiologist: Calvin W. Schwabe fathered a generation of veterinary epidemiologists. PMID- 23943942 TI - Viral disease affects U.S. pigs: porcine epidemic diarrhea found in at least 11 states. PMID- 23943943 TI - Banfield: spaying, neutering correlate with longer lives. PMID- 23943944 TI - Small changes are helping to meet travel rules. PMID- 23943945 TI - Study examines pet retention following adoption. PMID- 23943946 TI - Midwestern closer to accreditation. PMID- 23943947 TI - Betrayal of our ethics. PMID- 23943948 TI - Preventing food-borne illnesses. PMID- 23943949 TI - Navigating health insurance exchanges. PMID- 23943950 TI - Reconsidering employer-sponsored health care: four paths to long-term strategic change. AB - With Supreme Court and election uncertainty now resolved over the Patient Protection and Affordable Care Act (ACA), employers are recognizing the need for immediate action and reassessing the role they play in promoting and insuring the health of their population. Centered on a consistent need to have a workforce that is healthy, present and high-performing, employers face four possible strategic paths. This article discusses those paths along with their attendant risks and opportunities. PMID- 23943951 TI - Health care reform: implications for employers after the 2012 election. AB - While the regulatory landscape of the Affordable Care Act (ACA) continues to evolve, employers must focus on implementing upcoming group health plan mandates. This article provides a high-level checklist of the most common long-term requirements facing employers and some strategic considerations, outlining the three possible health care strategies employers generally should consider for 2014 and later. Although specific implementation will depend on each employer's particular situation, group health plan design, and regulatory guidance, the complexity involved means that employers are well advised to begin this process sooner rather than later. PMID- 23943952 TI - Leveraging private and public exchanges in an employee benefits strategy. AB - Health reform is helping to transform the health insurance marketplace and facilitate new opportunities to reevaluate and restructure the underlying framework of employer-sponsored benefits. Central to these opportunities is the emergence of public health exchanges at the state and federal levels offering a coordinated platform of diverse designs and health plans available on a guaranteed issue basis and often with government-provided subsidies. Parallel and complementary to this trend is the emergence of private health exchanges that similarly offer a diversity of plans on a variety of bases. This article shows why, together, these offerings provide potential streamlined solutions for employers as they reevaluate how they facilitate and support access to affordable coverage for their employees (and retirees). PMID- 23943953 TI - Health care reform the hourly challenge. AB - For those industries most likely to be transformed by the Patient Protection and Affordable Care Act (ACA), enacting the right strategy is the only strategy. A critical issue will be balancing cost and compliance factors with productivity concerns brought on by changes in the full- and part-time or hourly status of a given workforce. This article discusses industry perspectives in light of the ACA's 2014 implementation date, options for changing staffing models, and how the success of such changes depends on segmenting business units and locations while developing strategies for the different groups. Thus, the mix of full- and part time employees becomes a more complicated strategy, but an achievable one. PMID- 23943954 TI - Implementing the Patient Protection and Affordable Care Act: the time is now. AB - Employers all across the country should be in full swing as they prepare to implement the tougher parts of the Patient Protection and Affordable Care Act's (ACA) employer provisions, which are about to come online and take effect in 2014. This article reviews these more challenging requirements and their complications, including how employer calculations over whether to continue to offer coverage might vary by industry characteristics. The author then looks further ahead to the "Cadillac" tax and discusses how this liability may affect every employer's decision about its health care strategy leading up to 2018. PMID- 23943955 TI - The Affordable Care Act in brief: a look into January 2014 changes. AB - The Affordable Care Act (ACA) introduces many new mechanisms into the insurance marketplace that significantly impact business as usual. Although the changes are of great magnitude and, at times, intertwined with each other, this article sets out to introduce many of the changes in a simplified format. The 2014 changes will impact each market (individual, small-group, large-group and self-insured) in a different manner. This overview highlights those differences and includes a discussion of each. PMID- 23943957 TI - Early Retiree Reinsurance Program: bridge to 2014. AB - The Patient Protection and Affordable Care Act (ACA) established the Early Retiree Reinsurance Program (ERRP) to provide temporary stability to the employer supported retiree health care benefit market until the major provisions of the law ensuring every individual access to individual insurance become effective in 2014. The $5 billion appropriation was expected to last four years, but was expended in 18 months. This article reviews the development and motivation for the benefit. Further documentation is provided as to which recipients benefited from the reinsurance program. PMID- 23943956 TI - The employer's decision to provide health insurance under the health reform law. AB - This article considers the employer's decision to continue or to drop health insurance coverage for its workers under the provisions of the 2010 health reform law, on the presumption that the primary influence on that decision is what will produce a higher worker standard of living during working years and retirement. The authors incorporate the most recent empirical estimates of health care costs into their long-horizon, optimal savings consumption model for workers. Their results show that the employer sponsorship of health plans is valuable for maintaining a consistent and higher living standard over the life cycle for middle- and upper-income households considered here, whereas exchange-purchased and subsidized coverage is more beneficial for lower income households (roughly 4 6% of illustrative single workers and 15-22% of working families). PMID- 23943959 TI - Final HIPAA regulations require action by covered entities and business associates. PMID- 23943958 TI - Federal government releases additional proposed regulations under the Affordable Care Act. PMID- 23943960 TI - Time ticks down on ICD-10, but survey finds a lack of progress. PMID- 23943961 TI - ACOs are coming, will HIEs be there? PMID- 23943962 TI - X-ray vision. Analytic tools are beginning to transform medical imaging. PMID- 23943963 TI - Getting 'real' about claims processing. PMID- 23943964 TI - A custom job? PMID- 23943965 TI - Small changes, big results. Interview by Elizabeth Gardner. PMID- 23943967 TI - Infectious disease challenges. PMID- 23943966 TI - The end of chemo? Smarter cancer drugs with fewer side effects could make the drip history. PMID- 23943968 TI - Infectious disease offers diverse opportunities. PMID- 23943969 TI - Recurrent Clostridium difficile infection. PMID- 23943970 TI - Vaccine refusal by parents. PMID- 23943971 TI - Bacterial vaginosis update. PMID- 23943972 TI - Wrestling with a painful diagnosis. PMID- 23943973 TI - Biological markers and depression. PMID- 23943974 TI - Is obesity a disease? PMID- 23943975 TI - Vitamin D deficiency in children in Jerusalem: the need for updating the recommendation for supplementation. AB - BACKGROUND: Hypovitaminosis D is common worldwide, even in sunny regions. OBJECTIVES: To assess the prevalence and determinants of vitamin D deficiency in toddlers. METHODS: A cross-sectional prospective study was conducted in healthy Jewish children aged 1.5-6 years at five primary care pediatric clinics in the Jerusalem area during the period October 2009 to November 2010. Parents were interviewed regarding personal and demographic data and sun exposure. Blood samples were obtained for serum 25-hydroxyvitamin D [25-OHD] level. Vitamin D deficiency and insufficiency were defined as 25-OHD < 20 ng/ml and < 30 ng/ml, respectively. RESULTS: Of 247 children studied, 188 (76%) were ultra-Orthodox and 59 (24%) were Orthodox, traditional or secular. Mean (+/- SD) 25-OHD level was 25.7 +/- 10 ng/ml. Only 73 children (29.6%) had sufficient 25-OHD levels, 104 (42.1%) had insufficiency, and 70 (28.3%) had 25-OHD deficiency. The difference between ultra-Orthodox and others was insignificant (25 +/- 10 vs. 27.8 +/- 10.5 ng/ml respectively, P = 0.062). Children aged 1.5-3 years had higher 25-OHD levels than those aged 3-6 years (28.6 +/- 10.7 and 24 +/- 9.2 ng/ml respectively, P < 0.001). Vitamin D deficiency was more common in winter (53%) and autumn (360%) than in summer (19%) and spring (16%). Toddlers attending long day kindergartens had higher 25-OHD level than those staying at home or at short day kindergartens (28.8 +/- 11.5 and 24.7 +/- 9.6 ng/ml respectively, P < 0.05). CONCLUSIONS: A high prevalence of vitamin D deficiency was found in toddlers in our study, mainly in older children and in the winter and autumn. We recommend routine supplementation of vitamin D for children beyond the age of one year. PMID- 23943976 TI - Smoking habits among Israeli hospital doctors: a survey and historical review. AB - BACKGROUND: Smoking is a serious health issue worldwide. Smoking trends among physicians predict similar trends in the general population. Little is known about current smoking rates among physicians. OBJECTIVES: To investigate current smoking trends a Israeli physicians. METHODS: All practicing physicians at a tertiary university-affiliated medical center in central Israel were invited to complete a Web-based questionnaire on smoking habits and smoking-related issues via the institutional email. Findings were compared to those in the general population and between subgroups. RESULTS: Of the 90 responders (53 male, 88 Jewish), 54 (60%) had never smoked, 21 (23.3%) were past smokers, and 15 (16.7%) were current smokers. The rate of current smokers was lower than in the general population. The proportion of current smokers was higher among residents than attending physicians and among physicians in surgical compared to medical specialties. Past smokers accounted for 17.9% of the residents (average age at quitting 26.2 years) and 28.1% of the attending hysicians (average age at quitting 33.0 years). Non-smokers more frequently supported harsh anti-smoking legislation. CONCLUSIONS: The rate of smoking is lower in physicians than in the general population but has not changed over the last 15 years. Anti-smoking programs should particularly target physicians in surgical specialties. PMID- 23943977 TI - Incidence of cancer among diabetic and non-diabetic adult Israeli Arabs. AB - BACKGROUND: A worldwide epidemic of type 2 diabetes mellitus (T2DM) is in progress. This disease carries a heavy socioeconomic burden. OBJECTIVES: To compare the incidence rate of overall and site-specific cancers among Israeli Arabs with T2DM to that of Israeli Arabs without. METHODS: A retrospective cohort study of all adult Arab members of Clalit Health Care Services in northern Israel was conducted over a 10 year period (1999-2008). RESULTS: During the study period 752 and 2045 incident cases of cancer were diagnosed among 13,450 adults with diabetes and 74,484 without, respectively. The follow-up time involved 817,506 person-years. Diabetes was associated with a standard incidence ratio (SIR) of 3.27 (95% CI 1.49-5.05) and 2.87 (95% CI 1.25-4.50) for pancreatic cancer in men and women, respectively. A significantly reduced SIR (0.67, 95% CI 0.36-0.99) was observed for esophageal, stomach and intestinal cancers in men. CONCLUSIONS: Our findings support an association between T2DM and increased risk of cancer of the pancreas in Arab men and women. A significantly reduced risk of all other cancers was observed only in Arab men. Our findings underscore the need for effective diabetes and cancer prevention and intervention programs. PMID- 23943978 TI - Treatment with vitamin K in hip fracture patients receiving warfarin. AB - BACKGROUND: Hip fractures are common in the elderly population, but surgical treatment of these fractures within the first 48 hours decreases morbidity and mortality. The management of patients with hip fracture requiring surgery who are taking warfarin anticoagulation is unclear. OBJECTIVES: To determine the effect of vitamin K on hip fracture patients treated with warfarin. METHODS: We retrospectively examined the management of 21 patients with hip fractures who were being treated with warfarin at the time of admission. Vitamin K was given to 11 of the 21 patients. A third group, which served as a control, consisting of 35 hip fracture patients who were not being treated with anticoagulants was also evaluated. RESULTS: Patients who received vitamin K took fewer days to reach target international normalized ratio (INR) (1.73 +/- 0.90 vs. 4.30 +/- 1.89, P < 0.001) and had less preoperative time (2.64 +/- 1.12 vs. 5.10 +/- 2.42 days, P < 0.008) when compared with patients who did not receive vitamin K. In addition, these patients had statistically significantly shorter hospitalization stays (9.4 +/- 1.9 and 13.2 +/- 4.9 days, one-sided P < 0.06). There was no difference in the amount of blood found in the wound drains (111.8 +/- 68.5 vs. 103.0 +/- 69.4 ml) or the number of blood units administered (1.45 +/- 1.29 vs. 2.00 +/- 2.75 units). CONCLUSIONS: Treatment with vitamin K for hip fracture patients who receive warfarin shortens preoperative time, reduces the length of hospitalization and probably reduces morbidity and mortality. PMID- 23943979 TI - Persistent elevation of intraocular pressure following intravitreal injection of bevacizumab. AB - BACKGROUND: The number of patients treated with intravitreal injections has increased significantly over the past few years, mainly following the introduction of anti-vascular endothelial growth factor antibody intraocular drugs. Bevacizumab is mostly used in this group of medications. OBJECTIVES: To describe persistent elevation of intraocular pressure (IOP) following intravitreal injection of bevacizumab. METHODS: We reviewed consecutive cases of persistent IOP elevation after intravitreal bevacizumab injection for exudative age-related macular degeneration (AMD). A total of 424 patients (528 eyes) met the inclusion criteria and received 1796 intravitreal injections of bevacizumab. Persistent IOP elevation was found in 19 eyes (3.6%, 19/528) of 18 patients (4.2%, 18/424) with IOP elevated 30-70 mmHg 3-30 days after injection. RESULTS: Mean IOP was 42.6 mmHg (range 30-70); IOP elevations occurred after an average of 7.8 injections of bevacizumab (range 3-13). Injected eyes (19/528) had a significantly higher incidence of elevated IOP than uninjected eyes (fellow eyes), 1/328, P < 0.001. CONCLUSIONS: Like other anti-vascular endothelial growth factor (VEGF) substances reported in a few recent studies, intravitreal injection of bevacizumab for neovascular AMD may be associated with persistent IOP elevation. Providers should be aware that significant IOP elevation might occur after repeated treatments. PMID- 23943980 TI - An intervention study to reduce the loss of pathology specimens. AB - BACKGROUND: loss of an excised lesion can have devastating clinical and legal consequences. Previously, the incidence of pathological specimen loss was 1/1466 (0.07%) due to failure to place pathology specimens in correctly labeled containers. We theorized that a strict protocol for handling specimens would help reduce losses. OBJECTIVES: To devise a protocol to reduce the loss of pathology specimens. METHODS: In this study, 7105 specimens excised by one plastic surgeon were sent to the pathology laboratory using a strict protocol, which included: using a carefully labeled specimen container, inserting the specimen into the container immediately after excision (not at the end of the procedure), positioning the specimen container close to the surgical field during the surgery, and both the nurse and surgeon signing their names on the container at the end of the procedure to confirm the contents and labeling. RESULTS: One Mohs specimen was accidentally thrown away by a pathology laboratory technician after the frozen section report was written (an incidence of 1/7105, 0.00014%). All specimens arrived at the pathology department and no lesions were lost in the operating room. CONCLUSIONS: A strict written protocol for specimen handling significantly reduces loss of pathology specimens. PMID- 23943981 TI - How accurate is our clinical prediction of "minimal prostate cancer"? AB - BACKGROUND: Recommendations for active surveillance versus immediate treatment for low risk prostate cancer are based on biopsy and clinical data, assuming that a low volume of well-differentiated carcinoma will be associated with a low progression risk. However, the accuracy of clinical prediction of minimal prostate cancer (MPC) is unclear. OBJECTIVES: To define preoperative predictors for MPC in prostatectomy specimens and to examine the accuracy of such prediction. METHODS: Data collected on 1526 consecutive radical prostatectomy patients operated in a single center between 2003 and 2008 included: age, body mass index, preoperative prostate-specific antigen level, biopsy Gleason score, clinical stage, percentage of positive biopsy cores, and maximal core length (MCL) involvement. MPC was defined as < 5% of prostate volume involvement with organ-confined Gleason score < or = 6. Univariate and multivariate logistic regression analyses were used to define independent predictors of minimal disease. Classification and Regression Tree (CART) analysis was used to define cutoff values for the predictors and measure the accuracy of prediction. RESULTS: MPC was found in 241 patients (15.8%). Clinical stage, biopsy Gleason's score, percent of positive biopsy cores, and maximal involved core length were associated with minimal disease (OR 0.42, 0.1, 0.92, and 0.9, respectively). Independent predictors of MPC included: biopsy Gleason score, percent of positive cores and MCL (OR 0.21, 095 and 0.95, respectively). CART showed that when the MCL exceeded 11.5%, the likelihood of MPC was 3.8%. Conversely, when applying the most favorable preoperative conditions (Gleason < or = 6, < 20% positive cores, MCL < or = 11.5%) the chance of minimal disease was 41%. CONCLUSIONS: Biopsy Gleason score, the percent of positive cores and MCL are independently associated with MPC. While preoperative prediction of significant prostate cancer was accurate, clinical prediction of MPC was incorrect 59% of the time. Caution is necessary when implementing clinical data as selection criteria for active surveillance. PMID- 23943982 TI - Wandering in a dementia special care unit: behavioral aspects and the risk of falling. AB - BACKGROUND: Wandering is a common phenomenon among patients with dementia. While traditionally considered to be a behavioral problem, it also includes fundamental aspects of motor performance (e.g., gait and falls). OBJECTIVES: To examine the difference in motor function and behavioral symptoms between patients with severe dementia who wander and those who do not. METHODS: We conducted a retrospective study reviewing the medical records of 72 patients with severe dementia, all residents of a dementia special care unit. Motor and behavioral aspects were compared between "wanderers" and "non-wanderers." RESULTS: No difference was found in motor performance including the occurrence of falls between the wanderers and non-wanderers. A significant difference was found in aggressiveness and sleep disturbances, which were more frequent among the wanderers. There was no preference to wandering at a certain period of the day among the patients with sleep disturbances who wander. CONCLUSIONS: In a protected environment wandering is not a risk factor for falls. Sleep disturbances and wandering co-occur, but there is no circumstantial association between the two symptoms. PMID- 23943983 TI - Mortality in heart failure with worsening anemia: a national study. AB - BACKGROUND: Anemia is common in heart failure (HF), but there is controversy regarding its contribution to morbidity and mortality. OBJECTIVE: To examine the association of mild and severe anemia with acute HF severity and mortality. METHODS: Data were prospectively collected for patients admitted to all departments of medicine and cardiology throughout the country during 2 months in 2003 as part of the Heart Failure Survey in Israel. Anemia was defined as hemoglobin (Hb) < 12 g/dl for women and < 13 g/dl for men; Hb < 10 g/dl was considered severe anemia. Mortality data were obtained from the Israel population registry. Median follow-up was 33.6 months. RESULTS: Of 4102 HF patients, 2332 had acute HF and available hemoglobin data. Anemia was common (55%) and correlated with worse baseline HF. Most signs and symptoms of acute HF were similar among all groups, but mortality was greater in anemic patients. Mortality rates at 6 months were 14.9%, 23.7% and 26.3% for patients with no anemia, mild anemia and severe anemia, respectively (P < 0.0001), and 22.2%, 33.6% and 39.9% at one year, respectively (P < 0.0001). Compared to patients without anemia, multivariable adjusted hazard ratio was 1.35 for mild anemia and 1.50 for severe anemia (95% confidence interval 1.20-1.52 and 1.27-1.77 respectively). CONCLUSIONS: Anemia is common in patients with acuteHF and is associated with increased mortality correlated with the degree of anemia. PMID- 23943984 TI - Evaluation of a new immunochromatography test for rapid and simultaneous detection of Clostridium difficile antigen and toxins. AB - BACKGROUND: Clostridium difficile infection is considered the most common cause of nosocomial infectious diarrhea among adults in the developed world. It is responsible for virtually all cases of pseudomembranous colitis. The Tox A/B enzyme immunoassay (EIA) is the most widely used test for the detection of C. difficile toxins A and B. However, it is associated with poor sensitivity and an unacceptable high rate of false-negative results. OBJECTIVES: To evaluate the performance of the C. DIFF QUIK CHEK COMPLETE assay, designed to simultaneously detect C. difficile-produced glutamate dehydrogenase (GDH) and toxins A and B. METHODS: Using the C. DIFF QUIK CHEK COMPLETE assay, the Tox A/B EIA, and polymerase chain reaction (PCR), we tested 223 stool specimens from hospitalized patients with antibiotics-associated diarrhea. Sensitivity and specificity, and positive and negative predictive values (PPV, NPV) were calculated for the C. DIFF QUIK CHEK COMPLETE test and the Tox A/B EIA against PCR RESULTS: The C. DIFF QUIK CHEK COMPLETE test had a sensitivity of 83.5% and specificity of 94.3% compared to PCR for Tox A/B, with 93.7% correlation (PPV 98.5%, NPV 91.7%). The Tox A/B EIA yielded corresponding values of 72.1% and 93.1%, with 85.6% correlation (PPV 85.1%, NPV 85.8%). CONCLUSIONS: Given the importance of an early and appropriate diagnosis of Clostridium difficile-associated infection, the C. DIFF QUIK CHEK COMPLETE test may be of huge benefit to practitioners. PMID- 23943985 TI - Vitamin D deficiency and insufficiency. PMID- 23943986 TI - Time for setting a good example: physicians, quit smoking now. PMID- 23943987 TI - Central nervous system involvement in systemic lupus erythematosus: an imaging challenge. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving multiple organs. One of the main sites of SLE morbidity is the central nervous system (CNS), specifically the brain. In this article we review several imaging modalities used for CNS examination in SLE patients. These modalities are categorized as morphological and functional. Special attention is given to magnetic resonance imaging (MRI) and its specific sequences such as diffusion weighted imaging (DWI), diffuse tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). These modalities allow us to better understand CNS involvement in SLE patients, its pathophysiology and consequences. PMID- 23943988 TI - Heyde syndrome: resolution of anemia after aortic valve surgery. PMID- 23943989 TI - Meniere-like syndrome in Camurati-Engelmann disease. PMID- 23943991 TI - Some comments on male circumcision. PMID- 23943990 TI - Some comments on male circumcision. PMID- 23943992 TI - Some comments on male circumcision. PMID- 23943993 TI - The absurdity of the situation in the Middle East--a lesson for the Lancet. PMID- 23943994 TI - The absurdity of the situation in the Middle East--a lesson for the Lancet. PMID- 23943995 TI - The price of better public health. Cancer care will test the strength of the NHS. PMID- 23943996 TI - Getting down with the kids. PMID- 23943997 TI - Care and compassion for NHS staff. PMID- 23943998 TI - What's up doc? PMID- 23943999 TI - Don't mention the 'E' word. PMID- 23944000 TI - Leadership. A closer look at clinical leadership. PMID- 23944002 TI - The quest for prize integrated care. Interview by Claire Read. PMID- 23944001 TI - Francis report. Responding to the call of duty. PMID- 23944003 TI - Integration. Strength in numbers. PMID- 23944004 TI - Older people's services. Release the pressure. PMID- 23944005 TI - The NHS at 65. Where we're at, and where we need to be. PMID- 23944006 TI - Procurement. Challenging traditional methods of procurement. PMID- 23944007 TI - Reconfiguration. The OFT's role in NHS mergers. PMID- 23944008 TI - We are not amused. PMID- 23944009 TI - Service design. A new model for primary care. PMID- 23944010 TI - Leadership. What could Tesco bring to the NHS? PMID- 23944011 TI - Why data is key to better outcomes. Interview by Claire Read. PMID- 23944012 TI - PCMH: 6 ways to get started. Technology, care coordination, redefining staff roles keys to implementation success. PMID- 23944013 TI - The workplace policies that could make or break you. Even practices without union workers need to keep abreast of four of the NLRB's recent actions. PMID- 23944014 TI - The price of pain. Physicians cite need for better communication to successfully treat pain and monitor for possible abuse. PMID- 23944015 TI - Making sense of the new transitional care codes. How to maximize revenue related to the federal government's drive to reduce rehospitalizations. PMID- 23944016 TI - New TCM codes: case histories. PMID- 23944017 TI - 5 tech trends that will affect the way you practice medicine in 2013. PMID- 23944018 TI - Take steps to get ready for a HIPAA audit. PMID- 23944019 TI - Medical home pivotal to addressing healthcare reform, workforce issues. Interview by Lois A. Bowers. PMID- 23944020 TI - [Advance of experimental studies on protective effect of traditional Chinese medicines and their extracts on cerebral ischemia]. AB - This essay summarizes experimental studies on the protective effect of traditional Chinese medicines and their extracts on cerebral ischemia in the past decade. It classifies reported traditional Chinese medicines into three types plant medicines, animal medicines and mineral medicines, and specifies the advance of their effective components, extracts and their preparations in treating cerebral ischemia. PMID- 23944021 TI - [Advance in studies on anti-tumor activity of polysaccharides in latest five years]. AB - Polysaccharides widely exist in animals, plants, microorganisms, and possess various biological activities including anti-tumor, anti-virus, anti-oxidant and immunomodulatory. Polysaccharides shows notable anti-tumor activity and less toxicity, and becomes a hotspot in the studies of anti-tumor drugs. Therefore, there is huge potential for developing polysaccharides into a novel antitumor medicine. This article summarized polysaccharides derived from animals, plants, microorganisms which have significant antitumor effect in the latest 5 years; findings indicate that polysaccharides show the anti-tumor effect directly by inducing tumor cell apoptosis and indirectly as an immunoenhancement. This article also looks into the future of studies on anti-tumor activity of polysaccharides. PMID- 23944022 TI - [Advances in studies on toxicity of aconite]. AB - Aconite has the efficacy of reviving yang for resuscitation, dispelling cold and relieving pain, which is widely used in clinic, and shows unique efficacy in treating severe diseases. However, aconite has great toxicity, with obvious cardio-toxicity and neurotoxicity. Its toxicological mechanism main shows in the effect on voltage-dependent sodium channels, release of neurotransmitters and changes in receptors, promotion of lipid peroxidation and cell apoptosis in heart, liver and other tissues. Aconite works to reduce toxicity mainly through compatibility and processing. Besides traditional processing methods, many new modern processing techniques could also help achieve the objectives of detoxification and efficacy enhancement. In order to further develop the medicinal value of aconite and reduce its side effect in clinical application, this article gives comprehensive comments on aconite's toxicity characteristics, mechanism and detoxification methods on the basis of relevant reports for aconite's toxicity and the author's experimental studies. PMID- 23944023 TI - [Research on reserves estimation method of wild medicinal plants resource for generous species based on spatial information technology]. AB - Traditional Chinese medicinal resource survey method is time-consuming, strenuous, and having great human influence, the precision is not high enough. This paper, by using spatial information technology, carries on spatial sampling survey for wild medicinal plants resource for generous species to arrange the quadrat scientifically and estimate the suitable area, reserve precisely of medicinal plants. It not only improves the survey precision, but reduces the workload of field survey and provides scientific basis for survey method of pilot work on the fourth national traditional Chinese medicinal resource census. PMID- 23944024 TI - [Accurate identification of Psammosilene tunicoides and its confused species by systematic identification method]. AB - OBJECTIVE: To develop an effective identification method for accurately discriminating Psammosilene tunicoides and its confused species by the combined method of microscopic identification and molecular identification, so-called systematic identification of Chinese materia medica (SICMM). METHOD: P. tunicoides and its confused species were accurately discriminated by SICMM method, which was established by comprehensively use of microscopic identification and DNA identification method. The DNA identification included the following analysis: the BLAST alignment, specific bases and N-J phylogenetic tree analysis. RESULT: The cluster crystals were not observed in P. tunicoides, but great deals of them were found in Silene viscidula. Further more, big differences of ITS sequence were observed and analyzed between P. tunicoides and its confused specie of S. viscidula. CONCLUSION: The system method is a scientific and accurate method for the identification of P. tunicoides and its counterfeit species. PMID- 23944025 TI - [Growth and accumulation of shikonin compounds of two kinds of cells in suspension culture of Arnebia euchroma]. AB - Via studying the phenotype, growth curve and secondary metabolites of two kinds of suspension culture cell of Arnebia euchroma, the kinetics parameters of growth and accumulation of shikonin compounds in cell suspension culture of A. euchroma was obtained through simulating and modeling. This Study found that the red high yielding one was a fine cell line for producing shikonin compounds, and the white low-yielding one may be a mutant. The first-order and second-order derivative of the fitting function were obtained by fitting the Logistic model of growth curve to get the growth rate and growth acceleration curve of the suspended cells. It is found that the best period to subculture was the 15th day cultured in fresh medium, and the best period of the induction process was the 13th-14th day. When compared the growth rate of the red line and the shikonin compounds accumulation curve, it is found that the rapid growth of the biomass of cells was not conducive to the synthesis and accumulation of shikonin compounds. PMID- 23944026 TI - [Influence on AM fungi infection rate and medicine quality of Pinellia ternata in condition of three soil impact factors]. AB - OBJECTIVE: To explore the influence on AM fungi infection rate and medicine quality of Pinellia ternate in the condition of three soil impact factors. METHOD: Set the orthogonal test of three factors and levels. Determinate the AM fungi infection rate in early stage of mature & stage of mature of P. ternata, and the water content, water soluble extract, butanedioic acid content and alkaloid content of P. ternata tuber that be harvested also had be determinated. RESULT AND CONCLUSION: With the P levels to 30 mg x kg(-1) and 90 mg x kg(-1), AM fungi infection was the best when mixed inoculated of EM. Microbial agent inoculated played a decisive role in P. ternata growth and physiological activity, secondary influenced factor was P concentration, and the water stress was the minimal impact. Mixed inoculated of AM fungi and EM treatment with the low P levels (30, 90 mg x kg(-1)) proved better effect on enhancing the water extract content, anedioic acid and alkaloid content, while decreasing the water contents of P. ternata tuber. PMID- 23944027 TI - [Study on preparation of quercetin nanostructured lipid carriers and their physicochemical properties]. AB - OBJECTIVE: To prepare quercetin nanostuctured lipid carriers (QT-NLC), and detect their physicochemical properties. METHOD: QT-NLC was prepared by emulsification ultrasonic dispersion method, and the optimum prescription was screened out by orthogonal design. Transmission electron microscope was used to observe QT-NLC morphology. Granulometer was applied to determine zeta potential, particle size and distribution. DSC was adopted for phase analysis. Centrifugal ultra filtration method was used to determine entrapment efficiency. Dialysis method was adopted to detect drug release in vitro of preparations. RESULT: QT-NLC prepared under optimum conditions was mostly spherical grains, with the average particle size of (175 +/- 25) nm, which were distributed evenly, and zeta potential was (-23 +/- 0.3) mV. DSC results indicated that the drug was dispersed in nano-particles in a non-crystalline state, with an entrapment efficiency of (95.43 +/- 0.23)% and a drug-loading capacity of (2.38 +/- 0.24)%. The in vitro drug release was 32.2% in 2 hours, which was followed by a sustained release. CONCLUSION: Emulsification ultrasonic dispersion method is applicable for preparing QT-NLC, as nano-particles are distributed evenly, with good reliability. This processing technology is safe, reliable and highly reproducible. PMID- 23944028 TI - [Preparation of baicalin nanocrystal pellets and preliminary study on its pharmacokinetics]. AB - OBJECTIVE: To prepare baicalin nanocrystal (BC-NC) and evaluate its pharmacokinetics in rats. METHOD: Baicalin nanosuspensions (BC-NS) were prepared by the high pressure homogenization technology combined with ultrasonic, and then BC-NS were solidificated into BC-NC pellets by removing the water through fluid bed drying. Its morphology, mean diameter and Zeta-potential were determined. An HPLC method was employed to determine the concentration of baicalin in plasma, and the bioavailability of the nanocrystal was compared with the reference group by oral administration in Wistar rats. RESULT: The nanocrystals observed by scanning electron microscopy were irregular granulated, and the mean particle sizes of BC-NC were (248 +/- 6) nm. Its polydispersity index (PI) and zeta potential were (0.181 +/- 0.065), (-32.3 +/- 1.8) mV, respectively. The pharmacokinetic parameters showed that the C(max) was (16.54 +/- 1.73) mg x L(-1) and the AUC(0-24 h) was (206.96 +/- 21.23) mg x L(-1) x h, which were significantly enhanced compared with the baicalin bulk and baicalin physical mixture (BC-PM) formulation, respectively (P < 0.01). CONCLUSION: Baicalin nanocrystal can significantly improve the bioavailability of baicalin. PMID- 23944029 TI - [Study on preparation of ligustrazine ocular implant and correlation between in vivo and in vitro drug release]. AB - OBJECTIVE: To prepare ligustrazine (TMPZ) ocular sustained-release implant, and investigate its in vitro drug release, pharmacokinetics in rabbit vitreum and in vitro correlation. METHOD: Ligustrazine ocular sustained-release implants were prepared by micro-twin conical screw mixers with hot-melting extrusion method, with polyactic-co-glycolic acid (PLGA) as the matrix. HPLC was adopted to determine the concentration in vitreum after ligustrazine was implanted in rabbit eyes, in order to examine its in vivo sustained-release behavior, and study the correlation between in vitro and in vivo. RESULT: Ligustrazine implants were prepared with a drug-loading rate between 10% and 30%, which was in conformity to the pharmacopoeia in terms of the content uniformity. Its in vitro release was in conformity to the zero-order release model. With PLGA 5050, 2. 5A as a vector, ligustrazine implants with a drug-loading rate of 30% could slowly release drug for more than 3 weeks, indicating a good correlation between in vitro and in vivo release. CONCLUSION: Ligustrazine ocular implants prepared with hot-melting extrusion method is practicable. Ligustrazine ocular implants release drug smoothly in rabbit vitreous vitreums, suggesting good sustained-release effect. PMID- 23944030 TI - [Comparative study on mathematical set-based drug release kinetics method and Kalman filter method applied in evaluating drug release of multi-component traditional Chinese medicine preparations]. AB - OBJECTIVE: To provide a mathematical set-based method for evaluating drug release kinetics of multi-component traditional Chinese medicine preparations. METHOD: With Fuzheng Huayu prescription as the study model, a mathematical set-based method for evaluating drug release kinetics was established to guide the preparation of drug release system of Fuzheng Huayu prescription, and a quantitative evaluation was made for its multi-component drug release characteristics. Its accuracy was verified by Kalman filtering method. RESULT: The comparison between the two showed that the sample No. 4 of Fuzheng Huayu drug release system showed synchronized drug release with its reference preparation Fuzheng Huayu capsules. CONCLUSION: The results verified the accuracy and rationality of the evaluation method based on mathematics set. Meanwhile, it displayed the release of target preparations according to asynchronous coefficient (k) and other parameters, and found the orientation of regulating and improving the unit drug release dosage from relevant error parameters of various characteristic peak information, in order to purposefully regulate relevant components, and enable target preparations to meet the synchronized drug release requirements of the reference preparation. Meanwhile, it provided an effective measure for evaluating the quantitative characterization and synchronized release behavior of multi-component traditional Chinese medicines. PMID- 23944031 TI - [Chemical consitituents from root of Isatis indigotica]. AB - Thirty-three compounds were isolated from the root decoction of Isatis indigotica by using a combination of various chromatographic techniques including silica gel, macroporous adsorbent resin, Sephadex LH-20, and reversed-phase HPLC. Their structures were elucidated by spectroscopic data as (+)-dehydrovomifoliol (1), (S)-(+)-abscisic acid (2), vomifoliol (3), cyclo (L-Phe-L-Leu) (4), cyclo(L-Phe-L Tyr) (5), cyclo(L-Tyr-L-Leu) (6), cyclo(L-Pro-L-Tyr) (7), evofolin B (8), (+) syringaresinol (9), (-)-(7R,7'R,8S,8'S)-4,4'-dihydroxy-3-methoxy-7,9';7',9 diepoxy-lignan (10), (-)-medioresinol (11), (+) -(7R,7'R,8S,8'S) -neo-olivil (12), (-) -5-methoxyisolariciresinol (13), 1,3-dihydro-2H-indol-2-one (14), isalexin (15), dihydroneoascorbigen (16), indican (17), (-) -(S) -cyanomethyl-3 hydroxyoxindole (18), isoformononetein (19), calycosin (20), stigamast-5-ene 3beta-ol-7-one (21), acetovanillone (22), 3, 5-dimethoxy-4-hydroxyacetophenone (23), dihydroconiferyl alcohol (24), dihyroferulic acid (25), 3-hydroxy-1-(4 hydroxyphenyl) propan-1-one (26), beta-hydroxypropiovanillone (27), 4 aminobenzoic acid (28), 3-(4-hydroxyphenyl) propan-1-ol (29), 4-(2-hydroxyethyl) phenol (30), 2-methoxy-4-vinylphenol (31), pyrocatechol (32), and 4-pentenamide (33). These compounds were isolated from the root of I. indigotica for the first time. In preliminary in vitro assays, compound 19 showed activity against the influenza virus A/Hanfang/359/95 (H3N2), the herpes simplex virus 1 (HSV-1), and Coxsackie virus B3 (Cox-B3), with IC50 values of 2.06, 6.84, and 8.70 micromol x L(-1), respectively, but other compounds were in-active at a concentration of 1.0 x 10 x (-5) mol x L(-1). PMID- 23944032 TI - [Chemical constituents in Thunbergia from Africa]. AB - OBJECTIVE: To investigate the chemical compounds from the ethanol extract with inhibitory effects against aldose reductase from Thunbergia. METHOD: Guided by anti-aldose reductase assay, compounds from the bioactive fraction (ethyl acetate extract) were separated and purified by various chromatographic methods including silica gel, Sephadex LH-20, and reversed-phase HPLC. Their structures were indentified based on analysis of the spectroscopic data including 1D and 2D NMR data. RESULT: Eight compounds were obtained and identified as 8-hydroxy-8-methyl 9-methene-cyclopentane [7,11] -1,4, 6-trihydroxy-tetrahydronaphthalene-12-one, named as thunbergia A (1), 3,4-dihydro-4,5,8-trihydroxy-2-(3-methyl-2-butenyl) naphtha[2,3-b] oxiren-1(2H)-one (2), 8-(beta-gluco pyranosyloxy)-3,4-dihydro-2-(3 methyl-2-butenyl)naphtha [2,3-b] oxiren-1(2H)-one (3), galangin (4), quercetin (5), luteolin (6), 5,6,3',4'-tetrahydroxy -3,7-dimethoxy-flavone (7) and upeol (8). CONCLUSION: Thunbergia A was a new derivative of tetrahydronaphthalene, and compounds 2 and 3 were separated from the genus Thunbergia for the first time. PMID- 23944033 TI - [Alkaloids from bulbs of Lycoris radiata]. AB - Ten Amaryllidaceae alkaloids were isolated from the bulbs of Lycoris radiata. Their structures were identified as oxovittatine (1), apohaemanthamine (2), 9-O demethylhomolycorine N-oxide (3), incartine (4), ismine (5), 6-O methylpretazettine (6), tazettine (7), ungeremine (8), homolycorine (9), and O methyllycorenine (10) by spectroscopic data analyses. Compound 1 was a new natural product. Compounds 2 and 3 were reported form the genus Lycoris for the first time and compounds 4-6 were isolated form the title plant for the first time. PMID- 23944034 TI - Chemical constituents from leaves of Evodia lepta. AB - To explore the alternative material for the stems of Evodia lepta used in clinic, the leaves extract of E. lepta was chemically investigated by silica gel, Sephadex LH-20, ODS column chromatographies, and preparative HPLC and the structures of the compounds were identified mainly by spectroscopic methods. Ten known compounds 4-hydroxy-4, 7-dimethyl-1-tetralone (1), (6R, 7E) -4, 7 megastigmadien-3, 9-dione (2), 4-megastigmen-3, 9-dione (3), formononetin (4), daidzein (5), oroxylin A (6), wogonin (7), 5, 7-dihydroxy-3, 4'-dimethoxyflavone (8), N-trans-coumaroyltyranine (9) and (E) -p-hydroxycinnamic acid (10), have been obtained and identified. All these compounds were isolated from this species for the first time. The results revealed that there is a considerate chemical difference between the stems and leaves of E. lepta. PMID- 23944035 TI - [Analysis of alkaloids in Zanthoxylum nitidum by HPLC-DAD/ESI-Q-TOF-MS]. AB - The alkaloids in Zanthoxylum nitidum were identified by HPLC-DAD/ESI-Q-TOF-MS. Separation was performed on a Hanbon C18 column with acetonitrile (with 0.1% formic acid) and water(with 0.1% formic acid) as mobile phase. Based on the high resolution mass information, MS/MS fragmentation behaviors and chemical components from literatures, 48 components were identified or tentatively characterized including 6 new compounds. This work could be useful for the quality control and further studies of the plant. PMID- 23944036 TI - [Quality survey of different species of clematidis radix et rhizoma]. AB - Quality survey of different species of Clematidis Radix et Rhizoma was made by determining the content of hederagenin and oleanolic acid from Clematidis Radix et Rhizoma. The result showed that only a few samples of Clematis chinensis met the quality standard for Clematidis Radix et Rhizoma in Chinese Pharmacopoeia 2010 Edition. PMID- 23944037 TI - [Effect of Panax notoginseng saponins on expressions of MMP-13 and TIMP-1 in rats with hepatic fibrosis]. AB - OBJECTIVE: To investigate the effect of Panax notoginseng saponins (PNS) on the expressions of matrix metalloproteinase (MMP)-13 and its tissue inhibitor of metalloproteinase (TIMP)-1 in carbon tetrachloride (CCl4)-induced hepatic fibrosis rats, and explore the possible mechanism of PNS's effect against hepatic fibrosis. METHOD: The rats were randomly divided into 6 groups: the normal group, the model group, PNS (50, 100, 200 mg x kg(-1)) treatment groups and the Col (0.1 mg x kg(-1)) group. Apart from the normal group, all of the remaining groups were subcutaneously injected with CCl4 twice a week for 18 weeks, in order to establish the hepatic fibrosis rat model. Since the 9th weeks, each treatment group was orally administered with corresponding drugs, and the normal group and the model group were orally administered with equal volume of normal saline for 10 weeks. After the end of the experiment, liver and spleen indexes were calculated; the levels of serum ALT and AST were measured by chromatometry. Liver tissues were collected to detect the pathological alteration HE staining; protein expressions of MMP-13 and TIMP-1 were determined with immuninochemistry. Moreover, MMP-13 and TIMP-1 mRNA expressions was detected by RT-PCR technology. RESULT: Compared with the model group, PNS (100, 200 mg x kg(-1)) significantly mitigated hepatic fibrosis in rats, reduced liver and spleen indexes, ALT and AST contents in serum, and TIMP-1 expression, and notably increased MMP-13 expression in rats with hepatic fibrosis. CONCLUSION: P. notoginseng saponins have certain protective effect in rats with hepatic fibrosis. Its mechanism is related to up regulating MMP-3, inhibiting TIMP-1 expression and improving collagen degradation. PMID- 23944038 TI - [Study on evaluation system for gynecological disease model characterized by Qi stagnation and blood stasis syndrome with female SD rats]. AB - OBJECTIVE: To establish an evaluation system for animal model with gynecological disease characterized by Qi stagnation and blood stasis syndrome, in order to disprove syndrome characteristics of the model by classic clinical prescriptions, and evaluate the specificity and reliability of the model with macroscopic biological signs and symptoms. METHOD: The model characterized by Qi stagnation and blood stasis syndrome was established by injecting adrenaline into female SD rats and conducting unpredictable chronic stimulus such as reversal of day and night, swimming in cold water, thermal stimulation in oven, noise and tail suspension for two weeks. They were also orally administered with Xiangfu Siwu Tang, Shaofu Zhuyu Tang and positive control drug aspirin in groups. A comprehensive evaluation was conducted for the model on the basis of haemorheology, four blood coagulation indexes, four diagnostic information (digital imaging of tongue, paw and tail, temperature, weight, ingestion, electrocardiograph, and open filed test), and syndrome rating. RESULT: Compared with the normal group, the model group showed obvious changes in haemorheology, four blood coagulation indexes, animal behavior, weight, ingestion, syndrome rating and heart rate. Their tongue and paw pictures were analyzed with Photoshop 7.0, showing significant difference in red, green and blue percentage composition from the normal group. Groups given aspirin and Xiangfu Siwu Tang showed notable changes in haemorheology, four blood coagulation indexes, animal behavior, weight, ingestion, heart rate, syndrome rating, and red, green and blue percentage composition in tongue and paw pictures, whereas the group given Shaofu Zhuyu Tang showed no remarkable improvement. CONCLUSION: The evaluation system for the animal model with gynecological disease characterized by Qi stagnation and blood stasis syndrome is established to provide reference for studies on the evaluation system for qi stagnation and blood stasis syndrome models. PMID- 23944039 TI - [Antitumor effect of alcohol extracts from Stellera chamaejasme]. AB - OBJECTIVE: To screen the best antitumor components of Stellera chamaejasme and their sensitive cell lines. METHOD: Sixteen different components of alcohol extracts from S. chamaejasme, including HH, H1-H8, JH and J1-J8, were got by gradient column chromatography eluted with alcohol in different concentrations. In the first screening, the solvent control group, the drug group, the positive group and the blank group were set up. Then the human cancer cell lines such as hepatocarcinoma BEL-7402, SK-HEP-1, and lung cancer A549, NCI-H157 were processed with the components, and the concentration for each drug group was 100 mg x L( 1). Thus, the 48 hour suppression ratio to the four kinds of cancer cells for each component were compared by the SRB method, to select the most inhibitive components and the most sensitive cell lines, which were used as the subjects of the second screening. In the second screening, each component including the concentration of 6.25, 12.5, 25, 50, 100 mg x L(-1) was used to treat the sensitive cell lines and the inhibition rates to each cell line of 24, 48, 72 h by the SRB assay were detected. Also, the IC50 of each component was calculated and their main chemical composition was analyzed by UPLC-MS. RESULT: The inhibition effect to the proliferation of the different cancer cells has great difference among 16 components, and the lung cancer cells are more sensitive to them than the hepatocarcinoma cells. Besides, the inhibition rates of JS, J6 and H8 are higher than the other components and their effect has a certain time and concentration dependence. At 72 h, the inhibition rate of each component ranges from (60.57 +/- 3.83)% to (96.66 +/- 0.51)% for lung cancer cells, and IC50 from (9.61 +/- 0.79) mg x L(-1) to (55.76 +/- 2.31) mg x L(-1). J5, J6 and H8 are the biflavonoids. CONCLUSION: The biflavonoids in alcohol extracts from S. chamaejasme have exerted a satisfactory inhibitory effect on the lung cancer cell proliferation. PMID- 23944040 TI - [Protective effect of Tanreqing injection on acute hepatic injury induced by CCl4 in rats]. AB - OBJECTIVE: To observe the protective effect of Tanreqing injection(TRQ) on carbon tetrachloride-induced acute hepatic injury in rats. METHOD: Rats were randomly divided into the normal group and the model group, and injected subcutaneously with 100% CCl4 5 mL x kg(-1) to establish the single CCl4 infection model, in order to observe the changes in rat liver injury after 3 h and 6 h. Subsequently, the multiple CCl4 infection liver injury model was reproduced by subcutaneously injecting 100% CCl4 (5 mL x kg(-1)), 50% CCl4 olive oil solution (2 mL x kg(-1)) and then 20% CCl4 olive oil solution (2 mL x kg(-1)). At 6 h after the first CCl4 injection, the rats were divided into six groups: the model group, the control group, the diammonium glycyrrhizinate-treated group, and TRQ high, middle and low dose groups. They were injected through caudal veins, while a normal control group was set up. Their weight and liver-body ratio were observed. Hepatic inflammation was observed with HE staining. Assay kits were adopted to detect ALT, AST, T. Bil, D. Bil, CHE, TBA, gamma-GT and Alb. RESULT: According to the single injection model, serum AST and T. Bil of model rats were obviously increased at 6 h after single subcutaneous injection of CCl4, with disordered lobular structure in liver tissues, notable swollen liver cells and remarkable liver injury. According to the results of the multiple injection pharmacological experiment, compared with the normal group, the model group had higher serum ALT, AST, and gamma-GT activities (P < 0. 05), TBA and T. Bil contents (P < 0.05) and lower CHE activity (P < 0.05). HE staining showed disorganized lobular structure in liver tissues and notable ballooning degeneration in liver cells. Compared with the model group, TRQ high and middle dose groups and the diammonium glycyrrhizinate-treated group showed significant charges in serum liver function and inflammation in liver cells. Specifically, TRQ high and middle dose groups were superior to the diammonium glycyrrhizinate-treated group. CONCLUSION: Tanreqing injection has significant protective effect on CCl4-induced acute hepatic injury in rats. PMID- 23944041 TI - [Pharmacokinetic/pharmacodynamic modeling of antipyretic and reducing plasma concentration of NO effects of Rheum palmatum in rat]. AB - Pharmacokinetic-pharmacodynamic (PK-PD) modeling was used to characterize the antipyretic and anti-inflammatory effects in rats of Rhein, a major component in rhubarb. Twenty-four healthy male Sprague-Dawley (SD) rats were randomly into four groups, of 6 each. The rats in first group were injected intravenously with lipopolysaccharide (LPS, 100 microg x kg(-1)). The second group rats were given rhubarb decoction (RD, 1.54 g x kg(-1)) by oral administration alone. The rats belonging to third group were administered orally RD 30 min after LPS injection. The rest rats were given normal saline only as control group. Orbital sinus blood sampling was collected at different time points. The Rhein and NO concentration in plasma and body temperature (BT) were measured. Relevant data of PK-PD modeling were performed with Kinetica 5. 0. 11. RD could suppress the rise in BT and plasma NO concentration. The antipyretic and anti-inflammatory responses were best described by a Sigmod-E(max) model. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. The results showed that some parameters such as t1/2, C(max) and AUC were significantly increased in rats treated with LPS, compared to those in rats treated with normal saline. The EC50 for antipyretic effect and decrease of plasma NO concentration was respectively equal to 114.1, 90.80 microg x L(-1). The E(max) for antipyretic effect was about 111% of that for increase in BT after LPS injection. The E(max) for anti-inflammatory action was close to 8.399% of that for elevated NO level after modeling. Meanwhile, there was a difference in pharmacokinetic process of Rhein between the impact of normal saline and LPS. So, it can be concluded that the targets of regulating NO production and BT after RD administration may be at the same location. Not only do that, the antipyretic effect induced by RD maybe completely manifest through reducing the plasma concentration of NO. PMID- 23944042 TI - [Inhibitory effect of imperatorin and isoimperatorin on activity of cytochrome P450 enzyme in human and rat liver microsomes]. AB - Imperatorin (IM) and isoimperatorin (ISOIM) are major active components of common herbal medicines from Umbelliferae plants, and widely used in clinic. This article studies the inhibitory effect of IM and ISOIM on the activity of cytochrome P450 (CYP) enzyme, and assesses their potential drug-drug interaction. IM and ISOIM were incubated separately with human or rat liver microsomes for 30 min, with phenacetin, bupropion, tolbutamide, S-mephenytoin, dextromethorphan and midazolam as probe substrates. Metabolites of the CYP probe substrates were determined by LC-MS/MS, and IC50 values were calculated to assess the inhibitory effect of the two drugs on human CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4 enzymes, as well as on rat CYP1A2, 2B6, 2D2 and 3A1/2, and grade their inhibitory intensity. In human liver microsomes, IM and ISOIM showed different inhibitory effects on all of the six CYP isoenzymes. They were strong inhibitors for 1A2 and 2B6. The IC50 values were 0.05 and 0.20 micromol x L(-1) for 1A2, and 0.18 and 1.07 micromol x L(-1) for 2B6, respectively. They also showed moderate inhibitory effect on 2C19, and weak effect on 2C9, 2D6 and 3A4. In rat liver microsomes, IM and ISOIM were identified as moderate inhibitors for 1A2, with IC50 values of 1.95 and 2.98 micromol x L(-1). They were moderate and weak inhibitors for 2B6, with IC50 values of 6.22 and 21.71 micromol x L(-1), respectively. They also had weaker inhibitory effect on 2D2 and 3A1/2. The results indicated that IM and ISOIM had extensive inhibitory effects on human CYP enzymes. They are strong inhibitors of CYP1 A2 and 2B6 enzymes. However, it is worth noting the interaction arising from the inhibitory effect of CYP enzymes in clinic. PMID- 23944043 TI - [Study on tissue distribution of psoraleae fructus decoction in rats]. AB - Advanced technologies are used to clarify the meridian tropism theory of traditional Chinese medicine is an important part of theoretical studies of traditional Chinese medicine. In this article, modern pharmacokinetic method was used to investigate tissue distribution characteristics of psoralen and isopsoralen of Psoraleae Fructus decoction in rats, in order to provide research ideas and experimental basis for the meridian tropism theory. In this study, various tissue samples such as heart, liver, spleen, lung, kidney, brain and spermary were collected at different times after oral administration with FP decoction, in order to determine concentration of psoralen and isopsoralen by HPLC. Pharmacokinetic parameters were calculated by DAS 2.0 software. The study results showed that HPLC indexes of psoralen and isopsoralen in various tissues of rats met the determination requirements of biological samples. Both components were distributed in all of the tissues, with AUC(0-t) order of liver > lung approximately kidney > heart > brain approximately spleen > spermary. There was significant difference between liver, kidney, lung and other tissues (P < 0.05). MRT(0-t) of both psoralen and isopsoralen were about 10 h. Therefore, psoralen and isopsoralen showed stronger targeting selection in liver, kidney and lung. PMID- 23944044 TI - [Study on clinical efficacy of zhennaoning capsules in treatment of cerebral arteriosclerosis and analysis on its economic benefits]. AB - To study clinical efficacy of Zhennaoning capsules in treating cases with cerebral arteriosclerosis, and analyze its economic benefits. Totally 254 cases with cerebral arteriosclerosis were randomly divided into two groups according to their doctor-consulting sequence: the test group (n = 128) that was administered with Zhennaoning capsules, and the control group (n = 126) that was administered with Yangxueqingnao granules. A double-blind parallel-controlled study was conducted for four weeks, in order to observe the clinical efficacy and adverse effects of the two groups, and evaluate their pharmacoeconomics. Additionally, the clinical efficacy and safety of Zhennaoning capsules in treating cerebral arteriosclerosis, as well as its pharmacoeconomics were also discussed. This study showed that Zhennaoning capsules had a better efficacy than its control drug Yangxueqingnao granules in relieving traditional Chinese medicinal syndromes (according to traditional Chinese medicinal syndrome coring, efficacy and cure rate), suggesting a statistical significance (P < 0.01). Despite statistical significance showed from the differences in the remaining indexes and the occurrence rate of adverse effects, the test group displayed a lower cost effectives than the control group (P < 0.01). Zhennaoning capsules have a better clinical efficacy in treating cases with cerebral arteriosclerosis than Yangxueqingnao granules, demonstrating safe clinical application and better economic advantages. PMID- 23944045 TI - [Clinical application of therapy eliminating tuibidity and calming liver in treatment of essential hypertension with metabolic disorder]. AB - Hypertension is a common and frequently-occurring disease, as well as one of main causes for disability and death. With the social and economic development and the changes in lifestyle, risk factors of hypertension have also undergone significant changes, and thus the pathogenesis evolutional rules of hypertension in traditional Chinese medicine have also changed correspondingly. According to findings, metabolic disorder is an important feature of modern hypertension, as well as a significant cause for hypertension. Complementary and alternative medicine (CAM) plays a significant role in treating hypertension, with traditional Chinese medicines as major therapy. Turbidity and resistance, and liver-yang hyperactivity are the crucial pathogenesis of hypertension with metabolic disorder. In conclusion, therapy eliminating turbidity and calming liver is used to treat hypertension, which is worth promoting in clinical practice. PMID- 23944046 TI - [Preliminary analysis on morphological characteristics of traditional Chinese medicines in hot property]. AB - OBJECTIVE: To study morphological features of traditional Chinese medicinal herbs in hot property. METHOD: Altogether 114 traditional Chinese medicinal herbs in hot property were selected as study objects. EpiData 3.02 software was applied to establish a database, and SPSS 18.0 statistical software was used for data analysis. RESULT: In terms of shape, there were 25 cylindrical herbs, accounting for 21.9%, which was the largest proportion; 12 flaky herbs, taking up 10.5%; 11 sphere herbs, occupying 9.6%; 9 ovate and massive herbs, respectively, accounting for 7.9%; 8 oval herbs, taking up 7.0%; and the rest herbs were distributed dispersedly. By color, there were red cases, accounting for 39.5%, which was the largest proportion; 29 yellow cases, accounting for 25.4%; 16 black cases, accounting for 14.1%; 15 green cases, accounting for 13.2%; and 9 white cases, accounting for 8.9%. By odor, there were 62 cases with aroma (including slight aroma), accounting for 54.4%; 28 cases with slight odor, accounting for 24.6%; 13 cases without odor, accounting for 11.4%; 7 cases with specific odor, taking up 6.1%; 4 fishy cases, taking up 3.5%. By taste, there were 36 cases in pungent taste (including slight pungent), occuping 31.6%; 35 cases in bitter taste (including slight bitter), taking up 30.7%; 19 sweet cases (including slight sweet), occuping 16.6%; 5 salt cases (including slight salt), occuping 4.5%; 4 sour cases (including slight sour), occuping 3.5%; 11 cases in flat taste, occuping 9.6%; 3 astringent cases, occupying 2.6%; and 1 numb-taste case, occuping 0.9%. In terms of texture, hard herbs (including hard and solid ones) occupied 39.4%; crisp herbs occupied 24.6%; light-weigh herbs occupied 12.3%; heavy-weigh herbs occupied 3.5%; loose herbs occupied 2.6%; and tough herbs occupied 5.3%. CONCLUSION: The morphologic characteristics of traditional Chinese medicines in hot property show certain regularity. They are mostly cylindrical, red, pungent and hard, with aroma. PMID- 23944047 TI - [Study on effects and mechanism of traditional Mongolian medicine wuweifengshi capsule on adjuvant arthritis in rats]. AB - OBJECTIVE: To study the effects and immunoregulation mechanism of the traditional Mongolian medicine Wuweifengshi capsule on adjuvant arthritis (AA). METHOD: Wister rats were divided into several groups: normal group, AA model group, Wuweifengshi capsule groups (with low, moderate, high dose of 0.2, 0.4, 0.8 g x kg(-1) x d(-1) respectively), and Zhonglun-5 group (original dose of 1.68 g x kg( 1) x d(-1)). The edema degree, the level of IL-1beta, TNF-alpha, PGE2, NO and MDA and the activity of SOD in serum were detected. Through cell culture, the effects of the medicine on AA rat's splenic cell's multiplication capacity were studied. The influence of celiac macrophage cell culture fluid of AA rats' on C57BL/6J mice thymic cell multiplication capacity under the medicine was evaluated. RESULT: Wuweifengshi capsule showed an inhibiting function on the level of IL 1beta, TNF-alpha, PGE2, NO and increased the activity of SOD in serum, but showed no significant influence on MDA. It also inhibited the AA rat's splenic cell's multiplication capacity and the influence of celiac macrophage cell culture fluid of AA rat's on C57BL/6J mice thymic cell multiplication capacity. CONCLUSION: The anti-AA effect of Wuweifengshi capsule is possibly due to its inhibition of relevant cytokines and its adjustment of corresponding enzyme's activity and immunization organ's cell multiplication capacity. PMID- 23944048 TI - [Method for direct generation data for formatted case report forms based on requirement for data authenticity in actual clinical conditions]. AB - Data authenticity is the basic requirement of clinical studies. In actual clinical conditions how to establish formatted case report forms (CRF) in line with the requirement for data authenticity is the key to ensure clinical data quality. On the basis of the characteristics of clinical data in actual clinical conditions, we determined elements for establishing formatted case report forms by comparing differences in data characteristics of CRFs in traditional clinical studies and in actual clinical conditions, and then generated formatted case report forms in line with the requirement for data authenticity in actual clinical conditions. The data of formatted CRFs generated in this study could not only meet the requirement for data authenticity of clinical studies in actual clinical conditions, but also comply with data management practices for clinical studies, thus it is deemed as a progress in technical methods. PMID- 23944049 TI - [Special influence of molecular imprinting technology on traditional Chinese medicine theories]. AB - OBJECTIVE: To investigate the influence of molecular imprinting phenomena of traditional Chinese medicines (TCMs) on basic theories of TCMs according to current situations of molecular imprinting technology and experimental studies. METHOD: Fundamental principles of molecular imprinting theory were followed to analyze the material basis for TCM molecules to generate the imprinting phenomena, in order to find other material basis with more direct efficacy in line with the requirements of basic theories and modernization of TCMs. RESULT: Compared with single-component structures, TCMs and their compound components could create super-molecular compounds through complexation, composition, chelation, inclusion, neutralization, self-assembly and chemical reaction. The material basis of TCMs was super-molecular compounds including single ingredients, and there was an inter-molecule imprinting phenomenon. Therefore, special attention should be paid to inter-super-molecule imprinting actions in studies on TCM property, quality control, processing, drug preparation and pharmacology. The compatibility of TCM compounds could significantly change the action. CONCLUSION: The material basis of TCMs is super-molecular compounds based on single molecular groups. Super-molecules and molecular groups act rules, which is another difference between TCM compounds and single molecular drugs. PMID- 23944050 TI - [Study on method for formulating clinical practice guidelines of common Chinese patent medicines based on clinical practices]. AB - The clinical application of Chinese patent medicines has suffered sever problems and required guidelines for clinical practices. Currently, the expert consensus method is more suitable for formulating clinical practice guidelines of Chinese patent medicines than the evidence-based method. However, there remain problems in the application of the expert consensus method. This study proposed a derivative expert consensus method--a method for formulating clinical practice guidelines of common Chinese patent medicines based on clinical practices, and introduced the method in terms of research thought, methodology and implementation procedure. PMID- 23944051 TI - [Discussion on treatment of hypertension by tonifying kidney]. AB - Hypertension is one of the important risk factors of chronic non-communicable diseases such as stroke, myocardial infarction, heart failure and so on. It seriously affects heart, brain, kidney and other vital organs of the structure and function. In recent years, prevalence of hypertension in China is growing rapidly. The natural process of hypertension is changed directly because of constantly optimizing and widely using antihypertensive drugs, which results in the change of evolution law in traditional Chinese medicine pathology correspondingly. Kidney deficiency is the key pathology of hypertension nowadays. It is demonstrated that hypertension could be treated by the therapeutic principle of tonifying kidney. PMID- 23944052 TI - [Application of hyperspectral remote sensing in field of medicinal plants monitoring research]. AB - The paper introduces the basic concept and characteristics of hyperspectral remote sensing, and analyzed the application of hyperspectral remote sensing in the field of plants research. On the basis of the research advances of hyperspectral plant study, paper also analyzed the key facts that effects the application of hyperspectral remote sensing on the some researches which include distinguishing species,monitoring growth and quality etc. It proposed a new ideas and methods for people to research medicinal plants. PMID- 23944053 TI - [Effects of icariin on beta-amyloid and neurotrophic factors in brain of mitochondrial deficiency model rats]. AB - The purpose of the present study was to investigate the effects of icariin (ICA) on the content of beta-amyloid (Abeta) and the expression of neurotrophic factors in the brain of mitochondrial deficiency model rats. SD rats were infused subcutaneously with sodium azide, which is an inhibitor of mitochondrial respiratory chain complex IV, via a minipump (0. 5 mg . kg-1 h-1) for 28 days to establish the mitochondrial deficiency animal model. The activity of mitochondrial respiratory chain complex IV (i. e. cytochrome C oxidase, COX) in hippocampus was measured by biochemical methods. ELISA method was used to detect the content of Abeta in the brain. The expression of neurotrophic factors was detected by Western blot and immunohistochemistry methods. Image analysis was performed by Image-pro software. The results showed that chronic infusion of sodium azide by minipump induced a significant decrease in the activity of mitochondrial cytochrome C oxidase, an obvious increase in the content of Abeta, and a marked decline in the expression of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and its receptor TrkB in the brain of rats. Intragastrical administration of ICA (12 or 36 mg . kg-l) significantly ameliorated all these abnormalities in the model rats. In conclusion, ICA can increase mitochondrial activity, inhibit Abeta production, and enhance the expression of neurotrophic factors in the brain of model rats induced by sodium azide. The results suggested that ICA may have beneficial prospect for the treatment of Alzheimer's disease. PMID- 23944054 TI - [Effect of curcumin on hippocampal IRS-1 and p-IRS-1 expressions in APP/PS1 double transgenic mice]. AB - OBJECTIVE: To observe the effect of curcumin on the expressions of insulin receptor substrate-1 (IRS-1) and phosphated insulin receptor substrate-1 (p-IRS 1I) in APP/PS1 double transgenic mice of the AD model. METHOD: Three-month-old APP/ PSI double transgenic mice were randomly divided into the model group, the positive rosiglitazone control group and curcumin high (400 mg . kg-1 . d-1), medium (200 mg . kg-1 . d-1) and low (100 mg . kg-1 . d-1) dose groups. The normal group was composed of non-transgenic mice under the same background. After they were orally administered for three months, they were detected with immunohistochemistry, Western blot and RT-PCR. RESULT: According to IRS-1 and p IRS-1 immumohistochemical staining, the expression of IRS-1 positive cells in hippocampus CA1 area in model mice was significantly higher than that of the normal control group (P<0. 01). Compared with the model group, the number of IRS 1 positive cells in hippocampus CA1 area decreased (P <0. 05 or P <0. 01) and the number of p-IRS-1 positive cells in hippocampus CA1 area increased in all of curcumin intervention groups. Western blot results were consistent with IRS-1 and p-IRS-1 protein expressions and immunohistochemistry results. RT-PCR test showed opposite IRS-1 mRNA expression results with immunohistochemistry and Western blot results. CONCLUSION: Curcumin can recover increased IRS-1 and decreased p-IRS-1 in hippocampus of APP/PS1 double transgenic mice, increase IRS-1 mRNA expression, and improve the insulin-signaling transduction in APP/PS1 double transgenic mice. This suggests that curcumin can regulate the insulin-signaling transduction mechanism and show an anti-AD effect. PMID- 23944055 TI - [Effects of curcumin on expression of PI3K and p-pI3K in hippocampus of AD mice]. AB - OBJECTIVE: To observe the effect of curcumin on the expression of PI3K (phosphatidylinositol-3-kinase, PI3K) and p-P3 K (phosphated phosphatidylinositol 3-kinase, p-PI3K) in the hippocampus of Alzheimer's disease (AD) model (APP/PS1 double transgenic) mice. METHOD: A total of 60 three-month-old APP/PS1 double transgenic mice were randomly divided into model group, rosiglitazone group(10 mg . kg-1 . d-1) and curcumin large(400 mg . kg-1 . d-1), medium(200 mg- kg-1 . d-1) and small(100 mg . kg-1 . d-1) dose group. Twelve C57BL/6J mice in the same age and genetic background as APP/PS1 double transgenic mice were used as normal control group. All the 6 groups of mice were intragastrically administered for 3 months. After 3 months, the expression of PI3K and p-PI3K were detected by immunohistochemistry and Western blot. RESULT: The expression of PI3K and p-PI3K positive cells in hippocampus CA1 region significantly decreased in model group compared with normal control group (P < 0. 05) , while compared with model group, PI3K and p-PI3K positive cells of all the curcumin intervention groups increased to varying degrees in hippocampus CA1 region,especially the middle dose group(P <0. 01). Besides,Western blot results of the curcumin high dose group were also increased obviously (P <0. 05). CONCLUSION: Curcumin can recover the decreased PI3K and p-PI3K and improve the insulin-signaling transmission in the hippocampus of APP/PS1 double transgenic mice. The mechanism of curcumin maybe by regulating the insulin signal transduction to treat AD. PMID- 23944056 TI - [Effects of Shenwu capsule on learning-memory ability and cholinergic function of brain in AD-like rat model induced by chronic infusion of sodium azide by minipump]. AB - Because of the proposed importance of mitochondrial cytochrome C oxidase (COX) decrease in Alzheimer's disease (AD) , the protective effect of Shenwu capsule on mitochondrial deficiency model rats and its pharmacological mechanism were investigated in present study. Rats were administered with azide at 1 mg . kg-1 . h-1 subcutaneously via an Alzet minipump for 30 days. Tweny-four hours after the operation, the rats were administered intragastrically by Shenwu capsule with the dose of 0. 45, 0. 9 and 1. 8 g . kg-1 . d-1 for one month. Then learning-memory ability was determined by the watermaze test and passive avoidance tests. The activity of choline-acetyl-transfertase(ChAT) and acetylcholinesterase (AChE) in hippocampus and cortex of rats were measured by radiochemical method and hydroxylamine colorimetry separately. M-cholinergic receptor binding ability (M binding) was assayed by radio binding. Chronic infusion of sodium azide via minipump induced learning-memory deficiency of rats. Both ChAT activity and M binding decreased in hippocampus and cortex of model rats, however, the activity of AChE increased in hippocampus and was not affected at the cortex. As the result, the cholinergic function of the brain decreased in model rats. Shenwu capsule significantly improved learning and memory ability and the mechanism may be related with the improved cholinergic function in model brain: ChAT activity and M-binding significantly increased in Shenwu treated groups compared with model group; and the increased activity of AChE in hippocampus returned to normal. Mitochondria, especially mitochondrial cytochrome C oxidase, may play the key role in the early event of AD. Chronic, partial in vivo inhibition of mitochondrial cytochrome C oxidase in rats provides a suitable model mimicking several aspects of AD. Shenwu capsule indicate effectiveness in AD-like mitochondrial deficiency model rats, so it would be applied in the treatment of AD. PMID- 23944057 TI - [Protective effect of oligosaccharides from Morinda officinalis on beta-amyloid induced dementia rats]. AB - OBJECTIVE: To observe the effect of oligosaccharides of Morinda officinalis (OMO) on beta-amyloid-induced dementia rats, and study its pharmacological mechanism in treatment of dementia. METHOD: The dementia model rats were established by injecting Abeta25-35 10 microLg into bilateral hippocampus. OMO high-dose (60 mg . kg-1 . d-1) group, OMO low-dose (20 mg . kg-1 . d-1 ) groups, the blank group, the sham operation group and the positive donepezil HC1 group (0. 125 mg kg-1 . d 1) were designed for the experiment. They were continuously administered with drugs at the 15th day after operation for 25 days. Kit microplate method was used to detect the contents of super oxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione reductase (GSH-Px), acetylcholine (ACh) , acetylcholinesterase (AChE) and Na+ /K+ -ATPase. RESULT: Compared with the model group, all of administration groups showed higher SOD, CAT and GSH-Px levels, and lower MDA in the brain tissues. Besides, they also showed rise in the activities of ACh and Na+ /K+ -ATPase. CONCLUSION: OMO can ameliorate on beta-amyloid induced dementia rats by enhancing oxidation resistance, activating brain energy metabolism and improving the injury of cholinergic system. PMID- 23944059 TI - [Study on protective effect of cerebrospinal fluid containing Qingxin Kaiqiao Fang on sodium dithionite-induced PC12 cell injury]. AB - OBJECTIVE: To study the protective effect of cerebrospinal fluid containing Qingxin Kaiqiao Fang on sodium dithionite (Na2S2O4)-induced PC12 cell injury, in order to provide basis for clinical application of the prescription. METHOD: SD rats were orally administered with water decoction of Qingxin Kaiqiao Fang (7. 9 g . kg-1) once every 12 h, for a total of 7 times, in order to prepare cerebrospinal fluid containing Qingxin Kaiqiao Fang. The neurocyte injury model was established by adding Na2S2O4 with the final concentration of 8 m mol . L-1 into PC12 cells. With nimodipine (1 x 10(7)mol . L-1 ) as the positive control group, MTT method test was adopted to detect the impact of cerebrospinal fluid containing Qingxin Kaiqiao Fang on the activity of PC12 cells. The expression of Bax, Bel-2 and Caspase-3 mRNA was detected by RT-PCR. RESULT: The cerebrospinal fluid containing Qingxin Kaiqiao Fang groups showed a significantly higher activity in PC12 cells than the model group, with decrease in expressions of Bax mRNA and Caspase-3 mRNA and increase in expression of Bel-2 mRNA. There were significant differences compared with the model group (P< 0. 05,P <0. 01). CONCLUSION: Qingxin Kaiqiao Fang shows a notable protective effect on Na2S2 04 induced neurocyte injury. PMID- 23944058 TI - [Dynamic effect of curcumin on urine concentration of neuronal thread protein in AD mice]. AB - OBJECTIVE: Through the dynamic detection of the concentration change of the urine Alzheimer-associated neuronal thread protein (AD7C-NTP) in the curcumin treated Alzheimer's disease (AD) model (APP/PS1 double transgenic) mice, the therapeutic effect of curcumin in AD was determined. METHOD: Thirty three-month-old APP /PS1 double transgenic mice were randomly divided into 5 groups, 6 in each group, the model group, rosiglitazone group(10 mg . kg-1 . d-1) , high(400 mg . kg -1 . d-1) , medium(200 mg . kg-1. d-1) and low(100 mg . kg-1 . d-1) dose curcumin groups. Six C57BL/6J mice in the same age and genetic background were used as normal control group. All the 6 groups of mice were intragastrically administered for 6 months. Urine samples were collected on 4 month, 5 month and 6 month after intragastric administration, respectively. The changes of urinary AD7C-NTP concentration were detected by enzyme-linked immunosorbent assay (ELISA). RESULT: The concentration of AD7C-NTP of each group was compared at the same time point, the concentration of model group is higher than normal control group (P <0.05) ; the concentration of other groups is lower than model group. The concentration of high curcumin dose group with 4 months treatment, has no statistical difference compared with model group. The AD7C-NTP concentration of each group was elevated with the age growth, and all concentrations of the treatment groups were lower than the model group at the same period. With the treatment of 4, 5 and 6 months, the concentration of the normal control group has significant difference with the treatment groups(P <0. 01). There have no statistical difference between all the groups with the treatment of 6 months compared with 5 months. CONCLUSION: With the progression of the disease in AD mice, there are fluctuations in urinary AD7C NTP concentration, the compound curcumin from traditional Chinese medicine can delay the progression of AD. PMID- 23944060 TI - [Protective effects of paeoniflorin against aBETA25-35-induced oxidative stress in PC12 cells]. AB - OBJECTIVE: To investigate the neuroprotective effects and mechanism of paeoniflorin on Abeta25-35-induced oxidative stress in PC12 cells. METHOD: The proliferation of induced PC12 cells were investigated by the MTT method. The leakage rate of lactate dehydrogenase (LDH), the intracellular content of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH Px) were also measured. The changes of the intracellular reactive oxygen species (ROS) level and the mitochondrial membrane potential (MMP) were investigated by flow cytometry using DCFH-DA and Rh123 staining. The protein expression of HO-1, Cyt C and cleaved Caspase-3 was detected by Western blot. RESULT: The results showed that paeoniflorin at different doses (5, 10, 20 micromol . L-1) could increase the cell viability and activities of antioxidant enzyme (GSH-Px, SOD and HO-1), prevent LDH release and lipid peroxidation (MDA) production, decrease the level of intracellular ROS, increase MMP, inhibit the release of cytochrome c from the mitochondria and attenuate activation of Caspase-3. CONCLUSION: Paeoniflorin can protect PC12 cells from Abeta25-35 oxidative stress injuries. The mechanism may be related to its antioxidant action and inhibition of mitochondria-mediated caspase signaling pathways. PMID- 23944061 TI - [Study on protective effect of acteoside on cellular model of Alzheimer's disease induced by okadaic acid]. AB - OBJECTIVE: To investigate the effect of acteoside on SK-N-SH nerve cell injury induced by okadaic acid (OA). METHOD: SK-N-SH nerve cells were processed with 20 nmol * L OA to establish the Alzheimer's disease (AD) cellular model, and 5, 10, 20 mg . L-1 acteoside was used to antagonize against its effect. Cell morphology was observed under inverted microscope. The cell survival rate was detected with MTT, and the LDH release rate was measured by enzyme label kit. Western blot was applied to determine the expression of phosphorylation tau proteins in nerve cells. RESULT: The acteoside could significantly improve SK-N-SH cell morphology, enhance the cell survival rate, decrease the cell LDH release rate and the expression of phosphorylated tau proteins at p-Ser 199/202 and p-Ser 404 sites, up-regulated the expression of at non-phosphorylated tau proteins at Ser 202 site and Ser 404 sites. CONCLUSION: Acteoside has significant protective effect on nerve cell injury induced by OA. PMID- 23944062 TI - [Intervention effect of berberine on expressions of TNF-alpha and receptor type I in Abeta25-35-induced inflammatory reaction in SH-SY5Y cell lines]. AB - OBJECTIVE: To investigate the effect of berberine on expressions of tumor necrosis factor alpha (TNF-alpha) and receptor type I (TNFR1) in Abeta25-35 induced inflammatory reaction in SH-SYSY cell lines. METHOD: The 5 micromol . L-1 Abeta25-35 was used to treat SH-SY5Y cells for 24 hours, in order to establish the Alzheimer's disease (AD) model. Before modeling, berberine was given for pretreatment for 2 hours. The experiment included the normal control group, the AD model group, and indometacin low dose and high dose groups. Spectrophotometry was adopted to detect the activity of LDH. Meanwhile, the level of TNF-alpha was determined by ELISA, and the expression of TNFR1 genes was detected by RT-PCR. RESULT: Compared with the normal control group, the AD cell model group showed significant increase in LDH, TNF-alpha, and TNFR1 gene and protein expressions in the culture media. After intervention with berberine, the activity of LDH and TNF alpha reduced in cell supernatant. The intervention with berberine could down regulate TNFR1 gene and protein expressions, particularly 1, 10 x 10(-6) mol . L l berberine showed a more notable effect in regulating TNFR1. CONCLUSION: Berberine has the protective effect in Abeta-induced inflammatory injury in SH SY5Y cells. Its mechanism may be related to the expression of its anti inflammatory factor TNF-alpha and its type I receptor TNFR1. Specifically, its regulation to TNFR1 shows dose dependence. PMID- 23944063 TI - [Effects of cornel iridoid glycoside on activity of cholinesterases in vitro]. AB - The purpose of the present study was to investigate the effects of cornel iridoid glycoside (CIG) on the activity of cholinesterases in vitro, and to investigate the mechanism of CIG's treating Alzheimer's disease (AD). The sources of cholinesterases were prepared from human blood cells, rat brain homogenate and human blood plasma, respectively. The biochemical methods were used to detect the activity of acetylcholine esterase (AChE) and butyryl cholinesterase (BuChE) to investigate the influence of CIG on cholinesterases. The results showed that CIG inhibited the activity of AChE of human blood cells and rat brain homogenate, with the 50% inhibition rate (IC50) of 1.6 g . L-1 and 3.3 g . L-1, respectively; and the inhibition of AChE of CIG is reversible. CIG also inhibited the activity of BuChE of human blood plasma, with the IC50 of 2.9 g . L-1. In conclusion, CIG can inhibit the activity of AChE and BuChE in vitro, which may be one of the mechanisms of CIG to treat AD. PMID- 23944064 TI - [Hyperspectral characteristics of Carthamus tinctorius in Xinjiang region]. AB - Investigation of traditional Chinese medicine resources is the most important issue of the protection and use of traditional Chinese medicine resources. Real time monitoring of medicinal plant species and coverage of an area are of great significance to the sustainable development of the medicinal plant species diversity and ecological environment. Flower has unique spectral characteristics. Comparing the vegetative stage through the flowering stage it is easier to identify species. The flowering stage is a critical period for identifying species with remote sensing. Carthamus tinctorius as a traditional Chinese medicine resources in XinJiang region, attracted widespread attention in recent years. In this paper, the hyperspectral data of canopy and other vegetation canopy was measured in 2011. The spectral curve was analyzed, the result indicated that C. tinctorius canopy and the canopy after picking showed absorption peak near 770 nm, the first derivative of red edge spectra and invert Gaussian model were analyzed, the result indicated that there was significant difference between C. tinctorius canopy and other vegetation canopy. The proposed method is designed to provide initial theoretical foundation for growth condition and physiological parameters of C. tinctorius, and make theoretical groundwork for the distribution and elaborate monitoring of C. tinctorius in future. PMID- 23944065 TI - [Observations of in vitro pollen germination of Prunella vulgaris]. AB - To determine the optimal condition of pollen germination. The pollen of Prunella vulgaris was cultured in vitro. Pollen germination rates were recorded using 10% H3BO4, 30% Ca(NO3)2, 20% MgSO4 and 10% KNO3 as the basic mineral medium with PEG of different molecular weight, sucrose of various density and multiple pH value. The rates were also measured under different cultivation temperature and pollen acquisition time. The optimal condition of pollen germination is 10% H3 BO4, 30% Ca(NO3)2, 20% MgSO4, 10% KNO3, and 25% PEG-4000 as the medium, with pH about 6. 5 and pollen acquired at the beginning of blossom. PMID- 23944066 TI - [Analysis of quality variation and genetic diversity of Desmodium styracifolium from different provenances]. AB - OBJECTIVE: To explore the quality variation and genetic diversity of Desmodium styracifolium from different provenances, and lay a foundation for rational exploitation on germplasm resources and fine variety breeding of D. styracifolium. METHOD: Amplified fragment length polymorphism (AFLP) markers were developed to analyze genetic diversity in D. styracifolium from 18 resources. NTSYSpc-2. 11F software was used to analyze the similarity among the D. styracifolium germplasms and construct the genetic phylogenetic tree. The schaftoside content in D. styracifolium from different provenances was determined by HPLC. RESULT: A total of 844 fragments were amplified with 8 primers, in which 717 were polymorphic bands, accounting for 84. 27% of the total detected variation. All the specimens from 18 resources could be grouped into 3 clusters by cluster analysis. The schaftoside contents of D. styracifolium germplasms differed significantly, with the highest content in the germplasm from Sanya, Hainan. CONCLUSION: Significant quality variation and genetic diversity can be observed among D. styracifolium germplasms. The diverse germplasm resources should be explored and the fine variety should be selected to breed. PMID- 23944067 TI - [Allelopathic effect of artemisinin on green algae]. AB - To study the growth effects of differing concentrations of artemisinin on green algae and to evaluate the ecological risk. The effects of artemisinin on the growth and the content change of chlorophyll, protein, oxygen, conductivity, SOD, CAT, MDA in Chlorella pyrenoidosa and Scenedesmus oblique were studied through 96 h toxicity tests. Artemisinin accelerated the growth of algae at a lower concentration ( <40 microg . L-1) with content increase of chlorophyll or protein and so on, and it inhibited the growth of algae at higher concentration ( >80 microg . L-1). The content of chlorophyll or protein in algae cells reduced with the increasing concentration of artemisinin, exhibiting the good concentration effect relationship. SOD and CAT activity was stimulated at low concentrations ( <40 microg . L-1 ) and inhibited at high concentrations ( >80 microg . L- 1). However, MDA content increased significantly with the increase of concentration. According to the seven kinds of indicators changes, the time-response and dose response suggested that the surfactant first hurt in Ch. pyrenoidosa was damaging membrane by changing membrane lipid molecules soluble. And primary mechanism on Chlorophyta cells might be related to the oxidation damage of lipid and other biological large molecules caused by artemisinin. The large-scale intensive planting of Artemisia annua may reduce the surrounding water productivity. PMID- 23944068 TI - [Dynamic accumulation of three main triterpenic acids in submerged cultivation mycelium of Poria cocos]. AB - OBJECTIVE: To study the dymamic accumulation of triterpenic acids production in submerged cultivation mycelium of Poria cocos. METHOD: Liquid culture method of P. cocos was established and RP-HPLC was applied to determine the contents of three main triterpenic acids dehydrotumulosic acid (DTA), 3-epi-dehydrotumulosic acid (eDTA) and polyporenic acid C (PAC) in submerged cultivation mycelium P. cocos at different culture stages and the contents were compared with cultivated P. cocos. The HPLC method is as follows, column: Plastisil ODS (4.6 mm x 250 mm, 5 microm); mobile phase: ACN/0.5% phosphate (80:20); flow rate: 1.0 mL . min-1; detective wavelength: 242 nm. RESULT: The maximum biomass occurred at the 8th d after inoluctation, however, the contents and yield of three compounds increased till the 17th day. The contents of three compounds were 1. 2% (DTA), 0. 42% (eDTA) and 1.0% (PAC) at the 17th day after inoculation, which were significantly higher than that in cultivated material [0.2% (DTA), 0. 12(eDTA) and 0. 16% (PAC) ]. Furthermore, a correlation analysis between the content ratios of three independent compounds was carried out. The results showed that DTA negatively correlated with eDTA and PAC, with R2 of 0. 857 6 and 0. 971 7, respectively, which suggested the role of DTA as an important intermediate in the biosynthesis of triterpenic acids in P. cocos. CONCLUSION: The sum content of three main terpenoids in submerged cultivation mycelium P. cocos was 5. 55 times as that in cultivated material, which strongly suggested the possibility of fermentation in the production of medicinally important triterpenic acids in the future. PMID- 23944069 TI - [Evaluation of balanced release of complex components of Chuanping sustained tablets based on fingerprint]. AB - To combine fingerprint and drug release rate in vitro, in order to study in vitro release of complex components of Chuanping sustained tablets, compound traditional Chinese medicine preparation. A qualitative determination of the characteristic peaks of the compound preparations were conducted by the fingerprint. The results of the dissolution rate determination under different release conditions showed that the release of three index components (methamphetamine, pseudoephedrine and scopolamine) of Chuanping sustained tablets was less affected by gastrointestinal factors, with similarity factors being more than 80 with unknown component release curves of three major characteristic peaks in the fingerprint. The qualitative determination proved that multiple components of the compound traditional Chinese medicine preparation was dissolved in vitro at similar rates, realizing the balanced release of complex components of the compound traditional Chinese medicine preparation. This study layed a theoretical and experimental basis for quality evaluation for the compound traditional Chinese medicine preparation. PMID- 23944070 TI - [Study on preparation and thermosensitive release property of composite phospholipid liposomes containing total alkaloids from Strychnos nux-vomica]. AB - To prepare composite phospholipid liposomes containing total alkaloids of Strychnos nux-vomica with hydrogenated soybean phosphatidylcholine (HSPC) and 1, 2-dipalmitoyl-sn-glycero-3-phosphacholine (DPPC), and compare with normal DPPC thermosensitive liposomes for thermosensitive release property. Total alkaloids were extracted from S. nux-vomica with the impregnation method and further purified. Liposomes containing total alkaloids, thermosensitive liposomes and conventional thermosensitive liposomes without thermosensitive release property were prepared by ammonium sulfate transmembrane gradients and stealth liposome technique. Their encapsulation efficiency (EE), grain size, zeta potential and drug release behavior were compared. Their EEs and zeta potentials were almost identical; but the grain sizes of composite phospholipid liposomes and thermosensitive liposomes were significantly smaller than conventional liposomes. After comparing release behaviors of the three liposomes at 37, 43 degrees C, we found that the release of composite phospholipid liposomes was significantly lower than that of thermosensitive liposomes at 37 degrees C, but higher than that of thermosensitive liposomes at 43 degrees C. Meanwhile, conventional liposomes, with a very high phase-transition temperature, showed only slight release behavior at both temperatures. The study results showed that composite phospholipid liposomes had a better thermosensitive release behavior when the dosage of lysophosphatidic was reduced by 2. 5 times. PMID- 23944071 TI - [Study on preparation of testosterone undecanoate ethosomes and its in vitro transdermal penetration]. AB - Ethosomes, as a new vector for transdermal drug delivery, could obviously improve the transdermal penetration of drugs. In this study, we prepared testosterone undecanoate ethosomes, with TU ethosomes as the basic remedy, to determine its appearance, particle size, entrapment efficiency (EE) and membrane fluidity. Meanwhile, a transdermal test was conducted in mice, in order to determine the permeability characteristics of ethosomes as a vector for transdermal drug delivery, and compare transdermal behaviors of TU ethosomes, liposomes and their ethanol solutions. PMID- 23944072 TI - [Preliminary study on correlation between diversity of soluble proteins and producing area of Cordyceps sinensis]. AB - To analyze the content and type of soluble proteins in Cordyceps sinensis from different producing areas and processed with different methods with bradford method and 2-DE technology, in order to discover significant differences in soluble proteins in C. sinensis processed with different methods and from different producing areas. The preliminary study indicated that the content and diversity of soluble proteins were related to producing areas and processing methods to some extent. PMID- 23944073 TI - [Chemical constituents from flower buds of Lonicera japonica]. AB - Eighteen compounds were isolated by a combination of various chromatographic techniques including column chromatography over macroporous resin, MCI gel, silica gel, and sephadex LH-20 and reversed-phase HPLC. Their structures were elucidated by spectroscopic data analysis as adinoside A (1), stryspinoside (2), benzyl alcohol beta-glucopyranoside (3), benzyl 2-o-beta-D-glucopyranosyl-2,6 dihydroxybenzoate (4) , gentisic acid 2-O-beta-D-glucopyranoside (5), eugenyl beta-D-glucopyranoside (6) , eugenyl-P-xylopyranosyl-(1-->6)-beta-glucopyranoside (7), (-)-lyoniresinol 9-O-fP-D-glucopyranoside (8) , (+)-lyoniresinol 9-O-beta-D glucopyranoside (9) , apigenin-7-O-L-rhamnopyranoside (10), luteolin-3 '-O-L rhamnoside (11) , ursolic acid (12) , beta-sitosteryl-3beta-glucopyranoside-6'-O palmitate (13), abscisic acid (14), guanosine (15), 5-methyluracil (16), trans cinnamic acid (17), and 4-hydroxybenzaldehyde(18). These compounds were obtained from this plant for the first time. PMID- 23944074 TI - [Chemical constituents of Camellia sinensis var. assamica]. AB - To study the chemical constituents of Camellia sinensis var. assamica. The compounds were isolated by NKA Macroporous resin silica gel, Sephadex LH-20, RP C18 column chromatographies and semi-preparative HPLC,and their structures were elucidated by physicochemical properties and spectral analysis. Thirteen compounds were isolated and identified as caffeine (1), theobromine (2), gallic acid (3), (+)-catechin (4), ampelopsin (5), (-)-epicatechin (6), (-) epiafzelechin (7), (-)-epicatechin-3-O-gallate (8), (-)-epiafzelechin-3-O-gallate (9) , (+)-catechin-3-O-gallate (10) , (+)-afzelechin-3-O-gallate (11), quemefin-3 O-alpha-L-arabinopyranosid (12), and (-)-epicatechin-3-O-p-hydroxybenzoate (13). Compounds 2, 5, 10-13 were isolated from this plant for the first time, and compound 11 is a new natural product. PMID- 23944075 TI - [Chemical constituents from twigs and leaves of Melodinus hemsleyanus]. AB - To study the chemical constituents in the twigs and leaves of Melodinus hemsleyanus. The chemical constituents were isolated by silica gel, ODS and Sephadex LH-20 column chromatographies. Their structures were determined by chemical and spectroscopic methods. Fourteen compounds were isolated from the 95% ethanol extract of the twigs and leaves of M. hemsleyanus. Their structures were identified as 11-hydroxytabersonine (1) , venalstonid (2), sandine (3), oleanolic acid (4), ursolic acid (5), betulin (6) , (+)-pinoresinol (7), (-)-syringaresinol (8), 8-hydroxypinoresinol (9), (-)-latifolin (10) , cirsilineol (11) , loganin (12) , dibutylterephthalate (13) , and beta-sitosterol(14). Compounds 4-14 were obtained from this plant for the first time. PMID- 23944076 TI - [Simultaneous determination of five constituents in eight Qingyedan species derived from Swertia plants by HPLC]. AB - OBJECTIVE: To develop an HPLC method for simultaneous determination of swertiamarin, gentiopicroside, sweroside, mangiferin, erythrocentaurin, and to detect these five constituents in eight Qingyedans derived from Swertia mileensis, S. cincta, S. patens, S. punicea, S. delavayi, S. nervosa, S. macrosperma and S. yunnanensis. METHOD: The separation was carried out on a Thermo BDS Hypersil C18 (4. 6 mm x 250 mm, 5 microm) column eluted with mobile phase of water containing 0. 1% phosphoric acid and methanol (B) in gradient program (0-10 min, 18%-20% B; 10-30 min, 20%-35% B; 30-35 min, 35%-60% B). The column temperature was 32 degrees C , and the detection wavelength was set at 250, 260, 225 nm. The flow rate was 0. 7 mL . min-1 from 0 to 30 min, and be increased to 1. 0 mL . min-1 in 35 min. RESULT: The five compounds were well separated. The linear response ranges of swertiamarin, gentiopicroside, sweroside, mangiferin, erythrocentaurin were 0. 072-13. 39, 0. 1204. 518, 0. 060 5. 050, 0. 025-1. 518, and 0. 031-0. 210 microg, respectively. The mean recoveries of five compounds were 97.03% -102. 7% (RSD 1. 8% -6.2% ). There are swertiamarin, gentiopicroside and sweroside in most samples, and mangiferin in half samples. But erythrocentaurin was only detected in a few samples. The contents of five compounds were different in different samples. The contents of swertiamarin in S. mileensis, S. patens, S. yunnanensis and S. delavayi are up to 34. 47-118.05 mg . g-1, the contents of gentiopicroside are up to 25. 91 mg . g-1 in S. cincta. In S. puncea all contents of swertiamarin, gentiopicroside, sweroside and mangiferin are higher, especially the content of sweroside. There are Xiao-Qingyedans and Da-Qingyedans called in markets, and they can be identified by the contents of swertiamarin, gentiopicroside and sweroside. S. punicea can be identified by the content of sweroside, and the ratio gentiopicroside/total content can be used for identification of S. cincta from other seven Qingyedan species. CONCLUSION: The method was certified to be accurate and reliable and can be used for identification and quality evaluation of traditional Chinese medicine Qingyedan derived from Swertia species. PMID- 23944077 TI - [HPLC fingerprint and chemical pattern recognition method for Cichorium intybus and C. glandulosum]. AB - OBJECTIVE: To establish fingerprint analysis method by HPLC for the quality control of Cichorium intybus and effective identification of C. intybus and C. glandulosum. METHOD: The software "Similarity Evaluation System for Chromatographic Fingerprint of TCMs" (Version 2004A) was employed to generate the mean chromatogram and carry out the similarity analysis of the samples. Cluster analysis was adopted in combination with principal component analysis to study seventeen chicory's characteristic common peaks and to differentiate the two chicory resources. RESULT: The fingerprint of C. intybus and C. glandulosum has been set up, and the range of similarity for seventeen chicory samples was 0. 847 0. 988. The difference among chromatographic fingerprints of chicory samples between the two different varieties was identified by cluster analysis and principal component analysis. CONCLUSION: The method can be used to evaluate the quality of C. intybus and identify C. intybus and C. glandulosum conveniently. PMID- 23944078 TI - [Simultaneous quantitative analysis of five alkaloids in Sophora flavescens by multi-components assay by single marker]. AB - OBJECTIVE: To establish a new method for quality evaluation and validate its feasibilities by simultaneous quantitative assay of five alkaloids in Sophora flavescens. METHOD: The new quality evaluation method, quantitative analysis of multi-components by single marker (QAMS), was established and validated with S. flavescens. Five main alkaloids, oxymatrine, sophocarpine, matrine, oxysophocarpine and sophoridine, were selected as analytes to evaluate the quality of rhizome of S. flavescens, and the relative correction factor has good repeatibility. Their contents in 21 batches of samples, collected from different areas, were determined by both external standard method and QAMS. The method was evaluated by comparison of the quantitative results between external standard method and QAMS. RESULT: No significant differences were found in the quantitative results of five alkaloids in 21 batches of S. flavescens determined by external standard method and QAMS. CONCLUSION: It is feasible and suitable to evaluate the quality of rhizome of S. flavescens by QAMS. PMID- 23944079 TI - [Investigation of a compound, compatibility of Rhodiola crenulata, Cordyceps militaris, and Rheum palmatum, on metabolic syndrome treatment II - improving obesity]. AB - To investigate the effect of compound FF16, compatibility of Rhodiola crenulata, Cordyceps militaris, and Rheum palmatum, on obesity, both the insulin resistant obese IRF mouse model induced by high fat diet and the spontaneous type 2 diabetes KKAy obese mouse model were used. The results showed that the body weights and the energy uptake were markedly reduced by compound FF16 in both IRF mice in dose-dependent manner and KKAy mice, respectively. Meanwhile, with the administration of FF16, the hypercholesterolemia and the hypertriglyceridemia were improved significantly in KKAy mice; and the levels of serum cholesterol and fatty index were decreased obviously, and the value of serum HDL-C was increased significantly in IRF mice, respectively. Moreover, the activity of a-glycosidase was inhibited by compound FF16 in vitro. In conclusion, FF16 could improve the obesity by inhibiting alpha-glycosidase activity. PMID- 23944080 TI - [Study on intestinal absorption kinetics of apigenin in rats]. AB - To establish an in situ single-way intestinal perfusion model, in order to study the intestinal absorption kinetics of AP. The concentration of AP in the perfusate was determined by HLPC. The results showed different AP concentrations in all intestinal segments, with the fastest absorption rate in duodenum, which was followed by jejunum, ileum and colon. In general, the constant absorption rate (Ka) of AP in duodenum and jejunum first increased and then decreased with the rise in drug concentration (P <0. 05); the absorption mechanism may be related to active transport and facilitated diffusion factors. The constant absorption rate (Ka) of AP in ileum and colon generally kept unchanged with the rise diffusion in drug concentration, the absorption mechanism may be related to passive. PMID- 23944081 TI - [Study on pharmacokinetics and in vitro/in vivo correlation of menthol in Zhike Chuanbei Pipa dropping pills in rats]. AB - To determine the concentration of menthol in rat plasma by GC. Rats were administered with single dose of Zhike Chuanbei Pipa dropping pills (ZCPDP) and different doses of menthol herbs. DAS 3. 1.6 software was used to calculate pharmacokinetic parameters, and the accumulative absorption percentage of menthol was calculated by Loo-Riegelman method. The linear regression analysis was made in vitro/in vivo accumulative absorption percentages to detect the in vitro/in vivo correlation. The results of the study showed that the pharmacokinetics behavior of menthol in ZCPDP was in conformity with two-compartment model characteristics. The main parameters were: tmax was 10 min, t1/2beta was (183. 93 52. 75) min, CL/F was (0. 426 +/- 0. 194) L . min-1 . kg-1, all of which were no difference between ZCPDP and menthol herbs with the same dosage. There were significant differences in tmax, t1/2beta, CL/F between menthol herbs with different dosages (P <0. 05) , with indirect proportion between AUC0-infinity and dosage. The regression equation of ZCPDP's accumulative absorption percentage and accumulative release percentage was Fa = 1. 160 3Q - 19. 968, r = 0. 981 3. These results suggested that the pharmacokinetics behavior was similar between ZCPDP and menthol herbs with the same dosage in rats, with good in vitro/in vivo correlation. There were significant differences in pharmacokinetics of menthol in the range of 19.2-570 mg . kg-1. PMID- 23944082 TI - [Effect of comparability of Coptis chinensis and Scutellaria baicalensis on five sub-enzymatic activities of liver microsomes in rats]. AB - To study the mechanism of metabolic interaction between Coptis chinensis and Scutellaria baicalensis. Rats were given C. chinensis and S. baicalensis for 7 days to produce hepatic microsomal enzyme. Cocktail probe substrate and liver microsome in vitro temperature incubation method were adopted. Meanwhile, the metabolic elimination percentages of the five probe substrates were detected with HPLC, in order to evaluate the effect of each administration group on the enzymatic activity of rat liver microsome CYP450. Compared with the blank group, C. chinensis obviously inhibited CYP2D6 and CYP1A2, and S. baicalensis remarkably inhibited CYP1A2, CYP2E1 and CYP2C9. The compatibility of C. chinensis and S. baicalensis with the ratio of 1:1 not only inhibited CYP1A2, but also remarkably activated CYP2D6 and CYP3A4. However, their activation effect disappeared under the ratio of 2: 1, and turned into the inhibitory effect on CYP1A2 and CYP2C9. The results showed that C. chinensis and S. baicalensis had an inhibitory effect on CYP450, but their compatibility with certain ratio resulted in double effects of activation and inhibition, which was related to their compatibility ratio. It is speculated that the inhibitory and inducing effects of C. chinensis and S. baicalensis on metabolic enzymes are among causes for their attenuation and synergistic effects. PMID- 23944083 TI - [Meta-analysis on elemene injection combined with cisplatin chemotherapeutics in treatment of non-small cell lung cancer]. AB - To research databases of Cochrane library, Web of Science, PubMed, FMJS, CBM, VIP, CNKI and Wanfang Data Konwledge Service Platform by computers as at July 5, 2012, which was supplemented with other search results. The findings were included into randomized controlled trials (RCTs) of elemene injection combined with cisplatin chemotherapeuties in treating small cell lung cancer (NSCLC). Data was separately collected by two researchers for literature quality evaluation, and a Meta analysis was made with RevMan 5. 2 software, in order to assess the efficacy and safety of elemene injection combined with cisplatin chemotherapeutics in treating NSCLC. Totally 11 RCTs or 844 cases were included. Meta analysis results suggested that compared with cisplatin chemotherapy alone, the combination of elemene injection and cisplatin chemotherapeutics showed a higher clinical benefit rate ( OR = 2. 03, 95% CI:1.43-2. 88, P <0. 000 1) and a better quality of life (OR = 3.23, 95% CI:2. 20-4. 74, P <0. 000 01). Besides,the combination could also reduce leucopenia (OR =0. 50, 95% CI:0. 33-0. 76, P <0. 001) , and thrombocytopenia (OR =0. 38, 95% CI:0. 16-0. 85, P <0. 02), increase CD4 (MD = 3.32, 95% C1:2. 94-3.70, P <0. 000 01), and CD4/CD8 (MD = 0. 36, 95% CI:0. 28-0. 44, P < 0. 000 01) , and relieve gastrointestinal reactions such as nausea and vomiting (OR = 0. 37, 95% CI: 0. 19-0. 71, P = 0. 003). The analysis indicates that elemene can enhance the chemotherapeutic effect on NSCLC, improve the quality of life, and reduce adverse effect of platinum-contained chemotherapeutics, thereby being worth promoting in clinic. PMID- 23944084 TI - [Four properties law of nature data of Chinese materia medica in "Chinese herbal medicine (CHM)"]. AB - OBJECTIVE: In order to provide theoretical clues and data support for the use of Chinese medicine clinical drug, experimental study of Chinese materia medica and development of new resources of Chinese materia medica, the four properties as the core, the relationships of property, flavor, channel tropism and toxicity in nature data of Chinese materia medica were analyzed. METHOD: The spearman rank correlation method was employed to analyze 8 356 Chinese drugs with characteristic of four properties from " Chinese Herbal Medicine" based on data level coding. RESULT: It was discovered that four properties showed significant positive correlations with tastes of "pungent and sweet" , channels of "spleen" , "stomach" , "kidney" and "toxicity" , but also showed significant negative correlations with tastes of "bitter" and "light" and six channels such as "large intestine" , "heart", "bladder" , "gallbladder" , "small intestine" and "lung" (in descending order of correlation ) (P <0. 01). CONCLUSION: It was indicated that the more hot the Chinese medicine nature, the more possible it contained "toxicity" , tastes of "pungent" and "sweet" , and the more possible it was belong to channels of "spleen" , "stomach" and "kidney". As well, the more cold the Chinese medicine nature, the more possible it contained tastes of "bitter" and "light", and the more possible it was belong to six channels such as "large intestine", etc. PMID- 23944085 TI - [Preliminary study on main impacting factors on brand equity of listed traditional Chinese medicine companies]. AB - The brand equity is valuable intangible assets of traditional Chinese medicine companies, who are excellent representatives of traditional Chinese medicine enterprises and the most promising ones to good international medicine brands. However, there is still no systematic study on how to correctly evaluate the brand equity of listed traditional Chinese medicine companies at present. To make it clear, the main impacting factors on brand equity of listed traditional Chinese medicine companies, both structured open outline pre-research and closed questionnaire research were adopted for the field survey, and some suggestions for how to protect and enhance the brand equity were also presented on the basis of survey and analysis, in the hope of improving the brand management level of listed traditional Chinese medicine companies, and making a beneficial exploration for the development of brand theory of the traditional Chinese medicine industry. PMID- 23944086 TI - [Difficulties in registration for export of traditional Chinese medicines to EU under directive 2004/24/EC and countermeasures]. AB - During the seven-year transitional period of European Union Directive 2004/24/EC, only a few of traditional Chinese medicines had been approved for registration. In other words, the EU directive has become an unavoidable registration barrier to hinder Chinese enterprises from entering EU market. By analyzing difficulties of enterprises in registration in EU and studying the only successful case in China--Di Ao Group, this article proposes countermeasures in the hope of providing effective reference for Chinese enterprises in expanding EU market, and promoting the internationalization progress of traditional Chinese medicine. PMID- 23944087 TI - [A accurate identification method for Chinese materia medica--systematic identification of Chinese materia medica]. AB - This paper put forward a more accurate identification method for identification of Chinese materia medica (CMM), the systematic identification of Chinese materia medica (SICMM) , which might solve difficulties in CMM identification used the ordinary traditional ways. Concepts, mechanisms and methods of SICMM were systematically introduced and possibility was proved by experiments. The establishment of SICMM will solve problems in identification of Chinese materia medica not only in phenotypic characters like the mnorphous, microstructure, chemical constituents, but also further discovery evolution and classification of species, subspecies and population in medical plants. The establishment of SICMM will improve the development of identification of CMM and create a more extensive study space. PMID- 23944088 TI - [Brief introduction of geo-authentic herbs]. AB - The science of geo-authentic herbs is a characteristic discipline of traditional Chinese medicine established during thousands of years of clinical practices. It has a long history under the guidance of profound theories of traditional Chinese medicine. The words of "geo-authentic product" were derived from an administrative division unit in the ancient times, which layed stress on the good quality of products in particular regions. In ancient records of traditional Chinese medicine, the words of "geo-authentic product" were first found in Concise Herbal Foundation Compilation of the Ming dynasty, and the words of "geo authentic herbs" were first discovered in Peony Pavilion of the late Ming dynasty. After all, clinical effect is the fundamental evaluation standard of geo authentic herbs. PMID- 23944089 TI - [Application of computed tomography (CT) examination for forensic medicine]. AB - The aim of the study is to present a own experiences in usage of post mortem CT examination for forensic medicine. With the help of 16-slice CT scanner 181 corpses were examined. Obtained during acquisition imaging data are later developed with dedicated programmes. Analyzed images were extracted from axial sections, multiplanar reconstructions as well as 3D reconstructions. Gained information helped greatly when classical autopsy was performed by making it more accurate. A CT scan images recorded digitally enable to evaluate corpses at any time, despite processes of putrefaction or cremation. If possible CT examination should precede classical autopsy. PMID- 23944090 TI - [The influence of proficiency level of foreign language on the activation patterns of language areas]. AB - The of aim of the present study was the estimation of the influence of proficiency level of the second language on activation patterns of language areas. 30 volunteers participated in the experiment (15 females and 15 males) from 18 to 40 years of age. Mean age was 28 years. All participants were divided by linguist into two groups according to their proficiency level of the foreign language: high proficiency group (HP) and low proficiency group (LP). Block design method was used in the performed experiment. The experimental task was speech production in the form of sentences, the control tusk was silence. The experiment was performed using 1,5 T MR system. Functional data analysis was performed using SPM2 software (Wellcome Department of Cognitive Neurology, Great Britain). In low proficiency group (LP) stronger activation was found in right inferior frontal gyrus (pars tiangulris) incuding insula and in the left hemisphere on the border of supramarginal and superior temporal gyrus. In high proficiency group (HP) more activated in second language (L2) was the left inferior frontal gyrus (pars tiangulris), and a small part of left middle frontal gyrus. Proficiency level of the second language influences the pattern of activation of language areas. PMID- 23944091 TI - [Endovascular embolisation in epistaxis]. AB - Epistaxis because of frequent occurrence is an important clinical problem. Endovascular embolisation plays important role in treatment of patients with epistaxis which not un. dergoing with conservative therapy,. The aim of this study is presentation of own experiences with embolisation in epistaxis. Embolisation was performed in 36 patients with epistaxis using different embolic materials: coils, a sponge, cyjanoacrylic glue, PVA. In 35 cases embolisation of external carotid artery branches was done. In one case of direct carotid cavernous fistula em bolisation was performed through the internal carotid artery. Early success of embolisation was assessed in all cases. In 5 patients rebleeding occurred and additional embolisation or surgical procedure were done. There was no complica. tions after embolisation. Endovascular embolisation in epistaxis is en effective method and alternative to surgery. PMID- 23944092 TI - [Results of stent assisted endovascular treatment of intracranial aneurysms]. AB - Aim of the study was presentation of own experiences with stent assisted endovascular treatment of cerebral aneurysm. Employment of cerebral stents extended endovascular embolisation technique to wide neck cerebral aneurysms. From March 2007 and October 2011 40 patients - 28 (70%) women and 12 (30%) man with 43 intracranial aneurysms were treated with stent assisted embolisation technique. All aneurysms were saccular, 27 (79.4%) situated on internal carotid artery, 4 (11.8%) on basilar artery, 2 (5.9%) on posterior cerebral artery, 1 (2.9%) on vertebral artery. 3 (9%) aneurysms were ruptured and rest 31 (91%) were unruptured. Control angiography revealed in 16 (37%) cases complete embolisation, in 15 (34.8%) residual and in 10 (23.2%) uncompleted embolisation. Complications appeared in 4 (9%) cases - 3 times acute stent thrombosis and once intracranial bleeding. Stent assisted endovascular treatment of intracranial aneurysm allows to effectively treatment of wide neck aneurysm and decreases amount of recanalisation . However more complicated technique and higher risk of complication require experience and appropriate qualification for that treatment. PMID- 23944093 TI - [The assessment of left ventricular hypertrophy in patients with the primary hypertension with the use of Cardiac Magnetic Resonance]. AB - The aim of the study is to present usefulness of Cardiac Magnetic Resonance (CMR) to assess left ventricular hypertrophy in hypertensive patients. 48 patients were examined (24 females and 24 males) from 37 to 75 years of age (mean age was 56 years) with diagnosed cardiac hypertrophy in the course of 2nd and 3rd degree primary hypertension. All patients from this group underwent Cardio MR examination using MR 1.5 T Signa Excite (GE) system. Dedicated software was used for post-processing (MASS, Medis). We assessed left ventricular functional parameters such as: Ejection Fraction (EF), End-Diastolic Volume(EDV) and End Systolic Volume (ESV). We also assessed left ventricular diameters as well as left ventricular posterior wall (PWD) and interventricular septum (IVSD) thickness. We also calculated left ventricular mass (LVM) and left ventricular mass index (LVMI). In most cases (66.7%) patients had significant increase of LVM. On the base of LVMI hypertrophy of the left ventricle was found in 6.2% patients. We affirmed statistically significant changes of left ventricular's morphological and functional parameters. The significant correlation was found between posterior wall diameter (PWD) and LVM, as well as between interventricular septum (IVSD) and LVM. The significant correlation was found between posterior wall diameter (PWD) and left ventricular Ejection Fraction (EF) and End-Systolic Volume (ESV). Cardio MR is an effective method to detect left ventricular hypertrophy (LVH) in hypertensive patients. PMID- 23944094 TI - [A comparison between two investigator's difference of results of left ventricular parameters using echocardiography and cardio MR in hypertensive patients]. AB - The aim of the study is estimation of compatibility between morphological and functional results obtained from two independent evaluations used nowadays in cardiology procedures: echocardiography and Cardio MR. 48 patients were examined (24 fema les and 24 males) from 37 to 75 years of age (mean age was 56 years) with diagnosed cardiac hypertrophy in the course of 2nd and 3rd degree primary hypertension. All patients from this gro up underwent echocardiography exami nation obtained from two independent evaluations, using 2.5 M Hz transducer. Also all the patients underwent Cardio MR examination using MR 1.5 T Signa Excite (GE) system, obtained from two independent evaluations. Dedicated software was used for post-processing (MASS). The same left ventricular mor phological and functional parameters. were assessed in both procedures. Analysis of differences between results obtainedfromtwo independent doctors of the same parameter for each method separately was performed. It was assu med, that the method there were less differences between results obtained from two examiners foreach parameter, was more objective. Statistically significant differences in measurements between different examiners in echocardiography was demonstrated of the following left ven tricular parameters: LV end-diastolic diameter (LVDd), LV end-systolic dia meter (LVSd), end-diastolic long axis (LD), end-systolic long axis (LS), end diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF) and left ventricular mass (LVM). No statistically significant differences in measurements between both exami ners in Cardio MR for all measured LV parameters was demonstrated. Cardio MR examination is the procedure, where the result not depends on the operator. PMID- 23944095 TI - [Value of spiral CT in diagnosing metastatic lymph node in lower lip cancer]. AB - The aim of the research was to es timate the efficiency of the computed tomography (CT) in diagnosing meta stasis of submandibular and submen tal lymph nodes (level 1) in patients with diagnosed lower lip cancer. CT of neck lymph nodes was con ducted in 31 patients with diagnosed lower lip cancer. The total of 136 lymph nodes were identified, of which 16 were diagnosed as metastatic in histopathological examination. T investigated parameters were: shape, size (longitudinal and axial diameter and the surface of the cross-sections), presence of the fatty hilus, and level of enhancement after introvascular contrast agent administration. Correlation between the level of enhancement in the primary tumor and the enhancement in the metastatic lymph nodes was observed; density values before and after the admini stration of the contrast agent were in both cases at a similar level. It was also found that the best criterion in the diagnosis of metastatic lymph nodes is the minimal axial diameter: for this parameter, the highest accuracy (74%) was observed for the value of 6 mm. As for the surface of the cross-sections of the lymph node, it was found that the best criterion is the axial cross-section surface: the accuracy of 74% was ob tained for the surface of 38mm2. PMID- 23944096 TI - [Transcutaneal drainage intrahepatic biliary ducts as a method of paliative treatment of inoperative liver hilum tumours]. AB - The aim of the study is determine, that transhepatic,transcutaneal drainage of the bile ducts is the method of palliative treatment of inoperative liver hilum tumours. In the years 1998-2011, 211 patients with malignant obturation of the liver hilum were palliative treated by transcutanel, transhepatic drainage with US control. Patients with inoperative, malignant tumours of liver hilum in terminal state were included. More than 5 mm, minimal wideness of bile duct was the main term of qualification to procedure. The procedures were performed either with US puncture guide-line or with "free-hand" technique, using one or two steps Seldinger method drains. In cases of problem with US identification of the place of fixation of the drain, fluoroscopy examination was performed. Quality of life of the patients was increased. The icterus parameters were decreased, depends of the volume of drainage of the bile. Taking in account the improvement of overall patient status and relative prolongate of live, transcutaneal, transhepatic drainage of the bile ducts has a place as a method of palliative treatment of inoperative obturation of the liver hilum. PMID- 23944097 TI - [Ultrasound examination of median nerve in carpal tunnel syndrome]. AB - Carpal tunnel syndrome (CTS) is the most frequent compressive neuropathy, which give us characteristic features in ultrasound exam using high frequency probe. This article presents ultrasound features in patients with CTS and after surgical release of median nerve at the wrist level. PMID- 23944098 TI - [Proton spectroscopy of the lower leg muscles before and after exercise]. AB - The aim of this study was to at tempt to assess the suitability of proton spectroscopy (1HMRS) in deter mining the metabolic state of the lower leg muscles in healthy volunteers before and after intense exercise. 30 healthy volunteers participated in the study, performed on a 1.5T MR scanner using a point-resolved spectroscopy (PRESS) sequence. VOI (Volume of Interest) was localized in the tibialis anterior and soleus muscle lower leg. The data were processed using GE spectroscopy tools. We analyzed on all MR spectra the following metabo lits: intramyocellular lipids (IMCL), extramyocellular lipids (EMCL), carnitine (Ct), creatine (Cr), choline (Cho), trimethylamines (TMA), glucose (Glc), taurine (Tau) and lactate (Lac). We compared the resultant intensity ratios using t - test. Based on statistical analysis of results, there was no si gnificant difference between average value of relative (WSS) (p<0.05) before and after exercise for either the tibialis anterior muscle or soleus muscle. Only the division of the research group into subgroups showed statistical differences. For the tibialis anterior (TA) showed an increase in the TMA subgroup of male group, volunteers whom doing sport occasionally and non smoking. Ct decrease in subgroup volunteers whom exercise time was exactly 20 minutes. For soleus muscle (SOL) increase IMCL(CH2) in subgroup of volunteers whom exercise time was exactly 20 minuts and non smoking. In the subgroup of volunteers doing sports professionally Ct increase after exercise. 1HMRS allows noninvasive studies of muscle metabolism before and after exercises. PMID- 23944099 TI - [The influence of the time factor in diagnostic algorithm of knee joint trauma on diagnostic ability of the magnetic resonance imaging]. AB - In the clinical practice, diagnostics with magnetic resonance imaging (MRI) in patients with knee trauma is performed at different times after the injury. This is due to the limited availability of MRI. Related causes, but also clinical considerations, cause the performing of arthroscopy in a different time from the MRI examination. To assess whether the time that elapses between the injury and MRI has an impact on the magnetic resonance diagnostic ability and whether it is affected by the time interval between MRI and arthroscopy. The results of the MRI and arthroscopy were analyzed in the group of 128 patients, 56 (44%) women and 72 (56%) men aged 12.9-62.5 years (mean 30.6) after the knee trauma. Next, the group of patients was divided depends on whether MRI examination was performed in shorter or longer time then 6 weeks after the trauma, into two subgroups: 52 patients (21 women and 31 men) with recent injury and 76 patients (35 woman and 41 men) with inveterate injury. Moreover, the group of patients was divided into two subgroups: 60 patients (26 women and 34 men) with the time between MRI examination and arthroscopy no longer than 30 days and group of 68 patients (30 women and 38 men) with time of waiting for arthroscopy longer than 30 days. Damage to the structures of the knee observed in MRI were classified in terms of location and severity. We compared the diagnostic ability of MRI and arthroscopy in the presence and severity of posttraumatic lesions of the knee. The statistical significance of presence of the injury in MRI and arthroscopy was estimated by the X2 test. Statistical analysis of the structures of the knee joint which are most commonly damaged after the trauma, which means both menisci and the anterior cruciate ligament (ACL) - was performed in whole group and separately in each subgroup. The results were compared between corresponding subgroups, and also between each subgroup and whole group. The diagnostic efficacy indices were compared using the test for differences between two structure indicators. The estimation of statistically significant differences was performed at the level of p= 126 mg/dl) according to standard diagnostic criteria. Prevalence and incidence rates of diabetes were 2.97% and 7.53 per 1,000. Sensitivity, specificity, PPV, and NPV of the diabetes screening test were 80.23%, 61.67%, 2.2%, and 99.65%, respectively. The study revealed that the primary screening program in district health centers had an acceptable sensitivity (80.23%) and a low specificity (61.67%). PMID- 23944170 TI - Long-term care for older lesbian and bisexual women: an analysis of current research and policy. AB - The Canadian health care system's delivery and policies are often based on a heterosexual nuclear family model. Long-term care (LTC) policy in particular is built on specific assumptions about women and caregiving. Current health care and LTC policies can thus disadvantage and marginalize women who do not fit such constructions, such as older lesbian and bisexual women. Drawing from literature on lesbian, gay, bisexual, and transgender women's health, aging, and caregiving, this article uses a feminist political economy analysis to demonstrate that a gap exists in current research and policy with respect to the LTC needs of older lesbian and bisexual women. PMID- 23944171 TI - Cultural and social determinants of health among indigenous Mexican migrants in the United States. AB - Despite growing numbers, indigenous Mexican migrants are relatively invisible to health practitioners who group them with nonindigenous, mestizo Mexican-origin populations. Associations between indigenous and mestizo cultural identifications with psychosocial characteristics and health indicators among indigenous Mexican migrants were examined. Results revealed gender differences in cultural identifications, perceived discrimination, self-esteem, self-efficacy, and various health indicators including depression severity, culture-bound syndromes, and self-rated health. Multivariate regression and structural equation path modeling demonstrated how indigenous cultural identification and perceived discrimination affects health. Findings suggest that interventions should utilize indigenous community-based activities designed to promote self-esteem and the value of indigenous culture, with a focus on females. PMID- 23944172 TI - "We are talking about saving lives": the welfare state, health care policy, and nongovernability--a case study of an Israeli Hospital. AB - Literature about welfare states worldwide, and specifically in Israel, emphasizes economic and political variables and the importance of ideology in explaining a given social policy in those societies. According to this literature, ideology and strategic long-term goals account for the waning of the Israeli welfare state since the 1970s. At the same time, for upwards of a decade, the literature dealing with Israeli public policy has emphasized that Israeli society suffers from a crisis of "nongovernability" and a political culture that is characterized by illegality. The author defines nongovernability as the inability to formulate public policy and implement it effectively over time. In such an environment, long-term strategic considerations based on a coherent ideology take a back seat to short-term considerations in the conduct of the various players in the public policy arena. The author discusses the building of a hospital in Ashdod as a case study in nongovernability. The hospital's construction was steeped in political intrigue based wholly on short-term considerations and was built in a political culture characterized by either illegality or outright rejection of the law. This behavior is characteristic of Israeli politicians, bureaucrats, and interest groups. The author maintains that the creation of this hospital is emblematic of the Israeli health care policy overall, a policy shaped by bottom-up processes whose defining characteristic is a political culture based on illegality and narrow, short-term interests. PMID- 23944174 TI - An unprecedented octadecanuclear copper(II) pyrazolate-phosphonate nanocage: synthetic, structural, magnetic, and mechanistic study. AB - A novel octadecanuclear copper pyrazolate-phosphonate nanocage with a bowl-shaped arrangement of the copper(II) centers in the asymmetric unit is reported. Characterization of intermediates in both solid and solution states aids to propose the mechanism of such a giant aggregation. Magnetic studies affirm the presence of antiferromagnetic interactions between the adjacent copper(II) centers. Extensive supramolecular interactions result in a framework structure. PMID- 23944175 TI - Psychosocial rehabilitation and recovery: the role of physical activity. PMID- 23944176 TI - Service delivery for people with hereditary spastic paraparesis living in the South West of England. AB - PURPOSE: Hereditary Spastic Paraplegia (HSP) is an inherited nervous system disorder characterized by development of leg weakness, spasms and stiffness. While generally acknowledged that health and social care services can minimise symptoms and improve quality of life, there is a lack of research exploring this from the perspective of people affected by HSP. This qualitative study explored the users and providers experience of using rural services. METHOD: Focus groups and interviews were undertaken of people with HSP (n = 14), carers (n = 6) and professionals (n = 12), to describe their experience of service provision and to suggest improvements for care. These were taped, transcribed and analysed. RESULTS: Four themes emerged: (1) Diagnosis, symptoms and finding support; (2) Therapy, treatment and the delivery of care; (3) Managing the disease together; and (4) The way forward. CONCLUSIONS: Rehabilitation and support for self management is valued by those affected with HSP throughout the disease trajectory from diagnosis onwards. Key to this is the development of a partnership approach which includes carers. Single point, well-informed, gatekeepers may enhance the coordination and delivery of care in rural areas. These findings underline current guidance promoting a holistic approach for people with neurological conditions. PMID- 23944177 TI - Do community-based rehabilitation programmes promote the participation of persons with disabilities? A case control study from Mandya District, in India. AB - PURPOSE: In this paper, we measure the effectiveness of Community-Based Rehabilitation (CBR) programmes in promoting the well-being of people with disabilities and removing the barriers to their participation in family and community decision-making processes. METHOD: To evaluate the impact of the CBR programme, we use data from a large-scale control study in Karnataka, India. Propensity score matching is used to evaluate the impacts on disabled persons after 2, 4 and 7 years of entering the CBR. The theoretical framework for the analysis is based on the CBR guidelines, which are combined with the International Classification of Functionings (ICF), the United Nations Convention on the Rights of People with Disabilities (UN CRPD) and Amartya Sen's capability approach. RESULTS: CBR has a positive impact on the well-being of persons with disabilities participating in the programme and particularly on their participation within the family and the society at large. CONCLUSIONS: CBR programmes have a multidimensional and positive impact on individual and collective capabilities; on individual, agency and social empowerment. Implications for Rehabilitation Community-Based Rehabilitation (CBR) can make a lasting difference in the life of persons with disabilities. CBR improves participation and inclusion of persons with disabilities in the family and in the community. PMID- 23944178 TI - Bladder continence management in adult acquired brain injury. AB - PURPOSE: Persistence of urinary incontinence post acquired brain injury (ABI) carries important prognostic significance. We undertook to document the incidence of urinary incontinence, its management and complications in rehabilitation inpatients following ABI and to assess adherence to post ABI bladder management guidelines. METHOD: A retrospective chart survey of a convenience sample of consecutive admissions to two adult neurorehabilitation units Forster Green Hospital, Belfast, and the Scottish Brain Injury Rehabilitation Service, Edinburgh (SBIRSE). Bladder continence and management on transfer to and discharge from rehabilitation, trial removal of catheter, use of bladder drill, ultrasound investigation, anticholinergic medication and complications were recorded. RESULTS: One hundred and forty six patients were identified. Seventy seven (52.7%) were independent and continent of urine at rehabilitation admission and 109 (74.7%) on discharge. In all, 13 patients had urinary tract infection, 7 had urethral stricture and 1 developed haematuria whilst catheterised. Ultrasound of renal tracts was underused. Trial removal of catheter after transfer to rehabilitation occurred at a median of 10 days. CONCLUSIONS: Urinary continence was achieved in almost half of incontinent ABI patients during rehabilitation. There is potential for increased use of investigation of the renal tracts. Rehabilitation physicians should consider urethral stricture in the management of continence post ABI. PMID- 23944179 TI - Self-reported function and disability in late life - cross-cultural adaptation and validation of the Swedish version of the late-life function and disability instrument. AB - PURPOSE: To translate and perform a cross-cultural adaptation of the Late-Life Function and Disability Instrument (LLFDI) to Swedish, to investigate absolute and relative reliability, concurrent validity, and floor and ceiling effects within a Swedish-speaking sample of community-dwelling older adults with self reported balance deficits and fear of falling. METHOD: Translation, reliability and validation study of the LLFDI. Sixty-two community-dwelling, healthy older adults (54 women and 8 men) aged 68-88 years with balance deficits and fear of falling performed the LLFDI twice with an interval of 2 weeks. RESULTS: Test retest agreement, intra-class correlation coefficient was very good, 0.87-0.91 in the LLFDI function component and 0.82-0.91 in the LLFDI disability component. The standard error of measure was small, 5-9%, and the smallest real difference was 14-24%. Internal consistency (Cronbach's alpha) was high (0.90-0.96). Correlation with the SF-36 PCS and PF-10 was moderate in both LLFDI function, r = 0.39-0.68 and r = 0.35-0.52, and LLFDI disability, r = 0.40-0.63 and 0.34-0.57, respectively. There was no floor or ceiling effects. CONCLUSION: The Swedish version of the LLFDI is a highly reliable and valid instrument for assessing function and disability in community-dwelling older women with self-reported balance deficits and fear of falling. Implications for Rehabilitation The Swedish LLFDI is a highly reliable and valid instrument for assessing function and disability in older women with self-reported balance deficits and fear of falling. The instrument may be used both in clinical settings and in research. The instrument is sensitive to change and a reasonably small improvement is enough to detect changes in a group or a single individual. PMID- 23944180 TI - The relevance of the International Classification of Functioning, Disability and Health (ICF) in monitoring and evaluating Community-based Rehabilitation (CBR). AB - PURPOSE: To examine the relevance of the International Classification of Functioning, Disability and Health (ICF) to CBR monitoring and evaluation by investigating the relationship between the ICF and information in published CBR monitoring and evaluation reports. METHOD: A three-stage literature search and analysis method was employed. Studies were identified via online database searches for peer-reviewed journal articles, and hand-searching of CBR network resources, NGO websites and specific journals. From each study "information items" were extracted; extraction consistency among authors was established. Finally, the resulting information items were coded to ICF domains and categories, with consensus on coding being achieved. RESULTS: Thirty-six articles relating to monitoring and evaluating CBR were selected for analysis. Approximately one third of the 2495 information items identified in these articles (788 or 32%) related to concepts of functioning, disability and environment, and could be coded to the ICF. These information items were spread across the entire ICF classification with a concentration on Activities and Participation (49% of the 788 information items) and Environmental Factors (42%). CONCLUSIONS: The ICF is a relevant and potentially useful framework and classification, providing building blocks for the systematic recording of information pertaining to functioning and disability, for CBR monitoring and evaluation. Implications for Rehabilitation The application of the ICF, as one of the building blocks for CBR monitoring and evaluation, is a constructive step towards an evidence-base on the efficacy and outcomes of CBR programs. The ICF can be used to provide the infrastructure for functioning and disability information to inform service practitioners and enable national and international comparisons. PMID- 23944181 TI - The matrix effect of blueberry, oat meal and milk on polyphenols, antioxidant activity and potential bioavailability. AB - In recent years, ready-to eat breakfast cereals prepared with fruit ingredients have gained particular attention due to their polyphenolic contents and health promoting effects. In this study, the matrix effect of blueberry, oat meal, whole milk or skimmed milk on polyphenols, antioxidative potential as well as their potential bioavailability were investigated. The phenolic properties of whole milk, skimmed milk, blueberry and oat meal were investigated and the changes in combinations of the ingredients were determined. Milk addition decreased the total phenolic, flavonoid and anthocyanin content of samples statistically and had negative effect on antioxidant activity showing differences among different methods. According to HPLC results, it was not possible to detect catechin in mixtures due to milk addition. In vitro digestion method was used to determine potential bioavailability of phenolic compounds. According to in vitro digestion procedure results, whole or skimmed milk did not affect the total phenolic content of the proportion passing to the blood from intestine. PMID- 23944182 TI - Pituitary macroadenoma: a case report and review. AB - Pituitary adenomas are the most common tumours of the sellar region. They generally have a slow but severe impact on vision due to compression of the optic nerves, optic chiasm and cavernous sinus. This case report reviews the clinical presentation, management and treatment of the major classifications of pituitary adenoma. As Australian optometrists perform over 300,000 visual field assessments per year, it is vital they are aware of this important cause of visual field loss. PMID- 23944183 TI - Organizational fidelity to a medication management evidence-based practice in the treatment of schizophrenia. AB - Organizational support is essential for successful implementation of evidence based practice (EBP) in clinical settings. This 3-year study used a mixed qualitative and quantitative design to implement a medication management EBP in the treatment of schizophrenia in six community mental health clinics in a south central state of the United States. Findings from organizational fidelity assessments indicate that support for EBP implementation was moderate. Organizational support was highest for prescriber access to relevant patient information at each medication visit, scheduling flexibility for patients' urgent problems, and availability of medication guidelines. Organizational support was lowest for medication availability and identification of treatment refractory patients. Findings suggest that leadership is essential to support successful implementation. Nurse educators can incorporate implementation research and leadership training into graduate nursing programs to facilitate successful EBP implementation in practice settings. PMID- 23944184 TI - Editorial. AB - No abstract available for this article. PMID- 23944185 TI - Critical evaluation of standardized tests. AB - Occupational therapists are becoming increasingly aware of the importance of providing intervention that can be accurately measured and documented. Standardized evaluations not only provide a uniform administration and scoring procedure, but also allow for a comparison of an individual's performance to that of a normative sample. The effective and ethical use of standardized test scores requires that the examiner be proficient in test administration and understand the basic measurement and statistical concepts behind the interpretation process. This article addresses concepts relevant to the critical evaluation of a standardized test. PMID- 23944186 TI - A cost effective approach to functional assessment. AB - No abstract available for this article. PMID- 23944187 TI - Should choice be a component in occupational therapy assessments? AB - This paper addresses the issue of allowing clients the choice of activities to perform for evaluative purposes. Studies demonstrating that choice or control may improve performance in both occupational therapy and psychology literature are reviewed. It offers a description of the Assessment of Motor and Process Skills (Fisher, 1995) as an assessment that considers choice a critical component of the assessment process and describes a study that demonstrates client choice improves performance during the assessment process. PMID- 23944188 TI - The daily activities checklist:. AB - This paper introduces the Daily Activities Checklist (DAC), an assessment developed for use with individuals with severe mental illness living in the community. The DAC establishes a baseline of engagement in self-care and instrumental activities of daily living and involves the consumer in the data gathering process. Preliminary information related to the feasibility and reliability of the measure suggests individuals with severe mental illness can accurately complete the assessment. The DAC also discrimated between individuals with severe mental illness that were working and those that were not. PMID- 23944189 TI - Home environment considerations for people with Alzheimer's disease. AB - The purpose of this pilot study was to develop a home assessment specifically designed for people with Dementia of Alzheimer's type (DAT), and determine its effectiveness in designing appropriate environmental strategies. Since the home environment plays an integral role in monitoring ADL performance and behaviors of the AD population, an understanding of how environmental cues influence function and conduct is crucial when assessing and developing environmental intervention strategies. The new assessment, using a person-environment fit theoretical model, assisted the occupational therapist in evaluating the environment's legibility and stability to ensure a safe environment through specific physical, psychological, and social cues. PMID- 23944190 TI - Motivation for training:. AB - The purpose of this study was to explore and describe the motivation for training, in four persons with unilateral neglect, who participated in an intervention study aiming to improve sustained attention. Data about the participantsAE motivation was collected through observations and semi-structured interviews based on the terms used in the volitional subsystem in The Model of Human Occupation. Findings show that the four personsAE awareness of their own disabilities influenced their motivation toward training and that they sometimes overvalued their own capacities, especially concerning activities they had not practiced since before the stroke. This report concludes with a discussion on the implications of the study on occupational therapy practice. PMID- 23944192 TI - Efficient Diels-Alder addition of cyclopentadiene to lithium ion encapsulated [60]fullerene. AB - Much higher reactivity of [Li(+)@C60]PF6(-) for Diels-Alder cycloaddition toward cyclopentadiene (CpH), in comparison with that of empty C60, was observed. The synthetic method, electrochemical and light absorption properties, and X-ray crystal structure of the product [Li(+)@C60(CpH)]PF6(-) are discussed. PMID- 23944193 TI - Interictal interleukin-17A levels are elevated and correlate with seizure severity of epilepsy patients. AB - Interleukin 17A (IL-17A) is implicated in the pathogenesis of several neuroimmunologic diseases. We aimed to evaluate the relationship between IL-17A and seizure severity in patients with epilepsy. Seventy patients with probable symptomatic epilepsy and 68 healthy controls were included. Interictal serum IL 17A and related cytokine (IL-23, IL-6, IL-1beta, interferon gamma (IFN-gamma), and IL-10) levels were measured. The relationship between seizure severity and cytokine concentrations was assessed by Spearman correlation and multivariate linear regression test. IL-17A levels in the cerebrospinal fluid (CSF) were tested in 30 additional patients with epilepsy, either in the postictal or interictal period and 15 patients with idiopathic inflammatory demyelinating diseases (IIDDs). Interictal serum IL-17A levels were significantly elevated in patients with epilepsy compared to controls. IL-6, IFN-gamma, and IL-1beta levels were also markedly elevated. Spearman correlation analysis revealed positive correlation between IL-17A, IL-6 levels and Veterans Administration Seizures Frequency and Severity Rating Scale score(VA score); IFN-gamma, IL-10 levels, and National Hospital Seizure Severity Scale (NHS3) score. In addition, IL-17A levels correlated significantly with seizure frequency. Multivariate linear regression test showed that only IL-17A levels were independently positively correlated with VA scores (B = 0.288, p = 0.027). Postictal IL-17A levels in the CSF were significantly elevated compared to interictal patients and patients with IIDDs. Our results suggest that interictal IL-17A levels correlated highly with seizure severity. PMID- 23944195 TI - Phonetic complexity and stuttering in Arabic. AB - The current study investigated whether phonetic complexity affected stuttering rate in Jordanian Arabic speakers. Speakers were assigned to three age groups (6 11, 12-17 and 18+ years). An Arabic index of phonetic complexity (AIPC) was developed. Each word was given a score based on the number of complex phonetic properties out of a total of nine that it contained in the AIPC. The results showed that stuttering on function words for Jordanian Arabic did not correlate significantly with the AIPC score for any age group. The AIPC scores of content and function-content words correlated positively with stuttering rate for the 6 11 age group alone with the function-content words affecting fluency more severely than did the content words. The AIPC scores of stuttered function, content and stuttered function-content words were higher than those of fluent words. The non-stuttered words had lower AIPC scores than the stuttered corresponding classes. This showed that the higher the AIPC score on stuttered words, the greater the chance for these word categories to be stuttered. The AIPC factors that most affected fluency in Jordanian Arabic were place of articulation, manner of articulation, word length, word shape and consonant length. We conclude that Arabic is similar to other languages with regard to the loci of stuttering, their phonetic complexity and AIPC factors affecting stuttering most. The correlation between phonetic complexity and the order of the AIPC factors are different between Arabic and other languages. PMID- 23944194 TI - Effect of armodafinil on cognition in patients with HIV/AIDS and fatigue. AB - Fatigue and cognitive impairment are common in HIV+ adults and may occur independently or be causally linked. This study examined whether alleviation of fatigue with armodafinil in a placebo-controlled double-blind 4-week trial had an effect on cognitive function among those with and without mild neuropsychological impairment at baseline. Sixty-one patients completed a standard battery of neuropsychological tests at study entry and Week 4: A total of 33 were randomized to armodafinil and 28 to placebo. While there was a significant effect of active medication on fatigue, cognitive performance measured by a global change score did not differ between treatment groups, or in those on active treatment with or without mild neuropsychological impairment. PMID- 23944196 TI - Disparity surveillance of nonfatal motor vehicle crash injuries. AB - OBJECTIVE: The lack of race information for nonfatal motor vehicle crash injuries in the United States has limited the understanding of racial disparities in motor vehicle crashes (MVCs). In this article, we describe a pilot surveillance project in Nebraska that linked crash reports and driver's license records to investigate racial disparity among nonfatal MVC injuries. METHODS: The project linked 43,157 severely and nonseverely injured drivers from crash reports between 2006 and 2010 to the corresponding state driver's license database so that drivers' race information from each MVC could be retrieved. A log rate model was used to examine the likelihood of MVC injuries by drivers' race along the dimensions of age, sex, and place of residence. RESULTS: Black drivers had 31.6 and 87 percent more severe and nonsevere injuries, respectively, than white drivers. Rural residents were more likely than urban residents to have severe MVC injuries. Controlling for residence status, age, and sex did not alter the basic pattern that black drivers had higher rates of nonfatal MVC injuries. CONCLUSIONS: The linkage approach provides an effective way to obtain additional information for MVC injury disparity surveillance. To reduce racial disparities in severe and nonsevere MVC injuries, race-sex-, race-age-, and race-location-specific interventions should be considered based on their significant contributions to disparity. PMID- 23944197 TI - Gut microbiota: so much to explore! PMID- 23944198 TI - Characterization of dopant diffusion within semiconducting polymer and small molecule films using infrared-active vibrational modes and attenuated total reflectance infrared spectroscopy. AB - Understanding dopant diffusion within organic and polymeric semiconductors is of great importance toward the development of organic photovoltaic and electronic devices, many of which require layered structures with controlled doping profiles (e.g., p-n and p-i-n structures). The current paper demonstrates a new method to determine the diffusion and permeability coefficients for dopant diffusion within polymeric and small-molecule organic semiconductors using attenuated total reflectance infrared (ATR-IR) spectroscopy and taking advantage of the intense IR active vibrational bands created when dopants such as iodine accept charge from a semiconducting polymer to generate polaronic species. The diffusion and permeability coefficients for iodine within poly(3-hexylthiophene) (P3HT) are determined to be 2.5*10(-11)+/-1.2*10(-11) cm2/s and 2.4*10(-8)+/-1.2*10(-8) cm2/s.atm, respectively. The approach is applied to P3HT/PCBM (1:1 mass ratio) films, and the diffusion and permeability coefficients through these composite films are determined to be 7.8*10(-11)+/-2.8*10(-11) cm2/s and 4.8*10(-8)+/ 1.3*10(-8) cm2/s.atm, respectively. Finally, the approach is extended to determining iodine diffusion within the polycrystalline semiconductor tetraphenylporphyrin (TPP) in a bilayer film with P3HT, and the diffusion coefficient of iodine through TPP is determined to be 7.1*10(-14)+/-1.1*10(-14) cm2/s. Although the current paper determines diffusion and permeability for the dopant iodine, this approach should be applicable to a wide array of dopants and polymeric and small-molecule semiconductors of interest in photovoltaic and electronic applications. PMID- 23944199 TI - Why we must cluster and cross over. PMID- 23944200 TI - Is an age-of-blood transfusion trial in trauma patients in Australia and New Zealand feasible? PMID- 23944202 TI - A meta-analysis of complications and mortality of extracorporeal membrane oxygenation. AB - OBJECTIVE: To comprehensively assess published peer-reviewed studies related to extracorporeal membrane oxygenation (ECMO), focusing on outcomes and complications of ECMO in adult patients. DESIGN: Systematic review and meta analysis. DATA SOURCES: MEDLINE/PubMed was searched for articles on complications and mortality occurring during or after ECMO. DATA EXTRACTION: Included studies had more than 100 patients receiving ECMO and reported in detail fatal or nonfatal complications occurring during or after ECMO. Primary outcome was mortality at the longest follow-up available; secondary outcomes were fatal and non-fatal complications. DATA SYNTHESIS: Twelve studies were included (1763 patients), mostly reporting on venoarterial ECMO. Criteria for applying ECMO were variable, but usually comprised acute respiratory failure, cardiogenic shock or both. After a median follow-up of 30 days (1st-3rd quartile, 30-68 days), overall mortality was 54% (95% CI, 47%-61%), with 45% (95% CI, 42%-48%) of fatal events occurring during ECMO and 13% (95% CI, 11%-15%) after it. The most common complications associated with ECMO were: renal failure requiring continuous venovenous haemofiltration (occurring in 52%), bacterial pneumonia (33%), any bleeding (33%), oxygenator dysfunction requiring replacement (29%), sepsis (26%), haemolysis (18%), liver dysfunction (16%), leg ischaemia (10%), venous thrombosis (10%), central nervous system complications (8%), gastrointestinal bleeding (7%), aspiration pneumonia (5%), and disseminated intravascular coagulation (5%). CONCLUSIONS: Even with conditions usually associated with a high chance of death, almost 50% of patients receiving ECMO survive up to discharge. Complications are frequent and most often comprise renal failure, pneumonia or sepsis, and bleeding. PMID- 23944203 TI - A protocol for a multicentre randomised controlled trial of continuous beta lactam infusion compared with intermittent beta-lactam dosing in critically ill patients with severe sepsis: the BLING II study. AB - BACKGROUND AND RATIONALE: Beta-lactam antibiotics are largely administered by bolus dosing, despite displaying time-dependent pharmacokinetics and pharmacodynamics and there being a strong rationale for continuous administration. The randomised controlled trials conducted to date comparing the mode of betalactam administration have been inconclusive and limited by non equivalent dosing, unblinded administration and small sample sizes. OBJECTIVE: A multicentre, randomised controlled trial (the Beta-lactam Infusion Group [BLING] II study) is currently under way, comparing continuous infusion to standard bolus administration of beta-lactam antibiotics in critically ill patients, independent of dose. DESIGN, SETTINGS, PARTICIPANTS AND INTERVENTIONS: BLING II is a Phase IIB, double-blinded, randomised controlled trial recruiting 420 intensive care unit patients with severe sepsis to receive one of three beta-lactam study antibiotics (ticarcillin-clavulanate, piperacillin- tazobactam or meropenem) by either continuous infusion or intermittent bolus administration. MAIN OUTCOME MEASURES: The primary outcome is ICUfree days at Day 28. Secondary outcomes include 90-day survival, clinical cure 14 days after study antibiotic cessation, organ failure-free days at Day 14 and duration of bacteraemia. RESULTS AND CONCLUSIONS: The study started in July 2012 and will provide clinical evidence as to whether continuous infusion of beta-lactam antibiotics is superior to intermittent bolus administration in critically ill patients with severe sepsis. A Phase III study powered for a survival end point may be justified, based on the results of our study. PMID- 23944204 TI - Hyperoxia in the intensive care unit and outcome after out-of-hospital ventricular fibrillation cardiac arrest. AB - BACKGROUND: Laboratory and clinical studies have suggested that hyperoxia early after resuscitation from cardiac arrest may increase neurological injury and worsen outcome. Previous clinical studies have been small or have not included relevant prehospital data. We aimed to determine in a larger cohort of patients whether hyperoxia in the intensive care unit in patients admitted after out-of hospital cardiac arrest (OHCA) was associated with increased mortality rate after correction for prehospital variables. METHODS: Data from the Victorian Ambulance Cardiac Arrest Registry (VACAR) of patients transported to hospital after resuscitation from OHCA and an initial cardiac rhythm of ventricular fibrillation between January 2007 and December 2011 were linked to the Australian and New Zealand Intensive Care Society Adult Patient Database (ANZICS-APD). Patients were allocated into three groups (hypoxia [PaO2<60mmHg], normoxia [PaO2,60-299mmHg] or hyperoxia [PaO2>=300mmHg]) according to their most abnormal PaO2 level in the first 24 hours of ICU stay. The relationship between PaO2 and hospital mortality was investigated using multivariate logistic regression analysis to adjust for confounding prehospital and ICU factors. RESULTS: There were 957 patients identified on the VACAR database who met inclusion criteria. Of these, 584 (61%) were matched to the ANZICS-APD and had hospital mortality and oxygen data available. The unadjusted hospital mortality was 51% in the hypoxia patients, 41% in the normoxia patients and 47% in the hyperoxia patients (P=0.28). After adjustment for cardiopulmonary resuscitation by a bystander, patient age and cardiac arrest duration, hyperoxia in the ICU was not associated with increased hospital mortality (OR, 1.2; 95% CI, 0.51-2.82; P=0.83). CONCLUSIONS: Hyperoxia within the first 24 hours was not associated with increased hospital mortality in patients admitted to ICU following out-of-hospital ventricular fibrillation cardiac arrest. PMID- 23944201 TI - The Australasian Resuscitation in Sepsis Evaluation (ARISE) trial statistical analysis plan. AB - BACKGROUND: The Australasian Resuscitation in Sepsis Evaluation (ARISE) study is an international, multicentre, randomised, controlled trial designed to evaluate the effectiveness of early goal-directed therapy compared with standard care for patients presenting to the emergency department with severe sepsis. OBJECTIVE: In keeping with current practice, and considering aspects of trial design and reporting specific to non-pharmacological interventions, our plan outlines the principles and methods for analysing and reporting the trial results. The document is prepared before completion of recruitment into the ARISE study, without knowledge of the results of the interim analysis conducted by the data safety and monitoring committee and before completion of the two related international studies. METHODS: Our statistical analysis plan was designed by the ARISE chief investigators, and reviewed and approved by the ARISE steering committee. We reviewed the data collected by the research team as specified in the study protocol and detailed in the study case report form. We describe information related to baseline characteristics, characteristics of delivery of the trial interventions, details of resuscitation, other related therapies and other relevant data with appropriate comparisons between groups. We define the primary, secondary and tertiary outcomes for the study, with description of the planned statistical analyses. RESULTS: We have developed a statistical analysis plan with a trial profile, mock-up tables and figures. We describe a plan for presenting baseline characteristics, microbiological and antibiotic therapy, details of the interventions, processes of care and concomitant therapies and adverse events. We describe the primary, secondary and tertiary outcomes with identification of subgroups to be analysed. CONCLUSION: We have developed a statistical analysis plan for the ARISE study, available in the public domain, before the completion of recruitment into the study. This will minimise analytical bias and conforms to current best practice in conducting clinical trials. PMID- 23944205 TI - Development and validation of the critical care outcome prediction equation, version 4. AB - OBJECTIVE: To revise and validate the accuracy of the critical care outcome prediction equation (COPE) model, version 4. DESIGN, PARTICIPANTS AND SETTING: Observational cohort analysis of 214 616 adult consecutive intensive care unit admissions recorded from 23 ICUs over 12 years. Data derived from the Victorian Admitted Episode Database (VAED) were used to identify treatment-independent risk factors consistently associated with hospital mortality. A revised version of the COPE-4 model using a random intercept hierarchical logistic regression model was developed in a sample of 35 878 (16.7%) consecutive ICU separations. MAIN OUTCOME MEASURES: Accuracy was tested by comparing observed and predicted mortality in the remaining 178 741 (83.3%) records and in 23 institutional cohorts. Stability was assessed using the standardised mortality ratio, Hosmer-Lemeshow H10 statistic, calibration plot and Brier score. RESULTS: The COPE-4 model had satisfactory overall discrimination with an area under receiver operating characteristic curve of 0.82 for both datasets. The development and validation datasets demonstrated good overall calibration with H10 statistics of 13.38 (P = 0.10) and 14.84 (P = 0.06) and calibration plot slopes of 0.99 and 1.034, respectively. Discrimination was satisfactory in all 23 hospitals and one or more calibration criteria were achieved in 19 hospitals (83%). CONCLUSIONS: COPE-4 model prediction of hospital mortality for ICU admissions has satisfactory performance for use as a risk-adjustment tool in Victoria. Model refinement may further improve its performance. PMID- 23944206 TI - A randomised controlled trial of plasma filtration in severe paediatric sepsis. AB - OBJECTIVE: To determine whether plasma filtration improves 28-day survival in infants and children with severe sepsis. DESIGN: A multicentre randomised controlled trial. SETTING: Paediatric intensive care units in teaching hospitals. PATIENTS: Forty-eight infants and children with severe sepsis. INTERVENTIONS: Patients were randomly assigned to receive plasma filtration (n = 25) or standard therapy (n = 23) for the treatment of septic shock. The primary outcome measure was 28-day survival. Secondary outcome measures included the number of failed organ systems on Day 7, a requirement for extracorporeal membrane oxygenation (ECMO), and the modified Glasgow outcome score (MGOS) at 6 months (where 1 is normal and 6 is dead). RESULTS: The trial was stopped early due to poor recruitment. Patients in the plasma filtration group had higher initial disease severity as measured by serum lactate level, inotrope score and MGOS. Ten (40%) children died in the plasma filtration group and 4 (17%) died in the control group. With intention-to-treat analysis and adjustment for lactate level, ventilation index, inotrope score and MGOS at admission using logistic regression, the odds ratio for death with plasma filtration was 1.20 (95% CI, 0.23-6.20; P = 0.82). The median number of failing organ systems at 7 days was 2 (interquartile range [IQR], 1-4) in the plasma filtration group versus 2 (IQR, 1 3) in the control group. Two children in the plasma filtration group required ECMO for 2.5 and 123 hours, and one child in the control group required ECMO for 45 hours. The median MGOS at 6 months was 4 (IQR, 2-6) in the plasma filtration group and 2 (IQR, 1-4) in the control group. CONCLUSIONS: Our study did not recruit enough patients to test the hypothesis that addition of plasma filtration to our standard care protocol reduces 28-day mortality in children with severe sepsis. However, mortality in the treatment and control groups was not significantly different after adjustment for severity of illness at the time of randomisation. PMID- 23944207 TI - Comparison of the measurement properties of the AQoL and SF-6D in critical illness. AB - OBJECTIVE: Multiattribute utility (MAU) instruments are short instruments measuring quality of life, health utility scores and treatment cost effectiveness. Many studies have compared MAU instruments, but few have involved intensive care unit patients. Our aim was to compare the measurement properties of two MAUs, the assessment of quality of life (AQoL) and Medical Outcomes Study Short Form 6D (SF-6D), in a sample of patients with critical illness. METHODS: Prospective observational study conducted in an 18-bed mixed tertiary Australian ICU. Eligibility criteria were: admitted to the ICU > 48 hours, aged > 18 years, and not imminently at risk of death. Participants completed the AQoL and SF-6D on admission to the ICU as a "then-test" of pre-ICU status, and 6 months after ICU discharge. We assessed the reliability, validity, sensitivity and responsiveness of the instruments. RESULTS: Median age was 61 years (interquartile range [IQR], 49-73 years)], 60% were men, and the median Acute Physiology and Chronic Health Evaluation II score was 17 (IQR, 13-21). Cronbach's alpha was acceptable for the AQoL (alpha = 0.81) but not for the SF-6D (alpha = 0.65). The AQoL and SF-6D showed evidence of validity but, despite moderate agreement between their utilities, their scores were not interchangeable. This was likely due to the SF 6D's truncated scoring range. The AQoL was predictive of hospital readmission but the responsiveness and sensitivity of the instruments varied by clinical condition. CONCLUSIONS: The AQoL and SF-6D demonstrated acceptable measurement properties in the ICU population, but the findings raised questions about the reliability and predictive power of the SF-6D. Further research is required to determine the most appropriate instrument for use in measuring health utility in the ICU population. PMID- 23944208 TI - Patient comfort in the intensive care unit: a multicentre, binational point prevalence study of analgesia, sedation and delirium management. AB - OBJECTIVE: To measure the prevalence of assessment and management practices for analgesia, sedation and delirium in patients in Australian and New Zealand intensive care units. MATERIALS AND METHODS: We developed survey items from a modified Delphi panel and included them in a binational, point prevalence study. We used a standard case report form to capture retrospective patient data on management of analgesia, sedation and delirium at the end of a 4-hour period on the study day. Other data were collected during independent assessment of patient status and medication requirements. RESULTS: Data were collected on 569 patients in 41 ICUs. Pain assessment was documented in the 4 hours before study observation in 46% of patients. Of 319 assessable patients, 16% had moderate pain and 6% had severe pain. Routine sedation assessment using a scale was recorded in 63% of intubated and ventilated patients. When assessed, 38% were alert and calm, or drowsy and rousable, 22% were lightly to moderately sedated, 31% were deeply sedated (66% of these had a documented indication), and 9% were agitated or restless. Sedatives were titrated to a target level in 42% of patients. Routine assessment of delirium occurred in 3%, and at study assessment 9% had delirium. Wrist or arm restraints were used for 7% of patients. CONCLUSIONS: Only two thirds of sedated patients had their sedation levels formally assessed, half had pain assessed and very few had formal assessment of delirium. Our description of current practices, and other observational data, may help in planning further research in this area. PMID- 23944209 TI - Effects of non-invasive ventilation on reintubation rate: a systematic review and meta-analysis of randomised studies of patients undergoing cardiothoracic surgery. AB - OBJECTIVE: To estimate the effect of non-invasive mechanical ventilation (NIV) on the rate of reintubation among patients undergoing cardiothoracic surgery. DESIGN: A meta-analysis of randomised trials. DATA SOURCES: Medline, Embase, and the Cochrane Central Register of clinical trials were searched (April 2012) for pertinent studies by two trained investigators. International experts were contacted. DATA EXTRACTION: Articles were assessed by two trained investigators, with divergences resolved by consensus. Inclusion criterion was random allocation to NIV versus standard treatment without restrictions on duration or modalities of the treatment delivered. DATA SYNTHESIS: Fourteen studies enrolling 1211 patients were included in the meta-analysis. NIV reduced the reintubation rate (risk ratio [RR], 0.29; 95% CI, 0.16-0.53; P for efficacy < 0.0001; I2 = 0), hospital length of stay and mortality. Subgroup analyses suggested that the benefits of NIV are more important in patients with ongoing acute respiratory failure (RR, 0.25; 95% CI, 0.07-0.89) and in those at high risk of developing postoperative pulmonary complications (RR, 0.19; 95% CI, 0.04-0.84). Analyses including prophylactic studies in patients at low risk did not show a significant effect of NIV on reintubation rate (RR = 0.42; 95% CI, 0.12-1.48) and on any of the outcomes considered except for oxygenation. CONCLUSIONS: NIV seems to be effective in reducing reintubation rate after cardiothoracic surgery. The results of this meta-analysis should be confirmed by large randomised controlled studies. PMID- 23944210 TI - Temperature management of non-elective intensive care patients without neurological abnormalities: a point prevalence study of practice in Australia and New Zealand. AB - OBJECTIVE: To determine the frequency of pharmacological and physical cooling in non-elective general intensive care unit patients without neurological abnormalities in Australia and New Zealand, and to establish the indications for antipyretics, the prevalence of fever, and the methods of temperature measurement. DESIGN, SETTING AND PARTICIPANTS: A point prevalence study conducted on two days in 2010, in 38 ICUs in Australia and New Zealand, examining non elective (emergency) patients admitted with sepsis and other inflammatory abnormalities but without neurological abnormalities. RESULTS: Of 506 general ICU patients surveyed on the study days, 311 had sepsis or other inflammatory abnormalities and no neurological abnormalities. These patients had a mean peak temperature of 37.3 degrees C (SD, 0.8 degrees C). In 100 patients (32.2%), the peak temperature was above 38 degrees C. Paracetamol was the most common antipyretic used (152/311; 48.9%) and was administered for pain in 92/152 patients (60.5%), for pain and fever in 26/152 patients (17.1%), and for fever alone in 14/152 patients (9.2%). Patients who received paracetamol for fever had a mean peak recorded temperature of 38.3 degrees C (SD, 0.8 degrees C). Temperature measurements were mainly non-core (251/ 311; 81%) with axillary (116/311; 37%) and tympanic (110/ 311; 35%) measurements the most common. CONCLUSION: Pharmacological antipyretics are used regularly for pain management rather than fever management, with paracetamol the most common antipyretic therapy. The use of NSAIDS and physical cooling is rare. Non-core temperature measurements were common. PMID- 23944212 TI - A comparison of survival following out-of-hospital cardiac arrest in Sydney, Australia, between 2004-2005 and 2009-2010. AB - OBJECTIVE: To determine whether survival following out-of- hospital cardiac arrest (OHCA) in Sydney, Australia, improved between 2004-2005 and 2009-2010, and whether there was a change in incidence of OHCA. DESIGN: Retrospective study using the Ambulance Service of New South Wales and NSW Registry of Births, Deaths and Marriages databases. PARTICIPANTS AND SETTING: All patients who had an OHCA in the Sydney metropolitan area and who used the Ambulance Service of NSW between June 2009 and May 2010 (2009-2010), and between June 2004 and May 2005 (2004 2005). MAIN OUTCOME MEASURES: Survival to 90 days. Other outcome measures included the incidence of OHCA and survival to the day following OHCA, 28 days and 1 year following OHCA. Survival and incidence were also calculated according to initial electrocardiograph rhythm. RESULTS: Survival to 90 days was 12.3% in 2004-2005 and 10.2% in 2009-2010 (P = 0.015). In 2004-2005, the age standardised incidence of OHCA was 52.6 events per 100 000 person-years (95% CI, 51.6-53.6 events per 100 000 person-years), and in 2009-2010 it was 48.4 events per 100 000 person-years (95% CI, 46.3-50.4 events per 100 000 person-years). In 2004-2005, the incidence of ventricular fibrillation (VF) was 31.3% (95% CI, 28.4%- 33.9%) and in 2009-2010 it was 22.1% (95% CI, 20.0%- 24.3%). CONCLUSION: There was no improvement in survival following OHCA in Sydney between 2004-2005 and 2009- 2010. There has been a decrease in overall survival from OHCA and a decrease in the overall age-standardised incidence of OHCA. The decrease in overall survival may be due to a decline in the incidence of VF. PMID- 23944211 TI - Monitoring Organ Donors to Improve Transplantation Results (MOnIToR) trial methodology. AB - BACKGROUND: Despite efforts to increase organ donation, there remain critical shortages in organ donors and organs procured per donor. Our trial is a large scale, multicentre, randomised controlled trial in brain-dead donors, to compare protocolised care (using minimally invasive haemodynamic monitoring) with usual care. We describe the study design and discuss unique aspects of doing research in this population. METHODS: Our study will randomise brain-dead patients to protocolised or usual care. The primary end point is the number of organs transplanted per donor. Secondary end points include number of transplantable organs per donor, recipient 6-month hospital-free survival time, and the relationship between the level of interleukin-6 and the number and usability of organs transplanted. The primary analysis will be an intention-to-treat analysis; secondary analyses include modified intention-to-treat and as-treated analyses. The study will also compare the ratio of observed to expected number of organs transplanted per donor, by treatment arm, as a secondary end point. Preplanned subgroup analyses include restriction to extended criteria donors, and donors older or younger than 65 years. RESULTS AND CONCLUSIONS: Several unique challenges for study design and execution can be seen in our trial, and it should generate results that will inform and influence the fields of organ donation and transplantation. PMID- 23944213 TI - Left ventricular puncture after intercostal catheter insertion. PMID- 23944214 TI - From gestures to gaming: visible embodiment of remote actions. AB - Teleoperation is the act of controlling an object that exists in a space, real or virtual, physically disconnected from the user. During such situations, it is not uncommon to observe those controlling the remote object exhibiting movement consistent with the behaviour of the remote object. Though this behaviour has no obvious impact on one's control of the remote object, it appears tied to one's intentions, thus, possibly representing an embodied representation of ongoing cognitive processes. In the present investigation, we applied a natural behaviour approach to test this notion, (a) first by identifying the representational basis for the behaviour and (b) by identifying factors that influence the occurrence of the behaviour. Each study involved observing participant behaviour while they played a racing video game. Results revealed that the spontaneous behaviour demonstrated in a teleoperation setting is tied to one's remote actions, rather than local actions or some combination of remote and local actions (Experiment 1). In addition, increasing task demand led to an increase in the occurrence of the spontaneous behaviour (Experiment 2). A third experiment was conducted to rule out the possible confound of greater immersion that tends to accompany greater demand (Experiment 3). The implications of these results not only suggest that spontaneous behaviour observed during teleoperation reflects a form of visible embodiment, sensitive to task demand, but also further emphasizes the utility of natural behaviour approaches for furthering our understanding of the relationship between the body and cognitive processes. PMID- 23944215 TI - An anthropometric comparison of current ATDs with the U.S. adult population. AB - OBJECTIVE: The anthropomorphic test devices (ATDs, or crash dummies) used in the assessment of vehicle crash protection were created based on particular anthropometric targets. The Hybrid-III ATDs widely used in the U.S. are commonly called the "5(th)-percentile female", "50(th)-percentile male", and "95(th) percentile male" ATDs, referring to selection of the respective percentiles of the male and female U.S. adult populations as design targets for the ATDs. The objective of this work was to assess whether secular trends in U.S. anthropometry have affected the relationship between the ATDs and the population. METHOD: The corresponding percentiles were calculated from data obtained in the National Health and Nutrition Examination Survey (NHANES) for the years 2005-2008. RESULTS: The results showed that the ATD stature targets differ from the current population by less than 5 percentile points, but the discrepancies for mass are much larger for the two male ATDs. CONCLUSIONS: The reference mass for the midsize-male Hybrid-III ATD of 78.2 kg is now the 33(rd) percentile body mass for U.S. adults, and the large-male ATD reference body mass of 102.5 kg is now the 81(st) percentile. The implications of these differences are discussed in the context of restraint system design. PMID- 23944216 TI - The effect of surface charge of glycerol monooleate-based nanoparticles on the round window membrane permeability and cochlear distribution. AB - The aim of this study is to elucidate the impact of surface charge of glycerol monooleate-based nanoparticles (NPs) on the cellular uptake and its distribution in the cochlea. These NPs are modified using varied concentration of anionic or cationic lipid. Upon dilution, these lipid mixtures self-assemble to form a series of cubic NPs with various surface charges, but with similar particle size. Positively charged NPs exhibited dose-dependent cytotoxicities against L929 cells proportional to the concentration of cationic lipid; whereas negatively charged NPs did not show obvious cytotoxic properties as compared to unmodified NPs. Meanwhile, confocal microscopy and flow cytometry results suggested that NPs with high positive surface charge were taken up more efficiently by L929 cells. The permeability of round window membrane (RWM) was high for highly positively charged NPs, which is likely due to their highly cellular uptake efficiency and consequently high concentration gradient between RWM and cochlear fluid. More importantly, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) modified NPs greatly facilitated broadly distribution in cochlea, favoring the treatment of hearing loss of low frequencies. Taken together, these findings about charge dependent of NPs on RWM permeability and cochlear distribution could serve as guideline in the rational design of NP for drug and gene delivery to inner ear. PMID- 23944217 TI - Predictors of organizational commitment among occupational therapists. AB - Organizational commitment may have an important influence on work related outcomes (attrition, absenteeism, burnout, tardiness, and job performance) particularly during times of health care organizational turmoil and change. This study used a correlational research design with multiple regression analysis to determine the predictive power of extrinsic and intrinsic rewards as determinants of organizational commitment among occupational therapists (OTRs) working full time in ambulatory care and hospital settings. Task involvement was a significant predictor of OTRs' commitment in both ambulatory care and hospital settings. General working conditions and task autonomy were significant determinants of commitment among OTRs working in ambulatory care settings. Salary and supervision were significant predictors of commitment among hospital OTRs. Given the demand for OTRs in ambulatory care and hospital settings, a better understanding of significant determinants that influence organizational commitment among OTRs could prove beneficial in developing recruitment and retention job design strategies. PMID- 23944218 TI - Deriving directions through procedural task analysis. AB - Task analysis is one of the essential components of activity analysis. Procedural task analysis involves breaking down an activity into a sequence of steps. Directions are the sequence of steps resulting from the task analysis (i.e., the product of the task analysis). Directions become a guide for caregivers or trainers use in teaching clients a specific skill. However, occupational therapy students often have difficulty in writing directions that are clear enough for caregivers or trainers to carry out. Books on activity analysis only provide examples of directions without giving guidelines on how to perform the writing process. The purposes of this paper are to describe the process of procedural task analysis and to provide a guideline for writing steps of directions. PMID- 23944219 TI - The therapeutic value of the human-animal connection. AB - The purpose of this study was to explore the characteristics of pet therapy which promote positive experiences and health in the elderly. Data were obtained through observations of pet therapy sessions, through interviews with a pet therapy provider, and residents of a long-term care facility who participated in pet therapy, and from the reflections of my (first author) own experiences as a pet therapy volunteer. The results revealed four characteristics which contributed to the benefits received by participants: (a) humanness; (b) anticipation and continuity; (c) ability to facilitate reminiscence; and (d) social aspects. The findings supported previous research by providing evidence of the value of pet visitation. In addition, ways in which these four qualities may enhance the physical, cognitive and social-emotional benefits received by nursing home residents participating in pet therapy and other activities is discussed. PMID- 23944220 TI - Interdisciplinary team teaching of database management. AB - Advanced skills are needed by occupational therapy practitioners to integrate database management into various practice models and settings and to collaborate with professionals in health information to develop complex database systems. To meet this need, a demonstration project on interdisciplinary team teaching of database management was created by occupational therapy and health information faculty. The purposes of this article are to (1) explain how Davis' (1995) criteria for successful interdisciplinary team teaching were applied to teach graduate students database management, and (2) present information to assist occupational therapy clinicians in using database management in their practices. The planning, implementation, and evaluation of the team teaching project are described and a five phase approach to database management presented. Database applications in clinical settings in occupational therapy are described. The demonstration project successfully meets its objectives and the authors believe it can be adapted to assist occupational therapy educators and clinicians in the use of databases. PMID- 23944221 TI - Successful outcomes in stroke following forced use: what are the contributing factors? AB - Forced use is an experimental treatment designed to overcome nonuse of a hemiparetic upper extremity. It has demonstrated significant and long-lasting effects in regaining functional use of the affected arm with select chronic hemiparetic subjects. Occupational therapists, who frequently treat post-acute hemiparetic patients, may benefit from knowing this technique. Since a search of the OT literature uncovered no information on forced use, studies outside the standard OT resources were used. In particular, this review analyzes forced use in an attempt to determine the factors that contribute to its success. Although many factors such as subject criteria, psychological and motor learning factors, time, and use appeared likely to affect the success of forced use, they could not be confirmed through the existing experiments. Future controlled research on the clinical relevance of forced use is suggested. PMID- 23944222 TI - Antibacterial and mechanical properties of propolis added to glass ionomer cement. AB - OBJECTIVE: To investigate whether adding ethanolic extracts of propolis (EEP) might influence the antibacterial and mechanical (shear-peel band strength [SPBS]) properties of conventional glass ionomer cement (GIC) used in orthodontic band cementation. MATERIALS AND METHODS: The cement was divided into four groups: one using the original composition and three with 10%, 25%, and 50% EEP added to the liquid and then manipulated. An antimicrobial assay, broth-dilution method was used to determine the antibacterial capacity of the GIC containing EEP. Eighty teeth were used for the mechanical assay, and an Instron testing machine was used to evaluate the SPBS. Kolmogorov-Smirnov and Kruskal-Wallis tests were used for statistical analyses. RESULTS: GIC with the addition of 25% and 50% EEP activated inhibition of Streptococcus mutans (ATCC 25175) growth, but this effect did not occur in the group to which 10% EEP was added or in the control GIC group. There was no significant difference between the groups in terms of SPBS (P > .05). CONCLUSIONS: The addition of EEP may increase antibacterial properties without negatively modifying the mechanical properties of conventional GIC. PMID- 23944224 TI - Factors affecting orthodontists' management of the retention phase. AB - OBJECTIVE: To test the null hypothesis that orthodontist characteristics and factors related to retainer choice do not influence the management of the retention phase with regard to frequency and duration of follow-up care provided. MATERIALS AND METHODS: Orthodontists (n = 1000) were randomly selected to participate in an online survey divided into three categories: background, retainer choice, and time management. RESULTS: Of the 1000 selected participants, 894 responded. When deciding the type of retainer to use, the following were considered most frequently: pretreatment malocclusion (91%), patient compliance (87%), patient oral hygiene (84%), and patients' desires (81%). Orthodontists who considered the presence of third molars (P = .03) or "special needs" patients (P = .02) had significantly more follow-up visits than those who did not. When vacuum-formed retainers (VFRs) were prescribed, there were significantly fewer visits (P = .02) compared to when other types of retainers were used. As practitioner experience increased, so did the number of visits (P < .0001). Orthodontists who considered the primary responsibility of retention to fall on the patient had significantly fewer follow-up visits (P < .0001) than those who considered it either a joint or orthodontist-only responsibility. CONCLUSIONS: The null hypothesis was rejected because the number of follow-up visits during the retention phase was affected by practitioner experience, whether VFRs were used, whether the orthodontist considered the presence of third molars or special needs patients when choosing the type of retainer, and to whom the orthodontist attributed responsibility during the retention phase. PMID- 23944223 TI - Effect of post-orthognathic surgery condylar axis changes on condylar morphology as determined by 3-dimensional surface reconstruction. AB - OBJECTIVE: To evaluate the effect of postoperative condylar axis changes on mandibular condylar remodeling by comparing the condylar head in three dimensional (3D) surface reconstructions before and after surgery in skeletal Class III deformities (one-jaw [mandibular setback] or two-jaw surgery), and also to determine the relationship between condylar inward rotation and condylar surface remodeling after orthognathic surgery. MATERIALS AND METHODS: A retrospective analysis was conducted of 30 patients with skeletal Class III deformities who had received orthognathic surgery. Group 1 underwent one-jaw surgery (10 men, five women, age 22.4 +/- 3.3 years), and group 2 underwent two jaw surgery (10 men, five women, age 22.3 +/- 2.2 years). Sixty condyles were reconstructed and superimposed pre- and postoperatively to compare the changes of condylar surfaces. The relation between the condylar axis change and the surface change using the Pearson correlation were investigated from the 3D image software. RESULTS: Condylar surface changes before and after the surgery were significant. The postoperative inward rotation of the condyles was correlated with the average absolute deviation of the condyles, regardless of the surgery type (one- or 2-jaw surgery; r = .70, P < .05). CONCLUSION: After orthognathic surgery, condylar surface changes occurred, and condylar inward rotation was closely related to changes of condylar surface. PMID- 23944225 TI - The role of dietary patterns' assessment in the predictive ability of cardiovascular disease risk estimation models: a review. AB - Risk prediction scores have received much attention the past few years, especially in the primary prevention of cardiovascular disease (CVD). Although diet has been independently associated with CVD risk, its role in the accuracy of the developed scores has rarely been studied. Thus, in this review, the role of diet assessment on the performance of CVD risk scores and models was critically discussed. A computer-assisted literature search retrieved 15 relevant studies, but only two out of them evaluated the role of diet on the accuracy of the developed models; the inclusion of diet assessment improved significantly the accuracy of CVD risk models. The remaining studies suggested an independent, protective effect of healthy dietary habits on CVD risk, with an attributable risk varying from 9 to 37%. Inclusion of diet component in CVD risks scores, may increase the accuracy of the models, and better identify people at high risk. PMID- 23944226 TI - Dissecting hydrophobic hydration and association. AB - We use appropriately defined short-ranged reference models of liquid water to clarify the different roles local hydrogen bonding, van der Waals attractions, and long-ranged electrostatic interactions play in the solvation and association of apolar solutes in water. While local hydrogen bonding interactions dominate hydrophobic effects involving small solutes, longer-ranged electrostatic and dispersion interactions are found to be increasingly important in the description of interfacial structure around large solutes. The hydrogen bond network sets the solute length scale at which a crossover in solvation behavior between these small and large length scale regimes is observed. Unbalanced long-ranged forces acting on interfacial water molecules are also important in hydrophobic association, illustrated here by analysis of the association of model methane and buckminsterfullerene solutes. PMID- 23944227 TI - Stereoselective synthesis of dienyl phosphonates via extended tethered ring closing metathesis. AB - Allylphosphonates of allylic alcohols were converted to conjugated dienyl phosphonates in a one-flask reaction, comprising a ring-closing metathesis (RCM), a base-induced ring-opening, and an alkylation. The ring-opening proceeds with very high diastereoselectivity, giving exclusively the (1Z,3E)-configured dienes. Single diastereomers and mixtures of diastereomers can be used as starting materials without noticeable effect on the diastereoselectivity of the sequence. PMID- 23944228 TI - Hydrodynamic force depends not only on the viscosity of solution but also on the molecular weights of viscogens. AB - Many cellular processes, such as the diffusion of biomacromolecules, the movement of molecular motors, and the conformational dynamics of proteins, are subjected to hydrodynamic forces because of the high viscosities of cellular environments. However, it is still unknown how hydrodynamic forces are related to the physical properties of different viscogens. Here, using the atomic force microscope-based force spectroscopy technique, we directly measured the hydrodynamic forces acting on a moving cantilever in various viscogen solutions. We found that the hydrodynamic force is not only dependent on the viscosity but also related to the molecular weight of viscogens. Counterintuitively, at the same macroscopic viscosity, the hydrodynamic force rises with the increasing molecular weight of viscogens, although the local microscopic viscosity of the solution decreases. This finding provides insights into the origin of hydrodynamic forces in biomolecule solutions and could inspire many force-spectroscopy-based techniques to measure the molecular weight and conformational changes of biomacromolecules in biological settings directly. PMID- 23944229 TI - Enumeration of virtual libraries of combinatorial modular macrocyclic (bracelet, necklace) architectures and their linear counterparts. AB - A wide variety of cyclic molecular architectures are built of modular subunits and can be formed combinatorially. The mathematics for enumeration of such objects is well-developed yet lacks key features of importance in chemistry, such as specifying (i) the structures of individual members among a set of isomers, (ii) the distribution (i.e., relative amounts) of products, and (iii) the effect of nonequal ratios of reacting monomers on the product distribution. Here, a software program (Cyclaplex) has been developed to determine the number, identity (including isomers), and relative amounts of linear and cyclic architectures from a given number and ratio of reacting monomers. The program includes both mathematical formulas and generative algorithms for enumeration; the latter go beyond the former to provide desired molecular-relevant information and data mining features. The program is equipped to enumerate four types of architectures: (i) linear architectures with directionality (macroscopic equivalent = electrical extension cords), (ii) linear architectures without directionality (batons), (iii) cyclic architectures with directionality (necklaces), and (iv) cyclic architectures without directionality (bracelets). The program can be applied to cyclic peptides, cycloveratrylenes, cyclens, calixarenes, cyclodextrins, crown ethers, cucurbiturils, annulenes, expanded meso substituted porphyrin(ogen)s, and diverse supramolecular (e.g., protein) assemblies. The size of accessible architectures encompasses up to 12 modular subunits derived from 12 reacting monomers or larger architectures (e.g. 13-17 subunits) from fewer types of monomers (e.g. 2-4). A particular application concerns understanding the possible heterogeneity of (natural or biohybrid) photosynthetic light-harvesting oligomers (cyclic, linear) formed from distinct peptide subunits. PMID- 23944230 TI - Novel reversible Zn2+-assisted biological phosphate "turn-on" probing through stable aryl-hydrazone salicylaldimine conjugation that attenuates ligand hydrolysis. AB - A novel reversible zinc(II) chemosensing ensemble (2.Zn(2+)) allows for selective "turn-on" fluorescence sensing of ATP and PPi in aqueous media (detection limits: 2.4 and 1.0 MUM, respectively) giving selective binding patterns: ATP ~ PPi > ADP ? AMP > monophosphates ~ remaining ions tested. The conjugated hydrazone [C?N-NH R] resists hydrolysis considerably, compared to the imine [C?N-CH2-R, pyridin-2 ylmethanamine] functionality, and generalizes to other chemosensing efforts. Prerequisite Zn(2+).[O(phenol)N(imine)N(pyr)] binding is selective, as determined by UV-vis and NMR spectroscopy; ATP or PPi extracts Zn(2+) to regenerate the ligand-fluorophore conjugate (PPi: turn-on, 512 nm; detection limit, 1.0 MUM). Crystallography, 2-D NMR spectroscopy, and DFT determinations (B3LYP/631g*) support the nature of compound 2. 2-Hydrazinyl-pyridine-salicylaldehyde conjugation is unknown, as such; a paucity of chemosensing-Zn(2+) binding reports underscores the novelty of this modifiable dual cation/anion detection platform. A combined theoretical and experimental approach reported here allows us to determine both the potential uniqueness as well as drawbacks of this novel conjugation. PMID- 23944231 TI - Problem-based learning (PBL) and speech-language pathology: a tutorial. AB - The aim of this tutorial is to provide an introduction to problem-based learning (PBL), particularly as applied to speech-language pathology (SLP) programs. The tutorial is aimed at the reader who is less familiar with this learning approach. Additionally, it serves as a framework for the articles that follow in this special issue on PBL programs in SLP and other clinical education programs. A brief history of PBL is provided and the rationale and context for this approach are identified. PBL is defined and differentiated from related educational approaches. Different models and variations of PBL are outlined. The key components of PBL are further illustrated using the tutorial cycle. Finally, we present one specific case of a PBL-based SLP program in detail. This tutorial will provide a deeper understanding of PBL for many higher educators in SLP. The strengths of this approach are outlined and the challenges are identified, particularly for those contemplating converting an existing "traditional" course or curriculum. PMID- 23944232 TI - Short- and long-term relationships between neurocognitive performance and general function in bipolar disorder. AB - Bipolar disorder (BD) is associated with significant impairment in multiple domains of function that often persists after clinical recovery. Current literature suggests that neurocognitive function may contribute to functional impairment in adult populations (18-60 years). However, literature in this area is heterogeneous, and no consistent correlations have been found between neurocognitive domains and general function. This review examines literature on the cross-sectional and longitudinal relationships between neurocognitive function and general function restricted to BD aiming to clarify the symptomatic and prognostic relationships between the two important clinical domains. PMID- 23944234 TI - Source localization of rhythmic ictal EEG activity: a study of diagnostic accuracy following STARD criteria. AB - PURPOSE: Although precise identification of the seizure-onset zone is an essential element of presurgical evaluation, source localization of ictal electroencephalography (EEG) signals has received little attention. The aim of our study was to estimate the accuracy of source localization of rhythmic ictal EEG activity using a distributed source model. METHODS: Source localization of rhythmic ictal scalp EEG activity was performed in 42 consecutive cases fulfilling inclusion criteria. The study was designed according to recommendations for studies on diagnostic accuracy (STARD). The initial ictal EEG signals were selected using a standardized method, based on frequency analysis and voltage distribution of the ictal activity. A distributed source model-local autoregressive average (LAURA)-was used for the source localization. Sensitivity, specificity, and measurement of agreement (kappa) were determined based on the reference standard-the consensus conclusion of the multidisciplinary epilepsy surgery team. Predictive values were calculated from the surgical outcome of the operated patients. To estimate the clinical value of the ictal source analysis, we compared the likelihood ratios of concordant and discordant results. Source localization was performed blinded to the clinical data, and before the surgical decision. KEY FINDINGS: Reference standard was available for 33 patients. The ictal source localization had a sensitivity of 70% and a specificity of 76%. The mean measurement of agreement (kappa) was 0.61, corresponding to substantial agreement (95% confidence interval (CI) 0.38-0.84). Twenty patients underwent resective surgery. The positive predictive value (PPV) for seizure freedom was 92% and the negative predictive value (NPV) was 43%. The likelihood ratio was nine times higher for the concordant results, as compared with the discordant ones. SIGNIFICANCE: Source localization of rhythmic ictal activity using a distributed source model (LAURA) for the ictal EEG signals selected with a standardized method is feasible in clinical practice and has a good diagnostic accuracy. Our findings encourage clinical neurophysiologists assessing ictal EEGs to include this method in their armamentarium. PMID- 23944233 TI - Impact of lipid-lowering therapy on the prevalence of dyslipidaemia in patients at high-risk of cardiovascular events in UK primary care - a retrospective database study. AB - AIMS: To estimate the prevalence of dyslipidaemias in high-risk patients new to lipid-modifying therapy (LMT), and establish the extent to which these lipid abnormalities are addressed by treatment in UK clinical practice. METHODS: The PRIMULA study was a retrospective analysis, conducted using the UK General Practice Research Database. Two periods were studied as follows: a pretreatment period, defined as the 12 months before initiation of LMT (the index date), and a follow-up period of at least 12 months. Patients included in the study (n = 25,011) had dyslipidaemia with at least one abnormal lipid measurement [total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) or triglycerides (TG)] in the pretreatment period. All patients were at high risk of cardiovascular events, which was defined as having a history of cardiovascular disease, a 10-year Framingham risk score higher than 20%, diabetes or hypertension, as defined by the Joint British Societies 2 guidelines. RESULTS: At the index date, 98% of patients were initiated on statin monotherapy. After 12 months of treatment, 15.2% (sub-group range: 11.0-22.9%) of all high-risk patients had no lipid abnormalities. The proportions of patients with high TC or LDL-C levels decreased from 98.8% to 68.9%, and from 99.2% to 68.7%, respectively, over 12 months. The prevalence of high TG levels decreased from 45.0% to 26.9%, whereas that of low HDL-C levels increased, from 16.6% to 18.0%. Risk factors for cardiovascular events were not consistently associated with the likelihood of attaining optimal lipid levels. CONCLUSIONS: Despite widespread use of statins, many individuals at high risk of cardiovascular events have persistently abnormal lipid levels, with over two thirds of patients not achieving target levels of LDL-C or TC. Management of dyslipidaemia is therefore suboptimal in this important high-risk group in UK standard practice. PMID- 23944236 TI - Current status of artificial heart (assist/replacement) development in the United States. PMID- 23944235 TI - Transcriptomic analysis of inbreeding depression in cold-sensitive Drosophila melanogaster shows upregulation of the immune response. AB - In sexually reproducing species, increased homozygosity often causes a decline in fitness, called inbreeding depression. Recently, researchers started describing the functional genomic changes that occur during inbreeding, both in benign conditions and under environmental stress. To further this aim, we have performed a genome-wide gene expression study of inbreeding depression, manifesting as cold sensitivity and conditional lethality. Our focus was to describe general patterns of gene expression during inbreeding depression and to identify specific processes affected in our line. There was a clear difference in gene expression between the stressful restrictive environment and the benign permissive environment in both the affected inbred line and the inbred control line. We noted a strong inbreeding-by-environment interaction, whereby virtually all transcriptional differences between lines were found in the restrictive environment. Functional annotation showed enrichment of transcripts coding for serine proteases and their inhibitors (serpins and BPTI/Kunitz family), which indicates activation of the innate immune response. These genes have previously been shown to respond transcriptionally to cold stress, suggesting the conditional lethal effect is associated with an exaggerated cold stress response. The set of differentially expressed genes significantly overlapped with those found in three other studies of inbreeding depression, demonstrating that it is possible to detect a common signature across different genetic backgrounds. PMID- 23944237 TI - Vienna International Workshop on functional electrical stimulation chooses artificial organs as their official journal. PMID- 23944239 TI - Australian general medical practitioner referral pathways for people with different ocular conditions. AB - BACKGROUND: The aim was to obtain an overview of general medical practitioner (GP) referral pathways to ocular health care and allied services for people identified with age-related macular degeneration (AMD), diabetic retinopathy (DR) or glaucoma (GL). METHODS: A questionnaire was developed to survey GPs in Australia. Questions included demographic information and referral patterns to ocular and health service providers. The survey was posted to 1,050 randomly selected GPs across Australia. RESULTS: Fifty-eight GPs participated in this study amounting to a 6.5 per cent response rate. Nearly all GPs referred patients to ophthalmologists (AMD: 98 per cent; DR: 98 per cent; GL: 95 per cent). A smaller proportion of GPs also referred to low vision rehabilitation (LVR) services (AMD: 34 per cent; DR: 33 per cent; GL: 22 per cent), optometrists (AMD: 26 per cent; DR: 34 per cent; GL: 31 per cent), or support services (AMD: 17 per cent; DR: 40 per cent; GL: 19 per cent). For the three tested conditions, there were no statistically significant differences in the proportions of GPs, who referred to ophthalmologists (p = 0.43), optometrists (p = 0.48) or to low vision rehabilitation services (p = 0.31). The proportion of GPs who referred to support services was significantly higher for patients diagnosed with DR than AMD or GL (p < 0.05). CONCLUSION: The majority of GPs referred patients with AMD, DR or GL to ophthalmologists. Fewer GPs considered referrals to optometrists, low vision rehabilitation or support services. General practitioners may need to be more aware about the central role of optometrists in the delivery of primary eye health care. In the interest of optimising eye care, closer working relationships between GPs and optometrists should be fostered. PMID- 23944240 TI - Giant vesicles: a powerful tool to reconstruct bacterial division assemblies in cell-like compartments. AB - The use of artificial lipid membranes, structured as giant unilamellar vesicles (GUVs), provides the opportunity to investigate membrane-associated biological processes under defined experimental conditions. Due to their large size, they are uniquely adapted to investigate the properties and organization (in time and space) of macromolecular complexes incorporated in the vesicle interior by imaging and micro-spectroscopic techniques. Experimental methods to produce giant vesicles and to encapsulate proteins inside them are here reviewed. Previous experimental work to reconstitute elements of the bacterial division machinery in these membrane-like systems is summarized. Future challenges towards reconstructing minimal divisome assemblies in giant vesicles as cytomimetic containers are discussed. PMID- 23944241 TI - Antimicrobial activity against CA-MRSA and treatment of uncomplicated nonpurulent cellulitis. AB - Evaluation of: Pallin DJ, Binder WD, Allen MB et al. CLINICAL TRIAL: comparative effectiveness of cephalexin plus trimethoprim-sulfamethoxazole versus cephalexin alone for treatment of uncomplicated cellulitis: a randomized controlled trial. Clin. Infect. Dis. 56(12), 1754-1762 (2013). The rise of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has complicated the empirical antimicrobial treatment of cellulitis. CA-MRSA is frequently the cause of purulent infections, to include purulent cellulitis. The role of CA-MRSA in nonpurulent cellulitis is less clear. Published clinical practice guidelines suggest that CA-MRSA plays only a minor role in nonpurulent cellulitis and that initial treatment should be primarily directed at beta-hemolytic streptococci. Until now, there have been no data from prospective randomized control trials to support this recommendation. In this review, we examine the findings from a recent prospective, double-blind, randomized controlled trial that refutes the need for empirical coverage of CA-MRSA when treating nonpurulent cellulitis. PMID- 23944242 TI - Cultural psychiatry, medical anthropology, and the DSM-5 field trials. PMID- 23944243 TI - The multiple anxieties of getting older: tranquilizers and the ambivalence of effect. AB - Most studies on benzodiazepines emphasize overconsumption and warn of addiction, especially by older adults. This article is about the avoidance of benzodiazepine medications by 'aging' women living in a Brazilian village. This case study helps to support our central concern: to call attention to the ambiguities that exist in discussing these medications, and to stress the importance of a multilayered understanding of effect. We argue that benzodiazepines, like other psychopharmaka, induce bodily sensations that, at least in part, correspond to and are shaped by the situated self-image of individuals in distress. PMID- 23944244 TI - Medical returns as class transformation: situating migrants' medical returns within a framework of transnationalism. AB - Because studies of migrants' 'medical returns' have been largely confined to the field of public health, such forms of return migration are rarely contextualized within the rich social scientific literature on transnational migration. Drawing on ethnographic interviews with Mexican migrants in an immigrant enclave in central California, I show that migrants' reasons for returning to their hometowns for care must be understood within the class disjunctures facilitated by migration. While migrants' Medicaid insurance confined them to public clinics and hospitals in the United States, their migrant dollars enabled them to visit private doctors and clinics in Mexico. Yet medical returns were not mere medical arbitrage, but also allowed migrants to access care that had previously been foreclosed to them as poor peasants in Mexico. Thus crossing the border enabled a dual class transformation, as Mexican migrants transitioned from Medicaid recipients to cash-paying patients, and from poor rural peasants to 'returning royalty.' PMID- 23944245 TI - Structural violence in Afghanistan: gendered memory, narratives, and food. AB - Afghanistan has been subject to political amnesia by the occupying powers of the United States and its North Atlantic Treaty Organization allies. Using the Taliban as a reference point, they have ensured that they are not implicated in the everyday and structural violence to which the people of Afghanistan have been subject over the past three decades. But Afghan women remember. Based on my ethnographic research in Kabul (in fall 2008 and 2009), I show how women in Afghanistan engage in memory work through narratives and food preparation within spaces of devastation. I argue that through these mediums, structural violence becomes knowable. I also argue that memory work is a politicized enterprise through which people remember to seek justice, in the process evoking the attention of a listening audience. This focus fosters a conversation on how the anthropology of violence can engage with issues of representation and engaged accountability. PMID- 23944246 TI - "Tossing out the baby with the bath water": New Zealand general practitioners on maternity care. AB - A rapid decline in the number of general practitioners practicing obstetrics followed legislative changes in New Zealand during the early 1990s that changed the maternity care landscape. The resulting repositioning of maternity care professions has seen medical dominance give way to midwifery dominance in the maternity marketplace. Drawing on our research, we suggest that current and former general practitioner obstetricians harbor grievances relating to (1) the loss of obstetrics from the 'cradle to grave' philosophy of general practice, and (2) policies encouraging competition between maternity care providers. We argue that these perspectives represent truth games that are generated by the disciplinary blocks of the maternity care professions, and reveal the moral nature of the political economy of maternity care. PMID- 23944247 TI - Expressionists of the twenty-first century: the commodification and commercialization of expressed breast milk. AB - Breast milk expression has been promoted as liberating for women and as offering them more choices, but there has been little research on women's experiences of it and even less critical commentary on the consequences of its incorporation into mainstream behavior. Drawing on narratives of women in the United Kingdom about breastfeeding, we explore the increasingly popular practice of expressing and feeding expressed breast milk. We argue that breast milk has become commodified, breastfeeding commercialized and technologized, and the mother infant relationship disrupted. We suggest that breastfeeding as a process is being undermined by vested interests that portray it as unreliable and reconstruct it in artificial feeding terms, so playing on women's insecurities. The major beneficiaries of expression are fathers who want increased involvement in infant care and commercial enterprises that aim to maximize profits for shareholders. PMID- 23944248 TI - 'Not-belonging': illness narratives of Mexican patients with ankylosing spondylitis. AB - In the study that we describe in this article, we aimed to preserve the voices of people suffering from chronic pain by encouraging them to tell the story of their suffering. Participants' stories reflect how chronic pain has altered their lives. This is partly due to their discomfort, but also to the frustration they experience from delays in diagnosis and treatment. Patients often pursue a lengthy quest for medical care that culminates in the diagnosis of an 'incurable' disease and a prognosis of disability. This in turn affects patient interactions with doctors and their social network. We illustrate how chronic pain leads to a sense of alienation or 'not-belonging,' whereby patients perceive pain as an entity parallel to yet dominating their own lives. PMID- 23944249 TI - Self-reported health in adolescent girls varies according to the season and its relation to medication and hormonal contraception--a descriptive study. AB - OBJECTIVES: To study seasonal variations in self-rated health and depressive symptoms in adolescent girls and possible differences in reported health with regard to use of medications. METHOD: The SF-36 questionnaire was completed by 1250 girls with a mean age of 17 years, who visited a health centre in the course of one year. From January to July inclusive, depressive symptoms in 453 of the participants were also assessed using MADRS-S. Age and regular medication data were recorded. RESULTS: Significantly better mental health and less depressive symptoms were reported during the summer, than in winter months. Seasonality was more related to the SF-36 mental, than physical health subscales. Respondents treated with hormonal contraceptives (HCs) only and those not taking any medication scored better on several SF-36 subscales, than girls on antidepressives and other medications. Respondents taking HCs tended to report better physical health and less depressive symptoms on MADRS-S than those taking no medication. CONCLUSIONS: Adolescent girls showed seasonal variations in self reported health and depressive symptoms, with more symptoms during winter months. HC users tended to report better physical health and less depressive symptoms than those on no medication. The high prevalence of suspected depression during the winter months deserves attention. PMID- 23944250 TI - Versatile self-assembly of water-soluble thiol-capped CdTe quantum dots: external destabilization and internal stability of colloidal QDs. AB - In this paper, we report on the versatile self-assembly of water-soluble thiol capped CdTe quantum dots (QDs), nanoparticles (NPs), or nanocrystals induced by L cysteine (L-Cys). Major efforts are focused on the control of the self organization of QDs into nanosheets (NSs), for example, by altering the solution pH and the QD size. The as-prepared nanosheets exhibit bright photoluminescence (PL) and retain the size-quantized properties of initial CdTe QDs, since they are actually formed by a 2D network of assembled QDs. By optical techniques, TEM, EDX, powder XRD, etc., it is found that the unique L-Cys-induced external destabilization is responsible for the template-free self-organization process, with the further assistance of the specific NP-NP interactions. And the internal chemical stability of initial CdTe QDs also is proven for the first time to play an important role. These results help to enhance the current understanding about the mechanism for the destabilization of colloidal NPs and their self-assembly behavior. PMID- 23944251 TI - Rationalization of the solvation effects on the AtO+ ground-state change. AB - (211)At radionuclide is of considerable interest as a radiotherapeutic agent for targeted alpha therapy in nuclear medicine, but major obstacles remain because the basic chemistry of astatine (At) is not well understood. The AtO(+) cationic form might be currently used for (211)At-labeling protocols in aqueous solution and has proved to readily react with inorganic/organic ligands. But AtO(+) reactivity must be hindered at first glance by spin restriction quantum rules: the ground state of the free cation has a dominant triplet character. Investigating AtO(+) clustered with an increasing number of water molecules and using various flavors of relativistic quantum methods, we found that AtO(+) adopts in solution a Kramers restricted closed-shell configuration resembling a scalar-relativistic singlet. The ground-state change was traced back to strong interactions, namely, attractive electrostatic interactions and charge transfer, with water molecules of the first solvation shell that lift up the degeneracy of the frontier pi* molecular orbitals (MOs). This peculiarity brings an alternative explanation to the highly variable reproducibility reported for some astatine reactions: depending on the production protocols (with distillation in gas-phase or "wet chemistry" extraction), (211)At may or may not readily react. PMID- 23944252 TI - An investigation on the head injuries of adult pedestrians by passenger cars in China. AB - OBJECTIVE: To investigate the relative likelihood of pedestrian head injuries based on person, vehicular, and environmental factors in China. METHODS: A team was established to collect passenger car-pedestrian accident cases occurring between 2006 and 2011 in Beijing, Shanxi Province, and Chongqing, China. Some key variables for person-, vehicle-, and environment-related factors on head injuries were analyzed using multivariate logistic regression analysis to determine relative risk/likelihood. Pedestrians were classified according to injury outcome and age. Pedestrian head injuries were scored using the Abbreviated Injury Scale (AIS). RESULTS: A total of 285 vehicle-pedestrian crashes were collected and analyzed: 30 in Beijing, 20 in Shanxi Province, and 235 in Chongqing. The distribution in age and road type by study location differed. The injury outcome, head injury severity, and head contact site were different among 4 age groups. The variables including head contact site and impact speed were the common determinants for head injury severity. A higher pedestrian fatality risk was associated with age over 46, impact speeds over 40 km/h, and higher likelihoods of the victim's head striking the windscreen frame/A pillar and of the victim sustaining a head injury. Similarly, a higher risk of head injury was associated with being female, age over 60, impact speeds over 40 km/h, and a likelihood of the victim's head striking the vehicle rather than the ground. Impact speeds of over 40 km/h and head contact site on windscreen frame/A pillar retained a strong association with severe head injury (AIS 5-6) rate. CONCLUSIONS: Pedestrian age, vehicle impact speed, and head contact site were common pertinent factors for the risk of pedestrian head injury and the risk of death. Further studies would be valuable to fully characterize vehicle-pedestrian crashes in China and to develop targeted injury prevention strategies based on surveillance results. PMID- 23944254 TI - Theoretical investigation of the activity of cobalt oxides for the electrochemical oxidation of water. AB - The presence of layered cobalt oxides has been identified experimentally in Co based anodes under oxygen-evolving conditions. In this work, we report the results of theoretical investigations of the relative stability of layered and spinel bulk phases of Co oxides, as well as the stability of selected surfaces as a function of applied potential and pH. We then study the oxygen evolution reaction (OER) on these surfaces and obtain activity trends at experimentally relevant electro-chemical conditions. Our calculated volume Pourbaix diagram shows that beta-CoOOH is the active phase where the OER occurs in alkaline media. We calculate relative surface stabilities and adsorbate coverages of the most stable low-index surfaces of beta-CoOOH: (0001), (0112), and (1014). We find that at low applied potentials, the (1014) surface is the most stable, while the (0112) surface is the more stable at higher potentials. Next, we compare the theoretical overpotentials for all three surfaces and find that the (1014) surface is the most active one as characterized by an overpotential of eta = 0.48 V. The high activity of the (1014) surface can be attributed to the observation that the resting state of Co in the active site is Co(3+) during the OER, whereas Co is in the Co(4+) state in the less active surfaces. Lastly, we demonstrate that the overpotential of the (1014) surface can be lowered further by surface substitution of Co by Ni. This finding could explain the experimentally observed enhancement in the OER activity of Ni(y)Co(1-y)O(x) thin films with increasing Ni content. All energetics in this work were obtained from density functional theory using the Hubbard-U correction. PMID- 23944255 TI - Coordination versus competition in health care reform. PMID- 23944256 TI - Occupational therapy in the community: what, why, and how. AB - SUMMARY This paper discusses ways of defining community practice. It differentiates between the terms "community-based" and "community-built" and makes the argument that community-built occupational therapy practice is the best alternative. PMID- 23944257 TI - Community Practice: It's More than Geography. AB - SUMMARY Changing the arena of occupational practice to include the community requires more than physically establishing practice in a community site. Community practice will only thrive if practitioners are adequately prepared. This means post secondary educational institutions must develop curricula upon a broad base of knowledge, focus upon theory related to occupational science, and move from a teacher based to learner based educational program. PMID- 23944258 TI - Educating for community-based occupational therapy practice: a demonstration project. AB - SUMMARY This paper describes a demonstration program designed by one university Occupational Therapy program to prepare graduates to work in community-based practice settings. Faculty and students are involved in a partnership with designated community agencies to learn to assess needs, plan programs, and evaluate outcomes using a variety of research methodologies. Completion of the project is tied to the completion of a required master's degree research paper. Results of the first year of the project have been largely successful and those involved look forward to continuing the project in the future. The project is described and recommendations for change based on these results are presented. PMID- 23944259 TI - Helping occupational therapy students and faculty develop cultural competence. AB - SUMMARY Given the need for health professionals, including occupational therapists, to be able to work with individuals and populations from a variety of cultures, this paper describes a qualitative study in which faculty and students from an occupational therapy program have been immersed in a community-built program serving African American, elderly citizens. Cultural competency and its measurement are addressed and used to assess positive results from the study. PMID- 23944253 TI - Regulation of ATP-gated P2X channels: from redox signaling to interactions with other proteins. AB - SIGNIFICANCE: The family of purinergic P2X receptors (P2XRs) is a part of ligand gated superfamily of channels activated by extracellular adenosine-5' triphosphate. P2XRs are present in virtually all mammalian tissues as well as in tissues of other vertebrate and nonvertebrate species and mediate a large variety of functions, including fast transmission at central synapses, contraction of smooth muscle cells, platelet aggregation, and macrophage activation to proliferation and cell death. RECENT ADVANCES: The recent solving of crystal structure of the zebrafish P2X4.1R is a major advance in the understanding of structural correlates of channel activation and regulation. Combined with growing information obtained in the post-structure era and the reinterpretation of previous work within the context of the tridimensional structure, these data provide a better understanding of how the channel operates at the molecular levels. CRITICAL ISSUES: This review focuses on the relationship between redox signaling and P2XR function. We also discuss other allosteric modulation of P2XR gating in the physiological/pathophysiological context. This includes the summary of extracellular actions of trace metals, which can be released to the synaptic cleft, pH decrease that happens during ischemia and inflammation, and calcium, an extracellular and intracellular messenger. FUTURE DIRECTIONS: Our evolving understanding of activation and regulation of P2XRs is helpful in clarifying the mechanism by which these channels trigger and modulate cellular functions. Further research is required to identify the signaling pathways contributing to the regulation of the receptor activity and to develop novel and receptor specific allosteric modulators, which could be used in vivo with therapeutic potential. PMID- 23944260 TI - Professional expertise of community-based occupational therapists. AB - SUMMARY As the health care system changes, it is increasingly important to define the roles and contributions of individual professions. The goal of this study was to identify job roles, job skills, and professional expertise of community-based therapists. The Community Practice Project survey was mailed to 200 AOTA registered community-based therapists. There were 84 (42%) surveys returned. The results provided a profile of community-based therapists. Principal roles, job skills, and areas of professional expertise were identified. Educational preparation was assessed. Respondents reported that they were not prepared to use the skills of networking, consulting, and communication. They were not prepared in expertise areas such as community resources, self-directed learning, and client-centered approach to practice. Overall, therapists expressed satisfaction with work in community-based positions. PMID- 23944261 TI - The pizzi holistic wellness assessment. AB - SUMMARY This paper describes the Pizzi Holistic Wellness Assessment tool. Using theory from the field of health promotion and expertise gained in his private home health practice, the author developed and pilot tested this assessment on a variety of individuals. The assessment is designed to be used with different populations in a variety of settings to help clients self assess their health and well-being. PMID- 23944262 TI - Gateway to wellness: an occupational therapy collaboration with the national multiple sclerosis society. AB - SUMMARY Occupational therapy is well equipped to build wellness for people with disabilities, particularly when partnering with community agencies or organizations. This article describes the collaborative relationship with the National Multiple Sclerosis Society for the development of Gateway to Wellness, A Program for Individuals with Multiple Sclerosis. Using the metaphor of a journey, issues relating to the collaborative relationship include language and power, paths and directions, the model design and evaluation, and negotiating expansion. The authors conclude with a summary of recommendations for positive partnering between occupational therapy and organizations that serve persons with disabling conditions. PMID- 23944263 TI - Facilitating successful international adoptions: an occupational therapy community practice innovation. AB - SUMMARY Occupational therapists are encouraged to enter community practice as international adoption consultants. Pre-adoption workshops on risks of institutionalization and family preparation are discussed. Assessment methods for evaluating records and videos are suggested. Post-adoption use of developmental examinations and information on common medical conditions of Russian and Romanian adoptees are discussed. PMID- 23944264 TI - Using chaos theory to understand a community-built occupational therapy practice. AB - SUMMARY Community-built occupational therapy programs interact with a wide range of systems. This interaction does not occur in an orderly manner, but in an unpredictable fashion. The use of chaos theory may help program developers understand actual and potential interactions that may occur. To illustrate the use of chaos theory, a case study is presented. PMID- 23944265 TI - Development of a community-based return to work program for people with AIDS. AB - SUMMARY This article overviews the needs assessment and program development process conducted by an occupational therapist in partnership with a community based agency. The resulting work rehabilitation program for persons living with HIV/AIDS and based on the Model of Human Occupation is utilized as a case example to illustrate the process. The needs assessment of the target population, the processes of organizational and environmental assessment and the resulting program design and program evaluation are discussed. PMID- 23944266 TI - Development of occupational therapy in a homeless shelter. AB - SUMMARY This paper describes a program which provides occupational therapy services to a population of homeless individuals residing in an emergency shelter in Ft. Lauderdale, Florida. Principles of community-built practice were combined with the use of the Canadian Model of Occupational Performance to provide the theoretical approach for the program. A needs assessment was done and the programming developed and implemented based on identified needs is described. Outcomes and recommendations for the future are discussed. PMID- 23944267 TI - Quality of life issues in community occupational therapy practice. AB - SUMMARY Quality of life has long been purported to be an outcome of occupational therapy practice. Yet little outcome data is available illustrating the effectiveness of occupational therapy in enhancing quality of life. Recent authors have addressed health related quality of life issues. Community practice would also benefit from attention to global quality of life concepts and outcome measures. This article discusses global quality of life and reviews related outcome measures. PMID- 23944268 TI - Stably bridging a great divide: localization of the SpoIIQ landmark protein in Bacillus subtilis. AB - Many bacterial proteins involved in fundamental processes such as cell shape maintenance, cell cycle regulation, differentiation, division and motility localize dynamically to specific subcellular regions. However, the mechanisms underlying dynamic protein localization are incompletely understood. Using the SpoIIQ protein in Bacillus subtilis as a case study, two reports present important novel insights into how a protein finds its right place at the right time and remains stably bound. During sporulation, SpoIIQ localizes in clusters in the forespore membrane at the interface that separates the forespore and mother cell and functions as a landmark protein for SpoIIIAH in the mother cell membrane. The extracellular domains of SpoIIQ and SpoIIIAH interact directly effectively bridging the gap between the two membranes. Here, SpoIIQ localization is shown to depend on two pathways, one involves SpoIIIAH, the second involves two peptidoglycan-degrading enzymes SpoIIP and SpoIID; and, SpoIIQ is only delocalized in the absence of all three proteins. Importantly, in the absence of SpoIIIAH, SpoIIQ apparently localizes normally. However, FRAP experiments demonstrated that SpoIIQ is not stably maintained in the clusters in this mutant. Thus, a second targeting pathway can mask significant changes in the localization of a protein. PMID- 23944269 TI - hERG me out. AB - A detailed analysis of the hERG content inside the ChEMBL database is performed. The correlation between the outcome from binding assays and functional assays is probed. On the basis of descriptor distributions, design paradigms with respect to structural and physicochemical properties of hERG active and hERG inactive compounds are challenged. Finally, classification models with different data sets are trained. All source code is provided, which is based on the Python open source packages RDKit and scikit-learn to enable the community to rerun the experiments. The code is stored on github ( https://github.com/pzc/herg_chembl_jcim). PMID- 23944270 TI - On the track to silica-supported tungsten oxo metathesis catalysts: input from 17O solid-state NMR. AB - The grafting of an oxo chloro trisalkyl tungsten derivative on silica dehydroxylated at 700 degrees C was studied by several techniques that showed reaction via W-Cl cleavage, to afford a well-defined precatalyst for alkene metathesis. This was further confirmed by DFT calculations on the grafting process. (17)O labeling of the oxo moiety of a series of related molecular and supported tungsten oxo derivatives was achieved, and the corresponding (17)O MAS NMR spectra were recorded. Combined experimental and theoretical NMR studies yielded information on the local structure of the surface species. Assessment of the (17)O NMR parameters also confirmed the nature of the grafting pathway by ruling out other possible grafting schemes, thanks to highly characteristic anisotropic features arising from the quadrupolar and chemical shift interactions. PMID- 23944271 TI - Problem-based learning: student learning experiences and outcomes. AB - The aim of this article is to examine processes occurring within problem-based learning (PBL) courses (inside the black box) by contrasting these processes with outcome-based studies (from outside the black box). We review meta-analyses of input-output studies of PBL in comparison with traditional approaches and provide a summary of qualitative, phenomenographic and factor analytic analyses of student experiences when studying health sciences (dentistry and medicine) using PBL curricula. Results from meta-analyses showed PBL courses were preferred for the long-term retention of course content, short-term retention involving elaboration of new information and the application of clinical skills and reasoning. Traditional approaches were favoured for short-term retention of course content that did not require any elaboration. The qualitative studies reveal a diversity of student views about the concept of PBL pedagogy and approaches to learning in PBL curricula. They show that the ways in which students approach their studies in PBL in health sciences are closely related to how they conceive of PBL and that these dimensions are closely related to how the goals and standards of PBL courses are perceived. PMID- 23944273 TI - Endogenous fibrinolytic potential in tissue-plasminogen activator-modified thromboelastography analysis is significantly decreased in dogs suffering from diseases predisposing to thrombosis. AB - BACKGROUND: In people, studies have shown that resistance to fibrinolysis could be a contributing factor to thrombosis. Tissue-plasminogen-activated (t-PA) thromboelastography (TEG) has been used to evaluate endogenous fibrinolytic potential. In dogs, TEG has been used for the diagnosis of various hemostatic disorders, but studies evaluating fibrinolysis are limited. Investigations into the potential of t-PA-modified TEG to monitor endogenous fibrinolytic potential are lacking in both healthy dogs and dogs with diseases predisposing to development of thrombosis. OBJECTIVES: The aim of this study was to compare 3 t PA-modified TEG assays and compare the endogenous fibrinolytic potential in dogs suffering from diseases associated with thrombosis with a group of healthy dogs. METHODS: Three different TEG assays, such as native, tissue factor-activated, and kaolin-activated, were modified with t-PA and used to compare whole blood samples from 16 healthy control dogs and 20 diseased dogs. RESULTS: Thromboelastography lysis variables were significantly affected by addition of t-PA in all 3 assays. Lysis results in diseased dogs were comparable to those in healthy dogs prior to addition of t-PA. After addition of t-PA, lysis results were significantly decreased in the diseased group compared with healthy dogs. The lowest median lysis levels were found in dogs with systemic inflammation and protein-losing disorders. CONCLUSION: Addition of t-PA activates fibrinolysis in TEG of blood from both healthy dogs and dogs with diseases predisposing to thrombosis. The significantly decreased fibrinolysis in diseased dogs suggests that this may be a potential prothrombotic risk factor in dogs. PMID- 23944274 TI - Plasticity in reproduction and growth among 52 range-wide populations of a Mediterranean conifer: adaptive responses to environmental stress. AB - A plastic response towards enhanced reproduction is expected in stressful environments, but it is assumed to trade off against vegetative growth and efficiency in the use of available resources deployed in reproduction [reproductive efficiency (RE)]. Evidence supporting this expectation is scarce for plants, particularly for long-lived species. Forest trees such as Mediterranean pines provide ideal models to study the adaptive value of allocation to reproduction vs. vegetative growth given their among-population differentiation for adaptive traits and their remarkable capacity to cope with dry and low-fertility environments. We studied 52 range-wide Pinus halepensis populations planted into two environmentally contrasting sites during their initial reproductive stage. We investigated the effect of site, population and their interaction on vegetative growth, threshold size for female reproduction, reproductive-vegetative size relationships and RE. We quantified correlations among traits and environmental variables to identify allocation trade-offs and ecotypic trends. Genetic variation for plasticity was high for vegetative growth, whereas it was nonsignificant for reproduction. Size-corrected reproduction was enhanced in the more stressful site supporting the expectation for adverse conditions to elicit plastic responses in reproductive allometry. However, RE was unrelated with early reproductive investment. Our results followed theoretical predictions and support that phenotypic plasticity for reproduction is adaptive under stressful environments. Considering expectations of increased drought in the Mediterranean, we hypothesize that phenotypic plasticity together with natural selection on reproductive traits will play a relevant role in the future adaptation of forest tree species. PMID- 23944275 TI - Trends in observation care among Medicare fee-for-service beneficiaries at critical access hospitals, 2007-2009. AB - PURPOSE: Observation care is used to evaluate patients prior to admission or discharge. Often beneficial, such care also imposes greater financial liability on Medicare beneficiaries. While the use of observation care has increased recently, critical access hospitals (CAHs) face different policies than prospective payment (PPS) hospitals, which may influence their observation care use. METHODS: We used 100% Medicare inpatient and outpatient claims files and enrollment data for years 2007 to 2009, and the 2007 American Hospital Association data to compare trends in the likelihood, prevalence and duration of observation stays between CAHs and PPS hospitals in metro and non-metro areas among fee-for-service Medicare beneficiaries over age 65. FINDINGS: While PPS hospitals are more likely to provide any observation care, the 3-year increase in the proportion of CAHs providing any observation care is approximately 5 times as great as the increase among PPS hospitals. Among hospitals providing any observation care in 2007, the prevalence at CAHs was 35.7% higher than at non metro PPS hospitals and 72.8% higher than at metro PPS hospitals. By 2009, these respective figures had increased to 63.1% and 111%. Average stay duration increased more slowly for CAHs than for PPS hospitals. CONCLUSIONS: These data suggest that a growing proportion of CAHs are providing observation care and that CAHs provide relatively more observation care than PPS hospitals, but they have shorter average stays. This may have important financial implications for Medicare beneficiaries. PMID- 23944276 TI - Perceived barriers, resources, and training needs of rural primary care providers relevant to the management of childhood obesity. AB - PURPOSE: To explore the perceived barriers, resources, and training needs of rural primary care providers in relation to implementing the American Medical Association Expert Committee recommendations for assessment, treatment, and prevention of childhood obesity. METHODS: In-depth interviews were conducted with 13 rural primary care providers in Oregon. Transcribed interviews were thematically coded. RESULTS: Barriers to addressing childhood obesity fell into 5 categories: barriers related to the practice (time constraints, lack of reimbursement, few opportunities to detect obesity), the clinician (limited knowledge), the family/patient (family lifestyle and lack of parent motivation to change, low family income and lack of health insurance, sensitivity of the issue), the community (lack of pediatric subspecialists and multidisciplinary/tertiary care services, few community resources), and the broader sociocultural environment (sociocultural influences, high prevalence of childhood obesity). There were very few clinic and community resources to assist clinicians in addressing weight issues. Clinicians had received little previous training relevant to childhood obesity, and they expressed an interest in several topics. CONCLUSIONS: Rural primary care providers face extensive barriers in relation to implementing recommended practices for assessment, treatment, and prevention of childhood obesity. Particularly problematic is the lack of local and regional resources. Employing nurses to provide case management and behavior counseling, group visits, and telehealth and other technological communications are strategies that could improve the management of childhood obesity in rural primary care settings. PMID- 23944277 TI - Perspectives on healthy eating among Appalachian residents. AB - PURPOSE: Extensive attention has been focused on improving the dietary intake of Americans. Such focus is warranted due to increasing rates of overweight, obesity, and other dietary-related disease. To address suboptimal dietary intake requires an improved, contextualized understanding of the multiple and intersecting influences on healthy eating, particularly among those populations at greatest risk of and from poor diet, including rural residents. METHODS: During 8 focus groups (N = 99) and 6 group key informant interviews (N = 20), diverse Appalachian rural residents were queried about their perceptions of healthy eating, determinants of healthy food intake, and recommendations for improving the dietary intake of people in their communities. Participants included church members and other laypeople, public health officials, social service providers, health care professionals, and others. FINDINGS: Participants offered insights on healthy eating consistent with the categories of individual, interpersonal, community, physical, environmental, and society-level influences described in the socioecological model. Although many participants identified gaps in dietary knowledge as a persistent problem, informants also identified extraindividual factors, including the influence of family, fellow church members, and schools, policy, advertising and media, and general societal trends, as challenges to healthy dietary intake. We highlight Appalachian residents' recommendations for promoting healthier diets, including support groups, educational workshops, cooking classes, and community gardening. CONCLUSIONS: We discuss the implications of these findings for programmatic development in the Appalachian context. PMID- 23944278 TI - Does patients' place of residence affect the type of physician performing primary excision of cutaneous melanoma in northern Scotland? AB - BACKGROUND: Rural residence may adversely affect cancer outcomes, perhaps because rural cancer patients are managed differently. Current UK guidelines recommend all patients with suspected melanoma be referred urgently for specialist excision biopsy; however, up to 20% of patients receive their biopsy in primary care. This project explored if rural dwellers with melanoma were more likely to have their primary biopsy in primary care. METHODS: A clinical database of all primary cutaneous melanomas diagnosed in Northern Scotland between January 1991 and July 2007 was analyzed for patient demographics, clinical variables, and intermediate outcomes. Significant findings on univariate analysis were then included in a binary logistic regression model to adjust for confounders. RESULTS: On univariate analysis patients living in rural areas were significantly more likely to have their melanomas excised in primary care compared with those living in the city (26.3% compared with 17.7%, P < .001). There were no significant differences between rural and urban dwellers in Breslow thickness or completeness of excision. Following adjustment for key confounders, those living in suburban areas and remote small towns were significantly more likely to be treated contrary to current UK melanoma guidelines compared to those in cities. CONCLUSIONS: In Northern Scotland patients living in suburban areas and remote small towns are significantly more likely to have an initial melanoma excision in primary care, contrary to current UK guidelines. This geographical contrast signposts the way to further in-depth research into the interplay between place of residence and how the cancer journey is experienced. PMID- 23944279 TI - Access to care and impacts of cancer on daily life: do they differ for metropolitan versus regional hematological cancer survivors? AB - PURPOSE: Little is known about access to care for hematological cancer patients. This study explored patient experiences of barriers to accessing care and associated financial and social impacts of the disease. Metropolitan versus nonmetropolitan experiences were compared. METHODS: A state-based Australian cancer registry identified adult survivors of hematological cancers (including lymphoma, leukemia and myeloma) diagnosed in the previous 3 years. Survivors were mailed a self-report pen and paper survey. FINDINGS: Of the 732 eligible survivors, 268 (37%) completed a survey. Forty percent of participants reported at least one locational barrier which limited access to care. Only 2% reported cancer-related expenses had restricted their treatment choices. Almost two-thirds (64%) reported at least one financial or social impact on their daily lives related to cancer. The most frequently reported impacts were the need to take time off work (44%) and difficulty paying bills (21%). Survivors living in a nonmetropolitan location had 17 times the odds of reporting locational or financial barriers compared with those in metropolitan areas. Preferred potential solutions to alleviate the financial and social impacts of the disease were: free parking for tests or treatment (37%), free medications or treatments (29%), and being able to get treatment in their local region (20%). CONCLUSIONS: Providing more equitable access to care for hematological cancer patients in Australia requires addressing distances traveled to attend treatment and their associated financial and social impacts on nonmetropolitan patients. Greater flexibility in service delivery is also needed for patients still in the workforce. PMID- 23944280 TI - China's new rural cooperative medical scheme and underutilization of medical care among adults over 45: evidence from CHARLS pilot data. AB - PURPOSE: With its population rapidly aging, China needs prompt action to facilitate the middle-aged and senior citizens' utilization of health care. The New Rural Cooperative Medical Scheme (NCMS), a health care reform initiative started in 2003, is currently China's primary insurance program for the rural population. METHODS: With a 2-province pilot sample (Gansu, the poorest province, and Zhejiang, one of the richest) of people over age 45 from the China Health and Retirement Longitudinal Study (CHARLS), this paper used logistic regressions to examine the association between the coverage of New Rural Cooperative Medical Scheme and the underutilization of medical care. FINDINGS: Among those who had a need to visit a health care provider during the previous month, people covered by NCMS were more likely to underutilize outpatient care than the uninsured (Odds Ratio = 5.610, 2.035-15.466). As for those who had a need to be hospitalized in the past year, the association between NCMS coverage and the underutilization of inpatient care was not statistically significant (Odds Ratio = 1.907, 0.335 10.862). Low total household expenditure per capita, living in the inland province of Gansu, and being an urban resident were also associated with underutilizing outpatient care. CONCLUSION: Further research is needed to understand the negative association between NCMS coverage and outpatient care utilization. PMID- 23944281 TI - Rural-urban disparities in quality of life among patients with COPD. AB - PURPOSE: Limited evidence in the United States suggests that among patients with chronic obstructive pulmonary disease (COPD), rural residence is associated with higher hospitalization rates and increased mortality. However, little is known about the reasons for these disparities. This study's purpose was to describe the health status of rural versus urban residence among patients with COPD and to examine factors associated with differences between these 2 locations. METHODS: This was a cross-sectional study of baseline data from a representative sample of patients with COPD enrolled in a clinical trial. Rural-urban residence was determined from ZIP code. Health status was measured using the SF-12 and health care utilization. Independent sample t-tests, chi-square tests, and multiple linear and logistic regressions were performed to examine differences between rural and urban patients. FINDINGS: Rural residence was associated with poorer health status and higher health care utilization. Among rural patients unadjusted physical functioning scores were lower on the SF-12 (30.22 vs 33.49; P = .005) that persisted after adjustment for potential confounders (beta = -2.35; P = .04). However, after further adjustment for social and psychological factors only the body-mass index, airflow obstruction, dyspnea, and exercise (BODE) index was significantly associated with health status. CONCLUSIONS: In this representative sample of patients with COPD rural residence was associated with worse health status, primarily associated with greater impairment as measured by BODE index. While rural patients reported a higher dose of smoking, a number of other unmeasured factors associated with rural residence may contribute to these disparities. PMID- 23944282 TI - Depression, social factors, and farmworker health care utilization. AB - PURPOSE: Farmworkers frequently live in rural areas and experience high rates of depressive symptoms. This study examines the association between elevated depressive symptoms and health care utilization among Latino farmworkers. METHODS: Data were obtained from 2,905 Latino farmworkers interviewed for the National Agricultural Workers Survey. Elevated depressive symptoms were measured using the Center for Epidemiologic Studies Depression short-form. A dichotomous health care utilization variable was constructed from self-reported use of health care services in the United States. A categorical measure of provider type was constructed for those reporting use of health care. RESULTS: Over 50% of farmworkers reported at least 1 health care visit in the United States during the past 2 years; most visits occurred in a private practice. The odds of reporting health care utilization in the United States were 45% higher among farmworkers with elevated depressive symptoms. Type of provider was not associated with depressive symptoms. Women were more likely to seek health care; education and family relationships were associated with health care utilization. CONCLUSIONS: Latino farmworkers who live and work in rural areas seek care from private practices or migrant/Community Health Clinics. Farmworkers with elevated depressive symptoms are more likely to access health care. Rural health care providers need to be prepared to recognize, screen, and treat mental health problems among Latino farmworkers. Outreach focused on protecting farmworker mental health may be useful in reducing health care utilization while improving farmworker quality of life. PMID- 23944283 TI - Promoting use of booster seats in rural areas through community sports programs. AB - BACKGROUND: Booster seats reduce mortality and morbidity for young children in car crashes, but use is low, particularly in rural areas. This study targeted rural communities in 4 states using a community sports-based approach. OBJECTIVE: The Strike Out Child Passenger Injury (Strike Out) intervention incorporated education about booster seat use in children ages 4-7 years within instructional baseball programs. We tested the effectiveness of Strike Out in increasing correct restraint use among participating children. METHODS: Twenty communities with similar demographics from 4 states participated in a nonrandomized, controlled trial. Surveys of restraint use were conducted before and after baseball season. Intervention communities received tailored education and parents had direct consultation on booster seat use. Control communities received only brochures. RESULTS: One thousand fourteen preintervention observation surveys for children ages 4-7 years (Intervention Group [I]: N = 511, Control [C]: N = 503) and 761 postintervention surveys (I: N = 409, C: N = 352) were obtained. For 3 of 4 states, the intervention resulted in increases in recommended child restraint use (Alabama +15.5%, Arkansas +16.1%, Illinois +11.0%). Communities in 1 state (Indiana) did not have a positive response (-9.2%). Overall, unadjusted restraint use increased 10.2% in intervention and 1.7% in control communities (P = .02). After adjustment for each state in the study, booster seat use was increased in intervention communities (Cochran-Mantel-Haenszel odds ratio 1.56, 95% confidence interval [1.16-2.10]). CONCLUSIONS: A tailored intervention using baseball programs increased appropriate restraint use among targeted rural children overall and in 3 of 4 states studied. Such interventions hold promise for expansion into other sports and populations. PMID- 23944284 TI - Personal and family health in rural areas of Kentucky with and without mountaintop coal mining. AB - PURPOSE: This study investigates health disparities for adults residing in a mountaintop coal mining area of Appalachian Kentucky. Mountaintop mining areas are characterized by severe economic disadvantage and by mining-related environmental hazards. METHODS: A community-based participatory research study was implemented to collect information from residents on health conditions and symptoms for themselves and other household members in a rural mountaintop mining area compared to a rural nonmining area of eastern Kentucky. A door-to-door health interview collected data from 952 adults. Data were analyzed using prevalence rate ratio models. FINDINGS: Adjusting for covariates, significantly poorer health conditions were observed in the mountaintop mining community on: self-rated health status, illness symptoms across multiple organ systems, lifetime and current asthma, chronic obstructive pulmonary disease, and hypertension. Respondents in mountaintop mining communities were also significantly more likely to report that household members had experienced serious illness, or had died from cancer in the past 5 years. Significant differences were not observed for self-reported cancer, angina, or stroke, although differences in cardiovascular symptoms and household cancer were reported. CONCLUSIONS: Efforts to reduce longstanding health problems in Appalachia must focus on mountaintop mining portions of the region, and should seek to eliminate socioeconomic and environmental disparities. PMID- 23944285 TI - General dentist characteristics associated with rural practice location. AB - PURPOSE: To examine whether there is a difference in the likelihood that a general dentist practices in a rural location based on individual characteristics, including dental school attended, birth state, practice arrangement, sex, and age. METHODS: All private practice, general dentists in Iowa were included in this study. Data were extracted from the year 2010 version of the Iowa Dentist Tracking System, which monitors practice patterns of active dentists. Rurality of primary office location, categorized using Rural-Urban Commuting Area codes, served as the outcome variable. Chi-square tests and multivariable logistic regression were used to explain associations between rural practice location and dentist characteristics. FINDINGS: Fifteen percent of the state's population resided in isolated small rural towns, but only 8% of general dentists practiced here. Approximately 17% of dentists in isolated small rural towns were age 40 or younger, compared to 32% of dentists in urban areas. Among male dentists, those who were born in Iowa (P = .002) were older (P = .020), and graduated from dental schools other than the University of Iowa (P = .009) were more likely to practice in rural areas than were their counterparts. Conversely, among female dentists, solo practice (P = .016) was the only variable significantly associated with rural practice location. CONCLUSIONS: The dentist workforce in rural areas of Iowa is dominated by older males who were born in Iowa. As this generation retires and increasing numbers of women enter the profession, state policy makers and planners will need to monitor changing trends in the rural workforce. PMID- 23944286 TI - Reduced Myxobolus cerebralis actinospore production in a Colorado reservoir may be linked to changes in Tubifex tubifex population structure. AB - Elucidating the dynamics of a parasitic infection requiring two hosts in a natural ecosystem can be a daunting task. Myxobolus cerebralis (Mc), the myxozoan parasite that causes whirling disease in some salmonids, was detected in the Colorado River upstream of Windy Gap Reservoir (WGR) in 1988. Subsequently, whirling disease was implicated in the decline of wild Rainbow Trout Oncorhynchus mykiss in the river when WGR was identified as a point source of Mc triactinomyxons (TAMs). Between 1997 and 2004, numerous investigations began to elucidate the etiology of Mc in WGR. During this period, Mc TAM production in WGR declined more than 90%. Explanations for the decline have included differences in stream discharge between years, changes in the thermal regime of the lake, severe drought, changes in the fish population structure in WGR, and reductions in the prevalence and severity of Mc infection in salmonids in the Colorado and Fraser rivers upstream of WGR. All of these have been discredited as explanations for the reduced TAM production. In 2005, a new study was conducted to replicate the studies completed in 1998. In this paper, the results of a new real-time polymerase chain reaction assay utilized to quantify the mitochondrial 16S rDNA specific to each of four lineages of Tubifex tubifex in pooled samples of 50 oligochaetes are presented. These results suggest that compared with 1998, the densities of aquatic oligochaetes and T. tubifex have increased, TAM production has been greatly reduced, and the decline is congruent with the dominance of lineages I, V, and VI of T. tubifex-three lineages that are refractory or highly resistant to Mc infection-in the oligochaete population. While it is possible that the resistant lineages function as biofilters that deactivate Mc myxospores, the reason for the decline in TAM production in WGR remains an enigma. PMID- 23944287 TI - Retraction techniques in laparoscopic colorectal surgery: a literature-based review. AB - AIM: To systematically review the published literature and describe the various techniques of bowel and mesentery retraction available for use in laparoscopic colorectal resection. METHOD: A comprehensive search of the literature was undertaken using MESH terms 'retraction', 'laparoscopic' and 'colorectal'. All articles describing methods of retraction in laparoscopic colorectal surgery were included. RESULTS: Twelve methods of retraction in laparoscopic colorectal surgery were described. Five case-based series and three case studies were reported on 108 patients. Techniques were classified into those offering retraction of the small or large bowel or according to the mode of retraction. CONCLUSION: Many retraction methods are available to the surgeon varying in cost, invasiveness and complexity. Adequate retraction remains a challenge for optimal exposure and dissection during laparoscopic colorectal surgery. PMID- 23944288 TI - Beneficial effects of Rituximab in patients with anti-MAG (myelin-associated glycoprotein) neuropathy: case reports. AB - Anti-myelin-associated glycoprotein (MAG) neuropathy is a primary demyelinating sensorimotor polyneuropathy that can be very debilitating and is known to be resistant to treatment. There are only a few conflicting reports on the effect of Rituximab in anti-MAG neuropathy. We present three patients who improved remarkably with Rituximab infusions. Until the safety and efficacy of this drug are determined in larger controlled studies, use of Rituximab should be limited to patients with significant neurologic deficits. PMID- 23944289 TI - The fumaric acid ester BG-12: a new option in MS therapy. AB - In March 2013, BG-12 was approved by the US FDA and EMA for the treatment of relapsing-remitting multiple sclerosis (RRMS) after meeting the primary and most secondary end points in two global phase III trials (CONFIM and DEFINE). From these data, the optimal BG-12 dosage for the treatment of RRMS is 240 mg twice daily. In the DEFINE and CONFIRM trials, the relative reduction of annual relapse rates were 53 and 44% in the approval-relevant dosages, respectively. Moreover, in the DEFINE trial, progression of disability was significantly ameliorated with a relative risk reduction of 38%. In both studies, administration of BG-12 was generally well-tolerated and safe. Most common adverse events were flushing and gastrointestinal events, including diarrhea, nausea and upper abdominal pain, which were particularly common in the early phases of treatment. At present, the introduction of BG-12 into the European market and its position among current MS treatment regimens is awaited with great interest. PMID- 23944290 TI - Association between two functional fibrinogen-related polymorphisms and ischemic stroke: a case-control study. AB - OBJECTIVES: Currently, there is a debate regarding the roles of two functional fibrinogen-related variants (rs6050 and rs1800790) and ischemic stroke (IS). MATERIALS AND METHODS: A total of 1402 subjects (834 cases and 568 controls) were genotyped for single-nucleotide polymorphisms rs6050 and rs1800790 with the ligation detection reaction method. RESULTS: We found that the homozygous minor allele genotype (GG) of rs6050 significantly increased IS risk by 66%, whereas that of rs1800790 reduced risk by 59% (rs6050: odds ratio [OR]=1.660, 95% confidence intervals [CI]: 1.141-2.415, p=0.008; rs1800790: OR=0.413, 95% CI: 0.228-0.747, p=0.003). After stratifying IS by three common subtypes, consistent results were found in IS cases with large-artery atherosclerosis (rs6050: OR=2.116, 95% CI: 1.327-3.376, p=0.002; rs1800790: OR=0.191, 95% CI: 0.085-0.430, p=0.000), and we also observed that the homozygous minor allele genotype of rs6050 increased risk by 86% in IS cases with cardioembolism (OR=1.859, 95% CI: 1.243-2.782, p=0.003). However, a paradox of association was shown between these two sites and fibrinogen levels. In haplotype analysis, we found that those with haplotype AA (major allele of rs6050 and minor allele of rs1800790) could reduce susceptibility to IS by 35% (OR=0.650, 95% CI: 0.493-0.858, p=0.002). CONCLUSION: Our study suggested that minor allele G of rs6050 is a significant risk factor, which can increase IS risk in the Chinese Han population, while minor allele A of rs1800790 and the haplotype AA lower such risk. PMID- 23944292 TI - pH and salinity evolution of Europa's brines: Raman spectroscopy study of fractional precipitation at 1 and 300 bar. AB - Several lines of evidence indicate the existence of salty liquid water below the icy surface of the satellite Europa. Depending on the chemical composition of the original interior brines, minerals that precipitate will be varied as will be the resulting physicochemical parameters of the evolving solutions such as pH and salinity. These parameters are determinants apropos to the study of the possible habitability of the satellite. In this work, experiments of fractional precipitation by cooling of several brines with different chemical composition (acid, alkaline, and neutral) were performed at 1 and 300 bar. The gradual decrease in temperature leads to mineral precipitation and changes in salinity and pH values. During the experiment, Raman spectroscopy was used to analyze quantitatively the variation of the salt concentration in the aqueous solutions. The obtained laboratory data indicate the manner in which cryomagma differentiation might occur on Europa. These endogenous processes of differentiation require planetary energy, which seems to have been plentiful during Europa's geological history. Ultimately, the dissipation of part of that energy is translated to a higher complexity of the cryopetrology in Europa's crust. From the results, we conclude that fractional differentiation processes of briny cryomagmas produce several types of igneous salty mineral suites on icy moons. PMID- 23944291 TI - Association study between the polymorphisms of the fat mass- and obesity associated gene with the risk of intervertebral disc degeneration in the Han Chinese population. AB - OBJECTIVE: Insights gained from studies suggest that genetic factors are major contributors to the onset and progression of intervertebral disc degeneration (IVDD). The aim of this study is to investigate whether fat mass- and obesity associated (FTO) gene polymorphisms are related to the disease in Han Chinese People. METHODS: 118 IVDD cases and 113 healthy subjects were enrolled in this study. Forty-four single nucleotide polymorphisms (SNP) in the FTO gene were tested and analyzed by the VeraCode GoldenGate Genotyping Assay. RESULTS: A novel SNP rs11076008 was identified in the association analysis between the genotype and the phenotype. There was statistical significance in the expression of SNP rs11076008 in an allelic frequency distribution (p=0.003) and genotype (p=0.014) using the method of multi-test correction. CONCLUSION: SNP rs11076008 of the FTO gene is associated with IVDD and may play an important role in developing IVDD in Han Chinese People. Our findings provide valuable information regarding the genetic etiology of IVDD in the investigated cohort. PMID- 23944293 TI - The quest for extraterrestrial life: what about the viruses? AB - Recently, viruses have been recognized as the most numerous entities and the primary drivers of evolution on Earth. Historically, viruses have been mostly ignored in the field of astrobiology due to the view that they are not alive in the classical sense and if encountered would not present risk due to their host specific nature. What we currently know of viruses is that we are most likely to encounter them on other life-bearing planets; that while some are exquisitely host-specific, many viruses can utilize hundreds of different host species; that viruses are known to exist in our planet's most extreme environments; and that while many do not survive long outside their hosts, some can survive for extended periods, especially in the cold. In our quest for extraterrestrial life, we should be looking for viruses; and while any encountered may pose no risk, the possibility of an encounter with a virus capable of accessing multiple cell types exists, and any prospective contact with such an organism should be treated accordingly. PMID- 23944295 TI - The pharmacokinetics and pharmacodynamics of dehydroepiandrosterone during use of an ethinylestradiol- and drospirenone-containing oral contraceptive. AB - BACKGROUND: Combined oral contraceptives (COCs) reduce the levels of ovarian and adrenal androgens. Co-administration of dehydroepiandrosterone (DHEA) may normalise androgen levels during COC use. OBJECTIVE: To investigate the effect of the addition of DHEA to a COC on the pharmacokinetics (PK) and pharmacodynamics (PD) of DHEA and its sulphate (DHEA-S), and on levels of total and free testosterone (T). METHODS: In a prospective, randomised, double-blind, placebo controlled, cross-over study involving 21 female volunteers, the PK and PD of DHEA and DHEA-S were investigated during the use of one cycle of a COC containing 30 MUg ethinylestradiol (EE) and 3 mg drospirenone (DRSP) with and without daily co-administration of 50 mg DHEA. RESULTS: Treatment during one cycle with a COC containing EE and DRSP reduces the exposure to DHEA and DHEA-S by at least 20%. This loss of adrenal androgens can be fully compensated by daily oral co administration of 50 mg DHEA. With DHEA co-administration total T levels rise significantly (1.44 nmol/L with DHEA vs. 0.82 nmol/L with placebo; p < 0.001). Free T levels decrease significantly with both DHEA and placebo treatment, but significantly less during co-administration of DHEA (6.34 pmol/L with DHEA vs. 3.96 pmol/L with placebo; p < 0.001). CONCLUSION: By adding DHEA to a COC the loss of adrenal and ovarian androgens can be restored. PMID- 23944296 TI - Determination of new Cu+, Cu2+, and Zn2+ Lennard-Jones ion parameters in acetonitrile. AB - We present new Lennard-Jones (LJ) parameters for Cu(+), Cu(2+), and Zn(2+) ion acetonitrile interactions. The adjustment of ion parameters is made to reproduce simultaneously experimental solvation free energy and structural properties, namely ion-N distance and coordination numbers. Initially, the methodology has been validated deriving parameters for well-studied Na(+) and Cl(-) ions in acetonitrile being compared with experimental and theoretical data. The transferability of parameters is checked by the calculation of thermodynamic and structural properties with three different acetonitrile models. The results obtained for transition metal ions show an overall agreement with reference values. The solvation free energy calculated with new LJ trained parameters using a six-site acetonitrile model, and two older three- and six-site acetonitrile models presents, respectively, percent differences of 0.4, 4.8, and 7.3% when compared with experimental values. PMID- 23944297 TI - In the shadows. PMID- 23944298 TI - Long-term survival of participants in the prostate cancer prevention trial. AB - BACKGROUND: In the Prostate Cancer Prevention Trial (PCPT), finasteride significantly reduced the risk of prostate cancer but was associated with an increased risk of high-grade disease. With up to 18 years of follow-up, we analyzed rates of survival among all study participants and among those with prostate cancer. METHODS: We collected data on the incidence of prostate cancer among PCPT participants for an additional year after our first report was published in 2003 and searched the Social Security Death Index to assess survival status through October 31, 2011. RESULTS: Among 18,880 eligible men who underwent randomization, prostate cancer was diagnosed in 989 of 9423 (10.5%) in the finasteride group and 1412 of 9457 (14.9%) in the placebo group (relative risk in the finasteride group, 0.70; 95% confidence interval [CI], 0.65 to 0.76; P<0.001). Of the men who were evaluated, 333 (3.5%) in the finasteride group and 286 (3.0%) in the placebo group had high-grade cancer (Gleason score, 7 to 10) (relative risk, 1.17; 95% CI, 1.00 to 1.37; P=0.05). Of the men who died, 2538 were in the finasteride group and 2496 were in the placebo group, for 15-year survival rates of 78.0% and 78.2%, respectively. The unadjusted hazard ratio for death in the finasteride group was 1.02 (95% CI, 0.97 to 1.08; P=0.46). Ten-year survival rates were 83.0% in the finasteride group and 80.9% in the placebo group for men with low-grade prostate cancer and 73.0% and 73.6%, respectively, for those with high-grade prostate cancer. CONCLUSIONS: Finasteride reduced the risk of prostate cancer by about one third. High-grade prostate cancer was more common in the finasteride group than in the placebo group, but after 18 years of follow up, there was no significant between-group difference in the rates of overall survival or survival after the diagnosis of prostate cancer. (Funded by the National Cancer Institute.). PMID- 23944300 TI - Faldaprevir and deleobuvir for HCV genotype 1 infection. AB - BACKGROUND: Interferon-free regimens would be a major advance in the treatment of patients with chronic hepatitis C virus (HCV) infection. METHODS: In this phase 2b, randomized, open-label trial of faldaprevir (a protease inhibitor) and deleobuvir (a nonnucleoside polymerase inhibitor), we randomly assigned 362 previously untreated patients with HCV genotype 1 infection to one of five groups: faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, plus ribavirin, for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); or faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). The primary end point was a sustained virologic response 12 weeks after the completion of therapy. RESULTS: The primary end point was met in 59% of patients in the TID16W group, 59% of patients in the TID28W group, 52% of patients in the TID40W group, 69% of patients in the BID28W group, and 39% of patients in the TID28W-NR group. The sustained virologic response 12 weeks after the completion of therapy did not differ significantly according to treatment duration or dosage among ribavirin-containing regimens. This response was significantly higher with TID28W than with TID28W-NR (P=0.03). Rates of a sustained virologic response 12 weeks after the completion of therapy were 56 to 85% among patients with genotype 1b infection versus 11 to 47% among patients with genotype 1a infection and 58 to 84% among patients with IL28B CC versus 33 to 64% with non-CC genotypes. Rash, photosensitivity, nausea, vomiting, and diarrhea were the most common adverse events. CONCLUSIONS: The rate of a sustained virologic response 12 weeks after the completion of therapy was 52 to 69% among patients who received interferon free treatment with faldaprevir in combination with deleobuvir plus ribavirin. (Funded by Boehringer Ingelheim; SOUND-C2 ClinicalTrials.gov number, NCT01132313.). PMID- 23944299 TI - A trial comparing noninvasive ventilation strategies in preterm infants. AB - BACKGROUND: To reduce the risk of bronchopulmonary dysplasia in extremely-low birth-weight infants, clinicians attempt to minimize the use of endotracheal intubation by the early introduction of less invasive forms of positive airway pressure. METHODS: We randomly assigned 1009 infants with a birth weight of less than 1000 g and a gestational age of less than 30 weeks to one of two forms of noninvasive respiratory support--nasal intermittent positive-pressure ventilation (IPPV) or nasal continuous positive airway pressure (CPAP)--at the time of the first use of noninvasive respiratory support during the first 28 days of life. The primary outcome was death before 36 weeks of postmenstrual age or survival with bronchopulmonary dysplasia. RESULTS: Of the 497 infants assigned to nasal IPPV for whom adequate data were available, 191 died or survived with bronchopulmonary dysplasia (38.4%), as compared with 180 of 490 infants assigned to nasal CPAP (36.7%) (adjusted odds ratio, 1.09; 95% confidence interval, 0.83 to 1.43; P=0.56). The frequencies of air leaks and necrotizing enterocolitis, the duration of respiratory support, and the time to full feedings did not differ significantly between treatment groups. CONCLUSIONS: Among extremely-low-birth weight infants, the rate of survival to 36 weeks of postmenstrual age without bronchopulmonary dysplasia did not differ significantly after noninvasive respiratory support with nasal IPPV as compared with nasal CPAP. (Funded by the Canadian Institutes of Health Research; NIPPV ClinicalTrials.gov number, NCT00433212; Controlled-Trials.com number, ISRCTN15233270.). PMID- 23944301 TI - A pilot study of focused ultrasound thalamotomy for essential tremor. AB - BACKGROUND: Recent advances have enabled delivery of high-intensity focused ultrasound through the intact human cranium with magnetic resonance imaging (MRI) guidance. This preliminary study investigates the use of transcranial MRI-guided focused ultrasound thalamotomy for the treatment of essential tremor. METHODS: From February 2011 through December 2011, in an open-label, uncontrolled study, we used transcranial MRI-guided focused ultrasound to target the unilateral ventral intermediate nucleus of the thalamus in 15 patients with severe, medication-refractory essential tremor. We recorded all safety data and measured the effectiveness of tremor suppression using the Clinical Rating Scale for Tremor to calculate the total score (ranging from 0 to 160), hand subscore (primary outcome, ranging from 0 to 32), and disability subscore (ranging from 0 to 32), with higher scores indicating worse tremor. We assessed the patients' perceptions of treatment efficacy with the Quality of Life in Essential Tremor Questionnaire (ranging from 0 to 100%, with higher scores indicating greater perceived disability). RESULTS: Thermal ablation of the thalamic target occurred in all patients. Adverse effects of the procedure included transient sensory, cerebellar, motor, and speech abnormalities, with persistent paresthesias in four patients. Scores for hand tremor improved from 20.4 at baseline to 5.2 at 12 months (P=0.001). Total tremor scores improved from 54.9 to 24.3 (P=0.001). Disability scores improved from 18.2 to 2.8 (P=0.001). Quality-of-life scores improved from 37% to 11% (P=0.001). CONCLUSIONS: In this pilot study, essential tremor improved in 15 patients treated with MRI-guided focused ultrasound thalamotomy. Large, randomized, controlled trials will be required to assess the procedure's efficacy and safety. (Funded by the Focused Ultrasound Surgery Foundation; ClinicalTrials.gov number, NCT01304758.). PMID- 23944302 TI - Primary hyperoxaluria. PMID- 23944303 TI - Images in clinical medicine. Unblinded by the lights. PMID- 23944304 TI - Case records of the Massachusetts General Hospital. Case 25-2013. A 71-year-old man with hematuria and a mass in the bladder. PMID- 23944305 TI - Critical care--an all-encompassing specialty. PMID- 23944306 TI - A role for finasteride in the prevention of prostate cancer? PMID- 23944307 TI - Mediterranean diet for primary prevention of cardiovascular disease. PMID- 23944308 TI - Mediterranean diet for primary prevention of cardiovascular disease. PMID- 23944309 TI - Mediterranean diet for primary prevention of cardiovascular disease. PMID- 23944310 TI - Mediterranean diet for primary prevention of cardiovascular disease. PMID- 23944311 TI - Mediterranean diet for primary prevention of cardiovascular disease. PMID- 23944312 TI - Mediterranean diet for primary prevention of cardiovascular disease. PMID- 23944313 TI - Mediterranean diet for primary prevention of cardiovascular disease. PMID- 23944314 TI - Surgery versus physical therapy for meniscal tear and osteoarthritis. PMID- 23944315 TI - Surgery versus physical therapy for meniscal tear and osteoarthritis. PMID- 23944316 TI - Sofosbuvir for previously untreated chronic hepatitis C infection. PMID- 23944317 TI - Sofosbuvir for previously untreated chronic hepatitis C infection. PMID- 23944318 TI - Current and future therapies for hepatitis C virus infection. PMID- 23944319 TI - Current and future therapies for hepatitis C virus infection. PMID- 23944320 TI - "Sugary drinks" and obesity. PMID- 23944321 TI - "Sugary drinks" and obesity. PMID- 23944322 TI - Bilateral toxoplasmosis retinitis associated with ruxolitinib. PMID- 23944324 TI - Images in clinical medicine. Quincke's pulse. PMID- 23944325 TI - Interactive medical case. A patient with syncope. PMID- 23944326 TI - Estimating safety effects of pavement management factors utilizing Bayesian random effect models. AB - OBJECTIVE: Previous studies of pavement management factors that relate to the occurrence of traffic-related crashes are rare. Traditional research has mostly employed summary statistics of bidirectional pavement quality measurements in extended longitudinal road segments over a long time period, which may cause a loss of important information and result in biased parameter estimates. The research presented in this article focuses on crash risk of roadways with overall fair to good pavement quality. Real-time and location-specific data were employed to estimate the effects of pavement management factors on the occurrence of crashes. METHODS: This research is based on the crash data and corresponding pavement quality data for the Tennessee state route highways from 2004 to 2009. The potential temporal and spatial correlations among observations caused by unobserved factors were considered. Overall 6 models were built accounting for no correlation, temporal correlation only, and both the temporal and spatial correlations. These models included Poisson, negative binomial (NB), one random effect Poisson and negative binomial (OREP, ORENB), and two random effect Poisson and negative binomial (TREP, TRENB) models. The Bayesian method was employed to construct these models. The inference is based on the posterior distribution from the Markov chain Monte Carlo (MCMC) simulation. These models were compared using the deviance information criterion. RESULTS: Analysis of the posterior distribution of parameter coefficients indicates that the pavement management factors indexed by Present Serviceability Index (PSI) and Pavement Distress Index (PDI) had significant impacts on the occurrence of crashes, whereas the variable rutting depth was not significant. Among other factors, lane width, median width, type of terrain, and posted speed limit were significant in affecting crash frequency. CONCLUSIONS: The findings of this study indicate that a reduction in pavement roughness would reduce the likelihood of traffic-related crashes. Hence, maintaining a low level of pavement roughness is strongly suggested. In addition, the results suggested that the temporal correlation among observations was significant and that the ORENB model outperformed all other models. PMID- 23944327 TI - Rotational spectra and structures of the van der Waals dimers of argon with 2 fluoropyridine and 3-fluoropyridine. AB - The ground state rotational spectra of the van der Waals dimers of 2 fluoropyridine and 3-fluoropyridine with argon have been investigated using both Fourier transform microwave (FTMW) and chirped-pulse Fourier transform microwave (cp-FTMW) spectroscopies between 4 and 26 GHz. The rotational constants and (14)N nuclear quadrupole coupling constants derived from fitting the observed transitions were used to estimate the van der Waals coordinates of the two complexes. These are in good agreement with the lowest energy structures determined via MP2 calculations (6-311++G(2d, 2p)) and have the Ar atom sitting above the plane of the aromatic ring. The center of mass separation of the two moieties in the dimers is between 3.5 and 3.6 A and the Ar atom lies 5-11 degrees off the monomer c'-axis toward the nitrogen atom of the pyridine backbone. PMID- 23944328 TI - Construction of homogenous/heterogeneous hollow mesoporous silica nanostructures by silica-etching chemistry: principles, synthesis, and applications. AB - Colloidal hollow mesoporous silica nanoparticles (HMSNs) are aspecial type of silica-based nanomaterials with penetrating mesopore channels on their shells. HMSNs exhibit unique structural characteristics useful for diverse applications: Firstly, the hollow interiors can function as reservoirs for enhanced loading of guest molecules, or as nanoreactors for the growth of nanocrystals or for catalysis in confined spaces. Secondly, the mesoporous silica shell enables the free diffusion of guest molecules through the intact shell. Thirdly, the outer silica surface is ready for chemical modifications, typically via its abundant Si OH bonds. As early as 2003, researchers developed a soft-templating methodto prepare hollow aluminosilicate spheres with penetrating mesopores in a cubic symmetry pattern on the shells. However, adapting this method for applications on the nanoscale, especially for biomedicine, has proved difficult because the soft templating micelles are very sensitive to liquid environments, making it difficult to tune key parameters such as dispersity, morphology and structure. In this Account, we present the most recent developments in the tailored construction of highly dispersive and monosized HMSNs using simple silica-etching chemistry, and we discuss these particles' excellent performance in diverse applications. We first introduce general principles of silica-etching chemistry for controlling the chemical composition and the structural parameters (particle size, pore size, etching modalities, yolk-shell nanostructures, etc.) of HMSNs. Secondly, we include recent progress in constructing heterogeneous, multifunctional, hollow mesoporous silica nanorattles via several methods for diverse applications. These elaborately designed HMSNs could be topologically transformed to prepare hollow mesoporous carbon nanoparticles or functionalized to produce HMSN-based composite nanomaterials. Especially in biomedicine, HMSNs are excellent as carriers to deliver either hydrophilic or hydrophobic anti cancer drugs, to tumor cells, offering enhanced chemotherapeutic efficacy and diminished toxic side effects. Most recently, research has shown that loading one or more anticancer drugs into HMSNs can inhibit metastasis or reverse multidrug resistance of cancer cells. HMSNs could also deliver hydrophobic perfluorohexane (PFH) molecules to improve high intensity focused ultrasound (HIFU) cancer surgery by changing the tissue acoustic environment; and HMSNs could act as nanoreactors for enhanced catalytic activity and/or durability. The versatility of silica-etching chemistry, a simple but scalable synthetic methodology, offers great potential for the creation of new types of HMSN-based nanostructures in a range of applications. PMID- 23944329 TI - A message from the editors. PMID- 23944330 TI - Disability in context: a community-based learning experience. AB - SUMMARY This article describes a course in disability awareness that integrates didactic content with community-based Level 1 fieldwork experience. Course content includes the experience of disability, effective writing skills, peer review, interviewing techniques, and therapeutic relationships. In home and community settings, students interview and observe volunteers who have disabilities. In a teaching role, the volunteer exposes the student to resources utilized and barriers faced by a person with a disability living independently in the community. Professional documentation skills are developed through written assignments. This experiential course provides the opportunity for students to recognize the impact of dysfunction on human occupation and gain an appreciation of each individual's ability and responsibility for self-determination. PMID- 23944331 TI - Using instructional games: a teaching strategy for increasing student participation and retention. AB - SUMMARY Teaching occupational therapy intervention with sexual expression issues in the physically disabled population can be a challenging matter. Students are often uncomfortable with the subject matter, and this deters asking questions and becoming involved in the content to the extent of understanding the subject. Standard classroom approaches can be an ineffective match for teaching subjects requiring self-examination of attitudes. Rather than utilizing standard lecture or audiovisual techniques to engage students in knowledge transfer, this article describes an innovative game designed to help students explore their views on sexuality and learn about issues related to sexual expression for persons with physical disabilities. The rationale for such an activity is presented, as well as an overview of the game, rules, and procedures. Sample game items are included to give the reader a clearer idea of the game's content and focus. Student responses to the game are included. PMID- 23944332 TI - The fieldwork profile: a statistics assignment linked to the real world of occupational therapy students. AB - SUMMARY New accreditation standards state that an entry-level occupational therapist who graduates from an accredited program should be an effective research consumer and should possess basic skills as a researcher. Some of these basic skills include being able to organize, collect, and analyze data to evaluate practice outcomes and being able to understand, use, and interpret statistics, specifically those which are descriptive, correlational, and inferential. Facilitating the development of these skills requires innovative and meaningful research assignments during occupational therapy education. The purpose of this article is to describe an applied statistics assignment based on the premise of learning-by-doing. The assignment is known as the "fieldwork profile analysis" and provides students an opportunity to connect their field work experiences to their research class. Students responded positively to the assignment and indicated that their active involvement doing statistics facilitated their learning. PMID- 23944333 TI - Understanding others: a course to learn interactive clinical reasoning. AB - SUMMARY Teaching future practitioners to use clinical reasoning processes is necessary for entry-level practice. While there are numerous articles addressing some aspects of clinical reasoning, none describe a course solely focused on understanding another person's perspective-interactive clinical reasoning. The article describes an Interactive Clinical Reasoning course for entry-level graduate students-one of four seminars on clinical reasoning embedded in a curriculum that simultaneously uses an infusion model to increase cultural awareness and sensitivity. The underlying philosophy of the course includes using interpersonal intelligence (Gardner, 1985) to "treat a patient's illness experience" (Mattingly, 1992, p. 4). Clients are the experts of their own experience with illness or disability, and students must pay as much attention to their questions and their own reactions as to their interviewee's responses. Readings, videotapes, assignments, and class exercises designed to increase students' interviewing skills and their ability to understand each client's perspective are described. PMID- 23944334 TI - Parameters for adapting journal writing activities. AB - SUMMARY The purpose of this article is to discuss journal writing parameters, which have proven useful in shaping student journal assignments. In a qualitative audit of journal writing activities currently utilized in an occupational therapy curriculum at a midwestern university, the authors used four parameters-focus, temporality, feedback, and sharing-to analyze five student journal strategies: Video Journal, OT/OTA Collaborative Fieldwork Journal, Course Objectives Journal, Subject-Specific Journal, and Activity Response Journal. A student exemplar follows the parameter analysis for each journal writing strategy. Various outcome evaluation methods show journal writing activities to be valuable tools in a curriculum that emphasizes reflection, critical thinking skills, and learner centered educational approaches. Adaptable by means of the four parameters, these five generic student journal activities can be easily implemented in a variety of courses, allowing for development of professional attitudes, relationships, and skills. PMID- 23944335 TI - The reindeer of hope: an occupational therapy program in a homeless shelter. AB - SUMMARY This article describes a successfully designed and implemented program created for mentally ill homeless men by Level II occupational therapy students from Eastern Kentucky University. Outcomes for the clients, the staff and the students were extremely positive and have contributed to the appreciation and acceptance of occupational therapy as a discipline that can contribute to the health of this underserved population. This model demonstrates the effectiveness of University sponsored fieldwork in introducing occupational therapy to the community, creating awareness of what occupational therapy has to offer and developing a climate to bring needed services to clients and provide community based employment for occupational therapists. PMID- 23944336 TI - Collaborative learning applied to fieldwork education. AB - SUMMARY Occupational therapists of the 21st century must be educated to provide intervention within health, education, community, and policy-making areas. Therapists need to solve complex problems, often in collaboration with numerous stakeholders. This article proposes that preparing occupational therapists for current practice requires a fundamental change in our educational beliefs and that a collaborative approach among students and fieldwork educators is most congruent with the interactive environments of current practice. The philosophical principles of collaborative learning are reviewed and practical considerations to apply the principles to Level II fieldwork programs are described. PMID- 23944337 TI - Group co-leadership by occupational therapy students in community centers: learning transitional roles. AB - SUMMARY The experience of contact with community populations and settings at the beginning of fieldwork is essential in expanding the dimensions of non traditional skills and roles for occupational therapy students. This article describes an initial fieldwork experience which builds on an occupational therapy group process course to enable students to supplement a community-based program with activities designed to meet a need of their group at the appropriate level of group interaction. Pairs of students select a receptive community site prior to the beginning of fieldwork to open dialog with the center's coordinator regarding performance areas, components, or contexts needed by the group. Working to assess the current programmatic offerings and desires of the participants for new activities and planning activities in collaboration with local staff, the students propose to conduct a series of five sessions addressing a theme desired or needed by the group. Upon immersion in the site's program, students are able to provide an in-depth assessment of the community group's psychosocial skill needs using the Group Level of Function Profile (Donohue, 2000). PMID- 23944338 TI - The Betty Project: Jump-Starting Clinical Observation Skills in an OTA Curriculum. AB - SUMMARY In the practice environment of many therapy practitioners today, fieldwork educators may have limited time for instructing students in applying basic theoretical concepts. Educators are therefore challenged to develop students who have the tools necessary to be successful in the clinical world. Based on input from fieldwork educators, the "Betty Project" was developed to provide opportunities for occupational therapy assisting students to hone clinical observation and documentation skills while still in a classroom setting. This modified role-play project gives students an opportunity to treat, make clinical observations, and learn to process and prioritize data for effective documentation. After implementation of this project, student performance in these areas on Level II fieldwork was markedly improved, as evidenced by scores on the FWE as well as fieldwork educator comments. PMID- 23944339 TI - A Teacher's Guide to The Cheater's Handbook. AB - SUMMARY Faculty and students come from different eras of scholastic ethics. Students are exposed to vast amounts of information through technology. Enormous pressure to receive high grades leaves students susceptible to the temptations of cheating. Faculty need to be aware of these challenging students and their possible cheating methods so faculty can foster ethical responsibility. PMID- 23944340 TI - Developing and maintaining community partnerships within "a scholarship of practice". AB - SUMMARY This article describes the application of a model developed and adopted by the occupational therapy faculty at the University of Illinois at Chicago to utilize partnerships with community-based organizations to meet a tripartite mission of education, research, and service delivery. The model (A Scholarship of Practice) was developed and adopted in response to contextual influences occurring at multiple levels. These influences are identified and the actions taken by the faculty are described. "A Scholarship of Practice" is briefly described and the principles that have guided development and maintenance of successful partnerships with community-based organizations are discussed. Finally, the outcomes and benefits of partnering with community-based organizations are identified. PMID- 23944341 TI - Combining roles as an academic instructor and a clinical practitioner in occupational therapy: benefits, challenges, and strategies for success. AB - SUMMARY Approximately 28% of the total occupational therapy (OT) faculty in higher education are adjunct faculty members. Adjunct faculty (i.e., faculty who teach a course or part of a course) have been used in higher education to maintain quality educational experiences while providing positive community connections and educational resources with first-hand experience. In occupational therapy, practitioners often assume adjunct faculty responsibilities, thereby significantly increasing professional workloads. Despite added effort, there are several benefits to adjunct teaching. However, there are equally as many challenges. Objectives of this article were to describe rewards and challenges of adjunct teaching and suggest strategies for successfully negotiating adjunct roles. The article summarizes findings from needs assessments undertaken to develop adjunct faculty programs. Results are relevant to practitioners with both clinical and teaching roles, and to their supervisors and peers. PMID- 23944342 TI - Occupational therapy students' learning styles and application to professional academic training. AB - SUMMARY Methods of optimizing students' learning have been a major concern of educators over time. If occupational therapy educators know the students' learning styles at the onset of their training, teaching can be designed to enhance students' optimal learning throughout their education. This study determined learning styles of 201 junior students (age range = 18-57, mean age = 30.9), enrolled in an urban occupational therapy program from 1990 to 1999. Kolb's Learning Style Inventory, a 12-item questionnaire, was administered to the students in the spring of their junior years. Their learning styles were determined using Kolb's criteria. Results yielded: variations in students' preferred learning styles in each class from year to year; higher percentage of convergers (mean = 35%), fewer divergers (mean = 18%). Overall, students were mostly convergers (mean = 35%) and assimilators (mean = 25%). Applications of the findings to teaching students are discussed. PMID- 23944343 TI - Educating Scholars of Practice: An Approach to Preparing Tomorrow's Researchers. AB - SUMMARY Occupational therapy's scholarship too often fails to result in a cumulative body of knowledge that is directly relevant to practice, and links theory and research to practice. This problem has its basis in how therapists are prepared to make scholarly contributions to the field. This article describes an educational strategy for preparing scholars of practice whose work will contribute to building a knowledge base that examines and enhances practice. The strategy is based upon social learning theory, employs principles of situated learning and cognitive apprenticeship, and involves students as members of an ongoing community of scholars. Steps to and benefits of creating this scholarly community and implementing this educational strategy are discussed. PMID- 23944344 TI - Qualitative evaluation of a management course project: creating new job possibilities for occupational therapy. AB - SUMMARY A qualitative analysis of a ten-step management course project in occupational therapy education demonstrates the students changed perception of future job possibilities. The assignment, designed using a student-centered approach, bridges individual skills and interests with the creation of an occupational therapy position in an emerging market. The thematic analysis indicated the outcomes of the assignment were: a changed perception in the importance of a good fit between practitioner skills and the agency or program needs, added confidence in the students' skills based on a review of the two years of academic education, and a positive, anticipated transition of the academic knowledge base into real world experience. Student presentations served to measure the ability to articulate the services of occupational therapy within arenas unfamiliar to the profession. PMID- 23944345 TI - The partnering model: occupational therapy assistant and occupational therapy students working together. AB - SUMMARY Establishing a partnering relationship between the occupational therapy assistant (OTA) and the occupational therapist (OT) is imperative in order to create an optimal working environment and deliver effective client care. A developmental model that provides students with opportunities to practice such a relationship has been used by an OTA and OT program in southwestern Ohio. This developmental Partnering Model gives students an opportunity to interact, work as teams, and collaborate during their educational experience. Each aspect of the model provides students with experiential learning opportunities. Educators will serve their OTA and OT students well in providing opportunities for them to develop and practice the skills they will need to create an optimal working environment and deliver effective client care as occupational therapy practitioners. PMID- 23944346 TI - Reflections on education and learning in occupational therapy for the 21st century. PMID- 23944347 TI - A Review of AOTF Programs Directed Toward Education: 1965-2000. PMID- 23944348 TI - Creating education to meet health care predictions. PMID- 23944349 TI - Occupational Therapy Education: At the Heart of the Profession's Future. PMID- 23944350 TI - Entry level certification and the educational community. PMID- 23944351 TI - Positioning of chemosensory proteins and FtsZ through the Rhodobacter sphaeroides cell cycle. AB - Bacterial chemotaxis depends on signalling through large protein complexes. Each cell must inherit a complex on division, suggesting some co-ordination with cell division. In Escherichia coli the membrane-spanning chemosensory complexes are polar and new static complexes form at pre-cytokinetic sites, ensuring positioning at the new pole after division and suggesting a role for the bacterial cytoskeleton. Rhodobacter sphaeroides has both membrane-associated and cytoplasmic, chromosome-associated chemosensory complexes. We followed the relative positions of the two chemosensory complexes, FtsZ and MreB in aerobic and in photoheterotrophic R. sphaeroides cells using fluorescence microscopy. FtsZ forms polar spots after cytokinesis, which redistribute to the midcell forming nodes from which FtsZ extends circumferentially to form the Z-ring. Membrane-associated chemosensory proteins form a number of dynamic unit-clusters with mature clusters containing about 1000 CheW(3) proteins. Individual clusters diffuse randomly within the membrane, accumulating at new poles after division but not colocalizing with either FtsZ or MreB. The cytoplasmic complex colocalizes with FtsZ at midcells in new-born cells. Before cytokinesis one complex moves to a daughter cell, followed by the second moving to the other cell. These data indicate that two homologous complexes use different mechanisms to ensure partitioning, and neither complex utilizes FtsZ or MreB for positioning. PMID- 23944353 TI - Synthesis of diverse indene derivatives from 1-diazonaphthalen-2(1H)-ones via thermal cascade reactions. AB - A sequential Wolff rearrangement of 1-diazonaphthalen-2(1H)-ones followed by trapping of the ketene intermediate with primary and aromatic amines or alcohols and phenols in the presence of various aldehydes generates 1H-indene-3 carboxamides or 1H-indene-3-carboxylates. This constitutes an unprecedented three component coupling reaction that allows for the synthesis of functionalized indene derivatives under catalyst-free thermal conditions. PMID- 23944352 TI - A vision for vaccines built from fully synthetic tumor-associated antigens: from the laboratory to the clinic. AB - Cancer cells may be distinguished from normal cells by cell surface displays of aberrant levels and types of carbohydrate domains. Accordingly, these tumor associated carbohydrate antigens (TACAs) represent promising target structures for the design of anticancer vaccines. Over the past 20 years, our laboratory has sought to use the tools of chemical synthesis to develop TACA-based anticancer vaccine candidates. We provide herein a personal accounting of our laboratory's progress toward the long-standing goal of developing clinically viable fully synthetic carbohydrate-based anticancer vaccines. PMID- 23944354 TI - Water-soluble Tb3+ and Eu3+ complexes with ionophilic (ionically tagged) ligands as fluorescence imaging probes. AB - This article describes a straightforward and simple synthesis of ionically tagged water-soluble Eu(3+) and Tb(3+) complexes (with ionophilic ligands) applied for bioimaging of invasive mammal cancer cells (MDA-MB-231). Use of the task-specific ionic liquid 1-methyl-3-carboxymethyl-imidazolium chloride (MAI.Cl) as the ionophilic ligand (ionically tagged) proved to be a simple, elegant, and efficient strategy to obtain highly fluorescent water-soluble Eu(3+) (EuMAI) and Tb(3+) (TbMAI) complexes. TbMAI showed an intense bright green fluorescence emission selectively staining endoplasmic reticulum of MDA-MB-231 cells. PMID- 23944355 TI - The accumulation of exercise and postprandial endothelial function in boys. AB - The purpose of this study was to investigate the effect of accumulating 60 min of exercise on endothelial function and triacylglycerol concentrations following the ingestion of a high-fat breakfast and lunch in 14 adolescent boys (aged 12 to 14 years). Two, 2-day main trials (control and exercise) were completed in a counter balanced, cross-over design. Participants were inactive on day 1 of the control trial but on day 1 of the exercise trial completed 6 * 10 min runs at 70% of peak oxygen uptake, spread over the day. On day 2, triacylglycerol concentrations and flow-mediated dilation (FMD) were measured prior to, and following, ingestion of the high-fat meals. In the control trial, FMD was reduced by 30% and 33% (P < 0.001) following the high-fat breakfast and lunch; following exercise these reductions were negated (main effect trial, P = 0.002, interaction effect trial * time, P < 0.001). The total and incremental areas under the triacylglycerol concentration vs time curve were reduced by 11% and 16% in the exercise trial; however, these differences were not significant (P > 0.05). These results support the concept of accumulating physical activity for health in adolescents as the accumulated exercise attenuated the decline in FMD seen following the consumption of high-fat meals. PMID- 23944357 TI - Peimine impairs pro-inflammatory cytokine secretion through the inhibition of the activation of NF-kappaB and MAPK in LPS-induced RAW264.7 macrophages. AB - In the previous study, we found that peimine has good anti-inflammatory effects in vivo. However, the anti-inflammatory mechanism of peimine remains unclear. We, therefore, assessed the effects of peimine on inflammatory cytokines in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We found that peimine (0-25 mg/L) significantly inhibited tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta, and increased IL-10 production. Furthermore, peimine significantly inhibited the phosphorylation of p38, ERK and c-jun N terminal kinase (JNK) as well as decreased p65 and IkappaB. The present results indicate that peimine inhibits the production of inflammatory cytokines induced by LPS through blocking MAPKs and NF-kappaB signaling pathways. PMID- 23944358 TI - Anemia in patients with coinherited thalassemia and glucose-6-phosphate dehydrogenase deficiency. AB - Thalassemia and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency are genetic disorders that cause hemolytic anemia. In areas with high frequencies of both hematological disorders, coinheritance of G-6-PD deficiency with thalassemia can be found. Whether G-6-PD deficiency, coinherited with thalassemia, enhances severe anemia is still unclear. Hematological parameters between thalassemia carriers with G-6-PD deficiency and those without G-6-PD deficiency were compared. The G-6-PD deficiency was diagnosed in 410 blood samples from thalassemia patients using a fluorescent spot test. The levels of hemoglobin (Hb), packed cell volume (PCV), mean corpuscular volume (MCV) and Hb A2/Hb E [beta26(B8)Glu->Lys; HBB: c.79G>A] were measured using an automated blood counter and high performance liquid chromatography (HPLC), respectively. The G-6-PD deficiency was found in 37 samples (9.02%). Mean levels of Hb, PCV, MCV and Hb A2/E were similar between the two groups. Thus, G-6-PD deficiency did not enhance red blood cell pathology or induce more anemic severity in thalassemia patients. PMID- 23944360 TI - Editorial: Targeting cell death and proliferation receptors in cancer. PMID- 23944359 TI - Regulation of MET receptor signaling by SOCS1 and its implications for hepatocellular carcinoma. AB - The SOCS1 gene is a frequent target of epigenetic repression in hepatocellular carcinoma. Many other types of cancer also harbor methylated SOCS1 gene. Besides, recent studies implicate microRNAs targeting SOCS1 in cancer progression. These findings suggest a broad tumor suppressor role of SOCS1 and have stimulated the quest to elucidate the underlying molecular mechanisms. The essential physiological function of SOCS1 is to attenuate interferon gamma signaling in immune cells. SOCS1 binds activated JAK kinases and the receptor chains of several cytokines, some of which are implicated in cancer progression. SOCS1 also facilitates ubiquitination and proteasomal degradation of many signaling molecules downstream of cytokine and growth factor receptors. We have shown that SOCS1 inhibits signaling via the hepatocyte growth factor receptor c-MET in hepatocytes. Aberrant MET signaling, implicated in the progression of many types of cancers, also contributes to the development of chemoresistance to tyrosine kinase inhibitors and drugs targeting other oncogenic signaling pathways. Here, we discuss the SOCS1-dependent regulation of MET signaling as an important mechanism underlying the tumor suppressor role of SOCS1 that is relevant not only to hepatocellular carcinoma but also to other types of cancers. PMID- 23944361 TI - Crosstalk between IGF-1R and other tumor promoting pathways. AB - Insulin-like growth factor 1 receptor (IGF-1R) is important in cancer pathogenesis and progression. While its signaling pathway is an interesting therapeutic target, recent clinical trials have exhibited limited effects; however, significant crosstalks between IGF- 1R and other signaling pathways have garnered increasing attention. These complex networks include interactions between IGF-1R and receptor tyrosine kinases (RTKs), including insulin receptor (IR), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), mesenchymal-epithelial transition factor (MET), platelet derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Furthermore, IGF-1R also is related to steroid hormones, including estrogen receptors alpha and beta (ER! and ER"), androgen receptor (AR), and progesterone receptor (PR). Cumulatively, actions of crosstalk between IGF-1R, and RTKs/steroid hormones promote tumorigenesis, as demonstrated by the effectiveness of recently proposed therapeutic strategies. These therapeutic strategies, primarily pertaining to crosstalk-cotargeting, exhibited notable advantages in overcoming resistance to conventional chemotherapy and conventional endocrine therapy. Furthermore, these techniques offer benefits beyond the limited effects of single- agent targeting previously reported. Thus, the role of crosstalk between IGF-1R and RTKs/steroid hormones, including strategies to block these pathways in combination with recent development in this field, were reviewed and the potential future cancer therapeutics suggested by this rationale were considered. PMID- 23944362 TI - Advances in targeting insulin-like growth factor signaling pathway in cancer treatment. AB - Insulin-like growth factors (IGFs), along with their receptors and binding proteins, play key roles in human cell proliferation, differentiation and apoptosis. There is now substantial evidence suggesting that the IGF system is involved in the pathogenesis and progression of various malignancies. Recent studies have shown that targeting of the IGF-1 receptor (IGF-1R) signaling pathway might be a novel approach for the treatment of cancer. Presently numerous agents featuring different mechanisms of IGF targeting methods such as IGF-1R monoclonal antibodies, IGF-1R tyrosine kinase inhibitors and IGF ligand specific antibodies are being investigated in more than 170 clinical trials and appear to have potential therapeutic efficacy. However, advanced trials reiterate the importance of predictive biomarkers to guide the clinical efforts of these agents. As a result, current research strategies are emerging to identify the most suitable subpopulations of patients that might benefit from these treatments. Furthermore, newly presented toxicity and growth hormone response and implication of hybrid receptors in IGF signaling pathway pose unprecedented challenges in the design and application of anti-IGF agents. On the other hand, cross-talk in downstream signaling between IGF-1R and other tumor promoting pathways and the development of multi-target agents might encourage the IGF-1R targeted therapies further into comprehensive treatments of cancer. With both challenges and prospects ahead, this paper reviewed the progress in this particular field. PMID- 23944364 TI - C-KIT signaling in cancer treatment. AB - Tumor progression is strongly associated with the activity of receptor tyrosine kinases (RTKs) and their intracellular signal transduction pathways, which regulate several cell functions including proliferation, apoptosis, motility, adhesion and angiogenesis. Detailed structural and functional studies of RTKs, including the stem cell factor receptor c-KIT, revealed the complexity of these receptor systems and contributed to development of targeted clinical approaches with relevance in both prognosis and therapy. C-KIT signaling network has been the subject of intense research and pharmaceutical strategies to identify novel target-based approaches for cancer treatment. Evidence that c-KIT signaling promotes cell proliferation and survival, along with the frequency in which this pathway is aberrantly activated in cancer, support the current efforts to identify approaches for its efficient inhibition. C-KIT mutations are associatied with several human malignancies, such as gastrointestinal stromal tumors, acute myeloid leukemia, mast cell leukemia, and melanoma. Novel therapies are developed that target some of the identified genetic defects. It is therefore anticipated that newly-identified genetic markers will acquire a predictive value, that is, the ability to predict differential efficacy of a therapy. This review describes the evolving understanding of c-KIT/SCF axis and their downstream signaling in cancer, and the strategies for c-KIT-directed targeted cancer therapy. PMID- 23944365 TI - PDGF/PDGFR signaling and targeting in cancer growth and progression: Focus on tumor microenvironment and cancer-associated fibroblasts. AB - Traditionally, the studies on cancer growth and progression have been focused on the transformed, malignant cells. However, it is now well recognized that the tumour stroma represents a crucial parameter in tumour development, growth and progression. Indeed, several cancers are characterized by a prominent stromal compartment and it is the interactions between cancer cells, stromal cells and extracellular matrix (ECM) components that control the overall tumour growth. Among stromal cells, fibroblasts represent the most important type. They are responsible for deposition and remodeling of ECM components, as well as for the release of cytokines and growth factors, including platelet-derived growth factor (PDGF), acting in a paracrine manner on cancer cells. In this review we elucidate the role of tumor stroma interactions, the roles of PDGF receptor signaling in cancer-associated fibroblasts via alteration of stromal matrix composition and the mitogenic effects of cancer-derived PDGFs. Focus on the targeting of tumor microenvironment at the level of PDGF/PDGF receptor (PDGFR) is also presented as to stimulate further studies for designing and development of novel pharmaceutical agents and combined pharmaceutical interventions. Conclusively, PDGF/PDGFR axis is of paramount importance in the tumour microenvironment context and the inhibition of PDGF receptors' activation represents a major target for future anticancer therapies. PMID- 23944366 TI - TGF-beta signaling in cancer treatment. AB - The transforming growth factor-beta (TGF-beta ) belongs to a superfamily of cytokines that act on protein kinase receptors at the plasma membrane to induce a plethora of biological signals that regulate cell growth and death, differentiation, immune response, angiogenesis and inflammation. Dysregulation of its pathway contributes to a broad variety of pathologies, including cancer. TGF beta is an important regulatory tumor suppressor factor in epithelial cells, where it early inhibits proliferation and induces apoptosis. However, tumor cells develop mechanisms to overcome the TGF-beta -induced suppressor effects. Once this occurs, cells may respond to this cytokine inducing other effects that contribute to tumor progression. Indeed, TGF-beta induces epithelial-mesenchymal transition (EMT), a process that is favored in tumor cells and facilitates migration and invasion. Furthermore, TGF-beta mediates production of mitogenic growth factors, which stimulate tumor proliferation and survival. Finally, TGF beta is a well known immunosuppressor and pro-angiogenic factor. Many studies have identified the overexpression of TGF-beta 1 in various types of human cancer, which correlates with tumor progression, metastasis, angiogenesis and poor prognostic outcome. For these reasons, different strategies to block TGF beta pathway in cancer have been developed and they can be classified in: (1) blocking antibodies and ligand traps; (2) antisense oligos; (3) TbetaRII and/or ALK5 inhibitors; (4) immune response-based strategies; (5) other inhibitors of the TGF-beta pathway. In this review we will overview the two faces of TGF-beta signaling in the regulation of tumorigenesis and we will dissect how targeting the TGF-beta pathway may contribute to fight against cancer. PMID- 23944363 TI - Is fibroblast growth factor receptor 4 a suitable target of cancer therapy? AB - Fibroblast growth factors (FGF) and their tyrosine kinase receptors (FGFR) support cell proliferation, survival and migration during embryonic development, organogenesis and tissue maintenance and their deregulation is frequently observed in cancer development and progression. Consequently, increasing efforts are focusing on the development of strategies to target FGF/FGFR signaling for cancer therapy. Among the FGFRs the family member FGFR4 is least well understood and differs from FGFRs1-3 in several aspects. Importantly, FGFR4 deletion does not lead to an embryonic lethal phenotype suggesting the possibility that its inhibition in cancer therapy might not cause grave adverse effects. In addition, the FGFR4 kinase domain differs sufficiently from those of FGFRs1-3 to permit development of highly specific inhibitors. The oncogenic impact of FGFR4, however, is not undisputed, as the FGFR4-mediated hormonal effects of several FGF ligands may also constitute a tissue-protective tumor suppressor activity especially in the liver. Therefore it is the purpose of this review to summarize all relevant aspects of FGFR4 physiology and pathophysiology and discuss the options of targeting this receptor for cancer therapy. PMID- 23944368 TI - CD95 signaling in cancer treatment. AB - The CD95/CD95 ligand (CD95L) system regulates cell death, which plays a relevant role in cancer. The impairment of the CD95/CD95L system in cancer cells may lead to apoptosis resistance and contributes to tumor progression. However, a complete loss of CD95 is rarely seen in human cancers, and many cancer cells express large quantities of CD95. Furthermore, cancer patients frequently have elevated levels of the CD95L, which raise the possibility that CD95 could also participate in tumor growth through its non-apoptotic activities depending of cell lineages or tumor stage. For this reason, CD95 signaling has to be taken into account in tumor biology, and the multiple regulatory targets of CD95/CD95L suggest that they may be used as a potential therapeutic strategy to treat cancer. The present review is an update of anti-CD95-related cancer therapies such as anti-CD95 antibodies, CD95L fusion proteins, CD95 pro-drugs, as well as the new genetic CD95-based therapies. PMID- 23944367 TI - VEGF signaling in cancer treatment. AB - Induction of angiogenesis represents one of the major hallmarks of cancer. The growth of new vessels is crucial to provide malignant cells with an adequate supply of oxygen and nutrients. It is generally accepted that vascular endothelial growth factor (VEGF) is a major driver of the angiogenic process in physiological and pathological processes in both embryo and adult. VEGF is often found overexpressed in tumors, as well as its receptors VEGFR1 and VEGFR2. Hence, several different strategies have been designed to target VEGF signal transduction. In the last decades, multiple inhibitors have been therapeutically validated in preclinical models and several clinical trials. Neutralizing monoclonal antibodies against VEGF and small molecule tyrosine kinase inhibitors targeting VEGFRs have been shown to block its angiogenic activity, resulting in tumor vascular regression, anti-tumor effects and improvements in patient survival. However, side effects and lack of efficacy in some instances challenge the potential clinical impact of these therapies. This review examines the role of VEGF signaling in cancer and outlines the current status of anti-angiogenic therapies against VEGF pathway. PMID- 23944369 TI - The long and winding road to cancer treatment: the TRAIL system. AB - Activation of cell surface death receptors of the tumor necrosis factor (TNF) receptor superfamily by the appropriate ligands represents an attractive therapeutic strategy to induce cell death by apoptosis in cancer cells. However, the toxic effects of TNF-alpha and CD95/Fas ligand (FasL) in normal tissues have significantly hampered the clinical application of these ligands in cancer treatment. TNF-related apoptosis-inducing ligand (TRAIL/APO-2L), another member of the TNF family, has been shown to induce apoptosis selectively in many tumor cell lines. Interestingly, TRAIL treatment also results in significant growth suppression of TRAIL-sensitive human cancer xenografts in mice and nonhuman primates. At the same time, recombinant TRAIL and agonistic TRAIL receptor antibodies show no significant cytotoxicity in these studies. Despite some adverse effects of certain TRAIL preparations, activation of proapoptotic TRAIL receptors represents a promising approach in cancer therapy. Herein we review what is known about proapoptotic TRAIL signaling, the role of intracellular survival pathways in the regulation of resistance to TRAIL and the activation of non-apoptotic signaling by TRAIL. We also discuss the role of the TRAIL system in tumorigenesis and the results of clinical trials with recombinant TRAIL and various TRAIL receptor agonistic antibodies, either as monotherapy or in combination with targeted or conventional chemotherapy. PMID- 23944370 TI - Clinical aspects of tumor necrosis factor-alpha signaling in hepatocellular carcinoma. AB - Tumor necrosis factor alpha (TNF-alpha) is a multi-functional cytokine that regulates a variety of signaling pathways implicated in inflammation, immunity, cell death (apoptosis), cell survival (anti-apoptosis), and even tumorigenesis. TNF-alpha is predominantly produced by macrophages (or Kupffer cells within the liver), but generated by lymphoid cells, astrocytes, endothelial cells, and smooth muscle cells to some degree. In the liver, TNF-alpha not only serves as a key mediator of hepatocyte apoptosis resulting in the liver damage, but also plays an important role in cellular proliferation leading to liver regeneration or even hepatocarcinogenesis. TNF-alpha may indirectly contribute to carcinogenesis via various inflammatory conditions such as alcoholic and non alcoholic fatty liver diseases and chronic viral hepatitis. On the one hand, in inflammation, TNF-alpha induces apoptosis repeatedly and subsequently enhances the chance of formation of anomalous cells during the process of regeneration and dysplasia. On the other hand, TNF-alpha exerts as an anti-angiogenic factor depending on its concentration. It shows an anti-tumorous effect by increasing vascular permeability in the tumors. When it is perfused in combination with chemotherapeutic drugs using isolated hepatic infusion, TNF-alpha may increase the responsiveness of hepatocellular carcinoma (HCC) or metastatic cancers to anti-cancer agents as isolated limb perfusion methods in an unresectable soft tissue sarcoma or melanoma. This article reviews the TNF-alpha signaling pathway in hepatocarcinogenesis and the new challenge of TNF-alpha as a new therapeutic strategy in HCC. PMID- 23944371 TI - Serum paraoxonase 1 activity in dogs: preanalytical and analytical factors and correlation with C-reactive protein and alpha-2-globulin. AB - BACKGROUND: Serum activity of paraoxonase (PON1) decreases during inflammation in many species. Little information is available on paraoxon-based tests and the possible role of PON1 in dogs. OBJECTIVES: The objectives of the study were to validate an automated paraoxon-based assay to measure PON1 activity in canine serum, to determine its stability under different storage conditions, to determine a reference interval (RI) in healthy dogs, and to assess whether PON1 is of comparable diagnostic value as C-reactive protein (CRP) and alpha2 globulins. METHODS: Intra-assay and inter-assay imprecision, linearity under dilution (LUD), interference, and storage artifacts were evaluated. A PON1 RI was determined for healthy dogs, and PON1 activity, sensitivity, and specificity were compared with CRP and alpha2-globulins. RESULTS: Intra- and inter-assay CVs were below 1.6% and 7.8%, respectively. The LUD test fitted the linear model. PON1 activity measurements were increased after addition of hemolysates and lipids, and after storage for 12 hours at room temperature, 72 hours at 4 degrees C, and 6 months at -20 degrees C. PON1 activity and CRP or alpha2-globulins did not correlate well. PON1 activity decreased significantly only in dogs with very high CRP concentrations. In contrast to CRP and alpha2-globulins, PON1 activity was not significantly different between dogs with and without inflammation. CONCLUSIONS: The automated paraoxon-based method to assess serum canine PON1 activity was accurate and precise, but it was influenced by hemolysis, lipemia, and standard storage conditions. In this study, contrarily to CRP and alpha2 globulins, PON1 activity did not provide diagnostic value as a negative acute phase protein in dogs. PMID- 23944373 TI - Torsion-inversion tunneling patterns in the CH-stretch vibrationally excited states of the G12 family of molecules including methylamine. AB - Two torsion-inversion tunneling models (models I and II) are reported for the CH stretch vibrationally excited states in the G12 family of molecules. The torsion and inversion tunneling parameters, h(2v) and h(3v), respectively, are combined with low-order coupling terms involving the CH-stretch vibrations. Model I is a group theoretical treatment starting from the symmetric rotor methyl CH-stretch vibrations; model II is an internal coordinate model including the local-local CH stretch coupling. Each model yields predicted torsion-inversion tunneling patterns of the four symmetry species, A, B, E1, and E2, in the CH-stretch excited states. Although the predicted tunneling patterns for the symmetric CH stretch excited state are the same as for the ground state, inverted tunneling patterns are predicted for the asymmetric CH-stretches. The qualitative tunneling patterns predicted are independent of the model type and of the particular coupling terms considered. In model I, the magnitudes of the tunneling splittings in the two asymmetric CH-stretch excited states are equal to half of that in the ground state, but in model II, they differ when the tunneling rate is fast. The model predictions are compared across the series of molecules methanol, methylamine, 2-methylmalonaldehyde, and 5-methyltropolone and to the available experimental data. PMID- 23944372 TI - An epidemiological study of neovascular age-related macular degeneration in Germany. AB - OBJECTIVE: Neovascular or wet age-related macular degeneration (AMD) is one of the leading causes of blindness in industrialized countries; however, there is a lack of recent epidemiological data from Germany. The aim of this study was to collect epidemiological data from patients in Germany with suspected neovascular AMD and evaluate the diagnostic procedures performed and treatments used at clinics. METHODS: This was a Germany-based, multicentre, retrospective review of data from patients with suspected neovascular AMD visiting ophthalmology clinics over an 18 month period in 2008-10. Clinical characteristics, functional symptoms and examination results were recorded. In addition, ophthalmologists completed a questionnaire on neovascular AMD diagnosis and treatment. RESULTS: Ten sites collected data from 2498 patients (64.0% female) with a mean decimal visual acuity of 0.4 +/- 0.3 at the time of diagnosis of neovascular AMD. The mean age at the time of diagnosis was 76.9 +/- 8.9 years for patients with the right eye affected and 77.0 +/- 8.3 years for patients with the left eye affected. The most frequent pathological findings detected by routine ophthalmic examination were old lesions (31.2%), intra/subretinal fluid (18.1%), new lesions (13.0%), and intra/subretinal haemorrhage (11.4%). A confirmed diagnosis of neovascular AMD was most frequently based on fundoscopy (67.3%), fluorescein angiography (39.6%), and biomicroscopy (35.7%) tests but rarely on optical coherence tomography (8.9%). The most frequently documented comorbidity with neovascular AMD was hypertension and other cardiovascular diseases (57.5%). Seven ophthalmologists completed the questionnaire with the majority of ophthalmologists agreeing that regular ophthalmic examination can prevent the development of late-stage neovascular AMD. CONCLUSION: Neovascular AMD is a frequent diagnosis in German ophthalmology clinics. As visual acuity is already poor in most patients with suspected neovascular AMD, regular preventive ophthalmologic examinations should be considered in high risk patients. STUDY LIMITATIONS: Limitations of the study include the lack of a comparator cohort, which limited the amount of analyses that could be performed. Additionally, a study eye was not defined and information was collected separately for each affected eye and therefore analysed separately. Furthermore, a small number of ophthalmologists completed the questionnaire, limiting the objectivity. PMID- 23944374 TI - Memory B cells: a proposed new immunological correlate for protective efficacy of Japanese encephalitis vaccine. AB - Japanese encephalitis (JE) virus requires dissemination within the host via the circulation for disease development. Thus, a serum-neutralizing antibody is an effective factor to protect against disease. Current licensed JE vaccines induce neutralizing antibodies and titers of 1:10 or higher are the recommended immunological correlate of protection. In this paper, the authors demonstrated, using a highly susceptible knockout mouse model, that memory B cells are required for disease protection and that detectable neutralizing antibodies at the time of challenge are dispensable. The authors proposes that the extent of memory B cells would be an alternative and better immunological correlate for evaluating the efficacy of JE vaccine candidates in clinical trials. PMID- 23944375 TI - Phylogenetic signal, feeding behaviour and brain volume in Neotropical bats. AB - Comparative correlational studies of brain size and ecological traits (e.g. feeding habits and habitat complexity) have increased our knowledge about the selective pressures on brain evolution. Studies conducted in bats as a model system assume that shared evolutionary history has a maximum effect on the traits. However, this effect has not been quantified. In addition, the effect of levels of diet specialization on brain size remains unclear. We examined the role of diet on the evolution of brain size in Mormoopidae and Phyllostomidae using two comparative methods. Body mass explained 89% of the variance in brain volume. The effect of feeding behaviour (either characterized as feeding habits, as levels of specialization on a type of item or as handling behaviour) on brain volume was also significant albeit not consistent after controlling for body mass and the strength of the phylogenetic signal (lambda). Although the strength of the phylogenetic signal of brain volume and body mass was high when tested individually, lambda values in phylogenetic generalized least squares models were significantly different from 1. This suggests that phylogenetic independent contrasts models are not always the best approach for the study of ecological correlates of brain size in New World bats. PMID- 23944376 TI - Inflammasome and atherogenesis. AB - Atherosclerosis is a progressive disease starting with accumulation of lipids, lipoproteins, and immune cells in the arterial wall. Inflammation and the innate immune response are involved in the formation of early atherosclerotic lesion. A protein complex known as the inflammasome is stimulated to activate interleukin 1beta (IL-1beta) and IL-18, which are responsible for activation of inflammatory processes. Inflammasome-mediated processes are important in the process of atherosclerosis. The front of structure domains as well as IL-1, and IL-18 stands at the threshold of the adaptive immune response that accelerates full-blown atherosclerotic disease progression. This review is intended to provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for therapy of this disease. PMID- 23944377 TI - The critical roles of HSC70 in physiological and pathological processes. AB - The heat stress cognate 70 is one of the major cytoplasmic chaperones to supply a multitude of the housekeeping chaperoning functions. In addition to its high constitutive expression, recent studies have demonstrated that it is also inducible. Another exciting discovery is that the regulation of heat stress cognate 70 plays important roles in the aging process and aging-related diseases. Besides the chaperone functions, heat stress cognate 70 is involved in the inflammatory signal pathways via extracellular interaction with TLR2/TLR4. Furthermore, studies have validated the ability of extracellular heat stress cognate 70 to regulate cancer cell proliferation and sperm storage. The discovery of heat stress cognate 70 secretion, in normal and cancer cells undergoing stress, presents novel therapeutic strategies. PMID- 23944378 TI - Comparison of two molecular scaffolds, 5-methylisoxazole-3-carboxamide and 5 methylisoxazole-4-carboxamide. AB - Leflunomide is a disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). Structurally, it is a derivative of 5 methylisoxazole-4-carboxamide. Upon metabolism, the N-O bond in the isoxazole ring is cleaved to form the active metabolite, teriflunomide, which was recently approved by the FDA for the treatment of multiple sclerosis. Both leflunomide and teriflunomide inhibit dihydroorotate dehydrogenase (DHODH) thereby inhibiingt the synthesis of pyrimidine. For both drugs, the two major concerns are potential liver toxicity and teratogenicity. It was suspected that these undesirable effects might be related to the cleavage of the N-O bond. We herein summarize the metabolites-toxicity issues related to leflunomide/teriflunomide and discuss two related molecular platforms, UTL-4 and UTL-5. UTL-4 compounds are based on the same scaffold of leflunomide; their toxicological and pharmacological effects are not significantly different from those of leflunomide/teriflunomide. In UTL-5 series, the leflunomide scaffold is changed into 5-methylisoxazole-3-carboxamide. Unlike leflunomide, the N-O bond of a UTL-5 compound, UTL-5b, is not cleaved upon metabolism; instead, the peptide bond is cleaved to form its major metabolites. UTL-5b and its metabolites do not inhibit DHODH in vitro. In addition, UTL-5b and all other UTL-5 compounds have lower acute toxicity than leflunomide/teriflunomide. Furthermore, from leflunomide to UTL-5b/UTL-5g, the potential liver toxicity becomes liver protective effect. With the reduced toxicity, UTL-5 compounds still maintain significant pharmacological effects including anti-inflammatory and antiarthritic effects. In summary, our observations provide a valuable direction in drug optimization based on the modification of the leflunomide scaffold. PMID- 23944379 TI - Complementary and alternative medicine (CAM) in prostate and bladder cancer. AB - To provide an overview of the scientific and clinical studies underlying the most common vitamin and herbal preparations used in prostate and bladder cancer and evaluate the evidence behind them. A literature search was undertaken on PubMed using various keywords relating to the use of complementary and alternative medicine (CAM) in prostate and bladder cancer.Vitamin E and selenium supplementation can potentially have adverse effects by increasing the risk of prostate cancer. Initial clinical studies of pomegranate and green tea, investigating their chemotherapeutic properties in prostate and bladder cancer have yielded encouraging results. Curcumin, resveratrol, and silibinin have potential anticancer properties through multiple molecular targets; their clinical effectiveness in prostate and bladder cancer is yet to be evaluated. Zyflamend, like PC-SPES, is a combined CAM therapy used in prostate cancer. Acupuncture is popular among patients experiencing hot flushes who are receiving androgen-deprivation therapy for prostate cancer. Conclusive evidence for the use of CAM in prostate and bladder cancer is lacking and not without risk. PMID- 23944380 TI - Injuries in a Japanese Division I collegiate american football team: a 3-season prospective study. AB - CONTEXT: Previous research on American football injuries in Japan has focused on incidence proportion in terms of the number of injuries divided by the number of players. This is the first study to examine injury rates over several seasons. OBJECTIVE: To conduct a prospective study of injuries in a Japanese Division I collegiate American football team over the 2007 through 2009 seasons. DESIGN: Cohort study. SETTING: Collegiate football team at Doshisha University, Kyoto, Japan. PATIENTS OR OTHER PARTICIPANTS: All 289 athletes who played on the collegiate Division I football team during the 2007 through 2009 seasons. MAIN OUTCOME MEASURE(S): A certified athletic trainer kept a daily record of all practice and game injuries. Injury rates were calculated according to season, injury type, body part, severity, and mechanism. Injuries were also analyzed according to position of player, school year, and playing experience. RESULTS: The game injury rate (GIR; 32.7 injuries/1000 athlete-exposures) was higher than the practice injury rate (PIR; 10.9 injuries/1000 athlete-exposures) over the 3 seasons (P < .05). The PIR was higher among Japanese players than the comparable United States collegiate football injury rates (5.8-7.0 injuries/1000 athlete exposures). Ankle and foot injuries occurred more frequently during games, whereas thigh and gluteal injuries occurred more frequently during practices. CONCLUSIONS: Our data show differences between games and practices in terms of injury rates, body parts injured, and positions of players injured. The high PIR in Japan may be due to the increased contact during practices and length of practices compared with the United States. Further research involving multiple teams is recommended to validate the trends noted in this study. The expanded data set could assist in the development of safety regulations and preventive interventions for Japanese football. PMID- 23944381 TI - Lower extremity energy absorption and biomechanics during landing, part II: frontal-plane energy analyses and interplanar relationships. AB - CONTEXT: Greater sagittal-plane energy absorption (EA) during the initial impact phase (INI) of landing is consistent with sagittal-plane biomechanics that likely increase anterior cruciate ligament (ACL) loading, but it does not appear to influence frontal-plane biomechanics. We do not know whether frontal-plane INI EA is related to high-risk frontal-plane biomechanics. OBJECTIVE: To compare biomechanics among INI EA groups, determine if women are represented more in the high group, and evaluate interplanar INI EA relationships. DESIGN: Descriptive laboratory study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Participants included 82 (41 men, 41 women; age = 21.0 +/- 2.4 years, height = 1.74 +/- 0.10 m, mass = 70.3 +/- 16.1 kg) healthy, physically active volunteers. INTERVENTION(S): We assessed landing biomechanics with an electromagnetic motion capture system and force plate. MAIN OUTCOME MEASURE(S): We calculated frontal- and sagittal-plane total, hip, knee, and ankle INI EA. Total frontal-plane INI EA was used to create high, moderate, and low tertiles. Frontal-plane knee and hip kinematics, peak vertical and posterior ground reaction forces, and peak internal knee-varus moment (pKVM) were identified and compared across groups using 1-way analyses of variance. We used a chi (2) analysis to evaluate male and female allocation to INI EA groups. We used simple, bivariate Pearson product moment correlations to assess interplanar INI EA relationships. RESULTS: The high-INI EA group exhibited greater knee valgus at ground contact, hip adduction at pKVM, and peak hip adduction than the low-INI EA group (P < .05) and greater peak knee valgus, pKVM, and knee valgus at pKVM than the moderate- (P < .05) and low- (P < .05) INI EA groups. Women were more likely than men to be in the high-INI EA group (chi(2) = 4.909, P = .03). Sagittal-plane knee and frontal-plane hip INI EA (r = 0.301, P = .006) and sagittal-plane and frontal-plane ankle INI EA were associated (r = 0.224, P = .04). No other interplanar INI EA relationships were found (P > .05). CONCLUSIONS: Greater frontal-plane INI EA was associated with less favorable frontal-plane biomechanics that likely result in greater ACL loading. Women were more likely than men to use greater frontal-plane INI EA. The magnitudes of sagittal- and frontal-plane INI EA were largely independent. PMID- 23944383 TI - Metal-free borane-catalyzed highly stereoselective hydrogenation of pyridines. AB - A metal-free direct hydrogenation of pyridines was successfully realized by using homogeneous borane catalysts generated from alkenes and HB(C6F5)2 via in situ hydroboration. The reaction affords a broad range of piperidines in high yields with excellent cis stereoselectivities. PMID- 23944382 TI - Lower extremity energy absorption and biomechanics during landing, part I: sagittal-plane energy absorption analyses. AB - CONTEXT: Eccentric muscle actions of the lower extremity absorb kinetic energy during landing. Greater total sagittal-plane energy absorption (EA) during the initial impact phase (INI) of landing has been associated with landing biomechanics considered high risk for anterior cruciate ligament (ACL) injury. We do not know whether groups with different INI EA magnitudes exhibit meaningful differences in ACL-related landing biomechanics and whether INI EA might be useful to identify ACL injury-risk potential. OBJECTIVE: To compare biomechanical factors associated with noncontact ACL injury among sagittal-plane INI EA groups and to determine whether an association exists between sex and sagittal-plane INI EA group assignment to evaluate the face validity of using sagittal-plane INI EA to identify ACL injury risk. DESIGN: Descriptive laboratory study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 82 (41 men, 41 women; age = 21.0 +/- 2.4 years, height = 1.74 +/- 0.10 m, mass = 70.3 +/- 16.1 kg) healthy, physically active individuals volunteered. INTERVENTION(S): We assessed landing biomechanics using an electromagnetic motion-capture system and force plate during a double-legged jump-landing task. MAIN OUTCOME MEASURE(S): Total INI EA was used to group participants into high, moderate, and low tertiles. Sagittal- and frontal-plane knee kinematics; peak vertical and posterior ground reaction forces (GRFs); anterior tibial shear force; and internal hip extension, knee extension, and knee varus moments were identified and compared across groups using 1-way analyses of variance. We used a chi (2) analysis to compare male and female representation in the high and low groups. RESULTS: The high group exhibited greater knee-extension moment and posterior GRFs than both the moderate (P < .05) and low (P < .05) groups and greater anterior tibial shear force than the low group (P < .05). No other group differences were noted. Women were not represented more than men in the high group (chi(2) = 1.20, P = .27). CONCLUSIONS: Greater sagittal-plane INI EA likely indicates greater ACL loading, but it does not appear to influence frontal-plane biomechanics related to ACL injury. Women were not more likely than men to demonstrate greater INI EA, suggesting that quantification of sagittal-plane INI EA alone is not sufficient to infer ACL injury-risk potential. PMID- 23944384 TI - A fundamental reconsideration of the CRASH3 damage analysis algorithm: the case against uniform ubiquitous linearity between BEV, peak collision force magnitude, and residual damage depth. AB - OBJECTIVE: The objective of this study was a thorough reconsideration, within the framework of Newtonian mechanics and work-energy relationships, of the empirically interpreted relationships employed within the CRASH3 damage analysis algorithm in regards to linearity between barrier equivalent velocity (BEV) or peak collision force magnitude and residual damage depth. METHODS: The CRASH3 damage analysis algorithm was considered, first in terms of the cases of collisions that produced no residual damage, in order to properly explain the damage onset speed and crush resistance terms. Under the modeling constraints of the collision partners representing a closed system and the a priori assumption of linearity between BEV or peak collision force magnitude and residual damage depth, the equations for the sole realistic model were derived. RESULTS: Evaluation of the work-energy relationships for collisions at or below the elastic limit revealed that the BEV or peak collision force magnitude relationships are bifurcated based upon the residual damage depth. Rather than being additive terms from the linear curve fits employed in the CRASH3 damage analysis algorithm, the Campbell b 0 and CRASH3 AL terms represent the maximum values that can be ascribed to the BEV or peak collision force magnitude, respectively, for collisions that produce zero residual damage. Collisions resulting in the production of non-zero residual damage depth already account for the surpassing of the elastic limit during closure and therefore the secondary addition of the elastic limit terms represents a double accounting of the same. This evaluation shows that the current energy absorbed formulation utilized in the CRASH3 damage analysis algorithm extraneously includes terms associated with the A and G stiffness coefficients. This sole realistic model, however, is limited, secondary to reducing the coefficient of restitution to a constant value for all cases in which the residual damage depth is nonzero. CONCLUSION: Linearity between BEV or peak collision force magnitude and residual damage depth may be applicable for particular ranges of residual damage depth for any given region of any given vehicle. Within the modeling construct employed by the CRASH3 damage algorithm, the case of uniform and ubiquitous linearity cannot be supported. Considerations regarding the inclusion of internal work recovered and restitution for modeling the separation phase change in velocity magnitude should account for not only the effects present during the evaluation of a vehicle-to vehicle collision of interest but also to the approach taken for modeling the force-deflection response for each collision partner. PMID- 23944385 TI - Wet chemical synthesis of soluble gold nanogaps. AB - A central challenge in molecular electronics is to create electrode pairs separated by only a few nanometers that can accommodate a single molecule of interest to be optically or electrically characterized while residing in the gap. Current techniques for nanogap fabrication are largely based on top-down approaches and often rely on subsequent deposition of molecules into the nanogap. In such an approach, the molecule may bridge the gap differently with each experiment due to variations at the metal-molecule interface. Conversely, chemists can readily synthesize gold nanorods (AuNRs) in aqueous solution. Through controlled end-to-end assembly of the AuNRs into dimers or chains, facilitated via target molecules, they can be used as electrical contacts. In this way, the preparation of AuNR-molecule-AuNR junctions by wet chemical methods may afford a large number of identical devices with little variation in the interface between molecule and electrode (AuNR). In this Account, we highlight recent progress in using chemically synthesized AuNRs as building blocks for molecular electronic applications. We outline the general synthesis and properties of AuNRs and describe the aqueous growth of dimeric AuNR structures from an insulating molecule linked to AuNR precursors (gold seeds). Conjugated, electronically active molecules are typically not soluble under the conditions required for the bottom-up growth of AuNRs. Therefore, we present a strategy that utilizes host-guest chemistry in order to make such pi-systems compatible with the AuNR growth procedure. In order to electrically characterize the AuNR molecule-AuNR constructs, we must transfer them onto a substrate and contact external electrodes. We discuss the implications of using electron-beam lithography for making this contact. In addition, we introduce a novel fabrication approach in which we can grow AuNR nanogap electrodes in situ on prepatterned substrates, thus circumventing post-processing steps that potentially damage the nanogap environment. Due to the inherent optical properties of AuNRs, electromagnetic field enhancement in the nanogaps lets us spectroscopically characterize the molecules via surface-enhanced Raman scattering. We discuss the incorporation of oligopeptides functionalized with acetylene units having uniquely identifiable vibrational modes. This acetylene moiety allows chemical reactions to be performed in the gaps via click chemistry, and the oligopeptide linking platform opens for integration of larger biological components. PMID- 23944386 TI - Discovery of selective small molecule type III phosphatidylinositol 4-kinase alpha (PI4KIIIalpha) inhibitors as anti hepatitis C (HCV) agents. AB - Hepatitis C virus (HCV) assembles many host cellular proteins into unique membranous replication structures as a prerequisite for viral replication, and PI4KIIIalpha is an essential component of these replication organelles. RNA interference of PI4KIIIalpha results in a breakdown of this replication complex and cessation of HCV replication in Huh-7 cells. PI4KIIIalpha is a lipid kinase that interacts with the HCV nonstructural 5A protein (NS5A) and enriches the HCV replication complex with its product, phosphoinositol 4-phosphate (PI4P). Elevated levels of PI4P at the endoplasmic reticulum have been linked to HCV infection in the liver of HCV infected patients. We investigated if small molecule inhibitors of PI4KIIIalpha could inhibit HCV replication in vitro. The synthesis and structure-activity relationships associated with the biological inhibition of PI4KIIIalpha and HCV replication are described. These efforts led directly to identification of quinazolinone 28 that displays high selectivity for PI4KIIIalpha and potently inhibits HCV replication in vitro. PMID- 23944387 TI - Pharmacokinetic evaluation of sildenafil as a pulmonary hypertension treatment. AB - INTRODUCTION: Sildenafil citrate is a potent, selective phosphodiesterase type 5 inhibitor approved for the treatment of pulmonary arterial hypertension (PAH) and plays an important role in the management of the disease. AREAS COVERED: In this review, we focus on the current available information on the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of sildenafil citrate in PAH through a MEDLINE literature search. Comparison of sildenafil citrate with tadalafil, another phosphodiesterase type 5 inhibitor was also performed. EXPERT OPINION: In the last few years, considerable progress has been made in the understanding and treatment of PAH. Sildenafil citrate has multiple advantages and whether it is first-line treatment alone or in combination for the mild form of the disease, it is one of the treatments of choice. In terms of its future use, more studies are still needed to better evaluate the benefit/risk balance of sildenafil citrate in pediatric populations. PMID- 23944389 TI - Single-particle tracking data reveal anticorrelated fractional Brownian motion in crowded fluids. AB - Anomalous diffusion with a sublinear growth of the particles' mean-square displacement (subdiffusion) has been observed frequently in crowded fluids, e.g., in the cytoplasm of living cells or in artificial solutions. Based on a recently reported set of single-particle tracking data, it is shown here that trajectories of nanoparticles immersed in artificial crowded fluids display all signatures of anticorrelated fractional Brownian motion. Moreover, the trajectories' power spectrum follows a scaling that reports on the fluid's viscoelasticity. Macromolecular crowding therefore renders fluids viscoelastic which in turn leads to subdiffusion of immersed tracer particles with all the characteristics of fractional Brownian motion. PMID- 23944390 TI - Impact of granular drops. AB - We investigate the spreading and splashing of granular drops during impact with a solid target. The granular drops are formed from roughly spherical balls of sand mixed with water, which is used as a binder to hold the ball together during free fall. We measure the instantaneous spread diameter for different impact speeds and find that the normalized spread diameter d/D grows as (tV/D)(1/2). The speeds of the grains ejected during the "splash" are measured and they rarely exceed twice that of the impact speed. PMID- 23944391 TI - Athermal jamming versus thermalized glassiness in sheared frictionless particles. AB - Numerical simulations of soft-core frictionless disks in two dimensions are carried out to study the behavior of a simple liquid as a function of temperature T, packing fraction phi, and uniform applied shear strain rate gamma[over .]. Inferring the hard-core limit from our soft-core results, we find that it depends on the two parameters phi and T/gamma[over .]. Here T/gamma[over .]->0 defines the athermal limit in which a shear-driven jamming transition occurs at a well defined phi(J) and T/gamma[over .]->infinity defines the thermalized limit where an equilibrium glass transition may take place at phi(G). This conclusion argues that athermal jamming and equilibrium glassy behavior are not controlled by the same critical point. Preliminary results suggest phi(G)2/3. We demonstrate that this transition is accessible by numerical transfer matrix calculations in 1+1 dimensions and analyze the properties of the disorder-dominated phase in detail. On the basis of the two-replica problem, we propose a relation between the localization of stiff directed lines in 1+d dimensions and of directed lines under tension in 1+3d dimensions, which is strongly supported by identical free energy distributions. This shows that pair interactions in the replicated Hamiltonian determine the nature of directed line localization transitions with consequences for the critical behavior of the Kardar-Parisi-Zhang equation. We support the proposed relation to directed lines via multifractal analysis, revealing an analogous Anderson transition-like scenario and a matching correlation length exponent. Furthermore, we quantify how the persistence length of the stiff directed line is reduced by disorder. PMID- 23944411 TI - Adiabatically driven Brownian pumps. AB - We investigate a Brownian pump which, being powered by a flashing ratchet mechanism, produces net particle transport through a membrane. The extension of the Parrondo's approach developed for reversible Brownian motors [Parrondo, Phys. Rev. E 57, 7297 (1998)] to adiabatically driven pumps is given. We demonstrate that the pumping mechanism becomes especially efficient when the time variation of the potential occurs adiabatically fast or adiabatically slow, in perfect analogy with adiabatically driven Brownian motors which exhibit high efficiency [Rozenbaum et al., Phys. Rev. E 85, 041116 (2012)]. At the same time, the efficiency of the pumping mechanism is shown to be less than that of Brownian motors due to fluctuations of the number of particles in the membrane. PMID- 23944412 TI - Static cooperator-defector patterns in models of the snowdrift game played on cycle graphs. AB - Evolutionary graph theory is an extension of evolutionary game theory in which each individual agent, represented by a node, interacts only with a subset of the entire population to which it belongs (i.e., those to which it is connected by edges). In the context of the evolution of cooperation, in which individuals playing the cooperator strategy interact with individuals playing the defector strategy and game payoffs are equated with fitness, evolutionary games on graphs lead to global standoffs (i.e., static patterns) when all cooperators in a population have the same payoff as any defectors with which they share an edge. I consider the simplest type of regular-connected graph, the cycle graph, in which every node has exactly two edges (k = 2), for the prisoner's dilemma game and the snowdrift game, the two most important pairwise games in cooperation theory. I show that for simplified payoff structures associated with these games, standoffs are only possible for two valid cost-benefit ratios in the snowdrift game. I further show that only the greater of these two cost-benefit ratios is likely to be attracting in most situations (i.e., likely to spontaneously result in a global standoff when starting from nonstandoff conditions). Numerical simulations confirm this prediction. This work contributes to our understanding of the evolution of pattern formation in games played in finite, sparsely connected populations. PMID- 23944413 TI - Thermal fluctuations of hydrodynamic flows in nanochannels. AB - Flows at the nanoscale are subject to thermal fluctuations. In this work, we explore the consequences for a fluid confined within a channel of nanometric size. First, the phenomenon is illustrated on the basis of molecular dynamics simulations. The center of mass of the confined fluid is shown to perform a stochastic, non-Markovian motion, whose diffusion coefficient satisfies Einstein's relation, and which can be further characterized by the fluctuation relation. Next, we develop an analytical description of the thermally induced fluid motion. We compute the time- and space-dependent velocity correlation function, and characterize its dependence on the nanopore shape, size, and boundary slip at the surface. The experimental implications for mass and charge transports are discussed for two situations. For a particle confined within the nanopore, we show that the fluid fluctuating motion results in an enhanced diffusion. The second situation involves a charged nanopore in which fluid motion within the double layer induces a fluctuating electric current. We compute the corresponding contribution to the current power spectrum. PMID- 23944414 TI - Synchronization of stochastic oscillators in biochemical systems. AB - We investigate the synchronization of stochastic oscillations in biochemical models by calculating the complex coherence function within the linear noise approximation. The method is illustrated on a simple example and then applied to study the synchronization of chemical concentrations in social amoeba. The degree to which variation of rate constants in different cells and the volume of the cells affects synchronization of the oscillations is explored and the phase lag calculated. In all cases the analytical results are shown to be in good agreement with those obtained through numerical simulations. PMID- 23944415 TI - Matrix-valued Boltzmann equation for the nonintegrable Hubbard chain. AB - The standard Fermi-Hubbard chain becomes nonintegrable by adding to the nearest neighbor hopping additional longer range hopping amplitudes. We assume that the quartic interaction is weak and investigate numerically the dynamics of the chain on the level of the Boltzmann type kinetic equation. Only the spatially homogeneous case is considered. We observe that the huge degeneracy of stationary states in the case of nearest neighbor hopping is lost and the convergence to the thermal Fermi-Dirac distribution is restored. The convergence to equilibrium is exponentially fast. However for small next-nearest neighbor hopping amplitudes one has a rapid relaxation towards the manifold of quasistationary states and slow relaxation to the final equilibrium state. PMID- 23944416 TI - Statistical mechanics of a neutral point-vortex gas at low energy. AB - The statistics of a neutral point-vortex gas in an arbitrary two-dimensional simply connected and bounded container are investigated in the framework of the microcanonical ensemble, following the cumulant expansion method of Pointin and Lundgren [Phys. Fluids 19, 1459 (1976)]. The equation for vorticity fluctuations, obtained when a thermodynamic scaling limit is taken, is solved explicitly. The solution depends on an infinite sequence of negative "domain inverse temperatures," determined by the domain shape, which are obtained from solutions of a "vorticity mode" eigenvalue problem. An explicit expression for the thermodynamic curve relating inverse temperature and energy is found and is shown to depend on the geometry and not on the scale of the domain. Explicit formulas are then obtained for the time variance of the projection of the vorticity field onto each vorticity mode. The results are verified by two methods. First, for a chosen single-parameter family of domains, direct sampling of the microcanonical ensemble is used to demonstrate the accuracy of the formula for the thermodynamic curve. Second, direct numerical simulations are used to verify the formulas for the variance of the projections of the vorticity field, with convincing results. PMID- 23944417 TI - Metastability for the Blume-Capel model with distribution of magnetic anisotropy using different dynamics. AB - We investigate the relaxation time of magnetization or the lifetime of the metastable state for a spin S=1 square-lattice ferromagnetic Blume-Capel model with distribution of magnetic anisotropy (with small variances), using two different dynamics such as Glauber and phonon-assisted dynamics. At each lattice site, the Blume-Capel model allows three spin projections (+1, 0, -1) and a site dependent magnetic anisotropy parameter. For each dynamic, we examine the low temperature lifetime in two dynamic regions with different sizes of the critical droplet and at the boundary between the regions, within the single-droplet regime. We compute the average lifetime of the metastable state for a fixed lattice size, using both kinetic Monte Carlo simulations and the absorbing Markov chains method in the zero-temperature limit. We find that for both dynamics the lifetime obeys a modified Arrhenius-like law, where the energy barrier of the metastable state depends on the temperature and standard deviation of the distribution of magnetic anisotropy for a given field and magnetic anisotropy and that an explicit form of this dependence differs in different dynamic regions for different dynamics. Interestingly, the phonon-assisted dynamic prevents transitions between degenerate states, which results in a large increase in the energy barrier at the region boundary compared to that for the Glauber dynamic. However, the introduction of a small distribution of magnetic anisotropy allows the spin system to relax via lower-energy pathways such that the energy barrier greatly decreases. In addition, for the phonon-assisted dynamic, even the prefactor of the lifetime is substantially reduced for a broad distribution of magnetic anisotropy in both regions considered, in contrast to the Glauber dynamic. Our findings show that overall the phonon-assisted dynamic is more significantly affected by the distribution of magnetic anisotropy than the Glauber dynamic. PMID- 23944418 TI - Fluctuation effects in the pair-annihilation process with Levy dynamics. AB - We investigate the density decay in the pair-annihilation process A+A->? in the case when the particles perform anomalous diffusion on a cubic lattice. The anomalous diffusion is realized via Levy flights, which are characterized by long range jumps and lead to superdiffusive behavior. As a consequence, the critical dimension depends continuously on the control parameter of the Levy flight distribution. This instance is used to study the system close to the critical dimension by means of the nonperturbative renormalization group theory. Close to the critical dimension, the assumption of well-stirred reactants is violated by anticorrelations between the particles, and the law of mass action breaks down. The breakdown of the law of mass action is known to be caused by long-range fluctuations. We identify three interrelated consequences of these fluctuations. First, despite being a nonuniversal quantity and thus depending on the microscopic details, the renormalized reaction rate lambda(0) can be approximated by a universal law close to the critical dimension. The emergence of universality relies on the fact that long-range fluctuations suppress the influence of the underlying microscopic details. Second, as criticality is approached, the macroscopic reaction rate decreases such that the law of mass action loses its significance. And third, additional nonanalytic power law corrections complement the analytic law of mass action term. An increasing number of those corrections accumulate and give an essential contribution as the critical dimension is approached. We test our findings for two implementations of Levy flights that differ in the way they cross over to the normal diffusion in the limit sigma->2. PMID- 23944419 TI - Nonconvexity of the relative entropy for Markov dynamics: a Fisher information approach. AB - We show via counterexamples that relative entropy between the solution of a Markovian master equation and the steady state is not a convex function of time. We thus disprove the hypotheses that a general evolution principle of thermodynamics based on the decrease of the nonadiabatic entropy production could hold. However, we argue that a large separation of typical decay times is necessary for nonconvex solutions to occur, making concave transients extremely short lived with respect to the main relaxation modes. We describe a general method based on the Fisher information matrix to discriminate between generators that admit nonconvex solutions and those that do not. While initial conditions leading to concave transients are shown to be extremely fine-tuned, by our method we are able to select nonconvex initial conditions that are arbitrarily close to the steady state. Convexity does occur when the system is close to satisfying detailed balance or, more generally, when certain normality conditions of the decay modes are satisfied. Our results circumscribe the range of validity of a conjecture by Maes et al. [Phys. Rev. Lett. 107, 010601 (2011)] regarding monotonicity of the large deviation rate functional for the occupation probability, showing that while the conjecture might hold in the long-time limit, the conditions for Lyapunov's second criterion for stability are not met. PMID- 23944420 TI - Thermodynamics in the vicinity of a relativistic quantum critical point in 2+1 dimensions. AB - We study the thermodynamics of the relativistic quantum O(N) model in two space dimensions. In the vicinity of the zero-temperature quantum critical point (QCP), the pressure can be written in the scaling form P(T)=P(0)+N(T(3)/c(2))F(N)(Delta/T), where c is the velocity of the excitations at the QCP and |Delta| a characteristic zero-temperature energy scale. Using both a large-N approach to leading order and the nonperturbative renormalization group, we compute the universal scaling function F(N). For small values of N (N/~1) regimes, but fails to describe the nonmonotonic behavior of F(N) in the quantum critical regime. We discuss the renormalization-group flows in the various regimes near the QCP and make the connection with the quantum nonlinear sigma model in the renormalized classical regime. We compute the Berezinskii-Kosterlitz-Thouless transition temperature in the quantum O(2) model and find that in the vicinity of the QCP the universal ratio T(BKT)/rho(s)(0) is very close to pi/2, implying that the stiffness rho(s)(T(BKT)(-)) at the transition is only slightly reduced with respect to the zero-temperature stiffness rho(s)(0). Finally, we briefly discuss the experimental determination of the universal function F(2) from the pressure of a Bose gas in an optical lattice near the superfluid-Mott-insulator transition. PMID- 23944421 TI - Maximum power operation of interacting molecular motors. AB - We study the mechanical and thermodynamic properties of different traffic models for kinesin which are relevant in biological and experimental contexts. We find that motor-motor interactions play a fundamental role by enhancing the thermodynamic efficiency at maximum power of the motors, as compared to the noninteracting system, in a wide range of biologically compatible scenarios. We furthermore consider the case where the motor-motor interaction directly affects the internal chemical cycle and investigate the effect on the system dynamics and thermodynamics. PMID- 23944422 TI - Critical and umbilical points of a non-Gaussian random field. AB - Random fields in nature often have, to a good approximation, Gaussian characteristics. For such fields, the number of maxima and minima are the same. Furthermore, the relative densities of umbilical points, topological defects which can be classified into three types, have certain fixed values. Phenomena described by nonlinear laws can, however, give rise to a non-Gaussian contribution, causing a deviation from these universal values. We consider a random surface, whose height is given by a nonlinear function of a Gaussian field. We find that, as a result of the non-Gaussianity, the density of maxima and minima no longer match and we calculate the relative imbalance between the two. We also calculate the change in the relative density of umbilics. This allows us not only to detect a perturbation, but to determine its size as well. This geometric approach offers an independent way of detecting non-Gaussianity, which even works in cases where the field itself can not be probed directly. PMID- 23944423 TI - Linear response, fluctuation-dissipation, and finite-system-size effects in superdiffusion. AB - Levy walks (LWs) are a popular stochastic tool to model anomalous diffusion and have recently been used to describe a variety of phenomena. We study the linear response behavior of this generic model of superdiffusive LWs in finite systems to an external force field under both stationary and nonstationary conditions. These finite-size LWs are based on power-law waiting time distributions with a finite-time regularization at tau(c), such that the physical requirements are met to apply linear response theory and derive the power spectrum with the correct short frequency limit, without the introduction of artificial cutoffs. We obtain the generalized Einstein relation for both ensemble and time averages over the entire process time and determine the turnover to normal Brownian motion when the full system is explored. In particular, we obtain an exact expression for the long time diffusion constant as a function of the scaling exponent of the waiting time density and the characteristic time scale tau(c). PMID- 23944424 TI - Generalized potentials for a mean-field density functional theory of a three phase contact line. AB - We investigate generalized potentials for a mean-field density functional theory of a three-phase contact line. Compared to the symmetrical potential introduced in our previous article [Phys. Rev. E 85, 011120 (2012)], the three minima of these potentials form a small triangle located arbitrarily within the Gibbs triangle, which is more realistic for ternary fluid systems. We multiply linear functions that vanish at edges and vertices of the small triangle, yielding potentials in the form of quartic polynomials. We find that a subset of such potentials has simple analytic far-field solutions and is a linear transformation of our original potential. By scaling, we can relate their solutions to those of our original potential. For special cases, the lengths of the sides of the small triangle are proportional to the corresponding interfacial tensions. For the case of equal interfacial tensions, we calculate a line tension that is proportional to the area of the small triangle. PMID- 23944425 TI - Out-of-equilibrium one-dimensional disordered dipole chain. AB - We consider a chain of one-dimensional dipole moments connected to two thermal baths with different temperatures. The system is in nonequilibrium steady state and heat flows through it. Assuming that fluctuation of the dipole moment is a small parameter, we develop an analytically solvable model for the problem. The effect of disorder is introduced by randomizing the positions of the dipole moments. We show that the disorder leads to Anderson-like transition from conducting to a thermal insulating state of the chain. It is shown that considered chain supports both ballistic and diffusive heat transports depending on the strength of the disorder. We demonstrate that nonequilibrium leads to the emergence of the long-range order between dipoles along the chain and make the conjecture that the interplay between nonequilibrium and next-to-nearest-neighbor interactions results in the emergence of long-range correlations in low dimensional classical systems. PMID- 23944426 TI - Trajectory phase transitions and dynamical Lee-Yang zeros of the Glauber-Ising chain. AB - We examine the generating function of the time-integrated energy for the one dimensional Glauber-Ising model. At long times, the generating function takes on a large-deviation form and the associated cumulant generating function has singularities corresponding to continuous trajectory (or "space-time") phase transitions between paramagnetic trajectories and ferromagnetically or antiferromagnetically ordered trajectories. In the thermodynamic limit, the singularities make up a whole curve of critical points in the complex plane of the counting field. We evaluate analytically the generating function by mapping the generator of the biased dynamics to a non-Hermitian Hamiltonian of an associated quantum spin chain. We relate the trajectory phase transitions to the high-order cumulants of the time-integrated energy which we use to extract the dynamical Lee-Yang zeros of the generating function. This approach offers the possibility to detect continuous trajectory phase transitions from the finite time behavior of measurable quantities. PMID- 23944427 TI - Potential condensed-matter realization of space-fractional quantum mechanics: the one-dimensional Levy crystal. AB - We introduce and discuss the one-dimensional Levy crystal as a probable candidate for an experimentally accessible realization of space-fractional quantum mechanics (SFQM) in a condensed-matter environment. The discretization of the space-fractional Schrodinger equation with the help of shifted Grunwald-Letnikov derivatives delivers a straightforward route to define the Levy crystal of order alphaepsilon(1,2]. As key ingredients for its experimental identification we study the dispersion relation as well as the density of states for arbitrary alphaepsilon(1,2]. It is demonstrated that in the limit of small wave numbers all interesting properties of continuous-space SFQM are recovered, while for alpha->2 the well-established nearest-neighbor one-dimensional tight-binding chain arises. PMID- 23944428 TI - First-passage characteristics of biased diffusion in a planar wedge. AB - We obtain compact, exact, analytical expressions for the first-passage-time distribution for a particle undergoing biased diffusion in a planar wedge for wedge angles pi/p, where p is a positive integer. We then provide the long-time limit of the first-passage time and found it to be dependent on the drift direction and wedge angle. We finally provide exact expressions for the mean first-passage time for specific cases. PMID- 23944429 TI - Ising model of a glass transition. AB - Numerical simulations by Tanaka and co-workers indicate that glass-forming systems of moderately polydisperse hard-core particles, in both two and three dimensions, exhibit diverging correlation lengths. These correlations are described by Ising-like critical exponents, and are associated with diverging, Vogel-Fulcher-Tamann, structural relaxation times. Related simulations of thermalized hard disks indicate that the curves of pressure versus packing fraction for different polydispersities exhibit a sequence of transition points, starting with a liquid-hexatic transition for the monodisperse case, and crossing over with increasing polydispersity to glassy, Ising-like critical points. I propose to explain these observations by assuming that glass-forming fluids contain twofold degenerate, locally ordered clusters of particles, similar to the two-state systems that have been invoked to explain other glassy phenomena. This paper starts with a brief statistical derivation of the thermodynamics of thermalized, hard-core particles. It then discusses how a two-state, Ising-like model can be described within that framework in terms of a small number of statistically relevant, internal state variables. The resulting theory agrees accurately with the simulation data. I also propose a rationale for the observed relation between the Ising-like correlation lengths and the Vogel-Fulcher-Tamann formula. PMID- 23944430 TI - Noise-induced rupture process: phase boundary and scaling of waiting time distribution. AB - A bundle of fibers has been considered here as a model for composite materials, where breaking of the fibers occur due to a combined influence of applied load (stress) and external noise. Through numerical simulation and a mean-field calculation we show that there exists a robust phase boundary between continuous (no waiting time) and intermittent fracturing regimes. In the intermittent regime, throughout the entire rupture process avalanches of different sizes are produced and there is a waiting time between two consecutive avalanches. The statistics of waiting times follows a Gamma distribution and the avalanche distribution shows power-law scaling, similar to what has been observed in the case of earthquake events and bursts in fracture experiments. We propose a prediction scheme that can tell when the system is expected to reach the continuous fracturing point from the intermittent phase. PMID- 23944431 TI - Immigration-extinction dynamics of stochastic populations. AB - How high should be the rate of immigration into a stochastic population in order to significantly reduce the probability of observing the population become extinct? Is there any relation between the population size distributions with and without immigration? Under what conditions can one justify the simple patch occupancy models, which ignore the population distribution and its dynamics in a patch, and treat a patch simply as either occupied or empty? We answer these questions by exactly solving a simple stochastic model obtained by adding a steady immigration to a variant of the Verhulst model: a prototypical model of an isolated stochastic population. PMID- 23944432 TI - Residual discrete symmetry of the five-state clock model. AB - It is well known that the q-state clock model can exhibit a Kosterlitz-Thouless (KT) transition if q is equal to or greater than a certain threshold, which has been believed to be five. However, recent numerical studies indicate that helicity modulus does not vanish in the high-temperature phase of the five-state clock model as predicted by the KT scenario. By performing Monte Carlo calculations under the fluctuating twist boundary condition, we show that it is because the five-state clock model does not have the fully continuous U(1) symmetry even in the high-temperature phase while the six-state clock model does. We suggest that the upper transition of the five-state clock model is actually a weaker cousin of the KT transition so that it is q>=6 that exhibits the genuine KT behavior. PMID- 23944433 TI - Scattering and transport properties of tight-binding random networks. AB - We study numerically scattering and transport statistical properties of tight binding random networks characterized by the number of nodes N and the average connectivity alpha. We use a scattering approach to electronic transport and concentrate on the case of a small number of single-channel attached leads. We observe a smooth crossover from insulating to metallic behavior in the average scattering matrix elements <|S(mn)|(2)>, the conductance probability distribution w(T), the average conductance , the shot noise power P, and the elastic enhancement factor F by varying alpha from small (alpha->0) to large (alpha->1) values. We also show that all these quantities are invariant for fixed xi=alphaN. Moreover, we proposes a heuristic and universal relation between <|S(mn)|(2)>, , and P and the disorder parameter xi. PMID- 23944434 TI - Packing and self-assembly of truncated triangular bipyramids. AB - Motivated by breakthroughs in the synthesis of faceted nano- and colloidal particles, as well as theoretical and computational studies of their packings, we investigate a family of truncated triangular bipyramids. We report dense periodic packings with small unit cells that were obtained via numerical and analytical optimization. The maximal packing fraction phi(max) changes continuously with the truncation parameter t. Eight distinct packings are identified based on discontinuities in the first and second derivatives of phi(max)(t). These packings differ in the number of particles in the fundamental domain (unit cell) and the type of contacts between the particles. In particular, we report two packings with four particles in the unit cell for which both phi(max)(t) and phi(max)'(t) are continuous and the discontinuity occurs in the second derivative only. In the self-assembly simulations that we perform for larger boxes with 2048 particles, only one out of eight packings is found to assemble. In addition, the degenerate quasicrystal reported previously for triangular bipyramids without truncation [Haji-Akbari et al., Phys. Rev. Lett. 107, 215702 (2011)] assembles for truncations as high as 0.45. The self-assembly propensities for the structures formed in the thermodynamic limit are explained using the isoperimetric quotient of the particles and the coordination number in the disordered fluid and in the assembled structure. PMID- 23944435 TI - Thermal balance and quantum heat transport in nanostructures thermalized by local Langevin heat baths. AB - Modeling of thermal transport in practical nanostructures requires making tradeoffs between the size of the system and the completeness of the model. We study quantum heat transfer in a self-consistent thermal bath setup consisting of two lead regions connected by a center region. Atoms both in the leads and in the center region are coupled to quantum Langevin heat baths that mimic the damping and dephasing of phonon waves by anharmonic scattering. This approach treats the leads and the center region on the same footing and thereby allows for a simple and physically transparent thermalization of the system, enabling also perfect acoustic matching between the leads and the center region. Increasing the strength of the coupling reduces the mean-free path of phonons and gradually shifts phonon transport from ballistic regime to diffusive regime. In the center region, the bath temperatures are determined self-consistently from the requirement of zero net energy exchange between the local heat bath and each atom. By solving the stochastic equations of motion in frequency space and averaging over noise using the general fluctuation-dissipation relation derived by Dhar and Roy [J. Stat. Phys. 125, 801 (2006)], we derive the formula for thermal current, which contains the Caroli formula for phonon transmission function and reduces to the Landauer-Buttiker formula in the limit of vanishing coupling to local heat baths. We prove that the bath temperatures measure local kinetic energy and can, therefore, be interpreted as true atomic temperatures. In a setup where phonon reflections are eliminated, the Boltzmann transport equation under gray approximation with full phonon dispersion is shown to be equivalent to the self-consistent heat bath model. We also study thermal transport through two dimensional constrictions in square lattice and graphene and discuss the differences between the exact solution and linear approximations. PMID- 23944436 TI - Criticalities of the transverse- and longitudinal-field fidelity susceptibilities for the d=2 quantum Ising model. AB - The inner product between the ground-state eigenvectors with proximate interaction parameters, namely, the fidelity, plays a significant role in the quantum dynamics. In this paper, the critical behaviors of the transverse- and longitudinal-field fidelity susceptibilities for the d=2 quantum (transverse field) Ising model are investigated by means of the numerical-diagonalization method; the former susceptibility has been investigated rather extensively. The critical exponents for these fidelity susceptibilities are estimated as alpha(F)((t))=0.752(24) and alpha(F)((h))=1.81(13), respectively. These indices are independent, and suffice for obtaining conventional critical indices such as nu=0.624(12) and gamma=1.19(13). PMID- 23944437 TI - Quantum dynamical framework for Brownian heat engines. AB - We present a self-contained formalism modeled after the Brownian motion of a quantum harmonic oscillator for describing the performance of microscopic Brownian heat engines such as Carnot, Stirling, and Otto engines. Our theory, besides reproducing the standard thermodynamics results in the steady state, enables us to study the role dissipation plays in determining the efficiency of Brownian heat engines under actual laboratory conditions. In particular, we analyze in detail the dynamics associated with decoupling a system in equilibrium with one bath and recoupling it to another bath and obtain exact analytical results, which are shown to have significant ramifications on the efficiencies of engines involving such a step. We also develop a simple yet powerful technique for computing corrections to the steady state results arising from finite operation time and use it to arrive at the thermodynamic complementarity relations for various operating conditions and also to compute the efficiencies of the three engines cited above at maximum power. Some of the methods and exactly solvable models presented here are interesting in their own right and could find useful applications in other contexts as well. PMID- 23944438 TI - Critical behavior of the XY-rotor model on regular and small-world networks. AB - We study the XY rotors model on small networks whose number of links scales with the system size N(links)~N(gamma), where 1<=gamma<=2. We first focus on regular one-dimensional rings in the microcanonical ensemble. For gamma<1.5 the model behaves like a short-range one and no phase transition occurs. For gamma>1.5, the system equilibrium properties are found to be identical to the mean field, which displays a second-order phase transition at a critical energy density epsilon=E/N,epsilon(c)=0.75. Moreover, for gamma(c)~/=1.5 we find that a nontrivial state emerges, characterized by an infinite susceptibility. We then consider small-world networks, using the Watts-Strogatz mechanism on the regular networks parametrized by gamma. We first analyze the topology and find that the small-world regime appears for rewiring probabilities which scale as p(SW)[proportionality]1/N(gamma). Then considering the XY-rotors model on these networks, we find that a second-order phase transition occurs at a critical energy epsilon(c) which logarithmically depends on the topological parameters p and gamma. We also define a critical probability p(MF), corresponding to the probability beyond which the mean field is quantitatively recovered, and we analyze its dependence on gamma. PMID- 23944439 TI - Model for the catalytic oxidation of CO, including gas-phase impurities and CO desorption. AB - We present results of kinetic Monte Carlo simulations of a modified Ziff-Gulari Barshad model for the reaction CO+O -> CO(2) on a catalytic surface. Our model includes impurities in the gas phase, CO desorption, and a modification known to eliminate the unphysical O poisoned phase. The impurities can adsorb and desorb on the surface, but otherwise remain inert. In a previous work that did not include CO desorption [Buendia and Rikvold, Phys. Rev. E 85, 031143 (2012)], we found that the impurities have very distinctive effects on the phase diagram and greatly diminish the reactivity of the system. If the impurities do not desorb, once the system reaches a stationary state, the CO(2) production disappears. When the impurities are allowed to desorb, there are regions where the CO(2) reaction window reappears, although greatly reduced. Following experimental evidence that indicates that temperature effects are crucial in many catalytic processes, here we further analyze these effects by including a CO desorption rate. We find that the CO desorption has the effect to smooth the transition between the reactive and the CO rich phase, and most importantly it can counteract the negative effects of the presence of impurities by widening the reactive window such that now the system remains catalytically active in the whole range of CO pressures. PMID- 23944440 TI - Self-similar evolution of the A-particle island-semi-infinite B-particle sea reaction-diffusion system. AB - We consider diffusion-controlled evolution of the A-particle island-semi-infinite B-particle sea system at propagation of the sharp annihilation front A+B->0. We show that at a large initial number of island particles the system evolution is described by the universal scaling laws with nonmonotonous front trajectory and a constant velocity of the island center motion. We demonstrate that asymptotically the island moves self-similarly retaining its velocity, shape and width. PMID- 23944441 TI - Reentrant disordered phase in a system of repulsive rods on a Bethe-like lattice. AB - We solve exactly a model of monodispersed rigid rods of length k with repulsive interactions on the random locally tree-like layered lattice. For k>=4 we show that with increasing density, the system undergoes two phase transitions: first, from a low-density disordered phase to an intermediate density nematic phase and, second, from the nematic phase to a high-density reentrant disordered phase. When the coordination number is four, both phase transitions are continuous and in the mean field Ising universality class. For an even coordination number larger than four, the first transition is discontinuous, while the nature of the second transition depends on the rod length k and the interaction parameters. PMID- 23944442 TI - Collective transport in the discrete Frenkel-Kontorova model. AB - Through multiscale analysis of the adjoint Fokker-Planck equation, strict bounds are derived for the center of mass diffusivity of an overdamped harmonic chain in a periodic potential, often known as the discrete Frenkel-Kontorova model. Significantly, it is shown that the free energy barrier is a lower bound to the true finite temperature migration barrier for this general and popular system. Numerical simulation confirms the analysis, while effective migration potentials implied by the bounds are employed to give a surprisingly accurate prediction of the nonlinear response. PMID- 23944443 TI - Mechanical properties of warped membranes. AB - We explore how a frozen background metric affects the mechanical properties of planar membranes with a shear modulus. We focus on a special class of "warped membranes" with a preferred random height profile characterized by random Gaussian variables h(q) in Fourier space with zero mean and variance <|h(q)|(2)>~q(-d(h)) and show that in the linear response regime the mechanical properties depend dramatically on the system size L for d(h)>=2. Membranes with d(h)=4 could be produced by flash polymerization of lyotropic smectic liquid crystals. Via a self-consistent screening approximation we find that the renormalized bending rigidity increases as kappa(R)~L((d(h)-2)/2) for membranes of size L, while the Young and shear moduli decrease according to Y(R),MU(R)~L( (d(h)-2)/2) resulting in a universal Poisson ratio. Numerical results show good agreement with analytically determined exponents. PMID- 23944444 TI - Critical Casimir torques and forces acting on needles in two spatial dimensions. AB - We investigate the universal orientation-dependent interactions between nonspherical colloidal particles immersed in a critical solvent by studying the instructive paradigm of a needle embedded in bounded two-dimensional Ising models at bulk criticality. For a needle in an Ising strip, the interaction on mesoscopic scales depends on the width of the strip and the length, position, and orientation of the needle. By lattice Monte Carlo simulations we evaluate the free-energy difference between needle configurations being parallel and perpendicular to the strip. We concentrate on small but nonetheless mesoscopic needle lengths for which analytic predictions are available for comparison. All combinations of boundary conditions for the needles and boundaries are considered which belong to either the "normal" or the "ordinary" surface universality class, i.e., which induce local order or disorder, respectively. We also derive exact results for needles of arbitrary mesoscopic length, in particular for needles embedded in a half plane and oriented perpendicularly to the corresponding boundary as well as for needles embedded at the center line of a symmetric strip with parallel orientation. PMID- 23944445 TI - Nonlinear least-squares method for the inverse droplet coagulation problem. AB - If the rates, K(x,y), at which particles of size x coalesce with particles of size y is known, then the mean-field evolution of the particle size distribution of an ensemble of irreversibly coalescing particles is described by the Smoluchowski equation. We study the corresponding inverse problem which aims to determine the coalescence rates K(x,y) from measurements of the particle size distribution. We assume that K(x,y) is a homogeneous function of its arguments, a case which occurs commonly in practice. The problem of determining K(x,y), a function to two variables, then reduces to the simpler problem of determining a function of a single variable plus two exponents, MU and nu, which characterize the scaling properties of K(x,y). The price of this simplification is that the resulting least-squares problem is nonlinear in the exponents MU and nu. We demonstrate the effectiveness of the method on a selection of coalescence problems arising in polymer physics, cloud science, and astrophysics. The applications include examples in which the particle size distribution is stationary owing to the presence of sources and sinks of particles and examples in which the particle size distribution is undergoing self-similar relaxation in time. PMID- 23944446 TI - Capillary condensation in one-dimensional irregular confinement. AB - A lattice-gas model with heterogeneity is developed for the description of fluid condensation in finite sized one-dimensional pores of arbitrary shape. Mapping to the random-field Ising model allows an exact solution of the model to be obtained at zero-temperature, reproducing the experimentally observed dependence of the amount of fluid adsorbed in the pore on external pressure. It is demonstrated that the disorder controls the sorption for long pores and can result in H2-type hysteresis. Finite-temperature Metropolis dynamics simulations support analytical findings in the limit of low temperatures. The proposed framework is viewed as a fundamental building block of the theory of capillary condensation necessary for reliable structural analysis of complex porous media from adsorption-desorption data. PMID- 23944447 TI - Phase transitions of the p-spin model on pure Husimi lattices. AB - We consider the p-spin model with spin 1/2 on all pure Husimi lattices. Using an effective representation of the recursion relations, the phase transitions of the model on all pure Husimi lattices are investigated. First, the nonexistence of the second order phase transitions in the model on all pure Husimi lattices is proven exactly. Then the existence and properties of the first order phase transitions in a zero external magnetic field are studied in detail. An implicit polynomial equation for determining temperatures below which the paramagnetic and ferromagnetic phases coexist in the model on all pure Husimi lattices is found. In addition, an implicit equation for exactly determining the transition temperatures of the first order phase transitions in a zero external magnetic field on all pure Husimi lattices is derived and discussed. PMID- 23944448 TI - Oscillating gas flow induces reptation of granular droplets. AB - We report on the reptation of vertically vibrated droplets of fine particles lying on a solid incline. On the one hand, time-resolved measurements show that the gas pressure in the gap between the droplet bottom and the solid surface can be accounted for by a Darcy law. The cumulative effect of the viscous drag is responsible for the droplet formation. On the other hand, we show that the gap pressure is responsible for an effective horizontal acceleration whose cumulative effect is the upward reptation of the droplets. Using various geometries of the solid substrate, we manipulate the droplets and study the effects of the substrate geometry and of the experimental parameters on the droplet shape and dynamics. The experimental results are discussed in the light of theoretical arguments. This study demonstrates that, by the choice of a suitable geometry of the surface and characteristics of the vibration, one can develop tools for precise powder handling and control. PMID- 23944449 TI - How dynamical clustering triggers Maxwell's demon in microgravity. AB - In microgravity, the gathering of granular material can be achieved by a dynamical clustering whose existence depends on the geometry of the cell that contains the particles and the energy that is injected into the system. By compartmentalizing the cell in several subcells of smaller volume, local clustering is triggered and the so formed dense regions act as stable traps. In this paper, molecular dynamics simulations were performed in order to reproduce the phenomenon and to analyze the formation and the stability of such traps. Depending on the total number N of particles present in the whole system, several clustering modes are encountered and a corresponding bifurcation diagram is presented. Moreover, an iterative model based on the measured particle flux F as well as a theoretical model giving the asymptotical steady states are used to validate our results. The obtained results are promising and can provide ways to manipulate grains in microgravity. PMID- 23944450 TI - Granular avalanches in a two-dimensional rotating drum with imposed vertical vibration. AB - We present statistics on granular avalanches in a rotating drum with and without imposed vertical vibration. The experiment consists of a quasi-two-dimensional, vertical drum containing pentagonal particles and rotated at a constant angular velocity. The drum rests on an electromagnetic shaker to allow vibration of the assembly as it rotates. We measure time series of the slope of the interface and find that the critical angle for slope failure theta(c) and the resulting angle of repose theta(r) are broadly distributed with an approximate power-law distribution of avalanches theta(c)-theta(r) for large avalanches. The faceted pentagonal grains used lead to significant interlocking with critical and repose angles (theta(c)~45 degrees and theta(r)~39 degrees ) larger than experiments using spherical grains, even with vibration, and avalanche magnitudes correlated with the prior build-up and anti-correlated with the prior avalanche. We find that the stability of the assembly increases with small vibrations and is destabilized at vibration amplitudes above a dimensionless acceleration (peak acceleration divided by acceleration due to gravity) of Gamma=0.2. We also study history dependence of the avalanches by periodically oscillating the drum to compare the initial avalanche upon reversal of shear to steady-state distributions for avalanches during continuous rotation. We observe history dependence as an initial decrease in critical angle upon reversal of the drum rotation direction, indicating that a texture is induced to resist continued shear such that the surface is weaker to reversals in shear direction. Memory of this history is removed by sufficient external vibration (Gamma>=0.8), which leads to compaction and relaxation of the surface layer grains responsible for avalanching dynamics, as initial and steady-state avalanche distributions become indistinguishable. PMID- 23944451 TI - Lift and drag in intruders moving through hydrostatic granular media at high speeds. AB - Recently, experiments showed that forces on intruders dragged horizontally through dense, hydrostatic granular packings mainly depend on the local surface orientation and can be seen as the sum of the forces exerted on small surface elements. In order to understand such forces more deeply, we perform a two dimensional soft-sphere molecular dynamics simulation, on a similar setup, of an intruder dragged through a 50-50 bi-disperse granular packing, with diameters 0.30 and 0.34 cm. We measure, for both circular and half-circle shapes, the forces parallel (drag) and perpendicular (lift) to the drag direction as functions of the drag speed, with V=10.3-309 cm/s, and intruder depths, with D=3.75-37.5 cm. The drag forces on an intruder monotonically increase with V and D, and are larger for the circle. However, the lift force does not depend monotonically on V and D, and this relationship is affected by the shape of the intruder. The vertical force was negative for the half-circle, but for a small range of V and D, we measure positive lift. We find no sign change for the lift on the circle, which is always positive. The explanation for the nonmonotonic dependence is related to the decrease in contacts on the intruder as V increases. This is qualitatively similar to supersonic flow detachment from an obstacle. The detachment picture is supported by simulation measurements of the velocity field around the intruder and force profiles measured on its surface. PMID- 23944452 TI - Distribution of breakage events in random packings of rodlike particles. AB - Uniaxial compaction and breakage of rodlike particle packing has been studied using a discrete element method simulation. A scaling relationship between the applied stress, the number of breakage events, and the number-mean particle length has been derived and compared with computational experiments. Based on results for a wide range of intrinsic particle strengths and initial particle lengths, it seems that a single universal relation can be used to describe the incidence of breakage events during compaction of rodlike particle layers. PMID- 23944453 TI - Frequency bands of strongly nonlinear homogeneous granular systems. AB - Recent numerical studies on an infinite number of identical spherical beads in Hertzian contact showed the presence of frequency bands [Jayaprakash, Starosvetsky, Vakakis, Peeters, and Kerschen, Nonlinear Dyn. 63, 359 (2011)]. These bands, denoted here as propagation and attenuation bands (PBs and ABs), are typically present in linear or weakly nonlinear periodic media; however, their counterparts are not intuitive in essentially nonlinear periodic media where there is a complete lack of classical linear acoustics, i.e., in "sonic vacua." Here, we study the effects of PBs and ABs on the forced dynamics of ordered, uncompressed granular systems. Through numerical and experimental techniques, we find that the dynamics of these systems depends critically on the frequency and amplitude of the applied harmonic excitation. For fixed forcing amplitude, at lower frequencies, the oscillations are large in amplitude and governed by strongly nonlinear and nonsmooth dynamics, indicating PB behavior. At higher frequencies the dynamics is weakly nonlinear and smooth, in the form of compressed low-amplitude oscillations, indicating AB behavior. At the boundary between the PB and the AB large-amplitude oscillations due to resonance occur, giving rise to collisions between beads and chaotic dynamics; this renders the forced dynamics sensitive to initial and forcing conditions, and hence unpredictable. Finally, we study asymptotically the near field standing wave dynamics occurring for high frequencies, well inside the AB. PMID- 23944454 TI - Two-state model to describe the rheological behavior of vibrated granular matter. AB - In this paper, we present a model aimed at predicting the rheological response of a 3D dry granular system to nonstationary mechanical solicitations, subjected or not to vibrations. This model is based on a phenomenological two-state approach related to the inherent bimodal behavior of chain forces in granular packing. It is set up from a kinetic equation describing the dynamics of the contact network. To allow experimental assessment, the kinetic equation is transformed into a differential constitutive equation, relating stress to strain, from which rheological properties can be derived. Its integration allows predicting and describing several rheological behaviors, in stationary and nonstationary conditions, including viscous (Newtonian) and frictional (Coulombian) regimes, as well as elastic linear (Hookean and Maxwellian) and nonlinear behaviors. Despite its simplicity, since it involves only three independent parameters, the model is in very close agreement with experiments. Moreover, within experimental errors, the values of these parameters are independent of the type of test used to determine them, evidence of the self-consistency of the model. PMID- 23944455 TI - Slow axial drift in three-dimensional granular tumbler flow. AB - Models of monodisperse particle flow in partially filled three-dimensional tumblers often assume that flow along the axis of rotation is negligible. We test this assumption, for spherical and double cone tumblers, using experiments and discrete element method simulations. Cross sections through the particle bed of a spherical tumbler show that, after a few rotations, a colored band of particles initially perpendicular to the axis of rotation deforms: particles near the surface drift toward the pole, while particles deeper in the flowing layer drift toward the equator. Tracking of mm-sized surface particles in tumblers with diameters of 8-14 cm shows particle axial displacements of one to two particle diameters, corresponding to axial drift that is 1-3% of the tumbler diameter, per pass through the flowing layer. The surface axial drift in both double cone and spherical tumblers is zero at the equator, increases moving away from the equator, and then decreases near the poles. Comparing results for the two tumbler geometries shows that wall slope causes axial drift, while drift speed increases with equatorial diameter. The dependence of axial drift on axial position for each tumbler geometry is similar when both are normalized by their respective maximum values. PMID- 23944456 TI - Three-dimensional simulations of nanopowder compaction processes by granular dynamics method. AB - In order to describe and to study the processes of cold compaction within the discrete element method a three-dimensional model of nanosized powder is developed. The elastic forces of repulsion, the tangential forces of "friction" (Cattaneo-Mindlin), and the dispersion forces of attraction (van der Waals Hamaker), as well as the formation and destruction of hard bonds between the individual particles are taken into account. The monosized powders with the size of particles in the range 10-40 nm are simulated. The simulation results are compared to the experimental data of the alumina nanopowders compaction. It is shown that the model allows us to reproduce experimental data reliably and, in particular, describes the size effect in the compaction processes. A number of different external loading conditions is used in order to perform the theoretical and experimental researches. The uniaxial compaction (the closed-die compaction), the biaxial (radial) compaction, and the isotropic compaction (the cold isostatic pressing) are studied. The real and computed results are in a good agreement with each other. They reveal a weak sensitivity of the oxide nanopowders to the loading condition (compaction geometry). The application of the continuum theory of the plastically hardening porous body, which is usually used for the description of powders, is discussed. PMID- 23944457 TI - Flow pattern in the vicinity of self-propelling hot Janus particles. AB - We study the temperature field and the resulting flow pattern in the vicinity of a heated metal-capped Janus particle. If its thickness exceeds about 10 nm, the cap forms an isotherm and the flow pattern comprises a quadrupolar term that decays with the square of the inverse distance ~r(-2). For much thinner caps the velocity varies as ~r(-3). These findings could be relevant for collective effects in dense suspensions and for the circular tracer motion observed recently in the vicinity of a tethered Janus particle. PMID- 23944458 TI - Precursors of order in aggregates of patchy particles. AB - We study computationally the local structure of aggregated systems of patchy particles. By calculating the probability distribution functions of various rotational invariants we can identify the precursors of orientation order in amorphous phase. Surprisingly, the strongest signature of local order is observed for four-patch particles with tetrahedral symmetry, not for six-patch particles with the cubic one. This trend is exactly opposite to their known ability to crystallize. We relate this anomaly to the observation that a generic aggregate of patchy systems has a coordination number close to 4. Our results also suggest a significant correlation between rotational order in the studied liquids with the corresponding crystalline phases, making this approach potentially useful for a broader range of patchy systems. PMID- 23944459 TI - Anisotropic aggregation in a simple model of isotropically polymer-coated nanoparticles. AB - We report a numerical study of a simple, modified Asakura-Oosawa model for nanoparticles that are isotropically grafted with polymer chains. We perform canonical and grand-canonical Monte Carlo simulations to establish a qualitative morphology diagram, as well as quantitative phase diagrams. The morphology diagram qualitatively reproduces experimental observations and theoretical approaches employing more complex models. In addition, we establish the transition lines for a microphase separation and show that the phase behavior saturates for larger polymer sizes. An analytical treatment on the level of the second virial coefficient indicates that this saturation effect is caused by less effective shielding of nanoparticles by longer polymers. Our simple model enables large-scale particle-based simulations of self-assembly of polymer-coated particles. PMID- 23944460 TI - Mixing-demixing phase diagram for simple liquids in nonuniform electric fields. AB - We deduce the mixing-demixing phase diagram for binary liquid mixtures in an electric field for various electrode geometries and arbitrary constitutive relation for the dielectric constant. By focusing on the behavior of the liquid liquid interface, we produce simple analytic expressions for the dependence of the interface location on experimental parameters. We also show that the phase diagram contains regions where liquid separation cannot occur under any applied field. The analytic expression for the boundary "electrostatic binodal" line reveals that the regions' size and shape depend strongly on the dielectric relation between the liquids. Moreover, we predict the existence of an "electrostatic spinodal" line that identifies conditions where the liquids are in a metastable state. We finally construct the phase diagram for closed systems by mapping solutions onto those of an open system via an effective liquid composition. For closed systems at a fixed temperature and mixture composition, liquid separation occurs in a finite "window" of surface potential (or charge density). Higher potentials or charge densities counterintuitively destroy the interface, leading to liquid mixing. These results give valuable guides for experiments by providing easily testable predictions for how liquids behave in nonuniform electric fields. PMID- 23944461 TI - Reentrant phase behavior in active colloids with attraction. AB - Motivated by recent experiments, we study a system of self-propelled colloids that experience short-range attractive interactions and are confined to a surface. Using simulations we find that the phase behavior for such a system is reentrant as a function of activity: phase-separated states exist in both the low and high-activity regimes, with a homogeneous active fluid in between. To understand the physical origins of reentrance, we develop a kinetic model for the system's steady-state dynamics whose solution captures the main features of the phase behavior. We also describe the varied kinetics of phase separation, which range from the familiar nucleation and growth of clusters to the complex coarsening of active particle gels. PMID- 23944462 TI - Crystallization dynamics on curved surfaces. AB - We study the evolution from a liquid to a crystal phase in two-dimensional curved space. At early times, while crystal seeds grow preferentially in regions of low curvature, the lattice frustration produced in regions with high curvature is rapidly relaxed through isolated defects. Further relaxation involves a mechanism of crystal growth and defect annihilation where regions with high curvature act as sinks for the diffusion of domain walls. The pinning of grain boundaries at regions of low curvature leads to the formation of a metastable structure of defects, characterized by asymptotically slow dynamics of ordering and activation energies dictated by the largest curvatures of the system. These glassylike ordering dynamics may completely inhibit the appearance of the ground-state structures. PMID- 23944463 TI - Shape and symmetry of a fluid-supported elastic sheet. AB - A connection between the dynamics of a sine-Gordon chain and a certain static membrane folding problem was recently found. The one-dimensional membrane profile is a cross section of the position-time sine-Gordon amplitude profile. Here we show that when one system is embedded in a higher-dimensional system in this way, obvious symmetries in the larger system can lead to nontrivial symmetries in the embedded system. In particular, a thin buckled membrane on a fluid substrate has a continuous degeneracy that interpolates between a symmetric and an antisymmetric fold. We find the Hamiltonian generator of this symmetry and the corresponding conserved momentum by interpreting the simple translational symmetries of the sine-Gordon chain in terms of the embedded coordinates. We discuss possible extensions to other embedded dynamical systems. PMID- 23944464 TI - Stability of thin liquid films and sessile droplets under confinement. AB - The stability of nonvolatile thin liquid films and of sessile droplets is strongly affected by finite size effects. We analyze their stability within the framework of density functional theory using the sharp kink approximation, i.e., on the basis of an effective interface Hamiltonian. We show that finite size effects suppress spinodal dewetting of films because it is driven by a long wavelength instability. Therefore nonvolatile films are stable if the substrate area is too small. Similarly, nonvolatile droplets connected to a wetting film become unstable if the substrate area is too large. This instability of a nonvolatile sessile droplet turns out to be equivalent to the instability of a volatile drop which can attain chemical equilibrium with its vapor. PMID- 23944465 TI - Controlling negative and positive photothermal migration of centimeter-sized droplets. AB - The photoinduced motion of an oil droplet on an aqueous solution under local irradiation by a green laser is reported. The results showed that a repulsive force is generated on pure water, while an attractive force is observed with an aqueous solution containing a surfactant. The driving force is discussed in terms of a thermal Marangoni effect. The switching on the photothermal effect is interpreted by taking into account the advection caused by the spatial gradient of the surface tension under local heating by a laser. A numerical model revealed that the geometrical profile of the surface tension around the droplet determines the mode of advection around the droplet and causes switching in the direction of migrations. PMID- 23944466 TI - Evaporation dynamics of nanodroplets and their anomalous stability on rough substrates. AB - Nanodroplets sitting on substrates in an open system are usually assumed to be thermodynamically unstable, and will eventually either evaporate or grow. However, as a counterpart of nanodroplets, nanobubbles located at the solid liquid interface were recently demonstrated by numerous experiments to be unexpectedly stable. The accumulated evidence for the existence of stable nanobubbles poses a question of whether nanodroplets are stable. In this work we revisit the stability of nanodroplets upon smooth and rough substrates, concentrating on their evaporation dynamics. On smooth substrates, the droplets evaporate generally in the constant contact angle (CCA) mode, with a contact angle nonmonotonously depending on the fluid-substrate interaction, while on rough substrates, the droplets evaporate in the constant contact line (CCL) mode or the CCL-CCA mixed mode. Our results indeed predict the existence of stable nanodroplets on rough substrates: In situations where the contact line is pinned and the vapor is supersaturated but at a low level of supersaturation, nanodroplets are found to be anomalously stable. The stability of nanodroplets can be interpreted within the framework of the classical nucleation theory. PMID- 23944467 TI - Crystalline particle packings on constant mean curvature (Delaunay) surfaces. AB - We investigate the structure of crystalline particle arrays on constant mean curvature (CMC) surfaces of revolution. Such curved crystals have been realized physically by creating charge-stabilized colloidal arrays on liquid capillary bridges. CMC surfaces of revolution, classified by Delaunay in 1841, include the 2-sphere, the cylinder, the vanishing mean curvature catenoid (a minimal surface), and the richer and less investigated unduloid and nodoid. We determine numerically candidate ground-state configurations for 1000 pointlike particles interacting with a pairwise-repulsive 1/r(3) potential, with distance r measured in three-dimensional Euclidean space R(3). We mimic stretching of capillary bridges by determining the equilibrium configurations of particles arrayed on a sequence of Delaunay surfaces obtained by increasing or decreasing the height at constant volume starting from a given initial surface, either a fat cylinder or a square cylinder. In this case, the stretching process takes one through a complicated sequence of Delaunay surfaces, each with different geometrical parameters, including the aspect ratio, mean curvature, and maximal Gaussian curvature. Unduloids, catenoids, and nodoids all appear in this process. Defect motifs in the ground state evolve from dislocations at the boundary to dislocations in the interior to pleats and scars in the interior and then isolated sevenfold disclinations in the interior as the capillary bridge narrows at the waist (equator) and the maximal (negative) Gaussian curvature grows. We also check theoretical predictions that the isolated disclinations are present in the ground state when the surface contains a geodesic disk with integrated Gaussian curvature exceeding -pi/3. Finally, we explore minimal energy configurations on sets of slices of a given Delaunay surface, and we obtain configurations and defect motifs consistent with those seen in stretching. PMID- 23944468 TI - Independent control of polar and azimuthal anchoring. AB - Monte Carlo simulation, experiment, and continuum theory are used to examine the anchoring exhibited by a nematic liquid crystal at a patterned substrate comprising a periodic array of rectangles that, respectively, promote vertical and planar alignment. It is shown that the easy axis and effective anchoring energy promoted by such surfaces can be readily controlled by adjusting the design of the pattern. The calculations reveal rich behavior: for strong anchoring, as exhibited by the simulated system, for rectangle ratios >=2 the nematic aligns in the direction of the long edge of the rectangles, the azimuthal anchoring coefficient changing with pattern shape. In weak anchoring scenarios, however, including our experimental systems, preferential anchoring is degenerate between the two rectangle diagonals. Bistability between diagonally aligned and edge-aligned arrangement is predicted for intermediate combinations of anchoring coefficient and system length scale. PMID- 23944469 TI - Dielectric spectroscopy of T-shaped blue-phase-III liquid crystal. AB - Dielectric relaxation spectra of a liquid crystalline (LC) material showing blue phase-III (BPIII) for a considerably large temperature regime consisting of T shaped molecules are investigated. A low frequency relaxation mode is observed in the isotropic phase (I) as well as in BPIII of the investigating material which is attributed to the short axis rotation of the T-shaped molecules. The outcome of the temperature and dc bias field variation of dielectric strength (Deltaepsilon) and relaxation frequency (nu(c)) in the vicinity of the I-BPIII transition is also discussed. The temperature dependence of nu(c) in BPIII with a minor deviation from Arrhenius activities in the fluctuation-dominated nonlinear region (FDNLR) is found to follow the unusual thermal behavior of the activation energy (E(A)). The growth of pretransitional fluctuations is found to be nonlinear in the vicinity of the I-BPIII transition. A moderate growth of transition fluctuation commences from the value of the exponent alpha(eff)=0.38/ degrees C, which is obtained by an exponential variation of nu(c) with respect to temperature in BPIII. Observed dynamic phenomenon in the vicinity of the I-BPIII transition regions is explained on the basis of the Landau-de Gennes and Maier Saupe Theories. PMID- 23944470 TI - Controlling the thermodynamic stability of intermediate phases in a cationic amphiphile-water system with strongly binding counterions. AB - We have studied the influence of two structurally isomeric organic salts, namely, 2-sodium-3-hydroxy naphthoate (SHN) and 1-sodium-2-hydroxy naphthoate (SHN1), on the phase behavior of concentrated aqueous solutions of the cationic surfactant cetylpyridinium chloride (CPC). Partial phase diagrams of the two systems have been constructed using polarizing optical microscopy and x-ray diffraction techniques. A variety of intermediate phases is seen in both systems for a range of salt concentrations. The CPC-SHN-water system exhibits the rhombohedral and tetragonal mesh phases in addition to the random mesh phase, whereas the CPC-SHN1 water system shows only the tetragonal and random mesh phases. The CPC-SHN-water system also exhibits two nematic phases consisting of cylindrical and disk-like micelles at relatively low and high salt concentrations, respectively. These results show that the concentration of the strongly bound counterion provided by the organic salt can be used as a control parameter to tune the stability of different intermediate phases in amphiphile-water systems. PMID- 23944471 TI - Biaxial order parameter in the homologous series of orthogonal bent-core smectic liquid crystals. AB - The fundamental parameter of the uniaxial liquid crystalline state that governs nearly all of its physical properties is the primary orientational order parameter (S) for the long axes of molecules with respect to the director. The biaxial liquid crystals (LCs) possess biaxial order parameters depending on the phase symmetry of the system. In this paper we show that in the first approximation a biaxial orthogonal smectic phase can be described by two primary order parameters: S for the long axes and C for the ordering of the short axes of molecules. The temperature dependencies of S and C are obtained by the Haller's extrapolation technique through measurements of the optical birefringence and biaxiality on a nontilted polar antiferroelectric (Sm-AP(A)) phase of a homologous series of LCs built from the bent-core achiral molecules. For such a biaxial smectic phase both S and C, particularly the temperature dependency of the latter, are being experimentally determined. Results show that S in the orthogonal smectic phase composed of bent cores is higher than in Sm-A calamatic LCs and C is also significantly large. PMID- 23944472 TI - Oscillatory motion of sheared nanorods beyond the nematic phase. AB - We study the role of the control parameter triggering nematic order (temperature or concentration) on the dynamical behavior of a system of nanorods under shear. Our study is based on a set of mesoscopic equations of motion for the components of the tensorial orientational order parameter. We investigate these equations via a systematic bifurcation analysis based on a numerical continuation technique, focusing on spatially homogeneous states. Exploring a wide range of parameters we find, unexpectedly, that states with oscillatory motion can exist even under conditions where the equilibrium system is isotropic. These oscillatory states are characterized by a wagging motion of the paranematic director, and they occur if the tumbling parameter is sufficiently small. We also present full nonequilibrium phase diagrams in the plane spanned by the concentration and the shear rate. PMID- 23944473 TI - Frequency-dependent dielectric contribution of flexoelectricity allowing control of state switching in helicoidal liquid crystals. AB - The contribution of flexoelectric polarization to the dielectric susceptibility in helicoidal liquid crystals is formulated for the static equilibrium case, and further in the case of a time-varying field. A dispersion of the dielectric permittivity due to the frequency response of flexoelectric switching is described. The special case of a negative dielectric-anisotropy nematic material is considered and experimentally shown to agree with the analytical theory. It is further demonstrated how relaxation of the flexoelectric contribution to the dielectric tensor in this special case can be exploited to switch between states in cholesteric liquid crystal structures by altering the applied time-dependent field amplitude, if Deltaepsilon<0 and (e(1)-e(3))(2)/(K(1)+K(3))> Deltaepsilonepsilon(0). Consequentially, a versatile mechanism for driving between states in liquid crystal systems has been demonstrated and its implications for technology are suggested, and include dual-mode, bistable, and transflective displays. PMID- 23944474 TI - Unified molecular field theory of nematic, smectic-A, and smectic-C phases. AB - A unified mean-field molecular theory of nematic (N(U)), smectic A (SmA), and smectic C (SmC) liquid crystal phases, composed of uniaxial nonpolar molecules, is developed taking into account the variation of all orientational and translational order parameters in these phases. Numerical results, obtained by direct global minimization of the free energy, are presented in the form of three typical phase diagrams of different topology. Temperature variation of the relevant order parameters in different sequences of phases is analyzed for various cross sections of the phase diagrams. The present model enables one to reproduce all possible sequences of phase transitions between the given phases including isotropic (Iso)-N(U)-SmA-SmC, Iso-N(U)-SmC, Iso-SmA-SmC, and Iso-SmC. The properties of the NAC point, where the N(U), SmA, and SmC structures coexist, are considered in detail and the shape of the phase diagram in the vicinity of the NAC point is compared with existing experimental data. PMID- 23944475 TI - Confined nematic liquid crystal between two spherical boundaries with planar anchoring. AB - Nematic shells of liquid crystals have been provided in microscales. Defect structures in the shells are very essential in the electro-optical applications of such colloidal objects. We have numerically minimized the free energy of symmetric and asymmetric spherical shells of the nematic liquid crystal. Considering degenerate planar anchoring on the surfaces and isotropic nematic elasticity, a variety of defect structures are observed by controlling or varying the thicknesses of the shell and its degree of asymmetry. In symmetric shells, our calculations show that boojums (bipolar) defects appear in thick shells and tetrahedral (baseball) defects in thin shells. In asymmetric shells, while we are in the bipolar regime, the boojums defects transform to trigonal configurations. Free energy landscape shows that in this regime the inner droplet is not stable in the center and it is trapped in an off-center minimum energy position. For the case of thin shells, there are two degenerate director textures with similar tetrahedral configuration of the disclination lines. The levels are split in asymmetric shells. The stability of the inner droplet in the center position depends on director texture. It is stable for one texture and unstable for the other one. For an unstable pattern there is no minimum energy position for the inner droplet and it moves until it touches the outer boundary. PMID- 23944476 TI - Bifurcation properties of nematic liquid crystals exposed to an electric field: switchability, bistability, and multistability. AB - Bistable liquid crystal displays (LCDs) offer the potential for considerable power savings compared with conventional (monostable) LCDs. The existence of two (or more) stable field-free states that are optically distinct means that contrast can be maintained in a display without an externally applied electric field. An applied field is required only to switch the device from one state to the other, as needed. In this paper we examine the basic physical principles involved in generating multiple stable states and the switching between these states. We consider a two-dimensional geometry in which variable surface anchoring conditions are used to control the steady-state solutions and explore how different anchoring conditions can influence the number and type of solutions and whether or not switching is possible between the states. We find a wide range of possible behaviors, including bistability, tristability, and tetrastability, and investigate how the solution landscape changes as the boundary conditions are tuned. PMID- 23944477 TI - Dynamical properties of nematic liquid crystals subjected to shear flow and magnetic fields: tumbling instability and nonequilibrium fluctuations. AB - We investigate the dynamical properties of monodomain nematic liquid crystals under shear flow and magnetic fields on the basis of the Ericksen-Leslie theory. Stable and unstable states appear depending on the magnetic field and the shear rate. The trajectory of the unstable state shows tumbling motion. The phase diagram of these states is plotted as a function of the three components of the magnetic field at a constant shear rate. The phase diagram changes depending on the viscous properties of different types of nematic liquid crystals. In this nonequilibrium steady state, we calculate the correlation function of director fluctuations and the response function, and discuss the nonequilibrium fluctuations and the modified fluctuation-dissipation relation in connection with nonconservative forces due to shear flow. PMID- 23944478 TI - Orientational energy of anisometric particles in liquid-crystalline suspensions. AB - We obtain a general expression for the orientational energy of an individual anisometric particle suspended in uniform nematic liquid crystals when the main axis of the particle rotates with respect to the nematic director. We show that there is a qualitative and quantitative analogy between the internal and external problems for cylindrical volumes of nematic liquid crystals, and on this basis we obtain an estimate of the orientational energy of a particle of cylindrical (rodlike, needlelike, or ellipsoidal) shape. For an ensemble of such particles we propose a modified form of their orientational energy in the nematic matrix. This orientational energy has the usual second-order term, and additional fourth-order term in the scalar product of the nematic director and the vector which characterizes an average direction of the main axes of the particles. As an example we obtain the expression for the free energy density of ferronematics, i.e., colloidal suspensions of needlelike magnetic particles in nematic liquid crystals. Unlike previous models, the free energy density includes the proposed modified form of the particle orientational energy, and also a contribution describing the surface saddle-splay deformations of the liquid crystal matrix. PMID- 23944479 TI - Numerical study of stretched smectic-A elastomer sheets. AB - We present a numerical study of stretching monodomain smectic-A elastomer sheets, computed using the finite element method. When stretched parallel to their smectic layer normal the smectic layers are unstable to a transition to a buckled state. We model macroscopic deformations by replacing the microscopic energy with a coarse grained effective free energy that accounts for the fine-scale layer buckling. We augment this model with a term to describe the energy of deforming buckled layers, which is necessary to reproduce the experimentally observed Poisson ratios postbuckling. We examine the spatial distribution of the microstructure phases for various stretching angles relative to the layer normal and for different length-to-width aspect ratios. When stretching parallel to the layer normal the majority of the sample forms a bidirectionally buckled microstructure, except at the clamps where a unidirectionally buckled microstructure is predicted. When stretching at small inclinations to the layer normal the phase of the sample is sensitive to the aspect ratio of the sample, with the bidirectionally buckled phase persistent to large angles only for small aspect ratios. We relate these theoretical results to experiments on smectic-A elastomers. PMID- 23944480 TI - Simple model for chain packing and crystallization of soft colloidal polymers. AB - We study a simple bead-spring polymer model exhibiting competing crystallization and glass transitions. Constant-pressure molecular dynamics simulations are employed to study phase behavior and morphological order. For adequately slow quench rates, chain systems exhibit a first-order phase transition (crystallization) below a critical temperature T=T(cryst). We observe the formation of close-packed crystallites of FCC and/or HCP order, separated by domain walls, twin defects, and amorphous regions. Such crystal structures closely resemble the corresponding ordered morphologies of athermal polymer packings: fully flexible chains retain random-walk-like configurations in the crystalline state and do not form lamellae, while semiflexible chains do form lamellae. The model presented here is well suited to the modeling of granular and colloidal polymers, in particular for elucidating the factors that dictate the formation of specific ordered morphologies. PMID- 23944481 TI - Constitutive modeling of the Mullins effect and cyclic stress softening in filled elastomers. AB - The large strain behavior of filled rubbers is characterized by the strong Mullins effect, permanent set, and induced anisotropy. Strain controlled cyclic tests also exhibit a pronounced hysteresis as a strain rate independent phenomenon. Prediction of these inelastic features in elastomers is an important challenge with immense industrial and technological relevance. In the present paper, a micromechanical model is proposed to describe the inelastic features in the behavior of filled elastomers. To this end, the previously developed network decomposition concept [Dargazany and Itskov, Int. J. Solids Struct. 46, 2967 (2009)] is extended and an additional network (CP network) is added to the classical elastic rubber (CC) and polymer-filler (PP) networks. The new network is considered to account for the damage of filler aggregates in the cyclic deformation as the source of hysteresis energy loss. The accuracy of the resulting model is evaluated in comparison to a new set of experimental data. PMID- 23944482 TI - Polymer chain properties and thermodynamic stability in oriented-platelet nanocomposites. AB - We present a Monte Carlo study of the conformational properties of polymer chains in platelet nanocomposites. We find that high platelet orientation leads to an increase in chain confinement and to a substantial decrease in polymer entropy. The latter may be responsible for the observed aging of these systems in which the platelets gradually lose their orientation with time. As a test of our entropy-driven hypothesis, we suggest that aging could be substantially slowed down by the addition of small spherical nanoparticles. Using a generalized Stokes Einstein relation, a calculation of the thermal random motion of the platelets predicts a fivefold increase in shear modulus during aging, in agreement with experimental observation on compatibilized layered silicate nanocomposites. PMID- 23944483 TI - Partition function zeros and phase transitions for a square-well polymer chain. AB - The zeros of the canonical partition functions for flexible square-well polymer chains have been approximately computed for chains up to length 256 for a range of square-well diameters. We have previously shown that such chain molecules can undergo a coil-globule and globule-crystal transition as well as a direct coil crystal transition. Here we show that each of these transitions has a well defined signature in the complex-plane map of the partition function zeros. The freezing transitions are characterized by nearly circular rings of uniformly spaced roots, indicative of a discontinuous transition. The collapse transition is signaled by the appearance of an elliptical horseshoe segment of roots that pinches down towards the positive real axis and defines a boundary to a root-free region of the complex plane. With increasing chain length, the root density on the circular ring and in the space adjacent to the elliptical boundary increases and the leading roots move towards the positive real axis. For finite-length chains, transition temperatures can be obtained by locating the intersection of the ellipse and/or circle of roots with the positive real axis. A finite-size scaling analysis is used to obtain transition temperatures in the long-chain (thermodynamic) limit. The collapse transition is characterized by crossover and specific-heat exponents of phi~0.76(2) and alpha~0.66(2), respectively, consistent with a second-order phase transition. PMID- 23944484 TI - Enthalpy relaxation and annealing effect in polystyrene. AB - The effects of thermal history on the enthalpy relaxation in polystyrene are studied by differential scanning calorimetry. The temperature dependence of the specific heat in the liquid and the glassy states, that of relaxation time, and the exponent of the Kohlrausch-Williams-Watts function are determined by measurements of the thermal response against sinusoidal temperature variation. A phenomenological model equation previously proposed to interpret the memory effect in the frozen state is applied to the enthalpy relaxation and the evolution of entropy under a given thermal history is calculated. The annealing below the glass transition temperature produces two effects on enthalpy relaxation: the decay of excess entropy with annealing time in the early stage of annealing and the increase in relaxation time due to physical aging in the later stage. The crossover of these effects is reflected in the variation of temperature of the maximum specific heat observed in the heating process after annealing and cooling. PMID- 23944485 TI - Fluctuations in the coil-stretch transition of flexible polymers in good solvents: a peak due to nonlinear force relation. AB - Long flexible polymers undergo a coil to stretch transition (CST) in an elongational flow. Near the CST, a peak can be observed in the fluctuations of the size of a molecule (|R|). Solvent effects on the fluctuations are studied using Brownian dynamics simulations of a nonlinear spring force relation that can represent real molecules. Ignoring the influence of hydrodynamic interactions, a linear region in the spring force relation is known to cause the peak in |R| fluctuations. In contrast, we find that a peak in the fluctuations can be obtained even for the nonlinear spring force relation. We analyze the influence of hydrodynamic interactions on the fluctuations using a dumbbell model with a conformation-dependent drag coefficient. PMID- 23944486 TI - Localized buckling of a microtubule surrounded by randomly distributed cross linkers. AB - Microtubules supported by surrounding cross linkers in eukaryotic cells can bear a much higher compressive force than free-standing microtubules. Different from some previous studies, which treated the surroundings as a continuum elastic foundation or elastic medium, the present paper develops a micromechanics numerical model to examine the role of randomly distributed discrete cross linkers in the buckling of compressed microtubules. First, the proposed numerical approach is validated by reproducing the uniform multiwave buckling mode predicted by the existing elastic-foundation model. For more realistic buckling of microtubules surrounded by randomly distributed cross linkers, the present numerical model predicts that the buckling mode is localized at one end in agreement with some known experimental observations. In particular, the critical force for localized buckling, predicted by the present model, is insensitive to microtubule length and can be about 1 order of magnitude lower than those given by the elastic-foundation model, which suggests that the elastic-foundation model may have overestimated the critical force for buckling of microtubules in vivo. In addition, unlike the elastic-foundation model, the present model can capture the effect of end conditions on the critical force and wavelength of localized buckling. Based on the known data of spacing and elastic constants of cross linkers available in literature, the critical force and wavelength of the localized buckling mode, predicted by the present model, are compared to some experimental data with reasonable agreement. Finally, two empirical formulas are proposed for the critical force and wavelength of the localized buckling of microtubules surrounded by cross linkers. PMID- 23944487 TI - Simplified biased random walk model for RecA-protein-mediated homology recognition offers rapid and accurate self-assembly of long linear arrays of binding sites. AB - Inspired by RecA-protein-based homology recognition, we consider the pairing of two long linear arrays of binding sites. We propose a fully reversible, physically realizable biased random walk model for rapid and accurate self assembly due to the spontaneous pairing of matching binding sites, where the statistics of the searched sample are included. In the model, there are two bound conformations, and the free energy for each conformation is a weakly nonlinear function of the number of contiguous matched bound sites. PMID- 23944488 TI - Sacrificial bonds and hidden length in biomaterials: a kinetic constitutive description of strength and toughness in bone. AB - Sacrificial bonds and hidden length in structural molecules account for the greatly increased fracture toughness of biological materials compared to synthetic materials without such structural features by providing a molecular scale mechanism for energy dissipation. One example is in the polymeric glue connection between collagen fibrils in animal bone. In this paper we propose a simple kinetic model that describes the breakage of sacrificial bonds and the release of hidden length, based on Bell's theory. We postulate a master equation governing the rates of bond breakage and formation. This enables us to predict the mechanical behavior of a quasi-one-dimensional ensemble of polymers at different stretching rates. We find that both the rupture peak heights and maximum stretching distance increase with the stretching rate. In addition, our theory naturally permits the possibility of self-healing in such biological structures. PMID- 23944489 TI - Sawtooth patterns in force-extension curves of biomolecules: an equilibrium statistical-mechanics theory. AB - We analyze the force-extension curve for a general class of systems, which are described at the mesoscopic level by a free energy depending on the extension of its components. Similarly to what is done in real experiments, the total length of the system is the controlled parameter. This imposes a global constraint in the minimization procedure leading to the equilibrium values of the extensions. As a consequence, the force-extension curve has multiple branches in a certain range of forces. The stability of these branches is governed by the free energy: there are a series of first-order phase transitions at certain values of the total length, in which the free energy itself is continuous but its first derivative, the force, has a finite jump. This behavior is completely similar to that observed in real experiments with biomolecules like proteins and with other complex systems. PMID- 23944490 TI - Physical interactions of fish protamine and antisepsis peptide drugs with bacterial membranes revealed by combination of specular x-ray reflectivity and grazing-incidence x-ray fluorescence. AB - As a defined model of outer membranes of gram negative bacteria, we investigated the interaction of monolayers of lipopolysacchrides from Salmonella enterica rough strains R90 (LPS Ra) with natural and synthetic peptides. The fine structures perpendicular to the membrane plane and the ion distribution near the interface were determined by specular x-ray reflectivity (XRR) and grazing incidence x-ray fluorescence (GIXF) in the presence and absence of divalent cations. The unique combination of XRR and GIXF allows for the quantitative identification of different modes of interactions in a high spatial resolution, which cannot be assessed by other experimental methods. Natural fish protamine disrupts the stratified membrane structures in the absence of Ca(2+) ions, while staying away from the membrane surface in the presence of Ca(2+) ions. In contrast, synthetic antisepsis peptide Pep 19-2.5 weakly adsorbs to the membrane and stays near the uncharged sugar units even in the absence of Ca(2+). In the presence of Ca(2+), Pep 19-2.5 can reach the negatively charged inner core without destroying the barrier capability against ions. PMID- 23944491 TI - Reaction-subdiffusion front propagation in a comblike model of spiny dendrites. AB - Fractional reaction-diffusion equations are derived by exploiting the geometrical similarities between a comb structure and a spiny dendrite. In the framework of the obtained equations, two scenarios of reaction transport in spiny dendrites are explored, where both a linear reaction in spines and nonlinear Fisher Kolmogorov-Petrovskii-Piskunov reactions along dendrites are considered. In the framework of fractional subdiffusive comb model, we develop a Hamilton-Jacobi approach to estimate the overall velocity of the reaction front propagation. One of the main effects observed is the failure of the front propagation for both scenarios due to either the reaction inside the spines or the interaction of the reaction with the spines. In the first case the spines are the source of reactions, while in the latter case, the spines are a source of a damping mechanism. PMID- 23944492 TI - Correcting for bias of molecular confinement parameters induced by small-time series sample sizes in single-molecule trajectories containing measurement noise. AB - Several single-molecule studies aim to reliably extract parameters characterizing molecular confinement or transient kinetic trapping from experimental observations. Pioneering works from single-particle tracking (SPT) in membrane diffusion studies [Kusumi et al., Biophys. J. 65, 2021 (1993)] appealed to mean square displacement (MSD) tools for extracting diffusivity and other parameters quantifying the degree of confinement. More recently, the practical utility of systematically treating multiple noise sources (including noise induced by random photon counts) through likelihood techniques has been more broadly realized in the SPT community. However, bias induced by finite-time-series sample sizes (unavoidable in practice) has not received great attention. Mitigating parameter bias induced by finite sampling is important to any scientific endeavor aiming for high accuracy, but correcting for bias is also often an important step in the construction of optimal parameter estimates. In this article, it is demonstrated how a popular model of confinement can be corrected for finite-sample bias in situations where the underlying data exhibit Brownian diffusion and observations are measured with non-negligible experimental noise (e.g., noise induced by finite photon counts). The work of Tang and Chen [J. Econometrics 149, 65 (2009)] is extended to correct for bias in the estimated "corral radius" (a parameter commonly used to quantify confinement in SPT studies) in the presence of measurement noise. It is shown that the approach presented is capable of reliably extracting the corral radius using only hundreds of discretely sampled observations in situations where other methods (including MSD and Bayesian techniques) would encounter serious difficulties. The ability to accurately statistically characterize transient confinement suggests additional techniques for quantifying confined and/or hop diffusion in complex environments. PMID- 23944493 TI - Physiology-based model of cell viscoelasticity. AB - The measured viscoelastic properties of biological tissues is the result of the passive and active response of the cells. We propose an evolution law of the remodeling process in the cytoskeleton which is able to mimic the viscous properties of biological cellular tissues. Our model is based on dynamical changes of the resting length. We show that under the small strain regime, the linear rheology models are recovered, with the relaxation time being replaced by the cell resistance to remodel. We implement the one-dimensional model into network systems of two and three dimensions, and show that the same conclusions may be drawn for those systems. PMID- 23944494 TI - Winnerless competition in coupled Lotka-Volterra maps. AB - Winnerless competition is analyzed in coupled maps with discrete temporal evolution of the Lotka-Volterra type of arbitrary dimension. Necessary and sufficient conditions for the appearance of structurally stable heteroclinic cycles as a function of the model parameters are deduced. It is shown that under such conditions winnerless competition dynamics is fully exhibited. Based on these conditions different cases characterizing low, intermediate, and high dimensions are therefore computationally recreated. An analytical expression for the residence times valid in the N-dimensional case is deduced and successfully compared with the simulations. PMID- 23944495 TI - Effects of pacing magnitudes and forms on bistability width in a modeled ventricular tissue. AB - Bistability in periodically paced cardiac tissue is relevant to cardiac arrhythmias and its control. In the present paper, one-dimensional tissue of the phase I Luo-Rudy model is numerically investigated. The effects of various parameters of pacing signals on bistability width are studied. The following conclusions are obtained: (i) Pacing can be classified into two types: pulsatile and sinusoidal types. Pulsatile pacing reduces bistability width as its magnitude is increased. Sinusoidal pacing increases the width as its amplitude is increased. (ii) In a pacing period the hyperpolarizing part plays a more important role than the depolarizing part. Variations of the hyperpolarizing ratio in a period evidently change the width of bistability and its variation tendency. (iii) A dynamical mechanism is proposed to qualitatively explain the phenomena, which reveals the reason for the different effects of pulsatile and sinusoidal pacing on bistability. The methods for changing bistability width by external pacing may help control arrhythmias in cardiology. PMID- 23944496 TI - Optimal channel efficiency in a sensory network. AB - Spontaneous neural activity has been increasingly recognized as a subject of key relevance in neuroscience. It exhibits nontrivial spatiotemporal structure reflecting the organization of the underlying neural network and has proved to be closely intertwined with stimulus-induced activity patterns. As an additional contribution in this regard, we report computational studies that strongly suggest that a stimulus-free feature rules the behavior of an important psychophysical measure of the sensibility of a sensory system to a stimulus, the so-called dynamic range. Indeed in this paper we show that the entropy of the distribution of avalanche lifetimes (information efficiency, since it can be interpreted as the efficiency of the network seen as a communication channel) always accompanies the dynamic range in the benchmark model for sensory systems. Specifically, by simulating the Kinouchi-Copelli (KC) model on two broad families of model networks, we generically observed that both quantities always increase or decrease together as functions of the average branching ratio (the control parameter of the KC model) and that the information efficiency typically exhibits critical optimization jointly with the dynamic range (i.e., both quantities are optimized at the same value of that control parameter, that turns out to be the critical point of a nonequilibrium phase transition). In contrast with the practice of taking power laws to identify critical points in most studies describing measured neuronal avalanches, we rely on data collapses as more robust signatures of criticality to claim that critical optimization may happen even when the distribution of avalanche lifetimes is not a power law, as suggested by a recent experiment. Finally, we note that the entropy of the size distribution of avalanches (information capacity) does not always follow the dynamic range and the information efficiency when they are critically optimized, despite being more widely used than the latter to describe the computational capabilities of a neural network. This strongly suggests that dynamical rules allowing a proper temporal matching of the states of the interacting neurons is the key for achieving good performance in information processing, rather than increasing the number of available units. PMID- 23944497 TI - Delay-driven irregular spatiotemporal patterns in a plankton system. AB - An inhomogeneous distribution of species density over physical space is a widely observed scenario in plankton systems. Understanding the mechanisms resulting in these spatial patterns is a central topic in plankton ecology. In this paper we explore the impact of time delay on spatiotemporal patterns in a prey-predator plankton system. We find that time delay can trigger the emergence of irregular spatial patterns via a Hopf bifurcation. Moreover, a phase transition from a regular spiral pattern to an irregular one was observed and the latter gradually replaced the former and persisted indefinitely. The characteristic length of the emergent spatial pattern is consistent with the scale of plankton patterns observed in field studies. PMID- 23944498 TI - Fluctuating hydrodynamics simulations of coarse-grained lipid membranes under steady-state conditions and in shear flow. AB - The stochastic Eulerian-Lagrangian method (SELM) is used to simulate coarse grained lipid membrane models under steady-state conditions and in shear flow. SELM is an immersed boundary method which combines the efficiency of particle based simulations with the realistic solvent dynamics provided by fluctuating hydrodynamics. Membrane simulations in SELM are shown to give structural properties in accordance with equilibrium statistical mechanics and dynamic properties in agreement with previous simulations of highly detailed membrane models in explicit solvent. Simulations of sheared membranes are used to calculate surface shear viscosities and inter-monolayer friction coefficients. The membrane models are shown to be shear thinning under a wide range of applied shear rates. PMID- 23944499 TI - Order, intermittency, and pressure fluctuations in a system of proliferating rods. AB - Nonmotile elongated bacteria confined in two-dimensional open microchannels can exhibit collective motion and form dense monolayers with nematic order if the cells proliferate, i.e., grow and divide. Using soft molecular dynamics simulations of a system of rods interacting through short range mechanical forces, we study the effects of the cell growth rate, the cell aspect ratio, and the sliding friction on nematic ordering and on pressure fluctuations in confined environments. Our results indicate that rods with aspect ratios >3.0 reach quasiperfect nematic states at low sliding friction. At higher frictions, the global nematic order parameter shows intermittent fluctuations due to sudden losses of order and the time intervals between these bursts are power-law distributed. The pressure transverse to the channel axis can vary abruptly in time and shows hysteresis due to lateral crowding effects. The longitudinal pressure field is on average correlated to nematic order, but it is locally very heterogeneous and its distribution follows an inverse power law, in sharp contrast with nonactive granular systems. We discuss some implications of these findings for tissue growth. PMID- 23944500 TI - Hysteresis in the metachronal-tripod gait transition of insects: a modeling study. AB - Locomotion in biological systems involves various gaits, and hysteresis appears when the gaits change in accordance with the locomotion speed. That is, the gaits vary at different locomotion speeds depending on the direction of speed change. Although hysteresis is a typical characteristic of nonlinear dynamic systems, the underlying mechanism for the hysteresis in gait transitions remains largely unclear. In this study, we construct a neuromechanical model of an insect and investigate the dynamic characteristics of its gait and gait transition. The simulation results show that our insect model produces metachronal and tripod gaits depending on the locomotion speed through dynamic interactions among the body mechanical system, the nervous system, and the environment in a self organized manner. They also show that it undergoes the metachronal-tripod gait transition with hysteresis by changing the locomotion speed. We examined the hysteresis mechanism in the metachronal-tripod gait transition of insects from a dynamic viewpoint. PMID- 23944501 TI - Elastic properties and line tension of self-assembled bilayer membranes. AB - The elastic properties of a self-assembled bilayer membrane are studied using the self-consistent field theory, applied to a model system composed of flexible amphiphilic chains dissolved in hydrophilic polymeric solvents. Examining the free energy of bilayer membranes with different geometries allows us to calculate their bending modulus, Gaussian modulus, two fourth-order membrane moduli, and the line tension. The dependence of these parameters on the microscopic characteristics of the amphiphilic chain, characterized by the volume fraction of the hydrophilic component, is systematically studied. The theoretical predictions are compared with the results from a simple monolayer model, which approximates a bilayer membrane by two monolayers. The region of validity of the linear elasticity theory is analyzed by examining the higher-order contributions. PMID- 23944502 TI - Emergence and stability of intermediate open vesicles in disk-to-vesicle transitions. AB - The transition between two basic structures, a disk and an enclosed vesicle, of a finite membrane is studied by examining the minimum energy path (MEP) connecting these two states. The MEP is constructed using the string method applied to continuum elastic membrane models. The results reveal that, besides the commonly observed disk and vesicle, open vesicles (bowl-shaped vesicles or vesicles with a pore) can become stable or metastable shapes. The emergence, stability, and probability distribution of these open vesicles are analyzed. It is demonstrated that open vesicles can be stabilized by higher-order elastic energies. The estimated probability distribution of the different structures is in good agreement with available experiments. PMID- 23944503 TI - Effects of electrical polarization on the opening rate constant of a voltage gated ion channel. AB - Ion channel gating kinetics can be described using Kramers' diffusion theory of reaction rates between several closed and open states, where transition rates between states depend exponentially on the membrane potential V. It has been suggested that transition rates have a more complex dependence on V at voltage extremes, but this has never been quantified. We measured the rate constant of the last closed to open transition in a voltage-gated ion channel and show that it does not depend exponentially on membrane potential at values of V greater than ~150 mV. To explain this behavior, we estimate the effects of electrical polarization of the water contained in crevices within the channel protein, using an electrostatic model of the approximate three-dimensional geometry and the nonlinear effects of charges on the polarization of water. PMID- 23944504 TI - Crystallization of asymmetric patchy models for globular proteins in solution. AB - Asymmetric patchy particle models have recently been shown to describe the crystallization of small globular proteins with near-quantitative accuracy. Here, we investigate how asymmetry in patch geometry and bond energy generally impacts the phase diagram and nucleation dynamics of this family of soft matter models. We find the role of the geometry asymmetry to be weak, but the energy asymmetry to markedly interfere with the crystallization thermodynamics and kinetics. These results provide a rationale for the success and occasional failure of the proposal of George and Wilson for protein crystallization conditions as well as physical guidance for developing more effective protein crystallization strategies. PMID- 23944505 TI - Generation of oscillating gene regulatory network motifs. AB - Using an improved version of an evolutionary algorithm originally proposed by Francois and Hakim [Proc. Natl. Acad. Sci. USA 101, 580 (2004)], we generated small gene regulatory networks in which the concentration of a target protein oscillates in time. These networks may serve as candidates for oscillatory modules to be found in larger regulatory networks and protein interaction networks. The algorithm was run for 10(5) times to produce a large set of oscillating modules, which were systematically classified and analyzed. The robustness of the oscillations against variations of the kinetic rates was also determined, to filter out the least robust cases. Furthermore, we show that the set of evolved networks can serve as a database of models whose behavior can be compared to experimentally observed oscillations. The algorithm found three smallest (core) oscillators in which nonlinearities and number of components are minimal. Two of those are two-gene modules: the mixed feedback loop, already discussed in the literature, and an autorepressed gene coupled with a heterodimer. The third one is a single gene module which is competitively regulated by a monomer and a dimer. The evolutionary algorithm also generated larger oscillating networks, which are in part extensions of the three core modules and in part genuinely new modules. The latter includes oscillators which do not rely on feedback induced by transcription factors, but are purely of post transcriptional type. Analysis of post-transcriptional mechanisms of oscillation may provide useful information for circadian clock research, as recent experiments showed that circadian rhythms are maintained even in the absence of transcription. PMID- 23944506 TI - Stochastic microswimming model for the average translational velocity of the ribosome. AB - The motion of the ribosome is modeled here, assuming that its two subunits are subject to stochastic rearrangements, thus producing different conformations constituting its deformation cycle, or swimming stroke. Using a general statistical mechanical formulation, the mean propulsion velocity of the ribosome is obtained as a function of the transition rates among the different conformations and of the relevant deformation variables. A calculation with reasonable parameter estimations shows that the ribosome can match the average protein synthesis speed with deformations of a size comparable to its radius. PMID- 23944507 TI - First-passage properties of molecular spiders. AB - Molecular spiders are synthetic catalytic DNA-based nanoscale walkers. We study the mean first-passage time for abstract models of spiders moving on a finite two dimensional lattice with various boundary conditions and compare it with the mean first-passage time of spiders moving on a one-dimensional track. We evaluate by how much the slowdown on newly visited sites, owing to catalysis, can improve the mean first-passage time of spiders and show that in one dimension, when both ends of the track are an absorbing boundary, the performance gain is lower than in two dimensions, when the absorbing boundary is a circle; this persists even when the absorbing boundary is a single site. PMID- 23944508 TI - Steric contribution of macromolecular crowding to the time and activation energy for preprotein translocation across the endoplasmic reticulum membrane. AB - Protein translocation from the cytosol to the endoplasmic reticulum (ER) or vice versa, an essential process for cell function, includes the transport of preproteins destined to become secretory, luminal, or integral membrane proteins (translocation) or misfolded proteins returned to the cytoplasm to be degraded (retrotranslocation). An important aspect in this process that has not been fully studied is the molecular crowding at both sides of the ER membrane. By using models of polymers crossing a membrane through a pore, in an environment crowded by either static or dynamic spherical agents, we computed the following transport properties: the free energy, the activation energy, the force, and the transport times for translocation and retrotranslocation. Using experimental protein crowding data for the cytoplasm and ER sides, we showed that dynamic crowding, which resembles biological environments where proteins are translocated or retrotranslocated, increases markedly all the physical properties of translocation and retrotranslocation as compared with translocation in a diluted system. By contrast, transport properties in static crowded systems were similar to those in diluted conditions. In the dynamic regime, the effects of crowding were more notorious in the transport times, leading to a huge difference for large chains. We indicate that this difference is the result of the synergy between the free energy and the diffusivity of the translocating chain. That synergy leads to translocation rates similar to experimental measures in diluted systems, which indicates that the effects of crowding can be measured. Our data also indicate that effects of crowding cannot be neglected when studying translocation because protein dynamic crowding has a relevant steric contribution, which changes the properties of translocation. PMID- 23944509 TI - Modeling and analysis of propulsion in the multiflagellated micoorganism Giardia lamblia. AB - The goal of this work was to analyze the propulsion of multiflagellated microorganisms, and to draw insight to the underlying physics and biology of the movement. Giardia lamblia was chosen as the model organism due to its unique ability to mechanically attach to various surfaces, its rapid movement, and its fine control over steering and navigation. In this work, a mechanics model was utilized to study the mechanics and propulsive contribution of the ventral and anterior flagella in Giardia. It was discovered that energy is supplied mainly at the proximal portion of these flagella, supporting the hypothesis that a decreasing adenosine triphosphate (ATP) gradient along the length of the flagella would not affect the motion observed. Similarly, the elasticity of the flagella allows the energy input at the proximal portion to be transferred to the distal portion, where the majority of thrust is generated. Specifically, we found that the ventral flagella are the driving force for planar propulsion and turning, while the anterior flagella are used for steering and control. PMID- 23944510 TI - Improving zero-mode waveguide structure for enhancing signal-to-noise ratio of real-time single-molecule fluorescence imaging: a computational study. AB - We investigated the signal-to-noise ratio (S/N) of real-time single-molecule fluorescence imaging (SMFI) using zero-mode waveguides (ZMWs). The excitation light and the fluorescence propagating from a molecule in the ZMW were analyzed by computational optics simulation. The dependence of the S/N on the ZMW structure was investigated with the diameter and etching depth as the simulation parameters. We found that the SMFI using a conventional ZMW was near the critical level for detecting binding and dissociation events. We show that etching the glass surface of the ZMW by 60 nm enhances the S/N six times the conventional nonetched ZMWs. The enhanced S/N improves the temporal resolution of the SMFI at physiological concentrations. PMID- 23944511 TI - Fokker-Planck description of single nucleosome repositioning by dimeric chromatin remodelers. AB - Recent experiments have demonstrated that the ATP-utilizing chromatin assembly and remodeling factor (ACF) is a dimeric, processive motor complex which can move a nucleosome more efficiently towards longer flanking DNA than towards shorter flanking DNA strands, thereby centering an initially ill-positioned nucleosome on DNA substrates. We give a Fokker-Planck description for the repositioning process driven by transitions between internal chemical states of the remodelers. In the chemical states of ATP hydrolysis during which the repositioning takes place a power stroke is considered. The slope of the effective driving potential is directly related to ATP hydrolysis and leads to the unidirectional motion of the nucleosome-remodeler complex along the DNA strand. The Einstein force relation allows us to deduce the ATP-concentration dependence of the diffusion constant of the nucleosome-remodeler complex. We have employed our model to study the efficiency of positioning of nucleosomes as a function of the ATP sampling rate between the two motors which shows that the synchronization between the motors is crucial for the remodeling mechanism to work. PMID- 23944512 TI - Programmable ion-sensitive transistor interfaces. I. Electrochemical gating. AB - Electrochemical gating is the process by which an electric field normal to the insulator electrolyte interface shifts the surface chemical equilibrium and further affects the charge in solution [Jiang and Stein, Langmuir 26, 8161 (2010)]. The surface chemical reactivity and double-layer charging at the interface of electrolyte-oxide-semiconductor (EOS) capacitors is investigated. We find a strong pH-dependent hysteresis upon dc potential cycling. Varying salinity at a constant pH does not change the hysteretic window, implying that field induced surface pH regulation is the dominant cause of hysteresis. We propose and investigate this mechanism in foundry-made floating-gate ion-sensitive field effect transistors, which can serve as both an ionic sensor and an actuator. Termed the chemoreceptive neuron metal-oxide-semiconductor (CnuMOS) transistor, it features independently driven control gates (CGs) and sensing gates (SGs) that are capacitively coupled to an extended floating gate (FG). The SG is exposed to fluid, the CG is independently driven, and the FG is capable of storing charge Q(FG) of either polarity. Asymmetric capacitive coupling between the CG and SG to FG results in intrinsic amplification of the measured surface potential shifts and influences the FG charge injection mechanism. This modified SG surface condition was monitored through transient recordings of the output current, performed under alternate positive and negative CG pulses. Transient recordings revealed a hysteresis where the current was enhanced under negative pulsing and reduced after positive pulsing. This hysteresis effect is similar to that observed with EOS capacitors, suggesting a field-dependent surface charge regulation mechanism at play. At high CG biases, nonvolatile charge Q(FG) tunneling into the FG occurs, which creates a larger field and tunes the pH response and the point of zero charge. This mechanism gives rise to surface programmability. In this paper we describe the operational principles, tunneling mechanism, and role of electrolyte composition under field modulation. The experimental findings are then modeled by a Poisson-Boltzmann formulation with surface pH regulation. We find that surface ionization constants play a dominant role in determining the pH tuning effect. In the following paper [K. Jayant et al., Phys. Rev. E 88, 012802 (2013)] we extend the dual-gate operation to molecular sensing and demonstrate the use of Q(FG) to achieve manipulation of surface-adsorbed DNA. PMID- 23944513 TI - Programmable ion-sensitive transistor interfaces. II. Biomolecular sensing and manipulation. AB - The chemoreceptive neuron metal-oxide-semiconductor transistor described in the preceding paper is further used to monitor the adsorption and interaction of DNA molecules and subsequently manipulate the adsorbed biomolecules with injected static charge. Adsorption of DNA molecules onto poly-L-lysine-coated sensing gates (SGs) modulates the floating gate (FG) potential psi(O), which is reflected as a threshold voltage shift measured from the control gate (CG) V(th_CG). The asymmetric capacitive coupling between the CG and SG to the FG results in V(th_CG) amplification. The electric field in the SG oxide E(SG_ox) is fundamentally different when we drive the current readout with V(CG) and V(ref) (i.e., the potential applied to the CG and reference electrode, respectively). The V(CG)-driven readout induces a larger E(SG_ox), leading to a larger V(th_CG) shift when DNA is present. Simulation studies indicate that the counterion screening within the DNA membrane is responsible for this effect. The DNA manipulation mechanism is enabled by tunneling electrons (program) or holes (erase) onto FGs to produce repulsive or attractive forces. Programming leads to repulsion and eventual desorption of DNA, while erasing reestablishes adsorption. We further show that injected holes or electrons prior to DNA addition either aids or disrupts the immobilization process, which can be used for addressable sensor interfaces. To further substantiate DNA manipulation, we used impedance spectroscopy with a split ac-dc technique to reveal the net interface impedance before and after charge injection. PMID- 23944514 TI - Structural robustness of scale-free networks against overload failures. AB - We study the structural robustness of scale-free networks against overload failures induced by loads exceeding the node capacity, based on analytical and numerical approaches to the percolation problem in which a fixed number of nodes are removed according to the overload probability. Modeling fluctuating loads by random walkers in a network, we find that the degree dependence of the overload probability drastically changes with respect to the total load. We also elucidate that there exist two types of structural robustness of networks against overload failures. One is measured by the critical total load W(c) and the other is by the critical node removal fraction f(c). Enhancing the scale-free property, networks become fragile in both senses of W(c) and f(c). By contrast, increasing the node tolerance, scale-free networks become robust in the sense of the critical total load, while they come to be fragile in the sense of the critical node removal fraction. Furthermore, we show that these trends are not affected by degree degree correlations, although assortative mixing makes networks robust in both senses of W(c) and f(c). PMID- 23944515 TI - Characterizing the development of sectoral gross domestic product composition. AB - We consider the sectoral composition of a country's gross domestic product (GDP), i.e., the partitioning into agrarian, industrial, and service sectors. Exploring a simple system of differential equations, we characterize the transfer of GDP shares between the sectors in the course of economic development. The model fits for the majority of countries providing four country-specific parameters. Relating the agrarian with the industrial sector, a data collapse over all countries and all years supports the applicability of our approach. Depending on the parameter ranges, country development exhibits different transfer properties. Most countries follow three of eight characteristic paths. The types are not random but show distinct geographic and development patterns. PMID- 23944516 TI - Network growth model with intrinsic vertex fitness. AB - We study a class of network growth models with attachment rules governed by intrinsic node fitness. Both the individual node degree distribution and the degree correlation properties of the network are obtained as functions of the network growth rules. We also find analytical solutions to the inverse, design, problems of matching the growth rules to the required (e.g., power-law) node degree distribution and more generally to the required degree correlation function. We find that the design problems do not always have solutions. Among the specific conditions on the existence of solutions to the design problems is the requirement that the node degree distribution has to be broader than a certain threshold and the fact that factorizability of the correlation functions requires singular distributions of the node fitnesses. More generally, the restrictions on the input distributions and correlations that ensure solvability of the design problems are expressed in terms of the analytical properties of their generating functions. PMID- 23944517 TI - Evolution of correlation structure of industrial indices of U.S. equity markets. AB - We investigate the dynamics of correlations present between pairs of industry indices of U.S. stocks traded in U.S. markets by studying correlation-based networks and spectral properties of the correlation matrix. The study is performed by using 49 industry index time series computed by K. French and E. Fama during the time period from July 1969 to December 2011, which spans more than 40 years. We show that the correlation between industry indices presents both a fast and a slow dynamics. The slow dynamics has a time scale longer than 5 years, showing that a different degree of diversification of the investment is possible in different periods of time. Moreover, we also detect a fast dynamics associated with exogenous or endogenous events. The fast time scale we use is a monthly time scale and the evaluation time period is a 3-month time period. By investigating the correlation dynamics monthly, we are able to detect two examples of fast variations in the first and second eigenvalue of the correlation matrix. The first occurs during the dot-com bubble (from March 1999 to April 2001) and the second occurs during the period of highest impact of the subprime crisis (from August 2008 to August 2009). PMID- 23944518 TI - Combining a popularity-productivity stochastic block model with a discriminative content model for general structure detection. AB - Latent community discovery that combines links and contents of a text-associated network has drawn more attention with the advance of social media. Most of the previous studies aim at detecting densely connected communities and are not able to identify general structures, e.g., bipartite structure. Several variants based on the stochastic block model are more flexible for exploring general structures by introducing link probabilities between communities. However, these variants cannot identify the degree distributions of real networks due to a lack of modeling of the differences among nodes, and they are not suitable for discovering communities in text-associated networks because they ignore the contents of nodes. In this paper, we propose a popularity-productivity stochastic block (PPSB) model by introducing two random variables, popularity and productivity, to model the differences among nodes in receiving links and producing links, respectively. This model has the flexibility of existing stochastic block models in discovering general community structures and inherits the richness of previous models that also exploit popularity and productivity in modeling the real scale-free networks with power law degree distributions. To incorporate the contents in text-associated networks, we propose a combined model which combines the PPSB model with a discriminative model that models the community memberships of nodes by their contents. We then develop expectation maximization (EM) algorithms to infer the parameters in the two models. Experiments on synthetic and real networks have demonstrated that the proposed models can yield better performances than previous models, especially on networks with general structures. PMID- 23944519 TI - Collective motion of oscillatory walkers. AB - We study a system of interacting self-propelled particles whose walking velocity depends on the stage of the locomotion cycle. The model introduces a phase equation in the optimal velocity model for vehicular traffic. We find that the system exhibits novel types of flow: synchronized free flow, phase-anchoring free flow, orderly jam flow, and disordered jam flow. The first two flows are characterized by synchronization of the phase, while the others do not have the global synchronization. Among these, the disordered jam flow is very complex, although the underlying model is simple. This phenomenon implies that the crowd behavior of moving particles can be destabilized by coupling their velocity to the phase of their motion. We also focus on "phase-anchoring" phenomena. They strongly affect particle flow in the system, especially when the density of particles is high. PMID- 23944520 TI - Epidemic fronts in complex networks with metapopulation structure. AB - Infection dynamics have been studied extensively on complex networks, yielding insight into the effects of heterogeneity in contact patterns on disease spread. Somewhat separately, metapopulations have provided a paradigm for modeling systems with spatially extended and "patchy" organization. In this paper we expand on the use of multitype networks for combining these paradigms, such that simple contagion models can include complexity in the agent interactions and multiscale structure. Using a generalization of the Miller-Volz mean-field approximation for susceptible-infected-recovered (SIR) dynamics on multitype networks, we study the special case of epidemic fronts propagating on a one dimensional lattice of interconnected networks-representing a simple chain of coupled population centers-as a necessary first step in understanding how macroscale disease spread depends on microscale topology. Applying the formalism of front propagation into unstable states, we derive the effective transport coefficients of the linear spreading: asymptotic speed, characteristic wavelength, and diffusion coefficient for the leading edge of the pulled fronts, and analyze their dependence on the underlying graph structure. We also derive the epidemic threshold for the system and study the front profile for various network configurations. PMID- 23944521 TI - Influence of substrate potential shape on the dynamics of a sliding lubricant chain. AB - We investigate the frictional sliding of an incommensurate chain of interacting particles confined in between two nonlinear on-site substrate potential profiles in relative motion. We focus here on the class of Remoissenet-Peyrard parametrized potentials V(RP)(x,s), whose shape can be varied continuously as a function of s, recovering the sine-Gordon potential as a particular case. The observed frictional dynamics of the system, crucially dependent on the mutual ratios of the three periodicities in the sandwich geometry, turns out to be significantly influenced also by the shape of the substrate potential. Specifically, variations of the shape parameter s affect significantly and not trivially the existence and robustness of the recently reported velocity quantization phenomena [A. Vanossi et al., Phys. Rev. Lett. 97, 056101 (2006)], where the chain center-of-mass velocity to the externally imposed relative velocity of the sliders stays pinned to exact "plateau" values for wide ranges of the dynamical parameters. PMID- 23944522 TI - Reverse resonance in stock prices of financial system with periodic information. AB - We investigate the stochastic resonance of the stock prices in a finance system with the Heston model. The extrinsic and intrinsic periodic information are introduced into the stochastic differential equations of the Heston model for stock price by focusing on the signal power amplification (SPA). We find that for both cases of extrinsic and intrinsic periodic information a phenomenon of reverse resonance emerges in the behaviors of SPA as a function of the system and external driving parameters. Moreover, in both cases, a phenomenon of double reverse resonance is observed in the behavior of SPA versus the amplitude of volatility fluctuations, by increasing the cross correlation between the noise sources in the Heston model. PMID- 23944523 TI - International migration network: topology and modeling. AB - This paper studies international migration from a complex-network perspective. We define the international migration network (IMN) as the weighted-directed graph where nodes are world countries and links account for the stock of migrants originated in a given country and living in another country at a given point in time. We characterize the binary and weighted architecture of the network and its evolution over time in the period 1960-2000. We find that the IMN is organized around a modular structure with a small-world binary pattern displaying disassortativity and high clustering, with power-law distributed weighted-network statistics. We also show that a parsimonious gravity model of migration can account for most of observed IMN topological structure. Overall, our results suggest that socioeconomic, geographical, and political factors are more important than local-network properties in shaping the structure of the IMN. PMID- 23944524 TI - Impacts of subsidy policies on vaccination decisions in contact networks. AB - To motivate more people to participate in vaccination campaigns, various subsidy policies are often supplied by government and the health sectors. However, these external incentives may also alter the vaccination decisions of the broader public, and hence the choice of incentive needs to be carefully considered. Since human behavior and the networking-constrained interactions among individuals significantly impact the evolution of an epidemic, here we consider the voluntary vaccination on human contact networks. To this end, two categories of typical subsidy policies are considered: (1) under the free subsidy policy, the total amount of subsidy is distributed to a certain fraction of individual and who are vaccinated without personal cost, and (2) under the partial-offset subsidy policy, each vaccinated person is offset by a certain amount of subsidy. A vaccination decision model based on evolutionary game theory is established to study the effects of these different subsidy policies on disease control. Simulations suggest that, because the partial-offset subsidy policy encourages more people to take vaccination, its performance is significantly better than that of the free subsidy policy. However, an interesting phenomenon emerges in the partial-offset scenario: with limited amount of total subsidy, a moderate subsidy rate for each vaccinated individual can guarantee the group-optimal vaccination, leading to the maximal social benefits, while such an optimal phenomenon is not evident for the free subsidy scenario. PMID- 23944525 TI - Coauthorship and citation patterns in the Physical Review. AB - A large number of published studies have examined the properties of either networks of citation among scientific papers or networks of coauthorship among scientists. Here we study an extensive data set covering more than a century of physics papers published in the Physical Review, which allows us to construct both citation and coauthorship networks for the same set of papers. We analyze these networks to gain insight into temporal changes in citation and collaboration over the long time period of the data, as well as correlations and interactions between the two. Among other things, we investigate the change over time in the number of publishing authors, the number of papers they publish, and the number of others with whom they collaborate, changes in the typical number of citations made and received, the extent to which individuals tend to cite themselves or their collaborators more than others, the extent to which they cite themselves or their collaborators more quickly after publication, and the extent to which they tend to return the favor of a citation from another scientist. PMID- 23944526 TI - Coevolutionary networks of reinforcement-learning agents. AB - This paper presents a model of network formation in repeated games where the players adapt their strategies and network ties simultaneously using a simple reinforcement-learning scheme. It is demonstrated that the coevolutionary dynamics of such systems can be described via coupled replicator equations. We provide a comprehensive analysis for three-player two-action games, which is the minimum system size with nontrivial structural dynamics. In particular, we characterize the Nash equilibria (NE) in such games and examine the local stability of the rest points corresponding to those equilibria. We also study general n-player networks via both simulations and analytical methods and find that, in the absence of exploration, the stable equilibria consist of star motifs as the main building blocks of the network. Furthermore, in all stable equilibria the agents play pure strategies, even when the game allows mixed NE. Finally, we study the impact of exploration on learning outcomes and observe that there is a critical exploration rate above which the symmetric and uniformly connected network topology becomes stable. PMID- 23944527 TI - Effects of mixing in threshold models of social behavior. AB - We consider the dynamics of an extension of the influential Granovetter model of social behavior, where individuals are affected by their personal preferences and observation of the neighbors' behavior. Individuals are arranged in a network (usually the square lattice), and each has a state and a fixed threshold for behavior changes. We simulate the system asynchronously by picking a random individual and we either update its state or exchange it with another randomly chosen individual (mixing). We describe the dynamics analytically in the fast mixing limit by using the mean-field approximation and investigate it mainly numerically in the case of finite mixing. We show that the dynamics converge to a manifold in state space, which determines the possible equilibria, and show how to estimate the projection of this manifold by using simulated trajectories, emitted from different initial points. We show that the effects of considering the network can be decomposed into finite-neighborhood effects, and finite-mixing rate effects, which have qualitatively similar effects. Both of these effects increase the tendency of the system to move from a less-desired equilibrium to the "ground state." Our findings can be used to probe shifts in behavioral norms and have implications for the role of information flow in determining when social norms that have become unpopular in particular communities (such as foot binding or female genital cutting) persist or vanish. PMID- 23944528 TI - Anomalous biased diffusion in networks. AB - We study diffusion with a bias toward a target node in networks. This problem is relevant to efficient routing strategies in emerging communication networks like optical networks. Bias is represented by a probability p of the packet or particle to travel at every hop toward a site that is along the shortest path to the target node. We investigate the scaling of the mean first passage time (MFPT) with the size of the network. We find by using theoretical analysis and computer simulations that for random regular (RR) and Erdos-Renyi networks, there exists a threshold probability, p(th), such that for pp(th), the MFPT scales logarithmically with N. The threshold value p(th) of the bias parameter for which the regime transition occurs is found to depend only on the mean degree of the nodes. An exact solution for every value of p is given for the scaling of the MFPT in RR networks. The regime transition is also observed for the second moment of the probability distribution function, the standard deviation. For the case of scale-free (SF) networks, we present analytical bounds and simulations results showing that the MFPT scales at most as lnN to a positive power for any finite bias, which means that in SF networks even a very small bias is considerably more efficient in comparison to unbiased walk. PMID- 23944529 TI - Spreading in online social networks: the role of social reinforcement. AB - Some epidemic spreading models are usually applied to analyze the propagation of opinions or news. However, the dynamics of epidemic spreading and information or behavior spreading are essentially different in many aspects. Centola's experiments [Science 329, 1194 (2010)] on behavior spreading in online social networks showed that the spreading is faster and broader in regular networks than in random networks. This result contradicts with the former understanding that random networks are preferable for spreading than regular networks. To describe the spreading in online social networks, a unknown-known-approved-exhausted four status model was proposed, which emphasizes the effect of social reinforcement and assumes that the redundant signals can improve the probability of approval (i.e., the spreading rate). Performing the model on regular and random networks, it is found that our model can well explain the results of Centola's experiments on behavior spreading and some former studies on information spreading in different parameter space. The effects of average degree and network size on behavior spreading process are further analyzed. The results again show the importance of social reinforcement and are accordant with Centola's anticipation that increasing the network size or decreasing the average degree will enlarge the difference of the density of final approved nodes between regular and random networks. Our work complements the former studies on spreading dynamics, especially the spreading in online social networks where the information usually requires individuals' confirmations before being transmitted to others. PMID- 23944530 TI - Power-law exponent of the Bouchaud-Mezard model on regular random networks. AB - We study the Bouchaud-Mezard model on a regular random network. By assuming adiabaticity and independency, and utilizing the generalized central limit theorem and the Tauberian theorem, we derive an equation that determines the exponent of the probability distribution function of the wealth as x->infinity. The analysis shows that the exponent can be smaller than 2, while a mean-field analysis always gives the exponent as being larger than 2. The results of our analysis are shown to be in good agreement with those of the numerical simulations. PMID- 23944531 TI - Uniform asymptotic approximation of diffusion to a small target. AB - The problem of the time required for a diffusing molecule, within a large bounded domain, to first locate a small target is prevalent in biological modeling. Here we study this problem for a small spherical target. We develop uniform in time asymptotic expansions in the target radius of the solution to the corresponding diffusion equation. Our approach is based on combining expansions of a long-time approximation of the solution, involving the first eigenvalue and eigenfunction of the Laplacian, with expansions of a short-time correction calculated by a pseudopotential approximation. These expansions allow the calculation of corresponding expansions of the first passage time density for the diffusing molecule to find the target. We demonstrate the accuracy of our method in approximating the first passage time density and related statistics for the spherically symmetric problem where the domain is a large concentric sphere about a small target centered at the origin. PMID- 23944532 TI - Decohering localized waves. AB - In the absence of confinement, localization of waves takes place due to randomness or nonlinearity and relies on their phase coherence. We quantitatively probe the sensitivity of localized wave packets to random phase fluctuations and confirm the necessity of phase coherence for localization. Decoherence resulting from a dynamical random environment leads to diffusive spreading and destroys linear and nonlinear localization. We find that maximal spreading is achieved for optimal phase fluctuation characteristics, which is a consequence of the competition between diffusion due to decoherence and ballistic transport within the mean free path distance. PMID- 23944533 TI - Strong and weak chaos in networks of semiconductor lasers with time-delayed couplings. AB - Nonlinear networks with time-delayed couplings may show strong and weak chaos, depending on the scaling of their Lyapunov exponent with the delay time. We study strong and weak chaos for semiconductor lasers, either with time-delayed self feedback or for small networks. We examine the dependence on the pump current and consider the question of whether strong and weak chaos can be identified from the shape of the intensity trace, the autocorrelations, and the external cavity modes. The concept of the sub-Lyapunov exponent lambda(0) is generalized to the case of two time-scale-separated delays in the system. We give experimental evidence of strong and weak chaos in a network of lasers, which supports the sequence of weak to strong to weak chaos upon monotonically increasing the coupling strength. Finally, we discuss strong and weak chaos for networks with several distinct sub-Lyapunov exponents and comment on the dependence of the sub Lyapunov exponent on the number of a laser's inputs in a network. PMID- 23944534 TI - Time-delayed feedback control design beyond the odd-number limitation. AB - We present an algorithm for a time-delayed feedback control design to stabilize periodic orbits with an odd number of positive Floquet exponents in autonomous systems. Due to the so-called odd-number theorem such orbits have been considered as uncontrollable by time-delayed feedback methods. However, this theorem has been refuted by a counterexample and recently a corrected version of the theorem has been proved. In our algorithm, the control matrix is designed using a relationship between Floquet multipliers of the systems controlled by time delayed and proportional feedback. The efficacy of the algorithm is demonstrated with the Lorenz and Chua systems. PMID- 23944535 TI - Vortex dynamics in cubic-quintic Bose-Einstein condensates. AB - We study vortex dynamics in a trapped Bose-Einstein condensate with tunable two- and three-body interactions. The dynamics is governed by two-dimensional cubic quintic Gross-Pitaevskii equation. A time-dependent variational method has been used to obtain critical rotational frequency and surface mode frequency analytically and are compared with numerical simulation results. An imaginary time propagation method and Crank-Nicolson scheme for discretization have been used for numerical simulation. The numerically calculated average value of the angular momentum per particle shows very clearly its dynamical relation with the time development of the vortex formation. The rotational frequency dependence of the variation of average value of the angular momentum per particle with time shows that vortices form much faster in time for higher rotational frequency. Similarly, the vortex forms much faster in time with an increase of the strength of the repulsive three-body interaction. The simulation of the vortex lattice formation in the condensate shows that the presence of the three-body interactions does not alter the vortex lattice pattern but it helps in the shape deformations of the condensate thereby leading to vortex lattice formation. Likewise, the three-body interactions enable the vortex lattice formation in Bose Einstein condensates even with attractive two-body interactions and in purely quintic BEC. PMID- 23944536 TI - Noise-induced synchronization, desynchronization, and clustering in globally coupled nonidentical oscillators. AB - We study ensembles of globally coupled, nonidentical phase oscillators subject to correlated noise, and we identify several important factors that cause noise and coupling to synchronize or desynchronize a system. By introducing noise in various ways, we find an estimate for the onset of synchrony of a system in terms of the coupling strength, noise strength, and width of the frequency distribution of its natural oscillations. We also demonstrate that noise alone can be sufficient to synchronize nonidentical oscillators. However, this synchrony depends on the first Fourier mode of a phase-sensitivity function, through which we introduce common noise into the system. We show that higher Fourier modes can cause desynchronization due to clustering effects, and that this can reinforce clustering caused by different forms of coupling. Finally, we discuss the effects of noise on an ensemble in which antiferromagnetic coupling causes oscillators to form two clusters in the absence of noise. PMID- 23944537 TI - Scattering approach to fidelity decay in closed systems and parametric level correlations. AB - Based on an exact analytical approach to describe scattering fidelity experiments [Kober et al., Phys. Rev. E 82, 036207 (2010)], we obtain an expression for the fidelity amplitude decay of quantum chaotic or diffusive systems under arbitrary Hermitian perturbations. This allows us to rederive previous separately obtained results in a simpler and unified manner, as is shown explicitly for the case of a global perturbation. The general expression is also used to derive a so far unpublished exact analytical formula for the case of a moving S-wave scatterer. In the second part of the paper, we extend a relation between fidelity decay and parametric level correlations from the universal case of global perturbations to an arbitrary combination of global and local perturbations. Thereby, the relation becomes a versatile tool for the analysis of unknown perturbations. PMID- 23944538 TI - Characterization of edge oscillation in a traveling-wave field-effect transistor. AB - In this study, we characterize the oscillating pulse edges developed in a traveling-wave field-effect transistor (TWFET). Recently, it has been found that a stable shock front can develop on a TWFET, which can travel in one direction only. Once the reflected pulse edge at the far end is transmitted to the input, the shock front develops and begins to travel on the device again. This process establishes a permanent edge oscillation. This paper discusses the device setup necessary to excite such oscillations and how pulse edges oscillate on a TWFET. By applying the phase reduction scheme to the transmission equations of a TWFET, we obtain phase sensitivity, which appropriately explains the measured spatial dependence of the locking range in frequency. Moreover, multiple oscillating edges can develop simultaneously, which are mutually synchronized. The dynamics of these multiple edges are also described. PMID- 23944539 TI - Drift laws for spiral waves on curved anisotropic surfaces. AB - Rotating spiral waves organize spatial patterns in chemical, physical, and biological excitable systems. Factors affecting their dynamics, such as spatiotemporal drift, are of great interest for particular applications. Here, we propose a quantitative description for spiral wave dynamics on curved surfaces which shows that for a wide class of systems, including the Belousov-Zhabotinsky reaction and anisotropic cardiac tissue, the Ricci curvature scalar of the surface is the main determinant of spiral wave drift. The theory provides explicit equations for spiral wave drift direction, drift velocity, and the period of rotation. Depending on the parameters, the drift can be directed to the regions of either maximal or minimal Ricci scalar curvature, which was verified by direct numerical simulations. PMID- 23944540 TI - Super-rogue waves in simulations based on weakly nonlinear and fully nonlinear hydrodynamic equations. AB - The rogue wave solutions (rational multibreathers) of the nonlinear Schrodinger equation (NLS) are tested in numerical simulations of weakly nonlinear and fully nonlinear hydrodynamic equations. Only the lowest order solutions from 1 to 5 are considered. A higher accuracy of wave propagation in space is reached using the modified NLS equation, also known as the Dysthe equation. This numerical modeling allowed us to directly compare simulations with recent results of laboratory measurements in Chabchoub et al. [Phys. Rev. E 86, 056601 (2012)]. In order to achieve even higher physical accuracy, we employed fully nonlinear simulations of potential Euler equations. These simulations provided us with basic characteristics of long time evolution of rational solutions of the NLS equation in the case of near-breaking conditions. The analytic NLS solutions are found to describe the actual wave dynamics of steep waves reasonably well. PMID- 23944541 TI - Gating-signal propagation by a feed-forward neural motif. AB - We study the signal propagation in a feed-forward motif consisting of three bistable neurons: Two input neurons receive input signals and the third output neuron generates the output. We find that a weak input signal can be propagated from the input neurons to the output neuron without amplitude attenuation. We further reveal that the initial states of the input neurons and the coupling strength act as signal gates and determine whether the propagation is enhanced or not. We also investigate the effect of the input signal frequency on enhanced signal propagation. PMID- 23944542 TI - Collective motion of symmetric camphor papers in an annular water channel. AB - We investigate the collective motion of symmetric self-propelled objects that are driven by a difference in the surface tension. The objects move around an annular water channel spontaneously and interact through the camphor layer that develops on the water surface. We found that two collective motion modes, discrete and continuous density waves, are generated depending on the number of self-propelled objects. The two modes are characterized by examining the local and global dynamics, and the collective motion mechanism is discussed in relation to the distribution of camphor concentration in the annular water channel. We conclude that the difference between these two modes originates from that of the driving mechanism that pushes a camphor paper away from a cluster, through which mechanism density waves are generated and maintained. PMID- 23944543 TI - Attractive forces on hard and soft colloidal objects located close to the surface of an acoustic-thickness shear resonator. AB - Colloidal particles located close to the surface of an acoustic thickness shear resonator feel an attractive steady force, which is induced by the high-frequency tangential motion of the resonator surface. The range of the force is about half the penetration depth of the transverse viscous wave, that is, half of the thickness of the Stokes boundary layer. For an oscillation amplitude of 10 nm and a particle radius of 100 nm, the depth of attractive potential well corresponds to about 3 times the thermal energy, k(B)T. The force therefore suffices to overcome Brownian motion. PMID- 23944544 TI - Dynamo threshold detection in the von Karman sodium experiment. AB - Predicting dynamo self-generation in liquid metal experiments has been an ongoing question for many years. In contrast to simple dynamical systems for which reliable techniques have been developed, the ability to predict the dynamo capacity of a flow and the estimate of the corresponding critical value of the magnetic Reynolds number (the control parameter of the instability) has been elusive, partly due to the high level of turbulent fluctuations of flows in such experiments (with kinetic Reynolds numbers in excess of 10(6)). We address these issues here, using the von Karman sodium experiment and studying its response to an externally applied magnetic field. We first show that a dynamo threshold can be estimated from analysis related to critical slowing down and susceptibility divergence, in configurations for which dynamo action is indeed observed. These approaches are then applied to flow configurations that have failed to self generate magnetic fields within operational limits, and we quantify the dynamo capacity of these configurations. PMID- 23944545 TI - Effect of elongational flow on ferrofuids under a magnetic field. AB - To set up a mathematical model for the flow of complex magnetic fluids, noninteracting magnetic particles with a small volume or an even point size are typically assumed. Real ferrofluids, however, consist of a suspension of particles with a finite size in an almost ellipsoid shape as well as with particle-particle interactions that tend to form chains of various lengths. To come close to the realistic situation for ferrofluids, we investigate the effect of elongational flow incorporated by the symmetric part of the velocity gradient field tensor, which could be scaled by a so-called transport coefficient lambda(2). Based on the hybrid finite-difference and Galerkin scheme, we study the flow of a ferrofluid in the gap between two concentric rotating cylinders subjected to either a transverse or an axial magnetic field with the transport coefficient. Under the influence of a transverse magnetic field with lambda(2)=0, we show that basic state and centrifugal unstable flows are modified and are inherently three-dimensional helical flows that are either left-winding or right winding in the sense of the azimuthal mode-2, which is in contrast to the generic cases. That is, classical modulated rotating waves rotate, but these flows do not. We find that under elongational flow (lambda(2)?0), the flow structure from basic state and centrifugal instability flows is modified and their azimuthal vorticity is linearly changed. In addition, we also show that the bifurcation threshold of the supercritical centrifugal unstable flows under a magnetic field depends linearly on the transport coefficient, but it does not affect the general stabilization effect of any magnetic field. PMID- 23944546 TI - Quench cooling under reduced gravity. AB - We report quench cooling experiments performed with liquid O(2) under different levels of gravity, simulated with magnetic gravity compensation. A copper disk is quenched from 300 to 90 K. It is found that the cooling time in microgravity is very long in comparison with any other gravity level. This phenomenon is explained by the insulating effect of the gas surrounding the disk. A weak gas pressurization (which results in subcooling of the liquid with respect to the saturation temperature) is shown to drastically improve the heat exchange, thus reducing the cooling time (about 20 times). The effect of subcooling on the heat transfer is analyzed at different gravity levels. It is shown that this type of experiment cannot be used for the analysis of the critical heat flux of the boiling crisis. The film boiling heat transfer and the minimum heat flux of boiling are analyzed as functions of gravity and subcooling. PMID- 23944547 TI - Vorticity statistics and the time scales of turbulent strain. AB - Time scales of turbulent strain activity, denoted as the strain persistence times of first and second order, are obtained from time-dependent expectation values and correlation functions of Lagrangian rate-of-strain eigenvalues taken in particularly defined statistical ensembles. Taking into account direct numerical simulation data, our approach relies on heuristic closure hypotheses which allow us to establish a connection between the statistics of vorticity and strain. It turns out that softly divergent prefactors correct the usual "1/s" strain time scale estimate of standard turbulence phenomenology, in a way which is consistent with the phenomenon of vorticity intermittency. PMID- 23944548 TI - Fold-pitchfork bifurcation for maps with Z(2) symmetry in pipe flow. AB - This study aims to provide a better understanding of recently identified transition scenarios exhibited by traveling wave solutions in pipe flow. This particular family of solutions are invariant under certain reflectional symmetry transformations and they emerge from saddle-node bifurcations within a two dimensional parameter space characterized by the length of the pipe and the Reynolds number. The present work precisely provides a detailed analysis of a codimension-two saddle-node bifurcation arising in discrete dynamical systems (maps) with Z(2) symmetry. Normal form standard techniques are applied in order to obtain the reduced map up to cubic order. All possible bifurcation scenarios exhibited by this normal form are analyzed in detail. Finally, a qualitative comparison of these scenarios with the ones observed in the aforementioned hydrodynamic problem is provided. PMID- 23944549 TI - Analytical solution to predicting gaseous mass flow rates of microchannels in a wide range of Knudsen numbers. AB - To predict the gaseous mass flow rate of microchannels, conventional analytical solutions based on the Navier-Stokes equation or volume diffusion hydrodynamics (bivelocity hydrodynamics) associated with first-order or second-order slip boundary condition are not very successful, especially in high-Knudsen-number flow. An analytical solution which agrees with experimental data to a Knudsen number of 50 is presented in this paper. To achieve this goal, a concept of effective volume diffusion is defined. Then, with a general slip boundary condition, the gaseous mass flow rate of microchannel is derived by solving the momentum equation of this effective volume diffusion hydrodynamics. Compared with six other analytical solutions and one group of numerical solutions of the linearized Boltzmann equation, this solution is validated by three groups of experimental data. The results not only illustrate an improvement of this solution compared with other analytical solutions but also show the importance of the effective volume diffusion hydrodynamics for compressible microfluids. PMID- 23944550 TI - Lattice Boltzmann modeling of directional wetting: comparing simulations to experiments. AB - Lattice Boltzmann Modeling (LBM) simulations were performed on the dynamic behavior of liquid droplets on chemically striped patterned surfaces, ultimately with the aim to develop a predictive tool enabling reliable design of future experiments. The simulations accurately mimic experimental results, which have shown that water droplets on such surfaces adopt an elongated shape due to anisotropic preferential spreading. Details of the contact line motion such as advancing of the contact line in the direction perpendicular to the stripes exhibit pronounced similarities in experiments and simulations. The opposite of spreading, i.e., evaporation of water droplets, leads to a characteristic receding motion first in the direction parallel to the stripes, while the contact line remains pinned perpendicular to the stripes. Only when the aspect ratio is close to unity, the contact line also starts to recede in the perpendicular direction. Very similar behavior was observed in the LBM simulations. Finally, droplet movement can be induced by a gradient in surface wettability. LBM simulations show good semiquantitative agreement with experimental results of decanol droplets on a well-defined striped gradient, which move from high- to low contact angle surfaces. Similarities and differences for all systems are described and discussed in terms of the predictive capabilities of LBM simulations to model direction wetting. PMID- 23944551 TI - Performance evaluation of Maxwell and Cercignani-Lampis gas-wall interaction models in the modeling of thermally driven rarefied gas transport. AB - A systematic study on the performance of two empirical gas-wall interaction models, the Maxwell model and the Cercignani-Lampis (CL) model, in the entire Knudsen range is conducted. The models are evaluated by examining the accuracy of key macroscopic quantities such as temperature, density, and pressure, in three benchmark thermal problems, namely the Fourier thermal problem, the Knudsen force problem, and the thermal transpiration problem. The reference solutions are obtained from a validated hybrid DSMC-MD algorithm developed in-house. It has been found that while both models predict temperature and density reasonably well in the Fourier thermal problem, the pressure profile obtained from Maxwell model exhibits a trend that opposes that from the reference solution. As a consequence, the Maxwell model is unable to predict the orientation change of the Knudsen force acting on a cold cylinder embedded in a hot cylindrical enclosure at a certain Knudsen number. In the simulation of the thermal transpiration coefficient, although all three models overestimate the coefficient, the coefficient obtained from CL model is the closest to the reference solution. The Maxwell model performs the worst. The cause of the overestimated coefficient is investigated and its link to the overly constrained correlation between the tangential momentum accommodation coefficient and the tangential energy accommodation coefficient inherent in the models is pointed out. Directions for further improvement of models are suggested. PMID- 23944552 TI - Magnetohydrodynamic stability of stochastically driven accretion flows. AB - We investigate the evolution of magnetohydrodynamic (or hydromagnetic as coined by Chandrasekhar) perturbations in the presence of stochastic noise in rotating shear flows. The particular emphasis is the flows whose angular velocity decreases but specific angular momentum increases with increasing radial coordinate. Such flows, however, are Rayleigh stable but must be turbulent in order to explain astrophysical observed data and, hence, reveal a mismatch between the linear theory and observations and experiments. The mismatch seems to have been resolved, at least in certain regimes, in the presence of a weak magnetic field, revealing magnetorotational instability. The present work explores the effects of stochastic noise on such magnetohydrodynamic flows, in order to resolve the above mismatch generically for the hot flows. We essentially concentrate on a small section of such a flow which is nothing but a plane shear flow supplemented by the Coriolis effect, mimicking a small section of an astrophysical accretion disk around a compact object. It is found that such stochastically driven flows exhibit large temporal and spatial autocorrelations and cross-correlations of perturbation and, hence, large energy dissipations of perturbation, which generate instability. Interestingly, autocorrelations and cross-correlations appear independent of background angular velocity profiles, which are Rayleigh stable, indicating their universality. This work initiates our attempt to understand the evolution of three-dimensional hydromagnetic perturbations in rotating shear flows in the presence of stochastic noise. PMID- 23944553 TI - Sign cancellation and scaling in the vertical component of velocity and vorticity in rotating turbulence. AB - We study sign changes and scaling laws in the Cartesian components of the velocity and vorticity of rotating turbulence, in the helicity, and in the components of vertically averaged fields. Data for the analysis are provided by high-resolution direct numerical simulations of rotating turbulence with different forcing functions, with up to 1536(3) grid points, with Reynolds numbers between ~1100 and ~5100, and with moderate Rossby numbers between ~0.06 and ~8. When rotation is negligible, all Cartesian components of the velocity show similar scaling, in agreement with the expected isotropy of the flow. However, in the presence of rotation, only the vertical components of the fields show clear scaling laws, with evidence of possible sign singularity in the limit of an infinite Reynolds number. Horizontal components of the velocity are smooth and do not display rapid fluctuations for arbitrarily small scales. The vertical velocity and vorticity, as well as the vertically averaged vertical velocity and vorticity, show the same scaling within error bars, in agreement with theories that predict that these quantities have the same dynamical equation for very strong rotation. PMID- 23944554 TI - Path selection rules for droplet trains in single-lane microfluidic networks. AB - We investigate the transport of periodic trains of droplets through microfluidic networks having one inlet, one outlet, and nodes consisting of T junctions. Variations of the dilution of the trains, i.e., the distance between drops, reveal the existence of various hydrodynamic regimes characterized by the number of preferential paths taken by the drops. As the dilution increases, this number continuously decreases until only one path remains explored. Building on a continuous approach used to treat droplet traffic through a single asymmetric loop, we determine selection rules for the paths taken by the drops and we predict the variations of the fraction of droplets taking these paths with the parameters at play including the dilution. Our results show that as dilution decreases, the paths are selected according to the ascending order of their hydrodynamic resistance in the absence of droplets. The dynamics of these systems controlled by time-delayed feedback is complex: We observe a succession of periodic regimes separated by a wealth of bifurcations as the dilution is varied. In contrast to droplet traffic in single asymmetric loops, the dynamical behavior in networks of loops is sensitive to initial conditions because of extra degrees of freedom. PMID- 23944555 TI - Effect of hydrodynamic and fluid-solid interaction forces on the shape and stability of a droplet sedimenting on a horizontal wall. AB - In this paper, we study the sedimentation of droplet onto horizontal surfaces using a Shan and Chen multicomponent lattice Boltzmann model [Shan and Chen, Phys. Rev. E 47, 1815 (1993)]. Numerical simulations are performed for static nonwetting droplets and are compared with a theoretical model. Further simulations are performed using wetting droplets and changing the wetting characteristics of the surface. Novel study of droplet sedimentation with different wetting characteristics of wall surface shows three different regimes of droplet shapes. The process of different regimes can be controlled by changing the wetting characteristics of surface. It is observed that the droplet attains nonequilibrium region as the attraction force of surrounding droplet with the wall increases. This can lead to eventual breakup of the droplet. PMID- 23944556 TI - Breakup of a pendant magnetic drop. AB - We report experiments on a millimeter-sized pendant drop of ferrofluid in a horizontal magnetic field. The initial drop size is chosen just below the breakup threshold under gravity. As the magnetic field is increased, the drop tilts in order to align with the direction of the total volume force that is exerted on it: weight plus magnetic force. The breakup is controlled by a generalized Bond number based on this total force and on the radius of the neck of the drop. The evolution of drop shape turns out to be a complex process governed by many parameters such as the angle between the total force and the needle, the drop size relative to the needle radius, and the wettability of the liquid on the needle material. This suggests a certain universality, that a single value of the critical Bond number is found regardless of magnetic fluid properties and whether the force is inclined or not. PMID- 23944557 TI - Flagellar waveform dynamics of freely swimming algal cells. AB - We present quantitative measurements of time-dependent flagellar waveforms for freely swimming biflagellated algal cells, for both synchronous and asynchronous beating. We use the waveforms in conjunction with resistive force theory as well as a singularity method to predict a cell's time-dependent velocity for comparison with experiments. While net propulsion is thought to arise from asymmetry between the power and recovery strokes, we show that hydrodynamic interactions between the flagella and cell body on the return stroke make an important contribution to enhance net forward motion. PMID- 23944558 TI - Wavelength selection in Hele-Shaw flows: a maximum-amplitude criterion. AB - As in most interfacial flow problems, the standard theoretical procedure to establish wavelength selection in the viscous fingering instability is to maximize the linear growth rate. However, there are important discrepancies between previous theoretical predictions and existing experimental data. In this work we perform a linear stability analysis of the radial Hele-Shaw flow system that takes into account the combined action of viscous normal stresses and wetting effects. Most importantly, we introduce an alternative selection criterion for which the selected wavelength is determined by the maximum of the interfacial perturbation amplitude. The effectiveness of such a criterion is substantiated by the significantly improved agreement between theory and experiments. PMID- 23944559 TI - Lagrangian coherent structures separate dynamically distinct regions in fluid flows. AB - Using filter-space techniques, we study the scale-to-scale transport of energy in a quasi-two-dimensional, weakly turbulent fluid flow averaged along the trajectories of fluid elements. We find that although the spatial mean of this Lagrangian-averaged flux is nearly unchanged from its Eulerian counterpart, the spatial structure of the scale-to-scale energy flux changes significantly. In particular, its features appear to correlate with the positions of Lagrangian coherent structures (LCS's). We show that the LCS's tend to lie at zeros of the scale-to-scale flux, and therefore that the LCS's separate regions that have qualitatively different dynamics. Since LCS's are also known to be impenetrable barriers to advection and mixing, we therefore find that the fluid on either side of an LCS is both kinematically and dynamically distinct. Our results extend the utility of LCS's by making clear the role they play in the flow dynamics in addition to the kinematics. PMID- 23944560 TI - Nonequilibrium gaseous heat transfer in pressure-driven plane Poiseuille flow. AB - Nonequilibrium heat and mass transfer in a pressure-driven plane Poiseuille flow is investigated using the direct simulation Monte Carlo method from the early slip to the free molecular regime. Our investigations reveal several nonintuitive, nonequilibrium thermal flow patterns, including expansion cooling near the walls, a nonconstant pressure profile, and counter-gradient heat transfer along the channel center-line. A bimodal trend in the tangential heat flux is found in the slip and the early transition regime. In the upper transition and free molecular regime, the net heat flow in the entire channel is largely unidirectional and in the opposite direction of mass flow. However, in the slip and the early transition regime, a two-way heat flow is observed in the channel as the normal heat flux profile plays a key role in determining the net gaseous heat flow direction. Moreover, the heat flow rate profile exhibits a maximum value at an intermediate value of Knudsen number. The effects of incomplete surface accommodation on nonequilibrium heat flow are also investigated in this work. It is shown that for very low values of the accommodation coefficient, the gaseous heat flow direction is reversed and is consistently in the direction of mass flow. PMID- 23944561 TI - Numerical homogenization of electrokinetic equations in porous media using lattice-Boltzmann simulations. AB - We report the calculation of all the transfer coefficients which couple the solvent and ionic fluxes through a charged pore under the effect of pressure, electrostatic potential, and concentration gradients. We use a combination of analytical calculations at the Poisson-Nernst-Planck and Navier-Stokes levels of description and mesoscopic lattice simulations based on kinetic theory. In the absence of added salt, i.e., when the only ions present in the fluid are the counterions compensating the charge of the surface, exact analytical expressions for the fluxes in cylindrical pores allow us to validate a new lattice-Boltzmann electrokinetics (LBE) scheme which accounts for the osmotic contribution to the transport of all species. The influence of simulation parameters on the numerical accuracy is thoroughly investigated. In the presence of an added salt, we assess the range of validity of approximate expressions of the fluxes computed from the linearized Poisson-Boltzmann equation by a systematic comparison with LBE simulations. PMID- 23944562 TI - Chaotic particle heating due to an obliquely propagating wave in a magnetized plasma. AB - We study the dynamics of a relativistic charged particle in the presence of a uniform magnetic field and a stationary electrostatic wave that propagates at an arbitrary angle. The wave is considered as a series of periodic pulses which allows us to derive an exact map for the system. In particular, we investigate the heating process of an initially low-energy particle. It is found that abrupt changes in the maximum energy attained by the particle may occur as the angle between the wave propagation and the magnetic field varies. To determine what is the mechanism behind this phenomenon a reduced Hamiltonian that retains the important dynamical features is obtained. Using both Poincare plots and perturbation theory, we identify that a separatrix reconnection is the key mechanism for the abrupt change in particle response. PMID- 23944564 TI - Particle transport and radiation production in sub-Larmor-scale electromagnetic turbulence. AB - The relation of particle transport of relativistic particles in plasmas with high amplitude isotropic sub-Larmor-scale magnetic turbulence to the spectra of radiation simultaneously produced by these particles is investigated both analytically and numerically. We have found that in the asymptotic regime of very small particle deflections, the pitch-angle diffusion coefficient is directly related to the spectrum of the emitted radiation. Moreover, this spectrum provides much information about the statistical properties of the underlying magnetic turbulence. The transition from small- to large-scale jitter to synchrotron radiation regimes as a function of turbulence properties has also been explored. These results can readily be used to diagnose laboratory and astrophysical plasmas. PMID- 23944563 TI - Reduced coupled-mode approach to electron-ion energy relaxation. AB - We present a reduced model for the energy transfer via coupled collective modes in two-temperature plasmas based on quantum statistical theory. The model is compared with exact numerical evaluations of the coupled-mode (CM) energy transfer rate and with alternative reduced approaches over a range of conditions in the warm dense matter (WDM) and inertial confinement fusion (ICF) regimes. Our approach shows excellent agreement with an exact treatment of the CM rate and supports the importance of the coupled-mode effect for the temperature and energy relaxation in WDM and ICF plasmas. We find that electronic damping of collective ion density fluctuations is crucial for correctly describing the mode spectrum and, thus, the energy exchange. The reduced CM approach is studied over a wide parameter space, enabling us to establish its limits of applicability. PMID- 23944565 TI - Microwave guiding along double femtosecond filaments in air. AB - Microwave guiding along double parallel lines of femtosecond-laser-generated plasma filament has been demonstrated over a distance of about 8 cm in air, corresponding to a maximum microwave signal intensity enhancement more than sixfold the free-space propagation. It is shown that the operating frequency and the line electric width influence the propagation coefficient of microwaves propagating along this transmission line. Based on channeling microwaves along this line and by measuring and comparing the propagated microwave signals, the basic parameters of laser-generated plasma filament, namely, its electron density and conductivity, are obtained. PMID- 23944566 TI - Noble-gas resonant radiation effects on electron emission in plasma devices. AB - Experimental investigation results for photoemission affected by vacuum ultraviolet radiation of xenon and krypton atoms from a solid in vacuum and the target surface in contact with plasma (gas) are presented. It is demonstrated that, for adsorption (or implantation) of gas atoms into the target, the photoemission response considerably (to an order of magnitude) increases. This is caused by a change in the mechanism of photoemission from a solid surface in contact with plasma (gas), as compared to vacuum. This phenomenon can be characterized by the term adsorption- (implantation-) induced resonant photoemission. The inclusion of this phenomenon has largely transformed our view of gas discharge ignition and glowing, in addition to operating a variety of plasmic and photoelectron devices. A different class of gas discharge instruments can be realized on this basis as well. PMID- 23944567 TI - Transport properties of dense deuterium-tritium plasmas. AB - Consistent descriptions of the equation of states and information about the transport coefficients of the deuterium-tritium mixture are demonstrated through quantum molecular dynamic (QMD) simulations (up to a density of 600 g/cm(3) and a temperature of 10(4) eV). Diffusion coefficients and viscosity are compared to the one-component plasma model in different regimes from the strong coupled to the kinetic one. Electronic and radiative transport coefficients, which are compared to models currently used in hydrodynamic simulations of inertial confinement fusion, are evaluated up to 800 eV. The Lorentz number is discussed from the highly degenerate to the intermediate region. One-dimensional hydrodynamic simulation results indicate that different temperature and density distributions are observed during the target implosion process by using the Spitzer model and ab initio transport coefficients. PMID- 23944568 TI - Spectroscopic study of plasma evolution in runaway nanosecond atmospheric pressure He discharges. AB - Time- and space-resolved visible-emission spectroscopy measurements are applied to study plasma parameters in nanosecond electrical discharges in He gas at pressure of 10(5) Pa, using a 150 kV, 5 ns duration high-voltage pulse. The plasma evolution during the discharge is investigated by applying line-shape analysis of several He I spectral transitions, with the Stark and opacity effects accounted for. The analysis shows that the discharge plasma is not in equilibrium and that significant electric fields of several kV/cm are present in the plasma during the discharge. Regions of plasma with significantly different electron densities are identified and a qualitative model of the plasma formation and evolution is proposed. PMID- 23944569 TI - Current redistribution and generation of kinetic energy in the stagnated Z pinch. AB - The structure of magnetic fields was investigated in stagnated wire-array Z pinches using a Faraday rotation diagnostic at the wavelength of 266 nm. The distribution of current in the pinch and trailing material was reconstructed. A significant part of current can switch from the main pinch to the trailing plasma preheated by x-ray radiation of the pinch. Secondary implosions of trailing plasma generate kinetic energy and provide enhanced heating and radiation of plasma at stagnation. Hot spots in wire-array Z pinches also provide enhanced radiation of the Z pinch. A collapse of a single hot spot radiates 1%-3% of x-ray energy of the Z pinch with a total contribution of hot spots of 10%-30%. PMID- 23944570 TI - Avalanches, breathers, and flow reversal in a continuous Lorenz-96 model. AB - For the discrete model suggested by Lorenz in 1996, a one-dimensional long-wave approximation with nonlinear excitation and diffusion is derived. The model is energy conserving but non-Hamiltonian. In a low-order truncation, weak external forcing of the zonal mean flow induces avalanchelike breather solutions which cause reversal of the mean flow by a wave-mean flow interaction. The mechanism is an outburst-recharge process similar to avalanches in a sandpile model. PMID- 23944571 TI - Stochastic theory of an optical vortex in nonlinear media. AB - A stochastic theory is given of an optical vortex occurring in nonlinear Kerr media. This is carried out by starting from the nonlinear Schrodinger type equation which accommodates vortex solution. By using the action functional method, the evolution equation of vortex center is derived. Then the Langevin equation is introduced in the presence of random fluctuations, which leads to the Fokker-Planck equation for the distribution function of the vortex center coordinate by using a functional integral. The Fokker-Planck equation is analyzed for a specific form of pinning potential by taking into account an interplay between the strength of the pinning potential and the random parameters, diffusion and dissipation constants. This procedure is performed by several approximate schemes. PMID- 23944572 TI - Coupled backward- and forward-propagating solitons in a composite right- and left handed transmission line. AB - We study the coupling between backward- and forward-propagating wave modes, with the same group velocity, in a composite right- and left-handed nonlinear transmission line. Using an asymptotic multiscale expansion technique, we derive a system of two coupled nonlinear Schrodinger equations governing the evolution of the envelopes of these modes. We show that this system supports a variety of backward- and forward-propagating vector solitons of the bright-bright, bright dark, and dark-bright type. Performing systematic numerical simulations in the framework of the original lattice that models the transmission line, we study the propagation properties of the derived vector soliton solutions. We show that all types of the predicted solitons exist, but differ on their robustness: Only bright-bright solitons propagate undistorted for long times, while the other types are less robust, featuring shorter lifetimes. In all cases, our analytical predictions are in very good agreement with the results of the simulations, at least up to times of the order of the solitons' lifetimes. PMID- 23944573 TI - Optical mechanical analogy and Hamiltonization of a nonholonomic system. AB - It is well known that there is an analogy between optics and mechanics that prompted much of the classical theory of mechanics and indeed extended it to the theory of quantum mechanics. We develop here an optical mechanical analogy for a prototypical nonholonomic mechanical system, a knife edge moving on a plane under the influence of a potential. We show that this approach is related to but different from the classical theory of Hamiltonization of nonholonomic systems. PMID- 23944574 TI - Stationary solutions for the 1+1 nonlinear Schrodinger equation modeling repulsive Bose-Einstein condensates in small potentials. AB - Stationary solutions for the 1+1 cubic nonlinear Schrodinger equation modeling repulsive Bose-Einstein condensates (BEC) in a small potential are obtained through a form of nonlinear perturbation. In particular, for sufficiently small potentials, we determine the perturbation theory of stationary solutions, by use of an expansion in Jacobi elliptic functions. This idea was explored before in order to obtain exact solutions [Bronski, Carr, Deconinck, and Kutz, Phys. Rev. Lett. 86, 1402 (2001)], where the potential itself was fixed to be a Jacobi elliptic function, thereby reducing the nonlinear ODE into an algebraic equation, (which could be easily solved). However, in the present paper, we outline the perturbation method for completely general potentials, assuming only that such potentials are locally small. We do not need to assume that the nonlinearity is small, as we perform a sort of nonlinear perturbation by allowing the zeroth order perturbation term to be governed by a nonlinear equation. This allows us to consider even poorly behaved potentials, so long as they are bounded locally. We demonstrate the effectiveness of this approach by considering a number of specific potentials: for the simplest potentials, and we recover results from the literature, while for more complicated potentials, our results are new. Dark soliton solutions are constructed explicitly for some cases, and we obtain the known one-soliton tanh-type solution in the simplest setting for the repulsive BEC. Note that we limit our results to the repulsive case; similar results can be obtained for the attractive BEC case. PMID- 23944575 TI - Electromagnetic field of a charge moving in a chiral isotropic medium. AB - We analyze the electromagnetic field generated by a point charge moving with a constant velocity in an isotropic chiral medium. We work in the frame of the Condon dispersion model for the weak chirality and ultrarelativistic motion of the charge. We show that the field of a moving charge contains two low-frequency wave processes with right- and left-hand circular polarizations and a high frequency wave process with a right-hand polarization. The low-frequency wave field exists at an arbitrary charge velocity and oscillates at a frequency of the order of the resonant frequency of the medium. This effect is of most importance near the charge trajectory. The high-frequency wave field arises at an ultrahigh velocity and is essential near the plane of charge dislocation for a sufficiently large offset from the trajectory. This wave field oscillates at a frequency that is considerably greater (up to several orders) than the resonant frequency of the medium. Intriguingly, both of these phenomena exist in the domain in front of the charge, thus producing the low- and high-frequency wave forerunners correspondingly. PMID- 23944576 TI - Classifying the hierarchy of nonlinear-Schrodinger-equation rogue-wave solutions. AB - We present a systematic classification for higher-order rogue-wave solutions of the nonlinear Schrodinger equation, constructed as the nonlinear superposition of first-order breathers via the recursive Darboux transformation scheme. This hierarchy is subdivided into structures that exhibit varying degrees of radial symmetry, all arising from independent degrees of freedom associated with physical translations of component breathers. We reveal the general rules required to produce these fundamental patterns. Consequently, we are able to extrapolate the general shape for rogue-wave solutions beyond order 6, at which point accuracy limitations due to current standards of numerical generation become non-negligible. Furthermore, we indicate how a large set of irregular rogue-wave solutions can be produced by hybridizing these fundamental structures. PMID- 23944577 TI - Lattice Fokker Planck for dilute polymer dynamics. AB - We show that the actual diffusive dynamics, governing the momentum relaxation of a polymer molecule, and described by a Fokker-Planck equation, may be replaced by a BGK-type relaxation dynamics without affecting the slow (Smoluchowski) dynamics in configuration space. Based on the BGK-type description, we present a lattice Boltzmann (LB) based direct discretization approach for the phase-space description of inertial polymer dynamics. We benchmark this formulation by determining the bulk rheological properties for both steady and time-dependent shear and extensional flows at moderate to large Weissenberg numbers. Finally, we compare the usefulness of the different discrete velocity models, typically used in the LB framework, for solving diffusive dynamics based on the Fokker-Planck equation. PMID- 23944578 TI - Gaussian quadrature and lattice discretization of the Fermi-Dirac distribution for graphene. AB - We construct a lattice kinetic scheme to study electronic flow in graphene. For this purpose, we first derive a basis of orthogonal polynomials, using as the weight function the ultrarelativistic Fermi-Dirac distribution at rest. Later, we use these polynomials to expand the respective distribution in a moving frame, for both cases, undoped and doped graphene. In order to discretize the Boltzmann equation and make feasible the numerical implementation, we reduce the number of discrete points in momentum space to 18 by applying a Gaussian quadrature, finding that the family of representative wave (2+1)-vectors, which satisfies the quadrature, reconstructs a honeycomb lattice. The procedure and discrete model are validated by solving the Riemann problem, finding excellent agreement with other numerical models. In addition, we have extended the Riemann problem to the case of different dopings, finding that by increasing the chemical potential the electronic fluid behaves as if it increases its effective viscosity. PMID- 23944579 TI - Momentum-exchange method in lattice Boltzmann simulations of particle-fluid interactions. AB - The momentum exchange method has been widely used in lattice Boltzmann simulations for particle-fluid interactions. Although proved accurate for still walls, it will result in inaccurate particle dynamics without corrections. In this work, we reveal the physical cause of this problem and find that the initial momentum of the net mass transfer through boundaries in the moving-boundary treatment is not counted in the conventional momentum exchange method. A corrected momentum exchange method is then proposed by taking into account the initial momentum of the net mass transfer at each time step. The method is easy to implement with negligible extra computation cost. Direct numerical simulations of a single elliptical particle sedimentation are carried out to evaluate the accuracy for our method as well as other lattice Boltzmann-based methods by comparisons with the results of the finite element method. A shear flow test shows that our method is Galilean invariant. PMID- 23944580 TI - Extended lattice Boltzmann method for numerical simulation of thermal phase change in two-phase fluid flow. AB - In this article, a method based on the multiphase lattice Boltzmann framework is presented which is applicable to liquid-vapor phase-change phenomena. Both liquid and vapor phases are assumed to be incompressible. For phase changes occurring at the phase interface, the divergence-free condition of the velocity field is no longer satisfied due to the gas volume generated by vaporization or fluid volume generated by condensation. Thus, we extend a previous model by a suitable equation to account for the finite divergence of the velocity field within the interface region. Furthermore, the convective Cahn-Hilliard equation is extended to take into account vaporization effects. In a first step, a D1Q3 LB model is constructed and validated against the analytical solution of a one-dimensional Stefan problem for different density ratios. Finally the model is extended to two dimensions (D2Q9) to simulate droplet evaporation. We demonstrate that the results obtained by this approach are in good agreement with theory. PMID- 23944581 TI - Self-organization and solution of shortest-path optimization problems with memristive networks. AB - We show that memristive networks, namely networks of resistors with memory, can efficiently solve shortest-path optimization problems. Indeed, the presence of memory (time nonlocality) promotes self organization of the network into the shortest possible path(s). We introduce a network entropy function to characterize the self-organized evolution, show the solution of the shortest-path problem and demonstrate the healing property of the solution path. Finally, we provide an algorithm to solve the traveling salesman problem. Similar considerations apply to networks of memcapacitors and meminductors, and networks with memory in various dimensions. PMID- 23944582 TI - Interaction pressure tensor for a class of multicomponent lattice Boltzmann models. AB - We present a theory to obtain the pressure tensor for a class of nonideal multicomponent lattice Boltzmann models, thus extending the theory presented by X. Shan [Phys. Rev. E 77, 066702 (2008)] for single-component fluids. We obtain the correct form of the pressure tensor directly on the lattice and the resulting equilibrium properties are shown to agree very well with those measured from numerical simulations. Results are compared with those of alternative theories. PMID- 23944583 TI - Computational modeling of laser-plasma interactions: pulse self-modulation and energy transfer between intersecting laser pulses. AB - The nonlinear interaction of intense femtosecond laser pulses with a self-induced plasma channel in air and the energy transfer between two intersecting laser pulses were simulated using the finite-difference time-domain particle-in-cell method. Implementation of a simple numerical code enabled modeling of various phenomena, including pulse self-modulation in the spatiotemporal and spectral domains, conical emission, and energy transfer between two intersecting laser beams. The mechanism for energy transfer was found to be related to a plasma waveguide array induced by Moire patterns of the interfering electric fields. The simulation results provide a persuasive replication and explanation of previous experimental results, when carried out under comparable physical conditions, and lead to prediction of others. This approach allows us to further examine the effect of the laser and plasma parameters on the simulation results and to investigate the underlying physics. PMID- 23944584 TI - Accounting for adsorption and desorption in lattice Boltzmann simulations. AB - We report a Lattice-Boltzmann scheme that accounts for adsorption and desorption in the calculation of mesoscale dynamical properties of tracers in media of arbitrary complexity. Lattice Boltzmann simulations made it possible to solve numerically the coupled Navier-Stokes equations of fluid dynamics and Nernst Planck equations of electrokinetics in complex, heterogeneous media. With the moment propagation scheme, it became possible to extract the effective diffusion and dispersion coefficients of tracers, or solutes, of any charge, e.g., in porous media. Nevertheless, the dynamical properties of tracers depend on the tracer-surface affinity, which is not purely electrostatic and also includes a species-specific contribution. In order to capture this important feature, we introduce specific adsorption and desorption processes in a lattice Boltzmann scheme through a modified moment propagation algorithm, in which tracers may adsorb and desorb from surfaces through kinetic reaction rates. The method is validated on exact results for pure diffusion and diffusion-advection in Poiseuille flows in a simple geometry. We finally illustrate the importance of taking such processes into account in the time-dependent diffusion coefficient in a more complex porous medium. PMID- 23944585 TI - Axisymmetric multiphase lattice Boltzmann method. AB - A lattice Boltzmann method for axisymmetric multiphase flows is presented and validated. The method is capable of accurately modeling flows with variable density. We develop the classic Shan-Chen multiphase model [Phys. Rev. E 47, 1815 (1993)] for axisymmetric flows. The model can be used to efficiently simulate single and multiphase flows. The convergence to the axisymmetric Navier-Stokes equations is demonstrated analytically by means of a Chapmann-Enskog expansion and numerically through several test cases. In particular, the model is benchmarked for its accuracy in reproducing the dynamics of the oscillations of an axially symmetric droplet and on the capillary breakup of a viscous liquid thread. Very good quantitative agreement between the numerical solutions and the analytical results is observed. PMID- 23944586 TI - Unconditionally stable method and numerical solution of the hyperbolic phase field crystal equation. AB - The phase-field crystal model (PFC model) resolves systems on atomic length scales and diffusive time scales and lies in between standard phase-field modeling and atomistic methods. More recently a hyperbolic or modified PFC model was introduced to describe fast (propagative) and slow (diffusive) dynamics. We present a finite-element method for solving the hyperbolic PFC equation, introducing an unconditionally stable time integration algorithm. A spatial discretization is used with the traditional C^{0}-continuous Lagrange elements with quadratic shape functions. The space-time discretization of the PFC equation is second-order accurate in time and is shown analytically to be unconditionally stable. Numerical simulations are used to show a monotonic decrease of the free energy during the transition from the homogeneous state to stripes. Benchmarks on modeling patterns in two-dimensional space are carried out. The benchmarks show the applicability of the proposed algorithm for determining equilibrium states. Quantitatively, the proposed algorithm is verified for the problem of lattice parameter and velocity selection when a crystal invades a homogeneous unstable liquid. PMID- 23944587 TI - Improving the efficiency of Monte Carlo simulations of systems that undergo temperature-driven phase transitions. AB - Recently, Velazquez and Curilef proposed a methodology to extend Monte Carlo algorithms based on a canonical ensemble which aims to overcome slow sampling problems associated with temperature-driven discontinuous phase transitions. We show in this work that Monte Carlo algorithms extended with this methodology also exhibit a remarkable efficiency near a critical point. Our study is performed for the particular case of a two-dimensional four-state Potts model on a square lattice with periodic boundary conditions. This analysis reveals that the extended version of Metropolis importance sampling is more efficient than the usual Swendsen-Wang and Wolff cluster algorithms. These results demonstrate the effectiveness of this methodology to improve the efficiency of MC simulations of systems that undergo any type of temperature-driven phase transition. PMID- 23944588 TI - Comparative study of selected parallel tempering methods. AB - We review several parallel tempering schemes and examine their main ingredients for accuracy and efficiency. The present study covers two selection methods of temperatures and several choices for the exchange of replicas, including a recent novel all-pair exchange method. We compare the resulting schemes and measure specific heat errors and efficiency using the two-dimensional (2D) Ising model. Our tests suggest that an earlier proposal for using numbers of local moves related to the canonical correlation times is one of the key ingredients for increasing efficiency, and protocols using cluster algorithms are found to be very effective. Some of the protocols are also tested for efficiency and ground state production in 3D spin-glass models where we find that a simple nearest neighbor approach using a local n-fold-way algorithm is the most effective. Finally, we present evidence that the asymptotic limits of the ground state energy for the isotropic case and for an anisotropic case of the 3D spin-glass model are very close and may even coincide. PMID- 23944589 TI - Replication-based inference algorithms for hard computational problems. AB - Inference algorithms based on evolving interactions between replicated solutions are introduced and analyzed on a prototypical NP-hard problem: the capacity of the binary Ising perceptron. The efficiency of the algorithm is examined numerically against that of the parallel tempering algorithm, showing improved performance in terms of the results obtained, computing requirements and simplicity of implementation. PMID- 23944590 TI - Data structure and movement for lattice-based simulations. AB - We show that for the lattice Boltzmann model, the existing paradigm in computer science for the choice of the data structure is suboptimal. In this paper we use the requirements of physical symmetry necessary for recovering hydrodynamics in the lattice Boltzmann description to propose a hybrid data layout for the method. This hybrid data structure, which we call a structure of an array of structures, is shown to be optimal for the lattice Boltzmann model. Finally, the possible advantages of establishing a connection between group theoretic symmetry requirements and the construction of the data structure is discussed in the broader context of grid-based methods. PMID- 23944591 TI - Multilevel selection in a resource-based model. AB - In the present work we investigate the emergence of cooperation in a multilevel selection model that assumes limiting resources. Following the work by R. J. Requejo and J. Camacho [Phys. Rev. Lett. 108, 038701 (2012)], the interaction among individuals is initially ruled by a prisoner's dilemma (PD) game. The payoff matrix may change, influenced by the resource availability, and hence may also evolve to a non-PD game. Furthermore, one assumes that the population is divided into groups, whose local dynamics is driven by the payoff matrix, whereas an intergroup competition results from the nonuniformity of the growth rate of groups. We study the probability that a single cooperator can invade and establish in a population initially dominated by defectors. Cooperation is strongly favored when group sizes are small. We observe the existence of a critical group size beyond which cooperation becomes counterselected. Although the critical size depends on the parameters of the model, it is seen that a saturation value for the critical group size is achieved. The results conform to the thought that the evolutionary history of life repeatedly involved transitions from smaller selective units to larger selective units. PMID- 23944592 TI - Bond percolation in higher dimensions. AB - We collect results for bond percolation on various lattices from two to fourteen dimensions that, in the limit of large dimension d or number of neighbors z, smoothly approach a randomly diluted Erdos-Renyi graph. We include results on bond-diluted hypersphere packs in up to nine dimensions, which show the mean coordination, excess kurtosis, and skewness evolving smoothly with dimension towards the Erdos-Renyi limit. PMID- 23944593 TI - Gaussian field theory for the Brownian motion of a solvated particle. AB - An alternative derivation of Brownian motion is presented. Instead of supplementing the linearized Navier-Stokes equations with a fluctuating force, we directly assume a Gaussian action functional for solvent velocity fluctuations. Solvating a particle amounts to expelling the solvent and prescribing a boundary condition to the solvent on the interface that is shared with the solute. We study the dynamical effects of this boundary condition on the solvent and derive explicit expressions for the solvent mean flow and velocity correlations. Moreover, we show that the probability to observe solvent velocity fluctuations that are compatible with the boundary condition reproduces random Brownian motion of the solvated particle. We explicitly calculate the translational and rotational diffusion coefficients of a spherical particle using the presented formalism. PMID- 23944594 TI - Enhanced permeation of single-file water molecules across a noncylindrical nanochannel. AB - We utilize molecular dynamics simulations to study the effect of noncylindrical shapes of a nanochannel (which are inspired from the shape of real biological water nanochannels) on the permeation of single-file water molecules across the nanochannel. Compared with the cylindrical shape that has been tremendously adopted in the literature, the noncylindrical shapes play a crucial role in enhancing water permeation. Remarkably, the maximal enhancement ratio reaches a value of 6.28 (enhancement behavior). Meanwhile, the enhancement becomes saturated when the volume of the noncylindrical shape continues to increase (saturation behavior). The analysis of average diffusivity of water molecules helps to reveal the mechanism underlying the two behaviors whereas Poiseuille's law fails to explain them. These results pave a way for designing high-flow nanochannels and provide insight into water permeation across biological water nanochannels. PMID- 23944595 TI - Critical behavior of the quantum Ising model on a fractal structure. AB - We study the critical behavior of the transverse-field quantum Ising model on a fractal structure, namely the Sierpinski carpet. When a magnetic field Delta is applied perpendicular to the Ising spin direction, quantum fluctuations affect the transition between the ferromagnetic and the paramagnetic phases. Employing the continuous-time quantum Monte Carlo simulation method and the finite-size scaling analysis, we investigate the interplay between the quantum fluctuations and the exotic dimensionality of the fractal structure and its effect on the critical behavior. As the transverse magnetic field increases, the critical temperature monotonically decreases until it apparently vanishes at a critical field Delta(c), beyond which the system becomes paramagnetic at all temperatures. However, the critical exponents are independent of Delta and remain the same as in the purely classical(Delta=0) case. PMID- 23944596 TI - Phase-field model for reconstructed stepped surface. AB - We formulate a phase-field, or diffuse-interface, model for the evolution of stepped surfaces under surface diffusion in the presence of distinct material parameters across nanoscale terraces. In the sharp-interface limit, our model reduces to a Burton-Cabrera-Frank (BCF)-type theory for the motion of noninteracting steps separating inhomogeneous terraces. This setting aims to capture features of reconstructed semiconductor, e.g., Si surfaces below the roughening transition. Our work forms an extension of the phase-field construction by Hu et al. [Physica D 241, 77 (2012)]. PMID- 23944597 TI - Manipulation of extreme events on scale-free networks. AB - Extreme events taking place on networks are not uncommon. We show that it is possible to manipulate the extreme event occurrence probabilities and distribution over the nodes of a scale-free network by tuning the nodal capacity. This can be used to reduce the number of extreme event occurrences. However, monotonic nodal capacity enhancements, beyond a point, do not lead to any substantial reduction in the number of extreme events. We point out the practical implication of this result for network design in the context of reducing extreme event occurrences. PMID- 23944598 TI - Codimension-three bifurcations in a Benard-Marangoni problem. AB - This Brief Report studies the linear stability of a thermoconvective problem in an annular domain for relatively low (~1) Prandtl (viscosity effects) and Biot (heat transfer) numbers. The four possible patterns for the instabilities, namely, hydrothermal waves of first and second class, longitudinal rolls, and corotating rolls, are present in a small region of the Biot-Prandtl plane. This region can be split in four zones, depending on the sort of instability found. The boundary of these four zones is composed of codimension-two points. Authors have also found two codimension-three points, where some of the former curves intersect. Results shown in this Brief Report clarify some reported experiments, predict new instabilities, and, by giving a deeper insight into how physical parameters affect bifurcations, open a gateway to control those instabilities. PMID- 23944599 TI - Top-down vortices developed in a cylindrical annulus cooled on the top. AB - In this paper we study the generation of top-down vortices by thermoconvective mechanisms in a cylindrical annulus nonhomogeneously cooled on the top. Assuming axisymmetry we study the structure of the vortices, characterized by a spiral downward motion, similar to that observed in tornadoes generated in supercell storms. PMID- 23944600 TI - Vortex bubble formation in pair plasmas. AB - It is shown that delocalized vortex solitons in relativistic pair plasmas with small temperature asymmetries can be unstable for intermediate intensities of the background electromagnetic field. Instability leads to the generation of ever expanding cavitating bubbles in which the electromagnetic fields are zero. The existence of such electromagnetic bubbles is demonstrated by qualitative arguments based on a hydrodynamic analogy, and by numerical solutions of the appropriate nonlinear Schrodinger equation with a saturating nonlinearity. PMID- 23944601 TI - Solutions of the coupled Higgs field equations. AB - By an appropriate choice for the phase of the complex nucleonic field and going over to the traveling coordinate, we reduce the coupled Higgs equations to the Hamiltonian form and treat the resulting equation using the dynamical system theory. We present a phase-space analysis of its stable points. The results of our study demonstrate that the equation can support both traveling- and standing wave solutions. The traveling-wave solution appears in the form of a soliton and resides in the midst of doubly periodic standing-wave solutions. PMID- 23944602 TI - Effect of a 5-week static stretching program on hardness of the gastrocnemius muscle. AB - This study investigated the effects of a static stretching (SS) program on muscle hardnesses of the gastrocnemius medialis (MG) and gastrocnemius lateralis (LG). Nineteen young men participated in this study. Either the right or left leg was randomly selected to conduct three bouts of 2-min SS of the plantar flexors 6 days a week for 5 weeks in each subject (the SS group), and the other leg was assigned to a control group. Before (pretest) and after (posttest) conducting the SS program, MG and LG hardnesses were measured using shear wave ultrasound elastography. The SS program was found to decrease muscle hardnesses, but not to change the ratio of MG hardness to LG hardness. There were no significant differences between the relative changes in the MG and LG hardnesses from pretest to posttest in both the SS and control groups. Significant correlations between the muscle hardness ratios at pretest and posttest were found in both groups. The results of this study suggest that the current SS program is useful for improving muscle condition in the plantar flexors, and that its long-term effects on the MG and LG hardnesses are of the same degree. PMID- 23944605 TI - Is disseminated intravascular coagulation the major cause of mortality from radiation at relatively low whole body doses? PMID- 23944606 TI - A model of radiation-induced cell killing: insights into mechanisms and applications for hadron therapy. AB - A mechanism-based, two-parameter biophysical model of cell killing was developed with the aim of elucidating the mechanisms underlying radiation-induced cell death and predicting cell killing by different radiation types, including protons and carbon ions at energies and doses of interest for cancer therapy. The model assumed that certain chromosome aberrations (dicentrics, rings and large deletions, called "lethal aberrations") lead to clonogenic inactivation, and that aberrations derive from MUm-scale misrejoining of chromatin fragments, which in turn are produced by "dirty" double-strand breaks called "cluster lesions" (CLs). The average numbers of CLs per Gy per cell were left as a semi-free parameter and the threshold distance for chromatin-fragment rejoining was defined the second parameter. The model was "translated" into Monte Carlo code and provided simulated survival curves, which were compared with survival data on V79 cells exposed to protons, carbon ions and X rays. The agreement was good between simulations and survival data and supported the assumptions of the model at least for doses up to a few Gy. Dicentrics, rings and large deletions were found to be lethal not only for AG1522 cells exposed to X rays, as already reported by others, but also for V79 cells exposed to protons and carbon ions of different energies. Furthermore, the derived CL yields suggest that the critical DNA lesions leading to clonogenic inactivation are more complex than "clean" DSBs. After initial validation, the model was applied to characterize the particle and LET dependence of proton and carbon cell killing. Consistent with the proton data, the predicted fraction of inactivated cells after 2 Gy protons was 40-50% below 7.7 keV/MUm, increased by a factor ~1.6 between 7.7-30.5 keV/MUm, and decreased by a factor ~1.1 between 30.5-34.6 keV/MUm. These LET values correspond to proton energies below a few MeV, which are always present in the distal region of hadron therapy spread-out Bragg peaks (SOBP). Consistent with the carbon data, the predicted fraction of inactivated cells after 2 Gy carbon was 40-50% between 13.7-32.4 keV/MUm, it increased by a factor ~1.7 between 32.4-153.5 keV/MUm, and decreased by a factor ~1.1 between 153.5-339.1 keV/MUm. Finally, we applied the model to predict cell death at different depths along a carbon SOBP used for preclinical experiments at HIMAC in Chiba, Japan. The predicted fraction of inactivated cells was found to be roughly constant (less than 10%) along the SOBP, suggesting that this approach may be applied to predict cell killing of therapeutic carbon beams and that, more generally, dicentrics, rings and deletions at the first mitosis may be regarded as a biological dose for these beams. This study advanced our understanding of the mechanisms of radiation induced cell death and characterized the particle and LET dependence of proton and carbon cell killing along a carbon SOBP. The model does not use RBE values, which can be a source of uncertainty. More generally, this model is a mechanism based tool that in minutes can predict cell inactivation by protons or carbon ions of a given energy and dose, based on an experimental photon curve and in principle, a single (experimental) survival point for the considered ion type and energy. PMID- 23944607 TI - Difluorodioxophosphate-based hollow hexanuclear lanthanide(III) clusters decorated with tetrathiafulvalene ligands. AB - The galvanostatic reaction of the [4,5-bis(2-pyridyl-N-oxidemethylthio)]-4',5' methyldithiotetrathiafulvalene ligand with lanthanide ions in the presence of hexafluorophosphate (PF6(-)) anions afforded the highest-nuclearity lanthanide clusters decorated by tetrathiafulvalene-based ligands thanks to the original partial hydrolysis of the PF6(-) anions in difluorodioxophosphate (PO2F2(-)) bridging ligands. PMID- 23944604 TI - Association of genes in the NF-kappaB pathway with antibody-positive primary Sjogren's syndrome. AB - Primary Sjogren's syndrome (SS) is a systemic autoimmune inflammatory disease characterized by focal lymphocytic infiltrates in the lachrymal and salivary glands and autoantibodies against the SSA/Ro and SSB/La antigens. Experimental studies have shown an activation of NF-kappaB in primary SS. NF-kappaB activation results in inflammation and autoimmunity and is regulated by inhibitory and activating proteins. Genetic studies have shown an association between multiple autoimmune diseases and TNFAIP3 (A20) and TNIP1 (ABIN1), both repressors of NF kappaB and of IKBKE (IKKepsilon), which is an NF-kappaB activator. The aim of this study was to analyse single nucleotide polymorphisms (SNPs) in the IKBKE, NFKB1, TNIP1 and TNFAIP3 genes for association with primary SS. A total of 12 SNPs were genotyped in 1105 patients from Scandinavia (Sweden and Norway, n = 684) and the UK (n = 421) and 4460 controls (Scandinavia, n = 1662, UK, n = 2798). When patients were stratified for the presence of anti-SSA and/or anti-SSB antibodies (n = 868), case-control meta-analysis found an association between antibody-positive primary SS and two SNPs in TNIP1 (P = 3.4 * 10(-5) , OR = 1.33, 95%CI: 1.16-1.52 for rs3792783 and P = 1.3 * 10(-3) , OR = 1.21, 95%CI: 1.08-1.36 for rs7708392). A TNIP1 risk haplotype was associated with antibody-positive primary SS (P = 5.7 * 10(-3) , OR = 1.47, 95%CI: 1.12-1.92). There were no significant associations with IKBKE, NFKB1 or TNFAIP3 in the meta-analysis of the Scandinavian and UK cohorts. We conclude that polymorphisms in TNIP1 are associated with antibody-positive primary SS. PMID- 23944608 TI - beta- and alpha-Thalassemia intermedia in Basra, Southern Iraq. AB - Hemoglobinopathies are common in Iraq and beta-thalassemia major (beta-TM) is a leading health problem in Basra, Southern Iraq. However, beta- and alpha thalassemia intermedia (beta- and alpha-TI) have not been so well studied. This is a descriptive study of 152 consecutive beta- and alpha-TI patients registered at the Centre for Hereditary Blood Diseases (CHBD) in Basra, Southern Iraq from October 1 2010 through June 30 2012 including age at diagnosis, blood transfusions and complications. beta-Thalassemia intermedia was found in 80 (52.6%) patients with a mean age at diagnosis of 7.10 +/- 8.0 years. This was significantly different from that of Hb H (beta4) disease (12.95 +/- 14.8 years), p <0.05. Patients with beta-TI received significantly more blood transfusions (3.39 +/- 3.85)/year compared to those with Hb H disease (1.07 +/- 1.39)/year, p <0.05. Short stature, extramedullary erythropoiesis, pulmonary hypertension and iron overload were significantly higher among patients with beta-TI compared to those with Hb H disease, p <0.05. Iron overload is a significant risk factor for growth retardation among patients with Hb H and beta-TI. While age is a significant risk factor for osteoporosis in both types of thalassemia intermedia. Both alpha- and beta-thalassemia (alpha- and beta-thal) have been reported in Basra. Although beta-TI is associated with a more severe disease than alpha-TI, both are associated with considerable complications. Thus, genetic studies are needed to determine the types of mutation producing beta-TI and the exact alpha thal determinants producing Hb H disease as they are important in the prediction of the phenotype severity. PMID- 23944610 TI - Efficacy and toxicity of treatments for nephritis in a series of consecutive lupus patients. AB - OBJECTIVE: To study efficacy and toxicity of treatments for nephritis in a series of consecutive lupus patients. METHODS: The case records of 40 patients with lupus nephritis followed up in a single center between 1992 and 2011 (median duration = 8.37 years) were retrieved to determine efficacy and toxicity of the treatments. Patients with class III/IV/V lupus nephritis were included. RESULTS: Sustained responses were 21/40 (52.5%) at six months, 33/40 (82.5%) at 18 months and 30/40 (75.0%) at 36 months. Three deaths were observed after 18, 104 and 164 months of follow-up respectively, with one possibly associated with immunosuppression. Kidney survival was 100% at 18 months and 97.7% at 36 months. Kaplan-Meier's survival algorithm estimated a mean overall survival of 236.05 +/- 11.56 months and a kidney survival of 240.77 +/- 11.07 months. Kidney and overall survival were not significantly different among patients with different nephritis classes. Complications occurred in 12/40 (30.0%). Amenorrhea occurred in 20.7% of patients and was associated with higher cumulative doses of cyclophosphamide. Patients who achieved remission at 36 months or later had lower levels of proteinuria at 6 months (mean +/- SD = 0.93 +/- 0.97 g/24 h versus 2.60 +/- 2.11 g/24 h, p = 0.002) than non-responder patients. CONCLUSIONS: The data demonstrate that in the overall Caucasian population with lupus nephritis the combination of available therapeutic tools is effective and relatively well tolerated. PMID- 23944609 TI - Absolute quantitation of immunoglobulin G and its glycoforms using multiple reaction monitoring. AB - Studies aimed toward glycan biomarker discovery have focused on glycan characterization by the global profiling of released glycans. Site-specific glycosylation analysis is less developed but may provide new types of biomarkers with higher sensitivity and specificity. Quantitation of peptide-conjugated glycans directly facilitates the differential analysis of distinct glycoforms associated with specific proteins at distinct sites. We have developed a method using MRM to monitor protein glycosylation normalized to absolute protein concentrations to examine quantitative changes in glycosylation at a site specific level. This new approach provides information regarding both the absolute amount of protein and the site-specific glycosylation profile and will thus be useful to determine if altered glycosylation profiles in serum/plasma are due to a change in protein glycosylation or a change in protein concentration. The remarkable sensitivity and selectivity of MRM enable the detection of low abundance IgG glycopeptides, even when IgG was digested directly in serum with no cleanup prior to the liquid chromatography. Our results show a low limit of detection of 60 amol and a wide dynamic range of 3 orders magnitude for IgG protein quantitation. The results show that IgG glycopeptides can be analyzed directly from serum (without enrichment) and yield more accurate abundances when normalized to the protein content. This report represents the most comprehensive study so far of the use of multiple reaction monitoring for the quantitation of glycoproteins and their glycosylation patterns in biofluids. PMID- 23944611 TI - Terminally grafted chain layers in oligomer-monomer solutions: predictions from a density functional theory. AB - The structure of grafted chain layers immersed in an explicit solvent consisting of chain molecules is studied using density functional theory. We consider bonded layers built of short grafted chains at a moderate grafting density. We investigate the grafted layers in contact with oligomeric solvents and oligomer monomer solutions. The chain molecules are freely jointed spherical segments. The substrate is assumed to be inert with respect to the grafted chains. The mobile molecules interact with the surface via Lennard-Jones (9-3) potential. The interactions between mobile chains, monomers, as well as segments of the tethered chains are described by Lennard-Jones (12-6) potential. We discuss how the structure of the grafted chain layer depends on the length of mobile chains and strengths of grafted chain-oligomer, oligomer-substrate, oligomer-oligomer, and oligomer-monomer interactions. We study the impact of mixture composition on the height of the bonded layer for selected model systems. The results are consistent with previous experimental and simulation data. PMID- 23944613 TI - Behavioural phenotypes and neurodevelopmental disorders in Africa. PMID- 23944612 TI - Development of a tumor-specific photoactivatable doxorubicin prodrug. AB - This is a retrospective highlight on the publication by Ibsen and coworkers: Localized In Vivo Activation of a Photoactivatable Doxorubicin Prodrug in Deep Tumor Tissue, which appeared in a preceding issue of Photochem. Photobiol. (2013, 89:698-708). The authors describe the synthesis and properties of a novel doxorubicin (DOX) prodrug, DOX-PCB, which contains a photocleavable linker group. Systemic administration of the prodrug to a tumor-bearing animal followed by LED/fiber optic 365 nm light delivery allowed active DOX to be released site specifically in the tumor area. This elegant and timely study provides compelling evidence that photocleavable DOX-PCB can eliminate many of the toxic side effects of DOX that have plagued clinical use of this highly effective antitumor drug for many years. PMID- 23944615 TI - Effect of intra-abdominal volume increment on lungs in hemorrhagic shock. AB - PURPOSE: Intra-abdominal hypertension (IAH) causes lung dysfunction in patients after hemorrhagic shock resuscitation. We performed intra-abdominal volume increment (IAVI) to IAH and studied its effect on pulmonary function. METHODS: Eight minipigs established for IAH model by exsanquination until shock, incomplete blockage of portal vein and overload resuscitation were randomly divided into IAVI group (n=4) and sham-operated control group (n=4). Bladder pressure, arterial blood gas analysis and thoraco-abdominal computed tomography (CT) scans were measured. The minipigs were sacrificed 26 h after surgery, and lung samples were harvested for measuring the wet-to-dry weight ratio and hematoxylin-eosin staining. RESULTS: Compared with sham-operated control group, the respiratory rate and paCO2 remarkably decreased and paO2 notably increased at 8 and 12 h in the IAVI group. The bladder pressure also notably decreased at 8, 12, and 22 h after IAVI treatment. However, a significant improvement in diaphragm height was observed at 22 h after IAVI treatment. The wet-to-dry weight ratio of the lungs in IAVI group was also significantly higher than that that in the sham-operated control group. CONCLUSION: Our data indicate that IAVI surgery could improve the damaged pulmonary function caused by IAH after hemorrhagic shock resuscitation (Tab. 1, Fig. 7, Ref. 21). PMID- 23944616 TI - Immunohistochemical characterization of urothelial carcinoma. AB - From the archive of BB Biocyt company, 32 urinary bladder carcinomas (urothelium carcinomas, UC) and 7 cases of chronic cystitis were selected and examined in semiserial sections for the following antigens: 1) cell proliferation marker Ki 67 (expressed in the nuclei), 2) cell cycle regulator p16/INK4a polypeptide (expressed in the cytoplasm and nuclei), 3) urothelium marker p63 (expressed in the nuclei), 4) cytokeratin 7 (CK7). 5) cytokeratin 20 (CK20) and 6) high molecular weight cytokeratin (HMWCK). Invasive urothelium carcinomas showing a high grade dysplasia (invasive HG UC) comprised over the half (20 out of 32) of the investigated tumours. Microinvasion to lamina propria (seen in three HG papillary carcinomas) was regarded as an early infiltration even when the position of muscular layer could not be determined. Classical invasion across the urinary bladder wall and/or to surrounding tissues was found in 17 cases of low differentiated HG UCs. The rest (9 out of 32 neoplasms) were either non-invasive papillary carcinomas of high (non-invasive HG UC, 5 cases) or low malignant potential (noninvasive LG UC, 4 cases). Finally, 3 cases were papillary urothelium neoplasms of low malignant potential (PUNLMP). HMWCK was present in all invasive tumours, whereas the frequency of other urothelium markers ranged from 65 to 88 %. Nevertheless, at least two markers were expressed in each invasive tumour. Staining for Ki-67 antigen was positive in over 50 % of the nuclei of HG UCs, while in the LG UCs, the frequency of positive Ki-67 staining did not exceed 25 %. In PUNLMP, the positive rate of Ki-67 stained dysplastic cells was below 10 %. The staining for p16 antigen did not correlate with the degree of dysplasia within urothelium tumours. For routine diagnostic, we recommend to combine the Ki-67 staining with detection of HMWCK. In cases of chronic cystitis, which developed urothelial hyperplasia and/or squamous metaplasia, the presence of p63 antigen was a relevant marker confirming the urothelial origin of the altered transitional cells (Tab. 6, Fig. 4, Ref. 69). PMID- 23944617 TI - The prevalence and risk factors for osteoporosis in patients with inflammatory bowel disease. AB - AIM: Osteoporosis is a known chronic complication of inflammatory bowel diseases (IBD). The aim of our study was to describe the prevalence of reduced bone mineral density (BMD) in IBD patients and to identify crucial risk factors for osteoporosis. METHODS: The cohort consisted of 76 IBD patients, 40 with Crohn's disease (CD) and 36 with ulcerative colitis (UC). Clinical characteristics of every patient were recorded, i.e. age, sex, duration of the disease, clinical behavior, location of disease according to Montreal classification, surgeries, steroid medication, sIBDQ, and smoking habits. We examined the serum 25-hydroxyl vitamin D3 (25-OHD3) in each patient. The BMD was determined by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and femoral neck. RESULTS: Osteoporosis was documented in 10 IBD patients (13.2 %), while osteopenia in 35 of them (46.1 %). Patients with CD have significantly lower femoral Z score than patients with UC. Femoral Z score was strongly associated with disease duration, and in CD patients suffering from stricturing form, with ileic or ileocolic location and history of proctocolectomy or total colectomy. Patients with osteoporosis had a significantly lower level of 25-OHD3 than patients with normal BMD. CONCLUSION: Patients with long disease duration and those suffering from stricturing form of CD with ileic/ileocolic location and history of proctocolectomy/total colectomy are at higher risk of developing osteoporosis than other IBD patients. The high proportion of osteopenia/osteoporosis in our study underlines the importance of BMD measurement in all IBD patients as a base for initiating the appropriate treatment (Tab. 1, Fig. 3, Ref. 63). PMID- 23944618 TI - Therapy of melanocytic conjunctival tumors. AB - BACKGROUND: Clinical experience of our single center in dealing with pigmented epibulbar lesions - melanocytic conjunctival tumors is presented. Since 2008 we use the topical treatment with mitomycin C (MMC) as an alternative or adjunctive method for excision in the treatment of melanocytic neoplasia of the conjunctiva. METHODS: The retrospective case series of 85 patients with pigmented lesions of the conjunctiva - melanocytic conjunctival tumors, histopathologically examined in the period 2001-2010 is presented. Since 2008 we started to apply MMC in the treatment of primary acquired melanosis (PAM) and dysplastic nevi. We apply MMC topically directly after an excision as 2-times five minutes application. RESULTS: In 85 patients with pigmented lesions of the conjunctiva histopathological findings after excision of the lesion showed in 68 (80 %) cases melanocytic nevocelullar nevus, out of which 55 cases were combined and 13 cases were junctional nevi. In 60 (80 %) cases of melanocytic nevi atypia was found in 25 patients (42 %), nevus without atypia was present in 35 cases (58 %). PAM with atypia was found in 16 patients (classified since 2000). During the period of application of MMC we diagnosed only one patient with primary conjunctival melanoma. There was no presence of relapse of the pigmented lesion either after primary excision or after excision with MMC. CONCLUSION: Resection of more than one quadrant of bulbar conjunctiva in patients with pigmented lesions of the conjunctiva in cases of conjunctival nevus with atypia and PAM with atypia combined with topical MMC chemotherapy is an alternative therapy for residual pigmented lesions. There was no presence of relapse of pigmentation in area of excision with or without using MMC during the surgery in patients with PAM. The number of our patients is not sufficient yet to draw a conclusion (Fig. 6, Ref. 21). PMID- 23944619 TI - Use of intraabdominal VAC (Vacuum Assisted Closure) lowers mortality and morbidity in patients with open abdomen. AB - OBJECTIVE: Authors compare two groups of patients with open abdomen. The objective is to compare and evaluate two treatment modalities, namely Kern laparostomy and vacuum-assisted closure in terms of mortality, closure of abdominal wound, and fistula management, all these stratified by BMI and CRP. BACKGROUND: Open abdomen can be considered a "patient salvage technique", used in patients with abdominal sepsis, as well as in patients with abdominal compartment syndrome, and in damage control surgery. Various management techniques are known, of which Kern laparostomy is most widely used. Newer techniques using negative pressure have emerged, still waiting for their wider acceptance and use. The authors present their study, in which they compare Kern laparostomy and intraabdominal VAC in patients with open abdomen. MATERIAL AND METHODS: Study consists of 44 patients treated at the authors' clinics, while group KERN consisted of patients managed by Kern laparostomy, and group VAC was managed by intraabdominal VAC. The groups were compared in terms of mortality, abdominal closure, appearance of enteroatmospheric fistulas, primary closure of fistulas, and possibility of diversion of enteral contents. All outputs were stratified by CRP (C-reactive protein) and BMI (Body Mass Index). RESULTS: In VAC group, a significant decrease in mortality was seen, as well as significantly higher closure of abdominal wall, and significantly higher possibility of diversion of enteral content from fistulas. No statistically significant findings were observed in stratification with CRP and BMI. CONCLUSION: Intraabdominal VAC offers patients lower morbidity and mortality and should be defined as a treatment of choice in patients with open abdomen (Tab. 4, Fig. 3, Ref. 15). PMID- 23944620 TI - The relationship between serum adiponectin and prognosis in patients with heart failure. AB - BACKGROUND: The role of adiponectin in the development of cardiac disease remains less clear than in metabolic disorders. While some studies indicated that low adiponectin levels were associated with cardiovascular disease, not all studies have been able to show such association. Adiponectin levels may influence the development of chronic heart failure, but the epidemiological data are somewhat complex. Thus, the aim of this study was a survey of relationship between serum Adiponectin and prognosis of patients with heart failure in Iran. METHODS AND MATERIALS: In this cohort study, we evaluated 96 chronic heart failure patients. Patients with systolic dysfunction that was defined as left ventricular Ejection Fraction (EF) <=40 % or had a history of heart failure were included in the study. At the baseline visit, all patients were examined by a physician and the following information was obtained: medical history, physical examination, New York Heart Association (NYHA) classification. After the first evaluation, analyses of adiponectin, Pro BNP, creatinine and uric acid were performed. Then the patients were followed up for a median of 12 months. RESULTS: There was a significant relationship between the mean adiponectin and Pro BNP levels and the ejection fraction (p=0.003 and p=0.003 respectively). Higher levels of adiponectin and Pro BNP were associated with a lower ejection fraction and there were no such associations between creatinine and uric acid levels. There was a significant association between the functional capacity as assessed by NYHA class and the mean of adiponectin and uric acid, these means that higher levels of adiponectin and uric acid were associated with a higher functional class in patients with CHF (p=0.03 and p=0.04 respectively). During a 12 month follow-up, 22 (22.9 %) patients died. In subjects who died, the baseline mean plasma adiponectin and Pro BNP levels were higher compared to those who were alive at the follow-up and these difference were statistically significant (19+/-7.4 vs.15.8+/-8 ng/ml and 9520+/-10249 vs. 3172+/-4628 ng/L p=0.000). CONCLUSION: The present study demonstrated that the plasma adiponectin level increased according to the severity of heart failure and also there was such relationship between Pro BNP and heart failure (Tab. 3, Ref. 35). PMID- 23944621 TI - Determination of serological profiles and avidity of specific antibodies in the sera of patients with potential Epstein-Barr virus (EBV) infection. AB - BACKGROUND: Epstein-Barr Virus, frequently referred to as EBV, is a member of the herpesvirus family and one of the most common human viruses. The virus occurs worldwide, and most people become infected with EBV sometime during their lives. OBJECTIVES: The purpose of this study was to investigate the serological profiles of specific antibodies among the sera of suspected EBV infection patients along with VCA-IgG avidity. METHODS: A total of 522 patient's sera were sent to The Clinical Microbiology Laboratory for EBV specific antibody detection and were studied by IFA method during a two year period. The serum samples were tested for EBV specific VCA IgG, VCA IgM, EA, EBNA antibodies and VCA IgG aviditity. RESULTS: Among 33 patients those who had low avidity for VCA IgG, 27 (81.8 %) of them had a serologic profile as follows; positive VCA IgG, negative VCA IgM, negative EA and negative EBNA. CONCLUSION: While this profile is considered as a primary infection, the frequency of the coexistence of VCA IgG low avidity with this profile is interpreted that avidity may lead to detect primary infection (Tab. 2, Ref. 25) PMID- 23944622 TI - Thymic tumours associated with Myasthenia gravis: a long term observation study of operated patients. AB - Primary tumours of thymus, thymoma and thymic carcinoma, are very rare, they represent less than 1 % of all neoplasms. The most common manifestation of thymoma with appearance of 40 to 50 % of the neuromuscular autoimmune disease is myasthenia gravis (MG). The performance of a complete resection is the most predictive indicator for long-term survival of patients with thymic tumour, also important prognostic factors are the histological type of thymic tumour and its invasiveness. The aim of our study is to study the long-term survival of patients after the resection of the tumour, as well as enhanced efficiency of radical thymectomy in the complex treatment of myasthenia gravis. From 1989 to 2010 we operated on 369 patients with MG. Out of 49 patients (13.7 %) 38 cases (76.6 %) were thymomas and 11 cases (23.4 %) thymic carcinomas. Complete removal of tumours (stage I, II, and III) were performed in 45 (92 %) cases. Of the 41 living patients (83.7 %), three (7.3 %) were diagnosed with metastatic thymic carcinoma or thymoma, and treated with adjuvant therapy. In one case, the patient died due to generalization of the thymic carcinoma. Statistical analysis with Kaplan-Meier method showed better overall survival of patients with thymoma than patients with thymic carcinoma. The difference in survival curves was not significant. (Mantel-Cox p = 0.479, Generalized Wilcoxon p = 0.326). In terms of treatment of Myasthenia gravis associated with thymoma, we achieved 70 % successful clinical and pharmacological remission. On the other hand, paraneoplastic MGAT has the worst prognosis of all the other forms of MG. The difference between MGAT to every other form of MG was statistically significant (Tab. 6, Fig. 1,Ref. 28). PMID- 23944623 TI - Influence of neoadjuvant treatment of rectal carcinoma on operability and incidence of distant metastases. AB - In the Czech Republic, rectal carcinoma does not only represent a medical problem, but also a socio-economic one. At our department, we treated totally 266 patients with rectal carcinoma in the years 1998 through 2006. Among our patients, neoadjuvant treatment led to a reduction in size of the tumour in 37.6 %, in 50.8 % the size did not change. In T3 tumours, the reduction in size was observed in 36.7 % of the patients and did not change in 56 %; in T4 tumours, the reduction in size was observed in 60% of the patients. In 88 % of the patients who underwent the operation, no residual tumour was found, in 9 % of patients, a residual tumour was detected. In 19 % of the patients, a local recurrence of the tumour was detected. A statistically significant relationship was proved between the appearance of the metastatic disease and the presence of angioinvasion and the size of the primary tumour according to the Duke's classification (Tab. 1, Fig. 4, Ref. 20). PMID- 23944624 TI - The incidence of cleft lip and palate in the Czech Republic in 1994-2008. AB - OBJECTIVE: To determine the incidence of nonsyndromic cleft lip and/or palate in the Czech Republic among infants born during 1994-2008 as well as to define the ratio per live births and sex ratios. Another aim was to determine whether there was any trend in the incidence in this time period. DESIGN: Retrospective study. SETTING: Prague Center for the Treatment of Congenital Facial Anomalies. MATERIAL AND METHODS: Data were collected from the National Birth Defects Register (Institute of Health Information and Statistics), the Czech Statistical Office and the Czech Health Statistics Yearbooks. The incidence, ratios per live births and sex differences were calculated. Possible trends in the data series were investigated. RESULTS: Totally 2417 infants with a cleft defect were found among 1 471 789 newborns in time period 1994-2008. The overall incidence was 1.64 per 1000 live births or 1 in 600 live births. The incidence of cleft lip was 0.39/1000, the incidence of cleft palate was 0.68/1000 and the incidence of cleft lip and palate was 0.57/1000. The ratio per live births was 1 in 2648 in cleft lip, 1 in 1801 in cleft lip and palate and 1 in 1505 in cleft palate. The incidence was much higher among male babies in cleft lip patients (male to female ratio 2.07) and in patients with cleft lip and palate (males to females ratio 1.85). The male to female ratio in cleft palate newborns was 0.92. No traceable trend was found in the incidence. CONCLUSIONS: In the Czech Republic, every year approximately 170 infants with cleft lip and/or palate were born, the incidence was 1.64 per 1000 live born infants during considered period. Males were affected more frequently with isolated cleft lip and cleft lip and palate, on the other hand, in cleft palate patients, there was a slight dominance of females. Further long-term studies are necessary in order to elucidate reasons of the oscillations in incidence of cleft anomalies, to identify possible teratogens and to give a starting indication for planning health service resource requirements for this group of affected infants (Tab. 3, Fig. 4, Ref. 51). PMID- 23944625 TI - Mediastinal foregut duplication cyst of enteric type containing a persistent thymus, imitating a pericardial cyst. AB - Mediastinal foregut duplication cysts are rare congenital masses caused by developmental disorders of the anterior part of the embryonic primitive gut. In adults they can be discovered as an incidental finding on chest radiograph. They can mimic other intrathoracic pathologies as it was initially the case in our patient. A 51-year-old woman was incidentally found to have homogenous mass at the right cardiophrenic angle on the chest radiograph. Based on that finding and echocardiography a pericardial cyst was suspected. Computed tomography demonstrated a simple anterior mediastinal cyst. Because of the growth with a mild progression of the compression of the right atrium, the cyst was resected. Histology and immunohistochemistry revealed the mass to be a mediastinal foregut duplicatory cyst of enteric type containing persistent thymus. To our knowledge, this is the first report in which a mediastinal foregut cyst contained both enteric mucosa and ectopic persistent thymus (Fig. 9, Ref. 13). KEYWORDS: foregut cyst, mediastinal cyst, thymus, enteric cyst, pericardial cyst. PMID- 23944626 TI - Laparoscopic splenectomy in pregnancy - from contraindication to golden standard. AB - Laparoscopy has been holding its strong position within visceral surgery for decades. For several diagnoses, laparoscopy became the method of first choice. Laparoscopic splenectomy is a standardized procedure in patients indicated mostly due to haematological disorders. Apart from bleeding disorders, pregnancy used to be recognized as a contraindication to laparoscopic surgery. Splenic cysts are extremely rare during pregnancy; only seven cases have been described in literature. The authors had to deal with a patient treated and observed by haematologist for haemorrhagic splenic cyst and hypersplenism. Because of her low compliance, the patient did not undergo splenectomy in the past. Due to the gradual progression of disease and furthermore because of her pregnancy, the question of splenectomy became semi-urgent. The patient underwent laparoscopic splenectomy in second trimester, while not only the surgery alone, but also her early postoperative period and remaining pregnancy passed off uneventful. The authors suggest that even in pregnancy, the patients suffering from serious haematological disorders necessitating splenectomy could safely benefit from the advantages of laparoscopic approach, which also in these cases could become a gold standard (Fig. 2, Ref. 13). PMID- 23944627 TI - Mandibular Langerhans cell histiocytosis in an adult. AB - Langerhans cell histiocytosis (LCH) in the mandible is a rare disease. LCH was formerly known as histiocytosis X. Histiocytosis X is a granulomatous condition that derives form a clonal proliferation of histiocytes. It has a variable clinical course. LCG may be local or disseminated. It is a reactive disorder or a truly malignant process. This article describes a case of a 45 - year old man with Langerhans cell histiocytosis in his jaw (Fig. 4, Ref. 11). PMID- 23944628 TI - Interaction between temperature and male pheromone in sexual isolation in Drosophila melanogaster. AB - In Drosophila, female hydrocarbons are known to be involved in premating isolation between different species and pheromonal races. The role of male specific hydrocarbon polymorphism is not as well documented. The dominant cuticular hydrocarbon (CHC) in male D. melanogaster is usually 7-tricosene (7-T), with the exception of African populations, in which 7-pentacosene (7-P) is dominant. Here, we took advantage of a population from the Comoro Islands (Com), in which males fell on a continuum of low to high levels of 7-T, to perform temperature selection and selection on CHCs' profiles. We conducted several experiments on the selected Com males to study the plasticity of their CHCs in response to temperature shift, their role in resistance to desiccation and in sexual selection. We then compared the results obtained for selected lines to those from three common laboratory strains with different and homogenous hydrocarbon profiles: CS, Cot and Tai. Temperature selection modified the CHC profiles of the Com males in few generations of selection. We showed that the 7 P/7-T ratio depends on temperature with generally more 7-P at higher temperatures and observed a relationship between chain length and resistance to desiccation in both temperature- and phenotypically selected Com lines. There was partial sexual isolation between the flies with clear-cut phenotypes within the phenotypically selected lines and the laboratory strains. These results indicate that the dominant male pheromones are under environmental selection and may have played a role in reproductive isolation. PMID- 23944632 TI - NLRP3 inflammasome activation in coronary artery disease: results from prospective and randomized study of treatment with atorvastatin or rosuvastatin. AB - The NLRP-3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome has recently emerged as a pivotal regulator of chronic inflammation. The aim of the present study was to determine whether NLRP3 inflammasome is expressed in patients with CAD (coronary artery disease) and whether statins (atorvastatin or rosuvastatin) might affect NLRP3 levels. In an in vitro study, human THP-1 cells treated with statins were analysed for NLRP3 inflammasome levels. The present study included 60 patients with CAD and 30 subjects without CAD (non-CAD). Patients with CAD randomly received either 8 months of treatment with atorvastatin or rosuvastatin. PBMCs (peripheral blood mononuclear cells) were obtained from peripheral blood at baseline and after 8 months of statin therapy. Levels of NLRP3 inflammasome, IL (interleukin)-1beta and IL-18 were measured by real-time RT-PCR (reverse transcription-PCR) and FACS. Levels of NLRP3 inflammasome were higher in the CAD group than in the non-CAD group. There was a positive correlation between NLRP3 inflammasome and cytokines (IL-1beta and IL-18) levels. A randomized clinical study has shown that atorvastatin markedly diminished NLRP3 inflammasome levels, whereas rosuvastatin had no impact on these levels. Levels of NLRP3 inflammasome decreased in THP-1 cells treated with statins compared with those treated with vehicle, and the fold changes in NLRP3 inflammasome were higher in THP-1 cells treated with atorvastatin compared with those treated with rosuvastatin. The present study suggests that atorvastatin down-regulates NLRP3 inflammasome expression in CAD, possibly contributing to the inhibitory effects of atorvastatin on chronic inflammation and atherogenic progression in this disorder. PMID- 23944631 TI - Clinical inertia in the treatment of hyperglycemia in type 2 diabetes patients in primary care. AB - OBJECTIVE: To assess clinical inertia, defined as failure to intensify antidiabetic treatment of patients who have not achieved the HbA1c therapeutic goal (<=7%). RESEARCH DESIGN AND METHODS: Multicenter cross-sectional study. Clinical inertia was assessed in a random sample of type 2 diabetes mellitus (T2DM) patients seen in primary care centers. RESULTS: A total of 2783 patients (51.3% males; mean age: 68 [+/-11.5] years; diabetes duration: 7.1 [+/-5.6] years; mean HbA1c: 6.8 [+/-1.5]) were analyzed. Of those, 997 (35.8%) had HbA1c >7%. Treatment was intensified in 66.8% and consisted of: dose increase (40.5%); addition of oral antidiabetic (45.8%); or insulin treatment initiation (3.7%). Mean HbA1c values in patients for whom treatment was intensified vs. non intensified were 8.4% (+/-1.2) vs. 8.2% (+/-1.2), p < 0.05. Clinical inertia was detected in 33.2% of patients and diminished along with treatment complexity: lifestyle changes only (38.8%), oral monotherapy (40.3%), combined oral antidiabetics (34.5%), insulin monotherapy (26.1%) and combination of insulin and oral antidiabetics (21.4%). Clinical inertia decreased as HbA1c increased: 37.3% for HbA1c values ranging between 7.1%-8%; 29.4% for the 8.1%-9% HbA1c range and 27.1% for HbA1c >=9%. Multivariate analysis confirmed that diabetes duration, step of treatment and HbA1c were related to inertia. For each unit of HbA1c increase clinical inertia decreased 47% (OR: 0.53). LIMITATIONS: The retrospective design of the study precluded an accurate investigation about reasons for lack of intensification that could actually be justified by some patient conditions, especially patients' lack of adherence. CONCLUSIONS: Clinical inertia affected one third of T2DM patients with poor glycemic control and was greater in patients treated with only lifestyle changes or oral monotherapy. Treatment changes were performed when mean HbA1c values were 1.4 points above therapeutic goals. PMID- 23944633 TI - Ficolin-1 is up-regulated in leukocytes and glomeruli from microscopic polyangiitis patients. AB - Microscopic polyangiitis (MPA) is a systemic autoimmune disease that often has a fatal outcome. Although delineating the molecular pathogenesis is essential for its remedy, an understanding of its molecular mechanism has remained elusive. To search for new markers of active lesions that might help better understand the molecular basis of MPA and aid in its diagnosis, we here performed DNA microarray analysis with peripheral blood mononuclear cells (PBMCs). Compared to normal control, several genes were up- or down-regulated in MPA patients, including up regulation of the mRNA level of ficolin-1 (FCN1 or M-ficolin), an innate pattern recognition complement molecule. The amount of ficolin-1, as detected by immunohistochemistry, was higher in the glomeruli of another group of MPA patients than in the glomeruli of control patients who harbored almost normal glomeruli. Many of the ficolin-1 dots were also positive for CD68, suggesting that the ficolin-1-positive cells were monocytes, such as macrophages or dendritic cells. This is not due to the difference in the number of neutrophil or monocytes in the blood samples of MPA and control patients. Taken together, we conclude that increased ficolin-1 expression could serve as a new marker for the characterization of MPA, especially when it is associated with local active lesions. PMID- 23944634 TI - On occupational performance. AB - Occupational therapists use many complex and dynamic techniques and approaches in their interventions. The notion of occupational performance is emerging within our profession as one such approach that is unique to occupational therapy and that has great promise for our clients. The thesis of this article is that for occupational performance to be therapeutic, it must meet certain necessary conditions. In this article the author offers a definition of occupational performance, explores the three conditions of occupational performance, and explores the application of occupational performance in therapy. PMID- 23944635 TI - The effects of a sensory motor activities protocol based on the theory of sensory integration on children diagnosed with preprimary impairments. AB - According to the theory of sensory integration (SI), when an infant successfully meets the challenges of his/her environment, the brain learns to organize the sensation for production of adaptive responses. Research studies have shown mixed results about the effects of the SI therapy and most studies have used single system designs. The objective of this study was to evaluate the effectiveness of the Sensory Integrative Treatment Protocol (SITP) in treating children with preprimary impairments. Two intact classrooms were used as experimental and control groups. The experimental group consisted of 15 children and the control group consisted of 16 children diagnosed with preprimary impairments. Descriptive statistics and a 2 (group) * 2 (time) repeated measures ANOVA were employed in data analyses. DeGangi-Berk Test of Sensory Integration (TSI) and the Miller Assessment for Preschoolers (MAP) were used as the instruments to measure change within and between the two groups before and after the intervention. TSI and MAP scores went up considerably for the children in the experimental group following the intervention. Based on the results, the researchers suggest that "Sensory Integration Treatment Protocol" based on the theory of sensory integration was effective in reducing sensory integration dysfunction and improving preschool performance in children diagnosed with pre-primary impairments. PMID- 23944636 TI - Functional impact of shoulder taping in the hemiplegic upper extremity. AB - Few methods have been validated for treatment of the painful hemiplegic shoulder. Harness slings and other methods of support have traditionally been applied in an attempt to prevent pain and subluxation, but supports often lead to complications. This paper describes shoulder taping in a patient with right hemiplegia following a cerebrovascular accident and evaluates taping efficacy through measures of activities of daily living, range of motion, and pain before, during, and after treatment. Taping significantly reduced pain and relieved excessive tension on the involved structures. The positive outcome obtained in this patient, in conjunction with other case reports, suggests shoulder taping may be more useful than traditional immobilization methods in the treatment of hemiplegic shoulders. PMID- 23944637 TI - An approach to persons with chronic fatigue syndrome based on the model of human occupation: part one, impact on occupational performance and participation. AB - Chronic fatigue syndrome (CFS) is a prevalent and disabling condition that involves six or more months of unexplained fatigue severe enough to interfere with previous levels of occupational, educational, and/or social performance. The fatigue is accompanied by at least four of eight additional physical and cognitive symptoms (Fukuda et al., 1994). This paper conceptualizes the multiple factors that affect occupational adaptation in persons with CFS. The Model of Human Occupation (MOHO) if used as a framework for understanding the synergistic and evolving relationships between motivation, roles, habits, performance capacities, and the environment as they influence individuals with CFS. Examples from the literature, autobiographical accounts, and from practice experience are used to illustrate the experience and impact of CFS on everyday life. PMID- 23944638 TI - An occupational therapy approach to persons with chronic fatigue syndrome: part two, assessment and intervention. AB - Chronic Fatigue Syndrome (CFS) is a highly disabling condition that significantly interferes with occupational life. Occupational therapy services are very relevant for this population. Yet, information about the assessment and treatment of CFS is almost absent from occupational therapy literature. As a result, few occupational therapists possess expertise in evaluating and providing therapy for this complex condition. This paper describes an approach to evaluating and providing services for individuals with CFS according to the Model of Human Occupation. This model offers an integrative means of understanding the synergistic and evolving relationships between motivation, values, roles, habits, functional capabilities, and the environment as they influence individuals with CFS, and it provides a framework for the types of changes required in these different domains during the rehabilitation process. A case study illustrates recommended assessment and intervention approaches. PMID- 23944639 TI - Student perceptions of level I fieldwork supervision. AB - To prepare occupational therapy students to work in emerging practice areas, and meet standards of accreditation, we must provide them with Level I fieldwork opportunities which may not currently employ occupational therapists. This juncture causes us to examine the current fieldwork system and make recommendations for the future. The question is raised as to whether or not non occupational therapists should supervise occupational therapy students. A description of advantages and disadvantages of non-occupational therapist supervision is presented. The results of the 70 Eastern Michigan University students surveyed about their type of Level I fieldwork supervision and its effectiveness, revealed that though the overall ratings of non-occupational therapist supervisors were somewhat lower than those of the occupational therapists, data from this study support using Level I fieldwork sites with non occupational therapist supervisors. PMID- 23944640 TI - Internet connections. PMID- 23944642 TI - Anharmonic calculation of the structure, vibrational frequencies and intensities of the NH3...trans-HONO complex. AB - The equilibrium geometry of the NH3...trans-HONO complex and the harmonic vibrational frequencies and intensities are calculated in the MP2/aug-cc-pVTZ approximation with the basis set superposition error taken into account. Effects of anharmonic interactions on spectroscopic parameters are studied by solving vibrational Schrodinger equations in 1-4 dimensions using the variational method. Anharmonic vibrational equations are formulated in the space of normal coordinates of the complex. Detailed analysis is performed for the H-bond stretching vibration and internal vibrations of the trans-HONO isomer in the complex. The intermode anharmonicity and anharmonic coupling between two, three, and four vibrational modes are studied on the basis of correct ab initio potential energy surfaces calculated in the above approximation. The combinations of normal modes of the complex most strongly coupled to one another are examined. The calculated frequencies and intensities of vibrational bands are compared with the experimental data on the NH3...trans-HONO complex in an argon matrix and results of earlier calculations of monomeric HONO. In this calculation the strong resonance between the first excited state of the OH stretching vibration and the doubly excited state of the NOH bending vibration of trans-HONO isomer in the complex is thoroughly studied by solving vibrational equations in two and four dimensions. PMID- 23944643 TI - Synthesis of benziporphyrins and heterobenziporphyrins and an assessment of the diatropic characteristics of the protonated species. AB - Benzitripyrranes were prepared by reacting diphenyl-substituted benzenedicarbinols with excess pyrrole in the presence of BF3.Et2O. These dipyrrolic compounds underwent acid-catalyzed condensations with a pyrrole dialdehyde to afford good yields of diphenylbenziporphyrins, and further reaction with palladium(II) acetate gave stable organometallic derivatives. The X-ray crystal structure of a palladium(II) benziporphyrin showed that the system deviates significantly from planarity. Although the benzitripyrranes failed to give stable macrocyclic products with furan or thiophene dialdehydes, they afforded tetraphenyl heterobenziporphyrins upon reaction with diphenyl substituted furan- or thiophenedicarbinols and BF3.Et2O. Benziporphyrins and their heteroanalogues showed no indication of a diamagnetic ring current by proton NMR spectroscopy, but addition of TFA gave rise to the formation of weakly diatropic dications. PMID- 23944644 TI - Vaccines against tuberculosis: moving forward with new concepts. PMID- 23944645 TI - Women in the rural medical academic workforce. AB - INTRODUCTION: This study assessed the role of women as fractional full-time equivalent (FTE) rural academics in the context of significant workforce shortage and increasing academic demand. METHODS: The design was a cross-sectional cohort study conducted from June 2002 to June 2012. All Rural Clinical School teaching sites in Western Australia were included, numbering from 3 (at inception in 2002) to 13 in 2012. Participants were all clinicians employed as academic staff of The University of Western Australia since its inception. Teaching staff employed elsewhere were not included. Main outcome measures were the proportion of women employed in the Rural Clinical School and work characteristics including appointment fraction, duration and site leadership. RESULTS: Relative to the workforce at large, female academics were disproportionately employed in the Rural Clinical School with a relative risk of 1.28 (CI 1.0-1.64), chi2=2.0 p=0.46. Their likelihood of being Australian trained was 1.62 (CI 1.3-2.0), chi2=19.3, p=0.000 relative to the rural female GP workforce. Their FTE (t=1.0 p=0.295), time of tenure (t=1.19, p=0.24) and site leadership was indistinguishable from male Rural Clinical School academics. CONCLUSION: Female doctors who are willing to take on part-time work are supporting the rural medical teaching workforce. PMID- 23944647 TI - Microvessel area of immature vessels is a prognostic factor in renal cell carcinoma. AB - OBJECTIVES: To analyze the presence of immature vessels as a predictive factor of prognosis in patients with renal cell carcinoma. METHODS: Tissue samples were obtained from 50 renal cell carcinoma patients who underwent radical nephrectomy, and the blood vessels were stained using antibodies to cluster of differentiation 34 and alpha-smooth muscle actin. Immature vessels were defined as those positive for cluster of differentiation 34, and mature vessels as those positive for both cluster of differentiation 34 and alpha-smooth muscle actin. The extent of vascularization was quantified by calculating the microvessel area and microvessel density. RESULTS: The microvessel area of immature vessels was positively associated with tumor grade (P < 0.0001), T stage (P < 0.0001) and American Joint Committee on Cancer stage (P < 0.0001), and was significantly higher in tumors with metastasis than in those without metastasis (P < 0.0001). The microvessel density did not associate with tumor grade or T stage. The disease-free survival and overall survival were significantly shorter in patients with high microvessel area. CONCLUSIONS: The microvessel area of immature vessels seems to be associated with renal cell carcinoma aggressiveness, suggesting this might be considered as a novel prognostic factor in patients with these tumors. PMID- 23944648 TI - High doses of vascular endothelial growth factor 165 safely, but transiently, improve myocardial perfusion in no-option ischemic disease. AB - Gene therapy can induce angiogenesis in ischemic tissues. The aim of this study was to assess safety, feasibility, and results, both clinical and on myocardial perfusion, of gene therapy in refractory angina. This was a phase I/II, prospective, temporal-controlled series, clinical trial. Thirteen patients were maintained for minimum 6 months under optimized clinical management, and then received intramyocardial injections of 2000 MUg plasmid vascular endothelial growth factor 165 and were followed by single-photon emission computed tomography (SPECT), treadmill tests, Minnesota quality of life questionnaire (QOL), and New York Heart Association (NYHA) functional plus Canadian Cardiovascular Society (CCS) angina classifications. There were no deaths, early or late. During the optimized clinical treatment, we observed worsening of rest ischemia scores on SPECT (p<0.05). After treatment, there was a transitory increase in myocardial perfusion at the third-month SPECT under stress (pre-operative [pre-op] 18.38 +/- 7.51 vs. 3 months 15.31 +/- 7.30; p<0.01) and at the sixth month under rest (pre op 13.23 +/- 7.98 vs. 6 months: 16.92 +/- 7.27; p<0.01). One year after, there were improvements in treadmill test steps (pre-op 2.46 +/- 2.07 vs.12 months 4.15 +/- 2.23; p<0.01) and oxygen consumption (pre-op 7.66 +/- 4.47 vs.12 months 10.89 +/- 4.65; p<0.05), QOL (pre-op 48.23 +/- 18.35 vs.12 months 28.31 +/- 18.14; p<0.01) scores, and CCS (pre-op 3 [3-3.5] vs.12 months 2 [1-2.5]; p<0.01) and NYHA (pre-op 3 [3-3] vs. 2 [2-2] vs. 12 months 2 [1-2]; p<0.01) classes. Gene therapy demonstrated to be feasible and safe in this advanced ischemic cardiomyopathy patient sample. There were improvements in clinical evaluation parameters, and a transitory increase in myocardial perfusion detectable by SPECT scintigraphy. CLINICAL TRIAL REGISTRATION: NCT00744315 http://clinicaltrials.gov/ PMID- 23944646 TI - Metal-organic frameworks as a tunable platform for designing functional molecular materials. AB - Metal-organic frameworks (MOFs), also known as coordination polymers, represent an interesting class of crystalline molecular materials that are synthesized by combining metal-connecting points and bridging ligands. The modular nature of and mild conditions for MOF synthesis have permitted the rational structural design of numerous MOFs and the incorporation of various functionalities via constituent building blocks. The resulting designer MOFs have shown promise for applications in a number of areas, including gas storage/separation, nonlinear optics/ferroelectricity, catalysis, energy conversion/storage, chemical sensing, biomedical imaging, and drug delivery. The structure-property relationships of MOFs can also be readily established by taking advantage of the knowledge of their detailed atomic structures, which enables fine-tuning of their functionalities for desired applications. Through the combination of molecular synthesis and crystal engineering, MOFs thus present an unprecedented opportunity for the rational and precise design of functional materials. PMID- 23944649 TI - Strengthening impaired-driving enforcement in the United States. AB - OBJECTIVE: Progress in reducing alcohol-impaired driving crash fatalities in the United States has stagnated over the last 15 years. This article reviews 2 current U.S. driving-while-intoxicated (DWI) laws and their enforcement with an aim toward generating opportunities to improve their enforcement approaches. METHODS: Impaired-driving enforcement methods in Europe and Australia are compared with those in the United States, and the legal basis for current DWI criminal procedures is examined. RESULTS: An examination of relevant U.S. Supreme Court decisions and current legal practices indicates that the requirements for use of breath test technology to determine blood alcohol concentrations of drivers on public roads are not entirely clear. Several potential methods for using field breath test technology to improve the detection of impaired drivers are suggested. These include (a) breath testing all drivers stopped for certain violations that have a high probability of involving an impaired driver, (b) breath testing all drivers at sobriety checkpoints, and (c) breath testing all drivers involved in fatal and serious injury crashes. CONCLUSIONS: Breath test technology has enabled other countries around the world to adopt and implement enforcement strategies that serve as both general and specific deterrents to alcohol-impaired driving. Many of these enforcement strategies have been shown to be effective. If any one of these strategies can be adopted in the United States, further progress in reducing impaired driving is probable. It may be necessary to provide the U.S. Supreme Court with a test case of breath testing all drivers at a sobriety checkpoint, depending upon whether or not a police agency is willing to use that strategy. PMID- 23944650 TI - Self-ordering properties of functionalized acenes for annealing-free organic thin film transistors. AB - Presented here is a study of the molecular self-ordering properties of four bis(phenylethynyl) anthracene based organic semiconductors related to their electronic structure employing X-ray spectroscopy techniques and density functional theory (DFT) calculations. The local molecular order through polarization dependence of C 1s -> pi* transitions revealed ordered pi-stacking nearly perpendicular to the substrate due to van der Waals interactions between alkyl groups. DFT calculations were used to deconvolute the measured electronic structure and examine effects of small changes in molecular geometry in relation to measured charge carrier mobility in top contact field effect transistors. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are found to be conjugated from the anthracene core across the bridging ethynyl groups to the thiophene and phenyl end groups. The inclusion of ethynyl bridges connecting the thiophenes has a twofold effect of both reducing the rotational freedom of this functional group and increasing HOMO/LUMO conjugation across the molecules. These features help create a more rigid upright structure for HB-ant-THT with better molecular orbital conjugation and subsequent higher mobility. With this understanding of how different functional groups interact with an acene core, future synthesis of new materials may be directed toward annealing-free organic semiconducting materials. PMID- 23944651 TI - Immune-reactive soluble OX40 ligand, soluble CD40 ligand, and interleukin-27 are simultaneously oversecreted in platelet components associated with acute transfusion reactions. AB - BACKGROUND: Leukoreduction of labile blood components dramatically decreases the frequency of minor, intermediate, and severe adverse events (AEs), referred to as acute transfusion reactions (ATRs), especially after transfusion of platelet components (PCs). The pathophysiology of AEs may result from accumulation of soluble, secreted, platelet (PLT) factors with proinflammatory functions stored in PCs. Thus, several cosynergizing factors associated with PLT accumulation in PCs may contribute to clinically reported ATRs with inflammatory symptoms. STUDY DESIGN AND METHODS: We screened for 65 PLT-associated secretory products in PCs that caused ATRs and identified PLT molecules associated with ATRs and inflammation. A functional in vitro study using PC supernatants assayed on reporting immune cells was performed to indicate relevance. RESULTS: Among 10,600 apheresis PCs, 30 caused inflammatory ATRs and contained significantly elevated levels of soluble CD40 ligand (sCD40L), interleukin (IL)-27, and soluble OX40 ligand (sOX40L). Normal PLTs secreted IL-27 and sOX40L at bioactive concentrations upon thrombin stimulation and were up regulated in association with ATRs, similar to sCD40L. Other secreted products were identified but not investigated further as their positivity was not consistent. CONCLUSIONS: This study demonstrates the putative participation of PLT-derived sOX40L, IL-27, and sCD40L, which accumulate in PC supernatants, with inflammatory-type ATRs. Further studies are required to determine the clinical significance of these findings to forecast preventive measures whenever possible. PMID- 23944652 TI - Synthesis and properties of type-I clathrate phases Rb(8-x-t)K(x?t)Au(y)Ge(46-y). AB - Type-I clathrates Rb(8-x-t)K(x?t)Au(y)Ge(46-y) are synthesized from Rb4Ge9, K4Ge9, Au, and Ge. Crystal structures and compositions are determined by single crystal and powder X-ray diffraction methods. The lattice parameters are 10.8103(2), 10.7956(2), 10.7850(2), and 10.7723(2) A in space group Pm3n for Rb7.88(2)Au2.47(2)Ge43.53(2), Rb3.69(4)K4.31(4)Au2.17(2)Ge43.83(2), Rb1.66(5)K6.34(5)Au2.17(1)Ge43.83(1), and K6.71(4)Au2.28(2)Ge43.72(2), respectively. Bonding analysis for Rb8Au6Ge40 suggests ionic interaction of Rb with the framework besides covalent interactions between Ge and Au/Ge. Rb7.88Au2.47Ge43.53 and K6.71(4)Au2.28Ge43.72 are both diamagnetic. The heat capacity of K6.71Au2.28Ge43.72 is analyzed. Transport properties of Rb7.88Au2.47Ge43.53 reveal n-type conducting, and low thermal conductivity. PMID- 23944653 TI - Bioapplications for molecularly imprinted polymers. PMID- 23944655 TI - Abstracts of Strategies for Engineered Negligible Senescence (SENS), Sixth Conference. Cambridge, United Kingdom. September 3-7, 2013. PMID- 23944654 TI - PGE2 contributes to in vitro MSC-mediated inhibition of non-specific and antigen specific T cell proliferation in MS patients. AB - Current theories of multiple sclerosis (MS) induction and progression place autoreactive T cells in the focus of the pathogenesis. Mesenchymal/stromal stem cells (MSC) have become a promising alternative approach for pathogenic therapy of MS due to their immunomodulatory properties, underlying mechanisms of which are intensive study. The objective of the research was to investigate the contribution of PGE2 to MSC-mediated suppression in patients with MS using in vitro model of mitogen- and myelin-stimulated T cell cocultivation with autologous/allogeneic MSC. We have showed that PGE2 production depends on cell-to cell contact of MSC and lymphocytes. The antigenic stimulation did not affect PGE2 production following cocultivation of MSC and PBMC, and it is the presence of MSC in cell culture that significantly increases PGE2 production irrespective of antigenic cultivation conditions. Simultaneously, PGE2 synthesis correlated with indexes of MSC-mediated suppression of mitogen- and myelin-stimulated T cell proliferation in patients with MS. No significant differences in PGE2 production by autologous and allogeneic MSC have been established. These results have demonstrated that in patients with MS, PGE2 is one of the possible factors of MSC immunosuppression. The interrelation between PGE2 concentrations and T cell proliferation suppression mediated by MSC may explain one of the immune mechanisms of cell therapy, which is crucial for the further proper use of MSC in MS research and pathogenic treatment. PMID- 23944656 TI - Sialic acid linkage in glycosphingolipids is a molecular correlate for trafficking and delivery of extracellular cargo. AB - Gangliosides, glycosphingolipids containing sialic acid moieties, are well known mediators of transmembrane signaling and endocytosis at the plasma membrane. However, little is known about their precise regulatory role at the cell periphery for intracellular sorting of extracellular cargo. Here we inspected published scientific literature for two types of cargoes, namely bacterial toxins and viruses, regarding their usage of gangliosides. We derived a rather simple yet surprisingly consistent framework to classify 20 viruses from 12 different families and five type AB bacterial toxins into two broad categories. We propose that gangliosides with terminally attached sialic acids classify cargo for uptake and trafficking early in the endocytic pathway while gangliosides with internally attached sialic acids associate with uptake and trafficking of cargo late in the endocytic system. Our study provides a testable hypothesis for future investigations into a wide range of trafficking events. It could be utilized as a framework for other intracellular pathogens where lipids are known to be involved in recognition and trafficking. For instance, predictions can be put forward and evaluated based on ganglioside binding patterns and intracellular trafficking routes. Finally, incorporation of our classifier into large scale systems-biology studies could help reveal related molecular determinants in subcellular sorting. PMID- 23944657 TI - Prophylactic use of oxytocin at caesarean section: where are the guidelines? PMID- 23944658 TI - Phenotypic integration in flowers of neotropical lianas: diversification of form with stasis of underlying patterns. AB - Phenotypic integration is essential to the understanding of organismal evolution as a whole. In this study, a phylogenetic framework is used to assess phenotypic integration among the floral parts of a group of Neotropical lianas. Flowers consist of plant reproductive organs (carpels and stamens), usually surrounded by attractive whorls (petals and sepals). Thus, flower parts might be involved in different functions and developmental constraints, leading to conflicting selective forces. We found that Bignonieae flowers have very similar patterns of variance/covariance among traits and that such patterns are uncorrelated with the phylogenetic relationships between species. However, in spite of pattern stasis, our results also indicate that diversification of floral morphology in this group has occurred throughout the evolution of magnitudes of correlation among traits. Thus, we suggest that stabilizing selection has played an important role in phenotypic integration, resulting in the long-term stasis of covariance patterns underlying flower diversification during the ca. 50 Myr of evolution of Bignonieae. This is the first report of long-term stasis in the phenotypic integration of angiosperms, suggesting that patterns of floral morphology can be recognizable as specific attributes of distinct botanical families. PMID- 23944660 TI - Message from the editors. PMID- 23944659 TI - Cancer-free survival of psoriasis patients treated with methotrexate and cyclosporine combination. AB - CONTEXT: Combination of methotrexate and cyclosporine was used and reported to be effective for recalcitrant psoriasis patients. Also each agent is accused for development of malignancies. OBJECTIVE: To evaluate the cancer-free survival of psoriasis patients who received methotrexate and cyclosporine treatment at the same time. METHODS: Psoriasis patients who had been treated with combination of cyclosporine and methotrexate between March 2000 and April 2005 were questioned in 2011. A diagnosis of new cancer during follow-up period was asked and also each patient was evaluated by a questionnaire. RESULTS: Seventeen psoriasis patients were not treated due to a diagnosis of new cancer during the follow-up period. Also none of them complained of possible symptoms of skin or lymphoproliferative malignancies. The median follow-up time was 76 months. CONCLUSION: Psoriasis patients who had been treated with methotrexate and cyclosporine combination did not report a detected malignant disease. PMID- 23944661 TI - Supervisor and Student Expectations of Level II Fieldwork. AB - SUMMARY OBJECTIVE: The purpose was to learn if fieldwork supervisors have greater expectations of students beginning Level II fieldwork compared to five years ago and how these compared to student expectations. Supervision was examined. METHODS: Data were obtained through questionnaires from 81 fieldwork supervisors and 29 students doing second fieldwork rotations. RESULTS: Supervisors have higher expectations of students. Supervisor and student expectations agreed. Demands of health care environments and new educational requirements influenced these changes. Supervisors still use traditional supervisory techniques. CONCLUSION: Findings give insight into expectations of current students and help universities develop programs that better prepare students for fieldwork. PMID- 23944662 TI - An Exploratory Study of Web-Based Supports for Occupational Therapy Students During Level II Fieldwork. AB - SUMMARY Occupational therapy students often experience high levels of anxiety about transitioning from the academic student role to the fieldwork student role. The separation from their classmates and the geographical relocation may isolate some students. Additionally, the quality and quantity of on-site supports available to individual students vary with each placement. A web-based resource was designed to assist occupational therapy students from the University of South Alabama with the transition from student role in an academic environment to level II fieldwork in off-campus work environments. Participation was voluntary and no grades were assigned. Students were invited to participate as needed with their classmates for support and information sharing. Resources were provided asynchronously so students could access them whenever and wherever they could gain access to the Internet. Quantitative and qualitative analysis of the data was conducted. Data analysis included frequency of web-based communication, analysis of emerging themes based on the communication, outcome of student fieldwork performance, and students' perceptions based on their participation. The information gained during this exploratory study could be useful to other faculty in developing similar web-based resources to promote student success. Additionally, the technology skills gained by the students are hoped to improve their confidence to participate in web-based professional list serves and distance education opportunities in the future. PMID- 23944663 TI - Effects of Level II Fieldwork on Clinical Reasoning in Occupational Therapy. AB - SUMMARY Objective. Fieldwork has been described as an educational method that enhances clinical reasoning skills. The purpose of this study was to determine the effects of Level II fieldwork on the development of clinical reasoning skills of undergraduate occupational therapy students. Method. A quasi-experimental pretest-posttest design was used with a convenience sample of 48 undergraduate seniors. All students participated in two 12-week, full-time rotations of Level II fieldwork. The Self-Assessment of Clinical Reflection and Reasoning (SACRR) developed by Royeen, Mu, Barrett and Luebben (2000) was administered the week before the students left for fieldwork and the first day after they returned from fieldwork. Results. Paired t-tests revealed statistically significant differences in pretest and posttest scores for 13 of 26 items on the SACRR. In addition, the overall total score increased from 102.55 to 108.41 (p <. 01). Conclusion. The results suggest 24 weeks of full-time fieldwork experience, in the senior year of an undergraduate occupational therapy curriculum, can significantly facilitate the development of students' clinical reasoning skills. PMID- 23944664 TI - Brief or new: professional development of fieldwork students: occupational adaptation, clinical reasoning, and client-centeredness. AB - SUMMARY Fieldwork provides occupational therapy students with professional development readiness for entry-level practice. Thus, describing the results of the fieldwork learning process in terms of observed professional behaviors is valuable. This pilot study was initiated as part of program evaluation with the goal to assess fieldwork students' performance maturation, clinical reasoning development, and client-centered behaviors as a result of this specific fieldwork experience. Nine occupational therapy students who completed Level II fieldwork at the Way Station, Inc., in Frederick, MD were videotaped administering the Canadian Occupational Performance Measure (COPM) to a new client during the 2nd and 10th week of fieldwork to gather descriptions of changes in student professional behavior during the fieldwork experience. Observational analysis demonstrated that primitive and transitional behaviors decreased as mature behaviors increased, clinical reasoning shifted from primarily procedural to interactive and conditional, and client-centered behaviors developed. The findings enhance our understanding of the development of professional behaviors during fieldwork and provide indicants for future studies as well as a methodology for fieldwork supervision. PMID- 23944665 TI - Teaching undergraduate neuroscience with brain teaser experiments. AB - SUMMARY Neuroscience knowledge is of fundamental importance to the occupational therapist and other health care professionals, but neuroscience courses are often viewed in schools of health sciences as among the most arduous of the curriculum. To enhance student learning, the author has developed a series of in-class activities, "brainteasers," that are integrated into each subject module of a semester-long undergraduate neuroscience course. In the brain teaser activities, students experience intriguing sensory and motor phenomena, then use inductive reasoning to generate plausible hypotheses concerning the underlying neural mechanisms. Students profit doubly from these activities, learning neuroscience while practicing critical thinking. PMID- 23944666 TI - Laugh and learn: humor as a teaching strategy in occupational therapy education. AB - SUMMARY Humor use in education has been studied in fields such as psychology and nursing. Research has demonstrated that effective educational humor needs to be integrated into the topic and used in moderation. Used appropriately, humor can gain attention, facilitate creative thinking and memory, motivate students to attend class, and promote learning outcomes. No studies were located in the occupational therapy literature that specifically related to humor as an aspect of teaching. The purpose of this article is to explore the merits of humor as an educational tool and to give examples of ways that occupational therapy faculty and clinical instructors can employ humor. PMID- 23944667 TI - Promoting professional reflection through problem-based learning evaluation activities. AB - SUMMARY To become competent occupational therapy practitioners, students must develop the ability to reflect upon their current and future professional development. This paper presents one curriculum's approach (the University of New Mexico) to using evaluation activities in problem-based learning to enhance students' cultivation of professional reflection skills. A description of these evaluation activities and accompanying tools is provided along with a critique of their strengths and limitations. PMID- 23944668 TI - Personality type in occupational therapy students: implications for teaching and learning strategies. AB - SUMMARY In this descriptive study, 130 occupational therapy students completed a widely-used personality inventory (the MBTI-M) as part of coursework in their first semester. The majority of students evinced a preference for seven out of the 16 possible personality types; one type was not selected by anyone. These findings closely resembled data from the 1970s on practicing occupational therapists. Common characteristics, such as a high premium on personal connectedness and a dependable working environment, have important implications for faculty. Implications for findings relate to adjusting instructional delivery methods to best match type and learning preferences for this population. PMID- 23944669 TI - Brief or new: student learning portfolios: balancing tradition with innovation. AB - SUMMARY For decades, educators have used traditional assessment measures to evaluate student learning and performance. Though these measures may have been successful in the past, the shifting culture of universities requires educators to seek more innovative methods which not only assess student learning but also elicit professional development and higher thinking skills. To keep pace with a rapidly changing health care market, educators not only need to teach better, but also evaluate smarter. Student learning portfolios are one way educators can assess a student's performance based on a learning paradigm which encourages active learning, enhances professional development, and integrates cumulative knowledge. PMID- 23944670 TI - Student Development in an Online Post-Professional Master's Program. AB - SUMMARY Students' perceptions of personal and professional development in an online post-professional Master's degree program in occupational therapy were investigated. In-class postings, reflection papers, and e-mail surveys completed by 14 occupational therapists throughout the course of an online Master's program were coded and analyzed. Three themes were identified: the developmental process of post-professional education, the value of the online learning community, and the influence of positive and negative characteristics of online pedagogy in creating lifelong learners. Results indicated that the students perceived personal and professional growth that enhanced their clinical practice, and that the online learning community supported and enhanced this growth. Online pedagogy was effective in creating a cooperative learning environment that facilitated personal and professional development at the post-graduate level. PMID- 23944671 TI - Brief or new: the benefits of on-line learning in occupational therapy. AB - SUMMARY This paper discusses the benefits of incorporating an on-line program, such as Blackboard, into occupational therapy education to enhance the learning experience. An occupational therapy department at a midwestern university piloted the use of Blackboard in two classes in the spring semester of the junior year. Students (n = 16) ranging in age from 20-28 years participated in the pilot study, which lasted a period of 12 weeks. The students were given various assignments on Blackboard involving discussions, answering questions related to the lecture topic, and sharing evidence-based practice. Overall, the student perceptions of incorporating Blackboard into a traditional classroom were positive. Eighty-one percent of the students felt that Blackboard was easy to access, 75% felt that they could share thoughts and stories that they would not necessarily have shared in a classroom setting, and 81% felt that Blackboard expanded on lecture topics and relevant practice information. Data suggest that on-line learning can enhance the educational experience by building upon student fieldwork experiences, evidence-based practice, discussion of key concepts in the profession, and clinical reasoning. PMID- 23944672 TI - Brief or New: WebQuests: An Instructional Strategy for the Occupational Therapy Classroom. AB - SUMMARY WebQuests are an innovative teaching activity that promotes students to actively engage in their learning and work cooperatively in small groups. WebQuests have been widely used in K-12 environments in a variety of subjects and are gaining respect in universities. This paper will briefly describe the basic concept of a WebQuest and provide two examples of WebQuests developed for use in an occupational therapy curriculum. PMID- 23944673 TI - Constructing a program development proposal for community-based practice: a valuable learning experience for occupational therapy students. AB - SUMMARY Skills required to develop and fund programs can advance an occupational therapist professionally, and innovative occupation-based programs are necessary for the future of occupational therapy. This paper describes a community-based learning experience embedded within the occupational therapy curriculum of the Medical College of Ohio. While developing the Program Development Proposal, each student practices needs assessment; marketing; goals- and objectives-setting; occupation-based programming; budgeting; staffing; program evaluation; and grantsmanship. Outcome surveys of graduates indicate that the experience was positive and provided graduates with a solid foundation for program development. The experience also enhanced partnerships with community-based sites. PMID- 23944674 TI - Educating for community-based practice: a collaborative strategy. AB - SUMMARY This paper describes creative instruction strategies that prepare students for community-based practice. These educational innovations are designed to prepare graduates to understand occupation-based service delivery in community settings, to develop community-built programs that are responsive to community needs, and to understand how to both secure funding for and market occupational therapy services in the community. The process and products of collaboration between instructors in an administration and a community-based practice course are described. Outcome data from students and community partners are presented. Strategies for successful community partnerships and recommendations for continued development of these educational approaches are presented based on these data. PMID- 23944675 TI - The aware communicator: dialogues on diversity. AB - SUMMARY Developing cultural competence has taken on increased importance in occupational therapy curriculums. Cultural competency prepares occupational therapy students for emerging practice. This article describes a communication seminar that emphasizes dialogues on diversity as a method for developing cultural awareness, cultural sensitivity, and active listening skills. PMID- 23944676 TI - How does one develop and document the skills needed to assume a deanship in higher education? PMID- 23944677 TI - What Does the Move to Master's Level Education for the Occupational Therapist Mean for Occupational Therapy Assistant Education? PMID- 23944679 TI - Ab initio investigation of electronic properties of the magnesium hydride molecular ion. AB - In this work, adiabatic potential energy curves, spectroscopic constants, dipole moments, and vibrational levels for numerous electronic states of magnesium hydride molecular ion (MgH(+)) are computed. These properties are determined by the use of an ab initio method involving a nonempirical pseudopotential for the magnesium core (Mg), the core polarization potential (CPP), the l-dependent cutoff functions and the full valence configuration interaction (FCI). The molecular ion is thus treated as a two-electron system. Our calculations on the MgH(+) molecular ion extend previous theoretical works to numerous electronic excited states in the various symmetries. A good agreement with the available theoretical and experimental works is obtained for the spectroscopic constants, the adiabatic potential energy curves, and the dipole moments for the lowest states of MgH(+). PMID- 23944678 TI - Identification of autoantibodies against inner ear antigens in a cohort of children with idiopathic sensorineural hearing loss. AB - Immune-mediated pathogenesis has been suggested for idiopathic sensorineural hearing loss. Recent studies have investigated the relationship between idiopathic sensorineural hearing loss and autoantibodies against inner ear antigens. We conducted a prospective, observational study in a series of pediatric patients affected by idiopathic sensorineural hearing loss. Autoantibodies against inner ear (anti-Cogan peptide, anti-connexin 26, anti DEP1/CD148 and anti-reovirus), previously described in the serum of patients with Cogan's syndrome, were detected in our population. The characteristics of children whose results were positive were also evaluated to verify if clinical data, disease progression and response to treatment could confirm an immune mediated pathogenesis. Eleven patients were enrolled and 9 of them were positive for inner ear antibodies. Non-organ specific autoantibodies were present in 5 children out of 9. An immune-mediated condition was diagnosed in 2 cases and minor immune manifestations were found in 2 additional patients. In 5 cases hearing loss remained stable without therapy, while 4 children developed progression. Two subjects were treated with corticosteroids and methotrexate, achieving hearing improvement. Another subject showed stabilization on methotrexate. Inner ear autoantibodies can be positive in children with autoimmune sensorineural hearing loss, and in conjunction with clinical data may assist the clinician in identifying a subset amenable for immune modulation therapy. Large prospective studies are needed to investigate usefulness, diagnostic and prognostic role of these autoantibodies. PMID- 23944680 TI - Protein kinase D isoforms: new targets for therapy in invasive breast cancers? PMID- 23944681 TI - How nanoscience translates into technology: the case of self-assembled monolayers, electron-beam writing, and carbon nanomembranes. AB - One of the great quests in nanotechnology is to translate nanoprecision materials science into practical manufacturing processes. The paper by Angelova et al. in this issue of ACS Nano, which discusses the production of functional carbon-based membranes with a thickness of 0.5 to 3 nm, provides instructive insight into how researchers are pulling together complementary strands from a quarter century of nanoscience research to develop novel, hybrid processing schemes. In this Perspective, we reflect on the progress that is taking place in the two principal component technologies combined in this scheme, namely, (i) control of self assembled monolayers, including their detailed atomic structures, and (ii) electron-induced manipulation and processing of molecular layers, as well as considering (iii) remaining challenges for thin membrane production in the future. PMID- 23944682 TI - Halonium ion mediated synthesis of 2-halomethylene-3-oxoketoxime derivatives from isoxazoline N-oxides. AB - A protocol for the N-bromosuccinimide (NBS)- and trichloroisocyanuric acid (TCCA) mediated synthesis of novel 2-halomethylene-3-oxoketoximes via one-pot halogenation/oxidation of isoxazoline N-oxide derivatives is described here. The keto functionality of 3-ketoximes was selectively reduced by lithiumaluminum hydride to synthesize an unprecedented type of Baylis-Hillman oxime, which underwent N-O coupling to produce new isoxazoline N-oxide derivative. PMID- 23944683 TI - Social and psychological factors underlying adult vaccination behavior: lessons from seasonal influenza vaccination in the US and the UK. AB - This article reviews the evidence base on the social and psychological factors that facilitate or hinder vaccination among adults. The authors categorized these factors into eight themes: social influence, disease-related factors, vaccine related factors, habit, general attitudes toward health and vaccines, awareness and knowledge, practical barriers and motivators and altruism. Although there were many commonalities between both settings, the authors also indentifiedimportant differences. A better understanding of social and psychological aspects of vaccination across contexts and vaccines remains a priority. PMID- 23944684 TI - High-caloric food supplements in the treatment of amyotrophic lateral sclerosis: a prospective interventional study. AB - Weight loss is an independent prognostic factor in amyotrophic lateral sclerosis (ALS). We investigated whether the body weight of ALS patients who previously lost weight can be stabilized by a high-caloric diet. For this purpose we compared two different high-caloric food supplements: one with high fat content and one with high carbohydrate content. Twenty-six patients were randomly allocated to one of the therapeutic groups. Body weight, ALS functional rating scale-revised (ALSFRS-R), static vital capacity (SVC), bioelectrical impedance analysis (BIA), metabolic serum parameters, and adverse events were investigated. Results showed that body weight of ALS patients could be stabilized in both therapeutic groups after 12 weeks of therapy (p = 0.008). The effect was greater in the group with high fat supplement though not statistically significant (p = 0.37). In conclusion, high-caloric food supplements with high fat as well as high carbohydrate content are both suitable to stabilize the body weight of ALS patients. The effect of a high fat diet might be more pronounced. Since body weight is an independent prognostic factor in ALS it is possible that a high caloric food supplement improves survival in ALS. However, this hypothesis can only be tested by conducting a placebo-controlled double-blinded trial of sufficient power. PMID- 23944685 TI - Associations of maternal age with maternity care use and birth outcomes in primiparous women: a comparison of results in 1991 and 2008 in Finland. AB - OBJECTIVE: To compare birth outcomes and maternity care use in 1991 and 2008 by age among primiparous Finnish women. DESIGN: Register-based study. SETTING: Nationwide Medical Birth Register. POPULATION: All primiparous women in 1991 (n = 24,765) and 2008 (n = 23,511). METHODS: Women aged 35-39 and >=40 years were compared with women aged 20-34 years in 1991 and 2008, using logistic regression to adjust for women's background. MAIN OUTCOME MEASURES: Maternity care: prenatal visits, hospitalisation during pregnancy, labour induction, delivery mode, long postpartum hospital stay; and birth outcomes: birthweight, preterm birth, Apgar scores, intensive/observation unit, respiratory care, perinatal death. RESULTS: In both years, older women's deliveries were more often induced, instrumental, or by caesarean section. In 2008 compared with 1991, hospitalisations were lower and instrumental deliveries and labour induction were higher in older women. A significant decrease in adjusted odds ratios (OR, 95% confidence intervals) between 1991 and 2008 among women aged 35-39 was found for preterm birth (1.47, 1.18-1.84 versus 0.96, 0.86-1.07) and for intensive/observation unit (1.73, 1.47 2.05 versus 1.21, 1.07-1.37) and, among women aged >=40 years, for intensive/observation unit (3.14, 2.30-4.29 versus 1.64, 1.31-2.07). The risk for perinatal death (1.66, 0.60-4.60 versus 2.69, 1.07-6.79) was higher in 2008 than in 1991 among women aged >=40. CONCLUSIONS: In 2008, older primiparous women still used more maternity care, had more interventions, and poorer birth outcomes than younger women, regardless of care advances. Additional risks declined among women aged 35-39 but not among aged >=40. PMID- 23944686 TI - Ovarian hyperstimulation syndrome. PMID- 23944687 TI - Dual kidney transplantation from uncontrolled deceased donors after cardiac arrest: a possible option. AB - Organ shortage is a major problem in organ transplantation. For this reason, transplantation teams have found it necessary to revisit their organ acceptance criteria. Uncontrolled deceased donors after cardiac arrest could increase the donor pool by 20%, but at the same time there is a greater risk of delayed graft function and primary non-function. Dual kidney transplantation is an option when single kidney transplantation cannot be carried out because of lack of organ quality. We report for the first time our four first dual kidney transplantation from uncontrolled deceased donors after cardiac arrest with a follow up longer than 1 year. We described graft outcomes until 5 years, and histology at 3 and 12 months after transplantation. All organs were machine perfused in order to assess their quality leading to a single kidney transplantation or dual kidney transplantation decision. After 1 year of follow up, all grafts were functional with a mean estimated glomerular filtration rate of 44.5 +/- 3.3 mL/min/1.73 m(2), and a mean inulin clearance of 43.7 +/- 13.6 mL/mn/1.73 m(2). These findings suggest that dual kidney transplantation can represent a viable option for kidneys unsuitable for single kidney transplantation without increasing the rate of surgical complications. Successful transplantation is linked to histological, biological and donor clinical criteria, as well as perfusion parameters. PMID- 23944688 TI - Colloidal stability of self-assembled monolayer-coated gold nanoparticles: the effects of surface compositional and structural heterogeneity. AB - Surface heterogeneity plays an important role in controlling colloidal phenomena. This study investigated the self-aggregation and bacterial adsorption of self assembled monolayer coated gold nanoparticles (AuNPs) with different surface compositional and structural heterogeneity. Evaluation was performed on AuNPs coated with (1) one ligand with charged terminals (MUS), (2) two homogeneously distributed ligands with respectively charged and nonpolar terminals (brOT) and (3) two ligands with respectively charged and nonpolar terminals with stripe-like distribution (OT). The brOT particles have less negative electrophoretic mobility (EPM) values, smaller critical coagulation concentration (CCC) and larger adsorption rate on Escherichia coli than that of AuNPs with homogeneously charged groups, in good agreement with DLVO predictions. Although the ligand composition on the surface of AuNPs is the same, OT particles have less negative EPM values and faster rate of bacterial adsorption, but much larger CCC compared to brOT. The deviation of OT particles from brOT and MUS in their self-aggregation behavior reflects the effects of surface heterogeneity on electrical double layer structures at the interface. Results from the present study demonstrated that, besides chemical composition, organization of ligands on particle surface is important in determining their colloidal stability. PMID- 23944689 TI - Low-frequency Raman scattering in a Xe hydrate. AB - The physics of gas hydrates are rich in interesting phenomena such as anomalies for thermal conductivity, self-preservation effects for decomposition, and others. Some of these phenomena are presumably attributed to the resonance interaction of the rattling motions of guest molecules or atoms with the lattice modes. This can be expected to induce some specific features in the low-frequency (THz) vibrational response. Here we present results for low-frequency Raman scattering in a Xe hydrate, supported by numerical calculations of vibrational density of states. A number of narrow lines, located in the range from 18 to 90 cm(-1), were found in the Raman spectrum. Numerical calculations confirm that these lines correspond to resonance modes of the Xe hydrate. Also, low-frequency Raman scattering was studied during gas hydrate decomposition, and two scenarios were observed. The first one is the direct decomposition of the Xe hydrate to water and gas. The second one is the hydrate decomposition to ice and gas with subsequent melting of ice. In the latter case, a transient low-frequency Raman band is observed, which is associated with low-frequency bands (e.g., boson peak) of disordered solids. PMID- 23944690 TI - Impact of the penalty points system on severe road traffic injuries in Kuwait. AB - OBJECTIVE: This study aimed to examine the effect of a penalty points system (PPS) implemented in early July 2006 on the number of severe road traffic injuries (RTIs) in Kuwait. METHODS: Monthly counts of RTIs that occurred between January 2003 and December 2009 were analyzed. We used an interrupted seasonal autoregressive integrated moving average model (SARIMA) to estimate the intervention parameter along with its 95 percent confidence interval (CI) after accounting for seasonal and trend components in the data series. Based on the SARIMA model, we computed the number of RTIs that would have occurred post-PPS for 42 months after July 1, 2006, if it had not been implemented. RESULTS: During the study period, a total of 4696 RTIs occurred. The Poisson rates of injuries (per 10 million of mean mid-year population and per 10 million of annual mean number of registered vehicles) were significantly (P < .001) lower in the post PPS (lambda(post-PPS) = 7 and 16, respectively) than the pre-PPS (lambda(pre-PPS) = 9 and 23, respectively) implementation period. The intervention parameter's estimate was -7.68 (95% CI: -14.77, -0.60), suggesting that 322 (95% CI: 25, 620) individuals would have had RTIs in the 42 months post-PPS enactment, had it not been implemented. This translates to a 14.6 percent (95% CI: 1.1%, 28.0%) reduction. CONCLUSIONS: These findings suggest that PPS implementation in Kuwait appears to have resulted in a significant reduction in the number of RTIs in the ensuing period. Therefore, PPS seems a feasible and effective approach in reducing RTIs in Kuwait and other countries in the region, if adequately implemented. Future studies may focus on evaluating the long-term effects of PPS implementation. PMID- 23944691 TI - Efficient sensitization of dye-sensitized solar cells by novel triazine-bridged porphyrin-porphyrin dyads. AB - Two novel porphyrin-porphyrin dyads, the symmetrical Zn[Porph]-Zn[Porph] (2) and unsymmetrical Zn[Porph]-H2[Porph] (4), where Zn[Porph] and H2[Porph] are the metalated and free-base forms of 5-(4-aminophenyl)-10,15,20-triphenylporphyrin, respectively, in which two porphyrin units are covalently bridged by 1,3,5 triazine, have been synthesized via the stepwise amination of cyanuric chloride. The dyads are also functionalized by a terminal carboxylic acid group of a glycine moiety attached to the triazine group. Photophysical measurements of 2 and 4 showed broaden and strengthened absorptions in their visible spectra, while electrochemistry experiments and density functional theory calculations revealed negligible interaction between the two porphyrin units in their ground states but appropriate frontier orbital energy levels for use in dye-sensitized solar cells (DSSCs). The 2- and 4-based solar cells have been fabricated and found to exhibit power conversion efficiencies (PCEs) of 3.61% and 4.46%, respectively (under an illumination intensity of 100 mW/cm(2) with TiO2 films of 10 MUm thickness). The higher PCE value of the 4-based DSSC, as revealed by photovoltaic measurements (J V curves) and incident photon-to-current conversion efficiency (IPCE) spectra of the two cells, is attributed to its enhanced short-circuit current (J(sc)) under illumination, high open-circuit voltage (V(oc)), and fill factor (FF) values. Electrochemical impedance spectra demonstrated shorter electron-transport time (taud), longer electron lifetime (taue), and high charge recombination resistance for the 4-based cell, as well as larger dye loading onto TiO2. PMID- 23944692 TI - From the editor's desk. AB - No abstract available for this article. PMID- 23944693 TI - Visualization. AB - This paper presents the notion that visualization can be a useful strategy for decision-making in occupational therapy practice. Model building as a way or organizing and relating the ingredients to treatment decisions is presented in a variety of forms and applied to assessment and treatment situations. PMID- 23944695 TI - A review of initial assessments used by occupational therapists in mental health settings. AB - Factors affecting the selection and development of procedures used by occupational therapists for initial patient assessment in mental health settings are reviewed. The results of several national surveys of practicing therapists indicating those assessments most frequently taught in occupational educational programs and/or used in clinical settings are discussed. Some future trends in mental health practice are presented. PMID- 23944694 TI - Assessment. AB - The role of the occupational therapist in today's health care system is discussed in relation to the large numbers of patients with treatment problems and the relatively small numbers in the profession. The importance of good, efficient assessment procedures is emphasized in order to maximize the profession's helpfulness. Review of current practices among occupational therapists in carrying out the assessment function is presented along with data from a survey of therapists in physical disabilities practice. The article concludes with a plea for the increased use of standardized evaluation tools by occupational therapists to both make their efforts more effective and to build credibility for the services of the profession. PMID- 23944696 TI - Identifying leisure interests. AB - Helping adults learn to live with arthritis is a major responsibility for occupational therapists. There are a variety of instruments for therapists to use in evaluating the self-care and work components of occupational performance, however there are no instruments for assessing the leisure interests of persons with arthritis. The purpose of this investigation was to develop an instrument for assessing the leisure interests of adults with rheumatoid arthritis or degenerative joint disease. The instrument is patterned after Knowles self diagnostic competency model. Following Knowles' procedure of developing such a model, a literature review and a panel of occupational therapists with expertise in the treatment of rheumatic disease were used to identify a list of leisure activities. The list was categorized and applied to Knowles' suggested format for a self-diagnostic competency model. Strategies for using the instrument with the targeted population are presented. PMID- 23944697 TI - Occupational therapy assessment and treatment in a hospital setting for patients with epilepsy. AB - One Reed is a unit at the UCLA Neuropsychiatric Institute for the evaluation and treatment of patients with poorly controlled seizure disorders. Like many other patients with epilepsy, these individuals frequently experience problems in many facets of daily living. This paper describes the twofold purpose of occupational therapy on One Reed: to provide a program of activity and socialization during the extended period of medical evaluation, and to help patients identify problems in their daily life activities and develop the skills which will enable them to function better after hospitalization. The frame of reference which guides practice is identified and the methods and instruments of occupational therapy assessment for this patient population are described. Typical examples of daily living problems are given, and some occupational therapy methods for dealing with the problems are enumerated. PMID- 23944698 TI - Assessment of the hemiparetic upper extremity. AB - The Functional Test gives an accurate and immediate assessment of upper extremity capabilities for performance of functional activities. It has been used primarily with patients who have a residual hemiparetic upper extremity following a stroke. This seventeen task test is arranged in seven levels and can be administered in approximately thirty minutes. It is completely portable and can be used practically in many different treatment settings. The information obtained will allow therapists to set realistic functional goals and design effective programs for the patient's use of the involved upper extremity. The early research on this instrument implies that this test may be used as an alternative to some of the traditional objective and time consuming test measures that are currently used by occupational therapists. PMID- 23944699 TI - Adult Skills Evaluation Survey (ASES) for Persons with Mental Retardation. AB - This paper explains the reasons for developing an assessment tool that would answer the increasingly apparent need for an evaluation instrument to measure developmental levels of performance in programs training adults with mental impairment but little physical disability. The four sections of the assessment are described in terms of content and concepts. The results indicate findings from four years of testing and retesting, providing data useful for appropriate placement in therapy services, for writing measurable goals, for recording progress and for programming tailored to the needs of both individual trainees and groups. The unique contributions of occupational therapists in this field are discussed. PMID- 23944700 TI - A description of an occupational therapy program for students with disabilities who attend a community college. AB - An occupational therapy program for community college students who are disabled is described. The non-traditional program utilizes physical and psycho-social assessments to assist in treatment planning. Student role fulfillment is the central goal of treatment. The organizational context, the population served, and the assessment and therapy process are discussed. The description is designed to aid those who seek to develop community-based, treatment programs. PMID- 23944701 TI - Physiological monitoring. AB - Many patients with physical disabilities are limited by poor endurance. This could be due to the level of deconditioning, the disease or injury, and/or the demands of the activities they must perform. Occupational therapists historically have been involved in prescribing activity and teaching energy conservation. The purpose of this paper is to (1) review briefly the study of energy cost and its significance to occupational therapy practice and (2) to describe the Physiological Monitored Evaluation (PME). The PME can be used to assess the demands of activities on patients by measuring the heart rate, blood pressure, and symptomatic responses to activities. This procedure can be used to obtain baseline measurements to compare and document progress, set safe guidelines for activity so that the patient may increase endurance without becoming "overstressed", and collect data for research. PMID- 23944702 TI - Cardiac work tolerance screening. AB - The transition from inpatient to worker is often a difficult one for the individual recovering from an acute coronary event. While all activities are directed and closely monitored in the hospital, medical recommendations to the convalescent may be as general as, "do anything you want, within your limitations" or for performing work tasks, the occupational therapist may reduce a client's uncertainty and encourage him to maintain a health productive life. This paper describes the assessment procedure used in a community hospital occupational therapy department with a client recovering from an acute myocardial infarction. Method of job analysis, work simulation and cardiac monitoring which were applied in the assessment are discussed. The use of assessment results to assist the client in returning to his job as an elevator mechanic is explained. PMID- 23944703 TI - How to improve professional reporting of work evaluations. AB - One of the significant hindrances to more frequent participation by occupational therapists in the vocational rehabilitation process is ineffective communication. The authors contend that occupational therapists conducting work evaluations can help overcome this deficit by making changes in the orientation, language, and form of their evaluation reports. A recent research study by the authors comparing a survey of current occupational therapy practice and an assessment of needs of vocational rehabilitation counselors identified specific problems with work evaluation reports. These concerned uncertainty about who they were serving with their reports, use of language unfamiliar to persons not in the medical field, and presentation of data without interpretation or application to work situations. The authors offer specific suggestions for writing reports of work evaluation which will provide better bases for helping workers return to their jobs. PMID- 23944704 TI - Label-free fluorescence detection of aromatic compounds in chip electrophoresis applying two-photon excitation and time-correlated single-photon counting. AB - In this study, we introduce time-resolved fluorescence detection with two-photon excitation at 532 nm for label-free analyte determination in microchip electrophoresis. In the developed method, information about analyte fluorescence lifetimes is collected by time-correlated single-photon counting, improving reliable peak assignment in electrophoretic separations. The determined limits of detection for serotonin, propranolol, and tryptophan were 51, 37, and 280 nM, respectively, using microfluidic chips made of fused silica. Applying two-photon excitation microchip separations and label-free detection could also be performed in borosilicate glass chips demonstrating the potential for label-free fluorescence detection in non-UV-transparent devices. Microchip electrophoresis with two-photon excited fluorescence detection was then applied for analyses of active compounds in plant extracts. Harmala alkaloids present in methanolic plant extracts from Peganum harmala could be separated within seconds and detected with on-the-fly determination of fluorescence lifetimes. PMID- 23944705 TI - Assessing the HLA diversity of cord blood units collected from a birth clinic caring for pregnant women in an ethnically diverse metropolitan area. AB - BACKGROUND: New strategies are emerging in cord blood banking where focusing on birth clinics caring for a high number of mothers belonging to ethnic minorities could offer new possibilities for allotransplantation both for patients of European origin and for patients from ethnic minorities or mixed ancestries. STUDY DESIGN AND METHODS: Marseilles Cord Blood Bank works with one university birth clinic caring for a culturally and sociologically diverse population. Stringent French legal restrictions apply to recording the geographic origin of parents. To circumvent this limitation and evaluate the contribution of newly banked cord blood units (CBUs) to increasing HLA diversity, we applied an algorithm that allows for the determination of parents' putative haplotypes and thus grossly deduce information on their ancestry. Generic resolution HLA-A, HLA B, and allelic resolution HLA-DRB1 genotyping for 328 CBUs and 2691 unrelated donors (UDs) between January 2009 and May 2012 were performed. Enrichment from international CBU registry with nonreferenced generic HLA-A, HLA-B, and allelic HLA-DRB1 phenotypes was compared between CBUs identified with one or two non European haplotypes and CBUs identified with two European haplotypes. RESULTS: Marseilles CBUs display an increased proportion of HLA antigens frequently expressed in African populations compared to UDs. Whereas 93% of 199 CBUs identified with one or two non-European haplotypes enrich international CBU registry, this result is reduced to 42% for the 129 CBUs identified with two European haplotypes. CONCLUSION: This study supports a new method to assess HLA diversity. However, such an increased of HLA diversity raises questions about frequencies of CBUs released and clinical relevance from their uses. PMID- 23944707 TI - Pituitary insufficiency from large unruptured supraclinoid internal carotid artery aneurysm. AB - A 59-year-old female presented with headache and fatigue. Angiography revealed a giant superior hypophyseal aneurysm with intrasellar extension. Serum endocrine panel demonstrated pituitary insufficiency. The aneurysm was treated with a pipeline flow-diverting stent and the hypopituitarism was treated with hormone replacement. Pituitary insufficiency from aneurysmal compression is extremely rare. PMID- 23944708 TI - Crystal structures of hereditary vitamin D-resistant rickets-associated vitamin D receptor mutants R270L and W282R bound to 1,25-dihydroxyvitamin D3 and synthetic ligands. AB - The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, functions as a ligand-dependent transcription factor for various genes. Hereditary vitamin D-resistant rickets (HVDRR), an autosomal recessive disease, is caused by mutations in the VDR. In particular, the missense mutations R274L and W286R in the ligand-binding domain of the VDR can severely reduce or even eliminate natural hormone responsiveness. Here, we report a crystal structure analysis of the R270L and W282R mutants of rat VDR (human R274L and W286R, respectively) in complex with the natural hormone and synthetic ligands. We also studied the folding properties of the mutant proteins by using circular dichroism spectra. Our study indicates that these mutations result in only local structural modifications. We discuss why these mutations disrupt the VDR function and provide clues to develop effective ligands for the treatment of HVDRR. PMID- 23944709 TI - Absorptions between 3000 and 5500 cm(-1) of cyclic O4+ and O4- trapped in solid neon. AB - Recently, gas-phase absorptions in the 3000-4300 cm(-1) spectral region have been assigned to combination bands built on (nu1 + nu5) of ground-state cyc-O4(+). Other gas-phase experiments identified an electronic transition of cyc-O4(-) complexed with an argon atom between 4000 and 5300 cm(-1). Absorptions that correspond closely to these two groups of bands have been observed in neon-matrix experiments in which both cyc-O4(+) and cyc-O4(-) are trapped at 4.3 K in solid neon. The results are compared with the gas-phase data, and the proposed assignments are considered by taking into account the results of isotopic substitution. PMID- 23944710 TI - Impact of dose-finding studies on administration of oxytocin during caesarean section in the UK. AB - Debate continues over the dose and methods of administration of oxytocin for the prevention of haemorrhage during caesarean section. We surveyed 206 lead obstetric anaesthetists in the UK to determine standard practice in their unit as well as any differences in practice for high-risk cases. There were 150 responses (72.9% response rate). A total of 149 units use oxytocin. The majority use an initial 5-IU dose, whilst a small proportion (8; 5.3%) administer a dose < 5 IU for elective caesarean section. The administration of a 10-IU dose has ceased altogether. There is a broad range of administration methods, particularly with infusions. Forty (26.8%) respondents give a different oxytocin regimen following caesarean section in patients with severe pre-eclampsia, 72 (48.3%) in those with cardiac disease of New York Heart Association class 1-2, and 100 (66.7%) with class 3-4. In conclusion, there is a trend towards the use of lower doses of oxytocin in caesarean section, but there are still wide variations in detail. We suggest that there is a need for a national protocol to standardise oxytocin administration. PMID- 23944711 TI - Clinical and genetic features of 5 Chinese patients with X-linked lymphoproliferative syndrome. AB - In this study, we report the clinical and genetic features of Chinese patients with X-linked lymphoproliferative syndrome (XLP). Male patients with fulminant infectious mononucleosis (FIM), Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) or persistent EBV viremia were enrolled in this study. Direct sequencing was used to detect SH2D1A/XIAP gene mutations. The patients' clinical features were assessed by retrieval of data from medical records. Twenty-one male patients with FIM, EBV-associated HLH or persistent EBV viremia were evaluated. Four patients had SH2D1A mutations, and one patient had an XIAP mutation. All five of these patients had symptoms of HLH and EBV infection. Among the five patients, the youngest one was only 1 month old at onset. One patient exhibited hypogammaglobulinemia. Of four patients evaluated for immunological function, all exhibited reduced CD4/CD8 ratios. Three patients had rapid disease progression and died. One patient received haematopoietic stem cell transplantation and is well. The overall clinical phenotypes of Chinese patients with XLP matched previous reports. For patients with severe EBV associated HLH, our results indicate the need to examine the possibility of XLP. PMID- 23944712 TI - Antiangiogenic approach in soft-tissue sarcomas. AB - Soft-tissue sarcomas (STS) are a group of more than 50 malignancies characterized by their rarity. The most effective treatments available only achieve a response rate (RR) of around 20%. Therefore, new therapeutic strategies are needed. Neoangiogenesis is one of the most fundamental mechanisms in cancer and many studies suggest that it also plays a crucial role in STS. Positive results from two Phase III trials in STS with drugs that target angiogenesis have recently been reported, showing an increase in progression-free survival. These data, although promising, are still insufficient and further investigations are needed. STS are unusual among solid tumors, in which single agent angiogenesis inhibitors produce a significant benefit. Unfortunately, we are currently not able to reliably define according to the histological subtype who are the patients that may benefit from this strategy. Moreover, it is clear that single agent treatment is insufficient, hence the current focus is on combination studies. PMID- 23944713 TI - Arabidopsis exocyst subcomplex containing subunit EXO70B1 is involved in autophagy-related transport to the vacuole. AB - Autophagic transport to the vacuole represents an endomembrane trafficking route, which is widely used in plants, not only during stress situations, but also for vacuole biogenesis and during developmental processes. Here we report a role in autophagic membrane transport for EXO70B1--one of 23 paralogs of Arabidopsis EXO70 exocyst subunits. EXO70B1 positive compartments are internalized into the central vacuole and co-localize with autophagosomal marker ATG8f. This internalization is boosted by induction of autophagy. Loss of function (LOF) mutations in exo70B1 cause reduction of internalized autopagic bodies in the vacuole. Mutant plants also show ectopic hypersensitive response (HR) mediated by salicylic acid (SA) accumulation, increased nitrogen starvation susceptibility and anthocyanin accumulation defects. Anthocyanin accumulation defect persists in npr1x exo70B1 double mutants with SA signaling compromised, while ectopic HR is suppressed. EXO70B1 interacts with SEC5 and EXO84 and forms an exocyst subcomplex involved in autophagy-related, Golgi-independent membrane traffic to the vacuole. We show that EXO70B1 is functionally completely different from EXO70A1 exocyst subunit and adopted a specific role in autophagic transport. PMID- 23944714 TI - Recent status of the treatment of stress urinary incontinence. AB - The therapeutic options for management of stress urinary incontinence can be conservative, pharmacological or surgical. The treatment of patients with stress urinary incontinence should be tailored to the individual to optimize care. A multitude of surgical techniques have emerged to treat this condition in recent years. The objective of the present review was to present an overview of current practice in the management of stress urinary incontinence while considering the evidence supporting the clinical effectiveness of these procedures. PMID- 23944716 TI - Convection-enhanced drug delivery to the brain: therapeutic potential and neuropathological considerations. AB - Convection-enhanced delivery (CED) describes a direct method of drug delivery to the brain through intraparenchymal microcatheters. By establishing a pressure gradient at the tip of the infusion catheter in order to exploit bulk flow through the interstitial spaces of the brain, CED offers a number of advantages over conventional drug delivery methods-bypass of the blood-brain barrier, targeted distribution through large brain volumes and minimization of systemic side effects. Despite showing early promise, CED is yet to fulfill its potential as a mainstream strategy for the treatment of neurological disease. Substantial research effort has been dedicated to optimize the technology for CED and identify the parameters, which govern successful drug distribution. It seems likely that successful clinical translation of CED will depend on suitable catheter technology being used in combination with drugs with optimal physicochemical characteristics, and on neuropathological analysis in appropriate preclinical models. In this review, we consider the factors most likely to influence the success or failure of CED, and review its application to the treatment of high-grade glioma, Parkinson's disease (PD) and Alzheimer's disease (AD). PMID- 23944717 TI - The changing cultural and economic dynamics of polygyny and concurrent sexual partnerships in Iringa, Tanzania. AB - Polygyny has been identified both as a 'benign' form of concurrency and as the cultural basis of concurrent partnerships that are considered important drivers of the HIV epidemic in sub-Saharan Africa. This paper investigates the changing cultural and economic dynamics of polygyny in concurrency in Iringa, Tanzania, a region with traditions of polygyny and high prevalence of HIV. Our analysis of focus group discussions, in-depth interviews and key informant interviews indicate that contemporary concurrent partnerships differ from regional traditions of polygyny. Whereas in the past, polygyny reflected men's and their kin group's wealth and garnered additional prestige, polygyny today is increasingly seen as a threat to health, and as leading to poverty. Nevertheless, participants evoked the social prestige of polygyny to explain men's present-day concurrency, even outside the bounds of marriage, and despite continued social prohibitions against extramarital affairs. Difficult economic conditions, combined with this prestige, made it easier for men to engage in concurrency without the considerable obligations to wives and children in polygyny. Local economic conditions also compelled women to seek concurrent partners to meet basic needs and to access consumer goods, but risked greater moral judgement than men, especially if deemed to have excessive 'desire' for money. PMID- 23944718 TI - Bulls, bubbles, and biotech. PMID- 23944722 TI - Osteopath is incorrect term for osteopathic physicians. PMID- 23944720 TI - Safety and efficacy of faldaprevir with pegylated interferon alfa-2a and ribavirin in Japanese patients with chronic genotype-1 hepatitis C infection. AB - BACKGROUND & AIMS: Faldaprevir (BI 201335) is a potent once-daily (QD) NS3/4A protease inhibitor for the treatment of patients with genotype-1 (GT-1) hepatitis C virus (HCV). The aim of this study was to evaluate the safety, pharmacokinetics and efficacy of faldaprevir plus pegylated interferon alfa-2a (PegIFN) and ribavirin (RBV) in Japanese patients infected with chronic GT-1 HCV. METHODS: Part 1 of this phase II study was a randomized, double-blind, placebo-controlled, dose-ascending study. Treatment-naive patients received faldaprevir 120 or 240 mg QD, or placebo, plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. In Part 2 (open label), treatment-experienced patients received faldaprevir 240 mg QD plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. Efficacy was assessed using sustained virological response (SVR) 24 weeks after treatment completion. The pharmacokinetics, safety and tolerability of faldaprevir were also assessed. RESULTS: SVR was achieved by 4/6 (67%) treatment-naive patients treated with faldaprevir 120 mg QD, 5/6 (83%) patients treated with faldaprevir 240 mg QD and 2/4 (50%) patients who received placebo. Of the treatment experienced patients, 3/6 (50%) achieved SVR. Faldaprevir was well tolerated. There was one serious adverse event, which was not considered to be treatment related. Rash and hyperbilirubinaemia were more frequently reported with faldaprevir than with placebo in treatment-naive patients, but no cases were severe or serious and none led to discontinuation. Steady-state plasma concentrations of faldaprevir were reached within 7 days of QD dosing. CONCLUSIONS: Faldaprevir with PegIFN/RBV was efficacious and well tolerated, supporting further evaluation of this combination in Japanese patients. PMID- 23944724 TI - Risks associated with long-term benzodiazepine use. PMID- 23944725 TI - Relying on NPs and PAs does not avoid the need for policy solutions for primary care. PMID- 23944727 TI - Childhood eye examination. AB - Vision screening in children is an ongoing process, with components that should occur at each well-child visit. The purpose is to detect risk factors and visual abnormalities that necessitate treatment and to identify those patients who require referral to an ophthalmologist skilled in examining children. Screening can reveal conditions commonly treated in primary care and can aid in discussion of visual concerns with parents or caregivers. Vision screening begins with a review of family and personal vision history to identify risk factors requiring referral, including premature birth, Down syndrome, cerebral palsy, and a family history of strabismus, amblyopia, retinoblastoma, childhood glaucoma, childhood cataracts, or ocular or genetic systemic disease. Visual acuity measurement and external ocular examination are performed to recognize refractive error, childhood glaucoma, and various ocular conditions. Evaluation of fixation and alignment can identify amblyopia or strabismus. Red reflex examination is used to diagnose retinoblastoma, childhood cataracts, and other ocular abnormalities. PMID- 23944726 TI - Management of common sleep disorders. AB - Sleep disorders are common and affect sleep quality and quantity, leading to increased morbidity. Patients with sleep disorders can be categorized as those who cannot sleep, those who will not sleep, those with excessive daytime sleepiness, and those with increased movements during sleep. Insomnia, defined as difficulty initiating or maintaining sleep that results in daytime impairment, is diagnosed using history findings and treated with cognitive behavior therapy, with or without sleep hypnotics. Restless legs syndrome is characterized by an urge to move the legs that worsens with rest, is relieved by movement, and often occurs in the evening or at night. Restless legs syndrome is treated based on the frequency of symptoms. Narcolepsy is characterized by excessive sleepiness, cataplexy, hypnagogic or hypnopompic hallucinations, and sleep paralysis. It is diagnosed using a sleep log or actigraphy, followed by overnight polysomnography and a multiple sleep latency test. Narcolepsy is treated with stimulants, such as modafinil; selective serotonin reuptake inhibitors; or gamma hydroxybutyric acid (sodium oxybate). Patients with snoring and witnessed apneas may have obstructive sleep apnea, which is diagnosed using overnight polysomnography. Continuous positive airway pressure is the most common and effective treatment for obstructive sleep apnea. Rapid eye movement sleep behavior disorder is characterized by increased muscle tone during rapid eye movement sleep, resulting in the patient acting out dreams with possible harmful consequences. It is diagnosed based on history and polysomnography findings, and treated with environmental safety measures and melatonin or clonazepam. PMID- 23944728 TI - Parathyroid disorders. AB - Disorders of the parathyroid glands most commonly present with abnormalities of serum calcium. Patients with primary hyperparathyroidism, the most common cause of hypercalcemia in outpatients, are often asymptomatic or may have bone disease, nephrolithiasis, or neuromuscular symptoms. Patients with chronic kidney disease may develop secondary hyperparathyroidism with resultant chronic kidney disease mineral and bone disorder. Hypoparathyroidism most often occurs after neck surgery; it can also be caused by autoimmune destruction of the glands and other less common problems. Evaluation of patients with abnormal serum calcium levels includes a history and physical examination; repeat measurement of serum calcium level; and measurement of creatinine, magnesium, vitamin D, and parathyroid hormone levels. The treatment for symptomatic primary hyperparathyroidism is parathyroidectomy. Management of asymptomatic primary hyperparathyroidism includes monitoring symptoms; serum calcium and creatinine levels; and bone mineral density. Patients with hypoparathyroidism require close monitoring and vitamin D (e.g., calcitriol) replacement. PMID- 23944729 TI - A shiny red papule in an older person. Clear cell acanthoma. PMID- 23944730 TI - Vilazodone (viibryd) for the treatment of depression. PMID- 23944731 TI - ADHD interventions in children younger than six years. PMID- 23944732 TI - ACOG releases practice bulletin on osteoporosis. PMID- 23944733 TI - Interventions for lower-extremity lymphedema. PMID- 23944734 TI - Clinical variability and female penetrance in X-linked familial FTD/ALS caused by a P506S mutation in UBQLN2. AB - Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease leading to progressive paralysis that is generally fatal. Only 10% of cases are familial, a subset of which overlaps with frontotemporal dementia (FTD). Up to half of ALS patients have cognitive impairment, with 15% meeting the criteria for FTD. Clinical sequencing of UBQLN2 in a family with X-linked FTD/ALS with suspected incomplete penetrance, manifesting in both genders, revealed a P506S mutation in. Affected individuals were diagnosed with various conditions including hereditary spastic paraplegia (HSP), bulbar palsy and multiple sclerosis. The mutation in UBQLN2 was first identified in a 35-year-old female who presented with one year of progressive dysarthria, dyspnea, dysphagia, and cognitive decline. EMG suggested early motor neuron disease with prominent bulbar involvement. Her cognition declined rapidly and she developed extremity weakness. Her brother, initially diagnosed with HSP, and her second cousin, with primary lateral sclerosis, also have a P506S mutation in UBQLN2. In conclusion, the P506S mutation in UBQLN2 can affect both males and females and displays great phenotypic variability within the same family. Females can potentially have a more severe and rapidly progressive presentation than their male relatives. Additionally, the P506S mutation can also cause an FTD phenotype. PMID- 23944735 TI - Total synthesis of varitriol, varioxirane, and enantiomer of the proposed biosynthetic precursor. AB - The first stereoselective total synthesis of varioxirane was accomplished, and the proposed biosynthetic pathway was supported by converting varioxirane to (+) varitriol. The first total synthesis of enantiomer of the proposed biosynthetic precursor, (1E,3S,4R,5E)-1-(2-(hydroxymethyl)-3-methoxyphenyl)hepta-1,5-diene-3,4 diol, was also achieved by utilizing the unreacted allylic alcohol obtained during the Sharpless kinetic resolution step. Other key steps include the Horner Wadsworth-Emmons reaction and the diastereoselective reduction of alpha,beta unsaturated ketone to its corresponding alcohol. PMID- 23944736 TI - Creation of cross-linked bilayer membranes that can incorporate membrane proteins from oligo-Asp-based peptide gemini surfactants. AB - We designed novel bilayer-forming amphiphiles based on the cyclic oligo-Asp-based peptide gemini (PG) surfactants cr-D2C12 and cr-D3C12, which consist of Cys(Asp)nCys- (n = 2 or 3) as a core peptide and two Cys residues containing a dodecylamidomethyl group. Dynamic light scattering and transmission electron microscopy measurements revealed the formation of spherical bilayer membranes that could incorporate the light-harvesting antenna complex 2 (LH2) from Rhodopseudomonas acidophila . Furthermore, this proteoliposome-like conjugate could be assembled onto cationized glass and mica to form planar bilayer membranes incorporating LH2. Using atomic force microscopy, we observed LH2 protruding (ca. 1.2-1.5 nm) from flat terraces of the planar bilayer membranes formed from cr-D2C12 or cr-D3C12. Thus, our designed PG surfactants are a new class of bilayer-forming amphiphiles that may be applied to the study of various membrane proteins. PMID- 23944737 TI - Infrared spectra and electronic structure calculations for the NUN(NN)1-5 and NU(NN)1-6 complexes in solid argon. AB - Reactions of laser-ablated U atoms with N2 molecules in excess argon during co deposition at 4 K gave intense NUN and weaker UN absorptions. Annealing increased progressions of new absorptions for the NUN(NN)1,2,3,4,5 and NU(NN)1,2,3,4,5,6 uranium nitride complexes. Small matrix shifts are observed when the secondary coordination layers around the primary NUN(NN)1,2,3,4,5 and NU(NN)1,2,3,4,5,6 complexes are changed from argon to nitrogen. Electronic structure and energy and frequency calculations provide support for the identification of these complexes and further characterization of the N=U=N and U=N core molecules as terminal uranium nitrides with full triple bonds. PMID- 23944738 TI - Iron deficiency in Canadian blood donors. AB - BACKGROUND: The adequacy of communication and knowledge of donors and physicians regarding iron needs and the relationship between hemoglobin (Hb) and iron stores require evaluation to address donor iron deficiency. STUDY DESIGN AND METHODS: A prospective cohort study was performed on 550 successful donors and 50 donors deferred for low Hb (<125 g/L on repeat fingerstick). Donors participated in an on-clinic interview and had serum ferritin measured. They were mailed their results and recontacted regarding follow-up. RESULTS: Most donors are unaware of possible health impacts of donation and do not discuss donation with their physician. In successful donors, mean ferritin levels were 37 and 131 MUg/L in first-time and reactivated (no donation for 2 years) females and males and 19 and 29 MUg/L in frequent repeat females and males, respectively (p < 0.0001), with infrequent donors having intermediate results. Mean ferritin was 12 MUg/L in donors deferred for low Hb. Twenty of 22 donors failing initial Hb testing and passing on repeat testing had ferritin below 25 MUg/L. On follow-up, 63 of 164 donors (38%) with low ferritin were taking iron supplements 2 months postdonation. CONCLUSION: Iron deficiency is frequent, particularly in female donors and frequent donors. A fail on initial Hb testing followed by a pass on repeat testing is likely to be due to iron deficiency and borderline anemia. Donors and physicians need to be more aware of iron needs associated with blood donation and appropriate treatment for low iron stores. PMID- 23944739 TI - Catalytic mechanism of hyaluronate lyase from Streptococcus pneumonia [corrected] : quantum mechanical/molecular mechanical and density functional theory studies. AB - Hyaluronate lyase from Spectrococcus pneumonia can degrade hyaluronic acid, which is one of the major components in the extracellular matrix. The major functions of hyaluronan are to regulate water balance and osmotic pressure and act as an ion-exchange resin. It has been suggested in our previous molecular dynamics simulation that the binding of the substrate molecule could lead to the ionization of Y408 and protonation of H399. Followed by our recent molecular dynamics simulation of the enzyme-substrate complex, a unified proton abstraction and donation mechanism for this enzyme can be established using a combined quantum mechanical and molecular mechanical approach and density functional theory method. Y408 is shown to serve as the general base in the proton abstraction, while general acid is the next proton donation step. Overall, this reaction can be classified into syn-elimination reaction mechanism. The neutralization effects of C5 carboxylate group by several polar residues such as N349 and H399 were also examined. Finally, in combination of our previous molecular dynamics simulations, a complete catalytic cycle for the degradation of hyaluronan tetrasaccharide catalyzed by the hyaluronate lyase from Spectrococcus pneumonia is proposed. PMID- 23944740 TI - Effects of push/pull perfusion and ultrasonication on the extraction efficiencies of phthalate esters in sports drink samples using on-line hollow-fiber liquid phase microextraction. AB - In previous studies, we developed a process, on-line ultrasound-assisted push/pull perfusion hollow-fiber liquid-phase microextraction (UA-PPP-HF-LPME), combining the techniques of push/pull perfusion (PPP) and ultrasonication with hollow-fiber liquid-phase microextraction (HF-LPME), to achieve rapid extraction of acidic phenols from water samples. In this present study, we further evaluated three more-advanced and novel effects of PPP and ultrasonication on the extraction efficiencies of neutral high-molecular-weight phthalate esters (HPAEs) in sports drinks. First, we found that inner-fiber fluid leakage occurs only in push-only perfusion-based and pull-only perfusion-based HF-LPME, but not in the PPP mode. Second, we identified a significant negative interaction between ultrasonication and temperature. Third, we found that the extraction time of the newly proposed system could be shortened by more than 93%. From an investigation of the factors affecting UA-PPP-HF-LPME, we established optimal extraction conditions and achieved acceptable on-line enrichment factors of 92-146 for HPAEs with a sampling time of just 2 min. PMID- 23944741 TI - Histamine pharmacology: four years on. AB - The histamine field has moved on rapidly in the last four years, with expansion in roles and clinical development, particularly in the newest two of four histamine receptors. This themed volume is a testament to this expansion with 16 original and review articles spanning a wide spectrum of histamine-related topics, with therapeutic translational relevance to addiction, dementias, anxiety disorders, cancers, vestibular disorders, migraine and autoimmune disorders. PMID- 23944742 TI - Emergence of hyper empathy after right amygdalohippocampectomy. AB - We report a fascinating case of a patient with a hyper empathy that appeared after resective epilepsy surgery. This behavioral modification has remained unchanged since the surgery took place 13 years ago. Recent neuropsychological objective assessments confirmed hyper empathy in a self-report questionnaire, and revealed higher affective theory of mind than controls in a "Reading the Mind in the Eyes Task." Temporal lobe epilepsy is the most common form of epilepsy and the investigation of emotional processes after surgery in these patients deserves to be related. PMID- 23944743 TI - Aortic pulse wave velocity and HeartSCORE: improving cardiovascular risk stratification. a sub-analysis of the EDIVA (Estudo de DIstensibilidade VAscular) project. AB - BACKGROUND: HeartSCORE is a tool for assessing cardiovascular risk, basing its estimates on the relative weight of conventional cardiovascular risk factors. However, new markers of cardiovascular risk have been identified, such as aortic pulse wave velocity (PWV). The purpose of this study was to evaluate to what extent the incorporation of PWV in HeartSCORE increases its discriminative power of major cardiovascular events (MACE). METHODS AND RESULTS: This study is a sub analysis of the EDIVA project, which is a prospective cohort, multicenter and observational study involving 2200 individuals of Portuguese nationality (1290 men and 910 women) aged between 18 and 91 years (mean 46.33 +/- 13.76 years), with annual measurements of PWV (Complior). Only participants above 35 years old were included in the present re-analysis, resulting in a population of 1709 participants. All MACE - death, cerebrovascular accident, coronary accidents (coronary heart disease), peripheral arterial disease and renal failure - were recorded. During a mean follow-up period of 21.42 +/- 10.76 months, there were 47 non-fatal MACE (2.1% of the sample). Cardiovascular risk was estimated in all patients based on the HeartSCORE risk factors. For the analysis, the refitted HeartSCORE and PWV were divided into three risk categories. The event-free survival at 2 years was 98.6%, 98.0% and 96.1%, respectively in the low-, intermediate- and high-risk categories of HeartSCORE (log-rank p < 0.001). The multi-adjusted hazard ratio (HR) per 1 - standard deviation (SD) of MACE was 1.86 (95% CI 1.37-2.53, p < 0.001) for PWV. The risk of MACE by tertiles of PWV and risk categories of the HeartSCORE increased linearly, and the risk was particularly more pronounced in the highest tertile of PWV for any category of the HeartSCORE, demonstrating an improvement in the prediction of cardiovascular risk. It was clearly depicted a high discriminative capacity of PWV even in groups of apparent intermediate cardiovascular risk. Measures of model fit, discrimination and calibration revealed an improvement in risk classification when PWV was added to the risk-factor model. The C statistics improved from 0.69 to 0.78 (adding PWV, p = 0.005). The net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were also determined, and indicated further evidence of improvements in discrimination of the outcome when including PWV in the risk-factor model (NRI = 0.265; IDI = 0.012). CONCLUSION: The results clearly illustrate the benefits of integrating PWV in the risk assessment strategies, as advocated by HeartSCORE, insofar as it contributes to a better discriminative capacity of global cardiovascular risk, particularly in individuals with low or moderate cardiovascular risk. PMID- 23944744 TI - The effects of alcohol mixed with energy drinks (AmED) on traffic behaviors among Brazilian college students: a national survey. AB - OBJECTIVE: Drinking alcohol mixed with energy drinks (AmED) may be contributing to hazardous drinking practices and risk-taking behaviors among college students. In this regard, this study aimed to assess the frequency of AmED consumption in a national sample of Brazilian college students and to estimate the risk that energy drinks pose on drinking and traffic behaviors. METHOD: A sample of 12,711 college students from across the country was asked to complete a research questionnaire on the use of drugs and other behaviors. Students who reported drinking in the previous 12 months (N = 8672) were divided into 2 groups: (a) those who reported drinking only alcohol (N = 4192) and (b) those who reported drinking AmED (N = 1119). The college students who reported the use of at least one illicit drug were excluded from data analysis. Descriptive and inferential analyses were subsequently carried out using the R library survey software 2.15.0. The null hypothesis was rejected at the level of P < .05. RESULTS: AmED users are more likely to be hazardous drinkers. Being male, single, and involved with high-risk drinking behaviors are associated to AmED. After adjusting for demographic and drinking variables, the odds of being involved in high-risk traffic behaviors--for example, driving at high speed (odds ratio [OR] = 2.6; P < .001) and driving after binge drinking (OR = 2.8; P < .001)--were higher among AmED users than alcohol only users (AUs). CONCLUSION: The current findings are consistent with the results of previous studies. Drinking AmED may make college students more vulnerable to the occurrence of risky drinking and traffic behaviors. Educational campaigns targeted to young people should be developed warning them about the potential risks of mixing alcohol with energy drinks. PMID- 23944745 TI - Prophylactic and therapeutic effects of garlic extract on Nerium oleander-induced arrhythmia: a new approach to antiarrhythmic therapy in an ovine model. AB - CONTEXT: Oleander is a potent cardiotoxic plant and is a common cause of poisoning in human and animals. There is no affordable and cost-effective treatment for oleander poisoning. Objective. To evaluate the prophylactic and therapeutic effects of garlic extract (Allium sativum) on Nerium oleander (a potent cardiotoxic plant) intoxication in sheep. MATERIALS AND METHODS: Eight sheep were intravenously infused with an unsterilized hydro-ethanol extract of garlic (50 mg/kg) before or after receiving a lethal dose of dried leaves (as a powder) of oleander (100 mg/kg, orally). The cardiac rhythm was continuously monitored using biopotential wireless transmitters and telemetry system. For evaluation of therapeutic effects, six sheep received the lethal dose of oleander and were administered with garlic extract after development of cardiac arrhythmias. Subsequently, the survived animals from the therapeutic study (four sheep) were administered with oleander without receiving any medication. Some blood constituents, including total antioxidant capacity, malondialdehyde, and troponin I, were compared between treated and untreated animals. RESULTS: Pretreatment with garlic extract reversed the arrhythmia caused by oleander to its previous normal rhythm in seven sheep, but, one sheep died of ventricular fibrillation. On therapeutic treatment, four sheep survived while two died of ventricular fibrillation. Dosing with oleander without receiving garlic extract resulted in death of all sheep due to ventricular fibrillation. Blood constituents did not show any significant changes between treated and untreated sheep, and before and after intoxication. CONCLUSIONS: Garlic extract reduced the case fatality from 100% to 12.5% and 33.3% as a prophylactic or therapeutic agent, respectively. Additionally, garlic extract delayed the time of onset of arrhythmias and prolonged the interval between intoxication and death of the animals. Garlic extract could be considered to be a potential and affordable antidote in oleander poisoning. However additional studies with a larger sample size and in other species need to be performed to confirm the results in this study. PMID- 23944749 TI - Genetic diversity and antimicrobial resistance profiles of Salmonella enterica serotype derby isolated from pigs, pork, and humans in France. AB - In France, Salmonella enterica serotypes Typhimurium and Derby are the most often isolated serotypes in pigs. Moreover, serotype Derby usually ranks between third and fourth in prevalence among human isolates in France. The aim of this study was to evaluate the genetic relationships between human and pig Salmonella Derby isolates based on their pulsed-field gel electrophoresis (PFGE) patterns after XbaI, BlnI, and SpeI restriction and on their antimicrobial resistance profiles. The 196 studied isolates were isolated in 2006 and 2007: 73 from fattening pigs, 27 from pork, and 96 from humans. Forty-four PFGE XbaI patterns were identified. A major pattern (SDX01) was identified for 96 isolates (49%). This pattern was common to pig, pork, and human isolates. Among the 146 isolates tested for their antimicrobial resistance, 84.2% (n=123) showed resistance to at least one antibiotic and 69.2% (n=101) were simultaneously resistant to at least streptomycin, sulfonamides, and tetracycline. Most of the isolates that are resistant to these three antibiotics also displayed the major SDX01 pattern. The use of two other restriction enzymes on a part of the panel (155 isolates) brought a significant increase in the discriminatory index, in particular for SDX01 strains. As Salmonella Derby is essentially isolated from pigs, and major resistance and PFGE patterns of isolates from pigs and pork were very similar to human isolates, human salmonellosis due to Salmonella Derby may be related to pigs. PMID- 23944748 TI - A fundamental relationship between hydrophobic properties and biological activity for the duocarmycin class of DNA-alkylating antitumor drugs: hydrophobic-binding driven bonding. AB - Two systematic series of increasingly hydrophilic derivatives of duocarmycin SA that feature the incorporation of ethylene glycol units (n = 1-5) into the methoxy substituents of the trimethoxyindole subunit are described. These derivatives exhibit progressively increasing water solubility along with progressive decreases in cell growth inhibitory activity and DNA alkylation efficiency with the incremental ethylene glycol unit incorporations. Linear relationships of cLogP with -log IC50 for cell growth inhibition and -log AE (AE = cell-free DNA alkylation efficiency) were observed, with the cLogP values spanning the productive range of 2.5-0.49 and the -log IC50 values spanning the range of 11.2-6.4, representing IC50 values that vary by a factor of 10(5) (0.008 to 370 nM). The results quantify the fundamental role played by the hydrophobic character of the compound in the expression of the biological activity of members in this class (driving the intrinsically reversible DNA alkylation reaction) and define the stunning magnitude of its effect. PMID- 23944750 TI - Enumeration of salmonella in feces of naturally infected pigs. AB - Quantification of Salmonella in asymptomatic pigs can be used to institute control measures and to assess risk of carcass contamination during slaughter. The objective of this study was to quantify the fecal concentration of Salmonella in naturally infected pigs. Individual fecal samples (positive [n=443], negative [n=1225] determined by microbiological culture) were submitted for direct quantitative real-time polymerase chain reaction (q-PCR). Direct q-PCR categorized 99.6% (1220/1225) of culture negative samples as negative. For culture positive samples, 15.4% (68/443) were detected by q-PCR, but only 3.4% (15/443) were within the direct q-PCR quantifiable range (>= 10(3) colony-forming units [CFU]/g of feces). Of these latter samples, the concentration range was 1.06 * 10(3) to 1.73 * 10(6) CFU/g feces. Of the 15 samples with high Salmonella concentrations, seven were collected from one pig and three samples were collected from its penmates. Direct q-PCR may be an alternative to traditional culture-dependent methods for detection of pigs with high fecal concentrations of Salmonella, but not for detection of pigs shedding low concentrations of Salmonella, which represented the majority of pigs in this study. When high shedding was detected it was clustered within a single pig and its penmates. These data contribute to quantitative risk assessments of the association between concentrations of Salmonella shed by pigs during the finishing phase and risk of carcass contamination at slaughter. PMID- 23944751 TI - Phytochemicals in lowbush wild blueberry inactivate Escherichia coli O157:H7 by damaging its cell membrane. AB - The antimicrobial activity and model of action of polyphenolic compounds extracted from lowbush wild blueberries (LWB) were studied against Escherichia coli O157:H7. Polyphenols in LWB were extracted using 80% vol/vol methanol and designated as total blueberry phenolics (TBP). The fraction was further separated by a C-18 Sep-Pak cartridge into monomeric phenolics acids (MPA) and anthocyanins plus proanthocyanidins (A&P). The A&P fraction was further separated into anthocyanins and proanthocyanidins using a LH-20 Sephadex column. Each fraction was diluted in 0.85% wt/vol NaCl, inoculated with E. coli O157:H7 to achieve 8 log colony-forming units (CFU)/mL, and incubated at 25 degrees C for 1 h. The survival populations of E. coli O157:H7 in the phenolic fractions were determined by a viable cell counts method. The permeability of the cell membrane of E. coli O157:H7 was determined using LIVE/DEAD viability assay, and the damage was visualized by using transmission electron microscopy (TEM). Significant (p<0.05) reductions of 5 log CFU/mL of E. coli O157:H7 were observed for MPA at 0.4 g/L gallic acid equivalents (GAE), A&P at 0.9 g/L GAE, and anthocyanins at 0.65 g/L GAE. Reductions of 6-7 CFU/mL were observed for MPA at 0.8 g/L GAE, A&P at 1.8 g/L GAE, and anthocyanins at 1.3 g/L GAE compared to the control. The cell membrane of E. coli O157:H7 exhibited a significantly increased permeability when treated with proanthocyanidins (0.15 g/L GAE), A&P (0.45 g/L GAE), anthocyanins (0.65 g/L GAE), and TBP (0.14 g/L GAE). TEM confirmed the inactivation and increased membrane permeability of E. coli O157:H7. This study demonstrated the antimicrobial effect of polyphenols from LWB against E. coli O157:H7 and the probable mode of action. PMID- 23944752 TI - Stability of Newton black films under mechanical stretch--a molecular dynamics study. AB - The stability of Newton black films (NBFs) under lateral mechanical stretch was investigated by nonequilibrium molecular dynamics (NEMD) simulations using force field parameters validated by accurate prediction of surface tensions. The applied strains accelerated film ruptures, enabling efficient measurements of the critical thicknesses of the films. Two representative surfactants, sodium dodecyl sulfate (SDS) for ionic surfactant and pentaethylene glycol monododecyl ether (C12EO5H) for nonionic surfactant, were investigated and compared. The predicted critical thickness of C12EO5H-coated film is smaller than that of the SDS-coated film, which is consistent with previously reported experimental observations. Our simulation results show that while the two surfactant-coated films exhibit similar dynamic properties attributed to the Marangoni-Gibbs effect, their surface structural characteristics are quite different. Consequently the two films demonstrate distinct rupture mechanisms in which rupture starts at uncovered water domains in the SDS-coated film, but at lateral surfactant/water interfaces in the C12EO5H-coated film. Our findings provide new insights into the stabilization mechanisms of NBFs and will facilitate the design and development of new films with improved properties. PMID- 23944753 TI - Density functional theory for protein transfer free energy. AB - We cast the problem of protein transfer free energy within the formalism of density functional theory (DFT), treating the protein as a source of external potential that acts upon the solvent. Solvent excluded volume, solvent-accessible surface area, and temperature dependence of the transfer free energy all emerge naturally within this formalism, and may be compared with simplified "back of the envelope" models, which are also developed here. Depletion contributions to osmolyte induced stability range from 5 to 10 kBT for typical protein lengths. The general DFT transfer theory developed here may be simplified to reproduce a Langmuir isotherm condensation mechanism on the protein surface in the limits of short-ranged interactions, and dilute solute. Extending the equation of state to higher solute densities results in non-monotonic behavior of the free energy driving protein or polymer collapse. Effective interaction potentials between protein backbone or side chains and TMAO are obtained, assuming a simple backbone/side chain two-bead model for the protein with an effective 6-12 potential with the osmolyte. The transfer free energy deltag shows significant entropy: d(deltag)/dT ~ 20 kB for a 100-residue protein. The application of DFT to effective solvent forces for use in implicit-solvent molecular dynamics is also developed. The simplest DFT expressions for implicit-solvent forces contain both depletion interactions and an "impeded-solvation" repulsive force at larger distances. PMID- 23944754 TI - Gerstmann-Straussler-Scheinker syndrome with variable phenotype in a new kindred with PRNP-P102L mutation. AB - Gerstmann-Straussler-Scheinker syndrome (GSS) is a dominantly inherited disorder belonging to the group of transmissible human spongiform encephalopathies or prion diseases. Several families affected by GSS with patients carrying mutations in the prion protein gene have been described worldwide. We report clinical, genealogical, neuropathology and molecular study results from two members of the first Argentine kindred affected by GSS. Both family members presented a frontotemporal-like syndrome, one with and the other without ataxia, with different lesions on neuropathology. A Pro to Leu point mutation at codon 102 (P102L) of the prion protein gene was detected in one of the subjects studied. The pathogenic basis of phenotypic variability observed in this family remains unclear, but resembles that observed in other P102L GSS patients from the same family. PMID- 23944755 TI - The impact of CTLA4 and PTPN22 genes polymorphisms on long-term renal allograft function and transplant outcomes. AB - Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) downregulates the immune system. Lymphoid tyrosine phosphatase (Lyp)--PTPN22 protein--is suggested to be negative regulator of T-cell reaction. There are several polymorphisms in the CTLA4 and PTPN22 genes, which can influence the immune response and allograft function after kidney transplantation. The aim of this study was to examine the impact of CTLA4 and PTPN22 genes polymorphisms on the long-term renal transplant function and recipients' outcomes during a 5-year follow-up observation. The study enrolled 268 Caucasian renal transplant recipients. Genotyping of the rs231775 (+49AG) CTLA4 gene polymorphism was performed using real-time PCR and rs2476601 (C1858T) PTPN22 gene polymorphism using PCR-RFLP method. The 5-year graft survival rate was 81.7%. Dialysis was necessary in 22 (8%) patients, 7 (2.6%) patients died and 20 (7.4%) switched to another transplantation center. We found no association between studied polymorphisms and graft loss/dialysis. Comparison of the distribution of the +49AG CTLA4 and C1858T PTPN22 genes polymorphisms genotypes among dead and living patients showed no statistically significant differences. Above results suggest that the rs231775 (+49AG) CTLA4 and rs2476601 (C1858T) PTPN22 genes polymorphisms are not associated with long-term allograft failure, graft loss and mortality after transplantation. PMID- 23944756 TI - Bone dissemination of prostate cancer after holmium laser enucleation of the prostate: a case report and a review of the literature. AB - We report a case of dissemination of prostate cancer after holmium laser enucleation of the prostate in an 80-year-old patient. The patient presented at hospital because of nocturia. Transrectal ultrasound-guided biopsy was carried out because of high serum prostate-specific antigen (3.55 ng/mL), but it showed no malignancies. Benign prostate hyperplasia was diagnosed, and he was started on an alpha1-blocker. Although the urinary symptom improved with silodosin, acute urinary retention occurred 3 years after therapy began. Holmium laser enucleation of the prostate for relief of bladder outlet obstruction enabled discharge of urine. Pathological examination of the resected tissue found adenocarcinoma with a high Gleason score, 4 + 5. Serum alkaline phosphatase increased rapidly after holmium laser enucleation, and bone scintigraphy confirmed multiple bone metastases. Prostate cancer, T1bN0M1b, was diagnosed. PMID- 23944757 TI - Seminal androgens, oestradiol and progesterone in oligoasthenoteratozoospermic men with varicocele. AB - This study aimed to assess seminal androgens, oestradiol, progesterone levels in oligoasthenoteratozoospermic (OAT) men with varicocele (Vx). In all, 154 men with matched age and body mass index were investigated that were divided into healthy fertile controls (n = 35), OAT men with Vx (n = 55), OAT men without Vx (n = 64). They were subjected to assessment of semen parameters, seminal levels of testosterone (T), androstenedione (A), 5alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol), oestradiol (E2 ), 17-hydroxyprogesterone (17-OHP) and progesterone (P). Seminal levels of T and A were significantly decreased where seminal levels of 3 alpha-diol, E2 , 17-OHP, P were significantly higher in OAT men with/without Vx compared with fertile controls. Sperm count, sperm motility and sperm normal forms percentage demonstrated significant positive correlation with seminal T and A and significant negative correlation with seminal 3 alpha-diol, E2 , P. It is concluded that in fertile men, seminal T and A are significantly increased and seminal 3 alpha-diol, E2 , 17-OHP, P are significantly decreased compared with infertile OAT men with/without Vx. Association of Vx demonstrated a nonsignificant influence on these hormonal levels in OAT cases. Sperm count, sperm motility and sperm normal forms demonstrated significant positive correlation with seminal T, A and significant negative correlation with seminal 3 alpha-diol, E2 , P. PMID- 23944758 TI - mobilityRERC state of the science conference: Considerations for developing an evidence base for wheeled mobility and seating service delivery. AB - PURPOSE: This article, developed as background content for discussion during the Mobility Rehabilitation Engineering Research Center State of the Science Conference, reviews research surrounding wheeled mobility and seating (WMS) service delivery, discusses the challenges of improving clinical decision-making, and discusses research approaches used to study and improve health services in other practice areas that might be leveraged to develop the evidence base for WMS. METHODS: Narrative literature review. RESULTS AND CONCLUSIONS: An overview of existing research found general agreement across models of WMS service delivery but little high quality evidence to support the recommended approaches and few studies of the relationship between service delivery steps and individual patient outcomes. The definition of successful clinical decision-making is different for different stakeholders. Clinical decision-making should incorporate the best available evidence along with patient values, preferences, circumstances, and clinical expertise. To advance the evidence base for WMS service delivery, alternatives to randomized controlled trials should be considered and reliable and valid outcome measures developed. Technological advances offer tremendous opportunities for individuals with complex rehabilitation technology needs. However, with ongoing scrutiny of WMS service delivery there is an increased need for evidence to support the clinical decision making process and to support evidence-based coverage policies for WMS services and technologies. IMPLICATIONS FOR REHABILITATION: An evidence base for wheeled mobility and seating services is an important component of the clinical decision making process. At present, there is little evidence regarding essential components of the wheeled mobility and seating evaluation or the relationship between the evaluation process and patient outcomes. Many factors can confound this relationship and present challenges to research in this area. All stakeholders (i.e. clinicians, rehabilitation technology suppliers, manufacturers, researchers, payers, policy makers, and wheelchair users) need to work together to develop and support an evidence base for wheeled mobility and seating service delivery. PMID- 23944759 TI - Message from the editor. PMID- 23944760 TI - An exploratory study of older adults' perspectives of spirituality. AB - Spirituality is multifaceted as it is a nonphysical meaning placed upon existence and is unique to each individual. This exclusivity makes it difficult to measure or analyze, but the need remains to discover answers to questions regarding spirituality, human life, and its factors. This exploratory, pilot study involved interviewing three older adults to address issues of individual perceptions of spirituality, integration of spirituality in daily life, and utilization of spirituality to address individual needs. Thematic results indicate spirituality is a principle-based and intrinsic factor integrated into daily life. It involves motivation and meaning as spirituality addresses personal needs by providing strength and inspiration. Finally, spirituality affects chosen occupations by providing a sense of purpose. PMID- 23944761 TI - Exploring the spiritual meaning of suffering: a strategy of self-help, recovery, and hope. AB - This paper explores the meaning of suffering from the spiritual perspective of Anthroposophy, which considers suffering as a powerful force in achieving the inner knowledge necessary for change and transformation. Representing the philosophy of recovery-oriented models, which emphasize healing through empowerment, self-help, and transformation, Anthroposophy can be used as an effective strategy in treating people whose suffering cannot be prevented. The relationships between suffering and inner knowledge, as well as different aspects of the meaning of suffering, are described. Finally, the relevance of this inquiry to occupational therapy philosophy and practice is discussed, and examples of clinical interventions are presented. PMID- 23944762 TI - Toward a flexible framework for understanding spirituality. AB - Occupational therapy and nursing literature share a common theoretical journey of the concept, spirituality. This paper draws on the nursing literature's theoretical progress in the area of spirituality in order to propose a theoretical framework for occupational therapy models. It is suggested that discourse analysis and the examination of personal and professional worldviews will contribute to theorizing of the concept of spirituality within the discipline of occupational therapy and that it is preferable to represent spirituality as a flexible framework rather than a fixed definition. PMID- 23944763 TI - A model of occupational empowerment for marginalized populations in community environments. AB - Globally there are individuals who are marginalized from mainstream society due to problems such as physical or psychological impairment, poor socio-economic circumstances, and occupational deprivation. Many develop learned helplessness syndrome, rendering them unable to control their lives and their destinies. This paper proposes a Model of Occupational Empowerment for providing services to these community populations. The model, a grounded theory, emerged from our work at a homeless shelter for women and children. Disempowering environments in the past had caused learned helplessness in the women at the shelter. Occupational engagement was used to empower them. We contend that the model may be used to guide occupational therapy practice with marginalized individuals and families in a number of community environments. PMID- 23944765 TI - From the internet editor. PMID- 23944764 TI - An overview of evidence-based support for the therapeutic use of music in occupational therapy. AB - Music is a modality present in occupational therapy, yet little educational material about music exists within the field. This paper presents a myriad of possibilities for practitioners considering using music, providing a resource of research within and outside the field. Applications are organized around enhancement of occupational performance, utilizing three distinct methods: (1) Music-assisted occupation, (2) Music as occupation, and (3) Music in preparation for occupation. The potential effects of music in the areas of pain/discomfort, movement, emotion, cognition, self-expression/communication, relationships/groups, culture/society and community, and personal meaning/motivation, are discussed in terms of enhancing occupation. PMID- 23944768 TI - Evaluation of a dried blood and plasma collection device, SampleTanker((r)), for HIV type 1 drug resistance genotyping in patients receiving antiretroviral therapy. AB - Whatman 903 filter paper is the only filter paper that has been used for HIV drug resistance (HIVDR) genotyping in resource-limited settings. In this study, we evaluated another dried blood specimen collection device, termed SampleTanker((r)) (ST), for HIVDR genotyping. Blood specimens from 123 antiretroviral therapy (ART)-experienced patients were used to prepare ST whole blood and ST plasma specimens; they were then stored at ambient temperature for 2 or 4 weeks. The remaining plasma specimens were stored at -80 degrees C and used as frozen plasma controls. Frozen plasma viral load (VL) was determined using the Roche Amplicor HIV-1 Monitor test, v.1.5 and 50 specimens with VL >=3.00 log10 copies/ml were genotyped using the broadly sensitive genotyping assay. The medium VL for the 50 frozen plasma specimens with VL >=3.00 log10 was 3.58 log10 copies/ml (IQR: 3.32-4.11) and 96.0% (48/50) of them were genotyped. Comparing to frozen plasma specimens, significantly lower genotyping rates were obtained from ST whole blood (48.98% and 42.85%) and ST plasma specimens (36.0% and 36.0%) stored at ambient temperature for 2 and 4 weeks, respectively (p<0.001). Nucleotide sequence identity and resistance profile analyses between the matched frozen plasma and ST whole blood or ST plasma specimens revealed high nucleotide sequence identities and concordant resistance profiles (98.1% and 99.0%, and 96.6% and 98.9%, respectively). Our results indicate that with the current design, the ST may not be the ideal dried blood specimen collection device for HIVDR monitoring for ART patients in resource-limited settings. PMID- 23944769 TI - Correlation between functionality preference of Ru carbenes and exo/endo product selectivity for clarifying the mechanism of ring-closing enyne metathesis. AB - Functionality preferences of metathesis Ru carbenes to various alkenes and alkynes with electronic and steric diversity were determined by using time dependent fluorescence quenching. The functionality preferences depend not only on the properties of multiple bonds but also on the ligands on Ru. There was a good correlation between functionality preference and the metathesis reaction outcome. The correlation between functionality preference and exo/endo product ratio offers a solution to resolve the mechanistic issue related with alkene- vs alkyne-initiated pathway in ring-closing enyne metathesis. The correlation indicates the preference is likely to dictate the reaction pathway and eventually the outcome of the reaction. The Ru catalyst favoring alkyne over alkene provides more endo product, indicating that the reaction mainly initiates at the alkyne. By changing the substitution pattern, the preference can be reversed to give an exclusive exo product. PMID- 23944767 TI - Mitochondrial DNA variation and changes in adiponectin and endothelial function in HIV-infected adults after antiretroviral therapy initiation. AB - Studies in persons of European descent have suggested that mitochondrial DNA (mtDNA) haplogroups influence antiretroviral therapy (ART) toxicity. We explored associations between mtDNA variants and changes in endothelial function and biomarkers among non-Hispanic white, ART-naive subjects starting ART. A5152s was a substudy of A5142, a randomized trial of initial class-sparing ART regimens that included efavirenz or lopinavir/ritonavir with nucleoside reverse transcriptase inhibitors (NRTIs), or both without NRTIs. Brachial artery flow mediated dilation (FMD) and cardiovascular biomarker assessments were performed at baseline and at weeks 4 and 24. Ten haplogroup-defining mtDNA polymorphisms were determined. FMD and biomarker changes from baseline to week 24 by mtDNA variant were assessed using Wilcoxon rank-sum tests. Thirty-nine non-Hispanic white participants had DNA and 24-week data. The nonsynonymous m.10398A>G mtDNA polymorphism (N=8) was associated with higher median baseline adiponectin (5.0 vs. 4.2 MUg/ml; p=0.003), greater absolute (-1.9 vs. -0.2 MUg/ml) and relative ( 33% vs. -3%) adiponectin decreases (p<0.001 for both), and lower week 24 brachial artery FMD (3.6% vs. 5.4%; p=0.04). Individual mtDNA haplogroups, including haplogroups H (N=13) and U (N=6), were not associated with adiponectin or FMD changes. In this small pilot study, adiponectin and brachial artery FMD on ART differed in non-Hispanic whites with a nonsynonymous mtDNA variant associated with several human diseases. These preliminary findings support the hypothesis that mtDNA variation influences metabolic ART effects. Validation studies in larger populations and in different racial/ethnic groups that include m.10398G carriers are needed. PMID- 23944771 TI - Vascular progenitor cells with decalcifying potential: a step toward prevention or treatment of atherosclerotic vascular calcification? PMID- 23944770 TI - First test effect in intravenous glucose tolerance testing. AB - AIMS: Intravenous glucose tolerance testing (IVGTT) is a common test of beta-cell function in which a glucose load is administered and insulin and/or C-peptide responses are monitored. Since the first IVGTT may be more stressful and stress may alter beta-cell secretion or hepatic insulin extraction, we asked whether there was a first test effect. METHODS: Insulin and C-peptide responses were compared from two sequential IVGTTs performed within 6 months during staging for the Diabetes Prevention Trial-Type 1 (DPT-1) in 368 people at high risk for type 1 diabetes. Insulin data (1+3 min) were used because the first phase insulin response (and peak insulin concentration) occurs within this time frame. Areas under the curve (AUC) calculations represent early insulin or C-peptide responses from 0 through 10 min post-glucose challenge. RESULTS: More than half of all subjects were found to have first test values lower than the second. This was true for all measures of both insulin and C-peptide but the frequency was significantly different only for insulin measures corrected for basal and for insulin AUC (p < 0.05). However, for subjects (n = 99) whose 1+3 min insulin response was <10th percentile on the first test, there was a significant increase on the second test (p < 0.05). The C-peptide: insulin ratio did not change significantly between tests, indicating that differences are due to changes in beta-cell secretion rather than hepatic insulin uptake. CONCLUSIONS: A statistically significant first test effect occurs during the IVGTT attributable to variations in insulin secretion rather than hepatic uptake. PMID- 23944772 TI - Addition of plerixafor for CD34+ cell mobilization in six healthy stem cell donors ensured satisfactory grafts for transplantation. AB - BACKGROUND: In allogeneic hematopoietic stem cell (HSC) transplantation, collection of a sufficient number of HSCs at a fixed time point is crucial. For HSC mobilization into the peripheral blood, the standard regimen, that is, granulocyte-colony-stimulating factor (G-CSF), may be inadequate. Use of plerixafor as adjuvant to G-CSF is so far off-label in healthy donors. STUDY DESIGN AND METHODS: We present six cases in which the "just-in-time" addition of plerixafor ensured proper CD34+ collection from healthy donors with insufficient G-CSF mobilization. In four of these cases a high number of CD34+ cells was needed due to subsequent CD34+ selection or haploidentical transplantation. RESULTS: From all six donors a sufficient number of CD34+ cells was obtained by using plerixafor as an adjuvant to G-CSF. This treatment regimen resulted in only mild side effects for the donor. CONCLUSION: We have presented six cases with different causes leading to insufficient G-CSF mobilization in allogeneic donors and in which the administration of plerixafor just-in-time ensured a proper graft for transplantation. PMID- 23944773 TI - Nurse leaders must have better support. PMID- 23944791 TI - Revolving door of nurse directors prompts professional concern. PMID- 23944797 TI - Securing a shorter stay in hospital. AB - People with diabetes are experiencing life-threatening and preventable complications in hospital because of poor management of their diabetes. A shortage of specialist nursing staff is contributing to the problem. Improvements in inpatient care achieved by a nursing team in Gloucestershire show that progress is possible. PMID- 23944798 TI - After a baby has died. AB - Princess Alexandra Hospital in Harlow has developed and innovative staff training course, 'Death of a Baby', which has improved the care provided to parents who have lost a baby. It is open to all hospital staff, who are taught how to communicate sensitively and how to answer parents' questions about practical issues. The course also equips staff to cope with their own feelings of distress and loss in such a situation, and to be able to support each other. PMID- 23944799 TI - New light on Seacole. AB - The discovery of a signed letter by Crimean nursing heroine Mary Seacole to a War Office official may give an important clue that she was lobbying to be allowed to nurse British soldiers in India. Together with a letter from another anonymous nurse, and contemporary news reports, it reveals and active and well regarded nurse leader who knew how to network. PMID- 23944805 TI - Starting out - communication skills enabled me to reassure patient about operation. PMID- 23944812 TI - Schwartz Center Rounds are one way to boost compassion. PMID- 23944813 TI - Edith Cavell's life and work deserve to be remembered. PMID- 23944814 TI - It is time to speak loudly, lobby MPs and respond to poor media coverage. PMID- 23944816 TI - Obstructive GPs waste resources as well as delaying treatment. PMID- 23944817 TI - Private finance initiative is to blame for the crisis at Barts. PMID- 23944818 TI - Holby City boosts its ratings by undermining organ donation. PMID- 23944819 TI - Searching for London set 463 who started training in 1980. PMID- 23944820 TI - Patient concern calls for an observer in every hospital. PMID- 23944821 TI - Used compassionately, Liverpool Care Pathway is a useful tool. PMID- 23944823 TI - Raising awareness of men's risk of premature death. AB - There is growing evidence to suggest that men are at increased risk of premature death from a broad range of health conditions. With the government's mandate to reduce premature death, it is necessary to have an understanding of the health challenges faced by men. This article provides an overview of mortality data for men and women aged 15-64, with a focus on those aged 15-54, in England and Wales during 2011. Mortality data are viewed in relation to the main reasons for premature death in the male population. Initiatives aimed at addressing the health and social care needs of men are identified to raise awareness of the importance of targeting this population to reduce premature mortality. PMID- 23944824 TI - Reducing alcohol-related health risks: the role of the nurse. AB - The negative effects of alcohol consumption are increasingly being recognised in the UK, with statistics highlighting the health and social problems associated with the misuse of alcohol. Consequently, nurses need to consider their role in educating and advising patients about 'safe' drinking limits. This article identifies some of the problems with adhering to such safe drinking limits, for example, the miscalculation of alcohol units. In addition, the article highlights nursing interventions that can be used with all patients, not just those presenting with alcohol-related problems, to increase awareness of the negative effects of harmful alcohol consumption. PMID- 23944825 TI - Principles of temperature monitoring. AB - Maintaining optimum body temperature is essential to life, and taking and recording a patient's temperature is a fundamental nursing skill. Deviation from the normal range of body temperature can be an important clinical indicator of altered physiological status requiring further investigation. Correct technique and careful recording are important for accuracy because clinicians rely on clinical observations to make diagnoses and decide on treatment. Nurses need to be able to interpret single stand-alone temperature recordings as well as sequential pattern recordings in the context of safe and acceptable physiological boundaries. PMID- 23944826 TI - Back pain. PMID- 23944827 TI - Better safe than sorry. PMID- 23944829 TI - Players in theatre for emergencies. PMID- 23944830 TI - Ambassador for hospice care. PMID- 23944831 TI - Student life - tomorrow's leaders today. PMID- 23944832 TI - Cyclist-motorist crash patterns in Denmark: a latent class clustering approach. AB - OBJECTIVE: The current study aimed at uncovering patterns of cyclist-motorist crashes in Denmark and investigating their prevalence and severity. The importance of implementing clustering techniques for providing a holistic overview of vulnerable road users' crash patterns derives from the need to prioritize safety issues and to devise efficient preventive measures. METHOD: The current study focused on cyclist-motorist crashes that occurred in Denmark during the period between 2007 and 2011. To uncover crash patterns, the current analysis applied latent class clustering, an unsupervised probabilistic clustering approach that relies on the statistical concept of likelihood and allows partial overlap across clusters. RESULTS: The analysis yielded 13 distinguishable cyclist motorist latent classes. Specific crash patterns for urban and rural areas were revealed. Prevalent features that allowed differentiating the latent classes were speed limit, infrastructure type, road surface conditions, number of lanes, motorized vehicle precrash maneuvers, the availability of a cycle lane, cyclist intoxication, and helmet wearing behavior. After the latent class clustering, the distribution of cyclists' injury severity within each cluster was analyzed. CONCLUSIONS: The latent class clustering approach provided a comprehensive and clear map of cyclist-motorist crash patterns. The results are useful for prioritizing and resolving safety issues in urban areas, where there is a significant share of cyclists potentially involved in multiple hazardous situations or where extensive bicycle sharing programs are planned. PMID- 23944833 TI - HIV/AIDS in the Southern USA: a disproportionate epidemic. AB - This research synthesis examined HIV/AIDS surveillance and health care financing data and reviewed relevant research literature to describe HIV epidemiology, outcomes, funding, and contributing factors to the HIV epidemic in the Southern USA with particular focus on a group of Southern states with similar demographic and disease characteristics and comparable HIV epidemics (Alabama, Georgia, Florida, Los Angeles, Mississippi, North Carolina, South Carolina, Tennessee, and Texas). These states are hereafter referred to as "targeted Southern states." Eight of the 10 states with the highest HIV diagnosis rates in 2011 were in the Southern USA; six were targeted states. Forty-nine percent of HIV diagnoses were in the South in 2011, which contains only 37% of the US population. The targeted states region had the highest HIV diagnosis rate than any other US region in 2011. The South was also found to have the highest HIV-related mortality and morbidity rates in the USA. The high levels of poverty, HIV-related stigma, and STDs found in the South, particularly in the targeted Southern states, likely contribute to greater HIV incidence and mortality. The disproportionate impact of HIV in the South, particularly among targeted states, demonstrates a critical need to improve HIV prevention and care and address factors that contribute to HIV disease in this region. PMID- 23944834 TI - Comparing brain-derived neurotrophic factor and ciliary neurotrophic factor secretion of induced neurotrophic factor secreting cells from human adipose and bone marrow-derived stem cells. AB - Adipose derived stem cells (ADSCs) and bone marrow stem cells (BMSCs) may be equally beneficial in treating neurodegenerative diseases. However, ADSCs have practical advantages. In this study, we aimed to induce neurotrophic factors secreting cells in human ADSCs. Then, we compared the level of brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) secretion in neurotrophic factors secreting cells from human adipose and bone marrow-derived stem cells. Isolated human ADSCs and BMSCs were induced to neurotrophic factor (NTF)-secreting cells. The levels of expression and secretion of BDNF and CTNF of induced cells were assessed using immunocytochemical, Real-Time polymerase chain reaction, and enzyme linked immunosorbent assay (ELISA). The level of BDNF significantly increased in both the induced mesenchymal stem cells (MSCs) relative to ADSCs and the BMSCs (P < 0.01). Moreover, ELISA analysis showed that the release of BDNF in the induced BMSCs was almost twofold more than the induced ADSCs. Overall, NTF-secreting factor cells derived BMSCs and ADSCs could secret a range of different growth factors. Therefore, the variation in neurotrophic factors of different induced MSC populations suggest the possible beneficial effect of each specific kind of neurotrophic factor secreting cells for the treatment of a particular neurodegenerative disease. PMID- 23944835 TI - High-contrast, reversible thermal conductivity regulation utilizing the phase transition of polyethylene nanofibers. AB - Reversible thermal conductivity regulation at the nanoscale is of great interest to a wide range of applications such as thermal management, phononics, sensors, and energy devices. Through a series of large-scale molecular dynamics simulations, we demonstrate a thermal conductivity regulation utilizing the phase transition of polyethylene nanofibers, enabling a thermal conductivity tuning factor of as high as 12, exceeding all previously reported values. The thermal conductivity change roots from the segmental rotations along the polymer chains, which introduce along-chain morphology disorder that significantly interrupts phonon transport along the molecular chains. This phase transition, which can be regulated by temperature, strain, or their combinations, is found to be fully reversible in the polyethylene nanofibers and can happen at a narrow temperature window. The phase change temperature can be further tuned by engineering the diameters of the nanofibers, making such a thermal conductivity regulation scheme adaptable to different application needs. The findings can stimulate significant research interest in nanoscale heat transfer control. PMID- 23944836 TI - Characterization of micellar systems produced by new amphiphilic conjugates of poly(ethylene glycol). AB - This study proposes polymeric micelles produced using new amphiphilic conjugates between amino- or carboxy-mPEG2000 and three different alpha-lipoamino acids (PEG LAA). The characterization of these colloidal systems showed CMC values, in the order of 10(-5 )M, that are interesting in the view of an in vivo administration. The PEG-LAA micelles also showed a good stability at 37 degrees C and upon dilution in aqueous media. Using a colored probe as a model lipophilic compound, the loading efficiency and in vitro release profile were also outlined. PMID- 23944837 TI - Thermoresponsive ophthalmic poloxamer/tween/carbopol in situ gels of a poorly water-soluble drug fluconazole: preparation and in vitro-in vivo evaluation. AB - The purpose of the present study was to optimize the formulations of the thermoresponsive ophthalmic in situ gels of a poorly water-soluble drug fluconazole (FLU) and evaluate the in vitro and in vivo properties of the formulations. The thermoresponsive ophthalmic FLU in situ gels were prepared by mixing FLU, Poloxamer407, Tween80, benzalkonium chloride and carbopol934 in borate buffer solution. The in vivo eye irritation tests and ophthalmic absorption were carried out in rabbits. The formulation compositions influenced the physicochemical properties of FLU in situ gels. The amount of poloxamer407 in the formulation was the main factor that affected the sol-gel transition temperature of the products. Tween80 not only improved the solubility of the FLU but also affected the products' sol-gel transition temperature. In this study, sol-gel transition temperature was not affected by carbopol934. However, carbopol934 affected pH value, transparency and gelling capacity of the products. The product of the optimized formulation was a pseudoplastic fluid and its sol gel transition temperature was 30.6 +/- 1.2 degrees C. The autoclaving test showed that the sol-gel transition temperature, the flow ability and the flow behavior of the test samples did not change obviously after autoclaving sterilization at 121 degrees C and 15 psi for 20 min, thus the autoclaving was an acceptable sterilization method for this preparation. The thermoresponsive ophthalmic FLU in situ gels' in vivo ophthalmic absorption was superior to the conventional FLU eye drop. In conclusion, the thermoresponsive ophthalmic FLU in situ gel is a better alternative than the FLU eye drop. PMID- 23944838 TI - PLA-PEG-PLA copolymer-based polymersomes as nanocarriers for delivery of hydrophilic and hydrophobic drugs: preparation and evaluation with atorvastatin and lisinopril. AB - Tri-block poly(lactide)-poly(ethylene glycol)-poly(lactide) (PLA-PEG-PLA) copolymers were synthesized and used to prepare polymersomes loaded separately by the hydrophobic and hydrophilic model drugs, atorvastatin and lisinopril, respectively. The resulting nanostructures were characterized by various techniques such as FTIR, DSC, PCS and AFM. The polymersomes exhibited high encapsulation efficiencies of almost 78% and 70.8% for atorvastatin and lisinopril, respectively. Investigation on FTIR and DSC results revealed that such a high encapsulation efficiency is due to strong interaction between atorvastatin and the copolymer. The impact of drug/copolymer ratio and copolymer composition on drug-loading efficiency and drug release behavior were also studied. The results showed that in case of lisinopril, polymersomes exhibited a triphasic drug release, while for atorvastatin a biphasic release profile was obtained. Overall, the results indicated that PLA-PEG-PLA polymersomes can be considered as a promising carrier for both hydrophilic and hydrophobic drugs. PMID- 23944839 TI - Optimization and stabilization of electrodeposited Cu2ZnSnS4 photocathodes for solar water reduction. AB - Cu2ZnSnS4 (CZTS) is a promising p-type semiconductor that has not yet been extensively investigated for solar fuel production via water splitting. Here, we optimize and compare two different electrodeposition routes (simultaneous and sequential) for preparing CZTS electrodes. More consistent results are observed with the simultaneous route. In addition, the effect of etching and the presence of a CdS buffer layer on the photocurrent are investigated. Finally, we demonstrate for the first time the stabilization of these electrodes using protecting overlayers deposited by atomic layer deposition (ALD). Our best performing protected electrodes (Mo/CZTS/CdS/AZO/TiO2/Pt) exhibited a photocurrent of over 1 mA cm(-2) under standard one sun illumination conditions and a significant improvement in stability over unprotected electrodes. PMID- 23944840 TI - Dissociation between goal-directed and discrete response localization in a patient with bilateral cortical blindness. AB - We investigated localization performance of simple targets in patient TN, who suffered bilateral damage of his primary visual cortex and shows complete cortical blindness. Using a two-alternative forced-choice paradigm, TN was asked to guess the position of left-right targets with goal-directed and discrete manual responses. The results indicate a clear dissociation between goal-directed and discrete responses. TN pointed toward the correct target location in approximately 75% of the trials but was at chance level with discrete responses. This indicates that the residual ability to localize an unseen stimulus depends critically on the possibility to translate a visual signal into a goal-directed motor output at least in certain forms of blindsight. PMID- 23944842 TI - Probing the electronic properties of trimesic acid nanoporous networks on Au(111). AB - Nowadays molecular nanoporous networks have numerous uses in surface nanopatterning applications and in studies of host-guest interactions. Trimesic acid (TMA), a benzene derivative with three carboxylic groups, is a marvelous building block for forming 2D H-bonded porous networks. Here, we report a low temperature study of the nanoporous "chicken-wire" superstructure formed by TMA molecules adsorbed on a Au(111) surface. Distinct preferential orientations of the porous networks on Au(111) lead to the formation of peculiar TMA polymorphs that are stabilized only at the boundary between rotational molecular domains. Scanning tunneling microscopy (STM) and spectroscopy are used to investigate the electronic properties of both the molecular building blocks and the pores. Sub molecular-resolution imaging and spatially resolved electronic spectroscopy reveal a remarkable change in the appearance of the molecules in the STM images at energies in the range of the lowest unoccupied molecular orbital, accompanied by highly extended molecular wave functions into the pores. The electronic structure of the pores reflects a weak confinement of surface electrons by the TMA network. Our experimental observations are corroborated by density-functional theory-based calculations of the nanoporous structure adsorbed on Au(111). PMID- 23944843 TI - Lessons from (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3 b]pyridazin-3-yl)ethyl)quinoline (PF-04254644), an inhibitor of receptor tyrosine kinase c-Met with high protein kinase selectivity but broad phosphodiesterase family inhibition leading to myocardial degeneration in rats. AB - The hepatocyte growth factor (HGF)/c-Met signaling axis is deregulated in many cancers and plays important roles in tumor invasive growth and metastasis. An exclusively selective c-Met inhibitor (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl) [1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (8) was discovered from a highly selective high-throughput screening hit via structure-based drug design and medicinal chemistry lead optimization. Compound 8 had many attractive properties meriting preclinical evaluation. Broad off-target screens identified 8 as a pan-phosphodiesterase (PDE) family inhibitor, which was implicated in a sustained increase in heart rate, increased cardiac output, and decreased contractility indices, as well as myocardial degeneration in in vivo safety evaluations in rats. Compound 8 was terminated as a preclinical candidate because of a narrow therapeutic window in cardio-related safety. The learning from multiparameter lead optimization and strategies to avoid the toxicity attrition at the late stage of drug discovery are discussed. PMID- 23944844 TI - 3D motion of DNA-Au nanoconjugates in graphene liquid cell electron microscopy. AB - Liquid-phase transmission electron microscopy (TEM) can probe and visualize dynamic events with structural or functional details at the nanoscale in a liquid medium. Earlier efforts have focused on the growth and transformation kinetics of hard material systems, relying on their stability under electron beam. Our recently developed graphene liquid cell technique pushed the spatial resolution of such imaging to the atomic scale but still focused on growth trajectories of metallic nanocrystals. Here, we adopt this technique to imaging three-dimensional (3D) dynamics of soft materials instead, double strand (dsDNA) connecting Au nanocrystals as one example, at nanometer resolution. We demonstrate first that a graphene liquid cell can seal an aqueous sample solution of a lower vapor pressure than previously investigated well against the high vacuum in TEM. Then, from quantitative analysis of real time nanocrystal trajectories, we show that the status and configuration of dsDNA dictate the motions of linked nanocrystals throughout the imaging time of minutes. This sustained connecting ability of dsDNA enables this unprecedented continuous imaging of its dynamics via TEM. Furthermore, the inert graphene surface minimizes sample-substrate interaction and allows the whole nanostructure to rotate freely in the liquid environment; we thus develop and implement the reconstruction of 3D configuration and motions of the nanostructure from the series of 2D projected TEM images captured while it rotates. In addition to further proving the nanoconjugate structural stability, this reconstruction demonstrates 3D dynamic imaging by TEM beyond its conventional use in seeing a flattened and dry sample. Altogether, we foresee the new and exciting use of graphene liquid cell TEM in imaging 3D biomolecular transformations or interaction dynamics at nanometer resolution. PMID- 23944845 TI - KHA-CARI Guideline: peritonitis treatment and prophylaxis. PMID- 23944846 TI - Synthesis and antitumor activity of tetrandrine derivatives. AB - Tetrandrine possesses antitumor activity, however, only a few studies on its structure modification were reported. To improve the antitumor activity of tetrandrine, 20 new tetrandrine derivatives were designed and synthesized by Sonogashira and Suzuki reactions. Their antitumor activities were evaluated against three tumor cell lines including A549, HepG2, and BGC-823 by methyl thiazolyl tetrazolium assay with taxol as a positive control. The results showed that compounds 2c and 2g were highly potent against BGC-823 cell line, and compounds 1i and 1k showed particular activity against HepG2 cells. These results demonstrated that compounds 1i, 1k, 2c, and 2g were promising leads for further investigation. PMID- 23944847 TI - Editorial comment from Dr Smith to Standardized assessment of complications in a contemporary series of European patients undergoing radical cystectomy. PMID- 23944848 TI - Identification of candidate biomarkers for hepatocellular carcinoma in plasma of HCV-infected cirrhotic patients by 2-D DIGE. AB - BACKGROUND: The current methods available for screening and detecting hepatocellular carcinoma (HCC) have insufficient sensitivity and specificity, and only a low percentage of diagnosis of small tumours is based on these assays. Because HCC is usually asymptomatic at potentially curative stages, identification of biomarkers for the early detection of HCC is essential to improve patient survival. AIM: The aim of this study was to identify candidate markers for HCC development in the plasma from hepatitis C virus (HCV)-infected cirrhotic patients. METHODS: We compared protein expression profiles of plasma samples from HCV-infected cirrhotic patients with and without HCC, using two dimensional fluorescence difference gel electrophoresis (2-D DIGE) coupled with MALDI-TOF/TOF mass spectrometry. The 2-D DIGE results were analysed statistically using DecyderTM software, and verified by western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS: In the plasma of HCV-infected HCC patients, we observed decreased expression of complement component 9, ficolin-3 (FCN3), serum amyloid P component (SAP), fibrinogen-gamma and immunoglobulin gamma-1 chain, and increased expression of vitronectin (VTN) and galectin-3 binding protein (G3BP) by DIGE analysis. ELISA confirmed DIGE results for VTN and G3BP but not for SAP or FCN3 in a larger patient population. CONCLUSIONS: The proteins VTN and SAP are candidate biomarkers for HCC development in HCV-infected cirrhotic patients. PMID- 23944849 TI - Venous thrombo-embolism as a complication of cross-sex hormone treatment of male to-female transsexual subjects: a review. AB - Administration of cross-sex hormones to male-to-female transsexual subjects, usually oestrogens + often anti-androgens, such as cyproterone acetate, carries a risk of venous thromboembolism (VTE). VTE usually occurs in the first year of oestrogen administration. Ethinyl oestradiol, due to its chemical structure, was in 2003 identified as a major factor in the occurrence of VTE. Most clinics do not prescribe ethinyl oestradiol any longer, but people who take hormones without medical supervision use often oral contraceptives containing ethinyl oestradiol, many times in overdose. Cessation of use of ethinyl oestradiol and peri-operative thrombosis prophylaxis for surgery have reduced prevalence rate of VTE. Other oral oestrogens should not be overdosed, and transdermal oestrogen is to be preferred. Thrombosis prophylaxis for surgery is mandatory. It seems advisable to stop hormone use at least 2 weeks before major surgery, to be resumed only after 3 weeks following full mobilisation. PMID- 23944850 TI - From the editor's desk. AB - No abstract available for this article. PMID- 23944851 TI - Dysphagia in the adult population:. AB - Occupational therapists, traditionally concerned with activities of daily living, are now addressing the problems of eating caused by dysphagia. Adult-onset dysphagia results from either neurological or mechanical, i.e., structural, causes. Following a description of the normal swallowing process, this paper reviews the various disorders that cause dysphagia. General evaluation principles are offered with treatment methods appropriate to the category of disorders. Although specific treatment methods have been used clinically, many remain untested. More recently, a growing number of studies have been published which measure the effectiveness of rehabilitation for dysphagics. Active intervention in the problem of adult-onset dysphagia consists largely of detailed evaluation of oral structures, manipulation of diet, techniques to elicit normal swallowing mechanisms, and assistive devices to compensate for lost structures. In addition, cognitive status, nutrition, posture, and position are addressed in a comprehensive therapy program. The goal of treatment is to promote a safe and nutritional oral diet to the fullest extent possible. PMID- 23944852 TI - An occupational therapy program for patients with swallowing dysfunction following cancer treatment. AB - Eating, the intimate activity of daily living, carries with it many emotional, social and physical implications. Medical treatment of patients with cancers of the head and neck is frequently radical and almost certainly impacts on the patient's ability to eat. This paper outlines an occupational therapy program for patients with swallowing dysfunction following treatment for cancers of the head and neck. Discussed in this paper are the medical treatments particular to cancer treatment that directly affect swallowing function, along with evaluation and treatment by the occupational therapist. The paper concludes with a case study. PMID- 23944853 TI - The role of occupational therapy in planning dining programs in institutions for the frail elderly. AB - Dining rooms in institutions for the frail elderly often reflect an atmosphere of speed, congestion, eating and being fed with minimal social interaction between residents and service personnel. The role of the occupational therapist in helping to create a dining program in such facilities is described. The importance of attention to individual resident needs, careful design of the setting and environment as well as planned strategies for conducting a dining program are emphasized. The key roles of staff and their attitudes are described. PMID- 23944854 TI - Swallowing problems in patients with head and neck cancer:. AB - The restoration of swallowing skills in head and neck cancer surgery patients demands a two-pronged approach: thorough and systematic evaluation and simple, fundamental treatments. Therapists should begin with an assessment of their own biases and their knowledge of head and neck cancer and its surgeries. The patients themselves should be evaluated presurgically-to determine food preferences, other medical conditions, nutritional status, and current swallowing abilities, and postsurgically-to assess facial symmetry, oral mobility and strength, saliva management, aspiration risk, and altered swallowing skills. Treatment approaches should generally be basic, stressing oral exercises, positioning techniques, the use of feeding aids, and teaching the supraglottic swallow. Attention to special considerations, like problems with cuffed tracheostomies and the controversies over using variable food consistencies, will refine the treatment. PMID- 23944855 TI - Oral motor and feeding problems in the tube fed infant:. AB - Relatively little information has been available to prepare occupational therapists to meet the special needs of the tube fed infant. The purpose of this paper is to share specific information through a literature review regarding oral motor and feeding intervention for the tube fed infant who also may have a tracheostomy. Suggested treatment strategies are also discussed and illustrated in a case example. PMID- 23944856 TI - Behavioral feeding disorders in young children:. AB - Young children with behavioral feeding disorders are commonly seen in occupational therapy practice. This paper, based on clinical experience with these children, presents an expanded frame of reference which may be utilized in treatment. The combined use of food as play and treatment of choice is addressed and viewed from learning, developmental, psychodynamic and humanistic perspectives. Possible etiologies of these specific feeding behaviors are discussed. PMID- 23944857 TI - The role of the itinerant occupational therapist in conducting feeding programs for multi-handicapped children in a county school system. AB - Itinerant occupational therapists working in the school system encounter many problems when initiating and conducting feeding programs for their multi handicapped students. The occupational therapist provides direct treatment or consultative services to best meet the needs of her students and most efficiently and effectively utilize her treatment time. This paper describes feeding training programs and a case history to illustrate some feeding problems encountered by itinerant occupational therapists and how they have been handled. PMID- 23944858 TI - Systems theory and feeding programs:. AB - Eating, as one of the basic processes of life, is a skill vulnerable to disruption from a wide variety of insults. The typical mental retardation institution with residents of many age and ability levels provides a spectrum of eatinglfecding disorders. Thc institution also includes many service systems which interact to provide mealtime serviccs. These include training programs, direct care, dietary, and medical-nursing services. This paper describes the development of a complex, comprehensive feeding program in a 120-bed mental retardation institution. Components of the program include staff training, diagnostic and diet clinics, evaluation and resident training, and dining room management. The application of Gencral Systems Theory to the fceding program is described and implications for the development of similar programs are discussed. PMID- 23944859 TI - "In search of excellence-. AB - Peters and Waterman (1983) have reviewed and profiled some of America's leading corporations, in order to determine what might account for their success. This paper reviews Peters' and Waterman's basic tenets and draws parallels for occupational therapy. The outcome of their comprehensive review research is used to support these contentions and recommendations for action on a departmental or unit level are discussed. PMID- 23944860 TI - Managing occupational therapy burnout. AB - Burnout has been conceptualized as an ineffective coping response to stress experienced on the job. This article will explore the construct of burnout as reported in the literature of the helping professions. An emphasis will be placed on prevention and remediation strategies, particularly those aimed at organizational causes of burnout for occupational therapists. PMID- 23944861 TI - The RIC Combination Short-. AB - No abstract available for this article. PMID- 23944863 TI - Clinical survey on contrast-induced nephropathy after coronary angiography. AB - OBJECTIVE: To investigate the incidence and risk factors of contrast-induced nephropathy (CIN) in patients receiving coronary angiography (CAG) in a Chinese medical center. METHODS: The medical records of the patients receiving CAG at Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University from January 2008 to July 2009 were collected to analyze the incidence of CIN under different conditions and the clinical difference between CIN group and non-CIN group. RESULTS: There were 487 cases enrolled in this study and the total incidence of CIN was 10.5%. Through Mehran risk score stratification, incidence of CIN increased with risk scores and in an extremely high-risk group it was as high as 18.0%. Multi-factor regression analysis showed that preoperative hypotension, heart failure, anemia and low estimated glomerular filtration rate (<=30 mL/min) were risk factors of CIN after CAG. CONCLUSION: CIN post CAG is associated with preoperative hypotension, heart failure, anemia and renal function. Close attention should be paid to CIN in patients receiving CAG. PMID- 23944864 TI - Ambient carbon monoxide associated with reduced risk of hospital admissions for respiratory tract infections. AB - RATIONALE: Recent experimental and clinical studies suggest that exogenous carbon monoxide (CO) at lower concentrations may have beneficial effects under certain circumstances, whereas population-based epidemiologic studies of environmentally relevant CO exposure generated mixed findings. OBJECTIVES: To examine the acute effects of ambient CO on respiratory tract infection (RTI) hospitalizations. METHODS: A time series study was conducted. Daily emergency hospital admission and air pollution data in Hong Kong were collected from January 2001 to December 2007. Log-linear Poisson models were used to estimate the associations between daily hospital admissions for RTI and daily average concentrations of CO across three background air monitoring stations and three roadside stations, respectively, controlling for other traffic-related copollutants. MEASUREMENTS AND MAIN RESULTS: CO concentrations were low during the study period with a daily average of 0.6 ppm in background stations and 1.0 ppm in roadside stations. Negative associations were found between ambient CO concentrations and daily hospital admissions for RTI. One ppm increase in background CO at lag 0-2 days was associated with -5.7% (95% confidence interval, -9.2 to -2.1) change in RTI admissions from the whole population according to single-pollutant model; the negative association became stronger when nitrogen dioxide or particulate matter with aerodynamic diameter less than 10 MUm was adjusted for in two-pollutant models. The negative association seemed to be stronger in the adults than in the children and elderly. CONCLUSIONS: Short-term exposure to ambient CO was associated with decreased risk of hospital admissions for RTI, suggesting some acute protective effects of low ambient CO exposure on respiratory infection. PMID- 23944866 TI - Thioxanthone hydroquinone-O,O'-diacetic acid: photoinitiator or photostabilizer? AB - A photoinitiator for free-radical polymerization based on a thioxanthone chromophore containing two acetic acid functions was synthesized and characterized. Photophysical studies such as fluorescence, phosphorescence, and laser flash photolysis in addition to photopolymerization of acrylates were performed to elucidate the radical generation mechanism involving intramolecular electron transfer from the triplet state followed by decarboxylation. We found that the position of the acetic acid substituent is critical for the photoreactivity. In most solvents and acrylic monomers, if the acetic acid functionality is at the 1-position, the singlet excited states are deactivated rapidly before electron transfer can occur, resulting in negligible photoreactivity. The excited-state deactivation probably involves intramolecular H-bonding deactivation. The intramolecular H-bonding is disrupted by solvents that support intermolecular H-bonding, such as DMF and DMSO, leading to efficient intramolecular photoreaction. PMID- 23944867 TI - ICR SS protozoan data site-by-site: a picture of Cryptosporidium and Giardia in U.S. surface water. AB - The U.S. Environmental Protection Agency (USEPA) Information Collection Rule Supplemental Survey (ICR SS) required analysis of Cryptosporidium and Giardia in 10 L surface water samples twice a week for a year by USEPA Method 1623 at 80 representative U.S. public water systems (PWS). The resulting data are examined site-by-site in relation to objectives of the Federal drinking water regulation, The Long-Term (2) Enhanced Surface Water Treatment Rule (LT2), currently under formal 6-year review by the USEPA. The data describe Cryptosporidium and Giardia in watersheds nation-wide over a single annual cycle. Due to limited recovery efficiency measurement results are not fully quantified. In the required sample volumes of 10 L no Cryptosporidium were found in 86% of samples and no Giardia were found in 67% of samples. Yet, organisms were found in enough samples at 34 of 80 sites to detail a specrtum of occurrence and variability for both organisms. The data are shown to describe indivudual site risk essential for guidance of watershed and water treatment management by PWSs. The span of median occurrence for both organisms was about 2 orders of magnitude above the limit of detection (LD), ca. 0.05 raw no's/L for Cryptosporidium and ca. 0.10 raw no's/L for Giardia. Data analysis illustrates key features of Cryptosporidium and Giardia in surface water: presence is continuous not intermittent; zeros indicate presence below the LD; occurrence level and variations depend on watershed sources; risk depends on both magnitude and variability of concentration; accurate estimation of risk requires routine measurement of recovery efficiency and calculation of concentration. The data and analysis illustrate features of Cryptosporidium and Giardia occurrence in surface water relevant to their effective regulation for public health protection. PMID- 23944865 TI - Pediatric diabetes consortium T1D New Onset (NeOn) study: clinical outcomes during the first year following diagnosis. AB - OBJECTIVE: There have been few prospective, multicenter studies investigating the natural history of type 1 diabetes (T1D) from the time of diagnosis. The objective of this report from the Pediatric Diabetes Consortium (PDC) T1D New Onset (NeOn) study was to assess the natural history and clinical outcomes in children during the first year after diagnosis of T1D. RESEARCH DESIGN AND METHODS: Clinical measures from the first year following diagnosis were analyzed for 857 participants (mean age 9.1 yr, 51% female, 66% non-Hispanic White) not participating in an intervention study who had a HbA1c result at 12 months. RESULTS: Mean HbA1c +/- SD was 102 +/- 25 mmol/mol (11.4 +/- 2.3%) at diagnosis, 55 +/- 12 mmol/mol (7.2 +/- 1.1%) at 3 months, 56 +/- 15 mmol/mol (7.3 +/- 1.3%) at 6 months and 62 +/- 16 mmol/mol (7.8 +/- 1.5%) at 12 months from diagnosis. A severe hypoglycemic (SH) event occurred in 31 (4%) participants (44 events, 5.2 events per 100 person-years). Diabetic ketoacidosis (DKA) not including diagnosis occurred in 10 (1%) participants (13 events, 1.5 events per 100 person-years). CONCLUSIONS: After onset of T1D, mean HbA1c reaches its nadir at 3-6 months with a gradual increase through 12 months. SH and DKA are uncommon but still occur during the first year with T1D. Data from large cohorts, such as the PDC T1D NeOn study, provide important insights into the course of T1D during the first year following diagnosis, which will help to inform the development of models to target future interventions. PMID- 23944868 TI - Nutritional and antioxidant properties of wild edible plants and their use as potential ingredients in the modern diet. AB - Thirteen species of wild edible plants belonging to 11 botanical families consumed in the traditional Mediterranean diet were evaluated. Sanguisorba minor, Quercus ballota and Sedum sediforme showed the highest hydrophilic total antioxidant activity (H-TAA) and total phenols. Asparagus acutifolius, Allium ampeloprasum, Foeniculum vulgare and Malva sylvestris presented high levels of potassium, Malva and Asparagus are interesting due to their zinc content, and Urtica urens contains a high content of calcium. Sensory analysis indicated that fruits from Q. ballota could be considered very sweet and plants of Crithmum maritimum and Oxalis pes-caprae are very acidic. Moreover, testers highlighted the salty taste of C. maritimum. Mesembryanthemum nodiflorum and Mesembryanthemum cristalinum, the spicy taste of A. ampeloprasum, and the aroma of F. vulgare. Our results indicate that increased consumption of the investigated plant species could provide health benefits. Moreover, due to their sensorial properties, they could be used as new ingredients to improve the diversity in modern diet and highly creative cuisine. PMID- 23944869 TI - Left ventricular assist devices: an evolving journey. PMID- 23944870 TI - Normative data for the Dementia Rating Scale-2 in the French-Quebec population. AB - The Dementia Rating Scale-2 is used to measure cognitive status of adults with cognitive impairment, especially of the degenerative type, by assessing five cognitive functions, namely attention, initiation/perseveration, construction, conceptualization, and memory. The present study aimed to establish normative data for this test in the elderly French-Quebec population. A total of 432 French speaking elders from the province of Quebec (Canada), aged 50 to 85 years, were administered the Dementia Rating Scale-2. Age and education were found to be associated with the total score on the test, while gender was not. Percentile ranks were then calculated for age- and education-stratified groups. Previous studies have shown that cultural background can affect performance on the DRS and the development of culture-specific norms for French-speaking Quebecers could be very useful to clinicians and researchers working with this population. PMID- 23944872 TI - Comparative proteomic and physiological analyses reveal the protective effect of exogenous polyamines in the bermudagrass (Cynodon dactylon) response to salt and drought stresses. AB - Polyamines conferred enhanced abiotic stress tolerance in multiple plant species. However, the effect of polyamines on abiotic stress and physiological change in bermudagrass, the most widely used warm-season turfgrasses, are unknown. In this study, pretreatment of exogenous polyamine conferred increased salt and drought tolerances in bermudagrass. Comparative proteomic analysis was performed to further investigate polyamines mediated responses, and 36 commonly regulated proteins by at least two types of polyamines in bermudagrass were successfully identified, including 12 proteins with increased level, 20 proteins with decreased level and other 4 specifically expressed proteins. Among them, proteins involved in electron transport and energy pathways were largely enriched, and nucleoside diphosphate kinase (NDPK) and three antioxidant enzymes were extensively regulated by polyamines. Dissection of reactive oxygen species (ROS) levels indicated that polyamine-derived H2O2 production might play dual roles under abiotic stress conditions. Moreover, accumulation of osmolytes was also observed after application of exogenous polyamines, which is consistent with proteomics results that several proteins involved in carbon fixation pathway were mediated commonly by polyamines pretreatment. Taken together, we proposed that polyamines could activate multiple pathways that enhance bermudagrass adaption to salt and drought stresses. These findings might be applicable for genetically engineering of grasses and crops to improve stress tolerance. PMID- 23944871 TI - Circadian time organization of professional firemen: desynchronization-tau differing from 24.0 hours-documented by longitudinal self-assessment of 16 variables. AB - We investigated the circadian synchronization/desynchronization (by field-study assessment of differences in period, tau, of 16 coexisting and well-documented rhythms) of 30 healthy firemen (FM) exposed to irregular, difficult, and stressful nocturnal work hours who demonstrated excellent clinical tolerance (allochronism). Three groups of FM were studied (A = 12 FM on 24-h duty at the fire station; B = 9 FM on 24-h duty at the emergency call center; C = 9 day-shift administrative FM) of mostly comparable average age, body mass index, career duration, chronotype-morningness/eveningness, and trait of field dependence/independence. The self-assessed 16 circadian rhythms were (i) physiological ones of sleep-wake (sleep log), activity-rest (actography), body temperature (internal transmitter pill probe), right- and left-hand grip strength (hand dynamometer), systolic and diastolic blood pressure (BP) plus heart rate (ambulatory BP monitoring device); (ii) psychological ones (visual analog self rating scales) of sleepiness, fatigue, fitness for work, and capacity to cope with aggressive social behavior; and (iii) cognitive ones of eye-hand skill and letter cancellation, entailing performance speed (tasks completed/unit time) and accuracy (errors). Data (4-6 time points/24 h; 2 591 480 values in total) were gathered continuously throughout two 8-d spans, one in winter 2010-2011 and one in summer 2011. Each of the resulting 938 unequal-interval time series was analyzed by a special power spectrum analysis to objectively determine the prominent tau. The desynchronization ratio (DR: number of study variables with tau = 24.0 h/number of study variables * 100) served to ascertain the strength/weakness of each rhythm per individual, group, and season. The field study confirmed, independent of group and season, coexistence of rather strong and weak circadian oscillators. Interindividual differences in DR were detected between groups and seasons (chi(2), correlation tests, analysis of variance [ANOVA]). Moreover, in each group, both in winter and summer, a normal distribution was observed in the number of FM with rhythms with tau = 24.0 h, e.g., ranging from 5/16 (large desynchronization) to 16/16 (no desynchronization). Such a normal distribution with intraindividual stability over time (i.e., seasons) is consistent with the hypothesis of an inherited origin of a differential propensity to circadian desynchronization and which is supported by the distribution of taus in winter and summer following the Dian Circadian Genetic Model, i.e., with tau = 24.0 h, tau = 24.0 h + n(0.8 h), and tau = 24.0 h - n(0.8 h). PMID- 23944873 TI - Concordance of motor vehicle crash, emergency department, and inpatient hospitalization data sets in the identification of drugs in injured drivers. AB - OBJECTIVE: Prescription drug overdoses, abuse, and sales have increased dramatically in the United States in the last decade. The purpose of the present study was to link crash data with emergency department (ED) and inpatient hospitalization data to assess the concordance between the data sets in the identification of the presence of drugs among injured motor vehicle drivers (passenger cars, passenger trucks, light trucks, and semi-trucks) in Kentucky. METHODS: Kentucky CRASH data were probabilistically linked to ED data sets for years 2008-2010 and to inpatient hospitalization data sets for years 2000-2010. Statistical analyses were performed. RESULTS: Of the 72,529 linked crash/ED visits, there were 473 drivers with an associated nondependent abuse of drugs diagnosis in the ED, and 930 drivers had drug involvement recorded in the CRASH data (only 163 cases overlapped with drug involvement both recorded in CRASH data and coded as nondependent abuse of drugs in the ED); 64 drivers had multiple drug types present in their system. Of the 20,860 total linked crash/inpatient hospitalization cases, there were 973 drivers diagnosed with nondependent abuse of drugs in the inpatient hospitalization record and 499 drivers had drug involvement recorded in the CRASH data (only 207 overlapped); 250 drivers were diagnosed with multiple drugs in their system. CONCLUSIONS: Surveillance data from multiple public health data sets is necessary to identify the presence of drugs in injured drivers involved in motor vehicle crashes. The use of a single surveillance data set alone may significantly underreport the number of drugged drivers who were injured in a motor vehicle collision. PMID- 23944876 TI - From the editor's desk. AB - No abstract available for this article. PMID- 23944874 TI - Identification of binding domains on red blood cell glycophorins for Babesia divergens. AB - BACKGROUND: Invasion of red blood cells (RBCs) is one of the critical points in the lifecycle of Babesia. The parasite does not invade other host cells. Earlier work has shown that GPA and GPB function as putative receptors during parasite invasion. The primary focus of this study was the delineation of parasite-binding domains on GPA and GPB. STUDY DESIGN AND METHODS: The assay of choice to validate molecules that participate in invasion is an inhibition of invasion assay, in which changes in parasitemia are assessed relative to a wild-type assay (no inhibitors). Inhibition of invasion can be achieved by modification of different components of the assay or by the addition of competitors of the molecules that participate in invasion. In this study purified antibody fragments to various domains on GPA and GPB were tested for magnitude of inhibition of parasite invasion. Effects on invasion were monitored by assessment of Giemsa-stained smears every 24 hours. RESULTS: Among 10 selected antibodies directed at various epitopes on GPA and GPB, antibodies directed against GPA(M) epitopes had the most severe effect (up to 35%) on inhibition of invasion, followed by antibodies directed against GPB(S) epitope (up to 24%). CONCLUSION: This study confirms the role of RBC glycophorins A and B in Babesia divergens invasion and shows that the GPA(M) and GPB(S) epitopes are likely to play an important role in the entry process. PMID- 23944875 TI - Night glucose control with MD-Logic artificial pancreas in home setting: a single blind, randomized crossover trial-interim analysis. AB - BACKGROUND: Artificial pancreas (AP) systems have shown an improvement in glucose control and a reduced risk of nocturnal hypoglycemia under controlled conditions but remain to be evaluated under daily-life conditions. OBJECTIVE: To assess the feasibility, safety, and efficacy of the MD-Logic AP in controlling nocturnal glucose levels in the patient's home. METHODS: Two-arm study, each covering four consecutive nights comparing the MD-Logic AP ('closed-loop' arm) with sensor augmented pump therapy ('control' arm). Fifteen patients (mean age 19 +/- 10.4 yr, A1c 7.5 +/- 0.5% or 58 +/- 5.9 mmol/mol, diabetes duration 9.9 +/- 8.2 yr) were randomly assigned either to 'Group A' (first 'closed-loop', then 'control' arm) or to 'Group B' (vice versa). Investigators were masked to treatment intervention. Primary endpoints were the time spent with glucose levels below 70 mg/dL and the percentage of nights in which the mean overnight glucose levels were within 90-140 mg/dL. Endpoint analyses were based on unmodified sensor glucose readings of the four study nights. RESULTS: Time of glucose levels spent below 70 mg/dL was significantly shorter on the closed-loop nights than on control nights, median and interquartile range 3.8 (0, 11.6) and 48.7 (0.6, 67.9) min, respectively; p = 0.0034. The percentage of individual nights in which mean overnight glucose level was within 90-140 mg/dL was 67 (33, 88), and 50 (25, 75), under closed-loop and control nights, respectively, with no statistical difference. Secondary endpoint analyses demonstrated significant improvements in hypoglycemia parameters. No serious adverse events were reported. CONCLUSION: This interim analysis demonstrates the feasibility, safety, and efficiency of the MD-Logic AP system in home use, and demonstrates an improvement over sensor augmented pump therapy. (ClinicalTrials.gov identifier NCT01726829). PMID- 23944877 TI - Career ladder development for certified occupational therapy assistants. AB - Practice models which depict the interactions of Certified Occupational Therapy Assistants and Registered Occupational Therapists are described. These models portray career ladder development for the Certified Occupational Therapy Assistant. Job enrichment for the assistant facilitates the provision of qualitative and cost effective occupational therapy sessions. PMID- 23944878 TI - Supervision of the certified occupational therapy assistant. AB - As current trends in health care continue to develop, manpower demands within the profession of occupational therapy will continue to rise. Creative partnerships and collaborative efforts between therapists and assistants are rapidly becoming a necessity to provide cost-effective patient care within a variety of treatment settings. Several documents and resources concerning role delinieation and supervision of assistants are available within the literature; however, few resources have been compiled to address supervision and supervision strategies for the assistant. This paper addresses supervison of the assistant in a fairly broad and generic sense, and includes specific strategies that my be introduced to enhance the supervisory process. PMID- 23944879 TI - Calculating cost effectiveness with the certified occupational therapy assistant. AB - The need for occupational therapists continues to rise durin a time when those in health care management must also concern themselves with containing costs. This paper compares the expense of an all therapist department vs. a department comprised of therapists and assistants. Appropriate assignment of therapists vs. assistants in various clinical settings is discussed. The paper also describes how one multiclinic department redefined two assistant positions to enhance productivity. PMID- 23944880 TI - Designing job enrichment projects. AB - This paper describes a management strategy for a job satisfaction program utilized in a large occupational therapy department. The goal of the program is to retain satisfied, productive employees and reduce attrition of therapists and assistants. The use of job enrichment projects for occupational therapy assistants will be presented with brief descriptions of two projects. PMID- 23944881 TI - Certified occupational therapy assistants and microcomputers. AB - This article deals with the continually changing role of the Certified Occupational Therapy Assistant. When the need for Registered Occupational Therapists became greater than the number of available therapists, a program was instituted for assistants. At first these aides, as they were called at that time, were delegated the tasks of transporting patients to and from therapy and setting them up for therapy. Gradually, the assistant's role grew, and with the emergence of the team approach, the assistant's role changed once again. Today the assistant is a valuable member of the team and by specializing can enhance the quality of care provided for the patient. One area of specialization is computer-assisted therapy. The assistant can enhance the quality of care provided and offer a different treatment approach. This article will review software in current use at Rancho Los Amigos Medical Center and the involvement of assistants in computer-assisted therapy. PMID- 23944882 TI - Wheelchair clinics work. AB - The positioning problems and needs of severely disabled adults greatly influence their ability to function independently. This paper will describe an interdisciplinary approach in a wheelchair clinic, the functions of a wheelchair clinic, and the role of a Certified Occupational Therapy Assistant as part of the wheelchair clinic team. PMID- 23944883 TI - Splinting design and fabrication in physical disabilities. AB - An experienced Certified Occupational Therapy Assistant describes an identified need for splinting education for occupational therapists and students working in a multiclinic department. The occupational therapists, who are a responsible for treating patients on weekends and holidays, needed to maintain competency and consistency in completing splinting requests for a wide variety of medical and surgical services in a teaching hospital. The methods for developing and implementing a quarterly inservice program and its results are described. PMID- 23944884 TI - The autosyringe backpack for children with cancer. AB - A Certified Occupational Therapy Assistant, who was especially interested in the problems of the hospitalized pediatric oncology patient, describes an autosyringe backpack used during periods of chemotherapy administration. Use of the backpack permits greater mobility for the pediatric patient and enhances the ability of a child to accomplish physical, psychosocial and play development during periods of hospitalization. Construction information 1s included. PMID- 23944885 TI - Toy adaptations in pediatrics. AB - This report describes a special project of a Certified Occupational Therapy Assistant on a pediatric rehabilitation unit who learned to adapt battery operated toys for use by multihandicapped children. This led to the enhancement of patient treatment and requests for the assistant to consult with other professionals. Instructions are given for fabricating simple controls for use by handicapped children to activate battery operated toys. PMID- 23944886 TI - Occupational therapy and low vision rehabilitation. AB - This article addresses low vision rehabilitation programs and the certified occupational therapy assistant's role in a low vision, outpatient, ambulatory care service. An individual who acquires low vision secondary to eye or brain pathology may have some useful vision but not enough to facilitate ease in performing activities of dail living. Visual tasks, such as reading, writing, homemaking and leisure activities become quite difficult without medical and therapeutic intervention. In these instances, the efforts of eye care professionals and occupational therapists can be coordinated to provide a holistic approach to patient treatment. The primary objective in utilizing a low vision rehabilitation program is to provide instruction to patients with low vision problems in activities of daily living through the use of optical/nonoptical aids to achieve functional independence. PMID- 23944887 TI - The certified occupational therapy assistant as an activity director. AB - This article will discuss the philosophy and purpose of a Social Adult Day Care Program designed primarily for elderly citizens who may be frail, isolated, or in need of socialization and for their families, who wish to keep elderly relatives at home as long as possible. A second purpose is to maintain the "health" and independence of healthy senior citizens. The role of the Certified Occupational Therapy Assistant who is the Activity Director of this program will also be explored. The Social Adult Day Care Program is currently offered as a satellite program of the Homemaker Service of Orange County, Inc., in New York, with some funding, support and volunteer assistance provided by a variety of federal, state, and local public and non-profit agencles and voluntary organizations. PMID- 23944888 TI - A Certified Occupational Therapy Assistant's Contribution to a Substance Abuse Treatment Program. AB - Substance abuse patients lack skills in money management and frequently misuse credit cards and checks. They also often neglect physical exercise and are in poor physical condition. A COTA developed special programs to teach exercise and money management as part of a five week treatment program for substance abuse patients. Development and implementation of the programs are described. PMID- 23944889 TI - Role delineation of the registered occupational therapist and the certified occupational therapy assistant in child psychiatry. AB - This article describes the complementary roles of Registered Occupational Therapists and Certified Occupational Therapy Assistants working in an inpatient child psychiatry unit. Collaborative functions include assessment, treatment, program development and evaluation, and supervision. Supervisory strategies are also described. PMID- 23944890 TI - The roles of the certified occupational therapy assistant and the registered occupational therapist in adult psychiatry. AB - The certified occupational therapy assistant in a 64 bed inpatient psychiatry setting contributes to a high level of patient care and departmental efficiency. The certified occupational therapy assistant's responsibilities include direct patient care, student education, and clinical management and are described in this article. The methods and philosophy for supervision of the certified occupational therapy assistant are explored. In conclusion, two adult psychiatry programs which utilize the Certified Occupational Therapy Assistant's knowledge and education are described. PMID- 23944891 TI - Incorporating structured learning therapy into occupational therapy treatment of chronic psychiatric patientse. AB - Role playing activities, when incorporated into a group experience, have been shown to enhance social skills development in patients with chronic psychiatric conditions. This approach, adapted from the psychological therapeutic model of Structured Learning Therapy, addresses interpersonal skill development at three distinct levels: rudimentary interpersonal skills, community interpersonal skills, and abstract intepersonal skills. Unique to this therapeutic model is the concept of the patient taking an active role in formulating the dialogues used in each role playing situation. PMID- 23944892 TI - Job search skills for unemployed psychiatric patients. AB - Chronically mentally ill patients often lack skills for finding employment independently. A program based on "SCORE: Solving Community Obstacles and Restoring Employment" was implemented by a Certified Occupational Therapy Assistant in a teaching hospital. The program implemented two years ago as a Special Project has been successful. Fifteen low level patients trained in this program have obtained remunerative employment and two others are performing volunteer services on a regular basis. PMID- 23944893 TI - Strategies for resolution of intraprofessional conflict related to the role of the certified occupational therapy assistant. AB - The certified occupational therapy assistant's role continues to be of concern to our profession. Occupational therapy personnel have identified the same issues, especially role confusion and inadequate supervision, as problems without clear solutions for almost two decades. The author addresses these and other problems and proposes use of de Bono's lateral thinking style for problem analysis and resolution. PMID- 23944894 TI - Mysticism and skepticism. AB - This article will identify beliefs and values held by Certified Occupational Therapy Assistants. These beliefs and values differ from those held by the mainstream culture of the occupational therapy profession and have resulted in the evolution of a subculture among certified occupational therapy assistants. This subculture has the potential to become a force that positively or negatively influences its members as well as the occupational therapy profession. The author will propose strategies to resolve some of these differences, to support certified occupational therapy assistants who will accept responsibility for the challenges which confront them and become a positive force within the mainstream culture of the occupational therapy profession. PMID- 23944895 TI - Certified occupational therapy assistants. AB - The intent of this article is to identify changes in our professional environment and address ways in which Certified Occupational Therapy Assistants can prepare for and adapt to change. The emphasis is on individual responsibility for growth and survival. PMID- 23944896 TI - Some Messages for the COTA on Image, Imagery, and Imagination. AB - The purpose of this article is to convey some messages to the COTA with regard to a more active involvement in the profession. The paths that are taken to deliver these messages are the paths of myths and reality as they cross the issue of image, imagery and imagination. If there is an overall message conveyed, it is that COTAs must assume a greater responsibility for their own destiny, and that the reward for accepting this responsibility is inherent in the process of becoming. PMID- 23944897 TI - Practice watch: things to think about. AB - No abstract available for this article. PMID- 23944899 TI - Thoughts on leadership. AB - No abstract available for this article. PMID- 23944900 TI - Certified occupational therapy assistants. AB - No abstract available for this article. PMID- 23944901 TI - Changing of the guard. AB - No abstract available for this article. PMID- 23944902 TI - Sidewall morphology-dependent formation of multiple twins in Si nanowires. AB - Precise placement of twin boundaries and stacking faults promises new opportunities to fundamentally manipulate the optical, electrical, and thermal properties of semiconductor nanowires. Here we report on the appearance of consecutive twin boundaries in Si nanowires and show that sidewall morphology governs their spacing. Detailed electron microscopy analysis reveals that thin {111} sidewall facets, which elongate following the first twin boundary (TB1), are responsible for deforming the triple-phase line and favoring the formation of the second twin boundary (TB2). While multiple, geometrically correlated defect planes are known in group III-V nanowires, our findings show that this behavior is also possible in group IV materials. PMID- 23944903 TI - Editorial Comment to Metabolic syndrome correlates with peri-urethral fibrosis secondary to chronic prostate inflammation: evidence of a link in a cohort of patients undergoing radical prostatectomy. PMID- 23944904 TI - Electron-rich driven electrochemical solid-state amorphization in Li-Si alloys. AB - The physical and chemical behaviors of materials used in energy storage devices, such as lithium-ion batteries (LIBs), are mainly controlled by an electrochemical process, which normally involves insertion/extraction of ions into/from a host lattice with a concurrent flow of electrons to compensate charge balance. The fundamental physics and chemistry governing the behavior of materials in response to the ions insertion/extraction is not known. Herein, a combination of in situ lithiation experiments and large-scale ab initio molecular dynamics simulations are performed to explore the mechanisms of the electrochemically driven solid state amorphization in Li-Si systems. We find that local electron-rich condition governs the electrochemically driven solid-state amorphization of Li-Si alloys. This discovery provides the fundamental explanation of why lithium insertion in semiconductor and insulators leads to amorphization, whereas in metals, it leads to a crystalline alloy. The present work correlates electrochemically driven reactions with ion insertion, electron transfer, lattice stability, and phase equilibrium. PMID- 23944905 TI - Effect of preservative-free tafluprost on keratocytes, sub-basal nerves, and endothelium: a single-blind one-year confocal study on naive or treated glaucoma and hypertensive patients versus a control group. AB - PURPOSE: To record the impact of preservative-free Tafluprost on corneal status examined by in vivo confocal microscopy. METHODS: A prospective cohort study on consecutive naive or previously treated patients with a new prescription of preservative-free Tafluprost. All subjects underwent a complete ophthalmic examination [comprehensive of intraocular pressure (IOP) and central corneal thickness (CCT) measurements], and an in vivo corneal confocal microscopy evaluation, at baseline and 12 months later. A healthy control group was selected and examined at the same time. RESULTS: Seventy-five subjects (16 controls, 20 naive, and 39 treated) were enrolled. At baseline, IOP was 16 (13.8-18.6), 21.5 (18-23.7), and 18 (16-22) mmHg, (P=0.01); and CCT did not differ among the groups (P=0.25). Epithelial cells, keratocyte activation, a number of sub-basal nerves, and the grade of nerve tortuosity were similar (P=0.233, 0.11, 0.417, and 0.05, respectively), in naive and controls, while previously treated patients had significantly less epithelial cells and sub-basal corneal nerves (P<0.0001), keratocyte activation, increased number of bead-like formations, and nerve tortuosity (P<0.0001). At month 12, IOP decreased in both patient groups (P<0.001); CCT did not change. Previously treated patients showed an improvement in confocal parameters: increased epithelial cells (P=0.0006), reduced keratocyte activation (P=0.003), increased number of corneal nerves (P=0.0004), decreased number of bead-like formations (P=0.0013), and nerve tortuosity (P=0.0008). Naive patients did not show significant changes. CONCLUSION: The study confirmed the efficacy of preservative-free Tafluprost in reducing IOP, and underlined the drug's safety in naive glaucoma patients with regard to corneal status. In the balance between efficacy and tolerability, formulations with low cytotoxicity may ensure fewer side effects, with higher tolerability and better compliance. PMID- 23944906 TI - Antibiotic susceptibility of staphylococci isolates from patients with chronic conjunctivitis: including associated factors and clinical evaluation. AB - PURPOSE: To determine species of staphylococci in chronic conjunctivitis, their antibiotic susceptibility pattern, patient treatments, clinical course, and clinical conditions. METHODS: In this prospective study, 243 conjunctival cultures were taken from 191 patients with chronic conjunctivitis, we obtained staphylococci susceptibility patterns with E-test, and they were analyzed in coagulase-positive and negative. The minimum inhibitory concentration for 90% of isolates (MIC90) was determined for Staphylococcus aureus and Staphylococcus epidermidis. Additionally, clinical follow-up and associated factors of all patients were analyzed depending on methicillin resistance (MR) or susceptibility (MS) bacterial state. RESULTS: One hundred and eight (44%) cultures were positive; 81 positive cultures were Gram-positive of which, 77 were staphylococci, 29 coagulase-positive with S. aureus as the most prevalent, 89% MS, and 11% MR. And 48 were coagulase-negative with S. epidermidis as the most isolated with 36% of MS and 64% of MR. Poor susceptibility was found in the staphylococcus coagulase-negative/MR group. Moxifloxacin and vancomycin show the best in vitro activity for all isolates. The MIC90 of moxifloxacin and vancomycin were 0.064/1.5, 0.64/3.0, and 1/3.0 for S. aureus-MS, S. epidermidis-MS, and S. epidermidis-MR, respectively. The most frequently associated factors found in patients with positive culture for staphylococcus were exposure to the health care system 23 (29.87%) of 77 patients and dry eye 23 (29.87%) of 77 patients. Both with a proportion of 3 in 10. CONCLUSION: Coagulase-negative staphylococci were the most frequently isolated from the conjunctiva with 58.33% of MR; even though multiresistance was detected, their susceptibility to a fourth-generation fluoroquinolone, commonly used, such as moxifloxacin, was preserved. PMID- 23944907 TI - Challenges in estimation of glycated hemoglobin in India. AB - Glycated hemoglobin (HbA1c) is the most widely accepted index of long-term glycemic control. However, there are some clinical situations that make the accurate measurement of HbA1c difficult. Although some of these situations are general, others are more specific to some parts of the world like India. These conditions include hemoglobinopathies such as thalassemias and structural hemoglobin (Hb) variants such as HbS and HbD, as well as iron-deficiency anemia and the use of certain drugs. Because of the relatively frequent occurrence of some of these conditions in some parts of India, it is important that they are looked for when evaluating an inappropriately high or low HbA1c level. Alternative indices may have to be used for assessing glycemic control in these cases. PMID- 23944908 TI - A new cembrane glycoside in Asterothamnus centrali-asiaticus from Gobi Desert. AB - A new cembrane glycoside, nephthenol 15-O-beta-d-quinovoside, was isolated from the aerial parts of Asterothamnus centrali-asiaticus. Its structure was elucidated by 1D and 2D NMR spectroscopic analysis, as well as by mass spectrometry. This is the first report of the occurrence of a cembrane glycoside in vascular plants. PMID- 23944909 TI - Note from the editors. PMID- 23944910 TI - Augmented information and the acquisition of isometric tasks. AB - The experiments reported were designed to examine how the interaction of task and organismic constraints influences the effectiveness of augmented information on the acquisition of a given force-time trace in a finger press isometric task. Experiment 1 showed that kinetic information feedback facilitated acquisition of the gaussian force-time task criterion but that the superimposition of the task criterion information on the augmented information feedback did not further improve performance. Experiment 2 revealed that the addition of task criterion information to the kinetic information feedback was beneficial to performance when the force-time curve was unfamiliar and asymmetrical in shape. Collectively, the findings suggest that the interaction of task and organismic constraints dictates the degree to which both kinetic information feedback and criterion information facilitate the acquisition of skill in isometric tasks. PMID- 23944911 TI - Trends in the refinement and optimization of fine-motor trajectories. AB - Digitally recorded handwriting movements of primary school children exhibiting good or poor writing quality were examined from two perspectives. The first approach ascertained the extent to which differences existed in the refinement of individual pen movements, in terms of Hay's (1979) movement categories of "ballistic," "step," and "ramp." A second analysis explored the extent to which good writers appear to minimize the physical costs of such movements, in terms of impulse, force, power, and jerk estimates, calculated from kinematic data. The results provide a qualification of an earlier analysis of the data using crosscorrelation techniques, and the relevance of each approach as a description of the development of movement control is discussed. It is concluded that poorer writers tend to use less mature patterns of movement that allow greater visual control during execution, and they also appear to have less control over both normal force and effective planar force levels. PMID- 23944912 TI - Simulation studies of descending and reflex control of fast movements. AB - Several neurological control strategies for fast head movements are considered using computer simulations of a stretch reflex model. Each control strategy incorporates a different amount of proprioceptive feedback contributing to braking and/or clamping the movement. The model behavior for each control strategy is qualitatively compared to experimental data that includes the agonist and antagonist EMGs, and the head position, velocity, and acceleration. Significance of the study is discussed with respect to the characteristic tri phasic EMG pattern for fast voluntary movements and the possible roles that the stretch reflex may have in contributing to this pattern of activation. PMID- 23944913 TI - Are dynamic phenomena prior to stepping essential to walking? AB - The aim of our research was to examine the function of the pre-gait weight shifts in generating the dynamic forces needed to start walking at different speeds. Five subjects participated in the experiment, and a total of 105 gait initiation movements, executed on a large force plate, for three speed conditions (slow, normal, and fast), were examined. Results, which related to durations of the anticipation and of the step execution phases and to biomechanical parameters (progression velocity of the center of gravity, backward shift of the center of foot pressure, and magnitude of propulsive forces at heel-off time), suggested that dynamic phenomena prior to stepping are essential to walking as far as they contribute to the creation of convenient conditions for progression. The configuration of the support basis prior to stepping limits the progression velocity reached at the end of the first step. PMID- 23944914 TI - Programming sequences of hand postures. AB - The extent to which complex skills are programmed before movement is a concern for research in motor control. This study investigates a model which maintains that after a motor program is constructed, only the first response in a sequence is programmed prior to movement (Sternberg, Monsell, Knoll, & Wright, 1978). In a simple reaction time paradigm, subjects executed sequences of hand postures that varied in length, the number of different hand postures, and the location of a hand posture transition. For sequences containing repetitions of the same hand posture, sequence length had a small effect on RT when the number of responses ranged between two and five (Experiment 1) and no effect when the number of responses ranged between three and five (Experiment 2). For sequences containing clearly different hand postures, Experiment 2 showed that RT was influenced by the type of hand posture beyond the first response. The analysis of interresponse times suggested that the first two responses were completely preprogrammed before movement. These results were consistent with a model in which responses are hierarchically organized and some but not all information about each response in the sequence is preprogrammed before movement execution. PMID- 23944915 TI - Force control and its relation to timing. AB - Previous work (Keele & Hawkins, 1982; Keele, Pokorny, Corcos, & Ivry, 1985) has suggested two general factors of coordination that differentiate people across a variety of motor movements, factors of timing and maximum rate of successive movements. This study provides comparable evidence for a third general factor of coordination, that of force control. Subjects who exhibit low variability in reproducing a target force with one effector, the finger, tend to show low variability with two other effectors, the foot and forearm. In addition, ability in force control cuts across different force ranges and across situations where force control is either the primary goal or the secondary goal. Force records obtained during a periodic tapping task show that, although force control is largely independent of timing, there are some interactions between the two factors. Force variation appears to distort timing a small amount in part because larger forces speed up implementation of movement, thereby shortening preceding intervals and lengthening following ones, and in part because force variation alters central-timing mechanisms. PMID- 23944916 TI - Using relative motion plots to measure changes in intra-limb and inter-limb coordination. AB - Methods for determining the degree of similarity between relative motion plots are examined and computational methods outlined. Hypothetical examples are provided to simply illustrate the function of selected indices of pattern shape, size, and orientation. Methods of using a composite of these measures to assess asymmetry, abnormality, or refinements in motor function are discussed. Statistical procedures for determining the reliability of assessments of change in relative motions are presented. A modification to Freeman's (1961) pattern recognition method is suggested as a more parsimonious application to angle-angle data derived in human movement research. PMID- 23944917 TI - Muscle stiffness in down syndrome and other mentally handicapped subjects. AB - An attempt was made to determine the effects of strength training on elbow flexor stiffness of Down syndrome, non-Down syndrome mentally handicapped, and nonhandicapped subjects. It was hypothesized that stiffness would be affected by the training. Results showed that only half of the individual subjects increased their maximum voluntary contraction (MVC) level as a result of the training and that premeasures and postmeasures of MVC were not significantly different for any of the three groups. As expected, for both premeasures and postmeasures, nonhandicapped subjects had a significantly higher MVC than the other groups who were not significantly different. An important finding was that measures of stiffness (slopes of the IEMG * Torque) were not significantly different for the three groups. This finding is consistant with recent studies (Davis & Kelso, 1982; Shumway-Cook & Woollacott, in press) but raises serious doubts about the popularly held opinion that Down syndrome individuals are hypotonic. It was also found that both the Down syndrome and other mentally handicapped subjects produced significantly less torque at the maximum level than the nonhandicapped subjects. These findings suggest that deficits in mentally handicapping conditions result from a decrease in the range of a primary motor control parameter lambda (see Feldman, 1986). PMID- 23944918 TI - Physical activity parenting measurement and research: challenges, explanations, and solutions. AB - Physical activity (PA) parenting research has proliferated over the past decade, with findings verifying the influential role that parents play in children's emerging PA behaviors. This knowledge, however, has not translated into effective family-based PA interventions. During a preconference workshop to the 2012 International Society for Behavioral Nutrition and Physical Activity annual meeting, a PA parenting workgroup met to: (1) Discuss challenges in PA parenting research that may limit its translation, (2) identify explanations or reasons for such challenges, and (3) recommend strategies for future research. Challenges discussed by the workgroup included a proliferation of disconnected and inconsistently measured constructs, a limited understanding of the dimensions of PA parenting, and a narrow conceptualization of hypothesized moderators of the relationship between PA parenting and child PA. Potential reasons for such challenges emphasized by the group included a disinclination to employ theory when developing measures and examining predictors and outcomes of PA parenting as well as a lack of agreed-upon measurement standards. Suggested solutions focused on the need to link PA parenting research with general parenting research, define and adopt rigorous standards of measurement, and identify new methods to assess PA parenting. As an initial step toward implementing these recommendations, the workgroup developed a conceptual model that: (1) Integrates parenting dimensions from the general parenting literature into the conceptualization of PA parenting, (2) draws on behavioral and developmental theory, and (3) emphasizes areas which have been neglected to date including precursors to PA parenting and effect modifiers. PMID- 23944919 TI - Conceptual understanding of screen media parenting: report of a working group. AB - Screen media (television, computers, and videogames) use has been linked to multiple child outcomes, including obesity. Parents can be an important influence on children's screen use. There has been an increase in the number of instruments available to assess parenting in feeding and physical activity contexts, however few measures are available to assess parenting practices regarding children's screen media use. A working group of screen media and parenting researchers convened at the preconference workshop to the 2012 International Society for Behavioral Nutrition and Physical Activity (ISBNPA) annual meeting, "Parenting Measurement: Current Status and Consensus Reports," to identify and prioritize issues in assessing screen media parenting practices. The group identified that screen media use can pose different risks for children, depending on their age and developmental stage, across physiologic, psychosocial, and development outcomes. With that in mind, a conceptual framework of how parents may influence their child's screen-viewing behaviors was proposed to include the screen media content, context of viewing, and amount viewed. A research agenda was proposed to prioritize a validation of the framework and enhance the ability of researchers to best assess parenting influences across the three domains of content, context and amount of children's screen media use. PMID- 23944920 TI - Parenting dimensions and styles: a brief history and recommendations for future research. AB - Over the last decade, researchers have uncovered relationships between general parenting styles and children's obesity. This is an emerging area of research, and there currently is a great deal of interest in the parent's role. This review was written to provide researchers entering this area with a historical introduction to parenting research and to point to some directions for future inquiry. Over the last 75 years, considerable insight has been gained into individual differences in parenting behavior, especially regarding the dimensions underlying individual differences in general parenting approach, and parenting styles resulting from individual differences on these dimensions. The history of empirical attempts to identify parenting dimensions and styles is reviewed briefly, followed by a review of more recent studies of parenting styles. Next is a discussion of data analytic approaches to measuring parenting, with a particular emphasis on variable-centered versus person-centered approaches. Because investigators have often disagreed about which of these approaches is the most appropriate, the advantages and disadvantages of each are considered, along with recommendations for future research. PMID- 23944921 TI - General and food-specific parenting: measures and interplay. AB - BACKGROUND: Parental influence on child food intake is typically conceptualized at three levels-parenting practices, feeding style, and parenting style. General parenting style is modeled at the most distal level of influence and food parenting practices are conceptualized as the most proximal level of influence. The goal of this article is to provide insights into contents and explanatory value of instruments that have been applied to assess food parenting practices, feeding style, and parenting style. METHODS: Measures of food parenting practices, feeding style, and parenting style were reviewed, compared, and contrasted with regard to contents, explanatory value, and interrelationships. RESULTS: Measures that are used in the field often fail to cover the full scope and complexity of food parenting. Healthy parenting dimensions have generally been found to be positively associated with child food intake (i.e., healthier dietary intake and less intake of energy-dense food products and sugar-sweetened beverages), but effect sizes are low. Evidence for the operation of higher-order moderation has been found, in which the impact of proximal parental influences is moderated by more distal levels of parenting. CONCLUSIONS: Operationalizing parenting at different levels, while applying a contextual higher-order moderation approach, is advocated to have surplus value in understanding the complex process of parent-child interactions in the area of food intake. A research paradigm is presented that may guide future work regarding the conceptualization and modeling of parental influences on child dietary behavior. PMID- 23944922 TI - Food parenting: a selective review of current measurement and an empirical examination to inform future measurement. AB - BACKGROUND: Interactions between parents and children in regard to food are an important part of the development of food preferences and intake patterns for children. The measurement of this complex and multidimensional construct is very challenging. METHODS: This article examines the current status of measurement in this domain in a selective review, considers qualitative input from parents and adolescents in an empirical examination of the topic, and makes concrete recommendations for the future. RESULTS: Qualitatively, there were important differences between what the adolescents reported that their parents did to impact their eating habits, what parents of younger children report they currently do, and what researchers typically measure in research on parental feeding practices. CONCLUSIONS: On the basis of these empirical findings and our review of the literature, we recommend that food parenting be measured on three levels: Feeding styles (e.g., authoritative), food parenting practices (e.g., restriction), and specific feeding behaviors (e.g., putting food out of the child's reach). Specific recommendations for future study are given for each level of measurement. PMID- 23944923 TI - Measurement of general and specific approaches to physical activity parenting: a systematic review. AB - BACKGROUND: Parents play a significant role in shaping youth physical activity (PA). However, interventions targeting PA parenting have been ineffective. Methodological inconsistencies related to the measurement of parental influences may be a contributing factor. The purpose of this article is to review the extant peer-reviewed literature related to the measurement of general and specific parental influences on youth PA. METHODS: A systematic review of studies measuring constructs of PA parenting was conducted. Computerized searches were completed using PubMed, MEDLINE, Academic Search Premier, SPORTDiscus, and PsycINFO. Reference lists of the identified articles were manually reviewed as well as the authors' personal collections. Articles were selected on the basis of strict inclusion criteria and details regarding the measurement protocols were extracted. A total of 117 articles met the inclusionary criteria. Methodological articles that evaluated the validity and reliability of PA parenting measures (n=10) were reviewed separately from parental influence articles (n=107). RESULTS: A significant percentage of studies used measures with indeterminate validity and reliability. A significant percentage of articles did not provide sample items, describe the response format, or report the possible range of scores. No studies were located that evaluated sensitivity to change. CONCLUSION: The reporting of measurement properties and the use of valid and reliable measurement scales need to be improved considerably. PMID- 23944924 TI - Stimulating innovations in the measurement of parenting constructs. AB - Parents can play a crucial role in the development of children's behaviors associated with dietary habits, physical activity, and sedentary lifestyles. Many parenting practices and/or styles measures have been developed; however, there is little agreement as to how the influence of parenting should be measured. More importantly, our ability to relate parenting practices and/or styles to children's behaviors depends on its accurate assessment. While there is a need to standardize our assessment to further advance knowledge in this area, this article will discuss areas that may stimulate advances in the measurement of parenting constructs. Because self-report measures are important for the assessment of parenting, this article discusses whether solutions to improve self report measures may lie in: (1) Improving the questions asked; (2) improving the methods used to correct for social desirability or measurement errors; (3) changing our measurement paradigm to assess implicit parenting behaviors; (4) changing how self-report is collected by taking advantage of ecological momentary assessment methods; (5) using better psychometric methods to validate parenting measures or alternatively using advances in psychometric methods, such as item banking and computerized adaptive testing, to solve common administration issues (i.e., response burden and comparability of results across studies); and (6) employing novel technologies to collect data such as portable technologies, gaming, and virtual reality simulation. This article will briefly discuss the potential of technologies to measure parenting constructs. PMID- 23944925 TI - General and specific approaches to media parenting: a systematic review of current measures, associations with screen-viewing, and measurement implications. AB - BACKGROUND: Parent-focused interventions may help to reduce youth screen-viewing (SV). This review synthesized current information on the links between parenting styles, parenting practices, and youth SV with a focus on measurement. METHODS: A systematic review of electronic databases was conducted. RESULTS: In all, 29 of 1189 studies met the inclusion criteria. Parenting practices were divided into rule and nonrule-based practices. Seven rules: (1) Limits on total time (n studies=23); (2) limits on time of day (n=7); (3) content restriction (n=11); (4) mealtime rules (n=2); (5) parental supervision (n=3); (6) contingent screentime (n=3); and (7) no-TV policy (n=1) were reported. Two nonrule-based practices were reported: Co-viewing (n=6) and encouragement to view (n=2). Three studies (10.3%) provided information on parenting styles. Only 12 studies (41.4%) provided information on the reliability/validity of the outcome measure, 15 (51.7%) studies provided information on the reliability/validity of the parenting measure, and 6 (20.7%) provided information on the reliability/validity of both outcome and exposure measures. CONCLUSIONS: There is mixed evidence that parenting styles and media-related parenting practices are associated with youth SV. The assessment of parental influence of youth media use is hampered by the diversity of measures that have been used. There is a need for new measures that assess a range of media parenting practices that are relevant to multiple forms of SV. PMID- 23944926 TI - Parenting styles and practices in children's obesogenic behaviors: scientific gaps and future research directions. AB - Given the emerging global childhood obesity epidemic and the specter of a generation of children who will have a shorter life expectancy than that of their parents, recent research has focused on factors that influence children's weight status and obesogenic behaviors (i.e., eating, physical activity, and screen media use). Parents act as primary socializing agents for children, and thus growing evidence supports the role of parenting styles and practices in children's obesity-related behaviors and weight. Studying these processes in children and adolescents is important for several reasons. First, diet and physical activity behaviors and weight status track from childhood and adolescence into adulthood. Furthermore, diet and physical activity behaviors and weight status confer significant risk for cancer, diabetes, cardiovascular disease, and other chronic diseases. The purpose of this article is to describe the scientific gaps that need to be addressed to develop a more informed literature on parenting styles and practices in the domains of weight status and obesogenic behaviors, as identified by an expert panel assembled by the National Cancer Institute. PMID- 23944927 TI - Contemporary research on parenting: conceptual, methodological, and translational issues. AB - Researchers over the last decade have documented the association between general parenting style and numerous factors related to childhood obesity (e.g., children's eating behaviors, physical activity, and weight status). Many recent childhood obesity prevention programs are family focused and designed to modify parenting behaviors thought to contribute to childhood obesity risk. This article presents a brief consideration of conceptual, methodological, and translational issues that can inform future research on the role of parenting in childhood obesity. They include: (1) General versus domain specific parenting styles and practices; (2) the role of ethnicity and culture; (3) assessing bidirectional influences; (4) broadening assessments beyond the immediate family; (5) novel approaches to parenting measurement; and (6) designing effective interventions. Numerous directions for future research are offered. PMID- 23944928 TI - Food parenting measurement issues: working group consensus report. AB - Childhood obesity is a growing problem. As more researchers become involved in the study of parenting influences on childhood obesity, there appears to be a lack of agreement regarding the most important parenting constructs of interest, definitions of those constructs, and measurement of those constructs in a consistent manner across studies. This article aims to summarize findings from a working group that convened specifically to discuss measurement issues related to parental influences on childhood obesity. Six subgroups were formed to address key measurement issues. The conceptualization subgroup proposed to define and distinguish constructs of general parenting styles, feeding styles, and food parenting practices with the goal of understanding interrelating levels of parental influence on child eating behaviors. The observational subgroup identified the need to map constructs for use in coding direct observations and create observational measures that can capture the bidirectional effects of parent-child interactions. The self-regulation subgroup proposed an operational definition of child self-regulation of energy intake and suggested future measures of self-regulation across different stages of development. The translational/community involvement subgroup proposed the involvement of community in the development of surveys so that measures adequately reflect cultural understanding and practices of the community. The qualitative methods subgroup proposed qualitative methods as a way to better understand the breadth of food parenting practices and motivations for the use of such practices. The longitudinal subgroup stressed the importance of food parenting measures sensitive to change for use in longitudinal studies. In the creation of new measures, it is important to consider cultural sensitivity and context-specific food parenting domains. Moderating variables such as child temperament and child food preferences should be considered in models. PMID- 23944929 TI - Drug-induced hepatotoxicity: incidence of abnormal liver function tests consistent with volatile anaesthetic hepatitis in trauma patients. AB - BACKGROUND & AIMS: Volatile anaesthetic drug-induced liver injury can range from asymptomatic alanine transaminase elevations to fatal hepatic necrosis. There is very limited research regarding hepatotoxicity of modern volatile anaesthetic agents. The aim of this study was to determine how common liver injury consistent with volatile anaesthetic hepatitis is, following exposure to isoflurane, desflurane and sevoflurane; and to propose risk factors for its development. METHODS: Following ethics approval, we conducted a retrospective audit of adult trauma patients with abnormal liver biochemistry following volatile anaesthesia during January 1 to December 31, 2009. The data collected included patient demographics, volatile anaesthetic administration, concurrent medication, perioperative liver biochemistry results and comorbidities. The Council for International Organisations of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system was used to group cases according to the likelihood of volatile anaesthetic being the causative agent of drug-induced hepatotoxicity. RESULTS: Forty-seven (3%) of 1556 patients had abnormal post operative liver biochemistry potentially attributable to volatile anaesthetic. Of the 47, 12 patients (26%) had peak alanine transaminase levels greater than 200 U/L. No significant predictors of volatile anaesthetic drug-induced liver injury following isoflurane, desflurane or sevoflurane anaesthesia could be identified. CONCLUSION: Volatile anaesthetic drug-induced liver injury in adult trauma patients may be significantly more common than previously noted. This study suggests that about a quarter of patients with volatile anaesthetic drug-induced liver injury develop significant liver injury. Further prospective studies are required to define risk factors and clinical outcomes. PMID- 23944930 TI - Secretory carcinoma of the breast and its histopathological mimics: value of markers for differential diagnosis. AB - AIMS: Secretory carcinoma (SC) is a rare histological type of breast cancer, and ETV6-NTRK3 gene fusion is highly specific to it. The differential diagnoses of SC include acinic cell carcinoma (ACCA) and cystic hypersecretory carcinoma (CHC), as well as invasive ductal carcinoma (IDC). For patients with these rare but distinctive histological subtypes, SC and its histopathological mimics should be differentiated from each other. However, differential markers have not yet been assessed systematically, and we aimed to identify and evaluate novel and existing markers. METHODS AND RESULTS: We reviewed 19 cases diagnosed initially as SC using integrated diagnostic techniques, including morphology, immunohistochemistry and molecular pathology, and validated promising markers in 445 breast cancers. We reclassified 19 formerly diagnosed 'SCs' into nine SCs, three ACCAs, three CHCs, three IDCs and one microglandular adenosis. We confirmed that ETV6-NTRK3 gene rearrangement and amylase positivity are good diagnostic markers for SC and ACCA, respectively. Vacuolar staining for adipophilin, positivity for alpha-lactalbumin and negativity for ETV6 rearrangement are diagnostic markers for CHC. CONCLUSIONS: In this study, we propose a panel of four markers (ETV6 rearrangement, amylase, alpha-lactalbumin and adipophilin) for distinguishing SC, ACCA, CHC and IDC. This simple but robust panel will serve pathologists well as a practical guide for reaching an appropriate diagnosis. PMID- 23944931 TI - Frenolicins C-G, pyranonaphthoquinones from Streptomyces sp. RM-4-15. AB - Appalachian active coal fire sites were selected for the isolation of bacterial strains belonging to the class actinobacteria. A comparison of high-resolution electrospray ionization mass spectrometry (HRESIMS) and ultraviolet (UV) absorption profiles from isolate extracts to natural product databases suggested Streptomyces sp. RM-4-15 to produce unique metabolites. Four new pyranonaphthoquinones, frenolicins C-F (1-4), along with three known analogues, frenolicin (6), frenolicin B (7), and UCF76-A (8), were isolated from the fermentation of this strain. An additional new analogue, frenolicin G (5), along with two known compounds, deoxyfrenolicin (9) and UCF 13 (10), were isolated from the fermentation supplied with 18 mg/L of scandium chloride, the first example, to the best of our knowledge, wherein scandium chloride supplementation led to the confirmed production of new bacterial secondary metabolites. Structures 1-5 were elucidated on the basis of spectral analysis and chemical modification. While frenolicins are best known for their anticoccidial activity, the current study revealed compounds 6-9 to exhibit moderate cytotoxicity against the human lung carcinoma cell line (A549) and thereby extends the anticancer SAR for this privileged scaffold. PMID- 23944932 TI - Surgical management and long-term seizure outcome after epilepsy surgery for different types of epilepsy associated with cerebral cavernous malformations. AB - PURPOSE: Precise outcome data about the surgical therapy of cerebral cavernous malformation (CCM)-associated epilepsy is scarce regarding different epilepsy types, surgical approach, and outcome. Long-term outcome in patients with CCM associated epilepsy is analyzed in a large single-center series. METHODS: Seizure outcome data >24 months was available in 118 patients. The influence of different parameters of preoperative workup and surgical technique was analyzed with regard to seizure outcome. KEY FINDINGS: The study cohort comprised 76 patients with drug-resistant epilepsy (DRE), 20 patients with chronic epilepsy that did not meet the definition of DRE, as well as 22 patients with sporadic seizures. Temporal localization of CCMs predisposed to develop DRE. Detailed epileptologic workup was performed in 85 patients; invasive monitoring was done in 23 (37%) of 76 DRE cases. In 84% of DRE cases more extensive resections were performed. Mean follow-up varied between 107 and 137 months for the three groups. Seizure freedom in DRE was 88%, in chronic epilepsy 80%, and in sporadic seizures was 91%. Longer symptom duration was associated with worse seizure outcome. Outcome of patients who underwent invasive monitoring was not worse. The outcome in CCM-associated DRE can be good if more extensive resections are used and if noninvasive and/or invasive presurgical epileptologic workup is used whenever indicated. DRE was considerably more frequent in the temporal lobe, suggesting that temporal localization predisposes development of DRE. Seizure freedom rates were stable over a long period. SIGNIFICANCE: Surgical therapy of CCM-associated seizures and epilepsy can be successful if different surgical techniques according to presurgical evaluation are realized. To prevent clinical worsening into DRE, surgical intervention in CCM-associated epilepsy may be considered early. PMID- 23944933 TI - Toll-like receptor-mediated airway IL-17C enhances epithelial host defense in an autocrine/paracrine manner. AB - IL-17A, IL-17F, and IL-25 belong to the IL-17 family of cytokines, and are well known to play important roles in the host defense against infection and inflammatory diseases. IL-17C, also a member of the IL-17 family, is highly expressed in the epithelium; however, the function and regulatory mechanism of IL 17C in airway epithelium remain poorly understood. In this study, we demonstrate that polyinosinic-polycytidylic acid (polyI:C), the ligand to Toll-like receptor 3, is a potent inducer of IL-17C mRNA and protein expression in primary normal human bronchial epithelial (NHBE) cells. IL-17C induction by polyI:C was both time dependent and dose dependent, and was attenuated by inhibitors of the Toll IL-1 receptor domain-containing adaptor-inducing INF-beta (TRIF)-NF-kappaB pathway, Pepinh-TRIF, BAY11, NF-kappaB inhibitor III, and NF-kappaB p65 small interfering RNA, suggesting that IL-17C expression is induced by polyI:C via the Toll-like receptor 3-TRIF-NF-kappaB pathway. Both IL-17C and polyI:C increased the expression of antimicrobial peptides and proinflammatory cytokines, such as human beta-defensin (hBD) 2, colony-stimulating factor 3 (CSF3), and S100A12 in NHBE cells. Knockdown of IL-17 receptor (IL-17R) E, the specific receptor for IL 17C, using IL-17RE small interfering RNA, attenuated polyI:C-induced hBD2, CSF3, and S100A12 expression, without any reduction of polyI:C-induced IL-17C expression, which suggest that IL-17C enhances hBD2, CSF, and S100A12 expression in an autocrine/paracrine manner in NHBE cells. Knockdown of IL-17C also decreased polyI:C-induced hBD2, CSF3, and S100A12 expression. Thus, our data demonstrate that IL-17C is an essential epithelial cell-derived cytokine that enhances mucosal host defense responses in a unique autocrine/paracrine manner in the airway epithelium. PMID- 23944934 TI - Coarsening of silver nanoparticles in polyelectrolyte multilayers. AB - In polyelectrolyte multilayer (PEM) films assembled from poly(diallyldimethylammonium chloride) and poly(styrene sulfonate) via the layer by-layer deposition technique, the counterions were exchanged with silver ions, which were subsequently reduced in situ to produce silver (Ag) nanoparticles. The Ag nanoparticles embedded in the PEMs were found to undergo an interesting coarsening process over time, through which smaller Ag nanoparticles coalesce into larger ones until reaching an equilibrium. The process was investigated by monitoring the localized surface plasmon resonance of the Ag nanoparticles using UV-vis extinction spectroscopy, and the spectral evolution revealed an increase in nanoparticle size with time, a trend in qualitative agreement with theoretical calculation and further confirmed by transmission electron microscopy. The kinetics of the coarsening process and the size of Ag nanoparticles at equilibrium were found to be affected by the PEM structure as well as the temperature and relative humidity the PEM was exposed to, and coalescence was identified to be the mechanism. PMID- 23944935 TI - Gingiva as a source of stem cells with therapeutic potential. AB - Postnatal connective tissues contain phenotypically heterogeneous cells populations that include distinct fibroblast subpopulations, pericytes, myofibroblasts, fibrocytes, and tissue-specific mesenchymal stem cells (MSCs). These cells play key roles in tissue development, maintenance, and repair and contribute to various pathologies. Depending on the origin of tissue, connective tissue cells, including MSCs, have different phenotypes. Understanding the identity and specific functions of these distinct tissue-specific cell populations may allow researchers to develop better treatment modalities for tissue regeneration and find novel approaches to prevent pathological conditions. Interestingly, MSCs from adult oral mucosal gingiva possess distinct characteristics, including neural crest origin, multipotent differentiation capacity, fetal-like phenotype, and potent immunomodulatory properties. These characteristics and an easy, relatively noninvasive access to gingival tissue, and fast tissue regeneration after tissue biopsy make gingiva an attractive target for cell isolation for therapeutic purposes aiming to promote tissue regeneration and fast, scar-free wound healing. The purpose of this review is to discuss the identity, phenotypical heterogeneity, and function of gingival MSCs and summarize what is currently known about their properties, role in scar-free healing, and their future therapeutic potential. PMID- 23944936 TI - Aortic regurgitation after transcatheter aortic valve implantation. PMID- 23944937 TI - Cu-NHC-TEMPO catalyzed aerobic oxidation of primary alcohols to aldehydes. AB - Imidazolium salts bearing TEMPO groups react with commercially available copper powder affording Cu-NHC complexes. The in situ generated Cu-NHC-TEMPO complexes are quite efficient catalysts for aerobic oxidation of primary alcohols into aldehydes. The catalyst is easily available, and various primary alcohols were selectively converted to aldehydes in excellent yields. PMID- 23944938 TI - Effects of switching to lower sulfur marine fuel oil on air quality in the San Francisco Bay area. AB - Ocean-going vessels burning high-sulfur heavy fuel oil are an important source of air pollutants, such as sulfur dioxide and particulate matter. Beginning in July 2009, an emission control area was put into effect at ports and along the California coastline, requiring use of lower sulfur fuels in place of heavy fuel oil in main engines of ships. To assess impacts of the fuel changes on air quality at the Port of Oakland and in the surrounding San Francisco Bay area, we analyzed speciated fine particle concentration data from four urban sites and two more remote sites. Measured changes in concentrations of vanadium, a specific marker for heavy fuel oil combustion, are related to overall changes in aerosol emissions from ships. We found a substantial reduction in vanadium concentrations after the fuel change and a 28-72% decrease in SO2 concentrations, with the SO2 decrease varying depending on proximity to shipping lanes. We estimate that the changes in ship fuel reduced ambient PM2.5 mass concentrations at urban sites in the Bay area by about 3.1 +/- 0.6% or 0.28 +/- 0.05 MUg/m(3). The largest contributing factor to lower PM mass concentrations was reductions in particulate sulfate. Absolute sulfate reductions were fairly consistent across sites, whereas trace metal reductions were largest at a monitoring site in West Oakland near the port. PMID- 23944939 TI - Road traffic safety beliefs and driver behaviors among personality subtypes of drivers in the Norwegian population. AB - OBJECTIVE: To identify personality clusters of drivers in a population-based sample and to examine differences in safety beliefs, driver behaviors, and demographics between these clusters. METHODS: A mailed self-completion questionnaire survey was conducted in a random sample of Norwegian drivers obtained from the Norwegian Population Registry (n = 1731). RESULTS: Cluster analysis reflected 4 personality subtypes of drivers. The first cluster consisted of drivers with low normlessness and sensation seeking but high anxiety. The second cluster reported elevated scores on all 3 measured traits, whereas the third cluster had low scores on all traits. The fourth cluster reported low anxiety but high normlessness and sensation seeking. People in the latter cluster reported unsafe road traffic safety beliefs and driver behaviors. These individuals were also more likely to be males and adolescents. People with low normlessness and sensation seeking coupled with high anxiety reported the safest beliefs and behaviors, and this cluster mainly contained females and older individuals. CONCLUSIONS: Countermeasures aimed to reduce the frequency of road traffic accidents should be targeted to specific personality risk groups. Personality traits may also be used in early identification and intervention among risky drivers. PMID- 23944940 TI - Low-frequency electronic noise in single-layer MoS2 transistors. AB - Ubiquitous low-frequency 1/f noise can be a limiting factor in the performance and application of nanoscale devices. Here, we quantitatively investigate low frequency electronic noise in single-layer transition metal dichalcogenide MoS2 field-effect transistors. The measured 1/f noise can be explained by an empirical formulation of mobility fluctuations with the Hooge parameter ranging between 0.005 and 2.0 in vacuum (<10(-5) Torr). The field-effect mobility decreased, and the noise amplitude increased by an order of magnitude in ambient conditions, revealing the significant influence of atmospheric adsorbates on charge transport. In addition, single Lorentzian generation-recombination noise was observed to increase by an order of magnitude as the devices were cooled from 300 to 6.5 K. PMID- 23944941 TI - Bioactive molecules and antioxidant activity in durum wheat grains and related millstream fractions. AB - The present study was performed to evaluate the distribution of phytochemicals in wheat grains and millstreams and the contribution of these compounds to the antioxidant activity. Bioactive molecules, although related to genotype, were highly affected by the milling procedure applied. Carotenoids were unevenly distributed in the kernel and lutein resulted to be the main carotenoid in all samples considered. The WSB method was confirmed to be a useful tool to detect yellow color intensity of semolina but it was not suitable to get information on the true content of carotenoids of the sample. Water-methanol soluble components showed antioxidant activity which decreased from the outer to the inner parts of the kernel. Chloroform-methanol soluble compounds showed generally negligible or negative antioxidant activity due to the inadequate amount of antioxidants unable to counteract oxidative processes already in progress. PMID- 23944942 TI - Selenium@mesoporous carbon composite with superior lithium and sodium storage capacity. AB - Selenium-impregnated carbon composites were synthesized by infusing Se into mesoporous carbon at a temperature of 600 degrees C under vacuum. Ring structured Se8 was produced and confined in the mesoporous carbon, which acts as an electronic conductive matrix. During the electrochemical process in low-cost LiPF6/EC/DEC electrolyte, low-order polyselenide intermediates formed and were stabilized by mesoporous carbon, which avoided the shuttle reaction of polyselenides. Exceptional electrochemical performance of Se/mesoporous carbon composites was demonstrated in both Li-ion and Na-ion batteries. In lithium-ion batteries, Se8/mesoporous carbon composite cathodes delivered a reversible capacity of 480 mAh g(-1) for 1000 charge/discharge cycles without any capacity loss, while in Na-ion batteries, it provided initial capacity of 485 mAh g(-1) and retained 340 mAh g(-1) after 380 cycles. The Se8/mesoporous carbon composites also showed excellent rate capability. As the current density increased from 0.1 to 5 C, the capacity retained about 46% in Li-ion batteries and 34% in Na-ion batteries. PMID- 23944943 TI - Significance of cervical ripening in pre-induction treatment for premature rupture of membranes at term. AB - AIM: This study aimed to determine whether mechanical cervical dilatation with a laminaria tent in women with premature rupture of membranes (PROM) at term may influence the maternal/neonatal outcomes. METHODS: We reviewed the medical records and histopathologic results of the placenta in 782 women with PROM at term. Of the 486 women seen prior to 2010 (group 1), 85 had Bishop scores of 5 or less and underwent insertion of laminaria tents (group A). In the 296 women admitted after 2010 (group 2), 27 had Bishop scores of 5 or less and underwent labor management without insertion of laminaria tents (group B). The patient characteristics, delivery course and neonatal outcomes were compared between the groups. RESULTS: There were no significant differences in the maternal age, percentage of nulliparas, body mass index, gestational age at delivery or Bishop score between the groups. The Bishop score improved from 2.5 to 6.1 after laminaria tent insertion in group A. However, there were no significant intergroup differences in the frequency of use of labor-inducing agents or the time interval from PROM to delivery. The incidence of clinical/pathological chorioamnionitis was not higher in group A than in group B. No significant differences were found in the Apgar scores, umbilical artery pH or frequency of asphyxia neonatorum between the groups. Mechanical cervical dilatation by laminaria tent insertion neither increased the incidence of infection nor contributed to improvement of the perinatal prognosis. CONCLUSION: Mechanical cervical dilatation does not provide any benefit for women with PROM at term. PMID- 23944944 TI - Clinical significance of pathological eye movements in diagnosing posterior fossa stroke. AB - CONCLUSION: Close observation of pathological eye movements such as disconjugate eye movements, multi-directional gaze nystagmus, and persistent unilateral gaze nystagmus may facilitate the effort of clinicians to arrange magnetic resonance imaging (MRI) study, because physical examinations may overlook the posterior fossa lesions. OBJECTIVE: This paper reviews our experience of patients with posterior fossa stroke via observation of pathological eye movements over the past 10 years. METHODS: Seventy patients with posterior fossa stroke manifested as acute vertiginous attack were admitted. All patients underwent examination of eye movements, MRI, and a battery of audiovestibular function tests. RESULTS: Of the 70 patients, 22 (31%) demonstrated pathological eye movements including persistent (>24 h) unilateral gaze nystagmus in 12 patients, and multi directional gaze nystagmus in 10 patients. Conjugate eyes movements were identified in 18 patients, and disconjugate eye movements were shown in 4 patients including medial longitudinal fasciculus syndrome in 1, paramedian pontine reticular formation syndrome in 1, and one and a half syndrome in 2. The vestibular test battery revealed abnormal responses for >85% of the patients in each test. MRI demonstrated infarction or hemorrhage involving the brainstem in 12 patients, cerebellum in 8 patients, and both in 2 patients. PMID- 23944945 TI - Effects of FESS and additional fluticasone propionate nasal drops on psychological well-being in nasal polyposis with asthma. AB - CONCLUSION: A combined therapy of fluticasone propionate nasal drops (FPND) and functional endoscopic sinus surgery (FESS) can improve quality of life (QoL). When compared with prior data, the results imply that a generic measure of psychological aspects of QoL may be better than measures of respiratory symptoms and clinical parameters to capture a patient's perception of the disease and its treatment. OBJECTIVE: To better understand effects of FPND and FESS on generic QoL. METHODS: Sixty nasal polyposis patients with concomitant asthma completed participation in a randomized, double-blind, placebo-controlled, 14-week study in which they responded to the General Well-Being Schedule (GWBS). RESULTS: GWBS scores (i) increased significantly after administration of FPND, independent of FESS (from lower than normal to normal), (ii) increased after FESS independent of FPND (from lower than normal to normal), and (iii) increased additively after FPND and FESS. PMID- 23944946 TI - Management of post-traumatic cerebrospinal fluid (CSF) leak of anterior skull base: 10 years experience. AB - CONCLUSION: Anterior skull base cerebrospinal fluid (CSF) leak should be surgically repaired with an endonasal approach first for less morbidity. Pretherapeutic topographical diagnosis increases the success rate of surgical repair. OBJECTIVES: We aimed to evaluate our efficiency in taking care of post traumatic anterior skull base CSF leak, since no consensual algorithms for diagnosis and treatment have been established. METHODS: Data from 40 patients treated for post-traumatic CSF leak of the anterior skull base between January 1997 and December 2008 were retrospectively reviewed. Twenty-nine patients were treated with surgery, with an endonasal approach in 14 patients and a neurosurgical approach in 15 patients. A wait and see policy was applied in 11 patients. RESULTS: The overall risk of reccurence was 22.5%. Recurrence was represented by the presence of CSF rhinorrhea in 12.5% and the appearance of meningitis in 10% of patients. The overall risk of postoperative anosmia was 27.5%. A wait and see policy led to a higher risk of developing meningitis than surgical repair (p = 0.0003). The absence of pretherapeutic topographical diagnosis led to a higher risk of recurrence of CSF rhinorrhea (p = 0.01). The endonasal approach resulted in less postoperative anosmia (p = 0.006). PMID- 23944947 TI - Expression and localization of taste receptor genes in the vallate papillae of rats: effect of zinc deficiency. AB - CONCLUSION: We found a difference in expression sites between TAS2Rs and ENaC (epithelial sodium channels). The number of TAS2R-positive cells and ENaC positive cells were decreased in zinc-deficient diet rats. These findings suggest that decreased expression of taste receptor genes may play an important role in the onset of zinc deficiency-associated taste disorder. OBJECTIVE: The present study was aimed at histologically investigating the expression and localization of TAS2Rs and ENaC in the vallate taste buds of rats. Changes in expression of the taste receptor genes in zinc-deficient rats were also investigated. METHODS: The vallate papillae of five rats fed a normal diet and five rats fed a zinc deficient diet were used. In situ hybridization was performed to investigate the expression and localization of TAS2Rs and ENaC. TAS2R-positive cells per taste bud were counted, and differences in number between the normal and zinc-deficient diet rats were investigated. RESULTS: In the normal rats, expression of TAS2Rs was observed specifically in the taste bud cells. In contrast, ENaC-positive cells were observed in a part of the taste bud cells and a large number of epithelial cells. Fewer cells were positive for TAS2Rs and ENaC in the zinc deficient diet rats. PMID- 23944948 TI - Nodal yield in selective neck dissection. AB - CONCLUSION: The total lymph node yield in neck dissection is highly variable and depends on anatomical, surgical and pathological parameters. A minimum yield of six lymph nodes for a selective neck dissection (SND) as recommended in guidelines lies in the lower range of the reported clinical nodal yields. A future application of a lymph node ratio may improve the risk stratification of head and neck cancer patients. However, this will require a higher number of retrieved lymph nodes. OBJECTIVES: To compare the clinical guideline recommendations for nodal yield in SND with the number of lymph nodes obtained from cadavers and the clinical nodal yield reported in the literature. METHODS: Lymph nodes retrieved from SND specimens from nine fresh cadavers were quantified histopathologically. The literature on nodal yields reportedly obtained by clinicians performing neck dissections was reviewed. Finally, the discussion makes reference to the six lymph nodes currently recommended in international clinical guidelines. RESULTS: For clinical SNDs (I-III) the lowest mean nodal yield was 19.4, for SNDs (II-IV) it was 26.4. The cadaver SNDs (I-III and II-IV) yielded 8.8 (range 1-15) and 10.4 nodes (range 1-19), respectively. PMID- 23944949 TI - Human papilloma virus (HPV) is not implicated in the etiology of Warthin's tumor of the parotid gland. AB - CONCLUSION: The lack of human papilloma virus (HPV) sequences as well as potential HPV-activated cells such as cells that would be p16- and Ki-67 positive does not support a role of HPV in the pathogenesis of this lesion. OBJECTIVE: The exact etiopathogenesis of Warthin's tumor of the parotid gland is still unclear. The aim of the present study was to evaluate if HPV could play a role in the development of this parotid lesion. METHODS: Tissue samples from 40 Warthin's tumors of the parotid gland were investigated by PCR followed by in situ hybridization. The immunohistochemical expression of p16 and the dual immunostaining of p16 and Ki-67 were evaluated in all samples. RESULTS: Strong and diffuse p16 immunoreactivity was found in 7 of the 40 cases (17.5%). In situ hybridization showed a diffuse episomal signal in those samples. However, PCR could not reliably detect the presence of HPV genes. Furthermore, p16-expressing epithelial cells were mostly negative for the proliferation marker Ki-67. PMID- 23944950 TI - Clinical analysis of 21 cases of cervical tuberculous lymphadenitis without active pulmonary lesion. AB - CONCLUSION: The necessity of considering cervical tuberculous lymphadenitis (CTL) should be emphasized even today for the differential diagnosis of cervical lymphadenopathy, particularly when it is located in the posterior triangle and supraclavicular regions even in patients without active pulmonary tuberculosis (PTB). OBJECTIVE: This study was conducted to highlight the characteristics of patients with CTL without active PTB who were treated in our department. METHODS: Between 2004 and 2011, 21 cases of CTL without active PTB were included in this retrospective study. Histological examination after excisional biopsy of the affected lymph node was performed in 18 patients using hematoxylin and eosin staining and Ziehl-Neelsen (Z-N) staining for acid-fast bacilli (AFB) identification. Growth of Mycobacterium tuberculosis was detected by culturing and/or nucleic acid amplification tests including polymerase chain reaction (PCR) and transcription-mediated amplification (Mycobacterium Tuberculosis Direct: MTD). RESULTS: The male to female ratio was 1:1.3. Patient ages ranged from 22 to 89 years. Eighteen patients (85.7%) complained of indolent unilateral cervical lymphadenopathy in the posterior triangle (26.5%), internal jugular (24.5%), or supraclavicular nodes (18.4%). Positive rates of AFB according to Z-N staining and culturing of M. tuberculosis and/or PCR or MTD were 33.3% (6/18) and 72.2% (13/18), respectively. PMID- 23944951 TI - Recurrent loss of the FHIT gene and its impact on lymphatic metastasis in early oral squamous cell carcinoma. AB - CONCLUSION: Our findings show that copy number loss of FHIT is associated with lymph node metastasis (LNM) and suggest that the down-regulation of Fhit indicates poor prognosis in early oral squamous cell carcinoma (OSCC). OBJECTIVES: The purpose of this study was to identify alterations in genetic markers related to LNM in early OSCC. METHODS: Genome-wide copy number alterations were analyzed in 14 early OSCCs with (n = 7) or without (n = 7) cervical LNM using 180K array-comparative genomic hybridization. To explore the prognostic implications of the most significantly associated genetic alteration with cervical LNM, immunohistochemical analysis was conducted in 30 OSCCs. RESULTS: A total of 11 recurrently altered regions (RARs) were identified in the 14 OSCC cases. Six RARs on chromosomes 3p26-3p14, 5q22, and 9p21 were found to be significantly more common in early OSCC with LNM (p < 0.05). Among these, loss of 3p14.2 (where the FHIT gene is located) was the most frequent (five of seven patients with LNM, and none of seven without LNM), and most significantly associated with cervical LNM (p = 0.005). Fhit immunohistochemical staining of 30 OSCCs showed that Fhit negativity was associated with cervical LNM (p = 0.032) and poor disease-specific survival (p = 0.045). PMID- 23944952 TI - Editorial comment to Microvessel area of immature vessels is a prognostic factor in renal cell carcinoma. PMID- 23944953 TI - Two new C-methyl flavanones from the rhizomes and frond bases of Matteuccia struthiopteris. AB - Two new C-methyl flavanones, (2S)-5,7-dihydroxy-6,8-dimethyl-4' methoxydihydroflavone-7-O-(6"-O-acetyl)-beta-d-glucopyranoside (1) and (2S)-5,7 dihydroxy-6,8-dimethyldihydroflavone-7-O-(6"-O-acetyl)-beta-d-glucopyranoside (2), together with five known compounds, demethoxymatteucinol-7-O-beta-d glucopyranoside (3), matteucinol-7-O-beta-d-glucopyranoside (4), 5,7-dihydroxy-6 methyl-4'-methoxydihydroflavone (5), methoxymatteucin (6), and thunberginol C (7), were first isolated from the EtOH extract of the rhizomes and frond bases of Matteuccia struthiopteris. The structures were established by spectral analyses, mainly HR-ESI-MS and 1D and 2D NMR experiments (COSY, HSQC, and HMBC). PMID- 23944954 TI - Hepatic steatosis in diabetic patients does not predict adverse liver-related or cardiovascular outcomes. AB - BACKGROUND & AIMS: Steatosis is a defining feature of nonalcoholic fatty liver disease (NAFLD). However, evidence that severity of steatosis can predict adverse outcomes in NAFLD or nonalcoholic steatohepatitis (NASH) is lacking. The aim of this study was to determine whether steatosis assessed by computed tomography (CT) imaging predicts adverse outcomes in diabetic patients at risk for NAFLD/NASH. METHODS: We studied deaths, liver-related and cardiovascular adverse outcomes in a 5-year retrospective observational cohort of 2343 type 2 diabetic patients in a large care network who had noncontrast CT imaging for clinical indications. We measured steatosis by subtraction of spleen from liver attenuation, a method that showed low sensitivity (0.417) and high specificity (0.882) compared with histopathological scoring. We evaluated outcomes prediction using multivariate Cox proportional hazards modelling of steatosis both as a categorical (>= 30%) and continuous variable. RESULTS: Steatosis >= 30% was present in 233 (9.9%) of the cohort at baseline. Over 5 years, there were 372 total deaths, 18 liver-related and 99 cardiovascular deaths, 48 liver transplants, 51 occurrences of hepatic encephalopathy, 41 hepatocellular carcinomas, 653 myocardial infarctions, 66 strokes, 180 occurrences of angina, 735 occurrences of arrhythmia and 772 occurrences of congestive heart failure. Steatosis had no predictive value for any adverse outcome. Patients with steatosis averaged 8 years younger than those without it. Age had a strong covariate influence on occurrence of total deaths, cardiovascular deaths, myocardial infarctions, arrhythmias and congestive heart failure. CONCLUSION: Although steatosis on imaging is often the abnormality that triggers diagnosis and assessment of NAFLD/NASH, it lacks predictive value for adverse clinical outcomes. PMID- 23944955 TI - A multistep algorithm for processing and calibration of microdialysis continuous glucose monitoring data. AB - BACKGROUND: The deviation of continuous subcutaneous glucose monitoring (CGM) data from reference blood glucose measurements is substantial, and adequate signal processing is required to reduce the discrepancy between subcutaneous glucose and blood glucose values. The purpose of this study was to develop a multistep algorithm for the processing and calibration of continuous subcutaneous glucose monitoring data with high accuracy and short delay. Algorithm PRESENTATION: The algorithm comprises three steps: rate-limiting filtering, selective smoothing, and robust calibration. Initially, the algorithm detects nonphysiological glucose rate-of-change and corrects it with a weighted local polynomial. Noisy signal parts that require smoothing are then detected based on zero crossing count of the sensor signal first-order differences, and an exponentially weighted moving average smooths the noisy parts of the signal afterward. Finally, calibration is performed using a first-order polynomial as the conversion function, with coefficients being estimated using robust regression with a bi-square weight function. ALGORITHM PERFORMANCE: The performance of the algorithm was evaluated on 16 patients with type 1 diabetes mellitus. To compare the algorithm with state-of-the-art CGM data denoising and calibration, the rate-limiting filter and selective smoothing were replaced with an adaptive Kalman filter, and the calibration method was replaced with the calibration algorithm presented in one of the Medtronic (Northridge, CA) CGM patents. The median (mean) of the absolute relative deviation (ARD) of the sensor glucose values processed by the newly developed algorithm from capillary reference blood glucose measurements was 14.8% (22.6%), 10.6% (14.6%), and 8.9% (11.7%) in hypoglycemia, euglycemia, and hyperglycemia, respectively, whereas for the alternative algorithm, the median (mean) was 22.2% (26.9%), 12.1% (15.9%), and 8.8 (11.3%), respectively. The median (mean) ARD in all ranges was 10.3% (14.7%) for the new algorithm and 11.5% (15.8%) for the alternative algorithm. The new algorithm had an average delay of 2.1 min across the patients, and the alternative algorithm had an average delay of 2.9 min. CONCLUSIONS: The presented algorithm may increase the accuracy of CGM data. PMID- 23944956 TI - Regional increase of cerebral cortex thickness in juvenile myoclonic epilepsy. AB - The goal of this study was to characterize cerebral cortex thickness patterns in juvenile myoclonic epilepsy (JME). Surface-based morphometry (SBM) was applied to process brain magnetic resonance images acquired from 24 patients with JME and 40 healthy controls and quantify cerebral cortex thickness. Differences in cortical thickness between patients and controls were determined using generalized linear model (covariates: age and gender). In patients with JME, thickness increase was detected bilaterally within localized regions in the orbitofrontal and mesial frontal cortices. Such thickness patterns coexisted with significant bilateral reduction in thalamic volume. These findings confirm that the underlying mechanisms in JME are related to aberrant corticothalamic structure and indicate that frontal cortex abnormalities are possibly linked to regional increase in cerebral cortical thickness. PMID- 23944957 TI - Airway smooth muscle hyperproliferation is regulated by microRNA-221 in severe asthma. AB - Increased airway smooth muscle (ASM) mass is a feature of asthmatic airways, and could result from augmented proliferation. We determined whether proliferation and IL-6 release are abnormal in ASM cells (ASMCs) from patients with severe asthma, and whether these features could be mediated by microRNA-221 and microRNA 222, through modulation of the cyclin-dependent kinase inhibitors, p21(WAF1) and p27(kip1). ASMCs cultured from bronchial biopsies of healthy subjects and patients with nonsevere or severe asthma were studied. Proliferation was measured by the incorporation of bromodeoxyuridine and IL-6 by ELISA. FCS and transforming growth factor (TGF)-beta caused greater proliferation and IL-6 release in patients with severe compared with nonsevere asthma and normal subjects. FCS + TGF-beta inhibited p21(WAF1) and p27(kip1) expression, and increased microRNA-221 (miR-221) expression in ASMCs from individuals with severe asthma. miR-221, and not miR-222, mimics the increased proliferation and IL-6 release induced by FCS + TGF in healthy ASM, whereas in patients with severe asthma, the inhibition of miR 221, but not miR-222, inhibited proliferation and IL-6 release. miR-221 inhibition led to the increased expression of FCS + TGF-beta-induced p21(WAF1) and p27(kip1). Dexamethasone suppressed proliferation in healthy subjects, but not in subjects with asthma. IL-6 was less suppressible by dexamethasone in patients with nonsevere and severe asthma, compared with healthy subjects. miR 221 did not influence the effects of dexamethasone. ASM from patients with severe asthma shows greater proliferation and IL-6 release than in patients with nonsevere asthma, but both groups show corticosteroid insensitivity. miR-221 regulates p21(WAF1) and p27(kip1) expression levels. Furthermore, miR-221 regulates the hyperproliferation and IL-6 release of ASMCs from patients with severe asthma, but does not regulate corticosteroid insensitivity. PMID- 23944958 TI - Dysplastic extramedullary haematopoeisis with ringed sideroblasts mimicking adrenal adenoma. PMID- 23944959 TI - The disfluent speech of a Spanish-English bilingual child who stutters. AB - This study provides a detailed description of the disfluent speech behaviours produced by a 6;1-year-old bilingual Spanish-English speaking female with confirmed stuttering. Eight language samples across different contexts (narratives and conversations) with the clinician in English and Spanish and the parent in Spanish were analysed. Language samples were transcribed in the Systematic Analysis of Language Transcripts programme and coded for types of disfluencies based on guidelines for monolingual English speakers. Similarities and differences were noted in speech disfluencies produced in English as compared Spanish. Overall, the participant was more disfluent in English across both her narrative and her conversational output. However, she produced more stuttering like disfluencies in her Spanish narrative sample than her English narrative sample. Conversely, she produced more nonstuttering-like disfluencies in her English than her Spanish narrative sample. These findings suggest stuttering specific as well as language specific contributors to the fluency breakdowns that characterize the speech output of a bilingual Spanish English child who stutters. PMID- 23944960 TI - Validation of a residue analysis method for streptomycin and tetracycline and their food safety evaluation in pomegranate (Punica granatum L.). AB - A single-step methanol extraction based method was developed and validated for simultaneous estimation of the residues of streptomycin and tetracycline group compounds in pomegranate fruits by LC-MS/MS. The limits of quantification for all target compounds were <=0.005 mg kg(-1) with recoveries (%) at fortification levels of 0.005, 0.01, and 0.05 mg kg(-1) being within 90-116% (RSD <= 9%) and interday precision RSD <= 12% at 0.01 mg kg(-1). A field experiment on the dissipation of streptomycin and tetracycline (including 4-epimers) residues in pomegranate fruits with regards to field applications of the commercial formulation Streptocycline SP (streptomycin sulfate 90% + tetracycline hydrochloride 10%) at 200 and 400 g a.i. ha(-1) indicated preharvest intervals of 45 and 55 days for streptomycin and 12 and 15 days for tetracycline, respectively. The study will be useful in promoting effective residue monitoring and ensuring safe use of these antibiotics in managing bacterial diseases of pomegranate. PMID- 23944961 TI - Adsorption and release of active species into and from multifunctional ionic microgel particles. AB - We synthesize monodisperse ionic microgel particles which undergo a large change in volume in response to environmental stimuli such as pH and temperature. In addition, the study elucidates the effective uptake and release of rheology modifiers from these microgel particles to alter the bulk viscosity of a surrounding fluid. Moreover, we found that the prepared ionic microgel particles can demonstrate abilities to adsorb and repel iron oxide nanoparticles (Fe3O4 NPs) upon pH variation. The extent of the loading of Fe3O4-NPs within the colloidal particles and morphology can be manipulated by tunable interactions between the Fe3O4-NPs and ionic microgel particles. PMID- 23944962 TI - Analysis of extracted cardiac device leads for bacteria type: clinical impact. AB - The use of cardiac implantable electronic devices (CIED) increased over time, followed by rise of CIED-related complications, mainly infections and malfunctions. A clear diagnosis of CIED infection is of pivotal importance. When infection is confirmed, transvenous lead extraction (TLE) becomes mandatory, with associated risks and mortality. Local lesions at the device pocket often return negative swabs and tissue specimens, but conservative interventions are inconclusive, raising risks of systemic dissemination of infection and difficulties of subsequent TLE any more. When local bacteriological analyses are positive, once again, a contamination effect cannot be excluded. So traditional local swabs and tissue specimens exhibit low sensitivity and specificity for diagnosis of CIED infection. On the contrary, in cases sepsis, blood samples show high specificity, while the sensibility remains low, due to possible negative results in patients on antibiotics. In this scenario, the analysis of extracted device leads seems more appropriate for diagnostic purposes. PMID- 23944963 TI - Structures and potential antitumor activity of sesterterpenes from the marine sponge Hyrtios communis. AB - The extract of marine sponge Hyrtios communis was found to inhibit activation of the transcription factor hypoxia-inducible factor-1 (HIF-1) in T47D human breast tumor cells. Bioassay-guided isolation led to the identification of six new (1-6) and five previously reported (7-11) sesterterpene analogues and two unrelated sesterterpenes. Two new sesterterpenes, thorectidaeolide A (1) and 4 acetoxythorectidaeolide A (2), and luffariellolide (11) were among the most potent inhibitors of hypoxia (1% O2)-induced HIF-1 activation (IC50 values of 3.2, 3.5, and 3.6 MUM, respectively). Luffariellolide (11) exhibited a significant level of cytotoxicity that mirrored its HIF-1 inhibitory activity. Neither compound 1, compound 2, nor any of the other less active sesterterpenes suppressed breast tumor T47D or MDA-MB-231 cell viability. PMID- 23944964 TI - Development of aceclofenac nanovesicular system using biomaterial for transdermal delivery: physical characterization, ex vivo, in vivo, and anti-inflammatory studies. AB - CONTEXT: Aceclofenac is an important NSAID; however, it causes GI disturbances whereas employing transdermal route would require permeation enhancer for systemic application, thereby causing skin damage. Ceramide 2 is a natural lipid having an important role in the maintenance of skin. OBJECTIVE: Aceclofenac loaded nanovesicles of ceramide-2, cholesterol, palmitic acid, and cholesteryl sulfate were formulated and analyzed for physical and biological properties. MATERIALS AND METHOD: Film hydration method was used to prepare the vesicles and physical parameters, in vitro drug release and stability were evaluated. Then, they were formulated into gel and evaluated against a commercial formulation (CF) and gel-containing plain drug (CPG) for ex vivo, in vivo drug permeation, and anti-inflammatory activity. RESULTS: The developed formulations showed best physical profile and ACV-1 gave 92.89% drug release in in vitro studies. Ex vivo studies showed drug permeation between 15.32-31.12 MUg/cm(2), whereas CPG and CF released 0.47 and 2.81 MUg/cm(2), respectively. ACVG-1 and CF showed Cmax of 8.1 and 1.2 MUg/ml at 8 and 4 h, respectively. ACVG-1 showed 11.6 times AUC than CF. ACVG-1 inhibited edema by 44% in first hour itself. DISCUSSION: Ceramide 2 and palmitic acid played an important role in the formulation and promotes the drug permeation through stratum corneum and dermis. Ceramide content of the formulation also contributes towards stability and skin protection. CONCLUSION: The composition of the vesicle formulation performs an important role in physical properties and drug permeation, thereby producing an optimum formulation. PMID- 23944965 TI - Limits of the linear accumulation regime of DGT sensors. AB - A key question for the practical application of DGT (Diffusive Gradients in Thin films) as dynamic sensors in the environmental monitoring of trace metals is the influence of pH and dissolved ligands over the linear accumulation regime. Protons compete with metal ions for the binding to the DGT resin sites at relatively low pH, whereas high affinity dissolved ligands compete with resin sites for the binding of metals. Any of the two phenomena can lead to a departure from the linear accumulation regime and an underestimation of the actual species concentration in solution. These effects are studied here through numerical simulation of the diffusion-reaction processes in both gel and resin domains using a detailed chemical model of metal ions and protons interacting with resin sites. Results were tested successfully against experimental data of the Cd-NTA representative system. Charts to delimitate the range of experimental conditions (pH, ligand concentration and strength) where the linear accumulation regime prevails, can be helpful for designing sampling strategies in field conditions. For example, it is foreseen that perturbations of linear regime within 10 h of deployment are negligible above pH 5 and weak complexation (log K' < 0) or above pH 7 and strong complexation (log K' < 3), where K' is the effective stability constant. These plots can also be approximately used for partially labile systems whenever the time is replaced with the product lability degree times t. PMID- 23944966 TI - Toward the microscopic identification of anions and cations at the ionic liquid|Ag(111) interface: a combined experimental and theoretical investigation. AB - The interaction between an adsorbed 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide, [BMP][TFSA], ionic liquid (IL) layer and a Ag(111) substrate, under ultrahigh-vacuum conditions, was investigated in a combined experimental and theoretical approach, by high-resolution scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS), and dispersion-corrected density functional theory calculations (DFT-D). Most importantly, we succeeded in unambiguously identifying cations and anions in the adlayer by comparing experimental images with submolecular resolution and simulated STM images based on DFT calculations, and these findings are in perfect agreement with the 1:1 ratio of anions and cations adsorbed on the metal derived from XPS measurements. Different adlayer phases include a mobile 2D liquid phase at room temperature and two 2D solid phases at around 100 K, i.e., a 2D glass phase with short-range order and some residual, but very limited mobility and a long-range ordered 2D crystalline phase. The mobility in the different adlayer phases, including melting of the 2D crystalline phase, was evaluated by dynamic STM imaging. The DFT-D calculations show that the interaction with the substrate is composed of mainly van der Waals and weak electrostatic (dipole-induced dipole) interactions and that upon adsorption most of the charge remains at the IL, leading to attractive electrostatic interactions between the adsorbed species. PMID- 23944967 TI - Synthesis of chromeno[2,3-d]imidazol-9(1H)-ones via tandem reactions of 3 iodochromones with amidines involving copper-catalyzed C-H functionalization and C-O bond formation. AB - A novel six-membered heterocyclic skeleton of imidazochromone was prepared via an efficient one-pot reaction including a key step of copper-catalyzed aerobic C-H intramolecular cycloetherification. Notably, this process does not require the presence of strong para electron-withdrawing groups on the phenol component. Also, the results of this effort show that acyl phenols containing electron-rich heterocycles participate in an efficient C-H activation/C-O formation process. PMID- 23944968 TI - Creativity and improvisation as therapeutic tools within music therapy. AB - The neuroscience of creativity and music improvisation is a fascinating topic and one with strong implications for clinical music therapy. Music therapists are trained to use musical improvisation as a means to bring their clients into deeper therapeutic relationship as well as free up any inhibitions or limitations that may block recovery. Could recent fMRI studies of jazz musicians showing areas of brain activation during music improvisation provide a new framework to understand underlying mechanisms at work with neurologically impaired individuals? PMID- 23944969 TI - Normative concentrations of urine thiocyanate in cassava eating communities in Nigeria. AB - Exposure to cyanide is a major public health problem where highly cyanogenic cassava foods are consumed. Thiocyanate (SCN), the biomarker of exposure to cyanide is present in several foods, and produced endogenously. Concentrations of urine SCN were measured in endemic and non-endemic areas of ataxic polyneuropathy in Nigeria. Cassava food consumption in the endemic area was twice that of non endemic areas. Geometrical mean (95% CI) urine SCN was 20 umol/l (18-24) for no consumption of cassava foods, 56 umol/l (49-64) for daily consumption, 56 umol/l (48-65) for twice daily consumption and 85 umol/l (62-117) for thrice daily consumption. 95th percentile reference limit was 125 umol/l for no consumption of cassava food, but 360 umol/l for thrice daily consumption. Urine SCN is a useful biomarker of exposure to cyanide from cassava foods. There is strong ecological association of exposure to cyanide and endemicity of ataxic polyneuropathy. PMID- 23944970 TI - A national action plan for promoting preconception health and health care in the United States (2012-2014). AB - Preconception health and health care (PCHHC) has gained increasing popularity as a key prevention strategy for improving outcomes for women and infants, both domestically and internationally. The Action Plan for the National Initiative on Preconception Health and Health Care: A Report of the PCHHC Steering Committee (2012-2014) provides a model that states, communities, public, and private organizations can use to help guide strategic planning for promoting preconception care projects. Since 2005, a national public-private PCHHC initiative has worked to create and implement recommendations on this topic. Leadership and funding from the Centers for Disease Control and Prevention combined with the commitment of maternal and child health leaders across the country brought together key partners from the public and private sector to provide expertise and technical assistance to develop an updated national action plan for the PCHHC Initiative. Key activities for this process included the identification of goals, objectives, strategies, actions, and anticipated timelines for the five workgroups that were established as part of the original PCHHC Initiative. These are further described in the action plan. To assist other groups doing similar work, this article discusses the approach members of the PCHHC Initiative took to convene local, state, and national leaders to enhance the implementation of preconception care nationally through accomplishments, lessons learned, and projections for future directions. PMID- 23944971 TI - Approach to prophylactic measures for central venous catheter-related infections in hemodialysis: a critical review. AB - Vascular access is the major risk factor for bacteremia, hospitalization, and mortality among hemodialysis (HD) patients. The type of vascular access most associated with bloodstream infection is central venous catheter (CVC). The incidence of catheter-related bacteremia ranges between 0.6 and 6.5 episodes per 1000 catheter days and increases linearly with the duration of catheter use. Given the high prevalence of CVC use and its direct association with catheter related bacteremia, which adversely impacts morbidity and mortality rates and costs among HD patients, several prevention measures aimed at reducing the rates of CVC-related infections have been proposed and implemented. As a result, a large number of clinical trials, systematic reviews, and meta-analyses have been conducted in order to assess the effectiveness, clinical applicability, and long term adverse effects of such measures. In the following article, prophylactic measures against CVC-related infections in HD patients and their possible advantages and limitations will be discussed, and the more recent literature on clinical experience with prophylactic antimicrobial lock therapy in HD CVCs will be reviewed. PMID- 23944972 TI - Isolation and characterisation of a dwarf rice mutant exhibiting defective gibberellins biosynthesis. AB - We have isolated a severe dwarf mutant derived from a Ds (Dissociation) insertion mutant rice (Oryza sativa var. japonica c.v. Dongjin). This severe dwarf phenotype, has short and dark green leaves, reduced shoot growth early in the seedling stage, and later severe dwarfism with failure to initiate flowering. When treated with bioactive GA3 , mutants are restored to the normal wild-type phenotype. Reverse transcription PCR analyses of 22 candidate genes related to the gibberellin (GA) biosynthesis pathway revealed that among 22 candidate genes tested, a dwarf mutant transcript was not expressed only in one OsKS2 gene. Genetic analysis revealed that the severe dwarf phenotype was controlled by recessive mutation of a single nuclear gene. The putative OsKS2 gene was a chromosome 4-located ent-kaurene synthase (KS), encoding the enzyme that catalyses an early step of the GA biosynthesis pathway. Sequence analysis revealed that osks2 carried a 1-bp deletion in the ORF region of OsKS2, which led to a loss-of-function mutation. The expression pattern of OsKS2 in wild-type cv Dongjin, showed that it is expressed in all organs, most prominently in the stem and floral organs. Morphological characteristics of the dwarf mutant showed dramatic modifications in internal structure and external morphology. We propose that dwarfism in this mutant is caused by a point mutation in OsKS2, which plays a significant role in growth and development of higher plants. Further investigation on OsKS2 and other OsKS-like proteins is underway and may yield better understanding of the putative role of OsKS in severe dwarf mutants. PMID- 23944974 TI - Scalable synthesis of N-acylaziridines from N-tosylaziridines. AB - N-Acylaziridines are important starting materials for the synthesis of chiral amine derivatives. The traditional methods for producing these activated aziridines have significant drawbacks. The gram scale synthesis of N acylaziridines by deprotection of N-tosylaziridines and reprotection with N hydroxysuccinimide derivatives is described. Mono- and disubstituted aziridines perform well, with complete retention of stereochemical purity. The consistently moderate yields are linked to the N-tosylaziridine deprotection step, while acylation with N-hydroxysuccinimide derivatives is highly efficient. PMID- 23944973 TI - Physical activity measured by physical activity monitoring system correlates with glucose trends reconstructed from continuous glucose monitoring. AB - BACKGROUND: In type 1 diabetes mellitus (T1DM), physical activity (PA) lowers the risk of cardiovascular complications but hinders the achievement of optimal glycemic control, transiently boosting insulin action and increasing hypoglycemia risk. Quantitative investigation of relationships between PA-related signals and glucose dynamics, tracked using, for example, continuous glucose monitoring (CGM) sensors, have been barely explored. SUBJECTS AND METHODS: In the clinic, 20 control and 19 T1DM subjects were studied for 4 consecutive days. They underwent low-intensity PA sessions daily. PA was tracked by the PA monitoring system (PAMS), a system comprising accelerometers and inclinometers. Variations on glucose dynamics were tracked estimating first- and second-order time derivatives of glucose concentration from CGM via Bayesian smoothing. Short-time effects of PA on glucose dynamics were quantified through the partial correlation function in the interval (0, 60 min) after starting PA. RESULTS: Correlation of PA with glucose time derivatives is evident. In T1DM, the negative correlation with the first-order glucose time derivative is maximal (absolute value) after 15 min of PA, whereas the positive correlation is maximal after 40-45 min. The negative correlation between the second-order time derivative and PA is maximal after 5 min, whereas the positive correlation is maximal after 35-40 min. Control subjects provided similar results but with positive and negative correlation peaks anticipated of 5 min. CONCLUSIONS: Quantitative information on correlation between mild PA and short-term glucose dynamics was obtained. This represents a preliminary important step toward incorporation of PA information in more realistic physiological models of the glucose-insulin system usable in T1DM simulators, in development of closed-loop artificial pancreas control algorithms, and in CGM-based prediction algorithms for generation of hypoglycemic alerts. PMID- 23944975 TI - Individualized management of umbilical endometriosis: a report of seven cases. AB - AIM: The aim of this study was to review diagnostic/therapeutic strategies of umbilical endometriosis managed in our department and evaluate the effectiveness of these strategies. METHODS: Medical records for patients with diagnosis of endometriosis managed from 1999 through 2011 in the University of Tokyo Hospital were retrospectively reviewed. Cases with diagnosis of umbilical endometriosis were identified. Clinical information of age, gravida, parity, histories of surgery and oral contraceptive (OC), management for the disease prior to the first visit, symptoms, patients' desire for pregnancy, diagnostic/therapeutic methods and prognosis were reviewed and summarized. RESULTS: During the period, 2530 patients with diagnosis of endometriosis were identified. Seven patients had diagnosis of umbilical endometriosis, giving an incidence of 0.29% of all endometriosis cases and 5.6% of extragenital endometriosis cases. A definitive diagnosis was made by histological examination following a biopsy (two cases) or a resection (three cases). A clinical diagnosis was made by empirical treatment with OC (one case) or dienogest (one case). With regard to therapy, three patients chose expectant management and did not require therapeutic intervention. Three patients began OC and symptoms were well controlled in all patients. One patient who wished to conceive chose a wide resection followed by umbilical reconstruction. She became pregnant afterwards and recurrence was not reported. CONCLUSION: There are various options of diagnostic/therapeutic strategies, such as empirical treatments and OC that can provide individualized management of umbilical endometriosis, congruent with the severity of patient symptoms, age and desire for pregnancy. PMID- 23944976 TI - Impact of headway distance and car speed on drivers' decisions to answer an incoming call. AB - OBJECTIVE: Previous studies on factors affecting drivers' decisions to use their mobile phones while driving are mostly focused on psychological and sociocultural contexts. Few investigations have been carried out on the role of traffic circumstances on drivers' decisions to use or not to use a mobile phone. METHODS: In this research, the effects of headway distance, speed, and the type of road as well as individual variables including age and driving experience are investigated. Forty-two subjects participated in observing 24 scenarios in a driving simulator. RESULTS: Logistic regression models showed that car speed, headway distance, and age can predict whether drivers' answer an incoming call while driving. The results indicated that traffic circumstances at the onset of phone calls are stronger predictors of drivers' decisions to answer a cell phone compared to driver-related variables. CONCLUSIONS: Headway distance and car speed can be used by in-vehicle information systems (IVIS) to warn drivers against using a mobile phone in certain traffic situations. Traffic safety campaigns for young drivers should focus on keeping safe headway distance and speed while driving. PMID- 23944980 TI - Bedside ultrasound-guided celiac plexus neurolysis in upper abdominal cancer patients: a randomized, prospective study for comparison of percutaneous bilateral paramedian vs. unilateral paramedian needle-insertion technique. AB - INTRODUCTION: Percutaneous anterior abdominal ultrasound guidance for performing celiac plexus neurolysis is a relatively new but more economical, less time consuming, more comfortable bedside technique for interventional pain management. Paucity of studies evaluating the efficacy of single-site vs. double-site injections at celiac trunk for ultrasound-guided celiac plexus neurolysis (USCPN) prompted us to conduct a prospective, randomized, single-blind clinical trial to compare USCPN using bilateral paramedian (double needle) technique with unilateral paramedian (single needle) technique. METHODS: Sixty patients aged 18 years or older with unresectable upper abdominal cancers were randomized into two groups to receive USCPN. A 20-mL mixture of 50% ethanol with 0.25% bupivacaine was injected either unilaterally (20 mL*1 site) or bilaterally (10 mL*2 sites) depending on the randomization group. Subjects were assessed for the pain relief using Numerical rating scale (NRS) to assess their pain relief. RESULTS: Baseline parameters being comparable (P > 0.05), the site of drug injections (single or double needle) had no bearing on the onset of pain relief and patient satisfaction scores (P > 0.05). Pain relief during follow-up visits was comparable between the two groups (P > 0.05). The discomfort score correlated well with the pain relief scoring without any significant difference between the two groups except in the last visit (at 3 month). Incidences of the complications were comparable in the two groups (P > 0.05). CONCLUSION: Ultrasound-guided celiac plexus neurolysis using unilateral paramedian (single needle) needle insertion technique is comparable with bilateral paramedian (double needle) needle-insertion technique with regard to pain relief and side effects. PMID- 23944979 TI - Thermodynamic signatures of the antigen binding site of mAb 447-52D targeting the third variable region of HIV-1 gp120. AB - The third variable region (V3) of HIV-1 gp120 plays a key role in viral entry into host cells; thus, it is a potential target for vaccine design. Human monoclonal antibody (mAb) 447-52D is one of the most broadly and potently neutralizing anti-V3 mAbs. We further characterized the 447-52D epitope by determining a high-resolution crystal structure of the Fab fragment in complex with a cyclic V3 and interrogated the antigen-antibody interaction by a combination of site-specific mutagenesis, isothermal titration calorimetry (ITC) and neutralization assays. We found that 447-52D's neutralization capability is correlated with its binding affinity and at 25 degrees C the Gibbs free binding energy is composed of a large enthalpic component and a small favorable entropic component. The large enthalpic contribution is due to (i) an extensive hydrogen bond network, (ii) a pi-cation sandwiching the V3 crown apex residue Arg(315), and (iii) a salt bridge between the 447-52D heavy chain residue Asp(H95) and Arg(315). Arg(315) is often harbored by clade B viruses; thus, our data explained why 447-52D preferentially neutralizes clade B viruses. Interrogation of the thermodynamic signatures of residues at the antigen binding interface gives key insights into their contributions in the antigen-antibody interaction. PMID- 23944981 TI - Psychogenic nonepileptic seizures in children: a review. AB - One of the considerations when a child presents with paroxysmal events is psychogenic nonepileptic seizures (PNES). PNES are discernible changes in behavior or consciousness that resemble epileptic seizures but are not accompanied by electrophysiologic changes. They are usually understood as the manifestation of a conversion disorder that reflects underlying psychological distress. There is a lack of population-based data on the prevalence or incidence of PNES in pediatric populations. The prevalence of PNES in children would appear to be lower than that in the adult population, but the prevalence of PNES seems to increase with age, and nonepileptic paroxysmal events are more likely to be PNES in adolescence than earlier in childhood. In terms of manifestation, PNES in childhood have been described using various categorizations and terminology, making comparisons across studies difficult. There is some evidence that events are more likely to involve unresponsiveness in younger children and prominent motor symptoms in older children. The most common precipitating factors would appear to be school-related difficulties and interpersonal conflict within the child's family. In terms of psychopathology, children with PNES are at high risk for symptoms of depression and anxiety. Accurate diagnosis of PNES in children is likely to involve taking a comprehensive description of the episodes, garnering the child's medical/developmental history, video-electroencephalography (video EEG) to rule out epileptic seizures, and an evaluation of family functioning. The importance of effective and sensitive communication of the diagnosis of PNES has been emphasized and management approaches will typically involve multidisciplinary efforts to safely manage the events at home and at school. Interventions to reduce the effect of precipitating psychosocial stressors and the involvement of a mental health professional to treat comorbid psychopathology will also form part of an effective management plan. Outcome at follow-up is reported to be largely positive, although studies have not been able to follow all children, and few studies have focused on predictors of a good outcome. Future controlled intervention studies using a range of outcome measures are needed to identify efficacious approaches and predictors of best outcome. PMID- 23944982 TI - Facile preparation of raspberry-like superhydrophobic polystyrene particles via seeded dispersion polymerization. AB - A simple and facile approach was developed to fabricate raspberry-like or snowman like particles via seeded dispersion polymerization by just changing the ratio of second monomer styrene (St) to seeds in which poly(styrene-co-hydrolyzed methacryloxypropyltrimethoxysilane) [P(St-co-MPS)] latex was used as seeds with hydrolyzed-MPS as a cross-linking agent. The morphologies of final products were confirmed by field-emission scanning electron microscopy and transmission electron microscopy. Interestingly, the seed part of snowman-like particles showed raspberry-like with adsorbing quantities of PS particles while the other part smooth. The formation mechanism of the raspberry-like particles was also discussed. The superhydrophobic surface with both the static contact angle of 158 degrees and high adhesion to water could be achieved by the hydrophobization of the particulate film with octadecyltrimethoxysilane that was formed from the raspberry-like particles decorated by a thin layer of silica nanoparticles. Further, through encapsulating Ag nanoparticles within the surface, the obtained raspberry-like PS/Ag/SiO2 nanocomposite particles exhibited excellent antibacterial property simultaneously. PMID- 23944983 TI - Anti-inflammatory effects of prosapogenin III from the dried roots of Liriope platyphylla in LPS-stimulated RAW264.7 cells. AB - Liriope platyphylla has been reported to possess various biological activities, including anti-asthma, anti-inflammation, anti-diabetes, and neuriotogenic properties. In this study, we evaluated the effects of prosapogenin III isolated from the roots of L. platyphylla (Liriopis Tuber) on inflammatory responses in lipopolysaccharide (LPS) stimulated RAW264.7 mouse macrophages. We investigated LPS-induced production/expression of inflammatory mediators such as nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxigenase-2 (COX-2), and proinflammatory cytokines, including interleukin-1beta (IL-1beta) and interleukin (IL)-6 in RAW264.7 cells. We also performed Western blot analysis for determination of the phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK) 1/2, p38, and c Jun N-terminal kinase (JNK), and nuclear translocation of nuclear factor-kappaB (NF-kappaB) in LPS-stimulated cells. Treatment with prosapogenin III resulted in significant inhibition of NO production in LPS-stimulated Raw264.7 cells through suppression of iNOS expression. Treatment with prosapogenin III resulted in a significant decrease in expressions of COX-2, IL-1beta, and IL-6 through down regulation of their mRNA or protein in LPS-stimulated cells. In addition, treatment with prosapogenin III resulted in potently inhibited phosphorylation of three MAPKs, including ERK1/2, p38, and JNK in LPS-stimulated cells. Treatment with prosapogenin III also resulted in suppression of the nuclear translocation of NF-kappaB in LPS-stimulated cells. These results indicate that prosapogenin III of Liriopis Tuber has anti-inflammatory effects in activated macrophages through inhibition of production of inflammatory mediators by blockade of the MAPK/NF-kappaB pathway. PMID- 23944985 TI - Obesity in heart failure: impact on survival and treatment modalities. AB - Heart failure (HF) and obesity are commonly seen in the USA. Although obesity is associated with traditional cardiovascular disease, its relationship with HF is complex. Obesity is an accepted risk factor for incident HF. However, in patients with established HF, there exists a paradoxical correlation, with escalating BMI incrementally protective against adverse outcomes. Despite this relationship, patients with HF may desire to lose weight to reduce comorbidities or to improve quality of life. Thus far, studies have shown that intentional weight loss in obese patients with HF does not increase risk, with strategies including dietary modification, physical activity, pharmacotherapy, and/or surgical intervention. PMID- 23944986 TI - Myogenin expression in vulvovaginal spindle cell lesions: analysis of a series of cases with an emphasis on diagnostic pitfalls. AB - AIMS: Myogenin (myf4) is a nuclear transcription factor that is considered to be a sensitive and highly specific marker for skeletal muscle differentiation. Following the identification of focal strong nuclear staining with myogenin in two fibroepithelial polyps of the lower female genital tract (the index cases), we stained a series of vulvovaginal spindle cell lesions with this marker in order to investigate how widespread myogenin staining is in these lesions. METHODS AND RESULTS: Fibroepithelial polyps (n = 13), other vulvovaginal mesenchymal lesions (n = 21) and vulval or vaginal spindle cell squamous carcinomas (n = 4) were stained for myogenin. Apart from the index cases, all of the other cases were negative, except for one vaginal spindle cell squamous carcinoma, which showed focal weak nuclear immunoreactivity. Ten of 12 embryonal rhabdomyosarcomas of the lower female genital tract were myogenin-positive, as was a single vaginal rhabdomyoma. CONCLUSIONS: Our study illustrates that focal myogenin immunoreactivity occurs uncommonly in fibroepithelial polyps of the lower female genital tract. This may result in diagnostic confusion and misdiagnosis as a skeletal muscle neoplasm, especially the sarcoma botryoides variant of embryonal rhabdomyosarcoma. PMID- 23944987 TI - Modulation of isoflavonoid composition of Rhizopus oryzae elicited soybean (Glycine max) seedlings by light and wounding. AB - The isoflavonoid profile of soybean was altered in different ways by stimulation of defense response upon germination. The combination of simultaneous germination and induction by Rhizopus oryzae increased the total isoflavonoid content of soybeans over 2-fold. Pterocarpans became the predominant isoflavonoids, up to 50% (w/w) of total isoflavonoids. To modulate both isoflavonoid content and composition further, the treatment was extended with wounding or light stimuli. The total isoflavonoid content could be increased over 3-fold compared to untreated beans by growing fungus-elicited soybean seedlings in light, whereas wounding was less effective. Interestingly, light altered the composition of prenylated pterocarpans by mediating the position of prenylation. The 2 prenylated pterocarpan level increased 2-fold, whereas that of 4-prenylated pterocarpan remained similar. Taken together, fungus was the most effective elicitor to alter the isoflavonoid content and composition of soybean seedlings, the impact of which can be further enhanced and mediated by additional stimuli, particularly light. PMID- 23944989 TI - Beta-glucan feeding differentiated the regulation of mRNA expression of claudin genes and prevented an intestinal inflammatory response post Aeromonas hydrophila intubation in common carp, Cyprinus carpio L. PMID- 23944990 TI - Scopariusic acid, a new meroditerpenoid with a unique cyclobutane ring isolated from Isodon scoparius. AB - Scopariusic acid (1), a new ent-clerodane-based meroditerpenoid with a unique cyclobutane ring and an unusual 1-octen-3-ol substituent, together with its biosynthetic related compound 2, were isolated from the aerial parts of Isodon scoparius. The structures of 1 and 2, including their absolute configurations, were determined by spectroscopic methods, single-crystal X-ray diffraction analysis, and chemical methods. Compound 1 showed weak cytotoxicity and moderate immunosuppressive activity. PMID- 23944988 TI - Inhibition of epithelial-to-mesenchymal transition and pulmonary fibrosis by methacycline. AB - A high-throughput small-molecule screen was conducted to identify inhibitors of epithelial-mesenchymal transition (EMT) that could be used as tool compounds to test the importance of EMT signaling in vivo during fibrogenesis. Transforming growth factor (TGF)-beta1-induced fibronectin expression and E-cadherin repression in A549 cells were used as 48-hour endpoints in a cell-based imaging screen. Compounds that directly blocked Smad2/3 phosphorylation were excluded. From 2,100 bioactive compounds, methacycline was identified as an inhibitor of A549 EMT with the half maximal inhibitory concentration (IC50) of roughly 5 MUM. In vitro, methacycline inhibited TGF-beta1-induced alpha-smooth muscle actin, Snail1, and collagen I of primary alveolar epithelial cells . Methacycline inhibited TGF-beta1-induced non-Smad pathways, including c-Jun N-terminal kinase, p38, and Akt activation, but not Smad or beta-catenin transcriptional activity. Methacycline had no effect on baseline c-Jun N-terminal kinase, p38, or Akt activities or lung fibroblast responses to TGF-beta1. In vivo, 100 mg/kg intraperitoneal methacycline delivered daily beginning 10 days after intratracheal bleomycin improved survival at Day 17 (P < 0.01). Bleomycin-induced canonical EMT markers, Snail1, Twist1, collagen I, as well as fibronectin protein and mRNA, were attenuated by methacycline (Day 17). Methacycline did not attenuate inflammatory cell accumulation or alter TGF-beta1-responsive genes in alveolar macrophages. These studies identify a novel inhibitor of EMT as a potent suppressor of fibrogenesis, further supporting the concept that EMT signaling is important to lung fibrosis. The findings also provide support for testing the impact of methacycline or doxycycline, an active analog, on progression of human pulmonary fibrosis. PMID- 23944991 TI - Attenuation of alpha-adrenergic-induced vasoconstriction by dietary wild blueberries (Vaccinium angustifolium) is mediated by the NO-cGMP pathway in spontaneously hypertensive rats (SHRs). AB - The role of wild blueberries (WB) on key signaling steps of nitric oxide (NO) and cyclooxygenase (COX) pathways was examined in spontaneously hypertensive rats (SHRs) after eight weeks on a control (C) or an 8% w/w WB diet. Aortic rings from SHRs were stimulated with phenylephrine (Phe) in the absence or presence of inhibitors of: soluble guanylyl cyclase (sGC), phosphodiesterase-5 (PDE(5)), prostaglandin I(2) (PGI(2)) synthase and thromboxane A(2) (TXA(2)) synthase. Additionally, enzymatic activities in these pathways were determined by the concentration of NO, cyclic guanosine monophosphate (cGMP), PGI(2) and TXA(2). In the WB-fed SHR, attenuation of Phe-induced vasoconstriction was mediated by an increased synthesis or preservation of cGMP. Despite an increased release of PGI(2) in the WB group, neither inhibition of PGI(2) or TXA(2) synthase resulted in a different response to Phe between the control and the WB rings. Hence, in the SHR, WB decrease Phe-mediated vasoconstriction under basal conditions by enhancing NO-cGMP signaling without a significant involvement of the COX pathway. PMID- 23944992 TI - Unsubstantiated concerns over the safety of use of sulphonylureas and insulin for increased risk of diabetes complications. PMID- 23944993 TI - Bioaccumulation of CdTe quantum dots in a freshwater alga Ochromonas danica: a kinetics study. AB - The bioaccumulation kinetics of thioglycolic acid stabilized CdTe quantum dots (TGA-CdTe-QDs) in a freshwater alga Ochromonas danica was comprehensively investigated. Their photoluminescence (PL) was determined by flow cytometry. Its cellular intensity increased hyperbolically with exposure time suggesting real internalization of TGA-CdTe-QDs. This hypothesis was evidenced by the nanoparticle uptake experiment with heat-killed or cold-treated cells and by their localization in the vacuoles. TGA-CdTe-QD accumulation could further be well simulated by a biokinetic model used previously for conventional pollutants. Moreover, macropinocytosis was the main route for their internalization. As limited by their diffusion from the bulk medium to the cell surface, TGA-CdTe-QD uptake rate increased proportionally with their ambient concentration. Quick elimination in the PL of cellular TGA-CdTe-QDs was also observed. Such diminishment resulted mainly from their surface modification by vacuolar biomolecules, considering that these nanoparticles remained mostly undissolved and their expulsion out of the cells was slow. Despite the significant uptake of TGA-CdTe-QDs, they had no direct acute effects on O. danica. Overall, the above research shed new light on nanoparticle bioaccumulation study and would further improve our understanding about their environmental behavior, effects and fate. PMID- 23944994 TI - The cost of chronic pain: an analysis of a regional pain management service in Ireland. AB - OBJECTIVE: The objective of the study was to collect data on the direct and indirect economic cost of chronic pain among patients attending a pain management clinic in Ireland. SETTING: A tertiary pain management clinic serving a mixed urban and rural area in the West of Ireland. DESIGN: Data were collected from 100 patients using the Client Services Receipt Inventory and focused on direct and indirect costs of chronic pain. METHODS: Patients were questioned about health service utilization, payment methods, and relevant sociodemographics. Unit costs were multiplied by resource use data to obtain full costs. Cost drivers were then estimated. RESULTS: Our study showed a cost per patient of US$24,043 over a 12 month period. Over half of this was attributable to wage replacement costs and lost productivity in those unable to work because of pain. Hospital stays and outpatient hospital services were the main drivers for health care utilization costs, together accounting for 63% of the direct medical costs per study participant attending the pain clinic. CONCLUSION: The cost of chronic pain among intensive service users is significant, and when extrapolated to a population level, these costs represent a very substantial economic burden. PMID- 23944995 TI - Cytotoxic indole alkaloids from Tabernaemontana divaricata. AB - Five new vobasinyl-ibogan-type bisindole alkaloids, tabernaricatines A-E (1-5), two new monomers, tabernaricatines F and G (6 and 7), and 24 known indole alkaloids were isolated from the aerial parts of Tabernaemontana divaricata. Alkaloids 1 and 2 are the first vobasinyl-ibogan-type alkaloids possessing a six membered ring via an ether linkage between C-17 and C-21. All compounds except for 3 were evaluated for their cytotoxicity against five human cancer cell lines; conophylline showed significant bioactivity against HL-60, SMMC-7721, A-549, MCF 7, and SW480 cells with IC50 values of 0.17, 0.35, 0.21, 1.02, and 1.49 MUM, respectively. PMID- 23944996 TI - Synthesis of tetrazole-derived organocatalysts via azido-Ugi reaction with cyclic ketimines. AB - A new route to tetrazole-derived cyclic amines based on the TMSN3-modified Ugi reaction with 2-substituted cyclic imines was elaborated. The reaction allows the direct preparation of five-, six-, and seven-membered cyclic amines substituted with a tetrazole ring, which are important types of organocatalysts. The scope and limitations of this method are discussed. In the case of the Ugi reaction with benzyl isocyanide, the N-substituted tetrazoles can be easily debenzylated under catalytic hydrogenation conditions to form NH-tetrazoles in quantitative yields. It was demonstrated that both enantiomers of tetrazole-derived cyclic amines can be prepared by resolution with tartaric acid, thereby initiating a simple route to chiral derivatives. One of the obtained chiral tetrazoles was efficiently used as an organocatalyst in the amination reaction. PMID- 23944997 TI - Paralogous metabolism: S-alkyl-cysteine degradation in Bacillus subtilis. AB - Metabolism is prone to produce analogs of essential building blocks in the cell (here named paralogous metabolism). The variants result from lack of absolute accuracy in enzyme-templated reactions as well as from molecular aging. If variants were left to accumulate, the earth would be covered by chemical waste. The way bacteria cope with this situation is essentially unexplored. To gain a comprehensive understanding of Bacillus subtilis sulphur paralogous metabolism, we used expression profiling with DNA arrays to investigate the changes in gene expression in the presence of S-methyl-cysteine (SMeC) and its close analog, methionine, as sole sulphur source. Altogether, more than 200 genes whose relative strength of induction was significantly different depending on the sulphur source used were identified. This allowed us to pinpoint operon ytmItcyJKLMNytmO_ytnIJ_rbfK_ytnLM as controlling the pathway cycling SMeC directly to cysteine, without requiring sulphur oxygenation. Combining genetic and physiological experiments, we deciphered the corresponding pathway that begins with protection of the metabolite by acetylation. Oxygenation of the methyl group then follows, and after deprotection (deacetylation), N-formyl cysteine is produced. This molecule is deformylated by the second deformylase present in B. subtilis DefB, yielding cysteine. This pathway appears to be present in plant-associated microbes. PMID- 23944998 TI - Numerical solution for 5-layer laminate technique to determine saturation solubility of a drug in a thin film of pressure sensitive adhesive. AB - A numerical solution of the one-dimensional diffusion equation is presented to describe the 5-layer laminate technique for estimating the saturation solubility of a drug in a thin polymer film. The boundary and initial conditions encompass a donor layer, a separating membrane, and an acceptor layer. Alteration of the drug's partition coefficient between donor and separating membrane has little influence on drug accumulation with the acceptor. The diffusivity in the separating membrane should be high to promote a short experimental time to achieve saturation equilibrium in the acceptor layer. The essential parameter to give rapid equilibrium is the thickness of the acceptor polymer film. For values of diffusivity typical for drugs of molecular weight around 500 an acceptor layer thickness of 10 um-20 um is required to achieve equilibrium within less than 10 d. These simulations allow the selection of suitable experimental conditions to make the 5-layer laminate technique a viable method for routine use. PMID- 23944999 TI - A recessive resistance to rice yellow mottle virus is associated with a rice homolog of the CPR5 gene, a regulator of active defense mechanisms. AB - RYMV2 is a major recessive resistance gene identified in cultivated African rice (Oryza glaberrima) which confers high resistance to the Rice yellow mottle virus (RYMV). We mapped RYMV2 in an approximately 30-kb interval in which four genes have been annotated. Sequencing of the candidate region in the resistant Tog7291 accession revealed a single mutation affecting a predicted gene, as compared with the RYMV-susceptible O. glaberrima CG14 reference sequence. This mutation was found to be a one-base deletion leading to a truncated and probably nonfunctional protein. It affected a gene homologous to the Arabidopsis thaliana CPR5 gene, known to be a defense mechanism regulator. Only seven O. glaberrima accessions showing this deletion were identified in a collection consisting of 417 accessions from three rice species. All seven accessions were resistant to RYMV, which is an additional argument in favor of the involvement of the deletion in resistance. In addition, fine mapping of a resistance quantitative trait locus in O. sativa advanced backcrossed lines pinpointed a 151-kb interval containing RYMV2, suggesting that allelic variants of the same gene may control both high and partial resistance. PMID- 23945000 TI - Constitutive expression of the xylanase inhibitor TAXI-III delays Fusarium head blight symptoms in durum wheat transgenic plants. AB - Cereals contain xylanase inhibitor (XI) proteins which inhibit microbial xylanases and are considered part of the defense mechanisms to counteract microbial pathogens. Nevertheless, in planta evidence for this role has not been reported yet. Therefore, we produced a number of transgenic plants constitutively overexpressing TAXI-III, a member of the TAXI type XI that is induced by pathogen infection. Results showed that TAXI-III endows the transgenic wheat with new inhibition capacities. We also showed that TAXI-III is correctly secreted into the apoplast and possesses the expected inhibition parameters against microbial xylanases. The new inhibition properties of the transgenic plants correlate with a significant delay of Fusarium head blight disease symptoms caused by Fusarium graminearum but do not significantly influence leaf spot symptoms caused by Bipolaris sorokiniana. We showed that this contrasting result can be due to the different capacity of TAXI-III to inhibit the xylanase activity of these two fungal pathogens. These results provide, for the first time, clear evidence in planta that XI are involved in plant defense against fungal pathogens and show the potential to manipulate TAXI-III accumulation to improve wheat resistance against F. graminearum. PMID- 23945001 TI - Arabidopsis YELLOW STRIPE-LIKE7 (YSL7) and YSL8 transporters mediate uptake of Pseudomonas virulence factor syringolin A into plant cells. AB - Syringolin A (SylA), a virulence factor secreted by certain strains of the plant pathogen Pseudomonas syringae pv. syringae, is an irreversible proteasome inhibitor imported by plant cells by an unknown transport process. Here, we report that functional expression in yeast of all 17 members of the Arabidopsis oligopeptide transporter family revealed that OLIGOPEPTIDE TRANSPORTER1 (OPT1), OPT2, YELLOW STRIPE-LIKE3 (YSL3), YSL7, and YSL8 rendered yeast cells sensitive to growth inhibition by SylA to different degrees, strongly indicating that these proteins mediated SylA uptake into yeast cells. The greatest SylA sensitivity was conferred by YSL7 and YSL8 expression. An Arabidopsis ysl7 mutant exhibited strongly reduced SylA sensitivity in a root growth inhibition assay and in leaves of ysl7 and ysl8 mutants, SylA-mediated quenching of salicylic-acid-triggered PATHOGENESIS-RELATED GENE1 transcript accumulation was greatly reduced compared with the wild type. These results suggest that YSL7 and YSL8 are major SylA uptake transporters in Arabidopsis. Expression of a YSL homolog of bean, the host of the SylA-producing P. syringae pv. syringae B728a, in yeast also conferred strong SylA sensitivity. Thus, YSL transporters, which are thought to be involved in metal homeostasis, have been hijacked by bacterial pathogens for SylA uptake into host cells. PMID- 23945002 TI - Salicylic acid determines differential senescence produced by two Turnip mosaic virus strains involving reactive oxygen species and early transcriptomic changes. AB - Losses produced by virus diseases depend mostly on symptom severity. Turnip mosaic virus (TuMV) is one of the most damaging and widespread potyvirus infecting members of the family Brassicaceae, including Arabidopsis thaliana. We used JPN1 and UK1 TuMV strains to characterize viral infections regarding symptom development, senescence progression, antioxidant response, reactive oxygen species (ROS) accumulation, and transcriptional profiling. Both isolates, despite accumulating similar viral titers, induced different symptomatology and strong differences in oxidative status. Early differences in several senescence associated genes linked to the ORE1 and ORS1 regulatory networks as well as persistent divergence in key ROS production and scavenging systems of the plant were detected. However, at a later stage, both strains induced nutrient competition, indicating that senescence rates are influenced by different mechanisms upon viral infections. Analyses of ORE1 and ORS1 levels in infected Brassica juncea plants showed a similar pattern, suggesting a conserved differential response to both strains in Brassicaceae spp. Transcriptional analysis of the ORE1 and ORS1 regulons showed similarities between salicylic acid (SA) response and the early induction triggered by UK1, the most severe strain. By means of SA-defective NahG transgenic plants, we found that differential senescence progression and ROS accumulation between strains rely on an intact SA pathway. PMID- 23945003 TI - The Bdtf1 gene in Alternaria brassicicola is important in detoxifying brassinin and maintaining virulence on Brassica species. AB - Brassinin is an antifungal compound induced in Brassica plants after microbial infection. Molecular evidence is incomplete, however, in supporting the importance of brassinin in plant resistance to pathogens. To test the importance of brassinin in plant defense, we studied the functions of the gene Bdtf1 in the necrotrophic fungus Alternaria brassicicola. Several strains of mutants of this gene were weakly virulent on Brassica species, causing lesions 70% smaller in diameter than the wild type on three Brassica species. These mutants, however, were as virulent as the wild type on Arabidopsis thaliana. They were similar to the wild type in spore germination, colony morphology, and mycelial growth in nutrient-rich media, both with and without stress-inducing chemicals. Unlike wild type A. brassicicola, however, the mutants failed to germinate and their hyphal growth was arrested in the presence of 200 MUM brassinin. When grown in a medium containing 100 MUM brassinin, wild-type mycelium entirely converted the brassinin into a nontoxic derivative, of which the precise chemical nature was not established. Mutants of the Bdtf1 gene were unable to perform this conversion. Our results support the hypothesis that the ability of A. brassicicola to detoxify brassinin is necessary for successful infection of Brassica species. PMID- 23945004 TI - The ATF/CREB transcription factor Atf1 is essential for full virulence, deoxynivalenol production, and stress tolerance in the cereal pathogen Fusarium graminearum. AB - Fusarium graminearum is a necrotrophic plant pathogen of cereals that produces mycotoxins such as deoxynivalenol (DON) and zearalenone (ZEA) in grains. The stress-activated mitogen-activated protein kinase FgOS-2 is a central regulator in F. graminearum and controls, among others, virulence and DON and ZEA production. Here, we characterized the ATF/CREB-activating transcription factor FgAtf1, a regulator that functions downstream of FgOS-2. We created deletion and overexpression mutants of Fgatf1, the latter being also in an FgOS-2 deletion mutant. FgAtf1 localizes to the nucleus and appears to interact with FgOS-2 under osmotic stress conditions. Deletion mutants in Fgatf1 (DeltaFgatf1) are more sensitive to osmotic stress and less sensitive to oxidative stress compared with the wild type. Furthermore, sexual reproduction is delayed. DeltaFgatf1 strains produced higher amounts of DON under in vitro induction conditions than that of the wild type. However, during wheat infection, DON production by DeltaFgatf1 is strongly reduced. The DeltaFgatf1 strains displayed strongly reduced virulence to wheat and maize. Interestingly, constitutive expression of Fgatf1 in the wild type led to hypervirulence on wheat, maize, and Brachypodium distachyon. Moreover, constitutive expression of Fgatf1 in the DeltaFgOS-2 mutant background almost complements DeltaFgOS-2-phenotypes. These data suggest that FgAtf1 may be the most important transcription factor regulated by FgOS-2. PMID- 23945005 TI - Evaluation of obstetrical factors related to Sheehan syndrome. AB - AIM: To evaluate factors related to the occurrence of Sheehan syndrome. METHODS: The obstetrical disseminated intravascular coagulation score, total volume of hemorrhage, shock index, level of consciousness at the time of shock occurrence and pituitary magnetic resonance imaging findings were evaluated in nine women who showed massive hemorrhage during delivery. These clinical outcomes were analyzed in all these patients who were prospectively followed-up to identify any possible occurrence of Sheehan syndrome. RESULTS: Compared to six women with non Sheehan syndrome, three women who were diagnosed with Sheehan syndrome showed significant elevation of the obstetrical disseminated intravascular coagulation score, decrease in the level of consciousness during shock and remarkable pituitary gland atrophic change with an empty sella turcica detected by pituitary magnetic resonance imaging. The volume of hemorrhage during delivery and shock index were not significantly different between these two groups of women. CONCLUSION: Careful attention and follow-up should be paid to women with post partum massive hemorrhage for early detection and management of women with Sheehan syndrome. PMID- 23945008 TI - Identifying access management factors associated with safety of urban arterials mid-blocks: a panel data simultaneous equation models approach. AB - OBJECTIVE: The objective of this study was to evaluate the safety impact of selected access management techniques in urban areas because access management techniques play an important role in urban roadway safety on the roadway network. METHODS: In order to correct the interdependency between safety and mobility for heterogeneous mid-block segments, simultaneous equation models were adopted. The panel data structure of the model was used to address the heterogeneity issue for mid-block segments along a corridor. The integrated random coefficient simultaneous equation models were proposed to interpret both issues. RESULTS: The models developed were used to identify influential factors. The length of mid block segments, driveway density, and median opening density were among the significant factors found to be associated with crash rate on mid-block segments. CONCLUSIONS: From the results it can be concluded that the access management techniques, mid-block segment length, driveway density, and median opening density are significant factors that influence safety on mid-block segments. The longer the distance between signals, driveways, and median openings, the fewer the potential crashes are. In addition to these access management techniques, land use, especially the commercial land type, influences the safety on mid-block segments. PMID- 23945006 TI - Viroporins customize host cells for efficient viral propagation. AB - Viruses are intracellular parasites that must access the host cell machinery to propagate. Viruses hijack the host cell machinery to help with entry, replication, packaging, and release of progeny to infect new cells. To carry out these diverse functions, viruses often transform the cellular environment using viroporins, a growing class of viral-encoded membrane proteins that promote viral proliferation. Viroporins modify the integrity of host membranes, thereby stimulating the maturation of viral infection, and are critical for virus production and dissemination. Significant advances in molecular and cell biological approaches have helped to uncover some of the roles that viroporins serve in the various stages of the viral life cycle. In this study, the ability of viroporins to modify the cellular environment will be discussed, with particular emphasis on their role in the stepwise progression of the viral life cycle. PMID- 23945009 TI - Dialysis outcomes in those aged >=65 years. AB - BACKGROUND: The number of elderly people over the age of 65 commencing dialysis in NZ has increased by almost 400% in the past decade. Few data are available about health related outcomes and survival on dialysis in the elderly to help the individual, their family, clinicians and health planners with decision-making. METHODS/DESIGN: This study will provide the first comprehensive longitudinal survey of health-related quality of life (HRQOL) and other patient centred outcomes for individuals aged >=65 years on, or eligible for, dialysis therapy and will link these data to survival outcomes. Data collected by yearly structured interviews with participants will be linked to co-morbidity data, health service use, and laboratory information collected from health records, and analysed with respect to HRQOL and survival. The information obtained will inform the delivery of dialysis services in New Zealand and facilitate improved decision making by individuals, their family and clinicians, about the appropriateness and impact of dialysis therapy on subsequent health and survival. DISCUSSION: Results from this study will make possible more informed decision-making by future elderly patients and their families as they contemplate renal replacement therapy. Results will also allow health professionals to more accurately describe the impact of dialysis therapy on quality of life and outcomes for patients. TRIAL REGISTRATION: ACTRN12611000024943. PMID- 23945010 TI - Recent management advances in acute postoperative pain. AB - INTRODUCTION: Acute postoperative pain remains a major problem, with both undertreatment and overtreatment leading to serious consequences, including increased risk of persistent postoperative pain, impaired rehabilitation, increased length of stay and/or hospital readmission, and adverse events related to excessive analgesic use, such as oversedation. New analgesic medications and techniques have been introduced that target the preoperative, intraoperative, and postoperative periods to better manage acute postoperative pain, with improvements in analgesic efficacy and safety over more traditional pain management approaches. This review provides an overview of these new analgesic medications and techniques. Specific topics that are discussed include the use of preoperative nonsteroidal anti-inflammatory drugs, anxiolytics, and anticonvulsants; intraoperative approaches such as neuraxial analgesia, continuous local anesthetic wound infusion, transversus abdominis plane block, extended-release epidural morphine, intravenous acetaminophen, and intravenous ketamine; and postoperative use of intravenous ibuprofen, new opioids (eg, tapentadol) or opioid formulations (morphine-oxycodone), and patient-controlled analgesia. CONCLUSION: New, targeted, analgesic medications and techniques may provide a safer and more effective approach to the management of acute postoperative pain than traditional approaches such as postoperative oral analgesics. PMID- 23945011 TI - Frontier-based techniques in measuring hospital efficiency in Iran: a systematic review and meta-regression analysis. AB - BACKGROUND: In recent years, there has been growing interest in measuring the efficiency of hospitals in Iran and several studies have been conducted on the topic. The main objective of this paper was to review studies in the field of hospital efficiency and examine the estimated technical efficiency (TE) of Iranian hospitals. METHODS: Persian and English databases were searched for studies related to measuring hospital efficiency in Iran. Ordinary least squares (OLS) regression models were applied for statistical analysis. The PRISMA guidelines were followed in the search process. RESULTS: A total of 43 efficiency scores from 29 studies were retrieved and used to approach the research question. Data envelopment analysis was the principal frontier efficiency method in the estimation of efficiency scores. The pooled estimate of mean TE was 0.846 (+/ 0.134). There was a considerable variation in the efficiency scores between the different studies performed in Iran. There were no differences in efficiency scores between data envelopment analysis (DEA) and stochastic frontier analysis (SFA) techniques. The reviewed studies are generally similar and suffer from similar methodological deficiencies, such as no adjustment for case mix and quality of care differences. The results of OLS regression revealed that studies that included more variables and more heterogeneous hospitals generally reported higher TE. Larger sample size was associated with reporting lower TE. CONCLUSIONS: The features of frontier-based techniques had a profound impact on the efficiency scores among Iranian hospital studies. These studies suffer from major methodological deficiencies and were of sub-optimal quality, limiting their validity and reliability. It is suggested that improving data collection and processing in Iranian hospital databases may have a substantial impact on promoting the quality of research in this field. PMID- 23945012 TI - Pancreaticoduodenectomy versus local resection in the treatment of gastrointestinal stromal tumors of the duodenum. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms. However, duodenal GISTs compromise a small and rare subset and few studies have focused on them. We evaluated the surgical management of patients with duodenal GISTs treated by pancreaticoduodenectomy (PD) versus local resection (LR) in our institution and analyzed the postoperative outcomes. METHODS: This was a retrospective review of patients with duodenal GISTs managed in our institution from January 2006 to January 2012. Clinicopathologic findings and disease-free survival (DFS) of duodenal GIST patients were analyzed. RESULTS: A total of 48 patients were selected. The most common presentation was bleeding (60.4%), and the second portion of the duodenum (35.4%) was the most common dominant site. Of the patients, 34 (70.8%) underwent LR while 14 (29.2%) underwent PD. The surgical margins for all studied patients were free. Patients who ultimately underwent PD were more likely to present with a larger tumor (median size: PD, 6.3 cm vs LR, 4.0 cm; P = 0.02) and more commonly presented with a tumor in the second portion of the duodenum (second portion: PD, 64.3% vs LR, 23.5%; P = 0.007). The tumors treated by PD had a higher grade of risk compared with LR as defined by National Institutes of Health (NIH) criteria (P = 0.019). PD was significantly associated with a longer operation time and a longer hospital stay compared to LR (P < 0.001 and P = 0.001, respectively). In our study, the median follow-up period was 36 months (range: 0 to 81 months). The 1- and 3-year DFS was 100% and 88%, respectively. From multivariable analysis, the only significant factor associated with a worse DFS was an NIH high risk classification (hazard ratio = 4.24). CONCLUSIONS: The recurrence of duodenal GIST was correlated to tumor biology rather than type of operation. PD was associated with a longer hospital stay and longer operation time. Therefore, LR with clear surgical margins should be considered a reliable and curative option for duodenal GIST and PD should be reserved for lesions not amenable to LR. PMID- 23945013 TI - Therapeutic potential of genes in cardiac repair. AB - Cardiovascular diseases remain the primary reason of premature death and contribute to a major percentage of global patient morbidity. Recent knowledge in the molecular mechanisms of myocardial complications have identified novel therapeutic targets along with the availability of vectors that offer the chance for designing gene therapy technique for protection and revival of the diseased heart functions. Gene transfer procedure into the myocardium is demonstrated through direct injection of plasmid DNA or through the coronary vasculature using the direct or indirect delivery of viral vectors. Direct DNA injection to the myocardium is reported to be of immense value in research studies that aims at understanding the activities of various elements in myocardium. It is also deemed vital for investigating the effect of the myocardial pathophysiology on expression of the foreign genes that are transferred. Gene therapies have been reported to heal cardiac pathologies such as myocardial ischemia, heart failure and inherited myopathies in several animal models. The results obtained from these animal studies have also encouraged a flurry of early clinical trials. This translational research has been triggered by an enhanced understanding of the biological mechanisms involved in tissue repair after ischemic injury. While safety concerns take utmost priority in these trials, several combinational therapies, various routes and dose of delivery are being tested before concrete optimization and complete potential of gene therapy is convincingly understood. PMID- 23945014 TI - Novel autoproteolytic and DNA-damage sensing components in the bacterial SOS response and oxidized methylcytosine-induced eukaryotic DNA demethylation systems. AB - The bacterial SOS response is an elaborate program for DNA repair, cell cycle regulation and adaptive mutagenesis under stress conditions. Using sensitive sequence and structure analysis, combined with contextual information derived from comparative genomics and domain architectures, we identify two novel domain superfamilies in the SOS response system. We present evidence that one of these, the SOS response associated peptidase (SRAP; Pfam: DUF159) is a novel thiol autopeptidase. Given the involvement of other autopeptidases, such as LexA and UmuD, in the SOS response, this finding suggests that multiple structurally unrelated peptidases have been recruited to this process. The second of these, the ImuB-C superfamily, is linked to the Y-family DNA polymerase-related domain in ImuB, and also occurs as a standalone protein. We present evidence using gene neighborhood analysis that both these domains function with different mutagenic polymerases in bacteria, such as Pol IV (DinB), Pol V (UmuCD) and ImuA-ImuB-DnaE2 and also other repair systems, which either deploy Ku and an ATP-dependent ligase or a SplB-like radical SAM photolyase. We suggest that the SRAP superfamily domain functions as a DNA-associated autoproteolytic switch that recruits diverse repair enzymes upon DNA damage, whereas the ImuB-C domain performs a similar function albeit in a non-catalytic fashion. We propose that C3Orf37, the eukaryotic member of the SRAP superfamily, which has been recently shown to specifically bind DNA with 5-hydroxymethylcytosine, 5-formylcytosine and 5 carboxycytosine, is a sensor for these oxidized bases generated by the TET enzymes from methylcytosine. Hence, its autoproteolytic activity might help it act as a switch that recruits DNA repair enzymes to remove these oxidized methylcytosine species as part of the DNA demethylation pathway downstream of the TET enzymes. PMID- 23945015 TI - Locally advanced carcinoma of the cecum presenting as a right inguinal hernia: a case report and review of the literature. AB - INTRODUCTION: An inguinal hernia is a common surgical disease in elderly patients, but an association with intra-abdominal malignancies is rare. CASE PRESENTATION: We report a case of a 78-year-old Caucasian woman presenting with a right inguinal mass suspected to be an irreducible hernia. A computed tomography scan showed the presence of the cecum in her inguinal canal, with an irregular thickening of the cecal wall suggesting a neoplasm within the inguinal hernia. A colonoscopy was not completed owing to the huge involvement of the cecum into the hernia sac. A laparotomy was performed, at which time the cecum was herniated through her right inguinal canal and the cecal tumor had infiltrated her abdominal wall and femoral artery. A right inguinal incision was necessary for good vascular control and to carry out an en bloc resection of the tumor with the inguinal wall. A right colectomy was performed and the inguinal wall repaired. The postoperative course was uneventful and our patient received adjuvant radiochemotherapy. CONCLUSION: We describe a rare case of a locally advanced cecal tumor presenting as a right inguinal hernia. Both diagnosis and surgical treatment in elderly patients represent a challenge for the surgeon in cases of aggressive tumors as reported in this paper. PMID- 23945016 TI - Mechanisms of intermittent state transitions in a coupled heterogeneous oscillator model of epilepsy. AB - We investigate the dynamic mechanisms underlying intermittent state transitions in a recently proposed neural mass model of epilepsy. A low dimensional model is constructed, which preserves two key features of the neural mass model, namely (i) coupling between oscillators and (ii) heterogeneous proximity of these oscillators to a bifurcation between distinct limit cycles. We demonstrate that state transitions due to intermittency occur in the abstract model. This suggests that there is a general bifurcation mechanism responsible for this behaviour and that this is independent of the precise form of the evolution equations. Such abstractions of neural mass models allow a deeper insight into underlying dynamic and physiological mechanisms, and also allow the more efficient exploration of large scale brain dynamics in disease. PMID- 23945017 TI - Four new lignans from Schisandra sphenanthera. AB - Three new 7,8-secolignans, schisandlignans A-C (1, 2, and 4), one new dibenzocyclooctadiene lignan, schisandlignan D (5), together with nine known lignans 3',4'-dimethoxybenzoic acid (3",4"-dimethoxyphenyl)-2-methyl-3-oxobutyl ester (3), gomisin J (6), rubrisandrin A(1b) (7), interiotherin B (8), schisantherin D (9), ( - )-machilusin (10), ganschisandrine (11), henricine A (12), and (+)-1-hydroxy pinoresinol (13), were isolated from the rattan of Schisandra sphenanthera. Their structures were determined by analysis of 1D and 2D NMR spectroscopic data. PMID- 23945019 TI - Resolution of Lhermitte's sign with spinal cord stimulation. PMID- 23945018 TI - Identification of gingipain-specific I-A(b) -restricted CD4+ T cells following mucosal colonization with Porphyromonas gingivalis in C57BL/6 mice. AB - Chronic periodontitis is associated with Porphyromonas gingivalis infection. Although virulence factors of P. gingivalis are hypothesized to contribute to the pathogenesis of periodontitis, it is unclear whether the local CD4(+) T-cell mediated response they elicit prevents or contributes to periodontal bone destruction. We hypothesize that major histocompatibility complex class II I-A(b) -binding peptides existing in Kgp and RgpA are presented to CD4(+) T cells during P. gingivalis oral colonization. The protein sequences of gingipains RgpA and Kgp, and OMP40 and OMP41 of P. gingivalis were scanned using an I-A(b) -binding matrix. From this analysis we identified 53 candidate peptides that had the potential to engage the peptide-binding groove of the I-A(b) molecule of C57BL/6 mice. An ELISpot-based screen revealed those peptide-primed effector/memory CD4(+) T cells that could be re-stimulated in vitro with P. gingivalis or the peptide itself to produce interleukin-17A or interferon-gamma. Two immunodominant peptides, Kgp467-477 (pKgp) and RgpA1054-1064 /Kgp1074-1084 (pR/Kgp) were identified and engineered to be displayed on I-A(b) molecular tetramers. Peptide pR/Kgp is conserved across all sequenced P. gingivalis strains. C57BL/6 mice were orally inoculated with P. gingivalis strain 53977 and cervical lymph node cells were stained with phycoerythrin-conjugated pKgp::I-A(b) and pR/Kgp::I-A(b) tetramers. We found that only pR/Kgp::I-A(b) bound with the desired specificity to gingipain-specific CD4(+) T cells. The pR/Kgp::I-A(b) tetramer complex will allow the identification of effector/memory CD4(+) T cells specific for two virulence factors of P. gingivalis strains associated with periodontal disease. PMID- 23945020 TI - Synthesis and electrochemical studies of cobalt(III) monohydride complexes containing pendant amines. AB - Two new tetraphosphine ligands, P(nC-PPh2)2N(Ph)2 (1,5-diphenyl-3,7 bis((diphenylphosphino)alkyl)-1,5-diaza-3,7-diphosphacyclooctane; alkyl = (CH2)2, n = 2 (L2); (CH2)3, n = 3 (L3)), have been synthesized. Coordination of these ligands to cobalt affords the complexes [Co(II)(L2)(CH3CN)](2+) and [Co(II)(L3)(CH3CN)](2+), which are reduced by KC8 to afford [Co(I)(L2)(CH3CN)](+) and [Co(I)(L3)(CH3CN)](+). Protonation of the Co(I) complexes affords [HCo(III)(L2)(CH3CN)](2+) and [HCo(III)(L3)(CH3CN)](2+). The cyclic voltammetry of [HCo(III)(L2)(CH3CN)](2+), analyzed using digital simulation, is consistent with an ErCrEr reduction mechanism involving reversible acetonitrile dissociation from [HCo(II)(L2)(CH3CN)](+) and resulting in formation of HCo(I)(L2). Reduction of HCo(III) also results in cleavage of the H-Co bond from HCo(II) or HCo(I), leading to formation of the Co(I) complex [Co(I)(L2)(CH3CN)](+). Under voltammetric conditions, the reduced cobalt hydride reacts with a protic solvent impurity to generate H2 in a monometallic process involving two electrons per cobalt. In contrast, under bulk electrolysis conditions, H2 formation requires only one reducing equivalent per [HCo(III)(L2)(CH3CN)](2+), indicating a bimetallic route wherein two cobalt hydride complexes react to form 2 equiv of [Co(I)(L2)(CH3CN)](+) and 1 equiv of H2. These results indicate that both HCo(II) and HCo(I) can be formed under electrocatalytic conditions and should be considered as potential catalytic intermediates. PMID- 23945021 TI - Water and 2-propanol structured on calcite (104) probed by frequency-modulation atomic force microscopy. AB - The structure of liquid water and 2-propanol on the (104) surface of calcite (CaCO3) was probed by frequency-modulation atomic force microscopy. The microscope tip scanned each liquid to record the tip-surface force perturbed by the liquid structure at the interface. In water, the force distribution on planes cross-sectional to the surface presents a 0.5-nm-thick checkerboard-like pattern matching the corrugated topography of the calcite surface. This provides evidence that the local water density was laterally and vertically modulated. With 2 propanol, a laterally uniform, vertically layered structure was found between the first laterally structured layer and the bulk liquid. These results are consistent with the density distributions of water and ethanol proposed in earlier X-ray and simulation studies. PMID- 23945022 TI - Effectiveness and safety of orally administered immunotherapy for food allergies: a systematic review and meta-analysis. AB - The aim of using oral and sublingual immunotherapy with food allergies is to enable the safe consumption of foods containing these allergens in patients with food allergies. In the present study, a systematic review of intervention studies was undertaken; this involved the searching of eleven international databases for controlled clinical trials. We identified 1152 potentially relevant papers, from which we selected twenty-two reports of twenty-one eligible trials (i.e. eighteen randomised controlled trials and three controlled clinical trials). The meta analysis revealed a substantially lower risk of reactions to the relevant food allergen in those receiving orally administered immunotherapy (risk ratios (RR) 0.21, 95 % CI 0.12, 0.38). The meta-analysis of immunological data demonstrated that skin prick test responses to the relevant food allergen significantly decreased with immunotherapy (mean difference - 2.96 mm, 95 % CI - 4.48, - 1.45), while allergen-specific IgG4 levels increased by an average of 19.9 (95 % CI 17.1, 22.6) MUg/ml. Sensitivity analyses excluding studies at the highest risk of bias and subgroup analyses in relation to specific food allergens and treatment approaches generated comparable summary estimates of effectiveness and immunological changes. Pooling of the safety data revealed an increased risk of local (i.e. minor oropharyngeal/gastrointestinal) adverse reactions with immunotherapy (RR 1.47, 95 % CI 1.11, 1.95); there was a non-significant increased average risk of systemic adverse reactions with immunotherapy (RR 1.08, 95 % CI 0.97, 1.19). There is strong evidence that orally administered immunotherapy can induce immunomodulatory changes and thereby promote desensitisation to a range of foods. However, given the paucity of evidence on longer-term safety, effectiveness and cost-effectiveness, orally administered immunotherapy should not be used outside experimental conditions presently. PMID- 23945023 TI - Fibrosis inhibition of photobiomodulation promoted regeneration. PMID- 23945024 TI - Spontaneous uterine rupture at 32 weeks of gestation after previous uterine artery embolization. AB - Uterine artery embolization (UAE) is a common treatment for post-partum hemorrhage and uterine fibroids. However, the effects of UAE on subsequent pregnancies have not been established. Here, we present a case of spontaneous uterine rupture after previous UAE. A 31-year-old woman underwent UAE for a cervical ectopic pregnancy. Contrast-enhanced magnetic resonance imaging (MRI) at days 5 and 25 post-UAE suggested a regionally decreased blood supply in the mid posterior wall of the uterine fundus. During a subsequent pregnancy at age 35 years, she underwent an emergency cesarean delivery due to spontaneous uterine rupture at the mid-posterior wall of the uterus at 32 weeks of gestation. Obstetricians should be attentive to the possibility of spontaneous uterine rupture in pregnant women who have previously undergone UAE. Detection of ischemic uterine muscle on MRI may predict potential for uterine rupture in a subsequent pregnancy. PMID- 23945025 TI - Kinetic studies of the effect of a 17-nucleotide difference in the 0.3-kb region containing the R-U5-5' leader sequence of Friend murine leukemia virus on viral gene expression. AB - In addition to the env gene, a 0.3-kb fragment containing the R-U5-5' leader sequence is essential for the induction of spongiform neurodegeneration by Friend murine leukemia virus (Fr-MLV) clone A8 and it also influences expression of the Env protein. Kinetic studies were carried out using two recombinant viruses, R7f, carrying the A8 0.3-kb fragment, and Rec5, carrying the 0.3-kb fragment of the non-neuropathogenic Fr-MLV clone 57. These analyses suggested that the 0.3-kb fragment influenced the expression level of the Env protein by regulating the amount of spliced env-mRNA rather than the amount of total viral mRNA or viral production. PMID- 23945026 TI - Expression analysis of Foxp3 in T cells from bovine leukemia virus infected cattle. AB - In the present study, we monitored Foxp3(+) T cells in bovine leukemia virus (BLV)-infected cattle. By flow cytometric analysis, the proportion of Foxp3(+) CD4(+) cells from persistent lymphocytotic cattle was significantly increased compared to control and AL cattle. Interestingly, the proportion of Foxp3(+) CD4(+) cells correlated positively with the increased number of lymphocytes, virus titer and virus load, whereas it inversely correlated with IFN-gamma mRNA expression, suggesting that Foxp3(+) CD4(+) T cells in cattle have a potentially immunosuppressive function. Further studies are necessary to elucidate the detailed mechanism behind the increased Treg during BLV infection. PMID- 23945027 TI - Genus-wide acid tolerance accounts for the biogeographical distribution of soil Burkholderia populations. AB - Bacteria belonging to the genus Burkholderia are highly versatile with respect to their ecological niches and lifestyles, ranging from nodulating tropical plants to causing melioidosis and fatal infections in cystic fibrosis patients. Despite the clinical importance and agronomical relevance of Burkholderia species, information about the factors influencing their occurrence, abundance and diversity in the environment is scarce. Recent findings have demonstrated that pH is the main predictor of soil bacterial diversity and community structure, with the highest diversity observed in neutral pH soils. As many Burkholderia species have been isolated from low pH environments, we hypothesized that acid tolerance may be a general feature of this genus, and pH a good predictor of their occurrence in soils. Using a combination of environmental surveys at trans continental and local scales, as well as in vitro assays, we show that, unlike most bacteria, Burkholderia species have a competitive advantage in acidic soils, but are outcompeted in alkaline soils. Physiological assays and diversity analysis based on 16S rRNA clone libraries demonstrate that pH tolerance is a general phenotypic trait of the genus Burkholderia. Our results provide a basis for building a predictive understanding of the biogeographical patterns exhibited by Burkholderia sp. PMID- 23945028 TI - Temperature profiles of sleeveless and coaxial phacoemulsification. AB - PURPOSE: To study the temperature profile at the corneal wound during 2 sleeveless techniques versus 2 coaxial phacoemulsification techniques. SETTING: Department of Ophthalmology, Meir Medical Center, Kfar Saba and Ein-Tal Eye Center, Tel-Aviv, Israel. DESIGN: Experimental study. METHODS: Thirty-six porcine eyes were randomized into 4 groups: Group 1: conventional coaxial system (3.0 mm incision); Group 2: coaxial microincision cataract surgery (MICS) system (2.2 mm incision); Group 3: bimanual MICS (1.1 mm incision); Group 4: sleeveless tri-MICS (1.1 mm incision) using a 19-gauge anterior chamber maintainer as the sole fluid source. Temperature measurements were taken using a thermocouple and an infrared thermal imaging system. Measurements were taken in 2 settings; that is, with and without occlusion. RESULTS: With no occlusion, corneal burns did not occur in any group. However, corneal temperatures were lower with the sleeveless systems (Groups 3 and 4) than with the coaxial systems (Groups 1 and 2) (P=.0003). When occlusion was induced, temperatures were kept constantly low in the sleeveless groups, whereas in the coaxial groups, temperatures increased rapidly, causing corneal burns within seconds. The mean temperature elevations at the incision sites were 39 degrees C, 48.5 degrees C, 13.6 degrees C, and 11.3 degrees C in Groups 1, 2, 3, and 4, respectively (P<.0001). CONCLUSIONS: Sleeveless phacoemulsification maintained lower tissue temperatures than sleeved coaxial methods. During occlusion, fluid flow around the naked tip of the sleeveless systems prevented heat accumulation and corneal burns. PMID- 23945029 TI - Shape of the anterior cornea: comparison of height data from 4 corneal topographers. AB - PURPOSE: To compare the ability of clinical corneal topographers to describe the shape of the anterior cornea for optical modeling. SETTING: University Medical Center Groningen, Groningen, Netherlands. DESIGN: Cross-sectional study. METHODS: The anterior corneal shape of healthy subjects was assessed with 4 topographers (Atlas Placido disk, Galilei dual Scheimpflug, Orbscan scanning slit, Pentacam single Scheimpflug). Exported height data were fit with Zernike polynomials. Mean values with the standard deviation, interdevice variability, and test-retest variability were determined for the defocus Z(2,0), astigmatism Z(2,-2) and Z(2,2), coma Z(3,-1) and Z(3,1), and spherical aberration Z(4,0) coefficients for 5.5 mm and 8.0 mm diameters. RESULTS: At 5.5 mm, the single Scheimpflug topographer showed the smallest coefficient of repeatability; 0.31 MUm for Z(2,0); 0.40 and 0.34 MUm for Z(2,-2) and Z(2,2), respectively; 0.15 and 0.11 MUm for Z(3,-1) and Z(3,1), respectively; and 0.08 MUm for Z(4,0); the other topographers showed up to 10 times larger coefficients of repeatability. The (unsigned) mean differences between the topographers were in the range of 0.20 to 1.21 MUm for Z(2,0); 0.02 to 0.31 MUm and 0.06 to 0.42 MUm for Z(2,-2) and Z(2,2), respectively; 0.03 to 0.18 MUm and 0.03 to 0.35 MUm for Z(3,-1) and Z(3,1), respectively; and 0.00 to 0.14 MUm for Z(4,0). The Placido-disk topographer and single Scheimpflug topographer data corresponded best. Similar trends were found at 8.0 mm. CONCLUSION: Test-retest variability hampered a detailed description of the anterior corneal shape at the level of individual subjects; interdevice variability compromises the exchangeability of the devices. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23945030 TI - August editorial: impact factors. PMID- 23945031 TI - The clinical evaluation of International Normalized Ratio variability and control in conventional oral anticoagulant administration by use of the variance growth rate. AB - INTRODUCTION: The time in target International Normalized Ratio (INR) range (TIR) is used to assess the control and intensity of oral anticoagulation, but it does not measure variation in the INR. OBJECTIVES: The value of assessing INR variability by use of the variance growth rate (VGR) as a predictor of events was investigated in patients treated with warfarin. METHODS: Three different methods of VGR determination (A, B1, and B2) together with the TIR were studied. Method A measures both INR variability and control, but methods B1 and B2 measure variability only. The VGR and TIR were determined over three time periods: overall follow-up to an event, and 6 months and 3 months before an event. RESULTS: Six hundred and sixty-one control patients were matched to 158 cases (bleeding, thromboembolism, or death). With all VGR methods, the risk of an event was greater in unstable patients at 6 months before an event than in stable patients. Method A demonstrated the greatest risk 3 months before an event in the unstable VGR group as compared with the stable group (odds ratio 3.3, 95% confidence interval 1.9-5.7, P < 0.005). The risk of an event was 1.9 times greater in patients with a low TIR (< 39%) than in those with a high TIR (> 80%) in the 3-month period (P = 0.02). Risk of bleeding was significantly greater in the 3-month period in patients with unstable VGR, with the greatest risk found with method B2 (P < 0.01). CONCLUSIONS: Patients with unstable anticoagulation have a significantly increased risk of 'clinical events' at 3 and 6 months before an event. The VGR can be incorporated into computer-dosage programs, and may offer additional safety when oral anticoagulation is monitored. PMID- 23945032 TI - Fifteen-passenger vans and other transportation options: a comparison of driver, vehicle, and crash characteristics. AB - OBJECTIVE: Fifteen-passenger vans (15-PVs) are a convenient and economical way to transport small groups of people and many educational, community, and health organizations utilize them. Given recent tragic crashes involving 15-PVs, many organizations are reconsidering their use. The goal of this study was to examine driver, vehicle, and crash characteristics of fatal 15-PV collisions over the past 2 decades in comparison to 3 other common vehicle classes. METHODS: We used data from the Fatality Analysis Reporting System (years 1991-2008). Driver, vehicle, and crash characteristics were compared by vehicle classes (15-PV, cars, minivans, and intercity buses) using proportions along with odds ratios (using cars as the reference category) for dichotomous variables and means and mean differences for continuous variables. Logistic regression and analysis of variance were used to statistically compare odds and means, respectively. The odds and absolute risk of a first, subsequent, and either rollover by vehicle type and occupancy rate were also examined. Odds and absolute risk of a rollover event by occupancy rate were calculated. RESULTS: Compared to car drivers, van drivers typically had a better past 3-year driving record. Van drivers performed significantly fewer actions suggesting aggressive driving (e.g., speeding). However, the proportion of van drivers who were deemed to have followed improperly or to have overcorrected was greater. A vehicle rollover was cited almost twice as frequently in van crashes compared to other passenger vehicles. Of the 4 vehicle types studied, all were more likely to rollover as their occupancy rates increased. Fully loaded 15-PVs had almost 13 times the odds of rollover compared to fully loaded cars. Minivans when full (7 occupants), often seen as the replacement for 15-PVs, were found to have over 3.5 times the odds of rollover of fully loaded cars. CONCLUSIONS: Drivers need to be aware that as occupancy rates of the vehicles they drive rise so does the risk of rollover and fatalities, especially among minivans and 15-PVs. Organizations transporting groups need to balance cost and safety management by selecting vehicle types and drivers with acute awareness of the risks involved. PMID- 23945033 TI - Human adipose-derived stem cells cultured in keratinocyte serum free medium: Donor's age does not affect the proliferation and differentiation capacities. AB - BACKGROUND: Although donor age-related effects of characteristics of mesenchymal stem cells (MSC), such as a decrease in the proliferation and differentiation capacity and an increase of senescence and apoptosis, are evident, such effects are generally less prominent in adipose-derived stem cells (ASC). Using a hormone and growth factor rich medium (KFSM), this study cultured ASC from abdominal subcutaneous fat of 27 adult females in three age groups: 30-39 y, 40-49 y and 50 60 y, and investigated the growth and differentiation characteristics. RESULTS: The derived ASC had an immunophenotype similar to that of bone marrow derived MSC (BMSC). They could be stably expanded with an average population doubling time of 21.5 +/- 2.3 h. Other than a higher pre-adipogenic commitment and a lower adipogenic differentiation capability in ASC derived from the old age group, other characteristics including proliferation rate, doubling time, telomere length, as well as the osteogenic and chondrogenic differentiation capacity were the same regardless of the donor's age. CONCLUSIONS: The study demonstrates a promising proliferation and differentiation capabilities of ASC regardless of the donor's age. The compromised adipogenic potential in the older donors could be a benefit for their application in regeneration therapy. PMID- 23945034 TI - The effect of cooling prior to and during exercise on exercise performance and capacity in the heat: a meta-analysis. AB - Exercise is impaired in hot, compared with moderate, conditions. The development of hyperthermia is strongly linked to the impairment and as a result various strategies have been investigated to combat this condition. This meta-analysis focused on the most popular strategy: cooling. Precooling has received the most attention but recently cooling applied during the bout of exercise has been investigated and both were reviewed. We conducted a literature search and retrieved 28 articles which investigated the effect of cooling administered either prior to (n=23) or during (n=5) an exercise test in hot (wet bulb globe temperature >26 degrees C) conditions. Mean and weighted effect size (Cohen's d) were calculated. Overall, precooling has a moderate (d=0.73) effect on subsequent performance but the magnitude of the effect is dependent on the nature of the test. Sprint performance is impaired (d=-0.26) but intermittent performance and prolonged exercise are both improved following cooling (d=0.47 and d=1.91, respectively). Cooling during exercise has a positive effect on performance and capacity (d=0.76). Improvements were observed in studies with and without cooling induced physiological alterations, and the literature supports the suggestion of a dose-response relationship among cooling, thermal strain and improvements in performance and capacity. In summary, precooling can improve subsequent intermittent and prolonged exercise performance and capacity in a hot environment but sprint performance is impaired. Cooling during exercise also has a positive effect on exercise performance and capacity in a hot environment. PMID- 23945035 TI - Can resistance training change the strength, body composition and self-concept of overweight and obese adolescent males? A randomised controlled trial. AB - BACKGROUND/AIM: Resistance training is an exercise modality at which overweight and obese adolescents can excel and which can therefore positively affect their psychological well-being. The aim of this study was to determine the effect of a 6-month resistance training intervention on the self-concept strength and body composition of overweight and obese adolescent males. METHODS: 56 overweight and obese males aged 13-17 years were randomly allocated to an Intervention (n=30) or Control (n=26) group. Primary (psychological) and secondary (strength and body composition) outcomes were assessed at baseline as well as at 3 (halfway through the intervention), 6 (immediately postintervention) and 12 months follow-up. Random effects mixed modelling was used to determine the effects of the intervention. RESULTS: Statistically significant differences between the Intervention and Control groups were observed at 3-month and 6-month assessments for exercise self-efficacy, resistance training confidence and self-esteem. Large increases in strength for the Intervention group, relative to Controls, were also observed with no substantial changes in body composition shown for either group. Values for all variables returned to baseline following completion of the programme. CONCLUSIONS: A 6-month resistance training intervention can positively affect the self-concept and strength of overweight and obese adolescent boys. PMID- 23945036 TI - Insights on the HLA-G evolutionary history provided by a nearby Alu insertion. AB - The AluyHG element belongs to the AluYb8 subfamily. It is a polymorphic insertion, located approximately 20 kb from the HLA-G 3'-untranslated region (3' UTR), which has been used for evolution studies because it exhibits identity for descendants and it is still polymorphic in the human genome. To understand the evolutionary mechanisms acting on HLA-G, we evaluated the presence or absence of the AluyHG element, associating this variable site with others observed at HLA-G coding, 3'-UTR, or both regions in four distinct populations (Brazilian, French, Congolese, and Senegalese). The results were compared with the 1000Genomes Consortium data. The worldwide AluyHG frequencies showed an increment, starting lower in Africa and increasing following distance and time of human dispersion out of Africa. The same haplotype pattern was observed in all populations, indicating that most of the HLA-G haplotypes already detected were originated earlier in Africa, before Homo sapiens dispersion. The AluyHG insertion was associated with the G*01:01:01:01/UTR-1 haplotype, with rare recombinants. Despite its high frequency in worldwide populations, the G*01:01:01:01/UTR-1 haplotype should be very recent. The low frequency of recombinants indicates that the rate of recombination at the HLA-G gene is very low. PMID- 23945038 TI - High anxiety in clinically healthy patients and increased QT dispersion: a meta analysis. AB - BACKGROUND: Exaggerated dispersion of repolarization is likely to play a role in both the initiation and the maintenance of malignant ventricular arrhythmias. It was proposed that the inter-lead QT interval differences within a 12-lead ECG termed 'QT dispersion' might reflect regional differences in myocardial refractoriness, and that this might predict cardiac dysrhythmias. AIM: The study aimed to perform a meta-analysis of the relevant available publications. METHODS: A MEDLINE search from 1990 to 2012 at PubMed (NLM) was performed. An all-fields search for index terms 'QT dispersion' and 'anxiety' was done. Case-control studies and surveys were included in the analysis provided they encompassed physically healthy subjects who had been evaluated for anxiety disorders with validated inventories. Outcome measures were either crude or heart rate-corrected QT dispersions. RESULTS: Five studies were included in the analysis, which encompassed 580 patients with calculated mean age of 36.8 years (standard error = 5.5). The values of crude and heart rate-corrected QT dispersions across the studies were statistically significantly higher in the patients with anxiety disorders. Crude values of QT dispersion were available in 164 patients with anxiety and in 273 controls. Summarized standardized difference in the means (random effect model) was equal to 1.472 (95% confidence interval: 1.034-1.911). Heart rate-corrected QT dispersion values were available in 193 patients with anxiety and in 282 controls, and the summarized standardized difference in the means was equal to 3.299 (95% confidence interval: 1.215-5.384). CONCLUSION: High anxiety is associated with increased QT dispersion, which may predispose to cardiac arrhythmias. PMID- 23945037 TI - 2'-Phosphate cyclase activity of RtcA: a potential rationale for the operon organization of RtcA with an RNA repair ligase RtcB in Escherichia coli and other bacterial taxa. AB - RNA terminal phosphate cyclase catalyzes the ATP-dependent conversion of a 3' phosphate RNA end to a 2',3'-cyclic phosphate via covalent enzyme-(histidinyl Nepsilon)-AMP and RNA(3')pp(5')A intermediates. Here, we report that Escherichia coli RtcA (and its human homolog Rtc1) are capable of cyclizing a 2'-phosphate RNA end in high yield. The rate of 2'-phosphate cyclization by RtcA is five orders of magnitude slower than 3'-phosphate cyclization, notwithstanding that RtcA binds with similar affinity to RNA3'p and RNA2'p substrates. These findings expand the functional repertoire of RNA cyclase and suggest that phosphate geometry during adenylate transfer to RNA is a major factor in the kinetics of cyclization. RtcA is coregulated in an operon with an RNA ligase, RtcB, that splices RNA 5'-OH ends to either 3'-phosphate or 2',3'-cyclic phosphate ends. Our results suggest that RtcA might serve an end healing function in an RNA repair pathway, by converting RNA 2'-phosphates, which cannot be spliced by RtcB, to 2',3'-cyclic phosphates that can be sealed. The rtcBA operon is controlled by the sigma(54) coactivator RtcR encoded by an adjacent gene. This operon arrangement is conserved in diverse bacterial taxa, many of which have also incorporated the RNA-binding protein Ro (which is implicated in RNA quality control under stress conditions) as a coregulated component of the operon. PMID- 23945040 TI - The importance of a normal breathing pattern for an effective abdominal-hollowing maneuver in healthy people: an experimental study. AB - CONTEXT: A normal breathing pattern while performing the abdominal-hollowing (AH) maneuver or spinal-stabilization exercise is essential for the success of rehabilitation programs and exercises. In previous studies, subjects were given standardized instructions to control the influence of respiration during the AH maneuver. However, the effect of breathing pattern on abdominal-muscle thickness during the AH maneuver has not been investigated. OBJECTIVE: To compare abdominal muscle thickness in subjects performing the AH maneuver under normal and abnormal breathing-pattern conditions and to investigate the effect of breathing pattern on the preferential contraction ratio (PCR) of the transverse abdominis. DESIGN: Comparative, repeated-measures experimental study. SETTING: University research laboratory. PARTICIPANTS: 16 healthy subjects (8 male, 8 female) from a university population. MEASUREMENT: A real-time ultrasound scanner was used to measure abdominal-muscle thickness during normal and abnormal breathing patterns. A paired t test was used to assess the effect of breathing pattern on abdominal muscle thickness and PCR. RESULTS: Muscle thickness in the transverse abdominis and internal oblique muscles was significantly greater under the normal breathing pattern than under the abnormal pattern (P < .05). The PCR of the transverse abdominis was significantly higher under the normal breathing pattern compared with the abnormal pattern (P < .05). CONCLUSION: The results indicate that a normal breathing pattern is essential for performance of an effective AH maneuver. Thus, clinicians should ensure that patients adopt a normal breathing pattern before performing the AH maneuver and monitor transverse abdominis activation during the maneuver. PMID- 23945039 TI - Gamma-glutamyltransferase, insulin resistance and cardiometabolic risk profile in a middle-aged African population. AB - BACKGROUND: Mechanisms linking liver functions with cardiometabolic risk may involve insulin resistance (IR) and non-alcoholic fatty liver disease. We assessed the associations of gamma-glutamyltransferase (GGT) levels with IR and metabolic syndrome (MetS) in an adult South African urban cohort. METHODS: 1198 participants aged >15 years (297 men) were drawn from the Bellville-South suburb (Cape Town). The homeostatic model assessment of insulin (HOMA-IR), beta-cells function (HOMA-B%), fasting insulin resistance index (FIRI) and the quantitative insulin-sensitivity check index (QUICKI) were calculated, and MetS defined according to the Join Interim Statement 2009 criteria. Associations of GGT levels with covariates were assessed on a continuous scale and across sex-specific quarters of GGT, with adjustment for confounders via generalized linear and logistic regressions. RESULTS: Indicators of IR (HOMA-IR, FIRI and fasting insulin) increased, whereas those for insulin sensitivity (Sib and QUICKI) diminished significantly linearly and across increasing GGT quarters. In multivariable-adjusted models, adjustment for sex, age, BMI, cigarette smoking and alcohol intake yielded the strongest, significant associations between GGT and all markers of IR/IS and glycemia excluding glucose insulin ratio. In a similar level of adjustments, with/without further adjustment for markers of IR/insulin sensitivity, the prevalence of MetS significantly increased across quarters of GGT. CONCLUSIONS: GGT levels were independently associated with insulin sensitivity and MetS in this population. Unaccounted, chronic elevation of GGT may therefore be a cue to screen and monitor individuals for MetS and diabetes, and may warrant consideration as an indicator of high risk for the development of these metabolic disorders. PMID- 23945041 TI - Hierarchical guest exchange and step-by-step activation of a biporous coordination framework. AB - A unique step-by-step activation of the biporous material via formation of the intermediate host-guest complex with a labile ligand has been presented on the example of the metal-organic framework [Zn4(ur)2(ndc)4]. The difference in the chemical environment of channels allows highly selective separation of the mixture of S4N4 and benzene. PMID- 23945042 TI - MicroRNAs expression profiling of eutopic proliferative endometrium in women with ovarian endometriosis. AB - BACKGROUND: The eutopic endometrium of women with endometriosis, compared with disease-free individuals, contains certain molecular alterations, including the differential expression of microRNA (miRNA). The aim of the study was to compare the expression of the most relevant miRNAs in the eutopic endometrium of women with and without ovarian endometriosis. METHODS: A total of 46 regularly menstruating patients, 21 patients with ovarian endometriosis and 25 controls, underwent surgery in the proliferative phase of the cycle. The eutopic endometrium was collected through aspirating biopsy prior to laparoscopy. Only patients with advanced (stage III and IV) histopathologically confirmed ovarian endometriosis were included. TaqMan MicroRNA Array Cards were applied to examine the expression of 667 human miRNAs in 10 patients with endometriosis and 10 controls. Custom-made, low-density real-time PCR arrays were used to confirm the expression of 15 selected molecules in 21 endometriosis patients and 25 disease free individuals. RESULTS: Of 667 miRNAs, 2 were highly likely to be upregulated and 13 were downregulated in the eutopic endometrium of patients with endometriosis compared with the controls. Validation using real-time PCR showed that hsa-miR-483-5p (p = 0.012) and hsa-miR-629* (p = 0.02) are significantly downregulated in patients with endometriosis. CONCLUSIONS: Changes in the expression of select miRNAs might lead to or be a consequence of an early defect in the physiological activity of the proliferative endometrium, ultimately resulting in the overgrowth of this tissue outside the uterus. PMID- 23945043 TI - Trans-radial bilateral iliac artery stenting. AB - We describe a step-by-step instructional 'how to' case of trans-radial bilateral iliac stenting using a 5-Fr guide sheath in a symptomatic patient to illustrate an alternative to common femoral artery access. PMID- 23945044 TI - Skin infections in young people (aged 14-18 years): an integrative review. AB - Skin infections are a major cause of preventable hospitalization, with young people being particularly susceptible. Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infection typically presents as skin infection. CA-MRSA infection rates have increased rapidly in the past decade. Exploration of literature specific to young people aged 14-18 years is therefore timely. Integrative review using the methods described by Whittemore and Knafl was undertaken. Electronic databases of Medline, CINAHL, Scopus, Cochrane Database of Systematic Reviews, and Google databases were searched for English-language articles published after 1990. Twenty primary studies were included and the findings are reported here. Data analysis revealed factors influencing skin infections in young people may be host-, transmission-, or pathogen-specific. Strategies to address host and transmission factors may be effective in controlling skin infection rates in young people. PMID- 23945045 TI - Healthcare providers' knowledge, experience and challenges of reporting adverse events following immunisation: a qualitative study. AB - BACKGROUND: Healthcare provider spontaneous reporting of suspected adverse events following immunisation (AEFI) is central to monitoring post-licensure vaccine safety, but little is known about how healthcare professionals recognise and report to surveillance systems. The aim of this study was explore the knowledge, experience and attitudes of medical and nursing professionals towards detecting and reporting AEFI. METHODS: We conducted a qualitative study, using semi structured, face to face interviews with 13 Paediatric Emergency Department consultants from a tertiary paediatric hospital, 10 General Practitioners, 2 local council immunisation and 4 General Practice nurses, recruited using purposive sampling in Adelaide, South Australia, between December 2010 and September 2011. We identified emergent themes related to previous experience of an AEFI in practice, awareness and experience of AEFI reporting, factors that would facilitate or impede reporting and previous training in vaccine safety. Thematic analysis was used to analyse the data. RESULTS: AEFI reporting was infrequent across all groups, despite most participants having reviewed an AEFI. We found confusion about how to report an AEFI and variability, according to the provider group, as to the type of events that would constitute a reportable AEFI. Participants' interpretation of a "serious" or "unexpected" AEFI varied across the three groups. Common barriers to reporting included time constraints and unsatisfactory reporting processes. Nurses were more likely to have received formal training in vaccine safety and reporting than medical practitioners. CONCLUSIONS: This study provides an overview of experience and beliefs of three healthcare professional groups in relation to identifying and reporting AEFI. The qualitative assessment reveals differences in experience and awareness of AEFI reporting across the three professional groups. Most participants appreciated the importance of their role in AEFI surveillance and monitoring the ongoing safety of vaccines. Future initiatives to improve education, such as increased training to health care providers, particularly, medical professionals, are required and should be included in both undergraduate curricula and ongoing, professional development. PMID- 23945046 TI - kClust: fast and sensitive clustering of large protein sequence databases. AB - BACKGROUND: Fueled by rapid progress in high-throughput sequencing, the size of public sequence databases doubles every two years. Searching the ever larger and more redundant databases is getting increasingly inefficient. Clustering can help to organize sequences into homologous and functionally similar groups and can improve the speed, sensitivity, and readability of homology searches. However, because the clustering time is quadratic in the number of sequences, standard sequence search methods are becoming impracticable. RESULTS: Here we present a method to cluster large protein sequence databases such as UniProt within days down to 20%-30% maximum pairwise sequence identity. kClust owes its speed and sensitivity to an alignment-free prefilter that calculates the cumulative score of all similar 6-mers between pairs of sequences, and to a dynamic programming algorithm that operates on pairs of similar 4-mers. To increase sensitivity further, kClust can run in profile-sequence comparison mode, with profiles computed from the clusters of a previous kClust iteration. kClust is two to three orders of magnitude faster than clustering based on NCBI BLAST, and on multidomain sequences of 20%-30% maximum pairwise sequence identity it achieves comparable sensitivity and a lower false discovery rate. It also compares favorably to CD-HIT and UCLUST in terms of false discovery rate, sensitivity, and speed. CONCLUSIONS: kClust fills the need for a fast, sensitive, and accurate tool to cluster large protein sequence databases to below 30% sequence identity. kClust is freely available under GPL at http://toolkit.lmb.uni muenchen.de/pub/kClust/. PMID- 23945047 TI - Overexpression of an antimicrobial peptide derived from C. elegans using an aggregation-prone protein coexpression system. AB - Antibacterial factor 2 (ABF-2) is a 67-residue antimicrobial peptide derived from the nematode Caenorhabditis elegans. Although it has been reported that ABF-2 exerts in vitro microbicidal activity against a range of bacteria and fungi, the structure of ABF-2 has not yet been solved. To enable structural studies of ABF-2 by NMR spectroscopy, a large amount of isotopically labeled ABF-2 is essential. However, the direct expression of ABF-2 in Escherichia coli is difficult to achieve due to its instability. Therefore, we applied a coexpression method to the production of ABF-2 in order to enhance the inclusion body formation of ABF 2. The inclusion body formation of ABF-2 was vastly enhanced by coexpression of aggregation-prone proteins (partner proteins). By using this method, we succeeded in obtaining milligram quantities of active, correctly folded ABF-2. In addition, 15 N-labeled ABF-2 and a well-dispersed heteronuclear single quantum coherence (HSQC) spectrum were also obtained successfully. Moreover, the effect of the charge of the partner protein on the inclusion body formation of ABF-2 in this method was investigated by using four structurally homologous proteins. We concluded that a partner protein of opposite charge enhanced the formation of an inclusion body of the target peptide efficiently. PMID- 23945048 TI - An experimental clinical evaluation of EIT imaging with l1 data and image norms. AB - Electrical impedance tomography (EIT) produces an image of internal conductivity distributions in a body from current injection and electrical measurements at surface electrodes. Typically, image reconstruction is formulated using regularized schemes in which l2-norms are used for both data misfit and image prior terms. Such a formulation is computationally convenient, but favours smooth conductivity solutions and is sensitive to outliers. Recent studies highlighted the potential of l1-norm and provided the mathematical basis to improve image quality and robustness of the images to data outliers. In this paper, we (i) extended a primal-dual interior point method (PDIPM) algorithm to 2.5D EIT image reconstruction to solve l1 and mixed l1/l2 formulations efficiently, (ii) evaluated the formulation on clinical and experimental data, and (iii) developed a practical strategy to select hyperparameters using the L-curve which requires minimum user-dependence. The PDIPM algorithm was evaluated using clinical and experimental scenarios on human lung and dog breathing with known electrode errors, which requires a rigorous regularization and causes the failure of reconstruction with an l2-norm solution. The results showed that an l1 solution is not only more robust to unavoidable measurement errors in a clinical setting, but it also provides high contrast resolution on organ boundaries. PMID- 23945049 TI - Measuring the quality and quantity of professional intrapartum support: testing a computerised systematic observation tool in the clinical setting. AB - BACKGROUND: Continuous support in labour has a significant impact on a range of clinical outcomes, though whether the quality and quantity of support behaviours affects the strength of this impact has not yet been established. To identify the quality and quantity of support, a reliable means of measurement is needed. To this end, a new computerised systematic observation tool, the 'SMILI' (Supportive Midwifery in Labour Instrument) was developed.The aim of the study was to test the validity and usability of the 'Supportive Midwifery in Labour Instrument' (SMILI) and to test the feasibility and acceptability of the systematic observation approach in the clinical intrapartum setting. METHODS: Systematic observation was combined with a postnatal questionnaire and the collection of data about clinical processes and outcomes for each observed labour.The setting for the study was four National Health Service maternity units in Scotland, UK. Participants in this study were forty five midwives and forty four women.The SMILI was used by trained midwife observers to record labour care provided by midwives. Observations were undertaken for an average of two hours and seventeen minutes during the active first stage of labour and, in 18 cases, the observation included the second stage of labour. Content validity of the instrument was tested by the observers, noting the extent to which the SMILI facilitated the recording of all key aspects of labour care and interactions. Construct validity was tested through exploration of correlations between the data recorded and women's feelings about the support they received. Feasibility and usability data were recorded following each observation by the observer. Internal reliability and construct validity were tested through statistical analysis of the data. RESULTS: One hundred and four hours of labour care were observed and recorded using the SMILI during forty nine labour episodes. CONCLUSION: The SMILI was found to be a valid and reliable instrument in the intrapartum setting in which it was tested. The study identified that the SMILI could be used to test correlations between the quantity and quality of support and outcomes. The systematic observational approach was found to be an acceptable and feasible method of enquiry. PMID- 23945050 TI - Severe hyperkalemia following colon diversion surgery in a patient undergoing chronic hemodialysis: a case report. AB - INTRODUCTION: Potassium (K+) homeostasis in healthy subjects is maintained mainly by urinary excretion of K+. In patients with end-stage renal disease, the intestinal tract might assume an accessory K+ excretory role in the face of declining renal excretory function. Here, we report the case of a patient with end-stage renal disease who developed severe hyperkalemia following colon diversion surgery. CASE PRESENTATION: A 56-year-old Caucasian woman undergoing hemodialysis experienced ischemic colitis, leading to ileocecal resection and a temporary ileostomy. She made a good recovery and her dietary intake improved. However, her pre-dialysis serum K+ level three weeks later was 7.2mmol/L, which was much higher than her previous level (range 4.9 to 6.1mmol/L). Despite dietary restriction of K+ and use of oral cation-exchange resin and low K+ dialysate, her serum K+ level remained high (6.1 to 8.3mmol/L). Six months later, her bowel continuity was restored and her serum K+ decreased to the previous level. Her fecal K+ concentration before and after stoma reversal showed a marked difference: 23mmol/L before and 60mmol/L after. CONCLUSIONS: We assume that the severe hyperkalemia seen in our patient was caused by reduced colonic K+ secretion due to the colon diversion. Our patient's case demonstrates the importance of colonic K+ secretion for the maintenance of K+ homeostasis in patients with end-stage renal disease. PMID- 23945051 TI - Effect of periodontal treatment on the clinical parameters of patients with rheumatoid arthritis: study protocol of the randomized, controlled ESPERA trial. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disorder that leads to joint damage, deformity, and pain. It affects approximately 1% of adults in developed countries. Periodontitis is a chronic oral infection, caused by inflammatory reactions to gram-negative anaerobic bacteria, and affecting about 35 to 50% of adults. If left untreated, periodontitis can lead to tooth loss. A significant association has been shown to exist between periodontitis and RA in observational studies. Some intervention studies have suggested that periodontal treatment can reduce serum inflammatory biomarkers such as C-reactive protein, or erythrocyte sedimentation rate. We hypothesize that periodontitis could be an aggravating factor in patients with RA, and that its treatment would improve RA outcomes. The aim of this clinical trial is to assess the effect of periodontal treatment on the biological and clinical parameters of patients with RA. METHODS/DESIGN: The ESPERA (Experimental Study of Periodontitis and Rheumatoid Arthritis) study is an open-label, randomized, controlled trial. Subjects with both RA and periodontitis will be recruited at two university hospitals in southwestern France. In total, 40 subjects will be randomized into two arms (intervention and control groups), and will be followed up for 3 months. Intervention will consist of full-mouth supra-gingival and sub-gingival non surgical scaling and root planing, followed by systemic antibiotic therapy, local antiseptics, and oral hygiene instructions. After the 3-month follow-up period, the same intervention will be applied to the subjects randomized to the control group.The primary outcome will be change of in Disease Activity Score in 28 Joints (DAS28) at the end of the follow-up period. Secondary outcomes will be the percentages of subjects with 20%, 50%, and 70% improvement in disease according to the American College of Rheumatology criteria. Health-related quality of life assessments (the Health Assessment Questionnaire and the Geriatric Oral Health Assessment Index) will also be compared between the two groups. DISCUSSION: Evidence-based management of potential aggravating factors in subjects with active RA could be of clinical importance, yet there are few randomized controlled trials on the effect of periodontal treatment on the clinical parameters of RA. The ESPERA trial is designed to determine if non-surgical periodontal treatment could improve clinical outcomes in patients with active RA, and the quality of life of these patients. TRIAL REGISTRATION: The ESPERA Trial was registered in Current Controlled Trials [ISRCTN79186420] on 2012/03/20. The trial started recruiting on 2012/03/06. PMID- 23945052 TI - PLA/POSS nanofibers: a novel system for the immobilization of metal nanoparticles. AB - In this work, a novel catalytic system is developed, consisting of palladium nanoclusters homogenously dispersed on the surface of nanostructured polymer nanofibers based on poly(L-lactic acid) (PLLA) and polyhedral oligomeric silsesquioxanes (POSS). Indeed, PLLA nanofibers containing amino-functionalized silsesquioxane molecules (POSS-NH2), potentially capable of interacting with the metal precursor, are prepared by means of electrospinning. Conversely to the polymer matrix, which does not show any tendency to retain the metal precursor, the submicrometric dispersion of POSS-NH2 in the PLLA nanofibers, as demonstrated by SEM-EDS analysis, turns out to promote the formation of metal nanoclusters. TEM measurements show a uniform distribution of Pd nanoparticles, characterized by an average dimension of ca. 4 nm, along the fibers. The prepared system proves a relevant catalytic activity toward the hydrogenation of stilbene under heterogeneous conditions. Moreover, as demonstrated by XPS measurements, the support is capable of retaining the catalyst during the hydrogenation reaction, thus preventing its leaching. PMID- 23945053 TI - Longitudinal study of adolescents' attempts to promote and deter friends' smoking behavior. AB - PURPOSE: Little research has examined the extent to which adolescents directly attempt to influence friends' smoking. This study examines adolescents' reported actions to promote or deter friends' smoking, and whether actions vary by adolescents' smoking experience. METHODS: Data were collected between 2001 and 2004 at four time points across the 9th and 10th grades from an ethnically diverse school-based sample (N = 395; 53% female). RESULTS: Deterrence of smoking was reported by a greater percentage of adolescents than was promotion of smoking, both among those who had ever smoked and never smoked. By the end of the study, over 45% of ever smokers and less than 5% of never smokers had promoted smoking among friends. In contrast, over 70% of ever smokers and roughly 40% of never smokers had deterred smoking. Among adolescents who had ever smoked, positive consequences of smoking by fall of 10th grade predicted attempts to promote smoking by the end of 10th grade (OR = 4.37, p < .05). To a lesser extent, negative consequences of smoking predicted attempts to deter smoking (OR = 2.60, p < .08). These effects were independent of the opposite type of smoking consequences, level of personal smoking experience, having close friends who smoked, prior attempts to influence friends' behavior, and smoker's gender. CONCLUSIONS: Models of peer influence should account for both positive and negative influence of adolescents on friends' health behavior. Adolescents who have engaged in risk-taking and experienced negative consequences may be a resource in designing and delivering interventions; future research should evaluate their ability to change friends' behavior. PMID- 23945054 TI - Health insurance coverage predicts lower childbearing among near-poor adolescents. AB - PURPOSE: The impact of health insurance on adolescent childbearing takes on increased salience in the context of the ongoing United States health care debate. Health insurance coverage is important for accessing health care services, including reproductive health services, yet prior research has not examined the association between insurance coverage and childbearing. Consequently, the role of insurance in the prevention of adolescent childbearing has been unclear. METHODS: Using three panels (2001, 2004, and 2008) of the nationally representative Survey of Income and Program Participation data, hierarchical multilevel logistic regression models test the association between pre-pregnancy health insurance coverage and childbearing for a sample of 7,263 unmarried adolescent women (aged 16-19 years), controlling for known correlates of adolescent childbearing. Analyses examine variations in the association based on family income. RESULTS: The odds of reporting childbearing were almost twice as great for adolescents who were uninsured compared with those who were insured before a pregnancy occurred. Interaction models demonstrate this effect for near poor adolescents (who are less likely to have health insurance coverage) compared with poor and more advantaged adolescents. CONCLUSIONS: The findings of the current nationally representative study suggest that health insurance coverage is associated with a lower probability of childbearing for near-poor adolescents. Future research should examine potential mechanisms through which insurance coverage influences adolescent childbearing. PMID- 23945055 TI - Incorporation of parallel electrospun fibers for improved topographical guidance in 3D nerve guides. AB - Three dimensional (3D) conduits facilitate nerve regeneration. Parallel microfibers have been shown to guide axon extension and Schwann cell migration on flat sheets via topographical cues. However, incorporation of aligned microfibers into 3D conduits to accelerate nerve regeneration has proven challenging. We report an electrospinning technique to incorporate parallel microfibers into 3D constructs at high surface areas while retaining an open architecture. The nerve guide consists of many microchannels lined with a thin layer of longitudinally aligned microfibers. This design aims to maximize benefits of topographical cues without inhibiting cellular infiltration. We support this hypothesis by demonstrating efficient cell infiltration in vitro. Additionally, this new technique reduces wall thickness compared to our previous design, providing a greater total area for tissue growth. This approach results in an architecture that very closely mimics the structure of decellularized nerve but with larger microchannel diameters to encourage cell infiltration. We believe that reproducing the native architecture is the first step toward matching autograph efficacy. Furthermore, this design can be combined with other biochemical cues to promote nerve regeneration. PMID- 23945056 TI - Degradation of neutrophil extracellular traps co-varies with disease activity in patients with systemic lupus erythematosus. AB - INTRODUCTION: The ability to degrade neutrophil extracellular traps (NETs) is reduced in a subset of patients with systemic lupus erythematosus (SLE). NETs consist of chromatin covered with antimicrobial enzymes and are normally degraded by DNase-I, an enzyme which is known to have reduced activity in SLE. Decreased ability to degrade NETs is associated with disease activity. In the current study we investigated how the ability of serum from SLE patients to degrade NETs varies during the course of SLE as well as what impact this may have for the clinical phenotype of SLE. METHODS: Serum from 69 patients with SLE, included in a prospective study, was taken every 60 days for a median of 784 days. The ability of serum to degrade NETs was determined and associated with clinical parameters occurring before and at the time of sampling, as well as after sampling by using conditional logistic regression. RESULTS: As many as 41% of all patients in the study showed decreased ability to degrade NETs at least once, but with a median of 20% of all time points. Decreased degradation was associated with manifestations of glomerulonephritis as well as low complement levels and elevated levels of antibodies directed against histones and DNA. Furthermore, the odds ratio for the patient to develop alopecia and fever after an episode of decreased NETs degradation was increased by four to five times compared to normal. CONCLUSIONS: Decreased degradation of NETs is associated with clinical manifestations in SLE and may contribute to disease pathogenesis. Potential therapeutics restoring the ability to degrade NETs could be beneficial for certain patients with SLE. PMID- 23945057 TI - Brain and lung metastasis of Bartholin's gland adenoid cystic carcinoma: a case report. AB - INTRODUCTION: Adenoid cystic carcinoma of Bartholin's gland is a very rare disease. CASE PRESENTATION: A 48-year-old premenopausal woman of Caucasian origin was delivered adjuvant pelvic and inguinal radiotherapy after prior complete left Bartholin's gland tumor excision and inguinal lymph node dissection for adenoid cystic carcinoma of Bartholin's gland with one metastatic inguinal lymph node.Two years after primary treatment, she presented to the Emergency Room with acute headache, hypoacousia, decrease in visual acuity, and a decrease in right leg muscle strength. A cranial magnetic resonance imaging scan demonstrated three cystic brain lesions with associated perifocal edema. Chest and abdomen computed tomography scans and a magnetic resonance imaging scan of the pelvis did not find any metastatic or residual disease elsewhere. A physical examination found no local recurrence.Stereotactic brain biopsies with pathology examination revealed the presence of adenoid cystic carcinoma metastasis. She thus received 30Gy of brain radiotherapy but, three months later, the brain lesions did not decrease in size and left mid lobular lung lesions appeared on her chest computed tomography scan. A mid left lobe lung excision was undertaken followed by chemotherapy consisting of six cycles of cyclophosphamide, adriamycin and cisplatin. Five months after beginning chemotherapy, the brain disease progressed and our patient died. CONCLUSION: Our case report shows the difficulty in managing brain and lung metastasis of Bartholin's gland adenoid cystic carcinoma as no consensus on the optimal treatment exists. PMID- 23945058 TI - Number of metabolic syndrome risk parameters associated with TAFIa/ai antigen levels. AB - Thrombin activatable fibrinolysis inhibitor (TAFI) is an important procoagulant factor. Patients with metabolic syndrome (MetS) also have an elevated procoagulant status. However, TAFI and its association with MetS are still not well known. We aimed to investigate TAFI in type 2 diabetes mellitus patients with MetS. We enrolled a total of 55 patients who had MetS (n = 30) and 25 healthy controls. MetS was diagnosed using National Cholesterol Education Program Adult Treatment Panel III criteria. We measured activated and inactivated TAFI (TAFIa/ai) antigen in plasma samples using a commercially available ELISA kit (Imubind TAFIa/ai antigen ELISA; American Diagnostica Inc., Stamford, Connecticut, USA). TAFIa/ai levels were then evaluated for links to MetS parameters. Mean TAFIa/ai levels were 156.6 +/- 66.9 ng/dl in patients with MetS and 104.1 +/- 60.3 ng/dl in the control group (P = 0.005). None of the MetS parameters, including blood pressure, fasting plasma glucose, waist circumference, triglycerides or high-density lipoprotein cholesterol (HDL-C) levels were correlated with TAFIa/ai levels. However, TAFIa/ai level had a strong correlation with the number of metabolic risk components, which increased proportionally when MetS parameters were over three. When there were increased numbers of MetS risk components, we detected a rise in TAFIa/ai levels. TAFIa/ai levels could be an indicator of atherosclerotic tendency in patients with MetS. PMID- 23945059 TI - Antibody binding, platelet adhesion, and protein adsorption on various polymer surfaces. AB - Commercially available polymer surfaces for in vitro applications are characterized to different extents in terms of hydrophobicity, binding preferences, and immunoglobulin capacity. We compared five, well or poorly defined polystyrene plates, used as standard hydrophobic surfaces for studying biological interactions. Antibody binding (ELISA) and platelet adhesion (release of alkaline phosphatase from adhered platelets) were contrasted with total protein adsorption (alkaline phosphatase assay and bicinchoninic acid assay). In the assays, we utilized four plasma proteins: human serum albumin (HSA), C reactive protein (CRP), fibronectin, and fibrinogen. At 0.5 MUg antigen/well, all antibodies bound to their antigens most effectively on Nunc (MaxiSorp and MediSorp, Waltham, Massachusetts, USA) microplates, as compared to Sarstedt (Numbrecht, Germany) and Corning microplates (Tewksbury, Massachusetts, USA). The significant differences between Nunc and Corning were seen in the binding of anti HSA (P <= 0.01) and anti-fibronectin (P <= 0.0002). Similar patterns were shown in experiments of ADP-induced platelet adhesion to fibrinogen immobilized at 200 MUg/well. Platelet adhesion noted on Corning microplates was roughly three times lower compared to those observed on MaxiSorp (P < 0.01), MediSorp (P < 0.02), and Sarstedt (P < 0.05). In a parallel study, we have also shown the superiority of tissue culture-Sarstedt surface over micro test Sarstedt plate. Furthermore, the antibody binding, but not platelet adhesion, was positively correlated with total protein adsorption. Our findings indicate that of five polystyrene surfaces, Nunc microplates are optimal for studies of protein adsorption, as they had the highest binding capacity and relatively the least affected protein structure, pointing to the role of surface chemistry in protein adsorption and adsorption induced conformational changes in a protein structure. PMID- 23945060 TI - Platelet aggregation following trauma: a prospective study. AB - We aimed to elucidate platelet function in trauma patients, as it is pivotal for hemostasis yet remains scarcely investigated in this population. We conducted a prospective observational study of platelet aggregation capacity in 213 adult trauma patients on admission to an emergency department (ED). Inclusion criteria were trauma team activation and arterial cannula insertion on arrival. Blood samples were analyzed by multiple electrode aggregometry initiated by thrombin receptor agonist peptide 6 (TRAP) or collagen using a Multiplate device. Blood was sampled median 65 min after injury; median injury severity score (ISS) was 17; 14 (7%) patients received 10 or more units of red blood cells in the ED (massive transfusion); 24 (11%) patients died within 28 days of trauma: 17 due to cerebral injuries, four due to exsanguination, and three from other causes. No significant association was found between aggregation response and ISS. Higher TRAP values were associated with death due to cerebral injuries (P < 0.01, when corrected for ISS and platelet counts), whereas lower platelet counts were associated with massive transfusion (P < 0.01, when corrected for ISS and aggregation). An aggregation value of 145 IU by TRAP significantly identified death due to cerebral injury (sensitivity 71% and specificity 76%, P < 0.01) by receiver operating characteristic-curve analysis; the corresponding value of platelet counts for massive transfusion was 189 * 10/l (sensitivity 86%, specificity 75%, P < 0.01). We concluded there was no simple relationship between platelet aggregation and injury severity. Our results indicate that high platelet aggregation values are associated with fatality of cerebral injury. PMID- 23945061 TI - Mean platelet volume, in predicting severity of mitral regurgitation and left atrial appendage thrombosis. AB - The incidence of thromboembolism is higher in mitral regurgitation. Mean platelet volume (MPV), which is calculated automatically in the complete blood count tests, indicates platelet production, function and activation. Elevated MPV levels in cardiovascular diseases and some heart valve diseases have been shown before. We aimed to investigate the relationship between MPV and mitral regurgitation, and to evaluate the MPV levels according to the presence of atrial fibrillation or left atrial appendage thrombus in patients with mitral regurgitation for the first time. The study included 57 patients who had undergone transthoracic and transesophageal echocardiography for the classic symptoms and diagnosed with primary (organic) mitral regurgitation. The control group was composed of 46 age, sex and BMI-matched healthy individuals who had undergone transthoracic echocardiography and obtained normal findings. Echocardiographic evaluation was performed according to the recommendations of the American Echocardiography Society. Mean MPV values in patients with mitral regurgitation were significantly higher than the control group (P < 0.001). MPV levels and the thrombus risk were correlated with the severity of the disease. When the patients with mitral regurgitation were classified according to the presence of atrial fibrillation and left atrial appendage thrombus, patients with atrial fibrillation had higher MPV levels compared to patients with normal sinus rhythm (P < 0.001). In addition, highest MPV levels were found in patients with both atrial fibrillation and thrombosis (P < 0.001). In conclusion, measurement of MPV may be considered as a quick and reliable guide in the assessment of mitral regurgitation and thrombus, without any cost or any advanced expensive technology. PMID- 23945062 TI - Genetic diversity and population structure of rice landraces from Eastern and North Eastern States of India. AB - BACKGROUND: Adaptations to different habitats across the globe and consequent genetic variation within rice have resulted in more than 120,000 diverse accessions including landraces, which are vital genetic resources for agronomic and quality traits. In India the rice landraces of the states West Bengal, Assam, Mizoram, Manipur and Nagaland are worthy candidates for genetic assessment. Keeping the above in view, the present study was conducted with the aim to (i) calculate the genetic distances among the accessions of 83 landraces collected from these states along with 8 check accessions (total 91 accessions) using 23 previously mapped SSR markers and (ii) examine the population structure among the accessions using model-based clustering approach. RESULTS: Among the 91 accessions, 182 alleles were identified which included 51 rare and 27 null alleles. The average PIC value was 0.7467/marker. The non-aromatic landraces from West Bengal was most diverse with 154 alleles and an average PIC value of 0.8005/marker, followed by the aromatic landraces from West Bengal with 118 alleles and an average PIC value of 0.6524/marker, while the landraces from North East ranked third with 113 alleles and an average PIC value of 0.5745/marker. In the dendrogram distinct clusters consisting of predominantly aromatic landraces and predominantly North East Indian landraces were observed. The non-aromatic landraces from West Bengal were interspersed within these two clusters. The accessions were moderately structured, showing four sub-populations (A-D) with an Fst value of 0.398, 0.364, 0.206 and 0.281, respectively. The assigned clustering of accessions was well in agreement in both distance-based and model-based approaches. CONCLUSIONS: Each of the accessions could be identified unequivocally by the SSR profiles. Genetically the non aromatic landraces from West Bengal were most diverse followed by the aromatic landraces from the same state. The North Eastern accessions ranked third. Further, grouping of accessions based on their agronomic traits may serve as a resource for future studies, leading to the improvement of rice. Moreover in-situ preservation of the landraces is also a means of protection of biodiversity and cultural heritage. PMID- 23945063 TI - A qualitative study of experiences with and perceptions regarding long-acting injectable antipsychotics: Part I-patient perspectives. AB - OBJECTIVE: Despite the well-acknowledged problem of poor adherence to antipsychotic (AP) medication, long-acting injectables (LAIs) that could improve adherence are underused in Canada. Attitudes concerning LAIs among patients and psychiatrists may contribute to this underuse. Our objective was to investigate perceptions of and attitudes toward LAIs among patients in Canada. METHOD: Focus groups were conducted with 34 patients with a diagnosis of schizophrenia spectrum psychoses in 4 Canadian provinces. The focus groups inquired about experiences with and attitudes toward LAI APs. The sessions were audiotaped and transcribed verbatim, and transcripts were coded using a combination of deductive and inductive methods. RESULTS: Four themes emerged: awareness of and knowledge about LAIs; perceptions about LAIs; cost and convenience considerations; and issues arising from the coercive context under which LAIs were often prescribed. Nine patients had never heard about LAIs, and some others reported not having understood what was discussed with them regarding LAIs. Patients had typically heard about LAIs in either a context of coercion or of medication nonadherence. Patients had positive and negative perceptions concerning LAIs. The positive perceptions centred on relapse prevention and reduced effort in ensuring adherence, and the negative perceptions centred on financial costs and the inconvenience of appointments to receive injections. CONCLUSION: To enhance LAI usage, some of the issues that need to be addressed are the inadequacy of information given to patients, the element of coercion involved in LAI introduction, the pragmatic barriers to LAI uptake by patients, and negative subjective perceptions about LAIs. PMID- 23945064 TI - A qualitative study of experiences with and perceptions regarding long-acting injectable antipsychotics: part II-physician perspectives. AB - OBJECTIVE: In many countries, including Canada, a small proportion of people with psychotic disorders receive long-acting injectable (LAI) antipsychotics (APs), despite their demonstrated effectiveness and possible advantages for improving adherence rates. Attitudes regarding LAIs among physicians may influence their prescribing practices and thereby contribute to the underuse of LAIs. Here, we report on a qualitative study of perceptions and attitudes toward LAIs among psychiatrists in Canada. METHOD: Focus groups were conducted with 24 psychiatrists in 4 Canadian provinces. The focus groups inquired about experiences with and attitudes toward LAI APs. The sessions were audiotaped and transcribed verbatim, and transcripts were coded using a hybrid process of deductive and inductive methods. A brief pre-focus group questionnaire was administered. RESULTS: The pre-focus group questionnaires indicated that psychiatrists in our study prescribed the oral formulation of APs most of the time and had limited experience with LAIs. The focus groups yielded 4 main themes: limited knowledge about and experience with LAIs; attitudes toward LAIs (beliefs about negative perceptions of patients regarding LAIs, personal bias against needles, and consensus about some advantages of LAIs); prescribing practices around LAIs (generally seen as a last-resort option for patients with a history of nonadherence); and pragmatic barriers to using LAIs (for example, cost, storage, and staffing). CONCLUSION: Several factors may be contributing to the underuse of LAIs and the continuing stigmatized and coercive image of LAIs. Psychiatrists may benefit from better education about LAIs, and from self examination of their attitudes to LAIs and their prescribing practices. PMID- 23945065 TI - Long-acting injectable antipsychotics: recommendations for clinicians. AB - A major source of limitation to the real effectiveness of antipsychotics is the high rate of patient nonadherence or, more frequently, partial adherence. Using long-acting injectable (LAI) formulations is likely to reduce the impact of such adherence problems. Conversely, the use of LAIs in Canada remains low relative to many other jurisdictions. Based on effectiveness data from randomized control trials and other, less rigorous, studies, as well as our 2 qualitative studies exploring numerous issues around the use of LAIs, including their low use, we put forward 10 different recommendations for consideration by clinicians. These are also based on the experience of many clinicians and clinician scientists. These recommendations address mostly clinical challenges associated with the use of LAIs. Their application in clinical settings is illustrated in our report through several case examples highlighting the large variation across patients and different phases of illness. It is recommended that LAIs should be considered as a treatment option for psychotic disorders across all phases, including the first 2 to 5 critical years. PMID- 23945066 TI - Why are Canadians complacent about long-acting injectable antipsychotic therapies? Come on, Canada, you can do better! PMID- 23945067 TI - Long-acting injectable antipsychotics: evidence of effectiveness and use. AB - OBJECTIVE: To review the evidence for the role of long-acting injectable (LAI) antipsychotics (APs), especially the second-generation AP (SGA) LAIs, in the treatment of schizophrenia and to discuss the use rates of LAIs in Canada. METHOD: A search of online medical databases was conducted of the published literature (1995-2012) of the effects of LAIs on the domains of remission, adherence, relapse, and hospitalization. Results obtained from randomized controlled trials (RCTs), systematic reviews, meta-analyses, and large-scale observational studies were included. Expert consensus data were also solicited on LAI use within a Canadian context. RESULTS: While the efficacy of LAIs, compared with placebo, is well established, the evidence from RCTs is equivocal for any specific advantage for SGA LAIs, compared with oral medications, probably owing to challenges in conducting such RCTs. Evidence from methodologically less rigorous studies and from clinical practice suggests some advantages in achieving and maintaining remission, risk of relapse, and hospitalization. The rate of LAI (first-generation AP and SGA) use from published outpatient studies is low at 6.3% in Canada, compared with 15% to 80% worldwide. However, there is a relatively high rate of use in specific early psychosis programs and in conjunction with community treatment orders in Canada. CONCLUSIONS: LAIs are at least as effective as oral APs in the treatment of psychotic disorders. The former may have specific advantages for patients who demonstrate covert nonadherence. The underuse of LAIs in Canada needs to be better understood and addressed. PMID- 23945068 TI - A cross-sectional study examining shoulder pain and disability in Division I female swimmers. AB - CONTEXT: The prevalence of shoulder pain in the competitive swimming population has been reported to be as high as 91%. Female collegiate swimmers have a reported shoulder-injury rate 3 times greater than their male counterparts. There has been little information on how to best prevent shoulder pain in this population. The purpose of this study was to examine if differences exist in shoulder range of motion, upper-extremity strength, core endurance, and pectoralis minor length in NCAA Division I female swimmers with and without shoulder pain and disability. METHODS: NCAA Division I females (N = 37) currently swimming completed a brief survey that included the pain subscale of the Penn Shoulder Score (PSS) and the sports/performing arts module of the Disabilities of the Arm, Shoulder, and Hand (DASH) Outcome Measure. Passive range of motion for shoulder internal rotation (IR) and external rotation (ER) at 90 degrees abduction was measured using a digital inclinometer. Strength was measured using a handheld dynamometer for scapular depression and adduction, scapular adduction, IR, and ER. Core endurance was assessed using the side-bridge and prone-bridge tests. Pectoralis minor muscle length was assessed in both a resting and a stretched position using the PALM palpation meter. All measures were taken on the dominant and nondominant arms. RESULTS: Participants were classified as positive for pain and disability if the following 2 criteria were met: The DASH sports module score was >6/20 points and the PSS strenuous pain score was >=4/10. If these criteria were not met, participants were classified as negative for pain and disability. Significant differences were found between the 2 groups on the dominant side for pectoralis muscle length at rest (P = .003) and stretch (P = .029). CONCLUSIONS: The results provide preliminary evidence regarding an association between a decrease in pectoralis minor length and shoulder pain and disability in Division I female swimmers. PMID- 23945069 TI - Hydrogen sulphide suppresses human atrial fibroblast proliferation and transformation to myofibroblasts. AB - Cardiac fibroblasts are crucial in pathophysiology of the myocardium whereby their aberrant proliferation has significant impact on cardiac function. Hydrogen sulphide (H2S) is a gaseous modulator of potassium channels on cardiomyocytes and has been reported to attenuate cardiac fibrosis. Yet, the mechanism of H2S in modulating proliferation of cardiac fibroblasts remains poorly understood. We hypothesized that H2S inhibits proliferative response of atrial fibroblasts through modulation of potassium channels. Biophysical property of potassium channels in human atrial fibroblasts was examined by whole-cell patch clamp technique and their cellular proliferation in response to H2S was assessed by BrdU assay. Large conductance Ca(2+)-activated K(+) current (BK(Ca)), transient outward K(+) current (I(to)) and inwardly rectifying K(+) current (IK(ir)) were found in human atrial fibroblasts. Current density of BK(Ca) (IC50 = 69.4 MUM; n = 6), I(to) (IC50 = 55.1 MUM; n = 6) and IK(ir) (IC50 = 78.9 MUM; n = 6) was significantly decreased (P < 0.05) by acute exposure to NaHS (a H2S donor) in atrial fibroblasts. Furthermore, NaHS (100-500 MUM) inhibited fibroblast proliferation induced by transforming growth factor-beta1 (TGF-beta1; 1 ng/ml), Ang II (100 nM) or 20% FBS. Pre-conditioning of fibroblasts with NaHS decreased basal expression of Kv4.3 (encode I(to)), but not KCa1.1 (encode BK(Ca)) and Kir2.1 (encode IK(ir)). Furthermore, H2S significantly attenuated TGF-beta1 stimulated Kv4.3 and alpha-smooth muscle actin expression, which coincided with its inhibition of TGF-beta-induced myofibroblast transformation. Our results show that H2S attenuates atrial fibroblast proliferation via suppression of K(+) channel activity and moderates their differentiation towards myofibroblasts. PMID- 23945071 TI - Human motion classification based on a textile integrated and wearable sensor array. AB - A system for classification of motion patterns is presented based on a non contact magnetic induction monitoring device. This device is textile integrated, wearable, and able to measure pulse and respiratory activity. The proposed classifiers are a neural network, support vector machine, and a decision tree algorithm generated by bootstrap aggregating. Their performance is compared using a data set comprising five different types of motion patterns. In addition, the dependence of the misclassification error on the input sample length is investigated. The features used for classification were based on information derived by discrete wavelet transform and on lower and higher order statistical measures. With the presented magnetic induction device, all tested classifiers were able to classify the defined motion pattern with an accuracy of over 93%. The proposed bootstrap aggregating decision tree algorithm produces the best classification performance (accuracy of 96%). The support vector machine classifier shows the least dependence on the sample length. PMID- 23945072 TI - Efficacy and safety of lipegfilgrastim versus pegfilgrastim: a randomized, multicenter, active-control phase 3 trial in patients with breast cancer receiving doxorubicin/docetaxel chemotherapy. AB - BACKGROUND: Lipegfilgrastim is a novel glyco-pegylated granulocyte-colony stimulating factor in development for neutropenia prophylaxis in cancer patients receiving chemotherapy. This phase III, double-blind, randomized, active controlled, noninferiority trial compared the efficacy and safety of lipegfilgrastim versus pegfilgrastim in chemotherapy-naive breast cancer patients receiving doxorubicin/docetaxel chemotherapy. METHODS: Patients with high-risk stage II, III, or IV breast cancer and an absolute neutrophil count >=1.5 * 109 cells/L were randomized to a single 6-mg subcutaneous injection of lipegfilgrastim (n = 101) or pegfilgrastim (n = 101) on day 2 of each 21-day chemotherapy cycle (4 cycles maximum). The primary efficacy endpoint was the duration of severe neutropenia during cycle 1. RESULTS: Cycle 1: The mean duration of severe neutropenia for the lipegfilgrastim and pegfilgrastim groups was 0.7 and 0.8 days, respectively (lambda = -0.218 [95% confidence interval: 0.498%, 0.062%], p = 0.126), and no severe neutropenia was observed in 56% and 49% of patients in the lipegfilgrastim and pegfilgrastim groups, respectively. All cycles: In the efficacy population, febrile neutropenia occurred in three pegfilgrastim-treated patients (all in cycle 1) and zero lipegfilgrastim-treated patients. Drug-related adverse events in the safety population were reported in 28% and 26% of patients in the lipegfilgrastim and pegfilgrastim groups, respectively. CONCLUSION: This study demonstrates that lipegfilgrastim 6 mg is as effective as pegfilgrastim in reducing neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. TRIAL REGISTRATION: Eudra EEACTA200901599910. PMID- 23945073 TI - Association between health worker motivation and healthcare quality efforts in Ghana. AB - BACKGROUND: Ghana is one of the sub-Saharan African countries making significant progress towards universal access to quality healthcare. However, it remains a challenge to attain the 2015 targets for the health related Millennium Development Goals (MDGs) partly due to health sector human resource challenges including low staff motivation. PURPOSE: This paper addresses indicators of health worker motivation and assesses associations with quality care and patient safety in Ghana. The aim is to identify interventions at the health worker level that contribute to quality improvement in healthcare facilities. METHODS: The study is a baseline survey of health workers (n = 324) in 64 primary healthcare facilities in two regions in Ghana. Data collection involved quality care assessment using the SafeCare Essentials tool, the National Health Insurance Authority (NHIA) accreditation data and structured staff interviews on workplace motivating factors. The Spearman correlation test was conducted to test the hypothesis that the level of health worker motivation is associated with level of effort by primary healthcare facilities to improve quality care and patient safety. RESULTS: The quality care situation in health facilities was generally low, as determined by the SafeCare Essentials tool and NHIA data. The majority of facilities assessed did not have documented evidence of processes for continuous quality improvement and patient safety. Overall, staff motivation appeared low although workers in private facilities perceived better working conditions than workers in public facilities (P <0.05). Significant positive associations were found between staff satisfaction levels with working conditions and the clinic's effort towards quality improvement and patient safety (P <0.05). CONCLUSION: As part of efforts towards attainment of the health related MDGs in Ghana, more comprehensive staff motivation interventions should be integrated into quality improvement strategies especially in government-owned healthcare facilities where working conditions are perceived to be the worst. PMID- 23945074 TI - Electroacupuncture for chemotherapy-induced peripheral neuropathy: study protocol for a pilot multicentre randomized, patient-assessor-blinded, controlled trial. AB - BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose limiting side effect of neurotoxic chemotherapeutic agents. CIPN can lead not only to loss of physical function, difficulties in activities of daily living (ADLs), and decreased quality of life, but also to dose reduction, delay or even cessation of treatment. Currently, there are few proven effective treatments for CIPN. This randomized controlled clinical trial is designed to evaluate the effects and safety of electroacupuncture (EA) for patients with CIPN. METHODS/DESIGN: This is a multicenter, two-armed, parallel-design, patient assessor-blinded, randomized, sham-controlled clinical trial. Forty eligible patients with CIPN will be randomized in a ratio of 1:1 to the EA or sham EA arms. During the treatment phase, patients will undergo eight sessions of verum EA or sham EA twice weekly for four weeks, and then will be followed-up for eight weeks. Electrical stimulation in the EA group will consist of a mixed frequency of 2/120 Hz and 80% of bearable intensity. Sham EA will be applied to non acupoints, with shallow needle insertion and no current. All outcomes and analyses of results will be assessed by researchers blinded to treatment allocation. The effects of EA on CIPN will be evaluated according to both subjective and objective outcome measures. The primary outcome measure will be the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire to assess CIPN (QLQ-CIPN20). The secondary outcome measures will be the results on the numerical rating scale, the Semmes-Weinstein monofilament test, the nerve conduction study, and the EORTC QLQ-C30, as well as the patient's global impression of change and adverse events. Safety will be assessed at each visit. DISCUSSION: The results of this on-going study will provide clinical evidence for the effects and safety of EA for CIPN compared with sham EA. TRIAL REGISTRATION: Clinical Research Information Service: KCT0000506. PMID- 23945075 TI - The influence of gene flow on species tree estimation: a simulation study. AB - Gene flow among populations or species and incomplete lineage sorting (ILS) are two evolutionary processes responsible for generating gene tree discordance and therefore hindering species tree estimation. Numerous studies have evaluated the impacts of ILS on species tree inference, yet the ramifications of gene flow on species trees remain less studied. Here, we simulate and analyse multilocus sequence data generated with ILS and gene flow to quantify their impacts on species tree inference. We characterize species tree estimation errors under various models of gene flow, such as the isolation-migration model, the n-island model, and gene flow between non-sister species or involving ancestral species, and species boundaries crossed by a single gene copy (allelic introgression) or by a single migrant individual. These patterns of gene flow are explored on species trees of different sizes (4 vs. 10 species), at different time scales (shallow vs. deep), and with different migration rates. Species trees are estimated with the multispecies coalescent model using Bayesian methods (BEST and *BEAST) and with a summary statistic approach (MPEST) that facilitates phylogenomic-scale analysis. Even in cases where the topology of the species tree is estimated with high accuracy, we find that gene flow can result in overestimates of population sizes (species tree dilation) and underestimates of species divergence times (species tree compression). Signatures of migration events remain present in the distribution of coalescent times for gene trees, and with sufficient data it is possible to identify those loci that have crossed species boundaries. These results highlight the need for careful sampling design in phylogeographic and species delimitation studies as gene flow, introgression, or incorrect sample assignments can bias the estimation of the species tree topology and of parameter estimates such as population sizes and divergence times. PMID- 23945076 TI - Magnesium-enhanced enzymatically mineralized platelet-rich fibrin for bone regeneration applications. AB - Membranes of the autologous blood-derived biomaterial platelet-rich fibrin (PRF) were mineralized enzymatically with calcium phosphate (CaP) by the incorporation of alkaline phosphatase (ALP) followed by incubation for 3 days in solutions of either 0.1 M calcium glycerophosphate (CaGP) or a combination of CaGP and magnesium glycerophosphate (CaGP:MgGP; both 0.05 M), resulting in the formation of two different PRF-mineral composites. Fourier transform infrared spectroscopy, transmission electron microscopy and selected area electron diffraction examinations showed that the CaP formed was amorphous. Inductively coupled plasma optical emission spectroscopy analysis revealed similar amounts of Ca and P in both composite types, while a smaller amount of Mg (Ca:Mg molar ratio = 10) was detected in the composites formed in the CaGP:MgGP solution, which was supported by the results of energy-dispersive x-ray spectroscopy-based elemental mapping. Scanning electron microscopy (SEM) imaging showed that the mineral deposits in PRF incubated in the CaGP:MgGP solution were markedly smaller. The mass percentage attributable to the mineral phase was similar in both composite types. MTT and WST tests with SAOS-2 cells revealed that incubation in the CaGP:MgGP solution had no negative effect on cytocompatibility and cell proliferation compared to the CaGP solution. Cells on all samples displayed a well-spread morphology as revealed by SEM imaging. In conclusion, the incorporation of Mg reduces mineral deposit dimensions and promotes cell proliferation. PMID- 23945078 TI - Microstructured shape memory polymer surfaces with reversible dry adhesion. AB - We present a shape memory polymer (SMP) surface with repeatable, very strong (>18 atm), and extremely reversible (strong to weak adhesion ratio of >1 * 10(4)) dry adhesion to a glass substrate. This was achieved by exploiting bulk material properties of SMP and surface microstructuring. Its exceptional dry adhesive performance is attributed to the SMP's rigidity change in response to temperature and its capabilities of temporary shape locking and permanent shape recovery, which when combined with a microtip surface design enables time-independent control of contact area. PMID- 23945077 TI - Receptor-directed chimeric toxins created by sortase-mediated protein fusion. AB - Chimeric protein toxins that act selectively on cells expressing a designated receptor may serve as investigational probes and/or antitumor agents. Here, we report use of the enzyme sortase A (SrtA) to create four chimeric toxins designed to selectively kill cells bearing the tumor marker HER2. We first expressed and purified: (i) a receptor recognition-deficient form of diphtheria toxin that lacks its receptor-binding domain and (ii) a mutated, receptor-binding-deficient form of anthrax-protective antigen. Both proteins carried at the C terminus the sortase recognition sequence LPETGG and a H6 affinity tag. Each toxin protein was mixed with SrtA plus either of two HER2-recognition proteins--a single-chain antibody fragment or an Affibody--both carrying an N-terminal G5 tag. With wild type SrtA, the fusion reaction between the toxin and receptor-recognition proteins approached completion only after several hours, whereas with an evolved form of the enzyme, SrtA*, the reaction was virtually complete within 5 minutes. The four fusion toxins were purified and shown to kill HER2-positive cells in culture with high specificity. Sortase-mediated ligation of binary combinations of diverse natively folded proteins offers a facile way to produce large sets of chimeric proteins for research and medicine. PMID- 23945079 TI - Early identification of reading disabilities within an RTI framework. AB - Early and accurate identification of children at risk for reading disabilities (RD) is critical for the prevention of RD within a response to intervention framework. In this study, we investigated the use of universal screening and progress monitoring for the early identification of RD in kindergarten children. A total of 366 children were administered a battery of screening measures at the beginning of kindergarten and progress-monitoring probes across the school year. A subset of children who showed initial risk for RD also received a 26-week Tier 2 intervention. Participants' achievement in word reading accuracy and/or fluency was assessed at the end of first grade. Results indicated that a screening battery containing measures of letter naming fluency, phonological awareness, rapid naming, or nonword repetition accurately identified good and poor readers at the end of first grade. Findings also showed that children's response to supplemental and/or classroom instruction measured in terms of growth in letter naming fluency added significantly to the prediction of reading outcomes. PMID- 23945081 TI - Relative displacement of anastomotic site of pancreato-jejunostomy in pancreatico duodenectomy: a novel surgical reconstructive technique. AB - INTRODUCTION: Intra-abdominal hemorrhage following pancreatic fistula is a fatal complication after pancreatico-duodenectomy. Intra-abdominal hemorrhage has reportedly decreased with the use of fibrin glue or polyglycolic acid felt and wrapping of the skeletonized vessels by omentum or falciform ligament. However, there are no extremely effective methods for the prevention of hemorrhage. Here, we report our novel and simple method for the prevention of intra-abdominal hemorrhage due to pancreatic fistula. METHODS: The anastomotic site of the pancreato-jejunostomy in pancreatico-duodenectomy is displaced from the superior to inferior side of the transverse mesocolon through a small window created on the left side of the middle colic artery of the transverse mesocolon. This procedure is expected to prevent exposure of the skeletonized vessels to activated pancreatic juice from a pancreatic fistula after lymph node dissection, decreasing the incidence of hemorrhage. Two drains are placed on the superior and inferior sides of the transverse mesocolon. We performed this procedure in seven patients and compared the amylase level in the drainage fluid from the superior and inferior sides. RESULTS: There was no difference in the fluid amylase level from the drains between the superior and inferior sides, because a pancreatic fistula was not present in all our patients. Therefore, we could not evaluate the efficacy of this method in the current study. CONCLUSIONS: Our procedure is theoretically expected to prevent intra-abdominal hemorrhage and will be an option in pancreatico-duodenectomy, especially for patients with a soft pancreas. However, it is necessary to evaluate the performance and results of this procedure in many more patients. PMID- 23945080 TI - Double-antiangiogenic protein DAAP targeting vascular endothelial growth factor A and angiopoietins attenuates collagen-induced arthritis. AB - INTRODUCTION: Angiogenesis plays a critical role in synovial inflammation and joint destruction in rheumatoid arthritis (RA). Vascular endothelial growth factor A (VEGF-A) and angiopoietins are two important mediators of synovial angiogenesis. We have previously developed a novel chimeric decoy receptor, namely, double-antiangiogenic protein (DAAP), which can both bind VEGF-A and angiopoietins and block their actions. This study was performed to evaluate the antiarthritic effect of DAAP and the combination effect with the tumor necrosis factor alpha (TNF-alpha) inhibitor in collagen-induced arthritis (CIA). METHODS: Recombinant DAAP, VEGF-Trap, Tie2-Fc and dimeric Fc proteins were produced and purified from CHO cells in large-scale bioreactors. CIA was induced in DBA/1 mice with type II collagen. The preventive effect of DAAP was determined and compared with other decoy receptors such as VEGF-Trap or Tie2-Fc, which block VEGF-A or angiopoietins, respectively. The clinical, radiographic, pathologic and immunohistochemical analyses were performed in CIA mice. The levels of matrix metalloprotease 3 (MMP-3) and interleukin 1beta (IL-1beta) were quantified by enzyme-linked immunosorbent assay, and receptor activator of nuclear factor kappaB ligand (RANKL) mRNA levels were measured by polymerase chain reaction. Finally, we investigated the combination effects of DAAP with a low dose of TNF alpha decoy receptor (etanercept 10 mg/kg). RESULTS: On the basis of clinical and radiographic evaluation, DAAP had a much greater inhibitory effect than VEGF-Trap or Tie2-Fc on arthritis severity and bone destruction. These inhibitory effects were accompanied by significantly diminishing pathologic abnormalities, CD31 positive vasculature and synovial infiltration by F4/80-positive macrophages. The levels of MMP-3, IL-1beta and RANKL were much lower in the DAAP-injected group than those of the control. Furthermore, DAAP showed a therapeutic effect and a combination effect with etanercept when injected after arthritis onset in established CIA. CONCLUSIONS: DAAP has not only potent prophylactic effects on both inflammation and bone destruction but also therapeutic effects, alone and in combination with a TNF-alpha inhibitor in CIA mice. These results suggest that DAAP could be used as an effective new therapeutic agent for RA. PMID- 23945082 TI - A distinctive presentation of diplopodia: a Y-metatarsal combining the extra foot and the extra digit of the main foot. AB - Diplopodia is a rare congenital anomaly and has been described as extra digits, metatarsals, and tarsal bones that form an extra foot or foot-like structure. Various skeletal deformities and anomalies involving other organ systems can accompany diplopodia. Treatment consists of surgery, splinting, and physical therapy, planned according to each patient's specific condition. We present a patient who had diplopodia with distinctive anatomic features (with postaxial polydactyly and without any anomaly of the tibia or fibula) compared with the previously reported cases, and concomitant anomalies, including left renal agenesis and anal atresia. PMID- 23945083 TI - Characterization of constitutive CTCF/cohesin loci: a possible role in establishing topological domains in mammalian genomes. AB - BACKGROUND: Recent studies suggested that human/mammalian genomes are divided into large, discrete domains that are units of chromosome organization. CTCF, a CCCTC binding factor, has a diverse role in genome regulation including transcriptional regulation, chromosome-boundary insulation, DNA replication, and chromatin packaging. It remains unclear whether a subset of CTCF binding sites plays a functional role in establishing/maintaining chromatin topological domains. RESULTS: We systematically analysed the genomic, transcriptomic and epigenetic profiles of the CTCF binding sites in 56 human cell lines from ENCODE. We identified ~24,000 CTCF sites (referred to as constitutive sites) that were bound in more than 90% of the cell lines. Our analysis revealed: 1) constitutive CTCF loci were located in constitutive open chromatin and often co-localized with constitutive cohesin loci; 2) most constitutive CTCF loci were distant from transcription start sites and lacked CpG islands but were enriched with the full spectrum CTCF motifs: a recently reported 33/34-mer and two other potentially novel (22/26-mer); 3) more importantly, most constitutive CTCF loci were present in CTCF-mediated chromatin interactions detected by ChIA-PET and these pair-wise interactions occurred predominantly within, but not between, topological domains identified by Hi-C. CONCLUSIONS: Our results suggest that the constitutive CTCF sites may play a role in organizing/maintaining the recently identified topological domains that are common across most human cells. PMID- 23945084 TI - Effect of a 2-week joint mobilization intervention on single-limb balance and ankle arthrokinematics in those with chronic ankle instability. AB - CONTEXT: A single talocrural joint-mobilization treatment has improved spatiotemporal measures of postural control but not ankle arthrokinematics in individuals with chronic ankle instability (CAI). However, the effects of multiple treatment sessions on these aspects of function have not been investigated. OBJECTIVE: To examine the effect of a 2-wk anterior-to-posterior joint-mobilization intervention on instrumented measures of single-limb-stance static postural control and ankle arthrokinematics in adults with CAI. DESIGN: Repeated measures. SETTING: Research laboratory. PARTICIPANTS: 12 individuals with CAI (6 male, 6 female; age 27.4 +/- 4.3 y, height 175.4 +/- 9.78 cm, mass 78.4 +/- 11.0 kg). INTERVENTION: Subjects received 6 treatments sessions of talocrural grade II joint traction and grade III anterior-to-posterior joint mobilization over 2 wk. MAIN OUTCOME MEASURES: Instrumented measures of single limb-stance static postural control (eyes open and closed) and anterior and posterior talar displacement and stiffness were assessed 1 wk before the intervention (baseline), before the first treatment (preintervention), 24-48 h after the final treatment (postintervention), and 1 wk later (1-wk follow-up). Postural control was analyzed as center-of-pressure velocity, center-of-pressure range, the mean of time-to-boundary minima, and standard deviation of time-to boundary minima in the anteroposterior and mediolateral directions for each visual condition. RESULTS: No significant differences were identified in any measures of postural control (P > .08) or ankle arthrokinematics (P > .21). CONCLUSIONS: The 2-wk talocrural joint-mobilization intervention did not alter instrumented measures of single-limb-stance postural control or ankle arthrokinematics. Despite the absence of change in these measures, this study continues to clarify the role of talocrural joint mobilization as a rehabilitation strategy for patients with CAI. PMID- 23945085 TI - Domestic food preparation practices: a review of the reasons for poor home hygiene practices. AB - New Zealand has a much higher rate of reported campylobacteriosis cases than the rest of the developed world. It has been suggested that New Zealanders have worse home hygiene practices during food preparation than the citizens of other developed countries. Thus, it is necessary to recognize and understand the reasons for consumer's poor practices in order to help develop a more effective message to improve New Zealanders' practices in the domestic environment. This could in turn lead to a reduction in the number of campylobacteriosis cases. The objective is to review cited literature on consumer practices which is related to food poisoning and to attempt to list the factors related to poor consumer practice. There are many internationally identifiable reasons for the poor practices of consumers. These reasons include psychological, demographic and socioeconomic variables; personal interest in new information; prior knowledge; cultural influence; educational background; perception of risk, control and liability; and attitude towards the addressed practices or hazards. The results have indicated that 'optimistic bias', the 'illusion of control', habits and lack of knowledge concerning food safety during domestic food preparation are prevalent among consumers. The research indicated the influence of demographic factors (age, gender, level of education, income, work hours, race, location, culture), as they play a potential role in determining domestic food safety behaviour. It appears that all these factors are applicable for New Zealand consumers and should be addressed in any future education strategy aimed at improving New Zealanders' food handling practices. PMID- 23945087 TI - Culture matters: a case of school health promotion in Canada. AB - Rising concerns of poor health behaviours of children and youth have stimulated international support for a comprehensive approach to promoting the development of healthy behaviours in the early years. Health promoting schools (HPS) is increasingly adopted as an approach to guide supportive practices, but there is limited research that has reported how to effectively implement HPS at a population level. The purpose of this research was to qualitatively explore the factors preventing and facilitating implementation of HPS practices in the Canadian province of Nova Scotia. Interviews (n = 23) were conducted with school stakeholders (principals, teachers and parents) from a diverse sample of schools (n = 9) and data were analysed to develop an understanding of how school circumstances and experiences influenced HPS implementation. At a broad level, the reported barriers were structural and systemic, whereas the facilitating factors were related to organizational capacity and political leadership. It was evident that implementing and sustaining HPS required a shift in values and integration of supportive school health practices into school priorities. The results suggest that, without addressing the competing culture, which is persistently reinforced by strict academic mandates and unhealthy community norms, HPS will be vulnerable to circumstances that prevent implementation. Considering the emerging importance of mental wellbeing, it will also be important to provide schools with adequate and appropriate staff capacity and support to address this issue. Sustaining the positive effects of HPS will require continuous engagement and collaboration with multiple stakeholders to embed health promotion into school community norms. PMID- 23945086 TI - Privileging physical activity over healthy eating: 'Time' to Choose? AB - Physical activity and healthy eating have long been promoted as key strategies in tackling the 'wicked problem' of obesity. Both practices are assumed to go hand in-hand, but whether one dominates the other has largely remained unexamined. Moreover, time, a dimension beyond the socio-ecological model, is a critical factor of families' busy lives, but related challenges are rarely articulated. We conducted 47 family interviews as part of a mixed methods study examining environmental influences on youth obesity in Nova Scotia, Eastern Canada. Participants were recruited from six schools at the junior high school level (grades 7-9; age range 12-14 years) based on location (urban, suburban and rural) and neighborhood socioeconomic status (high and low socioeconomic status). Time pressure to meet the demands associated with scheduled physical activity for youth was the dominant theme across interviews from all neighborhoods. Physical activity and healthy eating were valued differently, with greater value placed on physical activity than healthy eating. The pressure to engage youth in organized physical activity appeared to outweigh the importance of healthy eating, which led to neglecting family meals at home and consuming fast food and take out options. Our findings further reinforce the need to move beyond the socio ecological model and integrate critical dimensions such as 'time', its challenges and opportunities, to allow for a more nuanced understanding of contemporary healthy living. It appears 'timely' to focus on healthy public policy in support of families, instead of unwittingly supporting a fast food industry that profits from time-pressured families. PMID- 23945088 TI - After Nairobi: can the international community help to develop health promotion in Africa? AB - The Nairobi Conference presaged a surge of interest in the development of health promotion in sub-Saharan Africa. A number of Africans have asserted that health promotion is underdeveloped in the continent, with the principles of the Ottawa Charter not widely adopted. This paper does not presume to say how health promotion could be developed in Africa, as that is for Africans to decide for themselves. Rather, it debates some issues which the international epistemic health promotion community could address in order to work in solidarity with African colleagues in taking forward the health promotion agenda in their continent. These issues include the Eurocentric nature of health promotion discourse, the different disease burden of Africa and the lack of training capacity in African universities. PMID- 23945089 TI - Circulating alpha-klotho levels are not disturbed in patients with type 2 diabetes with and without macrovascular disease in the absence of nephropathy. AB - BACKGROUND: Diabetes is associated with a high incidence of macrovascular disease (MVD), including peripheral and coronary artery disease. Circulating soluble Klotho (sKlotho) is produced in the kidney and is a putative anti-aging and vasculoprotective hormone. Reduced Klotho levels may therefore increase cardiovascular risk in diabetes. We investigated if sKlotho levels are decreased in type 2 diabetes and associate with MVD in the absence of diabetic nephropathy, and whether hyperglycemia affects renal Klotho production in vitro and in vivo. METHODS: sKlotho levels were determined with ELISA in diabetic and non-diabetic patients with and without MVD, and healthy control subjects. Human renal tubular epithelial cells (TECs) were isolated and exposed to high glucose levels (15 and 30 mM) in vitro and Klotho levels were measured with qPCR and quantitative immunofluorescence. Klotho mRNA expression was quantified in kidneys obtained from long term (3 and 8 months) diabetic Ins2Akita mice and normoglycemic control mice. RESULTS: No significant differences in sKlotho levels were observed between diabetic patients with and without MVD (527 (433-704) pg/mL, n = 35), non diabetic MVD patients (517 (349-571) pg/mL, n = 27), and healthy control subjects (435 (346-663) pg/mL, n = 15). High glucose (15 and 30 mM) did not alter Klotho expression in TECs. Long-term hyperglycemia in diabetic Ins2Akita mice (characterized by increased HbA1c levels [12.9 +/- 0.3% (3 months) and 11.3 +/- 2.0% (8 months)], p < 0.05 vs. non-diabetic mice) did not affect renal Klotho mRNA expression. CONCLUSIONS: These data indicate that sKlotho levels are not affected in type 2 diabetes patients with and without MVD. Furthermore, hyperglycemia per se does not affect renal Klotho production. As type 2 diabetes does not alter sKlotho levels, sKlotho does not seem to play a major role in the pathogenesis of MVD in type 2 diabetes. PMID- 23945091 TI - Superconductivity of the topological insulator Bi2Se3 at high pressure. AB - The pressure-induced superconductivity and structural evolution of Bi2Se3 single crystals are studied. The emergence of superconductivity at an onset transition temperature (Tc) of about 4.4 K is observed at around 12 GPa. Tc increases rapidly to a maximum of 8.2 K at 17.2 GPa, decreases to around 6.5 K at 23 GPa, and then remains almost constant with further increases in pressure. Variations in Tc with respect to pressure are closely related to the carrier density, which increases by over two orders of magnitude from 2 to 23 GPa. High-pressure synchrotron radiation measurements reveal structural transitions at around 12, 20, and above 29 GPa. A phase diagram of superconductivity versus pressure is also constructed. PMID- 23945090 TI - Systematic review of genome-wide gene expression studies of bipolar disorder. AB - BACKGROUND: Numerous genome-wide gene expression studies of bipolar disorder (BP) have been carried out. These studies are heterogeneous, underpowered and use overlapping samples. We conducted a systematic review of these studies to synthesize the current findings. METHODS: We identified all genome-wide gene expression studies on BP in humans. We then carried out a quantitative mega analysis of studies done with post-mortem brain tissue. We obtained raw data from each study and used standardized procedures to process and analyze the data. We then combined the data and conducted three separate mega-analyses on samples from 1) any region of the brain (9 studies); 2) the prefrontal cortex (PFC) (6 studies); and 3) the hippocampus (2 studies). To minimize heterogeneity across studies, we focused primarily on the most numerous, recent and comprehensive studies. RESULTS: A total of 30 genome-wide gene expression studies of BP done with blood or brain tissue were identified. We included 10 studies with data on 211 microarrays on 57 unique BP cases and 229 microarrays on 60 unique controls in the quantitative mega-analysis. A total of 382 genes were identified as significantly differentially expressed by the three analyses. Eleven genes survived correction for multiple testing with a q-value < 0.05 in the PFC. Among these were FKBP5 and WFS1, which have been previously implicated in mood disorders. Pathway analyses suggested a role for metallothionein proteins, MAP Kinase phosphotases, and neuropeptides. CONCLUSION: We provided an up-to-date summary of results from gene expression studies of the brain in BP. Our analyses focused on the highest quality data available and provided results by brain region so that similarities and differences can be examined relative to disease status. The results are available for closer inspection on-line at Metamoodics [http://metamoodics.igm.jhmi.edu/], where investigators can look up any genes of interest and view the current results in their genomic context and in relation to leading findings from other genomic experiments in bipolar disorder. PMID- 23945094 TI - Square grid and pillared square grid coordination polymers - fertile ground for crystal engineering of structure and function. AB - Square grid coordination polymers (CPs) based upon four-connected metal centres linked by linear bifunctional ligands such as 4,4'-bipyridine were first reported in 1990 and the study of their pillared variants began in 1995. It was quickly realized by crystal engineers that the modularity of such CPs creates families of related compounds or platforms which in turn affords opportunities for systematic study of structure/function relationships in the context of catalysis, magnetism and porosity. This review covers the historical development of this important class of CPs before addressing recent studies of variants which incorporate 4,4' bipyridine and related linkers to facilitate control over pore size and inorganic anion pillars to enable strong interactions with polarizable molecules such as CO2. Such pillared CPs offer relatively low cost, high stability and modularity. When these features are coupled with superior performance vs . other classes of porous materials in the context of carbon capture and other gas separations involving CO2, they are likely to gain increased attention in the future. PMID- 23945095 TI - Coordination polymers of small cyano anions. AB - Small cyano anions, and their derivatives, have proved to be remarkably versatile building blocks for coordination polymers. They have led to magnetically ordered materials, structures with new entangled motifs or novel topologies, and a significant structural diversity, including polymorphism, induced by subtle changes in anion, cation, co-ligands, preparative conditions, or even desolvation. PMID- 23945092 TI - Genome-wide identification, evolutionary and expression analysis of the aspartic protease gene superfamily in grape. AB - BACKGROUND: Aspartic proteases (APs) are a large family of proteolytic enzymes found in almost all organisms. In plants, they are involved in many biological processes, such as senescence, stress responses, programmed cell death, and reproduction. Prior to the present study, no grape AP gene(s) had been reported, and their research on woody species was very limited. RESULTS: In this study, a total of 50 AP genes (VvAP) were identified in the grape genome, among which 30 contained the complete ASP domain. Synteny analysis within grape indicated that segmental and tandem duplication events contributed to the expansion of the grape AP family. Additional analysis between grape and Arabidopsis demonstrated that several grape AP genes were found in the corresponding syntenic blocks of Arabidopsis, suggesting that these genes arose before the divergence of grape and Arabidopsis. Phylogenetic relationships of the 30 VvAPs with the complete ASP domain and their Arabidopsis orthologs, as well as their gene and protein features were analyzed and their cellular localization was predicted. Moreover, expression profiles of VvAP genes in six different tissues were determined, and their transcript abundance under various stresses and hormone treatments were measured. Twenty-seven VvAP genes were expressed in at least one of the six tissues examined; nineteen VvAPs responded to at least one abiotic stress, 12 VvAPs responded to powdery mildew infection, and most of the VvAPs responded to SA and ABA treatments. Furthermore, integrated synteny and phylogenetic analysis identified orthologous AP genes between grape and Arabidopsis, providing a unique starting point for investigating the function of grape AP genes. CONCLUSIONS: The genome-wide identification, evolutionary and expression analyses of grape AP genes provide a framework for future analysis of AP genes in defining their roles during stress response. Integrated synteny and phylogenetic analyses provide novel insight into the functions of less well-studied genes using information from their better understood orthologs. PMID- 23945096 TI - Coordination polymers constructed from oligonuclear nodes. AB - The node-and-spacer approach is widely employed in crystal engineering to construct coordination polymers. It consists of self-assembly processes involving mononuclear cationic species and exo-dentate ligands. We enlarged this strategy using preformed homo- and heterometallic complexes as nodes. The presence of two or more metal ions within a node leads to novel network topologies, as well as to new properties, arising from the intra- and internode interactions. This paper reviews some representative examples of coordination polymers obtained in our laboratory and constructed from: i) binuclear alkoxo-bridged complexes; ii) heterometallic 3d-3d' and 3d-4f complexes. PMID- 23945097 TI - A journey from supramolecular chemistry to nanoscale networks. AB - The use of the coordination properties of metal centres to organise organic ligands in space is a concept that dates back to the seminal work of Alfred Werner that was recognised by the award of the first Nobel Proze for Chemistry in inorganic chemistry 100 years ago. Metal ions may be used to control the assembly of one-, two- or three-dimensional structures by matching the coordination number and geometry with the number and arrangement of donor atoms within ligands. These so-called coordination polymers have recently emerged from the category of unwanted insoluble side-products to materials of high scietrific interest and economic potential. This short article presents the simple design principles that lie behind the synthesis of materials possessing useful properties and, often stunningly attractive structural motifs. PMID- 23945098 TI - Design and synthesis of new 1D and 2D R-isophthalic acid-based coordination polymers (R = hydrogen or bromine). AB - Three new R-isophthalic acid-based (R = H or Br) coordination polymers have been designed and synthesized. By changing the N-containing ligand in the system, we are able to tune the dimensionality of coordination polymers from one-dimension (1D) to two-dimensions (2D) with the same basic building unit. Also, different metal ions can be incorporated into the same structures. Compound 1 [Cu(bipa)(py)2].0.5(H2O) (H2bipa = 5-bromoisophthalic acid; py = pyridine) and compound 2 [Co(bipa)(py)2] are 1D chain structures. Compound 3 [Cu8(ipa)8(bpe)8].2(bpe).4(H2O) (bpe=1,2-bis(4-pyridyl)ethane) is a 2D layered structure. PMID- 23945099 TI - Synthesis and reactivity of Zn-biphenyl metal-organic frameworks, introducing a diphenylphosphino functional group. AB - Structural features, synthesis, and reactivity of Zn-biphenyl metal-organic frameworks with MOF-5 topology are presented to show the chemical flexibility of such materials and to demonstrate the challenges that can be encountered and solved to avoid interpenetration. We introduce the synthesis of a Zn-biphenyl MOF with diphenylphosphino functionalization and illustrate its structural and chemical properties. PMID- 23945100 TI - Coordination polymers and metal-organic frameworks derived from 4,4'-dicarboxy 2,2'-bipyridine and 4,4',6,6'-tetracarboxy-2,2'-bipyridine ligands: a personal perspective. AB - Presented herein is a personal overview of some of the contributions we have made over recent years to coordination polymer chemistry employing 2,2'-bipyridine polycarboxylic acid ligands in conjunction with first row transition, main group or lanthanide metal ions. Primarily the discussion is centred upon the two ligands with which we have enjoyed the most success: 4,4'-dicarboxy-2,2' bipyridine (4,4'-H2dcbp) and 4,4',6,6'-tetracarboxy-2,2'-bipyridine (4,4',6,6' H4tcbp). Initial discussion is focused upon the synthetic aspects of ligand formation and their structural characterisation and then moves on to the synthesis of metal complexes incorporating these ligands and the coordination polymers they form. Where possible the discussion is presented from a synthetic and structural perspective with highlight given to the pertinent properties of the coordination polymers formed e.g. thermal behaviour, magnetic, luminescent or small molecule sorption properties. We end the review with some conclusions and highlight some current work with a view to future research. PMID- 23945101 TI - Crystal engineering of Fe(II) spin crossover coordination polymers derived from triazole or tetrazole ligands. AB - The past decade has witnessed intense research activity in the area of Fe(II) spin crossover coordination polymers, which are structurally diverse and functionally intriguing materials. In this endeavor, a less exploited series of ligands have been selected among various N-donor triazole and tetrazole molecules. Developing conventions that allow the tailoring of such functional materials with predictable architecture and properties is an important objective and current interest in crystal engineering. However, detailed knowledge on the structure-property correlation is still scanty due to the small number of crystal structures of such compounds. The principal focus is to decipher the effect of various supramolecular factors such as intermolecular interactions, hydrogen bonding etc., on the resultant Fe(II) coordination polymers. This tutorial review aims at highlighting some of the developments of such structurally diverse and functionally intriguing 1D polymeric chains, 2D and 3D networks built from triazole or tetrazole ligands exhibiting fascinating spin crossover phenomena. PMID- 23945102 TI - Porous coordination polymers as novel sorption materials for heat transformation processes. AB - Porous coordination polymers (PCPs)/metal-organic frameworks (MOFs) are inorganic organic hybrid materials with a permanent three-dimensional porous metal-ligand network. PCPs or MOFs are inorganic-organic analogs of zeolites in terms of porosity and reversible guest exchange properties. Microporous water-stable PCPs with high water uptake capacity are gaining attention for low temperature heat transformation applications in thermally driven adsorption chillers (TDCs) or adsorption heat pumps (AHPs). TDCs or AHPs are an alternative to traditional air conditioners or heat pumps operating on electricity or fossil fuels. By using solar or waste heat as the operating energy TDCs or AHPs can significantly help to minimize primary energy consumption and greenhouse gas emissions generated by industrial or domestic heating and cooling processes. TDCs and AHPs are based on the evaporation and consecutive adsorption of coolant liquids, preferably water, under specific conditions. The process is driven and controlled by the microporosity and hydrophilicity of the employed sorption material. Here we summarize the current investigations, developments and possibilities of PCPs/MOFs for use in low-temperature heat transformation applications as alternative materials for the traditional inorganic porous substances like silica gel, aluminophosphates or zeolites. PMID- 23945103 TI - Cyclodextrin-based combinatorial polymers: efficient binders of pharmaceuticals in water. AB - Cyclodextrins are cyclic oligomers of glucose; they are widely used in a large range of industrial applications because of their molecular inclusion properties. We used cyclodextrins to prepare different libraries of polymers and tested their ability to selectively recognize pharmaceuticals in water. It was demonstrated that the chemical composition of the polymer strongly influences its binding properties. The developed strategy can be used to produce selective sorbent nanomaterials of pharmaceuticals. PMID- 23945105 TI - Determination of PCR products by capillary electrophoresis with contactless conductivity detection. PMID- 23945106 TI - Low-temperature preparation of functional carbon nanocapsules via self-assembly and carbonization of hexayne amphiphiles. PMID- 23945108 TI - miRNA profiling identifies candidate mirnas for bladder cancer diagnosis and clinical outcome. AB - Bladder cancer is a common cancer in the Western world. The current prognosticators such as tumor grade, stage, size, and multifocality do not accurately reflect the clinical outcome. It is of clinical interest to identify biomarkers that could improve diagnostic and/or prognostic predictions. The objectives of this study were to identify deregulated miRNAs in bladder cancer samples and evaluate their potential as diagnostic and prognostic biomarkers. We screened 723 miRNAs by microarray and selected a subset of 15 distinctively deregulated miRNAs for further validation by real-time quantitative RT-(q)PCR. Seven miRNAs (miR-20a, miR-106b, miR-130b, miR-141, miR-200a, miR-200a*, and miR 205) were found to be up-regulated and eight miRNAs (miR-100, miR-125b, miR-130a, miR-139-5p, miR-145*, miR-199a-3p, miR-214, and miR-222) were found to be down regulated in malignant bladder tissue samples compared to healthy tissue. Four miRNAs that have already been described in the literature (miR-141, miR-199a-3p, miR-205, and miR-214) were significantly differentially expressed between nonmuscle-invasive and muscle-invasive bladder cancer. Furthermore, real-time RT qPCR of all miRNAs provided high overall correct classification (>75%) of bladder cancer diagnosis. Two miRNAs (miR-141 and miR-205) were associated with overall survival time. The verification of tumor-specific miRNA expression profile, together with the observed association of miR-141 and miR-205 expression with overall survival, underline the potential of miRNAs to function as diagnostic and/or prognostic markers of bladder cancer. PMID- 23945109 TI - Ensiling of wheat straw decreases the required temperature in hydrothermal pretreatment. AB - BACKGROUND: Ensiling is a well-known method for preserving green biomasses through anaerobic production of organic acids by lactic acid bacteria. In this study, wheat straw is subjected to ensiling in combination with hydrothermal treatment as a combined pretreatment method, taking advantage of the produced organic acids. RESULTS: Ensiling for 4 weeks was accomplished in a vacuum bag system after addition of an inoculum of Lactobacillus buchneri and 7% w/w xylose to wheat straw biomass at 35% final dry matter. Both glucan and xylan were preserved, and the DM loss after ensiling was less than 0.5%. When comparing hydrothermally treated wheat straw (170, 180 and 190 degrees C) with hydrothermally treated ensiled wheat straw (same temperatures), several positive effects of ensiling were revealed. Glucan was up-concentrated in the solid fraction and the solubilisation of hemicellulose was significantly increased. Subsequent enzymatic hydrolysis of the solid fractions showed that ensiling significantly improved the effect of pretreatment, especially at the lower temperatures of 170 and 180 degrees C. The overall glucose yields after pretreatments of ensiled wheat straw were higher than for non-ensiled wheat straw hydrothermally treated at 190 degrees C, namely 74-81% of the theoretical maximum glucose in the raw material, which was ~1.8 times better than the corresponding yields for the non-ensiled straw pretreated at 170 or 180 degrees C. The highest overall conversion of combined glucose and xylose was achieved for ensiled wheat straw hydrothermally treated at 180 degrees C, with overall glucose yield of 78% and overall conversion yield of xylose of 87%. CONCLUSIONS: Ensiling of wheat straw is shown to be an effective pre-step to hydrothermal treatment, and can give rise to a welcomed decrease of process temperature in hydrothermal treatments, thereby potentially having a positive effect on large scale pretreatment costs. PMID- 23945110 TI - Magnetic spectroscopy of nanoparticle Brownian motion measurement of microenvironment matrix rigidity. AB - The rigidity of the extracellular matrix and of the integrin links to the cytoskeleton regulates signaling cascades, controlling critical aspects of cancer progression including metastasis and angiogenesis. We demonstrate that the matrix stiffness can be monitored using magnetic spectroscopy of nanoparticle Brownian motion (MSB). We measured the MSB signal from nanoparticles bound to large dextran polymers. The number of glutaraldehyde induced cross-links was used as a surrogate for material stiffness. There was a highly statistically significant change in the MSB signal with the number of cross-links especially prominent at higher frequencies. The p-values were all highly significant. We conclude that the MSB signal can be used to identify and monitor changes in the stiffness of the local matrix to which the nanoparticles are bound. PMID- 23945111 TI - Nucleolus detection in the Fuhrman grading system for application in CCRC. AB - The paper presents a method for nucleolus detection in images of nuclei in clear cell renal carcinoma (CCRC). The method is based on the similarity of the nuclei image and the two-dimensional paraboloidal window function. The results of numerical experiments performed on almost 2600 images of CCRC nuclei have confirmed the good accuracy of the method. The developed algorithm will be used to accelerate further research in computer-assisted diagnosis of CCRC. PMID- 23945112 TI - The impact of the nutritional state of patients on the results of the surgical treatment of Crohn's disease. AB - Crohn's disease (CD) patients are qualified for surgery in the acute phase of the disease or after ineffective medical therapy. The course of the disease and the medical treatment received to that point weaken the general state of patients, with that they also cause undernutrition. THE AIM OF THE STUDY: The assessment of the nutritional state of 168 CD patients, admitted for surgery and the evaluation of the influence of this state on the postoperative course. MATERIAL AND METHODS: We referred the results of the nutritional state assessment to the time of the postoperative hospitalization of patients. RESULTS: Applying the Kruskal-Wallis test we found statistically significant, but weakly expressed, differences between the values of nutritional state parameters and period of hospitalization of patients. The applied U Mann-Whitney test, with statistically significant results with p <0.05, showed that no one parameter of the nutritional state of patients expressed a statistically significant difference between dead and recovered groups. CONCLUSIONS: We propose the body mass loss in the 6 months period before admission, TLC and serum albumin level as parameters which well detect undernutrition in CD patients presenting for surgery. PMID- 23945113 TI - Portable VAC therapy improve the results of the treatment of the pilonidal sinus- randomized prospective study. AB - Multiple therapeutic approaches of the treatment of pilonidal sinuses have been described in the literature, but there are still controversies and lack of standardization. Vacuum Assisted Closure (VAC) therapy has potential beneficial effect on the wound healing after the sinus resection. THE AIM OF THE STUDY: To analyze the results of VAC therapy in the treatment of pilonidal sinuses. MATERIAL AND METHODS: After randomization in the control group (9 men) the simple excision of the pilonidal cyst was performed with the standard wound dressing. In the VAC group (10 men) the same surgical procedure was performed, but after the excision the VAC dressing with mobile VAC Freedom device was used. Both groups were treated in an outpatient setting under local anesthesia. The wound size, time of surgery, time of wound healing time of recovery and pain after the surgery (VAS score) were compared. RESULTS: In VAC treated group the wound size and time of surgery were similar to control group. Time of wound healing, recovery and the pain after surgery in days 4-7 were reduced in comparison to the standard treated group. CONCLUSIONS: VAC therapy can be easily used in an outpatient setting, mobile device is highly accepted, operation of the equipment is simple. VAC therapy significantly decreases the time of wound healing and absenteeism from work as well as the postoperative late pain. PMID- 23945114 TI - Migration of biomaterials used in gastroenterological surgery. AB - Mesh biomaterials have become the standard in the treatment of hernias, regardless the location. In addition to the obvious advantages of the methods based on implantable biomaterials, one should be aware of the possible complications, such as their migration to the abdominal organs. MATERIAL AND METHODS: The study group comprised patients operated at the Department of General, Gastroenterological Oncology, and Plastic Surgery during the period between 2008 and 2011, due to hernia surgery with mesh implantation. We also analysed the number of patients operated, due to complications of mesh migration during the same period. RESULTS: 368 patients were subject to mesh implantation, due to hernias during the period between 2008 and 2011. Three patients underwent surgery because of symptomatic migration of the mesh (ileus, fistula). CONCLUSIONS: The frequency of mesh migration is difficult to determine because of the different criteria of migration, observation period, and other factors. In patients after mesh implantation the potential migration of the biomaterial should be considered in case of unclear or acute abdominal symptoms. PMID- 23945115 TI - Life hazard ratio--a new scale for assessing the severity of injury in the populational stud. AB - The heterogeneous population of patients affected by trauma is extremely difficult to systematize. This is due to the diversity of mechanisms of injury, the nature and severity of the injury and the population, which relate to injuries, diverse in terms of gender, age, presence of comorbidities that make up the final severity of the injury and a certain degree of danger to life. THE AIM OF THE STUDY: To develop a universal method to assess the severity of injury and loss of life resulting from their consequences, using the parameters available in the Polish administrative databases, a similar diagnostic efficacy as other used scales to assess the severity of damage. MATERIAL AND METHODS: The study analyzed a group of 92,463 patients hospitalized due to injuries sustained as a result of injuries in all hospitals of the Lublin region in 2003-2005. Developed catalogs risk factors, reference to the population of the Lublin province. RESULTS: Developed five models predictive of injury severity scale counterparts, which include different combinations of risk factors associated with the type of injury, age of the patient and the mechanism of injury that have been evaluated for their diagnostic efficacy in differentiating the expected outcomes. Prediction model have the best diagnostic efficacy AUROC 0.9615, SE 0.0025 and 95% CI 0,9565-0,9665, hereinafter referred to as Life Hazard Ratio (LHR), which has a similarly high diagnostic efficacy as the other, examined in the work of the rock assess the severity of damage AUROC 0.9585, SE 0.0368, 95% CI0 0.8849-1. CONCLUSIONS: 1. The proposed method of use of the International Classification ICD-10 allows the use of regional administrative databases to conduct detailed analyzes of population and monitor trends in the epidemiology of injuries. 2. Developed Life Hazard Ratio (LHR)is a universal method for the objective evaluation of the severity of injuries and the associated risk of life threatening, can also conduct population studies. 3. LHR has a comparable rate of diagnostic efficacy as other commonly used scales assessing the severity of the injury. PMID- 23945116 TI - Repair of the peripheral nerve gap with epineural sheath conduit to prevent muscle denervation atrophy in the diabetic rat model. AB - Muscle denervation atrophy is a result of lower motor neuron injury, thus an early restitution of muscle stimulation is essential in prevention of atrophic changes. THE AIM OF THE STUDY: To evaluate the new application of naturally occurring epineural sheath conduit in repair of the peripheral nerve gap to prevent development of muscle denervation atrophy. MATERIAL AND METHODS: We used the model of 20 mm sciatic nerve gap, resulting in denervation atrophy of the gastrocnemius muscle in the diabetic rats (DM type 2, n=42, Zucker Diabetic Fatty strain). We applied the epineural sheath conduit created from the autologous sciatic nerve for gap repair. Muscle atrophy was assessed with the Gastrocnemius Muscle Index (GMI) and microscopic muscle morphometry (mean fiber area) at 6 and 12 postoperative week. Muscle regeneration in the experimental group was compared to the gold-standard technique of autologous nerve grafting for the repair of created nerve gap. RESULTS: The GMI evaluation revealed comparable muscle mass restoration in groups with nerve repair using both epineural sheath and standard autologous nerve grafting (reaching 28 and 35% of contralateral muscle mass at 12 postoperative week, respectively, p=0.1), and significantly better restoration when compared to the negative control group (no repair, 20%, p<0.01). Micromorphometry confirmed significantly larger area of the regenerated muscle fibers in groups with both nerve grafting and epineural sheath conduit repair (reaching for both ca. 42% of the non-operated side), when compared to severe atrophic outcome when no nerve repair was performed (14% of the control fiber area, p<0.0001). The effectiveness of epineural conduit technique in muscle mass restoration was observed between 6 and 12 weeks after nerve repair--when gastrocnemius muscle mass increased by 12%. CONCLUSIONS: Peripheral nerve gap repair with naturally occurring epineural sheath conduit is effective in prevention of muscle denervation atrophy. This method is applicable in diabetic model conditions, showing results of regeneration which are comparable to the autologous nerve graft repair. PMID- 23945117 TI - Risk of complications and 30-day mortality after laparoscopic and open appendectomy in a Danish region, 1998-2007; a population-based study of 18,426 patients. AB - Acute appendicitis is the most common abdominal surgical emergency, but population-based data on the risk of complications after laparoscopic appendectomy (LA) and open appendectomy (OA) are scarce. THE AIM OF THE STUDY: To describe the risk of complications and mortality after appendectomy for acute appendicitis during a 10-year period, and to compare outcomes after LA and OA. MATERIAL AND METHODS: Using population-based registry data, we conducted a historical cohort study in a Danish region (population 2,000,000) including all patients who underwent appendectomy for acute appendicitis during the period of 1998-2007. We used logistic regression to compare the risk of complications and 30-day mortality between LA and OA, adjusting for gender, age, severity of appendicitis, time of surgery, and calendar year. Analyses were stratified for severity of appendicitis and time period. RESULTS: We included 18,426 patients. From 1998 to 2007 the use of LA rose from 12% to 61%, while the risk of surgically-treated complications fell from 5.7% to 3.2%, the risk of intra abdominal infections fell from 2.4% to 1.1% and 30-day mortality fell from 0.30% to 0.23%. LA was associated with a lower risk of surgically-treated complications (adjusted odds ratio for LA vs. OA=0.70 (95% CI, 0.57-0.85), intraabdominal infections (OR=0.74 [95% CI, 0.55-0.99]) and mortality (OR=0.48 [95% CI, 0.18 1.30]). LA was safer than OA for simple and complicated appendicitis throughout the study period. CONCLUSIONS: Risk of complications and 30-day mortality decreased in Denmark between 1998 and 2007 concurrently with implementation of LA. The risk of complications was lower after LA than after OA. PMID- 23945118 TI - Brain metastasis as the first symptom of gastric cancer--case report and literature review. AB - The study presented a patient with asymptomatic gastric cancer, in whom the first symptom was metastasis to the brain. The patient was initially diagnosed by a neurologist and subject to surgical intervention in the area of residence, where he underwent craniotomy with the excision of the metastatic lesions located in the occipital lobe. The histopathological examination revealed the presence of adenocarcinoma metastases. Following complex diagnostics the patient was diagnosed with cardial carcinoma, being subject to cerebral radiotherapy and chemotherapy. The patient was then referred to surgery at the Wielkopolska Cancer Center in Poznan. After final exclusion of disease dissemination (by means of PET CT) the patient underwent total gastrectomy with D2 lymphadenectomy, and gastrointestinal tract reconstruction by means of the Roux-en-Y method. The histopathological examination result was as follows: tubular-papillary G2 adenocarcinoma (intestinal type), pT2 pN0 (23 evaluated lymph nodes without cancer metastasis), vascular neoplastic emboli, and positive HER2 protein expression. After surgery the patient was subject to adjuvant chemotherapy. Control brain CT examinations revealed the presence of 4 recurrent metastatic lesions-the patient was disqualified from stereotactic radiation therapy and was subject to palliative chemotherapy. The discussion presented the problem of treating patients with stage IV gastric cancer, including current management guidelines, as well as literature review concerning the treatment of patients with diagnosed gastric cancer and brain metastases. PMID- 23945119 TI - Bariatric surgery in morbidly obese patients with chronic renal failure, prepared for kidney transplantation--case reports. AB - Recent years, obesity is a growing health problem also in patients with chronic renal failure and end it's end stage. This situation has a negative impact both on the extension of the waiting period for transplantation, and the survival rate of the transplanted organ and the recipient. Weight loss through lifestyle modification before transplantation is ambiguous. Its well known fact of rapid body mass gain after transplantation, and finally the results of transplantation are not better than those of patients who have not reduced body weight. The paper presents preliminary experience associated with bariatric operations of three chronic dialysed patients with morbid obesity BMI> 35 kg/m2, all patients had been treated by Roux-en-Y gastric by-pass (RYGB). All operated patients were classified as potential recipients were listed by Poltransplant. One of them three months after RYGB surgery underwent without complications a renal transplantation. Preliminary experiences based on operating these three case confirmed the complete safety of this type of approach in patients with end-stage chronic kidney disease (CKD). PMID- 23945120 TI - Training in classic and laparoscopic surgery--needs and remedies. PMID- 23945121 TI - A pediatric patient with Cushing syndrome caused by ectopic ACTH syndrome and concomitant pituitary incidentalomas. AB - Ectopic ACTH syndrome is a rare but important cause of pediatric Cushing syndrome, for which management by a multidisciplinary team is required. Although diagnostic evaluation is similar to that in adults, the variation in epidemiology may sway investigations, leading to inappropriate and/or incomplete diagnostic interventions. We present a case of 15-year-old girl with symptoms of severe ACTH dependent Cushing syndrome and two pituitary adenomas. The ectopic source of ACTH production was confirmed after petrosal venous sampling was performed. Diagnostics and perioperative management of a pulmonary carcinoid tumor producing ectopic ACTH is reviewed. In pediatric patients, as in adult patients, a pituitary lesion <6 mm on MRI is not sufficient confirmation of Cushing's disease, and appropriate diagnostic work-up should be performed to assess the source of the ACTH overproduction. PMID- 23945122 TI - Teriparatide (rhPTH) treatment in children with syndromic hypoparathyroidism. AB - BACKGROUND: Subcutaneous recombinant human parathormone [rhPTH (1-34)] has been introduced for hypoparathyroidism treatment, allowing avoidance of vitamin D and calcium side effects. OBJECTIVE: Our objective was to evaluate rhPTH (1-34) safety and efficacy in pediatric patients with genetically proved syndromic hypoparathyroidism. METHODS: The study was a 2.5-year self-controlled trial on six pediatric patients (four males, two females, age 9.8+/-5.1 years) with syndromic hypoparathyroidism including three with autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED) syndrome, two with DiGeorge syndrome, and one with hypoparathyroidism-deafness-renal dysplasia syndrome. We compared patients' clinical and biochemical outcome of conventional treatment based on oral administration of calcium (1-1.5 g/day in three doses) plus oral calcitriol (6.5-33 ng/kg per day in two to three doses) with the outcome obtained with rhPTH (1-34) (teriparatide, 12.5 MUg bid). Therapy shift was conducted introducing rhPTH (1-34) while progressively withdrawing calcium and vitamin D. Blood calcium, phosphorus, alkaline phosphatase, and urinary calcium-to-creatinine ratio (mg/mg) before and during rhPTH therapy were compared. RESULTS: rhPTH treatment allowed complete calcium and vitamin D withdrawal in two patients, calcium withdrawal in three and reduction of vitamin D dose in two. During rhPTH (1-34), mean blood calcium, phosphorus, and alkaline phosphatase were not significantly modified, whereas significant reduction of the calciuria-to creatininuria ratio (0.55+/-0.31 vs. 0.1+/-0.1, p=0.02) was obtained. The number of tetanic episodes was reduced in four patients during teriparatide treatment compared to conventional treatment. CONCLUSION: In children with syndromic hypoparathyroidism, substitutive treatment with rhPTH (1-34) maintains adequate blood calcium levels and allows prompt normalization of urinary calcium excretion, through direct action on the kidney and through calcium and vitamin D therapy layoff. PMID- 23945123 TI - Remission of hypertension and electrolyte abnormalities following renal transplantation in a patient with apparent mineralocorticoid excess well documented throughout childhood. AB - Apparent mineralocorticoid excess syndrome (AME) is an autosomal recessive genetic disorder caused by a deficiency in the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD). We report a 36-year-old male who was hypertensive from birth and was diagnosed with AME at 8 years of age. There was continuous documentation of his hypertension and hypokalemic alkalosis throughout childhood, during which spironolactone and supplemental potassium were administered. At 33 years of age, the patient received a renal transplant, and following this the AME appears to have been cured clinically with remission of his low renin hypertension and hypokalemic alkalosis despite termination of treatment with spironolactone and potassium supplements. PMID- 23945124 TI - Detection of vascular risk markers in children and adolescents with type 1 diabetes. AB - OBJECTIVES: Type 1 diabetes is a chronic disease that causes persistent vascular injury. This study investigates the benefits of surrogate markers in early detection of vascular injury in children and adolescents with type 1 diabetes. METHODS: Eighty-four patients (35 male, 49 female) with type 1 diabetes for 5 or more years were included. Serum lipid profile, plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a) (Lpa) and homocystein, were investigated. Patients were divided into two groups according to the duration of diabetes. Patients with and without microvascular complications were also compared. RESULTS: Microvascular complications were present in 14 out of 48 patients in group-1 (29.1%; duration of diabetes: 5-10 years) and in 7 out of 36 patients in group-2 (19.4%; duration of diabetes: >10 years). Serum homocystein, Lpa, PAI-1 and serum lipids were not correlated with the duration of diabetes. Significantly increased triglyceride (TG) and HbA1C levels were associated with the presence of microvascular complications. CONCLUSION: Providing good glycemic control is very important for preventing vascular injury in children and adolescents with type 1 diabetes. It seems that traditional vascular surrogate markers like LDL/HDL ratio, triglycerides and HbA1C level correspond more to microvascular complications than newly defined surrogate markers that are not commonly available. PMID- 23945125 TI - Retinol and retinyl palmitate in fetal mice liver: sexual dimorphism. AB - We determined retinoids liver content in male and female mice fetuses to study a possible sex difference during prenatal development, and to ascertain if vitamin A metabolism is similar in both sexes. The study was performed between developmental days E15-E19, and the fetuses were collected from two main groups: control (no manipulation) and vitamin A (administration of vitamin A on developmental day E14). Each group was subdivided by sex and retinoids were analyzed by high performance liquid chromatography (HPLC). The control group did not have any retinol in the liver of both sexes. Fetuses from the vitamin A group began to accumulate retinol on day E16, until E19 and sexual dimorphism was exhibited. Retinyl palmitate content in the control group showed sexual dimorphism on some developmental days, and in the vitamin A group these differences were more significant. In conclusion, our study showed sexual dimorphism in the retinoids liver content during mice development and evidences a sex difference in vitamin A metabolism, with different capacities to store and metabolize retinoids. PMID- 23945126 TI - The first report of cabergoline-induced immune hemolytic anemia in an adolescent with prolactinoma. AB - Prolactinomas are common pituitary tumors that can cause gonadal dysfunction and infertility related to hyperprolactinemia. Dopamine agonists are the first-line treatment in these patients. Cabergoline leads to significant reduction in serum prolactin levels and tumor size in patients with prolactinoma. Dopamine agonists have been associated with adverse effects such as nausea, vomiting and psychosis. We report here a case with cabergoline-induced immune hemolytic anemia. The patient had cabergoline treatment history for prolactinoma and presented with weakness, fatigue, nausea, and paleness. Laboratory findings revealed severe anemia-related immune hemolysis. There were no causes identified to explain hemolytic anemia except cabergoline. Therefore, cabergoline therapy was stopped and subsequently hemolytic anemia resolved and did not occur again. This is the first reported pediatric case with prolactinoma and cabergoline-induced hemolytic anemia. Clinicians should be watchful for this rare side effect induced by cabergoline. PMID- 23945127 TI - The utility of thrombophilia testing. AB - In the past decades, the recognition of several inherited thrombophilic traits has greatly improved our knowledge of the pathogenesis of venous thromboembolism, explaining about half of all idiopathic cases. As a consequence, thrombophilia testing has enormously increased in the past years for various clinical conditions. In this paper, the current indications of the most commonly tested thrombophilic abnormalities (i.e., Factor V Leiden, prothrombin G20210A mutation, protein C, S and antithrombin deficiencies) are analysed. When used appropriately thrombophilia testing has a positive impact on the health care of the people tested and their relatives. PMID- 23945128 TI - Cucurbitacin covalent bonding to cysteine thiols: the filamentous-actin severing protein Cofilin1 as an exemplary target. AB - BACKGROUND: Cucurbitacins are a class of triterpenoid natural compounds with potent bioactivities that led to their use as traditional remedies, and which continue to attract considerable attention as chemical biology tools and potential therapeutics. One obvious target is the actin-cytoskeleton; treatment with cucurbitacins results in cytoskeletal rearrangements that impact upon motility and cell morphology. FINDINGS: Cucurbitacin reacted with protein cysteine thiols as well as dithiothreitol, and we propose that the cucurbitacin mechanism of action is through broad protein thiol modifications that could result in inhibition of numerous protein targets. An example of such a target protein is Cofilin1, whose filamentous actin severing activity is inhibited by cucurbitacin conjugation. CONCLUSIONS: The implications of these results are that cucurbitacins are unlikely to be improved for selectivity by medicinal chemistry and that their use as chemical biology probes to analyse the role of specific signalling pathways should be undertaken with caution. PMID- 23945129 TI - Vitamin D receptor (VDR) gene polymorphisms and susceptibility to systemic lupus erythematosus clinical manifestations. AB - Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical manifestations and target tissue damage. Currently, several genes have been associated with SLE susceptibility, including vitamin D receptor (VDR), which is a mediator of immune responses through the action of vitamin D. Polymorphisms in the VDR gene can impair the vitamin D (D3) function role, and since SLE patients show deficient D3 blood levels, it leads to a possible connection to the disease's onset. In our study we searched for an association between VDR polymorphisms and risk of developing SLE, as well as the disease's clinical manifestations. We enrolled 158 SLE patients and 190 Southeast Brazilian healthy controls, genotyped for five Tag single nucleotide polymorphisms (SNPs), covering most of the VDR gene region. We found an association between VDR SNPs and SLE for the following clinical manifestations: rs11168268 and cutaneous alterations (p=0.036), rs3890733 (p=0.003) rs3890733 and arthritis (p=0.001), rs2248098 and immunological alterations (p=0.040), rs4760648 and antibody anti dsDNA (p=0.036). No association was reported between VDR polymorphisms and SLE susceptibility. PMID- 23945131 TI - One-pot solvothermal synthesis of ZnSe.xN2H4/GS and ZnSe/N-GS and enhanced visible-light photocatalysis. AB - Doped-graphene has attracted considerable attention in many fields because doping element can alter the electrical properties of graphene. In this paper, we synthesized ZnSe.xN2H4/graphene (ZnSe.xN2H4/GS) and ZnSe/nitrogen-doped graphene (ZnSe/N-GS) nanocomposites with p-n junctions via one-pot solvothermal process. The structure, morphologies and catalytic performance of the ZnSe.xN2H4/GS and ZnSe/N-GS are characterized by X-ray diffraction pattern (XRD), field emission scanning electron microscopy (SEM), transmission electron microscopy (TEM), Raman spectroscopy (RS), X-ray photoelectron spectroscopy (XPS), and cathodoluminescence spectrum (CL), respectively. Our experiments show that the as prepared nanocomposites ZnSe.xN2H4/GS and ZnSe/N-GS exhibit remarkably enhanced photocatalytic activities for methylene blue (MB) dye under visible light irradiation. Even importantly, ZnSe/N-GS would make this degradation process more effective. Overall, this facile and catalyst-free synthesize method in this work could provide new insights into the fabrication of other composites based on doped graphene with high performance photocatalysts, which show their potential applications in producing of hydrogen through water splitting, environmental protection issues. PMID- 23945130 TI - Effectiveness of two antifolate prophylactic strategies against malaria in HIV positive pregnant women in Bangui, Central African Republic: study protocol for a randomized controlled trial (MACOMBA). AB - BACKGROUND: Co-infection with malaria parasite and HIV is an emerging public health problem in tropical areas, particularly in pregnant women, and management of the concurrent effects of these two infections is challenging. Co-trimoxazole is a sulfamide preparation used to prevent opportunistic infections in HIV infected patients, and many studies have reported that it has significant activity against malaria. As the efficacy of intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) against malaria is decreasing, co trimoxazole might be an alternative for preventing malaria among HIV-infected populations. The aim of this study is to compare the effectiveness of SP-IPT, which is recommended for the prevention of malaria during pregnancy in the Central African Republic, with that of a daily dose of co-trimoxazole against P. falciparum infections among HIV-infected pregnant women in Bangui, the capital of the Central African Republic. METHODS/DESIGN: The MACOMBA study (MAternity and COntrol of Malaria-HIV co-infection in BAngui) is a multicentre open-label randomized clinical trial conducted at four maternity hospitals in Bangui. All HIV-infected pregnant women presenting for an antenatal clinic visit between the weeks 16 and 28 of amenorrhoea, with a CD4 count of more than 350 cells/mm3, will be eligible. All the women will provide written consent before being enrolled in the study and will then be randomly allocated to either SP-IPT (25 mg of sulfadoxine and 1.25 mg of pyrimethamine) or daily co-trimoxazole doses (960 mg per dose). The primary end-point is the placental malaria parasitaemia rate at delivery. Other main outcome measures include the number of malaria episodes during pregnancy, safety, and treatment compliance. Furthermore, the frequency of molecular resistance markers dhfr and dhps will be measured. DISCUSSION: In this trial, we seek to confirm whether co-trimoxazole is operationally suitable to replace SP-IPT in order to prevent malaria among pregnant women infected with HIV in the Central African Republic. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01746199. PMID- 23945132 TI - Cerebral ischaemia and matrix metalloproteinase-9 modulate the angiogenic function of early and late outgrowth endothelial progenitor cells. AB - The enhancement of endogenous angiogenesis after stroke will be critical in neurorepair therapies where endothelial progenitor cells (EPCs) might be key players. Our aim was to determine the influence of cerebral ischaemia and the role of matrix metalloproteinase-9 (MMP-9) on the angiogenic function of EPCs. Permanent focal cerebral ischaemia was induced by middle cerebral artery (MCA) occlusion in MMP-9/knockout (MMP-9/KO) and wild-type (WT) mice. EPCs were obtained for cell counting after ischaemia (6 and 24 hrs) and in control animals. Matrigel(TM) assays and time-lapse imaging were conducted to monitor angiogenic function of WT and MMP9-deficient EPCs or after treatment with MMP-9 inhibitors. Focal cerebral ischaemia increased the number of early EPCs, while MMP-9 deficiency decreased their number in non-ischaemic mice and delayed their release after ischaemia. Late outgrowth endothelial cells (OECs) from ischaemic mice shaped more vessel structures than controls, while MMP-9 deficiency reduced the angiogenic abilities of OECs to form vascular networks, in vitro. Treatment with the MMP inhibitor GM6001 and the specific MMP-9 inhibitor I also decreased the number of vessel structures shaped by both human and mouse WT OECs, while exogenous MMP-9 could not revert the impaired angiogenic function in MMP-9/KO OECs. Finally, time-lapse imaging showed that the extension of vascular networks was influenced by cerebral ischaemia and MMP-9 deficiency early during the vascular network formation followed by a dynamic vessel remodelling. We conclude that focal cerebral ischaemia triggers the angiogenic responses of EPCs, while MMP-9 plays a key role in the formation of vascular networks by EPCs. PMID- 23945133 TI - A framework for the co-registration of hemodynamic forces and atherosclerotic plaque components. AB - Local hemodynamic forces, such as wall shear stress (WSS), are thought to trigger cellular and molecular mechanisms that determine atherosclerotic plaque vulnerability to rupture. Magnetic resonance imaging has emerged as a powerful tool to characterize human carotid atherosclerotic plaque composition and morphology, and to identify plaque features shown to be key determinants of plaque vulnerability. Image-based computational fluid dynamics has allowed researchers to obtain time-resolved WSS information of atherosclerotic carotid arteries. A deeper understanding of the mechanisms of initiation and progression of atherosclerosis can be obtained through the comparison of WSS and plaque composition and morphology. To date, however, advance in knowledge has been limited greatly due to the lack of a reliable infrastructure to perform such analysis. The aim of this study is to establish a framework that will allow for the co-registration and analysis of the three-dimensional distribution of WSS and plaque components and morphology. The use of this framework will lead to future studies targeted to determining the role of WSS in atherosclerotic plaque progression and vulnerability. PMID- 23945135 TI - Physics of protein motility and motor proteins. PMID- 23945134 TI - Serological identification of fast progressors of structural damage with rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) patients with structural progression are in most need of immediate treatment to maintain tissue integrity. The serum protein fingerprint, type I collagen degradation mediated by matrix metalloproteinases (MMP)-cleavage (C1M), is a biomarker of tissue destruction. We investigated whether baseline serum C1M levels could identify structural progressors and if the biomarker levels changed during anti-inflammatory treatment with tocilizumab (TCZ). METHODS: The LITHE-biomarker study (NCT00106535, n = 585) was a one-year phase III, double-blind, placebo (PBO) controlled, parallel group study of TCZ 4 or 8 mg/kg every four weeks, in RA patients on stable doses of methotrexate (MTX). Spearman's ranked correlation was used to assess the correlation between baseline C1M levels and structural progression at baseline and at weeks 24 and 52. Multivariate regression was performed for delta structural progression. Change in C1M levels were studied as a function of time and treatment. RESULTS: At baseline, C1M was significantly correlated to C-reactive protein (P <0.0001), visual analog scale pain (P <0.0001), disease activity score28-erythrocyte sedimentation rate (DAS28-ESR) (P <0.0001), joint space narrowing (JSN) (P = 0.0056) and modified total Sharp score (mTSS) (P = 0.0006). Baseline C1M was significantly correlated with delta-JSN at Week 24 (R2 = 0.09, P = 0.0001) and at Week 52 (R2 = 0.27, P <0.0001), and with delta-mTSS at 24 weeks (R2 = 0.006, P = 0.0015) and strongly at 52 weeks (R2 = 0.013, P <0.0001) in the PBO group. C1M levels were dose-dependently reduced in the TCZ + MTX group. CONCLUSIONS: Baseline C1M levels correlated with worsening joint structure over one year. Serum C1M levels may enable identification of those RA patients that are in most need of aggressive treatment TRIAL REGISTRATION: ClinicalTrials.gov: NCT00106535. PMID- 23945136 TI - Expression of neuroepithelial transforming gene 1 is enhanced in oesophageal cancer and mediates an invasive tumour cell phenotype. AB - INTRODUCTION: Neuroepithelial Transforming Gene 1 (NET1) is a well characterised oncoprotein and a proven marker of an aggressive phenotype in a number of cancers, including gastric adenocarcinoma. We aimed to investigate whether NET1 plays a functional role in oesophageal cancer (OAC) and its pre-malignant phenotype Barrett's oesophagus. METHODS: Baseline NET1 mRNA levels were determined by qPCR across a panel of six cell lines, including normal oesophageal, Barrett's and OAC derived cells. Quantification of NET1 protein in OAC cells was performed using Western blot and immunofluorescence. NET1 expression was modulated by treating with lysophosphatidic acid (LPA) and NET1 specific siRNA. The functional effects of NET1 knockdown were assessed in vitro using proliferation, migration and invasion assays. RESULTS: NET1 expression was increased in Barrett's and in OAC-derived cells in comparison to normal oesophageal cells. The highest expression was observed in OE33 a Barrett's related OAC cell line. NET1 protein and mRNA expression was enhanced by LPA treatment in OAC and furthermore LPA treatment caused increased proliferation, migration and invasion in a NET1-dependent manner. NET1 knockdown resulted in reduced OAC cell proliferation and invasion. CONCLUSIONS: As found in other malignancies, NET1 expression is elevated in OAC and its pre-malignant phenotype, Barrett's oesophagus. NET1 promotes OAC cell invasion and proliferation and it mediates LPA-induced OAC cell migration. PMID- 23945137 TI - CD137 ligand reverse signaling skews hematopoiesis towards myelopoiesis during aging. AB - CD137 is a costimulatory molecule expressed on activated T cells. Its ligand, CD137L, is expressed on the surface of hematopoietic progenitor cells, and upon binding to CD137 induces reverse signaling into hematopoietic progenitor cells promoting their activation, proliferation and myeloid differentiation. Since aging is associated with an increasing number of myeloid cells we investigated the role of CD137 and CD137L on myelopoiesis during aging. Comparing 3 and 12 months old WT, CD137-/- and CD137L-/- mice we found significantly more granulocytes and monocytes in the bone marrow of older WT mice, while this age dependent increase was absent in CD137-/- and CD137L-/- mice. Instead, the bone marrow of 12 months old CD137-/- and CD137L-/- mice was characterized by an accumulation of hematopoietic progenitor cells, suggesting that the differentiation of hematopoietic progenitor cells became arrested in the absence of CD137L signaling. CD137L signaling is initiated by activated CD137-expressing, CD4+ T cells. These data identify a novel molecular mechanisms underlying immune aging by demonstrating that CD137-expressing CD4+ T cells in the bone marrow engage CD137L on hematopoietic progenitor cells, and that this CD137L signaling biases hematopoiesis towards myelopoiesis during aging. PMID- 23945139 TI - Targeting of autoantigens to DEC205+ dendritic cells in vivo suppresses experimental allergic encephalomyelitis in mice. AB - The dendritic and epithelial cell receptor with a m.w. of 205 kDa (DEC205) is expressed by dendritic cells (DCs) and facilitates Ag presentation. After injection of Ags coupled to Abs specific for DEC205 into mice, Ag presentation occurs by nonactivated DCs, which leads to induction of regulatory T cells (Tregs). To test this system for tolerance induction in experimental allergic encephalomyelitis (EAE), we created single-chain fragment variables (scFv) specific for DEC205 and fused the scFv to the self-Ag myelin oligodendrocyte glycoprotein (MOG; scFv DEC:MOG). An anti-beta-galactosidase scFv:MOG fusion protein (scFv GL117:MOG) served as isotype control. After staining of DCs in vitro with purified scFv DEC:MOG, binding to DCs and colocalization with MHC class II was apparent, whereas isotype controls did not bind. We next injected scFv DEC:MOG into mice and observed elevated numbers of highly activated, IL-10 producing CD4+CD25+Foxp3+ Tregs (17% of CD4) in spleens, as compared with isotype controls and uninjected mice (12% of CD4). Furthermore, DCs isolated from scFv DEC:MOG-injected animals produced significantly increased levels of TGF-beta. Most importantly, when EAE was induced in scFv DEC:MOG-injected mice, 90% of the mice were protected from EAE, whereas all mice in the isotype controls (scFv GL117:MOG) experienced development of EAE. When applying scFv DEC:MOG to mice that had already experienced EAE symptoms, abrogation of the disease in 90% of the animals was apparent, whereas all animals in the control groups experienced development of severe EAE. Thus, these data indicate that targeting of MOG to "steady-state" DCs in vivo may provide a tool to prevent and to treat EAE by a DC/Treg-driven mechanism. PMID- 23945138 TI - Engineering online and in-person social networks to sustain physical activity: application of a conceptual model. AB - BACKGROUND: High rates of physical inactivity compromise the health status of populations globally. Social networks have been shown to influence physical activity (PA), but little is known about how best to engineer social networks to sustain PA. To improve procedures for building networks that shape PA as a normative behavior, there is a need for more specific hypotheses about how social variables influence PA. There is also a need to integrate concepts from network science with ecological concepts that often guide the design of in-person and electronically-mediated interventions. Therefore, this paper: (1) proposes a conceptual model that integrates principles from network science and ecology across in-person and electronically-mediated intervention modes; and (2) illustrates the application of this model to the design and evaluation of a social network intervention for PA. METHODS/DESIGN: A conceptual model for engineering social networks was developed based on a scoping literature review of modifiable social influences on PA. The model guided the design of a cluster randomized controlled trial in which 308 sedentary adults were randomly assigned to three groups: WalkLink+: prompted and provided feedback on participants' online and in-person social-network interactions to expand networks for PA, plus provided evidence-based online walking program and weekly walking tips; WalkLink: evidence-based online walking program and weekly tips only; Minimal Treatment Control: weekly tips only. The effects of these treatment conditions were assessed at baseline, post-program, and 6-month follow-up. The primary outcome was accelerometer-measured PA. Secondary outcomes included objectively-measured aerobic fitness, body mass index, waist circumference, blood pressure, and neighborhood walkability; and self-reported measures of the physical environment, social network environment, and social network interactions. The differential effects of the three treatment conditions on primary and secondary outcomes will be analyzed using general linear modeling (GLM), or generalized linear modeling if the assumptions for GLM cannot be met. DISCUSSION: Results will contribute to greater understanding of how to conceptualize and implement social networks to support long-term PA. Establishing social networks for PA across multiple life settings could contribute to cultural norms that sustain active living. TRIAL REGISTRATION: ClinicalTrials.gov NCT01142804. PMID- 23945140 TI - Toll IL-1R8/single Ig IL-1-related receptor regulates psoriasiform inflammation through direct inhibition of innate IL-17A expression by gammadelta T cells. AB - Expression of the orphan receptor Toll IL-1R8/single Ig IL-1-related receptor has been reported to be reduced in the peripheral blood of psoriatic arthritis patients. However whether TIR8/SIGIRR activity plays a specific role in regulating psoriatic inflammation is unknown. We report that Tir8/Sigirr deficient mice develop more severe psoriatic inflammation in both the chemical (Aldara)- and cytokine (rIL-23)-induced models of psoriasis. Increased disease severity was associated with enhanced infiltration of Vgamma4+ gammadelta T cells that express significantly elevated levels of IL-17A. Critically, we also demonstrate that TIR8/SIGIRR activity directly suppressed innate IL-17A expression by gammadelta T cells in vitro and in vivo. Importantly, treatment of Tir8/Sigirr-/- mice with an IL-17A neutralization Ab reversed the enhanced disease severity observed in these mice. This study identifies TIR8/SIGIRR as a novel intrinsic negative regulator of innate IL-17A expression and characterizes a novel mechanism involved in the regulation of psoriatic inflammation. PMID- 23945141 TI - Long-term IgG response to porcine Neu5Gc antigens without transmission of PERV in burn patients treated with porcine skin xenografts. AB - Acellular materials of xenogenic origin are used worldwide as xenografts, and phase I trials of viable pig pancreatic islets are currently being performed. However, limited information is available on transmission of porcine endogenous retrovirus (PERV) after xenotransplantation and on the long-term immune response of recipients to xenoantigens. We analyzed the blood of burn patients who had received living pig-skin dressings for up to 8 wk for the presence of PERV as well as for the level and nature of their long term (maximum, 34 y) immune response against pig Ags. Although no evidence of PERV genomic material or anti PERV Ab response was found, we observed a moderate increase in anti-alphaGal Abs and a high and sustained anti-non-alphaGal IgG response in those patients. Abs against the nonhuman sialic acid Neu5Gc constituted the anti-non-alphaGal response with the recognition pattern on a sialoglycan array differing from that of burn patients treated without pig skin. These data suggest that anti-Neu5Gc Abs represent a barrier for long-term acceptance of porcine xenografts. Because anti-Neu5Gc Abs can promote chronic inflammation, the long-term safety of living and acellular pig tissue implants in recipients warrants further evaluation. PMID- 23945142 TI - The tetraspanin CD63 is required for efficient IgE-mediated mast cell degranulation and anaphylaxis. AB - Mast cell (MC) activation through the high-affinity IgE receptor FcepsilonRI leads to the release of mediators involved in immediate-type allergic reactions. Although Abs against the tetraspanins CD63 and CD81 inhibit FcepsilonRI-induced MC degranulation, the intrinsic role of these molecules in FcepsilonRI-induced MC activation is unknown. In MCs, CD63 is expressed at the cell surface and in lysosomes (particularly secretory lysosomes that contain allergic mediators). In this study, we investigated the role of CD63 in MC using a CD63 knockout mouse model. CD63-deficiency did not affect in vivo MC numbers and tissue distribution. Bone marrow-derived MC developed normally in the absence of CD63 protein. However, CD63-deficient bone marrow-derived MC showed a significant decrease in FcepsilonRI-mediated degranulation, but not PMA/ionomycin-induced degranulation, as shown by beta-hexosaminidase release assays. The secretion of TNF-alpha, which is both released from granules and synthesized de novo upon MC activation, was also decreased. IL-6 secretion and production of the lipid mediator leukotriene C4 were unaffected. There were no ultrastructural differences in granule content and morphology, late endosomal/lysosomal marker expression, FcepsilonRI-induced global tyrosine phosphorylation, and Akt phosphorylation. Finally, local reconstitution in genetically MC-deficient Kit(w/w-v) mice was unaffected by the absence of CD63. However, the sites reconstituted with CD63-deficient MC developed significantly attenuated cutaneous anaphylactic reactions. These findings demonstrate that the absence of CD63 results in a significant decrease of MC degranulation, which translates into a reduction of acute allergic reactions in vivo, thus identifying CD63 as an important component of allergic inflammation. PMID- 23945143 TI - Cognitive deficits in Korean women treated with chemotherapy for breast cancer. AB - BACKGROUND: Cognitive deficits have been reported as detrimental side effects in chemotherapy-treated breast cancer patients and survivors. Korean women treated for breast cancer may experience unrecognized cognitive deficits related to their treatment. However, no research has examined cognitive test performance in chemotherapy-treated Korean breast cancer survivors. OBJECTIVE: The objectives of this study were 2-fold: (1) to examine differences in occurrence and severity of cognitive deficits in Korean women treated with adjuvant chemotherapy for breast cancer as compared with a control group of women without breast cancer and (2) to examine the relationship of selected demographic and cultural factors with cognitive test performance. METHODS: Sixty-four Korean women, 32 women treated for localized breast cancer and 32 healthy controls, were enrolled. Breast cancer participants were assessed with established cognitive measures within 4 months after chemotherapy, and healthy controls, within 6 months after negative screening mammography. RESULTS: The breast cancer group showed a significantly higher occurrence and greater severity of cognitive deficits than controls did. Importantly, older age, less education, greater collectivist tendency, and greater childrearing burden were reliably associated with poorer attention and working memory test performance. CONCLUSIONS: Cognitive deficits were found in chemotherapy-treated Korean women with moderate to large effect sizes compared with controls. Cultural characteristics contributed to worse cognitive performance. IMPLICATIONS FOR PRACTICE: Healthcare providers should recognize that Korean women may be highly vulnerable to cognitive deficits. Cultural factors also need to be considered when assessing cognitive function and designing therapeutic interventions to counteract negative cognitive outcomes. PMID- 23945144 TI - A qualitative exploration of district nurses' care of patients with advanced cancer: the challenges of supporting families within the home. AB - BACKGROUND: In the United Kingdom, district nurses (DNs) support patients with advanced cancer in their homes. Although evidence suggests that DNs emphasize the distinctiveness of home rather than hospital settings, little is known about the specific challenges of delivering care in family-home settings. OBJECTIVE: The objective of this study was to explore DNs' experiences of supporting patients within families. METHODS: Focus groups were conducted with 40 DNs from 4 areas in the United Kingdom. The groups were digitally recorded and facilitated by researchers using a flexible topic guide. ANALYSIS: Verbatim transcripts were analyzed using thematic content analysis. RESULTS: Case-load complexity (household volatility) and family dynamics posed distinct challenges for nurses supporting patients. Many family members struggled with accepting the patients' prognosis and were complicit in withholding information. At times, this foreclosed a consideration of palliative options. CONCLUSIONS: Carers provide a great deal of positive supportive care within the home. However, for some, the home is characterized by conflict rather than consensus. Complexities surrounding family relationships pose a distinctive and challenging environment for DNs. IMPLICATIONS FOR PRACTICE: Education and training of DNs should be designed to address the challenges of supporting patients within the family-home setting. PMID- 23945145 TI - Schoolyard physical activity of 6-11 year old children assessed by GPS and accelerometry. AB - BACKGROUND: Children's current physical activity levels are disturbingly low when compared to recommended levels. This may be changed by intervening in the school environment. However, at present, it is unclear to what extent schoolyard physical activity contributes towards reaching the daily physical activity guideline. The aim of this study was to examine how long and at what intensity children are physically active at the schoolyard during different time segments of the day. Moreover, the contribution of schoolyard physical activity towards achieving the recommended guideline for daily physical activity was investigated. METHODS: Children (n=76) between the age of 6-11 years were recruited in six different schools in five cities (>70.000 residents) in the Netherlands. During the weekdays of a regular school week, childrens' physical activity and location were measured with ActiGraph accelerometers and Travelrecorder GPS receivers. Data was collected from December 2008 to April 2009. From the data, the amount of moderate to vigorous physical activity (MVPA) on and outside the schoolyard was established. Moreover, the percentage of MVPA on the schoolyard was compared between the following segments of the day: pre-school, school, school recess, lunch break and post-school. Differences between boys and girls were compared using linear and logistic mixed-effects models. RESULTS: On average, children spent 40.1 minutes/day on the schoolyard. During this time, boys were more active on the schoolyard, with 27.3% of their time spent as MVPA compared to 16.7% among girls (OR=2.11 [95% CI 1.54 - 2.90]). The children were most active on the schoolyard during school recess, during which boys recorded 39.5% and girls recorded 23.4% of the time as MVPA (OR=2.55 [95% CI: 1.69 - 3.85]). Although children were only present at the schoolyard for 6.1% of the total reported time, this time contributed towards 17.5% and 16.8% of boys' and girls' minutes of MVPA. CONCLUSIONS: On the schoolyard, children's physical activity levels are higher than on average over the whole day. Physical activity levels are particularly high during school recess. The school environment seems to be an important setting for improving children's physical activity levels. Further research on the facilitators of these high activity levels may provide targets for further promotion of physical activity among children. PMID- 23945146 TI - Correction: Granulocyte-macrophage stimulating factor (GM-CSF) increases circulating dendritic cells but does not abrogate suppression of adaptive cellular immunity in patients with metastatic colorectal cancer receiving chemotherapy. PMID- 23945148 TI - Application of 300* enhanced fluorescence on a plasmonic chip modified with a bispecific antibody to a sensitive immunosensor. AB - The grating substrate covered with a metal layer, a plasmonic chip, and a bispecific antibody can play a key role in the sensitive detection of a marker protein with an immunosensor, because of the provision of an enhanced fluorescence signal and the preparation of a sensor surface densely modified with capture antibody, respectively. In this study, one of the tumor markers, a soluble epidermal growth factor receptor (sEGFR), was selected as the target to be detected. The ZnO- and silver-coated plasmonic chip with precise regularity and the appropriate duty ratio in the periodic structure further enhanced the fluorescence intensity. As for sensor surface modification with capture antibody, a bispecific antibody (anti-sEGFR and anti-ZnO antibody), the concentrated bispecific antibody solution was found to nonlinearly form a surface densely immobilized with antibody, because the binding process of a bispecific antibody to the ZnO surface can be a competitive process with adsorption of phosphate. As a result, the interface on the plasmonic chip provided a 300* enhanced fluorescence signal compared with that on a ZnO-coated glass slide, and therefore sEGFR was found to be quantitatively detected in a wide concentration range from 10 nM to 700 fM on our plasmonic surface. PMID- 23945147 TI - Functional requirements driving the gene duplication in 12 Drosophila species. AB - BACKGROUND: Gene duplication supplies the raw materials for novel gene functions and many gene families arisen from duplication experience adaptive evolution. Most studies of young duplicates have focused on mammals, especially humans, whereas reports describing their genome-wide evolutionary patterns across the closely related Drosophila species are rare. The sequenced 12 Drosophila genomes provide the opportunity to address this issue. RESULTS: In our study, 3,647 young duplicate gene families were identified across the 12 Drosophila species and three types of expansions, species-specific, lineage-specific and complex expansions, were detected in these gene families. Our data showed that the species-specific young duplicate genes predominated (86.6%) over the other two types. Interestingly, many independent species-specific expansions in the same gene family have been observed in many species, even including 11 or 12 Drosophila species. Our data also showed that the functional bias observed in these young duplicate genes was mainly related to responses to environmental stimuli and biotic stresses. CONCLUSIONS: This study reveals the evolutionary patterns of young duplicates across 12 Drosophila species on a genomic scale. Our results suggest that convergent evolution acts on young duplicate genes after the species differentiation and adaptive evolution may play an important role in duplicate genes for adaption to ecological factors and environmental changes in Drosophila. PMID- 23945150 TI - Variations in patient-centered medical home capacity: a linear growth curve analysis. AB - Increased interest in the patient-centered medical home (PCMH) among policy makers and practitioners has resulted in a growth of research on the factors that influence its adoption and implementation, yet this research often fails to capture the multidimensional nature of the PCMH and the longitudinal nature of the implementation process. This study documented physician practices' PCMH capacity across 12 different domains (e.g., extended access, specialist referral, use of patient registry) over a 3-year period (2008-2010). Linear growth models indicated that participation through different types of physician organizations and practice size were associated with different baseline levels of capacity and changes in capacity over time; however, the association varied as a function of the different PCMH dimensions. Differences in PCMH capacity across the 12 domains and time suggest that more attention should be paid to the longitudinal nature of PCMH implementation and the differential challenges associated with its component parts. PMID- 23945149 TI - Ischemic arterial events and atherosclerosis in patients with systemic sclerosis: a population-based case-control study. AB - INTRODUCTION: While microvascular disease is well described in systemic sclerosis (SSc), it is still unclear whether the occurrence of ischemic macrovascular events and atherosclerosis is enhanced among patients with SSc. METHODS: In this study, 111 SSc patients (74% of prevalent cases in Stockholm County) and 105 age- and sex-comparable population controls were investigated. Previous ischemic arterial events were tabulated. As surrogate measures of atherosclerosis, plaque occurrence and intima-media thickness (IMT) were determined with carotid ultrasound and the ankle-brachial index (ABI) was calculated. Traditional cardiovascular risk factors were recorded and we also measured biomarkers indicating systemic inflammation and endothelial activation/dysfunction. RESULTS: Mean age was 62 +/- 12 years for patients and controls. Ischemic arterial events were more common, due to increased occurrence of ischemic heart disease (IHD) and ischemic peripheral vascular disease (IPVD), in the patient group (12% vs. 4%, P = 0.03 and 9% vs. 0%, P = 0.003 respectively). On a group level, there was no difference regarding the occurrence of ischemic cerebrovascular disease, the frequency of plaques, IMT or ABI between SSc patients and controls. Subgroup analyses revealed that patients with anticentromere antibodies (ACA+) had more plaques and more ischemic arterial events compared to other SSc patients (67% vs. 39% and 32% vs. 11%; P = 0.006 and P = 0.01, respectively) and compared to controls (67% vs. 41% and 32% vs. 7%, P = 0.02 and P = 0.0003, respectively). Biomarkers of inflammation/endothelial activation were generally increased among SSc patients. CONCLUSIONS: Patients with SSc are at enhanced risk for IHD and IPVD. The ACA+ SSc subgroup was particularly affected with both ischemic arterial events and premature atherosclerosis. The microvascular vulnerability of ACA+ patients is previously well documented. We demonstrate that ACA+ SSc patients have an enhanced risk of macrovascular injury as well. This group should be followed closely and modifiable cardiovascular risk factors should be treated at an early stage. PMID- 23945151 TI - Towards true unipolar ECG recording without the Wilson central terminal (preliminary results). AB - We present an innovative bio-potential front-end capable of recording true unipolar ECG leads for the first time without making use of the Wilson central terminal. In addition to the convenience in applications such as continuous monitoring and rapid diagnosis, the information in unipolar recordings may yield unique diagnostic information as it avoids the need to essentially subtract data or make use of the averaging effect imposed from the Wilson central terminal. The system also allows direct, real-time software calculation of signals corresponding to standard ECG leads which achieve correlations in excess of 92% with a gold standard ECG during a parallel in vivo recording. In addition, the implemented circuit is wideband (0.05-1000 Hz), compatible with standard (Ag/AgCl) bio-potential electrodes, and dry (paste-less) textile electrodes. The circuit is also low power, requiring less than 50 mW (when powered at 12 V) per standard ECG lead (two channels required). It is therefore well suited for wearable, long-term applications. PMID- 23945152 TI - Retraction: Luminal B tumors are the most frequent molecular subtype in breast cancer of North African women: an immunohistochemical profile study from Morocco. PMID- 23945153 TI - Accelerated uptake of VWF/platelet complexes in macrophages contributes to VWD type 2B-associated thrombocytopenia. AB - Von Willebrand disease (VWD) type 2B is characterized by mutations causing enhanced binding of von Willebrand factor (VWF) to platelets. Bleeding tendency is associated with heterogeneous clinical manifestations, including moderate to severe thrombocytopenia. The underlying mechanism of the thrombocytopenia has remained unclear. Here, a mouse model of VWD type 2B was used to investigate pathways contributing to thrombocytopenia. Immunohistochemical analysis of blood smears revealed that mutant VWF was exclusively detected on platelets of thrombocytopenic VWD type 2B mice, suggesting that thrombocytopenic VWD type 2B mice were elevated two- to threefold upon chemical macrophage depletion. Colocalization of platelets with CD68-positive Kupffer cells and CD168-positive marginal macrophages in liver and spleen, respectively, confirmed the involvement of macrophages in the removal of VWF/platelet complexes. Significantly more platelets were found in liver and spleen of VWD type 2B mice compared with control mice. Finally, platelet survival was significantly shorter in VWD type 2B mice compared with control mice, providing a rationale for lower platelet counts in VWD type 2B mice. In conclusion, our data indicate that VWF type 2B binds to platelets and that this is a signal for clearance by macrophages, which could contribute to the thrombocytopenia in patients with VWD type 2B. PMID- 23945154 TI - Closing the gap between T-cell life span estimates from stable isotope-labeling studies in mice and humans. AB - Quantitative knowledge of the turnover of different leukocyte populations is a key to our understanding of immune function in health and disease. Much progress has been made thanks to the introduction of stable isotope labeling, the state-of the-art technique for in vivo quantification of cellular life spans. Yet, even leukocyte life span estimates on the basis of stable isotope labeling can vary up to 10-fold among laboratories. We investigated whether these differences could be the result of variances in the length of the labeling period among studies. To this end, we performed deuterated water-labeling experiments in mice, in which only the length of label administration was varied. The resulting life span estimates were indeed dependent on the length of the labeling period when the data were analyzed using a commonly used single-exponential model. We show that multiexponential models provide the necessary tool to obtain life span estimates that are independent of the length of the labeling period. Use of a multiexponential model enabled us to reduce the gap between human T-cell life span estimates from 2 previously published labeling studies. This provides an important step toward unambiguous understanding of leukocyte turnover in health and disease. PMID- 23945155 TI - A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates. AB - Iron maldistribution has been implicated in the etiology of many diseases including the anemia of inflammation (AI), atherosclerosis, diabetes, and neurodegenerative disorders. Iron metabolism is controlled by hepcidin, a 25 amino-acid peptide. Hepcidin is induced by inflammation and causes iron to be sequestered within cells of the reticuloendothelial system, suppressing erythropoiesis and blunting the activity of erythropoiesis stimulating agents (ESAs). For this reason, neutralization of hepcidin has been proposed as a therapeutic treatment of AI. The aim of the current work was to generate fully human anti-hepcidin antibodies (Abs) as a potential human therapeutic for the treatment of AI and other iron maldistribution disorders. An enzyme-linked immunosorbent assay was established using these Abs to identify patients likely to benefit from either ESAs or anti-hepcidin agents. Using human hepcidin knock in mice, the mechanism of action of the Abs was shown to be due to an increase in available serum iron leading to enhanced red cell hemoglobinization. One of the Abs, 12B9m, was validated in a mouse model of AI and demonstrated to modulate serum iron in cynomolgus monkeys. The 12B9m Ab was deemed to be an appropriate candidate for use as a potential therapeutic to treat AI in patients with kidney disease or cancer. PMID- 23945156 TI - Antibody-secreting cell responses after Vibrio cholerae O1 infection and oral cholera vaccination in adults in Bangladesh. AB - Infection with Vibrio cholerae and oral cholera vaccines (OCVs) induce transient circulating plasmablast responses that peak within approximately 7 days after infection or vaccination. We previously demonstrated that plasmablast responses strongly correlate with subsequent levels of V. cholerae-specific duodenal antibodies up to 6 months after V. cholerae infection. Hence, plasmablast responses provide an early window into the immunologic memory at the mucosal surface. In this study, we characterized plasmablast responses following V. cholerae infection using a flow cytometrically defined population and compared V. cholerae-specific responses in adult patients with V. cholerae O1 infection and vaccinees who received the OCV Dukoral (Crucell Vaccines Canada). Among flow cytometrically sorted populations of gut-homing plasmablasts, almost 50% of the cells recognized either cholera toxin B subunit (CtxB) or V. cholerae O1 lipopolysaccharide (LPS). Using a traditional enzyme-linked immunosorbent spot assay (ELISPOT), we found that infection with V. cholerae O1 and OCVs induce similar responses to the protein antigen CtxB, but responses to LPS were diminished after OCV compared to those after natural V. cholerae infection. A second dose of OCV on day 14 failed to boost circulating V. cholerae-specific plasmablast responses in Bangladeshi adults. Our results differ from those in studies from areas where cholera is not endemic, in which a second vaccination on day 14 significantly boosts plasmablast responses. Given these results, it is likely that the optimal boosting strategies for OCVs differ significantly between areas where V. cholerae infection is endemic and those where it is not. PMID- 23945157 TI - Characterization and optimization of the glucan particle-based vaccine platform. AB - Glucan particles (GPs) are hollow porous Saccharomyces cerevisiae cell walls that are treated so that they are composed primarily of beta-1,3-d-glucans. Our previous studies showed that GPs can serve as an effective vaccine platform. Here, we characterize CD4(+) T-cell and antibody responses in immunized mice as a function of antigen (ovalbumin) encapsulation, antigen dose, particle numbers, time, immunization schedule, and trapping methods. Although we found that GPs served as an effective adjuvant when admixed with free antigens for IgG1 antibody production, stronger CD4(+) T-cell and IgG2c antibody responses were stimulated when antigens were encapsulated inside GPs, suggesting that the GP platform acts as both an adjuvant and a delivery system. Vigorous T-cell and antibody responses were stimulated even at submicrogram antigen doses, as long as the number of GPs was kept at 5 * 10(7) particles per immunization. One prime and one boost were sufficient to elicit robust immune responses. In addition, strong antigen specific antibody and T-cell responses prevailed up to 20 months following the last immunization, including those of gamma interferon (IFN-gamma), interleukin 17A (IL-17A), and dual IFN-gamma/IL-17A-secreting CD4(+) T cells. Finally, robust immune responses were observed using generally recognized as safe (GRAS) materials (alginate and calcium, with or without chitosan) to trap antigens within GPs. Thus, these studies demonstrate that antigens encapsulated into GPs make an effective vaccine platform that combines adjuvanticity and antigen delivery to elicit strong durable immune responses at relatively low antigen doses using translationally relevant formulations. PMID- 23945158 TI - Immunodetection of Fasciola gigantica circulating antigen in sera of infected individuals for laboratory diagnosis of human fascioliasis. AB - Currently, the laboratory diagnosis of human fascioliasis is based on the parasitological examination of parasite eggs in stool specimens and serological detection of specific antibodies in serum samples, which are often unreliable diagnostic approaches. Ideally, a sensitive and specific diagnostic test for Fasciola infection should be based on the detection of circulating Fasciola antigen, which implies active infection. Here, a 27-kDa-molecular-mass antigen was identified in a Fasciola gigantica adult worm antigen preparation, excretory secretory products, and sera from F. gigantica-infected individuals, and it was not detected in antigenic extracts of other parasites and sera from noninfected individuals. The target antigen was isolated and partially characterized as a protein. Immunoperoxidase staining located the target epitope within teguments and guts of F. gigantica adult worms. The performance characteristics of a newly developed enzyme-linked immunosorbent assay (ELISA) based on F. gigantica circulating antigen detection in serum (FgCA-27 ELISA) were investigated using sera of 120 parasitologically diagnosed F. gigantica-infected individuals and 80 noninfected individuals. The area under the receiving operating characteristic (ROC) curve (AUC) for ELISA was significantly high (AUC = 0.961, P < 0.0001) for discriminating Fasciola-infected and noninfected individuals. The developed assay showed high degrees of sensitivity, specificity, and efficiency (>93%), and a significant correlation (r = 0.715, P < 0.0001) between antigen level and parasite egg count was shown. In conclusion, a 27-kDa Fasciola antigen was identified in sera of F. gigantica-infected individuals. A highly sensitive and specific Fasciola antigen detection assay, FgCA-27 ELISA, was developed for laboratory diagnosis of human fascioliasis. PMID- 23945159 TI - Evaluation of the recombinant protein TpF1 of Treponema pallidum for serodiagnosis of syphilis. AB - Syphilis is a chronic infection caused by Treponema pallidum subsp. pallidum, and diagnosis with sensitive and specific methods is a challenging process that is important for its prevention and treatment. In the present study, we established a recombinant protein TpF1-based indirect immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) and a Western blot assay for human and rabbit sera. The 20-kDa recombinant protein TpF1 was detected by Western blotting performed with sera from rabbits immunized with recombinant TpF1 and infected with the T. pallidum Nichols strain and T. pallidum clinical isolates but was not detected by Western blotting with sera from uninfected rabbits. The sensitivity of the recombinant protein was determined by screening sera from individuals with primary, secondary, latent, and congenital syphilis (n = 82). The specificity of the recombinant protein was determined by screening sera from uninfected controls (n = 30) and individuals with potentially cross-reactive infections, including Lyme disease (n = 30) and leptospirosis (n = 5). The sensitivities of TpF1-based ELISAs were 93.3%, 100%, 100%, and 100% for primary, secondary, latent, and congenital syphilis, respectively, and the specificities were all 100% for sera from uninfected controls and individuals with potentially cross-reactive infections. In Western blot assays, the sensitivities and specificities of TpF1 for human sera were all 100%. The reactivities of TpF1 with syphilitic sera were proportional to the titers of the T. pallidum particle agglutination (TPPA) assay. These data indicate that the recombinant protein TpF1 is a highly immunogenic protein in human and rabbit infections and a promising marker for the screening of syphilis. PMID- 23945160 TI - Diagnostic value of cytokines and chemokines in lyme neuroborreliosis. AB - The aims of the present study were to assess the concentrations of different cytokines and chemokines in blood serum and cerebrospinal fluid (CSF) samples of patients with Lyme neuroborreliosis and to identify the possible marker(s) that would enable a distinction between clinically evident and suspected Lyme neuroborreliosis, as well as between Lyme neuroborreliosis and tick-borne encephalitis (TBE). Our additional interest was to evaluate the relationship between cytokine and chemokine concentrations and Borrelia burgdorferi sensu lato isolation from CSF, as well as intrathecal synthesis of specific borrelial antibodies. We found that higher concentrations of CXCL13 and lower concentrations of interleukin 10 (IL-10) in serum were associated with higher odds for clinically evident Lyme neuroborreliosis compared to suspected Lyme neuroborreliosis, as well as to TBE. The concentrations of IL-2, IL-5, IL-6, IL 10, and CXCL13 in the CSF were higher in patients with evident Lyme neuroborreliosis than in those who were only suspected to have the disease. A comparison of CSF cytokine and chemokine levels in patients with and without intrathecal synthesis of specific borrelial antibodies revealed that CXCL13 CSF concentration is significantly associated with intrathecal synthesis of borrelial antibodies. A comparison of the cytokine and chemokine CSF concentrations in patients with clinically evident Lyme neuroborreliosis according to CSF culture results revealed that higher concentrations of gamma interferon (IFN-gamma) were associated with lower odds of Borrelia isolation. Although several differences in the blood serum and CSF concentrations of various cytokines and chemokines between the groups were found, the distinctive power of the majority of these findings is low. Further research on well-defined groups of patients is needed to appraise the potential diagnostic usefulness of these concentrations. PMID- 23945161 TI - Seroepidemiologies of human metapneumovirus and respiratory syncytial virus in young children, determined with a new recombinant fusion protein enzyme-linked immunosorbent assay. AB - We compared antibodies against human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) in children. The antibody nadirs for both viruses were at 3 to 5 months, and the majority of children were seropositive for both by 2 years. There was no significant difference in the kinetics of maternal antibody decline or seroconversion relative to the two viruses. PMID- 23945162 TI - A prospective study of the importance of life goal characteristics and goal adjustment capacities in longer term psychosocial adjustment to lower limb amputation. AB - OBJECTIVE: To explore the life goal characteristics and goal adjustment capacities of persons with lower limb amputation on admission to rehabilitation, and to examine their efficacy as predictors of psychosocial outcomes six months post discharge. DESIGN: Prospective, descriptive. SETTING: Two specialist inpatient rehabilitation facilities in Ireland. SUBJECTS: A consecutive sample of 64 patients with lower limb amputation. MAIN MEASURES: On admission to rehabilitation, life goal characteristics (goal importance, goal disturbance) were assessed using the Goal Facilitation Index and goal adjustment capacities (goal disengagement, goal re-engagement) were measured using the Goal Adjustment Scale. The Beck Depression Inventory-II and the Trinity Amputation and Prosthesis Experience Scales-Revised assessed depressive symptomatology and psychosocial adjustment to amputation at six months post discharge. RESULTS: The highest average importance ratings were assigned to goals associated with interpersonal relationships, independence and subjective well-being. Goals related to physical limitations and disruptions in daily activities received the highest hindrance ratings. Goal importance (beta = -0.33) and goal disengagement (beta = -0.29) on admission significantly predicted depressive symptomatology six months post discharge (P <= 0.05). Goal importance (beta = 0.32), goal disturbance (beta = 0.26), and goal re-engagement (beta = -0.21) on admission significantly predicted general adjustment to lower limb amputation at six months post discharge (P <= 0.05), while goal importance (beta = -0.32) and goal disturbance (beta = 0.30) significantly predicted social adjustment (P <= 0.05). CONCLUSIONS: Life goal characteristics and goal adjustment capacities on admission to rehabilitation predicted psychosocial outcomes six months post discharge among individuals with lower limb amputation. PMID- 23945163 TI - The feasibility and validity of the comprehensive ICF core set for stroke in Chinese clinical settings. AB - OBJECTIVE: To inspect the feasibility and content validity of the comprehensive International Classification of Functioning, Disability and Health (ICF) core set for stroke by describing relevant aspects of functioning, disability and environmental factors affected in Chinese patients post stroke. DESIGN: Multicentre, cross-sectional study. SETTING: Department of rehabilitation medicine. SUBJECTS: The content validity was evaluated using frequency and percentage of 208 patients with a mean age of 60 years post stroke in China. OUTCOME MEASURES: Aspects of body function and structure, activity and participation, and environmental factors in the comprehensive ICF core set for stroke. RESULTS: Six ICF categories of body function were identified as a problem in over 90% (n = 187) of the patients (functions of the cardiovascular system and neuromusculoskeletal and movement-related functions). Impairments of brain, upper and lower extremity were identified as a problem in over 50% (n = 104) of the patients. Four ICF categories of activities and participation were documented as a problem in 100% (n = 208) of the patients (domestic and civic life). In environmental factors, nine ICF categories were documented as barriers by more than 10% (n = 20) and fewer than 50% (n = 104) of the patients (products and technology, physical geography, societal attitudes, services, systems and polices). Six ICF categories were identified as facilitators in over 90% (n = 187) of the patients (support and relationships and attitudes). CONCLUSION: The findings suggest that it is feasible to apply the comprehensive ICF core set for stroke in the Chinese clinical setting, after the appropriate reduction of some categories according to Chinese patients' characteristics and culture. PMID- 23945164 TI - Botulinum toxin injection into the forearm muscles for wrist and fingers spastic overactivity in adults with chronic stroke: a randomized controlled trial comparing three injection techniques. AB - OBJECTIVE: To compare the outcome of manual needle placement, electrical stimulation and ultrasonography-guided techniques for botulinum toxin injection into the forearm muscles of adults with arm spasticity. DESIGN: Randomized controlled trial. SETTING: University hospital. SUBJECTS: Sixty chronic stroke patients with wrist and fingers spasticity. INTERVENTION: After randomization into three groups, each patient received botulinum toxin type A in at least two of these muscles: flexor carpi radialis and ulnaris, flexor digitorum superficialis and profundus (no fascicles selection). The manual needle placement group underwent injections using palpation; the electrical stimulation group received injections with electrical stimulation guidance; the ultrasonography group was injected under sonographic guidance. A sole injector was used. MAIN MEASURES: All patients were evaluated at baseline and four weeks after injection. OUTCOMES: Modified Ashworth Scale; Tardieu Scale; wrist and fingers passive range of motion. RESULTS: One month after injection, Modified Ashworth Scale scores improved more in the electrical stimulation group than the manual needle placement group (wrist: P = 0.014; fingers: P = 0.011), as well as the Tardieu angle (wrist: P = 0.008; fingers: P = 0.015) and passive range of motion (wrist: P = 0.004). Furthermore, Modified Ashworth Scale scores improved more in the ultrasonography group than in the manual needle placement group (wrist: P = 0.001; fingers: P = 0.003), as well as the Tardieu angle (wrist: P = 0.010; fingers: P = 0.001) and passive range of motion (wrist: P < 0.001; proximal interphalangeal joints: P = 0.009). No difference was found between the ultrasonography and electrical stimulation groups. CONCLUSIONS: Instrumental guidance may improve the outcome of botulinum toxin injections into the spastic forearm muscles of stroke patients. PMID- 23945165 TI - Smoking increases the risk of pre- and postoperative complications in patients with pilonidal disease. AB - BACKGROUND: Smoking has a negative impact on the natural history and on treatment results of many dermatological conditions. However, there are no data demonstrating a similar effect in patients with pilonidal disease. PATIENTS AND METHODS: Consecutive patients undergoing surgery for pilonidal disease between 1/2004 and 3/2012 were analyzed retrospectively. Two surgical methods were used: a minimally invasive "pit-picking" surgery for smaller primary disease and Karydakis flap for patients presenting with larger primary disease or those who have been operated previously. The aim of the present study was to analyze the impact of smoking on the natural history and on treatment results. RESULTS: Six hundred and ten patients underwent 660 surgeries: 475 pit-picking operations and 185 Karydakis procedures. Smokers had developed a pilonidal abscess at least once during their disease significantly more often than non-smokers (48% vs. 26%, p = 0.00001). The recurrence rate following the pit-picking procedure was significantly increased in smokers (1-year recurrence rate: 36% vs. 21%, p = 0.008). After the Karydakis procedure, smokers developed more wound complications than non-smokers (29% vs. 10%, p = 0.005). The recurrence rate after the Karydakis flap was non-significantly increased in smokers (9% vs. 7% at 1 year, p = 0.07). CONCLUSIONS: Smoking has a detrimental effect on the natural history and on treatment results of pilonidal disease. Patients should be encouraged to cease smoking prior to pilonidal surgery. PMID- 23945167 TI - Microbial communities in the respiratory tract of patients with interstitial lung disease. AB - BACKGROUND: Molecular methods based on phylogenetic differences in the 16S rRNA gene are able to characterise the microbiota of the respiratory tract in health and disease. OBJECTIVES: Our goals were (1) to characterise bacterial communities in lower and upper airways of patients with interstitial lung disease (ILD) and (2) to compare the results with the microbiota of patients with Pneumocystis pneumonia (PCP) and normal controls. METHODS: We examined the upper and lower respiratory tract of 18 patients with ILD of whom 5, 6, and 7 had idiopathic interstitial pneumonia (IIP), non-IIP and sarcoidosis, respectively. In addition, six immune-compromised patients with PCP and nine healthy subjects were included as controls. Exclusion criteria were recent bacterial/viral respiratory tract infection, HIV-positivity and subjects receiving antibiotic therapy. Bronchoalveolar lavage fluid and oropharyngeal swabs were simultaneously collected, and microbiota was characterised by ultra-deep 16S rRNA gene sequencing. RESULTS: The microbiota in lower airways of the majority of patients (30; 90%) primarily consisted of Prevotellaceae, Streptococcaceae and Acidaminococcaceae. alpha and beta diversity measurements revealed no significant differences in airway microbiota composition between the five different groups of patients. Comparison of bacterial populations in upper and lower respiratory tract showed significant topographical discontinuities for 7 (23%) individuals. CONCLUSIONS: IIP, non-IIP and sarcoidosis are not associated with disordered airway microbiota and a pathogenic role of commensals in the disease process is therefore unlikely. Nevertheless, molecular analysis of the topographical microbiota continuity along the respiratory tract may provide additional information to assist management of individual patients. PMID- 23945168 TI - Pulmonary rehabilitation following hospitalisation for acute exacerbation of COPD: referrals, uptake and adherence. AB - RATIONALE: Several randomised controlled trials support the provision of early pulmonary rehabilitation (PR) following hospitalisation for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, there is little real world data regarding uptake, adherence and completion rates. METHODS: An audit was conducted to prospectively document referral, uptake, adherence and completion rates for early post-hospitalisation outpatient PR in Northwest London over a 12-month period. RESULTS: Out of 448 hospital discharges for AECOPD, 90 referrals for post-hospitalisation PR were received. Only 43 patients received and completed PR (9.6% of all hospital discharges) despite a fully commissioned PR service. CONCLUSIONS: Despite the strong evidence base, there are poor referral and uptake rates for early outpatient PR following hospitalisation for AECOPD, with only a small proportion of the intended target population receiving this intervention. PMID- 23945166 TI - Intraflagellar transport complex structure and cargo interactions. AB - Intraflagellar transport (IFT) is required for the assembly and maintenance of cilia, as well as the proper function of ciliary motility and signaling. IFT is powered by molecular motors that move along the axonemal microtubules, carrying large complexes of IFT proteins that travel together as so-called trains. IFT complexes likely function as adaptors that mediate interactions between anterograde/retrograde motors and ciliary cargoes, facilitating cargo transport between the base and tip of the cilium. Here, we provide an up-to-date review of IFT complex structure and architecture, and discuss how interactions with cargoes and motors may be achieved. PMID- 23945169 TI - Identification of unique interactions between the flexible linker and the RecA like domains of DEAD-box helicase Mss116. AB - DEAD-box RNA helicases are ATP-dependent proteins implicated in nearly all aspects of RNA metabolism. The yeast DEAD-box helicase Mss116 is unique in its functions of splicing group I and group II introns and activating mRNA translation, but the structural understanding of why it performs these unique functions remains unclear. Here we used sequence analysis and molecular dynamics simulation to identify residues in the flexible linker specific for yeast Mss116, potentially associated with its unique functions. We first identified residues that are 100% conserved in Mss116 of different species of the Saccharomycetaceae family. The amino acids of these conserved residues were then compared with the amino acids of the corresponding residue positions of other RNA helicases to identify residues that have distinct amino acids from other DEAD-box proteins. Four residues in the flexible linker, i.e. N334, E335, P336 and H339, are conserved and Mss116-specific. Molecular dynamics simulation was conducted for the wild-type Mss116 structure and mutant models to examine mutational effects of the linker on the conformational equilibrium. Relatively short MD simulation runs (within 20 ns) were enough for us to observe mutational effects, suggesting serious structural perturbations by these mutations. The mutation of E335 depletes the interactions between E335 and K95 in domain 1. The interactions between N334/P336 and N496/I497 of domain 2 are also abolished by mutation. Our results suggest that tight interactions between the Mss116-specific flexible linker and the two RecA-like domains may be mechanically required to crimp RNA for the unique RNA processes of yeast Mss116. PMID- 23945170 TI - Marine n-3 fatty acids in adipose tissue and development of atrial fibrillation: a Danish cohort study. AB - OBJECTIVE: Consumption of fish and marine n-3 polyunsaturated fatty acids (PUFA) may be associated with a lower risk of atrial fibrillation (AF), but results have been inconsistent. The aim was to investigate this further by measurements of marine n-3 PUFA in adipose tissue. DESIGN: Cohort study. SETTING: A total of 57 053 Danish participants 50-64 years of age were enrolled into the Diet, Cancer and Health Cohort Study. PATIENTS: A randomly drawn subcohort of 3440 participants with available data from baseline adipose tissue biopsies. INTERVENTIONS: Exposure was the adipose tissue content of marine n-3 PUFA, which reflects the endogenous exposure and is also an objective marker of the long-term dietary intake. MAIN OUTCOME MEASURES: Incident AF during follow-up. RESULTS: 179 cases of AF occurred over 13.6 years. Multivariate, sex-stratified Cox proportional hazards regression analyses using cubic splines showed a monotonic, negative, dose-response trend, but not statistically significant association, between total marine n-3 PUFA in adipose tissue and incident AF. A similar trend towards a lower risk of AF was seen in the second (HR 0.87, 95% CI 0.60 to 1.24) and third tertiles (HR 0.77, 95% CI 0.53 to 1.10) of marine n-3 PUFA compared with the lowest tertile. Similar trends, but also not statistically significant, were found separately for eicosapentaenoic, docosahexaenoic and docosapentaenoic acids. CONCLUSIONS: There was no statistically significant association between the content of marine n-3 PUFA in adipose tissue and the development of AF; however, data showed a monotonic, negative dose-response trend suggestive of a negative association. PMID- 23945171 TI - Role of FDG-PET/CT in diagnosis of aortitis caused by Takayasu arteritis and IgG4 related systemic disease--the author's reply. PMID- 23945172 TI - Almanac 2013: acute coronary syndromes. AB - Unstable coronary artery plaque is the most common underlying cause of acute coronary syndromes (ACS) and can manifest as unstable angina, non-ST segment elevation infarction (NSTE-ACS), and ST elevation myocardial infarction (STEMI), but can also manifest as sudden cardiac arrest due to ischaemia induced tachyarrhythmias. ACS mortality has decreased significantly over the last few years, especially from the more extreme manifestations of ACS, STEMI, and cardiac arrest. This trend is likely to continue based on recent therapeutic progress which includes novel antiplatelet agents such as prasugrel, ticagrelor, and cangrelor. PMID- 23945173 TI - Application of the COOP/WONCA charts to aged patients with chronic obstructive pulmonary disease: a comparison between Japanese and Chinese populations. AB - BACKGROUND: The prevalence of chronic obstructive pulmonary disease (COPD) is similar in Japan and China and is increasing due to high rates of smoking in these countries. Reducing COPD is an important public health issue. The goals of this study were to verify the reliability and validity of the Japanese version of the COOP/WONCA charts, a tool for measuring health status, and to examine the qualitative differences in health status between Japanese and Chinese patients with COPD and between these patients and healthy subjects. METHODS: From 2008 to 2011, we examined the factors affecting the health status of Japanese and Chinese populations living in six cities. Participants were patients with COPD staged according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (140 Japanese, 201 Chinese) and healthy subjects (243 Japanese, 199 Chinese), all 50 to 79 years old. Health status was measured by using the COOP/WONCA charts, and basic information such as smoking status and medical history was reported by the participants. RESULTS: The Japanese and Chinese versions of the COOP/WONCA charts were shown to be reliable and valid by test retest, comparison with the SF-36 and respiratory symptoms, and correlation of results obtained from patients and their physicians. Stepwise multiple regression analyses demonstrated that "Physical fitness", "Daily activities", and "Social activities" were predicted by COPD status and/or respiratory symptoms; "Feelings" by nationality and respiratory symptoms; "Pain" by sex and respiratory symptoms; and "Overall health" by nationality. When the COOP/WONCA scores were stratified by nationality, age, sex, and COPD status, the difference of each score between the patients and healthy subjects was larger for the Chinese subjects than for the Japanese. The physical, psychosocial activities, and pain scores increased significantly as COPD status worsened in Chinese subjects, whereas these scores were not affected by sex, age, or COPD status for Japanese subjects. Brinkman index and use of smoky fuel indoors affected the COOP/WONCA scores in Chinese patients but not in Japanese patients. CONCLUSIONS: The Japanese COOP/WONCA charts are reliable and valid. COPD more severely affected the health status of Chinese participants than of Japanese participants. These results suggest that countermeasures against insufficient health care and smoky environments may improve the health status of Chinese patients with COPD. PMID- 23945174 TI - Pharmacoeconomics of anterior ocular inflammatory disease. AB - PURPOSE OF REVIEW: Anterior ocular inflammatory disease (AOID) affects more that 40% of the U.S. population, which includes ocular allergies, various forms of infectious conjunctivitis, and dry eye diseases (tear film dysfunction). This review evaluates the recent economic costs of AOID treatment. RECENT FINDINGS: Rapid advances in pharmacotherapy of the anterior surface of the eye have been made as the expansion of the immunopathophysiology underlying these disorders ranging from the innate Toll-like receptors to the more specific IgE receptors are being unravelled. Even with these advances in AOID immunopathophysiology, progressive new treatments that address inflammatory mediators and their receptors with advancements in the development of ophthalmic remain limited. In 2011, AOID represents 40% of cost associated with ophthalmic drugs focusing on dry eye (31%), anti-infectives (30%), anti-allergics (25%), and anti-inflammatory agents (14%). With rising treatment costs, a need for cost-effective medicines remains to be pursued along with the development of treatment algorithms to maximize the therapeutic outcomes. SUMMARY: The economic burden of AOID has dramatically increased in recent years, with prescription drug expenditure approaching approximately $7 billion. There is an increasing need for major investment in this sector to improve outcomes as well as provide more effective alternative treatment modalities to the current options. PMID- 23945175 TI - Shared genetic determinants between eczema and other immune-related diseases. AB - PURPOSE OF REVIEW: Eczema and other allergic disorders are complex diseases caused by multiple genetic and environmental factors. Here, we review recent success in the identification of novel susceptibility loci for eczema. RECENT FINDINGS: Genome-wide association studies led to marked progress in unraveling the genetic determinants of allergic disorders. In the past 4 years, a total of 14 new eczema susceptibility loci have been identified and nearly all of them were successfully replicated. Seven additional eczema loci were recently identified by alternative strategies utilizing the remarkable overlap in the genetic cause of diverse immune-related traits. Apart from underlining the importance of the skin barrier in eczema, these studies point to specific immunological functions altered in eczema pathogenesis. SUMMARY: The new findings demonstrate that common pathways are involved in the development of eczema and other immune-related traits. Moreover, the genetic determinants shared between eczema, asthma, and allergic rhinitis should aid in resolving the molecular mechanisms triggering disease progression along the atopic march. The identification of the underlying genes and causal variants will be the major challenge for upcoming studies. PMID- 23945176 TI - Genome-wide expression quantitative trait loci analysis in asthma. AB - PURPOSE OF REVIEW: Expression quantitative trait loci (eQTL) mapping studies are the next most important step in genomics to identify susceptibility genes and molecular pathways involved in human diseases following the completion of genome wide association studies (GWAS). This article reviews the emerging concepts in genetics of gene expression and the empirical value of eQTL mapping to refine GWAS asthma susceptibility loci. RECENT FINDINGS: eQTL mapping studies were paramount to reveal the cis and trans control of gene expression, the cell type and tissue specificity of eQTLs, and the pleiotropic nature of eQTL single nucleotide polymorphisms. A small number of eQTL studies were recently performed in tissues and cell types that are relevant for asthma and are used to interpret the biology underpinning GWAS loci including the most robust asthma susceptibility locus on 17q21. SUMMARY: The full potential of eQTL mapping studies is just starting to be revealed. Imminent progress is expected owing to the accelerating advances in sequencing technologies to map genetic variants and transcriptomes as well as the development of bioinformatics and computational algorithms to exploit integrative genomic approaches. A short-term challenge in the field of asthma is the creation of well powered eQTL datasets testing gene expression and other molecular phenotypes in disease-relevant tissues. PMID- 23945177 TI - Environmental and genetic contribution in airway epithelial barrier in asthma pathogenesis. AB - PURPOSE OF REVIEW: To examine the recent, most relevant genetic and epigenetic modifications of the epithelial barrier in response to the environmental factors, including allergens, viruses, and pollutants, susceptible to participate to asthma. RECENT FINDINGS: IL-33 and TSLP gene polymorphisms are found in almost all asthma studies. Recent data have highlighted a new population of innate lymphoid cells, activated by these two cytokines, and mediating type 2 innate immunity dependent asthma. Gene variants of innate pattern recognition receptors associated with asthma have been evidenced in early viral infected high-risk birth cohorts, as well as polymorphisms in pathways involved in type I interferon (IFN) production, giving further insight into the role of viruses in asthma development. Novel epigenetic mechanisms have been evidenced in asthma and in response to the environmental pollutants, and point out genes like TSLP, which may link environmental pollution and asthma. SUMMARY: Genetic data support the role of a specific set of epithelial-derived proTh2 cytokines, including IL-33 and TSLP, as well as the role of decreased type I IFN in virus-induced impaired epithelial barrier. Epigenetic modifications of epithelial genes are promising mechanisms that warrant further investigation. PMID- 23945178 TI - Genome-wide association studies in asthma; perhaps, the end of the beginning. AB - PURPOSE OF REVIEW: A large number of genetic loci contribute towards an individual's susceptibility to asthma and other complex diseases. Genome-wide association studies (GWASs) have provided us with a wealth of loci associated with asthma susceptibility, asthma endotypes and responsiveness to asthma medications. The reproducibility of these genetic loci across different studies highlights the interplay of general and population-specific risk alleles in asthma. Although GWASs have been successful in identifying disease-associated loci, there is still large potential for such studies to provide further insights into asthma pathogenesis. RECENT FINDINGS: GWASs over the past year have extended study design well beyond the simple case-control and continuous phenotype association formats, for example, including interactions with environmental factors, integrating GWAS data with epigenetic data and GWASs in animal models, incorporating pathway analyses and utilising emerging sequencing technologies. SUMMARY: Moving beyond traditional GWAS formats is likely to significantly enhance our understanding of the genetic basis for asthma. This review discusses where we are after half a decade of asthma GWASs, and focuses on advances over the past year that show where the GWAS field is headed in the future. PMID- 23945179 TI - A systematic review of the psychological and social benefits of participation in sport for children and adolescents: informing development of a conceptual model of health through sport. AB - BACKGROUND: There are specific guidelines regarding the level of physical activity (PA) required to provide health benefits. However, the research underpinning these PA guidelines does not address the element of social health. Furthermore, there is insufficient evidence about the levels or types of PA associated specifically with psychological health. This paper first presents the results of a systematic review of the psychological and social health benefits of participation in sport by children and adolescents. Secondly, the information arising from the systematic review has been used to develop a conceptual model. METHODS: A systematic review of 14 electronic databases was conducted in June 2012, and studies published since 1990 were considered for inclusion. Studies that addressed mental and/or social health benefits from participation in sport were included. RESULTS: A total of 3668 publications were initially identified, of which 30 met the selection criteria. There were many different psychological and social health benefits reported, with the most commonly being improved self esteem, social interaction followed by fewer depressive symptoms. Sport may be associated with improved psychosocial health above and beyond improvements attributable to participation in PA. Specifically, team sport seems to be associated with improved health outcomes compared to individual activities, due to the social nature of the participation. A conceptual model, Health through Sport, is proposed. The model depicts the relationship between psychological, psychosocial and social health domains, and their positive associations with sport participation, as reported in the literature. However, it is acknowledged that the capacity to determine the existence and direction of causal links between participation and health is limited by the fact that the majority of studies identified (n=21) were cross-sectional. CONCLUSION: It is recommended that community sport participation is advocated as a form of leisure time PA for children and adolescents, in an effort to not only improve physical health in relation to such matters as the obesity crisis, but also to enhance psychological and social health outcomes. It is also recommended that the causal link between participation in sport and psychosocial health be further investigated and the conceptual model of Health through Sport tested. PMID- 23945180 TI - Why do old flies die? PMID- 23945182 TI - The increasing weight of Crohn's disease subjects in clinical trials: a hypothesis-generatings time-trend analysis. AB - BACKGROUND: The incidence of obesity is increasing worldwide. Recent evidence shows that the incidence of Crohn's disease (CD) is increasing as well. Adipocytes release a variety of proinflammatory cytokines and peptides. Visceral adiposity may play an important role in the initiation and perpetuation of inflammation in CD. We report on an analysis of body weight in CD clinical trials between 1991 and 2008. METHODS: MEDLINE-based databases were searched for randomized controlled trials pertaining to CD. A time-trend analysis was carried out to investigate changes in weight and disease activity over time. Potential correlation between subject weight and clinical activity was studied. RESULTS: Forty randomized controlled trials involving a total of 10,282 patients with CD conducted between 1991 and 2008 were included. No significant change in gender distribution was noted throughout the follow-up. A significant increase in weight (r = 0.360; 95% confidence interval [CI]: 0.4556-0.8813) and body mass index (r = 0.1431; 95% CI: 0.02628-0.2272) was observed over the time period. Study subjects demonstrated a significant increase in clinical disease activity as measured by the Crohn's disease activity index (r = 0.1092; 95% CI: 2.101-9.087) and disease duration (r = 0.06340; 95% CI: 0.02421-0.2530) over the same time period. CONCLUSIONS: We demonstrate increasing body weight over time from 1991 to 2008 in CD as evidenced by baseline data from randomized clinical trials. Adiposity may play a potential role in initiating and perpetuating intestinal inflammation, a hypothesis that should be explored further. PMID- 23945181 TI - The antimicrobial lysine-peptoid hybrid LP5 inhibits DNA replication and induces the SOS response in Staphylococcus aureus. AB - BACKGROUND: The increase in antibiotic resistant bacteria has led to renewed interest in development of alternative antimicrobial compounds such as antimicrobial peptides (AMPs), either naturally-occurring or synthetically derived. Knowledge of the mode of action (MOA) of synthetic compounds mimicking the function of AMPs is highly valuable both when developing new types of antimicrobials and when predicting resistance development. Despite many functional studies of AMPs, only a few of the synthetic peptides have been studied in detail. RESULTS: We investigated the MOA of the lysine-peptoid hybrid, LP5, which previously has been shown to display antimicrobial activity against Staphylococcus aureus. At concentrations of LP5 above the minimal inhibitory concentration (MIC), the peptoid caused ATP leakage from bacterial cells. However, at concentrations close to the MIC, LP5 inhibited the growth of S. aureus without ATP leakage. Instead, LP5 bound DNA and inhibited macromolecular synthesis. The binding to DNA also led to inhibition of DNA gyrase and topoisomerase IV and caused induction of the SOS response. CONCLUSIONS: Our data demonstrate that LP5 may have a dual mode of action against S. aureus. At MIC concentrations, LP5 binds DNA and inhibits macromolecular synthesis and growth, whereas at concentrations above the MIC, LP5 targets the bacterial membrane leading to disruption of the membrane. These results add new information about the MOA of a new synthetic AMP and aid in the future design of synthetic peptides with increased therapeutic potential. PMID- 23945183 TI - Stable incidence of collagenous colitis and lymphocytic colitis in Orebro, Sweden, 1999-2008: a continuous epidemiologic study. AB - BACKGROUND: The incidence of microscopic colitis (MC) has increased in several centers, but long-term epidemiologic data are missing. We report an epidemiologic study of collagenous colitis (CC) and lymphocytic colitis (LC) during 1999-2008, as a follow-up of our previous studies 1984-1998. METHODS: Population-based study of residents of the catchment area of the hospital, with a new diagnosis of MC between 1999 and 2008. Patients were identified by diagnosis registers of the Departments of Medicine and Pathology. Medical files were reviewed, and colonic biopsies were reevaluated. RESULTS: Collagenous colitis was diagnosed in 96 patients (75 females) and LC in 90 patients (74 females). The mean annual age standardized incidence (per 100,000 inhabitants) was MC 10.2 (95% confidence interval: 8.7-11.7), CC 5.2 (4.2-6.3), and LC 5.0 (4.0-6.0). Age-specific incidence showed a peak in females older than 70 years. Prevalence (per 100,000 inhabitants) on December 31, 2008, was MC 123 (107.6-140.0), CC 67.7 (56.4-80.6), and LC 55.3 (45.2-67.1). A comparison of current study period with 1993-1998 showed unchanged mean incidence of MC, but a 2-fold increase in women older than 60 years with LC (standardized rate ratios 2.2, [1.2-3.7]) and increased female to male ratio (4.6:1 versus 2.1:1; P = 0.02) in LC. CONCLUSIONS: After an initial rise during 1980s and early 1990s, annual incidence of CC and LC has been stable during the last 15 years around 5/100,000 inhabitants for each disorder. The increasing incidence in older women with LC may be related to an increasing proportion of older individuals in the background population and increased colonoscopy frequency in elderly. PMID- 23945184 TI - Cost-effectiveness of QuantiFERON testing before initiation of biological therapy in inflammatory bowel disease. AB - BACKGROUND: Anti-tumor necrosis factor alpha drugs are known to reactivate latent tuberculosis (TB). Current guidelines recommend screening for latent tuberculosis infection, with either tuberculin skin test (TST) or interferon gamma release assays such as QuantiFERON-TB Gold (QFT-G). Given the high rates of anergy to TST among immunosuppressed inflammatory bowel disease (IBD) patients, there is considerable interest in evaluating the superiority of interferon gamma release assays over TST in this patient population to diagnose latent tuberculosis infection. We compared the performance of TST and QFT-G for screening latent TB among immunosuppressed IBD patients based on prevalence, mortality risk from reactivation TB, and costs. METHODS: A decision analytical model was constructed to compare 1-year outcomes and costs of using TST or interferon gamma release assay in an immunosuppressed IBD population. RESULTS: Under the base case scenario, for every 1000 patients screened, the QFT-G strategy resulted in 0.53 deaths from reactivation TB compared with 1.92 deaths using TST. The QFT-G strategy results in 1.85 reactivation TB versus 6.7 reactivation TB using TST. The model was not sensitive to background prevalence of latent TB. The cost of QFT-G would have to be more than double for the TST strategy to become more cost effective. QFT-G also remains the cost-effective option unless the sensitivity of the TST improves by 400%. CONCLUSIONS: Under a broad range of parameter values, the QFT-G strategy dominates the TST strategy in cost-effectiveness. Consideration should be given to QFT-G as the preferred method of identifying latent TB in all immunosuppressed IBD patients. PMID- 23945185 TI - Serum m 30 levels reflects ulcerative colitis activity. AB - BACKGROUND: Apoptosis plays a role in epithelial and mucosal injury, which is 1 of the mechanisms in the pathogenesis of ulcerative colitis. Apoptotic cells increase as a result of injured mucosa in ulcerative colitis and serum M 30 levels increase in epithelial cell apoptosis. In this study, we aimed to evaluate the relation between M 30 serum levels and ulcerative colitis activity. METHODS: Eighty patients with ulcerative colitis and 40 healthy controls were enrolled into the study. The patient group consisted of 31 extensive colitis, 30 left sided colitis, and 19 proctitis. The activity of ulcerative colitis was determined with clinical and endoscopic findings. Serum M 30 levels, acute phase reactants, and biochemical tests were analyzed in all subjects. RESULTS: Serum M 30 levels in patients with active ulcerative colitis were significantly higher when compared with the healthy controls (165.6 +/- 60.6 and 129.6 +/- 37.4; P = 0.003). Serum M 30 levels in active left-sided colitis patients was significantly higher when compared with patients in remission phase (180.6 +/- 58.5, 141.5 +/- 35.4; P = 0.044). When we exclude patients with ulcerative proctitis, M 30 levels in active ulcerative colitis patients were significantly higher than that the patients in remission phase (174.0 +/- 63.5, 135.0 +/- 29.9; P = 0.017). CONCLUSIONS: We found that M 30 levels increase in patients with active ulcerative colitis. Our findings support the role of apoptosis demonstrated by serum M 30 levels in the pathogenesis of active ulcerative colitis. PMID- 23945186 TI - Assessment of the relationship between quality of sleep and disease activity in inflammatory bowel disease patients. AB - PURPOSE: Poor sleep quality is associated with adverse health consequences. Sleep disturbances can impact the immune function and process of inflammation. The relationship between sleep quality and the inflammatory bowel disease (IBD) has not been well studied. METHODS: A prospective observational cohort study was performed to assess the correlation of the quality of sleep and disease activity in IBD. We used the Pittsburgh Sleep Quality Index (PSQI) to measure sleep quality. IBD disease activity was measured by using the Harvey-Bradshaw Index or Modified Mayo Score. RESULTS: Forty-one patients were enrolled with mean age of 37 +/- 15.4 years and 27 (66%) women. Abnormal PSQI was present in all 23 (100%) of the clinically active patients and in 13 (72%) of those with inactive disease (odds ratio = 2.8, P = 0.007). All 30 patients with histologic evidence of inflammation on recent ileocolonoscopy also had abnormal PSQI scores, which were independent of their clinical disease activity status. Only 6 of 11 patients with histologically quiescent disease had abnormal PSQI scores (odds ratio = 6.0, P < 0.0001). There was no difference in disease type, use of steroids, the presence of depression or anxiety, and body mass index between the patients with normal and abnormal sleep. An abnormal PSQI had a positive predictive value for histologic inflammatory activity of 83%. CONCLUSIONS: Our data show a strong association between clinically active IBD and poor sleep quality and demonstrate that patients in clinical remission with abnormal sleep have a high likelihood of subclinical disease activity. PMID- 23945187 TI - Management of fertility and pregnancy in women with inflammatory bowel disease: a practical guide. PMID- 23945188 TI - Acceptability and impact on anthropometry of a locally developed ready-to-use therapeutic food in pre-school children in Vietnam. AB - BACKGROUND: In South East Asia, concerns exist about the acceptability of peanut based Ready-to-Use-Therapeutic-Foods (RUTF) for the treatment of severe acute malnutrition (SAM). Therefore, an alternative, culturally acceptable RUTF made from locally available ingredients and complying with local food traditions and preferences was developed. The current study evaluated its acceptability and impact on anthropometry. METHODS: The study was a randomized, two-arm, cross-over intervention trial to test the acceptability of the local product (bar) against a commercially available, peanut-based RUTF paste (Plumpy'nut(r)). Children (n = 67) from two kindergartens in a rural area of North Vietnam were recruited. The age of the children was between 3 and 5 years. RESULTS: The Vietnamese RUTF was well-accepted, although overall acceptability was less than of Plumpy'nut(r), with the latter scoring higher on palatability (P < 0.05). In contrast, reluctance to eat Plumpy'nut(r) was higher than for the Vietnamese RUTF (P < 0.05). Impact on anthropmetrical indices was similar for both RUTF. The nutritional status of the children who consumed the two RUTF over a 4 week period improved significantly, with a mean weight gain of 0.64 (SD 0.27) Kg, and increases in WHZ and HAZ z-scores of 0.48 (SD 0.30) and 0.05 (SD 0.13) respectively (P < 0.01 both). Weight gain was similar between the 2 products (0.32 kg per 2 weeks for both). CONCLUSIONS: Both the commercial Plumpy'nut(r) and the local produced RUTF were accepted although the harder consistency of the local product might have caused the lower overall acceptance. The promising increase in nutritional status needs to be confirmed in a controlled trial in children with SAM. PMID- 23945189 TI - Bacteriological pathogen spectrum of chronic leg ulcers: Results of a multicenter trial in dermatologic wound care centers differentiated by regions. AB - BACKGROUND: In almost every chronic wound different bacteria species can be detected. PATIENTS AND METHODS: Retrospective, multicenter evaluation of bacterial swab results from 2010 and 2011 in patients with chronic leg ulcer treated in 10 dermatologic wound care centers from 5 regions in Germany. RESULTS: Data of 970 patients were analyzed. Staphylococcus aureus was detected in 47.6 % of the patients, 8.6% of these were methicillin-resistant (MRSA). Pseudomonas aeruginosa was found in 31.1 %, enterobacteria in 28.6 % and Proteus mirabilis in 13.7 % of the patients. The regional comparison showed a significant south-north gradient for S. aureus, P. aeruginosa, and enterobacteria. Moreover, a highly significant west-east gradient for MRSA was found with detection rates of 13.5 % in the west to 4.0 % in the east. Furthermore, nationally there was a significant negative correlation between S. aureus and P. aeruginosa or P. mirabilis, respectively, as well as a positive correlation of P. aeruginosa with respect to wound size and duration. In addition to climatic and therapeutic conditions, different regional health care structures are discussed as potentially relevant reasons for these significantly different regional detection rates. CONCLUSIONS: Our data show the regional variability of the spectrum of currently detected bacteria in patients with chronic leg ulcers in Germany. PMID- 23945193 TI - Learning, memory and brain plasticity in posttraumatic stress disorder: context matters. AB - We review evidence from our laboratory that suggests that in addition to enhanced cue conditioning and delayed cue extinction disturbed contextual learning may play an important role in the development and maintenance of posttraumatic stress disorder. Based on data from a longitudinal sample of rescue workers at high risk for posttraumatic stress disorder and data on single trauma exposed persons with and without posttraumatic stress disorder we show the crucial role of the hippocampus for contextual memory and impaired contextual learning along with enhanced cue conditioning and delayed extinction in PTSD. Using structural and functional magnetic resonance imaging we confirmed animal data on the role of the hippocampus in contextual and the importance of the amygdala in cue conditioning and the role of the frontal cortex in extinction. Genetic variants related to the modulation of the hypothalamus-pituitary-adrenal axis are associated with cue and genetic variants related to calcium signaling and memory processes and the regulation of the stress response are associated with context conditioning. These genes also play a role in PTSD. Further research needs to identify the predictive nature of these learning processes and plastic brain changes and their interaction with genetic characteristics changes for the transition into PTSD and its maintenance. A further focus needs to be on the identification of learning and memory mechanisms and the associated brain plasticity across disorders. PMID- 23945194 TI - Metabolic changes in psoriatic skin under topical corticosteroid treatment. AB - BACKGROUND: MR spectroscopy of intact biopsies can provide a metabolic snapshot of the investigated tissue. The aim of the present study was to explore the metabolic pattern of uninvolved skin, psoriatic skin and corticosteroid treated psoriatic skin. METHODS: The three types of skin biopsy samples were excised from patients with psoriasis (N = 10). Lesions were evaluated clinically, and tissue biopsies were excised and analyzed by one-dimensional 1H MR spectroscopy. Relative levels were calculated for nine tissue metabolites. Subsequently, relative amounts of epidermis, dermis and subcutaneous tissue were scored by histopathological evaluation of HES stained sections. RESULTS: Seven out of 10 patients experienced at least 40% reduction in clinical score after corticosteroid treatment. Tissue biopsies from psoriatic skin contained lower levels of the metabolites myo-inositol and glucose, and higher levels of choline and taurine compared to uninvolved skin. In corticosteroid treated psoriatic skin, tissue levels of glucose, myo-inositol, GPC and glycine were increased, whereas choline was reduced, in patients with good therapeutic effect. These tissue levels are becoming more similar to metabolite levels in uninvolved skin. CONCLUSION: This MR method demonstrates that metabolism in psoriatic skin becomes similar to that of uninvolved skin after effective corticosteroid treatment. MR profiling of skin lesions reflect metabolic alterations related to pathogenesis and treatment effects. PMID- 23945195 TI - The load dependence of the physical properties of a molecular motor. AB - The physical properties of a molecular motor with load changing in a wide range will be discussed in this study, in particular the mean velocity, output power and energy efficiency. The main difficulty of this study is that both the states of the molecular motor and the energy barriers between them change with the loading force. Moreover, with the change of load, the number of motor states may also change, so different models should be used to calculate the corresponding physical quantities in different ranges of load. The results show that, in contrast to the usual intuition, the mean velocity and output power of the molecular motor do not change continuously with load. PMID- 23945196 TI - Botanical identification of medicinal roots collected and traded in Morocco and comparison to the existing literature. AB - BACKGROUND: A literature review revealed heavy reliance on a few key publications for identification of medicinal plant species from local or vernacular names and a lack of citation of voucher specimens in many publications. There is a need for more reliable and standardized data on the identity of species used for medicine, especially because local names vary from region to region. This is especially true in the case of medicinal roots, for which identification of species is difficult. This paper contributes to existing data on the species sold as medicinal roots (and other underground plant parts such as bulbs, corms, rhizomes and tubers) in Morocco. METHODS: Data were collected in collaboration with herbalists in Marrakech and collectors in rural regions near Marrakech where species are collected from the wild. The ethno-medicinal uses of these species were also recorded. RESULTS: We identified the vernacular names for 67 medicinal roots (by free listing) used to treat a variety of human diseases. We were able to collect and identify one or more species for 39 of the recorded vernacular names. The ones we were not able to identify were either imported or no longer available in the markets. We collected more than one species for some of the vernacular names for a total of 43 species. We identified six new vernacular names and four species which had not been previously described in the literature. Our botanical identification matched at least one of the names listed in the literature 63% of the time and did not match any species listed in the literature 37% of the time. Of the three most commonly cited pieces of literature we compared to, we found the greatest overlap with the broader, more comprehensive work of Bellakhdar 1997 (as opposed to Benchaabane and Abbad 1997 which worked in a similarly focused geographical area). However there was only 63% agreement between Bellakhdar 1997 and our botanical identifications, and 29% of the time our identification didn't match even the genus of any of the species listed in any of the 3 most commonly cited pieces of literature. CONCLUSIONS: More rigorous methodology and reporting are needed for medicinal plant research in Morocco. This will ensure that studies are comparable, help to protect traditional medicine users from negative health effects, and, support efforts to conserve overharvested wild medicinal plants. PMID- 23945198 TI - The new technological trends in ultrasound-guided regional anesthesia. AB - PURPOSE OF REVIEW: Real-time two-dimensional ultrasound guidance is undoubtedly one of the most important evolutions in the field of regional anesthesia techniques, for peripheral nerve blocks and neuraxial anesthesia. The recent literature has been analyzed for studies concerning new technological trends in ultrasound-guided regional anesthesia. This review focuses on electromagnetic tracking systems for ultrasound guidance and three/four-dimensional ultrasound imaging in regional anesthesia. RECENT FINDINGS: Electromagnetic tracking can facilitate needle-beam alignment for in-plane approaches and indicates where the needle crosses the beam during out-of-plane ultrasound-guided procedures. Three dimensional ultrasound imaging can provide more detailed anatomical information and better spatial orientation than two-dimensional imaging. Four-dimensional ultrasound imaging enhances the visualization of a particular anatomy and offers real-time assessment of local anesthetic spread during ultrasound-guided regional anesthesia. These techniques have some limitations and drawbacks limiting their expansion. SUMMARY: This article describes the principles, technology and development of electromagnetic tracking system for ultrasound guidance and three/four-dimensional ultrasound imaging in regional anesthesia, considering whether these new technologies will have impending applications in clinical practice. PMID- 23945197 TI - Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study. AB - INTRODUCTION: Use of colistin methanesulfonate (CMS) was abandoned in the 1970s because of excessive nephrotoxicity, but it has been reintroduced as a last resort treatment for extensively drug-resistant infections caused by gram negative bacteria (Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumonia). We conducted a retrospective cohort study to evaluate risk factors for new-onset acute kidney injury (AKI) in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics. METHODS: The cohort consisted of 279 adults admitted to two general ICUs in teaching hospitals between 1 April 2009 and 30 June 2011 with 1) no evidence on admission of acute or chronic kidney disease; and 2) treatment for more than seven days with CMS and/or other nephrotoxic antimicrobials (NAs, that is, aminoglycosides, glycopeptides). Logistic regression analysis was used to identify risk factors associated with this outcome. RESULTS: The 279 cases that met the inclusion criteria included 147 patients treated with CMS, alone (n = 90) or with NAs (n = 57), and 132 treated with NAs alone. The 111 (40%) who developed AKI were significantly older and had significantly higher Simplified Acute Physiology Score II (SAPS II) scores than those who did not develop AKI, but rates of hypertension, diabetes mellitus and congestive heart failure were similar in the two groups. The final logistic regression model showed that in the 147 patients who received CMS alone or with NAs, onset of AKI during the ICU stay was associated with septic shock and with SAPS II scores >=43. Similar results were obtained in the 222 patients treated with CMS alone or NAs alone. CONCLUSIONS: In severely ill ICU patients without pre-existing renal disease who receive CMS high-dose for more than seven days, CMS therapy does not appear to be a risk factor for this outcome. Instead, the development of AKI was strongly correlated with the presence of septic shock and with the severity of the patients as reflected by the SAPS II score. PMID- 23945199 TI - Body mass index and prognosis of metastatic breast cancer patients receiving first-line chemotherapy. AB - BACKGROUND: The effect of body mass index (BMI) on the prognosis of metastatic breast cancer (MBC) has not been explored so far. METHODS: The relationship between BMI (kg/m(2)) and progression-free survival (PFS) or overall survival (OS) was assessed in 489 patients with MBC enrolled in three clinical trials of first-line chemotherapy. World Health Organization BMI categories were used: normal, 18.5-24.9 kg/m(2); overweight, 25-29.9 kg/m(2); and obese, 30+ kg/m(2). Univariate PFS and OS curves were estimated; multivariate Cox analysis was conducted adjusting for age, menopausal status, performance status (PS), hormonal status and site, and number of metastases. RESULTS: Overall, 39.9% of the patients were normal or underweight, 37.8% were overweight, and 22.3% were obese. Median age was 57 years (range 25-73); median PS was 0. Median PFS was 10.9 months [interquartile range (IQR) 5.5 to 19.9] in normal weight women, 13.0 months (IQR 7.8 to 23.7) in overweight, and 12.2 (IQR 7.1 to 23.0) in obese women, P = 0.17. Median OS was 32.0 months [95% confidence interval (CI), 14.5 88.3] versus 33.2 months (95% CI, 19.4-81.1) and 30.7 (95% CI, 17.6-50.8), respectively. In multivariate analyses, no statistically significant association between BMI category and PFS or OS was observed. CONCLUSIONS: In this study, BMI was not associated with the outcome of patients with MBC treated with first-line chemotherapy. IMPACT: In the absence of any evidence in support of a prognostic role of obesity in patients with MBC treated with chemotherapy, dietary restrictions, medical interventions aimed at reducing BMI/insulin resistance, or specific anticancer treatment strategies do not seem to be appropriate. PMID- 23945201 TI - Targeting redox biology to reverse mitochondrial dysfunction. PMID- 23945200 TI - Impact of baseline and nadir neutrophil index in non-small cell lung cancer and ovarian cancer patients: Assessment of chemotherapy for resolution of unfavourable neutrophilia. AB - BACKGROUND: Chronic inflammation has been recognized to foster tumour development. Whether chemotherapy can be used to neutralize chronic inflammation is unclear. METHODS: We evaluated baseline and nadir neutrophils in 111 patients (pts.) with non-small cell lung cancer (NSCLC) and 118 pts. with ovarian cancer (OC) treated with chemotherapy administered with dose-individualization to achieve nadir neutropenia of 1.5. We used predefined baseline neutrophil cut-offs 4.5 * 109/L (NSCLC) and 3.9 * 109/L (OC). RESULTS: Absence of chemotherapy induced nadir neutropenia (CTCAE grade 0, neutrophils >= LLN) was seen in 23% of OC and 25% of NSCLC pts. Absence of nadir neutropenia was associated with decreased overall survival (OS) compared with presence (>grade 0) of neutropenia (9 vs. 14 months, P=0.004 for NSCLC and 23 vs. 56 months; P=0.01 for OC). Obtaining grade 3/4 neutropenia did not improve survival compared with grade 1/2 neutropenia. In multivariate analyses, baseline neutrophils >= 4.5 * 109/L (HR: 2.0; 95% CI: 1.11-3.44;P = 0.02) and absence of nadir neutropenia (HR: 1.6; 95% CI: 1.02-2.65;P = 0.04) for NSCLC and absence of nadir neutropenia (HR: 1.7; 95% CI: 1.04;2.93;P = 0.04) for OC were independently associated with short OS. CONCLUSIONS: A neutrophil index comprising elevated baseline neutrophils and absence of neutropenia identified a high risk group of NSCLC and ovarian cancer patients with only modest effect of chemotherapy. New treatment options for this subset of patients are required. PMID- 23945202 TI - Treatment approach and outcomes of vaginal melanoma. AB - OBJECTIVE: To describe the characteristics of primary vaginal melanoma patients in the Surveillance, Epidemiology, and End Result database and to determine the outcome from the treatment approaches. MATERIALS/METHODS: From the Surveillance, Epidemiology, and End Result registry, 201 patients with vaginal melanoma were identified. Patients' characteristics and prognostic factors including age, race, extent of surgery, and use of radiation therapy were obtained. RESULTS: The median age was 68 years (range, 28-100 years). The population was 73% white, 11% black, and 16% Asian/American Indian. International Federation of Gynecology and Obstetrics staging results were stage I (46%), stage II (18%), stage III (3%), stage IVA (3%), stage IVB (12%), and unknown (18%). Treatment approach included surgical resection of the primary site in 70%, whereas 35% of the patients underwent lymph node resection. Approximately 40% of the patients received radiotherapy, which was primarily used in the adjuvant setting. Overall survival at 2 and 5 years was 24% and 15%, respectively. Presence of lymph nodes at diagnosis was associated with worse overall survival (hazard ratio, 1.98; P = 0.02). Adjuvant radiation did not offer a statistically significant overall survival advantage compared to surgery alone. CONCLUSIONS: Vaginal melanoma is a rare diagnosis primarily affecting the elderly. Overall survival is low even for patients presenting with disease limited to the vagina. Lymph node involvement at diagnosis is strongly predictive of worse overall survival. Most patients are treated with surgical resection with varying use of adjuvant radiotherapy. Further research is needed to identify the etiology and improve the outcome of this aggressive disease. PMID- 23945204 TI - Editorial for special issue on neurodynamics. AB - "Neurodynamics" is an interdisciplinary area of mathematics where dynamical systems theory (deterministic and stochastic) is the primary tool for elucidating the fundamental mechanisms responsible for the behaviour of neural systems (whether biological or synthetic). A meeting on this topic was held at the International Centre for Mathematical Sciences in Edinburgh from March 5-7 in 2012. In this special issue, we have invited seven of the main contributors to this event to expand on their presentations and highlight the use of mathematics in understanding the dynamics of neural systems. PMID- 23945203 TI - Diagnostic performance of fluorine-18-fluorodeoxyglucose positron emission tomography imaging in uterine sarcomas: systematic review and meta-analysis of the literature. AB - OBJECTIVE: We reviewed the medical literature on the application of fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) imaging in the management of uterine sarcomas and presented the results in systematic review and meta-analysis format. METHODS: Medline, SCOPUS, and ISI Web of Knowledge were searched electronically with "PET AND (Uterine OR Uterus)" as key words. All studies evaluating the accuracy of (18)F-FDG imaging in the staging or restaging of uterine sarcomas were included if enough data could be extracted for calculation of sensitivity and/or specificity. RESULTS: Eight studies were included in the systematic review. Only 2 studies reported the accuracy of (18)F FDG PET imaging in the primary staging of uterine sarcoma with low sensitivity for lymph node staging. For restaging (detection of recurrence), all 8 included studies had quantitative data, and the patient-based pooled sensitivity and specificity were 92.1% (95% confidence interval [95% CI], 82.4-97.4) and 96.2% (95% CI, 87-99.5), respectively. On a lesion-based analysis, sensitivity was 86.3% (95% CI, 76.7-92.9), and specificity was 94.4% (95% CI, 72.7-99.9). Device used (PET vs PET/CT), spectrum of studied patients, and histology of the sarcoma seem to be factors influencing the overall accuracy of (18)F-FDG PET imaging. CONCLUSIONS: (8)Fluorine-18-fluorodeoxyglucose PET and PET/CT seem to be accurate methods for detection and localization of recurrence in patients with uterine sarcoma. Further large multicenter studies are needed to validate our results and to correlate both sarcoma type and spectrum of patients to the diagnostic performance of (18)F-FDG PET imaging in recurrence detection. The studies evaluating the accuracy of (18)F-FDG PET imaging for the primary staging of uterine sarcoma are very limited, and no definite conclusion can be made in this regard. PMID- 23945205 TI - If a bird flies in the forest, does an insect hear it? AB - Birds are major predators of many eared insects including moths, butterflies, crickets and cicadas. We provide evidence supporting the hypothesis that insect ears can function as 'bird detectors'. First, we show that birds produce flight sounds while foraging. Eastern phoebes (Sayornis phoebe) and chickadees (Poecile atricapillus) generate broadband sounds composed of distinct repetitive elements (approx. 18 and 20 Hz, respectively) that correspond to cyclic wing beating. We estimate that insects can detect an approaching bird from distances of at least 2.5 m, based on insect hearing thresholds and sound level measurements of bird flight. Second, we show that insects with both high and low frequency hearing can hear bird flight sounds. Auditory nerve cells of noctuid moths (Trichoplusia ni) and nymphalid butterflies (Morpho peleides) responded in a bursting pattern to playbacks of an attacking bird. This is the first study to demonstrate that foraging birds generate flight sound cues that are detectable by eared insects. Whether insects exploit these sound cues, and alternatively, if birds have evolved sound-reducing foraging tactics to render them acoustically 'cryptic' to their prey, are tantalizing questions worthy of further investigation. PMID- 23945206 TI - Predicting the distribution of oceanic-stage Kemp's ridley sea turtles. AB - The inaccessibility of open ocean habitat and the cryptic nature of small animals are fundamental problems when assessing the distribution of oceanic-stage sea turtles and other marine animals sharing similar life-history traits. Most methods that estimate patterns of abundance cannot be applied in situations that are extremely data limited. Here, we use a movement ecology framework to generate the first predicted distributions for the oceanic stage of the Kemp's ridley sea turtle (Lepidochelys kempii). Our simulations of particle dispersal within ocean circulation models reveal substantial annual variation in distribution and survival among simulated cohorts. Such techniques can help prioritize areas for conservation, and supply inputs for more realistic demographic models attempting to characterize population trends. PMID- 23945207 TI - Is Rapoport's rule a recent phenomenon? A deep time perspective on potential causal mechanisms. AB - Macroecology strives to identify ecological patterns on broad spatial and temporal scales. One such pattern, Rapoport's rule, describes the tendency of species' latitudinal ranges to increase with increasing latitude. Several mechanisms have been proposed to explain this rule. Some invoke climate, either through glaciation driving differential extinction of northern species or through increased seasonal variability at higher latitudes causing higher thermal tolerances and subsequently larger ranges. Alternatively, continental tapering or higher interspecific competition at lower latitudes may be responsible. Assessing the incidence of Rapoport's rule through deep time can help to distinguish between competing explanations. Using fossil occurrence data from the Palaeobiology Database, we test these hypotheses by evaluating mammalian compliance with the rule throughout the Caenozoic of North America. Adherence to Rapoport's rule primarily coincides with periods of intense cooling and increased seasonality, suggesting that extinctions caused by changing climate may have played an important role in erecting the latitudinal gradients in range sizes seen today. PMID- 23945208 TI - Rules to limp by: joint compensation conserves limb function after peripheral nerve injury. AB - Locomotion persists across all manner of internal and external perturbations. The objective of this study was to identify locomotor compensation strategies in rodent models of peripheral nerve injury. We found that hip-to-toe limb length and limb angle was preferentially preserved over individual joint angles after permanent denervation of rat ankle extensor muscles. These findings promote further enquiry into the significance of limb-level function for neuromechanical control of legged locomotion. PMID- 23945209 TI - Diplostigmaty in plants: a novel mechanism that provides reproductive assurance. AB - Differentiation of female sexual organs in flowering plants is rare and contrasts with the wide range of male reproductive strategies. An unusual example involves diplostigmaty, the possession of spatially and temporally distinct stigmas in Sebaea (Gentianaceae). Here, the single pistil within a flower has an apical stigma, as occurs in most flowering plants, but also a secondary stigma that occurs midway down the style, which is physically discrete and receptive several days after the apical stigma. We examined the function of diplostigmaty in Sebaea aurea, an insect-pollinated species of the Western Cape of South Africa. Floral manipulations and measurements of fertility and mating patterns provided evidence that basal stigmas function to enable autonomous delayed self-pollination, without limiting opportunities for outcrossing and thus avoiding the costs of seed discounting. We suggest that delayed selfing serves as a mechanism of reproductive assurance in populations with low plant density. The possession of dimorphic stigma function provides a novel example of a flexible mixed-mating strategy in plants that is responsive to changing demographic conditions. PMID- 23945210 TI - Environmental perturbations influence telomere dynamics in long-lived birds in their natural habitat. AB - Telomeres are regarded as markers of biological or cellular ageing because they shorten with the degree of stress exposure. Accordingly, telomere lengths should show different rates of change when animals are faced with different intensities of environmental challenges. However, a relationship between telomere length and the environment has not yet been tested within a natural setting. Here, we report longitudinal telomere dynamics in free-living, black-tailed gulls (Larus crassirostris) through the recapture of birds of a known age over 2-5 consecutive years. The rate of change in telomere lengths differed with respect to year but not sex or age. The years when gulls showed stable telomere lengths or increases in telomere lengths (from 2009 to 2010) and decreases in telomere lengths (from 2010 to 2011) were characterized by El Nino and the Great Japan Earthquake, respectively. Both events are suspected to have had long-lasting effects on food availability and/or weather conditions. Thus, our findings that telomere dynamics in long-lived birds are influenced by dramatic changes in environmental conditions highlight the importance of environmental fluctuations in affecting stress and lifespan. PMID- 23945211 TI - How many and which ant species are being accidentally moved around the world? AB - Human transportation facilitates the dispersal of exotic ants, but few studies have quantified the magnitude and geography of these movements. We used several non-parametric indexes to estimate the number of species successfully introduced to or established in new regions. We also compared their source biogeographic realms to assess the importance of the geographical origin in determining the likelihood of establishment after introduction. Data on exotic ants derive from studies of three temperate regions. Our results suggest that the numbers of introduced or established ants may be much larger than the numbers so far documented. Ants introduced or established in new regions tend to arrive from the same or neighbouring realms, as would be expected if exotic species tend to match climates and if arrival/establishment is dependent upon higher trade rates from neighbouring countries. PMID- 23945212 TI - Protist predation can favour cooperation within bacterial species. AB - Here, we studied how protist predation affects cooperation in the opportunistic pathogen bacterium Pseudomonas aeruginosa, which uses quorum sensing (QS) cell-to cell signalling to regulate the production of public goods. By competing wild type bacteria with QS mutants (cheats), we show that a functioning QS system confers an elevated resistance to predation. Surprisingly, cheats were unable to exploit this resistance in the presence of cooperators, which suggests that resistance does not appear to result from activation of QS-regulated public goods. Instead, elevated resistance of wild-type bacteria was related to the ability to form more predation-resistant biofilms. This could be explained by the expression of QS-regulated resistance traits in densely populated biofilms and floating cell aggregations, or alternatively, by a pleiotropic cost of cheating where less resistant cheats are selectively removed from biofilms. These results show that trophic interactions among species can maintain cooperation within species, and have further implications for P. aeruginosa virulence in environmental reservoirs by potentially enriching the cooperative and highly infective strains with functional QS system. PMID- 23945213 TI - A pilot placebo-controlled, double-blind, and randomized study on the cognition enhancing benefits of a proprietary chicken meat ingredient in healthy subjects. AB - BACKGROUND: It has long been postulated that the relative abundance of specific nutrients can affect cognitive processes and emotions. Newly described influences of dietary factors on neuronal function and synaptic plasticity have revealed some of the vital mechanisms that could be responsible for the action of diet on brain health and cognitive function. Here, through a double-blind, randomized, placebo-controlled trial, we asked if the newly discovered chicken meat ingredient-168 (CMI-168) could be beneficial to the cognitive function in healthy adults. METHODS: Normal, healthy subjects were supplemented with either placebo or CMI-168 for 6 weeks. The subjects were given a series of cognitive tests to examine their levels of cognitive functioning at the beginning and end of supplementation, as well as two weeks after termination of supplementation. The combination of these tests, namely Digit Span Backwards, Letter-Number Sequencing, and the Rey Auditory Verbal Learning Test (RAVLT), was used to assess the subjects' attention and working memory. For all comparisons, the probability level of p < 0.05 was taken as statistically significant using repeated measure 2 way ANOVA followed by Bonferroni post-hoc test. RESULTS: Overall, subjects supplemented with CMI-168 showed significantly (p < 0.01) better performance in all cognitive tests after 6 weeks' supplementation compared to control and such superior performance was maintained even 2 weeks after termination of supplementation. CONCLUSIONS: The present study reveals the cognition-enhancing properties of a recently developed chicken meat ingredient, likely arising from the promotion of attention and prefrontal cortex functions. PMID- 23945214 TI - Contrasting academic and tobacco industry estimates of illicit cigarette trade: evidence from Warsaw, Poland. AB - OBJECTIVE: To compare two different methods for estimating the size of the illicit cigarette market with each other and to contrast the estimates obtained by these two methods with the results of an industry-commissioned study. METHODS: We used two observational methods: collection of data from packs in smokers' personal possession, and collection of data from packs discarded on streets. The data were obtained in Warsaw, Poland in September 2011 and October 2011. We used tests of independence to compare the results based on the two methods, and to contrast those with the estimate from the industry-commissioned discarded pack collection conducted in September 2011. RESULTS: We found that the proportions of cigarette packs classified as not intended for the Polish market estimated by our two methods were not statistically different. These estimates were 14.6% (95% CI 10.8% to 19.4%) using the survey data (N=400) and 15.6% (95% CI 13.2% to 18.4%) using the discarded pack data (N=754). The industry estimate (22.9%) was higher by nearly a half compared with our estimates, and this difference is statistically significant. CONCLUSIONS: Our findings are consistent with previous evidence of the tobacco industry exaggerating the scope of illicit trade and with the general pattern of the industry manipulating evidence to mislead the debate on tobacco control policy in many countries. Collaboration between governments and the tobacco industry to estimate tobacco tax avoidance and evasion is likely to produce upward-biased estimates of illicit cigarette trade. If governments are presented with industry estimates, they should strictly require a disclosure of all methodological details and data used in generating these estimates, and should seek advice from independent experts. PMID- 23945216 TI - Phylogeny and classification of Prunus sensu lato (Rosaceae). AB - The classification of the economically important genus Prunus L. sensu lato (s.l.) is controversial due to the high levels of convergent or the parallel evolution of morphological characters. In the present study, phylogenetic analyses of fifteen main segregates of Prunus s.l. represented by eighty-four species were conducted with maximum parsimony and Bayesian approaches using twelve chloroplast regions (atpB-rbcL, matK, ndhF, psbA-trnH, rbcL, rpL16, rpoC1, rps16, trnS-G, trnL, trnL-F and ycf1) and three nuclear genes (ITS, s6pdh and SbeI) to explore their infrageneric relationships. The results of these analyses were used to develop a new, phylogeny-based classification of Prunus s.l. Our phylogenetic reconstructions resolved three main clades of Prunus s.l. with strong supports. We adopted a broad-sensed genus, Prunus, and recognised three subgenera corresponding to the three main clades: subgenus Padus, subgenus Cerasus and subgenus Prunus. Seven sections of subgenus Prunus were recognised. The dwarf cherries, which were previously assigned to subgenus Cerasus, were included in this subgenus Prunus. One new section name, Prunus L. subgenus Prunus section Persicae (T. T. Yu & L. T. Lu) S. L. Zhou and one new species name, Prunus tianshanica (Pojarkov) S. Shi, were proposed. PMID- 23945215 TI - Characterization and in vitro properties of oral lactobacilli in breastfed infants. AB - BACKGROUND: Lactobacillus species can contribute positively to general and oral health and are frequently acquired by breastfeeding in infancy. The present study aimed to identify oral lactobacilli in breast and formula-fed 4 month-old infants and to evaluate potential probiotic properties of the dominant Lactobacillus species detected. Saliva and oral swab samples were collected from 133 infants who were enrolled in a longitudinal study (n=240) examining the effect of a new infant formula on child growth and development. Saliva was cultured and Lactobacillus isolates were identified from 16S rRNA gene sequences. Five L. gasseri isolates that differed in 16S rRNA sequence were tested for their ability to inhibit growth of selected oral bacteria and for adhesion to oral tissues. Oral swab samples were analyzed by qPCR for Lactobacillus gasseri. RESULTS: 43 (32.3%) infants were breastfed and 90 (67.7%) were formula-fed with either a standard formula (43 out of 90) or formula supplemented with a milk fat globule membrane (MFGM) fraction (47 out of 90). Lactobacilli were cultured from saliva of 34.1% breastfed infants, but only in 4.7% of the standard and 9.3% of the MFGM supplemented formula-fed infants. L. gasseri was the most prevalent (88% of Lactobacillus positive infants) of six Lactobacillus species detected. L. gasseri isolates inhibited Streptococcus mutans binding to saliva-coated hydroxyapatite, and inhibited growth of S. mutans, Streptococcus sobrinus, Actinomyces naeslundii, Actinomyces oris, Candida albicans and Fusobacterium nucleatum in a concentration dependent fashion. L. gasseri isolates bound to parotid and submandibular saliva, salivary gp340 and MUC7, and purified MFGM, and adhered to epithelial cells. L. gasseri was detected by qPCR in 29.7% of the oral swabs. Breastfed infants had significantly higher mean DNA levels of L. gasseri (2.14 pg/uL) than infants fed the standard (0.363 pg/uL) or MFGM (0.697 pg/uL) formula. CONCLUSIONS: Lactobacilli colonized the oral cavity of breastfed infants significantly more frequently than formula-fed infants. The dominant Lactobacillus was L. gasseri, which was detected at higher levels in breastfed than formula-fed infants and displayed probiotic traits in vitro. PMID- 23945217 TI - Stability properties of PrP(Sc) from cattle with experimental transmissible spongiform encephalopathies: use of a rapid whole homogenate, protease-free assay. AB - BACKGROUND: Transmissible Spongiform Encephalopathies (TSEs), including scrapie in sheep, chronic wasting disease (CWD) in cervids, transmissible mink encephalopathy (TME), and bovine spongiform encephalopathy (BSE), are fatal diseases of the nervous system associated with accumulation of misfolded prion protein (PrP(Sc)). Different strains of TSEs exist, associated with different PrP(Sc) conformations that can be probed by the stability assay, in which PrP(Sc) is treated with increasing concentrations of the denaturant guanidine hydrochloride (GdnHCl). RESULTS: Here, we provide the first comprehensive application of a rapid, protease-free version of the GdnHCl stability assay to brain tissue from cattle experimentally infected with various TSE isolates. Consistent with previous findings from a single Japanese isolate, the L-type isolates of BSE are not distinguishable from classical BSE in this assay. In contrast, H-type isolates of BSE, including our unique isolate of E211K BSE, exhibit higher stability than classical BSE, suggesting that its increased protection against protease digestion at the BSE N-terminus is associated with a higher stability in GdnHCl. While the difference in stability in our version of the assay is likely not large enough for effective use in a diagnostic laboratory setting, the use of alternative experimental conditions may enhance this effect. TSEs from other natural host species that have been passaged in cattle, including CWD and TME, were not distinguishable from classical BSE, while isolates of cattle passaged scrapie exhibited a slight increase in stability as compared to classical BSE. CONCLUSIONS: These results suggest that the core of PrP(Sc), as probed in this assay, has similar stability properties among cattle-passaged TSE isolates and that the conformational differences that lead to changes in the proteinase K cleavage site do not cause large changes in the stability of PrP(Sc) from TSE-affected cattle. However, the stability differences observed here will provide a basis of comparison for new isolates of atypical BSE observed in the future and in other geographic locations, especially in the case of H-type BSE. PMID- 23945219 TI - Microtubule organization by kinesin motors and microtubule crosslinking protein MAP65. AB - Microtubules are rigid, proteinaceous filaments required to organize and rearrange the interior of cells. They organize space by two mechanisms, including acting as the tracks for long-distance cargo transporters, such as kinesin-1, and by forming a network that supports the shape of the cell. The microtubule network is composed of microtubules and a bevy of associated proteins and enzymes that self-organize using non-equilibrium dynamic processes. In order to address the effects of self-organization of microtubules, we have utilized the filament gliding assay with kinesin-1 motors driving microtubule motion. To further enhance the complexity of the system and determine if new patterns are formed, we added the microtubule crosslinking protein MAP65-1. MAP65-1 is a microtubule associated protein from plants that crosslinks antiparallel microtubules, similar to mammalian PRC1 and fission yeast Ase1. We find that MAP65 can slow and halt the velocity of microtubules in gliding assays, but when pre-formed microtubule bundles are added to gliding assays, kinesin-1 motors can pull apart the bundles and reconstitute cell-like protrusions. PMID- 23945218 TI - Determinants of serum levels of vitamin D: a study of life-style, menopausal status, dietary intake, serum calcium, and PTH. AB - BACKGROUND: Low blood levels of vitamin D (25-hydroxy D3, 25OHD3) in women have been associated with an increased risk of several diseases. A large part of the population may have suboptimal 25OHD3 levels but high-risk groups are not well known. The aim of the present study was to identify determinants for serum levels of 25OHD3 in women, i.e. factors such as lifestyle, menopausal status, diet and selected biochemical variables. METHODS: The study was based on women from the Malmo Diet and Cancer Study (MDCS), a prospective, population-based cohort study in Malmo, Sweden. In a previous case-control study on breast cancer, 25OHD3 concentrations had been measured in 727 women. In these, quartiles of serum 25OHD3 were compared with regard to age at baseline, BMI (Body Max Index), menopausal status, use of oral contraceptives or menopausal hormone therapy (MHT) , life-style (e.g. smoking and alcohol consumption), socio-demographic factors, season, biochemical variables (i.e. calcium, PTH, albumin, creatinine, and phosphate), and dietary intake of vitamin D and calcium. In order to test differences in mean vitamin D concentrations between different categories of the studied factors, an ANOVA test was used followed by a t-test. The relation between different factors and 25OHD3 was further investigated using multiple linear regression analysis and a logistic regression analysis. RESULTS: We found a positive association between serum levels of 25OHD3 and age, oral contraceptive use, moderate alcohol consumption, blood collection during summer/ autumn, creatinine, phosphate, calcium, and a high intake of vitamin D. Low vitamin D levels were associated with obesity, being born outside Sweden and high PTH levels. CONCLUSIONS: The present population-based study found a positive association between serum levels of 25OHD3 and to several socio-demographic, life style and biochemical factors. The study may have implications e. g. for dietary recommendations. However, the analysis is a cross-sectional and it is difficult to suggest Lifestyle changes as cause- effect relationships are difficult to assess. PMID- 23945220 TI - Dietary approaches to assessing iron-related nutrition. AB - PURPOSE OF REVIEW: Both dietary and nondietary factors contribute to iron deficiency, the most common nutritional deficiency worldwide. Identifying dietary factors associated with iron deficiency is challenging due to the number of components in food affecting iron absorption. This review describes recent advances in dietary approaches to assessing iron-related nutrition. RECENT FINDINGS: Most research investigating the relationship between dietary intake and iron deficiency has focussed on individual foods and nutrients, despite several components in foods influencing iron absorption. More recently, studies have considered the overall diet and combinations of foods eaten, through the analysis of dietary patterns and practices. This includes the development and validation of dietary assessment tools to assess iron-related dietary patterns. SUMMARY: Dietary pattern analysis which considers the whole diet and combinations of foods eaten may enhance our understanding of how diet impacts on iron deficiency. The analysis of dietary patterns offers an alternative and complementary approach to the traditional focus on individual foods and nutrients when investigating dietary factors associated with iron deficiency. PMID- 23945221 TI - Zinc in traumatic brain injury: from neuroprotection to neurotoxicity. AB - PURPOSE OF REVIEW: In light of the recent recognition that even mild forms of traumatic brain injury (TBI) can lead to long-term cognitive and behavioral deficits, this review examines recent data on the neuroprotective and neurotoxic roles of zinc after brain injury. RECENT FINDINGS: Data show that treatment using dietary and parenteral zinc supplementation can reduce TBI-associated depression and improve cognitive function, specifically spatial learning and memory. However, excessive release of free zinc, particularly in the hippocampus associated with acute injury, can lead to increases in protein ubiquitination and neuronal death. SUMMARY: This work shows the need for future research to clarify the potentially contradictory roles of zinc in the hippocampus and define the clinical use of zinc as a treatment following brain injury in humans. This is particularly important given the finding that zinc may reduce TBI-associated depression, a common and difficult outcome to treat in all forms of TBI. PMID- 23945222 TI - Natriuretic peptides and fat metabolism. AB - PURPOSE OF REVIEW: Cardiac natriuretic peptides have emerged as potent metabolic hormones during the past decade. We here discuss recent work highlighting the potential importance of these hormones in metabolic physiology and diseases. RECENT FINDINGS: Natriuretic peptides signal through a cyclic guanosine monophosphate pathway to convey their biological effects at the cell level. Similarly to cyclic adenosine monophosphate, activation of cyclic guanosine monophosphate signaling induces a browning of white fat and thermogenesis. Natriuretic peptides also enhance oxidative capacity and fat oxidation in skeletal muscle of mice and humans. The molecular mechanism involves an upregulation of mitochondrial fat oxidative capacity and respiration. This may be particularly relevant to relay the physiological adaptations of chronic exercise. Population-based studies indicate that circulating natriuretic peptides are lowered in obesity and predict type 2 diabetes. Recent work also directly link natriuretic peptides with type 2 diabetes through a gut-heart axis. SUMMARY: Natriuretic peptides exhibit a wide range of biological actions to control metabolic homeostasis. Natriuretic peptides deficiency in obesity may trigger metabolic dysfunction and lead to type 2 diabetes. Increasing circulating natriuretic peptides level and tissue signaling may help to fight against metabolic complications of obesity. PMID- 23945223 TI - Prevalence of the polar vessel sign in parathyroid adenomas on the arterial phase of 4D CT. AB - BACKGROUND AND PURPOSE: The "polar vessel" sign has been previously described on sonography of parathyroid adenomas. We estimated the 4D CT prevalence of the polar vessel sign and determined features of parathyroid adenomas that are associated with this sign. MATERIALS AND METHODS: Twenty-eight consecutive patients with parathyroid adenomas underwent 4D CT between 2008 and 2012 at 2 institutions. 4D CT images were reviewed for the presence of the polar vessel sign and a second vascular finding of an enlarged ipsilateral inferior thyroid artery. The polar vessel sign was correlated with adenoma weight and size and arterial phase CT attenuation. RESULTS: Thirty-two parathyroid adenomas in 28 patients were studied, with a mean adenoma weight of 0.66 +/- 0.65 g, a mean maximal CT diameter of 11.1 +/- 4.9 mm, and a mean arterial attenuation of 148 +/ 47 HU. The polar vessel sign was seen in 20/32 (63%) adenomas. Adenomas with a polar vessel had higher arterial phase attenuation than adenomas without a polar vessel (163 and 122 HU, respectively, P < .01). Size and weight were not significantly different for adenomas with and without polar vessels. An enlarged inferior thyroid artery was seen in only 2/28 (7%) patients with unilateral disease. CONCLUSIONS: The polar vessel sign was present in nearly two-thirds of parathyroid adenomas on 4D CT and was more likely to be present in adenomas that had greater arterial phase enhancement. This sign can be used along with enhancement characteristics to increase the radiologist's confidence that a visualized lesion is a parathyroid adenoma rather than a thyroid nodule or lymph node. PMID- 23945224 TI - Clinical significance of trochlear calcifications in the orbit. AB - BACKGROUND AND PURPOSE: Trochlear calcification is frequently seen on CT scans that include the orbits, but prior studies linking this finding to diabetes mellitus were based on selected populations by using relatively thick sections. We assessed the relationship between trochlear calcification and diabetes mellitus and other chronic medical conditions in an unrestricted population by using thin-section CT. MATERIALS AND METHODS: Noncontrast head CT studies performed consecutively on 1000 patients between January and February 2011 were retrospectively reviewed for the presence of trochlear calcifications. Axial 1.25 mm-thick images acquired by 64-detector row CT were reviewed. Medical records were reviewed for chronic medical conditions, including diabetes mellitus, chronic kidney disease, alcoholism, autoimmune conditions, endocrine disorders, serum calcium and alkaline phosphatase levels, and HIV status. Motion-limited studies and patients with limited clinical data were excluded. Statistical analyses were performed by using the Fisher exact test. RESULTS: Thirty-two patients were excluded from analysis. Of the remaining 968 patients, 128 had trochlear calcification (13%). No significant association was observed between diabetes mellitus and trochlear calcifications in patients of any age (P = .40). There was no significant correlation between trochlear calcifications and chronic kidney disease, alcoholism, endocrine disorders, or HIV infection. Statistically significant associations among trochlear calcification, autoimmune conditions, and elevated alkaline phosphatase levels were observed (P < .0001 and P < .0001, respectively). CONCLUSIONS: On the basis of a large unrestricted population with thin-section CT imaging of the orbit, no significant association was observed between trochlear calcifications and diabetes mellitus. A statistically significant association was observed between trochlear calcification and autoimmune disease and elevated alkaline phosphatase levels. PMID- 23945225 TI - Subcortical cystic lesions within the anterior superior temporal gyrus: a newly recognized characteristic location for dilated perivascular spaces. AB - SUMMARY: Cystic parenchymal lesions may pose an important diagnostic challenge, particularly when encountered in unexpected locations. Dilated perivascular spaces, which may mimic cystic neoplasms, are known to occur in the inferior basal ganglia and mesencephalothalamic regions; a focal preference within the subcortical white matter has not been reported. This series describes 15 cases of patients with cystic lesions within the subcortical white matter of the anterior superior temporal lobe, which followed a CSF signal; were located adjacent to a subarachnoid space; demonstrated variable surrounding signal change; and, in those that were followed up, showed stability. Pathology study results obtained in 1 patient demonstrated chronic gliosis surrounding innumerable dilated perivascular spaces. These findings suggest that dilated perivascular spaces may exhibit a regional preference for the subcortical white matter of the anterior superior temporal lobe. Other features-lack of clinical symptoms, proximity to the subarachnoid space, identification of an adjacent vessel, and stability with time-may help in confidently making the prospective diagnosis of a dilated perivascular space, thereby preventing unnecessary invasive management. PMID- 23945226 TI - Arterial spin-labeling assessment of normalized vascular intratumoral signal intensity as a predictor of histologic grade of astrocytic neoplasms. AB - BACKGROUND AND PURPOSE: Pulsed arterial spin-labeling is a noninvasive MR imaging perfusion method performed with the use of water in the arterial blood as an endogenous contrast agent. The purpose of this study was to determine the inversion time with the largest difference in normalized intratumoral signal intensity between high-grade and low-grade astrocytomas. MATERIALS AND METHODS: Thirty-three patients with gliomas, histologically classified as low-grade (n = 7) or high-grade astrocytomas (n = 26) according to the World Health Organization brain tumor classification, were included. A 3T MR scanner was used to perform pulsed arterial spin-labeling measurements at 8 different inversion times (370 ms, 614 ms, 864 ms, 1114 ms, 1364 ms, 1614 ms, 1864 ms, and 2114 ms). Normalized intratumoral signal intensity was calculated, which was defined by the signal intensity ratio of the tumor and the contralateral normal brain tissue for all fixed inversion times. A 3-way mixed ANOVA was used to reveal potential differences in the normalized vascular intratumoral signal intensity between high grade and low-grade astrocytomas. RESULTS: The difference in normalized vascular intratumoral signal intensity between high-grade and low-grade astrocytomas obtained the most statistically significant results at 370 ms (P = .003, other P values ranged from .012-.955). CONCLUSIONS: The inversion time by which to differentiate high-grade and low-grade astrocytomas by use of normalized vascular intratumoral signal intensity was 370 ms in our study. The normalized vascular intratumoral signal intensity values at this inversion time mainly reflect the labeled intra-arterial blood bolus and therefore could be referred to as normalized vascular intratumoral signal intensity. Our data indicate that the use of normalized vascular intratumoral signal intensity values allows differentiation between low-grade and high-grade astrocytomas and thus may serve as a new, noninvasive marker for astrocytoma grading. PMID- 23945227 TI - Oxygen extraction fraction and stroke risk in patients with carotid stenosis or occlusion: a systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Increased oxygen extraction fraction on PET has been considered a risk factor for stroke in patients with carotid stenosis or occlusion, though the strength of this association has recently been questioned. We performed a systematic review and meta-analysis to summarize the association between increased oxygen extraction fraction and ipsilateral stroke risk. MATERIALS AND METHODS: A comprehensive literature search was performed. We included studies with baseline PET oxygen extraction fraction testing, ipsilateral stroke as the primary outcome, and at least 1 year of follow-up. A meta-analysis was performed by use of a random-effects model. RESULTS: After screening 2158 studies, 7 studies with 430 total patients with mean 30-month follow-up met inclusion criteria. We found that 6 of 7 studies were amenable to meta-analysis. Although 4 of the 6 studies independently did not reach statistical significance, meta-analysis revealed a significant positive relationship between abnormal oxygen extraction fraction and future ipsilateral stroke, with a pooled OR of 6.04 (95% CI, 2.58-14.12). There was no statistically significant difference in OR in the subgroup analyses according to testing method or disease site. CONCLUSIONS: Abnormal oxygen extraction fraction remains a powerful predictor of stroke in carotid stenosis or occlusion and is a valuable reference standard to compare and validate MR imaging-based measures of brain oxygen metabolism. However, there is a need for further evaluation of oxygen extraction fraction testing in patients with high-grade but asymptomatic carotid disease. PMID- 23945228 TI - Does the location of the arterial input function affect quantitative CTP in patients with vasospasm? AB - BACKGROUND AND PURPOSE: In recent years, there has been increasing use of CTP imaging in patients with aneurysmal SAH to evaluate for vasospasm. Given the critical role of the arterial input function for generation of accurate CTP data, several studies have evaluated the effect of varying the arterial input function location in patients with acute stroke. Our aim was to determine the effect on quantitative CTP data when the arterial input function location is distal to significant vasospasm in patients with aneurysmal SAH. MATERIALS AND METHODS: A retrospective study was conducted of patients with aneurysmal SAH admitted from 2005 to 2011. Inclusion criteria were the presence of at least 1 anterior cerebral artery or MCA vessel with a radiologically significant vasospasm and at least 1 of these vessels without vasospasm. We postprocessed each CTP dataset 4 separate times by using standardized methods, only varying the selection of the arterial input function location in the anterior cerebral artery and MCA vessels. For each of the 4 separately processed examinations for each patient, quantitative data for CBF, CBV, and MTT were calculated by region-of-interest sampling of the vascular territories. Statistical analysis was performed by using a linear mixed-effects model. RESULTS: One hundred twelve uniquely processed CTP levels were analyzed in 28 patients (mean age, 52 years; 24 women and 4 men) recruited from January 2005 to December 2011. The average Hunt and Hess scale score was 2.89 +/- 0.79. The average time to CTP from initial presentation was 8.2 +/- 5.1 days. For each vascular territory (right and left anterior cerebral artery, MCA, posterior cerebral artery), there were no significant differences in the quantitative CBF, CBV, and MTT generated by arterial input function locations distal to significant vasospasm compared with nonvasospasm vessels (P > .05). CONCLUSIONS: Arterial input function placement distal to significant vasospasm does not affect the quantitative CTP data in the corresponding vascular territory or any other vascular territory in aneurysmal SAH. PMID- 23945229 TI - Coiling of large and giant aneurysms: complications and long-term results of 334 cases. AB - BACKGROUND AND PURPOSE: Large and giant intracranial aneurysms are increasingly treated with endovascular techniques. The goal of this study was to retrospectively analyze the complications and long-term results of coiling in large and giant aneurysms (>= 10 mm) and identify predictors of outcome. MATERIALS AND METHODS: A total of 334 large or giant aneurysms (>= 10 mm) were coiled in our institution between 2004 and 2011. Medical charts and imaging studies were reviewed to determine baseline characteristics, procedural complications, and clinical/angiographic outcomes. Aneurysm size was 15 mm on average. Two hundred twenty-five aneurysms were treated with conventional coiling; 88, with stent-assisted coiling; 14, with parent vessel occlusion; and 7, with balloon-assisted coiling. RESULTS: Complications occurred in 10.5% of patients, with 1 death (0.3%). Aneurysm location and ruptured aneurysms predicted complications. Angiographic follow-up was available for 84% of patients at 25.4 months on average. Recanalization and retreatment rates were 39% and 33%, respectively. Larger aneurysm size, increasing follow-up time, conventional coiling, and aneurysm location predicted both recurrence and retreatment. The annual rebleeding rate was 1.9%. Larger aneurysm size, increasing follow-up time, and aneurysm location predicted new or recurrent hemorrhage. Favorable outcomes occurred in 92% of patients. Larger aneurysm size, poor Hunt and Hess grades, and new or recurrent hemorrhage predicted poor outcome. CONCLUSIONS: Coiling of large and giant aneurysms has a reasonable safety profile with good clinical outcomes, but aneurysm reopening remains very common. Stent-assisted coiling has lower recurrence, retreatment, and new or recurrent hemorrhage rates with no additional morbidity compared with conventional coiling. Aneurysm size was a major determinant of recanalization, retreatment, new or recurrent hemorrhage, and poor outcome. PMID- 23945230 TI - Facial reanimation procedures depicted on radiologic imaging. AB - Various facial reanimation procedures can be performed for treating patients with chronic facial nerve paralysis. The radiologic imaging features of static and dynamic techniques are reviewed in this article with clinical correlation, including brow lift, eyelid weights and springs, gracilis free flaps, fascia lata grafts, temporalis flaps, and Gore-Tex suspension slings. Although the anatomic alterations resulting from facial reanimation surgery may not necessarily be the focus of the imaging examination, it is important to recognize such changes and be familiar with MR imaging compatibility of the associated implanted materials. Furthermore, imaging is sometimes used to specifically evaluate the postoperative results, such as vessel patency following free gracilis transfer. PMID- 23945231 TI - Differentiation of skull base chordomas from chondrosarcomas by diffusion weighted MRI. PMID- 23945232 TI - Socioeconomic disparities in the utilization of mechanical thrombectomy for acute ischemic stroke in US hospitals. AB - BACKGROUND AND PURPOSE: Previous studies have demonstrated that socioeconomic disparities in the treatment of cerebrovascular diseases exist. We studied a large administrative data base to study disparities in the utilization of mechanical thrombectomy for acute ischemic stroke. MATERIALS AND METHODS: With the utilization of the Perspective data base, we studied disparities in mechanical thrombectomy utilization between patient race and insurance status in 1) all patients presenting with acute ischemic stroke and 2) patients presenting with acute ischemic stroke at centers that performed mechanical thrombectomy. We examined utilization rates of mechanical thrombectomy by race/ethnicity (white, black, and Hispanic) and insurance status (Medicare, Medicaid, self-pay, and private). Multivariate logistic regression analysis adjusting for potential confounding variables was performed to study the association between race/insurance status and mechanical thrombectomy utilization. RESULTS: The overall mechanical thrombectomy utilization rate was 0.15% (371/249,336); utilization rate at centers that performed mechanical thrombectomy was 1.0% (371/35,376). In the sample of all patients with acute ischemic stroke, multivariate logistic regression analysis demonstrated that uninsured patients had significantly lower odds of mechanical thrombectomy utilization compared with privately insured patients (OR = 0.52, 95% CI = 0.25-0.95, P = .03), as did Medicare patients (OR = 0.53, 95% CI = 0.41-0.70, P < .0001). Blacks had significantly lower odds of mechanical thrombectomy utilization compared with whites (OR = 0.35, 95% CI = 0.23-0.51, P < .0001). When considering only patients treated at centers performing mechanical thrombectomy, multivariate logistic regression analysis demonstrated that insurance was not associated with significant disparities in mechanical thrombectomy utilization; however, black patients had significantly lower odds of mechanical thrombectomy utilization compared with whites (OR = 0.41, 95% CI = 0.27-0.60, P < .0001). CONCLUSIONS: Significant socioeconomic disparities exist in the utilization of mechanical thrombectomy in the United States. PMID- 23945233 TI - PET approaches for diagnosis of dementia. AB - There is increasing use of neuroimaging modalities, including PET, for diagnosing dementia. For example, FDG-PET demonstrates hypometabolic regions in the posterior cingulate gyri, precuneus, and parietotemporal association cortices, while amyloid PET indicates amyloid deposition in Alzheimer disease and mild cognitive impairment due to Alzheimer disease. Furthermore, the use of combination PET with structural MR imaging can improve the diagnostic accuracy of dementia. In other neurodegenerative dementias, each disease exhibits a specific metabolic reduction pattern. In dementia with Lewy bodies, occipital glucose metabolism is decreased, while in frontotemporal dementia, frontal and anterior temporal metabolism is predominantly decreased. These FDG-PET findings and positive or negative amyloid deposits are important biomarkers for various neurodegenerative dementias. PMID- 23945234 TI - Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis. AB - The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohn's disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4(+)CD45RB(hi) T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of Vdr-deficient IECs with the hVDR transgene completely rescued Vdr-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive Vdr-deficient immune system. Mechanistically, VDR signaling attenuated PUMA induction in IECs by blocking NF-kappaB activation, leading to a reduction in IEC apoptosis. Together, these results demonstrate that gut epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this anticolitic activity is independent of nonepithelial immune VDR actions. PMID- 23945236 TI - Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts. AB - Mice deficient in Schnurri-3 (SHN3; also known as HIVEP3) display increased bone formation, but harnessing this observation for therapeutic benefit requires an improved understanding of how SHN3 functions in osteoblasts. Here we identified SHN3 as a dampener of ERK activity that functions in part downstream of WNT signaling in osteoblasts. A D-domain motif within SHN3 mediated the interaction with and inhibition of ERK activity and osteoblast differentiation, and knockin of a mutation in Shn3 that abolishes this interaction resulted in aberrant ERK activation and consequent osteoblast hyperactivity in vivo. Additionally, in vivo genetic interaction studies demonstrated that crossing to Lrp5(-/-) mice partially rescued the osteosclerotic phenotype of Shn3(-/-) mice; mechanistically, this corresponded to the ability of SHN3 to inhibit ERK-mediated suppression of GSK3beta. Inducible knockdown of Shn3 in adult mice resulted in a high-bone mass phenotype, providing evidence that transient blockade of these pathways in adults holds promise as a therapy for osteoporosis. PMID- 23945235 TI - Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. AB - Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13-dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production. PMID- 23945237 TI - Differentiation and functional regulation of human fetal NK cells. AB - The human fetal immune system is naturally exposed to maternal allogeneic cells, maternal antibodies, and pathogens. As such, it is faced with a considerable challenge with respect to the balance between immune reactivity and tolerance. Here, we show that fetal natural killer (NK) cells differentiate early in utero and are highly responsive to cytokines and antibody-mediated stimulation but respond poorly to HLA class I-negative target cells. Strikingly, expression of killer-cell immunoglobulin-like receptors (KIRs) did not educate fetal NK cells but rendered them hyporesponsive to target cells lacking HLA class I. In addition, fetal NK cells were highly susceptible to TGF-beta-mediated suppression, and blocking of TGF-beta signaling enhanced fetal NK cell responses to target cells. Our data demonstrate that KIR-mediated hyporesponsiveness and TGF-beta-mediated suppression are major factors determining human fetal NK cell hyporesponsiveness to HLA class I-negative target cells and provide a potential mechanism for fetal-maternal tolerance in utero. Finally, our results provide a basis for understanding the role of fetal NK cells in pregnancy complications in which NK cells could be involved, for example, during in utero infections and anti-RhD-induced fetal anemia. PMID- 23945238 TI - Predicting time to ovarian carcinoma recurrence using protein markers. AB - Patients with ovarian cancer are at high risk of tumor recurrence. Prediction of therapy outcome may provide therapeutic avenues to improve patient outcomes. Using reverse-phase protein arrays, we generated ovarian carcinoma protein expression profiles on 412 cases from TCGA and constructed a PRotein-driven index of OVARian cancer (PROVAR). PROVAR significantly discriminated an independent cohort of 226 high-grade serous ovarian carcinomas into groups of high risk and low risk of tumor recurrence as well as short-term and long-term survivors. Comparison with gene expression-based outcome classification models showed a significantly improved capacity of the protein-based PROVAR to predict tumor progression. Identification of protein markers linked to disease recurrence may yield insights into tumor biology. When combined with features known to be associated with outcome, such as BRCA mutation, PROVAR may provide clinically useful predictions of time to tumor recurrence. PMID- 23945239 TI - Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy. AB - Many oncology drugs are administered at their maximally tolerated dose without the knowledge of their optimal efficacious dose range. In this study, we describe a multifaceted approach that integrated preclinical and clinical data to identify the optimal dose for an antiangiogenesis agent, anti-EGFL7. EGFL7 is an extracellular matrix-associated protein expressed in activated endothelium. Recombinant EGFL7 protein supported EC adhesion and protected ECs from stress induced apoptosis. Anti-EGFL7 antibodies inhibited both of these key processes and augmented anti-VEGF-mediated vascular damage in various murine tumor models. In a genetically engineered mouse model of advanced non-small cell lung cancer, we found that anti-EGFL7 enhanced both the progression-free and overall survival benefits derived from anti-VEGF therapy in a dose-dependent manner. In addition, we identified a circulating progenitor cell type that was regulated by EGFL7 and evaluated the response of these cells to anti-EGFL7 treatment in both tumor bearing mice and cancer patients from a phase I clinical trial. Importantly, these preclinical efficacy and clinical biomarker results enabled rational selection of the anti-EGFL7 dose currently being tested in phase II clinical trials. PMID- 23945240 TI - Place field repetition and purely local remapping in a multicompartment environment. AB - Hippocampal place cells support spatial memory using sensory information from the environment and self-motion information to localize their firing fields. Currently, there is disagreement about whether CA1 place cells can use pure self motion information to disambiguate different compartments in environments containing multiple visually identical compartments. Some studies report that place cells can disambiguate different compartments, while others report that they do not. Furthermore, while numerous studies have examined remapping, there has been little examination of remapping in different subregions of a single environment. Is remapping purely local or do place fields in neighboring, unaffected, regions detect the change? We recorded place cells as rats foraged across a 4-compartment environment and report 3 new findings. First, we find that, unlike studies in which rats foraged in 2 compartments, place fields showed a high degree of spatial repetition with a slight degree of rate-based discrimination. Second, this repetition does not diminish with extended experience. Third, remapping was found to be purely local for both geometric change and contextual change. Our results reveal the limited capacity of the path integrator to drive pattern separation in hippocampal representations, and suggest that doorways may play a privileged role in segmenting the neural representation of space. PMID- 23945241 TI - [An experimental study on the Chinese lung adenocarcinoma cell clone CPA-Yang1-BR with brain metastasis potency in nude mice and in vivo imaging research]. AB - BACKGROUND AND OBJECTIVE: Lung cancer is the leading cause of cancer-related death in men and women. It is also the most common cause of brain metastases. A brain metastasis model is difficult to be established because of the presence of the blood-brain barrier (BBB) and the lack of optimal methods for detecting brain metastasis in nude mice. Thus, the establishment of a Chinese lung adenocarcinoma cell line and its animal model with brain metastasis potency and in vivo research is of great significance. METHODS: CPA-Yang1 cells were obtained from a patient with human lung adenocarcinoma by lentiviral vector-mediated transfection of green fluorescence protein. Intracardiac inoculation of the cells was performed in nude mice, and brain metastatic lesions were detected using micro 18F FDG PET/CT scanners, small animal in vivo imaging system for fluorescence, radionuclide and X ray fused imaging, magnetic resonance imaging (MRI) with sense body detection, and resection. The samples were divided into two parts for cell culture and histological diagnosis. The process was repeated in vivo and in vitro for four cycles to obtain a novel cell clone, CPA-Yang1-BR. RESULTS: A novel cell clone, CPA-Yang1-BR, was obtained with a brain metastatic rate of 50%. The use of MRI for the detection of brain metastases has obvious advantages. CONCLUSIONS: An experimental Chinese lung adenocarcinoma cell clone (CPA-Yang1-BR) and its animal model with brain metastasis potency in nude mice were established. MRI with sense body or micro MRI may be used as a sensitive, accurate, and noninvasive method to detect experimental brain metastases in intact live immunodeficient mice. The results of this study may serve as a technical platform for brain metastases from lung adenocarcinoma. PMID- 23945242 TI - [Identification and isolation of cancer stem cells from A549 cells]. AB - BACKGROUND AND OBJECTIVE: Lung cancer stem cells are the root causes of lung cancer malignant phenotype and potential therapeutic target, the aim of this study is to isolate and characterize the cancer stem cells in the lung adenoearcinomas cell line A549, so as to provide an experimental basis for further stem cell research. METHODS: The cancer stem cells were isolated from the lung adenoearcinomas cell line A549 using FACS. And the difference of colony formation, cell proliferation and tumorigenicity in vitro were also tested. The expression of CD133 and ABCG2 were evaluated by RT-PCR and Western blot. RESULTS: The percentage of SP cells was 5.93% of A549 and 0.32% of A549 after incubation with verapamil. The results showed that there were significantly higher expression of CD133 and ABCG2 on SP cells than that of non-SP cells. And the ability of colony formation, cell proliferation and tumorigenicity in SP cell group were remarkably higher than that in non-SP cell group. CONCLUSIONS: Our results suggested that the cancer stem cells with higher expression of CD133 and ABCG2 can be isolated from the lung adenoearcinomas cell line A549 using FACS and be used in the further research experiments. PMID- 23945243 TI - [A randomized clinical study of Gefitinib and pemetrexed as second line therapy for advanced non-squamous non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Gefitinib and Pemetrexed are drugs used as second-line therapy for advanced non-small cell lung cancer (NSCLC), although studies comparing the two drugs are limited. The aim of this study is to explore the effects, safety, and quality of life (QoL) of Gefitinib and Pemetrexed on patients with advanced non-squamous NSCLC. METHODS: Forty-six advanced non squamous NSCLC patients who failed to first-line therapy were randomly divided into two groups with 23 patients each, one using oral Gefitinib (Gefitinib group) and the other using intravenous injection Pemetrexed (Pemetrexed group). The effects, safety, and QoL were determined and analyzed. RESULTS: For the Pemetrexed group, objective response rate (ORR) was 13.0% (3/23), disease control rate (DCR) was 30.4% (7/23), and median progression-free survival (mPFS) was 3.1 months. In the Gefitinib group, ORR was 17.3% (4/23), DCR was 39.1% (9/23), and mPFS was 4.4 months. Compared with the Pemetrexed group, the ORR, DCR, and mPFS in the Gefitinib group exhibited no statistical significance (P>0.05). Furthermore, the most common toxicities in the Pemetrexed group were neutropenia (n=9, 39.13%) and fatigue (n=8, 34.78%), whereas those in the in Gefitinib group were skin rash (n=8, 34.78%) and diarrhea (n=4, 17.39%). Compared with baseline, the QoL improved in both groups but to different degrees. Likewise, emotional, functional well-being, and QoL aspects specifically related to lung cancer were better improved in the Gefitinib group than in the Pemetrexed group (P<0.05). CONCLUSIONS: The effects of Pemetrexed and Gefitinib as second line therapy were similar, although with different AEs. Both drugs could improve the QoL, but Gefitinib showed better overall results than Pemetrexed. PMID- 23945244 TI - [Clinical significance of detection of cathepsin X and cystatin C in the sera of patients with lung cancer]. AB - BACKGROUND AND OBJECTIVE: Cathepsin X (Cat X) has been identified as a member of cathepsin family. Studies have shown that Cat X is involved in tumorigenesis and tumor development of various cancers. The aim of this study is to investigate the relationship between the clinicopathological prognosis and the levels of Cat X and cystatin C in the serum of patients with lung cancer. METHODS: Blood samples were collected from 84 patients with lung cancer and 36 healthy control subjects. Cat X and cystatin C were determined by quantitative ELISA. RESULTS: Cat X and cystatin C levels were significantly higher in the patients with lung cancer than that in the healthy control subjects (P<0.01). Cat X level was correlated with the pathological types of lung cancer (P=0.076). Cystatin C was positively correlated with TNM stage (P=0.01). Furthermore, cystatin C/Cat X was correlated with lymph node metastasis (P=0.058). The patients with high Cat X levels experienced significantly shorter overall survival rates compared with those with low Cat X. Univariate analysis indicated that Cat X and TNM stage were related to overall survival. Multivariate Cox analysis indicated that TNM stage may be used as an independent prognostic variable in patients with lung cancer. CONCLUSIONS: Cat X and cystatin C levels were significantly higher in patients with lung cancer. Cat X and cystatin C detection in the sera may contribute to the diagnosis of lung cancer and may be used to evaluate the prognosis of patients with NSCLC. PMID- 23945245 TI - [Expression and related factors of Galectin-3 in non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Galectin-3 is involved in many physical and pathologic process, and is closely correlated with tumorigenesis, development and metastasis. The aim of this study is to investigate the gene expression and significance of Galectin-3 in normal lung tissue and non-small cell lung cancer (NSCLC) tissue. METHODS: Gene expression was examined using the immunohistochemical S-P method in 62 NSCLC cases and in 17 cases with normal lung tissue. RT-PCR verified the expression of Galectin-3 at the transcriptional level. RESULTS: The expression rate of Galectin-3 in NSCLC tissue was 83.8% (52/62), which was significantly higher than that in normal lung tissue (P<0.01). Galectin-3 expression was not correlated with sex (chi2=0.113, P>0.05), age (chi2=0.220, P>0.05), and histological type (chi2=0.012, P>0.05), but was negatively correlated with pathological differentiation (r=-0.292, P<0.05) and positively correlated with the clinical stage (r=0.336, P<0.05) in NSCLC tissue. RT-PCR results showed that the expression level of Galectin-3 in NSCLC tissue was significantly higher than in normal lung tissue. CONCLUSIONS: Galectin-3 may be useful in lung cancer diagnosis and may increase diagnosis rate when combined with other lung cancer markers. PMID- 23945246 TI - [P53 family proteins provide new insights into lung carcinogenesis and clinical treatment]. AB - The transcription activation of p53 plays an important role in the maintenance of genetic stability. P53 is an intensive study tumor suppressor, which has been called the "gene guider". The p53 family members p63, p73 have high homologous sequence with p53. Some of them can bind to the p53-responsive genes and transcript the downstream genes. Human lung cancer is one of the most common malignant tumors in the world. Abnormality of the p53 gene is the significant event in lung cancers, which leads to the poor prognosis and the resistance of chemotherapy. A deep understanding of the relationship between p53 family members and lung cancers can provide a more reasonably targeted clinical approach. This paper will focus on the special function of p53 family members in the development, chemosensitivity and target treatment of lung cancer. PMID- 23945247 TI - [Antitumor mechanism of metformin via adenosine monophosphate-activated protein kinase (AMPK) activation]. AB - Metformin, as a traditional oral hypoglycemic agent, is commonly used in the clinical treatment for type 2 diabetes. Recently, a large number of epidemiological researches have shown that metformin could reduce the tumor morbidity of type 2 diabetes, moreover, it has also been indicated that metformin could inhibit the growth, proliferation and transformation of cancer cells in metabolic pathways, cell cycle, oxidative stress and cancer/tumor stem cells transformation via AMPK pathway activation. But the antitumor effect of metformin via AMPK activation still exists arguments, and the definite mechanism remains to be further investigated and confirmed by extensive clinical trials. PMID- 23945248 TI - [Advances of VEGR gene polymorphism and its clinical values in lung cancer]. PMID- 23945249 TI - [Lung adenocarcinoma in situ which CT showed single pure ground-glass opacity: a case report and literature review]. PMID- 23945250 TI - [Personalized targeted therapy for lung cancer]. PMID- 23945251 TI - Dolutegravir pharmacokinetics in the genital tract and colorectum of HIV-negative men after single and multiple dosing. AB - OBJECTIVES: To describe first-dose and steady state pharmacokinetics (PKs) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy HIV-negative men. DESIGN: A phase 1, open-label, PK study that enrolled 12 healthy men taking 50 mg DTG daily for 8 days. METHODS: Eleven paired BP samples and 3 SF and RF samples were collected over 24 hours after first (PK1) and multiple (PK2) dosing. RT biopsies were collected at 1 of 6 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis was conducted with Phoenix WinNonlin v6.3, and Spearman rank correlations were determined using SAS v9.3. RESULTS: BP area under the concentration-time curves (AUCs) were similar to previous reports, and concentrations at 24 hours (C24 h) were 6- to 34-fold greater than the protein-adjusted concentration required for 90% viral inhibition (PA-IC90) of 64 ng/mL. SF exposures were <7% of BP and below the PA-IC90. RT exposures were 17% of BP and ~2-fold greater than the PA-IC90. RF AUCs were ~2% 5% of RT and did not correlate with RT (rho = 0.43, P = 0.17). Accumulation of DTG with multiple dosing was observed in BP, SF, and RT. CONCLUSIONS: DTG BP PKs were consistent with previously published values. SF concentrations were <7% BP, with SF C24 h below the PA-IC90. However, SF protein binding was not measured. Although the AUC of DTG in RT was <20% BP, RT C24 h remained ~2-fold higher than the PA-IC90. RF was not a strong surrogate for RT concentrations. PMID- 23945252 TI - Progression of carotid intima-media thickness and coronary artery calcium over 6 years in an HIV-infected cohort. AB - OBJECTIVE: To evaluate changes in cardiovascular disease risk surrogate markers in a longitudinal cohort of HIV-infected adults over 6 years. DESIGN: Internal carotid artery (ICA) and common carotid artery (CCA) intima-media thickness (IMT), coronary artery calcium (CAC), vascular, and HIV risk factors were prospectively examined over 6 years in HIV-infected adults from 2002 to 2010. SETTING: Longitudinal cohort study with participants from urban center and surrounding communities. SUBJECTS/PARTICIPANTS: Three hundred forty-five HIV infected participants were recruited from a longitudinal cohort study. Two hundred eleven participants completed the study and were included in this analysis. MAIN OUTCOME MEASURES: Total and yearly ICA and CCA IMT change; CAC score progression. RESULTS: Participants were 27% female and 49% nonwhite; mean age at start was 45 +/- 7 years. The median change in ICA and CCA over 6 years was 0.15 mm (0.08, 0.28) and 0.12 mm (0.09, 0.15), respectively. Age, baseline triglycerides >=150 mg/dL, and pack-years smoking were associated with ICA IMT change; age, cholesterol, nadir CD4 count, and protease inhibitor use were associated with CCA IMT change. Diabetes, HIV viral load, and highly active antiretroviral therapy duration were associated with CAC progression. CONCLUSIONS: Carotid IMT and CAC progressed in this HIV-infected cohort. Some HIV specific characteristics were associated with surrogate marker changes, but the majority of risk factors continue to be traditional. Aggressive identification and management of modifiable risk factors may reduce progression of cardiovascular disease risk in this population. PMID- 23945253 TI - Five-year trends in antiretroviral usage and drug costs in HIV-infected children in Thailand. AB - BACKGROUND: As antiretroviral treatment (ART) programs mature, data on drug utilization and costs are needed to assess durability of treatments and inform program planning. METHODS: Children initiating ART were followed up in an observational cohort in Thailand. Treatment histories from 1999 to 2009 were reviewed. Treatment changes were categorized as: drug substitution (within class), switch across drug class (non nucleoside reverse-transcriptase inhibitors (NNRTI) to/from protease inhibitor (PI)), and to salvage therapy (dual PI or PI and NNRTI). Antiretroviral drug costs were calculated in 6-month cycles (US$ 2009 prices). Predictors of high drug cost including characteristics at start of ART (baseline), initial regimen, treatment change, and duration on ART were assessed using mixed-effects regression models. RESULTS: Five hundred seven children initiated ART with a median 54 (interquartile range, 36-72) months of follow-up. Fifty-two percent had a drug substitution, 21% switched across class, and 2% to salvage therapy. When allowing for drug substitution, 78% remained on their initial regimen. Mean drug cost increased from $251 to $428 per child per year in the first and fifth year of therapy, respectively. PI-based and salvage regimens accounted for 16% and 2% of treatments prescribed and 33% and 5% of total costs, respectively. Predictors of high cost include baseline age >= 8 years, non nevirapine-based initial regimen, switch across drug class, and to salvage regimen (P < 0.005). CONCLUSIONS: At 5 years, 21% of children switched across drug class and 2% received salvage therapy. The mean drug cost increased by 70%. Access to affordable second- and third-line drugs is essential for the sustainability of treatment programs. PMID- 23945254 TI - Gonorrhea infections diagnosed among persons living with HIV/AIDS: identifying opportunities for integrated prevention services in New York City, Washington, DC, Miami/Dade County, and Arizona. AB - : Persons living with HIV/AIDS who acquire new sexually transmitted diseases (STDs) pose a risk for enhanced transmission of both HIV and STDs. To describe the frequency of HIV coinfection among gonorrhea cases (GC), HIV and GC surveillance databases (2000-2008) were cross-matched in New York City (NYC), Washington, DC (DC), Miami/Dade County (MDC), and Arizona (AZ). During 2000-2008, 4.6% (9471/205,689) of reported GCs occurred among persons with previously diagnosed HIV: NYC (5.5%), DC (7.3%), MDC (4%), and AZ (2%). The overall HIV-GC coinfection rates increased over the study period in all 4 sites. Real-time data integration could allow for enhanced prevention among persons with HIV infection and acute STDs. PMID- 23945255 TI - Anal sex role segregation and versatility among men who have sex with men: EXPLORE Study. AB - Anal sex role patterns and correlates during unprotected anal sex were examined longitudinally among HIV-negative men who have sex with men. Nearly 9.6% were exclusively receptive, 16.7% exclusively insertive, and 63.0% versatile. Versatility was more likely with primary and HIV-negative/unknown status partners and among younger men and substance users but less likely among Blacks and with higher number of partners. Exclusively receptive role was more likely with HIV negative/unknown status partners and among younger men and substance users but less likely with higher number of partners. Examining anal sex role patterns helps understand the factors that drive the epidemic among men who have sex with men. PMID- 23945256 TI - Annexin A2 is regulated by ovarian cancer-peritoneal cell interactions and promotes metastasis. AB - Our recent research identified the protein annexin A2 to be regulated by ovarian cancer-peritoneal cell interactions. This study investigated the role of annexin A2 in ovarian cancer metastasis and its potential utility as a novel therapeutic target, using in vitro and in vivo ovarian cancer models. Annexin A2 expression was examined by qRT-PCR and western blotting in ovarian cancer cell lines and immunohistochemistry in serous ovarian carcinoma tissues. Annexin A2 siRNAs were used to evaluate the effects of annexin A2 suppression on ovarian cancer cell adhesion, motility, and invasion. Furthermore, annexin A2 neutralizing antibodies were used to examine the role of annexin A2 in tumor invasion and metastasis in vivo using a chick chorioallantoic membrane assay and an intraperitoneal xenograft mouse model. Strong annexin A2 immunostaining was observed in 90% (38/42) of the serous ovarian cancer cells and was significantly increased in the cancer-associated stroma compared to non-malignant ovarian tissues. Annexin A2 siRNA significantly inhibited the motility and invasion of serous ovarian cancer cells and adhesion to the peritoneal cells. Annexin A2 neutralizing antibodies significantly inhibited OV-90 cell motility and invasion in vitro and in vivo using the chick chorioallantoic membrane assay. The growth of SKOV-3 cells and their peritoneal dissemination in nude mice was significantly inhibited by annexin A2 neutralizing antibodies. Annexin A2 plays a critical role in ovarian cancer metastasis and is therefore a potential novel therapeutic target against ovarian cancer. PMID- 23945257 TI - Flotillin-2 is associated with breast cancer progression and poor survival outcomes. AB - BACKGROUND: Flotillin-2 (FLOT2) has been implicated in several signaling pathways in tumor cells. Our study aimed to investigate the expression pattern and clinicopathological significance of FLOT2 in patients with breast cancer. METHODS: The expression level of FLOT2 in normal breast epithelial cells, breast cancer cell lines, and four breast cancer biopsies paired with adjacent noncancerous tissues were quantified using real-time RT-PCR and Western blotting. FLOT2 protein expression was analyzed in 171 archived paraffin-embedded breast cancer samples using immunohistochemistry (IHC). Statistical analyses were performed to evaluate the clinicopathological significance of FLOT2 expression. RESULTS: FLOT2 was significantly upregulated in breast cancer cell lines and tissue samples compared with normal cells and adjacent noncancerous breast tissues, respectively. IHC analysis revealed high expression levels of FLOT2 in 82 of 171 (48.0%) breast cancer specimens. Statistical analysis revealed that FLOT2 expression was significantly correlated with clinical stage (P < 0.001), T classification (P < 0.001), M classification (P < 0.001), histological differentiation (P = 0.005) and ErbB2 expression (P = 0.003). Patients with higher levels of FLOT2 expression had a shorter overall survival duration than patients with lower FLOT2 expression levels. Multivariate analysis suggested that FLOT2 expression was an independent prognostic marker for survival in patients with breast cancer. CONCLUSIONS: The current results demonstrated that high FLOT2 protein expression was associated with poor outcomes in patients with breast cancer. FLOT2 could be used as a prognostic biomarker for breast cancer progression. PMID- 23945258 TI - A computational study of spike time reliability in two types of threshold dynamics. AB - Spike time reliability (STR) refers to the phenomenon in which repetitive applications of a frozen copy of one stochastic signal to a neuron trigger spikes with reliable timing while a constant signal fails to do so. Observed and explored in numerous experimental and theoretical studies, STR is a complex dynamic phenomenon depending on the nature of external inputs as well as intrinsic properties of a neuron. The neuron under consideration could be either quiescent or spontaneously spiking in the absence of the external stimulus. Focusing on the situation in which the unstimulated neuron is quiescent but close to a switching point to oscillations, we numerically analyze STR treating each spike occurrence as a time localized event in a model neuron. We study both the averaged properties as well as individual features of spike-evoking epochs (SEEs). The effects of interactions between spikes is minimized by selecting signals that generate spikes with relatively long interspike intervals (ISIs). Under these conditions, the frequency content of the input signal has little impact on STR. We study two distinct cases, Type I in which the f-I relation (f for frequency, I for applied current) is continuous and Type II where the f-I relation exhibits a jump. STR in the two types shows a number of similar features and differ in some others. SEEs that are capable of triggering spikes show great variety in amplitude and time profile. On average, reliable spike timing is associated with an accelerated increase in the "action" of the signal as a threshold for spike generation is approached. Here, "action" is defined as the average amount of current delivered during a fixed time interval. When individual SEEs are studied, however, their time profiles are found important for triggering more precisely timed spikes. The SEEs that have a more favorable time profile are capable of triggering spikes with higher precision even at lower action levels. PMID- 23945259 TI - Is post-mortem ultrasonography a useful tool for forensic purposes? AB - PURPOSE: To investigate the interest of post-mortem ultrasonography in the diagnosis of pathological background, and manner and cause of death. METHODS: Post-mortem ultrasonography exams were carried out on 38 fresh human adult cadavers referred to the Department of Forensic Medicine and Pathology (Garches, France). Data obtained from ultrasonography were independently compared with further forensic autopsy findings. RESULTS: Two important limitations relative to ultrasound utilization appeared: hyper-echoic abdominal and thoracic walls, with gas distension of the whole digestive tube and subcutaneous tissues (due to precocious putrefactive gas releasing); and difficulty in accessing lateral and posterior structures (i.e. liver, spleen, kidneys, lung bases, aorta) due to rigor mortis and evident non-compliance of the subject. Post-mortem diagnoses (moderate ascites, gallbladder stones, bladder globe, chronic kidney disease, cirrhosis, thyroid gland cysts and hypertrophy, intrauterine device), were strongly limited. False negative diagnoses comprised fatty liver, pleural effusion, thoracic aortic dissection, and focal organ and/or soft tissues lesions (for example, wounds or infarcts). CONCLUSION: According to the results, post mortem ultrasonography seems to have a very limited role for forensic purposes. Other post-mortem utilizations are cited, proposed, and discussed. PMID- 23945260 TI - The relationship between NHS performance indicators and suicide rates. AB - AIMS AND METHOD: As mental health services have an important role in prevention of suicides, the relationship between Care Quality Commission performance ratings of mental health trusts and the local suicide rates were examined with the null hypothesis that there will be no relationship between them. Data on suicide rates for men and women aged 16-65 for each district covered by a mental health trust were ascertained from the Office of National Statistics for the year 2009. Data on performance ratings of mental health trusts for the same year were obtained from the Care Quality Commission Report. RESULTS: There was no significant relationship between suicide rates in the districts covered by 60 mental health trusts in England and Wales and their performance ratings. CLINICAL IMPLICATIONS: The negative findings suggest that the performance rating of mental health trusts do not influence local suicide rates. PMID- 23945261 TI - Coroner autopsy study of homicides in Rivers State of Nigeria: 11-year review. AB - As most developing countries, including Nigeria, grapple with economic crisis, poor human capital development and high levels of income inequality, violent crimes - especially homicides - continue to be a cause for concern. We studied the pathology and demographic distribution of homicides in Rivers State of Nigeria expecting that the findings would be useful in formulating preventive strategies. Reports of homicide autopsies in the state for 11 years were retrospectively scrutinized for age, gender, type of weapon, site of injury, circumstances, mechanisms and causes of death. The data were analyzed using SPSS version 17. Homicides constituted 50.5% of the medicolegal autopsies. Although the overall male:female ratio was 12.4 : 1, there was variation with weapon. Deaths by firearm had the highest male:female ratio of 24.6 : 1. The mean and peak ages were 29.2 +/- 11.4 and 21-30 years, respectively, while the range was 1 to 96 years. Firearms were the most common weapons, at 68.9%, hemorrhagic shock and head injuries at 61.5% and 28.2% respectively were the most common mechanisms and causes of death. Armed robbery incidents were the most common circumstances, while the head was the most common site of injury at 48.8%. The homicide rate is high in our environment and most homicides are committed during armed robberies using firearms. Improving medical care and providing emergency medical services will reduce cases of deaths from homicides, most of which occur due to manageable hemorrhagic shock. Increasing the drive towards controlling illegal arms acquisition and possession will reduce the present carnage in the state. PMID- 23945262 TI - Ultrasonography is unnecessary and misleading in evaluating boys with a nonpalpable testis and can be a cause of a legal process. AB - A 2-year-old boy came to our attention for a left non-palpable testis (NPT). The parents asked us to perform a laparoscopy to pull down a left intrabdominal testis (IAT), identified ultrasonographically before surgery. The ultrasonography (US) performed in another institution showed a right intrascrotal testis of normal size and a left IAT of 0.85 * 0.78 mm(2) located near the internal inguinal ring. We performed a laparoscopy that showed a blind-ending vas deferens and blind-ending inner spermatic vessels as in case of vanishing testis and a large lymphnode located near the internal inguinal ring that was closed. Parents were disappointed after laparoscopic diagnosis because the US performed before surgery showed them an IAT; for this reason they undertook a legal challenge against the pediatrician and the radiologist who had given them false information. In conclusion, we believe that in cases of NPT, laparoscopy is the gold standard for diagnosis and US is unnecessary and misleading. PMID- 23945263 TI - Assessing injury severity in bicyclists involved in traffic accidents to more effectively prevent fatal bicycle injuries in Japan. AB - The objective of this study was to clarify the relationship between injury severity in bicyclists involved in traffic accidents and patient outcome or type of vehicle involved in order to propose effective measures to prevent fatal bicycle injuries. Hospital records were reviewed for all patients from 2007 to 2010 who had been involved in a traffic accident while riding a bicycle and were subsequently transferred to the Shock Trauma Center of Dokkyo Medical University Koshigaya Hospital. Patient outcomes and type of vehicle that caused the injury were examined. The mechanism of injury, Abbreviated Injury Scale (AIS) score, and Injury Severity Score (ISS) of the patient were determined. A total of 115 patients' records were reviewed. The mean patient age was 47.1 +/- 27.4 years. The average ISS was 23.9, with an average maximum AIS (MAIS) score of 3.7. The ISS, MAIS score, head AIS score, and chest AIS score were well correlated with patient outcome. The head AIS score was significantly higher in patients who had died (mean of 4.4); however, the ISS, MAIS score, and head AIS score did not differ significantly according to the type of vehicle involved in the accident. The mean head AIS scores were as high as 2.4 or more for accidents involving any type of vehicle. This study provides useful information for forensic pathologists who suspect head injuries in bicyclists involved in traffic accidents. To effectively reduce bicyclist fatalities from traffic accidents, helmet use should be required for all bicyclists. PMID- 23945264 TI - Primary care clinicians' attitudes towards point-of-care blood testing: a systematic review of qualitative studies. AB - BACKGROUND: Point-of-care blood tests are becoming increasingly available and could replace current venipuncture and laboratory testing for many commonly used tests. However, at present very few have been implemented in most primary care settings. Understanding the attitudes of primary care clinicians towards these tests may help to identify the barriers and facilitators to their wider adoption. We aimed to systematically review qualitative studies of primary care clinicians' attitudes to point-of-care blood tests. METHODS: We systematically searched Medline, Embase, ISI Web of Knowledge, PsycINFO and CINAHL for qualitative studies of primary care clinicians' attitudes towards point-of-care blood tests in high income countries. We conducted a thematic synthesis of included studies. RESULTS: Our search identified seven studies, including around two hundred participants from Europe and Australia. The synthesis generated three main themes: the impact of point-of-care testing on decision-making, diagnosis and treatment; impact on clinical practice more broadly; and impact on patient clinician relationships and perceived patient experience. Primary care clinicians believed point-of-care testing improved diagnostic certainty, targeting of treatment, self-management of chronic conditions, and clinician-patient communication and relationships. There were concerns about test accuracy, over reliance on tests, undermining of clinical skills, cost, and limited usefulness. CONCLUSIONS: We identified several perceived benefits and barriers regarding point-of-care tests in primary care. These imply that if point-of-care tests are to become more widely adopted, primary care clinicians require evidence of their accuracy, rigorous testing of the impact of introduction on patient pathways and clinical practice, and consideration of test funding. PMID- 23945265 TI - Assessing socioeconomic vulnerability to dengue fever in Cali, Colombia: statistical vs expert-based modeling. AB - BACKGROUND: As a result of changes in climatic conditions and greater resistance to insecticides, many regions across the globe, including Colombia, have been facing a resurgence of vector-borne diseases, and dengue fever in particular. Timely information on both (1) the spatial distribution of the disease, and (2) prevailing vulnerabilities of the population are needed to adequately plan targeted preventive intervention. We propose a methodology for the spatial assessment of current socioeconomic vulnerabilities to dengue fever in Cali, a tropical urban environment of Colombia. METHODS: Based on a set of socioeconomic and demographic indicators derived from census data and ancillary geospatial datasets, we develop a spatial approach for both expert-based and purely statistical-based modeling of current vulnerability levels across 340 neighborhoods of the city using a Geographic Information System (GIS). The results of both approaches are comparatively evaluated by means of spatial statistics. A web-based approach is proposed to facilitate the visualization and the dissemination of the output vulnerability index to the community. RESULTS: The statistical and the expert-based modeling approach exhibit a high concordance, globally, and spatially. The expert-based approach indicates a slightly higher vulnerability mean (0.53) and vulnerability median (0.56) across all neighborhoods, compared to the purely statistical approach (mean = 0.48; median = 0.49). Both approaches reveal that high values of vulnerability tend to cluster in the eastern, north-eastern, and western part of the city. These are poor neighborhoods with high percentages of young (i.e., < 15 years) and illiterate residents, as well as a high proportion of individuals being either unemployed or doing housework. CONCLUSIONS: Both modeling approaches reveal similar outputs, indicating that in the absence of local expertise, statistical approaches could be used, with caution. By decomposing identified vulnerability "hotspots" into their underlying factors, our approach provides valuable information on both (1) the location of neighborhoods, and (2) vulnerability factors that should be given priority in the context of targeted intervention strategies. The results support decision makers to allocate resources in a manner that may reduce existing susceptibilities and strengthen resilience, and thus help to reduce the burden of vector-borne diseases. PMID- 23945266 TI - The effect of model uncertainty on cooperation in sensorimotor interactions. AB - Decision-makers have been shown to rely on probabilistic models for perception and action. However, these models can be incorrect or partially wrong in which case the decision-maker has to cope with model uncertainty. Model uncertainty has recently also been shown to be an important determinant of sensorimotor behaviour in humans that can lead to risk-sensitive deviations from Bayes optimal behaviour towards worst-case or best-case outcomes. Here, we investigate the effect of model uncertainty on cooperation in sensorimotor interactions similar to the stag hunt game, where players develop models about the other player and decide between a pay-off-dominant cooperative solution and a risk-dominant, non-cooperative solution. In simulations, we show that players who allow for optimistic deviations from their opponent model are much more likely to converge to cooperative outcomes. We also implemented this agent model in a virtual reality environment, and let human subjects play against a virtual player. In this game, subjects' pay-offs were experienced as forces opposing their movements. During the experiment, we manipulated the risk sensitivity of the computer player and observed human responses. We found not only that humans adaptively changed their level of cooperation depending on the risk sensitivity of the computer player but also that their initial play exhibited characteristic risk-sensitive biases. Our results suggest that model uncertainty is an important determinant of cooperation in two-player sensorimotor interactions. PMID- 23945267 TI - Phosphorylation-dependent trafficking of plasma membrane proteins in animal and plant cells. AB - In both unicellular and multicellular organisms, transmembrane (TM) proteins are sorted to and retained at specific membrane domains by endomembrane trafficking mechanisms that recognize sorting signals in the these proteins. The trafficking and distribution of plasma membrane (PM)-localized TM proteins (PM proteins), especially of those PM proteins that show an asymmetric distribution over the PM, has received much attention, as their proper PM localization is crucial for elementary signaling and transport processes, and defects in their localization often lead to severe disease symptoms or developmental defects. The subcellular localization of PM proteins is dynamically regulated by post-translational modifications, such as phosphorylation and ubiquitination. These modificaitons mostly occur on sorting signals that are located in the larger cytosolic domains of the cargo proteins. Here we review the effects of phosphorylation of PM proteins on their trafficking, and present the key examples from the animal field that have been subject to studies for already several decades, such as that of aquaporin 2 and the epidermal growth factor receptor. Our knowledge on cargo trafficking in plants is largely based on studies of the family of PIN FORMED (PIN) carriers that mediate the efflux of the plant hormone auxin. We will review what is known on the subcellular distribution and trafficking of PIN proteins, with a focus on how this is modulated by phosphorylation, and identify and discuss analogies and differences in trafficking with the well-studied animal examples. PMID- 23945268 TI - Comments on the "No-Prop" algorithm. AB - This letter points out that the main ideas and conclusions of the "The No-Prop algorithm" paper which has recently appeared in this journal were proposed earlier by G.-B. Huang et al. 10 years ago and intensively discussed and applied by other authors in the past 10 years. PMID- 23945270 TI - Cytotoxicity of Brazilian plant extracts against oral microorganisms of interest to dentistry. AB - BACKGROUND: With the emergence of strains resistant to conventional antibiotics, it is important to carry studies using alternative methods to control these microorganisms causing important infections, such as the use of products of plant origin that has demonstrated effective antimicrobial activity besides biocompatibility. Therefore, this study aimed to evaluate the antimicrobial activity of plant extracts of Equisetum arvense L., Glycyrrhiza glabra L., Punica granatum L. and Stryphnodendron barbatimam Mart. against Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mutans, Candida albicans, Candida tropicalis, and Candida glabrata, and to analyze the cytotoxicity of these extracts in cultured murine macrophages (RAW 264.7). METHODS: Antimicrobial activity of plant extracts was evaluated by microdilution method based on Clinical and Laboratory Standards Institute (CLSI), M7-A6 and M27-A2 standards. The cytotoxicity of concentrations that eliminated the microorganisms was evaluated by MTT colorimetric method and by quantification of proinflammatory cytokines (IL-1beta and TNF-alpha) using ELISA. RESULTS: In determining the minimum microbicidal concentration, E. arvense L., P. granatum L., and S. barbatimam Mart. extracts at a concentration of 50 mg/mL and G. glabra L. extract at a concentration of 100 mg/mL, were effective against all microorganisms tested. Regarding cell viability, values were 48% for E. arvense L., 76% for P. granatum L, 86% for S. barbatimam Mart. and 79% for G. glabra L. at the same concentrations. About cytokine production after stimulation with the most effective concentrations of the extracts, there was a significant increase of IL 1beta in macrophage cultures treated with S. barbatimam Mart. (3.98 pg/mL) and P. granatum L. (7.72 pg/mL) compared to control (2.20 pg/mL) and a significant decrease of TNF-alpha was observed in cultures treated with G. glabra L. (4.92 pg/mL), S. barbatimam Mart. (0.85 pg/mL), E. arvense L. (0.83 pg/mL), and P. granatum L. (0.00 pg/mL) when compared to control (41.96 pg/mL). CONCLUSIONS: All plant extracts were effective against the microorganisms tested. The G. glabra L. extract exhibited least cytotoxicity and the E. arvense L. extract was the most cytotoxic. PMID- 23945271 TI - Red blood cell transfusion: what is the evidence when to transfuse? AB - PURPOSE OF REVIEW: This review provides a summary of the clinical trials evaluating transfusion thresholds and recommendations for red blood cell transfusion. We highlight the trial results in patients in the critical care setting, undergoing surgery, and patients with gastrointestinal bleed, acute coronary syndrome, and acute brain injury. RECENT FINDINGS: Clinical trials in hip fracture patients with underlying cardiovascular disease or risk factors, and in cardiac surgery, support the findings from prior studies in intensive care unit patients that restrictive transfusion (7-8 g/dl) is well tolerated even in elderly high-risk patients. Restrictive transfusion strategy (7 g/dl) was further supported by the statistically lower mortality in patients with gastrointestinal bleeding compared with liberal transfusion (10 g/dl) strategy. Pilot trials in acute coronary syndrome raise the possibility that liberal transfusion improves outcome, but large trials are needed. SUMMARY: A restrictive transfusion strategy of administering red blood cell transfusion in patients with hemoglobin concentration of 7-8 g/dl in most patients is supported by randomized clinical trials. Further randomized clinical trials are needed to establish the optimal transfusion threshold in patients with acute coronary syndrome and brain injury, and to elucidate physiological triggers. PMID- 23945272 TI - Backtracking dynamics of RNA polymerase: pausing and error correction. AB - Transcription by RNA polymerases is frequently interrupted by pauses. One mechanism of such pauses is backtracking, where the RNA polymerase translocates backward with respect to both the DNA template and the RNA transcript, without shortening the transcript. Backtracked RNA polymerases move in a diffusive fashion and can return to active transcription either by diffusive return to the position where backtracking was initiated or by cleaving the transcript. The latter process also provides a mechanism for proofreading. Here we present some exact results for a kinetic model of backtracking and analyse its impact on the speed and the accuracy of transcription. We show that proofreading through backtracking is different from the classical (Hopfield-Ninio) scheme of kinetic proofreading. Our analysis also suggests that, in addition to contributing to the accuracy of transcription, backtracking may have a second effect: it attenuates the slow down of transcription that arises as a side effect of discriminating between correct and incorrect nucleotides based on the stepping rates. PMID- 23945274 TI - Blood pressure reduction induced by low dose of epinephrine via different routes in rats. AB - BACKGROUND: Epinephrine was recently shown to induce a hypotension episode. Activation of beta2-adrenoceptors with smooth muscle relaxation may be the underlying mechanism. This study investigated the effects of ICI 118551, a beta2 adrenoceptors antagonist, on epinephrine-induced blood pressure reduction via different administration routes in rats. METHODS: A total of 144 Sprague Dawley rats were equally randomized into 3 groups (intranasal, intravenous, and intra arterial administration), each with 4 subgroups: saline + saline, ICI 118551 + saline, saline + epinephrine, and ICI 118551 + epinephrine. All rats were anesthetized while spontaneously breathing. Epinephrine was administered at doses of 5 MUg/kg via nose, 0.25 MUg/kg via femoral vein, and 0.1 MUg/kg via aorta. Mean arterial pressure and heart rate were monitored. RESULTS: Mean arterial pressure decreased in all 3 saline + epinephrine subgroups after administration (P < 0.05), whereas it did not in other subgroups. Heart rate had no significant change in all subgroups. CONCLUSIONS: Epinephrine-induced blood pressure reduction can be prevented by ICI 118551 in rats, suggesting that the activation of beta2-adrenoceptors contributes to blood pressure reduction. PMID- 23945275 TI - Expanding the therapeutic frontier in atherosclerosis. PMID- 23945276 TI - HMGA1 promotes metastatic processes in basal-like breast cancer regulating EMT and stemness. AB - Breast cancer is a heterogeneous disease that progresses to the critical hallmark of metastasis. In the present study, we show that the High Mobility Group A1 (HMGA1) protein plays a fundamental role in this process in basal-like breast cancer subtype. HMGA1 knockdown induces the mesenchymal to epithelial transition and dramatically decreases stemness and self-renewal. Notably, HMGA1 depletion in basal-like breast cancer cell lines reduced migration and invasion in vitro and the formation of metastases in vivo. Mechanistically, HMGA1 activated stemness and key migration-associated genes which were linked to the Wnt/beta-catenin, Notch and Pin1/mutant p53 signalling pathways. Moreover, we identified a specific HMGA1 gene expression signature that was activated in a large subset of human primary breast tumours and was associated with poor prognosis. Taken together, these data provide new insights into the role of HMGA1 in the acquisition of aggressive features in breast cancer. PMID- 23945278 TI - Excitable neurons, firing threshold manifolds and canards. AB - We investigate firing threshold manifolds in a mathematical model of an excitable neuron. The model analyzed investigates the phenomenon of post-inhibitory rebound spiking due to propofol anesthesia and is adapted from McCarthy et al. (SIAM J. Appl. Dyn. Syst. 11(4):1674-1697, 2012). Propofol modulates the decay time-scale of an inhibitory GABAa synaptic current. Interestingly, this system gives rise to rebound spiking within a specific range of propofol doses. Using techniques from geometric singular perturbation theory, we identify geometric structures, known as canards of folded saddle-type, which form the firing threshold manifolds. We find that the position and orientation of the canard separatrix is propofol dependent. Thus, the speeds of relevant slow synaptic processes are encoded within this geometric structure. We show that this behavior cannot be understood using a static, inhibitory current step protocol, which can provide a single threshold for rebound spiking but cannot explain the observed cessation of spiking for higher propofol doses. We then compare the analyses of dynamic and static synaptic inhibition, showing how the firing threshold manifolds of each relate, and why a current step approach is unable to fully capture the behavior of this model. PMID- 23945279 TI - Infectious neuropathies. AB - PURPOSE OF REVIEW: Infectious neuropathies are heterogeneous neuropathies with multiple causes. They still represent an important world health burden and some of them have no current available therapy. RECENT FINDINGS: Leprosy incidence has decreased by 50% during the last years, but leprosy-related neuropathies still cause severe disability. The pure neuritic leprosy is a diagnostic challenge that may require nerve biopsy or nerve aspiration cytology. The treatment itself may lead to a 'reversal reaction', which further causes injuries to the nerve. HCV related neuropathies may be related or not to the presence of cryoglobulins. The absence of vasculitis, the most frequent form is a peripheral sensory neuropathy involving small nerve fibers, and more accurately diagnosed by pain-related evoked potentials. HIV-related neuropathy has become the major neurological complication of HIV infection. Both HIV-induced neuropathy and antiretroviral toxic neuropathy are clinically indistinguishable. The existence of an isolated chronic polyneuropathy due to Borrelia burgdorferi remains highly controversial. Lastly, an active infectious ganglioneuritis caused by varicella zoster virus, producing shingles, is the most frequent infectious neuropathy in the world and may cause various neurological complications. Zoster sine herpete remains frequently undiagnosed. SUMMARY: Recent data have improved our knowledge and diagnostic tools of infectious neuropathies. Treatment of the injured nerves is not yet available, and prevention and rapid diagnosis remain the main priorities for the clinician. PMID- 23945280 TI - The various Charcot-Marie-Tooth diseases. AB - PURPOSE OF REVIEW: This review focuses on recent advances in the diagnostic approaches and the underlying pathophysiological mechanisms of Charcot-Marie Tooth (CMT) disease. We also discuss the emerging therapies for this hereditary neuropathy. RECENT FINDINGS: To date, numerous genes are implicated in CMT, and new genes have recently been found to be associated with this neuropathy (INF2, FBLN5, etc.). Some specific or evocative clinical signs of CMT subtypes (proteinuria with INF2 mutations, etc.) have been identified. Characteristic pathological findings, which may suggest gene mutations, are also recognized by nerve biopsy (mainly ultrastructural lesions). SUMMARY: CMT disease is the most common inherited neuromuscular disorder, with a fairly homogeneous clinical phenotype (progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, and depressed tendon reflexes). With more than 40 genes implicated, an update of the present and rather confusing classification of CMT is needed. Over the last few years, new mutated genes have been discovered. Although nerve biopsy is not routinely carried out in CMT neuropathies, it may show characteristic features, which can orientate the search for the mutated gene. There are currently no effective medications for CMT, but clinical trials are ongoing or planned. PMID- 23945281 TI - Clinical implications of recent breakthroughs in amyotrophic lateral sclerosis. AB - PURPOSE OF REVIEW: This review examines the clinical implications of recent breakthroughs in amyotrophic lateral sclerosis (ALS). RECENT FINDINGS: ALS has been found to be a highly variable condition at the clinical, genetic and mechanistic level. The study of newly discovered genetic causes for ALS has demonstrated that in addition to the effect of toxic mutant proteins, abnormalities of RNA householding contribute to motor neuron degeneration. Furthermore, the classic distinction between gain of function and loss of function may be an oversimplification of the biological reality. The most important clinical breakthrough was the finding of intronic hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) as a common cause of ALS, frontotemporal lobar degeneration (FTLD) and ALS with concomitant FTLD. This provides unambiguous evidence that ALS and FTLD represent the ends of one spectrum of neurodegenerative diseases. The high prevalence of C9orf72 mutations in patients without family history further blurs the distinction between sporadic and familial forms of ALS and FTLD. It also opens opportunities for stratified clinical trials in ALS and for the development of targeted therapies. SUMMARY: ALS is a heterogeneous disorder that overlaps with FTLD. C9orf72 mutations are the most common cause of ALS, and add to the evidence that disturbances in RNA householding contribute to ALS. PMID- 23945277 TI - Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. AB - Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients. Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the 'frequent exacerbator' phenotype. This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes. These patients are therefore a priority for research and treatment. The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection. Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment. Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype. This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities. PMID- 23945282 TI - Myasthenia gravis and the neuromuscular junction. AB - PURPOSE OF REVIEW: Myasthenic disorders are a well characterized group of diseases of the neuromuscular junction. Their pathogenesis is diverse, including genetic and autoimmune mechanisms. We review recent findings on risk factors, pathogenesis and treatment of autoimmune myasthenia gravis. RECENT FINDINGS: Better knowledge of congenital myasthenia has led to the development of efficient diagnostic algorithms that have therapeutic implications. New epidemiological and genetic risk factors have been identified and are considered to play a role in the development of myasthenia gravis. The study of the role of innate immunity in myasthenia gravis has identified relevant pathways to explain myasthenia gravis causes. The description of the pathogenic role of IgG4 anti-MuSK antibodies has revealed heterogeneous immune mechanisms that should lead to more specific therapies. Rituximab seems to be particularly effective in MuSK myasthenia gravis, and eculizumab arises as an option in refractory AChR myasthenia gravis. Therapeutic algorithms need to be tailored to each myasthenia subtype. SUMMARY: Increasing knowledge about the environmental and genetic risk factors and basic immunopathogenesis of myasthenia gravis, including the role of innate immunity, regulatory T cell impairment and autoantibody heterogeneity, is providing a rationale for treatment with new biological agents. Current immunotherapies in myasthenia gravis undoubtedly provide benefits, but also cause side-effects. Controlled trials are, therefore, needed to confirm initial results from pilot studies. PMID- 23945283 TI - Megaconial congenital muscular dystrophy due to loss-of-function mutations in choline kinase beta. AB - PURPOSE OF REVIEW: Recessive mutations in CHKB cause a megaconial congenital muscular dystrophy whose most characteristic feature is mitochondrial enlargement at the periphery of muscle fibers and loss of mitochondria in the center of muscle fibers. This review will summarize clinicopathological features, genetic cause, and biochemical abnormalities of the disease, trying to decipher the mechanism of this complex disorder. RECENT FINDINGS: Since our report of CHKB mutations found in 15 cases with megaconial congenital muscular dystrophy from Japanese, Turkish, and British populations, we have further identified two British and one French patients. One African-American patient has also been reported by another group. All patients have relatively homogenous phenotype although severity varies to some extent. The peculiar distribution pattern of enlarged mitochondria on muscle section seems to be due to a compensatory mechanism after the elimination of functionally defective mitochondria by mitophagy. SUMMARY: CHKB encodes choline kinase beta, an enzyme that catalyzes the first de-novo biosynthetic step of phosphatidylcholine, the most abundant phospholipid in the eukaryotic membrane. The identification of a new muscle disease caused by the defect in phospholipid metabolism will pave the way for a novel biological pathway that connects phospholipid metabolism, mitochondria biology, and muscular dystrophy. PMID- 23945284 TI - Epidermal patterning genes impose non-cell autonomous cell size determination and have additional roles in root meristem size control. AB - The regulation of cellular growth is of vital importance for embryonic and postembryonic patterning. Growth regulation in the epidermis has importance for organ growth rates in roots and shoots, proposing epidermal cells as an interesting model for cellular growth regulation. Here we assessed whether the root epidermis is a suitable model system to address cell size determination. In Arabidopsis thaliana L., root epidermal cells are regularly spaced in neighbouring tricho- (root hair) and atrichoblast (non-hair) cells, showing already distinct cell size regulation in the root meristem. We determined cell sizes in the root meristem and at the onset of cellular elongation, revealing that not only division rates but also cellular shape is distinct in tricho- and atrichoblasts. Intriguingly, epidermal-patterning mutants, failing to define differential vacuolization in neighbouring epidermal cell files, also display non differential growth. Using these epidermal-patterning mutants, we show that polarized growth behaviour of epidermal tricho- and atrichoblast is interdependent, suggesting non-cell autonomous signals to integrate tissue expansion. Besides the interweaved cell-type-dependent growth mechanism, we reveal an additional role for epidermal patterning genes in root meristem size and organ growth regulation. We conclude that epidermal cells represent a suitable model system to study cell size determination and interdependent tissue growth. PMID- 23945285 TI - Older adults' transportation walking: a cross-sectional study on the cumulative influence of physical environmental factors. AB - BACKGROUND: The physical environment may play a crucial role in promoting older adults' walking for transportation. However, previous studies on relationships between the physical environment and older adults' physical activity behaviors have reported inconsistent findings. A possible explanation for these inconsistencies is the focus upon studying environmental factors separately rather than simultaneously. The current study aimed to investigate the cumulative influence of perceived favorable environmental factors on older adults' walking for transportation. Additionally, the moderating effect of perceived distance to destinations on this relationship was studied. METHODS: The sample was comprised of 50,685 non-institutionalized older adults residing in Flanders (Belgium). Cross-sectional data on demographics, environmental perceptions and frequency of walking for transportation were collected by self-administered questionnaires in the period 2004-2010. Perceived distance to destinations was categorized into short, medium, and large distance to destinations. An environmental index (=a sum of favorable environmental factors, ranging from 0 to 7) was constructed to investigate the cumulative influence of favorable environmental factors. Multilevel logistic regression analyses were applied to predict probabilities of daily walking for transportation. RESULTS: For short distance to destinations, probability of daily walking for transportation was significantly higher when seven compared to three, four or five favorable environmental factors were present. For medium distance to destinations, probabilities significantly increased for an increase from zero to four favorable environmental factors. For large distance to destinations, no relationship between the environmental index and walking for transportation was observed. CONCLUSIONS: Our findings suggest that the presence of multiple favorable environmental factors can motivate older adults to walk medium distances to facilities. Future research should focus upon the relationship between older adults' physical activity and multiple environmental factors simultaneously instead of separately. PMID- 23945286 TI - Teamwork in primary care: perspectives of general practitioners and community nurses in Lithuania. AB - BACKGROUND: A team approach in primary care has proven benefits in achieving better outcomes, reducing health care costs, satisfying patient needs, ensuring continuity of care, increasing job satisfaction among health providers and using human health care resources more efficiently. However, some research indicates constraints in collaboration within primary health care (PHC) teams in Lithuania. The aim of this study was to gain a better understanding of the phenomenon of teamwork in Lithuania by exploring the experiences of teamwork by general practitioners (GPs) and community nurses (CNs) involved in PHC. METHODS: Six focus groups were formed with 29 GPs and 27 CNs from the Kaunas Region of Lithuania. Discussions were recorded and transcribed verbatim. A thematic analysis of these data was then performed. RESULTS: The analysis of focus group data identified six thematic categories related to teamwork in PHC: the structure of a PHC team, synergy among PHC team members, descriptions of roles and responsibilities of team members, competencies of PHC team members, communications between PHC team members and the organisational background for teamwork. These findings provide the basis for a discussion of a thematic model of teamwork that embraces formal, individual and organisational factors. CONCLUSIONS: The need for effective teamwork in PHC is an issue receiving broad consensus; however, the process of teambuilding is often taken for granted in the PHC sector in Lithuania. This study suggests that both formal and individual behavioural factors should be targeted when aiming to strengthen PHC teams. Furthermore, this study underscores the need to provide explicit formal descriptions of the roles and responsibilities of PHC team members in Lithuania, which would include establishing clear professional boundaries. The training of team members is an essential component of the teambuilding process, but not sufficient by itself. PMID- 23945287 TI - Comparative study of an externship program versus a corporate-academic cooperation program for enhancing nursing competence of graduating students. AB - BACKGROUND: New graduates report intense stress during the transition from school to their first work settings. Managing this transition is important to reduce turnover rates. This study compared the effects of an externship program and a corporate-academic cooperation program on enhancing junior college students' nursing competence and retention rates in the first 3 months and 1 year of initial employment. METHODS: This two-phase study adopted a pretest and posttest quasi-experimental design. All participants were graduating students drawn from a 5-year junior nursing college in Taiwan. There were 19 and 24 students who participated in the phase I externship program and phase II corporate-academic cooperation program, respectively. The nursing competence of the students had to be evaluated by mentors within 48 hours of practicum training and after practicum training. The retention rate was also surveyed at 3 months and 1 year after beginning employment. RESULTS: Students who participated in the corporate academic cooperation program achieved a statistically significant improvement in nursing competence and retention rates relative to those who participated in the externship program (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: The corporate-academic cooperation program facilitates the transition of junior college nursing students into independent staff nurses, enhances their nursing competence, and boosts retention rates. PMID- 23945288 TI - Atoh7 promotes the differentiation of retinal stem cells derived from Muller cells into retinal ganglion cells by inhibiting Notch signaling. AB - INTRODUCTION: Retinal Muller cells exhibit the characteristics of retinal progenitor cells, and differentiate into ganglion cells under certain conditions. However, the number of ganglion cells differentiated from retinal Muller cells falls far short of therapeutic needs. This study aimed to develop a novel protocol to promote the differentiation of retinal Muller cells into ganglion cells and explore the underlying signaling mechanisms. METHODS: Muller cells were isolated and purified from rat retina and induced to dedifferentiate into retinal stem cells. Next the stem cells were transfected with lentivirus PGC-FU-GFP or lentivirus PGC-FU-Atoh7-GFP. In addition, the stem cells were transfected with Brn-3b siRNA or Isl-1 siRNA or treated with Notch inhibitor gamma-secretase inhibitor (GSI). RESULTS: The proportion of ganglion cells differentiated from Atoh7-tranfected stem cells was significantly higher than that of controls. Knockdown of Brn-3b or Isl-1 inhibited, while GSI promoted, the differentiation into retinal ganglion cells. Atoh7 promoted the expression of Brn-3b and Isl-1 but inhibited the expression of Notch1. CONCLUSIONS: Atoh7 promotes the differentiation of Muller cells-derived retinal stem cells into retinal ganglion cells by inhibiting Notch signaling, thus opening up a new avenue for gene therapy and optic nerve regeneration in glaucoma. PMID- 23945289 TI - Crucial role for early growth response-1 in the transcriptional regulation of miR 20b in breast cancer. AB - Transcriptional regulation of miRNAs that control the pathogenesis of breast cancer remains largely unknown. Here, we showed that ionizing radiation, a known breast carcinogen, triggered the differential expression of miR-20b in mammary tissues. We identified several GC-rich consensus binding motifs for the zinc finger transcription factor early growth response-1 (EGR1) in miR-20b promoter. miR-20b was upregulated by IR and its upregulation correlated with EGR1 expression in the breast cancer cell line HCC1806. Therefore, we used HCC1806 cells as a model system to explore the role of EGR1 in miR-20b transcription. siRNA knockdown of EGR1 attenuated miR-20b expression. Luciferase assays showed that whereas EGR1 stimulated luciferase activity driven by the wild-type miR-20b promoter, this induction was abolished in the mutant miR-20 promoter construct. We noted significant enrichment of EGR1 at miR-20b promoter in HCC1806 cells compared with normal human mammary epithelial cells. Suppression of miR-20b significantly inhibited HCC1806 cell proliferation and migration, and led to G0/G1 and S phase arrest. In vitro RNA-pull down assays indicated that miR-20b targets numerous tumor suppressors, including PTEN and BRCA1, which were downregulated in HCC1806. Conversely, suppression of miR-20b increased PTEN and BRCA1 levels. Moreover, immunohistochemical and FISH analyses showed that the miR 20b expression correlated significantly with EGR1 levels in breast cancer tissues. Our findings thus demonstrate for the first time that EGR1 is a key player in the transcriptional control of miR-20b, and miR-20b may in turn function as an oncogene by contributing to breast tumorigenesis via tumor suppressor targeting. PMID- 23945291 TI - New standards for safe patient handling and mobility. PMID- 23945290 TI - Efficacy of prosultiamine treatment in patients with human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis: results from an open label clinical trial. AB - BACKGROUND: Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic myelopathy characterized by motor dysfunction of the lower extremities and urinary disturbance. Immunomodulatory treatments are the main strategy for HAM/TSP, but several issues are associated with long-term treatment. We conducted a clinical trial with prosultiamine (which has apoptotic activity against HTLV-I-infected cells) as a novel therapy in HAM/TSP patients. METHODS: We enrolled 24 HAM/TSP patients in this open-label clinical trial. Prosultiamine (300 mg, orally) was administered once daily for 12 weeks. We monitored changes in the motor function of the lower extremities and urinary function as well as copy numbers of the HTLV I provirus in peripheral blood mononuclear cells (PBMCs). RESULTS: Improvement in the motor function of the lower extremities based on a reduction in spasticity (for example, decrease in time required for walking and descending a flight of stairs) was observed. In an urodynamic study (UDS), bladder capacity and detrusor pressure and then maximum flow rate increased significantly. Detrusor overactivity and detrusor-sphincter dyssynergia improved in 68.8% and 45.5% of patients observed at pretreatment, respectively. Improvement in UDS corresponded with improvements in the score of nocturia-quality of life questionnaire. HTLV-I proviral copy numbers in PBMCs decreased significantly (approximately 15.4%) compared with pretreatment levels. CONCLUSIONS: These data suggest that prosultiamine can safely improve motor dysfunction of the lower extremities and urinary disturbance as well as reduce HTLV-I provirus levels in peripheral blood. It therefore has potential as a new therapeutic tool for HAM/TSP patients. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number, UMIN000005969. Please see related commentary: http://www.biomedcentral.com/1741-7015/11/183. PMID- 23945292 TI - Effects of oral branched-chain amino acids on hepatic encephalopathy and outcome in patients with liver cirrhosis. AB - Branched-chain amino acids (BCAAs) constituting of valine, leucine, and isoleucine act as both substrates of proteins and as key regulators for various nutrient metabolisms. Patients with liver cirrhosis frequently lack sufficient BCAAs and therefore suffer from various metabolic disorders. Hepatic encephalopathy (HE) is a severe metabolic disorder with neurologic manifestations such as flapping tremors and coma in patients with liver cirrhosis. In addition, a mild form of HE known as minimal HE (MHE) is an important social issue because it occurs in up to 80% of patients with chronic liver disease and affects prognosis and activities of daily living, possibly resulting in falls and motor vehicle accidents. Although HE/MHE can be caused by various pathological conditions, including in an accumulation of mercaptans, short-chain fatty acids, and alterations in the gut flora, hyperammonemia has also been implicated in an important pathogenesis of HE/MHE. Besides urea cycle of liver, ammonia can be detoxified in the skeletal muscles by the amidation process for glutamine synthesis using BCAAs. Thus, BCAA supplementation may enhance detoxification of ammonia in skeletal muscle and may be a possible therapeutic strategy for HE/MHE. In this review, we summarize the clinical impacts of BCAA supplementation on HE/MHE and discuss possible mechanisms for a BCAA-induced improvement of HE/MHE. Furthermore, we present some modifications of oral BCAA therapy for improvement of efficacy in HE treatment. We also briefly describe pleiotropic benefits of BCAAs on life-threatening events and overall prognosis in patients with liver cirrhosis. PMID- 23945294 TI - First-passage problems in DNA replication: effects of template tension on stepping and exonuclease activities of a DNA polymerase motor. AB - A DNA polymerase (DNAP) replicates a template DNA strand. It also exploits the template as the track for its own motor-like mechanical movement. In the polymerase mode it elongates the nascent DNA by one nucleotide in each step. However, whenever it commits an error by misincorporating an incorrect nucleotide, it can switch to an exonuclease mode. In the latter mode it excises the wrong nucleotide before switching back to its polymerase mode. We develop a stochastic kinetic model of DNA replication that mimics an in vitro experiment where single-stranded DNA, subjected to a mechanical tension F, is converted to double-stranded DNA by a single DNAP. The F-dependence of the average rate of replication, which depends on the rates of both polymerase and exonuclease activities of the DNAP, is in good qualitative agreement with the corresponding experimental results. We introduce nine novel distinct conditional dwell times of a DNAP. Using the method of first-passage times, we also derive the exact analytical expressions for the probability distributions of these conditional dwell times. The predicted F-dependences of these distributions are, in principle, accessible to single-molecule experiments. PMID- 23945295 TI - Phase-amplitude response functions for transient-state stimuli. AB - The phase response curve (PRC) is a powerful tool to study the effect of a perturbation on the phase of an oscillator, assuming that all the dynamics can be explained by the phase variable. However, factors like the rate of convergence to the oscillator, strong forcing or high stimulation frequency may invalidate the above assumption and raise the question of how is the phase variation away from an attractor. The concept of isochrons turns out to be crucial to answer this question; from it, we have built up Phase Response Functions (PRF) and, in the present paper, we complete the extension of advancement functions to the transient states by defining the Amplitude Response Function (ARF) to control changes in the transversal variables. Based on the knowledge of both the PRF and the ARF, we study the case of a pulse-train stimulus, and compare the predictions given by the PRC-approach (a 1D map) to those given by the PRF-ARF-approach (a 2D map); we observe differences up to two orders of magnitude in favor of the 2D predictions, especially when the stimulation frequency is high or the strength of the stimulus is large. We also explore the role of hyperbolicity of the limit cycle as well as geometric aspects of the isochrons. Summing up, we aim at enlightening the contribution of transient effects in predicting the phase response and showing the limits of the phase reduction approach to prevent from falling into wrong predictions in synchronization problems. LIST OF ABBREVIATIONS: PRC phase response curve, phase resetting curve.PRF phase response function.ARF amplitude response function. PMID- 23945298 TI - [Surgical therapy of inflammatory bowel disease and its optimal timing]. PMID- 23945297 TI - [Multidisciplinary treatment of anal fistulae in Crohn's disease]. PMID- 23945296 TI - Cross-talk between HIF and p53 as mediators of molecular responses to physiological and genotoxic stresses. AB - Abnormal rates of growth together with metastatic potential and lack of susceptibility to cellular signals leading to apoptosis are widely investigated characteristics of tumors that develop via genetic or epigenetic mechanisms. Moreover, in the growing tumor, cells are exposed to insufficient nutrient supply, low oxygen availability (hypoxia) and/or reactive oxygen species. These physiological stresses force them to switch into more adaptable and aggressive phenotypes. This paper summarizes the role of two key mediators of cellular stress responses, namely p53 and HIF, which significantly affect cancer progression and compromise treatment outcomes. Furthermore, it describes cross talk between these factors. PMID- 23945299 TI - [The prevalence and characteristics of anemia in Crohn's disease in the Chinese]. AB - OBJECTIVE: To investigate the prevalence and characteristics of anemia among patients with Crohn's disease (CD) in Chinese population and identify the possible risk factors. METHODS: A cross-sectional study was performed in 441 patients with CD enrolled from the First Affiliated Hospital of Sun Yat-Sen University between January 2003 and May 2012. The prevalence, severity, type of anemia in these patients was assessed when diagnosis was confirmed. A multivariate logistic regression including 122 patients was performed to screen risk factors of anemia. RESULT: The prevalence of anemia was 64.4% (284/441) with 69.0% (196/284) mild anemia, 28.9% (82/284) moderate anemia and 2.1% (6/284) severe anemia. The most common morphological classification was hypochromic microcytic anemia (43.7%, 124/284). Multivariate logistic regression showed the predictive factors for anemia were higher levels of modified Crohn's disease activity index (CDAI) (OR = 1.007, 95% CI 1.002-1.013), platelet count (OR = 1.007, 95% CI 1.001-1.012), erythrocyte sedimentation rate (OR = 1.024, 95% CI 1.000-1.048), penetrating behavior (OR = 16.952, 95% CI 2.626-108.626), structuring behavior (OR = 6.717, 95% CI 1.583-28.507), older age at diagnosis (OR = 1.065, 95% CI 1.012-1.121),and lower body mass index (BMI) (OR = 0.769, 95% CI 0.633-0.935). CONCLUSIONS: Anemia is a common complication in patients with CD among Chinese population. Activity of the underlying disease, older age at diagnosis, penetrating or structuring disease behavior and low BMI are the risk factors. PMID- 23945300 TI - [The expression of peripheral Th1 and Th17 cells in inflammatory bowel disease and its potential clinical value]. AB - OBJECTIVE: To explore the probable role of Th1 and Th17 cells in the pathogenesis of inflammatory bowel disease (IBD). METHODS: The peripheral blood mononuclear cells (PBMCs) from peripheral blood specimens were collected in the study, including 40 healthy controls, 42 ulcerative colitis (UC) and 39 Crohn's disease (CD). The proportion of Th1 and Th17 cells in the PBMCs was detected with flow cytometry after stimulated by PMA and ionomycin. The result and the clinical data were analyzed. RESULT: The Th1 cell expression was increased in CD (38.32 +/- 16.18)% and UC group (34.23 +/- 11.60)%, compared with the controls (24.58 +/- 10.02)% (P < 0.01). During the convalescence, the Th1 expression in the CD and UC groups in vivo was significantly reduced without difference between the two groups (P > 0.05) . In the IBD group , significant difference in the frequency of Th17 cells could be found between the CD group (2.51 +/- 1.59)% and the UC group (4.15 +/- 2.75)%, while the Th17 cells were increased in both groups, compared with the controls (1.44 +/- 0.73)% (P < 0.05) . Obvious difference in the frequency of Th17 cells could be found between patients at different activity stages and remission stages. The proportion of Th17 cells were higher in the UC patients than that in the CD patients (P < 0.01) . The Th17/Th1 ratio of CD patients, UC patients were 0.08 +/- 0.06, 0.14 +/- 0.11, which were both higher that in the controls (0.07 +/- 0.06). Significant difference could be found between the UC group and the CD group (P < 0.01). CONCLUSIONS: The higher proportion of Th1 and Th17 cells are detected in the peripheral blood of IBD patients, which is correlated closely to the activity of the disease. Th1 and Th17 cells may play an important role in the pathogenesis of IBD. PMID- 23945301 TI - [The prevalence and risk factors of bronchiectasis in residents aged 40 years old and above in seven cities in China]. AB - OBJECTIVE: To investigate the prevalence and risk factors of bronchiectasis in urban city of China. METHODS: A cross-sectional survey was conducted in 17 urban areas in Beijing, Shanghai, Tianjin, Chongqing cities, and Guangdong, Liaoning, Shanxi provinces. In this study, urban population-based cluster samples were randomly selected from each city/province. In the selected city communities, all residents at least 40 years old were recruited, interviewed with questionnaires and tested with spirometry. Each participant was asked whether he/she was ever diagnosed as bronchiectasis by physician, whether had symptoms of respiratory diseases and possible risk factors, etc. RESULT: Data of 10 811 participants was enrolled for analysis, with a response rate of 75.4% (10 811/14 337). The overall prevalence of physician-diagnosed bronchiectasis was 1.2% (135/10 811), with 1.5% (65/4382) in male and 1.1% (70/6429) in female, without statistical difference in gender (chi2 = 3.289, P = 0.070). Prevalence of bronchiectasis increased with age (chi2 = 31.029, P < 0.001). There were no statistical significances in crude prevalences of bronchiectasis among cities (chi2 = 10.572, P = 0.103), while there was a significant difference among cities after adjustment with confounders (Wald value = 22.116, P = 0.001), by using logistic regression analysis. Logistic regression analysis showed, bronchiectasis was significantly associated with elder ( >= 70 years vs 40-49 years; OR = 4.11, 95% CI 2.29-7.36), the family history of respiratory diseases (having two subjects with respiratory diseases in family vs no suffered relatives; OR = 2.04, 95% CI 1.06-3.94), respiratory infection during childhood (suffering two kinds of respiratory diseases vs never; OR = 4.89, 95% CI 2.03-11.81), exposure to coal (OR = 2.30, 95% CI 1.17-4.52), chronic pharyngitis (OR = 3.96, 95% CI 1.38-11.40) and pulmonary tuberculosis (OR = 3.07, 95% CI 1.89-4.98), heart diseases (OR = 1.64, 95% CI 1.11-2.42) and lung cancer(OR = 18.61, 95% CI 7.67-45.18). CONCLUSION: The prevalence of bronchiectasis in population aged 40 years old and above in urban area in China is high and associated with multiple factors such as age, family history of respiratory diseases, respiratory infection during childhood, exposure to coal, chronic pharyngitis, pulmonary tuberculosis, heart diseases, lung cancer and so on. PMID- 23945302 TI - [The clinical analysis of 14 cases of systemic lupus erythematosus complicated by thrombotic thrombocytopenic purpura]. AB - OBJECTIVE: To analyze the clinical features, diagnosis and treatment of thrombotic thrombocytopenic purpura (TTP) in patients with systemic lupus erythematosus (SLE). METHODS: Clinical manifestations, laboratory findings, diagnosis,treatment and prognosis of 14 SLE patients with TTP were retrospectively analyzed. RESULT: Of the 14 patients diagnosed with SLE and TTP, 4 were men and 10 were women. The median age at diagnosis was 23 (17-69) years old. In five patients, the onset of SLE preceded TTP, and in nine patients SLE and TTP occurred simultaneously. All the 14 patients had thrombocytopenia and hemolytic anemia, 12 had fever, 11 had neurologic abnormalities, and 11 had renal dysfunction. Eight patients presented with the classic pentad of symptoms. Six patients were given steroids (alone or in combination with intravenous immunoglobulin and cyclophosphamide), and eight patients were treated with steroids in combination with plasmapheresis, with response rates of 2/6 and 6/8, respectively. Six patients died, with overall mortality rate of 6/14. No patients relapsed during the follow-up period. CONCLUSIONS: SLE and TTP share some similar clinical symptoms. As a result, repeated examinations of peripheral blood smears are very important for early diagnosis. The renal damage in patients of co existing diseases is more serious than those with TTP alone or SLE alone. Early diagnosis and prompt treatment with plasma exchange and steroids may improve the prognosis in SLE patients with TTP. PMID- 23945303 TI - [The compliance in elderly male with osteoporosis treated with oral alendronate]. AB - OBJECTIVE: To explore the compliance in elderly male with osteoporosis treated with oral alendronate and analyze the factors which affect the therapeutic compliance. METHODS: A total of 145 elderly male patients diagnosed with osteoporosis who had been initiated the treatment of oral alendronate in our clinic during January to June in 2011 were enrolled in the study. The medication compliance of one year was investigated. According to the different medication possession ratio (MPR), MPR >= 80% was considered as adherent and MPR < 80% was considered as non-adherent. The difference in the two groups was compared and the factors which affect the therapeutic compliance were analyzed. RESULT: A total of 139 patients had been followed up with 32 adherent cases (23.02%) and 107 non adherent cases (76.98%). Logistic regression analysis showed the factors which affected the therapeutic compliance as the following: ostealgia (OR = 0.69, P = 0.043), no-reminder (OR = 1.37, P = 0.025), concern about drug related side effect (OR = 1.49, P = 0.018), more than 7 kinds of drugs (OR = 1.30, P = 0.036) and uncertain long-term effect (OR = 1.39, P = 0.021). CONCLUSIONS: Compliance of oral alendronate to treat osteoporosis in elderly male patients is poor. Ostealgia can promote the drug compliance. The factors which could decrease the drug compliance are no-reminder, concern about drug related side effect, more than 7 kinds of drugs and uncertain long-term efficacy. PMID- 23945304 TI - [The efficacy and safety of unmanipulated haploidentical peripheral blood stem cell transplantation on hematologic diseases]. AB - OBJECTIVE: To evaluate the efficacy and safety of unmanipulated haploidentical allogeneic peripheral blood stem cells transplantation (PBSCT) on hematologic diseases. METHODS: Patients who underwent unmanipulated HLA mismatched/haploidentical PBSCT from July 2007 to December 2011 were investigated retrospectively. RESULT: Forty-nine patients with hematologic diseases underwent unmanipulated human leukocyte antigen (HLA)-mismatched/haploidentical PBSCT with myeloablative conditioning. All patients were mismatched at the allele level for HLA-A, HLA-B, HLA-Cw, HLA-DRB1 and HLA-DQ1. Fifteen patients were mismatched in 5 loci, 11 patients in 4 loci, 7 patients in 3 loci, 5 patients in 2 loci, and 11 patients in 1 locus. The median numbers of mononuclear cells and CD34+ cells infused at transplantation were 10.01(7.05-25.34) * 108/kg and 4.51 (2.01-11.47) * 106/kg, respectively. Patients achieved myeloid and platelet engraftment at a median of 14 (10-25) days and 22 (10-135) days, respectively. The cumulative incidence of acute graft versus host disease (aGVHD) on day 100 was (61.6 +/- 7.3)%, and the 2-year cumulative incidence of chronic graft versus host disease (cGVHD) was (42.6 +/- 8.5)%. One hundred-day transplantation related mortality (TRM) rate and 2-year cumulative TRM rate were (14.7 +/- 5.1)% and (30.9 +/- 8.8)%, respectively. The 2-year cumulative incidence estimate of relapse was (25.4 +/- 7.0)%. The 2-year cumulative overall survival rate was (58.1 +/- 8.8)% and 2-year disease-free survival rate was (53.9 +/- 8.4)% with an 11.5-months median follow-up. CONCLUSION: Unmanipulated PBSCT is a promising protocol for patients with hematologic diseases in HLA-mismatched/haploidentical transplant settings. PMID- 23945305 TI - [The immunological effect of anti-leukemic tumor induced by eosinophilic granulocyte]. AB - OBJECTIVE: To investigate the biological effect of anti-leukemic cells induced by eosinophilic granulocyte (EOS) in bone marrow of patients with chronic myelogenous leukemia (CML). METHODS: The BCR-ABL fusion gene as well as the expression of IL-12 and IL-17 mRNA were performed by RT-PCR. The serum concentrations of cytokine IL-12 and IL-17 were determined by enzyme-linked immuno sorbent assay (ELISA). Immunochemistry staining and cytochemistry staining were used to observe the peroxidase (POX) and human leukocyte antigen (HLA)-DR expression of EOS in bone marrow. Immunofluorescence staining was used to observe mannose receptor (MR), IL-12, IL-17A and IL-17 receptor A (IL-17RA) expression of EOS. The results between the CML patients and the healthy controls were compared. RESULT: Serum levels of IL-12 and IL-17 were higher in the 60 CML patients [(196.33 +/- 21.79) ng/L and (36.55 +/- 3.01) ng/L] than those in the controls [(96.60 +/- 4.92) ng/L and (23.74 +/- 1.36) ng/L]. In the 32 patients with activated EOS, the levels of IL-12 and IL-17 were (273.12 +/- 17.16) ng/L and (40.11 +/- 6.13) ng/L, which were significantly higher than those in the non activated EOS [(126.16 +/- 14.27) ng/L and (28.14 +/- 5.29) ng/L] (P values < 0.01). IL-12 and IL-17 mRNA were expressed in activated EOS, while BCR-ABL fusion gene was not found. The amounts of EOS were increased abnormally in the bone marrow and peripheral blood of the CML patients with POX positive staining in the cytoplasm and weakly positive HLA-DR staining. It was observed easily by a microscope that EOS could attack leukemic cells in bone marrow through adhesion, capture and phagocytosis. Activated EOS could express IL-12, IL-17A and MR, which was related with the serum levels of these cytokines. CONCLUSIONS: Activated EOS in bone marrow of CML patients could express IL-12 and IL-17. Activated EOS could induce coup injury to leukemic cell by releasing POX and expressing IL-12 and IL 17. It can also capture or swallow target cells via the expression of MR on the membrane. EOS may play an important role in the anti-tumor immunologic function in bone marrow of CML patients. PMID- 23945306 TI - [The clinical analysis of neurological symptoms in patients with aortic dissection]. AB - OBJECTIVE: To summarize the characteristics of neurological symptoms in patients with aortic dissection. METHODS: The clinical data including symptoms, signs, and imaging of 865 consecutive patients with aortic dissection were analyzed retrospectively. RESULTS: Neurological symptoms occurred in 225 cases (26.0%) with aortic dissection. The most common symptom was dizziness (56 cases, 6.5%), followed by syncope (49, 5.7%), single lower limb sensory disturbances (47, 5.4%), single lower extremity weakness (27, 3.1%), coma (22, 2.5%), paraplegia (19, 2.2%), headache (13,1.5%) and hemiplegia (9,1.0%). The first manifestation of five cases was the neurological symptoms, including syncope (2), dizziness (1) and headache (2). Patients with type A aortic dissection were more vulnerable to the neurological symptoms than those with type B aortic dissection (34.6% vs 14.7%), and the symptoms with significantly higher occurrence were syncope, coma, hemiplegia, paraplegia and lower limb sensory disturbances. CONCLUSION: Neurological symptoms are common in patients with aortic dissection,especially in those with type A aortic dissection. PMID- 23945307 TI - [Leukoencephalopathy with cerebral calcification and cysts: a case report and review of literature]. AB - OBJECTIVE: To improve the diagnostic ability of leukoencephalopathy with cerebral calcifications and cysts (LCC), a rare central nervous system disease. METHODS: The clinical manifestations, neuroimages and neuropathological features of a 19 year-old male patient were analyzed. A total of 20 cases from 14 literatures were reviewed. RESULT: The patient was admitted with right limb weakness, cognitive decline, headache and blurred eyesight. Head CT scan showed multiple calcifications, cysts formation and leukoencephalopathy. Brain MRI showed several cysts in bilateral hemisphere, basal ganglia, thalamus and paraventricular areas. A mural nodule was noted inside one of the cyst, which was enhanced on the contrasted MRI. The wall of the cysts was partially enhanced, but not with the fluid inside the cysts. The corresponding CT calcifications foci showed on T1 and T2 with either both hyperintensity or both hypointensity, which was also partial enhanced. Extensive leukoencephalopathy was formed around the cysts and the ventricles. But neither Cho nor NAA changed a lot on MRS. Amplitude diagram of SWI series exhibited multiple round small dark signals all over the affected areas with mixed signals showed in the phase diagram, which indicated both calcifications and microbleeding at the lesions. Neuropathological examinations found no tumor cells in the operated cyst, and showed angiomatous small blood cells were dominant in the cyst wall. Hyaline degenerations, microcalcifications and hemosiderin deposition were observed. No obvious demyelination was discovered, while gliosis, numerous Rosenthal fibers and fibrinoid vascular necrosis were found around the lesions. The clinical, neuroimaging and pathological features of this patient were in accordance with the cases reported in the literatures. CONCLUSIONS: Neuroimaging is the most important method for the diagnosis of LCC. As small vessel lesions are probably closely related to the pathophysiology of LCC, SWI could be recommended to further reveal the etiology of LCC. PMID- 23945308 TI - [The mechanism of inhibition of the increase in intracellular calcium concentration by the islet amyloid polypeptide in high glucose-stimulated INS-1 cells]. AB - OBJECTIVE: To explore the potential mechanism of the inhibition of increased intracellular free calcium concentration ([Ca2+]i) by short-term exposure to the islet amyloid polypeptide (IAPP) in high glucose-stimulated pancreatic beta cells. METHODS: The pancreatic beta cells were loaded with calcium sensitive fluorescent indicator Fluo-4/AM. The fluorescence intensity, which represented [Ca2+]i, was measured in time by laser scanning confocal microscope before and after stimulated by glucose, KCl, caffeine and carbachol. RESULT: The fluorescence intensity F/F0 in INS-1 cells, increased to about 2 folds after glucose stimulation. After the exposure to the IAPP with different concentration, the fluorescence intensity F/F0 was decreased slightly in the pretreated cells by 16.7 mmol/L glucose with 0.5 umol/L IAPP. However, after the pretreatment of IAPP with the concentration of 1.0, 5.0, 10.0 umol/L, the fluorescence intensity F/F0 showed a dose-dependent decrease with statistical difference. The fluorescence intensity F/F0 in the cells increased rapidly in a peak pattern after the stimulation of 30 mmol/L KCl. But with the pretreatment of 10.0 umol/L IAPP, the fluorescence intensity F/F0 decreased with statistical difference. With 20 mmol/L caffeine and 100 umol/L carbachol which stimulated Ca2+ release respectively from internal ryanodine receptor (RYR) and inositol triphosphate (IP3) Ca2+ storage, the fluorescence intensity F/F0 curve presented a peak pattern. After 10 umol/L IAPP pretreatment, the fluorescence intensity F/F0 showed no statistical difference from the control group. CONCLUSIONS: The short-term effect of IAPP on pancreatic beta cells has no influence on the caffeine and carbachol stimulated Ca2+ release from endoplasmic reticulum RYR and IP3 Ca2+ storage. The inhibition of calcium increase in INS-1 cells by short-term exposure to IAPP may mainly via inhibiting the voltage-gated L-calcium channels with intact release capacity of Ca2+ storage. PMID- 23945309 TI - HCV infected prisoners: should they be still considered a difficult to treat population? AB - BACKGROUND: The prevalence of chronic hepatitis C virus (HCV) infection in the Italian correctional population is estimated to be around 38%. In this setting HCV infection treatment is controversial because of several factors such as active drug substance abuse, psychiatric illness, length of treatment, risk of re infection, poor adherence and low success rate. METHODS: A retrospective data review of 159 inmates, positive for anti-Hepatitis C virus (HCV) antibody, evaluated to National Institute for Infectious Diseases "L. Spallanzani" (INMI) from January 2006 to December 2009, was conducted to evaluate rate of completion (feasibility) and outcome efficacy of chronic Hepatitis C Virus (HCV) infection treatment with Pegylated Interferon and Ribavirin in five correctional facilities in Rome. RESULTS: Of the 159 inmates evaluated in the study period, 50, all male (median age 39 years) were treated. Twenty patients (40%) did not complete treatment: 15 showed no response and therapy was stopped, 5 patients (10%) interrupted treatment because of adverse reactions. The global feasibility was 60%. The overall sustained virologic response (SVR) was 50% (32% for genotype 1 and 68% for genotype other than 1). The main predictors of SVR at the Multivariable Logistic Regression Odds Ratio (MLR-OR) were a better pretreatment histological diagnosis (absence of bridging fibrosis or cirrhosis [MLR-OR 11.85; 95% CI 1.96-71.62) and a HCV genotype other than 1 (MLR-OR 5.87; 95% CI 1.49 23.17). CONCLUSIONS: Chronic HCV infection treatment in correctional facilities is feasible and effective and should be strongly recommended, in combination with preventive measures, in appropriately screened patients because it represents an important opportunity to treat a population with a high prevalence of chronic HCV infection among whom treatment options post incarceration may be limited. PMID- 23945310 TI - Characterization and fine mapping of a novel rice narrow leaf mutant nal9. AB - A narrow leaf mutant was isolated from transgenic rice (Oryza sativa L.) lines carrying a T-DNA insertion. The mutant is characterized by narrow leaves during its whole growth period, and was named nal9 (narrow leaf 9). The mutant also has other phenotypes, such as light green leaves at the seedling stage, reduced plant height, a small panicle and increased tillering. Genetic analysis revealed that the mutation is controlled by a single recessive gene. A hygromycin resistance assay showed that the mutation was not caused by T-DNA insertion, so a map-based cloning strategy was employed to isolate the nal9 gene. The mutant individuals from the F2 generations of a cross between the nal9 mutant and Longtepu were used for mapping. With 24 F2 mutants, the nal9 gene was preliminarily mapped near the marker RM156 on the chromosome 3. New INDEL markers were then designed based on the sequence differences between japonica and indica at the region near RM156. The nal9 gene was finally located in a 69.3 kb region between the markers V239B and V239G within BAC OJ1212_C05 by chromosome walking. Sequence and expression analysis showed that an ATP-dependent Clp protease proteolytic subunit gene (ClpP) was most likely to be the nal9 gene. Furthermore, the nal9 mutation was rescued by transformation of the ClpP cDNA driven by the 35S promoter. Accordingly, the ClpP gene was identified as the NAL9 gene. Our results provide a basis for functional studies of NAL9 in future work. PMID- 23945311 TI - Ordering patterns for laboratory and radiology tests by students from different undergraduate medical curricula. AB - BACKGROUND: The overuse of laboratory tests and radiology imaging and their possible hazards to patients and the health care system is observed with growing concern in the medical community. With this study the authors wished to determine whether ordering patterns for laboratory and radiology tests by medical students close to their graduation are related to undergraduate training. METHODS: We developed an assessment for near graduates in the setting of a resident's daily routine including a consultation hour with five simulated patients, three hours for patient work up with simulated distracting tasks, and thirty minutes for reporting of patient management to a supervisor. In 2011, 60 students participated in this assessment: 30 from a vertically integrated (VI) curriculum (Utrecht, The Netherlands) and 30 from a traditional, non-VI curriculum (Hamburg, Germany). We assessed and compared the number of laboratory and radiology requests and correlated the results with the scores participants received from their supervisors for the facet of competence "scientifically and empirically grounded method of working". RESULTS: Students from a VI curriculum used significantly (p < .01) less total laboratory requests (N = 283 versus N = 466) which correlated with their scores for a "scientifically and empirically grounded method of working" (Pearson's r = .572). A significantly (p < .01) higher number of radiology imaging was ordered with a large effect size (V = .618) by near graduates from a non-VI curriculum (N = 156 versus N = 97) even when this was not supporting the diagnostic process. CONCLUSION: The focused ordering patterns from VI students might be a result of their early exposure to the clinical environment and a different approach to clinical decision making during their undergraduate education which further studies should address in greater detail. PMID- 23945312 TI - The functions of language: an experimental study. AB - We test between four separate hypotheses (social gossip, social contracts, mate advertising and factual information exchange) for the function(s) of language using a recall paradigm. Subjects recalled the social content of stories (irrespective of whether this concerned social behavior, defection or romantic events) significantly better than they did ecological information. Recall rates were no better on ecological stories if they involved flamboyant language, suggesting that, if true, Miller's "Scheherazade effect" may not be independent of content. One interpretation of these results might be that language evolved as an all-purpose social tool, and perhaps acquired specialist functions (sexual advertising, contract formation, information exchange) at a later date through conventional evolutionary windows of opportunity. PMID- 23945313 TI - Mexican American children have differential elevation of metabolic biomarkers proportional to obesity status. AB - OBJECTIVES: There is a health disparity for obesity among Mexican Americans compared with other racial/ethnic groups. In particular, Mexican American children who are obese are likely to become obese adults. The purpose of this study was to examine traditional and nontraditional risk factors in a subset of Mexican American children before their participation in a larger clinical weight loss study. METHODS: Venous blood samples were collected from self-identified Mexican American children (12-14 years old) who were assigned to 1 of 3 weight groups based on their standardized body mass index; normal weight (N = 66), overweight (N = 23), or obese (N = 39). Serum was analyzed for interleukin-6, tumor necrosis factor-alpha, C-peptide, ghrelin, glucagon-like protein, gastric inhibitory polypeptide-1, glucagon, insulin, leptin, macrophage chemoattractant protein 1, and pancreatic polypeptide using a Luminex MagPix-based assay. Total cholesterol, high-density lipoprotein-cholesterol, triglycerides, and glucose were analyzed using enzymatic assays. Data were analyzed for significance using separate analysis of variance tests, with significance set at P < 0.05. RESULTS: Relative to normal weight and overweight children, obese children had significantly elevated C-peptide (P < 0.0001), insulin (P < 0.0001), leptin (P < 0.0001), macrophage chemoattractant protein 1 (P = 0.005), and tumor necrosis factor-alpha (P = 0.006). CONCLUSIONS: We observed that Mexican American children as a function of body weight had elevated serum concentrations of several biomarkers that have been linked to chronic disease development in adults. More research is needed to understand how these differences affect disease risk in adulthood. PMID- 23945314 TI - Bear-down maneuver is a useful adjunct in the evaluation of children with chronic constipation. AB - BACKGROUND AND OBJECTIVES: Chronic constipation is a common problem in pediatrics and often the result of obstructed defecation. The aim of this study was to determine the use of the bear-down maneuver (BDM) in the evaluation of children with chronic constipation and to establish optimal conditions for its performance. METHODS: This retrospective study compares BDM with balloon expulsion testing (BET) during anorectal manometry in 38 children with chronic constipation. BDM was performed with 0-, 20-, 40-, and 60-mL balloon inflation. BET, performed with a 60-mL balloon, was considered normal if the balloon was expelled within 1 minute. RESULTS: Rectal pressure during BDM was 48% higher in patients able to expel the balloon during BET compared with those who could not (P < 0.05). Anal canal pressure was 46% lower in patients able to expel the balloon (P < 0.05). A rectoanal pressure differential greater than zero during BDM was 90% predictive that the subject would be able to expel the balloon. The optimal balloon inflation volume was 60 mL. CONCLUSIONS: BDM using an inflated balloon provides valuable mechanistic information in the evaluation of children with dyssynergic defecation. We found that patients often had either an insufficient rectal pressure during bear-down or an abnormally high anal canal pressure. This information may be useful in planning further treatment for these children. PMID- 23945316 TI - Plasma total antioxidant status in horses after 8-hours of road transportation. AB - BACKGROUND: The aim of this study was to investigate the effects of 8-hour road transport on plasma total antioxidant status (PTAS) and general clinical appearance in horses. FINDINGS: The study was conducted on a group of 60 horses of different breeds aged from 4 to 10 years. Venous blood was collected and a clinical examination was performed immediately before loading horses onto trailers for an 8 hour transport (I), immediately after unloading them from the trailer (II), and after a subsequent 24 hour stall rest (III). The ferric reducing ability of plasma (FRAP) was used to determine PTAS. The transportation significantly increased respiratory and heart rates. The average PTAS increased during the three subsequent samplings: I: 170+/-77 (MUmol/l) II: 204+/-70 (MUmol/l) III: 221+/-74 (MUmol/l). CONCLUSION: Long-distance transport increased the PTAS horses, as well as respiratory and heart rates. PMID- 23945317 TI - Edge-states in graphene nanoribbons: a combined spectroscopy and transport study. AB - Graphene structures of finite size are expected to reveal exceptional electronic and magnetic properties which are highly attractive for future nano-technological applications. In this study we have looked at the edge-states in graphene nanoribbons (GNR) grown by self-assembly on mesa structured SiC(0001) templates. By means of a 4-tip STM/SEM system, both local spectroscopy and lateral transport have been performed in situ on the same nanostructures. The conductance in these structures was found to be e(2)/h for temperatures up to 400 K. Scanning tunneling spectroscopy clearly reveals edge-localized states on these ribbons. The local bonding of these ribbons to their support turns out to be essential in order to preserve the metallicity of the edge-states. PMID- 23945318 TI - [Assessment of oral health using the general oral health assessment index in patients with overactive bladder]. AB - Patients administered anti-cholinergic agents, as first-line therapy for an overactive bladder (OAB) are often unable to continue medical treatment because of dry mouth. We assessed oral health in patients with OAB using the General Oral Health Assessment Index (GOHAI), an oral health-related quality of life questionnaire. We investigated 75 patients with OAB who were receiving continuous administration of anti-cholinergic agents. The OAB symptom score, as well as GOHAI and our original dry mouse score were determined by self-administered questionnaires. The mean age of the subjects was 70.9+/-10.2 years, the median period of anti-cholinergic agent use was 20 (1-116) months and the mean OAB symptom score was 6.3+/-3.1. The GOHAI score for all patients was 51.9+/-8.4 and not significantly different from the national normal value (p=0.22). On the other hand, the score in patients with a severely dry mouth was 49.2+/-8.6, which was worse than the national normal value (p=0.04). The psychosocial functioning score in patients with a severely dry mouth was significantly lower than in those with a slightly dry mouth (p=0.02). Our results indicate that dry mouth in patients with OAB is significantly associated with worsening of oral health. GOHAI is useful as a screening test to assess the quality of life in patients with OAB. PMID- 23945319 TI - [Neoadjuvant hormonal therapy versus surgery alone for radical prostatectomy in high-risk prostate cancer patients]. AB - We examined the effect of neoadjuvant hormonal therapy (NHT) on biochemical failure. We retrospectively analyzed 146 high-risk prostate cancer patients (clinically (c), T1c-3N0M0) who underwent radical prostatectomy between June 2002 and March 2008. Thirty-eight patients were treated with NHT for >=2 months (NHT group), and 108, with surgery alone (SA group). The study population comprised 89 cT1c-2N0M0 patients and 57 cT3N0M0 patients, and pathologically (p), 66 pT0-2N0M0 patients and 76 pT3N0M0 patients. Downstaging was noted in 36.4 and 0% of cT1c 2N0M0 patients and in 74.1 and 20.0% of cT3N0M0 patients in the NHT and SA groups, respectively. For both cT1c-2N0M0 and cT3N0M0 patients, the downstaging rate was significantly higher in the NHT group than in the SA group (p<0.01). Positive resection margin rates were significantly lower in the NHT group (34.2%) than in the SA group (65.7%) (p<0.01). The overall prostate-specific antigen (PSA) progression-free rate did not differ significantly between the 2 groups in both pT0-2N0M0 and pT3N0M0 patients. However, in pT0-2N0M0 patients with negative resection margins, the 5-year PSA progression-free rate was significantly lower in the NHT group than in the SA group (p<0.01), whereas this rate did not differ significantly between the groups in both pT0-2N0M0 and pT3N0M0 patients with positive resection margins. Although NHT seemed to have some effect on downstaging, its pathological effects could be underestimated. Thus, NHT was considered to have no significant effect on biochemical failure. PMID- 23945320 TI - [Successful control of hyper-cortisolemia due to ACTH-producing thyroid carcinoid by laparoscopic bilateral adrenalectomy : a case report]. AB - A 22-year-old man was referred to our hospital because of facial edema and increasing body weight. Under the diagnosis of Cushing syndrome due to an adrenocorticotropic (ACTH)-producing thyroid tumor, thyroidectomy with regional lymph node dissection was performed. Histopathological diagnosis was thyroid carcinoid. In spite of the operation, serum ACTH and cortisol concentrations increased again due to mediastinal lymph node metastasis. His hyper-cortisolemia was resistant to drug therapy. Then, laparoscopic bilateral adrenalectomy was performed. After the operation, hyper-cortisolemia and clinical symptoms markedly improved. An additional chemotherapy is implemented because of new metastasis in the mediastinum lymph nodes. PMID- 23945321 TI - [A case of schwannoma in the renal hilum]. AB - An 80-year-old woman was referred for evaluation and treatment of a left renal mass. An abdominal CT scan showed a 4.6 X 3.7 cm mass in the left kidney. The lesion was slightly enhanced by contrast medium. Since renal cell carcinoma could not be ruled out, radical nephrectomy was performed. The tumor weighed 190 g. Histological examination revealed Antoni A and Antoni B type schwannoma. Schwannoma is a tumor arising from the sheath of the peripheral nerves. The present case is the 6th case of schwannoma arising in the renal hilum reported in the English and Japanese literature. PMID- 23945322 TI - [Local recurrence of pheochromocytoma associated with von Hippel-Lindau disease 26 years after bilateral adrenalectomy : a case report]. AB - A 60-year-old man who had undergone left adrenalectomy and right partial adrenalectomy for bilateral pheochromocytoma 26 years ago was found to have an elevated serum noradrenaline (NA) and dopamine (DA) during a long-term follow-up. At the time of right partial adrenalectomy, the normal part of the right adrenal gland was preserved. His cousin and second cousin had pheochromocytoma associated with von Hippel-Lindau (VHL) disease. His eldest daughter had cerebellar hemangioblastoma. Computed tomography and magnetic resonance imaging revealed a tumor which was 17 mm in diameter with contrast enhancement in the vicinity of the S6 region in the liver. 123 I-metaiodobenzylguanidine (MIBG) scintigraphy showed an abnormal accumulation in the same area. The tumor was surgically removed under the diagnosis of recurrence of pheochromocytoma. Histopathological examination revealed findings consistent with recurrent pheochromocytoma. After operation, serum NA and DA returned to normal range and the abnormal up-take on 123I-MIBG scintigraphy disappeared. Genetic testing revealed that the patient and his daughter had VHL disease. An extensive genetic examination and long-term follow-up should be considered for the present family. PMID- 23945323 TI - [Ureteral endometriosis treated by hormonal therapy : a case report]. AB - A 40-year-old woman visited our hospital with asymptomatic macroscopic hematuria. A nonpapillary ureteral tumor protruding from the left orifice was identified by cystoscopy. Computed tomography revealed left hydronephrosis due to the ureteral tumor. Transurethral resection for the ureteral tumor was performed and histopathological examination for the specimen revealed intrinsic type ureteral endometriosis. Administration of luteinizing hormone-releasing hormone agonist for 6 months markedly improved the hydronephrosis. The patient received hormonal therapy for 2 years in total. At present, there is no evidence of disease recurrence 6 months after the termination of hormonal therapy. To our knowledge, the present case was the 14th Japanese case with intrinsic type ureteral endometriosis reported in the literature. PMID- 23945324 TI - [Amyloidosis of the ureter arising secondarily to the systemic lupus erythematosus : a case report]. AB - A 55-year-old man was referred to our department with the chief complaint of left flank pain. Computed tomography and magnetic resonance imaging demonstrated a left hydronephroureter due to the ureteral stenosis with a mass. We considered the possibility of a malignant neoplasm, and performed laparoscopic left total nephroureterectomy. Microscopic appearance showed ureteral wall thickening and perivascular deposition of heterogeneous amyloid. It stained positive by immune histochemical staining using Congo-red. In addition, it stained positive by immune-histochemical staining with an anti-AA antibody. These findings indicated that the amyloid was type AA. AA amyloidosis is a systemic amyloidosis that arises secondarily to an inflammatory disease. He had been treated for systemic lupus erythematosus. It is compatible to secondary amyloidosis. Eighty seven months after diagnosis, he died of lung cancer. There were no signs or symptoms of deposition of the AA amyloid proteins. PMID- 23945325 TI - [Pelvic arteriovenous malformation : a case report]. AB - A 70-year-old male presented with intermittent macroscopic hematuria. There was no history of previous trauma or pelvic operation. At first, we were unable to clarify the origin of the hematuria, but 3D computed tomography revealed an arteriovenous malformation (AVM) consisting of multiple feeding vessels arising from the bilateral, especially right, internal iliac artery. Treatment with transcatheter arterial embolization (TAE) with a combination of lipiodol and N butyl-2-cyanoacrylate twice was effective. He needs to be followed up carefully for recurrence of AVM. PMID- 23945326 TI - [A case of bladder cancer producing granulocyte colony-stimulating factor and interleukin-6 causing respiratory failure treated with neoadjuvant systemic chemotherapy along with sivelestat]. AB - A 67-year-old man visited an urological clinic with a chief complaint of urination pain. Cystourethroscopy and magnetic resonance imaging (MRI) examination revealed a bladder tumor (cT3bN0M0). Marked leukocytosis and respiratory distress with pleural effusion appeared. Pulse steroid therapy improved the general condition partially. The patient was sent to our hospital for further examination. Serum granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were high and the pathological findings of bladder tumor obtained by transurethral resection (TUR) revealed an urothelial carcinoma that produced G-CSF and IL-6. Neoadjuvant systemic chemotherapy was performed along with use of steroid and sivelestat, which ameliorated the respiratory distress. After three courses of systemic chemotherapy, serum G-CSF and IL-6 normalized and cystoprostatectomy was performed. The patient has been in good health at 20 months after the surgery with no evidence of recurrence. PMID- 23945327 TI - [A case of portal vein thrombosis during chemotherapy for bladder cancer]. AB - A 53-year-old man was diagnosed with bladder cancer with pelvic and para-aortic lymph node metastases. The clinical stage was cT3bN2M1. He underwent radical cystectomy and ileal conduit construction and retroperitoneal lymph node dissection after showing a partial response to 4 cycles of chemotherapy with methotrexate,vinblastine,doxorubicin and cisplatin (MVAC). Pathology showed prostatic invasion and para-caval lymph node metastasis. Pathological stage was pT4N0M1. After 3 cycles of MVAC therapy as adjuvant chemotherapy,new lymph node metastasis was revealed. He showed a complete response after 4 cycles of chemotherapy with gemcitabine and cisplatin (GC). He received 6 additional cycles of GC chemotherapy. Follow-up computed tomographic scan 3 months after the last chemotherapy showed portal vein thrombosis. He was treated with anticoagulant therapy,which dissolved the thrombus. PMID- 23945328 TI - [Effectiveness of DMSO intravesical therapy for lower urinary symptoms of primary amyloidosis localized in the urinary bladder : a case report]. AB - Primary amyloidosis localized in the urinary bladder is comparatively rare,and 40% of the patients complain of lower urinary tract symptoms (LUTS). Although standard management for amyloidosis localized in the urinary bladder is not established,transurethral resection (TUR) is performed in most of the cases to diagnose the disease and to control bleeding. TUR is not considered as radical therapy for amyloidosis localized in the urinary bladder because of frequent recurrence. Dimethyl sulfoxide (DMSO) administered through intravenous,percutaneous or intravesical route has been shown to be effective for treating and preventing recurrence of the disease,but its effect on LUTS due to amyloidosis localized in the urinary bladder has not been demonstrated. We report a case showing improvement of LUTS and in which recurrence of amyloidosis localized in the urinary bladder was prevented for 18 months by intravesical DMSO therapy. PMID- 23945329 TI - [Vesical tuberculosis after Bacillus Calmette-Guerin intravesical instillation therapy for bladder cancer]. AB - An 82-year-old man who had undergone transurethral resection (TUR) for superficial bladder cancer (pT1 G3) in June and Luly 2011 received intravesical Bacillus Calmette-Guerin therapy (80 mg weekly for 6 weeks) in September 2011. Seven months later, a follow-up cystoscopy revealed a slowly growing torose lesion at the site of the previous TUR. The lesion was removed by TUR in June 2012. Pathological examination showed an inflammatory response with small granulomatous lesions. The specimen stained positive for TB DNA-RTPCR. Mycobacterium bovis was detected from the bladder specimen and urine. He was administered antituberculous agents, isoniazid 300 mg and rifampicin 450 mg daily, for 3 months. He is well with no recurrence of bladder carcinoma and urinary cultures were negative during the follow-up. PMID- 23945330 TI - [A case of testicular abscess with low-grade inflammation]. AB - We report a case of testicular abscess with low-grade inflammation. A 55-year-old man was referred to our hospital because of right scrotal pain and swelling for approximately 3 weeks. Physical examination revealed mild tenderness and a hen's egg-sized mass in the right scrotum ; however, fever and scrotal erythema were absent. Magnetic resonance imaging (MRI) showed an enlarged right testis and spermatic cord, and an ultrasonography scan indicated loss of blood flow to these regions. Right testicular necrosis due to spermatic cord torsion or testicular cancer was suspected, and high orchiectomy was performed. However, abscess formation was detected in the testis, and testicular abscess caused by Escherichia coli was diagnosed. The clinical course of this case was unusual because of the small extent of inflammation observed. Typically, testicular abscess is characterized by severe systemic and local inflammation. PMID- 23945331 TI - A Tumor initiating cell-enriched prognostic signature for HER2+:ERalpha- breast cancer; rationale, new features, controversies and future directions. AB - The high intra- and inter-tumor heterogeneity of many types of cancers, including breast cancer (BC), poses great challenge to development of subtype-specific prognosis. In BC, the classification of tumors as either ERalpha+ (Luminal A and Luminal B), HER2+ (ERalpha+ or ERalpha-) or triple-negative (TNBC)(Basal-like, claudin-low) guides both prognostication and therapy. Indeed, prognostic signatures for ERalpha+ BC are being incorporated into clinical use. However, these signatures distinguish between luminal A (low risk) and Luminal B (high risk) BC; signatures that identify low/high risk patients with luminal B BC are yet to be developed. Likewise, no signature is in clinical use for HER2+ or TNBC. The major obstacles to development of robust signatures stem from diversity of BC, clonal evolution and heterogeneity within each subtype. We have recently generated a prognostic signature for HER2+:ERalpha- BC based on the identification of genes that were differentially expressed in a tumor-initiating cell (TIC)-enriched fraction versus non-TIC fraction from a mouse model of HER2+ BC (MMTV-Hers/Neu). Here we describe the rationale behind development of this prognosticator, and present new features of the signature, including elevated PI3K pathway activity and low TNFalpha and IFNgamma signaling in high-risk tumors. In addition, we address controversies in the field such as whether random gene expression signatures significantly associate with cancer outcome. Finally, we suggest a guideline for development of prognostic signatures and discuss future directions. PMID- 23945332 TI - Therapeutic benefits of an oral vitamin B1 derivative for human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). AB - Prosultiamine, a vitamin B1 derivative, has long been used for beriberi neuropathy and Wernicke's encephalopathy. Based on the finding that prosultiamine induces apoptosis in human T lymphotropic virus type I (HTLV-I)-infected T cells, Nakamura et al. conducted a clinical trial of prosultiamine in patients with HTLV I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). In this open label, single arm study enrolling 24 HAM/TSP patients recently published in BMC Medicine, oral prosultiamine (300 mg/day for 12 weeks) was found to be effective by neurological, urological and virological evaluations. Notably, it increased detrusor pressure, bladder capacity and maximum flow rate, and improved detrusor overactivity and detrusor-sphincter dyssynergia. A significant decrease in HTLV-I copy numbers in peripheral blood following the treatment provided a rationale for using the drug. The trial has some limitations, such as the small numbers of participants, the open-label design, the lack of a placebo arm, and the short trial period. Nevertheless, the observation that such a safe, cheap drug may have excellent therapeutic effects on HAM/TSP, a chronic devastating illness occurring mainly in developing countries, provides support for future large-scale randomized controlled trials.Please see related research: http://www.biomedcentral.com/1741-7015/11/182. PMID- 23945333 TI - Cirsium brevicaule A. GRAY leaf inhibits adipogenesis in 3T3-L1 cells and C57BL/6 mice. AB - BACKGROUND: Various flavonoids obtained from the genus Cirsium have been reported to exhibit beneficial effects on health. The present study evaluated the antiobesity effects of Cirsium brevicaule A. GRAY leaf (CL) by using 3T3-L1 cells and C57BL/6 mice that were fed a high-fat diet (HFD). METHODS: Dried CL powder was serially extracted with solvents of various polarities, and these extracts were tested for antiadipogenic activity using 3T3-L1 adipocytes. Mice were fed experimental HFD supplemented with dried CL powder for 4 wk. Lipid levels and mRNA levels of genes related to lipid metabolism were determined in 3T3-L1 adipocytes and the white adipose tissue (WAT) and liver of mice fed on a HFD. RESULTS: Treatment of 3T3-L1 adipocytes with a hexane extract of CL significantly reduced cellular lipid accumulation and expression of the fatty acid synthase (FASN) gene. Dietary CL reduced the serum levels of non-esterified fatty acids in HFD-fed mice. Significant decreases in subcutaneous WAT weight and associated FASN gene expression were observed in the mice fed the experimental CL diet. Dietary CL also reduced the hepatic lipid and serum levels of a hepatopathic indicator in the HFD-fed mice. A significant reduction in mRNA levels of FASN and HMG-CoA reductase were observed in the livers of the CL-diet group. Dietary CL, on the other hand, increased in the hepatic mRNA levels of genes related to beta oxidation, namely peroxisome proliferator-activated receptor alpha, calnitine palmitoyltrasferase 1A, and uncoupling protein 2. Expression of the insulin receptor gene was also significantly increased in the livers of mice-fed the CL diet. CONCLUSIONS: The present study therefore demonstrated that CL suppresses lipid accumulation in the WAT and liver partly through inhibiting mRNA levels of FASN gene and enhancing the lipolysis-related gene expression. PMID- 23945334 TI - [Some considerations in the revision of "the guideline for the diagnosis and treatment of chronic obstructive pulmonary disease"]. PMID- 23945335 TI - [Chronic obstructive pulmonary disease and associated comorbidities]. PMID- 23945336 TI - [Combined pulmonary fibrosis and emphysema]. PMID- 23945337 TI - [Pulmonary hypertension in chronic obstructive pulmonary disease can not be ignored]. PMID- 23945338 TI - [More attention should be paid to chronic obstructive pulmonary disease complicated with pulmonary embolism]. PMID- 23945339 TI - [Prevalence of chronic obstructive pulmonary disease in Ningxia Hui Autonomous Region of China]. AB - OBJECTIVE: To investigate the prevalence of chronic obstructive pulmonary disease (COPD) and its current status of diagnosis and management in Ningxia Hui Autonomous Region of China. METHODS: Using multi-stage cluster random sampling, all residents 40 years of age or older in Dawukou, Yinchuan, Wuzhong, and Jingyuan were randomly selected and interviewed with a standardized questionnaire. Spirometry was performed in all eligible participants and COPD diagnosis was made according to the spirometric criteria. The categorical variables were described by the constituent ratio or prevalence and compared by chi(2) test. RESULTS: Among 4626 sampling subjects, 4055 participants completed the questionnaire and spirometry. The mean age was (56 +/- 12) years. The overall prevalence of COPD was 8.9% (360/4055). The prevalence was significantly higher in males [13.0% (243/1869)] than in females [5.4% (117/2186)]. The prevalence of COPD was significantly higher in residents of Han nationality, rural residents and smokers (chi(2) = 4.10 - 94.65, P < 0.05 and P < 0.01). There was no significant difference in COPD prevalence among different regions of Ningxia; 8.7% (76/878), 8.1% (93/1142), 8.8% (90/1019) and 9.0% (101/1016) in Dawukou, Yinchuan, Wuzhong, and Jingyuan (chi(2) = 2.12, P > 0.05), respectively. Only 23.6% (85/360) of the COPD cases was diagnosed and only 23.3% (84/360) was treated. By lung function measurements, gradeII COPD accounted for 64.2% (231/360) of the cases. CONCLUSIONS: The prevalence of COPD in Ningxia was 8.9% (360/4055) in people 40 years of age or older. The current status of diagnosis and management of COPD in this region was far from satisfactory. It was necessary to strengthen the awareness of the importance of pulmonary function tests and early intervention of COPD. PMID- 23945340 TI - [The value of coexisting pneumonia and British Thoracic Society CURB-65 score in predicting early mortality rate in patients with acute exacerbation of chronic obstructive pulmonary disease]. AB - OBJECTIVE: To investigate the value of coexisting pneumonia and British Thoracic Society CURB-65 score in predicting early mortality in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: In this prospective study, 483 consecutive in-patients with AECOPD were recruited between January 2010 and September 2012, including 295 males and 188 females. The patients were aged 45 to 92 years. They were divided into 2 groups: non-pneumonia (npAECOPD) and with pneumonia (pAECOPD). The start point of this study was the date when the patients were admitted into the respiratory ward, and the endpoint was the 30 day mortality. Clinical and demographic data were collected for all the patients, and the value of coexisting pneumonia and CURB-65 in predicting in hospital mortality and 30 day mortality were assessed and compared. RESULTS: According to the inclusion/exclusion criteria, eventually 457 patients were included in this research, with 278 males and 179 females, and an average age of (75 +/- 9) years. Of the 457 patients, 120 (26.3%) patients were in the pAECOPD group and 337 (73.7%) patients in the npAECOPD group. The in-hospital mortality, the 30 day mortality and the assisted ventilation rate were significantly higher in the pAECOPD group as compared to the npAECOPD group 18.3% (22/120) vs 4.7% (16/337), 21.7% (26/120) vs 7.4% (25/337); 49.2% (59/120) vs 27.0% (91/337), chi(2) = 18.1 - 21.4, all P < 0.05, respectively. Furthermore, the in-hospital mortality of the pAECOPD patients with CURB-65 score < 2, = 2 and > 2 was 4.4% (2/45), 15.2% (7/46) and 44.8% (13/29), respectively, while that of the npAECOPD patients was 0.9% (1/113), 3.4% (4/119) and 10.5% (11/105), respectively. The 30 day mortality of the pAECOPD patients with CURB-65 score < 2, = 2 and > 2 was 4.4% (2/45), 19.6% (9/46) and 51.7% (15/29), respectively, while that of the npAECOPD patients was 0.9% (1/113), 5.0% (6/119) and 17.1% (18/105), respectively. Stratified by CURB-65 Score, the in-hospital and 30 day mortality were both significantly higher in the pAECOPD group than in the npAECOPD group when CURB-65 was >= 2 (chi(2) = 5.8 - 10.1, P < 0.05 and P < 0.01, respectively). The AUROC analysis of CURB-65 as a predictor for early mortality resulted in an area under curve of 0.744. CONCLUSIONS: In patients with AECOPD, coexisting pneumonia is not only a risk factor for in-hospital mortality, but also a predictor for the treatment of assisted ventilation. CURB-65 score may be a good predictor for early mortality in patients with AECOPD. PMID- 23945341 TI - [Correlation between the serum level of advanced oxidation protein products and the cognitive function in patients with obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To observe the change of the cognitive function and the serum level of advanced oxidation protein products (AOPP) in patients with obstructive sleep apnea hypopnea syndrome (OSAHS), and then to investigate the correlation between them. METHODS: Sixty seven patients with OSAHS, 20 healthy controls with matched age, BMI, and education, 15 patients with OSAHS after effective treatment of continuous positive airway pressure (CPAP) with matched age, BMI, and education were enrolled. Polysomnography (PSG), Epworth sleepiness scale (ESS), mini-mental state examination (MMSE), and clock drawing test (CDT) were performed in these groups. The serum level of AOPP, superoxide dismutase (SOD), and malondialdehyde (MDA) were measured. RESULTS: The MMSE and CDT scores of patients with OSAHS were decreased compared to those in healthy controls [(4.73 +/- 0.81) vs (2.69 +/- 1.38), (2.85 +/- 0.61) vs (1.92 +/- 0.62)], but the scores improved after effective CPAP treatment. The serum levels of AOPP [(78 +/- 20) vs (117 +/- 20) umol/L] and MDA [(2.9 +/- 1.0) vs (6.1 +/- 3.0) umol/L] in patients with OSAHS were increased compared to those in healthy controls, but the levels decreased after effective CPAP treatment. The serum SOD level in patients with OSAHS was decreased compared to that in healthy controls [(89 +/- 8) vs (57 +/- 9) U/ml], but it was increased after effective CPAP treatment. The MMSE and CDT scores of all the subjects including the 2 groups (the OSAHS group and the effective CPAP treatment group) were correlated with the results of PSG (baseline SaO2, lowest SaO2, AHI, LA/HT, SLT90%). The serum levels of AOPP, MDA and SOD of all the subjects were also correlated with the results of PSG (lowest SaO2, AHI, LA/HT, SLT90%). The serum levels of AOPP, MDA and SOD of all the subjects were correlated with the MMSE and CDT scores. The serum level of AOPP of all the subjects was also correlated with the serum levels of MDA and SOD. CONCLUSIONS: Cognitive impairment in patients with OSAHS is correlated with the severity of the disease. AOPP is a useful marker for oxidative stress and protein injury, and closely correlated with the cognitive impairment in patients with OSAHS. PMID- 23945342 TI - [A method for the primary culture of fibroblasts isolated from human airway granulation tissues]. AB - OBJECTIVE: To establish a feasible method to culture primary fibroblasts isolated from human airway granulation tissues, and therefore to provide experimental data for the investigation of the pathogenesis of benign airway stenosis. METHODS: The granulation tissues were collected from 6 patients during routine bronchoscopy at our department of Beijing Tiantan Hospital from April to June 2011. Primary fibroblasts were obtained by culturing the explanted tissues. Cell growth was observed under inverted microscope. RESULTS: All of these 6 primary cultures were successful. Fibroblast-like cells were observed to migrate from the tissue pieces 3 d after inoculation. After 9-11 d of culture, cells reached to 90% confluence and could be sub-cultured. After passage, the cells were still in a typical elongated spindle-shape and grew well. The cells could be sub-cultured further when they formed a monolayer. CONCLUSION: Explant culture is a reliable method for culturing primary fibroblasts from human airway granulation tissues. PMID- 23945343 TI - [Respiratory physicians' knowledge, attitude and practice of tobacco control and their smoking status in the city of Chongqing]. AB - OBJECTIVE: To investigate the smoking status, knowledge of smoking hazards, attitude of tobacco control and skill of assisting smoking cessation in respiratory physicians in the city of Chongqing and therefore to provide references for their further participation in social tobacco control. METHODS: With a self-designed questionnaire, a cross-sectional study was conducted on respiratory physicians of 8 hospitals in Chongqing, which were selected with stratified random sampling method. All the data were inputted with software Epidata 3.1 and were analyzed with SPSS 13.0. RESULTS: A total of 428 valid questionnaires were retrieved, with a valid rate of 95.1% (428/450). The total smoking rate was 12.4% (95%CI: 9.3% - 15.5%), with 7.4% in physicians of teaching hospitals, 8.13% in those of hospitals located in urban areas, and 19.0% in those of hospitals located in suburban district counties. The differences in smoking rates in the respiratory physicians among different hospitals showed statistical significance (chi(2) = 11.734, P = 0.014). The smoking rate of the male was higher than that of the female. Of the surveyed doctors, 80.14% had awareness that tobacco dependence was a neuropsychiatric disease characterized as nicotine addiction, while 34.8% claimed that they had no idea about quitting smoking drugs. Although all participants claimed that they knew the harm of secondhand smoke, 16.36% of them still had never come forward to prevent smoking behavior in hospitals. There was only 27.4% of the surveyed discouraging smoking behavior with the reason of unwillingness to breath in secondhand smoke, while 53.9% of the surveyed discouraged smoking behavior because of regulations of hospitals. Most of the surveyed did relatively well in routinely inquiring and recording the smoking status of patients, but only 27.1% of them had recommended specific quitting smoking methods to patients, and there were few successful cases in practice. The situations of smoking cessation assistance in hospitals located in urban areas and suburban district counties were better than that in teaching hospitals. CONCLUSIONS: The smoking rate of the respiratory physicians (especially male doctors) in Chongqing is high. There is lack of enthusiasm in preventing smoking behavior in public area of hospitals. The knowledge and skills of smoking cessation are lacking as well. Therefore more training programs for smoking control are needed. Respiratory physicians in primary hospitals or community health centers can play a more important role in smoking control. PMID- 23945344 TI - [The change and significance of vancomycin minimal inhibitory concentration against methicillin-resistant Staphylococcus aureus isolates from inpatients with lower respiratory tract infection]. AB - OBJECTIVE: To investigate the change and significance of vancomycin minimal inhibitory concentration (MIC) against methicillin-resistant Staphylococcus aureus (MRSA) isolates. METHODS: We analyzed the data of inpatients with lower respiratory tract infection, with positive cultures of MRSA from airway samples, at respiratory ward or respiratory intensive care unit (RICU) between 2000 and 2011. The MIC of vancomycin was determined by the agar dilution method. RESULTS: There were 295 patients [210 males, 85 females, mean age (73 +/- 12) years (range, 18 - 98)] with a positive culture of MRSA from airway samples. The arithmetic mean of vancomycin MIC against MRSA isolates fluctuated from 0.99 to 1.60 mg/L. The number of defined daily doses (DDDs) of vancomycin from the whole hospital had an influence on the mean of vancomycin MIC in the next year (r = 0.64, P = 0.04). But the vancomycin DDDs from respiratory department were not related with the mean of vancomycin MIC in the next year (r = 0.33, P = 0.32). The patients were divided into 2 groups according the MIC of vancomycin against MRSA isolates: MIC = 2 mg/L group (n = 43) and MIC < 2 mg/L group (n = 252). There was no difference in mortality [14 cases (32.6%) and 73 cases (29.0%)] (chi(2) = 0.23, P = 0.63), the clinical success rates [26 cases (60.5%) and 156 cases (61.9%)](chi(2) = 0.03, P = 0.85) and bacterial success rates [21 cases (48.8%) and 106 cases (42.1%)] (chi(2) = 1.20, P = 0.27) between the 2 groups. But the average hospitalization days were significantly prolonged (Z = 3.09, P = 0.00)in the MIC = 2 mg/L group [40(27, 93) days]as compared to that in the MIC < 2 mg/L group [30 (20, 52) days]. The average treatment time [10 (1, 19) days and 3(0, 12) days, Z = -2.79, P < 0.01] was also longer in the MIC = 2 mg/L group. In a multiple stepwise regression analysis, male gender (OR = 3.58) and acute physiology and chronic health evaluation II (APACHE II) scores (OR = 1.06) were independently associated with vancomycin MIC = 2 mg/L. CONCLUSIONS: In inpatients with MRSA lower respiratory tract infection at respiratory ward or RICU between 2000 and 2011, the vancomycin MIC fluctuated, which was related with vancomycin DDDs from the whole hospital. The average hospitalization days and treatment time were significantly prolonged in patients with MRSA isolates with a higher vancomycin MIC (= 2 mg/L). APACHE II score was an independent risk factor for vancomycin MIC being 2 mg/L. PMID- 23945345 TI - [Chronic obstructive pulmonary disease phenotypes and the related characteristics of treatment response]. PMID- 23945346 TI - Neurological and chest symptoms following sclerotherapy: a single centre experience. AB - OBJECTIVES: Documentation and analysis of adverse neurological and chest symptoms in a large single centre series of sclerotherapy treatments. METHOD: In this retrospective study, patient-reported adverse events occurring during liquid or foam sclerotherapy were recorded over a 30 month period and subsequently analyzed. The relevant patient records were reviewed to determine patient characteristics, treatment details and results of subsequent investigations. RESULTS: A total of 1744 ultrasound guided sclerotherapy treatments were performed during the study period. Almost all treatments were done with air-based sodium tetradecyl sulphate foam. During the same time period, 6504 direct vision surface vein sclerotherapy treatments were completed. Approximately 1/4 of these utilized air-based foam in varying concentrations. There were 14 adverse events in 14 patients involving neurological or chest symptoms for an incidence of 0.17%. Five patients injected with foam complained of isolated chest discomfort, tightness or shortness of breath. Nine patients reported various brief neurological symptoms. These events occurred with both liquid and foam, although the majority involved foam. More neurological events were associated with direct vision sclerotherapy of smaller superficial veins than with ultrasound guided injection of intrafascial truncular veins. Seven patients who experienced neurological symptoms had a history of migraine. Five of the patients who had neurological events were investigated for right to left shunts and found to be positive. CONCLUSIONS: These events were uncommon and brief. The incidence of neurological and chest symptoms was higher with foam sclerotherapy than with liquid. A history of migraine with aura was associated with an increased risk of post-treatment neurological symptoms. Events occurred with both large vein and small vein treatment. Some events were associated with liquid sclerotherapy rather than foam and with carbon dioxide based foam as well as air foam. There were no long-term adverse consequences. PMID- 23945347 TI - World Health Organization infant and young child feeding indicators and their associations with child anthropometry: a synthesis of recent findings. AB - As the World Health Organization (WHO) infant and young child feeding (IYCF) indicators are increasingly adopted, a comparison of country-specific analyses of the indicators' associations with child growth is needed to examine the consistency of these relationships across contexts and to assess the strengths and potential limitations of the indicators. This study aims to determine cross country patterns of associations of each of these indicators with child stunting, wasting, height-for-age z-score (HAZ) and weight-for-height z-score (WHZ). Eight studies using recent Demographic and Health Surveys data from a total of nine countries in sub-Saharan Africa (nine), Asia (three) and the Caribbean (one) were identified. The WHO indicators showed mixed associations with child anthropometric indicators across countries. Breastfeeding indicators demonstrated negative associations with HAZ, while indicators of diet diversity and overall diet quality were positively associated with HAZ in Bangladesh, Ethiopia, India and Zambia (P < 0.05). These same complementary feeding indicators did not show consistent relationships with child stunting. Exclusive breastfeeding under 6 months of age was associated with greater WHZ in Bangladesh and Zambia (P < 0.05), although CF indicators did not show strong associations with WHZ or wasting. The lack of sensitivity and specificity of many of the IYCF indicators may contribute to the inconsistent associations observed. The WHO indicators are clearly valuable tools for broadly assessing the quality of child diets and for monitoring population trends in IYCF practices over time. However, additional measures of dietary quality and quantity may be necessary to understand how specific IYCF behaviours relate to child growth faltering. PMID- 23945348 TI - An interactive channel model of the Basal Ganglia: bifurcation analysis under healthy and parkinsonian conditions. AB - Oscillations in the basal ganglia are an active area of research and have been shown to relate to the hypokinetic motor symptoms of Parkinson's disease. We study oscillations in a multi-channel mean field model, where each channel consists of an interconnected pair of subthalamic nucleus and globus pallidus sub populations.To study how the channels interact, we perform two-dimensional bifurcation analysis of a model of an individual channel, which reveals the critical boundaries in parameter space that separate different dynamical modes; these modes include steady-state, oscillatory, and bi-stable behaviour. Without self-excitation in the subthalamic nucleus a single channel cannot generate oscillations, yet there is little experimental evidence for such self-excitation. Our results show that the interactive channel model with coupling via pallidal sub-populations demonstrates robust oscillatory behaviour without subthalamic self-excitation, provided the coupling is sufficiently strong. We study the model under healthy and Parkinsonian conditions and demonstrate that it exhibits oscillations for a much wider range of parameters in the Parkinsonian case. In the discussion, we show how our results compare with experimental findings and discuss their possible physiological interpretation. For example, experiments have found that increased lateral coupling in the rat basal ganglia is correlated with oscillations under Parkinsonian conditions. PMID- 23945352 TI - An ab initio study of oxygen on strained graphene. AB - Graphene under strain exhibits new fascinating properties. In this work, I show that lattice strain introduced by uniform expansion of unit cells can strongly modify the chemical properties of graphene. By employing density functional theory calculations I found that strain enhances the bonding between atomic oxygen and graphene. Strain also increases the diffusion energy barrier of atomic oxygen on graphene; however, it reduces the activation energy for oxygen migrating through the graphene sheet. Strong stability enhancement of atomic oxygen on graphene induced by strain would also change molecular oxygen dissociation reactions from endothermic to exothermic. PMID- 23945351 TI - Using health impact assessment to integrate environmental justice into federal environmental regulatory analysis. AB - Regulatory interventions are the first line of action used by the U.S. Environmental Protection Agency to fulfill its mission to protect the environment and health. Although the Agency has prioritized the integration of environmental justice into its activities, uncertainty remains in how these considerations will be incorporated into its regulatory decision-making processes. In this article, we examine the emerging practice of Health Impact Assessment and argue for its use within the regulatory assessment paradigm to help answer policy-relevant environmental justice questions. Through the use of a health lens, Health Impact Assessments can lead to a better characterization of the potential impacts and benefits of a rule by introducing novel assessments of potentially significant health effects that would otherwise be excluded, revealing whether the rule is likely to exacerbate inequities or create new ones. This article proposes a framework to overcome analytic barriers in achieving a more comprehensive, equity focused regulatory analysis. PMID- 23945349 TI - New network topology approaches reveal differential correlation patterns in breast cancer. AB - BACKGROUND: Analysis of genome-wide data is often carried out using standard methods such as differential expression analysis, clustering analysis and heatmaps. Beyond that, differential correlation analysis was suggested to identify changes in the correlation patterns between disease states. The detection of differential correlation is a demanding task, as the number of entries in the gene-by-gene correlation matrix is large. Currently, there is no gold standard for the detection of differential correlation and statistical validation. RESULTS: We developed two untargeted algorithms (DCloc and DCglob) that identify differential correlation patterns by comparing the local or global topology of correlation networks. Construction of networks from correlation structures requires fixing of a correlation threshold. Instead of a single cutoff, the algorithms systematically investigate a series of correlation thresholds and permit to detect different kinds of correlation changes at the same level of significance: strong changes of a few genes and moderate changes of many genes. Comparing the correlation structure of 208 ER- breast carcinomas and 208 ER+ breast carcinomas, DCloc detected 770 differentially correlated genes with a FDR of 12.8%, while DCglob detected 630 differentially correlated genes with a FDR of 12.1%. In two-fold cross-validation, the reproducibility of the list of the top 5% differentially correlated genes in 140 ER- tumors and in 140 ER+ tumors was 49% for DCloc and 33% for DCglob. CONCLUSIONS: We developed two correlation network topology based algorithms for the detection of differential correlations in different disease states. Clusters of differentially correlated genes could be interpreted biologically and included the marker genes hydroxyprostaglandin dehydrogenase (PGDH) and acyl-CoA synthetase medium chain 1 (ACSM1) of invasive apocrine carcinomas that were differentially correlated, but not differentially expressed. Using random subsampling and cross-validation, DCloc and DCglob were shown to identify specific and reproducible lists of differentially correlated genes. PMID- 23945353 TI - ATM is activated in blood monocytes after tumor radiation. PMID- 23945354 TI - Transport Response is a filial-specific behavioral response to maternal carrying in C57BL/6 mice. AB - BACKGROUND: A mother carries her young in many altricial mammals, such as cats, lions, rats and mice. During maternal carrying, the transported young assume a compact posture. We have recently shown that, in both humans and mice, the carried infants immediately calmed down and showed reductions in heart rate, distress vocalizations, and voluntary movement. The loss of the calming response in mouse pups hindered maternal retrieval efficacy. These findings suggested that the infant calming response functioned to reduce the maternal burden of carrying and was therefore conserved in a variety of mammalian species. However, it remains unclear how and when each component of this calming response develops and whether it is a filial-specific behavior. RESULTS: We dissected various components of the carrying-induced responses in mouse pups, collectively called the "Transport Response" herein. We showed that during the second postnatal week, pups exhibited characteristic compact posture with limb ventroflexion. The body trunk remained paradoxically pliable, suggesting complex neural regulation throughout the body. Pups also showed an increased pain tolerance to a tail pinch during the Transport Response. Analyses of the developmental courses of distinct components of the Transport Response revealed the independent regulation of each component: in the first postnatal week, the cessation of ultrasonic vocalizations was exhibited prominently; in the second postnatal week, immobilization reached its peak; and toward the third postnatal week, the postural component became fully matured. At the end of the third postnatal week, when the pups are able to transport by themselves, the pups no longer exhibited the Transport Response. CONCLUSIONS: This study has revealed the mouse Transport Response as a complex set of behavioral and physiological components, each of which has a specific postnatal time window but is orchestrated in a well-matched manner with the maturation of ambulatory ability in the pups. These findings collectively indicate that the Transport Response is a filial-specific, innate behavioral reaction and is distinct from a simple reflex or defensive freezing response. The Transport Response could be a novel index of primitive filial attachment behaviors, acting to smooth mother-infant interaction. PMID- 23945350 TI - Co-infection of human parvovirus B19 with Plasmodium falciparum contributes to malaria disease severity in Gabonese patients. AB - BACKGROUND: High seroprevalence of parvovirus B19 (B19V) coinfection with Plasmodium falciparum has been previously reported. However, the impact of B19V infection on the clinical course of malaria is still elusive. In this study, we investigated the prevalence and clinical significance of B19V co-infection in Gabonese children with malaria. METHODS: B19V prevalence was analyzed in serum samples of 197 Gabonese children with P. falciparum malaria and 85 healthy controls using polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and direct DNA-sequencing. RESULTS: B19V was detected in 29/282 (10.28%) of Gabonese children. B19V was observed more frequently in P. falciparum malaria patients (14.21%) in comparison to healthy individuals (1.17%) (P<0.001). Notably, the mild-malaria group revealed significantly lower hematocrit levels in B19V/P. falciparum co-infection than in P. falciparum mono-infection (P<0.05). Genetic analysis revealed a predominance of B19V genotype-1 (71.43%) in the studied population. However, B19V-genotype 2 was observed significantly more often in children with severe-malaria than in mild-malaria (P=0.04). CONCLUSION: Our findings reveal that B19V-infection is frequent in Gabonese children with P. falciparum malaria and signifies a possible contribution of B19V on the clinical course of malaria in a genotype-dependent manner. B19V co-infection should be considered as a additional diagnostic measure in malaria patients with life threatening anemia. PMID- 23945355 TI - Quality of life impact of cardiovascular and affective conditions among older residents from urban and rural communities. AB - BACKGROUND: The demographic, health and contextual factors associated with quality of life impairment are investigated in older persons from New South Wales, Australia. We examine the impact of cardiovascular and affective conditions on impairment and the potential moderating influence of comorbidity and remoteness. METHODS: Data from persons aged 55 and over were drawn from two community cohorts sampling from across urban to very remote areas. Hierarchical linear regressions were used to assess: 1) the impact of cardiovascular and affective conditions on physical and psychological quality of life impairment; and 2) any influence of remoteness on these effects (N = 4364). Remoteness was geocoded to participants at the postal code level. Secondary data sources were used to examine the social capital and health service accessibility correlates of remoteness. RESULTS: Physical impairment was consistently associated with increased age, male gender, lower education, being unmarried, retirement, stroke, heart attack/angina, depression/anxiety, diabetes, hypertension, current obesity and low social support. Psychological impairment was consistently associated with lower age, being unmarried, stroke, heart attack/angina, depression/anxiety and low social support. Remoteness tended to be associated with lower psychological impairment, largely reflecting overall urban versus rural differences. The impacts of cardiovascular and affective conditions on quality of life were not influenced by remoteness. Social capital increased and health service accessibility decreased with remoteness, though no differences between outer regional and remote/very remote areas were observed. Trends suggested that social capital was associated with lower psychological impairment and that the influence of cardiovascular conditions and social capital on psychological impairment was greater for persons with a history of affective conditions. The beneficial impact of social capital in reducing psychological impairment was more marked for those experiencing financial difficulty. CONCLUSIONS: Cardiovascular and affective conditions are key determinants of physical and psychological impairment. Persons affected by physical-psychological comorbidity experience greater psychological impairment. Social capital is associated with community remoteness and may ameliorate the psychological impairment associated with affective disorders and financial difficulties. The use of classifications of remoteness that are sensitive to social and health service accessibility determinants of health may better inform future investigations into the impact of context on quality of life outcomes. PMID- 23945357 TI - New pharmacological models needed to care for dying patients at home. PMID- 23945356 TI - Proteome-wide analysis reveals clues of complementary interactions between mRNAs and their cognate proteins as the physicochemical foundation of the genetic code. AB - Despite more than 50 years of effort, the origin of the genetic code remains enigmatic. Among different theories, the stereochemical hypothesis suggests that the code evolved as a consequence of direct interactions between amino acids and appropriate bases. If indeed true, such physicochemical foundation of the mRNA/protein relationship could also potentially lead to novel principles of protein-mRNA interactions in general. Inspired by this promise, we have recently explored the connection between the physicochemical properties of mRNAs and their cognate proteins at the proteome level. Using experimentally and computationally derived measures of solubility of amino acids in aqueous solutions of pyrimidine analogs together with knowledge-based interaction preferences of amino acids for different nucleobases, we have revealed a statistically significant matching between the composition of mRNA coding sequences and the base-binding preferences of their cognate protein sequences. Our findings provide strong support for the stereochemical hypothesis of genetic code's origin and suggest the possibility of direct complementary interactions between mRNAs and cognate proteins even in present-day cells. PMID- 23945358 TI - Issues surrounding death certification in the community. PMID- 23945359 TI - Hospice ethos is the heart of caring for dying people in the community. PMID- 23945361 TI - What's in a name? From pathways to plans in end of life care. PMID- 23945360 TI - We need more care, less pathway at the end of life. PMID- 23945362 TI - Human health, animal health, and ecosystems are interconnected. PMID- 23945363 TI - Three quarters of guideline panellists have ties to the drug industry. PMID- 23945364 TI - Care of the dying patient: art or science? PMID- 23945365 TI - Getting it right for each dying person we care for. PMID- 23945366 TI - Bevacizumab must be specially prepared for intraocular use. PMID- 23945367 TI - The problem of duplicate systematic reviews. PMID- 23945368 TI - Emergency doctors call for more patients to be diverted from A&E to general practice. PMID- 23945369 TI - e-Mental health in South Australia: impact of age, gender and region of residence. AB - Respondents to the 2008 South Australian Health Omnibus survey (n=2996) indicated whether, in the previous 12 months, they had searched for information on the Internet relating to emotional issues such as depression, anxiety or relationship problems. Logistic regression was used to examine the penetration of e-mental health in rural and metropolitan areas (region of residence), and determine if other demographic variables (age group, gender) also impacted on the likelihood of an individual reporting that they had used the Internet to obtain such information. Overall, 9% of respondents reported that they had used the Internet for this purpose. The multivariate model was significant, F(11, 2985)=4.82, P<0.0001, with middle-aged rural females most likely to report doing so (18.1%), whereas older rural males were least likely to report doing so (2.2.%). These findings have important implications for the design of e-mental health promotional programs that provide information and interventions to improve mental health. PMID- 23945370 TI - Is metagenomics resolving identification of functions in microbial communities? AB - We are coming up on the tenth anniversary of the broad use of the method involving whole metagenome shotgun sequencing, referred to as metagenomics. The application of this approach has definitely revolutionized microbiology and the related fields, including the realization of the importance of the human microbiome. As such, metagenomics has already provided a novel outlook on the complexity and dynamics of microbial communities that are an important part of the biosphere of the planet. Accumulation of massive amounts of sequence data also caused a surge in the development of bioinformatics tools specially designed to provide pipelines for data analysis and visualization. However, a critical outlook into the field is required to appreciate what could be and what has currently been gained from the massive sequence databases that are being generated with ever-increasing speed. PMID- 23945373 TI - Whole genome sequencing analysis of intrapatient microevolution in Mycobacterium tuberculosis: potential impact on the inference of tuberculosis transmission. AB - BACKGROUND: It has been accepted that the infection by Mycobacterium tuberculosis (M. tuberculosis) can be more heterogeneous than considered. The emergence of clonal variants caused by microevolution events leading to population heterogeneity is a phenomenon largely unexplored. Until now, we could only superficially analyze this phenomenon by standard fingerprinting (RFLP and VNTR). METHODS: In this study we applied whole genome sequencing for a more in-depth analysis of the scale of microevolution both at the intrapatient and interpatient scenarios. RESULTS: We found that the amount of variation accumulated within a patient can be as high as that observed between patients along a chain of transmission. Intrapatient diversity was found both at the extrapulmonary and respiratory sites, meaning that this variability can be transmitted and impact on the inference of transmission events. One of the events studied allowed us to track for a single strain the complete process of (i) interpatient microevolution, (ii) intrapatient respiratory variation, and (iii) isolation of different variants at different infected sites of this patient. CONCLUSIONS: Our study adds new data to the understanding of variability in M. tuberculosis in a wide clinical scenario and alerts about the difficulties of establishing thresholds to differentiate relatedness in M. tuberculosis with epidemiological purposes. PMID- 23945371 TI - New, combined, and reduced dosing treatment protocols cure Trypanosoma cruzi infection in mice. AB - The development of treatment protocols with reduced toxicity and equivalent or improved efficacy for Trypanosoma cruzi infection is a priority. We tested the effectiveness of benznidazole (BZ), nifurtimox (NFX), other prospective drugs in intermittent and combined treatment protocols to cure T. cruzi infection initiated with susceptible and drug-resistant parasite strains. A 40-day course of BZ, NFX, or the oxaborale AN4169 cured 100% of mice, whereas posaconazole (POS), and NTLA-1 (a nitro-triazole) cured approximately 90% and 20% of mice, respectively. Reducing the overall dosage of BZ or NFX by using an intermittent (once every 5 days) schedule or combining 5 daily doses of POS with 7 intermittent doses of BZ also provided approximately 100% cure. T. cruzi strains resistant to BZ were also found to be resistant to other drugs (POS), and extending the time of treatment or combining drugs did not increase cure rates with these isolates. Thus, dosing schedules for anti-T. cruzi compounds should be determined empirically, and compounds targeting different pathways may be combined to yield effective therapies with reduced toxicity. This work also suggests that standard treatment protocols using BZ and NFX may be significantly overdosing patients, perhaps contributing to the adverse events. PMID- 23945372 TI - Cryptococcus neoformans ex vivo capsule size is associated with intracranial pressure and host immune response in HIV-associated cryptococcal meningitis. AB - BACKGROUND: The Cryptococcus neoformans polysaccharide capsule is a well characterized virulence factor with immunomodulatory properties. The organism and/or shed capsule is postulated to raise intracranial pressure (ICP) in cryptococcal meningitis (CM) by mechanical obstruction of cerebrospinal fluid (CSF) outflow. Little is known regarding capsule phenotype in human cryptococcosis. We investigated the relationship of ex vivo CSF capsular phenotype with ICP and CSF immune response, as well as in vitro phenotype. METHODS: In total, 134 human immunodeficiency virus (HIV)-infected Ugandan adults with CM had serial lumbar punctures with measurement of CSF opening pressures, quantitative cultures, ex vivo capsule size and shedding, viscosity, and CSF cytokines; 108 had complete data. Induced capsular size and shedding were measured in vitro for 48 C. neoformans isolates. RESULTS: Cryptococcal strains producing larger ex vivo capsules in the baseline (pretreatment) CSF correlated with higher ICP (P = .02), slower rate of fungal clearance (P = .02), and paucity of CSF inflammation, including decreased CSF white blood cell (WBC) count (P < .001), interleukin (IL)-4 (P = .02), IL-6 (P = .01), IL-7 (P = .04), IL-8 (P = .03), and interferon gamma (P = .03). CSF capsule shedding did not correlate with ICP. On multivariable analysis, capsule size remained independently associated with ICP. Ex vivo capsular size and shedding did not correlate with that of the same isolates grown in vitro. CONCLUSIONS: Cryptococcal capsule size ex vivo is an important contributor to virulence in human cryptococcal meningitis. PMID- 23945374 TI - Associations between human leukocyte antigen class I variants and the Mycobacterium tuberculosis subtypes causing disease. AB - BACKGROUND: The development of active tuberculosis disease has been shown to be multifactorial. Interactions between host and bacterial genotype may influence disease outcome, with some studies indicating the adaptation of M. tuberculosis strains to specific human populations. Here we investigate the role of the human leukocyte antigen (HLA) class I genes in this biological process. METHODS: Three hundred patients with tuberculosis from South Africa were typed for their HLA class I alleles by direct sequencing. Mycobacterium tuberculosis genotype classification was done by IS6110 restriction fragment length polymorphism genotyping and spoligotyping. RESULTS: We showed that Beijing strain occurred more frequently in individuals with multiple disease episodes (P < .001) with the HLA-B27 allele lowering the odds of having an additional episode (odds ratio, 0.21; P = .006). Associations were also identified for specific HLA types and disease caused by the Beijing, LAM, LCC, and Quebec strains. HLA types were also associated with disease caused by strains from the Euro-American or East Asian lineages, and the frequencies of these alleles in their sympatric human populations identified potential coevolutionary events between host and pathogen. CONCLUSIONS: This is the first report of the association of human HLA types and M. tuberculosis strain genotype, highlighting that both host and pathogen genetics need to be taken into consideration when studying tuberculosis disease development. PMID- 23945377 TI - Gap junctions, dendrites and resonances: a recipe for tuning network dynamics. AB - Gap junctions, also referred to as electrical synapses, are expressed along the entire central nervous system and are important in mediating various brain rhythms in both normal and pathological states. These connections can form between the dendritic trees of individual cells. Many dendrites express membrane channels that confer on them a form of sub-threshold resonant dynamics. To obtain insight into the modulatory role of gap junctions in tuning networks of resonant dendritic trees, we generalise the "sum-over-trips" formalism for calculating the response function of a single branching dendrite to a gap junctionally coupled network. Each cell in the network is modelled by a soma connected to an arbitrary structure of dendrites with resonant membrane. The network is treated as a single extended tree structure with dendro-dendritic gap junction coupling. We present the generalised "sum-over-trips" rules for constructing the network response function in terms of a set of coefficients defined at special branching, somatic and gap-junctional nodes. Applying this framework to a two-cell network, we construct compact closed form solutions for the network response function in the Laplace (frequency) domain and study how a preferred frequency in each soma depends on the location and strength of the gap junction. PMID- 23945375 TI - Common and new acyclovir resistant herpes simplex virus-1 mutants causing bilateral recurrent herpetic keratitis in an immunocompetent patient. AB - We investigated thymidine kinase (tk) mutants isolated during multiple episodes of recurrent bilateral acyclovir resistant herpes simplex keratitis in an immunocompetent patient. From one eye, we found a single guanine insertion, previously shown to greatly reduce TK expression, and from the other, a previously unidentified substitution, which genetic experiments confirmed confers drug resistance. The substitution, although distant from substrate binding sites, reduced thymidine phosphorylation 10-20-fold, and acyclovir phosphorylation >100 fold. This phenotype should permit reactivation from latency to cause recurrent disease. The results may have implications for the prevalence and prevention of acyclovir resistance in patients with herpes simplex keratitis. PMID- 23945376 TI - Residual Plasmodium falciparum parasitemia in Kenyan children after artemisinin combination therapy is associated with increased transmission to mosquitoes and parasite recurrence. AB - BACKGROUND: Parasite clearance time after artemisinin-based combination therapy (ACT) may be increasing in Asian and African settings. The association between parasite clearance following ACT and transmissibility is currently unknown. METHODS: We determined parasite clearance dynamics by duplex quantitative polymerase chain reaction (qPCR) in samples collected in the first 3 days after treatment of uncomplicated malaria with ACT. Gametocyte carriage was determined by Pfs25 quantitative nucleic acid sequence-based amplification assays; infectiousness to mosquitoes by membrane-feeding assays on day 7 after treatment. RESULTS: Residual parasitemia was detected by qPCR in 31.8% (95% confidence interval [CI], 24.6-39.8) of the children on day 3 after initiation of treatment. Residual parasitemia was associated with a 2-fold longer duration of gametocyte carriage (P = .0007), a higher likelihood of infecting mosquitoes (relative risk, 1.95; 95% CI, 1.17-3.24; P = .015), and a higher parasite burden in mosquitoes (incidence rate ratio, 2.92; 95% CI, 1.61-5.31; P < .001). Children with residual parasitemia were also significantly more likely to experience microscopically detectable parasitemia during follow-up (relative risk, 11.25; 95% CI, 4.08 31.01; P < .001). CONCLUSIONS: Residual submicroscopic parasitemia is common after ACT and is associated with a higher transmission potential. Residual parasitemia may also have consequences for individual patients because of its higher risk of recurrent parasitemia. PMID- 23945380 TI - Staging of the mediastinum: are we already there? PMID- 23945378 TI - Impact of a referral management "gateway" on the quality of referral letters; a retrospective time series cross sectional review. AB - BACKGROUND: Referral management centres (RMC) for elective referrals are designed to facilitate the primary to secondary care referral path, by improving quality of referrals and easing pressures on finite secondary care services, without inadvertently compromising patient care.This study aimed to evaluate whether the introduction of a RMC which includes triage and feedback improved the quality of elective outpatient referral letters. METHODS: Retrospective, time-series, cross sectional review involving 47 general practices in one primary care trust (PCT) in South-East England. Comparison of a random sample of referral letters at baseline (n = 301) and after seven months of referral management (n = 280). Letters were assessed for inclusion of four core pieces of information which are used locally to monitor referral quality (blood pressure, body mass index, past medical history, medication history) and against research-based quality criteria for referral letters (provision of clinical information and clarity of reason for referral). RESULTS: Following introduction of the RMC, the proportion of letters containing each of the core items increased compared to baseline. Statistically significant increases in the recording of 'past medical history' (from 71% to 84%, p < 0.001) and 'medication history' (78% to 87%, p = 0.006) were observed. Forty four percent of letters met the research-based quality criteria at baseline but there was no significant change in quality of referral letters judged on these criteria across the two time periods. CONCLUSION: Introduction of RMC has improved the inclusion of past medical history and medication history in referral letters, but not other measures of quality. In approximately half of letters there remains room for further improvement. PMID- 23945381 TI - Consolidation chemotherapy after chemoradiation? Not the right answer to not the right question? PMID- 23945382 TI - High T790M detection rate in TKI-naive NSCLC with EGFR sensitive mutation: truth or artifact? PMID- 23945383 TI - Lung cancer and prognosis in taiwan: a population-based cancer registry. AB - INTRODUCTION: Lung cancer is the leading cause of cancer death in Taiwan. This study investigated the prognostic factors affecting survival of patients with lung cancer in Taiwan. METHODS: Data were obtained from the National Health Insurance Research Database published in Taiwan. Clinicopathologic profiles and prognostic factors of 33,919 lung cancer patients were analyzed between 2002 and 2008 in this retrospective review. The impact of the clinicopathologic factors on overall survival was assessed. RESULTS: Nearly two thirds of the patients were men. The 5-year survival rate was 15.9%, with a median survival of 13.2 months. The clinical staging of the patients included stage I (n = 4254; 12.5%), stage II (n = 1140; 3.4%), stage III (n = 10,161; 30.0%), and stage IV (n = 18,364; 54.1%). In the multivariate analysis, age more than 65 years, sex, cell type, histologic grade, and primary tumor location were identified as independent prognostic factors. CONCLUSION: In additional to tumor-nodes-metastasis (TNM) staging system, patient sex and age, tumor location, cell type, and differentiation were independent prognostic factors. We recommend incorporation of these factors to subclassify lung cancer patients. PMID- 23945384 TI - Association of exon 19 and 21 EGFR mutation patterns with treatment outcome after first-line tyrosine kinase inhibitor in metastatic non-small-cell lung cancer. AB - BACKGROUND: This study investigated whether there were differential survival outcomes to first-line tyrosine kinase inhibitors (TKI) in patients with metastatic non-small-cell lung cancer harboring different subtypes of exon 19 and exon 21 mutations on epidermal growth factor receptor (EGFR). METHODS: Of 452 patients with stage IIIB and IV non-small-cell lung cancer, 192 patients (42.5%) harbored EGFR mutation and 170 (37.5%) received TKI as first-line treatment. EGFR mutation analysis was performed by direct sequencing. Survival and response outcome were compared among different subtypes of exon 19 and exon 21 EGFR mutations in these 170 patients. RESULTS: Patients harboring exon 19 18 nucleotide deletion (delL747_P753insS) had the shortest median progression-free survival (PFS) (6.5 months), followed by those with 15-nucleotide deletion (delE746_A750) (12.4 months) and mixed insertion/substitution mutations (22.3 months; p = 0.012). However, patients who had exon 19 deletions starting on codon E746 had better median PFS (14.2 months) than those starting on L747 (6.5 months; hazard ratio, 0.445; 95% confidence interval [0.219-0.903]; p = 0.021). Besides, exon 21 L858R derived a longer median PFS than L861R/L861Q (11.4 months versus 2.1 months, respectively; hazard ratio, 0.298; 95% confidence interval [0.090 0.980]; p = 0.034). CONCLUSIONS: Different subtypes of EGFR exon 19 and 21 mutations exhibited differential survival to first-line TKI therapy. Detailed sequence evaluation of exon 19 deletions may provide important prognostic information on survival outcome after TKI. PMID- 23945385 TI - microRNAs derived from circulating exosomes as noninvasive biomarkers for screening and diagnosing lung cancer. AB - INTRODUCTION: Lung cancer is the highest cause of mortality among tumor pathologies worldwide. There are no validated techniques for an early detection of pulmonary cancer lesions other than low-dose helical computed tomography scan. Unfortunately, this method has some negative effects. Recent studies have laid the basis for development of exosomes-based techniques to screen/diagnose lung cancers. As the isolation of circulating exosomes is a minimally invasive procedure, this technique opens new possibilities for diagnostic applications. METHODS: We used a first set of 30 plasma samples from as many patients, including 10 patients affected by lung adenocarcinomas, 10 with lung granulomas, and 10 healthy smokers matched for age and sex as negative controls. Wide-range microRNAs analysis (742 microRNAs) was performed by quantitative real time polymerase chain reaction. Data were compared on the basis of lesion characteristics, using WEKA software for statistics and modeling. Subsequently, selected microRNAs were evaluated on an independent larger group of samples (105 specimens: 50 lung adenocarcinomas, 30 lung granulomas, and 25 healthy smokers). RESULTS: This analysis led to the selection of four microRNAs to perform a screening test (miR-378a, miR-379, miR-139-5p, and miR-200b-5p), useful to divide population into two groups: nodule (lung adenocarcinomas + carcinomas) and non nodule (healthy former smokers). Six microRNAs (miR-151a-5p, miR-30a-3p, miR-200b 5p, miR-629, miR-100, and miR-154-3p) were selected for a second test on the nodule population to discriminate between lung adenocarcinoma and granuloma. CONCLUSIONS: The screening test showed 97.5% sensitivity, 72.0% specificity, and area under the curve receiver operating characteristic of 90.8%. The diagnostic test had 96.0% sensitivity, 60.0% specificity, and area under the curve receiver operating characteristic of 76.0%. Further evaluation is needed to confirm the predictive power of these models on larger cohorts of samples. PMID- 23945386 TI - WT1 promotes invasion of NSCLC via suppression of CDH1. AB - INTRODUCTION: The Wilms' tumor gene (WT1) has been identified as an oncogene in many malignant diseases, and aberrant WT1 expression has been linked to development, progression, and prognosis of non-small-cell lung cancer (NSCLC). We sought to investigate the underlying mechanism of WT1 and metastasis in NSCLC. METHODS: Real-time polymerase chain reaction was applied to detect WT1 and CDH1 mRNA in 159 NSCLC samples and corresponding adjacent tissues. Stable clones with overexpression and knockdown of WT1 were generated with plasmid and shRNA via lentivirus technology in H1568 and H1650 NSCLC cell lines. Wound-healing assay, transwell assays, and polymerase chain reaction array were carried out for invasion evaluation. Dual luciferase reporter assay was performed to validate the effect of WT1 on CDH1. RESULTS: The level of the WT1 mRNA was negatively correlated with that of E-cadherin (CDH1) and associated with pathological stage, metastasis, and survival rate of 159 NSCLC patients. A series of genes were regulated by WT1, and WT1 could suppress CDH1 transcription via direct binding to its promoter and may enhance the invasive ability of H1568 and H1650 NSCLC cell lines. CONCLUSIONS: WT1 expression was correlated with clinical stage, metastasis, and survival rate in 159 NSCLC patients. Via direct binding to the promoter, WT1 could suppress CDH1 and promote NSCLC invasion. PMID- 23945387 TI - A prediction model for pathologic N2 disease in lung cancer patients with a negative mediastinum by positron emission tomography. AB - INTRODUCTION: Guidance is limited for invasive staging in patients with lung cancer without mediastinal disease by positron emission tomography (PET). We developed and validated a prediction model for pathologic N2 disease (pN2), using six previously described risk factors: tumor location and size by computed tomography (CT), nodal disease by CT, maximum standardized uptake value of the primary tumor, N1 by PET, and histology. METHODS: A cohort study (2004-2009) was performed in patients with T1/T2 by CT and N0/N1 by PET. Logistic regression analysis was used to develop a prediction model for pN2 among a random development set (n = 625). The model was validated in both the development set, which comprised two thirds of the patients and the validation set (n = 313), which comprised the remaining one third. Model performance was assessed in terms of discrimination and calibration. RESULTS: Among 938 patients, 9.9% had pN2 (9 detected by invasive staging and 84 intraoperatively). In the development set, univariate analyses demonstrated a significant association between pN2 and increasing tumor size (p < 0.001), nodal status by CT (p = 0.007), maximum standardized uptake value of the primary tumor (p = 0.027), and N1 by PET (p < 0.001); however, only N1 by PET was associated with pN2 (p < 0.001) in the multivariate prediction model. The model performed reasonably well in the development (c-statistic, 0.70; 95% confidence interval, 0.63-0.77; goodness of fit p = 0.61) and validation (c-statistic, 0.65; 95% confidence interval, 0.56 0.74; goodness-of-fit p = 0.19) sets. CONCLUSION: A prediction model for pN2 based on six previously described risk factors has reasonable performance characteristics. Observations from this study may guide prospective, multicenter development and validation of a prediction model for pN2. PMID- 23945388 TI - Why do pathological stage IA lung adenocarcinomas vary from prognosis?: a clinicopathologic study of 176 patients with pathological stage IA lung adenocarcinoma based on the IASLC/ATS/ERS classification. AB - BACKGROUND: Patients with pathological stage IA adenocarcinoma (AC) have a variable prognosis, even if treated in the same way. The postoperative treatment of pathological stage IA patients is also controversial. METHODS: We identified 176 patients with pathological stage IA AC who had undergone a lobectomy and mediastinal lymph node dissection at the Shanghai Chest Hospital, Shanghai, China, between 2000 and 2006. No patient had preoperative treatment. The histologic subtypes of all patients were classified according to the 2011 International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) international multidisciplinary lung AC classification. Patients' 5-year overall survival (OS) and 5-year disease free survival (DFS) were calculated using Kaplan-Meier and Cox regression analyses. RESULTS: One hundred seventy-six patients with pathological stage IA AC had an 86.6% 5-year OS and 74.6% 5-year DFS. The 10 patients with micropapillary predominant subtype had the lowest 5-year DFS (40.0%).The 12 patients with solid predominant with mucin production subtype had the lowest 5-year OS (66.7%). Univariate and multivariate analysis showed that sex and prognositic groups of the IASLC/ATS/ERS histologic classification were significantly associated with 5 year DFS of pathological stage IA AC. CONCLUSION: Our study revealed that sex was an independent prognostic factor of pathological stage IA AC. The IASLC/ATS/ERS classification of lung AC identifies histologic categories with prognostic differences that could be helpful in clinical therapy. PMID- 23945389 TI - Frequency and type of epidermal growth factor receptor mutations in moroccan patients with lung adenocarcinoma. AB - INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer predict response to tyrosine kinase inhibitors. The frequency of EGFR mutations is ethnicity-dependent, with a higher proportion in Asian populations than in whites. The prevalence of these mutations among North African patients is unknown. The objective of this study was to report the frequency and spectrum of EGFR mutations in a group of Moroccan patients with lung adenocarcinoma (AC). METHODS: Tumor specimens from 137 Moroccan patients with lung AC were selected to determine frequency and spectrum of EGFR mutations. Mutation detection techniques were polymerase chain reaction amplification and sequencing of exons 18, 19, 20, and 21. RESULTS: The overall frequency of the EGFR mutation was 21%. Mutations were mainly detected in the exon 19 (69%), followed by exon 21 (21%) and exon 20 (7%), whereas mutations in the exon 18 were rare (3%). EGFR mutation rate was significantly higher in women and in never smokers. CONCLUSION: Some one fifth of lung AC tumors in Moroccan patients harbor EGFR mutations. This mutation frequency is higher than that found in whites but lower than in Asian population. Further studies, in larger numbers of patients, are needed to confirm these findings. PMID- 23945390 TI - Should patients with extrapulmonary small-cell carcinoma receive prophylactic cranial irradiation? AB - INTRODUCTION: Extrapulmonary small-cell carcinoma (EPSCC) is a rare disease. Management is based on small-cell lung carcinoma. Prophylactic cranial irradiation (PCI) is not routinely administered in EPSCC. This study investigates the role of PCI in EPSCC, by analyzing the incidence, treatment, and survival of patients with brain metastases in a national cohort. Disease biology and epidemiology are also investigated. METHODS: Patients diagnosed with primary EPSCC from the National Cancer Registry of Ireland from 1995 to 2007 were identified. The number of patients who developed brain metastases, their survival, and treatment data were documented. Patients who received PCI were investigated. Patient and disease characteristics, treatment, and survival data were stratified by stage and primary site. RESULTS: Two hundred eighty patients were identified; 141 (50.4%) were men and 139 (49.6%) were women. One hundred eighty six patients (66.4%) had extensive-stage disease, 65 (23.2%) had limited stage disease, and in 29 patients (10.3%) the stage was unknown. Eighteen patients (6.4%) developed brain metastases, with a median overall survival of 10.1 months. Eleven (61%) received cranial irradiation, and 12 (67%) received palliative chemotherapy. Two patients in the entire cohort (0.17%) received PCI. The most common primary sites included the esophagus (n = 43; 15.4%), cervix uteri (n = 17; 6.0%), bladder (n = 13; 4.6%), and prostate (n = 10; 3.6%). Median overall survival was 15.2 months (10.2-20.6) for limited-stage disease, 2.3 months (1.7-3.1) for extensive-stage EPSCC, and 3.7 months (1.3-8.3) for disease of unknown stage. CONCLUSION: Brain metastases were uncommon in EPSCC compared with small-cell lung carcinoma. PCI is thus probably not warranted in this disease. PMID- 23945391 TI - Sarcomatoid mesothelioma with osteoid differentiation. PMID- 23945392 TI - Erlotinib response in an NSCLC patient with a novel compound G719D+L861R mutation in EGFR. PMID- 23945393 TI - High-dose crizotinib for brain metastases refractory to standard-dose crizotinib. PMID- 23945394 TI - Tbx1 regulates brain vascularization. AB - The transcription factor TBX1 is the major gene involved in 22q11.2 deletion syndrome (22q11.2DS). Using mouse models of these diseases, we have previously shown that TBX1 activates VEGFR3 in endothelial cells (EC), and that this interaction is critical for the development of the lymphatic vasculature. In this study, we show that TBX1 regulates brain angiogenesis. Using loss-of-function genetics and molecular approaches, we show that TBX1 regulates the VEGFR3 and DLL4 genes in brain ECs. In mice, loss of TBX1 causes global brain vascular defects, comprising brain vessel hyperplasia, enhanced angiogenic sprouting and vessel network disorganization. This phenotype is recapitulated in EC-specific Tbx1 conditional mutants and in an EC-only 3-dimensional cell culture system (matrigel), indicating that the brain vascular phenotype is cell autonomous. Furthermore, EC-specific conditional Tbx1 mutants have poorly perfused brain vessels and brain hypoxia, indicating that the expanded vascular network is functionally impaired. In EC-matrigel cultures, a Notch1 agonist is able to partially rescue microtubule hyperbranching induced by TBX1 knockdown. Thus, we have identified a novel transcriptional regulator of angiogenesis that exerts its effect in brain by negatively regulating angiogenesis through the DLL4/Notch1 VEGFR3 regulatory axis. Given the similarity of the phenotypic consequences of TBX1 mutation in humans and mice, this unexpected role of TBX1 in murine brain vascularization should stimulate clinicians to search for brain microvascular anomalies in 22q11.2DS patients and to evaluate whether some of the anatomical and functional brain anomalies in patients may have a microvascular origin. PMID- 23945396 TI - Back to the future: how human induced pluripotent stem cells will transform regenerative medicine. AB - Based on cloning studies in mammals, all adult human cells theoretically contain DNA that is capable of creating a whole new person. Cells are maintained in their differentiated state by selectively activating some genes and silencing. The dogma until recently was that cell differentiation was largely fixed unless exposed to the environment of an activated oocyte. However, it is now possible to activate primitive pluripotent genes within adult human cells that take them back in time to a pluripotent state (termed induced pluripotent stem cells). This technology has grown at an exponential rate over the past few years, culminating in the Nobel Prize in medicine. Discussed here are recent developments in the field as they relate to regenerative medicine, with an emphasis on creating functional cells, editing their genome, autologous transplantation and how this ground-breaking field may eventually impact human aging. PMID- 23945397 TI - Supramolecular architectures and structural diversity in a series of lead (II) Chelates involving 5-Chloro/Bromo thiophene-2-carboxylate and N,N'-donor ligands. AB - BACKGROUND: Lead is a heavy toxic metal element in biological systems and is one of the major pollutants as a result of its widespread use in industries. In spite of its negative roles the coordination chemistry of Pb(II) complexes is a matter of interest. The N,N'-bidentate aromatic bases such as BPY,4-BPY and PHEN (BPY = 2,2'bipyridine, 4-BPY = 4,4'-dimethyl-2,2'-bipyridine, PHEN = 1,10 Phenanthroline) are widely used to build supramolecular architectures because of their excellent coordinating ability and large conjugated system that can easily form pi-pi interactions among their aromatic moieties. A series of novel Pb(II) complexes in concert with 5-CTPC, 5-BTPC (5-CTPC = 5-chlorothiophen-2 carboxylate, 5-BTPC = 5-bromothiophen-2-carboxylate) and corresponding bidentate chelating N.N' ligands have been synthesized and characterized. RESULTS: Five new Pb (II) complexes [Pb(BPY)(5-CTPC)2] (1), [Pb(4-BPY)(5-CTPC)2] (2), [Pb2(PHEN)2(5 CTPC)4] (3), [Pb(4-BPY)(5-BTPC)2] (4) and [Pb2(PHEN)2(5-BTPC)2(ACE)2] (5) have been synthesized. Even though in all these complexes the molar ratio of Pb, carboxylate, N,N-chelating ligand are the same (1:2:1), there is a significant structural diversity. These complexes have been characterised and investigated by elemental analysis, IR, 1H-NMR,13C-NMR, TGA, and photoluminescence studies. Single crystal X-ray diffraction studies reveal that complexes (1, 2) and (4) are mononuclear while (3 and 5) are dinuclear in nature which may result from the chelating nature of the ligands, various coordination modes of the carboxylates, and the coordination geometry of the Pb(II) ions. CONCLUSIONS: The observation of structures 2,4 and 3,5 show the structural changes made just chloro/bromo substituent of the thiophene ring. A detailed packing analysis has been undertaken to delineate the role of valuable non covalent interactions like X...pi, H...X, (X = Cl/Br). A quadruple hydrogen bond linking the monomeric units and generating a supramolecular architecture is observed in (1). The metal bite unit comprised of PbN2C2 (i.e. Pb-N-C-C-N-Pb) is the repeating unit in all the five complexes and they have almost same geometrical parameters. This metal bite has been identified as the self assembly unit in complexes. PMID- 23945398 TI - Recurrence after skin-sparing mastectomy and immediate transverse rectus abdominis musculocutaneous flap reconstruction for invasive breast cancer. AB - BACKGROUND: The aim of this study was to evaluate the recurrence pattern after skin-sparing mastectomy (SSM) and immediate breast reconstruction (IBR) using transverse rectus abdominis musculocutaneous (TRAM) flap in patients with invasive breast cancer. METHODS: From 1995 to 2010, patients with invasive breast cancer who underwent SSM followed by IBR using TRAM flap were retrospectively reviewed. The pattern of the first recurrence event was recorded. RESULTS: We identified 249 consecutive patients with invasive breast cancer, two-thirds of whom (67.1%) were diagnosed with stage II or stage III disease. During a median follow-up period of 53 months, three (1.2%) local, 13 (5.2%) regional, 34 (13.7%) distant, and five (2.0%) concurrent locoregional and distant recurrences were observed. The median time to recurrences was 26 months (range, 2 to 70 months) for all recurrences, 23 months (range, 2 to 64 months) for locoregional recurrences, and 26 months (range, 8 to 70 months) for distant recurrences. All local recurrent lesions were detectable by careful physical examination, and detection of local recurrence suggested the presence of distant metastasis (60.0%). In contrast to distant metastasis, the risk of locoregional recurrence did not increase significantly with an increase in disease stage. The 5-year overall, locoregional relapse-free, and distant relapse-free survival rates were 89.7%, 90.8%, and 81.6%, respectively. CONCLUSIONS: SSM followed by immediate reconstruction using TRAM flap is an oncologically safe procedure even in patients with advanced-stage disease. Detection of local recurrence is crucial and can be aided by a thorough physical examination. PMID- 23945403 TI - Iron status of the Pakistani population-current issues and strategies. AB - The present review aims to highlight the magnitude of iron status of Pakistani population and possible remedies to address iron deficiency among vulnerable groups. A computer-based search was carried out on "PubMed", "Google Search" and "Sciencedirect.com" to retrieve relevant scientific literature published in the last two decades. The search yielded 193 articles, of which 64 were culled and further screening was performed based on the type of vulnerable population groups, age, sex and pregnancy. A thorough review of current literature reveals that iron deficiency (ID) and iron deficiency anemia (IDA) widely persist in Pakistan and necessitate immediate remedial actions. Females of reproductive age and children under 5 years have been shown to be the most IDA affected population segment. Fortification of wheat flour has been suggested as the most viable approach aptly matching Pakistan's needs for combating IDA. The present review further stresses the need for global involvement to scale up efforts for mitigating ID and IDA to achieve Millennium Development Goals (MDGs) that are fundamentally based upon improving nutritional wellbeing of populations in developing economies by 2015. PMID- 23945402 TI - Poverty and the state of nutrition in India. AB - India is often thought of as a development paradox with relatively high economic growth rates in the past few years, but with lower progress in areas of life expectancy, education and standard of living. While serious inequalities in growth, development and opportunity explain the illusion of the paradox at the country level, still, a significant proportion of the world's poor live in India, as do a significant proportion of the world's malnourished children. Poverty and undernutrition coexist, and poor dietary quality is associated with poor childhood growth, as well as significant micronutrient deficiencies. Food security is particularly vulnerable to changes in the economic scenario and to inequities in wealth distribution. Migration from rural to urban settings with a large informal employment sector also ensures that migrants continue to live in food insecure situations. While food production has for the most part kept pace with the increasing population, it has been with regard to cereal rather than of pulses and millet production. Oil seeds, sugar cane and horticultural crops, along with non-food crops are also being promoted, which do not address nutrition security, and, coupled with the increase in the consumption of pre-prepared food, may indeed predispose towards the double burden of malnutrition. Access to food is also particularly susceptible to poverty and inequality. Many strategies and policies have been proposed to counter undernutrition in India, but their implementation has not been uniform, and it is still too early to assess their lasting impact at scale. PMID- 23945395 TI - Genome-wide association study identifies three novel loci for type 2 diabetes. AB - Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 * 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 * 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 * 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases. PMID- 23945404 TI - Relationship between anthropometric and dual energy X-ray absorptiometry measures to assess total and regional adiposity in Malaysian adolescents. AB - The main objective of this paper was to determine the utility of various anthropometric measures to assess total and regional body fatness using dual energy X-ray absorptiometry (DXA) as the criterion in 454 adolescent boys and girls aged 12-19 years. Multivariable regression analyses of gender-specific and gender-combined models were used to determine anthropometric measures on DXA derived body fatness models, after adjusting for known confounding biological factors. Partial correlation analyses, after adjusting for age, pubertal growth status and ethnicity in boys and girls, showed that body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-height ratio (WhtR) were significantly correlated with total body fat (TBF), percent body fat (%BF), android region fat (ARF) and trunk fat (TF) (all p<0.0001). BMI was the greatest independent determinant, contributing 43.8%-80.9% of the total variance for DXA derived body fatness models. Results confirmed that a simple anthropometric index such as the BMI is a good surrogate indicator of body fat levels in Malay and Chinese adolescents. PMID- 23945405 TI - Effect of soy isoflavone supplementation on vascular endothelial function and oxidative stress in postmenopausal women: a community randomized controlled trial. AB - A 12-month randomized double blind controlled trial was conducted among 182 Indonesian postmenopausal women aged 47 to 60 years to determine the effect of 100 mg/day soy isoflavone supplementation on vascular endothelial function such as vascular cell adhesion molecule-1 (VCAM-1), nitric oxide (NO) and malondialdehyde (MDA) as oxidative stress marker. The subjects were randomized to the intervention group receiving tablets consisting of 100 mg soy isoflavones and calcium carbonate 500 mg, and to the control group receiving 500 mg calcium carbonate. The concentrations of VCAM-1, NO and MDA were measured at baseline, and postsupplementation at 6 months and 12 months. After supplementation, the MDA concentrations were significantly lower in the soy isoflavone group compared with the control group (p=0.001). The concentrations of VCAM-1 and NO were not affected (p=0.992 and p=0.759, respectively). In all group the MDA concentration increased compared with baseline concentrations but the relative change of MDA concentrations was significantly lower in the soy isoflavone group compared with the control group. This study demonstrates that supplemental intake of soy isoflavones for 6 months and 12 months had an effect on oxidative stress by decreasing MDA concentration, but did not improve vascular endothelial function. PMID- 23945406 TI - Effect of Korean red ginseng on insulin sensitivity in non-diabetic healthy overweight and obese adults. AB - BACKGROUND: Korean red ginseng is one of the most popular herbs worldwide due to the belief that it contains ingredients that possess a variety of health enhancing effects including anti-diabetic effects. The objective of this study was to determine whether Korean red ginseng supplement has an effect on insulin sensitivity in healthy overweight or obese adults without overt diabetes and hypertension. METHODS: In a double-blinded, placebo controlled, randomized trial, a total of 68 participants (BMI >=23 kg/m2) received either 6 g of Korean red ginseng rootlets (n=34) or a placebo each day over a 12 week period. RESULTS: Similar insulin levels and insulin sensitivity index were observed at baseline in the Korean red ginseng and control groups. Korean red ginseng had no significant effect on improving the insulin sensitivity over time. Korean red ginseng does not improve the insulin sensitivity of overweight and obese subjects who do not have diabetes or hypertension. PMID- 23945407 TI - Effect of variety and cooking method on resistant starch content of white rice and subsequent postprandial glucose response and appetite in humans. AB - Rice is a staple carbohydrate throughout much of the world. Previous work indicated that resistant starch (RS) content of rice consumed in India varied with rice variety and cooking method. This study quantified RS in 4 white rice varieties (jasmine, long grain, medium grain, and short grain) cooked in three manners (oven baked, conventional rice cooker, and pressure cooker), and analyzed for RS content immediately after preparation or after 3 days of refrigeration at 4 degrees C. The rice varieties with the highest and lowest RS content were selected for a pilot- scale trial to characterize postprandial glycemic response and appetite ratings in healthy adults (n=21). Refrigerated long-grain rice cooked in a conventional rice cooker had the highest RS content (HRS, 2.55 g RS/100 g) and refrigerated short-grain rice cooked in a pressure cooker had the lowest RS content (LRS, 0.20 g RS/100 g). These rice samples were served reheated in the clinical trial. Glucose area under the curve (AUC) were significantly lower with HRS and LRS compared to glucose beverage; however, there was no difference between HRS and LRS. Glycemic indices did not differ significantly between HRS and LRS. Subjects reported an overall increased feeling of fullness and decreased desire to eat based on incremental area under the curve (iAUC) for both HRS and LRS compared to control. This study found that RS naturally occurring in rice had minimal impact on the postprandial glycemic response and appetite. PMID- 23945408 TI - Acute effects of oral preloads with increasing energy density on gastric emptying, gut hormone release, thermogenesis and energy intake, in overweight and obese men. AB - This study investigated the effect of high- and low-energy density preloads on gastrointestinal and metabolic factors, which act to regulate acute energy intake. Sixteen overweight and obese men (BMI range: 27.2-36.5 kg/m2) each received 3 oral preloads in randomised order: i) high-energy-density, high-fat (1.5 kcal/g), ii) low-energy density, high-fat (1.1 kcal/g), and iii) low-energy density, high-protein (1.1 kcal/g). Over 180 min, gastric emptying, plasma glucagon-like peptide-1 concentrations, and diet-induced thermogenesis were assessed, and subsequent energy intake was determined. Total energy intake did not differ between preloads (high-energy-density, high-fat, 2059+/-72 kilocalories (kcal); low-energy-density, high-fat, 1876+/-91 kcal; and low-energy density, high protein, 1867+/-63 kcal). Gastric emptying was slower following the high-energy-density, high-fat preload (158+/-8 min) compared with the low-energy density, high-protein preload (130+/-9 min) (p=0.05), but did not differ between the high-energy-density, high-fat and low-energy-density, high-fat (147+/-8 min) preloads. Plasma glucagon- like peptide-1 did not differ substantially between preloads. Diet-induced thermogenesis was lower following high-energy-density, high-fat (10.4+/-0.7 %) than low-energy-density, high-fat (14.9+/-1.2 %) and low energy density, high-protein (18.1+/-1.1 %) preloads (p<0.01 for both). We conclude that an increased energy density slows gastric emptying and reduces thermogenesis, but that a high fat content overrides the effect of energy density on gastric emptying. The counter-regulatory modulation of these gastric and metabolic factors may explain, at least in part, the lack of differences in subsequent energy intake in response to oral preloads with increasing energy density. PMID- 23945409 TI - Effects of sun exposure on 25(OH) vitamin D concentration in urban and rural women in Malaysia. AB - Ultraviolet B sunlight exposure is a primary source of vitamin D. There have been reports of low vitamin D status amongst the Malaysian population despite it being a tropical country. This study was conducted to determine the influence of sun exposure on 25(OH)D concentrations in urban and rural women in Malaysia and factors predicting 25(OH)D concentrations. Women aged above 45 years were recruited from urban (n=107) and rural areas (n=293). Subjects were interviewed regarding their outdoor activities and usual outdoor attire over the previous week. 25(OH)D concentrations were analyzed using the vitamin D3 (25-OH) electrochemiluminescence immunoassay. Median (Q1-Q3) age of the participants was 57 (53-61) years old. Median (Q1-Q3) 25(OH)D concentration of rural women was significantly higher [69.5 (59.0-79.1) nmol/L] compared to urban women [31.9 (26.1- 45.5) nmol/L] (p<0.001). Rural women spent more time in the sun compared to urban women (7.83 (3.67-14.7) vs 2.92 (1.17-4.92) hours, p<0.001), although the fraction of body surface area (BSA) exposed to sunlight was significantly higher in the urban group [0.21 (0.21-0.43) vs 0.12 (0.07-0.17), p<0.001]. The calculated sun index (hours of sun exposure per week * fraction of BSA) was significantly higher in rural [0.89 (0.42-1.83)] compared to urban women [0.72 (0.26-1.28)], p=0.018. In the stepwise linear regression, rural dwelling increased the serum 25(OH)D by 31.74 nmol/L and 25(OH)D concentrations increased by 1.93 nmol/L for every unit increment in sun index. Urban women in Malaysia had significantly lower vitamin D status compared to rural women. Rural dwelling and sun index were key factors influencing vitamin D status in Malaysian women. PMID- 23945410 TI - Serum ferritin and risk of the metabolic syndrome: a population-based study. AB - Ferritin concentrations in circulation reflect iron stores in healthy individuals. However, elevated serum ferritin (SF) concentrations have recently been implicated in the pathogenesis of the metabolic syndrome (MetS). We aim to investigate factors associated with elevated SF and to evaluate the association between SF and risk of MetS in Taiwanese adults. Data was collected from 2654 healthy individuals aged >=19 years old, who participated in the Nutrition and Health Survey in Taiwan (NAHSIT Adults 2005-2008). Mean concentrations of SF were 173+/-282 ng/mL (men 229+/-349 ng/mL and women 119+/-180 ng/mL). Prevalence proportion of MetS was 34.6% (men 43.1% and women 26.5%). Prevalence proportion of iron overload was 18.6% (men 21.5% and women 15.8%) and iron deficiency anemia was 5.2% (2.0% for men and 8.3% for women). Individuals with the highest SF tertile (T3) were more likely to consume higher amount of animal protein (p=0.001), betel nuts (p=0.004), and lower amounts of carbohydrates (p<0.0001), compared with the lowest SF group (T1). After adjustments, individuals with the highest SF tertile were associated with risk of MetS compared with those with the lowest (OR=1.724, 95% CI: 1.21-2.45). Serum ferritin concentrations showed a gradient relationship with individual components of MetS (all p<0.0001). Individuals with the highest SF tertile were significantly associated with fasting serum glucose (OR=2.16, 95% CI: 1.75-2.65) and serum triglyceride (OR=2.58, 95% CI: 1.07-3.22) than those with the lowest. In conclusions, our results highlight the crucial role of serum ferritin in the pathogenesis of the MetS in healthy Taiwanese adults. PMID- 23945411 TI - Overweight among primary school-age children in Malaysia. AB - This study is a secondary data analysis from the National Health Morbidity Survey III, a population-based study conducted in 2006. A total of 7,749 children between 7 and 12 years old were recruited into the study. This study seeks to report the prevalence of overweight (including obesity) children in Malaysia using international cut-off point and identify its associated key social determinants. The results show that the overall prevalence of overweight children in Malaysia was 19.9%. The urban residents, males, Chinese, those who are wealthy, have overweight or educated guardians showed higher prevalence of overweight. In multivariable analysis, higher likelihood of being overweight was observed among those with advancing age (OR=1.15), urban residents (OR=1.16, 95% CI: 1.01-1.36), the Chinese (OR=1.45, 95% CI: 1.19-1.77), boys (OR=1.23, 95% CI: 1.08-1.41), and those who came from higher income family. In conclusion, one out of five of 7-12 year-old-children in Malaysia were overweight. Locality of residence, ethnicity, gender, guardian education, and overweight guardian were likely to be the predictors of this alarming issue. Societal and public health efforts are needed in order to reduce the burden of disease associated with obesity. PMID- 23945412 TI - Overweight and obesity among internal migrants in India. AB - Migration, chiefly from rural to urban areas has been linked to precursor conditions of cardiovascular diseases. We estimated the odds of overweight/obesity ( BMI >=25 kg/m2) associated with different patterns of internal migration, using data from the National Family Health Survey 3, a cross sectional survey that covered 29 states of India in 2005/06. A total of 56,498 non-pregnant women, aged 15 to 49 years, and 42,190 men, aged 15 to 54 years, with BMI >18.5 kg/m2 were included in the final analysis. Odds ratios (ORs) for overweight/ obesity were computed for different groups of migrants after adjusting for age, socioeconomic status and parity using binomial logistic regression models. All analyses were performed separately for men and women and weighted using national sampling weights. Rural to urban migrant women but not men, had higher odds of being overweight/obese (adjusted OR (AOR): 1.50, 95% confidence interval (CI): 1.36-1.65) compared to non-migrant rural residents. Increased odds were also noted among women migrating from one urban area to another, compared to non-migrant urban women ( A OR: 1.10, 95% CI: 1.02-1.19). Women migrating from urban to rural areas, however had decreased odds (AOR: 0.75, 95% CI: 0.67-0.83) of overweight/ obesity. Thus, apart from confirming rural to urban migration as a risk factor for overweight, this study finds that other patterns of migration are also associated with overweight/obesity. PMID- 23945413 TI - Nutritional status and body composition are already affected before oncology treatment in ovarian cancer. AB - Poor nutritional status is a common problem among ovarian cancer patients. In order to detect changes in nutritional status and body composition this study investigates anthropometrical and biochemical parameters among these patients. This study included women with ovarian cancer and woman without cancer. Body composition was assessed by bioelectrical impedance analysis (BIA), anthropometrically, and with DXA scan, and total serum protein, albumin, transferrin, hemoglobin, hematocrit levels and total lymphocyte count was also measured. Data from DXA scan and body composition as assessed by BIA was collected from thirty-one women. Student t-test was used to compare differences in means between groups. This study included 120 women, 57 with ovarian cancer and 63 with benign tumors. Both groups of women were overweight. Body fat by skin fold thickness, arm circumference, serum albumin, total lymphocytes count, as well as transferrin levels were significantly lower in the ovarian cancer group (p<0.05). Ovarian cancer women had lower fat reserves by skin-fold thickness and lower serum proteins even though they were overweight. However, further studies need to use a body composition assessment on all subjects to confirm these results. PMID- 23945414 TI - The trans fatty acid content in human milk and its association with maternal diet among lactating mothers in Malaysia. AB - Excessive intake of trans fatty acids (TFA) could reduce the fat density of human milk and impair the desaturation of essential fatty acids. Because the mammary glands are unable to synthesize TFA, it is likely that the TFA in human milk come from dietary intake. Thus, the aim of this study was to investigate the sources of TFA intake for lactating mothers in one of the urban areas in Selangor. In this cross-sectional study, anthropometric measurements, FFQ including 7 food groups and dietary consumption data were collected from 101 lactating mothers. Five major TFA isomers (palmitoelaidic acid (16:1t9), petroselaidic acid (18:1t6), elaidic acid (18:1t9), vaccenic acid (18:1t11) and linoelaidic acid (18:2t9,12) in human milk were measured by gas chromatography (GC). The relationship between food consumption and TFA levels was assessed using the non parametric Spearman's rho test. The TFA content in human milk was 2.94+/-0.96 (SEM) % fatty acid; this is considered low, as it is lower than 4%. The most abundant TFA isomer was linoelaidic acid (1.44+/-0.60% fatty acid). A sub experiment (analyzing 3 days of composite food consumption) was conducted with 18 lactating mothers, and the results showed that linoelaidic acid was the most common TFA consumed (0.07+/-0.01 g/100 g food). Only 10 food items had an effect on the total TFA level and the isomers found in human milk. No association was found between TFA consumption and the TFA level in human milk. PMID- 23945415 TI - Determinants of breastfeeding at discharge in rural China. AB - This study aimed to investigate the rate of breastfeeding at discharge and associated influencing factors in rural China. A prospective cohort study of infant feeding practices was undertaken during 2010-2011 in Jiangyou city, Sichuan Province of China. Logistic regression analysis was performed to ascertain pertinent factors affecting the prevalence of any breastfeeding at discharge. The participants consisted of 695 mothers aged 18-44 years. The breastfeeding rate at discharge was 93.5% (95% CI: 91.7-95.3). Perceived paternal breastfeeding preference was positively associated with actual breastfeeding at discharge (OR=4.46, 95% CI: 2.15-9.28). Other significant determinants were 'receiving breastfeeding support' from staff during hospital stay (OR=3.41, 95% CI: 1.58-7.34) and making the decision on feeding method during pregnancy or after childbirth (OR=0.46, 95% CI: 0.22-0.93). In conclusion, provision of comprehensive breastfeeding support in hospital and education programs targeting expectant and future parents are recommended to further increase the rate of breastfeeding at discharge in rural areas of China. PMID- 23945416 TI - Seasonal variation in the nutritional status of children aged 6 to 60 months in a resettlement village in West Timor. AB - Childhood malnutrition remains a public health issue in Indonesia with a national prevalence of wasting of 13% and stunting of 36%. In rural areas nutritional status depends on local agriculture and may fluctuate in relation to harvest time. The aim of this study was to characterise seasonal variations in nutritional status in two resettlement villages in the Oesao district, Nusa Tenggara Timur. A cross sectional study was conducted in a convenience sample of children after the wet season (March). Children aged 6 to 60 months were assessed for nutritional status using anthropometric and biochemical measures. A subset of these children was re-assessed for anthropometry after the dry season (November). Weight-for-height z scores improved significantly from mean+/-SD of -1.7+/- 0.9 in March to -1.3+/-0.9 in November (p<0.001). There was no significant change in height between seasons. Prevalence of wasting, (weight-for-height z score <-2), was 42% in March and 19% in November (p<0.001). However, stunting rates increased significantly from 42% in March to 45% in November (p<0.001). Thirty six per cent of children were anaemic (Hb level <11 mg/100 mL), 68% were vitamin A deficient (plasma vitamin A level <0.8 MUmol/L) and 50% were zinc deficient (plasma zinc <9.94 MUmol/L). All children except one were positive for intestinal parasites. These data indicate seasonal changes in anthropometry with inconsistent effects depending on the anthropometric index measured. Wasting and stunting were higher than the national average, alongside high rates of anaemia, zinc and vitamin A deficiencies. PMID- 23945417 TI - Relationship of dietary factors and habits with sleep-wake regularity. AB - The purpose of this study was to evaluate the associations between dietary factors and sleep-wake regularity in the Japanese population. We analyzed 1368 eligible subjects (931 men and 437 women) aged 35-69 years who had participated in the baseline survey of a cohort study in Tokushima Prefecture, Japan. Information on individual lifestyle characteristics, including dietary habits and sleep-wake regularity, was obtained by a self administrated questionnaire. Logistic regression analyses were performed to evaluate adjusted associations of the intake energy ratios of macronutrients, as well as intake frequency, and the amount of staple foods with sleep wake regularity. The lowest quartile of protein intake as well as the highest quartile of carbohydrates showed significantly higher multivariable-adjusted odds ratios of 2.1 (95% confidence interval, 1.3 3.3) and 2.1 (1.3-3.5), respectively, for poor sleep-wake regularity compared with the respective second quartile that is thought to be moderate intake. Regarding intake of staple foods, low weekly intake frequency at breakfast (<5 times/week), the lowest intake amount (<1 bowl or slice/roll) at breakfast, and the highest intake amount (>=2 bowls or slices/ rolls) at lunch and dinner exhibited significantly high adjusted odds ratios for poor sleep-wake regularity. Additionally adjusting for sleep duration, these results did not substantially alter. Our results suggested that low intake energy ratio of proteins and high intake energy ratio of carbohydrates, skipping intake of the staple foods at breakfast, and excessive intake amount of the staple foods at lunch and dinner may be associated with poor sleep-wake regularity. PMID- 23945418 TI - Trend in gender disparities of BMI and height between 2004 and 2011 among adolescents aged 17-18 years in Changzhou China. AB - OBJECTIVES: to describe the trend in gender disparities of overweight/obesity and underweight, as well as height, among Chinese adolescents. METHODS: the study is based on population-based data from annual health checks of approximately 7,000 students finishing high school each year between 2004-2011. Height and weight were measured. Overweight/obesity and underweight were defined using International Obesity Task Force (IOTF) criteria. School level socioeconomic status (SES) was constructed based on real-estate prices near each school. RESULTS: there was a slight increase in the prevalence of obesity between 2004 and 2011; 3.7% to 4.7% in boys and 1.1% to 1.5% in girls. The prevalence of overweight was quite stable in both genders (boys: 12%-15%; girls: 7%-10%). In most years, the prevalence of underweight was above 10%. The prevalence of underweight in girls born after 1991 increased dramatically. However, the opposite trend was seen in boys. School SES was positively associated with overweight and inversely associated with underweight among boys. There was a significant increase in height in both genders. Height and BMI was positively associated in boys but this relation was inversely associated in girls. CONCLUSION: between 2004 and 2011, the prevalence of overweight/obesity was plateauing among adolescents finishing high school. A substantial increase in the prevalence of underweight was observed among girls born after 1991 but this seemed to be positively associated with high SES. PMID- 23945419 TI - Micronutrient deficiencies in obese Thai children. AB - We reported the cases of 3 obese children who presented variously with costochondral beading, numbness of both hands and feet, and hypochromic microcytic anemia. Serum ascorbic acid concentration, erythrocyte thiamin pyrophosphate effect, and serum hepcidin concentration were done to investigate these symptoms, respectively, with findings of ascorbic acid insufficiency, thiamin deficiency, and iron deficiency anemia from poor iron absorption due to a hyper-inflammatory state, respectively. This report indicated that obese children not only have energy excess but may also risk being micronutrient deficiencies; therefore, weight management with special attention to an adequate intake of vitamins and minerals should be provided. PMID- 23945420 TI - Optimized intelligent control of a 2-degree of freedom robot for rehabilitation of lower limbs using neural network and genetic algorithm. AB - BACKGROUND: There is an increasing trend in using robots for medical purposes. One specific area is rehabilitation. Rehabilitation is one of the non-drug treatments in community health which means the restoration of the abilities to maximize independence. It is a prolonged work and costly labor. On the other hand, by using the flexible and efficient robots in rehabilitation area, this process will be more useful for handicapped patients. METHODS: In this study, a rule-based intelligent control methodology is proposed to mimic the behavior of a healthy limb in a satisfactory way by a 2-DOF planar robot. Inverse kinematic of the planar robot will be solved by neural networks and control parameters will be optimized by genetic algorithm, as rehabilitation progress. RESULTS: The results of simulations are presented by defining a physiotherapy simple mode on desired trajectory. MATLAB/Simulink is used for simulations. The system is capable of learning the action of the physiotherapist for each patient and imitating this behaviour in the absence of a physiotherapist that can be called robotherapy. CONCLUSIONS: In this study, a therapeutic exercise planar 2-DOF robot is designed and controlled for lower-limb rehabilitation. The robot manipulator is controlled by combination of hybrid and adaptive controls. Some safety factors and stability constraints are defined and obtained. The robot is stopped when the safety factors are not satisfied. Kinematics of robot is estimated by an MLP neural network and proper control parameters are achieved using GA optimization. PMID- 23945421 TI - First-principles prediction of a new Dirac-fermion material: silicon germanide monolayer. AB - From first-principles calculations, we proposed a silicon germanide (SiGe) analog of silicene. This SiGe monolayer is stable and free from imaginary frequency in the phonon spectrum. The electronic band structure near the Fermi level can be characterized by Dirac cones with the Fermi velocity comparable to that of silicene. The Ge and Si atoms in SiGe monolayer exhibit different tendencies in binding with hydrogen atoms, making sublattice-selective hydrogenation and consequently electron spin-polarization possible. PMID- 23945422 TI - Screening for sexually transmitted diseases in short-term correctional institutions: summary of evidence reviewed for the 2010 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines. AB - Young persons entering US jails and youth detention facilities have high rates of sexually transmitted diseases (STDs). The Centers for Disease Control and Prevention added STD screening guidelines specific to correctional settings to the 2010 STD Treatment Guidelines. This article summarizes published evidence from 1990 to 2009 used to develop the recommendations. The literature supports routine screening of adolescents and young women (aged <=35 years, or on the basis of local institutional prevalence data) for chlamydia and gonorrhea because of high prevalence and the subsequent risk of adverse reproductive outcomes. Chlamydia positivity among young women (aged <20 years) in juvenile detention facilities and adult facilities is more than 14%. Men in correctional settings are also at high risk for chlamydia and gonorrhea. Among boys in juvenile detention facilities, chlamydia positivity is estimated at 6.6%; among young men in adult facilities, positivity is 16.6%. Screening men (to reduce sequelae among women) should be considered based on local epidemiology and resource availability. Syphilis screening is not strongly supported in published literature because of low prevalence and is not routinely recommended; however, some screening may be warranted based on local prevalence. Although there is a great diversity in the organization of correctional facilities, implementation of screening recommendations is possible owing to improvements in test technology (urine specimens) and through integration of a standard screening protocol. Based on the high burden of disease and substantial opportunities to reach a high-risk population, correctional facilities are important venues to target efforts to control STDs. PMID- 23945423 TI - Expanding the role of a pharmacist as a sexually transmitted infection provider in the setting of an urban free health clinic. AB - BACKGROUND: This study was designed to explore patient perceptions of sexually transmitted infection (STI) screening and treatment provided by a pharmacist in an urban free health clinic. With health care reform on the horizon, the role of a pharmacist is quickly evolving, making it necessary for pharmacists to sharpen their clinical skills to accurately serve their patients. One in 4 American adolescents is infected with an STI, placing pharmacists in a position to help decrease STI transmission and complications. METHODS: To assess patient attitudes toward pharmacists as STI providers, a convenience sample of patients who presented to an urban free health clinic in 2009 for STI testing were given a confidential survey of 12 statements relating to STI testing and the acceptability of a pharmacist-provider. RESULTS: Patients expressed overwhelming support of a pharmacist as their STI treatment provider (79.9%). The services they were comfortable with a pharmacist performing included running a urine screen (95.1%), performing a physical examination (81.1%), treating STIs (98.2%), and discussing STI test results (93.9%). Patients also approved of pharmacists working under a collaborative practice agreement with a physician (97.6%). CONCLUSIONS: Acceptance by patients of a pharmacist-provider for STI screening may lead to the adoption of pharmacists as providers in STI screening clinics. This would decrease barriers to treatment (eg, stigma and lack of access), increase accessibility to care, and greatly improve the identification of those infected with STIs, ultimately leading to a decrease in the spread and long-term sequelae of untreated STIs. PMID- 23945424 TI - Comparison of HIV behavioral indicators among men who have sex with men across two survey methodologies, San Francisco, 2004 and 2008. AB - BACKGROUND: Our goal was to examine whether community-based behavioral surveys can augment data collected for the National HIV Behavioral Surveillance System (NHBS) among men who have sex with men (MSM) in San Francisco. METHODS: We compared estimates of sexual risk behaviors among MSM using data from two cycles of NHBS (2004 and 2008) and outreach surveys conducted by STOP AIDS Project (SAP) during the same years. We compared estimates of unprotected anal intercourse (UAI) and other indicators to assess concordance of estimates across methodologies. RESULTS: Of the 3248 interviews conducted, the NHBS sample included more nonwhite and older MSM, more self-reported HIV positive, and less sexually active men than the SAP sample. Estimates of UAI in the last 6 months were slightly higher in the NHBS survey than in the SAP surveys (2004: 40% vs. 36%, P = 0.03; 2008: 44% vs. 38%, P = 0.08). In 2008, where respondent-partner HIV-discordant status could be measured, estimates of UAI with a potentially discordant partner were similar (12% vs. 12%, P = 0.87). Also, the NHBS and SAP surveys observed similar estimates of UAI by high-risk positioning with potentially discordant partners (HIV-positive men reporting insertive UAI with a potentially HIV-negative partner: 13% vs. 11%, P = 0.45; HIV-negative men reporting receptive UAI with a potentially HIV-positive person: 5% vs. 4%, P = 0.85). CONCLUSIONS: Behavioral estimates drawn from convenience sampling methods can provide informative surveillance estimates of key behavioral indictors that can augment data from more rigorous national HIV behavioral surveillance surveys. PMID- 23945425 TI - Modeling the impact of treatment failure on Chlamydia transmission and screening. AB - BACKGROUND: Standard current treatment regimens for chlamydia treatment have been widely considered to be highly effective, with a cure rate of around 97%. However, recent studies indicate that treatment failure may occur at a rate that is substantially higher than previously thought. METHODS: We use a mathematical dynamic transmission model to estimate the population-level impact of treatment failure on chlamydia transmission and on the effectiveness of screening strategies. RESULTS: The findings indicate that in high-resource settings such as Australia, there will be an approximately 0.16% linear increase in population prevalence for each incremental increase of 1% in the treatment failure rate. To compensate for higher assumed treatment failure, screening coverage will have to increase by between ~4% and ~16% to achieve a reduction of 50% in chlamydia prevalence within 5 years under the scenarios evaluated. Higher treatment failure rates also substantially lengthen the time required for screening to deliver the same reductions in prevalence as are predicted under the conservative assumption of only 3% treatment failure. The predicted relative increases are in the range ~6% to 35%, depending on the assumed treatment failure rate (8%-23%), screening strategy (female-only or male-plus-female) and the duration of screening (5 or 10 years). CONCLUSIONS: The rate of treatment failure may have a significant impact on the screening coverage and time required to achieve target reductions in chlamydia prevalence. The treatment failure rate should therefore be carefully considered when evaluating the potential effectiveness of proposed screening programs. PMID- 23945426 TI - Relationship of selected bacterial vaginosis-associated bacteria to Nugent score bacterial vaginosis among urban women early in pregnancy. AB - Among urban, primarily African American pregnant women, 74% were identified with Nugent score bacterial vaginosis (BV). All BV-associated bacteria were more prevalent among women with Nugent score BV. Bacterial vaginosis-associated bacteria 3 (BVAB3) had the highest positive predictive value, whereas Gardnerella vaginalis and Atopobium spp. had the highest sensitivity. Atopobium spp. levels had the most significant area under the curve. PMID- 23945427 TI - The evolving design and methods for trials evaluating the safety of candidate vaginal microbicides: a systematic review. AB - Vaginal preexposure prophylaxis is a promising biomedical tool for HIV prevention. Although guidelines for the clinical assessment of microbicides are available, validated markers for product safety are lacking. To inform future microbicide and multipurpose vaginal product research, we reviewed the current and past safety methods used. We searched the Cochrane, EMBASE, and Ovid MEDLINE databases for clinical studies of vaginal products for the prevention of HIV that included safety evaluations. Ninety-seven clinical studies involving 21 products were identified: 63 lasted 14 days or less, 19 were longer in duration, and 15 were effectivess studies that included also safety as an outcome. Median sample size in the safety studies was 48 participants (range, 10-799). All studies reported on urogenital endpoint, 71% included colposcopy, and 67% assessed the vaginal microflora. Markers of vaginal epithelial inflammation, systemic absorption, and systemic toxicology assessments were evaluated in 29%, 26%, and 43% of studies, respectively. Excluding the effectiveness studies, these same assessments were done before 1998 in 33%, 7%, and 27% and after 2001 in 38%, 44%, and 60% of studies, respectively. Soluble inflammatory markers were introduced after 2001. Adverse event collection was reported in 73% of studies before 1998 and in 98% after 2001. In a previous review, we recommended that larger and longer safety studies were necessary to detect clinically important toxicities and to provide assurance that agents are ready for large-scale effectiveness trials. Here, we propose a stepwise clinical assessment that can be used for future guidance. PMID- 23945428 TI - Neisseria gonorrhoeae multiantigen sequence typing is beneficial in further characterizing gonococcal populations in Alberta, Canada. AB - BACKGROUND: Antimicrobial resistance testing and behavioral data combined with Neisseria gonorrhoeae multiantigen sequence typing (NG-MAST) can help to define gonococcal populations and identify, characterize, and compare clusters of infection. METHODS: Antimicrobial resistance testing, using E test, was reviewed for gonococcal isolates in Alberta, Canada, from 2007 to 2011. Antimicrobial resistance testing was conducted on isolates demonstrating antimicrobial resistance and those with cefixime minimum inhibitory concentrations (MICs) of 0.06 MUg/mL or greater. Demographic and behavioral information was obtained from provincial surveillance data. NG-MAST typing was conducted on a proportion of isolates. RESULTS: Gonococcal isolates were available for 2250 (26.4%) of 8535 cases of gonorrhea in Alberta from 2007 to 2011. The proportion of cases with decreased susceptibility to cefixime (>=0.06 MUg/mL) increased from 0.7% to 2.4% between 2007 and 2009 to a high of 10.1% in 2010 and 8.9% in 2011. Six isolates with cefixime MIC of 0.25 MUg/mL were noted: 5 were from men who have sex with men (MSM) and 1 was a pharyngeal isolate from a heterosexual female. Twenty-four (1.1%) isolates were azithromycin resistant (MIC >=2.0 MUg/mL); there were no significant differences between cases resistant or susceptible to azithromycin. NG-MAST of gonococcal isolates in Alberta suggests the entry of multiple strains into the province. Three clusters were identified: Cluster A predominantly in MSM, including sequence type 1407, a ST previously associated with decreased susceptibility to expanded spectrum cephalosporins; Cluster B, a predominantly heterosexual cluster with most cases in Edmonton; and Cluster C among MSM. CONCLUSIONS: Our data highlight the use of NG-MAST in further defining gonococcal populations. PMID- 23945429 TI - [Volume standards: quality through quantity? relationship between treatment volume and outcomes not well founded]. AB - Three domains are accepted as indicators that make the quality of hospital care quantifiable and transparent: process, structure and outcome. In recent years volume thresholds for surgical interventions have been added as new quality indicators, rendering the assumption that more volume leads to better outcomes. This assumption has been established for many procedures in peer-reviewed literature since the 1970s. Although there is consensus about the fact that volume is a proxy measure for other factors influencing the outcome of care, available research does not shed much light on the mechanisms underlying the volume-outcome relationship. Moreover, the methodological quality of the available research has several limitations. Despite the incomplete substantiation, volume thresholds are now embedded in 'risk-based' supervision by the health inspectorate as well as purchasing policies by health insurers. PMID- 23945430 TI - [Hospitals as vital links]. AB - The reform of the system in 2006 aimed at reducing waiting lists in an efficient manner. Performance-linked funding and regulated competition did indeed lead to improved efficiency. The other side of the coin is overtreatment, and expensive and not infrequently damaging growth in volume. In order to control costs, three strategies have been determined: agreements with an annual cap on volume; (b) collaboration of regional health-care providers with the mission of improving results in health care (with profit-sharing if costs fall); and (c) fusions reducing the number of hospitals which reduces the burden of injuries (supply no longer creates its own demand). This article comments on these strategies. The author argues for a fourth approach: if the quality of health care improves, the number of complications will fall, overtreatment will decline and the outcome will be a decrease in burden of injuries. This requires the health care insurers to modify the way they manage their contracts and methods of payment, and stimulates competition based on quality. PMID- 23945431 TI - [Vitamin D supplementation in the elderly: guidelines and practice]. AB - OBJECTIVE: In 2008, the Health Council of the Netherlands published an advice on vitamin D supplementation for the elderly. Nevertheless, suspicion arose at the Ministry of Health, Welfare and Sport and the Netherlands Nutrition Centre that vitamin D supplementation in the elderly is still insufficient. We aimed to determine the extent to which general practitioners and elderly care physicians actually followed the advice of the Health Council. DESIGN: Questionnaire study. METHOD: Brief questionnaires were sent to all elderly care physicians in the Netherlands. Some questions were also posed to general practitioners at a network meeting of the Academic Network of GP Practices of the VU University Medical Center in Amsterdam. RESULTS: More than two-thirds of the respondents, both elderly care physicians and general practitioners, are familiar with the guidelines of the Health Council of the Netherlands on vitamin D supplementation in the elderly, but about half do not prescribe vitamin D when the guideline advises to do so. When supplementation is prescribed, about half of the elderly care physicians and a fifth of the general practitioners uses an insufficient dose. CONCLUSION: The guidelines of the Health Council of the Netherlands on vitamin D supplementation in the elderly are not sufficiently followed by elderly care physicians and general practitioners. Awareness of and support for the vitamin D supplementation guidelines among health care providers is still limited. PMID- 23945432 TI - [Severe bronchial asthma]. AB - The term 'difficult-to-treat asthma' indicates that the asthma is not sufficiently controlled despite prescription of high doses of asthma medication. The term 'severe asthma' is used when the asthma is still insufficiently controlled after exclusion or treatment of any complicating factors; an important complicating factor is poor compliance. Recent studies have focused on the heterogeneous character of asthma and on the definition of specific phenotypes, with the aim of developing phenotype-specific treatments. Treatment options for severe asthma are only partly evidence based. The decision to implement additional therapy for severe asthma depends on the individual patient, the asthma phenotype, and the adverse-event profile of the treatment. Many of the additional therapies should be given as a trial treatment under strict control, especially when efficacy has not been convincingly scientifically proven. PMID- 23945433 TI - [The fiscal position of medical specialists]. AB - Independent medical specialists in the Netherlands are treated as entrepreneurs for tax purposes and therefore enjoy tax benefits. A change in the legal relationship between medical specialists and hospitals is foreseen in 2015. Independent medical specialists will then no longer be considered to be entrepreneurs. This could negatively affect their tax position. The Dutch government has adopted a policy aimed at controlling expenses arising from medical specialists' fees. According to this policy, the formation of regional practices or mega-practices of specialists will be discouraged. In contrast, the current fiscal legislation encourages medical specialists to incorporate their practice into regional practices or mega-practices or to become shareholders of their hospitals. It has been proposed that fiscal benefits be linked to certain aspects of entrepreneurship, such as investing in medical equipment or employing medical personnel. PMID- 23945434 TI - [A woman with a swelling in the groin]. AB - A 75-years-old woman presented to the Emergency Department with a painfull swelling in the right groin. Clinical examination was suggestive of an incarcerated hernia. Echography and examination during surgery revealed an Amyand's hernia. Amyand's hernia is a rare type of a sliding hernia that is characterized bij protrusion of the appendix in the hernial sac. Surgical reduction of the hernial sac was followed by appendectomy because the appendix was inflamed: a rare complication of Amyand's hernia. PMID- 23945435 TI - [Thrombocytopenia during pregnancy]. AB - Thrombocytopenia during pregnancy can be caused by a broad variety of disorders. An early diagnosis is essential for timely and adequate therapy. In cases of severe thrombocytopenia, a multidisciplinary approach by a team of obstetricians, haematologists and anaesthesiologists is needed. We describe a 30-year-old patient at a gestational age of 35 weeks who presented with preterm rupture of membranes. Coincidentally, she also had severe thrombocytopenia that proved to be due to immune thrombocytopenia (ITP). The severe thrombocytopenia persisted despite standard first-line treatment with corticosteroids and intravenous immunoglobulins. Based on this case report we discuss the differential diagnosis of thrombocytopenia during pregnancy with a focus on the management of ITP in pregnant women. PMID- 23945436 TI - [A neonate with the 'blueberry muffin syndrome']. AB - A term born girl showed livid papules and macules disseminated over her body, directly postpartum. She was examined by the pediatrician, who recognized this as the 'blueberry muffin syndrome'. Blood examination showed a modest increase of erythroblasts. Skin biopsy indicated the presence of hematologic malignancy. Bone marrow puncture revealed the diagnosis 'acute myeloid leukemia'. Other causes of the blueberry muffin syndrome are congenital infections, neuroblastoma and rhabdomyosarcoma. PMID- 23945437 TI - [Is nighttime intensivist staffing beneficial?]. AB - If an intensive care unit (ICU) is managed by intensivists, the prognosis of critically ill patients improves. Some retrospective analyses of patient databases suggest that critically ill patients admitted to the ICU during off hours suffer a higher mortality rate compared to patients admitted during office hours. While this suggests that this difference might be related to the presence/absence of experienced intensivists at night, differences in case mix of patients admitted during the day/night may play an important role. Recently, the first prospective randomized controlled trial was published on this issue. Alternating every 7 nights an intensivist was present in the hospital or was available for consultation by telephone. No effect on ICU-length of stay, mortality or any of the secondary end points was found. Despite the compelling face value of nighttime intensivist staffing this practice should not be recommended in the absence of experimental evidence of its effectiveness. PMID- 23945438 TI - [Maintaining solidarity: is mutuality the solution?]. AB - Solidarity is essentially the willingness to contribute to the community and its demands, which may even involve contributing more than one is expecting to receive. Another principle is mutuality: this refers to a balance between rights and obligations or between mutual obligations. In its advisory document 'The importance of mutuality......solidarity takes work!', The Dutch Council for Public Health and Health Care underlines the importance of ensuring solidarity within the Dutch health care system, e.g. by encouraging patients to take responsibility for their own health, possibly by introducing elements of mutuality. In our contribution, we comment on the Council's advice. Although we fully agree with the overall conclusion that solidarity should be maintained within the system, we do not see how the introduction of increased mutuality will contribute to this goal. PMID- 23945439 TI - [Over-the-border evidence: the relevance of results of non-Western RCTs]. AB - Increasing numbers of randomised-controlled trials are performed in non-Western countries. The main reason for this tendency are the lower costs needed to perform trials in non-Western countries. It has been shown that results from trials performed in non-Western countries sometimes overestimate the effects compared to trials with the same intervention performed in Western countries. This means that results from trials performed in non-Western countries are not automatically generalisable to Western countries. PMID- 23945440 TI - Liver X receptor activation increases hepatic fatty acid desaturation by the induction of SCD1 expression through an LXRalpha-SREBP1c-dependent mechanism. AB - BACKGROUND: Liver X receptors (LXRs) including LXRalpha and LXRbeta are members of the nuclear hormone receptor superfamily of ligand activated transcription factors, which serve as lipid sensors to regulate expression of genes controlling many aspects of cholesterol and fatty acid metabolism. The liver is the central organ in controlling lipid metabolism. In the present study, we aimed at elucidating the role of LXR activation in hepatic fatty acid homeostasis. METHODS: We treated C57BL/6 mice with a synthetic non-selective LXR agonist TO901317. Fatty acid profile of lipid esters in the livers was analyzed by gas liquid chromatography. Real-time polymerase chain reaction (PCR) and western blot were used to determine the expression of SREBP1c and SCD1 in TO901317-treated livers and HepG2 cells. RESULTS: Oral administration of TO901317 resulted in increased fatty acid desaturation in the liver, with concomitant increase in hepatic stearoyl CoA desaturase-1 (SCD1) expression. TO901317-induced SCD1 expression was observed in LXRbeta-/- mice, but not in LXRalpha-/- mice. Furthermore, TO901317 significantly increased expression of sterol regulatory element-binding protein 1c (SREBP1c), the deficiency of which almost completely abolished the induction of SCD1 by TO901317. This drug induced both SREBP1c and SCD1 expression in HepG2 cells. Overexpression of SREBP1c resulted in a significant increase in SCD1 promoter activity and expression. CONCLUSIONS: Taken together, the present studies demonstrate that pan-LXR activation increases hepatic fatty acid desaturation via the induction of SCD1 expression in an LXRalpha-dependent and SREBP1c-mediated manner. PMID- 23945441 TI - Long-term survival after resection of pancreatic ductal adenocarcinoma with para aortic lymph node metastasis: case report. AB - Pancreatic cancer patients with para-aortic lymph node metastasis have a poor prognosis and patients living longer than 3 years are rare. We had a patient with pancreatic cancer who survived for more than 10 years after removal of the para aortic lymph node metastasis. A 57-year-old woman was diagnosed with pancreatic head cancer and underwent a pancreaticoduodenectomy with subtotal gastric resection following Whipple reconstruction in 2000. Para-aortic lymph node metastasis was detected during the operation by intraoperative pathological diagnosis and an extended lymphadenectomy was performed with vascular skeletonization of the celiac and superior mesenteric arteries. In 2004, a low density area was detected around the superior mesenteric artery (SMA) 5 cm from its root and she was treated with gemcitabine, and the area was undetectable after 3 years of treatment. In 2010, computed tomography showed a low-density area around the same lesion with an increased carcinoembryonic antigen level. After 4 months of gemcitabine treatment, we resected the tumor en bloc with the associated superior mesenteric vein and perineural tissue. Histopathological examination of the resected specimen revealed a well-differentiated tubular adenocarcinoma that closely resembled the original primary pancreatic cancer, indicating perineural recurrence 10 years after the initial resection. She had no recurrence around the SMA for more than one year. Although a meta-analysis has not proved the efficacy of preventive radical dissection, this case indicates that a patient with well-differentiated, chemotherapy-responsive pancreatic cancer with para-aortic lymph node metastasis could have a long survival time through extended dissection of the lymph nodes. PMID- 23945442 TI - Analytical insights on theta-gamma coupled neural oscillators. AB - In this paper, we study the dynamics of a quadratic integrate-and-fire neuron, spiking in the gamma (30-100 Hz) range, coupled to a delta/theta frequency (1-8 Hz) neural oscillator. Using analytical and semianalytical methods, we were able to derive characteristic spiking times for the system in two distinct regimes (depending on parameter values): one regime where the gamma neuron is intrinsically oscillating in the absence of theta input, and a second one in which gamma spiking is directly gated by theta input, i.e., windows of gamma activity alternate with silence periods depending on the underlying theta phase. In the former case, we transform the equations such that the system becomes analogous to the Mathieu differential equation. By solving this equation, we can compute numerically the time to the first gamma spike, and then use singular perturbation theory to find successive spike times. On the other hand, in the excitable condition, we make direct use of singular perturbation theory to obtain an approximation of the time to first gamma spike, and then extend the result to calculate ensuing gamma spikes in a recursive fashion. We thereby give explicit formulas for the onset and offset of gamma spike burst during a theta cycle, and provide an estimation of the total number of spikes per theta cycle both for excitable and oscillator regimes. PMID- 23945443 TI - The computerized adaptive diagnostic test for major depressive disorder (CAD MDD): a screening tool for depression. AB - OBJECTIVE: To develop a computerized adaptive diagnostic screening tool for depression that decreases patient and clinician burden and increases sensitivity and specificity for clinician-based DSM-IV diagnosis of major depressive disorder (MDD). METHOD: 656 individuals with and without minor and major depression were recruited from a psychiatric clinic and a community mental health center and through public announcements (controls without depression). The focus of the study was the development of the Computerized Adaptive Diagnostic Test for Major Depressive Disorder (CAD-MDD) diagnostic screening tool based on a decision theoretical approach (random forests and decision trees). The item bank consisted of 88 depression scale items drawn from 73 depression measures. Sensitivity and specificity for predicting clinician-based Structured Clinical Interview for DSM IV Axis I Disorders diagnoses of MDD were the primary outcomes. Diagnostic screening accuracy was then compared to that of the Patient Health Questionnaire 9 (PHQ-9). RESULTS: An average of 4 items per participant was required (maximum of 6 items). Overall sensitivity and specificity were 0.95 and 0.87, respectively. For the PHQ-9, sensitivity was 0.70 and specificity was 0.91. CONCLUSIONS: High sensitivity and reasonable specificity for a clinician-based DSM-IV diagnosis of depression can be obtained using an average of 4 adaptively administered self-report items in less than 1 minute. Relative to the currently used PHQ-9, the CAD-MDD dramatically increased sensitivity while maintaining similar specificity. As such, the CAD-MDD will identify more true positives (lower false-negative rate) than the PHQ-9 using half the number of items. Inexpensive (relative to clinical assessment), efficient, and accurate screening of depression in the settings of primary care, psychiatric epidemiology, molecular genetics, and global health are all direct applications of the current system. PMID- 23945444 TI - Lamotrigine in psychiatric disorders. AB - OBJECTIVE: Owing to the prevalence of medication side effects and treatment resistance, prescribers often consider off-label uses of US Food and Drug Administration (FDA)-approved agents for the treatment of persistent symptoms. The authors review the available literature on the FDA-approved and non-FDA approved uses of lamotrigine in adults with psychiatric disorders. DATA SOURCES: We used PubMed, MEDLINE, and a hand search of relevant literature to find studies published between 1990 and 2012 and available in English language. The following keywords were searched: lamotrigine, psychiatric, mood disorders, depression, personality disorders, anxiety, schizophrenia, side effects, and rash. STUDY SELECTION: Data were selected from 29 randomized controlled trials (RCTs). When RCTs were not available, open-label trials (6), retrospective case reviews (10), and case series (4) were summarized. DATA EXTRACTION: We extracted results of monotherapy and augmentation trials of lamotrigine on primary and secondary outcome measures. RESULTS: Lamotrigine is generally well tolerated, with the best evidence for the maintenance treatment of bipolar disorder, particularly in prevention of depressive episodes. In acute bipolar depression, meta-analyses suggested a modest benefit, especially for more severely depressed subjects, with switch rates similar to placebo. In unipolar depression, double-blind RCTs noted benefit on subsets of symptoms and improved response in more severely depressed subjects. Data are limited but promising in borderline personality disorder. Use of lamotrigine in schizophrenia and anxiety disorders has little supportive evidence. CONCLUSIONS: Lamotrigine is recommended in bipolar maintenance when depression is prominent. It also has a role in treating acute bipolar depression and unipolar depression, though the latter warrants more research. Data are too limited in other psychiatric disorders to recommend its use at this time. PMID- 23945446 TI - A case of persistent genital arousal disorder successfully treated with topiramate in a physically healthy individual. PMID- 23945445 TI - Treatment response, symptom remission, and wellness in obsessive-compulsive disorder. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is defined both by intrusive, unwanted thoughts, images, or impulses and by repetitive behavioral or mental acts that are often performed to try to alleviate anxiety. The ultimate goal of treatment for OCD is to reduce the symptoms as well as help patients achieve "wellness." Currently, however, there are no widely accepted, empirically supported criteria for determining wellness in OCD. METHOD: Building on previous research, the current study examined the Yale-Brown Obsessive Compulsive Scale (Y BOCS) score that most reliably identified patients who responded to treatment, those who achieved symptom remission, and those who achieved wellness. The current study pooled data from 4 randomized controlled OCD treatment trials (N = 288), which took place between 1990 and 2011 at 2 academic sites. Participants (mean age = 36.8 years) had a primary diagnosis of DSM-IV-TR OCD (mean Y-BOCS score = 25.9). RESULTS: Signal detection analyses showed that a pretreatment-to posttreatment reduction of >= 35% on the Y-BOCS was most predictive of treatment response as defined by the Clinical Global Impressions (CGI)-Improvement scale. A posttreatment Y-BOCS score of <= 14 was the best predictor of symptom remission, whereas a score of <= 12 was the best predictor of wellness, as defined by symptom remission (defined by the CGI-Severity scale), good quality of life (as measured by the Quality of Life Enjoyment and Satisfaction Questionnaire), and a high level of adaptive functioning (as assessed by the Social Adjustment Scale Self-Report). Because efficiency (0.86) and specificity (0.88) were highest at the cutoff of <= 12, this cutoff score was determined to be the best indicator of wellness. CONCLUSIONS: The present findings support the convergent validity of the Y-BOCS with other measures of well-being (quality of life, adaptive functioning) and highlight the utility of a Y-BOCS score <= 12 as a solo indicator of wellness in outcome studies. The use of empirically supported criteria for defining wellness in OCD is recommended to facilitate comparisons across treatment outcome studies and to inform clinical treatment planning. TRIAL REGISTRATION: Pooled data analyzed in this study were from 4 clinical trials, 3 of which are registered at ClinicalTrials.gov (identifiers: NCT00045903, NCT00389493, NCT00316316). PMID- 23945447 TI - Lisdexamfetamine dimesylate in adults with attention-deficit/ hyperactivity disorder who report clinically significant impairment in executive function: results from a randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: Behavioral rating scales that assess impairments in executive function commonly associated with attention-deficit/hyperactivity disorder (ADHD) may offer advantages over neuropsychological testing. The primary objective of this study was to evaluate the efficacy of lisdexamfetamine dimesylate for executive function deficits in adults with ADHD and clinically significant executive function impairment using self-reported Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A) assessments. METHOD: This randomized double blind study, conducted between May 2010 and November 2010, screened at least 1 participant at 35 of 39 registered US clinical research sites. Adults (aged 18-55 years) with a primary ADHD diagnosis (meeting full DSM-IV-TR criteria) and executive function deficits (assessed by baseline BRIEF-A Global Executive Composite [GEC] T-scores of at least 65) were randomized to treatment with optimized lisdexamfetamine dimesylate (30 mg/d, 50 mg/d, or 70 mg/d; n = 80) or placebo (n = 81) during a 10-week double-blind treatment period. Outcome measures included the BRIEF-A scales (GEC, index, and clinical subscales). RESULTS: At week 10 or at early termination, lisdexamfetamine dimesylate was associated with significantly greater reductions from baseline in mean BRIEF-A GEC T-scores than placebo (effect size, 0.74; P < .0001) and significantly greater reductions from baseline in mean T-scores for both BRIEF-A index scales (Behavioral Regulation Index and Metacognition Index) and all 9 clinical subscales (P <= .0056 for all). At week 10 or at early termination, mean T-scores for BRIEF-A indexes and clinical subscales were below levels of clinically significant executive function deficits (ie, < 65) with lisdexamfetamine dimesylate treatment. The mean (SD) GEC T-score was 57.2 (14.11) for the lisdexamfetamine dimesylate group and 68.3 (17.12) for the placebo group. The safety profile of lisdexamfetamine dimesylate was consistent with other long-acting psychostimulants. CONCLUSION: Among adults with ADHD and clinically significant executive function deficits, lisdexamfetamine dimesylate was associated with significant improvements in self reported executive function ratings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01101022. PMID- 23945449 TI - Positive affect and survival in patients with stable coronary heart disease: findings from the Heart and Soul Study. AB - OBJECTIVE: Positive affect can improve survival, but the mechanisms responsible for this association are unknown. We sought to evaluate the association between positive affect and mortality in patients with stable coronary heart disease and to determine biological and behavioral factors that might explain this association. METHOD: The Heart and Soul Study is a prospective cohort study of 1,018 outpatients with stable coronary heart disease. Participants were recruited between September 11, 2000, and December 20, 2002, and were followed up to June 2011. Baseline positive affect was assessed by using the 10-item positive affect subscale of the Positive and Negative Affect Schedule. Cox proportional hazards regression was used to estimate the risk of mortality (primary outcome measure) and cardiovascular events (heart failure, myocardial infarction, stroke, transient ischemic attack) associated with positive affect, adjusting for baseline cardiac disease severity and depression. We also evaluated the extent to which these associations were explained by potential biological and behavioral mediators. RESULTS: A total of 369 patients (36%) died during a mean +/- SD follow-up period of 7.1 +/- 2.5 years. Positive affect was not significantly associated with cardiovascular events (hazard ratio [HR]: 0.89; 95% CI, 0.79 1.00; P = .06). However, each standard deviation (8.8-point) increase in positive affect score was associated with a 16% decreased risk of all-cause mortality (HR: 0.84; 95% CI, 0.76-0.92; P = .001). After adjustment for cardiac disease severity and depressive symptoms, positive affect remained significantly associated with improved survival (HR: 0.87; 95% CI, 0.78-0.97; P = .01). The association was no longer significant after adjustment for behavioral factors, and particularly physical activity (HR: 0.92; 95% CI, 0.82-1.03; P = .16). Further adjustment for C-reactive protein and omega-3 fatty acids did not result in any meaningful changes (HR: 0.94; 95% CI, 0.84-1.06; P = .31). CONCLUSIONS: In this sample of outpatients with coronary heart disease, positive affect was associated with improved survival. This association was largely explained by physical activity. PMID- 23945448 TI - Less is more in antidepressant clinical trials: a meta-analysis of the effect of visit frequency on treatment response and dropout. AB - OBJECTIVE: We investigated how the number of follow-up visits affects response rates and dropout among patients in antidepressant trials for major depressive disorder (MDD). DATA SOURCES: MEDLINE, PsycINFO, and PubMed were searched to identify trials contrasting antidepressants to placebo or active comparator in adults with depression. The index terms depression-drug therapy, depressive disorder-drug therapy, and antidepressant agents, in addition to the classes and individual generic names of all antidepressants, were combined using the "or" operator. Results were limited to (1) English-language articles, (2) publication year 1985 or later, (3) age group >= 18 years, and (4) publication types including clinical trials, controlled clinical trials, meta-analysis, multicenter study, randomized controlled trial, or review. STUDY SELECTION: Included articles reported trials of approved antidepressant medications for MDD in outpatients aged 18-65 years, were 6-12 weeks in duration, and had response rates specified using a standardized measure. Trials were excluded for enrolling inpatients, pregnant women, psychotic subjects, or those with treatment-resistant depression. These criteria allowed 9,189 articles identified in the literature review to be narrowed to 111 reports. DATA EXTRACTION: Demographic characteristics, the number of study visits planned in each treatment cell, duration of active treatment, attrition rates, and response rates to medication and placebo were entered into a database. RESULTS: In a multilevel meta-analysis, active medication versus placebo (OR = 1.96, P < .001), active comparator versus placebo-controlled study design (OR = 1.82, P < .001), and longer versus shorter duration (OR = 1.87, P < .001) were associated with significantly increased odds of treatment response. After controlling for these variables, the number of study visits did not significantly influence response rates (OR = 0.97, P = .877). The odds of dropout were significantly decreased for active comparator versus placebo-controlled trials (OR = 0.67, P = .002) and longer versus shorter duration trials (OR = 0.54, P = .035), while increasing numbers of study visits significantly increased the odds of participant dropout (OR = 2.77, P < .001). CONCLUSIONS: Visit schedules that are much more frequent than are commonly practiced in the community treatment of depression may increase the expense of clinical trials and make them less generalizable to standard clinical treatment. PMID- 23945450 TI - Predicting diagnostic change among patients diagnosed with first-episode DSM-IV TR major depressive disorder with psychotic features. AB - OBJECTIVE: Longitudinal studies beginning from onset of major depressive disorder (MDD) with psychotic features in young adults are rare; therefore, in this study, subjects across a wide age range were included. Since psychotic MDD may be unstable diagnostically, we systematically evaluated such patients prospectively from first episode to ascertain predictors of later diagnostic change. METHOD: In this prospective naturalistic study, we recruited patients with DSM-IV-TR psychotic MDD from 1989 through 2003 at psychiatric inpatient units in Massachusetts and Italy and followed them from first hospitalization to compare demographic, antecedent, and first-episode clinical characteristics for associations with later changes of diagnosis based on interviews using the Structured Clinical Interview for DSM-III-R, Patient Version. RESULTS: Within a mean (SD) of 4.0 (2.7) years, diagnoses among 107 subjects aged 34.6 (16.2) years (range, 10-82 years) who were experiencing a first lifetime DSM-IV-TR psychotic MDD episode changed in 29.9% to DSM-IV-TR bipolar disorder (18.7%) or schizoaffective disorder (11.2%). Factors associated with stable diagnoses of psychotic MDD included ontological anguish (chi(2) = 13.8, P < .0001), nihilistic delusions (chi(2) = 4.47, P = .034), and weight loss (chi(2) = 4.69, P = .030) at initial syndromal presentation. Factors preceding diagnoses of bipolar disorder included antecedent impulsivity (chi(2) = 9.10, P = .003), ICD-10 mixed states at intake (chi(2) = 19.4, P < .0001), and previous hypomanic symptoms (chi(2) = 13.7, P = .002). Factors predicting later schizoaffective diagnoses included mood incongruent delusions (chi(2) = 9.17, P = .002) and somatosensory hallucinations (chi(2) = 9.53, P = .033) at intake, previous functional decline (chi(2) = 8.13, P = .008), initial Schneiderian first-rank symptoms (chi(2) = 10.6, P = .005), and meeting criteria for ICD-10 schizoaffective disorder at intake (chi(2) = 24.9, P < .0001). CONCLUSIONS: Among patients who initially met DSM-IV-TR criteria for first-episode psychotic MDD, early indications of features typically associated with bipolar disorder or with nonaffective psychoses, respectively, strongly predicted later diagnostic change to bipolar disorder or schizoaffective disorders. The findings support the value of psychopathological details in improving diagnostic and prognostic criteria for complex illnesses. PMID- 23945452 TI - Changes in the diagnostic criteria for autism in DSM-5: controversies and concerns. PMID- 23945451 TI - Omega-3 polyunsaturated fatty acid (PUFA) status in major depressive disorder with comorbid anxiety disorders. AB - BACKGROUND: Although lower levels of omega-3 polyunsaturated fatty acids (PUFAs) are found in major depressive disorder, less is known about PUFA status and anxiety disorders. METHOD: Medication-free participants with DSM-IV-defined major depressive disorder (MDD), with (n = 18) and without (n = 41) comorbid DSM-IV anxiety disorders, and healthy volunteers (n = 62) were recruited from October 2006 to May 2010 for mood disorder studies at the New York State Psychiatric Institute. Participants were 18-73 years of age (mean age, 35.8 +/- 12.6 years). Depression and anxiety severity was assessed using depression and anxiety subscales from the 17-item Hamilton Depression Rating Scale. Plasma PUFAs eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) and the ratio of arachidonic acid (AA; 22:4n-6) to EPA (AA:EPA) were quantified. This secondary analysis employed analysis of variance with a priori planned contrasts to test for diagnostic group differences in log-transformed PUFA levels (logDHA, logEPA, and logAA:EPA). RESULTS: Plasma levels of logDHA (F(2,118) = 4.923, P = .009), logEPA (F(2,118) = 6.442, P = .002), and logAA:EPA (F(2,118) = 3.806, P = .025) differed across groups. Participants with MDD had lower logDHA (t(118) = 2.324, P = .022) and logEPA (t(118) = 3.175, P = .002) levels and higher logAA:EPA levels (t(118) = -2.099, P = .038) compared with healthy volunteers. Lower logDHA (t(118) = 2.692, P = .008) and logEPA (t(118) = 2.524, P = .013) levels and higher logAA:EPA levels (t(118) = -2.322, P = .022) distinguished anxious from nonanxious MDD. Depression severity was not associated with PUFA plasma levels; however, anxiety severity across the entire sample correlated negatively with logDHA (r(p) = -0.22, P = .015) and logEPA (r(p) = -0.25, P = .005) levels and positively with logAA:EPA levels (r(p) = 0.18, P = .043). CONCLUSIONS: The presence and severity of comorbid anxiety were associated with the lowest EPA and DHA levels. Further studies are needed to elucidate whether omega-3 PUFA supplementation may preferentially alleviate MDD with more severe anxiety. PMID- 23945453 TI - Study data support the validity of the major depression bereavement exclusion. PMID- 23945454 TI - Dr Gilman and colleagues reply. PMID- 23945455 TI - Recognizing and addressing barriers to the effective management of ADHD in college students. AB - Several barriers can hinder the diagnosis of ADHD in college students, especially those with unrecognized symptoms, dysfunctional behavior, or psychiatric conditions. One specific barrier includes the misuse of prescription stimulants among college students, perhaps to improve academic performance or to self-treat undiagnosed ADHD symptoms. Because of the dangers, both medical and legal, that nonmedical stimulant use can cause, clinicians must recognize these undiagnosed students and initiate proper treatment. By establishing a therapeutic relationship with students, clinicians can provide education, monitoring, and treatment options that will help minimize misuse of prescriptions while giving students the support they need to successfully complete college. PMID- 23945456 TI - Evaluating and monitoring treatment response in depression using measurement based assessment and rating scales. AB - Even with many treatment options available for major depressive disorder, many patients fail to achieve remission and return to their presymptomatic levels of functioning at work, in leisure activities, and in relationships. Throughout treatment, clinicians should implement measurement-based care by systematically monitoring patients' response using self-rated scales, such as the PHQ-9, QIDS SR, or BDI. By tracking depressive symptoms, as well as suicidality, treatment adherence, and side effects, clinicians can adjust treatment to help patients achieve the best outcomes. Measurement-based care enables clinicians to make informed decisions at critical points throughout the treatment process and to involve patients in making those decisions. PMID- 23945457 TI - Antenatal exposure to selective serotonin reuptake inhibitors and duration of gestation. PMID- 23945458 TI - A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder. AB - BACKGROUND: Multiple treatments for patients with major depressive disorder (MDD) have demonstrated efficacy, but up to one-third of individuals with MDD do not achieve symptomatic remission despite various interventions. Existing augmentation or combination strategies can have substantial safety concerns that may limit their application. METHOD: This study investigated the antidepressant efficacy of a flexible dose of the dopamine agonist pramipexole as an adjunct to standard antidepressant treatment in an 8-week, randomized, double-blind, placebo controlled trial conducted in a tertiary-level depression center. We randomized 60 outpatients (aged 18 to 75 years) with treatment-resistant nonpsychotic MDD (diagnosed according to DSM-IV) to either pramipexole (n = 30) or placebo (n = 30). Treatment resistance was defined as continued depression (Montgomery-Asberg Depression Rating Scale [MADRS] score >= 18) despite treatment with at least 1 prior antidepressant in the current depressive episode. Patients were recruited between September 2005 and April 2008. The primary outcome measure was the MADRS score. RESULTS: The analyses that used a mixed-effects linear regression model indicated a modest but statistically significant benefit for pramipexole (P = .038). The last-observation-carried-forward analyses indicated that 40% and 33% of patients randomized to augmentation with pramipexole achieved response (chi(2) = 1.2, P = .27) and remission (chi(2) = 0.74, P = .61), respectively, compared to 27% and 23% with placebo; however, those differences were not statistically significant. Augmentation with pramipexole was well-tolerated, with no serious adverse effects identified. CONCLUSION: For patients who have failed to respond to standard antidepressant therapies, pramipexole is a safe and potentially efficacious augmentation strategy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00231959. PMID- 23945459 TI - Antipsychotics for primary alcohol dependence: a systematic review and meta analysis of placebo-controlled trials. AB - OBJECTIVE: We sought to meta-analytically assess the utility of antipsychotics in patients with primary alcohol dependence. DATA SOURCES: We searched PubMed, Cochrane Library, and PsycINFO without language restrictions from database inception until December 2012, using the following keywords: (randomized, random, OR randomly) AND (placebo) AND (alcohol dependence) AND (neuroleptic OR antipsychotic OR antidopaminergic OR the names of 34 individual antipsychotics). STUDY SELECTION: Included in this study were randomized, placebo-controlled trials of antipsychotics lasting >= 2 weeks in patients with primary alcohol dependence and without schizophrenia or bipolar disorder. DATA EXTRACTION: Two independent evaluators extracted data. Standardized mean difference (SMD), risk ratio (RR), and numbers needed to harm (NNH) +/- 95% confidence intervals (CIs) were calculated. RESULTS: Across 13 double-blind studies, 1,593 patients were randomly assigned to one of the following: amisulpride (1 study, n = 37), aripiprazole (2 studies, n = 163), flupenthixol decanoate (1 study, n = 142), olanzapine (2 studies, n = 62), quetiapine (4 studies, n = 174), tiapride (3 studies, n = 212), or placebo (13 studies, n = 803). Neither pooled nor individual antipsychotics outperformed placebo regarding relapse prevention (pooled RR = 1.05 [95% CI, 0.95 to 1.16], P = .38, 9 studies, n = 1,405). Antipsychotics were similar to placebo regarding heavy drinking days (P = .15), craving (P = .82), and first alcohol consumption time (P = .94). Placebo outperformed pooled antipsychotics regarding number or percentage of abstinent days/lack of drinking days (SMD = 0.17 [95% CI, 0.01 to 0.33], P = .04, 5 studies, n = 918), without significant group differences after removal of 1 outlying flupenthixol decanoate study (P = .24). Individually, flupenthixol decanoate (1 study, n = 281) was inferior to placebo regarding abstinence/drinking days (P = .004), whereas aripiprazole (1 study, n = 30) was superior regarding heavy drinking days (P < .00001). Antipsychotics caused greater all-cause discontinuation than placebo (RR = 1.24 [95% CI, 1.07 to 1.45], P = .005, NNH = 14), especially aripiprazole (P = .01) and flupenthixol decanoate (P = .001). Discontinuation due to intolerability was similar between antipsychotics and placebo (P = .12), but aripiprazole's risk was higher (P = .003). Drowsiness/sedation (P < .0001, NNH = 9), increased appetite (P = .02, NNH = 14), and dry mouth (P < .0001, NNH = 7) occurred more frequently with pooled antipsychotics. CONCLUSIONS: Except for 1 isolated outcome, the studied antipsychotics did not improve abstinence or reduce drinking or craving in patients with primary alcohol dependence. PMID- 23945460 TI - Randomized controlled trial to assess reduction of cardiovascular disease risk in patients with bipolar disorder: the Self-Management Addressing Heart Risk Trial (SMAHRT). AB - OBJECTIVES: Persons with bipolar disorder experience a disproportionate burden of medical conditions, notably cardiovascular disease (CVD), leading to impaired functioning and premature mortality. We hypothesized that the Life Goals Collaborative Care (LGCC) intervention, compared to enhanced usual care, would reduce CVD risk factors and improve physical and mental health outcomes in US Department of Veterans Affairs patients with bipolar disorder. METHOD: Patients with an ICD-9 diagnosis of bipolar disorder and >= 1 CVD risk factor (N = 118) enrolled in the Self-Management Addressing Heart Risk Trial, conducted April 2008 May 2010, were randomized to LGCC (n = 58) or enhanced usual care (n = 60). Life Goals Collaborative Care included 4 weekly self-management sessions followed by tailored contacts combining health behavior change strategies, medical care management, registry tracking, and provider guideline support. Enhanced usual care included quarterly wellness newsletters sent during a 12-month period in addition to standard treatment. Primary outcome measures included systolic and diastolic blood pressure, nonfasting total cholesterol, and physical health related quality of life. RESULTS: Of the 180 eligible patients identified for study participation, 134 were enrolled (74%) and 118 completed outcomes assessments (mean age = 53 years, 17% female, 5% African American). Mixed effects analyses comparing changes in 24-month outcomes among patients in LGCC (n = 57) versus enhanced usual care (n = 59) groups revealed that patients receiving LGCC had reduced systolic (beta = -3.1, P = .04) and diastolic blood pressure (beta = 2.1, P = .04) as well as reduced manic symptoms (beta = -23.9, P = .01). Life Goals Collaborative Care had no significant impact on other primary outcomes (total cholesterol and physical health-related quality of life). CONCLUSIONS: Life Goals Collaborative Care, compared to enhanced usual care, may lead to reduced CVD risk factors, notably through decreased blood pressure, as well as reduced manic symptoms, in patients with bipolar disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00499096. PMID- 23945461 TI - Viewpoints about collaboration between primary care and public health in Canada. AB - BACKGROUND: Although there is a global movement toward health system integration and collaboration, little is known about values, beliefs, and attitudes towards collaboration between stakeholders in public health (i.e. promotion, protection, and prevention with vulnerable groups and/or at the population level) and primary care (i.e., family practices, nurse-led clinics). The purpose of this study was to explore viewpoints of key stakeholders regarding primary care (PC) and public health (PH) collaboration in Canada. METHODS: We used Q-methodology to identify common viewpoints held by participants who attended a national meeting in Canada in 2010 to discuss PC and PH collaboration. The study was conducted in two phases. In Phase 1 a Q-sample, a Q-sort table, and a short demographic questionnaire were developed which were used in Phase 2 for data collection. The Q-sorts then were analysed to identify the salient factors and consensus statements. RESULTS: In total, 25 multidisciplinary individuals including researchers, policy-makers, directors, managers, and practitioners (e.g., nurses, family physicians, dietitians) participated. Using a by-person factor analysis, three factors (salient viewpoints) emerged. Factors were named based on their distinguishing statements as follows: a) System Driven Collaborators, b) Cautious Collaborators, and c) Competent Isolationists. System Driven Collaborators strongly believed that a clear mandate from the top is needed to enable PH, PC and the rest of the health system to effectively work together and that people in different branches in the Ministry/ Ministries have to strongly believe in collaboration, actively support it, and develop directed policies to foster organizations work together. Cautious Collaborators strongly supported the idea of having better consciousness-raising about what collaborations might be possible and beneficial, and also reflecting on the collaborations already in place. The Competent Isolationists strongly believed that it is necessary for PC and PH sectors to spend time to ensure that both parties clearly understand the differences between their roles. They believe that physicians, nurses, and social workers will not see the value in collaboration because they lack inter professional educational programs. CONCLUSIONS: Different viewpoints are held by stakeholders around PC and PH collaboration which have the potential to influence the success of collaborations. Understanding and managing these differences is important to assist change management processes required to build and maintain strong PC and PH collaborations. PMID- 23945462 TI - Flexible and dynamic nucleosome fiber in living mammalian cells. AB - Genomic DNA is organized three dimensionally within cells as chromatin and is searched and read by various proteins by an unknown mechanism; this mediates diverse cell functions. Recently, several pieces of evidence, including our cryomicroscopy and synchrotron X-ray scattering analyses, have demonstrated that chromatin consists of irregularly folded nucleosome fibers without a 30-nm chromatin fiber (i.e., a polymer melt-like structure). This melt-like structure implies a less physically constrained and locally more dynamic state, which may be crucial for protein factors to scan genomic DNA. Using a combined approach of fluorescence correlation spectroscopy, Monte Carlo computer simulations, and single nucleosome imaging, we demonstrated the flexible and dynamic nature of the nucleosome fiber in living mammalian cells. We observed local nucleosome fluctuation (~50 nm movement/30 ms) caused by Brownian motion. Our in vivo/in silico results suggest that local nucleosome dynamics facilitate chromatin accessibility and play a critical role in the scanning of genome information. PMID- 23945463 TI - Prevalence of cardiovascular risk factors among Latin American adolescents: a multilevel analysis. AB - High blood pressure (HBP) and obesity is a well-established major risk factor for stroke and coronary heart disease. However, the literatures are scarce about these informations in adolescents from low-and-middle income countries. This school-based survey was carried out among students from Maringa (Brazil) and Buenos Aires (Argentina) selected random sampling. We studied 991 Brazilian adolescents (54.5% girls) in the age range of 14-18 years. In Argentina, we studied 933 adolescents (45.9% female) in the age range of 11-17 years. The outcomes of this study are general obesity, abdominal obesity and HBP. The associated factors analysed were gender, age and health behaviours. The prevalence of obesity was 5.8% in Brazil and 2.8% in Argentina, the prevalence of abdominal obesity was 32.7% in Brazil and 11.1% in Argentina, the prevalence of HBP was 14.9% in Brazil and 13.5% in Argentina. The multilevel analysis showed that older adolescents (>14 years old) have a little likelihood of being overweight, whereas male adolescents are more likely to be obese and have HBP. The abdominal obesity in both indicators were not associated with the independent variables. The prevalence of cardiovascular risk factors is high in Latin American adolescents independent of each country, and was associated with male gender. PMID- 23945464 TI - During ablation for atrial fibrillation, is simultaneous renal artery ablation appropriate? AB - Over the past few decades, the mainstay of hypertension management has been pharmacological therapy; however, there is now a growing body of evidence that drug-resistant hypertension can be managed effectively by renal artery ablation. Several studies have documented the feasibility and safety of this treatment, although data regarding long-term outcomes are still emerging. Atrial fibrillation (AF) and hypertension commonly coexist, and recent work has demonstrated improved outcomes from catheter ablation of AF with concomitant renal artery denervation at little extra cost in terms of time and resource. The aim of this review is to explore the link between hypertension and AF, the synergistic effect of renal artery ablation on AF ablation, explain how this may work and address unanswered questions. PMID- 23945465 TI - Occurrence of bladder metastasis 10 years after surgical removal of a primary gastric cancer: a case report and review of the literature. AB - INTRODUCTION: Secondary bladder neoplasms are uncommon and they represent only 2% of all malignant bladder tumors. CASE PRESENTATION: The authors present a case of a 59-year-old Caucasian man with a primary gastric adenocarcinoma that had been surgically removed 10 years before he developed bladder metastasis. He presented with low abdominal pain after 10 years without any symptoms. Cystoscopy and an abdominal computed tomography scan showed a bladder tumor. A transurethral resection of the bladder tumor was performed. A histological examination revealed an adenocarcinoma, which turned out to be a metastasis of the primary gastric tumor. One year later, abdominal surgery revealed peritoneal metastases. CONCLUSION: This is the first known case in Europe where bladder metastasis occurred 10 years after surgical removal of a primary gastric neoplasm. There are only four cases in the literature where metastases of the peritoneum developed 11 years after surgical removal of a primary gastric tumor. PMID- 23945466 TI - How to decrease overtreatment in cancer. PMID- 23945469 TI - Estimating the tolerance of species to the effects of global environmental change. AB - Global environmental change is affecting species distribution and their interactions with other species. In particular, the main drivers of environmental change strongly affect the strength of interspecific interactions with considerable consequences for biodiversity. However, extrapolating the effects observed on pair-wise interactions to entire ecological networks is challenging. Here we propose a framework to estimate the tolerance to changes in the strength of mutualistic interaction that species in mutualistic networks can sustain before becoming extinct. We identify the scenarios where generalist species can be the least tolerant. We show that the least tolerant species across different scenarios do not appear to have uniquely common characteristics. Species' tolerance is extremely sensitive to the direction of change in the strength of mutualistic interaction, as well as to the observed mutualistic trade-offs between the number of partners and the strength of the interactions. PMID- 23945468 TI - Standardized, App-based disinfection of iPads in a clinical and nonclinical setting: comparative analysis. AB - BACKGROUND: With the use of highly mobile tools like tablet PCs in clinical settings, an effective disinfection method is a necessity. Since manufacturers do not allow cleaning methods that make use of anything but a dry fleece, other approaches have to be established to ensure patient safety and to minimize risks posed by microbiological contamination. OBJECTIVE: The ability of isopropanol wipes to decontaminate iPads was evaluated prospectively in a observer blinded, comparative analysis of devices used in a clinical and a nonclinical setting. METHODS: 10 new iPads were randomly deployed to members of the nursing staff of 10 clinical wards, to be used in a clinical setting over a period of 4 weeks. A pre-installed interactive disinfection application (deBac-app, PLRI MedAppLab, Germany) was used on a daily basis. Thereafter, the number and species of remaining microorganisms on the surface of the devices (13 locations; front and back) was evaluated using contact agar plates. Following this, the 10 iPads were disinfected and randomly deployed to medical informatics professionals who also used the devices for 4 weeks but were forbidden to use disinfecting agents. The quality of a single, standardized disinfection process was then determined by a final surface disinfection process of all devices in the infection control laboratory. No personal data were logged with the devices. The evaluation was performed observer blinded with respect to the clinical setting they were deployed in and personnel that used the devices. RESULTS: We discovered a 2.7 fold (Mann-Whitney U test, z=-3.402, P=.000670) lower bacterial load on the devices used in the clinical environment that underwent a standardized daily disinfection routine with isopropanol wipes following the instructions provided by "deBac-app". Under controlled conditions, an average reduction of the mainly Gram-positive normal skin microbiological load of 99.4% (Mann-Whitney U test, z= 3.1798, P=.001474) for the nonclinical group and 98.1% (Mann-Whitney U test, z=3.1808, P=.001469) for the clinical group was achieved using one complete disinfecting cycle. CONCLUSIONS: Normal use of tablet PCs leads to a remarkable amount of microbial surface contamination. Standardized surface disinfection with isopropanol wipes as guided by the application significantly reduces this microbial load. When performed regularly, the disinfection process helps with maintaining a low germ count during use. This should reduce the risk of subsequent nosocomial pathogen transmission. Unfortunately, applying a disinfection procedure such as the one we propose may lead to losing the manufacturer's warranty for the devices; this remains an unsolved issue. PMID- 23945470 TI - First-principles studies of the magnetic anisotropy of the Cu/FePt/MgO system. AB - Using first-principles density-functional theory calculations, we systematically investigate the magnetic anisotropy of the multilayer system Cu/(FePt)n/MgO, a promising spintronics structure. Particularly, we have studied the influence of the epitaxial strain, thickness of the ferromagnetic layer, and different interfaces on the magnetic anisotropy energy (MAE) of the system. It is found that the thickness of FePt has slight influence on the MAE, while the increase of the in-plane lattice constant a, or tensile strain, can significantly reduce and even change the sign of the MAE. The calculated density of states shows that the occupation number of the minority spin channel of Fe dx(2)-y(2) orbital decreases with the increase of a, which leads to the reduction of the orbital moment anisotropy of the Fe atom and therefore the decrease of MAE. We also consider the influence of the Cu/FePt and FePt/MgO interfaces on the MAE, and find that both interfaces can reduce the MAE. Especially, the effect of the Cu/FePt interface is more pronounced due to the increased occupation number of the minority spin channel of Fe dz(2) orbital. PMID- 23945471 TI - A baculovirus-mediated strategy for full-length plant virus coat protein expression and purification. AB - BACKGROUND: Garlic production is severely affected by virus infection, causing a decrease in productivity and quality. There are no virus-free cultivars and garlic-infecting viruses are difficult to purify, which make specific antibody production very laborious. Since high quality antisera against plant viruses are important tools for serological detection, we have developed a method to express and purify full-length plant virus coat proteins using baculovirus expression system and insects as bioreactors. RESULTS: In this work, we have fused the full length coat protein (cp) gene from the Garlic Mite-borne Filamentous Virus (GarMbFV) to the 3'-end of the Polyhedrin (polh) gene of the baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV). The recombinant baculovirus was amplified in insect cell culture and the virus was used to infect Spodoptera frugiperda larvae. Thus, the recombinant fused protein was easily purified from insect cadavers using sucrose gradient centrifugation and analyzed by Western Blotting. Interestingly, amorphous crystals were produced in the cytoplasm of cells infected with the recombinant virus containing the chimeric protein gene but not in cells infected with the wild type and recombinant virus containing the hexa histidine tagged Polh. Moreover, the chimeric protein was used to immunize rats and generate antibodies against the target protein. The antiserum produced was able to detect plants infected with GarMbFV, which had been initially confirmed by RT-PCR. CONCLUSIONS: The expression of a plant virus full-length coat protein fused to the baculovirus Polyhedrin in recombinant baculovirus-infected insects was shown to produce high amounts of the recombinant protein which was easily purified and efficiently used to generate specific antibodies. Therefore, this strategy can potentially be used for the development of plant virus diagnostic kits for those viruses that are difficult to purify, are present in low titers or are present in mix infection in their plant hosts. PMID- 23945472 TI - Influence of the solvent type on the morphology and mechanical properties of electrospun PLLA yarns. AB - An electrospinning technique based on the use of two oppositely charged nozzles was applied to fabricate continuous twisted yarns of poly(L-lactide) (PLLA) nano/micro fibers. In this study, the effect of solvent on the electrospinning of PLLA fibrous yarns was investigated. For this purpose, yarns were electrospun using chloroform, dichloromethane or 2,2,2-trifluoroethanol as solvents at a PLLA concentration of 7 wt%. The analysis of the morphology, diameter, crystallinity and mechanical properties of electrospun yarns revealed that the vapor pressure of the solvent plays an important role. Whereas the fiber diameter decreased, the crystallinity of the fibers increased using a solvent with lower vapor pressure. In addition, mechanical properties (e.g., tensile strength and modulus) revealed that the yarns composed of fibers with smaller diameters showed higher tensile strength and modulus. In summary, fine-tuning solvent properties resulted in a modulation of fiber diameter, crystallinity, and thereby yarn mechanical properties, and are important factors to consider in the fabrication and application of electrospun yarns. PMID- 23945473 TI - Genotoxicity biomarkers associated with exposure to traffic and near-road atmospheres: a review. AB - Diesel and gasoline emissions, which are the primary components of traffic exhaust, are known or possible human carcinogens, respectively, and working or living near high-traffic roads is associated with various health effects, including cancer. To help understand the mechanistic basis for this observation, the present article reviews 63 studies on genotoxicity biomarkers in traffic exposed subjects, with office workers being the typical control subjects. The six primary biomarkers used in these studies were the traditional cytogenetic end points, chromosome aberrations (CAs), micronucleus (MN) and sister chromatid exchange, and the standard molecular end points for DNA damage, (32)P postlabeling, the comet assay and urinary 8-hydroxydeoxyguanosine. These six assays accounted for 74 of the 87 biomarker assessments reported in the studies; all six effectively distinguished traffic-exposed from control populations, giving an average 89% positive results among exposed versus control subjects. In addition, three genomic biomarkers effectively distinguished between the exposed and control populations; these assays measured changes in gene expression, leukocyte telomere length and DNA methylation. Nearly half of all of the studies included exposure assessments involving blood (primarily protein adducts), urine (primarily 1-hydroxypyrene) or air (primarily polycyclic aromatic hydrocarbons); these assays distinguished the exposed from the control subjects for the vast majority of the studies. All but three of the 63 reports were environmental studies that investigated 18 general exposure categories, such as traffic police and automobile/bus mechanics. The studies were performed in 20 countries; however, nearly all of the environmental studies were performed in Europe and Asia, with only one each from Africa, North America and South America. Given that several of the biomarkers are associated with increased cancer risk, including CAs, MNs and altered telomere length, the data reviewed here provide strong mechanistic support for the ability of chronic exposure to traffic exhaust to increase cancer risk. PMID- 23945474 TI - Linear asymptomatic pneumatosis as an unexpected finding of computed tomography colonography: a case report. AB - INTRODUCTION: We discuss asymptomatic colonic pneumatosis, an unexpected finding of computed tomography colonography that we must see as distinct from perforation. Among the papers detailing complications with computed tomography colonography, we found only one report focusing on linear pneumatosis. CASE PRESENTATION: We report the case of a 75-year-old Caucasian woman who had a high level of carcinoembryonic antigen, and who underwent computed tomography colonography. Our patient accidentally fell from a chair in the radiology department just before the examination, experiencing a right hip trauma. The examination was negative for colonic lesions but revealed the presence of some air bubbles in her right colon. Our patient remained asymptomatic throughout the procedure and afterwards; no intervention or treatment was necessary. CONCLUSION: Radiologists should consider colonic linear pneumatosis among the potential complications of computed tomography colonography, even if it is a rare event, to avoid unnecessary therapy and anxiety for the patient. PMID- 23945475 TI - An update in the treatment of male urinary incontinence. AB - PURPOSE OF REVIEW: Male urinary incontinence affects a significant number of elderly men and the successful treatment has the potential to significantly improve their quality of life. RECENT FINDINGS: Stress urinary incontinence, overflow incontinence and detrusor overactivity are the major categories of urinary incontinence affecting men. Although the surgical standards of care have not changed significantly for urinary incontinence, there have been recent advances with minimally invasive techniques, which show promise. SUMMARY: The treatment of male urinary incontinence is constantly evolving, with recent advances in minimally invasive procedures. PMID- 23945476 TI - Epidemiology of male urinary incontinence. AB - PURPOSE OF REVIEW: Urinary incontinence is a common clinical problem, particularly in older adults. This review was designed to review current and recently updated information on the epidemiology of urinary incontinence in men. RECENT FINDINGS: There are an increasing number of urinary incontinence studies outside Europe and North America. However, overall, the trend indicates no remarkable increase in the number of publications relative to all areas. Prevalence studies have produced estimates with very wide ranges, mainly due to methodological differences. Studies have also examined risk factors and impact of urinary incontinence, including lifestyle, comorbidities and medications. SUMMARY: Recent research has focused less on urinary incontinence in men compared with women, despite urinary incontinence being relatively common and burdensome in men worldwide and strongly associated with age. Thus, the population burden is likely to increase with future demographic shifts. A wide variety of risk factors have been identified, and studies have shown that urinary incontinence can have substantial negative impacts on various clinical outcomes and quality of life. PMID- 23945477 TI - Peculiar properties of homoleptic Cu complexes with dipyrromethene derivatives. AB - In view of preparing Cu polynuclear complexes with dipyrromethene ligands, the mononuclear complexes [Cu(II)(dipy)2] (dipyH = 5-phenyldipyrromethene) and [Cu(II)(dpdipy)2] (dpdipyH = 1,5,9-triphenyldipyrromethene) have been prepared and characterized by X-ray crystallography, mass spectrometry and EPR spectroscopy. Their peculiar redox and spectroscopic (absorption/emission) behaviours are discussed. In contrast to Cu(II) complexes of 1,1'-bidypyrrin, the reduction electrolysis of [Cu(II)(dpdipy)2] leads to decomposition products on a time scale of a few hours. Moreover in relation to this observation, [Cu(I)(dpdipy)2](-) could not be synthesized in spite of the Cu(I) core protection by the phenyl substituents in ortho position of the nitrogen atoms. Theoretical calculations provide some explanations for this instability. Interestingly [Cu(II)(dipy)2] and [Cu(II)(dpdipy)2] display weak luminescence at room temperature, attributed to a ligand centered emission. PMID- 23945479 TI - Neonatal gastric outlet obstruction. PMID- 23945480 TI - Testicular lymphoma. PMID- 23945481 TI - Mediastinal teratoma diagnosed via ultrasound-guided biopsy. PMID- 23945482 TI - Diffuse lipomatosis of the thyroid gland. PMID- 23945478 TI - Effects of conditional central expression of HIV-1 tat protein to potentiate cocaine-mediated psychostimulation and reward among male mice. AB - As a major neuropathogenic factor associated with human immunodeficiency virus (HIV) infection, HIV-1 Tat protein is known to synergize with psychostimulant drugs of abuse to cause neurotoxicity and exacerbate the progression of central nervous system pathology. However, the functional consequences of the interaction between HIV-1 Tat and abused drugs on behavior are little known. We tested the hypothesis that HIV-1 Tat expression in brain would modulate the psychostimulant effects of cocaine. Using the GT-tg bigenic mouse model, where brain-selective Tat expression is induced by activation of a doxycycline (Dox) promotor, we tested the effects of Tat on cocaine (10 mg/kg, s.c.) induced locomotion and conditioned place preference (CPP). Compared with uninduced littermates or C57BL/6J controls, cocaine-induced hyperlocomotion was sustained for a significantly longer duration among Tat-induced mice. Moreover, although all groups displayed similar saline-CPP, Tat-induced GT-tg mice demonstrated a three fold increase in cocaine-CPP over the response of either uninduced littermates or Dox-treated C57BL/6J control mice. Induction of Tat also increased the magnitude of a previously established cocaine-CPP after an additional cycle of cocaine place-conditioning. Despite Tat-induced potentiation, extinction of place preference occurred within 21 days, commensurate with cocaine-extinction among saline-treated littermates and C57BL/6J controls. Re-exposure to cocaine produced reinstatement of an equivalent place preference in Tat-induced GT-tg or C57BL/6J mice; however, induction of Tat protein after the extinction of CPP also produced reinstatement without additional exposure to cocaine. Together, these data suggest that central HIV-1 Tat expression can potentiate the psychostimulant behavioral effects of cocaine in mice. PMID- 23945483 TI - Testicular yolk sac tumor. PMID- 23945485 TI - Inflammatory breast carcinoma. PMID- 23945484 TI - Adenomyomatosis. PMID- 23945486 TI - Gastrointestinal stromal tumor of the stomach. PMID- 23945487 TI - Prune belly with megalourethra. PMID- 23945488 TI - Right ovarian steroid tumor (not otherwise specified). PMID- 23945489 TI - Finger chondroid syringoma as a hypoechoic subcutaneous nodule in ultrasound. AB - Chondroid syringoma (CS) is an uncommon, benign epithelial skin mixed tumor. It is often located in the head and neck and is unusual in other parts of the body. It may be seen as a skin or soft tissue tumor. We present findings on high resolution ultrasound and histology in a case of benign CS located on the right index finger. High-resolution ultrasound showed a solid hypoechoic, well-defined subcutaneous mass, adjacent to the tendon. Complete surgical excision was performed, and histopathology demonstrated an apocrine mixed tumor (CS). Although CS histological findings are well described, radiological features have been reported only in few cases and mainly in magnetic resonance. Chondroid syringoma should be suspected by high-resolution ultrasound as a differential diagnosis for a solid slow-growing soft tissue nodule in a finger, especially if the lesion has no contact with the underlying tendon. PMID- 23945490 TI - Hepatobiliary cystadenoma. PMID- 23945491 TI - Morel-Lavallee lesion. PMID- 23945492 TI - Intramuscular myxoma. PMID- 23945493 TI - Growth disturbances-risk of intrauterine growth restriction. PMID- 23945494 TI - Testicular torsion and manual detorsion. PMID- 23945495 TI - Abdominal pain of vascular origin: nutcracker syndrome. PMID- 23945496 TI - Hydranencephaly. PMID- 23945497 TI - Heterozygous disruption of activin receptor-like kinase 1 is associated with increased renal fibrosis in a mouse model of obstructive nephropathy. AB - Tubulointerstitial fibrosis is characterized by an accumulation of extracellular matrix in the renal interstitium, myofibroblast activation, cell infiltration, and tubular cell apoptosis, leading to chronic renal failure. Activin receptor like kinase 1 (ALK1) is a transforming growth factor-beta1 type I receptor with a pivotal role in endothelial proliferation and migration, but its role in the development of renal fibrosis is unknown. To assess this we used the unilateral ureteral obstruction model of tubulointerstitial fibrosis in ALK1 haploinsufficient (ALK1(+/-)) and wild-type mice. After 15 days, there was an increase in extracellular matrix protein expression in the obstructed kidneys from both ALK1(+/+) and ALK1(+/-) mice, but obstructed kidneys from ALK1(+/-) mice showed significantly higher expression of type I collagen than those from wild-type mice. Ureteral obstruction increased kidney myofibroblasts markers (alpha-smooth muscle actin and S100A4), without differences between mouse genotypes. ALK1 expression was increased after ureteral obstruction, and this increased expression was located in myofibroblasts. Moreover, cultured renal fibroblasts from ALK1(+/-) mice expressed more collagen type I and fibronectin than fibroblasts derived from wild-type mice. Thus, ALK1 modulates obstruction induced renal fibrosis by increased extracellular matrix synthesis in myofibroblasts, but without differences in myofibroblast number. PMID- 23945498 TI - Neither pre-transplant rituximab nor splenectomy affects de novo HLA antibody production after renal transplantation. AB - The long-term effect of rituximab and splenectomy on de novo HLA antibody production and chronic antibody-mediated rejection after renal transplantation is uncertain. In order to gain insight on this, we studied 92 ABO-incompatible and 228 ABO-identical/compatible consecutive renal transplant patients and determined their de novo HLA antibody production and graft outcome. Patients with pretransplant donor-specific antibodies had been excluded. ABO-incompatible transplants included 30 recipients treated with rituximab, 51 by splenectomy, or 11 with neither, due to low anti-A or -B antibody titer. Graft survival in ABO identical/compatible patients (97.7% at 5 years) was significantly higher than in ABO-incompatible (87.0% at 5 years), rituximab (96.7% at 3 years), or splenectomy (85.7% at 5 years) patients. Only four patients had clinical chronic antibody mediated rejection (two each identical/compatible and incompatible). There was no significant difference in prevalence of de novo HLA antibody, including donor specific and nondonor-specific antibodies among ABO-identical/compatible patients (13.9%), patients receiving rituximab (14.3%) or splenectomy (13.2%), or among those receiving cyclosporine, tacrolimus, mycophenolate mofetil, mizoribine, and everolimus. Renal function remained stable in most recipients with de novo HLA antibody. Thus, neither pretransplant splenectomy nor rituximab treatment has an inhibitory effect on de novo HLA antibody production during medium-term follow up. Further study on long-term effects is needed. PMID- 23945500 TI - Development of an adverse outcome pathway from drug-mediated bile salt export pump inhibition to cholestatic liver injury. AB - Adverse outcome pathways (AOPs) have been recently introduced in human risk assessment as pragmatic tools with multiple applications. As such, AOPs intend to provide a clear-cut mechanistic representation of pertinent toxicological effects. AOPs are typically composed of a molecular initiating event, a series of intermediate steps and key events, and an adverse outcome. In this study, an AOP framework is proposed for cholestasis triggered by drug-mediated inhibition of the bile salt export pump transporter protein. For this purpose, an in-depth survey of relevant scientific literature was carried out in order to identify intermediate steps and key events. The latter include bile accumulation, the induction of oxidative stress and inflammation, and the activation of specific nuclear receptors. Collectively, these mechanisms drive both a deteriorative cellular response, which underlies directly caused cholestatic injury, and an adaptive cellular response, which is aimed at counteracting cholestatic insults. AOP development was performed according to Organisation for Economic Co-operation and Development (OECD) guidance, including critical consideration of the Bradford Hill criteria for weight of evidence assessment and the OECD key questions for evaluating AOP confidence. The postulated AOP is expected to serve as the basis for the development of new in vitro tests and the characterization of novel biomarkers of drug-induced cholestasis. PMID- 23945499 TI - The Nrf2 activator, tBHQ, differentially affects early events following stimulation of Jurkat cells. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that is activated by cellular stresses, such as oxidative compounds. After activation, Nrf2 induces transcription of its target genes, many of which have cytoprotective functions. Previously, we have shown that activation of Nrf2 by tert butylhydroquinone (tBHQ) skews murine CD4+ T-cell differentiation. Although the role of Nrf2 in murine T cells is somewhat characterized, it is largely uncharacterized in human T cells. Therefore, the aim of the current studies was to characterize the effects of the Nrf2 activator, tBHQ, on the early events of human CD4+ T-cell activation. Pretreatment of Jurkat T cells with tBHQ, prior to activation with anti-CD3/anti-CD28, diminished the production of interleukin-2 (IL-2) at both the transcript and protein levels. Similarly, the expression of CD25 also diminished, albeit to a lesser degree than IL-2, after pretreatment with tBHQ. The decrease in IL-2 production was not due to decreased nuclear translocation of c-fos or c-jun. Although tBHQ caused both a delay and a decrease in Ca2+ influx in activated Jurkat cells, no decrease in nuclear factor of activated T cells (NFAT) DNA binding or transcriptional activity was observed. In contrast to NFAT, tBHQ significantly decreased NFkappaB transcriptional activity. Collectively, our studies show that the Nrf2 activator, tBHQ, inhibits IL-2 and CD25 expression, which correlates with decreased NFkappaB transcriptional activity in activated Jurkat cells. Overall, our studies suggest that Nrf2 represents a novel mechanism for the regulation of both human and mouse T cell function. PMID- 23945501 TI - Scale-up of combination prevention and antiretroviral therapy for female sex workers in West Africa: time for action. PMID- 23945502 TI - HIV exposed seronegative individuals show antibodies specifically recognizing native HIV envelope glycoprotein. AB - BACKGROUND: Susceptibility to HIV transmission by sexual intercourse has been associated with cellular anti-HIV responses. We aimed to also evaluate potential systemic humoral responses against HIV in a group of HIV-exposed seronegative individuals (HESN) in stable relationship with HIV-infected partners. METHODS: We recruited 27 serodiscordant couples. HESN were classified according to HIV exposure into very low/low and moderate/high risk. Plasma from HESN and HIV partners were tested for neutralizing capacity and for the recognition of cell surface expressed and recombinant forms of HIV envelope glycoproteins (Env). Healthy individuals (healthy control, n=11) were used as controls. RESULTS: Recognition of cell-surface expressed Env by both immunoglobulin (Ig)G and IgA was higher in plasma samples from HESN than in healthy controls (P=0.0062 and P=0.0144, respectively). IgG binding to Env was significantly increased in HESN after unmasking CD4-induced epitopes (P=0.001), suggesting a wide range of targeted epitopes. Remarkably, ELISA assays using trimeric gp140 or monomeric gp120 failed to detect significant differences in reactivity between groups. Neutralization analysis showed residual activity in only three HESN samples (11%), whereas 70% of HIV-infected partners showed neutralizing activity. Although anti-Env humoral responses were found in 85% of HESN, their magnitude was not associated with the estimated level of exposure or the detection of HIV specific cellular immune responses. CONCLUSION: A high proportion of HESN show detectable plasma IgG or IgA recognizing different exposed and cryptic Env native epitopes unrelated to neutralizing capacity. Therefore, low but persistent HIV exposure induces new virus-specific systemic humoral responses or boosts preexisting natural antibodies. PMID- 23945503 TI - Differential penetration of raltegravir throughout gastrointestinal tissue: implications for eradication and cure. AB - OBJECTIVE: To investigate the concentration of the integrase strand inhibitor raltegravir (RAL) throughout gastrointestinal (GI) tissue, especially gut associated lymphoid tissue (GALT), as an adjunct to current prevention and cure strategies. DESIGN: Open-label pharmacokinetic (PK) study. METHODS: HIV-negative men received RAL 400 mg twice daily for 7 days. Seven blood plasma specimens were collected over 12-h intervals; timed tissue specimens from terminal ileum, splenic flexure, and rectum were also obtained by colonoscopy following the first dose and on day 7 [multiple dose (MD)]. RAL concentrations were measured by validated LC-MS assay with 1 ng/ml lower limit of detection. Data were analyzed by noncompartmental methods (WinNonlin 6). Tissue exposures are reported as composite medians and tissue density of 1.04 g/ml is assumed for comparisons. RESULTS: Fourteen men completed evaluations. Median (range) age was 24 (19-49) years and BMI 25 (19-31) kg/m2. After the first dose, area under the time concentration curve (AUC)(0-12h) was highest in the terminal ileum (594 MUg*h/ml). Exposures were 160, 68 and 39-fold greater than blood plasma at the terminal ileum, splenic flexure and rectum, respectively. After multiple doses, exposure was highest at the splenic flexure (2240 MUg*h/ml); exposure at the terminal ileum and rectum were equivalent (both 788 MUg*h/ml). Following multiple doses, exposures were 160 to 650-fold greater than blood plasma throughout the colon. CONCLUSION: RAL rapidly disseminates into GI tissue and concentrations remain significantly higher than blood plasma. RAL exposure in GI tissue remains higher than any antiretroviral investigated to date. These data suggest that RAL should result in full suppression of viral replication in GI tissue and GALT. PMID- 23945504 TI - Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers. AB - OBJECTIVE: To investigate the relationship between inflammatory [interleukin-6 (IL-6) and C-reactive protein (CRP)] and coagulation (D-dimer) biomarkers and cancer risk during HIV infection. DESIGN: A prospective cohort. METHODS: HIV infected patients on continuous antiretroviral therapy (ART) in the control arms of three randomized trials (N=5023) were included in an analysis of predictors of cancer (any type, infection-related or infection-unrelated). Hazard ratios for IL 6, CRP and D-dimer levels (log2-transformed) were calculated using Cox models stratified by trial and adjusted for demographics and CD4+ cell counts and adjusted also for all biomarkers simultaneously. To assess the possibility that biomarker levels were elevated at entry due to undiagnosed cancer, analyses were repeated excluding early cancer events (i.e. diagnosed during first 2 years of follow-up). RESULTS: During approximately 24,000 person-years of follow-up (PYFU), 172 patients developed cancer (70 infection-related; 102 infection unrelated). The risk of developing cancer was associated with higher levels (per doubling) of IL-6 (hazard ratio 1.38, P<0.001), CRP (hazard ratio 1.16, P=0.001) and D-dimer (hazard ratio 1.17, P=0.03). However, only IL-6 (hazard ratio 1.29, P=0.003) remained associated with cancer risk when all biomarkers were considered simultaneously. Results for infection-related and infection-unrelated cancers were similar to results for any cancer. Hazard ratios excluding 69 early cancer events were 1.31 (P=0.007), 1.14 (P=0.02) and 1.07 (P=0.49) for IL-6, CRP and D dimer, respectively. CONCLUSION: Activated inflammation and coagulation pathways are associated with increased cancer risk during HIV infection. This association was stronger for IL-6 and persisted after excluding early cancer. Trials of interventions may be warranted to assess whether cancer risk can be reduced by lowering IL-6 levels in HIV-positive individuals. PMID- 23945506 TI - HIV replication, inflammation and atherogenesis: dangerous liaisons. PMID- 23945505 TI - Association of HIV clinical disease progression with profiles of early immune activation: results from a cluster analysis approach. AB - OBJECTIVE: CD4 and CD8 T-cell activation are independent predictors of AIDS. The complete activation profile of both T-cell subtypes and their predictive value for AIDS risk is largely unknown. DESIGN: A total of 564 AIDS-free women in the Women's Interagency HIV Study were followed over 6.1 years (median) after T-cell activation assessment. A cluster analysis approach was used to evaluate the concurrent activation patterns of CD4 and CD8 T cells at the beginning of follow up in relation to AIDS progression. METHODS: Percentages of CD4 and CD8 T cells with HLA-DR+/- and CD38+/- were assessed by flowcytometry. Eight immunologic variables (four on each CD4+ and CD8+: DR+/- and CD38+/-) were assessed to yield a 4-cluster solution on samples obtained before clinical endpoints. Proportional hazards survival regression estimated relative risks for AIDS progression by cluster membership. RESULTS: Compared with the other three clusters, outstanding activation features of each distinct cluster of women were: Cluster 1: higher CD8(+)CD38(-)DR(-) (average=41% of total CD8 T-cell pool), CD4(+)CD38(-)DR(-) (average=53% of total CD4 T-cell pool), and CD8(+)CD38(-)DR(+) (28%); Cluster 2: higher CD8(+)CD38(+)DR(-) (44%) and CD4(+)CD38(+)DR(-) (58%); Cluster 3: higher CD8(+)CD38(+)DR(+) (49%) and CD4(+)CD38(+)DR(-) (48%); Cluster 4: higher CD8(+)CD38(+)DR(+) (49%), CD4(+)CD38(+)DR(+) (36%) and CD4(+)CD38(-)DR(+) (19%). Compared with cluster 1, women in cluster 4 had two-fold increased risk of AIDS progression (Hazard ratio=2.13; 95% confidence interval=1.30-3.50) adjusted for CD4 cell count, HIV RNA, and other confounders. CONCLUSION: A profile including CD4 and CD8 T-cell activation provided insight into HIV pathogenesis indicating concurrent hyperactivation of CD4 and CD8 T cells is associated with AIDS progression. PMID- 23945507 TI - Enforcing the law to obtain an HIV test in a minor: a follow-up. PMID- 23945508 TI - Electron transfer from CdSe-ZnS core-shell quantum dots to cobalt(III) complexes. AB - Fluorescence quenching of CdSe-ZnS quantum dots (core-shell QDs) is shown to be affected in the presence of cobalt(III) complexes with pyridyl anchors. Steady state and time-resolved fluorescence spectra indicate that the quenching has primarily a static component. The decrease in photoluminescence intensity can be best explained by charge transfer from the QDs to the Co(III) complexes whereas the energy transfer pathways have been methodically ruled out. The fact that quenching is a result of electron transfer is also supported by electrochemical data showing the positions of the energy levels. PMID- 23945509 TI - Novel parameters reflect changes in morphology of respiratory events during weight loss. AB - Apnea-hypopnea-index (AHI), disregarding the respiratory event morphology, is currently used in estimation of severity of obstructive sleep apnea (OSA). The purpose of the current study was to evaluate the potential of novel parameters in estimation of changes in severity of OSA during weight loss. Polygraphic data of 67 patients, 37 in the control (no weight loss) and 30 in the weight loss (>5%) groups was evaluated at baseline and after two year follow-up. Changes in the values of novel parameters, incorporating detailed information of respiratory event characteristics, were evaluated and compared with changes in AHI. The median AHI in the weight loss group decreased significantly during the follow-up. The number of shorter respiratory events decreased in the weight loss group, while the longer ones remained, increasing the median durations of the respiratory events by 20-62%. For this reason the decrease of the values of the novel parameters were smaller compared to AHI in the weight loss group. This suggests that the severity of OSA might not fall as linearly during weight loss as AHI suggests. Moreover, the novel parameters containing more detailed information on the morphology characteristics may provide valuable supplementary information for the assessment of the severity of OSA. PMID- 23945510 TI - The safety and efficacy of intranasal dexmedetomidine during electrochemotherapy for facial vascular malformation: a double-blind, randomized clinical trial. AB - PURPOSE: Intranasal dexmedetomidine is noninvasive and has been reported as premedication for children undergoing surgery. The aim of this study was to evaluate the safety and efficacy of intranasal dexmedetomidine during electrochemotherapy for facial vascular malformation under local anesthesia. MATERIALS AND METHODS: A placebo-controlled randomized clinical trial was designed. Patients with facial vascular malformation scheduled for electrochemotherapy under local anesthesia were randomly assigned to 1 of 3 groups (group IN, IV, or C). Patients in group IN received dexmedetomidine 1 MUg/kg intranasally. Patients in group IV received dexmedetomidine 1 MUg/kg intravenously. Patients in group C received 0.9% saline intranasally and intravenously. Sedation status and vital signs were assessed at baseline, 15 and 30 minutes after drug administration, before surgery, and 15 minutes after the start of surgery. Midazolam was used as a rescue. Data were analyzed by 2-way repeated measures analysis of variance. RESULTS: Sixty patients with American Society of Anesthesiologists physical status I or II were enrolled. Patients in groups IN and IV were significantly more sedated than those in group C before the beginning of surgery (P < .001 for the 2 comparisons). After nasal administration, adequate sedation was achieved within 30 to 45 minutes. In group IV, the onset of sedation was 15 to 20 minutes. There were no clinically significant adverse effects. CONCLUSIONS: Intranasal dexmedetomidine has a sedative effect under local anesthesia and offers a noninvasive, better-tolerated alternative to intravenous administration. PMID- 23945511 TI - Digital measurements of 120 mandibular angles to determine the ideal fibula wedge osteotomy to re-create the mandibular angle for microvascular reconstruction. AB - PURPOSE: Mandibular reconstruction continues to be a challenge, even for the seasoned reconstructive surgeon. The present study sought to determine the normal anatomic mandibular angle and to establish a predictable angle of resection for the fibula bone cut to re-create the neomandibular body-ascending ramus angle. MATERIALS AND METHODS: A total of 30 random male and female panoramic radiographs were selected from our database. The selection criteria included age older than 21 years and a full or near total complement of teeth. The exclusion criteria were an edentulous mandible or maxilla, a history of trauma or maxillary or mandibular pathologic features, and age younger than 21 years. A total of 120 total measurements were performed. The angle measured was determined from a line coinciding with the posterior border of the ramus and the lower mandibular border. The measurements were taken from each side and from each gender group. The institutional review board of our institution approved the present study. RESULTS: The mean female mandibular right angle was 122.62 degrees , and the left was 124.59 degrees (average, 123.61 degrees ). The mean male mandibular right angle was 122.66 degrees , and the left was 124.2 degrees (average, 123.43 degrees ). The mean and median values were very similar. A statistically significant difference was identified between the left and right sides but not between the genders. Given this information, one can calculate a wedge cut in the fibula of about 56 degrees to re-create the mean mandibular angle. CONCLUSIONS: This information can be used to make predictable fibula wedge closing osteotomies to re-create the normal mandibular ascending ramus body angle in a low-cost manner with the aid of an autoclavable metal wedge of 56 degrees . This method would obviate the need for costly prefabricated guides. PMID- 23945512 TI - Metastatic cancer identified in osteonecrosis specimens of the jaws in patients receiving intravenous bisphosphonate medications. AB - PURPOSE: The aim of the present study was to investigate the microscopic presence of metastatic cancer in jaw specimens clinically and histologically diagnosed as having osteonecrosis in patients receiving intravenous bisphosphonate medications. PATIENTS AND METHODS: A retrospective cohort multicenter study was designed. Patients from the University of Tennessee Medical Center, New York University Medical Center, and New York Center for Orthognathic and Maxillofacial Surgery were enrolled who had been treated with intravenous bisphosphonate medications for an underlying diagnosis of cancer and who had been clinically diagnosed with bisphosphonate-related osteonecrosis of the jaws (BRONJ). The institutional review boards approved the present study. The primary predictor variable was the clinical presence of BRONJ. The primary outcome variable was the microscopic presence of metastatic cancer in the osteonecrotic jaw specimens. RESULTS: A total of 744 sites of BRONJ were clinically diagnosed. Of these sites, 552 (74%) were diagnosed in patients who had received intravenous bisphosphonate medications. Of these 552 sites, 357 (65%) underwent microscopic evaluation through biopsy, sequestrectomy, or resection with curative intent. Of the 357 sites of BRONJ subjected to microscopic analysis, 19 (5.3%) sites were diagnosed with 20 cancers in 16 patients. CONCLUSIONS: Albeit rare, the presence of cancer in a BRONJ specimen represents 1 explanation for the development of osteonecrosis in patients exposed to intravenous bisphosphonate medications in whom a clinical diagnosis of BRONJ has been applied. Additional molecular information is needed to provide an explanation for this observation. PMID- 23945513 TI - Outcomes of pectoralis major myocutaneous flap in female patients for oral cavity defect reconstruction. AB - PURPOSE: Although much has been mentioned in the literature worldwide regarding the outcome of pectoralis major myocutaneous flaps (PMMFs), hardly any studies are available that mention the outcome of PMMFs in female patients. It has been presumed that complication rates after PMMF reconstruction in female patients are higher because of the presence of more adipose tissue in the flap. The objective of this study was to analyze our data regarding the outcomes of PMMFs in female patients with oral cancer undergoing reconstruction after tumor ablation. MATERIALS AND METHODS: In this retrospective study from January 2008 to May 2012, performed in a single institution in south India, we have analyzed our data on PMMFs in 140 female patients with oral cancer. The operative technique used was essentially the same as that described originally by Ariyan. However, to preserve the deltopectoral flap area, the incision was appropriately modified in a manner as described by Schuller. RESULTS: The mean age of the patients was 52.36 years, with a range from 30 to 76 years. They presented mostly with ulcers or ulceroproliferative lesions. Most of the patients had a history of tobacco and betel nut chewing. All of them underwent composite resection and reconstruction with PMMF under general anesthesia. Of the patients, 30 (21.4%) had complications, comprising infection (8), superficial flap necrosis (11), combined wound infection and superficial flap necrosis (3), total flap failure (2), and orocutaneous fistula (6). CONCLUSIONS: PMMF reconstruction is a reliable and cosmetically acceptable method of reconstruction in female patients for oral cavity defects after tumor ablation. PMID- 23945514 TI - Cavernous sinus thrombosis as a result of a fungal infection: a case report. AB - Cavernous sinus thrombosis (CST) is a rare disease with the potential for significant morbidity and even death. Rapid diagnosis and aggressive medical and surgical management are imperative for patients with CST. The cause may be aseptic or infectious. When the cause is infectious in nature, it is most commonly from a bacterial origin. However, we present the case of a 57-year-old man with a fungally related CST that ultimately led to his death. PMID- 23945515 TI - Rhytidectomy approach for mandibular reconstruction with microvascular free flaps after resection of mandibular benign tumors. AB - PURPOSE: Microvascular surgery has become the preferred method for mandibular reconstruction. A neck incision frequently is required for malignant tumor resections to carry out the dissection. The authors suggest a rhytidectomy approach for mandibular reconstruction with microvascular free flaps after the resection of benign tumors. PATIENTS AND METHODS: Seven patients with lateral mandibular defects resulting from resection of benign mandibular tumors were treated in the author's department. A combined rhytidectomy approach with an intraoral incision was used for mandibular resection and reconstruction of the defects using vascularized free osseous flaps. RESULTS: The study was comprised of 3 men and 4 women with a mean age of 37.57 years (range, 28 to 50 years). Follow-up ranged from 9 to 87 months after surgery (mean, 56.28 months). The iliac crest was used for reconstruction in 6 patients, whereas the fibula was used in 1 patient. Transient paresis of the marginal nerve was observed in 2 patients. Flap loss occurred in 1 patient and required repeat microvascular reconstructive surgery. Dental rehabilitation with osseointegrated implants was performed in 4 patients. At the end of the follow-up period, successful mandibular reconstruction was achieved in all patients. Functional outcome was regarded as excellent in all patients, whereas esthetic outcome was judged excellent in 6 patients and good in 1 patient. CONCLUSIONS: A rhytidectomy approach combined with an intraoral incision for microvascular mandibular reconstruction after the resection of benign tumors is a feasible technique that provides good exposure of the anatomic structures, an inconspicuous facial scar, and adequate facial contour and symmetry. Excellent clinical results are reported with the use of this technique, which should be included in the surgical armamentarium for mandibular reconstruction. PMID- 23945516 TI - Finite element analysis of bone stress after SARPE. AB - PURPOSE: This study investigated stress distribution in maxillas that underwent surgically assisted palatal expansion (SARPE). MATERIALS AND METHODS: Five maxillary models were built: no osteotomy (M1), Le Fort I osteotomy with a step in the zygomaticomaxillary buttress (M2), Le Fort I osteotomy with a step in the zygomaticomaxillary buttress and the pterygomaxillary disjunction (M3), Le Fort I osteotomy without a step (M4), and Le Fort I osteotomy with pterygomaxillary disjunction and no step (M5). Displacement coherence and maximum stress (MS) analyses were used for all models. RESULTS: Areas of tension spread to the maxilla and the region between the alveolar ridge and the palate and a critical point in the median suture for M2, M3, M4, and M5. In M2 and M4, MS spread farther toward and over the pterygoid process, contrary to what was found in M3 and M5. M3 had a better performance than the other models, and the tensile stress was interrupted by the posterior osteotomy, thus avoiding possible damage to the sphenoid bone or difficulties in expanding the posterior region of the maxilla. CONCLUSIONS: The steps in the zygomaticomaxillary buttress and the pterygomaxillary disjunction seem to be important to decrease the harmful dissipation of tensions during SARPE. PMID- 23945517 TI - The cause of cost in the management of odontogenic infections 2: multivariate outcome analyses. AB - PURPOSE: The purpose of this retrospective cohort study was to evaluate the demographic, social, treatment, and hospital course variables associated with length of stay (LOS), intensive care unit (ICU) use, and additional operating room (OR) use in patients admitted for odontogenic infections. MATERIALS AND METHODS: A retrospective chart review was conducted in patients admitted for odontogenic infections at Harborview Medical Center from July 1, 2001 through June 30, 2011. RESULTS: In total, 318 patient charts were reviewed and included. In the multivariate linear regression analysis on LOS, the variables drug abuse, location of treatment, number of spaces involved, side or location of infection, ICU use, length of ICU stay, additional OR use, peak temperature, admission white blood cell count, peak white blood cell count, and peak blood sugar accounted for 68.2% of the variation. In the multivariate logistic regression analysis on ICU use, the variables OR time, number of spaces involved, and peak blood sugar accounted for 32.5% of the variation. LOS was the only variable significantly associated with additional OR use in the multivariate analysis. CONCLUSION: An understanding of the key variables involved in LOS in patients with odontogenic infections has been greatly improved by recent studies and reinforced by the present study. The authors present a starting point for a greater understanding of the variables involved in ICU use, but much more work is needed to address variables identifying patients requiring reoperation. Future studies should aim to create multivariate models explaining all variations in these outcome variables. PMID- 23945518 TI - Obstructive parotitis from extraorally introduced foreign body in the Stensen duct. AB - A rare phenomenon, the extraoral traumatic penetration of a foreign body into the lumen of the parotid duct, is described. The ensuing obstructive symptomatology and its diagnostic approach and therapy are reviewed. PMID- 23945519 TI - Rapid growing myofibroma of the gingiva: report of a case and review of the literature. AB - PURPOSE: Myofibroma is a rare benign tumor of myofibroblasts that rarely exhibits rapid enlargement and is misinterpreted as a malignant lesion. The aim of this study was to investigate its growth potential and to evaluate the usefulness of preoperative immunohistochemical study for an accurate diagnosis. MATERIALS AND METHODS: A case of rapidly growing myofibroma of the lower gingiva was analyzed using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography fused with computed tomography (PET/CT) and immunohistochemical study of Ki-67 and p53. The English-language literature from 1981 to 2012 also was reviewed. RESULTS: An 18F FDG PET/CT image displayed a high accumulation (maximum standardized uptake value, 14.1) in the lesion. A biopsy specimen showed mitotic activity of spindle shaped cells, but atypia was not present. The MIB-1 labeling index was 10%, and the p53 test result was negative. The preoperative diagnosis of benign tumor of smooth muscle origin was made from the histopathologic and immunohistochemical features. In a review of 94 cases, tumors involved the mandible (33%), gingiva (23%), tongue (15%), cheek or buccal mucosa (12%), palate (8%), lip (4%), and other areas (5%). Nine cases (9.6%) were described as rapidly enlarging, and 8 cases (8.5%) were suspected of malignancy at initial diagnosis. The preoperative biopsy with immunohistochemical study established an accurate diagnosis in 83% of myofibromas, and no recurrences were reported in these patients. CONCLUSIONS: Careful diagnosis is necessary because these lesions sometimes present clinical and radiologic features that resemble those of malignant tumors. Preoperative immunohistochemical analysis should be performed to avoid misdiagnosis or unnecessary aggressive therapy. PMID- 23945520 TI - Prospective, randomized, blinded, comparative study of injectable micronized dehydrated amniotic/chorionic membrane allograft for plantar fasciitis--a feasibility study. AB - BACKGROUND: Specialized treatment of plantar fasciitis that can reduce inflammation and promote healing may be a possible alternative prior to surgical intervention. We report the results of a randomized clinical trial examining the efficacy of micronized dehydrated human amniotic/chorionic membrane (mDHACM) injection as a treatment for chronic refractory plantar fasciitis. METHODS: An institutional review board-approved, prospective, randomized, single-center clinical trial was performed. Forty-five patients were randomized to receive injection of 2 cc 0.5% Marcaine plain, then either 1.25 cc saline (controls), 0.5 cc mDHACM, or 1.25 cc mDHACM. Follow-up visits occurred over 8 weeks to measure function, pain, and functional health and well-being. RESULTS: Significant improvement in plantar fasciitis symptoms was observed in patients receiving 0.5 cc or 1.25 cc mDHACM versus controls within 1 week of treatment and throughout the study period. At 1 week, American Orthopaedic Foot and Ankle Society (AOFAS) Hindfoot scores increased by a mean of 2.2 +/- 17.4 points for controls versus 38.7 +/- 11.4 points for those receiving 0.5 cc mDHACM (P < .001) and 33.7 +/- 14.0 points for those receiving 1.25 cc mDHACM (P < .001). By week 8 AOFAS Hindfoot scores increased by a mean of 12.9 +/- 16.9 points for controls versus 51.6 +/- 10.1 and 53.3 +/- 9.4 for those receiving 0.5 cc and 1.25 cc mDHACM, respectively (both P < .001). No significant difference in treatment response was observed in patients receiving 0.5 cc versus 1.25 cc mDHACM. CONCLUSION: In patients with refractory plantar fasciitis, mDHACM is a viable treatment option. Larger studies are needed to confirm our findings. LEVEL OF EVIDENCE: Level I, prospective randomized study. PMID- 23945521 TI - Radiographic and clinical outcomes of joint-preserving procedures for hallux valgus in rheumatoid arthritis. AB - BACKGROUND: The standard treatment for hallux valgus in rheumatoid arthritis has been arthrodesis of the first metatarsophalangeal (MTP) joint. There is limited literature regarding the results of hallux valgus procedures which preserve the first MTP joint in rheumatoid patients. We investigated the radiographic and clinical outcomes of joint-preserving surgery for hallux valgus in a series of rheumatoid patients to evaluate the result of nonarthrodesis reconstruction. METHODS: Thirty-seven feet with hallux valgus in 27 patients with RA treated with a joint-preserving procedure of the first MTP joint were analyzed radiographically and clinically. Average follow-up was 42 (range, 12-111) months. Twenty feet had Ludloff osteotomies, 15 had scarf osteotomies, and 2 had chevron osteotomies. Radiographs were evaluated preoperatively and postoperatively for hallux valgus angle, 1-2 intermetatarsal angle, and degenerative narrowing of the first MTP joint based the Sharp score and the Larsen grade. Narrowing of the first interphalangeal (IP) joint was based on a modification of the classification of Hattrup and Johnson. Operative complications and required secondary surgeries were tabulated. Clinical outcomes were measured using preoperative and postoperative Short Form-36 (SF-36), AOFAS forefoot scale, and Visual Analogue Scale (VAS) pain questionnaires. RESULTS: The average hallux valgus angle improved from 37 degrees preoperatively to 15 degrees postoperatively. The average 1-2 intermetatarsal angle improved from 14 degrees preoperatively to 5 degrees postoperatively. The average Sharp score of the first MTP joint was 0.9 preoperatively and 1.6 postoperatively. The average Larsen grade of the first MTP joint was 0.6 preoperatively and 1.4 postoperatively. Range of motion of the first MTP joint was essentially unchanged between preoperative and postoperative measurements. Seven of 37 feet had progression of first IP joint space narrowing, but none were symptomatic. The AOFAS score improved from 45.2 preoperatively to 82.6 at final follow-up (P value < .01). The VAS decreased from 4.8 preoperatively to 1.5 at final follow-up (P value < .02). The SF-36 physical component score decreased from 40.3 preoperatively to 37.4 at final follow-up, and the mental component score remained unchanged, and neither was statistically significant. There were 7 feet (19%) that required a return to surgery: 3 wound infections, 2 arthrodeses for progression of deformity, and 1 each for revision for recurrence and hardware removal. CONCLUSION: Rheumatoid arthritis patients who undergo a bunionectomy rather than arthrodesis to preserve the first MTP joint have satisfactory clinical and radiographic outcomes. This procedure appeared to be a reasonable alternative to first MTP arthrodesis in patients with relatively preserved joints. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 23945522 TI - Episodes of microbial keratitis with therapeutic silicone hydrogel bandage soft contact lenses. AB - OBJECTIVE: To report the therapeutic practice patterns of silicone hydrogel (SiH) bandage soft contact lenses (BSCL) and the resultant rate of microbial keratitis (MK). METHODS: A retrospective case series of patients treated with therapeutic BSCLs for ocular surface disease from January 2006 to January 2009 in a tertiary care cornea practice. All patients had a history of ocular surface disease. RESULTS: Seventy-four patients were treated with a therapeutic SiH BSCL (102 intervals of use) for complicated ocular surface disease. Two patients developed infectious corneal infiltrates (2/102, 2.0%) [corrected]. Two of 3 MK episodes were in patients with limbal stem-cell deficiency (2/102, 2.0%). CONCLUSIONS: Therapeutic SiH BSCLs were safely used in most patients. However, results suggest that prophylactic antibiotic use did not eliminate the risk for MK with SiH BSCL use in patients with chronic ocular surface disease. PMID- 23945523 TI - Release of N-acetylcysteine and N-acetylcysteine amide from contact lenses. AB - OBJECTIVE: To investigate the use of contact lenses to release N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) that have frequently used for the treatment of some eye diseases. METHODS: Three commercial contact lenses were used: Soflens Multi-Focal, 1-Day ACUVUE TruEye, and Frequency 55. All contact lenses were individually kept for 3 days in 10 mL of 3 mM NAC or NACA solutions in phosphate-buffered saline (PBS). After the loading period, the lenses were removed from the solution and put into 5 mL of PBS for 3 days (static mode). During this period, samples were taken at specified times and analyzed by high pressure liquid chromatography. RESULTS: From the release profiles of NAC and NACA, it was found that both NAC and NACA could be released from the lenses within 72 hours. Frequency 55 released 95.9%+/-2.7% of loaded NAC and 60.0%+/ 2.1% of loaded NACA in 24 hours, whereas 1-Day ACUVUE TruEye released 80.9%+/ 1.2% of loaded NAC and 54.0%+/-1.9% of loaded NACA and Soflens Multi-Focal released 72.8%+/-2.8% of loaded NAC and 51.9%+/-2.3% of loaded NACA during that same period. CONCLUSIONS: The lenses could achieve the appropriate delivery of drugs during their intended time of wear. The amount of released NACA was less than that of NAC because of the more hydrophobic structure of NACA. According to the power law, the values of the exponential constant n were found to be below 0.5, indicating that the behavior observed was "less Fickian". PMID- 23945524 TI - Sutureless amniotic membrane ProKera for ocular surface disorders: short-term results. AB - OBJECTIVE: To evaluate the indications and outcomes of sutureless amniotic membrane transplant (AMT; ProKera) in the management of ocular surface disorders. METHODS: Chart review of patients who had ProKera (Bio-Tissue, Inc.) implantation for ocular surface disorders between June 2008 and May 2012 at 3 ophthalmology practices in Philadelphia, PA. The parameters evaluated included age, sex, indication for AMT, any other combined procedure, duration of retention of amniotic membrane, the effect of amniotic membrane on ocular surface healing, follow-up time, and complications. RESULTS: There were 35 eyes of 33 patients with a mean age of 68.2+/-19.5 years (range: 17-99 years). There were 25 male patients, and median follow-up was 110 days (mean: 164.6 days; range: 30-960 days). The indication for insertion of ProKera was nonhealing corneal ulcers of infective origin (group 1) in 9 eyes (25.7%), neurotrophic keratopathy (group 2) in 11 eyes (31.4%), chemical injury (group 3) in 5 eyes (14.3%), and other indications (group 4) in 10 eyes (28.6%). Complete or partial success was seen in a total of 44%, 64%, 80%, and 70% eyes in groups 1 to 4, respectively. Discomfort with the device was seen in 6 (17.1%) of 35 eyes, and recurrence of primary pathologic condition occurred in 5 (14.3%) of 35 eyes. CONCLUSION: ProKera treatment is easy to use and reasonably well tolerated, with moderate success in corneal ulcers and encouraging results in acute moderate chemical injury. Recurrence of primary pathologic condition is seen particularly associated with neurotrophic keratitis and dry eye syndrome. PMID- 23945525 TI - Polymicrobial versus monomicrobial keratitis: a retrospective comparative study. AB - OBJECTIVES: To compare the risk factors, clinical characteristics, microbiological profile, and treatment outcomes of polymicrobial versus monomicrobial keratitis. METHODS: In this retrospective comparative case series, eyes with polymicrobial and monomicrobial keratitis were identified from microbiological records at a tertiary academic referral center, from January 2002 to December 2010. Only culture positive cases were included. Eyes with infectious keratitis involving two or more pathogens were included in the polymicrobial group, whereas eyes infected solely by Pseudomonas aeruginosa were included in the monomicrobial group. Various parameters including demographics, risk factors, clinical and microbiological characteristics, and treatment outcomes were analyzed. RESULTS: Twenty-one eyes each with polymicrobial and monomicrobial keratitis were included in this study. The mean age of polymicrobial patients was significantly higher than monomicrobials. Use of contact lens was the commonest predisposing factor in both groups. Systemic (23.8%) and multiple (33.3%) risk factors were involved in eyes with polymicrobial keratitis only. The mean size of corneal infiltrates and mean duration for resolvement of infection were significantly greater in the polymicrobial group. Medical treatment was successful only in 80.9% eyes with polymicrobial keratitis, whereas all monomicrobial keratitis patients responded to it. A total of 44 organisms belonging to 18 species (bacteria = 13, fungi = 5) were isolated from the polymicrobial group. P. aeruginosa and Candida albicans were the most frequently isolated bacteria (n = 12) and fungi (n = 5), respectively. In the polymicrobial group, gram-negative organisms were most sensitive to gentamicin (87.8%), followed by ciprofloxacin (78.7%), whereas gram-positive organisms were 100% sensitive to ciprofloxacin and cefazolin. CONCLUSIONS: A high index of suspicion of polymicrobial keratitis should be made in patients with multiple and systemic risk factors. Contact lens usage was the most common risk factor in both groups. Size of corneal infiltrate is a fairly reliable indicator for suspecting polymicrobial keratitis. Prolonged course of the disease and decreased antibiotic sensitivity were the other notable features of polymicrobial keratitis. PMID- 23945527 TI - Microscopic characterisation of suspended graphene grown by chemical vapour deposition. AB - We present a multi-technique characterisation of graphene grown by chemical vapour deposition (CVD) and thereafter transferred to and suspended on a grid for transmission electron microscopy (TEM). The properties of the electronic band structure are investigated by angle-resolved photoelectron spectromicroscopy, while the structural and crystalline properties are studied by TEM and Raman spectroscopy. We demonstrate that the suspended graphene membrane locally shows electronic properties comparable with those of samples prepared by micromechanical cleaving of graphite. Measurements show that the area of high quality suspended graphene is limited by the folding of the graphene during the transfer. PMID- 23945528 TI - Comparison of irradiated versus nonirradiated DIEP flaps in patients undergoing immediate bilateral DIEP reconstruction with unilateral postmastectomy radiation therapy (PMRT). AB - INTRODUCTION: Patients with node positive or locally advanced breast cancer desiring deep inferior epigastric perforator (DIEP) flap reconstruction frequently require postmastectomy radiation therapy (PMRT). To avoid the deleterious effects of PMRT, surgeons will often delay reconstruction until after PMRT is complete. Drawbacks to this approach include additional surgery, recuperation, cost, and an extended reconstructive process. Even if a tissue expander is used to preserve the skin envelope during irradiation, the post-PMRT breast pocket is often distorted or constricted necessitating some skin replacement, resulting in a compromised aesthetic outcome. Therefore, a systematic approach to mitigate the deleterious effects of PMRT was developed, and primary DIEP flap reconstruction was offered to patients requiring PMRT. This study evaluates the outcome of this approach in a cohort of patients undergoing immediate bilateral DIEP flap reconstruction with unilateral PMRT, allowing comparison between irradiated and nonirradiated flaps. METHODS: One hundred twenty-five patients who underwent immediate DIEP reconstruction between 2009 and 2011 were identified. Eleven consecutive patients had bilateral DIEP reconstructions by a single surgeon and received unilateral PMRT. Preoperative, intraoperative, and postoperative steps were taken in all patients to ensure flap vascularity, prevent uncontrolled contracture, and limit radiation damage to the breast mound. Results were documented photographically and the irradiated and nonirradiated breasts were compared. The complication rates, incidence of clinically significant fat necrosis, and need for reoperation were examined. RESULTS: Median follow-up was 18 months (range, 8-21 months). Complications were minor and did not require readmission to the hospital or reoperation. There was no incidence of clinically significant fat necrosis in either the irradiated or nonirradiated DIEP flaps. Four operative revisions for breast symmetry were required in 3 of 11 patients. Aesthetic outcomes were deemed satisfactory in all patients. CONCLUSIONS: Primary reconstruction with DIEP flaps can be performed successfully in patients who require PMRT if steps are taken to ensure flap vascularity, minimize fibrosis, optimize contour, and modulate radiation dosing. PMID- 23945529 TI - Optimizing the fascial closure: an analysis of 1261 abdominally based free flap reconstructions. AB - BACKGROUND: Donor-site morbidity continues to be a significant complication in patients undergoing abdominally based breast reconstruction. The purposes of our study were to critically examine abdominal donor-site morbidity and to present our algorithm for optimizing donor site closure to reduce these complications. METHODS: We performed a retrospective cohort study examining all patients undergoing abdominally based free tissue transfer for breast reconstruction from 2005 to 2011 at our institution. Data were analyzed for overall donor site morbidity, as defined by hernia/bulge or reoperation for debridement and/or mesh removal and for hernia/bulge alone. RESULTS: A total of 812 patients underwent 1261 free tissue transfers. Fifty-three patients (6.5%) experienced donor-site morbidity, including 27 hernias/bulges (3.3%). No significant difference in overall abdominal morbidity was found between unilateral and bilateral reconstructions (P = 0.39) or the use of muscle in the flap (P = 0.11 unilateral msfTRAM, P = 0.76 bilateral). Prior lower abdominal surgery was associated with higher rates of donor-site morbidity (P = 0.04); hypertension (P = 0.012) and multiple medical comorbidities (P < 0.001) were also significantly more common in these patients. Obesity was the only patient characteristic associated with higher rates of hernia/bulge (P = 0.04). Delayed abdominal would healing was associated with hernia/bulge (P < 0.001); these patients were significantly more likely to develop this complication (odds ratio = 6.3, P < 0.001). CONCLUSIONS: Particular attention must be provided to donor-site closure in obese patients and those with hypertension and multiple medical comorbidities. Low rates of abdominal wall morbidity result from meticulous fascial reconstruction and reinforcement and careful attention to tension-free soft tissue closure. PMID- 23945530 TI - Predicting abdominal closure after component separation for complex ventral hernias: maximizing the use of preoperative computed tomography. AB - BACKGROUND: Component separation techniques (CSTs) have allowed for midline fascial reapproximation in large midline ventral hernias. In certain cases, however, fascial apposition is not feasible, resulting in a bridged repair that is suboptimal. Previous estimates on myofascial advancement are based on hernia location and do not take into account variability between patients. Examination of preoperative computed tomography (CT) may provide insight into these variabilities and may allow for prediction of abdominal closure with CST. STUDY DESIGN: A retrospective review was conducted of patients who underwent abdominal wall reconstruction from 2007 to 2012 with CST. Preoperative CT was obtained, and specific parameters were analyzed using image analysis software. Logistic regression was used to predict ideal operative closure. Multivariate analyses were adjusted for age and sex. An a priori value was set at P < 0.05. RESULTS: Fifty-four patients met the criteria and had preoperative CT available for analysis. Forty-eight patients had fascial reapproximation achieved, whereas 6 patients had a bridged repair. Age, sex, weight, and body mass index were similar between groups (P > 0.05). Significant differences were seen between groups in 3 variables: transverse defect size (19.8 vs 10 cm, P < 0.05), defect area (420 vs 184.2 cm, P < 0.05), and percent abdominal wall defect (18.9% vs 10.6%, P < 0.05). CONCLUSIONS: Preoperative determination of abdominal wall defect ratios and hernia defect areas may represent a more accurate method to predict abdominal wall closure after CST. Predicting midline approximation after CST is critical because outcomes after bridged repair can result in higher recurrence rates. PMID- 23945531 TI - Complex abdominal wall reconstruction: an outcomes review. AB - BACKGROUND: Complex abdominal wall reconstruction (AWR) remains challenging. Techniques for repair are numerous and include primary fascial approximation, separation of components (SOC), and use of various biologic and synthetic meshes. Given the vast expanse of available techniques and lack of consistent algorithms, an analysis of outcomes in AWR is presented. METHODS: A retrospective review was performed of complex AWRs performed by 2 surgeons at a single institution from July 2008 to October of 2011. Outcome differences for hernia repairs specifically addressing SOC with an acellular dermis inlay (retrorectus), underlay, or overlay mesh, as well as interposition biologic mesh placement were included. RESULTS: A total of 66 patients were identified. The average body mass index in this population was 35.5 kg/m. The average age was 53.7 years, with 62% females and 38% males. The overall rate of tobacco use history was 48%. Twenty-eight percent were diabetic. The overall hernia recurrence rate was 16%. Patients having SOC with inlay (retrorectus) mesh had a hernia recurrence rate of 9%. Hernia recurrence in those with SOC and biologic mesh reinforcement as an underlay or onlay was 12%; in those without mesh reinforcement, 22%; and for those with a biologic mesh interposition, 40%. CONCLUSIONS: The results of this review show that hernia recurrence rates are decreased with primary fascial repair. Further reduction occurs when biologic mesh reinforcement is used. The lowest recurrence rates were seen in the group with SOC and a porcine biologic mesh inlay. Abdominal wall reconstruction is challenging and with continued outcomes review a refined algorithm can be achieved. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic: III. PMID- 23945532 TI - Revision of Wise pattern breast reductions with vertical procedures. AB - A small percentage of patients who undergo Wise pattern mammaplasties request revisions to address recurrent macromastia or poor breast shape. Reuse of the Wise pattern method at times results in disappointing aesthetic results. Recently, in a series of 15 consecutive patients, we used vertical techniques with glandular reshaping to perform these revisions. Advantages include the ability to significantly improve breast shape and to avoid reopening of potentially problematic inframammary scars. No major complications occurred. Patients have been uniformly pleased with the significant improvement in their breast contour, width, and size. In summary, despite the use of the Wise pattern method for the original procedure, consideration should be given to use vertical techniques for revisions in that they are safe and can better address patient goals. Gratifying results can be achieved. PMID- 23945534 TI - An analysis of leading, lagging, and coincident economic indicators in the United States and its relationship to the volume of plastic surgery procedures performed: an update for 2012. AB - BACKGROUND: As physician compensation and reimbursement tightens throughout the United States, it is important for physicians to be aware of the influence that the economic environment has on the unique medical field of plastic and reconstructive surgery. This study will attempt to determine a relationship between the volume of different plastic surgical procedures and various economic indicators. METHODS: Information from the American Society of Plastic Surgeons' annual reports on plastic surgery statistics available on the Internet (http://www.plasticsurgery.org/Media/Statistics.html) was collected from the years 2000 through 2011. Yearly economic indicators were collected from readily available Web sites. RESULTS: In terms of the total number of plastic surgery procedures performed, there was a significant positive relationship with GDP, GDP per capita, personal income, consumer price index (CPI) (all), and CPI (medical), and a significant negative relationship with the issuance of new home permits. There was a significant positive relationship with total cosmetic procedures and GDP, GDP per capita, personal income, CPI (all), and CPI (medical), and a significant negative relationship with the issuance of new home permits. There was a significant positive relationship between cosmetic surgical procedures and the issuance of new home permits and the average prime rate charged by banks. There was a significant positive relationship with cosmetic minimally invasive procedures and GDP, GDP per capita, personal income, CPI (all), and CPI (medical), and a significant negative relationship with the issuance of new home permits. There was a significant negative relationship between reconstructive procedures and GDP, GDP per capita, personal income, CPI (all), and CPI (medical). CONCLUSIONS: Cosmetic minimally invasive procedures involve less downtime, are generally less expensive than surgical options, and are widely available, making it easier for patients to decide on them quickly during good economic times. Furthermore, it is apparent that plastic surgeons must be proficient at performing minimally invasive cosmetic procedures to maintain a clientele and offer patients a more affordable option during tough economic times. This may lead to further business growth during more favorable economic times. PMID- 23945533 TI - A novel pilot study using spatial frequency domain imaging to assess oxygenation of perforator flaps during reconstructive breast surgery. AB - INTRODUCTION: Although various methods exist for monitoring flaps during reconstructive surgery, surgeons primarily rely on assessment of clinical judgment. Early detection of vascular complications improves rate of flap salvage. Spatial frequency domain imaging (SFDI) is a promising new technology that provides oxygenation images over a large field of view. The goal of this clinical pilot study is to use SFDI in perforator flap breast reconstruction. METHODS: Three women undergoing unilateral breast reconstruction after mastectomy were enrolled for our study. The SFDI system was deployed in the operating room, and images acquired over the course of the operation. Time points included images of each hemiabdominal skin flap before elevation, the selected flap after perforator dissection, and after microsurgical transfer. RESULTS: Spatial frequency domain imaging was able to measure tissue oxyhemoglobin concentration (ctO2Hb), tissue deoxyhemoglobin concentration, and tissue oxygen saturation (stO2). Images were created for each metric to monitor flap status and the results quantified throughout the various time points of the procedure. For 2 of 3 patients, the chosen flap had a higher ctO2Hb and stO2. For 1 patient, the chosen flap had lower ctO2Hb and stO2. There were no perfusion deficits observed based on SFDI and clinical follow-up. CONCLUSIONS: The results of our initial human pilot study suggest that SFDI has the potential to provide intraoperative oxygenation images in real-time during surgery. With the use of this technology, surgeons can obtain tissue oxygenation and hemoglobin concentration maps to assist in intraoperative planning; this can potentially prevent complications and improve clinical outcome. PMID- 23945535 TI - Practice gaps: Delayed treatment and inadequate surgical margins for invasive melanoma in elderly patients. PMID- 23945537 TI - Comments on Varela-Mato, V.; Cancela, J.M.; Ayan, C.; Martin, V.; Molina, A. Lifestyle and health among Spanish university students: differences by gender and academic discipline. Int. J. Environ. Res. Public Health 2012, 9, 2728-2741. PMID- 23945538 TI - Response to Crespo et al. Comments on: Varela-Mato, V.; et al. Lifestyle and health among Spanish university students: differences by gender and academic discipline. Int. J. Environ. Res. Public Health 2012, 9, 2728-2741. PMID- 23945539 TI - Effects of compulsory schooling on mortality: evidence from Sweden. AB - Theoretically, there are several reasons to expect education to have a positive effect on health. Empirical research suggests that education can be an important health determinant. However, it has not yet been established whether education and health are indeed causally related, and the effects found in previous studies may be partially attributable to methodological weaknesses. Moreover, existing evidence on the education-health relationship generally uses information of fairly recent schooling reforms, implying that health outcomes are observed only over a limited time period. This paper examines the effect of education on mortality using information on a national roll-out of a reform leading to one extra year of compulsory schooling in Sweden. In 1936, the national government made a seventh school year compulsory; however, the implementation was decided at the school district level, and the reform was implemented over 12 years. Taking advantage of the variation in the timing of the implementation across school districts, by using county-level proportions of reformed districts, census data and administrative mortality data, we find that the extra compulsory school year reduced mortality. In fact, the mortality reduction is discernible already before the age of 30 and then grows in magnitude until the age of 55-60. PMID- 23945540 TI - Children's lifestyles pose "unacceptable" cardiovascular risk, warns charity. PMID- 23945541 TI - Cryptomarasmius gen. nov. established in the Physalacriaceae to accommodate members of Marasmius section Hygrometrici. AB - Phylogenetic placement of the infrageneric section Hygrometrici (genus Marasmius sensu stricto) in prior molecular phylogenetic studies have been unresolved and problematical. Molecular analyses based on newly generated ribosomal nuc-LSU and 5.8S sequences resolve members of section Hygrometrici to the family Physalacriaceae. The new genus Cryptomarasmius is proposed to accommodate members of Marasmius section Hygrometrici. Fourteen species belonging to section Hygrometrici whose available type specimens bear morphological features corresponding to the new genus are formally combined in Cryptomarasmius. Taxonomic transfers are made only for taxa in which type specimens have been studied and/or representative material sequenced. Although other species placed in section Hygrometrici may belong in Cryptomarasmius, further transfers are not proposed until additional studies on type material are conducted. PMID- 23945542 TI - The mixing effect of amine and carboxyl groups on electrorheological properties and its analysis by in situ FT-IR under an electric field. AB - Herein, the mixing effect of amine and carboxyl groups on electrorheological (ER) properties has been presented with the chitosan and alginic acid dispersed suspensions. Chitosan (for the amine group) and alginic acid (for the carboxyl group) are used to investigate the mixing effect of the amine and carboxyl groups on ER properties with the control of their mixing ratio in the silicone oil. The surface-chemical structure of the mixture of the chitosan and alginic acid particles in the silicone oil is demonstrated by in situ Fourier transform infrared (FT-IR) spectroscopy at various electric fields for the first time. This study focuses on whether the mixture of chemical groups in the ER fluid can promote ER properties or not, and in situ FT-IR analysis of the interface between ER particles in the silicone oil at various DC electric fields. The ER fluids exhibited the increase of the yield stress values with the increase of the counter group addition up to the weight ratio of 50 : 50 (chitosan : alginic acid). A noteworthy result is that the mixing effect of the amine and carboxyl groups resulting in enhanced ER properties is clearly proved. In the in situ FT IR study, the complex form of amine and carboxyl groups of particles in the ER fluid was confirmed under the electric field. PMID- 23945543 TI - Oligoclonal expansions of mucosal T cells in Crohn's disease predominate in NKG2D expressing CD4 T cells. AB - Crohn's disease (CD) is an inflammatory pathology of the mucosal intestine that results from uncontrolled immune response towards commensal microbes. Clonal expansions of T cells have been found in patients with CD suggesting an antigen specific stimulation of pathogenic T cells. Here we show, using T-cell receptor repertoire analysis by real-time PCR, that oligoclonal expansions are found in both CD8+ and CD4+ T cells in the blood and intestinal mucosa of CD patients. The majority of CD4+ T-cell-expanded clones are CD4+NKG2D+ T cells. These clonal expansions were found in both inflamed and neighboring healthy tissue and were persisting during the course of the disease. The presence of these CD4+NKG2D+ T cell clones at the macroscopically normal edge of the surgical resection might be predictive of inflammation relapse post surgery. PMID- 23945544 TI - Amelioration of ovalbumin-induced allergic airway disease following Der p 1 peptide immunotherapy is not associated with induction of IL-35. AB - In the present study, we show therapeutic amelioration of established ovalbumin (OVA)-induced allergic airway disease following house dust mite (HDM) peptide therapy. Mice were sensitized and challenged with OVA and HDM protein extract (Dermatophagoides species) to induce dual allergen sensitization and allergic airway disease. Treatment of allergic mice with peptides derived from the major allergen Der p 1 suppressed OVA-induced airway hyperresponsiveness, tissue eosinophilia, and goblet cell hyperplasia upon rechallenge with allergen. Peptide treatment also suppressed OVA-specific T-cell proliferation. Resolution of airway pathophysiology was associated with a reduction in recruitment, proliferation, and effector function of T(H)2 cells and decreased interleukin (IL)-17+ T cells. Furthermore, peptide immunotherapy induced the regulatory cytokine IL-10 and increased the proportion of Fox p3+ cells among those expressing IL-10. Tolerance to OVA was not associated with increased IL-35. In conclusion, our results provide in vivo evidence for the creation of a tolerogenic environment following HDM peptide immunotherapy, leading to the therapeutic amelioration of established OVA-induced allergic airway disease. PMID- 23945545 TI - Pregnancy-specific glycoprotein 1 (PSG1) activates TGF-beta and prevents dextran sodium sulfate (DSS)-induced colitis in mice. AB - Transforming growth factor-betas (TGF-betas) are secreted from cells as latent complexes and the activity of TGF-betas is controlled predominantly through activation of these complexes. Tolerance to the fetal allograft is essential for pregnancy success; TGF-beta1 and TGF-beta2 play important roles in regulating these processes. Pregnancy-specific beta-glycoproteins (PSGs) are present in the maternal circulation at a high concentration throughout pregnancy and have been proposed to have anti-inflammatory functions. We found that recombinant and native PSG1 activate TGF-beta1 and TGF-beta2 in vitro. Consistent with these findings, administration of PSG1 protected mice from dextran sodium sulfate (DSS) induced colitis, reduced the secretion of pro-inflammatory cytokines, and increased the number of T regulatory cells. The PSG1-mediated protection was greatly inhibited by the coadministration of neutralizing anti-TGF-beta antibody. Our results indicate that proteins secreted by the placenta directly contribute to the generation of active TGF-beta and identify PSG1 as one of the few known biological activators of TGF-beta2. PMID- 23945547 TI - Cationic Group-IV pincer-type complexes for polymerization and hydroamination catalysis. AB - Neutral Zr(IV) and Hf(IV) dimethyl complexes stabilized by unsymmetrical dianionic {N,C,N'} pincer ligands have been prepared from their corresponding bis amido complexes upon treatment with AlMe3. Their structure consists of a central sigma-bonded aryl donor group (C) capable of forming robust M-C bonds with the metal center, enforced by the synergic effect of both the coordination of peripheral donor groups (N) and the chelating rigid structure of the {N,C,N} ligand framework. Such a combination translates into systems having a unique balance between stability and reactivity. These Zr(IV) and Hf(IV) dimethyl complexes were converted in situ into cationic species [M(IV){N(-),C( ),N}Me][B(C6F5)4] which are active catalysts for the room temperature (r.t.) intramolecular hydroamination/cyclization of primary and secondary aminoalkenes as well as for the high temperature ethylene-1-octene copolymerizations. PMID- 23945546 TI - The intestinal micro-environment imprints stromal cells to promote efficient Treg induction in gut-draining lymph nodes. AB - De novo induction of Foxp3+ regulatory T cells (Tregs) is particularly efficient in gut-draining mesenteric and celiac lymph nodes (mLN and celLN). Here we used LN transplantations to dissect the contribution of stromal cells and environmental factors to the high Treg-inducing capacity of these LN. After transplantation into the popliteal fossa, mLN and celLN retained their high Treg inducing capacity, whereas transplantation of skin-draining LN into the gut mesenteries did not enable efficient Treg induction. However, de novo Treg induction was abolished in the absence of dendritic cells (DC), indicating that this process depends on synergistic contributions of stromal and DC. Stromal cells themselves were influenced by environmental signals as mLN grafts taken from germ-free donors and celLN grafts taken from vitamin A-deficient donors did not show any superior Treg-inducing capacity. Collectively, our observations reveal a hitherto unrecognized role of LN stromal cells for the de novo induction of Foxp3+ Tregs. PMID- 23945549 TI - Light induced DNA-protein conjugation. AB - DNA was modified with a photo-reactive caged diene allowing for the modification of dienophile containing proteins under mild irradiation conditions to afford fully functional DNA-protein conjugates. PMID- 23945551 TI - Body composition, muscle capacity, and physical function in older adults: an integrated conceptual model. AB - The aging process leads to adverse changes in body composition (increases in fat mass and decreases in skeletal muscle mass), declines in physical function (PF), and ultimately increased risk for disability and loss of independence. Specific components of body composition or muscle capacity (strength and power) may be useful in predicting PF; however, findings have been mixed regarding the most salient predictor of PF. The development of a conceptual model potentially aids in understanding the interrelated factors contributing to PF with the factors of interest being physical activity, body composition, and muscle capacity. This article also highlights sex differences in these domains. Finally, factors known to affect PF, such as sleep, depression, fatigue, and self-efficacy, are discussed. Development of a comprehensive conceptual model is needed to better characterize the most salient factors contributing to PF and to subsequently inform the development of interventions to reduce physical disability in older adults. PMID- 23945552 TI - Ocular vestibular evoked myogenic potentials in response to air-conducted sound and bone-conducted vibration in vestibular schwannoma. AB - OBJECTIVE: To clarify the origin and pathways of ocular vestibular evoked myogenic potentials (oVEMPs) to air-conducted sound (ACS), we compared the results of oVEMPs with ACS, with oVEMPs with bone-conducted vibration (BCV), cervical VEMPs (cVEMPs) with ACS, and the caloric test in patients with unilateral vestibular schwannoma (VS). STUDY DESIGN: Retrospective review. SETTING: Tertiary referral center. PATIENTS: Forty-five patients with untreated unilateral VS. MAIN OUTCOME MEASURE: Each patient underwent vestibular tests, including oVEMPs to ACS, oVEMPs to BCV, cVEMPs to ACS, and caloric tests. The correlations among these tests were evaluated. RESULTS: Of the 45 patients recruited, 28 patients (63%) showed reduced or absent oVEMPs to ACS solely on the affected side. There were no significant differences in abnormal response ratios among oVEMPs to ACS, oVEMPs to BCV, cVEMPs to ACS, or the caloric test. The results of oVEMPs to ACS had a significant correlation with those of oVEMPs to BCV and the caloric test (p < 0.05) but not with those of cVEMPs to ACS (p > 0.05). CONCLUSION: These findings support the hypothesis that oVEMP in response to ACS are predominantly mediated by the superior vestibular nerve and probably reflect the function of the utricle. PMID- 23945559 TI - Physico-chemical properties and phase behavior of the ionic liquid-beta cyclodextrin complexes. AB - The solubility of beta-cyclodextrin (beta-CD) in ionic liquids (ILs) and the activity coefficients at infinite dilution (gamma13(infinity)) of more than 20 solutes (alkanes, aromatic hydrocarbons, alcohols) were measured in four chosen ionic liquids, their mixtures with beta-CD, and in the beta-CD at high temperatures from 338 to 398 K using the inverse gas chromatography. The intermolecular interactions, inclusion complexes and the possible increasing of the solubility of beta-CD in water using the IL are presented. The solubility of beta-CD in ten chosen hydrophobic ILs at the temperature T = 423 K was detected. The solid-liquid phase diagrams (SLE) of {IL (1) + beta-CD (2)} binary systems at the high mole fraction of the IL were measured for three systems (1-ethyl-3 methylimidazolium chloride, [EMIM][Cl], 1-ethyl-3-methylimidazolium bromide, [EMIM][Br]; and for 1-butyl-3-methylimidazolium chloride, [BMIM][Cl]). The eutectic points were determined at the high IL concentration for all binary systems. The intermolecular interaction and the possibility of inclusion complexes of the IL and/or solvents with beta-CD were discussed. The infrared spectroscopy, IR was used for the description of the intermolecular interactions in the (beta-CD + IL) systems. It was shown via the activity coefficients at infinite dilution results that the inclusion complexes are dependent on the temperature. The addition of beta-CD to the IL does not improve the selectivity of the separation of the aliphatics from aromatics. PMID- 23945560 TI - Androgen receptor phosphorylation at serine 308 and serine 791 predicts enhanced survival in castrate resistant prostate cancer patients. AB - We previously reported that AR phosphorylation at serine 213 was associated with poor outcome and may contribute to prostate cancer development and progression. This study investigates if specific AR phosphorylation sites have differing roles in the progression of hormone naive prostate cancer (HNPC) to castrate resistant disease (CRPC). A panel of phosphospecific antibodies were employed to study AR phosphorylation in 84 matched HNPC and CRPC tumours. Immunohistochemistry measured Androgen receptor expression phosphorylated at serine residues 94 (pAR94), 308 (pAR308), 650(pAR650) and 791 (pAR791). No correlations with clinical parameters were observed for pAR94 or pAR650 in HNPC or CRPC tumours. In contrast to our previous observation with serine 213, high pAR308 is significantly associated with a longer time to disease specific death (p = 0.011) and high pAR791 expression significantly associated with a longer time to disease recurrence (p = 0.018) in HNPC tumours and longer time to death from disease recurrence (p = 0.040) in CRPC tumours. This observation in CRPC tumours was attenuated in high apoptotic tumours (p = 0.022) and low proliferating tumours (p = 0.004). These results demonstrate that understanding the differing roles of AR phosphorylation is necessary before this can be exploited as a target for castrate resistant prostate cancer. PMID- 23945561 TI - Molecular and functional analyses of the fast skeletal myosin light chain2 gene of the Korean oily bitterling, Acheilognathus koreensis. AB - We identified and characterized the primary structure of the Korean oily bitterling Acheilognathus koreensis fast skeletal myosin light chain 2 (Akmlc2f), gene. Encoded by seven exons spanning 3955 bp, the deduced 168-amino acid AkMLC2f polypeptide contained an EF-hand calcium-binding motif and showed strong homology (80%-98%) with the MLC2 proteins of Ictalurus punctatus and other species, including mammals. Akmlc2f mRNA was highly enriched in skeletal muscles, and was detectable in other tissues. The upstream regions of Akmlc2f included a TATA box, one copy of a putative MEF-2 binding site and several putative C/EBPbeta binding sites. The functional activity of the promoter region of Akmlc2f was examined using luciferase and red fluorescent protein reporters. The Akmlc2f promoter driven reporter expressions were detected and increased by the C/EBPbeta transcription factor in HEK293T cells. The activity of the promoter of Akmlc2f was also confirmed in the developing zebrafish embryo. Although the detailed mechanism underlying the expression of Akmlc2f remains unknown, these results suggest the muscle-specific expression of Akmlc2f transcript and the functional activation of Akmlc2f promoter by C/EBPbeta. PMID- 23945563 TI - Highly bright multicolor tunable ultrasmall beta-Na(Y,Gd)F4:Ce,Tb,Eu/beta-NaYF4 core/shell nanocrystals. AB - Herein, we report highly bright multicolor-emitting beta-Na(Y,Gd)F4:Ce,Tb,Eu/beta NaYF4 nanoparticles (NPs) with precise color tunability. First, highly bright sub 20 nm beta-Na(Y,Gd)F4:Ce,Tb,Eu NPs were synthesized via a heating-up method. By controlling the ratio of Eu(3+) to Tb(3+), we generated green, yellow-green, greenish yellow, yellow, orange, reddish orange, and red emissions from the NP solutions via energy transfer of Ce(3+)-> Gd(3+)-> Tb(3+) (green) and Ce(3+)-> Gd(3+)-> Tb(3+)-> Eu(3+) (red) ions under ultraviolet light illumination (254 nm). Because of Ce(3+) and Gd(3+) sensitization, Tb(3+) ions exhibited strong green emission. The decay time of Tb(3+) emission decreased from 4.0 to 1.4 ms as the Eu(3+) concentration was increased, suggesting that energy was transferred from Tb(3+) to Eu(3+). As a result, Eu(3+) emission peaks were generated and the emission color was transformed from green to red. Monodisperse sub-6 nm beta Na(Y,Gd)F4:Ce,Tb,Eu NPs were synthesized through a simple reduction of the reaction temperature. Although fine color tunability was retained, their brightness was considerably decreased owing to an increase in the surface-to volume ratio. The formation of a beta-NaYF4 shell on top of the sub-6 nm NP core to produce beta-Na(Y,Gd)F4:Ce,Tb,Eu/beta-NaYF4 significantly increased the emission intensity, while maintaining the sub-10 nm sizes (8.7-9.5 nm). Quantum yields of the ultrasmall NPs increased from 1.1-6.9% for the core NPs to 6.7 44.4% for the core/shell NPs. Moreover, highly transparent core/shell NP polydimethylsiloxane (PDMS) composites featuring a variety of colors, excellent color tunability, and high brightness were also prepared. PMID- 23945564 TI - Comment on "On the dual emission of p-dimethylaminobenzonitrile and its photophysical implications". PMID- 23945562 TI - Folding and biogenesis of mitochondrial small Tim proteins. AB - Correct and timely folding is critical to the function of all proteins. The importance of this is illustrated in the biogenesis of the mitochondrial intermembrane space (IMS) "small Tim" proteins. Biogenesis of the small Tim proteins is regulated by dedicated systems or pathways, beginning with synthesis in the cytosol and ending with assembly of individually folded proteins into functional complexes in the mitochondrial IMS. The process is mostly centered on regulating the redox states of the conserved cysteine residues: oxidative folding is crucial for protein function in the IMS, but oxidized (disulfide bonded) proteins cannot be imported into mitochondria. How the redox-sensitive small Tim precursor proteins are maintained in a reduced, import-competent form in the cytosol is not well understood. Recent studies suggest that zinc and the cytosolic thioredoxin system play a role in the biogenesis of these proteins. In the IMS, the mitochondrial import and assembly (MIA) pathway catalyzes both import into the IMS and oxidative folding of the small Tim proteins. Finally, assembly of the small Tim complexes is a multistep process driven by electrostatic and hydrophobic interactions; however, the chaperone function of the complex might require destabilization of these interactions to accommodate the substrate. Here, we review how folding of the small Tim proteins is regulated during their biogenesis, from maintenance of the unfolded precursors in the cytosol, to their import, oxidative folding, complex assembly and function in the IMS. PMID- 23945566 TI - LC/ESI-MS/MS detection of FAs by charge reversal derivatization with more than four orders of magnitude improvement in sensitivity. AB - Quantitative analysis of fatty acids (FAs) is an important area of analytical biochemistry. Ultra high sensitivity FA analysis usually is done with gas chromatography of pentafluorobenzyl esters coupled to an electron-capture detector. With the popularity of electrospray ionization (ESI) mass spectrometers coupled to liquid chromatography, it would be convenient to develop a method for ultra high sensitivity FA detection using this equipment. Although FAs can be analyzed by ESI in negative ion mode, this method is not very sensitive. In this study, we demonstrate a new method of FA analysis based on conversion of the carboxylic acid to an amide bearing a permanent positive charge, N-(4 aminomethylphenyl)pyridinium (AMPP) combined with analysis on a reverse-phase liquid chromatography column coupled to an ESI mass spectrometer operating in positive ion mode. This leads to an ~60,000-fold increase in sensitivity compared with the same method carried out with underivatized FAs. The new method is about 10-fold more sensitive than the existing method of gas chromatography/electron capture mass spectrometry of FA pentafluorobenzyl esters. Furthermore, significant fragmentation of the precursor ions in the nontag portion improves analytical specificity. We show that a large number of FA molecular species can be analyzed with this method in complex biological samples such as mouse serum. PMID- 23945568 TI - Practice gaps: Assuming that a subsequent infection in a patient with a prior MRSA infection will also be caused by MRSA. PMID- 23945569 TI - New research on community management of severe neonatal infections: an overview. PMID- 23945567 TI - Cellular uptake and antiproliferative effects of 11-oxo-eicosatetraenoic acid. AB - Cyclooxygenases (COX) metabolize arachidonic acid (AA) to hydroxyeicosatetraenoic acids (HETE), which can then be oxidized by dehydrogenases, such as 15 hydroxyprostaglandin dehydrogenase (15-PGDH), to oxo-eicosatetraenoic acids (ETE). We have previously established that 11-oxo-eicosatetraenoic acid (oxo-ETE) and 15-oxo-ETE are COX-2/15-PGDH-derived metabolites. Stable isotope dilution (SID) chiral liquid chromatography coupled with electron capture atmospheric pressure chemical ionization (ECAPCI) single reaction monitoring (SRM) MS has been used to quantify uptake of 11-oxo-ETE and 15-oxo-ETE in both LoVo cells and human umbilical vein endothelial cells (HUVEC). Intracellular 11-oxo- and 15-oxo ETE concentrations reached maximum levels within 1 h and declined rapidly, with significant quantitative differences in uptake between the LoVo cells and the HUVECs. Maximal intracellular concentrations of 11-oxo-ETE were 0.02 ng/4 * 105 cells in the LoVo cells and 0.58 ng/4 * 105 cells in the HUVECs. Conversely, maximal levels of 15-oxo-ETE were 0.21 ng/4 * 105 in the LoVo cells and 0.01 ng/4 * 105 in the HUVECs. The methyl esters of both 11-oxo- and 15-oxo-ETE increased the intracellular concentrations of the corresponding free oxo-ETEs by 3- to 8 fold. 11-oxo-ETE, 15-oxo-ETE, and their methyl esters inhibited proliferation in both HUVECs and LoVo cells at concentrations of 2-10 MUM, with 11-oxo-ETE methyl ester being the most potent inhibitor. Cotreatment with probenecid, an inhibitor of multiple drug resistance transporters (MRP)1 and 4, increased the antiproliferative effect of 11-oxo-ETE methyl ester in LoVo cells and increased the intracellular concentration of 11-oxo-ETE from 0.05 ng/4 * 105 cells to 0.18 ng/4 * 105 cells. Therefore, this study has established that the COX-2/15-PGDH derived eicosanoids 11-oxo- and 15-oxo-ETE enter target cells, that they inhibit cellular proliferation, and that their inhibitory effects are modulated by MRP exporters. PMID- 23945570 TI - Safety and efficacy of simplified antibiotic regimens for outpatient treatment of serious infection in neonates and young infants 0-59 days of age in Bangladesh: design of a randomized controlled trial. AB - BACKGROUND: Because access to care is limited in settings with high mortality, exclusive reliance on the current recommendation of 7-10 days of parenteral antibiotic treatment is a barrier to provision of adequate treatment of newborn infections. METHODS: We are conducting a trial to determine if simplified antibiotic regimens with fewer injections are as efficacious as the standard course of parenteral antibiotics for empiric treatment of young infants with clinical signs suggestive of severe infection in 4 urban hospitals and in a rural surveillance site in Bangladesh. The reference regimen of intramuscular procaine benzyl penicillin and gentamicin given once daily for 7 days is being compared with (1) intramuscular gentamicin once daily and oral amoxicillin twice daily for 7 days and (2) intramuscular penicillin and gentamicin once daily for 2 days followed by oral amoxicillin twice daily for additional 5 days. All regimens are provided in the infant's home. The primary outcome is treatment failure (death or lack of clinical improvement) within 7 days of enrolment. The sample size is 750 evaluable infants enrolled per treatment group, and results will be reported at the end of 2013. DISCUSSION: The trial builds upon previous studies of community case management of clinical severe infections in young infants conducted by our research team in Bangladesh. The approach although effective was not widely accepted in part because of feasibility concerns about the large number of injections. The proposed research that includes fewer doses of parenteral antibiotics if shown efficacious will address this concern. PMID- 23945571 TI - Simplified antibiotic regimens for the management of clinically diagnosed severe infections in newborns and young infants in first-level facilities in Karachi, Pakistan: study design for an outpatient randomized controlled equivalence trial. AB - BACKGROUND: Infection in young infants is a major cause of morbidity and mortality in low-middle income countries, with high neonatal mortality rates. Timely case management is lifesaving, but the current standard of hospitalization for parenteral antibiotic therapy is not always feasible. Alternative, simpler antibiotic regimens that could be used in outpatient settings have the potential to save thousands of lives. METHODS: This trial aims to determine whether 2 simplified antibiotic regimens are equivalent to the reference therapy with 7 days of once-daily (OD) intramuscular (IM) procaine penicillin and gentamicin for outpatient management of young infants with clinically presumed systemic bacterial infection treated in primary health-care clinics in 5 communities in Karachi, Pakistan. The reference regimen is close to the current recommendation of the hospital-based intravenous ampicillin and gentamicin therapy for neonatal sepsis. The 2 comparison arms are (1) IM gentamicin OD and oral amoxicillin twice daily for 7 days; and (2) IM penicillin and gentamicin OD for 2 days, followed by oral amoxicillin twice daily for 5 days; 2250 "evaluable" infants will be enrolled. The primary outcome of this trial is treatment failure (death, deterioration or lack of improvement) within 7 days of enrollment. Results are expected by early 2014. DISCUSSION: This trial will determine whether simplified antibiotic regimens with fewer injections in combination with high-dose amoxicillin are equivalent to 7 days of IM procaine penicillin and gentamicin in young infants with clinical severe infection. Results will have program and policy implications in countries with limited access to hospital care and high burden of neonatal deaths. PMID- 23945572 TI - Simplified regimens for management of neonates and young infants with severe infection when hospital admission is not possible: study protocol for a randomized, open-label equivalence trial. AB - BACKGROUND: In resource-limited settings, most young infants with signs of severe infection do not receive the recommended inpatient treatment with intravenous broad spectrum antibiotics for 10 days or more because such treatment is not accessible, acceptable or affordable to families. This trial was initiated in the Democratic Republic of Congo, Kenya and Nigeria to assess the safety and efficacy of simplified treatment regimens for the young infants with signs of severe infection who cannot receive hospital care. METHODS: This is a randomized, open label equivalence trial in which 3600 young infants with signs of clinical severe infection will be enrolled. The primary outcome is treatment failure in 7 days after enrollment, which includes death or worsening of the clinical condition on any day, or no improvement in the clinical condition by day 4 of treatment. Secondary outcomes include compliance with study therapy, adverse effects due to the study drugs and relapse or death during the week after completion of treatment. DISCUSSION: The results of this study, along with ongoing studies in Pakistan and Bangladesh, will inform the development of global policy for treatment of severe neonatal infections in resource-limited settings. PMID- 23945573 TI - An innovative multipartner research program to address detection, assessment and treatment of neonatal infections in low-resource settings. AB - BACKGROUND: In pursuit of innovative approaches for the management of severe infections in young infants, which is a major cause of mortality, a multipartner research program was conceptualized to provide right care in the right place. The primary objective was to generate evidence and identify a simple, safe and effective treatment regimen for young infants with severe infections that can be provided closer to home by trained health workers where referral is not possible. RESEARCH: Published and nonpublished data on community-based approaches for the management of neonatal sepsis were critically reviewed by an independent expert panel convened in 2007 by the World Health Organization in collaboration with the United States Agency for International Development and Save the Children/Saving Newborn Lives. These stakeholders agreed to 1) undertake research to improve the specificity of a diagnostic algorithm and revise World Health Organization/United Nations International Children's Emergency Fund Integrated Management of Childhood Illness guidelines to identify sick young infants for referral, 2) develop research studies with common research designs (1 site in each Bangladesh and Pakistan and a multicentre site in Democratic Republic of Congo, Kenya and Nigeria) and oversight mechanisms to evaluate antibiotic regimens (when referral is not accepted by the family) that are safe and efficacious, appropriate to the severity of infection, and deployable on a large scale and 3) utilize existing program delivery structures incorporating community health workers, skilled health workers to deliver simple antibiotic treatment when referral is not possible. CONCLUSIONS: This research program facilitated innovative research in different geographical, cultural and administrative milieus to generate recommendations for policy. PMID- 23945575 TI - Ensuring quality in AFRINEST and SATT: clinical standardization and monitoring. AB - BACKGROUND: Three randomized open-label clinical trials [Simplified Antibiotic Therapy Trial (SATT) Bangladesh, SATT Pakistan and African Neonatal Sepsis Trial (AFRINEST)] were developed to test the equivalence of simplified antibiotic regimens compared with the standard regimen of 7 days of parenteral antibiotics. These trials were originally conceived and designed separately; subsequently, significant efforts were made to develop and implement a common protocol and approach. Previous articles in this supplement briefly describe the specific quality control methods used in the individual trials; this article presents additional information about the systematic approaches used to minimize threats to validity and ensure quality across the trials. METHODS: A critical component of quality control for AFRINEST and SATT was striving to eliminate variation in clinical assessments and decisions regarding eligibility, enrollment and treatment outcomes. Ensuring appropriate and consistent clinical judgment was accomplished through standardized approaches applied across the trials, including training, assessment of clinical skills and refresher training. Standardized monitoring procedures were also applied across the trials, including routine (day to-day) internal monitoring of performance and adherence to protocols, systematic external monitoring by funding agencies and external monitoring by experienced, independent trial monitors. A group of independent experts (Technical Steering Committee/Technical Advisory Group) provided regular monitoring and technical oversight for the trials. CONCLUSIONS: Harmonization of AFRINEST and SATT have helped to ensure consistency and quality of implementation, both internally and across the trials as a whole, thereby minimizing potential threats to the validity of the trials' results. PMID- 23945574 TI - Treatment of fast breathing in neonates and young infants with oral amoxicillin compared with penicillin-gentamicin combination: study protocol for a randomized, open-label equivalence trial. AB - BACKGROUND: The World Health Organization recommends hospitalization and injectable antibiotic treatment for young infants (0-59 days old), who present with signs of possible serious bacterial infection. Fast breathing alone is not associated with a high mortality risk for young infants and has been treated with oral antibiotics in some settings. This trial was designed to examine the safety and efficacy of oral amoxicillin for young infants with fast breathing compared with that of an injectable penicillin-gentamicin combination. The study is currently being conducted in the Democratic Republic of Congo, Kenya and Nigeria. METHODS/DESIGN: This is a randomized, open-label equivalence trial. All births in the community are visited at home by trained community health workers to identify sick infants who are then referred to a trial study nurse for assessment. The primary outcome is treatment failure by day 8 after enrollment, defined as clinical deterioration, development of a serious adverse event including death, persistence of fast breathing by day 4 or recurrence up to day 8. Secondary outcomes include adherence to study therapy, relapse, death between days 9 and 15 and adverse effects associated with the study drugs. Study outcomes are assessed on days 4, 8, 11 and 15 after randomization by an independent outcome assessor who is blinded to the treatment being given. DISCUSSION: The results of this study will help inform the development of policies for the treatment of fast breathing among neonates and young infants in resource-limited settings. PMID- 23945576 TI - Ongoing trials of simplified antibiotic regimens for the treatment of serious infections in young infants in South Asia and sub-Saharan Africa: implications for policy. AB - BACKGROUND: The current World Health Organization (WHO) recommendation for treatment of severe infection in young infants is hospitalization and parenteral antibiotic therapy. Hospital care is generally not available outside large cities in low- and middle-income countries and even when available is not acceptable or affordable for many families. Previous research in Bangladesh and India demonstrated that treatment outside hospitals may be possible. RESEARCH: A set of research studies with common protocols testing simplified antibiotic regimens that can be provided at the lowest-level health-care facility or at home are nearing completion. The studies are large individually randomized controlled trials that are set up in the context of a program, which provides home visits by community health workers to detect serious illness in young infants with assessment and treatment at an outpatient health facility near home. This article summarizes the policy implications of the research studies. POLICY IMPLICATIONS: The studies are expected to result in information that would inform WHO guidelines on simple, safe and effective regimens for the treatment of clinical severe infection and pneumonia in newborns and young infants in settings where referral is not possible. The studies will also inform the inputs and process required to establish outpatient treatment of newborn and young infant infections at health facilities near the home. We expect that the information from research and the resulting WHO guidelines will form the basis of policy dialogue by a large number of stakeholders at the country level to implement outpatient treatment of neonatal infections and thereby reduce neonatal and infant mortality resulting from infection. PMID- 23945584 TI - Gene regulation: Long RNAs wire up cancer growth. PMID- 23945577 TI - Scientific rationale for study design of community-based simplified antibiotic therapy trials in newborns and young infants with clinically diagnosed severe infections or fast breathing in South Asia and sub-Saharan Africa. AB - BACKGROUND: Newborns and young infants suffer high rates of infections in South Asia and sub-Saharan Africa. Timely access to appropriate antibiotic therapy is essential for reducing mortality. In an effort to develop community case management guidelines for young infants, 0-59 days old, with clinically diagnosed severe infections, or with fast breathing, 4 trials of simplified antibiotic therapy delivered in primary care clinics (Pakistan, Democratic Republic of Congo, Kenya and Nigeria) or at home (Bangladesh and Nigeria) are being conducted. METHODS: This article describes the scientific rationale for these trials, which share major elements of trial design. All the trials are in settings of high neonatal mortality, where hospitalization is not feasible or frequently refused. All use procaine penicillin and gentamicin intramuscular injections for 7 days as reference therapy and compare this to various experimental arms utilizing comparatively simpler combination regimens with fewer injections and oral amoxicillin. CONCLUSION: The results of these trials will inform World Health Organization policy regarding community case management of young infants with clinical severe infections or with fast breathing. PMID- 23945585 TI - Onset of deglacial warming in West Antarctica driven by local orbital forcing. AB - The cause of warming in the Southern Hemisphere during the most recent deglaciation remains a matter of debate. Hypotheses for a Northern Hemisphere trigger, through oceanic redistributions of heat, are based in part on the abrupt onset of warming seen in East Antarctic ice cores and dated to 18,000 years ago, which is several thousand years after high-latitude Northern Hemisphere summer insolation intensity began increasing from its minimum, approximately 24,000 years ago. An alternative explanation is that local solar insolation changes cause the Southern Hemisphere to warm independently. Here we present results from a new, annually resolved ice-core record from West Antarctica that reconciles these two views. The records show that 18,000 years ago snow accumulation in West Antarctica began increasing, coincident with increasing carbon dioxide concentrations, warming in East Antarctica and cooling in the Northern Hemisphere associated with an abrupt decrease in Atlantic meridional overturning circulation. However, significant warming in West Antarctica began at least 2,000 years earlier. Circum-Antarctic sea-ice decline, driven by increasing local insolation, is the likely cause of this warming. The marine-influenced West Antarctic records suggest a more active role for the Southern Ocean in the onset of deglaciation than is inferred from ice cores in the East Antarctic interior, which are largely isolated from sea-ice changes. PMID- 23945586 TI - RNAi screens in mice identify physiological regulators of oncogenic growth. AB - Tissue growth is the multifaceted outcome of a cell's intrinsic capabilities and its interactions with the surrounding environment. Decoding these complexities is essential for understanding human development and tumorigenesis. Here we tackle this problem by carrying out the first genome-wide RNA-interference-mediated screens in mice. Focusing on skin development and oncogenic (Hras(G12V)-induced) hyperplasia, our screens uncover previously unknown as well as anticipated regulators of embryonic epidermal growth. Among the top oncogenic screen hits are Mllt6 and the Wnt effector beta-catenin, which maintain Hras(G12V)-dependent hyperproliferation. We also expose beta-catenin as an unanticipated antagonist of normal epidermal growth, functioning through Wnt-independent intercellular adhesion. Finally, we validate functional significance in mouse and human cancers, thereby establishing the feasibility of in vivo mammalian genome-wide investigations to dissect tissue development and tumorigenesis. By documenting some oncogenic growth regulators, we pave the way for future investigations of other hits and raise promise for unearthing new targets for cancer therapies. PMID- 23945587 TI - lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. AB - Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis, their potential involvement in regulated gene transcription programs remains rather poorly understood. The androgen receptor regulates a large repertoire of genes central to the identity and behaviour of prostate cancer cells, and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy. Here we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 (also known as PCAT8) and PCGEM1, bind successively to the androgen receptor and strongly enhance both ligand-dependent and ligand-independent androgen-receptor-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated androgen receptor on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the androgen receptor amino terminus that is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus 2 PHD domain enhances selective looping of androgen-receptor-bound enhancers to target gene promoters in these cells. In 'resistant' prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length androgen receptor, causing ligand-independent activation of the androgen receptor transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumour xenograft growth in vivo. Together, these results indicate that these overexpressed lncRNAs can potentially serve as a required component of castration resistance in prostatic tumours. PMID- 23945588 TI - A strong magnetic field around the supermassive black hole at the centre of the Galaxy. AB - Earth's nearest candidate supermassive black hole lies at the centre of the Milky Way. Its electromagnetic emission is thought to be powered by radiatively inefficient accretion of gas from its environment, which is a standard mode of energy supply for most galactic nuclei. X-ray measurements have already resolved a tenuous hot gas component from which the black hole can be fed. The magnetization of the gas, however, which is a crucial parameter determining the structure of the accretion flow, remains unknown. Strong magnetic fields can influence the dynamics of accretion, remove angular momentum from the infalling gas, expel matter through relativistic jets and lead to synchrotron emission such as that previously observed. Here we report multi-frequency radio measurements of a newly discovered pulsar close to the Galactic Centre and show that the pulsar's unusually large Faraday rotation (the rotation of the plane of polarization of the emission in the presence of an external magnetic field) indicates that there is a dynamically important magnetic field near the black hole. If this field is accreted down to the event horizon it provides enough magnetic flux to explain the observed emission--from radio to X-ray wavelengths--from the black hole. PMID- 23945589 TI - Metabolism: Sweet enticements to move. PMID- 23945590 TI - Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. AB - Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation (H3K9me3). Although therapy-induced senescence (TIS) improves long-term outcomes, potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Eu-myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TIS-competent lymphomas but not TIS incompetent Suv39h1(-) lymphomas show increased glucose utilization and much higher ATP production. We demonstrate that this is linked to massive proteotoxic stress, which is a consequence of the senescence-associated secretory phenotype (SASP) described previously. SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fashion. Accordingly, TIS lymphomas, unlike senescence models that lack a strong SASP response, were more sensitive to blocking glucose utilization or autophagy, which led to their selective elimination through caspase-12- and caspase-3-mediated endoplasmic-reticulum-related apoptosis. Consequently, pharmacological targeting of these metabolic demands on TIS induction in vivo prompted tumour regression and improved treatment outcomes further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting. PMID- 23945591 TI - Biological techniques: An embryonic view of tumour development. PMID- 23945593 TI - Community fall prevention programs: comparing three InSTEP models by levels of intensity. AB - The Fall Prevention Center of Excellence designed three progressive-intensity fall prevention program models, Increasing Stability Through Evaluation and Practice (InSTEP), to reduce risk in community-dwelling older adults. Each model included physical activity, medical risk, and home safety components and was implemented as a 12-week program for small class sizes (12-15 people) in community and senior centers. Change in fall rates and fall risk factors was assessed using a battery of performance tests, self-reports of function, and fall diaries in a 3-group within-subjects (N = 200) design measured at baseline, immediately postintervention, and at 3 and 9 months postintervention. Overall, participants experienced a reduction in falls, improved selfperception of gait and balance, and improved dynamic gait function. The medium-intensity InSTEP model significantly (p = .003) reduced self-reported falls in comparison with the other models. InSTEP is a feasible model for addressing fall risk reduction in community-dwelling older adults. PMID- 23945594 TI - In vitro monitoring of the formation of pentamers from the monomer of GST fused HPV 16 L1. AB - The recombinant GST fusion protein HPV 16 L1 from E. coli was proved to exist as a monomer rather than a pentamer, providing the possibility of real-time monitoring of the pentamer formation in vitro. Time-dependent kinetic studies of the process were performed for the first time by using static light scattering and western blot analysis, where the essential factors were revealed, offering a new biotechnical approach for virus control and/or the development of anti-viral agents. PMID- 23945595 TI - Copper T380 intrauterine device for emergency contraception: highly effective at any time in the menstrual cycle. AB - STUDY QUESTION: Does the efficacy of placing a copper intrauterine device (IUD) for emergency contraception (EC) to prevent pregnancy depend on menstrual cycle timing and timing of unprotected intercourse (UPI)? SUMMARY ANSWER: If the urine pregnancy test is negative prior to IUD placement, the copper IUD is highly effective for EC at any point in the menstrual cycle. WHAT IS KNOWN ALREADY: The use of the Copper T380A for EC has been encouraged by the failure of oral EC methods to decrease rates of unintended pregnancy and the documented success of the IUD in reducing unintended pregnancies. However scant data exist regarding the efficacy and safety of IUD insertion for EC when accounting for menstrual cycle timing and time since UPI. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis of data obtained from a previously published prospective cohort study of women who received the Copper T380A IUD for EC between July 1997 and January 2000. We included 1840 participants according to the study inclusion criteria of a known last menstrual period (LMP) and cycle lengths of 25-35 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: The original study included women aged between 18 and 44 years who presented for EC at 18 sites throughout China and who had regular menstrual cycles between 24 and 42 days, a known LMP, UPI within 120 h (5 days) and a negative urine pregnancy test (cutoff <25 IU/ml). Women with uncertain LMP dates were excluded. This study included only participants with cycle lengths of 25-35 days. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 1840 participants with usual cycle lengths of 25-35 days, 850 (46.2%) had their IUD inserted following UPI in the expected fertile window and 84 (4.6%) had the insertion >5 days after the predicted ovulation day and 52 (2.8%) had the insertion >5 days after UPI. There were no pregnancies in the first month among the 1771 women who had information available regarding their 1-month follow-up pregnancy test. LIMITATIONS, REASONS FOR CAUTION: This was a secondary analysis of an observational study, and thus participants were not randomized to an alternative postcoital method. There were a small number of women who had UPI >5 days after their predicted ovulation day thus limiting the confidence of assuring a low risk of pregnancy in this situation. The ovulation day was calculated based on the LMP prior to IUD insertion and not on the subsequent first day of menses following IUD insertion. WIDER IMPLICATIONS OF THE FINDINGS: If the urine pregnancy test is negative prior to IUD placement, the copper IUD is likely to be effective for EC at almost any point in the menstrual cycle. STUDY FUNDING/COMPETING INTEREST(S): The original study was funded by the UNDP/UNPFA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction. The donors and sponsors of the study had no role in the study design, data collection, data analysis, data interpretation, writing of the report or the decision to submit the paper for publication. PMID- 23945596 TI - Phthalates may promote female puberty by increasing kisspeptin activity. AB - STUDY QUESTION: Is there an association between exposure to phthalates and the timing of female puberty? SUMMARY ANSWER: Our study suggests that the early onset of puberty is related to increased kisspeptin secretion. WHAT IS KNOWN ALREADY: Girls are maturing earlier than in past decades and the quantity of phthalates used in consumer products has concurrently risen. The hypothesis that exposure to phthalates may increase kisspeptin secretion and thereby cause early-onset puberty is unexplored. STUDY DESIGN, SIZE, DURATION: This case-control study ran from 2006 to 2009. We enrolled 104 girls. Girls in the central precocious puberty (CPP) (case) group were recruited from a pediatric endocrinology policlinic in Taiwan; prepubescent controls were recruited from local elementary schools and all were categorized based on a pediatrician's diagnosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: The physical characteristics of puberty were assessed and levels of LH, FSH estradiol and kisspeptin-54 in blood samples were evaluated using radioimmunoassay. Reversed-phase high-performance liquid chromatography tandem mass spectrometry was used to analyze seven urinary phthalate metabolites. Non-parametric analyses, trend tests and linear regressions were performed on the data. MAIN RESULTS AND THE ROLE OF CHANCE: All seven urinary phthalate metabolites in the CPP group were significantly (P < 0.05) higher than in prepubescent controls. Serum kisspeptin-54 levels were higher (P = 0.022) in the CPP group than controls and were still significantly higher after adjusting for age (P = 0.03). There was a significant increasing trend (P(trend) = 0.005) between levels of kisspeptin and the stages of puberty. The concentration of kisspeptin-54 did not change in girls treated with leuprorelin acetate. There was a significant positive correlation between kisspeptin-54 and urinary mono-n-butyl phthalate (ng/ml: R(2) = 0.251, P < 0.001; MUg/g-creatinine: R(2) = 0.109, P = 0.024). LIMITATIONS, REASONS FOR CAUTION: The study duration was short and the sample size relatively small; therefore, we were unable to collect sufficient evidence to support the temporality between exposure to phthalates and the subsequent occurrence of PP. WIDER IMPLICATIONS OF THE FINDINGS: Kisspeptin may promote the onset of puberty in girls who are exposed to a high level of phthalates, especially di-n-butyl phthalate. These data suggest that developing a kisspeptin antagonist might be an alternative strategy for treating PP. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants NSC 96-2621-Z 006-013 and NSC 97-2621-M-006-001 from the Taiwan National Science Council. The authors have no conflicts of interest to disclose. PMID- 23945592 TI - Signatures of mutational processes in human cancer. AB - All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy. PMID- 23945597 TI - Visual-spatial cognition in women with polycystic ovarian syndrome: the role of androgens. AB - STUDY QUESTION: Are women with polycystic ovary syndrome (PCOS) better at three dimensional mental rotation than other women? SUMMARY ANSWER: Women with PCOS scored significantly higher on a mental rotation task than a female control group. WHAT IS KNOWN ALREADY: PCOS is a condition characterized by elevated testosterone levels. Some researches have found that three-dimensional mental rotation task performance is positively correlated with testosterone levels. STUDY DESIGN, SIZE, DURATION: This cross-sectional study was conducted between June 2006 and January 2009. The participants were 69 women with PCOS and 41 controls recruited from five gynaecology clinics in London. The control group consisted of non-PCOS women of comparable subfertility to PCOS group. These groups sizes gave roughly 80% power to detect moderate effect sizes for the main statistical test. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were recruited at London gynaecology clinics. The women were aged between 18 and 43. PCOS was diagnosed based on the Rotterdam criteria. Controls were women who experienced some degree of subfertility. Blood samples from participants were frozen for up to 4 months until being assayed by direct electrochemiluminescence. The mental rotation task was undertaken electronically. Some questionnaires and other tasks were completed as control measures. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS scored significantly higher than controls: median (range) 3.00 (0-9) and 2.00 (0-8), respectively (U = 1147.500, N1 = 69, N2 = 41, P < 0.047). Within the PCOS group, circulating levels of testosterone were significantly positively correlated with three-dimensional scoring (rs = 0.376, n = 56, P < 0.002), whereas estradiol was significantly negatively correlated with three-dimensional scoring (rs = -0.473, n = 29, P < 0.010). In the control group, the relationship between sex hormones and mental rotation was non-significant. Other factors, including general intelligence and social class, did not account for these findings. A subgroup analysis comparing hyperandrogenic PCOS cases, non hyperandrogenic PCOS cases and controls, in which age and body mass index were controlled for using ANCOVA, found a non-significant difference in three dimensional scoring between the three groups (F = 1.062, d.f. = 1, 73, P < 0.351). LIMITATIONS, REASONS FOR CAUTION: The small number of women in the control group meant that correlations were underpowered in this group. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to find a benefit of PCOS in visuospatial cognition, and the first to find a link between visuospatial cognition and sex hormones in PCOS. The fact that the correlations went in the opposite direction in the PCOS group compared with the controls might suggest the influence of increased prenatal exposure to androgen in PCOS. STUDY FUNDING/COMPETING INTEREST(S): The assays for this study were funded by the Department of Psychology, City University London. All authors report no conflicts of interest. PMID- 23945598 TI - Proton-exchange mechanism of specific Cs+ adsorption via lattice defect sites of Prussian blue filled with coordination and crystallization water molecules. AB - We have revealed the fundamental mechanism of specific Cs(+) adsorption into Prussian blue (PB) in order to develop high-performance PB-based Cs(+) adsorbents in the wake of the Fukushima nuclear accident. We compared two types of PB nanoparticles with formulae of Fe(III)4[Fe(II)(CN)6]3.xH2O (x = 10-15) (PB-1) and (NH4)0.70Fe(III)1.10[Fe(II)(CN)6].1.7H2O (PB-2) with respect to the Cs(+) adsorption ability. The synthesised PB-1, by a common stoichiometric aqueous reaction between 4Fe(3+) and 3[Fe(II)(CN)6](4-), showed much more efficient Cs(+) adsorption ability than did the commercially available PB-2. A high value of the number of waters of crystallization, x, of PB-1 was caused by a lot of defect sites (vacant sites) of [Fe(II)(CN)6](4-) moieties that were filled with coordination and crystallization water molecules. Hydrated Cs(+) ions were preferably adsorbed via the hydrophilic defect sites and accompanied by proton elimination from the coordination water. The low number of hydrophilic sites of PB-2 was responsible for its insufficient Cs(+) adsorption ability. PMID- 23945599 TI - Insights into the toxicological properties of a low molecular weight fraction from Zoanthus sociatus (Cnidaria). AB - The phylum Cnidaria is an ancient group of venomous animals, specialized in the production and delivery of toxins. Many species belonging to the class Anthozoa have been studied and their venoms often contain a group of peptides, less than 10 kDa, that act upon ion channels. These peptides and their targets interact with high affinity producing neurotoxic and cardiotoxic effects, and even death, depending on the dose and the administration pathway. Zoanthiniaria is an order of the Subclass Hexacorallia, class Anthozoa, and unlike sea anemone (order Actiniaria), neither its diversity of toxins nor the in vivo effects of the venoms has been exhaustively explored. In this study we assessed some toxicological tests on mice with a low molecular weight fraction obtained by gel filtration in Sephadex G-50 from Zoanthus sociatus crude extract. The gel filtration chromatogram at 280 nm revealed two major peaks, the highest absorbance corresponding to the low molecular weight fraction. The toxicological effects seem to be mostly autonomic and cardiotoxic, causing death in a dose dependent manner with a LD50 of 792 MUg/kg. Moreover, at a dose of 600 MUg/kg the active fraction accelerated the KCl-induced lethality in mice. PMID- 23945600 TI - Separacenes A-D, novel polyene polyols from the marine actinomycete, Streptomyces sp. AB - Separacenes A-D (1-4), novel polyene polyols, were isolated from Streptomyces sp. collected from the southern area of Jeju Island, Korea. The chemical structures of 1-4 were established by NMR, mass, UV, and IR spectroscopy as well as the modified Mosher's method. Separacenes A-B (1-2), which share an identical planar structure but possess different relative configurations, bear tetraene units flanked by two diol moieties, whereas the stereoisomeric separacenes C-D (3-4) possess a triene moiety between two diol substructures. Separacenes A-D each contain a terminal olefinic methylene. Separacene A displayed inhibitory activity against Candida albicans isocitrate lyase and weak cytotoxicity against both the colon carcinoma cell line HCT-116 and the lung cancer cell line A549. PMID- 23945602 TI - Anti-inflammatory components of the starfish Astropecten polyacanthus. AB - Inflammation is important in biomedical research, because it plays a key role in inflammatory diseases including rheumatoid arthritis and other forms of arthritis, diabetes, heart disease, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, allergies, asthma, and even cancer. In the present study, we describe the inhibitory effect of crude extracts and steroids isolated from the starfish Astropecten polyacanthus on pro-inflammatory cytokine (Interleukin-12 (IL-12) p40, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha)) production in lipopolysaccharide (LPS)-stimulated bone marrow derived dendritic cells (BMDCs). Among those tested, compounds 5 and 7 showed potent inhibitory effects on the production of all three pro-inflammatory cytokines with IC50 values ranging from 1.82 +/- 0.11 to 7.00 +/- 0.16 MUM. Potent inhibitory activities were also observed for compound 1 on the production of IL-12 p40 and IL-6 with values of 3.96 +/- 0.12 and 4.07 +/- 0.13 MUM, respectively, and for compounds 3 and 4 on the production of IL-12 p40 with values of 6.55 +/- 0.18 and 5.06 +/- 0.16 MUM, respectively. Moreover, compounds 2 (IC50 = 34.86 +/- 0.31 MUM) and 6 (IC50 = 79.05 +/- 2.05 MUM) exhibited moderate inhibitory effects on the production of IL-12 p40, whereas compounds 3 (IC50 = 22.80 +/- 0.21 MUM) and 4 (IC50 = 16.73 +/- 0.25 MUM) moderately inhibited the production of TNF-alpha and IL-6, respectively. PMID- 23945601 TI - Development of Synechocystis sp. PCC 6803 as a phototrophic cell factory. AB - Cyanobacteria (blue-green algae) play profound roles in ecology and biogeochemistry. One model cyanobacterial species is the unicellular cyanobacterium Synechocystis sp. PCC 6803. This species is highly amenable to genetic modification. Its genome has been sequenced and many systems biology and molecular biology tools are available to study this bacterium. Recently, researchers have put significant efforts into understanding and engineering this bacterium to produce chemicals and biofuels from sunlight and CO2. To demonstrate our perspective on the application of this cyanobacterium as a photosynthesis based chassis, we summarize the recent research on Synechocystis 6803 by focusing on five topics: rate-limiting factors for cell cultivation; molecular tools for genetic modifications; high-throughput system biology for genome wide analysis; metabolic modeling for physiological prediction and rational metabolic engineering; and applications in producing diverse chemicals. We also discuss the particular challenges for systems analysis and engineering applications of this microorganism, including precise characterization of versatile cell metabolism, improvement of product rates and titers, bioprocess scale-up, and product recovery. Although much progress has been achieved in the development of Synechocystis 6803 as a phototrophic cell factory, the biotechnology for "Compounds from Synechocystis" is still significantly lagging behind those for heterotrophic microbes (e.g., Escherichia coli). PMID- 23945603 TI - Electron beam induced local crystallization of HfO2 nanopores for biosensing applications. AB - We report the development of single, locally crystallized nanopores in HfO2 membranes for biosensing applications. HfO2 is chosen for its isoelectric point of 7.0, mechanical and chemical stability in solution, and for its potential as a high-k material for nanopore ionic field effect transistor applications. The HfO2 membrane is deposited on a graphene layer suspended over a 300 nm FIB hole, where graphene is used as the mechanical support. Exposure of the membrane to a focused electron beam causes crystallization in the vicinity of the nanopore during pore formation. We investigate the effects of crystallization on the electrical and surface properties of HfO2 films. Our surface analysis of HfO2 reveals improved hydrophilicity of crystallized HfO2, a notable advantage over the hydrophobicity of as-deposited HfO2. We also demonstrate detection of dsDNA translocation through HfO2 nanopores under various applied bias levels. In addition, our device architecture also presents a promising first step toward the realization of high k HfO2 nanopore transistors. PMID- 23945605 TI - Assessment of Maraviroc Exposure-Response Relationship at 48 Weeks in Treatment Experienced HIV-1-Infected Patients in the MOTIVATE Studies. AB - Efficacy exposure-response relationships of the CCR5 antagonist maraviroc were evaluated across two phase III clinical trials. This post-hoc analysis used 48 week efficacy data from 841 treatment-experienced patients infected with CCR5 tropic human immunodeficiency virus type 1 (HIV-1), identified by the enhanced sensitivity Trofile assay. Probability of treatment success (viral RNA <50 copies/ml) was modeled using generalized additive logistic regression, testing exposure, clinical, and virologic variables. Prognostic factors for treatment success (in decreasing order of Akaike information criterion (AIC) change) were: maraviroc treatment, high-weighted overall susceptibility to background treatment, absence of an undetectable maraviroc concentration, high baseline CD4 count (BCD4), low viral load (VL), race (other than black), absence of non-R5 baseline tropism (BTRP), and absence of fosamprenavir (FPV). No concentration response relationship was found with treatment (maraviroc vs. placebo) and presence/absence of undetectable maraviroc concentration (adherence marker) in the model. The maraviroc doses studied (300 or 150 mg with potent CYP3A4 inhibitors once (q.d.)/twice daily (b.i.d.)) deliver concentrations near the top of the concentration-response curve.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e64; doi:10.1038/psp.2013.42; published online 14 August 2013. PMID- 23945604 TI - Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development. PMID- 23945606 TI - A Generic Integrated Physiologically based Whole-body Model of the Glucose Insulin-Glucagon Regulatory System. AB - Models of glucose metabolism are a valuable tool for fundamental and applied medical research in diabetes. Use cases range from pharmaceutical target selection to automatic blood glucose control. Standard compartmental models represent little biological detail, which hampers the integration of multiscale data and confines predictive capabilities. We developed a detailed, generic physiologically based whole-body model of the glucose-insulin-glucagon regulatory system, reflecting detailed physiological properties of healthy populations and type 1 diabetes individuals expressed in the respective parameterizations. The model features a detailed representation of absorption models for oral glucose, subcutaneous insulin and glucagon, and an insulin receptor model relating pharmacokinetic properties to pharmacodynamic effects. Model development and validation is based on literature data. The quality of predictions is high and captures relevant observed inter- and intra-individual variability. In the generic form, the model can be applied to the development and validation of novel diabetes treatment strategies.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e65; doi:10.1038/psp.2013.40; published online 14 August 2013. PMID- 23945607 TI - Using a mandatory reporting database to recruit persons living with HIV/AIDS to study access to care in Mississippi. AB - Using funds provided by the Ryan White Care Act, we conducted a statewide needs assessment of persons living with HIV/AIDS (PLWHA) in Mississippi as required by provisions of the Act. Most published research addressing access to care for PLWHA is based on convenience samples of persons already accessing care in specified clinic locations. For this study of a single state with a well established mandatory reporting system, we conducted a cross-sectional study interviewing a random sample of PLWHA across the state of Mississippi. The Mississippi State Department of Health has maintained the Mississippi HIV/AIDS Reporting System since its inception in 1980. The database tracks all reported cases of HIV+ cases and includes name, age, last-known address, and other contact information. The sample was selected from a frame of all recorded PLWHA in Mississippi at that time, regardless of their association with care facilities. The purpose of this article is to describe the design and methodology of this study, difficulties encountered in locating this hard-to-reach population, multimethod recruiting strategies and outcomes, and lessons learned. Locating participants using a truly random sample from a mandatory reporting database was resource intensive. However, data collected as a result of these efforts have provided invaluable information on a number of topics important to PLWHA. PMID- 23945608 TI - Facile synthesis of photo-cleavable polymers via Passerini reaction. AB - Passerini three-component reaction and multicomponent polymerization (MCP) were demonstrated to be facile methods for the preparation of photo-cleavable polymers, photo- and redox-dually cleavable polymers, as well as block copolymers. PMID- 23945609 TI - Nutrition as a link between obesity and cardiovascular disease: how can we stop the obesity epidemic? AB - Overweight and obesity are associated with excess cardiovascular risk. To reduce cardiovascular risk at the population level, the prevention of overweight and obesity is key. This requires adoption of a healthy lifestyle, including less inactivity and more moderate-to-vigorous physical activity, and a healthy diet. Diet composition may facilitate weight gain prevention and weight loss. Effects of dietary fats, carbohydrates and proteins will be discussed in this context. Current evidence indicates that moderation of the intake of (saturated) fat, a moderate increase in protein content of the diet, a replacement of refined grain/high glucose index (GI) by whole-grain/low GI carbohydrates and limitation of the consumption of calorically-sweetened beverages are likely to facilitate weight control. PMID- 23945610 TI - Solution-processed small molecule:fullerene bulk-heterojunction solar cells: impedance spectroscopy deduced bulk and interfacial limits to fill-factors. AB - Using impedance spectroscopy, we demonstrate that the low fill factor (FF) typically observed in small molecule solar cells is due to hindered carrier transport through the active layer and hindered charge transfer through the anode interfacial layer (IFL). By carefully tuning the active layer thickness and anode IFL in BDT(TDPP)2 solar cells, the FF is increased from 33 to 55% and the PCE from 1.9 to 3.8%. These results underscore the importance of simultaneously optimizing active layer thickness and IFL in small molecule solar cells. PMID- 23945611 TI - Reddish-brown nodules and papules in an elderly man. Progressive nodular histiocytosis. PMID- 23945612 TI - 3D nanoporous Ag@BSA composite microspheres as hydrogen peroxide sensors. AB - 3D nanoporous Ag@BSA composite microspheres were successfully prepared through a protein-directed approach. Electrochemical measurements show that the nanoporous Ag@BSA composite microspheres exhibit excellent electrocatalytic activity towards the reduction of H2O2. A linear range of 5 MUM-1.5 mM and a lower detection limit of 0.16 MUM were recorded. The sensing performance might be attributed to the 3D micro/nano architecture and nanoporous characters. PMID- 23945622 TI - The influence of applied magnetic fields on the optical properties of zero- and one-dimensional CdSe nanocrystals. AB - Shape-dependent exciton relaxation dynamics of CdSe 0-D nanocrystals and 1-D nanorods were studied using low-temperature (4.2 K), time-resolved and intensity integrated magneto-photoluminscence (MPL) spectroscopy. Analysis of the average MPL rate constants from several different nanocrystal quantum dots and rods excited by 400 nm light in applied magnetic fields up to 17.5 T revealed size dependent energy gaps separating bright and dark exciton fine-structure states. For 1-D nanorods under strong cross-sectional confinement and large length-to diameter aspect ratios, efficient mixing of bright and dark exciton states was achieved using relatively low applied field strengths (<=4 T). The effect was attributed, in part, to decreased confinement of CdSe hole states associated with the long axis of the nanorod, which resulted in reduction of the energy gaps separating the bright and dark states. Increased control over the angle formed between the applied field vectors and the nanocrystal c-axis led to more efficient and uniform mixing of nanorod exciton states than for quantum dots. The findings suggest 1-D nanostructures are advantageous over 0-D ones for field responsive applications. PMID- 23945614 TI - Different thermodynamic signatures for DNA minor groove binding with changes in salt concentration and temperature. AB - The effects of salt concentration and temperature on the thermodynamics of DNA minor groove binding have quite different signatures: binding enthalpy is salt concentration independent but temperature dependent. Conversely, binding free energy is salt dependent but essentially temperature independent through enthalpy entropy compensation. PMID- 23945630 TI - Highly efficient and robust cathode materials for low-temperature solid oxide fuel cells: PrBa0.5Sr0.5Co(2-x)Fe(x)O(5+delta). AB - Solid oxide fuel cells (SOFC) are the cleanest, most efficient, and cost effective option for direct conversion to electricity of a wide variety of fuels. While significant progress has been made in anode materials with enhanced tolerance to coking and contaminant poisoning, cathodic polarization still contributes considerably to energy loss, more so at lower operating temperatures. Here we report a synergistic effect of co-doping in a cation-ordered double perovskite material, PrBa0.5Sr0.5Co(2-x)Fe(x)O(5+delta), which has created pore channels that dramatically enhance oxygen ion diffusion and surface oxygen exchange while maintaining excellent compatibility and stability under operating conditions. Test cells based on these cathode materials demonstrate peak power densities ~2.2 W cm(-2) at 600 degrees C, representing an important step toward commercially viable SOFC technologies. PMID- 23945631 TI - Effects of dance on depression, physical function, and disability in underserved adults. AB - This study documented the feasibility and immediate effects of a dance intervention two times per week for 12 weeks on depression, physical function, and disability in older, underserved adults. The one-group, pretest-posttest study had a convenience sample of 40 participants recruited from a federally subsidized apartment complex located in an economically depressed, inner-city neighborhood. Depression, physical function, and disability were measured at baseline and 12 weeks. Average age was 63 years (SD = 7.9), 92% were female, and 75% were African American. At baseline, participants reported increased depression (M = 20.0, SD = 12.4), decreased physical function (M = 56.6, SD = 10.9), and increased disability limitations (M = 65.7, SD = 14.9). At posttest, paired t tests showed that the dance intervention significantly decreased depression, t = 6.11, p < .001, and disability, t = -2.70, p = .014, and significantly increased physical function, t = -2.74, p = .013. The results indicate that the 12-week dance intervention may be an effective adjunct therapy to improve depression, disability, and physical function in underserved adults. PMID- 23945632 TI - Ga doping to significantly improve the performance of all-electrochemically fabricated Cu2O-ZnO nanowire solar cells. AB - Cu2O-ZnO nanowire solar cells have the advantages of light weight and high stability while possessing a large active material interface for potentially high power conversion efficiencies. In particular, electrochemically fabricated devices have attracted increasing attention due to their low-cost and simple fabrication process. However, most of them are "partially" electrochemically fabricated by vacuum deposition onto a preexisting ZnO layer. There are a few examples made via all-electrochemical deposition, but the power conversion efficiency (PCE) is too low (0.13%) for practical applications. Herein we use an all-electrochemical approach to directly deposit ZnO NWs onto FTO followed by electrochemical doping with Ga to produce a heterojunction solar cell. The Ga doping greatly improves light utilization while significantly suppressing charge recombination. A 2.5% molar ratio of Ga to ZnO delivers the best performance with a short circuit current density (Jsc) of 3.24 mA cm(-2) and a PCE of 0.25%, which is significantly higher than in the absence of Ga doping. Moreover, the use of electrochemically deposited ZnO powder-buffered Cu2O from a mixed Cu(2+)-ZnO powder solution and oxygen plasma treatment could reduce the density of defect sites in the heterojunction interface to further increase Jsc and PCE to 4.86 mA cm(-2) and 0.34%, respectively, resulting in the highest power conversion efficiency among all-electrochemically fabricated Cu2O-ZnO NW solar cells. This approach offers great potential for a low-cost solution-based process to mass manufacture high-performance Cu2O-ZnO NW solar cells. PMID- 23945633 TI - Distinctive features of melanoma and its management in elderly patients: a population-based study in France. AB - IMPORTANCE: Life expectancy is increasing in most developed countries, and elderly people have the highest incidence of melanoma. OBJECTIVE: To identify characteristics of melanoma and its management in the elderly compared with younger patients. DESIGN, SETTING, AND PARTICIPANTS: Retrospective population based study of incident cases of primary melanoma in 1621 patients with stage I or II melanoma in 2004 and 2008. Questionnaires administered to physicians and a survey of cancer registries and pathology laboratories were used to obtain data. The study was conducted in 5 regions in northeastern France. MAIN OUTCOMES AND MEASURES: Characteristics of patients and tumors, circumstances of diagnosis, and further management in older patients (>=70 years, 487 patients [30.0%]) compared with younger ones (<70 years, 1134 [70.0%]). RESULTS: Older patients had more frequent melanomas of the head and neck (29.4% vs 8.7%; P < .001) and of the nodular, lentigo maligna, or acral lentiginous histologic subtypes. They had thicker and more frequently ulcerated tumors, categorized as T3 or T4 in 36.7% of cases vs 20.1% in younger patients. Diagnosis of melanoma occurred more frequently in a general practice setting and less frequently in direct consultation with a dermatologist or regular screening for skin cancer. Time to definitive excision was longer in older patients, and 16.8% of them compared with 5.0% of the younger population had insufficient excision margins (P < .001). A sentinel lymph node biopsy was performed in 23.3% of the older patients with melanoma thicker than 1 mm vs 41.4% in the younger patients (P < .001). Adjuvant therapy was less frequently started in older patients and was prematurely stopped in a higher proportion of that population. CONCLUSIONS AND RELEVANCE: Age-related variations are observed at every step of melanoma management. The most important concerns are access of elderly people to settings for early diagnosis and excision with appropriate margins. PMID- 23945634 TI - Facile synthesis of nitrogen doped reduced graphene oxide as a superior metal free catalyst for oxidation. AB - Nitrogen (5.61 at%) doped reduced graphene oxide synthesized via a facile method was demonstrated as a superior metal-free catalyst for activation of peroxymonosulfate. Codoping with boron would further enhance the catalytic activity and the stability, providing a promising green material for environmental remediation. PMID- 23945635 TI - Novel clioquinol and its analogous platinum complexes: importance, role of the halogen substitution and the hydroxyl group of the ligand. AB - In this communication, we present the synthesis of new platinum complexes based on hydroxyquinoline ligands. We demonstrate the importance and the role of the halogen substitution as well as the chelation, which are essential structural characteristics for finding good cytotoxicities. PMID- 23945636 TI - High-speed optical coherence tomography as a reliable adjuvant tool to grade ocular anterior chamber inflammation. AB - PURPOSE: To evaluate the high-speed anterior segment optical coherence tomography (AS-OCT) grading of the AS inflammation in patients with ocular inflammation. METHODS: A retrospective consecutive case series study. Patients with clinically visible AS inflammation in at least one eye underwent AS-OCT (Visante; Zeiss Meditec) with three to eight line scans per eye, performed by a trained masked examiner. The images were reviewed for hyperreflective spots, noise, and artifact, and these were correlated to clinical examination. RESULTS: Seventy eight eyes of 41 patients were imaged. Forty-seven eyes had anterior chamber cells on clinical examination, and 68 had hyperreflective spots visible on AS OCT. There was a significant correlation (Spearman r = 0.7274) between clinical examination and Visante OCT images. Several patterns of inflammation and artifacts were apparent. CONCLUSION: The AS-OCT is a promising technique for grading anterior chamber cells. There was a significant correlation between clinical examination and Visante grading. PMID- 23945637 TI - Additional anti-vascular endothelial growth factor therapy for eyes with a retinal pigment epithelial tear after the initial therapy. AB - PURPOSE: To evaluate the effects of additional anti-vascular endothelial growth factor (VEGF) therapy for eyes with a retinal pigment epithelial (RPE) tear after anti-VEGF therapy and treated with additional anti-VEGF injections for recurrent or persistent exudative change. PATIENTS AND METHODS: Ten eyes (10 patients) followed up for >12 months after a recurrent RPE tear were evaluated retrospectively. The RPE tears on fundus autofluorescence images were measured and changes in the best-corrected visual acuity were evaluated. RESULTS: Patients were followed up for >12 months (mean, 27.3; range, 13-44 months). During 12 months of follow-up, additional anti-VEGF injections (mean, 3.3; range, 1-7) were administered. The mean size of the RPE tear at the onset was 6.5 mm2 (range, 1.3 16.3 mm2). At 12 months, the RPE tear increased in size >20% in 5 eyes and remained unchanged or decreased in the remaining half of eyes. The mean logarithm of the minimum angle of resolution best-corrected visual acuity was 0.43 at the time the RPE tear developed and 0.85 at 12 months. The RPE tear grade and age were prognostic factors for best-corrected visual acuity at 12 months. CONCLUSION: Under continued anti-VEGF therapy, RPE tears may be stable in size and visual acuity could be maintained in some eyes; however, the visual acuity prognosis is still unsatisfactory in nonresponsive eyes. PMID- 23945638 TI - Impact of intravitreal dexamethasone implant (Ozurdex) on macular morphology and function. AB - PURPOSE: To investigate the impact of intravitreal dexamethasone implant (Ozurdex) on macular morphology and function in eyes with macular edema secondary to central retinal vein occlusion. METHODS: Twelve treatment-naive patients with decreased visual acuity because of central retinal vein occlusion-related macular edema were enrolled in this prospective uncontrolled study. Patients were treated with intravitreal Ozurdex and followed up at 1 month and 3 months for the evaluation of morphologic and functional outcomes, by means of best-corrected visual acuity, microperimetry, multifocal electroretinography, and customized high-resolution enhanced depth imaging spectral-domain optical coherence tomography scans. RESULTS: Twelve eyes of 12 patients (10 men, 2 women; mean age 56.2 +/- 13.0 years) were included for analysis. At 1 month, mean best-corrected visual acuity, retinal sensitivity (microperimetry), multifocal electroretinography parameters, central macular thickness, and specific neurosensorial retinal measurements improved significantly. We found a significant negative correlation between retinal sensitivity and central macular thickness at 1 month and 3 months (r = -0.831, P = 0.001; r = -0.881, P = 0.001; respectively). Moreover, retinal sensitivity was negatively related to both outer and inner retinal thickness in all four intervals from the fovea. From baseline to Month 1, change in outer retinal thickness was positively related to multifocal electroretinography N1R1 amplitude change (r = 0.698, P = 0.012), whereas change in central macular thickness was negatively related to multifocal electroretinography P1R1 amplitude change (r = -0.701, P = 0.011). At 3 months, improvement of mean retinal sensitivity and central macular thickness slightly decreased. CONCLUSION: In eyes with macular edema secondary to central retinal vein occlusion, intravitreal dexamethasone provides functional benefits that correlate well with ultrastructural macular changes. PMID- 23945640 TI - To the editor. PMID- 23945639 TI - Incidence of presumed endophthalmitis after intravitreal injection performed in the operating room: a retrospective multicenter study. AB - PURPOSE: To evaluate the incidence of presumed endophthalmitis (EO) after intravitreal injection (IVI) of anti-vascular endothelial growth factor agents performed in the operating room. METHODS: Retrospective study at 2 Swiss eye hospitals between 2004 and 2012. Hospital records were used to identify patients treated with an IVI of an anti-vascular endothelial growth factor agent between 2004 and 2012 and those treated for EO, defined as any intraocular inflammation treated with intravitreal antibiotics. All IVIs were performed using standard sterile technique in a Swiss Class 1 operating room. No patient received preinjection topical antibiotics. Postinjection topical antibiotics were used only in one hospital. RESULTS: A total of 40,011 IVIs were performed at the 2 centers during the study period. Of the IVIs, ranibizumab was injected in 36,398 (91%), bevacizumab in 3,518 (9%), aflibercept in 89 (0.2%), and pegaptanib in 6 (<0.1%). Three cases of post-IVI presumed EO occurred, yielding a combined incidence of 0.0075% per injection (95% confidence interval: 0.0026-0.0220%) or 1 case per 13,337 IVIs. Two of the three cases of EO occurred in patients using post-IVI antibiotics. All three cases followed ranibizumab injection and were culture negative by anterior chamber tap or vitreous biopsy. CONCLUSION: The risk of EO after IVI performed under the sterile conditions of the operating room was very low. PMID- 23945641 TI - Three novel xanthones from Garcinia paucinervis and their anti-TMV activity. AB - Phytochemical investigations of the leaves of Garcinia paucinervis resulted in the isolation of three new xanthones 1-3 and five known analogues 4-8. Structural elucidations of 1-3 were performed by spectral methods such as 1D and 2D (HMQC, HMBC, and ROESY) NMR spectroscopy, in addition to high resolution mass spectrometry. Compounds 1-3 showed anti-TMV activities, with inhibition rates above 20%, especially for 1, which had a lower IC50 value of 21.4 uM. PMID- 23945642 TI - The emerging role of ferumoxytol-enhanced MRI in the management of cerebrovascular lesions. AB - Inflammation is increasingly being understood to be a key component to the pathophysiology of cerebrovascular lesions. Ferumoxytol, an iron oxide nanoparticle coated by a carbohydrate shell, has been used in MRI studies as an inflammatory marker because it is cleared by macrophages. Ferumoxytol-enhanced MRI has emerged as an important tool for noninvasive assessment of the inflammatory status of cerebrovascular lesions, namely aneurysms and arteriovenous malformations. Moreover, preliminary evidence suggests that ferumoxytol-enhanced MRI could be applied as a non-invasive tool to differentiate "unstable" lesions that require early intervention from "stable" lesions in which observation may be safe. Assessment of the effects of anti-inflammatory pharmacological interventions on cerebrovascular lesions is also a potentially crucial application of the technique. Future improvements in technique and MRI signal quantification will certainly pave the way for widespread and efficient use of ferumoxytol-enhanced MRI in clinical practice. In this paper, we review current data regarding ferumoxytol-enhanced MRI and discuss its current/potential applications and future perspectives. PMID- 23945643 TI - The synthesis and the biological evaluation of new thiazolidin-4-one derivatives containing a xanthine moiety. AB - Starting from theophylline (1,3-dimethylxanthine) new thiazolidin-4-one derivatives 7a1-7, 7b1-7 have been synthesized as potential antidiabetic drugs. The structure of the new derivatives was confirmed using spectral methods (FT-IR, 1H-NMR, 13C-NMR). The in vitro antioxidant potential of the synthesized compounds was evaluated according to the ferric reducing power, the total antioxidant activity and the DPPH and ABTS radical scavenging assays. Reactive oxygen species (ROS) and free radicals are considered to be implicated in a variety of pathological events, such as diabetes mellitus and its micro- and macrovascular complications. The results of chemical modulation of the thiazolidin-4-one intermediaries 6a, 6b through condensation with several aromatic aldehydes is the improvement of the antioxidant effect. All benzylidenethiazolidin-4-one derivatives 7a1-7, 7b1-7 are more active than their parent thiazolidin-4-ones. The most active compounds are the ones obtained by reaction of condensation with 4-hydroxybenzaldehyde (compounds 7a5, 7a6), 4-dimethylaminobenzaldehyde (compounds 7a6, 7b6) and 2-nitrobenzaldehyde (compounds 7a7, 7b7). PMID- 23945644 TI - Enzymatic synthesis of extremely pure triacylglycerols enriched in conjugated linoleic acids. AB - This work was objectively targeted to synthesize extremely pure triacylglycerols (TAG) enriched in conjugated linoleic acids (CLAs) for medical and dietetic purposes. Extremely pure CLA-enriched TAG was successfully synthesized by using the multi-step process: TAG was primarily synthesized by lipase-catalyzed esterification of CLA and glycerol and then the lower glycerides [monoacylglycerol (MAG) and diacylglycerol (DAG)] in the esterification mixtures was hydrolyzed to free fatty acids (FFAs) by a mono- and di-acylglycerol lipase (lipase SMG1), finally, the FFAs were further separated from TAG by low temperature (150 degrees C) molecular distillation. The operation parameters for the lipase SMG1-catalyzed hydrolysis were optimized using response surface methodology based on the central composite rotatable design (CCRD). The operation parameters included water content, pH and reaction temperature and all of these three parameters showed significant effects on the hydrolysis of lower glycerides. The optimal conditions were obtained with a water content of 66.4% (w/w, with respect to oil mass), pH at 5.7 and 1 h of reaction time at 19.6 degrees C. Under these conditions, the content of lower glycerides in the reaction mixture decreased from 45.2% to 0.3% and the purity of CLA-enriched TAG reached 99.7%. Further purification of TAG was accomplished by molecular distillation and the final CLA-enriched TAG product yielded 99.8% of TAG. These extremely pure CLA-enriched TAG would be used for in vivo studies in animals and humans in order to get specific information concerning CLA metabolism. PMID- 23945645 TI - Highly efficient biotransformation of polydatin to resveratrol by snailase hydrolysis using response surface methodology optimization. AB - Resveratrol (RV), a dietary antioxidant polyphenolic compound found in grapes and red wine, exerts a wide variety of pharmacological activities. However, lower content in plants compared with polydatin (PD, the glucoside of RV) limits its application in the food and pharmaceutical industries. In this paper, we carried out efficient biotransformation of PD to RV with 100% conversion yield by snailase hydrolysis. Moreover, response surface methodology (RSM) was used to optimize the effects of the reaction temperature, enzyme load, and reaction time on the conversion process. Validation of the RSM model was verified by the good agreement between the experimental and the predicted RV yield values. The optimum preparation conditions were as follows: temperature of 62.0 degrees C, enzyme load of 6.6%, and reaction time of 96 min. The proposed method may be highly applicable for the enzymatic preparation of RV for medicinal purposes. PMID- 23945646 TI - Microparticle-associated tissue factor is recycled by endothelial cells resulting in enhanced surface tissue factor activity. AB - In this study the uptake of tissue factor (TF)-positive microparticles by endothelial cells and the recycling of the TF component were examined. Human dermal blood endothelial cells (HDBEC) were incubated with microparticles derived from cancer cell lines for up to 6 hours. Measurement of HDBEC cell surface TF antigen revealed two distinct peaks at 30 and 180-240 minutes post-incubation with TF-positive, but not TF-deficient microparticles. However, only the second peak was concurrent with high TF activity as determined by a chromogenic thrombin generation assay. Annexin V-labelling of HDBEC showed phosphatidylserine exposure following 90 minutes incubation with microparticles, which explains the high TF activity associated with the second antigen peak. Analysis of TF mRNA levels revealed no de novo expression of TF mRNA in response to microparticles, and pre incubation of cells with cycloheximide did not prevent the appearance of TF. However, blocking endocytosis with a dynamin inhibitor prolonged the disappearance and prevented the reappearance of TF antigen on the cell surface. Incubation of HDBEC with microparticles containing TF-GFP revealed the early co localisation of TF with Rab4 and Rab5, followed by co-localisation with the late endosomal/trans-Golgi network marker Rab9, and the recycling endosome marker Rab11. siRNA-mediated suppression of Rab11 reduced the reappearance of TF on the cell surface. These data suggest a mechanism by which TF-containing microparticles are internalised by endothelial cells and the TF moiety recycled to the cell surface. Together with the exposure of phosphatidylserine, this is capable of inducing a substantial increase in the procoagulant potential of the surface of endothelial cells. PMID- 23945647 TI - Health staff exposed to HIV should take three or more antiretroviral drugs, say new US guidelines. PMID- 23945650 TI - [Pb(Tab)2(4,4'-bipy)](PF6)2: two-step ambient temperature quantitative solid state synthesis, structure and dielectric properties. AB - Ambient temperature solid-state reaction of Pb(OAc)2 with TabHPF6 afforded an intermediate product [Pb(Tab)2]2(PF6)4, which further reacted with 4,4'-bipy in the solid state to generate a unique 2D cationic coordination polymer [Pb(Tab)2(4,4'-bipy)](PF6)2 in quantitative yield. Both complexes possess a low dielectric constant and low dielectric loss in the high electric field frequency range. PMID- 23945652 TI - Discrimination of circulating tumor cells of breast cancer and colorectal cancer from normal human mononuclear cells using Raman spectroscopy. AB - Circulating tumor cells present an important marker of the progress of several cancer diseases including breast and colorectal cancer, and enables an interesting prognosis and diagnostic options that can complement convenient diagnostic techniques based on several imaging methods. Based on its relevance, the analysis of such kinds of cells is within the scope of many research and clinical institutes; however, it still presents a difficult task. Here we used a state-of-the-art micro-Raman microscopic technique to enhance possibilities in the study of circulating tumor cells and their further differentiation. As cytospins present a convenient form of sample collection and preparation, we used this form of sampling as the initial point. Raman presents a non-destructive form of sample analysis and thus the samples can be further used for a method validation. We have considered the influence of fixation methods of the cells, where we found out that the ability of Raman spectroscopy to differentiate between three cell lines strictly depends upon the sample preparation method used. Namely breast (BT 549) and colorectal (HCT 116) circulating tumor cell lines and human mononuclear cells were compared. Methanol and paraformaldehyde methods of fixation were compared to simple drying out of the sample. It has been shown that drying out of the cells enables the best performance to be obtained in cell differentiation and this is demonstrated by the use of principal component analysis, where all three given cell lines were differentiated with a high level of confidence. Next, the cells were also scanned using 1 MUm spatial resolution. The acquired data were visualized using both chemigrams and hierarchical clustering analysis. PMID- 23945656 TI - Nanocrystalline p-hydroxyacetanilide (paracetamol) and gold core-shell structure as a model drug deliverable organic-inorganic hybrid nanostructure. AB - We report on the generation of core-shell nanoparticles (NPs) having an organic nanocrystal (NC) core coated with an inorganic metallic shell, being dispersed in aqueous medium. First, NCs of p-hydroxyacetanilide (pHA)--known also as paracetamol--were generated in an aqueous medium. Transmission electron microscopy (TEM) and powder X-ray diffraction (XRD) evidenced the formation of pHA NCs and of their crystalline nature. The NCs were then coated with Au to form pHA@Au core-shell NPs, where the thickness of the Au shell was on the order of nanometers. The formation of Au nanoshell--surrounding pHA NC--was confirmed from its surface plasmon resonance (SPR) band in the UV/Vis spectrum and by TEM measurements. Further, on treatment of the core-shell particles with a solution comprising NaCl and HCl (pH < 3), the Au shell could be dissolved, subsequently releasing pHA molecules. The dissolution of Au shell was marked by a gradual diminishing of its SPR band, while the release of pHA molecules in the solution was confirmed from TEM and FTIR studies. The findings suggest that the core-shell NP could be hypothesized to be a model for encapsulating drug molecules, in their crystalline forms, for slow as well as targeted release. PMID- 23945651 TI - ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy. AB - Anticancer drug therapy activates both molecular cell death and autophagy pathways. Here we show that even sublethal concentrations of DNA-damaging drugs, such as etoposide and cisplatin, induce the expression of autophagy-related protein 5 (ATG5), which is both necessary and sufficient for the subsequent induction of mitotic catastrophe. We demonstrate that ATG5 translocates to the nucleus, where it physically interacts with survivin in response to DNA-damaging agents both in vitro and in carcinoma tissues obtained from patients who had undergone radiotherapy and/or chemotherapy. As a consequence, elements of the chromosomal passenger complex are displaced during mitosis, resulting in chromosome misalignment and segregation defects. Pharmacological inhibition of autophagy does not prevent ATG5-dependent mitotic catastrophe, but shifts the balance to an early caspase-dependent cell death. Our data suggest a dual role for ATG5 in response to drug-induced DNA damage, where it acts in two signalling pathways in two distinct cellular compartments, the cytosol and the nucleus. PMID- 23945661 TI - Dithia[3.3]paracyclophane-bridged bimetallic ruthenium acetylide complexes: synthesis, structures and influence of transannular pi-pi interactions on their electronic properties. AB - Two dithia[3.3]paracyclophane-bridged bimetallic ruthenium acetylide complexes 2 and 3, in which the upper deck of the cyclophanes were assembled with naphthalenyl and anthracenyl rings, have been designed and synthesized. X-ray crystal structures of 2 and 3 show that there are effective transannular pi-pi interactions between the two rings in the cyclophane unit. Electrochemistry studies revealed that the successive introduction of naphthalenyl and anthracenyl rings reduced the thermodynamic stability of the corresponding mixed-valence states of 2 and 3. Radical cations and dications of complexes 2 and 3 were generated after the addition of 1.0 or 2.0 equivalents of ferrocenium hexafluorophosphate ([FcH][PF6]). The nu(C=C) of radicals 2+ and 3+ shift 86 nm and 88 nm in contrast to 2 and 3, respectively. UV-Vis-NIR spectra of 2+ and 3+ exhibited three enveloped transitions in the NIR (10,000-4000 cm(-1)) range. DFT studies showed that the compositions of the FMOs of 2 and 3 are more naphthalenyl and anthracenyl in character than the upper deck of complex 1. Spectroscopy and DFT studies indicated that the influence of transannular pi-pi interactions on the electronic transitions is more pronounced than in complex 1. PMID- 23945662 TI - Electrochemical synthesis on single cells as templates. AB - The cell surface is made electrochemically active by interfacing with graphene sheets. The electrical and thermal properties of graphene allow the control of cell surface potential for electrochemical synthesis. Using this approach radially projecting ZnO nanorods are templated on the surface of single cells. This reported single cell photosensor has superior performance than similar devices made on planar surfaces. PMID- 23945663 TI - Magnonic band engineering by intrinsic and extrinsic mirror symmetry breaking in antidot spin-wave waveguides. AB - We theoretically study the spin-wave spectra in magnonic waveguides periodically patterned with nanoscale square antidots. We show that structural changes breaking the mirror symmetry of the waveguide can close the magnonic bandgap. The effect of these intrinsic symmetry breaking can be compensated by adjusted asymmetric external bias magnetic field, i.e., by an extrinsic factor. This allows for the recovery of the magnonic bandgaps. The described methods can be used for developing parallel models for recovering bandgaps closed due to a fabrication defect. The model developed here is particular to magnonics, an emerging field combining spin dynamics and spintronics. However, the underlying principle of this development is squarely based upon the translational and mirror symmetries, thus, we believe that this idea of correcting an intrinsic defect by extrinsic means, should be applicable to spin-waves in both exchange and dipolar interaction regimes, as well as to other waves in general. PMID- 23945664 TI - Differentiating haemostasis from thrombosis for therapeutic benefit. AB - The central role of platelets in the formation of the primary haemostatic plug as well as in the development of arterial thrombosis is well defined. In general, the molecular events underpinning these processes are broadly similar. Whilst it has long been known that disturbances in blood flow, changes in platelet reactivity and enhanced coagulation reactions facilitate pathological thrombus formation, the precise details underlying these events remain incompletely understood. Intravital microscopy studies have highlighted the dynamic and heterogeneous nature of thrombus development and demonstrated that there are considerable spatiotemporal differences in the activation states of platelets within a forming thrombus. In this review we will consider the factors regulating the activation state of platelets in a developing thrombus and discuss how specific prothrombotic factors may influence this process, leading to excessive thrombus propagation. We will also discuss some potentially novel therapeutic approaches that may reduce excess thrombus development whilst minimising bleeding risk. PMID- 23945665 TI - Older women's personal goals and exercise activity: an 8-year follow-up. AB - This study investigated the associations of personal goals with exercise activity, as well as the relationships between exercise-related and other personal goals, among older women. Both cross-sectional and longitudinal designs were used with a sample of 308 women ages 66-79 at baseline. Women who reported exercise-related personal goals were 4 times as likely to report high exercise activity at baseline than those who did not report exercise-related goals. Longitudinal results were parallel. Goals related to cultural activities, as well as to busying oneself around the home, coincided with exercise-related goals, whereas goals related to own and other people's health and independent living lowered the odds of having exercise-related goals. Helping older adults to set realistic exercise-related goals that are compatible with their other life goals may yield an increase in their exercise activity, but this should be evaluated in a controlled trial. PMID- 23945666 TI - Expanding the scope of metathesis: a survey of polyfunctional, single-site supported tungsten systems for hydrocarbon valorization. AB - Olefin metathesis is increasingly incorporated in polyfunctional industrial processes. The classical WO3/SiO2 olefin metathesis catalyst is combined to other catalysts in order to afford higher added-value chemicals. However, the combination of several reactions, not only in a single reactor, but also stemming from a single, multifunctional surface species is a desirable improvement regarding process issues. Well-defined surface organometallic tungsten species can be designed to implement targeted functionalities (carbene, hydride, alkyl, ...). By tuning the metal's coordination sphere, it is possible to combine metathesis with several reactions, such as (de)hydrogenation, dimerization or isomerization. Novel, unconventional reactions for the production and upgrading of alkanes and alkenes have thus been uncovered. The reactivity of this library of supported catalysts is discussed based on the type of mediated transformations: monofunctional (alkene and alkyne metathesis), bifunctional (1 butene or 2-butenes to propylene), trifunctional (ethylene to propylene, alkane metathesis, ...). Mechanistic considerations will be discussed to put these results in a wider perspective for future developments. PMID- 23945667 TI - Reversion of methicillin-resistant Staphylococcus aureus skin infections to methicillin-susceptible isolates. AB - IMPORTANCE: The rise of methicillin-resistant Staphylococcus aureus (MRSA) infections in the outpatient setting has led to a growing trend of empirical antibiotic treatment for MRSA. The limited oral antibiotics available and the growing resistance to these antibiotics make this a controversial practice. OBJECTIVE: To determine the frequency of patients with MRSA skin and soft-tissue infections (SSTIs) reverting to methicillin-susceptible Staphylococcus aureus (MSSA) positivity. DESIGN AND SETTING: Retrospective medical record review of inpatients and outpatients from our university hospital and clinics between January 1, 2000, and December 31, 2010. PARTICIPANTS: Patients in our institutional microbiological database were included if they had a MRSA-positive SSTI and subsequent culture-proven S aureus SSTI more than 1 month later. No sociodemographic restrictions were applied. A sample of at least 200 patients meeting the above criteria was desired. The database was sorted by ascending medical record number, with the first 1681 patients' medical records reviewed. Of these, 215 patients met our criteria. MAIN OUTCOMES AND MEASURES: Whether a patient remained MRSA positive in subsequent SSTIs or reverted to MSSA-positive infections. RESULTS: Of the total 215 patients, 64 (29.8%) had at least 1 incident of MSSA reversion, and 55 (25.6%) reverted to MSSA infections for the remainder of the study. We assessed various factors that might increase or decrease the likelihood of reversion. The presence of an invasive device was the only factor to demonstrate a statistically significant risk (relative risk, 1.20; 95% CI, 1.02-1.41; P = .03) toward remaining MRSA positive in subsequent infections. CONCLUSIONS AND RELEVANCE: Patients with MRSA SSTIs demonstrated the ability to revert to subsequent MSSA SSTIs with a significant frequency. Further study regarding MRSA risk factors and their effects on subsequent infections would be valuable in guiding empirical treatment. Reculturing new infections in previously MRSA-positive patients is a prudent management strategy as we recognize that susceptibilities of the S aureus organisms change. PMID- 23945674 TI - Impact of docosahexaenoic acid on gene expression during osteoclastogenesis in vitro--a comprehensive analysis. AB - Polyunsaturated fatty acids (PUFAs), especially n-3 polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are known to protect against inflammation-induced bone loss in chronic inflammatory diseases, such as rheumatoid arthritis, periodontitis and osteoporosis. We previously reported that DHA, not EPA, inhibited osteoclastogenesis induced by the receptor activator of nuclear factor-kappaB ligand (sRANKL) in vitro. In this study, we performed gene expression analysis using microarrays to identify genes affected by the DHA treatment during osteoclastogenesis. DHA strongly inhibited osteoclastogenesis at the late stage. Among the genes upregulated by the sRANKL treatment, 4779 genes were downregulated by DHA and upregulated by the EPA treatment. Gene ontology analysis identified sets of genes related to cell motility, cell adhesion, cell cell signaling and cell morphogenesis. Quantitative PCR analysis confirmed that DC-STAMP, an essential gene for the cell fusion process in osteoclastogenesis, and other osteoclast-related genes, such as Siglec-15, Tspan7 and Mst1r, were inhibited by DHA. PMID- 23945675 TI - Biological activities and bioavailability of mangosteen xanthones: a critical review of the current evidence. AB - Mangosteen (Garcinia mangostana L.) is a tropical tree native to Southeast Asia that produces a fruit whose pericarp contains a family of tricyclic isoprenylated polyphenols referred to as xanthones. Numerous in vitro studies have shown that these xanthones possess anti-oxidant, anti-proliferative, pro-apoptotic, anti inflammatory and anti-carcinogenic activities. Aggressive marketing of such health promoting benefits has resulted in mangosteen's classification as a "superfruit". This has led to sales of mangosteen containing beverages in USA alone exceeding $200 million in 2008 despite very limited animal and human studies. This review will (a) critically address recent reports of in vivo studies on the bioavailability and metabolism of mangosteen xanthones, (b) update the in vitro and in vivo data on anti-cancer and anti-inflammatory activities of mangosteen xanthones, and (c) suggest needed areas of inquiry regarding the absorption, metabolism and efficacy of mangosteen xanthones. PMID- 23945677 TI - Teleconsultations reduce greenhouse gas emissions. AB - OBJECTIVES: Health services contribute significantly to greenhouse gas emissions. New models of delivering care closer to patients have the potential to reduce travelling and associated emissions. We aimed to compare the emissions of patients attending a teleconsultation - an outpatient appointment using video conferencing equipment - with those of patients attending a face-to-face appointment. METHODS: We estimated the total distances travelled and the direct and indirect greenhouse gas emissions for 20,824 teleconsultations performed between 2004 and 2011 in Alentejo, a Portuguese region. These were compared to the distances and emissions that would have resulted if teleconsultations were not available and patients had to attend face-to-face outpatient appointments. Estimates were calculated using survey data on mode of transport, and national aggregate data for car engine size and fuel. A sensitivity analysis using the lower and upper quartiles for survey distances was performed. RESULTS: Teleconsultations led to reductions in distances and emissions of 95%. 2,313,819 km of travelling and 455 tonnes of greenhouse gas emissions were avoided (22 kg of carbon dioxide equivalent per patient). The incorporation of modes of transport and car engine size and fuel in the analysis led to emission estimates which were 12% smaller than those assuming all patients used an average car. CONCLUSIONS: The availability of remote care services can significantly reduce road travel and associated emissions. At a time when many countries are committed to reducing their carbon footprint, it is desirable to explore how these reductions could be incorporated into technology assessments and economic evaluations. PMID- 23945678 TI - The effect of the proximity of patients' nearest alternative hospital on their intention to search for information on hospital quality. AB - OBJECTIVE: In several countries, patients are encouraged to choose health care providers. Simultaneously, there is a tendency towards the concentration of health care, which might lessen the choice. Our aim was to assess the impact of patients' distances from their providers on their information-seeking, which is one element of choice. METHODS: Two thousand members of the Dutch Health Care Consumer Panel were sent a questionnaire that included a question on whether they would search for information about hospitals to inform their choice. Distances from providers were obtained from a database that includes the distances between all postcodes in the Netherlands. To assess the influence of distance on information-seeking, logistic regression analyses were conducted. RESULTS: There was a good response (75%). Older, less educated respondents were less inclined to seek information when their nearest alternative was located further away (OR 0.85; 95% CI: 0.79-0.92), and younger, more educated respondents were more inclined to search in this situation (OR 1.11; 95% CI: 1.01-1.22). CONCLUSIONS: As fewer older, less educated patients would search for information to guide their choice, they might not opt for the best hospital. Additionally, the need for providers to compete for the patronage of these patients might be lessened. PMID- 23945676 TI - Iron and zinc nutrition in the economically-developed world: a review. AB - This review compares iron and zinc food sources, dietary intakes, dietary recommendations, nutritional status, bioavailability and interactions, with a focus on adults in economically-developed countries. The main sources of iron and zinc are cereals and meat, with fortificant iron and zinc potentially making an important contribution. Current fortification practices are concerning as there is little regulation or monitoring of intakes. In the countries included in this review, the proportion of individuals with iron intakes below recommendations was similar to the proportion of individuals with suboptimal iron status. Due to a lack of population zinc status information, similar comparisons cannot be made for zinc intakes and status. Significant data indicate that inhibitors of iron absorption include phytate, polyphenols, soy protein and calcium, and enhancers include animal tissue and ascorbic acid. It appears that of these, only phytate and soy protein also inhibit zinc absorption. Most data are derived from single meal studies, which tend to amplify impacts on iron absorption in contrast to studies that utilize a realistic food matrix. These interactions need to be substantiated by studies that account for whole diets, however in the interim, it may be prudent for those at risk of iron deficiency to maximize absorption by reducing consumption of inhibitors and including enhancers at mealtimes. PMID- 23945679 TI - Impact of deprivation on occurrence, outcomes and health care costs of people with multiple morbidity. AB - OBJECTIVE: This study aimed to estimate the impact of deprivation on the occurrence, health outcomes and health care costs of people with multiple morbidity in England. METHODS: Cohort study in the UK Clinical Practice Research Datalink, using deprivation quintile (IMD2010) at individual postcode level. Incidence and mortality from diabetes mellitus, coronary heart disease, stroke and colorectal cancer, and prevalence of depression, were used to define multidisease states. Costs of health care use were estimated for each state from a two-part model. RESULTS: Data were analysed for 141,535 men and 141,352 women aged >=30 years, with 33,862 disease incidence events, and 13,933 deaths. Among incidences of single conditions, 22% were in the most deprived quintile and 19% in the least deprived; dual conditions, most deprived 26%, least deprived 16% and triple conditions, most deprived 29%, least deprived 14%. Deaths in participants without disease were distributed most deprived 22%, least deprived 19%; in participants with single conditions, most deprived 24%, least deprived 18%; dual conditions, most deprived 27%, least deprived 15%, and triple conditions, most deprived 33%, least deprived 17%. The relative rate of depression in most deprived participants with triple conditions, compared with least deprived and no disease, was 2.48 (1.74 to 3.54). Costs of health care use were associated with increasing deprivation and level of morbidity. CONCLUSIONS: The higher incidence of disease, associated with deprivation, channels deprived populations into categories of multiple morbidity with a greater prevalence of depression, higher mortality and higher costs. This has implications for the way that resources are allocated in England's National Health Service. PMID- 23945680 TI - Presentational approaches used in the UK for reporting evidence synthesis using indirect and mixed treatment comparisons. AB - OBJECTIVES: To establish current guidance and practice in UK on presentation of indirect comparison and mixed treatment comparison analyses; to provide recommendations to improve indirect comparison/mixed treatment comparison reporting and to identify research priorities for improved presentation. METHODS: Existing institutional guidance for conducting indirect comparison/mixed treatment comparison alongside current practice in health technology assessment was reviewed. Reports published in UK by the Health Technology Assessment programme since 1997, which utilized indirect comparison/mixed treatment comparison methods, were reviewed with respect to the presentation of study data, statistical models and results. Recommendations for presentation were developed. RESULTS: Guidance exists that provide the details necessary to conduct a successful indirect comparison/mixed treatment comparison analysis but recommendations on presentation are limited. Of 205 health technology assessment reports that contained evidence synthesis for effectiveness, 19 used indirect comparison/mixed treatment comparison methods. These reports utilized numerous presentational formats from which the following key components were identified: network table/diagram for presenting data; model description to allow reproducibility; and tables, forest plots, matrix tables and summary forest plots for presenting a range of results. Recommendations were developed to ensure that reporting is explicit, transparent and reproducible. Approaches most understandable by non-technical decision makers, and areas where future research is required, are outlined. CONCLUSIONS: There is no standard presentational style used in UK for reporting indirect comparison/mixed treatment comparison, and the use of graphical tools is limited. Standardization of reporting and innovation in graphical representation of indirect comparison/mixed treatment comparison results is required. PMID- 23945681 TI - Decoupling of morphological disparity and taxic diversity during the adaptive radiation of anomodont therapsids. AB - Adaptive radiations are central to macroevolutionary theory. Whether triggered by acquisition of new traits or ecological opportunities arising from mass extinctions, it is debated whether adaptive radiations are marked by initial expansion of taxic diversity or of morphological disparity (the range of anatomical form). If a group rediversifies following a mass extinction, it is said to have passed through a macroevolutionary bottleneck, and the loss of taxic or phylogenetic diversity may limit the amount of morphological novelty that it can subsequently generate. Anomodont therapsids, a diverse clade of Permian and Triassic herbivorous tetrapods, passed through a bottleneck during the end Permian mass extinction. Their taxic diversity increased during the Permian, declined significantly at the Permo-Triassic boundary and rebounded during the Middle Triassic before the clade's final extinction at the end of the Triassic. By sharp contrast, disparity declined steadily during most of anomodont history. Our results highlight three main aspects of adaptive radiations: (i) diversity and disparity are generally decoupled; (ii) models of radiations following mass extinctions may differ from those triggered by other causes (e.g. trait acquisition); and (iii) the bottleneck caused by a mass extinction means that a clade can emerge lacking its original potential for generating morphological variety. PMID- 23945682 TI - The evolution of complex gene regulation by low-specificity binding sites. AB - Requirements for gene regulation vary widely both within and among species. Some genes are constitutively expressed, whereas other genes require complex regulatory control. Transcriptional regulation is often controlled by a module of multiple transcription factor binding sites that, in combination, mediate the expression of a target gene. Here, we study how such regulatory modules evolve in response to natural selection. Using a population-genetic model, we show that complex regulatory modules which contain a larger number of binding sites must employ binding motifs that are less specific, on average, compared with smaller regulatory modules. This effect is extremely general, and it holds regardless of the selected binding logic that a module experiences. We attribute this phenomenon to the inability of stabilizing selection to maintain highly specific sites in large regulatory modules. Our analysis helps to explain broad empirical trends in the Saccharomyces cerevisiae regulatory network: those genes with a greater number of distinct transcriptional regulators feature less-specific binding motifs, compared with genes with fewer regulators. Our results also help to explain empirical trends in module size and motif specificity across species, ranging from prokaryotes to single-cellular and multi-cellular eukaryotes. PMID- 23945683 TI - The mitonuclear compatibility hypothesis of sexual selection. AB - Why females assess ornaments when choosing mates remains a central question in evolutionary biology. We hypothesize that the imperative for a choosing female to find a mate with nuclear oxidative phosphorylation (OXPHOS) genes that are compatible with her mitochondrial OXPHOS genes drives the evolution of ornaments. Indicator traits are proposed to signal the efficiency of OXPHOS function thus enabling females to select mates with nuclear genes that are compatible with maternal mitochondrial genes in the formation of OXPHOS complexes. Species typical pattern of ornamentation is proposed to serve as a marker of mitochondrial type ensuring that females assess prospective mates with a shared mitochondrial background. The mitonuclear compatibility hypothesis predicts that the production of ornaments will be closely linked to OXPHOS pathways, and that sexual selection for compatible mates will be strongest when genes for nuclear components of OXPHOS complexes are Z-linked. The implications of this hypothesis are that sexual selection may serve as a driver for the evolution of more efficient cellular respiration. PMID- 23945684 TI - Bone-eating worms from the Antarctic: the contrasting fate of whale and wood remains on the Southern Ocean seafloor. AB - We report the results from the first experimental study of the fate of whale and wood remains on the Antarctic seafloor. Using a baited free-vehicle lander design, we show that whale-falls in the Antarctic are heavily infested by at least two new species of bone-eating worm, Osedax antarcticus sp. nov. and Osedax deceptionensis sp. nov. In stark contrast, wood remains are remarkably well preserved with the absence of typical wood-eating fauna such as the xylophagainid bivalves. The combined whale-fall and wood-fall experiment provides support to the hypothesis that the Antarctic circumpolar current is a barrier to the larvae of deep-water species that are broadly distributed in other ocean basins. Since humans first started exploring the Antarctic, wood has been deposited on the seafloor in the form of shipwrecks and waste; our data suggest that this anthropogenic wood may be exceptionally well preserved. Alongside the new species descriptions, we conducted a comprehensive phylogenetic analyses of Osedax, suggesting the clade is most closely related to the frenulate tubeworms, not the vestimentiferans as previous reported. PMID- 23945685 TI - Responses to song playback vary with the vocal performance of both signal senders and receivers. AB - Mating signals of many animal species are difficult to produce and thus should indicate signaler quality. Growing evidence suggests that receivers modulate their behaviour in response to signals with varying performance levels, although little is known about if and how responses are affected by receiver attributes. To explore this topic we conducted two experiments with swamp sparrows, Melospiza georgiana, in which we challenged territorial males with playback of songs with trill rates that were natural, digitally reduced, or digitally elevated (control , low- and high-performance stimuli, respectively). In our first experiment, we found that males responded more aggressively to control songs than to low performance stimuli, that low-performance stimuli with the most severe trill-rate reductions elicited the weakest aggressive responses, and that the subjects' own trill rates predicted aggressive responses. In our second experiment, we found that male responses to high-performance stimuli varied significantly, in ways predicted by two factors: the degree to which we had elevated stimulus performance levels of high-performance stimuli, and subjects' own vocal performance levels. Specifically, males were less aggressive towards stimuli for which we had elevated performance levels to higher degrees, and subject males with higher vocal performances themselves responded more aggressively. These findings together offer a novel illustration of how responses to aggressive signals may rely not just on signal attributes, but also on attributes of responding animals themselves. PMID- 23945686 TI - Adrenocortical stress responses influence an invasive vertebrate's fitness in an extreme environment. AB - Continued range expansion into physiologically challenging environments requires invasive species to maintain adaptive phenotypic performance. The adrenocortical stress response, governed in part by glucocorticoid hormones, influences physiological and behavioural responses of vertebrates to environmental stressors. However, any adaptive role of this response in invasive populations that are expanding into extreme environments is currently unclear. We experimentally manipulated the adrenocortical stress response of invasive cane toads (Rhinella marina) to investigate its effect on phenotypic performance and fitness at the species' range front in the Tanami Desert, Australia. Here, toads are vulnerable to overheating and dehydration during the annual hot-dry season and display elevated plasma corticosterone levels indicative of severe environmental stress. By comparing unmanipulated control toads with toads whose adrenocortical stress response was manipulated to increase acute physiological stress responsiveness, we found that control toads had significantly reduced daily evaporative water loss and higher survival relative to the experimental animals. The adrenocortical stress response hence appears essential in facilitating complex phenotypic performance and setting fitness trajectories of individuals from invasive species during range expansion. PMID- 23945687 TI - Finding the 'lost years' in green turtles: insights from ocean circulation models and genetic analysis. AB - Organismal movement is an essential component of ecological processes and connectivity among ecosystems. However, estimating connectivity and identifying corridors of movement are challenging in oceanic organisms such as young turtles that disperse into the open sea and remain largely unobserved during a period known as 'the lost years'. Using predictions of transport within an ocean circulation model and data from published genetic analysis, we present to our knowledge, the first basin-scale hypothesis of distribution and connectivity among major rookeries and foraging grounds (FGs) of green turtles (Chelonia mydas) during their 'lost years'. Simulations indicate that transatlantic dispersal is likely to be common and that recurrent connectivity between the southwestern Indian Ocean and the South Atlantic is possible. The predicted distribution of pelagic juvenile turtles suggests that many 'lost years hotspots' are presently unstudied and located outside protected areas. These models, therefore, provide new information on possible dispersal pathways that link nesting beaches with FGs. These pathways may be of exceptional conservation concern owing to their importance for sea turtles during a critical developmental period. PMID- 23945688 TI - Tracking niche variation over millennial timescales in sympatric killer whale lineages. AB - Niche variation owing to individual differences in ecology has been hypothesized to be an early stage of sympatric speciation. Yet to date, no study has tracked niche width over more than a few generations. In this study, we show the presence of isotopic niche variation over millennial timescales and investigate the evolutionary outcomes. Isotopic ratios were measured from tissue samples of sympatric killer whale Orcinus orca lineages from the North Sea, spanning over 10 000 years. Isotopic ratios spanned a range similar to the difference in isotopic values of two known prey items, herring Clupea harengus and harbour seal Phoca vitulina. Two proxies of the stage of speciation, lineage sorting of mitogenomes and genotypic clustering, were both weak to intermediate indicating that speciation has made little progress. Thus, our study confirms that even with the necessary ecological conditions, i.e. among-individual variation in ecology, it is difficult for sympatric speciation to progress in the face of gene flow. In contrast to some theoretical models, our empirical results suggest that sympatric speciation driven by among-individual differences in ecological niche is a slow process and may not reach completion. We argue that sympatric speciation is constrained in this system owing to the plastic nature of the behavioural traits under selection when hunting either mammals or fish. PMID- 23945689 TI - Cutting the first 'teeth': a new approach to functional analysis of conodont elements. AB - The morphological disparity of conodont elements rivals the dentition of all other vertebrates, yet relatively little is known about their functional diversity. Nevertheless, conodonts are an invaluable resource for testing the generality of functional principles derived from vertebrate teeth, and for exploring convergence in a range of food-processing structures. In a few derived conodont taxa, occlusal patterns have been used to derive functional models. However, conodont elements commonly and primitively exhibit comparatively simple coniform morphologies, functional analysis of which has not progressed much beyond speculation based on analogy. We have generated high-resolution tomographic data for each morphotype of the coniform conodont Panderodus acostatus. Using virtual cross sections, it has been possible to characterize changes in physical properties associated with individual element morphology. Subtle changes in cross-sectional profile have profound implications for the functional performance of individual elements and the apparatus as a whole. This study has implications beyond the ecology of a single conodont taxon. It provides a basis for reinterpreting coniform conodont taxonomy (which is based heavily on cross-sectional profiles), in terms of functional performance and ecology, shedding new light on the conodont fossil record. This technique can also be applied to more derived conodont morphologies, as well as analogous dentitions in other vertebrates and invertebrates. PMID- 23945691 TI - When growth models are not universal: evidence from marine invertebrates. AB - The accumulation of body mass, as growth, is fundamental to all organisms. Being able to understand which model(s) best describe this growth trajectory, both empirically and ultimately mechanistically, is an important challenge. A variety of equations have been proposed to describe growth during ontogeny. Recently, the West Brown Enquist (WBE) equation, formulated as part of the metabolic theory of ecology, has been proposed as a universal model of growth. This equation has the advantage of having a biological basis, but its ability to describe invertebrate growth patterns has not been well tested against other, more simple models. In this study, we collected data for 58 species of marine invertebrate from 15 different taxa. The data were fitted to three growth models (power, exponential and WBE), and their abilities were examined using an information theoretic approach. Using Akaike information criteria, we found changes in mass through time to fit an exponential equation form best (in approx. 73% of cases). The WBE model predominantly overestimates body size in early ontogeny and underestimates it in later ontogeny; it was the best fit in approximately 14% of cases. The exponential model described growth well in nine taxa, whereas the WBE described growth well in one of the 15 taxa, the Amphipoda. Although the WBE has the advantage of being developed with an underlying proximate mechanism, it provides a poor fit to the majority of marine invertebrates examined here, including species with determinate and indeterminate growth types. In the original formulation of the WBE model, it was tested almost exclusively against vertebrates, to which it fitted well; the model does not however appear to be universal given its poor ability to describe growth in benthic or pelagic marine invertebrates. PMID- 23945690 TI - Vicariance across major marine biogeographic barriers: temporal concordance and the relative intensity of hard versus soft barriers. AB - The marine tropics contain five major biogeographic regions (East Pacific, Atlantic, Indian Ocean, Indo-Australian Archipelago (IAA) and Central Pacific). These regions are separated by both hard and soft barriers. Reconstructing ancestral vicariance, we evaluate the extent of temporal concordance in vicariance events across three major barriers (Terminal Tethyan Event (TTE), Isthmus of Panama (IOP), East Pacific Barrier, EPB) and two incomplete barriers (either side of the IAA) for the Labridae, Pomacentridae and Chaetodontidae. We found a marked lack of temporal congruence within and among the three fish families in vicariance events associated with the EPB, TTE and IOP. Vicariance across hard barriers separating the Atlantic and Indo-Pacific (TTE, IOP) is temporally diffuse, with many vicariance events preceding barrier formation. In marked contrast, soft barriers either side of the IAA hotspot support tightly concordant vicariance events (2.5 Myr on Indian Ocean side; 6 Myr on Central Pacific side). Temporal concordance in vicariance points to large-scale temporally restricted gene flow during the Late Miocene and Pliocene. Despite different and often complex histories, both hard and soft barriers have comparably strong effects on the evolution of coral reef taxa. PMID- 23945692 TI - Shared ancestry influences community stability by altering competitive interactions: evidence from a laboratory microcosm experiment using freshwater green algae. AB - The impact of biodiversity on the stability of ecological communities has been debated among biologists for more than a century. Recently summarized empirical evidence suggests that biodiversity tends to enhance the temporal stability of community-level properties such as biomass; however, the underlying mechanisms driving this relationship remain poorly understood. Here, we report the results of a microcosm study in which we used simplified systems of freshwater microalgae to explore how the phylogenetic relatedness of species influences the temporal stability of community biomass by altering the nature of their competitive interactions. We show that combinations of two species that are more evolutionarily divergent tend to have lower temporal stability of biomass. In part, this is due to negative 'selection effects' in which bicultures composed of distantly related species are more likely to contain strong competitors that achieve low biomass. In addition, bicultures of distantly related species had on average weaker competitive interactions, which reduced compensatory dynamics and decreased the stability of community biomass. Our results demonstrate that evolutionary history plays a key role in controlling the mechanisms, which give rise to diversity-stability relationships. As such, patterns of shared ancestry may help us predict the ecosystem-level consequences of biodiversity loss. PMID- 23945693 TI - Reciprocity explains food sharing in humans and other primates independent of kin selection and tolerated scrounging: a phylogenetic meta-analysis. AB - Helping, i.e. behaviour increasing the fitness of others, can evolve when directed towards kin or reciprocating partners. These predictions have been tested in the context of food sharing both in human foragers and non-human primates. Here, we performed quantitative meta-analyses on 32 independent study populations to (i) test for overall effects of reciprocity on food sharing while controlling for alternative explanations, methodological biases, publication bias and phylogeny and (ii) compare the relative effects of reciprocity, kinship and tolerated scrounging, i.e. sharing owing to costs imposed by others. We found a significant overall weighted effect size for reciprocity of r = 0.20-0.48 for the most and least conservative measure, respectively. Effect sizes did not differ between humans and other primates, although there were species differences in in kind reciprocity and trade. The relative effect of reciprocity in sharing was similar to those of kinship and tolerated scrounging. These results indicate a significant independent contribution of reciprocity to human and primate helping behaviour. Furthermore, similar effect sizes in humans and primates speak against cognitive constraints on reciprocity. This study is the first to use meta analyses to quantify these effects on human helping and to directly compare humans and other primates. PMID- 23945694 TI - Olfaction spontaneously highlights visual saliency map. AB - Attention is intrinsic to our perceptual representations of sensory inputs. Best characterized in the visual domain, it is typically depicted as a spotlight moving over a saliency map that topographically encodes strengths of visual features and feedback modulations over the visual scene. By introducing smells to two well-established attentional paradigms, the dot-probe and the visual-search paradigms, we find that a smell reflexively directs attention to the congruent visual image and facilitates visual search of that image without the mediation of visual imagery. Furthermore, such effect is independent of, and can override, top down bias. We thus propose that smell quality acts as an object feature whose presence enhances the perceptual saliency of that object, thereby guiding the spotlight of visual attention. Our discoveries provide robust empirical evidence for a multimodal saliency map that weighs not only visual but also olfactory inputs. PMID- 23945695 TI - Rates of dinosaur limb evolution provide evidence for exceptional radiation in Mesozoic birds. AB - Birds are the most diverse living tetrapod group and are a model of large-scale adaptive radiation. Neontological studies suggest a radiation within the avian crown group, long after the origin of flight. However, deep time patterns of bird evolution remain obscure because only limited fossil data have been considered. We analyse cladogenesis and limb evolution on the entire tree of Mesozoic theropods, documenting the dinosaur-bird transition and immediate origins of powered flight. Mesozoic birds inherited constraints on forelimb evolution from non-flying ancestors, and species diversification rates did not accelerate in the earliest flying taxa. However, Early Cretaceous short-tailed birds exhibit both phenotypic release of the hindlimb and increased diversification rates, unparalleled in magnitude at any other time in the first 155 Myr of theropod evolution. Thus, a Cretaceous adaptive radiation of stem-group birds was enabled by restructuring of the terrestrial locomotor module, which represents a key innovation. Our results suggest two phases of radiation in Avialae: with the Cretaceous diversification overwritten by extinctions of stem-group birds at the Cretaceous-Palaeogene boundary, and subsequent diversification of the crown group. Our findings illustrate the importance of fossil data for understanding the macroevolutionary processes generating modern biodiversity. PMID- 23945696 TI - Endovascular stenting with open surgery for reconstructions of the ascending aorta and the aortic arch: a review of indications and results of hybrid techniques. AB - Hybrid approaches for repair of aneurysms involving the ascending aorta and the aortic arch have been developed to avoid or reduce duration of cardiopulmonary bypass and circulatory arrest and to decrease operative time, blood loss, hospital stay, morbidity, and mortality. These include ascending aorta-based debranching or cervical extra-anatomical bypasses followed by stent-grafting. In patients with associated descending aortic aneurysms, the elephant trunk technique is used followed by stent-grafting of the descending thoracic aorta. A review of the literature of hybrid aortic arch reconstructions, published over past 7 years, reveals perioperative mortalities from 0% to 13%, stroke from 0% to 10%, and spinal cord injury in 0% to 13%. The outcomes are comparable to contemporary results from total open and total endovascular reconstructions in spite of the fact that the hybrid approach is generally taken in patients with high surgical risk for open repair and with prohibitive anatomy for total endovascular repair. PMID- 23945700 TI - Polyhedral oligomeric silsesquioxane (POSS)-based multifunctional organic-silica hybrid monoliths. AB - A facile polyhedral oligomeric silsesquioxane (POSS)-based hybrid monolith with multiple mechanisms was developed by an in situ polymerization. High mechanical stability and good separation capabilities to polar and hydrophobic analytes were successfully achieved. An ideal versatile organic-silica hybrid monolith was presented for easy access to the efficient separation of various analytes. PMID- 23945701 TI - Quantum criticality in electron-doped BaFe2-xNixAs2. AB - A quantum critical point is a point in a system's phase diagram at which an order is completely suppressed at absolute zero temperature (T). The presence of a quantum critical point manifests itself in the finite-T physical properties, and often gives rise to new states of matter. Superconductivity in the cuprates and in heavy fermion materials is believed by many to be mediated by fluctuations associated with a quantum critical point. In the recently discovered iron pnictide superconductors, we report transport and NMR measurements on BaFe(2 x)Ni(x)As2 (0<=x<=0.17). We find two critical points at x(c1)=0.10 and x(c2)=0.14. The electrical resistivity follows rho=rho0+AT(n), with n=1 around x(c1) and another minimal n=1.1 at x(c2). By NMR measurements, we identity x(c1) to be a magnetic quantum critical point and suggest that x(c2) is a new type of quantum critical point associated with a nematic structural phase transition. Our results suggest that the superconductivity in carrier-doped pnictides is closely linked to the quantum criticality. PMID- 23945704 TI - Exploring the role of the 5-substituent for the intrinsic fluorescence of 5-aryl and 5-heteroaryl uracil nucleotides: a systematic study. AB - Derivatives of UMP (uridine monophosphate) with a fluorogenic substituent in position 5 represent a small but unique class of fluorophores, which has found important applications in chemical biology and biomolecular chemistry. In this study, we have synthesised a series of derivatives of the uracil nucleotides UMP, UDP and UTP with different aromatic and heteroaromatic substituents in position 5, in order to systematically investigate the influence of the 5-substituent on fluorescence emission. We have determined relevant photophysical parameters for all derivatives in this series, including quantum yields for the best fluorophores. The strongest fluorescence emission was observed with a 5 formylthien-2-yl substituent in position 5 of the uracil base, while the corresponding 3-formylthien-2-yl-substituted regioisomer was significantly less fluorescent. The 5-(5-formylthien-2-yl) uracil fluorophore was studied further in solvents of different polarity and proticity. In conjunction with results from a conformational analysis based on NMR data and computational experiments, these findings provide insights into the steric and electronic factors that govern fluorescence emission in this class of fluorophores. In particular, they highlight the interplay between fluorescence emission and conformation in this series. Finally, we carried out ligand-binding experiments with the 5-(5 formylthien-2-yl) uracil fluorophore and a UDP-sugar-dependent glycosyltransferase, demonstrating its utility for biological applications. The results from our photophysical and biological studies suggest, for the first time, a structural explanation for the fluorescence quenching effect that is observed upon binding of these fluorophores to a target protein. PMID- 23945705 TI - Abnormal N-heterocyclic carbene main group organometallic chemistry: a debut to the homogeneous catalysis. AB - Abnormal N-heterocyclic carbene (aNHC) adducts of zinc(II) (1) and aluminum(III) (2) were synthesized. The compounds were characterized by NMR spectroscopy and elemental analysis. The solid state structures of these complexes (1 and 2) were determined by single crystal X-ray study. Furthermore, these organozinc and organoaluminum adducts (1 and 2) were tested for the ring opening polymerization of cyclic esters. These adducts were found to be quite efficient catalysts for the polymerization of cyclicesters such as rac-lactide (rac-LA), epsilon caprolactone (epsilon-CL), and delta-valerolactone (delta-VL). Furthermore, aNHC zinc adduct has been used as catalyst for the synthesis of a tri-block copolymer. PMID- 23945710 TI - Biodegradation-inspired bioproduction of methylacetoin and 2-methyl-2,3 butanediol. AB - Methylacetoin (3-hydroxy-3-methylbutan-2-one) and 2-methyl-2,3-butanediol are currently obtained exclusively via chemical synthesis. Here, we report, to the best of our knowledge, the first alternative route, using engineered Escherichia coli. The biological synthesis of methylacetoin was first accomplished by reversing its biodegradation, which involved modifying the enzyme complex involved, switching the reaction substrate, and coupling the process to an exothermic reaction. 2-Methyl-2,3-butanediol was then obtained by reducing methylacetoin by exploiting the substrate promiscuity of acetoin reductase. A complete biosynthetic pathway from renewable glucose and acetone was then established and optimized via in vivo enzyme screening and host metabolic engineering, which led to titers of 3.4 and 3.2 g l(-1) for methylacetoin and 2 methyl-2,3-butanediol, respectively. This work presents a biodegradation-inspired approach to creating new biosynthetic pathways for small molecules with no available natural biosynthetic pathway. PMID- 23945711 TI - [Adenoidectomy, myringotomy and timpani drainage: what to consider in a child with hyperekplexia]. PMID- 23945712 TI - [Obstruction of the upper respiratory tract by a subglottic expansive lesion. Part II]. PMID- 23945713 TI - [Complications in 312 cases of nasal and auricular reconstruction via autologous rib cartilage]. AB - BACKGROUND: We present the results and complications with autologous rib cartilage in comparison to other materials in nasal and auricular reconstruction using a large patient collective from our clinic. MATERIAL AND METHODS: The retrospective study included all cases of auricular and nasal reconstruction via rib cartilage between 2001 and 2009. The outcome was analysed by subjective and objective parameters. RESULTS: 51/321 patients underwent plastic reconstructive surgery of the nose, 270/321 received a partial or complete auricle reconstruction with autologous rib cartilage. The complication rate e.g. of hematomas, lesions of the pleura, postoperative pain and keloids at the donation site was small. Concerning the aesthetic results of the nose and auricles 273 of 321 (85%) were satisfied after the first operation. Only 3/51 nasal reconstructions underwent a second operation. In case of complete auricular reconstructions, all patients underwent at least 2 operations for the three dimensional look. CONCLUSIONS: The use of autologous rip cartilage is still a good option in the auricular and nasal reconstruction. Depending on the expertise of the surgeon the postoperative aesthetic results are good with a low complication rate. However concerning the bigger effort in several aspects for the surgeon as the patient it should be reserved to specific indication criterias. PMID- 23945714 TI - [An update: keratocystic odontogenic tumor--a cyst to a tumor]. AB - According to the 2005 WHO classification of head neck tumors the parakeratinized form of the odontogenic keratocyst (primordial cyst) is listed as benign odontogenic tumor and is classified as keratocystic odontogenic tumor (KCOT). In this short communication the surgical regimen as well as KCOT as an entity are discussed. PMID- 23945715 TI - Scope of controlled synthesis via chain-growth condensation polymerization: from aromatic polyamides to pi-conjugated polymers. AB - Conventional condensation polymerization proceeds in a step-growth polymerization manner, in which the generated polymers possess a broad molecular weight distribution, and control over molecular weight and polymer end groups is difficult. However, the mechanism of condensation polymerization of some monomers has been converted from step-growth to chain-growth by means of activation of the polymer end group, either due to the difference in substituent effects between the monomer and the polymer, or due to successive intramolecular transfer of catalyst to the polymer end. In this article, we review recent developments in chain-growth condensation polymerization (CGCP) in these two areas. The former approach has yielded many architectures containing aromatic polyamides and aromatic polyethers, with unique properties. In the latter case, the mechanism, catalysts, and initiators of Ni- and Pd-catalyzed coupling polymerizations leading to poly(alkylthiophene)s and poly(p-phenylene)s have been extensively investigated. Other well-defined pi-conjugated polymers, such as polyfluorenes, n type polymers, and alternating aryl polymers, have also been synthesized by means of catalyst-transfer condensation polymerization. Many pi-conjugated polymer architectures prepared by utilizing catalyst-transfer condensation polymerization are not covered in this article. PMID- 23945716 TI - Effects of sea buckthorn and bilberry on serum metabolites differ according to baseline metabolic profiles in overweight women: a randomized crossover trial. AB - BACKGROUND: Berries are associated with health benefits. Little is known about the effect of baseline metabolome on the overall metabolic responses to berry intake. OBJECTIVE: We studied the effects of berries on serum metabolome. DESIGN: Eighty overweight women completed this randomized crossover study. During the interventions of 30 d, subjects consumed dried sea buckthorn berries (SBs), sea buckthorn oil (SBo), sea buckthorn phenolics ethanol extract mixed with maltodextrin (SBe+MD) (1:1), or frozen bilberries. Metabolic profiles were quantified from serum samples by using (1)H nuclear magnetic resonance spectroscopy. RESULTS: All interventions induced a significant (P < 0.001-0.003) effect on the overall metabolic profiles. The effect was observed both in participants who had a metabolic profile that reflected higher cardiometabolic risk at baseline (group B: P = 0.001-0.008) and in participants who had a lower risk profile (group A: P < 0.001-0.009). Although most of the changes in individual metabolites were not statistically significant after correction for multiplicity, clear trends were observed. SB-induced effects were mainly on serum triglycerides and very-low-density lipoprotein (VLDL) and its subclasses, which decreased in metabolic group B. SBo induced a decreasing trend in serum total, intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) cholesterol and subfractions of IDL and LDL in group B. During the SBe+MD treatment, VLDL fractions and serum triglycerides increased. Bilberries caused beneficial changes in serum lipids and lipoproteins in group B, whereas the opposite was true in group A. CONCLUSION: Berry intake has overall metabolic effects, which depend on the cardiometabolic risk profile at baseline. This trial was registered at clinicaltrials.gov as NCT01860547. PMID- 23945718 TI - Whole grain and body weight changes in apparently healthy adults: a systematic review and meta-analysis of randomized controlled studies. AB - BACKGROUND: Whole grains have received increased attention for their potential role in weight regulation. A high intake has been associated with smaller weight gain in prospective cohort studies, whereas the evidence from randomized controlled studies has been less consistent. OBJECTIVE: We assessed the effects of whole-grain compared with non-whole-grain foods on changes in body weight, percentage of body fat, and waist circumference by using a meta-analytic approach. DESIGN: We conducted a systematic literature search in selected databases. Studies were included in the review if they were randomized controlled studies of whole-grain compared with a non-whole-grain control in adults. A total of 2516 articles were screened for eligibility, and relevant data were extracted from 26 studies. Weighted mean differences were calculated, and a metaregression analysis was performed by using the whole-grain dose (g/d). RESULTS: Data from 2060 participants were included. Whole-grain intake did not show any effect on body weight (weighted difference: 0.06 kg; 95% CI: -0.09, 0.20 kg; P = 0.45), but a small effect on the percentage of body fat was seen (weighted difference: 0.48%; 95% CI: -0.95%, -0.01%; P = 0.04) compared with that for a control. An examination of the impact of daily whole-grain intake could predict differences between groups, but there was no significant association (beta = -0.0013 kg * g/d; 95% CI: -0.011, 0.009 kg * g/d). CONCLUSIONS: Whole-grain consumption does not decrease body weight compared with control consumption, but a small beneficial effect on body fat may be present. The relatively short duration of intervention studies (<=16 wk) may explain the lack of difference in body weight and fat. Discrepancies between studies may be caused by differences in study design. PMID- 23945717 TI - Association between prehospital vitamin D status and hospital-acquired bloodstream infections. AB - BACKGROUND: Alterations in immune function can predispose patients to nosocomial infections. Few studies have explored potentially modifiable host factors that may improve immune function and decrease risk of hospital-acquired bloodstream infection (HABSI). Vitamin D is a key regulator of innate and adaptive immune systems that may influence host susceptibility to infections. OBJECTIVE: We investigated the association between prehospital serum 25-hydroxyvitamin D [25(OH)D] concentrations and risk of HABSI. DESIGN: We performed a retrospective cohort study of 2135 adult patients from 2 Boston teaching hospitals. All patients had 25(OH)D concentrations measured before hospitalization between 1993 and 2010. The main outcome measure was HABSI, which was defined as positive blood cultures from samples drawn 48 h after hospital admission. Coagulase-negative Staphylococcus isolates were not considered to be bloodstream infections. Associations between 25(OH)D groups and HABSI were estimated by using bivariable and multivariable logistic regression models. Adjusted ORs were estimated with the inclusion of covariate terms thought to plausibly interact with both 25(OH)D concentration and HABSI. RESULTS: Compared with patients with 25(OH)D concentrations >=30 ng/mL, patients with concentrations <30 ng/mL had higher odds of HABSI. For 25(OH)D concentrations <10 ng/mL, the OR was 2.33 (95% CI: 1.45, 3.74); for 25(OH)D concentrations from 10 to 19.9 ng/mL, the OR was 1.60 (95% CI: 1.04, 2.46); and for 25(OH)D concentrations from 20 to 29.9 ng/mL, the OR was 1.13 (95% CI: 0.69, 1.84). After adjustment for age, sex, race (nonwhite compared with white), patient type (medical compared with surgical), and Deyo-Charlson index, the ORs of HABSI were 1.95 (95% CI: 1.22, 3.12), 1.36 (95% CI: 0.89, 2.07), and 0.98 (95% CI: 0.60, 1.62), respectively. CONCLUSIONS: The analysis of 2135 adult patients showed that 25(OH)D concentrations <10 ng/mL before hospitalization were associated with significantly increased odds of developing HABSI. These data support the initiation of randomized trials to test the role of vitamin D supplementation in HABSI prevention. PMID- 23945719 TI - Effects of an intervention to promote breastfeeding on maternal adiposity and blood pressure at 11.5 y postpartum: results from the Promotion of Breastfeeding Intervention Trial, a cluster-randomized controlled trial. AB - BACKGROUND: Differences between mothers who do and do not succeed in breastfeeding are likely to confound associations of lactation with later maternal adiposity. OBJECTIVE: We compared adiposity and blood pressure (BP) in women randomly assigned to an intervention to promote prolonged and exclusive breastfeeding or usual care. DESIGN: We performed a cluster-randomized trial at 31 hospitals in Belarus in 1996-1997. RESULTS: Of 17,046 women enrolled at delivery, we assessed 11,867 women (69.6%) at 11.5 y postpartum. The prevalence of exclusive breastfeeding >=3 mo was 44.5% in 6321 women in the intervention group and 7.1% in 5546 women in the control group. At 11.5 y postpartum, mean (+/ SD) body mass index (BMI; in kg/m(2)) was 26.5 +/- 5.5, the percentage of body fat was 33.6% +/- 8.3%, and systolic BP was 124.6 +/- 14.6 mm Hg. On intention-to treat analysis (without imputation) with adjustment for clustering by hospital, mean outcomes were lower in intervention compared with control mothers for BMI (mean difference: -0.27; 95% CI: -0.91, 0.37), body fat (-0.49%; 95% CI: -1.25%, 0.27%), and systolic BP (-0.81 mm Hg; 95% CI: -3.33, 1.71 mm Hg), but effect sizes were small, CIs were wide, and results were attenuated further toward the null after adjustment for baseline characteristics. Results were similar in sensitivity analyses [ie, by using conventional observational analyses disregarding treatment assignment, instrumental variable analyses to estimate the causal effect of breastfeeding, and multiple imputation to account for missing outcome measures (n = 17,046)]. CONCLUSION: In women who initiated breastfeeding, an intervention to promote longer breastfeeding duration did not result in an important lowering of adiposity or BP. This trial was registered at clinicaltrials.gov as NCT01561612 and at Current Controlled Trials as ISRCTN37687716. PMID- 23945720 TI - Zinc supplementation improves bone density in patients with thalassemia: a double blind, randomized, placebo-controlled trial. AB - BACKGROUND: Patients with thalassemia major (Thal) frequently have low plasma zinc, which has been associated with low bone mass. OBJECTIVE: The objective was to determine the effect of zinc supplementation on bone mass in patients with Thal. DESIGN: Forty-two subjects (21 females aged 10-30 y) with Thal and low bone mass were randomly assigned to receive 25 mg Zn/d or placebo. Bone mineral content (BMC) and areal bone mineral density (aBMD) were assessed by using dual energy X-ray absorptiometry, and fasting blood was collected for the measurement of plasma zinc at 0, 12, and 18 mo. RESULTS: Thirty-two subjects, 81% of whom were transfusion dependent, completed the study (mean +/- SD: 17.1 +/- 5.2 y). Plasma zinc was <=70 MUg/dL in 11 subjects at baseline and increased significantly with zinc supplementation (P = 0.014). Use of intention-to-treat analysis and linear models for longitudinal data, adjusted for baseline and pubertal stage, showed that the zinc group had significantly greater increases in whole-body BMC (adjusted mean +/- SE: 63 +/- 15 g; P = 0.02), and aBMD (0.023 +/- 0.006 g/cm(2); P = 0.04) than did the placebo group after 18 mo. Furthermore, adjusted spine and hip aBMD z scores each decreased by 0.3 SDs (both P = 0.04) in the placebo compared with the zinc group over the 18-mo study. CONCLUSIONS: In young patients with Thal, zinc supplementation resulted in greater gains in total body bone mass than did placebo. Zinc was well tolerated and is worthy of investigation in larger trials in Thal patients across a range of ages and disease severity. This trial was registered at clinicaltrials.gov as NCT00459732. PMID- 23945721 TI - Near-elimination of folate-deficiency anemia by mandatory folic acid fortification in older US adults: Reasons for Geographic and Racial Differences in Stroke study 2003-2007. AB - BACKGROUND: The United States implemented mandatory folic acid fortification of enriched cereal grains in 1998. Although several studies have documented the resulting decrease in anemia and folate deficiency, to our knowledge, no one has determined the prevalence of folate-deficiency anemia after fortification. OBJECTIVE: We determined the prevalence of folate deficiency and folate deficiency anemia within a sample of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. DESIGN: The REGARDS cohort is a prospective cohort of 30,239 black and white participants living in the contiguous United States. We measured serum folate concentrations in a random sample of 1546 REGARDS participants aged >=50 y with baseline hemoglobin and red blood cell mean corpuscular volume measurements. Folate deficiency was defined as a serum folate concentration <6.6 nmol/L (<3.0 ng/mL), and anemia was defined as a hemoglobin concentration <13 g/dL in men and <12 g/dL in nonpregnant women (WHO criteria). Folate-deficiency anemia was defined as the presence of both folate deficiency and anemia. RESULTS: The mean hemoglobin concentration was 13.6 g/dL, and 15.9% of subjects had anemia. The median serum folate concentration was 34.2 nmol/L (15.1 ng/mL), and only 2 of 1546 participants 0.1%) were folate deficient. Both subjects were African American women with markedly elevated C-reactive protein concentrations, macrocytosis, and normal serum cobalamin concentrations; only one subject was anemic. Overall, the prevalence of folate-deficiency anemia was <0.1% (1 of 1546 subjects). CONCLUSION: Our data suggest that, after mandatory folic acid fortification, the prevalence of folate-deficiency anemia is nearly nonexistent in a community-dwelling population in the United States. PMID- 23945722 TI - Dairy products and the risk of type 2 diabetes: a systematic review and dose response meta-analysis of cohort studies. AB - BACKGROUND: The association between intake of dairy products and the risk of type 2 diabetes has been investigated in several studies, but the evidence is not conclusive. OBJECTIVE: We conducted an updated systematic review and dose response meta-analysis of dairy product intake and the risk of type 2 diabetes. DESIGN: We searched the PubMed database for prospective cohort and nested case control studies of dairy product intake and risk of type 2 diabetes up to 5 June 2013. Summary RRs were estimated by use of a random-effects model. RESULTS: Seventeen cohort studies were included in the meta-analysis. In the dose-response analysis, the summary RRs (95% CIs) were 0.93 (0.87, 0.99; I(2) = 33%) per 400 g total dairy products/d (n = 12), 0.98 (0.94, 1.03; I(2) = 8%) per 200 g high-fat dairy products/d (n = 9), 0.91 (0.86, 0.96; I(2) = 40%) per 200 g low-fat dairy products/d (n = 9), 0.87 (0.72, 1.04; I(2) = 94%) per 200 g milk/d (n = 7), 0.92 (0.86, 0.99; I(2) = 0%) per 50 g cheese/d (n = 8), and 0.78 (0.60, 1.02; I(2) = 70%) per 200 g yogurt/d (n = 7). Nonlinear inverse associations were observed for total dairy products (P-nonlinearity < 0.0001), low-fat dairy products (P nonlinearity = 0.06), cheese (P-nonlinearity = 0.05), and yogurt (P-nonlinearity = 0.004), and there was a flattening of the curve at higher intakes. CONCLUSIONS: This meta-analysis suggests that there is a significant inverse association between intakes of dairy products, low-fat dairy products, and cheese and risk of type 2 diabetes. Any additional studies should assess the association between other specific types of dairy products and the risk of type 2 diabetes and adjust for more confounding factors. PMID- 23945724 TI - Efficacy and safety of new complementary feeding guidelines with an emphasis on red meat consumption: a randomized trial in Bogota, Colombia. AB - BACKGROUND: Iron deficiency and poor linear growth are common in infants from deprived socioeconomic backgrounds and may be associated with inadequate complementary feeding (CF) practices. OBJECTIVE: We tested the hypothesis that new CF guidelines emphasizing meat as a source of iron and zinc would improve linear growth, iron, and zinc status in infants living in poor socioeconomic circumstances in Bogota, Colombia. DESIGN: A total of 85 term infants who were exclusively breastfed for >=4 mo were randomly assigned at 6 mo of age to a control group [CG (n = 43); current advice] or intervention group (new guidelines group [NGG (n = 42); with counseling to 1) continue breastfeeding, 2) offer red meat >=3 d/wk, and 3) offer fruit and vegetables daily]). Main outcomes were 1) linear growth from 6 to 12 mo of age; 2) hemoglobin, hematocrit, iron [serum ferritin (SF)], and zinc status at 12 mo of age; and 3) meat intake at 12 mo of age (by using a food-frequency questionnaire). RESULTS: A total of 38 infants/group provided data at 12 mo of age. NGG infants had significantly higher red meat intake [mean +/- SD: 5.4 +/- 1.8 compared with 3.5 +/- 1.7 d/wk at 12 mo of age; P < 0.001), higher hemoglobin and hematocrit at 12 mo of age, and a significantly greater increase in hemoglobin (mean +/- SD change: 0.41 +/- 0.8 compared with -0.13 +/- 1.0; P = 0.01) and hematocrit (1.04 +/- 2.2 compared with -0.15 +/- 2.4; P = 0.03) from 6 to 12 mo of age than those in CG infants. There were no significant differences in linear growth from 6 to 12 mo of age or in SF or zinc. CONCLUSIONS: The new guidelines showed efficacy with higher red meat intake and positive effects on hemoglobin and hematocrit. The intervention was acceptable and affordable for most mothers. These preliminary results suggest that the intervention merits investigation in a larger cohort with longer-term follow-up. This trial was registered at http://isrctn.org as ISRCTN57733004. PMID- 23945723 TI - Arginine appearance and nitric oxide synthesis in critically ill infants can be increased with a protein-energy-enriched enteral formula. AB - BACKGROUND: Arginine is considered an essential amino acid during critical illness in children, and supplementation of arginine has been proposed to improve arginine availability to facilitate nitric oxide (NO) synthesis. Protein-energy enriched enteral formulas (PE-formulas) can improve nutrient intake and promote anabolism in critically ill infants. However, the effect of increased protein and energy intake on arginine metabolism is not known. OBJECTIVE: We investigated the effect of a PE-formula compared with that of a standard infant formula (S formula) on arginine kinetics in critically ill infants. DESIGN: A 2-h stable isotope tracer protocol was conducted in 2 groups of critically ill infants with respiratory failure because of viral bronchiolitis, who received either a PE formula (n = 8) or S-formula (n = 10) in a randomized, blinded, controlled setting. Data were reported as means +/- SDs. RESULTS: The intake of a PE-formula in critically ill infants (aged 0.23 +/- 0.14 y) resulted in an increased arginine appearance (PE-formula: 248 +/- 114 MUmol . kg(-1) . h(-1); S-formula: 130 +/- 53 MUmol . kg(-1) . h(-1); P = 0.012) and NO synthesis (PE-formula: 1.92 +/- 0.99 MUmol . kg(-1) . h(-1); S-formula: 0.84 +/- 0.36 MUmol . kg(-1) . h(-1); P = 0.003), whereas citrulline production and plasma arginine concentrations were unaffected. CONCLUSION: In critically ill infants with respiratory failure because of viral bronchiolitis, the intake of a PE-formula increases arginine availability by increasing arginine appearance, which leads to increased NO synthesis, independent of plasma arginine concentrations. This trial was registered at www.trialregister.nl as NTR515. PMID- 23945725 TI - A worldwide survey to assess the current approach to the treatment of patients with cancer and venous thromboembolism. AB - Low-molecular-weight heparin (LWMH) is recommended as the preferred anticoagulant treatment over vitamin K antagonists (VKA) for venous thromboembolism (VTE) in patients with cancer. However, there is uncertainty about the duration and dose of LMWH treatment. Therefore, we designed this multinational survey to assess the current approach to the treatment of patients with cancer and VTE. An electronic survey tool was used to disseminate a survey containing 49 questions on different aspects of the treatment of patients with cancer and VTE, among both thrombosis and non-thrombosis specialists. A total of 229 invitations were sent, and 141 completed the survey (60% of the total). Fifty-eight percent of the respondents were from Europe, 35% from the US and the remaining 7% from other countries. Respondent's specialties included haematology (23%), oncology (18%), pulmonology (15%) and general internal medicine (15%). LMWH was indicated as the first choice for the long-term treatment by 82% of the respondents, of whom 60% used full therapeutic doses and 40% chose a dose reduction. When continuing anticoagulants after the long-term treatment period, 44% of respondents preferred LMWH, 10% VKA, while the remaining 45% chose per individual patient for either LMWH or VKA. In conclusion, we observed a relatively high observance rate of the guidelines with respect to the use of LMWH for the long-term treatment of VTE in cancer. In contrast, the dose of LMWH and the type of anticoagulant chosen after the initial 3-12 months varied substantially, probably reflecting the limited available evidence. PMID- 23945727 TI - Synthesis, structure and reactivity of rare-earth metal complexes containing anionic phosphorus ligands. AB - A comprehensive review of structurally characterized rare-earth metal complexes containing anionic phosphorus ligands is presented. Since rare-earth elements form hard ions and phosphorus is considered as a soft ligand, the rare-earth metal phosphorus coordination is regarded as a less favorite combination. Three classes of phosphorus ligands, (1) the monoanionic organophosphide ligands (PR2( )) bearing one negative charge on the phosphorus atom; (2) the dianionic phosphinidene (PR(2-)) and P(3-) ligands; and (3) the pure inorganic polyphosphide ligands (Pn(x-)), are included here. Particular attention has been paid to the synthesis, structure, and reactivity of the rare-earth metal phosphides. PMID- 23945726 TI - Community-based exergaming program increases physical activity and perceived wellness in older adults. AB - Exergaming may be an effective strategy to increase physical activity participation among rural older adults. This pilot project examined the effects of a 24-wk exergaming and wellness program (8 wk onsite exergaming, 16-wk wellness newsletter intervention) on physical activity participation and subjective health in 46 rural older adults. Sociodemographic data and self reported physical activity were analyzed using descriptive statistics and Cochran's Q, respectively. Qualitative data were reviewed, categorized on the basis of theme, and tabulated for frequency. Increased physical activity and perceived health were the most reported perceived positive changes. Significant increases in physical activity participation were maintained among participants who were physically inactive at baseline. Best-liked features were physical activity and socialization. Findings suggest that this pilot exergaming and wellness program is effective in increasing physical activity in sedentary rural older adults, increasing socialization, and increasing subjective physical health among rural older adults. PMID- 23945728 TI - Utilizing electronic effects in the modulation of BTPhen ligands with respect to the partitioning of minor actinides from lanthanides. AB - Effects of bromine substitution at the 5 and 5,6-positions of the 1,10 phenanthroline nucleus of BTPhen ligand on their extraction properties for Ln(III) and An(III) cations have been studied. Compared to C5-BTPhen, electronic modulation in BrC5-BTPhen and Br2C5-BTPhen enabled these ligands to be fine-tuned in order to enhance the separation selectivity of Am(III) from Eu(III). PMID- 23945729 TI - The effect of training doctors in communication skills on women's satisfaction with doctor-woman relationship during labour and delivery: a stepped wedge cluster randomised trial in Damascus. AB - OBJECTIVES: To determine the effect of training residents in interpersonal and communication skills on women's satisfaction with doctor-woman relationship in labour and delivery rooms. DESIGN: A stepped wedge cluster randomised trial. SETTING: 4 tertiary care teaching maternity hospitals in Damascus, Syria. PARTICIPANTS: 2000 women who gave birth to a living baby in the four study hospitals and consented to participate in the intervention took part in the study. Women with difficult labour and high-risk pregnancies were excluded. All were interviewed at home after discharge. INTERVENTIONS: A specially designed training package in communication skills was delivered to all resident doctors at the four hospitals. PRIMARY OUTCOME MEASURES: The main outcome measure was women's satisfaction with interpersonal relationships in labour and delivery rooms measured via a series of questions on a Likert scale modified from the Medical Interview Satisfaction Scale. RESULTS: At the individual level, the mean for the average satisfaction score was 3.23 (SD 0.72) of a possible score of 5 in the control group and 3.42 (SD 0.73) in the intervention group. Using generalised linear mixed models, we were unable to detect a difference between the mean for the average satisfaction score of women in the intervention arm and that of women in the control arm; the 95% CI associated with the effect of the intervention ranged from -0.08 to 0.15. CONCLUSIONS: Despite slight changes in the observed residents' communication skills, the training package in communication skills does not seem to be associated with higher satisfaction scores of women. This raises the question of whether training individuals without further structural changes in the delivery of care and without further reinforcement of the training can have an impact on improving the quality of doctor-patient communication. TRIAL REGISTRATION NUMBER: ISRCTN80243969. PMID- 23945730 TI - Cerebral blood flow velocity changes during upright positioning in bed after acute stroke: an observational study. AB - OBJECTIVES: National guidelines recommend mobilisation in bed as early as possible after acute stroke. Little is known about the influence of upright positioning on real-time cerebral flow variables in patients with stroke. We aimed to assess whether cerebral blood flow velocity (CBFV) changes significantly after upright positioning in bed in the acute stroke phase. DESIGN: Observational study. PARTICIPANTS: 47 patients with acute ischaemic stroke measured in the subacute phase after symptom onset and 20 healthy controls. PRIMARY AND SECONDARY OUTCOME MEASURES: We recorded postural changes in bilateral transcranial Doppler (primary outcome) and simultaneously recorded near-infrared spectroscopy, end tidal CO2, non-invasive blood pressure data and changes in neurological status (secondary outcomes). METHODS: Postures included the supine, half sitting (45 degrees ), sitting (70 degrees ) and Trendelenburg (-15 degrees ) positions. Using multilevel analyses, we compared postural changes between hemispheres, outcome groups (using modified Rankin Scale) as well as between patients and healthy controls. RESULTS: The mean patient age was 62+/-15 years and median National Institute of Health Stroke Scale score on admission was 7 (IQR 5-14). Mean proportional CBFV changes on sitting were not significantly different between healthy controls and affected hemispheres in patients with stroke. No significant differences were found between affected and unaffected stroke hemispheres and between patients with unfavourable and favourable outcomes. During upright positioning, no neurological worsening or improvement was observed in any of the patients. CONCLUSIONS: No indications were found that upright positioning in bed in mild to moderately affected patients with stroke compromises flow and (frontal)oxygenation significantly during the subacute phase of stroke. Supine or Trendelenburg positioning does not seem to augment real-time flow variables. PMID- 23945731 TI - Antiviral therapy for prevention of hepatocellular carcinoma and mortality in chronic hepatitis B: systematic review and meta-analysis. AB - OBJECTIVES: The effect of antiviral therapy on clinical outcomes in chronic hepatitis B virus (HBV) is not established. We aimed to assess the effects of interferon and/or nucleos(t)ide analogues versus placebo or no intervention on prevention of hepatocellular carcinoma (HCC) and mortality in chronic HBV. DESIGN: Random-effects pairwise meta-analysis of randomised trials and observational studies. SETTING: Electronic and manual searches were combined. Randomised controlled trials (RCTs) were included in the primary analyses. Observational studies were included in sensitivity analyses. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measures were HCC incidence and mortality. The secondary outcome measure was HCC mortality. RESULTS: We included 8 RCTs, 8 prospective cohort studies and 19 case-control studies with a total of 3433 patients allocated to antiviral therapy and 4625 controls. The maximum duration of follow-up was 23 years. Randomised trials found no effect of antiviral therapy on HCC or mortality. Cohort studies found that antiviral therapy increased the risk of HCC (risk ratio 1.43; 95% CI 1.06 to 1.95), whereas case-control studies found a decreased risk of HCC in the intervention group (risk ratio 0.69; 95% CI 0.54 to 0.88). There was a clear difference between the results of RCTs and observational studies (test for subgroup differences, p<0.001). Antiviral therapy did not affect mortality in cohort studies, but reduced mortality in case-control studies (relative risk 0.71; 95% CI 0.54 to 0.93; test for subgroup differences, p=0.406). CONCLUSIONS: The effect of antiviral therapy on clinical outcomes in HBV remains to be established. Although there was a positive effect in the sensitivity analyses, the strength of the evidence does not allow for extrapolation to clinical practice as research design plays an essential role in the overall assessment. TRIAL REGISTRATION NUMBER: Prospero number CRD42013003881. PMID- 23945732 TI - Undertreatment, treatment trends, and treatment dissatisfaction among patients with psoriasis and psoriatic arthritis in the United States: findings from the National Psoriasis Foundation surveys, 2003-2011. AB - IMPORTANCE: Psoriasis and psoriatic arthritis inflict significant morbidity. Data on undertreatment, treatment use, and treatment satisfaction are paramount to identify priority areas for advocacy, education, and research to improve patient outcomes. OBJECTIVES: To determine the extent of nontreatment and undertreatment of psoriatic diseases, trends in treatment use, treatment satisfaction, and reasons for medication discontinuation among patients with psoriasis and psoriatic arthritis. DESIGN, SETTING, AND PARTICIPANTS: We used the national survey data collected by the National Psoriasis Foundation via biannual surveys conducted from January 1, 2003, through December 31, 2011, in the United States. Survey data were collected from randomly sampled patients with psoriasis and psoriatic arthritis in the US population from a database of more than 76,000 patients with psoriatic diseases. MAIN OUTCOMES AND MEASURES: Nontreatment, undertreatment, and treatment trends determined by the use of prescription medication (topical, phototherapeutic, oral systemic, and biologic), as well as treatment satisfaction and reasons for medication discontinuation. RESULTS: A total of 5604 patients with psoriasis or psoriatic arthritis completed the survey. From 2003 through 2011, patients who were untreated ranged from 36.6% to 49.2% of patients with mild psoriasis, 23.6% to 35.5% of patients with moderate psoriasis, and 9.4% to 29.7% of patients with severe psoriasis. Among those receiving treatment, 29.5% of patients with moderate psoriasis and 21.5% of patients with severe psoriasis were treated with topical agents alone. The most frequently used phototherapy modality is UV-B, whereas methotrexate is the most commonly used oral agent. Although adverse effects and a lack of effectiveness were primary reasons for discontinuing biological agents, the inability to obtain adequate insurance coverage was among the top reasons for discontinuation. Overall, 52.3% of patients with psoriasis and 45.5% of patients with psoriatic arthritis were dissatisfied with their treatment. CONCLUSIONS AND RELEVANCE: Nontreatment and undertreatment of patients with psoriasis and psoriatic arthritis remain a significant problem in the United States. While various treatment modalities are available for psoriasis and psoriatic arthritis, widespread treatment dissatisfaction exists. Efforts in advocacy and education are necessary to ensure that effective treatments are accessible to this patient population. PMID- 23945734 TI - Development of the Drug Adherence Work-up (DRAW) tool. AB - OBJECTIVE: To develop and conduct an initial field test of the Drug Adherence Work-up (DRAW) tool, which was developed to guide pharmacists when addressing nonadherence during medication therapy management (MTM) visits. METHODS: The field test was a prospective cohort study, in which seven trained pharmacists used DRAW to evaluate patients by asking about possible reasons for nonadherence during an MTM visit. Pharmacists were notified of potentially nonadherent patients identified through drug claims data analyzed by Outcomes Pharmaceutical Health Care. The pharmacists reported on use of DRAW in an MTM claim and provided opinions about DRAW via an online survey. RESULTS: According to the online survey, pharmacists reported that DRAW helped them to improve the focus of their MTM services and address more adherence problems than their usual approach. They thought the tool was easy to use and well organized. Some commented that DRAW could be a useful tool for teaching pharmacists. The most common reasons reported for nonadherence were the presence of adverse effects (59.1%) or forgetting to take the medication (54.5%). More than three-fourths of patients (77.3%) indicated more than one reason for nonadherence. CONCLUSION: A brief, comprehensive tool to evaluate medication nonadherence, such as DRAW, may help pharmacists address various reasons for medication nonadherence. Often nonadherence is multifaceted, which makes an inclusive tool like DRAW a useful approach; however further research is needed. PMID- 23945733 TI - Profile of ospemifene in the breast. AB - Vulvar and vaginal atrophy (VVA) is a chronic, progressive medical condition prevalent among postmenopausal women, which produces symptoms such as dyspareunia, vaginal dryness, and vaginal irritation. Currently, the only prescription options are systemic and vaginal estrogen therapies that may be limited by concerns about long-term safety and breast cancer risk. Ospemifene is a tissue-selective estrogen agonist/antagonist (a selective estrogen receptor modulator) recently approved by the US Food and Drug Administration for treatment of dyspareunia, a symptom of VVA, due to menopause. Ospemifene, the first nonestrogen oral treatment for this indication, may provide an alternative to treatment with estrogen. Animal models with ospemifene suggest an inhibitory effect on growth of malignant breast tissue, but animal data cannot necessarily be extrapolated to humans. Clinical trials, including 3 long-term studies assessing the overall safety of ospemifene, support that ospemifene is generally well tolerated, with beneficial effects on the vagina, neutral effects on the breast, and minimal effects on the endometrium. PMID- 23945735 TI - Depinning probability of a magnetic domain wall in nanowires by spin-polarized currents. AB - Current-induced magnetic domain wall motion is attractive for manipulating magnetization direction in spintronics devices, which open a new era of electronics. Up to now, in spite of a crucial significance to applications, investigation on a current-induced domain wall depinning probability, especially in sub-nano to a-few-nanosecond range has been lacking. Here we report on the probability of the depinning in perpendicularly magnetized Co/Ni nanowires in this timescale. A high depinning probability was obtained even for 2-ns pulses with a current density of less than 1012 A m-2. A one-dimensional Landau-Lifshitz Gilbert calculation taking into account thermal fluctuations reproduces well the experimental results. We also calculate the depinning probability as functions of various parameters and found that parameters other than the coercive field do not affect the transition width of the probability. These findings will allow one to design high-speed and reliable magnetic devices based on the domain wall motion. PMID- 23945736 TI - An embedded Simplified Fuzzy ARTMAP implemented on a microcontroller for food classification. AB - In the present study, a portable system based on a microcontroller has been developed to classify different kinds of honeys. In order to do this classification, a Simplified Fuzzy ARTMAP network (SFA) implemented in a microcontroller has been used. Due to memory limits when working with microcontrollers, it is necessary to optimize the use of both program and data memory. Thus, a Graphical User Interface (GUI) for MATLAB(r) has been developed in order to optimize the necessary parameters to programme the SFA in a microcontroller. The measures have been carried out by potentiometric techniques using a multielectrode made of seven different metals. Next, the neural network has been trained on a PC by means of the GUI in Matlab using the data obtained in the experimental phase. The microcontroller has been programmed with the obtained parameters and then, new samples have been analysed using the portable system in order to test the model. Results are very promising, as an 87.5% recognition rate has been achieved in the training phase, which suggests that this kind of procedures can be successfully used not only for honey classification, but also for many other kinds of food. PMID- 23945737 TI - Application of a force sensor to improve the reliability of measurement with Articulated Arm Coordinate Measuring Machines. AB - A study of the operator contact force influence on the performance of Articulated Arm Coordinate Measuring Machines (AACMMs) is presented in this paper. After developing a sensor capable of measuring the contact force applied by an operator, a ring gauge has been used to analyse the relationship between the contact force and diameter and form errors measured with the AACMM. As a result, contact force has been proved as one of the main factors influencing the AACMM performance. A probe deflection model based on the Finite Element Method (FEM) has been also proposed in order to obtain the AACMM probe deflection caused by contact force. This allows measurement correction by comparing them with reference values, specifically, a ring gauge. Experimental test results show a significant measurement improvement that minimizes diameter error. Finally, an uncertainty evaluation for the contact force sensor and AACMM measurements with and without probe deflection model has been carried out in order to validate the ability of the sensor and the methodology followed. PMID- 23945738 TI - Spectroscopy, manipulation and trapping of neutral atoms, molecules, and other particles using optical nanofibers: a review. AB - The use of tapered optical fibers, i.e., optical nanofibers, for spectroscopy and the detection of small numbers of particles, such as neutral atoms or molecules, has been gaining interest in recent years. In this review, we briefly introduce the optical nanofiber, its fabrication, and optical mode propagation within. We discuss recent progress on the integration of optical nanofibers into laser cooled atom and vapor systems, paying particular attention to spectroscopy, cold atom cloud characterization, and optical trapping schemes. Next, a natural extension of this work to molecules is introduced. Finally, we consider several alternatives to optical nanofibers that display some advantages for specific applications. PMID- 23945739 TI - A comprehensive review of semiconductor ultraviolet photodetectors: from thin film to one-dimensional nanostructures. AB - Ultraviolet (UV) photodetectors have drawn extensive attention owing to their applications in industrial, environmental and even biological fields. Compared to UV-enhanced Si photodetectors, a new generation of wide bandgap semiconductors, such as (Al, In) GaN, diamond, and SiC, have the advantages of high responsivity, high thermal stability, robust radiation hardness and high response speed. On the other hand, one-dimensional (1D) nanostructure semiconductors with a wide bandgap, such as beta-Ga2O3, GaN, ZnO, or other metal-oxide nanostructures, also show their potential for high-efficiency UV photodetection. In some cases such as flame detection, high-temperature thermally stable detectors with high performance are required. This article provides a comprehensive review on the state-of-the-art research activities in the UV photodetection field, including not only semiconductor thin films, but also 1D nanostructured materials, which are attracting more and more attention in the detection field. A special focus is given on the thermal stability of the developed devices, which is one of the key characteristics for the real applications. PMID- 23945740 TI - I feel you: the design and evaluation of a domotic affect-sensitive spoken conversational agent. AB - We describe the work on infusion of emotion into a limited-task autonomous spoken conversational agent situated in the domestic environment, using a need-inspired task-independent emotion model (NEMO). In order to demonstrate the generation of affect through the use of the model, we describe the work of integrating it with a natural-language mixed-initiative HiFi-control spoken conversational agent (SCA). NEMO and the host system communicate externally, removing the need for the Dialog Manager to be modified, as is done in most existing dialog systems, in order to be adaptive. The first part of the paper concerns the integration between NEMO and the host agent. The second part summarizes the work on automatic affect prediction, namely, frustration and contentment, from dialog features, a non-conventional source, in the attempt of moving towards a more user-centric approach. The final part reports the evaluation results obtained from a user study, in which both versions of the agent (non-adaptive and emotionally adaptive) were compared. The results provide substantial evidences with respect to the benefits of adding emotion in a spoken conversational agent, especially in mitigating users' frustrations and, ultimately, improving their satisfaction. PMID- 23945741 TI - Application of visible and near infrared spectroscopy for rapid analysis of chrysin and galangin in Chinese propolis. AB - A novel method for the rapid determination of chrysin and galangin in Chinese propolis of poplar origin by means of visible and near infrared spectroscopy (Vis NIR) was developed. Spectral data of 114 Chinese propolis samples were acquired in the 325 to 1,075 nm wavelength range using a Vis-NIR spectroradiometer. The reference values of chrysin and galangin of the samples were determined by high performance liquid chromatography (HPLC). Partial least squares (PLS) models were established using the spectra analyzed by different preprocessing methods. The effective wavelengths were selected by successive projections algorithm (SPA) and employed as the inputs of PLS, back propagation-artificial neural networks (BP ANN), multiple linear regression (MLR) and least square-support vector machine (LS-SVM) models. The best results were achieved by SPA-BP-ANN models established with the Savitzky-Golay smoothing (SG) preprocessed spectra, where the r and RMSEP were 0.9823 and 1.5239 for galangin determination and 0.9668 and 2.4841 for chrysin determination, respectively. The results show that Vis-NIR demosntrates powerful capability for the rapid determination of chrysin and galangin contents in Chinese propolis. PMID- 23945744 TI - Push-pull systems bearing a quinoid/aromatic thieno[3,2-b]thiophene moiety: synthesis, ground state polarization and second-order nonlinear properties. AB - Chromophores bearing a 2-dicyanomethylenethieno[3,2-b]thiophene moiety in their quinoidal form have been synthesized, exploring for the first time the reactivity of this system towards aldehydes. Their ground state polarization and linear and second-order nonlinear optical (NLO) properties have been determined by a combined experimental and theoretical study, and compared to those of analogous compounds featuring an aromatic thienothiophene unit. Due to the gaining of aromaticity, quinoid systems have been found to display more polarized electronic ground states and higher NLO responses with respect to their aromatic counterparts. PMID- 23945745 TI - Multiplex microarray ELISA versus classical ELISA, a comparison study of pollutant sensing for environmental analysis. AB - The present study describes the development, optimization and performance comparison of three ELISAs and one multiplex immunoassay in a microarray format. The developed systems were dedicated to the detection of three different classes of pollutants (pesticide, explosive and toxin) in water. The characteristics and performances of these two types of assays were evaluated and compared, in order to verify that multiplex immunoassays can replace ELISA for multiple analyte sensing. 2,4-Dichlorophenoxyacetic acid, 2,4,6-trinitrotoluene and okadaic acid were chosen as model targets and were immobilized in classical microtiter plate wells or arrayed at the surface of a microarray integrated within a classical 96 well plate. Once optimized, the classical ELISAs and microarray-based ELISA performances were evaluated and compared in terms of limit of detection, IC50, linearity range and reproducibility. Classical ELISAs provided quite good sensitivity (limit of detection down to 10 MUg L(-1)), but the multiplex immunoassay was proven to be more sensitive (limit of detection down to 0.01 MUg L(-1)), more reproducible and an advantageous tool in terms of cost and time expenses. This multiplex tool was then used for the successful detection of the three target molecules in spiked water samples and achieved very promising recovery rates. PMID- 23945746 TI - Blue-coloured highly efficient dye-sensitized solar cells by implementing the diketopyrrolopyrrole chromophore. AB - The paradigm shift in dye sensitized solar cells (DSCs) - towards donor- pi bridge-acceptor (D-pi-A) dyes - increases the performances of DSCs and challenges established design principles. Framed by this shifting landscape, a series of four diketopyrrolopyrrole (DPP)-based sensitizers utilizing the donor-chromophore anchor (D-C-A) motif were investigated computationally, spectroscopically, and fabricated by systematic evaluation of finished photovoltaic cells. In all cases, the [Co(bpy)3](3+/2+) redox-shuttle afforded superior performance compared to I3( )/I(-). Aesthetically, careful molecular engineering of the DPP chromophore yielded the first example of a high-performance blue DSC - a challenge unmet since the inception of this photovoltaic technology: DPP17 yields over 10% power conversion efficiency (PCE) with the [Co(bpy)3](3+/2+) electrolyte at full AM 1.5 G simulated sun light. PMID- 23945747 TI - Monte Carlo modelling of 90Sr/90Y and 85Kr beta fields for Hp(3) measurements. AB - In support of research aimed at developing a thermoluminescence dosemeter capable of accurately measuring ionising radiation doses to the lens of the eye, Monte Carlo modelling of a standard beta exposure set-up has been performed. It was found that electrons with an energy distribution corresponding to the beta emission spectrum from (85)Kr deposit negligible doses at a depth of 3 mm in tissue, but doses from (90)Sr/(90)Y are significant; free in air and fluence-to Hp(3,theta degrees ) and -Hp(0.07,theta degrees ) conversion coefficient data were found for this field for exposures at 0 degrees , 30 degrees and 60 degrees angles of incidence, and the response characteristics of the new eye dosemeter were evaluated. It was shown that the results were not affected greatly by the shape of the calibration phantom. However, it was demonstrated that the presence of intermediating air and beam flattening filters hardens the energy distribution of the field at the point of test, relative to a raw (90)Sr/(90)Y source, and this impacts dose depositions. PMID- 23945748 TI - Contrasting modulation of enzyme activity exhibited by graphene oxide and reduced graphene. AB - Here we demonstrate that GO and RGO exhibit contrasting effects on modulation of the peroxidase activity of cyt c. GO could dramatically improve the enzyme activity of cyt c, while RGO showed a strong inhibition effect on cyt c. PMID- 23945749 TI - Direct beta-acylation of 2-arylidene-1,3-indandiones with acyl chlorides catalyzed by organophosphanes. AB - We have developed an organophosphane-catalyzed direct beta-acylation of a series of conjugated systems bearing ketone, amide and ester functionalities using acyl chlorides as trapping reagents. A wide variety of highly functional ketone derivatives were generated efficiently under very mild conditions with high yields according to our protocol. Our adducts can even be utilized as important building blocks for the synthesis of functional tri/tetracyclic pyridazine derivatives. PMID- 23945754 TI - Non-conventional methods and media for the activation and manipulation of carbon nanoforms. AB - Very often, chemical transformations require tedious and long procedures, which, sometimes, can be avoided using alternative methods and media. New protocols, enabling us to save time and solvents, allow us also to explore new reaction profiles. This Tutorial Review focuses on the physical and chemical behavior of carbon nanoforms, CNFs (fullerenes, nanotubes, nanohorns, graphene, etc.) when non-conventional methods and techniques, such as microwave irradiation, mechano chemistry or highly ionizing radiations are employed. In addition, the reactivity of CNFs in non-conventional media such as water, fluorinated solvents, supercritical fluids, or ionic liquids is also discussed. PMID- 23945759 TI - In vitro evaluation of schistosomicidal activity of essential oil of Mentha x villosa and some of its chemical constituents in adult worms of Schistosoma mansoni. AB - This study aimed to determine the composition of the essential oil of Mentha x villosa and to evaluate its biological effects in vitro on adult worms of S. mansoni. Rotundifolone (70.96 %), limonene (8.75 %), trans-caryophyllene (1.46 %), and beta-pinene (0.81 %) were shown to be the major constituents of this oil. Adult worms of S. mansoni were incubated with different concentrations of the essential oil (1, 10, 100, 250, 500, and 1000 ug/mL) and of its constituents rotundifolone (0.7, 3.54, 7.09, 70.96, 177.4, 354.8, and 700.96 ug/mL), limonene (43.75 ug/mL), trans-caryophyllene (7.3 ug/mL), and beta-pinene (4.03 ug/mL). No schistosomicidal activity was identified at the trans-caryophyllene and beta pinene concentrations studied. However, use of the essential oil (10 ug/mL), rotundifolone (7.09 ug/mL), and limonene (43.75 ug/mL) resulted in decreased worm motility continuing until 96 hours of observation. At higher concentrations (100 and 70.96 ug/mL, respectively), both the essential oil and rotundifolone caused mortality among adult worms of S. mansoni. The positive control praziquantel caused the death of all parasites after 24 h of evaluation. The results from this study suggest that the essential oil of Mentha x villosa presents schistosomicidal efficacy. PMID- 23945760 TI - Adductor longus activation during common hip exercises. AB - CONTEXT: Hip-adductor strains are among the most common lower-extremity injuries sustained in athletics. Treatment of these injuries involves a variety of exercises used to target the hip adductors. OBJECTIVE: To identify the varying activation levels of the adductor longus during common hip-adductor exercises. DESIGN: Descriptive study. SETTING: Laboratory. PARTICIPANTS: 24 physically active, college-age students. INTERVENTION: None. MAIN MEASUREMENT OUTCOMES: Peak and average electromyographic (EMG) activity of the adductor longus muscle during the following 6 hip-adductor rehabilitation exercises: side-lying hip adduction, ball squeezes, rotational squats, sumo squats, standing hip adduction on a Swiss ball, and side lunges. RESULTS: The side-lying hip-adduction exercise produced more peak and average activation than any other exercise (P < .001). Ball squeezes produced more peak and average activation than rotational squats, sumo squats, and standing adduction on a Swiss ball (P < .001). Ball squeezes had more average activation than side lunges (P = .001). All other variables for peak activation during the exercises were not statistically significant (P > .08). These results allowed the authors to provide an overall ranking system (highest to lowest muscle activation): side-lying hip adduction, ball squeezes, side lunges, standing adduction on a Swiss ball, rotational squats, and sumo squats. CONCLUSION: The study provides a ranking system on the activation levels of the adductor longus muscle for 6 common hip-adductor rehabilitation exercises, with the side-lying hip-adduction and ball-squeeze exercises displaying the highest overall activation. PMID- 23945761 TI - Too many excuses for not teaching in the operating room and one simple solution: faculty feedback. PMID- 23945763 TI - Age, gender, social contacts, and psychological distress: findings from the 45 and up study. AB - OBJECTIVE: The study examined the relationships between social contact types and psychological distress among mid-older adults. METHOD: Self-completed data from 236,490 Australian adults aged 45+ years. RESULTS: There was a consistent relationship between increased frequency in phone contacts, social visits, and social group contacts and reduced risk of psychological distress adjusted for demographic and health factors. However, stratified analyses by age showed, with one exception, that no significant associations were found between social group contact frequency and risk of psychological distress for those aged 85 years and older. Furthermore, significant interaction terms revealed that women experience a steeper reduction in risk than men at age 65 to 74 years and 75 to 84 years compared with those aged 45 to 64 years. DISCUSSION: Social contacts have age and gender differential effects on psychological distress of mid-older Australian adults. Interventions addressing social interaction need to be sensitive to gender and age differences. PMID- 23945762 TI - Stressful events, social support, and cognitive function in middle-aged adults with a family history of Alzheimer's disease. AB - OBJECTIVE: To examine the associations of stressful experiences and social support with cognitive function in a sample of middle-aged adults with a family history of Alzheimer's disease (AD). METHOD: Using data from the Wisconsin Registry for Alzheimer's Prevention (WRAP; N = 623), we evaluated relationships between stressful events experienced in the past year, as well as social support, and cognitive performance in four domains: speed and flexibility, immediate memory, verbal learning and memory, and working memory. We assessed interactions between psychosocial predictors, and with APOE epsilon4 status. RESULTS: Greater number of stressful events was associated with poorer performance on tests of speed and flexibility. Greater social support was associated with better performance in the same domain; this relationship was diminished by the presence of the epsilon4 allele. No associations were seen in the remaining three domains. DISCUSSION: Psychosocial factors may influence cognition in at-risk individuals; influence varies by cognitive domain and epsilon4 status. PMID- 23945764 TI - Hypertriglyceridemia: what the dermatologist needs to know. PMID- 23945768 TI - Cooling-by-measurement and mechanical state tomography via pulsed optomechanics. AB - Observing a physical quantity without disturbing it is a key capability for the control of individual quantum systems. Such back-action-evading or quantum non demolition measurements were first introduced in the 1970s for gravitational wave detection, and now such techniques are an indispensable tool throughout quantum science. Here we perform measurements of the position of a mechanical oscillator using pulses of light with a duration much shorter than a period of mechanical motion. Utilizing this back-action-evading interaction, we demonstrate state preparation and full state tomography of the mechanical motional state. We have reconstructed states with a position uncertainty reduced to 19 pm, limited by the quantum fluctuations of the optical pulse, and we have performed 'cooling-by measurement' to reduce the mechanical mode temperature from an initial 1,100 to 16 K. Future improvements to this technique will allow for quantum squeezing of mechanical motion, even from room temperature, and reconstruction of non classical states exhibiting negative phase-space quasi-probability. PMID- 23945769 TI - Adenovirus-associated epidemic keratoconjunctivitis outbreaks--four states, 2008 2010. AB - Epidemic keratoconjunctivitis (EKC) is a highly contagious, severe form of conjunctivitis. During 2008-2010, six unrelated EKC outbreaks associated with human adenovirus (HAdV) in four states were reported to CDC. In total, 411 EKC cases were identified in Florida, Illinois, Minnesota, and New Jersey. In each outbreak, health-care-associated transmission appeared to occur via ophthalmologic examination; however, community transmission was also documented. These outbreaks resulted in significant morbidity and cost resulting from the number of persons affected, duration of the outbreaks, and the temporary closure of a neonatal intensive-care unit (NICU) and several clinics. Clusters of EKC infections should be reported to the appropriate state or local health department. In settings where ophthalmologic care is provided, routine adherence to basic infection control measures and early implementation of enhanced outbreak control measures are essential to prevent HAdV transmission. PMID- 23945770 TI - Human rabies--South Carolina, 2011. AB - On December 3, 2011, a South Carolina woman visited a local emergency department (ED) with an overnight history of shortness of breath, diaphoresis, chills, and intermittent paresthesia. The patient was transferred to a referral hospital, where she became comatose and developed multiorgan failure. The patient did not report a history of an animal bite. However, family members subsequently revealed that bats had been observed in the patient's home during the previous summer. Family members also reported that the patient had sought information on bat removal from a local county service, but was not advised of the risk for rabies associated with bat exposures and was not referred for public health consultation. CDC confirmed infection with a rabies virus variant associated with Mexican free-tailed bats (Tadarida brasiliensis) on December 14, after which the patient received hospice care. She died on December 19. This report summarizes the patient's clinical course and the associated public health investigation. This case highlights the importance of strong partnerships among public health officials and diverse non-health-care partners to ensure appropriate referral of persons exposed to bats in their homes for prompt and appropriate risk assessment, postexposure prophylaxis (PEP) recommendations, and information on safe, effective, and humane bat exclusion methods. PMID- 23945771 TI - Locations and reasons for initial testing for hepatitis C infection--chronic hepatitis cohort study, United States, 2006-2010. AB - Chronic hepatitis C virus (HCV) infection causes substantial morbidity and mortality in the United States. Testing and treatment of asymptomatic persons might avert progression to more advanced disease. In 1998, CDC published guidelines for HCV testing based on risk factors for infection; however, recent studies indicate that at least one half of all persons living with HCV infection in the United States are unaware of their infection status. To increase testing rates, in 2012 CDC recommended one-time testing of all persons born during 1945 1965. To better understand where and why persons with chronic HCV infection sought their initial testing, 2006-2010 data were analyzed from a survey conducted as part of the ongoing Chronic Hepatitis Cohort Study. Of 4,689 patients with HCV infection who responded to the survey, 60.4% reported that their initial HCV test occurred in a physician's office. CDC's risk-based indications (e.g., injection drug use and hemodialysis) were cited by 1,045 (22.3%) of the patients as reasons for testing, whereas clinical indications (e.g., abnormal liver function tests or liver-related symptoms such as jaundice) were cited by 2,121 (45.2%), suggesting that many HCV infections were identified only after the patient had become symptomatic. Promoting U. S. Preventive Services Task Force and CDC recommendations for testing and identifying strategies that help physicians implement HCV testing in their offices might help facilitate timely identification of HCV infection and reduce morbidity and mortality. PMID- 23945772 TI - Notes from the field: repeat syphilis infection and HIV coinfection among men who have sex with men--Baltimore, Maryland, 2010-2011. AB - Syphilis diagnoses in the United States have increased substantially over the past decade, and most cases occurred among men who have sex with men (MSM). Nationally, rates of primary and secondary (P&S) syphilis reported among men increased, from 3.0 cases per 100,000 population in 2001 to 8.2 in 2011. In 2011, approximately 72% of P&S syphilis cases occurred among MSM*, among whom new diagnoses of human immunodeficiency virus (HIV) infection have increased in recent years. Infection with syphilis increases the likelihood of acquiring and transmitting HIV; moreover, the occurrence of syphilis in an HIV-infected person is an indication of behavior that might increase the likelihood of HIV transmission. The population of Baltimore, Maryland, is particularly affected by syphilis and HIV. In 2011, the Baltimore metropolitan statistical area (MSA) had the second highest rate of reported cases of P&S syphilis (11.4 per 100,000 population) and the sixth highest estimated rate of diagnoses of HIV infection (33.8 per 100,000 population) compared with other MSAs in the United States. Local public health officials have noted a subpopulation of MSM diagnosed with repeat syphilis infection; they believe that this subpopulation might bear a disproportionate burden of both syphilis and HIV infection and that intensifying syphilis and HIV prevention efforts among this subpopulation might reduce syphilis and HIV transmission overall in the Baltimore area. PMID- 23945773 TI - Association between neighbourhood green space and sedentary leisure time in a Danish population. AB - AIM: Sedentary behaviour is a risk factor for diabetes, cardiovascular disease etc., independently of level of physical activity. Availability of recreational green space is associated with physical activity, but is unknown in relation to sedentary behaviour. The aim of this study is to examine the association between availability of green space and sedentary leisure time in a Danish population. METHODS: The study was based on a random sample of 49,806 adults aged 16 + who answered a questionnaire in 2010, including sedentary leisure time. Objective measures of density green were calculated for each respondent using Geographical Information System (GIS). A multilevel regression analysis, taking neighbourhood and individual factors into account, was performed. RESULTS: 65% of the respondents were sedentary in leisure time for more than 3h/day. We found that poor availability of forest and recreational facilities in the neighbourhood is associated with more sedentary leisure time; OR: 1.11 (95% CL: 1.04-1.19), after adjusting for individual, and neighbourhood, level characteristics. CONCLUSIONS: Among adult inhabitants, sedentary leisure time of more than 3h/day was more frequent in neighbourhoods with less green surroundings. Intervention efforts may benefit from emphasising the importance of having recreations options in residential areas to provide alternatives to sedentary activities. PMID- 23945774 TI - Shame among long-term sickness absentees: correlates and impact on subsequent sickness absence. AB - AIMS: The contribution of general psychological aspects, such as emotions, has received little focus in research on sickness absence. We wanted to study the relationship between shame and sickness absence, which factors that explained differences in levels of shame, and if shame predicted subsequent sickness absence. METHODS: We employed a Swedish population-based cohort of current sickness absentees (19-64 years old), responding to a mailed questionnaire in 2008. Data was linked to national registries on sickness absence. RESULTS: The young, those born outside the Nordic countries, those on lower incomes and those with higher level of education reported being more ashamed of their sickness absence. Those with more sickness absence in the past were also more likely to report higher levels of shame. Level of shame was not associated with gender or occupational class. Compared to those absent for a somatic cause, mental or co morbid illness was associated with higher levels of shame. Those reporting high level of shame were more likely to have prolonged sickness absence the following year. Symptoms of depression at baseline only partly explained these associations. CONCLUSIONS: Our results suggest that shame might prolong sickness absence. Increased understanding of the impact of social and emotional aspects around sickness absence could be an important source for improved quality of rehabilitation. PMID- 23945776 TI - Metal free catalytic hydroboration of multiple bonds in methanol using N heterocyclic carbenes under open atmosphere. AB - An easy to operate method of catalytic hydroboration of unsaturated compounds has been developed with wide substrate scope. Reactions of various aldimines, ketimines, alpha,beta-unsaturated carbonyl compounds, and alkynes were successfully executed with bis(pinacolato)diboron and N-heterocyclic carbenes in methanol without requiring a transition metal or inert atmosphere. PMID- 23945777 TI - Electrokinetic tweezing: three-dimensional manipulation of microparticles by real time imaging and flow control. AB - Electrokinetic tweezing in three dimensions is achieved for the first time using a multi-layer microfluidic device, a model-based control algorithm, and a 3D imaging algorithm connected in a feedback loop. Here we demonstrate steering of microparticles along 3D trajectories and trapping in all three dimensions with accuracy as good as 1 MUm. PMID- 23945775 TI - The large conductance, calcium-activated K+ (BK) channel is regulated by cysteine string protein. AB - Large-conductance, calcium-activated-K(+) (BK) channels are widely distributed throughout the nervous system, where they regulate action potential duration and firing frequency, along with presynaptic neurotransmitter release. Our recent efforts to identify chaperones that target neuronal ion channels have revealed cysteine string protein (CSPalpha) as a key regulator of BK channel expression and current density. CSPalpha is a vesicle-associated protein and mutations in CSPalpha cause the hereditary neurodegenerative disorder, adult-onset autosomal dominant neuronal ceroid lipofuscinosis (ANCL). CSPalpha null mice show 2.5 fold higher BK channel expression compared to wild type mice, which is not seen with other neuronal channels (i.e. Cav2.2, Kv1.1 and Kv1.2). Furthermore, mutations in either CSPalpha's J domain or cysteine string region markedly increase BK expression and current amplitude. We conclude that CSPalpha acts to regulate BK channel expression, and consequently CSPalpha-associated changes in BK activity may contribute to the pathogenesis of neurodegenerative disorders, such as ANCL. PMID- 23945779 TI - Dendritic mechanisms contribute to stimulus-specific adaptation in an insect neuron. AB - Reduced neuronal activation to repetitive stimulation is a common feature of information processing in nervous systems. Such stimulus-specific adaptation (SSA) occurs in many systems, but the underlying neural mechanisms are not well understood. The Neoconocephalus (Orthoptera, Tettigoniidae) TN-1 auditory neuron exhibits an SSA-like process, characterized by reliably detecting deviant pulses after response cessation to common standard pulses. Therefore, TN-1 provides a model system to study the cellular mechanisms underlying SSA with an identified neuron. Here we test the hypothesis that dendritic mechanisms underlie TN-1 response cessation to fast-pulse rate repeated signals. Electrically stimulating TN-1 with either high-rate or continuous-current pulses resulted in a decreased ability in TN-1 to generate action potentials but failed to elicit cessation of spiking activity as observed with acoustic stimulation. BAPTA injection into TN-1 delayed the onset of response cessation to fast-pulse rate acoustic stimuli in TN 1 but did not eliminate it. These results indicate that calcium-mediated processes contribute to the fast cessation of spiking activity in TN-1 but are insufficient to cause spike cessation on its own. Replacing normal saline with low-Na(+) saline (replacing sodium chloride with either lithium chloride or choline chloride) eliminated response cessation, and TN-1 no longer responded selectively to the deviant pulses. Sodium-mediated potassium channels are the most likely candidates underlying sodium-mediated response suppression in TN-1, triggered by Na(+) influx in dendritic regions activated by acoustic stimuli. On the basis of these results, we present a model for a cellular mechanism for SSA in a single auditory neuron. PMID- 23945780 TI - Variability and information content in auditory cortex spike trains during an interval-discrimination task. AB - Processing of temporal information is key in auditory processing. In this study, we recorded single-unit activity from rat auditory cortex while they performed an interval-discrimination task. The animals had to decide whether two auditory stimuli were separated by either 150 or 300 ms and nose-poke to the left or to the right accordingly. The spike firing of single neurons in the auditory cortex was then compared in engaged vs. idle brain states. We found that spike firing variability measured with the Fano factor was markedly reduced, not only during stimulation, but also in between stimuli in engaged trials. We next explored if this decrease in variability was associated with an increased information encoding. Our information theory analysis revealed increased information content in auditory responses during engagement compared with idle states, in particular in the responses to task-relevant stimuli. Altogether, we demonstrate that task engagement significantly modulates coding properties of auditory cortical neurons during an interval-discrimination task. PMID- 23945778 TI - Supersensitive presynaptic dopamine D2 receptor inhibition of the striatopallidal projection in nigrostriatal dopamine-deficient mice. AB - The dopamine (DA) D2 receptor (D2R)-expressing medium spiny neurons (D2-MSNs) in the striatum project to and inhibit the GABAergic neurons in the globus pallidus (GP), forming an important link in the indirect pathway of the basal ganglia movement control circuit. These striatopallidal axon terminals express presynaptic D2Rs that inhibit GABA release and thus regulate basal ganglion function. Here we show that in transcription factor Pitx3 gene mutant mice with a severe DA loss in the dorsal striatum mimicking the DA denervation in Parkinson's disease (PD), the striatopallidal GABAergic synaptic transmission displayed a heightened sensitivity to presynaptic D2R-mediated inhibition with the dose response curve shifted to the left, although the maximal inhibition was not changed. Functionally, low concentrations of DA were able to more efficaciously reduce the striatopallidal inhibition-induced pauses of GP neuron activity in DA deficient Pitx3 mutant mice than in wild-type mice. These results demonstrate that presynaptic D2R inhibition of the striatopallidal synapse becomes supersensitized after DA loss. These supersensitive D2Rs may compensate for the lost DA in PD and also induce a strong disinhibition of GP neuron activity that may contribute to the motor-stimulating effects of dopaminergic treatments in PD. PMID- 23945781 TI - Experimental measure of arm stiffness during single reaching movements with a time-frequency analysis. AB - We tested an innovative method to estimate joint stiffness and damping during multijoint unfettered arm movements. The technique employs impulsive perturbations and a time-frequency analysis to estimate the arm's mechanical properties along a reaching trajectory. Each single impulsive perturbation provides a continuous estimation on a single-reach basis, making our method ideal to investigate motor adaptation in the presence of force fields and to study the control of movement in impaired individuals with limited kinematic repeatability. In contrast with previous dynamic stiffness studies, we found that stiffness varies during movement, achieving levels higher than during static postural control. High stiffness was associated with elevated reflexive activity. We observed a decrease in stiffness and a marked reduction in long-latency reflexes around the reaching movement velocity peak. This pattern could partly explain the difference between the high stiffness reported in postural studies and the low stiffness measured in dynamic estimation studies, where perturbations are typically applied near the peak velocity point. PMID- 23945783 TI - Tactile information processing in primate hand somatosensory cortex (S1) during passive arm movement. AB - Motor output mostly depends on sensory input, which also can be affected by action. To further our understanding of how tactile information is processed in the primary somatosensory cortex (S1) in dynamic environments, we recorded neural responses to tactile stimulation of the hand in three awake monkeys under arm/hand passive movement and rest. We found that neurons generally responded to tactile stimulation under both conditions and were modulated by movement: with a higher baseline firing rate, a suppressed peak rate, and a smaller dynamic range during passive movement than during rest, while the area under the response curve was stable across these two states. By using an information theory-based method, the mutual information between tactile stimulation and neural responses was quantified with rate and spatial coding models under the two conditions. The two potential encoding models showed different contributions depending on behavioral contexts. Tactile information encoded with rate coding from individual units was lower than spatial coding of unit pairs, especially during movement; however, spatial coding had redundant information between unit pairs. Passive movement regulated the mutual information, and such regulation might play different roles depending on the encoding strategies used. The underlying mechanisms of our observation most likely come from a bottom-up strategy, where neurons in S1 were regulated through the activation of the peripheral tactile/proprioceptive receptors and the interactions between these different types of information. PMID- 23945782 TI - Rat primary auditory cortex is tuned exclusively to the contralateral hemifield. AB - The rat is a widely used species for study of the auditory system. Psychophysical results from rats have shown an inability to discriminate sound source locations within a lateral hemifield, despite showing fairly sharp near-midline acuity. We tested the hypothesis that those characteristics of the rat's sound localization psychophysics are evident in the characteristics of spatial sensitivity of its cortical neurons. In addition, we sought quantitative descriptions of in vivo spatial sensitivity of cortical neurons that would support development of an in vitro experimental model to study cortical mechanisms of spatial hearing. We assessed the spatial sensitivity of single- and multiple-neuron responses in the primary auditory cortex (A1) of urethane-anesthetized rats. Free-field noise bursts were varied throughout 360 degrees of azimuth in the horizontal plane at sound levels from 10 to 40 dB above neural thresholds. All neurons encountered in A1 displayed contralateral-hemifield spatial tuning in that they responded strongly to contralateral sound source locations, their responses cut off sharply for locations near the frontal midline, and they showed weak or no responses to ipsilateral sources. Spatial tuning was quite stable across a 30-dB range of sound levels. Consistent with rat psychophysical results, a linear discriminator analysis of spike counts exhibited high spatial acuity for near-midline sounds and poor discrimination for off-midline locations. Hemifield spatial tuning is the most common pattern across all mammals tested previously. The homogeneous population of neurons in rat area A1 will make an excellent system for study of the mechanisms underlying that pattern. PMID- 23945785 TI - Noradrenergic interactions via autonomic nervous system: a promising target for extinction-based exposure therapy? AB - Fearful associations can be replaced by neutral associations through repetitive exposure of an individual to the fearful situation without the aversive component. Recently, Pena and colleagues (Pena DF, Engineer ND, McIntyre CK. Biol Psychiatry 73: 1071-1077, 2013) demonstrated that pairing activation of noradrenergic (NA) pathways through vagus nerve stimulation (VNS) with extinction learning accelerates consolidation of extinction memories in rats. Their findings stress the importance of activating the NA system through VNS in treatment of anxiety disorders such as PTSD or phobia. PMID- 23945786 TI - First trial and StartReact effects induced by balance perturbations to upright stance. AB - Postural responses (PR) to a balance perturbation differ between the first and subsequent perturbations. One explanation for this first trial effect is that perturbations act as startling stimuli that initiate a generalized startle response (GSR) as well as the PR. Startling stimuli, such as startling acoustic stimuli (SAS), are known to elicit GSRs, as well as a StartReact effect, in which prepared movements are initiated earlier by a startling stimulus. In this study, a StartReact effect paradigm was used to determine if balance perturbations can also act as startle stimuli. Subjects completed two blocks of simple reaction time trials involving wrist extension to a visual imperative stimulus (IS). Each block included 15 CONTROL trials that involved a warning cue and subsequent IS, followed by 10 repeated TEST trials, where either a SAS (TESTSAS) or a toes-up support-surface rotation (TESTPERT) was presented coincident with the IS. StartReact effects were observed during the first trial in both TESTSAS and TESTPERT conditions as evidenced by significantly earlier wrist movement and muscle onsets compared with CONTROL. Likewise, StartReact effects were observed in all repeated TESTSAS and TESTPERT trials. In contrast, GSRs in sternocleidomastoid and PRs were large in the first trial, but significantly attenuated over repeated presentation of the TESTPERT trials. Results suggest that balance perturbations can act as startling stimuli. Thus first trial effects are likely PRs which are superimposed with a GSR that is initially large, but habituates over time with repeated exposure to the startling influence of the balance perturbation. PMID- 23945784 TI - EEG analysis reveals widespread directed functional interactions related to a painful cutaneous laser stimulus. AB - During attention to a painful cutaneous laser stimulus, event-related causality (ERC) has been detected in recordings from subdural electrodes implanted directly over cortical modules for the treatment of epilepsy. However, these studies afforded limited sampling of modules and did not examine interactions with a nonpainful stimulus as a control. We now sample scalp EEG to test the hypothesis that attention to the laser stimulus is associated with poststimulus ERC interactions that are different from those with attention to a nonpainful stimulus. Subjects attended to (counted) either a painful laser stimulus (laser attention task) or a nonpainful electrical cutaneous stimulus that produced distraction from the laser (laser distraction task). Both of these stimuli were presented in random order in a single train. The intensities of both stimuli were adjusted to produce similar baseline salience and sensations in the same cutaneous territory. The results demonstrated that EEG channels with poststimulus ERC interactions were consistently different during the laser stimulus versus the electric stimulus. Poststimulus ERC interactions for the laser attention task were different from the laser distraction task. Furthermore, scalp EEG frontal channels play a driver role while parietal temporal channels play a receiver role during both tasks, although this does not prove that these channels are connected. Sites at which large numbers of ERC interactions were found for both laser attention and distraction tasks (critical sites) were located at Cz, Pz, and C3. Stimulation leading to disruption of sites of these pain-related interactions may produce analgesia for acute pain. PMID- 23945787 TI - Altered PKA modulation in the Na(v)1.1 epilepsy variant I1656M. AB - Genetic epilepsy with febrile seizures plus (GEFS(+)) is an inherited epilepsy that can result from mutations in at least four ion channel subunits. The majority of the known GEFS(+) mutations have been identified in SCN1A, the gene encoding Nav1.1 alpha-subunit. Protein kinases as critical modulators of sodium channels have been closely related to the genesis of epilepsy. However, little is known about how protein kinases affect the GEFS(+) mutant sodium channel. To gain insight into the protein kinases effect on channel properties and neuronal excitability of SCN1A mutant channels, we investigated the human SCN1A GEFS(+) mutation I1656M by using whole cell patch-clamp technique and an established computational neuron model. The results showed that the PKA inhibition of sodium current amplitude significantly decreased in the I1656M mutant channels, but the PKC inhibition did not. The responses of the voltage-dependent activation and fast inactivation to PKA activator disappeared in the I1656M mutant channels, but the response of the voltage dependence of the slow inactivation did not. Computational model analysis suggested that changes of the I1656M mutant channel gating behaviors in response to PKA activation altered neuronal excitability. These results indicate that altered responses of the mutant channels to PKA signaling may impair the delicate balances between chemical and electrical harmony and lead to abnormal neuronal excitability. PMID- 23945790 TI - An efficient route to chiral N-heterocycles bearing a C-F stereogenic center via asymmetric hydrogenation of fluorinated isoquinolines. AB - An efficient iridium-catalyzed asymmetric hydrogenation of the fluorinated isoquinoline derivatives has been successfully developed for the synthesis of chiral fluorinated tetrahydroisoquinoline derivatives with up to 93% ee. This methodology features the use of a hydrochloride salt as well as a catalytic amount of halogenated hydantoin which were vital for the reactivity, enantioselectivity, and inhibition of the hydrodefluorination pathway. PMID- 23945791 TI - Multi-component assembly and photophysical properties of europium polyoxometalates and polymer functionalized (mesoporous) silica through a double functional ionic liquid linker. AB - In this paper, we put forward a strategy to assemble a novel series of multi component photofunctional hybrid materials (named as Eu-Si-P1(2,3)) centered with europium polyoxometalates (Na9EuW10O36.32H2O, abbreviated as EuW10) and polyester modified silane (P1-Si, P2-Si, P3-Si, P1 = poly glycohol, P2 = bis(2 hydroxyethyl)ether, P3 = 2-hydroxyethyl methacrylate) through an ionic liquid compound (1-methyl-3-(trimethoxysilylpropyl) imidazolium chloride, IM(+)Cl(-)) as the double functional linker. Furthermore, using Pluronic P123 surfactant as a template to control the sol-gel process of organically modified siloxane precursors, Eu-SBA15-P1(2,3) hybrids with mesoporous silica are constructed correspondingly. The results reveal that Eu-Si-P1(2,3) hybrids present the lower red/orange intensity ratio, longer lifetime and higher quantum yield than Eu SBA15-P1(2,3) hybrids. The luminescent lifetime and quantum efficiency of Eu-Si P1(2,3) hybrids are comparable with EuW10 compounds in spite of their low concentration of photoactive EuW10, which is important for practical applications. The CIE chromatic coordinates of some systems are close to the cool white region and can be expected to be utilized as cool white lighting (close to sunlight). PMID- 23945792 TI - Impact of objectively assessing surgeons' teaching on effective perioperative instructional behaviors. AB - IMPORTANCE: Advancing surgical technology and decreasing resident learning hours have limited exposure to perioperative training, necessitating more effective and efficient perioperative teaching by faculty surgeons. Participation in collaborative efforts and process improvement can change behaviors and enhance teaching. OBJECTIVES: To promote deliberate teaching of residents, change resident perception of their teachers, and produce sustainable improvements by objectively measuring surgeons' perioperative teaching performance. DESIGN, SETTING, AND PARTICIPANTS: This 3-phase observational study of surgeons' perioperative teaching behaviors included university-based surgeons, general surgery residents, and preclinical student observers and involved elective cases at a 600+ bed tertiary hospital. Initially, we measured teaching behaviors by surgeons unaware of study objectives, provided aggregate and confidential individual feedback, and developed standardized preoperative briefings and postoperative debriefings. Phase 2 applied a deliberate teaching model and reinforced behaviors with continuous process improvement efforts (Plan, Do, Check, Act) and repeat observations. Phase 3 used resident prompts to enhance teaching behaviors and demonstrate sustainability. Resident surveys conducted 3 times assessed perceptions of deliberate guidance by faculty when compared with national benchmarks. INTERVENTIONS: Introduction of deliberate faculty preprocedural focusing and postprocedural reinforcement to facilitate resident learning. MAIN OUTCOMES AND MEASURES: More frequent and complete perioperative teaching by faculty and the perception of enhanced teaching by residents. RESULTS: Faculty more commonly and more completely performed the 10-step preoperative briefings and postoperative debriefings (P < .001) during phase 2 (250% improvement over baseline). Intraoperative teaching styles significantly improved and residents' survey-reported assessments of faculty teaching improved over national data for describing procedural steps (P = .02) and requests for resident self-evaluation (P = .006). CONCLUSIONS AND RELEVANCE: Objective recording of teaching behavior frequency motivated adoption of deliberate guided teaching behaviors by surgeons, resulting in both subjective reports by residents of more frequent teaching and objective recording of parallel improvements. A deliberate focus on objectively assessing surgeon educators' periprocedural teaching may motivate improved teaching. PMID- 23945793 TI - Kinematic analysis of selected reach directions of the Star Excursion Balance Test compared with the Y-Balance Test. AB - CONTEXT: The Star Excursion Balance Test (SEBT) and the Y-Balance Test (YBT) have 3 common reach directions: anterior (ANT), posteromedial (PM), and posterolateral (PL). Previous research has indicated that reach-distance performance on the ANT reach direction of the SEBT differs from that on the YBT. Kinematic patterns associated with the ANT reach direction of the SEBT and YBT need to be investigated to fully understand this difference, along with the PM and PL reach directions, to deduce any kinematic discrepancies between the 2 balance tests. OBJECTIVE: To compare and contrast the kinematic patterns associated with test performance on the reach directions common to the SEBT and YBT. DESIGN: Controlled laboratory study. SETTING: University laboratory. PARTICIPANTS: 15 healthy male (age 23.33 +/- 2.02 y, height 1.77 +/- 0.04 m, body mass 80.00 +/- 9.03 kg) and 14 healthy female (age 21.14 +/- 1.66 y, height 1.63 +/- 0.06 m, body mass 59.58 +/- 7.61 kg) volunteers. INTERVENTION: Each participant performed 3 trials of the ANT, PM, and PL reach directions of the SEBT and YBT on their dominant leg. MAIN OUTCOME MEASURES: Sagittal-plane lower-limb kinematic profiles were recorded using a 3-D motion-analysis system. Reach distances were also recorded for each reach direction. RESULTS: A significant main effect (P < .05) was observed for test condition with participants reaching farther on the ANT reach direction of the SEBT compared with the YBT. While reaching in the ANT direction participants were characterized by a more flexed position of the hip joint at the point of maximum reach on the YBT (27.94 degrees +/- 13.84 degrees ) compared with the SEBT (20.37 degrees +/- 18.64 degrees ). CONCLUSIONS: Based on these observed results, the authors conclude that test performance on the SEBT and YBT differ in terms of dynamic neuro-muscular demands, as evidenced by differences in reach distances achieved in the ANT reach direction and associated test kinematic profile. PMID- 23945795 TI - Interaction of independent single photons based on integrated nonlinear optics. AB - The parametric interaction of light beams in nonlinear materials is usually thought to be too weak to be observed when the fields involved are at the single photon level. However, such single-photon level nonlinearity is not only fundamentally fascinating but holds great potential for emerging technologies and applications involving heralding entanglement at a distance. Here we use a high efficiency waveguide to demonstrate the sum-frequency generation between a single photon and a single-photon level coherent state. The use of an integrated, solid state, room temperature device and telecom wavelengths makes this type of system directly applicable to future quantum communication technologies such as device independent quantum key distribution. PMID- 23945797 TI - Risk factors for early readmission to acute care for persons with schizophrenia taking antipsychotic medications. AB - OBJECTIVE The study examined risk factors for readmission to acute care among Florida Medicaid enrollees with schizophrenia treated with antipsychotics. METHODS Medicaid and service use data for 2004 to 2008 were used to identify adults with schizophrenia discharged from hospitals and crisis units who were taking antipsychotics. Data were extracted on demographic characteristics, service use before admission, psychopharmacologic treatment after discharge, and readmission to acute behavioral health care. Cox proportional hazards regression estimated readmission risk in the 30 days after discharge and in the period after 30 days for participants not readmitted in the first 30 days. RESULTS The mean+/ SD age of the 3,563 participants was 43.4+/-11.1; 61% were male, and 38% were white. Participants had 6,633 inpatient episodes; duration of hospitalization was 10.6+/-7.0 days. Readmission occurred for 84% of episodes, 23% within 30 days. Variables associated with an increased readmission risk in the first 30 days were shorter hospitalization (hazard ratio [HR]=1.18, 95% confidence interval [CI]=1.10-1.27, p<.001), shorter time on medication before discharge (HR=1.19, CI=1.06-1.35, p=.003), greater prehospitalization use of acute care (HR=2.64, CI=2.29-3.05, p<.001), serious general medical comorbidity (HR=1.21, CI=1.06 1.38, p=.005), and prior substance abuse treatment (HR=1.58, CI=1.37-1.83, p<.001). After 30 days, hospitalization duration and time on medication were not significant risk factors. CONCLUSIONS Short hospital stays for persons with schizophrenia may be associated with risk of early readmission, possibly because the person is insufficiently stabilized. More chronic risk factors include prior acute care, general medical comorbidity, and substance abuse. PMID- 23945798 TI - APhA Name Change, 2002 Election Results, and Pharmacy Technology. PMID- 23945800 TI - Autopsy: Coaxing Secrets From the Dead: Every drug is a poison; every poison, a drug. PMID- 23945799 TI - Filling a Prescription for the Public's Health. PMID- 23945801 TI - Extent of services provided by pharmacists in the iowa medicaid pharmaceutical case management program. AB - OBJECTIVE To summarize the start-up experience with patients identified as eligible during the first four quarters of the Iowa Pharmaceutical Case Management (PCM) program and to characterize the extent of the services proved by pharmacists in the program. DESIGN Prospective pharmaceutical care intervention project. SETTING One hundred seventeen community pharmacies in Iowa. PATIENTS Medicaid patients at high risk for drug-related problems based on using 4 or more nontopical medications and having 1 of 12 specific disease states. INTERVENTION To become eligible to provide PCM services, licensed pharmacists had to undergo training and submit five care plans to the Iowa Department of Human Services. Community pharmacists were provided names of newly eligible patients each calendar quarter for 1 year. For each patient, pharmacists were asked to indicate by fax whether they had met with the patient, performed a written work-up of the patient, sent recommendations to the patient's physician, and whether the physician replied. When pharmacists were unable to provide the service, they were asked to state the reason. Both the pharmacist and the physician receive $75 for the initial assessment, with additional payments after each follow-up visit performed. MAIN OUTCOME MEASURES An intensity score and the percentage of eligible patients for whom all steps were completed were calculated for each pharmacy. RESULTS Fax survey results were returned for 2,834 (96.7%) of the 2,931 patients eligible for PCM services. Pharmacists met with 943 (33.3%), worked up 763 (26.9%), sent recommendations to physicians for 500 (17.6%), and received replies from physicians for 327 (11.5%) patients. Pharmacists were unable to provide PCM services for 1,891 (66.7%) patients. The primary reasons given for this inability to provide services were patient access issues for 438(23.2%) patients, pharmacy staffing or start-up issues for 419(22.2%) patients, or no reason specified for 575(30.4%) patients. A PCM intensity score was developed to represent the scope of services provided and the number of patients served. A higher intensity score indicated pharmacies that provided PCM to more patients and/or that offered higher levels of care (e.g., provided a written set of recommendations to the physician rather than simply assessing the patient without preparing or sending recommendations). Future evaluations will determine the validity of the score on the basis of patient outcomes. CONCLUSION Some pharmacies implemented PCM services very effectively. However, 40% to 60% of the pharmacies provided little or no PCM services within 3 months of notification of patient eligibility. Future investigations will evaluate the quality of prescribing and quality of life for patients who received PCM services. PMID- 23945802 TI - Pain management content in curricula of u.s. Schools of pharmacy. AB - OBJECTIVES To identify individuals in schools of pharmacy in the United States who are responsible for covering the topic of pain management in courses for doctor of pharmacy students and to describe how and at what depth pain management is covered in pharmacy school curricula. DESIGN One-time qualitative assessment. SETTING Schools of pharmacy in the United States. PARTICIPANTS Twenty-eight faculty members with the rank of professor, associate professor, or assistant professor who had been employed in their current positions for at least 2 years and who were directly involved in preparing and teaching didactic courses that address pain management. INTERVENTION In-depth telephone interviews. MAIN OUTCOME MEASURES Qualitative responses to open-ended interview questions. RESULTS While pain management was included in the curricula of all 28 schools of pharmacy, it was generally covered in a fragmented way, usually as part of presentations on diseases with pain as a prominent feature (e.g., cancer pain addressed during oncology lectures) or as part of discussions of analgesics. Only two schools offered stand-alone courses in pain management, and both of those courses were electives that were taken by an average of 15 students per year. Three-fourths of respondents believed that pain was being given too little emphasis in their schools' curricula. Palliative care and the use of medications in the treatment of cancer pain was not presented in a standardized manner, and respondents were unsure of how the subject was covered in pharmacy law classes. Instruction about the diagnosis of pain, patient assessment, and physical examination was reported as "minimal" by most respondents. Respondents perceived a need for a single, complete reference and teaching resource that would address the entire spectrum of pain management as it applies to pharmacy. CONCLUSION The topic of pain management is poorly presented and inadequately developed in the curricula of many U.S. schools of pharmacy. PMID- 23945803 TI - Identification of essential elements in the documentation of pharmacist-provided care. AB - OBJECTIVES To develop guidelines for the documentation elements that need to be included in any record of pharmacist-provided care to allow the quality of the care to be assessed and to describe the use of these guidelines to improve the quality of pharmacist documentation. DESIGN An initial list of 85 potential documentation elements, developed through a review of the literature, was validated by a group of pharmacy practitioners. Then, through three rounds of a Delphi process and a group meeting, a panel of experts reached consensus on a refined list of 27 documentation data elements. RESULTS The documentation elements were formatted into a one-page Tool for Evaluation of Documentation (TED). The TED is a checklist for assessing the completeness of the documentation of pharmacist-provided care. CONCLUSION The TED and the consensus-building methodology used in the development of this tool can serve as cornerstones of a quality assessment process for documentation of pharmacist-provided care, enable further assessment of the quality of care, and, ultimately, be used to measure the impact of pharmacist-provided care on patient outcomes. Our results should provide guidance both to pharmacists providing care and to organizations that assess the quality of that care. PMID- 23945804 TI - Identifying at-risk patients through community pharmacy-based hypertension and stroke prevention screening projects. AB - OBJECTIVE To demonstrate whether a community pharmacist can be successful in identifying and referring patients with elevated blood pressure and/or increased risk of stroke. SETTING An independent community pharmacy and well-elderly housing facility in rural Iowa. PRACTICE DESCRIPTION The pharmacy had dedicated space for patient care activities, had a community pharmacy practice resident, and served as a clerkship site for a local school of pharmacy. One of three well elderly housing facilities in the same community was used as a screening site for the stroke prevention program. PRACTICE INNOVATION All adults entering the pharmacy during the time the blood pressure project was underway were offered a free blood pressure screening. If readings were elevated, patients were referred to their primary care provider. For stroke prevention, a screening using the American Heart Association stroke risk assessment protocol was held at the pharmacy and the well-elderly housing facility. MAIN OUTCOME MEASURES Blood pressure categories and stroke risk (normal, mild, moderate, and high) categories obtained during the screening. RESULTS A total of 351 patients were screened for hypertension. Of these, 216(62%) had readings greater than 140/90 mm Hg. Of the 121 patients referred to their physician, 43 (36%) had a regimen change. A total of 50 patients were screened for stroke risk. Results of the risk assessments for patients screened were normal, 4%; mild, 26%; moderate, 32%; high, 38%. CONCLUSION These projects demonstrated that, through ongoing screening programs, community pharmacists are in an ideal position to screen patients at risk for cardiovascular and cerebrovascular disease and refer patients to their physicians for further evaluation. PMID- 23945806 TI - Using health observances to promote wellness in community pharmacies. AB - OBJECTIVES To provide pharmacists in community practice a framework for using national health observances as opportunities to promote patients' health through education and screenings, to discuss obstacles pharmacists may encounter when developing services within their pharmacies, and to outline examples of activities pharmacists can perform for specific health observances. DATA SOURCES Articles published between January 1970 and April 2002 were identified through MEDLINE using the search terms Wellness, disease prevention, health promotion, Healthy People 2010, treatment of high cholesterol, treatment of high blood pressure, and levels of participation. Additional articles were identified from Web sites and reports from the federal Office of Disease Prevention and Health Promotion (ODPHP), American Heart Association, American Diabetes Association, National Osteoporosis Foundation, National Cancer Institute, American Cancer Society, National Heart, Lung, and Blood Institute, Consumer Product Safety Commission, and Centers for Disease Control and Prevention. DATA SYNTHESIS Healthy People 2010 is a federal program with the goal of increasing the quality and years of healthy life and eliminating health disparities among populations. ODPHP publishes a list of national health observances each year. Community pharmacists can use these month- and week-long observances as opportunities to work toward achieving Healthy People 2010 goals by advocating, facilitating, and/or providing education and screenings to their patients. This article presents advice for pharmacists who want to develop pharmacy-based health promotion activities at various levels of resources and commitment. Specific suggestions include tips on preparing for and implementing education and screening programs and overcoming potential obstacles. CONCLUSION As the most accessible health care professionals, pharmacists are in a unique position to help the nation achieve the goals of Healthy People 2010 through their involvement in the promotion of Wellness. PMID- 23945805 TI - Pharmacist involvement in healthy people 2010. AB - OBJECTIVE To review opportunities through which pharmacists can help the United States achieve its public health goals as expressed in Healthy People 2010, a document issued by the federal government that expresses the areas of focus for Americans in the first decade of the 21st century. SUMMARY Healthy People 2010 provides general goals for 10 leading health indicators (such as tobacco use, overweight and obesity, and immunizations), and these are then further subdivided into 28 focus areas, many of them with quantifiable goals (such as, "Reduce hospitalization rates for three ambulatory care-sensitive conditions-pediatric asthma, uncontrolled diabetes, and immunization-preventable pneumonia and influenza."). As health care professionals, pharmacists have the responsibility to help the country meet these goals. Ideas for increased pharmacist involvement are described in the article, including the conduct of screening programs and provision of specialized services that focus on such areas as hypertension, diabetes, asthma, patient education, smoking cessation, or general medication management. Pharmacists can build their efforts in these and similar areas by collaborating with physicians and other appropriate professionals, identifying target patients who have obtained services at the pharmacy, contacting patients in at-risk populations within the pharmacy's patient base and/or the community, choosing and monitoring an objective of interest, and maintaining efforts for sustained time periods. CONCLUSION The message of Healthy People 2010 is that the health of the individual is closely linked to the health of the community and hence the health of the nation. Pharmacists, uniquely positioned as the most accessible health care providers in the community, can dedicate their considerable strengths toward using Healthy People 2010 as a tool to organize their own efforts and motivate their patients. PMID- 23945807 TI - A proposed ethical framework for prescription drug benefit allocation policy. AB - OBJECTIVES To presentan ethical framework that could aid prescription drug benefit design and to propose that such a framework could be organized around a benefit allocation hierarchy. SUMMARY Four hierarchical levels of allocation are proposed, as follows: (1) drug categories and subcategories, (2) individual drugs within covered drug categories, (3) specific indications of covered drugs, and (4) special features of drug use, such as quantities covered for specific indications. Rationales for decision making should address the distinct ethical issues apparent at each level. CONCLUSION Ethical issues associated with designing and managing a pharmacy benefit can be identified by using a hierarchical prescription drug allocation scheme. Articulating these issues is an important first step toward arriving at a fully developed framework that will serve to produce rationales acceptable to typical stakeholders in prescription drug benefits. PMID- 23945809 TI - Clock drawing test and medication complexity index as indicators of medication management capacity: a pilot study. PMID- 23945808 TI - Issues and barriers related to the provision of pharmaceutical care in community health centers and migrant health centers. PMID- 23945810 TI - State of CAM Education in U.S. Schools of Pharmacy: Results of a National Survey. PMID- 23945811 TI - Sesquicentennial Stepping Stone Summits-Summit Two: Pharmacy Technicians: At the first national conference on pharmacy technicians since 1988, 34 experts and stakeholders gathered to project the future needs, education, and responsibilities of pharmacy's growing cadre of pharmacy technicians. PMID- 23945812 TI - White paper on pharmacy technicians (2002): needed changes can no longer wait. PMID- 23945814 TI - Journal of the american pharmaceutical association guidelines for authors. PMID- 23945813 TI - Journal of the american pharmaceutical association reviewers - 2002. PMID- 23945815 TI - Preventing meningococcal outbreaks: an opportunity for pharmacists. PMID- 23945816 TI - New biotechnology approvals for 2002. PMID- 23945817 TI - Evaluation of OTC Product Information in Three Drug Information Databases for PDAs. PMID- 23945818 TI - Aiming for, believing in, and achieving a target a1c of less than 7. PMID- 23945819 TI - Zada Mary cooper (1875-1961). PMID- 23945820 TI - The Sky is His Wife (2001)/Jim Alford (b. 1943). PMID- 23945821 TI - Spiral patterns of dislocations at nodes in (111) semi-coherent FCC interfaces. AB - In semi-coherent interface, a superposed network of interface dislocations accommodates the attendant coherency strains in the adjacent crystals and their intersections (referred to as nodes) can act as sinks and sources for point defects because of the low formation energy. Nodes in {111} semi-coherent interfaces are characterized with a spiral pattern (SP), wherein the line direction of each dislocation entering a node curves. The structure of SP nodes is able to switch between condensed and expanded by either reaction with point defects or mechanical deformation. Due to the switching of the node structures, point defect formation energies at nodes can be significantly reduced. Combining atomistic simulation and dislocation theory, these features are proven universal corresponding to the node density and the character of interface dislocations. PMID- 23945824 TI - Theoretical analysis of a magnetophoresis-diffusion T-sensor immunoassay. AB - We present the analytical investigation of a microfluidic homogeneous competitive immunoassay that incorporates antibody-conjugated superparamagnetic nanoparticles and magnetophoretic transport to enhance the limits of detection and dynamic range. The analytical model considers the advective, diffusive, and magnetophoretic transport of the antibody-coated nanoparticles relative to the labeled and sample antigens of interest in a T-sensor configuration. The magnetophoresis-diffusion immunoassay identified clear improvements to the assay response and reductions to the limit of detection for increased magnetophoretic velocities and larger nanoparticles. The externally applied magnetophoretic transport enriched the antibody-antigen accumulation region, while larger nanoparticles led to decreased diffusive peak broadening. The integration of nanoparticles to the diffusion immunoassay (NP-DIA) demonstrated an approximately 3-fold improvement to the limit of detection of the basic antibody/antigen system, while the integration of superparamagnetic nanoparticles and magnetophoretic transport (MIA) established an order of magnitude improvement in sensitivity as well as means to greatly reduce response time. The implementation of an external magnetic force enabled the detectable antigen size spectrum to extend from small molecules i.e., 10's Da to 100's Da, up to large proteins and macromolecules, i.e., 50 kDa to 150 kDa, for a single class of binding species, i.e., superparamagnetic nanoparticle. This investigation provides guidelines for the design and development of a magnetophoresis-diffusion T-sensor immunoassay, and clearly identifies the regimes for optimal operation. PMID- 23945822 TI - Pharmacometabolomics of statin response. AB - Statins reduce risk of cardiovascular disease (CVD) by decreasing plasma low density lipoprotein (LDL) concentrations, as well as reducing inflammation and improving endothelial function. Despite their documented efficacy, there is considerable interindividual variation in effects of statins on CVD biomarkers. In the studies summarized here, we used complementary metabolomics platforms to define global effects of a statin (simvastatin) on metabolism and to identify markers indicative of mechanisms that contribute to variation in plasma LDL response to statin treatment. PMID- 23945825 TI - Transparent, conductive gold nanowire networks assembled from soluble Au thiocyanate. AB - Extremely long gold nanowires spontaneously assemble in a water-dimethylsulfoxide (DMSO) solution of Au(SCN)4(-). The Au nanowires were crystalline, exhibited a very high aspect ratio, and, importantly, were produced without co-addition of reducing agents. Transparent conductive films were formed by surface deposition of the nanowires and plasma treatment. PMID- 23945826 TI - Ln3GaS6 (Ln = Dy, Y): new infrared nonlinear optical materials with high laser induced damage thresholds. AB - Two new ternary rare earth chalcogenides, Dy3GaS6 (1) and Y3GaS6 (2), are reported here. They both crystallize in the orthorhombic space group Cmc21 (no. 36). Both are synthesized in pure phase and show phase-matchable second harmonic generation (SHG) of about 0.2 and 0.5 times, respectively for 1 and 2, as strong as that of KTiOPO4 (KTP) based on the powder SHG measurement at the wavelength of 1910 nm. They possess high powder laser induced damage thresholds (LIDTs), respectively, about 14 and 18 times that of AgGaS2 (AGS) based on the powder LIDT measurements under 1064 nm laser irradiation. They both exhibit wide transparency in the IR region (2.5-25 MUm). It is believed that the title compounds are new candidates for nonlinear optical (NLO) materials in the IR region. To gain further insights into the NLO and LIDT properties of 1 and 2, the calculations of second-order NLO susceptibility and lattice energy density (LED) were also performed to explain their SHG efficiencies and high LIDTs. PMID- 23945828 TI - A facile avenue to conductive polymer brushes via cyclopentadiene-maleimide Diels Alder ligation. AB - Cyclopentadienyl end-capped poly(3-hexylthiophene) was employed to fabricate conductive surface tethered polymer brushes via a facile route based on cyclopentadiene-maleimide Diels-Alder ligation. The efficient nature of the Diels Alder ligation was further combined with a biomimetic polydopamine-assisted functionalization of surfaces, making it an access route of choice for P3HT surface immobilization. PMID- 23945829 TI - [Influence of carbapenem selection pressure on bacterial resistance]. AB - As a result of high resistance of bacterial pathogens to broad-spectrum penicillins and cephalosporins, carbapenems have been increa-singly used recently. The presented study aimed at analyzing the association between carbapenem consumption and resistance of selected Gramnegative pathogens to meropenem. Using linear regression analysis, a statistically significant association was found between carbapenem consumption and resistance of Pseudomonas aeruginosa. PMID- 23945830 TI - [Pharmacological characteristics of ertapenem]. AB - Ertapenem is a broad-spectrum bactericidal carbapenem antibiotic. It differs from the other substances of this group by the absence of action against Gram-negative non-fermenting bacilli and by a long elimination half-life, which allows once daily administration. It is administered once daily in a dose of 1 gram intravenously. Ertapenem is generally well-tolerated, with the most common side effects being diarrhea and phlebitis at the injection site. It is used for the treatment of community-acquired pneumonia, intra-abdominal and gynecological infections, and skin and soft tissue infections, including diabetic foot. PMID- 23945831 TI - [Severe eosinophilia in a patient with clostridium colitis and gastric cancer]. AB - A case of a 77-year-old male repeatedly hospitalized with the diagnosis of Clostridium difficile colitis associated with eosinophilia is presented. The percentage and number of eosinophils achieved maximal values (54 %, 5.4 times 1.000.000.000/l) during repeated treatment with metronidazole. Eosinophilia was accompanied by significant elevation of serum IgE and presence of Charcot-Leyden crystals in stool. Helminth infections and hemoblastosis were ruled out as the cause and a working diagnosis of eosinophilic gastroenterocolitis induced by antibiotics was established. The working diagnosis was supported by a decrease in eosinophils observed after a switch from metronidazole to vancomycin. After one month, the patient was hospitalized with gastrectasia, for which gastric biopsy was performed with a finding of infiltrating carcinoma. A differential diagnostic approach to patients with eosinophilia is discussed and the need for ruling out relatively rare causes such as tumors is stressed. PMID- 23945832 TI - [Immune thrombocytopenia as a complication of acute infectious diseases - case reports]. AB - Immune thrombocytopenia (immune thrombocytopenic purpura, ITP) is an acquired autoimmune disease, mediated by antibodies against platelet glycoproteins. ITP can develop in the context of other disorders (secondary ITP), including acute and chronic infections (HIV, H. pylori, HCV, HBV, CMV, EBV, VZV, parvovirus B19, rubella, etc.). The case reports present two children and one adult with ITP complicating VZV, EBV and HAV infections. Corticosteroids are usually initial drugs, but they are controversial in case of ITP during acute infections. Intravenous immunoglobulins are preferred, especially in children, because of their smaller suppression of inflammatory response. Two of the patients were successfully treated with intravenous immunoglobulins. In the remaining patient, corticosteroid therapy had good but delayed effects as compared to immunoglobulins. PMID- 23945833 TI - [RILPIVIRINE -- a novel HIV-1 non-nucleoside reverse transcriptase inhibitor]. AB - The article summarizes the basic facts about the pharmacokinetic profile, metabolism and drug interactions of rilpivirine (RPV). This is the latest orally administered second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for antiretroviral-naive patients with HIV-1 infection. Conformational flexibility and adaptability are the factors that dominantly determine the high resistance barrier of RPV and are the unique features of diarylpyrimidine inhibitors (DAPY inhibitors - 2nd generation NNRTIs). Multicentre studies ECHO and THRIVE are also reviewed. Current guidelines for the treatment of HIV/AIDS are mentioned as well as the role of RPV in current therapeutic regimens. PMID- 23945834 TI - Successful nonoperative management of the most severe blunt renal injuries: a multicenter study of the research consortium of New England Centers for Trauma. AB - IMPORTANCE: Severe renal injuries after blunt trauma cause diagnostic and therapeutic challenges for the treating clinicians. The need for an operative vs a nonoperative approach is debated. OBJECTIVE: To determine the rate, causes, predictors, and consequences of failure of nonoperative management (NOM) in grade IV and grade V blunt renal injuries (BRIs). DESIGN: Retrospective case series. SETTING: Twelve level I and II trauma centers in New England. PARTICIPANTS: A total of 206 adult patients with a grade IV or V BRI who were admitted between January 1, 2000, and December 31, 2011. MAIN OUTCOMES AND MEASURES: Failure of NOM, defined as the need for a delayed operation or death due to renal-related complications during NOM. RESULTS: Of 206 patients, 52 (25.2%) were operated on immediately, and 154 (74.8%) were managed nonoperatively (with the assistance of angiographic embolization for 25 patients). Nonoperative management failed for 12 of the 154 patients (7.8%) and was related to kidney injury in 10 (6.5%). None of these 10 patients had complications because of the delay in BRI management. The mean (SD) time from admission to failure was 17.6 (27.4) hours (median time, 7.5 hours; range, 4.5-102 hours), and the cause was hemodynamic instability in 10 of the 12 patients (83.3%). Multivariate analysis identified 2 independent predictors of NOM failure: older than 55 years of age and a road traffic crash as the mechanism of injury. When both risk factors were present, NOM failure occurred for 27.3% of the patients; when both were absent, there were no NOM failures. Of the 142 patients successfully managed nonoperatively, 46 (32.4%) developed renal-related complications, including hematuria (24 patients), urinoma (15 patients), urinary tract infection (8 patients), renal failure (7 patients), and abscess (2 patients). These patients were managed successfully with no loss of renal units (ie, kidneys). The renal salvage rate was 76.2% for the entire population and 90.3% among patients selected for NOM. CONCLUSIONS AND RELEVANCE: Hemodynamically stable patients with a grade IV or V BRI were safely managed nonoperatively. Nonoperative management failed for only 6.5% of patients owing to renal-related injuries, and three-fourths of the entire population retained their kidneys. PMID- 23945836 TI - Axonal and subcellular labelling using modified rabies viral vectors. AB - An important aspect of any neural circuit is the placement of its output synapses, at levels ranging from macroscopic to subcellular. The many new molecular tools for locating and manipulating synapses are limited by the viral vectors available for delivering them. Adeno-associated viruses are the best current means of labelling and manipulating axons and synapses, but they have never expressed more than one transgene highly enough to label fine axonal structure while also labelling or perturbing synapses. Their slow expression also makes them incompatible with retrograde and transsynaptic vectors, preventing powerful combinatorial experiments. Here we show that deletion-mutant rabies virus can be specifically targeted to cells local to an injection site, brightly labelling axons even when coexpressing two other transgenes. We demonstrate several novel capabilities: simultaneously labelling axons and presynaptic terminals, labelling both dendrites and postsynaptic densities, and simultaneously labelling a region's inputs and outputs using co-injected vectors. PMID- 23945837 TI - A borane-bithiophene-BODIPY triad: intriguing tricolor emission and selective fluorescence response towards fluoride ions. AB - The structure and photophysical properties of a new triad (borane-bithiophene BODIPY) 1 have been investigated. Triad 1 exhibits unprecedented tricolour emission when excited at the borane centred high energy absorption band and also acts as a selective fluorescent and colorimetric sensor for fluoride ions with ratiometric response. The experimental results are supported by computational studies. PMID- 23945838 TI - Optimal pain management in total abdominal hysterectomy. AB - Effective postoperative pain management provides improved patient comfort and satisfaction, earlier mobilization, fewer pulmonary and cardiac complications, reduced risk of deep vein thrombosis, faster recovery, and reduced cost of care. Although many therapeutic modalities are available for pain management, the optimal combination in managing postoperative pain in total abdominal hysterectomy is controversial. The objective of this study was to review the literature to formulate optimal, evidence-based preoperative, intraoperative, and postoperative pain management for women undergoing total abdominal hysterectomy. Using the OVID platform, we searched in MEDLINE and PubMed using MeSH terms postoperative pain and total abdominal hysterectomy for published articles from 1960 to the present; we found 545 studies. We screened and included only randomized clinical trials, publications in English, human studies, and abdominal hysterectomy for noncancerous indications. We excluded 456 studies that reported on animal studies; laparoscopic, vaginal, supracervical, or robotic hysterectomy; pharmacokinetic studies; primary outcome other than pain management; and chronic pain management. Studies with inadequate power, poor methodology, or inconclusive results were further excluded from this review. Thus, 89 studies constituted the cohort for our article. Pain control remains complex given variables such as age, anxiety, and extent of surgery. In general, regimens should be tailored to the needs of the individual patient, taking into account medical, psychological, and physical condition. A multimodality approach is better than conventional, single agent narcotic in achieving optimal pain management. After reading this article, the reader should be able to understand various modalities that can be considered for preoperative, intraoperative, and postoperative pain management in total abdominal hysterectomy. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this CME activity, physicians should be better able to understand various modalities that can be considered for preoperative, intraoperative, and postoperative pain management in total abdominal hysterectomy. PMID- 23945839 TI - Phenotypic expression of polycystic ovary syndrome in South Asian women. AB - Polycystic ovary syndrome (PCOS) occurs in 6% to 10% of women and, as the most common worldwide endocrinopathy of reproductive-aged women, is linked to a constellation of reproductive and metabolic abnormalities, including anovulatory infertility, hirsutism, acne, and insulin resistance in association with metabolic syndrome. Despite a genetic component to PCOS, ethnicity plays an important role in the phenotypic expression of PCOS, with South Asian PCOS women having more severe reproductive and metabolic symptoms than other ethnic groups. South Asians with PCOS seek medical care at an earlier age for reproductive abnormalities; have a higher degree of hirsutism, infertility, and acne; and experience lower live birth rates following in vitro fertilization than do whites with PCOS. Similarly, South Asians with PCOS have a higher prevalence of insulin resistance and metabolic syndrome than do other PCOS-related ethnic groups of a similar body mass index. Inheritance of PCOS appears to have a complex genetic basis, including genetic differences based on ethnicity, which interact with lifestyle and other environmental factors to affect PCOS phenotypic expression. TARGET AUDIENCE: Obstetricians and Gynecologists, Family Physicians Learning Objectives: After completing this CME activity, physicians should be better able to state an ethnic difference in reproductive dysfunction between South Asian and white women with polycystic ovary syndrome (PCOS), state an ethnic difference in metabolic dysfunction between South Asian and white women with PCOS, identify a genetic abnormality found in South Asian women with PCOS, and list 2 environmental factors that predispose South Asian women to metabolic dysfunction. PMID- 23945840 TI - Sex differences among obstetrician-gynecologists: a review of survey studies. AB - Whether practice differences exist between the sexes is a question of clinical and educational significance. The obstetrician-gynecologist (ob-gyn) workforce has been shifting to majority women. An examination of sex differences in ob-gyn practice contributes to the discussion about how the changing workforce may impact women's healthcare. We sought to review survey studies to assess whether there are specific topics in which differences in attitudes, opinions, and practice patterns between male and female ob-gyns are apparent. We conducted a systematic review to identify all survey studies of ob-gyns from the years 2002 2012. A total of 93 studies were reviewed to identify statements of sex differences and categorized by conceptual theme. Sex differences were identified in a number of areas. In general, women report more supportive attitudes toward abortion. A number of differences were identified with regard to workforce issues, such as women earning 23% less than their male counterparts as reported in 1 study and working an average of 4.1 fewer hours per week than men in another study. Men typically provide higher selfratings than women in a number of areas. Other noted findings include men tending toward more pharmaceutical therapies and women making more referrals for medical conditions. Although a number of areas of difference were identified, the impact of such differences is yet to be determined. Additional research may help to clarify the reasons for such differences and their potential impact on patients. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this CME activity, physicians should be better able to determine how the relevance of studying sex differences among physicians, specifically ob-gyns, can help improve patient care, assess whether there are topical areas in which male and female ob-gyns have reported different beliefs, practices, attitudes, and opinions, and examine how the limitations of survey studies and systematic reviews can affect the findings of these studies and reviews. PMID- 23945842 TI - Inflammation in laparoendoscopic single-site surgery versus laparoscopic cholecystectomy. AB - INTRODUCTION: Laparoendoscopic single-site surgery (LESS) uses a multiple-entry portal in a single 3.0- to 4.0-cm incision in a natural scar, the umbilicus. The present study aimed to compare the inflammatory impact of classic video laparoscopic cholecystectomy (LC) versus LESS cholecystectomy. METHODS: A prospective randomized controlled study was conducted from January to June 2011 at 2 university hospitals in Rio de Janeiro, Brazil. Fifty-seven patients (53 women, 4 men; mean age = 48.7 years) were randomly assigned to receive LC (n = 29) or LESS (n = 28) cholecystectomy. C-reactive protein (CRP) and interleukin 6 (IL-6) were measured from blood samples collected during induction of anesthesia and at 3 and 24 hours postoperatively. RESULTS: Median IL-6 levels in the LESS and LC groups, respectively, were 2.96 and 4.5 pg/mL preoperatively, 11.6 and 28.05 pg/mL at 3 hours postoperatively (P = .029), and 13.18 and 15.1 pg/mL at 24 hours postoperatively (P = .52). Median CRP levels in the LESS and LC groups, respectively, were 0.33 and 0.44 mg/mL preoperatively, 0.40 and 0.45 mg/mL (P = .73) at 3 hours postoperatively, and 1.7 and 1.82 mg/mL (P = .84) at 24 hours postoperatively. We did not find a significant association between IL-6 (and CRP) and body mass index in the LESS group. CONCLUSIONS: LESS cholecystectomy requires a larger size incision than LC. We found a tendency of less postoperative pain following LESS cholecystectomy than LC. There was also a tendency toward lower early inflammatory impact following LESS cholecystectomy versus LC. PMID- 23945843 TI - Metal ion directed metal-organic rotaxane frameworks with intrinsic features of self-penetration and interpenetration. AB - Three novel self-catenated 4-connected uninodal (6(5).8)- metal-organic rotaxane frameworks (MORFs) containing cucurbit[6]uril were constructed from the in situ trans/cis-configuration (1 : 1) of rotaxanes by taking advantage of a d(10) metal ion directed synthesis. It was revealed that the effect of hydrogen bonds and pi pi stacking interactions play significant roles in the self-assembly process. PMID- 23945841 TI - Validation of an interactive simulation module to train the use of a laparoscopic insufflator. AB - BACKGROUND: The purpose of this study was to determine construct and face validities of an interactive Web-based module for pneumoperitoneum and insufflator. METHODS: Participants were recruited from surgical departments in 2 academic hospitals and 1 large nonacademic teaching hospital. They were stratified into 3 groups based on their laparoscopic experience (A, no experience; B, experience as assistant; and C, experience as primary surgeon). Within each group the participants were randomized into a training subgroup and a control subgroup. All participants performed a theoretical and a practical test. The training participants first completed the module before they performed the tests. The control participants immediately performed the tests. Results were compared between the training and control participants. All training participants filled out a questionnaire on their opinion about the module. RESULTS: In total, 40 participants were enrolled in the study: group A consisted of 20 participants and groups B and C both consisted of 10 participants. The trained participants answered significantly more theoretical questions correctly (8.3 vs 6.6; P < .001), correctly identified more alarm causes (91% vs 86%; P = .014) and made significantly less errors in the practical test (1.5 vs 3.6; P = .001). All 20 trained participants rated the module fairly good and indicated the module to be of additive value to surgical training programs. CONCLUSIONS: Training with the interactive web-based module on installation of a pneumoperitoneum and use of an insufflator has a positive effect on both theoretical and practical competence. Construct and face validities were established for this module. PMID- 23945844 TI - Is type 2 diabetes mellitus associated with alterations in hearing? A systematic review and meta-analysis. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to systematically and quantitatively review the available evidence on the effects of type 2 diabetes mellitus on hearing function. DATA SOURCES AND REVIEW METHODS: Eligible studies were identified through searches of eight different electronic databases and manual searching of references. Articles obtained were independently reviewed by two authors using predefined inclusion criteria to identify eligible studies. Meta-analysis was performed on pooled data using Cochrane's Review Manager. RESULTS: Eighteen articles fulfilled the inclusion criteria. Hearing loss (HL) was defined by all studies as pure tone average greater than 25 dB in the worse ear. The incidence of HL ranged between 44% and 69.7% for type 2 diabetics, significantly higher than in controls (OR 1.91; 95% confidence interval 1.47 2.49). The mean PTA (pure tone audiometry) thresholds were greater in diabetics than in controls for all frequencies [test or overall effect Z = 3.68, P = 0.0002]. Auditory brainstem response (ABR) wave V latencies were also statistically significantly longer in diabetics when compared to control groups [OR 3.09, 95% CI 1.82- 4.37, P < 0.00001]. CONCLUSIONS: Type 2 diabetic patients had significantly higher incidence for at least the mild degree of HL when compared with controls. Mean PTA thresholds were greater in diabetics for all frequencies but were more clinically relevant at 6000 and 8000 Hz. Prolonged ABR wave V latencies in the diabetic group suggest retro-cochlear involvement. Age and duration of DM play important roles in the occurrence of DM-related HL. PMID- 23945845 TI - Intima media thickness measurement as a marker of subclinical atherosclerosis in SLE patient. AB - AIM: Accelerated atherosclerosis in systemic lupus erythematosus (SLE) is an important cause of morbidity and mortality. The pathophysiology of accelerated atherosclerosis in SLE is mediated by factors such as inflammatory processes in the vascular wall, specific antibodies, dyslipoproteinemia, endothelial dysfunction and the high prevalence of traditional risk factors for cardiovascular diseases. In this context, we evaluated the clinical significance of ultrasound examination of the carotic arteries in the early diagnosis of atherosclerosis. METHODS: The study included 63 patients with SLE (female: male 53:10, mean age 38.4+/-12.7 years, mean disease duration 143.0+/-82.6 months), 24 patients had lupus nephritis. The control group consisted of 24 volunteers (female: male 20:4 mean age 31.04+/-8.59). Intima media thickness (IMT) was measured by ultrasound on both sides. The results were correlated with markers of lipid spectrum, anti-dsDNA, antinucleosomal and anticardiolipin antibodies, lupus anticoagulant and complement components. Clinical disease activity and damage were evaluated by SLEDAI and SLICC indices. Lifestyle and other important factors were examined per protocol and by questionnaire. RESULTS: A significant difference of IMT (P<=0.03) was found between the lupus patients and sex-age adjusted healthy controls with an in mean IMT in SLE patients of 0.569+/-0.11 mm, in control group 0.495+/-0.05 mm. A significant correlation between IMT and disease duration, age, positivity of lupus anticoagulant, use of ACE inhibitors, glomerular filtration and serum creatinine were found. No difference in IMT was found between patients with or without lupus nephritis. CONCLUSION: IMT measurement could be used as a clinical predictor of risk of accelerated atherosclerosis in lupus patients. PMID- 23945846 TI - Towards an ideal source of mesenchymal stem cell isolation for possible therapeutic application in regenerative medicine. AB - BACKGROUND: The possibility of obtaining mesenchymal stem cells (MSCs) from fetal tissue such as amniotic fluid, chorionic villi and placenta is well-known and a comparison between MSCs originating in different sources such as fetal tissue and those from bone marrow in terms of yield and function is a topical issue. The mesenchymal stem cells isolated from bone marrow are well-characterized. Unfortunately the low quantitative yield during isolation is a major problem. For this reason, other tissue sources for MSCs are of paramount importance. CONCLUSION: In this review, starting from a description of the molecular and cellular biology of MSCs, we describe alternative sources of isolation other than bone marrow. Finally, we describe the potential therapeutic application of these cells. PMID- 23945847 TI - Resection versus biopsy of glioblastomas in eloquent brain areas. AB - AIM: The aim of this study was to compare resection and biopsy of glioblastoma (GBM) in eloquent brain areas (EBA). METHODS: This was a prospective evaluation of 38 patients with GBM in EBA. 22 were treated by surgical resection and 16 by biopsy. Preoperative KPS, neurological status and size of lesion on MRI were assessed. One week and three months postoperatively KPS, neurological status and Performance Status (PS) WHO were evaluated. Extent of resection (EOR) and overall survival (OS) were described. Overall mean age of the patients was 64.3 years, the mean lesion size in the resection group was 47.7 mm and in the biopsy group 51.0 mm. RESULTS: Worsening or development of permanent neurological deficits 3 months after surgery were significantly lower in the resection group (23%), than the biopsy group (94%). In the resection group the median pre and postoperative KPS three months after surgery was 80.0. In the biopsy group the median pre and postoperative KPS was 68.1 one week after the procedure. In the resection group, 3 months after surgery, the median PS was 1, in the biopsy group one week after surgery the median PS was 2. The difference was statistically insignificant. The mean OS after resection was 12.2 months, and after biopsy 3.5 months. The difference was highly statistically significant. The mean EOR was 90%. CONCLUSION: This is the first prospective study, to our knowledge, that compares the results of resection and biopsy of primary GBM in EBA. For patients in good clinical condition with tumors in or near EBA, recommended is as radical resection of GBM as possible. PMID- 23945848 TI - The effectiveness of foot orthotics in improving postural control in individuals with chronic ankle instability: a critically appraised topic. AB - CLINICAL SCENARIO: Chronic ankle instability (CAI) is a condition commonly experienced by physically active individuals. It has been suggested that foot orthotics may increase a CAI patient's postural control. CLINICAL QUESTION: For patients with CAI, is there evidence to suggest that an orthotic intervention will help improve postural control? SUMMARY OF KEY FINDINGS: The literature was searched for studies of level 2 evidence or higher that investigated the effects of foot orthotics on postural control in patients with CAI. The search of the literature produced 5 possible studies for inclusion; 2 studies met the inclusion criteria and were included. One randomized controlled trial and 1 outcomes study were included. Foot orthotics appear to be effective at improving postural control in patients with CAI. CLINICAL BOTTOM LINE: There is moderate evidence to support the use of foot orthotics in the treatment of CAI to help improve postural control. STRENGTH OF RECOMMENDATION: There is grade B evidence that foot orthotics help improve postural control in people with CAI. The Centre of Evidence Based Medicine recommends a grade of B for level 2 evidence with consistent findings. PMID- 23945849 TI - Illness severity and psychiatric hospitalization rates among Asian Americans and Pacific Islanders. AB - OBJECTIVE The study objective was to fill research gaps about inpatient psychiatric service utilization among Asian Americans and Pacific Islanders (AA/PIs). METHODS Rates of psychiatric hospitalization, illness severity, and length of stay were compared among AA/PI adults overall and across diagnoses (schizophrenia, depression, bipolar, anxiety, and other psychiatric disorders identified by All Patient Refined Diagnosis Related Groups) by using discharge data from all hospitalizations in Hawaii from December 2006 to 2010. Multivariable models adjusted for gender, age, payer, and residence. RESULTS In multivariable analyses of total psychiatric hospitalizations, Chinese (rate ratio [RR]=.22), Japanese (RR=.23), Filipinos (RR=.30), and Native Hawaiians (RR=.37) had significantly lower rates than whites. Native Hawaiians had significantly higher hospitalization rates compared with other AA/PI groups. Length of stay was significantly longer for Chinese (length of stay ratio [LOSR]=1.53), Filipinos (LOSR=1.20), and Japanese (LOSR=1.19) compared with whites, whereas severity of illness was significantly higher for Japanese (odds ratio [OR]=1.36) and Filipinos (OR=1.30). Within specific diagnoses, Native Hawaiians had higher hospitalization rates than other AA/PI groups for depression, bipolar disorder, and anxiety disorder. Chinese, Japanese, and Filipinos had significantly higher illness severity or longer stays than whites for at least one diagnostic category. CONCLUSIONS AA/PI subgroups had lower psychiatric hospitalization rates than whites, but rates varied across AA/PI subgroups. Native Hawaiians had higher hospitalization rates for many diagnoses. Chinese, Japanese, and Filipinos had greater illness severity or longer stays than whites overall and for some diagnoses, whereas Native Hawaiians did not. Disaggregating AA/PI groups provides important insight into mental health services utilization and need. PMID- 23945873 TI - Fluorescence-based high-throughput screening of dicer cleavage activity. AB - Production of small RNAs by ribonuclease III Dicer is a key step in microRNA and RNA interference pathways, which employ Dicer-produced small RNAs as sequence specific silencing guides. Further studies and manipulations of microRNA and RNA interference pathways would benefit from identification of small-molecule modulators. Here, we report a study of a fluorescence-based in vitro Dicer cleavage assay, which was adapted for high-throughput screening. The kinetic assay can be performed under single-turnover conditions (35 nM substrate and 70 nM Dicer) in a small volume (5 uL), which makes it suitable for high-throughput screening in a 1536-well format. As a proof of principle, a small library of bioactive compounds was analyzed, demonstrating potential of the assay. PMID- 23945874 TI - Are GPCRs still a source of new targets? AB - G-protein-coupled receptors (GPCRs) still offer enormous scope for new therapeutic targets. Currently marketed agents are dominated by those with activity at aminergic receptors and yet they account for only ~10% of the family. Progress up until now with other subfamilies, notably orphans, Family A/peptide, Family A/lipid, Family B, Family C, and Family F, has been, at best, patchy. This may be attributable to the heterogeneous nature of GPCRs, their endogenous ligands, and consequently their binding sites. Our appreciation of receptor similarity has arguably been too simplistic, and screening collections have not necessarily been well suited to identifying leads in new areas. Despite the relative shortage of high-quality tool molecules in a number of cases, there is an emerging, and increasingly substantial, body of evidence associating many as yet "undrugged" receptors with a very wide range of diseases. Significant advances in our understanding of receptor pharmacology and technical advances in screening, protein X-ray crystallography, and ligand design methods are paving the way for new successes in the area. Exploitation of allosteric mechanisms; alternative signaling pathways such as G12/13, Gbetagamma, and beta-arrestin; the discovery of "biased" ligands; and the emergence of GPCR-protein complexes as potential drug targets offer scope for new and much improved drugs. PMID- 23945878 TI - Synthesis of MnFe2O4@Mn-Co oxide core-shell nanoparticles and their excellent performance for heavy metal removal. AB - Magnetic nanomaterials that can be easily separated and recycled due to their magnetic properties have received considerable attention in the field of water treatment. However, these nanomaterials usually tend to aggregate and alter their properties. Herein, we report an economical and environmentally friendly method for the synthesis of magnetic nanoparticles with core-shell structure. MnFe2O4 nanoparticles have been successfully coated with amorphous Mn-Co oxide shells. The synthesized MnFe2O4@Mn-Co oxide nanoparticles have highly negatively charged surface in aqueous solution over a wide pH range, thus preventing their aggregation and enhancing their performance for heavy metal cation removal. The adsorption isotherms are well fitted to a Langmuir adsorption model, and the maximal adsorption capacities of Pb(II), Cu(II) and Cd(II) on MnFe2O4@Mn-Co oxide are 481.2, 386.2 and 345.5 mg g(-1), respectively. All the metal ions can be completely removed from the mixed metal ion solutions in a short time. Desorption studies confirm that the adsorbent can be effectively regenerated and reused. PMID- 23945876 TI - Significance of lipid composition in a blood-brain barrier-mimetic PAMPA assay. AB - Endothelial cells forming the blood-brain barrier limit drug access into the brain, due to tight junctions, membrane drug transporters, and unique lipid composition. Passive permeability, thought to mediate drug access, is typically tested using porcine whole-brain lipid. However, human endothelial cell lipid composition differs. This investigation evaluated the influence of lipid composition on passive permeability across artificial membranes. Permeability of CNS-active drugs across an immobilized lipid membrane was determined using three lipid models: crude extract from whole pig brain, human brain microvessel lipid, and microvessel lipid plus cholesterol. Lipids were immobilized on polyvinylidene difluoride, forming donor and receiver chambers, in which drug concentrations were measured after 2 h. The log of effective permeability was then calculated using the measured concentrations. Permeability of small, neutral compounds was unaffected by lipid composition. Several structurally diverse drugs were highly permeable in porcine whole-brain lipid but one to two orders of magnitude less permeable across human brain endothelial cell lipid. Inclusion of cholesterol had the greatest influence on bulky amphipathic compounds such as glucuronide conjugates. Lipid composition markedly influences passive permeability. This was most apparent for charged or bulky compounds. These results demonstrate the importance of using species-specific lipid models in passive permeability assays. PMID- 23945875 TI - Inhibition of microglia activation as a phenotypic assay in early drug discovery. AB - Complex biological processes such as inflammation, cell death, migration, proliferation, and the release of biologically active molecules can be used as outcomes in phenotypic assays during early stages of drug discovery. Although target-based approaches have been widely used over the past decades, a disproportionate number of first-in-class drugs have been identified using phenotypic screening. This review details phenotypic assays based on inhibition of microglial activation and their utility in primary and secondary screening, target validation, and pathway elucidation. The role of microglia, both in normal as well as in pathological conditions such as chronic neurodegenerative diseases, is reviewed. Methodologies to assess microglia activation in vitro are discussed in detail, and classes of therapeutic drugs known to decrease the proinflammatory and cytotoxic responses of activated microglia are appraised, including inhibitors of glutaminase, cystine/glutamate antiporter, nuclear factor kappaB, and mitogen-activated protein kinases. PMID- 23945881 TI - Visualizing charge separation in bulk heterojunction organic solar cells. AB - Solar cells based on conjugated polymer and fullerene blends have been developed as a low-cost alternative to silicon. For efficient solar cells, electron-hole pairs must separate into free mobile charges that can be extracted in high yield. We still lack good understanding of how, why and when carriers separate against the Coulomb attraction. Here we visualize the charge separation process in bulk heterojunction solar cells by directly measuring charge carrier drift in a polymer:fullerene blend with ultrafast time resolution. We show that initially only closely separated (<1 nm) charge pairs are created and they separate by several nanometres during the first several picoseconds. Charge pairs overcome Coulomb attraction and form free carriers on a subnanosecond time scale. Numerical simulations complementing the experimental data show that fast three dimensional charge diffusion within an energetically disordered medium, increasing the entropy of the system, is sufficient to drive the charge separation process. PMID- 23945885 TI - The effect of timing of decompression on neurologic recovery and histopathologic findings after spinal cord compression in a rat model. AB - Prior animal models have shown that rats sustaining 3-second immediate spinal cord compression had significantly better functional recovery and smaller lesion volumes than rats subjected to compression times of 1 hour, 6 hours, 3 weeks, and 10 weeks after spinal cord injury. We compare locomotor rating scales and spinal cord histopathology after 3 seconds and 10 minute compression times. . Ten rats were assigned into two early (3-second) and late (10-minute) compressive surgery groups. Compressive injury was produced using an aneurysmal clip method. Rats were followed-up for 11 weeks, and behavioral assessment was done by inclined plane test and tail-flick reflex. At the end of the study, the rats were sacrificed, and spinal cord specimens were studied in light and EM. Basso, Beattie and Bresnahan (BBB) locomotor rating scales were significantly better in the early compression group after the 4th week of evaluation (P<0.05) and persisted throughout the remainder of the study. Histopathology demonstrated decreased normal tissue, more severe gliosis and cystic formation in the late group compared to the early group (P<0.05). In EM study, injuries in the late group including injury to the myelin and axon were more severe than the early compression group, and there was more cytoplasmic edema in the late compression group. Spinal cord injury secondary to 3-second compression improves functional motor recovery, spares more functional tissue, and is associated with less intracellular edema, less myelin and axon damage and more myelin regeneration in rats compared to those with 10 minutes of compression. Inclined plane test and tail-flick reflex had no significant difference. PMID- 23945879 TI - A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk. AB - The main genetic determinant of soluble interleukin 6 receptor (sIL-6R) levels is the missense variant rs2228145 that maps to the cleavage site of IL-6R. For each Ala allele, sIL-6R serum levels increase by ~ 20 ng ml(-1) and asthma risk by 1.09-fold. However, this variant does not explain the total heritability for sIL 6R levels. Additional independent variants in IL6R may therefore contribute to variation in sIL-6R levels and influence asthma risk. We imputed 471 variants in IL6R and tested these for association with sIL-6R serum levels in 360 individuals. An intronic variant (rs12083537) was associated with sIL-6R levels independently of rs4129267 (P=0.0005), a proxy single-nucleotide polymorphism for rs2228145. A significant and consistent association for rs12083537 was observed in a replication panel of 354 individuals (P=0.033). Each rs12083537:A allele increased sIL-6R serum levels by 2.4 ng ml(-1). Analysis of mRNA levels in two cohorts did not identify significant associations between rs12083537 and IL6R transcription levels. On the other hand, results from 16,705 asthmatics and 30,809 controls showed that the rs12083537:A allele increased asthma risk by 1.04 fold (P=0.0419). Genetic risk scores based on IL6R regulatory variants may prove useful in explaining variation in clinical response to tocilizumab, an anti-IL-6R monoclonal antibody. PMID- 23945886 TI - The hemodynamic effects of spinal block with low dose of bupivacaine and sufentanil in patients with low myocardial ejection fraction. AB - The aim of this study was to assess the effect of spinal block with low dose of bupivacaine and sufentanil on patients with low cardiac output who underwent lower limb surgery. Fifteen patients who had ejection fraction less than 40% (group 1) were compared with 65 cases with ejection fraction more than 40% (group 2) in our study. Our subjects underwent spinal block with 7.5 mg hyperbaric bupivacaine 0.5% and 5 ug sufentanil. We recorded early events such as hypotension, bradycardia, vasopressor need and ST segment change in our cases. The average mean arterial pressure decreased 13% (110 mmHg to 95.7 mmHg) in group 1 and 20% (160 mmHg to 128 mmHg) in group 2 (P<0.001). Hypotension due to spinal anesthesia was observed in none of our subjects in both groups and none of our cases need to vasopressor support. All patients remained alert, and no ST segment changes were observed in two groups. In our study none of subjects complained of pain intraoperatively. The subjects were without complaints during the spinal anesthetic in both groups. Spinal block with low dose local anesthetic and sufentanil was a safe and effective method for lower limb surgery in patients with low ejection fraction. PMID- 23945887 TI - Comparison of different methods of femoral fixation anterior cruciate ligament reconstruction. AB - The aim of this study is to compare three modes of femoral fixation, namely Aperfix, Rigidfix and Endobutton, in anterior cruciate ligament (ACL) reconstruction. 120 patients were randomly assigned to three groups, each consisting of 40 patients, and each group was treated by one of the above mentioned methods of femoral fixation. All patients were examined prior to and 24 months after surgery, and they were compared for anterior tibial displacement using the Lysholm score and KT-1000. The three modes of femoral fixation were not significantly different in terms of time of surgery. In the Endobutton group, the Lysholm score rose from 63.21+/-18.59 prior to ACL reconstruction to 90.64+/-9.47 after the surgery, while it rose from 65.72+/-18.74 to 96.22+/-5.35 in the Aperfix group and from 69.21+/-17.45 to 90.64+/-9.47 in the Rigidfix group. Anterior tibial displacement was 3.96+/-1.58 mm for Endobutton, 4.28+/-1.48 mm for Rigidfix and 4.03+/-1.79 mm for Aperfix. Aperfix was indicated to yield a better outcome in terms of instant stability and general results. PMID- 23945888 TI - Diagnostic value of interferon-gamma assay in tuberculosis pericardial effusions: study on a cohort of Iranian patients. AB - Tuberculosis pericarditis as a potentially fatal complication of tuberculosis requires effective diagnosis and treatment. We evaluated the efficacy of interferon-gamma (IFN-gamma) and adenosine deaminase (ADA) for diagnosing tuberculosis pericarditis in a cohort of Iranian patients presenting with pericarditis. We enrolled 38 patients with presentation of pericarditis. All patients underwent diagnostic and therapeutic pericardiostomy with drainage and biopsy. Adenosine deaminase and interferon-gamma levels were determined in pericardial fluid samples of all patients. Pericardial tissue samples were submitted for histopathologic and microbiologic studies. Polymerase chain reaction (PCR) was performed on all pericardial fluid samples to detect Mycobacterium tuberculosis. From 38 patients with pericarditis, 7 cases were diagnosed as having tuberculosis pericarditis (18.4%). Mean concentration of interferon-gamma in tuberculosis group was significantly higher compared to non tuberculosis group (69257 pg/l [range: 26600-148000] vs. 329 pg/l [range: 0 2200], P<0.000). Receiver operating characteristic (ROC) curve showed a value of 14400 pg/l as the cutoff point with a sensitivity of 100% and specificity of 100% for diagnosing tuberculosis pericardial effusion. Adenosine deaminase was not found to be significantly higher in tuberculosis group in comparison with non tuberculosis causes of pericardial effusion (35.7 [range: 9-69] vs. 36.03 [range: 8-420], P=0.28). In this study interferon-gamma showed to be a valuable diagnostic test for detection of tuberculosis pericarditis among a cohort of Iranian patients. We suggest using interferon-gamma to diagnose tuberculosis pericarditis to make diagnose in case of suspicion. While in this study, adenosine deaminase measurement did not prove to have the characteristics of an accurate diagnostic test for tuberculosis pericarditis. PMID- 23945889 TI - Effect of door-to-antibiotic time on mortality of patients with sepsis in emergency department: a prospective cohort study. AB - Sepsis constitutes an important cause of hospital admission with a high mortality rate. Appropriate antibiotic therapy is the cornerstone of therapy in patients with sepsis. Although numerous studies have recommended early antibiotic initiation in severe sepsis or septic shock stages of sepsis syndrome, its role in treatment of patients with sepsis who have not entered these stages remains to be investigated. The purpose of this study is to investigate the effect of door to-antibiotic time in sepsis patients with various degrees of severity. This is a longitudinal prospective cohort study on adult patients admitted with sepsis to the emergency department. Sepsis was defined as presence of at least two criteria of systemic inflammatory response syndrome and procalcitonin levels >= 2MUg/l. Severity of sepsis was determined using the APACHE II (Acute Physiology and Chronic Health Evaluation II) scoring system. Time to antibiotic administration was recorded and its relationship with mortality was assessed. A total of 145 patients were eligible for enrollment. The mean age was 60.4 years and the mean APACHE score was 13.7. The overall in-hospital mortality was 21.4%, and the mean length of stay in hospital was 211.9 hours. The mean door-to-antibiotic time for our patients was 104.4 minutes. Antibiotic administration time and mortality in patients with APACHE scores of 21 or higher (P=0.05) were significantly related; whereas such a relationship was not observed for patients with APACHE scores of 11- 20 (P=0.46). We observed early antibiotic initiation for patients in sepsis phase with higher severity scores was associated with significant improvement in survival rate. PMID- 23945890 TI - Comparison of prophylactic effects of polyurethane cylindrical or tapered cuff and polyvinyl chloride cuff endotracheal tubes on ventilator-associated pneumonia. AB - Because microaspiration of contaminated supraglottic secretions past the endotracheal tube cuff is considered to be central in the pathogenesis of pneumonia, improved design of tracheal tubes with new cuff material and shape have reduced the size and number of folds, which together with the addition of suction ports above the cuff to drain pooled subglottic secretions leads to reduced aspiration of oropharyngeal secretions. So we conducted a study to compare the prophylactic effects of polyurethane-cylindrical or tapered cuff and polyvinyl chloride cuff endotracheal tubes (ETT) on ventilator-associated pneumonia. This randomized clinical trial was carried out in a 12 bed surgical intensive care unit. 96 patients expected to require mechanical ventilation more than 96 hours were randomly allocated to one of three following groups: Polyvinyl chloride cuff (PCV) ETT, Polyurethane (PU) cylindrical Sealguard ETT and PU Taperguard ETT. Cuff pressure monitored every three hours 3 days in all patients. Mean cuff pressure didn't have significant difference between three groups during 72 hours. Pneumonia was seen in 11 patients (34%) in group PVC, 8 (25%) in Sealguard and 7 (21%) in Taperguard group. Changes in mean cuff pressure between Sealguard and PVC tubes and also between Taperguard and PVC tubes did not show any significant difference. There was no significant difference in overinflation between three groups. The use of ETT with PU material results in reducing ventilator-associated pneumonia compared to ETT with PVC cuff. In PU tubes Taperguard has less incidence of ventilator-associated pneumonia compared to Sealguard tubes. PMID- 23945891 TI - Analysing the effect of early acetazolamide administration on patients with a high risk of permanent cerebrospinal fluid leakage. AB - In this study, we examined the role of early acetazolamide administration in reducing the risk of cerebrospinal fluid (CSF) leakage in patients with a high risk of permanent CSF leakage. In a randomised clinical trial, 57 patients with a high risk of permanent CSF leakage (rhinorrhea, otorrhea, pneumatocele or imaging based evidence of severe skull-base fracture) were analysed. In the experimental group, acetazolamide, at 25 mg/kg/day, was started in the first 48 hours after admission. In the control group, acetazolamide was administered after the first 48 hours at the same dose administered to the patients in the experimental group. The following factors were compared between the two groups: duration of CSF leakage, duration of hospital stay, incidence of meningitis, need for surgical intervention and need for lumbar puncture (LP) and lumbar drainage (LD). All of the patients in the experimental group stopped having CSF leakage less than 14 days after the first day of admission, but 6 out of 21 patients (22%) in the control group continued having CSF leakage after 14 days of admission, which was a significant difference (P=0.01). This study showed that early acetazolamide administration can prevent CSF leakage in patients with a high risk of permanent CSF leak. PMID- 23945892 TI - Extrinsic and intrinsic coagulation pathway, fibrinogen serum level and platelet count in HIV positive patients. AB - Infection with human immunodeficiency virus (HIV) is a progressive condition which may cause endothelial dysfunction and liver damage leading to coagulopathy. With adventure of highly active antiretroviral therapy (HAART), life expectancy has prolonged in HIV positive patients but several acquired immunodeficiency syndrome (AIDS)-related conditions such as coagulopathies are responsible for associated morbidity and mortality. This study aimed to evaluate the extrinsic and intrinsic pathways of coagulation, serum level of fibrinogen and platelet count in HIV positive patients and compare it with negative healthy individuals. Through a case-control study, 114 HIV seropositive patients were compared with 114 seronegative samples in terms of hematological and other coagulation parameters. Mean age of study patients was 37.48 years. Intra venous drug abuse was the most common route of infection transmission with a prevalence of more than 50%. HIV route of transmission had a direct relationship with PTT abnormal levels (P<0.0001). However, this relationship was not significant for PT values. Stages of HIV disease and administration of HAART did not reveal any significant relationship with PT and PTT. There was also a statistically significant correlation between CD4+< 200 and PT in case group (P=0.008). On the other hands, in control group, CD4+ had a weak relationship with PTT (P=0.02) and an inverse correlation with serum fibrinogen (P=0.013). Hematological parameters and serum fibrinogen are decreased in HIV positive patients especially in direct relation with CD4+ cell count<200 cell/ul. PT and PTT abnormal values are also more prevalent in this population. PMID- 23945893 TI - Uremic pruritus and serum phosphorus level. AB - Pruritus is a common and bothersome problem among uremic patients which negatively affects life quality and prognosis of the patient. Various factors are known to be involved in the development of pruritus. The aim of this study was to assess the frequency and the factors which may have relationship with uremic pruritus, especially bone mineral metabolism indicators. Current cross-sectional study was done on 99 hemodialysis patients. Having pruritus, its duration, severity and correlation with patient's laboratory data was evaluated. For each patient a questionnaire was filled. The mean age of patients was 55.9+/-15.4 (23 87) years and 35.7% were female. They were on hemodialysis for 74.79+/-75.04 months. Frequency of pruritus was 58.6% (58 patients). Considering the severity, 16.2% suffered from severe pruritus, measured by visual analogue scale (VAS). Pruritus was more common in those on dialysis for more than 2 years (0.014). 82.8% of those with VAS of less than 3, in comparison with 37.5% of those with VAS of greater than 7, had no complaint of awakening due to pruritus. The frequency of pruritus and its severity was more in patients with higher serum phosphorus level (P=0.048). It seems that phosphate control which is not mainly attributed to dialysis adequacy and efficiency, needs more attention not only by medical team but also by patient. Decreasing the phosphate content of regimen may be cheap and helpful modality in pruritus management. PMID- 23945894 TI - Detection and management of medication errors in internal wards of a teaching hospital by clinical pharmacists. AB - Any suboptimum treatment in the management of patients can lead to medication errors (MEs) that may increase morbidity and mortality in hospitalized individuals. By establishing well-designed patient care activities within the managed care setting, clinical pharmacists can cooperate with other health care professionals to provide quality care and maximize safety. The aim of this study was to evaluate the frequency and prevention of MEs by clinical pharmacists. This was a cross-sectional interventional study conducted in internal wards of a teaching hospital during a two-month period. During this period, patient records, and physician orders were reviewed by clinical pharmacists. Any prescription error identified was documented. Incorrect drug selection, dose, dosage form, frequency, or route of administration all were considered as medication errors. Then, the clinical pharmacist discuss about findings with the clinical fellows to change faulty orders. The frequency and types of MEs in different wards that were detected and prevented by clinical pharmacists was documented. During the study period, in 132 patients, 262 errors were detected (1.98 per each). Wrong frequency 71 (27%), forget to order 37 (14.1%), wrong selection 33 (12.5%), drug interactions 26 (9.9%), forget to discontinue 25 (9.5%) and inappropriate dose adjustment in renal impairment 25 (9.5%) were the most types of errors. Cardiovascular medications were the class with the highest detected errors (31.6%) followed by gastrointestinal agents (15.6%). Medication errors are common problems in medical wards that their frequency can be restricted by the intervention of clinical pharmacists. PMID- 23945895 TI - Air pollution: the knowledge and ideas of students in Tehran-Iran, and a comparison with other countries. AB - Study of students' knowledge about air pollution can help authorities to have better imagination of this critical environmental problem. This research examines guidance school and high school students' ideas about air pollution and the results may be useful for the respective authorities to improve cultural and educational aspects of next generation. In this cross-sectional study, a closed questionnaire was used to examine knowledge and ideas of 2140 randomly selected school students of Tehran-Iran about composition of unpolluted air, air pollution and its causes and consequences. Cognitive scores were also calculated. Outcomes were compared with results of similar researches in Australia, Hong Kong and the United Kingdom. While a student's 'cognitive score' could range from -16 to +16, Iranian students' mean cognitive score was equal to +2.97. There was not significant statistical difference between girls and boys (P=0.32). In response to question "most common gas in unpolluted air" nitrogen was mentioned by only 23.7%, While 45.1% of students mentioned oxygen. In general, student's knowledge was not acceptable and there were some misconceptions such as "supposing oxygen as the most prevalent gas in unpolluted air". The findings of this survey indicate that, this important stratum of society of Iran have been received no sufficient and efficient education and sensitization on this matter. PMID- 23945896 TI - Prevalence of smoking in 15-64 years old population of north of Iran: meta analysis of the results of non-communicable diseases risk factors surveillance system. AB - Smoking is known as a major cause of chronic obstructive pulmonary disease (COPD) and hence immediate and effective interventions are required for its elimination. This study aimed to collect valid data with regard to cigarette smoking in adult population of north of Iran for policy making by a meta-analysis of the documents of national non-communicable disease risk factors surveillance system. We investigated relevant evidences by searching in published and non-electronic databases. Data were extracted based on variables such as year of the study, sex, age group and prevalence of smoking habit. Based on results of heterogeneity, we applied fixed or random effects model to estimate the overall prevalence of cigarette smoking. All analyses were performed using STATA 11 software. A total of 20747 subjects (10381 males and 10366 females) in five age groups 15-24, 25 34, 35-44, 45-54 and 55-64 years were interviewed. Meta-analysis in men and women showed prevalence of 19.2% (15.8-22.6%) and 0.3% (0.2-0.5%) respectively. Results of the present meta-analysis showed as much as one fifth of male population of north of Iran are smoker. Subgroup analysis also revealed that the rate of smoking was higher among the middle-aged men. PMID- 23945897 TI - Evaluation of emergency medical technicians intermediate prediction about their transported patients final disposition in emergency department of Imam Khomeini Hospital. AB - This was a prospective cross-sectional study of consecutive transported patients by emergency medical service (EMS) to a referral hospital. The goal of this study was the evaluation of emergency medical technician intermediate prediction about their transported patients disposition in Emergency Department of Imam Khomeini Hospital. 2950 patients were transported to this hospital, Questionnaires were submitted in 300 of consecutive patient transports and completed data were obtained and available upon arrival at hospital for 267 of these cases. Emergency medical technicians intermediate (EMT-I) were asked to predict whether the transported patient would require admission to the hospital, and if so, what will be their prediction of patient actual disposition. Their predictions were compared with emergency specialist physicians. EMT-I predicted that 208 (78%) transports would lead to admission to the hospital, after actual disposition, 232 (%87) patients became admitted. The sensitivity of predicting any admission was 65%, with positive predictive value (PPV) of 39% and specificity of 86% with negative predictive value (NPV) of 94%. The sensitivity of predicting trauma patients (56.2% of total patients) was 55% with PPV of 38%, specificity of 86% and for Non-trauma patients' sensitivity was 80% with PPV of 40% and specificity of 82%. EMT-I in our emergency medical system have very limited ability in prediction of admission and disposition in transported patients and their prediction were better in Non-trauma patients. So in our EMS, the pre-hospital diversion and necessity of transporting policies should not be based on EMS personnel disposition. PMID- 23945898 TI - Successful surgical intervention in an unusual case of Aspergillus endocarditis with acute myeloid leukemia. AB - Endocarditis due to Aspergillus infection is a rare complication in patients with hematological malignancies. Here, we present a case of aspergillus endocarditis in a patient with acute myeloid leukemia (AML) successfully treated with antifungal therapy and surgical treatment. The patient was a 51 years old male, a known case of AML who was admitted to our medical center for evacuating his valvular vegetations and repairing his atrial septal defect. He underwent an open heart surgery to relinquish his thromboses and also received an antifungal regimen. The patient tolerated the procedure well and eight months after his surgery, the patient remains asymptomatic. Successful treatment of this severe case of aspergillus endocarditis justifies a multidisciplinary method to be as a safe and effective approach to manage these patients. PMID- 23945899 TI - Granular cell tumor on perianal region: a case report. AB - Granular cell tumor (GCT) was first described by Abrikossoff in 1926. GCT is a rarely seen soft tissue tumor and is generally benign. While the tumor can be seen in all parts of the body it is generally located on the head and neck region, and especially on the tongue. GCT is rarely seen in the anal-perianal region. In accordance with literature this case was reported because it was thought to be the 27th anal-perianal located GCT case. In this case report, approximately 0,5-1 cm pedunculated polypoid lesion was determined in the perianal region during the physical examination of a 23 year old female patient who applied with palpable mass complaint in the perianal region. Lesion in the patient was totally excited with healthy skin-subcutaneous tissue under local anesthesia. A benign granular cell tumor was detected in the histopathological examination. Positive staining was monitored immunohistochemically with S-100 and neuron specific enolase (NSE). GCT is a rarely seen tumor in the anal-perianal region and its malign transformation rate is very low. Even lesions seen in the perianal region have clinically a benign appearance, a histopathological examination should be conducted and also GCT should be kept in mind during diagnosis. Malign-benign separation of these lesions is difficult so histopathological examination should be conducted with great care. Large local excision in the treatment provides curative treatment. But for those presenting malign transformation further examination must be performed for metastasis. After the treatment local recurrence and metastasis should be considered carefully. Prognosis of metastatic disease is very bad. PMID- 23945900 TI - Serum ox-LDL level and severity of stenosis in coronary arteries. PMID- 23945903 TI - What is the best predictor of mortality in a very low birth weight infant population with a high mortality rate in a medical setting with limited resources? AB - OBJECTIVE: To determine the best predictor of mortality risk in very low birth weight (VLBW) infants in resource limited settings. METHODS: The Clinical Risk Index for Babies (CRIB) II score and the simplified age-weight-sex (SAWS) score for all VLBW infants born during the period January 2005 to June 2006 at the University Hospital of the West Indies were retrospectively calculated. The respective ability of each score, birth weight, and calculated or assessed gestational age to predict mortality was quantified using the area under receiver operating curves. RESULTS: Fifty two (48%) males and 57 (52%) females were entered into the study, out of which 58 (53%) infants died. The CRIB II score was found to be a better predictor of mortality (p = 0.02) when compared with calculated gestational age but had similar predictive power when compared with assessed gestational age. The SAWS score was found to have equal predictive value of mortality (p = 0.1) as the CRIB II score, however it was a better predictor of mortality than calculated gestational age (p = 0.002) but had no predictive advantage over assessed gestational age. Birth weight however, proved to be the best predictor of mortality (p < 0.01) with an area under the curve of 0.91 (standard error 0.03; 95% confidence interval 0.85-0.96). CONCLUSION: In resource poor settings where mortality of VLBW infants is high there may be no benefit in the addition of other variables to birth weight in predicting outcome. PMID- 23945904 TI - Periodic alternating nystagmus of peripheral vestibular origin. AB - OBJECTIVES/HYPOTHESIS: Periodic alternating nystagmus (PAN) is most commonly found either in its congenital form or after cerebellar/pontomedullary lesions. However, we identified PAN in 10 patients with peripheral vestibular disorders and will try to describe their characteristics to aid in the differential diagnosis between peripheral and central etiologies. STUDY DESIGN: Observation of a case series. METHOD: Peripheral vestibular lesions were confirmed by neurological examinations, vestibular function tests, and brain magnetic resonance imaging (MRIs). Eye movements of the patients were recorded using electronystagmography or video nystagmography for a minimum of 10 minutes to confirm the nystagmus change in direction. RESULTS: The final diagnoses of the patients included Meniere's disease (n = 3), acute labyrinthitis (n = 4), sudden sensorineural hearing loss with vertigo (n = 2), and vestibular schwannoma (n = 1). Direction-changing spontaneous horizontal nystagmus with quiescent intervals was observed in all patients under dark conditions. The nystagmus was suppressed by visual fixation; and the results of oculomotor tests were normal for saccadic and smooth pursuit eye movements and optokinetic nystagmus. All patients showed mild to complete canal paresis on a bithermal caloric test. PAN progressed into unidirectional nystagmus of the contra-lesion side in all patients within 48 hours. CONCLUSION: PAN can be observed in patients with peripheral vestibular disorders, but detecting PAN in this subpopulation is difficult because of its transitory nature. The absence of central symptoms and signs, the visual suppression of PAN, normal oculomotor tests, and transient persistence are important diagnostic clues for differentiating peripheral from central PAN. LEVEL OF EVIDENCE: 4. PMID- 23945910 TI - The oxidation states and chemical environments of iron and zinc as potential indicators of brain tumour malignancy grade - preliminary results. AB - Despite the enormous advances in medicine, brain tumours are still among the lesser-known types of tumours and carry the worst prognoses. Transition metals are believed to play an essential role in carcinogenesis. The aim of this study was to determine differences in the average oxidation state and trends in the changes in the chemical environment of iron and zinc contained in healthy and neoplastic tissues of the human brain. For this purpose, X-ray Absorption Spectroscopy was used, which enables the study of disordered matter. The samples were taken intraoperatively and then immediately frozen to slow down chemical processes. Sixteen tumour samples with various malignancy grades were studied as well as one control sample. For each sample four to eight spectra were recorded, with a shift between them not greater than 0.2 eV. In all of the samples, iron occurred in compounds with both Fe(2+) and Fe(3+). However, the ratio of Fe(ii) to Fe(iii) content in the tissue visibly increased with the tumour malignancy grade. The change in the oxidation state of iron did not correlate with the hypoxia level of the tissues. Analysis of EXAFS spectra of zinc atoms showed that the chemical environment of zinc atoms differed with the tumour malignancy grade. Additionally, cryogenic conditions were found to produce positive results in studies of biological samples, whose form under such conditions is close to their native state, without preparation-caused artefacts. PMID- 23945906 TI - Management of hypertension with fixed-dose triple-combination treatments. AB - The objective of this review is to evaluate the role of fixed-dose triple combination therapy for the management of hypertension. An assessment of clinical trials showed that half the patients with hypertension have uncontrolled blood pressure (BP), with underlying factors including therapeutic inertia and poor patient adherence. Many patients will require three antihypertensive agents to achieve BP goals, and current guidelines recommend combining drugs with complementary mechanisms of action. Three single-pill triple-combination treatments are available and each includes an agent affecting the renin angiotensin-aldosterone pathway (either a direct renin inhibitor or an angiotensin II receptor blocker) in combination with a calcium channel blocker and diuretic. These triple-combination therapies consistently demonstrated significantly greater BP reduction relative to the component dual combinations, with BP reductions documented across a range of patient populations. Triple combination treatments were well tolerated in all clinical trials reviewed. The use of single-pill, triple-combination antihypertensive therapy has been shown to be an effective, well-tolerated, and convenient treatment strategy that can help patients achieve BP control. PMID- 23945905 TI - Association of depression with accelerated cognitive decline among patients with type 2 diabetes in the ACCORD-MIND trial. AB - IMPORTANCE: Depression has been identified as a risk factor for dementia among patients with type 2 diabetes mellitus but the cognitive domains and patient groups most affected have not been identified. OBJECTIVE: To determine whether comorbid depression in patients with type 2 diabetes accelerates cognitive decline. DESIGN: A 40-month cohort study of participants in the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial. SETTING: Fifty-two clinics organized into 6 clinical networks across the United States and Canada. PARTICIPANTS: Two thousand nine hundred seventy-seven participants with type 2 diabetes at high risk for cardiovascular events. INTERVENTION: The Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and the modified Stroop test were used to assess cognition. The 9-item Patient Health Questionnaire was used to assess depression. MAIN OUTCOMES AND MEASURES: Mixed effects statistical models were used to analyze cognitive test outcomes incorporating depression as a time-dependent covariate. RESULTS: Participants with scores indicative of depression (9-item Patient Health Questionnaire, >=10) showed greater cognitive decline during 40-month follow-up on all tests, with the following differences in estimated least squares means: Digit Symbol Substitution Test, 0.72 (95% CI, 0.25 to 1.19; P = .003), Rey Auditory Verbal Learning Test, 0.18 (95% CI, 0.07 to 0.29; P = .001), and Stroop interference, -1.06 (95% CI, 1.93 to -0.18; P = .02). This effect of depression on risk of cognitive decline did not differ according to previous cardiovascular disease; baseline cognition or age; or intensive vs standard glucose-lowering treatment, blood pressure treatment, lipid treatment, or insulin treatment. Addition of demographic and clinical covariates to models did not significantly change the cognitive decline associated with depression. CONCLUSIONS AND RELEVANCE: Depression in patients with type 2 diabetes was associated with greater cognitive decline in all domains, across all treatment arms, and in all participant subgroups assessed. Future randomized trials will be necessary to determine if depression treatment can lower the risk of cognitive decline in patients with diabetes. PMID- 23945913 TI - Stepped care: an alternative to routine extended treatment for patients with borderline personality disorder. AB - This review examined evidence supporting stepped care for borderline personality disorder as an alternative to routine extended treatment. Empirical studies have shown that patients with borderline personality disorder have a heterogeneous course, but symptomatic improvement can sometimes be relatively rapid. Currently, there is no evidence that any long-term treatment is superior to briefer interventions for borderline personality disorder. Long-term therapy may not be necessary for all patients, and its routine use leads to access problems. A stepped-care model, similar to models applied to other severe mental disorders, might provide a better use of resources. Stepped care can be used to limit the use of expensive programs and reduce waiting lists. Not all patients with borderline personality disorder can be treated briefly, but a stepped-care model allows those with less severe symptoms to be managed with fewer resources, freeing up more time and personnel for the treatment of those who need treatment the most. PMID- 23945917 TI - Magnesium complexes supported by salan-like ligands: synthesis, characterization and their application in the ring-opening polymerization of rac-lactide. AB - A series of magnesium silylamido complexes bearing salan-like multidentate aminophenolate ligands, [(L(1-4))MgN(SiMe3)2] (1-4) and [(L1)MgN(SiHMe2)2] (1') (L(1-4) = -OAr1N(Me)(CH2)nN(Me)Ar2, n = 2 or 3), have been synthesized via the reaction of Mg[N(SiMe3)2]2 or Mg[N(SiHMe2)2] with 1 equiv. of the corresponding aminophenol. The monomeric nature of the magnesium complexes 1, 2, 3 and the main stoichiometric structure of 1' in the solid state were further confirmed by X-ray diffraction studies, where the four donors of the ligand and the silylamido group coordinated with the magnesium center constructing a distorted trigonal bipyramidal coordination geometry at the metal center. The existence of isomers in complexes 1' and 4 was verified by the variable temperature 1H NMR spectroscopy, and the non-coordination of OMe group with the central magnesium in complex 4 was deduced from the comparison of the proton chemical shifts in complex 4 and its proligand. All these complexes efficiently initiated the ring opening polymerization of rac-lactide with the presence/absence of isopropanol, affording isotactic bias polylactides with relatively broad molecular weight distributions (P(m) = 0.59-0.70, M(w)/M(n) = 1.28-2.21) in toluene at r.t. Declining the steric hindrance of the initiating group from N(SiMe3)2 to N(SiHMe2)2 increased the catalytic activity considerably. The steric and electronic characteristics of the ancillary ligands showed some influence on the polymerization performance of the corresponding magnesium complexes. The introduction of bulky ortho-substituents on the phenoxy moiety resulted in some changes both in activity and stereoselectivity, and either the elongation of the amine bridge from NCH2CH2N to NCH2CH2CH2N or the introduction of chloro substituent on the phenoxy moiety led to a significant decline of the catalytic activity. PMID- 23945918 TI - Cu(I)-catalyzed intramolecular oxidative C-H amination of 2-aminoacetophenones: a convenient route toward isatins. AB - 2-Aminoaryl methyl ketones undergo intramolecular oxidative C-H amination to give the corresponding substituted isatins under an oxygen atmosphere in the presence of [CuI(bpy)]2. PMID- 23945919 TI - Azygoesophageal fistula: a rare cause of upper gastrointestinal tract bleeding. PMID- 23945920 TI - Splenic laceration following ERCP. PMID- 23945921 TI - Endoscopic ultrasound-assisted endoscopic submucosal dissection of a gastric subepithelial tumor. PMID- 23945922 TI - Argon plasma coagulation before mechanical fragmentation of a large gastric persimmon bezoar: the woodworm technique. PMID- 23945923 TI - Extrahepatic cholangiocarcinoma in a patient with situs inversus totalis diagnosed by endoscopic ultrasound. PMID- 23945924 TI - Proximal duodenal obstruction--Bouveret's syndrome revisited. PMID- 23945925 TI - Feasibility of endoscopic ultrasound-guided hepaticogastrostomy in a patient with previous gastric banding. PMID- 23945926 TI - Large serrated polyp with KRAS mutation in inflammatory bowel disease: a "nondysplastic dysplasia-associated lesion or mass (DALM)"? PMID- 23945927 TI - Pharmacological treatment for Kleine-Levin syndrome. AB - BACKGROUND: This is an updated version of the original Cochrane review, published in Issue 2, 2009.Kleine-Levin syndrome (KLS) is a rare disorder that mainly affects adolescent men. It is characterised by recurrent episodes of hypersomnia, usually accompanied by hyperphagia, cognitive and mood disturbances, abnormal behavior such as hypersexuality and signs of dysautonomia.In 1990 the diagnostic criteria for Kleine-Levin syndrome were modified in the International Classification of Sleep Disorders, where KLS was defined as a syndrome composed of recurring episodes of undue sleepiness lasting some days, which may or may not be associated with hyperphagia and abnormal behavior.The cause of Kleine-Levin syndrome remains unknown, and several treatment strategies have been used. Some medications have been reported to provide benefit in the treatment of patients with KLS, but because of the rarity of the condition, no long-term follow-up therapies have yet been described. OBJECTIVES: This review aimed to evaluate:1. whether pharmacological treatment for Kleine Levin syndrome is effective and safe.2. which drug or category of drugs is effective and safe. SEARCH METHODS: We obtained relevant trials from the following sources: the Cochrane Epilepsy Group Specialized Register (2 May 2013); the Cochrane Central Register of Controlled Trials (CENTRAL Issue 4, The Cochrane Library, April 2013); MEDLINE (1946 to 2 May 2013); SCOPUS (2 May 2013); LILACS (2 May 2013); ClinicalTrials.gov (2 May 2013); WHO International Clinical Trials Registry Platform ICTRP (2 May 2013); reference lists of sleep medicine textbooks; review articles and reference lists of articles identified by the search strategies. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-randomised controlled trials looking at pharmacological interventions for Kleine-Levin syndrome were selected. We included both parallel-group and cross-over studies. DATA COLLECTION AND ANALYSIS: Two review authors (MMO and CC) extracted the data reported in the original articles. MAIN RESULTS: No studies met the inclusion criteria for this systematic review. AUTHORS' CONCLUSIONS: Therapeutic trials of pharmacological treatment for Kleine-Levin syndrome with a double-blind, placebo-controlled design are needed. PMID- 23945928 TI - Correspondence on "Clinical characterization of gastroenteritis-related seizures in children: impact of fever and serum sodium levels". PMID- 23945929 TI - A quick assessment tool for human-directed aggression in pet dogs. AB - Many test series have been developed to assess dog temperament and aggressive behavior, but most of them have been criticized for their relatively low predictive validity or being too long, stressful, and/or problematic to carry out. We aimed to develop a short and effective series of tests that corresponds with (a) the dog's bite history, and (b) owner evaluation of the dog's aggressive tendencies. Seventy-three pet dogs were divided into three groups by their biting history; non-biter, bit once, and multiple biter. All dogs were exposed to a short test series modeling five real-life situations: friendly greeting, take away bone, threatening approach, tug-of-war, and roll over. We found strong correlations between the in-test behavior and owner reports of dogs' aggressive tendencies towards strangers; however, the test results did not mirror the reported owner-directed aggressive tendencies. Three test situations (friendly greeting, take-away bone, threatening approach) proved to be effective in evoking specific behavioral differences according to dog biting history. Non-biters differed from biters, and there were also specific differences related to aggression and fear between the two biter groups. When a subsample of dogs was retested, the test revealed consistent results over time. We suggest that our test is adequate for a quick, general assessment of human-directed aggression in dogs, particularly to evaluate their tendency for aggressive behaviors towards strangers. Identifying important behavioral indicators of aggressive tendencies, this test can serve as a useful tool to study the genetic or neural correlates of human-directed aggression in dogs. PMID- 23945930 TI - Rotating-frame relaxation as a noise spectrum analyser of a superconducting qubit undergoing driven evolution. AB - Gate operations in a quantum information processor are generally realized by tailoring specific periods of free and driven evolution of a quantum system. Unwanted environmental noise, which may in principle be distinct during these two periods, acts to decohere the system and increase the gate error rate. Although there has been significant progress characterizing noise processes during free evolution, the corresponding driven-evolution case is more challenging as the noise being probed is also extant during the characterization protocol. Here we demonstrate the noise spectroscopy (0.1-200 MHz) of a superconducting flux qubit during driven evolution by using a robust spin-locking pulse sequence to measure relaxation (T(1rho)) in the rotating frame. In the case of flux noise, we resolve spectral features due to coherent fluctuators, and further identify a signature of the 1 MHz defect in a time-domain spin-echo experiment. The driven-evolution noise spectroscopy complements free-evolution methods, enabling the means to characterize and distinguish various noise processes relevant for universal quantum control. PMID- 23945931 TI - Discovery of cell-type specific regulatory elements in the human genome using differential chromatin modification analysis. AB - Chromatin modifications have been comprehensively illustrated to play important roles in gene regulation and cell diversity in recent years. Given the rapid accumulation of genome-wide chromatin modification maps across multiple cell types, there is an urgent need for computational methods to analyze multiple maps to reveal combinatorial modification patterns and define functional DNA elements, especially those are specific to cell types or tissues. In this current study, we developed a computational method using differential chromatin modification analysis (dCMA) to identify cell-type-specific genomic regions with distinctive chromatin modifications. We then apply this method to a public data set with modification profiles of nine marks for nine cell types to evaluate its effectiveness. We found cell-type-specific elements unique to each cell type investigated. These unique features show significant cell-type-specific biological relevance and tend to be located within functional regulatory elements. These results demonstrate the power of a differential comparative epigenomic strategy in deciphering the human genome and characterizing cell specificity. PMID- 23945932 TI - In silico abstraction of zinc finger nuclease cleavage profiles reveals an expanded landscape of off-target sites. AB - Gene-editing nucleases enable targeted modification of DNA sequences in living cells, thereby facilitating efficient knockout and precise editing of endogenous loci. Engineered nucleases also have the potential to introduce mutations at off target sites of action. Such unintended alterations can confound interpretation of experiments and can have implications for development of therapeutic applications. Recently, two improved methods for identifying the off-target effects of zinc finger nucleases (ZFNs) were described-one using an in vitro cleavage site selection method and the other exploiting the insertion of integration-defective lentiviruses into nuclease-induced double-stranded DNA breaks. However, application of these two methods to a ZFN pair targeted to the human CCR5 gene led to identification of largely non-overlapping off-target sites, raising the possibility that additional off-target sites might exist. Here, we show that in silico abstraction of ZFN cleavage profiles obtained from in vitro cleavage site selections can greatly enhance the ability to identify potential off-target sites in human cells. Our improved method should enable more comprehensive profiling of ZFN specificities. PMID- 23945934 TI - Functional assignment of KEOPS/EKC complex subunits in the biosynthesis of the universal t6A tRNA modification. AB - N(6)-threonylcarbamoyladenosine (t(6)A) is a universal tRNA modification essential for normal cell growth and accurate translation. In Archaea and Eukarya, the universal protein Sua5 and the conserved KEOPS/EKC complex together catalyze t(6)A biosynthesis. The KEOPS/EKC complex is composed of Kae1, a universal metalloprotein belonging to the ASHKA superfamily of ATPases; Bud32, an atypical protein kinase and two small proteins, Cgi121 and Pcc1. In this study, we investigated the requirement and functional role of KEOPS/EKC subunits for biosynthesis of t(6)A. We demonstrated that Pcc1, Kae1 and Bud32 form a minimal functional unit, whereas Cgi121 acts as an allosteric regulator. We confirmed that Pcc1 promotes dimerization of the KEOPS/EKC complex and uncovered that together with Kae1, it forms the tRNA binding core of the complex. Kae1 binds l threonyl-carbamoyl-AMP intermediate in a metal-dependent fashion and transfers the l-threonyl-carbamoyl moiety to substrate tRNA. Surprisingly, we found that Bud32 is regulated by Kae1 and does not function as a protein kinase but as a P loop ATPase possibly involved in tRNA dissociation. Overall, our data support a mechanistic model in which the final step in the biosynthesis of t(6)A relies on a strictly catalytic component, Kae1, and three partner proteins necessary for dimerization, tRNA binding and regulation. PMID- 23945933 TI - H1 histones: current perspectives and challenges. AB - H1 and related linker histones are important both for maintenance of higher-order chromatin structure and for the regulation of gene expression. The biology of the linker histones is complex, as they are evolutionarily variable, exist in multiple isoforms and undergo a large variety of posttranslational modifications in their long, unstructured, NH2- and COOH-terminal tails. We review recent progress in understanding the structure, genetics and posttranslational modifications of linker histones, with an emphasis on the dynamic interactions of these proteins with DNA and transcriptional regulators. We also discuss various experimental challenges to the study of H1 and related proteins, including limitations of immunological reagents and practical difficulties in the analysis of posttranslational modifications by mass spectrometry. PMID- 23945935 TI - Extracellular microRNAs are dynamic non-vesicular biomarkers of muscle turnover. AB - Extracellular microRNAs (miRNAs) are promising biomarkers of the inherited muscle wasting condition Duchenne muscular dystrophy, as they allow non-invasive monitoring of either disease progression or response to therapy. In this study, serum miRNA profiling reveals a distinct extracellular miRNA signature in dystrophin-deficient mdx mice, which shows profound dose-responsive restoration following dystrophin rescue. Extracellular dystrophy-associated miRNAs (dystromiRs) show dynamic patterns of expression that mirror the progression of muscle pathology in mdx mice. Expression of the myogenic miRNA, miR-206 and the myogenic transcription factor myogenin in the tibialis anterior muscle were found to positively correlate with serum dystromiR levels, suggesting that extracellular miRNAs are indicators of the regenerative status of the musculature. Similarly, extracellular dystromiRs were elevated following experimentally-induced skeletal muscle injury and regeneration in non-dystrophic mice. Only a minority of serum dystromiRs were found in extracellular vesicles, whereas the majority were protected from serum nucleases by association with protein/lipoprotein complexes. In conclusion, extracellular miRNAs are dynamic indices of pathophysiological processes in skeletal muscle. PMID- 23945936 TI - YoeB-ribosome structure: a canonical RNase that requires the ribosome for its specific activity. AB - As a typical endoribonuclease, YoeB mediates cellular adaptation in diverse bacteria by degrading mRNAs on its activation. Although the catalytic core of YoeB is thought to be identical to well-studied nucleases, this enzyme specifically targets mRNA substrates that are associated with ribosomes in vivo. However, the molecular mechanism of mRNA recognition and cleavage by YoeB, and the requirement of ribosome for its optimal activity, largely remain elusive. Here, we report the structure of YoeB bound to 70S ribosome in pre-cleavage state, revealing that both the 30S and 50S subunits participate in YoeB binding. The mRNA is recognized by the catalytic core of YoeB, of which the general base/acid (Glu46/His83) are within hydrogen-bonding distance to their reaction atoms, demonstrating an active conformation of YoeB on ribosome. Also, the mRNA orientation involves the universally conserved A1493 and G530 of 16S rRNA. In addition, mass spectrometry data indicated that YoeB cleaves mRNA following the second position at the A-site codon, resulting in a final product with a 3' phosphate at the newly formed 3' end. Our results demonstrate a classical acid base catalysis for YoeB-mediated RNA hydrolysis and provide insight into how the ribosome is essential for its specific activity. PMID- 23945937 TI - Structural and functional insights into the molecular mechanism of rRNA m6A methyltransferase RlmJ. AB - RlmJ catalyzes the m(6)A2030 methylation of 23S rRNA during ribosome biogenesis in Escherichia coli. Here, we present crystal structures of RlmJ in apo form, in complex with the cofactor S-adenosyl-methionine and in complex with S-adenosyl homocysteine plus the substrate analogue adenosine monophosphate (AMP). RlmJ displays a variant of the Rossmann-like methyltransferase (MTase) fold with an inserted helical subdomain. Binding of cofactor and substrate induces a large shift of the N-terminal motif X tail to make it cover the cofactor binding site and trigger active-site changes in motifs IV and VIII. Adenosine monophosphate binds in a partly accommodated state with the target N6 atom 7 A away from the sulphur of AdoHcy. The active site of RlmJ with motif IV sequence 164DPPY167 is more similar to DNA m(6)A MTases than to RNA m(6)2A MTases, and structural comparison suggests that RlmJ binds its substrate base similarly to DNA MTases T4Dam and M.TaqI. RlmJ methylates in vitro transcribed 23S rRNA, as well as a minimal substrate corresponding to helix 72, demonstrating independence of previous modifications and tertiary interactions in the RNA substrate. RlmJ displays specificity for adenosine, and mutagenesis experiments demonstrate the critical roles of residues Y4, H6, K18 and D164 in methyl transfer. PMID- 23945939 TI - Distinct isoforms of the Drosophila Brd4 homologue are present at enhancers, promoters and insulator sites. AB - Brd4 is a double bromodomain protein that has been shown to interact with acetylated histones to regulate transcription by recruiting Positive Transcription Elongation Factor b to the promoter region. Brd4 is also involved in gene bookmarking during mitosis and is a therapeutic target for the treatment of acute myeloid leukemia. The Drosophila melanogaster Brd4 homologue is called Fs(1)h and, like its vertebrate counterpart, encodes different isoforms. We have used ChIP-seq to examine the genome-wide distribution of Fs(1)h isoforms. We are able to distinguish the Fs(1)h-L and Fs(1)h-S binding profiles and discriminate between the genomic locations of the two isoforms. Fs(1)h-S is present at enhancers and promoters and its amount parallels transcription levels. Correlations between the distribution of Fs(1)h-S and various forms of acetylated histones H3 and H4 suggest a preference for binding to H3K9acS10ph. Surprisingly, Fs(1)h-L is located at sites in the genome where multiple insulator proteins are also present. The results suggest that Fs(1)h-S may be responsible for the classical role assigned to this protein, whereas Fs(1)h-L may have a new and unexpected role in chromatin architecture by working in conjunction with insulator proteins to mediate intra- or inter-chromosome interactions. PMID- 23945940 TI - Searching algorithm for type IV secretion system effectors 1.0: a tool for predicting type IV effectors and exploring their genomic context. AB - Type IV effectors (T4Es) are proteins produced by pathogenic bacteria to manipulate host cell gene expression and processes, divert the cell machinery for their own profit and circumvent the immune responses. T4Es have been characterized for some bacteria but many remain to be discovered. To help biologists identify putative T4Es from the complete genome of alpha- and gamma proteobacteria, we developed a Perl-based command line bioinformatics tool called S4TE (searching algorithm for type-IV secretion system effectors). The tool predicts and ranks T4E candidates by using a combination of 13 sequence characteristics, including homology to known effectors, homology to eukaryotic domains, presence of subcellular localization signals or secretion signals, etc. S4TE software is modular, and specific motif searches are run independently before ultimate combination of the outputs to generate a score and sort the strongest T4Es candidates. The user keeps the possibility to adjust various searching parameters such as the weight of each module, the selection threshold or the input databases. The algorithm also provides a GC% and local gene density analysis, which strengthen the selection of T4E candidates. S4TE is a unique predicting tool for T4Es, finding its utility upstream from experimental biology. PMID- 23945938 TI - To be or not to be: regulation of restriction-modification systems and other toxin-antitoxin systems. AB - One of the simplest classes of genes involved in programmed death is that containing the toxin-antitoxin (TA) systems of prokaryotes. These systems are composed of an intracellular toxin and an antitoxin that neutralizes its effect. These systems, now classified into five types, were initially discovered because some of them allow the stable maintenance of mobile genetic elements in a microbial population through postsegregational killing or the death of cells that have lost these systems. Here, we demonstrate parallels between some TA systems and restriction-modification systems (RM systems). RM systems are composed of a restriction enzyme (toxin) and a modification enzyme (antitoxin) and limit the genetic flux between lineages with different epigenetic identities, as defined by sequence-specific DNA methylation. The similarities between these systems include their postsegregational killing and their effects on global gene expression. Both require the finely regulated expression of a toxin and antitoxin. The antitoxin (modification enzyme) or linked protein may act as a transcriptional regulator. A regulatory antisense RNA recently identified in an RM system can be compared with those RNAs in TA systems. This review is intended to generalize the concept of TA systems in studies of stress responses, programmed death, genetic conflict and epigenetics. PMID- 23945941 TI - Replication fork collapse is a major cause of the high mutation frequency at three-base lesion clusters. AB - Unresolved repair of clustered DNA lesions can lead to the formation of deleterious double strand breaks (DSB) or to mutation induction. Here, we investigated the outcome of clusters composed of base lesions for which base excision repair enzymes have different kinetics of excision/incision. We designed multiply damaged sites (MDS) composed of a rapidly excised uracil (U) and two oxidized bases, 5-hydroxyuracil (hU) and 8-oxoguanine (oG), excised more slowly. Plasmids harboring these U-oG/hU MDS-carrying duplexes were introduced into Escherichia coli cells either wild type or deficient for DNA n-glycosylases. Induction of DSB was estimated from plasmid survival and mutagenesis determined by sequencing of surviving clones. We show that a large majority of MDS is converted to DSB, whereas almost all surviving clones are mutated at hU. We demonstrate that mutagenesis at hU is correlated with excision of the U placed on the opposite strand. We propose that excision of U by Ung initiates the loss of U oG-carrying strand, resulting in enhanced mutagenesis at the lesion present on the opposite strand. Our results highlight the importance of the kinetics of excision by base excision repair DNA n-glycosylases in the processing and fate of MDS and provide evidence for the role of strand loss/replication fork collapse during the processing of MDS on their mutational consequences. PMID- 23945943 TI - Selection on codon bias in yeast: a transcriptional hypothesis. AB - Codons that code for the same amino acid are often used with unequal frequencies. This phenomenon is termed codon bias. Here, we report a computational analysis of codon bias in yeast using experimental and theoretical genome-wide data. We show that the most used codons in highly expressed genes can be predicted by mRNA structural data and that the codon choice at each synonymous site within an mRNA is not random with respect to the local secondary structure. Because we also found that the folding stability of intron sequences is strongly correlated with codon bias and mRNA level, our results suggest that codon bias is linked to mRNA folding structure through a mechanism that, at least partially, operates before pre-mRNA splicing. Consistent with this, we report evidence supporting the adaptation of the tRNA pool to the codon profile of the most expressed genes rather than vice versa. We show that the correlation of codon usage with the gene expression level also includes the stop codons that are normally not decoded by aminoacyl-tRNAs. The results reported here are consistent with a role for transcriptional forces in driving codon usage bias via a mechanism that improves gene expression by optimizing mRNA folding structures. PMID- 23945942 TI - Genome-wide analysis of Staufen-associated mRNAs identifies secondary structures that confer target specificity. AB - Despite studies that have investigated the interactions of double-stranded RNA binding proteins like Staufen with RNA in vitro, how they achieve target specificity in vivo remains uncertain. We performed RNA co-immunoprecipitations followed by microarray analysis to identify Staufen-associated mRNAs in early Drosophila embryos. Analysis of the localization and functions of these transcripts revealed a number of potentially novel roles for Staufen. Using computational methods, we identified two sequence features that distinguish Staufen's target transcripts from non-targets. First, these Drosophila transcripts, as well as those human transcripts bound by human Staufen1 and 2, have 3' untranslated regions (UTRs) that are 3-4-fold longer than unbound transcripts. Second, the 3'UTRs of Staufen-bound transcripts are highly enriched for three types of secondary structures. These structures map with high precision to previously identified Staufen-binding regions in Drosophila bicoid and human ARF1 3'UTRs. Our results provide the first systematic genome-wide analysis showing how a double-stranded RNA-binding protein achieves target specificity. PMID- 23945944 TI - Baculoviral transduction facilitates TALEN-mediated targeted transgene integration and Cre/LoxP cassette exchange in human-induced pluripotent stem cells. AB - Safety and reliability of transgene integration in human genome continue to pose challenges for stem cell-based gene therapy. Here, we report a baculovirus transcription activator-like effector nuclease system for AAVS1 locus-directed homologous recombination in human induced pluripotent stem cells (iPSCs). This viral system, when optimized in human U87 cells, provided a targeted integration efficiency of 95.21% in incorporating a Neo-eGFP cassette and was able to mediate integration of DNA insert up to 13.5 kb. In iPSCs, targeted integration with persistent transgene expression was achieved without compromising genomic stability. The modified iPSCs continued to express stem cell pluripotency markers and maintained the ability to differentiate into three germ lineages in derived embryoid bodies. Using a baculovirus-Cre/LoxP system in the iPSCs, the Neo-eGFP cassette at the AAVS1 locus could be replaced by a Hygro-mCherry cassette, demonstrating the feasibility of cassette exchange. Moreover, as assessed by measuring gamma-H2AX expression levels, genome toxicity associated with chromosomal double-strand breaks was not detectable after transduction with moderate doses of baculoviral vectors expressing transcription activator-like effector nucleases. Given high targeted integration efficiency, flexibility in transgene exchange and low genome toxicity, our baculoviral transduction-based approach offers great potential and attractive option for precise genetic manipulation in human pluripotent stem cells. PMID- 23945945 TI - Characterization of novel inhibitors of HIV-1 replication that function via alteration of viral RNA processing and rev function. AB - Expression of the complete HIV-1 genome depends on the appropriate processing of viral RNA. Altering the balance of viral RNA processing impairs replication of the virus. In this report, we characterize two small molecule modulators of HIV-1 RNA processing, 8-azaguanine and 2-(2-(5-nitro-2-thienyl)vinyl)quinoline (5350150), which function by distinct mechanisms to suppress viral gene expression. Although only 8-Azaguanine dramatically decreased accumulation of HIV 1 unspliced and singly spliced RNAs and altered splice site usage, both compounds blocked Gag and Env expression without affecting production of Tat (p16) and Rev regulatory proteins. Subsequent analyses suggest that these compounds affect Rev mediated RNA transport by different mechanisms. Both compounds induced cytoplasmic accumulation of Rev, suggesting that they function, in part, by impairing Rev function. This conclusion is supported by the determination that both drugs block the nuclear export of genomic HIV-1 RNA to the cytoplasm. Testing confirmed that these compounds suppress HIV-1 expression in T cells at doses below those previously used in humans for tumour chemotherapy. Together, our observations demonstrate that small molecules can be used to inhibit HIV-1 replication by altering another avenue of viral RNA processing, offering the potential for the development of novel therapeutics for controlling this disease. PMID- 23945947 TI - Revision septoplasty: a prospective disease-specific outcome study. AB - OBJECTIVES/HYPOTHESIS: 1) Study outcomes of revision septoplasty using a validated disease-specific questionnaire and a patient satisfaction survey; 2) assess the effect of surgery on the use of medication to treat nasal congestion; and 3) report on sites of persistent septal deviation identified at revision septoplasty. STUDY DESIGN: Prospective, single-center outcome study of patients with symptomatic nasal obstruction and persisting septal deviation despite prior septal surgery. METHODS: The Nasal Obstruction Symptom Evaluation (NOSE) scale was administered preoperatively and at 3 and 6 months following revision surgery. Patients were also questioned regarding ease of breathing and medication use preoperatively and postoperatively, as well as satisfaction with the surgical outcome. Anatomic site(s) of residual septal deviation were recorded intraoperatively. RESULTS: Thirty-nine patients completed the study. Mean NOSE scores decreased significantly from 75.9 preoperatively to 14.9 3 months after revision surgery. Mean Ease-of-Breathing scores over this interval improved from 3/10 preoperatively to 8.5/10. Both results were sustained at 6 months (P <0.0001). Patient satisfaction was very high, and many patients required less medication to treat symptoms of nasal congestion postoperatively. Deviations persisting from prior surgery most commonly involved the dorsal or caudal septum. CONCLUSION: In patients who experience ongoing nasal obstruction with a persistent septal deviation despite prior septoplasty, revision surgery significantly improves disease-specific quality of life, results in high patient satisfaction, and may diminish the need for nasal medications postoperatively. Caudal or dorsal deflections may be more difficult to correct, leading to the need for revision surgery. LEVEL OF EVIDENCE: 2C. PMID- 23945948 TI - Allylic C-H alkylation with a CF3-containing nucleophile. AB - Allylic C-H alkylation of allylarenes with dimethyl 2-trifluoromethylmalonate was successfully developed. The reactions were carried out at room temperature in the presence of a catalytic amount of Pd(OAc)2/Ph3P and a stoichiometric amount of 2,6-dimethylbenzoquinone. The reactions avoided defluorination successfully, providing a new method to construct a CF3-containing all-carbon quaternary center. PMID- 23945946 TI - Yeast ribosomal protein L7 and its homologue Rlp7 are simultaneously present at distinct sites on pre-60S ribosomal particles. AB - Ribosome biogenesis requires >300 assembly factors in Saccharomyces cerevisiae. Ribosome assembly factors Imp3, Mrt4, Rlp7 and Rlp24 have sequence similarity to ribosomal proteins S9, P0, L7 and L24, suggesting that these pre-ribosomal factors could be placeholders that prevent premature assembly of the corresponding ribosomal proteins to nascent ribosomes. However, we found L7 to be a highly specific component of Rlp7-associated complexes, revealing that the two proteins can bind simultaneously to pre-ribosomal particles. Cross-linking and cDNA analysis experiments showed that Rlp7 binds to the ITS2 region of 27S pre rRNAs, at two sites, in helix III and in a region adjacent to the pre-rRNA processing sites C1 and E. However, L7 binds to mature 25S and 5S rRNAs and cross linked predominantly to helix ES7(L)b within 25S rRNA. Thus, despite their predicted structural similarity, our data show that Rlp7 and L7 clearly bind at different positions on the same pre-60S particles. Our results also suggest that Rlp7 facilitates the formation of the hairpin structure of ITS2 during 60S ribosomal subunit maturation. PMID- 23945954 TI - Cortical folding defects as markers of poor treatment response in first-episode psychosis. AB - IMPORTANCE: At present, no reliable predictors exist to distinguish future responders from nonresponders to treatment during the first episode of psychosis. Among potential neuroimaging predictors of treatment response, gyrification represents an important marker of the integrity of normal cortical development that may characterize, already at illness onset, a subgroup of patients with particularly poor outcome. OBJECTIVE: To determine whether patients with first episode psychosis who do not respond to 12 weeks of antipsychotic treatment already have significant gyrification defects at illness onset. DESIGN: Case control study with 12 weeks' longitudinal follow-up to determine treatment response. SETTING: Secondary psychiatric services in an inner-city area (South London, England). PARTICIPANTS: A total of 126 subjects, including 80 patients presenting with first-episode psychosis and 46 healthy controls. Patients were scanned at the outset and received various antipsychotic medications in a naturalistic clinical setting. They were followed up for 12 weeks and classified as responders or nonresponders if they reached criteria for symptom remission, evaluated with the Psychiatric and Personal History Schedule. OBSERVATION: Patients were exposed to naturalistic antipsychotic treatment for 12 weeks following a magnetic resonance imaging scan. MAIN OUTCOMES AND MEASURES: Cortical gyrification was assessed using local gyrification index in a vertexwise fashion across the entire cortical surface with correction for multiple testing using permutation analysis. Differences in local gyrification index were assessed between responders, nonresponders, and healthy controls. The effect of diagnosis (affective vs nonaffective psychosis) on the local gyrification index was also investigated in responders and nonresponders. RESULTS: Patients with first episode psychosis showed a significant reduction in gyrification (hypogyria) across multiple brain regions compared with healthy controls. Interestingly, nonresponders showed prominent hypogyria at bilateral insular, left frontal, and right temporal regions when compared with responders (all clusters significant at P < .05). These effects were present for both affective and nonaffective psychoses. CONCLUSIONS AND RELEVANCE: Gyrification appears to be a useful predictor of antipsychotic treatment response. Early neurodevelopmental aberrations may predict unfavorable prognosis in psychosis, irrespective of the existing diagnostic boundaries. PMID- 23945956 TI - Use of treatment services in a comparative effectiveness study of bipolar disorder. AB - OBJECTIVE Bipolar disorder is a severe, chronic mental illness with a high incidence of medical and psychological comorbidities that make treatment and prevention of future episodes challenging. This study investigated the use of services among outpatients with bipolar disorder to further understanding of how to maximize and optimize personalization and accessibility of services for this difficult-to-treat population. METHODS The Lithium Treatment-Moderate Dose Use Study (LiTMUS) was a six-month multisite, comparative effectiveness trial that randomly assigned 283 individuals to receive lithium plus optimized care-defined as personalized, guideline-informed care-or optimized care without lithium. Relationships between treatment service utilization, captured by the Cornell Service Index, and demographic and illness characteristics were examined with generalized linear marginal models. RESULTS Analyses with complete data (week 12, N=246; week 24, N=236) showed that increased service utilization was related to more severe bipolar disorder symptoms, physical side effects, and psychiatric and general medical comorbidities. Middle-aged individuals and those living in the United States longer tended to use more services than younger individuals or recent immigrants, respectively. CONCLUSIONS These data suggest that not all individuals with bipolar disorder seek treatment services at the same rate. Instead, specific clinical or demographic features may affect the degree to which one seeks treatment, conveying clinical and public health implications and highlighting the need for specific approaches to correct such discrepancies. Future research is needed to elucidate potential moderators of service utilization in bipolar disorder to ensure that those most in need of additional services utilize them. PMID- 23945955 TI - How linguistic closure and verbal working memory relate to speech recognition in noise--a review. AB - The ability to recognize masked speech, commonly measured with a speech reception threshold (SRT) test, is associated with cognitive processing abilities. Two cognitive factors frequently assessed in speech recognition research are the capacity of working memory (WM), measured by means of a reading span (Rspan) or listening span (Lspan) test, and the ability to read masked text (linguistic closure), measured by the text reception threshold (TRT). The current article provides a review of recent hearing research that examined the relationship of TRT and WM span to SRTs in various maskers. Furthermore, modality differences in WM capacity assessed with the Rspan compared to the Lspan test were examined and related to speech recognition abilities in an experimental study with young adults with normal hearing (NH). Span scores were strongly associated with each other, but were higher in the auditory modality. The results of the reviewed studies suggest that TRT and WM span are related to each other, but differ in their relationships with SRT performance. In NH adults of middle age or older, both TRT and Rspan were associated with SRTs in speech maskers, whereas TRT better predicted speech recognition in fluctuating nonspeech maskers. The associations with SRTs in steady-state noise were inconclusive for both measures. WM span was positively related to benefit from contextual information in speech recognition, but better TRTs related to less interference from unrelated cues. Data for individuals with impaired hearing are limited, but larger WM span seems to give a general advantage in various listening situations. PMID- 23945960 TI - Candidate genes revisited in the genetics of hypertension and blood pressure. PMID- 23945957 TI - Efficient preparation and metal specificity of the regulatory protein TroR from the human pathogen Treponema pallidum. AB - TroR is a putative metal-dependent regulatory protein that has been linked to the virulence of the human pathogen Treponema pallidum. It shares high homology with the well-known iron-dependent regulatory protein DtxR from Corynebacterium diphtheriae, as well as the manganese-dependent MntR from Bacillus subtilis. However, it has been uncertain whether manganese or zinc is the natural cofactor of TroR to date. Herein, we established an efficient method named "double-fusion tagging" to obtain soluble TroR for the first time. A series of studies, including ICP, CD, fluorescence, ITC, and electrophoresis mobility shift assay (EMSA), were performed to resolve the discrepancies in its metal-binding specificity. In addition, bioinformatic analysis as well as mutation studies were carried out to find the genetic relationships of TroR with its homology proteins. In conclusion, our findings indicate that TroR is a manganese-dependent rather than a zinc-dependent regulatory protein. PMID- 23945961 TI - Additive effects of mean blood pressure and bilateral notching in the second trimester on subsequent angiogenesis-related factors. AB - It has not been clarified whether high mean blood pressure (HBP) of >=90 mm Hg and bilateral notching (BN) on uterine artery Doppler additively affect the subsequent circulating levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng). Serum levels of PlGF, sFlt-1 and sEng at 17-25 weeks and 26-32 weeks were measured in all women with HBP+BN- (n=272), HBP-BN+ (n=130) and HBP+BN+ (n=60) in 1239 eligible women, and 338 consecutive women with HBP-BN- were selected from the remaining 777 women. Only data before the onset of preeclampsia were evaluated. The cutoff value of an abnormal decrease of PlGF was set at the 5th percentile, and those of an abnormal increase of sFlt-1, sFlt-1/PlGF and sEng were set at the 95th percentile. The frequency of HBP in those with BN- was almost the same as that in those with BN+ (25.9% vs. 26.7%). In women with HBP-BN-, HBP-BN+, HBP+BN- and HBP+BN+, the frequency of abnormal sFlt-1/PlGF ratio at 26-32 weeks was 6.6%, 9.2%, 14.4% and 22.8%, respectively; and the frequency of abnormal sFlt-1/PlGF ratio at 26-32 weeks in those with HBP+BN+ was significantly increased than in HBP-BN-. Similarly, in the four groups, the frequency of abnormal sEng at 26-32 weeks was 5.4%, 2.5%, 12.2% and 19.0%, respectively; and the frequency in those with HBP+BN+ was significantly increased than in HBP-BN-. In conclusion, high BP levels and abnormal uterine artery Doppler may be additively implicated in circulating abnormalities of angiogenesis-related factors. PMID- 23945962 TI - A meta-analysis of randomized trials of telmisartan versus losartan for reduction of ambulatory blood pressure. AB - A previous meta-analysis of a few randomized controlled trials (RCTs) suggests a significant reduction in ambulatory blood pressure (BP) with telmisartan as compared with losartan monotherapy. We performed an updated meta-analysis of RCTs of telmisartan versus losartan therapy for reduction of ambulatory BP in patients with hypertension. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched through July 2012 using PubMed and OVID. Eligible studies were RCTs of telmisartan versus valsartan therapy enrolling individuals with hypertension and reporting ambulatory BP as an outcome. For each study, data regarding changes from baseline in ambulatory (24 h, last 6 h, morning, daytime and nighttime) BP in both the telmisartan and losartan groups were used to generate mean differences (MDs) and 95% confidence intervals (CIs). Of 34 potentially relevant articles screened initially, 9 reports of RCTs enrolling a total of 2409 patients with hypertension were identified and included. Pooled analysis suggested significant reductions in all of 24-h (MD of systolic/diastolic BP, -2.09/-1.57 mm Hg; 95% CI, -3.39/-2.32 to -0.79/-0.82 mm Hg), last 6-h (-2.96/-2.15 mm Hg; -3.80/-2.72 to -2.13/-1.59 mm Hg), morning ( 2.71/-2.37 mm Hg; -3.73/-3.33 to -1.69/-1.41 mm Hg), daytime (-1.74/-1.73 mm Hg; 3.27/-2.84 to -0.20/-0.62 mm Hg) and nighttime BP (-2.70/-2.08 mm Hg; -4.07/-3.24 to -1.33/-0.92 mm Hg) among patients randomized to telmisartan versus losartan therapy. In conclusion, telmisartan therapy appears to reduce ambulatory BP more than losartan therapy in patients with hypertension. PMID- 23945963 TI - Microalbuminuria, macroalbuminuria and uncontrolled blood pressure among diagnosed hypertensive patients: the aspect of racial disparity in the NHANES study. AB - Accumulating evidence reveals that albuminuria may exacerbate uncontrolled blood pressure (BP) in hypertensive patients. However, racial differences in the associations of albuminuria with uncontrolled BP among diagnosed hypertensives have not been evaluated. A total of 6147 diagnosed hypertensive subjects aged >= 18 years were collected from the National Health and Nutrition Examination Survey 1999-2008 with stratified multistage sampling designs. Odds ratios (ORs), relative ORs and 95% confidence intervals (CIs) in uncontrolled BP, and the different effects of microalbuminuria and macroalbuminuria on continuous BP were estimated using weighted logistic models and linear regression models. Hypertensive subjects with microalbuminuria and macroalbuminuria were more likely to have uncontrolled BP and higher average systolic BP (SBP) in all individual racial groups. Microalbuminuria was associated with isolated uncontrolled SBP in non-Hispanic blacks and whites, and macroalbuminuria was associated with isolated uncontrolled SBP and diastolic BP (DBP) and high average DBP only in non-Hispanic blacks. Compared with non-Hispanic whites, non-Hispanic blacks and Mexicans had lower associations of microalbuminuria with uncontrolled BP (relative OR = 0.68, 95% CI = 0.48-0.97 for blacks vs whites; relative OR = 0.62, 95% CI = 0.42-0.93 for Mexicans vs. whites) and isolated uncontrolled SBP (relative OR = 0.62, 95% CI = 0.43-0.90 for blacks vs. whites; relative OR = 0.45, 95% CI = 0.29-0.71 for Mexicans vs. whites). The association of microalbuminuria with uncontrolled BP was lower in non-Hispanic blacks and Mexicans than in non-Hispanic whites. Health providers need to improve care for mildly elevated albumin excretion rates in non Hispanic white hypertensive patients while maintaining the quality of care in non Hispanic blacks and Mexicans. PMID- 23945964 TI - Normalized endothelial function but sustained cardiovascular risk profile 11 years following a pregnancy complicated by preeclampsia. AB - Women with a history of preeclampsia are at increased risk of future cardiovascular disease. Preeclampsia is associated with elevated blood pressure, inflammation and endothelial dysfunction, and these findings remain 1 year after delivery. Whether these abnormalities persist long after delivery, and whether they may contribute to future cardiovascular disease, is not well studied. We studied 15 women with a history of preeclampsia and 16 matched controls with an uncomplicated pregnancy 11 years following the index pregnancy; all had also been previously examined at 1 year. We assessed arterial stiffness (pulse wave analysis), 24 h ambulatory blood pressure and endothelial function (forearm flow mediated dilatation and pulse wave analysis following beta receptor agonist provocation), and determined markers of glucose and lipid metabolism, inflammation and vascular function. The preeclampsia group had higher blood pressures and reduced night/day blood pressure ratios, increased body mass index and reduced glucose tolerance, and increased levels of tissue necrosis factor receptor 1 and intracellular adhesion molecule-1, suggesting inflammatory and vascular activation. However, the endothelial impairment observed in the preeclampsia group at 1 year was normalized at 11 years, whereas the control group remained unchanged during follow-up. Our findings of higher blood pressures, impaired glucose tolerance and normalization of endothelial function 11 years after preeclampsia suggest cardiovascular risk factors present already before pregnancy to be more important than permanent endothelial damage for the increased risk of future cardiovascular complications in women with a history of preeclampsia. PMID- 23945965 TI - Nifedipine controlled-release 40 mg b.i.d. in Japanese patients with essential hypertension who responded insufficiently to nifedipine controlled-release 40 mg q.d.: a phase III, randomized, double-blind and parallel-group study. AB - This phase III, multicenter, randomized, double-blind, parallel-group study compared the efficacy and safety of nifedipine controlled-release (CR) 40 mg twice daily (b.i.d.) and once daily (q.d.) in 325 Japanese patients with essential hypertension uncontrolled with nifedipine CR 40 mg q.d. (ClinicalTrials.gov record: NCT01287260). The primary endpoint was the change from baseline in trough seated diastolic blood pressure (DBP) after 8 weeks. Nifedipine CR 40 mg b.i.d. showed significantly greater reductions in trough seated DBP (-7.7+/-0.6 mm Hg vs. -3.6+/-0.6 mm Hg) and trough seated systolic blood pressure (BP) (-11.1+/-0.9 mm Hg vs. -3.7+/-0.9 mm Hg) after 8 weeks of treatment compared with nifedipine CR 40 mg q.d. (both P<0.0001). At week 8, BP target achievement and responder rates were higher with nifedipine CR 40 mg b.i.d. (21.5% and 42.4% vs. 10.3% and 19.5%, respectively). Adverse events considered related to the study drug were reported in 9.0 and 9.7% of patients receiving nifedipine CR 40 mg b.i.d. and q.d., respectively. The frequency of drug-related adverse events commonly reported with nifedipine CR (headache, hot flush, palpitations, peripheral edema, hypotension, dizziness, tachycardia) was low and the results were similar between the treatment groups. In conclusion, a higher dose of nifedipine CR was associated with greater efficacy and a safety profile similar to that of the currently approved dose (40 mg q.d.) in Japanese patients with essential hypertension, and it may offer a valuable treatment choice for patients who do not achieve target BP levels with standard treatment. PMID- 23945966 TI - Control of salt and volume retention cannot be ruled out as a mechanism underlying the blood pressure-lowering effect of renal denervation. PMID- 23945971 TI - Hand-rim forces and gross mechanical efficiency in asynchronous and synchronous wheelchair propulsion: a comparison. AB - To compare the force application characteristics at various push frequencies of asynchronous (ASY) and synchronous (SYN) hand-rim propulsion, 8 able-bodied participants performed a separate sub-maximal exercise test on a wheelchair roller ergometer for each propulsion mode. Each test consisted of a series of 5, 4-min exercise blocks at 1.8 m . s-1 - initially at their freely chosen frequency (FCF), followed by four counter-balanced trials at 60, 80, 120 and 140% FCF. Kinetic data was obtained using a SMARTWheel, measuring forces and moments. The gross efficiency (GE) was determined as the ratio of external work done and the total energy expended. The ASY propulsion produced higher force measures for FRES, FTAN, rate of force development & FEF (P<0.05), while there was no difference in GE values (P=0.518). In pair-matched push frequencies (ASY80:SYN60, ASY100:SYN80, ASY120:SYN100 and ASY140:SYN120), ASY propulsion forces remained significantly higher (FRES, FTAN, rate of force development & FEF P<0.05), and there was no significant effect on GE (P=0.456). Both ASY and SYN propulsion demonstrate similar trends: changes in push frequency are accompanied by changes in absolute force even without changes in the gross pattern/trend of force application, FEF or GE. Matched push frequencies continue to produce significant differences in force measures but not GE. This suggests ASY propulsion is the predominant factor in force application differences. The ASY would appear to offer a kinetic disadvantage to SYN propulsion and no physiological advantage under current testing conditions. PMID- 23945967 TI - Heteroscorpionate aluminium complexes as chiral building blocks to engineer helical architectures. AB - Treatment of heteroscorpionate ligand precursors pbptamH, pbpamH, sbpamH and (S) mbpamH with 2 equivalents of AlR3 (R = Et, Me) yielded the corresponding binuclear organoaluminium complexes [Al2R4(MU-pbptam)] (R = Me 1, Et 2), [Al2R4(MU-pbpam)] (R = Me 3, Et 4), [Al2R4(MU-sbpam)] (R = Me 5, Et 6) and [Al2R4{MU-(S)-mbpam}] (R = Me 7, Et 8). These complexes have helical chirality due to the demands of the fixed pyrazole rings. The stereoisomerism and the self assembly processes of these helicates have been studied in some detail in solution by NMR and in the solid state by X-ray diffraction. Mixtures of M- and P handed enantiomers and mixtures of M- and P-handed diastereoisomers were obtained when achiral (1-4) and chiral (5-8) heteroscorpionate ligands were used as scaffolds, respectively. Re-crystallization from hexane allowed us to obtain M homochiral architectures in the solid state for the helical complexes [Al2Et4(MU sbpam)] (6) and [Al2Et4{MU-(S)-mbpam}] (8). The reaction of heteroscorpionate ligands with 3 equivalents of AlR3 (R = Me, Et) led to the corresponding trinuclear organoaluminium complexes [Al3R7(MU3-pbptam)] (R = Me 9, Et 10), [Al3R7(MU3-pbpam)] (R = Me 11, Et 12), [Al3R7(MU3-sbpam)] (R = Me 13, Et 14) and [Al3R7{MU3-(S)-mbpam}] (R = Me 15, Et 16). The extra AlR3 molecule contributes to the formation of a diastereomeric excess of the PS helicate for complexes 15 and 16. X-ray determination of some of the helical complexes allowed us to witness a versatile and efficient self-assembly process of the building blocks (heteroscorpionate aluminium complexes) directed by noncovalent intermolecular CH pi interactions. The structures of these complexes have been determined by spectroscopic methods and the X-ray crystal structures of 2, 6, 8, and 16 have also been established. Concentration-dependent 1H pulsed field-gradient spin echo (PFGSE) NMR experiments provided evidence for the self-assembly of the single molecular species of complex 2 in solution. The degree of aggregation was calculated for complex 2, with the average number of units constituting the aggregate (N) estimated to be a maximum of 4 molecules in solution before reaching the solid state. PMID- 23945972 TI - Early ventilation-heart rate breakpoint during incremental cycling exercise. AB - Previous observations having reported a transient hypoxia at the onset of incremental exercise, we investigated the existence of concomitant ventilatory and heart rate (HR) breakpoints.33 subjects executed a maximal cycling exercise with averaging for successive 5-s periods of HR, ventilation, tidal volume (VT), mean inspiratory flow rate (VT/Ti), and end-tidal partial pressures of O2 (PETO2) and CO2. In 10 subjects, the transcutaneous partial pressure of O2 (PtcO2) was recorded and the venous blood lactic acid (LA) concentration measured.At the beginning of exercise, PETO2 decreased, reaching a nadir, then progressively increased until the exercise ended. PtcO2 varied in parallel. Whether or not a 0 W cycling period preceded the incremental exercise, the rate of changes in VE, VT, VT/Ti and HR significantly increased when the nadir PO2 was reached. The ventilatory/ HR breakpoint was measured at 33+/-4% of VO2max, whereas the ventilatory threshold (VTh) was detected at 67+/-4% of VO2max and LA began to increase at 45 to 50% of VO2max.During incremental cycling exercise, we identified the existence of HR and ventilatory breakpoints in advance of both lactate and ventilatory thresholds which coincided with modest hypoxia and hypercapnia. PMID- 23945973 TI - The incidence of VO2 plateau at VO2max in a cardiac-diseased population. AB - We sought to determine the incidence of VO(2) plateau at VO(2)max in a cardiovascular-diseased (CVD) population using 4 different sampling intervals (15 breath moving average, 15 s, 30 s, and 60 s) and 3 different VO(2) plateau criteria (<=50 mL . min(-1), <=80 mL . min(-1), and <=150 mL . min(-1)). A total of 69 people (62 +/- 10 yrs.) with recently diagnosed CVD performed a maximal exercise test (10:07 +/- 2:24 min) on a treadmill. The test was classified as maximal (n = 57, 2 430 +/- 605 mL . min(-1)) if self-terminated due to fatigue or classified as symptom-limited (n = 12, 1 683 +/- 438 mL . min(-1)) if symptoms presented. Chi-square analysis revealed a significant (p < 0.05) effect of sampling interval on incidence of VO(2) plateau at VO(2)max across all 3 VO(2) plateau criteria. The sampling interval had an increasingly stronger influence on the incidence of VO(2) plateau at VO(2)max with smaller criterion thresholds as evidenced by the Cramer's V statistics: [<=50 mL . min(-1) (Cramer's V = 0.548, p < 0.05], <=80 mL . min(-1) [Cramer's V = 0.489, p < 0.05], <=150 mL . min(-1) [Cramer's V = 0.214, p < 0.05]. Incidence of VO(2) plateau at VO(2)max in CVD individuals is significantly influenced by the sampling interval applied. Based on our findings we recommend a15 breath moving average and VO(2) plateau criterion of <=50 mL . min(-1). PMID- 23945974 TI - Ventilatory thresholds determined from HRV: comparison of 2 methods in obese adolescents. AB - The development of personalised training programmes is crucial in the management of obesity. We evaluated the ability of 2 heart rate variability analyses to determine ventilatory thresholds (VT) in obese adolescents. 20 adolescents (mean age 14.3+/-1.6 years and body mass index z-score 4.2+/-0.1) performed an incremental test to exhaustion before and after a 9-month multidisciplinary management programme. The first (VT1) and second (VT2) ventilatory thresholds were identified by the reference method (gas exchanges). We recorded RR intervals to estimate VT1 and VT2 from heart rate variability using time-domain analysis and time-varying spectral-domain analysis. The coefficient correlations between thresholds were higher with spectral-domain analysis compared to time-domain analysis: Heart rate at VT1: r=0.91 vs. =0.66 and VT2: r=0.91 vs. =0.66; power at VT1: r=0.91 vs. =0.74 and VT2: r=0.93 vs. =0.78; spectral-domain vs. time-domain analysis respectively). No systematic bias in heart rate at VT1 and VT2 with standard deviations <6 bpm were found, confirming that spectral-domain analysis could replace the reference method for the detection of ventilatory thresholds. Furthermore, this technique is sensitive to rehabilitation and re-training, which underlines its utility in clinical practice. This inexpensive and non-invasive tool is promising for prescribing physical activity programs in obese adolescents. PMID- 23945975 TI - Cost-effectiveness of one- and two-step incomplete and complete excavations. AB - The treatment of deep caries lesions carries significant risks for the integrity of the pulp and often initiates a cascade of re-interventions. Incomplete caries removal may reduce these risks and avoid or delay re-treatment. The present study analyzed the cost-effectiveness of one- and two-step incomplete as well as complete excavations. We used Markov models to simulate treatment of a molar tooth with a deep caries lesion in a 15-year-old patient. Retention of the tooth and its vitality as effectiveness measures as well as accruing costs were analyzed over the patient's lifetime. The model adopted a public-private-payer perspective within German health care. Transition probabilities were calculated based on literature reviews. Monte-Carlo microsimulations were performed with 6 month cycles. One-step incomplete excavation resulted in lower long-term costs and in longer-retained teeth and their vitality (means: 53.5 and 41.0 yrs) compared with two-step incomplete (52.5 and 37.5 yrs) and complete excavations (49.5 and 31.0 yrs), and dominated the other strategies in 70% to 100% of simulations. Regardless of the assumed willingness-to-pay ceiling value, one-step incomplete excavation had the highest probability of being cost-effective. Despite limited evidence levels of input data, we expect one-step incomplete excavation to reduce costs while retaining deeply carious teeth and their vitality for longer. PMID- 23945976 TI - Grade as a prognostic factor in oral squamous cell carcinoma: a population-based analysis of the data. AB - OBJECTIVES/HYPOTHESIS: Historically, histologic grade has not been considered a useful prognostic factor in head and neck squamous cell carcinoma (SCC). However, in other solid tumors, grade is known to affect prognosis. We test the hypothesis that histologic grade is an independent predictor of prognosis in oral cavity SCC. STUDY DESIGN: Population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. METHODS: Fifteen year cause-specific survival. Multivariate analysis was performed on a subset of patients diagnosed between 2004 and 2008. RESULTS: Among patients 20 to 65 years of age with American Joint Committee on Cancer (AJCC) stage I or II cancer, the adjusted risk of death is 2.7 times greater (95% CI 1.72-4.11) if the tumor is poorly differentiated or undifferentiated than it is if the tumor is well differentiated. Among patients 66 to 94 years of age, the risk of death is 3.0 (95% CI 2.02-4.54) times greater. For those over age 65, moderately differentiated tumors also confer an estimated 42% increased risk of death, but this estimate is only borderline significant (P = 0.05). CONCLUSIONS: There is a strong association between histologic grade and survival in patients with AJCC stage I or II oral cavity SCC. High histologic grade in early stage oral cavity cancer is associated with poorer survival and carries independent prognostic value in addition to tumor size, node status, and presence of distant metastasis (TNM) stage. Thus, histologic grade should be considered clinically when making treatment decisions, and multivariable models of survival should include grade as a covariate to improve prognostic accuracy. PMID- 23945977 TI - Atomic-scale dynamic process of deformation-induced stacking fault tetrahedra in gold nanocrystals. AB - Stacking fault tetrahedra, the three-dimensional crystalline defects bounded by stacking faults and stair-rod dislocations, are often observed in quenched or irradiated face-centred cubic metals and alloys. All of the stacking fault tetrahedra experimentally observed to date are believed to originate from vacancies. Here we report, in contrast to the classical vacancy-originated ones, a new kind of stacking fault tetrahedra formed via the interaction and cross-slip of partial dislocations in gold nanocrystals. The complete atomic-scale processes of nucleation, migration and annihilation of the dislocation-originated stacking fault tetrahedra are revealed by in situ high-resolution observations and molecular dynamics simulations. The dislocation-originated stacking fault tetrahedra can undergo migration and annihilation due to mechanical loading in a manner that is not expected in bulk samples. These results uncover a unique deformation mechanism via dislocation interaction inside the confined volume of nanocrystals and have important implications regarding the size effect on the mechanical behaviour of small-volume materials. PMID- 23945980 TI - Acupuncture for induction of labour. AB - BACKGROUND: This is one of a series of reviews of methods of cervical ripening and labour induction using standardised methodology. The use of complementary therapies is increasing and some women look to complementary therapies during pregnancy and childbirth to be used alongside conventional medical practice. Acupuncture involves the insertion of very fine needles into specific points of the body. The limited observational studies to date suggest acupuncture for induction of labour appears safe, has no known adverse effects to the fetus, and may be effective. However, the evidence regarding the clinical effectiveness of this technique is limited. OBJECTIVES: To determine the effectiveness and safety of acupuncture for third trimester cervical ripening or induction of labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (23 November 2012), PubMed (1966 to 23 November 2012), Embase (1980 to 23 November 2012), Dissertation Abstracts (1861 to 23 November 2012), CINAHL (1982 to 23 November 2012), the WHO International Clinical Trials Registry Portal (ICTRP) (23 November 2012) and bibliographies of relevant papers. SELECTION CRITERIA: Clinical trials comparing acupuncture used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, evaluated methodological quality and extracted data. MAIN RESULTS: The original review included three trials and seven trials were excluded. This updated review includes 14 trials, and excludes eight trials. Three trials previously excluded due to no clinically relevant outcomes are now included. Eight new trials were included, and four new trials were excluded. We included 14 trials with data reporting on 2220 women.Trials reported on three primary outcomes only caesarean section, serious neonatal morbidity and maternal mortality. No trial reported on vaginal delivery not achieved within 24 hours; and uterine hyperstimulation with fetal heart rate (FHR) changes. There was no difference in caesarean deliveries between acupuncture and the sham control (average risk ratio (RR) 0.95, 95% confidence interval (CI) 0.69 to 1.30, six trials, 654 women), and acupuncture versus usual care (average RR 0.69, 95% CI 0.40, 1.20, six trials, 361 women). There was no difference in neonatal seizures between acupuncture and the sham group (RR 1.01, 95% CI 0.06 to 16.04, one trial, 364 women).There was some evidence of a change in cervical maturation for women receiving acupuncture compared with the sham control, (mean difference (MD) 0.40. 95%CI 0.11 to 0.69, one trial, 125 women), and when compared with usual care (MD 1.30, 95% CI 0.11 to 2.49, one trial, 67 women). The length of labour was shorter in the usual care group compared with acupuncture (average standardised mean difference (SMD) 0.67, 95% CI 0.18 to 1.17, one trial 68 women). There were no other statistically significant differences between groups. Few studies reported on many clinically relevant outcomes. One trial was at a low risk of bias on all domains. AUTHORS' CONCLUSIONS: Overall, there have been few studies assessing the role of acupuncture for induction of labour. Before implications for clinical practice can be made there is a need for well-designed randomised controlled trials to evaluate the role of acupuncture to induce labour and for trials to assess clinically meaningful outcomes. PMID- 23945982 TI - Pairomics, the omics way to mate choice. AB - The core aspects of the biology and evolution of sexual reproduction are reviewed with a focus on the diploid, sexually reproducing, outbreeding, polymorphic, unspecialized, altricial and cultural human species. Human mate choice and pair bonding are viewed as central to individuals' lives and to the evolution of the species, and genetic assistance in reproduction is viewed as a universal human right. Pairomics is defined as an emerging branch of the omics science devoted to the study of mate choice at the genomic level and its consequences for present and future generations. In pairomics, comprehensive genetic information of individual genomes is stored in a database. Computational tools are employed to analyze the mating schemes and rules that govern mating among the members of the database. Mating models and algorithms simulate the outcomes of mating any given genome with each of a number of genomes represented in the database. The analyses and simulations may help to understand mating schemes and their outcomes, and also contribute a new cue to the multicued schemes of mate choice. The scientific, medical, evolutionary, ethical, legal and social implications of pairomics are far reaching. The use of genetic information as a search tool in mate choice may influence our health, lifestyle, behavior and culture. As knowledge on genomics, population genetics and gene-environment interactions, as well as the size of genomic databases expand, so does the ability of pairomics to investigate and predict the consequences of mate choice for the present and future generations. PMID- 23945981 TI - Impact of cognitive behavioral therapy for social anxiety disorder on the neural dynamics of cognitive reappraisal of negative self-beliefs: randomized clinical trial. AB - IMPORTANCE: Cognitive behavioral therapy (CBT) for social anxiety disorder (SAD) is thought to enhance cognitive reappraisal in patients with SAD. Such improvements should be evident in cognitive reappraisal-related prefrontal cortex responses. OBJECTIVE: To determine whether CBT for SAD modifies cognitive reappraisal-related prefrontal cortex neural signal magnitude and timing when implementing cognitive reappraisal with negative self-beliefs. DESIGN Randomized clinical trial of CBT for SAD vs wait-list control group during a study that enrolled patients from 2007 to 2010. SETTING: University psychology department. PARTICIPANTS: Seventy-five patients with generalized SAD randomly assigned to CBT or wait list. INTERVENTION: Sixteen sessions of individual CBT for SAD. MAIN OUTCOME MEASURES: Negative emotion ratings and functional magnetic resonance imaging blood oxygen-level dependent signal when reacting to and cognitively reappraising negative self-beliefs embedded in autobiographical social anxiety situations. RESULTS During reactivity trials, compared with wait list, CBT produced (1) greater reduction in negative emotion ratings and (2) greater blood oxygen-level dependent signal magnitude in the medial prefrontal cortex. During cognitive reappraisal trials, compared with wait list, CBT produced (3) greater reduction in negative emotion ratings, (4) greater blood oxygen level-dependent signal magnitude in the dorsolateral and dorsomedial prefrontal cortex, (5) earlier temporal onset of dorsomedial prefrontal cortex activity, and (6) greater dorsomedial prefrontal cortex-amygdala inverse functional connectivity. CONCLUSIONS AND RELEVANCE: Modulation of cognitive reappraisal-related brain responses, timing, and functional connectivity may be important brain changes that contribute to the effectiveness of CBT for social anxiety. This study demonstrates that clinically applied neuroscience investigations can elucidate neurobiological mechanisms of change in psychiatric conditions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00380731. PMID- 23945983 TI - Higher-order repeat structure in alpha satellite DNA is an attribute of hominoids rather than hominids. AB - Alpha satellite DNA (AS), a major DNA component of primate centromeres, is composed of a tandem array of repeat units of approximately 170 bp. The AS of hominids (family Hominidae; humans and great apes) includes sequences organized into higher-order repeat (HOR) structures, with a periodic appearance of multiple copies of the basic repeat units. Here, we identified an HOR in AS of the siamang, a small ape phylogenetically distinct from hominids but included in hominoids (superfamily Hominoidea). We sequenced long stretches of genomic DNA, and found a repetition of blocks consisting of six and four basic repeat units. Thus, AS organization into HOR is an attribute of hominoids, rather than, as currently postulated, hominids. In addition to centromeres, siamangs carry AS in terminal heterochromatin blocks, and it cannot be determined at present whether these HOR-containing AS sequences originate from the centromere or from the terminal heterochromatin. Even if the latter is the case, these sequences might affect the composition of centromeric AS by being transferred to the centromere. PMID- 23945985 TI - Do employers know the quality of health care benefits they provide? Use of HEDIS depression scores for health plans. AB - OBJECTIVE Dissemination of health quality measures is a necessary ingredient of efforts to harness market-based forces, such as value-based purchasing by employers, to improve health care quality. This study examined reporting of Healthcare Effectiveness Data and Information Set (HEDIS) measures for depression to firms interested in improving depression care. METHODS During surveys conducted between 2009 and 2011, a sample of 325 employers that were interested in improving depression treatment were asked whether their primary health plan reports HEDIS scores for depression to the National Committee for Quality Assurance (NCQA) and if so, whether they knew the scores. Data about HEDIS reporting by the health plans were collected from the NCQA. RESULTS HEDIS depression scores were reported by the primary health plans of 154 (47%) employers, but only 7% of employers knew their plan's HEDIS scores. Because larger employers were more likely to report knowing the scores, 53% of all employees worked for employers who reported knowing the scores. A number of structural, health benefit, and need characteristics predicted knowledge of HEDIS depression scores by employers. CONCLUSIONS The study demonstrated that motivated employers did not know their depression HEDIS scores even when their plan publicly reported them. Measures of health care quality are not reaching the buyers of insurance products; however, larger employers were more likely to know the HEDIS scores for their health plan, suggesting that value-based purchasing may have some ability to affect health care quality. PMID- 23945990 TI - The interactions of nitrogen dioxide with graphene-stabilized Rh clusters: a DFT study. AB - We study the interactions of NO2 gas molecules with Rh nanoparticles supported on graphene, using first-principles molecular dynamics in the Car-Parrinello scheme. The stability, morphology, adsorption energies of various models of Rhx nanoparticles (x = 1, 3, 10, 20) supported on graphene, and the binding of NO2 molecules to the Rh clusters, together with its effect on the graphene properties, are reported. Metastable flat structures anchored to the substrate that can bind NO2 to Rh via both N and O atoms are identified, with adsorption energies in the range 60-70 kcal per mole per molecule. PMID- 23945991 TI - Construction of a series of coordination polymers from three imidazole-based multi-carboxylate ligands. AB - 2-Carboxylphenyl, 3-carboxylphenyl and 4-carboxylphenyl groups were introduced into the 2-position of imidazole-4,5-dicarboxylate system, respectively, obtaining three multi-functional ligands 2-(2-carboxylphenyl)-1H-imidazole-4,5 dicarboxylic acid (o-CPhH4IDC), 2-(3-carboxylphenyl)-1H-imidazole-4,5 dicarboxylic acid (m-CPhH4IDC) and 2-(4-carboxylphenyl)-1H-imidazole-4,5 dicarboxylic acid (p-CPhH4IDC). Then the three organic ligands are employed to react with Sr(II) and Cd(II) ions. Subsequently, five 3D or 2D polymers, [Sr(o CPhH2IDC)]n (1), [Sr3(m-CPhHIDC)2(H2O)3]n (2), [Sr(p-CPhH2IDC)(H2O)]n (3), [Cd(o CPhH2IDC)(H2O)2]n (4) and {[Cd3(m-CPhHIDC)2(H2O)8].2H2O}n (5), have been hydro(solvo)thermally synthesized and structurally characterized. Compound 1 is a (5,5)-connected 3D structure with unique "H-shape" channels. Three kinds of coordination environments around the Sr atoms are exhibited in compound 2. Both compounds 1 and 2 contain unusual irregular cages. Compound 3 displays a (4,6) connected 3D porous framework composed of right-handed helices connected by p CPhH2IDC(2-) anions. Both compounds 4 and 5 present net-like layer structures. These various architectures demonstrate the versatile coordination abilities of the three imidazole-based multi-carboxylate ligands. PMID- 23945984 TI - Nanomedicine for treating spinal cord injury. AB - Spinal cord injury results in significant mortality and morbidity, lifestyle changes, and difficult rehabilitation. Treatment of spinal cord injury is challenging because the spinal cord is both complex to treat acutely and difficult to regenerate. Nanomaterials can be used to provide effective treatments; their unique properties can facilitate drug delivery to the injury site, enact as neuroprotective agents, or provide platforms to stimulate regrowth of damaged tissues. We review recent uses of nanomaterials including nanowires, micelles, nanoparticles, liposomes, and carbon-based nanomaterials for neuroprotection in the acute phase. We also review the design and neural regenerative application of electrospun scaffolds, conduits, and self-assembling peptide scaffolds. PMID- 23945992 TI - Renal sympathetic denervation as antihypertensive therapy--a reappraisal of first results. AB - Renal sympathetic denervation (RSD) has previously been discussed in this journal. Since then, it has become a common procedure in many countries to use RSD to treat patients with putatively resistant hypertension. In Germany alone, RSD is now routinely used to treat resistant hypertension at the expense of the health-care system. The Germans have established a national registry to systematically and continuously follow up hypertensive patients who have undergone RSD. However, there are concerns because the registry is voluntary and physicians practicing the procedure may not have the accrual of new knowledge regarding the utility of RSD as their primary professional aim. Since the previous editorial on renal denervation, new results have been published. Therefore, it is appropriate to re-evaluate RSD. PMID- 23945993 TI - The effect of transoral robotic surgery on short-term outcomes and cost of care after oropharyngeal cancer surgery. AB - OBJECTIVES/HYPOTHESIS: Transoral surgery is an increasingly frequent treatment modality for tumors of the upper aerodigestive tract. This is in large part related to the introduction of transoral robotic surgery (TORS) for oropharyngeal cancer resection, which has demonstrated excellent oncologic and functional outcomes. There is limited data, however, on how TORS compares to traditional open surgery in overall costs and length of hospitalization. With increasing pressure to contain and reduce the costs of medical care, we sought to evaluate the impact of TORS on a national sample of patients undergoing surgery for oropharyngeal cancer. STUDY DESIGN: Retrospective cross-sectional study. METHODS: A cross-sectional analysis of 9,601 patients who underwent an extirpative procedure for a malignant oropharyngeal neoplasm in 2008 to 2009 was performed using discharge data from the Nationwide Inpatient Sample. RESULTS: TORS was performed in 116 (1.2%) of cases. TORS patients had a lower rate of gastrostomy tube placement (0% vs. 19%), tracheotomy tube placement (0% vs. 36%), and nonroutine discharge (0% vs. 44%) compared to patients undergoing non-TORS procedures. After controlling for all other variables, including comorbidity, extent of surgery, and teaching hospital status, TORS was associated with significantly decreased length of hospitalization (mean, -1.5 days) and hospital related costs (mean, -$4,285). CONCLUSIONS: TORS is becoming an increasingly frequent technique to treat tumors of the upper aerodigestive tract. These data demonstrate that TORS is associated with a decreased length of hospitalization and hospital-related costs compared to other surgical techniques. PMID- 23945994 TI - The Michigan Incontinence Symptom Index (M-ISI): a clinical measure for type, severity, and bother related to urinary incontinence. AB - AIMS: To develop a clinically relevant, easy to use, and validated instrument for assessing severity and bother related to urinary incontinence. METHODS: Survey items were piloted and refined following psychometric principles in five separate patient cohorts. Patient and expert endorsement of items, factor analyses, Spearman rank correlations and response distributions were employed for item selection. Formal reliability and validity evaluation were conducted for the final questionnaire items. RESULTS: Expert physicians and patient focus groups confirmed face and content validity for the measure. A 10-item measure called the Michigan Incontinence Symptom Index (M-ISI) was developed with two domains: a Total M-ISI Domain consisting of subdomains for stress urinary incontinence, urgency urinary incontinence, and pad use, and a Bother Domain. High construct validity was demonstrated with a Cronbach's alpha for the Total M-ISI Domain (items 1-8) of 0.90 and for the Bother Domain (items 9-10) of 0.82. Cronbach's alpha for the subdomains were all > 0.85. Construct validity, convergent and divergent validity, internal discriminant validity, and predictive validity were all robust. The minimally important difference for the measure was determined to be 4 points (out of 32) for the Total M-ISI Severity Domain, and 1-2 points (out of 8-12) for the individual subdomains. CONCLUSIONS: The M-ISI is a parsimonious measure that has established reliability and validity on several levels and complements current clinical evaluative methods for patients with urinary incontinence. PMID- 23945995 TI - Monochloramine suppresses the proliferation of colorectal cancer cell line Caco-2 by both apoptosis and G2/M cell cycle arrest. AB - The aim of this study was to assess a possible role of monochloramine (NH2 Cl), one of the reactive chlorine species, which induce oxidative stress, on the proliferation of colorectal cancer cell line Caco-2. At concentrations ranging from 10 to 200 MUM, NH2 Cl (14-61% inhibition), but not hypochlorous acid, dose dependently inhibited the cell viability of Caco-2 cells. Experiments utilizing methionine (a scavenger of NH2 Cl), taurine-chloramine and glutamine-chloramine revealed that only NH2 Cl affects the cancer cell proliferation among reactive chlorine species, with a relative specificity. Furthermore, flow-cytometry experiments showed that the anti-proliferative effect of NH2 Cl is partially attributable to both apoptosis and G2/M cell cycle arrest. These results suggest that NH2 Cl has the potential to suppress colorectal cancer cell proliferation. PMID- 23945996 TI - A beta-enaminone-initiated multicomponent domino reaction for the synthesis of indoloquinolizines and benzoquinolizines from acyclic precursors. AB - The cerium(IV) ammonium nitrate (CAN)-catalyzed sequential multicomponent reaction between tryptamine, alpha,beta-unsaturated aldehydes, and beta dicarbonyl compounds affords highly substituted indolo[2,3-a]quinolizines in a single synthetic operation. Two rings are generated through the creation of two C C and two C-N bonds by a domino process comprising initial beta-enaminone formation, followed by individual Michael addition, 6-exo-trig cyclization, iminium formation, and Pictet-Spengler steps. Furthermore, the reaction is diastereoselective and affords exclusively compounds with a trans relationship between the H-2 and H-12b protons. The use of amines bearing a less nucleophilic side chain aromatic ring (5-bromotryptamine, 3,4-dimethoxyphenylethylamine) prevents the Pictet-Spengler final step and leads to N-indolylethyl or N phenylethyl-1,4-dihydropyridines, which are cyclized to the corresponding indolo[2,3-a]quinolizines or benzo[a]quinolizines in the presence of HCl in methanol/water. Treatment of the fused quinolizine derivatives with sodium triacetoxyborohydride led to the corresponding indolo[2,3-a]quinolizidines or benzo[a]quinolizidines, possessing four stereogenic centers, as mixtures of two diastereomers. PMID- 23945997 TI - Altruism costs-the cheap signal from amygdala. AB - When people state their willingness to pay for something, the amount usually differs from the behavior in a real purchase situation. The discrepancy between a hypothetical answer and the real act is called hypothetical bias. We investigated neural processes of hypothetical bias regarding monetary donations to public goods using fMRI with the hypothesis that amygdala codes for real costs. Real decisions activated amygdala more than hypothetical decisions. This was observed for both accepted and rejected proposals. The more the subjects accepted real donation proposals the greater was the activity in rostral anterior cingulate cortex-a region known to control amygdala but also neural processing of the cost benefit difference. The presentation of a charitable donation goal evoked an insula activity that predicted the later decision to donate. In conclusion, we have identified the neural mechanisms underlying real donation behavior, compatible with theories on hypothetical bias. Our findings imply that the emotional system has an important role in real decision making as it signals what kind of immediate cost and reward an outcome is associated with. PMID- 23945998 TI - Temporal dynamics of motor cortex excitability during perception of natural emotional scenes. AB - Although it is widely assumed that emotions prime the body for action, the effects of visual perception of natural emotional scenes on the temporal dynamics of the human motor system have scarcely been investigated. Here, we used single pulse transcranial magnetic stimulation (TMS) to assess motor excitability during observation and categorization of positive, neutral and negative pictures from the International Affective Picture System database. Motor-evoked potentials (MEPs) from TMS of the left motor cortex were recorded from hand muscles, at 150 and 300 ms after picture onset. In the early temporal condition we found an increase in hand motor excitability that was specific for the perception of negative pictures. This early negative bias was predicted by interindividual differences in the disposition to experience aversive feelings (personal distress) in interpersonal emotional contexts. In the later temporal condition, we found that MEPs were similarly increased for both positive and negative pictures, suggesting an increased reactivity to emotionally arousing scenes. By highlighting the temporal course of motor excitability during perception of emotional pictures, our study provides direct neurophysiological support for the evolutionary notions that emotion perception is closely linked to action systems and that emotionally negative events require motor reactions to be more urgently mobilized. PMID- 23945999 TI - Cortisol modifies extinction learning of recently acquired fear in men. AB - Exposure therapy builds on the mechanism of fear extinction leading to decreased fear responses. How the stress hormone cortisol affects brain regions involved in fear extinction in humans is unknown. For this reason, we tested 32 men randomly assigned to receive either 30 mg hydrocortisone or placebo 45 min before fear extinction. In fear acquisition, a picture of a geometrical figure was either partially paired (conditioned stimulus; CS+) or not paired (CS-) with an electrical stimulation (unconditioned stimulus; UCS). In fear extinction, each CS was presented again, but no UCS occurred. Cortisol increased conditioned skin conductance responses in early and late extinction. In early extinction, higher activation towards the CS- than to the CS+ was found in the amygdala, hippocampus and posterior parahippocampal gyrus. This pattern might be associated with the establishment of a new memory trace. In late extinction, the placebo compared with the cortisol group displayed enhanced CS+/CS- differentiation in the amygdala, medial frontal cortex and nucleus accumbens. A change from early deactivation to late activation of the extinction circuit as seen in the placebo group seems to be needed to enhance extinction and to reduce fear. Cortisol appears to interfere with this process thereby impairing extinction of recently acquired conditioned fear. PMID- 23946000 TI - Brain structural basis of cognitive reappraisal and expressive suppression. AB - Cognitive reappraisal and expressive suppression, two major emotion regulation strategies, are differentially related to emotional well-being. The aim of this study was to test the association of individual differences in these two emotion regulation strategies with gray matter volume of brain regions that have been shown to be involved in the regulation of emotions. Based on high-resolution magnetic resonance images of 96 young adults voxel-based morphometry was used to analyze the gray matter volumes of the a priori regions of interest, including amygdala, insula, dorsal anterior cingulate and paracingulate cortex, medial and lateral prefrontal cortex (PFC) and their association with cognitive reappraisal and expressive suppression usage as well as neuroticism. A positive association of cognitive reappraisal with right and tendentially left amygdala volume and of neuroticism with left amygdala volume (marginally significant) was found. Expressive suppression was related to dorsal anterior cingulate/paracingulate cortex and medial PFC gray matter volume. The results of this study emphasize the important role of the amygdala in individual differences in cognitive reappraisal usage as well as neuroticism. Additionally, the association of expressive suppression usage with larger volumes of the medial PFC and dorsal anterior/paracingulate cortex underpins the role of these regions in regulating emotion-expressive behavior. PMID- 23946001 TI - Neural responses to unfairness and fairness depend on self-contribution to the income. AB - Self-contribution to the income (individual achievement) was an important factor which needs to be taken into individual's fairness considerations. This study aimed at elucidating the modulation of self-contribution to the income, on recipient's responses to unfairness in the Ultimatum Game. Eighteen participants were scanned while they were playing an adapted version of the Ultimatum Game as responders. Before splitting money, the proposer and the participant (responder) played the ball-guessing game. The responder's contribution to the income was manipulated by both the participant's and the proposer's accuracy in the ball guessing game. It turned out that the participants more often rejected unfair offers and gave lower fairness ratings when they played a more important part in the earnings. At the neural level, anterior insula, anterior cingulate cortex, dorsolateral prefrontal cortex and temporoparietal junction showed greater activities to unfairness when self-contribution increased, whereas ventral striatum and medial orbitofrontal gyrus showed higher activations to fair (vs unfair) offers in the other-contributed condition relative to the other two. Besides, the activations of right dorsolateral prefrontal cortex during unfair offers showed positive correlation with rejection rates in the self-contributed condition. These findings shed light on the significance of self-contribution in fairness-related social decision-making processes. PMID- 23946002 TI - Detection of deception based on fMRI activation patterns underlying the production of a deceptive response and receiving feedback about the success of the deception after a mock murder crime. AB - The ability of a deceiver to track a victim's ongoing judgments about the truthfulness of the deceit can be critical for successful deception. However, no study has yet investigated the neural circuits underlying receiving a judgment about one's lie. To explore this issue, we used a modified Guilty Knowledge Test in a mock murder situation to simultaneously record the neural responses involved in producing deception and later when judgments of that deception were made. Producing deception recruited the bilateral inferior parietal lobules (IPLs), right ventral lateral prefrontal (VLPF) areas and right striatum, among which the activation of the right VLPF contributed mostly to diagnosing the identities of the participants, correctly diagnosing 81.25% of 'murderers' and 81.25% of 'innocents'. Moreover, the participant's response when their deception was successful uniquely recruited the right middle frontal gyrus, bilateral IPLs, bilateral orbitofrontal cortices, bilateral middle temporal gyrus and left cerebellum, among which the right IPL contributed mostly to diagnosing participants' identities, correctly diagnosing 93.75% of murderers and 87.5% of innocents. This study shows that neural activity associated with being a successful liar (or not) is a feasible indicator for detecting lies and may be more valid than neural activity associated with producing deception. PMID- 23946003 TI - 'If you are good, I get better': the role of social hierarchy in perceptual decision-making. AB - So far, it was unclear if social hierarchy could influence sensory or perceptual cognitive processes. We evaluated the effects of social hierarchy on these processes using a basic visual perceptual decision task. We constructed a social hierarchy where participants performed the perceptual task separately with two covertly simulated players (superior, inferior). Participants were faster (better) when performing the discrimination task with the superior player. We studied the time course when social hierarchy was processed using event-related potentials and observed hierarchical effects even in early stages of sensory perceptual processing, suggesting early top-down modulation by social hierarchy. Moreover, in a parallel analysis, we fitted a drift-diffusion model (DDM) to the results to evaluate the decision making process of this perceptual task in the context of a social hierarchy. Consistently, the DDM pointed to nondecision time (probably perceptual encoding) as the principal period influenced by social hierarchy. PMID- 23946004 TI - Dorsomedial prefrontal metabolism and unawareness of current characteristics of personality traits in Alzheimer's disease. AB - Anosognosia is a complex symptom corresponding to a lack of awareness of one's current clinical status. Anosognosia for cognitive deficits has frequently been described in Alzheimer's disease (AD), while unawareness of current characteristics of personality traits has rarely been considered. We used a well established questionnaire-based method in a group of 37 AD patients and in healthy controls to probe self- and hetero-evaluation of patients' personality and we calculated differential scores between each participant's and his/her relative's judgments. A brain-behavior correlation was performed using 18 fluorodeoxyglucose positron emission tomography (FDG-PET) images. The behavioral data showed that AD patients presented with anosognosia for current characteristics of their personality and their anosognosia was primarily explained by impaired third perspective taking. The brain-behavior correlation analysis revealed a negative relationship between anosognosia for current characteristics of personality and dorsomedial prefrontal cortex (dMPFC) activity. Behavioral and neuroimaging data are consistent with the view that impairment of different functions subserved by the dMPFC (self-evaluation, inferences regarding complex enduring dispositions of self and others, confrontation of perspectives in interpersonal scripts) plays a role in anosognosia for current characteristics of personality in AD patients. PMID- 23946005 TI - Neural correlate of autistic-like traits and a common allele in the oxytocin receptor gene. AB - Sub-clinical autistic-like traits (ALTs) are continuously distributed in the general population and genetically linked to autism. Although identifying the neurogenetic backgrounds of ALTs might enhance our ability to identify those of autism, they are largely unstudied. Here, we have examined the neuroanatomical basis of ALTs and their association with the oxytocin receptor gene (OXTR) rs2254298A, a known risk allele for autism in Asian populations which has also been implicated in limbic-paralimbic brain structures. First, we extracted a four factor structure of ALTs, as measured using the Autism-Spectrum Quotient, including 'prosociality', 'communication', 'details/patterns' and 'imagination' in 135 neurotypical adults (79 men, 56 women) to reduce the genetic heterogeneity of ALTs. Then, in the same population, voxel-based morphometry revealed that lower 'prosociality', which indicates strong ALTs, was significantly correlated to smaller regional grey matter volume in the right insula in males. Males with lower 'prosociality' also had less interregional structural coupling between the right insula and the ventral anterior cingulate cortex. Furthermore, males with OXTR rs2254298A had significantly smaller grey matter volume in the right insula. These results show that decreased volume of the insula is a neuroanatomical correlate of ALTs and a potential intermediate phenotype linking ALTs with OXTR in male subjects. PMID- 23946006 TI - Effects of gaze direction, head orientation and valence of facial expression on amygdala activity. AB - There is increasing evidence for a role of the amygdala in processing gaze direction and emotional relevance of faces. In this event-related functional magnetic resonance study we investigated amygdala responses while we orthogonally manipulated head direction, gaze direction and facial expression (angry, happy and neutral). This allowed us to investigate effects of stimulus ambiguity, low level factors and non-emotional factors on amygdala activation. Averted vs direct gaze induced increased activation in the right dorsal amygdala regardless of facial expression and head orientation. Furthermore, valence effects were found in the ventral amygdala and strongly dependent on head orientation. We observed enhanced activation to angry and neutral vs happy faces for observer-directed faces in the left ventral amygdala while the averted head condition reversed this pattern resulting in increased activation to happy as compared to angry and neutral faces. These results suggest that gaze direction drives specifically dorsal amygdala activation regardless of facial expression, low-level perceptual factors or stimulus ambiguity. The role of the amygdala is thus not restricted to the detection of potential threat, but has a more general role in attention processes. Furthermore, valence effects are associated with activation of the ventral amygdala and strongly influenced by non-emotional factors. PMID- 23946009 TI - Two cases of pemphigus vegetans with IgG anti-desmocollin 3 antibodies. AB - IMPORTANCE: Pemphigus vegetans shows clinically vegetating and/or pustular skin lesions mainly on the intertriginous areas and histopathologically neutrophilic and eosinophilic pustules in the epidermis. Pemphigus vegetans shows IgG reactivity mainly with desmoglein (Dsg) 3, but also with other autoantigens, including Dsg1 and desmocollins (Dscs). OBSERVATIONS: We examined antigen profiles in 2 cases of pemphigus vegetans. (1) A women in her 80s presented with typical vegetating skin lesions on the right inguinal region with typical histopathological features. Immunoblotting using normal human epidermal extracts detected IgG antibodies to Dsg1 and Dscs. Enzyme-linked immunosorbent assays (ELISAs) revealed IgG antibodies to Dsg1 but not to Dsg3. Complementary DNA (cDNA) transfection method to COS-7 cells and novel ELISAs using eukaryotic recombinant proteins of human Dsc1, Dsc2, and Dsc3 confirmed specific IgG reactivity with Dsc3. (2) A women in her 70s presented with pustular skin lesions on the left fingers with typical histopathological features. Immunoblotting and ELISAs did not detect antibodies to either Dsg1 or Dsg3. Conversely, immunoblotting detected IgG antibodies to Dscs, cDNA transfection method revealed IgG reactivity only with Dsc3, and findings from ELISAs showed that IgG reacted weakly with Dsc2 and strongly with Dsc3. CONCLUSIONS AND RELEVANCE: Autoantibodies to Dscs, particularly to Dsc3, may play a pathogenic role in some cases of pemphigus vegetans. PMID- 23946010 TI - Ballistic interferences in suspended graphene. AB - The low-energy electronic excitations in graphene are described by massless Dirac fermions that have a linear dispersion relation. Taking advantage of this 'optics like' electron dynamics, generic optical elements like lenses and wave guides have been proposed for electrons in graphene. Tuning of these elements relies on the ability to adjust the carrier concentration in defined areas. However, the combination of ballistic transport and complex gating remains challenging. Here we report on the fabrication and characterization of suspended graphene p-n junctions. By local gating, resonant cavities can be defined, leading to complex Fabry-Perot interferences. The observed conductance oscillations account for quantum interference of electrons propagating ballistically over distances exceeding 1 MUm. Visibility of the interferences is demonstrated to be enhanced by Klein collimation at the p-n interface. This finding paves the way to more complex gate-controlled ballistic graphene devices and brings electron optics in graphene closer to reality. PMID- 23946011 TI - Quantum dot approaches for target-based drug screening and multiplexed active biosensing. AB - Biomolecule detection using quantum dots (Qdots), nanometer-sized semiconductor crystals, effectively addresses the limitations associated with conventional optical and biochemical techniques, as Qdots offer several key advantages over traditional fluorophores. In this minireview, we discuss the role of Qdots as a central nanoscaffold for the polyvalent assembly of multifunctional biomolecular probes and describe recent advances in Qdot-based biorecognition. Specifically, we focus on Qdot applications in target-based, drug screening assays and real time active biosensing of cellular processes. PMID- 23946012 TI - Best practices: The electronic medical record is an invaluable clinical tool: let's start using it. AB - This column describes the potential of an enhanced electronic medical record (EMR) to advance best practices by displaying patient history, measuring progress, and facilitating clinical research. To create a graphical, single-page display of patient history, the authors examined data in the Minneapolis Department of Veterans Affairs EMR system, including 1.8 million encounters for 50,000 mental health patients. The prototype dashboard presents information on a patient's current and past providers, diagnoses, therapeutic interventions, prescriptions, dosages, and outcomes. To provide needed outcome data to monitor patient progress, the authors tested two questions with 212 patients. Patient and clinician responses to the questions provide reliable and clinically useful data that can be used in the EMR to track patient change over time. Use of EMRs can bridge gaps between science and practice to inform diagnosis and treatment decisions and permit more accurate prognoses. PMID- 23946013 TI - Online health: Is this the end of family medicine? PMID- 23946015 TI - Novel approach to health care delivery for inner-city children. PMID- 23946016 TI - Travel medical insurance. PMID- 23946017 TI - Revolutionizing patient control of health information. PMID- 23946019 TI - Common bond. PMID- 23946020 TI - All together. PMID- 23946021 TI - A little deeper. PMID- 23946022 TI - Behavioural consequences of child abuse. AB - OBJECTIVE: To discuss the consequences of abuse on childhood behavioural development, to highlight some behavioural clues that might alert physicians to ongoing child abuse, and to explore the specific role of the family physician in this clinical situation. SOURCES OF INFORMATION: A systematic search was used to review relevant research, clinical review articles, and child protection agency websites. MAIN MESSAGE: A child's behaviour is an outward manifestation of inner stability and security. It is a lens through which the family physician can observe the development of the child throughout his or her life. All types of abuse are damaging to children-physically, emotionally, and psychologically-and can cause long-term difficulties with behaviour and mental health development. Family physicians need to be aware of and alert to the indicators of child abuse and neglect so that appropriate interventions can be provided to improve outcomes for those children. CONCLUSION: Child abuse might cause disordered psychological development and behaviour problems. Family physicians have an important role in recognizing behaviour clues that suggest child abuse and in providing help to protect children. PMID- 23946023 TI - Caring for children with phenylketonuria. AB - OBJECTIVE: To provide an overview of the diagnosis and management of phenylketonuria (PKU) in childhood with an emphasis on aspects relevant to family physicians providing ongoing care. SOURCES OF INFORMATION: The author's experience as the clinic physician in a regional pediatric PKU clinic is supplemented with references providing evidence for key points. MAIN MESSAGE: While metabolic clinics typically provide guidance regarding the specific management of PKU, the family doctor has an essential role in providing ongoing medical care. CONCLUSION: Children and families have much to gain from strong relationships with family doctors, and family doctors can confidently provide care with awareness of the very few potential special needs of patients with PKU. PMID- 23946024 TI - Optimizing pain relief during pregnancy using manual therapy. AB - QUESTION: Many of my pregnant patients have muscle and joint aches, and are reluctant to use analgesics. What is known about chiropractic care during pregnancy? ANSWER: As pregnant women move into their second and third trimesters, their centres of mass shift anteriorly, causing an increase in lumbar lordosis, which causes low back and pelvic girdle pain. Increasing recent evidence attests to the effectiveness and safety of treating this pain using manual therapy. Massage therapy and chiropractic care, including spinal manipulation, are highly safe and effective evidence-based options for pregnant women suffering from mechanical low back and pelvic pain. PMID- 23946025 TI - Bismuth salicylate for diarrhea in children. AB - QUESTION: Recently, I had a visit from a 5-year-old patient who had been given bismuth subsalicylate for a diarrheal illness by a local family physician during a trip to South America. Is this a practice we should encourage? ANSWER: Research from developing countries has found the use of bismuth subsalicylate to be effective in shortening the duration of diarrheal illness. Despite these findings, its limited effectiveness and concerns about it potentially causing Reye syndrome, compliance, and cost are the key reasons it is not routinely recommended for children. PMID- 23946027 TI - Daily multivitamins to reduce mortality, cardiovascular disease, and cancer. PMID- 23946028 TI - Choking caused by a homeopathic drug: in a previously healthy infant. PMID- 23946029 TI - Draining a subungual hematoma: procedures and assessments video series. PMID- 23946030 TI - Dermacase. Can you identify this condition? Scabies. PMID- 23946031 TI - Warfarin: its highs and lows. PMID- 23946033 TI - More than just a case study: an introduction to ondansetron for my son, "the dehydrated child". PMID- 23946035 TI - More committed than ever. PMID- 23946032 TI - Primary care role in expanded newborn screening: After the heel prick test. AB - OBJECTIVE: To examine the role of primary care providers in informing and supporting families who receive positive screening results. DESIGN: Cross sectional survey. SETTING: Ontario. PARTICIPANTS: Family physicians, pediatricians, and midwives involved in newborn care. MAIN OUTCOME MEASURES: Beliefs, practices, and barriers related to providing information to families who receive positive screening results for their newborns. RESULTS: A total of 819 providers participated (adjusted response rate of 60.9%). Of the respondents, 67.4% to 81.0% agreed that it was their responsibility to provide care to families of newborns who received positive screening results, and 64.2% to 84.8% agreed they should provide brochures or engage in general discussions about the identified conditions. Of the pediatricians, 67.3% endorsed having detailed discussions with families, but only 24.1% of family physicians and 27.6% of midwives endorsed this practice. All provider groups reported less involvement in information provision than they believed they should have. This discrepancy was most evident for family physicians: most stated that they should provide brochures (64.2%) or engage in general discussions (73.5%), but only a minority did so (15.3% and 27.7%, respectively). Family physicians reported insufficient time (42.2%), compensation (52.2%), and training (72.3%) to play this role, and only a minority agreed they were up to date (18.5%) or confident (16.5%) regarding newborn screening. CONCLUSION: Providers of primary newborn care see an information-provision role for themselves in caring for families who receive positive newborn screening results. Efforts to further define the scope of this role combined with efforts to mitigate existing barriers are warranted. PMID- 23946038 TI - Update on special interests and focused practices. PMID- 23946042 TI - Use of natural health products in children: experiences and attitudes of family physicians in Newfoundland and Labrador. AB - OBJECTIVE: To determine the experiences of family physicians in Newfoundland and Labrador with parents' use of natural health products (NHPs) for their children and to assess physicians' attitudes toward use of NHPs in children. DESIGN: A survey using the Dillman approach. SETTING: Newfoundland and Labrador. PARTICIPANTS: All family physicians in the province. MAIN OUTCOME MEASURES: Physician demographic characteristics; whether physicians inquire about the use of NHPs in children; the degree to which they think patients disclose use of NHPs in children; whether they counsel parents about the potential benefits or harms of NHPs; their own opinions about the usefulness of NHPs; whether they recommend NHPs in children and for what reasons; and the particular NHPs they have seen used in children and for what reasons. RESULTS: A total of 159 (33.1%) family physicians responded; 65.4% were men, 71.7% were Canadian medical graduates, and 46.5% practised in rural areas. Overall, 18.8% of family physicians said they regularly or frequently asked about NHP use; 24.7% counseled patients about potential harms. Only 1.9% of physicians believed NHPs were usually beneficial, but a similarly small number (8.4%) thought they were usually harmful. Most respondents were somewhat neutral; 59.7% said they never recommend NHPs for children, and a further 37.0% said they would only "sometimes" recommend NHPs. CONCLUSION: Most physicians believed that NHPs were probably of little benefit but not likely to be harmful. Most NHPs used were vitamins and minerals. Physicians recognized that NHPs were often used by parents for children, but in general they believed NHPs had little effect on their day-to-day medical practices. Thirty-eight (24.7%) of the 154 physicians had at least once recommended an NHP (including vitamins) for their pediatric patients. Physicians believed that parents did not often disclose use of NHPs for their children, but at the same time physicians generally did not actively inquire. PMID- 23946043 TI - Use of natural health products in children: survey of parents in waiting rooms. AB - OBJECTIVE: To determine how common it is for parents to give natural health products (NHPs) to their children, which NHPs are being used, why they are being used, and parents' assessments of the benefits and side effects of NHPs. DESIGN: Survey. SETTING: Newfoundland and Labrador. PARTICIPANTS: Parents waiting in their family doctors' offices. MAIN OUTCOME MEASURES: Parent and child demographic characteristics; pediatric chronic medical conditions affecting the children; prescribed medications, over-the-counter medications, and NHPs used by the children; why the medications and NHPs were being used, the dose, and parents' assessments of the effectiveness and side effects; and where parents had heard about the NHPs, whether they had told their physicians that the children were taking the products, and where they had obtained the products. RESULTS: A total of 202 (53.4%) of the 378 eligible adults who were approached completed the survey. This represented 333 children. Mean (SD) age of the children was 5.1 (3.3) years. Overall, 28.7% of parents reported using nonvitamin NHPs for their children. A total of 137 children (41.1%) had taken NHPs (including vitamins); 61.1% of the NHPs being used were vitamins. The remainder fell under teas (primarily chamomile and green teas), echinacea, fish or omega-3 oils, and a large category of "other" products. These NHPs were most commonly used to improve general health, improve immunity, and prevent colds and infections. Approximately half of the parents (51.7%) believed their children had benefited from taking NHPs, and 4.4% believed their children had experienced adverse side effects. Slightly less than half of the parents (45.0%) had informed their physicians that their children were taking NHPs. CONCLUSION: Overall, 45.5% of parents attending physicians' offices reported using NHPs in their children. If vitamins are not included in the definition of NHPs, this rate drops to 28.7%. Parents most commonly use NHPs to maintain the general health of their children, to prevent colds, and to boost children's immune systems. About half of the parents believed the NHPs helped, very few had noticed any side effects, and approximately half had informed their physicians that they were giving their children NHPs. PMID- 23946044 TI - Use of natural health products in children: qualitative analysis of parents' experiences. AB - OBJECTIVE: To gain a more thorough understanding of why parents choose to give their children natural health products (NHPs), parents' sources of information about NHPs, and the extent of disclosure and conversation with family doctors about the use of NHPs. DESIGN: Qualitative study. SETTING: Newfoundland and Labrador. PARTICIPANTS: Parents of children who were using NHPs (N = 20). METHODS: Individual, semistructured interviews were carried out with parents to obtain a better understanding of the reasoning behind the use of NHPs. Key themes emerging from the qualitative data were identified according to a number of criteria, including relevance to the research objectives, frequency with which a theme was mentioned, relative importance of the themes based on the amount of text taken up to address an issue, and emphasis (eg, emphatic or emotional speech). MAIN FINDINGS: The types of NHPs used by parents participating in this study varied, except for the use of multivitamins. In addition, use of the products themselves was variable and inconsistent. Parents reported few concerns about the use of NHPs. The most commonly reported source of information about NHPs was family and friends. Most participants had not spoken to their family doctors about the use of NHPs. CONCLUSION: Participants considered NHPs to be "natural" and seemed to equate this assessment with safety. This might explain why these parents sought advice and information from family and friends rather than from their family doctors and often failed to disclose the use of NHPs to their children's family doctors. PMID- 23946045 TI - Management of neonatal jaundice varies by practitioner type. AB - OBJECTIVE: To survey current practices among different types of medical practitioners in Ontario to assess if national guidelines for screening and management of neonatal hyperbilirubinemia were being followed. DESIGN: An anonymized, cross-sectional survey distributed by mail and e-mail. SETTING: Ontario. PARTICIPANTS: From each group (general practitioners, family medicine practitioners, and pediatricians), 500 participants were randomly selected, and all 390 registered midwives were selected. MAIN OUTCOME MEASURES: Compliance with national guidelines for screening, postdischarge follow-up, and management of newborns with hyperbilirubinemia. RESULTS: Of the 1890 potential respondents, 321 (17%) completed the survey. Only 41% of family physicians reported using national guidelines, compared with 75% and 69% of pediatricians and midwives, respectively (P < .001). Bilirubin was routinely measured for all newborns before discharge by 42% of family physicians, 63% of pediatricians, and 22% of midwives (P < .001). Newborn follow-up was completed within 72 hours after discharge by 60% of family physicians, 89% of pediatricians, and 100% of midwives. Management of neonatal hyperbilirubinemia differed significantly (P < .001), with 91% of family physicians, 99% of pediatricians, and 79% of midwives correctly managing a case scenario according to the guidelines. CONCLUSION: The management of jaundice varied considerably among the different practitioner types, with pediatricians both most aware of the guidelines and most likely to follow them. Increased knowledge translation efforts are required to promote adherence to the jaundice management guidelines across all practitioner types, but particularly among family physicians. PMID- 23946048 TI - Bayesian model aggregation for ensemble-based estimates of protein pKa values. AB - This article investigates an ensemble-based technique called Bayesian Model Averaging (BMA) to improve the performance of protein amino acid pKa predictions. Structure-based pKa calculations play an important role in the mechanistic interpretation of protein structure and are also used to determine a wide range of protein properties. A diverse set of methods currently exist for pKa prediction, ranging from empirical statistical models to ab initio quantum mechanical approaches. However, each of these methods are based on a set of conceptual assumptions that can effect a model's accuracy and generalizability for pKa prediction in complicated biomolecular systems. We use BMA to combine eleven diverse prediction methods that each estimate pKa values of amino acids in staphylococcal nuclease. These methods are based on work conducted for the pKa Cooperative and the pKa measurements are based on experimental work conducted by the Garcia-Moreno lab. Our cross-validation study demonstrates that the aggregated estimate obtained from BMA outperforms all individual prediction methods with improvements ranging from 45 to 73% over other method classes. This study also compares BMA's predictive performance to other ensemble-based techniques and demonstrates that BMA can outperform these approaches with improvements ranging from 27 to 60%. This work illustrates a new possible mechanism for improving the accuracy of pKa prediction and lays the foundation for future work on aggregate models that balance computational cost with prediction accuracy. PMID- 23946050 TI - Effects of polymorphic DNA on the fluorescent properties of silver nanoclusters. AB - Silver nanoclusters (Ag NCs) with emission wavelengths from 538 nm to 706 nm were synthesized using a series of G-/C-rich polymorphic DNA templates. Thermodynamic studies on the interactions of Ag(+) with polymorphic DNA indicate that the binding affinities greatly depend on the secondary structures of DNA templates, with a decreasing order: the coiled C-rich strand > the i-motif > the duplex > the G-quadruplex. Fluorescent Ag NCs prepared using these polymorphic DNA templates show that fluorescence stabilities are associated with the binding affinities between DNA templates and Ag(+), e.g., the coiled C-rich strand C4A4C3 with the highest binding constant (40.2 * 10(5) M(-1)) stabilizes Ag NCs for over 300 h, while the G-quadruplex G4T4G4 with the lowest binding constant (0.64 * 10(5) M(-1)) generates Ag NCs with the shortest shelf-life (55 h). The cluster sizes of Ag NCs are associated with the sequence lengths of DNA templates. In addition, the red emitting [C4A4C3]-Ag and the NIR emitting [G4T4G4-C4A4C4]-Ag are successfully used for HeLa cell transfection and exhibit good intracellular emission. These results provide a promising pathway to prepare silver nanomaterials with desirable physicochemical properties through designing suitable DNA templates. PMID- 23946049 TI - Use of antiepileptic drugs and risk of hypothyroidism. AB - PURPOSE: This study aimed to investigate the risk of clinically significant hypothyroidism among all the currently available antiepileptic drugs (AED). METHODS: The Taiwan National Health Insurance Research Database (NHIRD) from 2004 to 2010 was analyzed using a prescription sequence symmetry analysis, and thyroxine treatment was used as a proxy to identify a hypothyroidism event. A cohort of patients who have been treated with both AED and thyroxine was selected, and the chronological order of AED and thyroxine use constituted the basis of the prescription sequence symmetry analysis. A causal relationship was suspected if there was a significantly higher proportion of patients who initiated thyroxine after AED than those who initiated thyroxine before AED. The ratio of the two proportions was described as a sequence ratio. To benchmark the effect size of AEDs on thyroid function, amiodarone was selected as the reference indicator. RESULTS: A total of 1,878,189 AED users was found in the database, with 16,200 of them also used thyroxine. The adjusted sequence ratio of thyroxine use after each AED was 1.75 (99% confidence interval, 1.58-1.94) for phenytoin, 1.34 (1.20-1.49) for valproate, 1.25 (1.15-1.36) for phenobarbital, 1.21 (1.08 1.34) for carbamazepine, and 1.22 (1.03-1.46) for oxcarbazepine. The risk of hypothyroidism from phenytoin use within a shorter time frame was similar that associated with amiodarone use. No association was shown in most of the new generation AEDs. CONCLUSION: The results indicated an increased risk of hypothyroidism among patients using AEDs, especially phenytoin, valproate, phenobarbital, carbamazepine, and oxcarbazepine. The findings also provided strong grounds for further investigations on acute thyroid adverse effect induced by phenytoin. PMID- 23946051 TI - Minimizing trauma over 'no man's land' with flexor tendon retrieval. PMID- 23946052 TI - Efficient detection of hydrogen bonds in dynamic regions of RNA by sensitivity optimized NMR pulse sequences. AB - Improved Sensitivity: Efficient NMR experiments are presented for determining the secondary structure in large and dynamic RNAs using J-couplings across hydrogen bonds. The experiments provide up to eight-fold improved sensitivity and thus enable detection of base pairs in dynamic regions even in large RNAs. PMID- 23946053 TI - Antiplatelet and anticoagulation therapy in microlaryngeal surgery. AB - OBJECTIVES/HYPOTHESIS: Indications for antiplatelet and anticoagulation use are expanding. There is no evidence to direct therapeutic management in patients undergoing microlaryngeal surgeries. Our aim was to compare bleeding complications between microlaryngeal surgeries performed for patients preoperatively taken off and maintained on antiplatelet and/or anticoagulation therapy. STUDY DESIGN: Retrospective cohort study. METHODS: Patients undergoing microlaryngeal surgeries (2008-2009) on baseline antiplatelet and/or anticoagulation therapy were identified. Records were reviewed to determine whether therapy was stopped preoperatively. The primary outcome, bleeding complication, was compared between those taken off and maintained on therapy. Patient characteristics, surgical data, and outcomes were assessed. RESULTS: Of 287 microlaryngeal surgeries, 26% were performed for patients on antiplatelet (23%) and/or anticoagulation (3%) therapy. There was no difference in bleeding complications between patients' naive to and on baseline antiplatelet or anticoagulation therapy [naive: 3.8% vs. on: 5.3%, P = 0.58] and no thromboembolic events. Among surgeries performed for patients on baseline antiplatelet therapy, 35% preoperatively stopped therapy. No observed difference in bleeding complications was observed between those taken off or maintained on therapy [off: 8.0% vs. on: 4.9%, P = 0.63]. Of 3% of surgeries performed for patients on warfarin, no bleeding complications occurred, even among the 8/10 with therapeutic international normalized ratios. CONCLUSIONS: Perioperative management decisions regarding antiplatelet and anticoagulation therapy are becoming more common. Results suggest that antiplatelet therapy can be maintained during microlaryngeal surgery without increasing bleeding risk. Further prospective research is required to confirm findings and rigorously investigate the safety of continuing warfarin and other anticoagulation therapy in these surgeries. LEVEL OF EVIDENCE: 4. PMID- 23946054 TI - Strain rate viscoelastic analysis of soft and highly hydrated biomaterials. AB - Measuring the viscoelastic behavior of highly hydrated biological materials is challenging because of their intrinsic softness and labile nature. In these materials, it is difficult to avoid prestress and therefore to establish precise initial stress and strain conditions for lumped parameter estimation using creep or stress-relaxation (SR) tests. We describe a method ( EM or epsilon dot method) for deriving the viscoelastic parameters of soft hydrated biomaterials which avoids prestress and can be used to rapidly test degradable samples. Standard mechanical tests are first performed compressing samples using different strain rates. The dataset obtained is then analyzed to mathematically derive the material's viscoelastic parameters. In this work a stable elastomer, polydimethylsiloxane, and a labile hydrogel, gelatin, were first tested using the EM, in parallel SR was used to compare lumped parameter estimation. After demonstrating that the elastic parameters are equivalent and that the estimation of short-time constants is more precise using the proposed method, the viscoelastic behavior of porcine liver was investigated using this approach. The results show that the constitutive parameters of hepatic tissue can be quickly quantified without the application of any prestress and before the onset of time dependent degradation phenomena. PMID- 23946081 TI - Clinical implications of a feeling of incomplete emptying with little post-void residue in men with lower urinary tract symptoms. AB - AIM: It remains unclear why patients suffer from a feeling of incomplete emptying despite no or little post-void residual (PVR). Accordingly, we evaluated the clinical implications thereof in men with lower urinary tract symptoms (LUTS). METHODS: Records were obtained from a prospectively maintained database for 905 first-visit men with LUTS. Patients with comorbidities that may affect voiding function and with PVR > 20 ml were excluded. Finally, 421 patients were eligible for the study. RESULTS: By International Prostate Symptom Score (IPSS), a score for evaluating a feeling of incomplete emptying, 106 patients (25.2%) were characterized as experiencing no symptoms (score 0, 1), 201 (47.7%) as mild to moderate symptoms (score 2, 3), and 114 (27.1%) as severe symptoms (score 4, 5). The severity of a feeling of incomplete emptying was significantly associated with total IPSS and with subscores for both voiding and storage symptoms (P < 0.001). Comparing patients with severe symptoms (severe group, N = 114) with a propensity score-matched control group, adjusting for age, PVR, and maximum flow rate, total IPSS was significantly different between the two groups (23.04 +/- 5.68 vs. 13.21 +/- 5.48, respectively; P < 0.001). The subscores for both voiding and storage symptoms were also significantly worse in the severe group. The quality of life score was 4.51 +/- 0.80 in the severe group and 3.53 +/- 1.05 in control group (P < 0.001). CONCLUSIONS: A feeling of incomplete emptying despite little PVR was frequently observed and, notably, this was significantly associated with worsening of both voiding and storage symptoms, even after adjusting for relevant variables. PMID- 23946082 TI - Efficient formation of luminescent lanthanide(III) complexes by solid-phase synthesis and on-resin screening. AB - Time-resolved luminescence measurements of luminescent lanthanide complexes have advantages in biological assays and high-throughput screening, owing to their high sensitivity. In spite of the recent advances in their energy-transfer mechanism and molecular-orbital-based computational molecular design, it is still difficult to estimate the quantum yields of new luminescent lanthanide complexes. Herein, solid-phase libraries of luminescent lanthanide complexes were prepared through amide-condensation and Pd-catalyzed coupling reactions and their luminescent properties were screened with a microplate reader. Good correlation was observed between the time-resolved luminescence intensities of the solid phase libraries and those of the corresponding complexes that were synthesized by using liquid-phase chemistry. This method enabled the rapid and efficient development of new sensitizers for Sm(III), Eu(III), and Tb(III) luminescence. Thus, solid-phase combinatorial synthesis combined with on-resin screening led to the discovery of a wide variety of luminescent sensitizers. PMID- 23946088 TI - Intestinal colonization: how key microbial players become established in this dynamic process: microbial metabolic activities and the interplay between the host and microbes. AB - In this review, we provide an overview of the dynamic changes within the microbiota and its metabolites that are implicated in establishing and maintaining gastrointestinal homeostasis during various stages of microbial colonization. The gradual conversion of the gut microbiota toward a mutualistic microbial community involves replacement of pioneer gut colonizers with bacterial taxa that are characteristic for the adult gut. An important microbial signature of homeostasis in the adult gut is the prevalence and activity of a diverse spectrum of bacterial species that produce beneficial metabolites through metabolic interactions between microbial groups. Deciphering these microbial signatures and their metabolites that govern short and long-term equilibrium, as well as imbalances in host-microbial relationships, may provide novel diagnostic tools and/or therapeutic targets for specific disorders associated with intestinal dysbiosis and loss of homeostasis. PMID- 23946089 TI - Parechovirus as a cause of a sepsis-like syndrome with cerebral involvement in a 7-week old infant. PMID- 23946090 TI - Ambulatory care of children treated with anticonvulsants - pitfalls after discharge from hospital. AB - BACKGROUND: Anticonvulsants require special consideration particularly at the interface from hospital to ambulatory care. PATIENTS AND METHOD: Observational study for 6 months with prospectively enrolled consecutive patients in a neuropediatric ward of a university hospital (age 0-<18 years) with long-term therapy of at least one anticonvulsant. Assessment of outpatient prescriptions after discharge. Parent interviews for emergency treatment for acute seizures and safety precautions. RESULTS: We identified changes of the brand in 19/82 (23%) patients caused by hospital's discharge letters (4/82; 5%) or in ambulatory care (15/82; 18%). In 37/76 (49%) of patients who were deemed to require rescue medication, no recommendation for such a medication was included in the discharge letters. 17/76 (22%) of the respective parents stated that they had no immediate access to rescue medication. Safety precautions were applicable in 44 epilepsy patients. We identified knowledge deficits in 27/44 (61%) of parents. CONCLUSION: Switching of brands after discharge was frequent. In the discharge letters, rescue medications were insufficiently recommended. Additionally, parents frequently displayed knowledge deficits in risk management. PMID- 23946091 TI - Response of children with stage IV soft tissue sarcoma to topotecan and carboplatin: a phase II window trial of the cooperative soft tissue sarcoma group. AB - To investigate antitumor activity and toxicity associated with combined topotecan and carboplatin treatment in children and adolescents with metastasized, untreated soft tissue sarcoma (STS).Patients (n=34) less than 21 years old and untreated, stage IV STS. Patients were treated with topotecan (1 mg/m2/d for 4 days) and carboplatin (150 mg/m2/d for 4 days) (TC course) during week 1 and 4 of a chemotherapy window trial, which was followed by chemotherapy and local therapy from week 6 on. We evaluated the side effects, toxicity and tumor response (using RECIST criteria) 6 weeks after starting the 2 TC chemotherapy courses.The objective response rate (ORR) was 38% (n=13 patients with a partial response (PR)), and a stable disease (SD) was reached in 11 cases. No patient showed a complete response (CR) of all metastatic lesions, although 1 patient showed a CR of the target lesion. 2 patients died of progress of disease (PD). Toxicity was mainly hematological (grade III/IV toxicity 79%), and nonhematological toxicities mainly included infection, fever, nausea,and vomiting. Regarding adverse events, 4 probable and 8 possible events related to study medication occurred among the 66 courses of TC.In conclusion, TC was potent against high-risk STS, but results and toxicity data were not superior to former published monotherapeutic topotecan therapies. PMID- 23946092 TI - [Google translate is not sufficient to overcome language barriers in neonatal medicine]. AB - Language barriers hinder the interaction with patients and relatives. The use of language services increases knowledge, satisfaction and the use of medical care and thus improves patient's clinical outcome. The recommended use of professional interpreters (PI) is not always feasible. We tested an online translation tool as an alternative for PI for the transla-tion of standardized sentences from a neonatal doctor-/nurse-relative-interview.Translation of 20 sentences from a German neonatal intensive care unit parent information brochure to English, Portuguese and Arabic, using Google Translate (GT). Assessment of accuracy concerning grammar and content, in a second step simplification of all incorrect sentences, translation by GT and critical re-assessment and evaluation.An average of 42% of the sentences was correctly translated concerning grammar and content. The proportion of incorrectly translated sentences varied between 45-70%. By simpli-fication another 23% were translated correctly.Translations by GT were often incorrect in content and grammar. We suppose that the design of GT, which is a statistical translation engine, might be an explanation for this phenomenon. Presently, GT cannot guarantee unambiguous translations and cannot substitute PIs, only in particular circumstances, the use of GT or similar engines may be justified. For future use of electronic translation services, we suggest to compile a catalogue of sentences containing central information, which can be translated into defined foreign languages without misinterpretation or loss of information. PMID- 23946097 TI - Synthesis and characterization of pure and Li+ activated Alq3 complexes for green and blue organic light emitting diodes and display devices. AB - Pure and Li(+)-doped Alq3 complexes were synthesized by simple precipitation method at room temperature, maintaining the stoichiometric ratio. These complexes were characterized by X-ray diffraction, ultraviolet-visible absorption and Fourier transform infrared and photoluminescence (PL) spectra. X-ray diffraction analysis reveals the crystalline nature of the synthesized complexes, while Fourier transform infrared spectroscopy confirm the molecular structure, the completion of quinoline ring formation and presence of quinoline structure in the metal complex. Ultraviolet-visible and PL spectra revealed that Li(+) activated Alq3 complexes exhibit the highest intensity in comparison to pure Alq3 phosphor. Thus, Li(+) enhances PL emission intensity when doped into Alq3 phosphor. The excitation spectra lie in the range of 383-456 nm. All the synthesized complexes other than Liq give green emission, while Liq gives blue emission with enhanced intensity. Thus, he synthesized phosphors are the best suitable candidates for green- and blue-emitting organic light emitting diode, PL liquid-crystal display and solid-state lighting applications. PMID- 23946098 TI - An angiographic atlas of intracranial arterial diameters associated with cerebral aneurysms. AB - INTRODUCTION: The successful treatment of intracranial aneurysms is dependent on a full understanding of the anatomic relationship of a given aneurysm to its parent artery(s) and nearby branches. Furthermore, new endovascular technologies are often limited by size constraints. Currently, there is no complete atlas describing diameters for each major intracranial arterial segment. We sought to obtain these data by performing a systematic analysis of selected cerebral angiography images from the International Study of Unruptured Intracranial Aneurysms (ISUIA). METHODS: Four hundred and forty-five patients with unruptured intracranial aneurysms from the ISUIA database were reviewed. Using previously described techniques, artery diameters were measured for all arteries involved in the aneurysm neck for each patient. RESULTS: Measurements were obtained from 695 different aneurysm-associated arterial segments among 445 patient angiograms (mean 1.6 measurements per aneurysm). Artery diameters, mean, median, SEM and IQRs based upon the different arterial segments are presented. CONCLUSIONS: This angiographic almanac of aneurysm-associated intracranial arterial diameters may be of benefit in establishing standard norms through which devices, protocols and research aims may be developed. PMID- 23946099 TI - Mechanistic insights into the rhenium-catalyzed alcohol-to-olefin dehydration reaction. AB - Rhenium-based complexes are powerful catalysts for the dehydration of various alcohols to the corresponding olefins. Here, we report on both experimental and theoretical (DFT) studies into the mechanism of the rhenium-catalyzed dehydration of alcohols to olefins in general, and the methyltrioxorhenium-catalyzed dehydration of 1-phenylethanol to styrene in particular. The experimental and theoretical studies are in good agreement, both showing the involvement of several proton transfers, and of a carbenium ion intermediate in the catalytic cycle. PMID- 23946103 TI - Photochemical properties of squarylium cyanine dyes. AB - This study presents several new squarylium dyes derived from benzothiazole and benzoselenazole with several structural variations, namely the nature of the heteroaromatic ring and the length of the N,N'-dialkyl groups. Before being investigated in connection with their effect on living cells and/or tissues, these novel compounds were characterized, namely with respect to the determination of their main photophysical parameters. Therefore, a study of the ground state absorption, fluorescence emission (quantum yields and lifetimes) and singlet oxygen generation quantum yields was performed for all the compounds synthesized in order to evaluate their efficiency as photosensitizers. An increase of the alkyl chain length from ethyl to hexyl did not produce a clear change in the fluorescence quantum yields, showing no influence on the photoisomerization process. Heavy atom inclusion (Se instead of S) enhanced the singlet oxygen generation efficiency and decreased the intensity of the fluorescence emission. The external heavy atom effect (I(-) as a counterion instead of CF3SO3(-)) produced a significant increase in the singlet oxygen formation quantum yield (about 20%). Transient absorption studies in aerated and oxygen free samples revealed that the photoisomerization process, which could compete with the triplet state formation for all dyes in solution, is a negligible pathway for the excited state deactivation, in accordance with the rigidity introduced by the squaric ring into the polymethine chain of the dye, both in chloroform and ethanol. However, in the case of the chloroform solution a new transient was detected in air equilibrated solutions, resulting from a reaction of the excited squarylium dye in the singlet state with CHCl3, and assigned to the radical cation (SQ(+)) of the dye. PMID- 23946100 TI - Assessment of protein disorder region predictions in CASP10. AB - The article presents the assessment of disorder region predictions submitted to CASP10. The evaluation is based on the three measures tested in previous CASPs: (i) balanced accuracy, (ii) the Matthews correlation coefficient for the binary predictions, and (iii) the area under the curve in the receiver operating characteristic (ROC) analysis of predictions using probability annotation. We also performed new analyses such as comparison of the submitted predictions with those obtained with a Naive disorder prediction method and with predictions from the disorder prediction databases D2P2 and MobiDB. On average, the methods participating in CASP10 demonstrated slightly better performance than those in CASP9. PMID- 23946104 TI - Change point analysis of travel routes reveals novel insights into foraging strategies and cognitive maps of wild baboons. AB - Efficient space use is a critical challenge for animals relying on stationary resources. It is often difficult with purely observational methods to gain unambiguous insight into any ability of primates to manage and process spatial information. Investigating the visible signs of the decision processes underlying space use often leaves open important issues. We applied the change point test [Byrne et al. (2009). Anim Behav 77: 619-631], a statistical tool to objectively determine change points (CPs) in animal travel paths, to investigate to what degree directional changes in our study group's (Papio ursinus) dry season ranging were associated with important resources and prominent landmarks. One third of directional changes were associated with fruit feeding, 1/3 with traveling, and 1/3 with dry matter feeding, travel feeding and with drinking. When directional changes were associated with traveling, the subsequent directional changes were likely to result in fruit feeding. Fruit feeding mostly occurred at the apex of the day journeys, while drinking, dry matter feeding, and travel feeding often occurred along straight travel segments. The majority of directional changes did not occur in clusters at distinctive locations, but at distances of more than 120 m apart from each other, many of them along prominent landmarks. We conclude that the CPs do not represent nodes or route bends of a network map. Rather, they represent (1) locations where the decision to turn back to their sleeping site was taken, and (2) locations next to important landmarks (changes of slope, car tracks) where slight adjustment of a movement direction was possible. We found no evidence for a Euclidean map and discuss our findings in the light of a network map representation of space. PMID- 23946107 TI - Challenges and current evidence on the management of bladder pain syndrome. AB - INTRODUCTION: Bladder pain syndrome (BPS) is an enigmatic condition, which can be debilitating for the patients, affecting their quality of life. Its prevalence is believed to have become markedly higher (100-300/100,000 women) than in previous years. Its etiology and pathogenesis remain unknown, and a number of theories based on clinical and experimental observations have been developed. It is difficult to be diagnosed and treated. There is a worldwide effort to standardize its nomenclature, definition, diagnosis, and treatment algorithm. The aim of this review is to critically appraise the current evidence on the diagnosis and management of BPS. METHODS: We performed a review of the literature (Pubmed, Embase, Cochrane, Google Scholar, conference proceedings) as well as consensus statements and guidelines from relevant professional societies. We have critically compared these statements and guidelines with emphasis on the controversies. RESULTS: Patients may experience pain and lower urinary tract symptoms for a long time before diagnosis, affecting their mental health and work, causing stress, sleep disturbance, depression, and sexual dysfunction. BPS has been considered as one of a group of chronic pain syndromes rather than as primarily an inflammatory bladder disorder. Despite the wide range of treatments, most are empirical and inadequate, usually offering just symptom relief. There is often delay in commencing treatment, and this may result in worse prognosis. CONCLUSION: Efforts are focused on different pathways for the early identification of this syndrome, trying to elucidate the pathogenetic mechanism, as well as introducing effective treatments. PMID- 23946108 TI - Three-dimensional MoS2 hierarchical nanoarchitectures anchored into a carbon layer as graphene analogues with improved lithium ion storage performance. AB - Much attention has recently been focused on the synthesis and application of graphene analogues of layered nanomaterials owing to their better electrochemical performance than the bulk counterparts. We synthesized graphene analogue of 3D MoS2 hierarchical nanoarchitectures through a facile hydrothermal route. The graphene-like MoS2 nanosheets are uniformly dispersed in an amorphous carbon matrix produced in situ by hydrothermal carbonization. The interlaminar distance between the MoS2 nanosheets is about 1.38 nm, which is far larger than that of bulk MoS2 (0.62 nm). Such a layered architecture is especially beneficial for the intercalation and deintercalation of Li(+). When tested as a lithium-storage anode material, the graphene-like MoS2 hierarchical nanoarchitectures exhibit high specific capacity, superior rate capability, and enhanced cycling performance. This material shows a high reversible capacity of 813.5 mAh g(-1) at a current density of 1000 mA g(-1) after 100 cycles and a specific capacity as high as 600 mAh g(-1) could be retained even at a current density of 4000 mA g( 1). The results further demonstrate that constructing 3D graphene-like hierarchical nanoarchitectures can effectively improve the electrochemical performance of electrode materials. PMID- 23946111 TI - Vascular endothelial growth factor-loaded injectable hydrogel enhances plasticity in the injured spinal cord. AB - We hypothesized that vascular endothelial growth factor (VEGF)-containing hydrogels that gelify in situ after injection into a traumatized spinal cord, could stimulate spinal cord regeneration. Injectable hydrogels composed of 0.5% Pronova UPMVG MVG alginate, supplemented or not with fibrinogen, were used. The addition of fibrinogen to alginate had no effect on cell proliferation in vitro but supported neurite growth ex vivo. When injected into a rat spinal cord in a hemisection model, alginate supplemented with fibrinogen was well tolerated. The release of VEGF that was incorporated into the hydrogel was influenced by the VEGF formulation [encapsulated in microspheres or in nanoparticles or in solution (free)]. A combination of free VEGF and VEGF-loaded nanoparticles was mixed with alginate:fibrinogen and injected into the lesion of the spinal cord. Four weeks post injection, angiogenesis and neurite growth were increased compared to hydrogel alone. The local delivery of VEGF by injectable alginate:fibrinogen based hydrogel induced some plasticity in the injured spinal cord involving fiber growth into the lesion site. PMID- 23946112 TI - Generation of highly effective and stable murine alloreactive Treg cells by combined anti-CD4 mAb, TGF-beta, and RA treatment. AB - The transfer of alloreactive regulatory T (aTreg) cells into transplant recipients represents an attractive treatment option to improve long-term graft acceptance. We recently described a protocol for the generation of aTreg cells in mice using a nondepleting anti-CD4 antibody (aCD4). Here, we investigated whether adding TGF-beta and retinoic acid (RA) or rapamycin (Rapa) can further improve aTreg-cell generation and function. Murine CD4(+) T cells were cultured with allogeneic B cells in the presence of aCD4 alone, aCD4+TGF-beta+RA or aCD4+Rapa. Addition of TGF-beta+RA or Rapa resulted in an increase of CD25(+)Foxp3(+) expressing T cells. Expression of CD40L and production of IFN-gamma and IL-17 was abolished in aCD4+TGF-beta+RA aTreg cells. Additionally, aCD4+TGF-beta+RA aTreg cells showed the highest level of Helios and Neuropilin-1 co-expression. Although CD25(+)Foxp3(+) cells from all culture conditions displayed complete demethylation of the Treg-specific demethylated region, aCD4+TGF-beta+RA Treg cells showed the most stable Foxp3 expression upon restimulation. Consequently, aCD4+TGF-beta+RA aTreg cells suppressed effector T-cell differentiation more effectively in comparison to aTreg cells harvested from all other cultures, and furthermore inhibited acute graft versus host disease and especially skin transplant rejection. Thus, addition of TGF-beta+RA seems to be superior over Rapa in stabilising the phenotype and functional capacity of aTreg cells. PMID- 23946117 TI - Dynamically adaptive characteristics of resonance variation for selectively enhancing electrical performance of organic semiconductors. AB - Increased resonance: The selective tuning of the optoelectronic properties of organic semiconductors is possible by enantiotropic resonance variation. Using resonance forms of N(+)=P-O(-) in a series of arylamine-phosphine oxide hybrids afforded low-voltage-driven phosphorescent OLEDs with outstanding performances. PMID- 23946113 TI - Aerobic iron-based cross-dehydrogenative coupling enables efficient diversity oriented synthesis of coumestrol-based selective estrogen receptor modulators. AB - An iron-based cross-dehydrogenative coupling (CDC) approach was applied for the diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators (SERMs), representing the first application of CDC chemistry in natural product synthesis. The first stage of the two-step synthesis of coumestrol involved a modified aerobic oxidative cross-coupling between ethyl 2 (2,4-dimethoxybenzoyl)acetate and 3-methoxyphenol, with FeCl3 (10 mol%) as the catalyst. The benzofuran coupling product was then subjected to sequential deprotection and lactonization steps, affording the natural product in 59% overall yield. Based on this new methodology other coumestrol analogues were prepared, and their effects on the proliferation of the estrogen receptor (ER) dependent MCF-7 and of the ER-independent MDA-MB-231 breast cancer cells were tested. As a result, new types of estrogen receptor ligands having an acetamide group instead of the 9-hydroxyl group of coumestrol were discovered. Both 9 acetamido-coumestrol and 8-acetamidocoumestrol were found more active than the natural product against estrogen-dependent MCF-7 breast cancer cells, with IC50 values of 30 and 9 nM, respectively. PMID- 23946119 TI - A cost-effectiveness analysis of retropubic midurethral sling versus transobturator midurethral sling for female stress urinary incontinence. AB - AIMS: To compare the cost-effectiveness (CE) of retropubic midurethral sling (RMS) versus transobturator midurethral sling (TMS) for the treatment of female stress urinary incontinence (SUI). METHODS: A Markov chain decision model was created to simulate treatment of SUI with RMS versus TMS. Costing data were obtained from the Medicare RBRVS. Data regarding the efficacy and complications associated with RMS versus TMS was compiled from a literature review of 21 randomized RCTs with a minimum of 12 months follow-up, as were corresponding utilities for different continence states. Deterministic and probabilistic estimates of cost-effectiveness (CE) for each procedure were calculated and compared, and sensitivity analyses were performed. RESULTS: In the base-case deterministic analysis, the efficacy of RMS was 6.275 versus 6.272 QALYs for TMS. QALYs represent a measure of disease burden accounting for both quantity and quality of life lived and are used to assess the monetary value of a medical intervention. The average cost for treatment with RMS however was higher at $9,579 versus $9,017 with TMS. TMS was therefore overall more cost-effective than RMS (CE = $1,438/QALY vs. $1,527/QALY). Sensitivity analysis demonstrated that physician and sling characteristics such as device cost, surgeon fee, efficacy of treatment, operative time, and duration of hospitalization could all affect the relative CE of the therapies. CONCLUSIONS: Our study demonstrated that TMS was more cost-effective than RMS as a treatment for female SUI. The efficacy of the two treatments could be affected by physician and sling characteristic factors. PMID- 23946118 TI - Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene. AB - Dyskeratosis congenita (DC) is a telomere-mediated syndrome defined by mucocutaneous features. The X-linked mode of inheritance accounts for half the cases, and is thought to predominantly manifest in childhood as bone marrow failure. We identified two male probands who presented in the fifth decade with idiopathic pulmonary fibrosis and cancer. Their pedigrees displayed consecutively affected generations. Five of six females (83%) manifested mucocutaneous features of DC, and two had wound-healing complications. No mutations in autosomal dominant telomere genes were present, but exome sequencing revealed novel variants in the X-chromosome DKC1 gene that predicted missense mutations in conserved residues, p.Thr49Ser and p.Pro409Arg. Variants segregated with the telomere phenotype, and affected females were heterozygotes, showing skewed X inactivation. Telomerase RNA levels were compromised in cells from DKC1 mutation carriers, consistent with their pathogenic role. These findings indicate that females with heterozygous DKC1 mutations may be at increased risk for developing penetrant telomere phenotypes that, at times, may be associated with clinical morbidity. PMID- 23946122 TI - Preparation of single-handed helical carbon/silica and carbonaceous nanotubes by using 4,4'-biphenylene-bridged polybissilsesquioxane. AB - Single-handed, helical, 4,4'-biphenylene-bridged polybissilsesquioxane nanotubes were prepared by using the self-assemblies of a pair of chiral low-molecular weight gelators as templates. Single-handed, helical, carbon/silica nanotubes were obtained after carbonization of the self-assemblies, and single-handed helical carbonaceous nanotubes were then obtained by removal of silica with aqueous HF. Samples were characterized by using field-emission SEM, TEM, X-ray diffraction, thermogravimetric analysis, Raman spectroscopy, and circular dichroism. The polysilsesquioxane and carbonaceous structures exhibited optical activity. The walls of the carbon/silica and carbonaceous nanotubes were predominantly amorphous carbon. The surface area of the left-handed, helical, carbonaceous nanotubes was 1439 m(2) g(-1), and such materials have potential applications as catalyst supports, chirality sensors, supercapacitor electrodes, and adsorbents. PMID- 23946123 TI - A high-throughput inhibition screening of major human cytochrome P450 enzymes using an in vitro cocktail and liquid chromatography-tandem mass spectrometry. AB - A sensitive and high-throughput inhibition screening liquid chromatography-mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of five probe metabolites (7-hydroxycoumarin, CYP2A6; 4 hydroxytolbutamide, CYP2C9; 4'-hydroxymephenytoin, CYP2C19; alpha hydroxymetoprolol, CYP2D6; and 1-hydroxymidazolam, CYP3A4) for in vitro cytochrome P450 activity determination in human liver microsome and recombinant. All the metabolites and the internal standard, tramadol, were separated on a Waters 2695 series liquid chromatograph with a Phenomenex Luna C18 column (150 * 2.0 mm, 5 um). Quality control samples and a positive control CYP inhibitor were included in the method. The IC50 values determined for typical CYP inhibitors were reproducible and in agreement with the literature. The method was selective and showed good accuracy (99.13-103.37%), and inter-day (RSD < 6.20%) and intra day (RSD < 6.13%) precision. Also, the incubation extracts of the sample were stable at room temperature (20 degrees C) for 48 h and for 96 h in the autosampler (4 degrees C). The presented method is the first HPLC-MS/MS method of this combination for simultaneous detection of the five metabolites 7 hydroxycoumarin, 4-hydroxytolbutamide, 4'-hydroxymephenytoin, alpha hydroxymetoprolol and 1-hydroxymidazolam in a single-run process. It is possible that the high-quality and -throughput cocktail provides suitable information in drug discovery and screening for new drug entities. PMID- 23946124 TI - Empirical examination of the interpersonal maintenance model of anorexia nervosa. AB - OBJECTIVE: A cognitive interpersonal maintenance model of anorexia nervosa (AN) was first proposed in 2006 and updated in 2013 (Schmidt and Treasure, J Br J Clin Psychol, 45, 343-366, 2006; Treasure and Schmidt, J Eat Disorders, in press.). The aim of this study was to test the interpersonal component of this model in people with AN requiring intensive hospital treatment (inpatient/day patient). METHOD: On admission to hospital women with AN or eating disorder not otherwise specified (AN subtype; n = 152; P) and their primary carers (n = 152; C) completed questionnaires on eating symptoms (P), depression and anxiety (P, C), accommodation and enabling (C), and psychological control (C). Structural equation modeling was used to examine relationships among these components. RESULTS: Carers' expressed emotion and level of psychological control were significantly related to carers' distress, which in turn, was related to patients' distress. This pathway significantly predicted eating symptoms in patients. DISCUSSION: The cognitive interpersonal maintenance model of eating disorders (EDs) was confirmed in part and suggests that interventions targeting interpersonal maintaining factors such as carer distress might impact on patient outcomes. PMID- 23946125 TI - Global and local structural similarity in protein-protein complexes: implications for template-based docking. AB - The increasing amount of structural information on protein-protein interactions makes it possible to predict the structure of protein-protein complexes by comparison/alignment of the interacting proteins to the ones in cocrystallized complexes. In the predictions based on structure similarity, the template search is performed by structural alignment of the target interactors with the entire structures or with the interface only of the subunits in cocrystallized complexes. This study investigates the scope of the structural similarity that facilitates the detection of a broad range of templates significantly divergent from the targets. The analysis of the target-template similarity is based on models of protein-protein complexes in a large representative set of heterodimers. The similarity of the biological and crystal packing interfaces, dissimilar interface structural motifs in overall similar structures, interface similarity to the full structure, and local similarity away from the interface were analyzed. The structural similarity at the protein-protein interfaces only was observed in ~25% of target-template pairs with sequence identity <20% and primarily homodimeric templates. For ~50% of the target-template pairs, the similarity at the interface was accompanied by the similarity of the whole structure. However, the structural similarity at the interfaces was still stronger than that of the noninterface parts. The study provides insights into structural and functional diversity of protein-protein complexes, and relative performance of the interface and full structure alignment in docking. PMID- 23946126 TI - Cisplatin otoprotection using transtympanic L-N-acetylcysteine: a pilot randomized study in head and neck cancer patients. AB - OBJECTIVES/HYPOTHESIS: To evaluate the feasibility and efficacy of transtympanic L-N-Acetylcysteine (L-NAC) administration in patients receiving cisplatin chemotherapy for head and neck cancer. STUDY DESIGN: Prospective randomized nonblinded open-label clinical trial. METHODS: Transtympanic 2% L-NAC was administered to one randomly selected ear with the other ear as control in each patient. Primary outcome parameter was the difference in the loss of pure tone averages (PTA) at 2, 4, and 8 kHz between the L-NAC and control ear at 1 to 2 months following chemotherapy. RESULTS: Eleven patients completed the study, with two patients demonstrating significantly better hearing in the L-NAC treated ear (18.2%). However, for the overall group, the difference in hearing preservation did not reach significance. Two percent L-NAC administration was well tolerated in this patient population. There were no adverse effects associated with L-NAC. CONCLUSION: Although the study did not demonstrate a significant benefit overall, transtympanic L-NAC was associated with significantly better hearing in two patients. Better delivery methods may improve the efficacy of this treatment. L NAC remains a promising drug in preventing cisplatin-induced ototoxicity. PMID- 23946130 TI - Agglomeration of mesoporous silica by melt and steam granulation. part II: screening of steam granulation process variables using a factorial design. AB - The objectives of this study were to identify the key process parameters during steam granulation of disordered mesoporous silica material Syloid(r) 244 FP (244) and to compare two different binders: polyvinylpyrrolidone (PVP) K25 and hydroxypropylmethyl cellulose (HPMC). Itraconazole (ITZ) was selected as the model compound for the development of an oral dosage form for enhanced release. Six factors: binder content, steam amount, mixing time, impeller speed, spray pause time, and filler content were investigated using a two-level quarter fraction factorial design of experiment (DOE) for each binder type. As experimental responses, characteristics correlating to both granules and tablets were selected. Granules prepared from PVP resulted in an overall higher bulk density, granule size, increased flow properties, and better compression and compaction behavior. Although granulation with PVP resulted in the most ITZ to extract from the pores during processing, the premature drug release was less than 5%. The results of the DOE indicate that the risk of extracting the drug from the pores during processing is governed both by the process parameters and the binder properties. Centerpoint replicates of granules prepared with HPMC were highly variable. PMID- 23946131 TI - Solar fuels: photoelectrosynthesis of CO from CO2 at p-type Si using Fe porphyrin electrocatalysts. AB - Photoelectrocatalytic conversion of CO2 to CO can be driven at a boron-doped, hydrogen terminated, p-type silicon electrode using a meso-tetraphenylporphyrin Fe(III) chloride in the presence of CF3CH2OH as a proton source and 0.1 M [NBu4][BF4]/MeCN/5% DMF (v/v) as the electrolyte. Under illumination with polychromatic light, the photoelectrocatalysis operates with a photovoltage of about 650 mV positive of that for the dark reaction. Carbon monoxide is produced with a current efficiency >90% and with a high selectivity over H2 formation. Photoelectrochemical current densities of 3 mA cm(-2) at -1.1 V versus SCE are typical, and 175 turnovers have been attained over a 6 h period. Cyclic voltammetric data are consistent with a turnover frequency of k(Si)(obs)=0.24*10(4) s(-1) for the photoelectrocatalysis at p-type Si at -1.2 V versus SCE this compares with k(Si)(obs)=1.03*10(4) s(-1) for the electrocatalysis in the dark on vitreous carbon at a potential of -1.85 V versus SCE. PMID- 23946132 TI - Serum albumin-protamine conjugate for biocompatible platform for targeted delivery of therapeutic macromolecules. AB - A well-defined, one-to-one conjugate between human serum albumin (HSA) and protamine was synthesized and characterized as a biocompatible carrier for macromolecules. In circulation, the conjugate will camouflage drug molecules upon complex formation, while liberating free drug at the desired location using a triggering mechanism. The N-terminus of protamine was thiolated and conjugated with the unpaired Cysteine-34 of HSA, and was purified by ion-exchange chromatography. The molecular weight of the conjugate was 70.8 kDa, confirming one-to-one conjugation between HSA (66.6 KDa) and protamine (4200 Da). Superimposed fluorescence spectra of native HSA and HSA-protamine conjugate indicated no conformational change around the Trp-214. The conjugate had marked reduction in hemolytic and cytotoxic properties compared to protamine. When therapeutic potential was tested using tissue plasminogen activator as a model drug, HSA-protamine conjugate suppressed the enzymatic activity by 65%, which was fully recovered by a triggering agent, heparin. The construct showed binding characteristics with activated platelets upon conjugation with a targeting peptide, demonstrating flexibility to introduce suitable homing moiety on the surface. The camouflaged construct retained triggered release property in human plasma condition. Overall, the conjugate has a good potential to serve as a biocompatible platform for macromolecular drugs. PMID- 23946134 TI - Childhood orbital soft tissue sarcoma in xeroderma pigmentosum with good tolerance to chemotherapy and radiotherapy. PMID- 23946135 TI - Ruthenium-catalyzed direct methylation of primary and secondary aromatic amines using carbon dioxide and molecular hydrogen. PMID- 23946136 TI - A bloodless coup?: Already a force in forensic pathology, virtual autopsies may be edging toward the hospital. PMID- 23946137 TI - A systematic approach to emergent breast free flap takeback: Clinical outcomes, algorithm, and review of the literature. AB - BACKGROUND: Few evidence-based and detailed algorithms exist on the management of failing breast free flaps, including use of the numerous salvage tools that are available. The purpose of this study was to analyze our outcomes with an algorithmic approach to breast free flap salvage after vascular compromise. A review of the literature is also presented. METHODS: A retrospective review of all breast free flaps performed at our institution between 2007 and 2012 was performed. Flaps with intraoperative and postoperative vascular complications were analyzed. RESULTS: A total of 612 microsurgical breast reconstructions in 442 patients were reviewed. Of these, 72 (11.8%) flaps had intraoperative vascular complications, and 36 (5.9%) had postoperative vascular complications. The total flap loss rate was 2.8%. The most commonly used salvage modalities were anastomotic revision (72%), heparin irrigation (72%), systemic heparin (37%), Fogarty catheter thrombectomy (17.6%), thrombolytics (13%), and indocyanine green angiography (10.2%). In 53 (49.1%) cases, flap salvage involved use of 1 modality, whereas in 55 (50.9%) cases multiple modalities were used. Factors associated with failure of these flap salvage tools included intraoperative arterial rather than postoperative arterial compromise (P = 0.01), and situations requiring use of a greater number of salvage modalities (P < 0.001). CONCLUSIONS: We found that intraoperative compromise had significantly better prognosis than postoperative compromise. By organizing the numerous salvage modalities available to microsurgeons into a well-defined algorithm that is supported by the literature, we have established a best practices protocol that has achieved flap salvage rates that compare favorably to the published literature. PMID- 23946133 TI - Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations. AB - This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ~2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials. PMID- 23946139 TI - Do end of treatment assessments predict outcome at follow-up in eating disorders? AB - OBJECTIVE: To examine the predictive value of end of treatment (EOT) outcomes for longer term recovery status. METHOD: We used signal detection analysis to identify the best predictors of recovery based on outcome at EOT using five different eating disorder samples from randomized clinical treatment trials. We utilized a transdiagnostic definition of recovery that included normalization of weight and eating related psychopathology. RESULTS: Achieving a body weight of 95.2% of expected body weight by EOT is the best predictor of recovery for adolescents with anorexia nervosa (AN). For adults with AN, the most efficient predictor of weight recovery (BMI > 19) was weight gain to greater than 85.8% of ideal body weight. In addition, for adults with AN, the most efficient predictor of psychological recovery was achievement of an eating disorder examination (EDE) weight concerns score below 1.8. The best predictor of recovery for adults with Bulimia Nervosa (BN) was a frequency of compensatory behaviors less than two times a month. For adolescents with BN, abstinence from purging and reduction in the EDE restraint score of more than 3.4 from baseline to EOT were good predictors of recovery. For adults with binge eating disorder, reduction of the Global EDE score to within the normal range (<1.58) was the best predictor of recovery. DISCUSSION: The relationship between EOT response and recovery remains understudied. Utilizing a transdiagnostic definition of recovery, no uniform predictors were identified across all eating disorder diagnostic groups. PMID- 23946138 TI - A homozygous SLITRK6 nonsense mutation is associated with progressive auditory neuropathy in humans. AB - OBJECTIVES/HYPOTHESIS: SLITRK family proteins control neurite outgrowth and regulate synaptic development. In mice, Slitrk6 plays a role in the survival and innervation of sensory neurons in the inner ear, vestibular apparatus, and retina, and also influences axial eye length. We provide the first detailed description of the auditory phenotype in humans with recessive SLITRK6 deficiency. STUDY DESIGN: Prospective observational case study. METHODS: Nine closely related Amish subjects from an endogamous Amish community of Pennsylvania underwent audiologic and vestibular testing. Single nucleotide polymorphism microarrays were used to map the chromosome locus, and Sanger sequencing or high resolution melt analysis were used to confirm the allelic variant. RESULTS: All nine subjects were homozygous for a novel nonsense variant of SLITRK6 (c.1240C>T, p.Gln414Ter). Adult patients had high myopia. The 4 oldest SLITRK6 c.1240C>T homozygotes had absent ipsilateral middle ear muscle reflexes (MEMRs). Distortion product otoacoustic emissions (DPOAEs) were absent in all ears tested and the cochlear microphonic (CM) was increased in amplitude and duration in young patients and absent in the two oldest subjects. Auditory brainstem responses (ABRs) were dys-synchronised bilaterally with no reproducible waves I, III, or V at high intensities. Hearing loss and speech reception thresholds deteriorated symmetrically with age, which resulted in severe-to-profound hearing impairment by early adulthood. Vestibular evoked myogenic potentials were normal in three ears and absent in one. CONCLUSION: Homozygous SLITRK6 c.1240C>T (p.Gln414Ter) nonsense mutations are associated with high myopia, cochlear dysfunction attributed to outer hair cell disease, and progressive auditory neuropathy. PMID- 23946140 TI - Measuring abusive behaviors: is economic abuse a unique form of abuse? AB - Recent attention has been given by researchers to exploring economic abuse strategies used by abusers. However, little research has been conducted to understanding how to conceptualize economic abuse in relation to other forms of abuse. This article examines the factor structure of abusive items from the Scale of Economic Abuse--12 and the Abusive Behavior Inventory through confirmatory factor analyses using data collected with 457 female survivors of abuse. The findings provide evidence for conceptualizing economic abuse as a unique form of abuse moderately correlated with psychological, physical, and sexual forms of abuse. PMID- 23946142 TI - Chiral chromatographic resolution of antiepileptic drugs and their metabolites: a challenge from the optimization to the application. AB - A large number of the antiepileptic drugs (AEDs) presently available for clinical practice are chiral compounds while others, although achiral, may originate pharmacologically active chiral metabolites in vivo. The well-known implications of chirality in pharmacokinetics and pharmacodynamics demand the investigation of pharmacological properties for a racemic mixture and each enantiomer. To achieve these objectives, appropriate chiral analytical methods must be available. This article provides the first review of the current state of the art in chiral chromatographic methods available for quantifying enantiomers of AEDs in distinct matrices. Particular attention is paid to the methodological aspects and optimization strategies that successfully allow enantiomeric chromatographic separation of chiral AEDs and/or metabolites. Furthermore, the relevance of these methods in supporting the discovery and development of chiral AEDs is emphasized. In parallel and whenever available, the principal validation parameters are herein considered and related to the stage of drug discovery and development. In an attempt to optimize anticonvulsant activity and simultaneously diminish toxic effects, many pharmaceutical companies have started to manufacture single enantiomers. Therefore, chiral chromatographic techniques will be essential and the information herein compiled can be used as a framework for developing them. PMID- 23946141 TI - Substance use and intimate partner violence victimization among White, African American, and Latina women. AB - The existing literature on intimate partner violence (IPV) does not paint a consistent portrait of the impact of race/ethnicity. In addition, although research has clearly demonstrated that there is a relationship between substance use and IPV, the temporal ordering of these variables is not clearly established. This article seeks to examine the temporal ordering of IPV victimization and drug use using longitudinal data with a nationally representative racially and ethnically diverse sample. Data from Wave III (2001-2002) and Wave IV (2007-2008) of the National Longitudinal Study of Adolescent Health (Add Health) will serve as Time 1 and Time 2, respectively, to answer three research questions. First, does substance use during early young adulthood (Time 1) predict IPV victimization during young adulthood (Time 2) among women? Second, does IPV victimization during early young adulthood predict substance use during young adulthood for women? Finally, do these bidirectional relationships vary by race/ethnicity (i.e., White, African American, and Latina)? Four different forms of IPV (minor violence, major violence, rape/sexual coercion, and injury) are investigated along with binge drinking, marijuana use, and other drug use. Understanding not only the temporal relationship between substance use, trauma, and IPV but also the racial and ethnic differences in these relationships is critical to developing and refining culturally sensitive trauma-informed prevention and treatment services for women. PMID- 23946143 TI - Agglomeration of mesoporous silica by melt and steam granulation. Part I: a comparison between disordered and ordered mesoporous silica. AB - The objective of this study was to compare agglomerations by melt and steam granulation of ordered, COK-12, and disordered, Syloid((r)) 244 FP (244), mesoporous silica material. Poloxamer 188 (P188) and polyvinylpyrrolidone K25 (PVP) were chosen as binders for melt and steam granulation, respectively. The poorly water-soluble compound, itraconazole (ITZ), was selected for the development of an immediate-release oral dosage form. Steam granulation resulted in the largest granules, however, the slowest release. Compression behavior and tablet properties of steam-granulated material prepared with COK-12 and 244 were similar. As determined by X-ray powder diffraction, melt granulation resulted in the most ITZ to extract from the pores during processing. However, the enhanced release rate was still maintained when compared with the crystalline form. Moreover, no additional drug extraction was observed following the 6 month storage in 25 degrees C/60% relative humidity (RH) and 40 degrees C/75%RH. P188 diffraction peaks were present in the 244 melt-granulated material, but disappeared because of the degradation following 1 week in 40 degrees C/75%RH conditions. The differential scanning calorimetry analysis indicated that the degradation of P188 already occurred during the granulation process itself. Based on these results, steam granulation with PVP is the preferred method over melt granulation with P188. PMID- 23946145 TI - Sequential one-pot addition of excess aryl-Grignard reagents and electrophiles to O-alkyl thioformates. AB - The sequential addition of aromatic Grignard reagents to O-alkyl thioformates proceeded to completion within 30 s to give aryl benzylic sulfanes in good yields. This reaction may begin with the nucleophilic attack of the Grignard reagent onto the carbon atom of the O-alkyl thioformates, followed by the elimination of ROMgBr to generate aromatic thioaldehydes, which then react with a second molecule of the Grignard reagent at the sulfur atom to form arylsulfanyl benzylic Grignard reagents. To confirm the generation of aromatic thioaldehydes, the reaction between O-alkyl thioformates and phenyl Grignard reagent was carried out in the presence of cyclopentadiene. As a result, hetero-Diels-Alder adducts of the thioaldehyde and the diene were formed. The treatment of a mixture of the thioformate and phenyl Grignard reagent with iodine gave 1,2-bis(phenylsulfanyl) 1,2-diphenyl ethane as a product, which indicated the formation of arylsulfanyl benzylic Grignard reagents in the reaction mixture. When electrophiles were added to the Grignard reagents that were generated in situ, four-component coupling products, that is, O-alkyl thioformates, two molecules of Grignard reagents, and electrophiles, were obtained in moderate-to-good yields. The use of silyl chloride or allylic bromides gave the adducts within 5 min, whereas the reaction with benzylic halides required more than 30 min. The addition to carbonyl compounds was complete within 1 min and the use of lithium bromide as an additive enhanced the yields of the four-component coupling products. Finally, oxiranes and imines also participated in the coupling reaction. PMID- 23946144 TI - Development of an elastic cell culture substrate for a novel uniaxial tensile strain bioreactor. AB - Bioreactors can be used for mechanical conditioning and to investigate the mechanobiology of cells in vitro. In this study a polyurethane (PU), Chronoflex AL, was evaluated for use as a flexible cell culture substrate in a novel bioreactor capable of imparting cyclic uniaxial tensile strain to cells. PU membranes were plasma etched, across a range of operating parameters, in oxygen. Contact angle analysis and X-ray photoelectron spectroscopy showed increases in wettability and surface oxygen were related to both etching power and duration. Atomic force microscopy demonstrated that surface roughness decreased after etching at 20 W but was increased at higher powers. The etching parameters, 20 W 40 s, produced membranes with high surface oxygen content (21%), a contact angle of 66 degrees +/- 7 degrees and reduced topographical features. Etching and protein conditioning membranes facilitated attachment, and growth to confluence within 3 days, of MG-63 osteoblasts. After 2 days with uniaxial strain (1%, 30 cycles/min, 1500 cycles/day), cellular alignment was observed perpendicular to the principal strain axis, and found to increase after 24 h. The results indicate that the membrane supports culture and strain transmission to adhered cells. PMID- 23946146 TI - End-to-side venous anastomosis with an anastomotic coupling device coupler: the flower petal stenting technique. PMID- 23946147 TI - Automated acoustic analysis of task dependency in adductor spasmodic dysphonia versus muscle tension dysphonia. AB - OBJECTIVES/HYPOTHESIS: Distinguishing muscle tension dysphonia (MTD) from adductor spasmodic dysphonia (ADSD) can be difficult. Unlike MTD, ADSD is described as "task-dependent," implying that dysphonia severity varies depending upon the demands of the vocal task, with connected speech thought to be more symptomatic than sustained vowels. This study used an acoustic index of dysphonia severity (i.e., the Cepstral Spectral Index of Dysphonia [CSID]) to: 1) assess the value of "task dependency" to distinguish ADSD from MTD, and to 2) examine associations between the CSID and listener ratings. STUDY DESIGN: Case-Control Study. METHODS: CSID estimates of dysphonia severity for connected speech and sustained vowels of patients with ADSD (n = 36) and MTD (n = 45) were compared. The diagnostic precision of task dependency (as evidenced by differences in CSID estimated dysphonia severity between connected speech and sustained vowels) was examined. RESULTS: In ADSD, CSID-estimated severity for connected speech (M = 39. 2, SD = 22.0) was significantly worse than for sustained vowels (M = 29.3, SD = 21.9), [P = .020]. Whereas in MTD, no significant difference in CSID-estimated severity was observed between connected speech (M = 55.1, SD = 23.8) and sustained vowels (M = 50.0, SD = 27.4), [P = .177]. CSID evidence of task dependency correctly identified 66.7% of ADSD cases (sensitivity) and 64.4% of MTD cases (specificity). CSID and listener ratings were significantly correlated. CONCLUSION: Task dependency in ADSD, as revealed by differences in acoustically derived estimates of dysphonia severity between connected speech and sustained vowel production, is a potentially valuable diagnostic marker. PMID- 23946148 TI - Improved chiral SFC screening for analytical method development. AB - In this study we describe the evaluation of a recently developed supercritical fluid chromatography (SFC) instrument for automated chiral SFC method development. The greatly improved gradient dwell volume and liquid flow control of the new instrument in combination with the use of shorter columns containing smaller stationary phase particles affords chiral SFC method development that is faster and more universal than previous systems. PMID- 23946151 TI - A study of cortical morphology in children with fetal alcohol spectrum disorders. AB - Prenatal alcohol exposure is responsible for a broad range of brain structural malformations, which can be studied using magnetic resonance imaging (MRI). Advanced MRI methods have emerged to characterize brain abnormalities, but the teratogenic effects of alcohol on cortical morphology have received little attention to date. Twenty-four 9-year-old children with fetal alcohol spectrum disorders (9 with fetal alcohol syndrome, 15 heavy exposed nonsyndromal children) and 16 age-matched controls were studied to assess the effect of alcohol consumption during pregnancy on cortical morphology. An automated method was applied to 3D T1-weighted images to assess cortical gyrification using global and regional sulcal indices and two region-based morphological measurements, mean sulcal depth and fold opening. Increasing levels of alcohol exposure were related to reduced cortical folding complexity, even among children with normal brain size, indicating a reduction of buried cortical surface. Fold opening was the strongest anatomical correlate of prenatal alcohol intake, indicating a widening of sulci in all regions that were examined. These data identify cortical morphology as a suitable marker for further investigation of brain damage associated with prenatal alcohol exposure. PMID- 23946153 TI - A one-pot synthesis of a triblock copolymer from propylene oxide/carbon dioxide and lactide: intermediacy of polyol initiators. AB - Just add water: The copolymerization of propylene oxide and CO2 catalyzed by a cobalt complex is tolerant to the addition of water as chain-transfer reagent to afford polyols (HO-(PPC)-OH) with narrow molecular weight distributions (see picture; PPC=poly(propylene carbonate); PLA=polylactide). The addition of an organocatalyst to these polyols in the presence of lactides produces well-defined triblock copolymers (PLA-b-PPC-b-PLA). PMID- 23946152 TI - Effect of ritonavir-boosted danoprevir, a potent hepatitis C virus protease inhibitor, on the pharmacokinetics of methadone in healthy subjects undergoing methadone maintenance therapy. AB - STUDY OBJECTIVE: To investigate the steady-state pharmacokinetics of methadone when coadministered with ritonavir-boosted danoprevir (DNVr). DESIGN: Open-label, two-period, single-sequence pharmacokinetic study. SETTING: Two U.S. research centers. PATIENTS: Eighteen methadone-maintained healthy adults. MEASUREMENTS AND MAIN RESULTS: In Period 1 (Day -1), subjects received their daily methadone maintenance therapy (MMT). In Period 2 (Days 1-10), subjects received MMT plus DNVr 100/100 mg twice/day. Pharmacokinetic parameters for the total concentrations of (R)- and (S)-methadone on Days -1 and 10 were determined using noncompartmental methods. Unbound (R)- and (S)-methadone concentrations at 3 hours postdose were also assessed on Days -1 and 10. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare steady-state (R)- and (S) methadone pharmacokinetics when MMT was administered with or without DNVr. Methadone withdrawal was assessed using the Subjective Opiate Withdrawal Scale. Compared with MMT alone, methadone AUCtau and Cmax GMR (90% CI) following coadministration with DNVr were 1.02 (0.91-1.15) and 1.01 (0.90-1.13) for (R) methadone, and 1.01 (0.90-1.13) and 0.99 (0.89-1.10) for (S)-methadone, respectively. Unbound (R- and (S)-methadone concentrations were comparable with or without DNVr. No instances of methadone withdrawal were reported. MMT in combination with DNVr was well tolerated. CONCLUSION: Coadministration of DNVr with MMT resulted in no significant pharmacokinetic interactions or signs of methadone withdrawal. No dosage adjustment is needed for MMT when coadministered with DNVr. PMID- 23946154 TI - Synthesis and crystal structure of anhydrous analog of 1,25-dihydroxyvitamin d3. AB - As predicted by single crystal X-ray crystallography, and contrary to the reported suggestions, the anhydrous form of calcipotriol, a therapeutically important vitamin D analog, was found stable enough to be used as an active pharmaceutical ingredient. The crystal and molecular structure of calcipotriol anhydrate was solved and refined using single crystal X-ray diffraction. The analog was obtained by a novel convergent synthesis from the vitamin D C-22 sulfone, as an advanced intermediate and a side-chain fragment. The homo-chiral side-chain aldehyde was obtained from cyclopropanecarboxyaldehyde by the chromatographic separation of the intermediate diastereomeric salts with (S) naproxen. Calcipotriol anhydrate showed a single peak in differential scanning calorimetry and the absence of a peak from a water molecule, typical for the monohydrate. Calcipotriol anhydrate, as the only 1,25-dihydroxylated analog of vitamin D3 , exists as a mixture of both alpha- and beta-forms of the A-ring, present in the asymmetric part of the unit cell of the crystal lattice. The intermolecular hydrogen bonding between both conformers in the crystal lattice indicated that the stability of calcipotriol anhydrate might be at least the same as for the known monohydrate. The usefulness of calcipotriol anhydrate as an active pharmaceutical ingredient was confirmed by the stability study in the standard conditions used for the storage of vitamin D analogs. PMID- 23946155 TI - The effect of mobile phase composition in the enantioseparation of pharmaceutically relevant compounds with polysaccharide-based stationary phases. AB - Mobile phase variables have a deep influence on the chromatographic behavior with polysaccharide-based chiral stationary phases. Basic additives are generally used to minimize peak broadening arising from unwanted interactions between polar solutes and underivatized silanols. However, basic additives can improve enantioselectivity through disruption of hydrogen bonds and modification of the polymer morphology. Acidic additives are incorporated into the mobile phase during the analysis of acidic compounds as efficiency enhancers. Acidic additives can also improve enantioselectivity by minimizing within the chiral recognition site nonenantioselective retention. Peak shape without acidic additive in the eluent could be severely distorted during the analysis of salified compounds. Concentration and type of alcohol modifier can have an effect on the morphology of the polymer. The different winding of the chiral selector, caused by alcohol modifiers of different size/shape, ultimately results in different stereo environment of the chiral cavities in the polymer chain. Trace amounts of water in normal-phase eluents can affect retention time, tailing, and resolution. Deliberate addition of water to the eluent can improve peak resolution and save analysis time and solvent needs. Immobilized-type polysaccharide-derived chiral stationary phases offer new selectivity profiles and often improved enantioselectivity. PMID- 23946156 TI - Optimized butyl butyrate synthesis catalyzed by Thermomyces lanuginosus lipase. AB - Butyl butyrate is an ester present in pineapple flavor, which is very important for the food and beverages industries. In this work, the optimization of the reaction of butyl butyrate synthesis catalyzed by the immobilized lipase Lipozyme TL-IM was performed. n-Hexane was selected as the most appropriate solvent. Other reaction parameters such as temperature, substrate molar ratio, biocatalyst content and added water, and their responses measured as yield, were evaluated using a fractional factorial design, followed by a central composite design (CCD) and response surface methodology. In the fractional design 2(4-1) , the four variables were tested and temperature and biocatalyst content were statistically significant and then used for optimization on CCD. The optimal conditions for butyl butyrate synthesis were found to be 48 degrees C; substrate molar ratio 3:1 (butanol:butyric acid); biocatalyst content of 40% of acid mass. Under these conditions, over 90% of yield was obtained in 2 h. Enzyme reuse was tested by washing the biocatalyst with n-hexane or by direct reuse. The direct reuse produced a rapid decrease on enzyme activity, while washing with n-hexane allowed reusing the enzyme for five reactions cycles keeping approximately 85% of its activity. PMID- 23946157 TI - Novel processing of bioglass ceramics from silicone resins containing micro- and nano-sized oxide particle fillers. AB - Highly porous scaffolds with composition similar to those of 45S5 and 58S bioglasses were successfully produced by an innovative processing method based on preceramic polymers containing micro- and nano-sized fillers. Silica from the decomposition of the silicone resins reacted with the oxides deriving from the fillers, yielding glass ceramic components after heating at 1000 degrees C. Despite the limited mechanical strength, the obtained samples possessed suitable porous architecture and promising biocompatibility and bioactivity characteristics, as testified by preliminary in vitro tests. PMID- 23946158 TI - Duplicated facial nerve trunk with a first branchial cleft cyst. AB - OBJECTIVES/HYPOTHESIS: First branchial cleft anomalies are rare and their various anatomical relationships to the facial nerve have been described. We encountered a 15-year-old female with a type II first branchial cleft cyst presenting as a right neck mass that we found during surgical excision to transverse two main facial nerve trunks. To our knowledge, this is the first reported case of a first branchial cleft anomaly in conjunction with a duplicated facial nerve trunk. PMID- 23946159 TI - A non-parametric permutation method for assessing agreement for distance matrix observations. AB - Distance matrix data are occurring ever more frequently in medical research, particularly in fields such as genetics, DNA research, and image analysis. We propose a non-parametric permutation method for assessing agreement when the data under study are distance matrices. We apply agglomerative hierarchical clustering and accompanying dendrograms to visualize the internal structure of the matrix observations. The accompanying test is based on random permutations of the elements within individual matrix observations and the corresponding matrix mean of these permutations. We compare the within-matrix element sum of squares (WMESS) for the observed mean against the WMESS for the permutation means. The methodology is exemplified using simulations and real data from magnetic resonance imaging. PMID- 23946160 TI - Dehydrogenation of amine-borane Me2NH.BH3 catalyzed by a lanthanum-hydride complex. AB - The rare-earth-metal-hydride complexes [{(1,7-Me2TACD)LnH}4] (Ln=La 1 a, Y 1 b; (1,7-Me2TACD)H2 =1,7-dimethyl-1,4,7,10-tetraazacyclododecane, 1,7-Me2[12]aneN4) were synthesized by hydrogenolysis of [{(1,7-Me2TACD)Ln(eta(3)-C3H5)}2] with 1 bar H2. The tetrameric structures were confirmed by (1)H NMR spectroscopy and single-crystal X-ray diffraction of compound 1 a. Both complexes catalyze the dehydrogenation of secondary amine-borane Me2NH.BH3 to afford the cyclic dimer (Me2NBH2)2 and (Me2N)2BH under mild conditions. Whilst the complete conversion of Me2NH.BH3 was observed within 2 h with lanthanum-hydride 1 a, the yttrium homologue 1 b required 48 h to reach 95% conversion. Further reactions of compound 1 a with Me2NH.BH3 in various stoichiometric ratios gave a series of intermediate products, [{(1,7-Me2TACD)LaH}4](Me2NBH2)2 (2 a), [(1,7 Me2TACDH)La(Me2NBH3)2] (3 a), [(1,7-Me2TACD)(Me2NBH2)La(Me2NBH3)] (4 a), and [(1,7-Me2TACD)(Me2NBH2)2La(Me2NBH3)] (5 a). Complexes 2 a, 3 a, and 5 a were isolated and characterized by multinuclear NMR spectroscopy and single-crystal X ray diffraction studies. These intermediates revealed the activation and coordination modes of "Me2NH.BH3 " fragments that were trapped within the coordination sphere of a rare-earth-metal center. PMID- 23946161 TI - The effect of learning curve on flap selection, re-exploration, and salvage rates in free flaps; A retrospective analysis of 155 cases. AB - The purpose of this study is to report our experience and learning curve in avoiding complications at both the recipient and donor sites as well in choosing the best flap for different anatomic locations. For this purpose 155 free flaps done between October 2005 and August 2012 were retrospectively examined. Patient demographics, flap types, etiology, re-exploration indications, timing of the re explorations, and salvage rates were documented. In the first 60 cases, our re exploration rate was 26.7% (16 flaps), and the rate decreased to 15.0% for the second 60 flaps (9 flaps). In correlation with this decrease, in the last 35 cases, only three flaps were re-explored (8.6%). This decrease in re-exploration rates over time was statistically significant (P = 0.021). Re-exploration rates for axial and perforator flaps were 14.6% and 22.7%, respectively. Salvage rates were 76.9% in axial flaps and 53.3% in perforator flaps. The total success rate for axial flaps was 95.5% and for perforator flaps was 89.4%. Besides, re exploration rates were higher with lower salvage rates in perforator flaps compared to axial flaps causing lower overall success rates in the former group. The mean time of re-explorations was 21.4 hours. Salvage rates were significantly higher in re-explorations done within the first 12 hours after the initial surgery than in re-explorations done after 12 hours (83.3% vs. 47.3%) (P = 0.040). We can conclude that axial flaps have a steeper learning curve and are safer options for the inexperienced reconstructive micro-surgeons until they have adequate experience with the perforator dissection. PMID- 23946162 TI - Carbon-11 radiolabeling of an oligopeptide containing tryptophan hydrochloride via a Pictet-Spengler reaction using carbon-11 formaldehyde. AB - A procedure for the synthesis of a(11)C-labeled oligopeptide containing [1 (11)C]1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid ([1-(11)C]Tpi) from the corresponding Trp*HCl-containing peptides has been developed involving a Pictet Spengler reaction with [(11) C]formaldehyde. The synthesis of [1-(11)C]Tpi from Trp and [(11)C]formaldehyde was examined as a model reaction with the aim of developing a facile and effective method for the labeling of peptides with carbon 11. The Pictet-Spengler reaction of Trp and [(11)C]formaldehyde in acidic media (TsOH or HCl) afforded the desired [1-(11)C]Tpi in a moderate radiochemical yield. Herein, the application of a Pictet-Spengler reaction to an aqueous solution of Trp*HCl gave the desired product with a radiochemical yield of 45.2%. The RGD peptide cyclo[Arg-Gly-Asp-D-Tyr-Lys] was then selected as a substrate for the labeling reaction with [(11)C]formaldehyde. The radiolabeling of a Trp*HCl containing RGD peptide using the Pictet-Spengler reaction was successful. Furthermore, the remote-controlled synthesis of a [1-(11)C]Tpi-containing RGD peptide was attempted by using an automatic production system to generate [(11)C]CH3 I. The radiochemical yield of the [1-(11) C]Tpi-containing RGD at the end of synthesis (EOS) was 5.9 +/- 1.9% (n = 4), for a total synthesis time of about 35 min. The specific activity was 85.7 +/- 9.4 GBq/umol at the EOS. PMID- 23946163 TI - LEGO-NMR spectroscopy: a method to visualize individual subunits in large heteromeric complexes. AB - Seeing the big picture: Asymmetric macromolecular complexes that are NMR active in only a subset of their subunits can be prepared, thus decreasing NMR spectral complexity. For the hetero heptameric LSm1-7 and LSm2-8 rings NMR spectra of the individual subunits of the complete complex are obtained, showing a conserved RNA binding site. This LEGO-NMR technique makes large asymmetric complexes accessible to detailed NMR spectroscopic studies. PMID- 23946164 TI - A novel porous bioceramics scaffold by accumulating hydroxyapatite spherulites for large bone tissue engineering in vivo. II. Construct large volume of bone grafts. AB - In vivo engineering of bone autografts using bioceramic scaffolds with appropriate porous structures is a potential approach to prepare autologous bone grafts for the repair of critical-sized bone defects. This study investigated the evolutionary process of osteogenesis, angiogenesis, and compressive strength of bioceramic scaffolds implanted in two non-osseous sites of dogs: the abdominal cavity and the dorsal muscle. Hydroxyapatite (HA) sphere-accumulated scaffolds with controlled porous structures were prepared and placed in the two sites for up to 6 months. Analyses of retrieved scaffolds found that osteogenesis and angiogenesis were faster in scaffolds implanted in dorsal muscles compared with those placed in abdominal cavities. The abdominal cavity, however, can accommodate larger bone grafts with designed shape. Analyses of scaffolds implanted in abdominal cavities [an environment of a low mesenchymal stem cell (MSC) density] further demonstrated that angiogenesis play critical roles during osteogenesis in the scaffolds, presumably by supplying progenitor cells and/or MSCs as seed cells. This study also examined the relationship between the volume of bone grafts and the physiological environment of in vivo bioreactor. These results provide basic information for the selection of appropriate implanting sites and culture time required to engineer autologous bone grafts for the clinical bone defect repair. Based on these positive results, a pilot study has applied the grafts constructed in canine abdominal cavity to repair segmental bone defect in load-bearing sites (limbs). PMID- 23946165 TI - Lyophilization process design space. AB - The application of key elements of quality by design (QbD), such as risk assessment, process analytical technology, and design space, is discussed widely as it relates to freeze-drying process design and development. However, this commentary focuses on constructing the Design and Control Space, particularly for the primary drying step of the freeze-drying process. Also, practical applications and considerations of claiming a process Design Space under the QbD paradigm have been discussed. PMID- 23946166 TI - Stereoselective halocyclization of alkenes with N-acyl hemiaminal nucleophiles. AB - Halocyclization of alkenes was realized using N-acylhemiaminal nucleophiles. High diastereoselectivity could be achieved for the formation of three stereogenic centers in this halogen-mediated cyclization reaction. We also demonstrated that enantioselective bromocyclization of alkenes using N-acylhemiaminal nucleophiles was possible. PMID- 23946167 TI - Application of TLC, HPLC and GC methods to the study of amino acid and peptide enantiomers: a review. AB - Amino acids are very important organic compounds in nature. The biological activity of amino acids depends mainly on their stereoisomeric configuration (d- or l-). Thus, the stereochemical analysis of amino acids and peptides is an important aspect of their characterization. Owing to the increasing role of amino acid configuration in biomedical and pharmaceutical studies, numerous analytical methods have been described in the literature. Among a wide range of analytical techniques available for the steroselective separation of different amino acids, which were obtained from plants or biological samples, chromatographic methods such as thin-layer chromatography, high-performance chromatography and also gas chromatography are very useful. This review presents such systems developed for direct stereoisomeric separation and quantitative determination of amino acid and peptide enantiomers with emphasis on selected literature published during two last decades. Almost all aspects, including sample preparation prior chromatographic analysis, stationary phase, solvent system and detection system, are discussed. New possibilities in chiral amino acid analysis have been opened up by the application of mass spectrometry and infrared detection in thin-layer chromatography and mass spectrometry-selected ion monitoring detection system in gas chromatography. A modern trend in high-performance chromatography is two dimensional chromatography. These innovations have led to decreased development time and increased amino acid resolution and detectability. PMID- 23946169 TI - Lucky to be an oncologist. PMID- 23946168 TI - Translational genomics of acquired laryngotracheal stenosis. AB - OBJECTIVES/HYPOTHESIS: Acquired laryngotracheal stenosis (ALTS) results from abnormal mucosal wound healing after laryngeal and/or tracheal injury. Patients with ALTS often present late after significant reduction of the airway lumen and onset of symptoms. Motivated by the need for earlier detection of affected patients, we sought to investigate genetic markers for ALTS that would identify susceptible patients. STUDY DESIGN: Pilot Case-Control Study. METHODS: Seventy six patients were recruited, 40 patients with ALTS and 36 control patients with airway injury but without ALTS. DNA was isolated from whole blood and formalin fixed paraffin-embedded specimens from patients. Custom primers were designed and the TaqMan assay employing allele-specific polymerase chain reaction was used to interrogate single nucleotide polymorphisms (SNPs): rs2569190, rs1799750, and rs1800469 located in candidate genes CD14, matrix metalloproteinase-1 (MMP-1), and transforming growth factor-beta1 (TGF-beta1), respectively. A logistic regression model was used to examine the association of candidate gene polymorphisms with the presence or absence of ALTS. RESULTS: All 76 patients were successfully genotyped at the three loci of interest by optimizing the genotyping protocol. MMP-1 SNP rs1799750 was most significantly associated with development of ALTS (P = 0.005). CONCLUSION: Identification of SNPs associated with development of ALTS will provide new experimental targets to study wound healing in human subjects. The association found in the current study between ALTS and SNP rs1799750 is being validated in a larger population examining an expanded set of relevant SNPs. Identifying patients with genetic susceptibility to ALTS and poor wound healing in the upper airway will be useful for management of patients after upper-airway injury. PMID- 23946170 TI - Major response to cyclophosphamide and prednisone in recurrent castration resistant prostate cancer. AB - Prostate cancer is the most common noncutaneous cancer among men. This case report describes a 43-year-old man with rapidly progressing castration-resistant prostate cancer (CRPC) that responded initially to docetaxel and did not tolerate cabazitaxel. He subsequently received a third line of chemotherapy with cyclophosphamide and prednisone, and experienced a dramatic clinical and radiographic response in his liver metastases. This therapeutic intervention led to a significant clinical benefit and confirms the potential use of cyclophosphamide in patients with CRPC, particularly those with liver metastases. PMID- 23946171 TI - Head and neck cancers, version 2.2013. Featured updates to the NCCN guidelines. AB - These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org). PMID- 23946172 TI - Determinants of enrollment in cancer clinical trials: the relationship between the current state of knowledge, societal disease burden, and randomized clinical trial enrollment. AB - Whether clinical cancer research currently focuses on gaps in the evidentiary basis for clinical guidelines and/or on cancers that impose greater societal burden is unclear. This study assessed the relationship between cancer research efforts in terms of planned randomized controlled trial (RCT) enrollment, objective measures of evidence quality, and a cancer's burden on society. The authors calculated the planned RCT enrollment listed on ClinicalTrials.gov for the 17 most prevalent solid cancers. Using cancer type as the unit of analysis, linear regression was used to examine the association between planned enrollment in RCTs and 1) evidence quality, as measured by the absolute number and percent of highest quality category (category 1 [C1]) recommendations in the NCCN Clinical Practice Guidelines in Oncology for each cancer, and 2) measures of burden on society, including prevalence, incidence, person-years of life lost (PYLL), and disability-adjusted life years (DALY). Non-normal distributions were log transformed when appropriate. Overall, 15% of the NCCN recommendations were based on the highest quality evidence. Results produced 1260 RCTs. Planned RCT enrollment ranged from 2270 (testis) to 492,876 (breast) and was correlated neither with absolute number nor percent of C1 recommendations for that cancer. Planned RCT enrollment was positively correlated with a cancer's prevalence (P=.01), incidence (P<.01), PYLL (P<.01), and DALY (P<0.01). In multivariate analysis, prevalence (P<.01) and PYLL (P<.01) had the strongest association with planned RCT enrollment. Findings showed, therefore, that planned cancer RCT enrollment is associated with higher societal disease burden, not the quality of a cancer's clinical guidelines. PMID- 23946173 TI - Diagnostic strategies for invasive fungal infections in patients with hematologic malignancies and hematopoietic stem cell transplant recipients. AB - Invasive fungal infections (IFIs) frequently occur and are associated with high morbidity and mortality in patients with hematologic malignancies (HMs) and hematopoietic stem cell transplant (HSCT) recipients. Early diagnosis of IFI in these patients facilitates prompt institution of therapy and leads to improved clinical outcomes. This article reviews widely used methodologies for diagnosing IFIs in patients with HM and HSCT recipients. Advantages and limitations of radiologic studies; microbiologic and histopathologic techniques; fungal biomarker assays, including those for galactomannan antigen and beta-(1-3)-D glucan; and molecular assays that are available to establish an early diagnosis of clinically relevant invasive fungal infections are discussed. Recommendations are provided regarding effective use of these methodologies in clinical practice. PMID- 23946174 TI - Trimodality bladder preservation therapy for muscle-invasive bladder cancer. AB - Potentially curative treatments for patients with muscle-invasive bladder cancer (MIBC) are underused, especially in the elderly. Trimodality bladder preservation therapy, which includes a maximally safe transurethral resection of the bladder tumor, followed by concurrent chemoradiation, fulfills this currently unmet need. In multiple prospective clinical trials and large institutional series, trimodality therapy has demonstrated excellent 5-year overall survival rates of 48% to 65%, comparable to those reported in cystectomy studies. Approximately 75% to 80% of long-term survivors maintain their native bladders, which tend to function well and allow patients to maintain excellent quality of life. Salvage cystectomy for patients who develop a local invasive recurrence can be performed with acceptable operative complication rates, and results in excellent long-term disease control and survival outcomes. For patients with MIBC who are noncystectomy candidates, or select patients who are motivated to keep their native bladders, trimodality bladder preservation therapy is recognized by the International Consultation on Urological Diseases-European Association of Urology and the NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer as an effective alternative to radical cystectomy, and should be considered. In the future, biomarkers may allow improved selection of patients for whom trimodality bladder preservation therapy is most likely to succeed. PMID- 23946175 TI - Targeted therapy in relapsed classical hodgkin lymphoma. AB - Although frontline treatment of advanced Hodgkin lymphoma (HL) produces high cure rates, disease either will not respond to or will relapse after initial therapy in approximately a quarter of patients. Many patients with disease relapse can be successfully salvaged with second-line chemotherapy followed by autologous stem cell transplantation (ASCT). Patients whose disease relapses after ASCT are rarely cured. A unique pathophysiologic feature of HL is that the malignant Reed Sternberg (HRS) cell is rare and resides within a microenvironment of inflammatory and immune-related cells. The recent FDA approval of the anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) for patients with either primary refractory HL or those whose disease relapses after ASCT represents a major advance in therapy. This article focuses on BV and other novel agents that target the HRS cell surface, intracellular signaling pathways, and tumor microenvironment. PMID- 23946176 TI - Analysis of circulating tumor cells in breast cancer. AB - Over the past few decades, substantial progress has been made in the diagnosis and treatment of breast cancer. Early identification of relapsed and metastatic disease has been a primary focus of ongoing research. Circulating tumor cells (CTCs) are implicated as harbingers of metastases. With advances in detection technologies, CTCs offer the option for real-time liquid biopsies. Methods to identify CTCs in the bloodstream by physical or biochemical properties, although feasible, still require improvements to promote widespread, reproducible use. Sufficient data support enumeration and assessment of changes in the number of CTCs as prognostic indicators, but controversy around their predictive utility for selecting treatments remains. As the technology to detect CTCs and characterize their heterogeneous molecular profile evolves, additional information will likely be obtained to guide targeted and individualized therapies. PMID- 23946178 TI - Opioid misuse and abuse: risk assessment and management in patients with cancer pain. AB - The FDA's 2012 risk evaluation and mitigation strategy is a major step toward systematically reducing the inherent risks of chronic opioid therapy for pain, but does not distinguish between risks related to sources of pain. This article discusses the effect of risk mitigation in the treatment of cancer pain, with a focus on pretreatment screening and ongoing monitoring in this patient population that often requires pain management at some time during cancer treatment. Experience with screening, risk stratification, and interventions at one cancer center is shared, along with some recommendations for practice. A new screening checklist is proposed that summarizes known risk factors. Patients with cancer are not protected from the problems of opioid abuse/misuse, and the multidisciplinary cancer treatment team should coordinate an evaluation of risk and the monitoring of aberrant behaviors as part of the comprehensive care plan. PMID- 23946179 TI - Five questions about the NCCN foundation. PMID- 23946182 TI - Critical coagulation concentration-based salt titration for visual quantification in gold nanoparticle-based colorimetric biosensors. AB - In gold nanoparticle (GNP)-based colorimetric biosensors, the gradual color shift is often used to correlate with the concentration of target molecules, and therefore a UV-vis spectrometer is usually required for accurate quantification. Here, we present a critical coagulation concentration (CCC)-based salt titration as a generic and simple way to enable accurate quantification in GNP-based colorimetric biosensors without any analytical equipment. The titration is carried out by stepwise addition of a salt titrant to the premixture of sample and GNPs until the color changes rapidly from red to blue, determined solely by visual inspection. The number of titration steps or the final salt concentration required for a rapid color shift (i.e., CCC) is then used to quantitatively correlate with the concentration of target molecules in the sample. The salt titration-based quantification has been demonstrated with two previously reported GNP-based colorimetric biosensors. Compared with quantification based on the gradual color shift with a spectrometer, the visual quantification based on the rapid color shift in the salt titration eliminates the need for any analytical equipment without sacrificing the performance (i.e., sensitivity and accuracy) and therefore is highly suitable for applications in low-resource settings. PMID- 23946177 TI - Adult cancer pain. AB - Pain is a common symptom associated with cancer and its treatment. Pain management is an important aspect of oncologic care, and unrelieved pain significantly comprises overall quality of life. These NCCN Guidelines list the principles of management and acknowledge the range of complex decisions faced in the management oncologic pain. In addition to pain assessment techniques, these guidelines provide principles of use, dosing, management of adverse effects, and safe handling procedures of pharmacologic therapies and discuss a multidisciplinary approach for the management of cancer pain. PMID- 23946183 TI - Estimating successive cancer risks in Lynch Syndrome families using a progressive three-state model. AB - Lynch Syndrome (LS) families harbor mutated mismatch repair genes,which predispose them to specific types of cancer. Because individuals within LS families can experience multiple cancers over their lifetime, we developed a progressive three-state model to estimate the disease risk from a healthy (state 0) to a first cancer (state 1) and then to a second cancer (state 2). Ascertainment correction of the likelihood was made to adjust for complex sampling designs with carrier probabilities for family members with missing genotype information estimated using their family's observed genotype and phenotype information in a one-step expectation-maximization algorithm. A sandwich variance estimator was employed to overcome possible model misspecification. The main objective of this paper is to estimate the disease risk (penetrance) for age at a second cancer after someone has experienced a first cancer that is also associated with a mutated gene. Simulation study results indicate that our approach generally provides unbiased risk estimates and low root mean squared errors across different family study designs, proportions of missing genotypes, and risk heterogeneities. An application to 12 large LS families from Newfoundland demonstrates that the risk for a second cancer was substantial and that the age at a first colorectal cancer significantly impacted the age at any LS subsequent cancer. This study provides new insights for developing more effective management of mutation carriers in LS families by providing more accurate multiple cancer risk estimates. PMID- 23946184 TI - A co-catalyst-loaded Ta(3)N(5) photoanode with a high solar photocurrent for water splitting upon facile removal of the surface layer. AB - Surface exfoliation: A Ta3 N5 photoanode prepared by a thermal oxidation and nitridation method shows a high solar photocurrent. This photocurrent is currently the highest achieved by a Ta3 N5 photoanode. The photocurrent is obtained mainly because of facile thermal and mechanical exfoliation of the surface passivation layer of the Ta3 N5 photoanode. PMID- 23946185 TI - Ballooning method using a dull-tipped needle for patency maintenance during venous anastomosis. PMID- 23946186 TI - Thermodynamics of molecules strongly coupled to the vacuum field. AB - The thermodynamics of strong coupling between molecules and the vacuum field is analyzed and the Gibbs free energy, the enthalpy, and entropy of the coupling process are determined for the first time. The thermodynamic parameters are a function of the Rabi splitting and the microscopic solvation. The results provide a new framework for understanding light-molecule strong coupling. PMID- 23946187 TI - Replacement, refinement, and reduction: necessity of standardization and computational models for long bone fracture repair in animals. AB - In the field of fracture healing it is essential to know the impacts of new materials. Fracture healing of long bones is studied in various animal models and extrapolated for use in humans, although there are differences between the micro- and macrostructure of human versus animal bone. Unfortunately, recommended standardized models for fracture repair studies do not exist. Many different study designs with various animal models are used. Concerning the general principles of replacement, refinement and reduction in animal experiments (three "Rs"), a standardization would be desirable to facilitate better comparisons between different studies. In addition, standardized methods allow better prediction of bone healing properties and implant requirements with computational models. In this review, the principles of bone fracture healing and differences between osteotomy and artificial fracture models as well as influences of fixation devices are summarized. Fundamental considerations regarding animal model choice are discussed, as it is very important to know the limitations of the chosen model. In addition, a compendium of common animal models is assembled with special focus on rats, rabbits, and sheep as most common fracture models. Fracture healing simulation is a basic tool in reducing the number of experimental animals, so its progress is also presented here. In particular, simulation of different animal models is presented. In conclusion, a standardized fracture model is of utmost importance for the best adaption of simulation to experimental setups and comparison between different studies. One of the basic goals should be to reach a consensus for standardized fracture models. PMID- 23946188 TI - Hollow-shelled nanoreactors endowed with high catalytic activity. AB - Hollow-shelled nanoreactors have emerged as efficient structures to maximize the potential of nanoparticles in the field of catalysis. In this Concept article, we underline the importance of both the morphology of the active nanoparticles as well as the composition and porosity of the shell for the catalytic performance of the overall nanocomposite. Different configurations are discussed, with a focus on preparative methods and applications in organic synthesis. Perspectives on future designs that may offer new opportunities to improve the selectivity of the catalyzed transformations and add additional features are also addressed, in order to illustrate the potential of these unique nanostructures. PMID- 23946189 TI - High-volumetric performance aligned nano-porous microwave exfoliated graphite oxide-based electrochemical capacitors. AB - Ultra-high volumetric performance electrochemical double layer capacitors based on high density aligned nano-porous microwave exfoliated graphite oxide have been studied. Elimination of macro-, meso-, and larger micro-pores from electrodes and controlling the nano-morphology results in very high volumetric capacitance, energy, and power density values. PMID- 23946190 TI - Automated spine and vertebrae detection in CT images using object-based image analysis. AB - Although computer assistance has become common in medical practice, some of the most challenging tasks that remain unsolved are in the area of automatic detection and recognition. The human visual perception is in general far superior to computer vision algorithms. Object-based image analysis is a relatively new approach that aims to lift image analysis from a pixel-based processing to a semantic region-based processing of images. It allows effective integration of reasoning processes and contextual concepts into the recognition method. In this paper, we present an approach that applies object-based image analysis to the task of detecting the spine in computed tomography images. A spine detection would be of great benefit in several contexts, from the automatic labeling of vertebrae to the assessment of spinal pathologies. We show with our approach how region-based features, contextual information and domain knowledge, especially concerning the typical shape and structure of the spine and its components, can be used effectively in the analysis process. The results of our approach are promising with a detection rate for vertebral bodies of 96% and a precision of 99%. We also gain a good two-dimensional segmentation of the spine along the more central slices and a coarse three-dimensional segmentation. PMID- 23946191 TI - A new implant with solid core and porous surface: the biocompatability with bone. AB - This research investigated osteogenic potencies of Farthing-Fray-Chen Titanium (FFcTi) implant with transitional porous-solid structure. The material characteristics, biomechanical property, osteogenic performances were assessed. FFcTi showed similar roughness as sand-blasted and acid etched titanium (SA), but was more hydrophilic than SA and machined commercial pure titanium (MA). Young's modulus of FFcTi implant in compressive tests was 15.8 +/- 6.3 GPa, which was close to bone. In vitro observations manifested excellent spreading abilities of MC3T3-E1 cell on FFcTi and SA. Adhesion rates of MC3T3-E1 cells at 4 h gradually decreased on MA, SA, and FFcTi surfaces (MA > SA, p < 0.01; SA > FFcTi, p < 0.05), while cell proliferation ability on FFcTi was weaker than MA during 1-6 days (p < 0.01) and similar to MA and SA in day 11. ALP activity of cells on FFcTi at 14 day was higher than MA and lower than SA (p < 0.01). In a bone defect model of rabbits, BIC and bone volum ratio within 50 MUm were significantly higher for FFcTi than MA (BIC, p < 0.01; BT0.05, p < 0.05) while bone volume ratio within 100 and 500 MUm were of no differences. Micro CT analysis also showed similar results to the histomorphometric data. Thus, we conclude that FFcTi with melting sphere based multiporous structure has a hydrophilic, rough surface, and close modulus to bone. In vitro, its low proliferation and ALP activity promotion were similar to other micro scale roughed surface. In vivo test showed better osteogenesis ability when compared with MA at least in 2 weeks. Thus, this Farthing-Fray-Chen Titanium implant seems to hold considerable potential for bone implant applications. PMID- 23946192 TI - Regulating genomics: time for a broader vision. PMID- 23946193 TI - Making waves in consciousness research. PMID- 23946194 TI - A theoretically based index of consciousness independent of sensory processing and behavior. AB - One challenging aspect of the clinical assessment of brain-injured, unresponsive patients is the lack of an objective measure of consciousness that is independent of the subject's ability to interact with the external environment. Theoretical considerations suggest that consciousness depends on the brain's ability to support complex activity patterns that are, at once, distributed among interacting cortical areas (integrated) and differentiated in space and time (information-rich). We introduce and test a theory-driven index of the level of consciousness called the perturbational complexity index (PCI). PCI is calculated by (i) perturbing the cortex with transcranial magnetic stimulation (TMS) to engage distributed interactions in the brain (integration) and (ii) compressing the spatiotemporal pattern of these electrocortical responses to measure their algorithmic complexity (information). We test PCI on a large data set of TMS evoked potentials recorded in healthy subjects during wakefulness, dreaming, nonrapid eye movement sleep, and different levels of sedation induced by anesthetic agents (midazolam, xenon, and propofol), as well as in patients who had emerged from coma (vegetative state, minimally conscious state, and locked-in syndrome). PCI reliably discriminated the level of consciousness in single individuals during wakefulness, sleep, and anesthesia, as well as in patients who had emerged from coma and recovered a minimal level of consciousness. PCI can potentially be used for objective determination of the level of consciousness at the bedside. PMID- 23946195 TI - Fetal urinary peptides to predict postnatal outcome of renal disease in fetuses with posterior urethral valves (PUV). AB - Bilateral congenital abnormalities of the kidney and urinary tract (CAKUT), although are individually rare diseases, remain the main cause of chronic kidney disease in infants worldwide. Bilateral CAKUT display a wide spectrum of pre- and postnatal outcomes ranging from death in utero to normal postnatal renal function. Methods to predict these outcomes in utero are controversial and, in several cases, lead to unjustified termination of pregnancy. Using capillary electrophoresis coupled with mass spectrometry, we have analyzed the urinary proteome of fetuses with posterior urethral valves (PUV), the prototypic bilateral CAKUT, for the presence of biomarkers predicting postnatal renal function. Among more than 4000 fetal urinary peptide candidates, 26 peptides were identified that were specifically associated with PUV in 13 patients with early end-stage renal disease (ESRD) compared to 15 patients with absence of ESRD before the age of 2. A classifier based on these peptides correctly predicted postnatal renal function with 88% sensitivity and 95% specificity in an independent blinded validation cohort of 38 PUV patients, outperforming classical methods, including fetal urine biochemistry and fetal ultrasound. This study demonstrates that fetal urine is an important pool of peptides that can predict postnatal renal function and thus be used to make clinical decisions regarding pregnancy. PMID- 23946196 TI - Neutralizing antibodies against previously encountered influenza virus strains increase over time: a longitudinal analysis. AB - Antigenic diversity shapes immunity in distinct and unexpected ways. This is particularly true of the humoral response generated against influenza A viruses. Although it is known that immunological memory developed against previously encountered influenza A virus strains affects the outcome of subsequent infections, exactly how sequential exposures to antigenically variant viruses shape the humoral immune response in humans remains poorly understood. To address this important question, we performed a longitudinal analysis of antibody titers against various pandemic and seasonal strains of influenza virus spanning a 20 year period (1987 to 2008) with samples from 40 individuals (birth dates, 1917 to 1952) obtained from the Framingham Heart Study. Longitudinal increases in neutralizing antibody titers were observed against previously encountered pandemic H2N2, H3N2, and H1N1 influenza A virus strains. Antibody titers against seasonal strains encountered later in life also increased longitudinally at a rate similar to that against their pandemic predecessors. Titers of cross reactive antibodies specific to the hemagglutinin stalk domain were also investigated because they are influenced by exposure to antigenically diverse influenza A viruses. These titers rose modestly over time, even in the absence of major antigenic shifts. No sustained increase in neutralizing antibody titers against an antigenically more stable virus (human cytomegalovirus) was observed. The results herein describe a role for antigenic variation in shaping the humoral immune compartment and provide a rational basis for the hierarchical nature of antibody titers against influenza A viruses in humans. PMID- 23946197 TI - Metabolic imaging of patients with prostate cancer using hyperpolarized [1 13C]pyruvate. AB - This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-13C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo 13C MR data, it is possible to evaluate the distribution of agents such as [1-13C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1 13C]lactate in tumor, with the ratio of [1-13C]lactate/[1-13C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect 13C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-13C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-13C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-13C]lactate/[1-13C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials. PMID- 23946198 TI - Changing indications for maxillomandibular reconstruction with osseous free flaps: a 17-year experience with 620 consecutive cases at UCLA and the impact of osteoradionecrosis. AB - OBJECTIVES/HYPOTHESIS: To characterize the changing indications for osseous free flaps in maxillomandibular reconstruction at our institution. STUDY DESIGN: Retrospective chart review. METHODS: Database review of patients who underwent free-flap reconstruction of the jaws using vascularized bone-containing free tissue transfer from 1995 to 2012 at the University of California Los Angeles (UCLA). RESULTS: A total of 620 osseous free flaps were performed. The most common indications for surgery were squamous cell carcinoma (n = 442) and osteoradionecrosis (ORN)) of the mandible (n = 73). There were no significant differences in 90-day perioperative complication, flap viability, or mortality rates between any of the indications for surgery. Patients older than 60 years had a higher rate of major perioperative complication (P = 0.0028). ORN cases represented 1.3% +/- 1.2% of surgical volume from 1995 to 2000, 8.7% +/- 1.8% from 2001 to 2006, and 17.5% +/- 2.2% from 2007 to 2012 (P <0.0001). Among cases of ORN, 95.8% of patients had radiation therapy completed at centers outside of our hospital system. For patients with ORN, there was an average interval of 8.7 +/- 8.0 years from initiation of radiotherapy to the date of mandibulectomy (range 1-37 years). CONCLUSION: The incidence of ORN as an indication for free flap reconstruction has increased at our institution in recent years. This may reflect an increasing need for the surgical management of medically refractory ORN, a rising awareness or prevalence of ORN overall, and/or increasing comfort with free flaps as a treatment for ORN. Patients who undergo free-flap surgery for ORN do not have greater risks of 90-day perioperative complications or differences in free-flap viability as compared to patients who undergo free-flap reconstruction for other indications. LEVEL OF EVIDENCE: 2b. PMID- 23946199 TI - Secondary head and neck reconstruction using free flap to improve the postoperative function or appearance of cancer survivors. AB - BACKGROUND: Secondary reconstructive operations are needed when patients with head and neck cancers have complications such as tumor recurrence after initial treatment. These reconstructive procedures are also performed to improve the function and appearance of the head and neck region for many cancer survivors. We reviewed the patients who underwent secondary head and neck reconstruction to improve function and appearance and considered the significance of this procedure for cancer survivors, as well as its associated problems. METHODS: Among the secondary reconstruction patients, 20 patients underwent reconstruction to improve their function and/or appearance. The goal of reconstruction for the patients was functional improvement in eight cases, appearance improvement in ten cases, and both function and appearance in two cases. Chi-square analyses were performed between the secondary and primary reconstructive groups with regard to the incidence of postoperative complications. RESULTS: All transferred flaps survived completely. We performed a small postoperative modification procedure in four cases. Minor complications not requiring surgical correction occurred in 2 of 20 patients. Additional operations were required owing to major postoperative complications in 2 of 20 patients. No significant associations were identified between the secondary and primary reconstructive groups with regard to postoperative complications. CONCLUSION: The outcomes of the present report suggest that secondary reconstructive surgery is a relatively safe procedure. The decision to perform adaptation operations depends on various factors after sufficient discussion with patients. PMID- 23946200 TI - Estimation of the wild-type minimum inhibitory concentration value distribution. AB - Antimicrobial resistance has become one of the main public health burdens of the last decades, and monitoring the development and spread of non-wild-type isolates has therefore gained increased interest. Monitoring is performed based on the minimum inhibitory concentration (MIC) values, which are collected through the application of dilution experiments. In order to account for the unobserved population heterogeneity of wild-type and non-wild-type isolates, mixture models are extremely useful. Instead of estimating the entire mixture globally, it was our major aim to provide an estimate for the wild-type first component only. The characteristics of this first component are not expected to change over time, once the wild-type population has been confidently identified for a given antimicrobial. With this purpose, we developed a new method based on the multinomial distribution, and we carry out a simulation study to study the properties of the new estimator. Because the new approach fits within the likelihood framework, we can compare distinct distributional assumptions in order to determine the most suitable distribution for the wild-type population. We determine the optimal parameters based on the AIC criterion, and attention is also paid to the model-averaged approach using the Akaike weights. The latter is thought to be very suitable to derive specific characteristics of the wild-type distribution and to determine limits for the wild-type MIC range. In this way, the new method provides an elegant means to compare distinct distributional assumptions and to quantify the wild-type MIC distribution of specific antibiotic bacterium combinations. PMID- 23946201 TI - Catalysis with anion-pi interactions. AB - The conclusion is inevitable: Increasing stabilization of an anionic transition state with increasing pi-acidity of the catalyst is observed; thus, anion-pi interactions can contribute to catalysis. PMID- 23946202 TI - In situ generation of diimide from hydrazine and oxygen: continuous-flow transfer hydrogenation of olefins. PMID- 23946203 TI - Field-induced transition from room-temperature ferromagnetism to diamagnetism in proton-irradiated fullerene. AB - Room-temperature ferromagnetism in proton-irradiated C60 fullerene is demonstrated. The ferromagnetism turns into diamagnetism intrinsic to the fullerene as the magnetic field increases above a critical field. PMID- 23946205 TI - U.S. Supreme Court decision paves way for better genetic testing: ruling bars exclusive licensing, patents on naturally occurring genes. PMID- 23946204 TI - Chlorophyll breakdown in senescent banana leaves: catabolism reprogrammed for biosynthesis of persistent blue fluorescent tetrapyrroles. AB - Chlorophyll breakdown is a visual phenomenon of leaf senescence and fruit ripening. It leads to the formation of colorless chlorophyll catabolites, a group of (chlorophyll-derived bilin-type) linear tetrapyrroles. Here, analysis and structure elucidation of the chlorophyll breakdown products in leaves of banana (Musa acuminata) is reported. In senescent leaves of this monocot all chlorophyll catabolites identified were hypermodified fluorescent chlorophyll catabolites (hmFCCs). Surprisingly, nonfluorescent chlorophyll catabolites (NCCs) were not found, the often abundant and apparently typical final chlorophyll breakdown products in senescent leaves. As a rule, FCCs exist only fleetingly, and they isomerize rapidly to NCCs in the senescent plant cell. Amazingly, in the leaves of banana plants, persistent hmFCCs were identified that accounted for about 80 % of the chlorophyll broken down, and yellow leaves of M. acuminata display a strong blue luminescence. The structures of eight hmFCCs from banana leaves were analyzed by spectroscopic means. The massive accumulation of the hmFCCs in banana leaves, and their functional group characteristics, indicate a chlorophyll breakdown path, the downstream transformations of which are entirely reprogrammed towards the generation of persistent and blue fluorescent FCCs. As expressed earlier in related studies, the present findings call for attention, as to still elusive biological roles of these linear tetrapyrroles. PMID- 23946206 TI - Global alliance to create standards for sharing genomic data: group supports simplifying system for searches, but privacy a concern. PMID- 23946208 TI - Antimicrobial stewardship and Clostridium difficile-associated diarrhea. AB - Antimicrobial stewardship programs are essential to health care institutions to promote the appropriate use of antibiotics not only to decrease antimicrobial resistance but to prevent the spread and infection of Clostridium difficile. Clostridium difficile-associated diarrhea is increasing rapidly in the United States and is now considered a major public health problem that poses an immediate threat to the health of patients prescribed antibiotics, more so than antimicrobial resistance. Clostridium difficile-associated disease is the result of collateral damage to the normal bacterial flora of the human body, which is an inevitable consequence of any antibiotic use. Antimicrobial stewardship programs such as audit with feedback and antibiotic restriction are designed to help limit Clostridium difficile infections and other hospital-associated organisms by optimizing antimicrobial selection, dosing, de-escalation, and duration of therapy. These programs also incorporate implementation of hospital-wide guidelines, staff education, enforcement of infection-control policies, and the use of electronic medical records when possible to help control antibiotic use. This article reviews the literature on how antimicrobial stewardship programs impact Clostridium difficile rates and discusses experiences in designing, implementing, monitoring, and follow-through of such programs. PMID- 23946209 TI - Dental anomalies associated with buccally- and palatally-impacted maxillary canines. AB - AIM: The aim of the present study was to determine the association of both buccally- and palatally-impacted canines with other dental anomalies. METHODS: This retrospective study was conducted on a population of 533 southern Chinese children and adolescents who had impacted maxillary canines that had been treated in the Paediatric Dentistry and Orthodontics Clinic, Prince Philip Dental Hospital, The University of Hong Kong, Hong Kong. Descriptions of the impacted canine and other associated anomalies were obtained from the case notes and radiographs. Clinical photographs and study casts were used, where available. RESULTS: A total of 253 (47.5%) patients with impacted maxillary canines were diagnosed with other dental anomalies. Microdontia was the most frequently occurring anomaly reported in these patients, with the maxillary lateral incisor the most commonly affected tooth. Other odontogenic anomalies that were associated with both buccally- and palatally-impacted canines included hypodontia, supernumerary teeth, transposition of other teeth, enamel hypoplasia, other impacted teeth, and dens invaginatus. CONCLUSION: Both buccally- and palatally-impacted canines were found to be associated with other odontogenic anomalies. PMID- 23946210 TI - Effect of plasma components on the stability and permeability of microcapsule. AB - Immobilization of hepatocytes in microcapsules has been a potentially alternative methodology for bioartificial livers (BALs). Moreover, the stability and permeability are the key parameters of these microcapsules. However, these alginate-based microcapsules are unstable if the surrounding medium disrupts the ionic interactions between alginate and the polycation. As hundreds of components are included in human plasma, the stability and permeability in plasma of microcapsules need to be sufficiently investigated. In the present study, the stability of three kinds of alginate-based microcapsules was evaluated when they were immersed in plasma. Our results showed that stability of alginate-alpha-poly (L-lysine)-alginate (alpha-APA) microcapsules was well maintained, better than those of alginate-epsilon-poly (L-lysine)-alginate (epsilon-APA) and alginate chitosan-alginate (ACA) microcapsules. Also, factors affecting the stability of microcapsules in plasma were analyzed and it showed that heparin was the key factor that affected the stability of alpha-APA microcapsules, whereas heparin and low molecular electrolytes such as HCO3(-) and H2 PO4(-)/HPO4(2-) were the factors to epsilon-APA and ACA microcapsules. In addition, the permeability evaluation showed no decrease in permeability of microcapsules after incubation in plasma. Our study might provide a foundation for the selection and modification of materials for microcapsule-based BAL devices. PMID- 23946211 TI - Basaloid squamous cell carcinoma of the oral cavity: an analysis of 92 cases. AB - OBJECTIVES/HYPOTHESIS: Basaloid squamous cell carcinoma (BSCC) is considered a rare and possibly more aggressive squamous cell carcinoma (SCC) variant. Until now, a series of exclusively oral cavity BSCC patients has not been previously reported. We endeavored to compare BSCC and SCC of the oral cavity, focusing on epidemiologic factors and survival outcomes. STUDY DESIGN: Retrospective analysis of population-based data. METHODS: We compared epidemiologic factors, clinicopathologic data, and disease-specific survivals (DSS) between 92 patients with oral cavity BSCC and 15,181 patients with SCC. RESULTS: High-grade tumors and distant metastases were more common in the BSCC group (P<=0.001). On multivariable analysis controlling for disease stage, BSCC patients had similar DSS to those with typical SCC (P=0.231). Although there was a trend favoring definitive radiotherapy for BSCC, there were no significant differences in treatment approach between BSCC and SCC. The choice of treatment modality (radiation, surgery+/-radiation) did not reveal a difference in DSS between the two tumor subtypes. CONCLUSION: Analysis of the largest oral cavity BSCC series to date demonstrates that BSCC of the oral cavity carries a comparable prognosis to conventional-type oral SCC. LEVEL OF EVIDENCE: 2b. PMID- 23946212 TI - Efficacy and safety of deferasirox compared with deferoxamine in sickle cell disease: two-year results including pharmacokinetics and concomitant hydroxyurea. AB - We report a prospective, randomized, Phase II study of deferasirox and deferoxamine (DFO) in sickle cell disease patients with transfusional iron overload, with all patients continuing on deferasirox after 24 weeks, for up to 2 years. The primary objective was to evaluate deferasirox safety compared with DFO; long-term efficacy and safety of deferasirox was also assessed. We also report, for the first time, the safety and pharmacokinetics of deferasirox in patients concomitantly receiving hydroxyurea. Deferasirox (n = 135) and DFO (n = 68) had comparable safety profiles over 24 weeks. Adverse events (AEs) secondary to drug administration were reported in 26.7% of patients in the deferasirox cohort and 28.6% in the DFO cohort. Gastrointestinal disorders were more common with deferasirox, including diarrhea (10.4% versus 3.6%) and nausea (5.2% versus 3.6%). The most common AE in the DFO group was injection-site pain irritation, which occurred in 7% of patients. Acute renal failure occurred in one patient on deferasirox who was continued on medication despite progressive impairment of renal function parameters. Serum ferritin levels were reduced in both treatment groups. Patients continuing on deferasirox for up to 2 years demonstrated an absolute median serum ferritin decrease of -614 ng/mL (n = 96). Increasing deferasirox dose was associated with improved response and a continued manageable safety profile. Concomitant hydroxyurea administration (n = 28) did not appear to influence the efficacy, safety (including liver and kidney function), and pharmacokinetic parameters of deferasirox. PMID- 23946213 TI - Free fibular flap with periosteal excess for mandibular reconstruction. AB - BACKGROUND: In microvascular transfer of fibular osteocutaneous flap for mandible reconstruction after cancer ablation, good bone union is necessary to allow timely radiation therapy after surgery. As the area of bone contact between fibula and the original mandible at the edge of the mandibular defect is small, a periosteal excess at both ends of the fibula covering the bone junction can be used to increase the chance of bone union. The purpose of this study is to investigate whether a periosteal excess surrounding both ends of the fibula flap can provide better blood supply and, therefore, ensure bone union and wound healing at 6 weeks after surgery and before radiation therapy initiation. PATIENTS AND METHODS: The transfer of fibular osteocutaneous flap with periosteal excess was only applied to reconstruct segmental mandibular defects. As a consequence, only cases in which osteotomy of fibula was not performed were included in this study. A total of 34 fibular flaps without osteotomies were performed between 2000 and 2008; 17 with and 17 without the periosteal excess. The bone union was evaluated in terms of osseous callus formation using X-rays and CT three-dimensional images at 6 weeks after surgery, and results were assessed by three independent radiologists. RESULTS: There was a significant difference between reconstructions with and without the periosteal excess in terms of bone union (P = 0.022). With reference to postoperative complications, the group reconstructed without periosteal excess presented a higher number of complications, mainly consisting of partial and total flap necrosis, respectively six (35.29%) and two (11.76%) cases. In the group reconstructed with periosteal excess, no loss of the skin island has occurred. A significant difference was observed in terms of partial flap necrosis (P = 0.024), while the other complications did not reveal a statistically significant difference (P > 0.05). CONCLUSIONS: The use of a periosteal excess at both ends of the fibula flap provides better blood supply and is, therefore, able to ensure good bone healing and skin paddle survival regardless of the radiotherapy. PMID- 23946214 TI - Atomically thin tin dioxide sheets for efficient catalytic oxidation of carbon monoxide. AB - The thinner the better: SnO2 sheets that are five atomic layers thick are an efficient catalyst for the oxidation of CO. These sheets, which have 40% surface atom occupancy and are fabricated by a scalable ethylenediamine-assisted pathway, show remarkably improved catalytic performances compared to other SnO2 species, with the apparent activation energy lowered to 59.2 kJ mol(-1) and the full conversion-temperature lowered to 250 degrees C. PMID- 23946215 TI - Core/Shell photocatalyst with spatially separated co-catalysts for efficient reduction and oxidation of water. AB - A simple method allows the preparation of core/shell photocatalysts with spatially separated co-catalysts for efficient water splitting. The high activity was attributed to the core/shell structure and separated co-catalysts that assisted separation and collection of the electrons and holes at the respective co-catalysts, owing to active rectification of electron and hole transport (see picture; Eg =2.1 eV). PMID- 23946216 TI - A flexible approach to strained sandwich compounds: chiral [1]ferrocenophanes with boron, gallium, silicon, and tin in bridging positions. AB - The enantiomerically pure dibromoferrocene 3 [(Sp,Sp )-1,1'-dibromo-2,2' di(isopropyl)ferrocene], equipped with two iPr groups in alpha positions, was prepared using known "Ugi amine" chemistry. Species 3 was targeted in order to gain access to new [1]ferrocenophanes ([1]FCPs) to be used as monomers for ring opening polymerization. The iPr groups on the sandwich unit were introduced to stabilize bridging moieties, as well as to increase solubilities of targeted metallopolymers. The planar chiral dibromide 3 can quantitatively be lithiated at 0 degrees C [2 equiv nBuLi, hexanes/thf (9:1), 30 min]. Salt-metathesis reactions with respective element dichloride species gave chiral [1]FCPs with a variety of bridging moieties [ERx =Ga[2-(Me2NCH2)C6H4] (4 a), SiMe2 (4 b), SntBu2 (4 c), BNiPr2 (4 d)]. The new [1]FCPs were fully characterized including single-crystal X-ray analysis. The stabilizing iPr groups on the Cp rings increase the thermal stabilities of 4 b-d compared to known [1]FCPs, equipped with the same bridging moieties. All three compounds 4 b-d are volatile and could be isolated by vacuum sublimation. Our new approach to [1]FCPs has the potential to overcome many of the existing difficulties in ferrocenophane chemistry, such as limited stability of starting monomers and low solubilities of resulting polyferrocenes. PMID- 23946217 TI - Logic computation in phase change materials by threshold and memory switching. AB - Memristors, namely hysteretic devices capable of changing their resistance in response to applied electrical stimuli, may provide new opportunities for future memory and computation, thanks to their scalable size, low switching energy and nonvolatile nature. We have developed a functionally complete set of logic functions including NOR, NAND and NOT gates, each utilizing a single phase-change memristor (PCM) where resistance switching is due to the phase transformation of an active chalcogenide material. The logic operations are enabled by the high functionality of nanoscale phase change, featuring voltage comparison, additive crystallization and pulse-induced amorphization. The nonvolatile nature of memristive states provides the basis for developing reconfigurable hybrid logic/memory circuits featuring low-power and high-speed switching. PMID- 23946218 TI - Severity scoring index for Crimean-Congo hemorrhagic fever and the impact of ribavirin and corticosteroids on fatality. AB - BACKGROUND: Patients infected with Crimean-Congo hemorrhagic fever (CCHF) virus present with a wide clinical spectrum. In observational studies, the effects of therapeutic agents are confounded by severity. We describe use of a clinical severity scoring index (SSI) for CCHF patients and assess the effect of ribavirin and corticosteroid therapy on the case-fatality rate, stratified by SSI. METHODS: The study group included hospitalized patients who received a diagnosis of CCHF at the Infectious Diseases and Clinical Microbiology Clinic of Ankara Numune Education and Research Hospital between 2004 and 2011. The SSI included platelet count, bleeding, fibrinogen level, activated partial thromboplastin time, and somnolence. The effects of ribavirin and corticosteroid on the case-fatality rate were studied by univariate and multivariate analysis, stratified by SSI. RESULTS: Two hundred eighty-one confirmed cases of CCHF were included in the study. Of 281 patients, 23 (8%) died. The mean age (+/-SD) of the patients was 47 +/- 16 years. Forty-nine percent were female. The mean duration of stay at our clinic after onset of symptoms was 4.4 days, with a range of 1-14 days. In multivariate analysis of factors for the prediction of death, the SSI (odds ratio [OR], 3.27; 95% confidence interval [CI], 2.09-5.13) and ribavirin use (OR, 0.04; 95% CI, .004-.48) were found to be statistically significant factors. CONCLUSION: The SSI is an accurate predictor of death and will therefore be a useful tool for case management and for drug-assessment studies. After stratification of cases by SSI, ribavirin was found to be effective in reducing the case-fatality rate, especially among moderately ill patients, whereas steroids were found to be beneficial particularly among patients with severe disease. PMID- 23946219 TI - Reply to Monge-Maillo et al. PMID- 23946220 TI - A randomized controlled pilot trial of valacyclovir for attenuating inflammation and immune activation in HIV/herpes simplex virus 2-coinfected adults on suppressive antiretroviral therapy. AB - BACKGROUND: Human immunodeficiency virus (HIV) is associated with increased systemic inflammation and immune activation that persist despite suppressive antiretroviral therapy (ART). Herpes simplex virus type 2 (HSV-2) is a common coinfection that may contribute to this inflammation. METHODS: Sixty HIV type 1 (HIV-1)/HSV-2-coinfected adults on suppressive ART were randomized 1:1:1 to 12 weeks of placebo, low-dose valacyclovir (500 mg twice daily), or high-dose valacyclovir (1 g twice daily) in this 18-week trial. Co-primary outcome measures were the percentage of activated (CD38(+)HLA-DR(+)) CD8 T cells in blood, and highly sensitive C-reactive protein, interleukin 6, and soluble intercellular adhesion molecule 1 in plasma. Secondary outcomes included additional immune, inflammatory cytokine, and endothelial activation markers. The impact of valacyclovir (both groups combined) on each outcome was estimated using treatment * time interaction terms in generalized estimating equation regression models. RESULTS: Participants were mostly white (75%) men who have sex with men (80%). Median age was 51 (interquartile range [IQR], 47-56) years, median duration of HIV infection was 15 (IQR, 8-21) years, median CD4 count at enrollment was 520 (IQR, 392-719) cells/uL, and median nadir CD4 count was 142 (IQR, 42-240) cells/uL. Valacyclovir was not associated with significant changes in any primary or secondary immunological outcomes in bivariate or multivariable models. Medication adherence was 97% by self-report, 96% by pill count, and 84% by urine monitoring. Eight patients had adverse events deemed possibly related to the study drug (5 placebo, 1 low-dose, 2 high-dose), and 6 patients reported at least 1 HSV outbreak (3 placebo, 3 low-dose, 0 high-dose). CONCLUSIONS: Valacyclovir did not decrease systemic immune activation or inflammatory biomarkers in HIV 1/HSV-2-coinfected adults on suppressive ART. CLINICAL TRIALS REGISTRATION: NCT01176409. PMID- 23946221 TI - Virologic failure following persistent low-level viremia in a cohort of HIV positive patients: results from 12 years of observation. AB - BACKGROUND: The current goal of antiretroviral therapy (ART) is to maintain a suppressed human immunodeficiency virus (HIV) viral load below limits of assay detection. When viral loads remain in low-level viremia (LLV), especially between 50 and 200 copies/mL, the best management and clinical consequences remain unknown. Our objective was to study the long-term impact of persistent LLV on the subsequent risk of virologic failure in a cohort of people living with HIV in Montreal, Canada. METHODS: We compared the cumulative incidence of subsequent virologic failure (defined as an HIV RNA viral load of >1000 copies/mL) in patients receiving ART for at least 12 months by following 4 persistence categories (<50, 50-199, 200-499, and 500-999 copies/mL) for 6, 9, or 12 months, using Kaplan-Meier analysis. The association between subsequent virologic failure and persistence status were estimated using a Cox proportional hazards model. RESULTS: The cumulative incidence of virologic failure 1 year after having maintained a LLV for 6 months was 22.7% (95% confidence interval [CI], 14.9-33.6) for 50-199 copies/mL, 24.2% (95% CI, 14.5-38.6) for 200-499 copies/mL, and 58.9% (95% CI, 43.1-75.2) for 500-999 copies/mL, compared with 6.6% (95% CI, 5.3-8.2) for an undetectable HIV RNA viral load. Even after adjustment for potential confounders, a persistent LLV of 50-199 copies/mL for 6 months doubled the risk of virologic failure (hazard ratio, 2.22; 95% CI, 1.60-3.09), compared with undetectable viral loads for the same duration. Similar results have been found for persistent LLV of 9 or 12 months. CONCLUSIONS: In this cohort, all categories of persistent LLV between 50 and 999 copies/mL were associated with an increased risk of virologic failure. The results shed new light for the management of patients with LLV, especially with regard to LLV of 50-199 copies/mL. PMID- 23946223 TI - Concerns about topical treatment for new world cutaneous leishmanisis. PMID- 23946224 TI - Risk of liver decompensation among HIV/hepatitis C virus-coinfected individuals with advanced fibrosis: implications for the timing of therapy. AB - BACKGROUND: Most human immunodeficiency virus (HIV)/hepatitis C virus (HCV) infected patients who are currently receiving boceprevir or telaprevir-based therapy against HCV show cirrhosis. However, the risk of liver decompensation (DC) among HIV/HCV-coinfected patients with stage 3 fibrosis in the short term could be high enough to not allow delays. We aimed at assessing the risk of DC among HIV/HCV-coinfected individuals with advanced fibrosis (F3-F4). METHODS: Eight hundred ninety-two HIV/HCV-coinfected patients, naive or without sustained virologic response to HCV therapy, were included in this cohort. Fibrosis was staged by biopsy in 317 patients and by liver stiffness measurement (LSM) in 575 individuals. Precirrhosis was defined as an LSM of 9.5-14.6 kilopascals (kPa), and cirrhosis as an LSM of >=14.6 kPa. RESULTS: For patients with biopsy, the probability of remaining free of DC for F3 vs F4 was 99% (95% confidence interval [CI], 95%-100%) vs 96% (95% CI, 91%-98%) at 1 year, and 98% (95% CI, 94%-100%) vs 87% (95% CI, 81%-92%) at 3 years. The only factor independently associated with DC was fibrosis stage (F4 vs F3, subhazard ratio [SHR], 2.1; 95% CI, 1.07-4.1; P = .032). For patients with LSM, the probability of remaining free of DC for precirrhosis vs cirrhosis was 99% (95% CI, 96%-100%) vs 93% (95% CI, 89%-96%) at 1 year, and 97% (95% CI, 94%-99%) vs 83% (95% CI, 77%-87%) at 3 years. Factors independently associated with DC were platelet count (<100 * 10(3) vs >=100 * 10(3): SHR, 1.86; 95% CI, 1.01-3.42; P = .046) and LSM (cirrhosis vs precirrhosis: SHR, 5.67; 95% CI, 2.27-14.1; P < .0001). CONCLUSIONS: As in patients with cirrhosis, immediate therapy against HCV is warranted for patients with precirrhosis and HIV coinfection, as they are at risk of DC soon after the diagnosis of advanced fibrosis. PMID- 23946222 TI - The importance of long-term acute care hospitals in the regional epidemiology of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae. AB - BACKGROUND: In the United States, Klebsiella pneumoniae carbapenemase (KPC) producing Enterobacteriaceae are increasingly detected in clinical infections; however, the colonization burden of these organisms among short-stay and long term acute care hospitals is unknown. METHODS: Short-stay acute care hospitals with adult intensive care units (ICUs) in the city of Chicago were recruited for 2 cross-sectional single-day point prevalence surveys (survey 1, July 2010 January 2011; survey 2, January-July 2011). In addition, all long-term acute care hospitals (LTACHs) in the Chicago region (Cook County) were recruited for a single-day point prevalence survey during January-May 2011. Swab specimens were collected from rectal, inguinal, or urine sites and tested for Enterobacteriaceae carrying blaKPC. RESULTS: We surveyed 24 of 25 eligible short-stay acute care hospitals and 7 of 7 eligible LTACHs. Among LTACHs, 30.4% (119 of 391) of patients were colonized with KPC-producing Enterobacteriaceae, compared to 3.3% (30 of 910) of short-stay hospital ICU patients (prevalence ratio, 9.2; 95% confidence interval, 6.3-13.5). All surveyed LTACHs had patients harboring KPC (prevalence range, 10%-54%), versus 15 of 24 short-stay hospitals (prevalence range, 0%-29%). Several patient-level covariates present at the time of survey LTACH facility type, mechanical ventilation, and length of stay-were independent risk factors for KPC-producing Enterobacteriaceae colonization. CONCLUSIONS: We identified high colonization prevalence of KPC-producing Enterobacteriaceae among patients in LTACHs. Patients with chronic medical care needs in long-term care facilities may play an important role in the spread of these extremely drug resistant pathogens. PMID- 23946225 TI - Editorial commentary: long-term acute care hospitals and carbapenem-resistant Enterobacteriaceae: a reservoir for transmission. PMID- 23946226 TI - Transcatheter aortic valve-in-surgical aortic valve implantation: current status and future perspectives. PMID- 23946228 TI - Preparation, characterization, release kinetics, and in vitro cytotoxicity of calcium silicate cement as a risedronate delivery system. AB - Injectable bone cements have been well characterized and studied in non-load bearing bone fixation and bone screw augmentation applications. Current calcium phosphate cement or poly(methyl methacrylate) cement have drawbacks like low mechanical strength and in situ exothermic properties. This leads especially in patients with osteoporosis to worsening contact between implant and bone and can finally lead to implant failure. To improve these properties, a calcium silicate cement (CSC) was prepared, which additionally contained the bisphosphonate risedronate (RA) to promote osteoblast function. Cement setting rate and compressive strength were measured and found to be reduced by RA above 0.5 wt%. X ray diffraction, Rietveld refinement analysis, scanning electron microscopy, and porosity measurements by gas sorption revealed that RA reduces calcium silicate hydrate gel formation and changes the cement's microstructure. Cumulative release profiles of RA from CSC up to 6 months into phosphate buffer solution were analyzed by high-performance liquid chromatography, and the results were compared with theoretical release curves obtained from the Higuchi equation. Fourier transform infrared spectra measurements and drug release studies indicate that calcium-RA formed within the cement, from which the drug can be slowly released over time. An investigation of the cytotoxicity of the RA-CSC systems upon osteoblast-like cells showed no toxic effects of concentrations up to 2%. The delivery of RA from within a CSC might thus be a valuable and biocompatible new approach to locally deliver RA and to reconstruct and/or repair osteoporosis related bone fractures. PMID- 23946229 TI - Effects of chocolate supplementation on metabolic and cardiovascular parameters in ApoE3L mice fed a high-cholesterol atherogenic diet. AB - SCOPE: Dietary intake of cocoa and/or chocolate has been suggested to exhibit protective cardiovascular effects although this is still controversial. The aim of this study was to investigate the effects of chocolate supplementation on metabolic and cardiovascular parameters. METHODS AND RESULTS: Four groups of ApoE*3Leiden mice were exposed to the following diet regimens. Group 1: cholesterol-free control diet (CO). Group 2: high-dose (1.0% w/w) control cholesterol (CC). Group 3: CC supplemented chocolate A (CCA) and Group 4: CC supplemented chocolate B (CCB). Both chocolates differed in polyphenol and fiber content, CCA had a relatively high-polyphenol and low-fiber content compared to CCB. Mice fed a high-cholesterol diet showed increased plasma-cholesterol and developed atherosclerosis. Both chocolate treatments, particularly CCA, further increased plasma-cholesterol and increased atherosclerotic plaque formation. Moreover, compared to mice fed a high-cholesterol diet, both chocolate-treated groups displayed increased liver injury. Mice on high-cholesterol diet had elevated plasma levels of sVCAM-1, sE-selectin and SAA, which was further increased in the CCB group. Similar effects were observed for renal inflammation markers. CONCLUSION: The two chocolate preparations showed unfavorable, but different effects on cardiometabolic health in E3L mice, which dissimilarities may be related to differences in chocolate composition. We conclude that discrepancies reported on the effects of chocolate on cardiometabolic health may at least partly be due to differences in chocolate composition. PMID- 23946230 TI - Influence of flowable composite and restorative technique on microleakage of class II restorations. AB - AIM: The aim of the present study was to evaluate the microleakage in class II cavities restored with dental composite by varying the thickness of two flowable composite resins and the restorative technique. METHODS: A total of 130 cavities were prepared on proximal surfaces of bovine teeth and randomly divided in 13 groups. Twelve experimental groups were performed using flowable composite resin as the liner, and they were divided according to the type of flowable composite resin (Filtek Z350 Flow-Z350F and SureFil SDR Flow-SUR), the thickness of the flowable composite (0.5, 1, or 2 mm), and the restorative technique (flowable composite applied at the cavosurface angle or amelodentinal junction) (n = 10). A control group was performed without using a flowable composite. Following restorative procedures and thermocycling, the samples were immersed in Methylene Blue for 2 h, and prepared for analysis in an absorbance spectrophotometer. All results were statistically analyzed (alpha = 0.05). RESULTS: There was no significant difference between the flowable composites (P > 0.05). The restorative techniques influenced microleakage and were flowable composite dependent (P <= 0.05). The lower thickness of the flowable composite provided less microleakage (P <= 0.05). CONCLUSION: The use a lower thickness of a flowable composite resin provided less microleakage, suggesting a better sealing tooth-restoration interface. PMID- 23946231 TI - Distally based saphenous neurocutaneous perforator flap combined with vac therapy for soft tissue reconstruction and hardware salvage in the lower extremities. AB - The complex wound with the exposed hardware and infection is one of the common complications after the internal fixation of the tibia fracture. The salvage of hardware and reconstruction of soft tissue defect remain challenging. In this report, we presented our experience on the use of the distally based saphenous neurocutaneous perforator flap combined with vacuum-assisted closure (VAC) therapy for the coverage of the soft tissue defect and the exposed hardware in the lower extremity with fracture. Between January 2008 and July 2010, seven patients underwent the VAC therapy followed by transferring a reversed saphenous neurocutaneous perforator flap for reconstruction of the wound with exposed hardware around the distal tibia. The sizes of the flaps ranged from 6 * 3 cm to 15 * 6 cm. Six flaps survived completely. Partial necrosis occurred in one patient. There were no other complications of repair and donor sites. Bone healing was achieved in all patients. In conclusion, the reversed saphenous neurocutaneous perfortor flaps combined with the VAC therapy might be one of the options to cover the complex wound with exposed hardware in the lower extremities. PMID- 23946232 TI - Prediction of nuclear grade of clear cell renal cell carcinoma with MRI: intratumoral susceptibility signal intensity versus necrosis. AB - BACKGROUND: End-stage renal disease and dialysis patients have a higher incidence of renal cell carcinoma (RCC) than the general population. Preoperatively evaluating the biological behavior of RCC plays an important role in treatment decision-making. Susceptibility-weighted imaging (SWI) can visualize the distribution of microvenous structures and hemorrhage without contrast materials. PURPOSE: To evaluate the feasibility of SWI in grading clear cell RCCs (CRCC) and compare the ability of SWI and necrosis for grading CRCCs. MATERIAL AND METHODS: Retrospective reviews of 35 patients with pathologically-proven CRCCs were performed. All patients underwent both conventional magnetic resonance imaging (MRI) and SWI examinations. The morphology of the intratumoral susceptibility signal intensities (ITSS) was classified into hemorrhage and microvessels. The differences of ITSSs on SWI and necrosis between low- and high-grade CRCCs were assessed. The diagnostic values of ITSSs and necrosis in differentiating low- from high-grade CRCCs were compared by receiver-operating characteristics. RESULTS: ITSSs were seen in 31 of 35 patients. No ITSSs were seen in four patients with low-grade CRCCs. Mean scores of ITSSs on SWI were significantly lower for low-grade CRCCs (1.24 +/- 0.72) than that for the high-grade CRCCs (2.70 +/- 0.48). No significant necrosis was seen in 10 patients with low-grade CRCCs. There was a significant difference of the presence of intratumoral necrosis between low- and high-grade CRCCs. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were for ITSSs: 70%, 100%, 100%, and 89.3%, respectively; for necrosis: 100%, 40%, 40%, and 100%. CONCLUSION: SWI can evaluate ITSSs without contrast materials and can be an alternative to grading CRCCs preoperatively for some special patients. PMID- 23946233 TI - Persistent petrosquamosal sinus in adults: qualitative imaging evaluation on high resolution CT venography. AB - BACKGROUND: The persistent petrosquamosal sinus (PSS) is usually overlooked before or during otological surgeries, which may cause misdiagnosis or iatrogenic bleedings. Imaging characteristics have not been well summarized for PSS, especially for large consecutive cases. PURPOSE: To analyze the characteristics of PSS on high-resolution CT venography (HRCTV) in order to improve imaging diagnostic accuracy as well as to assist clinical management. MATERIAL AND METHODS: Five hundred and thirty-two consecutive patients with pulsatile tinnitus who underwent CT angiography and venography examinations in the last 4 years were reviewed. Thirty patients with PSS in 39 temporal bones (TBs) were identified by two radiologists' consensus. The characteristics of PSS were analyzed according to its embryological variations. Different types of PSS were divided according to the origin and course, respectively. RESULTS: The average diameter of the PSS was 1.4 mm. Twenty-nine TBs (74%) had PSS origin from the dorsolateral surface of the transverse sinus before its junction with the superior petrosal sinus (Position A); three TBs (8%) had PSS origin from the ventroinferior surface of the transverse sinus after or before the junction (Position B or C); seven TBs (18%) had PSS without definite origin (Position D). Eighteen TBs (46%) had PSS course in a lateral bony canal/groove (lateral canal type); 15 TBs (38%) had PSS course in petrosquamosal fissure (PSF) (PSF type); six TBs (15%) had PSS course in both (lateral canal/PSF type). For other imaging findings, a branch entering the cranial part of PSS was identified in 10 TBs (26%); a vascular mass was formed in five TBs (13%); focal defect of bony wall was observed in seven TBs (18%). A postglenoid foramen (PGF) was detected in 25 TBs (64%). CONCLUSION: HRCTV can mostly identify the characteristics of PSS similar to its anatomic findings and the optimal imaging technique has the potential to improve its clinical management. PMID- 23946234 TI - Onset of chiral adenine surface growth. AB - The structure and stability of adenine crystals and thin layers has been studied by using scanning tunneling microscopy, X-ray diffraction, and density functional theory calculations. We have found that adenine crystals can be grown in two phases that are energetically quasi-degenerate, the structure of which can be described as a pile-up of 2D adenine planes. In each plane, the structure can be described as an aggregation of adenine dimers. Under certain conditions, kinetic effects can favor the growth of the less stable phase. These results have been used to understand the growth of adenine thin films on gold under ultra-high vacuum conditions. We have found that the grown phase corresponds to the alpha phase, which is composed of stacked prochiral planes. In this way, the adenine nanocrystals exhibit a surface that is enantiopure. These results could open new insight into the applications of adenine in biological, medical, and enantioselective or pharmaceutical fields. PMID- 23946235 TI - Predicting kinetically unstable C-C bonds from the ground-state properties of a molecule. AB - Determining the weakest link: A simple analysis pinpoints kinetically unstable carbon-carbon bonds. No prior knowledge of reaction pathways is necessary and the approach is particularly helpful for the prediction of novel molecules. krel =relaxed force constant, req =bond length. PMID- 23946236 TI - Selective aerobic oxidation of methanol in the coexistence of amines by nanoporous gold catalysts: highly efficient synthesis of formamides. AB - Holey gold: Highly selective aerobic oxidation of methanol over alkylamines was achieved with a reusable nanoporous gold (AuNPore) catalyst that was fabricated from a Au-Ag alloy. This excellent chemoselectivity enabled direct N-formylation of alkylamines from a mixture of methanol and amines. The remarkable catalytic activity was attributed to the synergistic effect between gold and the residual silver remaining in the AuNPore. PMID- 23946238 TI - Response to angiotensin-(1-7) and kidney disease:friend or foe. PMID- 23946237 TI - Tri-diketopyrrolopyrrole molecular donor materials for high-performance solution processed bulk heterojunction solar cells. AB - Two new high-performance DPP-containing donor molecules employing a molecular architecture with three DPP chromorphores (tri-DPP) in conjugated backbones are synthesized and characterized. The two tri-DPP molecules with only a structural difference on alkyl substitutions, when blended with PC71 BM, lead to power conversion efficiencies up to 4.8 and 5.5%, respectively. PMID- 23946239 TI - Effect of polymerization mode and time of adhesive system on microleakage in composite resin restorations. AB - AIM: To quantify the microleakage on restorations carried out with a two-step etch-and-rise adhesive system and nanofilled composite resin after thermal and mechanical loading cycling. METHODS: Ninety cavities were prepared on proximal surfaces of incisive teeth, and were randomly divided according to the photoactivation time (10, 20, or 30 s) and light-curing mode (Quartz Tungsten Halogen (QTH) lamps, 450 mW/cm(2); Light Emitting Diode (LED) second generation, 1100 mW/cm(2); or LED third generation, 700 mW/cm(2)) of an adhesive system (n = 10). Following restorative procedures and thermal and mechanical loading cycling, the samples were immersed in Methylene Blue for 2 h. The samples were ground, and the powder was prepared for analysis in an absorbance spectrophotometer. All results were statistically analyzed by anova and Tukey's test at the 5% level of significance. RESULTS: There were no significant statistical difference in microleakage between the light-curing mode (P = 0.1212) and light-curing time (P = 0.2043). CONCLUSION: Different curing modes and increasing the curing time were not factors that influenced the process of microleakage. PMID- 23946241 TI - Ultrafast photoinduced electron transfer in viologen-linked BODIPY dyes. AB - New boron-dipyrromethene (BODIPY) dyes linked to viologen are prepared and their photophysical and electrochemical properties are investigated. Both synthesized molecules have similar electronic absorption spectra with the absorption maximum localized at 517 and 501 nm for dye 1 and dye 2, respectively. They exhibit well defined redox behavior, highlighting the presence of BODIPY and viologen subunits, with little perturbation of the redox potential of both subunits with respect to the parent compounds. Both dyes are heavily quenched by photoinduced electron transfer from the BODIPY to the viologen subunit. The transient absorption technique demonstrates that dye 2 forms the viologen radical within a timeframe of 7.1 ps, and that the charge-separated species has a lifetime of 59 ps. Sustained irradiation of dye 2 in the presence of a tertiary amine allows for the accumulation of BODIPY-methyl-4,4'-bipyridinium (BODIPY-MV(+)), as observed by its characteristic absorption at 396 and 603 nm. However, dye 2 does not generate catalytic amounts of hydrogen under standard conditions. PMID- 23946240 TI - Effects of SiO2, SrO, MgO, and ZnO dopants in tricalcium phosphates on osteoblastic Runx2 expression. AB - Calcium phosphate materials share a compositional similarity to natural bone, which makes them excellent for use in orthopedic applications. Although these materials are osteoconductive, they lack strong osteoinductive capabilities and recent research has focused on the addition of biologics and pharmacologics with varying successes. In this study, trace elements that have been proven to play important roles in bone health and bone formation were incorporated into beta tricalcium phosphate compacts in their oxide forms (SiO2, ZnO, SrO, and MgO). Cell material interactions were characterized using human fetal preosteoblastic cells. An MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was used to evaluate cellular proliferation. Cellular differentiation was evaluated using an enzymatic colorimetric alkaline phosphatase assay as well as immunohistochemistry for Runt-related transcription factor 2 (Runx2) expression. Results prove ZnO and MgO to be effective mitogenic factors and SiO2, ZnO, and SrO to be capable of inducing rapid cellular differentiation. MgO was found to have little effect on the modulation of osteoblastic differentiation, likely due to more aggressive inherent cellular regulation of Mg(2+). In addition to the results from the study, a signaling mechanism is proposed as to the action of the dopants for further consideration. PMID- 23946242 TI - Palladium/copper-catalyzed oxidative C-H alkenylation/N-dealkylative carbonylation of tertiary anilines. AB - C-H/C-N activation: The first palladium/copper-catalyzed aerobic oxidative C-H alkenylation/N-dealkylative carbonylation of tertiary anilines has been developed. Various functional groups were tolerated and acrylic ester could also be suitable substrates. This transformation provided efficient and straightforward synthesis of biologically active 3-methyleneindolin-2-one derivatives from cheap and simple substrates. PMID- 23946243 TI - Assessment of dispersive liquid-liquid microextraction for the simultaneous extraction, preconcentration, and derivatization of Hg2+ and CH3Hg+ for further determination by GC-MS. AB - This work reports the development of a dispersive liquid-liquid microextraction method for the simultaneous extraction, preconcentration, and derivatization of Hg(2+) and CH3Hg(+) species from water samples for further determination by GC MS. Some parameters of the proposed method, such as volume and type of disperser and extraction solvent, and Na[B(C6H5)4] concentration were investigated using response surface methodology. Suitable recoveries were obtained using 80 MUL C2 Cl4 (as extraction solvent), 1000 MUL ethanol (as disperser solvent), and 300 MUL 2.1 mmol/L Na[B(C6H5)4] (as derivatizing agent). Accuracy was evaluated in terms of recovery and ranged from 87 to 99% with RSD values <7%. In addition, a certified reference material of water (NIST 1641d) was analyzed and agreed with the certified value about 107% (for Hg(2+)), with RSD values <8.5%. LODs were 0.3 and 0.2 MUg/L, with enrichment factors of 112 and 115 for Hg(2+) and CH3Hg(+), respectively. The optimized method was applied for the determination of Hg(2+) and CH3Hg(+) in tap, well, and lake water samples. PMID- 23946244 TI - Scalable one-step assembly of an inexpensive photoelectrode for water oxidation by deposition of a Ti- and Ni-containing molecular precursor on nanostructured WO3. AB - Photoactive in one step! A nanocomposite water-oxidation photocatalyst was assembled by a straightforward and one-step spin-coating procedure of a Ti- and Ni-containing molecule on nanostructured WO3. The photoanode oxidizes water to O2 with good activity and stability in alkaline solution, and thereby features light absorption, charge separation and water-oxidation catalysis (see scheme). PMID- 23946245 TI - Near-incompressible faceted polymer microcapsules from metal-organic framework templates. AB - Faceted polymer microcapsules are prepared from metal-organic framework (MOF) templates. The MOF templates are removable under mild aqueous conditions. The obtained microcapsules are stiffer than their spherical counterparts, reflecting the near-incompressibility of the facet edges, and indicating that the faceting might be a useful strategy for controlling the mechanical properties of polymer microcapsules. PMID- 23946246 TI - Enantioseparation of tartaric acid by ligand-exchange capillary electrophoresis using contactless conductivity detection. AB - A method for the determination of tartaric acid enantiomers using CE with contactless conductivity detection has been developed. Cu(II) as a central metal ion together with L-hydroxyproline were used as a chiral selector, the BGE was composed of 7 mM CuCl2, 14 mM trans-4-hydroxy-L-proline, and 100 mM epsilon aminocaproic acid; the pH was adjusted to 5 by hydrochloric acid. Separation with a resolution of 1.9 was achieved in 9 min in a polyacrylamide-coated capillary to suppress the EOF. Various counterions of the BGE were studied, and migration order reversal was achieved when switching from epsilon-aminocaproic acid to L histidine. With detection limits of about 20 MUM, the method was applied to the analysis of wine and grape samples; only L-tartaric acid was found. PMID- 23946247 TI - The use of new surface-modified poly(2-hydroxyethyl methacrylate) hydrogels in tissue engineering: treatment of the surface with fibronectin subunits versus Ac CGGASIKVAVS-OH, cysteine, and 2-mercaptoethanol modification. AB - Superporous poly(2-hydroxyethyl methacrylate) is successfully used as a scaffold material for tissue engineering; however, it lacks functional groups that support cell adhesion. The objective of this study was to investigate the cell-adhesive properties of biomimetic ligands, such as laminin-derived Ac-CGGASIKVAVS-OH (SIKVAV) peptide and fibronectin subunits (Fn), as well as small molecules exemplified by 2-mercaptoethanol (ME) and cysteine (Cys), immobilized on a copolymer of 2-hydroxyethyl methacrylate (HEMA) with 2-aminoethyl methacrylate (AEMA) by a maleimide-thiol coupling reaction. The maleimide group was introduced to the P(HEMA-AEMA) hydrogels by the reaction of their amino groups with N-gamma maleimidobutyryl-oxysuccinimide ester (GMBS). Mesenchymal stem cells (MSCs) were used to investigate the cell adhesive properties of the modified hydrogels. A significantly larger area of cell growth as well as a higher cell density were found on Fn- and SIKVAV-modified hydrogels when compared to the ME- and Cys modified supports or neat P(HEMA-AEMA). Moreover, Fn-modification strongly stimulated cell proliferation. The ability of MSCs to differentiate into adipocytes and osteoblasts was maintained on both Fn- and SIKVAV-modifications, but it was reduced on ME-modified hydrogels and neat P(HEMA-AEMA). The results show that the immobilization of SIKVAV and Fn-subunits onto superporous P(HEMA AEMA) hydrogels via a GMBS coupling reaction improves cell adhesive properties. The high proliferative activity observed on Fn-modified hydrogels suggests that the immobilized Fn-subunits maintain their bioactivity and thus represent a promising tool for application in tissue engineering. PMID- 23946248 TI - Enantiomer-specific oriented attachment: formation of macroscopic homochiral crystal aggregates from a racemic system. AB - Let's get together: Racemic samples of d- and l-enantiomorphous NaBrO3 (or NaClO3) crystals aggregate with nearly complete enantioselection. Centimeter sized enantiopure megacrystals are often produced, and these can be sorted easily. PMID- 23946249 TI - Periodontal disease awareness among pregnant women in the central and eastern regions of Saudi Arabia. AB - AIM: The purpose of this study was to assess the knowledge and awareness regarding periodontal disease and its effects on pregnancy among pregnant women in the central and eastern regions of Saudi Arabia. METHODS: In this cross sectional survey, self-administered, structured questionnaires were distributed to 300 pregnant women who were chosen randomly from attendees of maternity health care centers in the central and eastern regions of Saudi Arabia. The questions were developed from literature reviews of articles. The questionnaire addressed personal and sociodemographic variables, periodontal health awareness, and knowledge of pregnant women. The questionnaire was translated into Arabic and was pretested during the pilot study on a random sample of 50 pregnant women. Data were analyzed by chi(2) -tests, with the level of significance set at P < 0.05. RESULTS: An overall response rate of 81% was obtained. Approximately 53% had a higher level of education, but only 21% knew how to define dental plaque and 30% knew its harmful effects. Almost 73% stated that gum disease could be prevented through toothbrushing and flossing. Approximately 97% of the respondents knew the negative effect of smoking, while only 12% knew there was a possible relationship between periodontal disease and adverse pregnancy outcomes. CONCLUSION: The results of this cross-sectional study found that there is limited knowledge and awareness about periodontal disease and its possible effects on pregnancy among pregnant women attending maternal health care centers in the central and eastern regions of Saudi Arabia. PMID- 23946250 TI - Imaging nanocarbon materials: soot particles in flames are not structurally homogeneous. AB - For the first time, nascent soot particles are probed by using helium-ion microscopy (HIM). HIM is a technique that is similar to scanning electron microscopy (SEM) but it can achieve higher contrast and improved surface sensitivity, especially for carbonaceous materials. The HIM microscope yields images with a high contrast, which allows for the unambiguous recognition of smaller nascent soot particles than those observed in previous transmission electron microscopy studies. The results indicate that HIM is ideal for rapid and reliable probing of the morphology of nascent soot, with surface details visible down to approximately 5 nm, and particles as small as 2 nm are detectable. The results also show that nascent soot is structurally and chemically inhomogeneous, and even the smallest particles can have shapes that deviate from a perfect sphere. PMID- 23946251 TI - Nanoparticles mimicking viral surface topography for enhanced cellular delivery. AB - Novel silica nanoparticles mimicking virus surface topography are prepared. It is demonstrated that increases in nanoscale surface roughness promote both binding of biomolecules and cellular uptake; thus, the cellular delivery efficiency is significantly increased (scale bars 20 MUm). PMID- 23946252 TI - Hyperpolarized singlet lifetimes of pyruvate in human blood and in the mouse. AB - Hyperpolarized NMR is a promising technique for non-invasive imaging of tissue metabolism in vivo. However, the pathways that can be studied are limited by the fast T1 decay of the nuclear spin order. In metabolites containing pairs of coupled nuclear spins-1/2, the spin order may be maintained by exploiting the non magnetic singlet (spin-0) state of the pair. This may allow preservation of the hyperpolarization in vivo during transport to tissues of interest, such as tumors, or to detect slower metabolic reactions. We show here that in human blood and in a mouse in vivo at millitesla fields the (13)C singlet lifetime of [1,2 (13)C2]pyruvate was significantly longer than the (13)C T1, although it was shorter than the T1 at field strengths of several tesla. We also examine the singlet-derived NMR spectrum observed for hyperpolarized [1,2-(13)C2]lactate, originating from the metabolism of [1,2-(13)C2]pyruvate. PMID- 23946253 TI - The process of advance care planning in HCT candidates and proxies: self efficacy, locus of control, and anxiety levels. AB - The purpose of this study was to examine the relationship between hematopoietic cell transplant candidate and proxy advance care planning (ACP) behavior and attitudes. A total of 49 candidates and 44 proxies completed the Advance Directive Attitudes Survey, Multidimensional Health Locus of Control Scale, Family Decision Making Self-Efficacy Scale, and the State-Trait Anxiety Inventory. In all, 45% of candidates reported completing an advance directive (AD), while only 26% had ADs on file; 80% of candidates discussed ACP wishes with their loved ones and 15% discussed ACP wishes with their medical team. The AD completers were significantly (1) older, (2) more positive about ADs, and (3) were less likely to believe that health events happen by chance. Discrepancies between reported ACP behavior and communication with health care practitioners have implications for end-of-life care. PMID- 23946254 TI - The influence of the family in conceptions of personhood in the palliative care setting in Singapore and its influence upon decision making. AB - Conceptions of personhood are critical to the preservation of dignity and quality of life key to a good death and pivotal to the provision of patient centred care. Increasingly there is speculation that this role may be wider still. It has been posited that it is Confucian inspired conceptions of personhood replete with its 'dualistic' view of personhood that sees family members as part of the individual's personhood that predispose to the prevailing practices of collusion and the trumping of patient autonomy. In a nation where family centric decision making still dominates end of life decision making, the need to appropriately conceptualise local conceptions of personhood are clear. To this end a mixed methods study of 30 Singaporean oncology and palliative care patients was undertaken. Data accrued revealed local conceptions of personhood to be evolving ideas that are determined by four equally important closely related dimensions. Here Innate Personhood which represents the belief that all persons irrespective of their clinical condition and level of development are deserving of personhood, Individual Personhood which relates to consciousness related faculties, Relational Personhood which relates to the social and familial connections important to the person and Societal Personhood which relates to the roles played in society; combine to proffer the Ring Theory of Personhood. This concept provides a better means of providing for the specific needs of patients with life threatening illnesses whilst providing a unique insight into the role families play in the manner local patients conceive themselves to be. PMID- 23946255 TI - Risk factors for long-term failure of the retropubic tension-free vaginal tape procedure. AB - AIMS: To investigate potential risk factors for long-term (10-year) subjective and objective failure of the retropubic tension-free vaginal tape procedure (TVT). METHODS: Secondary risk analysis was performed using data from a recently published multi-center study that were merged with additional preoperative and operative data individually stored in the Norwegian Female Incontinence Registry (NFIR). Subjective data from 483 women and objective data from 327 women were obtained 10 years after retropubic TVT surgery. A validated questionnaire was used for subjective outcome data and a stress test for objective outcome data. Uni- and multivariate logistic regression analyses were performed using preoperative and operative variables extracted from the NFIR. The outcomes were 10-year subjective failure defined as women stating not cured, and objective failure was defined as >=1 g urinary leakage during stress testing. RESULTS: Age >=56 years at the time of TVT surgery was associated with both long-term subjective failure (adjusted OR: 2.15, CI: 1.40-3.30) and long-term objective failure (adjusted OR: 2.81, CI: 1.30-6.09). Mixed incontinence was associated with subjective, but not objective failure if the urgency incontinence component was severe (adjusted OR: 2.33, CI: 1.27-4.28). Surgical complications occurring at or immediately following surgery were associated with both outcomes in the univariate analyses, but were only an independent risk factor for subjective failure in the multivariate analysis (adjusted OR: 3.02, CI: 1.53-5.95). CONCLUSIONS: Age >=56 years, a severe preoperative urgency incontinence component and surgical complications seem to represent independent risk factors for long term (10-year) failure. PMID- 23946256 TI - Reactivity of dicoordinated stannylones (Sn0) versus stannylenes (SnII): an investigation using DFT-based reactivity indices. AB - The reactivity of dicoordinated Sn(0) compounds, stannylones, is probed using density functional theory (DFT)-based reactivity indices and compared with the reactivity of dicoordinated Sn(II) compounds, stannylenes. For the former compounds, the influence of different types of electron-donating ligands, such as cyclic and acyclic carbenes, stannylenes and phosphines, on the reactivity of the central Sn atom is analyzed in detail. Sn(0) compounds are found to be relatively soft systems with a high nucleophilicity, and the plots of the Fukui function f( ) for an electrophilic attack consistently predict the highest reactivity on the Sn atom. Next, complexes of dicoordinated Sn compounds with different Lewis acids of variable hardness are computed. In a first part, the double-base character of stannylones is demonstrated in interactions with the hardest Lewis acid H(+). Both the first and second proton affinities (PAs) are high and are well correlated with the atomic charge on the Sn atom, probing its local hardness. These observations are also in line with electrostatic potential plots that demonstrate that the tin atom in Sn(0) compounds bears a higher negative charge in comparison to Sn(II) compounds. Stannylones and stannylenes can be distinguished from each other by the partial charges at Sn and by various reactivity indices. It also becomes clear that there is a smooth transition between the two classes of compounds. We furthermore demonstrate both from DFT based reactivity indices and from energy decomposition analysis, combined with natural orbitals for chemical valence (EDA-NOCV), that the monocomplexed stannylones are still nucleophilic and as reactive towards a second Lewis acid as towards the first one. The dominating interaction is a strong sigma-type interaction from the Sn atom towards the Lewis acid. The interaction energy is higher for complexes with the cation Ag(+) than with the non-charged electrophiles BH(3), BF(3), and AlCl(3). PMID- 23946257 TI - Oxygen-rich coating promotes binding of proteins and endothelialization of polyethylene terephthalate polymers. AB - The formation of endothelial cell monolayer on prosthetic implants has not sufficiently explored. The main reasons leading to the development of thrombosis and/or intimal hyperplasia is the lack of endothelialization. In the present work, we have studied the influence of oxygen and fluorine plasma treatment of polyethylene terephthalate (PET) polymers on human microvascular endothelial cell adhesion and proliferation. We characterized the polymer surface, wettability, and oxidation potential upon plasma treatment. Moreover, binding of serum and media compounds on PET surface was monitored by Quartz crystal microbalance method, X-ray photoelectron spectroscopy, and atomic force microscopy. Cell adhesion and morphology was assessed by light and scanning electron microscopy. The influence of plasma treatment on induction of cellular oxidative stress and cell proliferation was evaluated. The results obtained showed that treatment with oxygen plasma decreased the oxidation potential of the PET surface and revealed the highest affinity for binding of serum components. Accordingly, the cells reflected the best adhesion and morphological properties on oxygen-treated PET polymers. Moreover, treatment with oxygen plasma did not induce intracellular reactive oxygen species production while it stimulated endothelial cell proliferation by 25% suggesting the possible use of oxygen plasma treatment to enhance endothelialization of synthetic vascular grafts. PMID- 23946258 TI - Advances in regeneration of dental pulp--a literature review. AB - This review summarizes the biological response of dentin-pulp complexes to a variety of stimuli and responses to current treatment therapies and reviews the role of tissue engineering and its application in regenerative endodontics. An electronic search was undertaken based on keywords using Medline/PubMed, Embase, Web of Science and Ovid database resources up to March 2012 to identify appropriate articles, supplemented by a manual search using reference lists from relevant articles. Inclusion criteria were mainly based on different combinations of keywords and restricted to articles published in English language only. Biological approaches based on tissue engineering principles were found to offer the possibility of restoring natural tooth vitality, with distinct evidence that regeneration of lost dental tissues is possible. Studies to formulate an ideal restorative material with regenerative properties, however, are still under way. Further research with supporting clinical studies is required to identify the most effective and safe treatment therapy. PMID- 23946259 TI - Structural analysis of phenothiazine derivatives as allosteric inhibitors of the MALT1 paracaspase. PMID- 23946260 TI - Effectiveness of group reminiscence therapy for depressive symptoms in male veterans: 6-month follow-up. AB - OBJECTIVE: The purpose of this study was to use group reminiscence therapy (GRT) as a nursing intervention to evaluate the post-test, 3-month and 6-month effects on depressive symptoms for institutionalised male veterans after a 4-week intervention. METHODS: A quasi-experimental design and purposive sampling was conducted at a veteran's nursing home in Northern Taiwan. A total of 21 male veterans were studied to measure the effect of GRT. Eleven participants were in the experimental group and 10 in the control group. The experimental group activity was held twice weekly for 4 weeks. The Taiwan Geriatric Depression Scale was used to assess depressive symptoms and geriatric depression among male veterans. The generalised estimating equation was used for data analysis. RESULTS: The male veterans in this study had a mean age of 82 years (SD = 5.8); 47.62% were between 70 and 79 years old, 61.90% were illiterate and 90.48% were without a partner. After 4 weeks of GRT, the experimental group significantly improved their depressive symptoms and geriatric depression in the post-test, 3 month and 6-month follow-up data compared with the control group. These activities can reduce their depressive symptoms following the intervention. CONCLUSION: A 4-week, eight-session GRT can effectively reduce depressive symptoms among institutionalised male veterans for a 6-month period. PMID- 23946261 TI - A rapid and efficient self-healing thermo-reversible elastomer crosslinked with graphene oxide. AB - A self-healing thermo-reversible elastomer is synthesized by cross-linking a hydrogen bonding polymer network with chemically-modified graphene oxide. This nanocomposite allows for both rapid and efficient self-healing (in only several minutes) at room temperature, without the need for any external stimuli (e.g., heating or light exposure), healing agents, plasticizers or solvents. PMID- 23946262 TI - Identification of differentially expressed proteins by treatment with PUGNAc in 3T3-L1 adipocytes through analysis of ATP-binding proteome. AB - O-GlcNAc (2-acetamino-2-deoxy-beta-D-glucopyranose), an important modification for cellular processes, is catalyzed by O-GlcNAc transferase and O-GlcNAcase. O (2-acetamido-2-deoxy-D-glucopyranosylidene) amino-N-phenylcarbamate (PUGNAc) is a nonselective inhibitor of O-GlcNAcase, which increases the level of protein O GlcNAcylation and is known to induce insulin-resistance in adipose cells due to uncharacterized targets of this inhibitor. In this study, using ATP affinity chromatography, we applied a targeted proteomic approach for identification of proteins induced by treatment with PUGNAc. For optimization of proteomic methods using ATP affinity chromatography, comparison of two cell lines (3T3-L1 adipocytes and C2C12 myotubes) and two different digestion steps was performed using four different structures of immobilized ATP-bound resins. Using this approach, based on DNA sequence homologies, we found that the identified proteins covered almost half of ATP-binding protein families classified by PROSITE. The optimized ATP affinity chromatography approach was applied for identification of proteins that were differentially expressed in 3T3-L1 adipocytes following treatment with PUGNAc. For label-free quantitation, a gel-assisted method was used for digestion of the eluted proteins, and analysis was performed using two different MS modes, data-independent (671 proteins identified) and data-dependent (533 proteins identified) analyses. Among identified proteins, 261 proteins belong to nucleotide-binding proteins and we focused on some nucleotide-binding proteins, ubiquitin-activation enzyme 1 (E1), Hsp70, vasolin-containing protein (Vcp), and Hsp90, involved in ubiquitin-proteasome degradation and insulin signaling pathways. In addition, we found that treatment with PUGNAc resulted in increased ubiquitination of proteins in a time-dependent manner, and a decrease in both the amount of Akt and the level of phosphorylation of Akt, a key component in insulin signaling, through downregulation of Hsp90. In this study, based on a targeted proteomic approach using ATP affinity chromatography, we found four proteins related to ubiquitination and insulin signaling pathways that were induced by treatment with PUGNAc. This result would provide insight into understanding functions of PUGNAc in 3T3-L1 cells. PMID- 23946263 TI - Cost-effectiveness of percutaneous coronary intervention in patients with stable coronary artery disease and abnormal fractional flow reserve. AB - BACKGROUND: The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) 2 trial demonstrated a significant reduction in subsequent coronary revascularization among patients with stable angina and at least 1 coronary lesion with a fractional flow reserve <=0.80 who were randomized to percutaneous coronary intervention (PCI) compared with best medical therapy. The economic and quality-of-life implications of PCI in the setting of an abnormal fractional flow reserve are unknown. METHODS AND RESULTS: We calculated the cost of the index hospitalization based on initial resource use and follow-up costs based on Medicare reimbursements. We assessed patient utility using the EQ-5D health survey with US weights at baseline and 1 month and projected quality adjusted life-years assuming a linear decline over 3 years in the 1-month utility improvements. We calculated the incremental cost-effectiveness ratio based on cumulative costs over 12 months. Initial costs were significantly higher for PCI in the setting of an abnormal fractional flow reserve than with medical therapy ($9927 versus $3900, P<0.001), but the $6027 difference narrowed over 1-year follow-up to $2883 (P<0.001), mostly because of the cost of subsequent revascularization procedures. Patient utility was improved more at 1 month with PCI than with medical therapy (0.054 versus 0.001 units, P<0.001). The incremental cost-effectiveness ratio of PCI was $36 000 per quality-adjusted life year, which was robust in bootstrap replications and in sensitivity analyses. CONCLUSIONS: PCI of coronary lesions with reduced fractional flow reserve improves outcomes and appears economically attractive compared with best medical therapy among patients with stable angina. PMID- 23946264 TI - Stroke or transient ischemic attack in patients with transvenous pacemaker or defibrillator and echocardiographically detected patent foramen ovale. AB - BACKGROUND: A patent foramen ovale (PFO) may permit arterial embolization of thrombi that accumulate on the leads of cardiac implantable electronic devices in the right-sided cardiac chambers. We sought to determine whether a PFO increases the risk of stroke/transient ischemic attack (TIA) in patients with endocardial leads. METHODS AND RESULTS: We retrospectively evaluated all patients who had endocardial leads implanted between January 1, 2000, and October 25, 2010, at Mayo Clinic Rochester. Echocardiography was used to establish definite PFO and non-PFO cohorts. The primary end point of stroke/TIA consistent with a cardioembolic etiology and the secondary end point of mortality during postimplantation follow-up were compared in PFO versus non-PFO patients with the use of Cox proportional hazards models. We analyzed 6075 patients (364 with PFO) followed for a mean 4.7 +/- 3.1 years. The primary end point of stroke/TIA was met in 30/364 (8.2%) PFO versus 117/5711 (2.0%) non-PFO patients (hazard ratio, 3.49; 95% confidence interval, 2.33-5.25; P<0.0001). The association of PFO with stroke/TIA remained significant after multivariable adjustment for age, sex, history of stroke/TIA, atrial fibrillation, and baseline aspirin/warfarin use (hazard ratio, 3.30; 95% confidence interval, 2.19-4.96; P<0.0001). There was no significant difference in all-cause mortality between PFO and non-PFO patients (hazard ratio, 0.91; 95% confidence interval, 0.77-1.07; P=0.25). CONCLUSIONS: In patients with endocardial leads, the presence of a PFO on routine echocardiography is associated with a substantially increased risk of embolic stroke/TIA. This finding suggests a role of screening for PFOs in patients who require cardiac implantable electronic devices; if a PFO is detected, PFO closure, anticoagulation, or nonvascular lead placement may be considered. PMID- 23946266 TI - Baby or bathwater?: Early follow-up after hospital discharge. PMID- 23946265 TI - Association of early physician follow-up and 30-day readmission after non-ST segment-elevation myocardial infarction among older patients. AB - BACKGROUND: Hospital readmission rates within 30 days after acute myocardial infarction are a national performance metric. Previous data suggest that early physician follow-up after heart failure hospitalizations can reduce readmissions; whether these results can be extended to acute myocardial infarction is unclear. METHODS AND RESULTS: We analyzed data from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) Registry linked with Medicare claims from 2003 to 2006 for 25 872 non-ST-segment-elevation myocardial infarction patients >=65 years of age discharged home from 228 hospitals with >25 patients and full revascularization capabilities. After adjusting for patient, treatment, and hospital characteristics, we examined the relationship between hospital-level physician follow-up within 7 days of discharge and 30-day all-cause readmission using logistic regression. The median hospital-level percentage of patients receiving early physician follow-up was 23.3% (interquartile range, 17.1%-29.1%). Among 24 165 patients with Medicare fee-for-service eligibility 30 days after discharge, 18.5% of patients were readmitted within 30 days of index hospitalization. Unadjusted and adjusted rates of 30-day readmission did not differ among quartiles of hospital-level early physician follow-up. Similarly, each 5% increase in hospital early follow-up was associated with an insignificant change in risk for readmission (adjusted odds ratio, 0.99; 95% confidence interval, 0.97-1.02; P=0.60). Sensitivity analyses extended these null findings to 30-day cardiovascular readmissions, high-risk subgroups, and early cardiology follow-up. CONCLUSIONS: Although rates of early physician follow-up after acute myocardial infarction varied among US hospitals, hospitals with higher early follow-up rates did not have lower 30-day readmission rates. Targeting strategies other than early physician follow-up may be necessary to reduce readmissions in this population. PMID- 23946267 TI - Masculinizing effect of background color and cortisol in a flatfish with environmental sex-determination. AB - Environmental sex-determination (ESD) is the phenomenon by which environmental factors regulate sex-determination, typically occurring during a critical period of early development. Southern flounder (Paralichthys lethostigma) exhibit temperature-dependent sex-determination that appears to be restricted to the presumed XX female genotype with the extremes of temperature, both high and low, skewing sex ratios toward males. In order to evaluate other environmental factors that may influence sex-determination, we investigated the influence of background color and cortisol on sex-determination in southern flounder. Experiments involving three sets of tanks, each painted a different color, were conducted at different temperatures using southern flounder of mixed XX-XY genotype. The studies involved rearing juvenile southern flounder in either black, gray, or blue tanks and sex-determination was assessed by gonadal histology. In both studies, blue tanks showed significant male-biased sex ratios (95 and 75% male) compared with black and gray tanks. The stress corticosteroid cortisol may mediate sex-determining processes associated with environmental variables. Cortisol from the whole body was measured throughout the second experiment and fishes in blue tanks had higher levels of cortisol during the period of sex determination. These data suggest that background color can be a cue for ESD, with blue acting as a stressor during the period of sex-determination, and ultimately producing male-skewed populations. In a separate study using XX populations of southern flounder, cortisol was applied at 0, 100, or 300 mg/kg of gelatin-coated feed. Fish were fed intermittently prior to, and just through, the period of sex-determination. Levels of gonadal P450 aromatase (cyp19a1) and forkhead transcription factor L2 (FoxL2) messenger RNA (mRNA) were measured by qRT-PCR as markers for differentiation into females. Mullerian-inhibiting substance mRNA was used as a marker of males' gonadal development. Control fish showed female-biased sex ratios approaching 100%, whereas treatment with 100 mg/kg cortisol produced 28.57% females and treatment with 300 mg/kg cortisol produced only 13.33% females. These results suggest that cortisol is a critical mediator of sex-determination in southern flounder by promoting masculinization. This linkage between the endocrine stress axis and conserved sex-determination pathways may provide a mechanism for adaptive modification of sex ratio in a spatially and temporally variable environment. PMID- 23946268 TI - Site-targeted non-viral gene delivery by direct DNA injection into the pancreatic parenchyma and subsequent in vivo electroporation in mice. AB - The pancreas is considered an important gene therapy target because the organ is the site of several high burden diseases, including diabetes mellitus, cystic fibrosis, and pancreatic cancer. We aimed to develop an efficient in vivo gene delivery system using non-viral DNA. Direct intra-parenchymal injection of a solution containing circular plasmid pmaxGFP DNA was performed on adult anesthetized ICR female mice. The injection site was sandwiched with a pair of tweezer-type electrode disks, and electroporated using a square-pulse generator. Green fluorescent protein (GFP) expression within the injected pancreatic portion was observed one day after gene delivery. GFP expression reduced to baseline within a week of transfection. Application of voltages over 40 V resulted in tissue damage during electroporation. We demonstrate that electroporation is effective for safe and efficient transfection of pancreatic cells. This novel gene delivery method to the pancreatic parenchyma may find application in gene therapy strategies for pancreatic diseases and in investigation of specific gene function in situ. PMID- 23946269 TI - An initial assessment of haptics in preclinical operative dentistry training. AB - AIM: The purpose of this study was to assess novice student perception of haptic based manual dexterity training. The short-term impact of haptic training in the early phase of preclinical operative dentistry education was also investigated. METHODS: Dental students performed a class II amalgam and a class III resin tooth preparation in a typodont model at baseline. The experimental group performed exercises on the manual dexterity module of the IDEATM software using a haptic device. The exercises required removing the maximum amount of three-dimensional geometric shapes within a predetermined width and depth. Tooth preparations were repeated 2 weeks later. A questionnaire survey was given to assess the subjective evaluation of the haptic simulation exercise. RESULTS: Tooth preparations were scored regarding external outline, internal form, and integrity of adjacent tooth. Improvement of overall tooth preparation scores post-haptic use was not statistically significant compared to controls (P > 0.05). However, students found the game-feature of the haptic device made the learning experience more fun and interesting. CONCLUSION: The haptic exercises with the manual dexterity module software were not superior in improving the dexterity of students for tooth cavity preparations in short-term. Benefits of ease of use and fun learning experience can be further investigated in future studies. PMID- 23946270 TI - The effect of active ingredient-containing chitosan/polycaprolactone nonwoven mat on wound healing: in vitro and in vivo studies. AB - The use of an electrospun polycaprolactone (PCL) nonwoven mat that is coated with a layer of chitosan (CS) containing active ingredient [tea tree oil (TTO)] represents an effective strategy for producing functional dressings. CS-coated porous PCL nonwoven mat (CS3/PCLNM) with various concentrations of active ingredients were produced and investigated. In vitro, active ingredient containing CS3/PCLNM is effective in inhibiting the formation of nitrite and the growth of Staphylococcus aureus. Both active ingredient TTO and CS have been proven to reach their maximum amount of releases within 24 h of contact with water-based environment. In vivo, full-thickness skin removal (1.2 cm * 1.2 cm) was performed on the back of the C57BL6/J mice in noninfected and infected animal models. Four groups of functional dressings were tested in this work including TegdermTM, PCLNM, CS3/PCLNM, and 100 MUL TTO-CS3/PCLNM. After 7 days post treatment, the bacterial levels were found to be significantly lower in both CS3/PCLNM and 100 MUL TTO-CS3/PCLNM-treated groups than in the control group (81.6 +/- 18.1% and 93.7 +/- 9.57% of reductions in the bacterial load in the pus relative to the control group, respectively). Additionally, based on the histological analyses, the 100 MUL TTO-CS3/PCLNM-treated group outperformed all other groups in wound healing. PMID- 23946271 TI - Computational study of the one- and two-dimensional infrared spectra of a proton transfer mode in a hydrogen-bonded complex dissolved in a polar nanocluster. AB - The signatures of nanosolvation on the one- and two-dimensional (1D and 2D) IR spectra of a proton-transfer mode in a hydrogen-bonded complex dissolved in polar solvent molecule nanoclusters of varying size are elucidated by using mixed quantum-classical molecular dynamics simulations. For this particular system, increasing the number of solvent molecules successively from N=7 to N=9 initiates the transition of the system from a cluster state to a bulk-like state. Both the 1D and 2D IR spectra reflect this transition through pronounced changes in their peak intensities and numbers, but the time-resolved 2D IR spectra also manifest spectral features that uniquely identify the onset of the cluster-to-bulk transition. In particular, it is observed that in the 1D IR spectra, the relative intensities of the peaks change such that the number of peaks decreases from three to two as the size of the cluster increases from N=7 to N=9. In the 2D IR spectra, off-diagonal peaks are observed in the N=7 and N=8 cases at zero waiting time, but not in the N=9 case. It is known that there are no off-diagonal peaks in the 2D IR spectrum of the bulk version of this system at zero waiting time, so the disappearance of these peaks is a unique signature of the onset of bulk-like behavior. Through an examination of the trajectories of various properties of the complex and solvent, it is possible to relate the emergence of these off-diagonal peaks to an interplay between the vibrations of the complex and the solvent polarization dynamics. PMID- 23946272 TI - Graphene fibers with predetermined deformation as moisture-triggered actuators and robots. AB - Enough to make your hair curl! Moisture-responsive graphene (G) fibers can be prepared by the positioned laser reduction of graphene oxide (GO) counterparts. When exposed to moisture, the asymmetric G/GO fibers display complex, well controlled motion/deformation in a predetermined manner. These fibers can function not only as a single-fiber walking robot under humidity alternation but also as a new platform for woven devices and smart textiles. PMID- 23946274 TI - Additional risk minimisation measures in the EU - are they eligible for assessment? AB - PURPOSE: "Additional" risk minimisation measures (aRMMs) can be necessary to optimise the benefit-risk balance of a drug. Evaluation of effectiveness of these measures has become mandatory with the new European Union (EU) pharmacovigilance legislation in force since July 2012. The aim of this study was to classify the aRMMs in the EU with a special emphasis on the possibilities to analyse the effectiveness of these aRMMs in existing electronic healthcare databases (EHDs). METHODS: European Public Assessment Reports were reviewed to identify key elements of the aRMMs. Researchers categorised the key elements based on the objectives, i.e. knowledge change or behavioural change and sub-categorised the behavioural changes. They assessed for each key element if it would be eligible for analysis in existing EHDs. RESULTS: 68 drugs with aRMMs contained 801 key elements of which 57% aimed at behavioural changes. 22% of all key elements, all aimed behavioural changes, were assessed eligible for analysis in existing EHDs. These mainly concerned recommendations targeted at healthcare professionals regarding drug prescription, e.g. dose recommendations, contraindications or the need to perform laboratory tests for patient monitoring. CONCLUSIONS: Only a limited proportion of key elements of the aRMMs could potentially be monitored in existing EHDs as these data sources cannot capture all the required data. Due to difference between existing EHDs, not necessarily all available EHDs are appropriate for every drug or aRMM. To facilitate rapid evaluation of aRMM implementation and timely adjustments, industry and regulatory authorities should agree well-defined key elements of aRMMs leading to unambiguous actions of the target group. PMID- 23946273 TI - A novel method for applying reduced graphene oxide directly to electronic textiles from yarns to fabrics. AB - Conductive, flexible, and durable reduced RGO textiles with a facile preparation method are presented. BSA proteins serve as universal adhesives for improving the adsorption of GO onto any textile, irrespective of the materials and the surface conditions. Using this method, we successfully prepared various RGO textiles based on nylon-6 yarns, cotton yarns, polyester yarns, and nonwoven fabrics. PMID- 23946275 TI - Increased hypothalamic-pituitary-adrenal drive is associated with decreased appetite and hypoactivation of food-motivation neurocircuitry in anorexia nervosa. AB - OBJECTIVE: Corticotrophin-releasing hormone (CRH)-mediated hypercortisolemia has been demonstrated in anorexia nervosa (AN), a psychiatric disorder characterized by food restriction despite low body weight. While CRH is anorexigenic, downstream cortisol stimulates hunger. Using a food-related functional magnetic resonance imaging (fMRI) paradigm, we have demonstrated hypoactivation of brain regions involved in food motivation in women with AN, even after weight recovery. The relationship between hypothalamic-pituitary-adrenal (HPA) axis dysregulation and appetite and the association with food-motivation neurocircuitry hypoactivation are unknown in AN. We investigated the relationship between HPA activity, appetite, and food-motivation neurocircuitry hypoactivation in AN. DESIGN: Cross-sectional study of 36 women (13 AN, ten weight-recovered AN (ANWR), and 13 healthy controls (HC)). METHODS: Peripheral cortisol and ACTH levels were measured in a fasting state and 30, 60, and 120 min after a standardized mixed meal. The visual analog scale was used to assess homeostatic and hedonic appetite. fMRI was performed during visual processing of food and non-food stimuli to measure the brain activation pre- and post-meal. RESULTS: In each group, serum cortisol levels decreased following the meal. Mean fasting, 120 min post-meal, and nadir cortisol levels were high in AN vs HC. Mean postprandial ACTH levels were high in ANWR compared with HC and AN subjects. Cortisol levels were associated with lower fasting homeostatic and hedonic appetite, independent of BMI and depressive symptoms. Cortisol levels were also associated with between group variance in activation in the food-motivation brain regions (e.g. hypothalamus, amygdala, hippocampus, orbitofrontal cortex, and insula). CONCLUSIONS: HPA activation may contribute to the maintenance of AN by the suppression of appetitive drive. PMID- 23946276 TI - IGF1 modifications after bariatric surgery in morbidly obese patients: potential implications of nutritional status according to specific surgical technique. AB - OBJECTIVES: IGF1 is decreased in morbidly obese (MO) patients and its changes after bariatric surgery weight loss (WL) are not well known. The aim of this study was to analyse IGF1 modifications in MO patients after WL and its relationship to ghrelin and to different types of surgeries. DESIGN: Retrospective follow-up study at the University Medical Center. METHODS: One hundred and nine MO patients (age 44.19.3, BMI 51.748.75KG/M(2)) were evaluated at baseline and 1 year after surgery: 28 sleeve gastrectomy (SG), 31 distal modified (m), and 50 ringed (r) Roux-en-Y gastric bypass (RYGBP) surgery. Changes in IGF1, IGFBP3, ratio IGF1:IGFBP3, and ghrelin were evaluated 1 year after surgery. RESULTS: Baseline prevalence of low IGF1 (defined by s.d. IGF1<-2) was 22%, and %WL 1 year after surgery was 34.9+/-8.9%. There was a significant decrease in IGFBP3 in all the procedures, an increase in IGF1:IGFBP3 ratio in rRYGBP and SG, but total IGF1 only increased significantly in SG. Albumin concentrations decreased in mRYGBP, did not change in rRYGBP, but increased in SG after surgery. Total ghrelin concentrations increased after both RYGBPs and decreased after SG (P<0.05 in all cases). The prevalence of low IGF1 decreased in SG (28.6 vs 10.1%, P=0.03) and did not change in RYGPBP techniques. The %albumin change was the only dependent variable associated with the % total IGF1 change. CONCLUSIONS: Recovery of low IGF1 after bariatric surgery was specifically related to the albumin modifications induced by surgery and was not related to ghrelin modifications. PMID- 23946277 TI - Lack of influence of somatic mutations on steroid gradients during adrenal vein sampling in aldosterone-producing adenoma patients. AB - OBJECTIVE: Adrenal vein sampling (AVS) is a technically demanding procedure required for the identification of suitable candidates for unilateral adrenalectomy in primary aldosteronism. Recently, somatic KCNJ5 K(+)-channel mutations in aldosterone-producing adenoma (APA) patients have been shown to influence steroid gradients during AVS. These and other recently identified genetic modifiers (ATP1A1 and ATP2B3) might affect the final diagnosis and treatment of the affected patients. DESIGN: Fifty-nine patients with APAS who had undergone successful AVS (adrenal vein cortisol:peripheral cortisol ratio 2) and had undergone a mutation analysis of their tumor tissue were studied. the mutation status of the APAS was as follows: 19 KCNJ5 mutations, eight ATPase mutations (five ATP1A1 and three ATP2B3), and 32 patients with none of these mutations. METHODS: The lateralization index (ratio of aldosterone:cortisol on the side of the adenoma to aldosterone to cortisol on the contralateral side) and the contralateral suppression index (ratio of aldosterone:cortisol on the contralateral side to aldosterone to cortisol in the periphery) were calculated for the KCNJ5-mutated, ATPase-mutated, and the KCNJ5/ATPase mutation-negative APA patients. RESULTS: The lateralization indices of the ATPase mutation carriers had a median of 19.9 compared with a median of 16.0 in the KCNJ5 mutation carriers and that of 20.5 in the KCNJ5/ATPase mutation-negative patients. The contralateral suppression indices of the ATPase-mutated patients had a median of 0.1 compared with a median of 0.4 in the KCNJ5 mutation carriers and that of 0.2 in the KCNJ5/ATPase mutation-negative patients. The differences between the genetic groups were not statistically significant. CONCLUSIONS: We did not find evidence for a clinically important impact of mutation status on steroid gradients during AVS. PMID- 23946278 TI - Clinical phenotypes of Chinese primary hyperparathyroidism patients are associated with the calcium-sensing receptor gene R990G polymorphism. AB - OBJECTIVE: The purpose of this study was to investigate the distribution of the A986S and R990G polymorphisms of the calcium-sensing receptor (CASR) gene in the Chinese population and whether there is an association between genetic variants and the risk of developing primary hyperparathyroidism (PHPT) and its associated clinical phenotypes. METHODS: A total of 164 Chinese Han PHPT patients (M/F: 51/113) and 230 healthy controls (M/F: 50/180) were enrolled. The common clinical parameters of PHPT patients including biochemical markers, bone mineral density (BMD), kidney stone occurrence, and pathology results were analyzed. Genotyping was conducted for both the patients and controls, and it was carried out using standard procedures. RESULTS: The R990G variant was more frequently present than the A986S variant in this group of Chinese PHPT patients. The R allele increased the risk of PHPT (odds ratio=1.134, 95% CI: 1.008, 1.277, and P=0.036). Patients with either the RR or RG genotype had lower blood calcium levels and higher alkaline phosphate levels than patients with the GG genotype. The lumbar BMD T score was -2.20 (-2.63, -0.32) in patients with the GG genotype, and it was significantly lower in patients with the RR+RG genotype (-2.53 (-3.70, -1.72) P=0.036). Patients with the R allele had a significantly higher incidence of hyperplasia (25.0%) and carcinomas (7.1%) than those with the GG genotype (5.3 and 0% respectively; P=0.025). The prevalence of osteoporosis and parathyroid carcinomas was higher in Chinese PHPT patients with the R allele. CONCLUSION: The R990G polymorphism is most frequently present in the Chinese population and among patients with PHPT. Additional studies in the Chinese population are needed to elaborate the relationship between genetics and PHPT. PMID- 23946280 TI - Chondroitin sulfate and sulfated hyaluronan-containing collagen coatings of titanium implants influence peri-implant bone formation in a minipig model. AB - An improved osseous integration of dental implants in patients with lower bone quality is of particular interest. The aim of this study was to evaluate the effect of artificial extracellular matrix implant coatings on early bone formation. The coatings contained collagen (coll) in conjunction with either chondroitin sulfate (CS) or sulfated hyaluronan (sHya). Thirty-six screw-type, grit-blasted, and acid-etched titanium implants were inserted in the mandible of 6 minipigs. Three surface states were tested: (1) uncoated control (2) coll/CS (3) coll/sHya. After healing periods of 4 and 8 weeks, bone implant contact (BIC), bone volume density (BVD) as well as osteoid related parameters were measured. After 4 weeks, control implants showed a BIC of 44% which was comparable to coll/CS coated implants (48%) and significantly higher compared to coll/sHya coatings (37%, p = 0.012). This difference leveled out after 8 weeks. No significant differences could be detected for BVD values after 4 weeks and all surfaces showed reduced BVD values after 8 weeks. However, at that time, BVD around both, coll/CS (30%, p = 0.029), and coll/sHya (32%, p = 0.015), coatings was significantly higher compared to controls (22%). The osteoid implant contact (OIC) showed no significant differences after 4 weeks. After 8 weeks OIC for controls was comparable to coll/CS, the latter being significantly higher compared to coll/sHya (0.9% vs. 0.4%, p = 0.012). There were no significant differences in osteoid volume density. In summary, implant surface coatings by the chosen organic components of the extracellular matrix showed a certain potential to influence osseointegration in vivo. PMID- 23946279 TI - Nanoelectronics meets biology: from new nanoscale devices for live-cell recording to 3D innervated tissues. AB - High spatiotemporal resolution interfaces between electrical sensors and biological systems, from single live cells to tissues, is crucial for many areas, including fundamental biophysical studies as well as medical monitoring and intervention. Herein, we summarize recent progress in the development and application of novel nanoscale devices for intracellular electrical recording of action potentials and the effort of merging electronic and biological systems seamlessly in three dimensions by using macroporous nanoelectronic scaffolds. The uniqueness of these nanoscale devices for minimally invasive, large-scale, high spatial resolution, and three-dimensional neural activity mapping are highlighted. PMID- 23946281 TI - CdTe(1-x)Se(x)/Cd0.5Zn0.5S core/shell quantum dots: core composition and property. AB - Alloy CdTe(1-x)Se(x) quantum dots (QDs) have been fabricated by an organic route using Cd, Te and Se precursors in a mixture of trioctylamine and octadecylphosphonic acid at 280 degrees C. The variation of photoluminescence (PL) peak wavelength of the CdTe(1-x)Se(x) QDs compared with CdTe QDs confirmed the formation of an alloy structure. The Se component drastically affected the stability of CdTe(1-x)Se(x) QDs. A Cd0.5Zn0.5S shell coating on CdTe(1-x)Se(x) cores was carried out using oleic acid as a capping agent. CdTe(1 x)Se(x)/Cd0.5Zn0.5S core/shell QDs revealed dark red PL while a yellow PL peak was observed for the CdTe(1-x)Se(x) cores. The PL efficiency of the core/shell QDs was drastically increased (less than 1% for the cores and up to 65% for the core/shell QDs). The stability of QDs in various buffer solutions was investigated. Core/shell QDs can be used for biological applications because of their high stability, tunable PL and high PL efficiency. PMID- 23946282 TI - Self-other agreement and assumed similarity in neuroticism, extraversion, and trait affect: distinguishing the effects of form and content. AB - Trait Negative Affect (NA) and Positive Affect (PA) are strongly associated with Neuroticism and Extraversion, respectively. Nevertheless, measures of the former tend to show substantially weaker self-other agreement-and stronger assumed similarity correlations-than scales assessing the latter. The current study separated the effects of item content versus format on agreement and assumed similarity using two different sets of Neuroticism and Extraversion measures and two different indicators of NA and PA (N = 381 newlyweds). Neuroticism and Extraversion consistently showed stronger agreement than NA and PA; in addition, however, scales with more elaborated items yielded significantly higher agreement correlations than those based on single adjectives. Conversely, the trait affect scales yielded stronger assumed similarity correlations than the personality scales; these coefficients were strongest for the adjectival measures of trait affect. Thus, our data establish a significant role for both content and format in assumed similarity and self-other agreement. PMID- 23946283 TI - Evaluating the South Oaks Gambling Screen with DSM-IV and DSM-5 criteria: results from a diverse community sample of gamblers. AB - Despite widespread use, the South Oaks Gambling Screen (SOGS) has been criticized for excessive false positives as an indicator of pathological gambling (PG), and for items that misalign with PG criteria. We examine the relationship between SOGS scores and PG symptoms and convergent validity with regard to personality, mood, and addictive behaviors in a sample of 353 gamblers. SOGS scores correlated r = .66 with both DSM-IV and DSM-5 symptoms, and they manifested similar correlations with external criteria (intraclass correlation of .95). However, 195 false positives and 1 false negative were observed when using the recommended cut point, yielding an 81% false alarm rate. For uses with DSM-IV criteria, a cut point of 10 would retain high sensitivity with greater specificity and fewer false positives. For DSM-5 criteria, we advocate a cut point of 8 for use as a clinical screen and a cut point of 12 for prevalence and pseudo-experimental studies. PMID- 23946284 TI - Assessment of right ventricular volumes in hypoplastic left heart syndrome by real-time three-dimensional echocardiography: comparison with cardiac magnetic resonance imaging. AB - BACKGROUND: Accurate assessment of right ventricular (RV) volumes and function is important in patients with hypoplastic left heart syndrome (HLHS). We prospectively sought to determine the reproducibility of three-dimensional (3D) echocardiography and its agreement with cardiac magnetic resonance imaging (CMR) in HLHS. METHODS AND RESULTS: Twenty-eight patients underwent CMR followed immediately by transthoracic 3D echocardiography under general anaesthesia. Semi automated border detection software was used to determine echocardiographic RV volumes. Inter- and intra-observer variability, correlation and levels of agreement between techniques were determined. The median age was 0.37 years (0.18 9.28 years) and weight 6.24 kg (3.42-32.50 kg). Intra- and inter-observer variability was excellent for both techniques. Median (range) measurements for 3D echocardiography and CMR were; end-diastolic volume (EDV) 23.6 mL (6.5-63.2) and 30.6 mL (11.8-87.9), end-systolic volume (ESV) 12.6 mL (3.7-37.0) and 14.9 mL (5.8-33.9), stroke volume (SV) 11.2 mL (2.8-33.0) and 17.1 mL (6.0-54.1), ejection fraction (EF) 48.2% (31.2-64.9), and 56.5% (42.7-72.2). Correlation coefficients were r = 0.85, 0.84, 0.83, and 0.74, respectively (P < 0.01 for all). Volumetric data were expressed as a percentage of the echocardiographic volume to CMR volume. When compared with CMR, 3D echocardiography underestimated EDV, ESV and SV by 26.7% (SD +/- 20.2), 10.6% (+/-28.1), and 37.5% (+/-20.1), respectively. The difference in volume appeared largest at low ventricular volumes. EF was 8.3% (+/-7.3) lower by 3D echocardiography compared with CMR. CONCLUSION: Both 3D echocardiography and CMR volumes appear highly reproducible. Measurements obtained by 3D echocardiography are significantly lower than those obtained by CMR, with wide limits of agreement such that these two methods cannot be used interchangeably. PMID- 23946286 TI - MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis. AB - Micro (mi)RNAs are frequently dysregulated in the development of renal fibrosis. Exosomes are small membrane vesicles that could be isolated from urine secreted from all nephron segments. Here we sought to observe for the first time whether miRNA in urine exosome could serve as a potential biomarker of renal fibrosis. Urine samples were collected from 32 chronic kidney disease (CKD) patients who underwent kidney biopsy and 7 controls. Exosome was isolated and confirmed by immunogold staining of exosome marker. Members of miR-29, miR-200, and RNU6B as endogenous control were detected by RT quantitative PCR. Electronic microscopy verified a typical shape of exosome with average size of 65.1 nm and labeled it with anti-CD9 and anti-aquaporin 2 antibody. Members of miR-29 and miR-200 are readily measured with reduced levels compared with controls (P < 0.05) and can robustly distinguish CKD from controls [area under the curve (AUC) varied from 0.902 to 1 by receiver operating characteristics analysis]. miR-29c correlated with both estimated glomerular filtration rate (r = 0.362; P < 0.05) and degree of tubulointerstitial fibrosis (r = -0.359; P < 0.05) for CKD patients. Moreover, miRNA in exosome was decreased in mild fibrosis group compared with moderated to severe group. miR-29a and miR-29c could predict degree of tubulointerstitial fibrosis with AUC of 0.883 and 0.738 (P < 0.05). The sensitivity and specificity for distinguishing mild from moderate to severe fibrosis were 93.8 and 81.3% with the use of miR-29a and 68.8 and 81.3% for miR-29c. Overall, miR-29c in urinary exosome correlates with both renal function and degree of histological fibrosis, suggesting it as a novel, noninvasive marker for renal fibrosis. PMID- 23946285 TI - Hypoxia-inducible factor-2alpha and TGF-beta signaling interact to promote normoxic glomerular fibrogenesis. AB - Hypoxia-inducible factors (HIFs) are transcription factors consisting of an oxygen-sensitive alpha-subunit binding to a stable beta-subunit. HIFs regulate multiple signaling pathways that could contribute to fibrogenesis, supporting their potential role in hypoxia-mediated renal fibrosis. We previously reported that HIF-1 is upregulated and required for transforming growth factor (TGF)-beta induction of collagen in renal tubular cells. Here, we performed in vitro and in vivo studies of potential glomerular crosstalk between TGF-beta and normoxic HIF signaling. HIF-alpha has two major isoforms, HIF-1alpha and HIF-2alpha with different target gene sets. In cultured human mesangial cells, TGF-beta1 treatment increased both HIF-1alpha and HIF-2alpha expression in normoxia. TGF beta1 did not increase HIF-1alpha/2alpha mRNA levels nor decrease the rate of protein degradation, suggesting that it enhances HIF-1alpha/2alpha expression through translation. TGF-beta receptor (ALK5) kinase activity was required for increased, TGF-beta-stimulated HIF-alpha expression in response to TGF-beta, and inhibiting PI3-kinase markedly decreased HIF-alpha expression. Blocking HIF 1alpha/2alpha expression using siRNA decreased basal and TGF-beta1-stimulated type I collagen expression, while overexpressing nondegradable HIF-alpha increased the collagen response, with HIF-2alpha being significantly more effective than HIF-1alpha. In adriamycin-induced mouse glomerulosclerosis, HIF 2alpha target genes were upregulated in sclerosing glomeruli. Taken together, our data demonstrate potential signaling interaction between TGF-beta and HIFs to promote renal fibrogenesis in normoxia and suggest that the HIF-2alpha isoform is more important during glomerulosclerosis. PMID- 23946287 TI - Dietary salt intake modulates differential splicing of the Na-K-2Cl cotransporter NKCC2. AB - Both sodium reabsorption in the thick ascending limb of the loop of Henle (TAL) and macula densa salt sensing crucially depend on the function of the Na/K/2Cl cotransporter NKCC2. The NKCC2 gene gives rise to at least three different full length NKCC2 isoforms derived from differential splicing. In the present study, we addressed the influence of dietary salt intake on the differential splicing of NKCC2. Mice were subjected to diets with low-salt, standard salt, and high-salt content for 7 days, and NKCC2 isoform mRNA abundance was determined. With decreasing salt intake, we found a reduced abundance of the low-affinity isoform NKCC2A and an increase in the high-affinity isoform NKCC2B in the renal cortex and the outer stripe of the outer medulla. This shift from NKCC2A to NKCC2B during a low-salt diet could be mimicked by furosemide in vivo and in cultured kidney slices. Furthermore, the changes in NKCC2 isoform abundance during a salt restricted diet were partly mediated by the actions of angiotensin II on AT1 receptors, as determined using chronic angiotensin II infusion. In contrast to changes in oral salt intake, water restriction (48 h) and water loading (8% sucrose solution) increased and suppressed the expression of all NKCC2 isoforms, without changing the distribution pattern of the single isoforms. In summary, the differential splicing of NKCC2 pre-mRNA is modulated by dietary salt intake, which may be mediated by changes in intracellular ion composition. Differential splicing of NKCC2 appears to contribute to the adaptive capacity of the kidney to cope with changes in reabsorptive needs. PMID- 23946288 TI - Relaxin protects against renal ischemia-reperfusion injury. AB - Relaxin, a pregnancy hormone, has antiapoptotic and anti-inflammatory properties. The aim of this study was to determine the effects of relaxin on ischemia reperfusion (IR)-induced acute kidney injury. Male rats underwent unilateral nephrectomy and contralateral renal IR (45 min of renal pedicle clamping). Rats were divided into three groups: 1) sham group, 2) IR group, and 3) IR-RLX group (rats treated with relaxin before ischemia). In this group, relaxin was infused at 500 ng/h via subcutaneous osmotic minipump for 24 h beginning 2 h before renal ischemia. At 24 h after reperfusion, renal function was assessed and kidneys were removed for analysis. There was no significant difference in blood pressure among the three groups. IR increased plasma levels of creatinine and urea nitrogen, and relaxin provided protection against the increases in these two parameters. Relaxin significantly decreased plasma TNF-alpha levels and renal TNF receptor 1 mRNA expression, compared with the IR group. Semiquantitative assessment of the histological lesions showed marked structural damage in IR rats compared with the IR-RLX rats. RLX significantly reduced apoptotic cell counts compared with the IR group. Overexpression of caspase-3 observed in the IR kidneys was reduced in the IR-RLX group. The results demonstrated that relaxin provided protection against IR-induced renal injury by reducing apoptosis and inflammation. PMID- 23946289 TI - Angiotensin II AT2 receptor activation attenuates AT1 receptor-induced increases in the glomerular filtration of albumin: a multiphoton microscopy study. AB - In this study, we assessed the acute effects of angiotensin II on the albumin glomerular sieving coefficient (GSC) using intravital microscopy. The experiments were performed on Munich Wistar Froemter (MWF) rats. Alexa-Fluor-594 albumin was injected intravenously, and the fluorescence intensity in the glomerular capillaries and Bowman's space was determined to calculate the albumin GSC. The GSC was measured before and during the constant infusion of angiotensin II (10 ng.min(-1).kg(-1) body wt). Baseline mean arterial pressure (MAP) was 99 +/- 5 mmHg and stabilized at 137 +/- 5 mmHg during angiotensin II infusion. The baseline GSC averaged 0.00044 +/- 4.8 * 10(-5) and increased by 286 +/- 44% after angiotensin II infusion (P < 0.0001). The proximal tubular Alexa-Fluor-594 albumin uptake was enhanced during angiotensin II infusion (518% of the baseline value during angiotensin II vs. 218% in controls; P < 0.0001). No change in GSC was observed when the AT1 antagonist losartan was injected before the start of angiotensin II infusion. The AT2 antagonist PD123319 increased the baseline GSC from 0.00052 +/- 3.6 * 10(-5) to 0.00074 +/- 8.2 * 10(-5) (P = 0.02) without altering the MAP. During angiotensin II infusion with losartan, PD123319 increased the albumin GSC from 0.00037 +/- 5.8 * 10(-5) to 0.00115 +/- 0.00015 (P = 0.001). When the renal perfusion pressure was mechanically controlled, the GSC increased from 0.0007 +/- 0.00019 to 0.0025 +/- 0.00063 during angiotensin II infusion (P = 0.047), similar to what was observed when the renal perfusion pressure was allowed to increase. In summary, AT1 activation acutely increases the albumin GSC. This effect appears to be largely independent of changes in the renal perfusion pressure. The AT2 receptor partially attenuates the proteinuric effects of the AT1 receptor. PMID- 23946290 TI - Sex differences in ET-1 receptor expression and Ca2+ signaling in the IMCD. AB - The inner medullary collecting duct (IMCD) is the nephron segment with the highest production of endothelin-1 (ET-1) and the greatest expression of ET-1 receptors that function to adjust Na(+) and water balance. We have reported that male rats have reduced natriuresis in response to direct intramedullary infusion of ET-1 compared with female rats. Our aim was to determine whether alterations of ET-1 receptor expression and downstream intracellular Ca(2+) signaling within the IMCD could account for these sex differences. IMCDs from male and female rats were isolated for radioligand binding or microdissected for intracellular Ca(2+) ([Ca(2+)]i) measurement by fluorescence imaging of fura-2 AM. IMCD from male and female rats had similar ETB expression (655 +/- 201 vs. 567 +/- 39 fmol/mg protein, respectively), whereas male rats had significantly higher ETA expression (436 +/- 162 vs. 47 +/- 29 fmol/mg protein, respectively; P < 0.05). The [Ca(2+)]i response to ET-1 was significantly greater in IMCDs from male compared with female rats (288 +/- 52 vs. 118 +/- 32 AUC, nM * 3 min, respectively; P < 0.05). In IMCDs from male rats, the [Ca(2+)]i response to ET-1 was significantly blunted by the ETA antagonist BQ-123 but not by the ETB antagonist BQ-788 (control: 137 +/- 27; BQ-123: 53 +/- 11; BQ-788: 84 +/- 25 AUC, nM * 3 min; P < 0.05), consistent with greater ETA receptor function in male rats. These data demonstrate a sex difference in ETA receptor expression that results in differences in ET-1 Ca(2+) signaling in IMCD. Since activation of ETA receptors is thought to oppose ETB receptor activation, enhanced ETA function in male rats could limit the natriuretic effects of ETB receptor activation. PMID- 23946291 TI - Colchicine attenuates renal injury in a model of hypertensive chronic kidney disease. AB - Hypertension is a risk factor for chronic kidney disease, particularly when associated with impaired renal autoregulation and thereby increased intraglomerular pressure (Pgc). Elevated Pgc can be modeled in vitro by exposing glomerular mesangial cells to mechanical strain. We previously showed that RhoA mediates strain-induced matrix production. Here, we show that RhoA activation is dependent on an intact microtubule network. Upregulation of the profibrotic cytokine connective tissue growth factor (CTGF) by mechanical strain is dependent on RhoA activation and inhibited by microtubule disruption. We tested the effects of the microtubule depolymerizing agent colchicine in 5/6 nephrectomized rats, a model of chronic kidney disease driven by elevated Pgc. Colchicine inhibited glomerular RhoA activation and attenuated both glomerular sclerosis and interstitial fibrosis without affecting systemic blood pressure. Upregulation of the matrix proteins collagen I and fibronectin, as well as CTGF, was attenuated by colchicine. Activity of the profibrotic cytokine TGF-beta, as assessed by Smad3 phosphorylation, was also inhibited by colchicine. Microtubule disruption significantly decreased renal infiltration of lymphocytes and macrophages. Our studies thus indicate that colchicine modifies hypertensive renal fibrosis. Its protective effects are likely mediated by inhibition of RhoA signaling and renal infiltration of inflammatory cells. Already well-established in clinical practice for other indications, prevention of hypertension-associated renal fibrosis may represent a new potential use for colchicine. PMID- 23946293 TI - Quality of physical resources of health facilities in Indonesia: a panel study 1993-2007. AB - OBJECTIVE: The merits of mixed public and private health systems are debated. Although private providers have become increasingly important in the Indonesian health system, there is no comprehensive assessment of the quality of private facilities. This study examined the quality of physical resources of public and private facilities in Indonesia from 1993 to 2007. DESIGN AND SETTING: Data from the Indonesian Family Life Surveys in 1993, 1997, 2000 and 2007 were used to evaluate trends in the quality of physical resources for public and private facilities, stratified by urban/rural areas and Java-Bali/outer Java-Bali regions. MAIN OUTCOME MEASURES: The quality of six categories of resources was measured using an adapted MEASURE Evaluation framework. RESULTS: Overall quality was moderate, but higher in public than in private health facilities in all years regardless of the region. The higher proportion of nurses and midwives in private practice was a determinant of scope of services and facilities available. There was little improvement in quality of physical resources following decentralization. CONCLUSIONS: Despite significant increases in public investment in health between 2000 and 2006 and the potential benefits of decentralization (2001), the quality of both public and private health facilities in Indonesia did not improve significantly between 1993 and 2007. As consumers commonly believe the quality is better in private facilities and are increasingly using them, it is essential to improve quality in both private and public facilities. Implementation of minimum standards and effective partnerships with private practice are considered important. PMID- 23946292 TI - Combined losartan and nitro-oleic acid remarkably improves diabetic nephropathy in mice. AB - Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). The inhibitors of renin-angiotensin-aldosterone system (RAAS) can alleviate some of the symptoms of DN but fail to stop the progression to ESRD. Our previous studies demonstrate renoprotective action of nitro-oleic acid (OA-NO2) in several rodent models of renal disease. Here we examined the therapeutic potential and the underlying mechanism of combination of losartan and OA-NO2 in db/db mice. OA NO2 was infused at 5 mg.kg(-1).day(-1) via osmotic minipump, and losartan was incorporated into diet at 10 mg.kg(-1).day(-1), each administered alone or in combination for 2 wk. Diabetic db/db mice developed progressive albuminuria and glomerulosclerosis, accompanied by podocytes loss, increased indexes of renal fibrosis, oxidative stress, and inflammation. Treatment of the diabetic mice with OA-NO2 or losartan alone moderately ameliorated kidney injury; however, the combined treatment remarkably reduced albuminuria, restored glomerular filtration barrier structure, and attenuated glomerulosclerosis, accompanied with significant suppression of renal oxidative stress and inflammation. These data demonstrate that combination of losartan and OA-NO2 effectively reverses renal injury in DN. PMID- 23946294 TI - Is early treatment of acute chest pain provided sooner to patients who speak the national language? AB - OBJECTIVE: Identify differences in the early treatment of acute chest pain patients with regard to the language proficiency of patients and thus identify opportunities for improving equity in cardiac care. DESIGN: Retrospective cross sectional study comparing care delivered to Swedish-speaking (SS) and non-Swedish speaking (NSS) patients. SETTING: A Swedish university hospital that provides highly specialized care to 1.6 million inhabitants. PARTICIPANTS: All patients with acute chest pain or symptoms suggestive of acute coronary syndrome who sought care between mid-September and mid-December 2008 (2588 visits). Missing data on the patient group to which study subjects belonged were 2% (45 visits). NSS represented 8% of the 2543 visits (NSS = 2334; NNSS = 209). MAIN OUTCOME MEASURE(S): Delay times from arrival in hospital to admission to catheterization laboratory or ward (DeltaTHOSP-PCI), first physical contact to first electrocardiogram (DeltaTCONTACT-ECG), first physical contact to first aspirin (DeltaTCONTACT-ASA) and arrival in hospital to coronary angiography (DeltaTHOSP ANGIO). Also included baseline characteristics of patients, diagnosis and findings in hospital and secondary preventive activities. RESULTS: The median DeltaTHOSP-PCI was longer for NSS by 43 min [254 versus 211, 95% confidence interval (CI), odds ratio (OR) = (1.3; 2.8)]. The median DeltaTCONTACT-ECG and DeltaTHOSP-ANGIO were longer for NSS by 4 min [17 versus 13, 95% CI, OR = (0.8; 1.8)] and 14 h [44 versus 30, 95% CI, OR = (0.6; 3.6)], respectively. Conversely, the median DeltaTCONTACT-ASA was longer for SS by 20 min [81 versus 61, 95% CI, OR = (0.3; 1.6)]. CONCLUSIONS: Poorer language proficiency was associated with longer delay time from arrival in hospital to admission to catheterization laboratory or ward. No other delay times were found to be statistically significantly different with respect to the language proficiency of patients. PMID- 23946295 TI - Children affected by maternal HIV/AIDS: feasibility and acceptability trial of the Children United with Buddies (CUB) intervention. AB - Past research has shown that young children affected by maternal HIV present with elevated stress/anxiety and negative well-being. This pilot intervention for children aged 7-14 affected by maternal HIV targeted improving positive child mother communication, improving HIV/AIDS knowledge and reducing anxiety (especially related to transmission), and lessening feelings of stigma. Each of the three child intervention sessions included behavioral skills training and a themed craft exercise; mothers attended an open discussion group while the children attended their sessions. Study participants were 37 child-mother pairs. The study design was a randomized two-group pretest-posttest experimental design. The intervention sessions were audiotaped for transcription. Results showed significant decreases in anxiety and worry for children in the intervention group, and increases in happiness and knowledge regarding HIV/AIDS transmission. Intervention group mothers reported greater social support. Qualitative findings for the intervention group children and mothers also support these findings. Early intervention reduces child stress, and may affect longer-term outcomes. PMID- 23946296 TI - MicroRNA-31 predicts the presence of lymph node metastases and survival in patients with lung adenocarcinoma. AB - PURPOSE: We conducted genome-wide miRNA-sequencing (miRNA-seq) in primary cancer tissue from patients of lung adenocarcinoma to identify markers for the presence of lymph node metastasis. EXPERIMENTAL DESIGN: Markers for lymph node metastasis identified by sequencing were validated in a separate cohort using quantitative PCR. After additional validation in the The Cancer Genome Atlas (TCGA) dataset, functional characterization studies were conducted in vitro. RESULTS: MiR-31 was upregulated in lung adenocarcinoma tissues from patients with lymph node metastases compared with those without lymph node metastases. We confirmed miR-31 to be upregulated in lymph node-positive patients in a separate patient cohort (P = 0.009, t test), and to be expressed at higher levels in adenocarcinoma tissue than in matched normal adjacent lung tissues (P < 0.0001, paired t test). MiR-31 was then validated as a marker for lymph node metastasis in an external validation cohort of 233 lung adenocarcinoma cases of the TCGA (P = 0.031, t test). In vitro functional assays showed that miR-31 increases cell migration, invasion, and proliferation in an ERK1/2 signaling-dependent manner. Notably, miR 31 was a significant predictor of survival in a multivariate cox regression model even when controlling for cancer staging. Exploratory in silico analysis showed that low expression of miR-31 is associated with excellent survival for T2N0 patients. CONCLUSIONS: We applied miRNA-seq to study microRNomes in lung adenocarcinoma tissue samples for the first time and potentially identified a miRNA predicting the presence of lymph node metastasis and survival outcomes in patients of lung adenocarcinoma. PMID- 23946297 TI - Recognition and management of stroke in young adults and adolescents. AB - Approximately 15% of all ischemic strokes (IS) occur in young adults and adolescents. To date, only limited prior public health and research efforts have specifically addressed stroke in the young. Early diagnosis remains challenging because of the lack of awareness and the relative infrequency of stroke compared with stroke mimics. Moreover, the causes of IS in the young are heterogeneous and can be relatively uncommon, resulting in uncertainties about diagnostic evaluation and cause-specific management. Emerging data have raised public health concerns about the increasing prevalence of traditional vascular risk factors in young individuals, and their potential role in increasing the risk of IS, stroke recurrence, and poststroke mortality. These issues make it important to formulate and enact strategies to increase both awareness and access to resources for young stroke patients, their caregivers and families, and health care professionals. The American Academy of Neurology recently convened an expert panel to develop a consensus document concerning the recognition, evaluation, and management of IS in young adults and adolescents. The report of the consensus panel is presented herein. PMID- 23946298 TI - Autoimmune disease preceding amyotrophic lateral sclerosis: an epidemiologic study. AB - OBJECTIVE: To study whether the risk of amyotrophic lateral sclerosis (ALS) is increased in people with prior autoimmune disease. METHODS: An all-England hospital record-linkage dataset spanning 1999-2011 was used. Cohorts were constructed of people with each of a range of autoimmune diseases; the incidence of ALS in each disease cohort was compared with the incidence of ALS in a cohort of individuals without prior admission for the autoimmune disease. RESULTS: There were significantly more cases than expected of ALS associated with a prior diagnosis of asthma, celiac disease, younger-onset diabetes (younger than 30 years), multiple sclerosis, myasthenia gravis, myxedema, polymyositis, Sjogren syndrome, systemic lupus erythematosus, and ulcerative colitis. CONCLUSIONS: Autoimmune disease associations with ALS raise the possibility of shared genetic or environmental risk factors. PMID- 23946299 TI - Comment: Temperature and risk of stroke mortality in China. PMID- 23946300 TI - Freezing of gait in PD has a REM correlate: twice cursed with a shared pathophysiology? PMID- 23946301 TI - Increased REM sleep without atonia in Parkinson disease with freezing of gait. AB - OBJECTIVE: The objective of this cross-sectional study was to test the hypothesis that patients with Parkinson disease (PD) and freezing of gait (PD+FOG) would demonstrate sleep disturbances comparable to those seen in patients with REM sleep behavior disorder (RBD) and these changes would be significantly different from those in PD patients without FOG (PD-FOG) and age-matched controls. METHODS: We conducted overnight polysomnography studies in 4 groups of subjects: RBD, PD FOG, PD+FOG, and controls. Tonic and phasic muscle activity during REM sleep were quantified using EMG recordings from the chin, compared among study groups, and correlated with disease metrics. RESULTS: There were no significant differences in measures of disease severity, duration, or dopaminergic medications between the PD+FOG and PD-FOG groups. Tonic muscle activity was increased significantly (p < 0.007) in the RBD and PD+FOG groups compared to the PD-FOG and control groups. There was no significant difference in tonic EMG between the PD+FOG and RBD group (p = 0.364), or in tonic or phasic EMG between the PD-FOG and control group (p = 0.107). Phasic muscle activity was significantly increased in the RBD group compared to all other groups (p = 0.029) and between the PD+FOG and control group (p = 0.001), but not between the PD+FOG and PD-FOG groups (p = 0.059). CONCLUSIONS: These findings provide evidence that increased muscle activity during REM sleep is a comorbid feature of patients with PD who exhibit FOG as a motor manifestation of their disease. PMID- 23946302 TI - All choked up about the pseudotumor cerebri syndrome. AB - The diagnosis of pseudotumor cerebri, or idiopathic intracranial hypertension (IIH), is most confidently established in the typical patient with evidence of papilledema, imaging that does not suggest a structural lesion, and a CSF examination that shows both normal composition and elevated intracranial pressure (ICP). Prompted by an increasing number of reports over the past decade, Friedman et al.(1) propose a revised set of diagnostic criteria for IIH, taking into account the most recent observations from neuroimaging studies. Although the patient with IIH is often a young woman who is above ideal body weight or obese, it is well-recognized that the disorder may also occur in obese men and in children, who are less likely to be obese than their adult counterparts. Several advances in the field prompted the expert authors to provide new guidance. First, a large study of children has redefined normal CSF opening pressure for children.(2) In the obese or sedated child, an opening pressure of 280 mm H2O has been suggested as the requirement to claim confidently that the ICP is increased. Otherwise, the diagnostic criteria for children and adults continue to rely on a CSF lumbar opening pressure of 250 mm H2O or greater. PMID- 23946303 TI - Helsinki model cut stroke thrombolysis delays to 25 minutes in Melbourne in only 4 months. AB - OBJECTIVE: To test the transferability of the Helsinki stroke thrombolysis model that achieved a median 20-minute door-to-needle time (DNT) to an Australian health care setting. METHODS: The existing "code stroke" model at the Royal Melbourne Hospital was evaluated and restructured to include key components of the Helsinki model: 1) ambulance prenotification with patient details alerting the stroke team to meet the patient on arrival; 2) patients transferred directly from triage onto the CT table on the ambulance stretcher; and 3) tissue plasminogen activator (tPA) delivered in CT immediately after imaging. We analyzed our prospective, consecutive tPA registry for effects of these protocol changes on our DNT after implementation during business hours (8 am to 5 pm Monday-Friday) from May 2012. RESULTS: There were 48 patients treated with tPA in the 8 months after the protocol change. Compared with 85 patients treated in 2011, the median (interquartile range) DNT was reduced from 61 (43-75) minutes to 46 (24-79) minutes (p = 0.040). All of the effect came from the change in the in hours DNT, down from 43 (33-59) to 25 (19-48) minutes (p = 0.009), whereas the out-of-hours delays remain unchanged, from 67 (55-82) to 62 (44-95) minutes (p = 0.835). CONCLUSION: We demonstrated rapid transferability of an optimized tPA protocol to a different health care setting. With the cooperation of ambulance, emergency, and stroke teams, we succeeded in the absence of a dedicated neurologic emergency department or electronic patient records, which are features of the Finnish system. The next challenge is providing the same service out-of hours. PMID- 23946304 TI - What happens to cognitive function following surgery for hypothalamic hamartoma? PMID- 23946305 TI - Complex movement disorders in fatal familial insomnia: a clinical and genetic discussion. PMID- 23946306 TI - The complexities of acute stroke decision-making: a survey of neurologists. AB - OBJECTIVE: We hypothesized that low rates of tissue plasminogen activator (tPA) use are only partially explained by medical considerations, and that biases, beliefs, systems, and uncertainty affect acute stroke decision-making. METHODS: We generated a list of factors potentially influential in acute stroke decision making: uncertainty, patient demographics that may predispose to bias (age, sex, comorbidities), physician experiences and beliefs, and systems factors. An online survey was distributed to neurologists in the province of Ontario, Canada, to assess the influence of these elements. A response rate of 69% was achieved. RESULTS: Seventy-nine percent (79%) of respondents were less likely to administer IV tPA to patients with dementia, and many were less likely to treat patients from nursing homes, with more severe strokes, or over age 80. All respondents recognized the presence of diagnostic uncertainty, and 87% believed that uncertainty in interpreting advanced imaging affected their use of tPA. The majority of respondents (70%) believed that a large left middle cerebral artery territory stroke was a fate worse than death. Four percent did not believe that IV tPA is an effective treatment for stroke. CONCLUSIONS: This study provides evidence for the presence of uncertainty, beliefs, and biases in acute stroke decision-making. This survey should be considered a preliminary investigation of the multiple factors implicit in IV tPA administration. PMID- 23946307 TI - Cognitive functioning before and after surgical resection for hypothalamic hamartoma and epilepsy. AB - OBJECTIVE: To determine whether patients with hypothalamic hamartoma (HH) improve in their cognitive functioning after neurosurgical resection of their HH and explore what variables correlate with cognitive outcome. METHODS: Thirty-two patients underwent preoperative and postoperative neuropsychological testing. The age range of patients was between 3.3 and 39.3 years (mean 12.2 years, SD 7.0). The average time interval between surgery and postoperative neuropsychological testing was 23.4 months (range 5.1-47.2 months). Tests administered varied on the basis of the patient's age and clinical condition. RESULTS: As a group, measures of overall intelligence showed improvement postsurgery, with associated improvement in processing speed. Memory scores did not demonstrate consistent improvement or decline. Duration of epilepsy, age at surgery, and level of neurocognitive functioning prior to surgery were correlated with postsurgical cognitive status. Patients who had mental retardation but were testable generally showed the greatest gains. CONCLUSIONS: Despite the great variability in level of cognitive impairment in patients with HH and refractory epilepsy, level of intelligence may show mild to moderate improvements postsurgery if no surgical complications occur. The variables that predict cognitive outcome are not fully delineated, but testable individuals with the greatest presurgical cognitive impairment and those with the shortest duration of epilepsy appear to make the greatest gains in intellectual functioning. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that single surgical resection for HH was associated with improvement in some subset measures of intellectual functioning, but not memory. Factors that predict better outcomes cannot be determined. PMID- 23946308 TI - Microglia: Multiple roles in surveillance, circuit shaping, and response to injury. AB - Microglial cells are the immune cells in the CNS and represent approximately 10% of the total brain cell population. Their morphologic characterization by Pio del Rio-Hortega was first published almost a century ago, but the understanding of their function in the normal and injured CNS is still incomplete. Classically, microglia have been classified into 2 main types: "resting" microglia, with a ramified morphology, present in the uninjured CNS; and "activated" microglia, with an amoeboid morphology, present at the sites of injury. However, morphologic, molecular, and genetic studies indicate that this subdivision is a misleading oversimplification. Resting microglia actively survey their environment; activated microglia constitute a heterogeneous population that dynamically changes in phenotype depending on the type of stimulus and microenvironment, participating not only in mechanisms of injury but also in neuroprotection, repair, and circuit refinement in the CNS. The primary role of microglia is therefore to maintain cellular, synaptic, and myelin homeostasis both during development and normal function of the CNS and in response to CNS injury. Microglia have been implicated in mechanisms of CNS trauma, stroke, infection, demyelination, neoplasm, and neurodegeneration. Microglial dysfunction may also contribute to genetic neurobehavioral disorders, such as Rett syndrome. There are several comprehensive reviews on all these topics. PMID- 23946309 TI - Modeling depression in Parkinson disease: disease-specific and nonspecific risk factors. AB - OBJECTIVE: To construct a model for depression in Parkinson disease (PD) and to study the relative contribution of PD-specific and nonspecific risk factors to this model. METHODS: Structural equation modeling of direct and indirect associations of risk factors with the latent depression outcome using a cross sectional dataset of 342 patients with PD. RESULTS: A model with acceptable fit was generated that explained 41% of the variance in depression. In the final model, 3 PD-specific variables (increased disease duration, more severe motor symptoms, the use of levodopa) and 6 nonspecific variables (female sex, history of anxiety and/or depression, family history of depression, worse functioning on activities of daily living, and worse cognitive status) were maintained and significantly associated with depression. Nonspecific risk factors had a 3-times higher influence in the model than PD-specific risk factors. CONCLUSION: In this cross-sectional study, we showed that nonspecific factors may be more prominent markers of depression than PD-specific factors. Accordingly, research on depression in PD should focus not only on factors associated with or specific for PD, but should also examine a wider scope of factors including general risk factors for depression, not specific for PD. PMID- 23946310 TI - Late-onset anti-NMDA receptor encephalitis. AB - OBJECTIVE: To describe the clinical features and outcome of anti-NMDA receptor (NMDAR) encephalitis in patients >=45 years old. METHOD: Observational cohort study. RESULTS: In a cohort of 661 patients with anti-NMDAR encephalitis, we identified 31 patients >=45 years old. Compared with younger adults (18-44 years), older patients were more often male (45% vs. 12%, p < 0.0001), had lower frequency of tumors (23% vs. 51%, p = 0.002; rarely teratomas), had longer median time to diagnosis (8 vs 4 weeks, p = 0.009) and treatment (7 vs. 4 weeks, p = 0.039), and had less favorable outcome (modified Rankin Scale score 0-2 at 2 years, 60% vs. 80%, p < 0.026). In multivariable analysis, younger age (odds ratio [OR] 0.15, confidence interval [CI] 0.05-0.39, p = 0.0001), early treatment (OR 0.60, CI 0.47-0.78, p < 0.0001), no need for intensive care (OR 0.09, CI 0.04 0.22, p < 0.0001), and longer follow-up (p < 0.0001) were associated with good outcome. Rituximab and cyclophosphamide were effective when first-line immunotherapies failed (OR 2.93, CI 1.10-7.76, p = 0.031). Overall, 60% of patients older than 45 years had full or substantial recovery at 24 months follow up. CONCLUSIONS: Anti-NMDAR encephalitis is less severe in patients >=45 years old than in young adults, but the outcome is poorer in older patients. In this age group, delays in diagnosis and treatment are more frequent than in younger patients. The frequency of underlying tumors is low, but if present they are usually carcinomas instead of teratomas in younger patients. Early and aggressive immunotherapy will likely improve the clinical outcome. PMID- 23946312 TI - IV tissue plasminogen activator use in acute stroke: What are neurologists thinking? PMID- 23946311 TI - Both low and high temperature may increase the risk of stroke mortality. AB - OBJECTIVE: To examine temperature in relation to stroke mortality in a multicity time series study in China. METHODS: We obtained data on daily temperature and mortality from 8 large cities in China. We used quasi-Poisson generalized additive models and distributed lag nonlinear models to estimate the accumulative effects of temperature on stroke mortality across multiple days, adjusting for long-term and seasonal trends, day of the week, air pollution, and relative humidity. We applied the Bayesian hierarchical model to pool city-specific effect estimates. RESULTS: Both cold and hot temperatures were associated with increased risk of stroke mortality. The potential effect of cold temperature might last more than 2 weeks. The pooled relative risks of extreme cold (first percentile of temperature) and cold (10th percentile of temperature) temperatures over lags 0 14 days were 1.39 (95% posterior intervals [PI] 1.18-1.64) and 1.11 (95% PI 1.06 1.17), compared with the 25th percentile of temperature. In contrast, the effect of hot temperature was more immediate. The relative risks of stroke mortality over lags 0-3 days were 1.06 (95% PI 1.02-1.10) for extreme hot temperature (99th percentile of temperature) and 1.14 (95% PI 1.05-1.24) for hot temperature (90th percentile of temperature), compared with the 75th percentile of temperature. CONCLUSIONS: This study showed that both cold and hot temperatures were associated with increased risk of stroke mortality in China. Our findings may have important implications for stroke prevention in China. PMID- 23946313 TI - Benefits of putaminal GDNF infusion in Parkinson disease are maintained after GDNF cessation. AB - We previously reported clinical improvement, increase in putamen [(18)F]-dopa uptake on PET imaging, and neuropathologic evidence of sprouting of dopaminergic fibers following chronic intraputaminal delivery of glial cell line-derived neurotrophic factor (GDNF) in idiopathic Parkinson disease (PD).(1-3) We now provide clinical and PET evidence of persistent efficacy lasting for at least 3 years following cessation of GDNF infusion in a patient with PD. This is a single case observational study, providing Class IV evidence. PMID- 23946314 TI - De novo Huntington disease caused by 26-44 CAG repeat expansion on a low-risk haplotype. PMID- 23946315 TI - Ataxia telangiectasia presenting as dopa-responsive cervical dystonia. AB - OBJECTIVE: To identify the cause of cervical dopa-responsive dystonia (DRD) in a Muslim Indian family inherited in an apparently autosomal recessive fashion, as previously described in this journal. METHODS: Previous testing for mutations in the genes known to cause DRD (GCH1, TH, and SPR) had been negative. Whole exome sequencing was performed on all 3 affected individuals for whom DNA was available to identify potentially pathogenic shared variants. Genotyping data obtained for all 3 affected individuals using the OmniExpress single nucleotide polymorphism chip (Illumina, San Diego, CA) were used to perform linkage analysis, autozygosity mapping, and copy number variation analysis. Sanger sequencing was used to confirm all variants. RESULTS: After filtering of the variants, exome sequencing revealed 2 genes harboring potentially pathogenic compound heterozygous variants (ATM and LRRC16A). Of these, the variants in ATM segregated perfectly with the cervical DRD. Both mutations detected in ATM have been shown to be pathogenic, and alpha-fetoprotein, a marker of ataxia telangiectasia, was increased in all affected individuals. CONCLUSION: Biallelic mutations in ATM can cause DRD, and mutations in this gene should be considered in the differential diagnosis of unexplained DRD, particularly if the dystonia is cervical and if there is a recessive family history. ATM has previously been reported to cause isolated cervical dystonia, but never, to our knowledge, DRD. Individuals with dystonia related to ataxia telangiectasia may benefit from a trial of levodopa. PMID- 23946316 TI - The need to modify patient selection to improve the benefits of implantable cardioverter-defibrillator for primary prevention of sudden death in non ischaemic dilated cardiomyopathy. AB - Left ventricular ejection fraction (LVEF) <=35% is a major determinant for implantable cardioverter-defibrillator (ICD) therapy for primary prevention of sudden death (SD) in patients with non-ischaemic dilated cardiomyopathy (DCM). However, as a risk marker for SD, low LVEF has limited sensibility and specificity. Selecting patients according to the current guidelines shows that most DCM patients do not actually benefit from ICD implantation and may suffer collateral effects and that many patients who are at risk of SD are not identified because a large proportion of SD patients exhibit only mildly depressed LVEF. Identifying patients who are at risk of SD on the sole basis of LVEF appears to be an over-simplification which does not maximize the benefit of ICD therapy. Owing to the complexity of the substrates underlying SD, multiple risk factors used in combination could probably predict the risk of SD better than any individual risk marker. Among non-invasive tests, microvolt T-wave alternans and cardiac magnetic resonance with late gadolinium enhancement may contribute to a better SD risk stratification by their high negative predictive value. Genetics may further contribute because approximately one-third of DCM patients have evidence of familial disease, and mutations in some known disease genes, including LMNA, have been associated with a high risk of SD. In this review, we critically analyse the current indications for ICD implantation and we explore existing knowledge about potentially predicting markers for selecting DCM patients who are at high and low risk of SD. PMID- 23946317 TI - The training and learning process of transseptal puncture using a modified technique. AB - AIMS: As the transseptal (TS) puncture has become an integral part of many types of cardiac interventional procedures, its technique that was initial reported for measurement of left atrial pressure in 1950s, continue to evolve. Our laboratory adopted a modified technique which uses only coronary sinus catheter as the landmark to accomplishing TS punctures under fluoroscopy. The aim of this study is prospectively to evaluate the training and learning process for TS puncture guided by this modified technique. METHODS AND RESULTS: Guided by the training protocol, TS puncture was performed in 120 consecutive patients by three trainees without previous personal experience in TS catheterization and one experienced trainer as a controller. We analysed the following parameters: one puncture success rate, total procedure time, fluoroscopic time, and radiation dose. The learning curve was analysed using curve-fitting methodology. The first attempt at TS crossing was successful in 74 (82%), a second attempt was successful in 11 (12%), and 5 patients failed to puncture the interatrial septal finally. The average starting process time was 4.1 +/- 0.8 min, and the estimated mean learning plateau was 1.2 +/- 0.2 min. The estimated mean learning rate for process time was 25 +/- 3 cases. Important aspects of learning curve can be estimated by fitting inverse curves for TS puncture. CONCLUSIONS: The study demonstrated that this technique was a simple, safe, economic, and effective approach for learning of TS puncture. Base on the statistical analysis, approximately 29 TS punctures will be needed for trainee to pass the steepest area of learning curve. PMID- 23946318 TI - Consistency of eletriptan in treating migraine: Results of a randomized, within patient multiple-dose study. AB - OBJECTIVE: The current study evaluated the consistency of eletriptan response. METHODS: Using a within-patient crossover design, patients with migraine completed a three-attack, open-label, lead-in period, before being treated, double-blind for four attacks, with either eletriptan 40 mg (ELE-40; N = 539) or eletriptan 80 mg (ELE-80; N = 432); placebo was randomly substituted for the treatment of one attack. RESULTS: On an A PRIORI analysis of within-patient consistency, double-blind treatment was associated with similar 2 hour headache response rates using a >=2/3 response criterion for ELE-40 (77%) and ELE-80 (73%), and using a 3/3 response criterion for ELE-40 (46%) and ELE-80 (47%). Within-patient consistency in achieving pain-free status at 2 hours using a >=2/3 criterion was slightly higher on ELE-40 (42%) compared with ELE-80 (38%), and was similar using the 3/3 criterion (18% on ELE-40, 17% on ELE-80). On a repeated measures logistic regression analysis across all treated attacks, the probability of achieving a headache response at 2 hours ranged from 71% to 74% on ELE-40 vs. 17% to 28% on placebo ( P < 0.0001), and from 66% to 74% on ELE-80 vs. 21% to 27% on placebo ( P < 0.0001). The incidence, per attack, of adverse events was low for both ELE-40 and ELE-80. Few adverse events occurred with incidence >=10% on ELE-40 (asthenia, 5.0%) or ELE-80 (asthenia, 10%; nausea, 5.8%). Discontinuations because of adverse events were 0.2% on ELE-40, and 1.6% on ELE-80 CONCLUSION: In this multiple attack study, eletriptan was well-tolerated and demonstrated consistent and significant efficacy in the treatment of migraine. PMID- 23946319 TI - Treatment of classic Whipple's disease: from in vitro results to clinical outcome. AB - OBJECTIVES: Patients with classic Whipple's disease have a lifetime defect in immunity to Tropheryma whipplei and frequently develop treatment failures, relapses or reinfections. Empirical treatments were tested before culture was possible, but the only in vitro bactericidal treatment consists of a combination of doxycycline and hydroxychloroquine. METHODS: Our laboratory has been a reference centre since the first culturing of Tropheryma whipplei, and we have tested 27,000 samples by PCR and diagnosed 250 cases of classic Whipple's disease. We report here the clinical course of patients who were followed by one of our group. RESULTS: Of 29 patients, 22 (76%) were previously treated with immunosuppressive drugs, 26 (90%) suffered from arthralgias and 22 (76%) exhibited weight loss. Intravenous initial treatment was paradoxically associated with an increased risk of failure (P = 0.0282). Treatment with doxycycline and hydroxychloroquine (+/- sulfadiazine or trimethoprim/sulfamethoxazole) was associated with a better outcome (0/13 failures), whereas all 14 patients who were first treated with trimethoprim/sulfamethoxazole and referred to us (P < 0.0001) experienced failure. Among the patients treated with doxycycline and hydroxychloroquine after previous antibiotic treatments, two presented with a reinfection caused by different T. whipplei strains. Finally, serum therapeutic drug monitoring allowed us to detect a lack of compliance in the only patient with failure among the 22 patients treated with lifetime doxycycline. CONCLUSIONS: In vitro results were confirmed by clinical outcomes and trimethoprim/sulfamethoxazole was associated with failures. The recommended management is a combination of doxycycline and hydroxychloroquine for 1 year, followed by doxycycline for the patient's lifetime along with stringent therapeutic drug monitoring. PMID- 23946320 TI - De novo generation of short antimicrobial peptides with enhanced stability and cell specificity. AB - OBJECTIVES: Though antimicrobial peptides (AMPs) show great potential as novel antibiotics, therapeutic applications are hindered by their low stability, toxicity and high manufacturing cost. Various chemical modification strategies are employed to overcome these problems. However, chemical modifications often significantly increase the manufacturing cost of AMPs with only limited pharmacokinetic advantages. Therefore, we developed AMPs with enhanced stability and cell specificity that can be economically produced. METHODS: Peptides were designed by systematic amino acid arrangement without the incorporation of both non-natural amino acids and peptidomimetics. Antimicrobial activities were measured against Gram-positive bacteria, Gram-negative bacteria and fungi by MIC evaluation under both standard and physiologically relevant conditions. Cytotoxicity towards human cells was evaluated to verify selective antimicrobial activity. The antibacterial mechanism of the peptides was elucidated by beta galactosidase assay and scanning electron microscopy. RESULTS: Among the designed peptides, GNU6 and GNU7 showed potent antimicrobial activity against bacteria and fungi and maintained their activity in the presence of 150 mM NaCl and 10% serum. These peptides were not digested by exposure to trypsin, chymotrypsin and aureolysin for up to 12 h and showed potent antimicrobial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Moreover, they did not affect the viability of erythrocytes, keratinocytes and fibroblasts up to 128 mg/L. A membrane permeabilization assay and scanning electron microscopy analysis showed that GNU6 and GNU7 compromised membrane integrity and function in microorganisms. CONCLUSIONS: This study suggests that GNU6 and GNU7 might overcome serious problems that currently prevent the clinical use of AMPs and be developed as novel antimicrobial agents. PMID- 23946321 TI - Nutrient requirements differ in two Pedicularis species in the absence of a host plant: implication for driving forces in the evolution of host preference of root hemiparasitic plants. AB - BACKGROUND AND AIMS: Facultative root hemiparasitic plants generally have a wide host range, but in most cases show an obvious host preference. The reasons for the marked difference in growth performance of hemiparasites when attached to different hosts are not fully understood. In this study, the hypothesis was tested that hemiparasites showing a preference for different hosts have different nutrient requirements. METHODS: Two facultative root hemiparasitic Pedicularis species (P. rex and P. tricolor) with a different host dependency and preference were used to test their responses to inorganic solutes. The effects of nitrogen, phosphorus and potassium on growth of the hemiparasitic plants not attached to a host were determined, using an orthogonal design in pot cultivation under greenhouse conditions. Variables including biomass, shoot nutrient concentration, root:shoot (R:S) ratios and the number of haustoria were measured. KEY RESULTS: As in autotrophic plants, nutrient deficiency reduced dry weight (DW) and nutrient concentrations in the root hemiparasites. Nitrogen and phosphorus significantly influenced growth of both Pedicularis species, while potassium availability influenced only shoot DW of P. rex. Nitrogen had far more effect on growth of P. rex than on P. tricolor, while phosphorus deficiency caused more marked growth depression in P. tricolor than in P. rex. Pedicularis rex grew faster than P. tricolor in a range of nutrient supplies. Different patterns of biomass allocation between the two Pedicularis species were observed. While P. rex invested more into roots (particularly fine rootlets) than P. tricolor, the number of haustoria produced by P. rex was relatively much lower than that produced by P. tricolor, which had a much smaller root system. CONCLUSIONS: The two Pedicularis species differ in nutrient requirements and biomass allocation. Distinct interspecific traits in growth and nutrient requirements can be driving forces for the differential interactions between hemiparasites and their hosts. PMID- 23946322 TI - Direct and indirect influences of arbuscular mycorrhizal fungi on phosphorus uptake by two root hemiparasitic Pedicularis species: do the fungal partners matter at low colonization levels? AB - BACKGROUND AND AIMS: Because most parasitic plants do not form mycorrhizal associations, the nutritional roles of arbuscular mycorrhizal (AM) fungi in them have hardly been tested. Some facultative root hemiparasitic Pedicularis species form AM associations and hence are ideal for testing both direct and indirect effects of AM fungi on their nutrient acquisition. The aim of this study was to test the influence of AM inoculation on phosphorus (P) uptake by Pedicularis rex and P. tricolor. METHODS: (32)P labelling was used in compartmented pots to assess the contribution of the AM pathway and the influence of AM inoculation on P uptake from a host plant into the root hemiparasites. Laboratory isolates of fungal species (Glomus mosseae and G. intraradices) and the host species (Hordeum vulgare 'Fleet') to which the two Pedicularis species showed obvious responses in haustorium formation and growth in previous studies were used. KEY RESULTS: The AM colonization of both Pedicularis spp. was low (<15 % root length) and only a very small proportion of total plant P (<1 %) was delivered from the soil via the AM fungus. In a separate experiment, inoculation with AM fungi strongly interfered with P acquisition by both Pedicularis species from their host barley, almost certainly because the numbers of haustoria formed by the parasite were significantly reduced in AM plants. CONCLUSIONS: Roles of AM fungi in nutrient acquisition by root parasitic plants were quantitatively demonstrated for the first time. Evidence was obtained for a novel mechanism of preventing root parasitic plants from overexploiting host resources through AM fungal-induced suppression of the absorptive structures in the parasites. PMID- 23946324 TI - Nephrotic syndrome in Kawasaki disease. PMID- 23946323 TI - Are alcohol-attributable mortality estimates reliable? PMID- 23946325 TI - Affective and cognitive mediators of the impact of cigarette warning labels. AB - INTRODUCTION: Research conducted by the U.S. Food and Drug Administration to select graphic warning labels for cigarette packs has been challenged as inadequate for demonstrating effects on smokers' beliefs about smoking. The present study tested the prediction that warnings alter risk perceptions and thoughts of quitting indirectly through a cognitive pathway (warning believability) and an affective pathway (worry about health), both of which are important for encouraging smokers to consider quitting. METHODS: Using a national Internet panel, individuals who smoke were randomly assigned to view 1 of 3 types of warning labels: basic text only, graphic image with basic text, and graphic image with both basic and additional text elaborating on the reason for the health risk. Analyses were conducted to determine whether cognitive and affective reactions mediated effects on smoking-related outcomes. RESULTS: Images influenced perceived risk, immediate desire to smoke, and feelings toward quitting indirectly through affective reactions; elaborated text influenced these outcomes through cognitive believability, with little evidence of direct effects. Believability also enhanced positive feelings toward quitting among smokers who were less worried about health risks due to smoking. CONCLUSIONS: The findings indicate that (a) many effects of warnings on smokers' beliefs are mediated rather than direct, (b) both cognitive and affective responses are important mediators, and (c) elaborated text can help to increase effects of images through a cognitive pathway. Warning labels should be designed to maximize effects on these mediators in order to influence smoking outcomes. PMID- 23946326 TI - A double-blind placebo-controlled randomized trial of varenicline for smokeless tobacco dependence in India. AB - INTRODUCTION: The rate of smokeless tobacco use in India is 20%; its use causes serious health problems, and no trial has assessed behavioral or pharmacological treatments for this public health concern. This trial evaluated varenicline for treating smokeless tobacco dependence in India. METHODS: This was a double-blind placebo-controlled randomized trial of varenicline (12 weeks, 1mg, twice per day) with 237 smokeless tobacco users in India. All participants received behavioral counseling. Outcomes included self-reported and biochemically verified abstinence at the end of treatment (EOT), lapse and recovery events, safety, and medication adherence. RESULTS: Self-reported EOT abstinence was significantly greater for varenicline (43%) versus placebo (31%; adjusted odds ratio [AOR] = 2.6, 95% CI = 1.2-4.2, p = .009). Biochemically confirmed EOT abstinence was greater for varenicline versus placebo (25.2% vs. 19.5%), but this was not statistically different (AOR = 1.6, 95% CI = 0.84-3.1, p = .15). Compared with placebo, varenicline did not reduce the risk for a lapse (hazard ratio [HR] = 0.86, 95% CI = 0.69-1.1, p = .14), but it did increase the likelihood of recovery to abstinence (HR = 1.2, 95% CI = 1.02-1.4, p = .02). Greater adherence increased EOT cessation rates for varenicline (39% vs. 18%, p = .003) but not for placebo (28% vs. 14%, p = .06). There were no significant differences between varenicline and placebo in rate of side effects, serious adverse events, hypertension, or stopping or reducing medication. CONCLUSIONS: Varenicline is safe for treating smokeless tobacco dependence in India, and further examination of this medication for this important public health problem is warranted. PMID- 23946327 TI - Impact of the World Health Organization's Decision-Making Tool for Family Planning Clients and Providers on the quality of family planning services in Iran. AB - OBJECTIVE: We investigated whether use of the World Health Organization's (WHO's) Decision-Making Tool (DMT) for Family Planning Clients and Providers would improve the process and outcome quality indicators of family planning (FP) services in Iran. METHODS: The DMT was adapted for the Iranian setting. The study evaluated 24 FP quality key indicators grouped into two main areas, namely process and outcome. The tool was implemented in 52 urban and rural public health facilities in four selected and representative provinces of Iran. A pre-post methodology was undertaken to examine whether use of the tool improved the quality of FP services and client satisfaction with the services. Quantitative data were collected through observations of counselling and exit interviews with clients using structured questionnaires. RESULTS: Different numbers of FP clients were recruited during the baseline and the post-intervention rounds (n=448 vs 547, respectively). The DMT improved many client-provider interaction indicators, including verbal and non-verbal communication (p<0.05). The tool also impacted positively on the client's choice of contraceptive method, providers' technical competence, and quality of information provided to clients (p<0.05). Use of the tool improved the clients' satisfaction with FP services (from 72% to 99%; p<0.05). CONCLUSIONS: The adapted WHO's DMT has the potential to improve the quality of FP services. PMID- 23946328 TI - Comparison of pixantrone-based regimen (CPOP-R) with doxorubicin-based therapy (CHOP-R) for treatment of diffuse large B-cell lymphoma. AB - BACKGROUND: Pixantrone is an aza-anthracenedione with enhanced, preclinical antitumor activity and reduced cardiotoxicity compared with doxorubicin. PATIENTS AND METHODS: We compared the efficacy and toxic effect of CPOP-R (substituting pixantrone for doxorubicin) against CHOP-R in untreated, diffuse large B-cell lymphoma (DLBCL) patients. The primary objective was to demonstrate non inferiority of CPOP-R by complete response/complete response unconfirmed (CR/CRu) rate. RESULTS: The CR/CRu rate for CPOP-R was 75% versus 84% for CHOP-R. Three year overall survival was lower for CPOP-R (69% versus 85%) (P = 0.029). Median progression-free survival (PFS) was not reached for CPOP-R and was 40 months for CHOP-R [HR 95% confidence interval (CI) = 1.02 (0.60, 1.76), P = 0.934]. Fewer CPOP-R patients developed congestive heart failure (CHF) (0% versus 6%, P = 0.120), >= 20% declines in ejection fraction (2% versus 17%, P = 0.004), or elevations in troponin-T (P = 0.003). CONCLUSIONS: CPOP-R is an active regimen with modestly lower response rates than CHOP-R but similar PFS and event-free survival. This study demonstrates a substantially lower cardiotoxicity of pixantrone compared with doxorubicin when used as first-line therapy in DLBCL. PMID- 23946329 TI - Metastasis-free survival is associated with overall survival in men with PSA recurrent prostate cancer treated with deferred androgen deprivation therapy. AB - BACKGROUND: Clinical trials in men with biochemically recurrent prostate cancer (BRPC) have been hampered by long survival times, making overall survival (OS) a difficult end point to reach. Intermediate end points are needed in order to conduct such trials within a more feasible time frame. PATIENTS AND METHODS: This is a retrospective analysis of 450 men with BRPC following prostatectomy treated at a single institution between 1981 and 2010, of which 140 developed subsequent metastases. Androgen deprivation therapy (ADT) was deferred until after the development of metastases. Cox regression models were developed to investigate factors influencing OS. RESULTS: Median metastasis-free survival (MFS) was 10.2 years [95% confidence interval (CI) 7.6-14.0 years]; median OS after metastasis was 6.6 years (95%CI 5.8-8.4 years). Multivariable Cox regressions identified four independently prognostic variables for OS: MFS (HR 0.77; 95% CI 0.63-0.94), number of metastases (<=3 versus >=4; HR 0.50; 95% CI 0.29-0.85), pain (absent versus present; HR 0.43; 95% CI 0.25-0.72), and bisphosphonate use (yes versus no; HR 0.60; 95% CI 0.37-0.98). CONCLUSIONS: MFS emerged as an independent predictor of OS in men with BRPC treated with deferred ADT after the development of metastases. MFS may be a reasonable intermediate end point in future clinical trials. This observation requires prospective validation. PMID- 23946330 TI - Human papillomavirus detection and comorbidity: critical issues in selection of patients with oropharyngeal cancer for treatment De-escalation trials. AB - BACKGROUND: The presence of human papillomavirus (HPV)-infection in oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant in prognostic risk modeling. However, most risk models are based on clinical trials which only include a selected patient population. The clinical significance of HPV and other prognostic factors in patients with OPSCC remains to be evaluated in a large, unselected cohort, which also includes patients with stage I/II disease and patients with severe comorbidity. PATIENTS AND METHODS: All patients diagnosed with OPSCC in 2000-2006 in two Dutch university hospitals were included. The presence of an oncogenic HPV infection was determined by p16-immunostaining, followed by a high-risk HPV general primer 5+/6+ DNA PCR on the p16-positive cases. Cox regression analysis was carried out to compare survival rates between HPV-positive and HPV-negative patients and a prognostic model was generated by recursive partitioning. RESULTS: In total, 163 of 841 (19.4%) tumors were HPV positive. Patients with HPV-positive OPSCC had a more favorable overall survival [73.5% versus 40.9% after 5 years; P < 0.001; hazard ratio = 0.34, 95% confidence interval (CI) 0.25-0.48] compared with patients with HPV-negative OPSCC. Patients with p16-positive but HPV DNA-negative tumors showed a significantly less favorable survival than patients with p16-positive and HPV DNA-positive tumors (P < 0.001). A prognostic model was developed in which patients were classified into three risk groups according to HPV status, nodal stage and comorbidity. [Harrell's concordance index of 0.68 (95% CI 0.65-0.71)]. CONCLUSIONS: Tumor HPV status is a strong and independent prognostic factor for survival among patients with OPSCC. A prognostic risk model was proposed, based on our large, unselected cohort of patients with HPV status, comorbidity and nodal stage being the important prognostic factors. In addition, this study emphasizes the importance of performing an HPV DNA-specific test besides p16-immunostaining. PMID- 23946331 TI - Genomics of a metamorphic timing QTL: met1 maps to a unique genomic position and regulates morph and species-specific patterns of brain transcription. AB - Very little is known about genetic factors that regulate life history transitions during ontogeny. Closely related tiger salamanders (Ambystoma species complex) show extreme variation in metamorphic timing, with some species foregoing metamorphosis altogether, an adaptive trait called paedomorphosis. Previous studies identified a major effect quantitative trait locus (met1) for metamorphic timing and expression of paedomorphosis in hybrid crosses between the biphasic Eastern tiger salamander (Ambystoma tigrinum tigrinum) and the paedomorphic Mexican axolotl (Ambystoma mexicanum). We used existing hybrid mapping panels and a newly created hybrid cross to map the met1 genomic region and determine the effect of met1 on larval growth, metamorphic timing, and gene expression in the brain. We show that met1 maps to the position of a urodele-specific chromosome rearrangement on linkage group 2 that uniquely brought functionally associated genes into linkage. Furthermore, we found that more than 200 genes were differentially expressed during larval development as a function of met1 genotype. This list of differentially expressed genes is enriched for proteins that function in the mitochondria, providing evidence of a link between met1, thyroid hormone signaling, and mitochondrial energetics associated with metamorphosis. Finally, we found that met1 significantly affected metamorphic timing in hybrids, but not early larval growth rate. Collectively, our results show that met1 regulates species and morph-specific patterns of brain transcription and life history variation. PMID- 23946332 TI - Impact of gender on outcomes in ankylosing spondylitis. PMID- 23946333 TI - Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis. AB - OBJECTIVE: To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). METHODS: Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. RESULTS: The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). CONCLUSIONS: Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA. PMID- 23946334 TI - Is limitation of hip abduction a useful clinical sign in the diagnosis of developmental dysplasia of the hip? AB - AIM: The relationship between the presence and severity of sonographically diagnosed developmental dysplasia of the hip (DDH) and the clinical abnormality of limitation of hip abduction (LHA) was investigated. METHODS: A prospective, longitudinal, selective 'at risk' and neonatal instability hip ultrasound programme between 1 January 1996 and 31 December 2005. 2876 neonates/infants were initially screened for DDH by clinical examination and by hip ultrasound imaging. Pathological sonographically evaluated DDH was considered to be Graf Type III, IV and irreducible hip dislocation. Inclusion criteria were cases of unilateral or bilateral limitation of hip abduction hip. EXCLUSION CRITERIA: syndromal, neuromuscular and skeletal dysplasia cases. RESULTS: 492 children presented with LHA (55 unilateral LHA). The mean age of neonates/infants with either unilateral or bilateral LHA was significantly higher than those without (p<0.001). In the sonographic diagnosis of Graf Type III and IV dysplasias, unilateral LHA had a PPV of 40% compared with only 0.3% for bilateral LHA. The sensitivity of unilateral LHA increased to 78.3% and a PPV 54.7% after the age of 8 weeks for Graf Types III, IV and irreducible hip dislocation. CONCLUSIONS: This study identifies a time-dependent association with unilateral LHA in the diagnosis of 'pathological' DDH after the age of 8 weeks. The presence of bilateral LHA in the young infant may be a normal variant and is an inaccurate clinical sign in the diagnosis of pathological DDH. LHA should be actively sought after 8 weeks of age and if present should be followed by a formal ultrasound or radiographic examination to confirm whether or not the hip is developing in a satisfactory manner. PMID- 23946335 TI - Factors influencing ascertainment bias of microsatellite allele sizes: impact on estimates of mutation rates. AB - Microsatellite loci play an important role as markers for identification, disease gene mapping, and evolutionary studies. Mutation rate, which is of fundamental importance, can be obtained from interspecies comparisons, which, however, are subject to ascertainment bias. This bias arises, for example, when a locus is selected on the basis of its large allele size in one species (cognate species 1), in which it is first discovered. This bias is reflected in average allele length in any noncognate species 2 being smaller than that in species 1. This phenomenon was observed in various pairs of species, including comparisons of allele sizes in human and chimpanzee. Various mechanisms were proposed to explain observed differences in mean allele lengths between two species. Here, we examine the framework of a single-step asymmetric and unrestricted stepwise mutation model with genetic drift. Analysis is based on coalescent theory. Analytical results are confirmed by simulations using the simuPOP software. The mechanism of ascertainment bias in this model is a tighter correlation of allele sizes within a cognate species 1 than of allele sizes in two different species 1 and 2. We present computations of the expected average allele size difference, given the mutation rate, population sizes of species 1 and 2, time of separation of species 1 and 2, and the age of the allele. We show that when the past demographic histories of the cognate and noncognate taxa are different, the rate and directionality of mutations affect the allele sizes in the two taxa differently from the simple effect of ascertainment bias. This effect may exaggerate or reverse the effect of difference in mutation rates. We reanalyze literature data, which indicate that despite the bias, the microsatellite mutation rate estimate in the ancestral population is consistently greater than that in either human or chimpanzee and the mutation rate estimate in human exceeds or equals that in chimpanzee with the rate of allele length expansion in human being greater than that in chimpanzee. We also demonstrate that population bottlenecks and expansions in the recent human history have little impact on our conclusions. PMID- 23946336 TI - Comparison between southern blots and qPCR analysis of leukocyte telomere length in the health ABC study. AB - Only a few studies, primarily limited to small samples, have examined the relationship between leukocyte telomere length (LTL) data generated by Southern blots, expressed in kilobases, versus quantitative PCR data, expressed in the telomere product/a single gene product (T/S). In the present study, we compared LTL data generated by the two methods in 681 elderly participants (50% African Americans, 50% of European origin, 49.2% women, mean age 73.7+/-2.9 years) in the Health Aging and Body Composition Study. The correlation between the data generated by the two methods was modest (R (2) = .27). Both methods captured the age effect on LTL and the longer LTL in women than in men. However, only the Southern blot method showed a significantly longer LTL in African Americans than in European decent individuals, which might be attributed to the larger measurement error of the quantitative PCR-based method than the Southern blots. PMID- 23946337 TI - Response to the letter "medication exposure may confound the association between dietary intake and frailty". PMID- 23946338 TI - Nicotinamide phosphoribosyltransferase is required for the calorie restriction mediated improvements in oxidative stress, mitochondrial biogenesis, and metabolic adaptation. AB - Calorie restriction (CR) is one of the most reproducible treatments for weight loss and slowing aging. However, how CR induces these metabolic alterations is not fully understood. In this work, we studied whether nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for nicotinamide adenine dinucleotide biosynthesis, plays a role in CR-induced beneficial metabolic effects using a specific inhibitor of NAMPT (FK866). CR upregulated NAMPT mRNA and protein levels in rat skeletal muscle and white adipose tissue. Inhibition of NAMPT activity by FK866 in rats did not affect the SIRT1 upregulation by CR but suppressed the CR-induced SIRT1 activity and deacetylation of Forkhead box protein O1/peroxisome proliferator-activated receptor gamma coactivator-1alpha. Inhibition of NAMPT activity by FK866 also attenuated the CR induced SIRT3 activity, evidenced by deacetylation of superoxide dismutase-2. Furthermore, FK866 not only weakened the CR-induced decrease of oxidative stress (dichlorofluorescin signal, superoxide , and malondialdehyde levels), but also greatly attenuated the CR-induced improvements of antioxidative activity (total superoxide dismutase, glutathione, and glutathione/oxidized glutathione ratio) and mitochondrial biogenesis (mRNA levels of nuclear respiratory factor 1, cytochrome c oxidase IV, peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and transcription factor A, mitochondrial and citrate synthase activity). At last, FK866 blocked the CR-induced insulin sensitizing, Akt signaling activation, and endothelial nitric oxide synthase phosphorylation. Collectively, our data provide the first evidence that the CR-induced beneficial effects in oxidative stress, mitochondrial biogenesis, and metabolic adaptation require NAMPT. PMID- 23946339 TI - Diet quality of U.K. infants is associated with dietary, adiposity, cardiovascular, and cognitive outcomes measured at 7-8 years of age. AB - Whereas the influence of pregnancy diet and milk feeding on children's health and development is well characterized, the role of early food intake and eating behaviors is largely unexplored. This study aimed to determine whether the degree of adherence to complementary feeding guidelines was associated with dietary, obesity, cardiovascular, and cognitive outcomes at 7-8 y of age. Data were analyzed from the Avon Longitudinal Study of Parents and Children using parent completed dietary questionnaires at 6 mo of age to calculate a Complementary Feeding Utility Index score. Regression analysis was used to explore associations between the index score and dietary patterns derived via principal component analysis (n = 4326), body-mass index (BMI) (n = 4801), waist circumference (n = 4798), blood pressure (n = 4685), and lipids (n = 3232) measured at age 7 y; and intelligence quotient (IQ) measured at age 8 y (n = 4429) after adjustment for covariates. The index score was negatively associated with a "processed" dietary pattern (beta = -0.16; 95% CI: -0.20, -0.13; P < 0.001) but positively associated with a "health conscious" dietary pattern [beta = 0.18 (95% CI: 0.14, 0.21); P < 0.001]. A higher index score was also positively associated with total, verbal, and performance IQ scores at 8 y of age [beta = 1.92 (95%CI: 1.38, 2.47); P < 0.001 for total IQ). The index score was weakly associated with waist circumference [beta = -0.15 (95%CI: -0.31, -0.002); P = 0.046] and diastolic blood pressure [beta = -0.24 (95%CI: -0.47, -0.01); P = 0.043] at 7 y of age but was not associated with BMI or other cardiovascular risk factors. These findings suggest that adherence to current complementary feeding guidelines may have implications for some, but not all, health and development outcomes in childhood. PMID- 23946340 TI - Household food security is associated with agricultural livelihoods and diet quality in a marginalized community of rural Bedouins in Lebanon. AB - In the context of recent increases in international food prices, it is hypothesized that in rural communities retaining food production practices is important for protection against food insecurity at both the household and community levels, as well as for protection against the development of poor nutritional outcomes. To investigate this hypothesis, a cross-sectional study of household food security and nutritional status was carried out in a rural community of settled Bedouins in Lebanon comprising 84 households with 474 individuals; this tribe's recent history of settlement in 2 locations that differ by access to land and food production practices provides the context for this study. Food insecurity was found to be highly prevalent (49%) in this Bedouin community and was negatively associated with household food production (P < 0.05) and the consumption of fruits, chicken, meat, and fish (P < 0.05) and positively associated with consumption of cereal products (P < 0.01). This study shows that in small rural communities in a transitional country, sustaining food production may protect from food insecurity. Agricultural livelihood support programs that promote continued involvement in food production at the household and community level, in conjunction with other income-generating activities, may build resilience against food insecurity and improve dietary diversity. PMID- 23946342 TI - Higher food prices may threaten food security status among American low-income households with children. AB - Children in food-insecure households are more likely to experience poorer health function and worse academic achievement. To investigate the relation between economic environmental factors and food insecurity among children, we examined the relation between general and specific food prices (fast food, fruits and vegetables, beverages) and risk of low (LFS) and very low food security (VLFS) status among low-income American households with children. Using information for 27,900 child-year observations from the Early Childhood Longitudinal Study Kindergarten Class of 1998-1999 linked with food prices obtained from the Cost of Living Data of the Council for Community and Economic Research, formerly known as the American Chamber of Commerce Researchers' Association, fixed effects models were estimated within stratified income groups. Higher overall food prices were associated with increased risk of LFS and VLFS (coefficient = 0.617; P < 0.05). Higher fast food and fruit and vegetable prices also contributed to higher risk of food insecurity (coefficient = 0.632, P < 0.01 for fast food; coefficient = 0.879, P < 0.01 for fruits and vegetables). However, increasing beverage prices, including the prices of soft drinks, orange juice, and coffee, had a protective effect on food security status, even when controlling for general food prices. Thus, although food price changes were strongly related to food security status among low-income American households with children, the effects were not uniform across types of food. These relations should be accounted for when implementing policies that change specific food prices. PMID- 23946341 TI - Consumption of low-fat dairy products may delay natural menopause. AB - Later menopause is a risk factor for breast and endometrial cancer, yet few studies have investigated dietary predictors of this potentially modifiable event. In particular, dairy contains hormones and growth factors that could potentially affect menopausal timing. We therefore assessed the association between regular consumption of dairy foods and related nutrients and age at natural menopause. We conducted a prospective analysis with up to 20 y of follow up in 46,059 participants in the Nurses' Health Study who were premenopausal in 1980. We observed 30,816 events of natural menopause over 401,754 person-years. In the total population, the estimated mean age at natural menopause was 51.5 y for women who consumed no low-fat dairy and 51.5, 51.6, 51.7, and 51.8 y for women who consumed 0.1-1.0, 1.1-2.0, 2.1-3.0, and >3 servings of low-fat dairy daily, respectively. Premenopausal women <51 y of age consuming >3 servings of low-fat dairy per day were 14% less likely (HR: 0.86; 95% CI: 0.77, 0.96; P-trend < 0.0001) to report natural menopause in the next month relative to those consuming 0.1-1 servings/d. Similar results were obtained for skim milk (for >6 servings/wk vs. 0-1 servings/mo: HR: 0.93; 95% CI: 0.89, 0.97; P-trend < 0.0001) but not for total high-fat dairy or whole milk. Dairy foods were not associated with age at menopause among women >=51 y of age. These findings support the growing body of literature on the hormonally active nature of milk and dairy foods. PMID- 23946343 TI - Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12 induce different age-related metabolic profiles revealed by 1H-NMR spectroscopy in urine and feces of mice. AB - Age-related dysbioses of intestinal microbiota and decline in the overall metabolic homeostasis are frequently found in the elderly. Probiotic supplementation may represent a way to prevent or reduce the senescence associated metabolic disorders. The present study evaluated the metabolic impact of Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12 supplementation in relation to age by analyzing urine and feces metabolic profiles using (1)H nuclear magnetic resonance spectroscopy and multivariate analysis. Adult (3 mo old) and aged (16 mo old) mice received an oral supplementation of the 2 probiotics (1 * 10(9) colony-forming units/d each) or phosphate buffered saline (control) daily for 30 d. Urine and feces were collected for 48 h before the end of the study. Partial least squares-discriminant analysis showed that the urinary discriminant metabolites for the probiotic treatment included higher dimethylglycine in adult and aged mice, lower sarcosine and nicotinate in adult mice, higher N-methylnicotinamide in adult mice and lower N-methylnicotinamide in aged mice compared with their controls. These results indicate a probiotic induced modulation of homocysteine and NAD metabolism pathways, which have important implications because these pathways are involved in essential cellular processes that can be altered in senescence. The probiotic supplementation also modified the fecal metabolic profiles, inducing in both adult and aged mice higher 4-hydroxyphenylacetate and lower xylose in treated mice compared with their control mice, whereas valerate was greater in treated adult mice and lower in treated aged mice compared with their controls. The ANOVA simultaneous component analysis on urinary and fecal metabolic profiling showed an age * treatment interaction (P < 0.05), confirming the age-related modulation of the metabolic response to probiotic supplementation. The results suggest that L. acidophilus and B. lactis may prevent or reduce age-related metabolic dysfunction. PMID- 23946345 TI - Increasing the percentage of energy from dietary sugar, fats, and alcohol in adults is associated with increased energy intake but has minimal association with biomarkers of cardiovascular risk. AB - The optimal diet composition to prevent obesity and its complications is unknown. Study aims were to determine the association of diet composition with energy intake, homeostatic model assessment-insulin resistance (HOMA-IR), and C-reactive protein (CRP). Data were from the NHANES for eligible adults aged 20-74 y from 2005 to 2006 (n = 3073). Energy intake and diet composition were obtained by dietary recall. HOMA-IR was calculated from fasting insulin and glucose concentrations, and CRP was measured directly. Changes for a 1-point increase in percentage of sugar, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), and alcohol were determined across their means in exchange for a 1-point decrease in percentage of nonsugar carbohydrates. Regression analyses were performed, and means +/- SEs were estimated. Increasing the percentage of sugar was associated with increased energy intake in men (23 +/- 5 kcal; P < 0.001) and women (12 +/- 3 kcal; P = 0.002). In men, increasing percentages of SFAs (58 +/- 13 kcal; P = 0.001) and PUFAs (66 +/- 19 kcal; P < 0.001) were associated with increased energy intake. In women, increasing percentages of SFAs (27 +/- 10 kcal; P = 0.02), PUFAs (43 +/ 6 kcal; P < 0.001), and MUFAs (36 +/- 13 kcal; P = 0.01) were associated with increased energy intake. Increasing the percentage of alcohol was associated with increased energy intake in men (38 +/- 7 kcal; P < 0.001) and women (25 +/- 8 kcal; P = 0.001). Obesity was associated with increased HOMA-IR and CRP in both genders (all P <= 0.001). Increasing PUFAs was associated with decreasing CRP in men (P = 0.02). In conclusion, increasing the percentage of calories from sugar, fats, and alcohol was associated with substantially increased energy intake but had minimal association with HOMA-IR and CRP. PMID- 23946344 TI - Vitamin E secretion by Caco-2 monolayers to APOA1, but not to HDL, is vitamer selective. AB - The aim of this study was to characterize the pathways of basolateral secretion of common dietary tocopherols from polarized Caco-2 monolayers, a model of intestinal absorption. Given differences in structure and physical properties, we hypothesized that secretion may differ between different forms of vitamin E, thus potentially contribute to the selectivity seen in vivo. Monolayers were incubated apically and simultaneously with 10 MUmol/L alpha-, gamma-, and delta-tocopherol (1:1:1) in lipid micelles. Treatment with the microsomal triglyceride transfer protein inhibitor BMS201038 revealed that the triglyceride-rich particle secretory pathway (apolipoprotein B-dependent pathway) accounted for ~ 80% of total tocopherol secretion, without selectivity among the three forms of vitamin E. Apolipoprotein B-independent secretion of tocopherols (and cholesterol) was greatly enhanced by the liver X receptor agonist T0901317. T0901317 induced ATP binding cassette transporter A1 (ABCA1) protein expression and basolateral secretion of tocopherols to apolipoprotein A1. ABCA1-dependent secretion demonstrated vitamer selectivity such that efficiency of secretion of alpha- and gamma-tocopherols exceeded that of delta-tocopherol. Basal addition of HDL stimulated vitamin E secretion but without selectivity among the three forms, whereas LDL had no effect. Basal addition of scavenger receptor class B member I (SR-BI) blocking antibody, which inhibits the interaction between SR-BI and HDL, increased basal accumulation of all tocopherols, demonstrating a role for SR-BI in cellular re-uptake of secreted vitamin E. These findings demonstrated that vitamin E and cholesterol utilize common pathways of secretion and that secretion via the ABCA1 pathway favors certain forms of vitamin E. PMID- 23946346 TI - Carbohydrate quality and quantity affect glucose and lipid metabolism during weight regain in healthy men. AB - In this controlled, parallel-group feeding trial, we examined the impact of carbohydrate (CHO) intake and glycemic index (GI) on glucose and lipid metabolism during refeeding after weight loss. Healthy men (n = 32 total, age: 25.5 +/- 3.9 y, BMI: 23.5 +/- 2.0 kg/m2) overconsumed diets containing either 50% or 65% CHO for 1 wk (+50% of energy requirements) and then underwent 3 wk of calorie restriction (CR; -50%) followed by 2 wk of overconsuming (refeeding, +50%) the same diet but with either a low or high GI (40 vs.70 during CR, 41 vs.74 during refeeding) so that glycemic load (GL; dietary CHO content x GI) differed between groups during all phases. Glucose profiles were assessed by continuous interstitial glucose monitoring, insulin sensitivity (IS) by fasting blood sampling, oral glucose tolerance test (OGTT) and hyperinsulinemic-euglycemic clamp, and liver fat by MRI. Daytime area under the curve-glucose during refeeding was higher with high compared with low GI (P = 0.01) and 65% compared with 50% CHO intake (P = 0.05) and correlated with dietary GL (r = 0.71; P < 0.001). IS increased with CR and decreased again with refeeding in all groups. The decrease in OGTT-derived IS was greater with high- than with low-GI diets ( 41 vs. -15%; P-interaction = 0.01) and correlated with dietary GL during refeeding (r = -0.51; P < 0.01). Serum triglycerides (TGs) and liver fat also improved with CR (-17 +/- 38 mg/dL and -1.1 +/- 1.3%; P < 0.05 and <0.001) and increased again with refeeding (+48 +/- 48 mg/dL and +2.2 +/- 1.6%; P < 0.001). After refeeding, serum TGs and liver fat were elevated above baseline values with 65% CHO intake only (+59.9 +/- 37.5 mg/dL and +1.1 +/- 1.7%, P-interaction <0.001 and <0.05). In conclusion, a diet low in GI and moderate in CHO content (i.e., low GL) may have health benefits by positively affecting daylong glycemia, IS, and liver fat. PMID- 23946347 TI - Extracted oat and barley beta-glucans do not affect cholesterol metabolism in young healthy adults. AB - beta-Glucans are known to exhibit hypocholesterolemic effects. Increased intestinal viscosity is thought to be crucial for cholesterol lowering. It is suggested that concentration, molecular mass, and structure, including the ratio of (1->3) to (1->4) glucan bonds in the molecule, are of importance for beta glucan functionality. This study investigated the effects of 3 different beta glucan sources, incorporated into a beverage and yogurt, on blood lipids and fecal endpoints. Fourteen participants completed this randomized, crossover, single-blinded study with four 3-wk periods: control and 3.3 g/d oat, barley, and barley mutant beta-glucans of similar molecular mass. Before and after each period, fasting and postprandial blood samples were drawn and 3-d fecal samples were collected. Treatment did not affect changes in total, LDL, and HDL cholesterol compared with control; however, consumption of 3.3 g/d of oat beta glucans for 3 wk resulted in greater decreases in total (-0.29 +/- 0.09 mmol/L, P < 0.01), LDL (-0.23 +/- 0.07 mmol/L, P < 0.01), and HDL (-0.05 +/- 0.03 mmol/L, P < 0.05) cholesterol compared with baseline. Changes in LDL in the beta-glucan treatments were not related to beta-glucan structure (cellotriosyl:cellotetraosyl). Decreases in fasting triacylglycerol were substantially greater after oat beta-glucan treatment compared with control (P = 0.03). Fecal dry and wet weight, stool frequency, fecal pH, and energy excretion were unaffected. The results do not fully support the hypocholesterolemic effects by differently structured oat and barley beta-glucans. However, substantial differences compared with baseline suggest a potential for oat beta-glucan, presumably due to its higher solubility and viscosity. This underlines the importance of elusive structural beta-glucan features for beneficial physiologic effects. PMID- 23946348 TI - Prenatal low-protein and postnatal high-fat diets induce rapid adipose tissue growth by inducing Igf2 expression in Sprague Dawley rat offspring. AB - Maternal low-protein diets result in lower birth weight followed by accelerated catch-up growth that is accompanied by the development of obesity and glucose intolerance in later life. Whether postnatal high-fat (HF) diets further contribute to the development of obesity and insulin resistance in offspring by affecting adipose tissue metabolism and DNA methylation is currently unknown. Obese-prone Sprague-Dawley rats were fed 8% low protein (LP) or 20% normal protein diets for 3 wk prior to conception and throughout pregnancy and lactation to investigate whether prenatal LP and postnatal HF diets affect the rate of adipose tissue growth, insulin-like growth factor 2 (Igf2) expression, and DNA methylation in male offspring. At weaning, the offspring were fed 10% normal fat or 45% HF diets for 12 wk. The adipose tissue growth rate was increased (up to 26 fold) by the LP prenatal and HF postnatal diets. Adipose tissue Igf2 mRNAs and DNA methylation were increased by the LP prenatal and HF postnatal diets. The LP prenatal and HF postnatal diet increased the number of small adipocytes in adipose tissue and decreased insulin sensitivity. These findings suggest that prenatal LP and postnatal HF intake result in adipose tissue catch-up growth through alterations in the expression of the Igf2 gene and DNA methylation within adipocytes. These alterations in adiposity are accompanied by an increased risk of development of type 2 diabetes. PMID- 23946349 TI - Chain length of dietary alkylresorcinols affects their in vivo elimination kinetics in rats. AB - Two phenolic acids, 3,5-dihydroxybenzoic acid (DHBA) and 3-(3,5-dihydroxyphenyl)- propanoic acid (DHPPA), are the major metabolites of cereal alkylresorcinols (ARs). Like their precursors, AR metabolites have been suggested as biomarkers for intake of whole-grain wheat and rye and as such could aid the understanding of diet-disease associations. This study estimated and compared pharmacokinetic parameters of ARs and their metabolites in rats and investigated differences in metabolite formation after ingestion of different AR homologs. Rats were i.v. infused for 30 min with 2, 12, or 23 MUmol/kg DHBA or DHPPA or orally given the same amounts of the AR homologs, C17:0 and C25:0. Repeated plasma samples, obtained from rats for 6 h (i.v.) or 36 h (oral), were simultaneously analyzed for ARs and their metabolites by GC-mass spectrometry. Pharmacokinetic parameters were estimated by population-based compartmental modeling and noncompartmental calculation. A 1-compartment model best described C25:0 pharmacokinetics, whereas C17:0 and AR metabolites best fitted 2-compartment models. Combined models for simultaneous prediction of AR and metabolite concentration were more complex, with less reliable estimates of pharmacokinetic parameters. Although the AUC of C17:0 was lower than that of C25:0 (P < 0.05), the total amount and composition of AR metabolites did not differ between rats given C17:0 or C25:0. The elimination half-life of ARs and their metabolites increased with length of the side chain (P-trend < 0.001) and ranged from 1.2 h (DHBA) to 8.8 h (C25:0). The formation of AR metabolites was slower than their elimination, indicating that the rate of AR metabolism and not excretion of DHBA and DHPPA determines their plasma concentrations in rats. PMID- 23946351 TI - FAR-RED ELONGATED HYPOCOTYL3 and FAR-RED IMPAIRED RESPONSE1 transcription factors integrate light and abscisic acid signaling in Arabidopsis. AB - Light and the phytohormone abscisic acid (ABA) regulate overlapping processes in plants, such as seed germination and seedling development. However, the molecular mechanism underlying the interaction between light and ABA signaling is largely unknown. Here, we show that FAR-RED ELONGATED HYPOCOTYL3 (FHY3) and FAR-RED IMPAIRED RESPONSE1 (FAR1), two key positive transcription factors in the phytochrome A pathway, directly bind to the promoter of ABA-Insensitive5 and activate its expression in Arabidopsis (Arabidopsis thaliana). Disruption of FHY3 and/or FAR1 reduces the sensitivity to ABA-mediated inhibition of seed germination, seedling development, and primary root growth. The seed germination of the fhy3 mutant is also less sensitive to salt and osmotic stress than that of the wild type. Constitutive expression of ABA-Insensitive5 restores the seed germination response of fhy3. Furthermore, the expression of several ABA responsive genes is decreased in the fhy3 and/or far1 mutants during seed imbibition. Consistently, FHY3 and FAR1 transcripts are up-regulated by ABA and abiotic stresses. Moreover, the fhy3 and far1 mutants have wider stomata, lose water faster, and are more sensitive to drought than the wild type. These findings demonstrate that FHY3 and FAR1 are positive regulators of ABA signaling and provide insight into the integration of light and ABA signaling, a process that may allow plants to better adapt to environmental stresses. PMID- 23946352 TI - Difference in abscisic acid perception mechanisms between closure induction and opening inhibition of stomata. AB - Abscisic acid (ABA) induces stomatal closure and inhibits light-induced stomatal opening. The mechanisms in these two processes are not necessarily the same. It has been postulated that the ABA receptors involved in opening inhibition are different from those involved in closure induction. Here, we provide evidence that four recently identified ABA receptors (PYRABACTIN RESISTANCE1 [PYR1], PYRABACTIN RESISTANCE-LIKE1 [PYL1], PYL2, and PYL4) are not sufficient for opening inhibition in Arabidopsis (Arabidopsis thaliana). ABA-induced stomatal closure was impaired in the pyr1/pyl1/pyl2/pyl4 quadruple ABA receptor mutant. ABA inhibition of the opening of the mutant's stomata remained intact. ABA did not induce either the production of reactive oxygen species and nitric oxide or the alkalization of the cytosol in the quadruple mutant, in accordance with the closure phenotype. Whole cell patch-clamp analysis of inward-rectifying K(+) current in guard cells showed a partial inhibition by ABA, indicating that the ABA sensitivity of the mutant was not fully impaired. ABA substantially inhibited blue light-induced phosphorylation of H(+)-ATPase in guard cells in both the mutant and the wild type. On the other hand, in a knockout mutant of the SNF1 related protein kinase, srk2e, stomatal opening and closure, reactive oxygen species and nitric oxide production, cytosolic alkalization, inward-rectifying K(+) current inactivation, and H(+)-ATPase phosphorylation were not sensitive to ABA. PMID- 23946354 TI - Hydroxyethyl starch: here today, gone tomorrow. PMID- 23946353 TI - Arabidopsis tetraspanins are confined to discrete expression domains and cell types in reproductive tissues and form homo- and heterodimers when expressed in yeast. AB - Tetraspanins are evolutionary conserved transmembrane proteins present in all multicellular organisms. In animals, they are known to act as central organizers of membrane complexes and thought to facilitate diverse biological processes, such as cell proliferation, movement, adhesion, and fusion. The genome of Arabidopsis (Arabidopsis thaliana) encodes 17 members of the tetraspanin family; however, little is known about their functions in plant development. Here, we analyzed their phylogeny, protein topology, and domain structure and surveyed their expression and localization patterns in reproductive tissues. We show that, despite their low sequence identity with metazoan tetraspanins, plant tetraspanins display the typical structural topology and most signature features of tetraspanins in other multicellular organisms. Arabidopsis tetraspanins are expressed in diverse tissue domains or cell types in reproductive tissues, and some accumulate at the highest levels in response to pollination in the transmitting tract and stigma, male and female gametophytes and gametes. Arabidopsis tetraspanins are preferentially targeted to the plasma membrane, and they variously associate with specialized membrane domains, in a polarized fashion, to intercellular contacts or plasmodesmata. A membrane-based yeast (Saccharomyces cerevisiae) two-hybrid system established that tetraspanins can physically interact, forming homo- and heterodimer complexes. These results, together with a likely genetic redundancy, suggest that, similar to their metazoan counterparts, plant tetraspanins might be involved in facilitating intercellular communication, whose functions might be determined by the composition of tetraspanin complexes and their binding partners at the cell surface of specific cell types. PMID- 23946355 TI - Tetrastarch solutions: are they definitely dead? PMID- 23946356 TI - Neuraxial block, death and serious cardiovascular morbidity in patients in the POISE trial: propensities, probabilities, and possibilities. PMID- 23946357 TI - Does anaesthetic technique really matter for total knee arthroplasty? PMID- 23946358 TI - Ventilator associated pneumonia: can we ensure that a quality indicator does not become a game of chance? PMID- 23946359 TI - Reflective intubation: a simple and effective method to improve intubation conditions by elevating the tip of the tube without additional equipment. PMID- 23946360 TI - Working conditions, stress, fatigue, and depressive symptoms among Chinese anaesthetists. PMID- 23946361 TI - Application of emergency trauma score in a hub-and-spoke regional system. PMID- 23946362 TI - Is sickle cell disease a possible risk factor for peripheral neuropathy after popliteal sciatic nerve block? PMID- 23946363 TI - Accurate and easy to learn ultrasound sign to confirm correct tracheal intubation in cadaver model. PMID- 23946364 TI - Critical illness-related corticosteroid insufficiency in cardiogenic shock. PMID- 23946365 TI - Sometimes the best is the enemy of the good. PMID- 23946366 TI - Should cognitive impairment be an exclusion criterion for hip fracture studies? PMID- 23946367 TI - Reply from the authors. PMID- 23946368 TI - Perioperative goal-directed haemodynamic treatment and the equity of differing modalities. PMID- 23946369 TI - Reply from the authors. PMID- 23946370 TI - Potential confounder in the ethical dilemma of challenging authority. PMID- 23946371 TI - Effects of remifentanil on cognitive and psychomotor functioning and mood. PMID- 23946372 TI - Consent in Jehovah's Witnesses. PMID- 23946382 TI - The learning curve for detection of non-polypoid (flat and depressed) colorectal neoplasms. PMID- 23946381 TI - Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. AB - OBJECTIVE: In the past two decades, approximately 1000 reports have been published regarding associations between genetic variants in candidate genes and risk of colorectal cancer (CRC). Study results are inconsistent. We aim to provide a synopsis of the current understanding of genetic factors for CRC risk through systematically evaluating results from previous studies. DESIGN: We searched PubMed and Google Scholar to identify papers that investigated associations between genetic variants and CRC risk and published through 25 December 2012. With data from 950 papers, we conducted 910 meta-analyses for 267 genetic variants in 150 candidate genes with at least three data sources. We used Venice criteria and false-positive report probability tests to grade levels of cumulative epidemiological evidence of significant associations with CRC risk. RESULTS: Sixty-two variants in 50 candidate genes showed a nominally significant association with CRC risk (p<0.05). Cumulative epidemiological evidence for a significant association with CRC risk was graded strong for eight variants in five genes (adenomatous polyposis coli (APC), CHEK2, DNMT3B, MLH1 and MUTYH), moderate for two variants in two genes (GSTM1 and TERT), and weak for 52 variants in 45 genes. Additionally, 40 variants in 33 genes showed convincing evidence of no association with CRC risk in meta-analyses including at least 5000 cases and 5000 controls. CONCLUSIONS: Approximately 4% of genetic variants evaluated to date in candidate-gene association studies showed moderate to strong cumulative epidemiological evidence of an association with CRC risk. These genetic variants, if confirmed, may explain approximately 5% of familial CRC risk. PMID- 23946383 TI - Indirubin derivative 6BIO suppresses metastasis. AB - While metastasis is the chief cause of cancer mortality, there nonetheless remains a lack of antimetastatic therapies that are clinically available. In this study, we present the indirubin derivative 6-bromo-indirubin-3'-oxime (6BIO) as a promising antimetastatic agent. 6BIO strongly reduced formation of lung metastasis in the well-established 4T1 mouse model of aggressive breast cancer. Several major hallmarks of the metastatic process were affected by subtoxic concentrations of 6BIO, which inhibited adhesion, migration, and invasion of a variety of metastatic cell types in vitro. Mechanistic analyses focused on known targets of 6BIO, which were silenced by this compound. Unexpectedly, RNAi mediated silencing of glycogen synthase kinase 3beta (GSK3beta) and phosphoinositide-dependent protein kinase 1 (PDK1), both modulators of cellular metastasis targeted by 6BIO, were not found to affect invasive migration in this study. Instead, the Jak/STAT3 signaling pathway appeared to play a major role through modulation of its downstream migration regulators C-terminal tensin-like protein and matrix metalloproteinase 2. However, PDK1 and GSK3beta contributed to the overall response to 6BIO, as silencing of all three pathways resulted in almost complete inhibition of migration, phenocopying the 6BIO response. Taken together, our findings illustrate the antimetastatic activity of 6BIO on the basis of its ability to simultaneously inhibit several kinase cascades involved in metastasis of cancer cells, supporting the concept of "polypharmacology" in developing drugs to attack metastasis, the most deadly aspect of cancer. PMID- 23946384 TI - Tracking the roots of reading ability: white matter volume and integrity correlate with phonological awareness in prereading and early-reading kindergarten children. AB - Developmental dyslexia, an unexplained difficulty in learning to read, has been associated with alterations in white matter organization as measured by diffusion weighted imaging. It is unknown, however, whether these differences in structural connectivity are related to the cause of dyslexia or if they are consequences of reading difficulty (e.g., less reading experience or compensatory brain organization). Here, in 40 kindergartners who had received little or no reading instruction, we examined the relation between behavioral predictors of dyslexia and white matter organization in left arcuate fasciculus, inferior longitudinal fasciculus, and the parietal portion of the superior longitudinal fasciculus using probabilistic tractography. Higher composite phonological awareness scores were significantly and positively correlated with the volume of the arcuate fasciculus, but not with other tracts. Two other behavioral predictors of dyslexia, rapid naming and letter knowledge, did not correlate with volumes or diffusion values in these tracts. The volume and fractional anisotropy of the left arcuate showed a particularly strong positive correlation with a phoneme blending test. Whole-brain regressions of behavioral scores with diffusion measures confirmed the unique relation between phonological awareness and the left arcuate. These findings indicate that the left arcuate fasciculus, which connects anterior and posterior language regions of the human brain and which has been previously associated with reading ability in older individuals, is already smaller and has less integrity in kindergartners who are at risk for dyslexia because of poor phonological awareness. These findings suggest a structural basis of behavioral risk for dyslexia that predates reading instruction. PMID- 23946386 TI - ERK2-mediated phosphorylation of Par3 regulates neuronal polarization. AB - Axon formation is one of the most important events in neuronal polarization and is regulated by signaling molecules involved in cytoskeletal rearrangement and protein transport. We previously found that Partition-defective 3 (Par3) is associated with KIF3A (kinesin-2) and is transported into the nascent axon in a KIF3A-dependent fashion. Par3 interacts with the Rac-specific guanine nucleotide exchange factors (GEFs) Tiam1/2, which activate Rac1, and participates in axon formation in cultured hippocampal neurons. However, the regulatory mechanism of the Par3-KIF3A interaction is poorly understood, and the role of Par3 in neuronal polarization in vivo remains elusive. Here, we found that extracellular signal regulated kinase 2 (ERK2) directly interacts with Par3, that ERK2 phosphorylates Par3 at Ser-1116, and that the phosphorylated Par3 accumulates at the axonal tips in a manner dependent upon ERK2 activity. The phosphorylation of Par3 by ERK2 inhibited the interaction of Par3 with KIF3A but not with the other Par3 partners, including Par6 and aPKC. The phosphomimic mutant of Par3 (Par3-S1116D) showed less binding activity with the KIF3s and slower transport in the axons. The knockdown of Par3 by RNA interference impaired neuronal polarization, which was rescued with RNAi-resistant Par3, but not with the phosphomimic Par3 mutant, in cultured rat hippocampal neurons and mouse cortical projection neurons in vivo. These results suggest that ERK2 phosphorylates Par3 and inhibits its binding with KIF3A, thereby controlling Par3 transport and neuronal polarity. PMID- 23946385 TI - Proactive selective response suppression is implemented via the basal ganglia. AB - In the welter of everyday life, people can stop particular response tendencies without affecting others. A key requirement for such selective suppression is that subjects know in advance which responses need stopping. We hypothesized that proactively setting up and implementing selective suppression relies on the basal ganglia and, specifically, regions consistent with the inhibitory indirect pathway for which there is scant functional evidence in humans. Consistent with this hypothesis, we show, first, that the degree of proactive motor suppression when preparing to stop selectively (indexed by transcranial magnetic stimulation) corresponds to striatal, pallidal, and frontal activation (indexed by functional MRI). Second, we demonstrate that greater striatal activation at the time of selective stopping correlates with greater behavioral selectivity. Third, we show that people with striatal and pallidal volume reductions (those with premanifest Huntington's disease) have both absent proactive motor suppression and impaired behavioral selectivity when stopping. Thus, stopping goals are used to proactively set up specific basal ganglia channels that may then be triggered to implement selective suppression. By linking this suppression to the striatum and pallidum, these results provide compelling functional evidence in humans of the basal ganglia's inhibitory indirect pathway. PMID- 23946387 TI - Melanocortin signaling in the brainstem influences vagal outflow to the stomach. AB - Activation of melanocortin 4 receptors (MC4-Rs) in brain nuclei associated with food intake profoundly influences consummatory behavior. Of these nuclei, the dorsal motor vagal nucleus (DMV), which has a dense concentration of MC4-Rs, is an important regulator of gastric tone and motility. Hence, the present study sought to examine the role of MC4-Rs in this nucleus on these activities. Using an in vivo approach, MC4-R agonists, melanotan-II (MT-II) or alpha-melanocyte stimulating hormone (alpha-MSH), were unilaterally microinjected into the DMV of rats, and their effects were noted on gastric activity. MT-II decreased phasic contractions, whereas alpha-MSH increased their amplitude. Both effects were blocked by the MC4-R antagonist SHU9119 or by ipsilateral vagotomy. Microinjection of the agonists (MT-II and alpha-MSH) into the overlying nucleus of the solitary tract (NTS), an important component of "vago-vagal" gastric circuitry, decreased phasic contractions. In addition, alpha-MSH reduced gastric tone and mean arterial blood pressure. To study the underlying mechanisms of the effect of MC4-R stimulation on gastric activity, electrophysiological recordings were made from labeled DMV antrum neurons in rat pups and MC4-R(-/-) mice. Bath application of MT-II or alpha-MSH significantly reduced spontaneous action potentials (but not in MC4-R(-/-) mice). However, in low-calcium ACSF, MT-II decreased neuronal firing, whereas alpha-MSH increased it. These effects mirror those of our in vivo DMV studies. Altogether, our novel findings show that activation of MC4-Rs in the brainstem, particularly in the medial NTS by the endogenous peptide alpha-MSH, modulates gastric activity, which may have physiological relevance for food intake and gastric function. PMID- 23946388 TI - Reversal of neurofibrillary tangles and tau-associated phenotype in the rTgTauEC model of early Alzheimer's disease. AB - Neurofibrillary tangles (NFTs), a marker of neuronal alterations in Alzheimer's disease (AD) and other tauopathies, are comprised of aggregates of hyperphosphorylated tau protein. We recently studied the formation of NFTs in the entorhinal cortex (EC) and their subsequent propagation through neural circuits in the rTgTauEC mouse model (de Calignon et al., 2012). We now examine the consequences of suppressing transgene expression with doxycycline on the NFT associated pathological features of neuronal system deafferentation, NFT progression and propagation, and neuronal loss. At 21 months of age we observe that EC axonal lesions are associated with an abnormal sprouting response of acetylcholinesterase (AChE)-positive fibers, a phenotype reminiscent of human AD. At 24 months, NFTs progress, tau inclusions propagate to the dentate gyrus, and neuronal loss is evident. Suppression of the transgene expression from 18 to 24 months led to reversal of AChE sprouting, resolution of Gallyas-positive and Alz50-positive NFTs, and abrogation of progressive neuronal loss. These data suggest that propagation of NFTs, as well as some of the neural system consequences of NFTs, can be reversed in an animal model of NFT-associated toxicity, providing proof in principle that these lesions can be halted, even in established disease. PMID- 23946389 TI - Distance-dependent scaling of AMPARs is cell-autonomous and GluA2 dependent. AB - The extensive dendritic arbor of a pyramidal cell introduces considerable complexity to the integration of synaptic potentials. Propagation of dendritic potentials is largely passive, in contrast to regenerative axonal potentials that are maintained by voltage-gated sodium channels, leading to a declination in amplitude as dendritic potentials travel toward the soma in a manner that disproportionally affects distal synaptic inputs. To counteract this amplitude filtering, Schaffer collateral synapses onto CA1 pyramidal cells contain a varying number of AMPA receptors (AMPARs) per synapse that increases with distance from the soma, a phenomenon known as distance-dependent scaling. Here, we undertake an investigation into the molecular mechanisms of distance-dependent scaling. Using dendritic recordings from rat pyramidal neurons, we confirm the basic scaling phenomenon and find that it is expressed and can be manipulated cell autonomously. Finally, we show that it depends on the presence of both a reserve pool of AMPARs and the AMPAR subunit GluA2. PMID- 23946390 TI - CD33 Alzheimer's risk-altering polymorphism, CD33 expression, and exon 2 splicing. AB - Genome-wide association studies are identifying novel Alzheimer's disease (AD) risk factors. Elucidating the mechanism underlying these polymorphisms is critical to the validation process and, by identifying rate-limiting steps in AD risk, may yield novel therapeutic targets. Here, we elucidate the mechanism of action of the AD-associated polymorphism rs3865444 in the promoter of CD33, a member of the sialic acid-binding Ig-superfamily of lectins (SIGLECs). Immunostaining established that CD33 is expressed in microglia in human brain. Consistent with this finding, CD33 mRNA expression correlated well with expression of the microglial genes CD11b and AIF-1 and was modestly increased with AD status and the rs3865444C AD-risk allele. Analysis of CD33 isoforms identified a common isoform lacking exon 2 (D2-CD33). The proportion of CD33 expressed as D2-CD33 correlated robustly with rs3865444 genotype. Because rs3865444 is in the CD33 promoter region, we sought the functional polymorphism by sequencing CD33 from the promoter through exon 4. We identified a single polymorphism that is coinherited with rs3865444, i.e., rs12459419 in exon 2. Minigene RNA splicing studies in BV2 microglial cells established that rs12459419 is a functional single nucleotide polymorphism (SNP) that modulates exon 2 splicing efficiency. Thus, our primary findings are that CD33 is a microglial mRNA and that rs3865444 is a proxy SNP for rs12459419 that modulates CD33 exon 2 splicing. Exon 2 encodes the CD33 IgV domain that typically mediates sialic acid binding in SIGLEC family members. In summary, these results suggest a novel model wherein SNP-modulated RNA splicing modulates CD33 function and, thereby, AD risk. PMID- 23946391 TI - Organization and origin of spatial frequency maps in cat visual cortex. AB - It remains controversial whether and how spatial frequency (SF) is represented tangentially in cat visual cortex. Several models were proposed, but there is no consensus. Worse still, some data indicate that the SF organization previously revealed by optical imaging techniques simply reflects non-stimulus-specific responses. Instead, stimulus-specific responses arise from the homogeneous distribution of geniculo-cortical afferents representing X and Y pathways. To clarify this, we developed a new imaging method allowing rapid stimulation with a wide range of SFs covering more than 6 octaves with only 0.2 octave resolution. A benefit of this method is to avoid error of high-pass filtering methods which systematically under-represent dominant selectivity features near pinwheel centers. We show unequivocally that SF is organized into maps in cat area 17 (A17) and area 18 (A18). The SF organization in each area displays a global anteroposterior SF gradient and local patches. Its layout is constrained to that of the orientation map, and it is suggested that both maps share a common functional architecture. A17 and A18 are bound at the transition zone by another SF gradient involving the geniculo-cortical and the callosal pathways. A model based on principal component analysis shows that SF maps integrate three different SF-dependent channels. Two of these reflect the segregated excitatory input from X and Y geniculate cells to A17 and A18. The third one conveys a specific combination of excitatory and suppressive inputs to the visual cortex. In a manner coherent with anatomical and electrophysiological data, it is interpreted as originating from a subtype of Y geniculate cells. PMID- 23946392 TI - Laterality effect for faces in chimpanzees (Pan troglodytes). AB - Face perception in humans is governed more by right-hemispheric than left hemispheric neural correlate. Some but not all neurophysiological studies depict a right-side dominance for face responsive neurons in the brains of macaques. Hence, it is an open question whether and to what extent a right-hemisphere preference of processing faces exists across primate brains. We investigated chimpanzees discriminating chimeric faces of chimpanzees and humans, i.e., the combination of either left or right sides of a face vertically flipped and merged into a whole face. We found an effect of choosing the left-chimeric face more often than the right-chimeric face as being the one of the two that is closer to the original face, reflecting an advantage for the right side of the brain to process faces, as reported in humans. Moreover, we found a modulation by age of the participants, suggesting that the exposure history with a particular category shapes the right-hemispheric neural correlate to a configural/holistic processing strategy. In other words, the findings in chimpanzee participants parallel those in human participants and are suggestive for similar neural machineries in the occipital-temporal cortices in both species. PMID- 23946393 TI - Disintegration of multisensory signals from the real hand reduces default limb self-attribution: an fMRI study. AB - The perception of our limbs in space is built upon the integration of visual, tactile, and proprioceptive signals. Accumulating evidence suggests that these signals are combined in areas of premotor, parietal, and cerebellar cortices. However, it remains to be determined whether neuronal populations in these areas integrate hand signals according to basic temporal and spatial congruence principles of multisensory integration. Here, we developed a setup based on advanced 3D video technology that allowed us to manipulate the spatiotemporal relationships of visuotactile (VT) stimuli delivered on a healthy human participant's real hand during fMRI and investigate the ensuing neural and perceptual correlates. Our experiments revealed two novel findings. First, we found responses in premotor, parietal, and cerebellar regions that were dependent upon the spatial and temporal congruence of VT stimuli. This multisensory integration effect required a simultaneous match between the seen and felt postures of the hand, which suggests that congruent visuoproprioceptive signals from the upper limb are essential for successful VT integration. Second, we observed that multisensory conflicts significantly disrupted the default feeling of ownership of the seen real limb, as indexed by complementary subjective, psychophysiological, and BOLD measures. The degree to which self-attribution was impaired could be predicted from the attenuation of neural responses in key multisensory areas. These results elucidate the neural bases of the integration of multisensory hand signals according to basic spatiotemporal principles and demonstrate that the disintegration of these signals leads to "disownership" of the seen real hand. PMID- 23946394 TI - Serotonin 2A receptors differentially contribute to abuse-related effects of cocaine and cocaine-induced nigrostriatal and mesolimbic dopamine overflow in nonhuman primates. AB - Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT2A receptor antagonist M100907 on intravenous cocaine self administration and drug- and cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n = 4) and the caudate nucleus (n = 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug- and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse related effects of cocaine are mediated by distinct striatal dopamine projection pathways. PMID- 23946396 TI - Robust encoding of stimulus identity and concentration in the accessory olfactory system. AB - Sensory systems represent stimulus identity and intensity, but in the neural periphery these two variables are typically intertwined. Moreover, stable detection may be complicated by environmental uncertainty; stimulus properties can differ over time and circumstance in ways that are not necessarily biologically relevant. We explored these issues in the context of the mouse accessory olfactory system, which specializes in detection of chemical social cues and infers myriad aspects of the identity and physiological state of conspecifics from complex mixtures, such as urine. Using mixtures of sulfated steroids, key constituents of urine, we found that spiking responses of individual vomeronasal sensory neurons encode both individual compounds and mixtures in a manner consistent with a simple model of receptor-ligand interactions. Although typical neurons did not accurately encode concentration over a large dynamic range, from population activity it was possible to reliably estimate the log-concentration of pure compounds over several orders of magnitude. For binary mixtures, simple models failed to accurately segment the individual components, largely because of the prevalence of neurons responsive to both components. By accounting for such overlaps during model tuning, we show that, from neuronal firing, one can accurately estimate log-concentration of both components, even when tested across widely varying concentrations. With this foundation, the difference of logarithms, log A - log B = log A/B, provides a natural mechanism to accurately estimate concentration ratios. Thus, we show that a biophysically plausible circuit model can reconstruct concentration ratios from observed neuronal firing, representing a powerful mechanism to separate stimulus identity from absolute concentration. PMID- 23946395 TI - Hypoxia-induced developmental delays of inhibitory interneurons are reversed by environmental enrichment in the postnatal mouse forebrain. AB - Infants born premature experience hypoxic episodes due to immaturity of their respiratory and central nervous systems. This profoundly affects brain development and results in cognitive impairments. We used a mouse model to examine the impact of hypoxic rearing (9.5-10.5% O2) from postnatal day 3 to 11 (P3-P11) on GABAergic interneurons and the potential for environmental enrichment to ameliorate these developmental abnormalities. At P15 the numbers of cortical interneurons expressing immunohistochemically detectable levels of parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide were decreased in hypoxic-reared mice by 59%, 32%, and 38%, respectively, compared with normoxic controls. Hypoxia also decreased total GABA content in frontal neocortex by 31%. However, GAD67-EGFP knock-in mice reared under hypoxic conditions showed no changes in total number of GAD67-EGFP(+) cells and no evidence of increased interneuron death, suggesting that the total number of interneurons was not decreased, but rather, that hypoxic-rearing decreased interneuron marker expression in these cells. In adulthood, PV and SST expression levels were decreased in hypoxic-reared mice. In contrast, intensity of reelin (RLN) expression was significantly increased in adult hypoxic-reared mice compared with normoxic controls. Housing mice in an enriched environment from P21 until adulthood normalized phenotypic interneuron marker expression without affecting total interneuron numbers or leading to increased neurogenesis. Our data show that (1) hypoxia decreases PV and SST and increases RLN expression in cortical interneurons during postnatal cortical development and (2) enriched environment has the capacity to normalize the interneuron abnormalities in cortex. PMID- 23946398 TI - Rescue of peripheral and CNS axon defects in mice lacking NMNAT2. AB - NMNAT2 is an NAD(+)-synthesizing enzyme with an essential axon maintenance role in primary culture neurons. We have generated an Nmnat2 gene trap mouse to examine the role of NMNAT2 in vivo. Homozygotes die perinatally with a severe peripheral nerve/axon defect and truncated axons in the optic nerve and other CNS regions. The cause appears to be limited axon extension, rather than dying-back degeneration of existing axons, which was previously proposed for the NMNAT2 deficient Blad mutant mouse. Neurite outgrowth in both PNS and CNS neuronal cultures consistently stalls at 1-2 mm, similar to the length of truncated axons in the embryos. Crucially, this suggests an essential role for NMNAT2 during axon growth. In addition, we show that the Wallerian degeneration slow protein (Wld(S)), a more stable, aberrant NMNAT that can substitute the axon maintenance function of NMNAT2 in primary cultures, can also correct developmental defects associated with NMNAT2 deficiency. This is dose-dependent, with extension of life span to at least 3 months by homozygous levels of Wld(S) the most obvious manifestation. Finally, we propose that endogenous mechanisms also compensate for otherwise limiting levels of NMNAT2. This could explain our finding that conditional silencing of a single Nmnat2 allele triggers substantial degeneration of established neurites, whereas similar, or greater, reduction of NMNAT2 in constitutively depleted neurons is compatible with normal axon growth and survival. A requirement for NMNAT2 for both axon growth and maintenance suggests that reduced levels could impair axon regeneration as well as axon survival in aging and disease. PMID- 23946397 TI - Synaptic state-dependent functional interplay between postsynaptic density-95 and synapse-associated protein 102. AB - Activity-dependent regulation of AMPA receptor (AMPAR)-mediated synaptic transmission is the basis for establishing differences in synaptic weights among individual synapses during developmental and experience-dependent synaptic plasticity. Synaptic signaling scaffolds of the Discs large (DLG)-membrane associated guanylate kinase (MAGUK) protein family regulate these processes by tethering signaling proteins to receptor complexes. Using a molecular replacement strategy with RNAi-mediated knockdown in rat and mouse hippocampal organotypic slice cultures, a postsynaptic density-95 (PSD-95) knock-out mouse line and electrophysiological analysis, our current study identified a functional interplay between two paralogs, PSD-95 and synapse-associated protein 102 (SAP102) to regulate synaptic AMPARs. During synaptic development, the SAP102 protein levels normally plateau but double if PSD-95 expression is prevented during synaptogenesis. For an autonomous function of PSD-95 in regulating synaptic AMPARs, in addition to the previously demonstrated N-terminal multimerization and the first two PDZ (PSD-95, Dlg1, zona occludens-1) domains, the PDZ3 and guanylate kinase domains were required. The Src homology 3 domain was dispensable for the PSD-95-autonomous regulation of basal synaptic transmission. However, it mediated the functional interaction with SAP102 of PSD 95 mutants to enhance AMPARs. These results depict a protein domain-based multifunctional aspect of PSD-95 in regulating excitatory synaptic transmission and unveil a novel form of domain-based interplay between signaling scaffolds of the DLG-MAGUK family. PMID- 23946399 TI - Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: involvement of Ca(2+)-activated small conductance potassium channels. AB - It is well established that activation of NMDARs plays an essential role in spinal cord synaptic plasticity (i.e., central sensitization) and pain hypersensitivity after tissue injury. Despite prominent expression of NMDARs in DRG primary sensory neurons, the unique role of peripheral NMDARs in regulating intrinsic neuronal excitability and pain sensitivity is not well understood, in part due to the lack of selective molecular tools. To address this problem, we used Advillin-Cre driver to delete the NR1 subunit of NMDARs selectively in DRG neurons. In NR1 conditional knock-out (NR1-cKO) mice, NR1 expression is absent in DRG neurons but remains normal in spinal cord neurons; NMDA-induced currents are also eliminated in DRG neurons of these mice. Surprisingly, NR1-cKO mice displayed mechanical and thermal hypersensitivity compared with wild-type littermates. NR1-deficient DRG neurons show increased excitability, as indicated by increased frequency of action potentials, and enhanced excitatory synaptic transmission in spinal cord slices, as indicated by increased frequency of miniature EPSCs. This hyperexcitability can be reproduced by the NMDAR antagonist APV and by Ca(2+)-activated slow conductance K(+) (SK) channel blocker apamin. Furthermore, NR1-positive DRG neurons coexpress SK1/SK2 and apamin-sensitive afterhyperpolarization currents are elevated by NMDA and suppressed by APV in these neurons. Our findings reveal the hitherto unsuspected role of NMDARs in controlling the intrinsic excitability of primary sensory neurons possibly via Ca(2+)-activated SK channels. Our results also call attention to potential opposing effects of NMDAR antagonists as a treatment for pain and other neurological disorders. PMID- 23946400 TI - Copper block of extrasynaptic GABAA receptors in the mature cerebellum and striatum. AB - Inhibition of GABAA receptors by Cu(2+) has been appreciated for some time, but differences between synaptic and extrasynaptic GABAA receptors have not been explored. We show that Cu(2+) potently blocks steady-state GABA currents mediated by extrasynaptic delta subunit-containing GABAA receptors (delta-GABAARs) with an IC50 of 65 nM. This compares with an IC50 of 85 MUM for synaptic gamma subunit containing GABAARs (gamma-GABAARs). To test the significance of this subunit selectivity, we examined the blocking action of Cu(2+) on neurons of the mouse cerebellum and striatum, brain regions that are known to express both types of receptor. Cu(2+) was shown to significantly reduce tonic inhibition mediated by extrasynaptic delta-GABAARs with little action on phasic inhibition mediated by conventional synaptic gamma-GABAARs. We speculate on the implications of these observations for conditions, such as Wilson's disease, that can involve raised Cu(2+) levels in the brain. PMID- 23946401 TI - Number of spikes in climbing fibers determines the direction of cerebellar learning. AB - Cerebellar learning requires context information from mossy fibers and a teaching signal through the climbing fibers from the inferior olive. Although the inferior olive fires in bursts, virtually all studies have used a teaching signal consisting of a single pulse. Following a number of failed attempts to induce cerebellar learning in decerebrate ferrets with a nonburst signal, we tested the effect of varying the number of pulses in the climbing fiber teaching signal. The results show that training with a single pulse in a conditioning paradigm in vivo does not result in learning, but rather causes extinction of a previously learned response. PMID- 23946402 TI - Synaptic abnormalities in the infralimbic cortex of a model of congenital depression. AB - Multiple lines of evidence suggest that disturbances in excitatory transmission contribute to depression. Whether these defects involve the number, size, or composition of glutamatergic contacts is unclear. This study used recently introduced procedures for fluorescence deconvolution tomography in a well-studied rat model of congenital depression to characterize excitatory synapses in layer I of infralimbic cortex, a region involved in mood disorders, and of primary somatosensory cortex. Three groups were studied: (1) rats bred for learned helplessness (cLH); (2) rats resistant to learned helplessness (cNLH); and (3) control Sprague Dawley rats. In fields within infralimbic cortex, cLH rats had the same numerical density of synapses, immunolabeled for either the postsynaptic density (PSD) marker PSD95 or the presynaptic protein synaptophysin, as controls. However, PSD95 immunolabeling intensities were substantially lower in cLH rats, as were numerical densities of synapse-sized clusters of the AMPA receptor subunit GluA1. Similar but less pronounced differences (comparable numerical densities but reduced immunolabeling intensity for PSD95) were found in the somatosensory cortex. In contrast, non-helpless rats had 25% more PSDs than either cLH or control rats without any increase in synaptophysin-labeled terminal frequency. Compared with controls, both cLH and cNLH rats had fewer GABAergic contacts. These results indicate that congenital tendencies that increase or decrease depression-like behavior differentially affect excitatory synapses. PMID- 23946403 TI - Lateral entorhinal modulation of piriform cortical activity and fine odor discrimination. AB - The lateral entorhinal cortex (LEC) receives direct input from olfactory bulb mitral cells and piriform cortical pyramidal cells and is the gateway for olfactory input to the hippocampus. However, the LEC also projects back to the piriform cortex and olfactory bulb. Activity in the LEC is shaped by input from the perirhinal cortices, hippocampus, and amygdala, and thus could provide a rich contextual modulation of cortical odor processing. The present study further explored LEC feedback to anterior piriform cortex by examining how LEC top-down input modulates anterior piriform cortex odor evoked activity in rats. Retrograde viral tracing confirmed rich LEC projections to both the olfactory bulb and piriform cortices. In anesthetized rats, reversible lesions of the ipsilateral LEC increased anterior piriform cortical single-unit spontaneous activity. In awake animals performing an odor discrimination task, unilateral LEC reversible lesions enhanced ipsilateral piriform cortical local field potential oscillations during odor sampling, with minimal impact on contralateral activity. Bilateral LEC reversible lesions impaired discrimination performance on a well learned, difficult odor discrimination task, but had no impact on a well learned simple odor discrimination task. The simple discrimination task was impaired by bilateral reversible lesions of the anterior piriform cortex. Given the known function of LEC in working memory and multisensory integration, these results suggest it may serve as a powerful top-down modulator of olfactory cortical function and odor perception. Furthermore, the results provide potential insight into how neuropathology in the entorhinal cortex could contribute to early olfactory deficits seen in Alzheimer's disease. PMID- 23946404 TI - A dramatic increase of C1q protein in the CNS during normal aging. AB - The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement- and synapse elimination-independent role for C1q in CNS aging. PMID- 23946405 TI - Therapeutic margins in a novel preclinical model of retinitis pigmentosa. AB - The third-most common cause of autosomal recessive retinitis pigmentosa (RP) is due to defective cGMP phosphodiesterase-6 (PDE6). Previous work using viral gene therapy on PDE6-mutant mouse models demonstrated photoreceptors can be rescued if administered before degeneration. However, whether visual function can be rescued after degeneration onset has not been addressed. This is a clinically important question, as newly diagnosed patients exhibit considerable loss of rods and cones in their peripheral retinas. We have generated and characterized a tamoxifen inducible Cre-loxP rescue allele, Pde6b(Stop), which allows us to temporally correct PDE6-deficiency. Whereas untreated mutants exhibit degeneration, activation of Cre-loxP recombination in early embryogenesis produced stable long term rescue. Reversal at later time-points showed partial long-term or short lived rescue. Our results suggest stable restoration of retinal function by gene therapy can be achieved if a sufficient number of rods are treated. Because patients are generally diagnosed after extensive loss of rods, the success of clinical trials may depend on identifying patients as early as possible to maximize the number of treatable rods. PMID- 23946406 TI - Early experience shapes amygdala sensitivity to race: an international adoption design. AB - In the current study, we investigated how complete infant deprivation to out group race impacts behavioral and neural sensitivity to race. Although monkey models have successfully achieved complete face deprivation in early life, this is typically impossible in human studies. We overcame this barrier by examining youths with exclusively homogenous racial experience in early postnatal development. These were youths raised in orphanage care in either East Asia or Eastern Europe as infants and later adopted by American families. The use of international adoption bolsters confidence of infant exposure to race (e.g., to solely Asian faces or European faces). Participants completed an emotional matching task during functional MRI. Our findings show that deprivation to other race faces in infancy disrupts recognition of emotion and results in heightened amygdala response to out-group faces. Greater early deprivation (i.e., later age of adoption) is associated with greater biases to race. These data demonstrate how early social deprivation to race shapes amygdala function later in life and provides support that early postnatal development may represent a sensitive period for race perception. PMID- 23946407 TI - Plastic modification of anti-saccades: adaptation of saccadic eye movements aimed at a virtual target. AB - Saccades allow us to visually explore our environment. Like other goal-directed movements, their accuracy is permanently controlled by adaptation mechanisms that, in the laboratory, can be induced by systematic displacement of the "real" visual target during the saccade. However, in an anti-saccade (AS) task, the target is "virtual" because gaze has to be shifted away from the "real" visual target toward its mentally defined mirror position. Here, we investigated whether the brain can adapt movements aimed at a virtual target by trying, for the first time, to adapt AS. Healthy human volunteers produced leftward AS during three different exposure phases in which a visual target provided feedback after the AS. In the adaptation condition, the feedback target appeared after completion of the AS response at a location shifted outward from final eye position (immediate non-veridical feedback). In the two control conditions, adaptation was prevented by delaying (800 ms) the shifted feedback target (delayed-shift) or by providing an immediate but veridical feedback at the mirror position of the visual target (no-shift). Results revealed a significant increase of AS gain only in the adaptation condition. Moreover, testing pro-saccades (PS) before and after exposure revealed a significant increase of leftward PS gain in the adaptation condition. This transfer of adaptation supports the hypotheses of a motor level of AS adaptation and of a visual level of AS vector inversion. Together with data from the literature, these results also provide new insights into adaptation and planning mechanisms for AS and for other subtypes of voluntary saccades. PMID- 23946408 TI - The flickering wheel illusion: when alpha rhythms make a static wheel flicker. AB - alpha oscillations (8-14 Hz) greatly influence brain activity, yet we generally do not experience them consciously: the world does not appear to oscillate. Dedicated strategies must exist in the brain to prevent these oscillations from disrupting normal processing. Could suitable stimuli fool these strategies and lead to the conscious experience of our own brain oscillations? We describe and explore a novel illusion in which the center of a static wheel stimulus (with 30 40 spokes) is experienced as flickering when viewed in the visual periphery. The key feature of this illusion is that the stimulus fluctuations are experienced as a regular and consistent flicker, which our human observers estimated at ~9 Hz during a psychophysical matching task. Correspondingly, the occipital alpha rhythm of the EEG was the only oscillation that showed a time course compatible with the reported illusion: when alpha amplitude was strong, the probability of reporting illusory flicker increased. The peak oscillatory frequency for these flicker-induced modulations was significantly correlated, on a subject-by-subject basis, with the individual alpha frequency measured during rest, in the absence of visual stimulation. Finally, although the effect is strongest during eye movements, we showed that stimulus motion relative to the retina is not necessary to perceive the illusion: the flicker can also be perceived on the afterimage of the wheel, yet by definition this afterimage is stationary on the retina. We conclude that this new flickering illusion is a unique way to experience the alpha rhythms that constantly occur in the brain but normally remain unnoticed. PMID- 23946409 TI - Low-level laser therapy rescues dendrite atrophy via upregulating BDNF expression: implications for Alzheimer's disease. AB - Downregulation of brain-derived neurotrophic factor (BDNF) in the hippocampus occurs early in the progression of Alzheimer's disease (AD). Since BDNF plays a critical role in neuronal survival and dendrite growth, BDNF upregulation may contribute to rescue dendrite atrophy and cell loss in AD. Low-level laser therapy (LLLT) has been demonstrated to regulate neuronal function both in vitro and in vivo. In the present study, we found that LLLT rescued neurons loss and dendritic atrophy via upregulation of BDNF in both Abeta-treated hippocampal neurons and cultured APP/PS1 mouse hippocampal neurons. Photoactivation of transcription factor CRE-binding protein (CREB) increased both BDNF mRNA and protein expression, since knockdown CREB blocked the effects of LLLT. Furthermore, CREB-regulated transcription was in an ERK-dependent manner. Inhibition of ERK attenuated the DNA-binding efficiency of CREB to BDNF promoter. In addition, dendrite growth was improved after LLLT, characterized by upregulation of Rac1 activity and PSD-95 expression, and the increase in length, branching, and spine density of dendrites in hippocampal neurons. Together, these studies suggest that upregulation of BDNF with LLLT by activation of ERK/CREB pathway can ameliorate Abeta-induced neurons loss and dendritic atrophy, thus identifying a novel pathway by which LLLT protects against Abeta-induced neurotoxicity. Our research may provide a feasible therapeutic approach to control the progression of AD. PMID- 23946410 TI - Dendritic generation of mGluR-mediated slow afterdepolarization in layer 5 neurons of prefrontal cortex. AB - Many prefrontal cortex (PFC)-dependent tasks require individual neurons to fire persistently in response to brief stimuli. Persistent activity is proposed to involve changes in intrinsic properties, resulting in an increased sensitivity to inputs. The dendrite is particularly relevant to this hypothesis because it receives the majority of synaptic inputs and is enriched for conductances implicated in persistent firing. We provide evidence that dendritic conductances contribute to persistent activity-related changes in intrinsic properties. The effects of Group 1 metabotropic glutamate receptor (mGluR) activation on persistent activity-related properties were tested in two classes of rat L5 neurons with distinct membrane properties: those projecting to the pons (CPn) and those projecting across the commissure to the contralateral cortex (COM). mGluR activation produced long-term changes in the subthreshold properties of CPn, but not COM neurons. These changes were indicative of a decrease in hyperpolarization activated cation nonselective current (I(h)) at the soma and dendrite. mGluR activation also transiently increased the amplitude of the postburst slow afterdepolarization potential (sADP) at the soma of both neuron types. Interestingly, the sADP occurred along the extent of the apical dendrite in CPn and COM neurons. Simultaneous somatic/dendritic recordings revealed that the dendritic sADP does not result solely from passive propagation of the somatic sADP. Focal mGluR activation in L5, near the soma or at the border of L1/L2, near the tuft, generates a local sADP. This dendritic depolarization may act synergistically with synaptic input to regulate mnemonic activity in PFC. PMID- 23946411 TI - Fast modulation of executive function by language context in bilinguals. AB - Mastering two languages has been associated with enhancement in human executive control, but previous studies of this phenomenon have exclusively relied on comparisons between bilingual and monolingual individuals. In the present study, we tested a single group of Welsh-English bilinguals engaged in a nonverbal conflict resolution task and manipulated language context by intermittently presenting words in Welsh, English, or both languages. Surprisingly, participants showed enhanced executive capacity to resolve interference when exposed to a mixed compared with a single language context, even though they ignored the irrelevant contextual words. This result was supported by greater response accuracy and reduced amplitude of the P300, an electrophysiological correlate of cognitive interference. Our findings introduce a new level of plasticity in bilingual executive control dependent on fast changing language context rather than long-term language experience. PMID- 23946413 TI - Differential subcellular targeting of glutamate receptor subtypes during homeostatic synaptic plasticity. AB - Homeostatic processes are believed to contribute to the stability of neuronal networks that are perpetually influenced by Hebbian forms of synaptic plasticity. Whereas the rules governing the targeting and trafficking of AMPA and NMDA subtypes of glutamate receptors during rapid Hebbian LTP have been extensively studied, those that are operant during homeostatic forms of synaptic strengthening are less well understood. Here, we used biochemical, biophysical, and pharmacological approaches to investigate glutamate receptor regulation during homeostatic synaptic plasticity. We show in rat organotypic hippocampal slices that prolonged network silencing induced a robust surface upregulation of GluA2-lacking AMPARs, not only at synapses, but also at extrasynaptic dendritic and somatic regions of CA1 pyramidal neurons. We also detected a shift in NMDAR subunit composition that, in contrast to the cell-wide surface delivery of GluA2 lacking AMPARs, occurred exclusively at synapses. The subunit composition and subcellular distribution of AMPARs and NMDARs are therefore distinctly regulated during homeostatic synaptic plasticity. Thus, because subunit composition dictates key channel properties, such as agonist affinity, gating kinetics, and calcium permeability, the homeostatic synaptic process transcends the simple modulation of synaptic strength by also regulating the signaling and integrative properties of central synapses. PMID- 23946412 TI - Protein kinase Cepsilon is required for spinal analgesic synergy between delta opioid and alpha-2A adrenergic receptor agonist pairs. AB - We recently showed that spinal synergistic interactions between delta opioid receptors (deltaORs) and alpha2A adrenergic receptors (alpha2AARs) require protein kinase C (PKC). To identify which PKC isoforms contribute to analgesic synergy, we evaluated the effects of various PKC-isoform-specific peptide inhibitors on synergy between deltaORs and alpha2AARs using the tail flick assay of thermal nociception in mice. Only a PKCepsilon inhibitor abolished synergy between a deltaOR agonist and an alpha2AAR agonist. We tested a panel of combinations of opioid and adrenergic agonists in PKCepsilon knock-out mice and found that all four combinations of a deltaOR agonist and an alpha2AAR agonist required PKCepsilon for antinociceptive synergy. None of the combinations of a MUOR agonist with an alpha2AR agonist required PKCepsilon. Immunohistochemistry confirmed that PKCepsilon could be found in the population of peptidergic primary afferent nociceptors where deltaORs and alpha2AARs have been found to extensively colocalize. Immunoreactivity for PKCepsilon was found in the majority of dorsal root ganglion neurons and intensely labeled laminae I and II of the spinal cord dorsal horn. PKCepsilon is widespread in the spinal nociceptive system and in peptidergic primary afferents it appears to be specifically involved in mediating the synergistic interaction between deltaORs and alpha2AARs. PMID- 23946414 TI - The miR-223/nuclear factor I-A axis regulates glial precursor proliferation and tumorigenesis in the CNS. AB - Contemporary views of tumorigenesis regard its inception as a convergence of genetic mutation and developmental context. Glioma is the most common and deadly malignancy in the CNS; therefore, understanding how regulators of glial development contribute to its formation remains a key question. Previously we identified nuclear factor I-A (NFIA) as a key regulator of developmental gliogenesis, while miR-223 has been shown to repress NFIA expression in other systems. Using this relationship as a starting point, we found that miR-223 can suppress glial precursor proliferation via repression of NFIA during chick spinal cord development. This relationship is conserved in glioma, as miR-223 and NFIA expression is negatively correlated in human glioma tumors, and the miR-223/NFIA axis suppresses tumorigenesis in a human glioma cell line. Subsequent analysis of NFIA function revealed that it directly represses p21 and is required for tumorigenesis in a mouse neural stem cell model of glioma. These studies represent the first characterization of miR-223/NFIA axis function in glioma and demonstrate that it is a conserved proliferative mechanism across CNS development and tumorigenesis. PMID- 23946415 TI - Sarm1-mediated axon degeneration requires both SAM and TIR interactions. AB - Axon degeneration is an evolutionarily conserved pathway that eliminates damaged or unneeded axons. Manipulation of this poorly understood pathway may allow treatment of a wide range of neurological disorders. In an RNAi-based screen performed in cultured mouse DRG neurons, we observed strong suppression of injury induced axon degeneration upon knockdown of Sarm1 [SARM (sterile alpha-motif containing and armadillo-motif containing protein)]. We find that a SARM dependent degeneration program is engaged by disparate neuronal insults: SARM ablation blocks axon degeneration induced by axotomy or vincristine treatment, while SARM acts in parallel with a soma-derived caspase-dependent pathway following trophic withdrawal. SARM is a multidomain protein that associates with neuronal mitochondria. Deletion of the N-terminal mitochondrial localization sequence disrupts SARM mitochondrial localization in neurons but does not alter its ability to promote axon degeneration. In contrast, mutation of either the SAM (sterile alpha motif) or TIR (Toll-interleukin-1 receptor) domains abolishes the ability of SARM to promote axonal degeneration, while a SARM mutant containing only these domains elicits axon degeneration and nonapoptotic neuronal death even in the absence of injury. Protein-protein interaction studies demonstrate that the SAM domains are necessary and sufficient to mediate SARM-SARM binding. SARM mutants lacking a TIR domain bind full-length SARM and exhibit strong dominant negative activity. These results indicate that SARM plays an integral role in the dismantling of injured axons and support a model in which SAM-mediated multimerization is necessary for TIR-dependent engagement of a downstream destruction pathway. These findings suggest that inhibitors of SAM and TIR interactions represent therapeutic candidates for blocking pathological axon loss and neuronal cell death. PMID- 23946416 TI - Elevated occipital beta-amyloid deposition is associated with widespread cognitive impairment in logopenic progressive aphasia. AB - BACKGROUND: Most subjects with logopenic variant of primary progressive aphasia (lvPPA) have beta-amyloid (Abeta) deposition on Pittsburgh Compound B positron emission tomography (PiB-PET), usually affecting prefrontal and temporoparietal cortices, with less occipital involvement. OBJECTIVES: To assess clinical and imaging features in lvPPA subjects with unusual topographic patterns of Abeta deposition with highest uptake in occipital lobe. METHODS: Thirty-three lvPPA subjects with Abeta deposition on PiB-PET were included in this case-control study. Line plots of regional PiB uptake were created, including frontal, temporal, parietal and occipital regions, for each subject. Subjects in which the line sloped downwards in occipital lobe (lvPPA-low), representing low uptake, were separated from those where the line sloped upwards in occipital lobe (lvPPA high), representing unusually high occipital uptake compared to other regions. Clinical variables, atrophy on MRI, hypometabolism on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and presence and distribution of microbleeds and white matter hyperintensities (WMHs) were assessed. RESULTS: Seventeen subjects (52%) were classified as lvPPA-high. Mean occipital PiB uptake in lvPPA-high was higher than all other regions and higher than all regions in lvPPA-low. The lvPPA-high subjects performed more poorly on cognitive testing, including executive and visuospatial testing, but the two groups did not differ in aphasia severity. Proportion of microbleeds and WMH was higher in lvPPA-high than lvPPA-low. Parietal hypometabolism was greater in lvPPA-high than lvPPA-low. CONCLUSIONS: Unusually high occipital Abeta deposition is associated with widespread cognitive impairment and different imaging findings in lvPPA. These findings help explain clinical heterogeneity in lvPPA and suggest that Abeta influences severity of overall cognitive impairment but not aphasia. PMID- 23946417 TI - Neurological picture. Neurological ornithology. PMID- 23946419 TI - Oncolytic virotherapy trials--letter. PMID- 23946420 TI - Near-unity nuclear polarization with an open-source 129Xe hyperpolarizer for NMR and MRI. AB - The exquisite NMR spectral sensitivity and negligible reactivity of hyperpolarized xenon-129 (HP(129)Xe) make it attractive for a number of magnetic resonance applications; moreover, HP(129)Xe embodies an alternative to rare and nonrenewable (3)He. However, the ability to reliably and inexpensively produce large quantities of HP(129)Xe with sufficiently high (129)Xe nuclear spin polarization (P(Xe)) remains a significant challenge--particularly at high Xe densities. We present results from our "open-source" large-scale (~1 L/h) (129)Xe polarizer for clinical, preclinical, and materials NMR and MRI research. Automated and composed mostly of off-the-shelf components, this "hyperpolarizer" is designed to be readily implementable in other laboratories. The device runs with high resonant photon flux (up to 200 W at the Rb D1 line) in the xenon-rich regime (up to 1,800 torr Xe in 500 cc) in either single-batch or stopped-flow mode, negating in part the usual requirement of Xe cryocollection. Excellent agreement is observed among four independent methods used to measure spin polarization. In-cell P(Xe) values of ~90%, ~57%, ~50%, and ~30% have been measured for Xe loadings of ~300, ~500, ~760, and ~1,570 torr, respectively. P(Xe) values of ~41% and ~28% (with ~760 and ~1,545 torr Xe loadings) have been measured after transfer to Tedlar bags and transport to a clinical 3 T scanner for MR imaging, including demonstration of lung MRI with a healthy human subject. Long "in-bag" (129)Xe polarization decay times have been measured (T1 ~38 min and ~5.9 h at ~1.5 mT and 3 T, respectively)--more than sufficient for a variety of applications. PMID- 23946421 TI - Stapled alpha-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. AB - Stapled alpha-helical peptides have emerged as a promising new modality for a wide range of therapeutic targets. Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates the p53 pathway in tumors in vitro and in vivo. Specifically, ATSP-7041 binds both MDM2 and MDMX with nanomolar affinities, shows submicromolar cellular activities in cancer cell lines in the presence of serum, and demonstrates highly specific, on target mechanism of action. A high resolution (1.7-A) X-ray crystal structure reveals its molecular interactions with the target protein MDMX, including multiple contacts with key amino acids as well as a role for the hydrocarbon staple itself in target engagement. Most importantly, ATSP-7041 demonstrates robust p53-dependent tumor growth suppression in MDM2/MDMX-overexpressing xenograft cancer models, with a high correlation to on-target pharmacodynamic activity, and possesses favorable pharmacokinetic and tissue distribution properties. Overall, ATSP-7041 demonstrates in vitro and in vivo proof-of-concept that stapled peptides can be developed as therapeutically relevant inhibitors of protein-protein interaction and may offer a viable modality for cancer therapy. PMID- 23946422 TI - Two gigs of Munc18 in membrane fusion. PMID- 23946423 TI - Deoxynucleoside triphosphate (dNTP) synthesis and destruction regulate the replication of both cell and virus genomes. PMID- 23946424 TI - Signaling through dynamic linkers as revealed by PKA. AB - Protein kinase A (PKA) is a prototype of multidomain signaling proteins functioning as allosteric conformational switches. Allosteric transitions have been the subject of extensive structural and dynamic investigations focusing mainly on folded domains. However, the current understanding of the allosteric role of partially unstructured linkers flanking globular domains is limited. Here, we show that a dynamic linker in the regulatory subunit (R) of PKA serves not only as a passive covalent thread, but also as an active allosteric element that controls activation of the kinase subunit (C) by tuning the inhibitory preequilibrium of a minimally populated intermediate (apo R). Apo R samples both C-binding competent (inactive) and incompetent (active) conformations within a nearly degenerate free-energy landscape and such degeneracy maximally amplifies the response to weak (~2RT), but conformation-selective interactions elicited by the linker. Specifically, the R linker that in the R:C complex docks in the active site of C in apo R preferentially interacts with the C-binding incompetent state of the adjacent cAMP-binding domain (CBD). These unanticipated findings imply that the formation of the intermolecular R:C inhibitory interface occurs at the expense of destabilizing the intramolecular linker/CBD interactions in R. A direct implication of this model, which was not predictable solely based on protein structure, is that the disruption of a linker/CBD salt bridge in the R:C complex unexpectedly leads to increased affinity of R for C. The linker includes therefore sites of R:C complex frustration and frustration-relieving mutations enhance the kinase inhibitory potency of R without compromising its specificity. PMID- 23946425 TI - Salmonella typhimurium intercepts Escherichia coli signaling to enhance antibiotic tolerance. AB - Bacterial communication plays an important role in many population-based phenotypes and interspecies interactions, including those in host environments. These interspecies interactions may prove critical to some infectious diseases, and it follows that communication between pathogenic bacteria and commensal bacteria is a subject of growing interest. Recent studies have shown that Escherichia coli uses the signaling molecule indole to increase antibiotic tolerance throughout its population. Here, we show that the intestinal pathogen Salmonella typhimurium increases its antibiotic tolerance in response to indole, even though S. typhimurium does not natively produce indole. Increased antibiotic tolerance can be induced in S. typhimurium by both exogenous indole added to clonal S. typhimurium populations and indole produced by E. coli in mixed microbial communities. Our data show that indole-induced tolerance in S. typhimurium is mediated primarily by the oxidative stress response and, to a lesser extent, by the phage shock response, which were previously shown to mediate indole-induced tolerance in E. coli. Further, we find that indole signaling by E. coli induces S. typhimurium antibiotic tolerance in a Caenorhabditis elegans model for gastrointestinal infection. These results suggest that the intestinal pathogen S. typhimurium can intercept indole signaling from the commensal bacterium E. coli to enhance its antibiotic tolerance in the host intestine. PMID- 23946426 TI - Extensive diversity in circadian regulation of plasma lipids and evidence for different circadian metabolic phenotypes in humans. AB - The circadian system regulates daily rhythms in lipid metabolism and adipose tissue function. Although disruption of circadian clock function is associated with negative cardiometabolic end points, very little is known about interindividual variation in circadian-regulated metabolic pathways. Here, we used targeted lipidomics-based approaches to profile the time course of 263 lipids in blood plasma in 20 healthy individuals. Over a span of 28 h, blood was collected every 4 h and plasma lipids were analyzed by HPLC/MS. Across subjects, about 13% of lipid metabolites showed circadian variation. Rhythmicity spanned all metabolite classes examined, suggesting widespread circadian control of lipid mediated energy storage, transport, and signaling. Intersubject agreement for lipids identified as rhythmic was only about 20%, however, and the timing of lipid rhythms ranged up to 12 h apart between individuals. Healthy subjects therefore showed substantial variation in the timing and strength of rhythms across different lipid species. Strong interindividual differences were also observed for rhythms of blood glucose and insulin, but not cortisol. Using consensus clustering with iterative feature selection, subjects clustered into different groups based on strength of rhythmicity for a subset of triglycerides and phosphatidylcholines, suggesting that there are different circadian metabolic phenotypes in the general population. These results have potential implications for lipid metabolism disorders linked to circadian clock disruption. PMID- 23946428 TI - Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia. AB - Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants, with devastating short- and long-term consequences. The pathogenesis of BPD is multifactorial, but all triggers cause pulmonary inflammation. No therapy exists; therefore, we investigated whether the anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD. We precipitated BPD by perinatal inflammation (lipopolysaccharide injection to pregnant dams) and rearing pups in hyperoxia (65% or 85% O2). Pups were treated daily with IL-1Ra or vehicle for up to 28 d. Vehicle-injected animals in both levels of hyperoxia developed a severe BPD-like lung disease (alveolar number and gas exchange area decreased by up to 60%, alveolar size increased up to fourfold). IL-1Ra prevented this structural disintegration at 65%, but not 85% O2. Hyperoxia depleted pulmonary immune cells by 67%; however, extant macrophages and dendritic cells were hyperactivated, with CD11b and GR1 (Ly6G/C) highly expressed. IL-1Ra partially rescued the immune cell population in hyperoxia (doubling the viable cells), reduced the percentage that were activated by up to 63%, and abolished the unexpected persistence of IL 1alpha and IL-1beta on day 28 in hyperoxia/vehicle-treated lungs. On day 3, perinatal inflammation and hyperoxia each triggered a distinct pulmonary immune response, with some proinflammatory mediators increasing up to 20-fold and some amenable to partial or complete reversal with IL-1Ra. In summary, our analysis reveals a pivotal role for IL-1alpha/beta in murine BPD and an involvement for MIP (macrophage inflammatory protein)-1alpha and TREM (triggering receptor expressed on myeloid cells)-1. Because it effectively shields newborn mice from BPD, IL-1Ra emerges as a promising treatment for a currently irremediable disease that may potentially brighten the prognosis of the tiny preterm patients. PMID- 23946429 TI - Hot climates, high sensitivity. PMID- 23946427 TI - Retinoblastoma tumor suppressor protein in pancreatic progenitors controls alpha- and beta-cell fate. AB - Pancreatic endocrine cells expand rapidly during embryogenesis by neogenesis and proliferation, but during adulthood, islet cells have a very slow turnover. Disruption of murine retinoblastoma tumor suppressor protein (Rb) in mature pancreatic beta-cells has a limited effect on cell proliferation. Here we show that deletion of Rb during embryogenesis in islet progenitors leads to an increase in the neurogenin 3-expressing precursor cell population, which persists in the postnatal period and is associated with increased beta-cell mass in adults. In contrast, Rb-deficient islet precursors, through repression of the cell fate factor aristaless related homeobox, result in decreased alpha-cell mass. The opposing effect on survival of Rb-deficient alpha- and beta-cells was a result of opposing effects on p53 in these cell types. As a consequence, loss of Rb in islet precursors led to a reduced alpha- to beta-cell ratio, leading to improved glucose homeostasis and protection against diabetes. PMID- 23946430 TI - Pioglitazone does not improve insulin signaling in mice with GH over-expression. AB - Type 2 diabetes and obesity are very serious health problems in both developed and developing countries. An increased level of GH is known to promote insulin resistance. Transgenic (Tg) mice over-expressing bovine GH are short-living and characterized, among other traits, by hyperinsulinemia and increased insulin resistance in comparison with normal (N) mice. Pioglitazone (PIO) is a member of the thiazolidinediones - a group of insulin-sensitizing drugs that are selective agonists of peroxisome proliferator-activated receptor gamma (PPARgamma). The aim of the study was to analyze the effects of PIO on the insulin-signaling pathway in Tg and N mice. Plasma levels of insulin and glucose as well as hepatic levels of proteins involved in insulin signaling were analyzed by ELISA or western blot methods. Treatment with PIO decreased plasma level of glucose in N mice only. Similarly, PIO increased insulin sensitivity (expressed as the relative insulin sensitivity index; RISI) only in N mice. In the liver, PIO decreased the phosphorylation of insulin receptor substrate-1 (IRS1) at a serine residue (Ser(307)-pS-IRS1), which inhibits insulin action, and had a tendency to increase tyrosine phosphorylation of IRS2 (Tyr-pY-IRS2) only in N mice but did not affect either of these parameters in Tg mice. Levels of total and phosphorylated mammalian target of rapamycin were increased in Tg mice. Moreover, the level of AKT2 was decreased by PIO in N mice only. In conclusion, the lack of improvement of insulin sensitivity in insulin-resistant Tg mice during PIO treatment indicates that chronically elevated GH levels can inhibit the beneficial effects of PIO on insulin signaling. PMID- 23946431 TI - Metformin increases the novel adipokine adipolin/CTRP12: role of the AMPK pathway. AB - Adipolin is a novel adipokine with anti-inflammatory and glucose-lowering properties. Lower levels of adipolin are found in obese and diabetic mice. Polycystic ovary syndrome (PCOS) is a pro-inflammatory state associated with obesity and diabetes. To date, there are no human studies on adipolin. Therefore, we measured serum (ELISA) and adipose tissue adipolin mRNA expression (RT-PCR) and protein concentrations (western blotting) in PCOS and control subjects. We also investigated the ex vivo effect of glucose and metformin on adipolin protein production in human subcutaneous adipose tissue explants. We report novel data that serum and subcutaneous adipose tissue adipolin mRNA expression and protein concentrations were significantly lower in women with PCOS compared with control subjects. Furthermore, Spearman's rank analysis showed that serum adipolin concentrations were significantly negatively correlated with BMI, waist-to-hip ratio, and glucose (P<0.05). However, when subjected to multiple regression analysis, none of these variables were predictive of serum adipolin concentrations (P>0.05). Also, subcutaneous adipose tissue adipolin mRNA expression and protein concentrations were only significantly negatively correlated with glucose (P<0.05). No significant correlations were found with omental adipose tissue adipolin mRNA expression and protein concentrations (P>0.05). Moreover, glucose profoundly reduced and metformin significantly increased adipolin protein production in human adipose tissue explants respectively. Importantly, metformin's effects appear to be via the AMP-activated protein kinase signaling pathway. PMID- 23946432 TI - Rotating columns: relating structure-from-motion, accretion/deletion, and figure/ground. AB - We present a novel phenomenon involving an interaction between accretion deletion, figure-ground interpretation, and structure-from-motion. Our displays contain alternating light and dark vertical regions in which random-dot textures moved horizontally at constant speed but in opposite directions in alternating regions. This motion is consistent with all the light regions in front, with the dark regions completing amodally into a single large surface moving in the background, or vice versa. Surprisingly, the regions that are perceived as figural are also perceived as 3-D volumes rotating in depth (like rotating columns)-despite the fact that dot motion is not consistent with 3-D rotation. In a series of experiments, we found we could manipulate which set of regions is perceived as rotating volumes simply by varying known geometric cues to figure ground, including convexity, parallelism, symmetry, and relative area. Subjects indicated which colored regions they perceived as rotating. For our displays we found convexity to be a stronger cue than either symmetry or parallelism. We furthermore found a smooth monotonic decay of the proportion by which subjects perceive symmetric regions as figural, as a function of their relative area. Our results reveal an intriguing new interaction between accretion-deletion, figure ground, and 3-D motion that is not captured by existing models. They also provide an effective tool for measuring figure-ground perception. PMID- 23946433 TI - Depth spreading through empty space induced by sparse disparity cues. AB - A key goal of visual processing is to develop an understanding of the three dimensional layout of the objects in our immediate vicinity from the variety of incomplete and noisy depth cues available to the eyes. Binocular disparity is one of the dominant depth cues, but it is often sparse, being definable only at the edges of uniform surface regions, and visually resolvable only where the edges have a horizontal disparity component. To understand the full 3D structure of visual objects, our visual system has to perform substantial surface interpolation across unstructured visual space. This interpolation process was studied in an eight-spoke depth spreading configuration corresponding to that used in the neon color spreading effect, which generates a strong percept of a sharp contour extending through empty space from the disparity edges within the spokes. Four hypotheses were developed for the form of the depth surface induced by disparity in the spokes defining an incomplete disk in depth: low-level local (isotropic) depth propagation, mid-level linear (anisotropic) depth-contour interpolation or extrapolation, and high-level (anisotropic) figural depth propagation of a disk figure in depth. Data for both perceived depth and position of the perceived contour clearly rejected the first three hypotheses and were consistent with the high-level figural hypothesis in both uniform disparity and slanted disk configurations. We conclude that depth spreading through empty visual space is an accurately quantifiable perceptual process that propagates depth contours anisotropically along their length and is governed by high-level figural properties of 3D object structure. PMID- 23946434 TI - Editorial. Health Policy Planning magazine's editorial policies. PMID- 23946435 TI - Impact of biologic therapy on functional status in patients with rheumatoid arthritis--a meta-analysis. AB - OBJECTIVE: Using meta-analysis methods, this study aimed to estimate the impact of biologic agents on physical function in patients with RA. METHODS: A systematic literature search was conducted independently by two investigators. Double-blind randomized controlled trials (RCTs) investigating the efficacy of abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab or rituximab in approved dosages in comparison with treatment with non-biologic disease-modifying anti-rheumatic drugs (nbDMARDs) and placebo were included. The outcome parameter was improvement in function measured by the standardized mean difference (SMD) of HAQ scores. The SMD is the difference of the change in HAQ between biologic and DMARD comparator groups divided by the pooled standard deviation. Mixed effect models were applied separately for RCTs with DMARD-naive patients and those with DMARD inadequate responders (IRs). RESULTS: Thirty-five RCTs were included in the analysis, 10 with DMARD-naive patients and 25 with DMARD IRs. Overall, biologics led to a greater improvement of physical function than nbDMARDs, with an SMD of the HAQ of 0.44 (95% CI 0.38, 0.50). The improvement was greater for DMARD IRs (SMD 0.48, 95% CI 0.41, 0.56) than for DMARD-naive patients (SMD 0.32, 95% CI 0.23, 0.41). There were no significant differences between individual biologics in both groups. CONCLUSION: Treatment with biologics led to a clinically relevant greater improvement in physical function than treatment with nbDMARDs. Our results suggest that the improvement found on the group level was caused by a clinically relevant improvement on the patient level in more than 50% of the patients. PMID- 23946437 TI - Prevalence and clinical correlates of pruritus in patients with systemic sclerosis: an updated analysis of 959 patients. AB - OBJECTIVES: One previous study has estimated the prevalence of pruritus in SSc, but that study had important limitations due to a relatively small sample size. The present study updates the analyses of the previous study using a substantially larger patient sample. The objectives were to (i) document the proportion of patients who experience pruritus on most days overall and by disease duration and (ii) identify clinical correlates of pruritus. METHODS: Patients from the Canadian Scleroderma Research Group Registry >=1 year after registry enrolment were asked on two consecutive annual visits whether they had experienced pruritus in the past month on most days and underwent clinical history and medical examination. Multiple logistic regression was used to assess the association between sociodemographic and clinical variables and pruritus. RESULTS: Among 959 patients, 42.6% reported pruritus. Of 693 patients with data for both visits, 333 (48%) did not report pruritus at either visit, 209 (30%) reported pruritus at both visits and 151 (22%) reported pruritus at one, but not the other, visit. The presence of pruritus was independently associated with greater skin involvement [odds ratio (OR) = 1.02, 95% CI 1.00, 1.04, P = 0.017] and greater gastrointestinal involvement (OR = 1.24, 95% CI 1.04, 1.48, P = 0.018). CONCLUSION: Pruritus is common in SSc across the course of the disease and has small but statistically significant associations with the degree of skin involvement and gastrointestinal system involvement. PMID- 23946436 TI - The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. AB - The management of RA, SpA, psoriasis and inflammatory bowel disease has significantly improved over the last decade with the addition of tumour necrosis factor inhibitors (anti-TNFs) to the therapeutic armamentarium. Immunogenicity in response to monoclonal antibody therapies (anti-drug antibodies) may give rise to low serum drug levels, loss of therapeutic response, poor drug survival and/or adverse events such as infusion reactions. To combat these, the use of concomitant MTX may attenuate the frequency of anti-drug antibodies in RA, SpA and Crohn's disease. Although a similar effect to methotrexate has been observed with AZA usage in the management of Crohn's disease, there is insufficient evidence to suggest that other DMARDs impact immunogenicity. In this article we review the evidence to date on the effect of immunomodulatory therapy when co administered with anti-TNFs. We also discuss whether such a strategy should be employed in SpA and psoriasis, and if optimization of the MTX dose could improve biologic drug survival and thereby benefit disease management. PMID- 23946438 TI - Developmental stage-dependent transcriptional regulatory pathways control neuroblast lineage progression. AB - Neuroblasts generate neurons with different functions by asymmetric cell division, cell cycle exit and differentiation. The underlying transcriptional regulatory pathways remain elusive. Here, we performed genetic screens in C. elegans and identified three evolutionarily conserved transcription factors (TFs) essential for Q neuroblast lineage progression. Through live cell imaging and genetic analysis, we showed that the storkhead TF HAM-1 regulates spindle positioning and myosin polarization during asymmetric cell division and that the PAR-1-like kinase PIG-1 is a transcriptional regulatory target of HAM-1. The TEAD TF EGL-44, in a physical association with the zinc-finger TF EGL-46, instructs cell cycle exit after the terminal division. Finally, the Sox domain TF EGL-13 is necessary and sufficient to establish the correct neuronal fate. Genetic analysis further demonstrated that HAM-1, EGL-44/EGL-46 and EGL-13 form three transcriptional regulatory pathways. We have thus identified TFs that function at distinct developmental stages to ensure appropriate neuroblast lineage progression and suggest that their vertebrate homologs might similarly regulate neural development. PMID- 23946439 TI - Differential roles for 3-OSTs in the regulation of cilia length and motility. AB - As cells integrate molecular signals from their environment, cell surface receptors require modified proteoglycans for the robust activation of signaling pathways. Heparan sulfate proteoglycans (HSPGs) have long unbranched chains of repetitive disaccharide units that can be sulfated at specific positions by heparan sulfate O-sulfotransferase (OST) families. Here, we show that two members of the 3-OST family are required in distinct signaling pathways to control left right (LR) patterning through control of Kupffer's vesicle (KV) cilia length and motility. 3-OST-5 functions in the fibroblast growth factor pathway to control cilia length via the ciliogenic transcription factors FoxJ1a and Rfx2. By contrast, a second 3-OST family member, 3-OST-6, does not regulate cilia length, but regulates cilia motility via kinesin motor molecule (Kif3b) expression and cilia arm dynein assembly. Thus, two 3-OST family members cell-autonomously control LR patterning through distinct pathways that regulate KV fluid flow. We propose that individual 3-OST isozymes create distinct modified domains or 'glycocodes' on cell surface proteoglycans, which in turn regulate the response to diverse cell signaling pathways. PMID- 23946440 TI - Regulation of long-range planar cell polarity by Fat-Dachsous signaling. AB - Fat (Ft) and Dachsous (Ds) are large cadherins that bind each other and have conserved roles in regulating planar cell polarity (PCP). We quantitatively analyzed Ft-Ds pathway mutant clones for their effects on ommatidial polarity in the Drosophila eye. Our findings suggest that the Ft-Ds pathway regulates PCP propagation independently of asymmetric cellular accumulation of Ft or Ds. We find that the Ft effector Atrophin has a position-specific role in regulating polarity in the eye, and that asymmetric accumulation of the atypical myosin Dachs is not essential for production and propagation of a long-range PCP signal. Our observations suggest that Ft and Ds interact to modulate a secondary signal that regulates long-range polarity, that signaling by the Ds intracellular domain is dependent on Ft, and that ommatidial fate specification is genetically separable from long-range signaling. PMID- 23946441 TI - Foxp1 maintains hair follicle stem cell quiescence through regulation of Fgf18. AB - Hair follicles cyclically degenerate and regenerate throughout adult life and require regular stem cell activation to drive the cycle. In the resting phase of the hair cycle, hair follicle stem cells are maintained in a quiescent state until they receive signals to proliferate. We found that the forkhead transcription factor Foxp1 is crucial for maintaining the quiescence of hair follicle stem cells. Loss of Foxp1 in skin epithelial cells leads to precocious stem cell activation, resulting in drastic shortening of the quiescent phase of the hair cycle. Conversely, overexpression of Foxp1 in keratinocytes prevents cell proliferation by promoting cell cycle arrest. Finally, through both gain- and loss-of-function studies, we identify fibroblast growth factor 18 (Fgf18) as the key downstream target of Foxp1. We show that exogenously supplied FGF18 can prevent the hair follicle stem cells of Foxp1 null mice from being prematurely activated. As Fgf18 controls the length of the quiescent phase and is a key downstream target of Foxp1, our data strongly suggest that Foxp1 regulates the quiescent stem cell state in the hair follicle stem cell niche by controlling Fgf18 expression. PMID- 23946442 TI - Transgenic tools to characterize neuronal properties of discrete populations of zebrafish neurons. AB - The developing nervous system consists of a variety of cell types. Transgenic animals expressing reporter genes in specific classes of neuronal cells are powerful tools for the study of neuronal network formation. We generated a wide variety of transgenic zebrafish that expressed reporter genes in specific classes of neurons or neuronal progenitors. These include lines in which neurons of specific neurotransmitter phenotypes expressed fluorescent proteins or Gal4, and lines in which specific subsets of the dorsal progenitor domain in the spinal cord expressed fluorescent proteins. Using these, we examined domain organization in the developing dorsal spinal cord, and found that there are six progenitor domains in zebrafish, which is similar to the domain organization in mice. We also systematically characterized neurotransmitter properties of the neurons that are produced from each domain. Given that reporter gene expressions occurs in a wide area of the nervous system in the lines generated, these transgenic fish should serve as powerful tools for the investigation of not only the neurons in the dorsal spinal cord but also neuronal structures and functions in many other regions of the nervous system. PMID- 23946443 TI - Control of tissue morphology by Fasciclin III-mediated intercellular adhesion. AB - Morphogenesis is dependent on the orchestration of multiple developmental processes to generate mature functional organs. However, the signalling pathways that coordinate morphogenesis and the mechanisms that translate these signals into tissue shape changes are not well understood. Here, we demonstrate that changes in intercellular adhesion mediated by the transmembrane protein Fasciclin III (FasIII) represent a key mediator of morphogenesis. Using the embryonic Drosophila hindgut as an in vivo model for organogenesis, we show that the tightening of hindgut curvature that normally occurs between embryonic stage 12 and 15 to generate the characteristic shepherd's crook shape is dependent on localised JAK/STAT pathway activation. This localised pathway activity drives the expression of FasIII leading to its subcellular lateralisation at a stage before formation of septate junctions. Additionally, we show that JAK/STAT- and FasIII dependent morphogenesis also regulates folds within the third instar wing imaginal disc. We show that FasIII forms homophilic intercellular interactions that promote intercellular adhesion in vivo and in cultured cells. To explore these findings, we have developed a mathematical model of the developing hindgut, based on the differential interfacial tension hypothesis (DITH) linking intercellular adhesion and localised surface tension. Our model suggests that increased intercellular adhesion provided by FasIII can be sufficient to drive the tightening of tube curvature observed. Taken together, these results identify a conserved molecular mechanism that directly links JAK/STAT pathway signalling to intercellular adhesion and that sculpts both tubular and planar epithelial shape. PMID- 23946444 TI - FGF signaling regulates Wnt ligand expression to control vulval cell lineage polarity in C. elegans. AB - The interpretation of extracellular cues leading to the polarization of intracellular components and asymmetric cell divisions is a fundamental part of metazoan organogenesis. The Caenorhabditis elegans vulva, with its invariant cell lineage and interaction of multiple cell signaling pathways, provides an excellent model for the study of cell polarity within an organized epithelial tissue. Here, we show that the fibroblast growth factor (FGF) pathway acts in concert with the Frizzled homolog LIN-17 to influence the localization of SYS-1, a component of the Wnt/beta-catenin asymmetry pathway, indirectly through the regulation of cwn-1. The source of the FGF ligand is the primary vulval precursor cell (VPC) P6.p, which controls the orientation of the neighboring secondary VPC P7.p by signaling through the sex myoblasts (SMs), activating the FGF pathway. The Wnt CWN-1 is expressed in the posterior body wall muscle of the worm as well as in the SMs, making it the only Wnt expressed on the posterior and anterior sides of P7.p at the time of the polarity decision. Both sources of cwn-1 act instructively to influence P7.p polarity in the direction of the highest Wnt signal. Using single molecule fluorescence in situ hybridization, we show that the FGF pathway regulates the expression of cwn-1 in the SMs. These results demonstrate an interaction between FGF and Wnt in C. elegans development and vulval cell lineage polarity, and highlight the promiscuous nature of Wnts and the importance of Wnt gradient directionality within C. elegans. PMID- 23946445 TI - Hedgehog signaling regulates prosensory cell properties during the basal-to apical wave of hair cell differentiation in the mammalian cochlea. AB - Mechanosensory hair cells and supporting cells develop from common precursors located in the prosensory domain of the developing cochlear epithelium. Prosensory cell differentiation into hair cells or supporting cells proceeds from the basal to the apical region of the cochleae, but the mechanism and significance of this basal-to-apical wave of differentiation remain to be elucidated. Here, we investigated the role of Hedgehog (Hh) signaling in cochlear development by examining the effects of up- and downregulation of Hh signaling in vivo. The Hh effector smoothened (Smo) was genetically activated or inactivated specifically in the developing cochlear epithelium after prosensory domain formation. Cochleae expressing a constitutively active allele of Smo showed only one row of inner hair cells with no outer hair cells (OHCs); abnormal undifferentiated prosensory-like cells were present in the lateral compartment instead of OHCs and their adjacent supporting cells. This suggests that Hh signaling inhibits prosensory cell differentiation into hair cells or supporting cells and maintains their properties as prosensory cells. Conversely, in cochlea with the Smo conditional knockout (Smo CKO), hair cell differentiation was preferentially accelerated in the apical region. Smo CKO mice survived after birth, and exhibited hair cell disarrangement in the apical region, a decrease in hair cell number, and hearing impairment. These results indicate that Hh signaling delays hair cell and supporting cell differentiation in the apical region, which forms the basal-to-apical wave of development, and is required for the proper differentiation, arrangement and survival of hair cells and for hearing ability. PMID- 23946446 TI - Dual role of delta-like 1 homolog (DLK1) in skeletal muscle development and adult muscle regeneration. AB - Muscle development and regeneration is tightly orchestrated by a specific set of myogenic transcription factors. However, factors that regulate these essential myogenic inducers remain poorly described. Here, we show that delta-like 1 homolog (Dlk1), an imprinted gene best known for its ability to inhibit adipogenesis, is a crucial regulator of the myogenic program in skeletal muscle. Dlk1(-/-) mice were developmentally retarded in their muscle mass and function owing to inhibition of the myogenic program during embryogenesis. Surprisingly however, Dlk1 depletion improves in vitro and in vivo adult skeletal muscle regeneration by substantial enhancement of the myogenic program and muscle function, possibly by means of an increased number of available myogenic precursor cells. By contrast, Dlk1 fails to alter the adipogenic commitment of muscle-derived progenitors in vitro, as well as intramuscular fat deposition during in vivo regeneration. Collectively, our results suggest a novel and surprising dual biological function of DLK1 as an enhancer of muscle development, but as an inhibitor of adult muscle regeneration. PMID- 23946448 TI - "Modern medical science and the divine providence of god": rethinking the place of religion in postwar U.S. medical history. AB - Drawing on a large cache of letters to John and Frances Gunther after the death of their son as well as memoirs and fiction by bereaved parents, this essay challenges the assumptions of secularization that infuse histories of twentieth century American medicine. Many parents who experienced the death of children during the postwar period relied heavily on religion to help make sense of the tragedies medicine could not prevent. Parental accounts included expression of belief in divine intervention and the power of prayer, gratitude for God's role in minimizing suffering, confidence in the existence of an afterlife, and acceptance of the will of God. Historians seeking to understand how parents and families understood both the delivery of medical care and the cultural authority of medical science must integrate an understanding of religious experiences and faith into their work. PMID- 23946447 TI - TGFbeta signaling is required for sprouting lymphangiogenesis during lymphatic network development in the skin. AB - Dermal lymphatic endothelial cells (LECs) emerge from the dorsolateral region of the cardinal veins within the anterior trunk to form an intricate, branched network of lymphatic vessels during embryogenesis. Multiple growth factors and receptors are required for specification and maintenance of LECs, but the mechanisms coordinating LEC movements and morphogenesis to develop three dimensional lymphatic network architecture are not well understood. Here, we demonstrate in mice that precise LEC sprouting is a key process leading to stereotypical lymphatic network coverage throughout the developing skin, and that transforming growth factor beta (TGFbeta) signaling is required for LEC sprouting and proper lymphatic network patterning in vivo. We utilized a series of conditional mutants to ablate the TGFbeta receptors Tgfbr1 (Alk5) and Tgfbr2 in LECs. To analyze lymphatic defects, we developed a novel, whole-mount embryonic skin imaging technique to visualize sprouting lymphangiogenesis and patterning at the lymphatic network level. Loss of TGFbeta signaling in LECs leads to a severe reduction in local lymphangiogenic sprouting, resulting in a significant decrease in global lymphatic network branching complexity within the skin. Our results also demonstrate that TGFbeta signaling negatively regulates LEC proliferation during lymphatic network formation. These data suggest a dual role for TGFbeta signaling during lymphatic network morphogenesis in the skin, such that it enhances LEC sprouting and branching complexity while attenuating LEC proliferation. PMID- 23946449 TI - Different hydrolases involved in bioactivation of prodrug-type angiotensin receptor blockers: carboxymethylenebutenolidase and carboxylesterase 1. AB - Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor blocker (ARB). We recently identified carboxymethylenebutenolidase homolog (CMBL) as the responsible enzyme for OM bioactivation in humans. In the present study, we compared the bioactivating properties of OM with those of other prodrug-type ARBs, candesartan cilexetil (CC) and azilsartan medoxomil (AM), by focusing on interspecies differences and tissue specificity. In in-vitro experiments with pooled tissue subcellular fractions of mice, rats, monkeys, dogs, and humans, substantial OM-hydrolase activities were observed in cytosols of the liver, intestine, and kidney in all the species tested except for dog intestine, which showed negligible activity, whereas lung cytosols showed relatively low activities compared with the other tissues. AM-hydrolase activities were well correlated with the OM-hydrolase activities. In contrast, liver microsomes exhibited the highest CC-hydrolase activity among various tissue subcellular fractions in all the species tested. As a result of Western blot analysis with the tissue subcellular fractions, the band intensities stained with anti-human CMBL and carboxylesterase 1 (CES1) antibodies well reflected OM- and AM-hydrolase activities and CC-hydrolase activity, respectively, in animals and humans. Recombinant human CMBL and CES1 showed significant AM- and CC-hydrolase activities, respectively, whereas CC hydrolysis was hardly catalyzed with recombinant carboxylesterase 2 (CES2). In conclusion, OM is bioactivated mainly via intestinal and additionally hepatic CMBL not only in humans but also in mice, rats, and monkeys, while CC is bioactivated via hepatic CES1 rather than intestinal enzymes, including CES2. AM is a substrate for CMBL. PMID- 23946450 TI - Identification of novel third-generation synthetic cannabinoids in products by ultra-performance liquid chromatography and time-of-flight mass spectrometry. AB - Synthetic cannabinoids are a group of compounds that are structurally diverse and are commonly found in various herbal incense and potpourri blends, which are sold in convenience stores, smoke shops and over the Internet. During the past few years, multiple state and federal legislations have been enacted controlling various subsets of these compounds that have been detected in compound categories generally considered the first and second product generations. As shown in previous studies, as compounds become controlled, new compounds emerge and become prevalent. We report on the emergence and prevalence of five different compounds (A796,260, MAM-2201, UR-144, URB597 and XLR-11) in the state of Indiana through their qualitative detection in solid-dosage herbal products via rapid solvent extraction and ultra-performance liquid chromatography with time-of-flight mass spectrometry (UPLC/ToF). We demonstrate the use of UPLC/ToF to be a suitable tool in the identification of these substances in a crime laboratory or forensic laboratory setting, which ultimately enables a laboratory to design assays for the detection of specific analytes in biological specimens in regard to regional trends and prevalence. PMID- 23946451 TI - Prescription opioids. II. Metabolism and excretion patterns of hydrocodone in urine following controlled single-dose administration. AB - Hydrocodone (HC) is a highly misused prescription drugs in the USA. Interpretation of urine tests for HC is complicated by its metabolism to two metabolites, hydromorphone (HM) and dihydrocodeine (DHC), which are also available commercially and are misused. Currently, there is interest in including HC and HM in the federal workplace drug-testing programs. This study characterized the disposition of HC in human urine. Twelve healthy, drug-free, adults were administered a single, oral 20 mg immediate-release dose of HC in a controlled clinical setting. Urine specimens were collected at timed intervals for up to 52 h and analyzed by LC-MS-MS (limit of quantitation = 50 ng/mL) with and without enzymatic hydrolysis. All specimens were also analyzed for creatinine and specific gravity (SG). HC and norhydrocodone (NHC) appeared within 2 h followed by HM and DHC. Peak concentrations of HC and metabolites occurred at 3-9 h. Peak hydrolyzed concentrations were in the order: NHC > HC > HM > DHC. Only HM was excreted extensively as a conjugated metabolite. At a cutoff concentration of 50 ng/mL, detection times were ~28 h for HC, 40 h for NHC, 26 h for HM and 16 h for DHC. Some specimens did not contain HC, but most contained NHC, thereby facilitating interpretation that HC was the administered drug. Creatinine and SG measures were highly correlated. Creatinine corrections of HC urinary data had variable effects of lowering or raising concentrations. These data suggest that drug-testing requirements for HC should include a hydrolysis step and a test for HM. PMID- 23946452 TI - Detection of synthetic cannabinoids in oral fluid using ELISA and LC-MS-MS. AB - Synthetic cannabinoids are often referred to as 'Spice' or K2 compounds. Detection of these compounds in oral fluid has, to date, been limited to chromatographic procedures such as liquid chromatography with tandem mass spectrometry detection. We report the first analytical immunoassay for the screening of some synthetic cannabinoids in oral fluid specimens collected with the QuantisalTM device. JWH-200 was chosen as the calibration standard, because parent compounds, not metabolites, are predominantly detected in oral fluid. The immunoassay is capable of detecting JWH-200, JWH-018, JWH-073, JWH-022, AM-2201, AM-2232 and AM-1220. The assay was validated according to accepted laboratory protocols and applied to 32 authentic oral fluid specimens previously analyzed using LC-MS-MS at an accredited laboratory. The assay is sensitive, with a cutoff concentration of 0.25 ng/mL, and has a wide working range from 0.1 to 5 ng/mL. Intra- and interday precision were determined to be <10%. The screening method was completely validated and characterized; critical aspects of the screening included the incorporation of a preincubation step that improves the sensitivity of the assay to allow relevant concentrations of synthetic compounds in oral fluid to be detected. PMID- 23946453 TI - Human rhinovirus subviral a particle binds to lipid membranes over a twofold axis of icosahedral symmetry. AB - Minor group human rhinoviruses bind low-density lipoprotein (LDL) receptors for endocytosis. Once they are inside endosomes, the acidic pH triggers their dissociation from the receptors and conversion into hydrophobic subviral A particles; these attach to the membrane and transfer their single-strand, positive-sense RNA genome into the cytosol. Here, we allowed human rhinovirus 2 (HRV2) A particles, produced in vitro by incubation at pH 5.4, to attach to liposomes; cryo-electron microscopy 3-dimensional single-particle image reconstruction revealed that they bind to the membrane around a 2-fold icosahedral symmetry axis. PMID- 23946454 TI - Soluble interleukin-6 receptor-mediated innate immune response to DNA and RNA viruses. AB - The interleukin-6 (IL-6) receptor, which exists as membrane-bound and soluble forms, plays critical roles in the immune response. The soluble IL-6 receptor (sIL6R) has been identified as a potential therapeutic target for preventing coronary heart disease. However, little is known about the role of this receptor during viral infection. In this study, we show that sIL6R, but not IL-6, is induced by viral infection via the cyclooxygenase-2 pathway. Interestingly, sIL6R, but not IL-6, exhibited extensive antiviral activity against DNA and RNA viruses, including hepatitis B virus, influenza virus, human enterovirus 71, and vesicular stomatitis virus. No synergistic effects on antiviral action were observed by combining sIL6R and IL-6. Furthermore, sIL6R mediated antiviral action via the p28 pathway and induced alpha interferon (IFN-alpha) by promoting the nuclear translocation of IFN regulatory factor 3 (IRF3) and NF-kappaB, which led to the activation of downstream IFN effectors, including 2',5'-oligoadenylate synthetase (OAS), double-stranded RNA-dependent protein kinase (PKR), and myxovirus resistance protein (Mx). Thus, our results demonstrate that sIL6R, but not IL-6, plays an important role in the host antiviral response. PMID- 23946455 TI - A strain-specific epitope of enterovirus 71 identified by cryo-electron microscopy of the complex with fab from neutralizing antibody. AB - Enterovirus 71 (EV71) is a picornavirus that causes outbreaks of hand, foot, and mouth disease (HFMD), primarily in the Asia-Pacific area. Unlike coxsackievirus A16, which also causes HFMD, EV71 induces severe neuropathology leading to high fatalities, especially among children under the age of 6 years. Currently, no established vaccines or treatments are available against EV71 infection. The monoclonal antibody MA28-7 neutralizes only specific strains of EV71 that have a conserved glycine at amino acid VP1-145, a surface-exposed residue that maps to the 5-fold vertex and that has been implicated in receptor binding. The cryo electron microscopy structure of a complex between EV71 and the Fab fragment of MA28-7 shows that only one Fab fragment occupies each 5-fold vertex. A positively charged patch, which has also been implicated in receptor binding, lies within the Fab footprint. We identify the strain-specific epitope of EV71 and discuss the possible neutralization mechanisms of the antibody. PMID- 23946456 TI - Structural and functional studies on the interaction of adenovirus fiber knobs and desmoglein 2. AB - Human adenovirus (Ad) serotypes Ad3, Ad7, Ad11, and Ad14, as well as a recently emerged strain of Ad14 (Ad14p1), use the epithelial junction protein desmoglein 2 (DSG2) as a receptor for infection. Unlike Ad interaction with CAR and CD46, structural details for Ad binding to DSG2 are still elusive. Using an approach based on Escherichia coli expression libraries of random Ad3 and Ad14p1 fiber knob mutants, we identified amino acid residues that, when mutated individually, ablated or reduced Ad knob binding to DSG2. These residues formed three clusters inside one groove at the extreme distal end of the fiber knob. The Ad3 fiber knob mutant library was also used to identify variants with increased affinity to DSG2. We found a number of mutations within or near the EF loop of the Ad3 knob that resulted in affinities to DSG2 that were several orders of magnitude higher than those to the wild-type Ad3 knob. Crystal structure analysis of one of the mutants showed that the introduced mutations make the EF loop more flexible, which might facilitate the interaction with DSG2. Our findings have practical relevance for cancer therapy. We have recently reported that an Ad3 fiber knob containing recombinant protein (JO-1) is able to trigger opening of junctions between epithelial cancer cells which, in turn, greatly improved the intratumoral penetration and efficacy of therapeutic agents (I. Beyer, et al., Clin. Cancer Res. 18:3340-3351, 2012; I. Beyer, et al., Cancer Res. 71:7080-7090, 2011). Here, we show that affinity-enhanced versions of JO-1 are therapeutically more potent than the parental protein in a series of cancer models. PMID- 23946457 TI - Dual split protein-based fusion assay reveals that mutations to herpes simplex virus (HSV) glycoprotein gB alter the kinetics of cell-cell fusion induced by HSV entry glycoproteins. AB - Herpes simplex virus (HSV) entry and cell-cell fusion require glycoproteins gD, gH/gL, and gB. We propose that receptor-activated changes to gD cause it to activate gH/gL, which then triggers gB into an active form. We employed a dual split-protein (DSP) assay to monitor the kinetics of HSV glycoprotein-induced cell-cell fusion. This assay measures content mixing between two cells, i.e., fusion, within the same cell population in real time (minutes to hours). Titration experiments suggest that both gD and gH/gL act in a catalytic fashion to trigger gB. In fact, fusion rates are governed by the amount of gB on the cell surface. We then used the DSP assay to focus on mutants in two functional regions (FRs) of gB, FR1 and FR3. FR1 contains the fusion loops (FL1 and FL2), and FR3 encompasses the crown at the trimer top. All FL mutants initiated fusion very slowly, if at all. However, the fusion rates caused by some FL2 mutants increased over time, so that total fusion by 8 h looked much like that of the WT. Two distinct kinetic patterns, "slow and fast," emerged for mutants in the crown of gB (FR3), again showing differences in initiation and ongoing fusion. Of note are the fusion kinetics of the gB syn mutant (LL871/872AA). Although this mutant was originally included as an ongoing high-rate-of-fusion control, its initiation of fusion is so rapid that it appears to be on a "hair trigger." Thus, the DSP assay affords a unique way to examine the dynamics of HSV glycoprotein-induced cell fusion. PMID- 23946458 TI - Deep-sequencing analysis of the association between the quasispecies nature of the hepatitis C virus core region and disease progression. AB - Variation of core amino acid (aa) 70 of hepatitis C virus (HCV) has been shown recently to be closely correlated with liver disease progression, suggesting that the core region might be present as a quasispecies during persistent infection and that this quasispecies nature might have an influence on the progression of disease. In our investigation, the subjects were 79 patients infected with HCV genotype 1b (25 with chronic hepatitis [CH], 29 with liver cirrhosis [LC], and 25 with hepatocellular carcinoma [HCC]). Deep sequencing of the HCV core region was carried out on their sera by using a Roche 454 GS Junior pyrosequencer. Based on a plasmid containing a cloned HCV sequence (pCV-J4L6S), the background error rate associated with pyrosequencing, including the PCR procedure, was calculated as 0.092 +/- 0.005/base. Deep sequencing of the core region in the clinical samples showed a mixture of "mutant-type" Q/H and "wild-type" R at the core aa 70 position in most cases (71/79 [89.9%]), and the ratio of mutant residues to R in the mixture increased as liver disease advanced to LC and HCC. Meanwhile, phylogenetic analysis of the almost-complete core region revealed that the HCV isolates differed genetically depending on the mutation status at core aa 70. We conclude that the core aa 70 mixture ratio, determined by deep sequencing, reflected the status of liver disease, demonstrating a significant association between core aa 70 and disease progression in CH patients infected with HCV genotype 1b. PMID- 23946459 TI - Role of herpes simplex virus VP11/12 tyrosine-based motifs in binding and activation of the Src family kinase Lck and recruitment of p85, Grb2, and Shc. AB - Previous studies have shown that the abundant herpes simplex virus 1 (HSV-1) tegument protein VP11/12, encoded by gene UL46, stimulates phosphatidylinositol 3 kinase (PI3-kinase)/Akt signaling: it binds the Src family kinase (SFK) Lck, is tyrosine phosphorylated, recruits the p85 subunit of PI3-kinase, and is essential for the activation of Akt during HSV-1 infection. The C-terminal region of VP11/12 contains tyrosine-based motifs predicted to bind the SH2 domains of SFKs (YETV and YEEI), p85 (YTHM), and Grb2 (YENV) and the phosphotyrosine-binding (PTB) domain of Shc (NPLY). We inactivated each of these motifs in the context of the intact viral genome and examined effects on binding and activation of Lck and recruitment of p85, Grb2, and Shc. Inactivating the p85, Grb2, or Shc motif reduced (p85) or eliminated (Grb2 and Shc) the interaction with the cognate signaling molecule without greatly affecting the other interactions or activation of Lck. Inactivating either SFK motif had only a minor effect on Lck binding and little or no effect on recruitment of p85, Grb2, or Shc. In contrast, inactivation of both SFK motifs severely reduced Lck binding and activation and tyrosine phosphorylation of VP11/12 and reduced (p85) or eliminated (Grb2 and Shc) binding of other signaling proteins. Overall, these data demonstrate the key redundant roles of the VP11/12 SFK-binding motifs in the recruitment and activation of SFKs and indicate that activated SFKs then lead (directly or indirectly) to phosphorylation of the additional motifs involved in recruiting p85, Grb2, and Shc. Thus, VP11/12 appears to mimic an activated growth factor receptor. PMID- 23946460 TI - Norovirus genome circularization and efficient replication are facilitated by binding of PCBP2 and hnRNP A1. AB - Sequences and structures within the terminal genomic regions of plus-strand RNA viruses are targets for the binding of host proteins that modulate functions such as translation, RNA replication, and encapsidation. Using murine norovirus 1 (MNV 1), we describe the presence of long-range RNA-RNA interactions that were stabilized by cellular proteins. The proteins potentially responsible for the stabilization were selected based on their ability to bind the MNV-1 genome and/or having been reported to be involved in the stabilization of RNA-RNA interactions. Cell extracts were preincubated with antibodies against the selected proteins and used for coprecipitation reactions. Extracts treated with antibodies to poly(C) binding protein 2 (PCBP2) and heterogeneous nuclear ribonucleoprotein (hnRNP) A1 significantly reduced the 5'-3' interaction. Both PCBP2 and hnRNP A1 recombinant proteins stabilized the 5'-3' interactions and formed ribonucleoprotein complexes with the 5' and 3' ends of the MNV-1 genomic RNA. Mutations within the 3' complementary sequences (CS) that disrupt the 5'-3' end interactions resulted in a significant reduction of the viral titer, suggesting that the integrity of the 3'-end sequence and/or the lack of complementarity with the 5' end is important for efficient virus replication. Small interfering RNA-mediated knockdown of PCBP2 or hnRNP A1 resulted in a reduction in virus yield, confirming a role for the observed interactions in efficient viral replication. PCBP2 and hnRNP A1 induced the circularization of MNV-1 RNA, as revealed by electron microscopy. This study provides evidence that PCBP2 and hnRNP A1 bind to the 5' and 3' ends of the MNV-1 viral RNA and contribute to RNA circularization, playing a role in the virus life cycle. PMID- 23946461 TI - Vaccination against a virus-encoded cytokine significantly restricts viral challenge. AB - Identification of immune correlates of protection for viral vaccines is complicated by multiple factors, but there is general consensus on the importance of antibodies that neutralize viral attachment to susceptible cells. Development of new viral vaccines has mostly followed this neutralizing antibody paradigm, but as a recent clinical trial of human cytomegalovirus (HCMV) vaccination demonstrated, this singular approach can yield limited protective efficacy. Since HCMV devotes >50% of its coding capacity to proteins that modulate host immunity, it is hypothesized that expansion of vaccine targets to include this part of the viral proteome will disrupt viral natural history. HCMV and rhesus cytomegalovirus (RhCMV) each encode an ortholog to the cellular interleukin-10 (cIL-10) cytokine: cmvIL-10 and rhcmvIL10, respectively. Despite extensive sequence divergence from their host's cIL-10, each viral IL-10 retains nearly identical functionality to cIL-10. Uninfected rhesus macaques were immunized with engineered, nonfunctional rhcmvIL-10 variants, which were constructed by site directed mutagenesis to abolish binding to the cIL-10 receptor. Vaccinees developed antibodies that neutralized rhcmvIL-10 function with no cross neutralization of cIL-10. Following subcutaneous RhCMV challenge, the vaccinees exhibited both reduced RhCMV replication locally at the inoculation site and systemically and significantly reduced RhCMV shedding in bodily fluids compared to controls. Attenuation of RhCMV infection by rhcmvIL-10 vaccination argues that neutralization of viral immunomodulation may be a new vaccine paradigm for HCMV by expanding potential vaccine targets. PMID- 23946462 TI - Efficiency of E2-p7 processing modulates production of infectious hepatitis C virus. AB - Previous studies indicate that the processing of hepatitis C virus (HCV) E2-p7 NS2 precursor mediated by host signal peptidase is relatively inefficient, resulting in the accumulation of E2-p7-NS2 and E2-p7 precursors in addition to E2 in mammalian cells. In this study, we discovered that a significant inhibition of the processing at an E2-p7 junction site is detrimental for HCV production, whether it was caused by the mutations in p7 or by the strategic introduction of a mutation at a terminal residue of E2 to block the signal peptidase-mediated cleavage of this junction site. However, complete separation of E2 and p7 by inserting an encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES) between these two proteins also moderately inhibited virus production. These results indicate that optimal processing of the E2-p7 junction site is critical for efficient HCV production. We further demonstrated that disrupting E2 p7 processing inhibits both NS2 localization to the putative virus assembly sites near lipid droplets (LD) and NS2 interaction with NS3 and E2. However, the impact, if any, of the p7-NS2 processing efficiency on HCV production seems relatively minor. In conclusion, these results imply that effective release of E2 and p7 from the precursor E2-p7 promotes HCV production by enhancing NS2 associated virus assembly complex formation near LD. PMID- 23946463 TI - In situ evolution of virus-specific cytotoxic T cell responses in the lung. AB - Cytotoxic T cells (CTL) play a critical role in the clearance of respiratory viral infections, but they also contribute to disease manifestations. In this study, we infected mice with a genetically modified pneumonia virus of mice (PVM) that allowed visualization of virus-specific CTL and infected cells in situ. The first virus-specific T cells entered the lung via blood vessels in the scattered foci of PVM-infected cells, which densely clustered around the bronchi at day 7 after infection. At this time, overall pulmonary virus load was maximal, but the mice showed no overt signs of disease. On days 8 to 9, T cells gained access to the infected bronchial epithelium and to the lung interstitium, which was associated with a reduction in the number of virus-infected cells within the initial clusters but could not prevent further virus spread throughout the lung tissue. Interestingly, recruitment of virus-specific CTL throughout the parenchyma was still ongoing on day 10, when the virus infection was already largely controlled. This also represented the peak of clinical disease. Thus, disease was associated with an exuberant T cell infiltration late in the course of the infection, which may be required to completely eliminate virus at residual foci of infection. PVM-induced immunopathology may thus result from the need to generate widespread T cell infiltrates to complete the elimination of virus infected cells in a large organ like the lung. This experimental model provides the first insights into the spatiotemporal evolution of pulmonary antiviral T cell immunity in vivo. PMID- 23946464 TI - Self-management support has potential but is difficult to deliver in routine primary care. PMID- 23946466 TI - Moving vessel wall research beyond the plaque: basilar artery dilation as a window to systemic cardiovascular events. PMID- 23946465 TI - Genomic medicine for improved prediction and primordial prevention of cardiovascular disease. PMID- 23946469 TI - Medical students' attitudes towards conscientious objection: a survey. AB - OBJECTIVE: To examine medical students' views on conscientious objection and controversial medical procedures. METHODS: Questionnaire study among Norwegian 5th and 6th year medical students. RESULTS: Five hundred and thirty-one of 893 students (59%) responded. Respondents object to a range of procedures not limited to abortion (up to 19%)-notably euthanasia (62%), ritual circumcision for boys (52%), assisted reproduction for same-sex couples (9.7%) and ultrasound in the setting of prenatal diagnosis (5.0%). A small minority (4.9%) would object to referrals for abortion. In the case of abortion, up to 55% would tolerate conscientious refusals, whereas 42% would not. Higher proportions would tolerate refusals for euthanasia (89%) or ritual circumcision for boys (72%). DISCUSSION: A majority of Norwegian medical students would object to participation in euthanasia or ritual circumcision for boys. However, in most settings, many medical students think doctors should not be able to refuse participation on grounds of conscience. A minority would accept conscientious refusals for procedures they themselves do not object to personally. Most students would not accept conscientious refusals for referrals. CONCLUSIONS: Conscientious objection remains a live issue in the context of several medical procedures not limited to abortion. Although most would want a right to object to participation in euthanasia, tolerance towards conscientious objectors in general was moderate or low. PMID- 23946468 TI - Selective targeting of the cysteine proteome by thioredoxin and glutathione redox systems. AB - Thioredoxin (Trx) and GSH are the major thiol antioxidants protecting cells from oxidative stress-induced cytotoxicity. Redox states of Trx and GSH have been used as indicators of oxidative stress. Accumulating studies suggest that Trx and GSH redox systems regulate cell signaling and metabolic pathways differently and independently during diverse stressful conditions. In the current study, we used a mass spectrometry-based redox proteomics approach to test responses of the cysteine (Cys) proteome to selective disruption of the Trx- and GSH-dependent systems. Auranofin (ARF) was used to inhibit Trx reductase without detectable oxidation of the GSH/GSSG couple, and buthionine sulfoximine (BSO) was used to deplete GSH without detectable oxidation of Trx1. Results for 606 Cys-containing peptides (peptidyl Cys) showed that 36% were oxidized more than 1.3-fold by ARF, whereas BSO-induced oxidation of peptidyl Cys was only 10%. Mean fold oxidation of these peptides was also higher by ARF than BSO treatment. Analysis of potential functional pathways showed that ARF oxidized peptides associated with glycolysis, cytoskeleton remodeling, translation and cell adhesion. Of 60 peptidyl Cys oxidized due to depletion of GSH, 41 were also oxidized by ARF and included proteins of translation and cell adhesion but not glycolysis or cytoskeletal remodeling. Studies to test functional correlates showed that pyruvate kinase activity and lactate levels were decreased with ARF but not BSO, confirming the effects on glycolysis-associated proteins are sensitive to oxidation by ARF. These data show that the Trx system regulates a broader range of proteins than the GSH system, support distinct function of Trx and GSH in cellular redox control, and show for the first time in mammalian cells selective targeting peptidyl Cys and biological pathways due to deficient function of the Trx system. PMID- 23946470 TI - Tragic choices. PMID- 23946473 TI - A novel class of anticancer compounds targets the actin cytoskeleton in tumor cells. AB - The actin cytoskeleton is a potentially vulnerable property of cancer cells, yet chemotherapeutic targeting attempts have been hampered by unacceptable toxicity. In this study, we have shown that it is possible to disrupt specific actin filament populations by targeting isoforms of tropomyosin, a core component of actin filaments, that are selectively upregulated in cancers. A novel class of anti-tropomyosin compounds has been developed that preferentially disrupts the actin cytoskeleton of tumor cells, impairing both tumor cell motility and viability. Our lead compound, TR100, is effective in vitro and in vivo in reducing tumor cell growth in neuroblastoma and melanoma models. Importantly, TR100 shows no adverse impact on cardiac structure and function, which is the major side effect of current anti-actin drugs. This proof-of-principle study shows that it is possible to target specific actin filament populations fundamental to tumor cell viability based on their tropomyosin isoform composition. This improvement in specificity provides a pathway to the development of a novel class of anti-actin compounds for the potential treatment of a wide variety of cancers. PMID- 23946472 TI - Gleason grade progression is uncommon. AB - Gleason grade is universally used for pathologic scoring of the differentiation of prostate cancer. However, it is unknown whether prostate tumors arise well differentiated and then progress to less differentiated forms or if Gleason grade is an early and largely unchanging feature. Prostate-specific antigen (PSA) screening has reduced the proportion of tumors diagnosed at advanced stage, which allows assessment of this question on a population level. If Gleason grade progresses as stage does, one would expect a similar reduction in high-grade tumors. We studied 1,207 Physicians' Health Study and Health Professionals Follow up Study participants diagnosed with prostate cancer from 1982 to 2004 and treated with prostatectomy. We compared the distribution of grade and clinical stage across the pre-PSA and PSA screening eras. We re-reviewed grade using the ISUP 2005 revised criteria. The proportion of advanced stage tumors dropped more than six-fold, from the earliest period (12/1982-1/1993), 19.9% stage >= T3, to the latest (5/2000-12/2004), 3% stage T3, none T4. The proportion of Gleason score >= 8 decreased substantially less, from 25.3% to 17.6%. A significant interaction between stage and diagnosis date predicting grade (P = 0.04) suggests that the relationship between grade and stage varies by time period. As the dramatic shift in stage since the introduction of PSA screening was accompanied by a more modest shift in Gleason grade, these findings suggest that grade may be established early in tumor pathogenesis. This has implications for the understanding of tumor progression and prognosis, and may help patients diagnosed with lower grade disease feel more comfortable choosing active surveillance. PMID- 23946474 TI - Pathophysiology of neonatal acute bacterial meningitis. AB - Neonatal meningitis is a severe acute infectious disease of the central nervous system and an important cause of morbidity and mortality worldwide. The inflammatory reaction involves the meninges, the subarachnoid space and the brain parenchymal vessels and contributes to neuronal injury. Neonatal meningitis leads to deafness, blindness, cerebral palsy, seizures, hydrocephalus or cognitive impairment in approximately 25-50 % of survivors. Bacterial pathogens can reach the blood-brain barrier and be recognized by antigen-presenting cells through the binding of Toll-like receptors. They induce the activation of NFkappaB or mitogen activated protein kinase pathways and subsequently upregulate leukocyte populations and express numerous proteins involved in inflammation and the immune response. Many brain cells can produce cytokines, chemokines and other pro inflammatory molecules in response to bacterial stimuli, and polymorphonuclear leukocytes are attracted, activated and released in large amounts of superoxide anion and nitric oxide, leading to peroxynitrite formation and generating oxidative stress. This cascade leads to lipid peroxidation, mitochondrial damage and breakdown of the blood-brain barrier, thus contributing to cell injury during neonatal meningitis. This review summarizes information on the pathophysiology and adjuvant treatment of acute bacterial meningitis in neonates. PMID- 23946475 TI - Lophomonas blattarum and bronchopulmonary disease. AB - The natural habitat of the multiflagellate protozoon Lophomonas blattarum is as an endocommensal in the hindgut of insects such as cockroaches. However, it also causes bronchopulmonary disease in humans. The aim of this paper was to review the literature on this organism in the context of respiratory disease. The biology epidemiology, route of transmission, pathogenic mechanisms and diagnosis methods are also described. A total of 61 cases were identified in the literature. The majority of these reports were from China, with some cases from Peru and Spain. Most cases were adult males, although paediatric cases were reported in Peru. Clinical presentation was non-specific, including symptoms such as fever, cough and breathless. Antiprotozoal therapy was generally effective. PMID- 23946476 TI - Total lactate dehydrogenase in cerebrospinal fluid for identification of bacterial meningitis. PMID- 23946477 TI - Molecular and evolutionary analysis of HPV16 E6 and E7 genes in Greek women. AB - Human papillomavirus type 16 (HPV16) non-European variants have been associated with persistent infection and cervical cancer development, while the L83V variant of the E6 gene has been correlated with the progression of cervical malignancy. The present study investigated the presence of the HPV16 L83V variant in Greek women. Molecular evolutionary analysis of the HPV16 E6 and E7 oncogenes was conducted in order to estimate the evolution of the HPV16 genome in the Greek population. The E6 L83V variant was found in 78.2 % of high- and 64.28 % of low grade specimens. Moreover, the prototype and E6 L83V variants were both prevalent in high- and low-grade malignancies in Greek women. Selective pressure analysis of the individual amino acid residues of HPV16 sequences from the Greek population indicates that codon 83 of the E6 protein, as well as codon 85 of the E7 protein, are undergoing positive selection. Novel sequence variations were recorded within the E6 and E7 genes in cervical samples, characterized as (T350G) European variants. However, no signal of intratypic recombination event was identified within the E6-E7 region. Molecular and evolutionary analyses of HPV16 genomes from distinct geographical locations might provide valuable information about viral evolution and oncogenecity. PMID- 23946478 TI - Genetic diversity of emerging Panton-Valentine leukocidine/arginine catabolic mobile element (ACME)-positive ST8 SCCmec-IVa meticillin-resistant Staphylococcus aureus (MRSA) strains and ACME-positive CC5 (ST5/ST764) MRSA strains in Northern Japan. AB - Panton-Valentine leukocidine (PVL) is a distinctive virulence factor of community associated meticillin-resistant Staphylococcus aureus (CA-MRSA), and arginine catabolic mobile element (ACME) is a staphylococcal genomic island that enhances fitness and the ability of bacterial cells to colonize on skin and mucous membranes. ACME is characteristically found in USA300, which is a predominant CA MRSA clone [sequence type (ST) 8] in the USA and is spreading globally, and has also been detected in non-ST8 MRSA at low frequency. In Japan, spread of MRSA with PVL and/or ACME and their genetic traits have not yet been well characterized. In the present study, the prevalence and genetic diversity of PVL(+)/ACME(+) MRSA were investigated for 422 MRSA clinical isolates collected from outpatients in northern Japan over a period of 1 year. All the isolates were genotyped for the staphylococcal cassette chromosome mec (SCCmec) and coagulase genes (coa), and screened for PVL and ACME genes. The PVL(+)/ACME(+) isolates were studied further by genetic analysis, including single-nucleotide polymorphism (SNP) analysis based on PVL genes (lukS-PV-lukF-PV), ACME (arc and opp3 clusters) and the sarU promoter region. Among all the isolates examined, PVL genes and ACME were detected in eight (SCCmec-II, n = 1; SCCmec-IV, n = 6; SCCmec V, n = 1) and 20 (SCCmec-II, n = 14; SCCmec-IV, n = 5; SCCmec-V, n = 1) isolates, respectively. Five isolates were found to have both PVL genes and ACME (type I), and were classified into ST8/spa-t008/agr-I/coa-IIIa, which is the same genetic traits as USA300. Fifteen PVL(-)/ACME(+) isolates had type DeltaII-ACME, belonging to either ST5 or ST764 [clonal complex (CC) 5], and spa-t001, -t002 or t3557. All the ST8 PVL(+)/ACME-I(+) MRSA had identical sequences of PVL genes (haplotype R) and ACME arc/opp3 clusters as those of USA300. In contrast, in the CC5 PVL(-)/ACME-DeltaII(+) MRSA, SNPs in the arc cluster were detected in 11 sites (four haplotypes), with some different profiles of virulence/resistance factors. These results indicated single clonality of ST8 PVL(+)/ACME-I(+) MRSA and heterogeneity of CC5 PVL(-)/ACME-DeltaII(+) MRSA, and suggest their potential spread in northern Japan. PMID- 23946479 TI - Functional genomics of microbial pathogens. PMID- 23946480 TI - Automethylation of protein arginine methyltransferase 8 (PRMT8) regulates activity by impeding S-adenosylmethionine sensitivity. AB - Protein arginine methyltransferase (PRMT) 8 is unique among the PRMTs, as it has a highly restricted tissue expression pattern and an N terminus that contains two automethylation sites and a myristoylation site. PRMTs catalyze the transfer of a methyl group from S-adenosylmethionine (AdoMet) to a peptidylarginine on a protein substrate. Currently, the physiological roles, regulation, and cellular substrates of PRMT8 are poorly understood. However, a thorough understanding of PRMT8 kinetics should provide insights into each of these areas, thereby enhancing our understanding of this unique enzyme. In this study, we determined how automethylation regulates the enzymatic activity of PRMT8. We found that preventing automethylation with lysine mutations (preserving the positive charge of the residue) increased the turnover rate and decreased the Km of AdoMet but did not affect the Km of the protein substrate. In contrast, mimicking automethylation with phenylalanine (i.e. mimicking the increased hydrophobicity) decreased the turnover rate. The inhibitory effect of the PRMT8 N terminus could be transferred to PRMT1 by creating a chimeric protein containing the N terminus of PRMT8 fused to PRMT1. Thus, automethylation of the N terminus likely regulates PRMT8 activity by decreasing the affinity of the enzyme for AdoMet. PMID- 23946481 TI - An essential type I nitroreductase from Leishmania major can be used to activate leishmanicidal prodrugs. AB - Nitroaromatic prodrugs are used to treat a range of microbial infections with selectivity achieved by specific activation reactions. For trypanosomatid parasites, this is mediated by type I nitroreductases. Here, we demonstrate that the causative agent of leishmaniasis, Leishmania major, expresses an FMN containing nitroreductase (LmNTR) that metabolizes a wide range of substrates, and based on electron donor and acceptor preferences, it may function as an NADH:quinone oxidoreductase. Using gene deletion approaches, we demonstrate that this activity is essential to L. major promastigotes, the parasite forms found in the insect vector. Intriguingly, LmNTR(+/-) heterozygote promastigote parasites could readily differentiate into infectious metacyclic cells but these were unable to establish infections in cultured mammalian cells and caused delayed pathology in mice. Furthermore, we exploit the LmNTR activity evaluating a library of nitrobenzylphosphoramide mustards using biochemical and phenotypic screens. We identify a subset of compounds that display significant growth inhibitory properties against the intracellular parasite form found in the mammalian hosts. The leishmanicidal activity was shown to be LmNTR-specific as the LmNTR(+/-) heterozygote promastigotes displayed resistance to the most potent mustards. We conclude that LmNTR can be targeted for drug development by exploiting its prodrug activating property or by designing specific inhibitors to block its endogenous function. PMID- 23946482 TI - FAD synthesis and degradation in the nucleus create a local flavin cofactor pool. AB - FAD is a redox cofactor ensuring the activity of many flavoenzymes mainly located in mitochondria but also relevant for nuclear redox activities. The last enzyme in the metabolic pathway producing FAD is FAD synthase (EC 2.7.7.2), a protein known to be localized both in cytosol and in mitochondria. FAD degradation to riboflavin occurs via still poorly characterized enzymes, possibly belonging to the NUDIX hydrolase family. By confocal microscopy and immunoblotting experiments, we demonstrate here the existence of FAD synthase in the nucleus of different experimental rat models. HPLC experiments demonstrated that isolated rat liver nuclei contain ~300 pmol of FAD.mg(-1) protein, which was mainly protein-bound FAD. A mean FAD synthesis rate of 18.1 pmol.min(-1).mg(-1) protein was estimated by both HPLC and continuous coupled enzymatic spectrophotometric assays. Rat liver nuclei were also shown to be endowed with a FAD pyrophosphatase that hydrolyzes FAD with an optimum at alkaline pH and is significantly inhibited by adenylate-containing nucleotides. The coordinate activity of these FAD forming and degrading enzymes provides a potential mechanism by which a dynamic pool of flavin cofactor is created in the nucleus. These data, which significantly add to the biochemical comprehension of flavin metabolism and its subcellular compartmentation, may also provide the basis for a more detailed comprehension of the role of flavin homeostasis in biologically and clinically relevant epigenetic events. PMID- 23946483 TI - Protein kinase A-dependent phosphorylation of Rap1 regulates its membrane localization and cell migration. AB - The small G protein Rap1 can mediate "inside-out signaling" by recruiting effectors to the plasma membrane that signal to pathways involved in cell adhesion and cell migration. This action relies on the membrane association of Rap1, which is dictated by post-translational prenylation as well as by a stretch of basic residues within its carboxyl terminus. One feature of this stretch of acidic residues is that it lies adjacent to a functional phosphorylation site for the cAMP-dependent protein kinase PKA. This phosphorylation has two effects on Rap1 action. One, it decreases the level of Rap1 activity as measured by GTP loading and the coupling of Rap1 to RapL, a Rap1 effector that couples Rap1 GTP loading to integrin activation. Two, it destabilizes the membrane localization of Rap1, promoting its translocation into the cytoplasm. These two actions, decreased GTP loading and decreased membrane localization, are related, as the translocation of Rap1-GTP into the cytoplasm is associated with its increased GTP hydrolysis and inactivation. The consequences of this phosphorylation in Rap1 dependent cell adhesion and cell migration were also examined. Active Rap1 mutants that lack this phosphorylation site had a minimal effect on cell adhesion but strongly reduced cell migration, when compared with an active Rap1 mutant that retained the phosphorylation site. This suggests that optimal cell migration is associated with cycles of Rap1 activation, membrane egress, and inactivation, and requires the regulated phosphorylation of Rap1 by PKA. PMID- 23946484 TI - O-linked N-acetylglucosamine cycling regulates mitotic spindle organization. AB - Any defects in the correct formation of the mitotic spindle will lead to chromosomal segregation errors, mitotic arrest, or aneuploidy. We demonstrate that O-linked N-acetylglucosamine (O-GlcNAc), a post-translational modification of serine and threonine residues in nuclear and cytoplasmic proteins, regulates spindle function. In O-GlcNAc transferase or O-GlcNAcase gain of function cells, the mitotic spindle is incorrectly assembled. Chromosome condensation and centrosome assembly is impaired in these cells. The disruption in spindle architecture is due to a reduction in histone H3 phosphorylation by Aurora kinase B. However, gain of function cells treated with the O-GlcNAcase inhibitor Thiamet G restored the assembly of the spindle and partially rescued histone phosphorylation. Together, these data suggest that the coordinated addition and removal of O-GlcNAc, termed O-GlcNAc cycling, regulates mitotic spindle organization and provides a potential new perspective on how O-GlcNAc regulates cellular events. PMID- 23946485 TI - Prefoldin plays a role as a clearance factor in preventing proteasome inhibitor induced protein aggregation. AB - Prefoldin is a molecular chaperone composed of six subunits, PFD1-6, and prevents misfolding of newly synthesized nascent polypeptides. Although it is predicted that prefoldin, like other chaperones, modulates protein aggregation, the precise function of prefoldin against protein aggregation under physiological conditions has never been elucidated. In this study, we first established an anti-prefoldin monoclonal antibody that recognizes the prefoldin complex but not its subunits. Using this antibody, it was found that prefoldin was localized in the cytoplasm with dots in co-localization with polyubiquitinated proteins and that the number and strength of dots were increased in cells that had been treated with lactacystin, a proteasome inhibitor, and thapsigargin, an inducer of endoplasmic reticulum stress. Knockdown of prefoldin increased the level of SDS-insoluble ubiquitinated protein and reduced cell viability in lactacystin and thapsigargin treated cells. Opposite results were obtained in prefoldin-overexpressed cells. It has been reported that mice harboring a missense mutation L110R of MM 1alpha/PFD5 exhibit neurodegeneration in the cerebellum. Although the prefoldin complex containing L110R MM-1alpha was properly formed in vitro and in cells derived from L110R MM-1alpha mice, the levels of ubiquitinated proteins and cytotoxicity were higher in L110R MM-1alpha cells than in wild-type cells under normal conditions and were increased by lactacystin and thapsigargin treatment, and growth of L110R MM-1alpha cells was attenuated. Furthermore, the polyubiquitinated protein aggregation level was increased in the brains of L110R MM-1alpha mice. These results suggest that prefoldin plays a role in quality control against protein aggregation and that dysfunction of prefoldin is one of the causes of neurodegenerative diseases. PMID- 23946486 TI - Binding of the chaperone Jac1 protein and cysteine desulfurase Nfs1 to the iron sulfur cluster scaffold Isu protein is mutually exclusive. AB - Biogenesis of mitochondrial iron-sulfur (Fe/S) cluster proteins requires the interaction of multiple proteins with the highly conserved 14-kDa scaffold protein Isu, on which clusters are built prior to their transfer to recipient proteins. For example, the assembly process requires the cysteine desulfurase Nfs1, which serves as the sulfur donor for cluster assembly. The transfer process requires Jac1, a J-protein Hsp70 cochaperone. We recently identified three residues on the surface of Jac1 that form a hydrophobic patch critical for interaction with Isu. The results of molecular modeling of the Isu1-Jac1 interaction, which was guided by these experimental data and structural/biophysical information available for bacterial homologs, predicted the importance of three hydrophobic residues forming a patch on the surface of Isu1 for interaction with Jac1. Using Isu variants having alterations in residues that form the hydrophobic patch on the surface of Isu, this prediction was experimentally validated by in vitro binding assays. In addition, Nfs1 was found to require the same hydrophobic residues of Isu for binding, as does Jac1, suggesting that Jac1 and Nfs1 binding is mutually exclusive. In support of this conclusion, Jac1 and Nfs1 compete for binding to Isu. Evolutionary analysis revealed that residues involved in these interactions are conserved and that they are critical residues for the biogenesis of Fe/S cluster protein in vivo. We propose that competition between Jac1 and Nfs1 for Isu binding plays an important role in transitioning the Fe/S cluster biogenesis machinery from the cluster assembly step to the Hsp70-mediated transfer of the Fe/S cluster to recipient proteins. PMID- 23946487 TI - Widespread and enzyme-independent Nepsilon-acetylation and Nepsilon-succinylation of proteins in the chemical conditions of the mitochondrial matrix. AB - Alterations in mitochondrial protein acetylation are implicated in the pathophysiology of diabetes, the metabolic syndrome, mitochondrial disorders, and cancer. However, a viable mechanism responsible for the widespread acetylation in mitochondria remains unknown. Here, we demonstrate that the physiologic pH and acyl-CoA concentrations of the mitochondrial matrix are sufficient to cause dose- and time-dependent, but enzyme-independent acetylation and succinylation of mitochondrial and nonmitochondrial proteins in vitro. These data suggest that protein acylation in mitochondria may be a chemical event facilitated by the alkaline pH and high concentrations of reactive acyl-CoAs present in the mitochondrial matrix. Although these results do not exclude the possibility of enzyme-mediated protein acylation in mitochondria, they demonstrate that such a mechanism may not be required in its unique chemical environment. These findings may have implications for the evolutionary roles that the mitochondria-localized SIRT3 deacetylase and SIRT5 desuccinylase have in the maintenance of metabolic health. PMID- 23946488 TI - The mechanism of the amidases: mutating the glutamate adjacent to the catalytic triad inactivates the enzyme due to substrate mispositioning. AB - All known nitrilase superfamily amidase and carbamoylase structures have an additional glutamate that is hydrogen bonded to the catalytic lysine in addition to the Glu, Lys, Cys "catalytic triad." In the amidase from Geobacillus pallidus, mutating this glutamate (Glu-142) to a leucine or aspartate renders the enzyme inactive. X-ray crystal structure determination shows that the structural integrity of the enzyme is maintained despite the mutation with the catalytic cysteine (Cys-166), lysine (Lys-134), and glutamate (Glu-59) in positions similar to those of the wild-type enzyme. In the case of the E142L mutant, a chloride ion is located in the position occupied by Glu-142 O(epsilon1) in the wild-type enzyme and interacts with the active site lysine. In the case of the E142D mutant, this site is occupied by Asp-142 O(delta1.) In neither case is an atom located at the position of Glu-142 O(epsilon2) in the wild-type enzyme. The active site cysteine of the E142L mutant was found to form a Michael adduct with acrylamide, which is a substrate of the wild-type enzyme, due to an interaction that places the double bond of the acrylamide rather than the amide carbonyl carbon adjacent to the active site cysteine. Our results demonstrate that in the wild-type active site a crucial role is played by the hydrogen bond between Glu 142 O(epsilon2) and the substrate amino group in positioning the substrate with the correct stereoelectronic alignment to enable the nucleophilic attack on the carbonyl carbon by the catalytic cysteine. PMID- 23946489 TI - Cytochrome p450 cyp26a1 alters spinal motor neuron subtype identity in differentiating embryonic stem cells. AB - The ability to differentiate embryonic stem cells (ESCs) into specific cell types is critical for improved regenerative medicine strategies, cancer chemotherapeutic approaches, and regimens to combat chronic diseases associated with aging. Subclasses of motor neurons (MNs) are generated at different positions along the rostrocaudal axis of the spinal cord, and the signals that specify MN subtype fates remain poorly defined. We show here that the cytochrome P450 enzyme Cyp26a1, which metabolizes all-trans-retinoic acid (RA) and thereby reduces RA levels, plays a crucial role in specifying MN columnar subtypes. Lack of Cyp26a1 in ESCs during differentiation to spinal MNs increases Aldh1a2 (RALDH2) and Hoxc6, markers of the Hox-dependent, lateral motor column (LMC) subtype identity. In contrast, Lhx3, a marker for median motor column identity, showed lower expression in Cyp26a1(-/-)-derived MNs compared with WT. Without Cyp26a1, an increase in intracellular RA concentration plus sonic hedgehog agonist treatment confer an LMC fate on differentiating MNs. Our data suggest a strategy for increasing LMC-type MNs from ESCs by blocking Cyp26a1 in cell replacement/ESC differentiation therapy to treat neurodegenerative diseases, such as amyotrophic lateral sclerosis. PMID- 23946490 TI - Class I lysine deacetylases facilitate glucocorticoid-induced transcription. AB - Nuclear receptors use lysine acetyltransferases and lysine deacetylases (KDACs) in regulating transcription through histone acetylation. Lysine acetyltransferases interact with steroid receptors upon binding of an agonist and are recruited to target genes. KDACs have been shown to interact with steroid receptors upon binding to an antagonist. We have shown previously that KDAC inhibitors (KDACis) potently repress the mouse mammary tumor virus promoter through transcriptional mechanisms and impair the ability of the glucocorticoid receptor (GR) to activate it, suggesting that KDACs can play a positive role in GR transactivation. In the current study, we extended this analysis to the entire GR transcriptome and found that the KDACi valproic acid impairs the ability of agonist-bound GR to activate about 50% of its target genes. This inhibition is largely due to impaired transcription rather than defective GR processing and was also observed using a structurally distinct KDACi. Depletion of KDAC1 expression mimicked the effects of KDACi in over half of the genes found to be impaired in GR transactivation. Simultaneous depletion of KDACs 1 and 2 caused full or partial impairment of several more GR target genes. Altogether we found that Class I KDAC activity facilitates GR-mediated activation at a sizable fraction of GR-activated target genes and that KDAC1 alone or in coordination with KDAC2 is required for efficient GR transactivation at many of these target genes. Finally, our work demonstrates that KDACi exposure has a significant impact on GR signaling and thus has ramifications for the clinical use of these drugs. PMID- 23946491 TI - The transcription factor Foxf1 binds to serum response factor and myocardin to regulate gene transcription in visceral smooth muscle cells. AB - Smooth muscle cells (SMCs) modulate their phenotype from a quiescent contractile state to a dedifferentiated, proliferative and migratory state during the pathogenesis of many diseases, including intestinal pseudoobstruction. Understanding how smooth muscle gene expression is regulated in these different phenotypic states is critical for unraveling the pathogenesis of these diseases. In the current study we examined the specific roles of Foxf1 in visceral SMC differentiation. Data show that Foxf1 is specifically required for expression of several contractile and regulatory proteins such as telokin, smooth muscle gamma actin, and Cav1.2b in visceral SMCs. Mechanistically, Foxf1 directly binds to and activates the telokin promoter. Foxf1 also directly binds to serum response factor (SRF) and myocardin-related transcription factors (MRTFs). Unlike Foxo4 and Foxq1, which bind to MRTFs and block their interaction with SRF, Foxf1 acts synergistically with these proteins to regulate telokin expression. Knock-out of Foxf1 specifically in SMCs results in neonatal lethality, with mice exhibiting GI tract abnormalities. Mice heterozygous for Foxf1 in SMC exhibited impaired colonic contractility and decreased expression of contractile proteins. These studies together with previous studies, suggest that different forkhead proteins can regulate gene expression in SMCs through modulating the activity of the SRF myocardin axis to either promote or inhibit differentiation and proliferation thereby altering gastrointestinal contractility and development. PMID- 23946492 TI - Extracting reaction networks from databases-opening Pandora's box. AB - Large quantities of information describing the mechanisms of biological pathways continue to be collected in publicly available databases. At the same time, experiments have increased in scale, and biologists increasingly use pathways defined in online databases to interpret the results of experiments and generate hypotheses. Emerging computational techniques that exploit the rich biological information captured in reaction systems require formal standardized descriptions of pathways to extract these reaction networks and avoid the alternative: time consuming and largely manual literature-based network reconstruction. Here, we systematically evaluate the effects of commonly used knowledge representations on the seemingly simple task of extracting a reaction network describing signal transduction from a pathway database. We show that this process is in fact surprisingly difficult, and the pathway representations adopted by various knowledge bases have dramatic consequences for reaction network extraction, connectivity, capture of pathway crosstalk and in the modelling of cell-cell interactions. Researchers constructing computational models built from automatically extracted reaction networks must therefore consider the issues we outline in this review to maximize the value of existing pathway knowledge. PMID- 23946493 TI - Polyphosphate kinase 1, a central node in the stress response network of Mycobacterium tuberculosis, connects the two-component systems MprAB and SenX3 RegX3 and the extracytoplasmic function sigma factor, sigma E. AB - Polyphosphate (poly P) metabolism regulates the stress response in mycobacteria. Here we describe the regulatory architecture of a signal transduction system involving the two-component system (TCS) SenX3-RegX3, the extracytoplasmic function sigma factor sigma E (SigE) and the poly P-synthesizing enzyme polyphosphate kinase 1 (PPK1). The ppk1 promoter of Mycobacterium tuberculosis is activated under phosphate starvation. This is attenuated upon deletion of an imperfect palindrome likely representing a binding site for the response regulator RegX3, a component of the two-component system SenX3-RegX3 that responds to phosphate starvation. Binding of phosphorylated RegX3 to this site was confirmed by electrophoretic mobility shift assay. The activity of the ppk1 promoter was abrogated upon deletion of a putative SigE binding site. Pull-down of SigE from M. tuberculosis lysates of phosphate-starved cells with a biotinylated DNA harbouring the SigE binding site confirmed the likely binding of SigE to the ppk1 promoter. In vitro transcription corroborated the involvement of SigE in ppk1 transcription. Finally, the overexpression of RseA (anti-SigE) attenuated ppk1 expression under phosphate starvation, supporting the role of SigE in ppk1 transcription. The regulatory elements identified in ppk1 transcription in this study, combined with our earlier observation that PPK1 is itself capable of regulating sigE expression via the MprAB TCS, suggest the presence of multiple positive-feedback loops in this signalling circuit. In combination with the sequestering effect of RseA, we hypothesize that this architecture could be linked to bistability in the system that, in turn, could be a key element of persistence in M. tuberculosis. PMID- 23946494 TI - gamma-H2AX level in peripheral blood lymphocytes as a risk predictor for bladder cancer. AB - Identification of susceptibility to double-strand breaks (DSBs) may provide valuable information about individual bladder cancer (BC) risk. The formation of gamma-H2AX foci is a highly sensitive marker for DNA DSBs induction. We assessed whether levels of gamma-H2AX in peripheral blood lymphocytes (PBL) obtained after stimulation by ionizing radiation (IR) are able to predict BC risk. Patients were enrolled from an ongoing BC case-control study. Baseline- and IR-induced H2AX phosphorylation was assessed in PBL from 174 newly diagnosed and untreated BC patients and from 174 matched control subjects by a novel, image-based, high throughput phenotypic assay. The ratio of gamma-H2AX level of IR-treated cells to that of non-treated cells (baseline) was used as the parameter to assess the sensitivity to the mutagen. The mean gamma-H2AX ratios were significantly higher for cases than for controls (1.43+/-0.14 versus 1.35+/-0.12; P = 8.45*10(-8)). This trend was irrespective of age, sex and smoking status. The risk estimates of BC for induced DSBs by tertile distributions in controls showed also a significant trend for increased risk at the highest tertile for the whole cohort (odds ratio = 5.16; 95% confidence interval = 2.69, 9.89; P = 7.78 * 10(-7)) as well as for each category. Our findings suggest that a higher susceptibility to induction of DSBs as measured by the gamma-H2AX assay is significantly associated with an increased risk for BC. This might help to identify individuals at high risk for this cancer, adding new perspectives to established epidemiological and genetic risk factors. Further research of the role of gamma-H2AX in biological processes of BC is warranted. PMID- 23946497 TI - Crosstalk of lipids and inflammation in atherosclerosis: the PRO of PGRN? PMID- 23946495 TI - Enhanced inhibition of urinary bladder cancer growth and muscle invasion by allyl isothiocyanate and celecoxib in combination. AB - Allyl isothiocyanate (AITC) occurs in cruciferous vegetables that are commonly consumed by humans and has been shown to inhibit urinary bladder cancer growth and progression in previous preclinical studies. However, AITC does not significantly modulate cyclooxygenase-2 (Cox-2), whose oncogenic activity has been well documented in bladder cancer and other cancers. Celecoxib is a selective Cox-2 inhibitor and has been widely used for treatment of several diseases. Celecoxib has also been evaluated in bladder cancer patients, but its efficacy against bladder cancer as a single agent remains unclear. In a syngeneic rat model of orthotopic bladder cancer, treatment of the animals with the combination of AITC and celecoxib at low dose levels (AITC at 1 mg/kg and celecoxib at 10 mg/kg) led to increased or perhaps synergistic inhibition of bladder cancer growth and muscle invasion, compared with each agent used alone. The combination regime was also more effective than each single agent in inhibiting microvessel formation and stimulating microvessel maturation in the tumor tissues. The anticancer efficacy of the combination regime was associated with depletion of prostaglandin E2, a key downstream signaling molecule of Cox-2, caspase activation and downregulation of vascular endothelial growth factor in the tumor tissues. These data show that AITC and celecoxib complement each other for inhibition of bladder cancer and provide a novel combination approach for potential use for prevention or treatment of human bladder cancer. PMID- 23946499 TI - The effect of combined hyperbaric oxygen and iloprost treatment on the prevention of spinal cord ischaemia-reperfusion injury: an experimental study. AB - OBJECTIVES: Hyperbaric oxygen (HBO) has been shown to be effective in preventing neurological injuries in animal models of ischaemia, whereas iloprost (IL) prevents ischaemia-related mitochondrial dysfunction and reduces infarction size after focal cerebral ischaemia in animal models. The aim of the present study was to investigate the effect of combined HBO and IL treatment on spinal cord ischaemia-reperfusion (IR) injury by neurological, histopathological and biochemical methods in an experimental study. METHODS: Eighty New Zealand white male rabbits were randomly allocated into one of five study groups. The HBO group received a single session of HBO treatment and the IL group received an infusion of 25 ng/kg/min IL; the HBO + IL group received both HBO and IL and the control group received only 0.9% saline; the fifth group was the sham group. Levels of S100beta protein, neuron-specific enolase (NSE) and nitric oxide (NO) were measured at onset, at the end of ischaemia period and at the 24th and 48th hour of reperfusion. Physical activity was assessed using Tarlov criteria 24, and the spinal cords of the sacrificed rabbits were evaluated histopathologically. Additionally, tissue malondialdehyde (MDA) and antioxidant enzyme activities [total superoxide dismutase (SOD); catalase (CAT) and glutathione peroxidase (GSH Px) were assessed. RESULTS: Neurological scores in the HBO, IL and HBO + IL groups were statistically significantly better compared with the control group at the 24th (P = 0.001 for all) and 48th hour (P = 0.001 for all). Histopathological scores in the HBO, IL and HBO + IL groups were also significantly better compared with the control group (P = 0.003, 0.001 and 0.001, respectively). Whereas MDA, NSE, S100beta protein and NO concentrations were significantly lower, CAT and GSH PX levels were significantly higher in either sham or treatment groups compared with the control group. CONCLUSIONS: Since we demonstrated beneficial effects on spinal cord IR injury, we think that both HBO and IL, either alone or in combination, may be reasonable in the treatment of IR injury. Furthermore, there did not appear to be synergistic effects with combined treatment. More research is needed for practical application in humans, following thoracoabdominal aortic surgery. PMID- 23946498 TI - Epicardial calcineurin-NFAT signals through Smad2 to direct coronary smooth muscle cell and arterial wall development. AB - AIMS: Congenital coronary artery anomalies produce serious events that include syncope, arrhythmias, myocardial infarction, or sudden death. Studying the mechanism of coronary development will contribute to the understanding of the disease and help design new diagnostic or therapeutic strategies. Here, we characterized a new calcineurin-NFAT signalling which specifically functions in the epicardium to regulate the development of smooth muscle wall of the coronary arteries. METHODS AND RESULTS: Using tissue-specific gene deletion, we found that calcineurin-NFAT signals in the embryonic epicardium to direct coronary smooth muscle cell development. The smooth muscle wall of coronary arteries fails to mature in mice with epicardial deletion of calcineurin B1 (Cnb1), and accordingly these mutant mice develop cardiac dysfunction with reduced exercise capacity. Inhibition of calcineurin at various developmental windows shows that calcineurin NFAT signals within a narrow time window at embryonic Day 12.5-13.5 to regulate coronary smooth muscle cell development. Within the epicardium, NFAT transcriptionally activates the expression of Smad2, whose gene product is critical for transducing transforming growth factor beta (TGFbeta)-Alk5 signalling to control coronary development. CONCLUSION: Our findings demonstrate new spatiotemporal and molecular actions of calcineurin-NFAT that dictate coronary arterial wall development and a new mechanism by which calcineurin-NFAT integrates with TGFbeta signalling during embryonic development. PMID- 23946501 TI - isomiRID: a framework to identify microRNA isoforms. AB - SUMMARY: MicroRNAs (miRNAs) have been extensively studied owing to their important regulatory roles in genic expression. An increasingly number of reports are performing extensive data mining in small RNA sequencing libraries to detect miRNAs isoforms and also 5' and 3' post-transcriptional nucleotide additions, as well as edited miRNAs sequences. A ready to use pipeline, isomiRID, was developed to standardize and automatize the search for miRNAs isoforms in high-throughput small RNA sequencing libraries. AVAILABILITY: isomiRID is a command line Python script available at http://www.ufrgs.br/RNAi/isomiRID/. PMID- 23946500 TI - Recipient hyperbilirubinaemia protects cardiac graft in rat heterotopic heart transplantation. AB - OBJECTIVES: Since bilirubin is a known powerful antioxidant, this study examined whether recipient hyperbilirubinaemia protected heart grafts from ischaemia/reperfusion (I/R) injury and chronic rejection associated with rat cardiac transplantation. METHODS: Heterotopic heart transplantation (HTx) was performed using congenitally hyperbilirubinaemic GUNN (j/j) and normobilirubinaemic GUNN (+/+) rats. Syngenic grafts from +/+ rats were transplanted into +/+ or j/j rats with 6 or 18 h cold storage in University of Wisconsin solution to study I/R injury. To evaluate the effect on chronic rejection, Brown Norway rat heart grafts were transplanted into +/+ or j/j rats under short-course tacrolimus immunosuppression. RESULTS: The +/+ grafts in j/j rats demonstrated significantly lower serum creatine phosphokinase and higher left ventricular developed pressures and had smaller infarct areas than +/+ rats at 3 h after reperfusion. Graft survival with 18 h cold storage increased from 0% in +/+ rats to 41.7% in j/j rats. Malondialdehyde (a marker of lipid peroxidation), mRNA of the inflammatory mediators and phosphorylation of ERK1/2 were significantly decreased in the grafts transplanted into j/j rats compared with those transplanted into +/+ rats 1-3 h after reperfusion. The mean allograft survival in j/j recipients was prolonged to a median survival of 150 days from 84 days in +/+ recipients and was associated with less macrophage infiltrates and less intragraft inflammatory cytokine mRNA at d60. In vitro T-cell proliferation was significantly inhibited in the presence of bilirubin. CONCLUSIONS: Recipient hyperbilirubinaemia ameliorated cardiac I/R injury, as well as chronic allograft rejection following HTx via regulation of inflammatory responses or T-cell proliferation. PMID- 23946502 TI - High-accuracy prediction of transmembrane inter-helix contacts and application to GPCR 3D structure modeling. AB - MOTIVATION: Residue-residue contacts across the transmembrane helices dictate the three-dimensional topology of alpha-helical membrane proteins. However, contact determination through experiments is difficult because most transmembrane proteins are hard to crystallize. RESULTS: We present a novel method (MemBrain) to derive transmembrane inter-helix contacts from amino acid sequences by combining correlated mutations and multiple machine learning classifiers. Tested on 60 non-redundant polytopic proteins using a strict leave-one-out cross validation protocol, MemBrain achieves an average accuracy of 62%, which is 12.5% higher than the current best method from the literature. When applied to 13 recently solved G protein-coupled receptors, the MemBrain contact predictions helped increase the TM-score of the I-TASSER models by 37% in the transmembrane region. The number of foldable cases (TM-score >0.5) increased by 100%, where all G protein-coupled receptor templates and homologous templates with sequence identity >30% were excluded. These results demonstrate significant progress in contact prediction and a potential for contact-driven structure modeling of transmembrane proteins. AVAILABILITY: www.csbio.sjtu.edu.cn/bioinf/MemBrain/ PMID- 23946503 TI - omiRas: a Web server for differential expression analysis of miRNAs derived from small RNA-Seq data. AB - SUMMARY: Small RNA deep sequencing is widely used to characterize non-coding RNAs (ncRNAs) differentially expressed between two conditions, e.g. healthy and diseased individuals and to reveal insights into molecular mechanisms underlying condition-specific phenotypic traits. The ncRNAome is composed of a multitude of RNAs, such as transfer RNA, small nucleolar RNA and microRNA (miRNA), to name few. Here we present omiRas, a Web server for the annotation, comparison and visualization of interaction networks of ncRNAs derived from next-generation sequencing experiments of two different conditions. The Web tool allows the user to submit raw sequencing data and results are presented as: (i) static annotation results including length distribution, mapping statistics, alignments and quantification tables for each library as well as lists of differentially expressed ncRNAs between conditions and (ii) an interactive network visualization of user-selected miRNAs and their target genes based on the combination of several miRNA-mRNA interaction databases. AVAILABILITY AND IMPLEMENTATION: The omiRas Web server is implemented in Python, PostgreSQL, R and can be accessed at: http://tools.genxpro.net/omiras/. PMID- 23946504 TI - SubNet: a Java application for subnetwork extraction. AB - SUMMARY: The extraction of targeted subnetworks is a powerful way to identify functional modules and pathways within complex networks. Here, we present SubNet, a Java-based stand-alone program for extracting subnetworks, given a basal network and a set of selected nodes. Designed with a graphical user-friendly interface, SubNet combines four different extraction methods, which offer the possibility to interrogate a biological network according to the question investigated. Of note, we developed a method based on the highly successful Google PageRank algorithm to extract the subnetwork using the node centrality metric, to which possible node weights of the selected genes can be incorporated. AVAILABILITY: http://www.zdzlab.org/1/subnet.html PMID- 23946505 TI - Possible role of inter-domain salt bridges in oligopeptidase B from Trypanosoma brucei: critical role of Glu172 of non-catalytic beta-propeller domain in catalytic activity and Glu490 of catalytic domain in stability of OPB. AB - Oligopeptidase B (OPB) is a member of the prolyl oligopeptidase (POP) family of serine proteases. OPB in trypanosomes is an important virulence factor and potential pharmaceutical target. Characteristic structural features of POP family members include lack of a propeptide and presence of a beta-propeller domain (PD), although the role of the beta-PD has yet to be fully understood. In this work, residues Glu(172), Glu(490), Glu(524) and Arg(689) in Trypanosoma brucei OPB (Tb OPB), which are predicted to form inter-domain salt bridges, were substituted for Gln and Ala, respectively. These mutants were evaluated in terms of catalytic properties and stability. A negative effect on kcat/Km was obtained following mutation of Glu(172) or Arg(689). In contrast, the E490Q mutant exhibited markedly decreased thermal stability, although this mutation had less effect on catalytic properties compared to the E172Q and R689A mutants. Trypsin digestion showed that the boundary regions between the beta-PD and catalytic domains (CDs) of the E490Q mutant are unfolded with heat treatment. These results indicated that Glu(490) in the CD plays a role in stabilization of Tb OPB, whereas Glu(172) in the beta-PD is critical for the catalytic activity of Tb OPB. PMID- 23946506 TI - Endoplasmic reticulum aminopeptidases: biochemistry, physiology and pathology. AB - The human endoplasmic reticulum aminopeptidase (ERAP) 1 and 2 proteins were initially identified as homologues of human placental leucine aminopeptidase/insulin-regulated aminopeptidase. They are categorized as a unique class of proteases based on their subcellular localization on the luminal side of the endoplasmic reticulum. ERAPs play an important role in the N-terminal processing of the antigenic precursors that are presented on the major histocompatibility complex (MHC) class I molecules. ERAPs are also implicated in the regulation of a wide variety of physiological phenomena and pathogenic conditions. In this review, the current knowledge on ERAPs is summarized. PMID- 23946507 TI - Acyclic carotenoid and cyclic apocarotenoid cleavage by an orthologue of lignostilbene-alpha,beta-dioxygenase in Rhodopseudomonas palustris. AB - Carotenoid cleavage oxygenases catalyse formation of apocarotenoids and the precursors of phytohormones, abscisic acid and strigolactones through oxidative cleavage at specific double bonds of carotenoids. A gene encoding a presumed bacterial oxygenase homologous to lignostilbene-alpha,beta-dioxygenases has been found in the genome of Rhodopseudomonas palustris. By analysing apocarotenoids in recombinant Escherichia coli strains, it was found that the presumed oxygenase catalyses the 15,15' double bond cleavage of lycopene and neurosporene. Cell lysate containing the recombinant protein cleaved all-trans-beta-apo-8'-carotenal at the 15,15' double bond into retinal and apo-8',15'-apocarotene-dial. These data demonstrate for the first time that the orthologue of lignostilbene alpha,beta-dioxygenase found in the carotenogenic phototrophic bacterium has the 15,15' double bond cleavage activity towards both the acyclic carotenoids and cyclic apocarotenoid. PMID- 23946508 TI - Heterogeneous nuclear ribonucleoprotein Q is a novel substrate of SH2 domain containing phosphatase-2. AB - SH2 domain-containing phosphatase-2 (SHP2) is a protein-tyrosine phosphatase implicated in activation of cell signalling such as the Ras/extracellular signal regulated kinase pathway. The substrates of SHP2 and their roles in cell activation are not fully understood. By using the substrate-trapping method with the phosphatase-dead SHP2 mutant, in which C459 was substituted by serine, and the matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometric analysis, we found that heterogeneous nuclear ribonucleoprotein Q (hnRNP Q), a protein implicated in RNA metabolisms, was a novel substrate of SHP2. Tyrosine-phosphorylated hnRNP Q was detected in HL-60, Jurkat and human peripheral blood mononuclear cells, but not mature neutrophils, treated with pervanadate. Tyrosine-phosphorylated hnRNP Q was directly bound to SHP2 in vivo and in vitro, and dephosphorylated by SHP2 in vitro. These findings suggest that hnRNP Q is a novel substrate of SHP2 and the SHP2 activity may be also involved in RNA metabolisms via dephosphorylation of hnRNP Q. PMID- 23946509 TI - Fungal arthritis of the hip in patient with aplastic anaemia. AB - Aplastic anaemia is a rare and serious disease characterised by severe immunosuppression due to prolonged neutropenia and the use of immunosuppressants such as corticosteroids, cyclosporine and antithymocyte globulin. Candida species are pathogens of low virulence colonising the skin and the digestive tract of many healthy individuals. Nonetheless, the incidence of invasive candidal infection is increasing. The widespread use of central intravascular catheters, invasive procedures, broad-spectrum antibiotics and immunosuppresion predisposes patients to these infections. Eye, skin, cardiac, liver, spleen and brain infection are the most common sites of invasive candidiasis. Bone and joint infections are less frequent and Candida hip septic arthritis is extremely rare. We present here a patient treated for aplastic anaemia, who developed fungal arthritis of the hip and systemic candidaemia. PMID- 23946510 TI - Failure to obtain microbiological culture and its consequence in a mesh-related infection. AB - This report describes a case of a delayed diagnosis of a late-onset mesh infection due to an unexpected enteric pathogen, Enterobacter cloacae. A 62-year old woman with a history of prior incisional hernia repair with a prosthetic mesh presented to the emergency room with signs of an abscess with surrounding cellulitis of her abdomen over a year after her hernia repair. The patient manifested minimal response to 1 month of oral antibiotics. She underwent a complicated yet successful treatment course including surgical mesh removal (with a peri-operative complication), implantation of a biological mesh for the ventral hernia defect and ultimately, antibiotics tailored to the offending pathogen identified by postoperative culture of the infected mesh. PMID- 23946511 TI - Skin resurfacing in a circumferential full thickness burn to the penis: lessons learnt. AB - A circumferential full-thickness burn to the penis is a rarely encountered injury. However, when it does occur, it proves a management challenge to the plastic and burns surgeon in terms of reconstruction. This is due to the need of not only regaining adequate function of the organ, but also because of the need for a pleasing aesthetic outcome. Split-skin grafts have been utilised successfully to resurface full thickness burns of the penis and have given good results. Yet the success of split-skin grafts, especially those applied to an anatomically challenging region of the body such as the penis, depends on a number of carefully thought-out steps. We discuss the case of a circumferential full-thickness burn to the penis which was treated with split-skin grafting and highlight important pitfalls that the plastic and burns surgeon need to be aware of to ensure a successful outcome. PMID- 23946512 TI - Spindle cell lipoma. AB - Spindle cell lipomas (SCLs) are a group of benign lipogenic tumours, typically arising in the posterior neck, upper back and shoulder of elderly male patients. Approximately 80% of these tumours arise in characteristic location, but 20% arise in unusual locations, thereby making these cases more difficult to diagnose. We present a case of SCL occurring in the right periorbital region of a 14-year-old boy. The MRI was suggestive of possible malignancy. Diagnosis of neurofibroma was made on incisional biopsy. However, the histopathological and immunohistochemical analyses of the excised lesion confirmed the diagnosis of SCL. PMID- 23946513 TI - Oral lichen planus in a young Indian child. AB - Lichen planus (LP) is one of the most distinct mucocutaneous diseases. It is common with the middle aged and elderly population but has rarely been described in children. Incidences of oral LP in children is most commonly reported amongst Asians. We present a 10-year-old Indian girl with the documented clinical aspects and histopathological studies. PMID- 23946514 TI - Antepartum fetal bladder rupture leading to urinary ascitis: attempt to rescue by placement of peritoneo-amniotic shunt. AB - Fetal bladder rupture is a rare complication occurring due to bladder outlet obstruction, mostly posterior urethral valves. A 26-year-old primigravida presented to us at 27 weeks gestation with an ultrasound report showing gross fetal ascitis and mild oligohydramnios. A repeat scan was performed which showed fetal bladder rupture and urinary ascitis. In conjunction with paediatric surgeon, we performed ultrasound-guided placement of double-ended pigtail catheter connecting the fetal peritoneal cavity with the amniotic cavity at 28 weeks gestation. Ultrasound performed 3 days after the placement of the catheter showed its correct placement. Unfortunately, 1 week after the procedure at 29 weeks gestation, the patient had premature rupture of membranes and later went into labour and delivered vaginally. The neonate could not be revived and expired after few hours of birth due to prematurity-related complications. The placement of the shunt could have probably precipitated preterm rupture of membranes. PMID- 23946515 TI - Of little yellow men and a fear of the light. AB - We report the case of a 65-year-old woman presenting with recurrent vomiting for 3 days. She had been previously diagnosed with an atrial septal defect and was on treatment with diuretics and digoxin for paroxysmal supraventricular tachycardia. The clinical examination was consistent with an atrial septal defect with severe pulmonary hypertension. Electrocardiography showed complete heart block with ST segment changes suggestive of digitalis toxicity. Transthoracic echocardiography confirmed Eisenmengerisation. Serum digoxin levels were elevated. Following hospitalisation, she was diagnosed with photophobia when she persistently asked for ambient lighting to be switched off. Most interestingly, the patient kept reporting seeing little yellow men, which was how she perceived the attending doctors. Cessation of digoxin therapy led to progressive abatement of her symptoms. PMID- 23946516 TI - Cervical teratoma simulating thyroglossal cyst. PMID- 23946517 TI - Application of a newly developed high-sensitivity HBsAg chemiluminescent enzyme immunoassay for hepatitis B patients with HBsAg seroclearance. AB - We modified and automated a highly sensitive chemiluminescent enzyme immunoassay (CLEIA) for surface antigen (HBsAg) detection using a combination of monoclonal antibodies, each for a specific epitope of HBsAg, and by improving an earlier conjugation technique. Of 471 hepatitis B virus (HBV) carriers seen in our hospital between 2009 and 2012, 26 were HBsAg seronegative as determined by the Abbott Architect assay. The Lumipulse HBsAg-HQ assay was used to recheck those 26 patients who demonstrated seroclearance by the Abbott Architect assay. The performance of the Lumipulse HBsAg-HQ assay was compared with that of a quantitative HBsAg detection system (Abbott Architect) and the Roche Cobas TaqMan HBV DNA assay (CTM) (lower limit of detection, 2.1 log copies/ml) using blood serum samples from patients who were determined to be HBsAg seronegative by the Abbott Architect assay. Ten patients had spontaneous HBsAg loss. Of 8 patients treated with nucleotide analogues (NAs), two were HBsAg seronegative after stopping lamivudine therapy and 6 were HBsAg seronegative during entecavir therapy. Eight acute hepatitis B (AH) patients became HBsAg seronegative. Of the 26 patients, 16 were HBsAg positive by the Lumipulse HBsAg-HQ assay but negative by the Abbott Architect assay. The differences between the two assays in terms of detectable HBsAg persisted over the long term in the spontaneous loss group (median, 10 months), the NA-treated group (2.5 months), and the AH group (0.5 months). In 9 patients, the Lumipulse HBsAg-HQ assay detected HBsAg when HBV DNA was negative by the CTM assay. HBsAg was also detected by the Lumipulse HBsAg-HQ assay in 4 patients with an anti-HBs concentration of >10 mIU/ml, 3 of whom had no HBsAg escape mutations. The automatic, highly sensitive HBsAg CLEIA Lumipulse HBsAg-HQ is a convenient and precise assay for HBV monitoring. PMID- 23946518 TI - Identification of Mycobacterium species and Mycobacterium tuberculosis complex resistance determinants by use of PCR-electrospray ionization mass spectrometry. AB - PCR coupled with electrospray ionization mass spectrometry (PCR-ESI-MS) is a novel technology that has recently been used to identify pathogens from clinical specimens or after culture within about 6 h. We evaluated the MDR-TB (multidrug resistant tuberculosis) assay, which uses PCR-ESI-MS for detection and identification of Mycobacterium spp. and Mycobacterium tuberculosis complex (MTBC) resistance determinants from solid and broth Middlebrook culture media. The performance of the MDR-TB assay was compared to identification using nucleic acid hybridization probes and 16S rRNA gene sequencing for 68 MTBC and 97 nontuberculous mycobacterial (NTM) isolates grown on agar and 107 cultures grown in Bactec MGIT broth. MTBC resistance profiles from the MDR-TB assay were compared to results with the agar proportion method. The PCR-ESI-MS system correctly identified all MTBC isolates and 97.9% and 95.8% of the NTM isolates from characterized agar cultures and MGIT broth cultures to the species level, respectively. In comparison to the agar proportion method, the sensitivity and specificity for the detection of drug resistance using the MDR-TB assay were 100% and 92.3% for rifampin, 100% and 93.8% for isoniazid, 91.6% and 94.4% for ethambutol, and 100% and 100% for fluoroquinolones, respectively. The MDR-TB assay appears to be a rapid and accurate method for the simultaneous detection and identification of mycobacterial species and resistance determinants of MTBC from culture. PMID- 23946519 TI - Assessment of new culture method for detection of Borrelia species from serum of lyme disease patients. AB - A novel method of culturing spirochetes from the serum of U.S. Lyme disease patients was recently reported by Sapi and colleagues to have 94% sensitivity and 100% specificity for Borrelia species as assessed by microscopy and DNA sequence analysis of the pyrG gene (E. Sapi, N. Pabbati, A. Datar, E. M. Davies, A. Rattelle, and B. A. Kuo, Int. J. Med. Sci. 10:362-376, 2013). The majority of the spirochetes described were related by pyrG sequences to species of Borrelia previously undetected in North American patients without a reported history of travel to Europe or Asia. To better understand these unexpected findings, we determined pyrG sequences of the laboratory reference strains used by the investigators for method development and testing of culture medium. Eighty percent (41/51) of the reported patient-derived pyrG sequences were identical to one of the laboratory strains, and an additional 12% (6/51) differed by only a single nucleotide across a 603-bp region of the pyrG gene. Thus, false positivity due to laboratory contamination of patient samples cannot be ruled out, and further validation of the proposed novel culture method is required. PMID- 23946520 TI - Septicemia caused by Leifsonia aquatica in a healthy patient after retinal reattachment surgery. AB - Leifsonia aquatica is an aquatic bacterium that is typically found in environmental water habitats. Infections due to L. aquatica are rare and commonly catheter associated in immunocompromised patients. We report the first case of an acute septicemia caused by L. aquatica in a healthy immunocompetent host after cryopexy in the absence of a catheter. PMID- 23946521 TI - Preoperative aspiration culture for preoperative diagnosis of infection in total hip or knee arthroplasty. AB - This meta-analysis evaluated preoperative aspiration culture for diagnosing prosthetic joint infection (PJI) in total hip arthroplasty (THA) and total knee arthroplasty (TKA). The pooled sensitivity and specificity were 0.72 (95% confidence interval, 0.65 to 0.78) and 0.95 (0.93 to 0.97), respectively. Subgroup analyses revealed nonsignificant worse diagnostic performance for THA than for TKA (sensitivity, 0.70 versus 0.78; specificity, 0.94 versus 0.96). Preoperative aspiration culture has moderate to high sensitivity and very high specificity for diagnosing PJI. PMID- 23946522 TI - Evaluation of rabies biologics against Irkut virus isolated in China. AB - An Irkut virus (IRKV) was recently isolated from a bat in China. The protective ability of rabies biologics available in the Chinese market and experimental biologics against the rabies virus (RABV) and IRKV were assessed in a hamster model via preexposure prophylaxis (PrEP) and postexposure prophylaxis (PEP) experiments. The results demonstrated that a single dose of rabies vaccine did not induce adequate protection against IRKV infection. However, routine PrEP with three doses of vaccine induced complete protection against IRKV infection. Higher doses of RABV immunoglobulins and alpha interferon were required during PEP to protect hamsters against IRKV versus RABV infection. Experimental recombinant vaccines containing IRKV glycoproteins induced more-reliable protection against IRKV than against RABV infection. Those findings may be explained by limited cross-neutralization of these viruses (confirmed via in vitro tests) in conjunction with antigenic distances between RABV and IRKV. These results indicate that the development and evaluation of new biologics for PrEP and PEP are required to ensure sufficient protection against IRKV infection in China and other territories where this virus is present. PMID- 23946523 TI - In vitro activity of amikacin against isolates of Mycobacterium avium complex with proposed MIC breakpoints and finding of a 16S rRNA gene mutation in treated isolates. AB - Amikacin is a major drug used for the treatment of Mycobacterium avium complex (MAC) disease, but standard laboratory guidelines for susceptibility testing are not available. This study presents in vitro amikacin MICs for 462 consecutive clinical isolates of the MAC using a broth microdilution assay. Approximately 50% of isolates had amikacin MICs of 8 MUg/ml, and 86% had MICs of <=16 MUg/ml. Of the eight isolates (1.7%) with MICs of 64 MUg/ml, five had an MIC of 32 MUg/ml on repeat testing. Ten isolates (2.1%) had an initial amikacin MIC of >64 MUg/ml, of which seven (1.5%) had MICs of >64 MUg/ml on repeat testing. These seven isolates had a 16S rRNA gene A1408G mutation and included M. avium, Mycobacterium intracellulare, and Mycobacterium chimaera. Clinical data were available for five of these seven isolates, all of which had received prolonged (>6 months) prior therapy, with four that were known to be treated with amikacin. The 16S mutation was not detected in isolates with MICs of <=64 MUg/ml. We recommend primary testing of amikacin against isolates of the MAC and propose MIC guidelines for breakpoints that are identical to the CLSI guidelines for Mycobacterium abscessus: <=16 MUg/ml for susceptible, 32 MUg/ml for intermediate, and >=64 MUg/ml for resistant. If considered and approved by the CLSI, this will be only the second drug recommended for primary susceptibility testing against the MAC and should facilitate its use for both intravenous and inhaled drug therapies. PMID- 23946524 TI - Posterior reversible encephalopathy syndrome in a child with Henoch-Schonlein purpura. AB - Henoch-Schonlein purpura (HSP) is a small vessel vasculitis that affects the gastrointestinal and central nervous systems and the kidneys. The disease primarily affects children, but may occur in elderly children with allergic purpura and also in adults. Central nervous system involvement may be the first sign; however, it is rarely encountered. Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome of encephalopathy, headache, visual disturbance and seizures. Its radiological signs can be observed in grey and white matter at the posterior region of the cerebral hemispheres. HSP should be considered in children with PRES in the presence of rash, joint and gastrointestinal symptoms. We reported a 5-year-old patient who developed acute renal failure and PRES by reason of HSP. PMID- 23946525 TI - Cardio-respiratory failure secondary to ectopic Cushing's syndrome as the index presentation of small-cell lung cancer. AB - A 79-year-old woman, a smoker, presented to the emergency department with a 2 week history of progressive dyspnoea and peripheral oedema, preceded by flu-like symptoms that had failed to improve despite antibiotics. Examination identified severe hypertension and signs consistent with severe fluid overload. Baseline chest X ray showed a right-sided abnormality. In the context of an extensive smoking history CT thorax was indicated which demonstrated a right-sided hilar mass and lymphadenopathy. Blood tests showed an unexplained metabolic alkalosis with partial respiratory compensation and hypokalaemia prompting endocrinological tests investigating Cushing's syndrome. Urinary cortisol was measured at 3174 nmol/L/24 h (normal<560), serum adrenocorticotropic hormone (ACTH) of 215 ng/L (normal<46). Pleural fluid cytology confirmed a diagnosis of small-cell lung cancer (SCLC). The patient's condition deteriorated despite intravenous diuretics and nitrates, metyrapone and non-invasive ventilation. Treatment was withdrawn 1 week after admission. The clinical course in the presence of biochemical derangement and SCLC is highly suggestive of paraneoplastic ectopic ACTH secretion. PMID- 23946526 TI - Woman with chest pain and shortness of breath since age 18. AB - We present an interesting case of a 38-year-old woman who presented with a history of left-sided chest pain, dyspnoea and palpitations. The symptoms have been occurring since age 18, and were previously diagnosed as costochondritis. Because of the suspicious history, the patient underwent further cardiac investigations. The echocardiogram demonstrated an abnormal structure adjacent to the aortic valve. A diagnostic coronary angiogram revealed a large left circumflex artery fistulating into the right atrium. Surgery was performed to ligate the fistula. The patient recovered well and has been asymptomatic since. PMID- 23946527 TI - Target delineation for radiosurgery of a small brain arteriovenous malformation using high-resolution contrast-enhanced cone beam CT. AB - Three years following endovascular embolization of a 3 mm ruptured arteriovenous malformation (AVM) of the left superior colliculus in a 42-year-old man, digital subtraction angiography showed continuous regrowth of the lesion. Thin-slice MRI acquired for treatment planning did not show the AVM nidus. The patient was brought back to the angiography suite for high-resolution contrast-enhanced cone beam CT (VasoCT) acquired using an angiographic c-arm system. The lesion and nidus were visualized with VasoCT. MRI, CT and VasoCT data were transferred to radiation planning software and mutually co-registered. The nidus was annotated for radiation on VasoCT data by an experienced neurointerventional radiologist and a dose/treatment plan was completed. Due to image registration, the treatment area could be directly adopted into the MRI and CT data. The AVM was completely obliterated 10 months following completion of the radiosurgery treatment. PMID- 23946528 TI - Wandering peripherally inserted central catheter tip: an under-recognised intensivist challenge. PMID- 23946529 TI - Chronic empyema: importance of preventing complications in the management of pleural effusions. AB - We report a case of chronic empyema in a 63-year-old man with a history of asbestos exposure and alcohol overconsumption. In 2009, he presented with dyspnoea, exudative pleurisy on the right side with no symptoms of infection or malignancy. In 2013, the patient presented with increased dyspnoea and a massive chronic empyema had evolved. Culture of the pleural fluid was positive for Escherichia coli and anaerobic bacteria, and he was treated with antibiotics, chest drainage as well as surgical evacuation. After surgery, as the lung failed to expand, growth of opportunistic bacteria and rising C reactive protein obliged long-time treatment with broad-spectrum antibiotics as well as chest drainage with daily saline flushes. The patient still suffers from fatigue, poor nutritional status and anaemia, and further treatment with chest drainage and antibiotics is planned. Advanced chronic empyema is a difficult condition with poor response to treatment, and diagnostic delay is the main cause of complications. PMID- 23946530 TI - Giant intrascrotal lipoma. AB - Intrascrotal lipomas are rarely seen. Scrotal lipomas originate from the spermatic cord. We present a 64-year-old male patient, in the light of the literature, with painless swelling on the left half of the scrotum, histopathologically diagnosed with scrotal lipoma. PMID- 23946531 TI - Subacute bilateral vision loss resulting from dengue maculopathy. PMID- 23946532 TI - Complicated bile duct stones. AB - Common bile duct stones (CBDSs) are solid deposits that can either form within the gallbladder or migrate to the common bile duct (CBD), or form de novo in the biliary tree. In the USA around 15% of the population have gallstones and of these, 3% present with symptoms annually. Because of this, there have been major advancements in the management of gallstones and related conditions. Management is based on the patient's risk profile; young and healthy patients are likely to be recommended for surgery and elderly patients with comorbidities are usually recommended for endoscopic procedures. Imaging of gallstones has advanced in the last 30 years with endoscopic retrograde cholangiopancreatography evolving from a diagnostic to a therapeutic procedure in removing CBDSs. We present a complicated case of a patient with a CBDS and periampullary diverticulum and discuss the techniques used to diagnose and remove the stone from the biliary system. PMID- 23946533 TI - Novel stage classification of human spermatogenesis based on acrosome development. AB - To date, in the human seminiferous epithelium, only six associations of cell types have been distinguished, subdividing the epithelial cycle into six stages of very different duration. This hampers comparisons between studies on human and laboratory animals in which the cycle is usually subdivided into 12 stages. We now propose a new stage classification on basis of acrosomal development made visible by immunohistochemistry (IHC) for (pro)acrosin. IHC for acrosin gives results that are comparable to periodic acid Schiff staining. In the human too, we now distinguish 12 stages that differ from each other in duration by a factor of two at most. B spermatogonia are first apparent in stage I, preleptotene spermatocytes are formed in stage V, leptonema starts in stage VII, and spermiation takes place at the end of stage VI. A similar timing was previously observed in several monkeys. Stage identification by way of IHC for acrosin appeared possible for tissue fixed in formalin, Bouin fixative, diluted Bouin fixative, Cleland fluid, and modified Davidson fixative, indicating a wide applicability. In addition, it is also possible to distinguish the 12 stages in glutaraldehyde/osmium-tetroxide fixed/plastic embedded testis material without IHC for acrosin. The new stage classification will greatly facilitate research on human spermatogenesis and enable a much better comparison with results from work on experimental animals than hitherto possible. In addition, it will enable a highly focused approach to evaluate spermatogenic impairments, such as germ cell maturation arrests or defects, and to study details of germ cell differentiation. PMID- 23946534 TI - A microRNA (mmu-miR-124) prevents Sox9 expression in developing mouse ovarian cells. AB - In mammals, sex differentiation depends on gonad development, which is controlled by two groups of sex-determining genes that promote one gonadal sex and antagonize the opposite one. SOX9 plays a key role during testis development in all studied vertebrates, whereas it is kept inactive in the XX gonad at the critical time of sex determination, otherwise, ovary-to-testis gonadal sex reversal occurs. However, molecular mechanisms underlying repression of Sox9 at the beginning of ovarian development, as well as other important aspects of gonad organogenesis, remain largely unknown. Because there is indirect evidence that micro-RNAs (miRNA) are necessary for testicular function, the possible involvement of miRNAs in mammalian sex determination deserved further research. Using microarray technology, we have identified 22 miRNAs showing sex-specific expression in the developing gonads during the critical period of sex determination. Bioinformatics analyses led to the identification of miR-124 as the candidate gene for ovarian development. We knocked down or overexpressed miR 124 in primary gonadal cell cultures and observed that miR-124 is sufficient to induce the repression of both SOX9 translation and transcription in ovarian cells. Our results provide the first evidence of the involvement of a miRNA in the regulation of the gene controlling gonad development and sex determination. The miRNA microarray data reported here will help promote further research in this field, to unravel the role of other miRNAs in the genetic control of mammalian sex determination. PMID- 23946535 TI - Impairment of the interleukin system in equine endometrium during the course of endometrosis. AB - The aim of the study was to characterize endometrial mRNA transcription, immunolocalization, and protein expression of interleukin (IL) 1alpha, IL1beta, IL6, and IL1RI, IL1RII, and IL6Ralpha/beta in the course of endometrosis during the estrous cycle. Additionally, the influence of IL1alpha, IL1beta, and IL6 on prostaglandin (PG) secretion and PG synthase mRNA transcription in endometrial tissue during endometrosis was investigated. The endometrial samples were obtained at the early (n = 12), mid- (n = 12), and late (n = 12) luteal phases and at the follicular (n = 12) phase of the estrous cycle. Within each of these phases, there were four samples within each category I, II, and III of endometrium, according to the Kenney classification. In experiment 1, transcription of IL1alpha, IL1beta, IL6, and their receptor's (IL1RI, IL1RII, and IL6Ralpha/beta) mRNAs and their immunolocalization and protein expression were determined using real-time PCR and immunohistochemistry, respectively. In Experiment 2, endometrial samples (n = 5 samples within categories I, II, and III) were obtained for tissue culture in the midluteal phase of the estrous cycle. The endometrial tissues were stimulated with IL1alpha (10 ng/ml), IL1beta (10 ng/ml), IL6 (10 ng/ml), and oxytocin (positive control; 10-7 M) for 24 h. The PG concentration was determined using ELISA. In addition, transcription of PTGS 2, PGES, and PGFS mRNAs was determined using real-time PCR. ILs were found to regulate PG secretion via modulation of PG synthases in equine endometrium. The alterations in IL and the expression of their receptors, and in endometrial secretory functions, were observed during the course of endometrosis, and suggest serious changes in the endometrial microenvironment. The described disturbances may be closely related to impaired endometrial processes responsible for the subfertility or the infertility in endometrosis. PMID- 23946536 TI - Endogenous folate accumulation in oocytes and preimplantation embryos and its epigenetic implications. PMID- 23946537 TI - Oocyte-specific H2A variant H2af1o is required for cell synchrony before midblastula transition in early zebrafish embryos. AB - Oocyte-specific histone variants have been expected to play significant roles in early embryonic development, but the exact evidence and the biological function have remained unclear. Here, we present evidence that H2af1o, an oocyte-specific H2A variant, is required for cell synchrony before midblastula transition in early zebrafish embryos. The H2A variant is oocyte specific, peaks in mature eggs, and is supplied to early embryos. We constructed a series of deletion plasmids of the zebrafish h2af1o tagged with EGFP and determined the main key function regions including nuclear localization signal of N-terminal 25 amino acids and nucleosome binding region of 110-122 amino acid sequence in the C terminus by microinjecting them into one-cell-stage zebrafish embryos. In comparison with ubiquitous H2A.X, the H2af1o was revealed to confer a more open structure than canonical H2A in the nucleosomes. Furthermore, we conducted the h2af1o-specific morpholino knockdown analysis in early embryos of zebrafish and revealed its biological function for maintaining cell synchrony division because the H2af1o deficiency disturbed cell synchrony in early cleavages before midblastula transition. Therefore, our current findings provided the first case to understand the biological function of maternal oocyte-specific histone variants in vertebrates. PMID- 23946539 TI - Mechanisms by which a lack of germinal vesicle (GV) material causes oocyte meiotic defects: a study using oocytes manipulated to replace GV with primary spermatocyte nuclei. AB - Oocytes with germinal vesicles (GVs) replaced with somatic nuclei exhibit meiotic abnormalities. Although this suggests an exclusive role for GV material in meiosis, mechanisms by which a lack of GV material causes meiotic defects are unknown. Knowledge of these mechanisms will help us to understand meiotic control, nuclear-cytoplasmic interactions, and cellular reprogramming. This study showed that although oocytes with prometaphase I chromosomes replaced with primary spermatocyte nuclei (PSN) did not, oocytes with GV replaced with PSN (PSG oocytes) did display meiotic defects. Among the defects, insufficient chromosome condensation with chromosome bridges was associated with spindle abnormalities. Abnormal spindle migration, cortical nonpolarization, and the aberrant spindle caused randomly positioning of cleavage furrows, leading to large first polar bodies (PB1) and unequal allocation of chromosomes and mitogen-activated protein kinases (MAPK) between oocyte and PB1. Spindle assembly checkpoint was activated but did not stop the incorrect division. The unequal MAPK allocation resulted in differences in pronuclear formation and PB1 degeneration; oocytes receiving more MAPK were more capable of forming pronuclear rudiments, whereas PB1 receiving more MAPK degenerated sooner than those that received less. Because none of the PSG oocytes or the enucleated GV oocytes injected with sperm heads showed cortical polarization in spite of chromosome localization close to the oolemma and because the PSG oocytes receiving more MAPK could form only pronuclear rudiments and not normal pronuclei, we suggest that the GV material plays essential roles in polarization and pronuclear formation on top of those played by chromosomes or MAPK. In conclusion, using PSG oocytes as models, this study has revealed the primary pathways by which a lack of GV material cause meiotic defects, laying a foundation for future research on the role of GV material in oocyte meiotic control. PMID- 23946540 TI - Activation of FGF2-FGFR signaling in the castrated mouse prostate stimulates the proliferation of basal epithelial cells. AB - The prostate gland is unique in that it undergoes rapid regression following castration but regenerates completely once androgens are replaced. Residual ductal components play an important role in the regeneration of a fully functional prostate. In this study, to examine how androgen status affects prostate structure and components, we conducted histopathological studies of the involuted and regenerated mouse dorsolateral prostate (DLP). In the castrated mouse DLP, the number of luminal epithelial cells decreased in a time-dependent manner. On Day 14 postandrogen replacement, the number of luminal epithelial cells was completely restored to the baseline level. In contrast, the number of basal epithelial cells gradually increased in the castrated mouse prostate. The Ki67-labeling index of prostate basal epithelial cells was significantly increased after castration. The number of basal epithelial cells decreased to baseline after androgen replacement. After castration, mRNA expression levels of specific growth factors, such as Fgf2, Fgf7, Hgf, Tgfa, and Tgfb, were relatively abundant in whole mouse DLPs. In organ culture experiments, basal epithelial proliferation was recapitulated in the absence of dihydrotestosterone (DHT). The proliferation of basal epithelial cells in the absence of DHT was suppressed by treatment with an FGF receptor inhibitor (PD173074). Moreover, FGF2 treatment directly stimulated the proliferation of basal epithelial cells. Taken together, these data indicated that the FGF2-FGF receptor signal cascade in the prostate gland may be one of the pathways stimulating the proliferation of basal epithelial cells in the absence of androgens. PMID- 23946538 TI - Rho-associated kinase activity is required for proper morphogenesis of the inner cell mass in the mouse blastocyst. AB - The blastocyst consists of the outer layer of trophectoderm and pluripotent inner cell mass (ICM), the precursor of the placenta and fetus, respectively. During blastocyst expansion, the ICM adopts a compact, ovoidal shape, whose proper morphology is crucial for normal embryogenesis. Rho-associated kinase (ROCK), an effector of small GTPase RHO signaling, mediates the diverse cellular processes of morphogenesis, but its role in ICM morphogenesis is unclear. Here, we demonstrate that ROCK is required for cohesion of ICM cells and formation of segregated tissues called primitive endoderm (PrE) and epiblast (Epi) in the ICM of the mouse blastocyst. Blastocyst treatment with ROCK inhibitors Y-27632 and Fasudil caused widening or spreading of the ICM, and intermingling of PrE and Epi. Widening of ICM was independent of trophectoderm because isolated ICMs as well as colonies of mouse embryonic stem cells (mESC) also spread upon Y-27632 treatment. PrE, Epi, and trophectoderm cell numbers were similar between control and treated blastocysts, suggesting that ROCK inhibition affected ICM morphology but not lineage differentiation. Rock1 and Rock2 knockdown via RNA interference in mESC also induced spreading, supporting the conclusion that morphological defects caused by the pharmacological inhibitors were due to ROCK inactivation. When blastocysts were transferred into surrogates, implantation efficiencies were unaffected by ROCK inhibition, but treated blastocysts yielded greater fetal loss. These results show that proper ICM morphology is dependent on ROCK activity and is crucial for fetal development. Our studies have wider implication for improving efficiencies of human assisted reproductive technologies that diminish pregnancy loss and promote successful births. PMID- 23946541 TI - Cell-specific transcriptional profiling reveals candidate mechanisms regulating development and function of uterine epithelia in mice. AB - All mammalian uteri have luminal (LE) and glandular epithelia (GE) in their endometrium. The LE mediates uterine receptivity and blastocyst attachment for implantation, and the GE synthesize and secrete or transport bioactive substances involved in blastocyst implantation, uterine receptivity, and stromal cell decidualization. However, the mechanisms governing uterine epithelial development after birth and their function in the adult are not fully understood. Here, comprehensive microarray analysis was conducted on LE and GE isolated by laser capture microdissection from uteri on Postnatal Day 10 (PD 10) and day of pseudopregnancy (DOPP) 2.5 and 3.5. This data was integrated with analysis of uteri from gland-containing control and aglandular progesterone-induced uterine gland knockout mice from PD 10 and DOPP 3.5. Many genes were expressed in both epithelia, but there was greater expression of genes in the LE than in the GE. In the neonate, GE-expressed genes were enriched for morphogenesis, development, migration, and retinoic acid signaling. In the adult, LE-expressed genes were enriched for metabolic processes and steroid biosynthesis, whereas retinoid signaling, tight junction, extracellular matrix, and regulation of kinase activity were enriched in the GE. The transcriptome differences in the epithelia support the idea that each cell type has a distinct and complementary function in the uterus. The candidate genes and regulatory networks identified here provide a framework to discover new mechanisms regulating development of epithelia in the postnatal uterus and their functions in early pregnancy. PMID- 23946542 TI - When stresses collide. PMID- 23946543 TI - Clinical tibiofemoral angle in south Indian children. AB - OBJECTIVES: The development of tibiofemoral angle in children has shown ethnic variations. However this data is unavailable for our population. METHODS: We measured the tibiofemoral angle (TFA) and intercondylar and intermalleolar distances in 360 children aged between two and 18 years, dividing them into six interrupted age group intervals: two to three years; five to six years; eight to nine years; 11 to 12 years; 14 to 15 years; and 17 to 18 years. Each age group comprised 30 boys and 30 girls. Other variables recorded included standing height, sitting height, weight, thigh length, leg length and length of the lower limb. RESULTS: Children aged two to three years had a valgus angulation with a mean TFA of 1.8 degrees (sd 0.65) in boys and 2.45 degrees (sd 0.87) in girls. Peak valgus was seen in the five- to six-year age group, with mean TFAs of 6.7 degrees (sd 1.3) and 7.25 degrees (sd 0.64) for boys and girls, respectively. From this age the values gradually declined to a mean of 3.18 degrees (sd 1.74) and 4.43 degrees (sd 0.68) for boys and girls, respectively, at 17 to 18 years. Girls showed a higher valgus angulation than boys at all age groups. CONCLUSION: This study defines the normal range of the TFA in south Indian boys and girls using an easy and reliable technique of measurement with a standardised custom made goniometer. Cite this article: Bone Joint Res 2013;2:155-61. PMID- 23946544 TI - Support Groups, Marriage, and the Management of Ambiguity among HIV-Positive Women in Northern Nigeria. AB - In the context of the African HIV epidemic, support groups are not simply spaces for discussions of social and health well-being; neither are they institutions functioning solely to cultivate self-responsible and economically empowered patients. HIV-positive women in northern Nigeria have appropriated a support group to facilitate their marriage arrangements. In this group, women negotiate the threats of stigma and the promises of respectable marriage through what I call the management of ambiguity surrounding their HIV status. I further argue that the practice of support group matchmaking reveals the local political economic dynamics that shape social and illness trajectories in resource-poor settings. PMID- 23946545 TI - Adaptive regularization using the entire solution surface. AB - Several sparseness penalties have been suggested for delivery of good predictive performance in automatic variable selection within the framework of regularization. All assume that the true model is sparse. We propose a penalty, a convex combination of the L1- and Linfinity-norms, that adapts to a variety of situations including sparseness and nonsparseness, grouping and nongrouping. The proposed penalty performs grouping and adaptive regularization. In addition, we introduce a novel homotopy algorithm utilizing subgradients for developing regularization solution surfaces involving multiple regularizers. This permits efficient computation and adaptive tuning. Numerical experiments are conducted using simulation. In simulated and real examples, the proposed penalty compares well against popular alternatives. PMID- 23946546 TI - Pseudo-partial likelihood estimators for the Cox regression model with missing covariates. AB - By embedding the missing covariate data into a left-truncated and right-censored survival model, we propose a new class of weighted estimating functions for the Cox regression model with missing covariates. The resulting estimators, called the pseudo-partial likelihood estimators, are shown to be consistent and asymptotically normal. A simulation study demonstrates that, compared with the popular inverse-probability weighted estimators, the new estimators perform better when the observation probability is small and improve efficiency of estimating the missing covariate effects. Application to a practical example is reported. PMID- 23946547 TI - Marginal hazards model for case-cohort studies with multiple disease outcomes. AB - Case-cohort study designs are widely used to reduce the cost of large cohort studies while achieving the same goals, especially when the disease rate is low. A key advantage of the case-cohort study design is its capacity to use the same subcohort for several diseases or for several subtypes of disease. In order to compare the effect of a risk factor on different types of diseases, times to different events need to be modelled simultaneously. Valid statistical methods that take the correlations among the outcomes from the same subject into account need to be developed. To this end, we consider marginal proportional hazards regression models for case-cohort studies with multiple disease outcomes. We also consider generalized case-cohort designs that do not require sampling all the cases, which is more realistic for multiple disease outcomes. We propose an estimating equation approach for parameter estimation with two different types of weights. Consistency and asymptotic normality of the proposed estimators are established. Large sample approximation works well in small samples in simulation studies. The proposed methods are applied to the Busselton Health Study. PMID- 23946548 TI - Altar-Bound? The Effect of Disability on the Hazard of Entry into a First Marriage. AB - Researchers consistently find that the experience of disability in childhood can influence future life trajectories, particularly with regard to economic and educational outcomes. However, relatively little research has been conducted to explore the effect of disability on other dimensions of the transition to adulthood: namely, its effect on family-formation outcomes. This study uses data from waves I and IV of the National Longitudinal Study of Adolescent Health in order to assess the effect of various types of disabilities on the likelihood and timing of entry into a first marriage. Both bivariate and multivariate models show that individuals who have a disabling condition have a lower chance of entry into a first marriage than do individuals who do not have a disability. However, further analysis reveals that not all types of disabilities have the same effect on the chances of marriage-individuals with learning disabilities and those with multiple disabilities are at a significantly lower hazard of entry into a first marriage than are their peers without disabilities. PMID- 23946549 TI - Effects of Role and Assignment Rationale on Attitudes Formed During Peer Tutoring. AB - This study examined the role of contextual factors, such as assignment rationale, on the attitudinal effects of peer tutoring. Fourth-grade children engaged in brief tutoring experiences as either a tutor or tutee. Subjects received four rationales for being selected as tutor or tutee: (a) a competence rationale, (b) a physical characteristic rationale, (c) a chance rationale, or (d) no rationale. As predicted, tutors had more positive attitudes than tutees when they had been given a competence or physical characteristic rationale but not when the tutors were provided a chance rationale or no rationale. Additionally, the tutors' and tutees' attitudes were enhanced when no rationale was provided. Results are discussed in terms of their implications for a role-theory analysis of tutoring and their implications for applied programs. PMID- 23946550 TI - One's Enough for Now: Children, Disability, and the Subsequent Childbearing of Mothers. AB - This mixed-methods study explores the subsequent childbearing of mothers whose firstborn children have disabilities. I make use of matched data from the 1993 NHIS - 1995 NSFG (N = 4,468) to determine the effects of child disability on the hazard of a second birth and draw on a series of 24 in-depth interviews that explore the lived experience of raising children with disabilities. My findings suggest that mothers whose firstborn children are disabled have a lower hazard of a second birth. This reduction stems from mothers' recognition that children with disabilities have extensive needs and that, in order to meet those needs and maximize their potential, they need to make strategic choices such as delaying subsequent childbearing. PMID- 23946551 TI - Inequality in Landownership, the Emergence of Human-Capital Promoting Institutions, and the Great Divergence. AB - This paper suggests that inequality in the distribution of landownership adversely affected the emergence of human-capital promoting institutions (e.g. public schooling), and thus the pace and the nature of the transition from an agricultural to an industrial economy, contributing to the emergence of the great divergence in income per capita across countries. The prediction of the theory regarding the adverse effect of the concentration of landownership on education expenditure is established empirically based on evidence from the beginning of the 20th century in the U.S. PMID- 23946552 TI - Developmental Trajectories and Antecedents of Distal Parental Supervision. AB - Groups of adolescents were identified on the basis of developmental trajectories of their families' rules and their parents' knowledge of their activities. Characteristics of the adolescent, peer antisociality, and family context were tested as antecedents. In sum, 404 parent-adolescent dyads provided data for adolescents aged 10-16. Most adolescents were classified into groups characterized by low levels and reductions in family rules over time. However, low socioeconomic status and residence in unsafe neighborhoods increased membership in the group characterized by consistently high levels of family rules. Most adolescents were assigned membership in groups characterized by relatively stable moderate-to-high levels of parental knowledge of their activities. However, greater externalizing problems and peer antisociality, as well as residence in an unsafe neighborhood, increased membership in the group characterized by low and decreasing levels of knowledge. Results suggest that personal and contextual risk antecedes nonnormative decreases in parental knowledge, whereas contextual risk inhibits normative reductions in family rules. PMID- 23946553 TI - How important are dual economy effects for aggregate productivity? AB - This paper brings together development accounting techniques and the dual economy model to address the role that factor markets have in creating variation in aggregate total factor productivity (TFP). Development accounting research has shown that much of the variation in income across countries can be attributed to differences in TFP. The dual economy model suggests that aggregate productivity is depressed by having too many factors allocated to low productivity work in agriculture. Data show large differences in marginal products of similar factors within many developing countries, offering prima facie evidence of this misallocation. Using a simple two-sector decomposition of the economy, this article estimates the role of these misallocations in accounting for the cross country income distribution. A key contribution is the ability to bring sector specific data on human and physical capital stocks to the analysis. Variation across countries in the degree of misallocation is shown to account for 30-40% of the variation in income per capita, and up to 80% of the variation in aggregate TFP. PMID- 23946554 TI - The Future of Historical Family Demography. AB - An explosion of new data sources describing historical family composition is opening unprecedented opportunities for discovery and analysis. The new data will allow comparative multilevel analysis of spatial patterns and will support studies of the transformation of living arrangements over the past 200 years. Using measurement methods that assess family choices at the individual level and analytic strategies that assess variations across space and time, we can dissect the decline of patriarchal family forms in the developed world, and place Northwestern Europe and North America in global comparative context. PMID- 23946556 TI - The dual economy in long-run development. AB - A salient feature of developing economies is the coexistence of a modern commercial sector alongside a traditional subsistence sector-the dual economy. The apparent differences in productivity between sectors imply substantial losses in aggregate productivity. Existing theories of the dual economy rely on exogenous price distortions, and cannot explain why or if these distortions evolve over the course of development. This paper provides a model of the dual economy in which the productivity differences arise endogenously because of a non separability between the value of market and non-market time in the traditional sector. Incorporating endogenous fertility, the model then demonstrates how a dual economy will originate, persist, and eventually disappear within a unified growth framework. An implication is that traditional sector productivity growth will exacerbate the inefficiencies of a dual economy and produce slower overall growth than will modern sector productivity improvements. PMID- 23946555 TI - Mechanistic Insights into the Hydrolysis of Organophosphorus Compounds by Paraoxonase-1: Exploring the Limits of Substrate Tolerance in a Promiscuous Enzyme. AB - We designed, synthesized and screened a library of analogs of the organophosphate pesticide metabolite paraoxon against a recombinant variant of human serum paraoxonase-1. Alterations of both the aryloxy leaving group and the retained alkyl chains of paraoxon analogs resulted in substantial changes to binding and hydrolysis, as measured directly by spectrophotometric methods or in competition experiments with paraoxon. Increases or decreases in the steric bulk of the retained groups generally reduced the rate of hydrolysis, while modifications of the leaving group modulated both binding and turnover. Studies on the hydrolysis of phosphoryl azide analogs as well as amino-modified paraoxon analogs, the former being developed as photo-affinity labels, found enhanced tolerance of structural modifications, when compared with O-alkyl substituted molecules. Results from computational modeling predict a predominant active site binding mode for these molecules which is consistent with several proposed catalytic mechanisms in the literature, and from which a molecular-level explanation of the experimental trends is attempted. Overall, the results of this study suggest that while paraoxonase-1 is a promiscuous enzyme, there are substantial constraints in the active site pocket, which may relate to both the leaving group and the retained portion of paraoxon analogs. PMID- 23946557 TI - Using genetic information to test causal relationships in cross-sectional data. AB - Cross-sectional data from twins contain information that can be used to derive a test of causality between traits. This test of directionality is based upon the fact that genetic relationships between family members conform to an established structural pattern. In this paper we examine several common methods for empirically testing causality as well as several genetic models that we build on for the Direction of Causation (DoC) model. We then discuss the mathematical components of the DoC model and highlight limitations of the model and potential solutions to these limitations. We conclude by presenting an example from the personality and politics literature that has begun to explore the question whether or not personality traits cause people to hold specific political attitudes. PMID- 23946558 TI - Cytotoxic effects of the nickel release from the stainless steel brackets: An in vitro study. AB - AIMS: The purpose of the study is to determine whether the nickel released from the stainless steel brackets have any cytotoxic effects on gingival fibroblast. MATERIALS AND METHODS: Brackets are an important component of fixed orthodontics. Orthodontists are mainly concerned about the brands and various systems incorporated into the brackets. The manufactures claim bracket superiority without valid research. Since we are dealing with a biologic system factors like biocompatibility, cytotoxic potential should be taken into consideration before selecting an appliance to the patient. The cytotoxic activity of the media was investigated with MTT and comet assay. RESULTS: The results of the study show that the amount of nickel leached is capable of bringing damage to the fibroblast. CONCLUSION: Our study concludes that nickel solution at minimal concentration of 1.18 MUg could damage human gingival fibroblast and the nickel released from the different brands of the brackets are not uniform. PMID- 23946559 TI - The role of 3D plating system in mandibular fractures: A prospective study. AB - AIM: The aim of our study was to evaluate the advantages and disadvantages of 3D plating system in the treatment of mandibular fractures. PATIENTS AND METHODS: 20 mandibular fractures in 18 patients at various anatomic locations and were treated by open reduction and internal fixation using 3D plates. All patients were followed at regular intervals of 4(th), 8(th) and 12(th) weeks respectively. Patients were assessed post-operatively for lingual splay and occlusal stability. The incidence of neurosensory deficit, infection, masticatory difficulty, non union, malunion was also assessed. RESULTS: A significant reduction in lingual splay (72.2%) and occlusal stability (72.2%) was seen. The overall complication rate was (16.6%) which included two patients who developed post-operative paresthesia of lip, three patients had infection and two cases of masticatory difficulty which later subsided by higher antibiotics and 4 weeks of MMF. No evidence of non-union, malunion was noted. CONCLUSION: A single 3D 2 mm miniplate with 2 mm * 8 mm screws is a reliable and an effective treatment modality for mandibular fracture. PMID- 23946561 TI - Changing concepts of positive patient communication in dentistry and orthodontics: South Indian perspective. AB - The world of communication has changed greatly over the centuries of mankind from sounds, sign languages, speech, development of language and in modern times using machines like the computer, mobile and internet. Over the past five decades, the change in communication is remarkable. Similarly positive patient communication is always necessary to build confidence, increased rapport and cooperation and minimizes misunderstanding. Returning the patient in our fold promotes the patient for further preventive care and review and using them as a positive tool helps us in an ambassador of the growth of our health care unit. Our challenge is to provide the best environment for communication with a diverse population of interest, personalities and culture. PMID- 23946560 TI - Supplemental pulpal anesthesia for mandibular teeth. AB - Clinical pulpal anesthesia is dependent on the interaction of three major factors. (1) the dentist (2) the patient and (3) local anesthesia. Many patients fear endodontic treatment due to a concern about pain. Although pain treatment is well managed in many endodontic patients, there exists a group of patients who do not receive adequate local anesthesia. The purpose of this review article is to discuss the possible reasons for pulpal anesthetic failures and also to focus on the measures for developing effective approaches for the same. PMID- 23946562 TI - Interactions between magnetic resonance imaging and dental material. AB - Magnetic resonance imaging (MRI) has become a common and important life-saving diagnostic tool in recent times, for diseases of the head and neck region. Dentists should be aware of the interactions of various restorative dental materials and different technical factors put to use by an MRI scanning machine. Specific knowledge about these impacts, at the dentist level and at the level of the personnel at the MRI centers can save valuable time for the patient and prevent errors in MRI images. Artifacts from metal restorations are a major hindrance at such times, as they result in disappearance or distortion of the image and loss of important information. PMID- 23946563 TI - Evaluation of implant success: A review of past and present concepts. AB - Dental Implants have become the standard care of rehabilitation of missing teeth. This article intends to review the success criteria for implants from 1979 till date. Earlier days implant success was evaluated by immobility and peri-implant radiolucency. But currently, the width of the attached gingiva, co-existing medical conditions, smoking, and width of the implant also play a role in evaluating implant success. Genetic and immunological markers have also been identified. PMID- 23946564 TI - Role of provisional restorations in endodontic therapy. AB - Root-canal treatment can be carried out in single visit in vital, non-infected teeth, eliminating the need for dressing and provisionalization. Many clinical cases with infected canals require dressing with antibacterial medicaments in a multivisit treatment in which effective provisionalization for different periods of time becomes mandatory. Successful root-canal treatment requires effective mechanical and chemical debridement, elimination of bacteria and pulp tissue remnants and proper canal shaping to facilitate effective obturation. Lack of satisfactory temporary restorations during endodontic therapy ranked second amongst the contributing factors in continuing pain after the commencement of treatment. This review aims to provide an overview of the materials used for provisionalization during and immediately after endodontic treatment. PMID- 23946565 TI - Bone grafts in dentistry. AB - Bone grafts are used as a filler and scaffold to facilitate bone formation and promote wound healing. These grafts are bioresorbable and have no antigen antibody reaction. These bone grafts act as a mineral reservoir which induces new bone formation. PMID- 23946566 TI - Multidisciplinary approach of ectodermal dysplasia with implant retained fixed prosthesis. AB - Ectodermal dysplasia represents a group of rare inherited conditions in which two or more ectodermally derived anatomical structures fail to develop. Early dental intervention can improve patient's appearance, thereby minimizing associated emotional and psychological problems in these patients. Treatment requires a teamwork by medical personnel along with dental professionals of various specialties. Here, a rare case of a young female patient is presented with prosthetic management with implant supported fixed partial denture. PMID- 23946567 TI - Three different surgical techniques of crown lengthening: A comparative study. AB - INTRODUCTION: A short clinical crown may lead to poor retention form thereby leading to improper tooth preparation. Surgical crown lengthening procedure is done to increase the clinical crown length without violating the biologic width. Several techniques have been proposed for clinical crown lengthening which includes gingivectomy, apically displaced flap with or without resective osseous surgery, and surgical extrusion using periotome. OBJECTIVE: The aim of this paper is to compare clinically the three different surgical techniques of crown lengthening procedures. MATERIALS AND METHODS: Fifteen patients who reported to the department of Periodontology, were included in the study. Patients were randomly divided into three groups, which include patients who underwent gingivectomy (Group A), apically repositioned flap (Group B) and surgical extrusion using periotome (Group C). Clinical measurements such as clinical crown length, gingival zenith, interdental papilla height were taken at baseline and at 3(rd) month post-operatively. RESULTS: Clinical and radiographic evaluation at 3(rd) month suggest that surgical extrusion technique offers several advantages over the other conventional surgical techniques such as preservation of the interproximal papilla, gingival margin position and no marginal bone loss. CONCLUSIONS: This technique can be used to successfully treat a grossly damaged crown structure as a result of tooth fracture, dental caries and iatrogenic factors especially in the anterior region, where esthetics is of great concern. PMID- 23946568 TI - The effect of bleaching of teeth on the bond strength of brackets: An in vitro study. AB - AIM: To determine the reversal effect of 10% sodium ascorbate, on the bond strength of previously bleached teeth with hydrogen peroxide. MATERIALS AND METHODS: Sixty extracted maxillary premolars were selected and they were divided randomly into three groups. Group A teeth were etched and bonded; Group B bleached, etched and immediately bonded; Group C was subjected to bleaching, followed by treatment with 10% sodium ascorbate solution, then etched and bonded; Then all the three groups were subjected to testing procedure for bond strength. RESULTS: The bond strength analysis was carried out by using instron, universal testing machine. In this study Group A had the maximum bond strength of 12.24 Mpa followed by Group C 11.62 Mpa and Group B 10.96 Mpa. CONCLUSION: Group C the experimental group which was treated with 10% sodium ascorbate following bleaching with 35% hydrogen peroxide provided higher bond strength compared to Group B which was bonded immediately after bleaching even though it was not statistically significant. PMID- 23946569 TI - Prevalence of nutrient canals in diabetes mellitus and hypertension: A radiographic study. AB - AIM: The present study is undertaken primarily to determine if a correlation in the appearance of nutrient canals with hypertension and diabetes exists and to determine whether the presence of nutrient canals can be used as a clue for the detection of hypertensive and diabetic patients. PATIENTS AND METHODS: A total of 300 subjects were selected from the out-patient department comprising of 100 diabetic patients, 100 hypertensive patients and 100 patients without any systemic diseases as control group. Intraoral periapical radiograph of all these patients were taken for evaluation. STATISTICAL ANALYSIS USED: Statistical analysis of the data was done using the statistical package for the social sciences (SPSS 15.0) using Chi-square analysis. Differences were considered as significant when P <= 0.05. RESULTS: Of all these 300 patients, 162 patients exhibited nutrient canals whereas 118 patients didn't have nutrient canals. Of the 100 patients in Group I, 62 patients exhibited nutrient canals which accounts to 62% prevalence, 64 out of 100 patients in Group II, exhibited nutrient canals which account to 64% prevalence and 72 out of 100 patients in control group exhibited nutrient canals which account to 36% prevalence. CONCLUSION: As the study showed positive correlation, we conclude same that presence of nutrient canal can be used as an aid to rule out systemic diseases like diebeeis mellitus and hypertension. PMID- 23946570 TI - Cephalomteric changes in airway dimensions with twin block therapy in growing Class II patients. AB - INTRODUCTION: Myofunctional appliances are commonly used for correction of skeletal Class II malrelationship. These appliances influence craniofacial and nasopharyngeal dimensions. OBJECTIVES: The present study was done to evaluate changes in airway with twin block therapy. MATERIALS AND METHODS: Cephalometric assessment of airway was done in 25 growing children in the age group of 11-13 years with Class II skeletal pattern. All the patients were treated with twin block appliance. Pre and post treatment lateral cephalograms were taken to evaluate the changes in different airway and craniofacial dimensions during the treatment period. The average treatment duration was 14.5 months. RESULTS: AIRWAY: A significant increase was observed in upper and lower pharyngeal width and area of bony nasopharynx. Craniofacial dimension: There was a significant increase in effective mandibular length, ramal length and mandibular plane angle. There was an increase in SNB angle, which resulted in decreased ANB angle. CONCLUSION: There was a definite improvement in airway dimension following twin block therapy. PMID- 23946571 TI - Evaluation of oral health related quality of life in patient with mild periodontitis among young male population of Namakkal district. AB - AIM: The aim of the study is to assess the impact of oral health related quality of life (QOL) on patients presenting for scaling and oral prophylaxis using a the oral health-related quality of life (OHRQL) questionnaire. MATERIALS AND METHODS: This prospective study includes a total of 100 male patients of age group 25-35 years, who visited private clinic in Namakkal district, South India. They were assessed for their perceptions of oral health using OHRQL questionnaire before initial periodontal therapy including scaling and root planning. RESULTS: A total of 100 patients (mean age:29 years) participated in the study and completed initial periodontal therapy. Before treatment 98% of the patients perceived that their oral health status impacted on their QOL in one or more ways. Bad breath was the most common complaint. Social well-being, personality and psychological function were identified as compromised OHRQL domains. More than 60% of the patients stated their overall general health is affected by periodontal disease. CONCLUSION: Periodontitis negatively affected QOL in this Namakkal district population of young male patients with mild periodontitis. Conventional non surgical periodontal therapy and personality development counseling has a potential to ameliorate patient perceptions of oral health and improve their QOL. PMID- 23946572 TI - Maxillofacial trauma in Tamil Nadu children and adolescents: A retrospective study. AB - AIM: The aim of this retrospective study is to describe the incidence, aetiology, complexity and surgical indications of maxillofacial injuries in children and adolescents population of Tamil Nadu state of india during period of 4 years. MATERIALS AND METHODS: A retrospective review was conducted among 500 children and adolescents patients of age group 6 years to 16 years suffered or suffering with maxillofacial and skull fractures presenting to ten Level I trauma centers over a 4 year period.The data collected for this study included age, gender, etiology, associated maxillofacial trauma, anatomic site of fracture and treatment. RESULTS AND CONCLUSION: In our study the most common cause of trauma was traffic 35%, followed by falls 24% and sports 22%. Mandible was commenest bone prone to fracture, followed by maxilla and nasal bone. Mandible fractures accounted for 72% of all maxillofacial fractures. PMID- 23946573 TI - A study among dental students regarding the factors influenced dental students to choose dentistry as career. AB - INTRODUCTION: Career choice is a complex decision for students since it determines the kind of profession that they intend to pursue in life. As students try to make a career choice while in secondary school, they face the problem of matching their career choices with their abilities and school performance. AIMS: The purpose of this study was to examine factors influencing career choice among dental college students in private dental collages in Tamil Nadu, India. SETTINGS AND DESIGN: The study was conducted using descriptive survey design with a population of 989 students. The data for this study was collected using a questionnaire and interview schedules. MATERIALS AND METHODS: The data for this study was collected using questionnaire previously used by Swati Shah and Rajaraman and interview schedules. The analysis of the study was based on the factors: Outcome expectations, gender, personal interests, and other factors. RESULTS AND CONCLUSION: The most common reason for among the dental students to choose dental science as their career choice was self-interested followed by didn't get medicine degree, prestige and gives respect. The least common reasons observed in the study population were inspired by dentists. The findings of this study indicate that availability the most influential factors affecting career choices among students. PMID- 23946574 TI - An adjunctive minor surgical procedure for increased rate of retraction. AB - INTRODUCTION: Orthodontic treatment is based on the principle that if prolonged pressure is applied to the tooth, tooth movement will occur as the bone around the tooth re-models. In this study osteotomy of buccal alveolar plate and undermining of interseptal bone was performed at premolar extraction site and rate of en-masse retraction and canine retraction was evaluated. MATERIALS AND METHODS: Patients between the age of 18 and 25 years, requiring retraction of anterior teeth are selected for the study. Osteotomy with undermining of interseptal bone at the extraction site was performed. The procedure was performed on all four quadrants. RESULTS: The average retraction in the maxillary arch was 0.98 mm/quadrant in 3 weeks, i.e., a total retraction of 5.89 mm in a span of 9 weeks. The average retraction in the mandibular arch was 0.96 mm/quadrant in 3 weeks, i.e., a total retraction of 5.75 mm in a span of 9 weeks. CONCLUSION: This method of achieving faster en masse retraction immediately after extraction definitely reduced the initial retraction time. We recommend that such procedure must be carried out with appropriate anchorage conservation methods. PMID- 23946575 TI - Morphology of palatal rugae patterns among 5-15 years old children. AB - INTRODUCTION: "The fibers running anteroposteriorly within the core and in concentric curves across the base of each ruga" determine their orientation and forms. The varying shapes of palatal rugae can be attributed to the fact that rugae develop as localized regions of epithelial proliferation and thickening. Fibroblasts and collagen fibers then accumulate in the connective tissue beneath the thickened epithelium and assume distinct orientation. AIM: The aim of the present study was to assess the morphology, gender difference of rugae pattern in 5-15 year old children. MATERIALS AND METHODS: The various diagnostic dental stone cast available in Department of Pedodontics were analyzed by the method based on Thomas and Kotze classification in 1983. RESULTS: There was a female prediction in the total count and primary rugae pattern. Comparing the shapes of rugae both in male and female study models showed a predominance in wave shape followed by cure. No circular pattern was observed in the study population. No statistical difference in the direction and unification of rugae among males and females. CONCLUSION: The fingerprint-like uniqueness of rugae to each individual has become accepted as a possible aid to person identification. This may help narrow the field for identification and give results in conjunction with the other methods such as visual, fingerprints, and dental characteristics in forensic sciences. PMID- 23946576 TI - Effect of various concentrations of tetracycline hydrochloride demineralization on root dentin surface: A scanning electron microscopic study. AB - INTRODUCTION: Within the last 20 years root demineralization has attracted attention as a periodontal regenerative technique. Topical tetracycline application has been widely reported for use as a conditioner, to decontaminate the root surface and to promote periodontal regeneration. The purpose of this scanning electron microscopic (SEM) study is to evaluate the surface characteristics of demineralized diseased and non-diseased dentine root surfaces using different concentrations of tetracycline hydrochloride (TTC-HCl). MATERIAL AND METHODS: This SEM study was carried out in 20 dentin samples obtained from non-diseased human premolars and 20 dentin samples obtained from diseased human premolars. Pure TTC-HCl was applied to the dentin surface at 50 mg/ml, 100 mg/ml and 150 mg/ml concentrations for 3 min in experimental groups while distilled (0 mg/ml) water was applied to the control groups. STATISTICAL ANALYSIS: Mean and standard deviation were estimated from the sample for each study group. Mean values were compared by either one-way ANOVA with Tukey-Honestly significant difference procedure or Kruskal - Wallis one way ANOVA with Mann-Whitney u-test. Further Student's independent t-test/Mann-Whitney u-test was used appropriately to compare the mean values between two independent groups. RESULTS: In the present study using 100 mg/ml tetracycline seems to be more effective on both diseased and non-diseased dentin surfaces. CONCLUSIONS: The results of this study confirm that pure TTC-HCl conditioning produced comparable surface characteristics on dentin of both diseased and non-diseased roots with 100 mg/ml concentration for 3 min. PMID- 23946577 TI - A comparative evaluation of Oratest with the microbiological method of assessing caries activity in children. AB - AIMS: The aim of this study is to find out whether Oratest can be used as a diagnostic tool in assessing the caries activity by evaluating its relationship to the existing caries status and the salivary streptococcus mutans level. MATERIALS AND METHODS: The study sample consists of 90 students divided into two groups. Group I (test group) and Group II (control group) consisting of 30 children for control group and 60 children for test group. The sampling of unstimulated saliva for the estimation of streptococcus mutans was done as per the method suggested by Kohler and Bratthall. The plates were then incubated. Rough surface colonies were identified as streptococcus mutans on a pre determined area of the tip (approximately 1.5 cm(2)) were counted for each side of spatula pressed against mitis salivarius bacitracin agar using digital colony counter. The results were expressed in colony forming units (CFU). Oratest was carried out in the same patients after the collection of salivary sample for the microbiological method to evaluate the relationship between the two tests. STATISTICAL ANALYSIS USED: The tests used were ANOVA, Pearson Chi-square test, Pearson's correlation analysis, Mann-Whitney U test and Student's independent t test. RESULTS: In the control group and test group, when the streptococcus mutans count (CFU) and Oratest time (minutes) were correlated using Pearson's correlation analysis, the streptococcus mutans counts was found to be in a statistically significant negative linear relationship with the Oratest time. When the caries status of the children, participated in the test group were correlated with mutans count (CFU) and Oratest time, caries status were found to be in a statistically significant positive linear relationship with streptococcus mutans count and in a significant negative linear relationship with Oratest time. CONCLUSIONS: The test proved to be a simple, inexpensive and rapid technique for assessing caries activity since a significant relationship exists clinically with caries status and microbiologically with the streptococcus mutans count of the individual. PMID- 23946579 TI - Mesiodens: A clinical and radiographic study of 82 teeth in 55 children below 14 years. AB - INTRODUCTION: Supernumerary teeth refers to an excessive number of teeth and are relatively common in the oral cavity. The supernumerary tooth located in the midline of the maxilla between the central incisors is referred to as "mesiodens". The present study emphasizes the importance of multidisciplinary management and long-term follow-up of patients with mesiodens. AIM OF THE STUDY: This study investigates the characteristics of mesiodens among children in patients reported to department of pediatric and preventive dentistry in an institution in the state of Tamil Nadu, India. MATERIALS AND METHODS: The study population consisted of 55 children below 14 years. The characteristics of mesiodens were obtained from radiographs and clinical examination. And all these were confirmed as mesiodens by surgical intervention. RESULTS: Results showed that males were affected approximately 2 times as frequently as females. Predominant shape of the mesiodens was conical (79.7%). 27 (49.09%) of 55 patients had multiple mesiodens. 25 (45.45%) of 55 patients required orthodontic correction after surgery. CONCLUSIONS: Mesiodens can cause many complications. So routine radiographic examination of all pediatric patients is advised. And when identified, they should be extracted as early as possible in children and adolescents in order to avoid possible complications. PMID- 23946578 TI - Evaluation of the inclination of maxillary occlusal plane on mounted casts using a fixed value and customized nasion indicator in artex articulator: Facebow system - An in-vivo comparative study. AB - AIM: To evaluate and compare the variations in the inclination of occlusal plane of casts mounted on Artex articulator using a facebow with a fixed value and customized nasion indicator. MATERIALS AND METHODS: Twenty two subjects were selected for this investigation. Two maxillary impressions were made, and casts poured. For each of the twenty two subjects, the facebow records were made with, Artex face-bow using a fixed value nasion indicator and customized nasion indicator and mounted. The angle between the occlusal plane of upper cast and the upper articulator arm was measured with a Universal bevel protractor and compared with the gold standard cephalometric value. RESULTS: It shows that, when angle was measured between maxillary occlusal plane and upper member of the articulator, on the mounted cast using a customized nasion indicator and fixed value nasion indicator against the gold standard cephalometric value as a whole, it was found to be not significant. But, if each patient were evaluated individually, there found to be the difference in the angle. DISCUSSION AND CONCLUSION: Variation in occlusal plane was very minimal and close to the cephalometric value when using customized nasion indicator compared to fixed value nasion indicator on the Artex. PMID- 23946580 TI - Comparative evaluation of predictive value of three caries activity tests-snyder, lactobacillus count and cariostat in mixed dentition children with and without caries. AB - INTRODUCTION: Dental caries is a disease with multifactorial etiology. Early detection and preventive measures are essential for caries control. Caries activity tests are one of the methods of early detection, but all these are based on microbiological study. AIMS: Compare the sensitivity and specificity of Snyder test (ST), lactobacillus count (LBC) and Cariostat in mixed dentition children with and without caries. MATERIALS AND METHODS: 90 healthy mixed dentition children (79 boys and 11 girls) were selected and were divided into two groups, one with Decayed missing filled teeth (DMFT) 0 and another group with DMFT 3-5. The salivary samples were collected for ST and LBC and plaque samples were collected for Cariostat. Caries activity was assessed. RESULTS: The data obtained were analyzed for sensitivity, specificity, positive predictive value, negative predictive value and over all accuracy. CONCLUSIONS: Our present study showed that the LBC was found to have a higher correlation in caries as the caries increased the count also increased with positive caries activity. A good correlation was found between Snyder and LBC for the caries activity 1, 2 and 3. But no correlation was seen for score 0. To conclude, a combination of all these tests was found to be good for assessing caries risk groups. PMID- 23946581 TI - A comparison of enameloplasty sealant technique and conventional sealant technique: An in-vivo study. AB - AIM: THE AIM OF THE STUDY IS TO COMPARE TWO DIFFERENT METHODS: Enameloplasty sealant technique (EST) and conventional sealant technique (CST) in terms of the presence or loss of sealant and the presence or absence of caries after 6, 12, and 18 months. MATERIALS AND METHODS: A total of 15 children in the age group of 7-9 years participated in the study. After taking consent, status of occlusal surface was evaluated under standardized conditions. Only mandibular molars were used in the study. On each patient, one side molar was sealed using EST and other side molar was sealed using CST. All children were recalled and examined after 6 months, 12 months and 18 months. RESULTS: At the end of 18 months, no teeth were found carious in EST and CST group. At the end of 6, 12, 18 months there was no loss of sealants in both EST and CST group. There was no difference between EST and CST success rates. CONCLUSION: In our study both EST sand CST showed good results. So we can do EST in deep I-Type and K-Type pit and fissures. PMID- 23946582 TI - The relationship between dental age, bone age and chronological age in underweight children. AB - BACKGROUND AND OBJECTIVE: The knowledge of bone age and dental age is of great importance for pediatrician and pediatric dentist. It is essential for a pediatric dentist to formulate treatment plan and it is a source of complementary information for pediatrician. There are few studies, which showed the relationship between dental age, bone age and chronological age in underweight children. Therefore, objective of this study was to determine and compare dental age, bone age and chronological age in underweight children. MATERIALS AND METHODS: 100 underweight children between the age group of 18-14 years were selected. Chronological age was assessed by recording date of birth. Dental age assessment was done using orthopantamogram following the method described by Demirjian. Bone age assessment was carried out using hand wrist radiograph following Bjork, Grave and Brown's method. RESULTS: Dental age and Bone age was delayed compared to chronological age in both sexes. The correlation between chronological age, dental age and bone age were all positive in males. INTERPRETATION AND CONCLUSION: The data supports the concept that dental age and bone age delay is a significant feature in underweight children. It is important to consider dental age and bone age as variables for diagnosing underweight children. To support our findings further a well-designed, controlled as well as longitudinal studies with a larger sample size is required. PMID- 23946583 TI - A comparative evaluation of disinfection effect of exposures to ultra-violet light and direct current glow discharge on Candida Albicans colonies coated over elastomeric impression material: An in vitro study. AB - AIM: The aim of our study is to compare the efficacy of ultra-violet light (U-V light) and direct current glow discharge in disinfecting Candida Albicans coated elastomeric impression material. MATERIALS AND METHODS: Two hundred and forty samples of addition silicone material in the form of circular discs measuring (diameter-30 mm, thickness-3 mm) were prepared. Samples were divided into four groups namely A, B, C, D, with each group containing 60 samples. All samples in each group were sub grouped as follows for exposure time 15, 30, 60, 90, 120 and 180 s respectively. Group A samples were exposed to U-V light with 8 watts. Group B samples were exposed to U-V light with 16 watts. Group C samples were exposed to U-V light with 24 watts. Group D samples were exposed to direct current glow discharge. After exposure, the impression material was swabbed on sabourauds dextrose agar (SDA) plates and incubated at 37 degrees C for 48 h. The total number of colonies indicating the number of C. Albicans that survived the direct current glow discharge and U-V light treatment was then determined using a microscope. RESULTS AND CONCLUSION: Group A samples exhibited proportionate decrease in the number of colonies with each greater time of exposure. Group B samples exhibited proportionate decrease in the number of colonies with each greater time of exposure. Group C samples exhibited total absence of C. Albicans colonies at 90 s exposure. In Group D samples there was a proportionate decrease in number of C. Albicans colonies with exposure to direct current glow discharge for more seconds. Hence, this study reveals that exposure to U-V light drastically reduced the C. Albicans colonies compared with exposure to direct current glow discharge. It was observed that with greater wattage of U-V light tube in U-V light unit chamber, greater decrease in colony count was observed in lesser time of exposure. PMID- 23946584 TI - Pathogenesis and therapeutic intervention of oral submucous fibrosis. AB - Oral submucous fibrosis (OSF) is a chronic, progressive, potentially malignant condition affecting the oral cavity and frequently involving the upper part of the aerodigestive tract including the oropharynx and the upper part of the esophagus. It is characterized by juxtaepithelial inflammatory reaction and progressive fibrosis of lamina propria, leading to stiffening of the oral mucosa eventually causing trismus. This condition is associated with significant morbidity and high risk of malignancy. Over the years, several drugs and combinations have been tried for the treatment of submucous fibrosis, but with limited success, because of its unclear molecular pathogenesis. Till date, there are no known effective treatments for OSF. The aim of this article is to emphasize on the molecular changes taking place in OSF and possible therapeutic interventions. PMID- 23946585 TI - Application of ozone in the treatment of periodontal disease. AB - Gingivitis and periodontitis are most common inflammatory diseases of supporting tissues of teeth. Role of microbial etiology and host response in progression of gingival and periodontal diseases has been well established. Because of the beneficial biological effects of ozone, due to its antimicrobial and immunostimulating effect, it is well indicated in the treatment of gingival and periodontal diseases. The objective of this article is to provide a general review about clinical applications of ozone in treatment of periodontal diseases and to summarize the available in vitro and in vivo studies in Periodontics in which ozone has been used. PMID- 23946586 TI - Lip prints: Role in forensic odontology. AB - Identification plays a major role in any crime investigation. The pattern of wrinkles on the lips has individual characteristics like fingerprints. Cheiloscopy is a forensic investigation technique that deals with identification of humans based on lips traces. In the past decades, lip-print studies attracted the attention of many scientists as a new tool for human identification in both civil and criminal issues. The lip crease pattern is on the vermilion border of the lip, which is quite mobile and lip prints may vary in appearance according to the pressure, direction and method used in making the print. It concludes by enlightening the readers with the fact that the possibilities to use the red part of lips to identify a human being are wider than it is commonly thought. PMID- 23946587 TI - Implant surgical guides: From the past to the present. AB - Advent of osseointegration has rapidly led to use of dental implants over recent years. Implant complications are often inadvertent sequelae of improper diagnosis, treatment planning, surgical method, and placement. This can be overcome by using surgical guides for implant positioning. Although conventionally made surgical guide are used, the clinical outcome is often unpredictable, and even if the implants are well placed, the location and deviation of the implants may not meet the optimal prosthodontic requirements. High accuracy in planning and execution of surgical procedures is important in securing a high success rate without causing iatrogenic damage. This can be achieved by computed tomography, 3D implant planning software, image-guided template production techniques, and computer-aided surgery. This article evaluates about the various systems of conventionally made surgical guide using radiograph and also the newer computer generated surgical guide in detail. PMID- 23946588 TI - Acoustic radiation force impulse of the liver. AB - Acoustic radiation force impulse (ARFI) imaging is a new and promising ultrasound based diagnostic technique that, evaluating the wave propagation speed, allows the assessment of the tissue stiffness. ARFI is implemented in the ultrasound scanner. By short-duration acoustic radiation forces (less than 1 ms), localized displacements are generated in a selected region of interest not requiring any external compression so reducing the operator dependency. The generated wave scan provides qualitative or quantitative (wave velocity values) responses. Several non-invasive methods for assessing the staging of fibrosis are used, in order to avoid liver biopsy. Liver function tests and transient elastography are non invasive, sensitive and accurate tools for the assessment of liver fibrosis and for the discrimination between cirrhotic and non-cirrhotic liver. Many published studies analyse ARFI performance and feasibility in studying diffuse liver diseases and compare them to other diagnostic imaging modalities such as conventional ultrasonography and transient elastography. Solid focal liver lesions, both benign and malignant, are common findings during abdominal examinations. The accurate characterization and differential diagnosis are important aims of all the imaging modalities available today. Only few papers describe the application of ARFI technology in the study of solid focal liver lesions, with different results. In the present study, the existing literature, to the best of our knowledge, about ARFI application on diffuse and focal liver pathology has been evaluated and results and statistical analyses have been compared, bringing to the conclusion that ARFI can be used in the study of the liver with similar accuracy as transient elastography in diagnosing significant fibrosis or cirrhosis and has got some advantages in respect to transient elastography since it does not require separate equipment, better displays anatomical structures and measurements can be successfully carried out almost in every patient. PMID- 23946589 TI - New ultrasound techniques for lymph node evaluation. AB - Conventional ultrasound (US) is the recommended imaging method for lymph node (LN) diseases with the advantages of high resolution, real time evaluation and relative low costs. Current indications of transcutaneous ultrasound and endoscopic ultrasound include the detection and characterization of lymph nodes and the guidance for LN biopsy. Recent advances in US technology, such as contrast enhanced ultrasound (CEUS), contrast enhanced endoscopic ultrasound (CE EUS), and real time elastography show potential to improve the accuracy of US for the differential diagnosis of benign and malignant lymph nodes. In addition, CEUS and CE-EUS have been also used for the guidance of fine needle aspiration and assessment of treatment response. Complementary to size criteria, CEUS could also be used to evaluate response of tumor angiogenesis to anti-angiogenic therapies. In this paper we review current literature regarding evaluation of lymphadenopathy by new and innovative US techniques. PMID- 23946590 TI - Is diabetes mellitus a risk factor for pancreatic cancer? AB - The relationship between diabetes mellitus and the risk of pancreatic cancer has been a matter of study for a long period of time. The importance of this topic is due to two main causes: the possible use of recent onset diabetes as a marker of the disease and, in particular, as a specific marker of pancreatic cancer, and the selection of a population at risk for pancreatic cancer. Thus, we decided to make an in-depth study of this topic; thus, we carried out an extensive literature search in order to re-assess the current knowledge on this topic. Even if diabetes is found a decade before the appearance of pancreatic cancer as reported in meta-analytic studies, we cannot select those patients already having non detectable pancreatic cancer, at least with the imaging and biological techniques available today. We believe that more studies are necessary in order to definitively identify diabetes mellitus as a risk factor for pancreatic cancer taking into consideration that approximately 10 years are needed to diagnose symptomatic pancreatic cancer. At present, the answer to the as to whether diabetes and pancreatic cancer comes first similar to the adage of the chicken and the egg is that diabetes is the egg. PMID- 23946591 TI - MicroRNAs may solve the mystery of chronic hepatitis B virus infection. AB - Hepatitis B virus (HBV) infection is a global public health problem that causes persistent liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. A large amount of people die annually from HBV infection. However, the pathogenesises of the HBV-related diseases are ill defined and the therapeutic strategies for the diseases are less than optimum. The recently discovered microRNAs (miRNAs) are tiny noncoding RNAs that regulate gene expression primarily at the post-transcriptional level by binding to mRNAs. miRNAs contribute to a variety of physiological and pathological processes. A number of miRNAs have been found to play a pivotal role in the host-virus interaction including host-HBV interaction. Numerous studies have indicated that HBV infection could change the cellular miRNA expression patterns and different stages of HBV associated disease have displayed distinctive miRNA profiles. Furthermore, the differential expressed miRNAs have been found involved in the progression of HBV-related diseases, for instance some miRNAs are involved in liver tumorigenesis and tumor metastasis. Studies have also shown that the circulating miRNA in serum or plasma might be a very useful biomarker for the diagnosis and prognosis of HBV-related diseases. In addition, miRNA-based therapy strategies have attracted increasing attention, indicating a promising future in the treatment of HBV-related diseases. PMID- 23946592 TI - Thiopurines related malignancies in inflammatory bowel disease: local experience in Granada, Spain. AB - AIM: To investigate the incidence of neoplasms in inflammatory bowel disease (IBD) patients and the potential causative role of thiopurines. METHODS: We performed an observational descriptive study comparing the incidence of malignancies in IBD patients treated with thiopurines and patients not treated with these drugs. We included 812 patients which were divided in two groups depending on whether they have received thiopurines or not. We have studied basal characteristics of both groups (age when the disease was diagnosed, sex, type of IBD, etc.) and treatments received (Azathioprine, mercaptopurine, infliximab, adalimumab or other immunomodulators), as well as neoplasms incidence. Univariate analysis was performed with the student t test, chi(2) test or Wilcoxon exact test as appropriate. A logistic regression analysis was performed as multivariate analysis. Statistical significance was establish at P values of less than 0.05, and 95%CI were used for the odds ratios. RESULTS: Among 812 patients included, 429 (52.83%) have received thiopurines: 79.5% azathioprine, 14% mercaptopurine and 6.5% both drugs. 44.76% of patients treated with thiopurines and 46, 48% of patients who did not receive this treatment were women (P > 0.05). The proportion of ulcerative colitis patients treated with thiopurines was 30.3% compare to 66. 67% of patients not treated (P < 0.001). Mean azathioprine dose was 123.79 +/- 36.5 mg/d (range: 50-250 mg/d), mean usage time was 72.16 +/- 55.7 mo (range: 1 300 mo) and the accumulated dose along this time was 274.32 +/- 233.5 g (1.5-1350 g). With respect to mercaptopurine, mean dose was 74.7 +/- 23.9 mg/d (range: 25 150 mg/d), mean usage time of 23.37 +/- 27.6 mo (range: 1-118 mo), and the accumulated dose along this time was 52.2 +/- 63.5 g (range: 1.5-243 g). Thiopurine S-methyltransferase activity was tested in 66% of patients treated with thiopurines, among which 98.2% had an intermediate or high activity. Among the patients treated with thiopurines, 27.27% (112 patients) and 11.66% (50 patients) received treatment with Infliximab and Adalimumab respectively, but only 1.83% (7 patients) and 0.78% (3 patients) received these drugs in the group of patients who did not received thiopurines (P < 0.001 and P < 0.001 respectively). Finally, 6.8% (29 patients) among those treated with thiopurines have received other immunosuppressants (Methotrexate, Tacrolimus, Cyclosporin), compare to 1% (4 patients) of patients not treated with thiopurines (P < 0.001). Among patients treated with thiopurines, 3.97% developed a malignancy, and among those not treated neoplasms presented in 8.1% (P = 0.013). The most frequent neoplasms were colorectal ones (12 cases in patients not treated with thiopurines but none in treated, P < 0.001) followed by non-melanoma skin cancer (8 patients in treated with thiopurines and 6 in not treated, P > 0.05). CONCLUSION: In our experience, thiopurine therapy did not increase malignancies development in IBD patients, and was an effective and safe treatment for these diseases. PMID- 23946593 TI - Histopathology of type C liver disease for determining hepatocellular carcinoma risk factors. AB - AIM: To evaluate the histopathological findings of type C liver disease to determine risk factors for development of hepatocellular carcinoma (HCC). METHODS: We studied 232 patients, who underwent liver biopsy for type C chronic liver disease between 1992 and 2009, with sustained virological response (SVR) after interferon therapy. The patients were divided into two groups according to the F stage 0 + 1 + 2 group (n = 182) and F3 + 4 group (n = 50). We prospectively observed and compared the incidence of HCC of the patients with SVR in the F0 + 1 + 2 and F3 + 4 groups. Then, the background factors and liver histopathological findings, including the degree of fibrosis, F stage, inflammation, necrosis, bile duct obstruction, fat deposition, and degree of irregular regeneration (IR) of hepatocytes, were correlated with the risk of developing HCC. RESULTS: HCC developed in three of 182 (1.6%) patients in the F0 + 1 + 2 group, and four of 50 (8.0%) in the F3 + 4 group. The cumulative incidence of HCC in the former group was found to be significantly lower than in the F3 + 4 group (log rank test P = 0.0224). The presence of atypical hepatocytes among IR of hepatocytes in the F3 + 4 group resulted in a higher cumulative incidence of HCC, and was significantly correlated with risk of HCC development (RR = 20.748, 95%CI: 1.335-322.5, P = 0.0303). CONCLUSION: Atypical hepatocytes among the histopathological findings of type C liver disease may be an important risk factor for HCC development along with progression of liver fibrosis. PMID- 23946594 TI - Infective severe acute pancreatitis: a comparison of 99mTc-ciprofloxacin scintigraphy and computed tomography. AB - AIM: To evaluate (99m)Tc-ciprofloxacin scintigraphy compared with computed tomography (CT) for detecting secondary infections associated with severe acute pancreatitis (SAP) in swine. METHODS: Six healthy swine were assigned to a normal control group (group A, n = 6). SAP was induced in group B (n = 9) and C (n = 18), followed by inoculation of the resulting pancreatic necroses with inactive Escherichia coli (E. coli) (group B) and active E. coli (group C), respectively. At 7 d after inoculation, a CT scan and a series of analyses using infecton imaging (at 0.5, 1, 2, 3, 4 and 6 h after the administration of 370 MBq of intravenous infecton) were performed. The scintigrams were visually evaluated and semi-quantitatively analyzed using region of interest assignments. The differences in infecton uptake and changes in the lesion-background radioactive count ratios (L/B) in the 3 groups were recorded and compared. After imaging detection, histopathology and bacterial examinations were performed, and infected SAP was regarded as positive. The imaging findings were compared with histopathological and bacteriological results. RESULTS: In group A, 6 animals survived without infection in the pancreas. In group B, 7/9 swine survived and one suffered from infection. In group C, 15/18 animals survived with infection. Hence, the number of normal, non-infected and infected SAP swine was 6, 6 and 16, respectively. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of the infecton method were 93.8% (15/16), 91.7% (11/12), 92.9% (26/28), 93.8% (15/16) and 91.7% (11/12), whereas these values for CT were 12.5% (2/16), 100.0% (12/12), 50.0% (14/28), 100.0% (2/2) and 46.2% (12/26), respectively. The changes in L/B for the infected SAP were significantly different from those of the non-infected and normal swine (P < 0.001). The mean L/B of the infectious foci at 0.5, 1, 2, 3, 4 and 6 h was 1.17 +/- 0.10, 1.71 +/- 0.30, 2.46 +/- 0.45, 3.36 +/- 0.33, 2.04 +/- 0.37 and 1.1988 +/- 0.09, respectively. At 3 h, the radioactive counts (2350.25 +/- 602.35 k) and the mean L/B of the infectious foci were significantly higher than that at 0.5 h (P = 0.000), 1 h (P = 0.000), 2 h (P = 0.04), 4 h (P = 0.000) and 6 h (P = 0.000). CONCLUSION: (99m)Tc-ciprofloxacin scintigraphy may be an effective procedure for detecting SAP secondary infections with higher sensitivity and accuracy than CT. PMID- 23946595 TI - Pancreatitis in patients with pancreas divisum: imaging features at MRI and MRCP. AB - AIM: To determine the magnetic resonance cholangiopancreatography (MRCP) and magnetic resonance imaging (MRI) features of pancreatitis with pancreas divisum (PD) and the differences vs pancreatitis without divisum. METHODS: Institutional review board approval was obtained and the informed consent requirement was waived for this HIPAA-compliant study. During one year period, 1439 consecutive patients underwent successful MRCP without injection of secretin and abdominal MRI studies for a variety of clinical indications using a 1.5 T magnetic resonance scanner. Two experienced radiologists retrospectively reviewed all the studies in consensus. Disputes were resolved via consultation with a third experienced radiologist. The assessment included presence and the imaging findings of PD, pancreatitis, and distribution of abnormalities. The pancreatitis with divisum constituted the study group while the pancreatitis without divisum served as the control group. MRCP and MRI findings were correlated with final diagnosis. Fisher exact tests and Pearson * 2 tests were performed. RESULTS: Pancreatitis was demonstrated at MRCP and MRI in 173 cases (38 cases with and 135 cases without divisum) among the 1439 consecutive cases. The recurrent acute pancreatitis accounted for 55.26% (21 of 38) in pancreatitis patients associated with PD, which was higher than 6.67% (9 of 135) in the control group, whereas the chronic pancreatitis was a dominant type in the control group (85.19%, 115 of 135) when compared to the study group (42.11%, 16 of 38) (chi(2) = 40.494, P < 0.0001). In cases of pancreatitis with PD, the dorsal pancreatitis accounted for a much higher percentage than that in pancreatitis without PD (17 of 38, 44.74% vs 30 of 135, 22.22%) (chi(2) = 7.257, P < 0.05). CONCLUSION: MRCP and MRI can depict the features of pancreatitis associated with divisum. Recurrent acute pancreatitis and isolated dorsal involvement are more common in patients with divisum. PMID- 23946596 TI - Skp2-RNAi suppresses proliferation and migration of gallbladder carcinoma cells by enhancing p27 expression. AB - AIM: To explore the role of S-phase kinase-associated protein-2 (Skp2) in gallbladder carcinoma and to identify whether depletion of Skp2 by Skp2-RNAi could attenuate proliferation and migration of gallbladder carcinoma. METHODS: Skp2-RNAi was transduced into cells of the gallbladder carcinoma cell line GBC SD, using a lentiviral vector. The effect of Skp2-RNAi on the proliferation, migration, invasion and cell cycle of GBC-SD cells was studied using in vitro assays for cell proliferation, colony formation, wound healing and cell cycle. The expression of Skp2 and p27 was detected by real-time polymerase chain reaction and Western immunoblotting. The effect of Skp2-RNAi on the proliferation of GBC-SD cells in vivo was investigated by tumorigenicity experiments in nude mice. RESULTS: Lentivirus-mediated RNAi reduced the expression of Skp2 in cultured cells. The expression of the p27 protein increased along with the down regulation of Skp2, although no significant difference was found in p27 mRNA expression. Flow cytometry revealed that Skp2-RNAi transfection significantly increased the proportion of cells in the S phase and significantly decreased the proportion of cells in the G2/M phase. No significant difference in the frequency of cells in the G0/G1 phase was observed. The results from the cell proliferation, colony formation and wound healing assays revealed that Skp2-RNAi transfection markedly inhibited the proliferation and migration of GBC-SD cells in vitro. Additionally, tumorigenicity experiments showed that suppression of Skp2 significantly decreased the weights of the tumors (0.56 +/- 0.11 and 0.55 +/ 0.07 g in the control and Scr-RNAi groups vs 0.37 +/- 0.09 and 0.35 +/- 0.08 g in the Skp2-RNAi-L and Skp2-RNAi-H groups). CONCLUSION: The expression of Skp2 in GBC-SD cells was inhibited following Skp2-RNAi transfection. Silencing of the Skp2 gene inhibited proliferation, migration and invasiveness of GBC-SD cells by mechanisms dependent on enhanced expression of the p27 protein. PMID- 23946597 TI - Tumor necrosis factor-alpha mediates JNK activation response to intestinal ischemia-reperfusion injury. AB - AIM: To investigate whether tumor necrosis factor-alpha (TNF-alpha) mediates ischemia-reperfusion (I/R)-induced intestinal mucosal injury through c-Jun N terminal kinase (JNK) activation. METHODS: In this study, intestinal I/R was induced by 60-min occlusion of the superior mesenteric artery in rats followed by 60-min reperfusion, and the rats were pretreated with a TNF-alpha inhibitor, pentoxifylline, or the TNF-alpha antibody infliximab. After surgery, part of the intestine was collected for histological analysis. The mucosal layer was harvested for RNA and protein extraction, which were used for further real-time polymerase chain reaction, enzyme-linked immunosorbent assay and Western blotting analyses. The TNF-alpha expression, intestinal mucosal injury, cell apoptosis, activation of apoptotic protein and JNK signaling pathway were analyzed. RESULTS: I/R significantly enhanced expression of mucosal TNF-alpha at both the mRNA and protein levels, induced severe mucosal injury and cell apoptosis, activated caspase-9/caspase-3, and activated the JNK signaling pathway. Pretreatment with pentoxifylline markedly downregulated TNF-alpha at both the mRNA and protein levels, whereas infliximab pretreatment did not affect the expression of TNF alpha induced by I/R. However, pretreatment with pentoxifylline or infliximab dramatically suppressed I/R-induced mucosal injury and cell apoptosis and significantly inhibited the activation of caspase-9/3 and JNK signaling. CONCLUSION: The results indicate there was a TNF-alpha-mediated JNK activation response to intestinal I/R injury. PMID- 23946598 TI - Analysis of single nucleotide polymorphisms in the region of CLDN2-MORC4 in relation to inflammatory bowel disease. AB - AIM: To investigate a possible genetic influence of claudin (CLDN)1, CLDN2 and CLDN4 in the etiology of inflammatory bowel disease. METHODS: Allelic association between genetic regions of CLDN1, CLDN2 or CLDN4 and patients with inflammatory bowel disease, Crohn's disease (CD) or ulcerative colitis were investigated using both a case-control study approach (one case randomly selected from each of 191 Swedish inflammatory bowel disease families and 333 controls) and a family-based study (463 non-Swedish European inflammatory bowel disease -families). A nonsynonymous coding single nucleotide polymorphism in MORC4, located on the same linkage block as CLDN2, was investigated for association, as were two novel CLDN2 single nucleotide polymorphism markers, identified by resequencing. RESULTS: A single nucleotide polymorphism marker (rs12014762) located in the genetic region of CLDN2 was significantly associated to CD (case-control allelic OR = 1.98, 95%CI: 1.17-3.35, P = 0.007). MORC4 was present on the same linkage block as this CD marker. Using the case-control approach, a significant association (case control allelic OR = 1.61, 95%CI: 1.08-2.41, P = 0.018) was found between CD and a nonsynonymous coding single nucleotide polymorphism (rs6622126) in MORC4. The association between the CLDN2 marker and CD was not replicated in the family based study. Ulcerative colitis was not associated to any of the single nucleotide polymorphism markers. CONCLUSION: These findings suggest that a variant of the CLDN2-MORC4 region predisposes to CD in a Swedish population. PMID- 23946599 TI - Treatment of hemorrhagic radiation-induced proctopathy with a 4% formalin application under perianal anesthetic infiltration. AB - AIM: To evaluate the results of hemorrhagic radiation proctopathy treatment with a 4% formalin application. METHODS: A prospective study was performed. Over a three-year period, 38 patients underwent 4% formalin application under perianal anesthetic infiltration for hemorrhagic radiation proctopathy. All patients included in the study were irradiated for prostate cancer. The patients ranged in age from 56-77 years (average 70 +/- 5 years). All of the patients were referred for formalin therapy after noninvasive management had failed. Twenty-four (63.2%) patients underwent a single application, 10 (26.3%) patients underwent 2 applications, and 4 (10.5%) patients underwent 3 applications. RESULTS: Two to 36 mo (average 12 +/- 3 mo) following treatment, 34 patients were interviewed (four were lost to follow-up). Twenty (58.8%) subjects reported complete cure, 8 (23.5%) subjects reported significant improvement, and 6 (17.7%) subjects reported no change. One patient (who underwent a colostomy at a regional hospital with no specialized services available for previous bleeding episodes from radiation proctopathy) was cured, and the colostomy was closed. One patient (2.6%) developed rectal mucosal damage after the second application. CONCLUSION: A 4-min application of 4% formalin for hemorrhagic radiation-induced proctopathy under perianal anesthetic infiltration in patients who have received external radial radiation therapy for prostate cancer is simple, reasonably safe, inexpensive, generally well tolerated, and effective. PMID- 23946600 TI - Validation of the chronic liver disease questionnaire in Serbian patients. AB - AIM: To translate into Serbian and to investigate the validity of the cross culturally adapted the chronic liver disease questionnaire (CLDQ). METHODS: The questionnaire was validated in 103 consecutive CLD patients treated between October 2009 and October 2010 at the Clinic for Gastroenterology, Clinical Centre of Serbia, Belgrade (Serbia). Exclusion criteria were: age < 18 years, psychiatric disorders, acute complications of CLD (acute liver failure, variceal bleeding, and spontaneous bacterial peritonitis), hepatic encephalopathy (grade > 2) and liver transplantation. Evaluation of the CLDQ was done based on the following parameters: (1) acceptance is shown by the proportion of missing items; (2) internal reliabilities were assessed for multiple item scales by using Cronbach alpha coefficient; and (3) in order to assess whether the allocation of items in the domain corresponds to their distribution in the original questionnaire (construction validity), an exploratory factor analysis was conducted. Discriminatory validity was determined by comparing the corresponding CLDQ score/sub-score in patients with different severity of the diseases. RESULTS: The Serbian version of CLDQ questionnaire completed 98% patients. Proportion of missing items was 0.06%. The total time needed to fill the questionnaire was ranged from 8 to 15 min. Assistance in completing the questionnaire required 4.8% patients, while 2.9% needed help in reading, and 1.9% involved writing assistance. The mean age of the selected patients was 53.8 +/- 12.9 years and 54.4% were men. Average CLDQ score was 4.62 +/- 1.11. Cronbach's alpha for the whole scale was 0.93. Reliability for all domains was above 0.70, except for the domain "Activity" (0.49). The exploratory factor analysis model revealed 6 factors with eigenvalue of greater than 1, explaining 69.7% of cumulative variance. The majority of the items (66%) in the Serbian version of the CLDQ presented the highest loading weight in the domain assigned by the CLDQ developers: "Fatigue" (5/5), "Emotional function" (6/8), "Worry" (5/5), "Abdominal symptoms" (0/3), "Activity" (0/3), "Systemic symptoms" (3/5). The scales "Fatigue" and "Worry" fully corresponded to the original. The factor analysis also revealed that the factors "Activity" and "Abdominal symptoms" could not be replicated, and two new domains "Sleep" and "Nutrition" were established. Analysis of the CLDQ score/sub-score distribution according to disease severity demonstrated that patients without cirrhosis had lower total CLDQ score (4.86 +/- 1.05) than those with cirrhosis Child's C (4.31 +/- 0.97). Statistically significant difference was detected for the domains "Abdominal symptoms" [F (3) = 5.818, P = 0.001] and "Fatigue" [F (3) = 3.39, P = 0.021]. Post hoc analysis revealed that patients with liver cirrhosis Child's C had significantly lower sub score "Abdominal symptoms" than patients without cirrhosis or liver cirrhosis Child's A or B. For domain "Fatigue", patients with cirrhosis Child's C had significantly lower score, than non-cirrhotic patients. CONCLUSION: The Serbian version of CLDQ is well accepted and represents a valid and reliable instrument in Serbian sample of CLD patients. PMID- 23946601 TI - Low-dose amitriptyline combined with proton pump inhibitor for functional chest pain. AB - AIM: To investigate the efficacy of amitriptyline with proton pump inhibitor (PPI) for the treatment of functional chest pain (FCP). METHODS: This was a randomized, open-label trial investigating the addition of low dose amitriptyline (10 mg at bedtime) to a conventional dose of rabeprazole (20 mg/d) (group A, n = 20) vs a double-dose of rabeprazole (20 mg twice daily) (group B, n = 20) for patients with FCP whose symptoms were refractory to PPI. The primary efficacy endpoints were assessed by global symptom score assessment and the total number of individuals with > 50% improvement in their symptom score. RESULTS: The between-group difference in global symptom scores was statistically significant during the last week of treatment (overall mean difference; 3.75 +/- 0.31 vs 4.35 +/- 0.29, the between-group difference; P < 0.001). Furthermore, 70.6% of patients in group A had their symptoms improve by > 50%, whereas only 26.3% of patients in group B had a similar treatment response (70.6% vs 26.3%, P = 0.008). Specifically, patients in group A had a significantly greater improvement in the domains of body pain and general health perception than did patients in group B (52.37 +/- 17.00 vs 41.32 +/- 12.34, P = 0.031 and 47.95 +/- 18.58 vs 31.84 +/- 16.84, P = 0.01, respectively). CONCLUSION: Adding amitriptyline to a PPI was more effective than a double-dose of PPI in patients with FCP refractory to a conventional dose of PPI. PMID- 23946602 TI - Residual common bile duct stones on direct peroral cholangioscopy using ultraslim endoscope. AB - AIM: To detect and manage residual common bile duct (CBD) stones using ultraslim endoscopic peroral cholangioscopy (POC) after a negative balloon-occluded cholangiography. METHODS: From March 2011 to December 2011, a cohort of 22 patients with CBD stones who underwent both endoscopic retrograde cholangiography (ERC) and direct POC were prospectively enrolled in this study. Those patients who were younger than 20 years of age, pregnant, critically ill, or unable to provide informed consent for direct POC, as well as those with concomitant gallbladder stones or CBD with diameters less than 10 mm were excluded. Direct POC using an ultraslim endoscope with an overtube balloon-assisted technique was carried out immediately after a negative balloon-occluded cholangiography was obtained. RESULTS: The ultraslim endoscope was able to be advanced to the hepatic hilum or the intrahepatic bile duct (IHD) in 8 patients (36.4%), to the extrahepatic bile duct where the hilum could be visualized in 10 patients (45.5%), and to the distal CBD where the hilum could not be visualized in 4 patients (18.2%). The procedure time of the diagnostic POC was 8.2 +/- 2.9 min (range, 5-18 min). Residual CBD stones were found in 5 (22.7%) of the patients. There was one residual stone each in 3 of the patients, three in 1 patient, and more than five in 1 patient. The diameter of the residual stones ranged from 2-5 mm. In 2 of the patients, the residual stones were successfully extracted using either a retrieval balloon catheter (n = 1) or a basket catheter (n = 1) under direct endoscopic control. In the remaining 3 patients, the residual stones were removed using an irrigation and suction method under direct endoscopic visualization. There were no serious procedure-related complications, such as bleeding, pancreatitis, biliary tract infection, or perforation, in this study. CONCLUSION: Direct POC using an ultraslim endoscope appears to be a useful tool for both detecting and treating residual CBD stones after conventional ERC. PMID- 23946603 TI - A systematic analysis of pneumatosis cystoids intestinalis. AB - AIM: To increase the understanding, diagnosis and treatment of pneumatosis cystoides intestinalis (PCI) and to find the characteristics and potential cause of the disease in China. METHODS: We report here one case of PCI in a 70-year-old male patient who received a variety of treatment methods. Then, we systematically searched the PCI eligible literature published from an available Chinese database from May 2002 to May 2012, including CBM, CBMDisc, CMCC, VIP, Wanfang, and CNKI. The key words were pneumatosis cystoides intestinalis, pneumatosis, pneumatosis intestinalis, pneumatosis coli and mucosal gas. The patients' information, histories, therapies, courses, and outcomes were reviewed. RESULTS: The study group consisted of 239 PCI cases (male:female = 2.4:1) from 77 reported incidents. The mean age was 45.3 +/- 15.6 years, and the median illness course was 6 mo. One hundred and sixty patients (66.9%) were in high altitude areas. In addition, 43.5% (104/239) of the patients had potential PCI-related disease, and 16.3% had complications with intestinal obstruction and perforation. The most common symptom was abdominal pain (53.9%), followed by diarrhea (53.0%), distention (42.4%), nausea and vomiting (14.3%), bloody stool (12.9%), mucous stool (12.0%) and constipation (7.8%). Most multiple pneumocysts developed in the submucosa of the colon (69.9%). The efficacy of the treatments by combined modalities, surgery, endoscopic treatment, conservative approach, oxygen, and antibiotics were 100%, 100%, 100%, 93.3%, 68.3% and 26.3%, respectively. CONCLUSION: PCI can be safely managed by conservative treatments, presents more frequently in males, in the large bowel and submucosa, than in females, in the small intestine and subserosa. High altitude residence maybe associated with the PCI etiology. PMID- 23946604 TI - Appropriate treatment of acute sigmoid volvulus in the emergency setting. AB - AIM: To investigate an appropriate strategy for the treatment of patients with acute sigmoid volvulus in the emergency setting. METHODS: A retrospective review of 28 patients with acute sigmoid volvulus treated in the Department of Colorectal Surgery, Changhai Hospital, Shanghai from January 2001 to July 2012 was performed. Following the diagnosis of acute sigmoid volvulus, an initial colonoscopic approach was adopted if there was no evidence of diffuse peritonitis. RESULTS: Of the 28 patients with acute sigmoid volvulus, 19 (67.9%) were male and 9 (32.1%) were female. Their mean age was 63.1 +/- 22.9 years (range, 21-93 years). Six (21.4%) patients had a history of abdominal surgery, and 17 (60.7%) patients had a history of constipation. Abdominal radiography or computed tomography was performed in all patients. Colonoscopic detorsion was performed in all 28 patients with a success rate of 92.8% (26/28). Emergency surgery was required in the other two patients. Of the 26 successfully treated patients, seven (26.9%) had recurrent volvulus. CONCLUSION: Colonoscopy is the primary emergency treatment of choice in uncomplicated acute sigmoid volvulus. Emergency surgery is only for patients in whom nonoperative treatment is unsuccessful, or in those with peritonitis. PMID- 23946605 TI - Prevalence of minimal hepatic encephalopathy and quality of life evaluations in hospitalized cirrhotic patients in China. AB - AIM: To investigate the prevalence of minimal hepatic encephalopathy (MHE) and to assess corresponding health-related quality of life (HRQoL) in hospitalized cirrhotic patients in China. METHODS: This multi-center cross-sectional study included 16 teaching hospitals, which were members of "Hepatobiliary Cooperation Group, Society of Gastroenterology, Chinese Medical Association", from different areas of China carried out between June and October in 2011. All the eligible hospitalized cirrhotic patients (n = 538) were required to complete triplicate number connection tests combined with one digit symbol test for diagnosing MHE. Patients' clinical examination data were complemented by a modified questionnaire assessing HRQoL. Written informed consent was obtained from each patient. RESULTS: Male was predominant (68.6%) in 519 patients who met the criteria of the study, with a mean age of 49.17 +/- 11.02 years. The most common cause of liver cirrhosis was chronic hepatitis B (55.9%). The prevalence of MHE was 39.9% and varied by Child-Pugh-Classification score (CPC-A: 24.8%, CPC-B: 39.4% and CPC-C: 56.1%, P < 0.01). MHE (P < 0.01) and higher CPC scores (P < 0.01) were associated with a high HRQoL scores (reflecting poorer quality of life). The prevalence of MHE was proportionate to CPC (P = 0.01) and high quality of life scores (P = 0.01). CONCLUSION: Hospitalized cirrhotic patients have a high prevalence of MHE that is proportionate to the degree of liver function and HRQoL impairment. PMID- 23946606 TI - Laparoscopic splenic hilum lymph node dissection for advanced proximal gastric cancer: a modified approach for pancreas- and spleen-preserving total gastrectomy. AB - AIM: To investigate the feasibility and optimal approach for laparoscopic pancreas- and spleen-preserving splenic hilum lymph node dissection in advanced proximal gastric cancer. METHODS: Between August 2009 and August 2012, 12 patients with advanced proximal gastric cancer treated in Nanfang Hospital, Southern Medical University, Guangzhou, China were enrolled and subsequently underwent laparoscopic total gastrectomy with pancreas- and spleen-preserving splenic hilum lymph node (LN) dissection. The clinicopathological characteristics, surgical outcomes, postoperative course and follow-up data of these patients were retrospectively collected and analyzed in the study. RESULTS: Based on our anatomical understanding of peripancreatic structures, we combined the characteristics of laparoscopic surgery and developed a modified approach (combined supra- and infra-pancreatic approaches) for laparoscopic pancreas- and spleen-preserving splenic hilum LN dissection. Surgery was completed in all 12 patients laparoscopically without conversion. Only one patient experienced intraoperative bleeding when dissecting LNs along the splenic artery and was handled with laparoscopic hemostasis. The mean operating time was 268.4 min and mean number of retrieved splenic hilum LNs was 4.8. One patient had splenic hilum LN metastasis (8.3%). Neither postoperative morbidity nor mortality was observed. Peritoneal metastasis occurred in one patient and none of the other patients died or experienced recurrent disease during the follow-up period. CONCLUSION: Laparoscopic total gastrectomy with pancreas- and spleen-preserving splenic hilum LN dissection using the modified approach for advanced proximal gastric cancer could be safely achieved. PMID- 23946607 TI - Stent-grafts for the treatment of TIPS dysfunction: fluency stent vs Wallgraft stent. AB - AIM: To evaluate the clinical efficacy of an expanded polytetrafluoro-ethylene covered Fluency stent compared with that of a polyethylene terephthalate-covered Wallgraft stent for the management of transjugular intrahepatic portosystemic shunt (TIPS) dysfunction. METHODS: A retrospective review of patients who underwent TIPS revision with stent-grafts between May 2007 and June 2011 was conducted. The patients were divided into two groups according to the stent grafts implanted: the Fluency stent (Bard Incorporated, Karlsruhe, Germany) and the Wallgraft stent (Boston Scientific, Galway, Ireland). The primary patency rates were calculated and compared using the Kaplan-Meier method. RESULTS: A total of 73 patients were evaluated in this study: 33 with Fluency stents and 40 with Wallgraft stents. The primary patency rates at 12 and 24 mo were 91% and 85%, respectively, in the Fluency stent group and 78% and 63%, respectively, in the Wallgraft stent group. The primary shunt patency rates after TIPS revision were significantly better with the Fluency stent than with the Wallgraft stent (P = 0.033). CONCLUSION: TIPS revision with the Fluency stent has higher medium-term patency rates than that with the Wallgraft stent. PMID- 23946608 TI - Predicting a novel pathogenicity island in Helicobacter pylori by genomic barcoding. AB - AIM: To apply a new, integrated technique for visualizing bacterial genomes to identify novel pathogenicity islands in Helicobacter pylori (H. pylori). METHODS: A genomic barcode imaging method (converting frequency matrices to grey-scale levels) was designed to visually distinguish origin-specific genomic regions in H. pylori. The complete genome sequences of the six H. pylori strains published in the National Center for Biotechnological Information prokaryotic genome database were scanned, and compared to the genome barcodes of Escherichia coli (E. coli) O157:H7 strain EDL933 and a random nucleotide sequence. The following criteria were applied to identify potential pathogenicity islands (PAIs): (1) barcode distance distinct from that of the general background; (2) length greater than 10000 continuous base pairs; and (3) containing genes with known virulence related functions (as determined by PfamScan and Blast2GO). RESULTS: Comparison of the barcode images generated for the 26695, HPAG1, J99, Shi470, G27 and P12 H. pylori genomes with those for the E. coli and random sequence controls revealed that H. pylori genomes contained fewer anomalous regions. Among the H. pylori specific continuous anomalous regions (longer than 20 kbp in each strain's genome), two fit the criteria for identifying candidate PAIs. The bioinformatic based functional analyses revealed that one of the two anomalous regions was the known pathogenicity island cag-PAI, this finding also served as proof-of principle for the utility of the genomic barcoding approach for identifying PAIs, and characterized the other as a novel PAI, which was designated as tfs3-PAI. Furthermore, the cag-PAI and tfs3-PAI harbored genes encoding type IV secretion system proteins and were predicted to have potential for functional synergy. CONCLUSION: Genomic barcode imaging represents an effective bioinformatic-based approach for scanning bacterial genomes, such as H. pylori, to identify candidate PAIs. PMID- 23946609 TI - Milligan-Morgan hemorrhoidectomy with anal cushion suspension and partial internal sphincter resection for circumferential mixed hemorrhoids. AB - AIM: To identify a more effective treatment protocol for circumferential mixed hemorrhoids. METHODS: A total of 192 patients with circumferential mixed hemorrhoids were randomized into the treatment group, where they underwent Milligan-Morgan hemorrhoidectomy with anal cushion suspension and partial internal sphincter resection, or the control group, where traditional external dissection and internal ligation were performed. Postoperative recovery and complications were monitored. RESULTS: The time to wound healing was 12.96 +/- 2.25 d in the treatment group shorter than 19.58 +/- 2.71 d in the control group. Slight pain rate was 58.3% in the treatment group higher than 22.9% in the control group; moderate pain rate was 33.3% in the treatment group lower than 56.3% in the control group severe pain rate was 8.4% in the treatment group lower than 20.8% in the control group. No edema rate was 70.8% in the treatment group higher than 43.8% in the control group; mild local edema rate was 26% in the treatment group lower than 39.6% in the control group obvious local edema was 3.03% in the treatment group lower than 16.7% in the control group. No stenosis rate was 85.4% in the treatment group higher than 63.5% in the control group; moderate stenosis rate was 14.6% in the treatment group Lower than 27.1% in the control group severe anal stenosis rate was 0% in the treatment group lower than 9.4% in the control group. CONCLUSION: Milligan-Morgan hemorrhoidectomy with anal cushion suspension and partial internal sphincter resection is the optimal treatment for circumferential mixed hemorrhoids and can be widely applied in clinical settings. PMID- 23946610 TI - Bone metastasis from early gastric cancer following non-curative endoscopic submucosal dissection. AB - A 67-year-old male underwent endoscopic submucosal dissection (ESD) to treat early gastric cancer (EGC) in 2001. The lesion (50 mm * 25 mm diameter) was histologically diagnosed as poorly differentiated adenocarcinoma, with an ulcer finding. Although the tumor was confined to the mucosa with no evidence of lymphovascular involvement, the ESD was regarded as a non-curative resection due to the histological type, tumor size, and existence of an ulcer finding (as indicated by the 2010 Japanese gastric cancer treatment guidelines, ver. 3). Despite strong recommendation for subsequent gastrectomy, the patient refused surgery. An alternative follow-up routine was designed, which included five years of biannual clinical examinations to detect and measure serum tumor markers and perform visual assessment of recurrence by endoscopy and computed tomography scan after which the examinations were performed annually. The patient's condition remained stable for eight years, until a complaint of back pain in 2010 prompted further clinical investigation. Bone scintigraphy indicated increased uptake. Histological examination of biopsy specimens taken from the lumbar spine revealed adenocarcinoma resembling the carcinoma cells from the EGC that had been treated previously by ESD, and which was consistent with immunohistochemical findings of gastrointestinal tract cancer. Thus, the diagnosis of bone metastasis from EGC was made. The reported rates of EGC recurrence in surgically resected cases range 1.4%-3.4%, but among these bone metastasis is very rare. To our knowledge, this is the first reported case of bone metastasis from EGC following a non-curative ESD and occurring after an eight-year disease-free interval. PMID- 23946611 TI - Mucocele of the appendix due to endometriosis: a rare case report. AB - Mucocele of the appendix due to endometriosis is extremely rare, and there are only 10 previously reported cases in the English literature. We report a case of mucocele of the appendix due to endometriosis and provide the first review of the literature. A 43-year-old woman was admitted to the hospital because of recurrent right lower abdominal pain during her menstrual periods. Colonoscopy revealed submucosal tumor-like elevations of the appendiceal orifice. Computed tomography and magnetic resonance imaging of the abdomen suggested cystic lesions near the appendix. Consequently, mucocele of the appendix was suspected preoperatively. An open ileocecal resection was performed. Multiple cystic lesions were observed around the appendix. The cystic lesions contained mucus. Histopathological examination was consistent with a mucocele of the appendix due to endometriosis. The postoperative course was uneventful. We present the first review of the literature to clarify the clinical features. PMID- 23946613 TI - WAVELET-BASED BAYESIAN ESTIMATION OF PARTIALLY LINEAR REGRESSION MODELSWITH LONG MEMORY ERRORS. AB - In this paper we focus on partially linear regression models with long memory errors, and propose a wavelet-based Bayesian procedure that allows the simultaneous estimation of the model parameters and the nonparametric part of the model. Employing discrete wavelet transforms is crucial in order to simplify the dense variance-covariance matrix of the long memory error. We achieve a fully Bayesian inference by adopting a Metropolis algorithm within a Gibbs sampler. We evaluate the performances of the proposed method on simulated data. In addition, we present an application to Northern hemisphere temperature data, a benchmark in the long memory literature. PMID- 23946612 TI - Anticoagulation and delayed bowel resection in the management of mesenteric venous thrombosis. AB - Acute mesenteric venous thrombosis is potentially lethal because it can result in mesenteric ischemia and, ultimately, bowel infarction requiring surgical intervention. Systemic anticoagulation for the prevention of thrombus propagation is a well-recognized treatment modality and the current mainstay therapy for patients with acute mesenteric venous thrombosis. However, the decision between prompt surgical exploration vs conservative treatment with anticoagulation is somewhat difficult in patients with suspected bowel ischemia. Here we describe a patient with acute mesenteric venous thrombosis who presented with bowel ischemia and was treated with anticoagulation and delayed short-segment bowel resection. PMID- 23946614 TI - Financial Decision Making and the Aging Brain. PMID- 23946615 TI - FDA pushes plans for drug compounding: more scrutiny for hospital pharmacies. AB - FDA pushes plans for drug compounding. PMID- 23946617 TI - Pharmaceutical approval update. AB - Dimethyl fumarate capsules (Tecfidera) for multiple sclerosis, ado-trastuzumab emtansine injection (Kadcyla) for HER-2-positive breast cancer, and ospemifene tablets (Osphena) for painful intercourse in postmenopausal women. PMID- 23946616 TI - Improved safety needed in handling elastomeric reservoir balls used for pain relief. AB - Potential problems with pain pumps. PMID- 23946618 TI - New medical devices. AB - FDA approvals, drug indications, and updates. PMID- 23946619 TI - FDA strategies to prevent and respond to drug shortages: finding a better way to predict and prevent company closures. AB - To stave off a shortage of doxorubicin in 2011 and 2012, the FDA expedited the approval of a company's unapproved manufacturing process. Paying companies sufficiently so that they can invest in their facilities when needed is just one of many steps that could be taken to rectify future shortages. PMID- 23946620 TI - Biosimilars: part 1: proposed regulatory criteria for FDA approval. AB - Biosimilars, although not identical to their originator product, are expected to become essential in reducing health care costs and improving access to lifesaving drugs. The FDA must find a way to balance rigorous testing to ensure quality, as is done for generic chemical drugs, with providing a cost-efficient way to expedite approvals of these products. PMID- 23946621 TI - Comparison of adverse events and hospital length of stay associated with various amphotericin B formulations: sequential conventional amphotericin b/lipid versus lipid-only therapy for the treatment of invasive fungal infections in hospitalized patients. AB - PURPOSE: Patients with invasive fungal infections are often treated initially with conventional amphotericin B deoxycholate (CAB), followed by a switch to lipid-based formulations of amphotericin B (LF-AMB). Our study examined adverse events and hospital length of stay (LOS) among adults who received LF-AMB exclusively or CAB followed by LF-AMB (CAB/LF-AMB). METHODS: Data were extracted from the Cerner Health Facts database. The study included adults with evidence of infection by Aspergillus, Candida, or Cryptococcus in addition to either renal insufficiency, a clinical condition suggesting intolerance to CAB, or CAB exposure within 90 days of admission. Nephrotoxicity was defined as a serum creatinine (SCr) level exceeding a 100% increase from baseline and an absolute level above 1.2 mg/dL. We used a hierarchical mixed-effect logistic regression model with nephrotoxicity as the outcome for the multivariate analysis. RESULTS: The study included 327 LF-AMB and 81 CAB/LF-AMB patients with similar demographics and baseline SCr values. The mean pre-to-post percentage increase in SCr levels was greater for CAB/LF-AMB (122.9%) compared with LF-AMB (62.2%) (P < 0.001). The multivariate-adjusted odds ratio of nephrotoxicity was 5.93, for a 95% confidence interval of 2.92 to 12.05 (P < 0.001) for CAB/LF-AMB compared with LF-AMB. Hypokalemia, hypomagnesemia, and infusion-related reactions were more frequent with CAB/LF-AMB. Compared with the LF-AMB group, the CAB/LF-AMB patients had a longer post-amphotericin B LOS (24.1 days vs. 15.7 days, respectively; P < 0.001), with a marginal effect of 4.5 days longer for those receiving CAB/LF-AMB (P = 0.016). CONCLUSION: In this retrospective study, we noted a significantly longer post-amphotericin B LOS and a greater frequency of adverse events, including nephrotoxicity, for patients whose initial treatment was CAB and who were switched to LF-AMB, compared with patients who received LF-AMB only. PMID- 23946622 TI - American academy of dermatology cardiovascular research technologies 2013 american college of cardiology. AB - Dermatology topics include agents for psoriasis, urticaria, and infantile hemangiomas. The pros and cons of antiplatelet drugs prasugrel (Effient) and ticagrelor (Brilinta) are discussed, and an investigational agent, cangrelor, shows promise in reducing ischemic events when compared with clopidogrel (Plavix). PMID- 23946623 TI - Multiple brand names for the same generic drug can cause confusion. AB - Generic drugs with multiple brand names can cause confusion. PMID- 23946624 TI - Medicare changes include new part d rules and possible cuts to hospitals. AB - New medicare Part D rules and possible cuts to hospitals. PMID- 23946625 TI - New drugs/drug news. AB - FDA approvals, drug indications, and updates. PMID- 23946626 TI - Pharmaceutical approval update. AB - Extended-release carbinoxamine maleate oral suspension (Karbinaler) for allergicrhinitis; brinzolamide 1.0%/brimonidine tartrate 0.2% ophthalmic suspension (simbrinza) for open-angle glaucoma and ocular hypertension; and cysteamine bitartrate (Procysbi) for nephropathic cystinosis. PMID- 23946627 TI - Nuedexta for the treatment of pseudobulbar affect: a condition of involuntary crying or laughing. AB - Dextromethorphan/quinidine (nuedexta) for pseudobulbar affect. PMID- 23946628 TI - Biosimilars: part 2: potential concerns and challenges for p&t committees. AB - P&T committee members need a lot more information before they can evaluate the efficacy and safety, interchangeability, and cost-effectiveness of biosimilar products for inclusion on formularies. PMID- 23946629 TI - Polycystic ovary syndrome: a review of treatment options with a focus on pharmacological approaches. AB - Oral contraceptives, antidiabetes drugs, and statins are some of the therapies used to address the symptoms of this complex hormonal condition. Weight loss and surgery may also be beneficial as non-drug options. PMID- 23946630 TI - Drug-induced pancreatitis: A Potentially Serious and Underreported Problem. AB - There have been many published reports of possible cases of drug-induced pancreatitis. In addition, some disease states and patient characteristics predispose particular populations to the development of this condition. Three case histories are presented. PMID- 23946631 TI - 48th European association for the study of the liver: the international liver congress and american association for cancer research. PMID- 23946632 TI - Speech-Breathing Treatment and LSVT for a Patient With Hypokinetic-Spastic Dysarthria After TBI. AB - Previously, we reported improved speech breathing and intelligibility after behavioral treatment for a man with hypokinetic-spastic dysarthria following traumatic brain injury (TBI) (Solomon, McKee, & Garcia-Barry, 2001). Treatment included the Lee Silverman Voice Treatment(r) (LSVT) program followed by 6 weeks of speech-breathing training, physical therapy, and LSVT-type tasks. In this article, we report a new patient with similar speech characteristics post-TBI. Breathing-for-Speech Treatment (BST), custom designed to improve nonspeech- and speech-breathing coordination, was followed by LSVT. After BST, speech breathing approached normal levels; after LSVT, speech breathing improved further and intelligibility improved markedly. Gains generally were maintained up to 4 months, but were limited by the spastic characteristics of his dysarthria and sporadic medical complications. PMID- 23946633 TI - Identification of HMX1 target genes: a predictive promoter model approach. AB - PURPOSE: A homozygous mutation in the H6 family homeobox 1 (HMX1) gene is responsible for a new oculoauricular defect leading to eye and auricular developmental abnormalities as well as early retinal degeneration (MIM 612109). However, the HMX1 pathway remains poorly understood, and in the first approach to better understand the pathway's function, we sought to identify the target genes. METHODS: We developed a predictive promoter model (PPM) approach using a comparative transcriptomic analysis in the retina at P15 of a mouse model lacking functional Hmx1 (dmbo mouse) and its respective wild-type. This PPM was based on the hypothesis that HMX1 binding site (HMX1-BS) clusters should be more represented in promoters of HMX1 target genes. The most differentially expressed genes in the microarray experiment that contained HMX1-BS clusters were used to generate the PPM, which was then statistically validated. Finally, we developed two genome-wide target prediction methods: one that focused on conserving PPM features in human and mouse and one that was based on the co-occurrence of HMX1 BS pairs fitting the PPM, in human or in mouse, independently. RESULTS: The PPM construction revealed that sarcoglycan, gamma (35kDa dystrophin-associated glycoprotein) (Sgcg), teashirt zinc finger homeobox 2 (Tshz2), and solute carrier family 6 (neurotransmitter transporter, glycine) (Slc6a9) genes represented Hmx1 targets in the mouse retina at P15. Moreover, the genome-wide target prediction revealed that mouse genes belonging to the retinal axon guidance pathway were targeted by Hmx1. Expression of these three genes was experimentally validated using a quantitative reverse transcription PCR approach. The inhibitory activity of Hmx1 on Sgcg, as well as protein tyrosine phosphatase, receptor type, O (Ptpro) and Sema3f, two targets identified by the PPM, were validated with luciferase assay. CONCLUSIONS: Gene expression analysis between wild-type and dmbo mice allowed us to develop a PPM that identified the first target genes of Hmx1. PMID- 23946634 TI - All-trans retinoic acid modulates mitogen-activated protein kinase pathway activation in human scleral fibroblasts through retinoic acid receptor beta. AB - PURPOSE: All-trans retinoic acid (ATRA) is known to inhibit the proliferation of human scleral fibroblasts (HSFs) and to modulate the scleral intercellular matrix composition, and may therefore serve as a mediator for controlling eye growth. Cell proliferation is regulated by the mitogen-activated protein kinase (MAPK) pathway. The aim of the current study was to investigate whether changed activation of the MAPK pathway could be involved in the response of HSFs exposed to ATRA. METHODS: HSFs were cultured in Dulbecco Modified Eagle's Medium/F12 (DMEM/F12) and exposed to 1 MUmol/l ATRA for 10 min, 30 min, 1 h, 8 h, or 24 h. The activation of extracellular signal-regulated kinase (ERK 1/2), p38, and c-Jun N-terminal kinase (JNK) in HSFs was assessed with western blot analysis and immunocytofluorescence. RESULTS: After exposure to ATRA for 24 h, the HSFs appeared shrunken and thinner than the control cells. The intercellular spaces were wider, and the HSFs appeared less numerous than in the control culture. Western blot showed decreased activation of ERK 1/2 in the HSFs from 30 min (p=0.01) to 24 h (p<0.01) after the start of exposure to ATRA, and increased activation of the JNK protein from 10 to 30 min (p<0.01) after the start of exposure to ATRA. Indirect immunofluorescence confirmed changes in activation of ERK 1/2 and JNK in HSFs exposed to ATRA. No change in activation of p38 in HSFs was observed after exposure to ATRA. Pretreatment of the HSFs with LE135, an antagonist of retinoic acid receptor beta (RARbeta), abolished the ATRA-induced changes inactivation of ERK 1/2 and JNK. CONCLUSIONS: ATRA inhibits HSF proliferation by a mechanism associated with modulation of ERK 1/2 and JNK activation and depends on stimulation of retinoic acid receptor beta. PMID- 23946635 TI - Immune response against ocular tissues after immunization with optic nerve antigens in a model of autoimmune glaucoma. AB - PURPOSE: In recent years, numerous studies have investigated the involvement of immunological mechanisms in glaucoma. Until now, it has not been determined whether the altered antibody pattern detected in patients is harmful to retinal ganglion cells (RGCs) or triggers disease formation in any way. In a model of experimental autoimmune glaucoma, RGC loss can be induced through immunization with certain ocular antigens. In the current study, the time course of the levels of autoreactivity against ocular tissues after immunization was examined. METHODS: Intraocular pressure was measured regularly. Ten weeks after immunization with an optic nerve homogenate antigen (ONA), the number of RGCs was determined. Immunoglobulin G levels in aqueous humor were measured via enzyme linked immunosorbent assay at the same time point. Serum from different time points was used to analyze the possible occurrence of autoreactive antibodies against the retina or optic nerve in this autoimmune glaucoma model. Additionally, optic nerve and brain sections were evaluated for possible pathological findings. RESULTS: Intraocular pressure stayed within the normal range throughout this study. A continuous increase of autoreactive antibodies against the optic nerve and retina sections was observed. At 4, 6, and 10 weeks, antibody reactivity was significantly higher in ONA animals (p<0.01). Aqueous humor immunoglobulin G levels were also significantly higher in the ONA group (p=0.006). Ten weeks after immunization, significantly fewer RGCs were noted in the ONA group (p=0.00003). The optic nerves from ONA animals exhibited damaged axons. No pathological findings appeared in any brain sections. CONCLUSIONS: Our findings suggest that these modified antibodies play a substantial role in mechanisms leading to RGC death. The slow dissolution of RGCs observed in animals with autoimmune glaucoma is comparable to the slow progressive RGC loss in glaucoma patients, thus making this a useful model to develop neuroprotective therapies in the future. PMID- 23946636 TI - MicroRNA profile comparison of the corneal endothelia of young and old mice: implications for senescence of the corneal endothelium. AB - PURPOSE: To identify critical microRNAs (miRNAs) that play important roles in regulating the aging of corneal endothelial cells in mice aged 10-13 weeks and 2 years. METHODS: We collected the corneal endothelia from 30 mice aged 10-13 weeks and 30 mice aged 2 years. The samples were pooled into six groups (Y1, Y2, Y3 and S1, S2, S3). Each group comprised corneal endothelia from 10 mice, and these six groups were used for a genome-wide miRNA microarray study. The expression levels of eight selected miRNAs were further validated independently by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Target genes were predicted using a computational approach due to their base-pairing rules between miRNA and messenger RNA target sites. The locations of binding sequences were within the target's 3' untranslated regions (UTR), and the conservation of target binding sequences occurred within related genomes. Additional gene ontology and signaling pathway analyses were performed using bioinformatics tools. RESULTS: Twenty-seven miRNAs (7 upregulated and 20 downregulated) were found to be differentially expressed (fold change >2, p value <0.05) in the corneal endothelia of adult and old mice. The qRT-PCR results confirmed the differential expression of eight miRNAs between the corneal endothelia of adult and old mice. A computational approach demonstrated that the target genes of the differentially expressed miRNAs might be involved in several signaling pathways, including the glutamatergic synapse pathway (p=0.000313), the phosphatidylinositol signaling pathway (p=0.00197), the neurotrophin signaling pathway (p=0.00687), the transforming growth factor-beta signaling pathway (p=0.0143), and oxidative phosphorylation (p=0.0223). CONCLUSIONS: Our study identified miRNAs that are differentially expressed in the corneal endothelium during aging for the first time. We also identified fluctuations in the expression of these specific miRNAs that may be related to age-specific changes. Understanding miRNA expression and interactions in tissues such as the cornea may aid in the understanding of the basic and pathophysiological processes of age-related ocular pathologies. PMID- 23946637 TI - Increase in peripheral blood mononuclear cell Toll-like receptor 2/3 expression and reactivity to their ligands in a cohort of patients with wet age-related macular degeneration. AB - PURPOSE: To investigate Toll-like receptor (TLR) expression and reactivity in patients with the wet form age-related macular degeneration (AMD). METHODS: Blood samples were collected from 25 patients with wet AMD and 25 age-matched healthy controls. Peripheral blood mononuclear cells (PBMCs) were isolated with Ficoll Hypaque density gradient centrifugation. Expression of TLR1 to TLR10 mRNAs in PBMCs from 15 patients with wet AMD and 15 controls was assessed with real-time PCR. TLR2 and TLR3 protein levels in PBMCs from six patients with wet AMD and six controls were measured with flow cytometry. After PBMCs were stimulated with peptidoglycan (PGN) and poly(I:C), the specific ligands of TLR2 and TLR3, cytokines interleukin-6 (IL-6), IL-8, VEGF, and monocyte chemoattractant protein 1 (MCP-1) production in 11 patients with wet AMD and 11 controls were assessed. RESULTS: TLR2 and TLR3 mRNA and protein expression in the PBMCs of the patients with wet AMD was significantly higher than that in the controls. However, the difference in TLR1 and TLR4-10 mRNA expression between the two groups was not significant. The PBMCs of the patients with wet AMD produced more IL-6 and IL-8 proteins than the controls in response to PGN, a ligand for TLR2, and more IL-6 protein than the controls in response to poly(I:C), the ligand for TLR3. However, there was no significant difference in vascular endothelial growth factor and monocyte chemoattractant protein-1 production between the wet AMD group and the control group when the PBMCs were stimulated with PGN or poly(I:C). CONCLUSIONS: Our data suggested that upregulation of TLR2 and TLR3 may be associated with the pathogenesis of wet AMD. PMID- 23946638 TI - A novel missense mutation in the FERM domain containing 7 (FRMD7) gene causing X linked idiopathic congenital nystagmus in a Chinese family. AB - PURPOSE: Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous disease. Thus far, the disease gene has been identified as the FERM domain containing 7 (FRMD7) gene. The purpose of this study was to elucidate the clinical and genetic characteristics of a four- generation Chinese family with ICN. METHODS: The clinical data and the genomic DNA of a Chinese ICN family were collected following the provision of informed consent. All coding exons of the FRMD7 gene were amplified by PCR and then sequenced. Affinity GST-p21 activated kinase 2 (PAK2) precipitation was used to investigate whether this novel FRMD7 mutant influenced Rac1 signaling activation in the human embryonic kidney 293 T cells (HEK 293T) cells transiently cotransfected with wild-type or mutant FRMD7 and Rac1. RESULTS: A novel missense mutation (c.635T>C) was identified in all affected members. Obligate female carriers were heterozygous in these mutations and the affected males were homozygous, consistent with X-linked inheritance. This mutation is a substitution of proline for leucine. Function analysis showed that this novel mutant influences Rac1 signaling in human HEK 293T cells. CONCLUSIONS: This study widens the mutation spectrum of the FRMD7 gene. This mutant was shown to activate GTPase Rac1 signaling in vitro; however, the quantity of activated Rac1 was obviously decreased compared with the wild type (p<0.05). Taken together, our data strongly support the hypothesis that the identified FRMD7 mutant influences GTPase Rac1 signaling, which regulates neurite development. This mutation may be related to the pathogenesis of X-linked ICN. PMID- 23946640 TI - How to Attain an Ultralow Interfacial Tension and a Three-Phase Behavior with a Surfactant Formulation for Enhanced Oil Recovery: A Review. Part 2. Performance Improvement Trends from Winsor's Premise to Currently Proposed Inter- and Intra Molecular Mixtures. AB - The minimum interfacial tension occurrence along a formulation scan at the so called optimum formulation is discussed to be related to the interfacial curvature. The attained minimum tension is inversely proportional to the domain size of the bicontinuous microemulsion and to the interfacial layer rigidity, but no accurate prediction is available. The data from a very simple ternary system made of pure products accurately follows the correlation for optimum formulation, and exhibit a linear relationship between the performance index as the logarithm of the minimum tension at optimum, and the formulation variables. This relation is probably too simple when the number of variables is increased as in practical cases. The review of published data for more realistic systems proposed for enhanced oil recovery over the past 30 years indicates a general guidelines following Winsor's basic studies concerning the surfactant-oil-water interfacial interactions. It is well known that the major performance benefits are achieved by blending amphiphilic species at the interface as intermolecular or intramolecular mixtures, sometimes in extremely complex formulations. The complexity is such that a good knowledge of the possible trends and an experienced practical know-how to avoid trial and error are important for the practitioner in enhanced oil recovery. PMID- 23946639 TI - Increased malondialdehyde concentration and reduced total antioxidant capacity in aqueous humor and blood samples from patients with glaucoma. AB - PURPOSE: To evaluate the levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) in the blood and aqueous humor of glaucomatous and nonglaucomatous patients. To measure the adenosine triphosphate/adenosine diphosphate/adenosine monophosphate (ATP/ADP/AMP) concentration as a biomarker of the blood energy charge potential. METHODS: We examined 40 consecutive patients with primary open angle glaucoma scheduled for cataract surgery. Twenty-six age-matched subjects scheduled for cataract surgery were enrolled as a control group. Blood and aqueous humor samples were collected at the time of surgery. MDA concentrations and blood nucleotides were measured with high-performance liquid chromatography. The TAC of the samples was estimated with the oxygen-radical absorbance capacity method. RESULTS: Blood and aqueous humor MDA levels in glaucoma patients (respectively, 0.976+/-0.370 and 0.145+/-0.065 MUmol/ml) were significantly increased (p<0.001 for both) over those of the control group (respectively, 0.454+/-0.395 and 0.060+/-0.039 MUmol/ml). In contrast, the control group presented significantly higher TACs than did the glaucoma group in both the blood (control: 2.681+/-1.101 and glaucoma: 1.617+/-0.674 MUmol Trolox Equi/g; p<0.001) and aqueous humor (control: 0.963+/-0.302 and glaucoma: 0.788+/-0.346 MUmol Trolox Equi/g; p=0.039). The control group (0.869+/-0.037) exhibited statistically significant (p<0.001) higher values of blood adenosine triphosphate/adenosine diphosphate (ATP-ADP) levels than did the glaucoma group (0.791+/-0.037). CONCLUSIONS: Our data further support the hypothesis that oxidative stress and decreased antioxidant defenses are involved in glaucoma. High-performance liquid chromatography appears to be an effective and sensitive method to detect altered levels of oxidative stress markers in glaucoma patients. PMID- 23946641 TI - Postoperative rhabdomyolysis following pars-plana vitrectomy under general anesthesia. AB - IMPORTANCE: Rhabdomyolysis is a known, but rare, complication of general anesthesia. To the authors' knowledge, it has never before been reported following an ocular surgery, and we could find no similar cases in the surgical literature following any brief surgical procedure. We believe this case to be unique in those regards and aim to raise awareness among ophthalmologists of this postoperative complication, as timely intervention can prevent renal failure and death. OBSERVATIONS: We report the case of a 58-year-old male who developed rhabdomyolysis following vitrectomy for retinal detachment repair under general anesthesia. The patient had several risk factors for this complication including morbid obesity, type II diabetes mellitus, and American Society of Anesthesia class III risk profile. His postoperative course was notable for significant myalgias in the postoperative recovery area, followed several hours later by oliguria, "root beer" colored urine, and a markedly elevated creatinine kinase level. He was hospitalized for two days for intravenous hydration and monitoring of his renal function and has fully recovered. RELEVANCE: As the prevalence of obesity and type II diabetes mellitus increase worldwide, ophthalmologists need to be aware of the signs and symptoms of postoperative rhabdomyolysis. Treatment often requires inpatient hospitalization to prevent the associated morbidity and mortality. PMID- 23946642 TI - Hybrid microincision vitrectomy surgery combined with 20-gauge silicone cannulas for use with 20-gauge horizontal scissors in diabetic tractional retinal detachment. AB - PURPOSE: To verify the utility and preliminary safety of a 20-gauge silicone cannula for use with 20-gauge horizontal scissors delamination during microincision vitrectomy surgery (MIVS). METHODS: Thirty-eight eyes in 35 consecutive patients with diabetic tractional retinal detachment, who underwent MIVS between April 2010 and March 2012 and were followed for 3-24 months, were retrospectively assessed using a chart review. Twenty-gauge scissors delamination through a silicone cannula, with an additional 20-gauge port as a hybrid, was primarily selected when treating thick and rigid fibrovascular membranes, including fluctuating vessels over the detached retina near the macula. The main outcome measures included the proportion of patients treated with this hybrid method, the postoperative visual acuity, and the incidence of complications. RESULTS: Compared with the 26 eyes treated with MIVS only, 12 eyes (32%) required a hybrid technique with the use of 20-gauge instruments through a silicone cannula in addition to MIVS. Two patients underwent additional surgery. Temporary silicone oil tamponade was performed in one case of retinotomy and one case of schizophrenia. The mean visual acuity (logarithm of the minimum angle of resolution [logMAR]) improved from 1.43 +/- 0.85 to 0.72 +/- 0.47 at the last follow-up visit. No patients exhibited worsening of their visual acuity postoperatively. No sclerotomy-related complications were recorded during the intraoperative or postoperative periods. CONCLUSION: Hybrid MIVS combined with a 20-gauge silicone cannula for use with 20-gauge horizontal scissors in diabetic tractional retinal detachment eyes is useful and safe due to the reduced risk of sclerotomy-related retinal breaks. This procedure is a reasonable option when performing complex surgery for diabetic vitrectomy. PMID- 23946643 TI - Baseline central macular thickness predicts the need for retreatment with intravitreal triamcinolone plus laser photocoagulation for diabetic macular edema. AB - PURPOSE: To identify baseline characteristics that predict the number of treatments with intravitreal triamcinolone acetonide (IVTA) plus laser photocoagulation needed to treat diabetic macular edema over a 2-year period. METHODS: Individual data from 42 eyes of 42 participants treated with IVTA plus laser photocoagulation for diabetic macular edema during a prospective, randomized, double-masked, placebo-controlled trial were used for this post hoc analysis. Baseline characteristics - age, gender, best-corrected visual acuity, glycosylated hemoglobin, phakic status, intraocular pressure, and central macular thickness (CMT) - were correlated with the number of IVTA plus laser treatments received during the 2 years of this study. RESULTS: The median number of treatments received over the 2-year period was 2.5 (interquartile range 1.0-3.0), with 21 (50%) eyes needing three or more treatments. Eyes that received more IVTA plus laser treatments had a higher mean baseline CMT and eyes with a higher baseline CMT were more likely to receive three or more treatments (odds ratio 5.13, 95% confidence interval 1.75-15.04, P=0.003 per 100 MUm increase in CMT). No significant relationship was found between other baseline characteristics and the number of IVTA plus laser treatments received. CONCLUSION: Higher baseline CMT was strongly linked with receiving more IVTA plus laser treatments. These patients may be at higher risk of developing dose-dependent steroid-related adverse events, cataract progression, and intraocular pressure rise. PMID- 23946644 TI - Superior oblique surgery: when and how? AB - BACKGROUND: The purpose of this paper is to review different types of superior oblique muscle surgeries, to describe the main areas in clinical practice where superior oblique surgery is required or preferred, and to discuss the preferred types of superior oblique surgery with respect to their clinical outcomes. METHODS: A consecutive nonrandomized retrospective series of patients who had undergone superior oblique muscle surgery as a single procedure were enrolled in the study. The diagnosis, clinical features, preoperative and postoperative vertical deviations in primary position, type of surgery, complications, and clinical outcomes were reviewed. The primary outcome measures were the type of strabismus and the type of superior oblique muscle surgery. The secondary outcome measure was the results of the surgeries. RESULTS: The review identified 40 (20 male, 20 female) patients with a median age of 6 (2-45) years. Nineteen patients (47.5%) had Brown syndrome, eleven (27.5%) had fourth nerve palsy, and ten (25.0%) had horizontal deviations with A pattern. The most commonly performed surgery was superior oblique tenotomy in 29 (72.5%) patients followed by superior oblique tuck in eleven (27.5%) patients. The amount of vertical deviation in the fourth nerve palsy and Brown syndrome groups (P = 0.01 for both) and the amount of A pattern in the A pattern group were significantly reduced postoperatively (P = 0.02). CONCLUSION: Surgery for the superior oblique muscle requires experience and appropriate preoperative evaluation in view of its challenging nature. The main indications are Brown syndrome, fourth nerve palsy, and A pattern deviations. Superior oblique surgery may be effective in terms of pattern collapse and correction of vertical deviations in primary position. PMID- 23946645 TI - Amrubicin: potential in combination with cisplatin or carboplatin to treat small cell lung cancer. AB - Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer characterized by early metastasis and high mortality. In recent years, monotherapy and combination therapy of amrubicin with cisplatin or carboplatin has been actively studied and shown promise for the treatment of extensive disease SCLC (ED-SCLC). In this article, we summarize clinical trials of both monotherapy and combination therapy with amrubicin conducted in Japan, the USA, and the European Union. The results suggest that the clinical outcome of amrubicin therapy may be associated with genetic variations in patients. Further study of combination regimens in patients of different ethnicities is warranted. PMID- 23946646 TI - Quantification of imatinib in human serum: validation of a high-performance liquid chromatography-mass spectrometry method for therapeutic drug monitoring and pharmacokinetic assays. AB - BACKGROUND: Imatinib mesylate has been a breakthrough treatment for chronic myeloid leukemia. It has become the ideal tyrosine kinase inhibitor and the standard treatment for chronic-phase leukemia. Striking results have recently been reported, but intolerance to imatinib and noncompliance with treatment remain to be solved. Molecular monitoring by quantitative real-time polymerase chain reaction is the gold standard for monitoring patients, and imatinib blood levels have also become an important tool for monitoring. METHODS: A fast and cheap method was developed and validated using high-performance liquid chromatography-mass spectrometry for quantification of imatinib in human serum and tamsulosin as the internal standard. Remarkable advantages of the method includes use of serum instead of plasma, less time spent on processing and analysis, simpler procedures, and requiring reduced amounts of biological material, solvents, and reagents. Stability of the analyte was also studied. This research also intended to drive the validation scheme in clinical centers. The method was validated according to the requirements of the US Food and Drug Administration and Brazilian National Health Surveillance Agency within the range of 0.500-10.0 MUg/mL with a limit of detection of 0.155 MUg/mL. Stability data for the analyte are also presented. CONCLUSION: Given that the validated method has proved to be linear, accurate, precise, and robust, it is suitable for pharmacokinetic assays, such as bioavailability and bioequivalence, and is being successfully applied in routine therapeutic drug monitoring in the hospital service. PMID- 23946647 TI - Language impairment in Alzheimer's disease and benefits of acetylcholinesterase inhibitors. AB - Alzheimer's disease is characterized by progressively worsening deficits in several cognitive domains, including language. Language impairment in Alzheimer's disease primarily occurs because of decline in semantic and pragmatic levels of language processing. Given the centrality of language to cognitive function, a number of language-specific scales have been developed to assess language deficits throughout progression of the disease and to evaluate the effects of pharmacotherapy on language function. Trials of acetylcholinesterase inhibitors, used for the treatment of clinical symptoms of Alzheimer's disease, have generally focused on overall cognitive effects. However, in the current report, we review data indicating specific beneficial effects of acetylcholinesterase inhibitors on language abilities in patients with Alzheimer's disease, with a particular focus on outcomes among patients in the moderate and severe disease stages, during which communication is at risk and preservation is particularly important. PMID- 23946648 TI - Nanomechanical sensing of the endothelial cell response to anti-inflammatory action of 1-methylnicotinamide chloride. AB - BACKGROUND: There is increasing evidence that cell elastic properties should change considerably in response to chemical agents affecting the physiological state of the endothelium. In this work, a novel assay for testing prospective endothelium-targeted agents in vitro is presented. MATERIALS AND METHODS: The proposed methodology is based on nanoindentation spectroscopy using an atomic force microscope tip, which allows for quantitative evaluation of cell stiffness. As an example, we chose a pyridine derivative, 1-methylnicotinamide chloride (MNA), known to have antithrombotic and anti-inflammatory properties, as reported in recent in vivo experiments. RESULTS: First, we determined a concentration range of MNA in which physiological parameters of the endothelial cells in vitro are not affected. Then, cell dysfunction was induced by incubation with tumor necrosis factor-alpha (TNF-alpha) and the cellular response to MNA treatment after TNF-alpha incubation was studied. In parallel to the nanoindentation spectroscopy, the endothelium phenotype was characterized using a fluorescence spectroscopy with F-actin labeling, and biochemical methods, such as secretion measurements of both nitric oxide (NO), and prostacyclin (PGI2) regulatory agents. CONCLUSION: We found that MNA could reverse the dysfunction of the endothelium caused by inflammation, if applied in the proper time and to the concentration scheme established in our investigations. A surprisingly close correlation was found between effective Young's modulus of the cells and actin polymerization/depolymerization processes in the endothelium cortical cytoskeleton, as well as NO and PGI2 levels. These results allow us to construct the physiological model of sequential intracellular pathways activated in the endothelium by MNA. PMID- 23946649 TI - Zerumbone-loaded nanostructured lipid carriers: preparation, characterization, and antileukemic effect. AB - Zerumbone, a natural dietary lipophilic compound with low water solubility (1.296 mg/L at 25 degrees C) was used in this investigation. The zerumbone was loaded into nanostructured lipid carriers using a hot, high-pressure homogenization technique. The physicochemical properties of the zerumbone-loaded nanostructured lipid carriers (ZER-NLC) were determined. The ZER-NLC particles had an average size of 52.68 +/- 0.1 nm and a polydispersity index of 0.29 +/- 0.004 MUm. Transmission electron microscopy showed that the particles were spherical in shape. The zeta potential of the ZER-NLC was -25.03 +/- 1.24 mV, entrapment efficiency was 99.03%, and drug loading was 7.92%. In vitro drug release of zerumbone from ZER-NLC was 46.7%, and for a pure zerumbone dispersion was 90.5% over 48 hours, following a zero equation. Using the MTT (3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide) assay in human T-cell acute lymphoblastic leukemia (Jurkat) cells, the half maximal inhibitory concentration (IC50) of ZER NLC was 5.64 +/- 0.38 MUg/mL, and for free zerumbone was 5.39 +/- 0.43 MUg/mL after 72 hours of treatment. This study strongly suggests that ZER-NLC have potential as a sustained-release drug carrier system for the treatment of leukemia. PMID- 23946650 TI - Comparative proteomics of inhaled silver nanoparticles in healthy and allergen provoked mice. AB - BACKGROUND: Silver nanoparticles (AgNPs) have been associated with the exacerbation of asthma; however, the immunological basis for the adjuvant effects of AgNPs is not well understood. OBJECTIVE: The aim of the study reported here was to investigate the allergic effects of AgNP inhalation using proteomic approaches. METHODS: Allergen provoked mice were exposed to 33 nm AgNPs at 3.3 mg/m(3). Following this, bronchoalveolar lavage fluid (BALF) and plasma were collected to determine protein profiles. RESULTS: In total, 106 and 79 AgNP unique proteins were identified in the BALF of control and allergic mice, respectively. Additionally, 40 and 26 AgNP-unique proteins were found in the plasma of control and allergic mice, respectively. The BALF and plasma protein profiles suggested that metabolic, cellular, and immune system processes were associated with pulmonary exposure to AgNPs. In addition, we observed 18 proteins associated with systemic lupus erythematosus that were commonly expressed in both control and allergic mice after AgNP exposure. Significant allergy responses were observed after AgNP exposure in control and allergic mice, as determined by ovalbumin-specific immunoglobulin E. CONCLUSION: Inhaled AgNPs may regulate immune responses in the lungs of both control and allergic mice. Our results suggest that immunology is a vital response to AgNPs. PMID- 23946651 TI - Effects of mechanical loading on the degradability and mechanical properties of the nanocalcium-deficient hydroxyapatite-multi(amino acid) copolymer composite membrane tube for guided bone regeneration. AB - BACKGROUND AND METHODS: Guided bone regeneration (GBR) is a new treatment for bone defects, and the property of membrane is critical to the success of GBR. This study focuses on a novel membrane tube for GBR, which was prepared by a nanocalcium-deficient hydroxyapatite-multi(amino acid) copolymer (n-CDHA-MAC) composite. The biomechanical strength and degradability of this membrane tube under mechanical loading after immersion in phosphate-buffered solution were investigated to evaluate the effects of mechanical loading on the membrane tube. The membrane-tube group with no mechanical loading and femora bone were used as controls. RESULTS: The compressive strength and bending strength of n-CDHA-MAC membrane tubes were 66.4 +/- 10.2 MPa and 840.7 +/- 12.1 MPa, which were lower than those of the goats' femoral bones (69.0 +/- 5.5 MPa and 900.2 +/- 17.3 MPa), but there were no significant (P > 0.05) differences. In the in vitro degradability experiment, all membrane tubes were degradable and showed a surface erosion degradation model. The PH of solution fluctuated from 7.2 to 7.5. The weight and mechanical strength of loaded tubes decreased more quickly than nonloaded ones, with significant differences (P < 0.05). However, the strength of the loaded group after degradation achieved 20.4 +/- 1.2 MPa, which was greater than the maximum mechanical strength of 4.338 MPa based on goat femoral middle stationary state by three-dimensional finite-element analysis. CONCLUSIONS: n CDHA-MAC membrane tubes have good biomechanical strength during degradation under mechanical loading. Therefore, this membrane tube is an ideal GBR membrane for critical size defects of long bones in goats for animal experiments. PMID- 23946653 TI - Physicochemical characterization of a novel graphene-based magnetic resonance imaging contrast agent. AB - We report the synthesis and characterization of a novel carbon nanostructure based magnetic resonance imaging contrast agent (MRI CA); graphene nanoplatelets intercalated with manganese (Mn(2+)) ions, functionalized with dextran (GNP-Dex); and the in vitro assessment of its essential preclinical physicochemical properties: osmolality, viscosity, partition coefficient, protein binding, thermostability, histamine release, and relaxivity. The results indicate that, at concentrations between 0.1 and 100.0 mg/mL, the GNP-Dex formulations are hydrophilic, highly soluble, and stable in deionized water, as well as iso osmolar (upon addition of mannitol) and iso-viscous to blood. At potential steady state equilibrium concentrations in blood (0.1-10.0 mg/mL), the thermostability, protein-binding, and histamine-release studies indicate that the GNP-Dex formulations are thermally stable (with no Mn(2+) ion dissociation), do not allow non-specific protein adsorption, and elicit negligible allergic response. The r 1 relaxivity of GNP-Dex was 92 mM(-1)s(-1) (per-Mn(2+) ion, 22 MHz proton Larmor frequency); ~20- to 30-fold greater than that of clinical gadolinium (Gd(3+))- and Mn(2+)-based MRI CAs. The results open avenues for preclinical in vivo safety and efficacy studies with GNP-Dex toward its development as a clinical MRI CA. PMID- 23946652 TI - Prevention and treatment of biofilms by hybrid- and nanotechnologies. AB - Bacteria growing as adherent biofilms are difficult to treat and frequently develop resistance to antimicrobial agents. To counter biofilms, various approaches, including prevention of bacterial surface adherence, application of device applicators, and assimilation of antimicrobials in targeted drug delivery machinery, have been utilized. These methods are also combined to achieve synergistic bacterial killing. This review discusses various multimodal technologies, presents general concepts, and describes therapies relying on the principles of electrical energy, ultrasound, photodynamics, and targeted drug delivery for prevention and treatment of biofilms. PMID- 23946654 TI - Decreased Serum Hepatocyte Growth Factor (HGF) in Individuals with Bipolar Disorder Normalizes after Zinc and Anti-oxidant Therapy. AB - AIM: To assess serum HGF concentration in individuals with bipolar disorder and investigate the efficacy of zinc therapy on these levels. SUBJECTS AND METHODS: Serum from 35 individuals diagnosed with bipolar disorder and 19 age and gender similar controls were tested for HGF concentration using ELISAs, and copper and zinc plasma levels using inductively-coupled plasma-mass spectrometry. RESULTS: HGF serum levels of individuals with bipolar disorder were significantly lower than age and gender similar controls (P = 0.0021). HGF serum concentration was significantly lower in Bipolar patients pre-therapy (P = 0.0009) and HGF levels normalized post-therapy. Zinc levels in these same individuals also normalized (P = 0.0046) and patient's perceived severity of Bipolar symptoms significantly decreased after therapy (P = 0.0003). We also found a significant direct correlation between Zinc and HGF serum concentration in the bipolar patients (P = 0.04). DISCUSSION: These results suggest an association between low HGF levels and bipolar disorder and also demonstrate that zinc therapy may be associated with the normalization of HGF levels and decrease in severity of disease. PMID- 23946655 TI - An interaction of the pre- and post-weaning diets rich in omega-6 polyunsaturated fats alters plasma lipids, hepatic gene expression and aortic vascular reactivity in adult C57BL/6 mice. AB - AIM: To investigate the effects of diets rich in n-6 polyunsaturated fats (PUFA) fed during pre- and post-weaning time periods on the lipid metabolism and vascular reactivity in adult C57Bl/6 mice, in order to assess the impact of maternal nutrition and its interaction with the offspring diet on the metabolism of adult offspring. METHODS: Female C57Bl/6 mice were fed a high-fat diet enriched with n-6 PUFA (P) or control diet (C) for 2-weeks before, during mating, gestation and lactation, while their pups received either P or C for 8-weeks post weaning. RESULTS: A significant interaction between the maternal and post-weaning diets was observed for the offspring body weight, food-, caloric-intake, plasma lipids, hepatic mRNA expression of lecithin cholesterol acyltransferase, aortic contractile and relaxation responses (P < 0.05). CONCLUSION: The overall metabolic and physiological outcome in the offspring is dependent upon the interaction between the pre- and post-weaning dietary environments. PMID- 23946656 TI - Decreased zinc and increased copper in individuals with anxiety. AB - AIM: To assess plasma zinc and copper levels in individuals with anxiety and to test the hypothesis that there is a relationship between copper and zinc concentration and improved symptoms. SUBJECTS AND METHODS: Serum from 38 individuals with anxiety and 16 neurotypical age, gender and size similar controls were tested for plasma zinc and copper concentration using inductively coupled plasma-mass spectrometry. Zinc and copper levels, pre and post therapy, were compared and assessed for perceived anxiety symptoms. RESULTS: In this preliminary study, individuals with anxiety had significantly higher plasma levels of Cu (P = 0.0348), Cu/Zn (P = 0.0493) and lower Zn (P = 0.0294) compared to controls. Zn levels normalized (increased to the normal range) and Cu/Zn significantly decreased after zinc therapy (P = 0.0004, P = 0.0033, respectively), but Cu did not significantly decrease (0.3577). These same patients improved significantly with respect to perceived overall symptoms after zinc and anti-oxidant therapy (P = 0.013). DISCUSSION: These results suggest an association between Zn plasma levels and individuals with anxiety, demonstrate that zinc therapy is effective in increasing zinc plasma levels, and show that zinc supplementation may play a role in improved symptoms. PMID- 23946657 TI - Diets Enriched in Fish-Oil or Seal-Oil have Distinct Effects on Lipid Levels and Peroxidation in BioF1B Hamsters. AB - AIM: Fish-oil omega-3 polyunsaturated fatty acids (n-3 PUFAs) are mostly esterified to the sn-2 position of triglycerides, while in seal-oil triglycerides, these are mostly esterified to the sn-1 and -3 positions. We investigated whether fish-oil and seal-oil feeding has a different effect on the regulation of lipid metabolism and oxidative stress in BioF1B hamsters. METHODS: BioF1B hamsters were fed high fat diets rich in fish-oil or seal-oil for 4 weeks, and fasted for 14 hours prior to blood and tissue collection. RESULTS: Plasma and hepatic lipids and lipid peroxidation levels were significantly lower in seal-oil fed hamsters as compared to those fed fish-oil. There was a selective hindrance of clearance of lipids in fish-oil-fed hamsters as reflected by higher levels of plasma apoB48. CONCLUSION: Differences in the fatty acid composition and positional distribution of n-3 PUFAs in triglycerides of fish-oil and seal-oil are suggested to trigger metabolic differences. PMID- 23946658 TI - Analysis of plasma zinc and copper concentration, and perceived symptoms, in individuals with depression, post zinc and anti-oxidant therapy. AB - AIM: To assess plasma Zn and Cu levels in individuals with depression. SUBJECTS AND METHODS: Plasma from 73 clinically depressed individuals, 38 individuals with anxiety and 16 controls were tested for plasma Zn and Cu concentration using inductively-coupled plasma-mass spectrometry. RESULTS: Depressed individuals, with and without secondary anxiety, had decreased plasma Zn and elevated plasma Cu compared to controls. Zn normalized (increased to the level of normal controls) but Cu increased in individuals with depression (with and without secondary anxiety), after Zn therapy, whereas both plasma Zn increased and Cu levels decreased in anxiety, with and without secondary depression, after Zn therapy. Individuals with depression,with and without secondary anxiety, had significantly higher symptom severity when compared to neurotypical controls. Symptom severity in individuals with anxiety (both with and without secondary depression) significantly decreased after Zn therapy, whereas symptoms remained the same in individuals with primary depression. DISCUSSION: These data show an association between Zn and Cu plasma levels and clinically depressed individuals, and suggest that high Cu levels are associated with high symptom severity. PMID- 23946659 TI - Potential of Spirulina Platensis as a Nutritional Supplement in Malnourished HIV Infected Adults in Sub-Saharan Africa: A Randomised, Single-Blind Study. AB - BACKGROUND: Malnutrition is a major global public health issue and its impact on communities and individuals is more dramatic in Sub-Saharan Africa, where it is compounded by widespread poverty and generalized high prevalence of human immunodeficiency virus (HIV). Therefore, malnutrition should be addressed through a multisectorial approach, and malnourished individuals should have access to nutritional rehabilitation molecules that are affordable, accessible, rich in nutrient and efficient. We thus assessed the efficacy of two affordable and accessible nutritional supplements, spirulina platensis versus soya beans among malnourished HIV-infected adults. METHODS: Undernourished patients, naive of, but eligible to antiretroviral treatment (ART), aged 18 to 35 years were enrolled and randomly assigned to two groups. The first group received spirulina (Group A) as food supplement and the second received soya beans (Group B). Patients were initiated ART simultaneously with supplements. Food supplements were auto administered daily, the quantity being calculated according to weight to provide 1.5 g/kg body weight of proteins with 25% from supplements (spirulina and soya beans). Patients were monitored at baseline and followed-up during twelve weeks for anthropometric parameters, body composition, haemoglobin and serum albumin, CD4 count and viral load. RESULTS: Fifty-two patients were enrolled (Group A: 26 and Group B: 26). The mean age was 26.4 +/- 4.9 years (Group A) and 28.7 +/- 4.8 (Group B) with no significant difference between groups (P = 0.10). After 12 weeks, weight and BMI significantly improved in both groups (P < 0.001 within each group). The mean gain in weight and BMI in Group A and B were 4.8 vs. 6.5 kg, (P = 0.68) and 1.3 vs. 1.90 Kg/m(2), (P = 0.82) respectively. In terms of body composition, fat free mass (FFM) did not significantly increase within each group (40.5 vs. 42.2 Kg, P = 0.56 for Group A; 39.2 vs. 39.0 Kg, P = 0.22 for Group B). But when compared between the two groups at the end of the trial, FFM was significantly higher in the spirulina group (42.2 vs. 39.0 Kg, P = 0.01). The haemoglobin level rose significantly within groups (P < 0.001 for each group) with no difference between groups (P = 0.77). Serum albumin level did not increase significantly within groups (P < 0.90 vs. P < 0.82) with no difference between groups (P = 0.39). The increase in CD4 cell count within groups was significant (P < 0.01 in both groups), with a significantly higher CD4 count in the spirulina group compared to subjects on soya beans at the end of the study (P = 0.02). Within each group, HIV viral load significantly reduced at the end of the study (P < 0.001 and P = 0.04 for spirulina and soya beans groups respectively). Between the groups, the viral load was similar at baseline but significantly reduced in the spirulina group at the end of the study (P = 0.02). CONCLUSION: We therefore conclude in this preliminary study, firstly, that both spirulina and soja improve on nutritional status of malnourished HIV-infected patients but in terms of quality of nutritional improvement, subjects on spirulina were better off than subjects on soya beans. Secondly, nutritional rehabilitation improves on immune status with a consequent drop in viral load but further investigations on the antiviral effects of this alga and its clinical implications are strongly needed. PMID- 23946660 TI - A blend of phellodendron and crape myrtle improves glucose tolerance in exercise trained men. AB - BACKGROUND: The purpose of this study was to investigate the acute effects of a nutritional supplement containing a proprietary blend of Phellodendron and Crape Myrtle on serum glucose and insulin in response to a modified oral glucose tolerance test (OGTT). METHODS: Using a randomized, double-blind, cross-over design, 10 exercise-trained, non-diabetic men reported to the lab in a 10 hour fasted state, on two different mornings separated by 1-2 weeks, and were subjected to an OGTT by ingesting a 75 gram dextrose solution. Fifteen minutes prior to the OGTT subjects ingested either a dietary supplement containing a blend of Phellodendron and Crape Myrtle (SUPP) or a placebo (PLA). Blood samples were collected before ingestion of the SUPP or PLA and at 15, 30, 45, 60, and 75 minutes post-ingestion of the dextrose load. Samples were analyzed for serum glucose and insulin. RESULTS: In relation to serum glucose, a condition effect was noted (P = 0.01), with values lower for SUPP compared to PLA. In relation to serum insulin, a trend for a condition effect was noted (P = 0.06), with values lower for SUPP compared to PLA. CONCLUSION: These findings indicate that acute ingestion of a dietary supplement containing a blend of Phellodendron and Crape Myrtle can lower the serum glucose response to a modified OGTT, while resulting in a non-significant attenuation in insulin response. These data are specific to a small sample of exercise-trained, non-diabetic men. PMID- 23946661 TI - Increased Copper in Individuals with Autism Normalizes Post Zinc Therapy More Efficiently in Individuals with Concurrent GI Disease. AB - AIM: To assess plasma zinc and copper concentration in individuals with autism. SUBJECTS AND METHODS: Plasma from 79 autistic individuals, and 18 age and gender similar neurotypical controls, were tested for plasma zinc and copper using inductively-coupled plasma-mass spectrometry. RESULTS: Autistic individuals had significantly elevated plasma levels of copper and Cu/Zn and lower, but not significantly lower, plasma Zn compared to neurotypical controls. Zn levels increased significantly in autistic individuals with and without GI disease after zinc therapy. Cu decreased significantly after zinc therapy in the GI disease group but not in the autistic group without GI disease. Autistic children significantly improved with respect to hyperactivity and stimming after zinc therapy in autistic children with GI disease. Autistic children without GI disease did not improve in these symptoms after the same therapy. DISCUSSION: These results suggest an association between zinc and copper plasma levels and autism, and they suggest that zinc therapy may be most effective at lowering copper levels in autistic children with GI disease. PMID- 23946662 TI - A blend of chlorophytum borivilianum and velvet bean increases serum growth hormone in exercise-trained men. AB - BACKGROUND: Several isolated ingredients have been proposed to increase growth hormone (GH) release, including Chlorophytum borivilianum and Velvet bean. A combination of these two ingredients has been packaged within an investigational dietary supplement. It was the purpose of the present investigation to determine the impact of acute ingestion of this supplement on circulating GH in healthy, exercise-trained men. METHODS: Fifteen men ingested the dietary supplement on two different days, separated by one week. Blood was collected from subjects before ingestion of the supplement and at 20, 40, 60, 80, 100, and 120 minutes post ingestion. GH was analyzed in serum samples using an ELISA method. Values for GH for each subject, at each collection time, were averaged over both test days and used in the main analysis. RESULTS: Serum GH increased over time, with higher values at 60 minutes (1.56 +/- 0.65 ng . mL(-1); P = 0.04; +767%), 80 minutes (1.76 +/- 0.69 ng . mL(-1); P = 0.02; +878%), and 100 minutes (1.48 +/- 0.62 ng . mL(-1); P = 0.05; +722%) compared to pre ingestion (0.18 +/- 0.04 ng . mL(-1)). A great deal of subject variability existed in the area under the curve (AUC) for GH, with pooled values ranging from 0.49 to 61.2 ng . mL(-1) . 2 hr(-1.) CONCLUSION: Acute ingestion of an investigational dietary supplement containing the active ingredients Chlorophytum borivilianum and Velvet bean results in an increase in circulating GH in exercise-trained men. Additional placebo controlled investigations are needed to extend these findings. Moreover, studies are needed to determine if chronic use of such supplementation leads to favorable changes in health-related parameters associated with increased circulating GH. PMID- 23946663 TI - Effects of acute caffeinated coffee consumption on energy utilization related to glucose and lipid oxidation from short submaximal treadmill exercise in sedentary men. AB - OBJECTIVE: Aim of this study was to evaluate the short term effect of coffee drinking on energy utilization in sedentary men. METHODS: This study was performed in healthy sedentary men, who were randomized into three groups, control (n = 6), decaffeinated (n = 10), and caffeine (n = 10). The caffeine dose in coffee was rechecked and calculated for individual volunteers at 5 mg/kg. Baseline before drinking, complete blood count (CBC), glucose, antioxidant capacity, lipid peroxide, and caffeine in blood was evaluated. After drinking coffee for 1 hr, the submaximal exercise test with a modified Bruce protocol was carried out, and the VO2 and RER were analyzed individually at 80% maximal heart rate, then the blood was repeat evaluated. RESULTS: Three groups showed a nonsignificant difference in CBC results and physical characteristics. The caffeine group showed significant changes in all parameters; higher VO2 levels, (P = 0.037) and lower RER (P = 0.047), when compared to the baseline. Furthermore, the glucose level after exercise test increased significantly (P = 0.033) as well as lipid peroxide levels (P = 0.005), whereas antioxidant capacity did not change significantly (P = 0.759), when compared to the before exercise testing. In addition, the blood caffeine level also increased only in the caffeine group (P = 0.008). CONCLUSION: Short consumption of caffeinated coffee (5 mg/kg of caffeine), improves energy utilization and relates to glucose derivation and lipid oxidation. PMID- 23946664 TI - Prevalence of abdominal obesity in Abia State, Nigeria: results of a population based house-to-house survey. AB - BACKGROUND AND OBJECTIVE: Abdominal obesity is associated with the risk of developing disorders, such as diabetes and hypertension. The objective of this study was to investigate the prevalence of abdominal obesity in Abia State, Nigeria. MATERIALS AND METHODS: We carried out a cross-sectional study aimed at ascertaining the prevalence of abdominal obesity in Abia State, Nigeria. Participants in the study were recruited from communities in the three senatorial zones in the state. Screening for abdominal obesity was carried out in these subjects using waist circumference (the National Cholesterol Education Program Third Adult Treatment Panel criteria were used). The World Health Organization Stepwise Approach to Surveillance of chronic disease risk factors was used. Body mass index, anthropometric measurements, and other relevant data were also collected. RESULTS: Data on waist circumference were obtained from 2,807 subjects. The prevalence of obesity using body mass index in the population was 11.12%. In men and women, it was 7.73%, and 14.37%, respectively. The prevalence of abdominal obesity in the population was 21.75%. In men and women, it was 3.2% and 39.2%, respectively. CONCLUSION: The prevalence of abdominal obesity is high in Nigeria, and needs to be monitored because it is associated with increased cardiovascular risk. PMID- 23946665 TI - Long-term efficacy, safety and durability of Juvederm(r) XC. AB - Over the last decade, there has been increasing interest in minimally invasive cosmetic treatments, especially for facial rejuvenation. Next to botulinum toxin injection, the injection of soft tissue fillers is the second most frequent minimally invasive procedure performed in the USA. Hyaluronic acid (HA) is the most commonly used dermal filler. One of patients' main concerns about filler injections pertains to pain and discomfort. Topical anesthetics, nerve blocks, and/or the incorporation of lidocaine to the filler have been applied in order to reduce distress and pain. Despite nerve blocks being an effective form of anesthesia, they may distort the area to be treated, as well as lengthen and complicate the procedure. Studies have shown that the incorporation of lidocaine to HA fillers significantly reduces pain and discomfort. Yet, one of the dilemmas about the addition of lidocaine solution to HA fillers is the possible alteration of the physical characteristics of the product by negatively impacting the efficacy and/or duration of the filler. The concern is that the addition of lidocaine could dilute the product, creating less correction per mL, changing the product's viscosity and consequently the "lifting" ability. Also, this dilution could reduce the product's duration. There may be a difference between a physician adding an aqueous solution into a lidocaine-free version of HA and the pre-incorporated lidocaine version of HA. An aqueous solution might dilute the product, while the pre-incorporated powder lidocaine appears to avoid this problem. Juvederm(r) XC is manufactured with powder lidocaine 0.3%; it is associated with significantly less injection pain than Juvederm(r) and other lidocaine-free versions of HA. Studies have shown that lidocaine enhances treatment comfort and optimizes the injection experience while maintaining a similar safety and effectiveness profile. Regarding the longevity, further study is necessary to determine if there is any difference in durability. PMID- 23946666 TI - Association between muscle atrophy/weakness and health care costs and utilization among patients receiving total knee replacement surgery: a retrospective cohort study. AB - PURPOSE: The aim of the study reported here was to examine health care resource utilization, costs, and risk of rehospitalization for total knee replacement (TKR) patients with and without muscle atrophy/weakness (MAW). PATIENTS AND METHODS: Individuals aged 50-64 years with commercial insurance or 65+ years with Medicare Supplemental Insurance (Medicare) who had a hospitalization for TKR between January 1, 2006 and September 30, 2009 were identified from a large US claims database. First hospitalization for TKR was defined as the index stay. All patients were classified into three cohorts according to when MAW was diagnosed relative to TKR: pre-MAW, post-MAW, and no MAW. The association between MAW and health care costs over the 12-month post-index period and the probability of rehospitalization were assessed via multivariate regressions. RESULTS: The study sample included 53,696 Medicare and 46,058 commercial insurance TKR patients. Controlling for cross-cohort differences, both the pre- and post-MAW cohorts had significantly higher total health care costs (Medicare US$4,201 and US$9,404 higher, commercial insurance US$2,737 and US$6,640 higher, respectively) than the no MAW cohort (all P < 0.05). The post-MAW cohort in both populations was also more likely to have any all-cause or replacement-related rehospitalization compared with the no MAW cohort. CONCLUSION: Among US patients undergoing TKR, those with MAW had higher health care utilization and costs than patients without MAW. PMID- 23946667 TI - Evaluation of analgesic activity and toxicity of alkaloids in Myristica fragrans seeds in mice. AB - AIM: To examine the analgesic effect of alkaloids in Myristica fragrans seed in a mouse model of acetic acid-induced visceral pain. METHODS: Alkaloids were extracted from ground nutmeg seed kernels with 10% acetic acid in 95% ethyl alcohol. Visceral pain was induced in male and female BALB/c mice by intraperitoneal injection of 0.6% acetic acid. Analgesic effect of alkaloids (0.5 gram or 1 gram per kilogram [g/kg], by mouth) was assessed by evaluating writhing response. Acute toxicity was tested in response to 2, 3, 4, 5, or 6 g/kg of alkaloid extract; the median lethal dose (LD50) was determined by probit analysis. RESULTS: Alkaloid extract at a dose of 1 g/kg significantly reduced the number of writhing responses in female, but not male mice; 0.5 g/kg of alkaloid extract had no effect in either sex. The LD50 was 5.1 g/kg. Signs of abnormal behavior, including hypoactivity, unstable gait, and dizziness were seen in animals given a dose of 4 g/kg or higher; abnormal behavior lasted for several hours after administration of the alkaloids. CONCLUSION: According to the classification of Loomis and Hayes, M. fragrans seed alkaloids have analgesic activity and are slightly toxic. PMID- 23946668 TI - Detailed analysis of allergic cutaneous reactions to spinal cord stimulator devices. AB - The use of spinal cord stimulation (SCS) devices to treat chronic, refractory neuropathic pain continues to expand in application. While device-related complications have been well described, inflammatory reactions to the components of these devices remain underreported. In contrast, hypersensitivity reactions associated with other implanted therapies, such as endovascular and cardiac rhythm devices, have been detailed. The purpose of this case series is to describe the clinical presentation and course of inflammatory reactions as well as the histology of these reactions. All patients required removal of the entire device after developing inflammatory reactions over a time course of 1-3 months. Two patients developed a foreign body reaction in the lead insertion wound as well as at the implantable pulse generator site, with histology positive for giant cells. One patient developed an inflammatory dermatitis on the flank and abdomen that resolved with topical hydrocortisone. "In vivo" testing with a lead extension fragment placed in the buttock resulted in a negative reaction followed by successful reimplantation of an SCS device. Inflammatory reactions to SCS devices can manifest as contact dermatitis, granuloma formation, or foreign body reactions with giant cell formation. Tissue diagnosis is essential, and is helpful to differentiate an inflammatory reaction from infection. The role of skin patch testing for 96 hours may not be suited to detect inflammatory giant cell reactions that manifest several weeks post implantation. PMID- 23946669 TI - Anemia prevalence and treatment practice in patients with non-myeloid tumors receiving chemotherapy. AB - PURPOSE: To describe the prevalence and management of anemia in cancer patients. METHODS: This cross-sectional, observational survey was conducted in Italy and Austria. Centers prespecified one day, during a 4-month enrollment window, to report specific data collected during normal clinical practice for patients with non-myeloid tumors attending for chemotherapy (+/-radiotherapy) treatment. The primary endpoint was the prevalence of anemia as determined using a prespecified algorithm: hemoglobin (Hb) <=10 g/dL on/within 3 days prior to visit; ongoing anemia treatment; physician diagnosis of anemia, together with >=1 anemia symptom. RESULTS: Between November 18, 2010 and March 18, 2011, data for 1412 patients were collected (Italy n = 1130; Austria n = 282). Most patients (n = 1136; 80%) had solid tumors; 809 (57%) had received <=3 chemotherapy cycles. The prevalence of anemia was 32% (95% confidence interval: 29.4%-34.2%); 196 patients (14%) were deemed anemic based on Hb <=10 g/dL, 131 (9%) on ongoing anemia treatment, and 121 (9%) on physician diagnosis/anemia symptom. Overall, 1153 patients (82%) had Hb data; mean (standard deviation [SD]) Hb levels were 11.7 (1.7) g/dL. In total, 456 patients (32%) had anemia symptoms: fatigue (n = 392; 28%), depression (n = 122; 9%), and dyspnea (n = 107; 8%) were most common. Fifty one patients (4%) had had their current chemotherapy cycle delayed due to anemia. On visit day, or <=28 days prior, 91 (6%), 188 (13%), and 81 patients (6%) had evidence of whole blood/red blood cell transfusion, erythropoiesis-stimulating agent use, or iron use, respectively. CONCLUSION: On the prespecified study day, one-third of patients with non-myeloid tumors undergoing chemotherapy were found to be anemic and 13% had evidence of erythropoiesis-stimulating agent use then or in the 28 days prior. PMID- 23946670 TI - Validity of an algorithm to identify osteonecrosis of the jaw in women with postmenopausal osteoporosis in the Danish National Registry of Patients. AB - BACKGROUND: Osteonecrosis of the jaw (ONJ) is an adverse effect of drugs that suppress bone turnover - for example, drugs used for the treatment of postmenopausal osteoporosis. The Danish National Registry of Patients (DNRP) is potentially valuable for monitoring ONJ and its prognosis; however, no specific code for ONJ exists in the International Classification of Diseases 10th revision (ICD-10), which is currently used in Denmark. Our aim was to estimate the positive predictive value (PPV) of an algorithm to capture ONJ cases in the DNRP among women with postmenopausal osteoporosis. METHODS: We conducted this cross sectional validation study in the Central and North Denmark Regions, with approximately 1.8 million inhabitants. In total, 54,956 women with postmenopausal osteoporosis were identified from June 1, 2005 through May 31, 2010. To identify women potentially suffering from ONJ, we applied an algorithm based on ICD-10 codes in the DNRP originating from hospital-based departments of oral and maxillofacial surgery (DOMS). ONJ was adjudicated by chart review and defined by the presence of exposed maxillofacial bone for 8 weeks or more, in the absence of recorded history of craniofacial radiation therapy. We estimated the PPV for the overall algorithm and for each separate ICD-10 code used in the algorithm. RESULTS: Charts were obtained and reviewed for all 60 women with an ICD-10 code potentially representing ONJ. Nineteen potential ONJ cases were confirmed, corresponding to an overall PPV of 32% (95% confidence interval: 20%-45%). CONCLUSION: Among women with postmenopausal osteoporosis, only about one-third of the potential ONJ cases identified by our ICD-10 based algorithm were confirmed by medical chart review, despite the restriction to patients treated at DOMS. To capture true ONJ cases among women with postmenopausal osteoporosis, alternative approaches are needed. PMID- 23946671 TI - Comparative safety and efficacy of antithrombotics in the management of venous thromboembolism after knee or hip replacement surgery: focus on rivaroxaban. AB - Routine thromboprophylaxis represents the current standard of care in the management of patients following total hip or knee replacement. Legacy agents used to address the issue of risk of venous thromboembolism present barriers to use, either by the need for monitoring and dose adjustment (warfarin) or the need for injection (low molecular weight heparins and fondaparinux), or pose a risk of upper gastrointestinal bleeding (acetylsalicylic acid and all antithrombotic agents). The introduction of new pharmacologic agents in recent years has sought to address the issues of not only efficacy, but also safety, ease of use, and patient compliance. New orally administered agents, ie, apixaban, dabigatran, and rivaroxaban, have demonstrated various degrees of efficacy over enoxaparin while preserving safety. Indirect comparisons of the relative efficacies of apixaban, dabigatran, and rivaroxaban have shown rivaroxaban to be more efficacious than dabigatran and apixaban in reducing symptomatic and total venous thromboembolism following total hip or knee replacement surgery. A pooled analysis of the four RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent deep vein thrombosis and pulmonary embolism) trials (two in total hip replacement and two in total knee replacement) demonstrated rivaroxaban to be the first and only antithrombotic agent ever to demonstrate superiority in reducing symptomatic venous thromboembolism and all-cause mortality compared with another antithrombotic agent (enoxaparin). New oral antithrombotic agents have demonstrated efficacy in prophylaxis against venous thromboembolism following total hip or knee replacement surgery while preserving safety, with increased ease of administration of thromboprophylaxis for both the patient and the physician, which may contribute to improved compliance. PMID- 23946673 TI - Introductory editorial. PMID- 23946672 TI - Product wastage from modern human growth hormone administration devices: a laboratory and computer simulation analysis. AB - BACKGROUND: Treatment of growth hormone disorders typically involves daily injections of human growth hormone (GH) over many years, incurring substantial costs. We assessed the extent of undesired GH loss due to leakage in the course of pen preparation prior to injection, and differences between the prescribed dose, based on patient weight, and the actual delivered dose based on pen dosing increments in five GH administration devices. METHODS: Norditropin(r) prefilled FlexPro(r), NordiFlex(r), NordiLet(r), and durable NordiPen(r)/SimpleXx(r) 5 mg pens (Novo Nordisk A/S, Bagsvaerd, Denmark) and durable Omnitrope(r) Pen-5 devices (Sandoz, Holzkirchen, Germany) were tested (n = 40 for each device type). Product wastage was measured in accordance with validated protocols in an ISO (International Organization for Standardization) 11608-1 and Good Manufacturing Practice compliant laboratory. The average mass of wasted GH from each device type was measured in simulations of dripping with the needle attached prior to injection and while setting a dose. Statistical significance (P < 0.05) was confirmed by Student's t-test, and a model was constructed to estimate mean annual GH wastage per patient in cohorts of pediatric patients with GH disorders. RESULTS: Mean GH mass wasted with the needle on prior to injection was 0.0 MUg with Norditropin pens, relative to 98 MUg with Omnitrope Pen-5. During dose dialing, 0.0-2.3 MUg of GH was lost with Norditropin pens versus 0.8 MUg with Omnitrope Pen-5. All Norditropin and Omnitrope device comparisons were statistically significant. Modeling GH wastage in a US cohort showed 5.5 mg of annual GH wastage per patient with FlexPro versus 43.6 mg with Omnitrope, corresponding to 7-8 additional pens per patient annually. CONCLUSION: Overall, Norditropin pens resulted in significantly less wastage than the Omnitrope Pen-5. The study suggests that GH devices of the same nominal volume exhibit differences that may affect the frequency of GH prescription refills required to remain adherent to therapy. PMID- 23946674 TI - Low-grade inflammation as trade-off causing chronic complex diseases. PMID- 23946675 TI - Species-specific actions of incretin: from the evolutionary perspective. AB - Two modes of incretin-based therapy, incretin mimetics (ie, glucagon-like peptide 1 (GLP-1) agonists) and incretin enhancers (ie, inhibitors of dipeptidyl peptidase IV (DPP-IV)), have recently been introduced into the clinical use. From the viewpoint of evolutionary endocrinology of GLP-1 and their receptors, the incretin action of GLP-1 seems to be relatively recent. Exendin-3 and exendin-4 are paralogs of GLP-1 from the lizards, and the synthetic exendin-4, exenatide, is a paralog of GLP-1. It has recently been indicated that GLP-1 and its receptor are expressed in the taste buds of the tongue, suggesting their possible function in the taste sensing signal pathway. In order to elucidate unknown functions of GLP-1 and its agonists and enhancers, ie, other than incretin actions in humans, it is possibly useful to consider GLP-1 from the viewpoint of integrated systems biology and evolutionary endocrinology. PMID- 23946676 TI - Novel isoforms of periostin expressed in the human thyroid. AB - Periostin is an extracellular matrix protein. Five isoforms of human periostin cDNA have been reported, but the expression of periostin isoforms in the human thyroid tissue is by far unknown. A group of primer sets were designed to amplify the full length of cDNA sequence of periostin. Using human thyroid carcinoma and their paired non-neoplastic tissues together with anaplastic thyroid carcinoma cell lines, we examined the presence of periostin cDNA isoforms by RT-PCR and direct DNA sequence analysis. We identified eight coexisting cDNA isoforms in all the tissue samples and cell lines. Three of them were unique to this study. Especially two of them haven't been previously reported in any species. The eight periostin isoforms differ in the C-terminus from exon XII to exon XXI where alternative splicing usually happens. This is the first report that demonstrates all the eight isoforms of periostin cDNA expressed in the human thyroid gland and identifies three novel isoforms. PMID- 23946677 TI - Is it Possible to Extirpate Cardiovascular Events in Primary Aldosteronism After Surgical Treatment. AB - It is well known that primary aldosteronism (PA) due to aldosterone-producing adenoma (APA) is a surgically curable secondary hypertension. Thus, the differential diagnosis between unilateral hyperaldosteronemia due to APA and bilateral hyperaldosteronemia due to idiopathic hyperaldosteronism (IHA) is crucial to decide surgical indication for treatment in PA patients. Adrenal venous sampling (AVS) can diagnose the laterality of hypersecretion of aldosterone in those patients, while it is still impossible to differentiate bilateral hypersecretion of bilateral aldosterone-producing adenomas (Blt-APAs) from that of bilateral hyperplasia of IHA. To solve the problem, we try to develop a new method of supper-selective ACTH-stimulated adrenal venous sampling (SS-ACTH-AVS). We performed SS-ACTH-AVS by using a strip-tip type 2.2 Fr micro catheter (Koshin Medical Inc. Japan). Adrenal effluents were sampled super selectively at the central veins and at one or two tributaries of adrenal veins in each gland. We would like to emphasize that SS-ACTH-AVS can precisely analyze the situation of hyperfunction of steroidogenesis in each side of adrenals as well as in some tiny lesions inside the adrenal cortex which are not visible in the CT images. Moreover, we can differentiate Blt-APAs from IHA, and postulate the decision of surgical treatment, such as partial adrenalectomy. Thus, we should perform SS-ACTH-AVS especially in the case demonstrating the existence of bilateral adrenal lesions such as unilateral and bilateral tumors, or even no tumor in both sides in the patients with PA. PMID- 23946678 TI - A Case of Transient ACTH Deficiency Associated with Polymyalgia Rheumatica. AB - We report a case of 79-year-old man, who was diagnosed to have transient ACTH deficiency associated with polymyalgia rheumatica (PMR). The patient presented with sudden onset bilateral shoulder pain, which was gradually aggravated. Plasma ACTH was undetectable, and both serum cortisol and urinary 17-OHCS were very low. Other pituitary hormones were normal, suggesting that hypothalamo-pituitary adrenal (HPA) axis is selectively damaged. However, within several weeks, plasma ACTH returned to normal, and showed a normal increase response to corticotropin releasing hormone stimulation test. These results indicated that ACTH deficiency was only transient. After hydrocortisone (10 mg/day) was administered, his symptoms became suddenly improved. Based on those results and clinical course, ie, elevated erythrocyte sedimentation rate, negative rheumatoid factor and the typical symptoms, which showed improvement to glulcocorticoid therapy, the final diagnosis was PMR, which was associated with transient ACTH deficiency. This is the first report of a case of PMR, in which the HPA axis was examined in its very acute phase. It was demonstrated that the case was associated with the transient adrenocortical hypofunction, which was recovered during a short time. It is therefore possible that PMR may show a different responsiveness of HPA axis depending on its phases. PMID- 23946679 TI - Combination Therapy with a Dipeptidyl Peptidase-4 Inhibitor, Sulfonylurea, and Metformin Markedly Improves HbA1c Levels in Japanese Patients with Type 2 Diabetes Mellitus. AB - Combination therapy with a dipeptidyl peptidase (DPP)-4 inhibitor and metformin or sulfonylurea results in substantial and additive glucose-lowering effects in patients with type 2 diabetes mellitus (T2DM). However, it is not known whether triple combination therapy with a DPP-4 inhibitor, metformin, and sulfonylurea has greater additive effects or synergic effects. In the present report, we investigated the effect of addition of sitagliptin, the first-in-class DPP-4 inhibitor, to ongoing metformin and sulfonylurea therapy in three female Japanese patients with T2DM who refused insulin therapy. Combined treatment with all three drugs resulted in marked improvements in HbA1c. In the first patient, HbA1c levels decreased from 11.1% to 6.1% after the addition of sitagliptin to metformin 1000 mg, glibenclamide, and miglitol, even though the dose of glibenclamide was decreased. HbA1c levels decreased similarly in the second patient, who was being treated with metformin and glibenclamide, from 7.9% to 6.0% after addition of sitagliptin and an increase in metformin to 2250 mg; this patient ceased glibenclamide because of hypoglycemia and instead was started on low-dose glimepiride. In the third patient, HbA1c levels decreased from 8.6% to 7.1% after addition of glimepiride to ongoing sitagliptin and metformin therapy. All three patients had refused insulin therapy, despite the fact that ongoing combination therapy had failed to achieve satisfactory glycemic control. Based on these results, it is likely that the addition of sitagliptin to metformin and at least a small dose of sulfonylurea may be effective in reducing HbA1c levels without weight gain. This triple combination therapy may prove useful in at least some patients who need initiation of insulin therapy. PMID- 23946680 TI - Improvement of Quality of Life (QOL) in Osteoporotic Patients by Elcatonin Treatment: A Trial Taking the Participants' Preference into Account. AB - Osteoporosis is associated with compromised quality of life (QOL), to which pain has the most important contribution. Elcatonin, a derivative of calcitonin, is widely used in the treatment of osteoporosis in two ways. One is as the inhibitor of osteoclastic bone resorption. The other is for osteoporosis-related pain based on the unique analgesic effects of elcatonin. Since pain is subjective in nature, and QOL is the only clinical outcome representing the patients' subjective perception of health status, pain associated with osteoporosis would be best evaluated based on QOL assessment. Evidence based medicine gives the highest remarks to the double-blinded, randomized controlled trial, which, however, cannot be free from methodological problems on some occasions. For example, it is practically impossible to remain blinded in the trial of a potent analgesia, which in turn causes biases. Thus, the significance of taking the patients' preference into account is increasingly acknowledged. In this study, 45 osteoporotic patients were given brochures describing the pros and cons on the three treatment choices; calcium and alfacalcidol, additional use of elcatonin, and additional use of bisphosphonate. Those who favored elcatonin were older, had more vertebral fractures, and lower QOL scores. QOL was evaluated before and three months after the treatment using SF-8; the most widely used generic questionnaire, and RDQ; a lumbago-specific measure. Elcatonin treatment improved physical function, general health, and vitality of SF-8, and RDQ score. Although this is a preliminary study, our results suggest that patients with vertebral fracture(s) have impaired QOL and more likely to favor elcatonin treatment expecting analgesia. PMID- 23946681 TI - Estimation of Duration of Symptoms in Fulminant Type 1 Diabetes Mellitus Using HbA1c or Glycated Albumin. AB - Fulminant type 1 diabetes mellitus (FT1DM) develops as a result of very rapid and almost complete destruction of pancreatic beta cells. Because of an abrupt increase in plasma glucose, HbA1c and glycated albumin (GA) might increase along with duration of symptoms in FT1DM patients. We attempted to devise a formula to estimate duration of symptoms based on the increased levels in HbA1c or GA. Four patients who developed FT1DM during the course of type 2 diabetes mellitus and in whom HbA1c was measured before onset were investigated in this study. The percents of the estimated duration of symptoms calculated from HbA1c (four patients) and GA (two patients) to the actual duration were 137 +/- 88% and 122%, respectively. In FT1DM patients in whom HbA1c and/or GA before onset and at the time of ketoacidosis are measured, duration of symptoms might be estimated with using the increased levels in HbA1c or GA. PMID- 23946682 TI - Explanation of the insulin paradox from the evolutionary point of view. AB - No abstract supplied by author. PMID- 23946683 TI - Decreasing Effect of Lidocaine.HCl on the Thickness of the Neuronal and Model Membrane. AB - This study examined the mechanism of action of a local anesthetic, lidocaine.HCl. Energy transfer between the surface fluorescent probe, 1-anilinonaphthalene-8 sulfonic acid, and the hydrophobic fluorescent probe, 1,3-di(1-pyrenyl) propane, was used to determine the effect of lidocaine.HCl on the thickness (D) of the synaptosomal plasma membrane vesicles (SPMV) isolated from the bovine cerebral cortex, and liposomes of the total lipids (SPMVTL) and phospholipids (SPMVPL) extracted from the SPMV. The thickness (D) of the intact SPMV, SPMVTL and SPMVPL were 1.044+/-0.008, 0.914+/-0.005 and 0.890+/-0.003 (arbitrary units, n=5) at 37C (pH 7.4), respectively. Lidocaine.HCl decreased the thickness of the neuronal and model membrane lipid bilayers in a dose-dependent manner with a significant decrease in the thickness, even at 0.1 mM. The decreasing effect of lidocaine.HCl on the membrane thickness might be responsible for some, but not all of its anesthetic action. PMID- 23946684 TI - (-)-Epigallocatechin-3-gallate Modulates the Differential Expression of Survivin Splice Variants and Protects Spermatogenesis During Testicular Torsion. AB - The anti-apoptotic effect of (-)-epigallocatechin-3-gallate (EGCG) during unilateral testicular torsion and detorsion (TT/D) was established in our previous study. In mice, the smallest inhibitor of apoptosis, survivin, is alternatively spliced into three variants, each suggested to have a unique function. Here, we assessed how EGCG exerts its protective effect through the expression of the different survivin splice variants and determined its effect on the morphology of the seminiferous tubules during TT/D. Three mouse groups were used: sham, TT/D+vehicle and TT/D treated with EGCG. The expression of the survivin variants (140 and 40) and other apoptosis genes (p53, Bax and Bcl-2) was measured with semi-quantitative RT-PCR. Histological analysis was performed to assess DNA fragmentation, damage to spermatogenesis and morphometric changes in the seminiferous tubules. In the TT/D+vehicle group, survivin 140 expression was markedly decreased, whereas survivin 40 expression was not significantly different. In parallel, there was an increase in the mRNA level of p53 and the Bax to Bcl-2 ratio in support of apoptosis induction. Histological analyses revealed increased DNA fragmentation and increased damage to spermatogenesis associated with decreased seminiferous tubular diameter and decreased germinal epithelial cell thickness in the TT/D+vehicle group. These changes were reversed to almost sham levels upon EGCG treatment. Our data indicate that EGCG protects the testis from TT/D-induced damage by protecting the morphology of the seminiferous tubules and modulating survivin 140 expression. PMID- 23946685 TI - Curcumin attenuates radiation-induced inflammation and fibrosis in rat lungs. AB - A beneficial radioprotective agent has been used to treat the radiation-induced lung injury. This study was performed to investigate whether curcumin, which is known to have anti-inflammatory and antioxidant properties, could ameliorate radiation-induced pulmonary inflammation and fibrosis in irradiated lungs. Rats were given daily doses of intragastric curcumin (200 mg/kg) prior to a single irradiation and for 8 weeks after radiation. Histopathologic findings demonstrated that macrophage accumulation, interstitial edema, alveolar septal thickness, perivascular fibrosis, and collapse in radiation-treated lungs were inhibited by curcumin administration. Radiation-induced transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF) expression, and collagen accumulation were also inhibited by curcumin. Moreover, western blot analysis revealed that curcumin lowered radiation-induced increases of tumor necrosis factor-alpha (TNF-alpha), TNF receptor 1 (TNFR1), and cyclooxygenase-2 (COX-2). Curcumin also inhibited the nuclear translocation of nuclear factor kappa B (NF-kappaB) p65 in radiation-treated lungs. These results indicate that long-term curcumin administration may reduce lung inflammation and fibrosis caused by radiation treatment. PMID- 23946686 TI - Expression and activity of the na-k ATPase in ischemic injury of primary cultured astrocytes. AB - Astrocytes are reported to have critical functions in ischemic brain injury including protective effects against ischemia-induced neuronal dysfunction. Na-K ATPase maintains ionic gradients in astrocytes and is suggested as an indicator of ischemic injury in glial cells. Here, we examined the role of the Na-K ATPase in the pathologic process of ischemic injury of primary cultured astrocytes. Chemical ischemia was induced by sodium azide and glucose deprivation. Lactate dehydrogenase assays showed that the cytotoxic effect of chemical ischemia on astrocytes began to appear at 2 h of ischemia. The expression of Na-K ATPase alpha1 subunit protein was increased at 2 h of chemical ischemia and was decreased at 6 h of ischemia, whereas the expression of alpha1 subunit mRNA was not changed by chemical ischemia. Na-K ATPase activity was time-dependently decreased at 1, 3, and 6 h of chemical ischemia, whereas the enzyme activity was temporarily recovered to the control value at 2 h of chemical ischemia. Cytotoxicity at 2 h of chemical ischemia was significantly blocked by reoxygenation for 24 h following ischemia. Reoxygenation following chemical ischemia for 1 h significantly increased the activity of the Na-K ATPase, while reoxygenation following ischemia for 2 h slightly decreased the enzyme activity. These results suggest that the critical time for ischemia-induced cytotoxicity of astrocytes might be 2 h after the initiation of ischemic insult and that the increase in the expression and activity of the Na-K ATPase might play a protective role during ischemic injury of astrocytes. PMID- 23946687 TI - Korean Red Ginseng Induced Cardioprotection against Myocardial Ischemia in Guinea Pig. AB - This study was designed to evaluate the protective effect of Korean red ginseng (KRG) against ischemia/reperfusion (I/R) injury in isolated guinea pig heart. KRG has been shown to possess various ginsenosides, which are the major components of Panax ginseng. These components are known naturally occurring compounds with beneficial effects and free radical scavenging activity. The heart was induced to ischemia for 60 min, followed by 120 min reperfusion. The hearts were randomly allocated into five groups (n=8 for each group): normal control (N/C), KRG control, I/R control, 250 mg/kg KRG group and 500 mg/kg KRG group. KRG significantly increased hemodynamics parameters such as aortic flow, coronary flow and cardiac output. Moreover, KRG significantly increased left ventricular systolic pressure (LVSP), the maximal rate of contraction (+dP/dtmax) and maximal rate of relaxation (-dP/dtmax). Also, treatment of KRG ameliorated electrocardiographic index such as the QRS, QT and RR intervals. Moreover, KRG significantly suppressed the lactate dehydrogenase, creatine kinase-MB fraction and cardiac troponin I and ameliorated the oxidative stress markers such as malondialdehyde and glutathione. KRG was standardized through ultra performance liquid chromatograph analysis for its major ginsenosides. Taken together, KRG has been shown to prevent cardiac injury by normalizing the biochemical and oxidative stress. PMID- 23946688 TI - Mutant p53-Notch1 Signaling Axis Is Involved in Curcumin-Induced Apoptosis of Breast Cancer Cells. AB - Notch1 has been reported to be highly expressed in triple-negative and other subtypes of breast cancer. Mutant p53 (R280K) is overexpressed in MDA-MB-231 triple-negative human breast cancer cells. The present study aimed to determine whether the mutant p53 can be a potent transcriptional activator of the Notch1 in MDA-MB-231 cells, and explore the role of this mutant p53-Notch1 axis in curcumin induced apoptosis. We found that curcumin treatment resulted in an induction of apoptosis in MDA-MB-231 cells, together with downregulation of Notch1 and its downstream target, Hes1. This reduction in Notch1 expression was determined to be due to the decreased activity of endogenous mutant p53. We confirmed the suppressive effect of curcumin on Notch1 transcription by performing a Notch1 promoter-driven reporter assay and identified a putative p53-binding site in the Notch1 promoter by EMSA and chromatin immunoprecipitation analysis. Overexpression of mutant p53 increased Notch1 promoter activity, whereas knockdown of mutant p53 by small interfering RNA suppressed Notch1 expression, leading to the induction of cellular apoptosis. Moreover, curcumin-induced apoptosis was further enhanced by the knockdown of Notch1 or mutant p53, but it was decreased by the overexpression of active Notch1. Taken together, our results demonstrate, for the first time, that Notch1 is a transcriptional target of mutant p53 in breast cancer cells and suggest that the targeting of mutant p53 and/or Notch1 may be combined with a chemotherapeutic strategy to improve the response of breast cancer cells to curcumin. PMID- 23946689 TI - Neuronal Responses in the Globus Pallidus during Subthalamic Nucleus Electrical Stimulation in Normal and Parkinson's Disease Model Rats. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been widely used as a treatment for the movement disturbances caused by Parkinson's disease (PD). Despite successful application of DBS, its mechanism of therapeutic effect is not clearly understood. Because PD results from the degeneration of dopamine neurons that affect the basal ganglia (BG) network, investigation of neuronal responses of BG neurons during STN DBS can provide informative insights for the understanding of the mechanism of therapeutic effect. However, it is difficult to observe neuronal activity during DBS because of large stimulation artifacts. Here, we report the observation of neuronal activities of the globus pallidus (GP) in normal and PD model rats during electrical stimulation of the STN. A custom artifact removal technique was devised to enable monitoring of neural activity during stimulation. We investigated how GP neurons responded to STN stimulation at various stimulation frequencies (10, 50, 90 and 130 Hz). It was observed that activities of GP neurons were modulated by stimulation frequency of the STN and significantly inhibited by high frequency stimulation above 50 Hz. These findings suggest that GP neuronal activity is effectively modulated by STN stimulation and strongly dependent on the frequency of stimulation. PMID- 23946690 TI - High glucose induces connective tissue growth factor expression and extracellular matrix accumulation in rat aorta vascular smooth muscle cells via extracellular signal-regulated kinase 1/2. AB - Connective tissue growth factor (CTGF) is a potent pro-fibrotic factor, which is implicated in fibrosis through extracellular matrix (ECM) induction in diabetic cardiovascular complications. It is an important downstream mediator in the fibrotic action of transforming growth factor beta (TGFbeta) and is potentially induced by hyperglycemia in human vascular smooth muscle cells (VSMCs). Therefore, the goal of this study is to identify the signaling pathways of CTGF effects on ECM accumulation and cell proliferation in VSMCs under hyperglycemia. We found that high glucose stimulated the levels of CTGF mRNA and protein and followed by VSMC proliferation and ECM components accumulation such as collagen type 1, collagen type 3 and fibronectin. By depleting endogenous CTGF we showed that CTGF is indispensable for the cell proliferation and ECM components accumulation in high glucose-stimulated VSMCs. In addition, pretreatment with the MEK1/2 specific inhibitors, PD98059 or U0126 potently inhibited the CTGF production and ECM components accumulation in high glucose-stimulated VSMCs. Furthermore, knockdown with ERK1/2 MAPK siRNA resulted in significantly down regulated of CTGF production, ECM components accumulation and cell proliferation in high glucose-stimulated VSMCs. Finally, ERK1/2 signaling regulated Egr-1 protein expression and treatment with recombinant CTGF reversed the Egr-1 expression in high glucose-induced VSMCs. It is conceivable that ERK1/2 MAPK signaling pathway plays an important role in regulating CTGF expression and suggests that blockade of CTGF through ERK1/2 MAPK signaling may be beneficial for therapeutic target of diabetic cardiovascular complication such as atherosclerosis. PMID- 23946691 TI - Radicicol Inhibits iNOS Expression in Cytokine-Stimulated Pancreatic Beta Cells. AB - Here, we show that radicicol, a fungal antibiotic, resulted in marked inhibition of inducible nitric oxide synthase (iNOS) transcription by the pancreatic beta cell line MIN6N8a in response to cytokine mixture (CM: TNF-alpha, IFN-gamma, and IL-1beta). Treatment of MIN6N8a cells with radicicol inhibited CM-stimulated activation of NF-kappaB/Rel, which plays a critical role in iNOS transcription, in a dose-related manner. Nitrite production in the presence of PD98059, a specific inhibitor of the extracellular signal-regulated protein kinase-1 and 2 (ERK1/2) pathway, was dramatically diminished, suggesting that the ERK1/2 pathway is involved in CM-induced iNOS expression. In contrast, SB203580, a specific inhibitor of p38, had no effect on nitrite generation. Collectively, this series of experiments indicates that radicicol inhibits iNOS gene expression by blocking ERK1/2 signaling. Due to the critical role that NO release plays in mediating destruction of pancreatic beta cells, the inhibitory effects of radicicol on iNOS expression suggest that radicicol may represent a useful anti-diabetic activity. PMID- 23946692 TI - Changes in c-Fos Expression in the Forced Swimming Test: Common and Distinct Modulation in Rat Brain by Desipramine and Citalopram. AB - Rodents exposed to a 15-min pretest swim in the forced swimming test (FST) exhibit prolonged immobility in a subsequent 5-min test swim, and antidepressant treatment before the test swim reduces immobility. At present, neuronal circuits recruited by antidepressant before the test swim remain unclear, and also less is known about whether antidepressants with different mechanisms of action could influence neural circuits differentially. To reveal the neural circuits associated with antidepressant effect in the FST, we injected desipramine or citalopram 0.5 h, 19 h, and 23 h after the pretest swim and observed changes in c Fos expression in rats before the test swim, namely 24 h after the pretest swim. Desipramine treatment alone in the absence of pretest swim was without effect, whereas citalopram treatment alone significantly increased the number of c-Fos like immunoreactive cells in the central nucleus of the amygdala and bed nucleus of the stria terminalis, where this pattern of increase appears to be maintained after the pretest swim. Both desipramine and citalopram treatment after the pretest swim significantly increased the number of c-Fos-like immunoreactive cells in the ventral lateral septum and ventrolateral periaqueductal gray before the test swim. These results suggest that citalopram may affect c-Fos expression in the central nucleus of the amygdala and bed nucleus of the stria terminalis distinctively and raise the possibility that upregulation of c-Fos in the ventral lateral septum and ventrolateral periaqueductal gray before the test swim may be one of the probable common mechanisms underlying antidepressant effect in the FST. PMID- 23946693 TI - Neuroprotective Effects of AMP-Activated Protein Kinase on Scopolamine Induced Memory Impairment. AB - AMP-activated protein kinase (AMPK), an important regulator of energy metabolism, is activated in response to cellular stress when intracellular levels of AMP increase. We investigated the neuroprotective effects of AMPK against scopolamine induced memory impairment in vivo and glutamate-induced cytotoxicity in vitro. An adenovirus expressing AMPK wild type alpha subunit (WT) or a dominant negative form (DN) was injected into the hippocampus of rats using a stereotaxic apparatus. The AMPK WT-injected rats showed significant reversal of the scopolamine induced cognitive deficit as evaluated by escape latency in the Morris water maze. In addition, they showed enhanced acetylcholinesterase (AChE) reactive neurons in the hippocampus, implying increased cholinergic activity in response to AMPK. We also studied the cellular mechanism by which AMPK protects against glutamate-induced cell death in primary cultured rat hippocampal neurons. We further demonstrated that AMPK WT-infected cells increased cell viability and reduced Annexin V positive hippocampal neurons. Western blot analysis indicated that AMPK WT-infected cells reduced the expression of Bax and had no effects on Bcl-2, which resulted in a decreased Bax/Bcl-2 ratio. These data suggest that AMPK is a useful cognitive impairment treatment target, and that its beneficial effects are mediated via the protective capacity of hippocampal neurons. PMID- 23946694 TI - Effect of Lutein on L-NAME-Induced Hypertensive Rats. AB - We investigated the antihypertensive effect of lutein on N(G) -nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Daily oral administration of L-NAME (40 mg/kg)-induced a rapid progressive increase in mean arterial pressure (MAP). L-NAME significantly increased MAP from the first week compared to that in the control and reached 193.3+/-9.6 mmHg at the end of treatment. MAP in the lutein groups was dose-dependently lower than that in the L NAME group. Similar results were observed for systolic and diastolic blood pressure of L-NAME-induced hypertensive rats. The control group showed little change in heart rate for 3 weeks, whereas L-NAME significantly reduced heart rate from 434+/-26 to 376+/-33 beats/min. Lutein (2 mg/kg) significantly prevented the reduced heart rate induced by L-NAME. L-NAME caused hypertrophy of heart and kidney, and increased plasma lipid peroxidation four-fold but significantly reduced plasma nitrite and glutathione concentrations, which were significantly prevented by lutein in a dose-dependent manner. These findings suggest that lutein affords significant antihypertensive and antioxidant effects against L NAME-induced hypertension in rats. PMID- 23946696 TI - Mechanism of Relaxation Via TASK-2 Channels in Uterine Circular Muscle of Mouse. AB - Plasma pH can be altered during pregnancy and at labor. Membrane excitability of smooth muscle including uterine muscle is suppressed by the activation of K(+) channels. Because contractility of uterine muscle is regulated by extracellular pH and humoral factors, K(+) conductance could be connected to factors regulating uterine contractility during pregnancy. Here, we showed that TASK-2 inhibitors such as quinidine, lidocaine, and extracellular acidosis produced contraction in uterine circular muscle of mouse. Furthermore, contractility was significantly increased in pregnant uterine circular muscle than that of non-pregnant muscle. These patterns were not changed even in the presence of tetraetylammonium (TEA) and 4-aminopyridine (4-AP). Finally, TASK-2 inhibitors induced strong myometrial contraction even in the presence of L-methionine, a known inhibitor of stretchactivated channels in myometrium. When compared to non-pregnant myometrium, pregnant myometrium showed increased immunohistochemical expression of TASK-2. Therefore, TASK-2, seems to play a key role during regulation of myometrial contractility in the pregnancy and provides new insight into preventing preterm delivery. PMID- 23946695 TI - A review on renal toxicity profile of common abusive drugs. AB - Drug abuse has become a major social problem of the modern world and majority of these abusive drugs or their metabolites are excreted through the kidneys and, thus, the renal complications of these drugs are very common. Morphine, heroin, cocaine, nicotine and alcohol are the most commonly abused drugs, and their use is associated with various types of renal toxicity. The renal complications include a wide range of glomerular, interstitial and vascular diseases leading to acute or chronic renal failure. The present review discusses the renal toxicity profile and possible mechanisms of commonly abused drugs including morphine, heroin, cocaine, nicotine, caffeine and alcohol. PMID- 23946697 TI - Additive role of the vestibular end organ and baroreceptors on the regulation of blood pressure in rats. AB - Contribution of the vestibular end organ to regulation of arterial pressure was quantitatively compared with the role of baroreceptors in terms of baroreflex sensitivity and c-Fos protein expression in the rostral ventrolateral medulla (RVLM). Baroreflex sensitivity and c-Fos protein expression in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or baroreceptor unloading. BL attenuated baroreflex sensitivity during intravenous infusion of sodium nitroprusside (SNP), but did not significantly affect the sensitivity following infusion of phenylephrine (PE). Baroreflex sensitivity became positive following sinoaortic denervation (SAD) during infusion of PE and attenuated sensitivity during infusion of SNP. Baroreflex sensitivity also became positive following double ablation (BL+SAD) during infusion of PE, and attenuated sensitivity during infusion of SNP. c-Fos protein expression increased significantly in the RVLM in the sham group after SNP administration. However, the BL, SAD, and SAD+BL groups showed significant decreases in c-Fos protein expression compared with that in the sham group. The SAD group showed more reduced c-Fos protein expression than that in the BL group, and the SAD+BL group showed less expression than that in the SAD group. These results suggest that the vestibular system cooperates with baroreceptors to maintain arterial pressure during hypotension but that baroreceptors regulate arterial pressure during both hypotension and hypertension. Additionally, afferent signals for maintaining blood pressure from the vestibular end organs and the baroreceptors may be integrated in the RVLM. PMID- 23946698 TI - Examining Evidence for Autonomy and Relatedness in Urban Inuit Parenting. AB - Inuit have experienced significant lifestyle changes in the past 50 years. Most recently, urbanization has resulted in greater numbers of Inuit living in urban centres in southern Canada. Little is known about Inuit parenting, and nothing has been published on Inuit parenting in an urban context. The present study sought to address this gap by describing the parenting of Inuit living in a large Canadian city and examining emergent themes for evidence of autonomy and relatedness. In partnership with the Tungasuvvingat Inuit Family Resource Centre, 39 Inuit parents completed an interview about their parenting experiences. Based on interviews, major parenting themes included: child characteristics; parenting behaviours and beliefs; affection and love; stressors; and responsive and respectful parenting. The majority of parenting themes linked to relatedness, although there was evidence of autonomy in both parenting behaviours and child characteristics. Results are interpreted in light of the autonomy-relatedness framework and theoretical implications of findings are discussed. PMID- 23946699 TI - Examining Outcomes of Acute Psychiatric Hospitalization among Children. AB - Within the past two decades, few studies have examined outcomes of acute psychiatric hospitalization among children, demonstrating change in emotional and behavioral functioning. A secondary analysis of pre-test/post-test data collected on 36 children was conducted, using the Target Symptom Rating (TSR). The TSR is a 13-item measure with two subscales - Emotional Problems and Behavioral Problems and was designed for evaluation of outcome among children and adolescents in acute inpatient psychiatric settings. Results of this study, its limitations, and the barriers encountered in the implementation of the TSR scale as part of routine clinical practice are discussed. PMID- 23946700 TI - Sensor Network Localization by Eigenvector Synchronization Over the Euclidean Group. AB - We present a new approach to localization of sensors from noisy measurements of a subset of their Euclidean distances. Our algorithm starts by finding, embedding, and aligning uniquely realizable subsets of neighboring sensors called patches. In the noise-free case, each patch agrees with its global positioning up to an unknown rigid motion of translation, rotation, and possibly reflection. The reflections and rotations are estimated using the recently developed eigenvector synchronization algorithm, while the translations are estimated by solving an overdetermined linear system. The algorithm is scalable as the number of nodes increases and can be implemented in a distributed fashion. Extensive numerical experiments show that it compares favorably to other existing algorithms in terms of robustness to noise, sparse connectivity, and running time. While our approach is applicable to higher dimensions, in the current article, we focus on the two dimensional case. PMID- 23946701 TI - A movement to promote healthy sleep: the case for corporate involvement. PMID- 23946703 TI - Association of CPAP bacterial colonization with chronic rhinosinusitis. AB - STUDY OBJECTIVE: The purpose of our study was to investigate whether bacterial colonization of the continuous positive air-way pressure (CPAP) machine reservoirs occurred, and if so, if it was related to the development of chronic rhinosinusitis (CRS). DESIGN: Prospective cohort study. SETTING: London Health Sciences Center (LHSC). PATIENTS: Regular CPAP users with obstructive sleep apnea (OSA). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Patient demographics were recorded and they were asked to fill out the chronic sinusitis survey (CSS) form. Patients then had their CPAP machines swabbed. An ANOVA was used to determine if the presence of microbacterial colonization was related to CSS scores. In total, 72 patients were included in the study. There was no significant difference in any of the scores between the group with positive cultures and the group without positive cultures. CONCLUSIONS: Having a positive culture in the cpap reservoir does not seem to lead to an increased symptomatology of crs: although the reservoirs often become colonized, there seems to be no clinical impact. PMID- 23946702 TI - Blue-light-blocking intraocular lens implantation improves the sleep quality of cataract patients. AB - STUDY OBJECTIVES: To evaluate whether blue-light-blocking intraocular lens implantation affects the sleep quality of cataract patients. DESIGN: Pre test/post-test experiment. SETTING: N/A. PARTICIPANTS: 40 patients having bilateral cataracts with level higher than N3 (LOCS II) nucleus hardness, including 26 females (65%) and 14 males (35%). INTERVENTIONS: Cataract phacoemulsification followed by blue-light-blocking intraocular lens (IOLs, SN60WF, Alcon Laboratories, USA) implantation. MEASUREMENTS AND RESULTS: Patients were contacted in site before cataract surgery and followed by telephone at least 2 months later after second-eye surgery. Pittsburgh Sleep Quality Index (PSQI) questionnaires were administered to evaluate sleep quality. Median age of patients was 74 years (IQR 70 to 78). The median PSQI globe scores were 7 before surgery and 4 after surgery (Z = -2.121, p = 0.037). More specifically, there were significant differences on subjective sleep quality (Z = -2.064, p = 0.045), sleep duration (Z = -2.037, p = 0.047) and daytime dysfunction (Z = -2.142, p = 0.034) when compared between before and after surgeries. The ratio of poor sleepers (PSQI > 5) was reduced significantly after surgery (chi2 = 14.532, p < 0.001). CONCLUSIONS: Blue-light-blocking IOL had a significantly beneficial effect on the sleep quality of cataract patients. PMID- 23946704 TI - Efficacy and safety of adjunctive modafinil treatment on residual excessive daytime sleepiness among nasal continuous positive airway pressure-treated japanese patients with obstructive sleep apnea syndrome: a double-blind placebo controlled study. AB - STUDY OBJECTIVES: This double-blind study evaluated the efficacy and safety of modafinil for treating excessive daytime sleepiness in Japanese patients with obstructive sleep apnea syndrome (OSAS). METHODS: Patients with residual excessive sleepiness (Epworth Sleepiness Scale [ESS] >= 11) on optimal nasal continuous positive airway pressure (nCPAP) therapy (apnea-hypopnea index <= 10) were randomized to either 200 mg modafinil (n = 52) or placebo (n = 62) once daily for 4 weeks. Outcomes included baseline-week 4 changes in ESS total score, sleep latency on maintenance of wakefulness test (SL-MWT), nocturnal polysomnography, Pittsburgh Sleep Quality Index (PSQI), and safety. RESULTS: All 114 randomized patients completed the study. Mean change in ESS total score (-6.6 vs -2.4, p < 0.001) and SL-MWT (+2.8 vs -0.4 minutes, p = 0.009) were significantly greater with modafinil than with placebo. ESS total score decreased from > 11 to < 11 at the final assessment in 69.2% of modafinil-treated patients and 30.6% of placebo-treated patients (p < 0.001). Corresponding rates at week 1 were 57.7% and 33.9% (p = 0.014). Changes in nocturnal polysomnography, PSQI, and apnea-hypopnea index from baseline to the final assessment were similar in both groups. Adverse drug reactions occurred in 36.5% and 22.6% of patients in the modafinil and placebo groups, respectively (p = 0.146). CONCLUSIONS: Once-daily modafinil was effective and well tolerated for managing residual daytime sleepiness in Japanese OSAS patients with residual excessive daytime sleepiness on optimal nCPAP therapy. PMID- 23946705 TI - Responsiveness of jaw motor activation to arousals during sleep in patients with obstructive sleep apnea syndrome. AB - OBJECTIVES: We aimed to characterize the association between jaw muscle contractions and respiratory events in patients with obstructive sleep apnea syndrome (OSAS) and to investigate the responsiveness of the contractions to respiratory events in comparison with that of leg muscles in terms of arousal types and sleep states. METHODS: Polysomnographic (PSG) recordings were performed in 19 OSAS patients (F/M: 2/17; 53.1 +/- 13.7 years; AHI: 31.8 +/- 19.9/h) with no concomitant sleep bruxism or other sleep-related movement disorders. Muscle contractions of unilateral masseter (MAS) and anterior tibialis (AT) muscles were scored during sleep in association with graded arousals (microarousals and awakenings) related or unrelated to apneahypopnea events. RESULTS: Arousals were scored for 68.2% and 52.3% of respiratory events during light NREM and REM sleep, respectively. Respiratory events with arousals were associated with longer event duration and/or larger transient oxygen desaturation than those without (ANOVAs: p < 0.05). Median response rates of MAS events to respiratory events were 32.1% and 18.9% during NREM and REM sleep. During two sleep states, MAS muscle was rarely activated after respiratory events without arousals, while its response rate increased significantly in association with the duration of arousals (Friedman tests: p < 0.001). A similar response pattern was found for AT muscle. Motor responsiveness of the two muscles to arousals after respiratory events did not differ from responsiveness to spontaneous arousals in two sleep stages. CONCLUSION: In patients with OSAS, the contractions of MAS and AT muscles after respiratory events can be nonspecific motor phenomena, dependent on the duration of arousals rather than the occurrence of respiratory events. PMID- 23946706 TI - Impact of CPAP use and age on mortality in patients with combined COPD and obstructive sleep apnea: the overlap syndrome. AB - BACKGROUND: The overlap syndrome, defined by concurrent existence of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), is associated with poor outcomes. From a large outpatient cohort we aimed to define better the risk factors for increased mortality in the overlap syndrome and hypothesized that CPAP adherence would be associated with improved survival in patients with overlap syndrome. METHODS: A post hoc analysis from an outpatient database of 10,272 patients from 2007-2010, identified 3,396 patients which were classified in 6 groups; patients both alive or deceased, with the known diagnosis of COPD, OSA, and the overlap of COPD plus OSA. Information regarding their gender, age, pulmonary function, obstructive sleep apnea parameters, and CPAP compliance was collected. A multivariate Cox proportional hazards model was generated for the determinants of mortality. RESULTS: 1,112 COPD patients and 2,284 OSA patients were identified by diagnostic coding and then comprehensive chart review. Of these, 227 patients were identified with the overlap syndrome. From this group, 17 patients (7.4%) died. Multivariate analysis revealed hours of CPAP use and age as independent predictors of mortality (HR 0.71 and 1.14, p < 0.001, 0.002). Greater time on CPAP was associated with reduced mortality; although age did not correlate with CPAP use (p = 0.2), mean age of those with CPAP use < 2 hours per night was significantly higher than those using CPAP > 2 hours per night. CONCLUSIONS: From this observational cohort, mortality in the overlap syndrome is impacted by CPAP use. Age is also an independent factor which has a negative association with survival and CPAP usage. PMID- 23946707 TI - Differential timing of arousals in obstructive and central sleep apnea in patients with heart failure. AB - STUDY OBJECTIVES: In obstructive sleep apnea (OSA), arousals generally occur at apnea termination and help restore airflow. However, timing of arousals in central sleep apnea (CSA) has not been objectively quantified, and since arousals can persist even when CSA is alleviated, may not play the same defensive role as they do in OSA. We hypothesized that arousals following central events would occur longer after event termination than following obstructive events and would be related to circulation time. METHODS: We examined polysomnograms from 20 patients with heart failure (HF) (left ventricular ejection fraction <= 45%): 10 with OSA and 10 with CSA (apneahypopnea index >= 15). Twenty central or obstructive apneas or hypopneas were analyzed in each patient. RESULTS: Compared to the OSA group in whom arousals generally occurred at obstructive event termination, in the CSA group they occurred longer after central event termination (0.9 +/- 1.1 versus 8.0 +/- 4.1 s, p < 0.0001), but before peak hyperpnea. Time from arousal to peak hyperpnea did not differ between groups (4.3 +/- 1.1 vs 4.8 +/- 1.6 s, p = 0.416). Unlike the OSA group, latency from apnea termination to arousal correlated with circulation time in the CSA group (r = 0.793, p = 0.006). CONCLUSIONS: In HF patients with CSA, apnea-to-arousal latency is longer than in those with OSA, and arousals usually follow resumption of airflow. These observations provide evidence that arousals are less likely to act as a protective mechanism to facilitate resumption of airflow following apneas in CSA than in OSA. PMID- 23946708 TI - Prevalence and risk factors of sleep disordered breathing in patients with rheumatic valvular heart disease. AB - STUDY OBJECTIVES: Sleep disordered breathing (SDB) is common in patients with chronic heart failure secondary to non-valvular heart disease; however, the prevalence and characteristics of SDB in patients with rheumatic valvular heart disease (RVHD) are unclear. This study was designed to determine the prevalence, characteristics, and risk factors for SDB in RVHD patients. METHODS: A cross sectional study was conducted in 260 RVHD patients. The following data were recorded: types of heart valve lesions, electrocardiographic, echocardiographic, arterial blood gas analysis findings, baseline medication, 6-minute walk test (6MWT) distance, and sleep parameters. RESULTS: Compared to patients with single leftsided valve lesions, patients with left- and rightsided valve lesions had a higher prevalence of SDB (46.2% vs. 31.2%, p = 0.013); the increased prevalence of SDB only involved central sleep apnea (CSA) (31.1% vs. 14.1%, p = 0.001). Patients with obstructive sleep apnea (OSA) or CSA were older and had a shorter 6MWT distance, lower left ventricle ejection fraction and PaO2, a longer lung-to finger circulation time, and a higher prevalence of atrial fibrillation (AF) and hypertension (all p < 0.05) as compared with patients without SDB. Multinomial logistic regression analysis showed that PaO2 <= 85 mm Hg was the only risk factor for OSA. Male gender, AF, 6MWT distance <= 300 m, PaO2 <= 85 mmHg, and PaCO2 <= 40 mm Hg were risk factors for CSA. CONCLUSIONS: Patients with RVHD had a high prevalence of SDB (predominantly CSA). RVHD patients with SDB, particularly those who had CSA, manifested more severe symptoms and greater impairment of cardiac function. Assessments of clinical manifestations of cardiac dysfunction may be important for predicting the risk factors for SDB. PMID- 23946709 TI - Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. AB - STUDY OBJECTIVES: Differentiation of narcolepsy without cataplexy from idiopathic hypersomnia relies entirely upon the multiple sleep latency test (MSLT). However, the test-retest reliability for these central nervous system hypersomnias has never been determined. METHODS: Patients with narcolepsy without cataplexy, idiopathic hypersomnia, and physiologic hypersomnia who underwent two diagnostic multiple sleep latency tests were identified retrospectively. Correlations between the mean sleep latencies on the two studies were evaluated, and we probed for demographic and clinical features associated with reproducibility versus change in diagnosis. RESULTS: Thirty-six patients (58% women, mean age 34 years) were included. Inter -test interval was 4.2 +/- 3.8 years (range 2.5 months to 16.9 years). Mean sleep latencies on the first and second tests were 5.5 (+/- 3.7 SD) and 7.3 (+/- 3.9) minutes, respectively, with no significant correlation (r = 0.17, p = 0.31). A change in diagnosis occurred in 53% of patients, and was accounted for by a difference in the mean sleep latency (N = 15, 42%) or the number of sleep onset REM periods (N = 11, 31%). The only feature predictive of a diagnosis change was a history of hypnagogic or hypnopompic hallucinations. CONCLUSIONS: The multiple sleep latency test demonstrates poor test-retest reliability in a clinical population of patients with central nervous system hypersomnia evaluated in a tertiary referral center. Alternative diagnostic tools are needed. PMID- 23946710 TI - Plasma total ghrelin and leptin levels in human narcolepsy and matched healthy controls: basal concentrations and response to sodium oxybate. AB - STUDY OBJECTIVES: Narcolepsy is caused by a selective loss of hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with hypocretin neurons to influence energy homeostasis. Here, we evaluated whether human hypocretin deficiency, or the narcolepsy therapeutic agent sodium oxybate, alter the levels of these hormones. METHODS: Eight male, medication free, hypocretin deficient, narcolepsy with cataplexy patients, and 8 healthy controls matched for age, sex, body mass index (BMI), waisttohip ratio, and body fat percentage were assessed. Blood samples of total ghrelin and leptin were collected over 24 hours at 60 and 20-min intervals, respectively, during 2 study occasions: baseline, and during the last night of 5 consecutive nights of sodium oxybate administration (2 * 3.0 g/night). RESULTS: At baseline, mean 24-h total ghrelin (936 +/- 142 vs. 949 +/- 175 pg/mL, p = 0.873) and leptin (115 +/- 5.0 vs. 79.0 +/- 32 mg/L, p = 0.18) levels were not different between hypocretin deficient narcolepsy patients and controls. Furthermore, sodium oxybate did not significantly affect the plasma concentration of either one of these hormones. CONCLUSIONS: The increased BMI of narcolepsy patients is unlikely to be mediated by hypocretin deficiency-mediated alterations in total ghrelin or leptin levels. Thus, the effects of these hormones on hypocretin neurons may be mainly unidirectional. Although sodium oxybate may influence body weight, the underlying mechanism is unlikely to involve changes in total ghrelin or leptin secretion. PMID- 23946711 TI - Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the innsbruck narcolepsy cohort. AB - STUDY OBJECTIVES: Narcolepsy is reported to affect 26-56/100,000 in the general population. We aimed to describe clinical and polysomnographic features of a large narcolepsy cohort in order to comprehensively characterize the narcoleptic spectrum. METHODS: We performed a chart- and polysomnographybased review of all narcolepsy patients of the Innsbruck narcolepsy cohort. RESULTS: A total of 100 consecutive narcolepsy patients (87 with cataplexy [NC], 13 without cataplexy [N]) were included in the analysis. All subjects had either excessive daytime sleepiness or cataplexy as their initial presenting clinical feature. Age at symptom onset was 20 (6-69) years. Diagnostic delay was 6.5 (0-39) years. The complete narcolepsy tetrad was present in 36/100 patients; 28/100 patients had three cardinal symptoms; 29/100 had two; and 7/100 had only excessive daytime sleepiness. Severity varied broadly with respect to excessive daytime sleepiness (median Epworth Sleepiness Scale score: 18, range 10-24), cataplexy (8-point Likert scale: median 4.5, range 1-8), hypnagogic hallucinations (median 4.5, range 1-7), and sleep paralysis (median 3, range 1-7). Sleep comorbidity was highly prevalent and ranged from sleeprelated movement disorders (n = 55/100), parasomnias (n = 34/100), and sleeprelated breathing disorders (n = 24/100), to insomnia (n = 28/100). REM sleep without atonia or a periodic limb movement in sleep index > 5/h were present in most patients (90/100 and 75/100). A high percentage of narcoleptic patients in the present study had high frequency leg movements (35%) and excessive fragmentary myoclonus (22%). Of the narcolepsy patients with clinical features of REM sleep behavior disorder (RBD), 76.5% had EMG evidence for RBD on the multiple sleep latency test (MSLT), based on a standard cutoff of a minimum of 18% of 3-sec miniepochs. CONCLUSION: This study is one of the largest monocentric polysomnographic studies to date of patients with narcolepsy and confirms the frequent comorbidity of narcolepsy with many other sleep disorders. Our study is the first to evaluate the percentage of patients with high frequency leg movements and excessive fragmentary myoclonus in narcolepsy and is the first to demonstrate EMG evidence of RBD in the MSLT. These findings add to the growing body of literature suggesting that motor instability is a key feature of narcolepsy. PMID- 23946712 TI - Obstructive sleep apnea (OSA) in preadolescent girls is associated with delayed breast development compared to girls without OSA. AB - STUDY OBJECTIVE: Adults with obstructive sleep apnea (OSA) have lower sex steroid levels than controls. We sought to determine whether OSA also interferes with reproductive hormones in adolescence by tracking the pace of pubertal development. METHODS: One hundred seventy-two children in the Tucson Children's Assessment of Sleep Apnea study (TuCASA) underwent two home polysomnographic studies, spaced 4-5 years apart. Height and weight were measured at both visits, and Tanner staging of breasts/genitals and pubic hair were self-assessed by a pictorial questionnaire at follow-up. RESULTS: Eighty-seven girls and 85 boys, age 8.9 +/- 1.6 years (mean +/- SD) at baseline and 13.4 +/- 1.6 years at follow up, participated. Twenty-seven percent of participants were over-weight or obese at baseline, and the majority remained so at follow-up. Twenty-six percent of girls and 28% of boys met criteria for OSA, defined as a respiratory disturbance index (RDI) >= 1/h associated with a 3% desaturation (RDI 3%), at baseline. There was an inverse relationship between baseline log RDI 3% and Tanner breast stage at follow-up (coefficient -1.3, p = 0.02) in girls after adjusting for age (p < 0.001), body mass index (p < 0.005), and ethnicity. Girls with OSA at baseline were more than 1 Tanner breast stage behind girls without OSA at follow-up. OSA did not affect genital development in boys or pubic hair development in either sex. CONCLUSIONS: OSA in preadolescent girls predicts delayed breast development relative to girls without OSA. Sleep fragmentation and/or hypoxia seen in OSA may interfere with reproductive development in girls. PMID- 23946713 TI - Exercise to improve sleep in insomnia: exploration of the bidirectional effects. AB - BACKGROUND: Exercise improves sleep quality, mood, and quality of life among older adults with insomnia. The purpose of the study was to evaluate the daily bidirectional relationships between exercise and sleep in a sample of women with insomnia. METHODS: Participants included 11 women (age M = 61.27, SD 4.15) with insomnia who engaged in 30 min of aerobic exercise 3 times per week. Self reported sleep quality was assessed at baseline and at 16 weeks. Sleep and exercise logs and wrist activity were collected continuously. Sleep variables included subjective sleep quality and objective measures recorded via wrist actigraphy (sleep onset latency [SOL], total sleep time [TST], sleep efficiency [SE], wake after sleep onset [WASO], and fragmentation index [FI]). Age, subjective sleep quality, TST, SOL, and physical fitness at baseline were tested as moderators of the daily effects. RESULTS: TST, SE, and self-reported global sleep quality improved from baseline to 16 weeks (p values < 0.05). Baseline ratings of sleepiness were negatively correlated with exercise session duration (p < 0.05). Daily exercise was not associated with subjective or objective sleep variables during the corresponding night. However, participants had shorter exercise duration following nights with longer SOL (p < 0.05). TST at baseline moderated the daily relationship between TST and next day exercise duration (p < 0.05). The relationship between shorter TST and shorter next day exercise was stronger in participants who had shorter TST at baseline. CONCLUSION: Results suggest that sleep influences next day exercise rather than exercise influencing sleep. The relationship between TST and next day exercise was stronger for those with shorter TST at baseline. These results suggest that improving sleep may encourage exercise participation. PMID- 23946714 TI - Vallecular cyst as a cause of obstructive sleep apnea in an infant. AB - A 3-month-old baby was diagnosed with obstructive sleep apnea (OSA) on polysomnography (PSG) with a high apnea hypopnea index (AHI). On further investigations he was found to have a vallecular cyst that was successfully treated. We discuss the clinical presentation of vallecular cysts and the importance of polysomnography in identifying this rare condition. PMID- 23946715 TI - Sleep medicine care under one roof: a proposed model for integrating dentistry and medicine. AB - Integrating oral appliance therapy into the delivery of care for sleeprelated breathing disorders has been a challenge for dental and medical professionals alike. We review the difficulties that have been faced and propose a multidisciplinary care delivery model that integrates dental sleep medicine and sleep medicine under the same roof with educational and research components. The model promises to offer distinct advantages to improved patient care, continuity of treatment, and the central coordination of clinical and insurance-related benefits. PMID- 23946716 TI - Persistent insomnia despite long-term nightly use of sleeping pills. PMID- 23946719 TI - Amorphous computing: examples, mathematics and theory. AB - The cellular automata model was described by John von Neumann and his friends in the 1950s as a representation of information processing in multicellular tissue. With crystalline arrays of cells and synchronous activity, it missed the mark (Stark and Hughes, BioSystems 55:107-117, 2000). Recently, amorphous computing, a valid model for morphogenesis in multicellular information processing, has begun to fill the void. Through simple examples and elementary mathematics, this paper begins a computation theory for this important new direction. PMID- 23946717 TI - Organism-adapted specificity of the allosteric regulation of pyruvate kinase in lactic acid bacteria. AB - Pyruvate kinase (PYK) is a critical allosterically regulated enzyme that links glycolysis, the primary energy metabolism, to cellular metabolism. Lactic acid bacteria rely almost exclusively on glycolysis for their energy production under anaerobic conditions, which reinforces the key role of PYK in their metabolism. These organisms are closely related, but have adapted to a huge variety of native environments. They include food-fermenting organisms, important symbionts in the human gut, and antibiotic-resistant pathogens. In contrast to the rather conserved inhibition of PYK by inorganic phosphate, the activation of PYK shows high variability in the type of activating compound between different lactic acid bacteria. System-wide comparative studies of the metabolism of lactic acid bacteria are required to understand the reasons for the diversity of these closely related microorganisms. These require knowledge of the identities of the enzyme modifiers. Here, we predict potential allosteric activators of PYKs from three lactic acid bacteria which are adapted to different native environments. We used protein structure-based molecular modeling and enzyme kinetic modeling to predict and validate potential activators of PYK. Specifically, we compared the electrostatic potential and the binding of phosphate moieties at the allosteric binding sites, and predicted potential allosteric activators by docking. We then made a kinetic model of Lactococcus lactis PYK to relate the activator predictions to the intracellular sugar-phosphate conditions in lactic acid bacteria. This strategy enabled us to predict fructose 1,6-bisphosphate as the sole activator of the Enterococcus faecalis PYK, and to predict that the PYKs from Streptococcus pyogenes and Lactobacillus plantarum show weaker specificity for their allosteric activators, while still having fructose 1,6-bisphosphate play the main activator role in vivo. These differences in the specificity of allosteric activation may reflect adaptation to different environments with different concentrations of activating compounds. The combined computational approach employed can readily be applied to other enzymes. PMID- 23946720 TI - Drinking Patterns, Gender and Health I: Attitudes and Health Practices. AB - BACKGROUND: Despite considerable research, relationships among gender, alcohol consumption, and health remain controversial, due to potential confounding by health-related attitudes and practices associated with drinking, measurement challenges, and marked gender differences in drinking. We examined gender/alcohol consumption differences in health-related attitudes and practices, and evaluated how these factors affected relationships among gender, alcohol consumption, and health status. METHODS: A stratified random sample of adult health-plan members completed a mail survey, yielding 7884 respondents (2995 male/4889 female). Using MANCOVAs and adjusting for health-related attitudes, values, and practices, we examined gender differences in relationships between alcohol consumption and health. RESULTS: More frequent heavy drinking was associated with worse health related attitudes and values, worse feelings about visiting the doctor, and worse health-related practices. Relationships between health-related practices and alcohol use differed by gender, and daily or almost daily heavy drinking was associated with significantly lower physical and mental health for women compared to men. Drinking status (lifelong abstainers, former drinkers, and level of regular alcohol consumption) was related to health status and vitality, even after adjusting for health-related attitudes, values, and practices. Relationships did not differ by gender. Former drinkers reported lower physical and mental health status than either lifelong abstainers or current drinkers. CONCLUSIONS: Drinking status is independently related to physical health, mental health, and vitality, even after controlling for the health-related attitudes, values, and practices expected to confound these relationships. Among current drinkers, women who engage in very frequent heavy drinking have worse physical and mental health than their male counterparts. PMID- 23946721 TI - Urine catalytic iron and neutrophil gelatinase-associated lipocalin as companion early markers of acute kidney injury after cardiac surgery: a prospective pilot study. AB - BACKGROUND: Open heart surgery with cardiopulmonary bypass is recognized as a common cause of acute kidney injury (AKI). The conventional biomarker creatinine is not sensitive enough to detect AKI until a significant decline in renal filtration has occurred. Urine neutrophil gelatinase-associated lipocalin (NGAL), part of an acute response to the release of tissue iron from cells, is an early biomarker and a predictor of AKI in a variety of clinical settings. We sought to evaluate the relationship between urine catalytic iron (unbound iron) and NGAL over the course of AKI due to cardiac surgery. METHODS: FOURTEEN PATIENTS WHO UNDERWENT OPEN HEART SURGERY HAD THE FOLLOWING MEASURED: serum creatinine (0, 12, 24, 48 and 72 h postoperatively), urine NGAL and urine catalytic iron (0, 8, 24 and 48 h postoperatively). Urine NGAL and urine catalytic iron were quantified by immunoassay and bleomycin-detectable iron assay, respectively. AKI was defined by the Acute Kidney Injury Network (AKIN) criteria. RESULTS: Urine catalytic iron increased significantly (p < 0.05) within 8 h and peaked at 24 h postoperatively in patients who developed AKI (n = 8, baseline 101.96 +/- 177.48, peak 226.35 +/- 238.23 nmol/l, p = 0.006), but not in non-AKI patients (n = 6, baseline 131.08 +/ 116.21, peak 163.99 +/- 109.62 nmol/l, p = 0.380). Urine NGAL levels also peaked at 24 h with significant increase observed only in AKI patients: AKI - baseline 34.88 +/- 26.47, peak 65.50 +/- 27.03 ng/ml, p = 0.043; non-AKI - baseline 59.33 +/- 31.72, peak 71.00 +/- 31.76 ng/ml, p = 0.100. The correlation between baseline levels of urine catalytic iron and NGAL and peak levels of urine catalytic iron and NGAL was r = 0.86, p < 0.0001. CONCLUSION: Urine catalytic iron appears to rise and fall in concert with NGAL in patients undergoing cardiac surgery and may be indicative of early AKI. Future research into the role that catalytic iron plays in acute organ injury syndromes and its potential diagnostic and therapeutic implications is warranted. PMID- 23946722 TI - Intentional weight loss and dose reductions of antihypertensive medications: a retrospective cohort study. AB - BACKGROUND: Though it is well known that weight loss tends to decrease blood pressure, the quantitative association between the magnitude of weight loss and the effect on the need for antihypertensive medications is not well studied. We analyzed this association among overweight and obese attendees at two outpatient weight management centers. METHODS: Case records of patients with a body mass index >25 at baseline were analyzed. The weight loss intervention consisted of a calorie-restricted diet (~1,000 kcal/day deficit), a behavior modification plan, and a plan for increasing physical activity. RESULTS: The study cohort consisted of 100 participants, and the mean follow-up period was 15 +/- 3.5 months. Significant weight loss (12.2 +/- 3.4 kg) and systolic/diastolic blood pressure reductions (9.1/6.3 mm Hg) were observed by study exit. For 5, 10, and 15% weight loss, respectively, 3, 39, and 39% of the patients achieved at least 1 discontinuation of any antihypertensive medication, and 8, 42, and 21 dose reductions were achieved. Dose reductions or discontinuations occurred in all classes of antihypertensive medications with similar magnitudes of weight loss. CONCLUSIONS: Intentional weight loss can potentially result in dose reductions/discontinuations of antihypertensive medications. Our results should be validated with data from larger randomized controlled studies and may help to inform the conduct of a systematic review of prior randomized controlled trials that contain data on medication changes accompanying weight loss. PMID- 23946723 TI - Preclinical cardiorenal interrelationships in essential hypertension. AB - A diseased heart causes numerous adverse effects on kidney function, and vice versa renal disease can significantly impair cardiac function. Beyond these heart kidney interrelationships at the clinical level, a reciprocal association has been suggested to exist even in the early stages of those organs' dysfunction. The aim of the present review is to provide evidence of the presence of a preclinical cardiorenal syndrome in the particular setting of essential hypertension, focusing on the subsequent hypertensive sequelae on heart and kidneys. In particular, a plethora of studies have demonstrated not only the predictive role of kidney damage, as expressed by either decreased glomerular filtration or increased urine albumin excretion, for adverse left ventricular functional and structural adaptations but also preclinical heart disease, i.e. left ventricular hypertrophy that is associated with deterioration of renal function. Notably, these reciprocal interactions seem to exist even at the level of microcirculation, since both coronary flow reserve and renal hemodynamics are strongly related with clinical and preclinical renal and cardiac damage, respectively. In this preclinical setting, common pathophysiological denominators, including the increased hemodynamic load, sympathetic and renin angiotensin system overactivity, increased subclinical inflammatory reaction, and endothelial dysfunction, account not only for the reported associations between overt cardiac and renal damage but also for the parallel changes that occur in coronary and renal microcirculation. PMID- 23946724 TI - DPP-4 Inhibitors as Therapeutic Modulators of Immune Cell Function and Associated Cardiovascular and Renal Insulin Resistance in Obesity and Diabetes. AB - The prevalence of obesity and diabetes continues to rise in the United States and worldwide. These findings parallel the expansion of childhood obesity and diabetes. Obesity is a central component of the cardiorenal metabolic syndrome (CRS) which increases the risk for cardiovascular disease (CVD) and chronic kidney disease (CKD). The hallmark of obesity, CRS, and early type 2 diabetes is insulin resistance, a result of decreased insulin metabolic signaling due, in part, to enhanced serine phosphorylation and/or proteasome-mediated degradation of the insulin receptor substrate. Cardiovascular and renal insulin resistance significantly contributes to endothelial dysfunction, impaired cardiac diastolic and vascular relaxation, glomerular injury, and tubular dysfunction. In this context, multiple factors including oxidative stress, increased inflammation, and inappropriate activation of the renin-angiotensin-aldosterone and the sympathetic nervous system contribute to overweight- and obesity-induced systemic and tissue insulin resistance. One common link between obesity and the development of insulin resistance appears to be a low-grade inflammatory response resulting from dysfunctional innate and adaptive immunity. In this regard, there has been recent work on the role of dipeptidyl peptidase-4 (DPP-4) in modulating innate and adaptive immunity. The direct effects of DPP-4 on immune cells and the indirect effects through GLP-1-dependent and -independent pathways suggest effects of DPP 4 inhibition may have beneficial effects beyond glycemic control in improving CVD and renal outcomes. Accordingly, this review addresses new insights into the role of DPP-4 in immune modulation and the potential beneficial effects of DPP-4 inhibitors in insulin resistance and associated CVD and CKD prevention. PMID- 23946725 TI - Cardiorenal syndrome type 4: a review. AB - There is a bidirectional and complex relationship between the heart and kidneys. This interaction is physical, chemical as well as biological and is also reflected in a strong connection between renal and cardiovascular diseases. Cardiorenal syndrome type 4 (CRS type 4) is characterized by primary chronic kidney disease (CKD) leading to an impairment of cardiac function, with ventricular hypertrophy, diastolic dysfunction, and/or increased risk of adverse cardiovascular events. The incidence of CKD is increasing, and CRS type 4 is becoming a major public health problem associated with a high morbidity and mortality. In this study, we briefly review the epidemiology and pathophysiology of CRS type 4, the role of biomarkers in its early identification, and its management. PMID- 23946726 TI - The impact of integrating nephrologists into the postoperative cardiac intensive care unit: a cohort study. AB - BACKGROUND/AIMS: We evaluated the potential preventive effect of Nephrology On Site (i.e. nephrologists integrated into the postoperative cardiac intensive care unit, ICU, team) versus Nephrology On-Demand (i.e. nephrology consultation depending on intensivist criteria) in the ICU on in-hospital outcomes. METHODS: This was a retrospective cohort study comparing outcomes during 2 consecutive time periods: from March 1, 2009 to February 28, 2010 with Nephrology On-Demand, and from March 1, 2010 to February 28, 2011 with Nephrology On-Site. Adult patients admitted to the postoperative cardiac ICU in an academic hospital in Mexico City were eligible. Patients with chronic kidney disease stage 5 or minimally invasive procedures were excluded. RESULTS: We analyzed 1,096 patients, 558 and 538 in the respective periods. The patients were 52.4 +/- 16.2 years old, 56.1% were males, 17.2% had diabetes and 37.6% had hypertension. Further, the patients' median Euroscore was 5 (3-5) and their median Thakar score was 3 (2-4). With Nephrology On-Site, we observed a lower incidence of acute kidney injury [AKI; 25.7 vs. 31.9%, p = 0.02; adjusted OR 0.71 (0.53-0.95), p = 0.02], lower in hospital mortality among patients with severe AKI [34.1 vs. 55.9%, p = 0.06; adjusted OR 0.33 (0.12-0.95), p = 0.04] and higher renal recovery [61.0 vs. 35.3%, p = 0.03; adjusted OR 3.57 (1.27-10.11), p = 0.02]. No differences were found in the length of stay at the ICU and mechanical ventilation. CONCLUSION: Integrating nephrologists into the postoperative cardiac ICU team was associated with a lower incidence of AKI. Patients who developed severe AKI had lower in hospital mortality and higher renal recovery. PMID- 23946727 TI - The pleotropic role of statins: Could it be the imminent host modulation agent in periodontics? AB - Periodontal disease is a chronic inflammatory disease which represents a primarily anaerobic Gram-negative oral infection that results in gingival inflammation, loss of attachment, bone destruction. Bacterial endotoxins in the form of lipopolysaccharides (LPS) that are instrumental in generating a host mediated tissue destructive immune response by mobilizing their defensive cells and releasing cytokines like Interleukin-1beta (IL-1beta), Tumor Necrosis Factor alpha (TNF-alpha), and Interleukin-6 (IL-6), which lead to tissue destruction by stimulating the production of the collagenolytic enzymes: Matrix metalloproteinases (MMPs). Since the host-mediated tissue destruction is to be controlled, various means have been employed for modulating this response. Statins, 3-hydroxy-3-methylglutarylcoenzyme A (HMG CoA) reductase inhibitors, besides having lipid-lowering abilities also have antioxidant, antithrombotic, anti-inflammatory, immunomodulatory and osteomodulatory properties. All of these pleiotropic effects of statins point out to it perhaps becoming the novel host modulation agent in periodontics. PMID- 23946728 TI - Stem cells: Boon to dentistry and medicine. AB - Stem cell research has received considerable attention since the discovery that adult stem cells have the capacity to form many different tissue types. Stem cells are a booming field for the research and have been extensively studied in the field of medicine, as well as dentistry. Their application in oncology has been a boon to many of the patients. Dental stem cells have been novel approach to treat diseases like periodontitis, dental caries and many more. Their potential uses in dentistry have provided a new generation of treatments for dental diseases and stem cells have become the focus in dental research. This review highlights about the biology, sources and potential applications of stem cells in dentistry with emphasis on a dentist's role in enabling both medical and dental applications using stem cells from teeth. PMID- 23946729 TI - Length and anatomic routes of the greater palatine canal as observed by cone beam computed tomography. AB - BACKGROUND: Greater palatine canal is used for maxillary nerve block. This procedure has some complications such as proptosis, blindness, and intravascular injection. This study aimed to determine the mean greater palatine canal length (CL) and its typical anatomic routes, as well as provide a reliable facial index for computing the CL by using cone beam computed tomography (CBCT) data. MATERIALS AND METHODS: A total of 138 CBCT scans (65 females and 73 males) were evaluated. The path of the canal and the CL were determined by sex, age, and side. The mean distance from the inferior border of the infraorbital foramen (IOF) to the crest of alveolar bone between maxillary premolar(CMP) was measured and compared with the CL. Paired t-tests, independent t-test, and one-way analysis of variance (ANOVA) were used for statistical analysis. RESULTS: The mean of CL was 31.82 +/- 1.37 mm (31.70 +/- 2.44 mm on the right side and 31.94 +/- 2.40 mm on the left side), and the values were 32.49 +/- 2.37 mm in males and 30.55 +/- 1.76 mm among females (P = 0.001). The mean distance from the IOF to the CMP was 32.01 +/- 2.18 mm, which was not significantly different to the CL (P = 0.336). CONCLUSIONS: The mean CL was significantly different according to sex and side. The mean distance from the IOF to CMP was significantly different according to sex. On comparing the mean distance from the IOF to the CMP with the CL, no significant difference was observed. Therefore, the mean distance from the IOF to CMP may be a reliable clinical index. PMID- 23946730 TI - Demographic distribution of odontogenic cysts in Isfahan (Iran) over a 23-year period (1988-2010). AB - BACKGROUND: Odontogenic cysts are relatively common lesions which can cause different complications. As demographic information is lacking in Iran and specially in Isfahan, the aim of this study was to determine the prevalence of odontogenic cysts according to age, gender and affected area among patients referring to the Oral Pathology Department of the Dental School of Isfahan University of Medical Sciences (Iran) over a 23-year period. MATERIALS AND METHODS: A total of 7412 diagnosed lesions recorded in the Oral Pathology Department archives of Isfahan Dental School between 1988 and 2010 were reevaluated, then odontogenic cysts were separated through reviewing microscopic slides according to the 2005 World Health Organization classification and variables such as age, gender, the infected jaw, and its specific region were obtained by SPSS Version 16.0 from the recorded database. RESULTS: 21.62% of the lesions were odontogenic cysts, of which 48.72% were inflammatory and 51.28% were developmental cysts. These cysts were more common in the mandible. The mean age of patients was 29.53 +/- 16.1. Male to female ratio was 1.31:1. The four most frequent odontogenic cysts were radicular cysts (35.12%), dentigerous cysts (25.77%), odontogenic keratocysts (22.58%) and residual cysts (12.98%). CONCLUSION: Odontogenic cysts are fairly frequent jaw lesions (21.62%), of which radicular cyst was the most common cyst. The four most common lesions constituted a sum of 96.45% of the total. In general, the prevalence rates in our study are similar to the studies from other geographic parts of the world but with a lower incidence of inflammatory cysts, higher prevalence of dentigerous cysts and residual cysts and also mandibular predominance for residual cysts. PMID- 23946731 TI - A retrospective comparative study on clinico-pathologic features of oral lichen planus and oral lichenoid lesions. AB - INTRODUCTION: Oral Lichen Planus (OLP) and Oral Lichenoid Lesions (OLLs) are clinically and histopathologically similar lesions but with different etiologies and treatment plan, thus differentiating these two has been the center of many researches. Studies in different populations have been performed on clinical and histopathologic features of OLP and OLLs. Thus aim of the present study was to evaluate and also compare the clinical and histopathologic features of these two diseases in a 10-year period in Esfahan. MATERIALS AND METHODS: This descriptive analytic study was based on retrospective survey of 232 records with clinical and histopathologic diagnosis of OLP and OLLs available from archive of oral pathology, Esfahan dental school 2000-2010. Data was statistically analyzed by use of independent t-test, Fisher exact, and Chi-square. RESULTS: Involvement of lip was the only clinically significant difference between OLP and OLLs, most seen in OLLs. Band-like inflammatory infiltrate mainly composed of lymphocyte, saw toothed rete ridges, Max Joseph space, and atrophic epithelium was significantly seen in OLP. While hyperkeratosis, deep connective tissue infiltrate composed of eosinophil, neutrophil, and plasma cell were seen in OLLs. CONCLUSION: Involvement of lip was the only clinically significant difference between OLP and OLLs. Histopathologically strict band like infiltration, atrophic epithelium, saw toothed rete ridges, and Max Joseph space are reliable criteria for differentiation of OLP as deep connective tissue infiltration and hyperparakeratosis are for diagnosis of OLLs. PMID- 23946733 TI - Immunohistochemical comparison of cyclin D1 and P16 in odontogenic keratocyst and unicystic ameloblastoma. AB - BACKGROUND: The different growth mechanism and biologic behavior of the odontogenic keratocyst (OKC) compared to other odontogenic cysts might be related to the proliferating capacity of its epithelium. In this study, the aim was to evaluate and compare the distribution and staining intensity of P16 and cyclin D1 in OKC and unicystic ameloblastoma (UA). MATERIALS AND METHODS: In this descriptive analytic study, hematoxylin- and eosin-stained slides of OKCs and UAs available from the archives of the oral pathology laboratory of the Esfahan School of Dentistry were examined. Twenty-five noninflamed solitary odontogenic keratocysts and 25 unicystic ameloblastomas (of either type) were selected and stained immunohistochemically. Distribution and staining intensity score (SID score) for P16- and cyclin D1-positive cells was calculated in both groups. Results were analyzed statistically with Wilcoxon, Friedman, and Mann-Whitney tests; P < 0.05 was considered significant. RESULTS: The highest expression of Cyclin D1-positive cells was seen in the suprabasal layer of keratocysts (P < 0.05) and in the peripheral layer of UAs (P < 0.05). Likewise, the highest expression of P16-positive cells was observed in the basal and suprabasal layers of keratocysts (P > 0.05) and central portions of UAs (P > 0.05). Expression of Cyclin D1 was higher in UAs compared to keratocyts (P < 0.05), although P16 did not show a significant difference between the two study groups (P > 0.05). CONCLUSION: Cyclin D1 did show a higher staining intensity in UAs compared to the keratocysts, although the expression of P16 was similar in the studied groups. The invasive growth of OKC might be related to the state of expression of cyclin D1 and P16 in the epithelium of this cyst. PMID- 23946732 TI - Assessing the sedative effect of oral vs submucosal meperidine in pediatric dental patients. AB - BACKGROUND: THE GOAL OF THIS INVESTIGATION WAS TO COMPARE THE BEHAVIORAL AND PHYSIOLOGICAL EFFECTS OF THREE SEDATIVE DRUG REGIMENS: oral meperidine (OM), submucosal meperidine (SM) and oral midazolam (M) in healthy pediatric patients. MATERIALS AND METHODS: This study sample consisted of thirty children aged 24-72 months (mean = 41.1) exhibiting definitely negative behavior. Three sedative regimens including: Oral meperidine/hydroxyzine, oral midazolam/hydroxyzine and submucosal meperidine/oral hydroxyzine were administered randomly during three consecutive appointments with a crossover design. Houpt behavioral scale was employed for evaluating the sedation effect of each regimen by a calibrated independent Pediatric dentist. Physiologic parameters were also recorded including blood oxygen saturation and pulse rate. Data was analyzed using Wilcoxon-signed ranked test, Mc-Nemar, GEE Logistic regression, Friedman, Fisher exact and Cochran tests for significance. RESULTS: Overall success rates were 50%, 46.7% and 26.7% for submucosal meperidine, oral meperidine and oral midazolam, respectively (P = 0.03). The probability of achieving a success in behavior control was more in 48-72 month olds. Child's age and drug type were the two main predictors of altered behavior. Evaluating the differences between the effects of three tested regimens on recorded physiological parameters showed no significant differences. CONCLUSION: All three regimens were proved safe within the limits of the current study. Meperidine sedation in both routes was considered to be more effective. Although there was less sleep and more head/oral resistance in midazolam group, the difference between groups was not significant. PMID- 23946734 TI - Evaluation of hardness and wear resistance of interim restorative materials. AB - BACKGROUND: The interim restorative materials should have certain mechanical properties to withstand in oral cavity. The aim of this study was to evaluate the hardness and wear resistance of interim restorative materials. MATERIALS AND METHODS: Fifteen identical rectangular shape specimens with dimensions of 2 mm * 10 mm * 30 mm were made from 7 interim materials (TempSpan, Protemp 3 Garant, Revotek, Unifast LC, Tempron, Duralay, and Acropars). The Vickers hardness and abrasive wear of specimens were tested in dry conditions and after 1 week storage in artificial saliva. The depth of wear was measured using surface roughness inspection device. Data were subjected to Kruskal-Wallis and Mann-Whitney tests. The Pearson correlation coefficient was used to determine the relationship between hardness and wear (alpha =0.05). RESULTS: TempSpan had the highest hardness. The wear resistance of TempSpan (in dry condition) and Revotek (after conditioning in artificial saliva) was significantly higher (P < 0.05). There was no statistically significant correlation between degree of wear and hardness of the materials (P = 0.281, r = -0.31). CONCLUSION: Hardness and wear resistance of interim resins are material related rather than category specified. PMID- 23946735 TI - Comparison of osteogenic medium and uniaxial strain on differentiation of endometrial stem cells. AB - BACKGROUND: Mechanotransduction plays a pivotal role in remodeling and repair of skeletal tissues. This mechanism has been widely used in bone tissue engineering especially under in vitro conditions. To date, various stem cells have been used for this purpose. The present study was the first to evaluate the effect of mechanical loading on differentiation of human endometrial stem cells (hESCs) to osteoblasts. MATERIALS AND METHODS: Adhesion of endometrial stem cells after isolation and culture on a silicone membrane covered with collagen was evaluated under scanning electron microscope (SEM). Twenty-four hours after cell culture on the membrane and ensuring appropriate cell adhesion, a group of cells in a conventional culture medium received 3% static uniaxial strain. In the positive control group, cells cultured on the membrane were placed in an osteogenic medium without receiving any mechanical strain. The negative control group was placed in a regular medium and received no strain either. Two weeks later, cultured cells were evaluated for expression of osteogenic markers using immunofluorescence staining and real-time polymerase chain reaction (PCR). Data of real-time PCR was analyzed by ANOVA. P < 0.05 was considered statistically significant. RESULTS: SEM analysis revealed adequate cell adhesion to the membrane after 24 h. Two weeks after loading, expression of markers in the positive control group was significantly higher compared to test group. CONCLUSION: We can conclude that static uniaxial strain exerted on hESCs results in their differentiation to osteoblasts. However, this magnitude of static strain in the tested time period cannot yield excellent differentiation when compared to the osteogenic medium. PMID- 23946736 TI - The accuracy of single emulsion radiographic film in linear measurement of spiral tomography. AB - BACKGROUND: Conventional tomography used for evaluation of the small areas of the jaws provides acceptable information. It has some advantages of availability, less radiation dose and cost in comparison to computed tomography (CT) and cone beam CT. Double emulsion film usually used for taking tomograms requires less exposure than single emulsion film; on the other hand, the latter provides more sharpness and spatial resolution. The aim of this study was to compare diagnostic accuracy of these two kinds of films in the spiral tomography. MATERIALS AND METHODS: In an experimental study, 20 lines (10 lines anterior and 10 lines posterior to the mental foramen) were selected on two dry human mandibles and tomographic images were taken from each line with and without metal marker by single and double emulsion films. For quantitative assessment, the mandibular width and length was identified and measured on 80obtained tomograms. Afterwards, the mandibles were sectioned on each line and their actual width and height were measured. For each line, the data of tomograms were subtracted from gold standard as measurement error. These errors were divided into three groups: Greater than +1 mm, between +1 mm and -1 mm and less than -1 mm. Obtained data were analyzed by Pearson Chi-square test (alpha=0/05). RESULTS: There was no significant difference between the single and double emulsion films, with and without markers in the measurement of both height and width of mandible (P > 0.05). CONCLUSION: The single emulsion film is not recommended to be used for taking the spiral tomogram. PMID- 23946737 TI - Effects of mechanical and thermal load cycling on micro tensile bond strength of clearfil SE bond to superficial dentin. AB - BACKGROUND: Certain studies have been conducted on the effects of mechanical and thermal load cycling on the microtensile bond strength (microTBS) of composites to dentin, but the results were different. The authors therefore decided to evaluate these effects on the bonding of Clearfil SE bond to superficial dentin. MATERIALS AND METHODS: Flat dentinal surface of 42 molar teeth were bonded to Filtek-Z250 resin composite by Clearfil SE bond. The teeth were randomly divided into 7 groups and exposed to different mechanical and thermal load cycling. Thermocycling was at 5-55 degrees C and mechanical load cycling was created with a force of 125 N and 0.5 Hz. Then, the teeth were sectioned and shaped to hour glass form and subjected to microTBS testing at a speed of 0.5 mm/min. The results were statistically analyzed by computer with three-way analysis of variance and T-test at P < 0.05 significant. To evaluate the location and mode of failure, the specimens were observed under the stereomicroscope. Then, one of the specimens in each group was evaluated under Scanning Electron Microscopy (SEM) for mode of failure. RESULTS: All of the study groups had a significantly lower microTBS as compared to the control group (P < 0.001). There was no statistically significant difference between mechanical cycling with 50K (kilo = 1000) cycles, and 50K mechanical cycles plus 1K thermal cycles. Most of the fractures in the control group were of adhesive type and this type of fracture increased after exposure to mechanical and thermal load cycling. CONCLUSION: Thermal and mechanical load cycling had significant negative effects on microTBS and the significant effects of mechanical load cycling started to be significant at 100K cycles. PMID- 23946738 TI - X-tip intraosseous injection system as a primary anesthesia for irreversible pulpitis of posterior mandibular teeth: A randomized clinical trail. AB - BACKGROUND: Successful anesthesia during root canal therapy may be difficult to obtain. Intraosseous injection significantly improves anesthesia's success as a supplemental pulpal anesthesia, particularly in cases of irreversible pulpitis. The aim of this study was to compare the efficacy of X-tip intraosseous injection and inferior alveolar nerve (IAN) block in primary anesthesia for mandibular posterior teeth with irreversible pulpitis. MATERIALS AND METHODS: Forty emergency patients with an irreversible pulpitis of mandibular posterior teeth were randomly assigned to receive either intraosseous injection using the X-tip intraosseous injection system or IAN block as the primary injection method for pulpal anesthesia. Pulpal anesthesia was evaluated using an electric pulp tester and endo ice at 5-min intervals for 15 min. Anesthesia's success or failure rates were recorded and analyzed using SPSS version 12 statistical software. Success or failure rates were compared using a Fisher's exact test, and the time duration for the onset of anesthesia was compared using Mann-Whitney U test. P < 0.05 was considered significant. RESULTS: Intraosseous injection system resulted in successful anesthesia in 17 out of 20 patients (85%). Successful anesthesia was achieved with the IAN block in 14 out of 20 patients (70%). However, the difference (15%) was not statistically significant (P = 0.2). CONCLUSION: Considering the relatively expensive armamentarium, probability of penetrator separation, temporary tachycardia, and possibility of damage to root during drilling, the authors do not suggest intraosseous injection as a suitable primary technique. PMID- 23946739 TI - The effect of joint surface contours and glass fiber reinforcement on the transverse strength of repaired acrylic resin: An in vitro study. AB - BACKGROUND: Denture fracture is an unresolved problem in complete denture prosthodontics. However, the repaired denture often experiences a refracture at the repaired site due to poor transverse strength. Hence, this study was conducted to evaluate the effect of joint surface contours and glass fiber reinforcement on the transverse strength of repaired acrylic resins. MATERIALS AND METHODS: A total of 135 specimens of heat polymerized polymethyl methacrylate resin of dimensions 64 * 10 * 2.5 mm were fabricated. Fifteen intact specimens served as the control and 120 test specimens were divided into four groups (30 specimens each), depending upon the joint surface contour (butt, bevel, rabbet and round), with two subgroups based on type of the repair. Half of the specimens were repaired with plain repair resin and the other half with glass fibers reinforced repair resin. Transverse strength of the specimens was determined using three-point bending test. The results were analyzed using one-way ANOVA and Tukey post-hoc test (alpha= 0.05). RESULTS: Transverse strength values for all repaired groups were significantly lower than those for the control group (P < 0.001) (88.77 MPa), with exception of round surface design repaired with glass fiber reinforced repair resin (89.92 MPa) which was significantly superior to the other joint surface contours (P < 0.001). Glass fiber reinforced resin significantly improved the repaired denture base resins as compared to the plain repair resin (P < 0.001). CONCLUSION: Specimens repaired with glass fiber reinforced resin and round surface design exhibited highest transverse strength; hence, it can be advocated for repair of denture base resins. PMID- 23946740 TI - Accuracy of linear vertical measurements in posterior mandible on panoramic view. AB - BACKGROUND: One of the most frequent concerns encountered in dental implant treatments is inadequate pre-operative planning. Panoramic radiographs are readily accessible and cost efficient. The aim of this study is to assess the accuracy of vertical measurements in mandibular molar and premolar region on panoramic radiography. MATERIALS AND METHODS: Panoramic radiographs were made of a partially edentulous sheep mandible mounted in acryl. Measurements collected from the computer-generated images were compared to measurements made directly on the cross-sectioned hemi-mandibles using t-test. P < 0.05 was considered significant. RESULTS: The results show that panoramic image is overestimated in predicting the linear measurements in posterior mandible. By applying the magnification factor of 1.29 the difference became insignificant. CONCLUSION: It seems rational to use panoramic radiography for pre-surgical implant assessment of posterior mandible if a true magnification factor is applied. PMID- 23946741 TI - Evaluation of a bioresorbable collagen membrane of fish origin in the treatment of periodontal intrabony defects: A prospective clinical study. AB - BACKGROUND: Recently, there has been interest in non-mammalian collagen sources such as fish collagen in the development of biomatrices and scaffolds for periodontal regeneration. In the present study, a novel collagen barrier membrane of fish origin was assessed in the treatment of periodontal intra-bony defects. MATERIALS AND METHODS: Ten systemically healthy chronic periodontitis patients having an osseous defect in the mandibular posterior teeth were selected and following the open flap debridement, a collagen membrane was placed over the defect and the flap was sutured with interrupted sutures. Clinical parameters such as Plaque Index, Gingival Bleeding Index, probing pocket depth (PPD), relative attachment level (RAL), and recession (R) were recorded at baseline, 6 and 9 months, whereas radiographic evaluation was done to assess alveolar crestal bone level and defect depth fill at 6 and 9 months using Auto-computer aided design (ACAD) 2007 software. Statistical significance was set at 5% level of significance. RESULTS: There was statistical significant differences with respect to periodontal clinical parameters such as Plaque Index, Gingival Bleeding Index, PPD, RAL, and gingival recession assessed at baseline, at 6 and 9 months respectively (P < 0.05), and radiographic evaluation showed a defect fill of 58.62 median % at 9 months. CONCLUSION: This preliminary study has shown predictable results in using fish collagen membrane, for treating periodontal intra-bony defects. Further, long-term clinical trials are needed to validate the effectiveness of this membrane. PMID- 23946742 TI - Debris and smear layer removal efficacy and changes in morphology of dentinal tubules after using citric acid, tetracycline-hydrochloride and mixture of tetracycline and acid and detergent. AB - BACKGROUND: In periodontal diseases, contamination of roots with bacteria and their active biologic agents and smear layer formation following periodontal treatments, prevents reattachment of periodontal cells. As a matter of fact biomodification of root surface and removal of smear layer and debris is critical for regeneration of periodontal structures. The aim of this study was to compare the efficacy of smear layer removal by citric acid, tetracycline-hydrochloride (TTC-HCL) and mixture of tetracycline and acid and detergent (MTAD). MATERIALS AND METHODS: In this in vitro and experimental study, 12 impacted third molars were sectioned from cervical enamel junction (CEJ) to mid-root area into four dentinal specimens (n = 48). Three groups were conditioned by citric acid 3%, TTC HCL 50 mg/mL and MTAD by means of cotton pellets, which were changed every 30 s for 3 min. The control group was conditioned by distilled water. Images from scanning electron microscope (SEM) were examined by two different analyzers. Data was analyzed by Kroskal Wallis and Mann-Whitney statistical analysis. RESULTS: The mean of dentinal tubules diameter was the most in MTAD group and the least in TTC-HCL and this difference was statistically significant (P = 0.05). CONCLUSION: According to the present study, TTC-HCL could remove debris and smear layer but citric acid and MTAD had better debris and smear layer removal efficacy and demineralization effect in comparison with TTC-HCL. PMID- 23946743 TI - Evaluation of the effect of allograft with doxycycline versus the allograft alone in the treatment of infrabony defects: A controlled clinical and radiographical study. AB - BACKGROUND: Successful prevention and treatment of periodontal disease are contingent on effective control of periodontopathic microbiota based on the premise of periodontal disease being infectious disorders. An anti-microbial agent, i.e., doxycycline has been incorporated into the allograft to control infection and facilitate healing during and after periodontal therapy. MATERIALS AND METHODS: Using a split-mouth design, 15 patients showing clinical evidence of almost identical bilateral infrabony defects requiring bone grafting procedures were randomly selected. In each patient, infrabony defects on one side were designated as Group A (control group) and infrabony defects of the contralateral side of the same arch were designated as Group B (test group). Clinical assessment of probing pocket depth and attachment level and radiographic evaluation of the defect depth was done pre-operatively and at 12-week and 24 week post-operatively. The relative efficacy of the two treatment modalities was evaluated using paired Student's t-test and the comparative evaluation between the two groups over the 3 time intervals was done using independent Student's t test. RESULTS: Both the groups exhibited a highly significant reduction in probing depth and gain in clinical attachment level (CAL) and a linear bone fill at the end of 12 and 24 weeks. Comparative evaluation showed a statistically significant gain in bone fill in Group B as compared to Group A, whereas a non significant reduction in probing depth and gain in CALs between the two groups at the end of 24 weeks (whereas mean reduction in probing depth and gain in CAL were also greater in Group B but the difference was statistically non-significant). CONCLUSION: The increase in linear bone fill in Group B signifies the role of doxycycline in augmenting regenerative potential of allograft by combating residual infection and through host modulation. PMID- 23946744 TI - The influence of sleep deprivation on expression of apoptosis regulatory proteins p53, bcl-2 and bax following rat tongue carcinogenesis induced by 4 nitroquinoline 1-oxide. AB - BACKGROUND: The aim of this study was to evaluate whether paradoxical sleep deprivation could affects the mechanisms and pathways essentials for cancer cells in tongue cancer induced by 4-nitroquinole 1-oxide in Wistar rats. MATERIALS AND METHODS: For this purpose, the animals were distributed into 4 groups of 5 animals each treated with 50 ppm 4 nitroquinoline 1 oxide (4 NQO) solution through their drinking water for 4 and 12 weeks. The animals were submitted to paradoxical sleep deprivation (PSD) for 72 h using the modified multiple platform method, which consisted of placing 5 mice in a cage (41 * 34 * 16 cm) containing 10 circular platforms (3.5 cm in diameter) with water 1 cm below the upper surface. The investigations were conducted using immunohistochemistry of p53, Bax and Bcl-2 proteins related to apoptosis and its pathways. Statistical analysis was performed by Kruskal-Wallis non-parametric test followed by the Dunn's test using SPSS software pack (version 1.0). P value < 0.05 was considered for statistic significance. RESULTS: Although no histopathological abnormalities were induced in the epithelium after 4 weeks of carcinogen exposure in all groups, in 12 weeks were observed pre-neoplasic lesions. Data analysis revealed statistically significant differences (P < 0.05) in 4 weeks group for p53 and for bcl-2 and for all immunomarkers after 12 weeks of 4NQO administration. CONCLUSION: Our results reveal that sleep deprivation exerted alterations in proteins associated with proliferation and apoptosis in carcinogenesis. PMID- 23946745 TI - Optimizing human factors in dentistry. AB - Occupational health hazards among dental professionals are on a continuous rise and they have a significant negative overall impact on daily life. This review is intended to provide the information regarding risk factors and to highlight the prevention strategies for optimizing human factors in dentistry. Risk factors among dentists are multifactorial, which can be categorized into biomechanical and psychosocial. To achieve a realistic target of safety and health at work, prevention is clearly the best approach; therefore, musculoskeletal disorders can be reduced through proper positioning of dental worker and patient, regular rest breaks, general good health, using ergonomic equipment, and exercises designed to counteract the particular risk factors for the dental occupation. However, substantial evidences are still required to elucidate the potential risk factors and to formulate effective prevention programs. PMID- 23946746 TI - Taurodontism in a central anatolian population. AB - The aim of this retrospective study was to evaluate the frequency of the occurrence of taurodontism in a Turkish population with using panoromic radiographs. A retrospective study was performed using full-mouth periapical and panoramic radiographs of 6912 patients (3860 females and 3052 males) ranging in age from 15 to 50. A total of 97362 posterior (including third molars) were evaluated. A chi-square test was used to determine the difference in the prevalence of tauorodntism between genders. Eighteen patients were found to have a taurodont molar (10 women and 8 men [P = 0.98]). The overall incidence of patients with taurodont molars was 0.26 % and the prevalence of taurodont molars from all teeth examined was 0.024%, and the prevalence taurodonts were significantly more common in the mandibula compared with the maxilla (71.0% cf 29.0% respectively, P < 0.05). It was almost equally distributed between males and females. Taurodontism is not uncommon in Turkish population but further larger scale studies are required to assess its prevalence in the general population to compare it with other ethnic groups. PMID- 23946747 TI - The silent sinus syndrome. AB - The silent sinus syndrome (SSS) involves painless facial asymmetry and enophthalmos, which is the result of chronic maxillary sinus atelectasis. In most cases, it is diagnosed clinically, however, using the characteristic imaging features including maxillary sinus outlet obstruction, sinus opacification, and sinus volume loss caused by inward retraction of the sinus walls. Obstruction of the maxillary ostium appears to play a critical role in the development of SSS. Treatment involves functional endoscopic surgery. PMID- 23946748 TI - Laterally positioned flap-revised technique along with platelet rich fibrin in the management of Miller class II gingival recession. AB - Gingival recession is a complex phenomenon that may present numerous therapeutic challenges to the clinician. The laterally positioned flap is commonly used to cover isolated, denuded roots that have adequate donor tissue laterally and vestibular depth. Various modifications in laterally sliding flap have been proposed in order to avoid the reported undesirable results on the donor teeth. Recently, use of growth factors has been proposed in combination with surgical techniques. This article highlights the use of laterally positioned pedicle flap revised technique as a modification of laterally sliding flap technique along with autologous suspension of growth factors, platelet rich fibrin membrane (PRF) for the management of localized Miller class-II gingival recession. After 6 months of follow-up, the clinical condition was stable with 80% root coverage and satisfactory gingival tissue healing at both donor and recipient site with no signs of inflammation. An excellent esthetical outcome was achieved and the patient was satisfied with case resolution. PMID- 23946749 TI - Adenoid cystic carcinoma of palate: A case report and review of literature. AB - Adenoid cystic carcinoma is an uncommon, slow growing malignant salivary gland tumor that is characterized by wide local infiltration, perineural spread, propensity to local recurrence and distant metastasis. In this paper, the authors present a case of adenoid cystic carcinoma affecting the palate and involving the maxillary sinus in a 60-year-old male patient along with a brief review of literature. PMID- 23946750 TI - Aggressive adenomatoid odontogenic tumor of mandible showing root resorption: A histological case report. AB - Adenomatoid odontogenic tumor (AOT) is a benign odontogenic tumor with slow but progressive growth. The three variants: Follicular, extra follicular (both central type), and peripheral present with identical histologic findings. This case report describes a patient with a large AOT in the mandible of the extra follicular type which is the less common of the two central types. It also strikes as an unusual case as it shows significant root resorption of the involved displaced teeth which is not generally reported in AOT's. PMID- 23946751 TI - Primary tuberculous osteomyelitis of the mandible: A rare case report. AB - Tuberculosis (TB) has become a rare disease in the developed countries but it is still a serious problem in developing countries. Incidence of tuberculous osteomyelitis of the jaw bones is very low. This rare incidence is the primary reason that this lesion gets mis-diagnosed many times. Here we report the diagnosis, treatment and follow-up of a case, which is a classical presentation of tuberculous osteomyelitis of mandible. Primary tuberculous osteomyelitis is a very rare entity but in the recent times, increased incidence of TB as a coinfection of HIV, has posed a big challenge in developing countries. If not diagnosed, at the right time, this can lead to serious complications like internal organ damage, tuberculous meningitis etc., Early diagnosis of tuberculous osteomyelitis will certainly reduce the morbidity of this disease condition. PMID- 23946752 TI - Respiratory review of 2013: critical care medicine. AB - Several papers on respiratory and critical care published from March 2012 to February 2013 were reviewed. From these, this study selected and summarized ten articles, in which the findings were notable, new, and interesting: effects of high-frequency oscillation ventilation on acute respiratory distress syndrome (ARDS); safety and efficacy of hydroxyethyl starch as a resuscitation fluid; long term psychological impairments after ARDS; safety and efficacy of dexmedetomidine for sedation; B-type natriuretic peptide-guided fluid management during weaning from mechanical ventilation; adding of daily sedation interruptions to protocolized sedations for mechanical ventilation; unassisted tracheostomy collar of weaning from prolonged mechanical ventilations; and effects of nighttime intensivist staffing on the hospital mortality rates. PMID- 23946753 TI - Autophagy Inhibition with Monensin Enhances Cell Cycle Arrest and Apoptosis Induced by mTOR or Epidermal Growth Factor Receptor Inhibitors in Lung Cancer Cells. AB - BACKGROUND: In cancer cells, autophagy is generally induced as a pro-survival mechanism in response to treatment-associated genotoxic and metabolic stress. Thus, concurrent autophagy inhibition can be expected to have a synergistic effect with chemotherapy on cancer cell death. Monensin, a polyether antibiotic, is known as an autophagy inhibitor, which interferes with the fusion of autophagosome and lysosome. There have been a few reports of its effect in combination with anticancer drugs. We performed this study to investigate whether erlotinib, an epidermal growth factor receptor inhibitor, or rapamycin, an mammalian target of rapamycin (mTOR) inhibitor, is effective in combination therapy with monensin in non-small cell lung cancer cells. METHODS: NCI-H1299 cells were treated with rapamycin or erlotinib, with or without monensin pretreatment, and then subjected to growth inhibition assay, apoptosis analysis by flow cytometry, and cell cycle analysis on the basis of the DNA contents histogram. Finally, a Western blot analysis was done to examine the changes of proteins related to apoptosis and cell cycle control. RESULTS: Monensin synergistically increases growth inhibition and apoptosis induced by rapamycin or erlotinib. The number of cells in the sub-G1 phase increases noticeably after the combination treatment. Increase of proapoptotic proteins, including bax, cleaved caspase 3, and cleaved poly(ADP-ribose) polymerase, and decrease of anti apoptotic proteins, bcl-2 and bcl-xL, are augmented by the combination treatment with monensin. The promoters of cell cycle progression, notch3 and skp2, decrease and p21, a cyclin-dependent kinase inhibitor, accumulates within the cell during this process. CONCLUSION: Our findings suggest that concurrent autophagy inhibition could have a role in lung cancer treatment. PMID- 23946754 TI - Prevalence of Latent Tuberculosis Infection among Health Care Workers in South Korea: A Multicenter Study. AB - BACKGROUND: We investigated the prevalence of latent tuberculosis infection (LTBI) among the health care workers (HCWs) and analyzed its risk factors in South Korea. METHODS: A standard questionnaire regarding the baseline demographics and risk factors for LTBI was given to each participant and tuberculin skin test (TST), QuantiFERON-TB GOLD In-Tube (QFT-GIT) assay, and chest radiography were performed. RESULTS: A total of 493 participants, 152 (30.8%) doctors and 341 (69.2%) nurses were enrolled in eight tertiary referral hospitals. The mean age of the subjects was 30.6 years old, and 383 (77.7%) were female. Of the 152 doctors, 63 (41.4%) and 36 (23.7%) were positive by TST and by QTF-GIT, respectively, and among the 341 nurses, 119 (34.9%) and 49 (14.4%) had positive TST and QFT-GIT results, respectively. Overall, the agreement between the two tests was 0.22 by the chance corrected proportional agreement rate (kappa coefficient) in 493 subjects. Experience of working in tuberculosis (TB)-related departments was significantly associated with positive LTBI test results by QFT GIT assay, not by TST. In multivariate analysis, only age was independently associated with increased risk of a positive TST result, while age and experience of working in TB-related departments (odds ratio, 2.29; 95% confidence interval, 1.01-5.12) were independently associated with increased risk of a positive QFT GIT result. CONCLUSION: A high prevalence of LTBI was found among South Korean HCWs. Considering the association between the experience of working in TB-related departments and high risk of LTBI, QFT-GIT may be a better diagnostic test for LTBI than TST in HCWs. PMID- 23946755 TI - Normalization of Elevated CA 19-9 Level after Treatment in a Patient with the Nodular Bronchiectatic Form of Mycobacterium abscessus Lung Disease. AB - Carbohydrate antigen 19-9 (CA 19-9) is a widely-used tumor marker in patients with pancreatic cancer. However, some patients with respiratory disease also exhibit elevated serum CA 19-9 levels. We report a case of normalization of elevated serum CA 19-9 levels after treatment of the nodular bronchiectatic form of Mycobacterium ab scessus lung disease. A 40-year-old man visited our hospital because of chronic cough and sputum. A computed tomography scan revealed severe bronchiectasis in the right upper and right middle lobes. Nontuberculous mycobacteria were repeatedly isolated and identified as M. abscessus. The serum CA 19-9 level was elevated to 142.35 U/mL (normal range, <37 U/mL). Surgical resection was performed because of failure of sputum conversion after antibiotic treatment. The serum CA 19-9 level returned to the normal range after surgery. This case suggested that serum CA 19-9 levels could be elevated in patients with the nodular bronchiectatic form of M. abscessus lung disease. PMID- 23946756 TI - Mycobacterium intracellulare Pulmonary Disease with Endobronchial Caseation in a Patient Treated with Methotrexate. AB - Methotrexate (MTX) has been established as a standard disease-modifying anti rheumatic drug. If adequate disease control is achieved for a reasonable period of time, tapering the MTX dosage is recommended because the chronic use of MTX can result in opportunistic infection. We present here a case of a woman with rheumatoid arthritis taking MTX, and the woman developed actively caseating endobronchial Mycobacterium intracellulare disease with pulmonary infiltrations. After discontinuing the MTX, the patient was able to tolerate 18 months of antimycobacterial treatment without flare ups of rheumatoid arthritis, and she completely recovered from nontuberculous mycobacterial respiratory disease. PMID- 23946757 TI - Late-onset distant metastatic upper urinary tract urothelial carcinoma mimicking lung adenocarcinoma. AB - Urothelial carcinomas (UCs) can occur in the upper urinary tract or lower urinary tract. Upper urinary tract urothelial carcinoma (UUT-UC) is relatively a rare disease and accounts for only about 5% of UC cases. Sporadic cases of late-onset metastasis, associated with UC of the bladder, have occasionally been reported. In contrast, no late-onset distant metastatic UUT-UC without local recurrence has, to the best of our knowledge, been reported in the English literature. We report an extremely rare case of distant metastatic UC, mimicking lung adenocarcinoma that originated from UUT-UC 12 years previously. PMID- 23946758 TI - A case of capillary hemangioma of lingular segmental bronchus in adult. AB - Capillary hemangioma of the tracheobronchial tree is an extremely rare benign tumor in adults, especially those located in the bronchus. Characteristics and treatment of capillary hemangiomas of adult tracheobronchial trees have not been well known. We present a 61-year-old man with hemoptysis, which was caused by a small tiny nodule in the left lingular segmental bronchus. The nodule was removed by a forcep biopsy, via flexible bronchoscopy, and it was revealed to be capillary hemangioma. A small isolated endobronchial capillary hemangioma can be treated with excisional forcep biopsy, but a risk of massive bleeding should not be overlooked. PMID- 23946759 TI - The role of v2 receptor antagonists in the treatment of hyponatremia. PMID- 23946760 TI - Potassium balances in maintenance hemodialysis. AB - Potassium is abundant in the ICF compartment in the body and its excretion primarily depends on renal (about 90%), and to a lesser extent (about 10%) on colonic excretion. Total body potassium approximated to 50mmol/kg body weight and 2% of total body potassium is in the ECF compartment and 98% of it in the intracellular compartment.Dyskalemia is a frequent electrolyte imbalance observed among the maintenance hemodialysis patients. In case of hyperkalemia, it is frequently "a silent and a potential life threatening electrolyte imbalance" among patients with ESRD under maintenance hemodialysis. The prevalence of hyperkalemia in maintenance HD patients was reported to be about 8.7-10%. Mortality related to the hyperkalemia has been shown to be about 3.1/1,000 patient-years and about 24% of patients with HD required emergency hemodialysis due to severe hyperkalemia. In contrast to the hyperkalemia, much less attention has been paid to the hypokalemia in hemodialysis patients because of the low prevalence under maintenance hemodialysis patients. Severe hypokalemia in the hemodialysis patients usually was resulted from low potassium intake (malnutrition), chronic diarrhea, mineralocorticoid use, and imprudent use of K exchange resins. Recently, the numbers of the new patients with advanced chronic kidney disease undergoing maintenance hemodialysis are tremendously increasing worldwide. However, the life expectancy of these patients is still much lower than that of the general population. The causes of excess mortality in these patients seem to various, but dyskalemia is a common cause among the patients with ESRD undergoing hemodialysis. PMID- 23946761 TI - Pharmacologic Management of the Cardio-renal Syndrome. AB - Cardio-renal syndromes are disorders of the heart and kidney wherein acute or long-term dysfunction in one organ may induce acute or long-term dysfunction of the other. Because of this complex organ interaction, management of cardiorenal syndrome must be tailored to the underlying pathophysiology. Clinical guidelines exist for the treatment of heart failure or renal failure as separate conditions. Thus far, however, there has been no consensus about managing patients with cardio-renal and reno-cardiac syndromes. Pharmacologic treatment remains a controversial subject. Standard cardiac drugs such as diuretics and inotropes may have limited effect because resistance often develops after long-term use. Recent studies of patients with acute cardio-renal syndromes have focused on newer therapies, including phosphodiesterase inhibitors, vasopressin antagonists, adenosine A1 receptor antagonists, and renal protective dopamine. Initial clinical trials of these agents have shown encouraging results in some patients with heart failure, but have failed to demonstrate a clear superiority over more conventional treatments. Similarly, the benefits of diuretics, aspirin, erythropoietin agents, and iron supplements for management of chronic cardiorenal syndromes are unknown. PMID- 23946762 TI - Adrenergic genetic mechanisms in hypertension and hypertensive kidney disease. AB - Catecholamine secretory traits were significantly heritable, as were stress induced blood pressure changes. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. In the tyrosine hyroxylase promoter, significant associations were found for urinary catecholamine excretion and for blood pressure response to stress. TH promoter haplotype 2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. In hypertension, 2 independent case-control studies (1,266 subjects with 53% women and 927 subjects with 24% women) replicated the effect of C-824T in the determination of blood pressure. Chromogranin A (CHGA) plays a fundamental role in the biogenesis of catecholamine secretory granules. Changes in the storage and release of CHGA in clinical and experimental hypertension prompted us to study whether genetic variation at the CHGA locus might contribute to alterations in autonomic function, and hence hypertension and its target organ consequences such as hypertensive kidney disease (nephrosclerosis). Systematic polymorphism discovery across the human CHGA locus revealed such regulatory regions as the proximal promoter and 3'-UTR. In chromaffin cell-transfected CHGA 3'-UTR and promoter/luciferase reporter plasmids, the functional consequences of the regulatory/non-coding allelic variants were documented. Variants in both the proximal promoter and the 3'-UTR displayed statistical associations with hypertension and hypertensive end stage renal disease. Therefore, I would like to review the common genetic variation in TH and CHGA as a cause of inter-individual variation in sympathetic activity, and ultimately blood pressure and hypertensive kidney disease. PMID- 23946763 TI - Paranoid Adipsia-induced Severe Hypernatremia and Uremia treated with Hemodialysis. AB - We describe a patient with severe hypernatremia and uremia caused by paranoid adipsia who was treated successfully with hydration and hemodialysis. A previously healthy 40-year-old woman developed the paranoid idea that her water was poisoned, so she refused to drink any water. On admission, her blood urea nitrogen was 208mg/dL, creatinine 4.90mg/dL, serum osmolality 452mOsm/L, serum sodium 172mEq/L, urine specific gravity >=1.030, urine osmolality 698mOsm/L, and urine sodium/potassium/chloride 34/85.6/8mEq/L. We diagnosed her with uremic encephalopathy and started intravenous dextrose, but the sodium correction was incomplete. She underwent two sessions of hemodialysis to treat the uremic encephalopathy and hypernatremia, and recovered fully without neurological sequelae. Although the standard treatment for severe hypernatremia is hydration, hemodialysis can be an additional treatment in cases of combined uremic encephalopathy. PMID- 23946766 TI - RNAi2013: RNAi at Oxford. PMID- 23946765 TI - Sub-cellular temporal and spatial distribution of electrotransferred LNA/DNA oligomer. AB - Low biological activity and inefficient targeted delivery in vivo have hindered RNA interference (RNAi)-based therapy from realising its full clinical potential. To overcome these hurdles, progresses have been made to develop new technologies optimizing oligonucleotides chemistry on one hand and achieving its effective delivery on the other hand. In this report, we achieved, by using the electropulsation technique (EP), efficient cellular delivery of chemically modified oligonucleotide: The locked nucleic acid (LNA)/DNA oligomer. We used single cell level confocal fluorescence microscopy to follow the spatial and temporal distribution of electrotransferred cyanine 5 (Cy5)-labeled LNA/DNA oligomer. We observed that EP allowed LNA/DNA oligomer cellular uptake providing the oligomer a rapid access to the cytoplasm of HeLa cells. Within a few minutes after electrotransfer, Cy5-LNA/DNA oligomers shuttle from cytoplasm to nucleus whereas in absence of pulses application, Cy5-LNA/DNA oligomers were not detected. We then observed a redistribution of the Cy5 fluorescence that accumulated over time into cytoplasmic organelles. To go further and to identify these compartments, we used the HeLa GFP-Rab7 cell line to visualise late endosomes, and lysosomal or mitochondrial specific markers. Our results showed that the EP technique allowed direct entry into the cytoplasm of the Cy5-LNA/DNA oligomer bypassing the endocytosic pathway. However, in absence of pulses application, Cy5-LNA/DNA oligomer were able to enter cells through the endocytosic pathway. We demonstrated that EP is an efficient technique for LNA based oligonucleotides delivery offering strong advantages by avoiding the endolysosomal compartmentalization, giving a rapid and free access to the cytoplasm and the nucleus where they can find their targets. PMID- 23946764 TI - Tissue-specific HIV-1 infection: why it matters. AB - The human immunodeficiency virus displays a narrow tropism for CD4+ mononuclear cells, and activated CD4+ T lymphocytes are the main target. When these cells are depleted by viral replication, bystander apoptosis and increased cell turnover mediated by immune activation, there is a progressive immunodeficiency (i.e., AIDS). Despite this specific cell tropism, HIV-infected persons demonstrate pathology in nearly every organ system. This article reviews current understanding of tissue-specific HIV-1 infection in the CNS, the genital tract, and gastrointestinal-associated lymphoid tissue. PMID- 23946767 TI - Quantitative UPLC-MS/MS analysis of the gut microbial co-metabolites phenylacetylglutamine, 4-cresyl sulphate and hippurate in human urine: INTERMAP Study. AB - The role of the gut microbiome in human health, and non-invasive measurement of gut dysbiosis are of increasing clinical interest. New high-throughput methods are required for the rapid measurement of gut microbial metabolites and to establish reference ranges in human populations. We used ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) -- positive and negative electrospray ionization modes, multiple reaction monitoring transitions -- to simultaneously measure three urinary metabolites (phenylacetylglutamine, 4-cresyl sulphate and hippurate) that are potential biomarkers of gut function, among multi-ethnic US men and women aged 40-59 from the INTERMAP epidemiologic study (n = 2000, two timed 24-hr urine collections/person). Metabolite concentrations were quantified via stable isotope labeled internal standards. The assay was linear in the ranges 1ng/mL (lower limit of quantification) to 1000ng/mL (phenylacetylglutamine and 4-cresyl sulfate) and 3ng/mL to 3000ng/mL (hippurate). These quantitative data provide new urinary reference ranges for population-based human samples: mean (standard deviation) 24-hr urinary excretion for phenylacetylglutamine was: 1283.0 (751.7) MUmol/24-hr (men), 1145.9 (635.5) MUmol/24-hr (women); for 4-cresyl sulphate, 1002.5 (737.1) MUmol/24-hr (men), 1031.8 (687.9) MUmol/24-hr (women); for hippurate, 6284.6 (4008.1) MUmol/24-hr (men), 4793.0 (3293.3) MUmol/24-hr (women). Metabolic profiling by UPLC-MS/MS in a large sample of free-living individuals has provided new data on urinary reference ranges for three urinary microbial co-metabolites, and demonstrates the applicability of this approach to epidemiological investigations. PMID- 23946768 TI - A genetic variation of the p38beta promoter region is correlated with an increased risk of sporadic colorectal cancer. AB - p38 plays a critical role in the proliferation, survival, migration and metastasis of colorectal cancer (CRC) cells. The present study assessed the correlation between a single nucleotide polymorphism (SNP) in the p38beta promoter region (rs2235356, -1628A>G) and the predisposition of individuals to sporadic CRC in a case-control study. A genotyping method was developed to detect this SNP, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. A logistic regression analysis was used to determine the odds ratio (OR) and 95% confidence interval (CI). It was revealed that the -1628G variant allele was correlated with an increased risk of CRC (OR, 1.99; 95% CI, 1.60-2.47; P<0.0001). An in silico analysis revealed several transcription factors that either acquired or lost the ability to bind to -1628AA in the p38beta promoter region due to the SNP. Therefore, this allelic variant may be a genetic modifier for CRC susceptibility. PMID- 23946769 TI - Ewing's sarcoma with an uncommon clinical course: A case report. AB - Here, a case of Ewing's sarcoma family of tumors (ESFT) of the femur with an unusual clinical course is reported. At 20 years of age, the patient had undergone curettage of a bone tumor of the right femur which was diagnosed as ESFT. One cycle of chemotherapy with vincristine and cyclophosphamide and radiotherapy for a total dose of 40 Gy was administered. The patient did not develop any recurrence or metastases for the following 18 years, in spite of the inadequacy of the initial treatment. At 38 years of age, he was referred to our institution with right thigh pain that had persisted for several months. Radiographs and magnetic resonance imaging findings showed a mass lesion in his proximal femur extending to the soft tissue. An open biopsy was performed and the lesion was diagnosed as recurrence of ESFT, although a molecular biological investigation did not reveal any expression of the characteristic fusion genes that have previously been reported. The patient received standard multimodal therapy employing standard combination chemo-therapy for ESFT and wide surgical excision. The patient has been disease-free for 9 years since the treatment. This patient may have a rare subtype of ESFT with an unknown chromosomal translocation and relatively non-aggressive biological behavior. PMID- 23946771 TI - Immature teratoma of the posterior cranial fossa in a 4-month-old infant: A case report. AB - The present study analyzed a case of immature teratoma in the posterior cranial fossa of an infant and compared the clinical data with the associated literature. Ventricular drainage was initially performed upon the patient's admission to the hospital. Following adequate pre-operative preparations, the tumor in the posterior cranial fossa was resected on the third day. No significant neurological function deficiency was observed following the surgery and no recurrence was noted within an 18-month follow-up period. In such cases, treatment should be conducted in a stepwise manner, with the hydrocephalus relieved first, followed by complete tumor resection subsequent to full preparation. Post-operative chemotherapy was not performed by conventional means as the infant was too weak, therefore, periodic reviews and long-term follow-up were required. PMID- 23946770 TI - HER2 gene amplification in esophageal squamous cell carcinoma is less than in gastroesophageal junction and gastric adenocarcinoma. AB - The aim of the present study was to detect the amplification of the human epidermal growth factor receptor 2 (HER2) gene in esophageal squamous cell carcinoma (ESCC), gastroesophageal junction adenocarcinoma (GEJAC) and gastric cancer (GC), as well as to understand the pathological meaning of HER2 gene amplification with regard to clinico-pathological parameters in these types of cancer. HER2 gene amplification was evaluated by fluorescence in situ hybridization (FISH) in surgically obtained specimens from 76 cases of ESCC, 50 of GEJAC and 48 of GC, as well as 21 specimens of tumor-adjacent normal epithelium as a control group. The HER2 gene amplification rates in ESCC, GEJAC and GC were 3.9 (3/76), 24.0 (12/50) and 18.8% (9/48), respectively. The rates of HER2 gene amplification in GEJAC and GC were significantly higher compared with ESCC (chi2=11.563, P<0.001 and chi2=7.375, P<0.007, respectively). HER2 gene amplification was not detected in the normal esophageal or gastric mucosa samples. In ESCC, HER2 gene amplification was correlated with the invasion of the ESCC cells, vascular invasion and lymph node metastasis (chi2=4.789, 3.858 and 5.354, respectively; all P<0.05). However, in GEJAC and GC, no correlations were observed between HER2 amplification and the gender, age, degree of differentiation, invasion, vascular invasion and lymph node metastases of the patients (all P>0.05). The rate of HER-2 gene amplification was low in ESCC, although the amplification of HER-2 was correlated with tumor metastasis in these patients. The rates of HER-2 gene amplification in GEJAC and GC were higher compared with ESCC. Therefore, compared with ESCC, GEJAC may be more similar to GC with regard to HER-2 gene amplification features. PMID- 23946772 TI - Late post-operative recurrent osteosarcoma: Three case reports with a review of the literature. AB - The aim of the present study was to investigate the clinical characteristics and treatment of late recurrent osteosarcoma following surgery. The cases of three patients with late recurrent osteosarcoma, who were treated at the General Hospital of Jinan Military Command, General Hospital of Nanjing Military Command and Xinan Hospital of The Third Military Medical University, were analyzed retrospectively. Furthermore, 10 cases of late recurrent osteosarcoma were retrieved from the literature. In total, eight male and five female cases were selected for the present study. The mean age at recurrence was 25.56 years (range, 13-42 years). The locations of the osteosarcomas were as follows: five cases in the distal femur, two cases in the distal tibia and acetabulum, respectively, and one case in the proximal tibia (the remaining cases were not described). The tumors were histologically classified into three cases of fibroblastic, two cases of traditional-type; two cases of mixed-type and one case each of osteoblastic-, chondroblastic- and telangiectasia-type osteosarcoma (the remaining cases were not described). The mean recurrence time following surgery was 10.02 years (range, 5.2-19.3 years). With regard to the treatment modalities, five patients accepted surgery and chemotherapy, one patient accepted surgery and radiotherapy, two patients accepted surgery alone and one patient did not complete the treatment (the remaining cases were not described). From the 12 cases that were followed-up for between 0.5 and 4.7 years (mean, 2.28 years), one case was lost to follow-up, six patients survived (up to 4.5 years) and six patients succumbed to their condition (0.6-4.7 years). The present study highlights the fact that more focus should be placed upon the long-term follow-up of patients with osteosarcoma. A follow-up is required once every six months, from five years after the diagnosis. The abnormal changes in the surgical site should also receive further attention, in addition to the pulmonary and systemic metastases. Following a diagnosis of late post-operative recurrence, surgery and post-operative chemotherapy are commonly used in clinical treatment, however, the clinical outcome of osteosarcoma requires further observation. PMID- 23946773 TI - Diagnosis and preoperative predictive value of serum HE4 concentrations for optimal debulking in epithelial ovarian cancer. AB - The aim of this study was to evaluate serum human epididymis protein 4 (HE4) concentrations for the diagnosis and preoperative prediction of optimal debulking in epithelial ovarian cancer. The concentrations of serum HE4 and CA125 in 180 epithelial ovarian cancer patients, 40 benign ovarian tumor patients and 40 healthy female subjects were determined using enzyme-linked immunosorbent assays (ELISAs). The value of determining the serum HE4 concentrations for the diagnosis and preoperative prediction of optimal debulking in epithelial ovarian cancer was also analyzed. The concentration of serum HE4 was 355.2+/-221.29 pmol/l in ovarian cancer, 43.86+/-20.87 pmol/l in benign ovarian tumors and 30.22+/-9.64 pmol/l in healthy individuals, respectively. The serum HE4 levels of patients with ovarian cancer were significantly higher compared with those in the other two groups (P<0.01), although there were no statistically significant differences (P>0.05) between the benign ovarian tumors and healthy individuals. The maximum diagnostic value was identified at an HE4 serum concentration of 67.52 pmol/l and the sensitivity and specificity were 84 and 96%, respectively. The area under the ROC curve was 0.944 (95% CI, 0.912-0.976; P<0.001) and the kappa value of the diagnosis of epithelial ovarian cancer according to HE4 was 0.814 (P=0.000). The demarcation criterion was 600 pmol/l, where a value >600 mol/l indicates a lower possibility of optimal debulking. HE4 predicted that the sensitivity of the incomplete cytoreductive surgery was 77% and specificity was 32%. The concentration of serum HE4 is a useful marker for diagnosis and preoperative prediction for the ideal tumor cytoreductive surgery in epithelial ovarian cancer. PMID- 23946774 TI - Mitigating effects of L-selenomethionine on low-dose iron ion radiation-induced changes in gene expression associated with cellular stress. AB - Ionizing radiation associated with highly energetic and charged heavy (HZE) particles poses a danger to astronauts during space travel. The aim of the present study was to evaluate the patterns of gene expression associated with cellular exposure to low-dose iron ion irradiation, in the presence and absence of L-selenomethionine (SeM). Human thyroid epithelial cells (HTori-3) were exposed to low-dose iron ion (1 GeV/n) irradiation at 10 or 20 cGy with or without SeM pretreatment. The cells were harvested 6 and 16 h post-irradiation and analyzed by the Affymetrix U133Av2 gene chip arrays. Genes exhibiting a 1.5 fold expression cut-off and 5% false discovery rate (FDR) were considered statistically significant and subsequently analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) for pathway analysis. Representative genes were further validated by real-time RT-PCR. Even at low doses of radiation from iron ions, global genome profiling of the irradiated cells revealed the upregulation of genes associated with the activation of stress related signaling pathways (ubiquitin-mediated proteolysis, p53 signaling, cell cycle and apoptosis), which occurred in a dose-dependent manner. A 24-h pretreatment with SeM was shown to reduce the radiation effects by mitigating stress-related signaling pathways and downregulating certain genes associated with cell adhesion. The mechanism by which SeM prevents radiation-induced transformation in vitro may involve the suppression of the expression of genes associated with stress-related signaling and certain cell adhesion events. PMID- 23946775 TI - Expression and clinical significance of complement C3, complement C4b1 and apolipoprotein E in pancreatic cancer. AB - Pancreatic cancer (PC) remains a devastating disease with a five-year survival rate of <5%. The difficulty in making an early diagnosis and the frequent occurrence of metastasis are important reasons for this poor prognosis. In China, the incidence of PC has been increasing steadily. Therefore, the present study aimed to identify effective markers in the early and advanced stages of PC. The expression levels of complement C3, complement C4b1 and apolipoprotein E (ApoE) in the various stages of PC were assessed by immunohistochemistry, RT-PCR and western blotting. Additionally, the statistical significance of the results was analyzed. The expression levels of complement C3, complement C4b1 and apoE were higher in PC compared with normal pancreatic tissues. No correlations were observed between complement C3 and tumor TNM staging or lymph node metastasis. However, complement C4b1 and apoE were markedly correlated with tumor TNM staging and lymph node metastasis. Complement C3 may be used as a marker for the diagnosis of early-stage PC, while complement C4b1 and apoE are closely correlated with tumor development, reflecting the biological behavior of PC, and thus may be used as diagnostic markers of advanced PC. PMID- 23946776 TI - Aberrant expression of ZNF268 alters the growth and migration of ovarian cancer cells. AB - Ovarian cancer is one of the most lethal gynaecological cancers worldwide. However, the mechanisms underlying ovarian carcinogenesis are not well understood. The present study used immunostaining, western blotting and quantitative real-time PCR to demonstrate that ZNF268 is overexpressed in human ovarian carcinomas. ZNF268-knockdown increased the viability, colony formation and growth of in vivo xenografts of ovarian carcinoma SKOV-3 cells, whereas SKOV 3 cell migration was inhibited. Furthermore, it was demonstrated that the knockdown of ZNF268 may increase SKOV-3 cell growth by promoting cell cycle progression. The findings suggest that ZNF268 is a novel protein involved in ovarian carcinogenesis and that it may aid in the understanding of the mechanisms of ovarian carcinogenesis. PMID- 23946777 TI - The expression and clinical significance of melanoma-associated antigen-A1, -A3 and -A11 in glioma. AB - Melanoma-associated antigens (MAGEs) were initially identified in melanoma and have since been widely studied. Melanoma-associated antigen-As (MAGE-As), a subfamily of MAGEs, are expressed in germ cells and various types of cancer, and are considered to be ideal targets for cancer immunotherapy. Glial cells and melanocytes originate from the neural ectoderm, so tumors derived from these two types of cells, i.e. gliomas and melanomas, may have common biological characteristics. However, studies on the expression of the MAGE-A family in gliomas are limited and conflicting. In the present study, the expression levels of MAGE-A1, -A3 and -A11 were detected by immunohistochemistry, and the association of their expression levels with the clinicopathological parameters, overall survival (OS) and ki-67 labeling indices of glioma patients were analyzed. The results showed that i) the expression levels of MAGE-A1, -A3 and A11 proteins in the glioma tissues were 64.1, 51.3 and 57.7%, respectively and that no MAGE-A1, -A3 or -A11 expression was detected in the normal brain specimens; ii) the expression levels of MAGE-A1 and -A11 increased with ascending pathological grades and were positively correlated with the ki-67 labeling index; and iii) the OS of the patients in the groups with high MAGE-A1 (P=0.005) and A11 (P=0.019) expression was statistically lower compared with the groups with low expression and no significant differences in OS were detected between the patients in the groups with high and low MAGE-A3 expression (P=0.304). Based on these results, we conclude that MAGE-A1, -A3 and -A11 may be used as ideal targets for glioma immunotherapy, and that MAGE-A1 and -A11 expression may be involved in tumor cell proliferation. These proteins may be potential indicators of a poor prognosis in glioma patients. PMID- 23946778 TI - Characterization of p16 and E6 HPV-related proteins in uterine cervix high-grade lesions of patients treated by conization with large loop excision. AB - Cervical cancer and its precursor lesions represent a significant public health problem for developing and less-developed countries. Cervical carcinogenesis is strongly correlated with persistent high-risk human papillomavirus (HPV) infection, which is mostly associated with expression of the p16 and E6 HPV related proteins. The aim of this present study was to determine the expression of the p16 and E6 proteins in females with high-grade lesions treated with conization, and to discuss the role of these proteins as prognostic markers following treatment. In total, 114 females were treated for high-grade cervical intraepithelial neoplasia (CIN, grades 2/3) by conization with large loop excision of the transformation zone (LLETZ). Following surgery, the patients returned within 30-45 days for post-operative evaluation. A follow-up was conducted every 6 months for 2 years. At each follow-up appointment, a Pap smear, colposcopy and HPV DNA test were performed. E6 and p16 immunohistochemical tests were conducted on the surgical specimens. The positive expression of p16 was correlated with the presence of lesions with increased severity in the surgical specimens (P= 0.0001). The expression of E6 did not demonstrate the same correlation (P=0.131). The HPV DNA hybrid, collected in the first post-operative consultation as a predictor of the cytological abnormalities identified at the 24 month follow-up assessment, presented a sensitivity of 55.6%, a specificity of 84.8%, a positive predictive value of 33.3% and a negative predictive value of 93.3%. The role of p16INK4A as a marker of CIN was also demonstrated; the expression of p16 and E6, however, did not appear to be of any prognostic value in predicting the clearance of high-risk HPV following conization. A negative hybrid capture test was correlated with a disease-free outcome. PMID- 23946779 TI - Efficacy of combined axitinib with dacarbazine in a B16F1 melanoma xenograft model. AB - In this study, we evaluated the efficacy and intestinal side effects of the selective inhibitor of vascular endothelial growth factor (VEGF) receptors, axitinib and/or dacarbazine (DTIC), in a B16F1 melanoma xenograft model. C57BL/6 mice were subcutaneously inoculated with B16F1 melanoma cells. The study was randomized into four groups receiving either 0.5% carboxyl methylcellulose, DTIC, axitinib or a combination of DTIC and axitinib. When the experimental period was complete, the tumor tissues from each mouse were excised, photographed and weighed. The tumor and intestinal tissues were harvested with 4% paraformaldehyde, and paraffin-embedded sections were prepared for hematoxylin and eosin staining, immunohistochemical staining (with antibody specific to proliferating cell nuclear antibody) and terminal deoxynucleotidyl-transferase mediated dUTP nick end labeling assays. The expression of the VEGF and matrix metalloproteinase 9 genes was analyzed using real-time polymerase chain reaction. No significant benefit to treatment with a combination of axitinib and DTIC, as opposed to axitinib alone, was observed; however, the combined treatment did not enhance the level of enteritis compared with that observed in the axitinb group. In addition, axitinib, as a single agent, demonstrated an improved treatment efficacy compared with DTIC. Therefore, axitinib represents a potential novel, efficient and safe anticancer agent, suggesting a possible use for this schedule in treating melanomas that are less sensitive to DTIC. PMID- 23946780 TI - Telomerase reverse transcriptase promotes the proliferation of human laryngeal carcinoma cells through activation of the activator protein 1. AB - TERT is the main functional unit of telomerase, which maintains telomere length and chromosome structure stability. TERT has been shown to act as a key factor in various biological processes, such as cell proliferation, via uncharacterized mechanisms. We transfected HEp-2 laryngeal carcinoma cells with a TERT overexpressing adenovirus (Ad-TERT) and TERT shRNA silencing adenovirus (Ad-sh TERT), and examined the effect on TERT and the AP-1 transcription factor subunits c-Fos and c-Jun using RT-PCR and western blot analysis. TERT mRNA expression was quantified using RT-PCR in 24 human laryngeal carcinoma samples, and TERT protein co-expression with AP-1 was investigated in a human laryngeal carcinoma tissue microarray using quantum-dot based immunofluorescence. The effect of specific ERK and p38 inhibitors on ERK, p38, c-Jun and c-Fos phosphorylation was investigated in TERT-overexpressing HEp-2 cells. TERT overexpression led to increased TERT, c Jun and c-Fos mRNA and protein expression and increased cell proliferation, while TERT silencing had the opposite effects. TERT mRNA expression levels were positively correlated with c-Fos and c-Jun mRNA in human laryngeal carcinoma tissue. TERT and AP-1 protein were expressed at high levels and positively correlated in laryngeal carcinoma tissues. Treatment of TERT-overexpressing HEp-2 cells with specific p38 and ERK inhibitors indicated that TERT modulates the expression and phosphorylation of the AP-1 subunits c-Jun and c-Fos through the p38 and ERK signaling pathways. In conclusion, the results of this study indicate that TERT is capable of promoting cell proliferation via activation of the AP-1 subunits, c-Jun and c-Fos, in laryngeal carcinoma cells. PMID- 23946781 TI - Enhanced inhibitory effect of curcumin via reactive oxygen species generation in human nasopharyngeal carcinoma cells following purple-light irradiation. AB - Curcumin, a traditional medicine, exhibits anti-carcinogenic properties in various cell lines and animals. As a phenolic compound, curcumin is light sensitive and photoactived curcumin exhibits a greater anticancer effect compared with curcumin alone. However, the mechanisms by which curcumin inhibits tumor cell growth in human nasopharyngeal carcinoma (NPC) cells following purple light (PL) irradiation remains unclear. In the present study, CNE1 and CNE2 cells were treated with curcumin and exposed to PL at various energy densities to determine the anticancer activity of curcumin using MTT assays, staining and flow cytometry. The subsequent changes in the cell viability, morphology, cell cycle, apoptosis and reactive oxygen species (ROS) generation were measured. Curcumin inhibited cell growth in a dose-dependent manner. CNE1 and CNE2 cells tended to be arrested at the S or G2/M cell cycle stages following curcumin treatment and the levels of ROS increased in a time-dependent manner. However, after treatment with curcumin followed by PL irradiation, the levels of cytotoxicity and apoptotic cell death were significantly increased compared with the curcumin-only group. ROS generation was also enhanced in an energy-dependent manner. In summary, following PL irradiation, the anti-cancer effect of curcumin in human NPC cells was increased through apoptosis and cell cycle arrest. PMID- 23946782 TI - DNA methylation state of the galectin-3 gene represents a potential new marker of thyroid malignancy. AB - In order to supplement the cytopathological assessment of thyroid tumors, there is a need for new markers to correctly diagnose malignant thyroid lesions and avoid unnecessary and potentially harmful therapies for patients. The immunohistochemical expression of galectin-3 is currently considered to be the most accurate stand-alone marker for thyroid cancer diagnosis. The aim of this study was to establish whether the methylation state of the galectin-3 gene is a candidate molecular marker for thyroid malignancy. Thyroid specimens from 50 patients were analyzed, including 5 normal thyroid, 3 goiters, 39 papillary and 3 anaplastic thyroid carcinoma cases. High-resolution methylation analyses was performed to investigate the methylation state of a large genomic region (from 89 to +408) encompassing the galectin-3 transcriptional start site. Within this region, 5 CpG sites (nucleotide positions +134, +137, +142, +147 and +156) were observed to be differentially methylated among the samples and were further analyzed by the quantitative pyrosequencing technique. The hypomethylation of the +134, +137, +142, +147 and +156 CpG sites was observed to be markedly associated with cancer. Although the methylation degree of each single site was highly variable in non-neoplastic tissues, the average methylation state of the 5 CpG sites clearly distinguished cancer from the nonneoplastic thyroid tissues. PMID- 23946783 TI - Atypical chemokine receptor D6 inhibits human non-small cell lung cancer growth by sequestration of chemokines. AB - Chemokines and their receptors have been shown to play a vital role in lung cancer progression. D6 is an atypical chemokine receptor which is able to internalize and degrade chemokines. To investigate the potential role of D6 in lung cancer, we established D6-overexpressing A549 lung cancer cell lines by the transfection of human D6 cDNA. Results showed that D6 inhibited the proliferation of cancer cells in vitro and tumorigenesis in vivo. We also determined chemokine levels in the supernatant and showed that a number of chemokines (CCL2/4/5) had significantly decreased protein levels in D6-overexpressing cells compared with the controls, whereas no significant changes in mRNA expression levels of these chemokines were detected. The cell cycle distribution and expression of certain growth factors and their receptors did not change in the D6-overexpressing cells compared with parental cells. Thus, our results suggest that D6 is a negative regulator of growth in lung cancer, mainly by the sequestration of specific chemokines. PMID- 23946784 TI - Clinical significance of CD24 as a predictor of bladder cancer recurrence. AB - Cluster of differentiation (CD)24 was originally described as a B lymphocyte marker and has recently received considerable attention in cancer research as its overexpression has been observed in several types of carcinoma. The CD24 molecule is a glycosyl-phosphatidylinositol-linked cell surface protein that appears to be associated with aggressive cancers involving invasion and metastasis. However, the expression of CD24 in human bladder cancer and its clinical significance remains largely unknown and no association has been reported between CD24 overexpression and human bladder tumor recurrence. In the present study, the CD24 expression in cancer tissues obtained during transurethral surgery and the subsequent intra-bladder tumor recurrence following surgery were assessed. Immunohistochemical staining was performed and the intensity of CD24 staining was semi-quantitatively evaluated. CD24 expression was observed more frequently in high-grade bladder tumors (G2-G3) than low-grade tumors (G1). Positive CD24 expression was significantly associated with intra-bladder tumor recurrence following surgery and increased staining intensity was also correlated with recurrence. The positive association between CD24 expression and tumor recurrence was observed in each tumor category (stages Ta and T1, low and high grade). The results demonstrated that CD24 expression is significantly associated with bladder tumor recurrence. To the best of our knowledge, this is the first study to reveal the significance of CD24 as a predictor of bladder cancer recurrence. These insights may lead to future therapeutic strategies targeting CD24 to prevent the dissemination of bladder cancer cells and tumor recurrence. PMID- 23946785 TI - Downregulation of claudin-7 potentiates cellular proliferation and invasion in endometrial cancer. AB - Claudin-7, a tight junction protein, has been demonstrated to be abnormally regulated in several types of human cancer. The present study aimed to investigate the expression and function of claudin-7 in endometrial cancer. In total, 31 pairs of endometrial cancer samples and their adjacent normal tissues were used to detect the expression of claudin-7 by immunohistochemical staining. Compared with the corresponding normal tissues, 45.2% of the endometrial cancer tissues exhibited weak or absent claudin-7 protein expression. Low levels of claudin-7 were correlated with a late tumor stage (P=0.023) and low histological grade (P=0.018). Claudin-7 was either overexpressed in AN3CA endometrial cancer cells, via plasmid cDNA transfection, or silenced by RNA interference in Ishikawa cells. Following either type of experimental manipulation, cellular proliferation and invasion were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay, wound healing and transwell assays, respectively. The silencing of claudin-7 significantly increased cellular proliferation (P=0.032) and invasion (P=0.020) rates. Consistent with these results, the increased expression of claudin-7 decreased the proliferation (P=0.021) and invasiveness (P=0.012) of the AN3CA cells. A low expression of claudin-7 in the endometrial cancer cells was indicative of a late tumor stage and low histological grade. Additionaly, restoration of claudin-7 inhibited the proliferation and invasion of endometrial cancer cells, thus providing a potential therapeutic strategy. PMID- 23946786 TI - Downregulation of L-type amino acid transporter 1 expression inhibits the growth, migration and invasion of gastric cancer cells. AB - Gastric cancer is the second leading cause of cancer-related mortality worldwide. Identifying the molecules that play critical roles in the development of gastric cancer, and clarifying their mechanisms, will contribute to the development of novel molecularly targeted therapeutic drugs. Recently, the large (L)-type amino acid transporter 1 (LAT1), a glycoprotein that transports amino acids through the cell membrane when associated with CD98hc, has been demonstrated to be overexpressed in various types of cancer, and to regulate multiple biological process, including cell growth, migration and invasion. However, the involvement of LAT1 in gastric cancer remains unclear. In the present study, stable gastric cancer cell lines with a LAT1 knockdown were established by transfection of constructs with inserted short (sh) RNAs, in order to clarify the role of LAT1 in gastric caner. A significant decrease in LAT1 expression was observed in the established LAT1-silenced SGC7901 cells compared with the corresponding control cells; however, the expression levels of its partner, CD98hc, were not altered. Furthermore, downregulation of LAT1 expression inhibited the proliferation, migration and invasion of gastric cancer cells. In addition, the decreased expression of LAT1 induced cell cycle arrest in the G1/M phase. These findings suggested that LAT1 may be significant in the progression and metastasis of gastric cancer, and may be developed as a therapeutic target for cancer therapy. PMID- 23946787 TI - Gynura procumbens ethanolic extract suppresses osteosarcoma cell proliferation and metastasis in vitro. AB - Gynura procumbens is a traditional herb used for the treatment of inflammation, rheumatism and viral infections, although the antitumor effect and its potential mechanisms of action remain unclear. In the present study, the antitumor effect of Gynura procumbens ethanolic extract (GPE) on the osteosarcoma (OS) cell line, U2-OS, was investigated in vitro. Cell proliferation and apoptosis were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Transwell invasion and wound healing assays were performed to investigate the invasion and migration of the U2-OS cells. The results showed that GPE was able to inhibit U2-OS cell proliferation and metastasis and induce cell apoptosis. Furthermore, the expression of the NF kappaBp65 protein was detected by western blotting to evaluate the effects of GPE on the nuclear transfer of NF-kappaB. It was demonstrated that the expression of the NF-kappaBp65 protein was significantly decreased by GPE. This indicated that GPE was able to inhibit the nuclear transfer of NF-kappaB. The study shows that GPE is able to induce apoptosis and suppress proliferation and metastasis in U2 OS cells via the inhibition of the nuclear translocation of NF-kappaB. PMID- 23946788 TI - Phosphorylation of estrogen receptor alpha at serine 118 is correlated with breast cancer resistance to tamoxifen. AB - The aim of the present study was to explore the correlation between estrogen receptor alpha (ERalpha) phosphorylation at serines 118 and 167 and the responsiveness of patients with primary breast cancer to tamoxifen. Tumors from 104 patients with primary breast cancer who received adjuvant tamoxifen therapy at The Affiliated Cancer Hospital of Shantou University Medical College between January 2001 to December 2007 were subjected to immunohistochemical analysis with specific antibodies against ERalpha phosphorylated at either serine 118 (pERalpha S118) and/or serine 167 (pERalpha-S167). ERalpha phosphorylation at the two sites was correlated with either the disease-free survival or the overall survival rate of these patients using the Kaplan-Meier survival analysis. pERalpha-S118 and pERalpha-S167 were found to be expressed in the cell nucleus of 25.0% (26/104) and 26.9% (28/104) of breast cancers, respectively. The expression of pERalpha S118 was positively correlated with the human epidermal growth factor receptor-2 (HER-2) status (chi2=6.85, P=0.01). The Kaplan-Meier analysis revealed a poorer disease-free (P=0.022) and overall survival (P=0.013) in breast cancer patients expressing pERalpha-S118, but not in those expressing pERalpha-S167. In conclusion, pERalpha-S118 was correlated with the HER-2 status and predicted breast cancer resistance to tamoxifen. PMID- 23946789 TI - Annexin A2 is not a good biomarker for hepatocellular carcinoma in cirrhosis. AB - In China, hepatocellular carcinoma (HCC) usually develops following a long history of chronic hepatitis B infection or cirrhosis. To evaluate the diagnostic role of annexin A2 (ANXA2), a possible tumor marker, in patients with hepatitis B virus (HBV)-related HCC, particularly those with a history of cirrhosis, the present study prospectively enrolled 87 patients with HBV-related HCC (with cirrhosis), 39 patients with HBV-related cirrhosis and 27 healthy controls. The expression levels of serum and tissue ANXA2 were determined using an enzyme linked immunosorbent assay (ELISA) and immunohistochemical staining, respectively. The serum levels of ANXA2 were significantly elevated in the patients with HCC (median, 567.2 MUg/ml; P=0.003) and cirrhosis (median, 414.8 MUg/ml; P=0.011) compared with the healthy controls (median, 241.9 MUg/ml). However, no significant differences were observed in the serum ANXA2 levels between the patients with HCC and those with cirrhosis. The immunohistochemical staining analysis showed that the healthy controls did not show positive staining, while the number of cases immunoreactive for ANXA2 steadily increased from the liver cirrhosis tissues (20/39, 51.3%) to the non-cancer (53/87, 60.9%) and cancer tissues (68/87, 78.2%). The cancer tissues exhibited a significantly higher ANXA2-positive rate compared with the non-cancer (P=0.013) and liver cirrhosis tissues (P=0.002). Furthermore, marked ANXA2 staining was more prevalent in the cancer tissues (16/87, 18.4%) than the non-cancer (4/87, 4.6%; P=0.004) and liver cirrhosis (1/39, 2.6%; P=0.034) tissues. The sensitivity, specificity and diagnostic accuracy of tissue ANXA2 for HCC in cirrhosis were 78.2, 42.1 and 56.8%, respectively. The ANXA2 expression levels in the serum and cancer tissues were not associated with tumor-free survival or patient survival following liver transplantation. Serum or tissue ANXA2 is not a good diagnostic marker for HCC in HBV-related cirrhosis and is not associated with prognosis. PMID- 23946790 TI - Expression of p53, epidermal growth factor receptor, Ki-67 and O6-methylguanine DNA methyltransferase in human gliomas. AB - The present study aimed to evaluate the expression of p53, Ki-67, epidermal growth factor receptor (EGFR) and O6-methylguanine-DNA methyltransferase (MGMT), and to analyze the correlation between their expression and the histological grade of the tumors in 152 patients with gliomas. The tumors were classified according to the recommendations of the World Health Organization (WHO; 2007) into grade I (n=9), grade II (n=56), grade III (n=52) and grade IV (n=35). The expression of p53, Ki-67, EGFR and MGMT was analyzed using immunohistochemistry. The frequency of p53 immunopositivity was significantly lower in grade I gliomas than in grades II, III and IV. The frequency of EGFR immunopositivity was significantly higher in grade III and IV gliomas compared with grades I and II. The mean Ki-67 labelling index (LI) significantly increased in the higher glioma grades. The expression of MGMT in grade I and II tumors was not significantly different from that of grade III and IV tumors. The present data indicate that the expression of EGFR and Ki-67 is significantly correlated with the histological grade of the glioma, but that the expression of p53 and MGMT is not associated with the tumor grade. PMID- 23946791 TI - Proteomic analysis of protein expression profiles during hyperthermia-induced apoptosis in Tca8113 cells. AB - The aim of the present study was to explore protein expression profiles during cancer cell apoptosis induced by hyperthermia. A hyperthermia-induced apoptosis model was established using a Tca8113 cell line derived from a human tongue squamous cell carcinoma, which underwent fluorescent differential display two dimensional (2D) gel electrophoresis at 2, 6, 8, 12 and 24 h following the induction of hyperthermia. Proteins were identified by mass spectrometry analysis. Expression changes in the proteins were detected by western blot analysis. A total of 107 proteins were detected that exhibited different expression levels in the hyperthermia-treated cells compared with the controls, and 57 of these proteins were identified. Expression changes in the representative proteins were further verified by western blot analysis. These 57 proteins were identified according to the following functional groups: energy metabolism-related enzymes, cytoskeleton-related proteins, chaperones, transcription factors, protein synthesis-related proteins and cell division- and proliferation-related proteins. These groups included 44 upregulated and 13 downregulated proteins. Among the 44 upregulated proteins, 27 were upregulated continuously, eight were upregulated at an early time-point and nine were upregulated at a middle to late time-point. Among the 13 downregulated proteins, five were downregulated continuously, six were downregulated at an early time point and two were downregulated at a middle to late time-point. These results indicate that hyperthermia-induced Tca8113 cell apoptosis is controlled by multiple factors, which include time and regulatory proteins. PMID- 23946792 TI - Grave's disease induced by radiotherapy for nasopharyngeal carcinoma: A case report and review of the literature. AB - Radiotherapy is an effective treatment for nasopharyngeal carcinoma (NPC). A number of thyroid dysfunctions are induced by damage resulting from the relatively high doses of radiation administered to the thyroid and pituitary gland during radiotherapy. Hypothyroidism constitutes the most frequent type of thyroid dysfunction induced by NPC radiotherapy, while hyperthyroidism, particularly Grave's disease, is extremely rare. The present study describes the case of a 40-year-old male who presented with Grave's disease 2 years after receiving radiotherapy for the treatment of NPC. The patient exhibited swelling of the eyes, an increased appetite, decreased levels of thyroid-stimulating hormone, increased levels of triiodothyronine (T3) and thyroxine (T4) demonstrated by the examination of thyroid function and enlargement of the bilateral intraocular rectus revealed by CT scan. The patient's symptoms were ameliorated following treatment with propylthiouracil and propranolol for 1 month, and the levels of T3 and T4 were restored to normal. The pathophysiological mechanism of radiotherapy-induced hyperthyroidism has yet to be elucidated. Hyperthyroidism is often neglected as several of its clinical manifestations are similar to other complications observed during and following cancer treatment. Therefore, it is necessary to monitor thyroid function following head and neck radiotherapy. PMID- 23946793 TI - Recurrence of thymic neuroendocrine carcinoma 24 years after total excision: A case report. AB - A 77-year-old male presented with chest pain in March 2012. The individual had undergone surgery for an anterior mediastinal tumor 24 years earlier and the pathological diagnosis was that of a thymoma. The patient underwent a medical check-up every 6 months for the next 20 years. However, ~3 years following the final check-up, sudden chest pain was reported and the patient was referred again. Computed axial tomography revealed a mediastinal mass adjacent to the left lung, pericardium and sternum. There was no apparent invasion to the adjacent structures. The patient underwent surgical resection following a diagnosis of recurrent thymoma. A posterolateral thoracotomy was performed under video assisted thoracoscopy. Severe adhesions were observed around the tumor, which appeared to invade the left lung and pericardium, but not the chest wall. The tumor was extirpated in combination with partial resection of the left lung and pericardium. The pathological diagnosis of the tumor was of a well-differentiated neuroendocrine carcinoma (NEC) of the thymus. The specimen that was excised 24 years earlier was re-examined by a pathologist and was reported to exhibit the same histology. Primary NECs of the thymus are rare among anterior mediastinal tumors and the 5-year survival rate is ~30%. The present case study reports a case of a thymic NEC and describes the pathological and clinical features. PMID- 23946794 TI - An 11 kg Phyllodes tumor of the breast in combination with other multiple chronic diseases: Case report and review of the literature. AB - Phyllodes tumors (PTs) of the breast are a rare type of tumor that account for <1% of breast tumors in females and usually present as a large lump of 3-5 cm in size. Surgery is the first line of treatment for PTs, and chemotherapy and irradiation may be useful in certain patients but not all. In the present study, the case of a 63-year-old female patient with a huge PT in the left breast is described. On physical examination, the patient presented with a huge mass of ~45 cm in diameter, weighing ~11 kg, and a composite of multiple chronic diseases. The breast and pectoris major and minor were excised. Post-operatively, the patient recovered well and to date there has been no evidence of local recurrence or distant metastasis. PMID- 23946795 TI - Mature cystic teratoma of the fallopian tube associated with incomplete uterine mediastinum: A case report and literature review. AB - Neoplasms of the fallopian tube are extremely uncommon. In addition, the incidence of a mature teratoma of the fallopian tube with incomplete uterine mediastinum is extremely low. In the current case report, we present a case of mature cystic teratoma of the fallopian tube with incomplete uterine mediastinum in a 23-year-old female. This mass was noted on computed tomography (CT) scan and sonographic examination. The patient underwent left salpingectomy and uterine septum incision during surgery. One year later, the individual became pregnant. PMID- 23946796 TI - Involvement of post-transcriptional regulation of FOXO1 by HuR in 5-FU-induced apoptosis in breast cancer cells. AB - The post-transcriptional control of specific mRNAs is a widespread mechanism of gene regulation, which contributes to numerous biological processes in a number of cell types. The Forkhead box O (FoxO) transcription factor FOXO1 is an important tumor suppressor involved in apoptosis, the cell cycle, DNA damage repair and oxidative stress. Bioinformatic prediction identified that the 3' untranslated region (UTR) of FOXO1 is enriched with binding motifs for the human ELAV/Hu protein (HuR), indicating that FOXO1 is a potential target of HuR. Luciferase reporter assays demonstrate that HuR specifically regulates FOXO1 expression through AU-rich elements (AREs) within the FOXO1 3' UTR. Immunoprecipitation studies confirmed that HuR associates with FOXO1 mRNA in MDA MB-231 breast cancer cells and that HuR upregulates FOXO1 mRNA levels through increased mRNA stability. Using a HuR loss- and gain-of-function approach, we revealed that FOXO1 expression was correspondingly decreased or increased in MDA MB-231 cells. Functional assays demonstrated that HuR and FOXO1 expression levels were markedly enhanced upon 5-fluorouracil (5-FU) stimulation in MDA-MB-231 cells. Knockdown of HuR apparently abrogated 5-FU-induced apoptosis detected by caspase-3 activities. Furthermore, in HuR knockdown cells, additional overexpression of FOXO1 moderately recovered 5-FU-induced apoptosis, which verified that HuR-modulated apoptosis upon 5-FU treatment was partially mediated by its post-transcriptional regulation of FOXO1. Therefore, modulating FOXO1 expression has been suggested to lead to the development of new therapeutic treatments for certain types of cancer. PMID- 23946797 TI - PTEN mutation, methylation and expression in breast cancer patients. AB - The tumor suppressor gene, PTEN, has previously been demonstrated to be involved in breast tumorigenesis and tumor progression. The aim of the present study was to investigate the expression and significance of PTEN in breast carcinomas, to detect the mutation frequency of PTEN in sporadic breast carcinoma tissues and to determine the association between PTEN promoter methylation and gene expression. Immunohistochemical methods were used to analyze the expression of the PTEN gene in 146 cases of breast carcinoma and 10 cases of normal breast tissue closely adjacent to the carcinoma. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis was used to analyze conformation polymorphisms in 45 breast carcinoma and 10 normal breast tissues. Point mutations of abnormal single stranded conformation were detected by DNA sequencing. The methylation of the PTEN promoter was analyzed by methylation-specific PCR. Expression of PTEN was detected in 57.5% (84/146) of patients with breast carcinoma. By contrast, PTEN expression was detected in 100% of normal samples. Expression of PTEN was found to negatively correlate with the tumor size, the pathological stage and the expression of the estrogen receptor (ER) and the progesterone receptor (PR) in breast cancer. The 2-year disease-free survival of patients with a high expression of PTEN was higher compared with those with low PTEN expression (P<0.05). Missense mutations in exon 2 of PTEN were identified in 1/45 breast cancer cases. PTEN promoter methylation was detected in 31.1% (14/45) of breast carcinomas, of which 64.3% (9/14) were associated with a loss of PTEN expression. The tumor suppressor gene, PTEN, was abnormally expressed in the breast carcinomas. The number of PTEN mutations were low (1/45) in the sporadic breast cancer cases analyzed in the present study and PTEN promoter methylation may have been the main mechanism leading to the decreased expression of PTEN. These results indicate that PTEN is important for the tumorigenesis, development and prognosis of breast cancer. PMID- 23946798 TI - Twist2 promotes ovarian cancer cell survival through activation of Akt. AB - Hypoxia-inducible factor-1 alpha (HIF-1alpha) is an important prognostic factor in ovarian carcinoma. Hypoxia contributes to tumor progression and is involved in the epithelial-mesenchymal transition (EMT). Twist2 is an EMT regulator, however, it remains poorly understood in ovarian carcinoma. The present study evaluated the expression of HIF-1alpha and Twist2 and further investigated whether Twist2 is involved in hypoxia-induced apoptosis in ovarian cancer. A series of matched paraffin-embedded tissue sections from human primary ovarian cancer and normal ovarian tissues were examined through immunohistochemical analysis, a Twist2 overexpressing stable ovarian cancer cell line was established and deferoxamine (DFO) was introduced to simulate hypoxic conditions. DFO-induced apoptosis was examined by fluorescence microscopy, MTT assays and flow cytometry. In addition, a western blot analysis was performed to examine the molecular mechanism(s) of action. Twist2 increased in epithelial ovarian cancers associated with HIF-1alpha expression. The acquired expression of Twist2 was able to promote the survival of ovarian cancer cells through Akt phosphorylation under DFO-induced hypoxic stress. The results suggest that Twist2 activates the PI-3K-Akt pathway to protect cells from apoptosis in a hypoxic environment. Moreover, Twist2 may be involved in the HIF-1alpha signaling pathway in ovarian cancer. PMID- 23946799 TI - Correlation of the expression of vascular endothelial growth factor and its receptors with microvessel density in ovarian cancer. AB - The present study aimed to investigate the correlation between the expression of vascular endothelial growth factor (VEGF) and its receptors, the Flt-1 and KDR proteins, with clinical pathology and microvessel density (MVD) in ovarian cancer tissue. The protein expression levels of VEGF and its receptors, Flt-1 and KDR/Flk-1, were detected in 48 cases of ovarian cancer using the streptavidin biotin complex (SABC) immunohistochemical method, and tumor MVD was evaluated using F8 factor (FVIII-RA). The expression of the VEGF, Flt-1 and KDR proteins was not significantly associated with the pathological type, extent of differentiation or clinical stage of ovarian cancer. However, the co-expression of VEGF and Flt-1 was markedly correlated with differentiation and clinical stage (P<0.01). The co-expression levels of VEGF and receptor Flt-1 in malignant neoplasms with lymph node metastasis was significantly higher compared with malignant neoplasms without lymph node metastasis (P<0.05). The expression level of KDR in patients with hepatic metastasis was significantly higher compared with patients without hepatic metastasis (P<0.05). The co-expression level of VEGF and KDR in patients with hepatic metastasis was significantly higher compared with patients without hepatic metastasis (P<0.05) and the Flt-1 expression level in patients with ascites <1,000 ml was significantly lower than that in patients with ascites >=1000 ml (P<0.05). The mean MVD of VEGF- and KDR-positive patients was significantly higher compared with VEGF- and KDR-negative patients (P<0.05). The expression of VEGF and its receptors is involved in the malignant transformation of ovarian tumors, tumor progression and metastasis, as well as ascites formation and angiogenesis. PMID- 23946800 TI - Giant malignant mesothelioma in the upper mediastinum: A case report. AB - Malignant mesothelioma in the mediastinum is rare and the majority of known cases have been reported as 'localized mesothelioma'. The present study reports a case of an upper mediastinal tumor, which was diagnosed through thoracoscopic surgery and surgical biopsies of the mass. A computed tomography scan revealed a giant upper mediastinal tumor, adjacent to the aortic arch, trachea, superior vena cava and left pulmonary artery. The vessels in the mediastinum were compressed and were shifted to the lower right. The trachea became stenotic and a small amount of bilateral pleural effusion was observed. The mass was relatively well encapsulated. There was no pleural thickening or clearly swollen lymph nodes in the mediastinum. The histopathological and immunohistochemical examinations of the tumor verified the diagnosis of a malignant mesothelioma. The tumor was demonstrated to be derived from the mediastinal pleural mesothelium cells. The patient received pemetrexed disodium and cisplatin combination chemotherapy for four cycles. At present, the patient is undergoing follow-up. PMID- 23946801 TI - Surgical treatment of giant cell tumors of the sacrum and spine combined with pre operative transarterial embolization. AB - The pre-operative embolization of hypervascular spinal tumors is often performed to decrease intraoperative blood loss and facilitate tumor resection; however, few studies have been published on its effectiveness in giant cell tumors (GCT) of the sacrum and spine. The purpose of the present study was to investigate the value of surgical excision with pre-operative transarterial embolization for GCTs of the sacrum and spine, and to evaluate the follow-up outcomes. A retrospective study was performed on 28 patients with GCTs of the sacrum and spine, who underwent surgical treatment combined with pre-operative transarterial embolization between June 1995 and August 2011. The intraoperative blood loss, transfusion, duration of surgery, treatment, local recurrence, complications, follow-up status and functional outcome were reviewed. The average follow-up period was 86.3 months (range, 12-193 months). All the patients were treated with intralesional resection without any intraoperative shock or fatalities. The average intraoperative level of blood loss was 1,528.6 ml (range, 400-5,800 ml), the average transfusion volume was 1,514.3 ml (range, 400-6,000 ml) and the average duration of surgery was 225.4 min (range, 120-470 min). In total, eight (28.6%) patients developed recurrence and two patients succumbed. A total of eight (28.6%) patients experienced complications and 24 (85.7%) retained normal neurological function. Pre-operative embolization significantly decreases intraoperative blood loss and facilitates the maximal removal of the tumor. Pre operative embolization followed by intralesional resection is able to achieve satisfactory local control and clinical outcomes. It is an effective technique for excising GCTs of the sacrum and spine. PMID- 23946802 TI - Contribution of the BRAF oncogene in the pre-operative phase of thyroid carcinoma. AB - Numerous experiments have been conducted over the last few years aiming to identify molecular markers that show the diagnostic accuracy of fine-needle aspiration (FNA), particularly in thyroid lesions that are considered indeterminate. Using certain search arguments and previously defined criteria, 37 studies reporting experiments with the BRAF mutation in pre-operative FNA of the thyroid were selected from the electronic databases PUBMED, MEDLINE, SCOPUS and LILACS, in order to gather evidence with regard to the possible contribution of BRAF in the management of thyroid carcinoma. There were no cases positive for BRAF in follicular carcinomas (FTCs), Hurthle cell carcinomas (HCCs) or medullary thyroid carcinomas (MTCs). Among the 11 cases of anaplastic thyroid carcinomas (ATC), three showed positive results for the BRAF mutation. The number of cases positive for BRAF among the benign lesions was not significant. The average prevalence of BRAF-positive cases in papillary carcinomas (PTC) was 58.6%, while in follicular variants of papillary carcinoma (FVPTC), the average prevalence was 29.6%. For lesions diagnosed as indeterminate or suspicious, the average prevalence of BRAF positivity in PTC was 48.5%. The experiments included in the present study indicated a specificity of almost 100% and a high predominance of the BRAF mutation in PTC, distinguishing the marker in the planning and medical management of papillary carcinoma of the thyroid. PMID- 23946804 TI - Effect of DLK1 on tumorigenesis in CD34+CD38- bone marrow cells in myelodysplastic syndromes. AB - The myelodysplastic syndromes (MDSs) are a group of clonal stem cell disorders resulting from aberrations within hematopoietic stem cells (HSCs), which may lead to the onset of a number of diseases, including acute myeloid leukemia (AML). Recent studies have demonstrated that the expression levels of the DLK1 gene are increased in MDS. In order to determine whether the addition of DLK1 affects tumorigenesis, small interfering (si)RNAs were designed to target DLK1 in order to knockdown its expression in CD34+CD38- bone marrow cells in MDS. A lower proliferative rate was observed in the CD34+CD38- bone marrow cells following this knockdown of DLK1 expression. The suppression of DLK1 expression resulted in a less aggressive MDS phenotype, which suggests that the upregulation of DLK1 expression may play an oncogenic role in CD34+CD38- bone marrow cells. PMID- 23946803 TI - alpha-linolenic acid inhibits human renal cell carcinoma cell proliferation through PPAR-gamma activation and COX-2 inhibition. AB - omega-3 fatty acids have potential anticancer effects, and consuming food rich in omega-3 fatty acids reduces the human renal cell carcinoma (RCC) risk. However, the direct effect of omega-3 fatty acids on RCC in vitro is unknown. In the present study, the effects of alpha-linolenic acid (ALA), an omega-3 fatty acid, were observed on cell proliferation in the RCC cell line OS-RC-2. The activity and gene expression levels of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and cyclooxygenase-2 (COX-2) in the OS-RC-2 cells were measured by ELISA and real-time RT-PCR, respectively, following ALA treatment. ALA (20-80 MUM) dose-dependently suppressed the proliferation of the OS-RC-2 cells. PPAR gamma activity and gene expression were significantly increased by ALA at 20 and 40 MUM. COX-2 activity and gene expression levels were significantly decreased by ALA from 20 MUM. Use of purely the PPAR-gamma agonist, rosiglitazone, decreased the proliferation of the OS-RC-2 cells, while ALA induced further suppression of cell proliferation in the presence of rosiglitazone. The COX-2 inhibitor N-(3 Pyridyl)indomethacinamide induced further suppression of cell proliferation in the presence of rosiglitazone. N-(3-Pyridyl)indomethacinamide also suppressed the proliferation of the OS-RC-2 cells. In the presence of N-(3 Pyridyl)indomethacinamide, ALA and rosiglitazone further inhibited OS-RC-2 cell proliferation. In conclusion, ALA inhibits the cell proliferation of the OS-RC-2 human RCC cell line. PPAR-gamma activation and COX-2 inhibition serve as two signaling pathways for the inhibitory effects of ALA on RCC cell proliferation. PMID- 23946805 TI - Construction of a tumor-specific bioluminescent eukaryotic expression vector and analysis of its expression in vitro and in vivo. AB - The aims of this study were to construct a tumor-specific bioluminescent eukaryotic vector driven by the hTERT gene promoter and to establish a stable HeLa cell line expressing a modified firefly luciferase gene. PhTERTp-luc and pGL4.17 (luc2/Neo) were digested with SacI and HindIII, respectively, and the recombinant vector phTERTp-luc-neo was generated by ligating the desired fragments. The expression of phTERTp-luc-neo was tested in a non-transformed cell line (MRC-5), and in telomerase-positive (HeLa, MCF-7 and 293T) and -negative (U2OS and SaOS) transformed cell lines using a luciferase assay. Results showed that the recombinant vector had higher luciferase activity in telomerase-positive transformed cell lines. PhTERTp-luc-neo was transfected into a HeLa cell line, selected by G418 and bioluminescence imaging, and a cell clone HeLa-luc that constitutively expressed both neomycin and luciferase was obtained. We also conducted experiments in animals to observe luciferase activity in vivo using stable cell lines that were subcutaneously implanted into BALB/c nude mice and tumor growth was monitored by bioluminescence imaging. The HeLa-luc cell line retained its oncogenicity and tumors were detected on the fifth day following implantation by bioluminescence imaging. This study has formed a basis for the study of the expression and regulation of hTERT and early tumor detection. It also provides a convenient, sensitive and reliable platform for cervical cancer research. PMID- 23946806 TI - Gastric collision tumor: Case report of a rare adenocarcinoma and a typical carcinoid tumor. AB - We report a case with features of gastric adenocarcinoma colliding with a typical carcinoid component. A 51-year-old female was admitted to the Department of Internal Medicine with complaints of epigastric pain. On physical examination of the patient there was significant epigastric tenderness and the CA19-9 level was higher than the normal titer value. An upper gastrointestinal endoscopy showed an ulcerated polypoid mass located on the cardiac region of the stomach. Pathological and immunohistochemical findings diagnosed as a collision tumor comprising both adenocarcinoma and carcinoid tumor. Metastasis of adenocarcinoma was found in 7 perigastric lymph nodes, while metastasis of the carcinoid was not detected. The admixture of neoplastic endocrine and nonendocrine cells, have been found infrequently in gastric tumors. The mixed tumors can be further classified into composite tumors that show an admixture of two histological components with histological transitions and collision tumors where the two components are not intermixed In general it is not easy to morphologically distinguish a collision tumor, from composite tumor. Microscopically, hematoxylin and eosin-stained tissue sections from two different areas of the mass revealed two different types of tumor; an intestinal type adenocarcinoma and a carcinoid tumor. We report a case with features of adenocarcinoma colliding with a typical carcinoid component, along with a review of the literature. PMID- 23946807 TI - Results of cytology and high-risk human papillomavirus testing in females with cervical adenocarcinoma in situ. AB - The incidence rates of cervical adenocarcinoma have been increasing over the last two decades, contrary to those of squamous cell carcinoma. This trend is particularly evident among females aged <40 years and has occurred despite extensive cytology-based screening programs. The aim of the present retrospective database study was to investigate adenocarcinoma in situ (AIS) with respect to previous cytological results, high-risk (HR) human papillomavirus (HPV) infections and histological results from AIS-adjacent squamous mucosa. Databases were used to identify 32 female patients with AIS treated for various conditions between 2009 and 2012 at the Department of Gynecology, Uppsala University Hospital (Uppsala, Sweden) and previous cytological, HPV and histological results. Of the individuals in the study, 64.3% had a previously recorded cytological result showing squamous cell abnormalities; five had glandular cell abnormalities (18%) and two had AIS (7.1%). Among the patients with available HPV results, 95% were HR-HPV-positive; HPV18/45 predominated (77%), followed by HPV16 (27%). The patients with multiple HPV infections were aged <=32 years, while patients aged >=38 years were only infected with HPV18/45. All but three patients had cervical intraepithelial neoplasia (CIN) in the AIS-adjacent squamous mucosa, 79% of which was CIN2 or worse. The present retrospective database study suggests that AIS is detected at screening mainly due to simultaneous squamous precursor lesions and that HPV18/45 infection is an increasing cofactor for AIS in older patients. HPV analyses of glandular precursor lesions aid in the identification of female individuals at risk of progression to invasive disease, and thus have a favorable effect on adenocarcinoma prevention, together with vaccination. PMID- 23946808 TI - High expression levels of class III beta-tubulin in resected non-small cell lung cancer patients are predictive of improved patient survival after vinorelbine based adjuvant chemotherapy. AB - The aim of the present study was to determine the frequency and predictive value of the expression of tumor microtubule components in patients with resected non small cell lung cancer (R-NSCLC) subsequently treated with vinorelbine-based adjuvant chemotherapy. The expression of the microtubule components was evaluated in 85 R-NSCLC tumor samples using immunohistochemistry. All patients received vinorelbine-based chemotherapy. The predictive value of microtubule protein expression for disease-free survival (DFS) and overall survival (OS) was assessed. The expression of the microtubule components was not associated with any baseline clinicopathological factors in the R-NSCLC patients. High tumor expression levels of class III beta-tubulin were correlated with an improved DFS (P=0.033) and a trend towards a longer OS (P=0.226). Class II and IV beta tubulins were not correlated with patient outcome. Multivariate analysis of factors, including gender, age, histology, stage and class II, III and IV beta tubulin expression demonstrated that high levels of class III beta-tubulin expression were correlated independently with DFS (P= 0.031). These findings suggest that high class III beta-tubulin expression levels in resected tumors are predictive of improved DFS in R-NSCLC patients receiving vinorelbine-based chemotherapy. PMID- 23946809 TI - Purification of NAD+ glycohydrolase from human serum. AB - In the present study, NAD+ glycohydrolase was purified from serum samples collected from healthy individuals using ammonium sulfate fractionation, Affi-Gel blue (Cibacron Blue F3GA) affinity chromatography, Sephadex G-100 column chromatography and isoelectric focusing. The final step was followed by a second Sephadex G-100 column chromatography assay in order to remove the ampholytes from the isoelectric focusing step. In terms of enhancement of specific activity, the NAD+ glycohydrolase protein was purified ~480-fold, with a yield of 1% compared with the initial serum fraction. The purified fraction appeared to be homogeneous, with a molecular weight of 39 kDa, as revealed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis, and also corresponded to the soluble (monomeric) form of surface antigen CD38. PMID- 23946810 TI - Expression and significance of hypoxia-inducible factor-1alpha and MDR1/P glycoprotein in laryngeal carcinoma tissue and hypoxic Hep-2 cells. AB - The present study aimed to evaluate the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) and MDR1/P-glycoprotein (P-gp) in human laryngeal squamous cell carcinoma (LSCC) tissues, and also to investigate the regulation of MDR1 gene expression by HIF-1alpha in Hep-2 cells under hypoxic conditions. The expression of HIF-1alpha and MDR1/P-gp in human LSCC tissues was examined using immunohistochemistry. The HIF-1alpha and MDR1 gene expression in the Hep-2 cells was detected using real-time quantitative reverse transcription (QRT)-PCR and western blot analysis under normoxic and hypoxic conditions. In hypoxia, HIF 1alpha expression was inhibited by RNA interference. HIF-1alpha and MDR1/P-gp expression was high in the LSCC tissues and was associated with the clinical stage and lymph node metastasis (P<0.05). HIF-1alpha expression was positively correlated with MDR1/P-gp expression (P<0.01). In the Hep-2 cells, HIF-1alpha and MDR1/P-gp expression significantly increased in response to hypoxia. The inhibition of HIF-1alpha expression synergistically downregulated the expression of the MDR1 gene in hypoxic Hep-2 cells. HIF-1alpha expression is positively correlated with MDR1/P-gp expression in LSCC, and the two proteins may be able to serve as potential biomarkers for predicting the malignant progression and metastasis of LSCC. HIF-1alpha may be critical for the upregulation of MDR1 gene expression induced by hypoxia in Hep-2 cells. PMID- 23946811 TI - Comparison of percutaneous cryosurgery and surgical resection for the treatment of small hepatocellular carcinoma. AB - The present study aimed to compare the outcome of percutaneous cryosurgery (PC) with surgical resection (SR) in the treatment of solitary, small hepatocellular carcinoma (HCC), by performing a retrospective cohort study on 82 patients with solitary HCCs who had received either PC (24 patients) or SR (58 patients). All patients underwent pretreatment blood chemistry tests and an imaging evaluation and were regularly followed up with blood and radiological tests following treatment at The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. The primary endpoint was overall survival (OS) and the secondary endpoints were those of recurrence-free survival (RFS) and adverse events. In the study, the one-, three- and five-year OS rates following surgery were 100, 75.00 and 66.67%, respectively, in the PC group, and 100, 77.59 and 70.69%, respectively, in the SR group. The corresponding RFS rates at one, three and five years after PC and SR were 83.33, 45.83 and 29.17%, respectively, in the PC group and 84.48, 48.28 and 32.76%, respectively, in the SR group. There were no significant differences between these two groups in terms of OS and RFS. There were also no significant differences between the two groups in terms of OS and RFS when comparing the patients with liver cirrhosis (LC) in the PC group (n=16) and the patients with LC (n=39) in the SR group. No significant factors were identified in the multivariate analysis of the risk factors contributing to OS and RFS. Although there were no statistically significant differences between the two groups in terms of the rate of serious adverse events (P=0.82), the incidence of serious adverse events in the SR group was noticeably higher compared with the PC group. Moreover, the duration of hospitalization in the SR group was significantly longer compared with the PC group (P<0.01). These results suggested that PC is as effective as SR in the treatment of solitary, small HCC, while being less invasive, with a shorter duration of hospitalization and a reduction in patient expenditure compared with SR. Thus, PC may be the first choice for the treatment of solitary, small HCC. PMID- 23946812 TI - Differences between brainstem gliomas in juvenile and adult rats. AB - Clinical studies have shown that gliomas of the brainstem behave differently in children and adults. The aim of the present study was to compare and analyze the differences between these gliomas in juvenile and adult rats with regard to tumor growth, survival, pathology and magnetic resonance imaging (MRI). A total of 25 juvenile and 25 adult Wistar rats were divided into groups A (15 juvenile rats), B (10 juvenile rats), C (15 adult rats) and D (10 adult rats). The rats of groups A and C (experimental) were injected with glioma cells, while groups B and D (control) were injected with a physiological saline solution. Rat neurological signs, survival time, tumor size, hematoxylin and eosin (HE) staining and immunohistochemical staining for MMP-2, MMP-9 and beta-catenin were compared. The survival time of group A was 19.47+/-2.232 days, whereas that of group C was 21.47+/-2.232 days (P<0.05). The tumor sizes were 4.55 and 4.62 mm (P>0.05) in groups A and C, respectively. HE and immunohistochemical staining revealed no differences between the groups. The results suggest that the growth patterns and invasiveness of brainstem gliomas may vary in children compared with adults due to the varied biological behaviors of the tumor cells. PMID- 23946813 TI - Pre-operative embolization facilitating a posterior approach for the surgical resection of giant sacral neurogenic tumors. AB - The present study aimed to assess a posterior approach for the surgical resection of giant sacral neurogenic tumors, and to evaluate the oncological and functional outcomes. A total of 16 patients with giant sacral neurogenic tumors underwent pre-operative embolization and subsequent posterior sacral resection between January 2000 and June 2010. Benign tumors were identified in 12 cases, while four cases exhibited malignant peripheral nerve sheath tumors (MPNSTs). An evaluation of the operative techniques used, the level of blood loss, any complications and the functional and oncological outcomes was performed. All tumor masses were removed completely without intra-operative shock or fatalities. The mean tumor size was 17.5 cm (range, 11.5-28 cm) at the greatest diameter. The average level of intra-operative blood loss was 1,293 ml (range, 400-4,500 ml). Wound complications occurred in four patients (25%), including three cases of cutaneous necrosis and one wound infection. The mean follow-up time was 59 months (range, 24-110 months). Tumor recurrence or patient mortality as a result of the disease did not occur in any of the patients with benign sacral neurogenic tumors. The survival rate of the patients with malignant lesions was 75% (3/4 patients) since 25 % (1/4 patients) had multiple local recurrences and succumbed to the disease. The patients with benign tumors scored an average of 92.8% on the Musculoskeletal Tumor Society (MSTS) score functional evaluation, while the patients with malignant tumors scored an average of 60.3%. A posterior approach for the surgical resection of giant sacral neurogenic tumors, combined with pre-operative embolization may be safely conducted with satisfactory oncological and functional outcomes. PMID- 23946814 TI - Ethanol extract of Chaenomeles speciosa Nakai induces apoptosis in cancer cells and suppresses tumor growth in mice. AB - Chaenomeles speciosa Nakai is commonly used in traditional Chinese medicine for a variety of health-promoting effects. The present study aimed to investigate the antitumor effects of Chaenomeles speciosa Nakai. The tumor-inhibitory activity of the ethanol extract of Chaenomeles speciosa Nakai (EEC) was evaluated by in vitro growth assays of tumor cells and in vivo H22 tumor formation assays in mice. Mitochondrial membrane potential and DNA ladder assays were used to detect tumor cell apoptosis in the presence of EEC. To investigate the cellular targets of EEC, the immunomodulatory genes PD-L1, Foxp3 and TGF-beta were detected in the tumor tissue using reverse transcription polymerase chain reaction (RT-PCR). Immune responses were determined by hemolysis and lymphocyte proliferation assays. EEC markedly inhibited the proliferation of the H22 cells in a dose dependent manner. Moreover, it induced DNA fragmentation and decreased the mitochondrial membrane potential. In vivo, EEC inhibited tumor growth and enhanced the immune responses in mice, while the expression of PD-L1, Foxp3 and TGF-beta was inhibited in the tumor tissue. These results provide the first evidence that EEC may inhibit tumor growth by directly killing tumor cells and enhancing immune function. Thus, it is a natural source for safe anticancer medicine. PMID- 23946815 TI - Identification of four serum microRNAs from a genome-wide serum microRNA expression profile as potential non-invasive biomarkers for endometrioid endometrial cancer. AB - Serum microRNAs (miRNAs), with their remarkable stability and unique concentration profiles in patients with various diseases, are promising non invasive biomarkers for tumor detection. The present study investigated the altered profiles of serum microRNAs in patients with endometrioid endometrial cancer (EEC) in order to predict the malignancy of the disease at a relatively early stage. TaqMan(r) low-density arrays (TDLAs) were used to perform an analysis in the initial screening phase using serum samples pooled from seven EEC patients and 20 controls. The differential expression was validated using a hydrolysis probe-based stem-loop quantitative reverse transcription polymerase chain reaction (qRT-PCR) in samples taken from 26 EEC patients and 22 age- and gender-matched healthy controls. The data obtained from the TLDAs demonstrated that 22 serum miRNAs were markedly upregulated in the EEC patients compared with the controls. The qRT-PCR analysis further identified a profile of four serum miRNAs (miR-222, miR-223, miR-186 and miR-204) as a fingerprint for EEC detection. The area under the receiver operating characteristic (ROC) curve of this four-serum miRNA signature was 0.927, which was markedly higher than that of carbohydrate antigen 125 (CA-125; 0.673). The four-miRNA signature identified by genome-wide serum miRNA expression profiling analysis provides a novel, non invasive approach for EEC diagnosis. PMID- 23946816 TI - Gene expression profiling of the DNMT3A R882 mutation in acute leukemia. AB - DNA methyltransferase 3A (DNMT3A) is one of two human de novo DNA methyltransferases essential for the regulation of gene expression. DNMT3A mutations and deletions have been previously observed in acute myeloid leukemia (AML), myelodysplastic sydromes and myeloproliferative neoplasms. However, the involvement of DNMT3A in acute lymphoblastic leukemia (ALL) has rarely been reported. In the present study, PCR and direct sequencing was performed to analyze mutations of DNMT3A amino acid residue 882 in 99 acute leukemia patients, including 57 AML patients, 41 ALL patients and a single biphenotypic acute leukemia (BAL) patient. DNMT3A expression was detected in mono-nuclear cells of the bone marrow in these patients and in normal individuals using real-time quantitative polymerase chain reaction, and 17.5% (10/57) of AML patients were found to exhibit DNMT3A mutations. Four missense mutations were observed in the DNMT3A-mutated AML patients, including R882 mutations and a novel single nucleotide polymorphism resulting in the M880V amino acid substitution. However, the ALL and BAL patients were not found to exhibit DNMT3A mutations. The DNMT3A expression levels in the AML patients were significantly higher compared with those of the ALL patients or normal controls. The reduced expression levels of DNMT3A were associated with a significantly lower complete remission rate in the AML patients. However, in the ALL patients, no statistical significance was identified. The results of the present study indicate that DNMT3A may play varying roles in the regulation of DNA methylation in AML and ALL. PMID- 23946817 TI - Gene expression analysis of aberrant signaling pathways in meningiomas. AB - Examining aberrant pathway alterations is one method for understanding the abnormal signals that are involved in tumorigenesis and tumor progression. In the present study, expression arrays were performed on tumor-related genes in meningiomas. The GE Array Q Series HS-006 was used to determine the expression levels of 96 genes that corresponded to six primary biological regulatory pathways in a series of 42 meningiomas, including 32 grade I, four recurrent grade I and six grade II tumors, in addition to three normal tissue controls. Results showed that 25 genes that were primarily associated with apoptosis and angiogenesis functions were downregulated and 13 genes frequently involving DNA damage repair functions were upregulated. In addition to the inactivation of the neurofibromin gene, NF2, which is considered to be an early step in tumorigenesis, variations of other biological regulatory pathways may play a significant role in the development of meningioma. PMID- 23946819 TI - Corrigendum. AB - [This corrects the article on p. 261 in vol. 5, PMID: 23255932.]. PMID- 23946818 TI - mRNA expression and hypermethylation of tumor suppressor genes apoptosis protease activating factor-1 and death-associated protein kinase in oral squamous cell carcinoma. AB - Apoptosis protease activating factor-1 (Apaf-1) and death-associated protein kinase (DAPK) are p53 pathway-related genes that play significant roles in the activation of caspases, which are involved in mitochondrial-mediated apoptosis. The present study aimed to confirm the role of hyper-methylation of the Apaf-1 and DAPK gene promoter regions in oral squamous cell carcinoma (OSCC) and the effect of the demethylation drug, 5-aza-2'-deoxycytidine (DAC). mRNA from 53 OSCC samples, 23 normal oral mucosa samples and Tca8113 human tongue carcinoma cell lines was detected using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The DNA from each sample was analyzed using methylation specific PCR (MSP). The Tca8113 cells were demethylated using DAC and the demethylation and re-expression of Apaf-1 and DAPK were analyzed. The Apaf-1 and DAPK mRNA expression index was decreased in 51 (96.23%) and 50 (94.34%) cases, respectively, in the tumor tissues. Hypermethylation of the Apaf-1 and DAPK promoter regions was detected in 46 (86.79%) and 38 (71.69%) cases, respectively. Promoter hypermethylation of the two genes correlated with a decreased mRNA expression in the tumor tissues. Subsequent to being treated with DAC, Apaf-1 and DAPK were demethylated and re-expressed in the Tca8113 cells. Apaf-1 and DAPK promoter hypermethylation may be associated with low gene expression in OSCC. Furthermore, a loss of Apaf-1 and DAPK expression may recover following demethylation. The data provide evidence that methylation exists in OSCC and may play a role in the development of this disease. PMID- 23946820 TI - Labeling human mesenchymal stem cells with gold nanocages for in vitro and in vivo tracking by two-photon microscopy and photoacoustic microscopy. AB - Stem cell tracking is a highly important subject. Current techniques based on nanoparticle-labeling, such as magnetic resonance imaging, fluorescence microscopy, and micro-computed tomography, are plagued by limitations including relatively low sensitivity or penetration depth, involvement of ionizing irradiation, and potential cytotoxicity of the nanoparticles. Here we introduce a new class of contrast agents based on gold nanocages (AuNCs) with hollow interiors and porous walls to label human mesenchymal stem cells (hMSCs) for both in vitro and in vivo tracking using two-photon microscopy and photoacoustic microscopy. As demonstrated by the viability assay, the AuNCs showed negligible cytotoxicity under a reasonable dose, and did not alter the differentiation potential of the hMSCs into desired lineages. We were able to image the cells labeled with AuNCs in vitro for at least 28 days in culture, as well as to track the cells that homed to the tumor region in nude mice in vivo. PMID- 23946821 TI - Commercial nanoparticles for stem cell labeling and tracking. AB - Stem cell therapy provides promising solutions for diseases and injuries that conventional medicines and therapies cannot effectively treat. To achieve its full therapeutic potentials, the homing process, survival, differentiation, and engraftment of stem cells post transplantation must be clearly understood. To address this need, non-invasive imaging technologies based on nanoparticles (NPs) have been developed to track transplanted stem cells. Here we summarize existing commercial NPs which can act as contrast agents of three commonly used imaging modalities, including fluorescence imaging, magnetic resonance imaging and photoacoustic imaging, for stem cell labeling and tracking. Specifically, we go through their technologies, industry distributors, applications and existing concerns in stem cell research. Finally, we provide an industry perspective on the potential challenges and future for the development of new NP products. PMID- 23946822 TI - Non-invasive in-vivo imaging of stem cells after transplantation in cardiovascular tissue. AB - Stem cell therapy for degenerative diseases, including ischemic heart disease is now a clinical reality. In the search for the optimal cell type for each patient category, many different stem cell subpopulations have been used. In addition, different cell processing procedures and delivery methods have been utilized. Moreover, choices of endpoints have varied between studies. Diverging results have been reported from clinical experiences, with some studies demonstrating promising results with improved cardiac function and reduced mortality and clinical symptoms, and others have seen no improvements. To better understand the underlying mechanisms of these results, a reverse translation from bedside to bench has been opened. Non-invasive cell tracking after implantation has a pivotal role in this translation. Imaging based methods can help elucidate important issues such as retention, migration and efficacy of the transplanted cells. Great effort is being made in finding new and better imaging techniques for different imaging modalities, and much have already been learned. But there are still many unanswered questions. In this review, we give an overview of the imaging modalities used for cell tracking and summarize the latest advances within the field. PMID- 23946823 TI - Nanoparticles based stem cell tracking in regenerative medicine. AB - Stem cell therapies offer great potentials in the treatment for a wide range of diseases and conditions. With so many stem cell replacement therapies going through clinical trials currently, there is a great need to understand the mechanisms behind a successful therapy, and one of the critical points of discovering them is to track stem cell migration, proliferation and differentiation in vivo. To be of most use tracking methods should ideally be non invasive, high resolution and allow tracking in three dimensions. Magnetic resonance imaging (MRI) is one of the ideal methods, but requires a suitable contrast agent to be loaded to the cells to be tracked, and one of the most wide spread in stem cell tracking is a group of agents known as magnetic nanoparticles. This review will explore the current use of magnetic nanoparticles in developing and performing stem cell therapies, and will investigate their potential limitations and the future directions magnetic nanoparticle tracking is heading in. PMID- 23946824 TI - Novel molecular and nanosensors for in vivo sensing. AB - In vivo sensors are an emerging field with the potential to revolutionize our understanding of basic biology and our treatment of disease. In this review, we highlight recent advances in the fields of in vivo electrochemical, optical, and magnetic resonance biosensors with a focus on recent developments that have been validated in rodent models or human subjects. In addition, we discuss major challenges in the development and translation of in vivo biosensors and present potential solutions to these problems. The field of nanotechnology, in particular, has recently been instrumental in driving the field of in vivo sensors forward. We conclude with a discussion of emerging paradigms and techniques for the development of future biosensors. PMID- 23946826 TI - Nanoparticle-based Monitoring of Stem Cell Therapy. AB - This theme issue provides a timely overview on the current status of stem cell tracking with the nanoparticle-based contrast agents. PMID- 23946827 TI - Preparation of optically active bicyclodihydrosiloles by a radical cascade reaction. AB - Bicyclodihydrosiloles were readily prepared from optically active enyne compounds by a radical cascade reaction triggered by tris(trimethylsilyl)silane ((Me3Si)3SiH). The reaction was initiated by the addition of a silyl radical to an alpha,beta-unsaturated ester, forming an alpha-carbonyl radical that underwent radical cyclization to a terminal alkyne unit. The resulting vinyl radical attacked the silicon atom in an SHi manner to give dihydrosilole. The reaction preferentially formed trans isomers of bicyclosiloles with an approximately 7:3 to 9:1 selectivity. PMID- 23946825 TI - Superparamagnetic iron oxide nanoparticles as MRI contrast agents for non invasive stem cell labeling and tracking. AB - Stem cells hold great promise for the treatment of multiple human diseases and disorders. Tracking and monitoring of stem cells in vivo after transplantation can supply important information for determining the efficacy of stem cell therapy. Magnetic resonance imaging (MRI) combined with contrast agents is believed to be the most effective and safest non-invasive technique for stem cell tracking in living bodies. Commercial superparamagnetic iron oxide nanoparticles (SPIONs) in the aid of transfection agents (TAs) have been applied to labeling stem cells. However, owing to the potential toxicity of TAs, more attentions have been paid to develop novel SPIONs with specific surface coating or functional moieties which facilitate effective cell internalization in the absence of TAs. This review aims to summarize the recent progress in the design and preparation of SPIONs as cellular MRI probes, to discuss their applications and current problems facing in stem cell labeling and tracking, and to offer perspectives and solutions for the future development of SPIONs in this field. PMID- 23946828 TI - Lanostane- and cycloartane-type triterpenoids from Abies balsamea oleoresin. AB - Phytochemical analysis of A. balsamea oleoresin led to the isolation of three new 3,4-seco-lanostane triterpenoids 1-3, one new cycloartane triterpenoid 4 along with fourteen known terpenoids. Structure determinations were based on extensive 1D/2D NMR, IR and MS spectroscopic analyses, and comparison with literature data. The isolated compounds were evaluated in vitro for their cytotoxicity against human cell lines (A549, DLD-1, WS1) and their antibacterial activity against E. coli and S. aureus. Abiesonic acid (6) exhibited weak cytotoxic activity against A549 (IC50 = 22 uM) while compounds 1 and 4 were weakly active against S. aureus (MIC = 25 uM). PMID- 23946829 TI - A construction of 4,4-spirocyclic gamma-lactams by tandem radical cyclization with carbon monoxide. AB - A straightforward synthesis of 4,4-spirocyclic indol gamma-lactams by tandem radical cyclization of iodoaryl allyl azides with CO was achieved. The reaction of iodoaryl allyl azides, TTMSS and AIBN under CO pressure (80 atm) in THF at 80 degrees C gave the desired 4,4-spirocyclic indoline, benzofuran, and oxindole gamma-lactams in moderate to good yields. PMID- 23946830 TI - Total synthesis of ochnaflavone. AB - The first total syntheses of ochnaflavone, an asymmetric biflavone consisting of apigenin and luteolin moieties, and the permethyl ether of 2,3,2'',3'' tetrahydroochnaflavone have been achieved. The key steps in the synthesis of ochnaflavone were the formation of a diaryl ether and ring cyclization of an ether-linked dimeric chalcone to assemble the two flavone nuclei. Optimal experimental conditions for the oxidative cyclization to form ochnaflavone were established. PMID- 23946831 TI - True and masked three-coordinate T-shaped platinum(II) intermediates. AB - Although four-coordinate square-planar geometries, with a formally 16-electron counting, are absolutely dominant in isolated Pt(II) complexes, three-coordinate, 14-electron Pt(II) complexes are believed to be key intermediates in a number of platinum-mediated organometallic transformations. Although very few authenticated three-coordinate Pt(II) complexes have been characterized, a much larger number of complexes can be described as operationally three-coordinate in a kinetic sense. In these compounds, which we have called masked T-shaped complexes, the fourth position is occupied by a very weak ligand (agostic bond, solvent molecule or counteranion), which can be easily displaced. This review summarizes the structural features of the true and masked T-shaped Pt(II) complexes reported so far and describes synthetic strategies employed for their formation. Moreover, recent experimental and theoretical reports are analyzed, which suggest the involvement of such intermediates in reaction mechanisms, particularly C-H bond activation processes. PMID- 23946832 TI - Synthesis of the calcilytic ligand NPS 2143. AB - (R)-3 (NPS 2143) is a negative allosteric modulator of the human calcium-sensing receptor (CaSR) and as such represents an important pharmacological tool compound for studying the CaSR. Herein, we disclose for the first time a complete experimental description, detailed characterisation and assessment of enantiomeric purity for (R)-3. An efficient, reproducible and scalable synthesis of (R)-3 that requires a minimum of chromatographic purification steps is presented. (R)-3 was obtained in excellent optical purity (er > 99:1) as demonstrated by chiral HPLC and the pharmacological profile for (R)-3 is in full accordance with that reported in the literature. PMID- 23946833 TI - A(3)-Coupling catalyzed by robust Au nanoparticles covalently bonded to HS functionalized cellulose nanocrystalline films. AB - We decorated HS-functionalized cellulose nanocrystallite (CNC) films with monodisperse Au nanoparticles (AuNPs) to form a novel nanocomposite catalyst AuNPs@HS-CNC. The uniform, fine AuNPs were made by the reduction of HAuCl4 solution with thiol (HS-) group-functionalized CNC films. The AuNPs@HS-CNC nanocomposites were examined by X-ray photoelectron spectroscopy (XPS), TEM, ATR IR and solid-state NMR. Characterizations suggested that the size of the AuNPs was about 2-3 nm and they were evenly distributed onto the surface of CNC films. Furthermore, the unique nanocomposite Au@HS-CNC catalyst displayed high catalytic efficiency in promoting three-component coupling of an aldehyde, an alkyne, and an amine (A(3)-coupling) either in water or without solvent. Most importantly, the catalyst could be used repetitively more than 11 times without significant deactivation. Our strategy also promotes the use of naturally renewable cellulose to prepare reusable nanocomposite catalysts for organic synthesis. PMID- 23946834 TI - Copper(II)-salt-promoted oxidative ring-opening reactions of bicyclic cyclopropanol derivatives via radical pathways. AB - Copper(II)-salt-promoted oxidative ring-opening reactions of bicyclic cyclopropanol derivatives were investigated. The regioselectivities of these processes were found to be influenced by the structure of cyclopropanols as well as the counter anion of the copper(II) salts. A mechanism involving rearrangement reactions of radical intermediates and their competitive trapping by copper ions is proposed. PMID- 23946835 TI - alpha-Bromodiazoacetamides - a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C-H insertion reactions. AB - In this work, we introduce a new class of halodiazocarbonyl compounds, alpha halodiazoacetamides, which through a metal-free, ambient-temperature thermolysis perform intramolecular C-H insertions to produce alpha-halo-beta-lactams. When carried out with alpha-bromodiazoacetamides bearing cyclic side chains, the thermolysis reaction affords bicyclic alpha-halo-beta-lactams, in some cases in excellent yields, depending on the ring size and substitution pattern of the cyclic amide side chains. PMID- 23946836 TI - Thiourea-catalyzed Diels-Alder reaction of a naphthoquinone monoketal dienophile. AB - A variety of organocatalysts were screened for the catalysis of the naphthoquinone monoketal Diels-Alder reaction. In this study we found that Schreiner's thiourea catalyst 10 and Jacobson's thiourea catalyst 12 facilitate the cycloaddition of the sterically hindered naphthoquinone monoketal dienophile 3 with diene 4. The use of thiourea catalysis allowed for the first time the highly selective synthesis of the exo-product 2a in up to 63% yield. In this reaction a new quaternary center was built. The so formed cycloaddition product 2a represents the ABC tricycle of beticolin 0 (1) and is also a valuable model substrate for the total synthesis of related natural products. PMID- 23946837 TI - Dipolar addition to cyclic vinyl sulfones leading to dual conformation tricycles. AB - Dipolar addition of cyclic azomethine imines with cyclic vinyl sulfones gave rise to functionalized tricycles that exhibited fluxional behavior in solution at room temperature. The scope of the synthetic methodology was explored, and the origin of the fluxional behavior was probed by NMR methods together with DFT calculations. This behavior was ultimately attributed to stereochemical inversion at one of two nitrogen centers embedded in the tricyclic framework. Two tetracycles were also synthesized, and the degree of signal-broadening in the NMR spectra was found to depend on the presence of substitution next to the inverting nitrogen center. PMID- 23946838 TI - Practical synthesis of indoles and benzofurans in water using a heterogeneous bimetallic catalyst. AB - This paper describes the preparation of indoles, azaindoles and benzofurans in pure water by using a new heterogeneous Pd-Cu/C catalyst through a cascade Sonogashira alkynylation-cyclization sequence. Details of the optimization studies and the substrate scope are discussed. This procedure allows the preparation of heterocycles with good yields and is tolerant to a wide variety of functional groups. PMID- 23946839 TI - Diastereoselective radical addition to gamma-alkyl-alpha-methylene-gamma butyrolactams and the synthesis of a chiral pyroglutamic acid derivative. AB - The cis- and trans-stereoselective radical additions to alpha-methylene-gamma alkyl- gamma-lactams were investigated and the scope and limitation of the reaction were also revealed. This stereoselective radical reaction was used for synthesis of chiral pyroglutamic acid derivatives starting from a commercially available chiral amino acid. PMID- 23946840 TI - Hypervalent iodine/TEMPO-mediated oxidation in flow systems: a fast and efficient protocol for alcohol oxidation. AB - Hypervalent iodine(III)/TEMPO-mediated oxidation of various aliphatic, aromatic and allylic alcohols to their corresponding carbonyl compounds was successfully achieved by using microreactor technology. This method can be used as an alternative for the oxidation of various alcohols achieving excellent yields and selectivities in significantly shortened reaction times. PMID- 23946841 TI - Development of an additive-controlled, SmI2-mediated stereoselective sequence: Telescoped spirocyclisation, lactone reduction and Peterson elimination. AB - Studies on SmI2-mediated spirocyclisation and lactone reduction culminate in a telescoped sequence in which additives are used to "switch on" individual steps mediated by the electron transfer reagent. The sequence involves the use of two activated SmI2 reagent systems and a silicon stereocontrol element that exerts complete diastereocontrol over the cyclisation and is removed during the final stage of the sequence by Peterson elimination. The approach allows functionalised cyclopentanols containing two vicinal quaternary stereocentres to be conveniently prepared from simple starting materials. PMID- 23946842 TI - Electron self-exchange activation parameters of diethyl sulfide and tetrahydrothiophene. AB - Electron transfer between the title compounds and their radical cations, which were generated by photoinduced electron transfer from the sulfides to excited 2,4,6-triphenylpyrylium cations, was investigated by time-resolved measurements of chemically induced dynamic nuclear polarization (CIDNP) in acetonitrile. The strongly negative activation entropies provide evidence for an associative dissociative electron exchange involving dimeric radical cations. Despite this mechanistic complication, the free energies of activation were found to be well reproduced by the Marcus theory of electron transfer, with the activation barrier still dominated by solvent reorganization. PMID- 23946843 TI - Isolation and X-ray characterization of palladium-N complexes in the guanylation of aromatic amines. Mechanistic implications. AB - In the context of palladium-catalyzed guanylation of anilines herein, we have been able to characterize and isolate bis(anilino) and bis(guanidino)Pd(II) complexes using reaction conditions under which stoichiometric amounts of palladium salts are used. Characterization of these palladium complexes strongly supports a mechanistic proposal for the catalytic guanylation of anilines using PdCl2(NCCH3)2 as catalyst that involves the intermediacy of these Pd(II) complexes. PMID- 23946844 TI - A simple, enaminone-based approach to some bicyclic pyridazinium tetrafluoroborates. AB - Easily obtainable cyclic enaminones (piperidin-2-ylidenealkanones) can be transformed into substituted bicyclic pyridazinium tetrafluoroborates upon treatment with corresponding diazonium salts. The transformation can be performed either in a one-pot way or in a two-step process with the isolation of single azo coupled enaminone as the intermediate. The former method is superior. Under the optimized conditions, a number of pyridazinium salts substituted with both electron-donating and electron-withdrawing substituents was easily synthesized. A mechanism of the formation of the pyridazinium salts is suggested. A partial drawback is the possibility of the formation of a mixture of products when using a different diazonium salt in each step due to a reversibility of the azo coupling. This can be suppressed by using a more reactive diazonium salt before a less reactive one. PMID- 23946845 TI - Mechanistic studies on the CAN-mediated intramolecular cyclization of delta-aryl beta-dicarbonyl compounds. AB - The synthesis of 2-tetralones through the cyclization of delta-aryl-beta dicarbonyl substrates by using CAN is described. Appropriately functionalized aromatic substrates undergo intramolecular cyclizations generating 2-tetralone derivatives in moderate to good yields. DFT computational studies indicate that successful formation of 2-tetralones from delta-aryl-beta-dicarbonyl radicals is dependent on the stability of the subsequent cyclohexadienyl radical intermediates. Furthermore, DFT computational studies were used to rationalize the observed site selectivity in the 2-tetralone products. PMID- 23946846 TI - An organocatalytic route to 2-heteroarylmethylene decorated N-arylpyrroles. AB - A concise and regioselective preparation of 2-heteroarylmethylene decorated N arylpyrroles is described through a metal-free Mannich/Wittig/hydroamination sequence followed by isomerization of the N-arylpyrrolidine adducts. Furthermore, the C-H regioselective oxidation of these substrates is demonstrated, extending the molecular diversity and versatility of these scaffolds. PMID- 23946847 TI - Structures of the reaction products of the AZADO radical with TCNQF4 or thiourea. AB - While an addition product was formed by the reaction of AZADO (2-azaadamantane N oxyl) with TCNQF4 (2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane), the reaction of AZADO with thiourea provided an inclusion compound, in which AZADO molecules are incorporated in cylindrical channels formed by thiourea molecules. PMID- 23946848 TI - Controlled synthesis of poly(3-hexylthiophene) in continuous flow. AB - There is an increasing demand for organic semiconducting materials with the emergence of organic electronic devices. In particular, large-area devices such as organic thin-film photovoltaics will require significant quantities of materials for device optimization, lifetime testing and commercialization. Sourcing large quantities of materials required for the optimization of large area devices is costly and often impossible to achieve. Continuous-flow synthesis enables straight-forward scale-up of materials compared to conventional batch reactions. In this study, poly(3-hexylthiophene), P3HT, was synthesized in a bench-top continuous-flow reactor. Precise control of the molecular weight was demonstrated for the first time in flow for conjugated polymers by accurate addition of catalyst to the monomer solution. The P3HT samples synthesized in flow showed comparable performance to commercial P3HT samples in bulk heterojunction solar cell devices. PMID- 23946849 TI - ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans. AB - The National Institutes of Health Molecular Libraries and Probe Production Centers Network (NIH-MLPCN) screened >300,000 compounds to evaluate their ability to restore fluconazole susceptibility in resistant Candida albicans isolates. Additional counter screens were incorporated to remove substances inherently toxic to either mammalian or fungal cells. A substituted indazole possessing the desired bioactivity profile was selected for further development, and initial investigation of structure-activity relationships led to the discovery of ML212. PMID- 23946850 TI - Efficient continuous-flow synthesis of novel 1,2,3-triazole-substituted beta aminocyclohexanecarboxylic acid derivatives with gram-scale production. AB - The preparation of novel multi-substituted 1,2,3-triazole-modified beta aminocyclohexanecarboxylic acid derivatives in a simple and efficient continuous flow procedure is reported. The 1,3-dipolar cycloaddition reactions were performed with copper powder as a readily accessible Cu(I) source. Initially, high reaction rates were achieved under high-pressure/high-temperature conditions. Subsequently, the reaction temperature was lowered to room temperature by the joint use of both basic and acidic additives to improve the safety of the synthesis, as azides were to be handled as unstable reactants. Scale-up experiments were also performed, which led to the achievement of gram scale production in a safe and straightforward way. The obtained 1,2,3-triazole substituted beta-aminocyclohexanecarboxylates can be regarded as interesting precursors for drugs with possible biological effects. PMID- 23946851 TI - Coupling of C-nitro-NH-azoles with arylboronic acids. A route to N-aryl-C nitroazoles. AB - A method for the synthesis of N-aryl-C-nitroazoles is presented. A coupling reaction between variously substituted arylboronic acids and 3(5)-nitro-1H pyrazole catalyzed by copper salt has been carried out in methanol in the presence of sodium hydroxide to afford the desired N-aryl-C-nitroazoles in good yields. This synthetic route has also been successfully applied to obtain N phenyl derivatives of 4-nitropyrazole, 2-nitroimidazole, 4(5)-nitroimidazole and 3-nitro-1,2,4-triazole. PMID- 23946852 TI - Re2O7-catalyzed reaction of hemiacetals and aldehydes with O-, S-, and C nucleophiles. AB - Re(VII) oxides catalyze the acetalization, monoperoxyacetalization, monothioacetalization and allylation of hemiacetals. The reactions, which take place under mild conditions and at low catalyst loadings, can be conducted using hemiacetals, the corresponding O-silyl ethers, and, in some cases, the acetal dimers. Aldehydes react under similar conditions to furnish good yields of dithioacetals. Reactions of hemiacetals with nitrogen nucleophiles are unsuccessful. 1,2-Dioxolan-3-ols (peroxyhemiacetals) undergo Re(VII)-promoted etherification but not allylation. Hydroperoxyacetals (1-alkoxyhydroperoxides) undergo selective exchange of the alkoxide group in the presence of either Re2O7 or a Bronsted acid. PMID- 23946853 TI - A reductive coupling strategy towards ripostatin A. AB - Synthetic studies on the antibiotic natural product ripostatin A have been carried out with the aim to construct the C9-C10 bond by a nickel(0)-catalyzed coupling reaction of an enyne and an epoxide, followed by rearrangement of the resulting dienylcyclopropane intermediate to afford the skipped 1,4,7-triene. A cyclopropyl enyne fragment corresponding to C1-C9 has been synthesized in high yield and demonstrated to be a competent substrate for the nickel(0)-catalyzed coupling with a model epoxide. Several synthetic approaches toward the C10-C26 epoxide have been pursued. The C13 stereocenter can be set by allylation and reductive decyanation of a cyanohydrin acetonide. A mild, fluoride-promoted decarboxylation enables construction of the C15-C16 bond by an aldol reaction. The product of this transformation is of the correct oxidation state and potentially three steps removed from the targeted epoxide fragment. PMID- 23946854 TI - Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues. AB - Aurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad-Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization. PMID- 23946855 TI - Organocatalytic asymmetric selenofunctionalization of tryptamine for the synthesis of hexahydropyrrolo[2,3-b]indole derivatives. AB - A chiral phosphoric acid-catalyzed selenofunctionalization of tryptamine derivatives provides access to 3a-(phenylselenyl)-1,2,3,3a,8,8a hexahydropyrrolo[2,3-b]indole derivatives in high yields and with synthetically useful levels of enantioselectivity (up to 89% ee). PMID- 23946856 TI - Molecular assembly of amino acid interlinked, topologically symmetric, pi complementary donor-acceptor-donor triads. AB - Amino acid interlinked pyrene and naphthalenediimide (NDI) based novel donor acceptor-donor (D-A-D) triads are designed to exploit their topological symmetry and complementary pi-character for facile charge-transfer complexation. Consequently, free-floating high-aspect-ratio supercoiled nanofibres and hierarchical helical bundles of triads are realized by modulating the chemical functionality of interlinking amino acids. PMID- 23946857 TI - A Lewis acid-promoted Pinner reaction. AB - Carbonitriles and alcohols react in a Lewis acid-promoted Pinner reaction to carboxylic esters. Best results are obtained with two equivalents of trimethylsilyl triflate as Lewis acid. Good yields are achieved with primary alcohols and aliphatic or benzylic carbonitriles, but the straightforward synthesis of acrylates and benzoates starting with acrylonitrile and benzonitrile, respectively, is similarly possible. Phenols are not acylated under these reaction conditions. The method has been used for the first total synthesis of the natural product monaspilosin. In the reaction of benzyl alcohols variable amounts of amides are formed in a Ritter-type side reaction. PMID- 23946858 TI - Palladium(II)-catalyzed Heck reaction of aryl halides and arylboronic acids with olefins under mild conditions. AB - A series of general and selective Pd(II)-catalyzed Heck reactions were investigated under mild reaction conditions. The first protocol has been developed employing an imidazole-based secondary phosphine oxide (SPO) ligated palladium complex (6) as a precatalyst. The catalytic coupling of aryl halides and olefins led to the formation of the corresponding coupled products in excellent yields. A variety of substrates, both electron-rich and electron-poor olefins, were converted smoothly to the targeted products in high yields. Compared with the existing approaches employing SPO-Pd complexes in a Heck reaction, the current strategy features mild reaction conditions and broad substrate scope. Furthermore, we described the coupling of arylboronic acids with olefins, which were catalyzed by Pd(OAc)2 and employed N-bromosuccinimide as an additive under ambient conditions. The resulted biaryls have been obtained in moderate to good yields. PMID- 23946859 TI - Stability of SG1 nitroxide towards unprotected sugar and lithium salts: a preamble to cellulose modification by nitroxide-mediated graft polymerization. AB - The range of applications of cellulose, a glucose-based polysaccharide, is limited by its inherently poor mechanical properties. The grafting of synthetic polymer chains by, for example, a "grafting from" process may provide the means to broaden the range of applications. The nitroxide-mediated polymerization (NMP) method is a technique of choice to control the length, the composition and the architecture of the grafted copolymers. Nevertheless, cellulose is difficult to solubilize in organic media because of inter- and intramolecular hydrogen bonds. One possibility to circumvent this limitation is to solubilize cellulose in N,N dimethylformamide (DMF) or N,N-dimethylacetamide (DMA) with 5 to 10 wt % of lithium salts (LiCl or LiBr), and carry out grafted polymerization in this medium. The stability of nitroxides such as SG1 has not been studied under these conditions yet, even though these parameters are of crucial importance to perform the graft modification of polysaccharide by NMP. The aim of this work is to offer a model study of the stability of the SG1 nitroxide in organic media in the presence of unprotected glucose or cellobiose (used as a model of cellulose) and in the presence of lithium salts (LiBr or LiCl) in DMF or DMA. Contrary to TEMPO, SG1 proved to be stable in the presence of unprotected sugar, even with an excess of 100 molar equivalents of glucose. On the other hand, lithium salts in DMF or DMA clearly degrade SG1 nitroxide as proven by electron-spin resonance measurements. The instability of SG1 in these lithium-containing solvents may be explained by the acidification of the medium by the hydrolysis of DMA in the presence of LiCl. This, in turn, enables the disproportionation of the SG1 nitroxide into an unstable hydroxylamine and an oxoammonium ion. Once the conditions to perform an SG1-based nitroxide-mediated graft polymerization from cellobiose have been established, the next stage of this work will be the modification of cellulose and cellulose derivatives by NMP. PMID- 23946860 TI - Bioinspired total synthesis of katsumadain A by organocatalytic enantioselective 1,4-conjugate addition. AB - Katsumadain A, a naturally occurring influenza virus neuraminidase (NA) inhibitor, was synthesized by using a bioinspired, organocatalytic enantioselective 1,4-conjugate addition of styryl-2-pyranone with cinnamaldehyde, followed by a tandem Horner-Wadsworth-Emmons/oxa Michael addition. PMID- 23946861 TI - Organotellurium-mediated living radical polymerization under photoirradiation by a low-intensity light-emitting diode. AB - A low-intensity (6 W) light-emitting diode (LED) effectively activated an organotellurium chain transfer agent and the dormant species, promoting well controlled radical polymerization. The use of the LED provided many advantages over the previously reported high-intensity Hg lamp, including high energy efficiency during the polymerization, and easy availability of the low-cost light source. Structurally well-defined poly(methyl methacrylate), poly(methyl acrylate), and polystyrene, with narrow molecular weight distributions, were synthesized under LED irradiation with or without a neutral density filter. PMID- 23946862 TI - Synthetic biology as a source of global health innovation. AB - Synthetic biology has the potential to contribute breakthrough innovations to the pursuit of new global health solutions. Wishing to harness the emerging tools of synthetic biology for the goals of global health, in 2011 the Bill & Melinda Gates Foundation put out a call for grant applications to "Apply Synthetic Biology to Global Health Challenges" under its "Grand Challenges Explorations" program. A highly diverse pool of over 700 applications was received. Proposed applications of synthetic biology to global health needs included interventions such as therapeutics, vaccines, and diagnostics, as well as strategies for biomanufacturing, and the design of tools and platforms that could further global health research. PMID- 23946863 TI - A BAYESIAN GRAPHICAL MODELING APPROACH TO MICRORNA REGULATORY NETWORK INFERENCE. AB - It has been estimated that about 30% of the genes in the human genome are regulated by microRNAs (miRNAs). These are short RNA sequences that can down regulate the levels of mRNAs or proteins in animals and plants. Genes regulated by miRNAs are called targets. Typically, methods for target prediction are based solely on sequence data and on the structure information. In this paper we propose a Bayesian graphical modeling approach that infers the miRNA regulatory network by integrating expression levels of miRNAs with their potential mRNA targets and, via the prior probability model, with their sequence/structure information. We use a directed graphical model with a particular structure adapted to our data based on biological considerations. We then achieve network inference using stochastic search methods for variable selection that allow us to explore the huge model space via MCMC. A time-dependent coefficients model is also implemented. We consider experimental data from a study on a very well-known developmental toxicant causing neural tube defects, hyperthermia. Some of the pairs of target gene and miRNA we identify seem very plausible and warrant future investigation. Our proposed method is general and can be easily applied to other types of network inference by integrating multiple data sources. PMID- 23946865 TI - Improving Education in the Developing World: What Have We Learned from Randomized Evaluations? AB - Across a range of contexts, reductions in education costs and provision of subsidies can boost school participation, often dramatically. Decisions to attend school seem subject to peer effects and time-inconsistent preferences. Merit scholarships, school health programs, and information about returns to education can all cost-effectively spur school participation. However, distortions in education systems, such as weak teacher incentives and elite-oriented curricula, undermine learning in school and much of the impact of increasing existing educational spending. Pedagogical innovations designed to address these distortions (such as technology-assisted instruction, remedial education, and tracking by achievement) can raise test scores at a low cost. Merely informing parents about school conditions seems insufficient to improve teacher incentives, and evidence on merit pay is mixed, but hiring teachers locally on short-term contracts can save money and improve educational outcomes. School vouchers can cost-effectively increase both school participation and learning. PMID- 23946864 TI - Speech perception and production. AB - Until recently, research in speech perception and speech production has largely focused on the search for psychological and phonetic evidence of discrete, abstract, context-free symbolic units corresponding to phonological segments or phonemes. Despite this common conceptual goal and intimately related objects of study, however, research in these two domains of speech communication has progressed more or less independently for more than 60 years. In this article, we present an overview of the foundational works and current trends in the two fields, specifically discussing the progress made in both lines of inquiry as well as the basic fundamental issues that neither has been able to resolve satisfactorily so far. We then discuss theoretical models and recent experimental evidence that point to the deep, pervasive connections between speech perception and production. We conclude that although research focusing on each domain individually has been vital in increasing our basic understanding of spoken language processing, the human capacity for speech communication is so complex that gaining a full understanding will not be possible until speech perception and production are conceptually reunited in a joint approach to problems shared by both modes. Copyright (c) 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website. PMID- 23946866 TI - Malaria Eradication and Educational Attainment: Evidence from Paraguay and Sri Lanka. AB - Mid-twentieth century malaria eradication campaigns largely eliminated malaria from Paraguay and Sri Lanka. Using these interventions as quasi-experiments, I estimate malaria's effect on lifetime female educational attainment through the combination of pre-existing geographic variation in malarial intensity and cohort exposure based on the timing of the national anti-malaria campaigns. The estimates from Sri Lanka and Paraguay are similar and indicate that malaria eradication increased years of educational attainment and literacy. The similarity of the estimates across the countries reinforces our confidence in the validity of the identification strategy. PMID- 23946867 TI - AMP-Activated Protein Kinase alpha 2 Isoform Suppression in Primary Breast Cancer Alters AMPK Growth Control and Apoptotic Signaling. AB - Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic regulator that promotes energy conservation and restoration when cells are exposed to nutrient stress. Given the high metabolic requirement of cancer cells, AMPK activation has been suggested as a potential preventative and therapeutic target. However, previous findings have shown that AMPK activity is diminished in some cancers. Expression of the 2 catalytic isoforms, AMPKalpha1 and AMPKalpha2, was evaluated in primary breast cancer and matched nontumor-adjacent tissue samples using immunohistochemistry. AMPK-dependent growth signaling events were examined in primary human mammary epithelial cells (HMECs) using RNAi to understand the importance of AMPKalpha2 in normal growth regulation. To test whether AMPKalpha2 would reinstate growth control and apoptotic mechanisms in breast cancer cells, metabolic stress assays and tumor xenografts were performed in MCF-7 cells, expressing low levels of AMPKalpha2, with stable transfection of either green fluorescent protein (GFP) or AMPKalpha2 expression constructs. AMPKalpha2 was found to be significantly suppressed in breast cancer tissue samples, whereas AMPKalpha1 was not. In normal HMECs, low glucose stress resulted in AMPK-driven growth inhibition. Interestingly, this response was ablated when AMPKalpha2 was silenced. Metabolic stress assays in MCF-7 cells indicated that AMPKalpha2 expression reduced both mTOR signaling and cyclin D1 expression, contributing to G1-phase cell cycle arrest. Cells expressing AMPKalpha2 underwent apoptosis more readily than GFP control cells. Xenograft studies demonstrated that MCF-7 tumors expressing AMPKalpha2 display reduced proliferation and increased apoptotic events. Furthermore, AMPKalpha2 xenografts exhibited diminished cyclin D1 levels along with an increased amount of nuclear p53, thereby implicating the AMPKalpha2 p53 signaling axis as a mediator of cell apoptosis. Together, these results highlight the significance of reduced AMPK activity contributing to human carcinogenesis and, specifically, the role of AMPKalpha2 with respect to its control of normal mammary epithelial cell growth and its reduced expression in breast cancer. PMID- 23946868 TI - Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers. AB - The human GT198 gene (gene symbol PSMC3IP) is located at chromosome 17q21, 470 kb proximal to BRCA1, a locus previously linked to breast and ovarian cancer predisposition. Its protein product (also known as TBPIP and Hop2) has been shown to regulate steroid hormone receptor-mediated gene activation and to stimulate homologous recombination in DNA repair. Here, we screened germline mutations in GT198 in familial and early-onset breast and ovarian cancer patients. We have identified 8 germline variants in a total of 212 index patients including reoccurring nonsense mutation c.310C>T (p.Q104X) and 5' UTR mutation c.-37A>T, each found in 2 unrelated families. Most identified index patients from cancer families had early onsets with a median age of 35 years. c.310C>T was absent in a total of 564 control individuals analyzed. GT198 gene amplification with an imbalanced mutant copy gain was identified in the blood DNA of one of the patients carrying c.310C>T. When tested, this truncating mutation abolished DNA damage-induced Rad51 foci formation. In addition, we have identified 15 somatic mutations in 2 tumors from 1 patient carrying germline mutation c.-37A>T. The presence of a somatic mutation on the wild-type allele showed that GT198 was biallelically mutated in the tumor. The somatic mutations identified near a splicing junction site caused defective alternative splicing and truncated the open reading frame. Therefore, distinct mutations may cause a similar consequence by truncating the full-length protein and inducing a loss of the wild type. Our study provides the first evidence of the presence of inactivating mutations in GT198 in familial and early-onset breast and ovarian cancer patients. Mutations in GT198, a gene regulating DNA repair, potentially contribute to an increased risk in familial breast and ovarian cancers. PMID- 23946869 TI - GT198 Splice Variants Display Dominant-Negative Activities and Are Induced by Inactivating Mutations. AB - Alternative pre-mRNA splicing yields functionally distinct splice variants in regulating normal cell differentiation as well as cancer development. The putative tumor suppressor gene GT198 (PSMC3IP), encoding a protein also known as TBPIP and Hop2, has been shown to regulate steroid hormone receptor-mediated transcription and to stimulate homologous recombination in DNA repair. Here, we have identified 6 distinct GT198 splice variant transcripts generated by alternative promoter usage or alternative splicing. Various splice variant transcripts preserve a common open reading frame, which encodes the DNA binding domain of GT198. The splice variants act as dominant negatives to counteract wild type GT198 activity in transcription and to abolish Rad51 foci formation during radiation-induced DNA damage. In fallopian tube cancer, we have identified 44 point mutations in GT198 clustered in 2 mutation hotspot sequences. The mutation hotspots coincide with the regulatory sequences responsible for alternative splicing, strongly supporting that imbalanced alternative splicing is a selected consequence in cancer. In addition, splice variant-associated cytoplasmic expression is found in tumors carrying germline or somatic GT198 mutations. An altered alternative splicing pattern with increased variants is also present in lymphoblastoid cells derived from familial breast cancer patients carrying GT198 germline mutations. Furthermore, GT198 and its variant are reciprocally expressed during mouse stem cell differentiation. The constitutive expression of the GT198 variant but not the wild type induces tumor growth in nude mice. Our results collectively suggest that mutations in the GT198 gene deregulate alternative splicing. Defective alternative splicing promotes antagonizing variants and in turn induces a loss of the wild type in tumorigenesis. The study highlights the role of alternative splicing in tumor suppressor gene inactivation. PMID- 23946870 TI - Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy. AB - The Tousled-like kinases (TLKs) are involved in chromatin assembly, DNA repair, and transcription. Two TLK genes exist in humans, and their expression is often dysregulated in cancer. TLKs phosphorylate Asf1 and Rad9, regulating double strand break (DSB) repair and the DNA damage response (DDR). TLKs maintain genomic stability and are important therapeutic intervention targets. We identified specific inhibitors of TLKs from several compound libraries, some of which belong to the family of phenothiazine antipsychotics. The inhibitors prevented the TLK-mediated phosphorylation of Rad9(S328) and impaired checkpoint recovery and DSB repair. The inhibitor thioridazine (THD) potentiated tumor killing with chemotherapy and also had activity alone. Staining for gamma-H2AX revealed few positive cells in untreated tumors, but large numbers in mice treated with low doxorubicin or THD alone, possibly the result of the accumulation of DSBs that are not promptly repaired as they may occur in the harsh tumor growth environment. PMID- 23946871 TI - Distinct cancer-specific survival in metastatic prostate cancer patients classified by a panel of single nucleotide polymorphisms of cancer-associated genes. AB - Individual genetic variations may have a significant influence on the survival of metastatic prostate cancer (PCa) patients. We aimed to identify target genes and their variations involved in the survival of PCa patients using a single nucleotide polymorphism (SNP) panel. A total of 185 PCa patients with bone metastasis at the initial diagnosis were analyzed. Germline DNA in each patient was genotyped using a cancer SNP panel that contained 1,421 SNPs in 408 cancer related genes. SNPs associated with survival were screened by a log-rank test. Fourteen SNPs in 6 genes, XRCC4, PMS1, GATA3, IL13, CASP8, and IGF1, were identified to have a statistically significant association with cancer-specific survival. The cancer-specific survival times of patients grouped according to the number of risk genotypes of 6 SNPs selected from the 14 SNPs differed significantly (0-1 v. 2-3 v. 4-6 risk genotypes; P = 7.20 * 10(-8)). The high risk group was independently associated with survival in a multivariate analysis that included conventional clinicopathological variables (P = 0.0060). We identified 14 candidate SNPs in 6 cancer-related genes, which were associated with poor survival in patients with metastatic PCa. A panel of SNPs may help predict the survival of those patients. PMID- 23946872 TI - MicroRNA Profile to Predict Gemcitabine Resistance in Bladder Carcinoma Cell Lines. AB - MicroRNAs (miRNA) are small, noncoding RNAs with important regulatory roles in development, differentiation, cell proliferation, and death as well as the complex process of acquired drug resistance. The goal of this study was to identify specific miRNAs and their potential protein targets that confer acquired resistance to gemcitabine in urothelial carcinoma of the bladder (UCB) cell lines. Gemcitabine-resistant cells were established from 6 cell lines following exposure to escalating concentrations of the drug and by passaging cells in the presence of the drug over a 2- to 3-month period. Differential miRNA expression was identified in a microarray format comparing untreated controls with resistant cell lines, representing the maximum tolerated concentration, and results were validated via qRT-PCR. The involvement of specific miRNAs in chemoresistance was confirmed with transfection experiments, followed by clonogenic assays and Western blot analysis. Gemcitabine resistance was generated in 6 UCB cell lines. Microarray analysis comparing miRNA expression between gemcitabine-resistant and parental cells identified the differential expression of 66 miRNAs. Confirmation of differential expression was recorded via qRT-PCR in a subset of these miRNAs. Within this group, let-7b and let-7i exhibited decreased expression, while miR 1290 and miR-138 displayed increased expression levels in gemcitabine-resistant cells. Transfection of pre-miR-138 and pre-miR-1290 into parental cells attenuated cell death after exposure to gemcitabine, while transfection of pre miR-let-7b and pre-miR-let-7i into the resistant cells augmented cell death. Mucin-4 was up-regulated in gemcitabine-resistant cells. Ectopic expression of let-7i and let-7b in the resistant cells resulted in the down-regulation of mucin 4. These results suggest a role for miRNAs 1290, 138, let-7i, and let-7b in imparting resistance to gemcitabine in UCB cell lines in part through the modulation of mucin-4. Alterations in these miRNAs and/or mucin-4 may constitute a potential therapeutic strategy for improving the efficacy of gemcitabine in UCB. PMID- 23946873 TI - Burden of noncommunicable diseases and national strategies to control them in Korea. AB - Noncommunicable diseases (NCDs) are the most important causes of premature mortality and disability-adjusted life years in Korea. NCDs are also the main contributor to socioeconomic inequalities in mortality and life expectancy. Reduction of NCDs and NCD inequalities would result in significant improvement in healthy life expectancy and health equity in Korea. Major NCD risk factors such as dietary risks (including salt intake), alcohol consumption, cigarette smoking, and high blood pressure were found to be the leading modifiable risk factors of disability-adjusted life years in Korea, based on the 2010 Global Burden of Disease Study. Several Korean studies have shown that these risk factors play an important role in creating socioeconomic inequalities in NCD mortality and total mortality. Current international discussions on NCD policies in the United Nations and the World Health Organization would provide better opportunities for developing aggressive population-wide policy measures in Korea. Considering the paucity of population-wide policies to control major NCD risk factors in Korea, rigorous population approaches such as taxation and regulation of unhealthy commodities as well as public education and mass campaigns should be further developed in Korea. PMID- 23946874 TI - Noncommunicable diseases: current status of major modifiable risk factors in Korea. AB - A noncommunicable disease (NCD) is a medical condition or disease that is by definition non-infectious and non-transmissible among people. Currently, NCDs are the leading causes of death and disease burden worldwide. The four main types of NCDs, including cardiovascular disease, cancer, chronic lung disease, and diabetes, result in more than 30 million deaths annually. To reduce the burden of NCDs on global health, current public health actions stress the importance of preventing, detecting, and correcting modifiable risk factors; controlling major modifiable risk factors has been shown to effectively reduce NCD mortality. The World Health Organization's World Health Report 2002 identified tobacco use, alcohol consumption, overweight, physical inactivity, high blood pressure, and high cholesterol as the most important risk factors for NCDs. Accordingly, the present report set out to review the prevalence and trends of these modifiable risk factors in the Korean population. Over the past few decades, we observed significant risk factor modifications of improved blood pressure control and decreased smoking rate. However, hypertension and cigarette smoking remained the most contributable factors of NCDs in the Korean population. Moreover, other major modifiable risk factors show no improvement or even worsened. The current status and trends in major modifiable risk factors reinforce the importance of prevention, detection, and treatment of risk factors in reducing the burden of NCDs on individuals and society. PMID- 23946875 TI - Overview of noncommunicable diseases in Korean children and adolescents: focus on obesity and its effect on metabolic syndrome. AB - Obesity during childhood is a dominant risk factor for noncommunicable diseases (NCDs), and is itself considered a disease that needs to be treated. Recently, the growth in childhood obesity in Korea has become stagnant; however, two in every ten children are still overweight. In addition, 60% or more of overweight children have at least one metabolic syndrome risk factor. Thus, childhood obesity should be controlled through lifestyle modification. This paper reviews studies of the modifiable risk factors of obesity in Korean children. According to the life-course approach, preschool-aged children (<5 years) are influenced by their parents rather than individual habits because they are under mostly parental care. Elementary school-aged children (6 to 11 years) are affected by overlapping individual and parental effects. This may mean that the establishment of individual behavior patterns begins during this period. The conditions of poor eating habits such as skipping meals, eating out, and high fat intake, along with low physical activity, facilitate increased obesity among adolescents (12 to 18 years). Notably, adolescent girls show high rates of both underweight and obesity, which may lead to the development of NCDs in their offspring. Therefore, the problem of NCDs is no longer limited to adults, but is also prevalent among children. In addition, early intervention offers cost-effective opportunities for preventing NCDs. Thus, children need primary consideration, adequate monitoring, diagnosis, and treatment to reduce the burden of NCDs later in adulthood. PMID- 23946876 TI - Drinking patterns among Korean adults: results of the 2009 Korean community health survey. AB - OBJECTIVES: In Korea, the proportion of deaths due to alcohol is estimated at 8.9%, far exceeding the global estimate of 3.8%. Therefore, this study was performed to examine the factors associated with low-risk, moderate-risk, and high-risk drinking patterns in Korean adults and to identify target populations for prevention and control of alcohol-related diseases and deaths. METHODS: We analyzed data from 230 715 Korean adults aged 19 years and older who participated in the 2009 Korean Community Health Survey. Multinomial logistic regression analysis was used to examine associations between socio-demographic and health related factors and patterns of alcohol use. RESULTS: A substantially larger proportion of men than women engaged in high risk (21.2% vs. 3.4%) and moderate risk alcohol use (15.5% vs. 8.2%). In both sexes, moderate- and high-risk uses were associated with younger age, higher income, being currently employed, smoking, being overweight/obese, and good self-rated health. CONCLUSIONS: Given the large proportion of the population that is engaging in moderate- and high risk drinking and given the social norms that support this behavior, public health policies and campaigns to reduce alcohol consumption targeting the entire population are indicated. PMID- 23946877 TI - Behavioural determinants for obesity: a cross-sectional study among urban adolescents in India. AB - OBJECTIVES: To measure the prevalence of behavioural risk factors for obesity among urban adolescent school children in Chennai, India. METHODS: This study was performed as a cross-sectional study using a World Health Organization-designed Global School-based Student Health Survey questionnaire (modified for India) among adolescent school children studying in 30 randomly selected secondary and higher secondary schools in Chennai city. 1842 adolescents studying in the VIII to XII standards were randomly selected for the study. RESULTS: In the present study, 40.7% of the students ate fruit one or more times per day and 74.5% of the students ate vegetables one or more times per day. Nearly 20% of the students ate fast food items on 4 to 7 days during the previous week. Among the students, 30.4% watched television for more than two hours per day. Nearly 68% of the girls and 22% of the boys did not participate in outdoor sports activities. When the pattern of physical activity of the students was assessed, it was observed that 15.6% were inactive, 43.4% were minimally active, and the remaining 41.0% belonged to the category of health enhancing physical activity. Among the students, 6.2% were overweight and 5.2% were obese. CONCLUSIONS: The prevalence of risk factors for obesity was quite high among the adolescents. This study also showed that a great proportion of overweight/obese adolescents had a correct perception of their body weight and they were making efforts to modify risk factors such as television viewing, computer use, a sedentary lifestyle, and unhealthy dietary habits. PMID- 23946878 TI - Use of drug-eluting stents versus bare-metal stents in Korea: a cost-minimization analysis using population data. AB - OBJECTIVES: The goal of this study was to perform an economic analysis of a primary stenting with drug-eluting stents (DES) compared with bare-metal stents (BMS) in patients with acute myocardial infarction (AMI) admitted through an emergency room (ER) visit in Korea using population-based data. METHODS: We employed a cost-minimization method using a decision analytic model with a two year time period. Model probabilities and costs were obtained from a published systematic review and population-based data from which a retrospective database analysis of the national reimbursement database of Health Insurance Review and Assessment covering 2006 through 2010 was performed. Uncertainty was evaluated using one-way sensitivity analyses and probabilistic sensitivity analyses. RESULTS: Among 513 979 cases with AMI during 2007 and 2008, 24 742 cases underwent stenting procedures and 20 320 patients admitted through an ER visit with primary stenting were identified in the base model. The transition probabilities of DES-to-DES, DES-to-BMS, DES-to-coronary artery bypass graft, and DES-to-balloon were 59.7%, 0.6%, 4.3%, and 35.3%, respectively, among these patients. The average two-year costs of DES and BMS in 2011 Korean won were 11 065 528 won/person and 9 647 647 won/person, respectively. DES resulted in higher costs than BMS by 1 417 882 won/person. The model was highly sensitive to the probability and costs of having no revascularization. CONCLUSIONS: Primary stenting with BMS for AMI with an ER visit was shown to be a cost-saving procedure compared with DES in Korea. Caution is needed when applying this finding to patients with a higher level of severity in health status. PMID- 23946882 TI - Perfluorocarbon liquid for dissection of proliferative vitreoretinopathy: avoiding subretinal persistence. PMID- 23946881 TI - Positive affect, childhood adversity, and psychopathology in psychiatric inpatients. AB - BACKGROUND: Low positive affect is closely related to common pathological responses to childhood adversity, including posttraumatic stress disorder (PTSD) and depression, but little is known about how the characteristics of early adversity experiences might be related to positive affect in adulthood. OBJECTIVE: This study aimed to explore whether low positive affect is related to specific childhood adversities, including abuse, neglect, caretaker dysfunction, and low childhood social support. METHOD: Using structured interviews and self report measure data collected from 173 adult psychiatric inpatients, this study examined the relationship between positive affect and symptoms of psychopathology, as well as how the number of types of abuse experienced, severity of adversity types (physical abuse and sexual abuse), childhood environment (childhood social support, neglect, and caretaker dysfunction), and number of non-abuse traumas related to positive affect. RESULTS: Positive affect was significantly negatively related to several symptoms of psychopathology, including depression, dissociation, self-destructive behavior, PTSD, and global psychopathology. Individuals who experienced both physical and sexual abuse reported significantly less positive affect than those with only physical or no abuse experiences. Lower positive affect was predicted by lower childhood social support and greater severity of sexual abuse, with both factors accounting for unique variance in positive affect. CONCLUSION: These results suggest that individuals who experience multiple types of early adversity, more severe sexual abuse experiences, and less social support are at risk of psychological difficulties. Given the relatively strong association between positive affect and childhood social support, interventions to foster social support may be a means of increasing positive affect among individuals exposed to childhood adversity. PMID- 23946883 TI - Performing Taxometric Analysis to Distinguish Categorical and Dimensional Variables. AB - A fundamental question facing clinical scientists is whether the constructs they are studying are categorical or dimensional in nature. The taxometric method was developed expressly to answer this question and is being used by a growing number of investigators to inform theory, research, and practice in psychopathology. The current paper provides a practical introduction to the method, updating earlier tutorials based on the findings of recent methodological studies. We offer revised guidelines for data requirements, indicator selection, parameter estimation, and procedure selection and implementation. We illustrate our recommended approach to taxometric analysis using idealized data sets as well as data sets representative of those found in clinical research. We close with advice to help newcomers get started on their own taxometric analyses. PMID- 23946884 TI - In vitro anticancer effect of venom from Cuban scorpion Rhopalurus junceus against a panel of human cancer cell lines. AB - In Cuba the endemic species of scorpion Rhopalurus junceus has been used in traditional medicine for cancer treatment. However, there is little scientific evidence about its potential in cancer therapy. The effect of a range of scorpion venom concentrations (0.1, 0.25, 0.5, 0.75 and 1mg/ml) against a panel of human tumor cell lines from epithelial (Hela, SiHa, Hep-2, NCI-H292, A549, MDA-MB-231, MDA-MB-468, HT-29), hematopoietic origins (U937, K562, Raji) and normal cells (MRC-5, MDCK, Vero) was determined by the MTT assay. Additionally, the effect of venom on tumor cell death was assayed by Fluorescence microscopy, RT-PCR and western blot. Only the epithelial cancer cells showed significant cell viability reduction, with medium cytotoxic concentration (IC50) ranging from 0.6-1mg/ml, in a concentration-dependent manner. There was no effect on either normal or hematopoietic tumor cells. Scorpion venom demonstrated to induce apoptosis in less sensitive tumor cells (Hela) as evidenced by chromatin condensation, over expression of p53 and bax mRNA, down expression of bcl-2 mRNA and increase of activated caspases 3, 8, 9. In most sensitive tumor cells (A549), scorpion venom induced necrosis evidenced by acridine orange/ethidium bromide fluorescent dyes and down-expression of apoptosis-related genes. We concluded the scorpion venom from R. junceus possessed a selective and differential toxicity against epithelial cancer cells. This is the first report related to biological effect of R. junceus venom against a panel of tumor cells lines. All these results make R. junceus venom as a promise natural product for cancer treatment. PMID- 23946885 TI - A novel function for the conserved glutamate residue in the walker B motif of replication factor C. AB - In all domains of life, sliding clamps tether DNA polymerases to DNA to increase the processivity of synthesis. Clamp loaders load clamps onto DNA in a multi-step process that requires ATP binding and hydrolysis. Like other AAA+ proteins, clamp loaders contain conserved Walker A and Walker B sequence motifs, which participate in ATP binding and hydrolysis, respectively. Mutation of the glutamate residue in Walker B motifs (or DExx-boxes) in AAA+ proteins typically reduces ATP hydrolysis by as much as a couple orders of magnitude, but has no effect on ATP binding. Here, the Walker B Glu in each of the four active ATP sites of the eukaryotic clamp loader, RFC, was mutated to Gln and Ala separately, and ATP binding- and hydrolysis-dependent activities of the quadruple mutant clamp loaders were characterized. Fluorescence-based assays were used to measure individual reaction steps required for clamp loading including clamp binding, clamp opening, DNA binding and ATP hydrolysis. Our results show that the Walker B mutations affect ATP-binding-dependent interactions of RFC with the clamp and DNA in addition to reducing ligand-dependent ATP hydrolysis activity. Here, we show that the Walker B glutamate is required for ATP-dependent ligand binding activity, a previously unknown function for this conserved Glu residue in RFC. PMID- 23946886 TI - Primary clarithromycin resistance to Helicobacter pylori: Is this the main reason for triple therapy failure? AB - Conventional triple therapies for Helicobacter pylori (H. pylori) eradication have recently shown a disappointing reduction in effectiveness in many countries. The main reason for failure was found to be bacterial resistance to one of the most commonly used antibiotics, clarithromycin. An additional problem for conventional triple therapy is the high rate of resistance to metronidazole found in Europe, America and Asia. In Italy, in the last 15 years a 2-fold increase in resistance has occurred. A recent study of the whole of Italy included about 20 patients from each region at the first endoscopic diagnosis of H. pylori infection. The most surprising result was the patchy distribution of resistance, which was almost absent in two regions (one northern and one southern), although the highest prevalence was found in some regions of the South. In the paediatric population we found a 25% prevalence of resistance in a sample of H. pylori positive children observed between 2002 and 2007, mirroring data obtained in southern European countries. Clarithromycin resistance assessment is currently based on phenotypic detection performed after culture the agar dilution method or E-test, and genotypic methods based on polymerase chain reaction (PCR). In a recent comparative study we found a 71.2% agreement between the two methods. Culture-free techniques are highly accurate in finding even minimal traces of genotypically resistant strains. Moreover, PCR-based tools are accurate in detecting a heteroresistant status, defined as the co-existence of some strains that are susceptible and some resistant to the same antibiotic in an individual patient. Three point mutations, namely A2143G, A2142G and A2142C, are responsible for 90% of cases of primary clarithromycin resistance in H. pylori strains isolated in Western countries, although we previously demonstrated that the presence of the A2143G mutation, but not A2142G or A2142C, significantly lowered the H. pylori eradication rate. Treatment failure has considerable cost/benefit implications because of "waste" of National Health System and patient resources, in terms of drugs, further diagnostic tests and medical examination expenses. Therefore, in future it would be very useful to be able to test for clarithromycin resistance before starting conventional triple therapy. Hopefully, fast, effective non-invasive tests may soon be devised to determine this condition. PMID- 23946887 TI - Probiotics for the treatment of Clostridium difficile associated disease. AB - The purpose of this review paper is to update the current and potential future role of probiotics for Clostridium difficile-associated disease (CDAD). Included in this review, is an update on the testing of newer probiotics (e.g., Bacillus coagulans GBI-30, 6086) in animal models of CDAD. There is a focus on the modulation of signal transduction pathways (i.e., transcription factors like cAMP response element-binding, activator protein 1, and nuclear factor kappa B), as well as the inhibition of certain kinases (e.g., p38 mitogen activated protein kinases) by probiotics. Inhibition of signal transduction by probiotics, such as Saccharomyces boulardii, result in multiple effects on intestinal fluid secretion, neutrophil influx into the colon, inflammation, and colonocyte apoptosis that may positively impact CDAD. Recent clinical approaches with probiotics, for the prevention of primary and recurrent CDAD, are also summarized in this review paper. Future directions for the treatment of CDAD by probiotics are also mentioned in this review. In particular, the use of multi-strain probiotic formulations such as Ecologic((r)) AAD and VSL #3((r)) may represent a rationale pharmacological approach, particularly as adjunctive therapies for CDAD. Understanding the mechanistic basis of CDAD, and how probiotics interfere at ceratin steps in the pathogenic process, may also present the opportunity to design other multi-strain probiotics that could have a future impact on CDAD. PMID- 23946888 TI - Altered molecular pattern of mucosal healing in Crohn's disease fibrotic stenosis. AB - AIM: To investigate tumor necrosis factor-alpha (TNF-alpha), syndecan 1 and basic fibroblast growth factor (bFGF) balance in Crohn's disease (CD) strictures. METHODS: Our study was performed on 24 surgical specimens of CD fibrotic stenosis. Ten histological normal surgical samples were retrieved for both the large and small bowel from patients with benign conditions and healthy tissue represented control collection. Sex and age in controls did not differ from CD group. Three endoscopic biopsy specimens taken after informed consent in subjects with normal colon were also used as negative controls. TNF-alpha, syndecan 1 and bFGF were detected by both reverse transcriptase reverse transcriptase polymerase chain reaction after mRNA extraction (results expressed as fold-change) and immunohistochemistry. RESULTS: TNF-alpha did not show any significant difference between CD and control specimens (1.54 +/- 1.19; P > 0.05). Very high levels of bFGF were observed in CD (11.76 +/- 4.65; P < 0.001) unlike syndecan 1 which showed a moderate increase (5.53 +/- 2.18; P < 0.005). analysis of variance (ANOVA) plus Student-Neumann-Keuls showed: bFGF > syndecan 1 > TNF-alpha = control. Immunoreactivity for bFGF was observed in epithelial, stromal, endothelial cells and even in the muscular layer, whilst in normal tissue it was almost unexpressed. Syndecan 1 and TNF-alpha staining was confined to mucosal epithelial and stromal cells, while in controls syndecan 1 was found in its normal site, i.e., basolateral area of the crypts and TNF-alpha very poorly expressed. CONCLUSION: Fibrotic stenosis of CD may be the final result of an irreversible transformation of different cells into fibrogenic phenotype no longer inhibited by post-transcriptional regulation. PMID- 23946889 TI - Severe hemorrhagic colitis in a patient with chronic myeloid leukemia in the blastic phase after dasatinib use. AB - Dasatinib is a second-line tyrosine kinase inhibitor used in patients with imatinib resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute leukemia. Gastrointestinal bleeding may occur in up to 7% of patients using dasatinib, although, severe dasatinib-related acute colitis had rarely been reported. Here, we present the case of a 36-year-old female who progressed to acute myeloid leukemia after fourteen months of receiving imatinib for CML in the chronic phase and was treated with a dasatinib-containing chemotherapy regimen. On day 34 of treatment, the patient developed moderate abdominal pain and bloody diarrhea with mucous. Analyses of stool specimens were negative for parasites, Clostridium difficile, and other pathogenic bacteria. The cytomegalovirus pp65 antigen was negative in her blood leukocytes. A colonoscopy revealed acute colitis, and a mucosal biopsy showed nonspecific colitis. The patient was treated with broad-spectrum antibiotics, bowel rest and hydration, and dasatinib treatment was stopped. Her bloody diarrhea improved within 72 h. After confirming cytological remission, the patient received initial course of consolidation, and dasatinib treatment was reinstated. However, hemorrhagic colitis recurred. After discontinuing dasatinib, herhemorrhagic colitis drastically improved and did not recur following the administration of nilotinib. The characteristics of our patient suggest that dasatinib treatment can lead to hemorrhagic colitis, which typically resolves after discontinuation of the drug. PMID- 23946890 TI - Why is damage limited to the mucosa in ulcerative colitis but transmural in Crohn's disease? AB - It has been a big puzzle as why the inflammation of ulcerative colitis (UC) is limited to the mucosa, while in Crohn's disease (CD) the inflammation is transmural and can be seen in all layers of the gut. Here, I give a tentative explanation extended from the unified hypothesis I proposed on the etiology of inflammatory bowel disease. This hypothesis suggested that both UC and CD are caused by weakening of the gut barrier due to damage of the protective mucus layer and the underlying tissue by the poorly inactivated digestive proteases resulting from a reduction of gut bacteria by dietary chemicals like saccharin and sucralose. However, the large amounts of bacteria in the colon make the recruitment of neutrophils and formation of crypt abscess the main manifestation of UC, while the infiltration of antigens and dietary particles in the small and large intestine mainly cause the recruitment of macrophages and formation of granulomas as the main manifestations in CD. The fast reacting and short life span of neutrophils make the fight and damage limited to the surface of the mucosa. In contrast, the long life span and constant movement of macrophages may bring the harmful agents deep into the tissue. Therefore, the pathogenesis of UC may be more like bacterial pneumonia, while CD may be more like pneumoconiosis or tuberculosis of the lung. PMID- 23946891 TI - Expression of O6-Methylguanine-DNA Methyltransferase Examined by Alkyl-Transfer Assays, Methylation-Specific PCR and Western Blots in Tumors and Matched Normal Tissue. AB - The tumor selectivity of alkylating agents that produce guanine O6-chloroethyl (laromustine and carmustine) and O6-methyl (temozolomide) lesions, depends upon O6-methylguanine-DNA methyltransferase (MGMT) activity being lower in tumor than in host tissue. Despite the established role of MGMT as a tumor resistance factor, consensus on how to assess MGMT expression in clinical samples is unsettled. The aim of this study is to examine the relationship between the values derived from distinctive MGMT measurements in 13, 12, 6 and 2 pairs of human tumors and matched normal adjacent tissue from the colon, kidney, lung and liver, respectively, and in human cell lines. The MGMT measurements included (a) alkyl-transfer assays using [benzene-3H]O6-benzylguanine as a substrate to assess functional MGMT activity, (b) methylation-specific PCR (MSP) to probe MGMT gene promoter CpG methylations as a measure of gene silencing, and (c) western immunoblots to analyze the MGMT protein. In human cell lines, a strict negative correlation existed between MGMT activity and the extent of promoter methylation. In tissue specimens, by contrast, the correlation between these two variables was low. Moreover, alkyl-transfer assays identified 3 pairs of tumors and normal tissue with tumor-selective reduction in MGMT activity in the absence of promoter methylation. Cell line MGMT migrated as a single band in western analyses, whereas tissue MGMT was heterogeneous around its molecular size and at much higher molecular masses, indicative of multi-layered post-translational modifications. Malignancy is occasionally associated with a mobility shift in MGMT. Contrary to the prevalent expectation that MGMT expression is governed at the level of gene silencing, these data suggest that other mechanisms that can lead to tumor-selective reduction in MGMT activity exist in human tissue. PMID- 23946892 TI - Differential effect of aging on verbal and visuo-spatial working memory. AB - Working memory (WM) declines with age. However it seems unclear, whether age related decline is more pronounced on verbal WM or on visuo-spatial WM. The present study compares the effect of aging on verbal and visuo-spatial modality of WM on native Hindi healthy speakers, in the age range of 40-to-above 80 years. It was found that normal aging affect both the verbal and visual working memory in similar way. Both modality declines with a similar rate up to 50-60 years and after 60 years relative saturation in span take place. Although verbal WM span is higher than visuo-spatial WM span, but no significant difference between verbal and visuo-spatial WM span were observed. PMID- 23946895 TI - Antenatal and postnatal diagnosis of coxsackie b4 infection: case series. AB - Enteroviruses are a common cause of neonatal infection. In particular, Coxsackie B viruses are often associated with severe, fatal disease. The antenatal diagnosis of Coxsackie B viral infections is uncommon. We present a unique case of Coxsackie B4 virus ventriculitis and myocarditis causing fetal hydrops at 22 weeks gestation. Transmission was inferred by viral isolation from the amniotic fluid and by placental pathology. We also describe two additional cases of fatal neonatal Coxsackie B4 infection complicated by myocarditis and encephalitis with cerebral necrosis in a 4-day-old female and by myocarditis, spinal leptomeningitis, and hepatitis in a 4-day-old male. Transplacental acquisition of infection carries a poor prognosis. We propose that Coxsackie B virus should be considered in the investigation of nonimmune hydrops, particularly in the presence of cardiac dysfunction. PMID- 23946896 TI - Fetal-maternal hemorrhage: a case and literature review. AB - Nearly all pregnancies include an insignificant hemorrhage of fetal blood into the maternal circulation. In some cases, the hemorrhage is large enough to compromise the fetus, resulting in fetal demise, stillbirth, or delivery of a severely anemic infant. Unfortunately, the symptoms of a significant fetal maternal hemorrhage can be subtle, nonspecific, and difficult to identify at the time of the event. We present the case of a severely anemic newborn who was delivered in our facility with an extensive literature review. PMID- 23946897 TI - Asymptomatic (subclinical) meningitis in one of premature triplets with simultaneous enteroviral meningitis: a case report. AB - Most enterovirus infection in the neonate and young infant is asymptomatic, but serious disease may occur, especially if acquired perinatally. We report the first case, to our knowledge, of asymptomatic enterovirus aseptic meningitis, and of concurrent enterovirus aseptic meningitis in premature triplets. Ten-week-old, 31-week-estimated gestational age premature triplet boys were diagnosed with enterovirus aseptic meningitis on the same day. Two of the triplets developed symptoms on the day of admission, while the third remained symptom free throughout the infection. All three recovered completely and are healthy more than a decade later. PMID- 23946898 TI - Successful embolization of a large vein of galen malformation in a premature infant presenting with congestive heart failure and persistent pulmonary hypertension. AB - We report a case of a premature infant with a vein of Galen malformation (VGM) who presented with high-output heart failure, pulmonary hypertension, and respiratory distress. An echocardiogram showed normal cardiac anatomy, patent ductus arteriosus, and retrograde flow in the descending aorta. Ultrasonography and computed tomography of head confirmed the diagnosis of a large VGM. The patient developed multiorgan failure. Endovascular embolization of the VGM was successfully performed with an excellent outcome. PMID- 23946899 TI - A near miss: case report and literature review. AB - We report a 28-week gestation premature infant with rare complication of endotracheal intubation. A piece from the plastic sheath of the stylet was retrieved inside the endotracheal tube after extubation. PMID- 23946900 TI - Five cases of congenital chylothorax treated by intrapleural minocycline. AB - Minocycline pleurodesis was performed on five infants with congenital chylothorax in our institutions. They could not achieve sufficient efficacy though they had received other conservative therapies. Four of the five cases obtained reduction of pleural effusion using the minocycline pleurodesis. We concluded that minocycline pleurodesis is a safe and an effective technique for congenital chylothorax. PMID- 23946894 TI - T cell Receptor Signal Transduction in T lymphocytes. AB - The T cell receptor (TCR) recognizes self or foreign antigens presented by major histocompatibility complex (MHC) molecules. Engagement of the TCR triggers the formation of multi-molecular signalosomes that lead to the generation of second messengers and subsequent activation of multiple distal signaling cascades, such as the Ca+2-calcineurin-NFAT, RasGRP1-Ras-Erk1/2, PKCtheta-IKK-NFkappaB, and TSC1/2-mTOR pathways. These signaling cascades control many aspects of T cell biology. Mechanisms have been evolved to fine-tune TCR signaling to maintain T cell homeostasis and self-tolerance, and to properly mount effective responses to microbial infection. Defects or deregulation of TCR signaling has been implicated in the pathogenesis of multiple human diseases. PMID- 23946901 TI - Successful Treatment of a Neonate with Idiopathic Persistent Pulmonary Hypertension with Inhaled Nitric Oxide via Nasal Cannula without Mechanical Ventilation. AB - We report a case study of a term neonate presenting with oxygen desaturation without respiratory distress or acidosis, despite receiving 100% oxygen through a nasal cannula. Echocardiogram showed evidence of persistent pulmonary hypertension of the newborn (PPHN). She was successfully treated with inhaled nitric oxide (iNO) via nasal cannula without requiring mechanical ventilation. In a term neonate with idiopathic PPHN with adequate respiratory drive without any parenchymal lung disease, noninvasive methods of iNO delivery may treat the condition without the complications associated with mechanical ventilation. PMID- 23946902 TI - Pregnancy in a woman with homozygous familial hypercholesterolemia not on low density lipoprotein apheresis. AB - Pregnancy in women with homozygous familial hypercholesterolemia (FH) has been rarely reported and might pose risks on the mother and her fetus. Although most reported cases remained on low-density lipoprotein (LDL) apheresis, there are no clear guidelines regarding the management of this entity. We report the first case of an uncomplicated pregnancy in a 24-year-old homozygous FH woman who was not maintained on LDL apheresis. FH expresses a wide variability in the phenotype, and management of homozygous FH cases who desire to become pregnant should be individualized based on preconceptional assessment with frequent antenatal follow-up. Decisions on management should be made after weighing the risks versus benefits of LDL apheresis. PMID- 23946903 TI - Management of Thrombotic Thrombocytopenic Purpura with Autoantibodies to ADAMTS 13 and Concurrent Preeclampsia in Pregnancy: Multidisciplinary Team Approach. AB - Background Thrombotic thrombocytopenic purpura (TTP) can present with many laboratory features of preeclampsia, which can make an accurate diagnosis difficult in late pregnancy. Because the treatments of TTP and preeclampsia are different and the clinical sequelae of delayed therapy potentially lethal, a rapid and accurate diagnosis is important. Case Report We present a case of an acute episode of TTP secondary to acquired autoantibodies complicated by severe preeclampsia with headache and treated with corticosteroids, plasma exchange therapy, magnesium sulfate, and delivery. The postpartum course was complicated and resulted in a prolonged hospital stay. A multidisciplinary team was recruited as consultants. Conclusion Concurrent TTP and severe preeclampsia can result in life-threatening complications. To ensure the best possible clinical outcome, an awareness of the medical systems' resources is required. PMID- 23946904 TI - Sudden intrapartum fetal death in fetuses with absent pulmonary valve syndrome: report of two cases. AB - Objective To describe potential intrapartum complications for fetuses affected by absent pulmonary valve syndrome. Study Design Two cases of intrapartum fetal death at full term were collected from our institution's labor and delivery unit records. Results In both cases of intrapartum fetal death, the fetuses had been diagnosed with absent pulmonary valve syndrome and had likely experienced acute cardiac events during labor. Both were delivered as stillbirths despite emergency cesarean delivery. Conclusion Patients should be counseled prior to labor about potential intrapartum complications for a fetus with absent pulmonary valve syndrome. Plans for fetal monitoring and the extent of aggressive intervention should be in place before labor in case sudden complications occur. PMID- 23946905 TI - Changes in heart rate variability in a premature infant with hydrocephalus. AB - Objective To define changes of heart rate variability in premature infant with hydrocephalus before and after drainage procedure. Study Design The authors report a case of a premature infant with hydrocephalus with analysis of heart rate variability before and after drainage procedure. Three subsequent recordings of the electrocardiography and heart rate variability were done: the first at the age of 22 days before insertion of ventriculoperitoneal shunt, the second at the age of 36 days with functional shunt, the third at the age of 71 days (before discharge). Results Before drainage operation, there was reduced heart rate variability in time and spectral domains, and sympathetic activity was dominant. After surgery, an increase in heart rate variability parameters was found, particularly with spectral analysis. The ratio of low-frequency/high-frequency band and relative power of the low-frequency band decreased, reflecting enhanced parasympathetic activity. Conclusion Results of the heart rate variability analysis in a preterm infant with hydrocephalus before and after drainage procedure showed marked improvement in chronotropic cardiac regulation. Evaluation of heart rate variability in premature infants with hydrocephalus with increased intracranial pressure can be an additional method for monitoring of cardiac dysregulation and improvement of the cardiovascular control after successful drainage procedure. PMID- 23946906 TI - Intracranial hemorrhage in pregnancy. AB - A pregnant woman with a mechanical prosthetic mitral valve was anticoagulated with low-molecular-weight heparin in the first trimester followed by warfarin until 36 weeks' gestation. She was then switched to intravenous unfractionated heparin infusion to allow for regional anesthesia in anticipation of vaginal delivery. She developed severe headache on hospital day 2 that was refractory to pain medications. Cranial imaging demonstrated a large subdural hematoma with midline shift. She delivered a healthy baby girl by cesarean section. Eventually, symptoms and intracranial abnormalities resolved over time. In conclusion, subdural hematoma is a relatively rare complication that requires multidisciplinary management plan. PMID- 23946907 TI - Absent pulmonary valve syndrome with left hemitruncus. AB - Absent pulmonary valve syndrome (APVS) is a rare congenital heart defect, usually associated with tetralogy of Fallot (TOF), although other associations have been described. A pregnant woman was referred to fetal echocardiography clinic from the Maternal Fetal Medicine department due to abnormal findings on routine antenatal ultrasound, showing a pulsatile cystic mass above the left atrium and a suspected TOF. A fetal echocardiogram confirmed the presence of TOF/APVS. The pulsatile cystic mass was the aneurysmally dilated main pulmonary artery. The exact origin of the left pulmonary artery (LPA) was not clearly established prenatally. A postnatal echocardiogram of the neonate showed an abnormal origin of the LPA from the ascending aorta (hemitruncus). The neonate subsequently underwent surgical repair with a good outcome. We present a novel case of a TOF/APVS associated with an abnormal origin of the LPA from the ascending aorta. PMID- 23946908 TI - In utero detection of retinoblastoma with fetal magnetic resonance and ultrasound: initial experience. AB - Purpose Our aim was to evaluate and compare the ability of prenatal ultrasound (US) and fetal magnetic resonance imaging (MRI) to detect retinoblastoma lesions in utero. Methods Fetuses at risk for having bilateral retinoblastoma were enrolled in this prospective study. High-resolution US of the fetal eye was performed at 16 to 18 weeks' gestation, every 4 weeks until 32 weeks, then every 2 weeks until delivery. Fetal MRIs were performed every 8 weeks starting at 16 to 18 weeks of gestation. An exam under anesthesia (EUA) was performed postnatally, the gold standard of this study. Lesions were classified as being elevated or minimally elevated based upon their morphology. Results Of six fetuses suspected or confirmed to be at risk for developing bilateral retinoblastoma, one had tumors on her first postnatal EUA exam. A total of two minimally elevated lesions were seen by the EUA but not detected prenatally by imaging. One elevated lesion (2 mm in height) identified by postnatal EUA was initially identified by prenatal US. Fetal MRI did not detect any lesions. Conclusion Both prenatal US and fetal MRI are limited in the detection of minimally elevated retinoblastoma lesions. Prenatal US appears to be more sensitive than fetal MRI in the detection of elevated retinoblastoma lesions. PMID- 23946909 TI - Improving the management of an advanced extrauterine pregnancy using pelvic arteriography in a hybrid operating suite. AB - Advanced extrauterine pregnancy is an extremely rare, life-threatening pregnancy complication. Management of these pregnancies presents significant challenges, especially when they have progressed to an advanced stage of fetal viability. With high rates of maternal and fetal mortality associated with this complication, delivery or pregnancy interruption should be expedited following diagnosis. Localization of the placenta and its blood supply is critical to preoperative planning. Hybrid operating suites that can accommodate a multidisciplinary team of subspecialists may improve the chance of a successful outcome with this rare complication. PMID- 23946911 TI - Molecular dynamics simulations of mechanical failure in polymorphic arrangements of amyloid fibrils containing structural defects. AB - We examine how the different steric packing arrangements found in amyloid fibril polymorphs can modulate their mechanical properties using steered molecular dynamics simulations. Our calculations demonstrate that for fibrils containing structural defects, their ability to resist force in a particular direction can be dominated by both the number and molecular details of the defects that are present. The simulations thereby suggest a hierarchy of factors that govern the mechanical resilience of fibrils, and illustrate the general principles that must be considered when quantifying the mechanical properties of amyloid fibres containing defects. PMID- 23946912 TI - Magnetic anisotropy of graphene quantum dots decorated with a ruthenium adatom. AB - The creation of magnetic storage devices by decoration of a graphene sheet by magnetic transition-metal adatoms, utilizing the high in-plane versus out-of plane magnetic anisotropy energy (MAE), has recently been proposed. This concept is extended in our density-functional-based modeling study by incorporating the influence of the graphene edge on the MAE. We consider triangular graphene flakes with both armchair and zigzag edges in which a single ruthenium adatom is placed at symmetrically inequivalent positions. Depending on the edge-type, the graphene edge was found to influence the MAE in opposite ways: for the armchair flake the MAE increases close to the edge, while the opposite is true for the zigzag edge. Additionally, in-plane pinning of the magnetization direction perpendicular to the edge itself is observed for the first time. PMID- 23946910 TI - Beyond Widespread Mecp2 Deletions to Model Rett Syndrome: Conditional Spatio Temporal Knockout, Single-Point Mutations and Transgenic Rescue Mice. AB - Rett syndrome (RTT) is one of the leading causes of intellectual disabilities in women. In addition to a few autistic features, characteristic symptoms that distinguish from classical autism include stereotypic hand movements, motor coordination deficits, breathing abnormalities, seizures and loss of acquired speech as well as purposeful hand use. RTT is highly associated with MECP2, the gene encoding for the transcription factor that binds methylated Cytosine in C-p G islands in DNA, controlling gene expression and chromatin remodeling. In this review, we will briefly discuss current perspectives on MeCP2 function, and then will describe in detail novel mouse models of RTT based on loss-of-function of Mecp2 and their use for establishing rescue models, wherein we pay close attention to behavioral and morphological phenotypes. PMID- 23946913 TI - Synthesis and thermoelectric properties of Re3As6.6In0.4 with Ir3Ge7 crystal structure. AB - The Re3As7- x In x solid solution was prepared for x <= 0.5 by heating the elements in stoichiometric ratios in evacuated silica tubes at 1073 K. It crystallizes with the Ir3Ge7 crystal structure, space group Im-3m, with a unit cell parameter a ranging from 8.716 to 8.747 A. The crystal structure and properties were investigated for a composition with x = 0.4. It is shown that indium substitutes arsenic exclusively at one crystallographic site, such that the As-As dumbbells with d As-As = 2.54 A remain intact. Re3As6.6In0.4 behaves as a bad metal or heavily doped semiconductor, with electrons being the dominant charge carriers. It possesses high values of Seebeck coefficient and low thermal conductivity, but relatively low electrical conductivity, which leads to rather low values of the thermoelectric figure of merit. PMID- 23946914 TI - Digging gold: keV He(+) ion interaction with Au. AB - Helium ion microscopy (HIM) was used to investigate the interaction of a focused He(+) ion beam with energies of several tens of kiloelectronvolts with metals. HIM is usually applied for the visualization of materials with extreme surface sensitivity and resolution. However, the use of high ion fluences can lead to significant sample modifications. We have characterized the changes caused by a focused He(+) ion beam at normal incidence to the Au{111} surface as a function of ion fluence and energy. Under the influence of the beam a periodic surface nanopattern develops. The periodicity of the pattern shows a power-law dependence on the ion fluence. Simultaneously, helium implantation occurs. Depending on the fluence and primary energy, porous nanostructures or large blisters form on the sample surface. The growth of the helium bubbles responsible for this effect is discussed. PMID- 23946915 TI - Structural and thermoelectric properties of TMGa3 (TM = Fe, Co) thin films. AB - Based on chemically synthesized powders of FeGa3, CoGa3, as well as of a Fe0.75Co0.25Ga3 solid solution, thin films (typical thickness 40 nm) were fabricated by flash evaporation onto various substrates held at ambient temperature. In this way, the chemical composition of the powders could be transferred one-to-one to the films as demonstrated by Rutherford backscattering experiments. The relatively low deposition temperature necessary for conserving the composition leads, however, to 'X-ray amorphous' film structures with immediate consequences on their transport properties: A practically temperature independent electrical resistivity of rho = 200 MUOmega.cm for CoGa3 and an electrical resistivity of about 600 MUOmega.cm with a small negative temperature dependence for FeGa3. The observed values and temperature dependencies are typical of high-resistivity metallic glasses. This is especially surprising in the case of FeGa3, which as crystalline bulk material exhibits a semiconducting behavior, though with a small gap of 0.3 eV. Also the thermoelectric performance complies with that of metallic glasses: Small negative Seebeck coefficients of the order of -6 MUV/K at 300 K with almost linear temperature dependence in the range 10 K <= T <= 300 K. PMID- 23946916 TI - Characterization of electroforming-free titanium dioxide memristors. AB - Metal-insulator-metal (MIM) structures based on titanium dioxide have demonstrated reversible and non-volatile resistance-switching behavior and have been identified with the concept of the memristor. Microphysical studies suggest that the development of sub-oxide phases in the material drives the resistance changes. The creation of these phases, however, has a number of negative effects such as requiring an elevated voltage, increasing the device-to-device variability, damaging the electrodes due to oxygen evolution, and ultimately limiting the device lifetime. In this work we show that the deliberate inclusion of a sub-oxide layer in the MIM structure maintains the favorable switching properties of the device, while eliminating many of the negative effects. Electrical and microphysical characterization of the resulting structures was performed, utilizing X-ray and electron spectroscopy and microscopy. In contrast to structures which are not engineered with a sub-oxide layer, we observed dramatically reduced microphysical changes after electrical operation. PMID- 23946917 TI - Massive transcranial parotid pleomorphic adenoma: recurrence after 30 years. AB - Pleomorphic adenoma, also known as benign mixed tumor, is the most common tumor affecting the parotid gland and can reach massive size; however, intracranial invasion is rare. Recurrence of pleomorphic adenoma after excision is a well known phenomenon and can present decades after resection of the primary tumor. Here we present the case of a 53-year-old man who presented to our clinic with ear fullness, otalgia, and hearing loss 30 years after undergoing total parotidectomy and external beam radiotherapy for pleomorphic adenoma. Magnetic resonance imaging revealed a massive transcranial tumor invading the mastoid cavity, the dura of the posterior fossa, the fallopian and semicircular canals, the jugular foramen, the lateral infratemporal fossa skull base, the sigmoid and transverse sinuses, and the superior parapharyngeal region. Gross examination and histopathological studies confirmed that the mass was a recurrent pleomorphic adenoma. Here we discuss the features of recurrent pleomorphic adenoma and review the current literature. PMID- 23946918 TI - Calcium pyrophosphate deposition disease of the temporomandibular joint. AB - Calcium pyrophosphate dihydrate deposition disease (CPDD, tophaceous pseudogout) is a rare crystal arthropathy characterized by calcium pyrophosphate crystal deposition in joint spaces, episodes of synovitis, and radiological features of chondrocalcinosis. We present a case of 61-year-old woman who presented with left temporomandibular joint (TMJ) pain, difficulty chewing, left facial numbness, left-sided hearing loss, and left TMJ swelling. Imaging of the temporal fossa revealed a large mass emanating from the temporal bone at the TMJ, extending into the greater wing of the sphenoid and involving the mastoid bone and air cells posteriorly. Fine needle aspiration demonstrated polarizable crystals with giant cells. Intraoperatively, the TMJ was completely eroded by the mass. Final pathology was consistent with tophaceous pseudogout. CPDD has rarely been reported involving the skull base. None of the cases originally described by McCarty had TMJ pseudogout. Symptoms are generally pain, swelling, and hearing loss. Management is nearly always surgical with many patients achieving symptomatic relief with resection. CPDD is associated with many medical problems (including renal failure, gout, and hyperparathyroidism), but our patient had none of these risk factors. This case demonstrates that CPDD can involve the skull base and is best treated with skull base surgical techniques. PMID- 23946919 TI - Metastatic prostate mass to the intradural foramen magnum region: a case report. AB - Intradural metastatic tumors of the foramen magnum region are extremely rare tumors. We report a 73-year-old patient that presented with right hemiparesis and a recent history of prostate biopsy for an enlarged prostate. Imaging revealed an anterolateral intradural foramen magnum mass with compression of the medulla. A right far lateral approach with condyle preservation was used to resect the mass. Pathological examination revealed the tumor as a metastatic prostate mass. The patient had a significant recovery of motor function and was given adjuvant external beam radiation. At the time of last follow-up, the patient had good clinical relief from the preoperative symptoms. To our knowledge, this is the first reported case of an intradural foramen magnum prostate tumor metastasis. We report on multimodal management of this rare, yet morbid presentation of a common tumor. PMID- 23946920 TI - Jugular foramen syndrome as initial presentation of metastatic lung cancer. AB - Metastatic involvement of the cranial base and jugular foramen generally presents with headache and lower cranial neuropathy but may escape early diagnosis. In this report, a patient developed a jugular foramen syndrome as the initial presentation of metastatic lung cancer soon after being diagnosed and treated surgically for extracranial atherosclerotic internal carotid artery disease. With the appropriate diagnosis established, he underwent local fractionated radiation therapy and systemic chemotherapy but succumbed to the disease. This report analyses metastatic disease affecting the cranial base and in particular, the jugular foramen, with a discussion of the clinical syndromes that accompany this rare condition. PMID- 23946921 TI - A catecholamine-secreting skull base sinonasal paraganglioma presenting with labile hypertension in a patient with previously undiagnosed genetic mutation. AB - Sinonasal paragangliomas are very uncommon neuroendocrine tumors that can present as skull base lesions. Functional paragangliomas are exceedingly rare. They can be associated with genetic mutations that have been associated with increased risk of head and neck paragangliomas. We present a case of a rare functioning sinonasal paraganglioma of the skull base in a patient with distant history of prior abdominal paragangliomas. The patient underwent subtotal endoscopic resection of the skull base lesion limited by carotid encasement of the tumor. They were treated with postoperative adjuvant radiation and therapeutic metaiodobenzylguanidine (MIBG) therapy. Genetic testing revealed succinate dehydrogenase B (SDHB) mutation. Skull base paragangliomas are rare tumors that may preclude complete surgical resection. (131)Iodine-MIBG can be used as adjuvant therapy in postoperative external beam radiation and in MIBG avid tumors. Long-term follow-up is needed given locally aggressive nature of these tumors, especially for patients with history of genetic mutations such as SDHB mutations as recurrent paragangliomas may develop. PMID- 23946922 TI - Primary cerebellopontine angle melanocytoma: review. AB - Introduction Primary cerebellopontine angle melanocytomas (PCPAMs) are very rare. Their natural history and prognosis are not fully understood. We reviewed the literature and add a new case to analyze PCPAM's presentation, radiological features, and outcome of treatment. Methods We performed a literature review using Medline, Embase, PubMed, and Cochrane databases. We searched for melanocytoma, melanoma, and pigmented tumors in the posterior cranial fossa and CPA to identify PCPAM. We have also searched our institution's neuro-oncology database. Results We identified 23 PCPAM from the literature and one case of our own. The mean age at presentation was 44.4 years with slight male preponderance. PCPAM presented with cerebellopontine angle (CPA) syndrome with or without hydrocephalus. Preoperative diagnosis was difficult; they appeared hyperintense on T1 and isointense on T2 magnetic resonance imaging (MRI) and enhanced with gadolinium. However, the final diagnosis was only made by immunohistochemical examination. Total surgical resection of PCPAM was associated with prolonged survival while subtotal excision was associated with frequent recurrence. Conclusion PCPAM are very rare and should be considered in the differential diagnosis of all CPA lesions that appear hyperintense on T1 and isointense on T2 MRI images. Patients with PCPAM should undergo total surgical resection to avoid fatal recurrences. PMID- 23946923 TI - Large dumbbell-shaped c1 schwannoma presenting as a foramen magnum mass. AB - Schwannomas involving the foramen magnum commonly originate from the lower cranial nerves, but they are rarely found arising from the first cervical root. To date, very few cases have been described in the literature. The majority involve either the intradural or extradural compartment but not both. We report the second case of a dumbbell-shaped schwannoma arising from the first cervical root. Our patient presented with hemisensory deficits secondary to brainstem compression at the level of the foramen magnum. The patient underwent a far lateral approach, and a gross total resection was achieved. Preoperative suspicion of the diagnosis is helpful in anticipating displacement and avoiding damage to the surrounding neurovascular structures. PMID- 23946924 TI - A tentorial venous hemangioma presenting as an extra-axial mass in the ambient cistern: a case report. AB - Although venous hemangiomas are one of the most common soft-tissue tumors, venous hemangiomas in the central nervous system are extremely rare. We present an unusual case of venous hemangioma originating from the interdural space of the tentorium. A 32-year-old woman was incidentally found to have extra-axial mass occupying the left ambient cistern. This tumor was observed for the first 4 years as it was completely asymptomatic. Surgical resection was later recommended when the tumor grew. The mass originated from between the two layers of the anteromedial tentorial incisura. There were no findings indicative of previous hemorrhage inside the mass. The matrix of the mass was firm and vascular, resembling a fibrous meningioma. Gross total resection was achieved without any neurological deficit. Pathological examination revealed a dense fibrous connective tissue with a proliferation of vessels marked by thickened walls. A spindle cell proliferation in the vessel walls did not stain with the antibody to S-100 protein. Movat stain demonstrated the venous character of the vessels. These results were histologically compatible with a venous hemangioma. Albeit extremely rare, a venous hemangioma, a distinct clinical and pathological entity from a venous angioma, can present an intracranial mass lesion. PMID- 23946925 TI - Calcifying pseudoneoplasms of the skull base presenting with cranial neuropathies: case report and literature review. AB - Objectives We report our institutional experience with calcifying pseudoneoplasms of the skull base that presented with cranial neuropathies. These lesions are also known as fibro-osseous lesions, cerebral calculi, or brain stones. Results One patient presented with facial numbness and retro-orbital pain secondary to compression of the maxillary branch of the trigeminal nerve at the anterior portion of the infratemporal fossa. The other patient presented with occipital headaches and hypoglossal nerve palsy. This patient was found to have a calcified lesion in the posterior fossa, which eroded the left occipital condyle. Conclusion Calcifying pseudoneoplasms are benign, slow-growing masses that are apparently cured by gross total resection. Even with incomplete tumor resection, the prognosis is considered to be favorable. We advocate a minimally invasive surgical resection of such tumors involving the cranial nerves. PMID- 23946926 TI - A case of large anterior paraclinoid aneurysm with intraoperative premature rupture. AB - We report here troubleshooting of intraoperative premature rupture with large anterior paraclinoid aneurysm, which was successfully clipped. A 61-year-old woman with left nasal hemianopia was referred to our institute. Preoperative three-dimensional computed tomography angiography and a left internal carotid artery angiogram showed a large left anterior clinoid aneurysm adjacent to the anterior clinoid process. Aneurysm was ruptured prematurely and tentative clipping of the dome of the aneurysm was done incidentally to stop bleeding and to reduce the volume of the aneurysm. The anterior clinoid process and superior wall of the orbit were drilled out safely, since the tentative clipping had created sufficient space between the aneurysm and the anterior clinoid process to perform the procedure. The proximal neck was observed and tandem clipping was applied to the aneurysm. Intraoperative and postoperative angiography revealed complete disappearance of the aneurysm. PMID- 23946927 TI - Combined endoscopic endonasal transorbital approach with transconjunctival-medial orbitotomy for excisional biopsy of the optic nerve: technical note. AB - Background Access to the intraorbital optic nerve segment can be facilitated via a transcranial approach that allows access to the entire orbital cavity. The endoscopic endonasal approach (EEA) combined with a transconjunctival-medial orbitotomy represents an alternative technique to achieve the same goal. Objective Report a surgical technique that allows total resection of the intraorbital optic nerve with minimal trauma and excellent results. Further extend and define the limits and indications of the EEA to orbital surgery. Methods A patient with rapidly progressive, but asymmetric, vision loss underwent EEA for optic nerve biopsy. Due to the undetermined histopathological diagnosis and complete unilateral vision loss, diagnostic total optic nerve resection was indicated. The entire intraorbital length of the nerve was resected via an endoscopic endonasal transorbital approach combined with transconjunctival-medial orbitotomy. Results A 2-cm intraorbital nerve segment was sent for pathological examination. The patient maintained normal extraocular movements and experienced no complications. The postoperative course was uneventful and the patient was discharged the next day. Conclusion The EEA provides another option for access to the entire optic nerve. It is a safe and effective technique lacking cosmetic defects and providing an alternative corridor to traditional transcranial approaches to the orbit. PMID- 23946928 TI - Paranasal sinus involvement in metastatic carcinoma. AB - Metastatic carcinoma involving the paranasal sinuses is uncommon. One hundred sixty seven cases have been published in the literature since 1951. Symptoms, signs, and rhinoscopic and imaging findings are often nonspecific, and the diagnosis may be missed for considerable time. Therefore, a high level of suspicion is warranted in patients with known malignancies presenting with persistent or recurrent rhinosinusitis or facial complaints. PMID- 23946929 TI - Giant cell granuloma of the temporal bone in a mixed martial arts fighter. AB - Background and Importance Giant cell granuloma (GCG) is a rare, benign, non neoplastic lesion of the head and neck. More common in the jaw bones, there have been few reports of the lesion arising in the temporal bone. Initially referred to as a "giant cell reparative granuloma," due to the previously accepted notion of its nature in attempting to repair areas of injury, the term "giant cell granuloma" is now more frequently used as this lesion has been found in patients without a history of trauma. In addition, several cases with a destructive nature, in contrast to a reparative one, have been observed. Clinical Presentation We report a case of GCG presenting as a head and neck tumor with dural attachments and extension into the middle cranial fossa in a mixed martial arts fighter. Conclusion Giant cell granulomas are typically treated surgically and have a good prognosis; however, care must be taken when they present in unusual locations. This case supports the theory of trauma and inflammation as risk factors for GCG. PMID- 23946930 TI - Transforming growth factor-beta and the glomerular filtration barrier. AB - The increasing burden of chronic kidney disease worldwide and recent advancements in the understanding of pathologic events leading to kidney injury have opened up new potential avenues for therapies to further diminish progression of kidney disease by targeting the glomerular filtration barrier and reducing proteinuria. The glomerular filtration barrier is affected by many different metabolic and immune-mediated injuries. Glomerular endothelial cells, the glomerular basement membrane, and podocytes-the three components of the filtration barrier-work together to prevent the loss of protein and at the same time allow passage of water and smaller molecules. Damage to any of the components of the filtration barrier can initiate proteinuria and renal fibrosis. Transforming growth factor beta (TGF-beta) is a pleiotropic cytokine strongly associated with the fibrogenic response. It has a known role in tubulointerstitial fibrosis. In this review we will highlight what is known about TGF-beta and how it interacts with the components of glomerular filtration barrier and causes loss of function and proteinuria. PMID- 23946932 TI - Identification of genotypes of Giardia duodenalis human isolates in Isfahan, Iran, using polymerase chain reaction - Restriction Fragment Length polymorphism. AB - BACKGROUND: Giardia duodenalis is one of the most prevalent intestinal parasites of human. It also infects a wide range of mammals. Two genotype of G.duodenalis (A and B) were commonly reported among humans with different frequency of distribution in different geographical locations. This work was conducted to discriminate genotypes of Giardia duodenalis human isolates in Isfahan city using PCR- RFLP. This is the first molecular study on human isolates of G.duodenalis in the area. METHODS: Samples were collected from different health centers of Isfahan city during June 2011 and February 2012. From 175 Giardia positive stool samples 67 specimens were selected randomly. Cysts of Giardia positive samples were concentrated by flotation sucrose. Extraction of genomic DNA from trophozoite and cysts was performed using QIAamp Stool Mini kit with a modified protocol. PCR- RFLP method was used to amplify a fragment of 458bp at the glutamate dehydrogenase locus, and restriction enzymes BspLI and RsaI differentiated human genotypes A and B and their subgroups. RESULTS: PCR - RFLP assay of 67 isolates showed 40(59.7%) isolates as Genotype A group II, 23(34.32%) samples as Genotype B Group III and two (2.98%) sample as Genotype B group IV. Mixed genotype of (AII and B) was detected only in two isolates (2.98%). CONCLUSIONS: PCR - RFLP assay targeting gdh locus is a sensitive tool and discriminates genotypes, sub genotypes and mixed type of G.duodenalis. Results of our study suggest both anthroponotic and zoonotic origins for the infections respectively. PMID- 23946931 TI - Autophagy and Mitophagy in Cellular Damage Control. AB - Autophagy and mitophagy are important cellular processes that are responsible for breaking down cellular contents, preserving energy and safeguarding against accumulation of damaged and aggregated biomolecules. This graphic review gives a broad summary of autophagy and discusses examples where autophagy is important in controlling protein degradation. In addition we highlight how autophagy and mitophagy are involved in the cellular responses to reactive species and mitochondrial dysfunction. The key signaling pathways for mitophagy are described in the context of bioenergetic dysfunction. PMID- 23946933 TI - Lack of association between TNF-alpha gene polymorphisms at position -308 A, 850T and risk of simple febrile convulsion in pediatric patients. AB - BACKGROUND: Febrile convulsions (FCs), occurring between 6 months and 6 years of age is the most common seizure disorder during childhood. The febrile response is thought to be mediated by the release of pyrogenic cytokines, such as tumor necrosis factor and interleukin-1 (IL-1). There is a significant relationship between genetic components for susceptibility of FCs and different report mutation. We investigated association between two polymorphisms in the tumor necrosis factor (TNF)-alpha promoter region (G-308A, C-850T) and FCs in the southwest area of Iran. MATERIALS AND METHODS: In this matched case-control study, 100 patients with febrile convulsion as case group and 130 healthy children as control group were enrolled in the study. Peripheral blood samples were collected and DNA was extracted by standard phenol-chloroform method. The genotype and allele frequencies of TNF- alpha polymorphisms in case and control groups were determined by using PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism) method. Statistical analysis was done using Chi square test. RESULTS: The average age of case and control groups were 3.4 +/- 1.4 and 3.4 +/- 1.2 years, respectively. There was no significant difference between age and sex in both the groups (P > 0.05). A family history of febrile convulsion was detected in 44% of patients. Moreover, the simple febrile convulsion was detected in 85% of the case group. CONCLUSION: RFLP analysis of TNF- alpha promoter region polymorphisms, considering P = 0.146 and P = 0.084 for G-308A and C-850T, respectively, showed no correlation between TNF- alpha polymorphisms and predisposition to simple febrile, based on the kind of convulsion (atypical and simple febrile convulsion). We found a significant relation between genotype distribution of G-308A and atypical febrile convulsion in case group (P = 0.04). A significant correlation between genotype distribution of G-308A and atypical febrile convulsion in the case group was found, but there was no correlation between TNF- alpha polymorphisms at positions of -308A, and 850T and predisposition to simple febrile convulsion. Further studies are needed to understand clinical usefulness of this correlation. PMID- 23946934 TI - The assessment of 24 24-h urine volume by measurement of urine specific gravity with dipstick in adults with nephrolithiasis. AB - BACKGROUND: Nephrolithiasis is a recurrent disease, and one of the most effective methods for prevention of stone recurrence is increasing the urine output (>2 L/day), but it is difficult to achieve it. The aim of this study was to evaluate the effect of behavioral intervention by measurement of urine specific gravity using dipstick on 24-h urine volume in first renal stone patients. MATERIALS AND METHODS: In this prospective randomize clinical study, 80 adult patients with history of first renal stone were included. Patients were divided into two groups with 40 patients in each group. We explained the importance of high fluid intake and high urine volume in the prevention of renal stones for all patients. Group A patients were trained to measure 24-h urine volume every 15 days, and group B patients were trained to keep urine specific gravity below 1.010 by using dipstick. We measured 24-h urine volume in each group before intervention, and at 3 months and 6 months after intervention and compared them. RESULTS: There were no significant differences between the two groups in 24-h urine volume before intervention (P = 0.41), but it was significant 3 months (P = 0.01) and 6 months (P = 0.01) after intervention. Patients' compliance was 20% in group A and 90% in group B (P < 0.05). CONCLUSION: The use of behavioral modification with dipstick is an effective method for control and maintenance of optimal urine volume, and it has resulted in more patient compliance for drinking water and is more effective for prevention of renal stone. PMID- 23946937 TI - Learning Spatially-Smooth Mappings in Non-Rigid Structure from Motion. AB - Non-rigid structure from motion (NRSFM) is a classical underconstrained problem in computer vision. A common approach to make NRSFM more tractable is to constrain 3D shape deformation to be smooth over time. This constraint has been used to compress the deformation model and reduce the number of unknowns that are estimated. However, temporal smoothness cannot be enforced when the data lacks temporal ordering and its benefits are less evident when objects undergo abrupt deformations. This paper proposes a new NRSFM method that addresses these problems by considering deformations as spatial variations in shape space and then enforcing spatial, rather than temporal, smoothness. This is done by modeling each 3D shape coefficient as a function of its input 2D shape. This mapping is learned in the feature space of a rotation invariant kernel, where spatial smoothness is intrinsically defined by the mapping function. As a result, our model represents shape variations compactly using custom-built coefficient bases learned from the input data, rather than a pre-specified set such as the Discrete Cosine Transform. The resulting kernel-based mapping is a by-product of the NRSFM solution and leads to another fundamental advantage of our approach: for a newly observed 2D shape, its 3D shape is recovered by simply evaluating the learned function. PMID- 23946935 TI - Methylation pattern of SFRP1 promoter in stool sample is a potential marker for early detection of colorectal cancer. AB - BACKGROUND: To setup a non-invasive genetic screening method for colorectal cancer, we evaluated the promoter methylation status of secreted frizzled-related protein1 (sfrp1) in stool samples of colorectal cancer with respect to a series of healthy individuals, using methylation-specific polymerase chain reaction. MATERIALS AND METHODS: In stool samples from 25 patients with colorectal cancer and 25 healthy control subjects, isolated DNA was treated with sodium bisulfite and analyzed by methylation-specific polymerase chain reaction with primers specific for methylated or unmethylated promoter sequences of the SFRP1 gene. RESULT: Methylation of the SFRP1 promoter was present in the stool DNA of patients with colorectal cancer. A sensitivity of 52% and specificity of 92% were achieved in the detection of colorectal neoplasia. The difference in methylation status of the SFRP1 promoter between the patients with colorectal neoplasia and the control group was statistically highly significant (P = 0.006). CONCLUSIONS: The results indicate that this DNA stool test of methylation of the SFRP1 promoter is a sensitive and specific method. It is assumed that the test is potentially useful for the early detection of colorectal cancer. PMID- 23946938 TI - Reply to AG Longhi. PMID- 23946939 TI - Reply to R Pawlak. PMID- 23946940 TI - Reply to HC Stevens and C La Vecchia. PMID- 23946941 TI - Workplace measurements by the U.S. Occupational Safety and Health Administration since 1979: Descriptive analysis and potential uses for exposure assessment. AB - This letter summarizes modifications to the results presented in Lavoue et al. (2012): Lavoue, J., Burstyn, I.,Friesen, M. (2012) Workplace Measurements by the US Occupational Safety and Health Administration since1979: Descriptive Analysis and Potential Uses for Exposure Assessment. Annals of occupational hygiene57(1):77-97. Although several results were altered, the conclusions were not affected by the changes. PMID- 23946942 TI - Blood clotting at room temperature in cold agglutinin disease. PMID- 23946943 TI - Memoriam: Dick Heinegard 1942-2013. PMID- 23946944 TI - Guest editors' introduction: special section on learning deep architectures. PMID- 23946945 TI - The 'boom' in medical malpractice claims-patients could be losers. PMID- 23946946 TI - Affordability of the National Health Insurance... and definition of a billion. PMID- 23946947 TI - Dr. Craven responds. PMID- 23946948 TI - Who will do an ERCP on me when I'm retired? PMID- 23946949 TI - Legality of circumcision in South Africa. PMID- 23946950 TI - Impact and costs of algorithms for the diagnosis of adults with pulmonary tuberculosis in South Africa. PMID- 23946951 TI - Academy of Science of South Africa launches a mapping survey of life science research and diagnostic activity in South Africa. PMID- 23946952 TI - Justice through the J88: the doctor's role in the criminal justice system. PMID- 23946953 TI - Audit of medical records: use of a structured form in emergency departments. PMID- 23946954 TI - A physician 'quality of presence'- a vital therapeutic tool. PMID- 23946955 TI - How big pharma and regulators fail clinicians. PMID- 23946956 TI - Karabus saga raises wider issues. PMID- 23946957 TI - Regulatory environment needs a shake-up-Broomberg. PMID- 23946958 TI - Integrating recovery practices into psychiatric nursing: where are we in 2013? PMID- 23946959 TI - [Not Available]. PMID- 23946960 TI - [Not Available]. PMID- 23946961 TI - Feeling the outpatient pinch. Lower demand squeezes chains' quarterly earnings. PMID- 23946967 TI - A showcase for veterinarians: Smithsonian exhibition celebrates human-animal bond, marks 150th anniversary of AVMA. PMID- 23946970 TI - [Essay on a film for psychotherapists (Lars von Trier: Antichrist)]. PMID- 23946969 TI - Crosstalk of inflammatory mediators and lipid parameters as early markers of renal dysfunction in stable renal transplant recipients with regard to immunosuppression. AB - BACKGROUND: Kidney transplantation is still the treatment of choice for end-stage renal disease, therefore it is important to establish all modifiable risk factors for initiation of renal dysfunction. MATERIAL/METHODS: We enrolled 73 renal transplant recipients, who were more than 12 months post-renal transplant surgery, had a stable graft function, had no clinically present cardiovascular disease, and were on standard immunosuppressive therapy. The concentrations of intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM 1), CRP, lipids, and lipoproteins were measured. We used logistic regression to calculate non-adjusted, age, and multivariable-adjusted ORs and 95% confidence intervals for glomerular filtration rate, GFR <60 ml/min/1.73 m(2). RESULTS: Non adjusted OR showed that there was a significant risk of reduced GFR in patients with total cholesterol higher than 5.19 mmol/L, LDL cholesterol >= 4.1 mmol/L, non- HDL >= 4.2 mmol/L, and higher VCAM-1 concentration. After adjustment for age and in multivariable model, OR showed a significant risk for reduced GFR in patients with total cholesterol >= 5.2 mmol/L, LDL >= 4.1 mmol/L, non-HDL >= 4.2 mmol/L, and higher VCAM-1 concentration. HDL, triglycerides, CRP, and lipoprotein ratios did not have any significance as predictors of renal dysfunction. There were no differences in all evaluated parameters between groups in regard to immunosuppressive therapy. CONCLUSIONS: Total cholesterol, LDL, non-HDL, and VCAM 1 are strong and independent predictors of renal dysfunction in stable renal transplant recipients. In contrast, HDL, CRP, triglycerides, and ICAM-1 did not seem to have any impact on renal dysfunction. PMID- 23946971 TI - [The human iris, as a potential biomarker to personality]. PMID- 23946972 TI - [Clinical neurologist-Charles David Marsden]. PMID- 23946973 TI - Letter to the editor. PMID- 23946974 TI - Spinocerebellar ataxia presenting in the eighth decade of life. PMID- 23946976 TI - CT perfusion in the management of acute stroke. PMID- 23946975 TI - Role of midazolam in parkinsonian tremors: to use or not to use. PMID- 23946977 TI - Acute neurological complication in awake craniotomy;--a diagnostic dilemma. PMID- 23946979 TI - [The control by Mycobacterium tuberculosis of the expression of host resistance to infection]. PMID- 23946978 TI - NTDB(r) data points: Precious cargo. PMID- 23946980 TI - On the question of cognitive limits in diagnostic histopathology. AB - From a solely morphological point of view, histopathological diagnosis is subject to interpretation variables that may be investigated from an epistemological aspect. On the basis of the most suitable ways of approach, the authors examine some theoretical aspects involved in writing a histopathological report. In particular, the following are considered: problems regarding the perception of shapes, induction, deduction, abduction and some aspects of formal logic connected with the evaluation of immunohistochemical investigations. The main reasons for diagnostic mistakes are underlined, and the opportunity for an awareness of the logical and mental mechanisms involved in the evaluation of morphological data is outlined. PMID- 23946981 TI - Histological evaluation of papillary lesions of the breast from needle biopsy to the excised specimen: a single institutional experience. AB - BACKGROUND: The assessment and categorization of papillary lesions remains one of the most challenging areas in breast pathology. We evaluated the histological follow-up of papillary lesions of the breast from needle core biopsy to final excision to determine whether these lesions warrant excision, irrespective of histologic subtype. STUDY DESIGN: A total of 91 needle core biopsies from the breast diagnosed as "papillary lesions" at our institution from January 2001 to June 2011 were included in the study. Twenty-nine of these (mean patient age 54.93 +/- 12.5 SD) were reported as benign papillary lesions, and the remaining 62 (mean patient age 61.98 +/- 15.20 SD) were diagnosed as either atypical papillary lesions (17 cases) or malignant papillary lesions (45 cases). RESULTS. Of the 29 needle core biopsies reported as benign, 19 cases (65.5%) were diagnosed as benign and three (10.3%) were diagnosed as malignant on follow-up. The remaining seven cases did not proceed to excision. Sixty-two of the 91 cases were given a diagnosis of either atypical papillary lesion or malignant papillary lesion on needle core biopsy. Of the 45 cases initially diagnosed as malignant, 44 (97.7%) were eventually deemed malignant and one atypical ductal hyperplasia (ADH) was found upon excision. The initial diagnosis of atypical papillary lesion was rendered in 17 cases, of which 10 turned out to be malignant, five ADH, and two benign on excision. CONCLUSION: We conclude that if a benign papillary lesion is present on initial needle core biopsy, then the probability of malignancy is high (10.3%) on the final excision. Similarly, all malignant papillary lesions diagnosed on needle core biopsy should be excised due to the very high likelihood (97.7%) of a diagnosis of malignancy on final excision. Based on our results, we suggest surgical excision of any papillary lesion diagnosed on needle core biopsy. PMID- 23946982 TI - Pancreatic adenocarcinoma in duodenal ectopic pancreas: a case report and review of the literature. AB - Ectopic pancreas is defined as pancreatic tissue outside the normal location without connection to the normal pancreas. It occurs throughout the gastrointestinal tract, most commonly in the stomach (25-60%), followed by the duodenum (25-35%) and jejunum (16%). It may develop the same pathological changes of a normal pancreas such as acute pancreatitis and cyst formation. Malignant degeneration rarely occurs. We present a case of heterotopic pancreatic adenocarcinoma localized in the duodenal bulb presenting with symptoms of gastric obstruction. PMID- 23946983 TI - Pulse granuloma involving Meckel's diverticulum: a case report and literature review. AB - Pulse granuloma is a rare, benign entity that most likely represents a reaction to vegetable material and is characterized by hyaline rings and foreign-body giant cells. We report a case of a pulse granuloma involving Meckel's diverticulum. The patient presented with abdominal pain and radiological findings consistent with Meckel's diverticulum. Microscopic examination of the resected tissue confirmed diagnosis of Meckel's diverticulum with small bowel mucosa. Peridiverticular foreign-body giant cells, hyaline rings and circular structures containing calcified basophilic granules were also identified, consistent with pulse granuloma. Pulse granulomas have been reported in a variety of locations, most commonly in the oral cavity. To the best of our knowledge, this is the first reported example of pulse granuloma in Meckel's diverticulum. Familiarity with pulse granuloma allows for the timely and accurate diagnosis of this entity, particularly in sites not previously described in the literature. PMID- 23946984 TI - Diagnosis and clinical course of cardiac myxoma. AB - Cardiac myxomas are the most common benign tumours of the heart. In spite of their benign nature, these tumours may induce metastasis or recurrences. Their diagnosis is challenging because of the lack of specific signs, and positive diagnosis is based on microscopic findings. We report a case series of 6 patients documented by radiologic and microscopic findings. In addition, one case was unique due to its location in the right atrium. Tumours were detected by trans oesophageal ultra-sound examination in all cases. They were located in the left atrium in five cases and in the right side in one case. All patients underwent a successful surgical excision with en-bloc removal of the tumour. The outcome was fatal in one patient because of atrial arrhythmia. PMID- 23946985 TI - Lung metastasis from TTF-1 positive sigmoid adenocarcinoma. pitfalls and management. AB - The lung is a frequent site of metastatic involvement, and in many cases the differential diagnosis between a metastasis and a primary carcinoma is a substantial question. TTF-1 is considered as a reliable marker for differential diagnosis in distinguishing primary lung carcinoma and metastasis, especially when dealing with an adenocarcinoma or a large-cell carcinoma. It was generally thought that adenocarcinomas arising in the gastrointestinal tract do not express TTF-1. Recently, it has been reported that a small percentage (1.8%-5.8%) of intestinal adenocarcinoma TTF-1 positive show differences in sensitivity/specificity depending on the antibody clones. We report a case of lung localization of a TTF-1 positive adenocarcinoma in a patient with a history of colon adenocarcinoma. Based on the current results and previous reports, we propose the following criteria for diagnosing lung metastasis from TTF-1 positive intestinal adenocarcinoma. 1) Clinical features and anamnestic history are diagnostic milestones, and provide very important information as a prognostic parameter of primary carcinoma and the time interval between the two localizations (primary and metastasis). 2) The histologic features are compatible with an enteric differentiation. 3) TTF-1 must be tested in the primary carcinoma. 4) In lung lesions, in association with TTF-1, it could be useful to test other immunohistochemical markers such as CDX-2 and NapsinA. 5) Testing other immunohistochemical or molecular markers in either lesion is not very useful. Heterogeneity between primary and metastatic lesions has been reported in the literature. Application of the above-mentioned criteria would simplify diagnosis of lung metastases from TTF-1 positive intestinal adenocarcinoma. PMID- 23946986 TI - Primary tuberculosis of the adenoids in an 11-year-old male presenting with hearing loss: a case report. AB - Hypertrophy of adenoids is usually caused by repeated throat infections, especially viral and bacterial infections, that in microscopic examination reveal reactive lymphoid follicular hyperplasia. Herein, we present an 11-year-old boy who developed hearing loss in his left ear three months before admission, and in direct examination the adenoids were hypertrophied. Histopathological study of the resected adenoid revealed caseating granulomatous inflammation. Based on histopathological and clinical findings, primary tuberculosis of adenoids was suggested which was confirmed by PCR. PMID- 23946987 TI - Memoir of Antoine Zajdela. PMID- 23946989 TI - [Patient's aggression aimed at physicians. Legal interpretation of defense possibilities]. AB - The aim of the following study is to acquaint medical practitioners with legal possibilities of defense against patients'aggression. The occurrence of the described and discussed issue, namely the appearance of different forms of aggression aimed at physicians and other medical staff is a more and more frequently appearing phenomenon, which is very problematic, and difficult to interpret. The scope of the analysis has been limited to aggression of patients towards physicians only, as they are most often the aim of this aggression, and what should be emphasized, they lack practical and universal solutions and frequently also necessary knowledge to protect themselves against it. The idea behind this study is to present a rational solution to the afore mentioned situation, within legal limits. First, an outline of a conflict situation with a short specification of sources of aggression will be presented, than an appropriate legal taxonomy (including civil and criminal law) allowing for aid in such a situation will be offered and discussed.The authors will also present practical and legally permissible solutions aiming at defense, abandonment, and not allowing for the appearance of this reprehensible phenomenon. PMID- 23946990 TI - Total preperitoneal biological patch indirect inguinal hernioplasty. PMID- 23946991 TI - [Adverse events in therapeutics]. PMID- 23946992 TI - Unpicking the great clinical commissioning budget swindle. PMID- 23946993 TI - The NHS can learn from US success stories. PMID- 23946994 TI - Putting great service first. PMID- 23946995 TI - The value of public engagement. PMID- 23946996 TI - Where there's a will, there's a way. PMID- 23946997 TI - Take the hours out of out of hours care. PMID- 23946998 TI - It's all about self, self, self. PMID- 23946999 TI - Healthcare's top model. PMID- 23947000 TI - Hospitals without borders. PMID- 23947001 TI - [Human rights. Right to health. Right to health information. The Venezuelan biomedical journals]. AB - Venezuelan Biomedical journals have been confronting, for several years, a gradual decline both, from the standpoint of their management and in the quality of their editorial content. At its highest level, Venezuela had about sixty different titles. But irregular financial support, as well as the lack of a clear official policy, regarding these scientific activities, were some of the reasons that have contributed to this decline. Several recent Venezuelan and international documents provide an important legal support for the design of new official policies and government responsibilities. There is now a valid opportunity to profit from new tools to evaluate and improve the quality of our scientific and editorial activities. PMID- 23947002 TI - [Epidemiology of ophidism in Venezuela (1996-2004)]. AB - The data of accidents caused by snakebites in Venezuela, registered at the morbidity statistics of the Direction of Epidemiology and Strategic Analysis of the Ministry of Health and Social Development were analyzed. During the years of 1996-2004, 53,792 snakebites were registered in Venezuela (5,976 cases average per year), with a higher incidence during the year 2004 (7,486 incidents). Zulia reported the highest frequency of all the states (5,975 cases); meanwhile the Midwestern region, constituted by Lara, Portuguesa, Falc6n and Yaracuy states, had a higher morbidity for snake bites. The highest incidence, distributed per states was registered in Cojedes, during the year 2001, with 228.72 cases per 100,000 inhabitants. When it was determined by regions, the highest incidence occurred during the year 2004 at los Llanos with 63.81 per 100,000 inhabitants. The median of the incidence rate for Venezuela during the period was of 21.46 accidents per 100,000 inhabitants. The classification of the endemic areas for ophidism, according to the percentiles 23, 50, 75 and 90, organized the country in: (a) states and regions of very high endemicity, (b) high endemicity, (c) middle, (d) low and (e) very low endemicity. These epidemiological data indicated that the accidents caused by snakes constitute a collective health problem in Venezuela. PMID- 23947003 TI - [MMP-3 and MMP-8 levels in patients with chronic periodontitis before and after nonsurgical periodontal therapy]. AB - Immune-inflammatory processes are trigged in chronic periodontitis (CP), where matrix metalloproteinases (MMPs) are released and involved in the degradation of the extracellular matrix components that can be detected in the gingival crevicular fluid (GCF). The purpose of the study was to determine the levels of MMP-3 and MMP-8 in GCF, before and after nonsurgical periodontal treatment (NSPT), to evaluate disease activity and therapy response. Eleven patients with PC and eleven healthy controls were selected. Clinical measurements to evaluate gingival index (GI), plaque index (PI), probing depth (PD) and clinical attachment loss (CAL) were made in all the teeth of each individual and in six sites per tooth. GCF samples were taken from one tooth per quadrant, with a pocket depth > or =4 mm and a clinical attachment loss > or =5 mm, and the levels of MMP-3 and MMP-8 measured using an ELISA test. Statistically significant differences in clinical parameters were observed (p < 0.05) between patients with CP and control groups before the periodontal treatment, with significant decrease in all indexes after the NSPT. The initial concentrations of MMP-3 and MMP-8 were significantly higher than those obtained after the NSPT and in the control group, without observing a correlation between the clinical parameters and the levels of MMPs. Increased levels of MMP-3 and MMP-8 in the GCF of patients with PC declined significantly after NSPT, and the difference between the levels in healthy individuals and patients, suggests the important participation of these MMPs in tissue destruction in PC disease.. PMID- 23947004 TI - [Diagnosis of insulin resistance by indirect methods in obese school children]. AB - Obesity leads to a deterioration of glucose tolerance and the action of insulin. The purpose of this study was to determine insulin resistance (IR) by indirect methods, and its correlation with clinical, anthropometric and biochemical variables in obese normoglycemic school children. This was a descriptive correlational study of 72 school prepubescent children, who attended the ambulatory "El Concejo" of the University of Carabobo (UC) and at the Gastroenterology and Pediatric Nutrition service of the city hospital "Enrique Tejera" (CHET), in Valencia, Venezuela, between January-April 2011. INCLUSION CRITERIA: exogenous obesity. We assessed personal and family history, presence of Acanthosis Nigricans and nutritional and biochemical status. We found a higher percentage of IR, through the use of the QUICKI method (66.7%), followed by the HOMA (55.6%) and basal insulin (45.9%). The mean (chi) indexes of body mass and waist circumference were significantly greater (p < 0.05) in patients with IR, by HOMA and QUICKI techniques. The QUICKI method detected significant differences (p < 0.05) in the values of glycemia, basal insulin and postprandial insulin, among patients with diminished and normal insulin sensitivities. While HOMA, detected these differences (p < 0.05) in the values of glycemia and basal insulin. A statistically significant relationship was observed (p < 0.05), between the presence of Acanthosis Nigricans and IR, by the HOMA, QUICKI and basal insulin methods. In conclusion, the evaluated techniques, QUICKI, HOMA and basal insulin indexes, were most effective for detecting the IR. PMID- 23947005 TI - Minocycline, but not ascorbic acid, increases motor activity and extends the life span of Drosophila melanogaster. AB - In the present study we compared the effects of minocycline and ascorbic acid in the life span, motor activity and lipid peroxidation of Drosophila melanogaster, in an effort to find a substance capable of providing protection against oxidative stress in aging. In the flies treated with minocycline a very significant increase in the life span (101 +/- 1.33 days) was observed when compared to those treated with ascorbic acid and controls (42.3% and 38.4%, respectively). The motor activity of minocycline treated flies also increased significantly with respect to control and ascorbic acid fed flies, from the 3rd to the 9th week of treatment. With regard to lipid peroxidation, it was found that the levels of malondialdehyde (MDA) in flies treated with minocycline showed no statistical differences to the control on the first day of treatment, but a significantly lower content on the day of 50% survival. In contrast, in flies treated with ascorbic acid significantly elevated levels of MDA compared to control and minocycline treated flies were detected throughout. These results suggest a protective effect of minocycline against oxidative stress and aging in D. melanogaster. An inhibitory effect on reactive oxygen species production may be an important contributing factor. PMID- 23947006 TI - [Changes in the content of plasma lipoproteins in persons subjected to diets prepared with sunflower oil alone or mixed with palm olein]. AB - We analyzed in 31 subjects, regular guests of the University food service of the Central University of Venezuela (UCVFS), in Caracas, the effects of replacing sunflower oil, commonly used in the preparation of meals, by a mix of sunflower oil and palm olein 70/30 (v/v) respectively. Plasma concentrations of total cholesterol, low and very low density lipoproteins were not changed after 40 days of the substitution. On the contrary, concentrations of high density lipoprotein and total triglycerides increased. The resistance to the oxidation of low-density lipoproteins increased considerably (p < 0.01). Today this resistance is considered as a protective factor of great importance in the prevention of the initiation of the atherogenic process. Taking into account the favorable modifications of HDL cholesterol and the clear increased resistance to the oxidation of LDL, we think that palm olein, mixed with other oils with a high ratio linoleic/palmitic (sunflower, corn, soya an the likes), can be used as a healthy alternative in human nutrition. PMID- 23947007 TI - [Optic neuritis after a bee sting]. AB - Optic neuritis is an acute inflammation of the optic nerve and, in its atypical form, is caused by inflammation of the optic nerve as part of infectious, immune, granulomatous, or contiguity processes. Hymenoptera stings (bees, wasps and ants) have been associated with different clinical presentations, ranging from local events to systemic manifestations, such as anaphylaxis, glomerulonephritis and central nervous system involvement (ischemic vascular lesions, optic neuritis and demyelinating lesions). This is a report of the case of a 62-year-old woman that after three days of being stung by a bee in the left lower eyelid, showed decreased visual acuity of both eyes and central scotoma, concomitant bilateral headache and eye pain, exacerbated by eye movements. The ophthalmological examination showed that visual acuity was decreased and the bilateral fundus examination revealed blurred optic disks edges. Hyperintense thickening of the left optic nerve was observed with an ocular MRI. Due to the clinical manifestations and epidemiological history, the diagnosis of bilateral optic neuritis was established. Treatment with pulses of 1 g/daily of methylprednisolone was initiated, for three days, with clinical improvement within 24 hours after receiving the first dose. Since 1960, cases of optic neuritis associated with hymenoptera stings have been documented, which take the form of anterior optic neuritis. A case of a patient who presented clinical features of bilateral optic neuritis after been stung by a bee, with a good clinical outcome after treatment with methylprednisolone is reported. PMID- 23947008 TI - Epithelial-mesenchymal transition (EMT): principles and clinical impact in cancer therapy. AB - The epithelial-mesenchymal transition (EMT) is a biological phenomenon responsible for the formation of different tissues and organs during normal metazoan development. Because of the connection of the EMT with the pathogenesis of certain diseases, such as cancer, the attention of the scientific community has been directed towards the search for and identification of effective therapeutic targets. These targets include signal transduction in cancerous stem cells and the use of microRNAs, which would inhibit EMT-associated phenotypic changes and tumoral progression. In an attempt to compile relevant and current information, this work addresses concepts that define the EMT and the advances in this field. The wealth of knowledge gained from areas such as the loss of cell polarity and intracellular adhesion complexes, the signaling pathways implicated, microRNA participation in this process, and stemness acquisition in embryonic and cancerous cells, all of which allow for the visualization of promising perspectives, particularly, methods for targeting advanced malignancies, are presented herein. PMID- 23947009 TI - [Micrometastases: strategies for detection]. AB - Micrometastasis or minimal residual disease has become critically important in oncology since it represents a true clinical problem that must be solved, as the response of these tumor foci to the different treatments that are used for the control of cancer, is still unknown. Even though this is a fundamental specific problem to be solved, there are already immunohistochemical and molecular biology diagnostic methods that have allowed microfoci location of tumor cells in various organs and tissues, and different techniques are available to determine and quantify these lesions. Within these techniques, flow cytometry and different molecular methods are included, and they range from the traditional to the newest and most sophisticated. The goal of this review was aimed to evaluate new diagnostic methods that permit the identification of this residual disease, which would serve to establish individualized treatments and prevent the recurrence of the disease in cancer patients under treatment. PMID- 23947010 TI - [Clinical and epidemiological study of intestinal coccidioses in a rural population of a semiarid region from Falcon state, Venezuela]. PMID- 23947011 TI - Understanding the molecular targets for new therapeutical agents in hepatitis c infection. AB - Improved understanding of the HCV viral life cycle has led to the identification of numerous potential molecular targets for the development of new drugs. Direct acting antivirals -DAAs specifically target a viral encoded protein: the NS3-4A protease, involved in the posttranslational viral protein processing; the NS5B encoded viral polymerase, that conducts the nucleic acid replication and the NS5A encoded phosphoprotein, that participates in both replication and virus assembly. Host-targeted agents, both directed to the early steps of viral replication (receptors and coreceptors antagonists) or to the development of a functional viral replication complex (host cyclophilins) are also developed, to strengthen the antiviral efficacy of these drugs. The newly approved NS3-4A protease inhibitors (telaprevir and boceprevir), administered in combination with pegylated interferon and ribavirin for patients with HCV genotype I infection, determined a significant enhancement in the sustained virologic response rates (towards 66-75% in treatment-naive patients and 59-66% in treatment-experienced ones). Improved antiviral efficacy was shown in clinical trials by second generation protease inhibitors, while valuable alternatives are represented by nucleoside/nucleotide analogues and non-nucleoside inhibitors directed to the HCV RNA-dependent RNA polymerase, as well as by NS5A inhibitors (both direct acting or directed to the host cofactors). More recently, combinations of different drugs are tested as a potential cure for chronic hepatitis C. PMID- 23947012 TI - Growth of Entamoeba invadens in sediments with metabolically repressed bacteria leads to multicellularity and redefinition of the amoebic cell system. AB - Extracellular signaling and mechanisms of cell differentiation in Entamoeba are misunderstood. The main reason is the popular use of axenic media, which do not correspond to the natural habitats of Entamoeba. The axenic environment lacks the exogenous activators and repressors provided by natural habitats. Absent bacterial commensals understanding of the development of the amoebic cell system remains deficient. The present Aa(Sm) culture method using mixed sediments of antibiotically repressed Aerobacter aerogens and amoebae was developed to model in vitro extracellular signaling that induce multicellularity in cultures of E. invadens. Repressed oxygen consuming sediment bacteria supply E. invadens the hypoxic environment needed for differentiation and development. The amoebae themselves alter the environment by consuming the bacteria by phagocytosis thus reversing hypoxia. Exogenous activators are in this manner down regulated and suppressed. This feedback effect controls amoebic development and differentiation. Co-existing cell types and cell fractions with different life spans and cell cycle length could be identified. Aa(Sm) long term cultures contain continuous and non-continuous self renewing cell lines producing quiescent and terminally differentiated daughter cells (precysts) by asymmetric division. This culturing method helps to understand the intimate relationship between hypoxic environments and the multicellular behaviour of E. invadens and the interrelations existing between the distinct cell types. PMID- 23947013 TI - Two case reports on visceral leishmaniasis diagnosed in Romania. AB - Two cases of visceral leishmaniasis with a species from Leishmania donovani complex were detected in the Fundeni Clinical Institute. In one case, two infection sources were possible: one from Italy, where the patient worked three years, the other from the Southwest of Romania (Dolj County), where he was resident and where few human and canine leishmaniasis cases were registered in the past. In the second case, the patient lived in the Northeast of Romania (Iasi County), but worked in the same southwest zone. In both cases, a local transmission should be considered, situation that could amplify and extend in the future, supposing that increased temperatures will persist, favoring the persistence and multiplication of autochthonous and allochthonous Phlebotomus vector species. PMID- 23947014 TI - Adenylate cyclases involvement in pathogenicity, a minireview. AB - Cyclic AMP (cAMP), one of the most important secondary messengers, is produced by adenylate cyclase (AC) from adenosine triphosphate (ATP). AC is a widespread enzyme, being present both in prokaryotes and eukaryotes. Although they have the same enzymatic activity (ATP cyclization), the structure of these proteins varies, depending on their function and the producing organism. Some pathogenic bacteria utilize these enzymes as toxins which interact with calmodulin (or another eukaryote activator), causing intense cAMP synthesis and disruption of infected cell functions. In contrast, other pathogenic bacteria benefit of augmentation of AC activity for their own function. Based on sequence analysis ofAC catalytic domain from two pathogenic bacteria (Bacillus anthracis and Bordetellapertussis) with known three-dimensional structures, a possible secondary structure for 1-255 amino acid fragment from Pseudomonas aeruginosa AC (with 80TKGFSVKGKSS90 as the ATP binding site) is proposed. PMID- 23947015 TI - [Concentrations and ozone formation potentials of BTEX during 2008-2010 in urban Beijing, China]. AB - Benzene, toluene, ethylbenzene and dimethylbenzene are typical anthropogenic emitted organics in the atmosphere, which not only endanger human health but also actively participate in photochemical reactions, generating O3 and secondary organic aerosols. In order to investigate the pollution level and its ozone formation potentials, concentrations of BTEX and O3 were parallel measured by the passive sampler and analyzed using GC-MS and ICS-90 during 2008-2010 in urban Beijing. The results show that toluene was the most abundant compound (8.7 +/- 3.1) microg x m(-3), followed by benzene, ethylbenzene and m/p-xylene, with concentrations of (7.1 +/- 3.3), (4.2 +/- 1.4) and (3.4 +/- 1.5) microg x m(-3), respectively. Concentrations of BTEX peaked in winter, followed by autumn, summer, and spring, with values of (26.8 +/- 12.1), (25.9 +/- 4.9), (24.7 +/- 2.8) and (16.8 +/- 1.4) microg x m(-3), respectively. Benzene concentrations were the highest in winter, while for toluene, the concentration was higher in summer than that in winter. Based on the maximum incremental reactivity scale, m/p xylene was found to be the dominant contributor to ozone formation among BTEX. The ozone formation potentials of BTEX in Beijing were 65.2, 60.2, and 75.7 microg x m(-3) in 2008, 2009, and 2010, respectively, which were consistent with the measured values of 80.5, 65.0, and 101.9 microg x m(-3) during the corresponding period. Vehicular emission and solvent evaporation were the major sources of BTEX. Concentrations of benzene were affected by coal heating in winter, whereas BTEX concentration was more influenced by solvent evaporation in summer, which had an important contribution to the formation of O3 in urban Beijing. PMID- 23947016 TI - [Aging and mixing state of particulate matter during aerosol pollution episode in autumn Shanghai using a single particle aerosol mass spectrometer (SPAMS)]. AB - A single particle aerosol mass spectrometer (SPAMS) was applied to characterize the size distribution (200 nm-2.0 microm) and chemical compositions of ambient particles during a polluted event from 11th to 18th, November 2011. OCEC, METAL, EC, SECONDARY and K-Na types of particulates were the dominant groups observed in hazy day period, which were 27.4%, 3.4%, 7.3% , 45.6% and 5.4% of the overall measured particles, respectively. The observed five types of particles contained the secondary composition such as 18NH4(+), 80SO3(-), 96SO4(-), 97HSO4(-), 46NO2( ), 62NO3(-) and 125H (NO3) -, showing that they probably went through different aging processes, and the increasing of the SECONDARY particles during the event clearly indicated a secondary aerosol pollution. Heterogeneous reactions of SO2 and particles could be the reason of strong 97HSO4(-) signals in the mass spectrums of OCEC type particles while the existence of organic compounds might have an important influence on the aerosol formation with the gas-phase sulfuric acid. Fresh EC particles in the environment tended to be aging with above mentioned secondary ions by the analysis of particle size distribution and eventually lead to a particle type conversion from EC to SECONDARY. Organic amine in marine environment was brought to the land by the warm, moist marine air mass that dramatically removed atmospheric SECONDARY and OCEC particles from the air with a heavy rain and leading to the observation of amine particles in the clean day period. PMID- 23947017 TI - [Chemical characteristics and source assessment of rainwater at Shenyang]. AB - To understand the origin and chemical characteristics of precipitation in Shenyang, about 25 rainwater samples were collected in 2007. The pH of samples varied from 4.89 to 8.02, with the volume-weighted average of 6.89. The results showed that the concentration of the sum of anions and cations in Shenyang was higher than those in southern cities such as Hangzhou, whereas the acidification of rainwater was not very serious in Shenyang. The volume-weighted average concentrations of SO4(2-) and Cl(-) were 330.00 microeq x L(-1) and 85.05 microeq x L(-1), with the percent contribution to anions of 60.32% and 15.55%, respectively. Ca2+ and NH4(+) were the main cations with contribution of 49.51% and 29.78%, respectively. The seasonal variations of ions showed that the concentrations were higher in autumn and winter than in spring and summer. Investigations of fractional acidity (FA), neutralization factors (NF), and correlation coefficients among ionic constituents indicated that high pH values were controlled by the neutralization caused by the alkaline materials but not by the absence of acidic materials. Results of NF indicated that NH4(+) and Ca(2+) were the dominant neutralization substances. Calculation of enrichment factors for rainwater components relative to soil and seawater indicated that SO4(2-) and NO3(-) were mostly attributed by the anthropogenic activities, 53.1% of Cl(-) originated from sea sources, and NH4(+) and K(+) came from the soils and human activities. PMID- 23947018 TI - [Variation of atmospheric pollutants in Qinhuangdao City]. AB - To illuminate the air pollution situation of the tourist city of Qinhuangdao, the atmospheric pollutants were measured from autumn 2009 to summer 2010. The results showed that the mean average concentration of NO, NO2, SO2, O3 and PM10 during the observation period reached (18 +/- 18), (45 +/- 18), (42 +/- 46), (44 +/- 25) and (128 +/- 77) microg x m(-3), respectively. The particulate matter pollution was serious, and the rate of the annual mean value exceeded the National Ambient Air Quality Standard II by 28%. The average daily concentration and average max hourly O3 concentration were (64 +/- 21)microg x m(-3) and (126 +/- 42) microg x m(-3) in summer, and the air masses from the southern ocean aggravated the O3 pollution. The concentrations of NO(x) SO2 and PM10 in the heating period were 1.5, 4.9 and 1.5 times more than those in the period without heating and the daily average concentration of SO2 and PM10 exceeded the National Ambient Air Quality Standard II by 53% and 11% in the heating period, respectively. The superimposition effect of regional transport in the Beijing-Tianjin-Hebei region and industrial area surrounding the Bohai Bay and local harbor emission led to an increase of 17% (NO(x)), 27% (SO2) and 12% (PM10), resulting in average concentrations of up to (100 +/- 49), (110 +/- 84) and (215 +/- 108) microg x m( 3) in winter. The winds from northern inland and southern ocean can effectively remove the air pollutants. PMID- 23947020 TI - [Synergetic effects of silicon carbide and molecular sieve loaded catalyst on microwave assisted catalytic oxidation of toluene]. AB - Molecular sieve loaded catalyst was prepared by impregnation method, microwave absorbing material silicon carbide and the catalyst were investigated for catalytic oxidation of toluene by microwave irradiation. Research work examined effects of silicon carbide and molecular sieve loading Cu-V catalyst's mixture ratio as well as mixed approach changes on degradation of toluene, and characteristics of catalyst were measured through scanning electron microscope, specific surface area test and X-ray diffraction analysis. The result showed that the fixed bed reactor had advantages of both thermal storage property and low temperature catalytic oxidation when 20% silicon carbide was filled at the bottom of the reactor, and this could effectively improve the utilization of microwave energy as well as catalytic oxidation efficiency of toluene. Under microwave power of 75 W and 47 W, complete-combustion temperatures of molecular sieve loaded Cu-V catalyst and Cu-V-Ce catalyst to toluene were 325 degrees C and 160 degrees C, respectively. Characteristics of the catalysts showed that mixture of rare-earth element Ce increased the dispersion of active components in the surface of catalyst, micropore structure of catalyst effectively guaranteed high adsorption capacity for toluene, while amorphous phase of Cu and V oxides increased the activity of catalyst greatly. PMID- 23947019 TI - [NH3, N2O, CH4 and CO2 emissions from growing process of caged broilers]. AB - To obtain Ammonia and greenhouse gas (GHG) emission factors of caged broilers, ammonia (NH3), methane (CH4), nitrous oxide (N2O) and carbon dioxide (CO2) emissions of broilers aged 0 d to 42 days were monitored in caged broilers production systems located in Shandong province. Gas concentrations of incoming and exhaust air streams were measured by using INNOVA 1312 multi-gas monitor with multi-channel samplers. Building ventilation rates were determined by on site FANS (Fan Assessment Numeration System) measurement systems. The NH3 emission factors showed a trend of increase at the beginning and then decreased with the broiler ages. The NH3 emission rates were 8.5 to 342.1 mg x (d x bird)(-1) and the average daily emission rate was 137.9 mg x (d x bird)(-1) [48.6 g x (d x AU)( 1)] over the 42-d period. The GHGs emission rates were 19.5-351.9 mg x (d x bird)(-1) with an average of 154.5 mg x (d x bird)(-1) [54.4 g x (d x AU)(-1)] for CH4, and 2.2- 152.9 g x (d x bird)(-10 with an average of 65.9 g x (d x bird)(-1) [23.2 kg x (d x AU)(-1)] for CO2. No emission of N2O was observed. The CH4 and CO2 emission rates increased with the increase of broilers ages. The total NH3 emission over the 42 d growing period averaged (5.65 +/- 1.02) g x (bird x life cycle)(-1). The NH3 emission contribution in different growth phase to the total emission were 33.6% in growth phase 1 (0-17 day, GP1), 36.4% in GP2 (18-27 days), and 29.9% in GP3 (28-42 days), respectively. The NH3 emission in GP2 was significantly higher than emission in GP1 and GP3. CH4 and CO2 cumulative emission rates were (6.30 +/- 0.16) g x (bird(-1) x life cycle)(-1) and (2.68 +/- 0.18) kg x (bird x life cycle)(-1), respectively. The cumulative emission rates of CH4 and CO2 in GP3 were significantly higher than emission rates in GP2 and in GP1, accounting for 50% of total emissions. The results of this study could provide the data support for mitigation of gas emission from broilers production. PMID- 23947021 TI - [Removal of mixed waste gases by the biotrickling filter]. AB - A biotrickling filter (BTF) was designed for treating mixed waste gases, which contained hydrogen sulfide (H2S), tetrahydrofuran (THF) and dichloromethane (DCM) at the start-up and steady states. The removal efficiency of H2S and DCM could maintain about 99% and 60%, respectively, and the removal efficiency of DCM was reduced from 90% to 37% with the shortening empty bed retention time (EBRT) form 50 to 20 seconds when the inlet concentrations were 200, 100, 100 mg x m(-3) of H2S, THF, DCM, respectively. In the theoretical study, the biodegradation efficiency of contaminants was H2S > THF > DCM by analyzing the Michaelis-Menten Dynamic model. PMID- 23947022 TI - [Decomposion of carbon disulfide by pulse corona under oxidizing and reducing atmosphere]. AB - The removal of CS2 by a wire-in-tube pulsed corona reactor was experimentally investigated. The effects of O2 and H2 in Ar gas on the removal of CS2 were examined. It was shown that the removal of CS2 increased with the increase of input pulse voltage. The decomposition of CS2 was improved in the presence of O2 in gas stream and the maximal removal was over 97%. The main gaseous products of CS2 decomposition with the addition of O2 in Ar gas were CO, CO2 COS and SO2, while, with the presence of H2 in Ar gas, the main products of CS2 decomposition were H2S and CH4. It was found that with the co-existence of sorbent Ca(OH)2 in the reactor, the gaseous products of CS2 decomposition (SO2 and H2S) were not detected, showing that the products were absorbed by the sorbent Ca(OH)2. It was also found that the removal of CS2 decreased when there was water vapor in gas stream. PMID- 23947023 TI - [Effects of simulated elevation of atmospheric CO2 concentration on the physiological features of spring phytoplankton in Taihu Lake]. AB - To disclose the impact of different CO2 concentrations (270 x 10(-6), 380 x 10( 6), 750 x 10(-6)) on physiological features of spring phytoplankton, an in situ simulated experiment was carried out in Meiliang Bay of Taihu Lake from 29 April to 26 May in 2012. The results showed that atmospheric CO2 elevation would significantly alter the pH value and carbonate chemical environments of Taihu Lake, resulting in weakening the advantages of carbon concentrating mechanism (CCM) of phytoplankton. Phytoplankton in Taihu Lake tended to use more dissolved CO2 (CO2, aq) due to the deliberate CO2 sequestration under the high CO2 level treatment. When atmospheric CO2 concentration doubles at the end of century, the maximum growth rate constant of phytoplankton (U(max)), NPP, chlorophyll a (Chl a)-specific NPP would increase by 63.1%, 69.6% and 33.8%, respectively. Atmospheric CO2 elevation promoted the maximum photosynthetic efficiency of chlorophyta and bacillariophyta in Taihu Lake and its promotion effect on bacillariophyta was more notable than that on chlorophyta. However, it did not change the photosynthetic efficiency of cyanobacteria which was very low in spring. Meanwhile, the stoichiometry value of phytoplankton changed significantly due to the CO2 elevation, as phytoplankton cells assimilated more C and N, but less P under the treatment of high CO2 level. Our results indicated the enhanced CO2 level could dramatically change the physiological features of phytoplankton. This information would help us to understand and predict the response of phytoplankton in Taihu Lake to the future climate change. PMID- 23947024 TI - [A new method for estimation the lake quality reference condition]. AB - It's a key step to estimate the nutrient reference condition of lakes for their nutrient criteria development. A new method was established to calculate the lake nutrient reference condition based the generally extreme statistical theory in the paper. The deficiencies, which lead to artificial error by grouping observed values and difficulty to do statistical inference and reliability evaluation in descriptive statistical methods, taking the frequency analysis as an example, can be overcome. The confidence intervals of parameters and substance concentrations can be obtained by this new method. This method was applied to estimate the reference conditions of Taihu Lake. The calculated results on total nitrogen (TN), total phosphorus (TP) and chlorophyll a (Chl-a) observed by two sites located in the central of Taihu Lake show that the negative minima data of every year fit the generally extreme statistical model well and the feasibility of the approach has been verified. The 25th percentile was recommended as reference conditions. Thus, values of reference conditions show that TN is 0.71 mg x L(-1), TP is 0.025 mg x L(-1) and Chl-a is 1.81 microg x L(-1). The 95% confidence intervals of each measurement was also obtained. PMID- 23947025 TI - [Parameter sensitivity analysis of runoff simulation and model adaptability research based on HSPF]. AB - Based on the sensitivity analysis of key parameters, we calibrated and validated HSPF model in a typical small watershed of hilly region in Tai Lake, and then evaluated the adaptability of the model in the hilly region of Tai Lake. In this study, 5 sensitivity parameters AGWRC, UZSN, INFILT, LZSN, and DEEPFR were determined by using the relative sensitivity method which is based on perturbation analysis, and then the annual runoff from 2005 to 2010 was simulated. The results showed good agreement with percent differences of - 6.39%, - 8.76% and 9.66%, respectively, which were all below 10% during the calibration period, and the simulation results were in a good range with percent differences of -13.31% and 5.22% during the validation period. The Nash-Sutcliffe (Ens) coefficients reached 0.87 and 0.69, respectively, and relative errors were 1.63% and 4.14%, which met the simulation requirements and could reflect the variation of annual runoff in Zhongtian River Basin. The results show that the HSPF model in the study area has better adaptability to watershed runoff simulation which has scientific significance to the simulated hydrological processes in the region and also provides reference for application and promotion of HSPF model in different regions in our country. PMID- 23947026 TI - [Study on water quality monitoring scheme based on non-point source pollution]. AB - In order to improve standardization and normalization of non-point source pollution monitoring, this paper summarized the non-point source pollution monitoring scheme that based on conventional technology condition. The scheme firstly emphasized the preparation work before monitoring, including situation investigation and index selection of the monitoring area and so on; In the process of establishing monitoring scheme, the monitoring area was divided into three types: city, agriculture and watershed. Take urban area monitoring scheme for Xi'an as an example, through dividing function zone setting sampling point, summarized sampling time interval, frequency and sampling methods during a rainfall process. An irrigation district was an example for agricultural monitoring scheme, through unit division, setting sampling point at the approach channel and drain channel, introduced sampling times, interval time and so on in the process of irrigation. Watershed monitoring scheme's example was the Weihe GuanZhong section, raised the setting principle of each sample section, and analyzed each section's sampling law in the process of rainfall. Finally the principal character of different non-point source pollution monitoring areas was discussed, and concluded that non-point source pollution monitoring scheme is the base of non-point source pollution study and control. PMID- 23947027 TI - [Characteristics of nutrient loss by runoff in sloping arable land of yellow brown under different rainfall intensities]. AB - In order to investigate the loss characteristics of N and P through surface flow and interflow under different rainfall intensities, a field experiment was conducted on the sloping arable land covered by typical yellow-brown soils inXiangxi River watershed by artificial rainfall. The results showed that the discharge of surface flow, total runoff and sediment increased with the increase of rain intensity, while the interflow was negatively correlated with rain intensity under the same total rainfall. TN, DN and DP were all flushed at the very beginning in surface flow underdifferent rainfall intensities; TP fluctuated and kept consistent in surface flow without obvious downtrend. While TN, DN and DP in interflow kept relatively stable in the whole runoff process, TP was high at the early stage, then rapidly decreased with time and kept steady finally. P was directly influenced by rainfall intensity, its concentration in the runoff increased with the increase of the rainfall intensity, the average concentration of N and P both exceeded the threshold of eutrophication of freshwater. The higher the amount of P loss was, the higher the rain intensity. The change of N loss was the opposite. The contribution rate of TN loss carried by surface flow increased from 36.5% to 57.6% with the increase of rainfall intensity, but surface flow was the primary form of P loss which contributed above 90.0%. Thus, it is crucial to control interflow in order to reduce N loss. In addition, measures should be taken to effectively manage soil erosion to mitigate P loss. The proportion of dissolved nitrogen in surface flow elevated with the decrease of rainfall intensity, but in interflow, dissolved form was predominant. P was exported mainly in the form of particulate under different rainfall intensities and runoff conditions. PMID- 23947028 TI - [Distribution of dissolved inorganic nutrients and dissolved oxygen in the high frequency area of harmful algal blooms in the East China Sea in spring]. AB - According to two cruises in the high frequency area of Harmful Algal Blooms (HABs) in ECS from Apr. 8th to 26th and May 7th to 14th 2010, concentrations and distributions of biogenic elements before and after HABs were analyzed, and their influenced factors were also discussed. The results showed that April was the earlier stage of HAB breaking out, and diatom was the dominant species; while Dinoflagellate became the dominant species when large-scale HAB broke out in May. The concentrations of DIN and PO4(3-) -P decreased significantly from April to May. The Mean value of DIN decreased from 18.04 to 10.80 micromol x L(-1), its decline rate was 40%. As for PO4(3-) -P, its Mean value decreased from 0.47 to 0.27 micromol x L(-1), and its decline rate was 43%. This phenomenon indicated the significant depletion of nutrients by harmful algae in the process. However, the primary species of HABs in ECS was dinoflagellates in May. Since dinoflagellates did not consume SiO3(2-) -Si during the breed, as well as the supplement from Changjiang Diluted Water, the mean value of SiO3(2-) -Si increased slightly from 16. 15 to 16.96 micromol x L(11) in the researched area. The Mean value of DO decreased from 8.76 to 6.09 mg x L(-1) from April to May, because the effect of temperature to DO was more obvious than that of phytoplankton photosynthesis. The temperature was higher in May, and the solubility of oxygen decreased with increasing temperature, therefore, the concentration of DO was lower after the Harmful algal blooms. PMID- 23947029 TI - [Temporal-spatial distribution of algal cells during drought period in Daning River of Three Gorges]. AB - In order to provide basic data for algal bloom warning system, the study on temporal-spatial distribution of algal cells was carried out in Daning River of Three Gorges form April to September, 2011. The results of temporal distribution were as follows: the dominant algal species were blue algal, green algal and diatom. During the test, the density proportion of blue algae increased continuously, the density proportion of diatom decreased, while the density proportion of green algae did not change significantly. The results of spatial distribution were as follows: algal density was extremely significantly correlated with water temperature and chlorophyll a (Chl a), the correlation coefficient were 0.97 and 0.95, respectively; algal density was significantly correlated with light intensity (LI), dissolved oxygen (DO), pH and dissoluble total phosphorus (DTP), the correlation coefficient were 0.87, 0.83, 082 and 0.82, respectively; the algal density in 0 m of Caziba was higher than those in other water depths, and in Baishuihe the highest algal density occurred at 2.0 m water depth in June and July, in Shuanglong most algal cells were found in 0 m and 2.0 m in July, August and September, in Dachang algal density in different water depth did not change significantly during the test; the proportion of different algal species in vertical direction was different in the test, probably because different algal species fitted different environments. PMID- 23947030 TI - [Bioavailability of dissolved organic nitrogen components in the lake sediment to alage]. AB - Samples in the sediments of Wuliangsuhai and Erhai Lake were selected, and the technologies of XAD-8 resins separation and three dimensional fluorescence excitation-emission matrix (3DEEM) spectra were applied, in order to study the bioavailability of dissolved organic nitrogen components to alage under the room cultivation. The obtained results showed that: (1) Average loss of DON and DOC from sediments was below 5% after dividing DON into different groups, which means the technology of XAD- 8 resins separation could be used in the study of DON components in the lake sediment. (2) Through 3DEEM analysis, hydrophilic and hydrophobic DON was dominated by protein-like and humic-like materials in the lake sediment, respectively. (3) Under the hydrophilic component condition, growth curves of algae tended to show an "S" shape with a straight upward trend in the sediments of Wuliangsuhai and Erhai lake,with the maximum algal density reaching 535.5 x 10(4) and 709.5 x 10(4) per milliliter, respectively. Meanwhile, the DON concentrations were significantly reduced after cultivation to 2.46 and 2.98 mg x L(-1), respectively, which suggests that hydrophilic DON in the lake sediment was the bioavailable organic nitrogen for alage. (4) Under the hydrophbic component conditions, growth curves of algae tended to show a "unimodal" shape in the sediments of Wuliangsuhai and Erhai lake,with the maximum algal density reaching 113.5 x 10(4) and 275.5 x 10(4) per milliliter,respectively. The DON concentrations were significantly reduced during the early cultivation period, and then kept stable in the late period, which suggests that the hydrophobic DON component bioavailable to alage was low in short-term, and the hydrophobic DON component had hardly any positive effect on the growth of algae. PMID- 23947031 TI - [Influence of decomposition of Cladophora sp. on phosphorus concentrations and forms in the overlying water]. AB - Sediments were sampled in the dominated zone of Cladophora sp. in Rongcheng Swan Lake, and cultivated with algae in the laboratory to reveal the influence of Cladophora decomposition on concentrations and forms of phosphorus in the overlying water. Concentrations of total phosphorus (TP), dissolved total phosphorus (DTP), soluble reactive phosphorus (SRP), particulate phosphorus (PP) and dissolved organic phosphorus (DOP) in overlying water were investigated, and some physicochemical parameters, such as dissolved oxygen (DO), pH and conductivity were monitored during the experiment. In addition, the influence of algae decomposition on P release from sediments was analyzed. Due to the decomposition of Cladophora, DO concentration in the overlying water declined remarkably and reached the anoxic condition (0-0.17 mg x L(-1)). The pH value of different treatments also decreased, and treatments with algae reduced by about 1 unit. Concentrations of TP and different P forms all increased obviously, and the increasing extent was larger with the adding algae amount. TP concentrations of different treatments varied from 0.04 mg x L(-1) to 1.34 mg x L(-1). DOP and PP were the main P forms in the overlying water in algae without sediments treatments, but SRP concentrations became much higher in algae with sediments treatments. The result showed that P forms released from decomposing Cladophora were mainly DOP and PP, and the Cladophora decomposition could also promote the sediments to release P into the overlying water. PMID- 23947032 TI - [Phosphorus exchange between suspended solids sediments overlying water under repeated disturbance]. AB - The variation of phosphorus (P) exchange between suspended solids, sediments and overlying water under repeated disturbance was investigated, with the sediments from Meiliang Bay (MLB) and Moon Bay (MB) as materials. The results showed that the concentrations of total P (TP) and particulate P (PP) decreased under repeated disturbance. Dissolved total P (DTP) reached equilibrium at 8 d, and was kept at 0.019 mg x L(-1) (MLB) and 0.039 mg x L(-1) (MB). On the contrary, dissolved inorganic P (DIP) increased in the overlying water, due to the highest concentration of NH4Cl-P in the sediments, and then decreased. It reached equilibrium at 8 d, and was kept at 0.013 mg x L(-1) (MLB) and 0.028 mg x L(-1) (MB). It was coincided with the variation of DO. In addition, the concentrations of DTP and DIP in MLB were higher than those of MB under repeated disturbance. The distribution of P forms (NH4Cl-P, Fe/Al-P, HCl-P) changed due to repeated disturbance. During the repeated disturbance, the concentrations of NH4Cl-P, Fe/Al-P and HCl-P decreased gradually. At the same time, the concentrations of TP, PP, DTP and DIP decreased in the overlying water, but the NH4Cl-P, Fe/Al-P, HCl-P increased in the sediments gradually. The trend in MB was not obvious, but the trend was the same as MLB. The results suggested that suspended solids were the medium in the phosphorus exchange between sediments and overlying water under repeated disturbance. PMID- 23947033 TI - [Distribution characteristics of PBDEs in surface sediment from the Three Gorges Reservoir of Yangtze River]. AB - A total of 28 surface sediment samples (at the top 0-5 cm layer) were collected from the Three Gorges Reservoir of Yangtze River. The content of polybrominated diphenyl ethers (PBDEs) in sediments was measured with Varian GC-MS (NCI). The results showed that sigma26 PBDEs and BDE209 both had a low concentration in sediments, with a mass concentration of 35.24 pg x g(-1) and 11.92 pg x g(-1), respectively. Among the 26 PBDEs, BDE28, 47, 77 and 99 were the most predominant sigma26 PBDEs congeners. The highest concentrations of sigma26 PBDEs and BDE209 were detected in the sediment samples collected from Long River, with geometric mean of 146.07 and 502.63 pg x g(-1), respectively. A significant correlation was found between sigma26 PBDEs and BDE209, indicating that they might have the same pollution source. The concentrations of sigma26 PBDEs and BDE209 in the sediment were in the same order of magnitude with those reported on background levels in sediments of remote lakes in other countries, which shows the toxic biological effects on aquatic biota and potential risk due to sigma26 PBDEs and BDE209 contamination in sediments are negligible. PMID- 23947034 TI - [Study on UV and H2O2 combined inactivation of E. coli in drinking water]. AB - The inactivation effect of E. coli with both UV irradiation and hydrogen peroxide disinfection individually and in different combination modes was investigated. The results showed that hydrogen peroxide alone caused hardly any inactivation of E. coli. Only 0.02 lg inactivation was achieved by hydrogen peroxide with concentration of 20 mg x L(-1) and contact time of 30 min. UV irradiation was able to inactivate E. coli to a certain extent. The inactivation reached 4.51 lg at a UV dose of 10 mJ x cm(-2). The combination of UV and H2O2 could significantly improve the inactivation effect and the different combination modes affected the inactivation effect. The inactivation effect of UV-H2O2 was better than that of H2O2 -UV. The inactivation was increased by 0.09, 0.35, 0.38, 0.68 lg and 0.01, 0.07, 0.14, 0.53 lg when compared to the treatment with solely UV irradiation, respectively, at UV dose of 5 mJ x cm(-2) with hydrogen peroxide at contact time of 2.5, 5, 10, 20 minutes. UV/H2O2 achieved better results than sequential disinfection. The inactivation was enhanced by 0.43 lg and 0.58 lg when compared to UV-H2O2 and H2O2-UV, respectively, at UV dose of 5 mJ x cm(-2) with hydrogen peroxide at contact time of 20 minutes. The inactivation of E. coli increased with the enhancement of UV radiation intensity. PMID- 23947035 TI - [Kinetics and influencing factors of dimethyl phthalate degradation in aqueous solution by ozonation]. AB - The rate constants for the reaction of higher concentrations of DMP with ozone and hydroxyl radical (*OH) were determined by competition kinetics method, in which nitrobenzene (NB) was selected as the reference organic compound. The effects of *OH inhibitor tert-butyl alcohol, pH and a variety of ions on the degradation of DMP were discussed. Experimental results showed that the degradation of DMP by ozonation followed pseudo-first-order kinetics. The rate constants of DMP with ozone and *OH were (0.064 +/- 0.014) L x (mol x s)(-1) and 3.59 x 10(9) L x (mol x s)(-1), respectively. The system pH decreased due to the carboxylic acids intermediates generated by ozonation at initial pH of 6.08 and 9.07, but the system pH was stabilized in strong alkali or acidic solution. A large number of intermediates resulted in the removal rate of COD lagging behind the degradation efficiency of DMP, and part of the intermediates were difficult to be mineralized. The reaction of DMP with *OH was not inhibited by lower concentrations of tert-butyl alcohol. But the reaction was inhibited when the concentration of tert-butyl alcohol was 90.21 times as high as that of DMP, and the degradation efficiency of DMP decreased from 98.7% to 8.8%. The degradation efficiency of DMP was higher with phosphate buffer solution for pH adjustment than NaOH/H2SO4 solution. Low concentrations of cations and anions had no effects on the degradation efficiency of DMP. High concentrations of SO4(2-), NO3(-) and HPO4(2-) had no remarkable effects on ozonation. But high concentrations of Cl(-) and HCO3(-) inhibited the degradation and the inhibitory effect of HCO3(-) was stronger than Cl(-). The degradation efficiency of DMP was only 50.5% and 26.2%, respectively, after 40 min under 7 097 mg x L(-1) of Cl(-) and 6 093 mg x L(-1) of HCO3(-). PMID- 23947036 TI - [Effects of nitrate ion on monomethylmercury photodegradation in water body]. AB - To study effects of nitrate (NO3(-)) on monomethylmercury (MMHg) photodecomposition (PD), laboratory experiments were conducted to investigate the role of NO3(-) in MMHg PD under various light radiations, and to examine effects of NO3(-) concentration gradients on MMHg PD rates and end products. We analysed the react processes according to Hg2+ concentration. The results indicated that in the reactor exposed to natural and ultraviolet radiation, and treated with NO3(-), the rates of MMHg PD were calculated to be 0.10 L x (ng x h)(-1) and 0.046 L x (ng x h)(-1), respectively, Hg(0) fluxes were 1.05 and 1.27 ng, respectively, and Hg2+ concentrations were 16.97 ng x L(-1) and 28.92 ng x L(-1) respectively. In the experiments which were not spiked with nitrate or spiked with benzoic acid, MMHg PD rates were calculated to be 0.052 L x (ng x h)(-1) and 0.015 L x (ng x h)(-1), respectively, Hg(0) fluxes were 23.81 ng and 15.38 ng, respectively, and all concentrations of Hg2+ (< 10 ng x L(-1)) represented a trend of increasing firstly and then decreasing. There were no differences among the reactions exposed to visible light (P = 0.56), the PD rate was about 0.003 L x (ng x h)(-1), Hg(0) flux was about 5 ng, and Hg2+ concentrations showed a trend of increasing firstly and then decreasing. In the reactor exposed to natural light, with the increasing concentration of NO3(-), MMHg PD rate increased, Hg(0) flux decreased, and Hg2+ concentration increased with respect to time. All results indicate that NO3(-) has a significant effect on the react process, PD rate, and end products. PMID- 23947037 TI - [Chlorination of ethynyl estradiol: a kinetic and mechanistic study]. AB - The objective of this research is to explore the fundamentals of reactions between chlorine and ethynyl estradiol (EE2), which is expected to occur during the drinking water treatment. The first step of EE2 chlorination was shown to follow the second-order kinetics with the first order to concentrations of both target compound and chlorine, respectively. Apparent rate constants of EE2 chlorination exhibit the pH-dependent profile which indicates that the phenolic ring is the preferred site of attack by Cl. The transformation of EE2 is governed by 3 elementary reactions between different species of EE2 and HClO. The deprotonated EE2 anion is significantly more reactive than its neutral conjugate. HPLC/MS analysis revealed that several Cl atoms can be incorporated into this site via complex multi-step pathways, resulting in the formation of mono and di chlorine substituted EE2. The incorporation of the third Cl is accompanied by immediate broken down of the ring via hydrolysis. The results of this study are helpful to fully understand the behavior of EE2 in chlorinated drinking water disinfection, provide the basis for evaluating the potential exposure of this contaminant to human. The data of this work also give insights to the formation of chlorinated drinking water disinfection by-products (DBPs). PMID- 23947038 TI - [Metal ions restrain the elimination of 4-tert-octylphenol by delta-MnO2]. AB - The effect of metal ions on elimination of 4-t-OP by synthetic delta-MnO2 suspension at pH 4.0 was studied. Experiments indicated that the removal of 4-t OP by delta-MnO2 achieved 100% at reaction time of 150 min. However, the removal of 4-t-OP by delta-MnO2 was restrained when metal ions were added, and the higher concentration of metal ion was, the stronger the inhibition produced. Additionally, there were apparent differences among the inhibitory effect of the tested metal ions. Firstly, Pb2+ and Mn2+ had the strongest effect at pH 4.0, followed by the transition metal ions, then the alkaline earth ions, while the alkali metal ions had little influence on the removal of 4-t-OP by delta-MnO2. Also comparing the adsorption results of metal ions by delta-MnO2, Pb2+ showed the greatest attraction with delta-MnO2, and among the other metal ions, transition metal ions were adsorbed a little more strongly on delta-MnO2 than alkaline earth metal ions. Consequences showed that the inhibitory effects of metal ions were due to their occupying reactive sites on delta-MnO2 surface, which competed with 4-t-OP. Moreover, the dissimilar suppressions were contributed by the different adsorption capacities, surface structure change of MnO2 and the difference of free metal ion percentage in solution as well as metal ions radii. PMID- 23947039 TI - [Removal of bisphenol A in aqueous solutions by core-shell magnetic molecularly imprinted polymers]. AB - This paper reports the preparation of surface-imprinted polymer core-shell magnetic material as adsorbent for separating bisphenol A in the environmental water. The adsorbent prepared easily achieved the magnetic separation under an external magnetic field. The structures of the resulting composites were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier transform infrared (FT-IR) analysis. The adsorption selectivity of Fe3O4@SiO2-MIPs for bisphenol A was demonstrated by equilibrium rebinding experiments and Scatchard analysis. Freundlich adsorption model can well describe the adsorption isothermals of bisphenol A with the correlation coefficients R2 = 0.995 2. The dynamics of bisphenol A adsorbed by Fe3O4@SiO2-MIPs can be well described by the pseudo second-order model (R2 = 0.999 9). In the solutions with weak acidity, the Fe3O4@SiO2-MIPs showed higher removal rate and rapid adsorption dynamical process, requiring only 40 min to reach a removal rate of 90%; the presence of ions did not affect the adsorption rate of bisphenol A; when compared with the non-imprinted polymer (Fe3O4@SiO2-NIPs), the Fe3O4@SiO2-MIPs showed outstanding affinity toward bisphenol A; the performance of the resulting composites (Fe3O4@SiO2-MIPs) without obvious deterioration was demonstrated in seven repeated cycles. PMID- 23947040 TI - [Research on removal of tetrabromobisphenol A from synthetic wastewater by nanoscale zero valent iron supported on organobentonite]. AB - The removal of tetrabromobisphenol A (TBBPA) in methanol aqueous solutions by nanoscale zero valent iron supported on organobentonite (NZVI-CMT) was studied. The effects of temperature, initial concentration of TBBPA and the dose of NZVI CMT on the degradation and debromination of TBBPA were investigated. The removal rate by NZVI-CMT reached 97.5% within 12 hours at 25 degrees C, when the initial concentration of TBBPA was 10 mg x L(-1). And the removal rate of NZVI-CMT was higher than those of two simple materials, namely organobentonite (CMT) and nanoscale zero valent iron (NZVI), as well as the sum of those two simple materials. In addition, NZVI-CMT exhibited a better reusable attribute, and the rate of the materials remained above 90% after being used for 3 times. Based on the identification of degradation products and analysis of the TBBPA removal by NZVI-CMT, the main reaction mechanism was suggested as adsorption and debromination, and higher reaction temperature was preferable for debromination. PMID- 23947041 TI - [Measurement of dissolved organic nitrogen with nanofiltration pretreatment and its distribution characteristics in landscape water]. AB - In this study, we present a nanofiltration (NF90, NF270) pretreatment to increase the precision of dissolved organic nitrogen (DON) measurements in water samples. The variations of DON measurements with and without NF pretreatment were investigated. And the effects on the removal of dissolved inorganic nitrogen (DIN) by NF90 and NF270 were compared. As shown in the results, the average removal rates reached 30.7%, 55.9% of NH4(+)-N, 50.0%, 73.1% of NO3(-) -N and 42.9%, 72.0% of NO2(-)-N for NF90 and NF270 pretreatment, respectively. NF270 was obviously more effective to remove the DIN species. Concentrations of DON measured using traditional methods varied from 0.09 to 0.46 mg x L(-1), with negative concentration (-0.08 mg x L(-1)) at site 2 and the DIN/TDN ratio ranged from 85.3% to 105%; while the concentrations of DON measurements varied from 0.03 to 0.58 mg x L(-1), and the DIN/TDN ratio ranged from 76.1% to 90.6% for NF90 pretreatment and varied from 0.10 to 0.59 mg x L(-1), and the DIN/TDN ratio ranged from 47.5% to 84.5% for NF270 pretreatment. The results indicated that nanofiltration pretreatment could effectively remove the DIN species, decrease the standard deviation of DON measurements and increase the precision of DON measurements. The distribution of DON in water samples of Beijing Olympic Forest Park was investigated. The results showed that there was seasonal variation in the concentrations of DON in landscape water from the Olympic Forest Park. And there was significant difference between the north and south part. The DON concentrations were less than 0.2 mg x L(-1) in November, March and May and higher in July in the north part, while the DON concentrations were lower in May and higher in November and March in the south part, ranging from 0.40-0.65 mg x L(-1). PMID- 23947042 TI - [Preparation of a novel modified hydrogel and study of its adsorption performance]. AB - A novel copolymer hydrogel poly(Hydroxyethyl methacrylate/N-Vinylformamide) [p (HEA/NVF)] was prepared by 60Co-gamma induced copolymerization, using low temperature radiation technique. Triethylenetetramine(TETA) was applied to modify the prepared hydrogel into an ammoniated hydrogel poly (Hydroxyethyl methacrylate/N-Vinylformamide) -TETA [p (H/V) -T]. The two hydrogels prepared were characterized by using FTIR spectrometry and the p (HEA/NVF) was scanned by SEM. Moreover, the p (H/V) -T hydrogels were analyzed by XPS before and after adsorption. The adsorption capacities of Pb2+, Cd2+ on p (HEA/NVF) and p (H/V)-T were investigated. And the effects of pH, time and initial metal ion concentration on the adsorption of Pb2+, Cd2+ by p (H/V)-T were examined in batch experiments. SEM photos showed that p (HEA/NVF) hydrogel is a macroporous polymer material. Compared to the p (HEA/NVF) hydrogel, the adsorption capacities of Pb2+, Cd2+ on p(H/V)-T increased by 700% and 600%, respectively. The adsorption behaviors for Pb2+ and Cd2+ confirmed that the adsorption on p(H/V)-T followed the pseudo-second-order rate equation and was fitted to both Langmuir and Freundlich adsorption model (R2 > 0.95). Besides, the adsorption capacities of p (H/V)-T increased with increasing pH values. The FTIR spectra verified that p (HEA/NVF) was indeed a copolymer of HEA and NVF monomers, and the multi-amine groups have been successfully grafted to the surface of the copolymer hydrogel. The XPS analysis concluded that the mechanism of Pb2+ and Cd2+ by p (HEA/MALA) could be the chelation between -NH2 and metal ions. PMID- 23947043 TI - [Photocatalytic reductive degradation of direct red 4BE by phosphotungstic acid]. AB - The photoreductive degradation of Azo-dye Direct Red 4BE (4BE) in aqueous solution was studied in a batch photoreactor, with phosphatotungstic acid (H3PW12O40, PW12) as the homogeneous catalyst and isopropanol as the electron donor. The parameters such as concentrations of PW12, isopropanol and 4BE, ionic strength were carefully evaluated. The results showed that 4BE could be reductively decolorized by heteropoly blue, which was produced by phosphatotungstic acid in the presence of isopropanol under UV irradiation. The decolorization rate reached 90.39% within 50 min at a pH value of 2.0, a 4BE initial concentration of 50 mg x L(-1), a PW12 and IS concentration of 600 mg x L(-1) and 0.13 mol x L(-), respectively. The decolonization rate of 4BE increased with the increase of PW12 and isopropanol concentrations until reaching a constant value. However, the first-order rate constants k for the degradation of 4BE decreased with the increase of the 4BE initial concentration. Mutual effects were found between the concentration of isopropanol and PW12 on the photocatalytic degradation of 4BE. Moreover, the concentration of salt showed a negative effect on the photoreductive degradation of 4BE. It was assumed that the charge-transfer occurred within the complex formed by heteropoly bule and 4BE, which led to the reduction of 4BE and regeneration of heteropoly bule. This study indicates that PW12/isopropanol/UV system could be used for the reductive degradation of azo dyes. PMID- 23947044 TI - [Wastewater treatment using a microbubble aerated biofilm reactor]. AB - Microbubble aeration is supposed to be able to provide potential advantage for aerobic biological wastewater treatment due to enhancement of oxygen mass transfer. Biofilm reactor is considered to be feasible for application of microbubble aeration. Shirasu porous glass (SPG) membrane was used for microbubble aeration in a biofilm reactor to treat synthetic municipal wastewater. The air permeability of SPG membranes, dissolved oxygen (DO) concentration, pollutant removal and oxygen utilization were investigated during the continuous operation of the bioreactor. The long-term stable continuous operation of the experimental system demonstrated the successful application of microbubble aeration in aerobic wastewater treatment processes. The air permeability of SPG membranes was influenced by its surface wettability and pore size. The air permeability of hydrophobic membrane was better than that of hydrophilic membrane. The air permeability could also be improved by increasing the pore size. DO concentration was affected by organic loading mainly at a certain air flux. The optimal SPG membrane area-based COD removal capacity of the experimental system was determined as 6.88 kg x (m2 x d)(-1). NH4(+)-N removal was mainly affected by DO concentration and its diffusion inside the biofilm. The simultaneous nitrification and denitrification was observed at a high organic loading rate. The oxygen utilization was much more efficient in microbubble aeration, compared to traditional bubble aeration, and it might be close to 100% at optimal running conditions. PMID- 23947045 TI - [Research on Fenton treatment of the biochemical processes effluent of bamboo industry wastewater]. AB - The decolorization and organic matter reduction of bamboo wastewater using Fenton oxidation was studied. Considering the cost and the removal efficiency, the optimal conditions were t = 30 degrees C, pH = 3.5, p(H2O2) = 1 665 mg x L(-1), c(Fe2+)/c(H2O2) = 0.072 and reaction time 3 h, with an initial COD and color concentration of wastewater of 430 mg x L(-1) and 1 500 times, under these conditions, the removal efficiency of COD and color could achieve 87.5% and 94.4%, respectively. It was found that the color reduction was higher than that of organics, and less affected by operation factors. The GC-MS analysis revealed that the chromophoric groups and auxochromic groups were greatly removed after Fenton treatment. The intermediates were mainly ester derivatives, and the by products included 1-iodo-tridecane and 1,1'-oxybisoctane. PMID- 23947046 TI - [Effect of Fe2+ on fermentation hydrogen production in an UASB]. AB - Fe2+ has an important effect on the production of hydrogen in a biological way. With the brown sugar as the substrate, the effect of biotechnology hydrogen production capacity of the Fe2+ concentration ranging from 0-1650 mg x L(-1) on the condition of anaerobic fermentation was studied. The results showed that appropriate divalent ions had the ability to enhance the hydrogen production. Biogas amounts and hydrogen content increased with increasing Fe2+ concentration from 0-450 mg x L(-1). Compared with the control group increased by 40.75%, the maximum biogas amount of 17.72 L was obtained at Fe2+ concentration of 450 mg x L(-1). And at the same time, the hydrogen content was 60.01 percent. Biogas amounts and hydrogen content decreased gradually when the concentration of Fe2+ was higher than 450 mg x L(-1). Therefore Fe2+ is one of important engineering parameters for the fermentative hydrogen production. PMID- 23947047 TI - [Influence of substrate concentration on PHA production using fermented sugar cane as substrate]. AB - PHA was a kind of biodegradable polymer produced by mixed microorganisms. In recent years, 3-stage PHA synthesis process (including substrate hydrolysis, culture selection, and PHA synthesis) was commonly used for PHA production. In this kind of process, culture selection is the key stage, which directly affects the PHA production efficiency. In order to deal with sludge bulking occurred in the culture selection system, this paper analyzes the influence of substrate concentration on culture selection efficiency as well as operation stability. Under different influent substrate concentrations of 560 mg x L(-1), 1 120 mg x L(-1) and 1 680 mg x L(-1), we confirmed that influent substrate concentration (COD) of 1 120 mg x L(-1) is the most suitable parameter for the bacteria enriching process after a long period of time under short SRT. After 94 days of cultivation, we achieved 50% of PHA content, 0.7145 COD/COD of PHA conversion rate and 0.191 2 mg x (mg x h)(-1) of specific PHA storage rate at the end of batch tests with nutrient starvation. The study also confirmed that glycogen level in cells has a close relationship with its PHA synthesis ability, which shows its potential to predict the enrichment efficiency. PMID- 23947048 TI - [Study on rapid start-up of a nitrifying process using aerobic granular sludge as seed sludge]. AB - Using synthetic ammonia-rich wastewater as influent, rapid start-up of the nitrification reactor was attained in a laboratory-scale column-type sequencing batch reactor (SBR) inoculated with aerobic granular sludge, by gradually increasing the influent NH4(+) -N concentration (100-1000 mg x L(-1)) and decreasing the hydraulic retention time (8-4 h) under mesophilic condition (28-30 degrees C). The influent loading rate of NH4(+) -N reached 3.9 kg x (m3 x d)(-1) and the average ammonia removal efficiency was above 95% within one month. Values of ammonia oxidizing rate (AOR) as high as 5.0 kg x (m3 x d)(-1) was obtained in the following operational stage with extremely high nitrogen loading rate. Nitrite accumulation obviously occurred during the start-up period. The nitrite accumulation rate reached 2-4.5 kg x (m3 x d)(-1) from day 25 to 70. In spite of the change in the feeding composition (COD/N ratio) and the frequent fluctuations of nitrogen loading rate, the granules maintained their structures, with the SVI of 30-40 mL x g(-1). The amount of granules with diameter larger than 0.21 mm was about 93% (mass fraction) of the total on day 36. The granular color changed from yellow to brownish-yellow, and some turned brown in this study. All these results suggested the critical role of aerobic granular sludge as seed sludge for the rapid start-up of nitrifying processes and the formation of nitrifying granules. PMID- 23947049 TI - [Influencing factors of high-concentration lead removal using the phosphorus accumulating sludge]. AB - Phosphorus-accumulating activated sludge was used to remove lead [rho(Cu2+) = 150.0 mg x L(-1)] in wastewater in this experiment. The efficiency ratio and stability of Pb removal were studied at different dissolved oxygen concentration and different initial pH. The result showed that under anaerobic condition and pH 6, the Ph removal efficiency ratio increased with time elapsing, the value reached 99.8% after 32 days. Lead in form of organic and sulfide-bound lead and residual lead in residual sludge accounted for 41.8% and 52.6%, respectively, and the lead in the sludge showed a good stability. While under aerobic condition, the lead removal efficiency ratio increased with the increase of pH within the first 2 hours, the values reached 99.9%, 96.9% and 30.3% at pH 6, pH 4 and pH 2, respectively. In contrast, the residual lead was 3 072.3, 4 726.8 and 2 359.1 mg x kg(-1) under aerobic condition after 32 days, accounting for 41.8%, 65.8% and 88.8% of total lead in the sludge. Taking the lead removal efficiency ratio and lead stability into account, aerobic condition at pH 4 is the best for removing lead with phosphorus-accumulating sludge in theory. PMID- 23947050 TI - [Preliminary study on characteristics of volumetric oxygen transfer coefficient in granular sludge systems]. AB - The volumetric oxygen transfer coefficient (k(L)a) was tested with mature aerobic granules in the same aeration measurement device and under the same aeration conditions. The k(L)a (min(-1)) was 0.586 1 +/- 0.009 5, 0.586 1 +/- 0.0272, 0.555 6 +/- 0.016 8, 0.5338 +/- 0.0268 for floc sludge, and 0.645 5 +/- 0.027 6, 0.632 0 +/- 0.0755, 0.618 5 +/- 0.062 5, 0.640 6 +/- 0.055 5 for aerobic granules, when the sludge concentration MLSS (mg x L(-1)) was controlled at 2 000, 4 000, 6 000, 8 000, respectively. This indicated that granular sludge exhibited higher k(L)a values than the flocs, and the k(L)a value of floc sludge decreased with the increase of the sludge concentration; however, insignificant decease was found for granular sludge. After screening of granules with different diameter, the k(L)a values of the aerobic granular sludge with different sizes which had the same MLSS, volume, surface area and particle number were compared, and insignificant difference was found, suggesting that the effects of these factors on the k(L)a of granular sludge were negligible. The findings of this work may have significance for the energy-saving operation of wastewater treatment plants. PMID- 23947051 TI - [Ecological risk assessment of bisphenol A in Chinese freshwaters]. AB - Bisphenol A (BPA) has many toxic effects on aquatic organisms, of which the most obvious effect is the estrogenic effect. The data collected in the study were divided into two parts, based on the response of the tested organisms to the estrogenic effects of BPA and their exposed time, and the risk of BPA to Chinese aquatic water was assessed by using quotient method, quotient exponent and probability method, safety threshold value method and joint probability risk assessment, respectively. Similar results were derived from the above four methods. Aquatic organisms were more sensitive to the estrogenic effects of BPA than other toxic effects. The results of risk assessment from safety threshold value method were more accurate and confident than the other three methods. Using the chronic data of BPA's estrogenic effect on tested organisms as the endpoint for risk assessment in safety threshold value method, it was found that in 64.70% of the Chinese freshwaters more than 5% of aquatic organisms were affected by the estrogenic toxicity of BPA, and the maximum allowable concentration of BPA was 15.72 ng x L(-1). Using the acute data of such effects as endpoint in safety threshold value method, in about 20.43% volume of the Chinese freshwaters more than 5% of aquatic organisms were affected by the estrogenic toxicity of BPA, and the maximum allowable concentration was 2.24 x 10(2) ng x L(-1). PMID- 23947052 TI - [Species sensitivity evaluation of Pseudorasbora parva]. AB - Acute toxic effects of cadmium and copper to Pseudorasbora parva and copper to Daphnia magna were tested in this study. Then comparative analysis of species sensitivity of P. parva to six typical pollutants was performed with toxicity data from our experiments and published literatures. The result showed that: (1) P. parva was generally sensitive to various pollutants, especially to organic pollutants, and it was relatively most sensitive to pesticides. P. parva might be an indicator organism in organic pollution monitoring and a representative testing organism in the development of water quality criteria. (2) Cyprinidae was sensitive to various pollutants in fish sensitivity distribution, therefore the toxicity data of Cyprinidae should be given more attention in the study of water quality criteria and environmental monitoring. (3) P. parva was sensitive to various pollutants, and it had a stable position in fish sensitivity rank. This study indicated that P. parva might be an ideal indicator organism in environmental monitoring and a potential model organism in water quality criteria considering that it has a small size and is easy to obtain. PMID- 23947053 TI - [Comparison of aquatic predicted no-effect concentrations (PNECs) pentachlorophenol derived from different assessment approaches]. AB - Predicted no-effect concentration (PNEC) is the key for ecological risk assessment and has become a focus of the study. Generally, extrapolation was used to derive PNEC values by different evaluation approaches according to results of single species toxicity test. However, PNEC values were different for the same toxicity data for the same chemicals if extrapolation methods were different. To evaluate PNEC values derived by different assessment methods, PNEC values of pentachlorophenol (PCP) were calculated using three different approaches, i. e. point estimation, statistical evaluation as well as interval evaluation. At the same time, the main factors controlling PNEC values were analyzed. The results showed that PNEC values for PCP by different assessment factors were 0.420 microg x L(-1) for acute toxicity data and 0.500 microg x L(-1) for chronic toxicity data, respectively. The PNEC values for PCP by statistical evaluation were 10.1 microg x L(-1) for probit unit and 8.10 microg x L(-1) for logit unit. The values derived by interval evaluation were 6.00 microg x L(-1) for PNEC-L95% and 11.8 microg x L(-1) for PNEC-L50%, respectively. PNECs obtained by the point estimation were the lowest and lower one order of magnitude than the PNEC values obtained by the other two methods. The PNEC values derived by the statistical assessment and interval evaluation were very similar. In addition, toxicity data type and statistical models have little effect on PNEC value for PCP with a great body of toxicity data. The results indicated that statistical evaluation and interval evaluation methods should be selected to derive PNEC values for well studied substances like PCP, while point estimation should be used in preliminary screening assessment of chemicals to determine whether the effect is of concern. PMID- 23947054 TI - [Study on hair Hg and Pb content distribution of traffic polices, Guilin]. AB - 95 hair samples from traffic polices and 110 hair samples from ordinary people were collected from 6 areas of Guilin, China, and Hg, Pb contents in hairs were determined. The result shows that the heavier the traffic was, the higher hair Hg, Pb contents of traffic polices are. Hair Hg, Pb contents of traffic polices also increase with their working time. Average hair Hg, Pb contents of outdoor polices are higher than those of indoor polices. The average hair Hg content (1.340 microg x g(-1)) of traffic polices is 1.74 times as high as the Chinese average value (0.77 microg x g(-1)), while the average hair Pb content (2.877 microg x g(-1)) is below the Chinese average value (6.60 microg x g(-1)). The use of unleaded petrol reduced the air Pb pollution, but Hg pollution still exists. The average hair Hg content (1.504 microg x g(-1)) in male traffic polices is higher than that (1.176 microg x g(-1)) of female traffic polices,while the average hair Pb content (2.852 microg x g(-1) in male traffic polices lower than that (2. 902 microg x g(-1)) of female traffic polices. PMID- 23947055 TI - [Changes in phototaxical index of Daphnia carinata under electric field of direct current in response to Cr6+ and Hg2+]. AB - In order to detect toxicants sensitively in water by phototaxity of Daphnia, we studied the influence of DC electric field on phototaxity of self-bred Daphnia carinata, a mono-clone with high phototaxity, and the changes of their phototaxity in response to Cr6+ and Hg2+ after the treatment of DC electric field. The result indicated that the treatment of DC electric field changed their phototaxical indexes from positive to negative as the electric density increased and the time prolonged. The criteria values that showed no sign of changes in the phototaxical index of Daphnia carinata were 0.01 mA for 5 min. However, the limit for detecting Cr6+ and Hg2+ by their phototaxical index decreased significantly after treatment with 0.01 mA/5 min. The detection limits were only 32 microg x L( 1) for Cr6+ and 4.2 microg x L(-1) for Hg2+ after this treatment, much lower than those without pretreatment (56 microg x L(-1) for Cr6+ and 5.6 microg x L(-1) for Hg2+, respectively). Therefore, appropriate DC electric field to pre-treat Daphnia could decrease the detection limit, widen the concentration range of detection, and increased the sensibilities in water monitoring. PMID- 23947056 TI - [Effect of UV-B radiation on the chemical composition and subsequent decomposition of Cyclobalanopsis glauca leaf litter]. AB - A experiment on leaf litter decomposition was carried out to evaluate the effects of UV-B radiation on the chemical composition and subsequent decomposition of leaf litter in humid subtropical forest systems. The leaf litter was derived from Cyclobalanopsis glauca seedlings exposed to elevated and ambient ultraviolet B (UV-B) radiation treatments during growth for one year. The results showed that UV-B treatment significantly increased the original N, K and P content of leaf litter by 154.9%, 29.8% and 9.7%, respectively, and decreased the ratios of C: N, lignin: N and C: P of leaf litter by 60.5%, 61.7% and 8.5%, respectively (P < 0.05), but had no significant effect on C and lignin content. The decomposition of leaf litter derived from seedlings exposed to elevated UV-B treatment during growth was faster, but did not show significant difference from that of ambient UV-B treatment. Exposure to elevated UV-B radiation during growth did not significantly influence the K release, but promoted the P release and retarded the N accumulation during leaf litter decomposition. Our result will contribute to the better understanding of the role of UV-B radiation in moist subtropical forest ecosystem. PMID- 23947057 TI - [Leaf micro-morphology and features in adsorbing air suspended particulate matter and accumulating heavy metals in seven trees species]. AB - The purpose of this study was to assess the relationship between tree leaf micro morphology and features in adsorbing air suspended particulate matter and accumulating heavy metals. Seven tree species, including Ginkgo biloba, at heavy traffic density site in Huainan were selected to analyze the frequency of air particulate matter retained by leaves, the particle amount of different sizes per unit leaf area retained by leaves and its related micro-morphology structure, and the relationship between particle amount of different sizes per unit leaf area retained by leaves and its related accumulation of heavy metals. We found that the species characterized by small leaf area, special epidemis with abundant fax, and highly uneven cell wall, as well as big and dense stomata and without trichomes mainly absorbed fine particulate matter; while those species with many trichomes mainly retained coarse particulate matter. Accumulation of heavy metals in leaves of the seven species was significantly different except for Ph. Tree species with high capacities in heavy metal accumulation were Ginkgo biloba, Ligustrum lucidum, and Cinnamomum camphora. Accumulation of Cd, Cr, Ni, Zn, Cu and total heavy metal concentration for seven tree species was positively related to the amount of particulate matter absorbed. Correlation coefficients of d10 vs d2.5, d10 vs d1.0, d2.5 vs d1.0 were 0.987, 0.971, 0.996, respective, and the correlate level was significant. The ratios of d2.5/d10, d1.0/d10, d1.0/d2.5 were 0.844, 0.763, 0.822, indicating that the particulate matter from traffic was mainly fine particulates. PMID- 23947058 TI - [Effect of dissolved oxygen on microbial community in simultaneous removal of carbon, nitrogen and sulfur process]. AB - In order to investigate the effect of dissolved oxygen (DO) on microbial community in simultaneous removal of carbon, nitrogen and sulfur process and reveal the mechanism of high elemental sulfur conversion rate under aerobic condition, GeoChip was employed to characterize the structure of microbial community. The results indicated that the microbial community structure significantly changed with different aerobic conditions (P < 0.001). Diversity indices of microbial community increased at relatively high DO level. However, denitrifiers were greatly inhibited at this level due to the high sensitivity to DO. There was no significant change detected in the abundance of sulfate-reducing bacteria (SRB) with the changing DO. The relative abundance of sox gene showed significant difference between aeration rate of 20 mL x min(-1) and aeration rate of 0 mL x min(-1), which might suggest that the activity of sulfur-oxidizing bacteria (SOB) was obviously improved by DO. Moreover, cluster analysis of sox gene confirmed this suggestion, with higher signal intensity found in numbers of probes derived from SOB under such aerobic conditions. Overall, the results revealed a positive effect of micro-aerobic conditions on the simultaneous removal of carbon, nitrogen and sulfur process. PMID- 23947059 TI - [Microbial activity and community structure analysis under the different land use patterns in farmland soils: based on the methods PLFA and MicroResp]. AB - Soil microbe plays an essential role in terrestrial ecosystem through its role in cycling mineral compounds and decomposing organic matter. The objective of this paper is to determine the influences of different land use patterns on soil microbial activity and community structure, which were analyzed by phospholipids fatty acid (PLFA) and MicroResp method, based on a long-term fertilization experiment in Taoyuan County, Hunan Province. There were three land use patterns included, i. e. paddy fields (PS), paddy-upland rotation (PU) and upland land (US) soils. The results showed that the amounts of bacteria PLFA, fungi PLFA and the total PLFA were generally following the order PS > PU > US. The ratio of bacteria PLFA/fungi PLFA followed the order PU > US > PS, however, the ratio of Gram-positive bacteria PLFA (G+ PLFA) to Gram-negative bacteria PLFA (G(-) PLFA) in PU was the highest, and there's no significant difference in PU and US. In addition, principal components analysis (PCA) and the average concentration (mol x mol(-1)) of biomarker-PLFAs also revealed that the relative content of fungi and G(-) in PS was much higher than those of in PU and US (P < 0.05). However, the relative content of G(+) in PU was higher than those of other two land use patters. Therefore, Microbial community structure was influenced significantly by land use patterns in our study. Soil microbial biomass had significant relationships (P < 0.05) with SOC, TN and MBC, but had no significant correlation with CEC. Meanwhile, MicroResp analysis indicated that most of the carbon substrate addition enhanced the microbial respiration rates, although different substrate had different use efficiency. The average of carbon substrate use efficiency could be also ranked in the order: PS > PU > US. We conclude that microbial activity and community structure were influenced significantly by land use patterns in farmlands. PMID- 23947060 TI - [Effects of drying-rewetting alternation on nitrogen, dynamics in a typical coastal wetland: a simulation study]. AB - The coastal wetland, a key transitional zone between land and ocean, is a complex and sensitive ecosystem with special environmental processes and functional values. Sediment and sea water samples were taken from Chongming east intertidal flat, a typical coastal wetland in China. Sediment cores were incubated under simulated spring tides (approximately twice a month) and semi-diurnal tides (two almost equal high tides and two low tides in a lunar day), to define the responses of nitrogen to periodic alternation of drying and re-flooding. The contents of NO3(-) -N, NO2(-) -N, NH4(+) -N, dissolved organic N (DON), and the activities of nitrate reductase (Nar), nitrite reductase (Nir), and hydroxylamine reductase (Hyr) in sediments were determined during the incubation. Nitrification stood in a dominant position during the drying period with sediment moisture decreasing from 35% to 5% -7% in simulated spring tides. The NO3(-) -N and NO2(-) -N were found to be substantially converted into DON following a further exsiccation (the sediment moisture decreased from 5%-7% to 0%-3%). However, the conversion rates decreased with the increase of drying and rewetting cycles. Following the rewetting of dried sediments (from 0% -3% to 37% -45%), the contents of NO3(-) -N, NO2(-) -N, NH4(+) -N and DON increased to 1 to 3 times that of the dry sediments. Nar and Nir activities in sediments rapidly increased after the rewetting, indicating that the reduction of NO3(-) -N and NO2(-) -N were substantially enhanced. Significant positive correlations were found between Nar and Nir activities, and Hyr activities and NH4(+) -N contents during the simulated spring tides. Moreover, the decreases of NO3(-) -N and NO2(-) -N contents were observed to be significantly correlated to the increases of NH4(+) N contents. Combined with the fact that the sediment had a high organic carbon content but a very low NO3(-) -N content, it can be concluded that the reduction of NO3(-) -N and NO2(-) -N following the rewetting was dominated by nitrate ammonification. In contrast, NO3(-) -N, NO2(-) -N, NH4(+) -N and DON contents in sediments were relatively stable during semi-diurnal tides, which were (3.0 +/- 0.3), (1.2 +/- 0.1), (133.3 +/- 4.3) and (41.1 +/- 10.6) mg x kg(-1), respectively. This indicated that semi-diurnal tides slightly affected the variations of nitrogen contents in the wetlands. PMID- 23947061 TI - [Cadmium and selected heavy metals in soils of Jianping area in Wushan County, the Three Gorges region: distribution and source recognition]. AB - Abnormally high cadmium (Cd) concentrations were existed in soils of Jianping area in the Three Gorges region, but little information is available about the geochemical distribution of Cd and source identification. In the present paper, total contents of Cd and other selected heavy metal elements, the characteristics of soil, the contents of Cd in typical soil profiles, and chemical forms of Cd in selected soils were studied. The correlation analysis, the principal component analysis, and the comparison between different soil types were conducted. The concentration distribution of Cd and selected elements in local soils was investigated and their sources were identified. The results showed that Cd in local rocks, coal and coal wastes ranged from 0.22-101 mg x kg(-1), 0.42-42 mg x kg(-1) in the arable topsoil, and 0. 12-8.5 mg x kg(-1) in natural soils. The soils were also rich in other elements such as V, Cr, Ni and Zn. The weak acid fraction of Cd accounted for 17%-35% of total contents. This study demonstrated that soils from the Jianping area of Wushan County had a serious Cd pollution, and both local rocks and soils display a significant geochemical interrelation. Cd particularly accumulates in the topsoil, and it is mainly derived from the geogenic source. Human such as the historical coal mining may overload Cd in the soils. The local soils had a high portion of bioavailable Cd, through which Cd may easily transfer to and accumulate in the local crops growing in the Cd-rich soils and cause potential health risk to local residents. PMID- 23947062 TI - [Total contents of heavy metals and their chemical fractionation in agricultural soils at different locations of Beijing City]. AB - In this study, 23 groups of suited typical soil-wheat grain samples were collected from different locations of Beijing city (central city, suburban plain and exurban plain), the accumulation, chemical forms and bioavailability of heavy metals in arable soils under different human activity intensity were analyzed, and their source identifications and health risk were discussed. The results showed that (1) Urban soils exhibited Pb contamination with an average concentration (35.59 mg x kg(-1)) above the WHO limit, probably due to the emission of traffic activities and industrial processes. In addition, long-term sewage irrigation and other agricultural activities led to local metal contamination in the suburban agricultural soils. (2) Cu, Zn and Pb were predominantly associated with the residual (35%-75%) and organic (23%-53%) fractions, followed by Fe/Mn oxide (1%-19%), and very small proportion of carbonate (n. d.-5%) and exchangeable (n. d.-2%) fraction. Furthermore, compared with the suburban agricultural soils, Pb, Zn and Cu in the urban agricultural soils showed higher mobility, whereas the exurban agricultural soils presented the lowest mobility. For Cd, the order was contrary. Besides, Cd showed the highest bioavailability among the four metals in suburban and exurban arable soils due to its considerable proportion of exchangeable (13% -31%) and carbonate fractions (11%-27%). (3) Cd and Zn contents in wheat grains were largely dependent on the Fe/Mn ox. fractions in the studied soils (P < 0.05, r were 0.43 0.7). (4) Pb and Zn concentrations in wheat grains in some of the urban and suburban agricultural soils were above the standard limit, which might bring potential risk for the health of the local residents. PMID- 23947063 TI - [Influence of season change on the level of heavy metals in outdoor settled dusts in different functional areas of Guiyang City]. AB - To study the influence of season change on the level of heavy metal in outdoor settled dusts at both city and functional area scale, dust samples were collected in July 2010 and February 2011 from different functional areas in the Guiyang City. The results showed that among all heavy metal elements involved, Pb and As were most significantly affected by season change, with a significantly higher amount in winter than in summer, mostly accumulated in smaller particles of dust. Functional areas where heavy metal concentrations were most significantly affected by seasons were city square and school area, and followed by residential area. Elements that showed the greatest difference in distribution pattern in different fractions between summer and winter were As and Pb, while the functional areas that were most severely influenced were city square and school area, followed by residential area. The isotopic ratio analysis showed that the Pb in the outdoor settled dust in Guiyang was partly contributed by Diesel exhaust dust, paint chip and soil. Summer precipitation, coal-burning in winter and temperature difference between summer and winter may contribute to the seasonal change of the level of Pb and As in the dusts. PMID- 23947064 TI - [Characteristics of dioxin-like polychlorinated biphenyls contamination in soils of Gudao Region in Dongying]. AB - To investigate pollution characteristics of dioxin-like polychlorinated biphenyls (DL-PCBs) in Gudao Region, Dongying City, twenty surface soil samples were collected in April, 2011. The DL-PCBs in soil samples were determined by Soxhelt extraction-Florisil purification-Gas Chromatography(GC)-Electron Capture Detector (ECD). The concentration of DL-PCBs in surface soils ranged from 1.4 microg x kg( 1) to 7.4 microg x kg(-1), with the mean concentration of (3.5 +/- 1.7) microg x kg(-1). The total TEQ level was between 1.2 ng x kg(-1) and 31.8 ng x kg(-1), and the mean TEQ was 5.4 ng x kg(-1), which exceeded the Canadian soil environment quality guidelines (4.0 ng x kg(-1)). The congener profiles of DL-PCBs were similar among sites. Tetra-CB and penta-CB were the major homologues in all soil samples, together accounting for more than 80% of the total DL-PCBs. The level of DL-PCBs exhibited a decreasing trend with the increasing distance from the Gudao town to the suburb, which could be attributed to the chemical plants around the town. The correlation analysis showed that the concentration of DL-PCBs was positively correlated with the organic matter content and clay particle content (R2 were 0.732 and 0.687, separately, P < 0.01), but negatively correlated with the sand particle content (R2 = -0.438, P < 0.05). PMID- 23947065 TI - [Effects of simulated nitrogen deposition on organic matter leaching in forest soil]. AB - The impact of nitrogen deposition on the dynamics of carbon pool in forest soil was studied through a field experiment at Tieshanping, Chongqing in Southwest China. The changes of dissolved organic matter (DOM) concentration in soil water in different soil layers were monitored for five years after addition of ammonium nitrate (NH4NO3) or sodium nitrate (NaNO3) at the same dose as the current nitrogen deposition to the forest floor. The results indicated that the concentration and flux of dissolved organic carbon (DOC) were increased in the first two years and then decreased by fertilizing. Fertilizing also reduced the DOC/DON (dissolved organic nitrogen) ratio of soil water in the litter layer and the DOC concentration of soil water in the upper mineral layer, but had no significant effect on DOC flux in the lower soil layer. Although there was generally no effect of increasing nitrogen deposition on the forest carbon pool during the experimental period, the shift from C-rich to N-rich DOM might occur. In addition, the species of nitrogen deposition, i. e., NH4(+) and NO3(-), did not show difference in their effect on soil DOM with the same equivalence. PMID- 23947066 TI - [Ex-situ remediation of PAHs contaminated site by successive methyl-beta cyclodextrin enhanced soil washing]. AB - Polycyclic aromatic hydrocarbon (PAH) polluted sites caused by abandoned coking plants have attracted great attentions. This study investigated the feasibility of using methyl-beta-cyclodextrin (MCD) solution to enhance ex situ soil washing for extracting PAHs. Treatment with elevated temperature (50 degrees C) in combination with ultrasonication (35 kHz, 30 min) at 100 g x L(-1) was effective. It was found that 96.7% +/- 2.4% of 3-ring PAH, 89.7% +/- 3.2% of 4-ring PAH, 76.3% +/- 2.2% of 5 (+6)-ring PAH and 91.3% +/- 3.1% of total PAHs were removed from soil after five successive washing cycles. The desorption kinetics of PAHs from contaminated soil was determined before and after successive washings. The 400 h Tenax extraction of PAHs from soil was decreasing gradually with increasing washing times. Furthermore, the F(r), F(sl), k(r), k(sl) and k(vl) were significantly lower than those of CK (P < 0.01). Therefore, considering the removal efficiency and potential environmental risk after soil )ashing, successive washing three times was selected as a reasonable parameter. These results have practical implications for site risk assessment and cleanup strategies. PMID- 23947067 TI - [Effects of Bacillus mucilaginosus on the Cd content of rhizosphere soil and enzymes in soil of Brassica juncea]. AB - The effects of two inoculation concentrations of Bacillus mucilaginosus (1 x 10(10) (treatment A), 2 x 10(10) (treatment C) CFU x kg(-1)) on the Cd content of rhizosphere soil and enzymes in soil were investigated when Brassica as a hyperaccumulator grew in the pots experiment. The results showed that the removal rate of rhizosphere soil Cd in treatment A and C were 37.62% and 38.27%, respectively, which were 1.54 and 1.56 times as high as that of the control (24.47%). The activities of urease, phosphatase and catalase in rhizosphere were higher than those in non-rhizosphere. The urease, catalase and dehydrogenase activities increased firstly and then decreased, while the phosphatase activity increased gradually with time. However, the dehydrogenase activity in non rhizophere was higher than that in rhizosphere. Correlation analysis showed negative correlation between content of Cd and urease and phosphatase in the control treatment and significantly negative correlation between content of Cd and activities urease and phosphatase in treatment A and C in rhizosphere. The results indicated that inoculation of Bacillus mucilaginosus not only had some positive effect on urease, phosphatase, catalase and dehydrogenase in soil but also improved the purification effect of hyperaccumulator on soil Cd. This study provides theoretical guidance for the further mechanism study of Microbe Phytoremediation. PMID- 23947068 TI - [Concentrations of antibiotics in vegetables from manure-mended farm]. AB - Sixteen typical antibiotics including four tetracyclines, four quinolones, and eight sulfonamides in vegetables from manure-amended farm were determined using the ultra high performance liquid chromatography-tandem mass spectrometry and their health risks to human via the diet pathway was assessed. Most antibiotics were frequently detected in vegetable samples, with the detection rate from 11% to 90%. Concentrations of a single compound were mainly less than 5 microg x kg( 1) (D. W.), with the maximum of 23.88 microg x kg(-1) and the average of 0.91 microg x kg(-1), respectively. Norfloxacin, ciprofloxacin, sulfamehtaoid and sulfadiazine were the dominant compounds. At least one antibiotic was detected in a single vegetable samples, and even up to ten antibiotics. The concentration of quinolones in underground parts was higher than those in aboveground parts. Intake dose of antibiotics via the consumption of the detected vegetables was lower than ADI, suggesting a lower health risk. But combination toxicity and resistance of antibiotics should not be ignored. PMID- 23947069 TI - [Characteristics of organic nitrogen mineralization in organic waste compost amended soil]. AB - A laboratory aerobic incubation experiment was conducted under a constant temperature to investigate the differentiation rule of nitrogen form among soils amended with different organic wastes composted with food waste, chicken manure, cow manure, domestic waste, vegetable residue, sludge, turf and tomato residue. Experiment utilized soils amended with 0%, 5% and 50% (m/m) of eight organic waste composts. The purpose was to understand the effect of different organic wastes on nitrogen mineralization in soil. This study deals with eight organic waste compost treatments could rapidly increase NH4(+) -N concentrations, reduce the NO3(-)-N concentrations and promote nitrogen mineralization in soil after 3-4 weeks incubation. All parameter tended to be stable. The improved amplitude of the same compost-amended soil: 30% compost treatments > 15% compost treatments > 5% compost treatments. Within the same proportion, chicken manure compost, turf compost and sludge compost product treatments' relative N mineralization was higher than other compost product treatments, and the chicken manure compost treatment's relative N mineralization was significantly higher than other compost product treatments. Food waste compost and vegetable residue compost product treatments' mineralization was low, the lowest was domestic waste compost product treatment. All compost treatments could significantly improve the values of potentially mineralizable nitrogen(N(0)), mineralization rate (k), and promote nitrogen mineralization in soil. The results illustrated that the effect of organic waste compost on the mineralization of nitrogen varied with types of compost and the amount of input compost. PMID- 23947070 TI - [Characteristics and influence factors of the energy consumption and pollutant discharge of municipal solid waste transfer stations in Beijing]. AB - In this study, we investigated characteristics and influence factors of energy consumption and pollutant discharge (ECPD) of municipal solid waste transfer stations (MSW TSs) in Beijing by assessing four parameters including the amount of waste recycled, leachate production, water consumption and electricity consumption, based on three years' average data of MSW TSs in Beijing obtained through field investigations from 2009 to 2011. Meanwhile, integral performances of the stations with and without garbage sorting capacities (Sorting TS and Compressing TS) were also analyzed. Results showed that MSW TSs in Beijing differ greatly. For each ton of MSW, masses of waste recycled, leachate productions, water consumptions and electricity consumptions generally fall in the ranges of 12.9 kg x t(-1), 5.8-49.0 kg x t(-1), 40. 3-156.7 kg x t(-1) and 1.75-5.60 kWh x t(-1), respectively. Despite overall the higher energy consumption and more pollutant discharge than Compressing TS, Sorting TS could achieve waste reduction and reuse by recycling part of the municipal solid wastes, as well as the optimization of process by sorting wastes into different ingredients for corresponding waste disposal plants, which could reduce heavy burdens of landfills and extend their lifespans. PMID- 23947071 TI - [Influence of ammonia on leaching behaviors of incineration fly ash and its geochemical modeling]. AB - Incineration fly ash could be contaminated with NH3 that was slipped from the ammonia-based selective non-catalytic reduction(SNCR) process and from evaporation of municipal solid wastes' leachate involved in the wastes. This research was conducted to investigate the impacts of ammonia on leaching of dissolved organic carbon (DOC) and metals from incineration fly ash in the pH range of 3.66-12.44 with an active ammonia spike. A geochemical modeling software Visual MINTEQ was adopted to calculate the chemical speciation of metals under the leaching conditions to reveal the mechanism behind the impacts. It was proved that at pH > 9, the leaching of DOC increased significantly in the presence of high concentrations of ammonia (> or = 1 357 mg x L(-1)), but there was little effect when the ammonia level in eluates was not higher than 537 mg x L(-1). At pH < 6, metals in fly ash were released mainly in the form of free metal ions and chloride complexes, which were little influenced by ammonia; while at pH 8-12, higher concentrations of ammonia (> or = 3 253 mg x L(-1)) mobilized Cd, Cu, Ni and Zn significantly due to the formation of soluble metal-ammonia complexes, and the leaching rates reached their peaks at pH around 9; however, ammonia had little impacts on Al and Pb leaching within this pH range. At pH > 12, for Cd, Cu, Ni and Zn, their leaching species were predominantly in the form of hydroxide complexes. Under the ammonia concentration of 3253 mg x L(-1), the Visual MINTEQ modeling results were compared with the experimental data, and it was proved that the leaching of Al, Pb and Zn was mainly controlled by precipitation/dissolution modeling, while Cd, Cu and Ni were controlled by precipitation/dissolution and surface complexation/precipitation processes; Visual MINTEQ modeling could well describe the leaching behaviors of Al, Cu, Pb and Zn from incineration fly ash. PMID- 23947072 TI - [Pretreatment technology for fly ash from MSWI and the corresponding study of chloride behavior]. AB - The introduced pretreatment technology, WCCB (Washing + Calcination), was effective to reduce chlorides in fly ash by consuming relatively low energy for recycling fly ash as the raw material for cement industry. The washing conditions are: twice-washing, liquid/solid = 3, mixing speed = 150 r x min(-1), 1st mixing time = 5 min, and 2nd mixing time = 10 min. The original incinerator was used for the calcination process, 1 000 degrees C, 10% O2 and dwelling time of 1 hour were adopted. By adopting X-ray absorption near edge structure and X-ray diffraction, the behavior of chlorides was explained and NaCl, KCl and CaCl2 are the main form of chlorides existing in fly ash. The reagent used in the air pollution control system to neutralize the acid component in the discharged gas surely acted a very important role in the formation of chlorides. The insoluble chlorides in fly ash had a very similar structure as that of Friedel's salt, which was related with CaCl2. PMID- 23947073 TI - [Preparation, characterization and adsorption performance of mesoporous activated carbon with acidic groups]. AB - Mesoporous activated carbons containing acidic groups were prepared with cotton stalk based fiber as raw materials and H3PO4 as activating agent by one step carbonization method. Effects of impregnation ratio, carbonization temperature and heat preservation time on the yield, elemental composition, oxygen-containing acid functional groups and adsorptive capacity of activated carbon were studied. The adsorption capacity of the prepared activated carbon AC-01 for p-nitroaniline and Pb(II) was studied, and the adsorption mechanism was also suggested according to the equilibrium experimental results. The maximum yield of activated carbons prepared from cotton stalk fiber reached 35.5% when the maximum mesoporous volume and BET surface area were 1.39 cm3 x g(-1) and 1 731 m2 x g(-1), respectively. The activated carbon AC-01 prepared under a H3 PO4/precursor ratio of 3:2 and activated at 900 degrees C for 90 min had a total pore volume of 1.02 cm3 x g( 1), a micoporous ratio of 31%, and a mesoporous ratio of 65%. The pore diameter of the mesoporous activated carbon was mainly distributed in the range of 2-5 nm. The Langmuir maximum adsorption capacities of Pb(II) and p-nitroaniline on cotton stalk fiber activated carbon were 123 mg x g(-1) and 427 mg x g(-1), respectively, which were both higher than those for commercial activated carbon fiber ACF-CK. The equilibrium adsorption experimental data showed that mesopore and oxygen-containing acid functional groups played an important role in the adsorption. PMID- 23947074 TI - [Preliminary assessment of the potential of biochar technology in mitigating the greenhouse effect in China]. AB - The production of biochar by pyrolysis and its application to soil can sequester the CO2 which was absorbed by plants from atmosphere into soil, in addition it can also bring multiple benefits for agriculture production. On the basis of the available potential survey of the biomass residues from agriculture and forestry section, life cycle assessment was employed to quantify the potential of biochar technology in mitigation of greenhouse gases in our country. The results showed: In China, the amount of available biomass resource was 6.04 x 10(8) t every year and its net greenhouse effect potential was 5.32 x 10(8) t CO(2e) (CO(2e): CO2 equivalent), which was equivalent to 0.88 t CO(2e) for every ton biomass. The greatest of contributor to the total potential was plant carbon sequestration in soil as the form of biochar which accounts for 73.94%, followed by production of renewable energy and its percentage was 23.85%. In summary, production of biochar from agriculture and forestry biomass residues had a significant potential for our country to struggle with the pressure of greenhouse gas emission. PMID- 23947075 TI - [Research of potassium flow and circulation based on substance flow analysis]. AB - Mass of potassium is consumed in the process of crop production, which is the dominating section of potassium flow and circulation in China. However, the degree of self-sufficiency is relatively low due to the deficient domestic resource of potassium. This study analyzed the key links of potassium issues in crop production and consumptive use in 2009 based on substance flow analysis. The results indicated that the farmland nutrient balance of input/output couldn't make even, with a heavy deficit of 50.4 kg x hm(-2) at the national level. Meanwhile, about 2.31 million ton of potash fertilizer was washed away into the hydrologic cycle, which accounts for 40.97% of chemical fertilizer applied in the whole year. Domestic wastewater in urban and rural areas was identified as another primary source for the transformation of potassium from terrestrial ecosystem to water environment system, annually contributing 671 and 547 thousand tons, which takes up 19.00% and 15.50%, respectively. And the amount of potassium in effluent of wastewater treatment plants was 505 thousand tons per year, accounting for 75.25% of the total emission in urban areas. PMID- 23947076 TI - Comparison of operative risks associated with radical hysterectomy in pregnant and nonpregnant women. AB - OBJECTIVE: To compare the operative data and complications of radical hysterectomy performed on pregnant women versus nonpregnant women. STUDY DESIGN: Following institutional review board approval, we reviewed our surgical databases to identify pregnant women who had undergone a radical hysterectomy for cervical carcinoma from 1992-2005 (n = 7). A nonpregnant control group (n = 35) of women undergoing radical hysterectomy during the study interval were identified and matched for age, year of surgery, and surgeon. Pertinent operative and outcome data were abstracted and compared. RESULTS: Of the 7 women who had undergone a radical hysterectomy during pregnancy, 4 had a cesarean radical hysterectomy at a mean gestational age of 35.4 weeks (range, 32.3-38 weeks) and 3 had a radical hysterectomy with a previable fetus in situ at a mean gestational age of 14.2 weeks. Demographics were similar between groups. Transfusion rates were significantly higher among pregnant women (57%) as compared to nonpregnant controls (9%) (p = 0.0009). The overall incidence of operative complications was similar between the pregnant women (43%) and nonpregnant controls (40%) (p = NS). CONCLUSION: Radical hysterectomy performed in pregnant women was associated with higher blood loss and increased need for transfusion as compared to nonpregnant controls. No differences were observed in regards to other operative surgical complications between the two groups. PMID- 23947077 TI - Comparison of combined transcervical resection of the endometrium and levonorgestrel-containing intrauterine system treatment versus levonorgestrel containing intrauterine system treatment alone in women with adenomyosis: a prospective clinical trial. AB - OBJECTIVE: To compare the effect of transcervical resection of the endometrium (TCRE) combined with levonorgestrel-containing intrauterine system (LNG-IUS) versus LNG-IUS alone in the treatment of adenomyosis. STUDY DESIGN: A total of 43 patients with adenomyosis, suffering from dysmenorrhea and menorrhagia, were recruited. Twenty patients underwent TCRE first followed by insertion of the LNG IUS (group 1), while 23 patients were managed with the LNG-IUS alone (group 2). Both groups were followed up at 3, 6 and 12 months with regard to menstrual characteristics. Visual analogue scores, transvaginal ultrasound scans and routine gynecological examinations were performed on all patients during the follow-up visits. RESULTS: There was a significant reduction in menstrual flow and pain in both groups following treatment. The reduction in menstrual flow in group 1 was significantly (p < 0.001) greater than that of group 2 at 3, 6 and 12 months posttreatment. On the other hand, there was no significant difference (p = 0.061) in the reduction of pain between the two groups. CONCLUSION: TCRE combined with LNG-IUS for the treatment ofadenomyosis is more effective in reducing menstrual flow compared with the LNG-IUS alone. However, there was no demonstrable difference in the amount of pain reduction between the two treatment strategies. PMID- 23947078 TI - Accuracy of information on emergency contraception on the Internet. AB - OBJECTIVE: To assess the quality of information on the Internet regarding Plan B, the Yuzpe method, and the copper intrauterine device (IUD). STUDY DESIGN: An Internet search was performed using 4 common search engines with the terms morning after pill, emergency contraception, and Plan B. The first 20 websites generated by each search were evaluated. Websites were excluded if they were not informational sites. Descriptive analysis was performed. RESULTS: Fifty-one websites were unique and relevant to the study criteria. The majority of sites reported that Plan B should be taken within 72 hours of unprotected intercourse (92.2%) and could be obtained without a prescription (54.4%). The Yuzpe method and the copper IUD were less likely to be mentioned, though the information presented tended to be accurate. CONCLUSION: The majority of information regarding emergency contraception on the Internet is accurate, suggesting that the Internet could be used to increase emergency contraceptive knowledge for patients. PMID- 23947079 TI - Prognostic determinants in patients with uterine and ovarian carcinosarcoma. AB - OBJECTIVE: To analyze and compare the demographics, treatment, recurrence, and survival rates in patients with carcinosarcoma of the uterus and ovary. STUDY DESIGN: All patients with uterine and ovarian carcinosarcoma who underwent surgical staging at the 2 participating institutions between 1995 and 2007 were identified. The Kaplan-Meier method was used to generate overall survival (OS) data. Factors predictive of outcome were compared using the Cox proportional hazards model. RESULTS: Analysis of 87 women with uterine carcinosarcoma and 71 with ovarian carcinosarcoma was performed. Of those, 47% of the patients with uterine carcinosarcoma, compared to 14% of the patients with ovarian carcinosarcoma, were diagnosed with localized disease (p < 0.001). Age > 65 years old (p < 0.001), tumor extension (local versus regional versus distant, p < 0.001), and platinum-based chemotherapy (p = 0.05) were all independent predictors of survival. In a multivariate Cox regression model, age > 65 years old (hazard ratio [HR] = 2.5, p < 0.001), tumor extension (locoregional versus distant, HR = 3.9, p = 0.006), and uterine versus ovarian carcinosarcoma (HR = 2.2, p = 0.009) were identified as independent predictors of OS. CONCLUSION: Uterine carcinosarcoma presents at an earlier stage than does ovarian carcinosarcoma. In the multivariate analysis uterine carcinosarcoma demonstrated shorter survival than did ovarian carcinosarcoma after adjustment for extent of disease spread, age, and platinum-based chemotherapy. PMID- 23947080 TI - Metabolic hormones in follicular fluid in women undergoing in vitro fertilization. AB - OBJECTIVE: To determine the concentrations of metabolic hormones in follicular fluid (FF) and to find clinical correlates of these biochemical parameters. STUDY DESIGN: FF was obtained from 108 women by ultrasonography-guided transvaginal puncture following controlled ovarian hyperstimulation. FF insulin, leptin, adiponectin and resistin levels were measured by enzyme-linked immunosorbent assay, and ghrelin was analyzed with radioimmunoassay. RESULTS: It was demonstrated that oocyte number correlated negatively with FF leptin (r = -0.190, p < 0.050) and insulin (r = -0.209, p < 0.031) and positively with resistin (r = 0.236, p < 0.014). After adjustments for confounding hormone parameters, resistin remained a positive (p < 0.000) predictor and insulin (p < 0.039) and adiponectin (p < 0.033), negative predictors of oocyte number. When the embryo number was considered, FF leptin proved to be a strong negative (p < 0.012) whereas resistin proved to be a positive outcome predictor (p < 0.004). CONCLUSION: In women undergoing in vitro fertilization (IVF), FF metabolic hormones may be involved in regulating ovarian function and in determining fertilization outcome. Resistin appears to have beneficial effects on the outcome of IVF, while leptin, insulin, adiponectin and ghrelin appear to have adverse or no effects. PMID- 23947081 TI - Multiple repeat cesarean sections: operative difficulties, maternal complications and outcome. AB - OBJECTIVE: To determine maternal/neonatal complications and outcome in patients with multiple repeat cesarean sections (CSs). STUDY DESIGN: A retrospective case control study of 144 pregnant women with > or = 4 cesarean sections was compared with a control group of 288 women having 2-3 cesarean sections for maternal, operative and neonatal complications. RESULTS: The study patients had longer operating times (p = 0.0001) due to severe adhesions (p = 0.0005), with increased blood loss and blood transfusion (p = 0.0001). Rupture of the uterus (p = 0.0015), placenta previa (p = 0.0372), gestational age at delivery (p < 0.0002), preterm birth (p = 0.0497) and Apgar scores < 7 at 5 minutes (p = 0.0140) were significant in the study group. There was no significant difference of placenta accreta, bladder and bowel injury, cesarean hysterectomy, wound infection and postoperative pyrexia between the 2 groups. Among the neonates of the 2 groups, NICU admissions, small-for-gestational-age birth weights, large-for-gestational age birth weights and perinatal mortality were similar. No mother died in the series. The incidence of a single major complication was higher in women with > or = 4 cesarean deliveries (p = 0.0011). CONCLUSION: Repeated CS increases the risk of uterine rupture and intraoperative complications, making these patients a high-risk group. No absolute upper limit for the number of repeat cesarean deliveries can be given. Patients must be informed of the risks of multiple CSs and encouraged to have tubal ligation. PMID- 23947082 TI - Effect of strontium ranelate on serum leptin and bone turnover markers in women with established postmenopausal osteoporosis. AB - OBJECTIVE: To assess the association between leptin levels and bone mineral density (BMD) and bone metabolism markers in postmenopausal women taking strontium ranelate. STUDY DESIGN: In this longitudinal uncontrolled study, postmenopausal osteoporotic women were administered strontium ranelate and categorized into 1 of 2 groups: overweight and lean. BMD, serum leptin, bone specific alkaline phosphatase (ALP) and urinary deoxypyridinoline (Dpd) were assessed at baseline, 6 and 12 months of the therapy. RESULTS: For all 47 women, leptin levels increased at the sixth month (p = 0.001) and 1 year after treatment (p = 0.001), Dpd levels decreased at the sixth month (p = 0.001) and 1 year after treatment (p = 0.003), but ALP levels did not change with respect to basal levels. Spine and hip BMD also increased at the end of 1 year (p = 0.01 and p = 0.001, respectively). For overweight women leptin levels increased 6 months and 1 year after treatment (p = 0.003 and p = 0.001, respectively). Dpd levels decreased significantly at the sixth month and at 1 year (p = 0.001 and p = 0.041), but ALP levels did not change. Hip and spine BMD also increased (p = 0.036 and p = 0.002). The lean group had similar serum results and BMD scores after treatment. CONCLUSION: Our data supports a positive effect of leptin on bone metabolism in favor of bone resorption inhibition in postmenopausal osteoporotic women on strontium treatment. PMID- 23947083 TI - Diagnostic pitfalls in the evaluation and management of amenorrhea in adolescents. AB - Amenorrhea is a common menstrual problem seen in adolescents. Amenorrhea has been shown to have a negative impact on adolescents' quality of life. In this paper we discuss the various causes and investigations of amenorrhea in adolescents and address management dilemmas for specific conditions. Specific approaches in dealing with adolescents using the HEADSS (Home, Education, Activity, Drugs, Sexual activity, Suicidal) approach are discussed. PMID- 23947084 TI - Ectopic pregnancy after hysteroscopic tubal occlusion confirmed by hysterosalpingogram: a case report. AB - BACKGROUND: Even after demonstrated bilateral tubal occlusion during posthysteroscopic sterilization hysterosalpingogram (HSG), incorrect location of the micro-inserts can result in unplanned pregnancy and potential ectopic location. CASE: More than 4 years after HSG-confirmed hysteroscopic tubal occlusion, a patient presented with pelvic both absenceboh absence cy test. Surgical and pathologic evaluation ultimately revealed an ectopic pregnancy of likely cornual location. Review of her HSG confirmed bilateral tubal occlusion, but the location of one micro-insert was incorrect. CONCLUSION: Ectopic pregnancy after HSG-confirmed tubal occlusion is a rare event. Necessary measures to prevent this from occurring include not only confirmation of bilateral tubal occlusion, but also recognition of correct location of the micro-insert within the lumen of the fallopian tube. If the postprocedure HSG demonstrates incorrect micro-insert position, even in the absence of tubal dye spill, the patient cannot rely on this method for sterilization. PMID- 23947085 TI - Placental abruption and fetal demise secondary to placental metastases from unknown primary: a case report. AB - BACKGROUND: Although maternal malignancy is relatively common, maternal metastases to the products of conception remains a rare event. There is no available literature that describes the incidence of placental metastases as a cause of abruption and fetal death. importanc CASE: We present an unusual case of placental abruption and disseminated intravascular coagulation leading to fetal demise secondary to placental metastases of unknown origin. CONCLUSION: In our case placental abruption likely resulted from metastases to the intervillous space. PMID- 23947086 TI - Vaginal myofibroblastoma with prostatic glands: is there an association with tamoxifen use? A case report. AB - BACKGROUND: Both ectopic prostate tissue in the female genital tract and vaginal myofibroblastoma have rarely been reported in the literature. Tamoxifen use has been associated with the development of vaginal myofibroblastoma. CASE: A 76-year old, multiparous woman who had taken tamoxifen for breast cancer presented with postmenopausal bleeding and a vaginal mass. Endometrial work-up revealed a benign polyp, and the polypoid tumor in the vagina was found to be a myofibroblastoma harboring ectopic prostatic glands. CONCLUSION: To our knowledge this is the first case of these two rare pathologic entities occurring together. Of note, this patient also had a history of tamoxifen therapy, like some of the previous patients with vaginal myofibroblastoma. PMID- 23947087 TI - Severe delayed postpartum hemorrhage due to a neglected uterine diverticulum: a case report. AB - BACKGROUND: Symptomatic uterine diverticula are rare and, to our knowledge, have never been reported as a cause of postpartum hemorrhage. CASE: A 35-year-old woman presented with severe vaginal bleeding on the 47th day after a cesarean section. She had received endometrial curettage due to postpartum hemorrhage a few days earlier in another local hospital. Transvaginal ultrasound revealed a thickened heteroechoic endometrium and an isolated isthmic heteroechoic cystic lesion. Repeat endometriaI curettage was performed initially. However, recurrent vaginal bleeding and hypovolemic shock occurred 2 days later. Active bleeding from a debris-full diverticulum in the lateral wall of the uterine isthmus was found during an emergent hysterotomy. The myometrium was sutured to obliterate the diverticulum. The follow-up course was uneventful. CONCLUSION: Uterine diverticula may present as isolated isthmic heteroechoic cystic lesions and may be overlooked as a cause of severe delayed postpartum hemorrhage. PMID- 23947088 TI - The gynecologist's role in preventing overdiagnosis of ectopic molar pregnancy: a case report. AB - BACKGROUND: Ectopic hydatidiform mole is a rare, yet overdiagnosed, entity. A diagnosis of ectopic molar pregnancy requires close follow-up, has implications on future fertility, and may require chemotherapy. Patients diagnosed with a hydropic abortus do not require hormone surveillance or abstinence from pregnancy for the extended time period generally recommended for patients diagnosed with a complete or partial hydatidiform mole. The correct classification of products of conception is clinically important because each of the three diagnoses has a different potential for malignant transformation. CASE: A 29-year-old woman, G5P2104, with ectopic pregnancy and without clinical or laboratory data suspicious for molar pregnancy required ancillary histopathologic testing for accurate diagnosis. CONCLUSION: This case illustrates the vital role of the gynecologist in assimilating information to prevent over-diagnosis of ectopic molar pregnancy. General gynecologists must therefore understand the histopathologic options available for differentiating hydropic products of conception, partial hydatidiform mole and complete hydatidiform mole. PMID- 23947089 TI - Severe gynecologic sequelae of Stevens-Johnson syndrome and toxic epidermal necrolysis caused by ibuprofen: a case report. AB - BACKGROUND: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a serious, drug-induced, life-threatening condition characterized by an epidermal blistering rash with necrosis, desquamation and mucosal surface involvement. This patient represents the youngest and most significant case report in the literature of gynecologic damage due to TEN. CASE: A 31/2-year-old girl developed TEN involving 90% of her body surface area after exposure to pediatric ibuprofen. After onset of puberty she required surgery to treat vulvar, vaginal and cervical adhesions, stenosis and hematometra. CONCLUSION: While delaying evaluation and treatment of the extremely young child with this disorder until puberty has been the standard, consideration should be given to earlier evaluation and intervention. PMID- 23947091 TI - Synchronous carcinosarcoma uterus and primary serous carcinoma of bilateral fallopian tubes: a case report. AB - BACKGROUND: The coexistence of multiple primary tumors in the female genital tract is very rare. Carcinosarcoma of the uterus is very rarely encountered among multiple genital malignancies. CASE: A 63-year-old woman presented with synchronous carcinosarcoma of the uterus and primary serous carcinoma of bilateral fallopian tubes. The diagnosis was confirmed histopathologically and immunohistochemically. CONCLUSION: This case is presented for its rarity and unique presentation. To the best of our knowledge, ours is the first reported case of this unique combination of synchronous genital malignancies. PMID- 23947090 TI - Biliary cyst in pregnancy managed by percutaneous drainage: a case report. AB - BACKGROUND: A maternal biliary cyst diagnosed in pregnancy is extremely rare. The condition can be asymptomatic or can present with chronic and intermittent abdominal pain, rupture of the cyst, and liver function test abnormalities. Management depends on the gestational age and the patient's condition when it is diagnosed. CASE: We present a case of a symptomatic type IV biliary cyst with abnormal liver function tests diagnosed in the second trimester of pregnancy and treated with a percutaneous drainage. The patient delivered vaginally at term and developed obstruction of the percutaneous drain with superimposed bacterial infection postpartum. She was lost to follow-up intermittently throughout her treatment. CONCLUSION: Symptomatic biliary cyst in pregnancy may require palliative invasive intervention until delivery. PMID- 23947092 TI - Plexiform schwannoma of the clitoris in a young girl: a case report. AB - BACKGROUND: Schwannoma (neurilemoma) is a benign, slow-growing tumor of the nerve sheath. These tumors are rarely found in the female genitalia and to date only 1 case of clitoral schwannoma has been reported in a young girl. We report here the second case of schwannoma of the clitoris. CASE: A 6-year-old girl presented with an enlarging clitoris. An alteration in her clitoral appearance had first been noted at 2 years of age. However, the size had further increased in the year prior to presentation. On examination her clitoris was normal in size but beneath the clitoral hood, predominantly on the left, there was a 3 x 2 cm irregular mobile mass. Her karyotype revealed normal 46XX female genotype. Magnetic resonance imaging of the abdomen and pelvis showed an isolated finding of diffuse enlargement of the clitoris with edema of the mons pubis. Surgical excision of the paraclitoral mass was performed. Intraoperatively the clitoral tip and shaft did not appear to be involved. However, the mass was found to be more diffuse, less well-defined, and more extensive than the clinical findings had suggested. On histology long spindle cells with nuclear palisading and focal Verocay body like structures were found. There was mild to moderate pleomorphism. No mitotic figures were identified. There was diffuse staining of interweaving bundles for S100 protein and glial fibrillary acidic protein without staining for actin, desmin, or neurofilament. These features are consistent with a plexiform schwannoma. CONCLUSION: Although benign schwannomas rarely occur in the clitoris, we suggest that it should be considered as differential diagnosis for any young girl with clitoral or paraclitoral asymmetrical irregular mass. PMID- 23947093 TI - Medical boon or bust? Suits raise allegations of defects in da Vinci robot. PMID- 23947094 TI - FDA slaps regs on fecal transplants. Increased steps for C. diff treatment draw mixed reactions from providers. PMID- 23947095 TI - Dead, delayed, done. Failed merger efforts reflect increased activity. PMID- 23947096 TI - Mixed picture. Calif. proposed premiums lower than expected. PMID- 23947097 TI - Seeking shelter. As tornado bore down, residents flocked to hospital. PMID- 23947098 TI - Storm tests EHR. Medical records kept safe despite devastation. PMID- 23947099 TI - Inside institutionalization. Author-activist discusses lives of the disabled. PMID- 23947100 TI - Robots get to work. More hospitals are using automated machines, but jury's still out on success. PMID- 23947101 TI - A credible IRS is crucial. Attacks seek to undermine agency's ability to roll out reform law. PMID- 23947103 TI - Eating better for less. To treat the obesity epidemic, why not lower prices on healthier food. PMID- 23947102 TI - Transforming care delivery. Doctors, patients, families acting as a team can lead to improved healthcare. PMID- 23947104 TI - Caring for the community. Regional programs taking concept of ACOs to a much broader level. PMID- 23947105 TI - Big project in the big easy. Technology helps speed timetable for new UMC. PMID- 23947106 TI - Prescribe, but also know how to "deprescribe". PMID- 23947107 TI - Medical students' and junior doctors' attitudes to drug companies: a survey conducted in Lyon University Hospital, France. PMID- 23947108 TI - Junior doctors' attitudes towards drug companies. PMID- 23947109 TI - Newborn screening of inherited metabolic disorders by tandem mass spectrometry: past, present and future. AB - Inborn errors of metabolism are inherited biochemical disorders caused by lack of a functional enzyme, transmembrane transporter, or similar protein, which then results in blockage of the corresponding metabolic pathway. Taken individually, inborn errors of metabolism are rare. However, as a group these diseases are relatively frequent and they may account for most of neonatal mortality and need of health resources. The detection of genetic metabolic disorders should occur in a pre-symptomatic phase. Recently, the introduction of the tandem mass spectrometric methods for metabolite analysis has changed our ability to detect intermediates of metabolism in smaller samples and provides the means to detect a large number of metabolic disorders in a single analytical run. Screening panels now include a large number of disorders that may not meet all the criteria that have been used as a reference for years. The rationale behind inclusion or exclusion of a respective disorder is difficult to understand in most cases and it may impose an ethical dilemma. The current organization is an important tool of secondary preventive medicine, essential for children's healthcare, but the strong inhomogeneity of the regional models of screening applied today create in the Italian neonatal population macroscopic differences with regards to healthcare, which is in effect mainly diversified by the newborn's place of birth, in possible violation of the universal criterion of the equality of all citizens. Carefully weighed arguments are urgently needed since patient organizations, opinion leaders and politicians are pressing to proceed with expansion of neonatal population screening. PMID- 23947110 TI - [Update for the standard procedures of diagnosis and therapy in cases of congenital rubella]. AB - Congenital Rubella is the dramatic consequence of rubella during gestation. A combined strategy of Measles and Rubella universal vaccination on children and selective vaccination of susceptible women has been shown effective in the elimination of congenital rubella requiring an incidence of < 1 case of CRS per 100,000 live births. Verification processes of rubella elimination require that physicians early and appropriately diagnose all cases of congenital rubella, including those unpatent at birth. The paper highlights clinical and laboratory aspects channeling diagnosis of congenital rubella infection or syndrome even after the first year of life, and the short- and long-term management criteria. PMID- 23947111 TI - [Therapy with high-flow nasal prongs in preterm infants]. AB - Despite of improved survival of premature infants, the incidence of long-term pulmonary complications, mostly associated with ventilation-induced lung injury, remains high. Non invasive ventilation (NIV) is able to reduce the adverse effects of mechanical ventilation. Although nasal continuous positive airway pressure (NCPAP) is an effective mode of NIV, traumatic nasal complications and intolerance of the nasal interface are common. Recently high flow nasal cannula (HFNC) is emerging as an efficient, better tolerated form of NIV, allowing better access to the baby's face, which may improve nursing, feeding and bonding. The aim of this review is to discuss the available evidence of effectiveness and safety of HFNC in preterm newborns with respiratory distress syndrome (RDS). It is known that distending pressure generated by HFNC increases with increasing flow rate and decreasing infant size and varies according to the amount of leaks by nose and mouth. The effects of HFNC on lung mechanics, its clinical efficacy and safety are still insufficiently investigated. In conclusion, there is a growing evidence of the feasibility of HFNC as an alternative mode of NIV. However, further larger randomized trials are required, before being able to recommend HFNC in the treatment of moderate respiratory distress of preterm infants. PMID- 23947112 TI - [Laparoscopy-assisted jejunostomy in neurological patients with chronic malnutrition and GERD. Technical considerations and analysis of the results]. AB - BACKGROUND: Feeding difficulties and gastroesophageal reflux (GER) are major problems in severely neurologically impaired children. Many patients are managed with a simple gastrostomy, with or without fundoplication. Unfortunately, fundoplication and gastrostomy are not devoid of complications, indicating the need for other options in the management of these patients. METHODS: Between January 2002 and June 2010, ten patients (age range, 18 months-14 years) have been treated by creating a jejunostomy with the laparoscopic-assisted procedure. The procedure was performed using 2-3 trocars. The technique consists of identifying the first jeujnal loop, grasping it 20-30 cm away from the Treitz ligament, and exteriorizing it to the trocar orifice under visual guide. The jejunostomy was created outside the abdominal cavity during open surgery. At the end of the jejunostomy, the correct position of the intestinal loops was evaluated via laparoscopy. RESULTS: Surgery lasted 40 min on average, the laparoscopic portion about 10 min. Hospital stay was 3 or 7 days for all patients. At the longest follow-up (8 years), all patients had experienced a significant weight gain. One patient died 1 year after the procedure of unknown causes. As for the other complications: 4/10 patients experienced peristomal heritema, 2/10 device's dislocation and 1 patient a peristomal granuloma. CONCLUSIONS: Laparoscopic-assisted jejunostomy is a safe and effective procedure to adopt in neurologically impaired children with feeding problems and GER. We advocate the use of this procedure in neurologically impaired patients with feeding problems and reflux due to its overall practicability and because there is minimal surgical trauma. The improvement in the quality of life of these children after the jejunostomy seems to be the major advantage of this procedure. However the management of jejunostomy can be difficult for parents above all in the first postoperative months. PMID- 23947113 TI - [Nutritional rickets in twins: a case report]. AB - Vitamin D deficiency rickets in infants attributable to inadeguate vitamin D intake and decreased exposure to sunligh continue to be reported in the United States and other Western Countries. The American Academy of Pediatrics raccomend that all infants, children and adolescent have a minumin intake of 400 UI of vitamin D per day. We describe a case of deficiency-related rickets in two moroccan twins aged 10 months. PMID- 23947114 TI - [A case of micropenis with strong genetic basis]. AB - The early hormonotherapy of micropenis takes on a diagnostic significance too. The very good tolerance gives value to this behaviour. The Author shows the condition of a male infant 46,XY eighteen months old; the child appeared with a micropenis completely expressed and resulting from hypogonadotropic hypogonadism. He confirms the good response to hormonotherapy for this child. PMID- 23947115 TI - Multiple endocrinopathies (growth hormone deficiency, autoimmune hypothyroidism and diabetes mellitus) in Kearns-Sayre syndrome. AB - Kearns-Sayre syndrome is characterized by onset before 20 years, chronic progressive external opthalmoplegia, pigmentary retinal degeneration, and ataxia (and/or hearth block, and/or high protein content in the cerebrospinal fluid) in the presence of mtDNA rearrangements. Multiple endocrine dysfunction associated with this syndrome was rarely reported. In this paper, the Authors report on a female patient with Kearns-Sayre syndrome with large heteroplasmic mtDNA deletion, absence of cytochrome c oxidase in many muscle fibers, partial GH deficiency, hypothyroidism and subsequently insulin dependent diabetes mellitus (IDDM). Anti-thyroid peroxidase and antithyreoglobulin antibodies were present in high titer in serum while anti-islet cell antibodies were absent. The patient developed thyroiditis with Hashimoto encephalopathy. The presence of GH deficiency, autoimmune thyroiditis with hypothyroidism and IDDM distinguishes this case from others and confirms the association of Kearns-Sayre syndrome with multiple endocrine dysfunction. Hashimoto encephalopathy and anti-thyroideal antibodies suggest that in this patient, predisposed by a genetic factor (a mitochondrial deletion) anti-thyroideal antibodies may have contributed to the hypothyroidism and, by interfering with cerebral mitochondrial function, may have caused the encephalopathy. GH deficiency and IDDM can be attributed to oxidative phosphorylation deficiency but the autoimmunity may also have played a role in the production of glandular insufficiencies. It seems important to search for endocrine autoimmunity in every case of KSS. PMID- 23947116 TI - [Sexual abuse in a child or adolescent: the first approach in the Emergency Room]. PMID- 23947117 TI - [Advance in studies on gut microbiota in de-glycosylation of traditional Chinese medicine glycosides]. AB - Glycosides are important active components in traditional Chinese medicine (TCM). Their pharmacological activity, pharmacokinetic characteristics and in vivo existence become hotspots of current studies. The metabolic pathways of these glycosides are de-glycosylation mainly mediated by gut microbiota. After glycosides were metabolized into aglycones, they could be absorbed more easily and show better pharmacological effects. In this article, we reviewed the main glycosidase in gut microbiota which helps metabolize TCM glycosides, relevant bacterial strains which generate glycosidase, as well as the de-glycosylated metabolic pathways of the representative glycosides, on the basis of gut microbiota's important roles in in vivo metabolism and efficacy of TCM glycosides. We also preliminarily solved problems in studies on de-glycosylation of TCM glycosides. PMID- 23947118 TI - [Optinization of rapid propagation technique and induction and identification of autotetraploid of Polygonum multiflorum]. AB - OBJECTIVE: To establish and optimize the rapid propagation system of Polygonum multiflorum, as well as explore method for induction and identification of autotetraploid. METHOD: Propagation medium was optimized by orthogonal test. The buds were immersed in colchicine solution with different concentrations for different time to select induction conditions for autotetraploid of P. multiflorum. RESULT: The most appropriate propagation medium was MS medium supplemented with 1.0 mg x L(-1) 6-BA, 0.3 mg x L(-1) NAA, and 0.4 mg x L(-1) PP333. That the buds were soaked in 0.2% colchicine solution for 30 h, or soaked in 0.3% colchicine solution for 18 h, was optimal condition to induce autopolyploid of P. multiflorum with induction rate as high as 16.7%. CONCLUSION: Rapid propagation of P. multiflorum could be achieved by tissue culture. Furthermore, colchicine was an effective inducer of polyploidy, and 25 tetraploid lines were obtained through chromosome identification. The experiment laid a foundation for the wild resource conservation, superior varieties breeding of P. multiflorum. PMID- 23947119 TI - [Abnormal change of calcium signal system on consecutive monoculture problem of Rehmannia glutinosa]. AB - Based on the early transcriptome and digital differentially expressed profiling library construction in consecutive monoculture (two-year culturing) Rehmannia glutinosa, we screened and chose the twelve differentially expressed protein genes which might be related with calcium signal system. The spatiotemporal expression of these genes was measured by the real-time quantitative PCR, and the relative expression values of the genes related with calcium signal system in different development stages and tissues of normal growth (one-year culturing) and succession cropping of R. glutinosa (two-year culturing) was elaborated in detail. In addition, disposed succession cropping of R. glutinosa was treated with different levels of calcium signal blocking agents in order to verify the mode of action of calcium signal system on consecutive monoculture problem in R. glutinosa. Among the twelve genes, two calcium channels away from the cytoplasm were down-regulated expressed, while the ten calcium channels toward the cytoplasm were up-regulated expressed. The results implied that succession cropping caused calcium ions flowing from endoplasmic reticulum to cytoplasm. While the key genes in calcium signal respond components such as CBL, CBP, CIBP, PLC, etc. were down-regulated expressed significantly in succession cropping of R. glutinosa which were disposed with calcium signal blocking agents, the extent of the damage was relieved, and approached the normal growth (one-year culturing) level. This result strongly showed that calcium signal system participated in the perceiving, conducting and magnifying processes of succession cropping obstacles of R. glutinosa. PMID- 23947120 TI - [Genotype, environment and their interactions of major bioactive components in 2 year licorice (Glycyrrhiza uralensis) population]. AB - OBJECTIVE: This study aimed at analyzing the effect of genotype (G), environment (E) and their interactions (G x E) on the major bioactive components of 2-year licorice (Glycyrrhiza uralensis) population, in order to provide a theoretical basis for the licorice breeding with high content of bioactive components and quality improvement. METHOD: Four genotype licorice populations were transplanted under four different environments by using complete randomized block design with three replicates, and four major bioactive components, including glycyrrhizin (GL), total saponins (TS), liquiritin (LQ) and total flavonoids (TF) were determined by UV and by HPLC. RESULT: The major bioactive components of licorice were influenced by genotype and environment, and the genotype had more effect on all of the bioactive components. The contents of GL and LQ were codetermined by genotype and environment factors. CONCLUSION: There exist different selective effects on different growth region for quality breeding in cultivated population of licorice. PMID- 23947121 TI - [Effect of low-temperature vernalization on metabolism of carbon and nitrogen of Isatis indigotica]. AB - OBJECTIVE: The aim of the present study is to investigate the effect of low temperature vernalization on metabolism change of carbon and nitrogen of Isatis indigotica. METHOD: The Yunnan and Beijing I. indigotica seedlings with six leaves were vernalized at 4 degrees C for 25 days, and the metabolism indicators of carbon and nitrogen were measured. RESULT: There appeared a dramatic increase in the soluble sugar content, reducing sugar content and soluble protein content in response to the low temperature, after termination of vernalization it reached the maximum, however, starch and total nitrogen concentration decreased significantly, after termination of vernalization it reached the minimum. CONCLUSION: The high C/N value can promote the low temperature vernalization of I. indigotica. PMID- 23947122 TI - [Dynamic accumulation of dry substance and active components in root of Peucedanum praeruptorum]. AB - OBJECTIVE: To study the dynamic accumulation regulation of dry substance and four coumarin constituents in root of Peucedanum praeruptorum, so to provide the basis for optimal harvest time. METHOD: Roots of P. praeruptorum were collected periodically. The dry weight of the roots was measured and the content of four coumarins was determined by HPLC method. RESULT: The dry substance accumulation of the root reached the maximum amount and the coumarin contents maintain stability at the end of the vegetative growth period. The coumarins of roots decline significantly in the reproductive growth period. CONCLUSION: The most optimum collecting time of root of P. praeruptorum cultivated in Ningguo county in Anhui province should be from December to next February. PMID- 23947123 TI - [Effect of fertilization on phenolic components and antioxidant activities of Artemisia annua]. AB - OBJECTIVE: A pot experiment with variable fertilizer treatments was carried out to study the influence of fertilization on the concentration and accumulation of polyphenols, scopoletin, chrysosplenol-D and chrysosplenetin in roots, stems and leaves and their antioxidant activities. The main aims were to fertilize scientifically in cultivation of Artemisia annua and improve the quality of the harvest organs. METHOD: These active components in leaves, stems and roots in the squaring stage were analyzed by HPLC and antioxidant activities of the extracts were evaluated by ultraviolet visible light colorimetric method. RESULT: The result showed the highest concentration of polyphenols, scopoletin, chrysosplenol D and chrysosplenetin was in leaves, followed by stems and the lowest in roots. The antioxidant activities of the leaf extracts correlated positively with the concentrations of polyphenols, scopoletin, chrysosplenol-D and chrysosplenetin. Furthermore, fertilization promoted significantly the growth of A. annua, the biomass was increased by 57.37% (chemical fertilizer), 91.63% (mixture of chemical fertilizer and manure) and 92.27% (manure), respectively, compared to the blank control (without fertilizer). Fertilization, particularly mixture fertilization of chemical fertilizer and manure, increased generally the concentration and accumulation of polyphenols, scopoletin, chrysosplenol-D and chrysosplenetin as well as DPPH x scavenging ratio. CONCLUSION: Scopoletin, chrysosplenol-D and chrysosplenetin could be synthesized and stored mainly in leaves. The leaves might thus be the chief organ of A. annua for medical treatment. Finally, the mixture fertilization of chemical fertilizer and manure should be used to increase the yield and quality of A. annua. PMID- 23947124 TI - [Isolation and identification of pathogen of seedling blight of Platycodon grandiflorum]. AB - OBJECTIVE: To isolate and identify pathogen of the seedling blight occurred in Platycodon grandiflorum. METHOD: The morphological observation, rDNA ITS sequence analysis, and Koch's postulates were used to identify the isolates of the causal agent. RESULT: The isolates of the causal agent was Rhizoctonia solani. CONCLUSION: The result confirmed that R. solani is the pathogen of seedling blight of P. grandiflorum. PMID- 23947125 TI - [Optimization of extraction process for Baizhu Shaoyao San by multi-index orthogonal experiment]. AB - Baizhu Shaoyao San is a famous traditional Chinese medicine formula, which is efficient to diarrhea clinically. However, there are very few reports for extraction process of Baizhu Shaoyao San at present. In this article, an orthogonal test was conducted, with 10 major components and extractum of Baizhu Shaoyao San as indexes, and data was processed by the compound weight method, in order to detect four factors, including the concentration of ethanol, the dosage of ethanol, the soaking and extracting times, and optimize the extraction process of Baizhu Shaoyao San. The results showed that the optimal extraction process was adding 12-fold ethanol of 70% concentration, soaking for 1 hours, and extracting for twice, 2 hours each time. Among the indexes, the extracting time made significant impact. The optimized method is stable and reliable, and can provide reference for further development and utilization of the formula. PMID- 23947126 TI - [Comparative study on rat in situ nasal absorption of geniposide of Xingnaojing nasal drop and Xingnaojing microemulsion]. AB - Xingnaojing (XNJ) is an effective clinical drug used to treat acute stroke. Compared with injection administration, its nasal administration has better brain targeting. Therefore, through nasal administration, XNJ microemulsion could help solve the drug load of compound components of different polarities contained in large-dose and high-concentration traditional Chinese medicines, and reduce irritation to nasal mucosa In this study, the modified volume correction method and the improved rat in situ nasal perfusion model were adopted to compare the nasal absorption of geniposide contained in different XNJ preparations. The results showed that the constant absorption rate of geniposide (GE) in XNJ-D was (2.95 +/- 0.25) x 10(-3) min(-1), whereas the constant absorption rate of GE in XNJ-M was (2.16 +/- 0.21) x 10(-3) min(-1). This indicated that the rat nasal absorption of GE in different XNJ preparations complied with the first-order process and could be considered as passive absorption. GE in XNJ-D was absorbed faster than that in XNJ-M, which provided basis for the development of nasal preparations of XNJ. PMID- 23947127 TI - [Study on all-time multi-wavelength fusion fingerprint of Qizhiweitong granules and multi-component quantitative analysis]. AB - OBJECTIVE: To control the quality of Qizhiweitong granules with the all-time multi-wavelength fusion fingerprint quantification as the major technique. METHOD: Agilent TC-C18 (4.6 mm x 250 mm, 5 microm) chromatographic column was adopted, with 0.02% formic acid water-acetonitrile as the mobile phase for linear gradient elution. The flow rate was 1 mL x min(-1), column temperature was 30 degrees C, and detector wavelength was 230, 254, 283 nm. Matlab was adopted for all-time multiple-wavelength fusion for data in dif format. RESULT: A good relationship was shown for albiflorin in 56.5-452 mg x L(-1) (r = 0.999 8), paeoniflorin in 107-856 mg x L(-1) (r = 0.999 8), licorice glycoside in 73.4-687 mg x L(-1) (r = 0.999 8), naringin in 109-872 mg x L(-1) (r = 0.999 8), neohesperidin in 48.0-384 mg L(-1) (r = 0.999 8), and glycyrrhizic acid in 38.6 308 mg x L(-1) (r = 0.999 8), with recoveries of 0.999 8. CONCLUSION: The method is simple, accurate and highly reproducible, and can provide basis for quality control of Qizhiweitong granules. PMID- 23947128 TI - [Simultaneous determination of gallic acid and hesperidin contained in Xiaogu capsule by HPLC]. AB - OBJECTIVE: To develop an HPLC method for simultaneous determination of gallic acid and hesperidin in Xiaogu capsule, in order to provide a simple, rapid and accurate method for quality control of the compound preparation of traditional Chinese medicine. METHOD: Xiaogu capsule was extracted with methanol heating reflux method. Synergi 4 mu Hydro-RP 80A (4.6 mm x 250 mm, 5 microm) was adopted as the chromatographic column, with acetonitrile--0.04 mol x L(-1) phosphate monobasic sodium solution (20: 80) as the mobile phase. The flow rate was 1.0 mL x min(-1), the detection wavelength was 283 nm, and the column temperature was 25 degrees C. RESULT: Under the conditions, gallic acid and hesperidin reached the baseline resolved peak, with a good linearity within the range of 21.6-216.0 mg x L(-1) (r = 0.999 93) for gallic acid, and 4.5-45.0 mg x L(-1) (r = 0.999 95) for hesperidin, respectively. Their average recoveries (n = 9) were 101.5% (RSD 3.7%) and 94.7% (RSD 2.7%), respectively. The average contents of gallic acid and hesperidin contained in Xiaogu capsule were detected to 5.10% and 0.091 1%, respectively. CONCLUSION: The method established in this study can determine the content of gallic acid and hesperidin contained in Xiaogu capsule in a rapid and accurate manner, which provided reference for quality evaluation of the medicine. PMID- 23947129 TI - [Determination of aconitine, hypaconitine and mesaconitine in Shenfu injection]. AB - To establish a method for the content determination of indexes for measuring aconitic compounds contained in Shenfu injection, in order to provide basis for the evaluation of the curative effect of monkshood in Shenfu injection. The sample were purified and enriched with HF-LPME. ACQUITY UPLC BEH C18 column (2.1 mm x 50 mm, 1.7 microm) was adopted and eluted with a gradient program, with acetonitrile-10 mmol x L(-1) NH4HCO3 (pH 10) as the mobile phases. The flow rate was 0.45 mL x min(-1). The content was determined with ESI and MRM. The results showed that aconitine, hypaconitine and mesaconitine showed a good linear relationship, with r > 0.999, within the range of 0.1-100 ng x L(-1). The recoveries were detected to be 100.1%, 97.4%, 97.5%, with RSD being 1.2%, 1.1%, 1.5%, respectively. This method was used to prove the safety of Shenfu injection, and provide scientific basis for correct evaluation of curative effect of monkshood, as well as a reliable, simple and practical means for quality control of monkshood-containing Chinese materia medica preparations. PMID- 23947130 TI - [Study on HPLC chromatograms of different processed Euphorbia ebracteolata products and content change of three chemical components]. AB - To prepare processed products with different methods, in order to study the impact of auxiliary materials and temperature on chemical components of Euphorbia ebracteolata, and establish specific chromatograms of different processed products. Wel-chorm-C18 column (4.6 mm x 250 mm, 5 microm) was used and eluted with a gradient program, with acetonitrile (A)-water(B). The column temperature was 25 degrees C, and the detection wave length was set at 226 nm. The aim was to determine the content of effective components in different processed products- ebracteolata cpd B, ebracteolata cpd C and jolkinolide B and establish respective characteristic fingerprints to compare with similarity. The results showed that the content of ebracteolata cpd B, ebracteolata cpd C first increased and then decreased with the rise in temperature. Different processed products showed significant difference in HPLC spectrograms, with a low similarity. This study showed great impacts of auxiliary materials and temperature on chemical components of E. ebracteolata. As the vinegar processing method had higher attenuation and and synergistic effects than other methods, the auxiliary material vinegar cannot be replaced by chemical reagent acetic acid. PMID- 23947131 TI - [Phenylpropanoids and diphenylethene compounds from roots and rhizomes of Smilax scobinicaulis]. AB - The chemical constituents were separated and purified from the roots and rhizomes of Smilax scobinicaulis by various chromatographic methods including silica gel, Sephadex LH-20. Their structures were obtained and identified as resveratrol-3-O beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranoside (1), resveratrol (2), 8 viniferin (3), ethyl caffeate (4), 1-0-caffeoylglycerol (5), 1-O-p coumaroylglycerol (6), 1-0-feruloylglycerol (7), grossamide (8), moracin M (9) on the analysis of spectroscopic data. Compound 1 was a new compound and compounds 3 5, 8,9 were separated from this plant for the first time. PMID- 23947132 TI - [Chemical constituents of Periploca forrestii]. AB - The chemical constituents of Periploca forrestii were studied by means of macroporous resin, silica gel, ODS column chromatography and PHPLC. Nine compounds were isolated from this plant. By using ESI-MS and NMR, the structures of the nine compounds were determined as scopoletin (1), trans-3, 4 methylenedioxycinnamyl alcohol (2), syringaresinol (3), syringaresinol 4-0-beta-D glucopyranoside (4), 6'-0-(E)-feruloylsucrose (5), loliolide (6), 4-hydroxy-3 methoxyl-benzaidehyde (7), delta5-pregnene-3beta, 17alpha, 20alpha-triol (8) and delta5-pregnene-3 beta, 17alpha, 20 alpha-triol-20-0-beta-D-canaropyranoside (9), respectively. Compounds 1, 2 and 5-7 are isolated from Periplocagenus for the first time. PMID- 23947133 TI - [Flavonoids from Humulus lupulus]. AB - Nine compounds were isolated and purified by column chromatographic techniques including macroporous resin, silica gel, ODS, Sephadex LH-20, and preparative reversed-phase HPLC. Their structures were elucidated as taxifolin (1), naringenin (2), chalconaringenin (3), acacetin (4), quercetin 3-O-beta-D galactopyranoside (5), 6-prenylnaringenin (6) xanthohumol (7), desmethylxanthohumol (8), xanthohumol B (9) on the basis of MS and NMR spectroscopic data analysis. Compounds 1-5 were isolated from Humulus lupulus for the first time. PMID- 23947134 TI - [Chemical constituents of Conioselinum vaginatum]. AB - Sixteen compounds were isolated from Conioselinum vaginatum by silica column chromatography over silica gel and Sephadex LH-20, as well as recrystallization. On the basis of their physical and chemical properties and spectral data, their structures were identified as ligustilide (1), 1,3-dilinolein (2), coniferaldehyde (3), myristicin (4), stigmasterol (5), beta-sitosterol (6), vanillin (7), pregnenolone (8), bergapten (9), xanthotoxin (10), methyl indole-3 carboxylate (11), ferulic acid (12), (E)-3-methoxy-4,5-methylenedioxy-cinnamic alcohol (13), p-hydroxybenzaldehyde (14), 3-methoxy-4,5-methylenedioxy acetophenone (15), and alpha-(ethoxymethyl)-4-hydroxy- benzenemethanol (16). Among them, compound 15 was a new natural product, and compounds 2, 3, 10, 11, 14, and 16 were obtained from this genus for the first time. PMID- 23947135 TI - [Chemical constituents from twigs and leaves of Melodinus hemsleyanus]. AB - To study the chemical constituents in the twigs and leaves of Melodinus hemsleyanus. The chemical constituents were isolated by silica gel, ODS and Sephadex LH-20 column chromatographies. Their structures were determined by chemical and spectroscopic methods. Fourteen compounds were isolated from the 95% ethanol extract of the twigs and leaves of M. hemsleyanus. Their structures were identified as 11-hydroxytabersonine (1), venalstonid (2), sandine (3), oleanolic acid (4), ursolic acid (5), betulin (6), (+)-pinoresinol (7), (-)-syringaresinol (8), 8-hydroxypinoresinol (9), (-)-latifolin (10), cirsilineol (11), loganin (12), dibutylterephthalate (13), and beta-sitosterol (14). Compounds 4-14 were obtained from this plant for the first time. PMID- 23947136 TI - [Chemical constitutes of flavones from Pu-erh tea]. AB - The chemical constituents in the Pu-erh tea were isolated by various column chromatographic methods, and their structures were identified by spectral data and physic-chemical analysis. As a result, eleven flavonoids were isolated and identified as kaempferol (1), quercetin (2), kaempferol-3-O-beta-D glucopyranoside (3), kaempferol-3-O-beta-D-rutinoside (4), apigenin-6-C-alpha-L arabinopyranosyl-8-C-beta-D-glucopyranoside (5), vitexin-4"-O-beta-D glucopyranoside (6), kaempferol-3-O-[alpha-L-rhamnopyranosyl-(1--> 3)-alpha-L rhamnopyranosyl-(1-->6)-beta-D-glucopyranoside] (7), quercetin3-O-beta-D glucopyranoside (8), rutin (9), quercetin-3-0-alpha-L-rhamnopyranoside (10), and myricetin-3-0-beta-D-glucopyranoside (11). Compounds 5-7, 10 and 11 were isolated from Pu-erh tea for the first time. PMID- 23947137 TI - [Chemical constituents of Salvia chinensis]. AB - Chemical constituents were investigated on the ethyl acetate extract of Salvia chinensis. Compounds were separated and purified by various chromatograhic techniques including silica gel, Sephadex LH-20 and reversed-phase HPLC. Their structures were identified by spectroscopic data analysis. Eleven compounds were isolated and purified and their structures were identified as oresbiusin A(1), ethyl dihydrocaffeate (2), ethyl rosmarinate (3), rosmarinic acid (4), methyl rosmarinate (5), bis (2-ethylhexyl) phthalate (6), salvianol acid C (7), methyl salvianol acid C (8), methyl salvianolate A (9), dimethyl lithospermate B (10), and salvianolic acid A(11). Except for rosmarinic acid, the remaining compounds were isolated from S. chinensis for the first time. PMID- 23947138 TI - [HPLC fingerprints establishment of chemical constituents in genus Chimonanthus leaves]. AB - This study was aimed to establish the HPLC fingerprints of the genus Chimonanthus leaves and compare the constituents distribution among five Chimonanthus species . The analysis was conducted on a C15 column (4.6 mm x 250 mm, 5 microm) with the mobile phase containing acetonitrile-water in gradient program: acetonitrile (B), 0-20 min, 6%-20%; 20-30 min, 20%-25%; 30-40 min, 25%-45%; 40-50 min, 45%-80%; 50 80 min, 80%-85%; 80-90 min, 85%-100%; 90-110 min, 100%. Flow rate was 0.8 mL x min(-1) and detection wavelength was 228 nm. Column temperature was set at 30 degrees C. The HPLC fingerprints of the five Chimonanthus species have been established. Ch. praecox, Ch. nitens, Ch. salicifolius, Ch. Zhejiangensis and Ch. grammatus have significant difference in constituents distribution and contents. Five standard substances as common compounds were confirmed in chromatography fingerprints. The method can be used as quality evaluation and classicfication of the genus Chimonanthus. PMID- 23947139 TI - [Deconvolution of overlapped peaks in total ion chromatogram of essential oil from citri reticulatae pericarpium viride by automated mass spectral deconvolution & identification system]. AB - This experiment shows how to use the automated mass spectral deconvolution & identification system (AMDIS) to deconvolve the overlapped peaks in the total ion chromatogram (TIC) of volatile oil from Chineses materia medica (CMM). The essential oil was obtained by steam distillation. Its TIC was gotten by GC-MS, and the superimposed peaks in TIC were deconvolved by AMDIS. First, AMDIS can detect the number of components in TIC through the run function. Then, by analyzing the extracted spectrum of corresponding scan point of detected component and the original spectrum of this scan point, and their counterparts' spectra in the referred MS Library, researchers can ascertain the component's structure accurately or deny some compounds, which don't exist in nature. Furthermore, through examining the changeability of characteristic fragment ion peaks of identified compounds, the previous outcome can be affirmed again. The result demonstrated that AMDIS could efficiently deconvolve the overlapped peaks in TIC by taking out the spectrum of matching scan point of discerned component, which led to exact identification of the component's structure. PMID- 23947140 TI - [Investigation of a compound, compatibility of Rhodiola crenulata, Cordyceps militaris, and Rheum palmatum on metabolic syndrome treatment III--controlling blood glucose]. AB - Base on the improvement of compound FF16, compatibility of Rhodiola crenulata, Cordyceps militaris, and Rheum palmatum, on both insulin resistance and obesity, its effects on type 2 diabetes (T2DM ) was investigated here. The results showed that the levels of fasting and no-fasting blood glucose were controlled in the spontaneous type 2 diabetes KKAy mice; the impaired glucose tolerance (IGT)was improved by decreasing significantly the values of the glucose peaks and the area under the blood glucose-time curve (AUC ) after glucose-loading in glucose tolerance test (OGTT) in both high-fat-diet-induced pre-diabetes IRF mice and KKAy mice, respectively. The pancreatic histopathological analysis showed that the increased islet amount, the enlarged islet area, and the lipid accumulation in the pancreas were reversed by FF16 treatment in both IRF mice and KKAy mice. In the palmitate-induced RINm5f cell model, FF16 could effectively reduce the apoptosis and enhance the glucose-stimulated insulin secretion, respectively. In conclusion, FF16 could improve the T2DM by protecting the pancreatic beta-cells. PMID- 23947141 TI - [An approach to screen nephrotoxic components in traditional Chinese medicine based on fluorescent probe and HK-2 cells and its application]. AB - Using fluorescein diacetate labeled HK-2 cells, a fast method for screening nephrotoxic components in traditional Chinese medicines (TCMs) was proposed in this study. The methodology validation showed that the linearity, stability and accuracy of the proposed method were suitable for screening nephrotoxic components in vitro . This method was further applied on screen 352 components from 32 Chinese Pharmacopoeia-indexed toxic TCMs. The results indicated that 31 components from 14 toxic TCMs, including Badou, had significant toxicity on HK-2 cells, which suggested these components may cause nephrotoxicity. The components from the other 18 toxic TCMs had no significant toxicity on HK-2 cells. PMID- 23947142 TI - [Development of a rapid screening method for discovering neuroprotective components from traditional Chinese medicine]. AB - This study developed a method for rapid screening neuroprotective compounds with FDA (fluorescein diacetate) labeled SH-SYSY cells, which was injuried by Glu (L glutamic acid). The cell viability was determined by fluorescence automatic mi croscopy screening system. Then, neuroprotective components from Gegen Qinlian decoction were screened by the proposed method. The results demonstrated that 4 chemical components, C15, D06, D07 and E05 from Gegen Qinlian decoction, showed significantly neuroprotective effects. Furthermore, 8 compounds (i. e. daidzin, 3'-methoxydaidzin, liquiritin apioside, 6-C-L-alpha-arabinopyranosyl-8-C-beta-D glucopyranosyl chrysin, isoliquiritin apioside, baicalin, oroxylin-A-7-O-fP-D glucuronide and wogonoside) were identified from these active components by LC Q/TOF-MS technology (liquid chromatography quadrupole time of flight tandem mass spectrometry). These 8 compounds may be the potential neuroprotective substances in Gegen Qinlian decoction. PMID- 23947143 TI - [Screening of specific microRNA in hippocampus of depression model rats and intervention effect of Chaihu Shugan San]. AB - OBJECTIVE: To screen microRNAs with specific expression of in hippocampus of rats with chronic stress induced depression model, and observe the effect of traditional Chinese medicine Chaihu Shugan San on the expression of microRNA in hippocampus. METHOD: SD rats were randomly divided into 3 groups: the normal control group, the model control group and the Chaihu Shugan San group. The depression model was replicated by unpredictable chronic mild stress combined with separation. Behavioral changes of the rats were observed by Open-field test and sucrose solution consumption test, and the expression of microRNAs in hippocampus was assayed by microRNA micro-array. RESULT: Compared with the normal control group, there were 13 specific miRNAs in hippocampus in the model control group with the expression difference of more than 2 times. Among them, down regulating miRNAs included miR298, miR-130b, miR-135a, miR-323, miR-503, miR-15b, miR-532, and miR-125a, and the up-regulation miRNAs included miR7a, miR-212, miR 124, miR-139, and miR-182. Among the 13 specific miRNAs, miR-125a and miR-182 recovered to normal after intervention with Chaihu Shugan San in the Chaihu Shugan San group. CONCLUSION: This study preliminarily found that 13 specific miRNAs in hippocampus are related to depression. Among them, miR-125a and miR-182 recover to normal after intervention with Chaihu Shugan San, which may be the target points of the antidepressant effect of Chaihu Shugan San. We shall further analyze the target genes and their mechanisms. PMID- 23947144 TI - [Effect of baicalin on expression of TLR4 in RAW264.7 cells infected by ESBLs Escherichia coli]. AB - OBJECTIVE: To investigate the effect and mechanism of baicalin against beta lactamases Escherichia coli (ESBLs E. coli) mediated by toll-like receptor 4 (TLR4) signal transduction pathway. METHOD: The RAW264. 7 cells monolayer pretreated with different concentration of baicalin were inoculated with ESBLs E. coli. The expression of TLR4 mRNA and protein were analyzed by semi-quantitative RT-PCR and Immunofluorescence, respectively. The activity of NF-kappaB was detected by Western blot using total cellular protein. The production of TNF alpha in supernatant was determined by enzyme linked immunosorbnent assay (ELISA). RESULT: ESBLs E. coli significantly up-regulated the expression levels of TLR4 mRNA and protein in a time-dependent manner, induced the activation of NF KB in RAW264. 7, enhanced the production of TNF-alpha in supernatant. Baicalin down-regulated the expression of TLR4 mRNA and protein, decreased the activation of NF-KB in RAW264. 7 cells and reduced the production of TNF-alpha in supernatant in a dose-dependent manner. CONCLUSION: Baicailin could inhibit TLR4 signal transduction pathway. The mechanism of baicalin against ESBLs E. coli may be through inhibiting the expression of TLR4 and its signal transduction pathway. PMID- 23947145 TI - [Effect of Shenlian extracts on blood flow and vessel pathological changes in rabbits carotid atherosclerosis model induced by low shear stress]. AB - Lipid accumulation in the vessel wall and tunica intima vasorum pathological changes are important factors in the development of atherosclerosis, which are closely related with hemodynamics. In this paper, we established a model of local low shear stress in rabbits using carotid artery cannula and a high cholesterol diet for 2 weeks, 4 weeks and 8 weeks. The effects of Shenlian extract on blood flow, vascular pathology formation and lipid metabolism were assessed by electromagnetic blood flow meter and hematoxylin-eosin staining of the proximal end in carotid artery at different times. The results demonstrate that the relationship between blood flow and shear stress for control, atorvastatin, Shenlian extract high-dose, Shenlian extract middle-dose, and Shenlian extract low-dose were linearly related. The blood flow and the shear stress of proximal end in carotid artery of Shenlian extract (1.12, 2.24, 4.48 g x kg(-1)), and atorvastatin (4.7 x 10(-4) g x kg(-1)) were significantly (P < 0.05)increased compared with the control. Plasma total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) ,and high density lipoprotein cholesterol (HDL-C) were markedly decreased with the increasing of dose and time. This study is the first to prove that the inhibition of Shenlian extract on low shear stress (LSS) induces rabbits carotid atherosclerosis with increasing blood flow and decreasing lipids and vessel pathological changes. PMID- 23947146 TI - [Study on screening cardioprotective components from Zhishi Xiebai Guizhi Tang]. AB - Zhishi Xiebai Guizhi Tang (ZSXBGZT), a famous traditional Chinese formula from Synopsis of Golden Chamber, composing of five herbal medicines, has been routinely used for the therapy of cardiovascular diseases in clinical. However, the active components of ZSXBGZT have not been investigated thoroughly. A reliable cell model was established by H2O2-induced injury in neonatal rat cardiomyocytes (NRCMs), with fluorescein diacetate (FDA) labelling the live cells, to screen cardioprotective substances. Seven components were found to have obvious cardioprotective effects through screening ZSXBGZT, Vc as the positive control. Eleven compounds were identified by liquid chromatography-mass spectrometry (LC-MS) from the active components C18, D14, D15, D16 and E09, and 6 of them were investigated further, which showed that hesperidin, neohesperidin and eriodictyol could protect NRCMs from H2O2-induced injury. In particular, eriodictyol showed significant cardioprotective effects in a dose-response relationship. PMID- 23947147 TI - [Development and identification of monoclonal antibodies of cape jasmine proteins in Reduning injection]. AB - Liposoluble cape jasmine proteins were used to immunize BALB/C mice. Indirect ELISA was utilized to develop one monoclonal antibody by integrating SP2/0 cells and spleen cells from immunized BALB/C mice. The subclass of the monoclonal antibody was identified as IgG2b, with Kappa chain as its light chain. The ascite titer of 2H8 monoclonal antibody was 1:204 080. Western-blot analysis proved that 2H8 reacted with cape jasmine proteins to identify specific liposoluble protein with molecuar weight of around 58.5 kDa. Dot-ELISA was established with 2H8 ascites as the primary antibody, showing the minimum detectable amount of 19.5 ng. This study lays a foundation for the development of protein kits of Reduning injection. PMID- 23947149 TI - [Comparative study on effect of crude and different processed products of epimedium on pharmacokinetics characteristics in mice]. AB - To study different impacts of crude epimedium and extracts from different processed epimedium on pharmacokinetic characteristic parameters in mice. To explore the rationality of its processed products, mice were orally administered with crude epimedium and extracting solutions from heated epimedium and processed epimedium. With increased SOD value as an indicator, the relationship between time and equivalent body dose was obtained by using the pharmacological effect method. DAS 2.0 software was adopted to compare their pharmacokinetic parameters. The results showed significant differences in such pharmacokinetic parameters as Cmax and AUC of processed epimedium, heated epimedium and crude epimedium, namely processed epimedium > heated epimedium > crude epimedium. We could come to the conclusion that heated epimedium showed increased bioavailability, while epimedium processed with sheep oil could further promote in vivo absorption. PMID- 23947148 TI - [Comparative study on toxicity of extracts from Phytolaccae Radix before and after being processed with vinegar]. AB - OBJECTIVE: To extract and separate toxic components from Phytolaccae Radix, and to comare the changes in toxicity of Phytolaccae Radix before and after being processed with vinegar. METHOD: The mucous membrane irritation response, mouse peritoneal inflammation model and in vitro macrophages release NO model were applied to compared the changes in inflammatory toxicity of toxic components from Phytolaccae Radix before and after being processed with vinegar. RESULT: Toxic components of Phytolacca Radix had significant inflammatory toxicity, which could cause conjunctival edema in rabbits, and increase of PGE2 and macrophages release NO content in peritoneal exudate in mice. After being processed with vinegar, they showed reduced irritation, which resulted in decrease of PGE2 and macrophages release NO content in peritoneal exudate in mice. CONCLUSION: After being processed with vinegar, the toxicity of toxic components from Phytolacca Radix decreased obviously. PMID- 23947150 TI - [Research and analysis to Shui nationality medicine treatment orthopedics & traumatology]. AB - To investigated Shui nationality folk medicine's awareness to orthopedics & traumatology, the history of orthopedics & traumatology treatment, Shui nationality folk doctors' practicing medicine, heritage, diagnosis and treatment methods and tools, etc, through investigated drug resources category and distribution characteristics of Shui nationality medicine to orthopedics & traumatology treatment, explored and finished Shui nationality medicine orthopedics & traumatology treatment theoretical system. After more than 5 years' exploration and finishing, preliminarily formed the theoretical system framework and medicine application characteristics of Shui nationality medicine treating orthopedics & traumatology. Shui nationality medicine treatment orthopedics & traumatology has distinctive national style, and worthy to further exploration and research. PMID- 23947152 TI - [Mining rules on determination of four properties based on traditional Chinese medicine functional combination]. AB - OBJECTIVE: It laid the foundation of the large sample data mining for a comprehensive summary concerning four properties theory of traditional Chinese medicine (TCM), and also provided theory clues on determination of four properties for the new resource development of TCM and the clinical use of Chinese medicine. METHOD: Four properties data of 8 980 Chinese medicines from "Chinese herbal medicine (CHM)" and associated function index data were chose as data sets. Then, the IBM SPSS Clementine 14.1 data mining platform and Apriori model were adopted to mining classification-association rules, setting the minimum support threshold of rule antecedent and the minimum confidence threshold as 0.5% and 60%. RESULT: 11 classification-association rules involved in warm, cold and mild natures were found. CONCLUSION: It was discovered that the TCM with functions of "dispelling wind-cold, warming the middle, stopping pain and expelling wind-removing dampness, tonifying kidney yang, unblocking meridians and expelling wind-removing dampness, dispelling cold to stop pain, strengthening sinews-bones and expelling wind-removing dampness" was likely warm-natured, with functions of "tonifying the lung" was likely mild-natured, and with functions of " clearing heat and drying dampness, clearing heat and purging fire, eliminating restlessness" was likely cold-natured. PMID- 23947151 TI - [An introduction of Zuotai in Tibetan patent medicine]. AB - Zuotai is an essential part in Tibetan patent medicine, which plays an important role in treating diseases. This paper introduced the invention, preparing process, use, effectiveness, and safety of Zuotai, aimed to provide an insight for traditional Chinese medicine when using heavy mental within Chinese patent medicine. PMID- 23947153 TI - [Study on registration administration of extracts of traditional Chinese medicine and its preparation]. AB - This paper studied the status of registration administration of extracts of traditional Chinese medicine (TCM) and its preparation, discussed some factors which affect the quality of extracts of TCM and its preparation, and puted forward some suggestions to strengthen the registration administration of extracts of TCM and its preparation such as clear positioning and legal basis, improving and enhancing quality standards, implementing of record management and so on. PMID- 23947154 TI - [Study on syndrome quantification, differentiation and classification of traditional Chinese medicine with data envelopment analysis]. AB - To raise the syndrome sequence quantification, differentiation and classification algorithm based on data envelopment analysis for solving the modeling issue of syndrome differentiation and classification of traditional Chinese medicine (TCM). This algorithm has three steps: first, in order to obtain basic units for explaining pathogenesis, and establish a syndrome collection on this basis mechanisms of syndrome differentiation and classification were analyzed and classified according to TCM theory, mechanisms of syndrome differentiation and classification were analyzed and classified according to TCM theory; second, regularity and syndromes of corresponding prescriptions were sought according to the incidence and development progress of syndromes, and mathematical tools of data envelopment analysis were used to calculate state data of syndromes in each stage and obtain quantitative syndrome sequence; finally, syndrome sequence was taken as the measurement standard to quantify candidate syndromes and diagnostic information, and the similarity was calculated to obtain the matching degree between diagnostic information and candidate syndromes, so as to complete the syndrome differentiation and classification calculation. According to the results of model-based reasoning, the algorithm could indicate the regularity implied in prescription materials, and grasp the dynamic process of syndromes in an all round way, and its results were verified through calculation and analysis on clinical cases. At least, it provides an idea for quantitative modeling of TCM. PMID- 23947155 TI - [Status of reaching meridian research for Chinese matria medica and to raise "point-medicine" method]. AB - OBJECTIVE: To analyze the status of reaching meridian research for the Chinese Matria Medica and to raise point-medicine method. METHOD: To review and analyze the studied situation of the corresponding relationships between "materials", as the constituents in the Chinese materia medica (CMM) as reaching meridian material foundation, and "image", as the function states of the zang-fu viscera, to investigate the problems and the measures to solve it. RESULT: There are imprinting relationships among "materials", as the constituents alike metabolic pathway in the CMM as reaching meridian material foundation, and "image", as the function of the zang-fu viscera related with meridians, and "symptom", the states of them, retroacted, represented and explored by the corresponding meridianed constituents in the CMM as quantitative pharmacologic parameters,also modified by special acupuncture points, finally to establish the new method of reaching meridian according to meridian point-medicine action and also to investigate the relations between the constituents in the CMM and network targets of disease as to kill two birds with one arrow. CONCLUSION: There are imprinting relationships among "materials", "image", "symptom" versus CMM, zang-fu viscera function related with meridians, their function status respectively, which are modified by acupuncture merisian points. The point-medicine method for assuring reaching meridian is the most simple way to investigate reaching meridian for CMM, is also a important way to investigate visceral and meridianal manifestations. PMID- 23947156 TI - [Causes for change in producing areas of geo-authentic herbs]. AB - Geo-authentic herbs lay stress on their producing areas. The producing areas of most geo-authentic herbs have never changed since the ancient times. However, many other geo-authentic herbs have experienced significant changes in the long history. There are two main causes for the change in producing areas of herbs change of natural environment and development of human society, which are restricted by each other and play a great role throughout the development process of geo-authentic herbs. PMID- 23947157 TI - [Solved and unsolved problems of nutritional support in surgical gastroenterology]. AB - The article has revealed the relevance of nutriciology as a science, classification and types of nutritional support. Nutritional support--diagnostics and the metabolic correction of arising violations of various kinds of homeostasis, aimed at ensuring the functioning of the systems of protein-energy synthesis and intermediate exchange of nutrients, vitamins, macro--and microelements, or a temporary replacement therapy of their failure. The notions of "lack of food", "artificial" food, protein-energy insufficiency with the exception of the syndromes of malabsorption, alimentary anemia, the effects of protein-energy malnutrition, consumptive disease, starvation have been interpreted. It was noted that nutriciology has taken place as a science. The problems of prognostification of nutritional deficiency, assessment of nutritional risk, the organization of nutritional support in the hospital and at home have been presented. Some fundamental bases of enteral probe feeding have been described. PMID- 23947158 TI - [Digestive insufficiency of the stomach in children from the positions of clinical morphology and its role in the assessment of the indications for nutritional support ]. AB - The structure of gastric mucosa (GM) of the stomach fundus (SF) was studied in children with various gastrointestinal diseases. In children, the main structural parameters of the SF (GM thickness, depth of glands and thickness of the mucosal epithelium area) varied widely (3.5-5.3 times). The following ranges were allocated: hypotrophy ("atrophy"), eutrophy (area of mean values) and hypertrophy of SF GM thickness, depth of the glands and thickness of the mucosal epithelium area. Hypotrophy ("atrophy") of the SF glands was found in approximately one third of the children of different age which could lead to decrease in the digestive function of the stomach and cause specific clinical symptoms of dyspepsia. Atrophic changes of SF GM were observed in children of all age groups. Most often (49%), fundic glands hypotrophy was observed in children of early age. With age, the incidence of atrophic changes of SF GM decreased. Atrophic changes in the GM can be detected during microanatomical or histopathological (using morphometry) examination of the SF. PMID- 23947159 TI - [Changes in body composition of oncological patients receiving nutritional support]. AB - The article is devoted to problems of diagnostic and correction of malnutrition at patients with gastric cancer, undergoing the gastroectomy. AIMS: to study losses of body mass and dynamics of boby composition in organism of patients with gastric cancer, undergoing surgery, to estimate the efficiency of nutritional support. MATERIALS AND METHODS: open prospective cohort case-control study. Inspected 64 patients with cancer of stomach in II-IV phases, undergoing surgery. The duration of observation amounted to 12 months. 34 of these patients were obtained nutritional support (additional enteral nutrition) during 8 weeks. The efficiency of nutritional support estimated on dynamics of body mass, body composition, the content of total protein, albumin, hemoglobin, lymphocytes counts in the blood. When statistical processing of research results the non parametric criterion of Wilcoxon for dependent samples, as well as the dispersion rank analysis of Kraskel-Walles was used. CONCLUSION: oncological process is followed by the progression of undernutrition, independently of disease stage. The nutritional support (the additional enteral nutrition) allows to substantially to improve the nutritional status of oncological patients. PMID- 23947160 TI - [Deficiency of selenium in pneumonia: an accident or regularity? Problem of nutriciology and gastroenterology]. AB - THE AIM: Study of features of community-acquired pneumonia in young adults with deficiency of trace element selenium and the development directions of optimization of treatment. MATERIAL AND METHODS: The study of 114 patients with community-acquired pneumonia, were evaluated nutritional deficiencies, the level of selenium in the blood plasma and the efficiency of application selenium biologically active additives in treatment of community acquired pneumonia. THE RESULTS: The vast majority of the 114 patients with community-acquired pneumonia is marked by malnutrition and selenium varying degrees of symptoms. CONCLUSION: Application of selenium dietary supplement in patients with community-acquired pneumonia contributes to earlier periods of permission of pneumonia and increase outcomes from full resolution infiltrative pulmonary field changes according to the radiographic study in patients of this category. PMID- 23947161 TI - [System analysis of the relationship between the metabolism of vitamins by micro biota and the survival of the positive microflora of the digestive tract]. AB - A perspective direction of the treatment of dysbacteriosis is the use of so called metabolic prebiotics--products of metabolism of positive flora (for example, water substrate of the products of metabolism of E. coli, S. faecalis, L. acidophilus, L. helveticus (strains of DSM), out of which, as known, drug Hylak Forte is made. Our earlier systematic analysis of metabolomics, representatives of positive microflora, pointed to the fact that the latter contain specific biochemical mechanisms for biosynthesis and processing of a number of vitamins. In the present paper the results of a systematic analysis of the effects of vitamins B2, B6 and K on the survival of the representatives of the positive microflora on the basis of the substrate of metabolic products of positive flora have been presented. The results of the analysis allow us clarify the molecular mechanisms of the therapeutic effects of this drug with a very complex structure and confirm the available clinical data and are an important foundation for subsequent microbiological research. Metabolites in the preparation composition contribute to the normalization of metabolism of pyridoxalphosphate (vitamin B6), flavin adenin dinucleotide (FAD, a derivative of vitamin B2) and nicotinamide dinucleotide (NAD, a derivative of vitamin B3)- cofactors of enzymes that have a significant impact on the survival of microbiota. The proposed molecular mechanisms also indicate on a possible synergies between certain vitamins and micro elements, on the one hand, and molecular components of the preparations on the basis of waste products of microbiota on the other. PMID- 23947162 TI - [Experimental substantiation of the functional relationship of mineral elements of nutrition with intestinal mucus and the mucosa membrane of the intestine]. AB - Interaction of magnesium increased dietary level with enteral calcium metabolism through the gut wall and intestinal mucosa mechanism is described in ruminants. Magnesium excess was found in the endogenous fraction of chyme and in the intestinal mucosa and resulted in increased calcium concentration in these biological tissues. Magnesium itself did not penetrate into the internal gut environment, and calcium content in the organs and tissues was reduced. It is concluded that the interaction of minerals takes place in the gut prior to absorption, and that the intestinal mucosa is important for homeostatic balance of minerals in the digesta and in the internal body environment. PMID- 23947163 TI - [Nutritional support in surgical treatment of patients with post-gastroresection and post-gastrectomy syndromes]. AB - The aim of the research determine the character and peculiarities of nutritional support in surgical treatment of patients with gastroresection--and total gastrectomy syndromes. Analyzed are the results of the evaluation nourishing status of 68 patients who have had a resection intervention on the stomach. It was noted that the 26.5% of patients with clinical manifestations of diseases of operated stomach arise sub- and decompensated forms of disorders metabolism and nutrition, entailing numerous violations of homeostasis and requiring compliance with reconstructive surgical interventions. We studied the results of the implementation of the reconstructive operations with the formation of functionally active (see text for symbol) in 18 patients, suffering from the disease of stomach operated on. It is proved, that the rational nutritional support in the perioperative period allows to avoid gross violations of metabolism and provides a reasonably good compensation digestive function, significantly improving the quality of life of this category of patients. PMID- 23947164 TI - [Immuno-nutrition in intensive care and emergency surgery]. AB - The aim of the study is the improvement of nutritional support by immuno nutrition of patients, who are in critical conditions. The data on the impact of immuno active mixes (on the example of the mixture of Impact) on the immune and inflammatory response. In this, the number of postoperative infectious complications have been reliably decreased, the duration of the stay in the Department of R&IT and the hospital has been dicresed in whole, the cost of treatment in comparison with the use of standard schemes of patients with surgical and oncological profile has been significantly reduced. PMID- 23947165 TI - [Perspective applications of multi-species probiotics in the prevention of antibiotic-associated diarrhea]. AB - The problem of antibiotic-associated conditions is one of the most actual problems of clinical practice. The antibiotic-associated diarrhea is a multidisciplinary problem. Investigations of the small intestine microecological status and assessment of microflora at the patients receiving antibiotics testifies to dysbiosis existence. In article results of open-label investigation of a multispecies probiotic RioFlora Balance using for antibiotic-associated diarrhea prophylaxis in patients used antibacterial therapy are presented. PMID- 23947166 TI - [Selection of proton pump inhibitors in polymorbid patients]. PMID- 23947167 TI - [Nutricional support in the complex treatment of a patient with esophageal spasm]. AB - In the presented clinical case the theme of the need for an integrated therapeutic intervention has been disclosed, including nutritional support on the various links of the pathogenesis of esophagospasm to the effectiveness of the patient's treatment. PMID- 23947168 TI - [Syndrome of overlap of autoimmune hepatitis and primary biliary cirrhosis with the outcome in cirrhosis of the liver, complicated by fatal bleeding in the small intestine]. AB - The authors presents the clinical case of autoimmune overlap syndrome: autoimmune hepatitis and primary biliary cirrhosis with outcomes in the hepatic cirrhosis complicated fatal intestinal bleeding. PMID- 23947169 TI - [Opportunities of nutritional therapy and typical errors in the nutrition of patients with biliary tract diseases]. AB - This lecture intended for doctor describes the possibility to influence by nutrition the main mechanisms of pathogenesis in biliary tract diseases including cholestatic syndrome, disorders of bile physical-chemical properties, inflammation, biliary tract and intestinal disorders of motility. Typical mistakes in nutrition of patients with biliary tract pathology are discussed using clinical case history as an example. PMID- 23947170 TI - [Carbohydrates in clinical nutrition]. AB - The article presents data on role of carbohydrate in clinical nutrition. The review described carbohydrate metabolism, hormonal regulation of carbohydrate, carbohydrate energy source role, carbohydrate requirements in critical study. PMID- 23947171 TI - [Nutrition and metabolic syndrome from the positions of a gastroenterologist and a physiotherapist]. AB - Nutrition plays an important role in metabolic processes in the body. Studying the various parties of metabolic processes in the body in a number of diseases, considered in the framework of the metabolic syndrome, points to the systemic nature of the pathogenic mechanisms, including in addition to food factor sociology-economic, genetic, medical, pathology of the digestive system, etc., leading to a breach of the cell, receptor, enzyme interactions. PMID- 23947172 TI - [Immuno-nutrition and cellular therapy as stimulators of the regenerative reactions in the surgical patient's wound]. PMID- 23947173 TI - [Prospects for nutritional support of patients with ulcerative colitis]. AB - The article presents the data on the assessment of the degree of severity of ulcerative colitis and the selection of nutritional support with the account of the violations of the nutrition status with ulcerative colitis. PMID- 23947174 TI - [The basic research on the high-sensitive troponin I assay, and the application to evaluation of chronic heart failure]. AB - The mortality among patients with heart diseases increases steadily in an aging society like Japan. Among those, the patients with chronic heart failure (CHF) are thought to be increasing rapidly although the official report is missing. It is well-known that BNP or NT-proBNP is useful for a clinical diagnosis of CHF, but a role of the cardiac troponin (cTn) attracts attention as a novel biomarker of their prognosis. However, because the level of cTn in patients with CHF is far lower than that in cases of acute coronary syndrome (ACS), development of the high-sensitive method with precision is desired. In the present study, a new sensitive assay system with an analyzer, ARCHITECT STAT (cTnI hs-ARCH) was basically studied and found more sensitive than other conventional 2 sensitive methods. The performance of cTnI hs-ARCH was evaluated in patients with CHF by comparing it to findings with other 2 methods. When CHF patients are allocated into categories of NYHA classification according to their subjective symptoms, cTnI hs-ARCH was superior to other methods in discriminating subgroups. In addition, multivariable analysis disclosed that cTnI hs-ARCH is influenced by the level of renal function at the minimum among the 3 methods. Therefore, cTnI hs ARCH may be a useful method for evaluation of prognosis in patients with CHF who often have impaired renal function. PMID- 23947175 TI - [Performance of two matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) models for identification of bacteria isolated from blood culture]. AB - We compared the results of two bacterial identification methods: 1) a traditional method based on phenotypic identification of the causative organism using gram staining, culture and biochemical markers and 2) matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). A total of 111 isolates, including 107 strains of common bacteria species and 4 strains of 3 yeast species, were tested by the traditional method and MALDI-TOF MS method(VITEK MS and Micro flex LT). Data obtained using MALDI-TOF MS were classified as Level 1 and Level 2 according to the confidence level of identification results from the VITEK MS ver. 1.0 database (VITEK MS) and MALDI Biotyper ver. 2.0 database (Microflex LT). The proportions of measured samples identified as Level 1 were 98.2% with the VITEK MS database and 87.4% with the MALDI Biotyper database. The concordance rates of the traditional method were 93.7% with the VITEK MS database and 82.0% with the MALDI Biotyper database. Identification results of five strains were mismatched between the traditional method and MALDI-TOF MS. Their ribosomal RNA sequences were identical to the results obtained from MALDI-TOF MS. We concluded that the performance of VITEK MS is superior to that of the traditional method and Microflex LT. PMID- 23947176 TI - [Multi-course web-learning system for supporting students of medical technology]. AB - Web-Learning system was developed to support the self-learning for national qualification examination and medical engineering practice by students. The results from small tests in various situations suggest that the unit-learning systems are more effective, especially for the early stage of their self learning. In addition, the answers of some questionnaire suggest that the students' motivation has a certain relation with the number of the questions in the system. That is, the less number of the questions, the easier they are worked out with a higher learning motivation by students. Thus, the system was extended to enable students to study various subjects and/or units by themselves. The system enables them to have learning effects more easily by the exercise during lectures. The effectiveness of the system was investigated on medical associated subjects installed in the system. The concerning questions of Medical engineering and Pathological histology are adequately divided into several groups, of which sixteen Web-Learning subsystems were well composed for their practical application. Our concerning various unit-learning systems were confirmed much useful for most students comparing with the case of the overall Web-Learning system. PMID- 23947177 TI - [Immunoreaction and blood transfusion--chairmen's introductory remarks]. AB - Although blood transfusion is an extremely important therapeutic procedure that usually proceeds without complications, there are some risks associated with donated blood. Investigations into the causes of transfusion reactions and their prevention are important issues for transfusion therapy. In addition to nucleic acid amplification testing (NAT) for infectious diseases and the irradiation of blood to prevent post-transfusion GVHD, prestorage leukocyte reduction and diversion of the first part of the donation of blood were recently introduced into transfusion therapy. This symposium, entitled "Immunoreaction and blood transfusion", reviewed the immune responses associated with blood transfusion, which is probably the most frequent medical procedure performed in allogeneic organ transplantation, with four themes provided by the four featured invited speakers: transfusion-related acute lung injury (TRALI) and transfusion associated circulatory overload (TACO), high-dose intravenous immunoglobulin therapy for chronic inflammatory demyelinating polyradiculoneuropathy, transfusion-transmitted infectious disease surveillance, and transfusion-related immunomodulation. PMID- 23947178 TI - [Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO)]. AB - In recent years, much attention has been paid to respiratory complications of transfusion. Transfusion related acute lung injury (TRALI) is defined as an acute lung injury that is temporally associated with blood transfusion. TRALI is one of the leading causes of mortality. Although the etiology of TRALI is not fully understood, one of its main causes is thought to be anti-leukocyte antibodies, such as HLA antibody or HNA antibody. A precautionary male-predominant plasma strategy has been implemented in many developed countries, which has resulted in considerable achievements in reducing the incidence of TRALI. Meanwhile, transfusion-associated circulatory overload (TACO) has emerged as a major differential diagnosis of TRALI. TACO is a well-known complication of transfusion, which has been considered not as a side effect of transfusion but a result of erroneous medical practice. It has long been an under-reported complication of transfusion and has not been investigated scientifically. Recent data on transfusion mortality from the Food and Drug Administration revealed that TACO was the second highest cause of death in the United States. Our data also suggested a steep increase in the reported cases of TACO in Japan. Precautionary measures should also be implemented for this emerging complication. PMID- 23947179 TI - [Topics of chronic inflammatory demyelinating polyradiculoneuropathy--diagnosis and treatment situation in Japan]. AB - CIDP is a motor and sensory neuropathy characterized by chronic, step-wised, or relapsing progression. Both cellular and humoral autoimmunity targeting the myelin sheath is assumed as the main mechanism of CIDP pathogenesis. While the AAN diagnostic criteria have been the main method in Japan, the EFNS/PNS criteria recently replaced them because of their good diagnostic sensitivity and clinical superiority. The first-line therapy for CIDP patients in Japan is intravenous immunoglobulin (IVIg), corticosteroids, and phasmapheresis, the same as in other countries. Regarding therapeutics, two major differences between Japan and other countries exist. Firstly, while half-dose IVIg (1 g/kg body weight) every three weeks was established as maintenance therapy as a result of the ICE study in 2008, full-dose IVIg (2 g/kg body weight over five days) once a month is still accepted in Japan for highly recurrent patients. Secondly, Japanese clinicians prefer immune adsorption plasmapheresis (IAPP) instead of plasma exchange (PE) among three types of plasmapheresis (IAPP, PE, and double-filtered plasmapheresis [DFPP]). These differences could be due to the characteristic and independent health insurance system in Japan. Using recent knowledge and diagnostic criteria, clinical trials have been based on these global platforms. Recently, efforts have been made to share these platforms with a worldwide vision. PMID- 23947180 TI - [Blood transfusion and infectious diseases]. AB - Blood transfusion is essential in current medical treatment. In the era of selling blood, around 50% of recipients seemed to be infected by hepatitis virus. After the establishment of the blood donation system and many safety measures, the risk of blood contamination has decreased markedly; however, blood products still have a risk of known and unknown pathogens. In this manuscript, we discuss the remaining problems of HBV and HIV-1. As emerging infectious diseases, we examine Trypanosoma crusi, West Nile virus, Chikungunya virus, and Dengue virus. Finally, XMRV is exemplified as a rumored virus. Gathering accurate information about pathogens and preparing for outbreaks in advance are crucial for blood safety. PMID- 23947181 TI - [Introductory remarks by chairpersons]. AB - Personalized medicine (PM) is expected to change the healthcare system due to great progress in areas such as pharmacogenomics (PGx) and molecular diagnostics; however, PM is more popular in oncology than in clinic practice. Oncological therapies are easily personalized because accurate diagnostic tests are available to identify patients who can benefit from targeted therapies. Nevertheless, personalized medicine has become a more imminent reality for several reasons, such as the increased awareness of drugs with an adequate benefit/risk ratio to patients, better methods to optimize drug selection and dosing and so on. We invited four speakers to discuss the importance of PGx in the practice of PM from the viewpoint of basic and clinical research. PMID- 23947182 TI - [Challenge in genome-wide association study for establishment of personalized medicine: focusing on the pharmacogenomics of warfarin and carbamazepine]. AB - Drug efficacies and adverse drug reactions(ADRs) are often unpredictable, owing to the fact that responses to drugs vary among different individuals; however, it is believed that applying knowledge of pharmacogenomics (PGx) in clinical treatment can help to improve the prediction of drug responses, leading to the establishment of personalized medicine that aims to provide the right drug at the appropriate dose for each individual patient. In recent years, the FDA has recommended the genotyping of polymorphisms in drug-metabolizing enzymes and HLA prior to drug administration to avoid severe ADRs to many drugs, such as carbamazepine and abacavir. A genome-wide association study (GWAS) is useful to identify genomic biomarkers that can predict the efficacy or risk of ADRs to various drugs. In order to apply genomic biomarkers to clinical therapeutics, prospective clinical trials will be necessary to evaluate an intervention based on genetic tests. PMID- 23947183 TI - [Personalized medicine in transplantation therapy]. AB - Personalized medicine based on pharmacogenomics is being developed at the clinical stage. Various evidence is accumulating in transplantation therapy. Tacrolimus, a calcineurin inhibitor, is usually used for immunosuppressive therapy after transplantation. Tacrolimus is mainly metabolized by cytochrome P450 isozymes, CYP3A4 and CYP3A5, expressed in the intestine as well as in the liver. Recent studies of pharmacogenomics have reported that several single nucleotide polymorphisms (SNPs) of CYP3A5 are correlated with gene expression and enzyme activity. Phenotypes of CYP3A5 are typed as expressors (*1/*1 and *1/*3) or non-expressors (*3/*3) . In living-donor liver transplantation, CYP3A5 phenotypes could predict the blood concentration of tacrolimus. In particular, preoperative assessment of CYP3A5 genotypes in both recipients (intestine) and donors (graft liver) is required for predicting tacrolimus pharmacokinetics. In kidney transplantation, blood tacrolimus concentrations were significantly different between expressors and non-expressors. Genotyping and phenotyping of recipients were useful to predict blood tacrolimus levels in early phase of post transplantation. Furthermore, phenotypes of CYP3A5 could predict the initial dose of tacrolimus. Combination therapy was performed after bone marrow transplantation to prevent complications. Genotyping and phenotyping of metabolic enzymes for combination dugs would be useful for predicting drug actions. In conclusion, phenotyping based on pharmacogenomics supports personalized medicine in transplantation therapy. In future, multiplex testing should be developed to support personalized medicine in various fields. PMID- 23947184 TI - [Companion diagnostics and reimbursement system]. AB - Recently, Companion Diagnostics (CoDx) have been gaining importance to promote personalized medicine in order to improve the safety and cost effectiveness of therapy. In July 2011, the FDA published draft guidance for the development of CoDx, which recommends the co-development of CoDx and new drugs as the best practice, and then the FDA approved vemurafenib and the BRAF-V600-E gene mutation assay simultaneously as a typical example of the co-development of a new drug and its CoDx. Considering medical needs for multiple biomarker assays to select the right assay from various therapeutic candidates, more complicated assay technologies such as DNA sequencing will be required for CoDx in the near future. However, since it is quite difficult to standardize the validation process and manage test quality under the current regulatory criteria of in-vitro diagnostics using advanced and/or complicated assay technologies, the clinical use of laboratory-developed tests (LDT) should be recommended in order to avoid biomarker test lag. On the other hand, the current reimbursement system is not always suitable to assess the clinical and technological value of CoDx and it should be revised to encourage the development of CoDx. Although Health Technology Assessment (HTA) is a potential method to assess the value of CoDx, it is not easy to define appropriate indicators for CoDx because its clinical utility and cost effectiveness are completely dependent on the performance and value of available therapy. It is also suggested that the price and/or insurance rate of CoDx should be included in the price of the drug; however, there is no good solution to how to pay for CoDx with negative results for all therapies. It is said that the concept of personalized medicine with advanced technologies is a destructive innovation that could markedly change the current structure and system of medications; therefore, it is essential to create a quite new regulatory and reimbursement system to provide patients with the right medicine at the right time. PMID- 23947185 TI - [Effect of sample volumes and utilized anticoagulants on the measurement of complete blood counts including 3-part differentials using capillary blood]. AB - We collected the different volumes of venous blood(60 microL, 125 microL, 250 microL and 500 microL) into micro sample cups from respective volunteer to compare complete blood count (CBC) among 4 sample volumes, and found that 60 microL of sample volume seemed enough for CBC measurement using Microsemi LC-667 CRP (Horiba Co.). Subsequently, we measured CBC using 60 microL of peripheral blood after combining one of the 3 capillary tubes (heparin coated, EDTA coated and plain) with either EDTA coated or plain micro sample cups to examine the effect of anticoagulants contained into these commercially available maneuvers for capillary blood sampling. When we used the plain micro sample cup, platelet aggregation and false increase of white blood cell(WBC) count were observed irrespective to the combination of capillary tubes. We also tried whether commercially recommended volume (250 microL) of sample could be obtained by either fingertip or earlobe puncture from volunteers, and found that 7 of 16 fingertip and only 1 earlobe punctures could achieve sufficient volume. Whereas, at least 60 microL of sample were available more than 80% of volunteers by both methods, and CBC data obtained from these lesser samples obtained by fingertip puncture showed no statistically significant differences when compared with those of conventional venous samples (2 mL). From these findings, we concluded that at least 60 microL of capillary blood obtained from fingertip then collected into EDTA coated micro sample cup was enough to measure CBC using Microsemi LC-667 CRP. PMID- 23947186 TI - MLST analysis of multiple antimicrobial resistant Acinetobacter baumannii. AB - Multi-locus sequencing typing (MLST) of Acinetobacter baumannii, isolated at Showa University Hospital, was performed between November 2010 and March 2011. A. baumannii was isolated from 15 patients. Among the 15 isolates, the STs of three isolates were able to be determined, ST76, ST92, and ST146, and belonged to Clonal Complex (CC) 92, the global epidemic clone among carbapenem resistant A. baumannii. The other 12 strains were not applicable to the MLST classification. The ST76 strain was resistant to carbapenems, aminoglycosides, and fluoroquinolones. The ST92 strain was resistant to aminoglycosides and fluoroquinolones. The ST146 strain was resistant to fluoroquinolones. The other 12 strains were susceptible to either of the drugs. Neither the metallo beta lactamase gene (IMP type or VIM2) nor the OXA23 gene was detected in carbapenem resistant A. baumannii. These results indicate that A. baumannii of CC92 has spread as the drug resistant strain in Japan. Monitoring A. baumannii using molecular epidemiology is necessary. PMID- 23947187 TI - [The functional and pathological analysis of mitochondrial protein p32]. AB - p32 is an evolutionarily conserved and ubiquitously expressed multifunctional protein. Although p32 exists at diverse intra and extracellular sites, it is predominantly localized to the mitochondrial matrix near the nucleoid associated with mitochondrial transcription factor A. p32-deficient mice exhibited mid gestation lethality associated with a severe developmental defect of the embryo. Primary embryonic fibroblasts isolated from p32-knockout embryos showed severe dysfunction of the mitochondrial respiratory chain because of severely impaired mitochondrial protein synthesis. The RNA-binding ability of p32 is well correlated with mitochondrial translation. We also found that p32 is highly expressed in prostate tumor samples and its expression is significantly associated with the Gleason score, pathologic stage, and relapse. These data suggest that p32 is critical for prostate cancer cell proliferation and may be a novel marker of clinical progression in prostate cancer. PMID- 23947188 TI - [Japanese sentinel project and contribution of laboratory medicine]. AB - Ordinary passive surveillance (generally spontaneous reporting) of adverse effects of medical products is not enough to manage medical risks/safety. The Japanese government, following the "sentinel initiative" by the US government, started the "Japanese sentinel project" as an active surveillance of medical products with the Pharmaceuticals and Medical Devices Agency(PMDA). Using entire prescription data in the hospital information system, data on laboratory examinations, diagnosis, and therapy specific to an adverse effect are checked by detecting differences between before and after prescription of a specific medical product to extract adverse effects and calculate their correct frequency in the surveillance. The project uses standard masters and protocols to analyze data among medial institutes by installation of the SS-MIX standard storage system. Ten hospitals were selected in 2011 to join the project, and the entire system and network will be implemented in those hospitals and PMDA until 2013 fiscal year. JLAC10 is used in the project as the laboratory examination code of the Japanese Society of Laboratory Medicine. Many incorrect coding and ambiguous coding rules were found by voluntary surveillance of 6 of the 10 hospitals in the project. Thus, the Council on Standardized Master Operation of Clinical Laboratory Examinations will launch in 2013 to improve and maintain JLAC10, which is essential not only for the Japanese sentinel project but also for data utilization by many other projects. PMID- 23947189 TI - [Catheter-based intervention therapies for ischemic heart disease]. AB - Since the introduction of drug eluting stents (DES), the problem of restenosis, which had been an issue with percutaneous coronary intervention(PCI) for many years, has been overcome. Now that we understand the advantages and disadvantages of each device, the most important issue is whether or not the long term prognosis is better after PCI than after coronary artery bypass grafting (CABG). Comparing the evidence for PCI and CABG from this perspective has shown that PCI is still inferior with respect to the long term prognosis, emphasizing the importance of secondary prevention (lifestyle modification/drug therapy). By implementing OMT (Optimal Medical Therapy), which combines lifestyle modification with evidence-based and individualized drug therapy, to augment PCI, the long term prognosis may reach equivalence with that after CABG, and this will represent the start of an era in which coronary revascularization can be accomplished by minimally invasive treatment in the true sense. Now that the problem of restenosis has been overcome with the adoption of DES, the emphasis will be on secondary prevention in the future. PMID- 23947190 TI - [Laboratory management fee in national health insurance; what is required from clinical laboratory physicians? --message from Chairpersons]. AB - The laboratory management fee (LMF) in national health insurance ("Kentai-Kensa Kanri-Kasan" in Japanese) has had a major impact on Japanese clinical laboratories, especially in recent years. In 2012, the fee was raised to approximately 5,000 yen per admitted patient. In order to address this national support, clinical pathologists are required to increase their knowledge and skills. On the other hand, there are insufficient clinical pathologists in Japan. In order to solve this problem, the Japanese Society of Laboratory Medicine (JSLM) approved a new license for Qualified Clinical Laboratory Managing Physicians (CLMPs), in addition to Certified Clinical Laboratory Physicians (CCLPs). The requirements to become a CLMP are less strict than for CCLP. There are approximately 500 CLMPs and 600 CCLPs in this country. The aim of this symposium was to offer opportunities to increase attendees' clinical skills, especially CLMPs and young clinical pathologists. Four CCLPs were chosen as speakers from a university hospital, a major city hospital, a medium-sized acute care hospital, and a university hospital anatomical pathologist, together with a chief medical technologist from a university hospital. All the speakers presented their ideal role models of clinical pathologists matching LMF requirements. JSLM together with the Japanese Association of Clinical Laboratory Physicians (JACLaP) sponsored this symposium. It was a successful meeting with more than two hundred attendees. PMID- 23947191 TI - [Laboratory management fee; laboratory physician's work at university hospital]. AB - The laboratory additional management fee is subdivided into I to IV. Each additional management fee is a large source of income for hospitals. This is important in order to show the value to hospitals of laboratory physicians and clinical laboratory technologists. At this symposium, in order to charge an additional management fee correctly according to a laboratory physician's work at Surugadai Nihon University Hospital, an outline of a laboratory physician's duties is described. PMID- 23947192 TI - [Essential role of specialists in laboratory medicine--introduction to a novel logistic support system in our hospital]. AB - In cooperation with the clinical laboratory, our Department of Laboratory Medicine has established a novel logistic support system. The goal of this system is to improve the efficacy of laboratory medicine for both the clinician and patient through a new advisory service. Any abnormal patient laboratory data are detected by computer, printed and then checked and analyzed by medical technologists. The resulting comprehensive interpretation report is checked and confirmed by a clinical pathologist. After the results are analyzed, the clinical pathologist sends relevant clinical comments to a clinician via electric medical records. Additional comments are provided if further tests are needed. In serious cases, the clinical pathologist contacts the clinician directly by mobile phone. This system can benefit the clinician and patient in regards to both risk management and medical audit. In addition, other medical staff may become more aware of the role of the clinical laboratory and the Department of Laboratory Medicine. In a community hospital, specialists in laboratory medicine are gatekeepers for risk management and medical audits through advisory services. The day when the necessity and importance of specialists in laboratory medicine are properly recognized will surely come in the future. PMID- 23947193 TI - [Task analysis of clinical laboratory physician in acute hospital]. AB - Appropriate communications between clinical divisions and clinical laboratories are required to improve the quality of health care in hospitals. In this paper, the routine work of a clinical laboratory physician is presented. 1. In order to support attentive medical practice, we have established a consultation service system for handling questions from medical staff. The main clients are doctors and clinical laboratory technologists. 2. In order to improve the quality of infectious disease analysis, we have recommended obtaining two or more blood culture sets to achieve good sensitivity. The order rate of multiple blood culture sets increased 90% or more in 2011. 3. In order to provide appropriate blood transfusion, we intervene in inappropriate transfusion plans. 4. In order to support prompt decision making, we send E-mails to physicians regarding critical values. 5. We send reports on the morphology of cells(peripheral blood and bone marrow), IEP, flow cytometry, irregular antibodies, and so on. It has been realized that doctors want to know better solutions immediately rather than the best solution tomorrow morning. We would like to contribute to improving the quality of health care in Saitama Cooperative Hospital as clinical laboratory physicians. PMID- 23947194 TI - [Problems to be solved to qualify to receive laboratory examination management fee III or IV for board-certified doctors in the fields of both laboratory medicine and anatomical pathology]. AB - At least one full-time doctor in laboratory management and consultation on data analysis is required to receive laboratory examination management fee III or IV according to the rules for Japanese public health insurance medical fees. A qualified pathologist, board-certified as a clinical laboratory physician cannot receive this fee together with the pathological diagnosis management fee even if he or she manages laboratory examinations. As a result of this regulation, surgical pathologists working in laboratory examinations are gradually decreasing in Japan; however, it is possible for surgical pathologists working as full-time attending physicians in the Department of Laboratory Medicine to receive the laboratory examination management fee. Consultation regarding laboratory data analysis is required, and experience in diagnostic pathology is beneficial for data interpretation or tissue sample handling in the field of neoplastic diseases. PMID- 23947195 TI - [Bronchial asthma: progress in diagnosis and treatments. Editorial: Progress in diagnosis and treatment of bronchial asthma]. PMID- 23947196 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: I. Basic knowledge; 1. Paradigm shift in the treatment of asthma]. PMID- 23947197 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: I. Basic knowledge; 2. Japanese and global guidelines for asthma management]. PMID- 23947198 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: I. Basic knowledge; 3. Asthma in the elderly]. PMID- 23947199 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: I. Basic knowledge; 4. Differentiation and coexistence with COPD]. PMID- 23947200 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: II. Pathogenesis and pathophysiology; 1. The Dutch hypothesis and British hypothesis]. PMID- 23947201 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: II. Pathogenesis and pathophysiology; 2. Genes associated with asthma and asthma-related phenotypes]. PMID- 23947202 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: II. Pathogenesis and pathophysiology: 3. Roles of airway epithelium on the pathogenesis of allergic airway inflammation]. PMID- 23947203 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: II. Pathogenesis and pathophysiology; 4. Severe refractory asthma]. PMID- 23947204 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: III. Care and treatments; 1. Early intervention and out-grow for pediatric asthma]. PMID- 23947205 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: III. Care and treatments; 2. Pharmacotherapy]. PMID- 23947206 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: III. Care and treatments; 3. Treatment for acute exacerbation of asthma]. PMID- 23947207 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: IV. Subtype/particular type/comorbidities; 1. Asthma phenotypes]. PMID- 23947208 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: IV. Subtype/particular type/comorbidities; 2. Allergic rhinitis and obesity]. PMID- 23947209 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: IV. Subtype/particular type/comorbidities; 3. Cough variant asthma and similar conditions]. PMID- 23947210 TI - [Bronchial asthma: progress in diagnosis and treatments. Topics: IV. Subtype/particular type/comorbidities; 4. Aspirin-exacerbated respiratory disease (AERD)]. PMID- 23947211 TI - [Discussion meeting on the current status and future direction of asthma management]. PMID- 23947212 TI - [Case report: successful treatment with liraglutide in an insulin allergic patient with liver cirrhosis, hepatocellular carcinoma and poor glycemic control using high dose of insulin]. PMID- 23947213 TI - [Case report; a case of IgG4-related disease presented as pericardial effusion]. PMID- 23947214 TI - [Case report; a thromboembolic event in a patient with antiphospholipid antibody associated thrombocytopenia during eltrombopag therapy]. PMID- 23947215 TI - [Case report; suspected DPP-4 inhibitor-induced dropped head syndrome]. PMID- 23947216 TI - [Case report; differential diagnosis of post-transfusion graft-versus-host disease in a case with toxic epidermal necrolysis]. PMID- 23947217 TI - [Case report; a recurrent case of fulminant pneumococcal infection due to splenic hypoplasia under use of pneumococcal vaccine]. PMID- 23947218 TI - [The cutting-edge of medicine; novel therapeutic agents for the treatment of diabetes sodium-glucose co-transporter (SGLT) 2 inhibitors]. PMID- 23947219 TI - [The cutting-edge of medicine; role of hyperuricemia in cardiorenal syndrome]. PMID- 23947220 TI - [The cutting-edge of medicine; infectious gastroenteritis-norovirus infection]. PMID- 23947221 TI - [The cutting-edge of medicine; a new trend in hospital evaluation]. PMID- 23947222 TI - [Series: clinical study from Japan and its reflections; clinical trials about the gastroesophageal reflux disease]. PMID- 23947223 TI - [Series: for attending physicians; seeking to understand the diversity of medicine; education for clinical ethics practice and professionalism]. PMID- 23947224 TI - [Leukemia: recent progress in diagnosis and treatment. Editorial: Progress in research and development of therapy for leukemia]. PMID- 23947225 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: I. Recent findings in pathogenesis and pathophysiology; 1. Acute leukemia stem cells]. PMID- 23947226 TI - [Leukemia: recent progress in diagnosis and treatment topics: I. Recent findings in pathogenesis and pathophysiology; 2. Cytogenetic and genetic abnormalities in leukemia]. PMID- 23947227 TI - [Leukemia: recent progress in diagnosis and treatment topics: II. Approach to diagnosis; 1. FAB classification and WHO classification of leukemias]. PMID- 23947228 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: II. Approach to diagnosis; 2. Diagnostic process]. PMID- 23947229 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: II. Approach to diagnosis; 3. Clinical manifestations and complications in acute leukemia]. PMID- 23947230 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: III. Diagnosis and treatments; 1. Treatment for adult acute myeloid leukemia]. PMID- 23947231 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: III. Diagnosis and treatments: 2. Treatment for acute lymphoblastic leukemia]. PMID- 23947232 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: III. Diagnosis and treatments; 3. Treatment for acute promyelocytic leukemia]. PMID- 23947233 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: III. Diagnosis and treatments; 4. Diagnosis and treatment of chronic myeloid leukemia]. PMID- 23947234 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: III. Diagnosis and treatments; 5. Diagnosis and treatment of chronic lymphocytic leukemia]. PMID- 23947235 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: III. Diagnosis and treatments; 6. Indication and clinical outcome of hematopoietic stem cell transplantation for acute leukemia]. PMID- 23947236 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: III. Diagnosis and treatments; 7. Hematopoietic stem cell transplantation for leukemia: complications]. PMID- 23947237 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: IV. Recent topics; 1. Novel antibody therapy targeting CCR4 for adult T-cell leukemia/lymphoma]. PMID- 23947238 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: IV. Recent topics; 2. Recent advances in cell and immunogene therapy against leukemia]. PMID- 23947239 TI - [Leukemia: recent progress in diagnosis and treatment. Topics: IV. Recent topics; 3. The advances of bone marrow donor bank and cord blood bank]. PMID- 23947240 TI - [Discussion meeting on the daily practice of leukemia]. PMID- 23947241 TI - [Case report: a case in which vitamin B1 was effective for treatment of shoshin beriberi and Wernicke's encephalopathy]. PMID- 23947242 TI - [Case report; a case of gastorinoma with subclinical insulinoma presenting repeated episodes of hypoglycemic attack]. PMID- 23947243 TI - [Case report; a case of microscopic polyangitis presenting with acute tubulointerstitial nephritis]. PMID- 23947244 TI - [Case report; a case of monoclonal immunoglobulin deposition disease with membranoproliferative glomerulonephritis-like lesion]. PMID- 23947246 TI - [The cutting-edge of medicine; hyponatremia and water metabolism disorders in elderly]. PMID- 23947247 TI - [The cutting-edge of medicine; image-enhanced endoscopy for gastrointestinal carcinoma]. PMID- 23947245 TI - [Case report: a case of Epstein-Barr virus associated hemophagocytic syndrome with reversible leukoencephalopathy in the splenium of the corpus callosum]. PMID- 23947248 TI - [The cutting-edge of medicine; cutting edge of COPD therapy]. PMID- 23947249 TI - [Series: clinical study from Japan and its reflections; a nationwide survey of fulminant type 1 diabetes]. PMID- 23947250 TI - [Series: for attending physicians; seeking to understand the diversity of medicine; clinical research support in teaching hospital]. PMID- 23947251 TI - Redesigning healthcare. New delivery initiatives include ACOs, walk-in clinics, medical homes. AB - The CMS' laboratory for revamping the healthcare delivery system doesn't expect to produce policy changes for two more years. That has left lawmakers impatient for results. "Of course, we're all eager to see the results of these models, but we need to be realistic; this change is difficult," says Dr. Richard Gilfillan, left, director of the Center for Medicare & Medicaid Innovation. PMID- 23947252 TI - Doctor-approved. As health apps flourish, hospitals are beginning to sanction some for patients. PMID- 23947253 TI - Cutting out the middleman. Systems buying and developing insurance plans. PMID- 23947254 TI - Banking on wellness. Companies push to get workers into health programs. PMID- 23947255 TI - Combining efforts. Hospitals, health departments team up. PMID- 23947256 TI - Bucking the trend. Study: no advantage to knee surgery vs. therapy. PMID- 23947258 TI - Status check. Experts weigh in on ICD-10 conversion. PMID- 23947257 TI - Beyond the drugstore. Further expanding its scope, Walgreen inks deal with AmerisourceBergen. PMID- 23947259 TI - The Affordable Care Act at age 3. Despite many successes, healthcare reform law still faces challenges. PMID- 23947260 TI - Improving the patient experience. Panelists discuss moving beyond HCAHPS, focus on care, innovation. PMID- 23947261 TI - Medicaid's role in preventing crime. Expansion will help mentally ill offenders, but barriers to care will persist. PMID- 23947262 TI - The next level. Annual workforce report shows nurse practitioners pushing for increased autonomy in their roles. PMID- 23947263 TI - Data-driven. Nurses take diverse roads to informatics specialty. PMID- 23947264 TI - The wave As federal EHR incentives recede, the next surge in health IT spending begins to take shape. AB - Presbyterian Intercommunity hospital, part of PHI Health, is on the leading edge of a new surge in healthcare information technology. The hospital's plans include setting up a data warehouse for patient records and a patient portal, which is seen as key to involving patients in their own care. "It's really about patient engagement," said Dr. Davis Lee of PIH Health, left. "There are benefits to get the patients to go online and communicate with providers." PMID- 23947265 TI - Caught in the whirlwind D.C. scandals could impede ACA implementation. PMID- 23947266 TI - Celebrity impact. Benefits, risks seen in hype over Jolie's disclosure. PMID- 23947267 TI - Exclusion efforts. OIG pushes for monthly blacklist cross-check. PMID- 23947268 TI - Favorable direction? As prices drop, CBO lowers spending prediction. PMID- 23947269 TI - SGR hopes face tough realities. $139 billion, new payment formula still needed. PMID- 23947270 TI - Struggles for ex-military. Former medics starting careers face uphill battle,. PMID- 23947271 TI - Managing expectations. Tarwater talks Medicaid expansion, initiatives. Interview by Maureen McKinney. PMID- 23947272 TI - Scandal outbreak. Survival of reform depends on how administration weathers the storm. PMID- 23947273 TI - Cost sustainability. If payment reform fails, tie spending per beneficiary to GDP. PMID- 23947274 TI - Making progress. Sustained efforts to increase minority representation in healthcare executive ranks are delivering results, but barriers still remain. PMID- 23947275 TI - Bad medicine. Monitoring programs target substandard drugs. PMID- 23947276 TI - Toward a unified theory of objectification and dehumanization. AB - Objectification and dehumanization represent motivational conundrums because they are phenomena in which people are seen in ways that are fundamentally inaccurate; seeing people as objects, as animals, or not as people. The purpose of the 60th Nebraska Symposium on Motivation was to examine the motivational underpinnings of objectification and dehumanization of the self and others. To provide an overall context for this volume, we first provide classic conceptualizations of objectification and dehumanization and speculate about relations between the two. We then introduce a unified theory of objectification and dehumanization within the global versus local processing model (GLOMO) and provide initial supporting evidence. Finally, we introduce the chapters in this volume, which provide additional significant and novel motivational perspectives on objectification and dehumanization. PMID- 23947277 TI - The psychology of humanness. AB - This chapter explores the ways in which the concept of "humanness" illuminates a wide and fascinating variety of psychological phenomena. After introducing the concept--everyday understandings of what it is to be human--we present a model of the diverse ways in which humanness can be denied to people. According to this model people may be perceived as lacking uniquely human characteristics, and thus likened to animals, or as lacking human nature, and thus likened to inanimate objects. Both of these forms of dehumanization occur with varying degrees of subtlety, from the explicit uses of derogatory animal metaphors, to stereotypes that ascribe lesser humanness or simpler minds to particular groups, to nonconscious associations between certain humans and nonhumans. After reviewing research on dehumanization through the lens of our model we examine additional topics that the psychology of humanness clarifies, notably the perception of nonhuman animals and the objectification of women. Humanness emerges as a concept that runs an integrating thread through a variety of research literatures. PMID- 23947278 TI - Varieties of (de) humanization: divided by competition and status. AB - Recognizing or denying another's humanity varies predictably along apparently universal dimensions of the other's perceived warmth (trustworthiness) and competence. New data reveal distinct neural and behavioral signatures of (de)humanizing responses to distinct kinds of ingroups and outgroups on these dimensions. The most dehumanized outgroups (low on both warmth and competence) elicit disgust and avoidance, devalued as literally worth-less. In contrast, groups disliked for seeming cold but respected for competence elicit envy and Schadenfreude. Reactions to pitied outgroups--disrespected for seeming incompetent, but apparently likable enough for seeming trustworthy and warm- focus on prescriptions for their behavior. The humanization of ingroup members, who are both liked and respected, reflects individuating processes in impression formation, not necessarily accurate but at least three-dimensionally human. PMID- 23947279 TI - Immortal objects: the objectification of women as terror management. AB - Philosophical theorizing, research on self-objectification, and the newest empirical research on the objectification of others converge to support the notion that the objectification of women entails rendering women, quite literally, as objects. This chapter begins with a review of this literature and then moves onto the question of why women are viewed as objects. The answer offered is informed by terror management theory, and suggests that the need to manage a fear of death creates a fundamental problem with the physical body, and such difficulties resonate especially in reaction to women's--menstruating, lactating, childbearing--bodies, and men's attraction to them. Evidence is presented to support this, and for the position that this situation plays a role in, not just expectations for women to be beautiful, but in the literal transformation of women into inanimate--immortal--objects. PMID- 23947280 TI - On objects and actions: situating self-objectification in a system justification context. AB - Integrating objectification and system justification perspectives, this chapter offers a conception of self-objectification as a dominant cultural lens through which women come to view themselves that garners their compliance in the sexist status quo. This chapter begins with an overview of objectification theory (Fredrickson and Roberts 1997) and system justification theory (Jost and Banaji, 1994). Then, an integration of the two perspectives is presented that situates self-objectification in a system justification context, extending the scope of impact of self-objectification beyond the domains of body image and mental health. Empirical evidence is reviewed to demonstrate the direct and indirect ways that self-objectification works as a system-justifying device for many women. For example, as a self-perspective that increases in response to benevolently sexist ideology or as a potential obstacle to taking collective action on behalf of women, self-objectification functions as a motivational and ideological force that rationalizes and legitimizes a gender role hierarchy. This developing program of research attempts to deepen our understanding of self objectification and the broader system-level implications of this self perspective. The chapter concludes with a discussion of potential next steps and a call for continued scientific inquiry into the broader functions of self objectification. PMID- 23947281 TI - Motivated mind perception: treating pets as people and people as animals. AB - Human beings have a sophisticated ability to reason about the minds of others, often referred to as using one's theory of mind or mentalizing. Just like any other cognitive ability, people engage in reasoning about other minds when it seems useful for achieving particular goals, but this ability remains disengaged otherwise. We suggest that understanding the factors that engage our ability to reason about the minds of others helps to explain anthropomorphism: cases in which people attribute minds to a wide range of nonhuman agents, including animals, mechanical and technological objects, and supernatural entities such as God. We suggest that engagement is guided by two basic motivations: (1) the motivation to explain and predict others' actions, and (2) the motivation to connect socially with others. When present, these motivational forces can lead people to attribute minds to almost any agent. When absent, the likelihood of attributing a mind to others, even other human beings, decreases. We suggest that understanding the factors that engage our theory of mind can help to explain the inverse process of dehumanization, and also why people might be indifferent to other people even when connecting to them would improve their momentary wellbeing. PMID- 23947282 TI - Discrimination, objectification, and dehumanization: toward a pantheoretical framework. AB - In this chapter, I have called for greater attention to targets' experiences in theory and research on dehumanization. I have also argued that what we know from theory and research on targets' experiences of stigma and discrimination can inform how we pursue the understanding of targets' experiences of dehumanization. To this end, I have emphasized the utility of attention to the intersectionality of minority statuses in shaping discrimination experiences. I have also described theoretical frameworks grounded in different populations' experiences--including theories of discrimination as stressful life events or daily hassles, minority stress frameworks, and objectification theory--and offered examples of integrating these frameworks as a way to attend to intersectionality. As well, I have noted parallels between the areas of convergence across discrimination theories and emerging findings regarding the consequences of dehumanization for targets. Finally, I have described the broad outlines of a pantheoretical framework that reflects areas of convergence and complementary integration across the discrimination and dehumanization literatures. My hope is that this framework will encourage further attention to the potential distinctions between internalization and cognizance of discrimination, exploration of their potentially distinctive intermediary consequences, and consideration of a broader range of outcomes beyond individual health and well-being indicators, and including individual and collective social activism. I also hope that readers will contribute to the critical evaluation and refinement of this pantheoretical framework with continued attention to the intersectionality that characterizes people's identities and experiences of discrimination. PMID- 23947283 TI - Build your network with NEHA, 5,000 strong. PMID- 23947284 TI - Nanomaterials for environmental remediation: investigating the role of nanoinformatics in support of environmental, health, and safety oversight of nanotechnologies at the local level. AB - Nanotechnology is the science and practice of manipulating matter at or near atomic scale to create new materials of unique and novel properties for specific applications. Nanomaterials, including engineered nanoparticles (ENPs), have been used successfully for remediation since they are superior in technical performance and cost-effectiveness than traditional remedial technologies. Evidence indicates, however, that exposure to nanomaterials may lead to significant safety and health impacts. To protect human health against undesired risks from nanomaterials requires that safe and sustainable development of nanotechnology is in tandem with the availability of relevant information. State agencies responsible for the environment, safety, and public health were surveyed to understand their current and future information needs and capabilities to regulate nanomaterials. Because significant data gaps still exist on the toxicity and ecological impacts of nanomaterials, precautionary measures should be taken. Research to develop techniques for exposure assessments, surveillance and monitoring, databases, and characteristics of workplaces where ENPs are used is encouraged. PMID- 23947285 TI - Baseline knowledge survey of restaurant food handlers in suburban Chicago: do restaurant food handlers know what they need to know to keep consumers safe? AB - In the U.S., foodborne disease causes millions of illnesses annually, resulting in thousands of deaths. To reduce food poisoning, restaurant food handlers need accurate knowledge of food safety principles as a starting point for the outcome of optimal food safety behavior. The study described in this article determined food safety knowledge gaps among suburban Chicago restaurant food handlers. A cross-sectional survey of 729 food handlers at 211 suburban Chicago restaurants was conducted from June 2009 through February 2010. A 50-question survey was administered by a trained interviewer in either English or Spanish. Mixed-effects regression analysis identified risk factors associated with an overall food safety knowledge score. The mean overall knowledge score was only 72% and substantial knowledge gaps related to cross contamination, cooking, and holding and storage of food were identified. Spanish-speaking food handlers scored significantly lower than English-speaking food handlers (p < .05). Although certified food managers scored significantly higher than noncertified food handlers, their score was only 79%. These data provide targets for educational interventions to remedy knowledge gaps in food handlers in order to prevent food poisoning from restaurants. PMID- 23947286 TI - Can realtor education reduce lead exposures for vulnerable populations? AB - Lead is known for its devastating effects on people, particularly children under the age of six. Disturbed lead paint in homes is the most common source of lead poisoning of children. Preventive approaches including consumer education on the demand side of the housing market (purchasers and renters of housing units) and disclosure regulations on supply side of the housing market (landlords, homeowners, developers, and licensed realtors) have had mixed outcomes. The study described in this article considered whether a novel supply-side intervention that educates licensed real estate agents about the specific dangers of lead poisoning would result in better knowledge of lead hazards and improved behavior with respect to the information they convey to potential home buyers. Ninety-one licensed realtors were trained for four hours on lead hazards and their health impacts. Pre- and postsurveys and a six-month follow-up interview were conducted to assess the impact of the intervention on their knowledge and self-reported behaviors with clients. The findings suggest that supply-side education could have a salutary impact on realtor knowledge and behavior. PMID- 23947287 TI - Self-reported bed bug infestation among New York City residents: prevalence and risk factors. AB - Bed bug infestations have risen precipitously in urban areas. Little is known about risk factors for infestations or health outcomes resulting from these infestations. In the 2009 Community Health Survey, which is a representative population-based survey, 9,934 noninstitutionalized adults in New York City reported on bed bug infestations requiring an exterminator in the past year. The authors estimated infestation prevalence and explored predictors of infestation and associations between infestations and health outcomes using logistic regression. Seven percent of adults in New York City reported bed bug infestations. Significant individual and household risk factors were younger age, increased household poverty, and having three or more adults in the household. Environmental risk factors included living in high poverty neighborhoods and in buildings with more housing units, suggesting apartment-to-apartment transmission. Bed bug infestations were not associated with stress-related outcomes of alcohol consumption or recent depression, and, unlike cockroach infestation, were not associated with recent asthma episodes caused by allergens or contaminants. PMID- 23947288 TI - Environmental health--champions of One Health. AB - The authors find overwhelming evidence among environmental health practitioners that One Health disease reporting concepts are essential to the early detection of, and expedient recovery from, pandemic disease events. The authors also find, however, extraordinary evidence that local public health is not prepared, and potentially unaware of their responsibility, to be the initiator of the zoonotic infectious disease information intelligence necessary to make such early event mitigation possible. The authors propose that NEHA take an affirmative step towards the development of local public health-initiated biosurveillance systems by organizing and leading a tabletop study group that includes the Centers for Disease Control and Prevention, American Veterinary Medical Association, American Medical Association, Food and Drug Administration, U.S. Department of Agriculture, Institute of Medicine, and a robust panel of NEHA state affiliates. This study group should discuss the infrastructure necessary for local public health-the frontline against community-acquired infectious disease-to be the initiators of environmental health, veterinary, and medical One Health biosurveillance systems. The need to establish a community-focused, integrated disease prevention strategy that cautions people about the risks associated with food, water, animal, and contaminated environmental media, both prior to and during epidemic and pandemic events is equally important. PMID- 23947289 TI - An indicator framework to measure effects of Brownfields redevelopment on public health. PMID- 23947290 TI - Public health department accreditation and environmental public health: sustaining the collaboration. PMID- 23947291 TI - The rise of the city: a look at cities in a century. PMID- 23947292 TI - How NEHA helps you to keep your job and be employed. PMID- 23947296 TI - From the editor's desk. AB - No abstract available for this article. PMID- 23947293 TI - Modular microsystem for the isolation, enumeration, and phenotyping of circulating tumor cells in patients with pancreatic cancer. AB - In this manuscript, we discuss the development and clinical use of a thermoplastic modular microsystem for the high-throughput analysis of CTCs directly from whole blood. The modular system offers some innovative features that address challenges currently associated with many CTC platforms; it can exhaustively process 7.5 mL of blood in less than 45 min with recoveries >90%. In addition, the system automates the postselection CTC processing steps and thus, significantly reduces assay turnaround time (from selection to enumeration <1.5 h as compared to >8 h for many reported CTC platforms). The system is composed of 3 functional modules including (i) a thermoplastic CTC selection module composed of high aspect ratio (30 MUm * 150 MUm) channels containing anti-EpCAM antibodies that is scalable in terms of throughput by employing channel numbers ranging from 50 to 320; the channel number is user selected to accommodate the volume of blood that must be processed; (ii) an impedance sensor module for label-less CTC counting; and (iii) a staining and imaging module for the placement of released cells into a 2D array within a common imaging plane for phenotypic identification. To demonstrate the utility of this system, blood samples from patients with local resectable and metastatic pancreatic ductal adenocarcinoma (PDAC) were analyzed. We demonstrate the ability to select EpCAM positive CTCs from PDAC patients in high purity (>86%) and with excellent yields (mean = 53 CTCs per mL for metastatic PDAC patients) using our modular system. In addition, we demonstrate the ability to detect CTCs in PDAC patients with local resectable disease (mean = 11 CTCs per mL). PMID- 23947294 TI - The financial burden from non-communicable diseases in low- and middle-income countries: a literature review. AB - Non-communicable diseases (NCDs) were previously considered to only affect high income countries. However, they now account for a very large burden in terms of both mortality and morbidity in low- and middle-income countries (LMICs), although little is known about the impact these diseases have on households in these countries. In this paper, we present a literature review on the costs imposed by NCDs on households in LMICs. We examine both the costs of obtaining medical care and the costs associated with being unable to work, while discussing the methodological issues of particular studies. The results suggest that NCDs pose a heavy financial burden on many affected households; poor households are the most financially affected when they seek care. Medicines are usually the largest component of costs and the use of originator brand medicines leads to higher than necessary expenses. In particular, in the treatment of diabetes, insulin--when required--represents an important source of spending for patients and their families. These financial costs deter many people suffering from NCDs from seeking the care they need. The limited health insurance coverage for NCDs is reflected in the low proportions of patients claiming reimbursement and the low reimbursement rates in existing insurance schemes. The costs associated with lost income-earning opportunities are also significant for many households. Therefore, NCDs impose a substantial financial burden on many households, including the poor in low-income countries. The financial costs of obtaining care also impose insurmountable barriers to access for some people, which illustrates the urgency of improving financial risk protection in health in LMIC settings and ensuring that NCDs are taken into account in these systems. In this paper, we identify areas where further research is needed to have a better view of the costs incurred by households because of NCDs; namely, the extension of the geographical scope, the inclusion of certain diseases hitherto little studied, the introduction of a time dimension, and more comparisons with acute illnesses. PMID- 23947297 TI - From another perspective. AB - No abstract available for this article. PMID- 23947298 TI - Occupational therapy and the patient with pain. AB - The characteristics, implications, consequences and costs of pain, particularly those of chronic benign pain syndrome, are presented, and current approaches to treatment are briefly discussed. Contributions which occupational therapists are uniquely qualified to offer are described. Occupational therapists are grounded in the concept that mind, body and spirit are integrally related and that the patient must participate actively in the planning and implementation of any treatment program. The occupational therapist is a specialist in role functions and is skilled in assisting clients to plan and re-create structure for their lives that has been lost by virtue of their illness, disability, or pain. The occupational therapist provides an environmental laboratory in which people can experiment with new behaviors and attitudes to restructure and regain control of their lives and to reestablish hope, competence, confidence and success as part of their daily activities. These concepts are basic to the successful treatment of the patient with chronic benign pain syndrome. PMID- 23947299 TI - Stress management as a component of occupational therapy in acute care settings. AB - The recent explosion of stress literature in the medical community has created a new awareness of "stress" as a potentially destructive force in itself. Contributing the physical and psychological dysfunction, stress has now been linked with a wide range of diagnoses including cancer, cardiac disease and arthritis. The importance of incorporating stress management activities into daily life is increasingly apparent. Occupational therapists concerned with patients' ability to achieve health enhancing independent living skills are in a key position to help patients master stress management skills and incorporate them into activities of daily living. This article will explore the incorporation of stress management into occupational therapy programming for a variety of acute care patients. It will review the components of stress, the stress cycle, the relaxation response, the occupational therapy role based on a model of human occupation, and will review current programs through case study of four patients: one diagnosed with cancer (leukemia), one with anorexia nervosa, one with chronic pain and the fourth, a patient in medical intensive care. PMID- 23947300 TI - Occupational therapy intervention in chronic pain. AB - Chronic pain is one of the most costly health problems encountered in our society today. The problems constituting the Chronic Pain Syndrome are typically composed of a complex array of sensory, perceptual, psychological, environmental and other factors which require the coordinated efforts of an interdisciplinary team. Occupational behavior provides a very useful frame of reference for the occupational therapist treating the chronic pain patient. This biopsychosocial approach focuses on well behaviors and functional role performance. This paper provides an overview of chronic pain and presents occupational therapy assessment and treatment strategies with chronic pain patients. PMID- 23947301 TI - Perspectives on the pain of the hospice patient. AB - Behind the physical disfigurement and emotional ravages of advanced malignancy, it is the pain of cancer that is most dreaded. Severe biological pain is experienced by fewer than half of patients dying from cancer. Hospice physicians have the expertise to control the pain of those cancer patients who do experience it. The cancer patient may experience other forms of pain that can be equally devastating: pain of isolation, pain of abandonment, and pain of loss of role. It is important for the occupational therapist working in a hospice setting to understand all aspects of pain management, and the occupational therapy treatment strategies which can improve the quality of life and perception of pain for the hospice patient. Through presentation of case studies, the authors illustrate applications of occupational therapy assessments and interventions in respect to two hospice patients. The occupational therapy treatment strategies effected an improvement in the quality of life for these patients and consequently their perception of pain of loss of role. Occupational therapists, as part of the hospice team, play an important part in giving patients an opportunity to live out their lives in as dignified and purposeful a manner as their disease permits. PMID- 23947302 TI - The schultz structured interview for assessing upper extremity pain. AB - Trauma and disease processes in the upper extremity frequently cause pain as well as impairment in movement, strength and in function. While perception of pain occurs normally in response to bodily insult, prolonged or severe pain may interfere with attempts to maximize physical function and the return the involved person to optimal occupational role. Whether participating as a member on a medical or vocational rehabilitation team, the occupational therapist must adequately assess the area, nature and behavior of pain prior to providing appropriate intervention and recommendations to other team members. A structured interview to assess pain furnishes the therapist with a format for evaluation that is thorough and methodical. The structure and process of the interview allows the therapist to collect subjective information which can be coupled with objective findings from standard upper extremity evaluation and/or observation of task performance. Data gathered will assist the therapist in discovering the etiology of pain, in evaluating the appropriateness of complaints as they relate to pathology and in making appropriate recommendations about the patient's future work roles. PMID- 23947303 TI - Shoulder pain in the patient with hemiplegia. AB - Shoulder pain in the affected upper extremity of patients with hemiplegia is of fundamental concern to occupational therapists who are working for increased independence of patients. The author interviewed several other occupational therapists, reviewed recent literature and completed a survey of charts of 30 patients. The literature and the therapists' responses indicated a higher frequency of pain than the author anticipated. The chart review was completed (1) to determine objectively the frequency of shoulder pain or subluxation in patients with hemiplegia, and (2) to ascertain the use of the upper extremity and the performance of functional activities of those patients who had shoulder pain or subluxation. Although the number in the sample of charts was too small to yield more than an indication of problems, 3 group patterns emerged based on the differences in functional use of the upper extremity. These 3 patterns of function were compared with findings in the literature. Further study is suggested to assess pain and its responses to occupational therapy, during both the acute and chronic phases of care. The goal of research would be to better predict which patients would develop shoulder pain, thereby helping to prevent long-term complications. PMID- 23947304 TI - The role of occupational therapy in back school. AB - As 'Back Schools' are finding growing acceptance and recognition as a treatment for patients with back pain, occupational therapists are increasingly becoming involved in programming them. Traditionally such schools have been conceived and implemented by physicians and physical therapists. However as the Back School concept is analyzed, need for direct application of the skills and philosophies of the occupational therapy profession is quite evident. The core of the Back School program emphasizes that patients control back pain ultimately through the appropriate selection of and approach to their daily activities. Traditionally occupational therapists use directed performance in activities of daily living as ways to maximize patients' function. However, before hurling occupational therapists into the Back School setting one must ask "How much understanding of the biomechanics of the spine does the occupational therapist have?" A real "backbone" of understanding is essential in order for one to teach correct posture and body mechanics to persons who need to engage in all sorts of activities of daily living. An example of the occupational therapist role in two back school formats offered by the North Texas Back Institute is described. Results of follow-up surveys of back school 'graduates' from both programs are briefly reviewed. PMID- 23947305 TI - The use of biofeedback techniques in occupational therapy for persons with chronic pain. AB - The use of biofeedback in occupational therapy to aid the person with chronic pain in the resumption of his daily functional activities is discussed. The chronic pain syndrome and how it disrupts performance of activities is examined, as well as occupational therapy strategies for assessment and treatment using biofeedback, and indications for evaluating treatment outcomes. The authors assume readers have basic familiarity with biofeedback theory, equipment and its operation. PMID- 23947306 TI - The use of assertiveness training with chronic pain patients. AB - This paper describes one way that occupational therapy participates in a multidisciplinary program for chronic pain management. Assertiveness training as a means of acquiring improved communication skills is presented as one of the techniques used in reducing the emotional stress associated with pain. In addition, some of the other problems associated with the chronic pain syndrome are discussed along with occupational therapy's role in teaching assertiveness. Both the content of the assertion course and teaching examples are presented along with examples from patient participation. Although the assertiveness training has resulted in positive feedback and acceptance from patients, further study is needed to validate the results. PMID- 23947307 TI - The growth of the hospice movement. AB - This paper traces the history of the hospice movement, its present status and its projection for growth. It looks at hospices in the United States and in Great Britain, particularly examining the kinds of pain associated with terminal illness, and the allevation thereof. It compares the philosophy of hospice with the future of occupational therapy as an integral part of this humane program which provides palliative and supportive care for terminally ill patients and their families. PMID- 23947308 TI - What every therapist should know. AB - No abstract available for this article. PMID- 23947309 TI - Effectiveness of case management for homeless persons: a systematic review. AB - We reviewed the literature on standard case management (SCM), intensive case management (ICM), assertive community treatment (ACT), and critical time intervention (CTI) for homeless adults. We searched databases for peer-reviewed English articles published from 1985 to 2011 and found 21 randomized controlled trials or quasi-experimental studies comparing case management to other services. We found little evidence for the effectiveness of ICM. SCM improved housing stability, reduced substance use, and removed employment barriers for substance users. ACT improved housing stability and was cost-effective for mentally ill and dually diagnosed persons. CTI showed promise for housing, psychopathology, and substance use and was cost-effective for mentally ill persons. More research is needed on how case management can most effectively support rapid-rehousing approaches to homelessness. PMID- 23947310 TI - Prevalence of gender identity disorder and suicide risk among transgender veterans utilizing veterans health administration care. AB - OBJECTIVES: We estimated the prevalence and incidence of gender identity disorder (GID) diagnoses among veterans in the Veterans Health Administration (VHA) health care system and examined suicide risk among veterans with a GID diagnosis. METHODS: We examined VHA electronic medical records from 2000 through 2011 for 2 official ICD-9 diagnosis codes that indicate transgender status. We generated annual period prevalence estimates and calculated incidence using the prevalence of GID at 2000 as the baseline year. We cross-referenced GID cases with available data (2009-2011) of suicide-related events among all VHA users to examine suicide risk. RESULTS: GID prevalence in the VHA is higher (22.9/100 000 persons) than are previous estimates of GID in the general US population (4.3/100 000 persons). The rate of suicide-related events among GID-diagnosed VHA veterans was more than 20 times higher than were rates for the general VHA population. CONCLUSIONS: The prevalence of GID diagnosis nearly doubled over 10 years among VHA veterans. Research is needed to examine suicide risk among transgender veterans and how their VHA utilization may be enhanced by new VA initiatives on transgender care. PMID- 23947311 TI - Lusk et al. respond. PMID- 23947312 TI - Contribution of maternal age to preterm birth rates in Denmark and Quebec, 1981 2008. AB - OBJECTIVES: We sought evidence to support the hypothesis that advancing maternal age is potentially causing a rise in preterm birth (PTB) rates in high-income countries. METHODS: We assessed maternal age-specific trends in PTB using all singleton live births in Denmark (n = 1 674 308) and Quebec (n = 2 291 253) from 1981 to 2008. We decomposed the country-specific contributions of age-specific PTB rates and maternal age distribution to overall PTB rates over time. RESULTS: PTB rates increased from 4.4% to 5.0% in Denmark and from 5.1% to 6.0% in Quebec. Rates increased the most in women aged 20 to 29 years, whereas rates decreased or remained stable in women aged 35 years and older. The overall increase over time was driven by age-specific PTB rates, although the contribution of younger women was countered by fewer births at this age in both Denmark and Quebec. CONCLUSIONS: PTB rates increased among women aged 20 to 29 years, but their contribution to the overall PTB rates was offset by older maternal age over time. Women aged 20 to 29 years should be targeted to reduce PTB rates, as potential for prevention may be greater in this age group. PMID- 23947313 TI - An ongoing lack of knowledge about lead poisoning. PMID- 23947314 TI - Is poverty geographic or area-based? PMID- 23947315 TI - Niccolai et al. respond. PMID- 23947316 TI - Mexican American trial of community health workers: a randomized controlled trial of a community health worker intervention for Mexican Americans with type 2 diabetes mellitus. AB - OBJECTIVES: We assessed whether community health workers (CHWs) could improve glycemic control among Mexican Americans with diabetes. METHODS: We recruited 144 Mexican Americans with type 2 diabetes between January 2006 and September 2008 into the single-blinded, randomized controlled Mexican American Trial of Community Health Workers (MATCH) and followed them for 2 years. Participants were assigned to either a CHW intervention, delivering self-management training through 36 home visits over 2 years, or a bilingual control newsletter delivering the same information on the same schedule. RESULTS: Intervention participants showed significantly lower hemoglobin A1c levels than control participants at both year 1 Delta = -0.55; P = .021) and year 2 (Delta = -0.69; P = .005). We observed no effect on blood pressure control, glucose self-monitoring, or adherence to medications or diet. Intervention participants increased physical activity from a mean of 1.63 days per week at baseline to 2.64 days per week after 2 years. CONCLUSIONS: A self-management intervention delivered by CHWs resulted in sustained improvements in glycemic control over 2 years among Mexican Americans with diabetes. MATCH adds to the growing body of evidence supporting the use of CHWs to reduce diabetes-related health disparities. PMID- 23947317 TI - Developing a reporting guideline for social and psychological intervention trials. AB - Understanding randomized controlled trials of complex social and psychological interventions requires a detailed description of the interventions tested and the methods used to evaluate them. However, randomized controlled trial reports often omit, or inadequately report, this information. Incomplete and inaccurate reporting hinders the optimal use of research, wastes resources, and fails to meet ethical obligations to research participants and consumers. We explain how reporting guidelines have improved the quality of reports in medicine, and describe the ongoing development of a new reporting guideline for randomized controlled trials: an extension of the Consolidated Standards of Reporting Trials for social and psychological interventions. We invite readers to participate in the project by visiting our Web site, to help us reach the best-informed consensus on these guidelines ( http://tinyurl.com/consort-study ). PMID- 23947318 TI - An empirical evaluation of the US Beer Institute's self-regulation code governing the content of beer advertising. AB - OBJECTIVES: We evaluated advertising code violations using the US Beer Institute guidelines for responsible advertising. METHODS: We applied the Delphi rating technique to all beer ads (n = 289) broadcast in national markets between 1999 and 2008 during the National Collegiate Athletic Association basketball tournament games. Fifteen public health professionals completed ratings using quantitative scales measuring the content of alcohol advertisements (e.g., perceived actor age, portrayal of excessive drinking) according to 1997 and 2006 versions of the Beer Institute Code. RESULTS: Depending on the code version, exclusion criteria, and scoring method, expert raters found that between 35% and 74% of the ads had code violations. There were significant differences among producers in the frequency with which ads with violations were broadcast, but not in the proportions of unique ads with violations. Guidelines most likely to be violated included the association of beer drinking with social success and the use of content appealing to persons younger than 21 years. CONCLUSIONS: The alcohol industry's current self-regulatory framework is ineffective at preventing content violations but could be improved by the use of new rating procedures designed to better detect content code violations. PMID- 23947319 TI - A randomized trial of a hepatitis care coordination model in methadone maintenance treatment. AB - OBJECTIVES: We evaluated the efficacy of a hepatitis care coordination intervention to improve linkage to hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccination and clinical evaluation of hepatitis C virus (HCV) infection among methadone maintenance patients. METHODS: We conducted a randomized controlled trial of 489 participants from methadone maintenance treatment programs in San Francisco, California, and New York City from February 2008 through June 2011. We randomized participants to a control arm (n = 245) and an intervention arm (n = 244), which included on-site screening, motivational enhanced education and counseling, on-site vaccination, and case management services. RESULTS: Compared with the control group, intervention group participants were significantly more likely (odds ratio [OR] = 41.8; 95% confidence interval [CI] = 19.4, 90.0) to receive their first vaccine dose within 30 days and to receive an HCV evaluation within 6 months (OR = 4.10; 95% CI = 2.35, 7.17). A combined intervention adherence outcome that measured adherence to HAV-HBV vaccination, HCV evaluation, or both strongly favored the intervention group (OR = 8.70; 95% CI = 5.56, 13.61). CONCLUSIONS: Hepatitis care coordination was efficacious in increasing adherence to HAV-HBV vaccination and HCV clinical evaluation among methadone patients. PMID- 23947320 TI - Fraction of gestational diabetes mellitus attributable to overweight and obesity by race/ethnicity, California, 2007-2009. AB - OBJECTIVES: We calculated the racial/ethnic-specific percentages of gestational diabetes mellitus (GDM) attributable to overweight and obesity. METHODS: We analyzed 1 228 265 records of women aged 20 years or older with a live, singleton birth in California during 2007 to 2009. Using logistic regression, we estimated the magnitude of the association between prepregnancy body mass index and GDM and calculated the percentages of GDM attributable to overweight and obesity overall and by race/ethnicity. RESULTS: The overall estimated GDM prevalence ranged from 5.4% among White women to 11.9% among Asian/Pacific Islander women. The adjusted percentages of GDM deliveries attributable to overweight and obesity were 17.8% among Asians/Pacific Islander, 41.2% among White, 44.2% among Hispanic, 51.2% among Black, and 57.8% among American Indian women. Select Asian subgroups, such as Vietnamese (13.0%), Asian Indian (14.0%), and Filipino (14.2%), had the highest GDM prevalence, but the lowest percentage attributable to obesity. CONCLUSIONS: Elevated prepregnancy body mass index contributed to GDM in all racial/ethnic groups, which suggests that decreasing overweight and obesity among women of reproductive age could reduce GDM, associated delivery complications, and future risk of diabetes in both the mother and offspring. PMID- 23947321 TI - A successful asthma treatment program in Brazil. PMID- 23947322 TI - Cycle track safety remains unproven. PMID- 23947323 TI - The health of sexual minorities: a new frontier. PMID- 23947324 TI - Gender-equitable attitudes, bystander behavior, and recent abuse perpetration against heterosexual dating partners of male high school athletes. AB - OBJECTIVES: We assessed the relationship between gender attitudes, identified as a critical component of violence prevention, and abuse toward dating partners among adolescent male athletes. METHODS: Our sample comprised 1699 athletes from 16 high schools in northern California who were surveyed between December 2009 and October 2010 in the larger Coaching Boys Into Men trial. We used logistic regression to assess the association between gender-equitable attitudes, bystander behavior, and recent abuse incidents. RESULTS: Athletes with more gender-equitable attitudes and greater intention to intervene were less likely (adjusted odds ratio [AOR] = 0.36; 95% confidence interval [CI] = 0.28, 0.46; and AOR = 0.60; 95% CI = 0.48, 0.75, respectively) and athletes who engaged in negative bystander behavior were more likely (AOR = 1.22, 95% CI = 1.10, 1.35) to perpetrate abuse against their female dating partners. CONCLUSIONS: Despite the shift among bystander intervention programs toward gender neutrality, our findings suggest a strong association between gender attitudes and dating violence. Programs designed for adolescents should include discussion of gender attitudes and target bystander behavior, because these components may operate on related but distinct pathways to reduce abuse. PMID- 23947325 TI - Adolescent sexually transmitted infections and risk for subsequent HIV. AB - OBJECTIVES: We estimated the risk of HIV associated with sexually transmitted infection (STI) history during adolescence. METHODS: We retrospectively studied a cohort of adolescents (n = 75 273, born in 1985-1993) who participated in the Philadelphia High School STD Screening Program between 2003 and 2010. We matched the cohort to STI and HIV surveillance data sets and death certificates and performed Poisson regression to estimate the association between adolescent STI exposures and subsequent HIV diagnosis. RESULTS: Compared with individuals reporting no STIs during adolescence, adolescents with STIs had an increased risk for subsequent HIV infection (incidence rate ratio [IRR] for adolescent girls = 2.6; 95% confidence interval [CI] = 1.5, 4.7; IRR for adolescent boys = 2.3; 95% CI = 1.7, 3.1). Risk increased with number of STIs. The risk of subsequent HIV infection was more than 3 times as high among those with multiple gonococcal infections during adolescence as among those with none. CONCLUSIONS: Effective interventions that reduce adolescent STIs are needed to avert future STI and HIV acquisition. Focusing on adolescents with gonococcal infections or multiple STIs might have the greatest impact on future HIV risk. PMID- 23947326 TI - Evaluation of the New York City breakfast in the classroom program. AB - OBJECTIVES: We determined the impact of Breakfast in the Classroom (BIC) on the percentage of children going without morning food, number of locations where food was consumed, and estimated calories consumed per child. METHODS: We used a cross sectional survey of morning food consumed among elementary school students offered BIC and not offered BIC in geographically matched high-poverty neighborhood elementary schools. RESULTS: Students offered BIC (n = 1044) were less likely to report not eating in the morning (8.7%) than were students not offered BIC (n = 1245; 15.0%) and were more likely to report eating in 2 or more locations during the morning (51.1% vs 30%). Overall, students offered BIC reported consuming an estimated 95 more calories per morning than did students not offered BIC. CONCLUSIONS: For every student for whom BIC resolved the problem of starting school with nothing to eat, more than 3 students ate in more than 1 location. Offering BIC reduced the percentage of students not eating in the morning but may contribute to excess calorie intake. More evaluation of BIC's impact on overweight and obesity is needed before more widespread implementation. PMID- 23947327 TI - Bridging the gap between implementation science and parenting intervention. PMID- 23947329 TI - Zhang et al. respond. PMID- 23947328 TI - Risk of fatal injury in young children following abuse allegations: evidence from a prospective, population-based study. AB - OBJECTIVES: We examined variations in children's risk of an unintentional or intentional fatal injury following an allegation of physical abuse, neglect, or other maltreatment. METHODS: We linked records of 514 232 children born in California from 1999 to 2006 and referred to child protective services for maltreatment to vital birth and death data. We used multivariable Cox regression models to estimate variations in risk of fatal injury before age 5 years and modeled maltreatment allegations as time-varying covariates. RESULTS: Children with a previous allegation of physical abuse sustained fatal injuries at 1.7 times the rate of children referred for neglect. Stratification by manner of injury showed that children with an allegation of physical abuse died from intentional injuries at a rate 5 times as high as that for children with an allegation of neglect, yet faced a significantly lower risk of unintentional fatal injury. CONCLUSIONS: These data suggest conceptual differences between physical abuse and neglect. Findings indicate that interventions consistent with the form of alleged maltreatment may be appropriate, and heightened monitoring of young children referred for physical abuse may advance child protection. PMID- 23947330 TI - The importance of increased asthma education. PMID- 23947331 TI - Clark and Lachance respond. PMID- 23947332 TI - Kaminski et al. respond. PMID- 23947333 TI - Templated non-oxide sol-gel preparation of well-ordered macroporous (inverse opal) Ta3N5 films. AB - Reactions of Ta(NMe2)5 and n-propylamine are shown to be an effective system for sol-gel processing of Ta3N5. Ordered macroporous films of Ta3N5 on silica substrates have been prepared by infiltration of such a sol into close-packed sacrificial templates of cross-linked 500 nm polystyrene spheres followed by pyrolysis under ammonia to remove the template and crystallize the Ta3N5. Templates with long-range order were produced by controlled humidity evaporation. Pyrolysis of a sol-infiltrated template at 600 degrees C removes the polystyrene but does not crystallize Ta3N5, and X-ray diffraction shows nanocrystalline TaN plus amorphous material. Heating at 700 degrees C crystallizes Ta3N5 while retaining a high degree of pore ordering, whereas at 800 degrees C porous films with a complete loss of order are obtained. PMID- 23947334 TI - Effect of membrane stiffness and cytoskeletal element density on mechanical stimuli within cells: an analysis of the consequences of ageing in cells. AB - A finite element model of a single cell was created and used to compute the biophysical stimuli generated within a cell under mechanical loading. Major cellular components were incorporated in the model: the membrane, cytoplasm, nucleus, microtubules, actin filaments, intermediate filaments, nuclear lamina and chromatin. The model used multiple sets of tensegrity structures. Viscoelastic properties were assigned to the continuum components. To corroborate the model, a simulation of atomic force microscopy indentation was performed and results showed a force/indentation simulation with the range of experimental results. A parametric analysis of both increasing membrane stiffness (thereby modelling membrane peroxidation with age) and decreasing density of cytoskeletal elements (thereby modelling reduced actin density with age) was performed. Comparing normal and aged cells under indentation predicts that aged cells have a lower membrane area subjected to high strain as compared with young cells, but the difference, surprisingly, is very small and may not be measurable experimentally. Ageing is predicted to have a more significant effect on strain deep in the nucleus. These results show that computation of biophysical stimuli within cells are achievable with single-cell computational models; correspondence between computed and measured force/displacement behaviours provides a high-level validation of the model. Regarding the effect of ageing, the models suggest only small, although possibly physiologically significant, differences in internal biophysical stimuli between normal and aged cells. PMID- 23947335 TI - The expression of vasoactive intestinal polypeptide in visual cortex-17 in normal visual development and formation of anisometropic amblyopia. AB - AIMS: To document the expression of vasoactive intestinal polypeptide (VIP) in the visual cortex-17 of kittens with anisometropic amblyopia, and to investigate the relationship between VIP and the development of the visual system. METHODS: Sixteen normal kittens (4-wk of age) were randomly divided into two groups: control and amblyopic. Amblyopia was produced by atropinization of one eye in eight kittens. Four (2 normal and 2 amblyopia) kittens were sacrificed at weeks 3, 6, 9, or 12 post-treatment respectively. Expression of VIP-mRNA in the visual cortex-17 was detected through in-situ hybridization. Neurons in the visual cortex were visualized by transmission electron microscopy (TEM). The number of neurons was analyzed via light microscopy (LM). RESULTS: VIP-mRNA expression was increased with age in control kittens but remained nearly static in age-matched anisometropic amblyopic kittens (p < 0.05). The number of VIP-positive cells of amblyopic kittens decreased dramatically when compared to normal age-matched kittens (p < 0.05). The total comparison between different positive ranks suggested a significant difference. The degree of expression between these two groups was significantly different. Ultrastructurally, in the control group, the nuclear membrane of most neurons was discernable and chromatin was evenly distributed within the nucleus. Abundant cytoplasm and tubular-shaped mitochondria were observed. These cells were also rich in Golgi bodies, ribosomes, and endoplasmic reticulum. In amblyopic kittens, nuclei of most neurons were aggregated, the number of ribosomes and Golgi bodies was reduced, mitochondria were swollen, and mitochondrial cristae were shortened or even absent. The endoplasmic reticulum was distended and reduced in magnitude. CONCLUSIONS: VIP appears to play an important role in visual development, and its mRNA expression is affected by visual experiences. Visual dysfunction may down regulate the expression of VIP-mRNA by impairing the structure and function of the neurons in the visual cortex, finally leading to amblyopia. PMID- 23947336 TI - Public acceptability of government intervention to change health-related behaviours: a systematic review and narrative synthesis. AB - BACKGROUND: Governments can intervene to change health-related behaviours using various measures but are sensitive to public attitudes towards such interventions. This review describes public attitudes towards a range of policy interventions aimed at changing tobacco and alcohol use, diet, and physical activity, and the extent to which these attitudes vary with characteristics of (a) the targeted behaviour (b) the intervention and (c) the respondents. METHODS: We searched electronic databases and conducted a narrative synthesis of empirical studies that reported public attitudes in Europe, North America, Australia and New Zealand towards interventions relating to tobacco, alcohol, diet and physical activity. Two hundred studies met the inclusion criteria. RESULTS: Over half the studies (105/200, 53%) were conducted in North America, with the most common interventions relating to tobacco control (110/200, 55%), followed by alcohol (42/200, 21%), diet-related interventions (18/200, 9%), interventions targeting both diet and physical activity (18/200, 9%), and physical activity alone (3/200, 2%). Most studies used survey-based methods (160/200, 80%), and only ten used experimental designs. Acceptability varied as a function of: (a) the targeted behaviour, with more support observed for smoking-related interventions; (b) the type of intervention, with less intrusive interventions, those already implemented, and those targeting children and young people attracting most support; and (c) the characteristics of respondents, with support being highest in those not engaging in the targeted behaviour, and with women and older respondents being more likely to endorse more restrictive measures. CONCLUSIONS: Public acceptability of government interventions to change behaviour is greatest for the least intrusive interventions, which are often the least effective, and for interventions targeting the behaviour of others, rather than the respondent him or herself. Experimental studies are needed to assess how the presentation of the problem and the benefits of intervention might increase acceptability for those interventions which are more effective but currently less acceptable. PMID- 23947338 TI - Emergency nursing staff dispatch: sensitivity and specificity in detecting prehospital need for physician interventions during ambulance transport in Rovigo Emergency Ambulance Service, Italy. AB - INTRODUCTION: In Italy, administration of medications or advanced procedures dictates the prehospital presence of a physician to initiate treatment. Nursing staff is often used as dispatchers in Italian emergency medical ambulance services. There is little data about nursing dispatch performance in detecting high-acuity patients who need prehospital medications and procedures. OBJECTIVE: To determine the ability of a dispatch center staffed by emergency ambulance nurses to detect prehospital need for physician interventions in the context of a semi-rural area Emergency Medical Services system. METHODS: A retrospective analysis of 53,606 calls from the Rovigo Emergency Ambulance Services' database was undertaken. Physician prehospital interventions were defined as the administration of medications or procedures (advanced airway management and ventilation, pneumothorax decompression, fluid replacement therapy, external defibrillation, cardioversion and pacing). The dispatch codes (assigned by a subjective decision-making process as Red, Yellow, or Green) of all transported prehospital patient calls were matched with an out-of-hospital triage system staffed by clinicians to determine the number of correctly identified prehospital need of physician interventions. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: The sensitivity of subjective experience-based nursing dispatch in detecting the need for physician interventions was 78.0% (95% CI, 76.9%-79.1%), with a PPV of 36.6% (95% CI, 35.8%-37.5%). Specificity was 83.8% (95% CI: 83.4%-84.1%), with an NPV of 96.9% (95% CI, 96.8%-97.1%). CONCLUSION: A dispatch center staffed by nurses with six years of experience and three months of training correctly identified when not to send a doctor to the scene in the absence of need for physician interventions, using a subjective decision-making process. The nurses staffing the dispatch center also worked in the field. Dispatch center staff were not able to predict when there was no need for physician interventions in high-acuity dispatch code patients, resulting in an over-triage and use of emergency physicians on scene. PMID- 23947337 TI - Interspecies protein-protein interaction network construction for characterization of host-pathogen interactions: a Candida albicans-zebrafish interaction study. AB - BACKGROUND: Despite clinical research and development in the last decades, infectious diseases remain a top global problem in public health today, being responsible for millions of morbidities and mortalities each year. Therefore, many studies have sought to investigate host-pathogen interactions from various viewpoints in attempts to understand pathogenic and defensive mechanisms, which could help control pathogenic infections. However, most of these efforts have focused predominately on the host or the pathogen individually rather than on a simultaneous analysis of both interaction partners. RESULTS: In this study, with the help of simultaneously quantified time-course Candida albicans-zebrafish interaction transcriptomics and other omics data, a computational framework was developed to construct the interspecies protein-protein interaction (PPI) network for C. albicans-zebrafish interactions based on the inference of ortholog-based PPIs and the dynamic modeling of regulatory responses. The identified C. albicans zebrafish interspecies PPI network highlights the association between C. albicans pathogenesis and the zebrafish redox process, indicating that redox status is critical in the battle between the host and pathogen. CONCLUSIONS: Advancing from the single-species network construction method, the interspecies network construction approach allows further characterization and elucidation of the host pathogen interactions. With continued accumulation of interspecies transcriptomics data, the proposed method could be used to explore progressive network rewiring over time, which could benefit the development of network medicine for infectious diseases. PMID- 23947339 TI - Nursing diagnoses in pemphigus vulgaris: a case study. AB - PURPOSE: This case study illustrates the use of the nursing process based upon the standardized nursing diagnoses approved by NANDA International (NANDA-I), and using the Nursing Outcomes Classification (NOC) and the Nursing Interventions Classification (NIC) in the care of a patient with pemphigus vulgaris (PV). DATA SOURCES: The published literature on PV and the experience and expertise of the authors in working with people with impaired skin integrity and PV were used to develop this case study. DATA SYNTHESIS: The accuracy of nursing diagnoses and appropriateness of the nursing interventions were supported by the positive health outcomes of the patient. CONCLUSION: Impaired skin integrity is a human response diagnosed by nurses, and early treatment is important due to the vulnerability of these patients. IMPLICATIONS FOR NURSING PRACTICE: The case study contributes to nursing knowledge for professionals who care for patients with PV. PMID- 23947340 TI - Automated identification of pneumonia in chest radiograph reports in critically ill patients. AB - BACKGROUND: Prior studies demonstrate the suitability of natural language processing (NLP) for identifying pneumonia in chest radiograph (CXR) reports, however, few evaluate this approach in intensive care unit (ICU) patients. METHODS: From a total of 194,615 ICU reports, we empirically developed a lexicon to categorize pneumonia-relevant terms and uncertainty profiles. We encoded lexicon items into unique queries within an NLP software application and designed an algorithm to assign automated interpretations ('positive', 'possible', or 'negative') based on each report's query profile. We evaluated algorithm performance in a sample of 2,466 CXR reports interpreted by physician consensus and in two ICU patient subgroups including those admitted for pneumonia and for rheumatologic/endocrine diagnoses. RESULTS: Most reports were deemed 'negative' (51.8%) by physician consensus. Many were 'possible' (41.7%); only 6.5% were 'positive' for pneumonia. The lexicon included 105 terms and uncertainty profiles that were encoded into 31 NLP queries. Queries identified 534,322 'hits' in the full sample, with 2.7 +/- 2.6 'hits' per report. An algorithm, comprised of twenty rules and probability steps, assigned interpretations to reports based on query profiles. In the validation set, the algorithm had 92.7% sensitivity, 91.1% specificity, 93.3% positive predictive value, and 90.3% negative predictive value for differentiating 'negative' from 'positive'/'possible' reports. In the ICU subgroups, the algorithm also demonstrated good performance, misclassifying few reports (5.8%). CONCLUSIONS: Many CXR reports in ICU patients demonstrate frank uncertainty regarding a pneumonia diagnosis. This electronic tool demonstrates promise for assigning automated interpretations to CXR reports by leveraging both terms and uncertainty profiles. PMID- 23947341 TI - The role of FOXP3 in regulating immune responses. AB - Regulatory T cells (Tregs) act in trans to control immune responses. The suppressive function of Tregs relies heavily on high and stable expression of the transcription factor FOXP3, which, together with other transcription factors, activates anti-inflammatory genes and represses proinflammatory genes. FOXP3 is required to shape the unique signaling mechanisms in Tregs, creating a positive feedback pathway to further enhance its own expression. In addition, FOXP3 is thought to switch on a complex transcriptional network that leads to the stabilization of the Treg phenotype. Emerging data reveal that FOXP3 achieves this function in concert with several other transcription factors, many of which are associated with lineages of conventional T cells. In this review, we will discuss the structural features of FOXP3 and how it functions by interacting with other transcription factors. We will also summarize the role of FOXP3 in establishing the unique signaling cascades in Tregs. Finally, we will dissect the cooperative roles of FOXP3 and other T-cell lineage-defining transcription factors and discuss how these networks not only control the ability to Tregs to suppress different types of immune responses, but also enable Treg plasticity. PMID- 23947342 TI - Lipid-specific beta-sheet formation in a mussel byssus protein domain. AB - Intrinsically disordered proteins (IDP) or regions (IDR) can adopt multiple conformational states, depending on the interaction partners they encounter. This enables proteins or individual domains to fulfill multiple functions. Here, we analyzed the flank sequences of preCol-NG, one of three collagenous proteins of a mussel byssus thread governing its mechanical performance. preCol-NG comprises a collagen domain and nonrepetitive termini enclosing specific flank regions characterized by tandem repeats known from silk proteins, protein elastomers, and plant cell wall-associated proteins. We recombinantly produced a protein mimicking the M. galloprovincialis preCol-NG C-terminal flank region. The protein was intrinsically unfolded in solution, even at elevated temperatures. However, upon contact with small unilamellar vesicles (SUVs) reversible beta-structure formation occurred, reminiscent of partitioning-folding coupling. This behavior of preCol-NG flank domains likely impacts byssogenesis and sheds new light on a distinct mechanism of how fibrous protein materials might be achieved by lipid induced self-assembly in nature. PMID- 23947343 TI - Immunity to viruses. PMID- 23947344 TI - The expanding role of NLRs in antiviral immunity. AB - Nucleotide oligomerization and binding domain (NOD)-like receptors (NLRs) are a major constituent of the cytosolic innate immune-sensing machinery and participate in a wide array of pathways including nuclear factor kappaB (NF kappaB), mitogen-activated protein kinase (MAPK), inflammasome, and type I interferon (IFN) signaling. NLRs have known roles in autoimmune, autoinflammatory, and infectious diseases. With respect to virus infection, NLRP3 is the most extensively studied NLR, including mechanisms of activation and inhibition. Furthermore, the importance of NLRP3 in both innate and adaptive immunity has been demonstrated. In comparison to NLRP3, the roles of other NLRs during virus infection are only just emerging. NLRC2 is an important activator of innate antiviral signaling and was recently found to mitigate inflammation during virus infection through autophagy. Finally, functions for NLRX1 in immune modulation and reactive oxygen species production require further examination and the importance of NLRC5 as a transactivator of major histocompatibility complex (MHC) class I and antigen presentation is currently developing. In this review, we discuss current knowledge pertaining to viruses and NLRs as well as areas of potential research, which will help advance the study of NLR biology during virus infection. PMID- 23947346 TI - The impact of macroautophagy on CD8(+) T-cell-mediated antiviral immunity. AB - Macroautophagy is a catabolic recycling pathway, which can be induced by various stress stimuli. Viruses are able to manipulate autophagy in the cells that they infect. The impact of autophagy on the innate immune response to viruses and its stimulatory role in antigen presentation to CD4(+) T cells are well documented. Herein, we present the impact of autophagy on the activation of cytotoxic T lymphocyte (CTL)-mediated antiviral immune responses, which are required for the eradication or control of multiple viruses. We first discuss the general mechanisms by which viruses can either induce or block autophagy in cells. We then explore the cross-talk between autophagy and innate immune processes, which are both first line defenses against viruses; and constitute crucial steps for the initiation of potent adaptive immune responses. We describe the impact of autophagy on the presentation of viral peptide antigens on class I major histocompatibility complex (MHC I), a prerequisite for the priming of CTL responses. In sum, our review highlights the interplay between viruses and three integrated host response pathways - autophagy, innate and adaptive immunity - providing a framework for future mechanistic and pathogenesis-based research. PMID- 23947347 TI - The role of lung dendritic cell subsets in immunity to respiratory viruses. AB - Viral infections are a common cause of acute respiratory disease. The clinical course of infection and symptoms depend on the viral strain, the health status of the host, and the immunological status of the host. Dendritic cells (DCs) play a crucial role in recognizing and presenting viral antigens and in inducing adaptive immune responses that clear the virus. Because the lung is continuously exposed to the air, the lung is equipped with an elaborate network of DCs to sense incoming foreign pathogens. Increasing knowledge on DC biology has informed us that DCs are not a single cell type. In the steady state lung, three DC subsets can be defined: CD11b(+) or CD103(+) conventional DCs and plasmacytoid DCs. Upon inflammation, inflammatory monocyte-derived DCs are recruited to the lung. It is only recently that tools became available to allow DC subsets to be clearly studied. This review focuses on the activation of DCs and the function of lung DCs in the context of respiratory virus infection and highlights some cautionary points for interpreting older experiments. PMID- 23947345 TI - Interferon induction and function at the mucosal surface. AB - Interferons (IFNs) are produced in response to virus infection and induce an antiviral state in virtually all cell types. In addition to upregulating the transcription of genes that inhibit virus replication, type I (or -alpha/beta) IFNs also act to orchestrate the adaptive immune response to virus infection. Recently a new family of antiviral cytokines, the type III (or -lambda) IFNs, has been identified that activate the same antiviral pathways via a distinct receptor. Although the identical transcription factor, IFN-stimulated gene factor 3 is activated by either IFN-alpha/beta or IFN-lambda signaling, differences in the induction and action of these two cytokine families are beginning to be appreciated. In this article, we review this emerging body of literature on the differing roles these cytokines play in host defense of the mucosal surface. Although many viruses enter the body through the respiratory and gastrointestinal tracts, we have focused the discussion on influenza A virus, respiratory syncytial virus, and rotavirus, three ubiquitous human pathogens that target the epithelial lining and are associated with a major disease burden. PMID- 23947350 TI - Antiviral memory phenotype T cells in unexposed adults. AB - alphabeta T cells are an integral part of protective immunity against pathogens. After precursor cells arise in the adult bone marrow or fetal liver, they migrate to the thymus where they rearrange their T-cell receptor genes (TCR) and undergo selection on the basis of their interactions with ligands expressed by thymic stroma and other cells. Those that survive then exit the thymus to populate the peripheral immune compartment, where they patrol the blood and lymphoid systems. The composition of this pre-immune peripheral repertoire is critically important in determining the robustness of an immune response. In both mice and humans, the magnitude and diversity of a response are directly correlated with the frequency of precursor T cells. Equally relevant are the functional characteristics of these lymphocytes. Engagement of a specific antigen to the TCR activates signaling pathways in the naive T cell that result in cellular proliferation and the acquisition of particular effector functions. A portion of these persist following the resolution of infection and become memory cells. These memory cells can mount a faster and stronger response when they encounter the same antigen at a later time. As the molecular basis for TCR ligand interaction has become better defined, it is clear that some T cells can recognize multiple distinct ligands and therefore T-cell memory developed by exposure to one ligand may play a significant role in the response to a different antigen. Thus, there is an increasing focus on understanding how exposure to related or unrelated antigens influences the T-cell repertoire and impacts subsequent immunity. In this review, we discuss the issue of TCR cross-reactivity in the development of memory phenotype CD4(+) T cells and the implications for pathogen-specific responses. We review both the human and mouse data and discuss the therapeutic implications of these findings in the contexts of infection and vaccination. PMID- 23947349 TI - How specific is too specific? B-cell responses to viral infections reveal the importance of breadth over depth. AB - Influenza virus infection induces robust and highly protective B-cell responses. Knowledge gained from the analysis of such protective humoral responses can provide important clues for the design of successful vaccines and vaccination approaches and also provides a window into the regulation of fundamental aspects of B-cell responses that may not be at play when responses to non-replicating agents are studied. Here, I review features of the B-cell response to viruses, with emphasis on influenza virus infection, a highly localized infection of respiratory tract epithelial cells, and a response that is directed against a virus that continuously undergoes genetic changes to its surface spike protein, a major target of neutralizing antibodies. Two aspects of the B-cell response to influenza are discussed here, namely polyreactive natural antibodies and the role and function of germinal center responses. Both these features of the B-cell response raise the question of how important antibody fine-specificity is for long-term protection from infection. As outlined, the pathogenesis of influenza virus and the nature of the antiviral B-cell response seem to emphasize repertoire diversity over affinity maturation as driving forces behind the influenza-specific B-cell immunity. PMID- 23947348 TI - Natural killer cells: multifaceted players with key roles in hepatitis C immunity. AB - Natural killer cells (NKs) are involved in every stage of hepatitis C viral (HCV) infection, from protection against HCV acquisition and resolution in the acute phase to treatment-induced clearance. In addition to their direct antiviral actions, NKs are involved in the induction and priming of appropriate downstream T-cell responses. In the setting of chronic HCV, overall NK cell levels are decreased, subset distribution is altered, and changes in NK receptor (NKR) expression have been demonstrated, although the contribution of individual NKRs to viral clearance or persistence remains to be clarified. Enhanced NK cell cytotoxicity accompanied by insufficient interferon-gamma production may promote liver damage in the setting of chronic infection. Treatment-induced clearance is associated with activation of NK cells, and it will be of interest to monitor NK cell responses to triple therapy. Activated NK cells also have anti-fibrotic properties, and the same hepatic NK cell populations that are actively involved in control of HCV may also be involved in control of HCV-associated liver damage. We still have much to learn, in particular: how do liver-derived NKs influence the outcome of HCV infection? Do NK receptors recognize HCV-specific components? And, are HCV-specific memory NK populations generated? PMID- 23947352 TI - The contextual role of TNFR family members in CD8(+) T-cell control of viral infections. AB - Immunity to viruses must be tightly controlled to avoid pathology. Receptors and ligands of the tumor necrosis factor (TNF) family play important roles in controlling lymphocyte activation and survival during an immune response. The role of specific TNF receptor (TNFR) family members in antiviral immunity depends on the stage of the immune response and can vary with the virus type and its virulence. Here, we focus on five members of the TNFR family that are prominently expressed on CD8(+) T cells during viral infections, namely, 4-1BB (CD137), CD27, OX40 (CD134), GITR, and TNFR2. 4-1BB, CD27, OX40, and GITR have primarily prosurvival roles for CD8(+) T cells during viral infection, although under some circumstances 4-1BB, GITR, or CD27 signals can limit immunity. Although TNFR2 can be costimulatory under some circumstances, its main role in CD8(+) T-cell responses during viral infection appears to be in contraction of the response. Several TNF family ligands are being explored as adjuvants for viral vaccines, and agonistic antibodies to TNFR family members are being investigated for immunotherapy of chronic viral infection alone and in combination with checkpoint blockade. Such therapies will require thorough and specific optimization to avoid pathology induced by hyperstimulation of these pathways. PMID- 23947351 TI - The great balancing act: regulation and fate of antiviral T-cell interactions. AB - The fate of T lymphocytes revolves around a continuous stream of interactions between the T-cell receptor (TCR) and peptide-major histocompatibility complex (MHC) molecules. Beginning in the thymus and continuing into the periphery, these interactions, refined by accessory molecules, direct the expansion, differentiation, and function of T-cell subsets. The cellular context of T-cell engagement with antigen-presenting cells, either in lymphoid or non-lymphoid tissues, plays an important role in determining how these cells respond to antigen encounters. CD8(+) T cells are essential for clearance of a lymphocytic choriomeningitis virus (LCMV) infection, but the virus can present a number of unique challenges that antiviral T cells must overcome. Peripheral LCMV infection can lead to rapid cytolytic clearance or chronic viral persistence; central nervous system infection can result in T-cell-dependent fatal meningitis or an asymptomatic carrier state amenable to immunotherapeutic clearance. These diverse outcomes all depend on interactions that require TCR engagement of cognate peptide-MHC complexes. In this review, we explore the diversity in antiviral T cell behaviors resulting from TCR engagement, beginning with an overview of the immunological synapse and progressing to regulators of TCR signaling that shape the delicate balance between immunopathology and viral clearance. PMID- 23947353 TI - Multipronged CD4(+) T-cell effector and memory responses cooperate to provide potent immunity against respiratory virus. AB - Over the last decade, the known spectrum of CD4(+) T-cell effector subsets has become much broader, and it has become clear that there are multiple dimensions by which subsets with a particular cytokine commitment can be further defined, including their stage of differentiation, their location, and, most importantly, their ability to carry out discrete functions. Here, we focus on our studies that highlight the synergy among discrete subsets, especially those defined by helper and cytotoxic function, in mediating viral protection, and on distinctions between CD4(+) T-cell effectors located in spleen, draining lymph node, and in tissue sites of infection. What emerges is a surprising multiplicity of CD4(+) T cell functions that indicate a large arsenal of mechanisms by which CD4(+) T cells act to combat viruses. PMID- 23947354 TI - Tissue-resident memory T cells. AB - Tissues such as the genital tract, skin, and lung act as barriers against invading pathogens. To protect the host, incoming microbes must be quickly and efficiently controlled by the immune system at the portal of entry. Memory is a hallmark of the adaptive immune system, which confers long-term protection and is the basis for efficacious vaccines. While the majority of existing vaccines rely on circulating antibody for protection, struggles to develop antibody-based vaccines against infections such as herpes simplex virus (HSV) and human immunodeficiency virus (HIV) have underscored the need to generate memory T cells for robust antiviral control. The circulating memory T-cell population is generally divided into two subsets: effector memory (TEM ) and central memory (TCM ). These two subsets can be distinguished by their localization, as TCM home to secondary lymphoid organs and TEM circulate through non-lymphoid tissues. More recently, studies have identified a third subset, called tissue-resident memory (TRM ) cells, based on its migratory properties. This subset is found in peripheral tissues that require expression of specific chemoattractants and homing receptors for T-cell recruitment and retention, including barrier sites such as the skin and genital tract. In this review, we categorize different tissues in the body based on patterns of memory T-cell migration and tissue residency. This review also describes the rules for TRM generation and the properties that distinguish them from circulating TEM and TCM cells. Finally, based on the failure of recent T-cell-based vaccines to provide optimal protection, we also discuss the potential role of TRM cells in vaccine design against microbes that invade through the peripheral tissues and highlight new vaccination strategies that take advantage of this newly described memory T-cell subset. PMID- 23947355 TI - Role of regulatory T cells during virus infection. AB - The host response to viruses includes multiple cell types that have regulatory function. Most information focuses on CD4(+) regulatory T cells that express the transcription factor Foxp3(+) (Tregs), which are the topic of this review. We explain how viruses through specific and non-specific means can trigger the response of thymus-derived natural Tregs as well as induce Tregs. The latter derive under appropriate stimulation conditions either from uncommitted precursors or from differentiated cells that convert to become Tregs. We describe instances where Tregs appear to limit the efficacy of antiviral protective immunity and other, perhaps more common, immune-mediated inflammatory conditions, where the Tregs function to limit the extent of tissue damage that occurs during a virus infection. We discuss the controversial roles that Tregs may play in the pathogenesis of human immunodeficiency and hepatitis C virus infections. The issue of plasticity is discussed, as this may result in Tregs losing their protective function when present in inflammatory environments. Finally, we mention approaches used to manipulate Treg numbers and function and assess their current value and likely future success to manage the outcome of virus infection, especially those that are responsible for chronic tissue damage. PMID- 23947356 TI - Virus infection, antiviral immunity, and autoimmunity. AB - As a group of disorders, autoimmunity ranks as the third most prevalent cause of morbidity and mortality in the Western World. However, the etiology of most autoimmune diseases remains unknown. Although genetic linkage studies support a critical underlying role for genetics, the geographic distribution of these disorders as well as the low concordance rates in monozygotic twins suggest that a combination of other factors including environmental ones are involved. Virus infection is a primary factor that has been implicated in the initiation of autoimmune disease. Infection triggers a robust and usually well-coordinated immune response that is critical for viral clearance. However, in some instances, immune regulatory mechanisms may falter, culminating in the breakdown of self tolerance, resulting in immune-mediated attack directed against both viral and self-antigens. Traditionally, cross-reactive T-cell recognition, known as molecular mimicry, as well as bystander T-cell activation, culminating in epitope spreading, have been the predominant mechanisms elucidated through which infection may culminate in an T-cell-mediated autoimmune response. However, other hypotheses including virus-induced decoy of the immune system also warrant discussion in regard to their potential for triggering autoimmunity. In this review, we discuss the mechanisms by which virus infection and antiviral immunity contribute to the development of autoimmunity. PMID- 23947357 TI - Myeloid-derived suppressor cells: the dark knight or the joker in viral infections? AB - Myeloid derived suppressor cells (MDSCs) are immature cells of myeloid origin, frequently found in tumor microenvironments and in the blood of cancer patients. In recent years, MDSCs have also been found in non-cancer settings, including a number of viral infections. The evasion of host immunity employed by viruses to establish viral persistence strikingly parallels mechanisms of tumor escape, prompting investigations into the generation and function of MDSCs in chronic viral infections. Importantly, analogous to the tumor microenvironment, MDSCs effectively suppress antiviral host immunity by limiting the function of several immune cells including T cells, natural killer cells, and antigen-presenting cells. In this article, we review studies on the mechanisms of MDSC generation, accumulation, and survival in an effort to understand their emergent importance in viral infections. We include a growing list of viral infections in which MDSCs have been reported. Finally, we discuss how MDSCs might play a role in establishing chronic viral infections and identify potential therapeutics that target MDSCs. PMID- 23947358 TI - Dual role of commensal bacteria in viral infections. AB - With our abilities to culture and sequence the commensal bacteria that dwell on and within a host, we can now study the host in its entirety, as a supraorganism that must be navigated by the pathogen invader. At present, the majority of studies have focused on the interaction between the host's microbiota and bacterial pathogens. This is not unwarranted, given that bacterial pathogens must compete with commensal organisms for the limited territory afforded by the host. However, viral pathogens also enter the host through surfaces coated with microbial life and encounter an immune system shaped by this symbiotic community. Therefore, we believe that the microbiota cannot be ignored when examining the interplay between the host and viral pathogens. Here, we review work that details mechanisms by which the microbiota either promotes or inhibits viral replication and virally induced pathogenesis. The impact of the microbitota on viral infection promises to be a new and exciting avenue of investigation, which will ultimately lead to better treatments and preventions of virally induced disease. PMID- 23947359 TI - Advances in antiviral vaccine development. AB - Antiviral vaccines have been the most successful biomedical intervention for preventing epidemic viral disease. Vaccination for smallpox in humans and rinderpest in cattle was the basis for disease eradication, and recent progress in polio eradication is promising. Although early vaccines were developed empirically by passage in live animals or eggs, more recent vaccines have been developed because of the advent of new technologies, particularly cell culture and molecular biology. Recent technological advances in gene delivery and expression, nanoparticles, protein manufacturing, and adjuvants have created the potential for new vaccine platforms that may provide solutions for vaccines against viral pathogens for which no interventions currently exist. In addition, the technological convergence of human monoclonal antibody isolation, structural biology, and high-throughput sequencing is providing new opportunities for atomic level immunogen design. Selection of human monoclonal antibodies can identify immunodominant antigenic sites associated with neutralization and provide reagents for stabilizing and solving the structure of viral surface proteins. Understanding the structural basis for neutralization can guide selection of vaccine targets. Deep sequencing of the antibody repertoire and defining the ontogeny of the desired antibody responses can reveal the junctional recombination and somatic mutation requirements for B-cell recognition and affinity maturation. Collectively, this information will provide new strategic approaches for selecting vaccine antigens, formulations, and regimens. Moreover, it creates the potential for rational vaccine design and establishing a catalogue of vaccine technology platforms that would be effective against any given family or class of viral pathogens and improve our readiness to address new emerging viral threats. PMID- 23947366 TI - The P. aeruginosa heme binding protein PhuS is a heme oxygenase titratable regulator of heme uptake. AB - The Pseudomonas aeruginosa heme utilization (Phu) system encodes several proteins involved in the acquisition of heme as an iron source. Once internalized, heme is degraded by the iron-regulated heme oxygenase, HemO to biliverdin (BV) IXdelta and beta. In vitro studies have shown holo-PhuS transfers heme to the iron regulated HemO. This protein-protein interaction is specific for HemO as PhuS does not interact with the alpha-regioselective heme oxygenase, BphO. Bacterial genetics and isotopic labeling ((13)C-heme) studies confirmed extracellular heme is converted to (13)C-BVIX delta and beta through the catalytic action of HemO. In an effort to further understand the role of PhuS, similar studies were performed on the P. aeruginosa PAO1 DeltaphuS and DeltaphuS/DeltahemO strains. In contrast to wild-type strain, the absence of PhuS results in extracellular heme uptake and degradation via the catalytic action of HemO and BphO. At low heme concentrations, loss of PhuS leads to inefficient extracellular heme uptake supported by the fact the mRNA levels of PhuR, HemO, and BphO remain elevated when compared to the wild-type PAO1. On increasing extracellular heme concentrations, the elevated levels of PhuR, HemO, and BphO allow "leaky uptake" and degradation of heme via HemO and BphO. Similarly, in the DeltaphuS/DeltahemO strain, the higher heme concentrations combined with elevated levels of PhuR and BphO leads to nonspecific heme uptake and degradation by BphO. Thus we propose heme flux into the cell is driven by the catalytic action of HemO with PhuS acting as a "control valve" to regulate extracellular heme flux. PMID- 23947360 TI - Immunity to viruses: learning from successful human vaccines. AB - For more than a century, immunologists and vaccinologists have existed in parallel universes. Immunologists have for long reveled in using 'model antigens', such as chicken egg ovalbumin or nitrophenyl haptens, to study immune responses in model organisms such as mice. Such studies have yielded many seminal insights about the mechanisms of immune regulation, but their relevance to humans has been questioned. In another universe, vaccinologists have relied on human clinical trials to assess vaccine efficacy, but have done little to take advantage of such trials for studying the nature of immune responses to vaccination. The human model provides a nexus between these two universes, and recent studies have begun to use this model to study the molecular profile of innate and adaptive responses to vaccination. Such 'systems vaccinology' studies are beginning to provide mechanistic insights about innate and adaptive immunity in humans. Here, we present an overview of such studies, with particular examples from studies with the yellow fever and the seasonal influenza vaccines. Vaccination with the yellow fever vaccine causes a systemic acute viral infection and thus provides an attractive model to study innate and adaptive responses to a primary viral challenge. Vaccination with the live attenuated influenza vaccine causes a localized acute viral infection in mucosal tissues and induces a recall response, since most vaccinees have had prior exposure to influenza, and thus provides a unique opportunity to study innate and antigen-specific memory responses in mucosal tissues and in the blood. Vaccination with the inactivated influenza vaccine offers a model to study immune responses to an inactivated immunogen. Studies with these and other vaccines are beginning to reunite the estranged fields of immunology and vaccinology, yielding unexpected insights about mechanisms of viral immunity. Vaccines that have been proven to be of immense benefit in saving lives offer us a new fringe benefit: lessons in viral immunology. PMID- 23947361 TI - Bugs in the system. AB - Immunity to respiratory virus infection is governed by complex biological networks that influence disease progression and pathogenesis. Systems biology provides an opportunity to explore and understand these multifaceted interactions based on integration and modeling of multiple biological parameters. In this review, we describe new and refined systems-based approaches used to model, identify, and validate novel targets within complex networks following influenza and coronavirus infection. In addition, we propose avenues for extension and expansion that can revolutionize our understanding of infectious disease processes. Together, we hope to provide a window into the unique and expansive opportunity presented by systems biology to understand complex disease processes within the context of infectious diseases. PMID- 23947367 TI - Time-of-flight secondary ion mass spectrometry based molecular histology of human spinal cord tissue and motor neurons. AB - Secondary ion mass spectrometry is a powerful method for imaging biological samples with high spatial resolution. Whole section time-of-flight-secondary ion mass spectrometry (TOF-SIMS) scans and multivariate data analysis have been performed on the human spinal cord in order to delineate anatomical regions of interest based on their chemical distribution pattern. TOF-SIMS analysis of thoracic spinal cord sections was performed at 5 MUm resolution within 2 h. Multivariate image analysis by means of principal component analysis and maximum auto correlation factor analysis resulted in detection of more than 400 m/z peaks that were found to be significantly changed. Here, the results show characteristic biochemical distributions that are well in line with major histological regions, including gray and white matter. As an approach for iterative segmentation, we further evaluated previously outlined regions of interest as identified by multivariate image analysis. Here, further discrimination of the gray matter into ventral, lateral, and dorsal neuroanatomical regions was observed. TOF-SIMS imaging has been carried out at submicrometer resolution obtaining localization and characterization of spinal motor neurons based on their chemical fingerprint, including neurotransmitter precursors that serve as molecular indicators for motor neuron integrity. Thus, TOF-SIMS can be used as an approach for chemical histology and pathology. TOF SIMS holds immense potential for investigating the subcellular mechanisms underlying spinal cord related diseases including chronic pain and amyotrophic lateral sclerosis. PMID- 23947368 TI - How well does a funneled energy landscape capture the folding mechanism of spectrin domains? AB - Three structurally similar domains from alpha-spectrin have been shown to fold very differently. First, there is a contrast in the folding mechanism, as probed by Phi-value analysis, between the R15 domain and the R16 and R17 domains. Second, there are very different contributions from internal friction to folding: the folding rate of the R15 domain was found to be inversely proportional to solvent viscosity, showing no apparent frictional contribution from the protein, but in the other two domains, a large internal friction component was evident. Non-native misdocking of helices has been suggested to be responsible for this phenomenon. Here, I study the folding of these three proteins with minimalist coarse-grained models based on a funneled energy landscape. Remarkably, I find that, despite the absence of non-native interactions, the differences in folding mechanism of the domains are well captured by the model, and the agreement of the Phi-values with experiment is fairly good. On the other hand, within the context of this model, there are no significant differences in diffusion coefficient along the chosen folding coordinate, and the model cannot explain the large differences in folding rates between the proteins found experimentally. These results are nonetheless consistent with the expectations from the energy landscape perspective of protein folding, namely, that the folding mechanism is primarily determined by the native-like interactions present in the Go-like model, with missing non-native interactions being required to explain the differences in "internal friction" seen in experiment. PMID- 23947370 TI - Grip strength, perceived ability, and health status in individuals with arthritis: an exploratory study. AB - The purpose of this study is twofold: (1) to describe the hand strength, self reported manual ability and health status in individuals with osteo- or rheumatoid arthritis, and (2) to evaluate the scale (psychometric) properties of the 36-item Manual Ability Measure (MAM) as it applied to this sample. We administered four self-report assessments to the participants and measured their grip and pinch strength. The results indicated that persons with arthritis had decreased grip and pinch strength, more functional limitations, compromised health status and restricted participation in everyday occupations when compared to the general population. Manual ability was not related to grip strength, but was significantly related to role restriction (i. e., SF-36 Role Physical domain). The study provides evidence that the MAM has adequate psychometric properties when used with patients with osteo- or rheumatoid arthritis. PMID- 23947371 TI - Results from a survey of occupational therapy practitioners in low vision rehabilitation. AB - The purpose of this study was to provide practitioners working in low vision rehabilitation with a means for comparing service provision, including assessment, intervention, and program evaluation strategies, across a range of treatment facilities in the United States. Occupational therapy practitioners providing low vision services (N = 34) completed an online survey to address: (1) practitioner backgrounds in occupational therapy and low vision, (2) design, type, and location of practice, (3) client diagnoses and demographics, (4) referrals to and from occupational therapy, (5) types of assessments used, (6) types of interventions provided, and (7) follow-up and program evaluation procedures. Descriptive statistics were calculated for all items. Results suggest that practitioners seek adequate continuing education; use a combination of self designed and standardized assessment procedures, and both remedial and compensatory intervention strategies; frequently refer to other low vision professionals; and provide services primarily to older adults through a medical rehabilitation model. PMID- 23947369 TI - Activation state-dependent interaction between Galphaq subunits and the Fhit tumor suppressor. AB - BACKGROUND: The FHIT tumor suppressor gene is arguably the most commonly altered gene in cancer since it is inactivated in about 60% of human tumors. The Fhit protein is a member of the ubiquitous histidine triad proteins which hydrolyze dinucleoside polyphosphates such as Ap3A. Despite the fact that Fhit functions as a tumor suppressor, the pathway through which Fhit inhibits growth of cancer cells remains largely unknown. Phosphorylation by Src tyrosine kinases provides a linkage between Fhit and growth factor signaling. Since many G proteins can regulate cell proliferation through multiple signaling components including Src, we explored the relationship between Galpha subunits and Fhit. RESULTS: Several members of the Galphaq subfamily (Galpha16, Galpha14, and Galphaq) were found to co-immunoprecipitate with Fhit in their GTP-bound active state in HEK293 cells. The binding of activated Galphaq members to Fhit appeared to be direct and was detectable in native DLD-1 colon carcinoma cells. The use of Galpha16/z chimeras further enabled the mapping of the Fhit-interacting domain to the alpha2-beta4 region of Galpha16. However, Galphaq/Fhit did not affect either Ap3A binding and hydrolysis by Fhit, or the ability of Galphaq/16 to regulate downstream effectors including phospholipase Cbeta, Ras, ERK, STAT3, and IKK. Functional mutants of Fhit including the H96D, Y114F, L25W and L25W/I10W showed comparable abilities to associate with Galphaq. Despite the lack of functional regulation of Gq signaling by Fhit, stimulation of Gq-coupled receptors in HEK293 and H1299 cells stably overexpressing Fhit led to reduced cell proliferation, as opposed to an enhanced cell proliferation typically seen with parental cells. CONCLUSIONS: Activated Galphaq members interact with Fhit through their alpha2-beta4 region which may result in enhancement of the growth inhibitory effect of Fhit, thus providing a possible avenue for G protein-coupled receptors to modulate tumor suppression. PMID- 23947372 TI - A profile of canadian pediatric occupational therapy practice. AB - PURPOSE: This study established a current profile of Canadian pediatric occupational therapy practice in terms of theories/practice models, assessments, and interventions. METHOD: Respondents were 272 members of the Canadian Association of Occupational Therapists who indicated that pediatrics was their primary area of clinical practice. A purpose-designed survey was mailed to participants. RESULTS: The response rate was adequate at 27.2% (n = 272/1,000). The primary client groups seen by pediatric therapists were developmental delay, learning disability, neurology, and those requiring rehabilitation. Sensory Integration and Client-Centred Practice were the most frequently utilized theories/practice models. The most commonly used assessments were the Developmental Test of Visual Motor Integration, Peabody Developmental Motor Scales, Bruininks-Oseretsky Test of Motor Proficiency, and the Sensory Profile. The most frequently used intervention techniques with pediatric clients were the instruction of parents/caregivers and children; assistive devices, adaptive equipment, and technology; activities of daily living/self-care skills; and environmental modification/access/structuring/adaptation. CONCLUSIONS: Pediatric occupational therapists mainly used theories/ practice models that focused on three areas: Client-Centred practice, practice-oriented theories, and several theories/practice models based on occupation. Interventions focused on teaching, activities unique to occupational therapy, and on the functional needs of the client. PMID- 23947373 TI - The use of theory by occupational therapists working with adults with developmental disabilities. AB - This paper reports a national survey conducted to explore the practitioners' use of theoretical models to guide their practice of occupational therapy with adults with mental retardation. Results from 145 returned surveys (54%) indicated that only 26% of the respondents considered theory important as a guide for their daily practice. The value placed on theory decreased as years of experience increased. The most frequently used theoretical model was a remedial approach, but the most frequently used intervention was based on a compensational approach. PMID- 23947374 TI - Using personal projects to enhance students' first-person understanding of occupations. AB - A semester-long assignment was developed to emphasize occupational therapy students' real-life, first-person experience in establishing, modifying, and sustaining occupations. The overall goal of the assignment was to help students integrate core content on occupation, habits, and client-centered intervention within the context of ongoing, lived, personal experience. By pursuing their own personal projects, occupational therapy students developed, modified, or ceased occupations in their real-life context. This opportunity for students to experience as client was successful at illuminating in a very real way, the challenges, responsibilities and obligations that they will encounter as they learn to think like a therapist. PMID- 23947375 TI - From the internet editor. PMID- 23947376 TI - The effects of practice trials and prior learning on motor memory. AB - The effects of prior positions (PL), practice reinforcements of the criterion distance (CT), and retention intervals on proactive interference (PI) in a 20-cm. linear positioning task were examined. Independent treatment groups had either 0, 3, or 5 PL, with 1, 3, or 10 CT, and a 5-, 15-, or 50-sec. retention interval. Only absolute error scores at recall indicated PI. This forgetting occurred only under the highly restricted conditions of 5 PL and 1 CT after 15-and 50-sec. retention intervals. Since 0 PL groups showed no differences in recall over levels of retention intervals, PI alone apparently caused the forgetting. PMID- 23947377 TI - Measurements of muscular strength, endurance, and recovery over fifteen successive days. AB - Muscular output was measured in terms of strength, endurance, impulse, and recovery, with 10 Ss, 4 times per day over 15 successive days. A general index (the mean percentage of baseline performance with all measures) indicated that performance generally improved over the first 5 or 6 days, and remained relatively stable thereafter. The measures of strength were sensitive to within day effects, whereas endurance and recovery measures were not influenced by such circadian rhythms. PMID- 23947378 TI - Lateral dominance as a factor in learning selected motor skills. AB - Lateral dominance, as determined by tests of eye, hand, and foot preference, was investigated as a factor in motor skill acquisition. 3 groups of Ss, classified as right dominant, crossed dominant, or mixed dominant, practiced 3 motor skills for 18 practice sessions. All 3 groups showed significant learning of the 3 motor skills; however, there was no significant difference among the groups in performance or in rate of improvement on the skills. It was concluded that Ss displaying different dominance patterns, as defined in this study, appear equally capable of learning selected new motor skills. PMID- 23947379 TI - Relationships among selected tests of spatial orientation ability. AB - The purpose of this study was to investigate the relationships between selected tests of spatial orientation ability. 2 tests which have been used as predictors of spatial ability (Guilford-Zimmerman Aptitude Survey, Parts V and VI) plus 2 newly developed tests designed to measure that ability were given to 202 Junior high school boys aged 11-15 yr. 3 of these tests were of the paper and pencil type while one was a physical performance (tumbling) test. The paper-and-pencil tests correlated significantly with each other (.62, .61, .44) but the physical performance test did not correlate significantly with any of the other tests. PMID- 23947380 TI - Notes and comments trait-state anxiety and motor behavior. PMID- 23947381 TI - Poly-L-Lysine compacts DNA, kills bacteria, and improves protease inhibition in cystic fibrosis sputum. AB - RATIONALE: Neutrophil serine proteases in cystic fibrosis (CF) lung secretions partially resist inhibition by natural and exogenous inhibitors, mostly because DNA impairs their control. Cationic polypeptides display the property of condensing DNA and retain antimicrobial properties. We hypothesized that DNA condensation by cationic polypeptides in CF sputum would result in a better control of CF inflammation and infection. OBJECTIVES: We examined whether poly-L lysine would compact DNA in CF lung secretions and liquefy CF sputum, improve the control of extracellular proteases by exogenous inhibitors, and whether it displays antibacterial properties toward CF-associated bacteria. METHODS: We used fluorogenic methods to measure proteolytic activities and inhibition by protease inhibitors in whole sputum homogenates from patients with CF before and after treatment with poly-L-lysine. Antibacterial properties of poly-L-lysine were measured in bacterial cultures and in whole CF sputum. Poly-L-lysine toxicity was evaluated after aerosolization by histologic analysis, flow cytometry, and quantification of proinflammatory cytokines. MEASUREMENTS AND MAIN RESULTS: Poly L-lysine compacts CF sputum DNA, generating a liquid phase that improves ciliary beating frequency at the lung epithelial surface, and allows the control of neutrophil elastase and cathepsin G by their natural inhibitors. It retains antimicrobial properties against Pseudomonas aeruginosa and Staphylococcus aureus at doses that induce no inflammation in the mouse lung after aerosol administration. CONCLUSIONS: Poly-L-lysine may be an alternative to dornase-alpha to liquefy sputum with added benefits because it helps natural inhibitors to better control the deleterious effects of extracellularly released neutrophil serine proteases and has the ability to kill bacteria in CF sputum. PMID- 23947382 TI - Visible-light-induced photooxidation of ruthenium(II) complex with 2,2' biimidazole-like ligand by singlet oxygen. AB - Four new ruthenium(II) complexes [Ru(bpy)2(TMBiimH2)](ClO4)2 (Ru-5; bpy is 2,2' bipyridine and TMBiimH2 is 4,5,4',5'-tetramethyl-2,2'-biimidazole), [Ru(bpy)2(L1H2)](ClO4)2.H2O (Ru-6; L1H2 is 4,5-dimethyl-2-(N,N diacetyl)carboximidamide-1H-imidazole), [Ru(bpy)2(L2H2)](ClO4)2 (Ru-7; L2H2 is N(1),N(1),N(2),N(2)-tetrakis(acetyl)ethanediimidamide), and [Ru(phen)2(TMBiimH2)](ClO4)2 (Ru-8; phen is 1,10'-phenanthroline) have been synthesized and characterized. Their photophysical and electrochemical properties have been studied and compared to the previously reported [Ru(bpy)2(BiimH2)](PF6)2 (Ru-1), [Ru(bpy)2(BbimH2)](PF6)2 (Ru-2), [Ru(bpy)2(DMBbimH2)](PF6)2 (Ru-3), and [Ru(bpy)2(TMBbimH2)](PF6)2 (Ru-4). Under irradiation with either sunlight or household light in atmosphere, Ru-5 reacts with molecular oxygen to produce Ru-6 in an acetonitrile solution with a relatively high concentration and Ru-7 in a methanol or dilute acetonitrile solution, respectively. The mechanism studies show that singlet oxygen is the reactive oxygen species in the ring-opening reaction and the photooxidation reaction is solvent- and concentration-dependent. The photoreaction product Ru-6 is an intermediate, which has been isolated and structurally characterized by single-crystal X-ray diffraction. Ru-6 is stable in the solid state and an acetonitrile solution with a high concentration, but can be further oxidized to Ru-7 in a methanol or dilute acetonitrile solution. PMID- 23947383 TI - Hypopyon uveitis following panretinal photocoagulation in a diabetic patient. AB - We report the case of a 42-year-old man with uncontrolled diabetes mellitus who presented to us with diminution of vision in both eyes for the past two years. On examination, both eyes showed features of high-risk proliferative diabetic retinopathy and the patient was advised of panretinal photocoagulation (PRP). He underwent the first sitting of PRP in both eyes. On the following day, he developed hypopyon uveitis in the right eye. He was treated with topical steroid and cycloplegic, and complete resolution of hypopyon was achieved over the next three days. This case highlights the importance of adequately controlled diabetes mellitus before PRP. Hypopyon uveitis could be a complication of PRP in patients with uncontrolled diabetes mellitus who respond to frequent topical steroid and cycloplegic. PMID- 23947384 TI - Conjunctival attachment of a tick: case report. AB - PURPOSE: To describe a case of conjuctival tick attachment and the method of removal with blunt forceps. METHODS: Case report. RESULTS: A 36-year-old man presented with a complaint of foreign body sensation in his right eye. He was found to have a tick (Ixodes spp) embedded in his conjunctiva. The tick was removed completely mechanically with a blunt forceps. The patient was examined and followed for tick-transmitted diseases. The patient had no systemic signs and symptoms in follow-up. CONCLUSIONS: The ophthalmologist should maintain an index of suspicion that tick infestation of ocular tissues may present in urban locations. Careful examination, obtaining serology to check for zoonoses, and complete removal should be performed to ensure an uneventful recovery. PMID- 23947385 TI - Augmented multivariate image analysis applied to quantitative structure-activity relationship modeling of the phytotoxicities of benzoxazinone herbicides and related compounds on problematic weeds. AB - Two of major weeds affecting cereal crops worldwide are Avena fatua L. (wild oat) and Lolium rigidum Gaud. (rigid ryegrass). Thus, development of new herbicides against these weeds is required; in line with this, benzoxazinones, their degradation products, and analogues have been shown to be important allelochemicals and natural herbicides. Despite earlier structure-activity studies demonstrating that hydrophobicity (log P) of aminophenoxazines correlates to phytotoxicity, our findings for a series of benzoxazinone derivatives do not show any relationship between phytotoxicity and log P nor with other two usual molecular descriptors. On the other hand, a quantitative structure-activity relationship (QSAR) analysis based on molecular graphs representing structural shape, atomic sizes, and colors to encode other atomic properties performed very accurately for the prediction of phytotoxicities of these compounds against wild oat and rigid ryegrass. Therefore, these QSAR models can be used to estimate the phytotoxicity of new congeners of benzoxazinone herbicides toward A. fatua L. and L. rigidum Gaud. PMID- 23947386 TI - Is a standalone inertial measurement unit accurate and precise enough for quantification of movement symmetry in the horse? AB - Standalone 'low-cost' inertial measurement units (IMUs) could facilitate large scale studies into establishing minimal important differences (MID) for orthopaedic deficits (lameness) in horses. We investigated accuracy and limits of agreement (LoA) after correction of magnitude-dependent differences of a standalone 6 degree-of-freedom IMU compared with an established IMU-based gait analysis system (MTx) in six horses for two anatomical landmarks (sacrum and sternum). Established symmetry measures were calculated from vertical displacement: symmetry index (SI), difference between minima (MinDiff) and difference between maxima (MaxDiff). For the sacrum, LoA were +/- 0.095 for SI, +/- 6.6 mm for MinDiff and +/- 4.3 mm for MaxDiff. For the sternum, LoA values were +/- 0.088 for SI, +/- 5.0 mm for MinDiff and +/- 4.2 mm for MaxDiff. Compared with reference data from mildly lame horses, SI values indicate sufficient precision, whereas MinDiff and MaxDiff values are less favourable. Future studies should investigate specific calibration and processing algorithms further improving standalone IMU performance. PMID- 23947387 TI - Enhancement of perovskite-based solar cells employing core-shell metal nanoparticles. AB - Recently, inorganic and hybrid light absorbers such as quantum dots and organometal halide perovskites have been studied and applied in fabricating thin film photovoltaic devices because of their low-cost and potential for high efficiency. Further boosting the performance of solution processed thin-film solar cells without detrimentally increasing the complexity of the device architecture is critically important for commercialization. Here, we demonstrate photocurrent and efficiency enhancement in meso-superstructured organometal halide perovskite solar cells incorporating core-shell Au@SiO2 nanoparticles (NPs) delivering a device efficiency of up to 11.4%. We attribute the origin of enhanced photocurrent to a previously unobserved and unexpected mechanism of reduced exciton binding energy with the incorporation of the metal nanoparticles, rather than enhanced light absorption. Our findings represent a new aspect and lever for the application of metal nanoparticles in photovoltaics and could lead to facile tuning of exciton binding energies in perovskite semiconductors. PMID- 23947388 TI - Implementation of an educational intervention to improve hand washing in primary schools: process evaluation within a randomised controlled trial. AB - BACKGROUND: Process evaluations are useful for understanding how interventions are implemented in trial settings. This is important for interpreting main trial results and indicating how the intervention might function beyond the trial. The purpose of this study was to examine the reach, dose, fidelity, acceptability, and sustainability of the implementation of an educational hand washing intervention in primary schools, and to explore views regarding acceptability and sustainability of the intervention. METHODS: Process evaluation within a cluster randomised controlled trial, including focus groups with pupils aged 6 to 11, semi-structured interviews with teachers and external staff who coordinated the intervention delivery, and school reports and direct observations of the intervention delivery. RESULTS: The educational package was delivered in 61.4% of schools (85.2% of intervention schools, 37.8% of control schools following completion of the trial). Teachers and pupils reacted positively to the intervention, although concerns were raised about the age-appropriateness of the resources. Teachers adapted the resources to suit their school setting and pupils. Staff coordinating the intervention delivery had limited capacity to follow up and respond to schools. CONCLUSIONS: The hand washing intervention was acceptable to schools, but its reach outside of a randomised trial, evidenced in the low proportion of schools in the control arm who received it after the trial had ended, suggests that the model of delivery may not be sustainable. TRIAL REGISTRATION: ISRCTN: ISRCTN93576146. PMID- 23947390 TI - Sex-differences in quality of life and asthma control in Swedish asthma patients. AB - BACKGROUND: To study sex-related differences in quality of life, asthma control and asthma management in different age groups. METHODS: A cross-sectional survey and patient record study in primary and secondary care. A total of 1226 patients in primary and 499 in secondary care, ages 18-75 and randomly selected, with a response rate of 71%. Patients were classified into four groups, 18-34, 35-49, 50 64 and 65-75 years. RESULTS: Younger women (18-49 years) had a lower total MiniAQLQ score than men in the same age group (5.41 vs. 5.80, p < 0.001), while no significant difference was found between older women and men (50-75 years) (5.08 vs. 5.16, p = 0.42). The sex differences in the younger group remained significant after adjusting for medication, educational level, smoking, body mass index, allergy and depression (p = 0.008). The odds ratios for younger women to have night-awakenings was 1.7 (95%CI 1.07-2.57), for asthma exacerbations 1.9 (95%CI 1.21-2.98) and for not achieving asthma control 1.5 (95%CI 1.00-2.13) when adjusting for smoking, educational level and body mass index. No differences in asthma control were found when comparing older women with men of similar ages. CONCLUSIONS: Younger women had lower quality of life and less often asthma control than men in the same age range, while no corresponding sex differences were found between older women and men of similar ages. Female sex hormones could be an important factor affecting these outcomes. PMID- 23947389 TI - Improving metabolic parameters of antipsychotic child treatment (IMPACT) study: rationale, design, and methods. AB - BACKGROUND: Youth with serious mental illness may experience improved psychiatric stability with second generation antipsychotic (SGA) medication treatment, but unfortunately may also experience unhealthy weight gain adverse events. Research on weight loss strategies for youth who require ongoing antipsychotic treatment is quite limited. The purpose of this paper is to present the design, methods, and rationale of the Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) study, a federally funded, randomized trial comparing two pharmacologic strategies against a control condition to manage SGA-related weight gain. METHODS: The design and methodology considerations of the IMPACT trial are described and embedded in a description of health risks associated with antipsychotic-related weight gain and the limitations of currently available research. RESULTS: The IMPACT study is a 4-site, six month, randomized, open label, clinical trial of overweight/obese youth ages 8-19 years with pediatric schizophrenia-spectrum and bipolar-spectrum disorders, psychotic or non-psychotic major depressive disorder, or irritability associated with autistic disorder. Youth who have experienced clinically significant weight gain during antipsychotic treatment in the past 3 years are randomized to either (1) switch antipsychotic plus healthy lifestyle education (HLE); (2) add metformin plus HLE; or (3) HLE with no medication change. The primary aim is to compare weight change (body mass index z-scores) for each pharmacologic intervention with the control condition. Key secondary assessments include percentage body fat, insulin resistance, lipid profile, psychiatric symptom stability (monitored independently by the pharmacotherapist and a blinded evaluator), and all-cause and specific cause discontinuation. This study is ongoing, and the targeted sample size is 132 youth. CONCLUSION: Antipsychotic-related weight gain is an important public health issue for youth requiring ongoing antipsychotic treatment to maintain psychiatric stability. The IMPACT study provides a model for pediatric research on adverse event management using state-of-the art methods. The results of this study will provide needed data on risks and benefits of two pharmacologic interventions that are already being used in pediatric clinical settings but that have not yet been compared directly in randomized trials. TRIAL REGISTRATION: Clinical Trials.gov NCT00806234. PMID- 23947391 TI - Association between serotonin transporter gene polymorphisms and childhood asthma. AB - BACKGROUND: Asthma is a common chronic inflammatory disease of the airways in which genetic factors play a major role in its pathogenesis. High serotonin serum levels in patients with asthma suggest that serotonin is involved in the pathophysiology of the disease. Serotonin clearance is mediated by the serotonin reuptake transporter, and functional polymorphisms in this gene lead to altered serotonin reuptake efficiency. OBJECTIVE: The aim of this study was to investigate the relationship between serotonin transporter gene polymorphisms and asthma. METHODS: Serotonin transporter gene polymorphisms (5-HTTLPR, rs35521 and STin2.VNTR) were assessed by PCR-based methods in 100 children with mild to moderate persistent asthma and compared with 100 healthy controls. RESULTS: There were no significant differences in allele, genotype or haplotype frequencies between patients and controls. No association was observed between SERT gene polymorphisms after stratification of patients for sex, age, spirometry indices, family history, passive smoking behavior and concomitant allergic rhinitis. Significant differences were observed in the distribution of 5-HTTLPR alleles (p = 0.025) and genotypes (p = 0.021) between patients with and without atopic dermatitis. CONCLUSIONS: Despite strong evidence suggesting the role of serotonin in the pathophysiology of asthma, we found no association between serotonin transporter gene polymorphisms and mild to moderate persistent asthma. Further serotonin transporter gene analyses in patients with severe asthma may open up new horizons in the utilization of common serotonin regulators to treat asthma, based on their pharmacogenetic effects. However, serotonin may also be indirectly influenced by emotional stress during asthma attacks. PMID- 23947392 TI - Acid-base patterns in acute severe asthma. AB - BACKGROUND AND OBJECTIVES: Acid-base status in acute severe asthma (ASA) remains undefined; some studies report complete absence of metabolic acidosis, whereas others describe it as present in one fourth of patients or more. Conclusion discrepancies would therefore appear to derive from differences in assessment methodology. Only a systematic approach centering on patient clinical findings can correctly establish true acid-base disorder prevalence levels. METHODS: This study examines acid-base patterns in ASA (314 patients), taking into account both natural history of disease and treatment, in patients free of other diseases altering acid-base status. Data were collected from patients admitted for ASA without prior history of chronic bronchitis, emphysema, kidney or liver disease, heart failure, uncontrolled diabetes mellitus or gastrointestinal illness. Informed consent was obtained for all patients, after study protocol approval by the Institutional Review Board. RESULTS: Arterial blood gases, plasma electrolytes, lactate levels, and FEV(1) were measured on arrival. Severe airway obstruction was found with FEV(1) values of 25.6 +/- 10.0%, substantial hypoxemia (PaO(2) 66.1 +/- 11.9 mmHg) and increased A-a O(2) gradient (39.3 +/- 12.3 mmHg) breathing room air. While respiratory alkalosis occurred in patients with better preservation of FEV1, respiratory acidosis was observed with more severe airway obstruction, as was increased lactate in the majority of patients, independent of PaO(2) and PaCO(2) levels. CONCLUSIONS: Predominant acid-base patterns observed in ASA in this patient population included primary hypocapnia, or less frequently, primary hypercapnia. Lactic acidosis occurred in 11% of patients and presented consistently as a mixed acid-base disorder. These findings suggest lactic acidosis results from the combined effects of both ASA and medication related sympathetic effects. PMID- 23947394 TI - Insight into the isoelectronic character of azomethines and vinylenes using representative models: a spectroscopic and electrochemical study. AB - A series of azomethine and vinylene dyad and triad analogues were prepared. Their absorbance, fluorescence, and redox properties were examined experimentally and theoretically using density functional theory (DFT) calculations. These measurements were done to determine the effect of the heteroatom of the azomethine relative to its all-carbon counterpart and to assess the isoelectronic character of the two bonds. The orientation of the azomethine was found to have little effect on the absorbance, fluorescence, and electrochemical properties. In contrast, the spectral and electrochemical properties were highly contingent on the electronic groups and degree of conjugation. The spectral properties could be tuned 200 nm across the visible region. More importantly, the heteroatom in the conjugated bond was found to give rise to only a 20 nm bathochromic shift in the absorbance and fluorescence spectra. The fluorescence quantum yield (PhiFl) of the vinylene derivatives varied between 5% and 20% with fluorescence quenching occurring by photoisomerization from the E to Z isomers. In contrast, the fluorescence of the analogous azomethine derivatives was completely quenched. The collective spectroscopic and electrochemical ab initio DFT data additionally confirmed that the azomethine and its analogous vinylene are isoelectronic. It was also found that a conjugated thiophene vinylene dyad with primary amines in the alpha,alpha'-positions could be prepared and isolated. The compound was stable under aerobic conditions providing electron withdrawing (either ester or nitrile) groups were located in the adjacent positions. PMID- 23947393 TI - Asthma and severity of 2009 novel H1N1 influenza: a population-based case-control study. AB - BACKGROUND: Asthma has been shown to be associated with an increased risk of the 2009 novel H1N1 influenza (H1N1) infection among children. However, little is known about the role of asthma in severity of H1N1 infection. OBJECTIVE: To determine the association between asthma and other atopic conditions and severity of H1N1 infection. PATIENTS AND METHODS: We conducted a population-based case control study. Cases were all Olmsted County, MN residents admitted to the hospital within a week of a positive test for H1N1. Controls who had a positive H1N1 but were not admitted to hospital were individually matched to cases with regard to birth day, gender, clinic registration date, diagnostic method, and calendar month of influenza testing. Asthma was ascertained using predetermined criteria. Data were fit to conditional logistic regression models. RESULTS: There were 46 eligible individuals admitted to hospitals with H1N1 infection during the study period. Ninety-seven controls were individually matched to their corresponding cases. Among cases, 23 (50%) were male and 29 (63.0%) were Caucasians. The median age at hospitalization was 20.7 years. Twenty-five (54.4%) cases had asthma before the date of hospitalization, compared to 33 (34.0%) controls (matched OR: 2.31; 95% CI, 1.13-4.73; p = 0.02). This association approached statistical significance after adjusting for all pertinent covariates (adjusted matched OR: 2.55; 95% CI, 0.98-6.64; p = 0.055). CONCLUSION: Asthma may be associated with severe H1N1 infection. In addition to timely influenza vaccination for asthmatics, consideration for prophylactic treatment for unimmunized asthmatics with significant exposure to influenza and immunized asthmatics with early flu-like symptoms should be given. PMID- 23947395 TI - Early adolescent cortical thinning is related to better neuropsychological performance. AB - Adolescence is characterized by significant neuromaturation, including extensive cortical thinning, particularly in frontal regions. The goal of this study was to examine the behavioral correlates of neurostructural development in early adolescence. Participants were 185 healthy 12- to 14-year-olds (44% female) recruited from local schools. Participants completed a comprehensive neuropsychological test battery and magnetic resonance imaging session. Cortical surface reconstruction and thickness estimates were performed via FreeSurfer. Age and cortical thickness were negatively correlated in 10 brain regions, 7 of which were in frontal areas (beta = -.15 to -.25, ps <= .05). Hierarchical linear regressions examined the influence of cortical thickness on working memory, attention, verbal learning and memory, visuospatial functioning, spatial planning and problem solving, and inhibition, controlling for age and intracranial volume. Thinner parietal cortices predicted better performances on tests of verbal learning and memory, visuospatial functioning, and spatial planning and problem solving (beta = -.14 to -.24, ps <= .05). Age, spanning from 12 to 14 years, accounted for up to 6% of cortical thickness, suggesting substantial thinning during early adolescence, with males showing more accelerated thinning than females between ages 12 and 14. For both males and females, thinner parietal association cortices corresponded with better neurocognitive functioning above and beyond age alone. PMID- 23947396 TI - Mitochondrial DNA analysis in two heritage European breeds confirms Mesoamerican origin and low genetic variability of domestic turkey. PMID- 23947397 TI - Uncovering spider silk nanocrystalline variations that facilitate wind-induced mechanical property changes. AB - Spider major ampullate (MA) silk varies in mechanical properties when spun in different environments. Amino acid compositional changes induced by variations in MaSp1 and MaSp2 expression, and various biochemical and physiological glandular processes induce silk property variability. Quantifying the contributions of these mechanisms on silk variability may facilitate the development of silk biomimetics. Wind is a medium that induces variations in MA silk mechanics. We exposed the spider Cyclosa mulmeinensis to wind and measured the amino acid composition, tensile mechanics, and crystalline structure of its MA silk using HPLC, tensile tests, and X-ray diffraction. We found the mechanical properties of MA silks from spiders exposed to wind to differ from unexposed spiders. The amino acid compositions did not differ, but X-ray diffraction found a lower crystal density and greater beta-sheet alignment relative to the fiber axis in the silks of spiders exposed to wind. We found no evidence that the mechanical property variations were a product of profound changes to the alignment of the protein within the amorphous region. We conclude that variations in the density and alignment of the crystalline beta-sheets, probably accompanied by some alignment change in the amorphous region as a result of "stretching" during spinning of the silk, probably explains the mechanical property variations that we found across treatment subgroups. As C. mulmeinensis MA silk increases both in strength and elasticity when the spiders are exposed to wind, bioengineers may consider it as a model for the development of high-performance silk biomimetics. PMID- 23947398 TI - Differentiating innovation priorities among stakeholder in hospital care. AB - BACKGROUND: Decisions to adopt a particular innovation may vary between stakeholders because individual stakeholders may disagree on the costs and benefits involved. This may translate to disagreement between stakeholders on priorities in the implementation process, possibly explaining the slow diffusion of innovations in health care. In this study, we explore the differences in stakeholder preferences for innovations, and quantify the difference in stakeholder priorities regarding costs and benefits. METHODS: The decision support technique called the analytic hierarchy process was used to quantify the preferences of stakeholders for nine information technology (IT) innovations in hospital care. The selection of the innovations was based on a literature review and expert judgments. Decision criteria related to the costs and benefits of the innovations were defined. These criteria were improvement in efficiency, health gains, satisfaction with care process, and investments required. Stakeholders judged the importance of the decision criteria and subsequently prioritized the selected IT innovations according to their expectations of how well the innovations would perform for these decision criteria. RESULTS: The stakeholder groups (patients, nurses, physicians, managers, health care insurers, and policy makers) had different preference structures for the innovations selected. For instance, self-tests were one of the innovations most preferred by health care insurers and managers, owing to their expected positive impacts on efficiency and health gains. However, physicians, nurses and patients strongly doubted the health gains of self-tests, and accordingly ranked self-tests as the least preferred innovation. CONCLUSIONS: The various stakeholder groups had different expectations of the value of the nine IT innovations. The differences are likely due to perceived stakeholder benefits of each innovation, and less to the costs to individual stakeholder groups. This study provides a first exploratory quantitative insight into stakeholder positions concerning innovation in health care, and presents a novel way to study differences in stakeholder preferences. The results may be taken into account by decision makers involved in the implementation of innovations. PMID- 23947400 TI - Volatile and thermally stable mid to late transition metal complexes containing alpha-imino alkoxide ligands, a new strongly reducing coreagent, and thermal atomic layer deposition of Ni, Co, Fe, and Cr metal films. AB - Treatment of MCl2 (M = Cu, Ni, Co, Fe, Mn, Cr) with 2 equiv of alpha-imino alkoxide salts K(RR'COCNtBu) (R = Me, tBu; R' = iPr, tBu) afforded M(RR'COCNtBu)2 or [Mn(RR'COCNtBu)2]2 in 9-75% yields. These complexes combine volatility and high thermal stability and have useful atomic layer deposition (ALD) precursor properties. Solution reactions between Ni, Co, and Mn complexes showed that BH3(NHMe2) can reduce all to metal powders. ALD growth of Ni, Co, Fe, and Cr films is demonstrated. Mn film growth may be possible, but the films oxidize completely upon exposure to air. PMID- 23947401 TI - Crystallization features of normal alkanes in confined geometry. AB - How polymers crystallize can greatly affect their thermal and mechanical properties, which influence the practical applications of these materials. Polymeric materials, such as block copolymers, graft polymers, and polymer blends, have complex molecular structures. Due to the multiple hierarchical structures and different size domains in polymer systems, confined hard environments for polymer crystallization exist widely in these materials. The confined geometry is closely related to both the phase metastability and lifetime of polymer. This affects the phase miscibility, microphase separation, and crystallization behaviors and determines both the performance of polymer materials and how easily these materials can be processed. Furthermore, the size effect of metastable states needs to be clarified in polymers. However, scientists find it difficult to propose a quantitative formula to describe the transition dynamics of metastable states in these complex systems. Normal alkanes [CnH2n+2, n-alkanes], especially linear saturated hydrocarbons, can provide a well-defined model system for studying the complex crystallization behaviors of polymer materials, surfactants, and lipids. Therefore, a deeper investigation of normal alkane phase behavior in confinement will help scientists to understand the crystalline phase transition and ultimate properties of many polymeric materials, especially polyolefins. In this Account, we provide an in-depth look at the research concerning the confined crystallization behavior of n-alkanes and binary mixtures in microcapsules by our laboratory and others. Since 2006, our group has developed a technique for synthesizing nearly monodispersed n-alkane containing microcapsules with controllable size and surface porous morphology. We applied an in situ polymerization method, using melamine-formaldehyde resin as shell material and nonionic surfactants as emulsifiers. The solid shell of microcapsules can provide a stable three-dimensional (3-D) confining environment. We have studied multiple parameters of these microencapsulated n-alkanes, including surface freezing, metastability of the rotator phase, and the phase separation behaviors of n-alkane mixtures using differential scanning calorimetry (DSC), temperature-dependent X-ray diffraction (XRD), and variable-temperature solid-state nuclear magnetic resonance (NMR). Our investigations revealed new direct evidence for the existence of surface freezing in microencapsulated n alkanes. By examining the differences among chain packing and nucleation kinetics between bulk alkane solid solutions and their microencapsulated counterparts, we also discovered a mechanism responsible for the formation of a new metastable bulk phase. In addition, we found that confinement suppresses lamellar ordering and longitudinal diffusion, which play an important role in stabilizing the binary n-alkane solid solution in microcapsules. Our work also provided new insights into the phase separation of other mixed system, such as waxes, lipids, and polymer blends in confined geometry. These works provide a profound understanding of the relationship between molecular structure and material properties in the context of crystallization and therefore advance our ability to improve applications incorporating polymeric and molecular materials. PMID- 23947399 TI - Substantial increase in the frequency of circulating CD4+NKG2D+ T cells in patients with cervical intraepithelial neoplasia grade 1. AB - BACKGROUND: The NKG2D receptor confers important activating signals to NK cells via ligands expressed during cellular stress and viral infection. This receptor has generated great interest because not only is it expressed on NK cells, but it is also seen in virtually all CD8+ cytotoxic T cells and is classically considered absent in CD4+ T cells. However, recent studies have identified a distinctive population of CD4+ T cells that do express NKG2D, which could represent a particular cytotoxic effector population involved in viral infections and chronic diseases. On the other hand, increased incidence of human papillomavirus-associated lesions in CD4+ T cell-immunocompromised individuals suggests that CD4+ T cells play a key role in controlling the viral infection. Therefore, this study was focused on identifying the frequency of NKG2D expressing CD4+ T cells in patients with cervical intraepithelial neoplasia (CIN) 1. Additionally, factors influencing CD4+NKG2D+ T cell expansion were also measured. RESULTS: Close to 50% of patients with CIN 1 contained at least one of the 37 HPV types detected by our genotyping system. A tendency for increased CD4+ T cells and CD8+ T cells and decreased NK cells was found in CIN 1 patients. The percentage of circulating CD4+ T cells co-expressing the NKG2D receptor significantly increased in women with CIN 1 versus control group. Interestingly, the increase of CD4+NKG2D+ T cells was seen in patients with CIN 1, despite the overall levels of CD4+ T cells did not significantly increase. We also found a significant increase of soluble MICB in CIN 1 patients; however, no correlation with the presence of CD4+NKG2D+ T cells was seen. While TGF-beta was significantly decreased in the group of CIN 1 patients, both TNF-alpha and IL-15 showed a tendency to increase in this group. CONCLUSIONS: Taken together, our results suggest that the significant increase within the CD4+NKG2D+ T cell population in CIN 1 patients might be the result of a chronic exposure to viral and/or pro-inflammatory factors, and concomitantly might also influence the clearance of CIN 1-type lesion. PMID- 23947402 TI - Direct replacement of antibodies with molecularly imprinted polymer nanoparticles in ELISA--development of a novel assay for vancomycin. AB - A simple and straightforward technique for coating microplate wells with molecularly imprinted polymer nanoparticles (nanoMIPs) to develop assays similar to the enzyme-linked immunosorbent assay (ELISA) is presented here for the first time. NanoMIPs were synthesized by a solid-phase approach with an immobilized vancomycin (template) and characterized using Biacore 3000, dynamic light scattering, and electron microscopy. Immobilization, blocking, and washing conditions were optimized in microplate format. The detection of vancomycin was achieved in competitive binding experiments with a horseradish peroxidase vancomycin conjugate. The assay was capable of measuring vancomycin in buffer and in blood plasma within the range of 0.001-70 nM with a detection limit of 0.0025 nM (2.5 pM). The sensitivity of the assay was 3 orders of magnitude better than a previously described ELISA based on antibodies. In these experiments, nanoMIPs have shown high affinity and minimal interference from blood plasma components. Immobilized nanoMIPs were stored for 1 month at room temperature without any detrimental effects to their binding properties. The high affinity of nanoMIPs and the lack of a requirement for cold chain logistics make them an attractive alternative to traditional antibodies used in ELISA. PMID- 23947404 TI - Electromyographical study of reflex, premotor, and simple reaction time of relaxed muscle to joint displacement. AB - Ss (N=30) responded to a sudden arm drop from an electromagnet by abducting the failing arm and by abducting the nonstimulus arm from a RT switch. EGMs from 30 randomized trials were monitored from the middle portions of the relaxed deltoideus muscles. Ipsilateral reflex latencies averaged 24 msec. and were characterized by rapid EMG bursts followed by a silent period. The more sustained EMG bursts had shorter latencies in the contralateral limb (72 msec.) than in the ipsilateral limb (88 msec.). Contralateral RT averaged 180 msec. The presence of a stretch reflex in the form of a synchronous volley appeared to delay ipsilateral premotor times. PMID- 23947405 TI - Visual occlusion factors in a discrete ball-catching task. AB - Male university students (N=44) attempted to catch lawn-tennis balls delivered by a mechanical projection machine. The ball was always projected in the dark and caught in the dark but was illuminated for a constant, brief interval during its flight by a fluorescent tube. The portion of flight illuminated was varied by manipulating systematically the interval between light offset and ball-hand contact. This variable served as the single factor in a within-Ss design. ANOVA showed that catching success was reliably dependent upon this variable and related to it by an inverted 'U' function. Results were discussed in terms of prediction ability and a possible limitation in information processing time. PMID- 23947406 TI - Risk and effort measures of fatigue. AB - A method of measuring fatigue is suggested in which alternative routes, requiring different amounts of effort, lead to different probabilities of success or failure. An experiment designed to investigate a task which has these features shows it sensitive to the fatigue generated by a synthetic work battery. Fatigued Ss shifted their choices towards easier, riskier routes, compared with their own earlier performance and with that of a control group; they also showed an increased error rate on a subsidiary measure. In a second experiment, measurements on the task were shown to correlate with self-rated fatigue. PMID- 23947403 TI - Clinical experience with intravenous administration of ascorbic acid: achievable levels in blood for different states of inflammation and disease in cancer patients. AB - BACKGROUND: Ascorbic acid (vitamin C, ascorbate) is a key water soluble antioxidant that, when administered in doses well above its recommended dietary allowance, may have preventative and therapeutic value against a number of pathologies. The intravenous administration of high dose ascorbate (IVC) has increased in popularity among complementary and alternative medicine practitioners: thousands of patients received IVC, at an average dose of 0.5 g/kg, without significant side effects. While IVC may have a variety of possible applications, it has generated the most interest for its potential use in treating cancer. METHODS: Medical records of patients with cancer treated with IVC at the Riordan Clinic were retrospectively reviewed. Cancer patients, for whom plasma ascorbate concentration data before and after treatment were available, along with C-reactive protein (CRP) measurements, were chosen for analysis. RESULTS: The results of the analysis can be summarized as follows. IVC produces peak plasma ascorbate concentrations on the order of ten millimolars with lower peak plasma concentrations obtained in cancer patients as compared to healthy subjects. Cancer patients who are deficient in vitamin C prior to therapy tend to achieve lower plasma levels post infusion. High inflammation or tumor burdens, as measured by CRP or tumor antigen levels, tend to lower peak plasma ascorbate levels after IVC. When compared to patients with localized tumors, patients with metastatic tumors tend to achieve lower post infusion plasma ascorbate concentrations. CONCLUSIONS: The data indicate that, while potentially therapeutic plasma ascorbate concentrations can be achieved with IVC, levels attained will vary based on tumor burden and degree of inflammation (among other factors). Evidence suggests that IVC may be able to modulate inflammation, which in turn might improve outcomes for cancer patients. IVC may serve as a safe, adjunctive therapy in clinical cancer care. PMID- 23947407 TI - Eyes on hand-eyes on target? AB - Male Ss (N=60) were randomly selected to perform a modified version of a simple one-handed ballistic aiming task. Groups were aged 6-7 yr., 10-11 yr., and 19 or more yr.; within each group 10 Ss were able to see their hand and 10 Ss the target during task performance. A split-plot factorial design was used. Mean absolute error scores increased with distance, and at each age Ss with vision of target were more accurate than were Ss with vision of the hand. Vision, distance and the interactions of age and distance, and distance and vision were significant. PMID- 23947408 TI - Is proprioception important for skilled performance? AB - Two broad accounts of how we may have knowledge of the direction and extent of our own movements in the absence of exteroceptive feedback are sketched. The proprioceptive (inflow) model states that feedback signals to the central nervous system are compared to some central record of efference. The central monitoring of efference (outflow) model states that the central record of itself provides sufficient displacement information to time further efferent events. Physiological and human performance studies are critically reviewed and evidence favoring the commonly assumed inflow model is shown to be inadequate. The outflow model provides a more parsimonious explanation. PMID- 23947409 TI - Effects of classical predifferentiation on the functional properties of supplementary feedback cues. AB - Previous studies of the regulation of psychomotor learning by predifferentiated supplementary feedback cues lacked adequate controls for the unequivocal assignment of effects to the transfer of specific conditional cue properties as opposed, say, to the transfer of nonspecific factors such as warm-up and arousal. The present study employed 96 Ss in order to compare the performance level produced by differentiated cues with the levels achieved under CS-only, UCS-only, and neutral control conditions. The levels of learning achieved under the three control conditions were not significantly different from one another, while the level produced by differentiated cues was significantly superior to control levels. Thus, within the context of this study and its predecessors, classical differentiation of supplementary feedback cues was necessary as well as sufficient for performance enhancement; and the specific transfer hypothesis was upheld. PMID- 23947410 TI - Development of spatial and temporal elements of rhythmic ability. AB - Development of space-time characteristics of children's motor responses to auditory rhythmic stimuli was studied, Male and female Ss (N=20 each) were randomly selected from each of seven groupings representing ages 5 to 11 yr. Utilizing a rhythmic ability analysis system, Ss performed 16 consecutive motor responses in time with auditory rhythmic stimuli presented at .9-sec. intervals. ANOVA revealed a significant reduction of error in spatial and temporal accuracy with increasing age for boys and girls; no sex differences in performance were evidenced over all age groupings. Results are discussed in relation to underlying developmental mechanisms and implications. PMID- 23947411 TI - Recovery of muscular endurance following rhythmic or sustained activity. AB - Ss (N=72) were randomly assigned to four groups and performed two bouts of either 1 min. of sustained and/or 3 min. of rhythmic isometric grip-flexion exercise. The two activity bouts within each testing session were separated by a recovery interval of 5, 10, 20, 40, 80, 160, or 320 sec. Every S was tested following all recovery intervals. The criterion for assessing recovery was the summation of force exerted at each 5-sec. interval during the sustained task or at each 15 sec. interval during the rhythmic exercise. During a rhythmic second activity bout significantly greater force-time integrals were developed subsequent to an initial bout of rhythmic activity. During a sustained second bout, however, there was no difference between the groups exposed to the two types of initial exercise. In both cases significantly greater force-time integrals were exerted subsequent to longer inter-bout recovery intervals. The patterns of recovery appropriate to the four possible permutations of exercise were described capably by two-component, double-positive exponential equations. PMID- 23947412 TI - Adsorption of benzyldimethylhexadecylammonium chloride at the hydrophobic silica water interface studied by total internal reflection Raman spectroscopy: effects of silica surface properties and metal salt addition. AB - The adsorption of the cationic surfactant benzyldimethylhexadecylammonium (BDMHA(+)) chloride was studied at an octadecyltrichlorosilane (OTS)-monolayer modified silica-water interface by Raman spectroscopy in total internal reflection (TIR) geometry. The present study demonstrates the capabilities of this spectroscopic technique to evaluate thermodynamic and kinetic BDMHA(+)Cl(-) adsorption properties at the hydrophobic silica surface. The surface coverage of BDMHA(+) decreased by 50% at the hydrophobic OTS-silica surface relative to the surface coverage on bare silica; the dominating driving mechanisms for surfactant adsorption were identified as hydrophobic effects and head group charge screening by the electrolyte counterions. Addition of magnesium metal salt (MgCl2) to the aqueous solution (~ neutral pH) lowered the surface coverage and moderately increased the Langmuir adsorption constants relative to those of the pure surfactant. These trends were previously observed at the hydrophilic, negatively charged silica surface but with a smaller change in the Gibbs free energy of adsorption at the hydrophobic silica surface. The hydrophobic OTS-silica surface properties resulted in shorter times for the surfactant to reach steady-state adsorption conditions compared to the slow adsorption kinetics previously seen with the surfactant at the hydrophilic surface. Adsorption isotherms, based on Raman signal intensities from spectral analysis, were developed according to the Langmuir adsorption model for the pure surfactant at the OTS-silica-water interface; the modified Langmuir model was applied to the surfactant adsorption in the presence of 5, 10, 50, and 100 mM magnesium chloride. Spectral analysis of the Raman scattering intensities and geometric considerations suggests a hemimicelle-type surface aggregate as the most likely surfactant structure at the OTS-silica surface. The different kinetics observed at the hydrophilic versus the hydrophobic silica surface further indicate that the surface charge and potential influence the surfactant diffusion and kinetic rates of adsorption at the silica water interface. PMID- 23947413 TI - The concurrent validity of three visual perception tests used with adults. AB - Objective. Visual perception is a skill area commonly assessed by occupational therapists. Three newly revised tests of visual perception include the Developmental Test of Visual Perceptual Skills (Non-Motor)-Adolescent and Adult (DTVP-A), the Motor-Free Visual Perception Test-Third Edition (MVPT-3), and the Test of Visual Perceptual Skills-Third Edition (TVPS-3). The aim of this study was to investigate the concurrent validity of these three adult visual perceptual tests. Methods. Fifty healthy participants, aged 18-55 years, completed the DTVP A, MVPT-3, and TVPS-3. Spearman rho correlation coefficients were used to evaluate the relationships among the three tests. Results. The total scale score correlations for the DTVP-A, MVPT-3, and TVPS-3 ranged from 0.39 to 0.51. Conclusion. The three tests exhibited a moderate level of correlation, supporting the concurrent validity of the DTVP-A, MVPT-3, and TVPS-3. PMID- 23947414 TI - Engagement in occupation and adaptation to low vision. AB - The purpose of this grounded theory study was to explore how engagement in occupation affects the adaptation process for older women with visual impairment. Data were collected and analyzed for seven participants using a constant comparative method. Nine categories emerged and were grounded in the data. A theoretical model was developed with the core category of adaptation. The interactions of participants' visual impairment, concurrent issues, threats to performance, losses, getting help, methods of doing, abilities, integration of losses and abilities, and adaptation. For these participants, the adaptation process was aided by getting help and finding methods of doing their preferred occupations. PMID- 23947415 TI - The use of evidence-based practice by occupational therapists. AB - The purpose of this study was to explore occupational therapists' attitudes, knowledge, and use of evidence-based practice. Results indicated that therapists have positive attitudes toward evidence-based practice; however, use of research evidence in practice remains limited primarily due to lack of time. Suggestions for clinical and academic partnerships are offered. PMID- 23947416 TI - Helping hands for healthy living: a collaborative service learning project with occupational and physical therapy students. AB - The purpose of this article is to describe the development of a unique interdisciplinary service-learning course and to evaluate the impact of this experience on allied health students' professional development. One hundred and twenty-seven students from occupational and physical therapy programs served medically uninsured individuals (n = 170) at a community health clinic through provision of direct patient care services, depression screens, and a health promotion program. Surveys and personal reflections were used to measure the outcome of the course. The results indicated that student cognitive skills, ability to work with diverse populations, social responsibility, beliefs and opinions about service learning, and appreciation of each other's discipline were enhanced by their participation in the class. PMID- 23947417 TI - Foundations of pediatric practice for the occupational therapy assistant (2005). PMID- 23947418 TI - The last lecture (2008). PMID- 23947420 TI - Paediatric gastrointestinal conditions and their oral implications. AB - OBJECTIVES: The paediatric dentist must be familiar with a range of medical problems which can affect the mouth or general health of children. Dental clinicians are ideally placed to help with the detection of a range of gastrointestinal issues and should know when to refer to the paediatric specialist for advice. METHODS: This article reviews the common gastrointestinal tract (GIT) conditions that can affect children reviewing the conditions, their usual treatments, and how they can influence the mouth and the oral environment. This article will review how the different conditions may produce oral symptoms and signs. The management of the oral problems and appropriate photographs are covered well in other texts and will not be included here. CONCLUSION: The mouth is a specialised part of the GIT and can be involved in or affected by many of the diseases encountered in other GIT regions. PMID- 23947421 TI - Validation of the Hong Kong Oral Health Literacy Assessment Task for paediatric dentistry (HKOHLAT-P). AB - BACKGROUND: Oral health literacy is a newly emerging field with considerable research potential. AIM: To validate an original instrument, the Hong Kong Oral Health Literacy Assessment Task (HKOHLAT-P) for paediatric dentistry. DESIGN: A convenient sample of 200 child/parent dyads attending a dental hospital in Hong Kong was selected. Convergent validity was tested by examining the association of HKOHLAT-P scores with those derived from the Test of Functional Health Literacy in Dentistry (TOFHLiD) and Hong Kong Rapid Estimate of Adult Literacy in Dentistry (HKREALD-30). The predictive validity of HKOHLAT-P was determined by testing the association between HKOHLAT-P and children's caries experience (dmft) and the Chinese Early Childhood Oral Health Impact Scale (ECOHIS). The test retest reliability and internal consistency of HKOHLAT-P were also evaluated. RESULTS: HKOHLAT-P was positively correlated with TOFHLiD and HKREALD-30 (P < 0.01), and was negatively correlated with children's dmft and ECOHIS. In the regression model, HKOHLAT-P was associated with TOFHLiD, HKEALD-30, children's dmft, and ECOHIS (P < 0.05) after controlling for participants' demographic characteristics. The intra-class correlation coefficient of HKOHLAT-P was 0.63 and the Cronbach's alpha was 0.71. CONCLUSION: Initial testing of HKOHLAT-P suggested that it is a valid and reliable instrument. PMID- 23947422 TI - Respiratory and auditory cortical processing in children with obstructive sleep apnea syndrome. AB - RATIONALE: Children with obstructive sleep apnea syndrome (OSAS) have impaired cortical processing of respiratory afferent stimuli, manifested by blunted sleep respiratory-related evoked potentials (RREP). However, whether this impairment is limited to respiratory stimuli, or reversible after successful treatment, is unknown. We hypothesized that, during sleep, children with OSAS have (1) abnormal RREP, (2) normal cortical processing of nonrespiratory stimuli, and (3) persistence of abnormal RREP after treatment. OBJECTIVES: To measure sleep RREP and auditory evoked potentials in normal control subjects and children with OSAS before and after treatment. METHODS: Twenty-four children with OSAS and 24 control subjects were tested during N3 sleep. Thirteen children with OSAS repeated testing 4-6 months after adenotonsillectomy. MEASUREMENTS AND MAIN RESULTS: RREP were blunted in OSAS compared with control subjects (N350 at Cz -27 +/- 15.5 vs. -47.4 +/- 28.5 MUV; P = 0.019), and did not improve after OSAS treatment (N350 at Cz pretreatment -25.1 +/- 7.4 vs. -29.8 +/- 8.1 post treatment). Auditory evoked potentials were similar in OSAS and control subjects at baseline (N350 at Cz -58 +/- 33.1 vs. -66 +/- 31.1 MUV), and did not change after treatment (N350 at Cz -67.5 +/- 36.8 vs. -65.5 +/- 20.3). CONCLUSIONS: Children with OSAS have persistent primary or irreversible respiratory afferent cortical processing deficits during sleep that could put them at risk of OSAS recurrence. OSAS does not seem to affect the cortical processing of nonrespiratory (auditory) afferent stimuli during sleep. PMID- 23947423 TI - Bilateral macular folds as a diagnostic clue to late-presenting posterior microphthalmos. AB - Posterior microphthalmos with macular folds is a very uncommon condition. We report such an unusual late-presenting case of posterior microphthalmos where macular folds uncovered the diagnosis and discuss the possibility of worsening of macular folds with advancing age. PMID- 23947424 TI - Pneumatic displacement and intra-vitreal bevacizumab in management of sub-retinal and sub-retinal pigment epithelial hemorrhage at macula in polypoidal choroidal vasculopathy (PCV): rationale and outcome. AB - We report three cases of submacular haemorrhage due to polypoidal choroidal vasculopathy (PCV) treated with intravitreal bevacizumab and pneumatic displacement with perfluoropropane (C3F8) gas. The patients were between 45 to 55 years and presented with reduction of vision (20/400 to 20/80) within two weeks of onset of symptoms. The submacular (sub-retinal plus sub-retinal pigment epithelium [RPE]) hemorrhages was confirmed as PCV on indocyanine green angiography and optical coherence tomography in all of them. They were treated with intravitreal bevacizumab (1.25 mg/0.05 ml) and 0.3 ml of 100% C3F8 gas in the affected eye followed by prone positioning for two weeks. The vision and macular anatomy started improving within a week and continued up to three months. These cases demonstrate that pneumatic displacement combined with intravitreal anti-VEGF injection could be a promising option in patients with PCV and sub macular blood, even when the blood is beneath the RPE. PMID- 23947425 TI - Naturally occurring stable isotopes reflect changes in protein turnover and growth in gilthead sea bream (Sparus aurata) juveniles under different dietary protein levels. AB - Ideal nutritional conditions are crucial to sustainable aquaculture due to economic and environmental issues. Here we apply stable isotope analysis as an indicator of fish growth and feeding balance, to define the optimum diet for efficient growing conditions. Juveniles of gilthead sea bream were fed with six isoenergetic diets differing in protein to lipid proportion (from 41/26 to 57/20). As protein intake increased, delta15N and Deltadelta15N of muscle and Deltadelta15N and Deltadelta13C of its protein fraction decreased, indicating lower protein turnover and higher protein deposition in muscle. This is reflected in the inverse relationship found between Deltadelta15N and growth rate, although no differences were observed in either parameter beyond the protein/lipid proportion 47/23. Principal component analysis (PCA) also signaled 47/23 diet as the pivotal point with the highest growing efficiency, with isotopic parameters having the highest discrimination load. Thus, muscle isotope composition, especially 15N, can be used to evaluate nutritional status in farmed fish. PMID- 23947426 TI - Micro-computed tomography image-based evaluation of 3D anisotropy degree of polymer scaffolds. AB - Anisotropy is one of the most meaningful determinants of biomechanical behaviour. This study employs micro-computed tomography (MUCT) and image techniques for analysing the anisotropy of regenerative medicine polymer scaffolds. For this purpose, three three-dimensional anisotropy evaluation image methods were used: ellipsoid of inertia (EI), mean intercept length (MIL) and tensor scale (t scale). These were applied to three patterns (a sphere, a cube and a right prism) and to two polymer scaffold topologies (cylindrical orthogonal pore mesh and spherical pores). For the patterns, the three methods provided good results. Regarding the scaffolds, EI mistook both topologies (0.0158, [-0.5683; 0.6001]; mean difference and 95% confidence interval), and MIL showed no significant differences (0.3509, [0.0656; 0.6362]). T-scale is the preferable method because it gave the best capability (0.3441, [0.1779; 0.5102]) to differentiate both topologies. This methodology results in the development of non-destructive tools to engineer biomimetic scaffolds, incorporating anisotropy as a fundamental property to be mimicked from the original tissue and permitting its assessment by means of MUCT image analysis. PMID- 23947427 TI - Assembly, disassembly, and anomalous propulsion of microscopic helices. AB - Controlling the motion of small objects in suspensions wirelessly is of fundamental interest and has potential applications in biomedicine for drug delivery and micromanipulation of small structures. Here we show that magnetic helical microstructures that propel themselves in the presence of rotating weak magnetic fields assemble into various configurations that exhibit locomotion and a change in swimming direction. The configuration is tuned dynamically, that is, assembly and disassembly occur, by the field input. We investigate a system that consists of two identical right-handed helices assembled at their center in order to model the motion of assembled swimmers. The swimming properties are dependent on both the component design and the assembly configuration. For particular designs and configurations, a reversal in swimming direction emerges, yet with other designs, a reversal in motion never appears. Understanding the locomotion of clustered chiral structures enables uni- and multidirectional navigation of this class of active suspensions. PMID- 23947429 TI - An unusual case of central diabetes insipidus & hyperglycemic hyperosmolar state following cardiorespiratory arrest. AB - BACKGROUND: We are describing an unusual case of severe hyperglycemia and hypernatremia, resistant to treatment. CASE PRESENTATION: A thirty year old female with adenocarcinoma of rectum was admitted with increasing lethargy, headache and drowsiness. She deteriorated rapidly and had cardiac arrest, following which she remained comatose. Her initial serum glucose and sodium were normal, but after receiving dexamethasone and mannitol, the serum glucose progressively increased to 54.7 mmol/L and sodium to 175 mmol/L, despite receiving very high dose of intravenous (IV) insulin infusion. She was evaluated for diabetes insipidus because of continued polyuria even after correction of hyperglycemia. Her serum osmolality was 337 mmol/kg, and urine osmolality was 141 mmol/kg which rose to 382 mmol/kg, after receiving 4 mcg of IV Desmopressin. CONCLUSION: Our patient developed central diabetes insipidus post cardiac arrest and severe dehydration because of diabetes insipidus. Stress of critical illness, dehydration, dexamethasone and IV dextrose infusion were likely responsible for this degree of severe and resistant to treatment hyperglycemia. PMID- 23947428 TI - Metabolic abnormalities in adult HIV infected population on antiretroviral medication in Malaysia: a cross-sectional survey. AB - BACKGROUND: In the current two decades, dyslipidemia and increased blood glucose as metabolic abnormalities are the most common health threats with a high incidence among HIV/AIDS patients on antiretroviral (ARV) treatment. Scientific investigations and reports on lipid and glucose disorders among HIV infected communities are inadequate especially in those developing such as Malaysia. This cross-sectional survey was mainly aimed to evaluate the prevalence of metabolic abnormalities and associated risk factors among HIV infected population patients on ARV medication. METHODS: In a single reference health center in Malaysia, 2739 adult HIV positive patients on antiretroviral therapy (ART) were studied cross sectionally using medical records. Besides demographic variables and associated health disorders, those factors which can change the lipid and glucose levels were collected. Logistic Regression was used to find the potential risk factors (p < 0.05). RESULTS: Majority of the studied population were male (81.1%) and aged between 30-49 (68.6%). Mean CD4 count was 474.25 (cells/mm3) while undetectable RNA viral load was common among 83.3 (%) of subjects. Among 1,583 patients with the recent blood lipid and glucose tests, increased levels of triglyceride (TG) and total cholesterol (TC) were frequently prevalent in half of the population as 59 (%) and 54.2 (%) while 28.7 (%), 35.1 (%) and 38.2 (%) had declined level of high-density lipoprotein (HDL), raised low-density lipoprotein (LDL) and fasting plasma glucose (FPG) which were less common. Dyslipidemia was common in 82.3 (%) of the subjects. Notably, medication with protease inhibitor (PI) was a potential risk for elevated triglyceride (odds ratio (OR) = 2.309, 95% confidence interval (CI) = 1.605-3.324, P = 0.001), high TC (OR = 1.561, 95% CI = 1.123-2.169, P = 0.008) and low HDL (OR = 1.449, 95% CI = 1.037-2.024, P = 0.029). As lifestyle factor, alcohol consumption results as significant risk factor for raised TG (OR = 2.653, 95% CI = 1.353-5.202, P = 0.004). Also having hepatitis raised risk of high FPG level (OR = 1.630, 95% CI = 1.197-2.220, P = 0.002) in this sample population. CONCLUSIONS: Dyslipidemia is highly common in Malaysian HIV subjects receiving ARV medication. Lifestyle modification, changing PI and switch to other ARV regimen can help in reduction of these abnormalities. Also suitable strategies and plans are necessary to prevent cardiovascular diseases in future. PMID- 23947430 TI - Lewis acid catalysis and ligand exchange in the asymmetric binaphthol-catalyzed propargylation of ketones. AB - 1,1'-Bi-2-naphthol (BINOL)-derived catalysts catalyze the asymmetric propargylation of ketones. Density functional theory (DFT) calculations show that the reaction proceeds via a closed six-membered transition structure (TS) in which the chiral catalyst undergoes an exchange process with the original cyclic boronate ligand. This leads to a Lewis acid type activation mode, not a Bronsted acid process, which accurately predicts the stereochemical outcome observed experimentally. PMID- 23947432 TI - Rapid evaluation of the absence of inflammation after rupture of membranes. AB - OBJECTIVES: The aim of this study was to validate the results of an immunochromatographic bedside test to detect IL6 and IL8 in vaginal secretions after rupture of membranes (ROM) with results obtained by ELISA tests. METHODS: A prospective cohort of 60 women with ROM or preterm ROM (PROM) was recruited. An immunochromatographic bedside test was performed with vaginal secretions samplings at admission, every 48 hrs until labor and during labor. Remaining samples were frozen for ELISA analysis. The results of bedside tests were compared to those from ELISA analysis for 114 samples. RESULTS: With all samples combined, the positive predictive values were 50% for IL6 and 86.8% for IL8 and the negative predictive values were 97.4% for IL6 and 53.3% for IL8. Kappa coefficients were 0.54 for IL6 and 0.41 for IL8. CONCLUSION: Our findings show that a bedside test can detect the absence of IL6 in vaginal secretions. This result suggests that bedside test could be used for expectant management after premature PROM to inform the attending physician of the absence of inflammation in vaginal secretions. PMID- 23947431 TI - Hippocampal volume and memory and learning outcomes at 7 years in children born very preterm. AB - Using magnetic resonance imaging, this study compared hippocampal volume between 145 very preterm children and 34 children born full-term at 7 years of age. The relationship between hippocampal volume and memory and learning impairments at 7 years was also investigated. Manual hippocampal segmentation and subsequent three dimensional volumetric analysis revealed reduced hippocampal volumes in very preterm children compared with term peers. However, this relationship did not remain after correcting for whole brain volume and neonatal brain abnormality. Contrary to expectations, hippocampal volume in the very preterm cohort was not related to memory and learning outcomes. Further research investigating the effects of very preterm birth on more extensive networks in the brain that support memory and learning in middle childhood is needed. PMID- 23947433 TI - Bisphosphonate-linked hyaluronic acid hydrogel sequesters and enzymatically releases active bone morphogenetic protein-2 for induction of osteogenic differentiation. AB - Regeneration of bone by delivery of bone morphogenetic proteins (BMPs) from implantable scaffolds is a promising alternative to the existing autologous bone grafting procedures. Hydrogels are used extensively in biomaterials as delivery systems for different growth factors. However, a controlled release of the growth factors is necessary to induce bone formation, which can be accomplished by various chemical functionalities. Herein we demonstrate that functionalization of a hyaluronan (HA) hydrogel with covalently linked bisphosphonate (BP) ligands provides efficient sequestering of BMP-2 in the resulting HA-BP hydrogel. The HA BP hydrogel was investigated in comparison with its analogue lacking BP groups (HA hydrogel). While HA hydrogel released 100% of BMP-2 over two weeks, less than 10% of BMP-2 was released from the HA-BP hydrogel for the same time. We demonstrate that the sequestered growth factor can still be released by enzymatic degradation of the HA-BP hydrogel. Most importantly, entrapment of BMP-2 in HA-BP hydrogel preserves the growth factor bioactivity, which was confirmed by induction of osteogenic differentiation of mesenchymal stem cells (MSCs) after the cells incubation with the enzymatic digest of the hydrogel. At the same time, the hydrogels degradation products were not toxic to MSCs and osteoblasts. Furthermore, BP-functionalization of HA hydrogels promotes adhesion of the cells to the surface of HA hydrogel. Altogether, the present findings indicate that covalent grafting of HA hydrogel with BP groups can alter the clinical effects of BMPs in bone tissue regeneration. PMID- 23947434 TI - The arbovirus vector Culex torrentium is more prevalent than Culex pipiens in northern and central Europe. AB - Two species of arbovirus vector, Culex torrentium and Culex pipiens (Diptera: Culicidae), occur in several European countries, but difficulties in their accurate identification and discrimination have hampered both detailed and large scale distribution and abundance studies. Using a molecular identification method, we identified to species 2559 larvae of Cx. pipiens/torrentium collected from 138 sites in 13 European countries ranging from Scandinavia to the Mediterranean coast. In addition, samples of 1712 males of Cx. pipiens/torrentium collected at several sites in the Czech Republic were identified to species based on the morphology of their hypopygia. We found that the two species occur together in large areas of Europe, and that Cx. torrentium dominates in northern Europe and Cx. pipiens dominates south of the Alps. The transition in dominance occurs in central Europe, where both species are roughly equally common. There was a strong correlation between the length of the growing season at different sites and occurrences of the two species. As the growing season increases, the proportion and detection of Cx. torrentium decrease, whereas those of Cx. pipiens increase. The present findings have important consequences for the interpretation of the results of studies on major enzootic and link-vectors of mosquito-borne bird-associated viruses (i.e. Sindbis, West Nile and Usutu viruses), especially in central Europe and Scandinavia. PMID- 23947435 TI - Navigating veterans with an abnormal prostate cancer screening test: a quasi experimental study. AB - BACKGROUND: Prostate cancer disproportionately affects low-income and minority men. This study evaluates the impact of a patient navigation intervention on timeliness of diagnostic resolution and treatment initiation among veterans with an abnormal prostate cancer screen. METHODS: Participants were enrolled between 2006 and 2010. The intervention involved a social worker and lay health worker navigation team that assisted patients in overcoming barriers to care. For navigated (n = 245) versus control (n = 245) participants, we evaluated rates of diagnostic resolution and treatment and adjusted for race, age, and Gleason score. RESULTS: Of 490 participants, 68% were African American, 47% were >= 65 years old, and 35% had cancer. Among those with an abnormal screen, navigation did not have a significant effect on time to diagnostic resolution compared to controls (median days of 97 versus 111; adj. HR 1.17, 95% CI, 0.96-1.43, p = 0.12). On analysis of the period beyond 80 days, navigated men reached resolution faster than controls (median of 151 days versus 190 days; adj. HR 1.41, 95% CI, 1.07-1.86, p = 0.01). Among those with cancer, navigation did not have a significant effect on time to treatment initiation compared to controls (median of 93 days versus 87 days; adj. HR 1.15, 95% CI, 0.82-1.62, p = 0.41). CONCLUSION: Our navigation program did not significantly impact the overall time to resolution or treatment for men with prostate cancer compared to controls. The utility of navigation programs may extend beyond targeted navigation times, however, and future studies focusing on other outcomes measures are therefore needed. PMID- 23947437 TI - "Fibonacci's route" to regioregular oligo(3-hexylthiophene)s. AB - We describe a new synthetic approach to regioregular monodisperse oligo(3 alkylthiophene)s allowing for simple separation of regioregular material in gram quantities. The number of repeat units follows the Fibonacci numbers up to a length of 21. In a small adaption of this approach, introduction of a protecting group was used to synthesize an oligo(3-hexylthiophene) with 36 repeating units, the longest regioregular 3-hexylthiophene oligomer synthesized to date. PMID- 23947436 TI - Gentrepid V2.0: a web server for candidate disease gene prediction. AB - BACKGROUND: Candidate disease gene prediction is a rapidly developing area of bioinformatics research with the potential to deliver great benefits to human health. As experimental studies detecting associations between genetic intervals and disease proliferate, better bioinformatic techniques that can expand and exploit the data are required. DESCRIPTION: Gentrepid is a web resource which predicts and prioritizes candidate disease genes for both Mendelian and complex diseases. The system can take input from linkage analysis of single genetic intervals or multiple marker loci from genome-wide association studies. The underlying database of the Gentrepid tool sources data from numerous gene and protein resources, taking advantage of the wealth of biological information available. Using known disease gene information from OMIM, the system predicts and prioritizes disease gene candidates that participate in the same protein pathways or share similar protein domains. Alternatively, using an ab initio approach, the system can detect enrichment of these protein annotations without prior knowledge of the phenotype. CONCLUSIONS: The system aims to integrate the wealth of protein information currently available with known and novel phenotype/genotype information to acquire knowledge of biological mechanisms underpinning disease. We have updated the system to facilitate analysis of GWAS data and the study of complex diseases. Application of the system to GWAS data on hypertension using the ICBP data is provided as an example. An interesting prediction is a ZIP transporter additional to the one found by the ICBP analysis. The webserver URL is https://www.gentrepid.org/. PMID- 23947442 TI - Visual feedback and positioning movements. AB - Subjects (n = 60) performed both the reproduction and learning of a linear positioning movement under one of five visual feedback conditions. Results from two experiments indicated that visual cues from the task display augmented information available from visual feedback of the movement per se. Extraneous cues from the task display have clearly confounded the manipulation of visual feedback in previous positioning studies. When these cues are eliminated, visual distance information seems more useful than visual location information. PMID- 23947441 TI - Screening in silico predicted remotely acting NF1 gene regulatory elements for mutations in patients with neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1), a neuroectodermal disorder, is caused by germline mutations in the NF1 gene. NF1 affects approximately 1/3,000 individuals worldwide, with about 50% of cases representing de novo mutations. Although the NF1 gene was identified in 1990, the underlying gene mutations still remain undetected in a small but obdurate minority of NF1 patients. We postulated that in these patients, hitherto undetected pathogenic mutations might occur in regulatory elements far upstream of the NF1 gene. In an attempt to identify such remotely acting regulatory elements, we reasoned that some of them might reside within DNA sequences that (1) have the potential to interact at distance with the NF1 gene and (2) lie within a histone H3K27ac-enriched region, a characteristic of active enhancers. Combining Hi-C data, obtained by means of the chromosome conformation capture technique, with data on the location and level of histone H3K27ac enrichment upstream of the NF1 gene, we predicted in silico the presence of two remotely acting regulatory regions, located, respectively, approximately 600 kb and approximately 42 kb upstream of the NF1 gene. These regions were then sequenced in 47 NF1 patients in whom no mutations had been found in either the NF1 or SPRED1 gene regions. Five patients were found to harbour DNA sequence variants in the distal H3K27ac-enriched region. Although these variants are of uncertain pathological significance and still remain to be functionally characterized, this approach promises to be of general utility for the detection of mutations underlying other inherited disorders that may be caused by mutations in remotely acting regulatory elements. PMID- 23947440 TI - Effects of Zn2+ binding on the structural and dynamic properties of amyloid beta peptide associated with Alzheimer's disease: Asp1 or Glu11? AB - Extensive experimental and computational studies have suggested that multiple Zn(2+) binding modes in amyloid beta (Abeta) peptides could exist simultaneously. However, consistent results have not been obtained for the effects of Zn(2+) binding on Abeta structure, dynamics, and kinetics in particular. Some key questions such as why it is so difficult to distinguish the polymorphic states of metal ions binding to Abeta and what the underlying rationale is, necessitate elucidation. In this work, two 3N1O Zn(2+) binding modes were constructed with three histidines (His(6), His(13), and His(14)), and Asp(1)/Glu(11) of Abeta40 coordinated to Zn(2+). Results from molecular dynamics simulations reveal that the conformational ensembles of different Zn(2+)-Abeta40 complexes are nonoverlapping. The formation of turn structure and, especially, the salt bridge between Glu(22)/Asp(23) and Lys(28) is dependent on specific Zn(2+) binding mode. Agreement with available NMR observations of secondary and tertiary structures could be better achieved if the two simulation results are considered together. The free energy landscape constructed by combining both conformations of Abeta40 indicates that transitions between distinct Abeta40 conformations thar are ready for Zn(2+) binding could be possible in aqueous solution. Markov state model analyses reveal the complex network of conformational space of Abeta40 modeulated by Zn(2+) binding, suggesting various misfolding pathways. The binding free energies evaluated using a combination of quantum mechanics calculations and the MM/3D-RISM method suggest that Glu(11) is the preferred oxygen ligand of Zn(2+). However, such preference is dependent on the relative populations of different conformations with specific Zn(2+) binding modes, and therefore could be shifted when experimental or simulation conditions are altered. PMID- 23947443 TI - Varying the type and number of adaptive variables in continuous tracking. AB - To investigate the effectiveness of various types and numbers of adaptive variables, 48 subjects performed a two-dimensional pursuit tracking task for five 3-min training sessions. In the factorial design resulting in eight experimental conditions, three variables (frequency of the forcing function, ratio of acceleration to rate control, and control stick sensitivity) were either fixed or adaptive. A transfer and retention task in which the tracking situation changed periodically was used to evaluate the ability of subjects to adjust to change. Each adaptive variable was analyzed separately in training. The highest rate of adaptation in frequency occurred when frequency was the only adaptive variable. The rate of adaptation in acceleration was greater early in training when frequency also adapted. More adaptation occurred in gain when another variable also adapted. During transfer subjects trained adaptively generally showed more stable performance in the changing task situation. No reliable differences among conditions appeared in retention. Results are discussed in terms of stimulus and response similarity, the optimum number of adaptive variables, and the appropriateness of a changing task to evaluate adaptive training. PMID- 23947444 TI - The informational and motivational influence of social reinforcement on motor performance. AB - Two experiments were conducted to determine the effects of social reinforcement on the performance of a motor task. Subjects for both experiments were seventh and eighth-grade girls from a public junior high school. Experiment 1 examined the influence of knowledge of results (KR) and social reinforcement on 25 initial acquisition trials of a novel motor task in a KR * social reinforcement * experimenter blocks (2 * 2 * 2 * 5) factorial design. Experiment 2 examined the influence of KR and social reinforcement on 40 later performance trials in a KR * social reinforcement * blocks (2 * 2 * 8) factorial design. Actual and estimated performance scores were analyzed with MANOVA, discriminant function analyses, and step-down F tests. Experiment 1 suggested a combination of informational and motivational effects, with both KR and social reinforcement facilitating performance. Social reinforcement did not significantly affect performance in Experiment 2. PMID- 23947445 TI - Retention and coding in motor short-term memory. AB - A modified short-term memory design was employed in an attempt to structurally interfere with the codes subserving distance and location information. Location information was codable in that no forgetting occurred over an unfilled retention interval, and there was some evidence that distance information was also codable. The interference effects supported a mechanism whereby locations are stored in a visual-kinesthetic code, with distance information being stored in a kinesthetic code having no visual consequences. Variable error was found to be the measure sensitive to both decay and interference in keeping with the Laabs (1973) model. It was proposed that the integrated code for location information storage is the mechanism accounting for the greater relative precision and codability of location cues with respect to distance cues. PMID- 23947446 TI - Knowledge of results precision and motor skill acquisition. AB - The effect of varying KR precision levels on the initial acquisition and later performance of a linear positioning task was investigated with 40 female undergraduates serving as subjects. Subjective evaluations of performance and estimates of accuracy were recorded along with actual scores. KR precision level (centimeters or millimeters) did not affect actual performance, but extremely precise KR (millimeters) had detrimental effects on performance evaluations and the labeling process of estimate performance. PMID- 23947447 TI - The role of mental practice in skill acquisition. AB - Experiment 1 used mirror drawing to investigate the effects of mental practice on performance of a previously known, symbolic task. Experiment 2 used the pursuit rotor to study mental practice in relation to varying amounts of active practice and rest in a less symbolic task. For mirror drawing, only one mental-practice group was significantly better than the no-practice group, and that by a small amount on one variable only. With the pursuit rotor, subjects who trained only with mental practice did not differ significantly from those with no training, and mental practice was no more effective than rest. Mental practice was not clearly effective at any stage of learning. PMID- 23947448 TI - The effects of social reinforcement and audience presence upon the motor performance of boys with different levels of initial ability. AB - High-and low-ability subjects were tested for 25 trials on a stabilometer balancing task in order to investigate the interaction effect of audience and social reinforcement conditions upon complex motor performance. Audience (passive audience, no audience), social reinforcement (positive reinforcement, negative reinforcement, no reinforcement), and initial ability level (high, low) were incorporated in a 2 * 3 * 2 design. The performance data were blocked into five blocks of five trials each for analysis. Although there were no significant audience and social reinforcement effects over all trials, in later performance (Blocks 4-5) the positive reinforcement group performed significantly better than the no-reinforcement group, with the negative reinforcement group performing at an intermediate level. PMID- 23947449 TI - Comment on jones' query. AB - Based in part upon research reported by Notterman and Page (1962), Jones (1974) has argued in this Journal that the question "Is Proprioception Important for Skilled Performance?" should be answered largely in the negative. The earlier study is elucidated, and a conclusion opposite to that of Jones' is drawn. PMID- 23947450 TI - What Do Notterman and Page (1962) show? A Reply to Notterman. AB - Notterman (1975) argued, contrary to my 1974 article, that the data obtained by Notterman and Page (1962) confirm the important role of proprioception in skilled performance. I argue that these data are in fact ambiguous when it comes to distinguishing the effects of proprioception from those of outflow control. PMID- 23947451 TI - A note on motor learning without post-response knowledge of results. AB - The common conclusion that some form of extrinsic post-response error information is necessary in order for subjects to acquire a criterion motor response was contradicted in an experiment using a linear positioning task. Blindfolded subjects moved a lever to a stop and then attempted to replace the lever in the correct location with the stop removed. This procedure was repeated for 12 trials, and knowledge of results was never provided. Absolute and constant errors decreased significantly with practice, suggesting the development of an internal error-detection mechanism in the absence of vision and extrinsic error information. The findings were discussed in terms of recent theoretical positions by Adams (1971) and Schmidt (1975). PMID- 23947452 TI - Absolute Error vs "E" in Target Accuracy. AB - The composite error E (i.e.,? (v(2) + c(2)) yields a multiple R approximating unity with the variable error v and constant error c, however, v is not adequately represented in all of the absolute error scores Ae as verified by a lower multiple correlation. PMID- 23947453 TI - High solubilities of small hydrocarbons in trihexyl tetradecylphosphonium bis(2,4,4-trimethylpentyl) phosphinate. AB - Experimental solubilities are reported for methane, ethane, ethylene, propane, and propylene in trihexyl tetradecylphosphonium bis(2,4,4-trimethylpentyl) phosphinate [P(14)666][TMPP] from 313 to 353 K up to 6.7 MPa. A literature review on solubilities of small hydrocarbons in ionic liquids shows that solubilities in [P(14)666][TMPP] are appreciably larger than those in other ionic liquids. Contrary to solubilities in ionic liquids studied earlier, solubilities of paraffins (ethane and propane) in [P(14)666][TMPP] are larger than those of the corresponding olefins (ethylene and propylene). Because, at fixed temperature, the vapor pressure of an olefin is larger than that of the corresponding paraffin, the relative volatility of the olefin exceeds that of the corresponding paraffin, contrary to the relative volatility observed in conventional extractive distillation with polar solvents where the volatility of the paraffin exceeds that of the corresponding olefin. PMID- 23947454 TI - From the editor's desk. AB - No abstract available for this article. PMID- 23947455 TI - Glossary of microcomputer terminology and other suggested resources. AB - No abstract available for this article. PMID- 23947456 TI - Microcomputers. AB - Occupational therapists are becoming increasingly aware of the potential applications of microcomputers in various practice settings. The purpose of this paper is to describe the components of a microcomputer and provide an orientation to the multitude of applications in different areas of practice. Commonly asked questions such as "How do I get started?" and "How can the computer be used in my setting?" are addressed, and suggestions for determining the appropriate computer to fit specific needs are discussed. PMID- 23947457 TI - Evaluation of software and hardware for rehabilitation and management. AB - Occupational therapists entering the field of computer applications for rehabilitation and management are perplexed by the plethora of options in hardware and software. Compound this with the need to be computer literate and the problems can be overwhelming. Many therapists desire a structured format for decisionmaking prior to the purchase of various options as salesmen are seldom familiar with the unique needs for software and hardware in rehabilitation environments. The purpose of this paper is to present questions most frequently asked by novices in computer applications. Additionally, structured evaluations of software and hardware for occupational therapy application will be presented. This paper will provide methods for therapists to be informed, self-directed and effective in the selection, justification, and purchase of computers and software in rehabilitation and management. PMID- 23947458 TI - Ergonomics, occupational therapy, and computers. AB - The use of computers in our daily home and work environment is increasing. Occupational therapy computer users and clinicians need to be aware of the psychological and physical adaptations which are required by individuals using video display terminals (VDTs). Ergonomics, the study of the interaction between the worker and the work environment, is dedicated to the promotion of worker health, safety, and productivity. The rehabilitationist's goals have always been to bring the patient to his or her optimal level of functioning, often involving the adaptation of the individual workstation in a retrospective manner. However, it is the role of the ergonomist to design work environments which anticipate and adapt to the physical and psychological needs of its workers. This paper will review basic ergonomic design principles for VDT workstations, which can assist the occupational therapist. PMID- 23947460 TI - Introduction. AB - No abstract available for this article. PMID- 23947459 TI - Impact of technology on rehabilitation. AB - This paper surveys important aspects of how high technology impacts patientslclients and health professionals. Included is a description of how commercial devices provide computer access for the disabled. In addition information is provided on special devices for environinental control, augmentative communication and mobility. The article concludes by differentiating between clinical and educational approaches and introduces ways in which therapists may become involved in computer assisted treatment. PMID- 23947461 TI - Computer applications in occupational therapy. AB - Computer applications in occupational therapy have increased in frequency and variety in the past fifteen years. This paper briefly reviews articles from selected United States and international occupational therapy journals on this topic.hone=& PMID- 23947462 TI - Computers and the occupational therapy administrator - 1985. AB - Administrators have a unique and two-dimensional role in regard to the use of computers in occupational therapy. First, they must understand and advocate for appropriate purchase, accessibility, and application of computers for their overall occupational therapy program. Secondly, they must be adept in using the organizational computer data base and microcomputers in their administrative duties. To assist in the decision-making process for the occupational therapy administrator who feels foreign to computer systems and their functions, this paper identifies the administrative requirements of "computerizing" an occupational therapy program. Additionally, this paper describes the computer's contribution to specific administrative functions in occupational therapy. PMID- 23947463 TI - Using the Apple IIe Computer as an Administrative Tool in an Occupational Therapy Department. AB - The microcomputer can be an extremely effective tool in an occupational therapy department for accomplishing administrative tasks in a more efficient and accurate manner when compared to traditional methods. This paper is directed to the occupational therapy manager who would like to streamline secretarial and administrative record-keeping. The mystery is removed from the computer terms of data base, spreadsheet, and word processing. Hardware and software requirements are identified. The process of creating patient files, attendance records and monthly reports is described so that the reader can gain an understanding of how occupational therapists can actually use a computer program to carry out these tasks. Additional applications including budgeting, creating home programs, and calculating productivity are also discussed. The reader is encouraged to consider the computer as a useful tool and approach it in an organized fashion, rather than let a lack of experience cause hesitation in initiating a project that can lead to enormous savings in time and improved accuracy for an occupational therapy department. PMID- 23947464 TI - An apple for the teacher. AB - Occupational therapists in academia will find the personal computer a surprisingly versatile resource to improve both efficiency and effectiveness of one's teaching responsibilities. Some of the possible applications for educators are described. PMID- 23947465 TI - Using a personal computer for fieldwork scheduling in a university occupational therapy program. AB - An interactive computer program, written in Basic A, developed for fieldwork scheduling to reduce costs of having scheduling done by an outside agency is described. Developed for use with the available personal computers in the institution, this scheduling program can be used in any situations where N people have J choices during K time periods to be assigned to H sites. The data pool results from student requests for placements according to available fieldwork sites, aided by faculty advisement designed to help them choose sites that meet their individual needs. Information in the resulting printouts includes student assignments to fieldwork sites, identification of any students who did not receive a placement and a listing of unassigned fieldwork spaces. PMID- 23947466 TI - Microcomputer applications for the severely disabled. AB - Occupational therapists, with their interest in maximizing functional abilities, are learning that microcomputers offer the capability to assist in almost any aspect of impairment of human activity. Therapists are becoming increasingly familiar with various applications of computer technology to the daily lives and rehabilitation programs of individuals with physical andlor cognitive deficits. Case studies are presented illustrating use of computer-based systems to provide communication augmentation, motor training, cognitive evaluation and training, and expanded recreational options for two individuals with severe motor or cognitive deficits. An approach to assessment and decision-making is described, along with the systems and components used, with examples of their applications. PMID- 23947467 TI - Competence and computers. AB - What happens when severe physical disability interferes with the biological drive toward competence by limiting activity which influences the environment? The following case history explores the use of computer games as a vehicle to aid in the achievement of competence for a ten year-old girl with dermatomyositis. PMID- 23947468 TI - The therapeutic use of computers in occupational therapy with patients with closed head injuries. AB - Occupational therapists in various settings were surveyed to obtain information on their use of computers with closed head injured patients. The majority of therapists use micro-computers for cognitive rehabilitation followed by vocational rehabilitation. Respondents indicated that an efficient means of distributing information does not yet exist resulting in a high incidence of trial and error learning on the part of the therapist. PMID- 23947469 TI - The nature and implications of shifting patterns of practice in physical disabilities occupational therapy. AB - This paper reviews the findings of previous studies of practice patterns in physical disabilities and presents related findings from a national SUNey of physical disability therapists. Implications of the studies to date are described and discussed with specific reference to the growing debate over legitimate techniques and boundaries in physical disabilities practice. PMID- 23947470 TI - An empirical approach to setting priorities within a department of rehabilitation. AB - The current need to maintain or increase levels of service, despite shrinking budgets, has prompted hospital department heads to focus increased attention on their process of decisionmaking around resource allocation. This paper presents a rational method of decision-making through priority-setting. The method was developed in x department of rehabilitation to assist with the cost-effective assignment of staff to the various services in the hospital. The method is based on a set of seventeen weighted criteria, which evaluate the relative importance of services that the department staffs. While the method has specific reference to a rehabilitation department, the authors feel that it may have application to a variety of other departments or settings. PMID- 23947471 TI - Rivermead perceptual assessment battery. AB - No abstract available for this article. PMID- 23947475 TI - Use of acidic electrolyzed water ice for preserving the quality of shrimp. AB - Electrolyzed water ice is a relatively new concept developed in food industry in recent years. The effect of acidic electrolyzed water (AEW) ice on preserving the quality of shrimp (Litopenaeus vannamei) was investigated. Physical, chemical, and microbiological changes of the shrimp were examined during the storage. The results showed that compared with tap water (TW) ice, AEW ice displayed a potential ability in limiting the pH changes of shrimp flesh and significantly (p < 0.05) retarded the changes of color difference and the formation of total volatile basic nitrogen (TVBN). And AEW ice treatment had no adverse effects on the firmness of shrimp. Conventional plate count enumeration and PCR-DGGE demonstrated that AEW ice had a capability of inhibiting growth of bacteria on raw shrimp, and the maximum reductions of population reached >1.0 log CFU/g (>90%) on the sixth day. Moreover, AEW ice was clearly more efficient in maintaining the initial attachments between muscle fibers in shrimp according to histological section analysis. On the basis of above analysis, AEW ice can be a new alternative of traditional sanitizer to better preserve the quality of seafood in the future. PMID- 23947476 TI - Identification process based on shear wave propagation within a phantom using finite element modelling and magnetic resonance elastography. AB - Magnetic resonance elastography (MRE), based on shear wave propagation generated by a specific driver, is a non-invasive exam performed in clinical practice to improve the liver diagnosis. The purpose was to develop a finite element (FE) identification method for the mechanical characterisation of phantom mimicking soft tissues investigated with MRE technique. Thus, a 3D FE phantom model, composed of the realistic MRE liver boundary conditions, was developed to simulate the shear wave propagation with the software ABAQUS. The assumptions of homogeneity and elasticity were applied to the FE phantom model. Different ranges of mesh size, density and Poisson's ratio were tested in order to develop the most representative FE phantom model. The simulated wave displacement was visualised with a dynamic implicit analysis. Subsequently, an identification process was performed with a cost function and an optimisation loop provided the optimal elastic properties of the phantom. The present identification process was validated on a phantom model, and the perspective will be to apply this method on abdominal tissues for the set-up of new clinical MRE protocols that could be applied for the follow-up of the effects of treatments. PMID- 23947478 TI - Total synthesis of cyanthiwigins A, C, G, and H. AB - The first total synthesis of cyanthiwigins A, C, H and concise synthesis of cyanthiwigin G was achieved from a common intermediate. A modified formal [4 + 2] cycloaddition was developed to construct the key cis-hydrindanone (A-B). Stereospecific 1,4-addition, alkylation, and ring-closing metathesis were used to build the tricarbocyclic ring system (A-B-C). Various site-selective oxidations were applied to create the desired oxidation states of the different cyanthiwigins. PMID- 23947477 TI - Disentangling the effects of genetic, prenatal and parenting influences on children's cortisol variability. AB - Developmental plasticity models hypothesize the role of genetic and prenatal environmental influences on the development of the hypothalamic-pituitary-adrenal (HPA) axis and highlight that genes and the prenatal environment may moderate early postnatal environmental influences on HPA functioning. This article examines the interplay of genetic, prenatal and parenting influences across the first 4.5 years of life on a novel index of children's cortisol variability. Repeated measures data were obtained from 134 adoption-linked families, adopted children and both their adoptive parents and birth mothers, who participated in a longitudinal, prospective US domestic adoption study. Genetic and prenatal influences moderated associations between inconsistency in overreactive parenting from child age 9 months to 4.5 years and children's cortisol variability at 4.5 years differently for mothers and fathers. Among children whose birth mothers had high morning cortisol, adoptive fathers' inconsistent overreactive parenting predicted higher cortisol variability, whereas among children with low birth mother morning cortisol adoptive fathers' inconsistent overreactive parenting predicted lower cortisol variability. Among children who experienced high levels of prenatal risk, adoptive mothers' inconsistent overreactive parenting predicted lower cortisol variability and adoptive fathers' inconsistent overreactive parenting predicted higher cortisol variability, whereas among children who experienced low levels of prenatal risk there were no associations between inconsistent overreactive parenting and children's cortisol variability. Findings supported developmental plasticity models and uncovered novel developmental, gene * environment and prenatal * environment influences on children's cortisol functioning. PMID- 23947473 TI - Systemic soluble receptor for advanced glycation endproducts is a biomarker of emphysema and associated with AGER genetic variants in patients with chronic obstructive pulmonary disease. AB - RATIONALE: Emphysema in chronic obstructive pulmonary disease (COPD) can be characterized by high-resolution chest computed tomography (HRCT); however, the repeated use of HRCT is limited because of concerns regarding radiation exposure and cost. OBJECTIVES: To evaluate biomarkers associated with emphysema and COPD related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation endproducts (sRAGE), a candidate systemic biomarker identified in this study, with single-nucleotide polymorphisms (SNPs) in the gene coding for RAGE (AGER locus) and with clinical characteristics. METHODS: Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 patients with COPD enrolled in the TESRA study. sRAGE was also measured in the ECLIPSE cohort in 1,847 patients with COPD, 298 smokers and 204 nonsmokers. The association between 21 SNPs in the AGER locus with sRAGE levels and clinical characteristics was also investigated. MEASUREMENTS AND MAIN RESULTS: sRAGE was identified as a biomarker of diffusing capacity of carbon monoxide and lung density in the TESRA cohort. In the ECLIPSE cohort, lower sRAGE levels were associated with increased emphysema, increased Global Initiative for Chronic Obstructive Lung Disease stage, and COPD disease status. The associations with emphysema in both cohorts remained significant after covariate adjustment (P < 0.0001). One SNP in the AGER locus, rs2070600, was associated with circulating sRAGE levels both in TESRA (P = 0.0014) and ECLIPSE (7.07 * 10(-16)), which exceeded genome-wide significance threshold. Another SNP (rs2071288) was also associated with sRAGE levels (P = 0.01) and diffusing capacity of carbon monoxide (P = 0.01) in the TESRA study. CONCLUSIONS: Lower circulating sRAGE levels are associated with emphysema severity and genetic polymorphisms in the AGER locus are associated with systemic sRAGE levels. Clinical trial registered with www.clinicaltrials.gov (NCT 00413205 and NCT 00292552). PMID- 23947479 TI - 'Get Your Life Back': process and impact evaluation of an asthma social marketing campaign targeting older adults. AB - BACKGROUND: Asthma in older adults is underdiagnosed and poorly self-managed. This population has little knowledge about the key symptoms, the prevalence among older adults, and the serious consequences of untreated asthma. The purpose of this study was to undertake a multifaceted evaluation of a social marketing campaign to increase asthma awareness among older adults in a regional Australian community. METHODS: A cohort of older adults in an intervention region (n = 316) and a control region (n = 394) were surveyed immediately prior to and following the social marketing campaign. Campaign awareness, message recall, materials recognition, and actions taken as a result of the campaign were assessed in both regions. Asthma knowledge and perceptions, experience of asthma symptoms, and general health were also assessed in both regions at baseline and follow-up. Analyses were conducted to explore the effects of the campaign in the intervention region, and to examine outcomes among different audience segments. RESULTS: The survey data showed that those in the target segments (Wheezers and Strugglers) had better message recall, and were more likely to report having taken action to control their respiratory symptoms. The campaign significantly increased the number of calls to an asthma information line from the target audience in the intervention community. CONCLUSIONS: A theory-based social marketing campaign conducted over 3-months increased the asthma information seeking behaviours of older adults in the intervention community compared to the control community. Recommendations are outlined for future community health promotion campaigns targeting older adults. PMID- 23947480 TI - Tubule density and diameter in coronal dentin from primary and permanent human teeth. AB - This study compared dentinal tubule density and diameter of human primary and permanent teeth at different depths of the coronal dentin. Crowns of eight primary second molars and eight permanent third molars were serially sectioned into three disks of ~0.5 mm thickness (superficial, middle, and deep layers), perpendicular to the long axis. Tubule density and diameter were evaluated in 2,000* and 3,000* magnifications by scanning electron microscopy. Data obtained were subjected to two-way repeated measures ANOVA and Tukey's post hoc test (alpha = 0.05). Tubule density was greater in primary teeth compared with permanent ones, regardless of depth (primary: 124,329 +/- 43,594 mm2; permanent: 45,972 +/- 21,098 mm2). In general, the tubule density increased as the dentin depth increased, except to the superficial and middle layers from permanent teeth. Tubule diameter was larger in the dentin layer close to the pulp chamber (superficial: 2.4 +/- 0.07 MUm; middle: 3.70 +/- 0.06 MUm; deep: 4.28 +/- 0.04 MUm). No difference was observed between primary (3.48 +/- 0.81 MUm) and permanent teeth (3.47 +/- 0.73 MUm). The tubule diameter increases as the dentin depth increases for primary and permanent teeth; however, the tubule density is higher in primary teeth. PMID- 23947481 TI - Preparation of Z-alpha,beta-unsaturated diazoketones from aldehydes. Application in the construction of substituted dihydropyridin-3-ones. AB - The stereoselective preparation of alpha,beta-unsaturated diazoketones with Z geometry is described from aldehydes and a new olefination reagent. When prepared from amino aldehydes, these diazoketones could be converted to substituted dihydropyridin-3-ones in just one step, after an intramolecular N-H insertion reaction. The straightforward synthesis of a natural trihydroxylated piperidine demonstrates the utility of these unsaturated diazoketones for the rapid construction of piperidines. PMID- 23947482 TI - Photoactivatable lipid probes for studying biomembranes by photoaffinity labeling. PMID- 23947483 TI - De novo sequencing of sunflower genome for SNP discovery using RAD (Restriction site Associated DNA) approach. AB - BACKGROUND: Application of Single Nucleotide Polymorphism (SNP) marker technology as a tool in sunflower breeding programs offers enormous potential to improve sunflower genetics, and facilitate faster release of sunflower hybrids to the market place. Through a National Sunflower Association (NSA) funded initiative, we report on the process of SNP discovery through reductive genome sequencing and local assembly of six diverse sunflower inbred lines that represent oil as well as confection types. RESULTS: A combination of Restriction site Associated DNA Sequencing (RAD-Seq) protocols and Illumina paired-end sequencing chemistry generated high quality 89.4 M paired end reads from the six lines which represent 5.3 GB of the sequencing data. Raw reads from the sunflower line, RHA 464 were assembled de novo to serve as a framework reference genome. About 15.2 Mb of sunflower genome distributed over 42,267 contigs were obtained upon assembly of RHA 464 sequencing data, the contig lengths ranged from 200 to 950 bp with an N50 length of 393 bp. SNP calling was performed by aligning sequencing data from the six sunflower lines to the assembled reference RHA 464. On average, 1 SNP was located every 143 bp of the sunflower genome sequence. Based on several filtering criteria, a final set of 16,467 putative sequence variants with characteristics favorable for Illumina Infinium Genotyping Technology (IGT) were mined from the sequence data generated across six diverse sunflower lines. CONCLUSION: Here we report the molecular and computational methodology involved in SNP development for a complex genome like sunflower lacking reference assembly, offering an attractive tool for molecular breeding purposes in sunflower. PMID- 23947484 TI - Exploiting differential surface display of chondroitin sulfate variants for directing neuronal outgrowth. AB - Chondroitin sulfate (CS) proteoglycans (CSPGs) are known to be primary inhibitors of neuronal regeneration at scar sites. However, a variety of CSPGs are also involved in neuronal growth and guidance during other physiological stages. Sulfation patterns of CS chains influence their interactions with various growth factors in the central nervous system (CNS), thus influencing neuronal growth, inhibition, and pathfinding. This report demonstrates the use of differentially sulfated CS chains for neuronal navigation. Surface-immobilized patterns of CS glycosaminoglycan chains were used to determine neuronal preference toward specific sulfations of five CS variants: CS-A, CS-B (dermatan sulfate), CS-C, CS D, and CS-E. Neurons preferred CS-A, CS-B, and CS-E and avoided CS-C containing lanes. In addition, significant alignment of neurites was observed using underlying lanes containing CS-A, CS-B, and CS-E chains. To utilize differential preference of neurons toward the CS variants, a binary combinations of CS chains were created by backfilling a neuro-preferred CS variant between the microcontact printed lanes of CS-C stripes, which are avoided by neurons. The neuronal outgrowth results demonstrate for the first time that a combination of sulfation variants of CS chains without any protein component of CSPG is sufficient for directing neuronal outgrowth. Biomaterials with surface immobilized GAG chains could find numerous applications as bridging devices for tackling CNS injuries where directional growth of neurons is critical for recovery. PMID- 23947486 TI - Calorimetric and structural studies of tetrabutylammonium bromide ionic clathrate hydrates. AB - In the present work, characteristic properties of tetrabutylammonium bromide (TBAB) ionic clathrate hydrates structures were studied by single-crystal X-ray structure analysis. The structures of three different tetragonal TBAB ionic clathrate hydrates that were formed in our experiments were based on the same water lattice of tetragonal structure I (TS-I) differing in the ways of including bromide anions and arranging tetrabutylammonium cations. We demonstrated that (1) Br(-) can be included into the water lattice, replacing two water molecules, (2) the butyl group of the cation can be inserted not only in large T and P cavities but also in small D cavities of the water lattice TS-I, and (3) one of the reasons for polytypism of ionic clathrate hydrates on the basis of TS-I is the occurrence of alternative modes of arrangements of four-compartment cavities in adjacent layers of the water framework. The compositions of three TBAB ionic clathrate hydrates TBAB.38.1H2O, TBAB.32.5H2O, and TBAB.26.4H2O were determined by chemical analysis, and their enthalpies of fusion were measured by differential scanning calorimetry (DSC). From the obtained results, the enthalpies of the TBAB hydrate formation from TBAB and water were calculated thermodynamically. PMID- 23947485 TI - Focused fluorescent probe library for metal cations and biological anions. AB - A focused fluorescent probe library for metal cations was developed by combining metal chelators and picolinium/quinolinium moieties as combinatorial blocks connected through a styryl group. Furthermore, metal complexes derived from metal chelators having high binding affinities for metal cations were used to construct a focused probe library for phosphorylated biomolecules. More than 250 fluorescent probes were screened for identifying an ultraselective probe for dTTP. PMID- 23947487 TI - Nanoindentation-induced phase transformation and structural deformation of monocrystalline germanium: a molecular dynamics simulation investigation. AB - Molecular dynamics simulations were conducted to study the nanoindentation of monocrystalline germanium. The path of phase transformation and distribution of transformed region on different crystallographic orientations were investigated. The results indicate the anisotropic behavior of monocrystalline germanium. The nanoindentation-induced phase transformation from diamond cubic structure to beta tin-Ge was found in the subsurface region beneath the tool when indented on the (010) plane, while direct amorphization was observed in the region right under the indenter when the germanium was loaded along the [101] and [111] directions. The transformed phases extend along the < 110 > slip direction of germanium. The depth and shape of the deformed layers after unloading are quite different according to the crystal orientation of the indentation plane. The study results suggest that phase transformation is the dominant mechanism of deformation of monocrystalline germanium film in nanoindentation. PMID- 23947488 TI - Errors in motor responding, "rapid" corrections, and false anticipations. AB - Two experiments investigated the hypothesis that errors in step-tracking were caused by false anticipation of the up-coming stimulus direction. In Experiment 1, eliminating the subject's ability to anticipate temporally did not inhibit error production, suggesting that temporal anticipation is not necessary for error production. In Experiment 2, providing strong spatial expectancies with occasional deviations from the expected direction caused errors to occur, suggesting that errors are caused by false spatial anticipation. The data support the hypothesis that the subjects correct errors by detecting the error upon stimulus onset, a hypothesis that does not require assumptions about the internal monitoring of efference as has been suggested previously. PMID- 23947489 TI - The processing of knowledge of results information for a serial-motor task. AB - This study was designed to consider the effect of the length of and the type of activity during the post-KR interval on the acquisition of a serial positioning task. Male subjects (n=105) were assigned to one of seven experimental conditions. Six of these conditions were defined by the combination of three levels of interpolated activity (none, verbal, and tracking) and two levels of post-KR interval length (12 and 60 sec). The seventh condition controlled for interresponse-interval length. Subjects were required to learn three positions, in serial order, on a manual lever across 20 trials. Neither varying the length of the post-KR interval nor introducing interfering activity during that interval affected the rate of acquisition of the task. The potential application of the paralearning hypothesis (Harcum, 1975) is discussed. PMID- 23947490 TI - The spacing effect in short-term motor memory. AB - A study of the spacing effect was conducted within a short-term motor memory framework. In Experiment 1 subjects received one or six repetitions of a discrete linear movement at intervals of 5 or 60 sec, and with a constant retention interval of 30 sec. The performance over 10 trials was analyzed in terms of algebraic, absolute, and variable error. The facilitation associated with longer intervals found in verbal retention situations was obtained in the present study for algebraic error only. The results were discussed in terms of the several hypotheses offered by Hintzman (1974), and a mechanism for the operation of differential attention was suggested. Inconsistencies with previous data were discussed. Experiments 2 and 3 addressed some unresolved issues from Experiment 1 and additional support for the differential-attention hypothesis was obtained. PMID- 23947491 TI - Schema theory and practice variability within a neo-piagetian framework. AB - Schema theory and neo-Piagetian theory were combined to explain psychomotor performance of female children. A curvilinear repositioning task was employed to test motor recall of a novel response. Results indicated support for the schema theory postulation of symmetry of motor memory across varying spatial locations. High M-processors performed significantly better than low M-processors, supporting the tenets of neo-Piagetian theory. It was concluded that a combination of the two theories offers a viable beginning in the understanding of children's psychomotor performance. PMID- 23947492 TI - Incidental motor learning. AB - Sixty subjects experienced four linear arm-positioning movements in the absence of visual cues. Half the subjects had instructions to learn the movements and anticipated a recall test. The other subjects thought they were participating in an experiment to test accuracy of movement estimation, in which they attempted to guess the length of each movement. The groups were subdivided and experienced the series of movements 1, 5, or 10 times. All subjects completed a serial recall test. Intentional learners produced superior recall only with low levels of practice, and there was no difference between incidental and intentional learning with higher levels of practice. PMID- 23947493 TI - Efference and the conscious perception of movement. AB - Evidence was sought implicating efference in the conscious perception of movement by having subjects (n = 10) scale the time course of an active (efference present) and passive (efference absent) thumb movement Efference would presumably lead slightly in time the proprioceptive feedback from a movement and therefore cause active movements to be judged as occurring earlier than passive movements. A probe stimulus (10-msec light flash) was interjected at various temporal locations during an auditorily cued thumb movement made under the two conditions. Subjects estimated the temporal location of the flash relative to the occurrence of the thumb movement. Active movements were estimated to occur on the average 43 msec earlier than passive movements (p<.005), suggesting that efference contributed to the conscious perception of the movement. PMID- 23947494 TI - Spatial cues in memory for movement. AB - The purpose of this experiment was to investigate further the finding that location cues provide a reliable source of movement information in memory. Three movement conditions were employed: location cues only, extent cues only, and both location and extent cues. These movement conditions were observed over three retention-interval conditions: reproduction immediately following presentation of the standard and reproduction following a 20-sec delay which was either unfilled or filled with an attention-demanding task. The results tended to support the notion that location cues provide the more reliable source of information in that the extent condition had higher absolute and variable error than the other two conditions which were found not to be reliably different. PMID- 23947495 TI - The coding of location. AB - One prediction of the recent target hypothesis for movement control (MacNeilage, 1970; Russell, 1976) holds that location reproduction is not solely dependent upon stored kinesthetic information. Three experiments were performed to test this prediction by requiring the subject to reproduce the location with the limb opposite to the one used for criterion production. This switched-limb procedure was assumed to force the subject to rely upon more abstract information rather than the kinesthetic cues of the criterion movement. With movement direction invariant, switched-limb reproduction was equal to same-limb reproduction. The alteration of movement direction hampered switched-limb reproduction but same limb reproduction was not greatly affected. These findings gave some support to the target hypothesis but suggested that the context of the movement may affect the potency of the location code. Implications of the switched-limb technique for future research were briefly discussed. PMID- 23947496 TI - Task complexity, accuracy, and reaction time. AB - An attempt was made to examine one specific aspect of response complexity - accuracy demand. Three groups, each of 12 subjects, were presented with two parallel lines of dots on a moving paper strip. Dots were in pairs at random intervals, and subjects were required to cross over the dots with a pen when a tone sounded. Subjects were required to cross over either zero, one, or two dots sequentially. From zero dots to one dot, there was an increase in reaction time (RT), presumably due to the more stringest error limits required in the latter. RT did not increase from one dot to two dots, but increased movement time (MT) was found. Results suggest that RT involves programming of movement initiation, and that MT includes some programming of the ongoing response. Accuracy demand differentially influenced RT and MT. PMID- 23947497 TI - Patients attitudes towards sleep disturbances during chemotherapy. AB - Sleep disturbances are among the most distressing symptoms in cancer: they often co-occur with fatigue, pain and psychological distress. Despite the negative impact on quality of life, patients rarely seek help for managing their sleep disturbances. This paper presents the results of a multicentre observational study on patients' attitudes towards their sleep problems. The study also investigates symptom correlates. Patients responded to a semi-structured interview and completed the following questionnaires: Pittsburgh Sleep Quality Index; Brief Fatigue Inventory; Hospital Anxiety and Depression Scale; and European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life QLQ-C30 Questionnaire (QLQ-C30). Four hundred and three cancer patients were enrolled in the study. Bad sleepers constituted 66% of the sample. Thirty-eight per cent of them had not turned to any professional to solve their sleep disturbances because they had various beliefs about the importance of the problem and the possibility to be treated. The main correlates of sleep disturbances were psychological distress, reduced physical functioning and reduced overall quality of life. In conclusion, there is a need to sensitise patients to actively search for a solution to their sleep disturbances so they can be solved along with other co-occurring symptoms. Doctors could also be encouraged to dedicate more attention to routinely asking cancer patients about eventual sleep disturbances. PMID- 23947498 TI - From the editor's desk. AB - No abstract available for this article. PMID- 23947499 TI - Introduction. AB - No abstract available for this article. PMID- 23947500 TI - Maternal role preparation. AB - The Maternal Role Preparation (MRP) project demonstrates an innovative occupational therapy approach to increasing maternal competence in first time mothers. This four session program provided women with discussion, demonstration, practice and written materials covering topics concerning their infants (attachment, sensory systems, developmental abilities) and themselves (acquiring a new role as mother). Theoretical constructs from Behavioral Pediatrics, Sensory Integration and Occupational Behavior were evaluated for their compattbility and combined under the unifying framework of Occupational Behavior. The program represents an opportunity for occupational therapists to combine sensory integration theory and practice with other compatible treatment perspectives and approaches. PMID- 23947501 TI - Evaluation of praxis in preschoolers. AB - This article draws from the research and clinical work of A. Jean Ayres to present a rationale and set of procedures for occupational therapy evaluation of the preschooler whose presenting problems suggest dyspraxia. The concept of praxis is briefly discussed and the problems of evaluating praxis in the preschooler are outlined. Based on the literature in this area, two major domains for evaluation are examined: sensory processing and praxis. In the domain of sensory processing, special attention is given to assessment of tactile, proprioceptive, vestibular, auditory, and visual functions. The domam of praxis is organized according to three primary processes: ideation, motor planning, and execution. Procedures for each domain are suggested, including administration of standardized test items, parent interviews, and structured observations, as well as observation of behavior in unstructured situations. Precautions in interpretation of data and suggestions for presenting evaluation findings in the clinical report are delineated. Finally, consideration is given to issues related to recommendation of occupational therapy, referral to other professionals, and setting of treatment goals for the dyspraxic child. PMID- 23947502 TI - Movement is fun. AB - A movement program for children based on sensory integration theory, using movement education concepts, was developed by an occupational therapist for use in preschool settings. The goal of the program is to enhance normal growth and development in 3-5 year old children, and to provide a vehicle for early identification of children with developmental delays. The paper will describe the curriculum and provide examples of activities used as well as suggestions for instituting such a program elsewhere. Research has not been conducted on the effects of the program, but comments from teachers, parents and therapists involved indicate that the program is meeting its goals. PMID- 23947503 TI - Sensory integrative dysfunction. AB - Parental participation in the occuational therapy program for the child with sensory integrative dysfunction may significantly improve the achievement of therapy goals, as well as adaptive behaviors within the home. An individual plan for effective parent involvement is developed with consideration given to levels of parent/child interaction and to the parents' ability to accept their child's difficulties. Purposes of parental participation are outlined in conjunction with an existing model for evaluation and intervention. A case presentation is presented which illustrates optimal parental involvement and the resulting positive outcomes. PMID- 23947504 TI - Sensory integration and play behavior. AB - This paper presents a case study describing a developmentally delayed child and examines the changes in environmental interactions that occurred during a study period in occupational therapy in which sensory integration (SI) techniques were applied. Its purpose is to discuss the use of play observation as a means of measuring change in individuals involved in SI treatment and to demonstrate the relevance of qualitative research methodologies to the collection of data on play behavior. The study is a first step in a process of developing methods to evaluate the effectiveness of SI treatment in occupational therapy through collecting qualitative data on play and other behavioral measures of environmental interactions. PMID- 23947505 TI - A sensory-integrative approach to the education of the autistic child. AB - The history and current status of a four year old demonstration school for autistic children in Phoenix, Arizona is described. The curriculum is based on neurodevelopmental, sensory integrative principles as contrasted with operant conditioning models. An interdisciplinary staff integrates communication, daily living, academic and sensorimotor and music components. A neurological frame of reference is described for dealing with self-stimulating and self-abusive behaviors. Awareness of the problems of parents is emphasized. PMID- 23947506 TI - Sensory integration and ego development in a schizophrenic adolescent male. AB - This single case study of a schizophrenic adolescent presents a detailed analysis of gains in ego functions and clinical observations. A time out record was retrospectively compiled. The purpose of the time out record was to evaluate the generalized effects of sensory integrative treatment procedures on the client's ability to deal with anger and frustration in his living environment. Statistical analysis did not yield a significant difference between pre- and posttreatment data. The results of this study demonstrate the usefulness of statistical analysis verses visual comparison of pre- and post-treatment data in the validation of treatment effectiveness. Visual inspection might support a conclusion of a significant difference, when statistic analysis will not. Although marked decreases were noted in the client's time out record as he mastered hypersensitivity to movement, dcvelopment of protective extension, and gravitational security, no direct statistical link could be made to the sensory integration treatment intervention. This case study does however, lay a foundation for relating ego development to vestibular system function. PMID- 23947507 TI - A sensory integration based program with a severely retarded/autistic teenager. AB - This case report illustrates occupational therapy based on sensory integration philosophy and treatment principles with a severely mentally retarded/autistic fifteen year old boy. Evaluation, treatment and results are outlined and discussed retrospectively. An oral stimulation and feeding program is presented as an additional and integral part of his occupational therapy program. The integration of his occupational therapy program into his daily group home and school life is presented and the contribution of these other caregivers assessed. PMID- 23947508 TI - Using sensory integration principles with regressed elderly patients. AB - Sensory deprivation in the elderly is an acquired syndrome which responx to intervention based on sensory integration principles and a sensitivity to former roles and cultural influences. Clinical observations of a group of regressed nursing home residents revealed maladaptive responses similar to those described by King in a sample of non-paranoid schizophrenic patients. Observations of maladaptive behavior were noted in posture and motor activity, perception, communication, cognition and psychosocial behavior. In the demonstration project presented here, eleven nursing home residents displaying symptoms of sensory deprivation were randomly assigned to one of two groups, intervention or control. The control group participated in individualized treatment utilizing biomechanical principles. In the intervention group, sensory integration principles provrded the framework in a program which structured the environment to promote adaptive responses. The groups met for forty minutes twice weekly during a sixteen week period. A pretest-posttest comparison revealed significant improvement in the adaptive responses of the intervention group. PMID- 23947509 TI - The use of computer-assisted behavior observation in sensory integration practice and research. AB - In the past, occupational therapists have relied upon either indirect reports of client behavior or outcomes of standardized test paradigms to assess the efficacy of their treatment. The use of direct behavioral observations is proposed as an aid in the sensory integrative therapy process. Utilizing this method allows the therapist to quantify data, to devise and answer specific research questions, and to assess the progress of clients in treatment. Advice is given on how to best establish a behavior taxonomy to meet specific needs of the research or therapy situation. The benefits and drawbacks of computer-assisted direct behavioral observation are examined. It is concluded that computer-assisted direct behavioral observation could and should provide a valuable data collection tool in the occupational therapist's repertoire. PMID- 23947510 TI - The clinician as advocate for sensory integration. AB - This paper discusses professional advocacy as a means to promote occupational therapy services for clients. Although sensory integration is the focal point, the process discussed below for evaluating a system is valuable for promoting any aspect of occupational therapy. Examples of providing occupational therapy to children in a public school setting are used to illustrate the principles of the process. PMID- 23947511 TI - Improving the work potential of brain-injured adolescents and young adults. AB - Brain injured individuals have a unique set of skills and deficits which make them difficult to place in traditional lobs and work programs. Although they may function at a relatively high level intellectually, these individuals often demonstrate deficits in attention, motivation, memory, and social skills. A variety of strategies must be employed in assessing and developing the work potential of the brain injured individual. This paper describes a work program that has been designed to meet the unique needs of the brain injured population. Case examples are included to illustrate application of these strategies. PMID- 23947513 TI - Disseminated microsporidiosis in a renal transplant recipient: case report and review of the literature. AB - Microsporidia are opportunistic pathogens that usually cause a limited disease in the gastrointestinal tract. Occasionally, they can cause disseminated disease. In solid organ transplant recipients, disseminated disease has been reported only rarely. We describe a 68-year-old woman who presented with fever, cough, and acute kidney injury 6 months after kidney transplantation. Dissemination was confirmed by identification of microsporidial spores in urine and bronchoalveolar lavage fluid. Polymerase chain reaction analysis identified the species as Encephalitozoon cuniculi. PMID- 23947514 TI - The monocyte and acute respiratory distress syndrome: implicated, innocent bystander, or awash in research translation? PMID- 23947515 TI - Early intervention for newborns screened for cystic fibrosis. PMID- 23947516 TI - Diamonds in the rough: identification of usable donor lungs. PMID- 23947518 TI - High-frequency oscillatory ventilation, microRNAs in pulmonary hypertension, and gastric residual volumes. PMID- 23947517 TI - An official American Thoracic Society/European Respiratory Society statement: the role of the pulmonologist in the diagnosis and management of lung cancer. AB - BACKGROUND: Lung cancer is a common problem seen by pulmonologists. The American Thoracic Society (ATS) and European Respiratory Society (ERS) are professional organizations whose memberships are composed of large numbers of pulmonologists. PURPOSE: This document describes the key role of pulmonologists in the prevention, early diagnosis, and management of lung cancer. METHODS: A committee of ATS and ERS leaders and their oncology groups discussed the activities of pulmonologists in relation to lung cancer in various settings and reviewed available literature on the topic. The content of this statement was approved by the board of directors of both the ATS and ERS. RESULTS: Optimal lung cancer care requires a multidisciplinary team of specialists who care for a significant number of patients on a regular basis. Pulmonologists are responsible for and involved with patients from their initial diagnosis and staging through treatment and restaging. They are often involved with complications, palliative care, and end-of-life care, and thus have an important role in team leadership. CONCLUSIONS: Lung cancer is a disease with high mortality, profound effects on the quality of the lives of patients and their families, and an enormous cost and impact on society. To treat lung cancer optimally, care must be prompt, multidisciplinary, and patient-centered. In the entire process, pulmonologists have a key role. Pulmonologists and their professional societies should also enhance lung cancer research and education to provide better treatment options and patient care. PMID- 23947519 TI - HIV-associated follicular bronchiolitis. PMID- 23947520 TI - Reply: Tobacco, big pharma, and ATS. PMID- 23947521 TI - Tobacco, big pharma, and ATS. PMID- 23947522 TI - Reply. Severe sepsis: stay and play or scoop and run? PMID- 23947523 TI - Severe sepsis: stay and play or scoop and run? PMID- 23947524 TI - Survival benefits of liver transplant in severe hepatopulmonary syndrome. PMID- 23947525 TI - Pulmonary vascular complications include varices in the tracheobronchial tree. PMID- 23947527 TI - First elective thoracic endovascular aortic repair to treat hemoptysis due to bronchiectasis. PMID- 23947526 TI - Applicability of the global lung function spirometry equations in contemporary multiethnic children. PMID- 23947528 TI - Spontaneous regression of squamous cell lung cancer. PMID- 23947529 TI - A finite element evaluation of the moment arm hypothesis for altered vertebral shear failure force. AB - The mechanism of vertebral shear failure is likely a bending moment generated about the pars interarticularis by facet contact, and the moment arm length (MAL) between the centroid of facet contact and the location of pars interarticularis failure has been hypothesised to be an influential modulator of shear failure force. To quantitatively evaluate this hypothesis, anterior shear of C3 over C4 was simulated in a finite element model of the porcine C3-C4 vertebral joint with each combination of five compressive force magnitudes (0-60% of estimated compressive failure force) and three postures (flexed, neutral and extended). Bilateral locations of peak stress within C3's pars interarticularis were identified along with the centroids of contact force on the inferior facets. These measurements were used to calculate the MAL of facet contact force. Changes in MAL were also related to shear failure forces measured from similar in vitro tests. Flexed and extended vertebral postures respectively increased and decreased the MAL by 6.6% and 4.8%. The MAL decreased by only 2.6% from the smallest to the largest compressive force. Furthermore, altered MAL explained 70% of the variance in measured shear failure force from comparable in vitro testing with larger MALs being associated with lower shear failure forces. Our results confirmed that the MAL is indeed a significant modulator of vertebral shear failure force. Considering spine flexion is necessary when assessing low-back shear injury potential because of the association between altered facet articulation and lower vertebral shear failure tolerance. PMID- 23947530 TI - Covalent assembly of heterosequenced macrocycles and molecular cages through orthogonal dynamic covalent chemistry (ODCC). AB - Shape-persistent heterosequenced 2-D macrocycles and 3-D molecular cages have been prepared in one pot from two or three different monomers, through orthogonal dynamic covalent chemistry using dynamic imine and olefin metathesis. PMID- 23947531 TI - Structural and energetic properties of the potential HIV-1 reverse transcriptase inhibitors d4A and d4G: a comprehensive theoretical investigation. AB - A comprehensive quantum-chemical investigation of the conformational landscapes of two nucleoside HIV-1 reverse transcriptase inhibitors, 2',3'-didehydro-2',3' dideoxyadenosine (d4A), and 2',3'-didehydro-2',3'-dideoxyguanosine (d4G), has been performed at the MP2/6-311++G(d,p)//B3LYP/6-31G(d,p) level of theory. It was found that d4A can adopt 21 conformers within a 5.17 kcal/mol Gibbs free energy range, whereas d4G has 20 conformers within 6.23 kcal/mol at T = 298.15 K. Both nucleosides are shaped by a sophisticated network of specific noncovalent interactions, including conventional (OH[Formula: see text]O, NH[Formula: see text]O) and weak (CH[Formula: see text]O, CH[Formula: see text]N) hydrogen bonds, as well as dihydrogen (CH[Formula: see text]HC) contacts. For the OH[Formula: see text]O, NH[Formula: see text]O, and CH[Formula: see text]O hydrogen bonds, natural bond orbital analysis revealed hyperconjugative interactions between the oxygen lone pairs and the antibonding orbital of the donor group. For the CH[Formula: see text]HC contacts, the electron density migrates from the antibonding orbital, corresponding to the CH group of the sugar residue, to the bonding orbital relative to the same group in the nucleobase. The results confirm the current belief that the biological activity of d4A and d4G is connected with the termination of the DNA chain synthesis in the 5'-3' direction. Thus, these nucleosides act as competitive HIV-1 reverse transcriptase inhibitors. PMID- 23947532 TI - Histone deacetylases 1 and 2 maintain S-phase chromatin and DNA replication fork progression. AB - BACKGROUND: Histone deacetylases (HDACs) play a critical role in the maintenance of genome stability. Class I HDACs, histone deacetylase 1 and 2 (Hdac1 and Hdac2) are recruited to the replication fork by virtue of their interactions with the replication machinery. However, functions for Hdac1 and Hdac2 (Hdacs1,2) in DNA replication are not fully understood. RESULTS: Using genetic knockdown systems and novel Hdacs1,2-selective inhibitors, we found that loss of Hdacs1,2 leads to a reduction in the replication fork velocity, and an increase in replication stress response culminating in DNA damage. These observed defects are due to a direct role for Hdacs1,2 in DNA replication, as transcription of genes involved in replication was not affected in the absence of Hdacs1,2. We found that loss of Hdacs1,2 functions increases histone acetylation (ac) on chromatin in S-phase cells and affects nascent chromatin structure, as evidenced by the altered sensitivity of newly synthesized DNA to nuclease digestion. Specifically, H4K16ac, a histone modification involved in chromatin decompaction, is increased on nascent chromatin upon abolishing Hdacs1,2 activities. It was previously shown that H4K16ac interferes with the functions of SMARCA5, an ATP-dependent ISWI family chromatin remodeler. We found SMARCA5 also associates with nascent DNA and loss of SMARCA5 decreases replication fork velocity similar to the loss or inhibition of Hdacs1,2. CONCLUSIONS: Our studies reveal important roles for Hdacs1,2 in nascent chromatin structure maintenance and regulation of SMARCA5 chromatin-remodeler function, which together are required for proper replication fork progression and genome stability in S-phase. PMID- 23947533 TI - Budding pathway in the templated assembly of viruslike particles. AB - A new pathway for the assembly of viral capsid protein around inorganic nanoparticle cores was observed by time-course light scattering and cryo-electron tomography. Gold nanoparticles with an average diameter of 11.3 nm have been used as a template for the assembly of Brome mosaic virus (BMV) capsid protein at different concentrations. At least at low protein concentrations the kinetic features of the scattering and extinction measurements are consistent with the initial rapid formation of large nanoparticle-protein clusters, which subsequently separate into individual viruslike particles (VLPs). The occurrence of multiparticle clusters at short times after mixing nanoparticles and proteins was confirmed by cryo-EM. Cryo-electron tomography of the multiparticle clusters yielded an average surface-to-surface interparticle distance of ~7.5 nm, equivalent to ~1.5 times the thickness of a protein shell. We propose a scenario in which VLP generation may take place through monomer exchange between aggregated particles with defect-ridden or incomplete shells, leading to the formation of stable icosahedral shells, which eventually bud off the aggregate. Together with results from previous works, the findings highlight the astonishing versatility of plant virus capsid protein assembly. This previously unknown mechanism for VLP formation has features that may have relevance for the crowded environment characterizing virus factories in the cell. PMID- 23947534 TI - Strategy for the synthesis of pyridazine heterocycles and their derivatives. AB - The first synthesis of novel fused pyridazines has been realized starting from 1,3-diketones involving a Diaza-Wittig reaction as a key step. A convenient strategy was elaborated to access versatile pyridazine derivatives allowing the variation of substituents at position 6 of the heterocyclic ring. In a first part, pyridazines bearing an ester group were synthesized as a model to evaluate the methodology. In a second part, an improved procedure has been used for the synthesis of pyridazines bearing a ketone group and different methods of cyclization were carried out, leading to several hitherto unknown biheterocyclic compounds. This reaction scheme represents an attractive methodology for the synthesis of novel fused pyridazine derivatives. PMID- 23947537 TI - Survival following traumatic ventricular rupture and prolonged ambulance transport in a patient with previous coronary artery bypass surgery. AB - Patients presenting with traumatic cardiac rupture are unlikely to survive lengthy transfers from the trauma scene to a hospital. However, in patients with a previous sternotomy, adhesions may divert cardiac hemorrhage, allowing hemodynamic management to be successful. We present an 83-year-old male with a history of coronary artery bypass grafting (CABG) who sustained a right ventricular rupture. He underwent an immediate redo sternotomy and was discharged 10 days postoperatively with no complications. PMID- 23947536 TI - Transcriptional analysis of abdominal fat in genetically fat and lean chickens reveals adipokines, lipogenic genes and a link between hemostasis and leanness. AB - BACKGROUND: This descriptive study of the abdominal fat transcriptome takes advantage of two experimental lines of meat-type chickens (Gallus domesticus), which were selected over seven generations for a large difference in abdominal (visceral) fatness. At the age of selection (9 wk), the fat line (FL) and lean line (LL) chickens exhibit a 2.5-fold difference in abdominal fat weight, while their feed intake and body weight are similar. These unique avian models were originally created to unravel genetic and endocrine regulation of adiposity and lipogenesis in meat-type chickens. The Del-Mar 14K Chicken Integrated Systems microarray was used for a time-course analysis of gene expression in abdominal fat of FL and LL chickens during juvenile development (1-11 weeks of age). RESULTS: Microarray analysis of abdominal fat in FL and LL chickens revealed 131 differentially expressed (DE) genes (FDR<=0.05) as the main effect of genotype, 254 DE genes as an interaction of age and genotype and 3,195 DE genes (FDR<=0.01) as the main effect of age. The most notable discoveries in the abdominal fat transcriptome were higher expression of many genes involved in blood coagulation in the LL and up-regulation of numerous adipogenic and lipogenic genes in FL chickens. Many of these DE genes belong to pathways controlling the synthesis, metabolism and transport of lipids or endocrine signaling pathways activated by adipokines, retinoid and thyroid hormones. CONCLUSIONS: The present study provides a dynamic view of differential gene transcription in abdominal fat of chickens genetically selected for fatness (FL) or leanness (LL). Remarkably, the LL chickens over-express a large number of hemostatic genes that could be involved in proteolytic processing of adipokines and endocrine factors, which contribute to their higher lipolysis and export of stored lipids. Some of these changes are already present at 1 week of age before the divergence in fatness. In contrast, the FL chickens have enhanced expression of numerous lipogenic genes mainly after onset of divergence, presumably directed by multiple transcription factors. This transcriptional analysis shows that abdominal fat of the chicken serves a dual function as both an endocrine organ and an active metabolic tissue, which could play a more significant role in lipogenesis than previously thought. PMID- 23947538 TI - Design of the Bottom-up Innovation project--a participatory, primary preventive, organizational level intervention on work-related stress and well-being for workers in Dutch vocational education. AB - BACKGROUND: In the educational sector job demands have intensified, while job resources remained the same. A prolonged disbalance between demands and resources contributes to lowered vitality and heightened need for recovery, eventually resulting in burnout, sickness absence and retention problems. Until now stress management interventions in education focused mostly on strengthening the individual capacity to cope with stress, instead of altering the sources of stress at work at the organizational level. These interventions have been only partly effective in influencing burnout and well-being. Therefore, the "Bottom-up Innovation" project tests a two-phased participatory, primary preventive organizational level intervention (i.e. a participatory action approach) that targets and engages all workers in the primary process of schools. It is hypothesized that participating in the project results in increased occupational self-efficacy and organizational efficacy. The central research question: is an organization focused stress management intervention based on participatory action effective in reducing the need for recovery and enhancing vitality in school employees in comparison to business as usual? METHODS/DESIGN: The study is designed as a controlled trial with mixed methods and three measurement moments: baseline (quantitative measures), six months and 18 months (quantitative and qualitative measures). At first follow-up short term effects of taking part in the needs assessment (phase 1) will be determined. At second follow-up the long term effects of taking part in the needs assessment will be determined as well as the effects of implemented tailored workplace solutions (phase 2). A process evaluation based on quantitative and qualitative data will shed light on whether, how and why the intervention (does not) work(s). DISCUSSION: "Bottom-up Innovation" is a combined effort of the educational sector, intervention providers and researchers. Results will provide insight into (1) the relation between participating in the intervention and occupational and organizational self-efficacy, (2) how an improved balance between job demands and job resources might affect need for recovery and vitality, in the short and long term, from an organizational perspective, and (3) success and fail factors for implementation of an organizational intervention. TRIAL REGISTRATION NUMBER: Netherlands Trial Register NTR3284. PMID- 23947539 TI - Interprofessional leadership training in MCH social work. AB - The need to train health social workers to practice interprofessionally is an essential goal of social work education. Although most health social workers have exposure to multidisciplinary practice within their field work, few social work education programs incorporate interprofessional learning as an integrated component of both course work and field experiences (McPherson, Headrick, & Moss, 2001; Reeves, Lewin, Espin, & Zwaranstein, 2010; Weinstein, Whittington, & Leiba, 2003). In addition, little is written about the kinds of curricula that would effectively promote interdisciplinary training for social work students. These findings are particularly puzzling since there is increasing and compelling evidence that interdisciplinary training improves health outcomes (IOM, 2001). This article describes a social work education program that incorporates an Interprofessional education and leadership curriculum for Maternal and Child Health Social Work (MCHSW) at the University of Maryland's School of Social Work. The University of Maryland's Interprofesisonal Training Model is described along with the components needed to formulate an interdisciplinary learning experience. Various outcomes and lessons learned are discussed. PMID- 23947540 TI - Evaluation of an integrated services program to prevent subsequent pregnancy and birth among urban teen mothers. AB - This article details the evaluation of a clinical services program for teen mothers in the District of Columbia. The program's primary objectives are to prevent unintended subsequent pregnancy and to promote contraceptive utilization. We calculated contraceptive utilization at 6, 12, 18, and 24 months after delivery, as well as occurrence of subsequent pregnancy and birth. Nearly seven in ten (69.5%) teen mothers used contraception at 24 months after delivery, and 57.1% of contraceptive users elected long-acting reversible contraception. In the 24-month follow-up period, 19.3% experienced at least one subsequent pregnancy and 8.0% experienced a subsequent birth. These results suggest that an integrated clinical services model may contribute to sustained contraceptive use and may prove beneficial in preventing subsequent teen pregnancy and birth. PMID- 23947541 TI - Mental health in primary care: perceptions of augmented care for individuals with serious mental illness. AB - Individuals with serious mental illness are at increased risk of developing secondary physical illnesses because of lifestyle and psychiatric treatment related factors. Many individuals with mental illness participate in primary care clinics, such as Placer County Community Clinic (PCCC), which provides primary care and medication-only psychiatric services to low-income county residents. This qualitative study describes an augmented care program provided to this population at PCCC and explores participant experiences with that program. The augmented program consisted of a full-time social worker and part-time registered nurse working as a team to coordinate care between providers, and provide psychosocial education and illness management support. Previous studies have demonstrated that similar programs result in improved clinical outcomes for people with mental illness but have largely not included perspectives of participants in these pilot programs. This article includes participant reports about medical service needs, barriers, and beneficial elements of the augmented program. Medical service needs included the need to provide input in treatment and to be personally valued. Barriers ranged from doubts about provider qualifications to concerns about medication. Elements of the augmented care program that participants found beneficial were those involving care coordination, social support, and weight management support. PMID- 23947542 TI - International adaptation: psychosocial and parenting experiences of caregivers who travel to the United States to obtain acute medical care for their seriously ill child. AB - Despite the increasing trend of travel for medical purposes, little is known about the experience of parents and other caregivers who come to the United States specifically to obtain medical treatment for their seriously ill child. In this exploratory, descriptive qualitative study, we used a semi-structured narrative guide to conduct in-depth interviews with 22 Spanish- or English speaking caregivers about the challenges encountered and adaptation required when entering a new medical and cultural environment. Caregivers identified the language barrier and transnational parenting as challenges while reporting hospital staff and their own families as major sources of support. Using the results of the study as a guide, clinical and program implications are provided and recommendations for social work practice discussed. PMID- 23947544 TI - Hidden non-innocence in an expanded porphyrin: electronic structure of the Siamese-twin porphyrin's dicopper complex in different oxidation states. AB - The Siamese-twin porphyrin (2H4) is a unique pyrazole-expanded porphyrin providing two adjacent cavities each offering an {N4} binding motif. It was previously found to form stable dicopper(II) or dinickel(II) complexes where both metal ions are nested in a porphyrin-like environment. This work addresses the rich redox chemistry of the dicopper complex 2Cu2 that originates from the redox synergy of two proximate metal ions in combination with the potentially non innocent expanded porphyrin ligand. Complementing previous X-ray crystallographic and SQUID data for solid material, the electronic structure of parent 2Cu2 in solution was now investigated by MCD and EPR spectroscopy. This allowed the assignment of UV-vis absorptions and confirmed the drastic twist of the molecule with ferromagnetically coupled copper(II) ions. 2Cu2 was found to exhibit multiple redox events in the potential range from -2.4 to +1.7 V versus Fc/Fc(+), and singly oxidized [2Cu2](+) as well as doubly oxidized [2Cu2](2+) were characterized in detail by various analytical and spectroscopic methods. [2Cu2](+) was found by EPR spectroscopy and DFT calculations to have an S = 1/2 ground state, while [2Cu2](2+) is diamagnetic. Single crystal X-ray crystallography of [2Cu2(acetone)2](BF4)2 revealed that the 2Cu2 core is structurally invariant upon two-fold oxidation, while XAS measurements at the Cu K-edge for 2Cu2 and [2Cu2(acetone)2](BF4)2 showed that the copper ions remain in the +2 oxidation state throughout. The combined experimental and computational evidence identified the Siamese-twin porphyrin as a multi-electron redox-active ligand with hidden non-innocence. Each ligand subunit upon oxidation forms a ligand-centered radical, though the spin vanishes because of covalency and strong antiferromagnetic coupling between the ligand radical and the proximate metal ion. Complexes of the Siamese-twin porphyrin may thus serve as a valuable bioinspired platform that combines both metal-ligand and two-metal-ion cooperativities for use in multi-electron processes. PMID- 23947545 TI - Risk of second primary cancer after breast cancer treatment. AB - Technological advances in both diagnosis and treatment of breast cancer lead to early detection and better treatment management. Consequently, the population of long-term survivors is on the rise. The risk of developing second cancers among breast cancer survivors was shown to be higher than that for the general population. The aim of this work was to review the literature on the risk of second primary cancer (SPC) after breast irradiation. Pubmed search of population based studies on SPC after breast irradiation was conducted and the findings (in terms of Standardised Incidence Ratio) were collated and discussed. Several studies confirmed the link between breast tumour irradiation and risk of SPC, showing a small, but valid risk. There are, however, confounding factors that can either underestimate or overestimate risks: misclassification of tumour status, genetic inheritance, smoking, environmental factors, and the lack of accurate data in cancer registries. While isolating these potential triggers might be difficult, this approach would allow better discernability between radiotherapy related risks and those generated by other factors. It is also important to evaluate the current status of treatment-related late effects and to lower such risks by minimising the dose delivered to normal tissues. PMID- 23947547 TI - From the editor's desk. AB - No abstract available for this article. PMID- 23947548 TI - From the co-editor. AB - No abstract available for this article. PMID- 23947549 TI - Justification of staff positions in a tightening marketplace. AB - Recend economic and political changes in the health care environment have made justification of both new and vacant staff positions increasingly difficult. Occupational therapy managers have been forced with balancing higher program costs with reduced reimbursement. As a result, requests to increase or refill positions are closely scrutinized. Managers must be able to develop staff justifications utilizing program, productivity, wst, revenue and reimbursement projections based on viable marketing surveys. This paer resents guidelines for development of a marketing survey. &a& and rogram options based on the results of such a survey are examine ! and discussed. A staffing justification proposal is included which demonstrates an effective method whtch can use to develop dynamic programs and services to ensure continued growth of the profession of occupational therapy.nd=yes& PMID- 23947550 TI - Occupational therapy staff evaluation. AB - A competent staff is the greatest asset that any department manager can have. In order to attract and retain therapists in the current health care marketplace the management team at New England Rehabilitation Hospital developed a system for employee performance evaluation. This system includes position specific performance expectations, evaluation forms, employee self-evaluations, and a professional development plan. Background on the department, the events leading up to the decision to create a new system of staff evaluation, and the decisions surrounding implementation are discussed. By using the svstem, a manager can improve personnel management efficiency, foster program growth and contribute to institutional goals. PMID- 23947546 TI - MscS-like mechanosensitive channels in plants and microbes. AB - The challenge of osmotic stress is something all living organisms must face as a result of environmental dynamics. Over the past three decades, innovative research and cooperation across disciplines have irrefutably established that cells utilize mechanically gated ion channels to release osmolytes and prevent cell lysis during hypoosmotic stress. Early electrophysiological analysis of the inner membrane of Escherichia coli identified the presence of three distinct mechanosensitive activities. The subsequent discoveries of the genes responsible for two of these activities, the mechanosensitive channels of large (MscL) and small (MscS) conductance, led to the identification of two diverse families of mechanosensitive channels. The latter of these two families, the MscS family, consists of members from bacteria, archaea, fungi, and plants. Genetic and electrophysiological analysis of these family members has provided insight into how organisms use mechanosensitive channels for osmotic regulation in response to changing environmental and developmental circumstances. Furthermore, determining the crystal structure of E. coli MscS and several homologues in several conformational states has contributed to our understanding of the gating mechanisms of these channels. Here we summarize our current knowledge of MscS homologues from all three domains of life and address their structure, proposed physiological functions, electrophysiological behaviors, and topological diversity. PMID- 23947551 TI - The development of a fee structure for productivity analysis and program management. AB - Occupational therapists are frequently promoted to management level positions without prior instruction in financial accounting. Accounting information can enhance rational decision making processes at both the middle management and supervisory levels. Although today's literature encourages health care professionals to utilize accounting principles, the occupationd therapy manager is often uncertain as to how to apply these techniques to his own setting. This paper describes how one multiclinic department revised its existing fee structure and utilized the generated data to analyze therapists' productivity and to effect decisions regarding program management. PMID- 23947552 TI - Conflict management. AB - This case study illustrates alternative approaches to conflict resolution. Although the case is fictitious, it describes a situation that is common in the workplace, i.e., the attempt of a coworker to undermine the respect, power, and authority of another staff member. The purpose of this case is to not only identify several approaches to conflict resolution but also to illustrate why some approaches can be more effective than others. Clearly, conflict that is ignored and unresolved does not usually go away. It festers and eventually becomes an even more serious problem. PMID- 23947553 TI - Personnel and human resource management in the occupational therapy curriculum. AB - Personnel and human resource management has emerged as a dynamic, vital, and important component of the management of any organization. Persons involved in management at all levels are responsible for organizing, directing, motivating, coordinating, and controlling the people under them in the organizational hierarchy. Health care professionals are almost always in a position requiring them to supervise some aspect of human resources. Graduates of the health professions often find themselves unprepared to meet the rigors of human resource management and are not cognizant of the body of information available to assist them in becoming proficient managers. This article outlines the development of a graduate course in human resource management for occupational therapists. The course was designed to recognize the unique background, experience and needs the health care professional brings to management while offering the student a strong base of information appropriate to the discipline of human resource management. PMID- 23947554 TI - The occupational therapist as a consultant. AB - Current changes in the health care delivery system have resulted in expanded roles for many occupational therapists in which they have had no training and little previous experience. The occupational therapy manager and administrator, in particular, is asked frequently to consult with and engage in collaborative efforts with interdepartmental personnel, community agencies, and consortia of health care services. Also, occupational therapists in private practice and the school systems often are asked to assume the role of a consultant. The necessary background and skills to perform effectively as a consultant in a variety of systems, including political lobbying activities, are presented in this article in a case approach to the issues. The theoretical constructs and the process of consultation are described in the case presentation. PMID- 23947555 TI - Marketing. AB - A marketing approach, the process of controlling exchanges in order to accomplish objectives, should be a basic skill among those used by an occupational therapy manager. Departmental management can be greatly facilitated by using marketing techniques to identify, analyze, and improve relationships, developing them into successful exchanges. By avoiding a marketing attitude an occupational therapy manager may well be unresponsive to health care realities and changes. Accounts of two actual situations experienced by occupational therapy administrators are described. Each therapist is emoloyed in a different setting. Each achieved a successful solution to an aministrative problem using a well-planned marketing strategy. Each situation and resultt is unique, yet a similar thread can be traced from needs identification through enabling transactions to problem resolutions. PMID- 23947556 TI - Ethical and professional liability considerations for the administrator. AB - This paper follows the format suggested for the entire issue in each incident used. The content will focus on selected areas of the administrative functions of occupational therapy at any level, functions in which there are particular professional ethical and liability constraints. Principles and guidelines will be provided which should enable the therapist to avoid the problems raised by these and similar incidents. Aspects of supervision and consultation will be explored as will be dealing with standard care given by others and the safeguarding of the reputation of others. The incidents included under each major topic will be construed as having taken place in the same setting so that the reader may become better aquainted with the personnel in the program. PMID- 23947557 TI - Administrative considerations in designing and implementing changes in occupational therapy programs. AB - A suoervisor's review of existing programs offered by the occupational therapy department in a large teaching center led to realization that a swallowing dysfunction program then in place was not achieving the results, in quantity or quality, which department standards demanded. This is an account of the steps this supervisor took in planning how change could be implemented. This included identifying particular problems, specifying needs to correct them, determining staff and resource demands required, preparing others involved in the care of the targeted patient populations for the problems that could be created by introducing new program protocols and procedures in an established service. PMID- 23947558 TI - Developing and implementing an interdisciplinary feeding training program within a large institution. AB - Planning is a daily part of every manager's job. Occupational therapy managers are frequently involved in the planning process and its component functions of designing, making decisions, delegating, controlling and evaluating. A11 of these management skills were called upon when a small occupational therapy department was assigned the program planning responsibility for developing a comprehensive feeding training program for a large institution. PMID- 23947559 TI - A database approach to managing an occupational therapy department. AB - Changing and often conflicting incentives in the current reimbursement environment require occupational therapy managers to develop adaptive administrative strategies. They must maximize productivity, create budgets, and develop marketing strategies. Accurate information provides the key to success in these tasks. This paper discusses the role of management information systems in the administration of an occupational therapy department and some of the essential factors in implementation. Creation of a database description, establishment of a process for collecting information and report development are explored. PMID- 23947560 TI - Clinical decision making in treatment of learning disabled children. AB - This paper describes current theories and intervention strategies employed in the treatment of learning disabilities. Type, duration and effectiveness of approaches are considered. Criteria for choosing different types of treatment and the responsibility of therapists to provide specificity in treatment are explored. The future of public school based therapy is challenged directly by outcomes of treatment, its documentation and linkages to educational performance.s. PMID- 23947562 TI - In situ growth of CuInS2 nanocrystals on nanoporous TiO2 film for constructing inorganic/organic heterojunction solar cells. AB - Inorganic/organic heterojunction solar cells (HSCs) have attracted increasing attention as a cost-effective alternative to conventional solar cells. This work presents an HSC by in situ growth of CuInS2(CIS) layer as the photoabsorption material on nanoporous TiO2 film with the use of poly(3-hexylthiophene) (P3HT) as hole-transport material. The in situ growth of CIS nanocrystals has been realized by solvothermally treating nanoporous TiO2 film in ethanol solution containing InCl3 . 4H2O, CuSO4 . 5H2O, and thioacetamide with a constant concentration ratio of 1:1:2. InCl3 concentration plays a significant role in controlling the surface morphology of CIS layer. When InCl3 concentration is 0.1 M, there is a layer of CIS flower-shaped superstructures on TiO2 film, and CIS superstructures are in fact composed of ultrathin nanoplates as 'petals' with plenty of nanopores. In addition, the nanopores of TiO2 film are filled by CIS nanocrystals, as confirmed using scanning electron microscopy image and by energy dispersive spectroscopy line scan analysis. Subsequently, HSC with a structure of FTO/TiO2/CIS/P3HT/PEDOT:PSS/Au has been fabricated, and it yields a power conversion efficiency of 1.4%. Further improvement of the efficiency can be expected by the optimization of the morphology and thickness of CIS layer and the device structure. PMID- 23947563 TI - Declines in psychiatric care in inpatient settings in Israel mirror global trend. AB - Levinson and Lerner provide compelling evidence that reforms to the mental health system in Israel led to significant declines in institutional-based care. These declines are similar to those found in other high income countries over the same time period. Additional evidence on concurrent changes to the amount and quality of care in community settings is an important area for future research. PMID- 23947564 TI - Molecular imaging and depth profiling of biomaterials interfaces by femtosecond laser desorption postionization mass spectrometry. AB - Mass spectrometry (MS) imaging is increasingly being applied to probe the interfaces of biomaterials with invasive microbial biofilms, human tissue, or other biological materials. Laser desorption vacuum ultraviolet postionization with ~75 fs, 800 nm laser pulses (fs-LDPI-MS) was used to collect MS images of a yeast-Escherichia coli co-culture biofilm. The method was also used to depth profile a three-dimensionally structured, multispecies biofilm. Finally, fs-LDPI MS analyses of yeast biofilms grown under different conditions were compared with LDPI-MS using ultraviolet, nanosecond pulse length laser desorption as well as with fs laser desorption ionization without postionization. Preliminary implications for the use of fs-LDPI-MS for the analysis of biomaterials interfaces are discussed and contrasted with established methods in MS imaging. PMID- 23947566 TI - Hydrolysis of wheat gluten by combining peptidases of Flammulina velutipes and electrodialysis. AB - Wheat gluten hydrolysis, used to generate seasonings, was studied using peptidases from Flammulina velutipes or commercial Flavourzyme. L-amino acids were added in a range from 0.5 to 75.0 mM, and L-isoleucine, L-leucine, L-valine, and L-phenylalanine were identified as the strongest inhibitors for both enzyme mixtures. L-serine inhibited Flammulina velutipes peptidases only, while L histidine and L-glutamine inhibited Flavourzyme peptidases only. To reduce product inhibition by released L-amino acids, electrodialysis was explored. An increase of the degree of hydrolysis of up to 60% for Flammulina velutipes peptidases and 31% for Flavourzyme compared to that for the best control batch was observed after applying an electrodialysis unit equipped with an ultrafiltration membrane for two times 1 h during the 20 h of hydrolysis. The total transfer of free L-amino acids into the concentrate reached 25-30% per hour. Peptides passed the membrane less easily, although the nominal cutoff was 4 kDa. PMID- 23947565 TI - Comparative analysis of non-coding RNAs in the antibiotic-producing Streptomyces bacteria. AB - BACKGROUND: Non-coding RNAs (ncRNAs) are key regulatory elements that control a wide range of cellular processes in all bacteria in which they have been studied. Taking advantage of recent technological innovations, we set out to fully explore the ncRNA potential of the multicellular, antibiotic-producing Streptomyces bacteria. RESULTS: Using a comparative RNA sequencing analysis of three divergent model streptomycetes (S. coelicolor, S. avermitilis and S. venezuelae), we discovered hundreds of novel cis-antisense RNAs and intergenic small RNAs (sRNAs). We identified a ubiquitous antisense RNA species that arose from the overlapping transcription of convergently-oriented genes; we termed these RNA species 'cutoRNAs', for convergent untranslated overlapping RNAs. Conservation between different classes of ncRNAs varied greatly, with sRNAs being more conserved than antisense RNAs. Many species-specific ncRNAs, including many distinct cutoRNA pairs, were located within antibiotic biosynthetic clusters, including the actinorhodin, undecylprodigiosin, and coelimycin clusters of S. coelicolor, the chloramphenicol cluster of S. venezuelae, and the avermectin cluster of S. avermitilis. CONCLUSIONS: These findings indicate that ncRNAs, including a novel class of antisense RNA, may exert a previously unrecognized level of regulatory control over antibiotic production in these bacteria. Collectively, this work has dramatically expanded the ncRNA repertoire of three Streptomyces species and has established a critical foundation from which to investigate ncRNA function in this medically and industrially important bacterial genus. PMID- 23947567 TI - Ring-opening of the gamma-OH-PdG adduct promotes error-free bypass by the Sulfolobus solfataricus DNA polymerase Dpo4. AB - Acrolein, a mutagenic aldehyde, reacts with deoxyguanosine (dG) to form 3-(2' deoxy-beta-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a] purin-10(3H)-one (gamma-OH-PdG). When placed opposite deoxycytosine (dC) in DNA, gamma-OH-PdG undergoes ring-opening to the N(2)-(3-oxopropyl)-dG. Ring-opening of the adduct has been hypothesized to facilitate nonmutagenic bypass, particularly by DNA polymerases of the Y family. This study examined the bypass of gamma-OH PdG by Sulfolobus solfataricus Dpo4, the prototypic Y-family DNA polymerase, using templates that contained the adduct in either the 5'-CXG-3' or the 5'-TXG 3' sequence context. Although gamma-OH-PdG partially blocked Dpo4-catalyzed DNA synthesis, full primer extension was observed, and the majority of bypass products were error-free. Conversion of the adduct into an irreversibly ring opened derivative prior to reaction facilitated bypass and further improved the fidelity. Structures of ternary Dpo4.DNA.dNTP complexes were determined with primers that either were positioned immediately upstream of the lesion (preinsertion complexes) or had a 3'-terminal dC opposite the lesion (postinsertion complexes); the incoming nucleotides, either dGTP or dATP, were complementary to the template 5'-neighbor nucleotide. In both postinsertion complexes, the adduct existed as ring-opened species, and the resulting base-pair featured Watson-Crick hydrogen bonding. The incoming nucleotide paired with the 5'-neighbor template, while the primer 3'-hydroxyl was positioned to facilitate extension. In contrast, gamma-OH-PdG was in the ring-closed form in both preinsertion complexes, and the overall structure did not favor catalysis. These data provide insights into gamma-OH-PdG chemistry during replication bypass by the Dpo4 DNA polymerase and may explain why gamma-OH-PdG-induced mutations due to primer-template misalignment are uncommon. PMID- 23947569 TI - Enantioselective intermolecular formal [3 + 3] cycloaddition of 2,3-disubstituted indoles with acrolein. AB - An expedient enantioselective synthesis of highly substituted hydrocarbazoles has been realized by an organocatalyzed formal [3 + 3] cycloaddition between acrolein and 2,3-disubstituted indoles. Tricyclic hydrocarbazoles were obtained from a broad range of 2,3-disubstituted indoles and acrolein in good to excellent yields and excellent enantioselectivites. PMID- 23947568 TI - A comparative Kirkwood-Buff study of aqueous methanol solutions modeled by the CHARMM additive and Drude polarizable force fields. AB - A comparative study on aqueous methanol solutions modeled by the CHARMM additive and Drude polarizable force fields was carried out by employing Kirkwood-Buff analysis. It was shown that both models reproduced the experimental Kirkwood-Buff integrals and excess coordination numbers adequately well over the entire concentration range. The Drude model showed significant improvement over the additive model in solution densities, partial molar volumes, excess molar volumes, concentration-dependent diffusion constants, and dielectric constants. However, the additive model performed somewhat better than the Drude model in reproducing the activity derivative, excess molar Gibbs energy, and excess molar enthalpy of mixing. This is due to the additive achieving a better balance among solute-solute, solute-solvent, and solvent-solvent interactions, indicating the potential for improvements in the Drude polarizable alcohol model. PMID- 23947570 TI - O-H...S hydrogen bonds conform to the acid-base formalism. AB - Hydrogen bonding interaction between the ROH hydrogen bond donor and sulfur atom as an acceptor has not been as well characterized as the O-H...O interaction. The strength of O-H...O interactions for a given donor has been well documented to scale linearly with the proton affinity (PA) of the H-bond acceptor. In this regard, O-H...O interactions conform to the acid-base formalism. The importance of such correlation is to be able to estimate molecular property of the complex from the known thermodynamic data of its constituents. In this work, we investigate the properties of O-H...S interaction in the complexes of the H-bond donor and sulfur containing acceptors of varying proton affinity. The hydrogen bonded complexes of p-Fluorophenol (FP) with four different sulfur containing acceptors and their oxygen analogues, namely H2O/H2S, MeOH/MeSH, Me2O/Me2S and tetrahydrofuran (THF)/tetrahydrothiophene (THT) were characterized in regard to its S1-S0 excitation spectra and the IR spectra. Two-color resonantly enhanced multiphoton ionization (2c-R2PI), resonant ion-dip infrared (RIDIR) spectroscopy, and IR-UV hole burning spectroscopic techniques were used to probe the hydrogen bonds in the aforementioned complexes. The spectroscopic data along with the ab initio calculations were used to deduce the strength of the O-H...S hydrogen bonding interactions in these system relative to that in the O-H...O interactions. It was found that, despite being dominated by the dispersion interaction, the O-H...S interactions conform to the acid-base formalism as in the case of more conventional O-H...O interactions. The dissociation energies and the red shifts in the O-H stretching frequencies correlated very well with the proton affinity of the acceptors. However, the O-H...S interaction did not follow the same correlation as that in the O-H...O H-bond. The energy decomposition analysis showed that the dissociation energies and the red shifts in the O-H stretching frequencies follow a unified correlation if these two parameters were correlated with the sum of the charge transfer and the exchange component of the total binding energy. PMID- 23947571 TI - Three-dimensional finite element analysis of stress distribution in retention screws of different crown-implant ratios. AB - The retaining screw of the implant-supported dental prosthesis is the weakest point of the crown/implant system. Furthermore, crown height is another important factor that may increase the lever arm. Therefore, the aim of this study was to assess the stress distribution in implant prosthetic screws with different heights of the clinical crown of the prosthesis using the method of three dimensional finite element analysis. Three models were created with implants (3.75 mm * 10 mm) and crowns (heights of 10, 12.5 and 15 mm). The results were visualised by means of von Mises stress maps that increased the crown heights. The screw structure exhibited higher levels of stresses in the oblique load. The oblique loading resulted in higher stress concentration when compared with the axial loading. It is concluded that the increase of the crown was damaging to the stress distribution on the screw, mainly in oblique loading. PMID- 23947573 TI - Realigning government action with public health evidence: the legal and policy environment affecting sex work and HIV in Asia. AB - The HIV epidemic has shed light on how government regulation of sex work directly affects the health and well-being of sex workers, their families and communities. A review of the public health evidence highlights the need for supportive legal and policy environments, yet criminalisation of sex work remains standard around the world. Emerging evidence, coupled with evolving political ideologies, is increasingly shaping legal environments that promote the rights and health of sex workers but even as new legislation is created, contradictions often exist with standing problematic legislation. As a region, Asia provides a compelling example in that progressive HIV policies often sit side by side with laws that criminalise sex work. Data from the 21 Asian countries reporting under the UN General Assembly Special Session on HIV in 2010 were analysed to provide evidence of how countries' approach to sex-work regulation might affect HIV-related outcomes. Attention to the links between law and HIV-related outcomes can aid governments to meet their international obligations and ensure appropriate legal environments that cultivate the safe and healthy development and expression of sexuality, ensure access to HIV and other related services and promote and protect human rights. PMID- 23947572 TI - Statins in lymphangioleiomyomatosis. Simvastatin and atorvastatin induce differential effects on tuberous sclerosis complex 2-null cell growth and signaling. AB - Mutations of the tumor suppressor genes tuberous sclerosis complex (TSC)1 and TSC2 cause pulmonary lymphangioleiomyomatosis (LAM) and tuberous sclerosis (TS). Current rapamycin-based therapies for TS and LAM have a predominantly cytostatic effect, and disease progression resumes with therapy cessation. Evidence of RhoA GTPase activation in LAM-derived and human TSC2-null cells suggests that 3 hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor statins can be used as potential adjuvant agents. The goal of this study was to determine which statin (simvastatin or atorvastatin) is more effective in suppressing TSC2-null cell growth and signaling. Simvastatin, but not atorvastatin, showed a concentration dependent (0.5-10 MUM) inhibitory effect on mouse TSC2-null and human LAM-derived cell growth. Treatment with 10 MUM simvastatin induced dramatic disruption of TSC2-null cell monolayer and cell rounding; in contrast, few changes were observed in cells treated with the same concentration of atorvastatin. Combined treatment of rapamycin with simvastatin but not with atorvastatin showed a synergistic growth-inhibitory effect on TSC2-null cells. Simvastatin, but not atorvastatin, inhibited the activity of prosurvival serine-threonine kinase Akt and induced marked up-regulation of cleaved caspase-3, a marker of cell apoptosis. Simvastatin, but not atorvastatin, also induced concentration dependent inhibition of p42/p44 Erk and mTORC1. Thus, our data show growth inhibitory and proapoptotic effects of simvastatin on TSC2-null cells compared with atorvastatin. These findings have translational significance for combinatorial therapeutic strategies of simvastatin to inhibit TSC2-null cell survival in TS and LAM. PMID- 23947575 TI - Giant Candida mycetoma in an ascending aorta tubular graft. AB - We report the case of a 46-year-old male hospitalized for abdominal pain and fever with history of a David procedure followed by an aortic valve replacement due to severe aortic regurgitation. Transesophageal echocardiography (TEE) and computed tomography showed a large mass floating in the aorta. After surgical excision of the vegetation, attached to the Dacron prosthesis, histological examination revealed Candida hyphae and spores confirming the diagnosis of a mycetoma in an ascending aorta tubular graft. At six-month follow-up, the patient was in good clinical condition without recurrence of the fungal mass on TEE. PMID- 23947574 TI - Performance evaluation of the essential dimensions of the primary health care services in six localities of Bogota-Colombia: a cross-sectional study. AB - BACKGROUND: The high segmentation and fragmentation in the provision of services are some of the main problems of the Colombian health system. In 2004 the district government of Bogota decided to implement a Primary Health Care (PHC) strategy through the Home Health program. PHC was conceived as a model for transforming health care delivery within the network of the first-level public health care facilities. This study aims to evaluate the performance of the essential dimensions of the PHC strategy in six localities geographically distributed throughout Bogota city. METHODS: The rapid assessment tool to measure PHC performance, validated in Brazil, was applied. The perception of participants (users, professionals, health managers) in public health facilities where the Home Health program was implemented was compared with the perception of participants in private health facilities not implementing the program. A global performance index and specific indices for each primary care dimension were calculated. A multivariate logistic regression analysis was conducted to determine possible associations between the performance of the PHC dimensions and the self-perceived health status of users. RESULTS: The global performance index was rated as good for all participants interviewed. In general, with the exception of professionals, the differences in most of the essential dimensions seemed to favor public health care facilities where the Home Health program was implemented. The weakest dimensions were the family focus and community orientation--rated as critical by users; the distribution of financial resources- rated as critical by health managers; and, accessibility--rated as intermediate by users. CONCLUSIONS: The overall findings suggest that the Home Health program could be improving the performance of the network of the first-level public health care facilities in some PHC essential dimensions, but significant efforts to achieve its objectives and raise its visibility in the community are required. PMID- 23947576 TI - More of the same or a change of scenery: an observational study of variety and frequency of physical activity in British children. AB - BACKGROUND: Physical activity is important for children's health, but successful physical activity promotion is challenging. Whether performing many different types of activities (Variety) is associated with higher physical activity independent of the number of activity sessions (Frequency) is unknown, but this information could inform physical activity promotion and public health strategies in children. METHODS: In the SPEEDY study we measured moderate-to-vigorous intensity physical activity (MVPA; >=2000 counts/minute) over 7 days using GT1M Actigraph accelerometers in 1700 children from Norfolk, UK (56% girls, Mean +/- SD 10.3 +/- 0.3 years-old). Children reported participation in 28 leisure-time activities over the previous 7 days. Sex differences in activity participation were assessed using multilevel logistic regression, clustered by school. Associations of log-transformed MVPA with z-score-Variety (number of different activities/week) and z-score-Frequency (sum of all activity sessions/week) were examined using multilevel linear regression, adjusted for age, sex, parental education and age-standardised BMI. RESULTS: Children's activity participation often reflected gender stereotypes. Mean +/- SD Variety was 10.8 +/- 5.0 activities/week, and Frequency was 24.2+/-15.0 sessions/week. In separate models lnMVPA had similar strength, positive associations with z-score-Variety and z score-Frequency (Exp beta(95% CI); Variety 1.04(1.02-1.06), Frequency 1.04(1.02 1.06)). lnMVPA was not associated with z-score-Variety independent of z-score Frequency (Variety 1.01(0.98-1.04), Frequency 1.03(1.00-1.06)). CONCLUSIONS: Future physical activity interventions and public health strategies could allow for gender specific activity preferences and could target both Variety and Frequency of activities participated in by children. PMID- 23947577 TI - n-6:n-3 PUFA ratio is involved in regulating lipid metabolism and inflammation in pigs. AB - The objective of the present study was to investigate the optimal dietary n-6:n-3 PUFA ratios that regulate lipid metabolism and inflammation in pigs. A total of ninety-six cross-bred (Large White * Landrace) growing-finishing pigs (73.8 (SEM 1.6) kg) were chosen and fed one of the four isoenergetic diets with n-6:n-3 PUFA ratios of 1:1, 2.5:1, 5:1 and 10:1. The growth performance of pigs fed the diet with an n-6:n-3 PUFA ratio of 5:1 was the best, but the group fed the diet with an n-6:n-3 PUFA ratio of 1:1 had the highest muscle mass and the lowest adipose tissue mass (P< 0.05). The concentrations of IL-6 and IL-1beta of pigs fed the diet with an n-6:n-3 PUFA ratio of 1:1 were decreased compared with those of the other groups (P< 0.05). The concentration of adiponectin of pigs fed the diet with an n-6:n-3 PUFA ratio of 1:1 was also markedly decreased, but the concentration of leptin was increased compared with that of the groups fed the diets with n-6:n-3 PUFA ratios of 5:1 and 10:1 (P< 0.05). Additionally, the optimal dietary ratios of n-6:n-3 PUFA of 1:1 and 5:1 markedly suppressed the expression levels of lipid metabolism-related genes and proteins such as phosphoinositide-3-kinase-alpha, fatty acid transport protein-1 and PPARgamma. They also significantly suppressed the expression levels of the inflammatory cytokines IL-1beta, TNF-alpha and IL-6. The results indicated that the optimal n 6:n-3 PUFA ratios of 1:1 and 5:1 exerted beneficial effects on lipid metabolism and inflammatory system, leading to the availability of more energy and nutrients for high performance and homeostatic pathways. PMID- 23947578 TI - Copper-catalyzed carboarylation of alkynes via vinyl cations. AB - Copper-catalyzed arylation of electron rich alkynes reveals stabilized trisubstituted vinyl cation equivalents that react with pendant arene nucleophiles to form all carbon tetrasubstituted alkenes. The new process streamlines the synthesis of important medicinally relevant molecules. PMID- 23947579 TI - Treatment of refractory dry eye associated with graft versus host disease with 0.03% tacrolimus eyedrops. AB - PURPOSE: We investigate the efficacy of 0.03% topical tacrolimus eyedrops for the treatment of dry eye in graft versus host disease (GVHD) patients resistant/intolerant to 0.05% topical cyclosporine. METHODS: Forty-three patients were enrolled in this prospective study. After completing a 1-year run-in period of using artificial tears, 50% autologous serum eyedrops, and punctal plug occlusion, all the symptomatic patients (n=29) were treated with 0.05% topical cyclosporine (Restasis((r)); Allergan, Inc.). After 1 month, the patients who presented topical or systemic intolerance to cyclosporine were instructed to instill 0.03% topical tacrolimus once a day for 3 months (n=14). All the patients were allowed to continue with their basal dry eye treatment. Visual acuity, fluorescein staining, Schirmer test, fluorescein tear break-up time, and tear meniscus height measurement were evaluated fortnightly (minimum 3 months). Subjective assessments of symptoms were also reported at the beginning and at the end of the study. RESULTS: Dry eye symptoms and signs improved statistically (P<0.05) and significantly with tacrolimus and cyclosporine topical treatment. No significant differences were observed between both the groups. The mean follow-up time was 12.14+/-2.69 months (range 10-18 months). CONCLUSION: The findings of this prospective pilot study suggest that cyclosporine-intolerant patients with dry eye associated with GVHD can be effectively treated with topical tacrolimus. PMID- 23947580 TI - Mechanistic investigation of photon upconversion in Nd(3+)-sensitized core-shell nanoparticles. AB - A new type of core-shell upconversion nanoparticles which can be effectively excited at 795 nm has been designed and synthesized through spatially confined doping of neodymium (Nd(3+)) ions. The use of Nd(3+) ions as sensitizers facilitates the energy transfer and photon upconversion of a series of lanthanide activators (Er(3+), Tm(3+), and Ho(3+)) at a biocompatible excitation wavelength (795 nm) and also significantly minimizes the overheating problem associated with conventional 980 nm excitation. Importantly, the core-shell design enabled high concentration doping of Nd(3+) (~0 mol %) in the shell layer and thus markedly enhanced the upconversion emission from the activators, providing highly attractive luminescent biomarkers for bioimaging without autofluorescence and concern of overheating. PMID- 23947581 TI - A multimodal physiotherapy programme plus deep water running for improving cancer related fatigue and quality of life in breast cancer survivors. AB - The aim of the study was to assess the feasibility and effectiveness of aquatic based exercise in the form of deep water running (DWR) as part of a multimodal physiotherapy programme (MMPP) for breast cancer survivors. A controlled clinical trial was conducted in 42 primary breast cancer survivors recruited from community-based Primary Care Centres. Patients in the experimental group received a MMPP incorporating DWR, 3 times a week, for an 8-week period. The control group received a leaflet containing instructions to continue with normal activities. Statistically significant improvements and intergroup effect size were found for the experimental group for Piper Fatigue Scale-Revised total score (d = 0.7, P = 0.001), as well as behavioural/severity (d = 0.6, P = 0.05), affective/meaning (d = 1.0, P = 0.001) and sensory (d = 0.3, P = 0.03) domains. Statistically significant differences between the experimental and control groups were also found for general health (d = 0.5, P < 0.05) and quality of life (d = 1.3, P < 0.05). All participants attended over 80% of sessions, with no major adverse events reported. The results of this study suggest MMPP incorporating DWR decreases cancer-related fatigue and improves general health and quality of life in breast cancer survivors. Further, the high level of adherence and lack of adverse events indicate such a programme is safe and feasible. PMID- 23947583 TI - From the editor. AB - No abstract available for this article. PMID- 23947582 TI - Sensitivity of different MRI-techniques to assess gray matter atrophy patterns in Alzheimer's disease is region-specific. AB - The present study compares four different structural magnetic resonance imaging techniques used to measure gray matter (GM) atrophy in Alzheimer's disease (AD): manual and automated volumetry, cortical thickness (CT) and voxel-based morphometry (VBM). These techniques are used interchangeably in AD research and thus far it is unclear which technique is superior in detecting abnormalities early in the disease process. 18 healthy participants without any memory impairment, 18 patients with MCI, and 17 patients with mild AD were included and between-group differences were investigated in AD signature regions (areas in the prefrontal cortex (PFC), medial temporal lobe (MTL) and posterior parietal cortex (PPC)). Both manual volumetric measurements and VBM were able to detect GM atrophy in the early stages (differentiation controls and MCI), mainly in the MTL. In the early phase, automated volumetric measurements showed GM differences in the PPC but not in the MTL. In our sample, CT measurements were not sensitive for group differences in the early stages. PFC regions showed abnormalities in the later stages (controls vs AD) when manual volumetric measurements or VBM are employed. Manual volumetric measurements together with VBM are preferred techniques for assessing GM differences showing abnormalities in most of the investigated regions, with a predominance of the MTL in the early phase. Automated FreeSurfer volumetric measurements show similar performances in the early phase, displaying group differences in the PPC but not in MTL regions. Measurements of CT are less sensitive in the MCI stage and its sensitivity is restricted to the MTL and PPC regions in later stages of the disease (AD). PMID- 23947584 TI - Survey of HIV/AIDS-Related Curricula in Programs of Occupational Therapy. AB - AIDS has affected or will affect virtually every provider of health care. The purpose of this study was to determine the quantity of HIV/AIDS-related curricula in programs of occupational therapy across the United States. A survey was distributed to the program directors of all accredited technical, undergraduate, and graduate programs in the United States. Of the 137 surveys mailed, 95 were returned, yielding a 69%% response rate. Results of the survey indicated that graduate and undergraduate professional programs devoted an average of six classroom hours to this topic while technical programs averaged three classroom hours, with the majority of program directors indicating there is no need for further HIV/AIDS related curricula in their respective programs. PMID- 23947585 TI - The predictive value of selected job rewards on occupational therapists' job satisfaction in ambulatory care settings. AB - Using a perceived reward model of overall job satisfaction, this study utilized a correlational research design with multiple regression analysis to determine the predictive power of extrinsic rewards and intrinsic rewards, collectively and individually, as determinants of overall job satisfaction among registered occupational therapists (OTR) working full-time in ambulatory care settings. The intrinsic rewards (task involvement and task autonomy), collectively and individually, were perceived to be significant overall job satisfaction determinants. General working conditions was the only significant extrinsic reward. Given the demand for OTRs in ambulatory care settings, a better understanding of factors that influence overall job satisfaction among OTRs could prove beneficial in developing appropriate recruitment and retention job design strategies. PMID- 23947586 TI - A Client-Centered Model for Equipment Prescription (Client's Values and Roles, Effective Use of Adaptive Equipment). AB - Many studies of individuals with physical dysfunction have revealed significant under-use of equipment following initial rehabilitation. These studies collectively suggest that clients fail to use equipment because the therapist's equipment prescription focuses on the physical aspects of treatment and fails to incorporate client-centered factors. This paper describes a client-centered model for equipment prescription dksLgned to improve the use and efficacy of equipment prescribed to individuals with physical dysfunction. A demonstration case study of an individual-with a spinal injury is provided to illustrate the application of this model. PMID- 23947587 TI - The use of arts and crafts in the rehabilitation of the adult burn patient. AB - The purpose of this study was to gain insight into one small aspect of occupational therapy: the use of arts and crafts in the rehabilitation of the adult burn patient. While burn care literature is plentiful, that related specifically to occupational therapy treatment of burn patients is scarce. A survey was mailed to occupational therapists in 165 burn units across the United States. Responses to survey questions indicate that a majority of respondents (73%%) do not use arts and crafts in the rehabilitation of adult burn patients, while 26%% do use these modalities. Those respondents who do use arts and crafts stated that they use leatherwork, painting, and woodworking most frequently. Therapists who do not use arts and crafts indicated that their primary reasons for not doing so were the acutely ill status of the patients and wound drainage/sterility issues. The entire scope of occupational therapy treatment of burn patients deserves greater attention as it is a challenging and rapidly evolving area of practice. PMID- 23947588 TI - The effect of hand therapy on a patient with a colles' fracture:. AB - The purpose of this phenomenological study was to gain an understanding of the effect of disability, specifically a Colles' fracture, and the role of occupational therapy in the recovery of function. On three separate occasions, a person with a Colles' fracture was interviewed on videotape. Data from the interviews were transcribed and the emergent concepts were organized into themes. One theme, ''just the everyday things'' illustrates the participant's frustration with her disability and another, ''standard program,'' addresses the hand therapist's reliance on a canned program. Themes from the study are discussed in terms of the consumer's experience of dysfunction and receiving occupational therapy services. PMID- 23947589 TI - Foraging by a wood-decomposing fungus is ecologically adaptive. AB - We show that fungi that forage for wood do not conform to the paradigm of symmetric radial growth and grow asymmetrically by default. Asymmetry is further accentuated by contact with a resource that also partially polarizes growth in the direction of the resource. Despite marked changes at the perimeter, overall growth allocation on an area basis is, however, unchanged implying sophisticated regulation at the colony level. Using mathematical models, we show that this behaviour is best explained as a local response of the immediate segment contacting the resource. The model reveals that foraging behaviour is adaptive but only for resources that are clustered in space and is selectively neutral for randomly scattered resources. This clustered spatial distribution matches that found in the natural environment. Modelling also shows that the foraging strategy used by these fungi involves substantial risks as well as benefits. PMID- 23947591 TI - Compassion fatigue, burnout and compassion satisfaction among family physicians in the Negev area - a cross-sectional study. AB - BACKGROUND: Compassion fatigue among health care professionals has gained interest over the past decade. Compassion fatigue, as well as burnout, has been associated with depersonalization and suboptimal patient care. Professional caregivers in general are exposed to the risk of compassion fatigue (CF), burnout (BO) and low levels of compassion satisfaction (CS). While CF has been studied in health care professionals, few publications address its incidence among family physicians, specifically. The objectives of this study were to assess the prevalence and severity of CF among family practitioners (FPs) in the Negev (Israel's southern region), evaluating the correlations between CF, BO and CS and their relations with socio-demographic variables and work related characteristics. METHODS: Self-report anonymous Compassion Satisfaction and Fatigue Test questionnaires (CSFT) measuring CF, BO, and CS were distributed among 194 family physicians at Clalit Health Services clinics in the Negev between July 2007 and April 2008. Correlations between CF, BO and CS were assessed. Multivariable logistic regression models with backward elimination were constructed. RESULTS: 128 (66%) physicians responded. 46.1% of respondents scored extremely high and high for CF, 21.1% scored low for CS and 9.4% scored high for BO. Strong correlations were found between BO and CF (r = 0.769, p < 0.001), and between BO and CS (r = -0.241, p = 0.006), but no correlation was found between CS and CF. The logistic regression model showed that the only factor associated with a significantly increased risk for CF was former immigration to Israel. Increased risk for BO was associated with female gender, history of personal trauma and lack of academic affiliation. Higher CS was associated with holding management positions and teaching residents. CONCLUSIONS AND POLICY RECOMMENDATIONS: Family physicians in the Negev are at high risk for CF, with the potential for CF- associated patient dissatisfaction, compromised patient safety and increased medical error. We propose creation of a CF educational and early intervention treatment program for family physicians and other health care professionals. Such programs would train facilitators of physician well-being and resiliency building. We also recommend analyzing contributing variables and organizational factors related to higher CF. Policy recommendations include integrating such programs within required risk management continuing medical education. PMID- 23947590 TI - A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. AB - Systemic corticosteroids play an integral role in the management of many inflammatory and immunologic conditions, but these agents are also associated with serious risks. Osteoporosis, adrenal suppression, hyperglycemia, dyslipidemia, cardiovascular disease, Cushing's syndrome, psychiatric disturbances and immunosuppression are among the more serious side effects noted with systemic corticosteroid therapy, particularly when used at high doses for prolonged periods. This comprehensive article reviews these adverse events and provides practical recommendations for their prevention and management based on both current literature and the clinical experience of the authors. PMID- 23947593 TI - Human metabolic transformation of quercetin blocks its capacity to decrease endothelial nitric oxide synthase (eNOS) expression and endothelin-1 secretion by human endothelial cells. AB - The major dietary flavonol quercetin, which has been shown to improve endothelial function and decrease blood pressure, is extensively metabolized during absorption. This study examined the relative abilities of quercetin and its human metabolites to modulate the expression of eNOS and ET-1, which are involved in regulating endothelial homeostasis. Quercetin aglycone significantly reduced both eNOS protein and gene expression in HUVEC, mirroring the effects of the pro inflammatory cytokine TNFalpha. In the presence of TNFalpha the aglycone caused further reductions in eNOS, whereas the metabolites were without effect in either TNFalpha-stimulated or unstimulated cells. ET-1 expression was significantly reduced by quercetin in both TNFalpha-stimulated or unstimulated HUVECs. The metabolites had no effect on ET-1 expression with the exception of quercetin-3' sulfate, which caused a moderate increase in TNFalpha-stimulated cells. These results suggest that metabolic transformation of quercetin prevents it from causing a potentially deleterious decrease in eNOS in endothelial cells. PMID- 23947592 TI - Transcriptional profiling reveals progeroid Ercc1(-/Delta) mice as a model system for glomerular aging. AB - BACKGROUND: Aging-related kidney diseases are a major health concern. Currently, models to study renal aging are lacking. Due to a reduced life-span progeroid models hold the promise to facilitate aging studies and allow examination of tissue-specific changes. Defects in genome maintenance in the Ercc1(-/Delta) progeroid mouse model result in premature aging and typical age-related pathologies. Here, we compared the glomerular transcriptome of young and aged Ercc1-deficient mice to young and aged WT mice in order to establish a novel model for research of aging-related kidney disease. RESULTS: In a principal component analysis, age and genotype emerged as first and second principal components. Hierarchical clustering of all 521 genes differentially regulated between young and old WT and young and old Ercc1(-/Delta) mice showed cluster formation between young WT and Ercc1(-/Delta) as well as old WT and Ercc1( /Delta) samples. An unexpectedly high number of 77 genes were differentially regulated in both WT and Ercc1(-/Delta) mice (p < 0.0001). GO term enrichment analysis revealed these genes to be involved in immune and inflammatory response, cell death, and chemotaxis. In a network analysis, these genes were part of insulin signaling, chemokine and cytokine signaling and extracellular matrix pathways. CONCLUSION: Beyond insulin signaling, we find chemokine and cytokine signaling as well as modifiers of extracellular matrix composition to be subject to major changes in the aging glomerulus. At the level of the transcriptome, the pattern of gene activities is similar in the progeroid Ercc1(-/Delta) mouse model constituting a valuable tool for future studies of aging-associated glomerular pathologies. PMID- 23947594 TI - Identification of danger signals in nevirapine-induced skin rash. AB - Nevirapine (NVP) can cause serious skin rashes and hepatotoxicity. It also causes an immune-mediated skin rash in rats but not hepatotoxicity. This rash is caused by a metabolite of NVP; specifically, NVP is oxidized in the liver to a benzylic alcohol (12-OH-NVP), which travels to the skin where it forms a reactive benzylic sulfate. This could both act as a hapten and induce a danger signal. In contrast, most of the covalent binding in the liver involves oxidation of the methyl group leading to a reactive quinone methide. In this study, we examined the effects of NVP and 12-OH-NVP on gene expression in the liver and skin. Both NVP and 12-OH NVP induced changes in the liver, but the list of genes was different, presumably reflecting different bioactivation pathways. In contrast, many more genes were up regulated in the skin by 12-OH-NVP than by NVP, which is consistent with the fact that 12-OH-NVP is an obligate intermediate in the formation of the reactive sulfate in the skin. Genes up-regulated by 12-OH-NVP in the skin included TRIM63 (18-fold increase), S100a7a (7-fold increase), IL22-RA2 (4-fold increase), and DAPK1 (3-fold increase). TRIM63 acts as a ubiquitin ligase, which is consistent with protein damage leading to an increase in protein turnover. In addition, TRIM proteins are involved in inflammasome activation, and it appears that inflammasome activation is an essential step in the induction of NVP-induced skin rash. S100A7 is considered a danger signal, and its upregulation supports the danger hypothesis. Upregulation of the IL-22 RA2 gene marks an immune response. DAPK1 is involved with inflammasome assembly through binding directly to NLRP3, a NOD-like receptor expressed in keratinocytes. These results provide important clues to how NVP causes the induction of an immune response, in this case leading to skin rash. PMID- 23947595 TI - Dinuclear zinc-ProPhenol-catalyzed enantioselective alpha-hydroxyacetate aldol reaction with activated ester equivalents. AB - An enantioselective alpha-hydroxyacetate aldol reaction that employs N-acetyl pyrroles as activated ester equivalents and generates syn 1,2-diols in good yield and diastereoselectivity is reported. This dinuclear zinc-ProPhenol-catalyzed transformation proceeds with high enantioselectivity with a wide variety of substrates including aryl, alyl, and alkenyl aldehydes. The resulting alpha,beta dihydroxy activated esters are versatile intermediates for the synthesis of a variety of carboxylic acid derivatives including amides, esters, and unsymmetrical ketones. PMID- 23947596 TI - Multielement NMR studies of the liquid-liquid phase separation and the metal-to nonmetal transition in fluid lithium- and sodium-ammonia solutions. AB - (1)H, (7)Li, (14)N, and (23)Na high resolution nuclear magnetic resonance (NMR) measurements are reported for fluid solutions of lithium and sodium in anhydrous liquid ammonia across the metal-to-nonmetal transition (MNM transition), paying particular attention to the phenomenon of liquid-liquid phase separation which occurs in the composition/temperature region close to the MNM transition. Our results are discussed in terms of the electronic structure of fluid metal-ammonia solutions at low temperatures (ca. 240 K). We find that the electronic phase transition to the metallic state in these solutions, especially at temperatures close to the liquid-liquid critical consolute temperature, occurs from a nonmetallic, electrolytic solution containing a predominance of electron spin paired, (diamagnetic) charged bosonic states. The possible implications of these observations to the nature of the liquid-liquid phase separation are discussed, both from the views of N. F. Mott, regarding the MNM transition in sodium-ammonia solutions, and those of R. A. Ogg, regarding the possibility of high-temperature superconductivity in these solutions. Similarities between the electronic structure of metal-ammonia solutions and the high-temperature cuprate superconductors are also briefly emphasized. PMID- 23947597 TI - Effect of intercostal muscle and costovertebral joint material properties on human ribcage stiffness and kinematics. AB - Current finite element (FE) models of the human thorax are limited by the lack of local-level validation, especially in the ribcage. This study exercised an existing FE ribcage model for a 50th percentile male under quasi-static point loading and dynamic sternal loading. Both force-displacement and kinematic responses of the ribcage were compared against experimental data. The sensitivity of the model response to changes in the material properties of the costovertebral (CV) joints and intercostal muscles was assessed. The simulations found that adjustments to the CV joints tended to change the amount of rib rotation in the sagittal plane, while changes to the elastic modulus and thickness of the intercostal muscles tended to alter both the stiffness and the direction and magnitude of rib motions. This study can lend insight into the role that the material properties of these two thoracic structures play in the dynamics of the ribcage during a frontal loading condition. PMID- 23947598 TI - Pivotal role of the 5-lipoxygenase pathway in lung injury after experimental sepsis. AB - Postsepsis lung injury is a common clinical problem associated with significant morbidity and mortality. Leukotrienes (LTs) are important lipid mediators of infection and inflammation derived from the 5-lipoxygenase (5-LO) metabolism of arachidonate with the potential to contribute to lung damage after sepsis. To test the hypothesis that LTs are mediators of lung injury after sepsis, we assessed lung structure, inflammatory mediators, and mechanical changes after cecal ligation and puncture surgery in wild-type (WT) and 5-LO knockout (5-LO(-/ )) mice and in WT mice treated with a pharmacologic LT synthesis inhibitor (MK886) and LT receptor antagonists (CP105,696 and montelukast). Sixteen hours after surgery, WT animals exhibited severe lung injury (by histological analysis), substantial mechanical impairment (i.e., an increase in static lung elastance), an increase in neutrophil infiltration, and high levels of LTB4, cysteinyl-LTs (cys-LTs), prostaglandin E2, IL-1beta, IL-6, IL-10, IL-17, KC (CXCL1), and monocyte chemotactic protein-1 (CCL2) in lung tissue and plasma. 5 LO(-/-) mice and WT mice treated with a pharmacologic 5-LO inhibitor were significantly protected from lung inflammation and injury. Selective antagonists for BLT1 or cys-LT1, the high-affinity receptors for LTB4 and cys-LTs, respectively, were insufficient to provide protection when used alone. These results point to an important role for 5-LO products in sepsis-induced lung injury and suggest that the use of 5-LO inhibitors may be of therapeutic benefit clinically. PMID- 23947600 TI - Surgical management of a neonate with congenitally corrected transposition of the great vessels, hypoplastic right aortic arch, and Ebstein anomaly. AB - We report a neonate with a primary diagnosis of congenitally corrected transposition (ccTGA) of the great vessels, hypoplastic right aortic arch, and a severely regurgitant Ebstein tricuspid valve (TV). During the fetal period, she was listed for heart transplantation, and two weeks after birth due to a deterioration of her general condition, we performed a Norwood-Sano modified procedure. After 58 days a donor heart became available and the baby successfully received a orthotopic heart transplantation. PMID- 23947599 TI - Predictors of mortality among elderly dependent home care patients. AB - BACKGROUND: The purpose of this study is to identify which variables--among those commonly available and used in the primary care setting--best predict mortality in a cohort of elderly dependent patients living at home (EDPLH) that were included in a home care program provided by Primary Care Teams (PCT). Additionally, we explored the risk of death among a sub-group of these patients that were admitted to hospital the year before they entered the home care program. METHODS: A one-year longitudinal cohort study of a sample of EDPLH patients included in a home care programme provided by 72 PCTs. Variables collected from each individual patient included health and social status, carer's characteristics, carer's burden of care, health and social services received. RESULTS: 1,001 patients completed the study (91.5%), 226 were admitted to hospital the year before inclusion. 290 (28.9%) died during the one-year follow up period. In the logistic regression analysis women show a lower risk of death [OR= 0.67 (0.50-0.91)]. The risk of death increases with comorbidity [Charlson index OR= 1.14 (1,06-1.23)], the number of previous hospital admissions [OR= 1,16 (1.03-1.33)], and with the degree of pressure ulcers [ulcers degree 1-2 OR = 2.94 (1.92-4.52); ulcers degree 3-4 OR = 4.45 (1.90-10.92)]. The logistic predictive model of mortality for patients previously admitted to hospital identified male sex, comorbidity, degree of pressure ulcers, and having received home care rehabilitation as independent variables that predict death. CONCLUSIONS: Comorbidity, hospital admissions and pressure ulcers predict mortality in the following year in EDPLH patients. The subgroup of patients that entered home care programs with a previous record of hospital admission and a high score in our predictive model might be considered as candidates for palliative care. PMID- 23947601 TI - Alcohol consumption and sport: a cross-sectional study of alcohol management practices associated with at-risk alcohol consumption at community football clubs. AB - BACKGROUND: Excessive alcohol consumption is responsible for considerable harm from chronic disease and injury. Within most developed countries, members of sporting clubs participate in at-risk alcohol consumption at levels above that of communities generally. There has been limited research investigating the predictors of at-risk alcohol consumption in sporting settings, particularly at the non-elite level. The purpose of this study was to examine the association between the alcohol management practices and characteristics of community football clubs and at-risk alcohol consumption by club members. METHODS: A cross sectional survey of community football club management representatives and members was conducted. Logistic regression analysis (adjusting for clustering by club) was used to determine the association between the alcohol management practices (including alcohol management policy, alcohol-related sponsorship, availability of low- and non-alcoholic drinks, and alcohol-related promotions, awards and prizes) and characteristics (football code, size and location) of sporting clubs and at-risk alcohol consumption by club members. RESULTS: Members of clubs that served alcohol to intoxicated people [OR: 2.23 (95% CI: 1.26 3.93)], conducted 'happy hour' promotions [OR: 2.84 (95% CI: 1.84-4.38)] or provided alcohol-only awards and prizes [OR: 1.80 (95% CI: 1.16-2.80)] were at significantly greater odds of consuming alcohol at risky levels than members of clubs that did not have such alcohol management practices. At-risk alcohol consumption was also more likely among members of clubs with less than 150 players compared with larger clubs [OR:1.45 (95% CI: 1.02-2.05)] and amongst members of particular football codes. CONCLUSIONS: The findings of this study suggest a need and opportunity for the implementation of alcohol harm reduction strategies targeting specific alcohol management practices at community football clubs. PMID- 23947602 TI - Preparation and characterization of chitosan-based spray-dried microparticles for the delivery of clindamycin phosphate to periodontal pockets. AB - Biodegradable spray-dried chitosan microparticles loaded with clindamycin phosphate (CDP) were formulated to deliver drugs locally into the periodontal pocket. The effects of spray dryer conditions, drug/polymer ratio, and added amounts of glutaraldehyde (GA) solution on the characterization of microparticles were investigated by determining process yield, encapsulation efficiency, particle size and size distribution, surface morphology, drug release, release kinetics, thermal analysis, and antimicrobial efficacy of formulations. Burst release was obtained for all formulations due to the water solubility of the drug, but the increased amount of chitosan decreased the drug release rates. Microparticles with a more wrinkled surface were obtained by increasing the amount of the drug. Incorporation efficiencies higher than 80% were obtained for all preparation conditions. The addition of GA caused higher viscosity of the chitosan solution, leading to larger particles with more spherical and smooth surface characteristics. However, the increased GA amount did not significantly influence the drug release. The data obtained from in vitro release experiments were best fitted to the Weibull and Higuchi models. The amorphous nature of the drug-loaded microparticles was detected by differential scanning calorimetric (DSC) thermographs. A delayed drug release of more than one week could be obtained by loading the drug into the chitosan microparticles. Antimicrobial efficacy studies reflected a positive drug release profile. These results indicate that spray-dried clindamycin-loaded microparticles with sustained antimicrobial efficacy appear to be a promising periodontal therapy for drug delivery into the periodontal pocket. PMID- 23947603 TI - Phenotypic variation of the housefly, Musca domestica: amounts and patterns of wing shape asymmetry in wild populations and laboratory colonies. AB - Musca domestica L. (Diptera: Muscidae) is a vector of a range variety of pathogens infecting humans and animals. During a year, housefly experiences serial population bottlenecks resulted in reduction of genetic diversity. Population structure has also been subjected to different selection regimes created by insect control programs and pest management. Both environmental and genetic disturbances can affect developmental stability, which is often reflected in morphological traits as asymmetry. Since developmental stability is of great adaptive importance, the aim of this study was to examine fluctuating asymmetry (FA), as a measure of developmental instability, in both wild populations and laboratory colonies of M. domestica. The amount and pattern of wing shape FA was compared among samples within each of two groups (laboratory and wild) and between groups. Firstly, the amount of FA does not differ significantly among samples within the group and neither does it differ between groups. Regarding the mean shape of FA, contrary to non-significant difference within the wild population group and among some colonies, the significant difference between groups was found. These results suggest that the laboratory colonies and wild samples differ in buffering mechanisms to perturbations during development. Hence, inbreeding and stochastic processes, mechanisms dominating in the laboratory-bred samples contributed to significant changes in FA of wing shape. Secondly, general patterns of left-right displacements of landmarks across both studied sample groups are consistent. Observed consistent direction of FA implies high degrees of wing integration. Thus, our findings shed light on developmental buffering processes important for population persistence in the environmental change and genetic stress influence on M. domestica. PMID- 23947604 TI - Is butyrate the link between diet, intestinal microbiota and obesity-related metabolic diseases? AB - It is increasingly recognized that there is a connection between diet, intestinal microbiota, intestinal barrier function and the low-grade inflammation that characterizes the progression from obesity to metabolic disturbances, making dietary strategies to modulate the intestinal environment relevant. In this context, the ability of some Gram-positive anaerobic bacteria to produce the short-chain fatty acid butyrate is interesting. A lower abundance of butyrate producing bacteria has been associated with metabolic risk in humans, and recent studies suggest that butyrate might have an anti-inflammatory potential that can alleviate obesity-related metabolic complications, possibly due to its ability to enhance the intestinal barrier function. Here, we review and discuss the potential of butyrate as an anti-inflammatory mediator in metabolic diseases, and the potential for dietary interventions increasing the intestinal availability of butyrate. PMID- 23947605 TI - An analysis of petrous bone cholesteatomas treated with translabyrinthine transotic petrosectomy. AB - CONCLUSION: In cases of petrous apex cholesteatoma, radical removal should be prioritized over an unreasonable sparing of hearing or facial symmetry. Restoration of facial nerve function is achievable by reanimation procedures. OBJECTIVES: To analyze clinical manifestations, surgical findings, and postoperative functional results of petrous apex cholesteatoma. METHODS: From 1995 to 2012, 34 cases of petrous apex cholesteatoma underwent operations. Clinical and surgical findings and postoperative functional outcomes were analyzed retrospectively. RESULTS: Hearing loss was the most common symptom in 95% of patients, followed by otorrhea in 64% and facial palsy in 59%. Four patients had recurrent facial palsy. In eight (24%) patients petrous apex cholesteatomas were recurrent or iatrogenic in origin. The supralabyrinthine and massive type of petrous bone cholesteatoma were the most common types, followed by, infralabyrinthine-apical, infralabyrinthine, and apical. Among 18 cases with facial nerve paralysis, 8 underwent hypoglossal-facial nerve anastomosis, 4 underwent rerouting and end to end anastomosis, 3 of them did not undergo any treatment because of the duration of facial palsy (> 3 years), and another 3 patients for whom we had recommended facial-hypoglossal anastomosis did not accept the operation. There were no major complications. Recurrence was observed in two (5%) cases. PMID- 23947606 TI - Results of caloric and sensory organization testing of dynamic posturography in migrainous vertigo: comparison with Meniere's disease and vestibular neuritis. AB - CONCLUSION: Our findings suggest that migrainous vertigo (MV) has a substantial vestibulo-spinal abnormality that can be uncovered by posturography. Patients with MV also showed a difficulty in using multisystem information, especially somatosensory information. Caloric and sensory organization tests (SOTs) have complementary roles in assessing vestibulo-ocular and vestibulo-spinal function, particularly for Meniere's disease (MD) and MV. OBJECTIVES: To compare vestibular dysfunction through caloric testing and posturography in patients with MV, MD, and acute vestibular neuritis (VN). METHODS: Caloric tests and SOTs were performed in 31 patients with MV, 23 with MD, and 37 with VN. The abnormal results in caloric test, SOT conditions, and somatosensory, visual, and vestibular ratios were analyzed. RESULTS: Abnormal canal paresis was found in 7 patients with MV (23%), 11 with MD (48%), and 37 with VN (100%). An abnormal vestibular ratio in SOT was found in 14 patients with MV (45%), 6 with MD (26%), and 23 with VN (62%). In MV, an abnormal vestibular ratio was more common than canal paresis and an abnormal vestibular ratio was more common than in MD. An abnormal somatosensory ratio (19%) in MV was significantly more common than in VN and MD (3% and 0%). For condition 2, MV showed a significantly higher abnormal rate than VN. An abnormal visual ratio in MV was more common than in VN and MD but this was not significant. PMID- 23947607 TI - Clinical features of pediatric parotid tumors: 10-year experience of a single institute. AB - CONCLUSIONS: Parotidectomy remains the mainstay of treatment for both benign and malignant lesions of the pediatric parotid gland. Adjuvant radiation therapy should be used judiciously in pediatric patients due to the higher risk of post irradiation complications. OBJECTIVE: The purpose of this study was to define the incidence and treatment of pediatric parotid tumors, and to determine what factors are useful in the management of these lesions. METHODS: From June 2002 to June 2012, 22 patients <=18 years of age with parotid mass were treated at Chonnam National University Hospital. Information on patient characteristics, clinical and histopathologic tumor characteristics, and treatment modalities and their results was obtained from the medical records. RESULTS: The 22 patients comprised 11 males and 11 females. Eighteen patients had a benign tumor and four patients had a malignant tumor. The most common benign tumor was pleomorphic adenoma (63.6%) and the most common malignant tumor was mucoepidermoid carcinoma (9%). The most common treatment was superficial parotidectomy. Three patients required adjuvant radiotherapy. None of the patients had major complications or facial nerve palsy. PMID- 23947609 TI - Conformational selection is a dominant mechanism of ligand binding. AB - Molecular recognition in biological macromolecules is achieved by binding interactions coupled to conformational transitions that precede or follow the binding step, two limiting mechanisms known as conformational selection and induced fit, respectively. Sorting out the contribution of these mechanisms to any binding interaction remains a challenging task of general interest in biochemistry. Here we show that conformational selection is associated with a vast repertoire of kinetic behaviors, can never be disproved a priori as a mechanism of ligand binding, and is sufficient to explain the relaxation kinetics documented experimentally for a large number of systems. On the other hand, induced fit features a narrow spectrum of kinetic behaviors and can be disproved in many cases in which conformational selection offers the only possible explanation. This conclusion offers a paradigm shift in the analysis of relaxation kinetics, with conformational selection acquiring preeminence as a mechanism of ligand binding. The dominant role of conformational selection supports the emerging structural view of the macromolecule as a conformational ensemble from which the ligand selects the initial optimal fit to produce a biological response. PMID- 23947611 TI - Mono(imidazolin-2-iminato) titanium complexes for ethylene polymerization at low amounts of methylaluminoxane. AB - The polymerization of ethylene with titanium complexes bearing one bulky imidazolin-2-iminato ligand (L) in the presence of MAO and/or TTPB as cocatalysts have been explored. The complex LTiCl3 and its methylated forms were prepared to shed light on the nature of the active polymerization species. With some of these complexes, the best catalytic activity was obtained at an Al:Ti ratio of 8. PMID- 23947610 TI - Management of over-the-counter insomnia complaints in Australian community pharmacies: a standardized patient study. AB - OBJECTIVE: To evaluate the current management of over-the-counter (OTC) insomnia complaints in Australian community pharmacies using standardized patient methodology. METHODS: Trained standardized patients visited a sample of 100 randomly selected South East Queensland community pharmacies in June 2011. The standardized patients enacted two OTC insomnia scenarios: a direct product request (DPR) (n = 50) and a symptom-based request (SBR) (n = 50). Results of the interactions were documented immediately after each visit and evaluated using the Pharmaceutical Society of Australia's WHAT STOP GO protocol as a standard comparison. KEY FINDINGS: Of all DPRs, 30% were handled entirely by the pharmacist, 70% of staff enquired about specific symptoms and 28% investigated the cause of insomnia. No staff investigated the frequency of product use. The DPR scenario resulted in a 92% supply of the requested doxylamine product (Restavit). In the SBR scenario, 18% of requests were handled entirely by the pharmacist, 58% of staff enquired about specific symptoms and 44% investigated the cause of insomnia. Staff recommended medicated products (38%), or herbal (78%) or non-drug techniques (18%). Investigation into smoking and alcohol intake was not undertaken in DPR or SBR interactions, while questioning on caffeine intake was undertaken in 2 and 14% of cases respectively. There were no significant differences found in the handling of sleep requests by pharmacists compared to pharmacy assistants. CONCLUSION: The standardized patient methodology was a successful way to assess the community pharmacy counselling provided with OTC sleep requests and suboptimal staff responses were found when compared with recommended practice standards. PMID- 23947612 TI - Dual stimuli-responsive, rechargeable micropumps via "host-guest" interactions. AB - We demonstrate a supramolecular approach to the fabrication of self-powered micropumps based on "host-guest" molecular recognition between alpha- and beta cyclodextrin and trans-azobenzene. Both hydrogels and surface coatings based on host-guest partners were used as scaffolds to devise the micropumps. These soft micropumps are dual stimuli-responsive and can be actuated either by light or by introducing guest molecules. Furthermore, the micropumps can be recharged through reversible host-guest interaction. PMID- 23947614 TI - Addressing physician stress, burnout, and compassion fatigue: the time has come. AB - Stress, burnout, and compassion fatigue can have a significant adverse effect of physician well being and patient care. While the frequency and intensity of these negative influences appear to be increasing, there is little help available. We need to raise physician awareness as to the seriousness of this issue and at the same time gain a better understanding of some of the causative factors so we can provide the necessary support services that will enable our physicians to better adjust to the pressures and stresses of our health care environment and re energize their zest and idealism for medical care.This is a commentary on http://www.ijhpr.org/content/2/1/31. PMID- 23947613 TI - SIV infection of rhesus macaques of Chinese origin: a suitable model for HIV infection in humans. AB - Simian immunodeficiency virus (SIV) infection of Indian-origin rhesus macaques (RM) has been widely used as a well-established nonhuman primate (NHP) model for HIV/AIDS research. However, there have been a growing number of studies using Chinese RM to evaluate immunopathogenesis of SIV infection. In this paper, we have for the first time reviewed and discussed the major publications related to SIV or SHIV infection of Chinese RM in the past decades. We have compared the differences in the pathogenesis of SIV infection between Chinese RM and Indian RM with regard to viral infection, immunological response, and host genetic background. Given AIDS is a disease that affects humans of diverse origins, it is of importance to study animals with different geographical background. Therefore, to examine and compare results obtained from RM models of Indian and Chinese origins should lead to further validation and improvement of these animal models for HIV/AIDS research. PMID- 23947615 TI - Nasally administered Lactobacillus rhamnosus strains differentially modulate respiratory antiviral immune responses and induce protection against respiratory syncytial virus infection. AB - BACKGROUND: Some studies have shown that nasally administered immunobiotics had the potential to improve the outcome of influenza virus infection. However, the capacity of immunobiotics to improve protection against respiratory syncytial virus (RSV) infection was not investigated before. OBJECTIVE: The aims of this study were: a) to evaluate whether the nasal administration of Lactobacillus rhamnosus CRL1505 (Lr05) and L. rhamnosus CRL1506 (Lr06) are able to improve respiratory antiviral defenses and beneficially modulate the immune response triggered by TLR3/RIG-I activation; b) to investigate whether viability of Lr05 or Lr06 is indispensable to modulate respiratory immunity and; c) to evaluate the capacity of Lr05 and Lr06 to improve the resistance of infant mice against RSV infection. RESULTS: Nasally administered Lr05 and Lr06 differentially modulated the TLR3/RIG-I-triggered antiviral respiratory immune response. Lr06 administration significantly modulated the production of IFN-alpha, IFN-beta and IL-6 in the response to poly(I:C) challenge, while nasal priming with Lr05 was more effective to improve levels of IFN-gamma and IL-10. Both viable Lr05 and Lr06 strains increased the resistance of infant mice to RSV infection while only heat-killed Lr05 showed a protective effect similar to those observed with viable strains. CONCLUSIONS: The present work demonstrated that nasal administration of immunobiotics is able to beneficially modulate the immune response triggered by TLR3/RIG-I activation in the respiratory tract and to increase the resistance of mice to the challenge with RSV. Comparative studies using two Lactobacillus rhamnosus strains of the same origin and with similar technological properties showed that each strain has an specific immunoregulatory effect in the respiratory tract and that they differentially modulate the immune response after poly(I:C) or RSV challenges, conferring different degree of protection and using distinct immune mechanisms. We also demonstrated in this work that it is possible to beneficially modulate the respiratory defenses against RSV by using heat killed immunobiotics. PMID- 23947616 TI - Storage stability of a commercial hen egg yolk powder in dry and intermediate moisture food matrices. AB - Quality loss in intermediate-moisture foods (IMF) such as high-protein nutrition bars (HPNB) in the form of hardening, nonenzymatic browning, and free amino group loss is a general concern for the manufacturers. To measure the extent of quality loss over time in terms of these negative attributes, through changing the ratio by weight between two commercial spray-dried hen egg powders, egg white (DEW) and egg yolk (DEY), the storage stability of 10 IMF systems (water activity (aw) ~ 0.6) containing 5% glycerol, 10% shortening, 35% protein, and 50% sweetener (either maltitol or 50% high-fructose corn syrup/50% corn syrup (HFCS/CS)) were studied. Additionally, the storage stability of the DEY powder itself was investigated. Overall, during storage at different temperatures (23, 35, and 45 degrees C), the storage stability of DEY in dry and IMF matrices was mainly controlled by the coaction of three chemical reactions (disulfide bond interaction, Maillard reaction, and lipid oxidation). The results showed that by replacing 25% of DEW in an IMF model system with DEY, the rate of bar hardening was significantly lower than that of the models with only DEW at all temperatures due to the softening effect of the fat in DEY. Furthermore, the use of maltitol instead of HFCS/CS in all bar systems not only resulted in decreased hardness but also drastically decreased the change in the total color difference (DeltaE*). Interestingly, there was no significant loss of free amino groups in the maltitol systems at any DEW/DEY ratio. PMID- 23947617 TI - Cooperative slowdown of water rotation near densely charged ions is intense but short-ranged. AB - We investigate the reorientation dynamics of water at 300 K in solutions of magnesium sulfate and cesium chloride from classical atomistic molecular dynamics simulations using the "simple water model with four sites and negative Drude polarizability" (SWM4-NDP) and accompanying ion models; for SO4(2-), we derive SWM4-NDP-compatible parameters. Results indicate that pairs of ions have a cooperative effect on water rotation but do not support the model based on experiment whereby ion cooperativity increases the number of very slow water molecules well beyond the ions' first hydration shell. Instead, we find that cooperative slowdown beyond the first hydration shell is weak. Intense cooperative slowdown is limited to the first hydration shells, the magnitude of the slowdown being stronger for the multivalent ions. Cooperative effects for different salts differ in both the magnitude of rotational slowdown and the spatial range of the affected water subpopulations. PMID- 23947618 TI - Automated solution-phase synthesis of oligosaccharides via iterative electrochemical assembly of thioglycosides. AB - A new iterative one-pot sequential method for the solution-phase synthesis of oligosaccharides has been devised on the basis of the electrochemical oxidation of a propagating thioglycoside terminus to generate the corresponding triflate, followed by the reaction with a thioglycoside building block having a free hydroxyl group. A practical automated synthesizer was developed for the method and was effectively used for assembling up to six thioglycoside building blocks to synthesize partial structures of poly-beta-D-(1-6)-N-acetylglucosamine. PMID- 23947619 TI - Reaction-induced microsyneresis in oxide-based gels: the assembly of hierarchical microsphere networks. AB - Rigid and stable networks composed of litchi-shaped microspheres were formed via hierarchical self-assembly (SA) of oxide-based nanoparticles (NPs). The phenomenon of the apparent changes from NPs networks to microspheres networks after the gelation was similar to normal microsyneresis. However, in-situ composition evolution results indicate that the SA is driven by interparticle dehydration, but not affinity difference between the network for itself and for the solvent. In-situ small-angle X-ray scattering (SAXS), UV-vis-NIR, and electric conductivity were used to study the microsyneresis process. To further demonstrate the mechanism, extra complexant was added and successfully restrained the NPs-microsphere transition by inactivating the surface hydroxyl of the NPs. Considering the structural similarity, this work may provide a new approach to control the assemblies of diverse oxide-based NPs. PMID- 23947620 TI - Modelling organelle transport after traumatic axonal injury. AB - This paper is motivated by recent experimental research (Tang-Schomer et al. 2012) on the formation of periodic varicosities in axons after traumatic brain injury (TBI). TBI leads to the formation of undulated distortions in the axons due to their dynamic deformation. These distortions result in the breakage of some microtubules (MTs) near the peaks of undulations. The breakage is followed by catastrophic MT depolymerisation around the broken ends. Although after relaxation axons regain their straight geometry, the structure of the axon after TBI is characterised by the presence of periodic regions where the density of MTs has been decreased due to depolymerisation. We modelled organelle transport in an axon segment with such a damaged MT structure and investigated how this structure affects the distributions of organelle concentrations and fluxes. The modelling results suggest that organelles accumulate at the boundaries of the region where the density of MTs has been decreased by depolymerisation. According to the model, the presence of such damaged regions decreases the organelle flux by only about 12%. This provides evidence that axon degradation after TBI may be caused by organelle accumulation rather than by starvation due to insufficient organelle flux. PMID- 23947621 TI - Rho-kinase inhibitor prevents bleomycin-induced injury in neonatal rats independent of effects on lung inflammation. AB - Bleomycin-induced lung injury is characterized in the neonatal rat by inflammation dominated by neutrophils and macrophages, inhibited distal airway and vascular development, and pulmonary hypertension, similar to human infants with severe bronchopulmonary dysplasia. Rho-kinase (ROCK) is known to mediate lung injury in adult animals via stimulatory effects on inflammation. We therefore hypothesized that inhibition of ROCK may ameliorate bleomycin-induced lung injury in the neonatal rat. Pups received daily intraperitoneal bleomycin or saline from Postnatal Days 1 through 14 with or without Y-27632, a ROCK inhibitor. Treatment with Y-27632 prevented bleomycin-induced pulmonary hypertension, as evidenced by normalized pulmonary vascular resistance, decreased right-ventricular hypertrophy, and attenuated remodeling of pulmonary resistance arteries. Bleomycin-induced changes in distal lung architecture, including septal thinning, inhibited alveolarization, and decreased numbers of peripheral arteries and capillaries, were partially or completely normalized by Y-27632. Treatment with Y-27632 or a CXCR2 antagonist, SB265610, also abrogated tissue neutrophil influx, while having no effect on macrophages. However, treatment with SB265610 did not prevent bleomycin-induced lung injury. Lung content of angiostatic thrombospondin-1 (TSP1) was increased significantly in the lungs of bleomycin exposed animals, and was completely attenuated by treatment with Y-27632. Thrombin-stimulated TSP1 production by primary cultured rat pulmonary artery endothelial cells was also attenuated by Y-27632. Taken together, our findings suggest a preventive effect of Y-27632 on bleomycin-mediated injury by a mechanism unrelated to inflammatory cells. Our data suggest that improvements in lung morphology may have been related to indirect stimulatory effects on angiogenesis via down-regulation of TSP1. PMID- 23947622 TI - Does informal care reduce public care expenditure on elderly care? Estimates based on Finland's Age Study. AB - BACKGROUND: To formulate sustainable long-term care policies, it is critical first to understand the relationship between informal care and formal care expenditure. The aim of this paper is to examine to what extent informal care reduces public expenditure on elderly care. METHODS: Data from a geriatric rehabilitation program conducted in Finland (Age Study, n = 732) were used to estimate the annual public care expenditure on elderly care. We first constructed hierarchical multilevel regression models to determine the factors associated with elderly care expenditure. Second, we calculated the adjusted mean costs of care in four care patterns: 1) informal care only for elderly living alone; 2) informal care only from a co-resident family member; 3) a combination of formal and informal care; and 4) formal care only. We included functional independence and health-related quality of life (15D score) measures into our models. This method standardizes the care needs of a heterogeneous subject group and enabled us to compare expenditure among various care categories even when differences were observed in the subjects' physical health. RESULTS: Elder care that consisted of formal care only had the highest expenditure at 25,300 Euros annually. The combination of formal and informal care had an annual expenditure of 22,300 Euros. If a person received mainly informal care from a co-resident family member, then the annual expenditure was only 4,900 Euros and just 6,000 Euros for a person living alone and receiving informal care. CONCLUSIONS: Our analysis of a frail elderly Finnish population shows that the availability of informal care considerably reduces public care expenditure. Therefore, informal care should be taken into account when formulating policies for long-term care. The process whereby families choose to provide care for their elderly relatives has a significant impact on long-term care expenditure. PMID- 23947624 TI - Sheffield suction holder clips for endolaryngeal laser surgery. AB - BACKGROUND: There has been a major evolution in laryngeal surgery, largely due to an improved understanding of disease pathogenesis and advances in technology, especially the introduction of lasers. METHOD AND RESULTS: Continuous laser plume evacuation during endolaryngeal surgery improves visualisation of the surgical field. Hence, microlaryngoscopes are fitted with smoke evacuation channels on their sides. We have devised a new, simple and efficient suction holder clip for endolaryngeal surgery that has distinct advantages over other suction holders. PMID- 23947623 TI - Risks for HIV and other sexually transmitted infections among Asian men who have sex with men in Vancouver, British Columbia: a cross-sectional survey. AB - BACKGROUND: Individuals of Asian heritage represent the largest ethnic minority in Canada. Approximately 10% of the new HIV diagnoses in men in British Columbia occur among Asian-Canadians. However, the HIV risk patterns of Asian men who have sex with men (MSM) have not been extensively studied. METHODS: Participants aged >= 19 years were enrolled in a venue-based HIV serobehavioural survey of MSM in Vancouver, Canada. We compared the demographic characteristics, risk behaviours, and prevalence of HIV and other sexual and blood borne infections between Asian and non-Asian MSM using bivariate analysis and logistic regression confounder modelling. RESULTS: Amongst 1132 participants, 110 (9.7%) self-identified as Asian. Asian participants were younger than non-Asian participants (median age 29 vs. 32 years; p < 0.001), but otherwise did not differ from other study participants. HIV prevalence was lower among Asian MSM compared to Non-Asian MSM (3.7% vs 19.0%, p <0.001). Among men who self-reported as HIV negative or unknown we found no differences in unprotected anal intercourse (UAI) with a discordant or unknown serostatus partner in the previous six months (11 vs. 13%; p = 0.503). However, Asian MSM were less likely to report ever using injection drugs (10.8% vs. 19.2%; p = 0.043) or using alcohol before having sex (52% vs. 64.4%; p = 0.017). CONCLUSIONS: Asian MSM in our study reported similar rates of UAI as non Asian MSM, but had a lower prevalence of HIV infection. Other factors, such as the use of drugs and alcohol, in relation to sex, may partly explain these differences. However this requires further investigation. PMID- 23947625 TI - HSV-1 activates NF-kappaB in mouse astrocytes and increases TNF-alpha and IL-6 expression via Toll-like receptor 3. AB - OBJECTIVE: To investigate the effect of HSV-1 infection via TLR3 on the transcriptional activity of NF-kappaB and the expression of cytokines TNF-alpha and IL-6 in astrocytes. METHODS: HSV-1-infected primary astrocytes were cultured until the third passage and the mRNA and protein levels of TLR3, NF-kappaB, TNF alpha, and IL-6 were assessed by immunofluorescence, RT-PCR, and Western blot. The effects of the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) and TLR3-neutralizing antibody on the expression of NF-kappaB, TNF-alpha, and IL-6 were investigated. RESULTS: Uninfected astrocytes expressed TLR3 and NF-kappaB at the mRNA and protein levels. After infection with HSV-1, the TLR3 mRNA and protein levels were up-regulated and NF-kappaB protein was highly expressed. Also, the mRNA and protein levels of TNF-alpha and IL-6 were up-regulated. Pyrrolidine dithiocarbamate inhibited NF-kappaB activation, resulting in the down regulation of nuclear NF-kappaB protein, which led to the down-regulation of the mRNA and protein levels of TNF-alpha and IL-6. After blocking astrocyte membrane TLR3, the nuclear NF-kappaB protein expression was down-regulated and the mRNA and protein levels of TNF-alpha and IL-6 were increased. The antiviral functions of astrocytes were weaker, as reflected by higher HSV-1 glycoprotein D (gD) mRNA expression and increased HSV-1 titers. CONCLUSION: Astrocytes infected with HSV-1 can activate NF-kappaB via TLR3 so as to up-regulate the expression of TNF-alpha and IL-6 that have antiviral functions. PMID- 23947626 TI - Shedding patterns of Daubaylia potomaca (Nematoda: Rhabditida). AB - Daubaylia potomaca is a nematode parasite that exhibits an unusual direct life cycle in planorbid snails in which adult females are the infective stage, after being shed from a definitive host. The present study examined the shedding patterns of this nematode to determine what cues or mechanisms might lead to the parasite leaving its host. A correlation was found between host death and the frequency and number of D. potomaca shed, suggesting that the nematodes can detect that the host is dying and may leave in search of a new host. Furthermore, elevated intensities of D. potomaca in the snail induce shedding earlier, suggesting that competition for space and resources may also play a role in the shedding patterns of the nematode, but not when time to death is controlled. Finally, nematodes shed a longer time before host death were significantly longer and more likely to be gravid than those shed as time to snail death approached, implying that the nematode reaching maturity or being inseminated might also be cues for D. potomaca to leave its snail host. In summary, the shedding patterns of D. potomaca appear to be a complex mix of host death detection, competition, and nematode maturation. PMID- 23947627 TI - Severe menopausal symptoms are widespread among survivors of breast cancer treatment regardless of time since diagnosis. AB - BACKGROUND: The intensity and persistence of treatment-related symptoms among breast cancer survivors is incompletely understood. OBJECTIVE: The objective of the study was to estimate prevalence of severe symptoms well after initial treatment for breast cancer, to test whether symptom intensity diminishes with time or varies by treatment received. DESIGN, SETTING, SUBJECTS: This was a cross sectional survey of female survivors of stage I-III invasive breast cancer, seen for routine follow-up a year or more after diagnosis. MEASUREMENTS: Data was derived from three validated questionnaires indicating physical and emotional domains. Symptoms rated in the top two levels of four- or five-item Likert scales were "severe." Associations with symptom intensity were tested using multivariate linear regression. RESULTS: Survey response was 68.5% (50/73). Respondents were age 55.4 (+/-9.1) years, median 2.2 (1.0-13.1) years since diagnosis; 64% were receiving endocrine therapy. Severe levels of hot flashes (42% of respondents), weight gain (32%), low libido (32%), and joint pain (30%) were common; (36%) of respondents rated sleep "fairly poor" or "very bad;" 30% were fatigued at least half the day. For 34%, health typically limited vigorous activities "a lot." Most (84%) respondents were experiencing at least one severe symptom. Symptom intensity did not vary with time since diagnosis. Of seven symptoms, three (hot flashes, weight gain, low libido) were more intense when systemic treatment had included endocrine therapy. Time in past month feeling down, nervous, or worn out increased with intensity of physical symptoms. CONCLUSIONS: Given their severity, persistence, and association with emotional burden, treatment-related symptoms among breast cancer survivors (BCS) merit greater attention toward clinical management, patient education, and longitudinal study. PMID- 23947628 TI - Talk first, act later. PMID- 23947630 TI - Preconceptions in palliative care: a medical student's perspective. PMID- 23947632 TI - Postherpetic neuralgia #272. PMID- 23947633 TI - Why I no longer say "withdrawal of care" or "life sustaining technology". PMID- 23947634 TI - A Pd(0)-catalyzed direct dehydrative coupling of terminal alkynes with allylic alcohols to access 1,4-enynes. AB - A direct dehydrative coupling of terminal alkynes with allylic alcohols catalyzed by Pd(PPh3)4 with an N,P-ligand assisted by Ti(OiPr)4 has been developed. The coupling reaction tolerates various functional groups, providing a valuable synthetic tool to access 1,4-enynes. PMID- 23947635 TI - Total cavopulmonary direct anastomosis in the beating heart without prosthetic material: preliminary experience with modified extracardiac fontan procedure. AB - AIM: To describe modified extracardiac Fontan procedure characterized with total cavopulmonary direct anastomosis in the beating heart without using prosthetic material in seven patients and summarize the clinical experiences and follow-up results. METHODS: From April 2007 to April 2011, seven patients with complex cardiac anomalies underwent this operation. The main pulmonary artery (MPA) was transected at the base of the pulmonary valve and the pulmonary annulus was oversewn. Then the inferior vena cava (ICV) was transected at the junction with the atrium. The MPA was brought to the side of the ICV and anastomosed in an end to-end fashion. The superior vena cava (SVC) was transected at its entrance into the right atrium and was anastomosed to the right pulmonary artery. Five patients received transcatheter device closure of the fenestration with either a small atrial septal defect or ventricular septal defect occluder. RESULTS: All patients were in sinus rhythm and extubated on the first postoperative day. Immediate postoperative arterial oxygen saturation was 95% (93% to 96%). During the follow up period from 17 to 65 months (median 48 months), there were no deaths and reoperations. Arterial oxygen saturation ranged from 88% to 92% on room air. The fenestration was closed in five patients postoperatively and the arterial oxygen saturation rose to 95%. CONCLUSION: Total cavopulmonary direct anastomosis in the beating heart without the use of prosthetic material provides growth potential, and avoids the need for anticoagulation. Longer follow-up will be necessary to evaluate this modification. PMID- 23947636 TI - Dose response kinetics of CD8 lymphocytes from young animals transfused into old animals and challenged with influenza. AB - Transfusion of autologous leukocytes after prolonged storage has been proposed as a means of rejuvenating the immune system of older individuals. The rationale for this approach is that age related immune decline is associated with a diminished pool of naive T cells following atrophy of the thymus and reduction in thymic output. The presence of high levels of naive T cells within the blood of young individuals could provide a boost to the immune system of an older "self" through a rejuvenation of the naive T cell pool. However what remains unresolved is whether the cells could be incorporated effectively into the T cell pool of the host and whether effectors could be generated. Using CD45 congenic mice in our experiments we show that the transfusion of young donor cells into older congenic host animals leads to their successful incorporation into the peripheral T cell pool. When the recipients were challenged with influenza virus, specific effector CD8 cells were generated which were of both host and donor origin. We found no relationship between the number of responder cells of donor origin at the time of assay and the number of cells injected. PMID- 23947637 TI - Filling the gaps: opportunities for community pharmacies to help increase healthcare access for young people in New Zealand. AB - OBJECTIVES: To investigate whether there is potential for community pharmacies to help increase healthcare access and address unmet health needs of young people in New Zealand. METHODS: A descriptive secondary analysis of the Youth'07 health and wellbeing survey data was undertaken alongside discussion meetings with a youth advisory group. KEY FINDINGS: Seventeen per cent (n = 1485) of all students had been unable to access care when required in the previous 12 months. Of these students, 86.0% cited barriers to accessing health care that are unlikely to be barriers in a community pharmacy setting (e.g. not being able to get an appointment). Thirty per cent (n = 2475) of students had experienced difficulty accessing health care in the past 12 months for various health issues, with over half of these (n = 1326) citing a health issue for which community pharmacies could provide services (e.g. minor health issues, smoking cessation). CONCLUSIONS: Although young people are generally considered to be fit and healthy, many have health needs that are currently unmet by traditional health services. Community pharmacies offer services that are relevant to youth health and are readily accessible to young people, indicating potential to help address unmet health needs and improve healthcare access. Further research is needed to explore how community pharmacy models of care might be provided in an appropriate and acceptable manner for youth. PMID- 23947638 TI - Recent physician strike in Israel: a health system under stress? AB - In 2011, a series of physician strikes in Israel followed eight months of unsuccessful negotiations with the government (Ministry of Health and the Ministry of Finance). Strikes by physicians may be a warning that all is not well in a health system and protestors have claimed that they signify a system failure. In contrast, others argue that strikes have been a feature of the Israeli health system from its inception and should not be a cause for alarm. This paper analyses the Israeli health system from the perspective of the strikers' demands using the World Health Organisation's six health system building blocks as a framework, including: service delivery; health workforce; information; medical products, vaccines and technologies; leadership and governance; and financing. While we recognise that the immediate causes of the 2011 strikes were concerns about salaries and working conditions, we argue that a complex set of interacting factors underlie the strikers' demands, resonating with issues relating to five of the WHO building blocks. We argue that of the five, three are most significant and limit progress with all the others: a disgruntled health workforce, many of whom believe that striking is the only way to be heard; a lack of leadership by the government in understanding and responding to physicians' concerns; and a purported information insufficiency, manifest as a lack of critique and analysis that may have prevented those at the top from making a reliable diagnosis of the system's problems. This paper argues that there are cracks within the Israeli health system but that these are not irresolvable. The Israeli health system is a relatively new and popular health system, but there are no grounds for complacency. PMID- 23947639 TI - Highly monodispersed tin oxide/mesoporous starbust carbon composite as high performance Li-ion battery anode. AB - The widespread commercialization of today's plug-in hybrid and all electric vehicles will rely on improved lithium batteries with higher energy density, greater power, and durability.To take advantage of the high density of SnO2 anodes for Li ion batteries, we achieved a smart design of monodispersed SnO2/MSCS composite with very high content of SnO2 by a simple infiltration procedure. The synergistic effects of the unique nanoarchitecture of MSCS and the ultrafine size of SnO2 nanoparticle endowed the composite with superior electrochemical performance. Because of the high density of the composite resulting from its monodispersed submicrometer spherical morphology, an exceptionally high reversible lithium storage capacity (both gravimetric and volumetric), very close to the theoretical capacity (1491 mA h/g), can be achieved with good cyclability (capacity retention of 92.5% after 15 cycles). The SnO2/MSCS composite anode exhibited a high reversible average capacity of about 1200 mAh/g over 30 cycles at a current of 80 mAh/g, which corresponds to about 1440 mAh/cm(3) (practical volumetric capacity). In addition, a Coulombic efficiency close to 100% was achieved, and less than 25% first irreversible capacity loss was observed. PMID- 23947641 TI - EDITORIAL: Advances in Computational Structure Based Drug Discovery. PMID- 23947642 TI - Impact of computational structure-based methods on drug discovery. AB - Structure-based drug design has become an indispensible tool in drug discovery. The emergence of structure-based design is due to gains in structural biology that have provided exponential growth in the number of protein crystal structures, new computational algorithms and approaches for modeling protein ligand interactions, and the tremendous growth of raw computer power in the last 30 years. Computer modeling and simulation have made major contributions to the discovery of many groundbreaking drugs in recent years. Examples are presented that highlight the evolution of computational structure-based design methodology, and the impact of that methodology on drug discovery. PMID- 23947640 TI - General practitioners' views on polypharmacy and its consequences for patient health care. AB - BACKGROUND: Multimorbidity is defined as suffering from coexistent chronic conditions. Multimorbid patients demand highly complex patient-centered care which often includes polypharmacy, taking an average of six different drugs per day. Adverse drug reactions, adverse drug events and medication errors are all potential consequences of polypharmacy. Our study aims to detect the status quo of the health care situation in Saxony's general practices for multimorbid patients receiving multiple medications. We will identify the most common clinical profiles as well as documented adverse drug events and reactions that occur during the treatment of patients receiving multiple medications. We will focus on exploring the motives of general practitioners for the prescription of selected drugs in individual cases where there is evidence of potential drug-drug interactions and potentially inappropriate medications in elderly patients. Furthermore, the study will explore general practitioners' opinions on delegation of skills to other health professions to support medical care and monitoring of patients receiving multiple medications. METHODS/DESIGN: This is a retrospective cross sectional study using mixed methods. Socio-demographic data as well as diagnoses, medication regimens and clinically important events will be analyzed retrospectively using general practitioners documentation in patients' records. Based on these data, short vignettes will be generated and discussed by general practitioners in qualitative telephone interviews. DISCUSSION: To be able to improve outpatient health care management for patients receiving multiple medications, the current status quo of care, risk factors for deficient treatment and characteristics of concerned patients must be investigated. Furthermore, it is necessary to understand the physicians' decision making process regarding treatment. PMID- 23947643 TI - Structure-based beta-secretase (BACE1) inhibitors. AB - Alois Alzheimer identified first abnormal deformation in the brain of diseased people with mental disorder. The disorder is clinically characterized by a progression from episodic memory problems to a slow global decline of cognitive function, ending with the final stage when patients become bedridden and death occurs on average 9 years after diagnosis. The current standard of care does not cover the approved and effective treatment of both cognitive and non-cognitive symptoms. Tremendous effort was put in investigation of the disease development. The uncovered molecular mechanism shed light on aspartic proteases, the smallest protease class with about 15 members in the human genome. Here we summarise the most important structure-based developments on one of the most popular aspartic protease target BACE1. PMID- 23947644 TI - Methods for docking small molecules to macromolecules: a user's perspective. 2. Applications. AB - A large number of research articles describe novel methodologies of docking and/or scoring methods. An even larger number of publications report the successful use of these methods in the identification of novel hit molecules. What is less documented is the application of docking methods in other areas. We review herein the application of docking methods to not only hit identification but also to de novo design, fragment-based drug discovery, lead optimization, metabolism prediction, off-target binding, selectivity, protein structure prediction and drug-drug interaction. PMID- 23947645 TI - Methods for docking small molecules to macromolecules: a user's perspective. 1. The theory. AB - Over the last two decades, computationally docking potential protein ligands (e.g., enzyme inhibitors) has become one of the most widely used strategies in computer aided drug design. While these docking methods were developed, some effort focused on their user-friendliness up to a point where they can be used by non-experts with nearly no training, somewhat hiding the underlying theory. However, basic knowledge is still required to avoid pitfalls and misinterpretations of docking experiments. Over the years, we have collected the common mistakes and necessary information for the proper use of docking programs. In this review, we compiled this data for non-experts in the field. In a first section, we present the theory of docking and scoring approaches as well as their limitations, followed by the most recent progress towards the consideration of protein flexibility, water molecules, metal ions, and covalent drugs. In a second section, we describe what we believe are the necessary steps to ensure optimal docking. More specifically, we present the selection of a docking program, available databases of small molecules, macromolecules and biological data, the necessary steps for the preparation of proteins and small molecules, and finally post docking analysis techniques. In the following sections, we compile the sources of biases and describe docking to nucleic acids. PMID- 23947646 TI - Free energy calculations to estimate ligand-binding affinities in structure-based drug design. AB - Post-genomic era has led to the discovery of several new targets posing challenges for structure-based drug design efforts to identify lead compounds. Multiple computational methodologies exist to predict the high ranking hit/lead compounds. Among them, free energy methods provide the most accurate estimate of predicted binding affinity. Pathway-based Free Energy Perturbation (FEP), Thermodynamic Integration (TI) and Slow Growth (SG) as well as less rigorous end point methods such as Linear interaction energy (LIE), Molecular Mechanics Poisson Boltzmann./Generalized Born Surface Area (MM-PBSA/GBSA) and lambda dynamics have been applied to a variety of biologically relevant problems. The recent advances in free energy methods and their applications including the prediction of protein-ligand binding affinity for some of the important drug targets have been elaborated. Results using a recently developed Quantum Mechanics (QM)/Molecular Mechanics (MM) based Free Energy Perturbation (FEP) method, which has the potential to provide a very accurate estimation of binding affinities to date has been discussed. A case study for the optimization of inhibitors for the fructose 1,6- bisphosphatase inhibitors has been described. PMID- 23947647 TI - Conformational sampling techniques. AB - The potential energy hyper-surface of a protein relates the potential energy of the protein to its conformational space. This surface is useful in determining the native conformation of a protein or in examining a statistical-mechanical ensemble of structures (canonical ensemble). In determining the potential energy hyper-surface of a protein three aspects must be considered; reducing the degrees of freedom, a method to determine the energy of each conformation and a method to sample the conformational space. For reducing the degrees of freedom the choice of solvent, coarse graining, constraining degrees of freedom and periodic boundary conditions are discussed. The use of quantum mechanics versus molecular mechanics and the choice of force fields are also discussed, as well as the sampling of the conformational space through deterministic and heuristic approaches. Deterministic methods include knowledge-based statistical methods, rotamer libraries, homology modeling, the build-up method, self-consistent electrostatic field, deformation methods, tree-based elimination and eigenvector following routines. The heuristic methods include Monte Carlo chain growing, energy minimizations, metropolis monte carlo and molecular dynamics. In addition, various methods to enhance the conformational search including the deformation or smoothing of the surface, scaling of system parameters, and multi copy searching are also discussed. PMID- 23947648 TI - Strategies for small molecule library design. AB - Compilation of an appropriate set of compounds is essential for the success of a small molecule screen. When very little is known about the target and when no or few ligands have been identified, the screening file is often made as diverse as possible. When structural information on the target or target family is available or ligands of the target are known, it is more efficient to apply a ligand- or target-focused bias, so as to predominantly screen compounds that can be expected to modulate the target. One way to achieve this is to select subsets of existing collections; another is to specifically design and synthesize libraries focused on a particular target, target family or mechanism of action. Despite the number of success stories, designing such libraries is still challenging and requires specialized knowledge, especially in emerging target areas such as protein protein interactions (PPI), epigenetics and the ubiquitin proteasome pathway. BioFocus has successfully produced so-called SoftFocus((r)) libraries for many years, evolving their targets from kinases to GPCRs and ion channels to difficult targets in the epigenetics and PPI fields. This article outlines several of the principles applied to SoftFocus library design, showcasing successes achieved by BioFocus' clients. In addition, screening results for a comprehensive set of BioFocus' kinase libraries against 20 kinase targets are used to demonstrate the power of the SoftFocus approach in delivering both selective and less-selective compounds and libraries against these targets. Trademarks: BioFocus((r)), SoftFocus((r)), HDRATM, FieldFocusTM, Thematic AnalysisTM, ThemePairTM and ThemePair FragmentTM are trademarks of Galapagos NV and/or its affiliates. PMID- 23947649 TI - Quantum chemical approaches: semiempirical molecular orbital and hybrid quantum mechanical/molecular mechanical techniques. AB - The use of computational quantum chemical methods to aid drug discovery is surveyed. An overview of the various computational models spanning ab initio, density function theory, semiempirical molecular orbital (MO), and hybrid quantum mechanical (QM)/molecular mechanical (MM) methods is given and their strengths and weaknesses are highlighted, focussing on the challenge of obtaining the accuracy essential for them to make a meaningful contribution to drug discovery. Particular attention is given to hybrid QM/MM and semiempirical MO methods which have the potential to yield the necessary accurate predictions of macromolecular structure and reactivity. These methods are shown to have advanced the study of many aspects of substrate-ligand interactions relevant to drug discovery. Thus, the successful parametrization of semiempirical MO methods and QM/MM methods can be used to model noncovalent substrate-protein interactions, and to lead to improved scoring functions. QM/MM methods can be used in crystal structure refinement and are particularly valuable for modelling covalent protein-ligand interactions and can thus aid the design of transition state analogues. An extensive collection of examples from the areas of metalloenzyme structure, enzyme inhibition, and ligand binding affinities and scoring functions are used to illustrate the power of these techniques. PMID- 23947651 TI - Solvation models: theory and validation. AB - Water plays an active role in many fundamental phenomena in cellular systems such as molecular recognition, folding and conformational equilibria, reaction kinetics and phase partitioning. Hence, our ability to account for the energetics of these processes is highly dependent on the models we use for calculating solvation effects. For example, theoretical prediction of protein-ligand binding modes (i.e., docking) and binding affinities (i.e., scoring) requires an accurate description of the change in hydration that accompanies solute binding. In this review, we discuss the challenges of constructing solvation models that capture these effects, with an emphasis on continuum models and on more recent developments in the field. In our discussion of methods, relatively greater attention will be given to boundary element solutions to the Poisson equation and to nonpolar solvation models, two areas that have become increasingly important but are likely to be less familiar to many readers. The other focus will be upon the trending efforts for evaluating solvation models in order to uncover limitations, biases, and potentially attractive directions for their improvement and applicability. The prospective and retrospective performance of a variety of solvation models in the SAMPL blind challenges will be discussed in detail. After just a few years, these benchmarking exercises have already had a tangible effect in guiding the improvement of solvation models. PMID- 23947650 TI - Molecular mechanics. AB - Molecular Mechanics (MM) force fields are the methods of choice for protein simulations, which are essential in the study of conformational flexibility. Given the importance of protein flexibility in drug binding, MM is involved in most if not all Computational Structure-Based Drug Discovery (CSBDD) projects. This paper introduces the reader to the fundamentals of MM, with a special emphasis on how the target data used in the parametrization of force fields determine their strengths and weaknesses. Variations and recent developments such as polarizable force fields are discussed. The paper ends with a brief overview of common force fields in CSBDD. PMID- 23947652 TI - Investigation into the catalytic activity of porous platinum nanostructures. AB - The catalytic activity of porous platinum nanostructures, viz. platinum nanonets (PtNNs) and platinum nanoballs (PtNBs), synthesized by radiolysis were studied using two model reactions (i) electron transfer reaction between hexacyanoferrate (III) and sodium thiosulfate and (ii) the reduction of p-nitrophenol by sodium borohydride to p-aminophenol. The kinetic investigations were carried out for the platinum nanostructure-catalyzed reactions at different temperatures. The pseudofirst-order rate constant for the electron transfer reaction between hexacyanoferrate (III) and sodium thiosulfate catalyzed by PtNNs and PtNBs at 293 K are (9.1 +/- 0.7) * 10(-3) min(-1) and (16.9 +/- 0.6) * 10(-3) min(-1), respectively. For the PtNN- and PtNB-catalyzed reduction of p-nitrophenol to p aminophenol by sodium borohydride, the pseudofirst-order rate constant was (8.4 +/- 0.3) * 10(-2) min(-1) and (12.6 +/- 2.5) * 10(-2) min(-1), respectively. The accessible surface area of the PtNNs and PtNBs determined before the reaction are 99 and 110 m(2)/g, respectively. These nanostructures exhibit significantly higher catalytic activity, consistent with the largest accessible surface area reported so far for the solid platinum nanoparticles. The equilibrium of the reactants on the surface of the platinum nanostructures played an important role in the induction time (t0) observed in the reaction. A possible role of structural modifications of PtNBs catalyzed the reaction leading to change in the accessible surface area of PtNBs is being explored to explain the nonlinear behavior in the kinetic curve. The activation energy of the PtNN- and PtNB catalyzed reduction of p-nitrophenol are 26 and 6.4 kJ/mol, respectively. These observations open up new challenges in the field of material science to design and synthesize platinum nanostructures which could withstand such reaction conditions. PMID- 23947653 TI - Trans-tensor tympani facial nerve decompression in traumatic facial nerve palsy. AB - OBJECTIVE: The surgical approaches previously reported for facial nerve decompression have focussed on achieving good exposure of the lateral or superior aspects of the geniculate ganglion. This report aims to describe a unique case of facial nerve decompression beneath the geniculate ganglion. PATIENT: A 30-year old woman with right-sided facial palsy due to a temporal bone fracture. INTERVENTION: Bony fragments at the base of the geniculate ganglion were removed via a trans-tensor tympani approach with extended posterior tympanotomy. RESULTS: The patient's facial movement recovered successfully, without complications such as sensorineural hearing loss and conductive hearing loss. CONCLUSION: In rare cases requiring decompression of the facial nerve inferior to the perigeniculate area, the trans-tensor tympani approach should be considered as a valuable alternative option when surgical intervention is considered. PMID- 23947654 TI - Highly-branched poly(N-isopropylacrylamide) as a component in poly(dopamine) films. AB - Mixed one-step poly(dopamine) (PDA)/highly branched poly(N-isopropylacrylamide) (pNiPAAm) coatings have been assembled and characterized by X-ray photoelectron spectroscopy (XPS), UV-vis spectroscopy, atomic force microscopy, and quartz crystal microbalance with dissipation monitoring (QCM-D) depending on the deposition temperature below and above the lower critical solution temperature (LCST) of the pNiPAAm. Mixed films were confirmed. The protein adsorption at 24 degrees C was found to be reduced with increasing amount of pNiPAAm in the mixed coatings, while there was no difference observed for proteins deposition at 39 degrees C. Further, the ability of these mixed coatings in comparison to the pure PDA and pNiPAAm films to serve as capping layer for surface-immobilized zwitterionic or positively charged liposomes has been assessed by QCM-D. The adhesion of hepatocytes, macrophages, and myoblast to these liposomes-containing hybrid coatings and the uptake of fluorescent lipids from the surface by the adhering cells depending on the capping layers were compared. The latter aspect was found to be dependent on the used capping layer and the type of liposome as carrier for the fluorescent lipid, with the highest uptake found for positive liposomes and pure pNiPAAm as capping layer. Taken together, the assembled hybrid coatings have the potential to be used as functional coatings toward surface mediated drug delivery. PMID- 23947655 TI - Multi-institutional comparison of whole slide digital imaging and optical microscopy for interpretation of hematoxylin-eosin-stained breast tissue sections. AB - CONTEXT: Whole slide imaging (WSI) is now used for educational purposes, for consultation, and for archiving and quantitation of immunostains. However, it is not routinely used for the primary diagnosis of hematoxylin-eosin-stained tissue sections. OBJECTIVE: To compare WSI using the Aperio digital pathology system (Aperio Technologies, Inc, Vista, California) with optical microscopy (OM) for the interpretation of hematoxylin-eosin-stained tissue sections of breast lesions. DESIGN: The study was conducted at 3 clinical sites; 3 breast pathologists interpreted 150 hematoxylin-eosin-stained slides at each site, 3 times each by WSI and 3 times each by OM. For WSI, slides were scanned using an Aperio ScanScope and interpreted on a computer monitor using Aperio ImageScope software and Aperio Spectrum data management software. Pathologic interpretations were recorded using the College of American Pathologists breast checklist. WSI diagnoses were compared with OM diagnoses for accuracy, precision (interpathologist variation), and reproducibility (intrapathologist variation). Results were considered accurate only if the interpretation matched exactly between WSI and OM. The proportion of accurate results reported by each pathologist was expressed as a percentage for the comparison of the 2 platforms. RESULTS: The accuracy of WSI for classifying lesions as not carcinoma or as noninvasive (ductal or lobular) or invasive (ductal, lobular, or other) carcinoma was 90.5%. The accuracy of OM was 92.1%. The precision and reproducibility of WSI and OM were determined on the basis of pairwise comparisons (3 comparisons for each slide, resulting in 36 possible comparisons). The overall precision of WSI was 90.5% in comparison with 92.1% for OM; reproducibility of WSI was 91.6% in comparison with 94.5% for OM, respectively. CONCLUSIONS: In this study, we demonstrated that WSI and OM have similar accuracy, precision, and reproducibility for interpreting hematoxylin-eosin-stained breast tissue sections. Further clinical studies using routine surgical pathology specimens would be useful to confirm these findings and facilitate the incorporation of WSI into diagnostic practice. PMID- 23947656 TI - Training emergency services' dispatchers to recognise stroke: an interrupted time series analysis. AB - BACKGROUND: Stroke is a time-dependent medical emergency in which early presentation to specialist care reduces death and dependency. Up to 70% of all stroke patients obtain first medical contact from the Emergency Medical Services (EMS). Identifying 'true stroke' from an EMS call is challenging, with over 50% of strokes being misclassified. The aim of this study was to evaluate the impact of the training package on the recognition of stroke by Emergency Medical Dispatchers (EMDs). METHODS: This study took place in an ambulance service and a hospital in England using an interrupted time-series design. Suspected stroke patients were identified in one week blocks, every three weeks over an 18 month period, during which time the training was implemented. Patients were included if they had a diagnosis of stroke (EMS or hospital). The effect of the intervention on the accuracy of dispatch diagnosis was investigated using binomial (grouped) logistic regression. RESULTS: In the Pre-implementation period EMDs correctly identified 63% of stroke patients; this increased to 80% Post-implementation. This change was significant (p=0.003), reflecting an improvement in identifying stroke patients relative to the Pre-implementation period both the During implementation (OR=4.10 [95% CI 1.58 to 10.66]) and Post-implementation (OR=2.30 [95% CI 1.07 to 4.92]) periods. For patients with a final diagnosis of stroke who had been dispatched as stroke there was a marginally non-significant 2.8 minutes (95% CI -0.2 to 5.9 minutes, p=0.068) reduction between Pre- and Post implementation periods from call to arrival of the ambulance at scene. CONCLUSIONS: This is the first study to develop, implement and evaluate the impact of a training package for EMDs with the aim of improving the recognition of stroke. Training led to a significant increase in the proportion of stroke patients dispatched as such by EMDs; a small reduction in time from call to arrival at scene by the ambulance also appeared likely. The training package has been endorsed by the UK Stroke Forum Education and Training, and is free to access on-line. PMID- 23947658 TI - Arylations of substituted enamides by aryl iodides: regio- and stereoselective synthesis of (Z)-beta-amido-beta-arylacrylates. AB - Arylations of substituted enamides by aryl iodides were achieved for the first time via an unusual PdCl2(COD)/Ag3PO4 catalytic system. A broad range of (Z)-beta amido-beta-arylacrylates were prepared regio- and stereoselectively in a highly efficient manner. PMID- 23947657 TI - Amniotic membrane scaffolds enable the development of tissue-engineered urothelium with molecular and ultrastructural properties comparable to that of native urothelium. AB - The amniotic membrane (AM) is a naturally derived biomaterial that possesses biological and mechanical properties of great importance for tissue engineering. The aim of our study was to determine whether the AM enables the formation of a normal urinary bladder epithelium-urothelium--and to reveal any differences in the urothelial cell (UC) growth and differentiation when using different AM scaffolds. Cryopreserved human AM was used as a scaffold in three different ways. Normal porcine UCs were seeded on the AM epithelium (eAM), denuded AM (dAM), and stromal AM (sAM) and were cultured for 3 weeks. UC growth on AM scaffolds was monitored daily. By using electron microscopy, histochemical and immunofluorescence techniques, we here provide evidence that all three AM scaffolds enable the development of the urothelium. The fastest growth and the highest differentiation of UCs were demonstrated on the sAM scaffold, which enables the development of tissue-engineered urothelium with molecular and ultrastructural properties comparable to that of the native urothelium. Most importantly, the highly differentiated urothelia on the sAM scaffolds provide important experimental models for future drug delivery studies and developing tissue engineering strategies considering that subtle differences are identified before translation to the clinical settings. PMID- 23947660 TI - OH-induced oxidative cleavage of dimethyl disulfide in the presence of NO. AB - We report the results of the theoretical study of (*)OH-induced oxidative cleavage of dimethyl disulfide (DMDS) and the experimental study of the CH3SSCH3 + (*)OH reaction in the presence of (*)NO. Infrared low temperature argon matrix studies combined with ab initio calculations allowed us to identify cis-CH3SONO, which evidences the formation of the CH3SO(*) and CH3SH molecules in the course of the CH3SSCH3 + (*)OH reaction. Ab initio/quantum chemical topology calculations revealed details of the oxidative cleavage of dimethyl disulfide, which is a complex multistep process involving an alteration of S-O and S-S covalent bonds as well as a hydrogen atom transfer. The ability of delocalization of the unpaired electron density by sulfur atoms and a formation of a hydrogen bond by CH3SO(*) and CH3SH are the factors which seem to explain antiradical properties of DMDS. PMID- 23947659 TI - Integration of marker and force data to compute three-dimensional joint moments of the thumb and index finger digits during pinch. AB - This study presents methodology to determine joint moments of the digits of the hand during pinch function. This methodology incorporates steps to identify marker-based kinematic data defining aligned coordinate systems for individual digit segments and joint centre locations. The kinematic data are then transformed to a common reference frame along with the force data collected at pinch contact of a customised apparatus in three dimensions. These methods were demonstrated with a pilot investigation to examine the static joint moments occurring during two-digit oppositional precision pinch at a particular end point force level applied at the digit pads. Notable abduction joint moments at the proximal joints of both digits were observed, which implicate the role of respective intrinsic and extrinsic muscles in maintaining pinch grasp. Examining differences in joint moment results when substituting selected steps of this methodological approach suggested greater relative importance for joint centre identification and segment coordinate system alignment. PMID- 23947661 TI - A history of the Journal of Parasitology. AB - The present issue is Number 1 of Volume 100, The Journal of Parasitology. All 6 numbers of this, our Centennial Volume, are dedicated to those in the past who have contributed in any manner to the Journal's success as a national and international broker for parasitology. Our essay on the history of the Journal is divided into 3 parts. The first extends from 1914 to 1932, i.e., 'the beginning', when Henry Baldwin Ward was Editor and owned the Journal. The 'middle years' continue from 1933, when Ward gave the Journal to the American Society of Parasitologists, to 1961. The 'current period' carries on from 1961 to the present, our Centennial year. Obviously, we cannot provide a great many specific details for each era, but we have made an effort to identify some of the events, issues, and people that have played a significant role in our Journal's history. PMID- 23947662 TI - Nucleofection-mediated alpha1,3-galactosyltransferase gene inactivation and membrane cofactor protein expression for pig-to-primate xenotransplantation. AB - Xenotransplantation of pig organs into primates leads to hyperacute rejection (HAR). Functional ablation of the pig alpha 1,3-galactosyltransferase (GalT) gene, which abrogates expression of the Gal alpha 1-3Gal beta 1-4GlcNAc-R (Gal) antigen, which inhibits HAR. However, antigens other than Gal may induce immunological rejection by their cognate antibody responses. Ultimately, overexpression of complement regulatory proteins reduces acute humoral rejection by non-Gal antibodies when GalT is ablated. In this study, we developed a vector based strategy for ablation of GalT function and concurrent expression of membrane cofactor protein (MCP, CD46). We constructed an MCP expression cassette (designated as MCP-IRESneo) and inserted between the left and the right homologous arms to target exon 9 of the GalT gene. Nucleofection of porcine ear skin fibroblasts using the U-023 and V-013 programs resulted in high transfection efficiency and cell survival. We identified 28 clones in which the MCP-IRESneo vector had been successfully targeted to exon 9 of the GalT gene. Two of those clones, with apparent morphologically mitotic fibroblast features were selected through long-term culture. GalT gene expression was downregulated in these 2 clones. Importantly, MCP was shown to be efficiently expressed at the cell surface and to efficiently protect cell lysis against normal human complement serum attack in vitro. PMID- 23947663 TI - A missense mutation in the rabbit melanocortin 4 receptor (MC4R) gene is associated with finishing weight in a meat rabbit line. AB - In this study we resequenced 1729 bp of the rabbit melanocortin 4 receptor (MC4 R) gene in 31 rabbits from different breeds/lines and identified ten polymorphisms: one was an indel and 9 were single nucleotide polymorphisms (SNPs). The indel and 5 SNPs were in the 5'-flanking region, 3 were synonymous SNPs and one was a missense mutation (c.101G>A; p.G34D), located in a conserved position of the extracellular tail of the MC4 R protein. The missense mutation was analyzed in a panel of 74 rabbits of different breeds and in 516 performance tested rabbits of a commercial paternal line under selection for growth efficiency. Association analysis indicated that rabbits with the less frequent genotype in this population (DD) had a lighter weight at 70 postnatal days than animals with genotype GD (P < 0.10) and animals with genotype GG (P < 0.05). This is the third study on candidate genes, after those on GH1 and IGF2 that reported a marker associated with finishing weight. Therefore, it seems that a candidate gene approach in rabbit based on previous information accumulated in other livestock species could be useful to identify genes explaining a fraction of variability of performance traits with potential application on rabbit breeding and selection. PMID- 23947664 TI - Analysis on differential expressed genes of ovarian tissue between high- and low yield laying hen. AB - In order to elucidate molecular genetic mechanism of laying hen reproduction at the transcriptional level and the structure of significantly differential genes, the mRNA differential display and reverse northern dot-blot were used to detect the differential expression of genes in the ovary tissue of low-yield laying hens and high-yield laying hens in the present study. Sixteen 32-week-old CAU-pink laying hens divided into two groups were used and the laying performance was measured. The results showed that only the egg numbers were significantly different between the two groups; and from 15 primer pairs, a total of 336 bands were displayed of which 59 cDNA bands were found to be differentially expressed in both high-yield and low-yield laying hen. The sequence analysis indicated that the expression of such bands as H-AP5, H-P5, and H-P4 was significantly potentiated in high-yield laying hen using primer pairs AP5/HT11G, P5/HT11G and P4/HT11G and these transcripts had high homology (98%) to HoxDb, HoxCa, and HoxBa, respectively. The differentially expressed gene fragments may be relevant to the progression of the high-yield hens to the egg-laying stage. And further study is required to elucidate the molecular function to improve the productivity of laying hens. PMID- 23947665 TI - Y-SNPs haplotype diversity in four Chinese cattle breeds. AB - To investigate the genetic diversity of Chinese cattle, 96 male samples of 4 Chinese native cattle breeds were investigated using 5 single nucleotide polymorphisms specific to the bovine Y chromosome. Two previously described haplotypes (taurine Y2 and indicine Y3) were detected in 74 and 22 animals, respectively. The haplotype frequencies varied amongst the four native breeds. The taurine Y2 haplotype dominated in the Qinchuan, Dabieshan, and Yunba breeds. However, the indicine Y3 haplotype occurred in high frequency in the Enshi breed. Among the four native breeds, Yunba had the highest haplotype diversity (0.4330 +/- 0.0750), followed by Qinchuan (0.2899 +/- 0.1028) and Enshi (0.2222 +/- 0.1662), Dabieshan was the least differentiated (0.1079 +/- 0.0680). Compared with some foreign cattle breeds, the low level of haplotype diversity was detected in our breeds (0.2633 +/- 0.1030). PMID- 23947666 TI - Application of testis germ cell transplantation in breeding systems of food producing species: a review. AB - A major benefit of advanced reproduction technologies (ART) in animal breeding is the ability to produce more progeny per individual parent. This is particularly useful with animals of high genetic merit. Testis germ cell transplantation (TGCT) is emerging as a novel reproductive technology with application in animal breeding systems, including the potential for use as an alternative to artificial insemination (AI), an alternative to transgenesis, part of an approach to reducing generation intervals, or an approach toward development of interspecies hybrids. There is one major difference in TGCT between rodents and some other species associated with immunotolerance in heterologous transplantation. In particular, livestock and aquatic species do not require an immunesuppression procedure to allow donor cell survival in recipient testis. Testicular stem cells from a genetically elite individual transplanted into others can develop and produce a surrogate male-an animal that produces the functional sperm of the original individual. Spermatozoa produced from testis stem cells are the only cells in the body of males that can transmit genetic information to the offspring. The isolation and genetic manipulation of testis stem cells prior to transplantation has been shown to create transgenic animals. However, the current success rate of the transplantation procedure in livestock and aquatic species is low, with a corresponding small proportion of donor spermatozoa in the recipient's semen. The propagation of donor cells in culture and preparation of recipient animals are the two main factors that limit the commercial application of this technique. The current paper reviews and compares recent progress and examines the difficulties of TGCT in both livestock and aquatic species, thereby providing new insights into the application of TGCT in food producing animals. PMID- 23947667 TI - Comparative messenger RNA expression of FSHbeta, LHbeta, FSHR, LHR, and ERbeta in high and low prolific goat breeds. AB - Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) have a central role in follicle growth and maturation, but no clear differences between breeds with different ovulation rates have been found. Therefore, this study investigated mRNA expression of FSHbeta, LHbeta, FSH receptor (FSHR), LH receptor (LHR), and estrogen receptor-beta (ERbeta) genes in prolific Lezhi black (LB) goats and nonprolific Tibetan (TB) goats by real-time PCR. Follicles and pituitaries were recovered from goats at 12-24 h after onset of estrus. Real-time PCR analysis revealed that the expression levels of FSHbeta and LHbeta mRNA were significantly higher (p < 0.01) in pituitary of LB than in TB does, but the expression levels of FSHR and LHR mRNA in follicle of TB were greater (p < 0.05). Expression level of follicular ER beta was not different between the two breeds. Data provide evidence that the greater ovulation rate in the LB goat as compared to the TB breed is associated with a greater gonadotropin expression during follicular phase. PMID- 23947669 TI - Targeting iHSP 70 in vitiligo: a critical step for cure? AB - The group of Caroline Le Poole has produced a series of elegant papers suggesting an innovative rationale for the treatment of vitiligo by limiting native iHSP70 expression, with subsequent blockade of DC activation and melanocyte loss via T cell-specific autoimmune responses. The proof of concept was made in a mouse model of the use of a mutant iHSP70 blunting this response. The comment emphasizes that in vitiligo, a skin and possibly epidermal defect underlies the initial steps leading to inflammation and subsequent melanocyte demise and discusses the relevance of targeting iHSP in this context. PMID- 23947670 TI - Filaggrin compound heterozygous patients carry mutations in trans position. AB - More than 40 null mutations in the filaggrin (FLG) gene are described. It is therefore possible to find two different null mutations in one individual (compound heterozygosity). It has been generally perceived that homozygous and compound heterozygous individuals were genotypically comparable; however, this has not been scientifically investigated. Two different FLG null mutations in the same individual may be in trans position, meaning that each mutation locates to a different allele functionally equivalent to homozygosity, or may be in cis position, meaning that both mutations locate to the same allele functionally equivalent to heterozygosity. To experimentally investigate allelic in cis versus in trans configuration of the two most common filaggrin (FLG) mutations (R501X and 2282del4) in compound heterozygous individuals. Testing for in cis or in trans allele configuration was performed by means of allele-specific PCR amplification and analysis of PCR products by agarose gel electrophoresis. All R501X/2282del4 compound heterozygous samples collected over a 4-year period of routine FLG mutation testing were investigated. In total, 37 samples were tested. All thirty-seven R501X/2282del4 compound heterozygous individuals were found to carry the two mutations in trans position. FLG null mutation compound heterozygous individuals can be considered functionally equivalent to FLG null mutation homozygosity for any of the two mutations. PMID- 23947672 TI - Comparison between cold plasma, electrochemotherapy and combined therapy in a melanoma mouse model. AB - The study was undertaken to compare antitumor efficacy of electrochemotherapy (ECT) with cold plasma therapy (CP) in a melanoma mouse model. After melanoma implantation into the flank of C57BL/6N mice, CP by two different plasma sources (APPJ and DBD) was applied directly to the tumor surface. ECT was performed with bleomycin intravenously at a field strength of 1000 V/cm without or combined with CP. Primary endpoints were tumor growth acceleration (TGA), daily volume progression (DVP) and survival after treatment. Both plasma sources as single treatment showed a significant TGA delay, which proved less effective than ECT. CP (APPJ) combined with ECT (ECJ) significantly improved per cent mouse survival, with significant superiority compared with ECT. Plasma therapy alone albeit less effective seems a potential alternative to ECT in patients with melanoma and can be applied manifold in a session without general anaesthesia. Accordingly, CP alone and combined with ECT may serve as new option in palliative skin melanoma therapy. PMID- 23947671 TI - A pilot study of genetic variants in dopamine regulators with indoor tanning and melanoma. AB - Many people frequently tan indoors despite being aware of the increased risk of melanoma. Ultraviolet radiation is hypothesized to modify biological reward pathways, for example, through the dopamine neurotransmitter system, to reinforce tanning behaviour. In this pilot study, we relied on questionnaire and DNA data from a recently completed case-control study to examine 67 single-nucleotide polymorphisms (SNPs) and related haplotypes in five dopamine receptor and drug metabolism genes in relation to indoor tanning among controls. We also examined the association between individual SNPS and likelihood of melanoma, adjusting for or stratifying on indoor tanning status. In candidate and haplotype gene analyses, variants only in the DRD2 dopamine receptor and ANKK1 signalling genes were positively associated with indoor tanning use among controls; only associations for ANKK1 remained statistically significant (P < 0.05) after adjustment. Several SNPs in ANKK1 and DRD2 associated with indoor tanning among controls were also found to be associated with increased risk of melanoma. Upon stratifying for indoor tanning status, one ANKK1 SNP was positively associated with melanoma among non-tanners, while three DRD2 SNPS were positively associated with melanoma among tanners or non-tanners, depending on the SNP. These alleles represent important genomic regions to further explore addictive tanning behaviour. PMID- 23947673 TI - Different strains of Propionibacterium acnes modulate differently the cutaneous innate immunity. AB - Acne is a chronic inflammatory illness of the pilosebaceous follicle where innate immunity plays a central role. In acne, the density of Propionibacterium acnes is increased in the pilosebaceous unit. We hypothesized that the severity of acne is not only dependent on the proliferation of P. acnes but also dependent on the pro inflammatory potential of P. acnes strains and consequently constitutes potential triggering factor for acne scarring. We investigated pro-inflammatory potential of five different strains of P. acnes and P. avidum in skin explants and the preventive effect of zinc gluconate. The expression of immune markers was studied by immunohistochemistry, RT-qPCR and ELISA. P. acnes strains modulate differently the expression of immune markers both at gene and at protein levels. P. acnes type III had the highest pro-inflammatory potential by up-regulating the expression of PAR-2, TNF-alpha, MMP-13 and TIMP-2, whereas P. avidum had the weakest by up-regulating only MMP-13 and TIMP-2. Preincubation of zinc gluconate, which is a modulator of innate immunity, down-regulates the expression of most immune markers induced by P. acnes, PAR-2, TIMP-2, up-regulates MMP-1, TIMP-1. Our results demonstrate that different P. acnes strains have different inflammatory potential targeting markers of cutaneous innate immunity, and that inflammatory potential can be down-regulated by zinc gluconate. As such, the inflammatory potential of P. acnes strains on acne skin may influence the severity of inflammatory acne lesions and scars. PMID- 23947674 TI - The immune system of mouse vibrissae follicles: cellular composition and indications of immune privilege. AB - Although vibrissae hair follicles (VHFs) have long been a key research model in the life sciences, their immune system (IS) is essentially unknown. Therefore, we have characterized basic parameters of the VHF-IS of C57BL/6J mice by quantitative (immuno-)histomorphometry. Murine anagen VHF harbour few CD4+ and CD8+ T cells in the distal mesenchyme and sinuses but hardly any gamma-delta T cells in their distal epithelium. MHC class II+ Langerhans cells are seeded in the VHF infundibulum, which is also surrounded by MHC class II+ and CD11b+ cells (macrophages). The number of Langerhans cells then declines sharply in the VHF bulge, and the VHF bulb lacks MHC class II+ cells. Mast cells densely populate the VHF connective tissue sheath, where they strikingly cluster around the bulge. Both the bulge and the bulb of VHF display signs of immune privilege, that is, low MHC class I and MHC class II expression and local immunoinhibitor expression (CD200, TGFbeta1). This immunophenotyping study fills an important gap in the immunobiology of murine skin and identifies differences between the IS of VHF, mouse pelage and human terminal HFs. This facilitates utilizing murine VHF as a versatile organ culture model for general immunology and immune privilege research in situ. PMID- 23947675 TI - Keratinocyte cell lines derived from severe generalized recessive epidermolysis bullosa patients carrying a highly recurrent COL7A1 homozygous mutation: models to assess cell and gene therapies in vitro and in vivo. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is caused by deficiency of type VII collagen due to COL7A1 mutations such as c.6527insC, recurrently found in the Spanish RDEB population. Assessment of clonal correction-based therapeutic approaches for RDEB requires large expansions of cells, exceeding the replication capacity of human primary keratinocytes. Thus, immortalized RDEB cells with enhanced proliferative abilities would be valuable. Using either the SV40 large T antigen or papillomavirus HPV16-derived E6-E7 proteins, we immortalized and cloned RDEB keratinocytes carrying the c.6527insC mutation. Clones exhibited high proliferative and colony-forming features. Cytogenetic analysis revealed important differences between T antigen-driven and E6-E7-driven immortalization. Immortalized cells responded to differentiation stimuli and were competent for epidermal regeneration and recapitulation of the blistering RDEB phenotype in vivo. These features make these cell lines useful to test novel therapeutic approaches including those aimed at editing mutant COL7A1. PMID- 23947676 TI - Ageing and colony-forming efficiency of human hair follicle keratinocytes. AB - The decline of tissue regenerative potential of skin and hair is a hallmark of physiological ageing and may be associated with age-related changes in tissue specific stem cells and/or their environment. Human hair follicles (hHF) contain keratinocytes having the property of stem cells such as clonogenic potential. Growth capacity of hHF keratinocytes shows that most of the colony-forming cells are classified as holoclones, meroclones or paraclones when analysed in a clonal assay (Cell, Volume 76, page 1063). Despite the well-known impact of ageing on human hair growth, little is known about changes in hHF keratinocyte clonogenic potential with age. This study aimed at assessing the clone-forming efficiency (CFE) of hHF keratinocytes from three age groups of human donors. It demonstrates that ageing affects hHF keratinocyte CFE. PMID- 23947677 TI - Expressions of peroxisome proliferator-activated receptors (PPARs) are directly influenced by permeability barrier abrogation and inflammatory cytokines and depressed PPARalpha modulates expressions of chemokines and epidermal differentiation-related molecules in keratinocytes. AB - Previous studies have demonstrated that the activation of peroxisome proliferator activated receptors (PPARs) not only has positive effects on permeability barrier homoeostasis but also has anti-inflammatory effects by an as yet unknown mechanism. Reduced expression of PPARalpha in lesion of human atopic dermatitis (AD) and in epidermis of murine AD-like dermatitis has been demonstrated. This study revealed that expression of PPARalpha alone among PPARs (alpha, beta/delta and gamma) was suppressed by both permeability barrier abrogation and additional existence of Th2 cytokine in cultured normal human keratinocytes. In addition, expressions of transglutaminase 1 and loricrin and those of thymus and activation related chemokine and regulated on activation normal T-cell expressed in cultured human keratinocytes were reduced and enhanced, respectively, by transfection with siRNA for PPARalpha. In conclusion, depressed PPARalpha in keratinocytes might be involved in a relationship between permeability barrier abrogation and allergic inflammation and could be a therapeutic target which accounts for both the aspects in AD. PMID- 23947680 TI - Modulation of the oscillatory mechanics of lung tissue and the oxidative stress response induced by arginase inhibition in a chronic allergic inflammation model. AB - BACKGROUND: The importance of the lung parenchyma in the pathophysiology of asthma has previously been demonstrated. Considering that nitric oxide synthases (NOS) and arginases compete for the same substrate, it is worthwhile to elucidate the effects of complex NOS-arginase dysfunction in the pathophysiology of asthma, particularly, related to distal lung tissue. We evaluated the effects of arginase and iNOS inhibition on distal lung mechanics and oxidative stress pathway activation in a model of chronic pulmonary allergic inflammation in guinea pigs. METHODS: Guinea pigs were exposed to repeated ovalbumin inhalations (twice a week for 4 weeks). The animals received 1400 W (an iNOS-specific inhibitor) for 4 days beginning at the last inhalation. Afterwards, the animals were anesthetized and exsanguinated; then, a slice of the distal lung was evaluated by oscillatory mechanics, and an arginase inhibitor (nor-NOHA) or vehicle was infused in a Krebs solution bath. Tissue resistance (Rt) and elastance (Et) were assessed before and after ovalbumin challenge (0.1%), and lung strips were submitted to histopathological studies. RESULTS: Ovalbumin-exposed animals presented an increase in the maximal Rt and Et responses after antigen challenge (p<0.001), in the number of iNOS positive cells (p<0.001) and in the expression of arginase 2, 8-isoprostane and NF-kB (p<0.001) in distal lung tissue. The 1400 W administration reduced all these responses (p<0.001) in alveolar septa. Ovalbumin exposed animals that received nor-NOHA had a reduction of Rt, Et after antigen challenge, iNOS positive cells and 8-isoprostane and NF-kB (p<0.001) in lung tissue. The activity of arginase 2 was reduced only in the groups treated with nor-NOHA (p <0.05). There was a reduction of 8-isoprostane expression in OVA-NOR W compared to OVA-NOR (p<0.001). CONCLUSIONS: In this experimental model, increased arginase content and iNOS-positive cells were associated with the constriction of distal lung parenchyma. This functional alteration may be due to a high expression of 8-isoprostane, which had a procontractile effect. The mechanism involved in this response is likely related to the modulation of NF-kB expression, which contributed to the activation of the arginase and iNOS pathways. The association of both inhibitors potentiated the reduction of 8 isoprostane expression in this animal model. PMID- 23947682 TI - Ultrathin Na1.1V3O7.9 nanobelts with superior performance as cathode materials for lithium-ion batteries. AB - The Na1.1V3O7.9 nanobelts have been synthesized by a facile and scalable hydrothermal reaction with subsequent calcinations. The morphologies and the crystallinity of the nanobelts are largely determined by the calcination temperatures. Ultrathin nanobelts with a thickness around 20 nm can be obtained, and the TEM reveals that the nanobelts are composed of many stacked thinner belts. When evaluated as a cathode material for lithium batteries, the Na1.1V3O7.9 nanobelts exhibit high specific capacity, good rate capability, and superior long-term cyclic stability. A high specific capacity of 204 mA h g(-1) can be delivered at the current density of 100 mA g(-1). It shows excellent capacity retention of 95% after 200 cycles at the current density of 1500 mA g( 1). As demonstrated by the ex situ XRD results, the Na1.1V3O7.9 nanobelts have very good structural stability upon cycling. The superior electrochemical performances can be attributed to the ultra-thin nanobelts and the good structural stability of the Na1.1V3O7.9 nanobelts. PMID- 23947681 TI - The impact of missing data on analyses of a time-dependent exposure in a longitudinal cohort: a simulation study. AB - BACKGROUND: Missing data often cause problems in longitudinal cohort studies with repeated follow-up waves. Research in this area has focussed on analyses with missing data in repeated measures of the outcome, from which participants with missing exposure data are typically excluded. We performed a simulation study to compare complete-case analysis with Multiple imputation (MI) for dealing with missing data in an analysis of the association of waist circumference, measured at two waves, and the risk of colorectal cancer (a completely observed outcome). METHODS: We generated 1,000 datasets of 41,476 individuals with values of waist circumference at waves 1 and 2 and times to the events of colorectal cancer and death to resemble the distributions of the data from the Melbourne Collaborative Cohort Study. Three proportions of missing data (15, 30 and 50%) were imposed on waist circumference at wave 2 using three missing data mechanisms: Missing Completely at Random (MCAR), and a realistic and a more extreme covariate dependent Missing at Random (MAR) scenarios. We assessed the impact of missing data on two epidemiological analyses: 1) the association between change in waist circumference between waves 1 and 2 and the risk of colorectal cancer, adjusted for waist circumference at wave 1; and 2) the association between waist circumference at wave 2 and the risk of colorectal cancer, not adjusted for waist circumference at wave 1. RESULTS: We observed very little bias for complete-case analysis or MI under all missing data scenarios, and the resulting coverage of interval estimates was near the nominal 95% level. MI showed gains in precision when waist circumference was included as a strong auxiliary variable in the imputation model. CONCLUSIONS: This simulation study, based on data from a longitudinal cohort study, demonstrates that there is little gain in performing MI compared to a complete-case analysis in the presence of up to 50% missing data for the exposure of interest when the data are MCAR, or missing dependent on covariates. MI will result in some gain in precision if a strong auxiliary variable that is not in the analysis model is included in the imputation model. PMID- 23947683 TI - High degree of genetic differentiation in marine three-spined sticklebacks (Gasterosteus aculeatus). AB - Populations of widespread marine organisms are typically characterized by a low degree of genetic differentiation in neutral genetic markers, but much less is known about differentiation in genes whose functional roles are associated with specific selection regimes. To uncover possible adaptive population divergence and heterogeneous genomic differentiation in marine three-spined sticklebacks (Gasterosteus aculeatus), we used a candidate gene-based genome-scan approach to analyse variability in 138 microsatellite loci located within/close to (<6 kb) functionally important genes in samples collected from ten geographic locations. The degree of genetic differentiation in markers classified as neutral or under balancing selection-as determined with several outlier detection methods-was low (F(ST) = 0.033 or 0.011, respectively), whereas average FST for directionally selected markers was significantly higher (F(ST) = 0.097). Clustering analyses provided support for genomic and geographic heterogeneity in selection: six genetic clusters were identified based on allele frequency differences in the directionally selected loci, whereas four were identified with the neutral loci. Allelic variation in several loci exhibited significant associations with environmental variables, supporting the conjecture that temperature and salinity, but not optic conditions, are important drivers of adaptive divergence among populations. In general, these results suggest that in spite of the high degree of physical connectivity and gene flow as inferred from neutral marker genes, marine stickleback populations are strongly genetically structured in loci associated with functionally relevant genes. PMID- 23947684 TI - Accuracy of endoscopic diagnosis of Helicobacter pylori infection according to level of endoscopic experience and the effect of training. AB - BACKGROUND: Accurate prediction of Helicobacter pylori infection status on endoscopic images can contribute to early detection of gastric cancer, especially in Asia. We identified the diagnostic yield of endoscopy for H. pylori infection at various endoscopist career levels and the effect of two years of training on diagnostic yield. METHODS: A total of 77 consecutive patients who underwent endoscopy were analyzed. H. pylori infection status was determined by histology, serology, and the urea breast test and categorized as H. pylori-uninfected, infected, or -eradicated. Distinctive endoscopic findings were judged by six physicians at different career levels: beginner (<500 endoscopies), intermediate (1500-5000), and advanced (>5000). Diagnostic yield and inter- and intra-observer agreement on H. pylori infection status were evaluated. Values were compared between the two beginners after two years of training. The kappa (K) statistic was used to calculate agreement. RESULTS: For all physicians, the diagnostic yield was 88.9% for H. pylori-uninfected, 62.1% for H. pylori-infected, and 55.8% for H. pylori-eradicated. Intra-observer agreement for H. pylori infection status was good (K > 0.6) for all physicians, while inter-observer agreement was lower (K = 0.46) for beginners than for intermediate and advanced (K > 0.6). For all physicians, good inter-observer agreement in endoscopic findings was seen for atrophic change (K = 0.69), regular arrangement of collecting venules (K = 0.63), and hemorrhage (K = 0.62). For beginners, the diagnostic yield of H. pylori infected/eradicated status and inter-observer agreement of endoscopic findings were improved after two years of training. CONCLUSIONS: The diagnostic yield of endoscopic diagnosis was high for H. pylori-uninfected cases, but was low for H. pylori-eradicated cases. In beginners, daily training on endoscopic findings improved the low diagnostic yield. PMID- 23947686 TI - Fully reversible shape transition of soft spheres in elastomeric polymer opal films. AB - Core-interlayer-shell (CIS) beads featuring noncross-linked hard cores were used to prepare large and well-defined elastomeric opal films with remarkably distinct iridescent reflection colors. The matrix of the opal films was cross-linked by UV irradiation after compression molding of the CIS beads mixed with a bifunctional monomer. Stress-induced deformation of the embedded PS cores lead to hexagonally arranged spheroid oblates with an aspect ratio of 2.5. Optical characterization shows that bead deformation provokes a tremendous photonic band gap shift of about 160 nm. Fully reversible shape transition from the spheroid oblates back to the spherical beads and hence full recovery of the original photonic band gap can be achieved. PMID- 23947685 TI - Highly potent HIV-1 protease inhibitors with novel tricyclic P2 ligands: design, synthesis, and protein-ligand X-ray studies. AB - The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor's potent antiviral activity and excellent resistance profiles. PMID- 23947678 TI - What causes alopecia areata? AB - The pathobiology of alopecia areata (AA), one of the most frequent autoimmune diseases and a major unsolved clinical problem, has intrigued dermatologists, hair biologists and immunologists for decades. Simultaneously, both affected patients and the physicians who take care of them are increasingly frustrated that there is still no fully satisfactory treatment. Much of this frustration results from the fact that the pathobiology of AA remains unclear, and no single AA pathogenesis concept can claim to be universally accepted. In fact, some investigators still harbour doubts whether this even is an autoimmune disease, and the relative importance of CD8(+) T cells, CD4(+) T cells and NKGD2(+) NK or NKT cells and the exact role of genetic factors in AA pathogenesis remain bones of contention. Also, is AA one disease, a spectrum of distinct disease entities or only a response pattern of normal hair follicles to immunologically mediated damage? During the past decade, substantial progress has been made in basic AA related research, in the development of new models for translationally relevant AA research and in the identification of new therapeutic agents and targets for future AA management. This calls for a re-evaluation and public debate of currently prevalent AA pathobiology concepts. The present Controversies feature takes on this challenge, hoping to attract more skin biologists, immunologists and professional autoimmunity experts to this biologically fascinating and clinically important model disease. PMID- 23947687 TI - Evaluation of a miniature microscope objective designed for fluorescence array microscopy detection of Mycobacterium tuberculosis. AB - CONTEXT: A prototype miniature objective that was designed for a point-of-care diagnostic array microscope for detection of Mycobacterium tuberculosis and previously fabricated and presented in a proof of concept is evaluated for its effectiveness in detecting acid-fast bacteria. OBJECTIVE: To evaluate the ability of the microscope to resolve submicron features and details in the image of acid fast microorganisms stained with a fluorescent dye, and to evaluate the accuracy of clinical diagnoses made with digital images acquired with the objective. DESIGN: The lens prescription data for the microscope design are presented. A test platform is built by combining parts of a standard microscope, a prototype objective, and a digital single-lens reflex camera. Counts of acid-fast bacteria made with the prototype objective are compared to counts obtained with a standard microscope over matched fields of view. Two sets of 20 smears, positive and negative, are diagnosed by 2 pathologists as sputum smear positive or sputum smear negative, using both a standard clinical microscope and the prototype objective under evaluation. The results are compared to a reference diagnosis of the same sample. RESULTS: More bacteria are counted in matched fields of view in digital images taken with the prototype objective than with the standard clinical microscope. All diagnostic results are found to be highly concordant. CONCLUSIONS: An array microscope built with this miniature lens design will be able to detect M tuberculosis with high sensitivity and specificity. PMID- 23947688 TI - In(III)/PhCO2H binary acid catalyzed tandem [2 + 2] cycloaddition and Nazarov reaction between alkynes and acetals. AB - A facile tandem [2 + 2] cycloaddition and Nazarov reaction has been developed. The combination of In(OTf)3 and benzoic acid was found to synergistically promote the coupling of alkynes and acetals to form 2,3-disubstituted indanones in excellent yield and diastereoselectivity. PMID- 23947689 TI - Palladium-catalyzed carbene migratory insertion using conjugated ene-yne-ketones as carbene precursors. AB - Palladium-catalyzed cross-coupling reactions between benzyl, aryl, or allyl bromides and conjugated ene-yne-ketones lead to the formation of 2-alkenyl substituted furans. This novel coupling reaction involves oxidative addition, alkyne activation-cyclization, palladium carbene migratory insertion, beta hydride elimination, and catalyst regeneration. Palladium (2-furyl)carbene is proposed as the key intermediate, which is supported by DFT calculations. The palladium carbene character of the key intermediate is validated by three aspects, including bond lengths, Wiberg bond order indices, and molecular orbitals, by comparison to those reported for stable palladium carbene species. Computational studies also revealed that the rate-limiting step is ene-yne-ketone cyclization, which leads to the formation of the palladium (2-furyl)carbene, while the subsequent carbene migratory insertion is a facile process with a low energy barrier (<5 kcal/mol). PMID- 23947690 TI - The effects of topical Arnica on performance, pain and muscle damage after intense eccentric exercise. AB - The aim of the study was to determine if topical Arnica is effective in reducing pain, indicators of inflammation and muscle damage, and in turn improve performance in well-trained males experiencing delayed onset muscle soreness (DOMS). Twenty well-trained males matched by maximal oxygen uptake (VO2 Max) completed a double-blind, randomised placebo-controlled trial. Topical Arnica was applied to the skin superficial to the quadriceps and gastrocnemius muscles immediately after a downhill running protocol designed to induce DOMS. Topical Arnica was reapplied every 4 waking hours for the duration of the study. Performance measures (peak torque, countermovement and squat jump), pain assessments (visual analogue scale (VAS) and muscle tenderness) and blood analysis (interleukin-1 beta, interleukin-6, tumour necrosis factor-alpha, C reactive protein, myoglobin and creatine kinase) were assessed at seven time points over five days (pre-, post-, 4, 24, 48, 72 and 96 hours after the downhill run). Participants in the topical Arnica group reported less pain as assessed through muscle tenderness and VAS 72 hours post-exercise. The application of topical Arnica did not affect any performance assessments or markers of muscle damage or inflammation. Topical Arnica used immediately after intense eccentric exercise and for the following 96 hours did not have an effect on performance or blood markers. It did however demonstrate the possibility of providing pain relief three days post-eccentric exercise. PMID- 23947691 TI - Recent patents in autophagy and immune response. AB - Autophagy is a complex process in which cell homeostasis of proteins, organelles, exocytic and endocytic vacuoles is controlled. There is a direct link between autophagy and cell death with antigen processing, generation of inflammatory response and immune response. In different diseases, deficiencies in autophagy have been reported. In cancer, it has been proposed that autophagy, at its beginning, is capable of inducing cell death; however, in aggressive tumours and metastasis, the process is responsible for pharmacologic resistance and tumour survival. More research has to be done in order to allow us to understand the process and generate therapeutic options in different pathologies important for the human being. Some patents focused on methodology of autophagosome formation and analysis which seem to be important for pathological description and eventually in future therapeutic approaches have also been reviewed in this article. PMID- 23947692 TI - Imatinib mesylate: an innovation in treatment of autoimmune diseases. AB - Imatinib mesylate is a selective protein tyrosine kinase inhibitor, which can inhibit BCR/Abl, PDGF-R, c-KIT, c-fms, TCR/Abl, Lck, FLT-3 and MAPKs activities on various cell types. On immune system, imatinib has antiproliferative activity and immunomodulatory effects in lymphocytes, macrophages, mast cells and dendritic cells with abrogating multiple signal transduction pathways involved in pathogenesis of autoimmune diseases e.g. inhibiting IFN-gamma, TNF-alpha, IL 1beta and IL-17 pro-inflammatory cytokines and MMPs secretion. To date, the efficacy of imatinib in numerous animal model of autoimmune diseases (rheumatoid arthritis, multiple sclerosis, autoimmune diabetes and glomerulonephritis) has been demonstrated, but application of this drug in human autoimmune diseases should be tested in future clinical trials. This review provides an update on the use of tyrosine kinase inhibitor imatinib mesylate in treatment of autoimmune diseases and its related recent patents that could be developed as a novel and available therapy for the management of the autoimmunity improvement. PMID- 23947693 TI - Correlation between B7-H3 expression and matrix metalloproteinases 2 expression in pancreatic cancer. AB - BACKGROUND: B7-H3 and matrix metalloproteinases 2 (MMP-2) are reported highly expressed in malignant tumor, we investigate the relationship between B7-H3 expression and MMP-2 on malignant behavior and prognosis predictable value in pancreatic cancer. METHODS: We tested the expressions of B7-H3 and MMP-2 protein in 45 pancreatic surgical resected cancer samples; meanwhile, the clinicopathological data of enrolled patients were obtained for correlation analysis to obtain their relationship with pancreatic cancer progress. RESULTS: The expression of B7-H3 was up-regulated with infiltrating depth, lymph node metastasis and TNM stage (P < 0.01). Positive expression rate of MMP-2 in pancreatic cancer tissues was 44.35%, whereas negative in normal pancreatic tissues. Multivariate analysis of Logistic regression showed B7-H3 and MMP-2 expressions were hazardous makers correlated with infiltrating depth (P < 0.05). CONCLUSION: Our study showed combined detections of B7-H3 and MMP2 protein expression could identify patients at high risk in disease recurrence and prognosis more efficiently. PMID- 23947695 TI - Comparative study of flow in right-sided and left-sided aortas: numerical simulations in patient-based models. AB - A right-sided aorta is a rare malformation which may be associated with other various types of congenital heart disease. We utilised haemodynamic, echocardiographic measurements, computerised tomography and image reconstruction software packages that were integrated in a computational fluid dynamics model to determine blood flow patterns in patient-based aortas. In the left-sided aorta, a systolic clockwise rotational component was present, while helical flow was depicted in the aortic arch that was converted in the descending aorta as counter rotating vortices with accompanying retrograde flow. The right-sided configuration has not altered the orientation of the three-dimensional vortex, but intensification of polymorphic flow patterns, alterations in wall shear stress distribution and development of a lateral pressure gradient at the area of an aneurysmal anomaly was observed. Moreover, increments of Reynolds, Womersley and Dean numbers were evident. These phenomena along with the formation of the aneurysm might influence cardiovascular risk in patients with right-sided aortas. PMID- 23947694 TI - Joint-specific changes in locomotor complexity in the absence of muscle atrophy following incomplete spinal cord injury. AB - BACKGROUND: Following incomplete spinal cord injury (iSCI), descending drive is impaired, possibly leading to a decrease in the complexity of gait. To test the hypothesis that iSCI impairs gait coordination and decreases locomotor complexity, we collected 3D joint angle kinematics and muscle parameters of rats with a sham or an incomplete spinal cord injury. METHODS: 12 adult, female, Long Evans rats, 6 sham and 6 mild-moderate T8 iSCI, were tested 4 weeks following injury. The Basso Beattie Bresnahan locomotor score was used to verify injury severity. Animals had reflective markers placed on the bony prominences of their limb joints and were filmed in 3D while walking on a treadmill. Joint angles and segment motion were analyzed quantitatively, and complexity of joint angle trajectory and overall gait were calculated using permutation entropy and principal component analysis, respectively. Following treadmill testing, the animals were euthanized and hindlimb muscles removed. Excised muscles were tested for mass, density, fiber length, pennation angle, and relaxed sarcomere length. RESULTS: Muscle parameters were similar between groups with no evidence of muscle atrophy. The animals showed overextension of the ankle, which was compensated for by a decreased range of motion at the knee. Left-right coordination was altered, leading to left and right knee movements that are entirely out of phase, with one joint moving while the other is stationary. Movement patterns remained symmetric. Permutation entropy measures indicated changes in complexity on a joint specific basis, with the largest changes at the ankle. No significant difference was seen using principal component analysis. Rats were able to achieve stable weight bearing locomotion at reasonable speeds on the treadmill despite these deficiencies. CONCLUSIONS: Decrease in supraspinal control following iSCI causes a loss of complexity of ankle kinematics. This loss can be entirely due to loss of supraspinal control in the absence of muscle atrophy and may be quantified using permutation entropy. Joint-specific differences in kinematic complexity may be attributed to different sources of motor control. This work indicates the importance of the ankle for rehabilitation interventions following spinal cord injury. PMID- 23947697 TI - Life cycle analysis of solvent reduction in pharmaceutical synthesis using continuous adsorption for palladium removal. AB - The life cycle emissions associated with the reduction of wastes from an adsorption process to remove palladium complexes in drug manufacture have been evaluated. The study assessed a green improvement to a process step in an active pharmaceutical ingredient synthesis where palladium catalyst is removed from a reaction mixture. The greener process uses a continuous adsorption system, composed of a more efficient adsorbent, consuming less organic solvent and rinse water, which results in less waste disposal. The newer process is also more energy and cost efficient from an operational perspective. There is a 94% reduction in the carbon footprint of the new process when compared to the current operation. PMID- 23947696 TI - Potassium monopersulfate oxidation of 2,4,6-tribromophenol catalyzed by a SiO2 supported iron(III)-5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin. AB - Iron(III)-porphyrin complexes are generally regarded as green catalysts, since they mimic the catalytic center of cytochrome-P450 and widely used as green catalysts for degrading halogenated phenols in wastewater, such as landfill leachates. However, iron(III)-porphyrins are deactivated by self-oxidation in the presence of an oxygen donor, such as KHSO5. In the present study, to enhance the reusability of an iron(III)-porphyrin catalyst, iron(III)-5,10,15,20-tetrakis(4 carboxyphenyl) porphyrin (FeTCPP) was immobilized on a functionalized silica gel. The oxidative degradation of 2,4,6-tribromophenol (TrBP), a widely used brominated flame retardant that is found in landfill leachates, was examined using the prepared catalyst. In addition, the influence of humic substances (HSs), major components of leachates, on the TrBP oxidation was investigated. Concerning the effect of pH, more than 90% of the TrBP was degraded in the pH range of 3-8 in the absence of HS, while the optimal pH for the reaction was in the range of pH 5-7 in the presence of HS. Although the oxidation of TrBP was inhibited in the presence of HSs, more than 90% of the TrBP was degraded in the presence of 50 mg L(-1) of HS. Thus, the prepared catalyst, SiO2-FeTCPP, showed a high catalytic activity and could be reused up to 10 times even in the presence of HS. PMID- 23947698 TI - Pollutant interactions during the biodegradation of phenolic mixtures with either 2- or 3-mononitrophenol in a continuously operated packed bed reactor. AB - Pollutant interactions during the aerobic biodegradation of phenolic mixtures with either 2-nitrophenol (2-NP) or 3-nitrophenol (3-NP) by a NP-adapted microbial consortium in simulated wastewater were studied in a packed-bed bench scale bioreactor continuously operated in a flow mode. Phenol/2-NP and phenol/3 NP mixtures with varied phenol/nitrophenol ratios were shown to exhibit different biodegradability patterns. The presence of 2-NP led to a much lower overall elimination capacity and lower process stability in comparison to mixtures with 3 NP. In contrast to the expected greater degradation of a more biodegradable substrate in mixtures, phenol was degraded with a lower efficiency at higher phenol concentrations than NPs, although this difference became less pronounced with the gradual biofilm adaptation to phenol. This unusual substrate interaction, which appears to be common in the biotreatment of substituted phenol mixtures, was explained by prior biofilm adaptation to less degradable substrates, NPs. The biofilm composition was significantly altered during the long-term reactor operation. Although eukaryotes were not present in the inoculum, four fungal species were isolated from the biofilm after 1.5 years of operation. Of the initially present strains, only Chryseobacterium sp. and several Pseudomonas species persisted till the end of operation. PMID- 23947700 TI - Electrochemical and quantum chemical studies of N,N'-bis(4-hydroxybenzaldehyde) 2,2-dimethylpropandiimine Schiff base as corrosion inhibitor for low carbon steel in HCl solution. AB - A synthesized Schiff base N,N'-bis(4-hydroxybenzaldehyde)-2,2 dimethylpropandiimine (p-HBDP) was studied as green inhibitor for the corrosion of low carbon steel in 1 M HCl solution using electrochemical, surface and quantum chemical methods. Results showed that the inhibition occurs through the adsorption of the inhibitor molecules on the metal surface. The inhibition efficiency was found to increase with increasing inhibitor concentration and de creased with increasing temper-ature, which is due to the fact that the rate of corrosion of steel is higher than the rate of adsorption. Thermodynamic parameters for adsorp-tion and activation processes were determined. Polarization data indicated that this compound act as mixed-type inhibitors and the adsorption isotherm basically obeys the Langmuir adsorption isotherm. The calculations of reactivity indices of p-HBDP such as softness and natural charge distributions together with local reactivity by means of Fukui indices were used to explain the electron transfer mechanism between the p-HBDP molecules and the steel surface. PMID- 23947699 TI - Behavior of DNAPL mixture of organometallic and chlorinated solvent in the presence of surfactants and alcohols as density modifying agents. AB - This work evaluates the behavior of surfactant and alcohols in combination with a mixture of tributyltinchloride (TBT) and tetrachloroethylene (PCE) with the goal of modifying the mixed oil from being a dense non-aqueous phase liquid (DNAPL) to a light non-aqueous phase liquid (LNAPL). Phase behavior of the mixed oil was studied under various combinations of surfactant, alcohol, and salinity. Phase density conversion was examined using pseudo-ternary phase diagrams constructed between the mixed oil, surfactant solution (4 wt%), and two types of alcohols (n butyl alcohol (BuOH) and tert-butyl alcohol (TBA)). Aqueous phase solubilization and oil phase density modification were studied at varying alcohol to surfactant (A/S) ratios. The results showed that the optimum surfactant system was sodium dihexylsulfosuccinate (SDHS) and hexadecyl diphenyloxidedisulfonate (C16DPDS) (3.6 wt% and 0.4 wt%, respectively) with salt (NaCl) of 3 wt%. From pseudo ternary phase diagrams, BuOH was found to produce a larger LNAPL region than TBA. From solubilization studies, the surfactant system plus either TBA or BuOH caused PCE preferential solubilization and this preference was more pronounced at higher total surfactant concentration in the system with TBA addition. In terms of density modification, BuOH produced lower oil density than TBA at high A/S ratio. This phase behavior knowledge can be used to optimize site remediation of organometallic DNAPLs. PMID- 23947701 TI - Phenylmercury degradation by heterogeneous photocatalysis assisted by UV-A light. AB - Photocatalytic degradation of phenylmercury was studied using TiO2 in aqueous suspension assisted by UV-A irradiation. Reaction conditions, such as pH and amount of TiO2 were set using a factorial design of experiments resulting in a greater influence of pH on phenylmercury degradation. Hg (II) reduction and simultaneous oxidation of aromatic group was observed. Optimum reaction conditions were obtained under nitrogen atmosphere at pH 10 and 0.35 g/L(-1) TiO2. Under these conditions almost 100% reduction of mercury was reached after 30 min UV irradiation. Total mercury reduction was achieved after 40 min reaction under saturated oxygen. Furthermore, phenol and diphenylmercury were identified as intermediate products of oxidation. It was observed that a major fraction of the reduced mercury was removed as metallic vapor by gas stripping, whereas a minor fraction was adsorbed on the catalyst surface, probably as Hg(OH)2. Under optimal conditions obtained by multivariable analysis, total mineralization of organic matter was achieved after about 60-min irradiation. PMID- 23947702 TI - Removal of naphthenic acids using adsorption process and the effect of the addition of salt. AB - In this study, various types of adsorbents were examined for the removal of Naphthenic acids (NAs) in the preliminary stage of this study. Among them, activated carbon and nickel (Ni) based alumina (Ni-Al2O3) possess relatively high adsorption capacity of NAs. The removal of NAs was evaluated comparing the total organic carbon (TOC) of the solution before and after the adsorption process. The effect of Ni loading was investigated using Ni-Al2O4 with various nickel loadings. The highest adsorption capacity (20 mg of TOC/1 mg of adsorbent) was belong to Ni-Al2O4 with 10.7% Ni loading. By the addition of salt (1500 ppm NaCl) to NAs solutions having concentrations from of 15 to 38 ppm, it was observed that the adsorption decreased dramatically (up to 80%) depending on the concentration of TOC. The kinetics of the adsorption of TOC on Ni-based alumina was also investigated. The decrease of TOC was more that 40% in the first half hour, indicating that adsorption was very rapid in the beginning. The adsorption increased slightly for up to 5 h and then leveled off when the TOC reached to 50% of initial TOC concentration. However, when sodium chloride (NaCl) was added to the solution, the adsorption decreased to almost 9% within the first half hour, reaching to almost 5% after 3 h. These phenomena suggest that the effectiveness of adsorbents may be improved by decreasing the total dissolved salts in tailings pond wastewater. PMID- 23947703 TI - Efficiency of membrane technology, activated charcoal, and a micelle-clay complex for removal of the acidic pharmaceutical mefenamic acid. AB - The efficiency of sequential advanced membrane technology wastewater treatment plant towards removal of a widely used non-steroid anti-inflammatory drug (NSAID) mefenamic acid was investigated. The sequential system included activated sludge, ultrafiltration by hollow fibre membranes with 100 kDa cutoff, and spiral wound membranes with 20 kDa cutoff, activated carbon and a reverse osmosis (RO) unit. The performance of the integrated plant showed complete removal of mefenamic acid from spiked wastewater samples. The activated carbon column was the most effective component in removing mefenamic acid with a removal efficiency of 97.2%. Stability study of mefenamic acid in pure water and Al-Quds activated sludge revealed that the anti-inflammatory drug was resistant to degradation in both environments. Batch adsorption of mefenamic acid by activated charcoal and a composite micelle (otadecyltrimethylammonium (ODTMA)-clay (montmorillonite) was determined at 25.0 degrees C. Langmuir isotherm was found to fit the data with Qmax of 90.9 mg g(-1) and 100.0 mg g(-1) for activated carbon and micelle-clay complex, respectively. Filtration experiment by micelle-clay columns mixed with sand in the mg L(-1) range revealed complete removal of the drug with much larger capacity than activated carbon column. The combined results demonstrated that an integration of a micelle-clay column in the plant system has a good potential to improve the removal efficiency of the plant towards NSAID drugs such as mefenamic acid. PMID- 23947704 TI - Removal of sulfur compounds from diesel using ArF laser and oxygen. AB - A laser-based technique for deep desulfurization of diesel and other hydrocarbon fuels by removal of dimethyldibenzothiophene (DMDBT), a persistent sulfur contaminant in fuel oils has been developed. We report a selective laser excitation of DMDBT in diesel and model compounds such as n-hexane in a reaction chamber under oxygen environment where oxidative reactions can take place. ArF laser emitting at 193 nm was employed for excitation of oxygen and DMDBT, while for process optimization, the laser energy was varied from 50 to 200 mJ/cm(2). The laser-irradiated DMDBT solution under continuous oxygen flow was analyzed by UV absorption spectrometer to determine the photochemical oxidative degradation of DMDBT. In just 5 min of laser irradiation time, almost 95% DMDBT was depleted in a diesel containing 200 ppm of DMDBT. This article provides a new method for the removal of sulfur compounds from diesel by laser based photochemical process. PMID- 23947705 TI - Photocatalytic-based inactivation of E. coli by UV 282 nm XeBr Excilamp. AB - The impact of suspended TiO2 particles on the efficiency of UV inactivation of E. coli by XeBr excilamp (282 nm) was assessed using direct and integrating sphere spectroscopy for absorbance measurements in the calculations of UV doses. Complete disinfection (no quantifiable E. coli colonies) was observed at 30 (0.25 g/L of TiO2) and 40 mJ/cm(2) (0.1 g/L of TiO2), whereas UV alone and the treatment in the presence of 0.5 g/L of TiO2 produced tailing in the dose response curves. The optimum concentration of TiO2 was found to be 0.25 g/L, which correlates with the highest *OH exposure (CT value) and steady state concentration of *OH. This study demonstrates the importance of proper calculation of UV dose and inclusion of *OH exposure effects when reporting results from disinfection studies using technologies with multiple modes of inactivation such as with UV/TiO2. PMID- 23947706 TI - Effects of electrokinetic operation mode on removal of polycyclic aromatic hydrocarbons (PAHs), and the indigenous fungal community in PAH-contaminated soil. AB - Electrokinetic remediation is an emerging physical remediation technology for the removal of heavy metals and organic chemicals from contaminated soil. We set up a soil chamber (24 * 12 * 8 cm) with two stainless steel electrodes (12 * 0.5 cm), and a constant voltage gradient of 1.0 v cm(-1) or 2.0 v cm(-1) was applied to study the effects of unidirectional and altered directional electric field operation modes on the moisture content and pH, the removal rate of PAHs, and the abundance and diversity of indigenous fungi in a PAH-contaminated soil at the Benxi Iron and Steel Group Corporation (N41 degrees 17'24.4", E123 degrees 43'05.8"), Liaoning Province, Northeast China. Electrokinetic remediation increased the PAH removal rate, but had less effect on soil moisture content and pH, in comparison with the control. In the 1 v cm(-1) altered directional operation, in particular, the PAH removal rate by the end of the experiment (on day 23) had increased from 5.2% of the control to 13.84% and 13.69% at distances of 4 and 20 cm from the anode, respectively, and to 18.97% in the middle region of the soil chamber. On day 23, the indigenous fungal 18S rRNA gene copy numbers and community diversity were significantly higher in a voltage gradient of 1 v cm(-1) than in a voltage gradient 2 v cm(-1). An altered directional operation was more conducive to the fungal community's uniform distribution than was a unidirectional operation of the electric field. We found the major PAH-degrading fungi Fusarium oxysporum and Rhizophlyctis rosea to be present under EK remediation. We suggest that a 1 v cm(-1) altered directional operation could be an appropriate electrokinetic operation mode for PAH removal, and the maintenance of abundance and diversity of the indigenous fungal community. PMID- 23947707 TI - Hybrid Sargassum-sand sorbent: a novel adsorbent in packed column to treat metal bearing wastewaters from inductively coupled plasma-optical emission spectrometry. AB - Laboratory batch and column experiments were carried out to examine the efficiency of algal-based treatment technique to clean-up wastewaters emanating from inductively coupled plasma-optical emission spectrometry (ICP-OES). Chemical characterization revealed the extreme complexity of the wastewater, with the presence of 14 different metals under very low pH (pH = 1.1), high conductivity (6.98 mS/cm), total dissolved solid (4.46 g/L) and salinity (3.77). Batch experiments using Sargassum biomass indicated that it was possible to attain high removal efficiencies at optimum pH of 4.0. Efforts were also made to continuously treat ICP-OES wastewater using up-flow packed column. However, swelling of Sargassum biomass leads to stoppage of column. To address the problem, Sargassum was mixed with sand at a ratio of 40: 60 on volume basis. Remarkably, the hybrid Sargassum-sand sorbent showed very high removal efficiency towards multiple metal ions with the column able to operate for 11 h at a flow rate of 10 mL/min. Metal ions such as Cu, Cd, and Pb were only under trace levels in the treated water until 11 h. The results of the treatment process were compared with trade effluent discharge standards. Further the process evaluation and cost analysis were presented. PMID- 23947708 TI - A simple simulation of adsorption equilibrium of Pb(II) on Andosols in the presence of dissolved humic substances for monitoring soil contamination. AB - The adsorption equilibrium of Pb(II) on Andosols was investigated and described quantitatively in order to develop a simple method for the rapid monitoring of heavy metals in soils. The effect of solution pH on adsorption isotherms was investigated experimentally and in simulations. At pH 7, the considerable desorption of Pb(II) due to the extensive dissolution of humic substances (HS) from soils into aqueous phases is known to be an obstacle to carrying out simulations. In batch experiments, the total organic carbon (TOC) of the aqueous phases was shown to be enhanced by the addition of pre-extracted HS to soil suspensions. By combining the ion-exchange and Freundlich models, the adsorption equilibriums of free Pb(2+) ions and Pb(2+)-HS were simulated and were shown to be in good agreement with the experimental results. By estimating the concentrations and adsorption amounts of Pb(2+) and Pb(2+)-HS from measured CPb and TOC, it is possible to accurately simulate the soil contamination status even in in the presence of dissolved HS in the water in the solid-liquid extraction samples. PMID- 23947709 TI - Dual electrodes degradation of Amaranth using a thin-film photocatalytic reactor with dual slant-placed electrodes. AB - A dual slant-placed electrodes thin-film photocatalytic (PC) reactor was proposed and successfully applied to degrade Amaranth. In this PC reactor, both the TiO2/Ti photoanode and the Cu cathode are slant-placed in the reaction chamber, and aqueous thin-film formed on the surface of both electrodes as wastewater flowed over them. The degradation efficiency was significantly improved as a result of additional degradation at the cathode. When the TiO2 photocatalyst was irradiated with UV light, photogenerated electrons were spontaneously transferred from the anode to the cathode, driven by the electric field self-generated between the TiO2/Ti anode and the Cu cathode, based on the principle of establishing a Schottky barrier. On the Cu cathode surface, the transferred photoelectrons either reacted with dissolved oxygen to form H2O2, which then oxidized the dye, resulting in indirect oxidation decolourization, or reacted with the dye, resulting in direct reduction decolourization. The colour removal efficiency of the cathode was about half that of the photoanode. These processes together with direct oxidation of the photogenerated holes on the photoanode gave dual electrode degradation of the dye, and the degradation efficiency was significantly improved. PMID- 23947710 TI - Influence of organic loading rate on the anaerobic treatment of sugarcane vinasse and biogas production in fluidized bed reactor. AB - This study evaluated an anaerobic fluidized bed reactor (AFBR) that contained polystyrene particles as a support material for the treatment of vinasse that resulted from the alcoholic fermentation of sugarcane molasses. The AFBR was inoculated with sludge from an upflow anaerobic sludge blanket reactor that treated poultry slaughterhouse wastewater. The AFBR was operated with a hydraulic retention time of 24 h at a temperature of 30 degrees C with influent vinasse concentrations that ranged from 2273 to 20,073 mg COD L(-1). The reactor was subjected to increased organic loading rates (OLR) that ranged from 3.33 to 26.19 kg COD m(-3) d(-1), with COD removal efficiencies that ranged from 51% to 70% and maximum removal at an OLR of 13.93 +/- 2.18 kg COD m(-3) d(-1). The maximum biogas productivity was 5.37 m(3) CH4 m(-3) d(-1) for an OLR of 25.32 kg COD m( 3) d(-1) (average removal of 51%).. PMID- 23947711 TI - Leachate tests with sewage sludge contaminated by radioactive cesium. AB - The sewer systems of eastern Japan have transported radioactive fallout from the Fukushima Dai-ichi nuclear power plant accident to wastewater treatment plants, where the radioisotopes have accumulated. To better understand the potential problems associated with the disposal of contaminated sewage sludge in landfills, leachate tests were conducted with radioactive incinerator ash, cement solidification incinerator ash, and dewatered sludge cake. Radioactivity was undetectable in the eluate from incinerator ash and dewatered sludge cake, but about 30% of the radioactivity initially in cement solidification incinerator ash appeared in the eluate during the leaching experiments. Moreover, modification of test conditions revealed that the presence of Ca(2+) ions and strong alkali in the water that contacted the incinerator ash enhanced leaching of cesium. Lastly, the capacity of pit soil to absorb radioactive cesium was estimated to be at least 3.0 Bq/g (dry). PMID- 23947712 TI - Effect of trichloroethylene and tetrachloroethylene on methane oxidation and community structure of methanotrophic consortium. AB - The methane oxidation rate and community structure of a methanotrophic consortium were analyzed to determine the effects of trichloroethylene (TCE) and tetrachloroethylene (PCE) on methane oxidation. The maximum methane oxidation rate (Vmax ) of the consortium was 326.8 MUmol.g-dry biomass(-1).h(-1), and it had a half-saturation constant (Km ) of 143.8 MUM. The addition of TCE or PCE resulted in decreased methane oxidation rates, which were decreased from 101.73 to 5.47-24.64 MUmol.g-dry biomass(-1).h(-1) with an increase in the TCE-to methane ratio, and to 61.95-67.43 MUmol.g-dry biomass(-1).h(-1) with an increase in the PCE-to-methane ratio. TCE and PCE were non-competitive inhibitors for methane oxidation, and their inhibition constants (Ki ) were 33.4 and 132.0 MUM, respectively. When the methanotrophic community was analyzed based on pmoA using quantitative real-time PCR (qRT-PCR), the pmoA gene copy numbers were shown to decrease from 7.3 +/- 0.7 * 10(8) to 2.1-5.0 * 10(7) pmoA gene copy number . g dry biomass(-1) with an increase in the TCE-to-methane ratio and to 2.5-7.0 * 10(7) pmoA gene copy number . g-dry biomass(-1) with an increase in the PCE-to methane ratio. Community analysis by microarray demonstrated that Methylocystis (type II methanotrophs) were the most abundant in the methanotrophic community composition in the presence of TCE. These results suggest that toxic effects caused by TCE and PCE change not only methane oxidation rates but also the community structure of the methanotrophic consortium. PMID- 23947714 TI - Use of a passive bioreactor to reduce water-borne plant pathogens, nitrate, and sulfate in greenhouse effluent. AB - The goal of this study was to evaluate the use of passive bioreactors to reduce water-borne plant pathogens (Pythium ultimum and Fusarium oxysporum) and nutrient load (NO(-) 3 and SO(2-) 4) in greenhouse effluent. Sterilized and unsterilized passive bioreactors filled with a reactive mixture of organic carbon material were used in three replicates. After a startup period of 2 (sterilized) or 5 (unsterilized) weeks, the bioreactor units received for 14 weeks a reconstituted commercial greenhouse effluent composed of 500 mg L(-1) SO(2-) 4 and 300 mg L(-1) NO(-) 3 and were inoculated three times with P. ultimum and F. oxysporum (10(6) CFU mL(-1)). Efficacy in removing water-borne plant pathogens and nitrate reached 99.9% for both the sterilized and unsterilized bioreactors. However, efficacy in reducing the SO(2-) 4 load sharply decreased from 89% to 29% after 2 weeks of NO( ) 3-supply treatment for the unsterilized bioreactors. Although SO(2-) 4 removal efficacy for the sterilized bioreactors did not recover after 4 weeks of NO(-) 3 supply treatment, the unsterilized bioreactor nearly reached a similar level of SO(2-) 4 removal after 4 weeks of NO(-) 3-supply treatment compared with affluent loaded only with SO(2-) 4, where no competition for the carbohydrate source occurred between the denitrification process and sulfate-reducing bacteria activity. Performance differences between the sterilized and unsterilized bioreactors clearly show the predominant importance of sulfate-reducing bacteria. Consequently, when sulfate-reducing bacteria reach their optimal activity, passive bioreactors may constitute a cheap, low-maintenance method of treating greenhouse effluent to recycle wastewater and eliminate nutrient runoff, which has important environmental impacts. PMID- 23947713 TI - An eco-friendly treatment of tannery wastewater using bioaugmentation with a novel microbial consortium. AB - A novel microbial consortium (BM-S-1) enriched from natural soils was successfully used to treat tannery wastewater from leather manufacturing industries in Korea on a pilot scale. The objective of this study was to determine whether augmentation with a novel microbial consortium BM-S-1could successfully treat the recalcitrant wastewater without chemical pre-treatment in a tannery wastewater treatment system. Chemical oxygen demand (COD), total nitrogen (TN) and total phosphorus (TP) were monitored for water quality. The microbial population dynamics were analyzed using pyrosequencing, and denitrifying bacteria were quantified using real-time PCR (RT-PCR). The removal efficiencies for COD, TN and TP were greater than 91%, 79%, and 90%, respectively. The dominant phyla in the buffering tank (B), primary aeration (PA), secondary aeration (SA) and sludge digestion tank (SD) were Proteobacteria, Firmicutes, Bacteroidetes, Planctomycetes and Deinococcus-Thermus. Cluster analysis based on the UniFrac distance of the species in the different stages showed that the PA is similar to the SA, whereas the B is similar to the SD. qPCR of the nosZ genes showed the highest abundance of denitrifiers in B, which was increased 734-fold compared to the influent (I). It was hypothesized that anaerobic denitrifiers and the diverse microbial community may play important roles in the biological treatment of tannery wastewater. This technology may also contribute to the full-scale treatment of industrial wastewater containing food processing wastewater and marine sediment with high organic content. PMID- 23947715 TI - Chemical stabilization of cadmium in acidic soil using alkaline agronomic and industrial by-products. AB - In situ immobilization of heavy metals using reactive or stabilizing materials is a promising solution for soil remediation. Therefore, four agronomic and industrial by-products [wood biochar (WB), crushed oyster shell (OS), blast furnace slag (BFS), and fluidized-bed crystallized calcium (FBCC)] and CaCO3 were added to acidic soil (Cd = 8.71 mg kg(-1)) at the rates of 1%, 2%, and 4% and incubated for 90 d. Chinese cabbage (Brassica chinensis L.) was then planted in the soil to test the Cd uptake. The elevation in soil pH caused by adding the by products produced a negative charge on the soil surface, which enhanced Cd adsorption. Consequently, the diethylenetriamine pentaacetic acid (DTPA) extractable Cd content decreased significantly (P < 0.05) in the incubated soil. These results from the sequential extraction procedure indicated that Cd converted from the exchangeable fraction to the carbonate or Fe-Mn oxide fraction. The long-term effectiveness of Cd immobilization caused by applying the 4 by-products was much greater than that caused by applying CaCO3. Plant shoot biomass clearly increased because of the by-product soil amendment. Cd concentration in the shoots was < 10.0 mg kg(-1) following by-product application, as compared to 24 mg kg(-1) for plants growing in unamended soil. PMID- 23947716 TI - Nanoscale chains control the solubility of phosphate glasses for biomedical applications. AB - Bioactive phosphate-based glasses (PBGs) have several possible biomedical applications because of the chemical reactions they undergo with their surroundings when implanted into the body. The dissolution rate of PBGs in physiological conditions is a crucial parameter for these applications, to ensure, e.g., delivery of drugs or nutrients to the body at the correct rate. While it has been well-known that increasing the CaO content of these glasses at the expense of Na2O slows the dissolution rate, this paper provides an atomistic explanation of this for the first time. In this work, molecular dynamics simulations of five ternary P2O5-CaO-Na2O glasses reveal the structural properties at the atomic level that enhance the durability of PBGs as more Ca is added: (i) Ca binds together more fragments of the phosphate glass network than Na, (ii) Ca binds together more PO4 tetrahedra than Na, and (iii) Ca has a lower concentration of intratetrahedral phosphate bonding than Na. This behavior is rooted in the calcium ion's higher charge and field strength. These results open the path to precise control and optimization of the PBG dissolution rate for specific biomedical applications. PMID- 23947717 TI - Maximising impact of small cohort studies. PMID- 23947718 TI - Response to Gastaca. PMID- 23947719 TI - Congenital lower lip pits (van der Woude syndrome): what pathologists need to know. AB - Congenital lower lip pits are cardinal findings of van der Woude syndrome [OMIM 119300]. The nosologic context of how lower lip pits are catalogued is easily lost because of insufficient clinical history, subtle findings misidentified as artifacts, lack of awareness by the pathologist, the perception that these are identify/confirm descriptive-diagnosis only, not necessarily an element of an actionable report, and/or the rarity with which these specimens are accessioned (in the authors' experience, less than 1 case per year). We present the salient findings on 19 lower lip pits specimens from the files of a single institution collected over the last 25 years. PMID- 23947720 TI - Differences in risk factors for neurophysiologically confirmed carpal tunnel syndrome and illness with similar symptoms but normal median nerve function: a case-control study. AB - BACKGROUND: To explore whether risk factors for neurophysiologically confirmed carpal tunnel syndrome (CTS) differ from those for sensory symptoms with normal median nerve conduction, and to test the validity and practical utility of a proposed definition for impaired median nerve conduction, we carried out a case control study of patients referred for investigation of suspected CTS. METHODS: We compared 475 patients with neurophysiological abnormality (NP+ve) according to the definition, 409 patients investigated for CTS but classed as negative on neurophysiological testing (NP-ve), and 799 controls. Exposures to risk factors were ascertained by self-administered questionnaire. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated by logistic regression. RESULTS: NP+ve disease was associated with obesity, use of vibratory tools, repetitive movement of the wrist or fingers, poor mental health and workplace psychosocial stressors. NP-ve illness was also related to poor mental health and occupational psychosocial stressors, but differed from NP+ve disease in showing associations also with prolonged use of computer keyboards and tendency to somatise, and no relation to obesity. In direct comparison of NP+ve and NP-ve patients (the latter being taken as the reference category), the most notable differences were for obesity (OR 2.7, 95 % CI 1.9-3.9), somatising tendency (OR 0.6, 95% CI 0.4-0.9), diabetes (OR 1.6, 95% CI 0.9-3.1) and work with vibratory tools (OR 1.4, 95% CI 0.9-2.2). CONCLUSIONS: When viewed in the context of earlier research, our findings suggest that obesity, diabetes, use of hand-held vibratory tools, and repeated forceful movements of the wrist and hand are causes of impaired median nerve function. In addition, sensory symptoms in the hand, whether from identifiable pathology or non-specific in origin, may be rendered more prominent and distressing by hand activity, low mood, tendency to somatise, and psychosocial stressors at work. These differences in associations with risk factors support the validity of our definition of impaired median nerve conduction. PMID- 23947721 TI - Clinical evidence for allergy in orofacial granulomatosis and inflammatory bowel disease. AB - BACKGROUND: Orofacial granulomatosis (OFG) causes chronic, disfiguring, granulomatous inflammation of the lips and oral mucosa. A proportion of cases have co-existing intestinal Crohn's disease (CD). The pathogenesis is unknown but has recently been linked to dietary sensitivity. Although allergy has been suggested as an aetiological factor in OFG there are few published data to support this link. In this study, we sought clinical evidence of allergy in a series of patients with OFG and compared this to a series of patients with inflammatory bowel disease (IBD) without oral involvement and to population control estimates. METHODS: Prevalence rates of allergy and oral allergy syndrome (OAS) were determined in 88 patients with OFG using questionnaires, skin prick tests, total and specific serum IgE levels. Allergy was also determined in 117 patients with IBD without evidence of oral involvement (79 with CD and 38 with ulcerative colitis (UC)). RESULTS: Prevalence rates of allergy in patients with OFG were significantly greater than general population estimates (82% versus 22% respectively p = <0.0005). Rates of allergy were also greater in those with CD (39%) and, interestingly, highest in those with OFG and concurrent CD (87%). Conversely, whist OAS was common in allergic OFG patients (35%) rates of OAS were significantly less in patients with concomitant CD (10% vs 44% with and without CD respectively p = 0.006). Amongst CD patients, allergy was associated with perianal disease (p = 0.042) but not with ileal, ileocolonic or colonic disease location. Allergy in UC (18%) was comparable to population estimates. CONCLUSION: We provide compelling clinical evidence for the association of allergy with OFG whether occurring alone or in association with CD. The presence of gut CD increases this association but, conversely, reduces the expression of OAS in those with atopy. Interestingly, there is no evidence of increased allergy in UC. PMID- 23947722 TI - Accuracy of flexible versus rigid laryngoscopic photo-documentation in the diagnosis of early glottic cancer. AB - OBJECTIVE: To compare the image quality provided by rigid laryngoscopes versus flexible distal-chip laryngoscopes when documenting the same laryngeal pathology. METHODS: This paper reports a prospective single-blind study. Ten early stage glottic cancer cases were selected. Photographs of the pathologies were taken using both rigid and flexible distal-chip laryngoscopes (a total of 20 photographs). Nineteen clinicians were asked to review the laryngoscopic photographs; the clinicians were provided with a worksheet, which included questions regarding the clinical description, photograph quality and overall satisfaction with the images obtained. Clinicians' responses to the worksheet questions were then analysed. RESULTS: The overall accuracy rate for lesion sidedness, anatomical sub-site involvement, anterior commissure involvement and tumour staging were 94.7 per cent, 46.6 per cent, 53.7 per cent and 47.1 per cent respectively. There were no statistically significant differences in terms of the accuracy rates, photograph quality or overall satisfaction with the photographs obtained by either modality. CONCLUSION: There were no statistically significant differences demonstrated in overall clinical accuracy or perceived image quality between the use of the rigid or flexible endoscopes when interpreting images of early glottic cancer. PMID- 23947723 TI - Cooperation between the two heads of smooth muscle myosin is essential for full activation of the motor function by phosphorylation. AB - The motor function of smooth muscle myosin (SmM) is regulated by phosphorylation of the regulatory light chain (RLC) bound to the neck region of the SmM heavy chain. It is generally accepted that unphosphorylated RLC induces interactions between the two heads and between the head and the tail, thus inhibiting the motor activity of SmM, whereas phosphorylation of RLC interrupts those interactions, thus reversing the inhibition and restoring the motor activity to the maximal value. One assumption of this model is that single-headed SmM is fully active regardless of phosphorylation. To re-evaluate this model, we produced a number of SmM constructs with coiled coils of various lengths and examined their structure and regulation. With these constructs we identified the segment in the coiled-coil key for the formation of a stable double-headed structure. In agreement with the current model, we found that the actin-activated ATPase activity of unphosphorylated SmM increased with shortening of the coiled coil. However, contrary to the current model, we found that the actin-activated ATPase activity of phosphorylated SmM decreased with shortening coiled-coil and only the stable double-headed SmM was fully activated by phosphorylation. These results indicate that single-headed SmM is neither fully active nor fully inhibited. Based on our findings, we propose that cooperation between the two heads is essential, not only for the inhibition of unphosphorylated SmM, but also for the activation of phosphorylated SmM. PMID- 23947724 TI - Conjugated polymer chain and crystallite orientation induced by vertically aligned carbon nanotube arrays. AB - We report a method for controlling the orientations of conjugated polymers in the active layer of organic thin-film transistors (OTFTs) by annealing the film at the melting temperature in a vertically aligned multiwalled carbon nanotube (VA CNT) template under various load pressures. Poly(3-hexylthiophene) [P3HT] molecules are effectively aligned in the melting state annealing at 240 degrees C for 30 min, as a result of intermolecular pi-pi and CH3-pi interactions between the polymer and the VA-CNTs, which are separated from the conjugated polymer film after cooling to room temperature. In-plane and out-of-plane X-ray diffraction results show that the melt-annealed P3HT film with VA-CNTs has better crystallite ordering than a pristine 80 degrees C baked film and a melt-annealed film without VA-CNTs, and a larger number of crystallites in the treated P3HT film are oriented in the [100] direction, which is normal to the substrate. When we used the melt-aligned P3HT film with VA-CNTs as the active layer in OTFTs, the P3HT OTFT exhibits a better field-effect mobility value of 0.12 cm(2)/(V s) than a simply melt-annealed device without VA-CNTs [0.06 cm(2)/(V s)]. PMID- 23947725 TI - The impact of confounding and alcohol consumption patterns on the calculated risks of alcohol-related diseases. PMID- 23947726 TI - Significance of frequency patterns in 'moderate' drinkers for low-risk drinking guidelines. PMID- 23947727 TI - How do we formulate low-risk drinking guidelines if zero consumption is lowest risk? PMID- 23947728 TI - Fishy curves: a case of bias and confounding? PMID- 23947729 TI - Abounding confounding: sick quitters and healthy drinkers. PMID- 23947730 TI - Immoderately confounding: the effects of low-dose alcohol. PMID- 23947731 TI - Commentary on Callaghan et al. (2013): Minimum legal drinking age laws protect high school students from both crashes and alcohol abuse. PMID- 23947732 TI - How should network-based prevention for homeless youth be implemented? PMID- 23947733 TI - Response to Rice & Rhoades (2013). PMID- 23947734 TI - Commentary on Krupitsky et al.(2013): Refuge from the streets--parked on methadone, or seeking shelter of a depot? PMID- 23947735 TI - Commentary on Kotnowski and Hammond (2013): The importance of cigarette packaging innovation. PMID- 23947737 TI - Addition of objective data to identify risk for medication misuse and abuse: the inconsistency score. AB - OBJECTIVE: To identify and quantify the rate of aberrant drug-taking behaviors using objective data. DESIGN: Institutional Review Board-approved anonymous, voluntary, quality improvement project. SETTING: University-based, multidisciplinary pain management center. SUBJECTS: Consecutive initial visit patients. METHODS: Patients were interviewed, asked to provide a urine sample, and filled out a brief questionnaire about recent prescription, over-the-counter, and illicit drug use. Discrepancies between patient report (PQ), the Virginia State prescription monitoring program (PMP), referring physician records (MRs), and the point-of-care urine drug screen (POC UDS) results were scored from 0 (none) to a maximum of 2 points (2+ discrepancies) for each potential comparator between data sets. Maximum potential inconsistency score (IS) was 16 points. RESULTS: Two hundred nine patients were interviewed to yield 118 specimens. Mean age of participants was 48.2 years (22-83 year); 65.3% were female. IS scores ranged from 1 to 11, and 52.5% of the patients had an IS >= 3. Higher IS scores correlated with higher numbers of pharmacies, prescribing physicians, prescriptions on the PMP, and presence of illicit substances in the urine. Addition of either POC UDS or PMP to PQ and MR increased identification of inconsistencies by >400%, and PMP plus UDS by >900%. CONCLUSIONS: Patient report and the medical record are inadequate to screen for aberrant drug-related behaviors. Addition of PMP and POC UDS contribute significantly to identification of inconsistencies through higher IS scores and differentiate patients at higher risk of medication misuse, abuse, or diversion. Comparison of multiple sources of objective information provides better insight into inconsistencies of report and behavior, and may assist in more appropriate and safer prescribing decisions. PMID- 23947736 TI - Clostridium difficile exposure as an insidious source of infection in healthcare settings: an epidemiological model. AB - BACKGROUND: Clostridium difficile is the leading cause of infectious diarrhea in hospitalized patients. Its epidemiology has shifted in recent years from almost exclusively infecting elderly patients in whom the gut microbiota has been disturbed by antimicrobials, to now also infecting individuals of all age groups with no recent antimicrobial use. METHODS: A stochastic mathematical model was constructed to simulate the modern epidemiology of C. difficile in a healthcare setting, and, to compare the efficacies of interventions. RESULTS: Both the rate of colonization and the incidence of symptomatic disease in hospital inpatients were insensitive to antimicrobial stewardship and to the prescription of probiotics to expedite healthy gut microbiota recovery, suggesting these to be ineffective interventions to limit transmission. Comparatively, improving hygiene and sanitation and reducing average length of stay more effectively reduced infection rates. Although the majority of new colonization events are a result of within-hospital ward exposure, simulations demonstrate the importance of imported cases with new admissions. CONCLUSIONS: By analyzing a wide range of screening sensitivities, we identify a previously ignored source of pathogen importation: although capturing all asymptomatic as well as symptomatic introductions, individuals who are exposed but not yet colonized will be missed by even a perfectly sensitive screen on admission. Empirical studies to measure the duration of this latent period of infection will be critical to assessing C. difficile control strategies. Moreover, identifying the extent to which the exposed category of individual contributes to pathogen importation should be explicitly considered for all infections relevant to healthcare settings. PMID- 23947738 TI - Enantioselective Ullmann ether couplings: syntheses of (-)-myricatomentogenin, ( )-jugcathanin, (+)-galeon, and (+)-pterocarine. AB - The first enantioselective Ullmann cross-coupling reactions to prepare diaryl ethers are reported. The reactions were used to prepare the diarylether heptanoid natural products (-)-myricatomentogenin, (-)-jugcathanin, (+)-galeon, and (+) pterocarine. PMID- 23947739 TI - Multiscale simulations of protein G B1 adsorbed on charged self-assembled monolayers. AB - The orientation of an antibody plays an important role in the development of immunosensors. Protein G is an antibody binding protein, which specifically targets the Fc fragment of an antibody. In this work, the orientation of prototypical and mutated protein G B1 adsorbed on positively and negatively charged self-assembled monolayers was studied by parallel tempering Monte Carlo and all-atom molecular dynamics simulations. Both methods present generally similar orientation distributions of protein G B1 for each kind of surface. The root-mean-square deviation, DSSP, gyration radius, eccentricity, dipole moment, and superimposed structures of protein G B1 were analyzed. Moreover, the orientation of binding antibody was also predicted in this work. Simulation results show that with the same orientation trends, the mutant exhibits narrower orientation distributions than does the prototype, which was mainly caused by the stronger dipole of the mutant. Both kinds of proteins adsorbed on charged surfaces were induced by the competition of electrostatic interaction and vdW interaction; the electrostatic interaction energy dominated the adsorption behavior. The protein adsorption was also largely affected by the distribution of charged residues within the proteins. Thus, the prototype could adsorb on a negatively charged surface, although it keeps a net charge of -4 e. The mutant has imperfect opposite orientation when it adsorbed on oppositely charged surfaces. For the mutant on a carboxyl-functionalized self-assembled monolayer (COOH-SAM), the orientation was the same as that inferred by experiments. While for the mutant on amine-functionalized self-assembled monolayer (NH2-SAM), the orientation was induced by the competition between attractive interactions (led by ASP40 and GLU56) and repulsive interactions (led by LYS10); thus, the perfect opposite orientation could not be obtained. On both surfaces, the adsorbed protein could retain its native conformation. The desired orientation of protein G B1, which would increase the efficiency of binding antibodies, could be obtained on a negatively charged surface adsorbed with the prototype. Further, we deduced that with the packing density of 12,076 protein G B1 domain per MUm(2), the efficiency of the binding IgG would be maximized. The simulation results could be applied to control the orientation of protein G B1 in experiments and to provide a better understanding to maximize the efficiency of antibody binding. PMID- 23947740 TI - Palladium-catalyzed allylic C-H fluorination. AB - The first catalytic allylic C-H fluorination reaction using a nucleophilic fluoride source is reported. Under the influence of a Pd/Cr cocatalyst system, simple olefin substrates undergo fluorination with Et3N.3HF in good yields with high branched:linear regioselectivity. The mild conditions and broad scope make this reaction a powerful alternative to established methods for the preparation of allylic fluorides from prefunctionalized substrates. PMID- 23947741 TI - Increased sex ratio in Russia and Cuba after Chernobyl: a radiological hypothesis. AB - BACKGROUND: The ratio of male to female offspring at birth may be a simple and non-invasive way to monitor the reproductive health of a population. Except in societies where selective abortion skews the sex ratio, approximately 105 boys are born for every 100 girls. Generally, the human sex ratio at birth is remarkably constant in large populations. After the Chernobyl nuclear power plant accident in April 1986, a long lasting significant elevation in the sex ratio has been found in Russia, i.e. more boys or fewer girls compared to expectation were born. Recently, also for Cuba an escalated sex ratio from 1987 onward has been documented and discussed in the scientific literature. PRESENTATION OF THE HYPOTHESIS: By the end of the eighties of the last century in Cuba as much as about 60% of the food imports were provided by the former Soviet Union. Due to its difficult economic situation, Cuba had neither the necessary insight nor the political strength to circumvent the detrimental genetic effects of imported radioactively contaminated foodstuffs after Chernobyl. We propose that the long term stable sex ratio increase in Cuba is essentially due to ionizing radiation. TESTING OF THE HYPOTHESIS: A synoptic trend analysis of Russian and Cuban annual sex ratios discloses upward jumps in 1987. The estimated jump height from 1986 to 1987 in Russia measures 0.51% with a 95% confidence interval (0.28, 0.75), p value < 0.0001. In Cuba the estimated jump height measures 2.99% (2.39, 3.60), p value < 0.0001. The hypothesis may be tested by reconstruction of imports from the world markets to Cuba and by radiological analyses of remains in Cuba for Cs 137 and Sr-90. IMPLICATIONS OF THE HYPOTHESIS: If the evidence for the hypothesis is strengthened, there is potential to learn about genetic radiation risks and to prevent similar effects in present and future exposure situations. PMID- 23947743 TI - Left atrial deformation parameters in patients with non-alcoholic fatty liver disease: a 2D speckle tracking imaging study. AB - The presence of the metabolic syndrome is a strong predictor for the presence of NASH (non-alcoholic steatohepatitis) in patients with NAFLD (non-alcoholic fatty liver disease). In the present study, we assessed LA (left atrial) deformation parameters in patients with NAFLD using 2D-STE (speckle tracking echocardiography) and to investigate if any changes exist between subgroups of the NAFLD. A total of 55 NAFLD patients and 21 healthy controls were included in the study. The diagnosis of NAFLD was based on liver biopsy. After patients were categorized into groups according to histopathological analysis (simple steatosis, borderline NASH, definitive NASH), all patients underwent echocardiography with Doppler examination. In the 2D-STE analysis of the left atrium, LA-Res (peak LA strain during ventricular systole), LA-Pump (peak LA strain during atrial systole), LA-SR(S) (peak LA strain rate during ventricular systole), LA-SR(E) (peak LA strain rate during early diastole) and LA-SR(A) (peak LA strain rate during atrial systole) were obtained. LA-Res, LA-Pump and LA-SR(A) were lower in the NAFLD group than in the control group. LA-Res was found to be significantly lower in NAFLD subgroups compared with healthy subjects (43.9+/ 14.2 in healthy controls compared with 31.4+/-8.3 with simple steatosis, 32.8+/ 12.8 with borderline NASH and 33.8+/-9.0 with definitive NASH). LA-Pump was significantly lower in the NAFLD group (18.2+/-3.1 in healthy controls compared with 13.3+/-4.7 with borderline NASH and 14.4+/-4.7 with definitive NASH). There were significant differences in LA-SR(A) between healthy controls compared with simple steatosis and borderline NASH (-1.56+/-0.36 compared with 1.14+/-0.38 and 1.24+/-0.32 respectively). Correlation analysis showed significant correlation of LA-Res values with E (early diastolic peak velocity)/E(m) (early diastolic mitral annular velocity) ratio (r=-0.50, P<=0.001), with LAVI (LA volume index; r=-0.45, P<=0.001) and with V(p) (propagation velocity; r=0.39, P<=0.001). 2D-STE-based LA deformation parameters are impaired in patients with NAFLD with normal systolic function. Although LA-Res and pump function parameters might be useful in estimating LV (left ventricular) filling pressure in the NAFLD patient group, it could not be used for differentiating the subgroups. PMID- 23947742 TI - Transcranial pulsed electromagnetic fields for multiple chemical sensitivity: study protocol for a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Multiple chemical sensitivity (MCS) is a chronic condition of unknown etiology. MCS is characterized by recurrent nonspecific symptoms from multiple organ systems in response to chemical exposures in concentrations that are normally tolerated by the majority of the population. The symptoms may have severe impact on patients' lives, but an evidence-based treatment for the condition is nonexisting. The pathophysiology is unclarified, but several indicators point towards abnormal processing of sensory signals in the central nervous system. Pulsed electromagnetic fields (PEMF) offer a promising new treatment for refractory depression and can be targeted at the brain, thereby activating biochemical cell processes. METHODS/DESIGN: In a parallel, randomized, double-blind, placebo-controlled trial conducted at the Danish Research Centre for Chemical Sensitivities, the effects of PEMF in MCS patients will be assessed using the Re5 Independent System. Based on sample size estimation, 40 participants will be randomized to either PEMF therapy or placebo. The allocation sequence will be generated by computer. All involved parties (that is, participants, investigators, the research nurse, and the statistician) will be blinded to group allocation. The participants will receive PEMF therapy or placebo applied transcranially 30 minutes twice a day for 7 days a week over 6 consecutive weeks. Outcomes will be measured at baseline, once weekly during treatment, post treatment, and at 2.5-month and 4.5-month follow-up according to a predefined timetable. The primary outcome will be a measurement of the impact of MCS on everyday life. The secondary outcomes will be measurements of MCS symptoms, psychological distress (stress, anxiety or depressive symptoms), capsaicin-induced secondary punctate hyperalgesia, immunological markers in serum, and quality of life. DISCUSSION: This trial will assess the effects of PEMF therapy for MCS. Currently, there is no treatment with a documented effect on MCS, and in terms of healthcare there is very little to offer these patients. There is thus a great need for well-conducted randomized trials aimed at assessing possible treatment effects. A positive outcome will pave the way for improved healthcare and understanding of this very disabling and overlooked condition. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01834781. PMID- 23947744 TI - Campath induction in HCV and HCV/HIV-seropositive kidney transplant recipients. AB - Alemtuzumab (AZ) induction in hepatitis C-seropositive (HCV+) kidney transplant (KTX) recipients may negatively affect patient survival; however, available information is scant. Using US registry data from 2003 to 2010 of adult HCV+ deceased-donor KTXs (n = 4910), we examined outcomes by induction agent - AZ (n = 294), other T cell-depleting agents, (n = 2033; T cell), IL-2 receptor blockade (n = 1135; IL-2RAb), and no induction (n = 1448). On multivariate analysis, induction therapy was associated with significantly better overall patient survival with AZ [adjusted hazards ratio (aHR) 0.64, 95% confidence interval (CI) 0.45, 0.92], T cell (aHR 0.52, 95% CI 0.41, 0.65) or IL-2RAb (aHR 0.67, 95% CI 0.53, 0.87), compared to no induction. A significant protective effect was also seen with AZ (aHR 0.63, 95% CI 0.40, 0.99), T cell (aHR 0.62, 95% CI 0.49, 0.78), and IL2R-Ab (aHR 0.62, 95% CI 0.47, 0.82) in terms of death-censored graft survival relative to no induction. There were 88 HIV+/HCV+ coinfected recipients. Compared to noninduction, any induction (i.e. three induction groups combined) was associated with similar overall patient survival (P = 0.2255) on univariate analysis. Induction therapy with AZ, other T cell-depleting agents, or IL-2RAb in HCV+ KTX is associated with better patient and death-censored graft survival compared to noninduction. In HCV/HIV coinfected patients, induction is not contraindicated. PMID- 23947745 TI - A semi-automated method for patient-specific computational flow modelling of left ventricles. AB - Patient-specific computational fluid dynamics (CFD) modelling of the left ventricle (LV) is a promising technique for the visualisation of ventricular flow patterns throughout a cardiac cycle. While significant progress has been made in improving the physiological quality of such simulations, the methodologies involved for several key steps remain significantly operator-dependent to this day. This dependency limits both the efficiency of the process as well as the consistency of CFD results due to the labour-intensive nature of current methods as well as operator introduced uncertainties in the modelling process. In order to mitigate this dependency, we propose a semi-automated method for patient specific computational flow modelling of the LV. Using magnetic resonance imaging derived coarse geometry data of a patient's LV endocardium shape throughout a cardiac cycle, we then proceed to refine the geometry to eliminate rough edges before reconstructing meshes for all time frames and finally numerically solving for the intra-ventricular flow. Using a sample of patient-specific volunteer data, we demonstrate that our semi-automated, minimal operator involvement approach is capable of yielding CFD results of the LV that are comparable to other clinically validated LV flow models in the literature. PMID- 23947746 TI - Impact of carpal tunnel surgery according to pre-operative abnormality of sensory conduction in median nerve: a longitudinal study. AB - BACKGROUND: We have previously proposed that sensory nerve conduction (SNC) in the median nerve should be classed as abnormal when the difference between conduction velocities in the little and index fingers is > 8 m/s. In a prospective longitudinal study, we investigated whether this case definition distinguished patients who were more likely to benefit from surgical treatment. METHODS: We followed up 394 patients (response rate 56%), who were investigated by a neurophysiology service for suspected carpal tunnel syndrome. Information about symptoms, treatment and other possible determinants of outcome was obtained through questionnaires at baseline and after follow-up for a mean of 19.2 months. Analysis focused on 656 hands with numbness, tingling or pain at baseline. Associations of surgical treatment with resolution of symptoms were assessed by Poisson regression, and summarised by prevalence rate ratios (PRRs) and associated 95% confidence intervals (95% CIs). RESULTS: During follow-up, 154 hands (23%) were treated surgically, and sensory symptoms resolved in 241 hands (37%). In hands with abnormal median SNC, surgery was associated with resolution of numbness, tingling and pain (PRR 1.5, 95% CI 1.0-2.2), and of numbness and tingling specifically (PRR 1.8, 95% CI 1.3-2.6). In contrast, no association was apparent for either outcome when median SNC was classed as normal. CONCLUSIONS: Our definition of abnormal median SNC distinguished a subset of patients who appeared to benefit from surgical treatment. This predictive capacity gives further support to its validity as a diagnostic criterion in epidemiological research.